Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[C:2]1[C:10]([O:12][CH2:13][CH3:14])=[O:11].[C:15](O)(=[O:33])[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26]CCCCCC.FC(F)(F)C(OC(=O)C(F)(F)F)=O.[OH-].[Na+]>C(Cl)Cl>[C:15]([C:3]1[C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[NH:1][C:2]=1[C:10]([O:12][CH2:13][CH3:14])=[O:11])(=[O:33])[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26]
Reactant: CCCCCCCCCCCCCCCCCC(=O)O
Reactant: CCOC(=O)c1cc2ccccc2[nH]1
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Product: CCCCCCCCCCCC(=O)c1c(C(=O)OCC)[nH]c2ccccc12

Procedure:
A mixture of 3.8 g (20 mmol) of ethyl indole-2-carboxylate, 6.0 g (30 mmol) of octadecanoic acid, 1.0 g of polyphosphoric acid, 20 ml of absol. CH2Cl2 and 4.4 ml of trifluoroacetic anhydride is stirred at room temperature for 4 h. Then 1 M NaOH is added, and the mixture is extracted with ether. The ether phase is dried over Na2SO4 and the solvent is distilled off. The product precipitates after addition of petroleum ether.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:17])[CH2:4][C:5]1[CH:14]=[C:13]([OH:15])[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([F:16])[CH:11]=2)[CH:6]=1.[F:18][B-](F)(F)F.F[B-](F)(F)F.ClC[N+]12CC[N+](F)(CC1)CC2>C(#N)C.O>[CH3:1][O:2][C:3](=[O:17])[CH2:4][C:5]1[CH:14]=[C:13]([OH:15])[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([F:16])[CH:11]=2)[C:6]=1[F:18]
Reactant: COC(=O)Cc1cc(O)c2cc(F)ccc2c1
Reactant: F[B-](F)(F)F
Agent: F[N+]12CC[N+](CCl)(CC1)CC2
Solvent: O
Solvent: CC#N
Product: COC(=O)Cc1cc(O)c2cc(F)ccc2c1F
Temperature: 25 °C
Reaction time: 8 h
Yield: 85.9 %

Procedure:
To a solution of (6-fluoro-4-hydroxy-naphthalen-2-yl)-acetic acid methyl ester (100 mg, 0.277 mmol) in acetonitrile (3 mL) was added 1-chloromethyl-4-fluoro-1,4-diazoniabicyclo[2.2.2]octane bis(tetrafluoroborate) (255 mg, 0.72 mmol) at 0° C. The resulting mixture was stirred at room temperature overnight, and diluted with water, then extracted with ethyl acetate (20 mL×3). The combined organic layers were washed with brine (20 mL×3), dried over sodium sulfate, and concentrated in vacuo. The residue was purified by flash column chromatography (30% ethyl acetate in petroleum ether) to give (1,6-difluoro-4-hydroxy-naphthalen-2-yl)acetic acid methyl ester (60 mg, 86%) as a yellow solid. MS cald. for C13H10F2O3 252, obsd. (ESI+) [(M+H)+] 253.
Reaction SMILES: Br[CH2:2][C:3](=O)/[C:4](=[N:10]/[O:11][C@H:12]1[CH2:17][CH2:16][C@H:15]([CH3:18])[CH2:14][CH2:13]1)/[C:5]([O:7][CH2:8][CH3:9])=[O:6].[NH2:20][C:21]([NH2:23])=[S:22]>>[NH2:23][C:21]1[S:22][CH:2]=[C:3](/[C:4](=[N:10]/[O:11][C@H:12]2[CH2:17][CH2:16][C@H:15]([CH3:18])[CH2:14][CH2:13]2)/[C:5]([O:7][CH2:8][CH3:9])=[O:6])[N:20]=1
Reactant: CCOC(=O)/C(=N\O[C@H]1CC[C@H](C)CC1)C(=O)CBr
Reactant: NC(N)=S
Product: CCOC(=O)/C(=N\O[C@H]1CC[C@H](C)CC1)c1csc(N)n1

