Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: OC[CH:3]1[C:12]2([CH2:15][CH2:14][CH2:13]2)[O:11][C:10]2[C:5](=[C:6]([CH3:19])[C:7]([OH:18])=[C:8]([CH3:17])[C:9]=2[CH3:16])[CH2:4]1.Cl.[CH3:21][O:22][NH2:23]>N1C=CC=CC=1>[CH3:21][O:22][N:23]=[CH:4][C:3]1[C:12]2([CH2:13][CH2:14][CH2:15]2)[O:11][C:10]2[C:9](=[C:8]([CH3:17])[C:7]([OH:18])=[C:6]([CH3:19])[CH:5]=2)[CH:16]=1
Reactant: Cc1c(C)c2c(c(C)c1O)CC(CO)C1(CCC1)O2
Reactant: CON
Agent: Cl
Solvent: c1ccncc1
Product: CON=CC1=Cc2c(cc(C)c(O)c2C)OC12CCC2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 6-hydroxy-5,7-dimethylspiro[chromene-2,1′-cyclobutane]-3-carbaldehyde (421 mg, prepared as described in Example 19) in 8 mL of pyridine was added methoxyamine hydrochloride (628 mg). The reaction mixture was allowed to stir at room temperature overnight. The mixture was extracted with ethyl acetate and washed with 1N HCl. The organic solvent was evaporated in vacuo, the residue was purified by flash chromatography eluted with 10% ethyl acetate in hexane to give 6-hydroxy-5,7-dimethylspiro[chromene-2,1′-cyclobutane]-3-carbaldehyde O-methyloxime as a yellow solid. 1H-NMR (300 MHz, CDCl3) δ=7.82 (s, 1H), 6.68 (s, 1H), 6.60 (s, 1H), 4.45 (s, 1H), 3.98 (s, 3H), 2.75 (m, 2H), 2.44 (m, 2H), 2.40 (s, 3H), 2.22 (s, 3H), 1.98 (m, 2H) ppm. 13C-NMR (75 MHz, CDCl3) δ=148.6, 146.5, 146.4, 131.2, 125.8, 125.1, 119.9, 119.6, 116.0, 80.5, 62.1, 34.2, 16.6, 13.6, 11.4 ppm. MS: (m/z)=274.0 (M+H+).
Reaction SMILES: [OH:1][C:2]1[N:3]=[C:4]2[CH:12]=[C:11](/[CH:13]=[CH:14]/[C:15]3[S:16][CH:17]=[C:18]([CH:20]([CH3:22])[CH3:21])[N:19]=3)[CH:10]=[CH:9][N:5]2[C:6](=[O:8])[CH:7]=1.C(N(C(C)C)CC)(C)C.I[CH2:33][CH:34]1[CH2:38][CH2:37][O:36][CH2:35]1>CN(C)C=O>[CH:20]([C:18]1[N:19]=[C:15](/[CH:14]=[CH:13]/[C:11]2[CH:10]=[CH:9][N:5]3[C:6](=[O:8])[CH:7]=[C:2]([O:1][CH2:33][CH:34]4[CH2:38][CH2:37][O:36][CH2:35]4)[N:3]=[C:4]3[CH:12]=2)[S:16][CH:17]=1)([CH3:22])[CH3:21]
Reactant: ICC1CCOC1
Reactant: CC(C)c1csc(/C=C/c2ccn3c(=O)cc(O)nc3c2)n1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)c1csc(/C=C/c2ccn3c(=O)cc(OCC4CCOC4)nc3c2)n1
Temperature: 80 °C
Reaction time: 8 h

