Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([N:14]1[CH2:17][C@@H:16]([OH:18])[C@@H:15]1[CH3:19])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.I[CH3:21].[H-].[Na+].O>C1COCC1>[CH:1]([N:14]1[CH2:17][C@@H:16]([O:18][CH3:21])[C@@H:15]1[CH3:19])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CI
Reactant: C[C@H]1[C@H](O)CN1C(c1ccccc1)c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CO[C@@H]1CN(C(c2ccccc2)c2ccccc2)[C@H]1C
Reaction time: 1.5 h

Procedure:
To a solution of racemic-(trans)-1-benzhydryl-2-methylazetidin-3-ol (0.198 g, 0.782 mmol) in THF (16 mL) was added iodomethane (98 μL, 1.6 mmol) and sodium hydride (0.035 g, 0.86 mmol, 60% in mineral oil). After 1.5 h, water was added and the mixture was extracted with EtOAc (3×). The combined organic phases were washed with brine, dried with sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified via FCC (0-15% EtOAc/n-heptanes) to give the title compound. MS (ESI+) m/z 268.2 (M+H)+.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([C@H:9]2[CH2:13][N:12]([C@H:14]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH3:15])[C:11](=O)[C@H:10]2[F:23])[CH2:8][CH2:7]1)=[O:5])[CH3:2].COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:33])=CC=1>C1(C)C=CC=CC=1>[CH2:1]([O:3][C:4]([C:6]1([C@H:9]2[CH2:13][N:12]([C@H:14]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH3:15])[C:11](=[S:33])[C@H:10]2[F:23])[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)C1([C@H]2CN([C@@H](C)c3ccccc3)C(=O)[C@H]2F)CC1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: Cc1ccccc1
Product: CCOC(=O)C1([C@H]2CN([C@@H](C)c3ccccc3)C(=S)[C@H]2F)CC1
Temperature: 60 °C
Yield: 150.1 %

Procedure:
4-(S)-(1-Ethoxycarbonylcyclopropyl)-3-(S)-fluoro-1-[1-(S)-phenylethyl]-2-pyrrolidone (6.86 g, 21.48 mmol) was dissolved in dry toluene (100 ml). After adding Lawesson's reagent (5.21 g, 12.89 mmol), the mixture was heated at 60° C. for 30 minutes. After allowing the liquid reaction mixture to cool, toluene was evaporated under reduced pressure and the residue was subjected to flash silica gel column chromatography (eluent: n-hexane:ethyl acetate=4:1) to obtain 6.49 g (90.1%) of the title compound as a pale yellow oily substance.
Reaction SMILES: [O:1]1[CH2:5][CH2:4][CH2:3][C@@H:2]1[CH2:6][O:7][C:8]1[CH:9]=[C:10]2[C:15](=[CH:16][CH:17]=1)[C:14](=[O:18])O[CH:12]=[CH:11]2.[Br:19][C:20]1[CH:25]=[CH:24][C:23]([NH2:26])=[CH:22][C:21]=1[F:27]>>[Br:19][C:20]1[CH:25]=[CH:24][C:23]([N:26]2[CH:12]=[CH:11][C:10]3[C:15](=[CH:16][CH:17]=[C:8]([O:7][CH2:6][C@H:2]4[CH2:3][CH2:4][CH2:5][O:1]4)[CH:9]=3)[C:14]2=[O:18])=[CH:22][C:21]=1[F:27]
Reactant: Nc1ccc(Br)c(F)c1
Reactant: O=c1occc2cc(OC[C@H]3CCCO3)ccc12
Product: O=c1c2ccc(OC[C@H]3CCCO3)cc2ccn1-c1ccc(Br)c(F)c1

