Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:3]2[CH:17]=[CH:16][NH:15][C:4]=2[N:5]=[C:6]([NH:8][C:9]2[CH:10]=[N:11][N:12]([CH3:14])[CH:13]=2)[N:7]=1.[Cl:18]N1C(=O)CCC1=O.O>CN(C=O)C>[Cl:1][C:2]1[C:3]2[C:17]([Cl:18])=[CH:16][NH:15][C:4]=2[N:5]=[C:6]([NH:8][C:9]2[CH:10]=[N:11][N:12]([CH3:14])[CH:13]=2)[N:7]=1
Reactant: O=C1CCC(=O)N1Cl
Reactant: Cn1cc(Nc2nc(Cl)c3cc[nH]c3n2)cn1
Solvent: O
Solvent: CN(C)C=O
Product: Cn1cc(Nc2nc(Cl)c3c(Cl)c[nH]c3n2)cn1
Temperature: 50 °C
Reaction time: 8 h
Yield: 22.1 %

Procedure:
To a solution of 4-chloro-N-(1-methyl-1H-pyrazol-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-2-amine (2 g, 8 mmol) in DMF (35 mL) was added N-chlorosuccinimide (1.28 g, 9.6 mmol). The reaction mixture was stirred at 50° C. overnight. Water (50 mL) was added and the solution was extracted with EtOAc (three×25 mL) and the combined organic layers were dried over Na2SO4, and concentrated to dryness. The residue was purified by preparative HPLC to afford the title compound (0.5 g, 22% yield) as a gray solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 11.99 (brs, 1H), 9.62 (brs, 1H), 7.88 (s, 1H), 7.52 (s, 1H), 7.38 (s, 1H), 3.35 (s, 3H). m/z for C10H8Cl2N6: 283.0 (M+H)+.
Reaction SMILES: Br[C:2]1[C:3](=O)[CH2:4][CH2:5][CH2:6][C:7]=1[O:8]CC.Cl.[CH3:13][CH:14]([CH3:18])[C:15](=[NH:17])[NH2:16].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH3:13][CH:14]([C:15]1[NH:17][C:3]2[CH2:4][CH2:5][CH2:6][C:7](=[O:8])[C:2]=2[N:16]=1)[CH3:18]
Reactant: CC(C)C(=N)N
Reactant: CCOC1=C(Br)C(=O)CCC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)c1nc2c([nH]1)CCCC2=O
Temperature: 80 °C
Reaction time: 2 h
Yield: 45 %

Procedure:
To 2-bromo-3-(ethyloxy)-2-cyclohexen-1-one (38.8 g) in a 1 L round-bottom flask in N,N-Dimethylformamide (DMF) (500 mL) was added 2-methylpropanimidamide hydrochloride (26.1 g) and potassium carbonate (61.2 g). The suspension was then stirred at 80° C. under nitrogen for 2 h. The mixture was filtered and as much DMF as possible was evaporated off under high vacuum. The sample was loaded in dichloromethane and purified by column chromatography over silica using a 0-30% methanol-dichloromethane gradient. The appropriate fractions were combined and evaporated in vacuo to give the required product 14.2 g as a brown solid. LC/MS MH+ 179, Rt 1.4 min (5 min run).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]([CH3:37])([CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[CH2:10][O:11][CH2:12][C:13]1[CH:18]=[C:17]([N:19]([S:23]([CH3:26])(=[O:25])=[O:24])[CH2:20][CH2:21][CH3:22])[N:16]=[C:15]([C:27]([OH:29])=O)[CH:14]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(C(C)C)CC)(C)C.[F:47][C:48]1[CH:53]=[CH:52][C:51]([CH:54]([NH2:56])[CH3:55])=[CH:50][CH:49]=1.CN([P+](ON1N=NC2C=CC=CC1=2)(N(C)C)N(C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[CH2:30]([C:9]([NH:8][C:6](=[O:7])[O:5][C:1]([CH3:3])([CH3:2])[CH3:4])([CH3:37])[CH2:10][O:11][CH2:12][C:13]1[CH:18]=[C:17]([N:19]([S:23]([CH3:26])(=[O:24])=[O:25])[CH2:20][CH2:21][CH3:22])[N:16]=[C:15]([C:27]([NH:56][CH:54]([C:51]2[CH:52]=[CH:53][C:48]([F:47])=[CH:49][CH:50]=2)[CH3:55])=[O:29])[CH:14]=1)[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1
Reactant: CCCN(c1cc(COCC(C)(Cc2ccccc2)NC(=O)OC(C)(C)C)cc(C(=O)O)n1)S(C)(=O)=O
Reactant: CC(N)c1ccc(F)cc1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCCN(c1cc(COCC(C)(Cc2ccccc2)NC(=O)OC(C)(C)C)cc(C(=O)NC(C)c2ccc(F)cc2)n1)S(C)(=O)=O
Reaction time: 0.67 h

