Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[N:2]1([CH:7]2[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]2)[CH:6]=[CH:5][N:4]=[N:3]1.C1CCN2C(=NCCC2)CC1.[F:24][C:25]1[C:26](F)=[C:27]2[O:32][CH2:31][C@H:30]([CH3:33])[N:29]3[CH:34]=[C:35]([C:40]([OH:42])=[O:41])[C:36](=[O:39])[C:37]([CH:38]=1)=[C:28]23>C(#N)C>[F:24][C:25]1[C:26]([N:10]2[CH2:11][CH2:12][CH:7]([N:2]3[CH:6]=[CH:5][N:4]=[N:3]3)[CH2:8][CH2:9]2)=[C:27]2[O:32][CH2:31][C@H:30]([CH3:33])[N:29]3[CH:34]=[C:35]([C:40]([OH:42])=[O:41])[C:36](=[O:39])[C:37]([CH:38]=1)=[C:28]23
Reactant: c1cn(C2CCNCC2)nn1
Reactant: C[C@H]1COc2c(F)c(F)cc3c(=O)c(C(=O)O)cn1c23
Agent: Cl
Solvent: CC#N
Solvent: C1CCC2=NCCCN2CC1
Product: C[C@H]1COc2c(N3CCC(n4ccnn4)CC3)c(F)cc3c(=O)c(C(=O)O)cn1c23
Temperature: 25 °C
Reaction time: 48 h

Procedure:
4-(1,2,3-triazol-1-yl)piperidine hydrochloride (100 mg) and DBU (80 mg) were added to a suspension of (-)-9,10-difluoro-3(S)-methyl-7-oxo-2,3-dihydro-7H-pyrido [1,2,3-de]-1,4-benzoxazine-6-carboxylic acid in acetonitrile (5 ml). The reaction mixture was refluxed for 48 hrs followed by stirring at room temperature for an additional 48 hrs. The reaction mixture was concentrated and the residue was diluted with water. The separated solid was filtered, washed with water and dried to yield 30 mg of desired product. m.p. 254°-255° C. (dec). 1H NMR (TFA) δ: 9.4 (s, 1H), 8.67 (s, 1H), 8.57 (s, 1H), 8.16 (d, 11.43Hz, 1H), 5.6-5.1 (m, 2H), 5.0-4.7 (m, 2H), 4.45-4.05 (m, 4H), 3.1-2.6 (m, 4H), 1.86 (d, 6.3Hz, 3H). Anal. calcd. for C 20 H20FN5O4 . H2O; C, 55.68; H, 5.14; N, 16.23.Found C, 55.88; H, 4.762; N, 15.92.
Reaction SMILES: C[C:2]([O:4][CH2:5][C:6]1[CH2:15][S:14][C@@H:9]2[C@H:10]([NH2:13])[C:11](=[O:12])[N:8]2[C:7]=1[C:16]([OH:18])=[O:17])=O.C([O-])([O-])OC>[Cl-].[Zn+2].[Cl-].S1(CCCC1)(=O)=O>[NH2:13][CH:10]1[C:11](=[O:12])[N:8]2[C:7]([C:16]([OH:18])=[O:17])=[C:6]([CH2:5][O:4][CH3:2])[CH2:15][S:14][C@H:9]12
Reactant: CC(=O)OCC1=C(C(=O)O)N2C(=O)[C@@H](N)[C@H]2SC1
Agent: COC([O-])[O-]
Agent: [Cl-]
Agent: [Zn+2]
Solvent: O=S1(=O)CCCC1
Product: COCC1=C(C(=O)O)N2C(=O)C(N)[C@H]2SC1
Temperature: 50 °C

