Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([NH:4][C:5]1[C:18]2[C:17](=[O:19])[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][C:15]=3[O:20][CH3:21])[C:10](=[O:22])[C:9]=2[CH:8]=[CH:7][CH:6]=1)([CH3:3])[CH3:2].[Br:23]Br>Cl>[CH:1]([NH:4][C:5]1[C:18]2[C:17](=[O:19])[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][C:15]=3[O:20][CH3:21])[C:10](=[O:22])[C:9]=2[C:8]([Br:23])=[CH:7][CH:6]=1)([CH3:3])[CH3:2]
Reactant: COc1cccc2c1C(=O)c1c(NC(C)C)cccc1C2=O
Reactant: BrBr
Agent: Cl
Product: COc1cccc2c1C(=O)c1c(NC(C)C)ccc(Br)c1C2=O
Temperature: 25 °C
Reaction time: 18 h

Procedure:
50 g of 1-isopropylamino-8-methoxy-anthraquinone are dissolved in 500 ml of 30% strength hydrochloric acid; 33 g of bromine are added dropwise to the clear solution over the course of 15 minutes at 10°-15° and the mixture is stirred for a further 18 hours at room temperature. It is stirred into 5,000 ml of ice-cold water, excess bromine is removed by means of the amount of bisulphite just required, and the product is filtered off, washed until neutral and dried in vacuo. Yield: 62 g. Bromine content: 21.1%.
Reaction SMILES: [C:1]([O:5][C:6](=[O:19])[N:7]([C:12]1[CH:13]=[N:14][CH:15]=[CH:16][C:17]=1I)[CH2:8][CH2:9][O:10][CH3:11])([CH3:4])([CH3:3])[CH3:2].[Cl:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1B(O)O>CCCCCCC.CCOC(C)=O>[C:1]([O:5][C:6](=[O:19])[N:7]([C:12]1[CH:13]=[N:14][CH:15]=[CH:16][C:17]=1[C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=1[Cl:20])[CH2:8][CH2:9][O:10][CH3:11])([CH3:4])([CH3:3])[CH3:2]
Reactant: OB(O)c1ccccc1Cl
Reactant: COCCN(C(=O)OC(C)(C)C)c1cnccc1I
Solvent: CCCCCCC
Solvent: CCOC(C)=O
Product: COCCN(C(=O)OC(C)(C)C)c1cnccc1-c1ccccc1Cl

Procedure:
The title compound was prepared in analogy to example 72, from (4-iodo-pyridin-3-yl)-(2-methoxy-ethyl)-carbamic acid tert-butyl ester and 2-chlorophenylboronic acid (CAS RN 1679-18-1) and using a gradient of n-heptane:EtOAc (100:0 to 50:50) for the chromatographic purification. Colorless oil (70%). MS (ESI): m/z=363.147 [M+H]+.
Reaction SMILES: Br[C:2]1[CH:17]=[CH:16][C:5]2[N:6]([C:9]3[CH:14]=[CH:13][C:12]([F:15])=[CH:11][CH:10]=3)[N:7]=[N:8][C:4]=2[CH:3]=1.C([Li])CCC.[F:23][C:24]([F:38])([F:37])[C:25]([C:27]1[C:35]2[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=2)[N:29]([CH3:36])[CH:28]=1)=[O:26]>C1COCC1>[F:38][C:24]([F:23])([F:37])[C:25]([C:2]1[CH:17]=[CH:16][C:5]2[N:6]([C:9]3[CH:14]=[CH:13][C:12]([F:15])=[CH:11][CH:10]=3)[N:7]=[N:8][C:4]=2[CH:3]=1)([C:27]1[C:35]2[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=2)[N:29]([CH3:36])[CH:28]=1)[OH:26]
Reactant: Cn1cc(C(=O)C(F)(F)F)c2ccccc21
Reactant: Fc1ccc(-n2nnc3cc(Br)ccc32)cc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: Cn1cc(C(O)(c2ccc3c(c2)nnn3-c2ccc(F)cc2)C(F)(F)F)c2ccccc21
Reaction time: 0.25 h
Yield: 18.2 %