Procedure:
To a solution of 4-({2-[(tert-butoxycarbonyl)amino]-2-methyl-3-phenylpropoxy}methyl)-6-[(methylsulfonyl)(propyl)amino]pyridine-2-carboxylic acid (10 mg, 0.019 mmol, intermediate VII) in DMF (0.5 mL) was added diisopropylethyl amine (0.05 mL, 0.028 mmol), [1-(4-fluorophenyl)ethyl]amine (0.008 mL, 0.056 mmol) and BOP reagent (10 mg, 0.022 mmol), and the reaction mixture was allowed to stand at rt for 40 min, purified by preparative HPLC (5->95% CH3CN/H2O, 0.1% added TFA, C18 PRO YMC 20×150 mm) to afford tert-butyl [1-benzyl-2-({2-({[1-(4-fluorophenyl)ethyl]amino}carbonyl)-6-[(methylsulfonyl)(propyl)amino]pyridin-4-yl}methoxy)-1-methylethyl]carbamate. Boc removal in HCl(g) saturated EtOAc and lyophilization from dioxane/water provided 4-[(2-amino-2-methyl-3-phenylpropoxy)methyl]-N-[1-(4-fluorophenyl)ethyl]-6-[(methylsulfonyl)(propyl)amino]pyridine-2-carboxamide as an hydrochloride white solid. 1H NMR (400 MHz, CD3OD) δ 8.61 (d, J=8.0 Hz, 1H), 7.97 (s, 1H), 7.65 (s, 1H), 7.46-7.41 (m, 2H), 7.38-7.25 (m, 3H), 7.24-7.19 (m, 2H), 7.11-7.03 (m, 2H), 5.30-5.20 (m, 1H), 4.75 (s, 2H), 4.03-3.94 (m, 2H), 3.51 (A of AB, d, J=10.4 Hz, 1H), 3.46 (B of AB, d, J=10.4 Hz, 1H), 3.11 (A of AB, d, J=13.6 Hz, 1H), 3.10 (s, 3H), 2.92 (B of AB, d, J=13.6 Hz, 1H), 1.64-1.54 (m, 2H), 1.62 (d, J=7.2 Hz, 3H), 1.29 (s, 3H), 0.92 (t, J=7.6 Hz, 3H). HRMS (ES, M+H) calcd. for C29H37FN4O4S: 557.2593, found: 557.2613.
Reaction SMILES: [NH2:1][CH2:2][C@H:3]1[N:10]([C:11]([C:13]2[N:14]=[C:15]([CH3:25])[S:16][C:17]=2[C:18]2[CH:19]=[C:20]([CH3:24])[CH:21]=[CH:22][CH:23]=2)=[O:12])[CH2:9][C@H:8]2[C@@H:4]1[CH2:5][C:6]([F:27])([F:26])[CH2:7]2.[O:28]1[C:33]2[CH:34]=[CH:35][CH:36]=[C:37]([C:38](O)=[O:39])[C:32]=2[O:31][CH2:30][CH2:29]1>>[F:26][C:6]1([F:27])[CH2:5][C@H:4]2[C@H:8]([CH2:9][N:10]([C:11]([C:13]3[N:14]=[C:15]([CH3:25])[S:16][C:17]=3[C:18]3[CH:19]=[C:20]([CH3:24])[CH:21]=[CH:22][CH:23]=3)=[O:12])[C@@H:3]2[CH2:2][NH:1][C:38]([C:37]2[C:32]3[O:31][CH2:30][CH2:29][O:28][C:33]=3[CH:34]=[CH:35][CH:36]=2)=[O:39])[CH2:7]1
Reactant: Cc1cccc(-c2sc(C)nc2C(=O)N2C[C@@H]3CC(F)(F)C[C@@H]3[C@H]2CN)c1
Reactant: O=C(O)c1cccc2c1OCCO2
Product: Cc1cccc(-c2sc(C)nc2C(=O)N2C[C@@H]3CC(F)(F)C[C@@H]3[C@H]2CNC(=O)c2cccc3c2OCCO3)c1

