Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:16][CH2:15][C:14]2[NH:13][C:12]3[N:17]=[CH:18][C:19](Cl)=[CH:20][C:11]=3[C:10]=2[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[O:22]([C:29]1[CH:35]=[CH:34][C:32]([NH2:33])=[CH:31][CH:30]=1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C.[OH-].[K+]>C(O)(CC)(C)C.CC([O-])=O.CC([O-])=O.[Pd+2]>[C:1]([O:5][C:6]([N:8]1[CH2:16][CH2:15][C:14]2[NH:13][C:12]3[N:17]=[CH:18][C:19]([NH:33][C:32]4[CH:31]=[CH:30][C:29]([O:22][C:23]5[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=5)=[CH:35][CH:34]=4)=[CH:20][C:11]=3[C:10]=2[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCc2[nH]c3ncc(Cl)cc3c2C1
Reactant: Nc1ccc(Oc2ccccc2)cc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Solvent: CCC(C)(C)O
Product: CC(C)(C)OC(=O)N1CCc2[nH]c3ncc(Nc4ccc(Oc5ccccc5)cc4)cc3c2C1
Temperature: 95 °C
Reaction time: 8 h
Yield: 26.7 %

Procedure:
3-Chloro-5,7,8,9-tetrahydro-dipyrido[2,3-b;3′,4′-d]pyrrole-6-carboxylic acid tert-butyl ester (100 mg, 0.32 mmol), 4-phenoxyaniline (120 mg, 0.65 mmol), Pd(OAc)2 (3 mg, 0.01 mmol), X-Phos (12 mg, 0.03 mmol), and KOH (0.03 ml, 0.97 mmol) were suspended in tert-amyl alcohol (2 mL), and stirred overnight at 95° C. The crude mixture was added directly to a Biotage column. The crude product was purified via Biotage eluting with a gradient of 0 to 100% EtOAc in hexanes to provide 43 (39 mg, 26% yield) as a brown solid. LC-MS (M+H=457, obsd.=457).
Reaction SMILES: [Cl:1][C:2]1[C:7](F)=[C:6]([S:9]([CH2:12][CH3:13])(=[O:11])=[O:10])[CH:5]=[CH:4][C:3]=1[NH:14][C:15](=[O:23])[C@:16]([OH:22])([CH3:21])[C:17]([F:20])([F:19])[F:18].[C:24]([N:27]1[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1)(=[O:26])[CH3:25]>CN1C(=O)CCC1>[Cl:1][C:2]1[C:7]([N:30]2[CH2:31][CH2:32][N:27]([C:24](=[O:26])[CH3:25])[CH2:28][CH2:29]2)=[C:6]([S:9]([CH2:12][CH3:13])(=[O:11])=[O:10])[CH:5]=[CH:4][C:3]=1[NH:14][C:15](=[O:23])[C@:16]([OH:22])([CH3:21])[C:17]([F:20])([F:19])[F:18]
Reactant: CC(=O)N1CCNCC1
Reactant: CCS(=O)(=O)c1ccc(NC(=O)[C@@](C)(O)C(F)(F)F)c(Cl)c1F
Solvent: CN1CCCC1=O
Product: CCS(=O)(=O)c1ccc(NC(=O)[C@@](C)(O)C(F)(F)F)c(Cl)c1N1CCN(C(C)=O)CC1
Temperature: 147 °C
Yield: 34.8 %

