Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([C:5]1[N:6]([C:18]([OH:20])=[O:19])[C:7]2[C:12]([CH:13]=1)=[CH:11][C:10]([Br:14])=[C:9]([Cl:15])[C:8]=2[CH:16]=[O:17])(C)(C)C.P([O-])(O)(O)=O.[Na+].[CH3:27][C:28](=[CH:30]C)[CH3:29].Cl([O-])=[O:33].[Na+]>O1CCOCC1.O>[Br:14][C:10]1[CH:11]=[C:12]2[C:7](=[C:8]([C:16]([OH:17])=[O:33])[C:9]=1[Cl:15])[N:6]([C:18]([O:20][C:28]([CH3:30])([CH3:29])[CH3:27])=[O:19])[CH:5]=[CH:13]2
Reactant: CC(C)(C)c1cc2cc(Br)c(Cl)c(C=O)c2n1C(=O)O
Reactant: CC=C(C)C
Reactant: [O-][Cl+][O-]
Agent: O=P([O-])(O)O
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: CC(C)(C)OC(=O)n1ccc2cc(Br)c(Cl)c(C(=O)O)c21
Reaction time: 5 h
Yield: 102.3 %

Procedure:
To a mixture of tert-butyl 5-bromo-6-chloro-7-formyl 1H-indole-1-carboxylic acid (2.9 g), sodium dihydrogen phosphate (2.0 g), 2-methyl-2-butene (2.6 g), water (10 mL), and 1,4-dioxane (30 mL) was added sodium chlorite (1.8 g) under ice-cooling. The reaction mixture was stirred under ice-cooling for 1 hour, and then at room temperature for 5 hours. The reaction mixture was concentrated under reduced pressure, and ethyl acetate and water were added thereto, and a liquid-separation operation was carried out. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and then evaporated under reduced pressure to obtain 5-bromo-1-(tert-butoxycarbonyl)-6-chloro-1H-indole-7-carboxylic acid (3.1 g).
Reaction SMILES: OS(O)(=O)=O.O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O.[F:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[C:27]1([C:33]([CH:35]([C:41]([O:43][CH2:44][CH3:45])=[O:42])[C:36](OCC)=[O:37])=[O:34])[CH2:32][CH2:31][O:30][CH2:29][CH2:28]1>CCOC(C)=O.CCCCCC>[F:20][C:21]1[CH:26]=[CH:25][CH:24]=[C:23]2[C:22]=1[C:27]1([CH2:32][CH2:31][O:30][CH2:29][CH2:28]1)[C:33](=[O:34])[C:35]([C:41]([O:43][CH2:44][CH3:45])=[O:42])=[C:36]2[OH:37]
Reactant: CCOC(=O)C(C(=O)OCC)C(=O)C1(c2ccccc2F)CCOCC1
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Agent: O=S(=O)(O)O
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: CCOC(=O)C1=C(O)c2cccc(F)c2C2(CCOCC2)C1=O
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 51.1 %

Procedure:
A flask containing H2SO4 (12 mL, 218 mmol) and P2O5 (12 g, 87 mmol) was cooled in an ice bath for 20 minutes under nitrogen, and then diethyl 2-(4-(2-fluorophenyl)-tetrahydro-2H-pyran-4-carbonyl)malonate (8.0 g, 22 mmol) was added dropwise over 10 minutes. The reaction was stirred an additional 10 minutes at 0° C., and then was stirred at room temperature for 1 hour. The reaction was poured over ice and allowed to melt. The aqueous mixture was extracted with EtOAc (3×100 mL) and then the separated organic extracts were dried (Na2SO4), filtered and concentrated to provide an oil. Flash chromatography (20% EtOAc/hexane) afforded an oil (3.6 g). MS m/e=321.0 (M+H)+.
Reaction SMILES: [C:1]1([C:7]2[C:8]([O:10][C:11](=[O:13])[CH:12]=2)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.S(Cl)([Cl:16])=O.N1C=CC=CC=1>C1(C)C=CC=CC=1>[Cl:16][C:12]1[C:11](=[O:13])[O:10][C:8](=[O:9])[C:7]=1[C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C1C=C(c2ccccc2)C(=O)O1
Reactant: O=S(Cl)Cl
Solvent: Cc1ccccc1
Solvent: c1ccncc1
Product: O=C1OC(=O)C(c2ccccc2)=C1Cl
Temperature: 11 °C
Reaction time: 0.17 h

