Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([S:7](Cl)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[F:11][C:12]([F:21])([F:20])[C:13]1[CH:19]=[CH:18][CH:17]=[CH:16][C:14]=1[NH2:15].N1C=CC=CC=1>ClCCl.CN(C1C=CN=CC=1)C>[F:11][C:12]([F:20])([F:21])[C:13]1[CH:19]=[CH:18][CH:17]=[CH:16][C:14]=1[NH:15][S:7]([C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)(=[O:9])=[O:8]
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: Nc1ccccc1C(F)(F)F
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: O=S(=O)(Nc1ccccc1C(F)(F)F)c1ccccc1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
Benzenesulfonyl chloride (400 g, 2.26 moles) was dissolved in dichloromethane (2 L). To this was added o-trifluoromethylaniline (250 mL, 320 g, 1.99 mol), pyridine (222 mL), and DMAP (7.5 g). The resulting solution was stirred at room temperature for 3 days (72 h), then heated to reflux for 1 hour. The cooled solution was then concentrated on the rotary evaporator, with the bath temperature gradually raised to 70° C. The residue was taken up in ether (3 L) and 1N HCl (1.5 L). The ether layer was separated, washed 2×500 mL with 1N HCl, 1×1 L with brine, 1×1 L with saturated sodium bicarbonate, and once more with 1 L of brine. It was then dried over magnesium sulfate, filtered with suction, and concentrated on the rotary evaporator without heat. The product formed fine crystals as the ether evaporated, and when most of the ether was gone, the crystals were slurried with hexane (2 L), collected with suction and dried. Yield 571 g, 84%.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][O:5][C:6]1[C:7]([O:17][CH2:18][CH3:19])=[CH:8][C:9]2[O:14][C:13](=[O:15])[CH:12]=[CH:11][C:10]=2[CH:16]=1.Cl.[CH3:21][O:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[N:29]1[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]1.C(O)(C)C.C([O-])(=O)/C=C/C([O-])=O>C(O)C>[CH2:18]([O:17][C:7]1[C:6]([O:5][CH2:4][CH2:3][CH2:2][N:32]2[CH2:31][CH2:30][N:29]([C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=3[O:22][CH3:21])[CH2:34][CH2:33]2)=[CH:16][C:10]2[CH:11]=[CH:12][C:13](=[O:15])[O:14][C:9]=2[CH:8]=1)[CH3:19]
Reactant: CCOc1cc2oc(=O)ccc2cc1OCCCCl
Reactant: COc1ccccc1N1CCNCC1
Agent: Cl
Agent: O=C([O-])/C=C/C(=O)[O-]
Solvent: CCO
Solvent: CC(C)O
Product: CCOc1cc2oc(=O)ccc2cc1OCCCN1CCN(c2ccccc2OC)CC1
Yield: 49 %

Procedure:
Method A (48 h at 60° C.); starting materials: 6-(3-chloropropoxy)-7-ethoxy-2H-1-benzopyran-2-one (example 70) and 1(2-methoxyphenyl)piperazine hydrochloride; yield 49%; fusion point 78°-80° C. (from isopropanol). Fumarate: method E; yield 82%; fusion point 149°-150° C. (from ethanol).
