Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[N:23]([CH2:24][O:25][CH2:26][CH2:27][Si:28]([CH3:31])([CH3:30])[CH3:29])[C:22]3[C:21](=[O:32])[N:20]([CH2:33][CH2:34][CH3:35])[C:19](Cl)=[N:18][C:17]=3[N:16]=2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:37][C:38]([F:49])([F:48])[C:39]1[CH:40]=[C:41](B(O)O)[CH:42]=[CH:43][CH:44]=1.C([O-])(O)=O.[Na+]>C1COCC1.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>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[N:23]([CH2:24][O:25][CH2:26][CH2:27][Si:28]([CH3:31])([CH3:30])[CH3:29])[C:22]3[C:21](=[O:32])[N:20]([CH2:33][CH2:34][CH3:35])[C:19]([C:43]4[CH:42]=[CH:41][CH:40]=[C:39]([C:38]([F:49])([F:48])[F:37])[CH:44]=4)=[N:18][C:17]=3[N:16]=2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCCn1c(Cl)nc2nc(-c3ccc(OCc4ccccc4)cc3)n(COCC[Si](C)(C)C)c2c1=O
Reactant: OB(O)c1cccc(C(F)(F)F)c1
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: C1CCOC1
Product: CCCn1c(-c2cccc(C(F)(F)F)c2)nc2nc(-c3ccc(OCc4ccccc4)cc3)n(COCC[Si](C)(C)C)c2c1=O
Temperature: 85 °C
Reaction time: 28 h
Yield: 11.2 %

Procedure:
A mixture of 8-(4-benzyloxy-phenyl)-2-chloro-1-propyl-7-(2-trimethylsilanyl-ethoxymethyl)-1,7-dihydro-purin-6-one (50.0 mg, 0.96 mmol), 3-Trifluoromethyl phenyl boronic acid (31.0 mg, 1.4 mmol) were taken in THF (5 ml) and degassed for 10 minutes. To above degassed solution NaHCO3 (20.0 mg, 0.24 mmol) in water (1 ml) and Pd(PPh3)4 were added and degassed for another 20 minutes. The reaction mixture was stirred for 28 hours at 80-90° C. The mixture was cooled to 25-27° C. and diluted with water (5 ml). The aqueous layer was extracted with DCM (3×5 ml). The organic layer was washed with brine (2×10 ml), dried over Na2SO4, and the solvent was evaporated. The residue obtained was purified by preparative TLC (35% Ethyl acetate in hexane) to obtain pure 8-(4-Benzyloxy-phenyl)-1-propyl-2-(3-trifluoromethyl-phenyl)-7-(2-trimethylsilanyl-ethoxymethyl)-1,7-dihydro-purin-6-one (68 mg, quantitative) as a yellow solid.
Reaction SMILES: [CH3:1][N:2]1[C:14]2[C:5](=[N:6][C:7]3[CH:8]=[CH:9][C:10]([O:15][CH2:16][CH2:17][CH2:18][C:19]([OH:21])=O)=[CH:11][C:12]=3[CH:13]=2)[NH:4][C:3]1=[O:22].[CH:23]1([NH2:29])[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1>>[CH:23]1([NH:29][C:19](=[O:21])[CH2:18][CH2:17][CH2:16][O:15][C:10]2[CH:9]=[CH:8][C:7]3[N:6]=[C:5]4[NH:4][C:3](=[O:22])[N:2]([CH3:1])[C:14]4=[CH:13][C:12]=3[CH:11]=2)[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1
Reactant: NC1CCCCC1
Reactant: Cn1c(=O)[nH]c2nc3ccc(OCCCC(=O)O)cc3cc21
Product: Cn1c(=O)[nH]c2nc3ccc(OCCCC(=O)NC4CCCCC4)cc3cc21

