Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH2:2][CH:3]([C:5]1[CH:10]=[CH:9][C:8]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:7][CH:6]=1)[OH:4].C(N(CC)CC)C.[C:26](Cl)(=[O:29])[CH2:27][CH3:28]>ClCCl>[CH2:12]([O:11][C:8]1[CH:9]=[CH:10][C:5]([CH:3]([OH:4])[CH2:2][NH:1][C:26](=[O:29])[CH2:27][CH3:28])=[CH:6][CH:7]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: NCC(O)c1ccc(OCc2ccccc2)cc1
Reactant: CCC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCC(=O)NCC(O)c1ccc(OCc2ccccc2)cc1
Temperature: 25 °C
Yield: 112.2 %

Procedure:
The amine from example 24 (24.8 g, 0.10 mol) was dissolved in dichloromethane (700 ml) and to this was added triethylamine (20.86 ml, 0.15 mol). The reaction mixture was stirred and cooled to 0° C., before propionyl chloride (7.12 ml, 0.082 mol) was added dropwise. The reaction mixture was then allowed to warm to room temperature over 16 hours before quenching with 3M HCl (aq) (20 ml) and water (100 ml). The reaction mixture was then extracted with dichloromethane (3×200 ml) and the combined organic layers dried over anhydrous magnesium sulphate, filtered and concentrated in vacuo to give the title compound as a clear viscous gum (27.5 g, 0.092 mol, 90%). 1H NMR (CDCl3, 400 MHz) δ: 1.10 (t, 3H), 2.19 (q, 2H), 3.32-3.43 (m, 4H), 4.81 (s, 2H), 5.11 (m, 1H), 6.99 (d, 2H), 7.25-7.42 (m, 7H). LRMS: m/z 298 (M-H−).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][C@H:9]([C:11]2[N:16]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:15](=[O:23])[C:14]3=[C:24]([CH3:27])[CH:25]=[CH:26][N:13]3[N:12]=2)[CH3:10])[C:3]=1Br.[CH3:29][O:30][C:31]1[CH:36]=[C:35]([O:37][CH3:38])[CH:34]=[CH:33][C:32]=1[S:39]([NH:42][C:43]1[CH:48]=[CH:47][CH:46]=[C:45](B2OC(C)(C)C(C)(C)O2)[CH:44]=1)(=[O:41])=[O:40].C(=O)([O-])[O-].[Cs+].[Cs+]>>[NH2:1][C:2]1[C:3]([C:45]2[CH:44]=[C:43]([NH:42][S:39]([C:32]3[CH:33]=[CH:34][C:35]([O:37][CH3:38])=[CH:36][C:31]=3[O:30][CH3:29])(=[O:41])=[O:40])[CH:48]=[CH:47][CH:46]=2)=[C:4]([NH:8][C@H:9]([C:11]2[N:16]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:15](=[O:23])[C:14]3=[C:24]([CH3:27])[CH:25]=[CH:26][N:13]3[N:12]=2)[CH3:10])[N:5]=[CH:6][N:7]=1
Reactant: COc1ccc(S(=O)(=O)Nc2cccc(B3OC(C)(C)C(C)(C)O3)c2)c(OC)c1
Reactant: Cc1ccn2nc([C@H](C)Nc3ncnc(N)c3Br)n(-c3ccccc3)c(=O)c12
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: COc1ccc(S(=O)(=O)Nc2cccc(-c3c(N)ncnc3N[C@@H](C)c3nn4ccc(C)c4c(=O)n3-c3ccccc3)c2)c(OC)c1
Yield: 71.9 %

