Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:28])[CH:4]([N:11]1[C:16](=[O:17])[C:15](Cl)=[C:14]([O:19][C:20]2[N:25]=[C:24]([CH3:26])[CH:23]=[C:22]([CH3:27])[N:21]=2)[CH:13]=[N:12]1)[CH2:5][CH:6]1[CH2:10][CH2:9][CH2:8][CH2:7]1.C([O-])=O.[NH4+]>C(O)C.[Pd]>[CH3:1][O:2][C:3](=[O:28])[CH:4]([N:11]1[C:16](=[O:17])[CH:15]=[C:14]([O:19][C:20]2[N:25]=[C:24]([CH3:26])[CH:23]=[C:22]([CH3:27])[N:21]=2)[CH:13]=[N:12]1)[CH2:5][CH:6]1[CH2:10][CH2:9][CH2:8][CH2:7]1
Reactant: COC(=O)C(CC1CCCC1)n1ncc(Oc2nc(C)cc(C)n2)c(Cl)c1=O
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CCO
Product: COC(=O)C(CC1CCCC1)n1ncc(Oc2nc(C)cc(C)n2)cc1=O
Temperature: 25 °C
Yield: 132.8 %

Procedure:
A solution of 2-[5-chloro-4-(4,6-dimethyl-pyrimidin-2-yloxy)-6-oxo-6H-pyridazin-1-yl]-3-cyclopentyl-propionic acid methyl ester (0.37 g, 0.91 mmol) in ethanol (10 mL) was treated with palladium on carbon (0.037 g) and ammonium formate (0.14 g, 2.27 mmol). The resulting mixture was refluxed for 30 min. After cooling to 25° C., the reaction was filtered and the solid was rinsed with ethanol. The filtrate was concentrated in vacuo to afford crude 3-cyclopentyl-2-[4-(4,6-dimethyl-pyrimidin-2-yloxy)-6-oxo-6H-pyridazin-1-yl]-propionic acid methyl ester (0.45 g), which could be further purified by chromatography (5/1 petroleum ether/ethyl acetate).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:12])[CH2:5][C:6]1[N:7]=[C:8]([NH2:11])[S:9][CH:10]=1)[CH3:2].[Cl:13][C:14]1[CH:15]=[CH:16][C:17]([O:37][CH3:38])=[C:18]([S:20]([N:23]2[CH2:29][CH2:28][CH2:27][CH2:26][C:25]3[CH:30]=[CH:31][C:32]([C:34](O)=[O:35])=[CH:33][C:24]2=3)(=[O:22])=[O:21])[CH:19]=1>>[CH2:1]([O:3][C:4](=[O:12])[CH2:5][C:6]1[N:7]=[C:8]([NH:11][C:34]([C:32]2[CH:31]=[CH:30][C:25]3[CH2:26][CH2:27][CH2:28][CH2:29][N:23]([S:20]([C:18]4[CH:19]=[C:14]([Cl:13])[CH:15]=[CH:16][C:17]=4[O:37][CH3:38])(=[O:21])=[O:22])[C:24]=3[CH:33]=2)=[O:35])[S:9][CH:10]=1)[CH3:2]
Reactant: COc1ccc(Cl)cc1S(=O)(=O)N1CCCCc2ccc(C(=O)O)cc21
Reactant: CCOC(=O)Cc1csc(N)n1
Product: CCOC(=O)Cc1csc(NC(=O)c2ccc3c(c2)N(S(=O)(=O)c2cc(Cl)ccc2OC)CCCC3)n1

