Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([NH:7][C:8](=[O:28])[CH2:9][C:10]2[CH:15]=[C:14]([I:16])[C:13]([O:17][C:18]3[CH:23]=[C:22]([I:24])[C:21]([OH:25])=[C:20]([I:26])[CH:19]=3)=[C:12]([I:27])[CH:11]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C([O-])([O-])=O.[Cs+].[Cs+].[CH2:35]([CH:37]1[O:39][CH2:38]1)Br.CCOC(C)=O>O1CCOCC1>[CH:1]1([NH:7][C:8](=[O:28])[CH2:9][C:10]2[CH:15]=[C:14]([I:16])[C:13]([O:17][C:18]3[CH:23]=[C:22]([I:24])[C:21]([O:25][CH2:35][CH:37]4[CH2:38][O:39]4)=[C:20]([I:26])[CH:19]=3)=[C:12]([I:27])[CH:11]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: BrCC1CO1
Reactant: O=C(Cc1cc(I)c(Oc2cc(I)c(O)c(I)c2)c(I)c1)NC1CCCCC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: O=C(Cc1cc(I)c(Oc2cc(I)c(OCC3CO3)c(I)c2)c(I)c1)NC1CCCCC1
Temperature: 25 °C
Reaction time: 12 h
Yield: 4.8 %

Procedure:
Compound 4 (2.0 g, 2.1 mmol, 1.0 eq.) was dissolved in anhydrous dioxane (30 mL), then anhydrous Cs2CO3 (684 mg, 2.1 mmol, 1.0 eq.) was added and then epibromohydrin (1.8 mL, 21.0 mmol, 10.0 eq.) was added dropwise. The reaction medium was then slowly heated to reflux. The mixture was stirred during 12 hours upon reflux then cooled to room temperature. EtOAc (10 mL) was then poured and the precipitate was filtered. EtOH (20 mL) was then added to the solution and the precipitate was filtered off. The remaining solution was analyzed by TLC. The first precipitate was washed thoroughly with EtOAc (30 mL). The organic solution was then evaporated and purified by column chromatography using silica gel (DCM/hexanes 80/20). The product was further recrystallized to give N-cyclohexyl-2-(4-(3,5-diiodo-4-(oxiran-2-ylmethoxy)phenoxy)-3,5-diiodophenyl)acetamide (93 mg, 0.1 mmol) as a powder. The second filtrate and the remaining solution were revealed by TLC to be the starting material which did not react.
Reaction SMILES: S(O)([O:4][CH2:5][CH2:6][CH2:7][CH3:8])(=O)=O.S([O-])([O:13][CH2:14][CH2:15][CH2:16]C)(=O)=O>>[C:14]([O:4][CH2:5][CH2:6][CH2:7][CH3:8])(=[O:13])[CH:15]=[CH2:16]
Reactant: CCCCOS(=O)(=O)O
Reactant: CCCCOS(=O)(=O)[O-]
Product: C=CC(=O)OCCCC

Procedure:
The process is performed as in Reference Example 1, but arrangement is made for elimination of the butyl hydrogen sulphate by acid hydrolysis of the neutral butyl sulphate contained in the aqueous phase (A1). Experimentally, this reaction was carried out in two ways:
Reaction SMILES: [O:1]1[CH:5]=[CH:4][C:3]([C:6]([OH:8])=O)=[N:2]1.C(N(CC)CC)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH2:40][CH2:41][CH2:42][CH2:43][CH2:44][C:45]1[N:50]=[C:49]2[N:51]([CH3:60])[C:52](=[O:59])[N:53]([CH2:54][C:55]([CH3:58])([CH3:57])[CH3:56])[C:48]2=[CH:47][CH:46]=1>ClCCl>[CH3:56][C:55]([CH3:58])([CH3:57])[CH2:54][N:53]1[C:48]2[C:49](=[N:50][C:45]([CH2:44][CH2:43][CH2:42][CH2:41][NH:40][C:6]([C:3]3[CH:4]=[CH:5][O:1][N:2]=3)=[O:8])=[CH:46][CH:47]=2)[N:51]([CH3:60])[C:52]1=[O:59]
Reactant: Cn1c(=O)n(CC(C)(C)C)c2ccc(CCCCN)nc21
Reactant: O=C(O)c1ccon1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cn1c(=O)n(CC(C)(C)C)c2ccc(CCCCNC(=O)c3ccon3)nc21
Reaction time: 0.33 h

