Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH:15]=[CH:14][C:12]([NH2:13])=[CH:11][CH:10]=2)O1.Br[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=1.C([O-])([O-])=O.[Cs+].[Cs+]>C1(C)C=CC=CC=1.C(O)CCC.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>[N:19]1[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=1[C:9]1[CH:10]=[CH:11][C:12]([NH2:13])=[CH:14][CH:15]=1
Reactant: Brc1ccccn1
Reactant: CC1(C)OB(c2ccc(N)cc2)OC1(C)C
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: [Cs+]
Solvent: Cc1ccccc1
Solvent: CCCCO
Solvent: O
Product: Nc1ccc(-c2ccccn2)cc1
Temperature: 25 °C
Yield: 78.7 %

Procedure:
To a solution of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (2.66 g, 12.1 mmol) in toluene (20 mL) and n-butanol (7 mL), a solution of 2-bromopyridine (0.991 g, 6.27 mmol) and Cs2CO3 (6.10 g, 18.7 mmol) in H2O (20 mL) was added. The mixture was degassed three times with Ar/vacuum cycle before being charged with Pd(Ph3P)4 (540 mg, 0.46 mmol, 7% mol). It was then heated at reflux under Ar overnight. The reaction mixture was allowed to cool at room temperature, and then in an ice-bath. The precipitates were collected, dried on vacuum to give a solid (0.840 g)
Reaction SMILES: O=C1C2C(=CC=CC=2)C(=O)[N:3]1[CH2:12][CH2:13][CH2:14][CH2:15][C:16]1[CH:21]=[CH:20][C:19]([O:22][C:23](=[S:27])[N:24]([CH3:26])[CH3:25])=[CH:18][CH:17]=1.CN>>[NH2:3][CH2:12][CH2:13][CH2:14][CH2:15][C:16]1[CH:21]=[CH:20][C:19]([O:22][C:23](=[S:27])[N:24]([CH3:25])[CH3:26])=[CH:18][CH:17]=1
Reactant: CN(C)C(=S)Oc1ccc(CCCCN2C(=O)c3ccccc3C2=O)cc1
Agent: CN
Product: CN(C)C(=S)Oc1ccc(CCCCN)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 58.4 %

Procedure:
A mixture of dimethylthiocarbamic acid 0-{4-[4-(1,3-dioxo-1,3-dihydroisoindol-2-yl)-butyl]phenyl}ester 9 (0.30 g, 0.80 mmol) and methylamine (2M in methanol, 10 mL, 20 mmol) was stirred at room temperature overnight. Solvent was removed by rotary evaporation and the residue was purified by flash silica gel column chromatography (Biotage) eluting with chloroform/methanol/concentrated ammonium hydroxide (10:1:0.1, v/v) to give dimethylthiocarbamic acid O-[4-(4-aminobutyl)phenyl]ester (10) as a clear colorless oil (118 mg, 46% yield). 1H NMR (300 MHz, CD3OD) δ 1.70 (m, 4H), 2.70 (m, 4H), 3.34 (s, 3H), 3.46 (s, 3H), 6.96 (d, 2H), 7.20 (d, 2H). m/z (ESI): 253 [C13H20N2OS+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][C:11]=1[N+:12]([O-:14])=[O:13])[C:6]([OH:8])=O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Br)(Br)(Br)Br.[NH2:39][CH2:40][CH2:41]O>C1(C)C=CC=CC=1>[N:39]1([C:6]([C:5]2[CH:9]=[CH:10][C:11]([N+:12]([O-:14])=[O:13])=[C:3]([O:2][CH3:1])[CH:4]=2)=[O:8])[CH2:41][CH2:40]1
Reactant: NCCO
Reactant: COc1cc(C(=O)O)ccc1[N+](=O)[O-]
Agent: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: COc1cc(C(=O)N2CC2)ccc1[N+](=O)[O-]
Temperature: 80 °C
Reaction time: 1 h
Yield: 34 %