Procedure:
2-Hydroxy-8-[(E)-2-(4-isopropyl-1,3-thiazol-2-yl)-1-ethenyl]-4H-pyrido[1,2-a]-pyrimidin-4-one (210 mg, 0.670 mmol) was suspended in dimethylformamide (6.0 ml), added with diisopropylethylamine (600 μl) and 3-(iodomethyl)tetrahydrofuran (334 μl), and stirred overnight at 80° C. The reaction solution was further added with diisopropylethylamine (600 μl) and 3-(iodomethyl)tetrahydrofuran (334 μl) and stirred overnight at 80° C. The reaction mixture was concentrated, and the residue was purified by silica gel column chromatography (chloroform:methanol=100:0→100:1→100:2→100:5, v/v) to obtain the title compound (277 mg, quantitative).
Reaction SMILES: C[O-].[Na+].C([O:7][C@@H:8]1[C@@H:21]([O:22][CH2:23][CH:24]=[CH2:25])[C@@H:20]([O:26]C(=O)C)[C@@H:19]([CH2:30][O:31][CH2:32][CH:33]=[CH2:34])[O:18][C@H:9]1[O:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)(=O)C.C(O)(=O)C>CO>[CH2:23]([O:22][C@H:21]1[C@@H:20]([OH:26])[C@@H:19]([CH2:30][O:31][CH2:32][CH:33]=[CH2:34])[O:18][C@@H:9]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C@@H:8]1[OH:7])[CH:24]=[CH2:25]
Reactant: C=CCOC[C@H]1O[C@@H](OCc2ccccc2)[C@H](OC(C)=O)[C@@H](OCC=C)[C@H]1OC(C)=O
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: C=CCOC[C@H]1O[C@@H](OCc2ccccc2)[C@H](O)[C@@H](OCC=C)[C@H]1O
Temperature: 25 °C
Reaction time: 48 h
Yield: 77.9 %

Procedure:
Sodium methoxide (134 mg, 2.5 mmol) was added to a solution of Compound 10 (10.84 g, 24.9 mmol) in methanol (30 ml), and the mixture was stirred at room temperature under nitrogen gas atmosphere for 48 hours. The reaction mixture was neutralized with acetic acid, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (toluene:ethyl acetate=4:1) to obtain Compound 11 (6.8 g, 78%).
Reaction SMILES: [ClH:1].[NH2:2][C:3]1[S:4][CH:5]=[C:6]([CH3:8])[N:7]=1.[Br:9]N1C(=O)CCC1=O.C(OC(C)C)(C)C>C(O)(=O)C>[ClH:1].[NH2:2][C:3]1[S:4][C:5]([Br:9])=[C:6]([CH3:8])[N:7]=1
Reactant: Cc1csc(N)n1
Reactant: O=C1CCC(=O)N1Br
Agent: Cl
Solvent: CC(=O)O
Solvent: CC(C)OC(C)C
Product: Cc1nc(N)sc1Br
Yield: 89.7 %

Procedure:
To a solution of 2-amino-4-methylthiazole hydrochloride (3.0 g) in acetic acid (20 ml) was added once N-bromosuccinimide (4.0 g) at room temperature with stirring. The mixture was stirred at room temperature for 1.5 hours and the reaction mixture was poured into isopropyl ether under ice cooling. The precipitates were collected by filtration, washed with ethyl ether and dried in vacuo to give 2-amino-5-bromo-4-methylthiazole hydrochloride (4.1 g, yield: 89.1%).
Reaction SMILES: [C:1]([N:9]1[CH2:13][CH:12]([CH2:14][O:15][C:16]2[CH:31]=[CH:30][C:19]([C:20]([O:22]CC3C=CC=CC=3)=[O:21])=[CH:18][CH:17]=2)[O:11][C:10]1=[O:32])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H][H]>C(O)(=O)C.CN(C)C=O.[C].[Pd]>[C:1]([N:9]1[CH2:13][CH:12]([CH2:14][O:15][C:16]2[CH:17]=[CH:18][C:19]([C:20]([OH:22])=[O:21])=[CH:30][CH:31]=2)[O:11][C:10]1=[O:32])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(OCc1ccccc1)c1ccc(OCC2CN(C(=O)c3ccccc3)C(=O)O2)cc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CN(C)C=O
Solvent: CC(=O)O
Product: O=C(O)c1ccc(OCC2CN(C(=O)c3ccccc3)C(=O)O2)cc1
Yield: 7.8 %

Procedure:
A 1.0 g quantity of 10% palladium carbon was added to a solution of 3.8 g of benzyl 4-(3-benzoyl-2-oxooxazolidin-5-yl)methoxybenzoate (compound 120) obtained in Example 5 in 50 ml of acetic acid and 25 ml of N,N-dimethylformamide. The mixture was stirred at 60° C. for 5 hours in a stream of hydrogen. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure. Ethanol was added to the obtained residue to collect the crystals by filtration. Thus, 235 mg of the title compound (compound 134) was obtained (yield 8%).
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:16])=[C:11](F)[C:12]=3[F:14])[C:7](=[O:17])[C:6]([C:18]([OH:20])=[O:19])=[CH:5]2)[CH2:3][CH2:2]1.[Br:21][C:22]1[CH:30]=[CH:29][CH:28]=[C:27]2[C:23]=1[CH2:24][NH:25][CH2:26]2.C1CCN2C(=NCCC2)CC1>CN(C=O)C>[Br:21][C:22]1[CH:30]=[CH:29][CH:28]=[C:27]2[C:23]=1[CH2:24][N:25]([C:11]1[C:12]([F:14])=[C:13]3[C:8]([C:7](=[O:17])[C:6]([C:18]([OH:20])=[O:19])=[CH:5][N:4]3[CH:1]3[CH2:2][CH2:3]3)=[CH:9][C:10]=1[F:16])[CH2:26]2
Reactant: O=C(O)c1cn(C2CC2)c2c(F)c(F)c(F)cc2c1=O
Reactant: Brc1cccc2c1CNC2
Solvent: CN(C)C=O
Solvent: C1CCC2=NCCCN2CC1
Product: O=C(O)c1cn(C2CC2)c2c(F)c(N3Cc4cccc(Br)c4C3)c(F)cc2c1=O
Yield: 18.6 %

