Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([N:8]1[CH2:12][CH2:11][CH:10]([O:13][C:14](=[O:21])[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:9]1)C1C=CC=CC=1.ClC(OC(Cl)C)=O>ClCCl.CO>[C:14]([O:13][C@H:10]1[CH2:11][CH2:12][NH:8][CH2:9]1)(=[O:21])[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: O=C(OC1CCN(Cc2ccccc2)C1)c1ccccc1
Agent: CC(Cl)OC(=O)Cl
Solvent: ClCCl
Solvent: CO
Product: O=C(O[C@H]1CCNC1)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a crude mixture of N-benzyl-3-benzoyloxypyrrolidine (114 mg, 0.41 mmol) in dichloromethane (1 mL) is added α-chloroethyl chloroformate (57 μL, 0.49 mmol) at 0° C., and the mixture is stirred for 1 hour while warming to room temperature. After removing dichloromethane, resulting mixture is diluted with MeOH. The reaction mixture is heated to 80° C. for 0.5 hour. After cooling to room temperature, solvent is evaporated under reduced pressure to obtain (S)-(−)-3-benzoyloxypyrrolidine which is used for next reaction without further purification.
Reaction SMILES: [C:1]([OH:4])(=[O:3])[CH3:2].[CH2:5]([S:7]([C:10]1[CH:11]=[C:12]([C:16]2[CH:24]=[C:23](C(F)(F)F)[C:22](C)=[C:21]3[C:17]=2[C:18]2[CH:33]=[C:32]([CH3:34])[CH:31]=[N:30][C:19]=2[NH:20]3)[CH:13]=[CH:14][CH:15]=1)(=[O:9])=[O:8])[CH3:6]>OS(O)(=O)=O>[CH2:5]([S:7]([C:10]1[CH:11]=[C:12]([C:16]2[CH:24]=[C:2]([C:1]([OH:4])=[O:3])[C:22]([CH3:23])=[C:21]3[C:17]=2[C:18]2[CH:33]=[C:32]([CH3:34])[CH:31]=[N:30][C:19]=2[NH:20]3)[CH:13]=[CH:14][CH:15]=1)(=[O:9])=[O:8])[CH3:6]
Reactant: CCS(=O)(=O)c1cccc(-c2cc(C(F)(F)F)c(C)c3[nH]c4ncc(C)cc4c23)c1
Reactant: CC(=O)O
Agent: O=S(=O)(O)O
Product: CCS(=O)(=O)c1cccc(-c2cc(C(=O)O)c(C)c3[nH]c4ncc(C)cc4c23)c1
Temperature: 120 °C

Procedure:
5-(3-(ethylsulfonyl)phenyl)-3,8-dimethyl-7-(trifluoromethyl)-9H-pyrido[2,3-b]indole acetate (3.6 g, 7.3 mmol) was dissolved in concentrated H2SO4 (30 mL) and heated at 120° C. for 30 min. The reaction was cooled to room temperature and poured over ice affording a white precipitate. The resulting suspension was filtered, rinsed with H2O (3×30 mL) followed by IPA (3×10 mL) and dried in vacuo to 3.2 g (quant.) to give the title compound as a white solid. 1H NMR (400 MHz, DMSO-d6): δ 12.20 (s, 1H), 8.36 (s, 1H), 8.12 (s, 1H), 8.02-8.07 (m, 2H), 7.89 (t, 1H), 7.61 (s, 1H), 7.54 (s, 1H), 3.43 (q, 2H), 2.85 (s, 3H), 2.28 (s, 3H), 1.18 (t, 3H). MS (ES) [m+H] calc'd for C22H20N2O4S, 409; found 409.3.
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]2[C:9]([CH:10]=1)=[CH:8][C:7]([N+:11]([O-])=O)=[CH:6][CH:5]=2.[H][H]>C(O)C.C1COCC1.[Pd]>[NH2:11][C:7]1[CH:8]=[C:9]2[C:4](=[CH:5][CH:6]=1)[NH:3][C:2]([CH3:1])=[CH:10]2
Reactant: Cc1cc2cc([N+](=O)[O-])ccc2[nH]1
Reactant: [H][H]
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CCO
Product: Cc1cc2cc(N)ccc2[nH]1
Yield: 99.6 %

