Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1([C:8]2[N:13]=[C:12]([C:14]([C:16]3[C:17]([NH2:23])=[N:18][CH:19]=[C:20]([Br:22])[CH:21]=3)=[O:15])[CH:11]=[CH:10][CH:9]=2)[CH2:7][CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[F:24][C:25]([F:31])([F:30])[CH2:26][C:27](O)=[O:28].ON1C2C=CC=CC=2N=N1.C(N(CC)CC)C.N=C=N>ClCCl>[NH2:23][C:17]1[N:18]=[CH:19][C:20]([Br:22])=[CH:21][C:16]=1[C:14]([C:12]1[N:13]=[C:8]([N:1]2[CH2:7][CH2:6][CH2:5][N:4]([C:27](=[O:28])[CH2:26][C:25]([F:31])([F:30])[F:24])[CH2:3][CH2:2]2)[CH:9]=[CH:10][CH:11]=1)=[O:15]
Reactant: O=C(O)CC(F)(F)F
Reactant: Nc1ncc(Br)cc1C(=O)c1cccc(N2CCCNCC2)n1
Agent: N=C=N
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Nc1ncc(Br)cc1C(=O)c1cccc(N2CCCN(C(=O)CC(F)(F)F)CC2)n1
Temperature: 25 °C
Reaction time: 18 h
Yield: 53.7 %

Procedure:
(6-(1,4-diazepan-1-yl)pyridin-2-yl)(2-amino-5-bromopyridin-3-yl)methanone (650 mg, 1.36 mmol) was added to a stirred suspension of 3,3,3-trifluoropropionic acid (0.13 ml, 1.50 mmol), 1-hydroxybenzotriazole (184 mg, 1.36 mmol), triethylamine (1.33 ml, 9.52 mmol) and PS-carbodiimide (2.08 g, 2.72 mmol) in dichloromethane (20 ml). The resulting mixture was stirred at room temperature for 18 hours. The crude mixture was filtered and concentrated in vacuo. The residue was purified on silica gel by flash column chromatography (ISCO Companion|, 40 g column, 0-50% EtOAc/Petroleum ether) to afford the title compound as an orange solid (355 mg, 54% yield).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:32])[CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([S:12][CH:13]([C:15]2[S:16][C:17]([C:21]3[CH:26]=[CH:25][C:24]([C:27]([F:30])([F:29])[F:28])=[CH:23][CH:22]=3)=[CH:18][C:19]=2I)[CH3:14])=[CH:8][C:7]=1[CH3:31].[CH2:33]([Sn](CCCC)(CCCC)C=C)[CH2:34]CC>C1(C)C=CC=CC=1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:1][O:2][C:3](=[O:32])[CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([S:12][CH:13]([C:15]2[S:16][C:17]([C:21]3[CH:26]=[CH:25][C:24]([C:27]([F:30])([F:29])[F:28])=[CH:23][CH:22]=3)=[CH:18][C:19]=2[CH:33]=[CH2:34])[CH3:14])=[CH:8][C:7]=1[CH3:31]
Reactant: COC(=O)CCc1ccc(SC(C)c2sc(-c3ccc(C(F)(F)F)cc3)cc2I)cc1C
Reactant: C=C[Sn](CCCC)(CCCC)CCCC
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: C=Cc1cc(-c2ccc(C(F)(F)F)cc2)sc1C(C)Sc1ccc(CCC(=O)OC)c(C)c1
Temperature: 80 °C

Procedure:
The solution of 3-(4-{1-[3-Iodo-5-(4-trifluoromethyl-phenyl)-thiophen-2-yl]-ethylsulfanyl}-2-methyl-phenyl)-propionic acid methyl ester (0.195 g, 0.348 mmole) and tributyl(vinyl)tin (0.331 g, 1.04 mmole) in toluene (3 mL) is bubbled with nitrogen gas for 10 minutes. To it is added tetrakis(triphenylphosphine)palladium(0) (0.20 g). The reaction is heated under 80° C. overnight. The mixture is concentrated, loaded to a silica gel column, eluted with ethyl acetate in hexane (0-15%) and concentrated to provide the titled compound as colorless oil.
Reaction SMILES: CS(O[CH:6]1[CH2:11][CH2:10][CH:9]([NH:12][C:13](=[O:19])[O:14][C:15]([CH3:18])([CH3:17])[CH3:16])[CH2:8][CH2:7]1)(=O)=O.[CH3:20][C:21]1[O:25][C:24]([C:26]2[CH:35]=[CH:34][C:29]([C:30]([O:32][CH3:33])=[O:31])=[CH:28][CH:27]=2)=[N:23][C:22]=1[CH2:36][SH:37].C(=O)([O-])[O-].[Cs+].[Cs+].O>CN(C)C=O>[C:15]([O:14][C:13]([NH:12][CH:9]1[CH2:8][CH2:7][CH:6]([S:37][CH2:36][C:22]2[N:23]=[C:24]([C:26]3[CH:35]=[CH:34][C:29]([C:30]([O:32][CH3:33])=[O:31])=[CH:28][CH:27]=3)[O:25][C:21]=2[CH3:20])[CH2:11][CH2:10]1)=[O:19])([CH3:16])([CH3:17])[CH3:18]
Reactant: CC(C)(C)OC(=O)NC1CCC(OS(C)(=O)=O)CC1
Reactant: COC(=O)c1ccc(-c2nc(CS)c(C)o2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1ccc(-c2nc(CSC3CCC(NC(=O)OC(C)(C)C)CC3)c(C)o2)cc1
Yield: 27.3 %