Procedure:
Ethyl 4-bromo-(Z)-2-(trans-4-methylcyclohexyloxyimino)-3-oxobutyrate (1.46 g) was treated with thiourea as described in Example 4d. Crystallisation from cyclohexane gave the title compound as a cream solid (0.80 g, 58%), m.p. 133°-5° C. [Found: M+, 311.1300, C14H21N3O3S requires M, 311.13O3 ]. νmax (KBr) 3447, 3119, 2940, 1723, 1616, 1538 cm-1, δH (CDCl3) 0.89 (3H, d), 0.98 (2H, m), 1.36 (6H, t+m), 1.72 (2H, m), 2.11 (2H, m), 4.16 (1H, m), 4.39 (2H, q), 5.44 (2H, s, exch. D2O) 6.68 (1H, s).
Reaction SMILES: [CH3:1][CH:2]([CH2:12][C:13]([O:15]CC)=O)[C@@H:3]([C:5]([O:7][C:8]([CH3:11])([CH3:10])[CH3:9])=[O:6])[NH2:4]>C1(C)C=CC=CC=1>[CH3:1][CH:2]1[CH2:12][C:13](=[O:15])[NH:4][C@@H:3]1[C:5]([O:7][C:8]([CH3:11])([CH3:10])[CH3:9])=[O:6]
Reactant: CCOC(=O)CC(C)[C@H](N)C(=O)OC(C)(C)C
Solvent: Cc1ccccc1
Product: CC1CC(=O)N[C@@H]1C(=O)OC(C)(C)C
Temperature: 110 °C
Yield: 88.1 %

Procedure:
1-(1,1-Dimethylethyl) 5-ethyl 3-methylglutamate (1.1 g, 4.5 mmol) was left to stand, attached to a high vacuum line, overnight and then over a weekend. Starting material was still evident at this stage so toluene (30 ml) was added and the resulting mixture was heated at 110° C. overnight. Evaporation gave 1,1-dimethylethyl 3-methyl-5-oxoprolinate (0.79 g) which was used in the next step without further purification.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[C:10]([CH2:22][O:23][C:24](=[O:32])[C:25]2[CH:30]=[CH:29][C:28]([CH3:31])=[CH:27][CH:26]=2)=[C:11]2[C:16](=[CH:17][CH:18]=1)[NH:15][C:14]([CH3:20])([CH3:19])[CH:13]=[C:12]2[CH3:21]>C(OCC)(=O)C>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:3](=[O:2])[CH2:4][C:9]2[CH:10]=[CH:11][CH:16]=[CH:17][CH:18]=2)=[CH:5][C:4]=1[C:9]1[C:10]([CH2:22][O:23][C:24](=[O:32])[C:25]2[CH:30]=[CH:29][C:28]([CH3:31])=[CH:27][CH:26]=2)=[C:11]2[C:16](=[CH:17][CH:18]=1)[NH:15][C:14]([CH3:20])([CH3:19])[CH:13]=[C:12]2[CH3:21]
Reactant: COc1ccccc1-c1ccc2c(c1COC(=O)c1ccc(C)cc1)C(C)=CC(C)(C)N2
Solvent: CCOC(C)=O
Product: COc1ccc(C(=O)Cc2ccccc2)cc1-c1ccc2c(c1COC(=O)c1ccc(C)cc1)C(C)=CC(C)(C)N2
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 82 %

Procedure:
6-(2-methoxyphenyl)-5-(4-methylbenzoyloxymethyl)-2,2,4-trimethyl-1,2-dihydroquinoline (Compound No. 13-3, 49.7 mg, 0.12 mmol) were added thereto and the reaction mixture was stirred at room temperature for 1.5 hours. Ethyl acetate (100 mL) was added to the reaction mixture, and the whole was washed with water (100 mL) and saturated brine (50 mL) successively, dried over anhydrous magnesium sulfate, and then the solvent was removed under reduced pressure. The residue was purified by silica gel column chromatography (hexane-ethyl acetate) to give the titled compound (53.6 mg) as a pale yellow amorphous product. (Yield 82%)
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:20]=[CH:21][C:22]=1[F:23])[CH2:5][N:6]([O:18][CH3:19])[C:7](=[O:17])[CH:8]=[C:9]1[C:13](=[O:14])[O:12][C:11](C)(C)[O:10]1>CO>[CH3:11][O:12][C:13](=[O:14])[C:9]([OH:10])=[CH:8][C:7](=[O:17])[N:6]([CH2:5][C:4]1[CH:20]=[CH:21][C:22]([F:23])=[C:2]([Cl:1])[CH:3]=1)[O:18][CH3:19]
Reactant: CON(Cc1ccc(F)c(Cl)c1)C(=O)C=C1OC(C)(C)OC1=O
Solvent: CO
Product: COC(=O)C(O)=CC(=O)N(Cc1ccc(F)c(Cl)c1)OC
Yield: 54 %

