Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC(N1CC[CH:10]([N:13]([CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([C:25]3[CH:30]=[CH:29][N:28]=[C:27]([NH:31][CH2:32][CH2:33][C:34]4[CH:39]=[CH:38][C:37]([OH:40])=[CH:36][CH:35]=4)[N:26]=3)[CH:20]=2)[S:14]([CH3:17])(=[O:16])=[O:15])[CH2:9]1)=O)(C)(C)C.CS([Cl:45])(=O)=O>>[Cl:45][C:36]1[CH:35]=[C:34]([CH2:33][CH2:32][NH:31][C:27]2[N:26]=[C:25]([C:21]3[CH:20]=[C:19]([CH:24]=[CH:23][CH:22]=3)[CH2:18][N:13]([CH2:10][CH3:9])[S:14]([CH3:17])(=[O:16])=[O:15])[CH:30]=[CH:29][N:28]=2)[CH:39]=[CH:38][C:37]=1[OH:40]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(C)OC(=O)N1CCC(N(Cc2cccc(-c3ccnc(NCCc4ccc(O)cc4)n3)c2)S(C)(=O)=O)C1
Product: CCN(Cc1cccc(-c2ccnc(NCCc3ccc(O)c(Cl)c3)n2)c1)S(C)(=O)=O

Procedure:
Compound 94 was coupled with methanesulfonyl chloride following procedure D. LC-MS showed the product had the expected M+H+ of 461. 1H NMR (Varian 300 MHz, DMSO-d6, shifts relative to the solvent peak at 2.49 ppm) δ 8.3 (d, 1H) 8.1 (s, 1H) 8.0 (s, 1H) 7.5 (d, 2H) 7.3 (m, 1H) 7.2 (s, 1H) 7.1 (d, 1H) 7.0 (d, 1H) 6.9 (d, 1H) 4.4 (s, 2H) 3.5 (m, 2H) 3.2 (m, 2H) 3.0 (s, 3H) 2.8 (m, 2H) 1.0 (m, 3H).
Reaction SMILES: FC(F)(F)S(O[C:7]1[C:8]([CH3:36])([CH3:35])[C@H:9]2[C@:22]([CH3:25])([CH2:23][CH:24]=1)[C@@H:21]1[C@:12]([CH3:34])([C@@:13]3([CH3:33])[C@H:18]([CH2:19][CH2:20]1)[C@H:17]1[C@H:26]([C:29]([CH3:31])=[CH2:30])[CH2:27][CH2:28][C@:16]1([NH2:32])[CH2:15][CH2:14]3)[CH2:11][CH2:10]2)(=O)=O.CC1(C)C(C)(C)OB([C:47]2[CH2:52][CH2:51][C:50]([C:58]([O:60][CH2:61][CH3:62])=[O:59])([C:53]([O:55][CH2:56][CH3:57])=[O:54])[CH2:49][CH:48]=2)O1.O.C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[NH2:32][C@:16]12[CH2:28][CH2:27][C@@H:26]([C:29]([CH3:31])=[CH2:30])[C@@H:17]1[C@@H:18]1[C@@:13]([CH3:33])([CH2:14][CH2:15]2)[C@@:12]2([CH3:34])[C@@H:21]([C@:22]3([CH3:25])[C@@H:9]([CH2:10][CH2:11]2)[C:8]([CH3:35])([CH3:36])[C:7]([C:47]2[CH2:52][CH2:51][C:50]([C:53]([O:55][CH2:56][CH3:57])=[O:54])([C:58]([O:60][CH2:61][CH3:62])=[O:59])[CH2:49][CH:48]=2)=[CH:24][CH2:23]3)[CH2:20][CH2:19]1
Reactant: C=C(C)[C@@H]1CC[C@]2(N)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(OS(=O)(=O)C(F)(F)F)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Reactant: CCOC(=O)C1(C(=O)OCC)CC=C(B2OC(C)(C)C(C)(C)O2)CC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: C=C(C)[C@@H]1CC[C@]2(N)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(C6=CCC(C(=O)OCC)(C(=O)OCC)CC6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Temperature: 85 °C