Procedure:
A solution of tert-butyl N-[4-(methanesulfonyloxy)cyclohexyl]carbamate (2.24 g, 7.64 mmol, 1.00 equiv), methyl 4-[5-methyl-4-(sulfanylmethyl)-1,3-oxazol-2-yl]benzoate (3.0 g, 11.39 mmol, 1.20 equiv) and cesium carbonate (5.55 g, 16.98 mmol, 2.00 equiv) in N,N-dimethylformamide (30 mL) was stirred at 50° C. under nitrogen atmosphere for 3 h. Water (100 mL) was added to quench the reaction. The resulting solution was extracted with 3×80 mL of ethyl acetate. The combined organic layers was washed with 2×200 mL of brine, dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was purified on a silica gel column eluted with ethyl acetate/petroleum ether (1:15-2:1) to give 960 mg (27%) of methyl 4-(4-[[(4-[[(tert-butoxy)carbonyl]amino]cyclohexyl)sulfanyl]methyl]-5-methyl-1,3-oxazol-2-yl)benzoate as a yellow solid. LC-MS: (ES, m/z): 461 [M+H]+, 405, 271, 230, 102.
Reaction SMILES: [NH:1]([CH2:5][CH2:6][OH:7])[CH2:2][CH2:3][OH:4].[Cl:8][C:9]([Cl:15])([Cl:14])[CH2:10][CH:11]1[O:13][CH2:12]1>C(O)C>[OH:4][CH2:3][CH2:2][N:1]([CH2:12][CH:11]([OH:13])[CH2:10][C:9]([Cl:15])([Cl:14])[Cl:8])[CH2:5][CH2:6][OH:7]
Reactant: OCCNCCO
Reactant: ClC(Cl)(Cl)CC1CO1
Solvent: CCO
Product: OCCN(CCO)CC(O)CC(Cl)(Cl)Cl

Procedure:
To a solution of 52.5g (0.5 mole) diethanolamine in 100 ml ethanol heated to reflux was added 87.7g (0.5 mole) 4,4,4-trichloro-1,2-epoxybutane over a period of 105 minutes. After refluxing with agitation for an additional 5 hours the solvent was removed via vacuum leaving 135.7g (96.5%) of N,N-bis(2-hydroxyethyl)-4,4,4-trichloro-2-hydroxy-1-butylamine, a clear dark, highly viscous liquid; hydroxyl number = 600. This product is soluble in water (pH≈8) and in xylene. Analysis: (Calculated) %N, 5.00; %Cl, 37.96. (Found) %N, 5.00; %Cl, 37.09.
Reaction SMILES: [CH2:1]([C:3]1[NH:4][C:5]2[C:10]([CH:11]=1)=[C:9]([O:12][CH3:13])[CH:8]=[CH:7][CH:6]=2)[CH3:2].[H-].[Na+].[CH2:16](Br)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>CN(C=O)C.O>[CH2:1]([C:3]1[N:4]([CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:5]2[C:10]([CH:11]=1)=[C:9]([O:12][CH3:13])[CH:8]=[CH:7][CH:6]=2)[CH3:2]
Reactant: CCc1cc2c(OC)cccc2[nH]1
Reactant: BrCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCc1cc2c(OC)cccc2n1Cc1ccccc1
Reaction time: 1.5 h
Yield: 48.7 %

