Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[C:7]([C:9](OC)=[O:10])[CH:6]=[CH:5][CH:4]=1.[H-].[H-].[H-].[H-].[Li+].[Al+3].O.O.O.O.O.O.O.O.O.O.S([O-])([O-])(=O)=O.[Na+].[Na+]>CCOCC>[CH3:1][O:2][C:3]1[N:8]=[C:7]([CH2:9][OH:10])[CH:6]=[CH:5][CH:4]=1
Reactant: COC(=O)c1cccc(OC)n1
Agent: O=S(=O)([O-])[O-]
Agent: [Al+3]
Agent: [H-]
Solvent: O
Solvent: CCOCC
Product: COc1cccc(CO)n1
Reaction time: 4 h
Yield: 86.9 %

Procedure:
To methyl 6-methoxypicolinate (4.65 g, 27.8 mmol) in Et2O (100 mL) was added LAH (1.06 g). The reaction mixture was stirred for 4 hours. Celite (10 g) was added, followed by sodium sulfate-decahydrate (5 g). The reaction mixture was filtered and concentrated to provide the desired product (3.36 g).
Reaction SMILES: [Cl:1][C:2]1[CH:28]=[CH:27][C:5]2[N:6]3[C:10]([CH2:11][NH:12][CH2:13][C:4]=2[CH:3]=1)=[N:9][N:8]=[C:7]3[C@H:14]1[CH2:19][CH2:18][C@H:17]([C:20]2[C:25]([F:26])=[CH:24][CH:23]=[CH:22][N:21]=2)[CH2:16][CH2:15]1.C(=O)([O-])[O-].[Cs+].[Cs+].[CH3:35][O:36][CH2:37][CH2:38]Br>C(#N)C>[Cl:1][C:2]1[CH:28]=[CH:27][C:5]2[N:6]3[C:10]([CH2:11][N:12]([CH2:38][CH2:37][O:36][CH3:35])[CH2:13][C:4]=2[CH:3]=1)=[N:9][N:8]=[C:7]3[C@H:14]1[CH2:19][CH2:18][C@H:17]([C:20]2[C:25]([F:26])=[CH:24][CH:23]=[CH:22][N:21]=2)[CH2:16][CH2:15]1
Reactant: Fc1cccnc1[C@H]1CC[C@H](c2nnc3n2-c2ccc(Cl)cc2CNC3)CC1
Reactant: COCCBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: COCCN1Cc2cc(Cl)ccc2-n2c(nnc2[C@H]2CC[C@H](c3ncccc3F)CC2)C1
Temperature: 70 °C

Procedure:
A mixture of trans-8-chloro-1-[4-(3-fluoro-pyridin-2-yl)-cyclohexyl]-5,6-dihydro-4H-2,3,5,10b-tetraaza-benzo[e]azulene (50.0 mg, 0.126 mmol), cesium carbonate (81.9 mg, 0.251 mmol) and 2-bromoethyl methyl ether (0.024 ml, 0.25 mmol) in acetonitrile (0.6 ml) was heated at 70° C. for 20 h. The reaction mixture was partitioned between a water-brine mixture (1:1) (2 ml) and ethyl acetate (5 ml). The layers were separated. The aqueous layer was extracted with two 5-ml portions of ethyl acetate. The combined organic layers were concentrated in vacuo. Preparative RP-HPLC with water (0.05% formic acid)/methanol as eluent gave the title compound (13 mg, 23%) as light yellow solid. MS m/e: 456 ([M+H]+)
Reaction SMILES: Cl[CH2:2][CH2:3][N:4]1[CH2:9][CH2:8][O:7][CH2:6][CH2:5]1.[N+:10]([C:13]1[CH:18]=[CH:17][C:16]([S:19]([CH2:22][CH2:23][CH2:24][CH2:25][O:26][CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)(=[NH:21])=[O:20])=[CH:15][CH:14]=1)([O-:12])=[O:11]>>[N:4]1([CH2:3][CH2:2][N:21]=[S:19]([C:16]2[CH:15]=[CH:14][C:13]([N+:10]([O-:12])=[O:11])=[CH:18][CH:17]=2)([CH2:22][CH2:23][CH2:24][CH2:25][O:26][CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)=[O:20])[CH2:9][CH2:8][O:7][CH2:6][CH2:5]1
Reactant: N=S(=O)(CCCCOCc1ccccc1)c1ccc([N+](=O)[O-])cc1
Reactant: ClCCN1CCOCC1
Product: O=[N+]([O-])c1ccc(S(=O)(CCCCOCc2ccccc2)=NCCN2CCOCC2)cc1