Procedure:
6-[(R)-1-(Tetrahydrofuran-2-yl)methoxy]-isochromen-1-one and 4-bromo-3-fluorophenylamine were reacted according to Method AJ. In this way the product was obtained with molecular weight 418.27 (C20H17BrFNO3); MS (ESI): 418 and 420 (M+H+).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:6]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[C:5]2[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.[CH2:29]([CH2:33][C:34](=O)[CH3:35])[C:30]([CH3:32])=O>C1(C)C=CC=CC=1>[CH2:11]([N:7]1[C:8]2[C:4](=[CH:3][C:2]([N:1]3[C:34]([CH3:35])=[CH:33][CH:29]=[C:30]3[CH3:32])=[CH:10][CH:9]=2)[C:5]([C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)=[C:6]1[C:18]([O:20][CH2:21][CH3:22])=[O:19])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: CCOC(=O)c1c(-c2ccccc2)c2cc(N)ccc2n1Cc1ccccc1
Reactant: CC(=O)CCC(C)=O
Solvent: Cc1ccccc1
Product: CCOC(=O)c1c(-c2ccccc2)c2cc(-n3c(C)ccc3C)ccc2n1Cc1ccccc1
Yield: 89.2 %

Procedure:
A mixture of ethyl 5-amino-1-benzyl-3-phenyl-1H-indole-2-carboxylate (0.93 g, 2.5 mmol), acetonylacetone (2.5 mL, 21.3 mmol), and toluene (25 mL) was heated at reflux under nitrogen using a Dean-Stark trap for 6 h. The reaction was cooled and concentrated. The residue was then purified by flash silica gel chromatography (hexanes/ethyl acetate 4/1) to afford 1.0 g (89%) of ethyl 1-benzyl-5-(2,5-dimethyl-1H-pyrrol-1-yl)-3-phenyl-1H-indole-2-carboxylate as a white solid: 1H NMR (CDCl3) δ 0.99 (t, J=7.1 Hz, 3 H), 2.00 (s, 6 H), 4.15 (q, J=7.1 Hz, 2 H), 5.83 (s, 2 H), 5.86 (s, 2 H), 7.10-7.51 (m, 13 H); MS (ESI) m/z (MH+) 449; Anal. calcd for C30H28N2O2.0.25 H2O: C, 79.53; H, 6.34; N, 6.18. Found: C, 79.67; H, 6.40; N, 5.91.
Reaction SMILES: [C:1]1([CH:7]([O:14][C:15]([C:17]2[N:22]3[C:23](=[O:26])[C@@H:24]([NH2:25])[C@H:21]3[S:20][CH2:19][C:18]=2[O:27][CH3:28])=[O:16])[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.N1C=CC=CC=1.[C:35]1([CH2:41][C:42](Cl)=[O:43])[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1>C(Cl)Cl>[C:1]1([CH:7]([O:14][C:15]([C:17]2[N:22]3[C:23](=[O:26])[C@@H:24]([NH:25][C:42](=[O:43])[CH2:41][C:35]4[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=4)[C@H:21]3[S:20][CH2:19][C:18]=2[O:27][CH3:28])=[O:16])[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(Cl)Cc1ccccc1
Reactant: COC1=C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)[C@@H](N)[C@H]2SC1
Solvent: ClCCl
Solvent: c1ccncc1
Product: COC1=C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)[C@@H](NC(=O)Cc3ccccc3)[C@H]2SC1
Reaction time: 0.5 h

