Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][CH:6]=[CH:5][C:3]=1[NH2:4].[C:9](Cl)(Cl)=[S:10].C(N(C(C)C)C(C)C)C>>[Cl:1][C:2]1[CH:8]=[CH:7][CH:6]=[CH:5][C:3]=1[N:4]=[C:9]=[S:10]
Reactant: Nc1ccccc1Cl
Reactant: S=C(Cl)Cl
Solvent: CCN(C(C)C)C(C)C
Product: S=C=Nc1ccccc1Cl
Yield: 37.5 %

Procedure:
The title compound was prepared following the procedure described for intermediate-2 using 2-chloro aniline (2.0 g, 15.74 mmol), thiophosgene (1.81 g, 15.73 mmol), and N-ethyl di-isopropyl amine (4.0 g, 31.00 mmol) to afford 1.0 g of the desired product. 1HNMR (DMSO-d6): δ 7.62 (m, 3H), 7.39 (t, J=7.8 Hz, 1H).
Reaction SMILES: [CH2:1]([C:3]1[C:8](=[O:9])[NH:7][C:6]([CH3:10])=[C:5]([C:11]2[S:15][C:14]([S:16](Cl)(=[O:18])=[O:17])=[CH:13][CH:12]=2)[CH:4]=1)[CH3:2].[O:20]1[CH:24]=[CH:23][CH:22]=[C:21]1[CH2:25][NH2:26]>>[O:20]1[CH:24]=[CH:23][CH:22]=[C:21]1[CH2:25][NH:26][S:16]([C:14]1[S:15][C:11]([C:5]2[CH:4]=[C:3]([CH2:1][CH3:2])[C:8](=[O:9])[NH:7][C:6]=2[CH3:10])=[CH:12][CH:13]=1)(=[O:18])=[O:17]
Reactant: CCc1cc(-c2ccc(S(=O)(=O)Cl)s2)c(C)[nH]c1=O
Reactant: NCc1ccco1
Product: CCc1cc(-c2ccc(S(=O)(=O)NCc3ccco3)s2)c(C)[nH]c1=O
Yield: 78 %

Procedure:
5-(5-Ethyl-2-methyl-6-oxo-1,6-dihydropyridin-3-yl)thiophene-2-sulfonyl chloride is reacted with (furan-2-yl)methylamine as described in Step 5, Example 24 to give the title compound as a light orange solid (78% yield). LC/MS: RT 2.75 min; m/e 379 (M+H); 1H NMR (δ, ppm): 11.3 (1H, s), 8.42 (1H, t), 7.54 (1H, s), 7.50 (1H, t), 7.30 (1H, s), 7.11 (1H, d), 6.35 (1H, d), 6.22 (1H, s), 4.12 (2H, d), 2.41 (2H, q), 2.30 (3H, s), 1.10 (3H, t).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]=[C:6]2[CH:15]1[CH2:20][CH2:19][N:18]([C:21](Cl)=[O:22])[CH2:17][CH2:16]1.[N:24]1([C:29]2[CH:34]=[CH:33][C:32]([NH2:35])=[CH:31][CH:30]=2)[CH:28]=[CH:27][N:26]=[CH:25]1.CCN(C(C)C)C(C)C>C1COCC1>[N:24]1([C:29]2[CH:34]=[CH:33][C:32]([NH:35][C:21]([N:18]3[CH2:19][CH2:20][CH:15]([C:6]4[C:5]5[C:10](=[CH:11][C:12]([O:13][CH3:14])=[C:3]([O:2][CH3:1])[CH:4]=5)[N:9]=[CH:8][N:7]=4)[CH2:16][CH2:17]3)=[O:22])=[CH:31][CH:30]=2)[CH:28]=[CH:27][N:26]=[CH:25]1
Reactant: Nc1ccc(-n2ccnc2)cc1
Reactant: COc1cc2ncnc(C3CCN(C(=O)Cl)CC3)c2cc1OC
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: COc1cc2ncnc(C3CCN(C(=O)Nc4ccc(-n5ccnc5)cc4)CC3)c2cc1OC
Temperature: 65 °C
Reaction time: 3 h
Yield: 8.7 %