Procedure:
2-Ethyl-4-methoxy-1H-indole (4.2 g, 24 mmol) was dissolved in 30 mL of DMF and 960 mg (24 mmol) of 60% NaH/mineral oil was added. After 1.5 hours, 2.9 mL(24 mmol) of benzyl bromide was added. After 4 hours, the mixture was diluted with water and extracted twice with ethyl acetate. The combined ethyl acetate was washed with brine, dried (MgSO4) and concentrated at reduced pressure. The residue was chromatographed on silica gel and eluted with 20% EtOAc/hexane to give 3.1 g (49% yield) of 2-ethyl-4-methoxy-1-(phenylmethyl)-1H-indole.
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.[F:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[N:17]=[C:18]([CH3:21])[S:19][CH:20]=2)=[CH:12][CH:11]=1>C(Cl)(Cl)(Cl)Cl.C(Cl)Cl>[Br:1][CH2:21][C:18]1[S:19][CH:20]=[C:16]([C:13]2[CH:12]=[CH:11][C:10]([F:9])=[CH:15][CH:14]=2)[N:17]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1nc(-c2ccc(F)cc2)cs1
Solvent: ClCCl
Solvent: ClC(Cl)(Cl)Cl
Product: Fc1ccc(-c2csc(CBr)n2)cc1
Temperature: 80 °C
Yield: 101.3 %

Procedure:
N-Bromosuccinimide (3.22 g, 18.13 mmol) was added to a solution of 4-(4-fluorophenyl)-2-methylthiazole (3.5 g, 18.13 mmol) in CCl4 (30.0 mL) and the reaction was refluxed at 80° C. overnight. The reaction mixture was then diluted with CH2Cl2, washed with water and brine, dried over anhydrous Na2SO4, and concentrated under reduced pressure to yield crude 2-(bromomethyl)-4-(4-fluorophenyl)thiazole (5 g), which was carried through without further purification. 1H NMR (400 MHz, DMSO) δ 8.18 (s, 1H), 7.93-8.01 (m, 2H), 7.26-7.31 (m, 2H), 5.07 (s, 2H). MS (ESI) m/z: Calculated for C10H7BrFNS: 272.94. found: 273.9 (M+H)+
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[C:5]([CH:16]=[CH:17][C:18]=1[N+:19]([O-:21])=[O:20])[O:6][CH2:7][CH2:8][CH2:9][CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])=O.[OH:22][C:23]1[NH:24][C:25](=[O:47])[CH2:26][C:27]=1[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[OH-]>C(O)C>[O:22]=[C:23]1[NH:24][C:25](=[O:47])[CH2:26]/[C:27]/1=[CH:1]\[C:3]1[CH:4]=[C:5]([CH:16]=[CH:17][C:18]=1[N+:19]([O-:21])=[O:20])[O:6][CH2:7][CH2:8][CH2:9][CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12]
Reactant: CCOC(=O)CCCCOc1ccc([N+](=O)[O-])c(C=O)c1
Reactant: O=C1CC([P+](c2ccccc2)(c2ccccc2)c2ccccc2)=C(O)N1
Agent: [OH-]
Solvent: CCO
Product: CCOC(=O)CCCCOc1ccc([N+](=O)[O-])c(/C=C2\CC(=O)NC2=O)c1
Yield: 61 %

Procedure:
A mixture of ethyl 5-(3-formyl-4-nitrophenoxy)pentanoate (0.60 mol) and (4,5-di-hydro-2-hydroxy-5-oxo-1H-pyrrol-3-yl)triphenylphosphonium, hydroxide, inner salt (0.57 mol) in ethanol (1500 ml) was stirred and refluxed for 1 hour. The solvent was removed. The residue was stirred in methylbenzene. The resulting precipitate was filtered off, washed with methylbenzene, 2,2'-oxybispropane and dried, yielding 137.3 g (61%) of (E)-ethyl 5-[3-[(2,5-dioxo-3-pyrrolidinylidene)methyl]-4-nitrophenoxy]pentanoate; mp. 112.4° C. (interm. 1).
Reaction SMILES: ClC1C=CC=C(C(OO)=[O:9])C=1.[OH:12][CH:13]([CH2:26][C:27]1[CH:32]=[N:31][CH:30]=[CH:29][N:28]=1)[C:14]([CH3:25])([CH3:24])[O:15][C:16]1[CH:23]=[CH:22][C:19]([C:20]#[N:21])=[CH:18][CH:17]=1>ClCCl>[C:20]([C:19]1[CH:18]=[CH:17][C:16]([O:15][C:14]([CH3:24])([CH3:25])[CH:13]([OH:12])[CH2:26][C:27]2[CH:32]=[N:31][CH:30]=[CH:29][N+:28]=2[O-:9])=[CH:23][CH:22]=1)#[N:21]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CC(C)(Oc1ccc(C#N)cc1)C(O)Cc1cnccn1
Solvent: ClCCl
Product: CC(C)(Oc1ccc(C#N)cc1)C(O)Cc1cncc[n+]1[O-]
Reaction time: 24 h
Yield: 30.4 %