Procedure:
A suspension of 0.250 g of 7β-amino-3 -methoxy-3-cephem-4-carboxylic acid diphenylmethyl ester in 25 ml of methylene chloride is treated with 1 ml of pyridine and 0.5 ml of phenylacetic acid chloride at 0° C. under a nitrogen atmosphere and stirred for 30 minutes at this temperature. The reaction mixture is evaporated under reduced pressure; the residue is stirred for 10 minutes with 20 ml of a 1:1 mixture of dioxane and water and the mixture is diluted with methylene chloride. The aqueous phase is separated off and extracted with methylene chloride. The combined organic phases are washed with a saturated aqueous sodium bicarbonate solution and a saturated aqueous sodium chloride solution, dried over sodium sulphate and evaporated under reduced pressure. The crude product is purified by means of preparative thin layer chromatography, using a 1:1 mixture of toluene and ethyl acetate as the solvent. The zone visible under ultraviolet light of λ=254 mμ (Rf~0.35) is eluted with a 4:1 mixture of acetone and methanol and yields 3-methoxy-7β-phenylacetylamino-3-cephem-4-carboxylic acid diphenylmethyl ester, which is identical with the product obtainable according to the process of Example 1.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]([C:12]2[CH2:21][CH2:20][C:19]3[C:14](=[CH:15][C:16]([C:22]4[CH:27]=[CH:26][C:25]([CH3:28])=[CH:24][CH:23]=4)=[CH:17][CH:18]=3)[CH:13]=2)=[O:11])=[CH:5][CH:4]=1.[CH3:29][O:30][C:31]1[CH:32]=[C:33]([CH:41]=[C:42]([O:46][CH3:47])[C:43]=1[O:44][CH3:45])[CH2:34][N:35]1[CH2:40][CH2:39][NH:38][CH2:37][CH2:36]1.C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[CH3:47][O:46][C:42]1[CH:41]=[C:33]([CH:32]=[C:31]([O:30][CH3:29])[C:43]=1[O:44][CH3:45])[CH2:34][N:35]1[CH2:40][CH2:39][N:38]([CH2:2][C:3]2[CH:8]=[CH:7][C:6]([NH:9][C:10]([C:12]3[CH2:21][CH2:20][C:19]4[C:14](=[CH:15][C:16]([C:22]5[CH:27]=[CH:26][C:25]([CH3:28])=[CH:24][CH:23]=5)=[CH:17][CH:18]=4)[CH:13]=3)=[O:11])=[CH:5][CH:4]=2)[CH2:37][CH2:36]1
Reactant: Cc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(CCl)cc2)CC3)cc1
Reactant: COc1cc(CN2CCNCC2)cc(OC)c1OC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1cc(CN2CCN(Cc3ccc(NC(=O)C4=Cc5cc(-c6ccc(C)cc6)ccc5CC4)cc3)CC2)cc(OC)c1OC
Temperature: 25 °C
Reaction time: 48 h
Yield: 64.9 %

Procedure:
In DMF (3 ml) was dissolved N-[4-(chloromethyl)phenyl]-7-(4-methylphenyl)-3,4-dihydronaphthalene-2-carboxamide (150 mg), and to the solution were added 1-(3,4,5-trimethoxybenzyl)piperazine (138 mg) and potassium carbonate (268 mg). The mixture was stirred at room temperature for 48 hours, and to the mixture was added water (50 ml). The mixture was extracted with ethyl acetate. The organic layer was washed with saturated sodium chloride solution, dried with anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was recrystallized from ethyl acetate-diisopropylether to give N-[4-[1-(3,4,5-trimethoxybenzyl)-4-piperazinylmethyl]-phenyl]-7-(4-methylphenyl)-3,4-dihydronaphthalene-2-carboxamide (Compound 45) (155 mg) as pale yellow crystals.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]#[C:15][C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=2)=[CH:10][C:9]=1[NH:23][C:24](=[O:39])[CH2:25][C:26](=O)[C:27]1[CH:32]=[CH:31][CH:30]=[C:29]([N:33]2[CH:37]=[N:36][CH:35]=[N:34]2)[CH:28]=1)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[F:22][C:19]1[CH:20]=[CH:21][C:16]([C:15]#[C:14][C:11]2[CH:12]=[CH:13][C:8]3[N:7]=[C:26]([C:27]4[CH:32]=[CH:31][CH:30]=[C:29]([N:33]5[CH:37]=[N:36][CH:35]=[N:34]5)[CH:28]=4)[CH2:25][C:24](=[O:39])[NH:23][C:9]=3[CH:10]=2)=[CH:17][CH:18]=1
Reactant: CC(C)(C)OC(=O)Nc1ccc(C#Cc2ccc(F)cc2)cc1NC(=O)CC(=O)c1cccc(-n2cncn2)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C1CC(c2cccc(-n3cncn3)c2)=Nc2ccc(C#Cc3ccc(F)cc3)cc2N1

