Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]=[S:2]1(=[O:24])[CH2:7][CH2:6][N:5]([C:8]2[C:13]([F:14])=[CH:12][C:11]([NH:15]C(=O)OCC(C)C)=[CH:10][C:9]=2[F:23])[CH2:4][CH2:3]1.[CH3:25][C:26]([CH3:29])([O-:28])[CH3:27].[Li+:30].CO.[C:33]([O:36][C@H:37]([CH2:43]Cl)[CH2:38][NH:39][C:40](=[O:42])[CH3:41])(=[O:35])C.C(O)(=O)C>C1COCC1.O>[CH3:25][C:26]([CH3:29])([O-:28])[CH3:27].[Li+:30].[O:24]=[S:2]1(=[O:1])[CH2:7][CH2:6][N:5]([C:8]2[C:13]([F:14])=[CH:12][C:11]([N:15]3[CH2:43][C@H:37]([CH2:38][NH:39][C:40](=[O:42])[CH3:41])[O:36][C:33]3=[O:35])=[CH:10][C:9]=2[F:23])[CH2:4][CH2:3]1
Reactant: CC(C)COC(=O)Nc1cc(F)c(N2CCS(=O)(=O)CC2)c(F)c1
Reactant: CC(=O)NC[C@@H](CCl)OC(C)=O
Agent: CC(C)(C)[O-]
Agent: [Li+]
Solvent: CC(=O)O
Solvent: C1CCOC1
Solvent: CO
Product: CC(=O)NC[C@H]1CN(c2cc(F)c(N3CCS(=O)(=O)CC3)c(F)c2)C(=O)O1
Temperature: 7.5 °C
Reaction time: 0.25 h
Yield: 73 %

Procedure:
A slurry of lithium t-butoxide (18.0 g, 223.5 mmol, 3.00 eq) in THF (100 ml) is prepared. Isobutyl 4-(1,1-dioxido-4-thiomorpholinyl)-3,5-difluorophenylcarbamate (27.0 g, 74.5 mmol) is dissolved in THF (180 ml) then added to the lithium t-butoxide slurry while maintaining less than 20° C. The mixture is stirred for 15 min then methanol (6.1 ml, 149 mmol, 2.0 eq) is added. (S)-N-[2-(acetyloxy)-3-chloropropyl]acetamide (28.9 g, 149 mmol, 2.0 eq) is dissolved in THF (1100 mL) and added to the reaction mixture over 1 h while maintaining the reaction temperature between 15 and 17° C. The cloudy light yellow/brown solution is stirred at 15 to 16° C. for 16 h. The reaction is then quenched with concentrated acetic acid (8.6 ml, 149 mmol, 2.0 eq) while maintaining less than 20° C. Water (75 ml) is added via addition funnel over 3 min. The phases are separated and the organic phase washed with water (20 ml). The organic phase is concentrated to approximately 200 ml total volume. Isopropanol (300 ml) is added slowly to the stirred orange solution via syringe pump at a rate of 2 ml/min. The yellow slurry is then cooled to approximately 5 to 10° C. and stirred for 30 min. The product is collected by vacuum filtration, washed with cold isopropanol (2×100 ml) and dried in vacuo at 60° C. overnight to give the title compound (22.0 g, 73%): HPLC retention time=3.0 min (99.8 area %); HPLC detection at 254 nm, isocratic elution solvent: 479.5 g buffer (1 l water, 1.57 g ammonium formate, formic acid to pH=3.2) and 409.1 g acetonitrile.
Reaction SMILES: [ClH:1].O1CCOCC1.C(OC(=O)[NH:14][CH:15]([C:34]1[CH:39]=[CH:38][C:37]([C:40]#[N:41])=[CH:36][C:35]=1[S:42][CH3:43])[C:16]1[C:21](=[O:22])[CH2:20][CH2:19][CH2:18][C:17]=1[NH:23][C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([C:30]([F:33])([F:32])[F:31])[CH:25]=1)(C)(C)C>C(#N)C>[ClH:1].[NH2:14][CH:15]([C:16]1[C:21](=[O:22])[CH2:20][CH2:19][CH2:18][C:17]=1[NH:23][C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([C:30]([F:33])([F:31])[F:32])[CH:25]=1)[C:34]1[CH:39]=[CH:38][C:37]([C:40]#[N:41])=[CH:36][C:35]=1[S:42][CH3:43]
Reactant: CSc1cc(C#N)ccc1C(NC(=O)OC(C)(C)C)C1=C(Nc2cccc(C(F)(F)F)c2)CCCC1=O
Agent: Cl
Solvent: CC#N
Solvent: C1COCCO1
Product: CSc1cc(C#N)ccc1C(N)C1=C(Nc2cccc(C(F)(F)F)c2)CCCC1=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of hydrogen chloride in 1,4-dioxane (4 M, 4.5 mL, 18 mmol) is added to a mixture of {(4-cyano-2-methylsulfanyl-phenyl)-[6-oxo-2-(3-trifluoromethyl-phenylamino)cyclohex-1-enyl]-methyl}-carbamic acid tert-butyl ester (INTERMEDIATE 4, 2.16 g, 3.25 mmol) in acetonitrile (4.5 mL) and the mixture is stirred at room temperature for 1 h. The precipitate is filtered off, washed with acetonitrile and dried. Yield: 1.19 g. ESI mass spectrum: [M+H-NH3]+=415; Retention time HPLC: 0.88 min (Z018_S04).
Reaction SMILES: [CH2:1]([O:3][CH:4]([O:7][CH2:8][CH3:9])[CH2:5][NH2:6])[CH3:2].[N+:10]([CH:13]=[C:14](SC)[S:15]([CH3:17])=O)([O-:12])=[O:11]>CO>[N+:10]([CH:13]=[C:14]([S:15][CH3:17])[NH:6][CH2:5][CH:4]([O:7][CH2:8][CH3:9])[O:3][CH2:1][CH3:2])([O-:12])=[O:11]
Reactant: CSC(=C[N+](=O)[O-])S(C)=O
Reactant: CCOC(CN)OCC
Solvent: CO
Product: CCOC(CNC(=C[N+](=O)[O-])SC)OCC
Yield: 49 %

