Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]([CH2:4][C:5]1[CH:39]=[CH:38][C:8]([O:9][CH2:10][C:11]([N:13]2[CH2:18][CH2:17][N:16]([C:19]3[CH:24]=[CH:23][C:22]([N:25]4[CH2:29][C@H:28]([CH2:30][NH:31][C:32](=[S:35])[CH2:33][CH3:34])[O:27][C:26]4=[O:36])=[CH:21][C:20]=3[F:37])[CH2:15][CH2:14]2)=[O:12])=[CH:7][CH:6]=1)[CH3:3].[CH:40]1(C(SCC)=S)CC1>C(N(CC)CC)C>[CH3:1][N:2]([CH2:4][C:5]1[CH:6]=[CH:7][C:8]([O:9][CH2:10][C:11]([N:13]2[CH2:18][CH2:17][N:16]([C:19]3[CH:24]=[CH:23][C:22]([N:25]4[CH2:29][C@H:28]([CH2:30][NH:31][C:32]([CH:33]5[CH2:40][CH2:34]5)=[S:35])[O:27][C:26]4=[O:36])=[CH:21][C:20]=3[F:37])[CH2:15][CH2:14]2)=[O:12])=[CH:38][CH:39]=1)[CH3:3]
Reactant: CCSC(=S)C1CC1
Reactant: CCC(=S)NC[C@H]1CN(c2ccc(N3CCN(C(=O)COc4ccc(CN(C)C)cc4)CC3)c(F)c2)C(=O)O1
Solvent: CCN(CC)CC
Product: CN(C)Cc1ccc(OCC(=O)N2CCN(c3ccc(N4C[C@H](CNC(=S)C5CC5)OC4=O)cc3F)CC2)cc1

Procedure:
As described for the preparation of 27, the reaction of 26 (prepared from 357 mg of 25) with ethyl cyclopropanecarbodithioate and triethylamine gave the thioamide which was mixed with saturated NaHCO3 and extracted with CH2Cl2. The extract was dried (MgSO4) and concentrated. Chromatography of the residue on silica gel with 5% MeOH-0.5% NH4OH—CH2Cl2 and crystallization of the product from Et2O—CH2Cl2-heptane gave 74 mg of 28: mp 169–170° C.; 1H NMR [300 MHz, (CD3)2SO] δ 0.84 (m, 2H), 1.01 (m, 2H), 2.12 (s, 7H), 2.93. 3.00 (s, s, 4H), 3.25 (s, 2H), 3.60 (s, 4H), 3.79 (dd, 1H), 3.94 (m, 2H), 4.12 (t, 1H), 4.83 (s, 2H), 4.92 (m, 1H), 6.86 (d, 2H), 7.07 (t, 1H), 7.17 (m, 3H), 7.49 (dd, 1H).
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8](B(O)O)[CH:9]=2)[CH:4]=[CH:3]1.[OH:14]O>CCOCC>[CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([OH:14])[CH:9]=2)[CH:4]=[CH:3]1
Reactant: Cn1ccc2ccc(B(O)O)cc21
Reactant: OO
Solvent: CCOCC
Product: Cn1ccc2ccc(O)cc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 47 %

Procedure:
1-Methyl-1H-indol-6-yl-boronic acid (1.4 g, 8.0 mmol) was dissolved in ether (25 mL). Hydrogen peroxide (15%, 6 mL) was added over 5 minutes and the reaction mixture was stirred at room temperature for 1 h. The mixture was extracted with NaOH (1N, 2×50 mL) and the aqueous extracts were washed with ether (2×50 mL). The aqueous layers were cooled to 0° C. and acidified to pH 4.0 with 6 N HCl. The mixture was extracted with ether (3×100 mL) and the organic extracts were washed with water. The organic extracts were dried (MgSO4), filtered through a pad of silica gel and the pad was washed with ether (100 mL). After the filtrate was concentrated, the residue was chromatographed over silica gel with 10% to 20% ethyl acetate/hexanes to give 1-methyl-1H-indol-6-ol as a yellow solid (0.56 g, 47%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:16]2[CH:15]=[C:14]([N+:17]([O-:19])=[O:18])[C:13]3[CH:20]=[CH:21][CH:22]=[CH:23][C:12]=3[C:11]=2[CH:10]([CH2:24]O)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].S([Cl:30])(C)(=O)=O.S([O-])(=O)(=O)C.[Li+].[Cl-]>N1C=CC=CC=1.O.CN(C=O)C.C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[C:16]2[CH:15]=[C:14]([N+:17]([O-:19])=[O:18])[C:13]3[CH:20]=[CH:21][CH:22]=[CH:23][C:12]=3[C:11]=2[CH:10]([CH2:24][Cl:30])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CC(CO)c2c1cc([N+](=O)[O-])c1ccccc21
Reactant: CS(=O)(=O)Cl
Agent: CS(=O)(=O)[O-]
Agent: [Cl-]
Agent: [Li+]
Solvent: c1ccncc1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CC(CCl)c2c1cc([N+](=O)[O-])c1ccccc21
Temperature: 20 °C
Reaction time: 2 h
Yield: 76.8 %