Procedure:
To a chilled (−78° C.) solution of 5-bromo-1-(4-fluorophenyl)-1H-benzotriazole (145 mg, 0.5 mmol) in anhydrous THF (3 mL) was added n-butyllithium (0.25 mL of a 2.5 M solution in hexanes, 0.625 mmol) over a 1 minute period followed by a chilled (−78° C.) solution of 2,2,2-trifluoro-1-(1-methyl-1H-indol-3-yl)ethanone (170 mg, 0.75 mmol) in 1 mL of THF. After 15 minutes, the mixture quenched with brine (50 mL) and extracted with three 50 mL portions of methylene chloride. The combined organic layers were washed with water, dried over anhydrous sodium sulfate and concentrated in vacuo to afford a yellow oil. The residue was purified by column chromatography over silica gel eluting with 0-50% ethyl acetate in hexanes to afford 40 mg of the title compound as a light yellow solid. MS m/z 441 (MH+).
Reaction SMILES: B1(C)OC(C2C=CC=CC=2)(C2C=CC=CC=2)[C@H]2N1CCC2.[Cl:22][CH2:23][CH2:24][C:25]([C:27]1[S:28][CH:29]=[CH:30][CH:31]=1)=[O:26]>C1COCC1>[Cl:22][CH2:23][CH2:24][C@H:25]([C:27]1[S:28][CH:29]=[CH:30][CH:31]=1)[OH:26]
Reactant: O=C(CCCl)c1cccs1
Agent: CB1OC(c2ccccc2)(c2ccccc2)[C@@H]2CCCN12
Solvent: C1CCOC1
Product: O[C@H](CCCl)c1cccs1
Temperature: 25 °C
Reaction time: 1 h
Yield: 83.1 %

Procedure:
Borane dimethylsulfide complex (2.75 mL, 28.6 mmol) was added at room temperature to a stirred solution of (S)-2-methyl-CBS-oxazaborolidine (2.87 mL, 1M) in dry TXF (50 mL). The resulting solution was stirred at room temperature to 10 mins before a solution of 3-chloro-1-(2-thienyl)-1-propanone (2.5 g, 14.3 mmol) in dry THF (100 mL) was added dropwise over 1 hr. After complete addition the resulting solution was stirred at room temperature for a further 1 hr before the solvent was removed in vacuo. The residue was taken up in ether (200 mL) and washed with NH4Cl (sat, 100 mL). The organic phase was dried (MgSO4) and concentrated in vacuo. The residue was purified by flash chromatography eluting silica gel with hexane:ether [7:3] to yield a colourless oil (2.1 g, 84%); Optical purity determined by capillary electrophoresis to be 83% ee; δH (300 MHz, CDCl3) 7.25 (1H, d, Ar), 7.08-6.9 (2H, m, Ar), 5.28-5.20 (1H, m, CHO), 3.80-3.52 (2H, m, CH2), 2.35-2.12 (2H, m, CH2).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][N:5]([CH3:16])[C:6]=1[C:7]1[CH:8]=[C:9]([C:13]([OH:15])=O)[O:10][C:11]=1[CH3:12].[NH2:17][C@@H:18]([CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=1[C:38]([F:41])([F:40])[F:39])[CH2:19][N:20]1[C:28](=[O:29])[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[C:21]1=[O:30].C(N(C(C)C)CC)(C)C.F[P-](F)(F)(F)(F)F.Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[N:4][N:5]([CH3:16])[C:6]=1[C:7]1[CH:8]=[C:9]([C:13]([NH:17][C@@H:18]([CH2:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=2[C:38]([F:41])([F:39])[F:40])[CH2:19][N:20]2[C:28](=[O:29])[C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[C:21]2=[O:30])=[O:15])[O:10][C:11]=1[CH3:12]
Reactant: N[C@@H](Cc1ccccc1C(F)(F)F)CN1C(=O)c2ccccc2C1=O
Reactant: Cc1oc(C(=O)O)cc1-c1c(Cl)cnn1C
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1oc(C(=O)N[C@@H](Cc2ccccc2C(F)(F)F)CN2C(=O)c3ccccc3C2=O)cc1-c1c(Cl)cnn1C
Temperature: 25 °C
Reaction time: 12 h
Yield: 48.2 %

