Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1]C(C)([O-])C.[K+].[Cl:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[N:18]([OH:19])[CH:17]=[C:16]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH:15]=2)=[CH:10][CH:9]=1.CI>O1CCCC1.O>[Cl:7][C:8]1[CH:9]=[CH:10][C:11]([C:14]2[N:18]([O:19][CH3:1])[CH:17]=[C:16]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH:15]=2)=[CH:12][CH:13]=1
Reactant: CCOC(=O)c1cc(-c2ccc(Cl)cc2)n(O)c1
Reactant: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Solvent: CI
Product: CCOC(=O)c1cc(-c2ccc(Cl)cc2)n(OC)c1
Reaction time: 3 h
Yield: 94.5 %

Procedure:
Potassium tert-butoxide (4.32 g, 0.0385 mol) is added portionwise to a 0° C. solution of ethyl 5-(p-chlorophenyl)-1-hydroxypyrrole-3-carboxylate (9.3 g, 0.035 mol) in anhydrous tetrahydrofuran. Methyl iodide (5.46 g, 0.0385 mol) is then added slowly to the solution at room temperature. The reaction mixture is stirred for 3 hours, diluted with water and extracted with ether. The combined ether extracts are washed sequentially with water and brine, dried over anhydrous sodium sulfate and concentrated in vacuo to give a solid. Crystallization from hexanes gives the title compound as a white crystalline solid (9.25 g, 94%), mp 65°-66° C.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:18]=[CH:17][C:16]([C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:15][CH:14]=2)=[CH:9][C:8]=1[C:24]1[CH:33]=[CH:32][C:31]2[C:30]([CH3:35])([CH3:34])[CH2:29][CH2:28][C:27]([CH3:37])([CH3:36])[C:26]=2[CH:25]=1.[CH:38]1([NH2:41])[CH2:40][CH2:39]1>C(O)C>[CH:38]1([NH:41][CH:4]([CH2:3][CH3:2])[CH2:5][O:6][C:7]2[CH:12]=[CH:11][C:10]([C:13]3[CH:18]=[CH:17][C:16]([C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:15][CH:14]=3)=[CH:9][C:8]=2[C:24]2[CH:33]=[CH:32][C:31]3[C:30]([CH3:35])([CH3:34])[CH2:29][CH2:28][C:27]([CH3:37])([CH3:36])[C:26]=3[CH:25]=2)[CH2:40][CH2:39]1
Reactant: CCOC(=O)c1ccc(-c2ccc(OCCCCCl)c(-c3ccc4c(c3)C(C)(C)CCC4(C)C)c2)cc1
Reactant: NC1CC1
Solvent: CCO
Product: CCOC(=O)c1ccc(-c2ccc(OCC(CC)NC3CC3)c(-c3ccc4c(c3)C(C)(C)CCC4(C)C)c2)cc1
Yield: 25.7 %