Procedure:
A solution of 2-methyl-5-nitroindole (1 g, 5.7 mmol) in ethanol (25 ml) and THF (25 ml) containg 10% palladium on charcoal (128 mg) was hydrogenated until uptake of hydrogen ceased. The mixture was filtered and the filtrate was evaporated to give 5-amino-2-methylindole (830 mg, quant.).
Reaction SMILES: [BH4-].[K+].[Br:3][C:4]1[CH:13]=[CH:12][C:11]([N+:14]([O-])=O)=[C:10]2[C:5]=1[CH2:6][CH2:7][CH2:8][C:9]2=[O:17]>CO>[NH2:14][C:11]1[CH:12]=[CH:13][C:4]([Br:3])=[C:5]2[C:10]=1[CH:9]([OH:17])[CH2:8][CH2:7][CH2:6]2
Reactant: O=C1CCCc2c(Br)ccc([N+](=O)[O-])c21
Agent: [BH4-]
Agent: [K+]
Solvent: CO
Product: Nc1ccc(Br)c2c1C(O)CCC2
Reaction time: 0.33 h
Yield: 67 %

Procedure:
To prepare this compound, potassium borohydride (0.28 g, 5.2 mmol) was added in portions to a suspension of 5-bromo-3,4-dihydro-8-nitro-2H-naphthalen-1-one (0.20 g, 0.74 mmol) and Cu2Cl2 (0.22 g, 2.2 mmol) in 2 mL anhydrous methanol at room temperature. After 20 minutes, the methanol was evaporated under reduced pressure. The residue was extracted with a mixture of EtOAc and water. The EtOAc layer was washed sequentially with water and brine, dried over sodium sulfate, filtered, and concentrated. Flash chromatography (18% EtOAc/hexanes) afforded 0.12 g (70%) of 8-amino-5-bromo-1,2,3,4-tetrahydronaphthalen-1-ol, a light brown solid. 1H NMR (500 MHz, CDCl3) δ 7.27 (d, J=8.5, 1H), 6.47 (d, J=8.5, 1H), 4.77 (dd, J=4.0, 3.4, 1H), 2.9-4.0 (very broad, 3H), 2.82-2.90 (m, 1H), 2.46-2.56 (m, 1H), 2.00-2.08 (m, 1H), 1.7-1.9 (m, 3H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[CH:9]=[C:8]([S:15]([NH:18][CH:19]1[CH2:23][CH2:22][N:21]([CH:24]([C:34]([N:36]3[CH2:41][CH2:40][CH2:39][CH2:38][CH2:37]3)=[O:35])[CH2:25][C:26]3[CH:31]=[CH:30][C:29]([C:32]#[N:33])=[CH:28][CH:27]=3)[C:20]1=[O:42])(=[O:17])=[O:16])[CH:7]=[CH:6]2.[SH2:43].Cl>C(N(CC)CC)C.N1C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[CH:9]=[C:8]([S:15]([NH:18][CH:19]1[CH2:23][CH2:22][N:21]([CH:24]([C:34]([N:36]3[CH2:37][CH2:38][CH2:39][CH2:40][CH2:41]3)=[O:35])[CH2:25][C:26]3[CH:31]=[CH:30][C:29]([C:32]([NH2:33])=[S:43])=[CH:28][CH:27]=3)[C:20]1=[O:42])(=[O:17])=[O:16])[CH:7]=[CH:6]2
Reactant: S
Reactant: COc1cc2ccc(S(=O)(=O)NC3CCN(C(Cc4ccc(C#N)cc4)C(=O)N4CCCCC4)C3=O)cc2cc1OC
Agent: Cl
Solvent: c1ccncc1
Solvent: CCN(CC)CC
Product: COc1cc2ccc(S(=O)(=O)NC3CCN(C(Cc4ccc(C(N)=S)cc4)C(=O)N4CCCCC4)C3=O)cc2cc1OC
Temperature: 25 °C
Reaction time: 8 h