Procedure:
4-(6,7-Dimethoxy-quinazolin-4-yl)-piperidine-1-carbonyl chloride (16.5 mg, 0.05 mmol), prepared as described in Example 3a, was dissolved in anhydrous THF (2 mL) and to it was added 4-imidazol-1-yl-phenylamine (12 mg, 0.075 mmol) followed by DIEA (14 μL, 0.075 mmol) and the mixture was stirred at 65° C. for 3 h. It was then concentrated in vacuo and the residue was purified by Preparative TLC (silica gel, 5% MeOH/DCM) to obtain 2 mg (5%) of pure 4-(6,7-dimethoxy-quinazolin-4-yl)-piperidine-1-carboxylic acid (4-imidazol-1-yl-phenyl)-amide. 1H-NMR (300 MHz, CDCl3) δ 9.04 (s, 2H), 7.63 (m, 3H), 7.55-7.40 (m, 5H), 7.33 (s, 1H), 4.37 (m, 2H), 4.07 (s, 6H), 3.76-3.58 (m, 2H), 3.14 (m, 2H), 2.18-1.90 (m, 3H). LC/MS (ESI): calcd mass 458.2, found 459.5 (MH)+.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[NH:11][C:12]3[C:17]([C:18]=2[CH2:19][CH2:20][C:21]([N:23]2[CH2:28][CH2:27][N:26]([C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=4[O:35][CH3:36])[CH2:25][CH2:24]2)=[O:22])=[CH:16][C:15]([CH3:37])=[CH:14][CH:13]=3)=[CH:6][CH:5]=1.I[CH3:39].O>CN(C)C=O>[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[N:11]([CH3:39])[C:12]3[C:17]([C:18]=2[CH2:19][CH2:20][C:21]([N:23]2[CH2:28][CH2:27][N:26]([C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=4[O:35][CH3:36])[CH2:25][CH2:24]2)=[O:22])=[CH:16][C:15]([CH3:37])=[CH:14][CH:13]=3)=[CH:6][CH:5]=1
Reactant: CI
Reactant: COc1ccccc1N1CCN(C(=O)CCc2c(-c3ccc(Cl)cc3)[nH]c3ccc(C)cc23)CC1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccccc1N1CCN(C(=O)CCc2c(-c3ccc(Cl)cc3)n(C)c3ccc(C)cc23)CC1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 97.2 %

Procedure:
Sodium hydride (60% dispersion in mineral oil, 2.5 mg, 0.062 mmol) was added to a solution of 1-{3-[2-(4-chlorophenyl)-5-methyl-1H-indol-3-yl]-1-oxopropyl}-4-(2-methoxyphenyl)piperazine (Example 119, 20 mg, 0.041 mmol) in N,N-dimethylformamide (1 mL) and the mixture was stirred at room temperature for 10 min. Iodomethane (5 μl, 0.12 mmol) was added and the mixture was stirred at room temperature for 10 min. Water (25 mL) was added and the mixture was extracted with ethyl acetate. The combined organic fractions were dried (MgSO4), the solvent was evaporated under reduced pressure and the residue was purified by flash column chromatography on silica gel, eluting with hexane/ether (35:65) to give the title compound as a pale yellow foam (20 mg, 97%). 1H NMR (360 MHz, CDCl3) δ7.48-7.43 (3H, m), 7.33-7.31 (2H, m), 7.24-7.21 (1H, m), 7.11-7.02 (2H, m), 6.91-6.84 (3H, m), 3.86 (3H, s), 3.76 (2H, m), 3.53 (3H, s), 3.38 (2H, m), 3.04 (2H, m), 2.94 (2H, m), 2.77 (2H, m), 2.57 (2H, m), and 2.49 (3H, s). m/z (ES+) 502, 504 (M+1).
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:16]2[CH2:21][CH2:20][O:19][CH2:18][CH2:17]2)[C:5]2[S:10][CH:9]=[C:8]([C:11]3[S:15][CH:14]=[N:13][CH:12]=3)[C:6]=2[N:7]=1.CC1(C)C(C)(C)OB([C:30]2[CH:31]=[C:32]3[CH:38]=[CH:37][NH:36][C:33]3=[N:34][CH:35]=2)O1>>[O:19]1[CH2:20][CH2:21][N:16]([C:4]2[C:5]3[S:10][CH:9]=[C:8]([C:11]4[S:15][CH:14]=[N:13][CH:12]=4)[C:6]=3[N:7]=[C:2]([C:30]3[CH:31]=[C:32]4[CH:38]=[CH:37][NH:36][C:33]4=[N:34][CH:35]=3)[N:3]=2)[CH2:17][CH2:18]1
Reactant: CC1(C)OB(c2cnc3[nH]ccc3c2)OC1(C)C
Reactant: Clc1nc(N2CCOCC2)c2scc(-c3cncs3)c2n1
Product: c1cc2cc(-c3nc(N4CCOCC4)c4scc(-c5cncs5)c4n3)cnc2[nH]1