Procedure:
Following the procedures used in Example 2, the title compound is prepared from 4-(2-chloroethyl)morpholine and S-(4-nitrophenyl)-S-[4-(phenylmethoxy)butyl]sulfoximine.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6](Cl)=[O:7].[NH2:9][C:10]1[CH:11]=[C:12]([NH:17][C:18](=[O:31])[C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([N:25]3[CH2:30][CH2:29][O:28][CH2:27][CH2:26]3)[CH:20]=2)[CH:13]=[CH:14][C:15]=1[CH3:16].C(N(CC)CC)C>C(Cl)Cl>[CH3:16][C:15]1[CH:14]=[CH:13][C:12]([NH:17][C:18](=[O:31])[C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([N:25]3[CH2:26][CH2:27][O:28][CH2:29][CH2:30]3)[CH:20]=2)=[CH:11][C:10]=1[NH:9][C:6]([C:2]1[S:1][CH:5]=[CH:4][CH:3]=1)=[O:7]
Reactant: Cc1ccc(NC(=O)c2cccc(N3CCOCC3)c2)cc1N
Reactant: O=C(Cl)c1cccs1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1ccc(NC(=O)c2cccc(N3CCOCC3)c2)cc1NC(=O)c1cccs1
Yield: 33.4 %

Procedure:
Thiophene-2-carbonyl chloride (0.069 g) was added to a stirred suspension of N-(3-amino-4-methylphenyl)-3-morpholinobenzamide (0.104 g), triethylamine (0.15 ml) and methylene chloride (20 ml) and the resultant mixture was stirred at ambient temperature for 4 hours. The organic phase was washed with water and with a saturated aqueous sodium bicarbonate solution, dried (MgSO4) and evaporated. The residue was dissolved in methylene chloride (2 ml) and diethyl ether (20 ml) was added to give a precipitate which was isolated by filtration, washed with diethyl ether and dried. There was thus obtained the title compound (0.047 g); NMR Spectrum: (DMSOd6) 2.18 (t, 3H), 3.18 (t, 4H), 3.76 (t, 4H), 7.14 (d, 1H), 7.20 (m, 2H), 7.38 (m, 2H), 7.41 (s, 1H), 7.58 (m, 1H), 7.78 (s, 1H), 7.82 (d, 1H), 7.98 (d, 1H), 9.93 (s, 1H), 10.13 (s, 1H); Mass Spectrum: M+H+ 422.
Reaction SMILES: B(F)(F)F.CSC.C[O:9][C:10]1[CH:11]=[C:12]([C:17]2[N:21]([CH2:22][C:23]#[N:24])[N:20]=[CH:19][C:18]=2[C:25]2[CH:30]=[CH:29][N:28]=[C:27]([C:31]3[CH:32]=[N:33][CH:34]=[CH:35][CH:36]=3)[CH:26]=2)[CH:13]=[C:14]([CH3:16])[CH:15]=1>ClCCl>[OH:9][C:10]1[CH:11]=[C:12]([C:17]2[N:21]([CH2:22][C:23]#[N:24])[N:20]=[CH:19][C:18]=2[C:25]2[CH:30]=[CH:29][N:28]=[C:27]([C:31]3[CH:32]=[N:33][CH:34]=[CH:35][CH:36]=3)[CH:26]=2)[CH:13]=[C:14]([CH3:16])[CH:15]=1
Reactant: COc1cc(C)cc(-c2c(-c3ccnc(-c4cccnc4)c3)cnn2CC#N)c1
Agent: FB(F)F
Solvent: CSC
Solvent: ClCCl
Product: Cc1cc(O)cc(-c2c(-c3ccnc(-c4cccnc4)c3)cnn2CC#N)c1
Reaction time: 24 h

