Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CON(C)[C:4]([C:6]1[N:7]=[CH:8][N:9]([C:11]2[CH:12]=[C:13]([C:17]3[CH:22]=[C:21]([F:23])[CH:20]=[CH:19][C:18]=3[O:24][CH3:25])[CH:14]=[CH:15][CH:16]=2)[CH:10]=1)=[O:5].Br[C:28]1[C:33]([CH3:34])=[CH:32][CH:31]=[CH:30][N:29]=1>>[F:23][C:21]1[CH:20]=[CH:19][C:18]([O:24][CH3:25])=[C:17]([C:13]2[CH:14]=[CH:15][CH:16]=[C:11]([N:9]3[CH:10]=[C:6]([C:4]([C:28]4[C:33]([CH3:34])=[CH:32][CH:31]=[CH:30][N:29]=4)=[O:5])[N:7]=[CH:8]3)[CH:12]=2)[CH:22]=1
Reactant: Cc1cccnc1Br
Reactant: COc1ccc(F)cc1-c1cccc(-n2cnc(C(=O)N(C)OC)c2)c1
Product: COc1ccc(F)cc1-c1cccc(-n2cnc(C(=O)c3ncccc3C)c2)c1

Procedure:
This compound was prepared by Method C using compound 12b and 2-bromo-3-methylpyridine. HRMS (ESI+): m/z=388.1471 [M+H]
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5](F)=[C:4]([N+:9]([O-:11])=[O:10])[CH:3]=1.[CH2:12]([O:14][C:15](=[O:23])[CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=1)[CH3:13].[CH3:24]I.[H-].[Na+]>>[CH2:12]([O:14][C:15](=[O:23])[C:16]([C:5]1[CH:6]=[CH:7][C:2]([Br:1])=[CH:3][C:4]=1[N+:9]([O-:11])=[O:10])([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=1)[CH3:24])[CH3:13]
Reactant: CI
Reactant: CCOC(=O)Cc1ccccn1
Reactant: O=[N+]([O-])c1cc(Br)ccc1F
Agent: [H-]
Agent: [Na+]
Product: CCOC(=O)C(C)(c1ccccn1)c1ccc(Br)cc1[N+](=O)[O-]
Yield: 83.6 %

Procedure:
Following similar methods to those described in Preparation 332 starting from 4-bromo-1-fluoro-2-nitro-benzene (5 g, 22.7 mmol), pyridin-2-yl-acetic acid ethyl ester (4.5 g, 27.3 mmol), MeI (5.6 mL, 91 mmol) and NaH (60% in mineral oil, 3 g, 77.1 mmol) gave the title compound (7.2 g) as a yellow solid. MS: [M+H]+=379.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[CH:5][C:6]([OH:30])=[C:7]([S:9]([NH:12][CH2:13][CH2:14][C:15]2[CH:20]=[CH:19][C:18]([CH:21]([CH3:23])[CH3:22])=[CH:17][C:16]=2[O:24][CH2:25][C:26]([NH:28][NH2:29])=[O:27])(=[O:11])=[O:10])[CH:8]=1)#[N:2].Cl[C:32](Cl)([O:34]C(=O)OC(Cl)(Cl)Cl)Cl.O>O1CCCC1>[C:1]([C:3]1[CH:4]=[CH:5][C:6]([OH:30])=[C:7]([S:9]([NH:12][CH2:13][CH2:14][C:15]2[CH:20]=[CH:19][C:18]([CH:21]([CH3:23])[CH3:22])=[CH:17][C:16]=2[O:24][CH2:25][C:26]2[O:27][C:32](=[O:34])[NH:29][N:28]=2)(=[O:10])=[O:11])[CH:8]=1)#[N:2]
Reactant: CC(C)c1ccc(CCNS(=O)(=O)c2cc(C#N)ccc2O)c(OCC(=O)NN)c1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: C1CCOC1
Solvent: O
Product: CC(C)c1ccc(CCNS(=O)(=O)c2cc(C#N)ccc2O)c(OCc2n[nH]c(=O)o2)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 95.1 %