Reaction SMILES: [CH2:1]([C@H:8]1[CH2:13][N:12]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[C:16]([O:22][CH:23]3[CH2:27][CH2:26][CH2:25][CH2:24]3)[CH:15]=2)[CH2:11][CH2:10][N:9]1[CH2:28][C:29]([NH:31][O:32]CC1C=CC=CC=1)=[O:30])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>CO>[CH2:1]([C@H:8]1[CH2:13][N:12]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[C:16]([O:22][CH:23]3[CH2:27][CH2:26][CH2:25][CH2:24]3)[CH:15]=2)[CH2:11][CH2:10][N:9]1[CH2:28][C:29]([NH:31][OH:32])=[O:30])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1ccc(N2CCN(CC(=O)NOCc3ccccc3)[C@@H](Cc3ccccc3)C2)cc1OC1CCCC1
Solvent: CO
Product: COc1ccc(N2CCN(CC(=O)NO)[C@@H](Cc3ccccc3)C2)cc1OC1CCCC1
Reaction time: 4 h
Yield: 55.9 %

Procedure:
A solution of 2-[(S)-2-Benzyl-4-(3-cyclopentyloxy-4-methoxy-phenyl)-piperazin-1-yl]-N-benzyloxy-acetamide (30 mg, 0.057 mmol) was dissolved in MeOH (10 mL), purged with a stream of nitrogen, treated with 20% Pd/C (100 mg, 50% water content), and hydrogenated under 40 psi pressure of hydrogen for 4 h. The crude reaction mixture was then purged with nitrogen, filtered, and evaporated. The crude product was then dissolved in chloroform (5 mL) and filtered through a nylon syringe filter to remove residual Pd/C. The organic solution was evaporated to afford the title compound as a colorless foam (14 mg, 56%). LC/MS (Method A) 5.03 min, [M+1]+ 440.
Reaction SMILES: [C:1]([O:4][C@H:5]([C@H:8]([C@@H:13]([C@@H:18]([CH2:23][O:24][C:25](=[O:27])[CH3:26])[O:19][C:20](=O)C)[O:14][C:15](=[O:17])[CH3:16])[O:9][C:10](=[O:12])[CH3:11])C=O)(=[O:3])[CH3:2].[BrH:28]>C(O)(=O)C>[CH3:26][C:25]([O:24][CH2:23][C@H:18]1[O:19][C@H:20]([Br:28])[C@H:5]([O:4][C:1]([CH3:2])=[O:3])[C@@H:8]([O:9][C:10]([CH3:11])=[O:12])[C@@H:13]1[O:14][C:15]([CH3:16])=[O:17])=[O:27]
Reactant: CC(=O)OC[C@@H](OC(C)=O)[C@@H](OC(C)=O)[C@H](OC(C)=O)[C@H](C=O)OC(C)=O
Reactant: Br
Solvent: CC(=O)O
Product: CC(=O)OC[C@H]1O[C@H](Br)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Reaction time: 69 h
Yield: 74 %

Procedure:
First, 14 g of glucose pentaacetate, from Sigma Chemical Company, was dissolved in 60 ml of 30% HBr in acetic acid and allowed to stand a 4° C. for 69 hours. The acetic acid was removed. The residue was dissolved in 100 ml of chloroform, washed twice with 100 ml of saturated NaHCO3, dried over MgSO4, concentrated, and crystallized from 95% ethanol to give 10.88 g (74%) of acetobromoglucose.
Reaction SMILES: [CH2:1]([Li])CCC.[CH:6]([C:8]1[N:9]=[C:10](/[CH:13]=[CH:14]/[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[O:11][CH:12]=1)=O.O.C(OCC)(=O)C>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O1CCCC1>[CH:13](/[C:10]1[O:11][CH:12]=[C:8]([CH:6]=[CH2:1])[N:9]=1)=[CH:14]\[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: [Li]CCCC
Reactant: O=Cc1coc(/C=C/c2ccccc2)n1
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: O
Product: C=Cc1coc(/C=C/c2ccccc2)n1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
n-Butyllithium (1.54N hexane solution, 14.2 ml) was added dropwise to a solution of methyl-triphenylphosphonium bromide (8.16 g) in tetrahydrofuran (80 ml) at 0° C., and the mixture was stirred at room temperature for 30 minutes. The reaction mixture was cooled again to 0° C., a solution of 4-formyl-2-(trans-styryl)oxazole (3.64 g) in tetrahydrofuran (20 ml) was added, and the mixture was warmed to room temperature. After stirring for 2 hours, water (200 ml) and ethyl acetate (100 ml) were added and an organic layer was separated. The water layer was extracted with ethyl acetate (50 ml). After the organic layers were combined, washed with saturated saline (100 ml) and dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure. The residue was purified by column chromatography on silica gel (hexane:ethyl acetate=4:1→3:1) to obtain the title compound (2.84 g) as a pale yellow oil.
