Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]2[CH2:18][C:17]([CH3:20])([CH3:19])[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([C:21](NS(C)(=O)=O)=[O:22])[CH:15]=3)[NH:10]2)[CH:6]=[CH:7][CH:8]=1.[OH-:28].[Na+].O.Cl>C(#N)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]2[CH2:18][C:17]([CH3:20])([CH3:19])[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([C:21]([OH:22])=[O:28])[CH:15]=3)[NH:10]2)[CH:6]=[CH:7][CH:8]=1
Reactant: [OH-]
Reactant: COc1cccc(C2CC(C)(C)c3cc(C(=O)NS(C)(=O)=O)ccc3N2)c1
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CC#N
Product: COc1cccc(C2CC(C)(C)c3cc(C(=O)O)ccc3N2)c1
Temperature: 60 °C
Reaction time: 12 h
Yield: 90.4 %

Procedure:
A mixture of N-[2-(3-methoxy-phenyl)-4,4-dimethyl-1,2,3,4-tetrahydro-quinoline-6-carbonyl]-methanesulfonamide (1.0 g, 2.95 mmol), sodium hydroxide (0.59 g, 14.75 mmol), water (15 mL) in acetonitrile (30 mL) was stirred at 60° C. for 12 h. The mixture was neutralized with a 3 N aqueous hydrochloric acid solution and extracted with ethyl acetate (2×50 mL), washed with water, dried over anhydrous sodium sulfate and then concentrated in vacuo to afford 2-(3-methoxy-phenyl)-4,4-dimethyl-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid (0.83 g, 90%) as a white solid which was used for next step without further purification: MS (ESI) M+1=312.2.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:9](=[O:11])[CH2:8][C:7]([CH3:13])([CH3:12])[CH2:6][C:5]=2[C:4]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[N:3]1.[O-:19][CH2:20]C.[Na+].O>C(OCC)=O>[OH:19][CH:20]=[C:8]1[C:9](=[O:11])[C:10]2[N:2]([CH3:1])[N:3]=[C:4]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[C:5]=2[CH2:6][C:7]1([CH3:13])[CH3:12]
Reactant: CC[O-]
Reactant: CCOC(=O)c1nn(C)c2c1CC(C)(C)CC2=O
Agent: [Na+]
Solvent: O
Solvent: CCOC=O
Product: CCOC(=O)c1nn(C)c2c1CC(C)(C)C(=CO)C2=O
Temperature: 25 °C
Yield: 79.1 %

Procedure:
A solution of ethyl 1,5,5-trimethyl-7-oxo-4,5,6,7-tetrahydro-1H-indazole-3-carboxylate (1.00 g, 4 mmol) in anhydrous ethyl formate (10 mL) was treated with sodium ethoxide (0.54 g, 8 mmol) and refluxed for 3 hours. The mixture was cooled to room temperature and poured into cold water (40 mL). The aqueous layer was washed with diethyl ether (40 mL) to remove unreacted starting material, acidified with a 20% NaH2PO4 solution and extracted with ethyl acetate (50 mL×2). The organic extracts were collected, dried on Na2SO4 and evaporated to dryness to obtain the title compound (0.88 g, 78.8% yield) as a brown solid.
Reaction SMILES: [CH2:1]([N:4]([CH:12]([C:33]1[CH:38]=[CH:37][C:36]([O:39][C:40](=[O:44])[N:41]([CH3:43])[CH3:42])=[CH:35][C:34]=1C=C)[CH2:13][CH2:14][O:15][Si:16]([C:29]([CH3:32])([CH3:31])[CH3:30])([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:5](=[O:11])[O:6][C:7]([CH3:10])([CH3:9])[CH3:8])[CH:2]=[CH2:3]>ClCCl.CC1C=C(C)C(N2[CH-]N(C3C(C)=CC(C)=CC=3C)CC2)=C(C)C=1.C1CCC([PH+](C2CCCCC2)C2CCCCC2)CC1.C1C=CC(C=[Ru](Cl)Cl)=CC=1>[C:29]([Si:16]([C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1)([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[O:15][CH2:14][CH2:13][CH:12]1[C:33]2[CH:34]=[CH:35][C:36]([O:39][C:40](=[O:44])[N:41]([CH3:42])[CH3:43])=[CH:37][C:38]=2[CH:3]=[CH:2][CH2:1][N:4]1[C:5]([O:6][C:7]([CH3:8])([CH3:10])[CH3:9])=[O:11])([CH3:31])([CH3:30])[CH3:32]
Reactant: C=CCN(C(=O)OC(C)(C)C)C(CCO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C)c1ccc(OC(=O)N(C)C)cc1C=C
Agent: Cl[Ru](Cl)=Cc1ccccc1
Agent: C1CCC([PH+](C2CCCCC2)C2CCCCC2)CC1
Agent: Cc1cc(C)c(N2[CH-]N(c3c(C)cc(C)cc3C)CC2)c(C)c1
Solvent: ClCCl
Product: CN(C)C(=O)Oc1ccc2c(c1)C=CCN(C(=O)OC(C)(C)C)C2CCO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C
Temperature: 45 °C
Reaction time: 3 h
Yield: 95.8 %