Procedure:
5-Cyano-N-[2-(2-hydrazinocarbonylmethoxy-4-isopropylphenyl)ethyl]-2-hydroxybenzenesulfonamide (0.258 g) was dissolved in 10 mL of tetrahydrofuran. To the stirred solution was added 0.177 g of triphosgene under ice-cooling, and the mixture was stirred at room temperature for 30 minutes. To the reaction mixture was added water, and the mixture was extracted with ethyl acetate. The organic layer was washed with brine, and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure to give 0.26 g of 5-cyano-2-hydroxy-N-[2-[4-isopropyl-2-(5-oxo-4,5-dihydro[1,3,4]-oxadiazol-2-ylmethoxy)phenyl]ethyl]benzenesulfonamide.
Reaction SMILES: [NH2:1][OH:2].[C:3]([C:5]1[CH:21]=[CH:20][C:8]([CH2:9][N:10]([CH3:19])[CH2:11][C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])=[CH:7][CH:6]=1)#[N:4]>CCO>[NH2:4][C:3](=[N:1][OH:2])[C:5]1[CH:6]=[CH:7][C:8]([CH2:9][N:10]([CH3:19])[CH2:11][C:12]([O:14][C:15]([CH3:16])([CH3:17])[CH3:18])=[O:13])=[CH:20][CH:21]=1
Reactant: NO
Reactant: CN(CC(=O)OC(C)(C)C)Cc1ccc(C#N)cc1
Solvent: CCO
Product: CN(CC(=O)OC(C)(C)C)Cc1ccc(C(N)=NO)cc1

Procedure:
A 50% aqueous solution of hydroxylamine (13.25 mL, 225 mmol) was added at once into a solution of tert-butyl N-(4-cyanobenzyl)-N-methylglycinate (11.70 g, 45 mmol) in EtOH (75 mL).
Reaction SMILES: [CH:1]([NH:3][C:4]1[S:5][CH:6]=[C:7]([CH2:9][S:10][C:11]2[CH:16]=[CH:15][C:14]([N+:17]([O-])=O)=[CH:13][CH:12]=2)[N:8]=1)=[O:2].[Cl-].[NH4+].C(O)C.O>O1CCCC1.[Fe]>[CH:1]([NH:3][C:4]1[S:5][CH:6]=[C:7]([CH2:9][S:10][C:11]2[CH:16]=[CH:15][C:14]([NH2:17])=[CH:13][CH:12]=2)[N:8]=1)=[O:2]
Reactant: O=CNc1nc(CSc2ccc([N+](=O)[O-])cc2)cs1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: O
Solvent: CCO
Product: Nc1ccc(SCc2csc(NC=O)n2)cc1
Yield: 80.9 %

Procedure:
To a mixture of 2-formylamino-4-(4-nitrophenylthiomethyl)thiazole (2.2 g) and ammonium chloride (0.5 g) in a mixture of tetrahydrofuran (30 ml), ethanol (50 ml) and water (10 ml) was added portionwise the iron powder at 80° C. with stirring. The mixture was refluxed for 2 hours with stirring. The reaction mixture was filtered by suction and the residue was triturated with water. The precipitates were collected by filtration, washed with water and dried in vacuo to give 2-formylamino-4-(4-aminophenylthiomethyl)thiazole (1.6 g, yield: 81%). mp: 180°-182° C.
Reaction SMILES: Cl[C:2]1[C:7]2[CH2:8][N:9]([CH:12]([C:14]3[CH:15]=[N:16][C:17]([O:21][CH2:22][C:23]([F:26])([F:25])[F:24])=[C:18]([CH3:20])[CH:19]=3)[CH3:13])[C:10](=[O:11])[C:6]=2[CH:5]=[CH:4][N:3]=1.[CH:27]([O:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)=[O:28].C1(P(C2C=CC=CC=2)C2C3OC4C(=CC=CC=4P(C4C=CC=CC=4)C4C=CC=CC=4)C(C)(C)C=3C=CC=2)C=CC=CC=1>CC#N.O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH3:20][C:18]1[CH:19]=[C:14]([CH:12]([N:9]2[C:10](=[O:11])[C:6]3[CH:5]=[CH:4][N:3]=[C:2]([C:27]([O:29][C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=4)=[O:28])[C:7]=3[CH2:8]2)[CH3:13])[CH:15]=[N:16][C:17]=1[O:21][CH2:22][C:23]([F:26])([F:25])[F:24]
Reactant: O=COc1ccccc1
Reactant: Cc1cc(C(C)N2Cc3c(ccnc3Cl)C2=O)cnc1OCC(F)(F)F
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Solvent: O
Solvent: CC#N
Product: Cc1cc(C(C)N2Cc3c(ccnc3C(=O)Oc3ccccc3)C2=O)cnc1OCC(F)(F)F
Temperature: 80 °C
Yield: 73.4 %

