Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1]CN=C=NCCCN(C)C.[CH2:12]([O:19][C:20]([N:22]1[CH2:27][CH2:26][CH:25]([N:28]2[CH2:33][CH2:32][CH2:31][N:30]([CH2:34][C:35](O)=[O:36])[C:29]2=[O:38])[CH2:24][CH2:23]1)=[O:21])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.CN.C1C=CC2N(O)N=NC=2C=1>C1COCC1.C1COCC1.ClCCl>[CH3:1][C:35]([CH2:34][N:30]1[CH2:31][CH2:32][CH2:33][N:28]([CH:25]2[CH2:24][CH2:23][N:22]([C:20]([O:19][CH2:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)=[O:21])[CH2:27][CH2:26]2)[C:29]1=[O:38])=[O:36]
Reactant: CCN=C=NCCCN(C)C
Reactant: O=C(O)CN1CCCN(C2CCN(C(=O)OCc3ccccc3)CC2)C1=O
Agent: CN
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Solvent: ClCCl
Product: CC(=O)CN1CCCN(C2CCN(C(=O)OCc3ccccc3)CC2)C1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 100.5 %

Procedure:
WSC (0.39 g) was added to a solution of [3-{1-[(benzyloxy)carbonyl]piperidin-4-yl}-2-oxotetrahydropyrimidin-1(2H)-yl]acetic acid (0.70 g) obtained in Example 36a), a solution of methylamine in THF (1.85 mL) and HOBt (0.31 g) in THF/dichloromethane (1/1, 30 mL) and the mixture was stirred at room temperature overnight. The solvent were distilled off under reduced pressure, and the residue was diluted with ethyl acetate. The mixture was washed with an aqueous saturated sodium bicarbonate solution and saturated saline solution, dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The residue was purified with basic silica gel column chromatography (ethyl acetate) to obtain the title compound (0.70 g, 97%) as a white powder.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([S:8](Cl)(=[O:10])=[O:9])=[CH:4][CH:3]=1.Cl.[CH3:13][NH:14][CH3:15]>O1CCCC1.CN(C)C1C=CN=CC=1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:14]([CH3:15])[CH3:13])(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: O=S(=O)(Cl)c1ccc(F)cc1
Reactant: CNC
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: C1CCOC1
Product: CN(C)S(=O)(=O)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 50.2 %

Procedure:
A solution of 4-fluorobenzenesulfonyl chloride (1.95 g, 10 mmol) and dimethylamine hydrochloric acid salt (978 mg, 12 mmol) in tetrahydrofuran (10 mL) was added to a solution of 4-dimethylaminopyridine (3.05 g, 25 mmol) in tetrahydrofuran (10 mL) dropwise at room temperature. The resulting mixture was stirred at room temperature overnight and concentrated in vacuo. The residue was purified by flash column (elution with 20% ethyl acetate in petroleum ether) to afford 4-fluoro-N,N-dimethyl-benzenesulfonamide (1.02 g, 50%) as a white solid.
Reaction SMILES: [NH2:1][S:2]([C:5]1[CH:10]=[CH:9][C:8](B(O)O)=[CH:7][CH:6]=1)(=[O:4])=[O:3].C(=O)([O-])[O-].[K+].[K+].Br[C:21]1[CH:22]=[C:23]([C:29]2[S:33][C:32]([C:34]([O:36]CC)=[O:35])=[N:31][C:30]=2[CH3:39])[CH:24]=[CH:25][C:26]=1[O:27][CH3:28].C(O)C>C1(C)C=CC=CC=1.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>[CH3:28][O:27][C:26]1[C:21]([C:8]2[CH:9]=[CH:10][C:5]([S:2](=[O:4])(=[O:3])[NH2:1])=[CH:6][CH:7]=2)=[CH:22][C:23]([C:29]2[S:33][C:32]([C:34]([OH:36])=[O:35])=[N:31][C:30]=2[CH3:39])=[CH:24][CH:25]=1
Reactant: NS(=O)(=O)c1ccc(B(O)O)cc1
Reactant: CCOC(=O)c1nc(C)c(-c2ccc(OC)c(Br)c2)s1
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: [K+]
Solvent: CCO
Solvent: Cc1ccccc1
Product: COc1ccc(-c2sc(C(=O)O)nc2C)cc1-c1ccc(S(N)(=O)=O)cc1
Temperature: 92.5 °C
Yield: 88.1 %