Procedure:
This compound, m.p. 282°-284° C., was prepared analogous to Example 15 from 4-[(2,3-dihydro-1-methyl-2-oxo-1H-imidazo[4,5-b]quinolin-7-yl)oxy]butanoic acid and cyclohexylamine.
Reaction SMILES: C1C=CC=CC=1.[H-].[Na+].[OH:9][CH2:10][C:11]1[S:12][CH:13]=[CH:14][CH:15]=1.Cl[CH2:17][C:18]([OH:20])=[O:19]>O>[S:12]1[CH:13]=[CH:14][CH:15]=[C:11]1[CH2:10][O:9][CH2:17][C:18]([OH:20])=[O:19]
Reactant: OCc1cccs1
Reactant: O=C(O)CCl
Agent: [H-]
Agent: [Na+]
Solvent: c1ccccc1
Solvent: O
Product: O=C(O)COCc1cccs1
Temperature: 25 °C
Reaction time: 3 h
Yield: 66 %

Procedure:
To a stirred benzene suspension of NaH (0.39 g, 32.2 mmol) was added a benzene solution of 2-hydroxymethylthiophene (2.0 g, 15.1 mmol). The reaction was stirred 3 h and a benzene solution (10 mL) of chloroacetic acid (1.56 g, 16.6 mmol) was added. The reaction was heated to reflux for 15 h then cooled to room temperature and a small amount of water was cautiously added. The aqueous layer was diluted, separated, acidified and extracted with methylene chloride (3×50 mL). The combined organic layers were dried over MgSO4. Evaporation afforded thien-2-ylmethoxyacetic acid as a tan oil (66%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH2:9])[CH:5]=[N:6][C:7]=1[CH3:8].CCN(C(C)C)C(C)C.[F:19][C:20]([F:31])([F:30])[C:21]1[CH:22]=[C:23]([CH:27]=[CH:28][CH:29]=1)[C:24](Cl)=[O:25]>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[C:4]([NH:9][C:24](=[O:25])[C:23]2[CH:27]=[CH:28][CH:29]=[C:21]([C:20]([F:19])([F:30])[F:31])[CH:22]=2)[CH:5]=[N:6][C:7]=1[CH3:8]
Reactant: Cc1ncc(N)cc1Br
Reactant: O=C(Cl)c1cccc(C(F)(F)F)c1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ncc(NC(=O)c2cccc(C(F)(F)F)c2)cc1Br
Temperature: 25 °C
Reaction time: 3 h
Yield: 98 %

Procedure:
To a 0.4 M solution of 5-bromo-6-methylpyridin-3-amine (1.00 equiv.) in DCM was added DIEA (1.00 equiv.) and 3-(trifluoromethyl)benzoyl chloride (1.00 equiv.). The mixture was stirred at ambient temperature for 3 hr. The reaction mixture was diluted with DCM, washed with saturated aqueous sodium bicarbonate, dried over sodium sulfate, filtered, and concentrated to give N-(5-bromo-6-methylpyridin-3-yl)-3-(trifluoromethyl)benzamide as an off-white solid in 98% yield. LCMS (m/z) (M+H)=359.0/361.0, Rt=0.86 min.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[C:8]([OH:10])[CH:7]=[CH:6][C:5]=1[OH:11])([O-])=O.[H][H]>C(O)C.[Pd]>[NH2:1][C:4]1[CH:9]=[C:8]([OH:10])[CH:7]=[CH:6][C:5]=1[OH:11]
Reactant: O=[N+]([O-])c1cc(O)ccc1O
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: Nc1cc(O)ccc1O