Procedure:
A stirred solution of 12 (0.42 g, 1.22 mmol) in pyridine (1.8 mL) was treated dropwise at 0° C. with mesyl chloride (1.13 mL, 1.46 mmol) and then stirred at 20° C. for a further 2 h. The mixture was diluted with water and the resulting solid was collected, dissolved in CH2Cl2, and the solution was washed twice with water, dried (Na2SO4) and evaporated under reduced pressure below 30° C. A mixture of the resulting crude mesylate and LiCl (0.21 g, 5 mmol) in DMF (4 mL) was stirred at 80° C. for 30 min, then cooled and diluted with water. The precipitated solid was dissolved in CH2Cl2 and filtered through a column of silica gel to give a crude product which was triturated with iPr2O/petroleum ether, yielding 3-(tert-butyloxycarbonyl)-1-chloromethyl-5-nitro-1,2-dihydro-3H-benz[e]indole (13) (0.34 g, 77%). A sample recrystallised from iPr2 o/petroleum ether had mp 168-169° C. 1H NMR (CDCl3) δ8.88 (br s, 1 H, H-9), 8.42 (br s, 1 H, H-7), 7.80 (d, J=8.1 Hz, 1 H, H-4), 7.67-7.51 (m, 2 H, H-5,6), 4.34 (br s, 1 H, H-2), 4.20 (t, J=10.2 Hz, 1 H, H-2), 4.17-4.08 (m, 1 H, H-3), 3.92 (dd, J=11.2, 2.5 Hz, 1 H, CHHCl), 3.54 (t, J=10.3 Hz, CHHCl), 1.62 (s, 9 H, C(CH3)3).
Reaction SMILES: [ClH:1].O1CCOCC1.[OH:8][CH:9]([C:20]1[CH:21]=[N:22][C:23]([O:26][CH3:27])=[CH:24][CH:25]=1)[CH2:10][N:11](C)[C:12](=O)OC(C)(C)C>CO>[ClH:1].[ClH:1].[CH3:27][O:26][C:23]1[N:22]=[CH:21][C:20]([CH:9]([OH:8])[CH2:10][NH:11][CH3:12])=[CH:25][CH:24]=1
Reactant: COc1ccc(C(O)CN(C)C(=O)OC(C)(C)C)cn1
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: CNCC(O)c1ccc(OC)nc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of HCl-dioxane (4.0 M, 50 mL) was added tert-butyl 2-hydroxy-2-(6-methoxypyridin-3-yl)ethyl(methyl)carbamate (1.0 g, 3.5 mmol). The suspension was stirred at room temperature for 16 hours. The solvent and excess HCl was evaporated, leaving a white solid. The solid was dissolved in methanol and purified with a silica gel column, diluting with 1% NH4OH/5% Methanol/dichloromethane, to yield the title compound (0.63 g) as a colorless oil.
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[C:7]([F:9])[CH:6]=[CH:5][C:4]=1[F:10].[P:11]([O:18]CC)([O:15][CH2:16][CH3:17])[O:12][CH2:13][CH3:14]>>[F:10][C:4]1[CH:5]=[CH:6][C:7]([F:9])=[CH:8][C:3]=1[CH2:2][P:11](=[O:18])([O:15][CH2:16][CH3:17])[O:12][CH2:13][CH3:14]
Reactant: CCOP(OCC)OCC
Reactant: Fc1ccc(F)c(CBr)c1
Product: CCOP(=O)(Cc1cc(F)ccc1F)OCC
Temperature: 160 °C
Reaction time: 4 h
Yield: 93.3 %