Procedure:
1-(5-Chloro-2-methoxy-benzenesulfonyl)-2,3,4,5-tetrahydro-1H-benzo[b]azepine-8-carboxylic acid was converted to the title compound in analogy to example 8, steps 3 and 4. Step 3 was performed using (2-amino-thiazol-4-yl)-acetic acid ethyl ester and 1-(5-chloro-2-methoxy-benzenesulfonyl)-2,3,4,5-tetrahydro-1H-benzo[b]azepine-8-carboxylic acid and yielded (2-{[1-(5-chloro-2-methoxy-benzenesulfonyl)-2,3,4,5-tetrahydro-1H-benzo[b]azepine-8-carbonyl]-amino}-thiazol-4-yl)-acetic acid ethyl ester, which was hydrolyzed to (2-{[1-(5-chloro-2-methoxy-benzenesulfonyl)-2,3,4,5-tetrahydro-1H-benzo[b]azepine-8-carbonyl]-amino}-thiazol-4-yl)-acetic acid in step 4, MS (ISP): m/e=536.1 (M+H).
Reaction SMILES: Br[C:2]1[CH:9]=[CH:8][C:5]([CH2:6][OH:7])=[CH:4][C:3]=1[F:10].[CH3:11][N:12](C=O)C>[C-]#N.[C-]#N.[Zn+2].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>[C:11]([C:2]1[CH:9]=[CH:8][C:5]([CH2:6][OH:7])=[CH:4][C:3]=1[F:10])#[N:12]
Reactant: CN(C)C=O
Reactant: OCc1ccc(Br)c(F)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Agent: [Zn+2]
Product: N#Cc1ccc(CO)cc1F
Temperature: 90 °C
Reaction time: 8 h

Procedure:
To a degassed solution of the product from Step I (11.4 g, 55.6 mmol) in 100 mL of DMF was added Zn(CN)2 (3.92 g, 33.4 mmol) and Pd(PPh3)4 (5.1 g, 4.45 mmol). The reaction was stirred at 90° C. overnight, cooled to room temperature, and concentrated in vacuo. Purification of this material by silica gel chromatography (50% EtOAc/hexane) provided the titled product as a light yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:25]=[CH:26][C:27]=1[O:28][CH3:29])[CH2:5][N:6]1[C:14]2[C:9](=[N:10][CH:11]=[C:12]([C:15]#[N:16])[CH:13]=2)[N:8]([C@H:17]2[CH2:22][CH2:21][C@H:20]([OH:23])[CH2:19][CH2:18]2)[C:7]1=[O:24].[C:30](O)(=[O:32])[CH3:31].N(C(OCC)=O)=NC(OCC)=O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O1CCCC1>[C:30]([O:23][C@@H:20]1[CH2:19][CH2:18][C@H:17]([N:8]2[C:9]3=[N:10][CH:11]=[C:12]([C:15]#[N:16])[CH:13]=[C:14]3[N:6]([CH2:5][C:4]3[CH:25]=[CH:26][C:27]([O:28][CH3:29])=[C:2]([Cl:1])[CH:3]=3)[C:7]2=[O:24])[CH2:22][CH2:21]1)(=[O:32])[CH3:31]
Reactant: COc1ccc(Cn2c(=O)n([C@H]3CC[C@H](O)CC3)c3ncc(C#N)cc32)cc1Cl
Reactant: CC(=O)O
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COc1ccc(Cn2c(=O)n([C@H]3CC[C@@H](OC(C)=O)CC3)c3ncc(C#N)cc32)cc1Cl
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture of 1-(3-chloro-4-methoxybenzyl)-6-cyano-3-(trans-4-hydroxycyclohexyl)-2,3-dihydro-1H-imidazo[4,5-b]pyridin-2-one (500 mg), acetic acid (76.9 mg) and diethyl azodicarboxylate (221 mg) in anhydrous tetrahydrofuran (5 mL) was added triphenylphosphine (334 mg). The mixture was stirred at ambient temperature for overnight. The mixture was evaporated in vacuo, and the residue was purified by a silica gel column chromatography eluting with a mixture of n-hexane and ethyl acetate (3:1) to give 3-(cis-4-acetoxycyclohexyl)-1-(3-chloro-4-methoxybenzyl)-6-cyano-2,3-dihydro-1H-imidazo[4,5-b]pyridin-2-one (150 mg) as a pale yellow gum.
Reaction SMILES: [Cl:1][C:2]1[CH:13]=[C:12]([O:14]C)[CH:11]=[CH:10][C:3]=1[O:4][C:5]1[S:6][CH:7]=[CH:8][N:9]=1.B(Br)(Br)Br>ClCCl>[Cl:1][C:2]1[CH:13]=[C:12]([OH:14])[CH:11]=[CH:10][C:3]=1[O:4][C:5]1[S:6][CH:7]=[CH:8][N:9]=1
Reactant: COc1ccc(Oc2nccs2)c(Cl)c1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: Oc1ccc(Oc2nccs2)c(Cl)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 69.9 %