Procedure:
Prepared from {4-(4-fluoro-phenylethynyl)-2-[3-oxo-3-(3-[1,2,4]triazol-1-yl-phenyl)-propionylamino]-phenyl}-carbamic acid tert.-butyl ester (Example K37) by treatment with TFA in CH2Cl2 according to the general procedure M. Obtained as a yellow solid (156 mg).
Reaction SMILES: [NH:1]([C:6]([O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:7])[CH2:2][C:3]([OH:5])=O.[NH2:16][C@H:17]([C:26]([O:28][CH3:29])=[O:27])[CH2:18][C:19](=[O:25])[O:20][C:21]([CH3:24])([CH3:23])[CH3:22]>CCCCCC>[NH:1]([C:6]([O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:7])[CH2:2][C:3]([NH:16][C@H:17]([C:26]([O:28][CH3:29])=[O:27])[CH2:18][C:19](=[O:25])[O:20][C:21]([CH3:22])([CH3:23])[CH3:24])=[O:5]
Reactant: COC(=O)[C@@H](N)CC(=O)OC(C)(C)C
Reactant: O=C(O)CNC(=O)OCc1ccccc1
Solvent: CCCCCC
Product: COC(=O)[C@H](CC(=O)OC(C)(C)C)NC(=O)CNC(=O)OCc1ccccc1
Yield: 89 %

Procedure:
Analogously to Example 1 B)a), by coupling Z-Gly-OH and H-Asp(OtBu)-OMe there is obtained Z-Gly-Asp(OtBu)-OMe, m.p. 92°-95° C.(hexane), yield: 89% of theory.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:9][CH:10]=[C:11]([C:13]([OH:15])=O)[N:12]=2)=[C:4]([F:16])[CH:3]=1.[CH:17]([NH:20][N:21]=[C:22]([NH2:24])[CH3:23])([CH3:19])[CH3:18].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:9][CH:10]=[C:11]([C:13]([N:24]=[C:22]([NH:21][NH:20][CH:17]([CH3:19])[CH3:18])[CH3:23])=[O:15])[N:12]=2)=[C:4]([F:16])[CH:3]=1
Reactant: O=C(O)c1c[nH]c(-c2ccc(Cl)cc2F)n1
Reactant: CC(N)=NNC(C)C
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Product: CC(=NC(=O)c1c[nH]c(-c2ccc(Cl)cc2F)n1)NNC(C)C

Procedure:
Scheme 15 shows the synthesis of 5-(2-(4-chloro-2-fluorophenyl)-1H-imidazol-4-yl)-1-isopropyl-3-methyl-1H-1,2,4-triazole 44 from 4-chloro-2-fluorobenzonitrile 38. Addition of hydroxylamine to the nitrile of 38 gave 4-chloro-2-fluoro-N-hydroxybenzimidamide 39. Michael addition of 39 to ethyl propiolate gave ethyl 3-(4-chloro-2-fluorobenzimidamidooxy)acrylate 40. Heating 40 in diphenyl oxide gave cyclized imidazole, ethyl 2-(4-chloro-2-fluorophenyl)-1H-imidazole-4-carboxylate 41. Saponification of the ester of 41 with aqueous sodium hydroxide in tetrahydrofuran gave 2-(4-chloro-2-fluorophenyl)-1H-imidazole-4-carboxylic acid 42. Reaction of 42 with N′-isopropylacetohydrazonamide 6 and coupling reagent HBTU in DMF gives intermediate, 2-(4-chloro-2-fluorophenyl)-N-(1-(2-isopropylhydrazinyl)ethylidene)-1H-imidazole-4-carboxamide 43 which cyclizes upon heating to give 44.
Reaction SMILES: Cl[C:2]1[C:7]([NH2:8])=[CH:6][CH:5]=[CH:4][N:3]=1.[S-:9][C:10]#[N:11].[K+].Cl>C(O)C>[NH2:11][C:10]1[S:9][C:2]2[C:7]([N:8]=1)=[CH:6][CH:5]=[CH:4][N:3]=2
Reactant: N#C[S-]
Reactant: Nc1cccnc1Cl
Agent: Cl
Agent: [K+]
Solvent: CCO
Product: Nc1nc2cccnc2s1

