Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[N:9]=[CH:8][C:7]([N:10]2[CH2:15][CH2:14][O:13][CH2:12][CH2:11]2)=[CH:6][CH:5]=1)([O-])=O>C1COCC1.[Ni]>[N:10]1([C:7]2[CH:6]=[CH:5][C:4]([NH2:1])=[N:9][CH:8]=2)[CH2:15][CH2:14][O:13][CH2:12][CH2:11]1
Reactant: O=[N+]([O-])c1ccc(N2CCOCC2)cn1
Agent: [Ni]
Solvent: C1CCOC1
Product: Nc1ccc(N2CCOCC2)cn1
Reaction time: 4 h
Yield: 77.8 %

Procedure:
4-(6-Nitro-pyridin-3-yl)-morpholine (2.86 g, 13.7 mmol) was dissolved in THF (100 mL) to which Raney Nickel (1.03 g) was added. The reaction mixture was shaken under a hydrogen atmosphere (50 psi) for 4 hours. The catalyst was removed by filtration and the solvent evaporated to give 5-morpholin-4-yl-pyridin-2-ylamine as a purple solid (1.91 g, 78.0%). 1H NMR δ (400 MHz, CDCl3) 7.76 (d, J=2.0 Hz, 1H), 7.16 (dd, J=2.7, 8.8 Hz, 1H), 6.50 (d, J=8.8 Hz, 1H), 4.24 (s, 2H), 3.84 (m, 4H), 3.16 (m, 4H), 3.01 (m, 4H).
Reaction SMILES: [C:1](Cl)(=O)C.[OH:5][C@@H:6]1[C@H:10]([OH:11])[CH:9]([OH:12])[O:8][C@@H:7]1[CH2:13][OH:14].C[O-].[Na+].CO>CO.C1(C)C=CC=CC=1>[OH:5][C@@H:6]1[C@H:10]([OH:11])[CH:9]([O:12][CH3:1])[O:8][C@@H:7]1[CH2:13][OH:14]
Reactant: CC(=O)Cl
Reactant: OC[C@H]1OC(O)[C@@H](O)[C@H]1O
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: Cc1ccccc1
Product: COC1O[C@H](CO)[C@H](O)[C@@H]1O
Reaction time: 1 h

Procedure:
720 mL of acetyl chloride was added dropwise to 1200 mL of a methanol solution of 12.0 kg of (2R,3R,4S)-3,4,5-trihydroxy-2-hydroxymethyloxolane at a temperature of 15° C. or lower over 30 minutes, and the obtained mixture was then stirred at a temperature of 20° C. to 30° C. for 1 hour. Thereafter, 2100 mL of a 28% sodium methoxide/methanol solution and 1000 mL of toluene were added to the reaction mixture, and methanol was then distilled away under reduced pressure, to obtain 4500 mL of a toluene solution of (2R,3R,4S)-3,4-dihydroxy-2-hydroxymethyl-5-methoxyoxolane.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:10][C:11]([OH:13])=[O:12])[CH:6]=[CH:7][C:8]=1[CH3:9].[CH3:14][C:15]1C=CC(S(O)(=O)=O)=CC=1>C(O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH:6]=[CH:7][C:8]=1[CH3:9]
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: COc1cc(CC(=O)O)ccc1C
Solvent: CCO
Product: CCOC(=O)Cc1ccc(C)c(OC)c1