Procedure:
To a solution of t-butyl allyl-[3-(t-butyl-diphenyl-silanyloxy)-1-(4-dimethylcarbamoyloxy-2-vinyl-phenyl)-propyl]-carbamate (360 mg, 0.56 mmol) synthesized in step (j) of Example 192 in dichloromethane (40 ml) was added tricyclohexylphosphine [1,3-bis(2,4,6-trimethylphenyl)-4,5-dihydroimidazol-2-ylidene] [benzylidene] ruthenium(IV) dichloride (47.5 mg, 0.0560 mmol), and the resulting mixture was stirred for 3 hours at 45° C. under a nitrogen atmosphere. After stirring, the reaction mixture was evaporated in vacuo, and the residue was purified by chromatography on a silica gel column using a mixed solvent of hexane and ethyl acetate (5:1-2:1) as the eluent to afford the title compound (330 mg, yield: 96%) as a colorless oil
Reaction SMILES: [CH:1]1([N:6]2[CH2:12][C:11]([F:14])([F:13])[C:10](=[O:15])[N:9]([CH3:16])[C:8]3[CH:17]=[N:18][C:19]([NH:21][C:22]4[C:30]([F:31])=[CH:29][C:25]([C:26]([OH:28])=O)=[C:24]([F:32])[CH:23]=4)=[N:20][C:7]2=3)[CH2:5][CH2:4][CH2:3][CH2:2]1.ON1C2C=CC=CC=2N=N1.F[P-](F)(F)(F)(F)F.CN(C(N(C)C)=[N+]1C2C=CC=CC=2[N+]([O-])=N1)C.C(N(C(C)C)CC)(C)C.[NH2:76][CH:77]1[CH2:82][CH2:81][N:80]([CH2:83][CH3:84])[CH2:79][CH2:78]1>CN(C)C=O>[CH:1]1([N:6]2[CH2:12][C:11]([F:13])([F:14])[C:10](=[O:15])[N:9]([CH3:16])[C:8]3[CH:17]=[N:18][C:19]([NH:21][C:22]4[C:30]([F:31])=[CH:29][C:25]([C:26]([NH:76][CH:77]5[CH2:82][CH2:81][N:80]([CH2:83][CH3:84])[CH2:79][CH2:78]5)=[O:28])=[C:24]([F:32])[CH:23]=4)=[N:20][C:7]2=3)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CN1C(=O)C(F)(F)CN(C2CCCC2)c2nc(Nc3cc(F)c(C(=O)O)cc3F)ncc21
Reactant: CCN1CCC(N)CC1
Agent: CN(C)C(N(C)C)=[N+]1N=[N+]([O-])c2ccccc21
Agent: F[P-](F)(F)(F)(F)F
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCN1CCC(NC(=O)c2cc(F)c(Nc3ncc4c(n3)N(C3CCCC3)CC(F)(F)C(=O)N4C)cc2F)CC1
Reaction time: 0.17 h
Yield: 70.2 %

