Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([CH2:7][C:8]([NH:10][C@@H:11]2[C:32](=[O:33])[N:13]3[C:14]([C:20]([O:22][CH2:23][C:24]4[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][CH:25]=4)=[O:21])=[C:15]([CH2:18]Cl)[CH2:16][S:17][C@H:12]23)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[I-].[Na+].[CH:55]([C:57]1[CH:61]=[CH:60][S:59][N:58]=1)=O.C(=O)([O-])O.[Na+]>CN(C)C=O>[C:1]1([CH2:7][C:8]([NH:10][C@@H:11]2[C:32](=[O:33])[N:13]3[C:14]([C:20]([O:22][CH2:23][C:24]4[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][CH:25]=4)=[O:21])=[C:15]([CH:18]=[CH:55][C:57]4[CH:61]=[CH:60][S:59][N:58]=4)[CH2:16][S:17][C@H:12]23)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=Cc1ccsn1
Reactant: COc1ccc(COC(=O)C2=C(CCl)CS[C@@H]3[C@H](NC(=O)Cc4ccccc4)C(=O)N23)cc1
Agent: O=C([O-])O
Agent: [I-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc(COC(=O)C2=C(C=Cc3ccsn3)CS[C@@H]3[C@H](NC(=O)Cc4ccccc4)C(=O)N23)cc1
Reaction time: 2 h
Yield: 73.5 %

Procedure:
To 20 ml of dimethylformamide were dissolved 3.0 g (6.16 mmol) of p-methoxybenzyl 7β-phenylacetamido-3-chloromethyl-3-cephem-4carboxylate and 1.70 g (6.48 mmol) of triphenylphosphine, and 0.97 g (6.47 mmol) of sodium iodide was added therein, and the stirring was effected for 2 hrs. at the room temperature. The reaction solution was concentrated and dried under the reduced pressure and 10 ml of methylene chloride was added therein. To this solution were added 767 mg (6.78 mmol) of 3-formylisothiazole and 10 ml of saturated sodium hydrogen carbonate aqueous solution, and the stirring was effected for 5.5 hrs. at the room temperature. The layer of methylene chloride was separated, and the aqueous layer was extracted with methylene chloride. The layers of methylene chloride were combined, washed with saturated saline solution; and dried over anhydrous magnesium sulfate, and then, the solvent was evaporated off to give 6.8 g of a caramel. This caramel was column chromatographed on silica gel by eluting with chloroform-ethyl acetate to give 2.48 g of p-methoxybenzyl 7β-phenylacetamido-3-[2-(isothiazol-3-yl)vinyl]-3-cephem-4-carboxylate.
Reaction SMILES: [NH:1]([C:5]1[CH:12]=[CH:11][C:10]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:9][C:6]=1[CH2:7]Br)[C:2]([CH3:4])=[O:3].[CH2:18]([NH:20][CH2:21][CH3:22])[CH3:19]>C(Cl)(Cl)Cl.C(O)C>[NH:1]([C:5]1[CH:12]=[CH:11][C:10]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:9][C:6]=1[CH2:7][N:20]([CH2:21][CH3:22])[CH2:18][CH3:19])[C:2]([CH3:4])=[O:3]
Reactant: CCNCC
Reactant: CCOC(=O)c1ccc(NC(C)=O)c(CBr)c1
Solvent: ClC(Cl)Cl
Solvent: CCO
Product: CCOC(=O)c1ccc(NC(C)=O)c(CN(CC)CC)c1