Procedure:
To a solution of 3-methoxy-4-nitrobenzoic acid (1 equiv) in toluene (0.21 M) was added triphenyl phosphine (1.5 equiv), carbon tetrabromide (1.6 equiv), TEA (2 equiv) and 2-aminoethanol (0.7 equiv). Then the resulting mixture was stirred at 80° C. for 1 h. The reaction mixture was filtered, the filtrate was concentrated and the crude was purified by reverse phase HPLC (10%-95% acetonitrile in water) to give the title compound (34% yield) as a yellow solid. MS (ESI) m/z 223.1 [M+1]+.
Reaction SMILES: [C:1]12[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=1)[NH:6][C:5](=[O:12])[O:4][C:2]2=[O:3].CC(N(C)C)=O.[H-].[Na+].[F:21][C:22]1[CH:29]=[CH:28][C:25]([CH2:26]Cl)=[CH:24][CH:23]=1>O>[F:21][C:22]1[CH:29]=[CH:28][C:25]([CH2:26][N:6]2[C:5](=[O:12])[O:4][C:2](=[O:3])[C:1]3=[CH:11][CH:10]=[CH:9][CH:8]=[C:7]23)=[CH:24][CH:23]=1
Reactant: Fc1ccc(CCl)cc1
Reactant: O=c1[nH]c2ccccc2c(=O)o1
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Solvent: O
Product: O=c1oc(=O)n(Cc2ccc(F)cc2)c2ccccc12
Temperature: 60 °C
Reaction time: 1 h

Procedure:
To a solution of 3.2 kgs. isatoic anhydride in 15 kgs. dimethylacetamide is added under nitrogen with stirring sodium hydride obtained from 880 gms. of a 57% dispersion in mineral oil, while maintaining the temperature below 25°C. The resulting mixture is heated to about 60°C. and held at about 55°-60°C. for 1 hour. The reaction mixture is then cooled to 20°-30°C. and to it is added 3.0 kgs. p-fluorobenzyl chloride. The mixture is then reheated to about 60°C. and held there for about 4 hours. It is then cooled again to 20°C. and to it is added 17.4 kgs. of ice and then 24 kgs. water. The mixture is stirred for 15 minutes, the solids collected by filtration, washed with several 2 kg. portions of water and then three times with 0.7 kg. diethylether. The washed solids are dried to obtain N-(p-fluorobenzyl)isatoic anhydride, m.p. 140°-143°C.
Reaction SMILES: [Mg].BrCCBr.Br[C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([Br:13])[CH:8]=1.[C:14]([O:17][C@@H:18]1[C@@H:23]([O:24][C:25](=[O:27])[CH3:26])[C@H:22]([O:28][C:29](=[O:31])[CH3:30])[C@@H:21]([CH2:32][O:33][C:34](=[O:36])[CH3:35])[O:20][C@@H:19]1Br)(=[O:16])[CH3:15]>C(OCC)C.O>[C:14]([O:17][C@@H:18]1[C@@H:23]([O:24][C:25](=[O:27])[CH3:26])[C@H:22]([O:28][C:29](=[O:31])[CH3:30])[C@@H:21]([CH2:32][O:33][C:34](=[O:36])[CH3:35])[O:20][C@H:19]1[C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([Br:13])[CH:8]=1)(=[O:16])[CH3:15]
Reactant: Brc1cccc(Br)c1
Reactant: CC(=O)OC[C@H]1O[C@H](Br)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Agent: [Mg]
Solvent: O
Solvent: BrCCBr
Solvent: CCOCC
Product: CC(=O)OC[C@H]1O[C@@H](c2cccc(Br)c2)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Temperature: 25 °C
Reaction time: 20 h
Yield: 45 %