Procedure:
0.18 g of m-chloroperbenzoic acid was added to a stirred solution of 0.28 g of 4-[2-hydroxy-1,1-dimethyl-3-(2-pyrazinyl)propoxy]benzonitrile in 10 ml of dichloromethane. After 16 hours a further 36 mg of m-chloroperbenzoic acid were added and the mixture was stirred for 24 hours. The solvents were then removed by evaporation and the residue was chromatographed on silica gel using diethyl ether/methanol (95:5) for the elution to give 0.09 g of 2-[3-(4-cyanophenoxy)-2-hydroxy- 3-methylbutyl]-pyrazine 1-oxide in the form of a white solid of melting point 103°-104° C. (from diethyl ether).
Reaction SMILES: [CH3:1][C:2]([CH3:18])([CH3:17])[C:3]([NH:5][C:6]1[CH:15]=[CH:14][CH:13]=[C:12]([OH:16])[C:7]=1[C:8]([O:10][CH3:11])=[O:9])=[O:4].[CH2:19](Br)[C:20]#[CH:21].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH3:1][C:2]([CH3:18])([CH3:17])[C:3]([NH:5][C:6]1[CH:15]=[CH:14][CH:13]=[C:12]([O:16][CH2:21][C:20]#[CH:19])[C:7]=1[C:8]([O:10][CH3:11])=[O:9])=[O:4]
Reactant: C#CCBr
Reactant: COC(=O)c1c(O)cccc1NC(=O)C(C)(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: C#CCOc1cccc(NC(=O)C(C)(C)C)c1C(=O)OC

Procedure:
A mixture of methyl 2-(2,2-dimethylpropionylamino)-6-hydroxybenzoate (Intermediate 47, 4.57 g), propargyl bromide (80% solution in toluene, 2.03 mL) and potassium carbonate (3.74 g) in acetone (35 mL) was heated at reflux for 8 hours. After cooling, the mixture was filtered and the filtrate was concentrated in vacuo. The residue was purified by chromatography on silica, eluting with a mixture of ethyl acetate and cyclohexane, with a gradient of 5-20% to give methyl 2-(2,2-dimethylpropionylamino)-6-(prop-2-ynyloxy)benzoate (4.74 g) as an oil which crystallised on standing to give a white solid.
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([C:7]2[S:8][CH:9]=[CH:10][CH:11]=2)=[CH:4][CH:3]=1.[Li]CCCC.CN([CH:20]=[O:21])C.[BH4-].[Na+]>C1COCC1.O>[Cl:1][C:2]1[S:6][C:5]([C:7]2[S:8][C:9]([CH2:20][OH:21])=[CH:10][CH:11]=2)=[CH:4][CH:3]=1
Reactant: CN(C)C=O
Reactant: Clc1ccc(-c2cccs2)s1
Agent: [BH4-]
Agent: [Li]CCCC
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: OCc1ccc(-c2ccc(Cl)s2)s1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 64.8 %

Procedure:
To a solution of 5-chloro-[2,2′]bithiophenyl (3.00 g, 14.9 mmol) in 30 mL of THF at 0° C. is added n-BuLi (9.8 mL of a 1.6M solution in hexanes, 15.7 mmol) dropwise. DMF (2.30 mL, 30 mmol) is added dropwise and the resulting solution is heated at reflux for 1 hour. The solution is diluted with H2O and extracted with Et2O. The organic layer is washed with H2O and saturated NaCl solution, then dried over MgSO4, filtered and concentrated. The crude aldehyde is dissolved in 40 mL of anhydrous MeOH and sodium borohydride (0.85 g, 22.5 mmol) is added portionwise. The mixture is stirred at room temperature for 10 min, then quenched with water. The mixture is diluted with Et2O and the layers separated. The organic layer is washed with H2O, then dried over MgSO4, filtered and concentrated to yield the title compound (2.23 g, 9.66 mmol) which is used in the subsequent step without further purification. 1H NMR (CDCl3, 300 MHz) δ6.95 (d, 1H), 6.90 (m, 2H), 6.86 (d, 1H), 4.82 (s, 2H), 1.88 (bs, 1H).
Reaction SMILES: [C:1]([C:4]1[CH:11]=[CH:10][C:7]([CH:8]=[O:9])=[CH:6][CH:5]=1)([OH:3])=O.O[NH:13][C:14](=[NH:23])[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22]>>[CH2:15]([C:14]1[N:13]=[C:1]([C:4]2[CH:11]=[CH:10][C:7]([CH:8]=[O:9])=[CH:6][CH:5]=2)[O:3][N:23]=1)[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22]
Reactant: O=Cc1ccc(C(=O)O)cc1
Reactant: CCCCCCCCC(=N)NO
Product: CCCCCCCCc1noc(-c2ccc(C=O)cc2)n1
Yield: 34 %