Procedure:
30 gm of 2-acetamino-5-carbethoxy-benzyl bromide were dissolved in a mixture of 400 ml of chloroform and 100 ml of ethanol, and the solution was refluxed with 22 gm of diethylamine for 1 hour. Thereafter, the reaction solution was cooled, then evaporated in vacuo, the residue was distributed between a mixture of dilute ammonia and chloroform, and the chloroform phase was dried over sodium sulfate and evaporated in vacuo. The residue was purified by chromatography on silicagel (elution agent: ethyl acetate) and recrystallized from ethanol, yielding 2-acetamino-5-carbethoxy-N,N-diethyl-benzylamine, m.p. 57-59° C.
Reaction SMILES: [OH-].[K+].[CH3:3][O:4][C:5]1[CH:6]=[C:7]([C:11]2[S:18][C:17]3[CH:16]=[N:15][NH:14][C:13]=3[CH:12]=2)[CH:8]=[CH:9][CH:10]=1.[I:19]I>CN(C)C=O>[I:19][C:16]1[C:17]2[S:18][C:11]([C:7]3[CH:8]=[CH:9][CH:10]=[C:5]([O:4][CH3:3])[CH:6]=3)=[CH:12][C:13]=2[NH:14][N:15]=1
Reactant: COc1cccc(-c2cc3[nH]ncc3s2)c1
Reactant: II
Agent: [K+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: COc1cccc(-c2cc3[nH]nc(I)c3s2)c1
Reaction time: 0.17 h
Yield: 91.3 %

Procedure:
Crushed potassium hydroxide (1.35 g, 24.1 mmol) was added in one portion to a solution of 5-(3-methoxyphenyl)-1H-thieno[3,2-c]pyrazole [1.85 g, 8.03 mmol, Intermediate (53)] and dimethylformamide at 0° C. with stirring. After 10 minutes, iodine (3.05 g, 12.0 mmol) was added in one portion and the dark reaction was stirred at 0° C. for 30 minutes and then at room temperature for 5 hours. The reaction was quenched with 10% aqueous NaHSO3 (100 mL), the resulting white mixture diluted with water (100 ml) and the mixture aged at 5° C. overnight. The solid was collected by filtration, washed with water (3×30 mL) and dried under vacuum at 40° C. to give 3-iodo-5-(3-methoxyphenyl)-1H-thieno[3,2-c]pyrazole [2.61 g, 91%, Intermediate (54)] as a tan powder. mp 159-163° C.; TLC Rf 0.54 (silica, 80% ethyl acetate/heptane); LC/MS: 357.0 (M+H), RT=3.60 minutes; 1H NMR (300 Mhz, CDCl3) δ 11.3 (br s, 1H), 7.33 (m, 1H), 7.28-7.20 (m, 2H), 7.14 (m, 1H), 6.91 (m, 1H), 3.87 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6](F)[CH:5]=[CH:4][C:3]=1[S:9]([C@H:12]1[CH2:16][N:15]([C:17]2[N:21]([CH:22]3[CH2:27][CH2:26][O:25][CH2:24][CH2:23]3)[N:20]=[C:19]([CH3:28])[CH:18]=2)[C@H:14]([C:29]([NH:31][C:32]2([C:35]#[N:36])[CH2:34][CH2:33]2)=[O:30])[CH2:13]1)(=[O:11])=[O:10].[F:37][C:38]([F:42])([F:41])[CH2:39][OH:40]>>[CH2:39]([OH:40])[C:38]([F:42])([F:41])[F:37].[C:35]([C:32]1([NH:31][C:29]([C@@H:14]2[CH2:13][C@@H:12]([S:9]([C:3]3[CH:4]=[CH:5][C:6]([O:40][CH2:39][C:38]([F:42])([F:41])[F:37])=[CH:7][C:2]=3[Cl:1])(=[O:11])=[O:10])[CH2:16][N:15]2[C:17]2[N:21]([CH:22]3[CH2:27][CH2:26][O:25][CH2:24][CH2:23]3)[N:20]=[C:19]([CH3:28])[CH:18]=2)=[O:30])[CH2:33][CH2:34]1)#[N:36]
Reactant: Cc1cc(N2C[C@H](S(=O)(=O)c3ccc(F)cc3Cl)C[C@H]2C(=O)NC2(C#N)CC2)n(C2CCOCC2)n1
Solvent: OCC(F)(F)F
Product: Cc1cc(N2C[C@H](S(=O)(=O)c3ccc(OCC(F)(F)F)cc3Cl)C[C@H]2C(=O)NC2(C#N)CC2)n(C2CCOCC2)n1