Procedure:
Borontrifluoride-dimethylsulfide (0.13 mL, 1.2 mmol) was dropwise added to a solution of the methoxy compound (45.7 mg, 0.12 mmol) prepared in Example 34 in dichloromethane (4 mL) at room temperature under nitrogen atmosphere, and stirred for 24 hours. The reaction mixture was concentrated by vacuum distillation. The residue was treated in ethyl acetate (100 mL) and brine (50 mL), and the organic layer was dried over anhydrous magnesium sulfate and distilled under vacuum. Purification through column chromatography (silica gel, ethyl acetate) afforded pure hydroxy products (24 mg, 55%).
Reaction SMILES: C(OC([N:8]1[C@H:13]2[CH2:14][CH2:15][C@:10]([CH2:16][CH2:17][N:18]3[CH2:23][CH2:22][C@H:21]([O:24]C(=O)C(C)(C)C)[C@@H:20]([CH3:31])[CH2:19]3)([CH:11]=[CH:12]2)[O:9]1)=O)(C)(C)C.[ClH:32]>O>[ClH:32].[CH3:31][C@@H:20]1[C@@H:21]([OH:24])[CH2:22][CH2:23][N:18]([CH2:17][CH2:16][C:10]23[CH2:15][CH2:14][CH:13]([CH2:12][CH2:11]2)[NH:8][O:9]3)[CH2:19]1
Reactant: C[C@H]1CN(CC[C@]23C=C[C@H](CC2)N(C(=O)OC(C)(C)C)O3)CC[C@@H]1OC(=O)C(C)(C)C
Agent: Cl
Solvent: O
Product: C[C@H]1CN(CCC23CCC(CC2)NO3)CC[C@@H]1O
Temperature: 100 °C
Reaction time: 16 h

Procedure:
(1S,4S)-1-{2-[(3S,4S)-4-(2,2-Dimethyl-propionyloxy)-3-methyl-piperidin-1-yl]-ethyl}-2-oxa-3-aza-bicyclo[2.2.2]oct-5-ene-3-carboxylic acid tert-butyl ester (12) (880 mg, 2 mmol) is dissolved in 20 ml of water and after addition of concentrated aqueous HCl (38%, 1.2 ml) the mixture is stirred for 16 h at 100° C. Then the mixture is evaporated to dryness. The residue s treated three times with methanol and evaporated under educed pressure. The residue is diluted with ethyl acetate, extracted with 2M K2CO3, dried over Na2SO4 and evaporated under reduced pressure. The product was used in the next step without further purification.
Reaction SMILES: C([O:4][C:5]1[CH:10]=[C:9]([O:11][CH3:12])[CH:8]=[CH:7][C:6]=1[O:13][CH3:14])(=O)C.[OH-].[Na+].OS([O-])(=O)=O.[Na+]>CO>[CH3:14][O:13][C:6]1[CH:7]=[CH:8][C:9]([O:11][CH3:12])=[CH:10][C:5]=1[OH:4]
Reactant: COc1ccc(OC)c(OC(C)=O)c1
Agent: O=S(=O)([O-])O
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COc1ccc(OC)c(O)c1
Reaction time: 12 h
Yield: 100.1 %

Procedure:
A mixture of intermediate 56, 2,5-Dimethoxyphenyl Acetate (13.9 g, 0.07 mol) and NaOH (4.26 g, 0.11 mol) in MeOH (150 mL) was stirred for 12 h in a flow of argon. A 5 M solution of NaHSO4 (21 mL) was added, and the mixture was evaporated. The residue was distributed between CH2Cl2 and H2O (300 mL, 1:1). The aqueous layer was separated, and the product was extracted with CH2Cl2 (2×100 mL). The combined extracts were dried and evaporated to give the title compound (10.8 g, 99%). LCMS data: 156.0 and 155.1 (M+H)+ (calculated for C8H10O3 154.1). 1H NMR data (DMSO-d6): 8.96 (s, 1H, Ar—OH), 6.80 (d, 1H, J=8.8 Hz, Ar—H), 6.39 (d, 1H, J=2.9 Hz, Ar—H), 6.39 (dd, 1H, J1=2.9 Hz, J2=8.8 Hz, Ar—H), 3.70 (s, 3H, —OCH3), 3.64 (s, 3H, —OCH3).
Reaction SMILES: [NH:1]1[C:5]2=[N:6][CH:7]=[C:8]([CH:10]=[O:11])[CH:9]=[C:4]2[CH:3]=[CH:2]1.[H-].[Na+].[S:14](Cl)([C:17]1[CH:23]=[CH:22][C:20]([CH3:21])=[CH:19][CH:18]=1)(=[O:16])=[O:15]>C1COCC1>[S:14]([N:1]1[C:5]2=[N:6][CH:7]=[C:8]([CH:10]=[O:11])[CH:9]=[C:4]2[CH:3]=[CH:2]1)([C:17]1[CH:23]=[CH:22][C:20]([CH3:21])=[CH:19][CH:18]=1)(=[O:16])=[O:15]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: O=Cc1cnc2[nH]ccc2c1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1ccc(S(=O)(=O)n2ccc3cc(C=O)cnc32)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 56.5 %