Procedure:
142 mg of 1-cyclopropyl-6,7,8-trifluoro-1,4-dihydro-4- oxoquinoline-3-carboxylic acid, 149 mg of 4-bromoisoindoline, 114 mg of DBU, and 1.5 ml of anhydrous DMF were processed in the same manner as in Example 20 to produce 43 mg of the target compound.
Reaction SMILES: [CH2:1]([C:3]1([C:28]#[N:29])[CH2:7][CH2:6][N:5]([C:8]2[CH:13]=[CH:12][N:11]=[C:10]([NH:14][C:15]3[CH:20]=[CH:19][C:18]([N:21]4[CH2:26][CH2:25][O:24][CH2:23][CH2:22]4)=[CH:17][CH:16]=3)[N:9]=2)[C:4]1=[O:27])[CH3:2].OO.C(=O)([O-])[O-:33].[K+].[K+].O>CS(C)=O>[CH2:1]([C:3]1([C:28]([NH2:29])=[O:33])[CH2:7][CH2:6][N:5]([C:8]2[CH:13]=[CH:12][N:11]=[C:10]([NH:14][C:15]3[CH:16]=[CH:17][C:18]([N:21]4[CH2:26][CH2:25][O:24][CH2:23][CH2:22]4)=[CH:19][CH:20]=3)[N:9]=2)[C:4]1=[O:27])[CH3:2]
Reactant: CCC1(C#N)CCN(c2ccnc(Nc3ccc(N4CCOCC4)cc3)n2)C1=O
Reactant: O=C([O-])[O-]
Agent: OO
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: CCC1(C(N)=O)CCN(c2ccnc(Nc3ccc(N4CCOCC4)cc3)n2)C1=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 3-ethyl-1-(2-((4-(morpholin-4-yl)phenyl)amino)pyrimidin-4-yl)-2-oxopyrrolidine-3-carbonitrile (36 mg) obtained in Example 2 in dimethylsulfoxide (1 mL) were added a solution of 30% aqueous hydrogen peroxide (28 μL) and 2M aqueous potassium carbonate (0.14 mL), and the mixture was stirred overnight at room temperature. Water was added thereto in an ice bath, and the precipitated solid was collected by filtration. The obtained crude crystals were recrystallized (diisopropyl ether/ethanol) to give the title compound (13 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[N:5][CH:6]=[CH:7][C:8]=2Cl)[N:3]=1.[NH2:13][C:14]1[CH:19]=[C:18]([CH3:20])[CH:17]=[CH:16][C:15]=1[S:21][C:22]1[CH:27]=[CH:26][C:25]([OH:28])=[CH:24][CH:23]=1>C(O)C>[Cl:1][C:2]1[N:3]=[C:4]2[C:9]([C:8]([NH:13][C:14]3[CH:19]=[C:18]([CH3:20])[CH:17]=[CH:16][C:15]=3[S:21][C:22]3[CH:27]=[CH:26][C:25]([OH:28])=[CH:24][CH:23]=3)=[CH:7][CH:6]=[N:5]2)=[CH:10][CH:11]=1
Reactant: Cc1ccc(Sc2ccc(O)cc2)c(N)c1
Reactant: Clc1ccc2c(Cl)ccnc2n1
Solvent: CCO
Product: Cc1ccc(Sc2ccc(O)cc2)c(Nc2ccnc3nc(Cl)ccc23)c1
Temperature: 25 °C