Reaction SMILES: C(N(C(C)C)CC)(C)C.Br[CH2:11][C:12]([C:14]1[C:15]([CH3:23])=[C:16]([C:19]([F:22])=[CH:20][CH:21]=1)[C:17]#[N:18])=[O:13].[C:24]([N:31]1[CH2:36][CH2:35][NH:34][C@@H:33]([CH2:37][OH:38])[CH2:32]1)([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25]>C1COCC1.CCOC(C)=O>[C:27]([O:26][C:24]([N:31]1[CH2:36][CH2:35][N:34]2[C@@H:33]([CH2:37][O:38][C@:12]([C:14]3[CH:21]=[CH:20][C:19]([F:22])=[C:16]([C:17]#[N:18])[C:15]=3[CH3:23])([OH:13])[CH2:11]2)[CH2:32]1)=[O:25])([CH3:30])([CH3:29])[CH3:28]
Reactant: CC(C)(C)OC(=O)N1CCN[C@@H](CO)C1
Reactant: Cc1c(C(=O)CBr)ccc(F)c1C#N
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: Cc1c([C@@]2(O)CN3CCN(C(=O)OC(C)(C)C)C[C@@H]3CO2)ccc(F)c1C#N
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Diisopropylethylamine (156 mL, 894 mmol) was added to a stirred, room temperature mixture of 3-(2-Bromo-acetyl)-6-fluoro-2-methyl-benzonitrile (176 g, 688 mmol) and (R)-4-N-Boc-2-hydroxymethyl-piperazine (149 g, 688 mmol) in THF (3500 mL) and the mixture was stirred at room temperature for 18 h. The reaction was diluted with 3 L EtOAc, washed 2× with 1500 mL 10% w/w NaHCO3 aqueous solution, dried over MgSO4, filtered and concentrated. The residue was purified by column chromatography on silica gel (40-80% EtOAc/Hexanes, linear gradient), to provide the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][S:9]([CH:12]2[C:17]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:16][CH2:15][CH2:14][CH2:13]2)(=[O:11])=[O:10])=[C:4]([F:23])[CH:3]=1.CI.[C:26](=O)([O-])[O-].[K+].[K+]>CN(C)C=O.C(OCC)(=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]([CH3:26])[S:9]([CH:12]2[C:17]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:16][CH2:15][CH2:14][CH2:13]2)(=[O:11])=[O:10])=[C:4]([F:23])[CH:3]=1
Reactant: O=C([O-])[O-]
Reactant: CCOC(=O)C1=CCCCC1S(=O)(=O)Nc1ccc(Cl)cc1F
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CI
Product: CCOC(=O)C1=CCCCC1S(=O)(=O)N(C)c1ccc(Cl)cc1F
Temperature: 25 °C
Reaction time: 1 h
Yield: 96.3 %

Procedure:
To a solution of ethyl 6-[N-(4-chloro-2-fluorophenyl)sulfamoyl]-1-cyclohexene-1-carboxylate (Compound 1; 250 mg) obtained in Example 1 was 1.60 g) in N,N-dimethylformamide (2.5 ml), methyl iodide (118 mg), potassium carbonate (191 mg) were added and the mixture was stirred at room temperature for 1 hour. The reaction mixture was diluted with ethyl acetate (30 ml), washed with water (30 ml×2) and dried over anhydrous magnesium sulfate, and then the solvent was distilled off. The residue was purified by silica gel chromatography (eluent: ethyl acetate/hexane=1/4) to yield ethyl 6-[N-(4-chloro-2-fluorophenyl)-N-methylsulfamoyl]-1-cyclohexene-1-carboxylate (Compound 2; 250 mg) as a colorless oil.