Procedure:
prepared by reaction of (1S,2S,5R)-(2-aminomethyl-7,7-difluoro-3-aza-bicyclo[3.3.0]-oct-3-yl)-(2-methyl-5-m-tolyl-thiazol-4-yl)-methanone with 2,3-dihydro-benzo[1,4]dioxine-5-carboxylic acid.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([NH2:10])=[CH:6][C:5]=1[CH2:11][CH3:12])[CH3:2].[C:13](OC(=O)C)(=[O:15])[CH3:14]>N1C=CC=CC=1.O>[CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:13](=[O:15])[CH3:14])=[CH:6][C:5]=1[CH2:11][CH3:12])[CH3:2]
Reactant: CCOc1ccc(N)cc1CC
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Solvent: O
Product: CCOc1ccc(NC(C)=O)cc1CC
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of 4-ethoxy-3-ethyl-phenylamine [0.6 g, Reference Example 30(t)] in pyridine (5 mL) was added acetic anhydride (1 mL) and the mixture was stirred 18 hours at ambient temperature. The reaction mixture was diluted with water (100 mL) and the aqueous mixture was extracted twice with ethyl acetate (100 mL). The combined extracts were evaporated to give N-(4-ethoxy-3-ethyl-phenyl) acetamide (0.6 g) as a pink foam. GC-MS one peak, RT=9.16 minutes, MS 207 (M)+. (f) N-(4-Methoxy-3-methyl-phenyl)-acetamide
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:12][C:13](=[O:27])[CH2:14][O:15][C:16]2[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][C:17]=2[Cl:26])[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][CH:10]=O.[CH2:28]([NH:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[CH3:29]>>[Cl:1][C:2]1[CH:3]=[C:4]([NH:12][C:13](=[O:27])[CH2:14][O:15][C:16]2[CH:21]=[CH:20][C:19]([C:22]([F:23])([F:24])[F:25])=[CH:18][C:17]=2[Cl:26])[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][CH2:10][N:30]([CH2:28][CH3:29])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1
Reactant: O=CCOc1ccc(NC(=O)COc2ccc(C(F)(F)F)cc2Cl)cc1Cl
Reactant: CCNc1ccccc1
Product: CCN(CCOc1ccc(NC(=O)COc2ccc(C(F)(F)F)cc2Cl)cc1Cl)c1ccccc1

Procedure:
The product was obtained according to general working method V starting from 0.422 g (0.616 mmol) N-[3-chloro-4-(2-oxo-ethoxy)-phenyl]-2-(2-chloro-4-trifluoromethyl-phenoxy)-acetamide (Z3d) and 0.094 mL (0.739 mmol) N-ethylaniline.
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]=[C:8]([S:15][CH3:16])[CH:7]=[C:6]2[O:17][C:18]1[CH:23]=[CH:22][C:21]([NH2:24])=[CH:20][C:19]=1[F:25].[F:26][C:27]1[CH:32]=[CH:31][C:30]([NH:33][C:34]([C:36]2([C:39](O)=[O:40])[CH2:38][CH2:37]2)=[O:35])=[CH:29][CH:28]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.O>CN(C=O)C>[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]=[C:8]([S:15][CH3:16])[CH:7]=[C:6]2[O:17][C:18]1[CH:23]=[CH:22][C:21]([NH:24][C:39]([C:36]2([C:34]([NH:33][C:30]3[CH:31]=[CH:32][C:27]([F:26])=[CH:28][CH:29]=3)=[O:35])[CH2:38][CH2:37]2)=[O:40])=[CH:20][C:19]=1[F:25]
Reactant: O=C(O)C1(C(=O)Nc2ccc(F)cc2)CC1
Reactant: COc1cc2nc(SC)cc(Oc3ccc(N)cc3F)c2cc1OC
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CN(C)C=O
Product: COc1cc2nc(SC)cc(Oc3ccc(NC(=O)C4(C(=O)Nc5ccc(F)cc5)CC4)cc3F)c2cc1OC
Temperature: 25 °C
Reaction time: 8 h
Yield: 113 %