Procedure:
To a stirred solution of 2-(3-methoxy-4-methylphenyl)acetic acid (Step A, 4.64 g, 25.7 mmol) in ethanol (100 ml) was added p-TsOH (0.7 g, 3.7 mmol) at room temperature under argon and the reaction mixture was refluxed for 12 hours or until all the starting material is consumed, concentrated, diluted in EtOAc and washed with 0.1N HCl, brine, dried over Na2SO4, filtered, concentrated and purified by flash chromatography on a silica gel column (hexane:ethyl acetate, 2:1) to give the title compound.
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[O:6]1[C:11]([C:12](=[N:16][O:17][CH2:18][CH2:19][CH3:20])[C:13]([OH:15])=O)=[CH:10][S:9][CH2:8][CH2:7]1.[NH2:21][CH:22]1[C:42](=[O:43])[N:24]2[C:25]([C:29]([O:31][CH2:32][C:33]3[CH:38]=[CH:37][C:36]([N+:39]([O-:41])=[O:40])=[CH:35][CH:34]=3)=[O:30])=[CH:26][CH2:27][S:28][C@H:23]12.C[Si](CC(N)=O)(C)C.C[Si](C([Si](C)(C)C)C(N)=O)(C)C>C(OCC)(=O)C.O.CN(C)C=O>[O:6]1[C:11]([C:12](=[N:16][O:17][CH2:18][CH2:19][CH3:20])[C:13]([NH:21][CH:22]2[C:42](=[O:43])[N:24]3[C:25]([C:29]([O:31][CH2:32][C:33]4[CH:34]=[CH:35][C:36]([N+:39]([O-:41])=[O:40])=[CH:37][CH:38]=4)=[O:30])=[CH:26][CH2:27][S:28][C@H:23]23)=[O:15])=[CH:10][S:9][CH2:8][CH2:7]1
Reactant: NC1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=CCS[C@H]12
Reactant: CCCON=C(C(=O)O)C1=CSCCO1
Agent: C[Si](C)(C)C(C(N)=O)[Si](C)(C)C
Agent: C[Si](C)(C)CC(N)=O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O
Product: CCCON=C(C(=O)NC1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=CCS[C@H]12)C1=CSCCO1
Reaction time: 2 h
Yield: 83.1 %

Procedure:
Dry N,N-dimethylformamide (1.26 ml.), phosphoryl chloride (1.48 ml.), 2-(2,3-dihydro-1,4-oxathiin-6-yl)-2-n-propoxyiminoacetic acid (syn isomer, 3.48 g.) and dry ethyl acetate (5 ml.) were treated in a conventional manner to give an activated acid solution. On the other hand, a solution of 4-nitrobenzyl 7-amino-3-cephem-4-carboxylate (5.0 g.) trimethylsilylacetamide (12.6 g.) and bis(trimethylsilyl)acetamide (8.3 g.) in ethyl acetate (700 ml.) was stirred at 40° C. for an hour. The activated acid solution was added all at once to the solution at -30° C. and stirred at -10° to -30° C. for 2 hours. After adding water (50 ml.) to the resultant solution, the ethyl acetate layer was separated. The solution was washed with a saturated aqueous solution of sodium bicarbonate and a saturated aqueous solution of sodium chloride in turn, dried over magnesium sulfate and concentrated in vacuo. The residue was pulverized with diisopropyl ether, and the precipitates were collected by filtration and washed with diisopropyl ether to give 4-nitrobenzyl 7-[2-(2,3-dihydro-1,4-oxathiin-6-yl)-2-n-propoxyiminoacetamido]-3-cephem-4-carboxylate (syn isomer, 6.80 g.).
Reaction SMILES: [C:1]1([C:7]2[N:11]3[CH:12]=[C:13]([C:20]([O:22]C)=[O:21])[C:14]4[C:19]([C:10]3=[CH:9][N:8]=2)=[CH:18][CH:17]=[CH:16][CH:15]=4)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[Na+]>CO.O>[C:1]1([C:7]2[N:11]3[CH:12]=[C:13]([C:20]([OH:22])=[O:21])[C:14]4[C:19]([C:10]3=[CH:9][N:8]=2)=[CH:18][CH:17]=[CH:16][CH:15]=4)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: COC(=O)c1cn2c(-c3ccccc3)ncc2c2ccccc12
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C(O)c1cn2c(-c3ccccc3)ncc2c2ccccc12
Yield: 96.7 %