Procedure:
A solution of aminoacetaldehyde diethylacetal (11 g, 0.08 mol) and 1-nitro-2-methylthio-2-methylsulphinylethylene (15 g, 0.08 mol) in methanol (200 ml) was stirred for 21/2 hours at room temperature. The solvent was removed in vacuo leaving a yellow oil residue which after trituration with propan-2-ol gave 1-nitro-2-methylthio-2-(2,2-diethoxyethylamino)ethylene (9.8, 49%) m.p. 72°-74°.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[CH3:11][N:12]([CH:22]1[CH2:26][CH:25]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH:24]([CH2:33][OH:34])[CH2:23]1)[S:13]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)(=[O:15])=[O:14].CCN(C(C)C)C(C)C.Cl>C(Cl)Cl>[CH3:11][N:12]([CH:22]1[CH2:26][CH:25]([C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH:24]([CH:33]=[O:34])[CH2:23]1)[S:13]([C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1)(=[O:14])=[O:15]
Reactant: CN(C1CC(CO)C(c2ccccc2)C1)S(=O)(=O)c1ccccc1
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Product: CN(C1CC(C=O)C(c2ccccc2)C1)S(=O)(=O)c1ccccc1
Temperature: -70 °C
Reaction time: 0.25 h
Yield: 83 %