Procedure:
N-(3-Chloro-4-fluorobenzyl)-2-(2,2-dimethyl-5-oxo-[1,3]-dioxolan-4-ylidene)-N-methoxy-acetamide was treated with methanol as described in the preparation of Compound 44-D and gave the title ester as white crystals (54% yield); mp 97–98° C. 1HNMR 400 MHz (CDCl3) δ (ppm): 3.72 (3H, s, OCH3), 3.90 (3H, s, OCH3), 4.77 (2H, s, NCH2), 6.45 (1H, s, CH), 7.11 (1H, m, aromatic), 7.2 (1H, m, aromatic), 7.38 (1H, m, aromatic). Anal. calcd for C13H13ClFNO5: C, 49.14; H, 4.12; N, 4.40. Found: C, 48.95; H, 3.96; N, 4.16.
Reaction SMILES: [OH:1][C@H:2]1[C@H:7]([O:8][C:9]2[CH:10]=[CH:11][CH:12]=[C:13]3[C:18]=2[N:17]=[C:16]([C:19]2[N:23]4[CH:24]=[CH:25][C:26]([O:28][CH2:29][CH2:30][O:31][CH3:32])=[CH:27][C:22]4=[N:21][CH:20]=2)[CH:15]=[CH:14]3)[CH2:6][CH2:5][N:4]([C:33]([O:35][CH2:36][C:37]2[CH:46]=[CH:45][C:44]3[C:39](=[CH:40][CH:41]=[CH:42][CH:43]=3)[CH:38]=2)=[O:34])[CH2:3]1.[C:47](O)(=[O:54])[C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1>[C:47]([O:1][C@H:2]1[C@@H:7]([O:8][C:9]2[CH:10]=[CH:11][CH:12]=[C:13]3[C:18]=2[N:17]=[C:16]([C:19]2[N:23]4[CH:24]=[CH:25][C:26]([O:28][CH2:29][CH2:30][O:31][CH3:32])=[CH:27][C:22]4=[N:21][CH:20]=2)[CH:15]=[CH:14]3)[CH2:6][CH2:5][N:4]([C:33]([O:35][CH2:36][C:37]2[CH:46]=[CH:45][C:44]3[C:39](=[CH:40][CH:41]=[CH:42][CH:43]=3)[CH:38]=2)=[O:34])[CH2:3]1)(=[O:54])[C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=1
Reactant: COCCOc1ccn2c(-c3ccc4cccc(O[C@@H]5CCN(C(=O)OCc6ccc7ccccc7c6)C[C@H]5O)c4n3)cnc2c1
Reactant: O=C(O)c1ccccc1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COCCOc1ccn2c(-c3ccc4cccc(O[C@H]5CCN(C(=O)OCc6ccc7ccccc7c6)C[C@H]5OC(=O)c5ccccc5)c4n3)cnc2c1
Temperature: 25 °C
Reaction time: 40 h