Procedure:
A mixture of 2-(bromomethyl)-1,4-difluorobenzene (3 g, 14.49 mmol) and triethyl phosphite (7.72 ml, 43.5 mmol) was heated to 160° C. with stirring for 4 hours, cooled to ambient temperature and concentrated under high vacuum to remove most triethyl phosphite. The resulting residue was purified by column chromatography (20% to 30% EtOAc/Toluene) providing diethyl 2,5-difluorobenzylphosphonate (3.76 g, 13.52 mmol, 93% yield) as colorless oil. 1H NMR (500 MHz, DMSO-d6) δ 7.30-7.10 (m, 3H), 4.05-3.91 (m, 4H), 3.31-3.20 (m, 2H), 1.18 (t, J=7.0 Hz, 6H). MS Anal. Calcd. for [M+H]+ C11H16F2O3P: 265.2. found 265.3.
Reaction SMILES: [OH:1][C:2]1[CH:14]=[CH:13][C:5]2[N:6]=[C:7]([S:9]([NH2:12])(=[O:11])=[O:10])[S:8][C:4]=2[CH:3]=1.[C:15]1([CH3:25])[CH:20]=[CH:19][C:18]([S:21](Cl)(=[O:23])=[O:22])=[CH:17][CH:16]=1.Cl>CN(C)C1C=CN=CC=1.N1C=CC=CC=1>[CH3:25][C:15]1[CH:20]=[CH:19][C:18]([S:21]([O:1][C:2]2[CH:14]=[CH:13][C:5]3[N:6]=[C:7]([S:9](=[O:11])(=[O:10])[NH2:12])[S:8][C:4]=3[CH:3]=2)(=[O:23])=[O:22])=[CH:17][CH:16]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: NS(=O)(=O)c1nc2ccc(O)cc2s1
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)Oc2ccc3nc(S(N)(=O)=O)sc3c2)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a stirred mixture of 6-hydroxy-2-benzothiazolesulfonamide (2.3 g., 0.01 mole) and 4-dimethylaminopyridine (200 mg) in pyridine (25 ml) was added p-toluenesulfonyl chloride (1.9 g, 0.01 mole). The reaction mixture was stirred at 25° C. for 21/2 hours, treated with p-toluenesulfonyl chloride (0.3 g.), stirred 1 hour then poured into ice water plus excess hydrochloric acid. The product was extracted into ether, washed with water, dried over magnesium sulfate, concentrated to dryness and chromatographed on silica (150 g., 70-230 mesh) eluting with ethyl acetate-hexane (1:1) to obtain 1.4 g. of (2-sulfamoyl-6-benzothiazolyl) 4-methylphenyl sulfonate which melts at 142° C. after recrystallization from toluene.
Reaction SMILES: [CH:1]([NH:3][C:4]1[S:5][CH:6]=[C:7]([C:9](=[N:13][O:14][CH2:15][CH2:16][CH2:17][CH3:18])[C:10]([OH:12])=O)[N:8]=1)=[O:2].P(Cl)(Cl)(Cl)=O.Cl.[NH2:25][CH:26]1[C:48](=[O:49])[N:28]2[C:29]([C:35]([O:37][CH2:38][C:39]3[CH:44]=[CH:43][C:42]([N+:45]([O-:47])=[O:46])=[CH:41][CH:40]=3)=[O:36])=[C:30]([O:33][CH3:34])[CH2:31][S:32][C@H:27]12.C[Si](CC(N)=O)(C)C.C[Si](C([Si](C)(C)C)C(N)=O)(C)C>C(OCC)(=O)C.CN(C)C=O>[CH:1]([NH:3][C:4]1[S:5][CH:6]=[C:7]([C:9](=[N:13][O:14][CH2:15][CH2:16][CH2:17][CH3:18])[C:10]([NH:25][CH:26]2[C:48](=[O:49])[N:28]3[C:29]([C:35]([O:37][CH2:38][C:39]4[CH:40]=[CH:41][C:42]([N+:45]([O-:47])=[O:46])=[CH:43][CH:44]=4)=[O:36])=[C:30]([O:33][CH3:34])[CH2:31][S:32][C@H:27]23)=[O:12])[N:8]=1)=[O:2]
Reactant: COC1=C(C(=O)OCc2ccc([N+](=O)[O-])cc2)N2C(=O)C(N)[C@H]2SC1
Reactant: CCCCON=C(C(=O)O)c1csc(NC=O)n1
Agent: C[Si](C)(C)C(C(N)=O)[Si](C)(C)C
Agent: C[Si](C)(C)CC(N)=O
Agent: Cl
Solvent: CN(C)C=O
Solvent: O=P(Cl)(Cl)Cl
Solvent: CCOC(C)=O
Product: CCCCON=C(C(=O)NC1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(OC)CS[C@H]12)c1csc(NC=O)n1
Yield: 77.9 %