Procedure:
To a solution of oxalyl chloride (0.045 mL, 0.50 mmol) in methylene chloride (2 mL) at −70° C. was added dropwise DMSO (0.045 mL, 1.0 mmol). After 15 min, a solution of 1-(RS)-(N-(methyl)-N-(phenylsulfonyl)amino)-3-(SR)-(hydroxymethyl)-4-(SR)-phenylcyclopentane (Higher Rf isomer from Step C) (65 mg, 0.2 mmol) in methylene chloride (2 mL) was added. The reaction was stirred at −70° C. for 1.5 h and then DIPEA (0.35 mL, 2.0 mmol) was added. After a further 10 min, the mixture was allowed to warm to RT for 1 h and was then diluted with methylene chloride and poured into dilute aq. HCl and the layers were separated. The aq. layer was reextracted with a second portion of methylene chloride and the organic layers were each washed with brine, dried over sodium sulfate, combined and concentrated in vacuo. The residue was purified by FC using a gradient of 20 to 30% ethyl acetate in hexanes to give the title product (57 mg) as an oil.
Reaction SMILES: C(OC(N1[CH2:35][CH2:34][C:11]2(OC[CH2:14][N:13]([CH2:17][C:18]3[S:26][C:25]4[C:24]([N:27]5[CH2:32][CH2:31][O:30][CH2:29][CH2:28]5)=[N:23][C:22]([Cl:33])=[N:21][C:20]=4[CH:19]=3)[CH2:12]2)CC1)=O)(C)(C)C.[N:36]1(C2CCNCC2)[CH2:39][CH2:38][CH2:37]1>>[N:36]1([CH:34]2[CH2:35][CH2:14][N:13]([CH2:17][C:18]3[S:26][C:25]4[C:24]([N:27]5[CH2:32][CH2:31][O:30][CH2:29][CH2:28]5)=[N:23][C:22]([Cl:33])=[N:21][C:20]=4[CH:19]=3)[CH2:12][CH2:11]2)[CH2:39][CH2:38][CH2:37]1
Reactant: CC(C)(C)OC(=O)N1CCC2(CC1)CN(Cc1cc3nc(Cl)nc(N4CCOCC4)c3s1)CCO2
Reactant: C1CN(C2CCNCC2)C1
Product: Clc1nc(N2CCOCC2)c2sc(CN3CCC(N4CCC4)CC3)cc2n1

Procedure:
Prepared according to the method used in the preparation of 4-(2-chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidin-6-ylmethyl)-1-oxa-4,9-diaza-spiro[5.5]undecane-9-carboxylic acid tert-butyl ester using 4-azetidin-1-yl-piperidine in place of 4-ethoxy-4-methylaminomethyl-piperidine-1-carboxylic acid tert-butyl ester. The title compound was obtained as an off-white solid (219 mg, 48%).
Reaction SMILES: [C:1]([C:3]1[S:7][C:6]([S:8][CH3:9])=[N:5][C:4]=1[N:10]=[CH:11][N:12](C)C)#[N:2].N[C:16]1[CH:21]=[C:20]([CH3:22])[CH:19]=[CH:18][C:17]=1[S:23][C:24]1[CH:29]=[CH:28][C:27]([NH:30][C:31](=[O:33])[CH3:32])=[CH:26][CH:25]=1.NC1C=C(OCC2C=CC=C(Br)C=2)C=CC=1SC1C=CC(O)=CC=1>>[CH3:22][C:20]1[CH:21]=[CH:16][C:17]([S:23][C:24]2[CH:29]=[CH:28][C:27]([NH:30][C:31](=[O:33])[CH3:32])=[CH:26][CH:25]=2)=[C:18]([NH:2][C:1]2[C:3]3[S:7][C:6]([S:8][CH3:9])=[N:5][C:4]=3[N:10]=[CH:11][N:12]=2)[CH:19]=1
Reactant: CC(=O)Nc1ccc(Sc2ccc(C)cc2N)cc1
Reactant: CSc1nc(N=CN(C)C)c(C#N)s1
Agent: Nc1cc(OCc2cccc(Br)c2)ccc1Sc1ccc(O)cc1
Product: CSc1nc2ncnc(Nc3cc(C)ccc3Sc3ccc(NC(C)=O)cc3)c2s1
Yield: 83 %

Procedure:
A solution of the product from Example 167A and the product from Example 7b were reacted according to the procedure from Example 167B substituting the product from Example 7b for the product from Example 15A to provide the crude material which was purified by trituration with methanol to provide the title compound (110 mg, 83%). 1H NMR (300 MHz, DMSO-D6) δ ppm: 2.03 (s, 3H), 2.29 (s, 3H), 2.76 (s, 3H), 6.96 (d, J=8.09 Hz, 1H), 7.14 (d, J=8.09 Hz, 1H), 7.18-7.26 (m, J=8.82 Hz, 3H), 7.54 (d, J=8.46 Hz, 2H), 8.45 (s, 1H), 9.74 (s, 1H), 10.04 (s, 1H); MS (ESI)+ m/z 454 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[O:9][CH2:8][CH2:7][N:6]3[C:10](=[O:26])[C:11]([CH:18]([C:24]#[N:25])[C:19]([O:21][CH2:22][CH3:23])=[O:20])([CH2:14][N+:15]([O-])=O)[C:12]([CH:13]=1)=[C:5]23.P(Cl)(Cl)Cl.O>N1C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]2[O:9][CH2:8][CH2:7][N:6]3[C:10](=[O:26])[C:11]([CH:18]([C:24]#[N:25])[C:19]([O:21][CH2:22][CH3:23])=[O:20])([C:14]#[N:15])[C:12]([CH:13]=1)=[C:5]23
Reactant: CCOC(=O)C(C#N)C1(C[N+](=O)[O-])C(=O)N2CCOc3cc(Cl)cc1c32
Solvent: c1ccncc1
Solvent: ClP(Cl)Cl
Solvent: O
Product: CCOC(=O)C(C#N)C1(C#N)C(=O)N2CCOc3cc(Cl)cc1c32
Temperature: 25 °C
Reaction time: 4.5 h

