Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([N:9]2[C:13]3([CH2:17][CH2:16][CH2:15][CH2:14]3)[C:12](=N)[NH:11][C:10]2=[O:19])=[CH:4][C:3]=1[CH3:20].O.C(=O)([O-])[OH:23].[Na+]>C(O)(=O)C>[Br:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([N:9]2[C:13]3([CH2:17][CH2:16][CH2:15][CH2:14]3)[C:12](=[O:23])[NH:11][C:10]2=[O:19])=[CH:4][C:3]=1[CH3:20]
Reactant: O=C([O-])O
Reactant: Cc1cc(N2C(=O)NC(=N)C23CCCC3)cc(C)c1Br
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: Cc1cc(N2C(=O)NC(=O)C23CCCC3)cc(C)c1Br
Temperature: 65 °C
Reaction time: 17 h

Procedure:
A mixture of 1-(4-bromo-3,5-dimethylphenyl)-4-imino-1,3-diazaspiro[4.4]nonan-2-one (the crude product obtained in the previous reaction) in acetic acid (1.0 mL) and water (0.25 mL) was stirred for 1.5 hours at 65° C. under nitrogen atmosphere. After further addition of acetic acid (1.0 mL) and water (0.25 mL), the mixture was stirred for 17 hours at 65° C. under nitrogen atmosphere. The reaction mixture was cooled, followed by dilution with water and adjustment of its pH to 8 using a saturated aqueous sodium hydrogen carbonate solution, and extracted with ethyl acetate. The organic layer was washed with water and brine, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate-hexane) to afford 1-(4-bromo-3,5-dimethylphenyl)-1,3-diazaspiro[4.4]nonane-2,4-dione (121 mg).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][CH:11]=1)[CH2:7][NH2:8])([O-:3])=[O:2].[CH:12]1([N:18]=[C:19]=[O:20])[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1>C1COCC1>[CH:12]1([NH:18][C:19]([NH:8][CH2:7][C:6]2[CH:9]=[CH:10][CH:11]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=2)=[O:20])[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1
Reactant: NCc1cccc([N+](=O)[O-])c1
Reactant: O=C=NC1CCCCC1
Solvent: C1CCOC1
Product: O=C(NCc1cccc([N+](=O)[O-])c1)NC1CCCCC1
Reaction time: 2 h

Procedure:
3-Nitro-benzyl-amine (5 g) was suspended in THF (130 ml) and cyclohexyl isocyanate (7 ml) was added dropwise at 25° C. After stirring for 2 h the resulting precipitate was filtered off, washed with diethyl ether and treated with 5% aqueous NH4OH. After filtering and drying the title compound was isolated (4.5 g, FP 168-169° C.)
Reaction SMILES: [C:1]1(=[O:8])[O:7][C:5](=[O:6])[CH2:4][CH2:3][CH2:2]1.[CH2:9]([NH2:16])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C(OCC)C>ClCCl>[O:6]=[C:5]([NH:16][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[CH2:4][CH2:3][CH2:2][C:1]([OH:7])=[O:8]
Reactant: NCc1ccccc1
Reactant: O=C1CCCC(=O)O1
Solvent: CCOCC
Solvent: ClCCl
Product: O=C(O)CCCC(=O)NCc1ccccc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 50.9 %

Procedure:
To a solution of 25 gm (220 mMol) glutaric anhydride in dichloromethane (250 ml) was added a solution of 26.4 ml (242 mMol) benzylamine in dichloromethane (50 ml) dropwise. The reaction mixture was stirred for 3 hours at room temperature. The reaction mixture was then poured into diethyl ether (500 ml) and the resulting solid was filtered. The filter cake was washed with diethyl ether, dried under vacuum and then recrystallized from ethyl acetate to give 24.8 gm (51%) 5-oxo-5-(phenylmethylamino)pentanoic acid as a crystalline solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:9][CH2:10][CH2:11][N:12]=[C:13]=[S:14])[CH:5]=[C:6]([F:8])[CH:7]=1.[N-:15]=[N+:16]=[N-:17].[Na+]>CN(C)C=O.O>[F:1][C:2]1[CH:3]=[C:4]([CH2:9][CH2:10][CH2:11][N:12]2[C:13]([SH:14])=[N:17][N:16]=[N:15]2)[CH:5]=[C:6]([F:8])[CH:7]=1
Reactant: Fc1cc(F)cc(CCCN=C=S)c1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Fc1cc(F)cc(CCCn2nnnc2S)c1
Reaction time: 1 h
Yield: 26.5 %