Procedure:
The same procedure as employed in the preparation of Example 277 (step a) but using 4-carboxybenzaldehyde and N-hydroxynonanimidamide gave the title compound as a beige solid (34%). 1H NMR (CDCl3, 300 MHz) δ 10.1 (s, 1H), 8.29 (d, 2H, J=8.3 Hz), 8.03 (d, 2H, J=8.3 Hz), 2.81 (t, 2H, J=7.4 Hz), 1.86-1.75 (m, 2H), 1.46-1.21 (m, 10H), 0.87 (m, 3H). HPLC (Condition A), Rt: 5.16 min (HPLC purity: 95.4%).
Reaction SMILES: Cl[C:2]1[C:3](=[O:15])[N:4]([C@@H:9]([CH:12]2[CH2:14][CH2:13]2)[CH2:10][CH3:11])[CH:5]=[C:6]([Cl:8])[N:7]=1.[Br:16][C:17]1[CH:18]=[C:19]2[C:23](=[C:24]([Br:26])[CH:25]=1)[NH:22][CH2:21][CH2:20]2>>[Cl:8][C:6]1[N:7]=[C:2]([N:22]2[C:23]3[C:19](=[CH:18][C:17]([Br:16])=[CH:25][C:24]=3[Br:26])[CH2:20][CH2:21]2)[C:3](=[O:15])[N:4]([C@@H:9]([CH:12]2[CH2:14][CH2:13]2)[CH2:10][CH3:11])[CH:5]=1
Reactant: Brc1cc(Br)c2c(c1)CCN2
Reactant: CC[C@H](C1CC1)n1cc(Cl)nc(Cl)c1=O
Product: CC[C@H](C1CC1)n1cc(Cl)nc(N2CCc3cc(Br)cc(Br)c32)c1=O

Procedure:
Part B: Prepared in a similar fashion as described for Example 413 using 3,5-dichloro-1-[(1R)-1-cyclopropylpropyl]-2(1H)-pyrazinone and 5,7-dibromoindoline as the starting materials. mp 164–165° C.; 1H NMR (300 MHz, CDCl3): δ 7.42 (d, J=1.8 Hz, 1 H), 7.22 (d, J=1.5 Hz, 1 H), 6.96 (s, 1 H), 4.26 (t, J=8.1 Hz, 2 H), 3.99 (app. q, J=8.3 Hz, 1 H), 3.08 (t, J=7.9 Hz, 2 H), 1.94–1.69 (m, 2 H), 1.02–0.92 (m, 1 H), 0.87 (t, J=7.5 Hz, 3 H), 0.78–0.68 (m, 1 H), 0.50–0.39 (m, 2 H), 0.29–0.22 (m, 1 H); HRMS (ESI) calcd for C18H19N3OBr2Cl (M+H)+: 485.9583; found m/z 485.9592.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:29]=[C:30]([N:32]2[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]2)[CH:31]=1)[C:5]([NH:7][C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]([O:18][C:19]2[CH:24]=[CH:23][N:22]=[C:21](S(C)(=O)=O)[N:20]=2)=[CH:10][CH:9]=1)=[O:6].[CH2:38]([O:40][C:41]([N:43]1[CH2:48][CH2:47][NH:46][CH2:45][CH2:44]1)=[O:42])[CH3:39]>>[F:1][C:2]1[CH:3]=[C:4]([CH:29]=[C:30]([N:32]2[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]2)[CH:31]=1)[C:5]([NH:7][C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]([O:18][C:19]2[CH:24]=[CH:23][N:22]=[C:21]([N:46]3[CH2:45][CH2:44][N:43]([C:41]([O:40][CH2:38][CH3:39])=[O:42])[CH2:48][CH2:47]3)[N:20]=2)=[CH:10][CH:9]=1)=[O:6]
Reactant: CCOC(=O)N1CCNCC1
Reactant: CS(=O)(=O)c1nccc(Oc2ccc(NC(=O)c3cc(F)cc(N4CCCCC4)c3)c3ccccc23)n1
Product: CCOC(=O)N1CCN(c2nccc(Oc3ccc(NC(=O)c4cc(F)cc(N5CCCCC5)c4)c4ccccc34)n2)CC1