Procedure:
To a solution of ethyl 2-(8-chloro-2,3-dihydro-6-nitromethyl-5-oxopyrrolo[1,2,3-de]-1,4-benzoxazine-6-yl)-2-cyanoacetate (3 g) in pyridine (30 ml) was added phosphorous trichloride (1.6 g) on an ice bath, and stirred at room temperature for 4.5 hours. The reaction mixture was poured into water and extracted with ethyl acetate. After removal of solvent, the title compound was obtained as dark reddish oil (0.9 g, 33%) by purification.
Reaction SMILES: [C:1]1([C:7]2[C:8]([C:16]3[CH:23]=[CH:22][C:19]([CH:20]=O)=[CH:18][CH:17]=3)=[N:9][C:10]3[N:11]([N:13]=[CH:14][CH:15]=3)[CH:12]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH:24]1[CH2:29][CH2:28][CH:27]([N:30]2[C:34]3=[N:35][CH:36]=[N:37][C:38]([NH2:39])=[C:33]3[CH:32]=[N:31]2)[CH2:26][CH2:25]1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>>[C:1]1([C:7]2[C:8]([C:16]3[CH:23]=[CH:22][C:19]([CH2:20][N:24]4[CH2:29][CH2:28][CH:27]([N:30]5[C:34]6=[N:35][CH:36]=[N:37][C:38]([NH2:39])=[C:33]6[CH:32]=[N:31]5)[CH2:26][CH2:25]4)=[CH:18][CH:17]=3)=[N:9][C:10]3[N:11]([N:13]=[CH:14][CH:15]=3)[CH:12]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Nc1ncnc2c1cnn2C1CCNCC1
Reactant: O=Cc1ccc(-c2nc3ccnn3cc2-c2ccccc2)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Product: Nc1ncnc2c1cnn2C1CCN(Cc2ccc(-c3nc4ccnn4cc3-c3ccccc3)cc2)CC1
Reaction time: 8 h
Yield: 25.6 %

Procedure:
250 mg (0.84 mmol) 4-(6-phenylpyrazolo[1,5-a]pyrimidin-5-yl)benzaldehyde and 257 mg (1 mmol) 1-piperidine-4-yl-1H-pyrazolo[3,4-d]pyrimidin-4-ylamine were treated as previously described. Additional NaBH(OAc)3 has been added after one, two and three hours (two equivalents each). After a further stirring at room temperature additional 26 mg 1-piperidine-4-yl-1H-pyrazolo[3,4-d]pyrimidin-4-ylamine and two equivalents NaBH(OAc)3 were added. After stirring overnight and two further additions of NaBH(OAc)3 the solvents were evaporated. Workup und purification yields 108 mg of the desired compound.
Reaction SMILES: [O:1]=[C:2]1[NH:7][CH2:6][C@@H:5]([NH:8]C(OC(C)(C)C)=O)[CH2:4][CH2:3]1.C([Cl:19])(=O)C.C1(N)C(F)=C(F)C(F)=C(N)C=1F.Cl.Cl>C(O)C>[ClH:19].[NH2:8][C@@H:5]1[CH2:6][NH:7][C:2](=[O:1])[CH2:3][CH2:4]1
Reactant: CC(C)(C)OC(=O)N[C@H]1CCC(=O)NC1
Reactant: CC(=O)Cl
Agent: Cl
Agent: Nc1c(F)c(N)c(F)c(F)c1F
Solvent: CCO
Product: N[C@H]1CCC(=O)NC1
Temperature: 0 °C
Reaction time: 1 h
Yield: 99 %