Procedure:
In a manner similar to that of Example 1c, by reaction of 700 mg (1.3 mmol) of ethyl 4′-(4-chlorobutoxy)-3′-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphth-2-yl)biphenyl-4-carboxylate with 800 μl (11.5 mmol) of cyclopropylamine in 100 ml of ethanol. 180 mg of ethyl 4′-(2-cyclopropylaminobutoxy)-3′-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphth-2-yl)biphenyl-4-carboxylate are obtained in the form of a yellow oil (yield=26%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH:7]=[CH:8][C:9](=[O:16])[N:10]2[CH2:13][CH:14]=O)=[N:5][CH:4]=1.[NH:17]1[CH2:22][CH2:21][O:20][C@@H:19]([CH2:23][NH:24][C:25](=[O:31])[O:26][C:27]([CH3:30])([CH3:29])[CH3:28])[CH2:18]1.[O-]S([O-])(=O)=O.[Na+].[Na+].[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>CO.C(Cl)(Cl)Cl>[CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH:7]=[CH:8][C:9](=[O:16])[N:10]2[CH2:13][CH2:14][N:17]2[CH2:22][CH2:21][O:20][C@@H:19]([CH2:23][NH:24][C:25](=[O:31])[O:26][C:27]([CH3:29])([CH3:28])[CH3:30])[CH2:18]2)=[N:5][CH:4]=1
Reactant: CC(C)(C)OC(=O)NC[C@H]1CNCCO1
Reactant: COc1cnc2ccc(=O)n(CC=O)c2c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=S(=O)([O-])[O-]
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: CO
Product: COc1cnc2ccc(=O)n(CCN3CCO[C@@H](CNC(=O)OC(C)(C)C)C3)c2c1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of [7-(methoxy)-2-oxo-1,5-naphthyridin-1(2H)-yl]acetaldehyde (as the methyl hemiacetal) (0.500 g, 2.29 mmol) in 1:1 (MeOH/CHCl3) (25 mL) were added 1,1-dimethylethyl [(2R)-2-morpholinyl-methyl]carbamate (0.500 g, 2.29 mmol) and Na2SO4 (0.100 g) and the resulting solution stirred at ambient temperature for 18 h. Na(OAc)3BH (1.46 g, 6.87 mmol) was added and the solution stirred an additional 2 g. The reaction mixture was concentrated onto silica gel and chromatographed on a silica gel column) [0-100% Hexanes/EtOAc] to yield a yellowish oil. (0.460 g, 48%)
Reaction SMILES: O[C@@:2]1([CH3:23])[CH2:19][C@@:17]2([CH3:18])[C@@H:13]([CH2:14][CH2:15][C:16]2=[O:20])[C@H:12]2[C@H:3]1[C@:4]1([CH3:22])[C:9]([CH2:10][CH2:11]2)=[CH:8][C:7](=[O:21])[CH2:6][CH2:5]1.[OH-].[Na+]>C(O)=O>[CH2:23]=[C:2]1[CH2:19][C@@:17]2([CH3:18])[C@@H:13]([CH2:14][CH2:15][C:16]2=[O:20])[C@H:12]2[C@H:3]1[C@:4]1([CH3:22])[C:9]([CH2:10][CH2:11]2)=[CH:8][C:7](=[O:21])[CH2:6][CH2:5]1
Reactant: C[C@]1(O)C[C@]2(C)C(=O)CC[C@H]2[C@@H]2CCC3=CC(=O)CC[C@]3(C)[C@H]21
Agent: [Na+]
Agent: [OH-]
Solvent: O=CO
Product: C=C1C[C@]2(C)C(=O)CC[C@H]2[C@@H]2CCC3=CC(=O)CC[C@]3(C)[C@@H]12
Temperature: 0 °C
Reaction time: 6 h
Yield: 58.9 %

Procedure:
9 g of 11β-hydroxy-11α-methylandrost-4-ene-3,17-dione is allowed to react with 100 ml of concentrated formic acid at 50° C. After 6 hours, the solution is stirred into ice/water that contains sodium hydroxide. The precipitated product is suctioned off, washed with water, dissolved in ethyl acetate, dried, and concentrated under vacuum. The crude product is chromatographed on silica gel with a methylene chloride-ethyl acetate gradient, thus obtaining 5 g of 11-methyleneandrost-4-ene-3,17-dione, mp 157°-160° C. (from acetone/hexane).
Reaction SMILES: [C:1]12([CH2:11][C:12]([NH:14][C:15]3[CH:24]=[CH:23][CH:22]=[C:21]4[C:16]=3[CH:17]=[CH:18][O:19][C:20]4=O)=[O:13])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.[F:26][C:27]1[CH:34]=[CH:33][C:30]([CH2:31][NH2:32])=[CH:29][CH:28]=1>>[C:1]12([CH2:11][C:12]([NH:14][C:15]3[CH:24]=[CH:23][CH:22]=[C:21]4[C:16]=3[CH:17]=[CH:18][N:32]([CH2:31][C:30]3[CH:33]=[CH:34][C:27]([F:26])=[CH:28][CH:29]=3)[C:20]4=[O:19])=[O:13])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2
Reactant: NCc1ccc(F)cc1
Reactant: O=C(CC12CC3CC(CC(C3)C1)C2)Nc1cccc2c(=O)occc12
Product: O=C(CC12CC3CC(CC(C3)C1)C2)Nc1cccc2c(=O)n(Cc3ccc(F)cc3)ccc12
Temperature: 145 °C
Yield: 75.3 %