Procedure:
To a solution of Example 9A (5.4 g, 0.022 mol) in dichloromethane at −78° C. was added a solution of BBr3 (0.066 mol) drop wise and the reaction mixture was stirred overnight while warming up to room temperature. The mixture was poured into ice and then stirred at room temperature for 24 hours. The organic layer was washed with brine, dried over magnesium sulfate and filtered. The filtrate was concentrated under vacuum to give 3.5 g of product as an off-white solid (70% yield). 1H NMR (300 MHz, CDCl3) δ ppm 6.59 (dd, J=8.82, 2.94 Hz, 1H) 6.67 (d, J=2.57 Hz, 1H) 6.88 (d, J=3.68 Hz, 1H) 7.07 (d, J=8.82 Hz, 1H) 7.19 (d, J=3.68 Hz, 1H). MS (ESI) M/z 227.9 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[C:14]([F:15])=[CH:13][C:12]([NH:16][C:17]([C:19]3[C:20](=[O:32])[N:21]([C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)[N:22]([CH3:25])[C:23]=3[CH3:24])=[O:18])=[C:11]([F:33])[CH:10]=2)[CH:5]=[CH:4][N:3]=1.CCN(CC)CC.[O:41](C(C)=O)[C:42]([CH3:44])=O>>[C:42]([NH:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[C:14]([F:15])=[CH:13][C:12]([NH:16][C:17]([C:19]3[C:20](=[O:32])[N:21]([C:26]4[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=4)[N:22]([CH3:25])[C:23]=3[CH3:24])=[O:18])=[C:11]([F:33])[CH:10]=2)[CH:5]=[CH:4][N:3]=1)(=[O:41])[CH3:44]
Reactant: CC(=O)OC(C)=O
Reactant: Cc1c(C(=O)Nc2cc(F)c(Oc3ccnc(N)c3)cc2F)c(=O)n(-c2ccccc2)n1C
Solvent: CCN(CC)CC
Product: CC(=O)Nc1cc(Oc2cc(F)c(NC(=O)c3c(C)n(C)n(-c4ccccc4)c3=O)cc2F)ccn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 73 %

Procedure:
To a solution of N-(4-((2-aminopyridin-4-yl)oxy)-2,5-difluorophenyl)-1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazole-4-carboxamide (220 mg, 0.48 mmol) in (Ac)2O (8 mL) was added Et3N (0.5 mL, 1.32 mmol). The reaction mixture was stirred at rt for 8 hours and concentrated in vacuo. The residue was purified by a silica gel column chromatography (DCM/CH3OH (v/v)=10/1) to give the title compound as a white solid (175 mg, 73%).
Reaction SMILES: [Cl-].[Br:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]([OH:15])=O.[CH3:16][N:17]([CH3:28])[CH2:18][C:19]([CH3:27])([CH3:26])[CH:20]1[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1.C(N(CC)CC)C>ClC(Cl)Cl.O>[Br:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]([N:23]1[CH2:24][CH2:25][CH:20]([C:19]([CH3:27])([CH3:26])[CH2:18][N:17]([CH3:16])[CH3:28])[CH2:21][CH2:22]1)=[O:15]
Reactant: O=C(O)CCCCCCCCCCBr
Reactant: CN(C)CC(C)(C)C1CCNCC1
Agent: [Cl-]
Solvent: O
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CN(C)CC(C)(C)C1CCN(C(=O)CCCCCCCCCCBr)CC1
Temperature: 0 °C
Reaction time: 3 h
Yield: 57 %

Procedure:
17.5 g (6.2×10-2 mole) of the chloride of 11-bromoundecanoic acid diluted in 100 ml of trichloromethane was added dropwise to a solution of N,N,β,β-tetramethyl-4-piperidineethanamine in 120 ml of trichloromethane and 19.2 ml (14.7×10-2 mole) of N,N-diethylethanamine, cooled to 0° C. The reaction mixture was stirred for 3 hours at 0° C. then for 20 hours at room temperature. The reaction mixture was poured into water and allowed to settle. The organic phase was recovered and dried over magnesium sulphate and the solvents were evaporated off under reduced pressure. 12 g (yield: 57%) of the desired product was obtained as an oil.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[O:8][CH2:7][CH2:6][CH:5]2O.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C(=O)(O)[O-].[Na+]>C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[O:8][CH2:7][CH:6]=[CH:5]2
Reactant: OC1CCOc2ccc(Br)cc21
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Product: Brc1ccc2c(c1)C=CCO2
Temperature: 50 °C
Yield: 133.4 %