Procedure:
In analogy to the procedure described in example 392, (2S,4R)-4-(2-chloro-4-fluorophenylsulfonyl)-N-(1-cyanocyclopropyl)-1-(3-methyl-1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-5-yl)pyrrolidine-2-carboxamide (example 464d) was reacted with 2,2,2,-trifluoroethanol (CAS Reg. No. 75-89-8 99) to give the title compound after purification by preparative chiral HPLC as colorless oil. MS (ESI): m/z=616.1 [M+H]+.
Reaction SMILES: CC1N=C(N2C(=O)N(CC3C=CC(C(F)(F)F)=CC=3)N=C2)SC=1C(O)=O.[F:27][C:28]1[CH:49]=[CH:48][C:31]([CH2:32][N:33]2[C:37](=[O:38])[N:36]([C:39]3[S:40][C:41]([C:45]([OH:47])=O)=[C:42]([CH3:44])[N:43]=3)[CH:35]=[N:34]2)=[CH:30][CH:29]=1.[N:50]1[CH:55]=[CH:54][CH:53]=[C:52]([CH2:56][NH2:57])[CH:51]=1>>[F:27][C:28]1[CH:49]=[CH:48][C:31]([CH2:32][N:33]2[C:37](=[O:38])[N:36]([C:39]3[S:40][C:41]([C:45]([NH:57][CH2:56][C:52]4[CH:51]=[N:50][CH:55]=[CH:54][CH:53]=4)=[O:47])=[C:42]([CH3:44])[N:43]=3)[CH:35]=[N:34]2)=[CH:30][CH:29]=1
Reactant: Cc1nc(-n2cnn(Cc3ccc(F)cc3)c2=O)sc1C(=O)O
Reactant: NCc1cccnc1
Agent: Cc1nc(-n2cnn(Cc3ccc(C(F)(F)F)cc3)c2=O)sc1C(=O)O
Product: Cc1nc(-n2cnn(Cc3ccc(F)cc3)c2=O)sc1C(=O)NCc1cccnc1
Yield: 68 %

Procedure:
Following the procedure as described in Example 21, making variations as required to replace 4-methyl-2-(5-oxo-1-(4-(trifluoromethyl)benzyl)-1H-1,2,4-triazol-4(5H)-yl)thiazole-5-carboxylic acid with 2-(1-(4-fluorobenzyl)-5-oxo-1H-1,2,4-triazol-4(5H)-yl)-4-methylthiazole-5-carboxylic acid to react with pyridin-3-ylmethanamine, the title compound was obtained as a white solid in 68% yield: mp 178-179° C. (ethyl acetate/hexane); 1H NMR (300 MHz, CDCl3) δ 8.58 (br s, 1H), 8.51 (br s, 1H), 8.27 (s, 1H), 7.72-7.64 (m, 1H), 7.63-7.54 (m, 2H), 7.51-7.42 (m, 2H), 7.33-7.21 (m, 1H), 6.46 (t, J=5.8 Hz, 1H), 5.04 (s, 2H), 4.59 (d, J=5.8 Hz, 2H), 2.63 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 164.3, 161.7, 161.0, 153.4, 150.9, 149.9, 149.3, 149.1, 135.7, 130.9, 130.3, 130.2, 121.6, 115.9, 115.7, 48.9, 41.6, 17.2; MS (ES+) m/z 425.3 (M+1).
Reaction SMILES: CC(OC(/N=N/C(OC(C)C)=O)=O)C.[F:15][C:16]([F:34])([F:33])[C:17]1[N:21]2[N:22]=[C:23]([N:26]3[CH2:31][CH2:30][CH:29]([OH:32])[CH2:28][CH2:27]3)[CH:24]=[CH:25][C:20]2=[N:19][N:18]=1.[CH2:35]([O:42][C:43]1[CH:48]=[CH:47][C:46](O)=[CH:45][CH:44]=1)[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1COCC1>[CH2:35]([O:42][C:43]1[CH:48]=[CH:47][C:46]([O:32][CH:29]2[CH2:30][CH2:31][N:26]([C:23]3[CH:24]=[CH:25][C:20]4[N:21]([C:17]([C:16]([F:15])([F:33])[F:34])=[N:18][N:19]=4)[N:22]=3)[CH2:27][CH2:28]2)=[CH:45][CH:44]=1)[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1
Reactant: OC1CCN(c2ccc3nnc(C(F)(F)F)n3n2)CC1
Reactant: Oc1ccc(OCc2ccccc2)cc1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: FC(F)(F)c1nnc2ccc(N3CCC(Oc4ccc(OCc5ccccc5)cc4)CC3)nn12
Temperature: 25 °C
Reaction time: 4 h
Yield: 51.6 %