Procedure:
To a solution of 3-(3,5-difluorophenyl)propyl isothiocyanate (0.0177 mol) in dimethylformamide (35 ml) was added water (12 ml), followed by sodium azide (0.0361 mol). The reaction was stirred one hour, then it was diluted with water and washed with ethyl acetate. The aqueous phase was acidified with 3N aqueous hydrogen chloride, extracted into ethyl acetate, washed with water, dried over sodium sulfate and was concentrated. The residue was dissolved in ethyl ether and dicyclohexylamine (1.9 ml) was added. The resulting salt was filtered and partitioned, with stirring, between ethyl ether and 3N aqueous hydrogen chloride. The ethereal layer was washed with water, dried over sodium sulfate and concentrated. The crude product was recrystallized from pet. ether to yield 1.2 g (27%) white crystals: mp 80°-81° (pet. ether).
Reaction SMILES: [CH:1]([NH:3][CH:4](P(OCCCC)(OCCCC)=O)[C:5]([O:7][CH2:8][C:9]([C:11]1[CH:16]=[CH:15][C:14]([Br:17])=[CH:13][CH:12]=1)=[O:10])=[O:6])=[S:2].C(=O)([O-])[O-].[K+].[K+].Cl[CH2:37][C:38](=O)[CH2:39][O:40][C:41](=[O:45])[CH:42]([CH3:44])[CH3:43]>CC(C)=O>[C:41]([O:40][CH2:39][C:38]1[CH2:37][S:2][CH:1]=[N:3][C:4]=1[C:5]([O:7][CH2:8][C:9]([C:11]1[CH:12]=[CH:13][C:14]([Br:17])=[CH:15][CH:16]=1)=[O:10])=[O:6])(=[O:45])[CH:42]([CH3:44])[CH3:43]
Reactant: CCCCOP(=O)(OCCCC)C(NC=S)C(=O)OCC(=O)c1ccc(Br)cc1
Reactant: CC(C)C(=O)OCC(=O)CCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CC(C)C(=O)OCC1=C(C(=O)OCC(=O)c2ccc(Br)cc2)N=CSC1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A solution of p-bromophenacyl α-thioformamido-dibutylphosphonoacetate (6.10 g) in acetone (50 ml) is treated with powdered potassium carbonate (4.98 g). The mixture is stirred under a nitrogen atmosphere while 1-chloro-3-isobutyryloxy-2-propanone (2.32 g) in acetone (10 ml) is added dropwise over 10 minutes. The reaction mixture is stirred an additional 3 hours at room temperature, then filtered. Evaporaton of the filtrate under reduced pressure leaves a dark oil which is extracted with carbon tetrachloride (2 × 50 ml). The combined extracts are washed with 0.5 M dipotassium hydrogen phosphate, water, and saturated brine, dried over magnesium sulfate, and evaporaged in vacuo to give crude p-bromophenacyl 5-isobutyryloxymethyl-6H-1,3-thiazine-4-carboxylate.
Reaction SMILES: [OH:1][C:2]1[C:6]([CH3:15])([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14])[S:5][C:4](=[O:16])[CH:3]=1.C(N(CC)CC)C.[CH3:24][Si:25](Cl)([CH3:27])[CH3:26]>>[CH3:15][C:6]1([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14])[S:5][C:4](=[O:16])[CH:3]=[C:2]1[O:1][Si:25]([CH3:27])([CH3:26])[CH3:24]
Reactant: C[Si](C)(C)Cl
Reactant: CCCCCCCCC1(C)SC(=O)C=C1O
Solvent: CCN(CC)CC
Product: CCCCCCCCC1(C)SC(=O)C=C1O[Si](C)(C)C
Temperature: 25 °C
Reaction time: 4 h