Procedure:
4-aminosulfonylbenzene boronic acid (1.15 g, 5.73 mmol) and potassium carbonate (1.97 g, 14.31 mmol) were added to a solution of ethyl 5-(3-bromo-4-methoxyphenyl)-4-methylthiazole-2-carboxylate (Step 1, 1.70 g, 4.77 mmol) in a mixture of toluene:ethanol (15 ml:40 ml) in a tube at 25° C. Nitrogen gas was bubbled through reaction mixture for 15 minutes and to it was added tetrakis(triphenylphosphine)palladium (0) (0.28 g, 0.24 mmol) under nitrogen and the tube was sealed. The reaction mixture was heated at 90-95° C. for 18 hr with stirring. The progress of the reaction was monitored by TLC. The reaction mixture was then cooled to 25° C. and filtered through celite. The celite cake was then washed with 10% methanol in dichloromethane (3×30 ml). The filtrate was dried over sodium sulphate and was concentrated under reduced pressure to obtain the title compound 8b (1.70 g, 88.08%).
Reaction SMILES: [CH3:1][C:2]1O[C:4]([CH3:7])=[N:5][N:6]=1.[NH2:8][CH2:9][CH2:10][CH2:11][CH2:12][OH:13]>CN1CCCC1=O>[CH3:1][C:2]1[N:8]([CH2:9][CH2:10][CH2:11][CH2:12][OH:13])[C:4]([CH3:7])=[N:5][N:6]=1
Reactant: NCCCCO
Reactant: Cc1nnc(C)o1
Solvent: CN1CCCC1=O
Product: Cc1nnc(C)n1CCCCO
Yield: 77.8 %

Procedure:
2,5-Dimethyl-1,3,4-oxadiazole (3.8 g), 4-aminobutanol (3.5 g) and N-methylpyrrolidone (10 ml) were heated at 150° for 18 hours. The mixture was evaporated under high vacuum and the residue chromatographed on silica eluting with a mixture of ethyl acetate and methanol. The fractions containing the product were evaporated under vacuum to leave the title compound, (5.1 g), which was used directly.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([C:17]([OH:19])=O)[CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.[CH2:21]([O:28][C:29](=[O:35])[C@@H:30]1[CH2:34][CH2:33][CH2:32][NH:31]1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.C1C=CC2N(O)N=NC=2C=1.C(N(CC)CC)C.CCN=C=NCCCN(C)C.Cl>C(Cl)Cl>[CH2:21]([O:28][C:29](=[O:35])[C@@H:30]1[CH2:34][CH2:33][CH2:32][N:31]1[C:17](=[O:19])[C@H:9]([CH2:10][C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1)[NH:8][C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)C(=O)O
Reactant: O=C(OCc1ccccc1)[C@@H]1CCCN1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)C(=O)N1CCC[C@H]1C(=O)OCc1ccccc1
Reaction time: 2 h
Yield: 82.8 %

Procedure:
N-t-butyloxycarbonyl-L-phenylalanine (36.54 g, 137.7 mmole), L-proline benzylester hydrochloride (33.84 g, 140 mmole) and HOBT (18.91 g, 140 mmole) were dissolved in methylene chloride (500 ml), and triethylamine (14.17 g, 140 mmole) and WSC hydrochloride (26.40 g, 137.7 mmole) were added thereto at -30° C. The solution was stirred for 2 hours at less than 0° C. and then overnight at room temperature. The solution was washed with 5% aqueous sodium bicarbonate (400 ml, twice), 5% aqueous citric acid (400 ml, twice) and water (400 ml) in the order given, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure. The oily residue thus obtained was crystallized from ethyl acetate and n-hexane to give N-t-butyloxycarbonyl-L-phenylalanyl-L-proline benzylester (yield: 51.61 g, 82.8%).
Reaction SMILES: Br[C:2]1[CH:6]=[CH:5][S:4][C:3]=1[C:7]1[S:8][CH:9]=[CH:10][CH:11]=1.C([Li])CCC.[C:17]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)(=[O:24])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>C(OCC)C>[S:4]1[CH:5]=[CH:6][C:2]([C:17]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[OH:24])=[C:3]1[C:7]1[S:8][CH:9]=[CH:10][CH:11]=1
Reactant: Brc1ccsc1-c1cccs1
Reactant: O=C(c1ccccc1)c1ccccc1
Agent: [Li]CCCC
Solvent: CCOCC
Product: OC(c1ccccc1)(c1ccccc1)c1ccsc1-c1cccs1
Reaction time: 0.25 h
Yield: 32 %