Reaction SMILES: C([BH3-])#N.[Na+].[C:5](#N)[CH3:6].[CH3:8][N:9]([CH3:12])[CH:10]=O.C=O.O1C[CH2:18][CH2:17][CH2:16]1>>[CH3:8][N:9]([CH3:12])[C:10]1[CH:6]=[CH:5][CH:18]=[CH:17][CH:16]=1
Reactant: CC#N
Reactant: C1CCOC1
Reactant: CN(C)C=O
Agent: C=O
Agent: [BH3-]C#N
Agent: [Na+]
Product: CN(C)c1ccccc1

Procedure:
Alternatively the reduction can be accomplished with sodium cyanoborohydride in an inert solvent such as acetonitrile, dimethylformamide, or tetrahydrofuran. An alkyl aldehyde such as formaldehyde can be used in excess to obtain a dimethyl aniline of formula (24) (R5 and R6 each represent methyl). The reaction is accomplished at room temperture to the reflux temperature of the solvent for about 4 to 48 hours. The product can be isolated by common extractive techniques and purified by silica gel chromatography.
Reaction SMILES: [Cl:1][C:2]1[CH:19]=[CH:18][C:5]2[O:6][C:7]3[CH:17]=[CH:16][CH:15]=[CH:14][C:8]=3[CH2:9][N:10]([C:11](Cl)=[O:12])[C:4]=2[CH:3]=1.[NH2:20][C:21]([CH3:35])([CH3:34])[CH2:22][NH:23][C:24](=[O:33])[O:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.C(N(CC)CC)C>C(Cl)Cl>[Cl:1][C:2]1[CH:19]=[CH:18][C:5]2[O:6][C:7]3[CH:17]=[CH:16][CH:15]=[CH:14][C:8]=3[CH2:9][N:10]([C:11]([NH:20][C:21]([CH3:35])([CH3:34])[CH2:22][NH:23][C:24](=[O:33])[O:25][CH2:26][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)=[O:12])[C:4]=2[CH:3]=1
Reactant: CC(C)(N)CNC(=O)OCc1ccccc1
Reactant: O=C(Cl)N1Cc2ccccc2Oc2ccc(Cl)cc21
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(CNC(=O)OCc1ccccc1)NC(=O)N1Cc2ccccc2Oc2ccc(Cl)cc21
Reaction time: 17 h
Yield: 90.7 %

Procedure:
The title compound of Example 2 (5.0 g, 17.0 mmol) in 100 mL of CH2Cl2 was combined with molecular sieves #5A (5 g), the product of Example 17 (3.8 g, 17.0 mmol), and triethylamine (Et3N, 2.4 mL, 17.2 mmol). After stirring the reaction at room temperature for 17 hours, another 3.1 g of the product of Example 17 was added and stirring was continued for another 17 hours. The reaction was filtered and the filtrate was stripped of all solvent under reduced pressure to yield a white foam solid that was purified by HPLC on silica gel to give 7.4 g of the title material as a white solid.
Reaction SMILES: [F:1][C:2]([F:10])([F:9])[C:3]([OH:8])([CH3:7])[C:4](O)=[O:5].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[NH2:44][C:45]1[C:46]([C:55]([NH:57][NH2:58])=[O:56])=[N:47][CH:48]=[C:49]([C:51]([F:54])([F:53])[F:52])[CH:50]=1>CN1C(=O)CCC1.O>[NH2:44][C:45]1[C:46]([C:55]([NH:57][NH:58][C:4](=[O:5])[C:3]([OH:8])([CH3:7])[C:2]([F:10])([F:9])[F:1])=[O:56])=[N:47][CH:48]=[C:49]([C:51]([F:53])([F:52])[F:54])[CH:50]=1
Reactant: CC(O)(C(=O)O)C(F)(F)F
Reactant: NNC(=O)c1ncc(C(F)(F)F)cc1N
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN1CCCC1=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: CC(O)(C(=O)NNC(=O)c1ncc(C(F)(F)F)cc1N)C(F)(F)F
Reaction time: 1 h

Procedure:
To 3,3,3-trifluoro-2-hydroxy-2-methylpropanoic acid (324 mg, 2.049 mmol) in NMP (5 ml) was added HATU (935 mg, 2.458 mmol) and DIPEA (1.073 ml, 6.15 mmol). After stirring for 5 minutes 3-amino-5-(trifluoromethyl)picolinohydrazide (Intermediate I) (451 mg, 2.049 mmol) was added and stirring continued at RT for 1 h. The reaction mixture was diluted with water and extracted with EtOAc. The combined organic extracts were washed with 1M HCl (100 ml), water (2×100 ml), brine and dried (phase separator) and concentrated in vacuo. Purification by chromatography on silica eluting with 0-30% EtOAc in iso-hexane afforded the title compound; 1H NMR 400 MHz, DMSO-d6: δ 10.3 (1H, s), 10.0 (1H, s), 8.0 (1H, s), 7.5 (1H, s), 7.1 (3H, s, overlap), 1.5 (3H, s). LC-MS Rt=0.98 min [M+H]+ 361.2 Method 2minLC_v003.