Procedure:
step2: To a solution of 1H-pyrrolo[2,3-b]pyridine-5-carbaldehyde (500 mg, 3.42 mmol) in THF (50 mL) at 0° C. was added NaH (205 mg, 60% in oil, 5.13 mmol) with vigorous stirring. After 30 min, TsCl (845 mg, 4.45 mmol) was added. The reaction mixture was stirred at RT for 18 h, and then the solvent was removed in vacuo. The residue was partitioned between DCM (300 mL) and water (100 mL). The organic layer was separated, dried (MgSO4), filtered, and concentrated to afford 580 mg (56%) of 1-tosyl-1H-pyrrolo[2,3-b]pyridine-5-carbaldehyde as yellow solid. MS (ESI) m/z: 301.2 [M+1]+.
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:31])=[C:4]([CH:8]2[C:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[F:22])([C:13]#[N:14])[CH:11]([CH2:23][C:24]([CH3:27])([CH3:26])[CH3:25])[NH:10][CH:9]2[C:28](O)=[O:29])[CH:5]=[CH:6][CH:7]=1.[NH2:32][CH2:33][C:34]1[CH:43]=[CH:42][C:37]([C:38]([O:40][CH3:41])=[O:39])=[C:36]([F:44])[CH:35]=1.CCN(C(C)C)C(C)C.C1C=CC2N(O)N=NC=2C=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C)C=O>[CH3:41][O:40][C:38](=[O:39])[C:37]1[CH:42]=[CH:43][C:34]([CH2:33][NH:32][C:28]([C@H:9]2[C@H:8]([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[C:3]=3[F:31])[C@:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[F:22])([C:13]#[N:14])[C@H:11]([CH2:23][C:24]([CH3:25])([CH3:26])[CH3:27])[NH:10]2)=[O:29])=[CH:35][C:36]=1[F:44]
Reactant: CC(C)(C)CC1NC(C(=O)O)C(c2cccc(Cl)c2F)C1(C#N)c1ccc(Cl)cc1F
Reactant: COC(=O)c1ccc(CN)cc1F
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)c1ccc(CNC(=O)[C@@H]2N[C@@H](CC(C)(C)C)[C@](C#N)(c3ccc(Cl)cc3F)[C@H]2c2cccc(Cl)c2F)cc1F
Yield: 98 %

Procedure:
In a manner similar to the method described in Example 379, rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (66.1 mg, 0.141 mmol) and methyl 4-(aminomethyl)-2-fluorobenzoate (51.0 mg, 0.278 mmol in N,N-dimethyl formamide (5 mL) were reacted with DIPEA (111 mg, 0.857 mmol), HOBt (37.6 mg, 0.277 mmol) and HBTU (104.9 mg, 0.275 mmol) at room temperature to give rac-4-({[(2R,3S,4R,5S)-4-(4-Chloro-2-fluoro-phenyl)-3-(3-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carbonyl]-amino}-methyl)-2-fluoro-benzoic acid methyl ester (88.5 mg, 98%). HRMS (ES+) m/z Calcd C32H30Cl2F3N3O3+H [(M+H):632.1689. Found: 632.1692.
Reaction SMILES: [Cl:1][C:2]1[C:3]([N+:16]([O-:18])=[O:17])=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([C:11]([O:13]CC)=[O:12])=[CH:5]2.ClC1C=C2C(=C(Cl)C=1)NC(C(O)=O)=C2>>[N+:16]([C:3]1[C:2]([Cl:1])=[CH:10][CH:9]=[C:8]2[C:4]=1[CH:5]=[C:6]([C:11]([OH:13])=[O:12])[NH:7]2)([O-:18])=[O:17]
Reactant: CCOC(=O)c1cc2c([N+](=O)[O-])c(Cl)ccc2[nH]1
Agent: O=C(O)c1cc2cc(Cl)cc(Cl)c2[nH]1
Product: O=C(O)c1cc2c([N+](=O)[O-])c(Cl)ccc2[nH]1