Procedure:
To a solution of 6-bromochroman-4-ol (3.98 kg, 17.4 mol) in toluene (18 L) add p-toluenesulfonic acid monohydrate (95 g, 499.42 mmol) at room temperature. Attach a Dean-Stark trap and reflux for 3 hr. and 50 min. Allow the mixture to cool to 50° C. in air and pour into saturated aqueous sodium bicarbonate (10 L) and ice (about 3 kg) with stirring. Separate the two layers. Back extract the aqueous layer with methyl tert-butyl ether (4 L). Wash the organic layer with saturated sodium bicarbonate (10 L) and brine (1×10 L), and evaporate the solvent under reduced pressure to obtain the title compound as a brown oil (4.90 kg, >100%, contains toluene). LCMS m/z (79Br) 209 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:16]([CH3:23])([CH3:22])[C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH:5]=[C:6](OC(=O)C(F)(F)F)[C:7]=1[F:8].[Cl-].[Li+].[CH:26]([Sn](CCCC)(CCCC)CCCC)=[CH2:27].[F-].[K+]>CN(C=O)C.C(OCC)(=O)C>[CH:26]([C:6]1[CH:5]=[C:4]([C:16]([CH3:22])([CH3:23])[C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH:3]=[C:2]([F:1])[C:7]=1[F:8])=[CH2:27]
Reactant: CCOC(=O)C(C)(C)c1cc(F)c(F)c(OC(=O)C(F)(F)F)c1
Reactant: C=C[Sn](CCCC)(CCCC)CCCC
Agent: [Cl-]
Agent: [F-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: C=Cc1cc(C(C)(C)C(=O)OCC)cc(F)c1F
Temperature: 25 °C
Reaction time: 22 h
Yield: 59.2 %

Procedure:
To a solution of ethyl 2-{3,4-difluoro-5-[(trifluoroacetyl)oxy]phenyl}-2-methylpropanoate (113 mg, 0.332 mmol) in DMF (6 mL, deoxygenated with N2) under N2 was added (t-Bu3P)2Pd (25 mg, 0.05 mmol), lithium chloride (42 mg, 0.996 mmol), and vinyl(tributyl)tin (0.11 mL, 0.365 mmol). The reaction was stirred at room temperature for 22 hours. To the reaction mixture was added ethyl acetate and 20% KF (aq.) and the reaction stirred for an additional 2 h. The suspension was filtered through and rinsed with ethyl acetate. The organic layer was washed with 20% KF (aq.). The combined aqueous layers were washed with ethyl acetate. The combined organic layers were then washed with H2O and brine, dried, and purified by Biotage purification system using (0-80% DCM:hexane) yielded the desired product (50 mg, 60%).
Reaction SMILES: Br[CH2:2][CH2:3][CH:4]=[C:5]([CH3:7])[CH3:6].[N+:8]([C:11]1[NH:12][CH:13]=[CH:14][N:15]=1)([O-:10])=[O:9]>CN(C)C=O.C(OCC)C>[CH3:6][C:5]([CH3:7])=[CH:4][CH2:3][CH2:2][N:12]1[CH:13]=[CH:14][N:15]=[C:11]1[N+:8]([O-:10])=[O:9]
Reactant: CC(C)=CCCBr
Reactant: O=[N+]([O-])c1ncc[nH]1
Solvent: CN(C)C=O
Solvent: CCOCC
Product: CC(C)=CCCn1ccnc1[N+](=O)[O-]
Temperature: 75 °C
Reaction time: 48 h