Procedure:
DIAD (2.262 mL, 11.49 mmol) was added to 1-[3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazin-6-yl]piperidin-4-ol (3 g, 10.44 mmol), 4-(benzyloxy)phenol (2.300 g, 11.49 mmol) and triphenylphosphine (3.01 g, 11.49 mmol) in THF (50 mL) under nitrogen. The resulting solution was stirred at ambient temperature for 4 hours. The crude oil was triturated with MeOH to give a solid which was collected by filtration and dried under vacuum to give 6-[4-[4-(benzyloxy)phenoxy]piperidin-1-yl]-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine (2.53 g, 52%) as a solid.
Reaction SMILES: [CH3:1][NH:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]([F:12])([F:11])[F:10])=[C:5]([N+:13]([O-])=O)[CH:4]=1>[Pd]>[NH2:13][C:5]1[CH:4]=[C:3]([NH:2][CH3:1])[CH:8]=[CH:7][C:6]=1[C:9]([F:11])([F:12])[F:10]
Reactant: CNc1ccc(C(F)(F)F)c([N+](=O)[O-])c1
Agent: [Pd]
Product: CNc1ccc(C(F)(F)F)c(N)c1
Reaction time: 1 h

Procedure:
A mixture of N-methyl-3-nitro-4-trifluoromethylbenzenamine (20 g., 0.09 mole) and absolute alcohol (200 ml.) was reduced with 5% palladium on carbon 50% wet. The material absorbed 24 lbs. of hydrogen (100% theory) in 1 hr. The catalyst was removed by filtration and the filtrate stripped in vacuo. The dark oil crystallized to give 17 g. (99%). The material used as an intermediate in Part C.
Reaction SMILES: [C:1]1([C:7]2[C:8](=[O:20])[O:9][C:10]3[C:15]([C:16]=2[OH:17])=[CH:14][CH:13]=[CH:12][C:11]=3[O:18][CH3:19])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[O:21]1[CH2:26][CH2:25][N:24]([CH2:27][CH2:28]Cl)[CH2:23][CH2:22]1>>[CH3:19][O:18][C:11]1[CH:12]=[CH:13][CH:14]=[C:15]2[C:10]=1[O:9][C:8](=[O:20])[C:7]([C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)=[C:16]2[O:17][CH2:28][CH2:27][N:24]1[CH2:25][CH2:26][O:21][CH2:22][CH2:23]1
Reactant: COc1cccc2c(O)c(-c3ccccc3)c(=O)oc12
Reactant: ClCCN1CCOCC1
Product: COc1cccc2c(OCCN3CCOCC3)c(-c3ccccc3)c(=O)oc12
Yield: 74 %

Procedure:
This compound is prepared according to the method of Example 8 from 45.6 g. (0.17 mol) of 3-phenyl-4-hydroxy-8-methoxy-coumarin and 30.5 g. (0.24 mol) of 2-morpholino-1-chlorethane. After recrystallisation from isopropanol, 48 g. are isolated; M.P. 90°-91° C. Yield 74% (theoretical yield 65.0 g.).
Reaction SMILES: C(O)(C(F)(F)F)=O.C(Cl)Cl.C(OC([N:18]1[CH2:23][CH2:22][CH:21]([N:24]2[C:28]3[N:29]=[CH:30][N:31]=[C:32]([NH2:33])[C:27]=3[C:26]([C:34](=[O:53])[C:35]3[CH:40]=[CH:39][CH:38]=[C:37]([NH:41][C:42]([NH:44][C:45]4[CH:50]=[C:49]([Cl:51])[CH:48]=[C:47]([Cl:52])[CH:46]=4)=[O:43])[CH:36]=3)=[CH:25]2)[CH2:20][CH2:19]1)=O)(C)(C)C>C(Cl)Cl>[NH2:33][C:32]1[C:27]2[C:26]([C:34]([C:35]3[CH:36]=[C:37]([NH:41][C:42]([NH:44][C:45]4[CH:50]=[C:49]([Cl:51])[CH:48]=[C:47]([Cl:52])[CH:46]=4)=[O:43])[CH:38]=[CH:39][CH:40]=3)=[O:53])=[CH:25][N:24]([CH:21]3[CH2:20][CH2:19][NH:18][CH2:23][CH2:22]3)[C:28]=2[N:29]=[CH:30][N:31]=1
Reactant: CC(C)(C)OC(=O)N1CCC(n2cc(C(=O)c3cccc(NC(=O)Nc4cc(Cl)cc(Cl)c4)c3)c3c(N)ncnc32)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Nc1ncnc2c1c(C(=O)c1cccc(NC(=O)Nc3cc(Cl)cc(Cl)c3)c1)cn2C1CCNCC1
Temperature: 25 °C
Reaction time: 12 h
Yield: 95.3 %