Procedure:
(S)-2-(1-((6-Amino-5-bromopyrimidin-4-yl)amino)ethyl)-5-methyl-3-phenylpyrrolo[2,1-f][1,2,4]triazin-4(3H)-one (100 mg, 0.23 mmol) was treated with 2,4-dimethoxy-N-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)benzenesulfonamide (191 mg, 0.45 mmol), 2N cesium carbonate (340 μl, 3.08 mmol) and bis(diphenylphosphino)ferrocene-palladium(II)dichloride dichloromethane complex (20 mg, 0.02 mmol) according to the method described in Example 3 to give 108 mg (73% yield) of the title compound as a solid. Purity 100%.
Reaction SMILES: [C:1]([O:5][C:6](=[O:20])[N:7]([C:13]1[CH:14]=[N:15][CH:16]=[CH:17][C:18]=1I)[CH2:8][C:9]([F:12])([F:11])[F:10])([CH3:4])([CH3:3])[CH3:2].[Cl:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1B(O)O>CCCCCCC.CCOC(C)=O>[C:1]([O:5][C:6](=[O:20])[N:7]([C:13]1[CH:14]=[N:15][CH:16]=[CH:17][C:18]=1[C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=1[Cl:21])[CH2:8][C:9]([F:12])([F:11])[F:10])([CH3:4])([CH3:3])[CH3:2]
Reactant: OB(O)c1ccccc1Cl
Reactant: CC(C)(C)OC(=O)N(CC(F)(F)F)c1cnccc1I
Solvent: CCOC(C)=O
Solvent: CCCCCCC
Product: CC(C)(C)OC(=O)N(CC(F)(F)F)c1cnccc1-c1ccccc1Cl

Procedure:
The title compound was prepared in analogy to example 72, from (4-iodo-pyridin-3-yl)-(2,2,2-trifluoro-ethyl)-carbamic acid tert-butyl ester and 2-chlorophenylboronic acid (CAS RN 1679-18-1) and using a gradient of n-heptane:EtOAc (100:0 to 30:70) for the chromatographic purification. Colorless oil (69%). MS (ESI): m/z=403.012 [M+H]+.
Reaction SMILES: [N+:1]([C:4]1[C:9]2[N:10]=[C:11]([C:13]([F:16])([F:15])[F:14])[O:12][C:8]=2[CH:7]=[CH:6][CH:5]=1)([O-])=O>CCOC(C)=O.[Fe]>[NH2:1][C:4]1[C:9]2[N:10]=[C:11]([C:13]([F:16])([F:15])[F:14])[O:12][C:8]=2[CH:7]=[CH:6][CH:5]=1
Reactant: O=[N+]([O-])c1cccc2oc(C(F)(F)F)nc12
Agent: [Fe]
Solvent: CCOC(C)=O
Product: Nc1cccc2oc(C(F)(F)F)nc12
Temperature: 65 °C
Reaction time: 6 h
Yield: 75 %

Procedure:
Compound 476A (10.75 g, 46.30 mmol) was dissolved in 1:1 EtOAc/10% HOAc (250 mL) and heated to 65° C. Iron powder (12.93 g, 231.5 mmol) was added portionwise and the reaction was stirred for 6 h at 65° C. After cooling, the mixture was filtered through Celite rinsing with EtOAc. The organic layer was separated, washed with H2O (3×100 mL), brine (100 mL), dried over MgSO4, and concentrated in vacuo to give a brown oil. The crude material was purified by flash chromatography on silica gel eluting with 70/30 CH2Cl2/hexanes to give compound 476B (7.02 g, 75%) as a yellow crystalline solid. HPLC: 96.7% at 2.68 min (retention time) (YMC S5 ODS column, 4.6×50 mm, eluting with 10–90% aqueous methanol over 4 min containing 0.2% phosphoric acid, 4 mL/min, monitoring at 220 nm).
Reaction SMILES: C(N(S(F)(F)[F:7])CC)C.[Cl:10][C:11]1[CH:12]=[C:13]2[C:17](=[CH:18][CH:19]=1)[NH:16][CH:15]=[C:14]2[CH2:20][CH2:21][NH:22][C:23]([C:25]1[CH:29]=[C:28]([CH:30]([C:32]2[CH:37]=[C:36]([F:38])[CH:35]=[CH:34][C:33]=2[F:39])O)[O:27][N:26]=1)=[O:24]>ClCCl>[Cl:10][C:11]1[CH:12]=[C:13]2[C:17](=[CH:18][CH:19]=1)[NH:16][CH:15]=[C:14]2[CH2:20][CH2:21][NH:22][C:23]([C:25]1[CH:29]=[C:28]([CH:30]([C:32]2[CH:37]=[C:36]([F:38])[CH:35]=[CH:34][C:33]=2[F:39])[F:7])[O:27][N:26]=1)=[O:24]
Reactant: O=C(NCCc1c[nH]c2ccc(Cl)cc12)c1cc(C(O)c2cc(F)ccc2F)on1
Reactant: CCN(CC)S(F)(F)F
Solvent: ClCCl
Product: O=C(NCCc1c[nH]c2ccc(Cl)cc12)c1cc(C(F)c2cc(F)ccc2F)on1
Temperature: 25 °C
Reaction time: 3 h
Yield: 6.7 %