Procedure:
A solution of 2-(2-formamidothiazol-4-yl)-2-butoxyiminoacetic acid (syn isomer, 1.09 g.), N,N-dimethylformamide (322 mg.) and phosphoryl chloride (675 mg.) in ethyl acetate (9.2 ml.) and a solution of 4-nitrobenzyl 7-amino-3-methoxy-3-cephem-4-carboxylate hydrochloride (1.5 g.), trimethylsilylacetamide (5 g.) and bis(trimethylsilyl)acetamide (2 ml.) in ethyl acetate (30 ml.) were treated in a similar manner to that of Example 3-(1) to give 4-nitrobenzyl 7-[2-(2-formamidothiazol-4-yl)-2-butoxyiminoacetamido]-3-methoxy-3-cephem-4-carboxylate (syn isomer, 1.8 g.).
Reaction SMILES: [Br:1][C:2]1[NH:3][C:4]([Br:7])=[CH:5][N:6]=1.[H-].[Na+].[CH3:10][Si:11]([CH2:14][CH2:15][O:16][CH2:17]Cl)(C)[CH3:12]>CN(C=O)C>[Br:1][C:2]1[N:3]([CH2:17][O:16][CH2:15][CH2:14][SiH:11]([CH3:12])[CH3:10])[C:4]([Br:7])=[CH:5][N:6]=1
Reactant: Brc1cnc(Br)[nH]1
Reactant: C[Si](C)(C)CCOCCl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C[SiH](C)CCOCn1c(Br)cnc1Br
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a stirred solution of 2,5-dibromo-1H-imidazole (1 eq.) in DMF at 0° C. under Ar was added NaH (1.2 eq.) and the mixture stirred for 30 min at 0° C. Then SEM-Cl (1.1 eq.) was added dropwise, and the mixture stirred 16 h warming to RT. The reaction was quenched by slow addition of H2O and the desired product was extracted with EtOAc. The organic layer was washed with brine, dried (Na2SO4) and concentrated under reduced pressure. The crude was purified by column chromatography eluting with 10% EtOAc/Petroleum ether to afford the desired product. 1H NMR (300 MHz, CD3CN) δ: 7.10 (1H, s), 5.21 (2H, s), 3.53 (2H, t, J=7.3 Hz), 0.90 (2H, t, J=7.3 Hz), 0.10 (9H, s). MS (ES) C9H16Br2N2OSi requires: 354:356:358 [1:2:1], found: 355:357:359 [1:2:1] (M+H)+.
Reaction SMILES: [I-].[CH3:2][S+](C)(C)=O.[H-].[Na+].[CH3:9][S:10]([N:13]1[CH2:17][CH2:16][CH2:15][CH:14]1[CH:18]=[O:19])(=[O:12])=[O:11].[Cl-].[Na+]>O1CCCC1.CS(C)=O>[CH3:9][S:10]([N:13]1[CH2:17][CH2:16][CH2:15][CH:14]1[CH:18]1[CH2:2][O:19]1)(=[O:12])=[O:11]
Reactant: CS(=O)(=O)N1CCCC1C=O
Reactant: C[S+](C)(C)=O
Agent: [Cl-]
Agent: [H-]
Agent: [I-]
Solvent: C1CCOC1
Solvent: CS(C)=O
Product: CS(=O)(=O)N1CCCC1C1CO1
Reaction time: 1 h