Procedure:
To 10 ml of sulfolane were added 1.41 g of 7-ACA, 0.99 g of ferric chloride, 5.00 g of zinc chloride and 0.92 ml of methyl orthoformate. The mixture was heated at 50° C. for 6 hours to advance a reaction. After completion of the reaction, substantially the same procedure as in Example 1 was repeated, to thereby obtain a desired product, namely 7-amino-3-methoxymethyl-3-cephem-4-carboxylic acid. The amount of the desired product was 0.81 g. The yield of the desired product was 64%.
Reaction SMILES: [CH3:1][C@H:2]([NH2:12])[C:3]1[CH:8]=[CH:7][C:6]([N+:9]([O-:11])=[O:10])=[CH:5][CH:4]=1.C([O:17][C:18]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[C:26]1[CH:31]=[CH:30][C:29]([CH2:32][N:33]2[C:41]3[C:36](=[CH:37][C:38]([C:42](O)=[O:43])=[CH:39][CH:40]=3)[C:35]([CH3:45])=[C:34]2[CH3:46])=[CH:28][CH:27]=1)=[O:19])(C)(C)C>>[CH3:46][C:34]1[N:33]([CH2:32][C:29]2[CH:30]=[CH:31][C:26]([C:21]3[C:20]([C:18]([OH:19])=[O:17])=[CH:25][CH:24]=[CH:23][CH:22]=3)=[CH:27][CH:28]=2)[C:41]2[C:36]([C:35]=1[CH3:45])=[CH:37][C:38]([C:42](=[O:43])[NH:12][C@H:2]([C:3]1[CH:4]=[CH:5][C:6]([N+:9]([O-:11])=[O:10])=[CH:7][CH:8]=1)[CH3:1])=[CH:39][CH:40]=2
Reactant: C[C@H](N)c1ccc([N+](=O)[O-])cc1
Reactant: Cc1c(C)n(Cc2ccc(-c3ccccc3C(=O)OC(C)(C)C)cc2)c2ccc(C(=O)O)cc12
Product: Cc1c(C)n(Cc2ccc(-c3ccccc3C(=O)O)cc2)c2ccc(C(=O)N[C@@H](C)c3ccc([N+](=O)[O-])cc3)cc12

Procedure:
The title compound was prepared following the same general protocol as described in Steps 8-9, Example 1, using (S)-α-methyl-4-nitrobenzylamine and 1-((2′-(tert-butoxycarbonyl)biphenyl-4-yl)methyl)-2,3-dimethyl-1H-indole-5-carboxylic acid. LC-MS 548 (M+H).
Reaction SMILES: [Br:1][C:2]1[N:7]=[CH:6][C:5](/[C:8](=[N:11]/[S:12]([C:14]([CH3:17])([CH3:16])[CH3:15])=[O:13])/[CH2:9][CH3:10])=[CH:4][CH:3]=1.CCC(C)[BH-](C(C)CC)C(C)CC.[Li+].[BH4-].[Li+]>C1COCC1>[Br:1][C:2]1[N:7]=[CH:6][C:5]([C@@H:8]([NH:11][S:12]([C:14]([CH3:15])([CH3:17])[CH3:16])=[O:13])[CH2:9][CH3:10])=[CH:4][CH:3]=1
Reactant: CC/C(=N\S(=O)C(C)(C)C)c1ccc(Br)nc1
Agent: CCC(C)[BH-](C(C)CC)C(C)CC
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CC[C@H](NS(=O)C(C)(C)C)c1ccc(Br)nc1
Reaction time: 6 h

Procedure:
To a chilled (−78° C.) solution of 2-methyl-propane-2-sulfinic acid [1-(6-bromopyridin-3-yl)-prop-(E)-ylidene]-amide (10.4 g, 32.78 mmol) in THF (150 mL) is added a 1 M solution of L-Selectride (33.0 mL, 33.0 mmol) in THF. The reaction is monitored by TLC (EtOAc-ether 3:7) indicating a single diastereomer (when compared to a mixture of diastereomers prepared by a reduction of 2-methyl-propane-2-sulfinic acid [1-(6-bromopyridin-3-yl)-prop-(E)-ylidene]-amide with lithium borohydride in THF). After 6 hours, the mixture is quenched with saturated aqueous ammonium chloride (100 mL) and extracted with EtOAc (3×100 mL). The combined organic layers are washed with saturated aqueous ammonium chloride (2×50 mL), brine (50 mL), dried over magnesium sulfate, filtered and concentrated. The crude material is purified by silica gel chromatography eluting with ether-dichloromethane (0:100, then 5:95, then 1:9, then 2:8). The material from the chromatography is triturated with ether to afford in two crops material which by 1H NMR is consistent with a single diastereomer however an impurity is present by TLC (EtOAc-ether 3:7). This material and the filtrate is purified by silica gel chromatography separately using EtOAc-dichloromethane (0:100, then 4:96, then 8:98, then 12:88, then 2:8, then 3:7, then 4:6). The material from the two purifications is combined and crystallized from dichloromethane-hexanes-ether to afford in 3 crops 2-methyl-propane-2-sulfinic acid [(S)-1-(6-bromopyridin-3-yl)-propyl]-amide.
Reaction SMILES: [C:1]([NH2:5])([CH3:4])([CH3:3])[CH3:2].[Cl:6][C:7]1[N:12]=[C:11](Cl)[CH:10]=[C:9]([Cl:14])[N:8]=1.C(N(C(C)C)CC)(C)C>>[C:1]([NH:5][C:11]1[CH:10]=[C:9]([Cl:14])[N:8]=[C:7]([Cl:6])[N:12]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)N
Reactant: Clc1cc(Cl)nc(Cl)n1
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)Nc1cc(Cl)nc(Cl)n1
Reaction time: 72 h