Procedure:
To a stirred solution of 3-isoxazolecarboxylic acid (0.02 g, 0.18 mmol), and triethylamine (0.1 mL, 0.72 mmol) in dichloromethane (2 mL) was added HATU (0.07 g, 0.18 mmol). The resulting mixture was stirred 20 minutes. To this mixture was added 38-2 (0.04 g, 0.14 mmol) and the resulting mixture was stirred room temperature overnight. The mixture was washed with water and concentrated. Flash column separation using a 10-70% ethyl acetate/hexane gradient gave 38-3. (0.045 g, 85%). HRMS (M+H)+: observed=386.2188, calculated=386.2187
Reaction SMILES: [C:1]([C:3]1[CH:15]=[C:14]2[C:6]([C:7]3[C:8](=[O:35])[C:9]4[CH:21]=[CH:20][C:19]([O:22][CH2:23][C:24]([NH:26][CH2:27][CH2:28][O:29]C(=O)C(C)=C)=[O:25])=[CH:18][C:10]=4[C:11]([CH3:17])([CH3:16])[C:12]=3[NH:13]2)=[CH:5][CH:4]=1)#[N:2].[OH-].[K+]>CO.O>[C:1]([C:3]1[CH:15]=[C:14]2[C:6]([C:7]3[C:8](=[O:35])[C:9]4[CH:21]=[CH:20][C:19]([O:22][CH2:23][C:24]([NH:26][CH2:27][CH2:28][OH:29])=[O:25])=[CH:18][C:10]=4[C:11]([CH3:17])([CH3:16])[C:12]=3[NH:13]2)=[CH:5][CH:4]=1)#[N:2]
Reactant: C=C(C)C(=O)OCCNC(=O)COc1ccc2c(c1)C(C)(C)c1[nH]c3cc(C#N)ccc3c1C2=O
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CC1(C)c2cc(OCC(=O)NCCO)ccc2C(=O)c2c1[nH]c1cc(C#N)ccc21
Temperature: 25 °C
Reaction time: 18 h
Yield: 26 %

Procedure:
2-Methyl-acrylic acid 2-[2-(3-cyano-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazol-8-yloxy)-acetylamino]-ethyl ester (Compound A9-13, 40 mg, 0.085 mmol) was dissolved in a mixture solvent of methanol (2 mL) and water (2 mL), added with potassium hydroxide (48 mg, 0.85 mmol), and then stirred at room temperature for 18 hr. After the neutralization with 1 N hydrochloric acid, the reaction solution was concentrated under reduced pressure. The resulting residues were purified by amino silica gel to obtain the title compound (white solid, 8.9 mg, 26%).
Reaction SMILES: C(OC([N:11]1[CH2:17][C@@H:16]2[C@@:13]([NH:19][C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])([CH2:14][C@H:15]2[CH3:18])[CH2:12]1)=O)C1C=CC=CC=1.[H][H]>CO.O1CCCC1.[C].[Pd]>[C:23]([O:22][C:20]([NH:19][C@@:13]12[CH2:14][C@@H:15]([CH3:18])[C@@H:16]1[CH2:17][NH:11][CH2:12]2)=[O:21])([CH3:26])([CH3:24])[CH3:25]
Reactant: [H][H]
Reactant: C[C@@H]1C[C@@]2(NC(=O)OC(C)(C)C)CN(C(=O)OCc3ccccc3)C[C@@H]12
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CO
Product: C[C@@H]1C[C@@]2(NC(=O)OC(C)(C)C)CNC[C@@H]12