Procedure:
To a solution of 2-nitrobenzene-1,4-diol (3.00 g, 19.34 mmol) in ethanol (100 mL) was added 10% palladium on carbon (0.600 g, 0.564 mmol). After shaking under 40 psi of hydrogen for 2 hours, the mixture was filtered and the filtrated was concentrated under reduced pressure to provide the product as solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[NH:9][C:10]([NH:12][C:13]1[CH:39]=[CH:38][C:16]([O:17][C:18]2[CH:23]=[CH:22][N:21]=[C:20]([C:24]3[NH:28][CH:27]=[C:26]([C:29]([NH:31][CH2:32][CH2:33][CH2:34][C:35]([OH:37])=O)=[O:30])[CH:25]=3)[CH:19]=2)=[CH:15][CH:14]=1)=[O:11].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C.[NH:73]1[CH2:77][CH2:76][C@@H:75]([OH:78])[CH2:74]1.Cl>CN(C=O)C.O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[NH:9][C:10]([NH:12][C:13]1[CH:39]=[CH:38][C:16]([O:17][C:18]2[CH:23]=[CH:22][N:21]=[C:20]([C:24]3[NH:28][CH:27]=[C:26]([C:29]([NH:31][CH2:32][CH2:33][CH2:34][C:35]([N:73]4[CH2:77][CH2:76][CH:75]([OH:78])[CH2:74]4)=[O:37])=[O:30])[CH:25]=3)[CH:19]=2)=[CH:15][CH:14]=1)=[O:11]
Reactant: Cc1ccc(F)c(NC(=O)Nc2ccc(Oc3ccnc(-c4cc(C(=O)NCCCC(=O)O)c[nH]4)c3)cc2)c1
Reactant: O[C@@H]1CCNC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1ccc(F)c(NC(=O)Nc2ccc(Oc3ccnc(-c4cc(C(=O)NCCCC(=O)N5CCC(O)C5)c[nH]4)c3)cc2)c1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
A mixture of 4-{[(5-{4-[4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]pyridin-2-yl}-1H-pyrrol-3-yl)carbonyl]amino}butanoic acid (60 mg, 0.11 mmol), HATU (50 mg, 0.13 mmol) and N,N-diisopropylethylamine (43 mg, 0.33 mmol) in anhydrous DMF (8 ml) was stirred at room temperature for 10 minutes, followed by addition of (R)-3-pyrrolidinol (14 mg, 0.16 mmol). The mixture was stirred for another 10 minutes and poured into 100 ml of water. 2M HCl was added dropwise until pH=4˜5. The precipitates were filtered, washed with water and dried in vacuo to give 5-{4-[4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]pyridin-2-yl}-N-[4-(3-hydroxypyrrolidin-1-yl)-4-oxobutyl]-1H-pyrrole-3-carboxamide as white solid. Yield: 40 mg, 59%.
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][C:8]2[NH:7][C:6]3[CH2:11][CH2:12][N:13]([C:15]4[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][CH:16]=4)[CH2:14][C:5]=3[C:4]=2[CH:3]=1.[CH3:22][C:23]1[CH:28]=[CH:27][C:26]([CH:29]=[CH2:30])=[CH:25][N:24]=1.[OH-].[K+]>CN1C(=O)CCC1>[CH3:1][C:2]1[CH:10]=[CH:9][C:8]2[N:7]([CH2:30][CH2:29][C:26]3[CH:25]=[N:24][C:23]([CH3:22])=[CH:28][CH:27]=3)[C:6]3[CH2:11][CH2:12][N:13]([C:15]4[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][CH:16]=4)[CH2:14][C:5]=3[C:4]=2[CH:3]=1
Reactant: Cc1ccc2[nH]c3c(c2c1)CN(c1ccc(O)cc1)CC3
Reactant: C=Cc1ccc(C)nc1
Agent: [K+]
Agent: [OH-]
Solvent: CN1CCCC1=O
Product: Cc1ccc2c(c1)c1c(n2CCc2ccc(C)nc2)CCN(c2ccc(O)cc2)C1

Procedure:
The title compound is prepared from a mixture of 4-(3,4-dihydro-8-methyl-1H-pyrido[4,3-b]indol-2(5H)-yl)phenol, 2-methyl-5-vinylpyridine and KOH (5-7 equiv) in NMP at a temperature ranging between 25 deg C. to 100 deg C. The product obtained is isolated by preparative HPLC.
Reaction SMILES: [CH2:1]([NH-:5])[CH2:2][CH2:3][CH3:4].[CH2-]C(C)=[O:8].[CH:10]12[CH2:18][CH:14]([C:15]1([CH3:17])[CH3:16])C[CH2:12][CH:11]2C.F[C:21](F)(F)[C:22]([OH:24])=O>>[CH2:1]([NH-:5])[CH2:2][CH2:3][CH3:4].[C:14]12([OH:8])[CH2:18][CH:10]([C:15]1([CH3:17])[CH3:16])[CH2:11][CH2:12][C:22]2([OH:24])[CH3:21]
Reactant: [CH2-]C(C)=O
Reactant: CC1CCC2CC1C2(C)C
Reactant: O=C(O)C(F)(F)F
Agent: CCCC[NH-]
Product: CC1(O)CCC2CC1(O)C2(C)C