Procedure:
(trans)-Naphthalen-2-ylmethyl 3-hydroxy-4-(2-(7-(2-methoxyethoxy)imidazo[1,2-a]pyridin-3-yl)quinolin-8-yloxy)piperidine-1-carboxylate (Example 28, Steps A-D; 0.075 g, 0.121 mmol) was dissolved in THF (0.50 mL) and treated with benzoic acid (0.022 g, 0.181 mmol), PPh3 (0.036 g, 0.139 mmol) and diisopropylazodicarboxylate (0.026 ml, 0.133 mmol). The mixture was stirred at ambient temperature for 40 hours, and then the whole reaction mixture was applied to a column of SiO2 and eluted with a gradient from 1-20% (6% NH4OH in MeOH)/ethyl acetate (75 mg). MS ESI (+) m/z 723.2 (M+1) detected.
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][C:6]([N+:9]([O-:11])=[O:10])=[CH:5][C:3]=1[NH2:4].Cl[C:13]1[C:18]([Cl:19])=[CH:17][C:16]([C:20]([F:23])([F:22])[F:21])=[CH:15][N:14]=1>[Cu]>[Cl:19][C:18]1[C:13]([NH:4][C:3]2[CH:5]=[C:6]([N+:9]([O-:11])=[O:10])[CH:7]=[CH:8][C:2]=2[Cl:1])=[N:14][CH:15]=[C:16]([C:20]([F:22])([F:21])[F:23])[CH:17]=1
Reactant: FC(F)(F)c1cnc(Cl)c(Cl)c1
Reactant: Nc1cc([N+](=O)[O-])ccc1Cl
Agent: [Cu]
Product: O=[N+]([O-])c1ccc(Cl)c(Nc2ncc(C(F)(F)F)cc2Cl)c1
Yield: 22.7 %

Procedure:
3.4 g (0.02 mol) of 2-chloro-5-nitroaniline, 8.6 g (0.04 mol) of 2,3-dichloro-5-trifluoromethylpyridine and 400 mg of copper powder are maintained at 230° C. overnight in a small bomb tube (25 ml). After cooling, the crude product is purified by column chromatography (silica gel, petroleum ether:methylene chloride=6:1), affording 1.6 g of N-(3-chloro-5-trifluoromethyl-2-pyridyl)-2-chloro-5-nitroaniline in the form of a yellow powder (m.p. 122°-124° C.).
Reaction SMILES: COC([C:5]([S:29]([CH3:32])(=[O:31])=[O:30])([CH2:16][CH2:17][CH2:18][CH:19]([O:25]C(=O)C)[CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]([O:14]C)=[O:13])=O.[Cl-].[Na+].CS(C)=O.Cl>O>[CH3:32][S:29]([CH:5]([CH2:16][CH2:17][CH2:18][CH:19]([OH:25])[CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]([OH:14])=[O:13])(=[O:30])=[O:31]
Reactant: CCCCCC(CCCC(CCCCCCC(=O)OC)(C(=O)OC)S(C)(=O)=O)OC(C)=O
Agent: Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: CCCCCC(O)CCCC(CCCCCCC(=O)O)S(C)(=O)=O
Temperature: 185 °C
Yield: 110.4 %

Procedure:
A mixture of methyl 8-methoxycarbonyl-8-methylsulfonyl-12-acetoxyheptadecanoate (36.7 g., 0.077 mole), sodium chloride (4.68 g., 0.08 mole), water (1 ml.) and dimethylsulfoxide (60 ml.) is heated in a bath maintained at 185° C. under nitrogen for 5 hours. The resulting reaction mixture is concentrated in vacuo at 100° C. providing an oily residue which is diluted with water. The aqueous mixture is acidified to Congo Red with 6N hydrochloric acid and extracted with ether. The organic extract is washed with water, dried over magnesium sulfate, filtered and evaporated in vacuo leaving the title compound as a viscous oil (31 g., 95%), pmr (CDCl3) δ 2.0 (s, 3H), 2.82 (s, 3H), 3.63 (s, 3H) and 4.9 (b, H).
Reaction SMILES: Cl[C:2]1[C:3]2[CH:10]=[CH:9][N:8]([CH2:11][O:12][CH2:13][CH2:14][Si:15]([CH3:18])([CH3:17])[CH3:16])[C:4]=2[N:5]=[CH:6][N:7]=1.C([Si](C(C)C)(C(C)C)[N:23]1[CH:27]=[CH:26][C:25](B(O)O)=[CH:24]1)(C)C.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.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>[NH:23]1[CH:27]=[CH:26][C:25]([C:2]2[C:3]3[CH:10]=[CH:9][N:8]([CH2:11][O:12][CH2:13][CH2:14][Si:15]([CH3:18])([CH3:17])[CH3:16])[C:4]=3[N:5]=[CH:6][N:7]=2)=[CH:24]1
Reactant: CC(C)[Si](C(C)C)(C(C)C)n1ccc(B(O)O)c1
Reactant: C[Si](C)(C)CCOCn1ccc2c(Cl)ncnc21
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: [Na+]
Solvent: O
Solvent: COCCOC
Product: C[Si](C)(C)CCOCn1ccc2c(-c3cc[nH]c3)ncnc21
Yield: 57.2 %