Procedure:
(R)-N-[2-Chloro-3-fluoro-4-(ethylsulphonyl)phenyl]-2-hydroxy-2-methyl-3,3,3-trifluoropropanamide (Example 15; 2.0 g) was added to a solution of 1-acetylpiperazine (2.0 g, 3 eq) in anhydrous NMP (3 ml) under argon and the mixture was stirred and heated to 147° C. for 24 hours. The reaction mixture was cooled and partitioned between a saturated aqueous solution of ammonium chloride (80 ml) and ether (4×200 ml). The combined ether extracts were washed with brine (200 ml), dried and concentrated to give a gum. The residue was purified by chromatography on a Mega Bond Elut column (50 g) eluting with 0-4% MeOH/DCM to give the title compound (0.895 g) as a white foam. NMR: 1.14 (t, 3H), 1.61 (s, 3H), 2.05 (s, 3H), 2.75-2.82 (m, 1H), 2.94 (brm, 2H), 3.25-3.44 (m, 3H), 3.49-3.56 (q, 2H), 3.85 (d, 1H), 4.39 (d, 1H), 7.94 (d, 1H), 8.07 (brs, 1H), 8.26 (d, 1H), 9.94 (brs, 1H); m/z: 484.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[NH:9][CH2:8][CH2:7][CH2:6]2.[CH:13]([O:16][C:17]1[CH:25]=[CH:24][C:23]([S:26]([CH3:29])(=[O:28])=[O:27])=[CH:22][C:18]=1[C:19](O)=[O:20])([CH3:15])[CH3:14]>>[CH:13]([O:16][C:17]1[CH:25]=[CH:24][C:23]([S:26]([CH3:29])(=[O:28])=[O:27])=[CH:22][C:18]=1[C:19]([N:9]1[C:10]2[C:5](=[CH:4][C:3]([O:2][CH3:1])=[CH:12][CH:11]=2)[CH2:6][CH2:7][CH2:8]1)=[O:20])([CH3:15])[CH3:14]
Reactant: COc1ccc2c(c1)CCCN2
Reactant: CC(C)Oc1ccc(S(C)(=O)=O)cc1C(=O)O
Product: COc1ccc2c(c1)CCCN2C(=O)c1cc(S(C)(=O)=O)ccc1OC(C)C

Procedure:
Prepared in analogy to example 1.1 from 6-methoxy-1,2,3,4-tetrahydro-quinoline (CA [120-15-0]) and 2-isopropoxy-5-methanesulfonyl-benzoic acid (Example 2.1).
Reaction SMILES: [N+:1]([C:4]1[CH:19]=[CH:18][C:7]([CH2:8][CH:9]2[CH2:12][CH:11]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH2:10]2)=[CH:6][CH:5]=1)([O-:3])=[O:2].[C:20]1(C2CC(C(C)C(OCC)=O)C2)C=CC=CC=1>>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([CH:8]2[CH2:9][CH:12]([CH:11]([CH3:10])[C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH2:20]2)=[CH:18][CH:19]=1)([O-:3])=[O:2]
Reactant: CCOC(=O)C1CC(Cc2ccc([N+](=O)[O-])cc2)C1
Reactant: CCOC(=O)C(C)C1CC(c2ccccc2)C1
Product: CCOC(=O)C(C)C1CC(c2ccc([N+](=O)[O-])cc2)C1

Procedure:
Following the general procedure described for ethyl 3-(4-nitrobenzyl)cyclobutanecarboxylate (Intermediate 93i), replacing ethyl 3-benzylcyclobutanecarboxylate with ethyl 2-(3-phenylcyclobutyl)propanoate the title compound was obtained which was used directly in the next step.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:9]=[C:10]=[O:11])[CH:5]=[CH:6][C:7]=1[Cl:8].[N:12]1([CH2:18][CH2:19][CH2:20][N:21]2[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]2)[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1>CN(C=O)C.ClCCl>[Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]([N:24]2[CH2:23][CH2:22][N:21]([CH2:20][CH2:19][CH2:18][N:12]3[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17]3)[CH2:26][CH2:25]2)=[O:11])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: O=C=Nc1ccc(Cl)c(Cl)c1
Reactant: C1CCN(CCCN2CCNCC2)CC1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=C(Nc1ccc(Cl)c(Cl)c1)N1CCN(CCCN2CCCCC2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 3,4-dichlorophenylisocyanate (0.3 g; 1.5 mmol) in a mixture of DMF (0.5 ml) and dichloromethane (5 ml) was added to 1-(3-piperidinopropyl)-piperazine (0.21 g; 1 mmol) at room temperature. The resulting mixture was stirred at room temperature overnight.
Reaction SMILES: [C:1]([C:6]1[CH:7]=[C:8]2[C:17]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[NH:11][CH2:10][N:9]2[CH:18]=1)([O:3][CH2:4][CH3:5])=[O:2]>C(#N)C=C>[C:1]([C:6]1[CH:7]=[C:8]2[C:17]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[N:11]([CH2:6][CH2:7][C:8]#[N:9])[CH2:10][N:9]2[CH:18]=1)([O:3][CH2:4][CH3:5])=[O:2]
Reactant: CCOC(=O)c1cc2n(c1)CNc1ccccc1-2
Solvent: C=CC#N
Product: CCOC(=O)c1cc2n(c1)CN(CCC#N)c1ccccc1-2
Reaction time: 0.05 h