Procedure:
To a mixture of 0.0606 g (0.134 mmole) of 4-(9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-2,5-difluoro-benzoic acid (I-232) and 4 mL of dimethylformamide was added 0.0292 g (0.216 mmole) of 1-hydroxybenzotriazole, 0.0784 g (0.207 mmole) of 1-[bis(dimethylamino)methylene]-1H-benzotriazolium-3-oxide hexafluorophosphate and 0.1083 g (0.804 mmole) of diisopropylethylamine. The mixture was stirred for 10 minutes, then 0.0256 g (0.20 mmole) of 4-amino-1-ethylpiperidine was added. The reaction mixture was stirred for 2 hours and then concentrated under reduced pressure. The residue was dissolved in 80 mL of ethyl acetate and washed three times with 10 mL of 1M sodium hydroxide, twice with 15 mL of brine, dried, filtered and concentrated under reduced pressure. Purification by silica gel chromatography, eluting with dichloromethane-methanol (gradient, 95:5-80:20) gave 0.053 g of 4-(9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-N-(1-ethyl-piperidin-4-yl)-2,5-difluoro-benzamide (I-234) as a white solid.
Reaction SMILES: [NH2:1][C:2]1[C:7]2[C:8](=[O:18])[C:9]3[CH:17]=[CH:16][CH:15]=[CH:14][C:10]=3[NH:11][C:12](=[O:13])[C:6]=2[CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[CH3:21]I.O>CN(C)C=O>[NH2:1][C:2]1[C:7]2[C:8](=[O:18])[C:9]3[CH:17]=[CH:16][CH:15]=[CH:14][C:10]=3[N:11]([CH3:21])[C:12](=[O:13])[C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: CI
Reactant: Nc1cccc2c(=O)[nH]c3ccccc3c(=O)c12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cn1c(=O)c2cccc(N)c2c(=O)c2ccccc21

Procedure:
To 5 g 10-amino-5,6-dihydro-11H-dibenzo(b,e)azepine-6,11-dione in 25 ml dimethylformamide are added 0.8 g 60% sodium hydride in mineral oil and then 1.5 ml methyl iodide. After leaving for 24 hours at ambient temperature, with stirring, the mixture is poured into water, filtered and dried: melting point 171°-3° C. (water).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[S:9][CH:10]=[CH:11][CH:12]=1.[Br:13][C:14]1[CH:15]=[CH:16][C:17]([F:22])=[C:18]([CH:21]=1)[CH:19]=O>>[Br:13][C:14]1[CH:15]=[CH:16][C:17]([F:22])=[C:18]([CH2:19][C:10]2[S:9][C:8]([C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=3[F:1])=[CH:12][CH:11]=2)[CH:21]=1
Reactant: O=Cc1cc(Br)ccc1F
Reactant: Fc1ccccc1-c1cccs1
Product: Fc1ccc(Br)cc1Cc1ccc(-c2ccccc2F)s1

Procedure:
2-(2-Fluorophenyl)thiophene obtained in Reference Example 66-(1) and 5-bromo-2-fluorobenzaldehyde were treated in a manner similar to Reference Example 7 to give the target compound. APCI-Mass m/Z 365/367 (M+H).
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].[Cl:5][C:6]1[NH:7][C:8]2[CH:14]=[CH:13][CH:12]=[CH:11][C:9]=2[N:10]=1>>[Cl:5][C:6]1[NH:7][C:8]2[CH:14]=[C:13]([N+:1]([O-:4])=[O:2])[CH:12]=[CH:11][C:9]=2[N:10]=1
Reactant: O=[N+]([O-])O
Reactant: Clc1nc2ccccc2[nH]1
Product: O=[N+]([O-])c1ccc2nc(Cl)[nH]c2c1
Reaction time: 8 h