Yield: 11.3 %

Procedure:
To a sealable vial containing (1R,3aS,5aR,5bR,7aR,11aR,11bR,13aR,13bR)-3a-amino-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl trifluoromethanesulfonate (0.25 g, 0.448 mmol) was added diethyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclohex-3-ene-1,1-dicarboxylate (0.374 g, 0.531 mmol), sodium carbonate hydrate (0.167 g, 1.345 mmol), and palladium tetrakis (0.016 g, 0.013 mmol). The mixture was diluted with 1,4-dioxane (4 mL) and water (1 mL) then was flushed with nitrogen and was sealed and heated to 85° C. in an oil bath. After 5 h of heating, the mixture was cooled to rt, was diluted with water (20 mL), and was extracted with ethyl acetate (3×20 mL). The combined organic layers were washed with brine, dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography using a 10-50% ethyl acetate in hexanes gradient. diethyl 4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-amino-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)cyclohex-3-ene-1,1-dicarboxylate, a white solid, was recovered as the minor isolate (0.032 g, 0.05 mmol, 11.3% yield). LCMS: m/e 634.6 (M+H)+, 2.10 min (method 1).
Reaction SMILES: [C:1]1(=[O:14])[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:11]([OH:13])=[O:12])[CH:9]=2)[CH2:4][CH2:3][CH2:2]1.[CH3:15]O.Cl>>[CH3:15][O:12][C:11]([C:8]1[CH:9]=[C:10]2[C:5]([CH2:4][CH2:3][CH2:2][C:1]2=[O:14])=[CH:6][CH:7]=1)=[O:13]
Reactant: O=C(O)c1ccc2c(c1)C(=O)CCC2
Reactant: CO
Agent: Cl
Product: COC(=O)c1ccc2c(c1)C(=O)CCC2
Temperature: 0 °C
Yield: 48.6 %

Procedure:
Part A--A mixture of 1-tetralon-7-carboxylic acid (7.0 g, 0.037 mol) in methanol (13.6 mL, 10.8 g, 0.30 mol) with a catalytic amount of hydrochloric acid (0.07 mL, 0.12 g, 0.0012 mol) was stirred at reflux over 5 hours. The cooled reaction mixture was poured into ice water and extracted with ethyl acetate. The combined organic layers were backwashed with water and brine, dried over anhydrous magnesium sulfate and evaporated to dryness under reduced pressure. The resulting solid was purified by flash chromatography using hexane:ethyl acetate::75:25. The resulting solid was triturated with hexane to give 1-tetralon-7-carboxylic acid methyl ester (3.61 g, 0.018 mol, 49%) as a yellow solid. mp=170°-172° C.; 1H NMR (CDCl3) d 8.7 (s, 1H), 8.15 (d, 1H, J=8.1 Hz), 7.35 (d, 1H, J=8.1 Hz), 3.95 (s, 3H), 3.05 (d, 2H, J=6.1 Hz), 2.7 (t, 2H, J=6.4 Hz), 2.15 (quintet, 2H, J=6.2 Hz).