Procedure:
4.6 g (7.78 mmol) of 3-(6,7-dimethoxynaphthalene-2-sulfonylamino)-1-[2-(4-cyanophenyl)-1-piperidinocarbonylethyl]-2-pyrrolidinone were dissolved in 5 ml of triethylamine and 80 ml of pyridine, and hydrogen sulfide was passed into saturation. The mixture was left to stand overnight and subsequently added dropwise to a mixture of 600 g of ice and 100 ml of concentrated hydrochloric acid. The precipitate was filtered off with suction and dissolved in THF, and the solution was dried over magnesium sulfate and concentrated. The residue was mixed with ether and, after stirring at room temperature for 30 min, the precipitate was filtered off with suction. The slightly impure 3-(6,7-dimethoxynaphthalene-2-sulfonylamino)-1-[2-(4-aminothiocarbonylphenyl)-1-piperidinocarbonylethyl]-2-pyrrolidinone was used without further purification in the next stage.
Reaction SMILES: C1C=C(Cl)C=C(C(OO)=[O:9])C=1.[N:12]1[CH:17]=[CH:16][CH:15]=[C:14]2[CH2:18][N:19]([C:21]([O:23][CH2:24][CH3:25])=[O:22])[CH2:20][C:13]=12.O>C(Cl)Cl>[N+:12]1([O-:9])[CH:17]=[CH:16][CH:15]=[C:14]2[CH2:18][N:19]([C:21]([O:23][CH2:24][CH3:25])=[O:22])[CH2:20][C:13]=12
Reactant: CCOC(=O)N1Cc2cccnc2C1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Solvent: O
Product: CCOC(=O)N1Cc2ccc[n+]([O-])c2C1
Reaction time: 2 h
Yield: 73.9 %

Procedure:
mCPBA (7.3 g, 30 mmol) was added into a solution of ethyl 5H-pyrrolo[3,4-b]pyridine-6(7H)-carboxylate (5 g, 26 mmol) in CH2Cl2 (200 mL) and stirred for 2 hours. The reaction was poured into water and extracted with CH2Cl2. The organic layer was washed with aqueous sodium bisulfate, NaHCO3 and brine, dried with Na2SO4, filtered and concentrated to afford the title compound (4 g, 74% yield) as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([CH2:11]O)[CH:10]=1)[N:7]([CH2:13][CH:14]([CH3:16])[CH3:15])[N:6]=[CH:5]2.[CH3:17][O:18][C:19]([C:21]1[CH:22]=[C:23]2[C:27](=[CH:28][CH:29]=1)[NH:26][N:25]=[CH:24]2)=[O:20]>>[CH3:17][O:18][C:19]([C:21]1[CH:22]=[C:23]2[C:27](=[CH:28][CH:29]=1)[N:26]([CH2:11][C:9]1[CH:10]=[C:2]([F:1])[CH:3]=[C:4]3[C:8]=1[N:7]([CH2:13][CH:14]([CH3:16])[CH3:15])[N:6]=[CH:5]3)[N:25]=[CH:24]2)=[O:20]
Reactant: CC(C)Cn1ncc2cc(F)cc(CO)c21
Reactant: COC(=O)c1ccc2[nH]ncc2c1
Product: COC(=O)c1ccc2c(cnn2Cc2cc(F)cc3cnn(CC(C)C)c23)c1
Yield: 53 %

Procedure:
Compound 27 was prepared following general method 3A, using compound 19 as a starting material and 1H-indazole-5-carboxylic acid methyl ester as the heterocycle. Yield: 53%.
Reaction SMILES: F[C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[C:4]([NH:12][C:13]1[CH:14]=[C:15]3[C:19](=[CH:20][CH:21]=1)[N:18]([CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([F:29])[CH:24]=1)[N:17]=[CH:16]3)=[N:5][CH:6]=[N:7]2.[C:30]([O:35][CH3:36])(=[O:34])[C@@H:31]([CH3:33])[OH:32]>>[F:29][C:25]1[CH:24]=[C:23]([CH:28]=[CH:27][CH:26]=1)[CH2:22][N:18]1[C:19]2[C:15](=[CH:14][C:13]([NH:12][C:4]3[C:3]4[C:8](=[CH:9][CH:10]=[CH:11][C:2]=4[O:32][C@@H:31]([CH3:33])[C:30]([O:35][CH3:36])=[O:34])[N:7]=[CH:6][N:5]=3)=[CH:21][CH:20]=2)[CH:16]=[N:17]1
Reactant: Fc1cccc(Cn2ncc3cc(Nc4ncnc5cccc(F)c45)ccc32)c1
Reactant: COC(=O)[C@@H](C)O
Product: COC(=O)[C@H](C)Oc1cccc2ncnc(Nc3ccc4c(cnn4Cc4cccc(F)c4)c3)c12