Procedure:
To a mixture of 4-(6,7-dimethoxy-2-methylsulfanyl-quinolin-4-yloxy)-3-fluoro-phenylamine (0.22 g, 0.61 mmol) and 1-(4-Fluoro-phenylcarbamoyl)-cyclopropanecarboxylic acid (0.16 g, 0.73 mmol) in DMF (5 mL) was added TEA (0.25 mL, 1.8 mmol) followed by HATU (0.57 g, 1.5 mmol). The resulting solution was stirred overnight at room temperature. The reaction mixture was dumped into water and extracted with DCM (2×). The combined extracts were washed with 5% LiCl(aq) (3×), water, (1×) and brine (1×), followed by drying over Na2SO4 and concentration in vacuo. The crude solids were purified by preparatory HPLC with ammonium acetate, affording N-(4-{[6,7-bis(methyloxy)-2-(methylthio)quinolin-4-yl]oxy}-3-fluorophenyl)-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide (0.39 g, 11% yield) as a white solid. 1H NMR (DMSO-d6) δ 10.34 (s, 1H), 9.94 (s, 1H), 7.83 (d, 1H), 7.59 (m, 2H), 7.56 (m, 1H), 7.40 (m, 2H), 7.23 (s, 1H), 7.09 (t, 2H), 6.12 (s, 1H), 3.88 (s, 3H), 3.85 (s, 3H), 2.48 (s, 3H), 1.40 (m, 4H).
Reaction SMILES: [C:1]1(=[O:11])[O:6][C:4](=[O:5])[C:3]2=CC=CC=[C:2]12.[NH2:12][C:13]1[CH:14]=[C:15]2[C:19](=[CH:20][CH:21]=1)[NH:18][N:17]=[CH:16]2>CC(C)=O>[NH:18]1[C:19]2[C:15](=[CH:14][C:13]([NH:12][C:1](=[O:11])[CH2:2][CH2:3][C:4]([OH:6])=[O:5])=[CH:21][CH:20]=2)[CH:16]=[N:17]1
Reactant: Nc1ccc2[nH]ncc2c1
Reactant: O=C1OC(=O)c2ccccc21
Solvent: CC(C)=O
Product: O=C(O)CCC(=O)Nc1ccc2[nH]ncc2c1
Yield: 102.2 %

Procedure:
Phthalic anhydride (827 mg, 8.26 mmol) was added to a solution of 5-aminoindazole (1.0 g, 7.51 mmol) in acetone (60 ml) at room temperature, and the resulting mixture was refluxed for 4 hours. The solid precipitated was collected by filtration and dried under reduced pressure to obtain 4-(1H-indazol-5-ylamino)-4-oxobutanoic acid (1.79 g, 100%).
Reaction SMILES: [NH2:1][C:2]1[CH:6]=[CH:5][NH:4][N:3]=1.[CH3:7][C:8](=O)[CH2:9][CH2:10][C:11](=O)[CH3:12].O>C(O)(=O)C>[CH3:12][C:11]1[N:1]([C:2]2[CH:6]=[CH:5][NH:4][N:3]=2)[C:8]([CH3:7])=[CH:9][CH:10]=1
Reactant: CC(=O)CCC(C)=O
Reactant: Nc1cc[nH]n1
Solvent: CC(=O)O
Solvent: O
Product: Cc1ccc(C)n1-c1cc[nH]n1
Temperature: 25 °C
Reaction time: 2.4 h