Procedure:
5-Bromo-2-methyl-2-pentene (25 g, 0.154 mol) was dissolved in dry dimethylformamide (DMF) (200 mL). To the solution was added K2 CO3 (21.3 g, 0.154 mol) and 2-nitroimidazole (17.4 g, 0.154 mol). The mixture was stirred under N2 atmosphere at 75° C. for 48 hours. DMF was evaporated on a rotary evaporator. The yellow gummy residue was stirred with water (150 mL) to give yellow solid, which was dissolved in diethyl ether (150 mL), dried over Na2SO4 and evaporated on a rotary evaporator to yield the title product. Yield 27.8 g (92%). mp: 49°-51° C. MS: (M+H)+ =196, M+ =195. 1H NMR (CDCl3) δ 1.45 and 1.68 (s, 6H, gem-di-CH3), 2.52 (q, 2H, CH2CH=), 4.43 [t, 2H, CH2 -(2-nitroimidazolyl)], 5.08 (t, 1H, CH2CH=), 7.05 and 7.14 (s, 2H, 2-nitroimidazolyl-H).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[N:7]1[CH2:12][CH2:11][N:10](C(OC(C)(C)C)=O)[CH2:9][CH2:8]1.[OH-].[Na+]>C(Cl)Cl.C(O)(C(F)(F)F)=O>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[N:7]1[CH2:8][CH2:9][NH:10][CH2:11][CH2:12]1
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccccn2)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: c1ccc(N2CCNCC2)nc1
Temperature: 30 °C
Reaction time: 1 h
Yield: 96.7 %

Procedure:
A solution of t-butyl 4-(pyridin-2-yl)piperazine-1-carboxylate (500 mg, 1.90 mmol, 1.00 equiv) in DCM/CF3COOH (10/3 mL) was placed in a 50-mL round bottom flask and stirred for 1 h at 30° C. in an oil bath. The pH value of the solution was adjusted to 9 with aqueous sodium hydroxide (1M), then extracted with 3×10 mL of dichloromethane. The organic layers combined, dried over anhydrous sodium sulfate, and filtered to remove solids. The resulting solution was concentrated under vacuum, yielding 300 mg (97%) of 1-(pyridin-2-yl)piperazine as yellow oil.
Reaction SMILES: [Br:1][C:2]1[C:3]([NH2:9])=[N:4][CH:5]=[N:6][C:7]=1Cl.Cl.[N:11]1([CH2:15][CH2:16][N:17]2[CH:21]=[C:20]([C:22]3[CH:27]=[CH:26][N:25]=[C:24]([C:28]([F:31])([F:30])[F:29])[CH:23]=3)[N:19]=[C:18]2[CH:32]2[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]2)[CH2:14][CH2:13][CH2:12]1.C(N(C(C)C)C(C)C)C>C(#N)C>[N:11]1([CH2:15][CH2:16][N:17]2[CH:21]=[C:20]([C:22]3[CH:27]=[CH:26][N:25]=[C:24]([C:28]([F:31])([F:29])[F:30])[CH:23]=3)[N:19]=[C:18]2[CH:32]2[CH2:33][CH2:34][N:35]([C:7]3[N:6]=[CH:5][N:4]=[C:3]([NH2:9])[C:2]=3[Br:1])[CH2:36][CH2:37]2)[CH2:12][CH2:13][CH2:14]1
Reactant: Nc1ncnc(Cl)c1Br
Reactant: FC(F)(F)c1cc(-c2cn(CCN3CCC3)c(C3CCNCC3)n2)ccn1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: Nc1ncnc(N2CCC(c3nc(-c4ccnc(C(F)(F)F)c4)cn3CCN3CCC3)CC2)c1Br
Temperature: 80 °C
Reaction time: 8 h

Procedure:
A reaction mixture of 5-Bromo-6-chloro-pyrimidin-4-ylamine (53.00 mg; 0.25 mmol; 1.00 eq.), 4-[1-(2-azetidin-1-yl-ethyl)-2-piperidin-4-yl-1H-imidazol-4-yl]-2-trifluoromethyl-pyridine hydrochloride (4) (133.56 mg; 0.25 mmol; 1.00 eq.), and ethyl-diisopropyl-amine (0.23 ml; 1.27 mmol; 5.00 eq.) in ACN 3 ml was stirred at 80° C. for overnight. Purified by HPLC (basic), collected title compound, 30 mg, yield, 21%. LC-MS: (M+1=551, obsd.=551).
Reaction SMILES: [Li]C(CC)C.BrC1C=CC(Cl)=CN=1.C[Si](C)(C)C#CC(=O)C.C(=O)([O-])[O-].[K+].[K+].[Cl:29][C:30]1[CH:31]=[CH:32][C:33]([C:36]([OH:44])([C:38]#[C:39][Si](C)(C)C)[CH3:37])=[N:34][CH:35]=1>C(OCC)C.CO>[Cl:29][C:30]1[CH:31]=[CH:32][C:33]([C:36]([OH:44])([C:38]#[CH:39])[CH3:37])=[N:34][CH:35]=1
Reactant: CC(O)(C#C[Si](C)(C)C)c1ccc(Cl)cn1
Agent: CC(=O)C#C[Si](C)(C)C
Agent: Clc1ccc(Br)nc1
Agent: O=C([O-])[O-]
Solvent: CCOCC
Solvent: CO
Product: C#CC(C)(O)c1ccc(Cl)cn1
Reaction time: 1 h