Procedure:
With ice-cooling, 10.0 g (57 mmol) of phenylmaleic anhydride were added to 57 ml of thionyl chloride, and the mixture was, over a period of 10 min, admixed dropwise with 9.08 g (115 mmol) of pyridine, the temperature being maintained at 10-12° C. The mixture was stirred at 10-12° C. for 30 min, heated at 75° C. for 10 min. using a preheated heating bath and allowed to cool, and excess thionylchloride was stripped off at 60° C. at reduced pressure. The residue was then boiled with 120 ml of toluene and filtered, and the residue was washed with 50 ml of hot toluene. The filtrate was concentrated under reduced pressure, titrated with petroleum ether and dried. Yield: 8.5 g, m.p. 82-83° C.
Reaction SMILES: [Br:1][C:2]1[C:3](=[O:10])[N:4]([CH3:9])[C:5](Cl)=[N:6][CH:7]=1.[Br-].[CH:12]1([CH2:18][Zn+])[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1>C1COCC1.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[Br:1][C:2]1[C:3](=[O:10])[N:4]([CH3:9])[C:5]([CH2:18][CH:12]2[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]2)=[N:6][CH:7]=1
Reactant: [Zn+]CC1CCCCC1
Reactant: Cn1c(Cl)ncc(Br)c1=O
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Solvent: C1CCOC1
Product: Cn1c(CC2CCCCC2)ncc(Br)c1=O
Temperature: 100 °C
Reaction time: 1.5 h
Yield: 37 %

Procedure:
A solution of 5-bromo-2-chloro-3-methylpyrimidin-4(3H)-one (0.100 g, 0.448 mmol; prepared according to the procedure of Example 46, Step B) and PdCl2(PPh3)2 (0.016 g, 0.022 mmol) in THF (2.5 mL) was sparged with N2, and then (cyclohexylmethyl)zinc(II)bromide (0.904 ml, 0.452 mmol; 0.5 M solution in THF) was added. The reaction mixture was stirred at 100° C. for 1.5 hours. The reaction mixture was cooled to room temperature and then partitioned between EtOAc and H2O. The aqueous layer was re-extracted with EtOAc (1×). The combined organic layers were dried over Na2SO4, filtered and concentrated. The crude material was purified by flash column chromatography, eluting with 10:1 CH2Cl2/EtOAc to afford 0.047 g (37%) of the product as a waxy yellow solid. LRMS (APCI pos) m/e 285, 287 (M+, Br pattern).
Reaction SMILES: [ClH:1].[C:2]1([N:8]([CH2:32][CH2:33][C:34]([O:36]CC)=[O:35])[C:9]([C:11]2[CH:31]=[CH:30][C:14]3[N:15]([CH3:29])[C:16]([CH2:18][O:19][C:20]4[CH:25]=[CH:24][C:23]([C:26](=[NH:28])[NH2:27])=[CH:22][CH:21]=4)=[N:17][C:13]=3[CH:12]=2)=[O:10])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+]>ClCCl.C(O)C>[ClH:1].[C:2]1([N:8]([CH2:32][CH2:33][C:34]([OH:36])=[O:35])[C:9]([C:11]2[CH:31]=[CH:30][C:14]3[N:15]([CH3:29])[C:16]([CH2:18][O:19][C:20]4[CH:25]=[CH:24][C:23]([C:26](=[NH:27])[NH2:28])=[CH:22][CH:21]=4)=[N:17][C:13]=3[CH:12]=2)=[O:10])[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)CCN(C(=O)c1ccc2c(c1)nc(COc1ccc(C(=N)N)cc1)n2C)c1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CCO
Product: Cn1c(COc2ccc(C(=N)N)cc2)nc2cc(C(=O)N(CCC(=O)O)c3ccccc3)ccc21
Yield: 82 %