Procedure:
Tert-butylamine (II, 6.23 ml) is slowly added to 2,4,6-trichloropyrimidine (I, 10.0 g) at -20° (temp. rose to -14°). Diisopropylethylamine (9.50 ml) is added and the mixture is stirred at 20°-25° for 72 hours. Basic workup (ethyl acetate, 1N potassium bicarbonate, magnesium sulfate) and purification by flash chromatography eluting with hexane/ethyl acetate (9/1), pooling and concentrating the desired fractions gives the title compound, mp 192°-193°; NMR (CDCl3) 6.29, 1.44δ.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[C:6]([O:10][C:11]([N:13]1[CH2:17][C@H:16]([OH:18])[CH2:15][C@H:14]1[C:19](=[O:21])[NH2:20])=[O:12])([CH3:9])([CH3:8])[CH3:7].C(N(CC)CC)C.[Cl-].[Na+]>O1CCCC1>[C:6]([O:10][C:11]([N:13]1[CH2:17][C@H:16]([O:18][S:2]([CH3:1])(=[O:4])=[O:3])[CH2:15][C@H:14]1[C:19](=[O:21])[NH2:20])=[O:12])([CH3:9])([CH3:7])[CH3:8]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(C)OC(=O)N1C[C@H](O)C[C@H]1C(N)=O
Agent: [Cl-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1C[C@H](OS(C)(=O)=O)C[C@H]1C(N)=O
Reaction time: 1 h

Procedure:
1.85 ml of methanesulfonyl chloride was added, whilst ice-cooling, to a solution of 5.0 g of (2S, 4R)-1-(t-butoxycarbonyl)-2-carbamoyl-4-hydroxypyrrolidine [prepared as described in step (2) above] in 250 ml of dry tetrahydrofuran, followed by 3.31 ml of triethylamine. The mixture was then stirred at 0° to 5° C. for 1 hour, after which it was poured into an aqueous solution of sodium chloride and extracted with ethyl acetate. The extract was washed with an aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate, and the solvent was removed by distillation under reduced pressure. The residue was purified by chromatography through silica gel (eluted with a 9:1 by volume mixture of ethyl acetate and methanol) to afford 5.5 g of the title compound as colorless crystals.
Reaction SMILES: [C:1]([Si:5]([CH3:21])([CH3:20])[O:6][CH:7]([CH3:19])[CH2:8][N:9]1[C:17]2[C:12](=[CH:13][CH:14]=[C:15]([OH:18])[CH:16]=2)[CH:11]=[N:10]1)([CH3:4])([CH3:3])[CH3:2].[Br:22]N1C(=O)CCC1=O.S(=O)(O)[O-].[Na+]>C1COCC1>[Br:22][C:16]1[C:15]([OH:18])=[CH:14][CH:13]=[C:12]2[C:17]=1[N:9]([CH2:8][CH:7]([O:6][Si:5]([C:1]([CH3:3])([CH3:4])[CH3:2])([CH3:21])[CH3:20])[CH3:19])[N:10]=[CH:11]2
Reactant: CC(Cn1ncc2ccc(O)cc21)O[Si](C)(C)C(C)(C)C
Reactant: O=C1CCC(=O)N1Br
Agent: O=S([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(Cn1ncc2ccc(O)c(Br)c21)O[Si](C)(C)C(C)(C)C
Yield: 65.5 %