Procedure:
The title compound was prepared by hydrolysis of ethyl 5-chloro4-nitro-1H-indole-2-carboxylate as described for the preparation of 5,7-dichloro-1H-indole-2-carboxylic acid.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[CH3:7][C:8]1[C:12]([C:13]([OH:15])=O)=[CH:11][O:10][N:9]=1.[Cl:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]23[NH:40][CH2:39][CH2:38][N:24]2[C:25](=[O:37])[C:26]2[N:27]([CH:29]=[C:30]([C:32]([N:34]([CH3:36])[CH3:35])=[O:33])[CH:31]=2)[CH2:28]3)=[CH:19][CH:18]=1.C(#N)C>CN(C=O)C.C(Cl)Cl.N1C=CC=CC=1.C([O-])(O)=O.[Na+].O>[Cl:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]23[N:40]([C:13]([C:12]4[C:8]([CH3:7])=[N:9][O:10][CH:11]=4)=[O:15])[CH2:39][CH2:38][N:24]2[C:25](=[O:37])[C:26]2[N:27]([CH:29]=[C:30]([C:32]([N:34]([CH3:36])[CH3:35])=[O:33])[CH:31]=2)[CH2:28]3)=[CH:19][CH:18]=1
Reactant: CN(C)C(=O)c1cc2n(c1)CC1(c3ccc(Cl)cc3)NCCN1C2=O
Reactant: Cc1nocc1C(=O)O
Agent: O=C(Cl)C(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Solvent: c1ccncc1
Solvent: CN(C)C=O
Product: Cc1nocc1C(=O)N1CCN2C(=O)c3cc(C(=O)N(C)C)cn3CC12c1ccc(Cl)cc1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 20.7 %

Procedure:
To generate the acid chloride, oxalyl chloride (45 μL, 0.54 mmol) and DMF (1 drop) were added to a suspension of 3-methyl-1,2-oxazole-4-carboxylic acid (35 mg, 0.28 mmol) in CH2Cl2 (0.5 mL) at 0° C. The suspension was allowed to stir for a further 15 min at 0° C., followed by 2 h at room temperature. The resulting solution was concentrated in vacuo to give a oil that was twice suspended in n-hexanes (2×1 mL) and concentrated in vacuo. To a chilled (ice bath) suspension of the acid chloride (generated as above; 0.28 mmol) in pyridine (0.5 mL) and CH2Cl2 (0.5 mL) was added 10a-(4-chlorophenyl)-N,N-dimethyl-5-oxo-2,3,10,10a-tetrahydro-1H,5H-imidazo[1,2-a]pyrrolo[1,2-d]pyrazine-7-carboxamide (12 mg, 33 μmol) in pyridine (0.5 mL). The brown reaction mixture was warmed to room temperature and stirred for 16 h (monitored by LCMS). The reaction mixture was diluted with saturated aqueous solution of NaHCO3 (25 mL) and extracted with CH2Cl2 containing 20% of propan-2-01 (3×25 mL). The organic fractions were combined, dried (MgSO4) and concentrated in vacuo to yield a residue that was purified by flash chromatography (Biotage SP4.12 g cartridge; 0-10% MeOH gradient in CH2Cl2) and reverse phase chromatography (Biotage SP4, 12 g cartridge, C18 phase; 20-40% acetonitrile gradient in water) to give 10a-(4-chlorophenyl)-N,N-dimethyl-1-[(3-methyl-1,2-oxazol-4-yl)carbonyl]-5-oxo-2,3,10,10a-tetrahydro-1H,5H-imidazo[1,2-a]pyrrolo[1,2-d]pyrazine-7-carboxamide (38) as a white solid (3.2 mg, yield 20%).
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:6]=[C:7]([C:11]2[S:15][C:14]([CH2:16][NH:17][S:18]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[C:27]([F:30])([F:29])[F:28])(=[O:20])=[O:19])=[CH:13][CH:12]=2)[CH:8]=[CH:9][CH:10]=1)(=[O:4])=[O:3].Cl[CH2:32][C:33]1[C:34]([CH3:39])=[N:35][O:36][C:37]=1[CH3:38].C(=O)([O-])[O-].[Cs+].[Cs+]>[I-].C([N+](CCCC)(CCCC)CCCC)CCC.CN(C)C(=O)C>[CH3:39][C:34]1[C:33]([CH2:32][N:17]([CH2:16][C:14]2[S:15][C:11]([C:7]3[CH:8]=[CH:9][CH:10]=[C:5]([S:2]([CH3:1])(=[O:3])=[O:4])[CH:6]=3)=[CH:12][CH:13]=2)[S:18]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=2[C:27]([F:30])([F:28])[F:29])(=[O:20])=[O:19])=[C:37]([CH3:38])[O:36][N:35]=1
Reactant: CS(=O)(=O)c1cccc(-c2ccc(CNS(=O)(=O)c3ccccc3C(F)(F)F)s2)c1
Reactant: Cc1noc(C)c1CCl
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(=O)N(C)C
Product: Cc1noc(C)c1CN(Cc1ccc(-c2cccc(S(C)(=O)=O)c2)s1)S(=O)(=O)c1ccccc1C(F)(F)F