Procedure:
Magnesium (0) (400 mg) was suspended in 17 mL of anhydrous diethyl ether, and to the suspension was added 100 μL of 1,2-dibromoethane. 1,3-dibromobenzene (3.8 g, 16.08 mmol) was added at a rate to keep a moderate reflux. After Grignard formation was complete (magnesium consumed and the reaction cooled), 2,3,4,6-tetra-O-acetyl-α-D-glucopyranosyl bromide (0.34 g, 0.80 mmol in 8 mL of anhydrous diethyl ether) was added drop-wise. The reaction was refluxed for 5 h, cooled to room temperature and poured into a separatory funnel with 20 mL of water. The flask was rinsed with 50 mL of diethyl ether and 3 mL of acetic acid (to dissolve the magnesium salts) and added to the seperatory funnel. The layers were separated and the aqueous layer was collected and concentrated in vacuo. The white pasty solid was dissolved in 15 mL of pyridine and 10 mL of acetic anhydride. After 20 h at room temperate the reaction was poured into 150 mL of water and extracted into dichloromethane (3×150 mL). The organic layers were combine, washed with 1 N hydrochloric acid (3×50 mL), dried over sodium sulfate, filtered, concentrated and purified by column chromatography (12 g silica gel, 5% to 95% ethyl acetate-hexane) to afford (1S)-2,3,4,6-tetra-O-acetyl-1,5-anhydro-1-(3-bromophenyl)-D-glucitol (0.178 g, 0.36 mmol, 45% yield) as a white foam; Rf 0.4 (40% ethyl acetate-hexane); 1H NMR (300 MHz, CDCl3) δ 7.44 (m, 2H) 7.25 (m, 2H), 5.27-5.35 (m, 1H), 5.21 (t, J=9.6 Hz, 1H), 5.03 (t, J=9.7 Hz, 1H), 4.36 (d, J=9.9 Hz, 1H), 4.23-4.32 (m, 1H) 4.08-4.18 (m, 1H) 3.80-3.85 (m, 1H) 2.09 (s, 3H), 2.06 (s, 3H), 1.99 (s, 3H), 1.84 (s, 3H) ppm; MS [M+H]+ 488.4.
Reaction SMILES: [C:1]([O:4][C@@H:5]1[C@@H:18]([O:19][C:20](=[O:22])[CH3:21])[C@H:17]([O:23][C:24](=[O:26])[CH3:25])[CH2:16][S:15][C@H:6]1[O:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10](Br)[CH:9]=1)(=[O:3])[CH3:2].CC1(C)C(C)(C)OB([C:35]2[C:36]([CH3:42])=[N:37][N:38]([CH3:41])[C:39]=2[CH3:40])O1>>[C:1]([O:4][C@@H:5]1[C@@H:18]([O:19][C:20](=[O:22])[CH3:21])[C@H:17]([O:23][C:24](=[O:26])[CH3:25])[CH2:16][S:15][C@H:6]1[O:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([C:35]2[C:36]([CH3:42])=[N:37][N:38]([CH3:41])[C:39]=2[CH3:40])[CH:9]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)O[C@@H]1[C@@H](OC(C)=O)[C@H](OC(C)=O)CS[C@H]1Oc1cccc(Br)c1
Reactant: Cc1nn(C)c(C)c1B1OC(C)(C)C(C)(C)O1
Product: CC(=O)O[C@@H]1[C@@H](OC(C)=O)[C@H](OC(C)=O)CS[C@H]1Oc1cccc(-c2c(C)nn(C)c2C)c1
Yield: 46 %

Procedure:
By carrying out the operation analogously to example 3, starting from 3-bromophenyl 2,3,4-tri-O-acetyl-5-thio-β-D-xylopyranoside, obtained according to preparation VII, and 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,5-trimethyl-1H-pyrazole, the expected product is obtained in the form of a white solid with a yield of 46%.
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[C:7]([Cl:9])[CH:6]=[C:5]([N+:10]([O-])=O)[C:3]=1[NH2:4].[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([CH:20]2[CH2:26][C:25](=O)[O:24][C:22](=[O:23])[CH2:21]2)=[CH:16][CH:15]=1>O1CCOCC1>[Cl:9][C:7]1[CH:8]=[C:2]([Cl:1])[C:3]2[N:4]=[C:25]([CH2:26][CH:20]([C:17]3[CH:16]=[CH:15][C:14]([Cl:13])=[CH:19][CH:18]=3)[CH2:21][C:22]([OH:24])=[O:23])[NH:10][C:5]=2[CH:6]=1.[ClH:1]
Reactant: Nc1c(Cl)cc(Cl)cc1[N+](=O)[O-]
Reactant: O=C1CC(c2ccc(Cl)cc2)CC(=O)O1
Solvent: C1COCCO1
Product: Cl
Product: O=C(O)CC(Cc1nc2c(Cl)cc(Cl)cc2[nH]1)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 51.6 %