Procedure:
Diethylaminosulfur trifluoride (0.033 mL; 0.197 mmol) was added to a solution of N-(2-(5-chloro-1H-indol-3-yl)ethyl)-5-((2,5-difluorophenyl)(hydroxy)methyl)isoxazole-3-carboxamide (0.074 g; 0.171 mmol) in dichloromethane (5 mL) at −78° C., the resulting mixture was stirred at room temperature for 3 hours, cooled to 0° C. and quenched with water. The layers were separated, the aqueous layer was extracted with dichloromethane. The organic layers rejoined were dried over magnesium sulphate and concentrated under reduced pressure. The crude material was purified by flash chromatography on silica (eluent 20 to 100% ethyl acetate in heptane) and by preparative HPLC method 2 to yield 0.005 g (7%) of N-(2-(5-chloro-1H-indol-3-yl)ethyl)-5-((2,5-difluorophenyl)fluoromethyl)isoxazole-3-carboxamide as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:12]2[O:16][N:15]=[C:14]([C:17]3[C:27]4[O:26][CH2:25][CH2:24][N:23]([CH2:28][CH2:29][C:30]([O:32]CC)=[O:31])[CH2:22][C:21]=4[CH:20]=[CH:19][CH:18]=3)[N:13]=2)[CH:5]=[N:6][C:7]=1[O:8][CH:9]([CH3:11])[CH3:10].[OH-].[Na+]>C(O)C>[Cl:1][C:2]1[CH:3]=[C:4]([C:12]2[O:16][N:15]=[C:14]([C:17]3[C:27]4[O:26][CH2:25][CH2:24][N:23]([CH2:28][CH2:29][C:30]([OH:32])=[O:31])[CH2:22][C:21]=4[CH:20]=[CH:19][CH:18]=3)[N:13]=2)[CH:5]=[N:6][C:7]=1[O:8][CH:9]([CH3:11])[CH3:10]
Reactant: CCOC(=O)CCN1CCOc2c(cccc2-c2noc(-c3cnc(OC(C)C)c(Cl)c3)n2)C1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CC(C)Oc1ncc(-c2nc(-c3cccc4c3OCCN(CCC(=O)O)C4)no2)cc1Cl
Temperature: 60 °C
Reaction time: 4 h
Yield: 97.7 %

Procedure:
Ethyl 3-[9-(5-{5-chloro-6-[(1-methylethyl)oxy]-3-pyridinyl}-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1,4-benzoxazepin-4(5H)-yl]propanoate (Preparation 91) (28 mg, 0.058 mmol) was dissolved in ethanol (5 ml). 2M sodium hydroxide (0.144 ml, 0.288 mmol) was added and the reaction mixture stirred at 60° C. for 4 hours. The solvent was evaporated and the reaction mixture diluted with water, neutralised with 2M hydrochloric acid and extracted with ethyl acetate. The organic phase was washed with water, dried and evaporated to give the product as a white solid (26 mg).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].Cl.Cl[CH2:14][CH2:15][N:16]([CH3:18])[CH3:17].C([O-])([O-])=O.[K+].[K+]>CC(=O)CC>[CH3:17][N:16]([CH3:18])[CH2:15][CH2:14][O:8][C:5]1[CH:6]=[CH:7][C:2]([CH3:1])=[C:3]([N+:9]([O-:11])=[O:10])[CH:4]=1
Reactant: Cc1ccc(O)cc1[N+](=O)[O-]
Reactant: CN(C)CCCl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: Cc1ccc(OCCN(C)C)cc1[N+](=O)[O-]
Yield: 89.2 %