Procedure:
A solution of TFA/CH2Cl2 (0.49 mL/3.5 mL) was added to a solution of 4-(4-amino-5-{3-[3-(3,5-dichloro-phenyl)-ureido]-benzoyl}-pyrrolo[2,3-d]pyrimidin-7-yl)-piperidine-1-carboxylic acid tert-butyl ester (0.2 g, 0.32 mmol) in CH2Cl2 (1 mL) at 0 C. The reaction mixture was warmed to room temperature, stirred for 12 h, and concentrated in vacuo. The crude reaction mixture was quenched with H2O (5 mL) and Na2CO3 (5 mL) and extracted with CH2Cl2 (4×5 mL). The combined organic extracts were dried (MgSO4), filtered, and concentrated in vacuo to provide the title compound as a yellow solid (0.16 g, 93%). MS: 525.5 (MH+); HPLC Rf: 5.35 min. (HPLC method 4); HPLC purity: 84%.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6](B2OC(C)(C)C(C)(C)O2)[CH:5]=[CH:4][C:3]=1[C:17]1[S:21][C:20]([NH2:22])=[N:19][N:18]=1.Br[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[S:30]([NH:33][C:34]([CH3:37])([CH3:36])[CH3:35])(=[O:32])=[O:31]>>[NH2:22][C:20]1[S:21][C:17]([C:3]2[CH:4]=[CH:5][C:6]([C:24]3[C:25]([S:30]([NH:33][C:34]([CH3:37])([CH3:36])[CH3:35])(=[O:31])=[O:32])=[CH:26][CH:27]=[CH:28][CH:29]=3)=[CH:7][C:2]=2[F:1])=[N:18][N:19]=1
Reactant: CC1(C)OB(c2ccc(-c3nnc(N)s3)c(F)c2)OC1(C)C
Reactant: CC(C)(C)NS(=O)(=O)c1ccccc1Br
Product: CC(C)(C)NS(=O)(=O)c1ccccc1-c1ccc(-c2nnc(N)s2)c(F)c1

Procedure:
The title compound was prepared using analogous conditions to those described in Example 6 utilizing 5-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-1,3,4-thiadiazol-2-amine and 2-bromo-N-(tert-butyl)benzenesulfonamide. MS (ESI): mass calcd. for C18H19FN4O2S2, 406.09; m/z found, 407.1 [M+H]+. 1H NMR (300 MHz, CD3OD) δ 8.20-8.10 (m, 2H), 7.69-7.56 (m, 2H), 7.46-7.36 (m, 3H), 1.08 (s, 9H).
Reaction SMILES: C(Cl)Cl.[F:4][C:5]1[CH:6]=[C:7]2[C:25](=[CH:26][CH:27]=1)[O:24][CH2:23][CH2:22][NH:21][CH2:20][C:19]1=[C:28]3[N:29]=[C:13]([CH:14]=[CH:15][N:16]3[N:17]=[CH:18]1)[N:12]1[C@@H:8]2[CH2:9][CH2:10][CH2:11]1.CCN(C(C)C)C(C)C.[CH3:39][S:40](Cl)(=[O:42])=[O:41]>CO>[F:4][C:5]1[CH:6]=[C:7]2[C:25](=[CH:26][CH:27]=1)[O:24][CH2:23][CH2:22][N:21]([S:40]([CH3:39])(=[O:42])=[O:41])[CH2:20][C:19]1=[C:28]3[N:29]=[C:13]([CH:14]=[CH:15][N:16]3[N:17]=[CH:18]1)[N:12]1[C@@H:8]2[CH2:9][CH2:10][CH2:11]1
Reactant: Fc1ccc2c(c1)[C@H]1CCCN1c1ccn3ncc(c3n1)CNCCO2
Reactant: CS(=O)(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: CO
Product: CS(=O)(=O)N1CCOc2ccc(F)cc2[C@H]2CCCN2c2ccn3ncc(c3n2)C1
Yield: 51 %