Procedure:
To a solution of the product from Step B (6.00 g, 19.6 mmol) in anhydrous THF (300 mL) at 0° C. was added N-bromosuccinimide (3.49 g, 19.6 mmol) in 10 portions over 20 min. The mixture was poured into a saturated aqueous solution of sodium bisulfite (300 mL) and extracted with EtOAc (3×100 mL). The combined extracts were dried (MgSO4) and evaporated to a residue (6.39 g). Chromatography (silica, 10% EtOAc/hexane) gave a solid (4.95 g, 66%): LC/MS (+APCI) m/z 385, 387 (M+H).
Reaction SMILES: [CH:1]1[C:13]2[NH:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.Cl(O)(=O)(=O)=O.[C:19](OC(=O)C)(=[O:21])[CH3:20]>>[C:19]([N:12]1[C:11]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=2[C:5]2[C:13]1=[CH:1][CH:2]=[CH:3][CH:4]=2)(=[O:21])[CH3:20]
Reactant: c1ccc2c(c1)[nH]c1ccccc12
Reactant: CC(=O)OC(C)=O
Agent: [O-][Cl+3]([O-])([O-])O
Product: CC(=O)n1c2ccccc2c2ccccc21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 90 %

Procedure:
This compound is obtained according to Tetrahedron (1980), 36, 3017-3019. The carbazole (10 g; 60 mmol) is suspended in 150 ml of acetic anhydride. 70% perchloric acid (0.5 ml) is added. After stirring for 30 minutes at ambient temperature, the mixture is poured into ice and the precipitate formed is filtered. After drying under vacuum, redissolving in dichloromethane and treatment with bone charcoal, the suspension is filtered on celite, the solvents are evaporated off and the product recrystallized from heptane. 12 g of brown crystals (yield of 90%) is obtained in this way. Melting point: 70-71° C. (literature: 72-74° C.).
Reaction SMILES: OO.[OH:3][CH2:4][CH2:5][N:6]1[CH2:11][CH2:10][S:9][CH2:8][C:7]1=[O:12].C(OC(=O)C)(=[O:15])C.C(OC(C)C)(C)C.C(O)(C)C>>[OH:3][CH2:4][CH2:5][N:6]1[CH2:11][CH2:10][S:9](=[O:15])[CH2:8][C:7]1=[O:12]
Reactant: O=C1CSCCN1CCO
Reactant: CC(=O)OC(C)=O
Agent: OO
Solvent: CC(C)OC(C)C
Solvent: CC(C)O
Product: O=C1CS(=O)CCN1CCO

Procedure:
This sulfoxide is prepared by reacting, for a week, one equivalent of H2O2 with 4-(2-hydroxyethyl) 3-thiamorpholinone (obtained in Example 9) solubilized at 0° C. in an acetic acid-acetic anhydride mixture. After concentration of the mixture the resulting liquid is solubilized in a minimum of an isopropyl ether-isopropyl alcohol mixture. Starting with this solution, placed at -25° C., white crystals whose melting point is 45° C. are isolated.
Reaction SMILES: Br[C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4]1([C:34]3[C:25](=[CH:26][C:27]4[O:32][CH2:31][CH2:30][O:29][C:28]=4[CH:33]=3)[O:24][CH2:23]1)[C:5](=[O:22])[N:6]2[CH2:11][C:12]1[C:17]([C:18]([F:21])([F:20])[F:19])=[CH:16][CH:15]=[CH:14][N:13]=1.CC(C)([O-])C.[Na+].C1(P(C2C=CC=CC=2)C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH2:87]([NH2:94])[C:88]1[CH:93]=[CH:92][CH:91]=[CH:90][CH:89]=1>C1(C)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]>[CH2:87]([NH:94][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4]1([C:34]3[C:25](=[CH:26][C:27]4[O:32][CH2:31][CH2:30][O:29][C:28]=4[CH:33]=3)[O:24][CH2:23]1)[C:5](=[O:22])[N:6]2[CH2:11][C:12]1[C:17]([C:18]([F:21])([F:20])[F:19])=[CH:16][CH:15]=[CH:14][N:13]=1)[C:88]1[CH:93]=[CH:92][CH:91]=[CH:90][CH:89]=1
Reactant: NCc1ccccc1
Reactant: O=C1N(Cc2ncccc2C(F)(F)F)c2cccc(Br)c2C12COc1cc3c(cc12)OCCO3
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1
Product: O=C1N(Cc2ncccc2C(F)(F)F)c2cccc(NCc3ccccc3)c2C12COc1cc3c(cc12)OCCO3
Temperature: 105 °C
Yield: 31 %