Procedure:
3-Bromo-2,2′-bithiophene (IIIa) (0.50 g, 2.04 mmol) in dry diethylether (20 mL) was added slowly to a solution of n-butyllithium (1.6 M in hexane, 1.25 mL, 2.04 mmol) in dry diethylether (20 mL) at −78° C. over 2 h under N2. The mixture was stirred for 15 minutes at the same temperature. Benzophenone (0.33 g, 1.81 mmol) was added to the mixture at −78° C., followed by stirring overnight at room temperature. The reaction was quenched with an aqueous NH4Cl-solution (2.5 M, 10 mL) and water (10 mL) at 0° C. The organic phase was separated and the aqueous phase was extracted with diethylether. The combined organic phases were washed with brine, dried over MgSO4 and evaporated under reduced pressure to give a crude oil. The oily residue was purified by column chromatography (eluent hexane/EtOAc 90:10) to afford the title compound (IIj) as a yellow oil (0.202 g, 29.0%). 1H-NMR (CDCl3): δ=7.35-7.26 (m, 10H), 7.23 (dd, J=5.1, J=1.2 Hz, 1H), 7.11 (d, J=5.4 Hz, 1H), 6.85 (dd, J=5.1, J=3.5 Hz, 1H), 6.66 (dd, J=3.5 Hz, J=1.2 Hz, 1H), 6.38 (d, J=5.4, 1H), 3.43 (br s, 1H).
Reaction SMILES: Cl.Cl.[NH:3]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[N:5]=[C:4]1[CH:12]([NH2:14])[CH3:13].CCN(C(C)C)C(C)C.C([N:32]=[C:33]=[S:34])(=O)C1C=CC=CC=1>C(Cl)Cl>[NH:3]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[N:5]=[C:4]1[CH:12]([NH:14][C:33]([NH2:32])=[S:34])[CH3:13]
Reactant: CC(N)c1nc2ccccc2[nH]1
Reactant: O=C(N=C=S)c1ccccc1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(NC(N)=S)c1nc2ccccc2[nH]1
Reaction time: 2.5 h
Yield: 71.3 %

Procedure:
To a suspension of 1-(1H-Benzoimidazol-2-yl)-ethylamine dihydrochloride (0.50 g, 2.1 mmol) in CH2Cl2 (10 mL) was added DIPEA (0.74 mL, 4.3 mmol). After 5 minutes benzoyl isothiocyanate (0.32 mL, 2.4 mmol) was added and the reaction mixture was stirred for 2.5 h, followed by evaporation in vacuo. Ammonia (7M in MeOH, 20 mL) was then added and the reaction was stirred another 2.5 h. The excess ammonia was removed in vacuo and CH2Cl2 (10 mL) was added, the solid was collected by filtration giving the title compound (0.33 g, 70%). MS (ESI) m/z 221 (M+1).
Reaction SMILES: [C:1]([N:6]([CH2:8][C:9]([NH2:11])=[S:10])[CH3:7])([O:3][CH2:4][CH3:5])=[O:2].Br[CH2:13][C:14](=O)[C:15]([O:17][CH2:18][CH3:19])=[O:16]>C(O)C>[C:1]([N:6]([CH2:8][C:9]1[S:10][CH:13]=[C:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[N:11]=1)[CH3:7])([O:3][CH2:4][CH3:5])=[O:2]
Reactant: CCOC(=O)C(=O)CBr
Reactant: CCOC(=O)N(C)CC(N)=S
Solvent: CCO
Product: CCOC(=O)c1csc(CN(C)C(=O)OCC)n1