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][C:5]([NH2:8])=[CH:4][CH:3]=1.CC(O)=O.[C:13]([O:17][C:18](=[O:28])[NH:19][CH:20]1[CH2:25][CH2:24][CH:23]([CH:26]=O)[CH2:22][CH2:21]1)([CH3:16])([CH3:15])[CH3:14].[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C(Cl)Cl.CCOCC>[C:13]([O:17][C:18](=[O:28])[NH:19][C@H:20]1[CH2:21][CH2:22][C@H:23]([CH2:26][NH:8][C:5]2[CH:6]=[CH:7][C:2]([I:1])=[CH:3][CH:4]=2)[CH2:24][CH2:25]1)([CH3:16])([CH3:14])[CH3:15]
Reactant: Nc1ccc(I)cc1
Reactant: CC(C)(C)OC(=O)NC1CCC(C=O)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCOCC
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)N[C@H]1CC[C@H](CNc2ccc(I)cc2)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 4-iodo-phenylamine (1 g, 4.57 mmol) in DCM (25 ml) were successively added AcOH (0.523 ml, 9.13 mmol), (4-formyl-cyclohexyl)-carbamic acid tert-butyl ester (1.14 g, 5.02 mmol) and NaBH(OAc)3 (1.94 g, 9.13 mmol) at RT. The reaction mixture was stirred at RT for 1 h then diluted with Et2O and washed successively with a 2M aqueous HCl solution and a 2M aqueous Na2CO3 solution. The organic phase was dried over Na2SO4, filtered and evaporated to dryness. The resulting crude material was purified by Combi-Flash Companion™ (Isco Inc.) column chromatography (SiO2; gradient elution, heptane/AcOEt 95:5→1:1) to yield the title compound (1.56 g, 3.62 mmol, 79%) as a colorless solid. TLC: RF=0.72 (heptane/AcOEt 1:1); HPLC: AtRet=2.64 min; LC-MS: m/z 431.4 [M+H]+; 1H NMR (400 MHz, DMSO-d6): 0.87-1.03 (m, 2H), 1.03-1.17 (m, 2H), 1.32-1.48 (m, 1H), 1.37 (s, 9H), 1.70-1.86 (m, 4H), 2.76-2.86 (m, 2H), 3.08-3.25 (m, 1H), 5.77-5.89 (m, 1H), 6.34-6.46 (m, 2H), 6.59-6.71 (m, 1H), 7.24-7.35 (m, 2H).
Reaction SMILES: ClC1C=C(C=CC=1)C(OO)=[O:6].[C:12]([C:14]1[C:15]([NH:44][CH2:45][CH2:46][O:47][CH3:48])=[CH:16][C:17]([NH:20][C:21]([N:23]2[C:32]3[C:27](=[CH:28][C:29]([CH2:35][N:36]4[CH2:41][CH2:40][N:39]([CH3:42])[CH2:38][C:37]4=[O:43])=[C:30]([CH:33]=[O:34])[N:31]=3)[CH2:26][CH2:25][CH2:24]2)=[O:22])=[N:18][CH:19]=1)#[N:13]>C(Cl)(Cl)Cl.C(Cl)Cl>[C:12]([C:14]1[C:15]([NH:44][CH2:45][CH2:46][O:47][CH3:48])=[CH:16][C:17]([NH:20][C:21]([N:23]2[C:32]3[N:31]=[C:30]([CH:33]=[O:34])[C:29]([CH2:35][N:36]4[CH2:41][CH2:40][N+:39]([O-:6])([CH3:42])[CH2:38][C:37]4=[O:43])=[CH:28][C:27]=3[CH2:26][CH2:25][CH2:24]2)=[O:22])=[N:18][CH:19]=1)#[N:13]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: COCCNc1cc(NC(=O)N2CCCc3cc(CN4CCN(C)CC4=O)c(C=O)nc32)ncc1C#N
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Product: COCCNc1cc(NC(=O)N2CCCc3cc(CN4CC[N+](C)([O-])CC4=O)c(C=O)nc32)ncc1C#N
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