Procedure:
To a suspension of the product of Example IV (1.5 g, 0.0062 m) in acrylonitrile (5 ml), cooled to 0°-5°, was added, dropwise, 0.4 ml of Triton B over 3 min. An exothermic reaction resulted and a brown colored solution formed. After 5 hr. of reflux, the excess of acrylonitrile was distilled in vacuo, and the semi-solid residue (0.95 g) was crystallized from methanol to afford the desired product; m.p. 102°-104° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:11](=[CH:12][C:13]=1[O:14][CH3:15])[C:9](=[O:10])O[C:7]([C:16]([OH:18])=[O:17])=[C:6]2[C:19]1[CH:24]=[C:23]([O:25][CH3:26])[C:22]([O:27][CH3:28])=[C:21]([O:29][CH3:30])[CH:20]=1.[NH3:31]>CO>[C:16]([C:7]1[NH:31][C:9](=[O:10])[C:11]2[C:5]([C:6]=1[C:19]1[CH:20]=[C:21]([O:29][CH3:30])[C:22]([O:27][CH3:28])=[C:23]([O:25][CH3:26])[CH:24]=1)=[CH:4][C:3]([O:2][CH3:1])=[C:13]([O:14][CH3:15])[CH:12]=2)([OH:18])=[O:17]
Reactant: COc1cc2c(-c3cc(OC)c(OC)c(OC)c3)c(C(=O)O)oc(=O)c2cc1OC
Reactant: N
Solvent: CO
Product: COc1cc2c(-c3cc(OC)c(OC)c(OC)c3)c(C(=O)O)[nH]c(=O)c2cc1OC
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of a solution of 6,7-dimethoxy-4-(3,4,5-trimethoxyphenyl)-isocoumarin-3-carboxylic acid (the compound obtained in Reference Example 50) (2.4 g) in methanol (50 ml) and a 5.5M solution of ammonia in methanol (50 ml) is stirred at room temperature overnight. The reaction solution is concentrated under reduced pressure to remove the ammonia, and further the solvent is distilled off. The residue thus obtained is extracted with chloroform, and the extract is washed with water, dried, and concentrated under reduced pressure. To the residue is added a 4M solution of hydrogen chloride in ethyl acetate (30 ml), and the mixture is stirred at room temperature overnight. The mixture is concentrated under reduced pressure, and the resulting residue is extracted with chloroform. The extract is washed with water, dried, and concentrated under reduced pressure to give 3-carboxy-6,7-dimethoxy-4-(3,4,5-trimethoxyphenyl)-1(2H)-isoquinolinone (1.89 g) as listed in Table 8.
Reaction SMILES: C[O:2][C:3]([C:5]1[C:6](=[O:23])[N:7]([CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:8]=[CH:9][C:10]=1[C:11]([O:13][CH2:14][CH3:15])=[O:12])=[O:4].[Li+].[I-]>N1C=CC=CC=1>[CH2:14]([O:13][C:11]([C:10]1[CH:9]=[CH:8][N:7]([CH2:16][C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[C:6](=[O:23])[C:5]=1[C:3]([OH:4])=[O:2])=[O:12])[CH3:15]
Reactant: CCOC(=O)c1ccn(Cc2ccccc2)c(=O)c1C(=O)OC
Agent: [I-]
Agent: [Li+]
Solvent: c1ccncc1
Product: CCOC(=O)c1ccn(Cc2ccccc2)c(=O)c1C(=O)O
Temperature: 25 °C
Yield: 59.9 %