Procedure:
To a DCM (0.5 mL) solution of (6R)-9-fluoro-13-oxa-2,16,20,21,24-pentaazapentacyclo-[16.5.2.02,6.07,12.021,25]pentacosa-1(24),7,9,11,18(25),19,22-heptaene (Example 21, 5 mg, 0.0141 mmol) was added DIEA (2.46 μL, 0.0141 mmol), followed by methanesulfonyl chloride (1.10 μL, 0.0141 mmol). The reaction was stirred at ambient temperature for 1 hour before MeOH (0.1 mL) was added. The reaction was concentrated and purified by reverse-phase column chromatography eluting with 0-80% acetonitrile/H2O to provide the title product (3.1 mg, 50.8% yield). MS (apci) m/z=432.3 (M+H).
Reaction SMILES: [C:1]([C:3]([C:6]1[CH:7]=[C:8]([CH:29]=[CH:30][CH:31]=1)[C:9]([NH:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([O:18][C:19]2[CH:24]=[CH:23][C:22]([N+:25]([O-])=O)=[CH:21][C:20]=2[F:28])[CH:13]=1)=[O:10])([CH3:5])[CH3:4])#[N:2].[Cl-].[Ca+2].[Cl-].O>C(O)C>[NH2:25][C:22]1[CH:23]=[CH:24][C:19]([O:18][C:14]2[CH:13]=[C:12]([NH:11][C:9](=[O:10])[C:8]3[CH:29]=[CH:30][CH:31]=[C:6]([C:3]([C:1]#[N:2])([CH3:5])[CH3:4])[CH:7]=3)[CH:17]=[CH:16][CH:15]=2)=[C:20]([F:28])[CH:21]=1
Reactant: CC(C)(C#N)c1cccc(C(=O)Nc2cccc(Oc3ccc([N+](=O)[O-])cc3F)c2)c1
Agent: [Ca+2]
Agent: [Cl-]
Solvent: O
Solvent: CCO
Product: CC(C)(C#N)c1cccc(C(=O)Nc2cccc(Oc3ccc(N)cc3F)c2)c1
Temperature: 80 °C

Procedure:
A suspension of 3-(1-cyano-1-methylethyl)-N-[3-(2-fluoro-4-nitrophenoxy)phenyl]benzamide (2.03 g, 4.83 mmol), calcium chloride (1.41 g, 12.1 mmol) and reduced iron (2.97 g, 53.1 mmol) in ethanol (300 mL)/water (30 mL) was stirred with heating at 80° C. for 12 hr. The reaction mixture was cooled to room temperature, and passed through a pad filled with celite to separate insoluble material, and the insoluble materials were washed with ethanol. The filtrate and washing were combined and concentrated under reduced pressure. The obtained residue was diluted with ethyl acetate (300 mL), washed with 5% aqueous sodium hydrogencarbonate solution (300 mL), water (200 mL×2) and saturated brine (200 mL), successively, and dried over anhydrous sodium sulfate. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate=70/30→0/100), and the obtained solution was concentrated under reduced pressure to give the title compound (1.94 g, quantitatively) as a yellow amorphous substance.
Reaction SMILES: [CH:1]1([C:7](Cl)=[O:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[NH2:10][C:11]1[S:12][CH:13]=[CH:14][N:15]=1.C(N(C(C)C)CC)(C)C>ClCCl>[S:12]1[CH:13]=[CH:14][N:15]=[C:11]1[NH:10][C:7]([CH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1)=[O:8]
Reactant: O=C(Cl)C1CCCCC1
Reactant: Nc1nccs1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=C(Nc1nccs1)C1CCCCC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 72.8 %