Procedure:
Compound is prepared from 3-fluoro-N-[4-(2-methanesulfonyl-pyrimidin-4-yloxy)-naphthalen-1-yl]-5-piperidin-1-yl-benzamide and piperazine-1-carboxylic acid ethyl ester according to conditions described in general procedure C. Mp: 105-106° C.; 1H NMR (400 MHz, DMSO-d6) δ 1.14-1.18 (m, 3 H), 1.60-1.62 (m, 6 H), 3.11-3.33 (m, 8 H), 3.52 (s, 4 H), 4.00-4.05 (m, 2 H), 6.22-6.24 (m, 1 H), 6.97 (d, J=11.3 Hz, 2H), 7.17 (d, J=9.1 Hz, 1 H), 7.42-7.45 (m, 1 H), 7.48 (s, 1 H), 7.57-7.62 (m, 3 H), 7.85 (d, J=8.0 Hz, 1 H), 7.99 (d, J=8.0 Hz, 1 H), 8.29-8.30 (m, 1 H), 10.46 (s, 1 H).
Reaction SMILES: [CH2:1](Br)[C:2]#[CH:3].[OH:5][C:6]1[CH:7]=[C:8]([CH2:12][CH2:13][CH2:14][NH:15][C:16]([CH:18]2[CH2:20][CH2:19]2)=[O:17])[CH:9]=[CH:10][CH:11]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH2:1]([O:5][C:6]1[CH:7]=[C:8]([CH2:12][CH2:13][CH2:14][NH:15][C:16]([CH:18]2[CH2:19][CH2:20]2)=[O:17])[CH:9]=[CH:10][CH:11]=1)[C:2]#[CH:3]
Reactant: O=C(NCCCc1cccc(O)c1)C1CC1
Reactant: C#CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: C#CCOc1cccc(CCCNC(=O)C2CC2)c1
Temperature: 25 °C

Procedure:
Propargyl bromide (80% in toluene, 0.091 ml) was added dropwise to a mixture of cyclopropanecarboxylic acid [3-(3-hydroxy-phenyl)-propyl]-amide (122 mg) and potassium carbonate (154 mg) in dry DMF (10 ml) in an ice bath under nitrogen. The mixture was allowed to warm to room temperature, then heated at 65° C. for 18 h. The cooled mixture was partitioned between water (50 ml) and ethyl acetate (3×15 ml). The combined organic extracts were washed with brine/water 1:1 (3×20 ml) and dried (MgSO4). The solvent was evaporated and the residue purified by column chromatography on silica. Elution with hexane/ethyl acetate 2:1 gave the title compound as a colourless solid (79 mg)
Reaction SMILES: [C:1]([C:5]1[N:6]=[C:7]([N:16]2[CH2:20][CH2:19][C:18]([F:22])([F:21])[CH2:17]2)[C:8]2[N:13]=[N:12][N:11]([CH2:14][CH3:15])[C:9]=2[N:10]=1)([CH3:4])([CH3:3])[CH3:2].C(C1N=C(N2CCC(F)(F)C2)C2N=NNC=2N=1)(C)(C)C.ClCC1[O:49][N:48]=[C:47]([CH3:50])[N:46]=1>>[C:1]([C:5]1[N:6]=[C:7]([N:16]2[CH2:20][CH2:19][C:18]([F:21])([F:22])[CH2:17]2)[C:8]2[N:13]=[N:12][N:11]([CH2:14][C:15]3[O:49][N:48]=[C:47]([CH3:50])[N:46]=3)[C:9]=2[N:10]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: Cc1noc(CCl)n1
Reactant: CCn1nnc2c(N3CCC(F)(F)C3)nc(C(C)(C)C)nc21
Agent: CC(C)(C)c1nc(N2CCC(F)(F)C2)c2nn[nH]c2n1
Product: Cc1noc(Cn2nnc3c(N4CCC(F)(F)C4)nc(C(C)(C)C)nc32)n1