Procedure:
A solution of 1-benzyl-2-oxo-1,2-dihydro-pyridine-3,4-dicarboxylic acid 4-ethyl ester 3-methyl ester (5.77 g, 18.3 mmol) in 10 mL of pyridine was added to a refluxing mixture of LiI (9.8 g, 73.3 mmol) and 70 mL of pyridine. The resulting mixture was refluxed for 1 h. After the mixture was cooled to r.t., solvent was evaporated in vacuo. The residue was taken up in water and acidified with 6M HCl. The resulting suspension was extracted several times with CHCl3, and the organic layers were combined and dried over MgSO4. After solvent was evaporated in vacuo, the crude product was chromatographed (100% EtOAc) to give 3.3 g of the title compound as a yellow solid. 1H NMR (CDCl3, 200 MHz): δ=14.26 (s, 1H), 7.65 (d, 1H, J=7.0 Hz), 7.22-7.50 (m, 5H), 6.41 (d, 1H, J=6.8 Hz), 5.26 (s, 2H), 4.44 (q, 2H, J=7.6 Hz), 1.38 (t, 3H, J=7.0 Hz).
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:20]([O:24][C:25]([N:27]1[CH2:32][CH2:31][CH:30]([CH2:33][CH2:34][CH2:35][N:36]=[N+]=[N-])[CH2:29][CH2:28]1)=[O:26])([CH3:23])([CH3:22])[CH3:21].CC#N.O>C1COCC1>[C:20]([O:24][C:25]([N:27]1[CH2:32][CH2:31][CH:30]([CH2:33][CH2:34][CH2:35][NH2:36])[CH2:29][CH2:28]1)=[O:26])([CH3:23])([CH3:22])[CH3:21]
Reactant: CC(C)(C)OC(=O)N1CCC(CCCN=[N+]=[N-])CC1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: C1CCOC1
Solvent: CC#N
Product: CC(C)(C)OC(=O)N1CCC(CCCN)CC1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Triphenylphosphine (0.657 g, 2.50 mmol) is added to a stirred solution of 4-(3-azido-propyl)-piperidine-1-carboxylic acid tert-butyl ester (0.560 g, 2.09 mmol) in THF (2 mL)/CH3CN (5 mL)/H2O (1 mL) and the mixture is stirred at ambient temperature for 18 hours. After concentration and subsequent chromatography purification on silica gel, eluting with 2 M NH3/MeOH in dichloromethane 0-15%, the title compound is obtained as a clear oil (0.420 g, 83% yield).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH2:9])[CH:5]=[CH:6][C:7]=1[Cl:8].C1C(=O)N([I:17])C(=O)C1>CC(O)=O>[Br:1][C:2]1[C:7]([Cl:8])=[CH:6][C:5]([I:17])=[C:4]([NH2:9])[CH:3]=1
Reactant: O=C1CCC(=O)N1I
Reactant: Nc1ccc(Cl)c(Br)c1
Solvent: CC(=O)O
Product: Nc1cc(Br)c(Cl)cc1I
Temperature: 25 °C
Reaction time: 16 h
Yield: 15.5 %

Procedure:
To a solution of 3-bromo-4-chlorobenzenamine (10.0 g, 48.5 mmol) in CH3COOH (50 mL), NIS (10.9 g, 48.5 mmol) was added in portions and the resulting mixture was stirred at room temperature for 16 h. The mixture was concentrated in vacuo. The residue was dissolved in ethyl acetate, washed with saturated NaHCO3 solution and brine, dried over Na2SO4 and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel (petroleum ether/ethyl acetate=50:1) to afford the desired product (2.5 g, 15.5% yield). ESI-MS m/z: 329.9 [M−H]−.
Reaction SMILES: Cl.[F:2][C:3]1[CH:8]=[CH:7][C:6]([F:9])=[CH:5][C:4]=1[C:10]1(O)[CH2:14][CH2:13][CH2:12][N:11]1C(OC(C)(C)C)=O.[OH-].[Na+]>CO>[F:2][C:3]1[CH:8]=[CH:7][C:6]([F:9])=[CH:5][C:4]=1[C:10]1[CH2:14][CH2:13][CH2:12][N:11]=1
Reactant: CC(C)(C)OC(=O)N1CCCC1(O)c1cc(F)ccc1F
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Fc1ccc(F)c(C2=NCCC2)c1
Temperature: 70 °C