Procedure:
Pinane acetonide butylamide 8 (107 mg, 0.35 mmol) was stirred with a 1:1 mixture of trifluoroacetic acid (TFA)/water (3 ml) at room temperature. The reaction was monitored by TLC and showed about 75% conversion to the cis-diol after 2 hours, then the reaction stalled and the intensity of a new spot between starting material and product started to build up. The unknown byproduct may be formed from fragmentation of the pinane ring in product 9 under the acidic condition. The optimal reaction time was about 3.5 hours. The reaction mixture was neutralized with saturated NaHCO3 solution, and then was extracted 3 times with 50% EtOAc/hex. The combined organic extract was washed with H2O, dried over anhydrous Na2SO4 and concentrated. Residual unreacted starting material 8 and byproduct from the pinanediol butylamide 9 was not removed by silica chromatography. IR (CHCl3): 3455, 3390, 3000, 2960, 2930, 2875, 1647, 1530, 1463, 1385, 1140, 1117, 1054, 1033 and 1018 cm−1.
Reaction SMILES: [OH:1][C:2]1[CH:16]=[CH:15][C:5]2[N:6]=[C:7]([NH:9][C:10]([CH:12]3[CH2:14][CH2:13]3)=[O:11])[S:8][C:4]=2[CH:3]=1.F[C:18]1[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[CH:20][C:19]=1[F:27].C(=O)([O-])[O-].[Cs+].[Cs+].O>CS(C)=O>[F:27][C:19]1[CH:20]=[C:21]([N+:24]([O-:26])=[O:25])[CH:22]=[CH:23][C:18]=1[O:1][C:2]1[CH:16]=[CH:15][C:5]2[N:6]=[C:7]([NH:9][C:10]([CH:12]3[CH2:13][CH2:14]3)=[O:11])[S:8][C:4]=2[CH:3]=1
Reactant: O=[N+]([O-])c1ccc(F)c(F)c1
Reactant: O=C(Nc1nc2ccc(O)cc2s1)C1CC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CS(C)=O
Product: O=C(Nc1nc2ccc(Oc3ccc([N+](=O)[O-])cc3F)cc2s1)C1CC1
Temperature: 50 °C
Reaction time: 5 h
Yield: 65.4 %

Procedure:
A suspension of N-(6-hydroxy-1,3-benzothiazol-2-yl)cyclopropanecarboxamide (1.17 g, 5.00 mmol), 1,2-difluoro-4-nitrobenzene (0.96 g, 6.00 mmol) and cesium carbonate (3.26 g, 10.0 mmol) in dimethyl sulfoxide (10 mL) was stirred at 50° C. for 5 hr. After cooling to room temperature, water was added to the reaction mixture, and the mixture was extracted 3 times with ethyl acetate/tetrahydrofuran. The organic layer was washed with water, dried over anhydrous sodium sulfate and filtered. The solvent was evaporated under reduced pressure, and the residue was washed with ethyl acetate and collected by filtration to give the title compound (1.22 g, 65%) as a pale-yellow solid.
Reaction SMILES: [Br:1][C:2]1[C:3]([OH:13])=[C:4]([C:10](=[O:12])[CH3:11])[CH:5]=[C:6]([Cl:9])[C:7]=1[CH3:8].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O[CH2:34][CH2:35][NH:36][C:37](=[O:43])[O:38][C:39]([CH3:42])([CH3:41])[CH3:40].N(C(OC(C)C)=O)=NC(OC(C)C)=O>C(Cl)Cl.O>[C:10]([C:4]1[C:3]([O:13][CH2:34][CH2:35][NH:36][C:37](=[O:43])[O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[C:2]([Br:1])[C:7]([CH3:8])=[C:6]([Cl:9])[CH:5]=1)(=[O:12])[CH3:11]
Reactant: CC(=O)c1cc(Cl)c(C)c(Br)c1O
Reactant: CC(C)(C)OC(=O)NCCO
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: O
Product: CC(=O)c1cc(Cl)c(C)c(Br)c1OCCNC(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 23 h
Yield: 59.8 %