Procedure:
To 21 0 mL of fuming HNO3, 2-chlorobenzimidazole (13.42 g, 87.95 mmole) was added portionwise over a period of 10 min with stirring and ice-H2O cooling. After the addition, the cooling bath was removed and stirring was continued at room temperature overnight. This reaction mixture was cooled to ~ 0° C., poured into 300 mL of ice, and neutralized carefully with conc. NH4OH to ~ pH 8. The resulting suspension was filtered. The yellowish solid product was washed with portions of H2O and air-dried. The filtrate and washings were combined and extracted with EtOAc (200 mL×2). The EtOAc solution was washed with sat. NaCl solution (200 mL×2), dried (Na2SO4), and evaporated to give 1.3 g of a yellowish solid. The solid was combined with the major part of the product and was recrystallized from MeOH to give 16.34 g (5 crops, 94%) of 19 as yellowish crystals. mp 235°-237° C. MS (El) m/e 196.9984 (100%, M+ =196.9992). 1H NMR (DMSO-d6) d 14.06 (br. s, 1, 1-NH), 8.41 (s, 1, 4-H), 8.14 (dd,. 1, 6-H, J6-4 =2.0 Hz, J6-7 =9.0 Hz), 7.71 (d, 1, 7-H).
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[C:11](=[O:15])[NH:10][C:9](=[O:16])[CH2:8]2)([CH3:4])([CH3:3])[CH3:2].[CH3:17][O:18][CH:19](OC)OC>CN(C)C=O.C(OC(=O)C)(=O)C>[C:1]([C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[C:11](=[O:15])[NH:10][C:9](=[O:16])[C:8]2=[CH:17][O:18][CH3:19])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1ccc2c(c1)CC(=O)NC2=O
Reactant: COC(OC)OC
Solvent: CN(C)C=O
Solvent: CC(=O)OC(C)=O
Product: COC=C1C(=O)NC(=O)c2ccc(C(C)(C)C)cc21
Temperature: 120 °C

Procedure:
6-tert-Butyl-4H-isoquinoline-1,3-dione (45 mg, 0.21 mmol) is dissolved in N,N-dimethylformamide (1 mL) and acetic anhydride (2 mL). Trimethylorthoformate (0.2 mL) is added and the mixture is heated to 120° C. for 1 hour. The volatiles were removed under vacuum and the residue passed through a column to afford the crude product, is used directly in the next step. MS (ESI): 258.3 (M−1)−1.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:12]([C:13]([O:15]CC)=[O:14])=[CH:11][N:10]([CH3:18])[N:9]=1.[OH-].[K+].O>C(O)C>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:12]([C:13]([OH:15])=[O:14])=[CH:11][N:10]([CH3:18])[N:9]=1
Reactant: CCOC(=O)c1cn(C)nc1-c1ccccc1Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: Cn1cc(C(=O)O)c(-c2ccccc2Cl)n1
Temperature: 25 °C
Reaction time: 72 h
Yield: 94.8 %

Procedure:
A mixture of 0.72 g of ethyl 3-(2-chlorophenyl)-1-methyl-1H-pyrazole-4-carboxylate, 0.23 g of potassium hydroxide, 1 ml of water and 5 ml of ethanol was stirred at room temperature for 3 days. After the reaction mixture was concentrated under reduced pressure, water was poured into the resulting residue and the mixture was washed with methyl tert-butyl ether. The aqueous layer was adjusted to around pH 3 by an addition of a 10% aqueous citric acid, and then extracted with ethyl acetate. The organic layer was washed with water, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain 0.61 g of 3-(2-chlorophenyl)-1-methyl-1H-pyrazole-4-carboxylic acid of the formula:
Reaction SMILES: [CH:1]1[C:9]([Br:10])=[CH:8][N:7]2[C:3](=[N:4][CH:5]=[CH:6]2)[CH:2]=1.C[O:12][C:13]1[C:18]2C=CNC=2N=C(N)[N:14]=1.N1C=CC=CC=1.CC(OCC1C2C(=CC=CC=2)C(COC(C)=O)=C2C=1C=CC=C2)=O>CN(C1C=CN=CC=1)C.C(Cl)Cl>[Br:10][C:9]1[CH:1]=[CH:2][C:3]2[N:7]([CH:6]=[C:5]([NH:14][C:13](=[O:12])[CH3:18])[N:4]=2)[CH:8]=1
Reactant: Brc1ccc2nccn2c1
Reactant: COc1nc(N)nc2[nH]ccc12
Agent: CC(=O)OCc1c2ccccc2c(COC(C)=O)c2ccccc12
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(=O)Nc1cn2cc(Br)ccc2n1
Temperature: 35 °C
Reaction time: 3 h
Yield: 49.4 %