Procedure:
In analogy to the procedure described for the synthesis of 5-tert-butyl-7-(3,3-difluoropyrrolidin-1-yl)-3-ethyl-3H-[1,2,3]triazolo[4,5-d]pyrimidine (example 61), the title compound was prepared from 5-tert-butyl-7-(3,3-difluoropyrrolidin-1-yl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine and 5-(chloromethyl)-3-methyl-1,2,4-oxadiazole and isolated as light-yellow gum. MS (m/e): 379.3 (MH+).
Reaction SMILES: P([O-])([O-])([O-])=O.[K+].[K+].[K+].[CH:9]1(B(O)O)[CH2:11][CH2:10]1.Cl[C:16]1[C:17]([CH:44]([F:46])[F:45])=[CH:18][C:19]([O:42][CH3:43])=[C:20]([C:22]2[C:31]3[C:26](=[CH:27][C:28]([S:32]([NH:35][C:36]4[CH:41]=[CH:40][N:39]=[CH:38][N:37]=4)(=[O:34])=[O:33])=[CH:29][CH:30]=3)[CH:25]=[CH:24][N:23]=2)[CH:21]=1.Cl>O1CCOCC1>[CH:9]1([C:16]2[C:17]([CH:44]([F:45])[F:46])=[CH:18][C:19]([O:42][CH3:43])=[C:20]([C:22]3[C:31]4[C:26](=[CH:27][C:28]([S:32]([NH:35][C:36]5[CH:41]=[CH:40][N:39]=[CH:38][N:37]=5)(=[O:33])=[O:34])=[CH:29][CH:30]=4)[CH:25]=[CH:24][N:23]=3)[CH:21]=2)[CH2:11][CH2:10]1
Reactant: OB(O)C1CC1
Reactant: COc1cc(C(F)F)c(Cl)cc1-c1nccc2cc(S(=O)(=O)Nc3ccncn3)ccc12
Agent: Cl
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: COc1cc(C(F)F)c(C2CC2)cc1-c1nccc2cc(S(=O)(=O)Nc3ccncn3)ccc12
Reaction time: 0.17 h
Yield: 37.1 %

Procedure:
A solution of 2-dicyclohexylphosphino-2′,6′-dimethoxy-1′1′-biphenyl (4.59 mg, 0.011 mmol), chloro(2-dicyclohexylphosphino-2′,6′-dimethoxy-1,1′-biphenyl)[2-(2-aminoethylphenyl)]palladium(ii) methyl-t-butylether (8.48 mg, 0.011 mmol), potassium phosphate (0.190 g, 0.895 mmol), cyclopropylboronic acid (0.038 g, 0.448 mmol), and 1-(5-chloro-4-(difluoromethyl)-2-methoxyphenyl)-N-(pyrimidin-4-yl)isoquinoline-6-sulfonamide (From Example 457; 0.108 g, 0.224 mmol) in 1.5 mL dioxane/0.5 mL water was heated to 180° C. in the microwave for 45 minutes. LC/MS showed product, so the aqueous layer was removed. The reaction mixture was treated with HCl (4N in dioxane) (0.224 ml, 0.895 mmol) and was allowed to stir for 10 minutes. The reaction mixture was then concentrated. Purification of the crude residue by reverse phase column chromatography [Puriflash C18, 10-100% (0.1% NH4OH in MeOH)/(0.1% NH4OH in water)] gave 1-(5-cyclopropyl-4-(difluoromethyl)-2-methoxyphenyl)-N-(pyrimidin-4-yl)isoquinoline-6-sulfonamide (0.040 g, 0.083 mmol, 37.0% yield). 1H NMR (MeCN-d3) δ: 8.65 (d, J=5.7 Hz, 1H), 8.58 (s, 1H), 8.44 (s, 1H), 8.14 (d, J=6.3 Hz, 1H), 7.86-7.95 (m, 2H), 7.63-7.69 (m, 1H), 7.15-7.45 (m, 2H), 7.12 (s, 1H), 6.96 (s, J=6.3, 1H), 3.67 (s, 3H), 2.03-2.14 (m, 1H), 0.88-1.00 (m, 2H), 0.59-0.70 (m, 2H); (M+H)+=483.0.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([CH3:8])[N:5]=[C:4]([CH3:9])[CH:3]=1.FC(F)(F)C(O)=O.S(=O)(=O)(O)O.C1C(=O)N([Br:29])C(=O)C1.[OH-].[Na+]>>[Br:29][C:3]1[C:4]([CH3:9])=[N:5][C:6]([CH3:8])=[CH:7][C:2]=1[Cl:1]
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1cc(Cl)cc(C)n1
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc(Cl)c(Br)c(C)n1
Temperature: 25 °C
Reaction time: 12 h
Yield: 21.4 %