Procedure:
A mixture of 2-adamantan-1-yl-N-(1-oxo-1H-isochromen-5-yl)-acetamide (0.3 g, 0.89 mmol) and 4-fluorobenzylamine 0.668 g (5.33 mmol) in an 8 mL sealed vial was heated at 145° C. for 48 h. The reaction vessel was cooled to room temperature. The crude product was purified by prep. HPLC to yield 2-adamantan-1-yl-N-[2-(4-fluoro-benzyl)-1-oxo-1,2-dihydro-isoquinolin-5-yl]-acetamide (0.298 g, 0.67 mmol, 75%) as a pale yellow powder.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][CH:9]([C:20]2[CH:25]=[C:24]([F:26])[CH:23]=[CH:22][C:21]=2[F:27])[C:10]2[C:11]([CH3:19])=[CH:12][C:13]([C:16]([OH:18])=O)=[N:14][CH:15]=2)=[CH:4][CH:3]=1.F[P-](F)(F)(F)(F)F.[N:35]1(O[P+](N2CCCC2)(N2CCCC2)N2CCCC2)C2C=CC=CC=2N=N1.ON1C2C=CC=CC=2N=N1.[Cl-].[NH4+].C(N(C(C)C)C(C)C)C>CN(C)C=O.C(OCC)(=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([S:8][CH:9]([C:20]2[CH:25]=[C:24]([F:26])[CH:23]=[CH:22][C:21]=2[F:27])[C:10]2[C:11]([CH3:19])=[CH:12][C:13]([C:16]([NH2:35])=[O:18])=[N:14][CH:15]=2)=[CH:6][CH:7]=1
Reactant: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Reactant: Cc1cc(C(=O)O)ncc1C(Sc1ccc(Cl)cc1)c1cc(F)ccc1F
Agent: F[P-](F)(F)(F)(F)F
Agent: On1nnc2ccccc21
Agent: [Cl-]
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Cc1cc(C(N)=O)ncc1C(Sc1ccc(Cl)cc1)c1cc(F)ccc1F
Temperature: 25 °C
Reaction time: 12 h
Yield: 98 %

Procedure:
To a solution of 5-[[(4-chlorophenyl)thio](2,5-difluorophenyl)methyl]-4-meth ylpyridine-2-carboxylic acid (406 mg, 1.00 mmol) in N,N-dimethylformamide (10 ml), (benzotriazol-1-yloxy)tripyrrolidinophosphonium hexafluorophosphate (781 mg, 1.50 mmol), 1-hydroxybenzotriazole (203 mg, 1.50 mmol), ammonium chloride (107 mg, 2.00 mmol), and N-ethyldiisopropylamine (0.697 ml, 4.00 mmol) were added in an argon atmosphere at room temperature. After stirring for 12 hours at room temperature, ethyl acetate was added to the reaction mixture, and the mixture was washed with 0.5 N hydrochloric acid. The organic layer was dried over anhydrous sodium sulfate and filtered, the filtrate was concentrated under reduced pressure, and the resulting residue was subjected to flash silica gel chromatography. The fraction obtained from an elution with hexane:ethyl acetate=2:1 was concentrated under reduced pressure, to obtain the title compound (398 mg, 0.98 mmol, 98%) as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6](/[CH:9]=[N:10]/[C@H:11]([CH2:14][O:15][C:16]2[CH:21]=[CH:20][C:19]([C:22]3[CH:27]=[CH:26][C:25]([O:28][C:29]([F:32])([F:31])[F:30])=[CH:24][CH:23]=3)=[CH:18][CH:17]=2)[CH2:12]O)=[CH:5][CH:4]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH3:52][C:53]1([CH3:60])[NH:57][C:56](=[O:58])[NH:55][C:54]1=[O:59].N(C(OC(C)C)=O)=NC(OC(C)C)=O>C1COCC1>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6](/[CH:9]=[N:10]/[C@H:11]([CH2:14][O:15][C:16]2[CH:21]=[CH:20][C:19]([C:22]3[CH:27]=[CH:26][C:25]([O:28][C:29]([F:30])([F:32])[F:31])=[CH:24][CH:23]=3)=[CH:18][CH:17]=2)[CH2:12][N:55]2[C:54](=[O:59])[C:53]([CH3:60])([CH3:52])[NH:57][C:56]2=[O:58])=[CH:5][CH:4]=1
Reactant: COc1ccc(/C=N/[C@@H](CO)COc2ccc(-c3ccc(OC(F)(F)F)cc3)cc2)cc1
Reactant: CC1(C)NC(=O)NC1=O
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COc1ccc(/C=N/[C@H](COc2ccc(-c3ccc(OC(F)(F)F)cc3)cc2)CN2C(=O)NC(C)(C)C2=O)cc1