Procedure:
A mixture of 4-chloro-7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidine (12.9 g, 45.4 mmol) (prepared as in WO 2007/070514, Ex.65) and [1-(triisopropylsilyl)-1H-pyrrol-3-yl]boronic acid (Frontier Scientific) (10.4 g, 38.9 mmol) and sodium carbonate (4.36 g, 41.2 mmol) in 1,2-dimethoxyethane (100 mL) and water (35 mL) was degassed by purging with a stream of nitrogen for 20 minutes. Tetrakis(triphenylphosphine)palladium(0) (2.25 g, 1.94 mmol) was then added and the reaction was heated to reflux for 9 hours. As the coupling reaction proceeded, the TIPS protecting group was also slowly removed. The solvent was removed by rotary evaporation and the product was purified by flash column chromatography, eluting with a gradient from 10-50% ethyl acetate in hexanes to afford the desired product (7 g, 57%).
Reaction SMILES: C1C=C(O[C:8](OC2N=CC=CC=2)=[S:9])N=CC=1.[NH2:17][C:18]1[CH:33]=[CH:32][C:21]2[N:22]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH:23]=[N:24][C:20]=2[C:19]=1[CH3:34]>CN(C)C1C=CN=CC=1.C(Cl)Cl.ClCl>[C:28]([O:27][C:25]([N:22]1[C:21]2[CH:32]=[CH:33][C:18]([N:17]=[C:8]=[S:9])=[C:19]([CH3:34])[C:20]=2[N:24]=[CH:23]1)=[O:26])([CH3:29])([CH3:30])[CH3:31]
Reactant: Cc1c(N)ccc2c1ncn2C(=O)OC(C)(C)C
Reactant: S=C(Oc1ccccn1)Oc1ccccn1
Agent: CN(C)c1ccncc1
Agent: ClCl
Solvent: ClCCl
Product: Cc1c(N=C=S)ccc2c1ncn2C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a solution of di-2-pyridyl thionocarbonate (DPT) (14.3 g) and 4-dimethylaminopyridine (0.1 g) in CH2Cl2 (500 mL) is added dropwise over 30 minutes a solution of 5-amino-1-tert-butoxycarbonyl-4-methylbenzimidazole (7.82 g) in CH2 Cl2 (250 mL). The mixture is stirred for 15 minutes at room temperature then rotary evaporated. The residue is purified by flash chromatography on silica gel, eluting with 10% ethyl acetate/hexane to afford 1-tert-butoxycarbonyl-4-methyl-5-benzimidazolylisothiocyanate as a white solid.
Reaction SMILES: O[CH2:2][CH2:3][CH2:4][O:5][C:6]1[C:11]([CH3:12])=[CH:10][C:9]([C:13]2[NH:22][C:21](=[O:23])[C:20]3[C:15](=[CH:16][C:17]([O:26][CH3:27])=[CH:18][C:19]=3[O:24][CH3:25])[N:14]=2)=[CH:8][C:7]=1[CH3:28].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C(Br)(Br)(Br)[Br:49]>CN(C=O)C>[Br:49][CH2:2][CH2:3][CH2:4][O:5][C:6]1[C:11]([CH3:12])=[CH:10][C:9]([C:13]2[NH:22][C:21](=[O:23])[C:20]3[C:15](=[CH:16][C:17]([O:26][CH3:27])=[CH:18][C:19]=3[O:24][CH3:25])[N:14]=2)=[CH:8][C:7]=1[CH3:28]
Reactant: COc1cc(OC)c2c(=O)[nH]c(-c3cc(C)c(OCCCO)c(C)c3)nc2c1
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Product: COc1cc(OC)c2c(=O)[nH]c(-c3cc(C)c(OCCCBr)c(C)c3)nc2c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 2-[4-(3-hydroxy-propoxy)-3,5-dimethyl-phenyl]-5,7-dimethoxy-3H-quinazolin-4-one (1.39 g, 3.62 mmol) in DMF (15 mL) were added PPh3 (1.04 g, 3.98 mmol) and CBr4 (1.32 g, 3.98 mmol). The reaction mixture was stirred at room temperature for 16 hours. Then, solvent was removed under reduced pressure. The residue was triturated with ether and ethyl acetate. The solids were dried and purified by the Simpliflash system, using 2% methanol in CH2Cl2, to give 2-[4-(3-bromo-propoxy)-3,5-dimethyl-phenyl]-5,7-dimethoxy-3H-quinazolin-4-one as a white solid. Yield: 940 mg (58%).
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:19](Cl)=O)=[N:4][C:5]([N:8]2[CH2:13][CH2:12][N:11]([S:14]([CH2:17][CH3:18])(=[O:16])=[O:15])[CH2:10][CH2:9]2)=[CH:6][N:7]=1.[NH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[SH:29]>C(#N)C>[S:29]1[C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=2[N:22]=[C:19]1[C:3]1[C:2]([NH2:1])=[N:7][CH:6]=[C:5]([N:8]2[CH2:13][CH2:12][N:11]([S:14]([CH2:17][CH3:18])(=[O:16])=[O:15])[CH2:10][CH2:9]2)[N:4]=1
Reactant: Nc1ccccc1S
Reactant: CCS(=O)(=O)N1CCN(c2cnc(N)c(C(=O)Cl)n2)CC1
Solvent: CC#N
Product: CCS(=O)(=O)N1CCN(c2cnc(N)c(-c3nc4ccccc4s3)n2)CC1
Temperature: 70 °C
Yield: 19.1 %