Procedure:
Prepared analogously to Example 26 from 1-methyl-2-[(4-amidinophenyl)oxymethyl]-benzimidazol-5-yl-carboxylic acid-N-phenyl-N-(2-ethoxycarbonylethyl)-amide-hydrochloride and sodium hydroxide solution. Yield: 82% of theory, C26H25N5O4 (471.5) Rf value: 0.11 (silica gel; dichloromethane/ethanol=4:1) ##EQU33##
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH2:23][CH2:24][C:25](=[O:32])[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])[CH:12]=[CH:13][C:14]=1[O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:33]COCC.[Mg].CI>O1CCCC1>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH2:23][CH2:24][C:25]([CH3:33])([OH:32])[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])[CH:12]=[CH:13][C:14]=1[O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOCC
Reactant: CCCCCCC(=O)CCc1ccc(OCc2ccccc2)c(OCc2ccccc2)c1
Agent: [Mg]
Solvent: CI
Solvent: C1CCOC1
Product: CCCCCCC(C)(O)CCc1ccc(OCc2ccccc2)c(OCc2ccccc2)c1

Procedure:
A solution of 1.75 g of 1-(3,4-dibenzyloxyphenyl)-3-nonanone in 10 ml of tetrahydrofuran was cooled to 0° to 5° C. and then an ether solution of a Grignard reagent prepared from 0.24 g of metallic magnesium and 1.7 g of methyl iodide was added dropwise to the mixture. Thereafter, the resultant mixture was stirred for 15 minutes and after adding thereto 50 ml of an aqueous 5% hydrochloric acid solution, the product was extracted with toluene. The extract was washed with water, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure to provide 1.6 g of 1-(3,4-dibenzyloxyphenyl)-3-methyl-3-nonanol.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:10]=[CH:11][CH:12]=1)[C:5]([O:7][CH2:8][CH3:9])=[O:6].Cl[C:14](Cl)([O:16]C(=O)OC(Cl)(Cl)Cl)Cl.C(N(CC)CC)C.[C:32]([C:36]([CH2:38][N:39]1[C:45]2[CH:46]=[C:47]([CH3:50])[CH:48]=[CH:49][C:44]=2[N:43]([C:51]2[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=2)[CH2:42][CH:41]([NH2:57])[C:40]1=[O:58])=[O:37])([CH3:35])([CH3:34])[CH3:33]>O1CCCC1>[C:32]([C:36]([CH2:38][N:39]1[C:45]2[CH:46]=[C:47]([CH3:50])[CH:48]=[CH:49][C:44]=2[N:43]([C:51]2[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=2)[CH2:42][CH:41]([NH:57][C:14]([NH:1][C:2]2[CH:12]=[CH:11][CH:10]=[C:4]([C:5]([O:7][CH2:8][CH3:9])=[O:6])[CH:3]=2)=[O:16])[C:40]1=[O:58])=[O:37])([CH3:35])([CH3:33])[CH3:34]
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: Cc1ccc2c(c1)N(CC(=O)C(C)(C)C)C(=O)C(N)CN2c1ccccc1
Reactant: CCOC(=O)c1cccc(N)c1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCOC(=O)c1cccc(NC(=O)NC2CN(c3ccccc3)c3ccc(C)cc3N(CC(=O)C(C)(C)C)C2=O)c1
Reaction time: 0.5 h
Yield: 593.5 %