Procedure:
A mixture of 4-chloro-2-(1-(5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one (50 mg, 0.13 mmol, Intermediate-2, single enantiomer), phenyl formate (32 mg, 0.26 mmol, single enantiomer), palladium acetate (II) (0.87 mg, 0.039 mmol), and 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (9.0 mg, 0.016 mmol) in MeCN (1.0 mL) is heated at 80° C. overnight (T. Ueda et al, Org. Lett., 2012, 14, 3100-3103). The mixture is diluted with water, and extracted with EtOAc. The organic layer is dried over sodium sulfate and filtered. The filtrate is concentrated under reduced pressure. The residue is purified by column chromatography on silica gel eluting with n-hexane/EtOAc (2:1 to 1:2) to give 45 mg (74% yield) of the title compound as off white solid.
Reaction SMILES: [OH:1][CH:2]([C:6]1[CH:11]=[CH:10][C:9]([C:12]2[N:16]=[C:15]([C:17]3[O:21][N:20]=[C:19]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[C:18]=3[C:28]([F:31])([F:30])[F:29])[O:14][N:13]=2)=[CH:8][CH:7]=1)[C:3]([OH:5])=O.[NH2:32][CH2:33][CH2:34][CH2:35][OH:36].CN1CCOCC1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[OH:1][CH:2]([C:6]1[CH:11]=[CH:10][C:9]([C:12]2[N:16]=[C:15]([C:17]3[O:21][N:20]=[C:19]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[C:18]=3[C:28]([F:29])([F:30])[F:31])[O:14][N:13]=2)=[CH:8][CH:7]=1)[C:3]([NH:32][CH2:33][CH2:34][CH2:35][OH:36])=[O:5]
Reactant: NCCCO
Reactant: O=C(O)C(O)c1ccc(-c2noc(-c3onc(-c4ccccc4)c3C(F)(F)F)n2)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: O=C(NCCCO)C(O)c1ccc(-c2noc(-c3onc(-c4ccccc4)c3C(F)(F)F)n2)cc1
Reaction time: 1 h
Yield: 25.7 %

Procedure:
(R/S)-2-Hydroxy-2-(4-(5-(3-phenyl-4-(trifluoromethyl)isoxazol-5-yl)-1,2,4-oxadiazol-3-yl)phenyl)acetic acid (Int-V, 30 mg, 0.070 mmol), 3-aminopropan-1-ol (7.84 mg, 0.104 mmol), 4-methylmorpholine (28.1 mg, 0.278 mmol), and HATU (34.4 mg, 0.090 mmol) were dissolved in DMF (1 mL). The mixture was stirred for 1 h and then purified by prep HPLC (PHENOMENEX® Luna 5u 21×250 mm, gradient elution with Method 1—MeOH/water containing 0.1% trifluoroacetic acid as defined above, 0% B to 100% B over 30 min, 25 mL/min, 220 nM, product retention=29.4 min) to provide (R/S)-2-hydroxy-N-(3-hydroxypropyl)-2-(4-(5-(3-phenyl-4-(trifluoromethyl)isoxazol-5-yl)-1,2,4-oxadiazol-3-yl)phenyl)acetamide (12 mg, 0.018 mmol, 26.5% yield): LCMS=489.1 [M+H]+; 1H NMR (400 MHz, chloroform-d) δ ppm 8.20 (2 H, d, J=8.35 Hz), 7.50-7.71 (7 H, m), 6.82-6.90 (1 H, m), 5.20 (1 H, s), 3.41-3.62 (4 H, m), 3.34 (3 H, s) HPLC peak RT=9.1 min (Method A).
Reaction SMILES: IC.[CH3:3][C:4]([C:7]1[CH:8]=[C:9]([CH:18]=[C:19]2[N:23]([CH3:24])[C:22](=[S:25])[NH:21][C:20]2=[O:26])[CH:10]=[C:11]([C:14]([CH3:17])([CH3:16])[CH3:15])[C:12]=1[OH:13])([CH3:6])[CH3:5].[CH:27](N(C(C)C)CC)(C)C.O1CCCC1>C(O)C>[CH3:6][C:4]([C:7]1[CH:8]=[C:9]([CH:18]=[C:19]2[N:23]([CH3:24])[C:22]([S:25][CH3:27])=[N:21][C:20]2=[O:26])[CH:10]=[C:11]([C:14]([CH3:15])([CH3:16])[CH3:17])[C:12]=1[OH:13])([CH3:3])[CH3:5]
Reactant: CN1C(=S)NC(=O)C1=Cc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Reactant: CCN(C(C)C)C(C)C
Solvent: CI
Solvent: CCO
Solvent: C1CCOC1
Product: CSC1=NC(=O)C(=Cc2cc(C(C)(C)C)c(O)c(C(C)(C)C)c2)N1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 63.4 %