Procedure:
Cyclohexanecarbonyl chloride (4.38 g, 30 mmol) was added dropwise to a solution of 2-aminothiazole (3.00 g, 30 mmol) and di-isopropylethylamine (3.87 g, 30 mmol) in dichloromethane (50 ml) at 0° C. The mixture was warmed to room temperature, stirred for 18 h, washed with 1 N--HCl (2×50 ml) and 1 N--NaOH (2×50 ml), dried (MgSO4), and evaporated in vacuo to give the product (4.59 g) as white crystals.
Reaction SMILES: Cl.[N:2]1[CH:7]=[CH:6][CH:5]=[C:4](/[CH:8]=[CH:9]/[C:10]([OH:12])=[O:11])[CH:3]=1.[C:13]([O-])([CH3:16])([CH3:15])[CH3:14].[K+]>CCOCC.O1CCCC1>[N:2]1[CH:7]=[CH:6][CH:5]=[C:4](/[CH:8]=[CH:9]/[C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH:3]=1
Reactant: CC(C)(C)[O-]
Reactant: O=C(O)/C=C/c1cccnc1
Agent: Cl
Agent: [K+]
Solvent: CCOCC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)/C=C/c1cccnc1
Temperature: 5 °C
Reaction time: 1 h

Procedure:
Ethereal HCl is added to a solution of 45 g of (2E)-3-(3-pyridyl)-2-propenoic acid in 300 ml of ether until the pH is acid. The precipitate obtained is filtered off, washed with ether and dried under reduced pressure. The product is then taken up in 600 ml of thionyl chloride and heated at reflux for 2 hours, and is then concentrated under reduced pressure and taken up successively in toluene and then ether. The residue obtained is then diluted with 1 liter of tetrahydrofuran, stirred at 5° C., and 67 g of potassium tert-butanolate in 2.5 liters of tetrahydrofuran are added. After reacting for 3 hours at 5° C. and for 1 hour at 20° C., the reaction mixture is subjected to customary treatment, allowing the expected product to be obtained after evaporation under reduced pressure.
Reaction SMILES: [C:1]([O:4][C@@H:5]1[CH2:9][N:8]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[C@H:7]([CH2:17][O:18][Si](C(C)(C)C)(C2C=CC=CC=2)C2C=CC=CC=2)[CH2:6]1)(=[O:3])[CH3:2].C(O)(=O)C.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C1COCC1>[C:1]([O:4][C@@H:5]1[CH2:9][N:8]([C:10]([O:12][C:13]([CH3:15])([CH3:14])[CH3:16])=[O:11])[C@H:7]([CH2:17][OH:18])[CH2:6]1)(=[O:3])[CH3:2]
Reactant: CC(=O)O[C@H]1C[C@@H](CO[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)N(C(=O)OC(C)(C)C)C1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: CC(=O)O[C@H]1C[C@@H](CO)N(C(=O)OC(C)(C)C)C1
Reaction time: 24 h
Yield: 79.8 %