Procedure:
To a 100 mL round-bottomed flask was added 6-bromoH-imidazo[1,2-a]pyridin-2-amine (0.771 g, 3.6 mmol), DCM (30 mL), pyridine (0.44 mL, 5.5 mmol), acetic anhyride (0.41 mL, 4.4 mmol) and DMAP (0.0022 g, 0.018 mmol). The mixture was stirred at 35° C. for 3 h. After cooling to rt, the mixture was concentrated and then taken up in water (100 mL) and extracted with 25% iPrOH/CHCl3 (3×75 mL). The combined extracts were washed with brine (75 mL), dried (Na2SO4) and concentrated in vacuo. The residue was dissolved in MeOH (2 M in NH3)/CH2Cl2 and concentrated onto silica. Purification by silica gel chromatography MeOH (2 M in NH3)/CH2Cl2) afforded the title compound as an orange solid (0.452 g, 49%). MS (ESI, positive ion) m/z: 254 (M(79Br)+1).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:16][C:17]([CH3:32])([CH3:31])[CH2:18][CH2:19][O:20][Si:21]([CH:28]([CH3:30])[CH3:29])([CH:25]([CH3:27])[CH3:26])[CH:22]([CH3:24])[CH3:23])[C@@H:10]([OH:15])[CH2:11][CH2:12][CH:13]=[CH2:14])=[O:7])([CH3:4])([CH3:3])[CH3:2].CO[C:35](OC)([CH3:37])[CH3:36].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[C@@H:9]([CH2:16][C:17]([CH3:31])([CH3:32])[CH2:18][CH2:19][O:20][Si:21]([CH:25]([CH3:26])[CH3:27])([CH:22]([CH3:23])[CH3:24])[CH:28]([CH3:30])[CH3:29])[C@H:10]([CH2:11][CH2:12][CH:13]=[CH2:14])[O:15][C:35]1([CH3:37])[CH3:36])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: C=CCC[C@H](O)[C@H](CC(C)(C)CCO[Si](C(C)C)(C(C)C)C(C)C)NC(=O)OC(C)(C)C
Reactant: COC(C)(C)OC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: ClCCl
Solvent: O
Product: C=CCC[C@@H]1OC(C)(C)N(C(=O)OC(C)(C)C)[C@H]1CC(C)(C)CCO[Si](C(C)C)(C(C)C)C(C)C

Procedure:
1.80 g of 6(S)-tert-butoxycarbonylamino-8,8-dimethyl-5(S)-hydroxy-10-triisopropylsilyloxydec1-ene are stirred in 10 ml each of methylene chloride and dimethoxypropane with 50 mg of p-toluenesulfonic acid hydrate at room temperature for 2 h. After the mixture has been concentrated, the residue is purified over 250 g of silica gel with a 1:20 mixture of ethyl acetate and hexane as the mobile phase: Rf (1:20 mixture of ethyl acetate and hexane)=0.40.
Reaction SMILES: Cl.[NH2:2][C:3]1[CH:8]=[CH:7][C:6]([F:9])=[CH:5][C:4]=1[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.[CH3:16][N:17]([CH3:20])[C:18]#[N:19].C1C(O)=CC=CC=1C>>[F:9][C:6]1[CH:7]=[CH:8][C:3]([NH:2][C:18]([N:17]([CH3:20])[CH3:16])=[NH:19])=[C:4]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:5]=1
Reactant: CN(C)C#N
Reactant: Nc1ccc(F)cc1-c1ccccc1
Agent: Cl
Solvent: Cc1cccc(O)c1
Product: CN(C)C(=N)Nc1ccc(F)cc1-c1ccccc1