Procedure:
A mixture of iodomethane (0.7 mL, 11 mmoles), 5-[[3,5-bis(1,1-dimethylethyl)-4-hydroxyphenyl]methylene]-1-methyl-2-thioxo-4-imidazolidinone (2.5 g, 7 mmoles) and diisopropylethylamine (1.5 mL, 8.5 mmoles) in 25 mL of ethanol with enough tetrahydrofuran added to effect solution is stirred overnight under N2 at room temperature, then stirred into 250 mL of ice water. The precipitate is filtered off, rinsed with water, dried, and recrystallized from ethyl acetate to afford the product (1.6 g) 5-[[3,5-bis(1,1-dimethylethyl)-4-hydroxyphenyl]methylene]-1,5-dihydro-l-methyl-2-(methylthio)-4H-imidazol-4-one, mp 177°-178° C., retaining 0.25 equivalent of solvent of recrystallization.
Reaction SMILES: [NH2:1][C:2]1[C:3]([F:21])=[CH:4][C:5]([Cl:20])=[C:6]([N:8]2[C:13](=[O:14])[NH:12][C:11](=[O:15])[N:10]([CH2:16][C:17]#[CH:18])[C:9]2=[O:19])[CH:7]=1.[C:22]1(=O)[O:27][C:25](=[O:26])[C:24]2[CH2:28][CH2:29][CH2:30][CH2:31][C:23]1=2.C(OCC)(=O)C>C(O)(=O)C>[Cl:20][C:5]1[C:6]([N:8]2[C:13](=[O:14])[NH:12][C:11](=[O:15])[N:10]([CH2:16][C:17]#[CH:18])[C:9]2=[O:19])=[CH:7][C:2]([N:1]2[C:22](=[O:27])[C:23]3[CH2:31][CH2:30][CH2:29][CH2:28][C:24]=3[C:25]2=[O:26])=[C:3]([F:21])[CH:4]=1
Reactant: O=C1OC(=O)C2=C1CCCC2
Reactant: C#CCn1c(=O)[nH]c(=O)n(-c2cc(N)c(F)cc2Cl)c1=O
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: C#CCn1c(=O)[nH]c(=O)n(-c2cc(N3C(=O)C4=C(CCCC4)C3=O)c(F)cc2Cl)c1=O
Yield: 55.9 %

Procedure:
A solution of 1-(5-amino-2-chloro-4-fluorophenyl)-3-(2-propynyl)-s-triazine-2,4,6-(1H,3H,5H)-trione (1.50 g, 4.83 mmol), and 3,4,5,6-tetrahydrophthalic anhydride (0.73 g, 4.83 mmol) in acetic acid (3 mL) is heated at 100° C. for 5 hours, cooled, and poured into ethyl acetate. The organic mixture is washed sequentially with water, saturated sodium hydrogen carbonate solution and brine, dried over anhydrous magnesium sulfate, and concentrated in vacuo to obtain a yellow semi-solid. Flash column chromatography of the semi-solid using silica gel and an ethyl acetate/hexanes (1:2) solution gives the title product as a white solid (1.20 g, mp 127°-135° C.).
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@H:12]1[CH2:17][CH2:16][CH2:15][NH:14][C:13]1=[O:18])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[P:19](Cl)(Cl)(Cl)=[O:20].[CH2:24]([NH2:30])[CH2:25][CH2:26][CH2:27][CH2:28][CH3:29]>O1CCCC1>[CH2:1]([O:8][C:9]([NH:11][C@H:12]1[CH2:17][CH2:16][CH2:15][N:14]([P:19]([NH:30][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])([NH:30][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])=[O:20])[C:13]1=[O:18])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: O=C(N[C@H]1CCCNC1=O)OCc1ccccc1
Reactant: CCCCCCN
Solvent: C1CCOC1
Product: CCCCCCNP(=O)(NCCCCCC)N1CCC[C@H](NC(=O)OCc2ccccc2)C1=O
Reaction time: 0.17 h