Procedure:
To a solution of (N-carbethoxy-N-methylamino)thioacetamide (30.7 g; 0.17 mole) [prepared in Step B] in 180 ml of absolute ethanol was added a solution of ethyl bromopyruvate (25.0 ml; 0.20 mole) in 130 ml of absolute ethanol. The reaction mixture was heated at reflux temperature for 17 hours and then evaporated under reduced pressure, and the residue was partitioned between ether and water. The organic layer was washed with water and saturated sodium chloride solution, dried, filtered and evaporated under reduced pressure to give an oil which was placed on silica gel and chromatographed using diethyl ether as the eluting solvent. The appropriate fractions yielded the title compound as an oil; TLC [Silica/CH2Cl2 :CH3 --CN (85:15)] gave Rf=0.50. The NMR spectrum (60 MHz) in d6 dimethyl sulfoxide gave the following resonances δ: 8.49 (s, 1H); 4.79 (s, 2H); 4.23 (m, 4H); 3.00 (s, 3H); 1.30 (q, 6H).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:17]=[C:16]2[C:12]([CH:13]=[N:14][N:15]2[CH2:18][C@@H:19]([OH:21])[CH3:20])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[C:24]([Si:28](Cl)([CH3:30])[CH3:29])([CH3:27])([CH3:26])[CH3:25].[Na+].[I-]>C1COCC1.CN(C=O)C>[CH2:1]([O:8][C:9]1[CH:17]=[C:16]2[C:12]([CH:13]=[N:14][N:15]2[CH2:18][C@@H:19]([O:21][Si:28]([C:24]([CH3:27])([CH3:26])[CH3:25])([CH3:30])[CH3:29])[CH3:20])=[CH:11][CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C[C@H](O)Cn1ncc2ccc(OCc3ccccc3)cc21
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: C[C@@H](Cn1ncc2ccc(OCc3ccccc3)cc21)O[Si](C)(C)C(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 98.4 %

Procedure:
To a mixture of (S)-1-(6-benzyloxyindazol-1-yl)-propan-2-ol (2.03 g, 7.20 mmol) in anhydrous THF/DMF (100 mL/35 mL) under nitrogen was added sodium hydride (60% in mineral oil, 0.40 g, 10.0 mmol). After 30 min tert-butyl-chloro-dimethyl-silane (1.52 g, 110 mmol) and a catalytic amount of NaI were added and the mixture was stirred overnight at ambient temperature. Additional NaH (5 mmol) and tert-butyl-chloro-dimethyl-silane (5 mmol) were added to the reaction mixture, which was stirred for 6 h. The reaction mixture was evaporated to a residue that was mixed with a saturated aqueous solution of sodium bicarbonate and extracted with ethyl acetate (2×200 mL). Purification by chromatography (silica, EtOAc/hexane) gave an oil (2.81 g, 99%).
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[NH2:6][C:7]1[CH:16]=[CH:15][CH:14]=[C:13]2[C:8]=1[CH:9]=[CH:10][N:11]=[CH:12]2.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>N1C=CC=CC=1>[CH3:1][S:2]([NH:6][C:7]1[CH:16]=[CH:15][CH:14]=[C:13]2[C:8]=1[CH:9]=[CH:10][N:11]=[CH:12]2)(=[O:4])=[O:3]
Reactant: Nc1cccc2cnccc12
Reactant: CS(=O)(=O)Cl
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: c1ccncc1
Product: CS(=O)(=O)Nc1cccc2cnccc12
Reaction time: 72 h
Yield: 45.6 %