Procedure:
The product from Example 21d (0.67 g, 3.36 mmol) and the product from Example 9c (0.78 g, 3.36 mmol) in 10 mL ethanol were heated under reflux for 5.5 hr. The reaction mixture was cooled to room temperature and the solvent was removed concentrated under vacuum leaving yellow solid that was used without further purification (1.43 g, 100%).
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[C:8]([O:10][CH3:11])[C:7]([O:12][CH3:13])=[CH:6][C:3]=1[CH:4]=O.[CH3:14][O:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[CH2:22][CH2:23][C:24]#[N:25]>>[CH3:13][O:12][C:7]1[CH:6]=[C:3]2[C:2](=[CH:9][C:8]=1[O:10][CH3:11])[N:1]=[C:24]([NH2:25])[C:23]([CH2:22][C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=1[O:15][CH3:14])=[CH:4]2
Reactant: COc1ccccc1CCC#N
Reactant: COc1cc(N)c(C=O)cc1OC
Product: COc1ccccc1Cc1cc2cc(OC)c(OC)cc2nc1N

Procedure:
The title compound was synthesized according to EXAMPLE 11 from 2-amino-4,5-dimethoxybenzaldehyde and 3-(2-methoxyphenyl)propionitrile.
Reaction SMILES: C([O:8][C:9]([C@H:11]1[CH2:16][N:15]([C:17]2[S:18][C:19]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])=[C:20]([CH3:22])[N:21]=2)[CH2:14][CH2:13][N:12]1[S:30]([C:33]1[CH:38]=[CH:37][C:36]([O:39][C:40]([F:43])([F:42])[F:41])=[CH:35][CH:34]=1)(=[O:32])=[O:31])=[O:10])C1C=CC=CC=1.C(O)(=O)C>CO.[C].[Pd]>[C:26]([O:25][C:23]([C:19]1[S:18][C:17]([N:15]2[CH2:14][CH2:13][N:12]([S:30]([C:33]3[CH:34]=[CH:35][C:36]([O:39][C:40]([F:43])([F:41])[F:42])=[CH:37][CH:38]=3)(=[O:32])=[O:31])[C@@H:11]([C:9]([OH:10])=[O:8])[CH2:16]2)=[N:21][C:20]=1[CH3:22])=[O:24])([CH3:29])([CH3:28])[CH3:27]
Reactant: Cc1nc(N2CCN(S(=O)(=O)c3ccc(OC(F)(F)F)cc3)[C@@H](C(=O)OCc3ccccc3)C2)sc1C(=O)OC(C)(C)C
Agent: [Pd]
Solvent: CO
Solvent: CC(=O)O
Product: Cc1nc(N2CCN(S(=O)(=O)c3ccc(OC(F)(F)F)cc3)[C@@H](C(=O)O)C2)sc1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 3 h
Yield: 79.3 %