Procedure:
In analogy to example 10, step 3, N-[5-(3-methanesulfonyl-phenyl)-thiophen-2-ylmethyl]-2-trifluoromethyl-benzenesulfonamide (example 27, step 1) was reacted with 4-(chloromethyl)-3,5-dimethylisoxazole, cesium carbonate and 10 mol-% tetrabutylammonium iodide as a catalyst in N,N-dimethylacetamide to give N-(3,5-dimethyl-isoxazol-4-ylmethyl)-N-[5-(3-methanesulfonyl-phenyl)-thiophen-2-ylmethyl]-2-trifluoromethyl-benzenesulfonamide as a colorless semi-solid. MS: 584.6 ([M+H]+)
Reaction SMILES: [CH3:1][NH:2][C:3]1[N:8]=CC=C[N:4]=1.Br[CH2:10][C:11]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=O.O.NN.O>C(#N)C>[CH3:1][N:2]1[C:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:10][N:4]=[C:3]1[NH2:8]
Reactant: O=C(CBr)c1ccccc1
Reactant: CNc1ncccn1
Agent: NN
Solvent: O
Solvent: CC#N
Product: Cn1c(-c2ccccc2)cnc1N
Temperature: 130 °C

Procedure:
To a microwave vial containing a solution of N-methylpyrimidin-2-amine (90b, 290 mg, 2.7 mmol) in acetonitrile (5 mL) was added 2-bromo-1-phenylethanone (714 mg, 3.6 mmol). The vial was sealed and heated in a microwave reactor at 130° C. for 20 minutes and then cooled to room temperature. The reaction mixture was treated with hydrazine hydrate (0.65 mL, 13.3 mmol) and then heated in a microwave reactor at 100° C. for 5.0 minutes. The solution was poured into water and filtered the precipitate to give 1-methyl-5-phenyl-1H-imidazol-2-ylamine (90c).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[NH:9][C:10]([C:12]1[CH:13]=[C:14]([CH:16]=[C:17]([Cl:21])[C:18]=1[O:19][CH3:20])[NH2:15])=[O:11].C(N(CC)[C:25](Cl)=[S:26])C.ClC1C=CC=CC=1.O>C(Cl)Cl>[CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[NH:9][C:10]([C:12]1[CH:13]=[C:14]([N:15]=[C:25]=[S:26])[CH:16]=[C:17]([Cl:21])[C:18]=1[O:19][CH3:20])=[O:11]
Reactant: CCN(CC)C(=S)Cl
Reactant: COc1c(Cl)cc(N)cc1C(=O)Nc1c(C)cccc1C
Solvent: O
Solvent: ClCCl
Solvent: Clc1ccccc1
Product: COc1c(Cl)cc(N=C=S)cc1C(=O)Nc1c(C)cccc1C
Yield: 46 %