Procedure:
The 5-fluoro-N-[1-(3-fluorobenzyl)-1H-indazol-5-yl]quinazolin-4-amine (2.4 g, 6.48 mmol) was reacted as in Example 5 starting material, except that (R)-methyl lactate was used instead of (s)-methyl lactate, to give methyl (2S)-2-[(4-{[1-(3-fluorobenzyl)-1H-indazol-5-yl]amino}quinazolin-5-yl)oxy]propanoate:
Reaction SMILES: [C:1]([C:4]1[C:18]([OH:19])=[CH:17][C:7]([O:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][C:15]#[N:16])=[C:6]([CH2:20]Cl)[CH:5]=1)(=[O:3])[CH3:2].[CH3:22][SH:23].C(N(CC)CC)C>C(Cl)Cl>[C:1]([C:4]1[C:18]([OH:19])=[CH:17][C:7]([O:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][C:15]#[N:16])=[C:6]([CH2:20][S:23][CH3:22])[CH:5]=1)(=[O:3])[CH3:2]
Reactant: CS
Reactant: CC(=O)c1cc(CCl)c(OCCCCCCC#N)cc1O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CSCc1cc(C(C)=O)c(O)cc1OCCCCCCC#N
Temperature: 0 °C
Reaction time: 8 h

Procedure:
A mixture of 600 mg of the compound from Example 127 was dissolved in 50 ml of methylene chloride and cooled to 0° C. Fifteen grams of methanethiol were added followed by the addition of 2 ml of triethylamine. The reaction was allowed to warm to room temperature and was stirred overnight. The reaction mixture was concentrated in vacuo and partitioned between ethyl acetate and an acidic sodium chloride solution. The organic layer was separated, dried over sodium sulfate, and concentrated in vacuo. The residue was purified by preparative thin layer chromatography over silica gel eluting with 40% ethyl acetate in hexane providing 200 mg of the desired title product, m.p.=78° C.
Reaction SMILES: [CH3:1][NH:2][C:3]1[C:8]([NH2:9])=[CH:7][C:6]([C:10]([F:13])([F:12])[F:11])=[CH:5][N:4]=1.[Cl:14][C:15]1[C:20]([C:21](O)=[O:22])=[CH:19][CH:18]=[C:17]([C:24]([F:27])([F:26])[F:25])[N:16]=1.CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1>O.N1C=CC=CC=1>[CH3:1][NH:2][C:3]1[C:8]([NH:9][C:21]([C:20]2[C:15]([Cl:14])=[N:16][C:17]([C:24]([F:27])([F:25])[F:26])=[CH:18][CH:19]=2)=[O:22])=[CH:7][C:6]([C:10]([F:13])([F:11])[F:12])=[CH:5][N:4]=1
Reactant: O=C(O)c1ccc(C(F)(F)F)nc1Cl
Reactant: CNc1ncc(C(F)(F)F)cc1N
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: c1ccncc1
Solvent: O
Product: CNc1ncc(C(F)(F)F)cc1NC(=O)c1ccc(C(F)(F)F)nc1Cl
Temperature: 25 °C
Reaction time: 7 h
Yield: 92.5 %