Procedure:
(66, 67). To 32 (247 mg, 1.02 mmol) dissolved in hexanes was added triethylamine (0.23 mL, 1.68 mmol) and trimethylsilylchloride (0.21 mL, 1.64 mmol) and the solution was allowed to stir at room temperature for 4 h. The mixture was filtered over celite and evaporated to provide 5-methyl-5-octyl-4-trimethylsilanyloxy-5-H-thiopen-2-one. To a solution of TiCl4 (0.7 mL, 0.7 mmol) in CH2Cl2 (1.95 mL) at −78° C. was added acetaldehyde (54 μL, 0.97 mmol) and this solution was allowed to stir for 5 min at −78° C. Then, 5-methyl-5-octyl-4-trimethylsilanyloxy-5-H-thiopen-2-one dissolved in CH2Cl2 (0.4 mL) was cannulated into TiCl4/acetaldehyde solution giving a bright orange color. This mixture was allowed to warm and stir for 20 min at 0° C. The mixture was poured into NH4Cl(sat) (15 mL) and extracted with CH2Cl2 (3×15 mL). The organics were combined, dried (MgSO4), filtered and evaporated. Flash chromatography (10% EtOAc/Hexanes) provided pure 66 (34 mg) and 67 (24 mg) (50%). (66) 1H NMR (300 MHz, CDCl3) δ 0.86 (t, J=6.9 Hz, 3H), 1.05-1.08 (m, 1H), 1.24 (bs, 11H), 1.49 (d, J 6.5 Hz, 3H, rotamer) 1.55 (d, J=5.2 Hz, 3H, rotamer), 1.62 (s, 3H), 1.78-1.82 (m, 2H), 4.68 (q, J=6.5 Hz, 1H, rotamer), 5.04 (q, J=5.2 Hz, 1H, rotamer). HRMS (ES) m/z calculated for C16H28O3SNa+ (M+CH2+Na+) 323.1660 obsd. 323.1660.
Reaction SMILES: [CH3:1][C:2]1[CH:8]=[C:7]([CH3:9])[CH:6]=[CH:5][C:3]=1[NH2:4].C1(CN)CCCCC1.[O:18]=[C:19]1[C:27]2([CH2:31][O:30][C:29]3[CH:32]=[C:33]4[C:37](=[CH:38][C:28]2=3)[CH2:36][CH2:35][O:34]4)[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[N:20]1[CH2:39][C:40]1[CH:48]=[CH:47][C:43]([C:44](O)=[O:45])=[CH:42][CH:41]=1.O=C1C2(COC3C=C4C(=CC2=3)CCO4)C2C(=CC=CC=2)N1CC1C=C(C=CC=1)C(O)=O>>[CH3:1][C:2]1[CH:8]=[C:7]([CH3:9])[CH:6]=[CH:5][C:3]=1[NH:4][C:44](=[O:45])[C:43]1[CH:47]=[CH:48][C:40]([CH2:39][N:20]2[C:21]3[C:26](=[CH:25][CH:24]=[CH:23][CH:22]=3)[C:27]3([CH2:31][O:30][C:29]4[CH:32]=[C:33]5[C:37](=[CH:38][C:28]3=4)[CH2:36][CH2:35][O:34]5)[C:19]2=[O:18])=[CH:41][CH:42]=1
Reactant: O=C(O)c1ccc(CN2C(=O)C3(COc4cc5c(cc43)CCO5)c3ccccc32)cc1
Reactant: Cc1ccc(N)c(C)c1
Agent: NCC1CCCCC1
Agent: O=C(O)c1cccc(CN2C(=O)C3(COc4cc5c(cc43)CCO5)c3ccccc32)c1
Product: Cc1ccc(NC(=O)c2ccc(CN3C(=O)C4(COc5cc6c(cc54)CCO6)c4ccccc43)cc2)c(C)c1