Procedure:
The method described in J. Het. Chem., 14(1), 129(1977) was followed to react 2-chloro-3-aminopyridine with potassium thiocyanate and hydrochloric acid in ethanol to produce 45.3 g of 2-aminothiazolo[5,4-b]pyridine. M+Theory 151; Found 151.
Reaction SMILES: C([O:3][C:4]([C:6]1[N:7]([CH3:29])[CH:8]=[C:9]([NH:11][C:12]([C:14]2[N:15]([CH3:28])[CH:16]=[C:17]([NH:19][C:20]([C:22]3[N:23]([CH3:27])[CH:24]=[CH:25][N:26]=3)=[O:21])[CH:18]=2)=[O:13])[N:10]=1)=[O:5])C.[OH-].[Na+:31].Cl.C(O)(C)C>CO>[CH3:29][N:7]1[CH:8]=[C:9]([NH:11][C:12]([C:14]2[N:15]([CH3:28])[CH:16]=[C:17]([NH:19][C:20]([C:22]3[N:23]([CH3:27])[CH:24]=[CH:25][N:26]=3)=[O:21])[CH:18]=2)=[O:13])[N:10]=[C:6]1[C:4]([O-:5])=[O:3].[Na+:31]
Reactant: CCOC(=O)c1nc(NC(=O)c2cc(NC(=O)c3nccn3C)cn2C)cn1C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: CC(C)O
Product: Cn1cc(NC(=O)c2nccn2C)cc1C(=O)Nc1cn(C)c(C(=O)[O-])n1
Temperature: 50 °C
Reaction time: 1 h
Yield: 96.6 %

Procedure:
The compound 9 (3.0 g, 7.5 mmol) was dissolved in methanol (37.6 ml), mixed with aqueous solution of sodium hydroxide (37.6 ml, 7.89 mmol) and stirred for one hour at 50° C. After being cooled to a room temperature, the resulting solution was mixed with hydrochloric acid (1N) to reach pH 2.0, and then mixed with isopropylalcohol to give the white powder, which was then filtered to give the compound 10 (2.85 g, 94%).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[N:4][C:5]([Cl:9])=[CH:6][C:7]=1Cl.C(=O)([O-])[O-].[Na+].[Na+].CN(C)C(=O)C.[NH:22]1[CH2:27][CH2:26][CH:25]([CH2:28][CH2:29][OH:30])[CH2:24][CH2:23]1>O>[Cl:1][C:2]1[N:3]=[N:4][C:5]([Cl:9])=[CH:6][C:7]=1[N:22]1[CH2:27][CH2:26][CH:25]([CH2:28][CH2:29][OH:30])[CH2:24][CH2:23]1
Reactant: Clc1cc(Cl)c(Cl)nn1
Reactant: OCCC1CCNCC1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Solvent: O
Product: OCCC1CCN(c2cc(Cl)nnc2Cl)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 43.5 %

Procedure:
To a 50 mL round bottom flask, 9.18 g (0.05 mol) of 3,4,6-trichloro-pyridazine, 5.30 g (0.05 mol) of anhydrous sodium carbonate and 20 mL of N,N-dimethylacetamide (DMA) were added, stirred at room temperature, then 6.54 g (0.05 mol) of 2-(piperidin-4-yl)-ethanol (dissolved in 10 mL DMA) was added dropwise slowly, after the dropwise addition, the agitation was kept overnight, the reaction liquid was poured into 100 mL of distilled water on the next day, extracted for three times by using total 200 mL of dichloromethane, the extract solutions were combined together, dried over anhydrous Na2SO4, concentrated, and separated by using column chromatograph (eluent, petroleum ether:acetone=10:3) to obtain 6 g of 2-[1-(3,6-dichloro-pyridazin-4-yl)-piperidin-4-yl]-ethanol, yield: 43.6%, 1H-NMR(400 MHz, DMSO-D6) δppm: 1.21˜1.31(m, 2H), 1.39˜1.43(m, 2H), 1.59 ˜1.67(m, 1H), 1.76 ˜1.79(dbrs, 2H), 2.82 ˜2.88(dt, 2H, J=11 Hz), 3.45˜3.49(m, 2H), 3.70˜3.73(dbrs, 2H), 4.40˜4.42(t, 1H, J=5 Hz), 7.35(s, 1H).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C@@H:9]2[CH2:14][CH2:13][CH2:12][CH2:11][C@H:10]2[NH:15][S:16]([CH3:19])(=[O:18])=[O:17])[C:5]([Cl:20])=[CH:4][N:3]=1.[NH2:21][C:22]1[CH:37]=[CH:36][C:25]2[N:26]([CH2:34][CH3:35])[C:27](=[O:33])[CH2:28][CH2:29][C:30]([CH3:32])([CH3:31])[C:24]=2[CH:23]=1.Cl>O1CCOCC1.COCCO>[Cl:20][C:5]1[C:6]([NH:8][C@@H:9]2[CH2:14][CH2:13][CH2:12][CH2:11][C@H:10]2[NH:15][S:16]([CH3:19])(=[O:18])=[O:17])=[N:7][C:2]([NH:21][C:22]2[CH:37]=[CH:36][C:25]3[N:26]([CH2:34][CH3:35])[C:27](=[O:33])[CH2:28][CH2:29][C:30]([CH3:31])([CH3:32])[C:24]=3[CH:23]=2)=[N:3][CH:4]=1
Reactant: CCN1C(=O)CCC(C)(C)c2cc(N)ccc21
Reactant: CS(=O)(=O)N[C@@H]1CCCC[C@H]1Nc1nc(Cl)ncc1Cl
Agent: Cl
Solvent: C1COCCO1
Solvent: COCCO
Product: CCN1C(=O)CCC(C)(C)c2cc(Nc3ncc(Cl)c(N[C@@H]4CCCC[C@H]4NS(C)(=O)=O)n3)ccc21
Yield: 38.4 %