Procedure:
The solution of commercial 2,4-dichloro-6-nitroaniline (621 mg) and 3-(4-chlorophenyl)glutaric anhydride (674 mg) in 1,4-dioxane (2 ml) was heated to reflux shortly and stirred at rt for 1 h. The solvent was removed by distillation and the residue dried in vacuo. The oily residue was dissolved in acetic acid (6 ml) and heated to reflux. Iron powder (1.01 g) was added and the mixture stirred under reflux for 1 h. Then conc. HCl (6 ml) was added cautiously and the green-yellow solution was refluxed for additional 2 h. All volatiles were removed at the water aspirator and the residue precipitated from acetic acid/conc. HCl solution with water. The solid was collected by suction filtration and washed well with 1M HCl and water. The crude was recrystallised from acetic acid to give 4-(5,7-dichloro-2-benzimidazolyl)-3-(4-chlorophenyl)butanoic acid•HCl (325 mg) as colourless crystals.
Reaction SMILES: [CH3:1][N:2]([CH3:6])[CH2:3][CH2:4][OH:5].C(N(CC)CC)C.[CH3:14][S:15](Cl)(=[O:17])=[O:16]>C1COCC1>[CH3:14][S:15]([O:5][CH2:4][CH2:3][N:2]([CH3:6])[CH3:1])(=[O:17])=[O:16]
Reactant: CS(=O)(=O)Cl
Reactant: CN(C)CCO
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CN(C)CCOS(C)(=O)=O

Procedure:
The N,N-dimethylethanolamine (Aldrich, 0.11 g, 1.2 mmol), triethylamine (0.56 mL, 4.1 mmol), and methanesulfonyl chloride (0.15 mL, 1.9 mmol) in 10 mL THF were processed as described in Example 1C to give the title compound that was used directly in the next reaction.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[C:9]([NH:10][C:11]3[CH:16]=[CH:15][N:14]=[CH:13][CH:12]=3)=[CH:8][S:7][C:6]=2[CH:17]=1.[H-].[Na+].S(OCC)(O[CH2:24][CH3:25])(=O)=O>CN(C)C=O>[ClH:1].[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[C:9]([N:10]([CH2:24][CH3:25])[C:11]3[CH:16]=[CH:15][N:14]=[CH:13][CH:12]=3)=[CH:8][S:7][C:6]=2[CH:17]=1
Reactant: Clc1ccc2c(Nc3ccncc3)csc2c1
Reactant: CCOS(=O)(=O)OCC
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCN(c1ccncc1)c1csc2cc(Cl)ccc12
Product: Cl
Temperature: 0 °C
Yield: 267.3 %