Procedure:
2-Chloro-4-morpholin-4-yl-7-thiazol-5-yl-thieno[3,2-d]pyrimidine and 5-(4,4,5,5-tetramethyl-[1.3.2]dioxaborolan-2-yl)-1H-pyrrolo[2,3-b]pyridine were reacted according to General Procedure A to give 318. NMR (DMSO, 400 MHz), 3.86 (4 H, t, J=4.4), 4.09 (4 H, t, J=5.2), 6.61-6.63 (1 H, m), 7.54-7.57 (1 H, m), 8.78 (2 H, s), 9.03 (1 H, s), 9.20 (1 H, s), 9.44-9.46 (1 H, m), 11.88 (1 H, s). MS: (ESI+): MH+=421
Reaction SMILES: [CH3:1][O:2][C:3]([C@@H:5]1[CH2:9][C@@H:8]([OH:10])[CH2:7][N:6]1[C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])=[O:4].[Cl:18][C:19]1[CH:24]=[CH:23][C:22](O)=[CH:21][CH:20]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1>[CH3:1][O:2][C:3]([C@@H:5]1[CH2:9][C@H:8]([O:10][C:22]2[CH:23]=[CH:24][C:19]([Cl:18])=[CH:20][CH:21]=2)[CH2:7][N:6]1[C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])=[O:4]
Reactant: COC(=O)[C@@H]1C[C@@H](O)CN1C(=O)OC(C)(C)C
Reactant: Oc1ccc(Cl)cc1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COC(=O)[C@@H]1C[C@H](Oc2ccc(Cl)cc2)CN1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 69 %

Procedure:
(2S,4R)-4-Hydroxy-pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester 2-methyl ester (CAS Reg. No. 74844-91-0) (1.10 g, 4.08 mmol) was dissolved in THF (25 ml) and 4-chlorophenol (0.78 g, 6.12 mmol) and triphenylphosphine (1.6 g, 6.12 mmol) were added. The solution was cooled in and ice bath and DIAD (0.96 ml, 4.88 mmol) added dropwise. The reaction was stirred at room temperature overnight. After evaporation of the solvent, the residue was dissolved in diethylether (20 ml) and pentane added until solution was only just maintained. The solution was seeded with triphenylphosphine oxide and cooled in ice. The resultant precipitate was filtered and the filtrate evaporated. The residue was purified by flash chromatography on silica (100 g), loading with pentane:diethylether (2:1 by volume) and eluting with pentane : diethylether (1: 1 by volume) to give the title compound as a colourless oil (1.35 g, 69%) containing a small impurity of diisopropylbicarbamate (CAS Reg. No.19740-72-8) by NMR.
Reaction SMILES: [F:1][C:2]([F:29])([F:28])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:14]=[CH:13][N:12]=[C:11]([O:15][C:16]3[CH:25]=[C:24]4[C:19]([CH:20]=[C:21]([CH:26]=[O:27])[CH:22]=[N:23]4)=[CH:18][CH:17]=3)[CH:10]=2)=[CH:5][CH:4]=1.[CH3:30][Mg]Br.[NH4+].[Cl-]>C1COCC1>[F:29][C:2]([F:1])([F:28])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:14]=[CH:13][N:12]=[C:11]([O:15][C:16]3[CH:25]=[C:24]4[C:19]([CH:20]=[C:21]([CH:26]([OH:27])[CH3:30])[CH:22]=[N:23]4)=[CH:18][CH:17]=3)[CH:10]=2)=[CH:5][CH:4]=1
Reactant: O=Cc1cnc2cc(Oc3cc(-c4ccc(C(F)(F)F)cc4)ncn3)ccc2c1
Reactant: C[Mg]Br
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CC(O)c1cnc2cc(Oc3cc(-c4ccc(C(F)(F)F)cc4)ncn3)ccc2c1
Temperature: -78 °C
Reaction time: 0.08 h