Procedure:
A mixture of 3-amino-6-(4-ethylsulfonylpiperazin-1-yl)pyrazine-2-carbonyl chloride (100 mg, 0.2996 mmol) and 2-aminobenzenethiol (112.5 mg, 96.98 μL, 0.8988 mmol) in acetonitrile was heated at 70° C. overnight. The reaction mixture was allowed to cool to RT, filtered and the resultant residue was purified by reverse phase preparative HPLC [Waters Sunfire C18, 10 uM, 100A column, gradient 10%-95% B (solvent A: 0.05% TFA in water, solvent B: CH3CN) over 16 minutes at 25 mL/min]. The fractions were combined but still contained an impurity. The mixture was therefore purified on silica gel by flash column chromatography (50% EtOAc/Hexanes) to afford the title compound as a bright orange solid (23.2 mg, 20% Yield). 1H NMR (400.0 MHz, DMSO) d 1.24 (3H, t), 3.12 (2H, q), 3.36 masked signal, 3.54 (4H, m), 7.39 (2H, br s), 7.44-7.48 (1H, d), 7.52-7.57 (1H, d), 8.06 (1H, m), 8.11 (1H, m), 8.24 (1H, s) ppm; MS (ES+) 405
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-])=O)=[CH:4][C:3]=1[NH:11][C:12]1[S:13][CH:14]=[C:15]([C:17]2[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=2)[N:16]=1.[H][H]>[Ni].CO>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([NH2:8])=[CH:4][C:3]=1[NH:11][C:12]1[S:13][CH:14]=[C:15]([C:17]2[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=2)[N:16]=1
Reactant: Cc1ccc([N+](=O)[O-])cc1Nc1nc(-c2cccnc2)cs1
Reactant: [H][H]
Agent: [Ni]
Solvent: CO
Product: Cc1ccc(N)cc1Nc1nc(-c2cccnc2)cs1

Procedure:
In a reactor, a mixture of (2-methyl-5-nitro-phenyl)-(4-pyridin-3-yl-thiazol-2-yl)-amine (40 kg, 128.06 mol), Raney Nickel (2.7 kg, 46.00 mol) and methanol (600 L), was warmed to 40-45° C. and hydrogenated under hydrogen pressure (5 kg/cm2) for 2 hours. The reaction mixture was filtered and concentrated. Water was added to the residue under stirring. The product was then filtered and dried in a tray drier at 45-50° C.
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH2:4][NH2:5].[CH3:10][O:11][C:12]1[CH:13]=[C:14]([N:18]=[C:19]=S)[CH:15]=[CH:16][CH:17]=1>>[N:1]1[C:2]2[C:3](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][NH:5][C:19]=1[NH:18][C:14]1[CH:15]=[CH:16][CH:17]=[C:12]([O:11][CH3:10])[CH:13]=1
Reactant: COc1cccc(N=C=S)c1
Reactant: NCc1ccccc1N
Product: COc1cccc(NC2=Nc3ccccc3CN2)c1