Procedure:
Methanesulfonyl chloride (3.2 ml, 0.042 mol) was added to a solution of 5-aminoisoquinoline (5.0 g, 0.035 mol) in pyridine (40 ml) and the mixture was allowed to stand for 72 hours. The reaction mixture was then poured into aqueous citric acid (10%, 400 ml) and extracted with ethyl acetate (2×230 ml). The organic layer was evaporated to give a residue which was purified on silica gel, eluting with dichloromethane:methanol (95:5, v/v), to afford the subtitle compound as a solid (3.55 g, 46%). Rf 0.03 (CH2Cl2 :diethyl ether 4:1, v/v). 1H NMR (D6 -DMSO) δ: 3.07 (3H, s), 7.68 (1H, t), 7.75 (1H, d), 8.03 (1H, d), 8.10 (1H, d), 8.54 (1H, d), 9.32 (1H, s), 9.79 (1H, bs).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8]([C:12]([O:14]C)=[O:13])=[CH:7][CH:6]=[C:5]2[CH3:16].C(=O)([O-])[O-].[Cs+].[Cs+].Cl[C:24]1[C:33]2[C:28](=[CH:29][C:30]([O:36][CH3:37])=[C:31]([O:34][CH3:35])[CH:32]=2)[N:27]=[CH:26][CH:25]=1>CN(C=O)C>[CH3:35][O:34][C:31]1[CH:32]=[C:33]2[C:28](=[CH:29][C:30]=1[O:36][CH3:37])[N:27]=[CH:26][CH:25]=[C:24]2[O:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8]([C:12]([OH:14])=[O:13])=[CH:7][CH:6]=[C:5]2[CH3:16]
Reactant: COC(=O)c1ccc(C)c2cc(O)ccc12
Reactant: COc1cc2nccc(Cl)c2cc1OC
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: COc1cc2nccc(Oc3ccc4c(C(=O)O)ccc(C)c4c3)c2cc1OC
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
A resealable tube was charged with methyl 6-hydroxy-4-methyl-1-naphthoate (0.087 g, 0.402 mmol), cesium carbonate (0.393 g, 1.21 mmol), and DMF (2 mL). The system was flushed with argon, the tube was sealed, and the mixture stirred at RT for 15 min. 4-Chloro-6,7-dimethoxyquinoline (0.090 g, 0.40 mmol) was added, and the system was again flushed with argon. The tube was sealed and the mixture stirred at 100° C. for 18 h. Additional cesium carbonate (0.393 g, 1.21 mmol) was added and the system was again flushed with argon. The tube was sealed and the mixture stirred at 100° C. for 16 h. The mixture was partitioned between CH2Cl2 and water. The aqueous phase was separated and extracted with CH2Cl2. The aqueous phase was acidified to pH 5-6 with 6 N HCl (aq). The resulting precipitate was filtered and washed with water. The filter cake was dried under vacuum to afford 6-(6,7-dimethoxyquinolin-4-yloxy)-4-methyl-1-naphthoic acid as a light brown solid. MS (ESI, pos. ion) m/z: 390.1 (M+H). Mass Calc'd for C23H19NO5: 389.
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]1[C@H:8]([CH3:9])[CH2:7][CH2:6][CH2:5][N:4]1[C:10]([C:12]1[CH:17]=[C:16]([CH3:18])[CH:15]=[CH:14][C:13]=1[C:19]1[CH:20]=[N:21][N:22]([CH3:24])[CH:23]=1)=[O:11].Br[C:26]1[C:31]([CH3:32])=[CH:30][CH:29]=[CH:28][N:27]=1>>[CH3:9][C@@H:8]1[CH2:7][CH2:6][CH2:5][N:4]([C:10]([C:12]2[CH:17]=[C:16]([CH3:18])[CH:15]=[CH:14][C:13]=2[C:19]2[CH:20]=[N:21][N:22]([CH3:24])[CH:23]=2)=[O:11])[C@@H:3]1[CH2:2][NH:1][C:26]1[C:31]([CH3:32])=[CH:30][CH:29]=[CH:28][N:27]=1
Reactant: Cc1ccc(-c2cnn(C)c2)c(C(=O)N2CCC[C@@H](C)[C@H]2CN)c1
Reactant: Cc1cccnc1Br
Product: Cc1ccc(-c2cnn(C)c2)c(C(=O)N2CCC[C@@H](C)[C@H]2CNc2ncccc2C)c1

Procedure:
The title compound was prepared following the same general protocol as described for Example A44 using ((2S,3R)-2-(aminomethyl)-3-methylpiperidin-1-yl)(5-methyl-2-(1-methyl-1H-pyrazol-4-yl)phenyl)methanone and 2-bromo-3-methylpyridine. ESI-MS (m/z): 418 [M+1]+.
Reaction SMILES: S(Cl)(Cl)=O.[NH:5]1[C:9]2[CH:10]=[CH:11][C:12]([C:14]([OH:16])=[O:15])=[CH:13][C:8]=2[N:7]=[CH:6]1.[CH3:17]O>>[NH:5]1[C:9]2[CH:10]=[CH:11][C:12]([C:14]([O:16][CH3:17])=[O:15])=[CH:13][C:8]=2[N:7]=[CH:6]1
Reactant: O=C(O)c1ccc2[nH]cnc2c1
Reactant: CO
Solvent: O=S(Cl)Cl
Product: COC(=O)c1ccc2[nH]cnc2c1
Temperature: 0 °C
Yield: 90 %

Procedure:
Thionyl chloride (10 mL) was added dropwise to a solution of 1H-benzo[d]imidazole-5-carboxylic acid (4.8 g, 30 mmol) in MeOH (150 mL) cooled to 0° C. The reaction mixture was heated at reflux for 18 h, and then solvent (about 2/3) was concentrated under reduced pressure. After cooling, a yellow solid was precipitated from the solution and was filtered to afford 4 g (90%) of methyl 1H-benzo[d]imidazole-5-carboxylate (20): MS (ESI) m/z=177 [M+1]+.
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[N:2]1.C=O.[C:12](O)(=[O:14])C>O>[OH:14][CH2:12][N:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[N:2]1
Reactant: c1ccc2[nH]nnc2c1
Reactant: CC(=O)O
Agent: C=O
Solvent: O
Product: OCn1nnc2ccccc21
Yield: 90 %