Procedure:
6-Chloro-3-(4-pyridinylamino)benzo[b]thiophene (3 g, 11.5 mmol) was added portionwise as a powder to an ice-cooled suspension of sodium hydride (60% oil dispersion, 0.7 g, 17.5 mmol, washed with heptane) in 25 mL of dimethylformamide. After the anion formation was completed, diethyl sulfate (1.8 g, 11.7 mmol) was added. After one hour the reaction mixture was poured into ice-water and extracted with ether. The organic extract was washed with water and saturated sodium chloride solution, and dried (anhydrous magnesium sulfate), filtered and concentrated to give 5 g of a brown oil. Elution through silica with 10% methanol in ethyl acetate via flash column chromatography yielded 2.3 g of an amber oil. Conversion to the hydrochloride salt in 10% methanol in ether afforded 1.8 g of yellow crystals, mp 288-290°.
Reaction SMILES: [Si:1]([O:8][CH2:9][C@@H:10]1[C@@H:14]([C:15]2[O:16][CH:17]=[CH:18][CH:19]=2)[CH2:13][NH:12][CH2:11]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].C(=O)(O)[O-].[Na+].Cl[C:26]([O:28][C:29]1[CH:38]=[CH:37][C:32]([C:33]([O:35][CH3:36])=[O:34])=[CH:31][CH:30]=1)=[O:27]>O1CCCC1.O>[Si:1]([O:8][CH2:9][C@@H:10]1[C@@H:14]([C:15]2[O:16][CH:17]=[CH:18][CH:19]=2)[CH2:13][N:12]([C:26]([O:28][C:29]2[CH:30]=[CH:31][C:32]([C:33]([O:35][CH3:36])=[O:34])=[CH:37][CH:38]=2)=[O:27])[CH2:11]1)([C:4]([CH3:7])([CH3:5])[CH3:6])([CH3:3])[CH3:2]
Reactant: COC(=O)c1ccc(OC(=O)Cl)cc1
Reactant: CC(C)(C)[Si](C)(C)OC[C@H]1CNC[C@@H]1c1ccco1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: COC(=O)c1ccc(OC(=O)N2C[C@H](CO[Si](C)(C)C(C)(C)C)[C@@H](c3ccco3)C2)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A 350 mg portion of (3R,4R)-3-({[tert-butyl(dimethyl)silyl]oxy}methyl)-4-(2-furyl)pyrrolidine and 470 mg of sodium bicarbonate were suspended in 20 ml of a tetrahydrofuran-water (3:1) mixed solvent, and 320 mg of methyl 4-[(chlorocarbonyl)oxy]benzoate (mfd. by Fluka) was added in one portion thereto at room temperature. After 1Hour of stirring at room temperature, 80 mg of methyl 4-[(chlorocarbonyl)oxy]benzoate was further added thereto at room temperature. After 2 hours of further stirring, the reaction solution was concentrated under a reduced pressure. The residue was separated by diluting it with water and diethyl ether, and then extracted with diethyl ether. The organic layer was washed with water and saturated brine in that order and dried with anhydrous sodium sulfate. This was concentrated under a reduced pressure, and the thus obtained residue was purified by a silica gel column chromatography (chloroform-ethyl acetate) to obtain 571 mg of 4-(methoxycarbonyl)phenyl (3R,4R)-3-({[tert-butyl(dimethyl)silyl]oxy}methyl)-4-(2-furyl)pyrrolidine-1-carboxylate as a colorless oily substance.
Reaction SMILES: [C:1]([NH:14][C@H:15]([CH2:45][O:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][CH2:58][CH2:59][CH2:60][CH2:61][CH3:62])[CH2:16][S:17][CH2:18][C@@H:19]([C:38]([O:40]C(C)(C)C)=[O:39])[NH:20][C:21](=[O:37])[O:22][CH2:23][CH:24]1[C:36]2[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=2[C:30]2[C:25]1=[CH:26][CH:27]=[CH:28][CH:29]=2)(=[O:13])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]>C(O)(C(F)(F)F)=O.C(Cl)Cl.CC(OC)(C)C>[C:1]([NH:14][C@H:15]([CH2:45][O:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][CH2:58][CH2:59][CH2:60][CH2:61][CH3:62])[CH2:16][S:17][CH2:18][C@@H:19]([C:38]([OH:40])=[O:39])[NH:20][C:21](=[O:37])[O:22][CH2:23][CH:24]1[C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][C:30]=2[C:31]2[C:36]1=[CH:35][CH:34]=[CH:33][CH:32]=2)(=[O:13])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: CCCCCCCCCCCCCCCCOC[C@H](CSC[C@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)OC(C)(C)C)NC(=O)CCCCCCCCCCC
Solvent: O=C(O)C(F)(F)F
Solvent: COC(C)(C)C
Solvent: ClCCl
Product: CCCCCCCCCCCCCCCCOC[C@H](CSC[C@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)O)NC(=O)CCCCCCCCCCC