Procedure:
The title compound (MS: m/e=254.1 [M+H+]) was prepared in analogy to example 1 from 2-aminobenzylamine and 3-methoxyphenylisothiocyanate.
Reaction SMILES: O[N:2]1[C:23](=[O:24])[NH:22][C@H:21]2[C@@H:3]1[CH2:4][S:5][C@H:6]2[CH2:7][CH2:8][CH2:9][CH:10](N1C(=O)CCC1=O)[C:11](=[O:13])O.[NH2:25][CH2:26][CH2:27][N:28]1[C:40]2[C:39]3[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=3[N:33]=[C:32]([NH2:41])[C:31]=2[N:30]=[CH:29]1>>[NH2:41][C:32]1[C:31]2[N:30]=[CH:29][N:28]([CH2:27][CH2:26][NH:25][C:11](=[O:13])[CH2:10][CH2:9][CH2:8][CH2:7][CH:6]3[CH:21]4[CH:3]([NH:2][C:23](=[O:24])[NH:22]4)[CH2:4][S:5]3)[C:40]=2[C:39]2[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=2[N:33]=1
Reactant: NCCn1cnc2c(N)nc3ccccc3c21
Reactant: O=C(O)C(CCC[C@@H]1SC[C@H]2[C@@H]1NC(=O)N2O)N1C(=O)CCC1=O
Product: Nc1nc2ccccc2c2c1ncn2CCNC(=O)CCCCC1SCC2NC(=O)NC21
Yield: 75.2 %

Procedure:
Using the general method of Example 24, N-hydroxysuccinimidobiotin (0.6 g, 1.76 mmol) was reacted with 1-(2-aminoethyl)-1H-imidazo[4,5-c]quinolin-4-amine (0.4 g, 1.76 mmol) to provide 0.6 g of N1-[2-(4-amino-1H-imidazo[4,5-c]quinolin-1-yl)ethyl]-5-(2-oxoperhydrothieno[3,4-d]imidazol-4-yl)pentanamide as a solid, m.p. 169° C.
Reaction SMILES: [CH:1]1([CH2:5][O:6][C:7]2[CH:15]=[CH:14][C:13]([S:16]([CH3:19])(=[O:18])=[O:17])=[CH:12][C:8]=2[C:9]([OH:11])=O)[CH2:4][CH2:3][CH2:2]1.[N:20]1([C:26]2[S:27][C:28]([C:31]#[N:32])=[CH:29][N:30]=2)[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1>>[CH:1]1([CH2:5][O:6][C:7]2[CH:15]=[CH:14][C:13]([S:16]([CH3:19])(=[O:18])=[O:17])=[CH:12][C:8]=2[C:9]([N:23]2[CH2:24][CH2:25][N:20]([C:26]3[S:27][C:28]([C:31]#[N:32])=[CH:29][N:30]=3)[CH2:21][CH2:22]2)=[O:11])[CH2:2][CH2:3][CH2:4]1
Reactant: N#Cc1cnc(N2CCNCC2)s1
Reactant: CS(=O)(=O)c1ccc(OCC2CCC2)c(C(=O)O)c1
Product: CS(=O)(=O)c1ccc(OCC2CCC2)c(C(=O)N2CCN(c3ncc(C#N)s3)CC2)c1
Yield: 61 %