Reaction SMILES: [CH:1]1[CH:2]=C[C:4]2[N:9](O)N=[N:7][C:5]=2[CH:6]=1.[N:11]1([C:17]([C:19]2[CH:20]=[CH:21][C:22]([O:28][CH2:29][C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)=[C:23]([CH:27]=2)[C:24]([OH:26])=O)=[O:18])[CH2:16][CH2:15][O:14][CH2:13][CH2:12]1.N1C=CC=C(N)C=1.C(Cl)CCl>CN(C)C=O.O>[N:11]1([C:17]([C:19]2[CH:20]=[CH:21][C:22]([O:28][CH2:29][C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)=[C:23]([CH:27]=2)[C:24]([NH:7][C:5]2[CH:4]=[N:9][CH:2]=[CH:1][CH:6]=2)=[O:26])=[O:18])[CH2:16][CH2:15][O:14][CH2:13][CH2:12]1
Reactant: On1nnc2ccccc21
Reactant: O=C(O)c1cc(C(=O)N2CCOCC2)ccc1OCc1ccccc1
Agent: Nc1cccnc1
Solvent: O
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: O=C(Nc1cccnc1)c1cc(C(=O)N2CCOCC2)ccc1OCc1ccccc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
Neat HOBT (90 mg, 0.59 mmol) was added in one charge to a stirred solution of 5-(4-morpholinylcarbonyl)-2-[(phenylmethyl)oxy]benzoic acid (may be prepared as described in Description 57; 200 mg, 0.59 mmol), 3-pyridinamine (55.1 mg, 0.59 mmol) and EDC (112 mg, 0.59 mmol) in N,N-dimethylformamide (5 ml) under nitrogen at room temperature. The reaction mixture was stirred at room temperature for 4 h. The mixture was diluted with water (50 ml) and extracted with ethyl acetate (3×50 ml). The organic phase was washed with sodium hydroxide solution (1 mol/l, 25 ml), saturated brine (25 ml), dried over sodium sulfate, and evaporated in vacuo to give the crude product. The crude product was washed with ether (5 ml) and dried to yield the title compound as a white solid. 67 mg.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[N:11]3[C:12]([CH2:15]Cl)=[N:13][N:14]=[C:10]3[CH2:9][N:8]=[C:7]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[Cl:23])[C:6]=2[CH:24]=1.[CH2:25](N)[C:26]#[CH:27].[I-].[K+].C[N:32](C)C=O>>[CH2:27]([C:9]1([NH2:32])[N:8]=[C:7]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[Cl:23])[C:6]2[CH:24]=[CH:2][CH:3]=[CH:4][C:5]=2[N:11]2[C:12]([CH3:15])=[N:13][N:14]=[C:10]12)[C:26]#[CH:25]
Reactant: CN(C)C=O
Reactant: C#CCN
Reactant: ClCc1nnc2n1-c1ccc(Cl)cc1C(c1ccccc1Cl)=NC2
Agent: [I-]
Agent: [K+]
Product: C#CCC1(N)N=C(c2ccccc2Cl)c2ccccc2-n2c(C)nnc21

Procedure:
In the manner given in Preparation 19, 8-chloro-1-(chloromethyl)-6-(o-chlorophenyl)-4H-s-triazolo[4,3-a]-[1,4]benzodiazepine in dimethylformamide is reacted at room temperature with propargylamine in the presence of potassium iodide to give 8-chloro-1-[[(2-propynyl)amino[methyl]-6-(o-chlorophenyl)-4H-s-triazolo[4,3-a][1,4]benzodiazepine. Preparation 21 8-Fluoro-1-[[(2-propynyl)amino]methyl]-6-(o-chlorophenyl)-4H-s-triazolo[4,3-a][1,4]benzodiazepine
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][S:5][C:6]1[C:15]2[O:14][C:13]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[C:12]([CH3:22])[C:11](=[O:23])[C:10]=2[CH:9]=[CH:8][CH:7]=1.[CH3:24][O:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[N:32]1[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]1.[I-].[K+].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.O>[CH3:24][O:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[N:32]1[CH2:37][CH2:36][N:35]([CH2:2][CH2:3][CH2:4][S:5][C:6]2[C:15]3[O:14][C:13]([C:16]4[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=4)=[C:12]([CH3:22])[C:11](=[O:23])[C:10]=3[CH:9]=[CH:8][CH:7]=2)[CH2:34][CH2:33]1