Procedure:
Anhydrous dimethylsulfoxide (0.750 mL) was added to trimethylsulfoxonium iodide (0.187 g, 0.85 mmol) and sodium hydride (60% mineral oil dispersion, 0.034 g, 0.85 mmol), and the resulting suspension was stirred for 1 hour. To the stirring solution was added 1-(methylsulfonyl)pyrrolidine-2-carbaldehyde (0.100 g, 0.56 mmol) in anhydrous tetrahydrofuran (1 mL) and the mixture was stirred for 2 hours at room temperature. Saturated aqueous sodium chloride (3 mL) was added, and the mixture was extracted with ethyl acetate (3×30 mL). The combined organics were dried (anhydrous sodium sulfate), filtered, and concentrated under reduced pressure to give a dimethylsulfoxide solution (0.473 g) containing crude product, which was used directly in the next step.
Reaction SMILES: [C:1]([OH:20])(=O)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]/[CH:9]=[CH:10]\[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].C(=O)(O)O.[NH2:25][NH:26][C:27]([NH2:29])=[NH:28].C1(C)C=CC=CC=1.C(=O)=O>[Ag].O>[C:1]([NH2:25])(=[O:20])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]/[CH:9]=[CH:10]\[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].[NH2:25][NH:26][C:27]([NH2:29])=[NH:28]
Reactant: CCCCCCCC/C=C\CCCCCCCC(=O)O
Agent: [Ag]
Agent: N=C(N)NN
Agent: O=C(O)O
Solvent: Cc1ccccc1
Solvent: O
Product: CCCCCCCC/C=C\CCCCCCCC(N)=O
Temperature: 138 °C

Procedure:
The reaction product of oleic acid and aminoguanidine bicarbonate useful as a silver protective agent in the lubricating composition of the present invention is prepared as follows: to a 5-liter, 3-neck flask was added oleic acid (847.5 g, 3 mols), aminoguanidine bicarbonate (408.33 g, 3 mols), 300 ml of toluene, and 15 drops of a silicon anti-foamant. The reaction mixture was heated to reflux under a nitrogen blanket. Vigorous foaming was noted as carbon dioxide gas evolved. When the foaming subsided, water evolution began. A total 57 ml of water was collected from the reaction by means of a Dean-Stark trap. The temperature of the reaction mixture was then raised to approximately 138° C. to facilitate the removal of toluene. To 1,040 g of the product, believed primarily to be oleyl amide of aminoguanidine, was added 1,040 g of process oil. The yellow oil solution was then filtered. Upon standing in air, this solution became red in color and had the following analysis: 3.83% nitrogen; activity, 50%; and Infra-red absorption (cm-1) as follows: 3380-3040 (broad peak); 2920; 2850; 1665; 1530; 1465; and 1400.
Reaction SMILES: Br[C:2]1[N:3]=[C:4]([S:14][CH3:15])[C:5](=[O:13])[N:6]([CH:8]([CH2:11][CH3:12])[CH2:9][CH3:10])[CH:7]=1.[CH3:16][Al](C)C>C1COCC1.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH2:9]([CH:8]([N:6]1[CH:7]=[C:2]([CH3:16])[N:3]=[C:4]([S:14][CH3:15])[C:5]1=[O:13])[CH2:11][CH3:12])[CH3:10]
Reactant: C[Al](C)C
Reactant: CCC(CC)n1cc(Br)nc(SC)c1=O
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: C1CCOC1
Product: CCC(CC)n1cc(C)nc(SC)c1=O
Temperature: 0 °C
Yield: 73 %

Procedure:
A solution of XXXI (2.0 g, 6.9 mmol) and dichlorobis(triphenylphosphine)palladium(II) (484 mg, 0.7 mmol) in THF (40 mL) was treated with trimethylaluminum (6.2 mL, 12.4 mmol, 2M/toluene) dropwise at 0° C. The reaction was refluxed for 4 h, cooled to 0° C. quenched with water (50 mL) and extracted with ethyl acetate (100 mL). The organic phase was dried (MgSO4), filtered, and concentrated in vacuo to give crude residue. Purification by flash column chromatography (silica, ethyl acetate:hexane 1:1) gave the product XXXII (1.14 g, 73%) as a pale yellow solid.
Reaction SMILES: Br[C:2]1[C:3]([N:22]2[CH2:25][CH:24]([C:26]([OH:29])([CH3:28])[CH3:27])[CH2:23]2)=[N:4][CH:5]=[C:6]([CH:21]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=1)=[O:8].[N:30]1[CH:35]=[CH:34][CH:33]=[C:32](B(O)O)[CH:31]=1>>[OH:29][C:26]([CH:24]1[CH2:25][N:22]([C:3]2[C:2]([C:32]3[CH:31]=[N:30][CH:35]=[CH:34][CH:33]=3)=[CH:21][C:6]([C:7]([NH:9][C:10]3[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=3)=[O:8])=[CH:5][N:4]=2)[CH2:23]1)([CH3:28])[CH3:27]
Reactant: OB(O)c1cccnc1
Reactant: CC(C)(O)C1CN(c2ncc(C(=O)Nc3ccc(OC(F)(F)F)cc3)cc2Br)C1
Product: CC(C)(O)C1CN(c2ncc(C(=O)Nc3ccc(OC(F)(F)F)cc3)cc2-c2cccnc2)C1