Procedure:
A solution of (5R,9R)-tert-butyl 9-dodecanamido-1-(9H-fluoren-9-yl)-3-oxo-2,11-dioxa-7-thia-4-azaheptacosane-5-carboxylate in 40% TFA in DCM (0.3 M) was stirred at room temperature until complete deprotection of tert-butyl group (2 hours). The reaction mixture was diluted in MTBE, washed three times with 1 M citric acid (pH 3), and once with 1:2 HCl (3 M)/brine. The organic layer was dried over anhydrous Na2SO4 and concentrated en vaccuo to give (5R,9R)-9-dodecanamido-1-(9H-fluoren-9-yl)-3-oxo-2,11-dioxa-7-thia-4-azaheptacosane-5-carboxylic acid.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:7]=[C:8]([C:12]([N:14]2[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]2)=[O:13])[CH:9]=[CH:10][CH:11]=1.[NH2:20][S:21]([C:24]1[C:25]([C:29](Cl)=[O:30])=[CH:26][S:27][CH:28]=1)(=[O:23])=[O:22]>O1CCCC1>[OH2:5].[NH2:20][S:21]([C:24]1[C:25]([C:29]([NH:1][CH2:2][CH2:3][CH2:4][O:5][C:6]2[CH:11]=[CH:10][CH:9]=[C:8]([C:12]([N:14]3[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]3)=[O:13])[CH:7]=2)=[O:30])=[CH:26][S:27][CH:28]=1)(=[O:23])=[O:22]
Reactant: NS(=O)(=O)c1cscc1C(=O)Cl
Reactant: NCCCOc1cccc(C(=O)N2CCCCC2)c1
Solvent: C1CCOC1
Product: NS(=O)(=O)c1cscc1C(=O)NCCCOc1cccc(C(=O)N2CCCCC2)c1
Product: O
Reaction time: 0.25 h

Procedure:
To a solution of 0.26 g. (0.001 mole) of 1-[[3-(3-aminopropoxy)phenyl]carbonyl]piperidine in 30 ml. of dry tetrahydrofuran is added 0.23 g. (0.001 mole) of 4-(aminosulfonyl)-3-thiophenecarbonyl chloride. The mixture is allowed to stand at room temperature for 15 minutes. The tetrahydrofuran is removed in a rotary evaporator and the residue is dissolved in 50 ml. of chloroform. The chloroform solution is extracted with 50 ml. of 10% aqueous sodium hydroxide solution followed by 50 ml. of 10% aqueous hydrochloric acid. The chloroform layer is washed with water, is dried over magnesium sulfate and is filtered. The filtrate is evaporated in a rotary evaporator to give 0.15 g. of an amorphous product, m.p. 70°-80° C.; mass spectrum CI m/e 452 MH+.
Reaction SMILES: [OH:1][CH:2](CO)[CH2:3][N:4]([CH3:44])[C:5]([C:7]1[N:16]2[C:10]([CH2:11][N:12]([C:25]([C:27]3[CH:32]=[CH:31][C:30]([C:33]4[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=4[C:39]([F:42])([F:41])[F:40])=[C:29]([CH3:43])[CH:28]=3)=[O:26])[C:13]3[CH:20]=[C:19]([O:21][CH3:22])[C:18]([O:23][CH3:24])=[CH:17][C:14]=3[CH2:15]2)=[CH:9][CH:8]=1)=[O:6].[O:47]=[C:48](Cl)OC(Cl)(Cl)Cl.C(N(CC)CC)C.N(CCO)CCO>ClCCl>[OH:47][CH2:48][CH2:44][N:4]([CH2:3][CH2:2][OH:1])[C:5]([C:7]1[N:16]2[C:10]([CH2:11][N:12]([C:25]([C:27]3[CH:32]=[CH:31][C:30]([C:33]4[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=4[C:39]([F:41])([F:40])[F:42])=[C:29]([CH3:43])[CH:28]=3)=[O:26])[C:13]3[CH:20]=[C:19]([O:21][CH3:22])[C:18]([O:23][CH3:24])=[CH:17][C:14]=3[CH2:15]2)=[CH:9][CH:8]=1)=[O:6]
Reactant: O=C(Cl)OC(Cl)(Cl)Cl
Reactant: COc1cc2c(cc1OC)N(C(=O)c1ccc(-c3ccccc3C(F)(F)F)c(C)c1)Cc1ccc(C(=O)N(C)CC(O)CO)n1C2
Solvent: ClCCl
Solvent: OCCNCCO
Solvent: CCN(CC)CC
Product: COc1cc2c(cc1OC)N(C(=O)c1ccc(-c3ccccc3C(F)(F)F)c(C)c1)Cc1ccc(C(=O)N(CCO)CCO)n1C2
Reaction time: 8 h