Procedure:
To a solution of 3-aminopyrazole (100 g) in acetic acid (1000 ml) was added 2,5-hexanedione (148 ml), and the mixture was stirred for 2.4 hours at reflux. This reaction solution was cooled to room temperature, water (1000 ml) was added thereto, and the precipitated solid was collected by filtration. The resulting solid was washed with water (1000 ml), and dried under reduced pressure to give the titled compound (183 g).
Reaction SMILES: Cl.[CH2:2]1[CH:11]2[CH:6]([CH2:7][CH2:8][CH2:9][CH2:10]2)[CH2:5][CH2:4][N:3]1[CH2:12][C:13]([OH:15])=O.[NH2:16][C@@H:17]([CH2:35][O:36][CH2:37][C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)[C:18]([NH:20][C:21]1[CH:26]=[CH:25][C:24]([O:27][C:28]2[CH:33]=[CH:32][C:31]([F:34])=[CH:30][CH:29]=2)=[CH:23][CH:22]=1)=[O:19]>>[CH2:37]([O:36][CH2:35][C@H:17]([NH:16][C:13](=[O:15])[CH2:12][N:3]1[CH2:4][CH2:5][CH:6]2[CH:11]([CH2:10][CH2:9][CH2:8][CH2:7]2)[CH2:2]1)[C:18]([NH:20][C:21]1[CH:26]=[CH:25][C:24]([O:27][C:28]2[CH:33]=[CH:32][C:31]([F:34])=[CH:30][CH:29]=2)=[CH:23][CH:22]=1)=[O:19])[C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1
Reactant: O=C(O)CN1CCC2CCCCC2C1
Reactant: N[C@@H](COCc1ccccc1)C(=O)Nc1ccc(Oc2ccc(F)cc2)cc1
Agent: Cl
Product: O=C(CN1CCC2CCCCC2C1)N[C@@H](COCc1ccccc1)C(=O)Nc1ccc(Oc2ccc(F)cc2)cc1
Yield: 46 %

Procedure:
Proceeding as in Example 1, but substituting 2-(octahydroisoquinolin-2(1H)-yl)acetic acid hydrochloride and (S)-2-amino-3-(benzyloxy)-N-(4-(4-fluorophenoxy)phenyl)propanamide, gave Compound 222, (2S)-3-(benzyloxy)-N-(4-(4-fluorophenoxy)phenyl)-2-(2-(octahydroisoquinolin-2(1H)-yl)acetamido)propanamide (20.6 mg, 46%); Major isomer: 1H-NMR (400 MHz, DMSO-D6): 10.21 (s, 1H), 7.96 (d, 1H), 7.60 (d, 2H), 7.29-7.31 (m, 5H), 7.19-7.23 (m, 2H), 6.98-7.04 (m, 4H), 4.68 (m, 1H), 4.49 (s, 2H), 3.29-3.79 (m, 2H), 2.77-3.01 (m, 2H), 2.63-2.73 (m, 2H), 2.01-2.99 (m, 2H), 0.81-1.86 (m, 12H). MS (EI) for C33H38FN3O4. found 560.6 (MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4](F)[CH:3]=1.[OH:11][C:12]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[C:15]([CH:22]=[O:23])=[CH:14][CH:13]=1.C(=O)([O-])[O-].[Cs+].[Cs+].O>CN(C=O)C>[Cl:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([O:11][C:12]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[C:15]([CH:22]=[O:23])=[CH:14][CH:13]=2)[CH:3]=1
Reactant: O=Cc1ccc(O)c2ccccc12
Reactant: N#Cc1ccc(Cl)cc1F
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: N#Cc1ccc(Cl)cc1Oc1ccc(C=O)c2ccccc12
Yield: 55.2 %

Procedure:
4-Chloro-2-fluorobenzonitrile (0.31 g, 2.0 mmol), 4-hydroxy-1-naphthaldehyde (0.34 g, 2.0 mmol) and cesium carbonate (0.64 g, 2.0 mmol) were heated with stirring in dry DMF (4 mL) at ambient temperature for 10 days. The reaction mixture was poured into water and extracted with ethyl acetate. The ethyl acetate layer was separated, washed with 1N sodium hydroxide solution (2×), water (1×), brine (1×), and dried over MgSO4. After filtration, the solvent was removed in vacuo to yield 4-chloro-2-(4-formylnaphthalen-1-yloxy)benzonitrile (0.34 g, 56%) as a tan solid, which was used without further purification.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[OH:7][C:8]1[CH:9]=[C:10]([CH:13]=[CH:14][CH:15]=1)[CH:11]=[O:12].Br[CH2:17][C:18]([O:20][CH3:21])=[O:19].O>CC(C)=O>[CH3:21][O:20][C:18](=[O:19])[CH2:17][O:7][C:8]1[CH:15]=[CH:14][CH:13]=[C:10]([CH:11]=[O:12])[CH:9]=1
Reactant: COC(=O)CBr
Reactant: O=Cc1cccc(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: O
Product: COC(=O)COc1cccc(C=O)c1
Yield: 93.3 %