Procedure:
This compound was prepared according to a procedure similar to that described in Procedure C. to a 100-mL 3-necked round-bottom flask, s-BuLi (1.3M in hexane, 10 mL) was added into a solution of 2-bromo-5-chloropyridine (1.92 g, 9.98 mmol, 1.00 equiv) in ethyl ether (20 mL) under −76° C., Stirred for 1 h at this temp., 4-(trimethylsilyl)but-3-yn-2-one (1.54 g, 10.98 mmol, 1.10 equiv) was added. The resulting solution was stirred for 2 h at −76° C. The reaction was then quenched by the addition of 10 mL of ammonium chloride (sat., aq.). The resulting solution was extracted with 3×20 mL of ethyl acetate and the organic layers combined. The resulting mixture was washed with 1×20 mL of brine. The solid was dried in an oven under reduced pressure. This resulted in 2.5 g (crude) of 1-(5-chloropyridin-2-yl)-3-(trimethylsilyl)prop-2-yn-1-one as brown oil. In a 50-mL round-bottom flask, potassium carbonate (2.8 g, 20.29 mmol, 2.06 equiv) was added batchwise into a solution of 2-(5-chloropyridin-2-yl)-4-(trimethylsilyl)but-3-yn-2-ol (2.5 g, 9.85 mmol, 1.00 equiv) in methanol (25 mL). The resulting solution was stirred for 2 h at room temperature. TLC indicated the reaction completed, the solvent was concentrated under vacuum. The residue was diluted with 20 mL of water. The resulting solution was extracted with 3×20 mL of ethyl acetate and the organic layers combined. The resulting mixture was washed with 1×20 mL of brine. The solids were filtered out. The mixture was dried over anhydrous sodium sulfate and concentrated under vacuum, the residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1:10). This resulted in 800 mg (45%) of 2-(5-chloropyridin-2-yl)but-3-yn-2-ol as brown oil.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH2:8][CH2:9][C:10]2[CH:15]=[C:14]([NH:16][C:17](=[O:23])[O:18][C:19]([CH3:22])([CH3:21])[CH3:20])[CH:13]=[CH:12][N:11]=2)[CH:5]=[CH:6][CH:7]=1.[Cl:24][C:25]1[N:30]=[C:29](Cl)[C:28]([F:32])=[CH:27][N:26]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[Cl:24][C:25]1[N:30]=[C:29]([NH:1][C:2]2[CH:3]=[C:4]([CH2:8][CH2:9][C:10]3[CH:15]=[C:14]([NH:16][C:17](=[O:23])[O:18][C:19]([CH3:20])([CH3:22])[CH3:21])[CH:13]=[CH:12][N:11]=3)[CH:5]=[CH:6][CH:7]=2)[C:28]([F:32])=[CH:27][N:26]=1
Reactant: Fc1cnc(Cl)nc1Cl
Reactant: CC(C)(C)OC(=O)Nc1ccnc(CCc2cccc(N)c2)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)Nc1ccnc(CCc2cccc(Nc3nc(Cl)ncc3F)c2)c1
Yield: 36.5 %

Procedure:
To a solution of tert-butyl {2-[2-(3-aminophenyl)ethyl]pyridin-4-yl}carbamate (240 mg, 0.76 mmol) and 2,4-dichloro-5-fluoropyrimidine (134 mg, 0.80 mmol) in N,N-dimethylformamide (3.5 mL) was added potassium carbonate (318 mg, 0.23 mmol). The resultant mixture was stirred overnight at room temperature. The reaction mixture was filtered first to remove K2CO3, followed by quenching with water. EtOAc was added and the layers were separated. The aqueous layer was extracted with EtOAc twice. The combined organic layers were washed with water and brine, then dried (Na2SO4), filtered and concentrated to give the residue, which was purified by silica gel column chromatography to give the desired product as an off-white solid (123 mg, 36%). LCMS for C22H24ClFN5O2 (M+H)+: m/z=444.1.
Reaction SMILES: C(N(CC)CC)C.[CH3:8][NH:9][CH2:10][CH2:11][Br:12].Br.[P:14](Cl)([Cl:17])([Cl:16])=[O:15]>C(Cl)Cl>[CH3:8][N:9]([CH2:10][CH2:11][Br:12])[P:14]([Cl:17])([Cl:16])=[O:15]
Reactant: O=P(Cl)(Cl)Cl
Reactant: CNCCBr
Agent: Br
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CN(CCBr)P(=O)(Cl)Cl
Reaction time: 8 h
Yield: 93 %