Procedure:
A solution of (3S)-3-benzyloxycarbonylamino-2-piperidone (2.48 g, 9.99 mmol) in tetrahydrofuran (25 mL) was cooled at an external temperature of −78° C., followed by adding dropwise thereto an n-butyllithium-hexane solution (1.54 M, 6.2 mL, 9.548 mmol) over a period of 10 minutes, and the resulting mixture was stirred at the same temperature for 1.5 hours. Subsequently, a solution of phosphorus oxychloride (1.53 g, 9.98 mmol) in tetrahydrofuran (5 mL) was added thereto and stirred for 1.25 hours, after which n-hexylamine (d=0.76, 6.0 mL, 45.06 mmol) was added thereto and the resulting mixture was stirred at room temperature for 10 minutes.
Reaction SMILES: [NH2:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([C@H:9]2[CH2:13][O:12][C:11](=[O:14])[NH:10]2)=[C:4]([CH3:15])[CH:3]=1.Cl[C:17]1[N:22]=[C:21]([NH:23][C:24]2[CH:28]=[C:27]([CH3:29])[NH:26][N:25]=2)[C:20]([Cl:30])=[CH:19][N:18]=1.Cl>CC(O)C>[Cl:30][C:20]1[C:21]([NH:23][C:24]2[CH:28]=[C:27]([CH3:29])[NH:26][N:25]=2)=[N:22][C:17]([NH:1][C:2]2[C:7]([CH3:8])=[CH:6][C:5]([C@H:9]3[CH2:13][O:12][C:11](=[O:14])[NH:10]3)=[C:4]([CH3:15])[CH:3]=2)=[N:18][CH:19]=1
Reactant: Cc1cc([C@H]2COC(=O)N2)c(C)cc1N
Reactant: Cc1cc(Nc2nc(Cl)ncc2Cl)n[nH]1
Agent: Cl
Solvent: CC(C)O
Product: Cc1cc(Nc2nc(Nc3cc(C)c([C@H]4COC(=O)N4)cc3C)ncc2Cl)n[nH]1
Temperature: 130 °C

Procedure:
To a reaction tube was added (S)-4-(4-amino-2,5-dimethylphenyl)oxazolidin-2-one (48 mg, 0.23 mmol), 2,5-dichloro-N-(5-methyl-1H-pyrazol-3-yl)pyrimidin-4-amine (77 mg, 0.32 mmol), iPrOH (2 mL) and HCl (0.13 mL, 0.52 mmol, 4N in dioxane). The tube was then sealed and heated at 130° C. for 6 h. After cooling down to room temperature, the mixture was concentrated and purified by preparative RP-HPLC to provide (S)-4-(4-(5-chloro-4-(5-methyl-1H-pyrazol-3-ylamino)pyrimidin-2-ylamino)-2,5-dimethyl-phenyl)oxazolidin-2-one; ESMS m/z 414.1 (M+H+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([SH:11])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].Cl[CH2:13][CH2:14][CH2:15][CH2:16][O:17][C:18]1[CH:19]=[C:20]2[C:25](=[CH:26][CH:27]=1)[NH:24][C:23](=[O:28])[CH2:22][CH2:21]2.OC1C=C2C(=CC=1)NC(=O)C=C2.C1(S(OCCCCCl)(=O)=O)C=CC=CC=1>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([S:11][CH2:13][CH2:14][CH2:15][CH2:16][O:17][C:18]2[CH:19]=[C:20]3[C:25](=[CH:26][CH:27]=2)[NH:24][C:23](=[O:28])[CH2:22][CH2:21]3)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: O=C1CCc2cc(OCCCCCl)ccc2N1
Reactant: COc1ccc(S)cc1OC
Agent: O=S(=O)(OCCCCCl)c1ccccc1
Agent: O=c1ccc2cc(O)ccc2[nH]1
Product: COc1ccc(SCCCCOc2ccc3c(c2)CCC(=O)N3)cc1OC