Procedure:
N-((3S)-6-oxo(3-piperidyl))(tert-butoxy)carboxamide (3.9 mmol, 0.83 g) were dissolved in ethanol (10 mL) and cooled to 0° C. Acetyl chloride (2 mL) was added and the reaction was allowed to reach room temperature. The reaction was stirred for 1 hour after which the solvent was removed in vacuo to yield the title compound (725 mg, 99% yield) as the dihydrochloride salt. ES-MS: 115 (M+1).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH3:27])[CH2:9][CH2:10][CH2:11][N:12]1[CH2:21][CH2:20][C:19]2[C:14](=[CH:15][CH:16]=[C:17](C(OC)=O)[CH:18]=2)[C:13]1=[O:26])=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+].Cl.[N-:31]=[N+]=[N-].P([O-])(OC1C=CC=CC=1)(OC1C=CC=CC=1)=O.C(N(CC)CC)C.C(O)C1C=CC=CC=1>O1CCCC1.CO.C(OCC)(=O)C>[NH2:31][C:17]1[CH:18]=[C:19]2[C:14](=[CH:15][CH:16]=1)[C:13](=[O:26])[N:12]([CH2:11][CH2:10][CH2:9][N:8]([CH3:27])[C:6](=[O:7])[O:5][C:1]([CH3:4])([CH3:3])[CH3:2])[CH2:21][CH2:20]2
Reactant: [N-]=[N+]=[N-]
Reactant: COC(=O)c1ccc2c(c1)CCN(CCCN(C)C(=O)OC(C)(C)C)C2=O
Agent: Cl
Agent: O=P([O-])(Oc1ccccc1)Oc1ccccc1
Agent: [Na+]
Solvent: OCc1ccccc1
Solvent: CCN(CC)CC
Solvent: CO
Product: CN(CCCN1CCc2cc(N)ccc2C1=O)C(=O)OC(C)(C)C
Temperature: 60 °C
Reaction time: 5 h
Yield: 40.6 %

Procedure:
The compound (535 mg, 1.41 mmol) obtained in Example 61c was dissolved in a mixed solvent (6 mL) of tetrahydrofuran and methanol (1:1), a 1 N aqueous sodium hydroxide solution (1 mL) was added, and the mixture was stirred at 60° C. for 5 hours. After the reaction was completed, a 1 N aqueous hydrochloric acid solution (10 mL) was added to the reaction mixture under ice cooling, and ethyl acetate was further added to separate the layers. The resulting organic layer was separated, washed with saturated sodium chloride solution, and then dried with anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The resulting residue was dissolved in 1,4-dioxane (6 mL), diphenyl phosphate azide (0.238 mL, 1.10 mmol), triethylamine (0.154 mL, 1.10 mmol) and benzyl alcohol (0.228 mL, 2.21 mmol) were added under ice cooling, and the mixture was stirred at 100° C. under a nitrogen atmosphere for 16 hours. After the reaction was completed, the solvent was evaporated under reduced pressure. The resulting residue was dissolved in a mixed solvent (12 mL) of ethyl acetate and methanol (1:2), 10% palladium-carbon (53 mg) was added, and the mixture was stirred at room temperature under a hydrogen atmosphere for 1 hour. After the reaction was completed, the reaction mixture was filtered through celite, the filtrate was washed with ethanol, and the solvent was evaporated under reduced pressure. The residue was purified by NH silica gel column chromatography (ethyl acetate:methanol, 10:1, v/v) to give the title compound (149 mg; yield, 81%) as a colorless oily substance.
Reaction SMILES: [CH:1]1([CH2:11][C:12](=O)[CH3:13])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][O:2]1.C([O-])(=O)C.[NH4+].CO.C([BH3-])#[N:23].[Na+]>C(O)(=O)C.C1COCC1>[CH:1]1([CH2:11][CH:12]([NH2:23])[CH3:13])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][O:2]1
Reactant: [BH3-]C#N
Reactant: CC(=O)CC1OCCc2ccccc21
Agent: CC(=O)[O-]
Agent: [NH4+]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CC(=O)O
Solvent: CO
Product: CC(N)CC1OCCc2ccccc21
Reaction time: 0.42 h