Procedure:
4-Methyl-3-nitrophenol (2.0 g, 13 mmol), 1-chloro-2-dimethylaminoethane hydrochloride (3.8 g, 26 mmol), and K2CO3 (5.4 g, 39 mmol) were added to 2-butanone (30 mL). The mixture was refluxed for 12 h after which TLC analysis revealed consumption of the starting phenol. The reaction was cooled, diluted with saturated NH4Cl, and extracted with EtOAc. The organic layers were dried (Mg2SO4), filtered, concentrated, and purified via flash silica gel chromatography to afford the title compound (2.6 g, 89% yield). 1H NMR (400 MHz, CDCl3) δ ppm 2.34 (s, 6H), 2.53 (s, 3H), 2.74 (t, J=5.6 Hz, 2H), 4.09 (t, J=5.5 Hz, 2H), 7.10 (dd, J=8.4, 2.7 Hz, 1H), 7.22 (d, J=8.6 Hz, 1H), 7.53 (d, J=2.6 Hz, 1H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:16]=[CH:15][CH:14]=[C:13]3[C:9]=2/[C:10](=[CH:18]/[C:19]2[NH:20][C:21]([CH3:27])=[CH:22][C:23]=2[C:24](O)=[O:25])/[C:11](=[O:17])[NH:12]3)[CH:5]=[CH:6][CH:7]=1.[CH:28]1([NH:31][C:32]([C@@H:34]2[CH2:39][CH2:38][CH2:37][NH:36][CH2:35]2)=[O:33])[CH2:30][CH2:29]1.C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl>CN(C=O)C>[CH:28]1([NH:31][C:32]([C@@H:34]2[CH2:39][CH2:38][CH2:37][N:36]([C:24]([C:23]3[CH:22]=[C:21]([CH3:27])[NH:20][C:19]=3/[CH:18]=[C:10]3\[C:11](=[O:17])[NH:12][C:13]4[C:9]\3=[C:8]([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[CH:3]=3)[CH:16]=[CH:15][CH:14]=4)=[O:25])[CH2:35]2)=[O:33])[CH2:30][CH2:29]1
Reactant: Cc1cc(C(=O)O)c(/C=C2\C(=O)Nc3cccc(-c4cccc(F)c4)c32)[nH]1
Reactant: O=C(NC1CC1)[C@@H]1CCCNC1
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: Cc1cc(C(=O)N2CCC[C@@H](C(=O)NC3CC3)C2)c(/C=C2\C(=O)Nc3cccc(-c4cccc(F)c4)c32)[nH]1
Yield: 37.1 %

Procedure:
2-[4-(3-Fluoro-phenyl)-2-oxo-1,2-dihydro-indol-(3Z)-ylidenemethyl]-5-methyl-1H-pyrrole-3-carboxylic acid (108 mg, 0.3 mmol) was coupled with (R)-piperidine-3-carboxylic acid cyclopropylamide (69.3 mg, 1.5 eq.), HOBt (40.5 mg, 1 eq.), EDC (86 mg, 1.5 eq.) and TEA (0.06 mL) in DMF (1 mL) to give 57 mg (37%) of the titled compound.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[N:6][C:5]([N:8]2[CH2:13][CH2:12][C:11]([CH2:15][O:16][C:17]3[CH:28]=[CH:27][C:20]([C:21]([NH:23][CH2:24][CH2:25]O)=[O:22])=[CH:19][CH:18]=3)(O)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.S(Cl)(Cl)=O>C(OCC)(=O)C>[Cl:1][C:2]1[N:7]=[N:6][C:5]([N:8]2[CH2:13][CH:12]=[C:11]([CH2:15][O:16][C:17]3[CH:28]=[CH:27][C:20]([C:21]4[O:22][CH2:25][CH2:24][N:23]=4)=[CH:19][CH:18]=3)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1
Reactant: O=C(NCCO)c1ccc(OCC2(O)CCN(c3ccc(Cl)nn3)CC2)cc1
Solvent: O=S(Cl)Cl
Solvent: CCOC(C)=O
Product: Clc1ccc(N2CC=C(COc3ccc(C4=NCCO4)cc3)CC2)nn1
Reaction time: 8 h
Yield: 10.7 %