Procedure:
4′-Bromo-1′-{[3-(trifluoromethyl)pyridin-2-yl]methyl}-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one (0.700 g, 1.31 mmol), tris(dibenzylideneacetone)dipalladium(0) (0.14 g, 0.16 mmol), sodium tert-butoxide (0.252 g, 2.62 mmol), 2,2′-bis(diphenylphosphino)-1,1′-binaphthalene (0.29 g, 0.47 mmol) and benzylamine (0.22 mL, 2.0 mmol) were combined in anhydrous toluene (20 mL) and heated at 105° C. for 60 h. The reaction mixture was filtered through a pad of diatomaceous earth and the pad was washed with ethyl acetate (150 mL). The filtrate was washed with saturated aqueous sodium bicarbonate (100 mL), water (100 mL) and brine (100 mL), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography and eluted with a 0% to 25% gradient of ethyl acetate in dichloromethane to afford 4′-(benzylamino)-1′-{[3-(trifluoromethyl)pyridin-2-yl]methyl}-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one (0.227 g, 31%) as a colorless solid: 1H NMR (300 MHz, CDCl3) δ8.67 (d, J=4.5 Hz, 1H), 7.95 (d, J=7.9 Hz, 1H), 7.34-7.17 (m, 5H), 7.02 (d, J=7.7 Hz, 1H), 6.95 (dd, J=8.3, 8.3 Hz, 1H), 6.83 (s, 1H), 6.40 (s, 1H), 6.15 (ABq, 2H), 5.23 (ABq, 2H), 4.86 (ABq, 2H), 4.20-4.15 (m, 4H).
Reaction SMILES: [O:1]1CCCO[CH:2]1[CH2:7][CH2:8][CH2:9][C:10]1[N:11]([CH3:26])[C:12]([C:15]2[CH:16]=[C:17]3[C:22](=[CH:23][CH:24]=2)[N:21]=[C:20]([CH3:25])[CH:19]=[CH:18]3)=[N:13][N:14]=1.S(=O)(=O)(O)O.C(=O)(O)[O-].[Na+]>O>[CH3:26][N:11]1[C:12]([C:15]2[CH:16]=[C:17]3[C:22](=[CH:23][CH:24]=2)[N:21]=[C:20]([CH3:25])[CH:19]=[CH:18]3)=[N:13][N:14]=[C:10]1[CH2:9][CH2:8][CH2:7][CH:2]=[O:1]
Reactant: Cc1ccc2cc(-c3nnc(CCCC4OCCCO4)n3C)ccc2n1
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Product: Cc1ccc2cc(-c3nnc(CCCC=O)n3C)ccc2n1
Temperature: 25 °C
Yield: 83.3 %

Procedure:
6-[5-(3-[1,3]Dioxan-2-yl-propyl)-4-methyl-4H-[1,2,4]triazol-3-yl]-2-methyl-quinoline (109 mg, 0.31 mmol) was heated in water (20 ml) and concentrated sulphuric acid (0.5 ml) at 100° C. for 3 h. The mixture was cooled to room temperature, basified with solid sodium bicarbonate and extracted with dichloromethane (3×50 ml). The combined organic portions were dried (Na2SO4), filtered and evaporated to give the desired compound as an off-white solid (76 mg, 84%).
Reaction SMILES: CC1C(C)=C(C)C(C)=C(C)C=1.CCCCCCC.B(Cl)(Cl)Cl.[S:23]1[C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=2[CH:25]=[C:24]1[CH2:32][C:33]1[CH:34]=[C:35]([C@@H:40]2[O:69][C@H:68]([CH2:70][O:71]CC3C=CC=CC=3)[C@@H:59]([O:60]CC3C=CC=CC=3)[C@H:50]([O:51]CC3C=CC=CC=3)[C@H:41]2[O:42]CC2C=CC=CC=2)[CH:36]=[CH:37][C:38]=1[F:39]>ClCCl.CO>[S:23]1[C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=2[CH:25]=[C:24]1[CH2:32][C:33]1[CH:34]=[C:35]([C@@H:40]2[O:69][C@H:68]([CH2:70][OH:71])[C@@H:59]([OH:60])[C@H:50]([OH:51])[C@H:41]2[OH:42])[CH:36]=[CH:37][C:38]=1[F:39]
Reactant: Fc1ccc([C@@H]2O[C@H](COCc3ccccc3)[C@@H](OCc3ccccc3)[C@H](OCc3ccccc3)[C@H]2OCc2ccccc2)cc1Cc1cc2ccccc2s1
Agent: Cc1cc(C)c(C)c(C)c1C
Agent: ClB(Cl)Cl
Solvent: CO
Solvent: CCCCCCC
Solvent: ClCCl
Product: OC[C@H]1O[C@@H](c2ccc(F)c(Cc3cc4ccccc4s3)c2)[C@H](O)[C@@H](O)[C@@H]1O
Temperature: 25 °C
Reaction time: 2 h
Yield: 83.2 %