Procedure:
A mixture of the compound (1.82 g) obtained in Step 5, 10% palladium carbon (250 mg) and acetic acid (4.0 ml) in methanol (50 ml) was stirred under a hydrogen atmosphere (4 atm) at room temperature for 3 hr. The reaction mixture was filtered through celite, and concentrated under reduced pressure. 10% Palladium carbon (1.8 g), acetic acid (4.0 ml) and methanol (50 ml) were added again to the residue, and the mixture was stirred under a hydrogen atmosphere (4 atm) at room temperature for 30 min. The reaction mixture was filtered through celite, and the filtrate was concentrated under reduced pressure. Toluene was added to the residue, and the mixture was concentrated under reduced pressure (repeated 4 times). The obtained powder was suspended in water, collected by filtration and dried to give the title compound (1.24 g).
Reaction SMILES: [F:1][C:2]([F:6])([CH3:5])[CH2:3]O.N1C=CC=CC=1.C(#N)C.FC(F)(F)S(OS(C(F)(F)F)(=O)=O)(=O)=O.C(=O)([O-])[O-].[K+].[K+].[CH3:37][O:38][C:39]1[C:49]([N+:50]([O-:52])=[O:51])=[CH:48][C:42]2[CH2:43][CH2:44][NH:45][CH2:46][CH2:47][C:41]=2[CH:40]=1>>[F:1][C:2]([F:6])([CH3:5])[CH2:3][N:45]1[CH2:46][CH2:47][C:41]2[CH:40]=[C:39]([O:38][CH3:37])[C:49]([N+:50]([O-:52])=[O:51])=[CH:48][C:42]=2[CH2:43][CH2:44]1
Reactant: COc1cc2c(cc1[N+](=O)[O-])CCNCC2
Reactant: CC(F)(F)CO
Agent: O=C([O-])[O-]
Agent: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Agent: [K+]
Solvent: CC#N
Solvent: c1ccncc1
Product: COc1cc2c(cc1[N+](=O)[O-])CCN(CC(C)(F)F)CC2
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To mixture of 2,2-Difluoro-propan-1-ol (0.26 g, 0.0027 mol) and Pyridine (0.27 mL, 0.0034 mol) in Acetonitrile (25 mL, 0.48 mol) at 0-5° C. was added dropwise Trifluoromethanesulfonic anhydride (0.48 mL, 0.0028 mol). The mixture was stirred for 30 minutes then Potassium carbonate (0.37 g, 0.0027 mol) and 7-Methoxy-8-nitro-2,3,4,5-tetrahydro-1H-benzo[d]azepine (0.30 g, 0.0013 mol) were added. The reaction mixture was warmed to room temperature then heated to 50° C. for 18 hours. The mixture was evaporated. The residue was dissolved in dichloromethane (50 mL) and washed with water (50 mL), dried over magnesium sulfate, filtered and evaporated. The material was purified via silica gel chromatography using 0%→10% Methanol:Dichloromethane solvent gradient. 3-(2,2-Difluoro-propyl)-7-methoxy-8-nitro-2,3,4,5-tetrahydro-1H-benzo[d]azepine isolated as a yellow solid (0.316 g, 78%).
Reaction SMILES: Cl.[NH2:2][C@@H:3]1[CH2:7][CH2:6][N:5]([S:8]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([OH:17])[CH:12]=2)(=[O:10])=[O:9])[CH2:4]1.[C:18]([C:20]1[CH:33]=[CH:32][C:23]([CH2:24][N:25]2[C:29]([CH:30]=O)=[CH:28][N:27]=[CH:26]2)=[CH:22][C:21]=1[F:34])#[N:19].C(N(CC)C(C)C)(C)C.[BH3-]C#N.[Na+]>CO>[F:34][C:21]1[CH:22]=[C:23]([CH2:24][N:25]2[C:29]([CH2:30][NH:2][C@@H:3]3[CH2:7][CH2:6][N:5]([S:8]([C:11]4[CH:16]=[CH:15][CH:14]=[C:13]([OH:17])[CH:12]=4)(=[O:10])=[O:9])[CH2:4]3)=[CH:28][N:27]=[CH:26]2)[CH:32]=[CH:33][C:20]=1[C:18]#[N:19]
Reactant: N#Cc1ccc(Cn2cncc2C=O)cc1F
Reactant: N[C@@H]1CCN(S(=O)(=O)c2cccc(O)c2)C1
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CCN(C(C)C)C(C)C
Product: N#Cc1ccc(Cn2cncc2CN[C@@H]2CCN(S(=O)(=O)c3cccc(O)c3)C2)cc1F
Temperature: 25 °C
Reaction time: 1 h

Procedure:
(R)-3-Amino-1-(3-hydroxyphenylsulfonyl)pyrrolidine hydrochloride, as described above in Step F. (360 mg, 1.29 nimol) and 1-(4-cyano-3-fluorobenzyl)-5-imidazolecarboxaldehyde, as described in Example 1, Step G. (326 mg, 1.42 mmol) were stirred in MeOH (8 mL) and N,N-diisopropylethylamine was added dropwise adjust the mixture to ca. pH 5, as judged by wetted pH paper. The mixture was stirred for 1 hour at ambient temperature then NaCNBH3 (97 mg, 1.54 mmol) was added and stirring was continued for 18 hours. The reaction was quenched with saturated aqueous NaHCO3 (2 mL) and most of the MeOH was removed under reduced pressure. The residual solution was partitioned between saturated aqueous NaHCO3 (10 mL) and CHCl3 (20 mL). The aqueous layer was extracted further with CHCl3 (3×15 mL). The combined organic extracts were dried over MgSO4, filtered, and concentrated in vacuo. The crude product was purified by flash column chromatography on silica, eluting with a gradient of EtOAc—5% MeOH—0.5% NH4OH to EtOAc—10% MeOH—1% NH4OH to yield the titled product as a white foam.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]([C:15]([O:17][CH3:18])=[O:16])[C:11](=[O:14])[NH:12][N:13]=2)=[CH:4][C:3]=1[CH3:19].CS(O[CH2:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[Cl:33])(=O)=O>>[Cl:33][C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=1[CH2:26][CH2:25][N:12]1[C:11](=[O:14])[C:10]([C:15]([O:17][CH3:18])=[O:16])=[CH:9][C:8]([C:5]2[CH:6]=[CH:7][C:2]([F:1])=[C:3]([CH3:19])[CH:4]=2)=[N:13]1
Reactant: CS(=O)(=O)OCCc1ccccc1Cl
Reactant: COC(=O)c1cc(-c2ccc(F)c(C)c2)n[nH]c1=O
Product: COC(=O)c1cc(-c2ccc(F)c(C)c2)nn(CCc2ccccc2Cl)c1=O
Yield: 59.8 %