Procedure:
Triethylamine (12.24 g, 121 mmol) was added dropwise to a stirred solution of N-methyl-N-bromoethylamine.HBr (12.04 g, 55 mmol) and phosphorus oxychloride (8.44 g, 55 mmol) in CH2Cl2 (100 ml) at 0° C. under N2. The mixture was allowed to stir overnight and then poured over ice. The layers were separated, and the aqueous layer was extracted with CH2Cl2 (3×100 ml). The organic layers were combined and dried (MgSO4). The filtrate was concentrated under reduced pressure and the residue purified by chromatography (1:4 EtOAc:hexanes) to give N-methyl-N-(2-bromoethyl)phosphoramidic dichloride as an oil (13 g, 93%): Rf 0.67 (1:4 EtOAc:hexanes); 1H NMR (CDCl3) 3.65(dt, 2H, J=14.10 Hz), 3.50(t, 2H, J=6.52 Hz), 2.93(d, 3H, J=15.46 Hz)ppm; 31P NMR (CDCl3) -6.57 ppm; IR (neat) 2980, 2940, 2880, 1740, 1450, 1370, 1340, 1280, 1250, 1210, 1105, 1050, 1005, 980, 975, 940, 915, 865, 755, 700 cm-1.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[C:7]([C:14]#[C:15][C:16]3[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=3)[C:8]([O:12][CH3:13])=[CH:9][CH:10]=2)[CH:5]=[N:4][N:3]=1.[Cl:22][C:23]1[CH:24]=[N:25][CH:26]=[C:27]([Cl:30])[C:28]=1[CH3:29].[H-].[Na+]>CN(C=O)C>[Cl:22][C:23]1[CH:24]=[N:25][CH:26]=[C:27]([Cl:30])[C:28]=1[CH2:29][C:2]1[C:11]2[C:6](=[C:7]([C:14]#[C:15][C:16]3[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=3)[C:8]([O:12][CH3:13])=[CH:9][CH:10]=2)[CH:5]=[N:4][N:3]=1
Reactant: Cc1c(Cl)cncc1Cl
Reactant: COc1ccc2c(Cl)nncc2c1C#Cc1ccncc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc2c(Cc3c(Cl)cncc3Cl)nncc2c1C#Cc1ccncc1
Yield: 40.4 %