Procedure:
Pentamethylbenzene (4.85 g) and a n-heptane solution (16.3 mL) containing 1.0 M of boron trichloride were added to a solution of (1s)-1,5-anhydro-1-[3-(1-benzothien-2-ylmethyl)-4-fluorophenyl]-2,3,4,6-tetra-O-benzyl-D-glucitol (2.5 g) dissolved in dichloromethane (50 mL, cooled to −78° C.) in an argon stream. The mixture was stirred at the same temperature for 2 hours. After the completion of the reaction, methanol (100 mL) was added for decomposition of the excessive reagent, and the solvents were removed by vacuum distillation. The residue was purified by silica gel column chromatography (chloroform-methanol). The obtained residue was suspended in a mixed solvent of ethanol and water and was refluxed with heating to dissolve. The resulting solution was slowly cooled to room temperature for recrystallization. The obtained crystal was collected by filtration and then dried under vacuum and heating to obtain (1S)-1,5-anhydro-1-[3-(1-benzothien-2-ylmethyl)-4-fluorophenyl]-D-glucitol (known compound A) (1.1 g) as a white crystal. The differential scanning calorimetry analysis chart (DSC analysis chart) of the known compound A obtained is shown in FIG. 1, and its X-ray powder diffraction chart is shown in FIG. 2.
Reaction SMILES: [BH4-].[Na+].[O:3]([C:10]1[CH:17]=[CH:16][C:13]([CH:14]=[O:15])=[CH:12][CH:11]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1>C(O)C>[O:3]([C:10]1[CH:11]=[CH:12][C:13]([CH2:14][OH:15])=[CH:16][CH:17]=1)[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: O=Cc1ccc(Oc2ccccc2)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: OCc1ccc(Oc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 96.6 %

Procedure:
Sodium borohydride (0.48 g) was added to a solution of 4.96 g of 4-phenoxybenzaldehyde in 20 ml of ethanol, and the mixture was stirred at room temperature for 1.5 hours. After the completion of the concentration, the residue was extracted with tert-butylmethyl ether and with water. The organic layer was concentrated to give 4.84 g of 4-phenoxybenzyl alcohol.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]2[NH:8][C:9](=[O:36])[C:10]3([CH:15]([C:16]4[CH:21]=[C:20]([Cl:22])[CH:19]=[CH:18][C:17]=4[O:23][CH2:24][C:25]([C:28]([O:30]C)=[O:29])([CH3:27])[CH3:26])[CH2:14][C:13](=[O:32])[NH:12][CH:11]3[C:33]([CH3:35])=[CH2:34])[C:5]2=[CH:4][CH:3]=1.[OH-].[Na+].O>CO>[Cl:1][C:2]1[CH:7]=[C:6]2[NH:8][C:9](=[O:36])[C:10]3([CH:15]([C:16]4[CH:21]=[C:20]([Cl:22])[CH:19]=[CH:18][C:17]=4[O:23][CH2:24][C:25]([C:28]([OH:30])=[O:29])([CH3:27])[CH3:26])[CH2:14][C:13](=[O:32])[NH:12][CH:11]3[C:33]([CH3:35])=[CH2:34])[C:5]2=[CH:4][CH:3]=1
Reactant: C=C(C)C1NC(=O)CC(c2cc(Cl)ccc2OCC(C)(C)C(=O)OC)C12C(=O)Nc1cc(Cl)ccc12
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: C=C(C)C1NC(=O)CC(c2cc(Cl)ccc2OCC(C)(C)C(=O)O)C12C(=O)Nc1cc(Cl)ccc12
Temperature: 80 °C
Yield: 77 %