Procedure:
Following the procedure as described in EXAMPLE 12 and making non-critical variations using 2,4-dimethylaniline to replace cyclohexanemethylamine, and 4-[(2′-oxo-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-1′(2′H)-yl)methyl]benzoic acid to replace 3-[(2′-oxo-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-1′(2′H)-yl)methyl]benzoic acid, N-(2,4-dimethylphenyl)-4-[(2′-oxo-5,6-dihydrospiro[benzo[1,2-b:5,4-b']difuran-3,3′-indol]-1′(2′H)-yl)methyl]benzamide was obtained (59%) as a colorless solid: mp 249-251° C.; 1H NMR (300 MHz, CDCl3) δ7.91-7.83 (m, 2H), 7.76-7.69 (m, 1H), 7.56 (s, 1H), 7.50-7.43 (m, 2H), 7.28-7.17 (m, 2H), 7.09-7.01 (m, 3H), 6.80-6.74 (m, 1H), 6.49 (s, 1H), 6.44 (s, 1H), 5.03 (ABq, 2H), 4.86 (ABq, 2H), 4.60-4.51 (m, 2H), 3.11-2.92 (m, 2H), 2.32 (s, 3H), 2.28 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 178.0, 165.2, 161.9, 161.3, 141.7, 139.6, 135.3, 134.6, 132.9, 132.6, 131.2, 129.8, 128.7, 127.7, 127.4, 124.0, 123.6 (2C), 120.0 (2C), 118.8, 109.1, 93.3, 80.6, 72.4, 57.7, 43.8, 29.0, 20.9, 17.8; MS (ES+) m/z 517.2 (M+1).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([C:20]([NH:22][C@H:23]([C:31]([C@:33]([C@H:38]([C@@H:40]([C@@H:42]([CH2:44][NH2:45])[OH:43])[OH:41])[OH:39])([OH:37])[C:34]([OH:36])=[O:35])=[O:32])[CH2:24][S:25][CH2:26][NH:27][C:28](=[O:30])[CH3:29])=[O:21])[CH2:10][CH:11]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])[C:12](=[O:14])[OH:13])=[O:7])([CH3:4])([CH3:3])[CH3:2].CN1CCOCC1.C(OC(Cl)=O)C(C)C.[CH3:61][Si:62]([CH:65](O)[CH3:66])([CH3:64])[CH3:63]>CN(C)C=O>[CH3:61][Si:62]([CH2:65][CH2:66][O:35][C:34]([C@@:33]([C:31](=[O:32])[C@H:23]([CH2:24][S:25][CH2:26][NH:27][C:28](=[O:30])[CH3:29])[NH:22][C:20](=[O:21])[C@H:9]([CH2:10][CH:11]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])[C:12](=[O:13])[OH:14])[NH:8][C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])([C@H:38]([C@@H:40]([C@@H:42]([CH2:44][NH2:45])[OH:43])[OH:41])[OH:39])[OH:37])=[O:36])([CH3:64])[CH3:63]
Reactant: CC(O)[Si](C)(C)C
Reactant: CC(=O)NCSC[C@H](NC(=O)[C@H](CC(OC(C)(C)C)C(=O)O)NC(=O)OC(C)(C)C)C(=O)[C@](O)(C(=O)O)[C@@H](O)[C@H](O)[C@H](O)CN
Agent: CC(C)COC(=O)Cl
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: CC(=O)NCSC[C@H](NC(=O)[C@H](CC(OC(C)(C)C)C(=O)O)NC(=O)OC(C)(C)C)C(=O)[C@](O)(C(=O)OCC[Si](C)(C)C)[C@@H](O)[C@H](O)[C@H](O)CN
Reaction time: 0.33 h