Procedure:
Prepared analogous to Example 1 from 3,4-dimethoxy-thiophenol and 6-(4-chlorobutoxy)-3,4-dihydro-carbostyril [prepared from 6-hydroxy-carbostyril (see F. Mayer et al. in Ber. Dtsch. Chem. Ges. 60, 858 (1927) and 4-chloro-butyl benzenesulfonate].
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][C:11]2([C:21]3[C:16](=[CH:17][C:18]([O:22][CH3:23])=[CH:19][CH:20]=3)[C:15]([OH:30])([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[O:14]2)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:31]O.Cl.[OH-].[Na+]>O>[CH2:1]([N:8]1[CH2:13][CH2:12][C:11]2([C:21]3[C:16](=[CH:17][C:18]([O:22][CH3:23])=[CH:19][CH:20]=3)[C:15]([O:30][CH3:31])([C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=3)[O:14]2)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1ccc2c(c1)C(O)(c1ccccc1)OC21CCN(Cc2ccccc2)CC1
Reactant: CO
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: COc1ccc2c(c1)C(OC)(c1ccccc1)OC21CCN(Cc2ccccc2)CC1

Procedure:
A solution of 1'-benzyl-1,3-dihydro-3-hydroxy-5-methoxy-3-phenylspiro[isobenzofuran-1,4'-piperidine] (prepared by method of Example 1), methanol, and a catalytic amount of methanolic hydrogen chloride is heated under reflux, cooled, made basic with sodium hydroxide, and diluted with water. The mixture is extracted with ethyl acetate, and the ethyl acetate solution is dried over sodium sulfate and concentrated to a solid. Recrystallization from acetone-water provides colorless crystals, m.p. 129°-133°.
Reaction SMILES: C[C:2]1[C:11]2[C:6](=[C:7]([C:13]#[C:14]CO)[CH:8]=[CH:9][C:10]=2[F:12])[N:5]=[C:4](C)[C:3]=1[CH3:18].[OH-].[Na+].C1(C)C=CC=CC=1>C(OCC)C>[F:12][C:10]1[CH:9]=[CH:8][C:7]([C:13]#[CH:14])=[C:6]2[C:11]=1[CH:2]=[C:3]([CH3:18])[CH:4]=[N:5]2
Reactant: Cc1nc2c(C#CCO)ccc(F)c2c(C)c1C
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Solvent: Cc1ccccc1
Product: C#Cc1ccc(F)c2cc(C)cnc12
Temperature: 120 °C
Yield: 50.9 %

Procedure:
Dimethylhydroxymethyl-5-fluoro-3-methyl-8-quinolylacetylene (336 mg, 1.38 mmol) and NaOH (55.2 mg, KISHIDA CHEMICAL CO., Ltd., 0.7 mm granular, 98 mass %, 1.38 mmol) were placed in a 300 mL two-neck flask equipped with a reflux condenser and the air inside the flask was replaced with Ar. 3.0 mL of toluene was added thereto and the mixture was refluxed at 120° C. for 30 minutes. Diethyl ether was added to the reaction mixture and the mixture was washed with a saturated aqueous ammonium chloride solution and dried over magnesium sulfate, followed by distilling off of the solvent under reduced pressure by an evaporator. The crude reaction product was purified by column chromatography (Hexane/AcOEt=100/0→1/10) using silica gel to give 130 mg of the desired compound as a brownish brown solid (yield: 50.7%).
Reaction SMILES: [H-].[Na+].[C:3]([O:7][C:8]([N:10]1[CH2:14][C@H:13]([OH:15])[C@@H:12]([NH:16][C:17]([C:19]2[S:20][C:21]([Cl:24])=[CH:22][CH:23]=2)=[O:18])[CH2:11]1)=[O:9])([CH3:6])([CH3:5])[CH3:4].FC(F)(F)S(O[CH2:31][CH:32]([F:34])[F:33])(=O)=O>CN(C=O)C.CCOC(C)=O>[C:3]([O:7][C:8]([N:10]1[CH2:14][C@H:13]([O:15][CH2:31][CH:32]([F:34])[F:33])[C@@H:12]([NH:16][C:17]([C:19]2[S:20][C:21]([Cl:24])=[CH:22][CH:23]=2)=[O:18])[CH2:11]1)=[O:9])([CH3:6])([CH3:4])[CH3:5]
Reactant: O=S(=O)(OCC(F)F)C(F)(F)F
Reactant: CC(C)(C)OC(=O)N1C[C@H](NC(=O)c2ccc(Cl)s2)[C@@H](O)C1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1C[C@H](NC(=O)c2ccc(Cl)s2)[C@@H](OCC(F)F)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 49.1 %