Procedure:
To a solution of 4-(4-chloro-1-methyl-1H-pyrazol-5-yl)-5-methyl-2-furancarboxylic acid (200 mg, 0.83 mmol), 2-{(2S)-2-amino-3-[2-(trifluoromethyl)phenyl]propyl}-1H-isoindole-1,3(2H)-dione (320 mg, 0.83 mmol)[prepared according to Preparation 6] and diisopropylethylamine (0.72 ml, 4.16 mmol) in DCM at 25° C. was added bromo-tris-pyrrolidino-phosphonium hexafluorophosphate (427 mg, 0.91 mmol) in one portion. The solution stirred at 25° C. for 12 h and was then dry loaded onto silica and purified via column chromatography (silica, 30-70% EtOAc in hexanes) yielding 4-(4-chloro-1-methyl-1H-pyrazol-5-yl)-N-((1S)-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-1-{[2-(trifluoromethyl)phenyl]methyl}ethyl)-5-methyl-2-furancarboxamide (246 mg, 0.40 mmol, 49% yield) as a clear oil: LCMS (ES) m/e 571, 573 (M, M+2)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N+:9]([O-:11])=[O:10])=[CH:5][C:4]=1[C:12]1[CH:13]=[C:14]([CH:17]=O)[O:15][CH:16]=1.[CH3:19][N:20]1[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl.CN1CCCC1=O.C(O)(=O)C>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N+:9]([O-:11])=[O:10])=[CH:5][C:4]=1[C:12]1[CH:13]=[C:14]([CH2:17][N:23]2[CH2:24][CH2:25][N:20]([CH3:19])[CH2:21][CH2:22]2)[O:15][CH:16]=1
Reactant: CN1CCNCC1
Reactant: COc1ccc([N+](=O)[O-])cc1-c1coc(C=O)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CN1CCCC1=O
Solvent: CC(=O)O
Product: COc1ccc([N+](=O)[O-])cc1-c1coc(CN2CCN(C)CC2)c1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 18.5 %

Procedure:
A mixture of 4-(2-methoxy-5-nitrophenyl)-2-furaldehyde (230 mg, 0.93 mmol) and N-methylpiperazine (0.90 mL, 8.1 mmol) in 20 mL of dichloromethane and 2 mL of 1-methylpyrolidinone was cooled to 0° C. Sodium triacetoxyborohydride (1.21 g, 5.7 mmol) was added in portions followed by a few drops of acetic acid. The resulting mixture was stirred at 0° C. for 10 minutes then at room temperature for 1.5 hours. The mixture was partitioned between ethyl acetate and saturated aqueous sodium bicarbonate. The organic phase was dried over magnesium sulfate, filtered and concentrated in vacuo. The residue was purified by flash column chromatography eluting with a gradient of 20% methanol in ethyl acetate to 1% ammonium hydroxide in 20% methanol in ethyl acetate. Trituration with diethyl ether and hexane provided 57 mg (18%) of 1-{[4-(2-methoxy-5-nitrophenyl)-2-furyl]methyl}-4-methylpiperazine as a light yellow solid, 1H NMR (DMSO-d6) δ 2.14 (s, 3H), 2.25-2.36 (broad s, 4H), 2.38-2.46 (broad s, 4H), 3.52 (s, 2H), 4.04 (s, 3H), 6.96 (s, 1H), 7.31 (d, J=8 Hz, 1H), 8.14-8.20 (m, 2H), 8.38 (d, J=3 Hz, 1H); MS 332.1 (M+H)+.
Reaction SMILES: P(Cl)(Cl)([Cl:3])=O.[F:6][C:7]1[CH:12]=[C:11]([Cl:13])[C:10]([O:14][CH:15]2[CH2:19][CH2:18][CH2:17][CH2:16]2)=[CH:9][C:8]=1[N:20]1[C:28]2[CH2:27][CH2:26][CH2:25][CH2:24][C:23]=2[C:22](=O)[NH:21]1>[OH-].[Na+]>[Cl:3][C:28]1[N:20]([C:8]2[CH:9]=[C:10]([O:14][CH:15]3[CH2:19][CH2:18][CH2:17][CH2:16]3)[C:11]([Cl:13])=[CH:12][C:7]=2[F:6])[N:21]=[C:22]2[C:27]=1[CH2:26][CH2:25][CH2:24][CH2:23]2
Reactant: O=P(Cl)(Cl)Cl
Reactant: O=c1[nH]n(-c2cc(OC3CCCC3)c(Cl)cc2F)c2c1CCCC2
Agent: [Na+]
Agent: [OH-]
Product: Fc1cc(Cl)c(OC2CCCC2)cc1-n1nc2c(c1Cl)CCCC2
Temperature: 160 °C
Reaction time: 0.5 h
Yield: 26.5 %