Procedure:
Powdered potassium carbonate (5 g) was added to a solution of 3-hydroxybenzaldehyde (3.1 g, 25 mmol) and methyl bromoacetate (4.6 g, 30 mmol) dissolved in acetone (40 mL), and the mixture was stirred under reflux for 4 hours. The reaction mixture was then poured into excess water, extracted with dichloromethane, and evaporated. The resultant yellow oil was distilled on the Kugelrohr (1 mmHg, 150° C.) to give (3-formylphenoxy)acetic acid methyl ester as a colorless oil (4.53 g, 93%).
Reaction SMILES: [CH2:1]([C:5]1=[CH:6][N:7]([C:21]([CH3:24])([CH3:23])[CH3:22])[S:8]/[C:9]/1=[N:10]\[C:11](=[O:20])[C:12]1[CH:17]=[C:16]([Cl:18])[CH:15]=[CH:14][C:13]=1[OH:19])[CH2:2][CH2:3][CH3:4].[H-].[Na+].Br[CH2:28][C:29]#[N:30]>C1COCC1.CN(C=O)C>[CH2:1]([C:5]1=[CH:6][N:7]([C:21]([CH3:23])([CH3:22])[CH3:24])[S:8]/[C:9]/1=[N:10]\[C:11](=[O:20])[C:12]1[CH:17]=[C:16]([Cl:18])[CH:15]=[CH:14][C:13]=1[O:19][CH2:28][C:29]#[N:30])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1cn(C(C)(C)C)s/c1=N\C(=O)c1cc(Cl)ccc1O
Reactant: N#CCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: CCCCc1cn(C(C)(C)C)s/c1=N\C(=O)c1cc(Cl)ccc1OCC#N
Temperature: 80 °C
Reaction time: 8 h
Yield: 4.5 %

Procedure:
To a solution of Example 135 (300 mg, 0.82 mmol) in THF/DMF (1:1, 4 mL) were added sodium hydride (39.2 mg, 0.98 mmol) and 2-bromoacetonitrile (65 μl, 0.98 mmol). The reaction was stirred at 40° C. for 4 hrs and at 80° C. for overnight. The reaction mixture was cooled to room temperature, quenched with saturated NaHCO3 (10 mL) and extracted with ethyl acetate (3×20 mL). The combined organic extracts were dried (Na2SO4), filtered and concentrated. The residue was purified by column chromatography using an Analogix® Intelliflash280™ (SiO2, 0-50% ethyl acetate in dichloromethane) to afford 15 mg of the title compound. 1H NMR (300 MHz, DMSO-d6) δ ppm 0.93 (t, J=7.3 Hz, 3 H), 1.20-1.48 (m, 2 H), 1.53-1.77 (m, 2 H), 1.63 (s, 9 H), 2.62-2.82 (m, 2 H), 5.22 (s, 2 H), 7.29 (d, J=9.1 Hz, 1H), 7.58 (dd, J=8.7, 2.8 Hz, 1 H), 7.86 (d, J=2.8 Hz, 1 H), 8.67 (s, 1 H); MS (ESI+) m/z 406 (M+H)+; Anal. Calculated C20H24ClN3O2S: C, 59.17; H, 5.96; N, 10.35. Found: C, 59.18; H, 5.78; N, 10.37.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([OH:11])=O)=[CH:4][CH:3]=1.S(Cl)([Cl:14])=O>C(Cl)(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([Cl:14])=[O:11])=[CH:4][CH:3]=1
Reactant: O=C(O)Cc1ccc(Cl)cc1
Reactant: O=S(Cl)Cl
Solvent: ClC(Cl)Cl
Product: O=C(Cl)Cc1ccc(Cl)cc1

Procedure:
To 100 mL of chloroform is added 4-chlorobenzeneacetic acid (17 g, 0.1 mol) and 24 g (0.2 mol) of thionyl chloride. Reflux the reaction mixture for 3 hours and remove the solvent in vacuo to give the title compound.
Reaction SMILES: ClC1C=CC=C(C(OO)=[O:9])C=1.[F:12][C:13]1[CH:14]=[C:15]([CH:23]=[CH:24][CH:25]=1)[O:16][C:17]1[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=1.S([O-])(O)=O.[Na+]>C(Cl)Cl>[F:12][C:13]1[CH:14]=[C:15]([CH:23]=[CH:24][CH:25]=1)[O:16][C:17]1[CH:18]=[N+:19]([O-:9])[CH:20]=[CH:21][CH:22]=1
Reactant: Fc1cccc(Oc2cccnc2)c1
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=S([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: [O-][n+]1cccc(Oc2cccc(F)c2)c1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 85 %