Procedure:
A mixture of 0.42 g of N2-methyl-5-trifluoromethylpyridine-2,3-diamine, 0.50 g of 2-chloro-6-trifluoromethylpyridine-3-carboxylic acid, 0.64 g of EDCI hydrochloride, 30 mg of HOBt and 2.5 ml of pyridine was stirred at room temperature for 7 hours. Water was poured to the reaction mixture, and the precipitated solid was filtered. The resulting solid was washed with water and n-hexane, and then dried to obtain 0.81 g of 2-chloro-6-trifluoromethylpyridine-3-carboxylic acid (2-methylamino-5-trifluoromethylpyridin-3-yl)-amide. 2-Chloro-6-trifluoromethylpyridine-3-carboxylic acid (2-methylamino-5-trifluoromethylpyridin-3-yl)-amide
Reaction SMILES: FC(F)(F)C([O-])=O.[CH2:8]([O:15][C:16]([NH:18][C@H:19]([C:28]1[NH:29][C:30]([I:33])=[CH:31][NH+:32]=1)[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][C:25]([OH:27])=O)=[O:17])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.CN.[CH3:36][N:37](C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[I:33][C:30]1[NH:29][C:28]([C@@H:19]([NH:18][C:16](=[O:17])[O:15][CH2:8][C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][C:25]([NH:37][CH3:36])=[O:27])=[N:32][CH:31]=1
Reactant: O=C(O)CCCCC[C@H](NC(=O)OCc1ccccc1)c1[nH]c(I)c[nH+]1
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: CN
Agent: F[P-](F)(F)(F)(F)F
Agent: O=C([O-])C(F)(F)F
Solvent: CN(C)C=O
Product: CNC(=O)CCCCC[C@H](NC(=O)OCc1ccccc1)c1ncc(I)[nH]1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a stirred solution of D5 in DMF (0.3 M) was added methylamine (2.0 M solution in THF, 5.0 eq.) followed by HBTU (2.0 eq.). Solution pH was adjusted to basic value by addition of methylamine (2.0 M solution in THF, 2.5 eq.). Reaction mixture was stirred at room temperature for 1 h, then two more addition of HBTU (4.47 g, 28.5 mmol, 1.0 eq.) and methylamine (2.0 M solution in THF, 2.5 eq.) every 30 min were performed to reach completion of reaction. Solvent was concentrated under reduced pressure and the resulting residue was diluted with EtOAc, washed with sat. aq. NaHCO3, Brine, dried over Na2SO4 and concentrated under reduced pressure. The resulting crude was purified by column chromatography (eluent: petroleum ether/EtOAc from 4:1 to EtOAc) to give the title compound as a white solid. 1H-NMR (400 MHz, 300K, CDCl3) δ 12.11 (br s, 1H), 7.69-7.59 (m, 2H), 7.41-7.27 (m, 4H), 7.19 (s, 1H), 5.06 (d, 1H, J 12.8 Hz), 5.00 (d, 1H, J 12.8 Hz), 4.57 (m, 1H), 2.54 (d, 3H, J 4.8 Hz), 2.01 (t, 2H, J 7.4 Hz), 1.85-1.60 (m, 2H), 1.50-1.38 (m, 2H), 1.32-1.12 (m, 4H). MS (ES+) C19H25IN4O3: 485 (M+H)+.
Reaction SMILES: [N:1]1([C:7](=O)[CH2:8][C:9]#[N:10])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:21])=CC=1>C1COCC1>[N:1]1([C:7](=[S:21])[CH2:8][C:9]#[N:10])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1
Reactant: N#CCC(=O)N1CCOCC1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: C1CCOC1
Product: N#CCC(=S)N1CCOCC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 131.2 %

Procedure:
To a solution of 3-morpholin-4-yl-3-oxopropanenitrile (3.0 g, 19.5 mmol) in anhydrous THF (45 mL) was added Lawesson's reagent (4.2 g, 10.3 mmol). The reaction mixture was allowed to stir at rt for 16 h and was then concentrated to small volume. A solid precipitated and was filtered. The solid was washed with diethyl ether to give 3-morpholin-4-yl-3-thioxopropanenitrile (2.3 g, 70%). LCMS: (AA) ES+ 171.2. 1H NMR (400 MHz, d1-chloroform) δ: 4.29-4.27 (m, 2H), 4.00 (s, 2H) and 3.83-3.81 (m, 6H).
Reaction SMILES: [F:1][C:2]([C:5]1[O:9][C:8]([CH2:10][N:11]2[CH:15]=[CH:14][C:13]([NH2:16])=[N:12]2)=[CH:7][CH:6]=1)([F:4])[CH3:3].[CH3:17][O:18][C:19]1[C:24]([O:25][CH3:26])=[CH:23][CH:22]=[CH:21][C:20]=1/[CH:27]=[CH:28]/[C:29](O)=[O:30]>>[F:4][C:2]([C:5]1[O:9][C:8]([CH2:10][N:11]2[CH:15]=[CH:14][C:13]([NH:16][C:29](=[O:30])/[CH:28]=[CH:27]/[C:20]3[CH:21]=[CH:22][CH:23]=[C:24]([O:25][CH3:26])[C:19]=3[O:18][CH3:17])=[N:12]2)=[CH:7][CH:6]=1)([F:1])[CH3:3]
Reactant: CC(F)(F)c1ccc(Cn2ccc(N)n2)o1
Reactant: COc1cccc(/C=C/C(=O)O)c1OC
Product: COc1cccc(/C=C/C(=O)Nc2ccn(Cc3ccc(C(C)(F)F)o3)n2)c1OC