Procedure:
(1S,5R,6R)-1-tert-Butoxycarbonylamino-6-methyl-3-azabicyclo[3.2.0]heptane-3-carboxylic acid benzyl ester (1.1 g, 3.1 mmol) was dissolved in a mixed solvent of methanol (20 mL) and tetrahydrofuran (10 mL). A small amount of 10% palladium-carbon (50% wet) was added, and the mixture was stirred in a hydrogen atmosphere for three hours. After removing the catalyst by filtration, the filtrate was concentrated under reduced pressure to give 0.70 g (quantitative) of the title compound as a colorless oil.
Reaction SMILES: [NH2:1][C:2]1[C:7]2[CH2:8][C:9]([CH3:12])([CH3:11])[O:10][C:6]=2[C:5]([C:13]([OH:15])=O)=[CH:4][C:3]=1[Cl:16].ClC(OCC)=O.[NH2:23][CH:24]1[CH2:29][CH2:28][N:27]([C:30]([O:32][CH2:33][CH3:34])=[O:31])[CH2:26][CH:25]1[O:35][CH3:36]>ClC(Cl)Cl.C(N(CC)CC)C>[NH2:1][C:2]1[C:7]2[CH2:8][C:9]([CH3:11])([CH3:12])[O:10][C:6]=2[C:5]([C:13]([NH:23][C@H:24]2[CH2:29][CH2:28][N:27]([C:30]([O:32][CH2:33][CH3:34])=[O:31])[CH2:26][C@H:25]2[O:35][CH3:36])=[O:15])=[CH:4][C:3]=1[Cl:16]
Reactant: CCOC(=O)N1CCC(N)C(OC)C1
Reactant: CC1(C)Cc2c(N)c(Cl)cc(C(=O)O)c2O1
Agent: CCOC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CCOC(=O)N1CC[C@H](NC(=O)c2cc(Cl)c(N)c3c2OC(C)(C)C3)[C@H](OC)C1
Temperature: 10 °C
Reaction time: 0.5 h
Yield: 93.2 %

Procedure:
To a solution of 8.1 parts of 4-amino-5-chloro-2,3-dihydro-2,2-dimethyl-7-benzofurancarboxylic acid in 218 parts of trichloromethane and 3.43 parts of N,N-diethylethanamine were added dropwise 3.63 parts of ethyl chloroformate, keeping the temperature below 10° C. After stirring for 1/2 hour at 10° C., the whole was added to a solution of 6.26 parts of ethyl 4-amino-3-methoxy-1-piperidinecarboxylate in 145 parts of trichloromethane at 10° C. Stirring was continued for 1/2hour at room temperature. The reaction mixture was washed with water, NaOH 5% and water and was then dried, filtered and evaporated. The residue was suspended in 2,2'-oxybispropane. The product was filtered off and dried, yielding 12.3 parts (93.2%) of ethyl cis-4-[(4-amino-5-chloro-2,3-dihydro-2,2-dimethyl-7-benzofuranyl)carbonylamino ]-3-methoxy-1-piperidinecarboxylate (interm. 1).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[OH:8].Br[CH2:10][C@H:11]([CH3:14])[CH2:12][Cl:13]>>[Cl:13][CH2:12][C@@H:11]([CH3:14])[CH2:10][O:8][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[F:1]
Reactant: C[C@H](CCl)CBr
Reactant: Oc1ccccc1F
Product: C[C@H](CCl)COc1ccccc1F

Procedure:
Prepared by Procedure U and Scheme AK using 2-fluorophenol and (2R)-1-bromo-3-chloro-2-methylpropane.
Reaction SMILES: [CH2:1]([N:3]([CH2:6][C:7]1[CH:16]=[C:15]([NH:17][C:18]([CH3:20])=O)[C:14]2[CH2:13][CH2:12][CH2:11][CH2:10][C:9]=2[C:8]=1[OH:21])[CH2:4][CH3:5])[CH3:2].[ClH:22]>C(O)C>[Cl:22][C:8]1[CH:7]=[C:6]2[C:20]([C:18]([NH:17][C:15]3[C:14]4[CH2:13][CH2:12][CH2:11][CH2:10][C:9]=4[C:8]([OH:21])=[C:7]([CH2:6][N:3]([CH2:4][CH3:5])[CH2:1][CH3:2])[CH:16]=3)=[CH:2][CH:1]=[N:3]2)=[CH:14][CH:9]=1
Reactant: Cl
Reactant: CCN(CC)Cc1cc(NC(C)=O)c2c(c1O)CCCC2
Solvent: CCO
Product: CCN(CC)Cc1cc(Nc2ccnc3cc(Cl)ccc23)c2c(c1O)CCCC2
Yield: 90 %