Procedure:
Phosphorus oxychloride (6.6 g, 43.0 mmol) was added to the resulting 2N-(2-fluoro-4-chloro-5-cyclopentyloxyphenyl)-1,2,4,5,6,7-hexahydro-3H-indazol-3-one (15.0 g, 42.8 mmol), followed by stirring for 30 minutes while heating at 160° C. After cooling the reaction solution, an ice-cooled dilute aqueous solution of sodium hydroxide (50 ml) was added thereto, and the mixture was extracted with methylene chloride (200 ml×4). The extract was washed with a dilute aqueous sodium hydroxide (400 ml) and a saturated aqueous solution of sodium chloride (400 ml), and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (development solvent: ethyl acetate/hexane=1/9-1/5) to obtain 3-chloro-2N-(2-fluoro-4-chloro-5-cyclopentyloxyphenyl)-4,5,6,7-tetrahydro-2H-indazole as a white solid (4.3 g 26.5% yield).
Reaction SMILES: [NH2:1][CH:2]([C:7]1[CH:12]=[CH:11][C:10]([C:13]#[N:14])=[CH:9][CH:8]=1)[CH2:3][C:4]([OH:6])=[O:5].C(=O)([O-])[O-].[Na+].[Na+].C(N1[C:30](=[O:31])[C:29]2=[CH:32][CH:33]=[CH:34][CH:35]=[C:28]2[C:27]1=[O:36])(OCC)=O>O>[C:27]1(=[O:36])[N:1]([CH:2]([C:7]2[CH:8]=[CH:9][C:10]([C:13]#[N:14])=[CH:11][CH:12]=2)[CH2:3][C:4]([OH:6])=[O:5])[C:30](=[O:31])[C:29]2=[CH:32][CH:33]=[CH:34][CH:35]=[C:28]12
Reactant: N#Cc1ccc(C(N)CC(=O)O)cc1
Reactant: CCOC(=O)N1C(=O)c2ccccc2C1=O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Product: N#Cc1ccc(C(CC(=O)O)N2C(=O)c3ccccc3C2=O)cc1
Reaction time: 2 h
Yield: 23.4 %