Procedure:
To a stirred and cooled mixture of 10 parts of 4-[[1-(6-chloro-3-pyridazinyl)-4-hydroxy-4-piperidinyl]methoxy]-N-(2-hydroxyethyl)benzamide and 228 parts of ethyl acetate were added dropwise 8.4 parts of thionyl chloride. Upon complete addition, stirring was continued first overnight at room temperature and then for 1 hour at 60° C. The reaction mixture was evaporated and the residue was dissolved in a solution of 20 parts of sodium hydrogen carbonate in 160 parts of ethanol. The whole was stirred overnight at reflux temperature. After evaporation, the residue was taken up in water. The precipitated product was filtered off and purified by column chromatography over silica gel using a mixture of trichloromethane and methanol (98:2 by volume) as eluent. The pure fractions were collected and the eluent was evaporated. The residue was crystallized from 2-propanol. The product was filtered off and dried, yielding 1 part (10.7%) of 3-chloro-6-[4-[[4-(4,5-dihydro-2-oxazolyl)phenoxy]methyl]-3,6-dihydro-1(2H)-pyridinyl]pyridazine; mp. 176.0° C. (comp. 168).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([N+:8]([O-:10])=[O:9])=[N:6][CH:7]=1.[NH:11]1[CH2:16][CH2:15][NH:14][CH2:13][C:12]1=[O:17].CCN(C(C)C)C(C)C>CS(C)=O>[N+:8]([C:5]1[N:6]=[CH:7][C:2]([N:14]2[CH2:15][CH2:16][NH:11][C:12](=[O:17])[CH2:13]2)=[CH:3][CH:4]=1)([O-:10])=[O:9]
Reactant: O=C1CNCCN1
Reactant: O=[N+]([O-])c1ccc(Br)cn1
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C1CN(c2ccc([N+](=O)[O-])nc2)CCN1
Temperature: 120 °C
Reaction time: 16 h

Procedure:
To a sealed tube were added 5-bromo-2-nitropyridine 141-1 (1.01 g, 5 mmol), piperazin-2-one 141-2 (0.6 g, 6 mmol), DIEA (1.8 mL, 18 mmol) and DMSO (6 mL). The reaction was heated to 120° C. and stirred for 16 hours. The reaction was cooled down to room temperature. DIEA was removed by rotary evaporation. The residue was triturated in 15 mL ethyl acetate. The solid was collected by filtration and washed with small amount of ethyl acetate to give 4-(6-nitropyridin-3-yl)piperazin-2-one 141-3 as light yellow solid. MS m/z 223.2 (M+1).
Reaction SMILES: [CH:1]1[C:11]2[C:10]3[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=3[CH2:8][N:7]([C:16]#[N:17])[CH2:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.[CH2:18]([OH:26])[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25]>>[CH:1]1[C:11]2[C:10]3[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=3[CH2:8][N:7]([C:16](=[NH:17])[O:26][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])[CH2:6][C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: CCCCCCCCO
Reactant: N#CN1Cc2ccccc2-c2ccccc2C1
Product: CCCCCCCCOC(=N)N1Cc2ccccc2-c2ccccc2C1

Procedure:
starting from 5,7-dihydro-6H-dibenz[c,e]azepine-6-carbonitrile and 1-octanol there is obtained octyl 5,7-dihydro-6H-dibenz[c,e]azepine-6-carboximidate as a resinous product, 1H-NMR(CDCl3): 0.88 (t, CH3), 1.0-2.0 (12H), 4.15 (t, OCH2), 4.23 (s, 4H), 4.87 (broad s, NH), 7.3-7.7 (8H);
Reaction SMILES: [O:1]=[C:2]1[CH2:11][CH2:10][CH2:9][C:8]2[CH:7]=[C:6]([C:12]([OH:14])=[O:13])[CH:5]=[CH:4][C:3]1=2.CO.[CH3:17][Si](C=[N+]=[N-])(C)C>C1COCC1>[O:1]=[C:2]1[CH2:11][CH2:10][CH2:9][C:8]2[CH:7]=[C:6]([C:12]([O:14][CH3:17])=[O:13])[CH:5]=[CH:4][C:3]1=2
Reactant: C[Si](C)(C)C=[N+]=[N-]
Reactant: O=C(O)c1ccc2c(c1)CCCC2=O
Solvent: CO
Solvent: C1CCOC1
Product: COC(=O)c1ccc2c(c1)CCCC2=O
Yield: 99.8 %