Procedure:
A solution of 2 g of 2-diethylaminomethyl-4-acetamino-5,6,7,8-tetrahydro-I-naphthol, and 50 ml of concentrated hydrochloric acid in 200 ml of absolute ethanol was refluxed for 12 hours. Thereafter the solvent was distilled and the residue treated with ammonium hydroxide then extracted with ether. The etherial extract was washed with water and dried over magnesium sulphate. Then the ether was distilled to reside the amine. From this residual amine 6 g was mixed with 4 g of 4,7-dihchloroquinoline and few drops of conc. HCl in 50 ml of absolute ethanol and refluxed for 12 hours. Thereafter, the reaction mixture was cooled and diluted with water to double its volume then poured over a cold solution of ammonia. The formed precipitate was collected and washed with water. After drying, it weighed 9.2 g (90 % yield) of 4-(7-chloro-4-quinolylamino)-2-diethylaminomethyl-5,6,7,8-tetrahydro-I-naphthol (III). After recrystallization, it melted at 215°-217°C.
Reaction SMILES: [Cl:1][C:2]1[C:7]([S:8](Cl)(=[O:10])=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=1.[CH3:12][O:13][C:14]1[CH:19]=[C:18]([NH2:20])[CH:17]=[C:16]([O:21][CH3:22])[N:15]=1.N1C=CC=CC=1>C(Cl)Cl>[Cl:1][C:2]1[C:7]([S:8]([NH:20][C:18]2[CH:17]=[C:16]([O:21][CH3:22])[N:15]=[C:14]([O:13][CH3:12])[CH:19]=2)(=[O:10])=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=1
Reactant: O=S(=O)(Cl)c1cccnc1Cl
Reactant: COc1cc(N)cc(OC)n1
Solvent: c1ccncc1
Solvent: ClCCl
Product: COc1cc(NS(=O)(=O)c2cccnc2Cl)cc(OC)n1
Yield: 75.6 %

Procedure:
The title compound (623 mg, 1.89 mmol) was prepared from 2-chloropyridine-3-sulfonyl chloride (530 mg, 2.5 mmol), 2,6-dimethoxy-4-pyridinamine (424 mg, 2.8 mmol) and pyridine (0.6 mL, 7.5 mmol) in DCM (10 mL) using the methods of (IntC1).
Reaction SMILES: Br[C:2]1[S:6][C:5]([C:7](=[O:12])[C:8]([F:11])([F:10])[F:9])=[CH:4][CH:3]=1.B([C:16]1[CH:17]=[N:18][CH:19]=[C:20]([CH:24]=1)[C:21]([OH:23])=[O:22])(O)O>>[F:9][C:8]([F:11])([F:10])[C:7]([C:5]1[S:6][C:2]([C:16]2[CH:17]=[N:18][CH:19]=[C:20]([CH:24]=2)[C:21]([OH:23])=[O:22])=[CH:3][CH:4]=1)=[O:12]
Reactant: O=C(O)c1cncc(B(O)O)c1
Reactant: O=C(c1ccc(Br)s1)C(F)(F)F
Product: O=C(O)c1cncc(-c2ccc(C(=O)C(F)(F)F)s2)c1
Yield: 82 %

Procedure:
This compound was synthesized from 1-(5-bromothiophen-2-yl)-2,2,2-trifluoroethanone and 5-borononicotinic acid as described in example 88 step 3 (470 mg, yield 82%). 1H NMR (300 MHz, DMSO-d6) δ 13.74 (br s, 1H), 9.30-9.29 (s, 1H), 9.11-9.10 (m, 1H), 8.59-8.58 (t, J=2.0 Hz, 1H), 8.20-8.19 (m, 1H), 8.07-8.05 (m, 1H).
Reaction SMILES: C([O:5][C:6](=[O:16])[C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([C:13](=[NH:15])[NH2:14])[CH:8]=1)(C)(C)C.CN([CH:20]=[CH:21][C:22]([C:24]1[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=1)=O)C.[H-].[Na+]>C(O)C>[F:30][C:27]1[CH:28]=[CH:29][C:24]([C:22]2[CH:21]=[CH:20][N:14]=[C:13]([C:9]3[CH:8]=[C:7]([CH:12]=[CH:11][CH:10]=3)[C:6]([OH:5])=[O:16])[N:15]=2)=[CH:25][CH:26]=1
Reactant: CC(C)(C)OC(=O)c1cccc(C(=N)N)c1
Reactant: CN(C)C=CC(=O)c1ccc(F)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CCO
Product: O=C(O)c1cccc(-c2nccc(-c3ccc(F)cc3)n2)c1
Yield: 49.8 %