Procedure:
A slurry of the product from part 8 (488 mg) and NaOH (226 mg) in 15 ml of methanol and 10 ml of water is stirred at 60° C. until a solution forms. The methanol is then evaporated in vacuo, and the remaining mixture is diluted with water. After adjusting the pH to 5-6 with 1N HCl, the solid is collected by filtration, washed with water and dried to give the title compound (450 mg) as a yellow solid, m.p. 187-90° C.
Reaction SMILES: [O:1]=[C:2]1[N:7]2[CH:8]=[C:9]([C:12](O)=[O:13])[CH:10]=[CH:11][C:6]2=[N:5][C:4]2[CH2:15][S:16][CH2:17][C:3]1=2.C[N:19](C)C=O>O1CCCC1>[O:1]=[C:2]1[N:7]2[CH:8]=[C:9]([C:12]([NH2:19])=[O:13])[CH:10]=[CH:11][C:6]2=[N:5][C:4]2[CH2:15][S:16][CH2:17][C:3]1=2
Reactant: O=C(O)c1ccc2nc3c(c(=O)n2c1)CSC3
Reactant: CN(C)C=O
Solvent: C1CCOC1
Product: NC(=O)c1ccc2nc3c(c(=O)n2c1)CSC3

Procedure:
A mixture of 3,10-dihydro-10-oxo-1H-pyrido[1,2-a]thieno[3,4-d]pyrimidine-7-carboxylic acid (4.4 g., 0.018 mol) and 1,1'-carboxyldiimidazole (2.9 g., 0.018 mol) in tetrahydrofuran (300 ml) and dimethylformamide (4 ml) is refluxed under nitrogen for 3.5 hours. The solution is cooled in an ice bath and anhydrous ammonia is bubbled through for 45 minutes. The precipitate is filtered off, washed with hot 0.5 M. aqueous sodium bicarbonate solution, with hot dimethylformamide with ether and dried to give a yellow powder (2.9 g.). mp 285° C. (dec).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([O:12][CH3:13])[C:9]=1[O:10][CH3:11])[CH:5]=[O:6].N1C=CN=C1.Cl[Si:20]([CH:27]([CH3:29])[CH3:28])([CH:24]([CH3:26])[CH3:25])[CH:21]([CH3:23])[CH3:22].O>CN(C=O)C.C(OCC)(=O)C>[CH3:13][O:12][C:8]1[CH:7]=[C:4]([CH:3]=[C:2]([O:1][Si:20]([CH:27]([CH3:29])[CH3:28])([CH:24]([CH3:26])[CH3:25])[CH:21]([CH3:23])[CH3:22])[C:9]=1[O:10][CH3:11])[CH:5]=[O:6]
Reactant: COc1cc(C=O)cc(O)c1OC
Reactant: CC(C)[Si](Cl)(C(C)C)C(C)C
Agent: c1c[nH]cn1
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COc1cc(C=O)cc(O[Si](C(C)C)(C(C)C)C(C)C)c1OC
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 3.2 g of 3-hydroxy-4,5-dimethoxybenzaldehyde in 50 ml of DMF there were added 1.49 g of imidazole and 4.5 ml of chlorotriisopropylsilane. The mixture was stirred at room temperature for 21 hours and 30 minutes. Water was added to the reaction mixture and extraction was performed with ethyl acetate. The organic layer was washed with ice-cooled 1N hydrochloric acid, water, saturated aqueous sodium hydrogencarbonate, water and saturated brine in that order, and dried over anhydrous magnesium sulfate. The desiccating agent was filtered off and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate-heptane) to give 3,4-dimethoxy-5-triisopropylsilanyloxybenzaldehyde (6.08 g) as a light yellow oil.
Reaction SMILES: C([O:3][C:4]([C:6]1[C:7]2[CH2:8][C@H:9]3[CH2:21][C@H:10]3[C:11]=2[N:12]([C:14]2[CH:19]=[C:18]([I:20])[CH:17]=[CH:16][N:15]=2)[N:13]=1)=[O:5])C.[OH-].[Na+]>CO.C1COCC1>[I:20][C:18]1[CH:17]=[CH:16][N:15]=[C:14]([N:12]2[C:11]3[C@@H:10]4[CH2:21][C@@H:9]4[CH2:8][C:7]=3[C:6]([C:4]([OH:5])=[O:3])=[N:13]2)[CH:19]=1
Reactant: CCOC(=O)c1nn(-c2cc(I)ccn2)c2c1C[C@H]1C[C@@H]21
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: O=C(O)c1nn(-c2cc(I)ccn2)c2c1C[C@H]1C[C@@H]21
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of (1aR,5aR)-2-(4-iodo-pyridin-2-yl)-1a,2,5,5a-tetrahydro-1H-2,3-diaza-cyclopropa[a]pentalene-4-carboxylic acid ethyl ester in MeOH (10.00 mL) and THF (10.00 mL) was added a 2 M aqueous solution of sodium hydroxide (5.20 mL, 10.40 mmol). The mixture was stirred at room temperature for 2 h then concentrated. The remaining solid was dissolved in water (30 mL). The solution was acidified to pH ˜2 by addition of 6 M aqueous HCl. The resulting precipitate was collected by filtration, rinsed with water, then dried to give the title compound (190 mg) as a white solid. LCMS m/z=368.1 [M+H]+.
Reaction SMILES: [I:1][C:2]1[C:19]([O:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[CH:18][C:5]2[CH2:6][CH2:7][N:8](C(OC(C)(C)C)=O)[CH2:9][CH2:10][C:4]=2[CH:3]=1.C(OC1C=CC2CCNCCC=2C=1)C1C=CC=CC=1>>[I:1][C:2]1[C:19]([O:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[CH:18][C:5]2[CH2:6][CH2:7][NH:8][CH2:9][CH2:10][C:4]=2[CH:3]=1
Reactant: CC(C)(C)OC(=O)N1CCc2cc(I)c(OCc3ccccc3)cc2CC1
Agent: c1ccc(COc2ccc3c(c2)CCNCC3)cc1
Product: Ic1cc2c(cc1OCc1ccccc1)CCNCC2