Procedure:
A suspension of 1-(3-bromo-5-chloro-2-hydroxy-4-methylphenyl)ethanone (8.0 g, 30 mmol) in methylene chloride (304 mL) was heated with a heat gun to dissolve the solids and cooled to 0° C. To the mixture was added triphenylphosphine (11 g, 43 mmol) and tert-butyl (2-hydroxyethyl)carbamate (9.4 mL, 61 mmol). Diisopropyl azodicarboxylate (8.4 mL, 43 mmol) was added dropwise. The mixture was stirred for 23 hours at room temperature. The reaction mixture was poured into water and extracted with methylene chloride. The organic layer was separated, washed with brine, dried with sodium sulfate, filtered, and concentrated. The oil was dissolved in methylene chloride and was purified on silica using ethyl acetate in hexanes (0-25%) to give the desired compound (7.3 g, 59%). LCMS calculated for C16H21BrClNO4Na (M+Na)+: m/z=428.0, 430.0; found: 428.0, 430.0.
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]([C:8]([CH3:10])=[CH2:9])[C:5]([F:11])=[CH:4][CH:3]=1.[OH2:12].C[N+]1([O-])CC[O:17]CC1.S(S([O-])=O)([O-])=O.[Na+].[Na+]>CC(C)=O.O.[Os](=O)(=O)(=O)=O>[Br:1][C:2]1[N:7]=[C:6]([C:8]([OH:17])([CH3:10])[CH2:9][OH:12])[C:5]([F:11])=[CH:4][CH:3]=1
Reactant: C=C(C)c1nc(Br)ccc1F
Reactant: O
Reactant: C[N+]1([O-])CCOCC1
Agent: O=[Os](=O)(=O)=O
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: CC(C)=O
Product: CC(O)(CO)c1nc(Br)ccc1F
Temperature: 25 °C
Reaction time: 44 h
Yield: 91 %

Procedure:
To a solution of 6-bromo-3-fluoro-2-isopropenyl-pyridine (17.35 g, 80 mmol) in acetone (45 ml) and water (90 ml) was added N-methylmorpholine-N-oxide hydrate (11.4 g, 84 mmol) and osmium tetroxide (5.04 ml, 0.402 mmol). The resulting reaction mixture was stirred at room temperature for 44 hours. Sodium dithionite (2 g) in water (70 ml) was added and the reaction mixture was stirred for 15 minutes and was then filtered and concentrated in vacuo. Ethyl acetate was added and the organic layer was washed with brine, dried over sodium sulfate, filtered and evaporated. 18.29 g slightly yellow solid (91% yield). LCMS RtH5=0.64 min (ES+250, 252); 1H-NMR (360 MHz, CDCl3): 7.46 (dd, 1H), 7.35 (dd, 1H), 5.09 (s, 1H, OH), 3.96 (d, 1H), 3.78 (d, 1H), 2.45 (broad, 1H, OH), 1.53 (s, 3H, CH3).
Reaction SMILES: Cl[C:2]1[C:3]2[C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=3[S:18][C:4]=2[N:5]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([O:16][CH3:17])=[O:15])=[CH:10][CH:9]=2)[N:7]=1.[S].N1C2SC3CCCCC=3C=2C=NC=1.P(Cl)(Cl)(Cl)=O.CNC.[Cl:47][C:48]1[CH:49]=[C:50]([CH:53]=[CH:54][C:55]=1[O:56][CH3:57])[CH2:51][NH2:52]>CN1CCCC1=O>[Cl:47][C:48]1[CH:49]=[C:50]([CH:53]=[CH:54][C:55]=1[O:56][CH3:57])[CH2:51][NH:52][C:2]1[C:3]2[C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=3[S:18][C:4]=2[N:5]=[C:6]([C:8]2[CH:9]=[CH:10][C:11]([C:14]([O:16][CH3:17])=[O:15])=[CH:12][CH:13]=2)[N:7]=1
Reactant: COC(=O)c1ccc(-c2nc(Cl)c3c(n2)sc2ccccc23)cc1
Reactant: COc1ccc(CN)cc1Cl
Agent: CNC
Agent: [S]
Agent: c1ncc2c3c(sc2n1)CCCC3
Solvent: O=P(Cl)(Cl)Cl
Solvent: CN1CCCC1=O
Product: COC(=O)c1ccc(-c2nc(NCc3ccc(OC)c(Cl)c3)c3c(n2)sc2ccccc23)cc1
Yield: 125.5 %