Reactant: Cc1c(-c2ccccc2)oc2c(SCCCCl)cccc2c1=O
Reactant: COc1ccccc1N1CCNCC1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccccc1N1CCN(CCCSc2cccc3c(=O)c(C)c(-c4ccccc4)oc23)CC1
Temperature: 100 °C
Reaction time: 3 h
Yield: 61.1 %

Procedure:
A mixture of 4.4 g of Intermediate XXXIV, 2.5 g of 1-(2-methoxyphenyl)-piperazine, 1 g of potassium iodide and 1.8 g of anhydrous potassium carbonate in 40 ml of dimethylformamide was stirred at 100° C. for 3 hours. After cooling to 20°-25° C., the reaction mixture was poured into 350 ml of water and extracted with dichloromethane. The organic extracts were washed with water and dried on anhydrous sodium sulfate, and the solvent was then evaporated off in vacuo. The residue was purified by column chromatography on silica gel, eluting with ethyl acetate:petroleum ether 3:2, and by crystallization from ethanol, yielding 3.9 g of the title compound, m.p. (70) 96°-99° C.
Reaction SMILES: [N:1]([CH2:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[C:17]#[N:18])=[CH:7][CH:6]=1)=[N+]=[N-].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:38](=[S:40])=S.O.[NH2:42][NH2:43]>O>[C:17]([C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=1[C:8]1[CH:7]=[CH:6][C:5]([CH2:4][NH:1][C:38](=[S:40])[NH:42][NH2:43])=[CH:10][CH:9]=1)#[N:18]
Reactant: S=C=S
Reactant: N#Cc1ccccc1-c1ccc(CN=[N+]=[N-])cc1
Reactant: NN
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Product: N#Cc1ccccc1-c1ccc(CNC(=S)NN)cc1
Temperature: 25 °C
Reaction time: 5.5 h

Procedure:
A mixture of 1.12 g (4.8 mmole) of 4-azidomethyl-2'-cyanobiphenyl, 1.57 g (6.0 mole) of triphenylphoshine, and 8 ml of carbon disulfide was stirred at room temperature under nitrogen for 5.5 hours and then was warmed (water bath) and evaporated to dryness first under a stream of nitrogen and then under reduced pressure. This residue (presumably (2'-cyanobiphenyl-4-yl)methyl isothiocyanate) was dissolved in 12 ml of THF and stirred vigorously at room temperature as 0.699 ml (720 mg, 14.4 mmole) of hydrazine hydrate was added in one bolus. The mixture immediately turned opaque and milky but soon clarified with the separation of a small additional liquid phase. After ten minutes the mixture was partitioned between 40 ml of ether, 25 ml of CH2Cl2, and 75 ml of H2O. Some solid formed and this was filtered off (1.04 g after drying over P2O5 in vacuo) and recrystallized from EtOAc to give 661 mg of the title compound as white crystals, mp 163°-163.5°, Additional material was obtained by reworking the mother liquors and the organic layer of the filtrate affording a, total yield (three crops) was 1.01 g (75% from 4-azidomethyl-2'-cyanobiphenyl), satisfactory purity by TLC in 19:1CH2Ci:MeOH; mass spectrum (FAB) m/e 283 (M+1)+.