Procedure:
Following the procedure of Example 1(6), 6-(4-fluoro-3-methylphenyl)-4-methoxycarbonyl-2H-pyridazin-3-one and 2-(2-chlorophenyl)ethanol methanesulfonate were reacted to yield the title compound as a pale yellow solid (yield: 59.8%).
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([O:11]C)[CH:9]=2)[C:4](SC(C)(C)C)=[C:3]1[CH2:18][C:19]([CH3:25])([CH3:24])[C:20]([O:22][CH3:23])=[O:21].C(S)C.[Al+3].[Cl-].[Cl-].[Cl-]>C(Cl)Cl>[CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([OH:11])[CH:9]=2)[CH:4]=[C:3]1[CH2:18][C:19]([CH3:25])([CH3:24])[C:20]([O:22][CH3:23])=[O:21]
Reactant: COC(=O)C(C)(C)Cc1c(SC(C)(C)C)c2ccc(OC)cc2n1C
Agent: [Al+3]
Agent: [Cl-]
Solvent: CCS
Solvent: ClCCl
Product: COC(=O)C(C)(C)Cc1cc2ccc(O)cc2n1C
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a cold solution of 940 mg of the indole ester from Step B and 1.6 mL of ethanethiol in CH2Cl2 (50 mL) was added portion-wise 4.3 g of AlCl3. After complete addition, the mixture was stirred at R.T. for 2 h. The mixture was then cooled to 0 ° C. and carefully quenched with a solution of 0.5M Na,K tartrate (200 mL) and extracted with CH2Cl2. The organic layer was dried over Na2SO4 and evaporated to dryness to give a solid which was chromatographed on flash silica gel using ethyl acetate:hexane (30:70) as eluant to afford the title compound; m.p. 125°-126° C.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH2:8][O:9][C:10](=[O:12])[CH3:11])[CH:5]=[N:6][CH:7]=1.[F:13][C:14]1[CH:19]=[CH:18][C:17](B(O)O)=[CH:16][CH:15]=1>>[C:10]([O:9][CH2:8][C:4]1[CH:5]=[N:6][CH:7]=[C:2]([C:17]2[CH:18]=[CH:19][C:14]([F:13])=[CH:15][CH:16]=2)[CH:3]=1)(=[O:12])[CH3:11]
Reactant: OB(O)c1ccc(F)cc1
Reactant: CC(=O)OCc1cncc(Br)c1
Product: CC(=O)OCc1cncc(-c2ccc(F)cc2)c1

Procedure:
5-Bromo-3-acetoxymethylpyridine is reacted with 4-fluorobenzeneboronic acid as described in Example 1. The 5-(4-fluorophenyl)pyridin-3-ylmethyl acetate obtained is saponified by conventional methods and subsequently oxidized to give 5-(4-fluorophenyl)nicotinic acid.
Reaction SMILES: I[C:2]1[CH:20]=[CH:19][C:5]2[O:6][CH2:7][C:8]([F:18])([F:17])[C:9]3[N:10]([N:11]=[C:12]([C:14]([NH2:16])=[O:15])[CH:13]=3)[C:4]=2[CH:3]=1.[C:21]([C@:23]1([OH:29])[CH2:27][CH2:26][NH:25][C:24]1=[O:28])#[CH:22]>>[F:17][C:8]1([F:18])[CH2:7][O:6][C:5]2[CH:19]=[CH:20][C:2]([C:22]#[C:21][C@:23]3([OH:29])[CH2:27][CH2:26][NH:25][C:24]3=[O:28])=[CH:3][C:4]=2[N:10]2[N:11]=[C:12]([C:14]([NH2:16])=[O:15])[CH:13]=[C:9]12
Reactant: NC(=O)c1cc2n(n1)-c1cc(I)ccc1OCC2(F)F
Reactant: C#C[C@]1(O)CCNC1=O
Product: NC(=O)c1cc2n(n1)-c1cc(C#C[C@]3(O)CCNC3=O)ccc1OCC2(F)F