Procedure:
Combined N-[(1R,2R)-2-(2,5-Dichloro-pyrimidin-4-ylamino)-cyclohexyl]-methanesulfonamide (114 mg, 0.336 mmol), 7-Amino-1-ethyl-5,5-dimethyl-1,3,4,5-tetrahydro-benzo[b]azepin-2-one (80 mg, 0.344 mmol), 4 N HCl in dioxane (103 ul) and 2-methoxyethanol (5 mL). Heated reaction to 120° C. for 2.5 hours. Evaporated off solvent and purified with normal phase chromatography to yield a white solid, N-{(1R,2R)-2-[5-Chloro-2-(1-ethyl-5,5-dimethyl-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b]azepin-7-ylamino)-pyrimidin-4-ylamino]-cyclohexyl}-methanesulfonamide (69 mg, 38%). LCMS: m/z=535.34 (M+H+), 1H NMR (400 MHz, CDCl3) δ 7.98 (s, 1H), 7.65 (dd, 1H, J=8.6, 1.3 Hz), 7.36 (d, 1H, J=2.3 Hz), 7.21 (d, 1H, J=8.6 Hz), 6.91 (s, 1H), 5.44 (d, 1H, J=7.6 Hz), 5.36 (d, 1H, J=6.8 Hz), 3.87 (m, 3H), 3.24 (m, 1H), 2.82 (s, 3H), 2.17 (m, 6H), 1.84 (m, 2H), 1.37 (m, 13H).
Reaction SMILES: Br[C:2]1[C:3]([N:22]2[CH2:26][CH2:25][C@H:24]([CH2:27][OH:28])[CH2:23]2)=[N:4][CH:5]=[C:6]([CH:21]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([S:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=1)=[O:8].[N:29]1[CH:34]=[C:33](B(O)O)[CH:32]=[N:31][CH:30]=1>>[OH:28][CH2:27][C@H:24]1[CH2:25][CH2:26][N:22]([C:3]2[C:2]([C:33]3[CH:34]=[N:29][CH:30]=[N:31][CH:32]=3)=[CH:21][C:6]([C:7]([NH:9][C:10]3[CH:15]=[CH:14][C:13]([S:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=3)=[O:8])=[CH:5][N:4]=2)[CH2:23]1
Reactant: OB(O)c1cncnc1
Reactant: O=C(Nc1ccc(SC(F)(F)F)cc1)c1cnc(N2CC[C@H](CO)C2)c(Br)c1
Product: O=C(Nc1ccc(SC(F)(F)F)cc1)c1cnc(N2CC[C@H](CO)C2)c(-c2cncnc2)c1