Procedure:
Part B. To a mixture of 3-carbamimidoyl-benzoic acid tert-butyl ester (220.2 mg, 0.94 mmol), 3-dimethylamino-1-(4-fluoro-phenyl)-propenone (182.6 mg, 0.95 mmol) and sodium hydride (39.2 mg, 1.63 mmol, 60% in hexanes) is added dry ethanol (5.0 mL). The resulting mixture is stirred at refluxing for 8 h until complete consumption of the starting material as determined by TLC. The solvent is removed, and the residue is added to 1N HCl (15 mL) to precipitate a yellow solid. The title product (137.8 mg, 41.3% yield) is produced after washing with water, then ethyl ether in sequence, m.p. 239-241° C. 1H NMR (300 MHz, DMSO-d6): δ 9.05 (1H, s), 8.97 (1H, d, J=5.0 Hz), 8.73 (1H, dd, J=7.7, 1.2 Hz), 8.38 (2H, m), 8.11 (1H, dd, J=8.0, 1.2 Hz), 8.04 (1H, d, J=5.3 Hz), 7.68 (1H, t, J=7.8 Hz), 7.43 (2H, m). MS (ES+): m/e 295.27.
Reaction SMILES: [CH3:1]C(C)([O-])C.[K+].[Cl:7][C:8]1[N:13]=[CH:12][C:11]([CH2:14][OH:15])=[CH:10][CH:9]=1.IC>C1COCC1>[Cl:7][C:8]1[CH:9]=[CH:10][C:11]([CH2:14][O:15][CH3:1])=[CH:12][N:13]=1
Reactant: OCc1ccc(Cl)nc1
Reactant: CC(C)(C)[O-]
Agent: [K+]
Solvent: CI
Solvent: C1CCOC1
Product: COCc1ccc(Cl)nc1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
2.6 g (23.0 mmol) of potassium tert-butoxide are dissolved in 50 ml of THF. 3.0 g (20.9 mmol) of (6-chloropyridin-3-yl)methanol are added, and the mixture is stirred at RT for 15 min. 4.4 g (31.3 mmol) of iodomethane are then added slowly, and the mixture is stirred for about 30 min until the slightly exothermic reaction has subsided. The solvent is removed, and the residue is taken up in dichloromethane and washed twice with water. The organic phase is dried over magnesium sulfate and concentrated, and the residue is purified by column chromatography on silica gel (Biotage chromatography, mobile phase: cyclohexane/ethyl acetate 85:15).
Reaction SMILES: O1[C:5]2([CH2:10][CH2:9][CH:8]([CH:11]([N:14]([CH3:16])[CH3:15])[CH2:12][CH3:13])[CH2:7][CH2:6]2)[O:4]CC1.Cl>CC#N>[CH3:16][N:14]([CH3:15])[CH:11]([CH:8]1[CH2:9][CH2:10][C:5](=[O:4])[CH2:6][CH2:7]1)[CH2:12][CH3:13]
Reactant: CCC(C1CCC2(CC1)OCCO2)N(C)C
Agent: Cl
Solvent: CC#N
Product: CCC(C1CCC(=O)CC1)N(C)C

Procedure:
A solution of (1-{1,4-dioxaspiro[4.5]decan-8-yl}propyl)dimethylamine (as prepared in the previous step, 80 mg, 0.35 mmol, 1.00 equiv) in CH3CN (5 mL) and HCl (1M, 1 mL) was stirred for 2 h at room temperature. The resulting mixture was concentrated under vacuum. The residue was diluted with 10 mL of aq. sodium bicarbonate (1M). The resulting solution was extracted with 2×20 mL of dichloromethane. The organic layers were combined, dried over anhydrous sodium sulfate and concentrated under vacuum to give the title compound as a yellow oil.
Reaction SMILES: [CH2:1]([OH:7])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].[CH:8]1[N:12]=[CH:11][N:10]([C:13](N2C=NC=C2)=[O:14])[CH:9]=1>O1CCCC1>[N:10]1([C:13]([O:7][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH3:6])=[O:14])[CH:9]=[CH:8][N:12]=[CH:11]1
Reactant: CCCCCCO
Reactant: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: CCCCCCOC(=O)n1ccnc1
Temperature: 30 °C