Procedure:
A mixture of benzotriazole (60 g, 0.5 mole), formalin (40 ml, 40% by volume), acetic acid (50 ml) and water (100 ml) (gave a white color precipitate after few minutes) was allowed to stand for over two hours at room temperature. The product which had precipitated was filtered off, and dried and recrystallized from 1200 ml of hot (80°-85° C.) not boiling water to give 68 g of (90% yield) the desired product; mp 148° C. (lit. 148°-151° C.).
Reaction SMILES: [N+:1]([C:4]1[CH:10]=[CH:9][C:7]([NH2:8])=[CH:6][CH:5]=1)([O-:3])=[O:2].[Cl:11]OC(C)(C)C>C(Cl)Cl>[N+:1]([C:4]1[CH:10]=[CH:9][C:7]([NH:8][Cl:11])=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: CC(C)(C)OCl
Reactant: Nc1ccc([N+](=O)[O-])cc1
Solvent: ClCCl
Product: O=[N+]([O-])c1ccc(NCl)cc1

Procedure:
To a suitable reaction vessel there was added 6.07 g (0.044 mol) of 4-nitroaniline dissolved in 300 ml of methylene chloride. The solution was cooled with vigorous stirring to -65°, giving a suspension of the nitro compound. A solution of 5.75 g (0.055 mol) of t-butyl hypochlorite in 10 ml of methylene chloride was added to form the 4-nitro-N-chloroaniline and subsequently after 3 hr, 7.4 g (0.071 mol) of methylthio-2-propanone in 10 ml of methylene chloride was added, while stirring was continued for 10 hr. to form the azasulfonium chloride salt. The triethylamine, 4.4 g (0.044 mol), dissolved in 10 ml of methylene chloride was added and the solution was warmed to room temperature to form the 2-methyl-3-methylthio-5-nitroindole. A 50-ml portion of water was added and after separation, the organic layer was extracted thoroughly with a 2N aqueous hydrochloric acid. Drying over anhydrous magnesium sulfate and filtration of the organic solution was followed by evaporation, leaving a solid residue that was stirred for several hr with 30 ml of benzene. The remaining precipitate was collected by filtration giving 2.92 g (0.013 mol, 30%) of 2-methyl-3-methylthio-5-nitroindole, mp 197.5°-198.5° (recr. from 95% ethanol); ir (KBr) 3250 cm-1 (NH); pmr (acetone-d6) 1.40 (1H, br, s, NH), 1.02 (1H, d, J=2.0Hz,4-aryl H), 2.02 (1H, dd, J=8.0 and 2.0 Hz, 6-aryl H), 2.57 (1H, d J=9.0 Hz, 7-aryl H) and 7.42 and 7.73 (3H, s, SCH3 and CH3).
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][C:7]([C:11](Cl)=[O:12])=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[F:14][C:15]1[CH:16]=[C:17]2[C:22](=[CH:23][CH:24]=1)[CH:21]=[C:20]([CH2:25][N:26]1[CH2:31][CH2:30][CH:29]([NH:32][C:33]([NH2:35])=[O:34])[CH2:28][CH2:27]1)[CH:19]=[CH:18]2.N1C=CC=CC=1>ClCCCl>[F:14][C:15]1[CH:16]=[C:17]2[C:22](=[CH:23][CH:24]=1)[CH:21]=[C:20]([CH2:25][N:26]1[CH2:27][CH2:28][CH:29]([NH:32][C:33]([NH:35][C:11]([C:7]3[CH:6]=[C:5]4[C:10](=[CH:9][CH:8]=3)[N:1]=[CH:2][CH:3]=[CH:4]4)=[O:12])=[O:34])[CH2:30][CH2:31]1)[CH:19]=[CH:18]2
Reactant: O=C(Cl)c1ccc2ncccc2c1
Reactant: NC(=O)NC1CCN(Cc2ccc3cc(F)ccc3c2)CC1
Solvent: ClCCCl
Solvent: c1ccncc1
Product: O=C(NC(=O)c1ccc2ncccc2c1)NC1CCN(Cc2ccc3cc(F)ccc3c2)CC1