Procedure:
To a solution of 5-oxo-5,6,7,8-tetrahydronaphthalene-2-carboxylic acid (10.0 g, 52.6 mmol) in THF (52.6 mL) and MeOH (10.64 mL, 263 mmol) at rt was added trimethylsilyldiazomethane (2.0 M in diethyl ether, 79 mL, 158 mmol) dropwise until the solution turned yellow and gas evolution ceased. The reaction was then concentrated under reduced pressure to give methyl 5-oxo-5,6,7,8-tetrahydronaphthalene-2-carboxylate (10.72 g, 52.5 mmol, 100% yield) as a brown solid. MS ESI calcd for C12H12O3 [M+H]+ 205, found 205. 1H NMR (500 MHz, DMSO) δ 7.94 (d, J=8.1 Hz, 1H), 7.91 (s, 1H), 7.85 (dd, J=8.1, 1.6 Hz, 1H), 3.86 (s, 3H), 2.99 (t, J=6.0 Hz, 2H), 2.66-2.61 (m, 2H), 2.09-2.00 (m, 2H).
Reaction SMILES: Br[C:2]1[S:16][C:5]2=[N:6][C:7]([CH3:15])=[CH:8][C:9]([NH:10][S:11]([CH3:14])(=[O:13])=[O:12])=[C:4]2[C:3]=1[C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([O:23][CH3:24])[CH:18]=1.[NH:25]1[CH:29]=[C:28](B(O)O)[CH:27]=[N:26]1.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1.O.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>[CH3:15][C:7]1[N:6]=[C:5]2[S:16][C:2]([C:28]3[CH:29]=[N:25][NH:26][CH:27]=3)=[C:3]([C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([O:23][CH3:24])[CH:18]=3)[C:4]2=[C:9]([NH:10][S:11]([CH3:14])(=[O:13])=[O:12])[CH:8]=1
Reactant: COc1cccc(-c2c(Br)sc3nc(C)cc(NS(C)(=O)=O)c23)c1
Reactant: OB(O)c1cn[nH]c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: COc1cccc(-c2c(-c3cn[nH]c3)sc3nc(C)cc(NS(C)(=O)=O)c23)c1
Temperature: 130 °C
Yield: 34.1 %

Procedure:
To a suspension of N-{2-bromo-6-methyl-3-[3-(methyloxy)phenyl]thieno[2,3-b]pyridin-4-yl}methanesulfonamide (Example 97) (109 mg, 0.255 mmol), 1H-pyrazol-4-ylboronic acid (60 mg, 0.536 mmol) and potassium carbonate (118 mg, 0.854 mmol) in 1,4-dioxane (1.5 mL) and water (0.6 mL), was added tetrakis(triphenylphosphine)palladium(0) (31 mg, 0.027 mmol). The reaction mixture was heated at 130° C. in a microwave reactor for 1 h, followed by the addition of another portion of 1H-pyrazol-4-ylboronic acid (41 mg, 0.366 mmol) and tetrakis(triphenylphosphine)palladium(0) (15 mg, 0.013 mmol). The reaction mixture was heated at 130° C. in a microwave reactor for another 1 h and was then directly loaded onto a silica column, eluting with a gradient of 0-75% of ethyl acetate in cyclohexane and then further purified by MDAP (acidic conditions), to give the title compound (36 mg). LCMS (A) m/z: 413 [M−1]−, Rt 0.97 min (acidic).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH:9]([NH2:16])[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:4][CH:3]=1.[C:17]1([CH:23]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C:24](O)=[O:25])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C1C=CC2N(O)N=NC=2C=1.CN1CCOCC1.CCN=C=NCCCN(C)C.Cl>CN(C)C=O>[C:10]1([CH:9]([NH:16][C:24](=[O:25])[CH:23]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH2:8][C:5]2[CH:4]=[CH:3][C:2]([NH2:1])=[CH:7][CH:6]=2)[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: Nc1ccc(CC(N)c2ccccc2)cc1
Reactant: O=C(O)C(c1ccccc1)c1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: Nc1ccc(CC(NC(=O)C(c2ccccc2)c2ccccc2)c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 88.4 %