Procedure:
Description D45 (D45) was prepared from 1,1-dimethylethyl 7-iodo-8-[(phenylmethyl)oxy]-1,2,4,5-tetrahydro-3H-3-benzazepine-3-carboxylate (D44) using the analogous method to that described for Description 2 (D2); MS (ES+) m/e 380 [M+H]+.
Reaction SMILES: C[O-].[Na+].C(=O)(O)O.[NH2:8][C:9]([NH2:11])=[NH:10].[NH2:12][C:13]1[C:29]([O:30][CH3:31])=[CH:28][C:16]([CH2:17][C:18](=[CH:21]N2CCOCC2)[C:19]#[N:20])=[CH:15][C:14]=1[O:32][CH3:33]>CS(C)=O.O>[NH2:10][C:9]1[N:11]=[C:19]([NH2:20])[C:18]([CH2:17][C:16]2[CH:15]=[C:14]([O:32][CH3:33])[C:13]([NH2:12])=[C:29]([O:30][CH3:31])[CH:28]=2)=[CH:21][N:8]=1
Reactant: N=C(N)N
Reactant: COc1cc(CC(C#N)=CN2CCOCC2)cc(OC)c1N
Agent: C[O-]
Agent: O=C(O)O
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: COc1cc(Cc2cnc(N)nc2N)cc(OC)c1N
Temperature: 120 °C
Reaction time: 60 h

Procedure:
A mixture of 6.5 g of sodium methylate, 21.6 g of guanidine carbonate and 12.8 g of α-(4-amino-3,5-dimethoxy-benzyl)-β-morpholino - acrylonitrile in 120 ml of absolute dimethyl sulphoxide was stirred at 120° C. for 60 hours. Subsequently, the mixture was diluted with 1.2 liters of water and extracted with two 2 liter portions of ethyl acetate. The ethyl acetatae extract was washed with two 1 liter portions of water, dried over magnesium sulphate and evaporated in vacuo. After recrystallisation of the residue from methanol, there was obtained 2,4-diamino-5-(4-amino-3,5-dimethoxy-benzyl)-pyrimidine of melting point 215°-216° C.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[C:9]([F:12])([F:11])[F:10].C(N(CC)CC)C.[C:20](OC(=O)C)(=[O:22])[CH3:21]>C1COCC1>[C:20]([O:8][C:5]1[CH:6]=[CH:7][C:2]([CH3:1])=[C:3]([C:9]([F:10])([F:11])[F:12])[CH:4]=1)(=[O:22])[CH3:21]
Reactant: CC(=O)OC(C)=O
Reactant: Cc1ccc(O)cc1C(F)(F)F
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(=O)Oc1ccc(C)c(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 97.5 %