Procedure:
A solution of 7-{6-[4-(trifluoromethyl)phenyl]pyrimidin-4-yloxy}quinoline-3-carbaldehyde, (Example 60b), (220 mg, 0.56 mmol) in anhydrous THF (10 mL) was magnetically stirred under N2 in a −78° C. bath while methylmagnesium bromide (0.22 mL, 0.66 mmol, 3.0 M in Et2O, Aldrich) was added quickly. The reaction mixture was stirred at −78° C. for 5 min, then treated with satd NH4Cl (5 mL). The bath was removed and the mixture was stirred for 5 min, then diluted with EtOAc (60 mL) and washed with satd NH4Cl (20 mL), water (20 mL), satd NaHCO3 (20 mL), satd NaCl (20 mL), dried over Na2SO4, filtered and concentrated in vacuum. Purification by silica gel chromatography (gradient: 60A-85% EtOAc in hexanes) provided the title compound as an off-white solid. Mp: 156–157° C. MS (ESI, pos. ion.) m/z: 412 (M+1). Anal. Calcd for C22H16F3N3O2: C, 64.23; H, 3.92; N, 10.21; F, 13.85. Found: C, 63.99; H, 4.05; N, 10.01; F, 13.63.
Reaction SMILES: Br[C:2]1[C:7]2[S:8][CH:9]=[CH:10][C:6]=2[CH:5]=[CH:4][CH:3]=1.[N:11]1[CH:16]=[CH:15][C:14](B(O)O)=[CH:13][CH:12]=1>>[S:8]1[CH:9]=[CH:10][C:6]2[CH:5]=[CH:4][CH:3]=[C:2]([C:14]3[CH:15]=[CH:16][N:11]=[CH:12][CH:13]=3)[C:7]1=2
Reactant: Brc1cccc2ccsc12
Reactant: OB(O)c1ccncc1
Product: c1cc(-c2ccncc2)c2sccc2c1

Procedure:
This compound was prepared in analogy to the procedure described in Example 16i) starting from 7-bromo-benzo[b]thiophene (Focus synthesis, CAS:1423-61-6) using 4-pyridineboronic acid as reagent to obtain 4-benzo[b]thiophen-7-yl-pyridine as a grey solid. MS (ISP): m/e 212.1 (M+H)+
Reaction SMILES: [CH2:1]([N:5]1[CH:10]=[CH:9][CH:8]=[C:7]([OH:11])[C:6]1=[S:12])[CH2:2][CH2:3][CH3:4]>C(O)C>[CH2:1]([N:5]1[CH:10]=[CH:9][C:8]([CH2:1][N:5]([CH3:10])[CH3:6])=[C:7]([OH:11])[C:6]1=[S:12])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCn1cccc(O)c1=S
Solvent: CCO
Product: CCCCn1ccc(CN(C)C)c(O)c1=S
Temperature: 75 °C
Reaction time: 24 h
Yield: 198.2 %

Procedure:
To a solution of 1-butyl-3-hydroxypyridine-2-thione (2-034-04) (1.0 g) in ethanol containing 10% water (20 mL) was added N, N, N′, N′-teteramethyldiaminomethane (1.70 g) at room temperature. After the reaction mixture was stirred at 75° C. for 24 h, the solvent was evaporated under reduced pressure to give 1-butyl-3-hydroxy-4(N,N-dimethylaminomethyl)pyridine-2-thione (2-034-05) (1.3 g, 95%) as an oil.
Reaction SMILES: [NH2:1][C:2]1[N:3]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH:4]=[C:5]([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]#[CH:13])[N:6]=1.[N:21]([CH2:24][CH2:25][NH:26][C:27](=[O:35])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1[I:34])=[N+:22]=[N-:23]>>[NH2:1][C:2]1[N:3]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH:4]=[C:5]([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]2[N:23]=[N:22][N:21]([CH2:24][CH2:25][NH:26][C:27](=[O:35])[C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=3[I:34])[CH:13]=2)[N:6]=1
Reactant: [N-]=[N+]=NCCNC(=O)c1ccccc1I
Reactant: C#CCCCCCc1cn(C(=O)OC(C)(C)C)c(N)n1
Product: CC(C)(C)OC(=O)n1cc(CCCCCc2cn(CCNC(=O)c3ccccc3I)nn2)nc1N