Procedure:
The title compound was prepared in an analogous fashion to that described in Example 128 using 5-bromo-6-(3-(2-hydroxypropan-2-yl)azetidin-1-yl)-N-(4-(trifluoromethoxy)phenyl)nicotinamide (Stage 142.1) and pyridin-3-ylboronic acid to afford an off-white powder. HPLC (Condition 4) tR=4.61 min, UPLC-MS (Condition 7) m/z=473.1 [M+H]+; 1H-NMR (400 MHz, DMSO-d6) δ ppm 0.93 (s, 6H) 3.24-3.34 (m, 1H) 3.59 (m, J=8.60 Hz, 4H) 4.36 (s, 1H) 7.33 (d, J=8.60 Hz, 2H) 7.49 (dd, J=7.82, 4.69 Hz, 1H) 7.84 (d, J=8.99 Hz, 3H) 8.00 (d, J=1.95 Hz, 1H) 8.53-8.62 (m, 1H) 8.65 (d, J=1.95 Hz, 1H) 8.74 (d, J=1.96 Hz, 1H) 10.18 (s, 1H).
Reaction SMILES: [Br:1][C:2]1[C:10]2[S:9][C:8](Cl)=[N:7][C:6]=2[CH:5]=[CH:4][CH:3]=1.[CH3:12][NH:13][CH3:14]>>[Br:1][C:2]1[C:10]2[S:9][C:8]([N:13]([CH3:14])[CH3:12])=[N:7][C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: CNC
Reactant: Clc1nc2cccc(Br)c2s1
Product: CN(C)c1nc2cccc(Br)c2s1
Temperature: 70 °C
Yield: 98.2 %

Procedure:
7-Bromo-2-chlorobenzothiazole (100 mg, 0.40 mmol) was added to dimethylamine (2.0 M in MeOH, 1 mL, 2 mmol) and the solution was heated at 70° C. for 1 h. The crude mixture was purified by ISCO chromatography (100% DCM) to afford 101 mg (98%) of the title compound as white solid. MS (ESI): 257.33, 259.36 [M+H]+; HPLC tR=1.40 min (HPLC: Anayltical—2 min).
Reaction SMILES: [CH3:1][N:2]1[CH2:7]N(C)CN(C)C1.[ClH:10].[C:11]([SH:15])([CH3:14])([CH3:13])[CH3:12]>C(#N)C>[ClH:10].[C:11]([S:15][CH2:7][NH:2][CH3:1])([CH3:14])([CH3:13])[CH3:12]
Reactant: CC(C)(C)S
Reactant: CN1CN(C)CN(C)C1
Agent: Cl
Solvent: CC#N
Product: CNCSC(C)(C)C
Temperature: -30 °C
Reaction time: 8 h

Procedure:
Two hundred ml. of acetonitrile and 6.45 g. (0.05 mole) of 1,3,5-trimethylhexahydro-s-triazine are charged to a 500 ml. 3-neck round bottom flask equipped with a stirrer, thermometer and dropping funnel. The mixture is stirred and cooled to -30° C. with a dry ice/acetone bath. Six grams of hydrogen chloride gas are added, followed by slow addition of 13.5 g. (0.15 mole) of tert.-butyl mercaptan dissolved in 50 ml. of acetonitrile. The mixture is then allowed to warm to room temperature and stand overnight.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([Cl:10])[C:3]=1[CH:4]=O.[S:11]1[CH2:17][C:15](=[O:16])[NH:14][C:12]1=[S:13].C([O-])(=O)C.[Na+]>C(O)(=O)C>[Cl:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([Cl:10])[C:3]=1[CH:4]=[C:17]1[S:11][C:12](=[S:13])[NH:14][C:15]1=[O:16]
Reactant: O=Cc1c(Cl)cccc1Cl
Reactant: O=C1CSC(=S)N1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: O=C1NC(=S)SC1=Cc1c(Cl)cccc1Cl
Temperature: 25 °C