Procedure:
In step 6A-2, concentrated hydrochloric acid (23 mL, 260 mmol) was added to a solution of tert-butyl 2-(2,5-difluorophenyl)-2-hydroxypyrrolidine-1-carboxylate (6-3) (15.6 g, 52 mmol) in methanol. The reaction mixture was heated to 70° C. while stirring and was then stirred at 70° C. for 6 hours. The reaction mixture was cooled to room temperature and neutralized with a 7.5 M solution of sodium hydroxide (35 mL, 263 mmol). The methanol was removed and the resulting slurry was reconstituted with ethyl acetate (250 mL). The organic layer was washed with brine (3×150 mL), and then dried with sodium sulfate. The ethyl acetate was then removed to yield 5-(2,5-difluorophenyl)-3,4-dihydro-2H-pyrrole (6-4) as a light yellow oil. m/z=182.2 [M+1].
Reaction SMILES: [CH2:1]([NH:8][C:9]1[CH:10]=[C:11]([CH:14]=[C:15]([S:24](=[O:27])(=[O:26])[NH2:25])[C:16]=1[S:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[CH2:12][OH:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.OO.C(O)(=[O:32])C>O>[CH2:1]([NH:8][C:9]1[CH:10]=[C:11]([CH:14]=[C:15]([S:24](=[O:27])(=[O:26])[NH2:25])[C:16]=1[S:17]([C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1)=[O:32])[CH2:12][OH:13])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(=O)O
Reactant: NS(=O)(=O)c1cc(CO)cc(NCc2ccccc2)c1Sc1ccccc1
Agent: OO
Solvent: O
Product: NS(=O)(=O)c1cc(CO)cc(NCc2ccccc2)c1S(=O)c1ccccc1
Reaction time: 24 h

Procedure:
A mixture of 3-benzylamino-4-phenylthio-5-sulfamylbenzyl alcohol (8.0 g; prepared as described in Example 24), hydrogenperoxide (10 ml, 30% in water) and acetic acid (80 ml) is stirred at 22°-25° C. for 24 hours. The resulting solution is diluted with water (40 ml) and cooled to precipitate crude 3-benzylamino-4-phenylsulfinyl-5-sulfamylbenzyl alcohol. After recrystallization from a mixture of ethanol and 2-methoxyethanol it is obtained with a melting point of 213°-214° C.
Reaction SMILES: C([O:3][C:4](=[O:29])[CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1/[CH:15]=[CH:16]/[CH:17]=[CH:18]/[CH:19]([OH:28])[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])C.[OH-].[Na+].S(=O)(=O)(O)O.C(OCC)(=O)C>CO>[OH:28][CH:19]([CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])/[CH:18]=[CH:17]/[CH:16]=[CH:15]/[C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=1[O:8][CH2:7][CH2:6][CH2:5][C:4]([OH:29])=[O:3]
Reactant: CCCCCCCCC(O)/C=C/C=C/c1ccccc1OCCCC(=O)OCC
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CO
Product: CCCCCCCCC(O)/C=C/C=C/c1ccccc1OCCCC(=O)O
Yield: 64.5 %

Procedure:
A solution of 130 mg of 4-[2-[(1E,3E)-(5RS)-5-hydroxy-1,3-tridecadienyl]-phenoxy]butyric acid ethyl ester in 10 ml of methanol and 2.5 ml of 0.5 n sodium hydroxide solution is stirred under argon atmosphere for 3 hours at room temperature. The reaction mixture is poured on ice water, acidified to pH 5 with 0.5 n sulfuric acid and shaken out with ethyl acetate. The organic phase is dried, concentrated by evaporation and the residue is chromatographed on silica gel with n-hexane/diethyl ether=7/3. 78 mg of the title compound is obtained as a colorless oil.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[NH:7]1[C:15]2[C:10](=[CH:11][C:12]([O:16][CH:17]3[CH2:22][CH2:21][CH:20]([C:23](OCC)=[O:24])[CH2:19][CH2:18]3)=[CH:13][CH:14]=2)[CH:9]=[N:8]1.O.[OH-].[Na+]>O1CCCC1>[NH:7]1[C:15]2[C:10](=[CH:11][C:12]([O:16][CH:17]3[CH2:18][CH2:19][CH:20]([CH2:23][OH:24])[CH2:21][CH2:22]3)=[CH:13][CH:14]=2)[CH:9]=[N:8]1
Reactant: CCOC(=O)C1CCC(Oc2ccc3[nH]ncc3c2)CC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: OCC1CCC(Oc2ccc3[nH]ncc3c2)CC1
Reaction time: 2 h
Yield: 84.2 %