Procedure:
A mixture of 2-amino-5-fluorobiphenyl hydrochloride (3.6 g), N,N-dimethylcyanamide (1.68 g) and m-cresol (25 ml) was heated at 90°-95° C. for 8 hours to give N-(5-fluoro-2-biphenylyl)-N',N'-dimethylguanidine (m.p. 160°-161° C.) which was recrystallised from hexane.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[N:9]1[CH:13]=[CH:12][C:11]([CH3:14])=[N:10]1.BrC1C=CC(Cl)=CC=1N1C(C)=CC=N1.C([Mg]Cl)(C)C.C=O.CN([CH:39]=[O:40])C>C1COCC1>[Cl:8][C:5]1[CH:6]=[CH:7][C:2]([CH:39]=[O:40])=[C:3]([N:9]2[CH:13]=[CH:12][C:11]([CH3:14])=[N:10]2)[CH:4]=1
Reactant: CN(C)C=O
Reactant: Cc1ccn(-c2cc(Cl)ccc2Br)n1
Agent: C=O
Agent: CC(C)[Mg]Cl
Agent: Cc1ccnn1-c1cc(Cl)ccc1Br
Solvent: C1CCOC1
Product: Cc1ccn(-c2cc(Cl)ccc2C=O)n1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
1-(2-bromo-5-chlorophenyl)-3-methyl-1H-pyrazole/1-(2-bromo-5-chlorophenyl)-5-methyl-1H-pyrazole mixture (Intermediate 3, step 1) (1.00 g, 3.68 mmol) was dissolved in THF (6 mL) then cooled to 0° C. i-Propyl magnesium chloride (2.76 mL, 2.0 M in THF, 5.52 mmol) was added dropwise and the reaction was warmed to RT for 30 min. The reaction was then cooled to −15° C. and paraformaldehyde (166 mg, 5.5 mmol) was added. The reaction mixture was allowed to warm to RT and stirred for 1 h. DMF (500 mL) was added and the reaction was stirred for an additional 1 h. The reaction was quenched with HCl (2 N, 4 mL), diluted with water, extracted with EtOAc, washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo. Purification by normal phase silica gel column chromatography (EtOAc/heptane) provided 4-chloro-2-(3-methyl-pyrazol-1-yl)-benzaldehyde.
Reaction SMILES: [CH2:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([CH:14]([CH3:19])[C:15]([O:17][CH3:18])=[O:16])=[CH:11][CH:12]=2)[CH:7]=[CH:6][C:5]1([CH3:21])[CH3:20])[CH:2]=[CH2:3].C(O)C>[H][H].[Pd]>[CH3:21][C:5]1([CH3:20])[CH2:6][CH2:7][C:8]2[C:13](=[CH:12][CH:11]=[C:10]([CH:14]([CH3:19])[C:15]([O:17][CH3:18])=[O:16])[CH:9]=2)[N:4]1[CH2:1][CH2:2][CH3:3]
Reactant: C=CCN1c2ccc(C(C)C(=O)OC)cc2C=CC1(C)C
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: CCCN1c2ccc(C(C)C(=O)OC)cc2CCC1(C)C
Yield: 80 %

Procedure:
3.7 g of methyl 2-(1-allyl-1,2-dihydro-2,2-dimethylquinolin-6-yl)propionate (Compound 20) was added to ethanol. Palladium-on-carbon was further added to the solution, and the mixture were reacted with stirring at room temperature for 20 hours under atmospheric pressure in hydrogen atmosphere. After the catalyst was filtered off, the filtrate was concentrated, and then purified by column chromatography on silica gel (ether:hexane=1:4) to give 3.0 g of methyl 2-(1,2,3,4-tetrahydro-2,2-dimethyl-1-propylquinolin-6-yl)propionate (Compound 14).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5](/[CH:8]=[CH:9]/[C:10]2[CH:11]=[C:12]([CH:16]=[CH:17][C:18]=2[O:19][CH3:20])[C:13](O)=[O:14])=[CH:4][CH:3]=1.Cl.[CH3:22][NH2:23]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5](/[CH:8]=[CH:9]/[C:10]2[CH:11]=[C:12]([CH:16]=[CH:17][C:18]=2[O:19][CH3:20])[C:13]([NH:23][CH3:22])=[O:14])=[CH:4][CH:3]=1
Reactant: COc1ccc(C(=O)O)cc1/C=C/c1ccc(Cl)cc1
Reactant: CN
Agent: Cl
Product: CNC(=O)c1ccc(OC)c(/C=C/c2ccc(Cl)cc2)c1

Procedure:
The captioned compound was synthesized from 3-[(E)-2-(4-chlorophenyl)vinyl]-4-methoxy-benzoic acid and methylamine hydrochloride in accordance with the same procedure as in the manufacturing method described in step G of Example 1-2-1.
Reaction SMILES: [CH:1]1([O:6][C:7]2[CH:8]=[C:9]([CH:12]=[CH:13][C:14]=2[O:15][CH3:16])[CH:10]=[O:11])[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:17][Li]>O1CCCC1>[CH3:17][CH:10]([OH:11])[C:9]1[CH:12]=[CH:13][C:14]([O:15][CH3:16])=[C:7]([O:6][CH:1]2[CH2:2][CH2:3][CH2:4][CH2:5]2)[CH:8]=1
Reactant: COc1ccc(C=O)cc1OC1CCCC1
Reactant: [Li]C
Solvent: C1CCOC1
Product: COc1ccc(C(C)O)cc1OC1CCCC1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 98.8 %