Procedure:
2-(4-aminophenyl)-1-phenylethylamine (0.40 g, 1.9 mMol) and diphenylacetic acid (0.40 g, 1.9 mMol) were dissolved in dimethylformamide (DMF) (4 mL) at room temperature. To this was added HOBT (0.26 g, 1.9 mMol), NMM (0.19 g, 1.9 mMol) and EDCl (0.36 g) and the mixture was stirred at room temperature for 18 hours. The DMF was removed under vacuum and the oily residue was taken up in 100 mL ethyl acetate. The ethyl acetate was washed with saturated sodium bicarbonate and with brine, dried over magnesium sulfate, and evaporated to give 0.683 grams of a semi-solid. This was purified on 30 grams of flash-grade silica gel eluting with 100% dichloromethane to give 0.512 grams of the title compound, m.p. 161°-163° C.
Reaction SMILES: C([O:8][C:9]1[CH:14]=[C:13]([C:15]([CH3:23])([CH3:22])[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])[CH:12]=[CH:11][C:10]=1[CH:24]1[CH2:29][CH2:28][CH2:27][C:26](=[O:30])[CH2:25]1)C1C=CC=CC=1.C(=O)(O)[O-].[Na+].[H][H]>[Pd].C(O)C>[CH3:23][C:15]([C:13]1[CH:12]=[CH:11][C:10]([CH:24]2[CH2:29][CH2:28][CH2:27][C:26](=[O:30])[CH2:25]2)=[C:9]([OH:8])[CH:14]=1)([CH3:22])[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21]
Reactant: [H][H]
Reactant: CCCCCCC(C)(C)c1ccc(C2CCCC(=O)C2)c(OCc2ccccc2)c1
Agent: [Pd]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: CCCCCCC(C)(C)c1ccc(C2CCCC(=O)C2)c(O)c1
Yield: 62 %

Procedure:
A mixture of 19.5 g. (0.0468 mol.) of 3-[2-benzyloxy-4-(1,1-dimethylheptyl)phenyl]cyclohexanone, 12.3 g. of sodium bicarbonate, 3.00 g. of 10% palladium-on-carbon and 250 ml. of ethanol was stirred under one atmosphere of hydrogen pressure for 1.5 hours. The reaction mixture was then filtered through diatomaceous earth with ethyl acetate and the filtrate evaporated to a solid. The crude solid was purified via column chromatography on 280 g. of silica gel eluted with 20% ethercyclohexane to yield a solid. Recrystallization of this solid from aqueous methanol gave 9.1 g. (62%) of the title product, m.p. 87° C., principally in the hemiketal form.
Reaction SMILES: [F:1][C:2]1[C:3]([C:9]2[CH:14]=[C:13]([NH:15][C:16]3[CH:21]=[CH:20][N:19]=[C:18]4[CH:22]=[N:23][NH:24][C:17]=34)[C:12]([CH3:25])=[CH:11][N:10]=2)=[N:4][C:5]([CH3:8])=[CH:6][CH:7]=1.[N:26]([CH2:29][CH3:30])=[C:27]=[O:28]>N1C=CC=CC=1.C(#N)C>[CH2:29]([NH:26][C:27]([N:24]1[C:17]2[C:18](=[N:19][CH:20]=[CH:21][C:16]=2[NH:15][C:13]2[C:12]([CH3:25])=[CH:11][N:10]=[C:9]([C:3]3[C:2]([F:1])=[CH:7][CH:6]=[C:5]([CH3:8])[N:4]=3)[CH:14]=2)[CH:22]=[N:23]1)=[O:28])[CH3:30]
Reactant: Cc1ccc(F)c(-c2cc(Nc3ccnc4cn[nH]c34)c(C)cn2)n1
Reactant: CCN=C=O
Solvent: CC#N
Solvent: c1ccncc1
Product: CCNC(=O)n1ncc2nccc(Nc3cc(-c4nc(C)ccc4F)ncc3C)c21
Temperature: 75 °C