Procedure:
A solution of N-(2,3-dihydroxypropyl)-7,8-dimethoxy-N-methyl-10-{[2-methyl-2′-trifluoromethyl-[1,1′-biphenyl]-4-yl]carbonyl}-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxamide of Example 18, Step D (0.31 mmol), diphosgene (1.1 equiv.) and triethylamine (1.5 equiv.) in dichloromethane (5 mL), was stirred at room temperature overnight. The solvent was removed in vacuo and the residue was dissolved in dichloromethane (5 mL). To the solution was added triethylamine (1.5 equiv.) and diethanolamine (1.5 equiv.) and the reaction was stirred overnight. The reaction mixture was then washed with water, dried over anhydrous magnesium sulfate, filtered and evaporated to dryness. The residue was first chromatographed on silica gel eluting with 2% methanol in dichloromethane and then rechromatographed with 2% methanol in ethyl acetate to provide the title compound (0.036 g) as a white solid, m.p. 130-132° C.
Reaction SMILES: [N+:1]([C:4]1[CH:19]=[CH:18][C:7]2[N:8]=[C:9]([CH2:11][C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[NH:10][C:6]=2[CH:5]=1)([O-])=O.NC1C=C2C(=CC=1)N(CC1C=CC=CC=1)C=C2>>[NH2:1][C:4]1[CH:19]=[CH:18][C:7]2[NH:8][C:9]([CH2:11][C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[N:10][C:6]=2[CH:5]=1
Reactant: O=[N+]([O-])c1ccc2nc(Cc3ccccc3)[nH]c2c1
Agent: Nc1ccc2c(ccn2Cc2ccccc2)c1
Product: Nc1ccc2[nH]c(Cc3ccccc3)nc2c1

Procedure:
The title compound was prepared from 5-nitro-2-benzylbenzimidazole by an analogous reduction method to that described above for 5-amino-1benzyl-1H-indole; m/z (M+1)+224. Also note the published method (J. Het. Chem., 23, 1109-13, (1986)).
Reaction SMILES: C(O[C:4](=[O:17])[C:5]1[CH:10]=[C:9]([F:11])[C:8]([F:12])=[CH:7][C:6]=1[NH:13][CH:14]1[CH2:16][CH2:15]1)C.ClS[N:20]=[C:21]=[O:22]>ClCCl>[CH:14]1([N:13]2[C:6]3[C:5](=[CH:10][C:9]([F:11])=[C:8]([F:12])[CH:7]=3)[C:4](=[O:17])[NH:20][C:21]2=[O:22])[CH2:15][CH2:16]1
Reactant: O=C=NSCl
Reactant: CCOC(=O)c1cc(F)c(F)cc1NC1CC1
Solvent: ClCCl
Product: O=c1[nH]c(=O)n(C2CC2)c2cc(F)c(F)cc12
Temperature: -20 °C
Yield: 38.2 %