Reaction SMILES: [CH3:1][C:2](=[CH:6][CH2:7][CH2:8][C:9]([CH3:21])=[CH:10][CH2:11][CH2:12][C:13]([CH3:20])=[CH:14][CH2:15][CH2:16][C:17](=[O:19])[CH3:18])[C:3](O)=O.[CH2:22]([NH2:24])[CH3:23].[C:25](Cl)(=[O:28])[CH2:26][CH3:27]>>[CH2:22]([N:24]([CH2:3][C:2]([CH3:1])=[CH:6][CH2:7][CH2:8][C:9]([CH3:21])=[CH:10][CH2:11][CH2:12][C:13]([CH3:20])=[CH:14][CH2:15][CH2:16][C:17](=[O:19])[CH3:18])[C:25](=[O:28])[CH2:26][CH3:27])[CH3:23]
Reactant: CC(=O)CCC=C(C)CCC=C(C)CCC=C(C)C(=O)O
Reactant: CCN
Reactant: CCC(=O)Cl
Product: CCC(=O)N(CC)CC(C)=CCCC(C)=CCCC(C)=CCCC(C)=O

Procedure:
Starting materials: 2,6,10-trimethyl-14-oxo-2,6,10-pentadecatrienoic acid; ethylamine (70% aqueous ethylamine solution) and propionyl chloride.
Reaction SMILES: [CH3:1][C:2]1([CH3:9])[CH2:6][C:5](=O)[C:4](=O)[CH2:3]1.COP([CH2:16][C:17]([C:19]1[CH:20]=[N:21][N:22]([C:28]([CH3:31])([CH3:30])[CH3:29])[C:23]=1[C:24]([F:27])([F:26])[F:25])=O)(=O)OC.O.[NH2:33][NH2:34]>>[C:28]([N:22]1[C:23]([C:24]([F:27])([F:26])[F:25])=[C:19]([C:17]2[N:34]=[N:33][C:4]3[CH2:3][C:2]([CH3:9])([CH3:1])[CH2:6][C:5]=3[CH:16]=2)[CH:20]=[N:21]1)([CH3:31])([CH3:30])[CH3:29]
Reactant: NN
Reactant: COP(=O)(CC(=O)c1cnn(C(C)(C)C)c1C(F)(F)F)OC
Reactant: CC1(C)CC(=O)C(=O)C1
Solvent: O
Product: CC1(C)Cc2cc(-c3cnn(C(C)(C)C)c3C(F)(F)F)nnc2C1

Procedure:
light yellow crystalline solid. MS (ESI): 339.0 (MH+). Prepared from 4,4-dimethyl-cyclopentane-1,2-dione, [2-(1-tert-Butyl-5-trifluoromethyl-1H-pyrazol-4-yl)-2-oxo-ethyl]-phosphonic acid dimethyl ester, hydrazine monohydrate.