Procedure:
Following general procedure B, starting from 1-[5-(1,1-difluoro-ethyl)-furan-2-ylmethyl]-1H-pyrazol-3-ylamine and (E)-3-(2,3-dimethoxy-phenyl)-acrylic acid. LC-MS-conditions 05b: tR=1.09 min; [M+H]+=418.09.
Reaction SMILES: [OH-].[Na+:2].[O:3]=[C:4]([OH:16])[C@@H:5]([C@H:7]([C@@H:9]([C@@H:11]([C:13]([O-:15])=[O:14])[OH:12])[OH:10])[OH:8])[OH:6].[K+:17]>O>[O:3]=[C:4]([O-:16])[C@@H:5]([C@H:7]([C@@H:9]([C@@H:11]([C:13]([O-:15])=[O:14])[OH:12])[OH:10])[OH:8])[OH:6].[K+:17].[Na+:2]
Reactant: O=C([O-])[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C(=O)O
Agent: [K+]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=C([O-])[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C(=O)[O-]

Procedure:
Aqueous sodium hydroxide solution (33 mL, 6 M) was added to a slurry of monopotassium D-glucarate (50.0 g. 0.201 mol) in water (150 mL) until all of the solid dissolved and a constant pH of 9.7 was reached. The solution was concentrated to a syrup and seeded with the title compound. A solid crystalline cake formed over 24 h. The crystals were isolated by filtration, washed with cold 1:1 ethanol/water (3×15 mL), and dried under reduced pressure to give sodium potassium D-glucarate as colorless crystals (48.2 g, 0.157 mol as the dihydrate, 78.3%).
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[C:12]2[N:11]=[C:10]3[N:13]([C:17]4[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][C:18]=4[C:24]([F:27])([F:26])[F:25])[CH2:14][CH2:15][CH2:16][N:9]3[C:8]=2[C:7]([CH:28]([OH:31])[CH2:29][CH3:30])=[CH:6][CH:5]=1.[CH3:32]I>CN(C)C=O.O>[Cl:3][C:4]1[C:12]2[N:11]=[C:10]3[N:13]([C:17]4[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][C:18]=4[C:24]([F:25])([F:27])[F:26])[CH2:14][CH2:15][CH2:16][N:9]3[C:8]=2[C:7]([CH:28]([O:31][CH3:32])[CH2:29][CH3:30])=[CH:6][CH:5]=1
Reactant: CCC(O)c1ccc(Cl)c2nc3n(c12)CCCN3c1ccc(Cl)cc1C(F)(F)F
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCC(OC)c1ccc(Cl)c2nc3n(c12)CCCN3c1ccc(Cl)cc1C(F)(F)F
Reaction time: 0.08 h
Yield: 78.3 %

Procedure:
Sodium hydride (60% in oil, 40.0 mg, 1.00 mmol) was added to a stirred solution of 1-{9-chloro-1-[4-chloro-2-(trifluoromethyl)phenyl]-1,2,3,4-tetrahydropyrimido[1,2-a]benzimidazol-6-yl}propan-1-ol (370 mg, 0.833 mmol) in N,N-dimethylformamide (3.0 mL) at room temperature. After stirring 5 min, methyl iodide (177 mg, 1.25 mmol) was added to the mixture, and the mixture was stirred at room temperature for 4 hr. The mixture was diluted with water, and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel eluting with a 10-40% ethyl acetate/n-hexane gradient mixture. The filtrate was concentrated in vacuo to give the solid, which was recrystallized from ethyl acetate/diisopropyl ether to give the title compound as a colorless crystal (299 mg, 0.652 mmol, 78%).
Reaction SMILES: Br[C:2]1[C:3]2[S:11][C:10]3[CH:12]=[C:13]([C:16]([F:19])([F:18])[F:17])[CH:14]=[CH:15][C:9]=3[C:4]=2[C:5]([OH:8])=[N:6][CH:7]=1.[C:20]([Cu])#[N:21].Cl>CN(C=O)C.CN1C(=O)CCC1>[OH:8][C:5]1[C:4]2[C:9]3[CH:15]=[CH:14][C:13]([C:16]([F:19])([F:18])[F:17])=[CH:12][C:10]=3[S:11][C:3]=2[C:2]([C:20]#[N:21])=[CH:7][N:6]=1
Reactant: N#C[Cu]
Reactant: Oc1ncc(Br)c2sc3cc(C(F)(F)F)ccc3c12
Agent: Cl
Solvent: CN1CCCC1=O
Solvent: CN(C)C=O
Product: N#Cc1cnc(O)c2c1sc1cc(C(F)(F)F)ccc12
Temperature: 150 °C