Procedure:
4-chloro-2,6-dimethylpyridine (1.5 g) was added to a mixed solvent of trifluoroacetic acid (3 mL) and concentrated sulfuric acid (6 mL). NBS (22 g) was added to the solution, and the mixture was stirred at room temperature for 12 hours. A 5 N aqueous sodium hydroxide solution was added to the reaction mixture, followed by separation with ethyl acetate. The organic layer was washed with brine and then dried over anhydrous magnesium sulfate. The desiccant was removed by filtration, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (ethyl acetate/n-heptane, 5% to 30%) to give the title compound (500 mg).
Reaction SMILES: ClCl.[Cl:3][C:4]1([C:7]([OH:23])([CH2:16][N:17]2[C:21]([SH:22])=[N:20][CH:19]=[N:18]2)[CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[Cl:15])[CH2:6][CH2:5]1.[C-:24]#[N:25].[K+]>C(O)(=O)C.ClCCl>[Cl:3][C:4]1([C:7]([OH:23])([CH2:16][N:17]2[C:21]([S:22][C:24]#[N:25])=[N:20][CH:19]=[N:18]2)[CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[Cl:15])[CH2:6][CH2:5]1
Reactant: [C-]#N
Reactant: OC(Cc1ccccc1Cl)(Cn1ncnc1S)C1(Cl)CC1
Agent: ClCl
Agent: [K+]
Solvent: ClCCl
Solvent: CC(=O)O
Product: N#CSc1ncnn1CC(O)(Cc1ccccc1Cl)C1(Cl)CC1
Temperature: 20 °C
Reaction time: 20 h
Yield: 65 %

Procedure:
At 20° C., chlorine gas is introduced into a mixture of 1.72 g (5 mmol) of 2-(1-chloro-cyclopropyl)-1-(2-chloro-phenyl)-3-(5-mercapto-1,2,4-triazol-1-yl)-propan-2-ol and 0.65 g (10 mmol) of potassium cyanide in 20 ml of acetic acid. The reaction mixture is stirred at 20° C. for 20 hours and then diluted with dichloromethane. The mixture is then extracted repeatedly with dilute aqueous sodium hydroxide solution and the organic phase is dried over sodium sulphate and concentrated under reduced pressure. The product that remains is purified over silica gel using petroleum ether/ethyl acetate=1:1 as mobile phase. Concentration of the eluate gives 1.2 g (64% of theory) of 2-(1-chloro-cyclopropyl)-1-(2-chloro-phenyl)-3-(5-thiocyanato-1,2,4-triazol-1-yl)-propan-2-ol in the form of an oil.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]2[C:8]([C:11]([NH:13][C:14]3[CH:22]=[CH:21][CH:20]=[C:19]4[C:15]=3[C:16]([CH:31]3[CH2:33][CH2:32]3)=[N:17][N:18]4[CH2:23][C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([CH3:30])[N:25]=3)=[O:12])=[CH:9][N:10]=[C:4]2[CH:3]=1.[CH3:34][S-:35].[Na+].O>CS(C)=O>[CH:31]1([C:16]2[C:15]3[C:19](=[CH:20][CH:21]=[CH:22][C:14]=3[NH:13][C:11]([C:8]3[N:5]4[CH:6]=[CH:7][C:2]([S:35][CH3:34])=[CH:3][C:4]4=[N:10][CH:9]=3)=[O:12])[N:18]([CH2:23][C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([CH3:30])[N:25]=3)[N:17]=2)[CH2:33][CH2:32]1
Reactant: Cc1cccc(Cn2nc(C3CC3)c3c(NC(=O)c4cnc5cc(Cl)ccn45)cccc32)n1
Reactant: C[S-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: CSc1ccn2c(C(=O)Nc3cccc4c3c(C3CC3)nn4Cc3cccc(C)n3)cnc2c1
Temperature: 55 °C
Yield: 82.5 %

Procedure:
A mixture of 7-chloro-N-(3-cyclopropyl-1-((6-methylpyridin-2-yl)methyl)-1H-indazol-4-yl)imidazo[1,2-a]pyridine-3-carboxamide (200 mg, 0.44 mmol; prepared as in Example 65, step C) and sodium methanethiolate (61 mg, 0.88 mmol) was dissolved in DMSO (2 mL). The reaction mixture was heated at 55° C. for 4 hours. The mixture was cooled to ambient temperature, transferred into water (100 mL) with stirring, and the resulting solid was collected by vacuum filtration and dried under vacuum to give the product (0.17 g). MS (ES+APCI) m/z=468.9 (M+H).