3-Chlorobenzoperoxoic acid (9.3 mg, 0.041 mmol) was added to a solution of N-(5-cyano-4-((2-methoxyethyl)amino)pyridin-2-yl)-7-formyl-6-((4-methyl-2-oxopiperazin-1-yl)methyl)-3,4-dihydro-1,8-naphthyridine-1(2H)-carboxamide (Example 83, 20 mg, 0.039 mmol) in CHCl3 (0.1 ml) at 0° C. After stirring for 20 min, the mixture was warmed to room temperature and stirred for another 2 h. The reaction mixture was diluted with DCM and washed with sat. aq. NaHCO3. The aqueous layer was back-extracted with DCM (2×). The combined organic layers were dried over Na2SO4 and evaporated. The residue was triturated with Et2O to give the title compound as a light purple solid.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[S:9]([NH2:12])(=[O:11])=[O:10].[CH2:13]([N:19]=[C:20]=S)[CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]>C(OCC)(=O)C>[Cl:8][C:6]1[CH:5]=[CH:4][C:3]2[S:9](=[O:11])(=[O:10])[N:12]=[C:20]([NH:19][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])[NH:1][C:2]=2[CH:7]=1
Reactant: Nc1cc(Cl)ccc1S(N)(=O)=O
Reactant: CCCCCCN=C=S
Solvent: CCOC(C)=O
Product: CCCCCCNC1=NS(=O)(=O)c2ccc(Cl)cc2N1

Procedure:
The title compound was prepared from 2-amino-4-chlorobenzenesulfonamide and hexyl isothiocyanate by a method analogous to the one described in Example 4; m.p. 244-247° C. (ethyl acetate); 1H-NMR (DMSO-d6): δ 0.88 (distorted t, 3H, CH3), 1.31 (m, 6H, 3×CH2), 1.53 (m, 2H, CH2), 3.22 (q, 2H, NHCH2), 7.2-7.4 (m, 3H, ArH+NH), 7.68 (d, 1H, ArH), 10.55 (br.s, 1H, NH); MS: m/e 315/317 (M+); (C13H18N3Cl1O2S1) caic. C, 49.44; H, 5.74 N, 13.31; found C, 49.59; H, 6.01; N, 13.25.
Reaction SMILES: C(N(CC)CC)C.[C:8]([O:14][CH2:15][C:16]1[CH:21]=[CH:20][C:19]([N+:22]([O-:24])=[O:23])=[CH:18][CH:17]=1)(=[O:13])[CH2:9][C:10]([CH3:12])=[O:11].C1(C)C=CC(S([N:34]=[N+:35]=[N-])(=O)=O)=CC=1>C(#N)C>[N+:34](=[C:9]([C:10](=[O:11])[CH3:12])[C:8]([O:14][CH2:15][C:16]1[CH:17]=[CH:18][C:19]([N+:22]([O-:24])=[O:23])=[CH:20][CH:21]=1)=[O:13])=[N-:35]
Reactant: Cc1ccc(S(=O)(=O)N=[N+]=[N-])cc1
Reactant: CC(=O)CC(=O)OCc1ccc([N+](=O)[O-])cc1
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CC(=O)C(=[N+]=[N-])C(=O)OCc1ccc([N+](=O)[O-])cc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 55.1 %

Procedure:
35.0 ml (0.25 mole - 1.8 equivalent) of triethylamine were added dropwise to a solution, which had been cooled to 0° C., of 33.18 g (0.14 mole) of 4-nitrobenzyl acetoacetate and 30.40 g (0.15 mole) of p-toluenesulphonyl azide in 280 ml of anhydrous acetonitrile. The mixture was stirred at 0° C. for 2 h, and then the resulting precipitate was filtered off with suction, washed with ether and dried over P4O10 under high vacuum. 20.3 g (55%) of the title compound were obtained as colorless crystals, melting point 132° C. A further 6.3 g (17%) of the title compound were obtained by chromatography of the filtrate solution on 400 g of silica gel (toluene:ethyl acetate 9:1), Rf: 0.35 (toluene:ethyl acetate 9:1).