Procedure:
tert-butyl 2-amino-4-(hept-6-ynyl)-1H-imidazole-1-carboxylate (0.083 g, 0.299 mmol) was reacted with N-(2-azidoethyl)-2-iodobenzamide (0.095 g, 0.299 mmol) following the general click procedure to give tert-butyl 2-amino-4-(5-(1-(2-(2-iodobenzamido)ethyl)-1H-1,2,3-triazol-4-yl)pentyl)-1H-imidazole-1-carboxylate 1H NMR (300 MHz, CDCl3) δ 7.74 (d, 2H), δ 7.57 (t, 1H), δ 7.36 (s, 1H), δ 7.22 (s, 2H0, δ 6.97 (m, 1H0, δ 6.39 (s, 1H), δ 5.97 (s, 2H), δ 4.48 (t, 2H0, δ 3.85 (m, 2H0, δ 2.44 (t, 2H), δ 2.18 (t, 2H), δ 1.45 (m, 13H, δ 1.18 (m, 2H) ppm; 13C NMR (75 MHz, CDCl3) δ 170.3, 150.4, 149.5, 148.2, 141.8, 139.9, 138.7, 131.3, 128.4, 128.3, 122.3, 106.5, 92.8, 84.9, 49.2, 40.5, 29.2, 28.9, 28.3, 28.2, 28.0, 25.5 ppm; HRMS (ESI) calcd for C24H32IN7O3 (M+) 593.1611. found 593.1603, which was subsequently deprotected to give N-(2-(4-(5-(2-amino-1H-imidazol-4-yl)pentyl)-1H-1,2,3-triazol-1-yl)ethyl)-2-iodobenzamide hydrochloride (0.125 g, 79% yield). 1H NMR (400 MHz, CD3OD) δ 8.35 (s, 1H), δ 7.88*d, 1H), δ 7.45 (t, 1H), δ 7.34 (d, 1H), δ 7.15 (t, 1H), δ 6.47 (s, 1H), δ 4.78 (s, 2H), δ 3.99 (s, 2H), δ 2.83 (s, 2H), δ 2.44 (t, 2H), δ 1.76 (s, 2H), δ 1.64 (s, 2H), δ 1.29 (s, 2H) ppm; 13C NMR (75 MHz, CD3OD) δ 171.6, 159.2, 147.3, 142.1, 139.8, 131.2, 128.2, 127.7, 124.4, 92.1, 52.2, 40.8, 39.4, 31.2, 28.3, 28.1, 27.7, 24.1, 20.9, 15.9, 10.7 ppm; HRMS (ESI) calcd for C19H24IN7O (M+) 493.1087. found 493.1085.
Reaction SMILES: [CH3:1][C:2]1([CH3:14])[O:7][CH2:6][C:5]2=[CH:8][C:9]([N+:11]([O-])=O)=[N:10][N:4]2[CH2:3]1>[Pd].CO>[CH3:1][C:2]1([CH3:14])[O:7][CH2:6][C:5]2=[CH:8][C:9]([NH2:11])=[N:10][N:4]2[CH2:3]1
Reactant: CC1(C)Cn2nc([N+](=O)[O-])cc2CO1
Agent: [Pd]
Solvent: CO
Product: CC1(C)Cn2nc(N)cc2CO1
Temperature: 25 °C
Reaction time: 2 h
Yield: 79.9 %

Procedure:
A 50-mL single-neck round-bottomed flask was purged with nitrogen and charged with 330f (0.21 g, 1.25 mmol), 10% palladium on carbon (50% wet, 125 mg), and methanol (10 mL). The mixture was evacuated, charged with hydrogen gas, and stirred at room temperature for 2 h. The hydrogen was then evacuated and nitrogen was charged into the flask. The catalyst was removed by filtration through a pad of CELITE® and the filtrate was concentrated under reduced pressure to afford 330g (167 mg, 93%). MS-ESI: [M+H]+ 168.1
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[C:5]([F:9])=[CH:4][N:3]=1.[CH3:10][N:11]([CH3:18])[C:12]1[NH:16][N:15]=[C:14]([NH2:17])[CH:13]=1.CCN(C(C)C)C(C)C>C(O)C>[Cl:1][C:2]1[N:7]=[C:6]([NH:17][C:14]2[CH:13]=[C:12]([N:11]([CH3:18])[CH3:10])[NH:16][N:15]=2)[C:5]([F:9])=[CH:4][N:3]=1
Reactant: CN(C)c1cc(N)n[nH]1
Reactant: Fc1cnc(Cl)nc1Cl
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Product: CN(C)c1cc(Nc2nc(Cl)ncc2F)n[nH]1
Yield: 39 %

Procedure:
2,4-dichloro-5-fluoropyrimidine (166 mg, 1 mmol), N5,N5-dimethyl-1H-pyrazole-3,5-diamine (Method 34, 150 mg, 1.2 mmol), and DIEA (0.35 ml, 2 mmol) in ethanol (3 ml) was heated at 55° C. overnight. Solvent was removed, and the residue was purified by silica gel chromatography (by ISCO Combiflash with a gradient of 0-5% methanol in methylene chloride with 1% NH4OH). 100 mg product was obtained as a white solid (40%). MS: 257 (M+1); NMR (DMSO-d6, 400 MHz, 80° C.) δ11.60 (br, 1H), 10.26 (br, 1H), 8.23 (s, 1H), 5.73 (s, 1H), 2.76 (s, 6H).
Reaction SMILES: [F:1][C:2]([F:10])([F:9])[C:3]1([CH2:6][C:7]#[N:8])[CH2:5][CH2:4]1.[ClH:11]>C1COCC1.CSC>[ClH:11].[F:1][C:2]([F:10])([F:9])[C:3]1([CH2:6][CH2:7][NH2:8])[CH2:5][CH2:4]1
Reactant: N#CCC1(C(F)(F)F)CC1
Agent: Cl
Solvent: C1CCOC1
Solvent: CSC
Product: NCCC1(C(F)(F)F)CC1
Temperature: 0 °C
Yield: 40 %