Procedure:
Similar to as described in General Procedure G, 9-iodo-4,4-difluoro-4,5-dihydrobenzo[b]pyrazolo[1,5-d][1,4]oxazepine-2-carboxamide was reacted with (R)-3-ethynyl-3-hydroxypyrrolidin-2-one to give a mixture of titled compound after purification by prep HPLC.
Reaction SMILES: C[CH:2]1[CH2:7][CH2:6][CH2:5][CH2:4][N:3]1[CH2:8][C:9]1[CH:14]=[CH:13][C:12]([F:15])=[C:11]([F:16])[CH:10]=1.B.[CH2:18]1[CH2:22]O[CH2:20][CH2:19]1.CO>C1COCC1>[C:18]1([CH:22]([NH:3][CH2:2][CH2:7][CH:6]2[CH2:7][CH2:2][N:3]([CH2:8][C:9]3[CH:14]=[CH:13][C:12]([F:15])=[C:11]([F:16])[CH:10]=3)[CH2:4][CH2:5]2)[C:11]2[CH:10]=[CH:9][CH:14]=[CH:13][CH:12]=2)[CH:4]=[CH:5][CH:6]=[CH:20][CH:19]=1
Reactant: CC1CCCCN1Cc1ccc(F)c(F)c1
Reactant: C1CCOC1
Agent: B
Solvent: CO
Product: Fc1ccc(CN2CCC(CCNC(c3ccccc3)c3ccccc3)CC2)cc1F
Temperature: 25 °C
Yield: 90 %

Procedure:
To the solution of 4-[2-diphenylmethyl)aminocarbonyl]methyl-1-[(3,4-difluorophenyl)methyl]piperidine (0.12 g, 0.28 mmol) in dry THF 20 ml was added 1M BH3/THF (1.0 ml). The reaction solution was refluxed for 6 hours. After the solution was cooled to room temperature, MeOH (5 ml) was added slowly. The solvent was removed under reduced pressure. 10% HCl/MeOH (10 ml) was added into the residue and the solution was refluxed for 1 hour. Solid NaHCO3 was added after MeOH was evaporated. The mixture was extracted with EtOAc. The combined organic phase was dried over Na2SO4 and evaporated to give the crude product, which was purified by chromatography (Hexane/EtOAc/Et3N=1/2/1%) to a white solid, 0.11 g (90% yield) (“Procedure E”). 1H NMR (CD3Cl) δ 7.39-6.99 (13H, m, Ar—H), 4.79 (1H, s, Ph2CH), 3.39 (2H, s, F2PhCH2), 2.80-2.76 (2H, d, J=11.1 Hz, N(CH)2), 2.60-2.55 (2H, t, J=7.0 Hz, NCH2), 1.93-1.86 (2H, t, J=11.1 Hz, N(CH)2), 1.62-1.58 (2H, d, J=12 Hz), 1.49-1.42 (2H, q, J=6.3 Hz, NCH2CH2), 1.35-1.31 (1H, m, NCH2CH2CH(CH2)2), 1.26-1.19 (2H, t, J=12.0 Hz). The free base was converted into its HCl salt, m.p.=280-281° C. Anal: (C17H30N2F2·2HCl·0.25H2O) Calculated: C, 65.12; H, 6.85; N, 5.62; Found: C, 65.13; H, 6.80, N, 5.28.
Reaction SMILES: [NH2:1][C:2]1[CH:6]=[C:5]([C:7]2[CH:12]=[CH:11][C:10]([CH3:13])=[CH:9][CH:8]=2)[NH:4][N:3]=1.[CH2:14]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH2:16][CH:15]1[C:23](O)=[O:24].Cl.CN(C)CCCN=C=NCC>N1C=CC=CC=1.C(OCC)(=O)C>[CH2:16]1[C:17]2[C:22](=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH2:14][CH:15]1[C:23]([NH:1][C:2]1[CH:6]=[C:5]([C:7]2[CH:12]=[CH:11][C:10]([CH3:13])=[CH:9][CH:8]=2)[NH:4][N:3]=1)=[O:24]
Reactant: Cc1ccc(-c2cc(N)n[nH]2)cc1
Reactant: O=C(O)C1Cc2ccccc2C1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: Cc1ccc(-c2cc(NC(=O)C3Cc4ccccc4C3)n[nH]2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 53 %