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[F:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:15]=[C:16]([NH:20][CH2:21][CH2:22]O)[N:17]=[N:18][CH:19]=2)=[CH:10][CH:9]=1.C(N(CC)CC)C.C(O)(C)C>ClCCl.CS(C)=O.C(OCC)(=O)C>[F:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[N:18][N:17]3[CH:22]=[CH:21][N:20]=[C:16]3[CH:15]=2)=[CH:10][CH:9]=1
Reactant: OCCNc1cc(-c2ccc(F)cc2)cnn1
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: Fc1ccc(-c2cnn3ccnc3c2)cc1
Temperature: -78 °C
Reaction time: 0.33 h

Procedure:
Oxalyl chloride (3.33 mL, 38.1 mmol) was slowly added to a stirred mixture of DMSO (2.70 mL, 38.1 mmol) in Dichloromethane (25 mL) at −78° C. The mixture was stirred at −78° C. for 10 min before 2-{[5-(4-fluorophenyl)pyridazin-3-yl]amino}ethanol (888 mg, 3.81 mmol) in 3.5 mL DMSO was added. The reaction mixture was left to stir at −78° C. for 20 min, treated with triethylamine (5.31 ml, 38.1 mmol), left to stir at −78° C. for 10 min, and allowed to warm to room temp. The mixture was treated with isopropanol (9 mL), diluted with ethyl acetate (200 mL), and washed with 2% sodium hypochlorite (200 mL) and water (200 mL). The aqueous layer was extracted with chloroform:isopropanol (3:1). The combined organics were dried over anhydrous MgSO4, filtered, and concentrated under reduced pressure to afford the title compound. LRMS (APCI) calc'd for (C12H9FN3) [M+H]+, 214.1. found 214.0.
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[C:5]([CH3:22])[CH:6]=[C:7]2[C:12]=1[O:11][CH:10]([C:13]([F:16])([F:15])[F:14])[C:9]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:8]2)=[O:2].[BH4-].[Na+]>C1COCC1.C(O)C>[OH:2][CH2:1][C:3]1[CH:4]=[C:5]([CH3:22])[CH:6]=[C:7]2[C:12]=1[O:11][CH:10]([C:13]([F:15])([F:16])[F:14])[C:9]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:8]2
Reactant: CCOC(=O)C1=Cc2cc(C)cc(C=O)c2OC1C(F)(F)F
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: C1CCOC1
Product: CCOC(=O)C1=Cc2cc(C)cc(CO)c2OC1C(F)(F)F
Temperature: 0 °C
Reaction time: 1 h
Yield: 93 %

Procedure:
The ethyl 8-formyl-6-methyl-2-(trifluoromethyl)-2H-chromene-3-carboxylate from Example 605a, Step 1 (0.32 g, 1.02 mmole) was dissolved in a mixture of THF (1.5 mL) and ethanol (1.5 mL) and the solution was chilled to 0° C. (ice bath). Sodium borohydride (0.04 g, 1.02 mmole) was added portionwise to the above solution and the mixture was allowed to stir for 1 hour. The reaction was quenched with 0.5N HCl (5 mL) and extracted with CH2Cl2 (2×10 mL). The combined extracts were washed with brine (20 mL), dried over MgSO4, filtered and concentrated in vacuo to give a yellow oil (0.3 g, 93%): GCMS m/z 316.0 (M+). 1H NMR (CDCl3/400 MHz) 7.78 (s, 1H), 7.11 (s, 1H), 6.96 (s, 1H), 5.71 (q, 1H, J=7.0 Hz), 4.67 (m, 2H), 4.30 (m, 2H), 2.27 (s, 3H), 1.33 (m, 3H).
Reaction SMILES: [NH2:1][CH:2]([CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([C:19]([F:22])([F:21])[F:20])[CH:14]=1)[CH:3]([C:5]1[CH:10]=[CH:9][C:8]([F:11])=[CH:7][CH:6]=1)[OH:4].[C:23]1([CH2:29][CH2:30][CH2:31][C:32](O)=[O:33])[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.Cl.C(N=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1>C(#N)C.O>[F:11][C:8]1[CH:7]=[CH:6][C:5]([CH:3]([OH:4])[CH:2]([NH:1][C:32](=[O:33])[CH2:31][CH2:30][CH2:29][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([C:19]([F:22])([F:20])[F:21])[CH:14]=2)=[CH:10][CH:9]=1
Reactant: O=C(O)CCCc1ccccc1
Reactant: NC(Cc1cccc(C(F)(F)F)c1)C(O)c1ccc(F)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CC#N
Solvent: O
Product: O=C(CCCc1ccccc1)NC(Cc1cccc(C(F)(F)F)c1)C(O)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 65.3 %

Procedure:
To a solution of (1RS,2SR)-2-amino-1-(4-fluorophenyl)-3-(3-(trifluoromethyl)phenyl)-1-propanol (450 mg, 1.44 mmol) in acetonitrile (30 ml) were added 4-phenyl-n-butyric acid (236 mg, 1.44 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (358 mg, 1.87 mmol) and 1-hydroxy-1H-benzotriazole (220 mg, 1.44 mmol) and the mixture was stirred overnight at room temperature. The reaction solution was diluted with water (100 ml) and extracted with ethyl acetate (100 ml×2). The extract was washed with saturated brine, dried over anhydrous magnesium sulfate and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate). Recrystallization from ethyl acetate-hexane gave the title compound (432 mg, 65%).