Procedure:
A solution of n-hexanol (30.6 g) in tetrahydrofuran (400 ml) was slowly added to solution of N,N-carbonyldiimidazole (55.08 g) in tetrahydrofuran (100 ml) and stirred for 2½ hour at 25-35° C. to provide hexyl 1H-imidazole-1-carboxylate compound of formula-4. 1-methyl-2-[N-[4-amidinophenyl]aminomethyl]benzimidazol-5-yl-carboxylicacid-N-(2-pyridyl)-N-(2-ethoxycarbonylethyl)amide compound of formula-5 (100 g), tetrahydrofuran (700 ml), water (800 ml) and potassium carbonate (138 g) were added to the reaction mixture and stirred for 20 hours at 25-30° C. After completion of the reaction, filtered the solid, washed with tetrahydrofuran and then dried to get title compound.
Reaction SMILES: C[O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:13]3[CH2:14][CH2:15][N:16]=[C:17]([CH3:18])[C:12]3=[CH:11][CH:10]=2)=[CH:5][CH:4]=1.Br.C(Cl)Cl.[C:23]([OH:30])(=[O:29])/[CH:24]=[CH:25]/[C:26]([OH:28])=[O:27]>CO>[C:23]([OH:30])(=[O:29])/[CH:24]=[CH:25]/[C:26]([OH:28])=[O:27].[OH:2][C:3]1[CH:4]=[CH:5][C:6]([C:9]2[N:13]3[CH2:14][CH2:15][N:16]=[C:17]([CH3:18])[C:12]3=[CH:11][CH:10]=2)=[CH:7][CH:8]=1
Reactant: COc1ccc(-c2ccc3n2CCN=C3C)cc1
Agent: Br
Agent: O=C(O)/C=C/C(=O)O
Solvent: ClCCl
Solvent: CO
Product: CC1=NCCn2c1ccc2-c1ccc(O)cc1
Reaction time: 2 h
Yield: 62 %

Procedure:
3,4-Dihydro-6-(p-methoxyphenyl)-1-methylpyrrolo[1,2-a]pyrazine (20.9 g) was boiled with 500 ml of 48% hydrobromic acid in an argon atmosphere while stirring for 11/2 hours. The hydrobromic acid was removed in a vacuum and the residue was dissolved in 900 ml of ethyl acetate with the addition of 100 ml of methanol. The solution was stirred for 15 minutes with a mixture of 500 ml of saturated sodium hydrogen carbonate solution and 100 ml of 2N sodium hydroxide solution. The aqueous phase was brought to a pH value of 8-9 with 2N hydrochloric acid and extracted four times with 500 ml of an ethyl acetate/methanol mixture (9:1) each time. The aqueous phase was neutralized (pH=7) with 2N hydrochloric acid and continuously extracted overnight with 1000 ml of ethyl acetate. The organic phases were filtered, combined and concentrated to 150 ml. Then, 150 ml of ethyl acetate were added, the suspension was boiled and stored in a refrigerator overnight. 16.3 g of crude product were filtered off. 1.6 g thereof were dissolved in a 50-fold amount of methanol and a 10-fold amount of methylene chloride and treated with 1.1 equivalents of fumaric acid in 20 ml of methanol. There were obtained 1.8 g (62%) of 3,4-dihydro-6-(4-hydroxyphenyl)-1-methylpyrrolo[1,2-a]pyrazine fumarate (1:1 ); m.pt.: 209°-213° C. (dec.).
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH:10]([C:18]([O:20]C(C)(C)C)=[O:19])[C:11]([O:13]C(C)(C)C)=[O:12])=[CH:9][C:4]=2[CH:3]=[CH:2]1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[S:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH:10]([C:11]([OH:13])=[O:12])[C:18]([OH:20])=[O:19])=[CH:9][C:4]=2[CH:3]=[CH:2]1
Reactant: CC(C)(C)OC(=O)C(C(=O)OC(C)(C)C)c1ccc2sccc2c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: O=C(O)C(C(=O)O)c1ccc2sccc2c1
Yield: 82.6 %