Procedure:
To a solution of 4-methyl-3-(trifluoromethyl)phenol (5 g) and triethylamine (4.75 mL) in THF (40 mL) was added acetic anhydride (3.48 g), and the mixture was stirred at room temperature overnight. The reaction mixture was concentrated, saturated aqueous sodium hydrogen carbonate solution was added to the residue, and the mixture was extracted with ethyl acetate. The extract was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure to give the title compound (6.04 g).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH:7]=O)[CH:2]=1.[CH2:9]([NH2:11])[CH3:10]>C1COCC1>[CH2:9]([NH:11][CH2:7][C:3]1[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=1)[CH3:10]
Reactant: CCN
Reactant: O=Cc1cccnc1
Solvent: C1CCOC1
Product: CCNCc1cccnc1

Procedure:
prepared by reaction of the commercially available pyridin-3-carbaldehyde with 2M ethylamine in THF.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:20]([OH:42])[CH2:21][NH:22][C:23]([CH3:41])([CH3:40])[CH2:24][C:25]2[CH:39]=[CH:38][C:28]([O:29][CH2:30][CH2:31][CH2:32][C:33]([O:35]CC)=[O:34])=[CH:27][CH:26]=2)[C:12]2[O:17][CH2:16][C:15](=[O:18])[NH:14][C:13]=2[CH:19]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+].Cl>CO>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:20]([OH:42])[CH2:21][NH:22][C:23]([CH3:40])([CH3:41])[CH2:24][C:25]2[CH:26]=[CH:27][C:28]([O:29][CH2:30][CH2:31][CH2:32][C:33]([OH:35])=[O:34])=[CH:38][CH:39]=2)[C:12]2[O:17][CH2:16][C:15](=[O:18])[NH:14][C:13]=2[CH:19]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)CCCOc1ccc(CC(C)(C)NCC(O)c2cc(OCc3ccccc3)cc3c2OCC(=O)N3)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC(C)(Cc1ccc(OCCCC(=O)O)cc1)NCC(O)c1cc(OCc2ccccc2)cc2c1OCC(=O)N2

Procedure:
A solution of 1.00 g (1.73 mmol) of ethyl 4-(4-{2-[2-(6-benzyloxy-3-oxo-3,4-dihydro-2H-benzo[1,4]oxazin-8-yl)-2-hydroxyethylamino]-2-methylpropyl}phenoxy)butyrate in 25 mL methanol is combined with 2.5 mL of 1 N sodium hydroxide solution, refluxed for 30 minutes, and then neutralized with 1 N hydrochloric acid. The solution is evaporated down and the residual oil is dissolved by heating in 5 mL of n-butanol. After the addition of a crystallization aid, a solid is precipitated out which is suction filtered and washed with acetone and diethyl ether. Yield: 0.75 g (79%); melting point: 216° C.-218° C.
Reaction SMILES: Cl[Sn]Cl.Cl.[CH2:5]([O:7][P:8]([CH2:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][C:16]=1[N+:23]([O-])=O)([O:10][CH2:11][CH3:12])=[O:9])[CH3:6]>CO>[CH2:11]([O:10][P:8]([CH2:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][C:16]=1[NH2:23])([O:7][CH2:5][CH3:6])=[O:9])[CH3:12]
Reactant: CCOP(=O)(COc1ccc(OC)cc1[N+](=O)[O-])OCC
Agent: Cl
Agent: Cl[Sn]Cl
Solvent: CO
Product: CCOP(=O)(COc1ccc(OC)cc1N)OCC
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A solution of SnCl2 (4 mmole) in freshly prepared methonolic HCl (10 mL) was added to a cold (0° C.) solution of 2-diethylphosphonomethyloxy-5-methoxynitrobenzene (1 mmole) in MeOH (5 mL). The mixture was warmed to room temperature and stirred for 3 h. Evaporation, extraction and chromatography provided 2-diethylphosphonomethyloxy-5-methoxyaniline.
Reaction SMILES: [Cl:1][CH2:2][C:3]([C:15]1[CH:20]=[CH:19][C:18]([F:21])=[CH:17][C:16]=1[F:22])([OH:14])[CH:4]([O:6][Si](C(C)(C)C)(C)C)[CH3:5].CCCC[N+](CCCC)(CCCC)CCCC.[F-].O.C(OCC)(=O)C>C1COCC1>[Cl:1][CH2:2][C@@:3]([C:15]1[CH:20]=[CH:19][C:18]([F:21])=[CH:17][C:16]=1[F:22])([OH:14])[C@H:4]([OH:6])[CH3:5]
Reactant: CC(O[Si](C)(C)C(C)(C)C)C(O)(CCl)c1ccc(F)cc1F
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: C[C@@H](O)[C@](O)(CCl)c1ccc(F)cc1F
Reaction time: 1.5 h
Yield: 15 %