Procedure:
To 5 mL of a solution containing 1 mmol of the above acid 5, anhydrous dimethylformamide, and 1 mmol of N-methylmorpholine maintained at 0°-5° C., 1 mmol of isobutylchloroformate is added, and the mixture is kept at this temperature for 20 minutes. To this solution is added a solution of 1 mmol of trimethylsilylethanol in 2 mL of anhydrous dimethylformamide (previously cooled to 0°-5° C.), and the solution is stirred for 1 hour at this temperature and allowed to come to room temperature. The solvent is removed in vacuo and the residue is dissolved in 20 mL of ethyl acetate and washed with water. The organic layer is dried and evaporated to give 6.
Reaction SMILES: [NH2:1][S:2]([C:5]1[N:9]([CH3:10])[C:8]([C:11]([OH:13])=[O:12])=[CH:7][CH:6]=1)(=[O:4])=[O:3].[C:14]1(C)C=CC=CC=1.C[Si](C=[N+]=[N-])(C)C>CO>[NH2:1][S:2]([C:5]1[N:9]([CH3:10])[C:8]([C:11]([O:13][CH3:14])=[O:12])=[CH:7][CH:6]=1)(=[O:4])=[O:3]
Reactant: Cn1c(C(=O)O)ccc1S(N)(=O)=O
Reactant: Cc1ccccc1
Agent: C[Si](C)(C)C=[N+]=[N-]
Solvent: CO
Product: COC(=O)c1ccc(S(N)(=O)=O)n1C
Temperature: 25 °C
Reaction time: 2 h
Yield: 61 %

Procedure:
5-(Aminosulfonyl)-1-methyl-1H-pyrrole-2-carboxylic acid (1310 mg; 6.42 mmol; 1 eq.), commercially available (ASDI), is dissolved in MeOH (24 ml), then toluene (8 ml) is added followed by the dropwise addition of (trimethylsilyl)diazomethane (9.62 ml; 2M; 19.25 mmol; 3 eq). The solution is stirred at r.t. for 2 hr and another equivalent of (trimethylsilyl)diazomethane (3.21 ml; 2 M; 6.42 mmol; 1 eq) is added to reaction mixture. After 1 hr stirring, the solvent is concentrated to dryness and the resulting off white solid is recrystallized in MeOH to afford 851.1 mg (61%) of the title compound. 1H NMR (DMSO-d6) δ 7.58 (d, J=1.5 Hz, 1H), 7.13 (s, 2H), 7.06 (d, J=1.9 Hz, 1H), 3.88 (s, 3H), 3.77 (s, 3H). HPLC (max plot) 100%; Rt 1.19 min. LC/MS: (ES−) 217.1.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[CH:4][N:5]([CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:6]=1[C:7]([NH2:9])=[O:8].[F:17][C:18]1[CH:26]=[CH:25][C:21]([C:22](Cl)=[O:23])=[CH:20][CH:19]=1.C(Cl)(=O)C1C=CC=CC=1>>[CH2:10]([N:5]1[C:6]([C:7]([NH2:9])=[O:8])=[C:2]([NH:1][C:22](=[O:23])[C:21]2[CH:25]=[CH:26][C:18]([F:17])=[CH:19][CH:20]=2)[N:3]=[CH:4]1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: O=C(Cl)c1ccc(F)cc1
Reactant: NC(=O)c1c(N)ncn1Cc1ccccc1
Solvent: O=C(Cl)c1ccccc1
Product: NC(=O)c1c(NC(=O)c2ccc(F)cc2)ncn1Cc1ccccc1
Yield: 78 %

Procedure:
An amidation reaction and post-treatment were carried out under the same conditions as in Example 1, using 2.16 g (9.99 mmol) of 4-amino-1-benzyl-5-imidazolecarboxamide which was prepared in the same manner as in Reference Example 2 and 4-fluorobenzoyl chloride, instead of benzoyl chloride, to obtain 2.63 g of 1-benzyl-4-(4-fluorobenzoylamino)-5-imidazolecarboxamide (yield 78%).
Reaction SMILES: [O:1]1[CH2:5][CH2:4][C@@H:3]([OH:6])[CH2:2]1.[H-].[Na+].CC1C=CC(S(O[CH2:20][CH2:21][O:22][C:23]2[CH:28]=[CH:27][C:26]([CH2:29][C:30]3[CH:35]=[C:34]([Br:36])[CH:33]=[CH:32][C:31]=3[Cl:37])=[CH:25][CH:24]=2)(=O)=O)=CC=1>O1CCCC1>[Br:36][C:34]1[CH:33]=[CH:32][C:31]([Cl:37])=[C:30]([CH:35]=1)[CH2:29][C:26]1[CH:25]=[CH:24][C:23]([O:22][CH2:21][CH2:20][O:6][C@H:3]2[CH2:4][CH2:5][O:1][CH2:2]2)=[CH:28][CH:27]=1
Reactant: Cc1ccc(S(=O)(=O)OCCOc2ccc(Cc3cc(Br)ccc3Cl)cc2)cc1
Reactant: O[C@@H]1CCOC1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Clc1ccc(Br)cc1Cc1ccc(OCCO[C@H]2CCOC2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 79.6 %