Procedure:
A solution of Example 1H (2.80 kg), triphenylphosphine (2.475 kg), and 5,5-dimethylhydantoin (1.37 kg) in THF (24.89 kg) at 1-2° C. was treated with diisopropyl azodicarboxylate (2.01 kg) over 75 minutes to provide a solution of the desired product.
Reaction SMILES: C([O:4][CH:5]1[C:11]2=[N:12][C:13]([CH3:21])=[C:14]([C:16](OCC)=[O:17])[CH:15]=[C:10]2[CH2:9][CH2:8][CH2:7][CH2:6]1)(=O)C.Cl.[NH2:23][C:24]([NH2:26])=[NH:25]>>[OH:4][CH:5]1[C:11]2=[N:12][C:13]([CH3:21])=[C:14]([C:16]([NH:25][C:24]([NH2:26])=[NH:23])=[O:17])[CH:15]=[C:10]2[CH2:9][CH2:8][CH2:7][CH2:6]1
Reactant: CCOC(=O)c1cc2c(nc1C)C(OC(C)=O)CCCC2
Reactant: N=C(N)N
Agent: Cl
Product: Cc1nc2c(cc1C(=O)NC(=N)N)CCCCC2O
Yield: 58.5 %

Procedure:
When the method of Inventive Example 1 was repeated using ethyl 9-acetoxy-2-methyl-6,7,8,9-tetrahydro-5H-cyclohepta[b]pyridine-3-carboxylate (450.0 mg, 1.55 mmol) and guanidine hydrochloride (2.67 g, 28.0 mmol), hydrolysis of the acetoxy group occurred at the same time, and the title compound (237.8 mg, 58.9%) was obtained as white powder.
Reaction SMILES: C([O:3][C:4](=[O:43])[CH2:5][CH:6]([C:33]1[CH:34]=[N:35][C:36]2[C:41]([CH:42]=1)=[CH:40][CH:39]=[CH:38][CH:37]=2)[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]1[N:18]=[C:17]([NH:19]C(=O)C(C)(C)C)[N:16]=[C:15]([NH:26]C(=O)C(C)(C)C)[CH:14]=1)C.[Li+].[OH-]>O>[NH2:19][C:17]1[N:16]=[C:15]([NH2:26])[CH:14]=[C:13]([CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH:6]([C:33]2[CH:34]=[N:35][C:36]3[C:41]([CH:42]=2)=[CH:40][CH:39]=[CH:38][CH:37]=3)[CH2:5][C:4]([OH:43])=[O:3])[N:18]=1
Reactant: CCOC(=O)CC(CCCCCCc1cc(NC(=O)C(C)(C)C)nc(NC(=O)C(C)(C)C)n1)c1cnc2ccccc2c1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Product: Nc1cc(CCCCCCC(CC(=O)O)c2cnc3ccccc3c2)nc(N)n1

Procedure:
The ester 7-8 (1 g, 1.7 mmol) was dissolved in TBF (20 mL) and water (20 mL) and treated with 1N LiOH (7 mL) at room temperature for 16 hours. After neutralization with 3N HCl, the solution was concentrated in vacuo, filtered through a bed of silica gel (EtOH:H2O:NH4OH 10:1:1) and the residue purified by reverse phase HPLC (preppak C-18 column; water/acetonitrile/0.1% TFA gradient). After lyophilization, the title compound 7-9 (TFA salt) was obtained as a white powder.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH3:14])[C:5]([O:12][CH3:13])=[C:6]([CH:11]=1)[C:7]([O:9]C)=[O:8].[OH-].[Na+].O.Cl>C1COCC1>[Br:1][C:2]1[CH:3]=[C:4]([CH3:14])[C:5]([O:12][CH3:13])=[C:6]([CH:11]=1)[C:7]([OH:9])=[O:8]
Reactant: COC(=O)c1cc(Br)cc(C)c1OC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: COc1c(C)cc(Br)cc1C(=O)O
Temperature: 25 °C
Reaction time: 5 h
Yield: 73.4 %