Procedure:
A solution of 0.45 g (1.28 mmol) of 1-chloro-2-(2,4-difluorophenyl)-3-(tert-butyldimethylsilyloxy)butan-2-ol ((2S,3R)/(2R,3R)=91/9) in 5 mL of THF was cooled in ice, and 1.3 mL of a 1.0 M solution of TBAF in THF was added dropwise. After the completion of the dropwise addition, reaction was performed for 1.5 hours and then at room temperature for another 11 hours. Next, 10 mL of water was added to stop the reaction, and extraction was performed with 20 mL of ethyl acetate. The resulting organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain a crude product as a colorless oil. A quantitative analysis was performed by HPLC (under the same HPLC measurement conditions as those in Example 6). Thereby, the title compound was obtained in a yield of 15% ((2S,3R)/(2R,3R)=91/9).
Reaction SMILES: [CH2:1]1[C:7]2=[C:8]3[C:12](=[CH:13][CH:14]=[C:6]2[O:5][CH2:4][CH2:3][N:2]1C(OC(C)(C)C)=O)[NH:11][CH:10]=[CH:9]3.[H-].[Na+].CN(C=O)C.[F:29][C:30]1[CH:31]=[CH:32][C:33]([CH3:40])=[C:34]([S:36](Cl)(=[O:38])=[O:37])[CH:35]=1>N.CO>[F:29][C:30]1[CH:31]=[CH:32][C:33]([CH3:40])=[C:34]([S:36]([N:11]2[C:12]3[C:8](=[C:7]4[CH2:1][NH:2][CH2:3][CH2:4][O:5][C:6]4=[CH:14][CH:13]=3)[CH:9]=[CH:10]2)(=[O:38])=[O:37])[CH:35]=1
Reactant: CC(C)(C)OC(=O)N1CCOc2ccc3[nH]ccc3c2C1
Reactant: Cc1ccc(F)cc1S(=O)(=O)Cl
Agent: N
Agent: [H-]
Agent: [Na+]
Solvent: CO
Solvent: CN(C)C=O
Product: Cc1ccc(F)cc1S(=O)(=O)n1ccc2c3c(ccc21)OCCNC3
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 15 %

Procedure:
tert-Butyl 1,3,4,8-tetrahydro-2H-[1,4]oxazepino[6,7-e]indole-2-carboxylate (Intermediate 18, 14 mg, 0.050 mmol), NaH (60% in mineral oil, 6.4 mg, 0.10 mmol) and dry DMF (0.2 mL) were shaken at room temperature for 10 minutes. 5-Fluoro-2-methylbenzenesulfonyl chloride (21 mg, 0.10 mmol, in 0.15 mL of dry DMF) was added to the solution. The reaction mixture was shaken at room temperature for another 20 minutes and a mixture of MeOH/1 M HCl (3:1, 1 mL) was added. The reaction mixture was stirred overnight and evaporated. The residue was dissolved in 1 M NH3 in MeOH (1 mL, 1 mmol) and MeOH (1 mL). The crude product was purified by preparative HPLC (XTerra C18, 50 mM NH4HCO3 pH 10-CH3CN) to give the title compound as an off-white solid (2.7 mg). MS m/z 361 [M+H]+.
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][C:12]([N:15]2[CH:23]=[C:22]3[C:17]([CH:18]=[CH:19][C:20]([O:24][CH3:25])=[CH:21]3)=[N:16]2)=[CH:11][CH:10]=1)C1C=CC=CC=1.CO>[Pd].C1COCC1>[CH3:25][O:24][C:20]1[CH:19]=[CH:18][C:17]2[C:22](=[CH:23][N:15]([C:12]3[CH:13]=[CH:14][C:9]([OH:8])=[CH:10][CH:11]=3)[N:16]=2)[CH:21]=1
Reactant: COc1ccc2nn(-c3ccc(OCc4ccccc4)cc3)cc2c1
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CO
Product: COc1ccc2nn(-c3ccc(O)cc3)cc2c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 104 %