Procedure:
To a magnetically-stirred solution of 3-cyclopentyloxy-4-methoxybenzaldehyde (59.0 mmol, 13.0 g) in dry tetrahydrofuran (500 mL) at -78° C. is added methyllithium (100 mmol, 90.0 mL; 1.4M solution in ethyl ether) dropwise over 30 minutes. The resulting solution is stirred at -78° C. for 30 minutes and quenched at -78° C. by the rapid addition of aqueous saturated NH4Cl (140 mL). After warming to room temperature, water is added to dissolve the solids and the tetrahydrofuran was removed in vacuo. The residue is partitioned between water (500 mL) and ethyl acetate (500 mL), the aqueous phase extracted with ethyl acetate (500 mL) and the combined organic layers are washed with water (500 mL). The organics are dried (Na2SO4) and concentrated in vacuo to afford the title compound as a light yellow oil (58.3 mmol, 13.7 g; 99%). This material is of sufficient purity by TLC and NMR to be used as such in the subsequent transformation.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]1[CH2:14][C@@H:13]([F:15])[CH2:12][N:11]([C:16](OCC2C=CC=CC=2)=O)[CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CCN(C(C)C)C(C)C.ClC1[CH:41]=[CH:40][N:39]=[CH:38][C:37]=1[N+:42]([O-:44])=[O:43]>[Pd].CO>[F:15][C@H:13]1[CH2:12][N:11]([C:16]2[CH:41]=[CH:40][N:39]=[CH:38][C:37]=2[N+:42]([O-:44])=[O:43])[CH2:10][C@@H:9]([NH:8][C:6](=[O:7])[O:5][C:1]([CH3:2])([CH3:3])[CH3:4])[CH2:14]1
Reactant: O=[N+]([O-])c1cnccc1Cl
Reactant: CC(C)(C)OC(=O)N[C@H]1C[C@@H](F)CN(C(=O)OCc2ccccc2)C1
Agent: [Pd]
Solvent: CO
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N[C@H]1C[C@@H](F)CN(c2ccncc2[N+](=O)[O-])C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 90 %

Procedure:
To a solution of (3S,5R)-benzyl 3-(tert-butoxycarbonylamino)-5-fluoropiperidine-1-carboxylate (1 eq) in 28 methanol was added 10% Pd/C (0.1 eq). The resulting suspension was stirred at H2 atmosphere for 1 hours. The crude solids were filtered through a pad of Celite on a paper lined Buchner funnel, washed with MeOH, then concentrated in vacuo. The residue was dissolved in 33 mL of isopropanol and DIPEA (2.5 eq) and 4-chloro-3-nitropyridine (1.5 eq) were added. The reaction mixture was stirred at 80° C. for 2 hours, at which point the reaction mixture was allowed to cool to room temperature and concentrated under reduced pressure. The residue was diluted with 150 mL of EtOAc, washed with brine, then dried over anhydrous MgSO4, filtered, and concentrated in vacuo. The crude residue was purified by flash chromatography (5% methanol in EtOAc:hexanes=1:1) to yield tert-butyl(3S,5R)-5-fluoro-1-(3-nitropyridin-4-yl)piperidin-3-ylcarbamate (90%). LC/MS (m/z): 341.1 (MH+). HPLC: Rt: 2.12 min.
Reaction SMILES: [NH2:1][C@@H:2]([CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:3]([NH:5][C:6]1[C:11]([CH:12]([CH3:14])[CH3:13])=[CH:10][CH:9]=[CH:8][C:7]=1[CH:15]([CH3:17])[CH3:16])=[O:4].[CH:25](=O)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.O>C1(C)C=CC=CC=1.[Ni]>[CH3:13][CH:12]([C:11]1[CH:10]=[CH:9][CH:8]=[C:7]([CH:15]([CH3:16])[CH3:17])[C:6]=1[NH:5][C:3](=[O:4])[C@@H:2]([NH:1][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[CH2:18][C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1)[CH3:14]
Reactant: CC(C)c1cccc(C(C)C)c1NC(=O)[C@@H](N)Cc1ccccc1
Reactant: O=Cc1ccccc1
Agent: [Ni]
Solvent: O
Solvent: Cc1ccccc1
Product: CC(C)c1cccc(C(C)C)c1NC(=O)[C@H](Cc1ccccc1)NCc1ccccc1
Temperature: 25 °C
Reaction time: 1.37 h
Yield: 21 %