Procedure:
2,6-Dichlorobenzaldehyde (77.0 g), rhodanine (58.6 g), and acetic acid (539 ml) were suspended with stirring at room temperature. Anhydrous sodium acetate (116 g) was added to the suspension, and the resulting mixture was heated under reflux for 3 hours. The reaction mixture was cooled to 45° C., and ice water (700 ml) was added. After the mixture was stirred for 0.2 hours, the precipitated crystals were collected by filtration, washed with water, and then dried to obtain 2,6-dichlorobenzylidenerhodanine. Even in non-dried form, this product could be subjected to the subsequent step.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([N:9]2[C@@H:14]([CH3:15])[CH2:13][N:12](C(OC(C)(C)C)=O)[C@H:11]([CH3:23])[CH2:10]2)=[CH:5][C:4]=1[F:24])#[N:2].FC(F)(F)C(O)=O>ClCCl>[CH3:15][C@H:14]1[CH2:13][NH:12][C@H:11]([CH3:23])[CH2:10][N:9]1[C:6]1[CH:7]=[CH:8][C:3]([C:1]#[N:2])=[C:4]([F:24])[CH:5]=1
Reactant: C[C@@H]1CN(c2ccc(C#N)c(F)c2)[C@@H](C)CN1C(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: C[C@@H]1CN(c2ccc(C#N)c(F)c2)[C@@H](C)CN1
Temperature: 25 °C
Reaction time: 8 h
Yield: 114.3 %

Procedure:
Into 150 ml of dichloromethane was dissolved 15.0 g of tert-butyl (2R,5S)-4-(4-cyano-3-fluorophenyl)-2,5-dimethylpiperazine-1-carboxylate, and then 30 ml of trifluoroacetic acid was added thereto, followed by stirring at room temperature overnight. After the reaction solution was removed by evaporation, 1M hydrochloric acid was added thereto, followed by washing with chloroform. The aqueous phase was made basic with a 5M sodium hydroxide aqueous solution, followed by extraction with chloroform. After the organic layer was dried over anhydrous magnesium sulfate, the solvent was removed by evaporation to obtain 12.0 g of the title compound.
Reaction SMILES: [N:1]1([CH2:7][CH2:8][NH2:9])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[CH3:10][O:11][C:12]([C:14]1[CH:15]=[C:16]([CH3:36])[C:17]2[O:23][C:22]3[C:24]([Cl:32])=[CH:25][C:26]([NH:28][CH2:29][CH2:30]Cl)=[CH:27][C:21]=3[CH2:20][S:19](=[O:34])(=[O:33])[C:18]=2[CH:35]=1)=[O:13].O>[I-].C([N+](CCCC)(CCCC)CCCC)CCC.CN(C=O)C>[CH3:10][O:11][C:12]([C:14]1[CH:15]=[C:16]([CH3:36])[C:17]2[O:23][C:22]3[C:24]([Cl:32])=[CH:25][C:26]([NH:28][CH2:29][CH2:30][NH:9][CH2:8][CH2:7][N:1]4[CH2:6][CH2:5][O:4][CH2:3][CH2:2]4)=[CH:27][C:21]=3[CH2:20][S:19](=[O:33])(=[O:34])[C:18]=2[CH:35]=1)=[O:13]
Reactant: NCCN1CCOCC1
Reactant: COC(=O)c1cc(C)c2c(c1)S(=O)(=O)Cc1cc(NCCCl)cc(Cl)c1O2
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [I-]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1cc(C)c2c(c1)S(=O)(=O)Cc1cc(NCCNCCN3CCOCC3)cc(Cl)c1O2
Temperature: 120 °C
Reaction time: 3 h