Procedure:
To a stirred mixture of (2S,4S)-4-acetoxy-1-tert-butoxycarbonyl-2-tert-butyldiphenylsilyloxymethypyrrolidine (23.3 g, 46.9 mmol) and acetic acid (6.0 ml, 104.8 mmol) in THF (470 ml) was added TBAF (93.8 ml, 93.8 mmol) at 0° C. After 24 h stirring, the mixture was concentrated in vacuo. The resulting residue was diluted with EtOAC and aq. NH4Cl and extracted with EtOAc. The combined extracts were washed with brine, which were dried over Na2SO4 and concntrated in vacuo. The residue was chromatographed on silica gel (700 g, CHCl3/EtOAc (4/1)], to give (2S,4S)-4-acetoxy-1-tert-butoxycarbonyl-2-pyrrolidinemethanol (9.70 g, 8%) as a colorless oil. 1H-NMR (CDCl3) δ1.47 (s, 9H), 1.63 (m, 1H), 1.81 (m, 1H), 2.07 (s, 3H), 234 (m, 1H), 3.42 (dd, J=12.7, 0.9 Hz, 1H), 3.62-3.85 (m, 3H), 4.48 (br, 1H), 5.20 (br, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[C@H:13]([OH:14])[C@@H:12]([OH:15])[C@H:11]([OH:16])[C@@H:10]([S:17][CH2:18][CH3:19])[O:9]2)=[CH:4][C:3]=1[CH2:20][C:21]1[CH:26]=[CH:25][C:24]([O:27][CH2:28][CH3:29])=[CH:23][CH:22]=1.[OH:30]O>CC(O)=O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[C@H:13]([OH:14])[C@@H:12]([OH:15])[C@H:11]([OH:16])[C@@H:10]([S:17]([CH2:18][CH3:19])=[O:30])[O:9]2)=[CH:4][C:3]=1[CH2:20][C:21]1[CH:22]=[CH:23][C:24]([O:27][CH2:28][CH3:29])=[CH:25][CH:26]=1
Reactant: OO
Reactant: CCOc1ccc(Cc2cc([C@@H]3O[C@H](SCC)[C@@H](O)[C@H](O)[C@H]3O)ccc2Cl)cc1
Solvent: CC(=O)O
Product: CCOc1ccc(Cc2cc([C@@H]3O[C@H](S(=O)CC)[C@@H](O)[C@H](O)[C@H]3O)ccc2Cl)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of compound from step A (10 mg, 0.023 mmol) in AcOH (0.5 ml) was added H2O2 (35 wt % solution in H2O, 3 mg, 0.092 mmol, 9 μl). The mixture was stirred at ambient temperature for 2 hours before being concentrated under vacuum. Purification of the mixture by silica gel chromatography (5% MeOH/CH2Cl2) afforded (2S,3R,4R,5S,6R)-2-[4-chloro-3-(4-ethoxy-benzyl)-phenyl]-6-ethanesulfinyl-tetrahydro-pyran-3,4,5-triol (as a mixture of diastereomers at sulfur) (2 mg, 19%) and (2S,3R,4R,5S,6R)-2-[4-Chloro-3-(4-ethoxy-benzyl)-phenyl]-6-ethanesulfonyl-tetrahydro-pyran-3,4,5-triol (5 mg, 46%) both as white solids.
Reaction SMILES: [CH2:1]([O:8][CH2:9][N:10]1[C:14]2[CH:15]=[N:16][NH:17][C:18](=[O:19])[C:13]=2[CH:12]=[C:11]1[Br:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)C(C)C)(C)C.[CH3:30][Si:31]([CH3:38])([CH3:37])[CH2:32][CH2:33][O:34][CH2:35]Cl>ClCCl>[CH2:1]([O:8][CH2:9][N:10]1[C:14]2[CH:15]=[N:16][N:17]([CH2:35][O:34][CH2:33][CH2:32][Si:31]([CH3:38])([CH3:37])[CH3:30])[C:18](=[O:19])[C:13]=2[CH:12]=[C:11]1[Br:20])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C[Si](C)(C)CCOCCl
Reactant: O=c1[nH]ncc2c1cc(Br)n2COCc1ccccc1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: C[Si](C)(C)CCOCn1ncc2c(cc(Br)n2COCc2ccccc2)c1=O
Temperature: 40 °C
Reaction time: 3 h
Yield: 71.3 %

Procedure:
To 300 ml of dichloromethane solution containing 33.4 g (0.100 mol) of 1-benzyloxymethyl-2-bromo-1,5-dihydropyrrolo[2,3-d]pyridazin-4-one obtained in Reference example 17-(d) was added 25.8 g (0.200 mol) of N,N-diisopropylethylamine, and 25.0 g (0.15 mol) of (2-trimethylsilylethoxy)methyl chloride was added dropwise to the mixture under ice-cooling. After completion of the dropwise addition, the mixture was stirred at 40° C. for 3 hours. After completion of the reaction, the reaction mixture was washed successively with 1N hydrochloric acid, a saturated aqueous solution of sodium hydrogencarbonate and a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. To the obtained concentrate was added 300 ml of cyclohexane, and precipitated solid was collected by filtration. The obtained solid was washed with cyclohexane, and dried under reduced pressure to obtain 33.1 g of the title compound as a beige solid. (Yield: 71%)