Procedure:
To a stirred mixture of 3-amino-3-(4-cyanophenyl)propionic acid (3.80 g, 20.0 mmol) and sodium carbonate (2.23 g, 21 mmol) in 100 mL of water is added N-carboethoxyphthalimide (4.52 g, 20.0 mmol). After 2 hour, the reaction slurry is filtered and the pH of the stirred filtrate adjusted to 1-2 with 4N hydrochloric acid. The resulting gel is extracted with ethyl acetate (3×30 mL). The extract is dried over magnesium sulfate and concentrated in vacuo. The crude product is recrystallized from 10% aqueous acetonitrile and then recrystallized from 20% aqueous methanol. The product is dried in vacuo (60° C., <1 mm) to afford 1.5 g (23%) of 3-phthalimido-3-(4-cyanophenyl)propionic acid as a white powder: mp 134°-137° C.; 1H NMR (DMSO-d6, 250 MHz ) δ 12.5 (br s, 1H), 7.95-7.56 (m, 8 H),.5.76 (t, 1 H, J=7.7), 3.57-3.15 (m, 2 H); 13C NMR (DMSO-d6) δ 171.5, 167.6, 144.2, 134.8, 132.6, 131.1, 128.1, 123.3, 118.5, 49.7, 35.5.
Reaction SMILES: O.[N:2]([CH:5]([C:7]1[S:11][C:10]([C:12]2[CH2:16][C:15]([C:21]3[CH:26]=[C:25]([Cl:27])[CH:24]=[C:23]([Cl:28])[CH:22]=3)([C:17]([F:20])([F:19])[F:18])[O:14][N:13]=2)=[CH:9][C:8]=1[CH3:29])[CH3:6])=[N+]=[N-].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O1CCCC1>[Cl:28][C:23]1[CH:22]=[C:21]([C:15]2([C:17]([F:18])([F:20])[F:19])[O:14][N:13]=[C:12]([C:10]3[S:11][C:7]([CH:5]([NH2:2])[CH3:6])=[C:8]([CH3:29])[CH:9]=3)[CH2:16]2)[CH:26]=[C:25]([Cl:27])[CH:24]=1
Reactant: Cc1cc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)sc1C(C)N=[N+]=[N-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: O
Product: Cc1cc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)sc1C(C)N
Reaction time: 18 h
Yield: 37.7 %

Procedure:
Water (2 ml) is added to a mixture of 3-[5-(1-azido-ethyl)-4-methyl-thiophen-2-yl]-5-(3,5-dichloro-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazole (0.80 g) and triphenylphosphine (0.93 g) in tetrahydrofuran (9 ml). After 18 hours at 50° C., the reaction mixture is concentrated in vacuo. The crude product is purified on a semi-preparative HPLC to yield 1-{5-[5-(3,5-dichloro-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]-3-methyl-thiophen-2-yl}-ethylamine (0.284 g) as an orange solid.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[C:19]([Cl:20])=[CH:18][CH:17]=[CH:16][N:15]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.Cl>CO.CCOC(C)=O>[ClH:20].[Cl:20][C:19]1[C:14]([N:11]2[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]2)=[N:15][CH:16]=[CH:17][CH:18]=1
Reactant: CC(C)(C)OC(=O)N1CCN(c2ncccc2Cl)CC1
Agent: Cl
Solvent: CO
Solvent: CCOC(C)=O
Product: Clc1cccnc1N1CCNCC1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of the ester from step (a) above (2.98 g, 10 mmol) in MeOH (5 mL) was added saturated solution of hydrogen chloride in EtOAc (50 mL) and the mixture was stirred at room temperature for 4 h. The solvent was removed in vacuo, and the residue was washed with EtOAc and dried in the air to provide the title compound as a light-yellow solid. MS (ESI, pos. ion) m/z: 198 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([C:7]([O:13][CH2:14][C:15]3[N:19]4[N:20]=[C:21]([C:24]5[S:32][C:31]6[CH2:30][CH2:29][N:28](C(OC(C)(C)C)=O)[CH2:27][C:26]=6[CH:25]=5)[CH:22]=[CH:23][C:18]4=[N:17][N:16]=3)=[CH:8][CH:9]=[N:10]2)=[CH:5][CH:4]=1.FC(F)(F)C(O)=O>>[CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([C:7]([O:13][CH2:14][C:15]3[N:19]4[N:20]=[C:21]([C:24]5[S:32][C:31]6[CH2:30][CH2:29][NH:28][CH2:27][C:26]=6[CH:25]=5)[CH:22]=[CH:23][C:18]4=[N:17][N:16]=3)=[CH:8][CH:9]=[N:10]2)=[CH:5][CH:4]=1
Reactant: COc1ccc2c(OCc3nnc4ccc(-c5cc6c(s5)CCN(C(=O)OC(C)(C)C)C6)nn34)ccnc2c1
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc2c(OCc3nnc4ccc(-c5cc6c(s5)CCNC6)nn34)ccnc2c1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a solution of tert-butyl 2-(3-((7-methoxyquinolin-4-yloxy)methyl)-[1,2,4]triazolo[4,3-b]pyridazin-6-yl)-6,7-dihydrothieno[3,2-c]pyridine-5(4H)-carboxylate (0.27 g, 0.50 mmol) (prepared according to general method A) was added trifluoroacetic acid (0.77 mL, 10 mmol). The mixture was stirred at room temperature for 90 minutes, then was concentrated, taken up in 2.0 M ammonia in methanol and purified by MPLC (eluted with a gradient of 0 to 10% methanol in dichloromethane) to yield the product as a pink solid. MS m/z=445.0 [M+1]+ Calc'd for C23H20N6O2S: 444.51.
Reaction SMILES: [OH:1][N:2]1[C:6](=[O:7])[C:5]2=[CH:8][CH:9]=[CH:10][CH:11]=[C:4]2[C:3]1=[O:12].[CH2:13](Br)[C:14]#[CH:15].C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>C(O)C>[CH2:15]([O:1][N:2]1[C:3](=[O:12])[C:4]2=[CH:11][CH:10]=[CH:9][CH:8]=[C:5]2[C:6]1=[O:7])[C:14]#[CH:13]
Reactant: C#CCBr
Reactant: O=C1c2ccccc2C(=O)N1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: CN(C)C=O
Product: C#CCON1C(=O)c2ccccc2C1=O
Yield: 63.3 %