Procedure:
Treat a solution of 2-(1-(trifluoromethyl)cyclopropyl)acetonitrile (2.2 g, 14.7 mmol) in THF (60 mL), under N2, with BH3 (10 M in dimethyl sulfide, 3 mL, 30 mmol) and heat at 70° C. overnight. Cool the mixture to 0° C., treat dropwise with methanolic HCl, concentrate to dryness, dissolve in MeOH, re-concentrate and treat the residue with EtOAc. Collect the solids via filtration and dry to afford the title compound (1.1 g, 40% yield). 1H NMR (400 MHz, DMSO-d6): δ 8.05 (s, 3H), 2.87 (t, J=8.4 Hz, 2H), 1.90-1.86 (m, 2H), 0.96-0.93 (m, 2H), 0.82-0.81 (m, 2H).
Reaction SMILES: Cl[C:2]([O:4][CH2:5][C:6]([Cl:9])([Cl:8])[Cl:7])=[O:3].N1C=CC=CC=1.[NH2:16][C:17]1[C:31]([O:32][CH3:33])=[C:30]([CH3:34])[C:29]([O:35][CH3:36])=[CH:28][C:18]=1[C:19]([N:21]1[CH2:25][CH2:24][CH2:23][CH:22]1[CH2:26][OH:27])=[O:20]>C(Cl)Cl>[CH3:34][C:30]1[C:29]([O:35][CH3:36])=[CH:28][C:18]([C:19]([N:21]2[CH2:25][CH2:24][CH2:23][CH:22]2[CH2:26][OH:27])=[O:20])=[C:17]([NH:16][C:2]([O:4][CH2:5][C:6]([Cl:9])([Cl:8])[Cl:7])=[O:3])[C:31]=1[O:32][CH3:33]
Reactant: COc1cc(C(=O)N2CCCC2CO)c(N)c(OC)c1C
Reactant: O=C(Cl)OCC(Cl)(Cl)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: COc1cc(C(=O)N2CCCC2CO)c(NC(=O)OCC(Cl)(Cl)Cl)c(OC)c1C
Reaction time: 6 h
Yield: 69.7 %

Procedure:
A solution of 2,2,2-trichloroethyl chloroformate (1.38 g, 6.5 mmol) in distilled DCM (25 mL) was added dropwise over 0.5 hours to a solution of anhydrous pyridine (1.03 g, 13 mmol) and 191 (1.91 g, 6.5 mmol) in distilled DCM (25 mL) at 0° C. After 6 hours at room temperature, the reaction mixture was diluted with anhydrous DCM (100 mL) and washed with 1 N HCl (2×100 mL), H2O (100 mL), brine (100 mL) and dried over anhydrous MgSO4. Evaporation of the solvent yielded a brown oil which was purified by flash column chromatography (silica gel, EtOAc) to afford the product (192) as a yellow glass (2.13 g, 4.53 mmol, 70%); 1H NMR (270 MHz, CDCl3) δ7.59 (br s, 1H), 6.56 (s, 1H), 4.78 (br s, 2H), 4.25-4.23 (m, 1H), 3.82-3.79 (m, 3H+1H), 3.69-3.63 (m, 3H+1H), 3.52 (m, 1H), 3.42-3.33 (m, 1H), 2.13-2.06 (m, 3H+1H), 1.88-1.64 (m, 3H); 13C NMR (67.8 MHZ, CDCl3) δ169.95, 156.82, 156.67, 154.02, 153.34, 131.92, 121.74, 119.33, 103.94, 95.43, 74.42, 66.04, 61.01, 60.60, 60.27, 55.73, 50.46, 28.53, 24.47, 9.13.
Reaction SMILES: [CH2:1]([Zn]CC)C.[O:6]1[C:10]2[CH:11]=[CH:12][CH:13]=[C:14](/[CH:15]=[CH:16]\[CH2:17][OH:18])[C:9]=2[CH2:8][CH2:7]1>C(Cl)Cl>[O:6]1[C:10]2[CH:11]=[CH:12][CH:13]=[C:14]([C@H:15]3[CH2:1][C@H:16]3[CH2:17][OH:18])[C:9]=2[CH2:8][CH2:7]1
Reactant: CC[Zn]CC
Reactant: OC/C=C\c1cccc2c1CCO2
Solvent: ClCCl
Product: OC[C@@H]1C[C@@H]1c1cccc2c1CCO2
Temperature: -15 °C
Reaction time: 1 h
Yield: 85.9 %