Procedure:
To a solution of 46.3 g of m-chloroperbenzoic acid in 460 ml of methylene chloride, 37.35 g of 3-(3-fluorophenoxy)pyridine was added at room temperature, and the mixture was stirred at room temperature for 1.5 hours. An aqueous sodium hydrogen sulfite solution (20%, 120 ml) was added to the mixture and then the mixture was stirred for a few minutes. The organic layer separated was washed with 10% aqueous sodium hydroxide solution and with water, dried over anhydrous sodium sulfate, and concentrated. The residue was crystallized by trituration with isopropyl ether. The crystals were collected by filtration and washed with isopropyl ether to yield 34.44 g of pale yellow crystals, which were recrystallized from ethyl acetate to give colorless needles, mp 59°-61° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:14][CH2:13][C:12]2[C:15]([C:20]3[NH:21][N:22]=[N:23][C:24]=3[C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)=[C:16]([Cl:19])[CH:17]=[CH:18][C:11]=2[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:31](=O)([O-])[O-].[K+].[K+].IC>CC(C)=O>[C:1]([O:5][C:6]([N:8]1[CH2:14][CH2:13][C:12]2[C:15]([C:20]3[C:24]([C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)=[N:23][N:22]([CH3:31])[N:21]=3)=[C:16]([Cl:19])[CH:17]=[CH:18][C:11]=2[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCc2ccc(Cl)c(-c3[nH]nnc3-c3ccccc3)c2CC1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CC(C)=O
Product: Cn1nc(-c2ccccc2)c(-c2c(Cl)ccc3c2CCN(C(=O)OC(C)(C)C)CC3)n1

Procedure:
Dissolve 3-tert-butoxycarbonyl-7-chloro-6-(5-phenyl-3H-[1,2,3]triazol-4-yl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine (24 mg, 0.06 mmol) in acetone (1.4 mL). Add potassium carbonate (41 mg, 0.3 mmol) and iodomethane (7.4 μL, 0.12 mmol) and stir for 16 h at room temperature. Filter the mixture through a fritted glass funnel and evaporate the filtrate. Purify the crude mixture by chromatography on silica gel to obtain the desired intermediate as the first of the three methylation isomers (7.8 mg, 25%).
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]2[C:5]([NH:6][CH:7]=[N:8]2)=[C:4]([Cl:11])[N:3]=1.[CH2:12]=[CH:13][CH:14]1[O:16][CH2:15]1>CN(C)C=O>[NH2:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH2:12]/[CH:13]=[CH:14]\[CH2:15][OH:16])=[C:4]([Cl:11])[N:3]=1
Reactant: Nc1nc(Cl)c2[nH]cnc2n1
Reactant: C=CC1CO1
Solvent: CN(C)C=O
Product: Nc1nc(Cl)c2ncn(C/C=C\CO)c2n1
Temperature: 60 °C