Procedure:
Prepared in analogy to example 1 (b) from 2-cyclobutylmethoxy-5-methanesulfonyl-benzoic acid (Example A6) and 2-piperazin-1-yl-thiazole-5-carbonitrile (Example 6(a)). The crude material was purified by chromatography (SiO2, ethyl acetate/heptane) followed by trituration in ether to yield the title compound as a white crystalline solid (yield 61%). MS (m/e): 461.3 (M+H+, 100%).
Reaction SMILES: [NH:1]([C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[C@H:2]([C:11]([NH:13][C@@H:14]([C:16]([NH:18][CH2:19][C:20]([NH:22][C@H:23]([C:31]([NH:33]N)=[O:32])[CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=[O:21])=[O:17])[CH3:15])=[O:12])[CH2:3][C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1.Cl.C(N(CC)CC)C.N[C@H:51]([C:56]([OH:58])=[O:57])[CH2:52][CH2:53][S:54][CH3:55].[NH2:59][CH:60]([CH2:63][OH:64])[CH2:61][OH:62]>CN(C=O)C.O1CCOCC1.C(ON=O)(C)(C)C>[NH:1]([C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[C@H:2]([C:11]([NH:13][C@@H:14]([C:16]([NH:18][CH2:19][C:20]([NH:22][C@H:23]([C:31]([NH:33][C@H:51]([C:56]([OH:58])=[O:57])[CH2:52][CH2:53][S:54][CH3:55])=[O:32])[CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=[O:21])=[O:17])[CH3:15])=[O:12])[CH2:3][C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1.[NH2:59][CH:60]([CH2:63][OH:64])[CH2:61][OH:62]
Reactant: CSCC[C@H](N)C(=O)O
Reactant: C[C@@H](NC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)OC(C)(C)C)C(=O)NCC(=O)N[C@@H](Cc1ccccc1)C(=O)NN
Agent: CC(C)(C)ON=O
Agent: Cl
Agent: NC(CO)CO
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: CSCC[C@H](NC(=O)[C@H](Cc1ccccc1)NC(=O)CNC(=O)[C@@H](C)NC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)OC(C)(C)C)C(=O)O
Reaction time: 0.17 h

Procedure:
To 2.5 g of Boc-Tyr-(D)-Ala-Gly-Phe-NHNH2 in 40 ml of DMF are added 2.7 ml of 5.6 N HCl in dioxane and 0.52 ml of tert.butylnitrite at -20° and, after 10 minutes, 3.4 ml of triethylamine and 2 g of H-Met-serinol trifuloroacetate. After 4 hours at 0° and 15 hours at room temperature, the mixture is concentrated under vacuum, the residue taken up in ethyl acetate and washed repeatedly with dilute HCl and water and the organic phase evaporated. The residue crystallizes from methanol/ether to yield the title compound. M.P. 140° (decomp.). [α]D20 =-15 (C=1 in DMF).
Reaction SMILES: [C:1]1([OH:11])[C:10]2[CH2:9][CH2:8][CH2:7][CH2:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.C(NC(C)C)(C)C.[Br:19]N1C(=O)CCC1=O.Cl>ClCCl.CCCCCC.O>[Br:19][C:2]1[CH:3]=[CH:4][C:5]2[CH2:6][CH2:7][CH2:8][CH2:9][C:10]=2[C:1]=1[OH:11]
Reactant: Oc1cccc2c1CCCC2
Reactant: O=C1CCC(=O)N1Br
Agent: Cl
Solvent: ClCCl
Solvent: CC(C)NC(C)C
Solvent: CCCCCC
Product: Oc1c(Br)ccc2c1CCCC2
Temperature: 0 °C
Reaction time: 1 h
Yield: 72.9 %

Procedure:
To a stirred mixture of 5,6,7,8-tetrahydronaphthalen-1-ol (29.2 g, 195 mmol) in dichloromethane (300 mL) was added diisopropylamine (2.75 mL, 19.5 mmol) at room temperature. The reaction mixture was cooled to 0° C., and N-bromosuccinimide (36.62 g, 205 mmol) dissolved in dichloromethane (1.0 L) was added dropwise over 6.5 h. The mixture was then allowed to stir at room temperature for an additional 1 h. At this point 1N HCl was slowly added until the mixture reached pH 1, added H2O (100 mL), separated the dichloromethane solvent layer, dried the organic extracts over anhydrous sodium sulfate, and filtered. Concentrated the filtrate in vacuo at ambient temperature to produce a clear oil, added hexane (1.0 L) to precipitate unreacted N-bromosuccinimide, collected the resulting precipitate and washed with hexane. The filtrate was concentrated in vacuo, and the resultant oil purified by column chromatography on silica gel (elution with 2.5% ethyl acetate/hexane) to afford 32.3 g (73%) of the title compound of 2-bromo-5,6,7,8-tetrahydronaphthalen-1-ol as an off-white solid (MW 227.10, C10H11BrO).