Procedure:
A mixture of (-)-(isochroman-1-yl)acetone (LXXXIV, 0.73 g), ammonium acetate (1.48 g), methanol (2.5 ml), and THF (2.5 ml) is stirred for 25 min and then acetic acid (1.5 ml) and sodium cyanoborohydride (0.48 g) are added. After stirring for 2 hr, the mixture is concentrated and the residue is stirred with dichloromethane and sodium hydroxide (4N). The mixture is extracted with dichloromethane and washed with saline/sodium hydroxide (1N). The organic phase is separated and dried over sodium sulfate to give 2-[(-)-isochroman-1-yl]-(±)-1-methylethylamine.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[N:6]([CH3:19])[C:7]([S:10]([N:13]2[CH2:17][CH2:16][C@H:15]([OH:18])[CH2:14]2)(=[O:12])=[O:11])=[CH:8][CH:9]=1)=[O:4].C(N(CC)CC)C.[CH3:27][S:28](Cl)(=[O:30])=[O:29]>C(Cl)Cl>[CH3:1][O:2][C:3]([C:5]1[N:6]([CH3:19])[C:7]([S:10]([N:13]2[CH2:17][CH2:16][C@H:15]([O:18][S:28]([CH3:27])(=[O:30])=[O:29])[CH2:14]2)(=[O:11])=[O:12])=[CH:8][CH:9]=1)=[O:4]
Reactant: COC(=O)c1ccc(S(=O)(=O)N2CC[C@H](O)C2)n1C
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)c1ccc(S(=O)(=O)N2CC[C@H](OS(C)(=O)=O)C2)n1C
Temperature: 25 °C
Reaction time: 2 h
Yield: 100.4 %

Procedure:
To a solution of (S)-5-(3-hydroxy-pyrrolidine-1-sulfonyl)-1-methyl-1H-pyrrole-2-carboxylic acid methyl ester (Ex. 13a, 6.1 g, 21.2 mmol) and triethylamine (8.9 mL, 63.5 mmol) in methylene chloride (75 mL) at 0° C. was added methanesulfonyl chloride (2.4 mL, 31.8 mmol). The resulting solution was warmed to room temperature and stirred at room temperature for 2 h. Upon completion, as determined by HPLC, the reaction was quenched with 1N HCl (150 mL) and diluted with water (100 mL). The layers were cut and the organic layer was washed with 1N HCl (2×100 mL), a 50% aqueous brine solution (1×100 mL) and brine (1×100 mL), dried over Na2SO4, and concentrated under reduced pressure to afford 7.8 g (99%) of (S)-5-(3-methanesulfonyloxy-pyrrolidine-1-sulfonyl)-1-methyl-1H-pyrrole-2-carboxylic acid methyl ester as an orange foam. This material was used without further purification. 1H-NMR (400 MHz, CDCl3): δ 7.27 (d, 1H, J=2.0 Hz), 7.17 (d, 1H, J=2.0 Hz), 5.15-5.17 (m, 1H), 3.97 (s, 3H), 3.84 (s, 3H), 3.43-3.60 (m, 3H), 3.30-3.37 (m, 1H), 2.94 (s, 3H), 2.17-2.23 (m, 1H), 2.09-2.16 (m, 1H). mp 79-81° C. Anal. Calcd. for C12H18N2O7S2: C, 39.34; H, 4.95; N, 7.65; S, 17.50. Found: C, 39.20; H, 5.00; N, 7.56; S, 17.66.
Reaction SMILES: [S:1]1[CH2:6][CH2:5][CH2:4][S:3][CH2:2]1.C([Li])CCC.[CH2:12]([O:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C@@H:13]1[O:15][CH2:14]1>C1COCC1>[CH2:17]([O:16][CH2:12][C@H:13]([OH:15])[CH2:14][CH:2]1[S:3][CH2:4][CH2:5][CH2:6][S:1]1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: c1ccc(COC[C@H]2CO2)cc1
Reactant: C1CSCSC1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: O[C@@H](COCc1ccccc1)CC1SCCCS1
Temperature: -30 °C
Reaction time: 1 h
Yield: 84.9 %