Procedure:
Under a hydrogen atmosphere, a mixture of 2-[4-(benzyloxy)phenyl]-5-methoxy-2H-indazole (160 mg), 10% palladium/carbon (containing water (50%), 52 mg), methanol (10 mL) and THF (5 mL) was stirred at room temperature for 1 hr. The catalyst was removed by filtration, and the obtained filtrate was concentrated under reduced pressure to give the title compound (121 mg).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:11][C:12]1[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH:15]=[CH:14][CH:13]=1)[C:6]1[C:22](=[O:27])[O:23][C:24](=[O:26])[CH2:25][C:5]2=1.[CH:28]1([NH2:31])[CH2:30][CH2:29]1>>[CH:28]1([NH:31][C:24]([CH2:25][C:5]2[C:4]3[C:8](=[CH:9][CH:10]=[C:2]([F:1])[CH:3]=3)[N:7]([CH2:11][C:12]3[C:21]4[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=4)[CH:15]=[CH:14][CH:13]=3)[C:6]=2[C:22]([OH:23])=[O:27])=[O:26])[CH2:30][CH2:29]1
Reactant: NC1CC1
Reactant: O=C1Cc2c(n(Cc3cccc4ccccc34)c3ccc(F)cc23)C(=O)O1
Product: O=C(Cc1c(C(=O)O)n(Cc2cccc3ccccc23)c2ccc(F)cc12)NC1CC1

Procedure:
6-Fluoro-9-naphthalen-1-ylmethyl-4,9-dihydro-pyrano[3,4-b]indole-1,3-dione (from Example 68.1.) was ring opened with cyclopropylamine at 22° C. to give the title compound as a white solid. MS: 415.0 ([M−H]−).
Reaction SMILES: [C:1]([O:5][C:6]([C:8]1[C:16]2[CH2:15][CH2:14][O:13][CH:12]([CH2:17][NH2:18])[C:11]=2[S:10][C:9]=1[NH2:19])=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[C:27](Cl)(=[O:29])[CH3:28]>ClCCl>[C:1]([O:5][C:6]([C:8]1[C:16]2[CH2:15][CH2:14][O:13][CH:12]([CH2:17][NH:18][C:27](=[O:29])[CH3:28])[C:11]=2[S:10][C:9]=1[NH2:19])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(=O)Cl
Reactant: CC(C)(C)OC(=O)c1c(N)sc2c1CCOC2CN
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)NCC1OCCc2c1sc(N)c2C(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 17.4 %