Procedure:
To toluene (2.5 mL) solution of 0.25 g of di(tert-butyl) 2-(1-benzothiophen-5-yl)malonate was added 0.01 g of p-toluenesulfonic acid monohydrate, which was then refluxed for 1 hour. After cooling the reaction mixture, the precipitate was collected by filtration to provide 0.14 g of 2-(1-benzothiophen-5-yl)malonic acid as white solid form.
Reaction SMILES: [Br:1][C:2]1[N:3]=[CH:4][C:5]([OH:8])=[N:6][CH:7]=1.CS(O[CH2:14][CH:15]1[CH2:20][CH2:19][N:18]([C:21]([O:23][CH:24]([CH3:26])[CH3:25])=[O:22])[CH2:17][CH2:16]1)(=O)=O.C([O-])([O-])=O.[K+].[K+].O>CN(C=O)C>[Br:1][C:2]1[N:3]=[CH:4][C:5]([O:8][CH2:14][CH:15]2[CH2:20][CH2:19][N:18]([C:21]([O:23][CH:24]([CH3:26])[CH3:25])=[O:22])[CH2:17][CH2:16]2)=[N:6][CH:7]=1
Reactant: Oc1cnc(Br)cn1
Reactant: CC(C)OC(=O)N1CCC(COS(C)(=O)=O)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)OC(=O)N1CCC(COc2cnc(Br)cn2)CC1
Temperature: 70 °C

Procedure:
A mixture of 5-bromo-2-pyrazinol (and tautomers thereof) (0.2 g, 1.14 mmol), 1-methylethyl 4-{[(methylsulfonyl)oxy]methyl}-1-piperidinecarboxylate (prepared as in Example 131, Step 4, 0.51 g, 1.71 mmol) and K2CO3 (0.32 g, 2.29 mmol) in DMF (12 mL) was stirred at ambient temperature for 30 min, then heated at 70° C. overnight. The mixture was cooled to ambient temperature and poured into water, and then extracted with EtOAc (60 mL×2). The combined organic extract was washed with water, brine and dried over Na2SO4, filtered, and the filtrate was concentrated to give crude 1-methylethyl 4-{[(5-bromo-2-pyrazinyl)oxy]methyl}-1-piperidinecarboxylate a brown oil, which was used without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:25]=[CH:26][C:27]=1[Cl:28])[CH2:5][N:6]1[CH2:10][C@@H:9]([N:11]([CH2:13][C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][C:15]=2[F:21])[CH3:12])[CH2:8][C@H:7]1[C:22](O)=[O:23].[CH:29]1([C:35]2[NH:39][C:38](=[O:40])[C:37]3([CH2:45][CH2:44][NH:43][CH2:42][CH2:41]3)[N:36]=2)[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]1>>[CH:29]1([C:35]2[NH:39][C:38](=[O:40])[C:37]3([CH2:41][CH2:42][N:43]([C:22]([C@@H:7]4[CH2:8][C@H:9]([N:11]([CH2:13][C:14]5[CH:19]=[CH:18][C:17]([F:20])=[CH:16][C:15]=5[F:21])[CH3:12])[CH2:10][N:6]4[CH2:5][C:4]4[CH:25]=[CH:26][C:27]([Cl:28])=[C:2]([Cl:1])[CH:3]=4)=[O:23])[CH2:44][CH2:45]3)[N:36]=2)[CH2:30][CH2:31][CH2:32][CH2:33][CH2:34]1
Reactant: CN(Cc1ccc(F)cc1F)[C@H]1C[C@@H](C(=O)O)N(Cc2ccc(Cl)c(Cl)c2)C1
Reactant: O=C1NC(C2CCCCC2)=NC12CCNCC2
Product: CN(Cc1ccc(F)cc1F)[C@H]1C[C@@H](C(=O)N2CCC3(CC2)N=C(C2CCCCC2)NC3=O)N(Cc2ccc(Cl)c(Cl)c2)C1
Yield: 6 %

Procedure:
As described for Example 64e, (2S,4S)-1-(3,4-dichloro-benzyl)-4-[(2,4-difluoro-benzyl)-methyl-amino]-pyrrolidine-2-carboxylic acid (1 mmol) was converted, using 2-cyclohexyl-1,3,8-triaza-spiro[4.5]dec-1-en-4-one to the title compound (38.8 mg) by preparative HPLC in 6% yield as colorless oil. MS m/e=647.6 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:9]2[NH:8][C:7]3[C:12](=O)[CH2:13][CH2:14][C:6]=3[C:5]=2[CH:4]=1.Cl.[NH2:17][OH:18].C([O-])(=O)C.[Na+]>CCO.O>[OH:18][N:17]=[C:12]1[C:7]2[NH:8][C:9]3[CH:10]=[CH:11][C:3]([O:2][CH3:1])=[CH:4][C:5]=3[C:6]=2[CH2:14][CH2:13]1
Reactant: COc1ccc2[nH]c3c(c2c1)CCC3=O
Reactant: NO
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: COc1ccc2[nH]c3c(c2c1)CCC3=NO
Reaction time: 8 h
Yield: 28.6 %