Procedure:
A solution containing 1,3-dithiane (11 g) in THF (190 mL) was cooled to −70° C. n-Butyllithium (2.64 M solution in hexane, 35 mL) was added to the reaction solution, and then the mixture was heated to −30° C. and stirred for one hour. The reaction solution was cooled to −70° C., and a solution containing benzyl (R)-(−)-glycidyl ether (16.5 g) in THF (18 mL) was added dropwise. The cooling bath was removed and the mixture was gradually warmed to room temperature. After stirring overnight, a saturated ammonium chloride solution, brine and t-butyl methyl ether were added to the reaction solution, and the organic layer was separated. The organic layer was washed with brine and dried over anhydrous magnesium sulfate. The drying agent was removed by filtration and then the filtrate was concentrated under reduced pressure to obtain a residue. The residue was subjected to silica gel column chromatography to obtain the title compound (22.1 g).
Reaction SMILES: [NH2:1][C:2]1[C:11]([F:12])=[C:10](F)[CH:9]=[C:8]2[C:3]=1[C:4](=[O:20])[C:5]([C:17]([OH:19])=[O:18])=[CH:6][N:7]2[CH:14]1[CH2:16][CH2:15]1.[C:21]([N:24]1[CH2:29][CH2:28][NH:27][CH2:26][CH:25]1[CH3:30])(=[O:23])[CH3:22]>N1C=CC=CC=1>[C:21]([N:24]1[CH2:29][CH2:28][N:27]([C:10]2[CH:9]=[C:8]3[C:3]([C:4](=[O:20])[C:5]([C:17]([OH:19])=[O:18])=[CH:6][N:7]3[CH:14]3[CH2:16][CH2:15]3)=[C:2]([NH2:1])[C:11]=2[F:12])[CH2:26][CH:25]1[CH3:30])(=[O:23])[CH3:22]
Reactant: CC(=O)N1CCNCC1C
Reactant: Nc1c(F)c(F)cc2c1c(=O)c(C(=O)O)cn2C1CC1
Solvent: c1ccncc1
Product: CC(=O)N1CCN(c2cc3c(c(N)c2F)c(=O)c(C(=O)O)cn3C2CC2)CC1C

Procedure:
A mixture of 5-amino-1-cyclopropyl-6,7-difluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid, 1-acetyl-2-methylpiperazine and pyridine was heated under reflux for 5 hours. The reaction mixture was concentrated under reduced pressure, and the residue was dissolved in aqueous ammonia. The solution was neutralized with an aqueous solution of acetic acid and cooled with ice. The crystals were collected by filtration to give 7-(4-acetyl-3-methyl-1-piperazinyl)-5-amino-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid. It was recrystallized from ethanol/chloroform. m.p. 269°-271° C.
Reaction SMILES: [SH2:1].[Na].Cl[C:4]1[CH:17]=[CH:16][C:7]([C:8]([C:10]2[CH:15]=[CH:14][N:13]=[CH:12][CH:11]=2)=[O:9])=[CH:6][CH:5]=1.O>CN(C=O)C>[SH:1][C:4]1[CH:17]=[CH:16][C:7]([C:8]([C:10]2[CH:15]=[CH:14][N:13]=[CH:12][CH:11]=2)=[O:9])=[CH:6][CH:5]=1
Reactant: S
Reactant: O=C(c1ccncc1)c1ccc(Cl)cc1
Agent: [Na]
Solvent: O
Solvent: CN(C)C=O
Product: O=C(c1ccncc1)c1ccc(S)cc1
Yield: 48.5 %

Procedure:
A suspension of sodium hydrogen sulfide (6 g) in DMF (100 ml) was heated to reflux for 1 h, then cooled and 4-(4-chlorobenzoyl)pyridine (5 g) was added. The mixture was heated at reflux for 2 h, then cooled and added to water. The brown solution was washed with ether, then acidified with citric acid and extracted with dichloromethane (2×100 ml). The solvent was dried and evaporated to give the title compound as beige powder (2.4 g, 50%).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10](F)[CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].C(=O)([O-])[O-].[K+].[K+].[CH3:19][C:20]1[CH:24]=[CH:23][NH:22][N:21]=1.O>CN1CCCC1=O>[Cl:1][C:2]1[CH:11]=[C:10]([N:22]2[CH:23]=[CH:24][C:20]([CH3:19])=[N:21]2)[CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5]
Reactant: COC(=O)c1ccc(F)cc1Cl
Reactant: Cc1cc[nH]n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN1CCCC1=O
Solvent: O
Product: COC(=O)c1ccc(-n2ccc(C)n2)cc1Cl
Temperature: 120 °C
Reaction time: 3 h