Procedure:
To a ice water cooled solution of the above 2-amino-7-aminomethyl-4,7-dihydro-5H-thieno[2,3-c]pyran-3-carboxylic acid tert-butyl ester (1.5 g, 5.27 mmol) and triethylamine (1.5 ml) in dichloromethane (50 ml) was added dropwise acetylchloride (0.46 g, 5.80 mmol). The reaction mixture was allowed to reach room temperature and stirred for an additional 0.5 h. The reaction mixture was washed with water (2×25 ml), dried (Na2SO4), filtered and the solvent evaporated in vacuo. The residue was purified by column chromatography on silicagel (1 L) using first ethyl acetate and later on a mixture of ethyl acetate and ethanol (20:1) as eluents. Pure fractions were collected and the solvent evaporated in vacuo affording 0.3 g (17%) of 7-(acetylamino-methyl)-2-amino-4,7-dihydro-5H-thieno[2,3-c]pyran-3-carboxylic acid tert-butyl ester as a solid.
Reaction SMILES: [Si:1]([O:8][CH:9]1[C:13]2([CH2:15][CH2:14]2)[C:12](=[O:16])[NH:11][C@H:10]1[CH2:17][CH3:18])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].I[C:20]1[CH:27]=[CH:26][C:23]([C:24]#[N:25])=[C:22]([C:28]([F:31])([F:30])[F:29])[CH:21]=1.C(=O)([O-])[O-].[Cs+].[Cs+].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>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[Si:1]([O:8][C@@H:9]1[C:13]2([CH2:14][CH2:15]2)[C:12](=[O:16])[N:11]([C:20]2[CH:27]=[CH:26][C:23]([C:24]#[N:25])=[C:22]([C:28]([F:29])([F:31])[F:30])[CH:21]=2)[C@H:10]1[CH2:17][CH3:18])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:2])[CH3:3]
Reactant: N#Cc1ccc(I)cc1C(F)(F)F
Reactant: CC[C@@H]1NC(=O)C2(CC2)C1O[Si](C)(C)C(C)(C)C
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Product: CC[C@H]1[C@H](O[Si](C)(C)C(C)(C)C)C2(CC2)C(=O)N1c1ccc(C#N)c(C(F)(F)F)c1

Procedure:
Using (6S)-7-(tert-butyldimethylsilyloxy)-6-ethyl-5-azaspiro[2.4]heptan-4-one (397.8 mg), 4-iodo-2-trifluoromethylbenzonitrile (482 mg), cesium carbonate (721 mg), tris(dibenzylideneacetone)dipalladium(0) (68 mg) and 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (171 mg), and in the same manner as in Reference Example 3, the title compound was obtained as a colorless solid (yield: 433.7 mg, yield: 67%).
Reaction SMILES: Br[C:2]1[C:7]([N:8]([CH2:23][O:24][CH3:25])[S:9]([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[C:14]([C:19]([F:22])([F:21])[F:20])[CH:13]=2)(=[O:11])=[O:10])=[CH:6][C:5]([Cl:26])=[CH:4][N:3]=1.C([Mg]Cl)(C)C.CN([CH:35]=[O:36])C>C1COCC1>[Cl:18][C:15]1[CH:16]=[CH:17][C:12]([S:9]([N:8]([C:7]2[C:2]([CH:35]=[O:36])=[N:3][CH:4]=[C:5]([Cl:26])[CH:6]=2)[CH2:23][O:24][CH3:25])(=[O:11])=[O:10])=[CH:13][C:14]=1[C:19]([F:22])([F:21])[F:20]
Reactant: CN(C)C=O
Reactant: COCN(c1cc(Cl)cnc1Br)S(=O)(=O)c1ccc(Cl)c(C(F)(F)F)c1
Agent: CC(C)[Mg]Cl
Solvent: C1CCOC1
Product: COCN(c1cc(Cl)cnc1C=O)S(=O)(=O)c1ccc(Cl)c(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
To a stirred solution of N-(2-bromo-5-chloro-pyridin-3-yl)-4-chloro-N-methoxymethyl-3-trifluoromethyl-benzenesulfonamide (280 mg, 0.566 mmol) in anhydrous THF (3 mL) was added 2 M isopropylmagnesiumchloride in THF (700 L, 1.36 mmol) at 0° C. It was stirred at the same temperature for 20 minutes and then DMF (174 L, 1.36 mmol) was added in dropwise and the progress of the reaction was followed by LCMS. The reaction mixture was warmed to room temperature and stirred for 6 h. It was then quenched with saturated aqueous NH4Cl (2 mL), and extracted with EtOAc. The combined extracts were dried (Na2SO4), filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography to provide 4-Chloro-N-(5-chloro-2-formyl-pyridin-3-yl)-N-methoxymethyl-3-trifluoromethyl-benzenesulfonamide Mass spectrum m/z: 443.0 (M+H).