Reaction SMILES: [CH3:1][S:2][CH2:3][C:4](OCC)=[O:5].S(Cl)(Cl)(=O)=O.[NH2:14][C:15]1[CH:24]=[CH:23][C:18]([C:19]([O:21][CH3:22])=[O:20])=[CH:17][CH:16]=1.CN(C1C2C(N(C)C)=CC=CC=2C=CC=1)C>ClCCl>[CH3:22][O:21][C:19]([C:18]1[CH:23]=[C:24]2[C:15](=[CH:16][CH:17]=1)[NH:14][C:4](=[O:5])[CH:3]2[S:2][CH3:1])=[O:20]
Reactant: CCOC(=O)CSC
Reactant: COC(=O)c1ccc(N)cc1
Agent: CN(C)c1cccc2cccc(N(C)C)c12
Solvent: ClCCl
Solvent: O=S(=O)(Cl)Cl
Product: COC(=O)c1ccc2c(c1)C(SC)C(=O)N2
Temperature: -70 °C
Yield: 42.1 %

Procedure:
A solution of 2.66 g (20.0 mmol) of ethyl (methylthio)acetate dissolved in 200 mL of dichloromethane was cooled with stirring to −70° C. and 2.7 g (20.0 mmol) of sulfuryl chloride was added. The reaction was stirred for 30 min. at −70° C., and a solution of 3.0 g (20 mol) of methyl 4-aminobenzoate and 4.39 (20 mmol) of Proton Sponge® in 250 mL of dichloromethane was added dropwise over 1 h. The resulting pink slurry was treated with 2.3 g (23 mmol) of TEA in one portion, and the solution was allowed to warm to rt. The solution was washed with three 250-mL portions of water, dried over MgSO4, and concentrated to give an oil. This was chromatographed on silica gel eluting with hexane:EtOAc (1:1) to yield 2.0 g (42% yield) of 3-methylthio-2-oxo-2,3-dihydro-1H-indole-5-carboxylic acid methyl ester: 1H NMR (DMSO-d6): δ 1.97 (s, 3H), 3.35 (s, 3H), 4.67 (s, 1H), 6.97 (d, J=8.2 Hz, 1H), 7.84 (s, 1H). 7.91 (d, J=8.2 Hz, 1H), 10.97 (s, 1H). A solution of 2.0 g (8.4 mmol) of 3-methylthio-2-oxo-2,3-dihydro-1H-indole-5-carboxylic acid methyl ester in 20 mL of acetic acid was treated with 10 g of zinc powder. The reaction mixture was stirred for 2 h at rt, filtered through celite and concentrated to dryness. The residue was chromatographed on silica gel eluting with hexane:EtOAc (1:1) to yield 1.6 g (99% yield) of 2oxo-2,3-dihydro-1H-indole-5-carboxylic acid methyl ester as a pink solid: 1H NMR (DMSO-d6): δ 3.52 (s, 2H), 3.77 (s, 3H), 6.87 (d, J=8.2 Hz, 1H), 7.74 (s, J=1H), 7.80 (d, J=8.2 Hz, 1H), 10.72 (br s, 1H). Conversion to the 3-dimethylaminomethylene-2-oxo-2,3-dihydro-1H-indole-5-carboxylic acid methyl ester (mixture of E and Z isomers) was carried out via Procedure G in 49% yield: 1H NMR (DMSO-d6): δ 3.29 Z (s, 6H), 3.31 E (s, 6H), 3.76 Z (s, 3H), 3.76 E (s, 3H), 6.74 Z (d, J=8.1 Hz, 1H), 6.81 E (d. J=8.2 Hz, 1H), 7.47-7.50 Z (m, 1H), 7.50-7.52 E (m, 1H), 7.57 E (dd, J=1.3, 8.2 Hz, 1H), 7.74 Z (s, 1H), 7.89 Z (s, 1H), 7.94 E (s, 1H), 10.33 Z (bs, 1H), 10.43 E (bs, 1H). The title compound was prepared in 41% yield from 3-[(dimethylamino)methylene]oxindole-5-carboxylic acid methyl ester and 4-aminobenzenesulfonamide according to Procedure J: 1H NMR (DMSO-d6): δ 3.81 (s, 3H), 6.92 (d, J=8.2 Hz, 1H), 7.26 (s, 2H), 7.60 (d, J=8.4 Hz, 2H), 7.69 (d, J=8.2 Hz, 1H). 7.75 (d, J=8.4 Hz, 2H), 8.29 (s, 1H), 8.86 (d, J=12.4 Hz, 1H), 10.80 (d, J=12.4 Hz, 1H), 10.94 (s, 1H); APCI−MS m/z 372 (M−1)−. Anal. Calcd for C17H15N3O5S: C, 54.68, H, 4.05; N, 11.25; S, 8.59. Found C, 54.65, H, 4.12; N, 11.17; S. 8.49.