Procedure:
Diethylzinc (63 mmol, 1.0 M in hexanes) was added dropwise to a mixture of (cis)-3-(2,3-dihydrobenzofuran-4-yl)prop-2-en-1-ol (12.6 mmol) in 10 mL of CH2Cl2 at −15° C. The resulting mixture was stirred at −15° C. for 1 h followed by the dropwise addition of CH2CI2 (63 mmol). The resulting mixture was warmed to RT and stirred overnight. The crude reaction mixture was then quenched with saturated aqueous NH4Cl solution at 0° and extracted with ether (2×100 mL). The combined organic extracts were washed with saturated aqueous NH4Cl solution, dried over magnesium sulfate, filtered and concentrated in vacuo. Purification by silica gel column chromatography (Hexanes:EtOAc, 4:1) provided 2.06 g (86%) of the desired product.
Reaction SMILES: [NH2:1][C:2]1[C:3]([F:36])=[C:4]([C:9]2[N:10]=[C:11]([CH:33]3[CH2:35][CH2:34]3)[N:12](COCC[Si](C)(C)C)[C:13]=2[C:14]2[CH:19]=[CH:18][N:17]=[C:16]([NH:20][CH2:21][CH2:22][C:23]#[N:24])[N:15]=2)[CH:5]=[C:6]([Cl:8])[CH:7]=1.Cl>CCO>[NH2:1][C:2]1[C:3]([F:36])=[C:4]([C:9]2[N:10]=[C:11]([CH:33]3[CH2:35][CH2:34]3)[NH:12][C:13]=2[C:14]2[CH:19]=[CH:18][N:17]=[C:16]([NH:20][CH2:21][CH2:22][C:23]#[N:24])[N:15]=2)[CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: C[Si](C)(C)CCOCn1c(C2CC2)nc(-c2cc(Cl)cc(N)c2F)c1-c1ccnc(NCCC#N)n1
Agent: Cl
Solvent: CCO
Product: N#CCCNc1nccc(-c2[nH]c(C3CC3)nc2-c2cc(Cl)cc(N)c2F)n1
Temperature: 25 °C
Yield: 75 %

Procedure:
To a solution of 3-(4-(4-(3-amino-5-chloro-2-fluorophenyl)-2-cyclopropyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-5-yl)pyrimidin-2-ylamino)propanenitrile (0.58 g, 1.1 mmol) in EtOH (10 mL) was added concentrated HCl (1 mL). The resulting reaction was maintained at room temperature for 9 hours after which the reaction mixture was concentrated and partitioned between water (60 mL) and EtOAc (250 mL). The layers were separated and the aqueous portion was neutralized with solid NaHCO3, and then extracted with EtOAc (200, 100 mL). The combined organic portions were then extracted with 0.1 M aqueous HCl solution (2×100 mL). The combined acidic aqueous extracts were neutralized with solid NaHCO3 and extracted with EtOAc (2×100 mL). The combined organic phases were washed with brine, dried (Na2SO4), and then concentrated to furnish 3-(4-(4-(3-amino-5-chloro-2-fluorophenyl)-2-cyclopropyl-1H-imidazol-5-yl)pyrimidin-2-ylamino)propanenitrile (328 mg) as an amber residue which was carried forward without further purification: LCMS(m/z) 398.1 (MH+), tR=0.55 minute.
Reaction SMILES: [CH3:1][Si](C=[N+]=[N-])(C)C.[Br:8][C:9]1[CH:14]=[CH:13][C:12]([NH:15][C:16]2[C:21]([C:22]([OH:24])=[O:23])=[CH:20][N:19]=[C:18]([Cl:25])[C:17]=2[F:26])=[C:11]([F:27])[CH:10]=1.C1COCC1>CO>[CH3:1][O:23][C:22](=[O:24])[C:21]1[C:16]([NH:15][C:12]2[CH:13]=[CH:14][C:9]([Br:8])=[CH:10][C:11]=2[F:27])=[C:17]([F:26])[C:18]([Cl:25])=[N:19][CH:20]=1
Reactant: O=C(O)c1cnc(Cl)c(F)c1Nc1ccc(Br)cc1F
Reactant: C[Si](C)(C)C=[N+]=[N-]
Solvent: C1CCOC1
Solvent: CO
Product: COC(=O)c1cnc(Cl)c(F)c1Nc1ccc(Br)cc1F
Temperature: 25 °C
Reaction time: 1 h
Yield: 92.3 %