Procedure:
The title compound was prepared in an analogous fashion to that described in Example 185 using (S)-5-bromo-6-(3-(hydroxymethyl)pyrrolidin-1-yl)-N-(4-((trifluoromethyl)thio)phenyl)nicotinamide (Stage 189.1) and pyrimidin-5-ylboronic acid. HPLC (Condition 4) tR=5.13 min, UPLC-MS (Condition 3) tR=1.01 min, m/z=476.3 [M+H]+; 1H-NMR (400 MHz, DMSO-d6) δ ppm 1.48-1.64 (m, 1H) 1.84 (m, J=6.30 Hz, 1H) 2.15-2.31 (m, 1H) 2.96 (dd, J=10.95, 7.04 Hz, 1H) 3.08-3.42 (m, 5H) 4.60 (t, J=5.28 Hz, 1H) 7.68 (d, J=8.60 Hz, 2H) 7.90 (d, J=8.99 Hz, 2H) 8.08 (d, J=2.35 Hz, 1H) 8.78 (d, J=2.35 Hz, 1H) 8.88 (s, 2H) 9.17 (s, 1H) 10.25 (s, 1H).
Reaction SMILES: [SH:1][CH:2]([CH2:6][CH2:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[Cl:20])=[CH:10][CH:9]=1)[C:3]([OH:5])=[O:4].Cl[C:22]([O:24][CH2:25][CH3:26])=[O:23].C(=O)(O)[O-].[Na+].Cl>CCOCC.N1C=CC=CC=1>[CH2:25]([O:24][C:22]([S:1][CH:2]([CH2:6][CH2:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[Cl:20])=[CH:10][CH:9]=1)[C:3]([OH:5])=[O:4])=[O:23])[CH3:26]
Reactant: CCOC(=O)Cl
Reactant: O=C(O)C(S)CCc1ccc(-c2ccccc2Cl)cc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOCC
Solvent: c1ccncc1
Product: CCOC(=O)SC(CCc1ccc(-c2ccccc2Cl)cc1)C(=O)O

Procedure:
A solution of α-mercapto-γ-(2'-chloro-4-biphenylyl)butyric acid 0.02 moles in 25 ml. of pyridine is cooled in an ice bath. To this is added dropwise 2.1 ml. (0.022 moles) of ethyl chloroformate. The mixture is basified with 10% sodium bicarbonate solution. The alkaline mixture is worked with ether, then acidified with 10% hydrochloric acid, washed with ether, dried and filtered, the solvent is removed and the residue is triturated with hexane to obtain α-ethoxycarbonylthio-γ-(2'-chloro-4-biphenylyl)butyric acid.
Reaction SMILES: [Cl:1][C:2]1[C:7]([F:8])=[CH:6][C:5]([C:9]2[NH:14][C:13]3[CH:15]=[CH:16][S:17][C:12]=3[C:11](=O)[N:10]=2)=[C:4]([F:19])[CH:3]=1.P(Cl)(Cl)([Cl:22])=O>>[Cl:22][C:11]1[C:12]2[S:17][CH:16]=[CH:15][C:13]=2[N:14]=[C:9]([C:5]2[CH:6]=[C:7]([F:8])[C:2]([Cl:1])=[CH:3][C:4]=2[F:19])[N:10]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: O=c1nc(-c2cc(F)c(Cl)cc2F)[nH]c2ccsc12
Product: Fc1cc(-c2nc(Cl)c3sccc3n2)c(F)cc1Cl
Temperature: 90 °C
Reaction time: 4 h

Procedure:
A mixture of 2-(4-chloro-2,5-difluorophenyl)thieno[3,2-d]pyrimidine-4(1H)-one and phosphorus oxychloride was stirred for four hours at 90° C. to give 4-chloro-2-(4-chloro-2,5-difluorophenyl)thieno[3,2-d]pyrimidine.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9]([C:11]1[C:12]2[CH:13]=[CH:14][NH:15][C:16]=2[CH:17]=[CH:18][CH:19]=1)=[O:10].[OH-].[Na+].[N:22]1([CH2:28][CH2:29]Cl)[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1>C1C=CC=CC=1>[N:22]1([CH2:28][CH2:29][O:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=2[NH:8][C:9]([C:11]2[C:12]3[CH:13]=[CH:14][NH:15][C:16]=3[CH:17]=[CH:18][CH:19]=2)=[O:10])[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1
Reactant: O=C(Nc1ccccc1O)c1cccc2[nH]ccc12
Reactant: ClCCN1CCCCC1
Agent: [Na+]
Agent: [OH-]
Solvent: c1ccccc1
Product: O=C(Nc1ccccc1OCCN1CCCCC1)c1cccc2[nH]ccc12