Reaction SMILES: [O:1]=[C:2]1[CH2:6][CH2:5][CH2:4][N:3]1[CH2:7][C:8]([OH:10])=O.ClC(OCC(C)C)=O.C(N(CC)CC)C.[NH2:26][CH2:27][C:28]([N:30]1[CH2:35][CH2:34][CH:33]([C:36]([NH2:38])=[O:37])[CH2:32][CH2:31]1)=[O:29]>O1CCCC1>[O:1]=[C:2]1[CH2:6][CH2:5][CH2:4][N:3]1[CH2:7][C:8]([NH:26][CH2:27][C:28]([N:30]1[CH2:35][CH2:34][CH:33]([C:36]([NH2:38])=[O:37])[CH2:32][CH2:31]1)=[O:29])=[O:10]
Reactant: NCC(=O)N1CCC(C(N)=O)CC1
Reactant: O=C(O)CN1CCCC1=O
Agent: CC(C)COC(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: NC(=O)C1CCN(C(=O)CNC(=O)CN2CCCC2=O)CC1
Reaction time: 0.25 h

Procedure:
27.8 g of (2-oxo-1-pyrrolidinyl)acetic acid was suspended in 450 ml of tetrahydrofuran, to which 27.8 g of isobutyl chloroformate at -15° C. and 20.3 g of triethylamine at -15° to -5° C. were added. After stirring at -10° to -5° C. for 15 minutes, 36.0 g of 1-glycyl-4-piperidinecarboxamide was added at -10° to -5° C. and then the reaction liquid was allowed to stand so as to rise its temperature to room temperature over 2 hours. The insoluble matter was filtered off and suspended in 500 ml of chloroform. The suspension was filtered off to obtain the crude crystal. The crude crystal was recrystallized from methanol to obtain the titled compound.
Reaction SMILES: [C:1]1([S:7]([N:10]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:12]([CH:19]=[O:20])=[CH:11]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[BH4-].[Na+]>ClCCl>[C:1]1([S:7]([N:10]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:12]([CH2:19][OH:20])=[CH:11]2)(=[O:8])=[O:9])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=Cc1cn(S(=O)(=O)c2ccccc2)c2ccccc12
Agent: [BH4-]
Agent: [Na+]
Solvent: ClCCl
Product: O=S(=O)(c1ccccc1)n1cc(CO)c2ccccc21
Reaction time: 3.5 h

Procedure:
In a three necked round bottom flask equipped with pressure equalizing funnel, 1-Benzenesulfonyl-1H-indole-3-carboxaldehyde (D1, 2.86 g, 0.01 mole) and dichloromethane (8 mL) were taken. Sodiumborohydride (0.005-0.01 mole) was added slowly at room temperature and the reaction mixture was stirred well for next 3-4 hours. After the completion of reaction (TLC, 3-5 hours), the product was isolated by distillation under reduced pressure. The residue was extracted with ethyl acetate (2×25 mL). The combined organic extracts were washed with water, followed by brine, dried over anhydrous sodium sulfate. The organic layer was evaporated under vacuum. The residue was generally an oily liquid, which was isolated and purified by flash chromatography (silica gel, EtOAc/Hexane, 2/8) to afford the title compound, which was identified by IR, NMR and mass spectral analyses.