Procedure:
Lithium aluminum hydride (52 mg, 1.39 mmol) was added to a solution of the ethyl 4-(1H-indazol-5-yloxy)cyclohexanecarboxylate (100 mg, 0.347 mmol) obtained in Example 367 in tetrahydrofuran (2 ml), and the resulting mixture was refluxed. After 2 hours, water (52 μl), a 2M-aqueous sodium hydroxide solution (0.104 ml) and then water (0.156 ml) were added to the reaction mixture, and the resulting solution was filtered by the use of Celite. The filtrate was concentrated under reduced pressure, and the resulting oil was crystallized by the addition of diisopropyl ether. The crystals were filtered under reduced pressure and then dried to obtain [4-(1H-indazol-5-yloxy)cyclohexyl]methanol (72 mg, 84%, trans/cis=4/1).
Reaction SMILES: CON(C)[C:4]([C:6]1[C:15](=[O:16])[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[N:8]([CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([CH3:24])[N:19]=2)[CH:7]=1)=[O:5]>C1COCC1.[Br-]>[CH3:7][N:8]([CH3:17])[C:9]1[CH:14]=[CH:13][C:12]([C:4]([C:6]2[C:15](=[O:16])[C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[N:8]([CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([CH3:24])[N:19]=3)[CH:7]=2)=[O:5])=[CH:11][CH:10]=1
Reactant: CON(C)C(=O)c1cn(Cc2cccc(C)n2)c2ccccc2c1=O
Agent: [Br-]
Solvent: C1CCOC1
Product: Cc1cccc(Cn2cc(C(=O)c3ccc(N(C)C)cc3)c(=O)c3ccccc32)n1

Procedure:
Experimental conditions analogous to those described for Step 6 of Example 60, from 138 mg (0.41 mmol) of 1-(6-methyl-pyridin-2-ylmethyl)-4-oxo-1,4-dihydro-quinoline-3-carboxylic acid methoxy-methyl-amide in 2 mL THF and 2 mL 0.5M 4-N,N-dimethylanilinemagnesium bromide. Yield: 17 mg of a white solid. LC-MSD, m/z for C25H23N3O2 [M+H]+=398.1; HPLC retention time: 1.9 min.
Reaction SMILES: [Cl:1][C:2]1[CH:14]=[CH:13][CH:12]=[CH:11][C:3]=1[CH:4]([C:6]1[O:7][CH:8]=[CH:9][CH:10]=1)[OH:5].[H-].[Na+].[CH3:17]I>CN(C)C=O.C(OCC)C>[Cl:1][C:2]1[CH:14]=[CH:13][CH:12]=[CH:11][C:3]=1[CH:4]([C:6]1[O:7][CH:8]=[CH:9][CH:10]=1)[O:5][CH3:17]
Reactant: OC(c1ccco1)c1ccccc1Cl
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CCOCC
Solvent: CN(C)C=O
Product: COC(c1ccco1)c1ccccc1Cl
Reaction time: 1 h
Yield: 89.8 %