Procedure:
A mixture of racemic (2′R,3R,4′S)-6-chloro-4′-[5-chloro-2-(2-methoxycarbonyl-2-methyl-propoxy)-phenyl]-2′-isopropenylspiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione (20 mg), NaOH (80 mg), H2O (5 mL) and MeOH (1 mL) was heated at 80° C. for 2 h. Then the mixture was concentrated. The remaining aqueous solution was acidified by concentrated aqueous HCl solution (1.5 mL). The white precipitate was collected by filtration to give title compound (15 mg).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[C:12](=O)[C:10]2=[O:11])=[CH:5][CH:4]=1.[OH-:20].[K+]>>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]2[C:5](=[C:12]([C:10]([OH:20])=[O:11])[C:14]3[C:19]([N:9]=2)=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH:4]=1
Reactant: [OH-]
Reactant: COc1ccc(N2C(=O)C(=O)c3ccccc32)cc1
Agent: [K+]
Product: COc1ccc2nc3ccccc3c(C(=O)O)c2c1
Reaction time: 4 h

Procedure:
The crude N-(4-methoxyphenyl)isatin from the above was suspended in 10% aqueous potassium hydroxide (150 ml) and refluxed under a nitrogen atmosphere. After 4 hours, the reflux was stopped and the reaction was filtered while still hot. The filtrate was diluted with water (˜150 ml) and ice. This solution was then acidified with concentrated hydrochloric acid. A yellow precipitate appeared which was collected by filtration. The precipitate was rinsed with cold water and ether and then air-dried. The dried residue was then transferred to a round-bottom flask with the aid of methanol and the partial solution was evaporated to dryness. The resulting residue was evaporated to dryness from toluene twice. A yellowish-brown powder was recovered in 1.15 g. TLC (1:4, methanol:chloroform) indicated a clean reaction; Rf (product)=0.14. This material was used as such for the next reaction.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:43]=[C:42]([O:44][CH3:45])[CH:41]=[CH:40][C:4]=1[CH2:5][NH:6][C:7]1[C:8]2[CH:15]=[CH:14][N:13]([C@H:16]3[C@@H:20]4[O:21][C:22]([CH3:25])([CH3:24])[O:23][C@@H:19]4[C@@H:18]([CH2:26][N:27]([CH:37]([CH3:39])[CH3:38])[CH:28]4[CH2:31][CH:30]([CH2:32][CH2:33][C:34](O)=O)[CH2:29]4)[CH2:17]3)[C:9]=2[N:10]=[CH:11][N:12]=1.[C:46]([C:50]1[CH:51]=[C:52]([NH2:57])[C:53]([NH2:56])=[CH:54][CH:55]=1)([CH3:49])([CH3:48])[CH3:47].C(N(CC)C(C)C)(C)C>CN(C)C=O>[C:46]([C:50]1[CH:55]=[CH:54][C:53]2[NH:56][C:34]([CH2:33][CH2:32][CH:30]3[CH2:31][CH:28]([N:27]([CH2:26][C@@H:18]4[C@H:19]5[O:23][C:22]([CH3:24])([CH3:25])[O:21][C@H:20]5[C@H:16]([N:13]5[C:9]6[N:10]=[CH:11][N:12]=[C:7]([NH:6][CH2:5][C:4]7[CH:40]=[CH:41][C:42]([O:44][CH3:45])=[CH:43][C:3]=7[O:2][CH3:1])[C:8]=6[CH:15]=[CH:14]5)[CH2:17]4)[CH:37]([CH3:38])[CH3:39])[CH2:29]3)=[N:57][C:52]=2[CH:51]=1)([CH3:49])([CH3:47])[CH3:48]
Reactant: COc1ccc(CNc2ncnc3c2ccn3[C@@H]2C[C@H](CN(C(C)C)C3CC(CCC(=O)O)C3)[C@H]3OC(C)(C)O[C@H]32)c(OC)c1
Reactant: CC(C)(C)c1ccc(N)c(N)c1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COc1ccc(CNc2ncnc3c2ccn3[C@@H]2C[C@H](CN(C(C)C)C3CC(CCc4nc5cc(C(C)(C)C)ccc5[nH]4)C3)[C@H]3OC(C)(C)O[C@H]32)c(OC)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 3-(3-((((3aR,4R,6R,6aS)-6-(4-((2,4-dimethoxybenzyl)amino)-7H-pyrrolo [2,3-d]pyrimidin-7-yl)-2,2-dimethyltetrahydro-3aH-cyclopenta[d][1,3]dioxol-4-yl)methyl)(isopropyl)amino)cyclobutyl)propanoic acid (490 mg, 0.79 mmol) and 4-tert-butylbenzene-1,2-diamine (155 mg, 0.946 mmol) in N,N-Dimethylformamide (8.1 ml) was treated with N,N-Diisopropylethylamine (0.453 ml, 2.60 mmol) dropwise followed by N,N,N′,N′-Tetramethyl-0-(7-azabenzotriazol-1-yl)uronium Hexafluorophosphate (449 mg, 1.18 mmol) in one portion. The reaction mixture was stirred at RT overnight. The reaction mixture was concentrated under high vacuum and the residue was partitioned between 50 ml EtOAc and 50 ml 1/1 H2O/sat NaHCO3. The aqueous phase was extracted with 30 ml EtOAc and the combined organic phase was washed with 30 ml portions of H2O and brine. The organic phase was dried over Na2SO4, filtered and concentrated to give a glass/stiff foam. The crude material was purified by flash chromatography (SiO2, eluting with 4% 7N NH3 in CH3OH/CH2Cl2) to give the desired intermediate as a mixture of amide regioisomers (400 mg). A solution of intermediate (0.40 g) in Acetic acid (15 ml) was heated at 65° C. for 2.5 h, the reaction mixture was cooled and placed under high vacuum to remove the acetic acid. The residue was taken up in 60 ml CH2Cl2 and washed with 40 ml portions of sat NaHCO3 and 2% Na2CO3 solution. The organic phase was dried over Na2SO4, filtered and concentrated to yield a glass/stiff foam. The material was placed on high vacuum and used directly in the next step (380 mg)
Reaction SMILES: C1(N2C3C(=C(OC)C=C(C(O)=O)C=3)C=C2)CC1.[CH:18]1([N:21]2[C:29]3[C:24](=[C:25]([O:35][CH2:36][CH3:37])[CH:26]=[C:27]([C:30]([O:32]CC)=[O:31])[CH:28]=3)[CH:23]=[CH:22]2)[CH2:20][CH2:19]1>>[CH:18]1([N:21]2[C:29]3[C:24](=[C:25]([O:35][CH2:36][CH3:37])[CH:26]=[C:27]([C:30]([OH:32])=[O:31])[CH:28]=3)[CH:23]=[CH:22]2)[CH2:19][CH2:20]1
Reactant: CCOC(=O)c1cc(OCC)c2ccn(C3CC3)c2c1
Agent: COc1cc(C(=O)O)cc2c1ccn2C1CC1
Product: CCOc1cc(C(=O)O)cc2c1ccn2C1CC1