Procedure:
To a solution of methyl 5-bromo-2-methoxy-3-methyl-benzoate (2.6 g, 10.0 mmol, 1.0 eq) in THF (20 mL) was added an aqueous solution of NaOH (2M, 20 mL, 40 mmol, 4.0 eq). The mixture was stirred at room temperature for 5 h. Water was added and the aqueous layer was acidified to pH 9 by addition of 1M HCl. The THF was removed in vacuo and the aqueous layer was further acidified to pH 4-5 with 1M HCl. The solid that precipitated from the reaction was collected by filtration and dried to give the title compound as a white solid (1.8 g, 73%).
Reaction SMILES: [F:1][C:2]1([F:33])[O:6][C:5]2[CH:7]=[CH:8][C:9]([C:11]3([C:14]([NH:16][C:17]4[N:22]=[C:21]([C:23]5[CH:24]=[C:25]([CH:29]=[CH:30][CH:31]=5)[C:26](O)=[O:27])[C:20]([CH3:32])=[CH:19][CH:18]=4)=[O:15])[CH2:13][CH2:12]3)=[CH:10][C:4]=2[O:3]1.[CH3:34][S:35]([NH2:38])(=[O:37])=[O:36].C(N(CC)CC)C>ClCCl>[F:33][C:2]1([F:1])[O:6][C:5]2[CH:7]=[CH:8][C:9]([C:11]3([C:14]([NH:16][C:17]4[N:22]=[C:21]([C:23]5[CH:24]=[C:25]([CH:29]=[CH:30][CH:31]=5)[C:26]([NH:38][S:35]([CH3:34])(=[O:37])=[O:36])=[O:27])[C:20]([CH3:32])=[CH:19][CH:18]=4)=[O:15])[CH2:13][CH2:12]3)=[CH:10][C:4]=2[O:3]1
Reactant: Cc1ccc(NC(=O)C2(c3ccc4c(c3)OC(F)(F)O4)CC2)nc1-c1cccc(C(=O)O)c1
Reactant: CS(N)(=O)=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1ccc(NC(=O)C2(c3ccc4c(c3)OC(F)(F)O4)CC2)nc1-c1cccc(C(=O)NS(C)(=O)=O)c1
Reaction time: 16 h
Yield: 30.3 %

Procedure:
3-(6-(1-(2,2-Difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido)-3-methylpyridin-2-yl)benzoic acid (200 mg, 0.442 mmol) and methanesulfonamide (46.4 mg, 0.488 mmol) were dissolved in dichloromethane (2 mL) containing triethylamine (0.247 mL, 1.76 mmol). O-(7-Azabenzotriazol-1-yl)-N,N,N′-tetramethyluronium hexafluorophosphate (HATU, 185 mg, 0.487 mmol) was added and the solution was allowed to stir for 16 hours. The crude product was purified on 12 g of silica gel utilizing a gradient of 0-100% ethyl acetate in hexanes to yield 3-(6-(1-(2,2-difluorobenzo[d][1,3]-dioxol-5-yl)cyclopropanecarboxamido)-3-methylpyridin-2-yl)-N-(methylsulfonyl)-benzamide (71 mg, 30%) as a white solid. ESI-MS m/z calc. 529.1, found 529.9 (M+1)+Retention time 1.83 minutes. 1H NMR (400 MHz, CD3CN) δ 9.57 (s, 1H), 8.01 (d, J=8.4 Hz, 1H), 7.91-7.87 (m, 1H), 7.75 (s, 1H), 7.68-7.66 (m, 2H), 7.58-7.53 (m, 1H), 7.36-7.32 (m, 2H), 7.21 (d, J=8.2 Hz, 1H), 3.30 (s, 3H), 2.25 (s, 3H), 1.63-1.58 (m, 2H), 1.20-1.16 (m, 2H).
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]([N:12]1[CH2:15][CH:14]([C:16]2[C:21](Cl)=[N:20][CH:19]=[CH:18][N:17]=2)[CH2:13]1)=[O:11].[NH:23]1[CH2:28][CH2:27][CH:26]([OH:29])[CH2:25][CH2:24]1.C(N(CC)CC)C.CS(C)=O>O>[NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]([N:12]1[CH2:15][CH:14]([C:16]2[C:21]([N:23]3[CH2:28][CH2:27][CH:26]([OH:29])[CH2:25][CH2:24]3)=[N:20][CH:19]=[CH:18][N:17]=2)[CH2:13]1)=[O:11]
Reactant: O=C(c1nc2ccccc2[nH]1)N1CC(c2nccnc2Cl)C1
Reactant: OC1CCNCC1
Solvent: O
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: O=C(c1nc2ccccc2[nH]1)N1CC(c2nccnc2N2CCC(O)CC2)C1
Temperature: 120 °C
Yield: 84 %