Procedure:
A stirred solution of 163.1 grams (1.00 mole) of N-hydroxyphthalimide, 448.0 grams (3.74 moles) of 2-propynyl bromide, 72.0 grams (0.52 mole) of potassium carbonate and 60.0 grams (0.82 mole) of dimethylformamide was heated under reflux for 16 hours. The reaction mixture containing a hardened solid was cooled. The solid was broken up by the addition of ethanol and stirring. The solid was collected by filtration and washed with additional ethanol, then with water until the washings were free of bromide ion when tested with silver ion. The solid was dried in a vacuum desiccator then recrystallized from hot ethanol to give 127.3 grams of N-2-propynoxyphthalimide; mp 146°-148.5°.
Reaction SMILES: [CH3:1][N:2]1[CH2:8][CH2:7][CH2:6][C@:5]2([C:12]3[CH:17]=[CH:16][CH:15]=[C:14]([O:18]C)[CH:13]=3)[CH2:9][CH2:10][CH2:11][C@H:4]2[CH2:3]1.[ClH:20].CN1CCC[C@]2(C3C=CC=C(O)C=3)CCC[C@H]2C1>>[ClH:20].[CH3:1][N:2]1[CH2:8][CH2:7][CH2:6][C@:5]2([C:12]3[CH:17]=[CH:16][CH:15]=[C:14]([OH:18])[CH:13]=3)[CH2:9][CH2:10][CH2:11][C@@H:4]2[CH2:3]1
Reactant: COc1cccc([C@@]23CCC[C@H]2CN(C)CCC3)c1
Agent: CN1CCC[C@]2(c3cccc(O)c3)CCC[C@H]2C1
Agent: Cl
Product: CN1CCC[C@]2(c3cccc(O)c3)CCC[C@@H]2C1

Procedure:
By following the procedure set forth in Example 12, dl-trans-2-methyl-5a-(3-methoxyphenyl)-decahydrocyclopent[c]azepine was converted to dl-trans-2-methyl-5a-(3-hydroxyphenyl)-decahydrocyclopent[c]azepine hydrochloride. M.P. 160°-162° C.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[C:3]([C:10]2[C:19]([N:20]3[CH2:24][CH2:23][CH2:22][C@@H:21]3[CH3:25])=[N:18][C:17]3[C:12](=[CH:13][CH:14]=[C:15]([C:26]([O:28]C)=[O:27])[CH:16]=3)[N:11]=2)=[CH:2]1.[OH-].[Na+]>CO.O>[O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[C:3]([C:10]2[C:19]([N:20]3[CH2:24][CH2:23][CH2:22][C@@H:21]3[CH3:25])=[N:18][C:17]3[C:12](=[CH:13][CH:14]=[C:15]([C:26]([OH:28])=[O:27])[CH:16]=3)[N:11]=2)=[CH:2]1
Reactant: COC(=O)c1ccc2nc(-c3coc4ccccc34)c(N3CCC[C@@H]3C)nc2c1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: C[C@H]1CCCN1c1nc2cc(C(=O)O)ccc2nc1-c1coc2ccccc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 76.6 %