Procedure:
30.1 A suspension of 37 mg NaH (55% in oil) in 2 ml DMF was treated at 0° C. under an argon atmosphere with a solution of 270 mg (3S,4S)-3-[(5-chloro-thiophene-2-carbonyl)-amino]-4-hydroxy-pyrrolidine-1-carboxylic acid tert-butyl ester (example 22.4). The reaction mixture was stirred for 1 hr at r.t. Then, 334 mg 2,2-difluoroethyl trifluoromethanesulfonate were added at 0° C. The reaction mixture was stirred for 2 days at r.t., then diluted with EtOAc and washed with water. The organic layer was dried over MgSO4, filtered and concentrated. The crude product was isolated by chromatography (silica gel; gradient: cyclohexane->cyclohexane/EtOAc 9:1) to give 157 mg (3S,4S)-3-[(5-chloro-thiophene-2-carbonyl)-amino]-4-(2,2-difluoro-ethoxy)-pyrrolidine-1-carboxylic acid tert-butyl ester. Colorless solid. MS 409.0 ([M+H]+)
Reaction SMILES: [Mg:1].[CH3:2][N:3]1[CH2:8][CH2:7][CH2:6][CH:5]([CH2:9]Cl)[CH2:4]1.C(Br)CBr.[Cl:15]CC1CCCNC1>O1CCCC1>[CH3:2][N:3]1[CH2:8][CH2:7][CH2:6][CH:5]([CH2:9][Mg:1][Cl:15])[CH2:4]1
Reactant: CN1CCCC(CCl)C1
Reactant: [Mg]
Reactant: ClCC1CCCNC1
Solvent: C1CCOC1
Solvent: BrCCBr
Product: CN1CCCC(C[Mg]Cl)C1
Temperature: 25 °C

Procedure:
To 12.9 g of magnesium turnings of 50 ml of tetrahydrofuran, under nitrogen, was added several ml of a solution of 71.4 g of 1-methyl-3-chloromethylpiperidine in about 50 ml of tetrahydrofuran. Reaction was initiated by adding about 0.6 ml of ethylene dibromide. The remaining 3-chloromethylpiperidine solution then was added at a rate sufficient to maintain the reaction mixture at reflux temperature, with the concomitant addition of about 100 ml of tetrahdrofuran. When the addition of the 3-chloromethylpiperidine solution was complete, and additional 150 ml of tetrahydrofuran was added. The reaction mixture was warmed to maintain the reaction, after which the reaction mixture was heated at reflux for 1 hour. The reaction mixture then was cooled to ambient temperature and filtered through glass wool to remove excess magnesium.
Reaction SMILES: [F:1][C:2]1[C:12]([C:13]([OH:15])=O)=[CH:11][C:5]2[NH:6][C:7](=[O:10])[CH2:8][S:9][C:4]=2[CH:3]=1.[C:16]1([N:26]2[CH:34]=[C:33]3[C:28]([CH2:29][CH2:30][CH:31]([NH2:35])[CH2:32]3)=[N:27]2)[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH:19]=[CH:18][CH:17]=1.C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl>CN(C=O)C.CCOC(C)=O.[OH-].[Na+]>[C:16]1([N:26]2[CH:34]=[C:33]3[C:28]([CH2:29][CH2:30][CH:31]([NH:35][C:13]([C:12]4[C:2]([F:1])=[CH:3][C:4]5[S:9][CH2:8][C:7](=[O:10])[NH:6][C:5]=5[CH:11]=4)=[O:15])[CH2:32]3)=[N:27]2)[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH:19]=[CH:18][CH:17]=1
Reactant: O=C1CSc2cc(F)c(C(=O)O)cc2N1
Reactant: NC1CCc2nn(-c3cccc4ccccc34)cc2C1
Agent: On1nnc2ccccc21
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: O=C1CSc2cc(F)c(C(=O)NC3CCc4nn(-c5cccc6ccccc56)cc4C3)cc2N1
Temperature: 25 °C
Reaction time: 8 h
Yield: 8.6 %