Procedure:
A mixture of 3-[N-(2,6-dimethylphenyl)carbamoyl]-4-methoxy-5-chloroaniline (650 mg), diethylthiocarbamoyl chloride (360 mg) and chlorobenzene (6 ml) is refluxed for 30 minutes. The reaction mixture is mixed with water and shaken with methylene chloride. The organic layer is washed with water, dried over Glauber's salt and concentrated to remove the solvent. The residue is chromatographed on a column of silica gel, which is eluted with methylene chloride. The eluted fractions are collected and the solvent is evaporated. The residue is recrystallized from ethyl acetate to give 3-[N-(2,6-dimethylphenyl)carbamoyl]-4-methoxy-5-chlorophenyl isothiocyanate (340 mg) as crystals melting at 191°-192.5° C.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[C:10]=2[CH2:11][N:12]2[CH2:16][CH:15]([CH2:17][CH2:18][CH3:19])[CH2:14][C:13]2=[O:20])[CH:7]=1.[O-:27]P([O-])([O-])=O.[K+].[K+].[K+]>O.[Pd]>[OH:27][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[C:10]=2[CH2:11][N:12]2[CH2:16][CH:15]([CH2:17][CH2:18][CH3:19])[CH2:14][C:13]2=[O:20])[CH:7]=1
Reactant: O=P([O-])([O-])[O-]
Reactant: CCCC1CC(=O)N(Cc2c(-c3ccccc3)nn3cc(Br)cnc23)C1
Agent: [Pd]
Agent: [K+]
Solvent: O
Product: CCCC1CC(=O)N(Cc2c(-c3ccccc3)nn3cc(O)cnc23)C1
Temperature: 130 °C
Reaction time: 8 h
Yield: 22 %

Procedure:
To a solution of 1-[(6-bromo-2-phenylpyrazolo[1,5-a]pyrimidin-3-yl)methyl]-4-propylpyrrolidin-2-one 186 (24 mmol, 1 eq, 10 g) in 100 ml of water are added successively palladium on activated carbon (10%, 1.2 mmol, 0.05 eq, 1.2 g) and K3PO4 (48 mmol, 2 eq, 10.25 g). The mixture is degassed and stirred vigorously at 130° C. for 8 hours. After cooling to room temperature, the reaction mixture is filtered on celite and a 5 N hydrochloric acid solution (10 ml) is added (until pH 7). The water is removed under reduce pressure and the crude is triturated with hot THF. After filtration and evaporation of THF, 1-[(6-hydroxy-2-phenyl pyrazolo[1,5-a]pyrimidin-3-yl)methyl]-4-propylpyrrolidin-2-one x149 is obtained (1.9 g).
Reaction SMILES: [NH2:1][C:2]1[C:11]2[CH2:10][CH2:9][CH2:8][CH2:7][C:6]=2[CH:5]=[CH:4][N:3]=1.C(O[CH:15]=[C:16]([C:22]#[N:23])[C:17]([O:19][CH2:20][CH3:21])=[O:18])C.CCCCCC>C1(C)C=CC=CC=1>[C:22]([C:16](=[CH:15][NH:1][C:2]1[C:11]2[CH2:10][CH2:9][CH2:8][CH2:7][C:6]=2[CH:5]=[CH:4][N:3]=1)[C:17]([O:19][CH2:20][CH3:21])=[O:18])#[N:23]
Reactant: Nc1nccc2c1CCCC2
Reactant: CCOC=C(C#N)C(=O)OCC
Solvent: CCCCCC
Solvent: Cc1ccccc1
Product: CCOC(=O)C(C#N)=CNc1nccc2c1CCCC2
Temperature: 105 °C
Yield: 75.6 %

Procedure:
A solution of 1-amino-5,6,7,8-tetrahydroisoquinoline [2.96 g., 0.02 mole; E. Ochiai and Y. Kawazoe, Pharm. Bull. (Tokyo), 5, 606 (1957)] and ethyl ethoxymethylenecyanoacetate (3.38 g., 0.02 mole) in toluene (8 ml.) was heated by means of an oil bath maintained at 105° C. for 15 minutes. The cooled solution was poured into Skellysolve B (175 ml.) with good stirring. The mixture was triturated and cooled with an ice bath. The mixture was filtered and the collected gummy solid recrystallized from cyclohexane to give the title compound (4.1 g., 75%), m.p. 116°-120° C. The product was recrystallized from cyclohexane to give analytical material, m.p. 121°-123° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([OH:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]([C:12]1[C:13](=[O:25])[N:14]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[N:15]([CH3:18])[C:16]=1[CH3:17])=[O:11].CC([O-])(C)C.[K+].CN(C=O)C.Cl[C:38]1[CH:43]=[CH:42][N:41]=[C:40]([C:44]([NH2:46])=[O:45])[CH:39]=1>CCOC(C)=O.O>[CH3:18][N:15]1[C:16]([CH3:17])=[C:12]([C:10]([NH:9][C:3]2[CH:4]=[CH:5][C:6]([O:8][C:38]3[CH:43]=[CH:42][N:41]=[C:40]([C:44]([NH2:46])=[O:45])[CH:39]=3)=[CH:7][C:2]=2[F:1])=[O:11])[C:13](=[O:25])[N:14]1[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: Cc1c(C(=O)Nc2ccc(O)cc2F)c(=O)n(-c2ccccc2)n1C
Reactant: NC(=O)c1cc(Cl)ccn1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: Cc1c(C(=O)Nc2ccc(Oc3ccnc(C(N)=O)c3)cc2F)c(=O)n(-c2ccccc2)n1C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 91.2 %