Reaction SMILES: [CH3:1][NH:2][C:3](=[O:22])[C:4]1[CH:9]=[CH:8][C:7]([N+:10]([O-])=O)=[C:6]([O:13][C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][C:15]=2[F:21])[CH:5]=1.[Cl-].[NH4+]>C(O)C.O.[Fe]>[CH3:1][NH:2][C:3](=[O:22])[C:4]1[CH:9]=[CH:8][C:7]([NH2:10])=[C:6]([O:13][C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][C:15]=2[F:21])[CH:5]=1
Reactant: CNC(=O)c1ccc([N+](=O)[O-])c(Oc2ccc(F)cc2F)c1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CCO
Product: CNC(=O)c1ccc(N)c(Oc2ccc(F)cc2F)c1
Yield: 100.3 %

Procedure:
A mixture of N-methyl-3-(2,4-difluorophenoxy)-4-nitrobenzamide (0.85 g), iron powder (0.8 g) and ammonium chloride (80 mg) in ethanol (20 ml) and water (10 ml) was refluxed with stirring for an hour. The insoluble materials were filtered, and the filtrate was concentrated under reduced pressure. The residue was dissolved in ethyl acetate, washed with a saturated aqueous solution of sodium chloride, dried over magnesium sulfate, and concentrated to give a powder of N-methyl-4-amino-3-(2,4-difluorophenoxy)benzamide (0.77 g).
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][C:6]([Cl:12])=[CH:7][CH:8]=2)[N:3]=1.Br[CH2:14][C:15](=O)[C:16]([O:18][CH2:19][CH3:20])=[O:17].C1OC1C>C(COC)OC>[Cl:12][C:6]1[CH:5]=[C:4]2[C:9]([CH:10]=[CH:11][C:2]3[N:3]2[CH:14]=[C:15]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[N:1]=3)=[CH:8][CH:7]=1
Reactant: CCOC(=O)C(=O)CBr
Reactant: Nc1ccc2ccc(Cl)cc2n1
Agent: CC1CO1
Solvent: COCCOC
Product: CCOC(=O)c1cn2c(ccc3ccc(Cl)cc32)n1
Reaction time: 1 h

Procedure:
2.0 g of 2-amino-7-chloroquinoline [Chem. Abs., Vol. 79, p. 92024t] were dissolved in 40 ml of dimethoxyethane and then a mixture of 2.5 g of ethyl bromopyruvate and 0.5 g of propylene oxide in 5 ml of dimethoxyethane was added thereto. The mixture obtained was allowed to stand at room temperature for 1 hour and the quaternary salt thus precipitated was filtered off, washed with ether and then was dissolved in 50 ml of ethanol. The solution was refluxed for 1 hour and on subsequent cooling in ice, the solution precipitated ethyl 8-chlorimidazo-[1,2-a]-quinoline-2-carboxylate hydrobromide as pale lemon hygroscopic crystals. This salt was partitioned between 50 ml of dilute sodium carbonate solution and 100 ml of chloroform and the organic solution was separated, washed with 50 ml of water, dried over MgSO4 and was evaporated to dryness under reduced pressure. The residue was crystallized from chloroform/diethyl ether to give colorless crystals of ethyl 8-chloroimidazo-[1,2-a]-quinoline-2-carboxylate melting at 221°-222° C.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH:20]([OH:22])=[O:21].O[CH:24]([C@@H:26]1[C@@H:29]([S:30][CH3:31])[N:28]([C:32](=[C:37]([CH3:39])[CH3:38])[C:33]([O:35][CH3:36])=[O:34])[C:27]1=[O:40])[CH3:25].N(C(OCC)=O)=NC(OCC)=O>O1CCCC1>[CH:20]([O:22][CH:24]([C@@H:26]1[C@@H:29]([S:30][CH3:31])[N:28]([C:32](=[C:37]([CH3:39])[CH3:38])[C:33]([O:35][CH3:36])=[O:34])[C:27]1=[O:40])[CH3:25])=[O:21]