Procedure:
To a stirred solution of (R)-tetrahydrofuran-3-ol (320 mg, 3.63 mmol) in dry tetrahydrofuran (10 mL) was added sodium hydride (145 mg, 3.63 mmol, 60%) slowly under 0° C. The reaction was stirred at this temperature for 30 min and then 2-(4-(5-bromo-2-chlorobenzyl)phenoxy)ethyl 4-methylbenzenesulfonate (intermediate AB) (300 mg, 0.61 mmol) was added. The reaction was warmed to room temperature and then heated to reflux overnight. The reaction was quenched with saturated ammonium chloride and extracted with ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate and concentrated to a yellow oil. The crude oil was purified by flash chromatography to get 200 mg of colorless oil (80% yield).
Reaction SMILES: C(N(CC)CC)C.[NH2:8][C@@H:9]([CH2:12][CH3:13])[CH2:10][OH:11].[N+:14]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[S:23](Cl)(=[O:25])=[O:24])([O-:16])=[O:15].C(=O)([O-])O.[Na+]>O1CCCC1>[OH:11][CH2:10][C@@H:9]([NH:8][S:23]([C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=1[N+:14]([O-:16])=[O:15])(=[O:24])=[O:25])[CH2:12][CH3:13]
Reactant: O=[N+]([O-])c1ccccc1S(=O)(=O)Cl
Reactant: CC[C@H](N)CO
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC[C@@H](CO)NS(=O)(=O)c1ccccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 99.1 %

Procedure:
Triethylamine (0.94 ml, 6.74 mmol) was added to a solution of 400 mg (4.49 mmol) of (S)-2-aminobutan-1-ol in tetrahydrofuran (5 ml), and the mixture was stirred at room temperature for 10 min. 2-Nitrobenzenesulfonyl chloride (995.1 mg, 4.49 mmol) was added to the solution, and the mixture was stirred at room temperature for 15 min. A saturated aqueous sodium hydrogencarbonate solution was added thereto to stop the reaction, and the reaction solution was then extracted with ethyl acetate, was dried over anhydrous sodium sulfate, and was filtered. The filtrate was concentrated under the reduced pressure, and the residue was purified by column chromatography on silica gel (hexane:ethyl acetate=2:1) to give 1.22 g (yield 99%) of the title compound.
Reaction SMILES: [OH:1][CH2:2][C:3]1[N:4]([CH3:12])[C:5]2[CH:10]=[CH:9][N:8]=[CH:7][C:6]=2[N:11]=1.O[C:14]1[CH:46]=[CH:45][C:17]([CH2:18][CH:19]2[S:23][C:22](=[O:24])[N:21]([C:25]([C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=3)([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)[C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[C:20]2=[O:44])=[CH:16][CH:15]=1.C(P(CCCC)CCCC)CCC.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O>C1(C)C=CC=CC=1>[CH3:12][N:4]1[C:5]2[CH:10]=[CH:9][N:8]=[CH:7][C:6]=2[N:11]=[C:3]1[CH2:2][O:1][C:14]1[CH:46]=[CH:45][C:17]([CH2:18][CH:19]2[S:23][C:22](=[O:24])[N:21]([C:25]([C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=3)([C:32]3[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=3)[C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[C:20]2=[O:44])=[CH:16][CH:15]=1
Reactant: Cn1c(CO)nc2cnccc21
Reactant: O=C1SC(Cc2ccc(O)cc2)C(=O)N1C(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: Cc1ccccc1
Product: Cn1c(COc2ccc(CC3SC(=O)N(C(c4ccccc4)(c4ccccc4)c4ccccc4)C3=O)cc2)nc2cnccc21