Procedure:
To a solution of methyl 2-(1-benzofuran-3-yl)-3-[(2S)-2-methylpyrrolidin-1-yl]quinoxaline-6-carboxylate (80 mg, 0.21 mmol) in methanol (40 mL) and water (1 mL) was added sodium hydroxide (33 mg, 0.83 mmol) with stirring overnight at room temperature. The resulting mixture was concentrated under vacuum, dissolved in water (50 ml) adjusted to pH 6 with HCl (3N), and collected by filtration to give 2-(1-benzofuran-3-yl)-3-[(2S)-2-methylpyrrolidin-1-yl]quinoxaline-6-carboxylic acid as a yellow solid (60.1 mg, 78%).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[S:10][C:9]([NH2:11])=[N:8][C:7]=1[CH3:12])=[O:5])[CH3:2].C(N(CC)CC)C.[C:20]1([C:26](Cl)([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>CN(C)C=O>[CH2:1]([O:3][C:4]([C:6]1[S:10][C:9]([NH:11][C:26]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)([C:33]2[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=2)[C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)=[N:8][C:7]=1[CH3:12])=[O:5])[CH3:2]
Reactant: CCOC(=O)c1sc(N)nc1C
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCOC(=O)c1sc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)nc1C
Temperature: 2 °C
Reaction time: 48 h
Yield: 99.4 %

Procedure:
A mixture of 2-amino-4-methyl-thiazole-5-carboxylic acid ethyl ester (1.0 g, 5.4 mmol) in N,N-dimethylformamide at 25° C. was treated with triethylamine (1.89 mL, 13.5 mmol) and triphenylmethylchloride (1.66 g, 5.94 mmol). The reaction was stirred at 2° C. for 2 days. At this time, the reaction was concentrated in vauco. The residue was dissolved in dichloromethane (100 mL) and was washed with a 1N aqueous hydrochloric acid solution (1×20 mL), a saturated aqueous sodium bicarbonate solution (1×20 mL), and a saturated aqueous sodium chloride solution (1×20 mL). The organics were dried over magnesium sulfate, filtered, and concentrated in vacuo to afford 4-methyl-2-(trityl-amino)-thiazole-5-carboxylic acid ethyl ester (2.3 g, quant.). The product was used without further purification: LR-MS for C26H24N2O2S (M−H)+ at m/z=427.
Reaction SMILES: [Cl-].[Mg+2].[Cl-].[CH-:4]1[CH:8]=[CH:7][CH:6]=[CH:5]1.[Na+].[CH2:10]([C:17]([C:19]1[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=1)=O)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>C1COCC1>[CH2:10]([C:17]([C:19]1[CH:20]=[CH:21][C:22]([Cl:25])=[CH:23][CH:24]=1)=[C:4]1[CH:8]=[CH:7][CH:6]=[CH:5]1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: c1cc[cH-]c1
Reactant: O=C(Cc1ccccc1)c1ccc(Cl)cc1
Agent: [Cl-]
Agent: [Mg+2]
Agent: [Na+]
Solvent: C1CCOC1
Product: Clc1ccc(C(Cc2ccccc2)=C2C=CC=C2)cc1