Procedure:
To a mixture of (1H-benzoimidazol-2-yl)-[3-(3-chloro-pyrazin-2-yl)-azetidin-1-yl]-methanone (0.170 g, 0.50 mmol) and piperidin-4-ol (0.101 g, 1.0 mmol) was added triethylamine (0.10 g, 1.0 mmol) and DMSO (4 mL). The solution was heated to 120° C. for 4 h. Then the mixture was diluted with water (10 mL) and extracted with EtOAc (2×20 mL). The combined organic extracts were washed with water (10 mL) and brine (10 mL), dried over Na2SO4 and filtered. The filtrate was evaporated in vacuo and the residue was purified by flash column chromatography on silica gel (20% to 50% EtOAc in petroleum ether) to give (1H-benzoimidazol-2-yl)-{3-[3-(4-hydroxy-piperidin-1-yl)-pyrazin-2-yl]-azetidin-1-yl}-methanone (0.16 g, 0.42 mmol, 85% yield) as a white solid.
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4](F)[CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:17]([OH:19])[CH3:18]>CN(C=O)C>[Br:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([O:19][CH2:17][CH3:18])[CH:3]=1
Reactant: N#Cc1ccc(Br)cc1F
Reactant: CCO
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOc1cc(Br)ccc1C#N
Temperature: 60 °C
Yield: 100.9 %

Procedure:
A mixture of 4-Bromo-2-fluoro-benzonitrile (5 g, 25.00 mmol), potassium carbonate (10.37 g, 75.0 mmol), ethanol (6.86 mL, 117 mmol) in DMF (50 mL) was heated at 60° C. for overnight. After filtration and concentration, the redisue was dissolved in ethyl acetate (150 mL), and the solution was washed with water (30 mL) and brine (50 mL). After drying over Na2SO4, filtration and concentration, a light brown solid (5.7 g) was obtained without further purification. 1H NMR (400 MHz, CDCl3): δ 1.49 (t, J=7 Hz, 3H), 4.14 (q, J=7 Hz, 2H), 7.11 (d, J=1.7 Hz, 1H), 7.14 (dd, J=8.1, 1.7 Hz, 1H), 7.40 (d, J=8.1 Hz, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[CH:4][CH:3]=1.[C:10]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=1)(=[O:12])[CH3:11]>>[Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[CH:11][C:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=2)=[O:12])=[CH:4][CH:3]=1
Reactant: O=Cc1ccc(Cl)cc1
Reactant: CC(=O)c1ccccn1
Product: O=C(C=Cc1ccc(Cl)cc1)c1ccccn1

Procedure:
By a procedure similar to that of example 1.59.1, starting from 4-chlorobenzaldehyde and commercial 2-acetylpyridine, 3-(4-chlorophenyl)-1-(2-pyridinyl)prop-2-en-1-one was obtained as yellowish solid.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([S:9][CH2:10][C:11](=O)[CH2:12][C:13]([O:15][CH3:16])=[O:14])[CH:5]=[C:6]([OH:8])[CH:7]=1>S(O)(C)(=O)=O>[CH3:16][O:15][C:13](=[O:14])[CH2:12][C:11]1[C:5]2[C:6]([OH:8])=[CH:7][C:2]([OH:1])=[CH:3][C:4]=2[S:9][CH:10]=1
Reactant: COC(=O)CC(=O)CSc1cc(O)cc(O)c1
Agent: CS(=O)(=O)O
Product: COC(=O)Cc1csc2cc(O)cc(O)c12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 51.3 %

Procedure:
To MsOH (50 mL) was added methyl 4-((3,5-dihydroxyphenyl)sulfanyl)-3-oxobutanoate (15.1 g) at room temperature. The mixture was stirred at room temperature for 30 min. The mixture was poured into ice-water at 0° C. and extracted with EtOAc. The organic layer was separated, washed successively with water and brine, dried over MgSO4 and concentrated in vacuo. The residue was purified by silica gel column chromatography (EtOAc/hexane). The product was crystallized from EtOAc-IPE to give the title compound (7.20 g).
Reaction SMILES: [CH3:1][C:2]1([CH3:21])[C:6]([CH3:8])([CH3:7])[O:5][B:4]([C:9]2[CH:14]=[CH:13][C:12]([NH:15][S:16]([CH:19]=[CH2:20])(=[O:18])=[O:17])=[CH:11][CH:10]=2)[O:3]1.[CH2:22]([NH:24][CH2:25][CH3:26])[CH3:23].C(OCC)(=O)C.ClCCl>CO>[CH3:8][C:6]1([CH3:7])[C:2]([CH3:21])([CH3:1])[O:3][B:4]([C:9]2[CH:10]=[CH:11][C:12]([NH:15][S:16]([CH2:19][CH2:20][N:24]([CH2:25][CH3:26])[CH2:22][CH3:23])(=[O:18])=[O:17])=[CH:13][CH:14]=2)[O:5]1
Reactant: C=CS(=O)(=O)Nc1ccc(B2OC(C)(C)C(C)(C)O2)cc1
Reactant: CCNCC
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: CO
Product: CCN(CC)CCS(=O)(=O)Nc1ccc(B2OC(C)(C)C(C)(C)O2)cc1
Temperature: 25 °C
Yield: 56.3 %