Procedure:
A procedure similar to that described in Preparation 4 was repeated, except that 1.94 g of 2-hydroxymethyl-1-methyl-1H-imidazo[4,5-c]pyridine (prepared as described in Preparation 73), 5.71 g of 5-(4-hydroxybenzyl)-3-triphenylmethylthiazolidine-2,4-dione, 3.1 ml of tributylphosphine, 3.09 g of 1,1'-(azodicarbonyl)dipiperidine and 50 ml of toluene were used, to give the title compound as a crude product. This crude product was purified by column chromatography through silica gel, using a gradient elution method, with mixtures of ethyl acetate and methanol in ratios ranging from 1:0 to 10:1 by volume as the eluent, to give 3.55 g of the title compound having Rf=0.08 (on silica gel thin layer chromatography using ethyl acetate as the developing solvent).
Reaction SMILES: [H-].[Na+].[C:3]([CH2:5][C:6]([O:8][CH2:9][CH3:10])=[O:7])#[N:4].F[C:12]1[C:21]([F:22])=[CH:20][C:19]2[C:23](=[O:31])[C:24]([C:26]([O:28][CH2:29][CH3:30])=[O:27])=[CH:25][N:17]3[C:18]=2[C:13]=1[CH2:14][CH2:15][N:16]3[CH3:32]>CN(C)C=O>[F:22][C:21]1[C:12]([CH:5]([C:3]#[N:4])[C:6]([O:8][CH2:9][CH3:10])=[O:7])=[C:13]2[C:18]3=[C:19]([C:23](=[O:31])[C:24]([C:26]([O:28][CH2:29][CH3:30])=[O:27])=[CH:25][N:17]3[N:16]([CH3:32])[CH2:15][CH2:14]2)[CH:20]=1
Reactant: CCOC(=O)CC#N
Reactant: CCOC(=O)c1cn2c3c(c(F)c(F)cc3c1=O)CCN2C
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1cn2c3c(c(C(C#N)C(=O)OCC)c(F)cc3c1=O)CCN2C
Temperature: 25 °C
Reaction time: 1 h
Yield: 56.1 %

Procedure:
168 mg (4.2 mmol) of 60% sodium hydride was added to 20 ml of N,N-dimethylformamide, and while cooling on ice, 452 mg (4 mmol) of ethyl cyanoacetate was dropped to the solution. The solution was stirred for 1 hour at room temperature. 612 mg (2 mmol) of ethyl 4,5-difluoro-2,3-dihydro-1-methyl-7-oxo-1H,7H-pyrido[3,2,1-ij]cinnoline-8-carboxylate was added to the solution, and the solution was stirred overnight at room temperature. The solution was heated at 70° C. for 2 hours, and the solvent was removed by distillation. 80 ml of chloroform and 20 ml of water were added to the residue, and the solution was acidified with citric acid. The organic layer was separated and after drying over magnesium sulfate, the solvent was removed by distillation. The residue was purified by column chromatography (silica gel 20 g, eluent solvent; ethyl acetate) to obtain 450 mg of the subject compound (161).
Reaction SMILES: C(=O)=O.[F:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[S:15][C:14]3[CH:16]=[CH:17][C:18]([O:20][CH3:21])=[CH:19][C:13]=3[C:12]=2I)=[CH:7][CH:6]=1.C([Li])CCC.[CH3:28][O:29][C:30](Cl)=[O:31]>C1COCC1.CC(C)=O>[F:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[S:15][C:14]3[CH:16]=[CH:17][C:18]([O:20][CH3:21])=[CH:19][C:13]=3[C:12]=2[C:30]([O:29][CH3:28])=[O:31])=[CH:7][CH:6]=1
Reactant: COC(=O)Cl
Reactant: COc1ccc2sc(-c3ccc(F)cc3)c(I)c2c1
Agent: O=C=O
Agent: [Li]CCCC
Solvent: CC(C)=O
Solvent: C1CCOC1
Product: COC(=O)c1c(-c2ccc(F)cc2)sc2ccc(OC)cc12
Temperature: -78 °C
Reaction time: 15 h