Procedure:
N-(3′-Fluoro-5,6′-dimethyl-2,2′-bipyridin-4-yl)-1H-pyrazolo[4,3-b]pyridin-7-amine (81 mg, 0.242 mmol) was combined with acetonitrile (2.4 mL) and isocyanatoethane (23.78 μl, 0.303 mmol) along with 1 drop of pyridine. The mixture was heated at 75° C. The reaction was then cooled to give a solid which was collected by filtration, rinsed with acetonitrile to give the title compound. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.35 (3H, t, J=7.20 Hz) 2.47 (3H, s) 2.64 (3H, s) 3.51-3.63 (2H, m) 7.17-7.23 (1H, m) 7.33 (1H, d, J=4.55 Hz) 7.43 (1H, dd, J=10.48, 8.46 Hz) 7.51-7.59 (1H, m) 8.08 (1H, br. s.) 8.27 (1H, s) 8.41 (1H, d, J=5.31 Hz) 8.65 (1H, br. s.) 11.00 (1H, br. s.). MS [M+H] found 406.4.
Reaction SMILES: I[C:2]1[C:3]([NH:17][CH3:18])=[N:4][C:5]([NH:8][C:9]2[CH:16]=[CH:15][C:12]([C:13]#[N:14])=[CH:11][CH:10]=2)=[N:6][CH:7]=1.[CH3:19][N:20]([C@@H:28]([CH3:37])[C:29](=[O:36])[NH:30][CH2:31][CH2:32][CH2:33][C:34]#[CH:35])[C:21](=[O:27])[O:22][C:23]([CH3:26])([CH3:25])[CH3:24]>>[C:13]([C:12]1[CH:15]=[CH:16][C:9]([NH:8][C:5]2[N:4]=[C:3]([NH:17][CH3:18])[C:2]([C:35]#[C:34][CH2:33][CH2:32][CH2:31][NH:30][C:29](=[O:36])[C@@H:28]([N:20]([CH3:19])[C:21](=[O:27])[O:22][C:23]([CH3:24])([CH3:26])[CH3:25])[CH3:37])=[CH:7][N:6]=2)=[CH:10][CH:11]=1)#[N:14]
Reactant: CNc1nc(Nc2ccc(C#N)cc2)ncc1I
Reactant: C#CCCCNC(=O)[C@H](C)N(C)C(=O)OC(C)(C)C
Product: CNc1nc(Nc2ccc(C#N)cc2)ncc1C#CCCCNC(=O)[C@H](C)N(C)C(=O)OC(C)(C)C

Procedure:
By using 4-((5-iodo-4-(methylamino)pyrimidin-2-yl)amino)benzonitrile (F224) and (S)-tert-butyl methyl(1-oxo-1-(4-pentyn-1-ylamino)propan-2-yl)carbamate (U4), (S)-tert-butyl (1-((5-(2-((4-cyanophenyl)amino)-4-(methylamino)pyrimidin-5-yl)-4-pentyn-1-yl)amino)-1-oxopropan-2-yl)(methyl)carbamate (J17) was obtained in the same manner as that of Example 38, (2).
Reaction SMILES: ONC(=O)C1C=CC(OCC[N:13]2[C:19](=[O:20])[C:18]3[CH:21]=[CH:22][CH:23]=[N:24][C:17]=3[O:16][C:15]3[CH:25]=[CH:26][CH:27]=[CH:28][C:14]2=3)=CC=1.[OH-].[Na+].O>CN(C=O)C>[N:24]1[C:17]2[O:16][C:15]3[CH:25]=[CH:26][CH:27]=[CH:28][C:14]=3[NH:13][C:19](=[O:20])[C:18]=2[CH:21]=[CH:22][CH:23]=1
Reactant: O=C(NO)c1ccc(OCCN2C(=O)c3cccnc3Oc3ccccc32)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: O
Product: O=C1Nc2ccccc2Oc2ncccc21
Temperature: 130 °C
Reaction time: 5 h
Yield: 57.6 %

Procedure:
Title compound 430 (3.65 g, 14.7 mmol) was dissolved in DMF (25.0 mL) and sodium hydroxide powder (0.706 g, 17.7 mmol) was added. The reaction mixture was stirred at 130° C. for 5 hours. The mixture was cooled down to room temperature and ice cooled water was added. The precipitate was filtered. The solid was triturated in ethanol to afford title compound 431 (1.798 g, 58%) as a white solid. 1H NMR (DMSO-d6) δ (ppm): 10.75 (s, 1H), 8.50 (dd, J=4.8, 2.1 Hz, 1H), 8.27 (dd, J=7.6, 2.0 Hz, 1H), 7.46 (dd, J=7.5, 4.8 Hz, 1H), 7.34 (dd, J=7.8, 1.2 Hz, 1H), 7.25-7.14 (m, 3H). MS (m/z): 213.2 (M+H).