Procedure:
Operating analogously to what described in example 15 starting from 1-chloro-6-methoxy-5-pyridin-4-ylethynyl-phthalazine (1.38 g, 4.66 mmoles), prepared as described in example 142, 3,5-dichloro-4-methylpyridine (1.887 mg, 11.65 mmoles), DMF (20 ml), NaH (466 mg, 11.65 mmoles), 793 mg of the title compound were obtained.
Reaction SMILES: C[N+]1([O-])CCOCC1.C([N+](CCC)(CCC)CCC)CC.[CH3:22][C:23]1([CH3:30])[CH:28]2[CH:24]1[CH2:25][CH2:26][CH:27]2[OH:29]>C(Cl)Cl>[CH3:22][C:23]1([CH3:30])[CH:28]2[CH:24]1[CH2:25][CH2:26][C:27]2=[O:29]
Reactant: CC1(C)C2CCC(O)C21
Agent: CCC[N+](CCC)(CCC)CCC
Agent: C[N+]1([O-])CCOCC1
Solvent: ClCCl
Product: CC1(C)C2CCC(=O)C21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A chilled (0° C.) solution of N-methylmorpholine N-oxide (3.11 g, 26.5 mmol) and tetrapropylammonium perrethenate (VII) (0.280 g, 0.796 mmol) in DCM (40 mL) was prepared containing 4 Å molecular sieves (ca 0.3 g). A solution of (±)-6,6-dimethyl-bicyclo[3.1.0]hexan-2-ol (1.67 g, 13.3 mmol) in DCM (10 mL) was added dropwise and the solution allowed to warm to room temperature and stirred for 1 hour under argon. The solution was filtered through a silica plug, solvent removed under reduced pressure and the resulting oil purified by column chromatography (0–100% DCM/n-hexane, silica). 6,6-Dimethyl-bicyclo[3.1.0]hexan-2-one was obtained as a brown oil. 1H NMR (CDCl3): δ 2.35–2.15 (m, 2H), 2.10–2.00 (m, 1H), 1.97–1.85 (m, 2H), 1.66 (d, 1H, J=4.7), 1.16 (s, 3H), 1.12 (s, 3H).
Reaction SMILES: [CH3:1][C:2]1[N:6]=[C:5]([CH3:7])[N:4]([C:8]2[C:12]([CH3:13])=[N:11][NH:10][C:9]=2[OH:14])[N:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH:22]([CH3:33])[C:23]([C:25]1[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][C:26]=1[Cl:32])=[O:24]>CN(C=O)C>[Cl:32][C:26]1[CH:27]=[C:28]([Cl:31])[CH:29]=[CH:30][C:25]=1[C:23](=[O:24])[CH:22]([O:14][C:9]1[NH:10][N:11]=[C:12]([CH3:13])[C:8]=1[N:4]1[C:5]([CH3:7])=[N:6][C:2]([CH3:1])=[N:3]1)[CH3:33]
Reactant: CC(Br)C(=O)c1ccc(Cl)cc1Cl
Reactant: Cc1nc(C)n(-c2c(C)n[nH]c2O)n1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: Cc1nc(C)n(-c2c(C)n[nH]c2OC(C)C(=O)c2ccc(Cl)cc2Cl)n1
Temperature: 50 °C
Reaction time: 1.5 h

Procedure:
To a stirring solution of 4-(3,5-dimethyl-[1,2,4]triazol-1-yl)-5-methyl-2H-pyrazol-3-ol (Intermediate KF) (97 mg, 0.502 mmol) and cesium carbonate (164 mg, 0.502 mmol) in DMF (1.158 ml) at 50° C. is added 2-bromo-1-(2,4-dichloro-phenyl)-propan-1-one (Intermediate AA) (142 mg, 0.502 mmol) in DMF (0.772 ml). The reaction mixture is stirred under N2 at 50° C. for 1.5 hours and then left to stand @ RT overnight. The resulting suspension is filtered and the filtrate is concentrated in vacuo. Purification by trituration from EtOAc affords the title product; MS: m/z 394.0 [M+H]+
Reaction SMILES: O=[C:2]1[CH2:7][CH2:6][CH2:5][CH2:4][CH:3]1[CH2:8][C:9]1[CH:16]=[CH:15][C:12]([C:13]#[N:14])=[CH:11][CH:10]=1.[CH3:17][N:18]([CH3:20])[NH2:19]>CCO>[CH3:17][N:18]([CH3:20])[N:19]=[C:2]1[CH2:7][CH2:6][CH2:5][CH2:4][CH:3]1[CH2:8][C:9]1[CH:16]=[CH:15][C:12]([C:13]#[N:14])=[CH:11][CH:10]=1
Reactant: N#Cc1ccc(CC2CCCCC2=O)cc1
Reactant: CN(C)N
Solvent: CCO
Product: CN(C)N=C1CCCCC1Cc1ccc(C#N)cc1

Procedure:
A solution of 4-[(2-oxocyclohexyl)methyl]-benzonitrile (7 g) (0.033 mol) and anhydrous N,N-dimethylhydrazine (9.2 ml) (3,7 eq.) in EtOH (100 ml) was refluxed for 8 h. After cooling, the reaction mixture was concentrated to dryness. The residue was partitioned between tBuOMe and water, the organic phase washed twice with water, dried over magnesium sulfate, and concentrated to yield 4-[[2-(dimethylhydrazono)cyclohexyl]methyl]-benzonitrile (6.1 g) as a orange oil. 1H NMR (CDCl3): 7.55 (2H, d), 7.30 (2H, d), 3.15 (1H, dd), 2.9-2.15 (6H, m), 2.3 (6H, s), 1.8-1.3 (4H, m).