Procedure:
A solution of 4-bromo-7-(trifluoromethyl)[1]benzothieno[3,2-c]pyridin-1-ol in a 4:1 mixture of DMF/NMP (0.9 M) in the presence of CuCN (2.5 equiv) was heated in a microwave reactor at 150° C. for 25 min. The reaction was poured into 0.1 N HCl and the title product filtered as a solid.
Reaction SMILES: [CH3:1][N:2]([CH3:6])[C:3](Cl)=[S:4].[CH3:7][C:8]1[C:20]([CH3:21])=[CH:19][CH:18]=[CH:17][C:9]=1[O:10][CH2:11][C:12]1[NH:13][CH2:14][CH2:15][N:16]=1.C(N(CC)CC)C>C(Cl)(Cl)Cl>[CH3:7][C:8]1[C:20]([CH3:21])=[CH:19][CH:18]=[CH:17][C:9]=1[O:10][CH2:11][C:12]1[N:16]([C:3](=[S:4])[N:2]([CH3:6])[CH3:1])[CH2:15][CH2:14][N:13]=1
Reactant: Cc1cccc(OCC2=NCCN2)c1C
Reactant: CN(C)C(=S)Cl
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: Cc1cccc(OCC2=NCCN2C(=S)N(C)C)c1C

Procedure:
A solution of dimethylthiocarbamoyl chloride (2.47 g; 0.020 mole) in chloroform (10 ml) was added dropwise during 10 minutes, to a stirred solution of 2-(2,3-dimethylphenoxymethyl)-2-imidazoline (4.08 g; 0.020 mole) prepared as in Example 1--and triethylamine (2.0 g; 0.20 mole) in chloroform (50 ml) cooling to keep the reaction below 5° C. The reaction temperature was then allowed to rise to room temperature and finally the reaction was refluxed for 5 hours. After cooling the reaction mixture was washed with water, dried and evaporated. The residue was recrystallised from isopropanol to yield white crystals of 2-(2,3-dimethylphenoxymethyl)-1-(N,N-dimethylthiocarbamoyl)-2-imidazoline, m.p. 124°-127° C. Analysis: Calculated C 61.84, H 7.27, N 14.42%. Found: C 62.15, H 7.64, N 14.35%.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH3:20][C:21]([NH:28][S:29]([CH:32]=[CH2:33])(=[O:31])=[O:30])([CH3:27])[CH2:22][C:23]([CH3:26])([CH3:25])[CH3:24].Br[C:35]1[S:36][CH:37]=[CH:38][CH:39]=1.C(N(CC)CC)C>CN(C)C=O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH3:27][C:21]([NH:28][S:29](/[CH:32]=[CH:33]/[C:35]1[S:36][CH:37]=[CH:38][CH:39]=1)(=[O:31])=[O:30])([CH3:20])[CH2:22][C:23]([CH3:24])([CH3:25])[CH3:26]
Reactant: Brc1cccs1
Reactant: C=CS(=O)(=O)NC(C)(C)CC(C)(C)C
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(C)(C)CC(C)(C)NS(=O)(=O)/C=C/c1cccs1
Temperature: 140 °C
Yield: 21.2 %

Procedure:
Palladium acetate (169 mg, 0.75 mmol) and triphenylphosphine (420 mg, 1.6 mmol) were added to a solution of ethenesulfonic acid (1,1,3,3-tetramethyl-butyl)-amide (10 g, 45.7 mmol) and 2-bromo-thiophene (3.74 mL, 39.1 mmol) in N,N-dimethylformamide (75 mL). Triethylamine (14.7 mL, 105.5 mmol) was added and the mixture was flushed with nitrogen and heated at 140° C. for 16 hours. The mixture was cooled to room temperature and 1N HCl (250 mL) was added in one portion. The mixture was extracted with ethyl acetate (3×200 mL) and the combined organics were dried over MgSO4, filtered and concentrated in vacuo to afford a solid. The solid was purified by dry flash chromatography (SiO2, heptane to 1:1 heptane: ethyl acetate). The fractions were combined to afford (E)-2-thiophen-2-yl-ethenesulfonic acid (1,1,3,3-tetramethyl-butyl)-amide (2.5 g, 21% yield).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:8][C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[OH:17])=[O:10])[CH:5]=[CH:6][CH:7]=1.[C:18](OC(=O)C)(=O)[CH3:19].C([O-])(=O)C.[Na+]>>[F:1][C:2]1[CH:3]=[C:4]([C:8]2[C:9](=[O:10])[C:11]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[O:17][C:18]=2[CH3:19])[CH:5]=[CH:6][CH:7]=1
Reactant: CC(=O)OC(C)=O
Reactant: O=C(Cc1cccc(F)c1)c1ccccc1O
Agent: CC(=O)[O-]
Agent: [Na+]
Product: Cc1oc2ccccc2c(=O)c1-c1cccc(F)c1
Temperature: 25 °C
Yield: 68 %