Procedure:
A stirred solution of 1,2-cyclopentadione mono-4-methoxyphenylhydrazone (6.0 g) in 100 ml of 10% aqueous H2SO4 was heated on a steam bath for 4 hours and thereafter allowed to cool to room temperature and filtered to give 1,4-dihydro 7-methoxycyclopent[b]indol-3(2H)-one as a solid. To the indole (2.6 g) in 25 ml of 95% EtOH was added hydroxylamine hydrochloride (1.7 g) in 15 ml water followed by sodium acetate (2.1 g) in 15 ml water. The mixture was heated at reflux for 2.5 hours and allowed to stand overnight. The EtOH was removed in vacuo and the solid material which formed was collected and purified by flash chromatography to give 0.8 g of a mixture of oxime isomers.
Reaction SMILES: [CH3:1][C:2]1[S:13][C:5]2[CH2:6][N:7]([CH3:12])[CH2:8][CH2:9][CH:10]([OH:11])[C:4]=2[CH:3]=1.F[C:15]1[CH:24]=[CH:23][C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH:16]=1>>[CH3:1][C:2]1[S:13][C:5]2[CH2:6][N:7]([CH3:12])[CH2:8][CH2:9][CH:10]([O:11][C:15]3[CH:24]=[CH:23][C:22]4[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=4)[CH:16]=3)[C:4]=2[CH:3]=1
Reactant: Fc1ccc2ccccc2c1
Reactant: Cc1cc2c(s1)CN(C)CCC2O
Product: Cc1cc2c(s1)CN(C)CCC2Oc1ccc2ccccc2c1

Procedure:
The same method as in Example 1 was conducted using 2,7-dimethyl-5,6,7,8-tetrahydro-4H-thieno[2,3-c]azepin-4-ol (Reference Example 23) instead of 6-methyl-4,5,6,7-tetrahydrothieno[2,3-c]pyridin-4-ol (Reference Example 6) and was conducted using 2-fluoronaphthalene instead of 1-fluoronaphthalene to give the objective compound.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=O)[C:9](=[CH:26]N2CCCC2)[CH2:10][CH2:11][N:12]2[CH2:17][CH2:16][C:15](=[CH:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[F:25])[CH2:14][CH2:13]2)=[CH:4][CH:3]=1.[OH-].[K+].[NH2:35][C:36]([NH2:38])=[S:37]>C(O)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([CH2:10][CH2:11][N:12]3[CH2:13][CH2:14][C:15](=[CH:18][C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=4[F:25])[CH2:16][CH2:17]3)=[CH:26][N:38]=[C:36]([SH:37])[N:35]=2)=[CH:4][CH:3]=1
Reactant: O=C(C(=CN1CCCC1)CCN1CCC(=Cc2ccccc2F)CC1)c1ccc(F)cc1
Reactant: NC(N)=S
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: Fc1ccc(-c2nc(S)ncc2CCN2CCC(=Cc3ccccc3F)CC2)cc1
Reaction time: 5 h
Yield: 35.4 %

Procedure:
To 3.70 g of the crude 1-[4-(4-fluorophenyl)-4-oxo-3-pyrrolidinomethylenebutyl]-4-(2-fluorobenzylidene)piperidine obtained in Example 5 were added a solution of 0.45 g of potassium hydroxide in 40 ml of ethanol and 1.23 g of thiourea, followed by reflux with heating with stirring for 5 hours. The reaction solution was concentrated under reduced pressure, and to the residue were added a saturated aqueous ammonium chloride solution and a little amount of ethyl acetate. The precipitated crystals were collected by filtration, and recrystallized from ethyl acetate to give 1.27 g of 4-(4-fluorophenyl)-5-[2-[4-(2-fluorobenzylidene)piperidin-1-yl]ethyl]-2-mercaptopyrimidine.