Procedure:
3 g of N-(2-hydroxyphenyl)-1H-indol-4-carboxamide in 50 ml of benzene, 25 ml of acetronitrile and 50 ml of a 5N aqueous solution of sodium hydroxide were heated to 60° C. for 3 hours with stirring under an inert atmosphere with 0.4 g of 2-tetrabutylammonium hydrogensulfate and 2.2 g of 2-piperidino-1-chloroethane. After cooling, decanting, extracting with ethyl acetate and purifying by chromatography over silica (eluent:ethyl acetate--triethylamine, 9-1), 3.6 of N-[2-[2-(1-piperidinyl)ethoxy]phenyl]-1H-indol-4-carboxamide were obtained.
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[O:3][C:4]1[CH:15]=[CH:14][C:7]2[NH:8][C:9](=O)[CH2:10][CH2:11][CH2:12][C:6]=2[CH:5]=1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:27])=CC=1>C1(C)C=CC=CC=1>[F:1][C:2]([F:17])([F:16])[O:3][C:4]1[CH:15]=[CH:14][C:7]2[NH:8][C:9](=[S:27])[CH2:10][CH2:11][CH2:12][C:6]=2[CH:5]=1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: O=C1CCCc2cc(OC(F)(F)F)ccc2N1
Solvent: Cc1ccccc1
Product: FC(F)(F)Oc1ccc2c(c1)CCCC(=S)N2
Temperature: 100 °C
Reaction time: 2 h

Procedure:
To a solution of 7-(trifluoromethoxy)-4,5-dihydro-1H-benzo[b]azepin-2(3H)-one (30 g, 122 mmol) in toluene (2000 ml) was added Lawesson's reagent (29.7 g, 73.5 mmol) and the mixture was stirred at 100° C. for 2 hrs. The resulting mixture was cooled to room temperature and concentrated under reduced pressure. The crude product was purified by column chromatography on silica eluting with 5% ethyl acetate in petroleum ether to give the title compound.
Reaction SMILES: [CH3:1][N:2]=[C:3]=[O:4].[OH:5][C:6]1[CH:7]=[N:8][C:9]2[C:14]([CH:15]=1)=[CH:13][CH:12]=[CH:11][CH:10]=2>C(Cl)Cl>[CH3:1][NH:2][C:3]([O:5][C:6]1[CH:7]=[N:8][C:9]2[C:14]([CH:15]=1)=[CH:13][CH:12]=[CH:11][CH:10]=2)=[O:4]
Reactant: CN=C=O
Reactant: Oc1cnc2ccccc2c1
Solvent: ClCCl
Product: CNC(=O)Oc1cnc2ccccc2c1

Procedure:
0.98 ml of methyl isocyanate is added to a suspension of 1.0 g of 3-hydroxyquinoline in 8 ml of methylene chloride and the reaction mixture is heated under reflux for 5 h. Purification by chromatography over 50 g silica gel (mobile phase J) gives 3-(methylaminocarbonyloxy)quinoline as a solid: Rf (L)=0.26.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][O:5][C:6]1[NH:7][C:8]2[C:13]([C:14]=1[C:15]([O:17][CH3:18])=[O:16])=[CH:12][CH:11]=[CH:10][CH:9]=2.[OH-].[Na+]>C1(C)C=CC=CC=1>[O:5]1[C:6]2=[C:14]([C:15]([O:17][CH3:18])=[O:16])[C:13]3[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=3[N:7]2[CH2:2][CH2:3][CH2:4]1
Reactant: COC(=O)c1c(OCCCCl)[nH]c2ccccc12
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Product: COC(=O)c1c2n(c3ccccc13)CCCO2
Temperature: 40 °C
Yield: 92.5 %

Procedure:
Methyl 2-(3-chloropropoxy)indole-3-carboxylate (5.0 g, 18.7 mmol) was added to a stirred mixture of 5.4 M aqueous M NaOH (3.8 ml) and toluene (50 ml) and heated at 40° C. for 4 h. The aqueous layer was separated and the organic layer washed with H2O (3×25 ml) while maintaining the temperature at 60° C. The organic solvent was evaporated in vacuo to leave the product as a white solid (4.0 g, 93.2%).