Procedure:
To a mixture of N-(2-fluoro-4-hydroxyphenyl)-1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazole-4-carboxamide (300 mg, 0.879 mmol) and t-BuOK (118 mg, 1.05 mmol) was added DMF (2.5 mL). The resulted mixture was stirred at rt for 30 minutes, then 4-chloropicolinamide (165 mg, 1.05 mmol) was added. The mixture was heated at 120° C. for 5 hours, then cooled to rt, and H2O (50 mL) and EtOAc (2 mL) was added. The resulted mixture was stirred at rt overnight. Filtered and the precipitation was washed with water (5 mL) to give the title compound as a dark brown solid (370 mg, 91.2%).
Reaction SMILES: [CH3:1][N:2]1[CH2:6][C@H:5]([CH2:7][OH:8])[C@H:4]([CH2:9][OH:10])[CH2:3]1.C(N(CC)CC)C.[CH3:18][S:19](Cl)(=[O:21])=[O:20]>ClCCl>[CH3:1][N:2]1[CH2:6][C@H:5]([CH2:7][O:8][S:19]([CH3:18])(=[O:21])=[O:20])[C@H:4]([CH2:9][O:10][S:19]([CH3:18])(=[O:21])=[O:20])[CH2:3]1
Reactant: CN1C[C@@H](CO)[C@@H](CO)C1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CN1C[C@@H](COS(C)(=O)=O)[C@@H](COS(C)(=O)=O)C1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 74.1 %

Procedure:
To an ice cooled solution of 6.2 gm (43 mMol) 1-methyl-cis-3,4-di(hydroxymethyl) pyrrolidine and 14.5 gm(143 mMol ) triethylamine in 200 mL dichloromethane was added a solution of 14.7 gm (129 mMol) methanesulfonyl chloride in 20 mL dichloromethane. Once this addition was complete the reaction mixture was stirred for 15 minutes at 0° C. and then for 1.5 hours at ambient. The reaction mixture was then quenched with dilute aqueous sodium hydroxide solution and then was extracted with dichloromethane. The organic phase was dried over sodium sulfate and then concentrated in vacuo to give 9.6 gm of the desired compound as an orange oil.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[C:11]([CH3:12])=[C:10]([CH3:13])[CH:9]=[C:7]([CH3:8])[C:6]=1[CH3:14])=[O:4].CN(C)C=O.[NH:20]1[CH:24]=[CH:23][N:22]=[CH:21]1>O>[N:20]1([CH2:2][C:3]([C:5]2[C:11]([CH3:12])=[C:10]([CH3:13])[CH:9]=[C:7]([CH3:8])[C:6]=2[CH3:14])=[O:4])[CH:24]=[CH:23][N:22]=[CH:21]1
Reactant: c1c[nH]cn1
Reactant: Cc1cc(C)c(C)c(C(=O)CBr)c1C
Solvent: O
Solvent: CN(C)C=O
Product: Cc1cc(C)c(C)c(C(=O)Cn2ccnc2)c1C
Temperature: 80 °C
Reaction time: 8 h
Yield: 61.9 %

Procedure:
A mixture containing 2.55 g of 3-bromoacetyl-durene, prepared as described in Example 4, 3 ml of dimethylformamide and 3.40 g of imidazole, was stirred for 8 hours at 80° C. At the end of the reaction, the mixture was cooled to room temperature and 25 ml of water were added. The precipitate thus obtained was filtered off, dried and crystallized from benzene to give 1.5 g of the title compound. M.P. 176°-8° C., yield 62%.