Procedure:
To a solution of 2-cyclopropylamino-4,5-difluorobenzoic acid ethyl ester (Example 22) (5.0 g, 22.0 mmol) in dry dichloromethane (120 mL) under a N2 atmosphere is added chlorosulfanyl isocyanate (3.11 g, 22 mmol). The solution is reacted at room temperature for 4 hours, and the solvent is removed under reduced pressure. The residue is cooled to −20° C., and a cold brine solution (100 mL) buffered with NaHCO3 is added. The solution is warmed to room temperature for 1 hour. The volume is reduced by half with a stream of air, and the solid is collected by filtration. The dry solid is added to a solution of triethylamine (5 mL) in THF (250 mL) and refluxed overnight. The reaction is cooled, the solvent removed under reduced pressure, dissolved in water (100 mL), and acidified to pH 1-2 with 1.0 M hydrochloric acid. The resulting precipitate is collected via filtration to afford 2.0 g of the title compound. MS CI: m/z 239 (MH+).
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8](B(O)O)=[CH:9][C:4]=2[O:3][CH2:2]1.Br[C:14]1[S:22][C:21]2[C:16](=[N:17][CH:18]=[CH:19][C:20]=2[NH:23][C:24]2[CH:25]=[C:26]3[C:30](=[CH:31][CH:32]=2)[NH:29][C:28]([CH3:33])=[CH:27]3)[CH:15]=1>>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:14]3[S:22][C:21]4[C:16](=[N:17][CH:18]=[CH:19][C:20]=4[NH:23][C:24]4[CH:25]=[C:26]5[C:30](=[CH:31][CH:32]=4)[NH:29][C:28]([CH3:33])=[CH:27]5)[CH:15]=3)=[CH:9][C:4]=2[O:3][CH2:2]1
Reactant: OB(O)c1ccc2c(c1)OCO2
Reactant: Cc1cc2cc(Nc3ccnc4cc(Br)sc34)ccc2[nH]1
Product: Cc1cc2cc(Nc3ccnc4cc(-c5ccc6c(c5)OCO6)sc34)ccc2[nH]1

Procedure:
The title compound was prepared from 1,3-benzodioxole-5-boronic acid and (2-bromothieno[3,2-b]pyridin-7-yl)-(2-methyl-1H-indol-5-yl)-amine by the procedure analogous to example 2 above. 1H NMR (400 MHz, CD3OD) δ8.00 (d, 1H), 7.38 (s, 1H), 7.26 (m, 2H), 7.13 (m, 2H), 6.93 (d, 1H), 6.77 (d, 1H), 6.52 (d, 1H), 6.08 (s, 1h), 5.92 (s, 2H), 2.39 (s, 3H); RP18-HPLC RT: 6.09 minutes; API MS: 400 (M+1).
Reaction SMILES: Cl.[S:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[CH:4]=[C:3]1[C:11]([NH:13][C:14]1([C:20]([NH:22][CH:23]2[CH2:28][CH2:27][NH:26][CH2:25][CH:24]2[OH:29])=[O:21])[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1)=[O:12].Br[C:31]1[CH:36]=[CH:35][C:34]([Cl:37])=[CH:33][C:32]=1[F:38]>>[S:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[CH:4]=[C:3]1[C:11]([NH:13][C:14]1([C:20]([NH:22][CH:23]2[CH2:28][CH2:27][N:26]([C:31]3[CH:36]=[CH:35][C:34]([Cl:37])=[CH:33][C:32]=3[F:38])[CH2:25][C:24]2=[O:29])=[O:21])[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1)=[O:12]
Reactant: Fc1cc(Cl)ccc1Br
Reactant: O=C(NC1(C(=O)NC2CCNCC2O)CCCCC1)c1cc2ccccc2s1
Agent: Cl
Product: O=C(NC1(C(=O)NC2CCN(c3ccc(Cl)cc3F)CC2=O)CCCCC1)c1cc2ccccc2s1

Procedure:
In accordance with the same procedure as in Example 85, except that 4-[N-[1-[N-(benzothiophen-2-ylcarbonyl)amino]cyclohexanecarbonyl]amino]-3-piperidinol hydrochloride was used instead of 4-[N-[1-[N-(furan-2-ylcarbonyl)amino]cyclohexanecarbonyl]amino]-3-piperidinol hydrochloride and 1-bromo-2-fluoro-4-chlorobenzene was used instead of 1-bromo-4-fluoro-2-thiomethoxybenzene in Step 1 thereof, 76 mg of the titled compound was prepared