Procedure:
A solution of (S)-α-amino-N-[2,6-bis(1-Methylethyl)phenyl]benzenepropanamide (1.0 g, 3.1 mmol) and benzaldehyde (0.33 g, 3.1 mmol) in toluene (100 mL) was heated under reflux for 1 hour with the azeotropic removal of water then cooled (25° C.). To the resulting solution was added one equivalent of Raney nickel, and the resulting slurry was shaken vigorously under hydrogen (53 psi, 82 min 25° C.). The resulting slurry was filtered, and the filtrate was concentrated. The resulting oil was triturated with ether/hexane (1:1), and the resulting precipitate was collected by filtration to yield 0.27 g (21%) of the title compound, mp 120°-124° C.
Reaction SMILES: [NH3:1].C([O:4][C:5](=O)[CH2:6][S:7]([NH:10][C:11]1[CH:16]=[C:15]([CH:17]([S:26]([C:29]2[CH:34]=[CH:33][C:32]([Cl:35])=[CH:31][CH:30]=2)(=[O:28])=[O:27])[C:18]2[CH:23]=[C:22]([F:24])[CH:21]=[CH:20][C:19]=2[F:25])[C:14]([Cl:36])=[CH:13][N:12]=1)(=[O:9])=[O:8])C>CO>[Cl:36][C:14]1[C:15]([CH:17]([S:26]([C:29]2[CH:30]=[CH:31][C:32]([Cl:35])=[CH:33][CH:34]=2)(=[O:28])=[O:27])[C:18]2[CH:23]=[C:22]([F:24])[CH:21]=[CH:20][C:19]=2[F:25])=[CH:16][C:11]([NH:10][S:7]([CH2:6][C:5]([NH2:1])=[O:4])(=[O:8])=[O:9])=[N:12][CH:13]=1
Reactant: CCOC(=O)CS(=O)(=O)Nc1cc(C(c2cc(F)ccc2F)S(=O)(=O)c2ccc(Cl)cc2)c(Cl)cn1
Reactant: N
Solvent: CO
Product: NC(=O)CS(=O)(=O)Nc1cc(C(c2cc(F)ccc2F)S(=O)(=O)c2ccc(Cl)cc2)c(Cl)cn1
Temperature: 25 °C
Reaction time: 72 h
Yield: 89 %

Procedure:
To a methanol solution (5 ml) of 7N ammonia was added the ethyl[[[5-chloro-[(4-chlorophenylsulfonyl)(2,5-difluorophenyl)methyl]pyridin-2-yl]amino]sulfonyl]acetate (78 mg, 0.135 mmol) obtained in Example 283. The resulting mixture was stirred at room temperature for 3 days, followed by concentration under reduced pressure. The residue thus obtained was subjected to flash silica gel column chromatography. The fraction obtained from the methanol:methylene chloride (=1:25) eluate was concentrated under reduced pressure to give the title compound (66 mg, 0.120 mmol, 89%) as a white solid.
Reaction SMILES: [O:1]1[C@@:5]2([CH:10]3[CH2:11][CH2:12][N:7]([CH2:8][CH2:9]3)[CH2:6]2)[CH2:4][NH:3][C:2]1=[O:13].Br[C:15]1[O:16][CH:17]=[CH:18][CH:19]=1>>[O:16]1[CH:17]=[CH:18][CH:19]=[C:15]1[N:3]1[CH2:4][C@:5]2([CH:10]3[CH2:11][CH2:12][N:7]([CH2:8][CH2:9]3)[CH2:6]2)[O:1][C:2]1=[O:13]
Reactant: Brc1ccco1
Reactant: O=C1NC[C@@]2(CN3CCC2CC3)O1
Product: O=C1O[C@]2(CN3CCC2CC3)CN1c1ccco1

Procedure:
The title compound was prepared by a method analogous to that described in Preparation 3 from (S)-spiro[1-azabicyclo[2.2.2]octan-3,5′-oxazolidin]-2′-one and 2-bromofuran. The title compound (1.49 g) was obtained as a pale-yellow solid, m/z 249 (MH+).