Procedure:
2-Amino-6-chloropurine (3.4 g), butadiene monoepoxide (1.65 g) and tetrakis (triphenylphosphine)palladium (0) (1.0 g) in dry dimethylformamide (75 ml) were stirred under a nitrogen atmosphere and heated at 60° C. for 45 minutes. The solvent was evaporated in vacuum (0.1 mm Mg) and the residue was triturated with hot chloroform (4×50 ml). The combined chloroform solutions were concentrated (25 ml volume) and diluted with ether (100 ml). The gummy precipitate was collected, dried and triturated with hot 1,2-dimethoxyethane (3×50 ml). The combined solutions were evaporated in vacuum (0.1 m Hg) to give a crude mixture (4 g) which was separated on a column of silica gel (500 g) eluted with chloroform+methanol 10+1 (800 ml) followed by chloroform+methanol 8+1. Fractions of about 15 ml were collected and the compound cis-4-(2-Amino-6-chloropurin-9-yl)-2-buten-1-ol was obtained as a minor product (0.2 g) in fractions 74-78. M.p. 160°-165° C.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][C:7]3([CH2:26][N:25]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:24]3)[C:8]2([NH:14][S:15]([CH2:18][CH2:19][Si:20]([CH3:23])([CH3:22])[CH3:21])(=[O:17])=[O:16])[C:11]([OH:13])=[O:12])=[CH:4][CH:3]=1.[Si](C=[N+]=[N-])(C)(C)[CH3:35]>C(Cl)Cl.CO>[Br:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][C:7]3([CH2:24][N:25]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:26]3)[C:8]2([NH:14][S:15]([CH2:18][CH2:19][Si:20]([CH3:23])([CH3:21])[CH3:22])(=[O:17])=[O:16])[C:11]([O:13][CH3:35])=[O:12])=[CH:4][CH:3]=1
Reactant: C[Si](C)(C)C=[N+]=[N-]
Reactant: CC(C)(C)OC(=O)N1CC2(Cc3ccc(Br)cc3C2(NS(=O)(=O)CC[Si](C)(C)C)C(=O)O)C1
Solvent: ClCCl
Solvent: CO
Product: COC(=O)C1(NS(=O)(=O)CC[Si](C)(C)C)c2cc(Br)ccc2CC12CN(C(=O)OC(C)(C)C)C2
Temperature: 25 °C
Reaction time: 19 h
Yield: 72 %

Procedure:
A mixture of 6′-bromo-1-(tert-butoxycarbonyl)-1′-(2-(trimethylsilyl)ethylsulfonamido)-1′,3′-dihydrospiro[azetidine-3,2′-indene]-1′-carboxylic acid, obtained as described above, and TMSCHN2 (2.0 Min hexane, 1 mL) in CH2Cl2 (6 mL) and MeOH (3 mL) was stirred at room temperature for 19 h. After the solvent was evaporated under reduced pressure, the residue was purified by chromatography on silica gel eluted with hexanes/ethyl acetate to afford 0.3263 g (72% in three steps) of 1-tert-butyl 1′-methyl 6′-bromo-1′-(2-(trimethylsilyl)ethylsulfonamido)-1′,3′-dihydrospiro[azetidine-3,2′-indene]-1,1′-dicarboxylate as foam. LC-MS tR=2.20 min in 3 min chromatography, m/z 575, 577 (MH+), 547, 549 (MH+-28), 519, 521 (MH+-56).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[F:11])[C:5](O)=[O:6].C(Cl)(=O)C([Cl:15])=O.CN(C=O)C>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[F:11])[C:5]([Cl:15])=[O:6]
Reactant: O=C(Cl)C(=O)Cl
Reactant: O=C(O)c1ccc(F)c(Br)c1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=C(Cl)c1ccc(F)c(Br)c1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 94.4 %

Procedure:
A solution of 3-bromo-4-fluorobenzoic acid (976 mg, 4.46 mmol) in DCM (25 mL) was stirred at rt and treated with oxalyl chloride (1.950 mL, 22.28 mmol), followed by a drop of DMF, causing gas evolution to commence. After 2.5 h, the solution was heated to boiling for 1-2 min and allowed to cool to rt. After 3 h total, the solution was concentrated to provide 3-bromo-4-fluorobenzoyl chloride as a white solid (1.00 g, 94%). A portion of this material (200 mg, 0.842 mmol) was added to an ice-cold solution of 4-fluoroaniline (0.081 mL, 0.842 mmol) in pyridine (4 mL), and the solution was stirred at rt for 65 h The solution was concentrated and the residue was stirred in 1 M hydrochloric acid, forming a precipitate which was collected by filtration, washed with water and dried to provide 3-bromo-4-fluoro-N-(4-fluorophenyl)benzamide as an off-white solid (227.5 mg, 80%). 1H NMR (400 MHz, DMSO-d6) δ 10.38 (s, 1H) 8.29 (dd, J=6.7, 2.1 Hz, 1H) 8.01 (ddd, J=8.6, 4.8, 2.2 Hz, 1H) 7.75 (dd, J=9.0, 5.1 Hz, 2H) 7.55 (t, J=8.6 Hz, 1H) 7.20 (t, J=8.9 Hz, 2H). Mass spectrum m/z 312, 314 (M+H)+.