Procedure:
Intermediate 65 (1.50 g, 6.51 mmoles) was taken in a RB flask and to this acetic anhydride (15 ml) and sodium acetate (3.74 g, 45.60 mmoles) were added and the mixture was refluxed for 12 h. After cooling to RT, the reaction mixture was quenched by the addition of ice cold water. The solid formed was filtered and washed with water. The product was dried under vacuum to afford the title compound as colourless solid (1.1 g, 68% yield). 1H-NMR (δ ppm, DMSO-d6, 400 MHz): δ 8.05(dd, J=7.9,1.6 Hz, 1H), 7.83(m,1H), 7.66(d, J=8.1 Hz, 1H), 7.50(m, 2H), 7.24-7.13(m, 3H), 2.29(s, 3H).
Reaction SMILES: [CH3:1][C:2]([CH3:27])([CH3:26])[CH2:3][O:4][C:5]1[C:10]([O:11][CH3:12])=[CH:9][CH:8]=[CH:7][C:6]=1/[CH:13]=[CH:14]/[C:15]1[N:16]=[C:17]2[N:21]([C:22]=1[C:23](O)=[O:24])[CH:20]=[CH:19][S:18]2.[F:28][C:29]([F:37])([F:36])[C:30]1[S:34][C:33]([NH2:35])=[N:32][N:31]=1.CCN=C=NCCCN(C)C.Cl>CN(C1C=CN=CC=1)C.C(Cl)Cl.CN(C=O)C>[CH3:1][C:2]([CH3:27])([CH3:26])[CH2:3][O:4][C:5]1[C:10]([O:11][CH3:12])=[CH:9][CH:8]=[CH:7][C:6]=1/[CH:13]=[CH:14]/[C:15]1[N:16]=[C:17]2[N:21]([C:22]=1[C:23]([NH:35][C:33]1[S:34][C:30]([C:29]([F:37])([F:36])[F:28])=[N:31][N:32]=1)=[O:24])[CH:20]=[CH:19][S:18]2
Reactant: Nc1nnc(C(F)(F)F)s1
Reactant: COc1cccc(/C=C/c2nc3sccn3c2C(=O)O)c1OCC(C)(C)C
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: COc1cccc(/C=C/c2nc3sccn3c2C(=O)Nc2nnc(C(F)(F)F)s2)c1OCC(C)(C)C

Procedure:
The title compound was prepared according to the general procedure (Method B) by coupling Intermediate 3 (150 mg, 0.388 mmol) with 5-(trifluoromethyl)-1,3,4-thiadiazol-2-amine (78 mg, 0.465 mmol) in the presence of EDCI hydrochloride (148 mg, 0.776 mmol) and DMAP (71 mg, 0.582 mmol) in a mixture of DCM and DMF (4:1, 10 mL) to give 80 mg of the product as an off-white solid; 1H NMR (300 MHz, CDCl3) δ 1.02 (s, 9H), 3.56 (s, 2H), 3.83 (s, 3H), 6.79-6.82 (m, 2H), 6.84-6.94 (m, 2H), 7.28 (d, J=16.5 Hz, 1H), 7.66 (d, J=15.9 Hz, 1H), 8.11 (d, J=4.5 Hz, 1H); ESI-MS (m/z) 538.27 (MH)+.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[O:7][C:8]2[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][C:9]=2[CH:10]=1)=[O:5])[CH3:2].[Br:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21]Br>>[CH2:1]([O:3][C:4]([C:6]1[O:7][C:8]2[CH:14]=[CH:13][C:12]([O:15][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][Br:16])=[CH:11][C:9]=2[CH:10]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cc2cc(O)ccc2o1
Reactant: BrCCCCCBr
Product: CCOC(=O)c1cc2cc(OCCCCCBr)ccc2o1
Yield: 73 %

Procedure:
Starting with 2.41 g (11.69 mmol) of 5-hydroxy-2-benzofurancarboxylic acid ethyl ester, and 8.06 g (35.06 mmol) of 1,5-dibromopentane, the title compound (3.03 g; 73%) was obtained as a white solid, mp 31° C., using the procedure of example 21.