Procedure:
A hexanes solution of TMSCH2N2 (9.46 mL, 18,9 mmol) was added to 4-(4-bromo-2-fluorophenylamino)-6-chloro-5-fluoro-nicotinic acid (4.59 g, 12.62 mmol) in a solution of 3:1 THF:MeOH (48 mL) at 0° C. The reaction mixture was warmed to room temperature and stirred for 1 hour. After quenching with AcOH, the reaction mixture was diluted with ethyl acetate and water. The layers were separated and the organic layer was washed with water, saturated NaHCO3 solution and brine. The organic layer was dried (MgSO4) and concentrated to give 4.40 g (92%) clean desired product.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][NH:4][C:5]([N:7]([CH2:19][CH2:20][CH2:21][CH3:22])[CH:8]1[O:16][C@H:15]([CH2:17][OH:18])[C@@H:13]([OH:14])[C@H:11]([OH:12])[C@H:9]1[OH:10])=[O:6].C(=O)([O-])[O-].[Na+].[Na+].[N+:29]([O-])([N+]([O-])=O)=[O:30]>O1CCCC1.C(Cl)Cl>[Cl:1][CH2:2][CH2:3][N:4]([N:29]=[O:30])[C:5]([N:7]([CH2:19][CH2:20][CH2:21][CH3:22])[CH:8]1[O:16][C@H:15]([CH2:17][OH:18])[C@@H:13]([OH:14])[C@H:11]([OH:12])[C@H:9]1[OH:10])=[O:6]
Reactant: O=[N+]([O-])[N+](=O)[O-]
Reactant: CCCCN(C(=O)NCCCl)C1O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: C1CCOC1
Product: CCCCN(C(=O)N(CCCl)N=O)C1O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O
Yield: 78.6 %

Procedure:
3.4 g of 1-(2-chloroethyl)-3-n-butyl-3-D-glucopyranosylurea are dissolved in a mixture of 60 ml of tetrahydrofuran and 60 ml of methylene chloride, and 15 g of sodium carbonate anhydrate are added thereto. 5 g of nitrogen tetroxide gas are introduced into the mixture for 10 minutes under ice-cooling. The mixture is treated in the same manner as described in Example 2. 2.9 g of 1-(2-chloroethyl)-1-nitroso-3-n-butyl-3-D-glucopyranosylurea are thereby obtained as yellow caramel.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([CH:11]=1)=[CH:9][C:8]([CH2:12][C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])=[CH:7][CH:6]=2.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH3:39][O:40][CH2:41][CH2:42]O.N(C(OC(C)(C)C)=O)=NC(OC(C)(C)C)=O>CCOC(C)=O.C1C=CC=CC=1>[CH3:39][O:40][CH2:41][CH2:42][O:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([CH:11]=1)=[CH:9][C:8]([CH2:12][C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])=[CH:7][CH:6]=2
Reactant: CC(C)(C)OC(=O)Cc1ccc2ncc(O)cc2c1
Reactant: COCCO
Agent: CC(C)(C)OC(=O)N=NC(=O)OC(C)(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: c1ccccc1
Product: COCCOc1cnc2ccc(CC(=O)OC(C)(C)C)cc2c1
Temperature: 0 °C
Yield: 0.3 %

Procedure:
A flask was charged with tert-butyl 2-(3-hydroxyquinolin-6-yl)acetate (581.04 mg, 2.241 mmol) and triphenylphosphine (1.175 g, 4.482 mmol) then sealed with a septum and an placed under N2. Benzene (10 mL) was added, followed by 2-methoxyethanol (0.8838 ml, 11.20 mmol). The heterogeneous solution was cooled to 0° C., and di-tert-butyl azodicarboxylate (1.032 g, 4.482 mmol) was added as a solid in a single portion. The solution was allowed to warm to rt and maintained 20 h. The solution was then partitioned between saturated aqueous. NH4Cl, and the layers separated. The aqueous layer was extracted with EtOAc (2×50 mL), and the combined organic layers were washed with brine, dried (MgSO4), and concentrated in vacuo. The resulting residue was purified by MPLC (Teledine Isco combiFlash Companion), 80 g SiO2, solvent system: 90:10 hexanes:EtOAc gradient to 50:50 hexanes:EtOAc to give tert-butyl 2-(3-(2-methoxyethoxy)quinolin-6-yl)acetate (585. 2 mg, 82% yield). LRMS (ESI) m/z calcd for C18H24NO4 (M+H) 318.2. found 318.3.