Procedure:
The compound was prepared according to the procedure for 1-Cyclopropyl-4-methoxy-1H-indole-6-carboxylic acid but using ethyl 1-cyclopropyl-4-ethoxy-1H-indole-6-carboxylate in place of ethyl 1-cyclopropyl-4-methoxy-1H-indole-6-carboxylate.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:12][CH3:13])=[CH:9][CH:10]=2)[CH:5]=[C:4]([NH:14][C:15]2[CH:19]=[CH:18][NH:17][N:16]=2)[N:3]=1.[CH3:20][N:21]1[CH:25]=[C:24](B2OC(C)(C)C(C)(C)O2)[CH:23]=[N:22]1>>[CH3:13][O:12][C:8]1[CH:7]=[C:6]2[C:11](=[CH:10][CH:9]=1)[C:2]([C:24]1[CH:23]=[N:22][N:21]([CH3:20])[CH:25]=1)=[N:3][C:4]([NH:14][C:15]1[CH:19]=[CH:18][NH:17][N:16]=1)=[CH:5]2
Reactant: COc1ccc2c(Cl)nc(Nc3cc[nH]n3)cc2c1
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Product: COc1ccc2c(-c3cnn(C)c3)nc(Nc3cc[nH]n3)cc2c1

Procedure:
Similar procedure as described in example 131 was used, starting from (1-chloro-6-methoxy-isoquinolin-3-yl)-(1H-pyrazol-3-yl)-amine and 1-methyl-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-pyrazole to give [6-methoxy-1-(1-methyl-1H-pyrazol-4-yl)-isoquinolin-3-yl]-(1H-pyrazol-3-yl)-amine. LC-MS m/e 321(MH+).