Procedure:
A mixture of 1.5 g of methyl 4-(4-chlorobenzothieno[2, 3-d]pyrimidin-2-yl)phenylcarboxylate (“B”), prepared by dehydrogenation of the corresponding 5,6,7,8-tetrahydrobenzothieno[2,3-d]pyrimidine compound with sulfur and subsequent chlorination with phosphorus oxychloride/dimethylamine, and 1.5 g of 3-chloro-4-methoxybenzylamine in 20 ml of N-methylpyrrolidone is heated at 110° for 4 hours. After cooling, the mixture is worked up in the customary manner. 2.6 g of methyl 4-[4-(3-chloro-4-methoxybenzylamino)benzothieno[2,3-d]pyrimidin-2-yl]-benzoate, m.p. 203-204°, are obtained.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3](Cl)=[O:4].[CH3:8][S:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][NH:15][C:16]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[N:19]=[CH:18][C:17]=1[NH2:26]>C1(C)C=CC=CC=1.N1C=CC=CC=1>[F:1][C:2]([F:7])([F:6])[C:3]([NH:26][C:17]1[CH:18]=[N:19][C:20]2[C:25]([C:16]=1[NH:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][S:9][CH3:8])=[CH:24][CH:23]=[CH:22][CH:21]=2)=[O:4]
Reactant: CSCCCCCNc1c(N)cnc2ccccc12
Reactant: O=C(Cl)C(F)(F)F
Solvent: c1ccncc1
Solvent: Cc1ccccc1
Product: CSCCCCCNc1c(NC(=O)C(F)(F)F)cnc2ccccc12
Yield: 153.8 %

Procedure:
A cool solution of trifluoroacetyl chloride (3.5 g, 26.5 mmol) in toluene was slowly added to a solution of N4-[5-(methylthio)pentyl]quinoline-3,4-diamine (6 g, 23.1 mmol) in a mixture of toluene and pyridine. A heavy yellow precipitate formed. The reaction mixture was stirred over the weekend and then concentrated under reduced pressure to provide 13.2 g of crude 2,2,2-trifluoro-N-(4-{[5-(methylthio)pentyl]amino}quinolin-3-yl)acetamide.
Reaction SMILES: [CH2:1](C1C=CC=CC=1N)C.[CH2:10]([C:12]1[CH:17]=[CH:16][C:15]([N+:18]([O-:20])=[O:19])=[CH:14][C:13]=1[OH:21])[CH3:11].C([O-])([O-])=O.[K+].[K+].CI>CC(C)=O.O>[CH2:10]([C:12]1[CH:17]=[CH:16][C:15]([N+:18]([O-:20])=[O:19])=[CH:14][C:13]=1[O:21][CH3:1])[CH3:11]
Reactant: CCc1ccccc1N
Reactant: CCc1ccc([N+](=O)[O-])cc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CC(C)=O
Solvent: O
Product: CCc1ccc([N+](=O)[O-])cc1OC
Temperature: 70 °C