Procedure:
Under a nitrogen atmosphere, 2.45 g (25.7 mmol) of anhydrous magnesium chloride and 20 mL of dry THF were put into a 100-mL Schlenk flask and then stirred. To this mixed solution, 10.6 mL (21.2 mmol) of a solution of sodium cyclopentadienide having a concentration of 2.0 mol/L in THF was added. Then, the product was heated and refluxed for an hour, the obtained pink slurry was cooled in an ice bath, and a solution in which 3.5 g (17.8 mmol) of benzyl(p-chlorophenyl)ketone had been dissolved in 15 mL of dry THF was subsequently added thereto. Then, the product was stirred at room temperature for 18 hours, and the obtained orange solution was quenched with dilute aqueous hydrochloric acid. Then, 30 mL of diethyl ether was added thereto, the soluble part in diethyl ether was extracted, and the organic phase was neutralized and washed with an aqueous solution of saturated sodium hydrogen carbonate, water, and a saturated salt solution and then dehydrated with anhydrous magnesium sulfate. The solvent was distilled off, the residue was subsequently purified by silica gel column chromatography to obtain an objective that was a reddish orange solid (amount: 2.7 g), and the objective was directly used in the subsequent process.
Reaction SMILES: ClCC[C:4]1[C:9](=[O:10])[N:8]2[CH:11]=[CH:12][S:13][C:7]2=[N:6][C:5]=1[CH3:14].C(=O)([O-])[O-].[Na+].[Na+].CC(C)CC(=O)C>O>[CH3:14][C:5]1[N:6]=[C:7]2[S:13][CH:12]=[CH:11][N:8]2[C:9](=[O:10])[CH:4]=1
Reactant: Cc1nc2sccn2c(=O)c1CCCl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)CC(C)C
Product: Cc1cc(=O)n2ccsc2n1
Reaction time: 72 h

Procedure:
A mixture of 2.75 g of 6-(2-chloroethyl)-7-methyl-5H-thiazolo[3,2-a]pyrimidin-5-one, 3.1 g of the base of compound (1), 1.6 g of sodium carbonate and 100 ml of 4-methyl-2-pentanone was stirred for 72 hours at reflux temperature. After cooling, water was added and the whole was stirred. The separated aqueous layer was extracted with dichloromethane. The combined organic layers were dried, filtered and evaporated. The residue was purified by column chromatography (silica gel; CH2Cl2 /CH3OH 95:5→CH2Cl2 /CH3OH(NH3) 95:5). The eluent of the desired fraction was evaporated and the residue was crystallized from acetonitrile. The precipitate was filtered off and dried, yielding 1.70 g (32.7%) of 6-[2-[4-(5,6-dihydro-7-methyl-10(7H)-imidazo[1,2-a]-pyrrolo]3,2-d]azepin-10-ylidene)-1-piperidinyl]ethyl]-7-methyl-5H-thiazolo[3,2-a]-pyrimidin-5-one; mp. 201.4° C. (comp. 5).
Reaction SMILES: [Li+].[OH-].C([O:5][C:6]([CH:8]1[C:16]2[C:11](=[CH:12][C:13]([N:17]3[C:21]4=[N:22][CH:23]=[CH:24][CH:25]=[C:20]4[N:19]=[CH:18]3)=[CH:14][CH:15]=2)[CH2:10][CH2:9]1)=[O:7])C.[OH-].[Na+].Cl>C1COCC1.O.CCO>[N:19]1[C:20]2[C:21](=[N:22][CH:23]=[CH:24][CH:25]=2)[N:17]([C:13]2[CH:12]=[C:11]3[C:16](=[CH:15][CH:14]=2)[CH:8]([C:6]([OH:7])=[O:5])[CH2:9][CH2:10]3)[CH:18]=1
Reactant: CCOC(=O)C1CCc2cc(-n3cnc4cccnc43)ccc21
Agent: Cl
Agent: [Li+]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Solvent: CCO
Product: O=C(O)C1CCc2cc(-n3cnc4cccnc43)ccc21
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
1M LiOH (1.8 mL, 1.8 mmol) is added to a solution of (R/S)-5-imidazo[4,5-b]pyridine-3-yl-indan-1-carboxylic acid ethyl ester (550 mg, 1.8 mmol) in THF (2 mL). EtOH (2 mL) is added and after 10 min, 1N NaOH (2.5 mL) is added. The mixture is stirred at rt for 1.5 h and then acidified with 1M HCl. Water is added to the reaction mixture and the compound extracted with EtOAc. The organic layers are combined and washed with brine, dried with MgSO4, filtered and concentrated to give (R/S)-5-imidazo[4,5-b]pyridine-3-yl-indan-1-carboxylic acid as a white solid. Title compound: ES-MS: 280.09 [M+H]+; tR=1.0 min (System 2).