Procedure:
20.85 g of methyl 2-chloro-4-fluorobenzoate were dissolved in 150 ml of N-methylpyrrolidone, 30.68 g of potassium carbonate and 9.38 ml of 3-methylpyrazole were added thereto, and the mixture was stirred at 120° C. for 3 hours. Additionally, thereto was added 1.79 ml of 3-methylpyrazole, and the mixture was stirred at 120° C. for 3 hours. The reaction solution was cooled, mixed with water, and extracted with EtOAc. The organic layer was washed with water and brine, and then dried over magnesium sulfate. The solvent was evaporated, and then the residue was purified by silica gel column chromatography (hexane-EtOAc (20:1)) to obtain 9.25 g of methyl 2-chloro-4-(3-metyl-1H-pyrazol-1-yl)benzoate.
Reaction SMILES: [C:1]1([CH2:7][C:8](Cl)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[S-:11][C:12]#[N:13].[K+].O>C(#N)C>[C:1]1([CH2:7][C:8]([N:13]=[C:12]=[S:11])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: N#C[S-]
Reactant: O=C(Cl)Cc1ccccc1
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: O=C(Cc1ccccc1)N=C=S
Temperature: 80 °C

Procedure:
According to the descrition of technical literature, commercially available 2-phenylethanoyl chloride (80 mg) was dissolved in acetonitrile (20 ml). Potassium thiocyanate (300 mg) was added to the solution, and the mixture was heated at 80° C. for 2 hr. Water was added to the reaction solution, and the organic layer was extracted and was concentrated to give 2-phenylethanoyl isothiocyanate. 2-Phenylethanoyl isothiocyanate thus obtained was dissolved in ethanol (1 ml) to prepare a solution. 4-[(6,7-Dimethoxy-4-quinolyl)oxy]-3-fluoroaniline (50 mg), toluene (5 ml), and ethanol (1 ml) were added to the solution, and the mixture was stirred at room temperature for 2 hr. The reaction solution was concentrated, and the residue was purified by chromatography on silica gel using chloroform/acetone for development to give the title compound (66 mg, yield 85%) (Referenc: Elmore, D. T. et al., Journal of chemical Society 1956, 4458).
Reaction SMILES: N(C(OCC)=O)=NC(OCC)=O.[CH3:13][C:14]1[O:18][C:17]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[N:16][C:15]=1[CH:25]([OH:27])[CH3:26].[CH3:28][O:29][C:30]1[CH:31]=[C:32]([CH:37]=[O:38])[CH:33]=[CH:34][C:35]=1O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O1CCCC1>[CH3:28][O:29][C:30]1[CH:31]=[C:32]([CH:33]=[CH:34][C:35]=1[O:27][CH:25]([C:15]1[N:16]=[C:17]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[O:18][C:14]=1[CH3:13])[CH3:26])[CH:37]=[O:38]
Reactant: COc1cc(C=O)ccc1O
Reactant: Cc1oc(-c2ccccc2)nc1C(C)O
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COc1cc(C=O)ccc1OC(C)c1nc(-c2ccccc2)oc1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 54 %

Procedure:
Diethyl azodicarboxylate (DEAD) (4.71 g) was added dropwise, under ice-cooling, to a mixture of 1-(5-methyl-2-phenyl-4-oxazolyl)ethanol (5.0 g), vanilline (3.75 g), triphenylphosphine (Ph3P) (7.1 g) and tetrahydrofuran (THF) (80 ml). The reaction mixture was stirred for 8 hours at room temperature and concentrated under reduced pressure. The residue was subjected to column chromatography on silica gel. From the fraction eluted with ethyl acetate-hexane (1:4, v/v), was obtained 3-methoxy-4-[1-(5-methyl-2-phenyl-4-oxazolyl)ethoxy]benzaldehyde (4.48 g, 54%), which was recrystallized from ethyl acetate-hexane to give colorless needles, m.p.104-105° C.