Reactant: COC(=O)C(=C(C)C)N1C(=O)[C@H](C(C)O)[C@H]1SC
Reactant: O=CO
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COC(=O)C(=C(C)C)N1C(=O)[C@H](C(C)OC=O)[C@H]1SC
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a solution of triphenylphosphine (1.647 g), formic acid (0.20 ml), and a mixture (1:3) of methyl 2-[(3S,4R)-3-{(1RS)-1-hydroxyethyl}-4-methylthio-2-oxoazetidin-1-yl]-3-methylbut-2-enoate (1.145 g) in tetrahydrofuran (14 ml) was added dropwise diethyl azodicarboxylate (0.83 ml) at 0° C. under a nitrogen atmosphere. After keeping at the same temperature for 15 minutes, the solution was allowed to warm to room temperature and stirred for two hours. The mixture was cooled to 0° C. and additional fornic acid (24 μl) and diethyl azodicarboxylate (0.10 ml) were added. After stirring at room temperature for one hour, the solution was concentrated, taken up into ethyl acetate (60 ml) and washed with a chilled dilute aqueous sodium bicarbonate, water, and brine. The organic layer was dried over magnesium sulfate, evaporated and re-dissolved in benzene (20 ml) to result in precipitation of crystals. These crystals were collected and washed with benzene. The combined filtrate and washings were evaporated and chromatographed on silica gel (60 g) eluting with 10-30% ethyl acetate in hexane to give a mixture (5:1) of methyl 2-[(3S,4R)-3-{(1RS)-1-formyloxyethyl}-4-methylthio-2-oxoazetidin-1-yl]-3-methylbut-2-enoate (889 mg).
Reaction SMILES: [OH:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([O:8][C:9]2[C:14]([NH:15][C:16]3[C:17]4[C:24]([CH3:25])=[C:23]([C:26](O)=[O:27])[S:22][C:18]=4[N:19]=[CH:20][N:21]=3)=[CH:13][CH:12]=[CH:11][N:10]=2)[CH2:4][CH2:3]1.[NH3:29]>CO.CN(C=O)C>[OH:1][C@H:2]1[CH2:3][CH2:4][C@H:5]([O:8][C:9]2[C:14]([NH:15][C:16]3[C:17]4[C:24]([CH3:25])=[C:23]([C:26]([NH2:29])=[O:27])[S:22][C:18]=4[N:19]=[CH:20][N:21]=3)=[CH:13][CH:12]=[CH:11][N:10]=2)[CH2:6][CH2:7]1
Reactant: N
Reactant: Cc1c(C(=O)O)sc2ncnc(Nc3cccnc3O[C@H]3CC[C@H](O)CC3)c12
Solvent: CN(C)C=O
Solvent: CO
Product: Cc1c(C(N)=O)sc2ncnc(Nc3cccnc3O[C@H]3CC[C@H](O)CC3)c12

Procedure:
Prepared analogously to 1.4 from 0.1 g 4-[2-(trans-4-hydroxy-cyclohexyloxy)-pyridin-3-ylamino]-5-methyl-thieno[2,3-d]pyrimidine-6-carboxylic acid and ammonia in methanol (7M) in DMF. Separated from cis isomer by chromatography.
Reaction SMILES: C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1.[C:19]([O:36]C1CCCCC1)(=[O:35])[C:20]1[C:21](=[CH:31][CH:32]=[CH:33][CH:34]=1)[C:22]([O:24]C1CCCCC1)=O>>[C:22]1(=[O:24])[O:36][C:19](=[O:35])[CH:20]2[CH2:34][CH2:33][CH2:32][CH2:31][CH:21]12
Reactant: O=C(OC1CCCCC1)c1ccccc1C(=O)OC1CCCCC1
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Product: O=C1OC(=O)C2CCCCC12

Procedure:
5.10 g of a 50 (wt) % benzoyl peroxide solution in dicyclohexyl phthalate;