Procedure:
2-Morpholin-4-yl-ethylamine (0.18 mL, 1.44 mmol) and tetrabutylammonium iodide (0.075 g, 0.2 mmol) were sequentially added with stirring to a solution of the carboxylic acid of Example 56k (0.5 g, 1.2 mmol) in dry DMF (1 mL). The reaction mixture was then stirred at 120° C. for 3 h in an atmosphere of nitrogen. It was treated with cold water and the solid that precipitated was filtered, washed with water, and dried. The solid was treated with a methanolic HCl solution (10 mL), and refluxed at 70° C. for 3 h. The reaction mixture was concentrated and treated with an aqueous sodium bicarbonate solution. The solid that precipitated was filtered, washed with water, dried and purified using flash chromatography (silica gel, 2% methanol/chloroform) to obtain the title compound. Yield: 0.150 g, (24.19%); 1H NMR (DMSO-d6): δ 2.40 (t, 4H, 2CH2), 2.50-2.60 (m, 4H, 2CH2), 3.10 (m, 4H, 2CH2), 3.15-3.20 (m, 4H, 2CH2), 3.90 (s, 3H, OCH3), 4.50 (t, 1H, NH), 5.15 (s, 2H, CH2), 6.10 (t, 1H, NH), 6.7 (s, 2H, 2Ar), 8.10 (s, 1H, Ar), 8.25 (s, 1H, Ar); MS : m/e (EI+) 524 (M+).
Reaction SMILES: [P:1]([O:8]CC)([O:5][CH2:6][CH3:7])[O:2][CH2:3][CH3:4].[CH:11]1[CH:16]=[C:15]2[C:17](Br)=[C:18](Br)[S:19][C:14]2=[CH:13][CH:12]=1>C(Cl)Cl.Cl[Pd]Cl>[CH2:3]([O:2][P:1]([C:18]1[S:19][C:14]2[CH:13]=[CH:12][CH:11]=[CH:16][C:15]=2[C:17]=1[P:1]([O:2][CH2:3][CH3:4])([O:5][CH2:6][CH3:7])=[O:8])([O:5][CH2:6][CH3:7])=[O:8])[CH3:4]
Reactant: Brc1sc2ccccc2c1Br
Reactant: CCOP(OCC)OCC
Agent: Cl[Pd]Cl
Solvent: ClCCl
Product: CCOP(=O)(OCC)c1sc2ccccc2c1P(=O)(OCC)OCC
Reaction time: 0.5 h
Yield: 47.9 %

Procedure:
A suspension of PdCl2 (0.15 g) in 2,3-dibromothianaphthene (2.4 g) was brought to the temperature of 115° C., and P(OEt)3 (3.3 g) was then dropped under stirring and in an inert atmosphere. Once dropping was completed, the red solution was brought to 160° C. After 1 h 30 min, the mixture was diluted with CH2Cl2, washed twice with water and dehydrated. The solvent was evaporated at reduced pressure to yield a residue that underwent chromatography on silica gel by flash chromatography (AcOEt), to yield 2,3-bis(diethoxyphosphoryl)-benzo[b]thiophene (1.6 g) (yield 60%).
Reaction SMILES: C[O:2][C:3]1[CH:8]=[C:7]([CH2:9][NH:10][C:11]([C:13]2[NH:14][C:15]3[C:20]([C:21]=2[S:22]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)(=[O:24])=[O:23])=[CH:19][C:18]([Cl:31])=[CH:17][CH:16]=3)=[O:12])[CH:6]=[CH:5][N:4]=1.B(Br)(Br)Br>C(Cl)Cl>[Cl:31][C:18]1[CH:19]=[C:20]2[C:15](=[CH:16][CH:17]=1)[NH:14][C:13]([C:11]([NH:10][CH2:9][C:7]1[CH:6]=[CH:5][NH:4][C:3](=[O:2])[CH:8]=1)=[O:12])=[C:21]2[S:22]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)(=[O:24])=[O:23]
Reactant: COc1cc(CNC(=O)c2[nH]c3ccc(Cl)cc3c2S(=O)(=O)c2ccccc2)ccn1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: O=C(NCc1cc[nH]c(=O)c1)c1[nH]c2ccc(Cl)cc2c1S(=O)(=O)c1ccccc1

Procedure:
Reaction of N-(2-methoxy-4-pyridylmethyl)-5-chloro-3-phenylsulfonylindole-2-carboxamide with boron tribromide in methylene chloride at 0° C. to room temperature, according to the procedure described in Example 39, provides the title compound.