Procedure:
Following published procedures 2-ethyl aniline was nitrated (Bergman, J.; Sand, P. Tetrahedron 1990, 46, 1085) and then converted to 2-ethyl-5-nitrophenol (PCT WO 1995/15954). A mixture of 2-ethyl-5-nitrophenol (0.320 g, 1.92 mmol), K2CO3 (0.200 g, 1.44 mmol) and MeI (0.300 g, 2.11 mmol) in acetone (4.0 mL) was heated at 70° C. for 15 h. The solution was cooled to rt, diluted with H2O, concentrated and extracted with CH2Cl2 (3×30 mL). The combined organic layers were dried over anhydrous Na2SO4 and concentrated under reduced pressure to afford the title compound (0.347 g) as an orange oil which was used in the next step without further purification. HPLC (Method #1): 3.46 min retention time, (75%); LCMS (ES): m/z 182 [M+H]+.
Reaction SMILES: N.[NH2:2][C:3]1([C:8]([NH2:10])=[O:9])[CH2:7][CH2:6][CH2:5][CH2:4]1.[CH:11](=O)[CH2:12][CH2:13][CH2:14][CH3:15].CC(CC(C)=O)C>O>[CH2:12]([CH:11]1[NH:10][C:8](=[O:9])[C:3]2([CH2:7][CH2:6][CH2:5][CH2:4]2)[NH:2]1)[CH2:13][CH2:14][CH3:15]
Reactant: CCCCC=O
Reactant: NC(=O)C1(N)CCCC1
Agent: N
Solvent: CC(=O)CC(C)C
Solvent: O
Product: CCCCC1NC(=O)C2(CCCC2)N1
Temperature: 70 °C
Reaction time: 7 h

Procedure:
Ammonia solution (20%; 20 g, 0.30 mol.) is added to a solution of 126 g of 1-aminocyclopentanecarboxamide (>98%, 0.98 mol.) in 150 g of water. 86 g of valeraldehyde (0.99 mol.) are then added at 15° C., during which the temperature rises to 32° C. The reaction mixture is heated to 70° C. and stirred for 7 hours at that temperature. 350 ml of MIBK are added to the emulsion, and the mixture is cooled, with stirring, and the organic phase is separated off. The extract is extensively concentrated by evaporation (200 g), and 200 g of n-hexane are added, and the crystals are filtered off. After drying there remain 125 g of 2-butyl-1,3-diaza-spiro [4.4]nonan4-one (HPLC: 98.6%).
Reaction SMILES: [Cl:1][C:2]1[C:10]([F:11])=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4](=[O:13])[C:5](=[O:12])[NH:6]2.S(=O)(=O)(O)[OH:15].OO>C(O)(=O)C>[Cl:1][C:2]1[C:10]([F:11])=[CH:9][CH:8]=[C:7]2[NH:6][C:5](=[O:15])[O:12][C:4](=[O:13])[C:3]=12
Reactant: O=C1Nc2ccc(F)c(Cl)c2C1=O
Reactant: O=S(=O)(O)O
Agent: OO
Solvent: CC(=O)O
Product: O=c1[nH]c2ccc(F)c(Cl)c2c(=O)o1

Procedure:
7.8 g (0.039 mol) of 4-chloro-5-fluoro-isatin are suspended in 50 ml of 100 percent acetic acid, treated with 0.25 ml of concentrated sulphuric acid and then 4.4 ml (0.043 mol) of 30 percent hydrogen peroxide are added dropwise thereto. The mixture is subsequently heated to 70° for 2.5 hours, then cooled to 10° and filtered. The crude product is recrystallized from acetone/hexane, there being obtained 6-chloro-5-fluoro-isatoic acid anhydride of melting point 275°-278° (decomposition).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[O:12][CH3:13])[N:8]=[N:7][C:6]([C:14]([NH2:16])=O)=[C:5]2[Cl:17].O=P(Cl)(Cl)Cl.C(N(CC)CC)C.C([O-])(O)=O.[Na+]>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[O:12][CH3:13])[N:8]=[N:7][C:6]([C:14]#[N:16])=[C:5]2[Cl:17]
Reactant: COc1cc2nnc(C(N)=O)c(Cl)c2cc1Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O=P(Cl)(Cl)Cl
Product: COc1cc2nnc(C#N)c(Cl)c2cc1Br
Temperature: 25 °C
Yield: 86.6 %