Procedure:
To a solution of 7-fluoro-3-oxo-3,4-dihydro-2H-benzo[1,4]thiazine-6-carboxylic acid (17 mg, 0.076 mmol), 2-naphthalen-1-yl-4,5,6,7-tetrahydro-2H-indazol-5-ylamine (18 mg, 0.069 mmol), and HOBT (24.0 mg, 0.103 mmol) in DMF (1 mL) was added EDC (20.0 mg, 0.103 mmol). The reaction mixture was stirred overnight at RT. The reaction was diluted with EtOAc (10 mL) and 1 N NaOH (5 mL). The aqueous layer was extracted with EtOAc (3×10 mL). The combined organic layers were washed with 1 N HCl (10 mL), brine (10 mL), dried (MgSO4), filtered, and concentrated. The crude was purified by acidic reverse phase HPLC. The TFA salt of the title compound was diluted in CH3OH (10 mL) and treated with anionic exchange resin (550 Å, OH). The mixture was stirred at RT for 20 min. The mixture was filtered and the filtrate was concentrated to afford 2.8 mg (8%) of the title compound. MS (ESI): exact mass calculated for C26H21FN4O2S, 472.14; m/z found, 473.3 [M+H]+. 1H NMR (500 MHz, CDCl3): 8.76 (br s, 1H), 7.91-7.84 (m, 4H), 7.54-7.49 (m, 5H), 7.11 (d, J=11.4, 1H), 6.97-6.92 (m, 1H), 4.73-4.71 (m, 1H), 3.46 (s, 2H), 3.20 (dd, J=15.5, 5.0, 1H), 3.08-3.02 (m, 1H), 3.00-2.94 (m, 1H), 2.74 (dd, J=15.5, 7.0, 1H), 2.26-2.22 (m, 1H), 2.17-2.11 (m, 1H).
Reaction SMILES: [F-].C([N+](CCCC)(CCCC)CCCC)CCC.[Si]([O:26][CH2:27][CH2:28][CH2:29][CH2:30][C:31]([C:43]1[CH:48]=[C:47]([F:49])[CH:46]=[CH:45][C:44]=1[F:50])([S:33]([C:36]1[CH:41]=[CH:40][C:39]([Cl:42])=[CH:38][CH:37]=1)(=[O:35])=[O:34])[CH3:32])(C(C)(C)C)(C)C>O1CCCC1.C(OCC)C>[Cl:42][C:39]1[CH:38]=[CH:37][C:36]([S:33]([C:31]([C:43]2[CH:48]=[C:47]([F:49])[CH:46]=[CH:45][C:44]=2[F:50])([CH3:32])[CH2:30][CH2:29][CH2:28][CH2:27][OH:26])(=[O:35])=[O:34])=[CH:41][CH:40]=1
Reactant: CC(C)(C)[Si](C)(C)OCCCCC(C)(c1cc(F)ccc1F)S(=O)(=O)c1ccc(Cl)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: CCOCC
Product: CC(CCCCO)(c1cc(F)ccc1F)S(=O)(=O)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
After addition of tetrabutylammonium fluoride (a 1M tetrahydrofuran solution, 0.978 ml, 0.978 mmol) to a solution of 2-[5-(t-butyldimethylsilyloxy)-1-[(4-chlorophenyl)sulfonyl]-1-methylpentyl]-1,4-difluorobenzene (164 mg, 0.326 mmol) in tetrahydrofuran (4 ml), the mixture was stirred at room temperature for 3 hours. The reaction mixture was diluted with diethyl ether, washed successively with saturated ammonium chloride, water and brine, dried over MgSO4, and then concentrated. The residue thus obtained was purified by medium-pressure chromatography on a silica gel column (50% ethyl acetate-hexane), whereby the title compound (122 mg, 96%) was obtained as a colorless oil.