Procedure:
To a cooled solution (−78° C., dry ice, acetone) containing 2-(4-fluorophenyl)-3-iodo-5-methoxybenzo[b]thiophene (1.0 g, 2.6 mmol,) and THF (26 mL) was added n-butyllithium (2.0 mL, 1.0 M THF) over 5 min. The solution was maintained at −78° C. for 1 h. Methylchloroformate (0.80 mL, 10.4 mmol) was then added quickly in a steady stream via syringe. The solution was removed from cooling and allowed to stand at ambient temperature for 15 h. The solution was concentrated and purified on silica gel (0-10% ethyl acetate/hexanes, 40 min. gradient) to afford methyl 2-(4-fluorophenyl)-5-methoxybenzo[b]thiophene-3-carboxylate as a yellow residue. 1H NMR (500 MHz, CHLOROFORM-D) δ ppm 7.88 (d, J=2.44 Hz, 1H), 7.66 (d, J=8.85 Hz, 1H), 7.47 (dd, J=8.85, 5.19 Hz, 2H), 7.12 (t, J=8.70 Hz, 2H), 7.05 (dd, J=8.70, 2.59 Hz, 1H), 3.91 (s, 3H), 3.74 (s, 3H). LCMS: retention time: 3.355 min. LC data was recorded on a Shimadzu LC-10AS liquid chromatograph equipped with a Phenomenex-Luna, 10 micron, C18, 4.6×50 mm column using a SPD-10AV UV-Vis detector at a detector wave length of 220 nM. The elution conditions employed a flow rate of 4 mL/min, a gradient of 100% solvent A/0% solvent B to 0% solvent A/100% solvent B, a gradient time of 4 min, a hold time of 1 min, and an analysis time of 5 min where solvent A was 5% CH3CN/95% H2O/10 mM ammonium acetate and solvent B was 5% H2O/95% CH3CN/10 mM ammonium acetate. MS data was determined using a Micromass Platform for LC in electrospray mode. m/z 317 (MH+).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([Cl:11])[C:3]=1[C:4]([OH:6])=O.[CH3:12][O:13][C:14]1[C:15]([NH2:20])=[CH:16][CH:17]=[CH:18][CH:19]=1>C1C=CC=CC=1.C(Cl)(Cl)Cl>[NH2:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([Cl:11])[C:3]=1[C:4]([NH:20][C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=1[O:13][CH3:12])=[O:6]
Reactant: Nc1cccc(Cl)c1C(=O)O
Reactant: COc1ccccc1N
Solvent: ClC(Cl)Cl
Solvent: c1ccccc1
Product: COc1ccccc1NC(=O)c1c(N)cccc1Cl
Temperature: 25 °C

Procedure:
SO2Cl2 (5.4 mL, 74 mmol, 2.5 eq) was added to a rapidly stirring solution of 2-amino-6-chlorobenzoic acid (5 g, 29.14 mmol) in benzene (146 mL) and the mixture was stirred at reflux for 24 h. The mixture was concentrated under reduced pressure, and stripped down twice with benzene to give brown oil. The resulting oil was dissolved in CHCl3 (146 mL) and to that solution was added o-anisidine and the mixture was stirred at 65° C. for 2 h. The mixture was cooled to rt and the resulting precipitate was removed by filtration. The filtrate was concentrated under reduced pressure and purified by column chromatography on a 120 g of Redi-Sep™ column using 0 to 100% gradient of EtOAc in hexane over 20 min as eluent to provide 2-amino-6-chloro-N-(2-methoxyphenyl)benzamide as yellow solid. 1H NMR (DMSO-d6) δ ppm 9.44 (1 H, s), 7.86 (1 H, dd, J=7.9, 1.3 Hz), 7.13-7.21 (1 H, m), 7.04-7.11 (2 H, m), 6.97 (1 H, t, J=7.6 Hz), 6.66 (2 H, dd, J=28.0, 7.9 Hz), 5.37 (2 H, s), 3.81 (3 H, s). Mass Spectrum (ESI) m/e=277.0 (M+1).