Procedure:
A soluton of (±) 2-(2-chloro-α-hydroxybenzyl)furan [prepared as described in (j) above] (31.3 g.) in dimethylformamide (100 ml.) was treated with sodium hydride (4.1 g.) with ice cooling. Methyl iodide (28.4 g.) was added to the stirred solution over 15 minutes at 15°-30° C. with ice cooling and the mixture was allowed to stand at ambient temperature for 1 hour. The mixture was then diluted with diethyl ether (300 ml.) and filtered. The filtrate was washed with water (3 × 500 ml.), dried over sodium sulphate and evaporated to give a light red oil, which was distilled to give (±) 2-(2-chloro-α-methoxybenzyl)furan (30 g.), b.p. 115° C./0.1 mm.Hg.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[CH:5][N:4]=[CH:3]1.[Li]CCCC.[Si](Cl)(CC)(CC)CC.[Cl:20][C:21]1[N:26]=[CH:25][C:24]([C:27](N(OC)C)=[O:28])=[CH:23][CH:22]=1.Cl.[OH-].[Na+]>O1CCCC1.O>[Cl:20][C:21]1[CH:22]=[CH:23][C:24]([C:27]([C:6]2[N:2]([CH3:1])[CH:3]=[N:4][CH:5]=2)=[O:28])=[CH:25][N:26]=1
Reactant: Cn1ccnc1
Reactant: CON(C)C(=O)c1ccc(Cl)nc1
Agent: CC[Si](Cl)(CC)CC
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Product: Cn1cncc1C(=O)c1ccc(Cl)nc1
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
To a 250-mL 3-necked round-bottom flask containing a solution of 1-methyl-1H-imidazole (5.00 g, 60.9 mmol) and tetrahydrofuran (40 mL) was added n-BuLi (29.3 mL, 73.3 mmol, 2.5 M in hexanes) at −78° C., and stirred for 45 minutes. To this mixture Et3SiCl (9.15 g, 61.0 mmol) was added, and stirring was continued for 1 hour at −78° C. To the mixture was added n-BuLi (26.0 mL, 65.0 mmol, 2.5 M in hexanes). After stirring for another 45 minutes, a solution of 6-chloro-N-methoxy-N-methylpyridine-3-carboxamide (8.13 g, 40.5 mmol, Intermediate 4, step b) in tetrahydrofuran (20 mL) was added at −78° C. The resulting mixture was allowed to warm up to room temperature overnight. To the mixture was added 1.0 M aqueous HCl until pH 3-4. After stirring for 2 hours at room temperature, the mixture was basified with 1.5 M aqueous sodium hydroxide until pH 9-10. The resulting mixture was diluted with 100 mL of H2O and extracted with 3×100 mL of dichloromethane. The organic layers were combined, dried over anhydrous sodium sulfate, filtered and concentrated under vacuum. The residue was purified by silica gel flash chromatography eluting with dichloromethane/methanol (100:0 to 15:1) to afford the title compound as a yellow solid.
Reaction SMILES: [OH-].[Na+].O.[NH2:4][CH:5]1[CH2:9][CH2:8][N:7]([C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH2:6]1.C(Cl)(=O)OCC.[C:21](=S)=[S:22]>>[N:4]([CH:5]1[CH2:9][CH2:8][N:7]([C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH2:6]1)=[C:21]=[S:22]
Reactant: S=C=S
Reactant: CCOC(=O)N1CCC(N)C1
Agent: CCOC(=O)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CCOC(=O)N1CCC(N=C=S)C1
Reaction time: 3 h
Yield: 100 %

Procedure:
A mixture of 8.6 parts of sodium hydroxide and 120 parts of water was stirred at a temperature below 10° C. and there were added successively 17 parts of carbon disulfide and 35 parts of ethyl 3-amino-1-pyrrolidinecarboxylate. Stirring was continued for 3 hours. Then there were added dropwise 23.5 parts of ethyl carbonochloridate. Upon completion, stirring was continued for 2 hours at 60° C. The reaction mixture was extracted with methylbenzene. The extract was dried, filtered and evaporated, yielding 55 parts (100%) of ethyl 3-isothiocyanato-1-pyrrolidinecarboxylate (12).
Reaction SMILES: [C:1]1([C:7]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)Cl)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.O.[OH:22][CH:23]1[C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][C:28]=2[CH2:27][O:26][C:25]2[CH:34]=[CH:35][C:36]([CH2:38][CH2:39][OH:40])=[CH:37][C:24]1=2>N1C=CC=CC=1>[OH:22][CH:23]1[C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][C:28]=2[CH2:27][O:26][C:25]2[CH:34]=[CH:35][C:36]([CH2:38][CH2:39][O:40][C:7]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)([C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=3)[C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)=[CH:37][C:24]1=2
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: OCCc1ccc2c(c1)C(O)c1ccccc1CO2
Solvent: O
Solvent: c1ccncc1
Product: OC1c2ccccc2COc2ccc(CCOC(c3ccccc3)(c3ccccc3)c3ccccc3)cc21
Temperature: 50 °C
Reaction time: 5 h
Yield: 64.9 %

Procedure:
In this process, 17.2 g of 11-hydroxy-2-(2-hydroxyethyl)-6,11-dihydrodibenz[b,e]oxepin is dissolved in 50 ml of pyridine. To the solution is added 30 g of triphenylchloromethane and the mixture is stirred at 50° C. for 5 hours. After adding water and stirring the mixture for 2 hours, the solvent is distilled away under reduced pressure. The mixture is extracted with 1000 ml of ethyl acetate, washed with saturated aqueous sodium chloride solution, and dried over anhydrous sodium sulfate. The solvent is distilled away under reduced pressure and the resultant residue is purified by column chromatography on silica gel (eluent: hexane:ethyl acetate=3:1 ) to obtain 21.7 g of the desired product as a colorless amorphous.