Procedure:
To a solution of ethenesulfonic acid [4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-amide (0.500 g, 1.6 mmol) in methanol (5 mL) was added diethylamine (0.707 g, 4.0 mmol) in methanol (5 mL), and the reaction was stirred at room temperature and monitored by TLC (1:1 Ethyl acetate:hexanes). After 2 hr the reaction was concentrated in vacuum and the residue partitioned between ethyl acetate (50 mL) and water (50 mL). The ethyl acetate was then washed with 50% brine (1×50 mL), dried over anhydrous sodium sulfate, filtered and concentrated in vacuum. Crude product was purified using a 10 g prepacked silica gel column, eluting with 1:1 ethyl acetate: dichloromethane to provide 2-diethylamino-ethanesulfonic acid [4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-amide as a white solid (0.346 g, 0.90 mmol, 56%). 1H NMR (CDCl3, 300 MHz) δ 7.78 (d, J=6.65, 2H) 7.15 (d, J=6.66, 2H), 3.20 (m, 2H), 3.0 (m, 2H), 2.55 (q, J=7.15, 7.16 4H), 1.34 (s, 12H), 1.05 (t, J=7.19, 6H).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4](Cl)[C:5]2[C:10]([C:11]3[CH:20]=[CH:19][C:14]4[N:15]=[C:16]([CH3:18])[O:17][C:13]=4[CH:12]=3)=[CH:9][N:8]([CH2:21][O:22][CH2:23][CH2:24][Si:25]([CH3:28])([CH3:27])[CH3:26])[C:6]=2[N:7]=1.[CH:30]1([OH:35])[CH2:34][CH2:33][CH2:32][CH2:31]1.CC(C)([O-])C.[Na+].CCCCCC>O1CCOCC1.C(Cl)Cl>[Cl:1][C:2]1[N:3]=[C:4]([O:35][CH:30]2[CH2:34][CH2:33][CH2:32][CH2:31]2)[C:5]2[C:10]([C:11]3[CH:20]=[CH:19][C:14]4[N:15]=[C:16]([CH3:18])[O:17][C:13]=4[CH:12]=3)=[CH:9][N:8]([CH2:21][O:22][CH2:23][CH2:24][Si:25]([CH3:27])([CH3:28])[CH3:26])[C:6]=2[N:7]=1
Reactant: OC1CCCC1
Reactant: Cc1nc2ccc(-c3cn(COCC[Si](C)(C)C)c4nc(Cl)nc(Cl)c34)cc2o1
Agent: CC(C)(C)[O-]
Agent: [Na+]
Solvent: CCCCCC
Solvent: ClCCl
Solvent: C1COCCO1
Product: Cc1nc2ccc(-c3cn(COCC[Si](C)(C)C)c4nc(Cl)nc(OC5CCCC5)c34)cc2o1
Temperature: 70 °C
Reaction time: 3 h
Yield: 88 %