Procedure:
To a suspension of 6-bromo-4-chloro-7-methoxycinnoline-3-carboxamide (Method 21) (12 g, 37.9 mmol) in DCM (400 ml) was added POCl3 (200 ml). Triethylamine (15 ml) was then added carefully to the mixture which was stirred at reflux for 7 h. The reaction was then allowed to cool to rt and conc. in vacuo. The crude residue was then carefully treated with sat'd aqueous NaHCO3 at 0° C. A precipitate formed which was collected via vacuum filtration. The filter cake washed with water (˜100 mL), collected, and dried in vacuo to provide the title compound as a grey solid (9.80 g, 87%) which was used without further purification. 1H NMR: 8.71 (s, 1H), 8.29 (s, 1H), 4.30 (s, 3H); m/z: 299.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[C:13]3[C:18]([CH:19]=2)=[CH:17][C:16]([CH2:20][N:21]2[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]2)=[CH:15][CH:14]=3)=[C:7]2[C:3]=1[CH2:4][NH:5][C:6]2=[O:34].C(N(CC)CC)C.[Cl:42][C:43]1[CH:44]=[C:45]([S:50](Cl)(=[O:52])=[O:51])[CH:46]=[C:47]([Cl:49])[CH:48]=1>C(#N)C>[Cl:49][C:47]1[CH:46]=[C:45]([S:50]([O:1][C:2]2[CH:10]=[CH:9][C:8]([C:11]3[N:12]([C:27]([O:29][C:30]([CH3:31])([CH3:33])[CH3:32])=[O:28])[C:13]4[C:18]([CH:19]=3)=[CH:17][C:16]([CH2:20][N:21]3[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]3)=[CH:15][CH:14]=4)=[C:7]3[C:3]=2[CH2:4][NH:5][C:6]3=[O:34])(=[O:51])=[O:52])[CH:44]=[C:43]([Cl:42])[CH:48]=1
Reactant: O=S(=O)(Cl)c1cc(Cl)cc(Cl)c1
Reactant: CC(C)(C)OC(=O)n1c(-c2ccc(O)c3c2C(=O)NC3)cc2cc(CN3CCCCC3)ccc21
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)n1c(-c2ccc(OS(=O)(=O)c3cc(Cl)cc(Cl)c3)c3c2C(=O)NC3)cc2cc(CN3CCCCC3)ccc21
Yield: 44 %

Procedure:
In a similar manner to Step 1 of Example 233, 4-hydroxy-7-[1-(tert-butoxycarbonyl)-5-(piperidinomethyl)indol-2-yl]isoindolinone (0.0332 g, 0.0719 mmol) was dissolved in acetonitrile (0.650 mL), and the solution was treated with triethylamine (0.0600 mL, 0.432 mmol) and 3,5-dichlorobenzenesulfonylchloride (0.0530 g, 0.216 mmol) to obtain 4-(3,5-dichlorobenzenesulfonyloxy)-7-[1-(tert-butoxycarbonyl)-5-(piperidinomethyl)indol-2-yl]isoindolinone (0.0212 g, yield 44%).
Reaction SMILES: Cl[C:2]([O:4][CH2:5][CH3:6])=[O:3].[CH:7]([NH2:10])([CH3:9])[CH3:8]>CCOCC>[CH3:8][CH:7]([NH:10][C:2](=[O:3])[O:4][CH2:5][CH3:6])[CH3:9]
Reactant: CC(C)N
Reactant: CCOC(=O)Cl
Solvent: CCOCC
Product: CCOC(=O)NC(C)C

Procedure:
To a solution of ethyl chloroformate (21.7 g, 0.2 mol) in 200 ml ether cooled to 0° C. was added dropwise 35.7 ml of isopropylamine with stirring and cooling. After complete addition of the amine, the reaction mixture was stirred at room temperature for an additional 0.5 hour. The reaction mixture was filtered, and the ether solution was washed with water, and dried over magnesium sulfate. Evaporation of the ether and distillation of the residue in a Kugelrohr apparatus resulted in 22.6 g of the title compound B.p.: 50°-66° C. (bath temperature) at 1.5 mm Hg.