Procedure:
3-Amino-5-(4-methylphenyl)pyrazole (35 mg) and indan-2-carboxylic acid (33 mg) were dissolved in pyridine (2 ml) to which was subsequently added 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (58 mg), and the mixture was stirred at room temperature overnight. The reaction solution was diluted with ethyl acetate (30 ml), washed with water (30 ml), saturated aqueous sodium bicarbonate (30 ml) and saturated brine (30 ml) and then dried over anhydrous magnesium sulfate. Then, the solvent was distilled away. The resulting crystalline residue was washed with ethyl ether to obtain the title compound (34 mg) as white crystals (melting point: 220-225° C.).
Reaction SMILES: CN(C)CCCN=C=NCC.[CH:12]([NH:15][C:16]1[C:17]([NH2:22])=[CH:18][CH:19]=[CH:20][CH:21]=1)([CH3:14])[CH3:13].[N:23]([C:26]1[CH:35]=[CH:34][C:29]([C:30]([O:32][CH3:33])=[O:31])=[CH:28][CH:27]=1)=[C:24]=S>O1CCCC1.C(OCC)(=O)C>[CH:12]([N:15]1[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[N:22]=[C:24]1[NH:23][C:26]1[CH:35]=[CH:34][C:29]([C:30]([O:32][CH3:33])=[O:31])=[CH:28][CH:27]=1)([CH3:14])[CH3:13]
Reactant: COC(=O)c1ccc(N=C=S)cc1
Reactant: CC(C)Nc1ccccc1N
Agent: CCN=C=NCCCN(C)C
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COC(=O)c1ccc(Nc2nc3ccccc3n2C(C)C)cc1
Temperature: 25 °C
Yield: 58.9 %

Procedure:
N-(3-Dimethylaminopropyl)-N′-ethylcarbodiimide (EDC, 206 mg, 1.34 mmol) is added to a solution of N1-isopropylbenzene-1,2-diamine (100 mg, 0.67 mmol) and methyl 4-isothiocyanatobenzoate (138 mg, 0.67 mmol) in tetrahydrofuran. The reaction may be heated to reflux for a time period (for example 2 hours) and cooled to room temperature. The mixture may be diluted with ethyl acetate, filtered and concentrated. The residue may be purified by any method, including Biotage column chromatography to give methyl 4-(1-isopropyl-1H-benzo[d]imidazol-2-ylamino)benzoate (122 mg)
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[C:7]([C:9]1[CH:14]=[CH:13][C:12]([NH:15][C:16]([C:18]2[CH2:19][CH2:20][O:21][C:22]3[CH:28]=[CH:27][C:26]([C:29]4[CH:34]=[CH:33][C:32]([CH3:35])=[CH:31][CH:30]=4)=[CH:25][C:23]=3[CH:24]=2)=[O:17])=[CH:11][CH:10]=1)=[O:8].CI.[CH:38](N(C(C)C)CC)(C)C>ClCCl>[CH3:38][N:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[C:7]([C:9]1[CH:10]=[CH:11][C:12]([NH:15][C:16]([C:18]2[CH2:19][CH2:20][O:21][C:22]3[CH:28]=[CH:27][C:26]([C:29]4[CH:30]=[CH:31][C:32]([CH3:35])=[CH:33][CH:34]=4)=[CH:25][C:23]=3[CH:24]=2)=[O:17])=[CH:13][CH:14]=1)=[O:8]
Reactant: Cc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(C(=O)C4CCCCN4)cc2)CCO3)cc1
Reactant: CCN(C(C)C)C(C)C
Solvent: CI
Solvent: ClCCl
Product: Cc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(C(=O)C4CCCCN4C)cc2)CCO3)cc1
Temperature: 25 °C

Procedure:
In dichloromethane (35ml) was dissolved N-(4(piperidin-2-ylcarbonyl)-phenyl)-7-(4-methylphenyl)-2,3-dihydro-1-benzoxepine-4-carboxamide (0.3g), and to the solution were added methyl iodide (0.08ml) and diisopropyl-ethylamine (0.17ml). The mixture was stirred at room temperature over night. The solvent was evaporated, and to the residue was added water. The mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated sodium chloride solution, and dried with anhydrous magnesium sulfate. Under reduced pressure, the solvent was evaporated, and the residue was purified with silica gel column (ethyl acetate/methanol/triethylamine) to give crude crystals, which were recrystallized from ethyl acetate-hexane to give N-(4-(1-methylpiperidin-2-ylcarbonyl)-phenyl)-7-(4-methylphenyl)-2,3-dihydro-1-benzoxepine-4-carboxamide (Compound 157) (0.17g) as colorless crystals.