Procedure:
A solution of 6-(2,4-dichloro-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-2-methylbenzo[d]oxazole (1 equiv), cyclopentanol (1.1 equiv), and sodium tert-butoxide (1 equiv) in 1,4-dioxane (0.22 M) was taken in a sealable flask. The reaction mixture was put under a nitrogen atmosphere, the sealable flask was sealed and the mixture was stirred at 70° C. for 3 h. The mixture was cooled to room temperature and concentrated to afford an oil, which was suspended in DCM and loaded onto a silica column (packed with hexane). The column was eluted with 0-30% ethyl acetate in hexane. The fractions containing product were combined and concentrated to dryness to give the target product as a light yellow oil (Yield: 88%) that solidified upon standing. MS (ESI) m/z 499.4 [M+1]+.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:10]=[CH:11][C:12]=1[NH:13][CH:14]1[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1)[C:5]([O:7][CH2:8][CH3:9])=[O:6].Cl.[OH:21][C:22]1[CH:31]=[CH:30][C:25]([C:26](=N)OC)=[CH:24][CH:23]=1>CO>[CH:14]1([N:13]2[C:12]3[CH:11]=[CH:10][C:4]([C:5]([O:7][CH2:8][CH3:9])=[O:6])=[CH:3][C:2]=3[N:1]=[C:26]2[C:25]2[CH:30]=[CH:31][C:22]([OH:21])=[CH:23][CH:24]=2)[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1
Reactant: COC(=N)c1ccc(O)cc1
Reactant: CCOC(=O)c1ccc(NC2CCCCC2)c(N)c1
Agent: Cl
Solvent: CO
Product: CCOC(=O)c1ccc2c(c1)nc(-c1ccc(O)cc1)n2C1CCCCC1
Yield: 72.5 %

Procedure:
Ethyl 3-amino-4-cyclohexylaminobenzoate (130 g) obtained in Example 1, Step 3, and methyl 4-hydroxybenzimidate hydrochloride (139 g) were added to methyl alcohol (1500 ml), and the mixture was refluxed under heating for 4 hr. The reaction mixture was allowed to cool and the precipitated crystals were collected by filtration to give the title compound (131 g, yield 72%).
Reaction SMILES: [NH2:1][C:2]1[C:9]([CH3:10])=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=1[Cl:11].OC1C(C)=CC(C([NH:19][OH:20])=N)=CC=1C>>[NH2:1][C:2]1[C:9]([CH3:10])=[CH:8][C:5]([C:6]([NH:19][OH:20])=[NH:7])=[CH:4][C:3]=1[Cl:11]
Reactant: Cc1cc(C(=N)NO)cc(C)c1O
Reactant: Cc1cc(C#N)cc(Cl)c1N
Product: Cc1cc(C(=N)NO)cc(Cl)c1N

Procedure:
The title compound is prepared from commercially available 4-amino-3-chloro-5-methylbenzonitrile in analogy to 4,N-dihydroxy-3,5-dimethyl-benzamidine; LC-MS: tR=0.50 min; [M+1]+=200.01; 1H NMR (D6-DMSO): δ 2.15 (s, 3H), 5.20 (s, 2H), 5.61 (s, 2H), 7.28 (s, 1H), 7.40 (s, 1H), 9.33 (s, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]2[CH:13]([CH:14]([O:16][C:17]3[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:19][N:18]=3)[CH3:15])[CH2:12][N:11]([C:27](Cl)=[O:28])[CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8].CCN(CC)CC.[CH3:37][N:38]1[C:42]([CH2:43][NH2:44])=[CH:41][N:40]=[CH:39]1>C(Cl)Cl>[CH3:37][N:38]1[C:42]([CH2:43][NH:44][C:27]([N:11]2[CH2:12][CH:13]([CH:14]([O:16][C:17]3[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:24])[F:25])=[CH:19][N:18]=3)[CH3:15])[CH:9]([C:4]3[CH:5]=[CH:6][C:7]([Cl:8])=[C:2]([Cl:1])[CH:3]=3)[CH2:10]2)=[O:28])=[CH:41][N:40]=[CH:39]1
Reactant: CC(Oc1ccc(C(F)(F)F)cn1)C1CN(C(=O)Cl)CC1c1ccc(Cl)c(Cl)c1
Reactant: Cn1cncc1CN
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(Oc1ccc(C(F)(F)F)cn1)C1CN(C(=O)NCc2cncn2C)CC1c1ccc(Cl)c(Cl)c1
Reaction time: 8 h
Yield: 40 %

Procedure:
To a stirred solution of (3SR,4RS)-3-(3,4-dichloro-phenyl)-4-[(SR)-1-(5-trifluoromethyl-pyridin-2-yloxy)-ethyl]-pyrrolidine-1-carbonyl chloride (30 mg, 0.064 mmol) in CH2Cl2 (3 mL) were added Et3N (0.015 mL, 0.11 mmol) and C-(3-Methyl-3H-imidazol-4-yl)-methylamine (commercially available) (8 mg, 0.070 mmol). Stirring was continued overnight, and the reaction mixture was concentrated under vacuo and directly purified by flash chromatography (SiO2, CH2Cl2/MeOH 98/2) to yield 14 mg (40%) the title compound as a white solid. ES-MS m/e: 542.2 (M+H+).