Procedure:
A mixture of 6-quinolinoyl chloride (4.77 g, 22 mmol), N-[[(6-fluoro-2-naphthalenyl)methyl]-4-piperidinyl]urea (6.02 g, 20 mmol), dry pyridine (2.5 ml) and 1,2-dichloroethane (30 ml) is stirred at reflux for 18 hours. The solution is then cooled, washed with aqueous sodium carbonate solution, dried and evaporated. The residue is crystallised from ethanol to give the title compound, mp 200°-201° C. (softens, maleate salt).
Reaction SMILES: C([NH:4][CH2:5][CH2:6][CH2:7][N:8]1[C:12]([SH:13])=[N:11][N:10]=[N:9]1)(=O)C.[ClH:14]>>[ClH:14].[NH2:4][CH2:5][CH2:6][CH2:7][N:8]1[C:12]([SH:13])=[N:11][N:10]=[N:9]1
Reactant: CC(=O)NCCCn1nnnc1S
Agent: Cl
Product: NCCCn1nnnc1S

Procedure:
A mixture of 1-(3-acetamidopropyl)-1H-tetrazole-5-thiol (85 g) and 6 N hydrochloric acid (1 l) was refluxed for 75 minutes under stirring. The reaction mixture was concentrated in vacuo and precipitates were collected by filtration and washed with hexane and diethyl ether to give 1-(3-aminopropyl)-1H-tetrazole-5-thiol hydrochloride (67.15 g).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([OH:8])[C:3]=1[CH3:9].[C:10](=O)([O-])[O-].[K+].[K+].CI>CN(C=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([O:8][CH3:10])[C:3]=1[CH3:9]
Reactant: Cc1c(O)cccc1Cl
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Product: COc1cccc(Cl)c1C
Temperature: 80 °C
Reaction time: 2 h
Yield: 95.4 %

Procedure:
To 100 ml DMF, was dissolved 3-chloro-o-cresol in an amount of 13.6 g (0.095 mole), and the resulting solution was then stirred for 2 hours at 80° C. following to the addition of potassium carbonate in an amount of 14.5 g (0.105 mole) and methyl iodide in an amount of 17.6 g (0.124 mole) into the solution at an ambient temperature. After cooling the mixture, insoluble materials therein were separated by filtration, and the mixture was then poured into water and extracted with ethyl ether. The organic layer obtained was washed with saturated saline solution and dried with anhydrous magnesium sulfate, and the solvent remained in the layer was distillated out to obtain 2-chloro-6-methoxytoluene in an amount of 14.6 g. The yield was 95.4%.
Reaction SMILES: Cl.[CH3:2][NH:3][CH:4]1[CH2:12][C:11]2[C:6](=[CH:7][CH:8]=[C:9]([N+:13]([O-:15])=[O:14])[CH:10]=2)[CH2:5]1.[N+:16]([C:19]1[CH:27]=[CH:26][C:22]([CH2:23][CH2:24]Br)=[CH:21][CH:20]=1)([O-:18])=[O:17].C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[CH3:2][N:3]([CH:4]1[CH2:12][C:11]2[C:6](=[CH:7][CH:8]=[C:9]([N+:13]([O-:15])=[O:14])[CH:10]=2)[CH2:5]1)[CH2:24][CH2:23][C:22]1[CH:21]=[CH:20][C:19]([N+:16]([O-:18])=[O:17])=[CH:27][CH:26]=1
Reactant: CNC1Cc2ccc([N+](=O)[O-])cc2C1
Reactant: O=[N+]([O-])c1ccc(CCBr)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CN(CCc1ccc([N+](=O)[O-])cc1)C1Cc2ccc([N+](=O)[O-])cc2C1

Procedure:
2-Methylamino-5-nitroindane hydrochloride (0.45 g), 4-nitrophenethyl bromide (0.46 g) and potassium carbonate (2 g) were heated under reflux in acetonitrile (30 ml) for 3 days. The reaction mixture was then filtered, the filtrate evaporated in vacuo, and the residue purified by column chromatography on silica eluting with methylene chloride containing methanol (0% up to 1%). The product-containing fractions were combined and evaporated in vacuo to give a gum which was crystallised from ethanol affording the title compound, yield 0.16 g, m.p. 138°-141°.