Procedure:
Ethyl 3-aminobenzoate (14 mg) was dissolved in anhydrous tetrahydrofuran (10 ml), under ice-cooling triphosgene (68 mg) was added and triethylamine (60 μl ) was added thereto five times. The mixture was stirred for 30 minutes at same temperature. A solution of 1-tert-butylcarbonylmethyl-2-oxo-3-amino-5-phenyl-8-methyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepine (227 mg) in anhydrous tetrahydrofuran (10 ml) was added, the resultant mixture was allowed to come to room temperature, and stirred for 30 minutes. The reaction mixture was concentrated under reduced pressure, Water (50 ml) was added, and extracted with methylene chloride. The organic layer was dried over anhydrous sodium sulfate, the solvent was evaporated under reduced pressure, and diethyl ether was added to the residue for trituration, collected by filtration, to thereby obtain 280 mg of the titled compound (Yield: 81.1%).
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][C:11](=O)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:15][C:16]1[CH:21]=[CH:20][C:19]([C:22]([OH:31])([C:27]([F:30])([F:29])[F:28])[C:23]([F:26])([F:25])[F:24])=[CH:18][CH:17]=1.C[Si]([C:36]#[N:37])(C)C.[NH4+].[OH-]>C(O)(=O)C>[CH2:1]([N:8]1[CH2:13][CH2:12][C:11]([NH:15][C:16]2[CH:17]=[CH:18][C:19]([C:22]([OH:31])([C:23]([F:24])([F:25])[F:26])[C:27]([F:28])([F:29])[F:30])=[CH:20][CH:21]=2)([C:36]#[N:37])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Nc1ccc(C(O)(C(F)(F)F)C(F)(F)F)cc1
Reactant: O=C1CCN(Cc2ccccc2)CC1
Reactant: C[Si](C)(C)C#N
Agent: [NH4+]
Agent: [OH-]
Solvent: CC(=O)O
Product: N#CC1(Nc2ccc(C(O)(C(F)(F)F)C(F)(F)F)cc2)CCN(Cc2ccccc2)CC1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 106.2 %

Procedure:
To a stirred solution of 1-benzyl-4-piperidone (1.3 mL, 7.0 mmol) and 2-(4-aminophenyl)-1,1,1,3,3,3-hexafluoropropan-2-ol (Oakwood, 2.0 g, 7.7 mmol) in glacial acetic acid (6.6 mL) was added trimethylsilyl cyanide (0.9 mL, 7.0 mmol) over 5 minutes. After 30 minutes, the reaction was poured in to a mixture of ice (6.5 g) and NH4OH (6.5 mL). Additional NH4OH was added until pH=10. The product was extracted with CH2Cl2 (3×), then washed with brine, dried (Na2SO4), and concentrated to afford the title compound as an off-white solid (3.4 g, quantitative yield). MS (ES+) m/z 458 (MH+).
Reaction SMILES: [C:1]([C:5]1[O:9][N:8]=[C:7]([NH:10][C:11]([NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([S:20][C:21]3[C:30]4[C:25](=[CH:26][C:27](OC)=[C:28]([O:31][CH2:32][CH2:33][CH2:34]Cl)[CH:29]=4)[N:24]=[CH:23][N:22]=3)[CH:15]=2)=[O:12])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[NH:38]1[CH2:43][CH2:42][S:41](=[O:45])(=[O:44])[CH2:40][CH2:39]1.CCN(C(C)C)C(C)C>[I-].C([N+](CCCC)(CCCC)CCCC)CCC.CN(C=O)C>[C:1]([C:5]1[O:9][N:8]=[C:7]([NH:10][C:11]([NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([S:20][C:21]3[C:30]4[C:25](=[CH:26][CH:27]=[C:28]([O:31][CH2:32][CH2:33][CH2:34][N:38]5[CH2:43][CH2:42][S:41](=[O:45])(=[O:44])[CH2:40][CH2:39]5)[CH:29]=4)[N:24]=[CH:23][N:22]=3)[CH:15]=2)=[O:12])[CH:6]=1)([CH3:3])([CH3:2])[CH3:4]
Reactant: COc1cc2ncnc(Sc3cccc(NC(=O)Nc4cc(C(C)(C)C)on4)c3)c2cc1OCCCCl
Reactant: O=S1(=O)CCNCC1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [I-]
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)(C)c1cc(NC(=O)Nc2cccc(Sc3ncnc4ccc(OCCCN5CCS(=O)(=O)CC5)cc34)c2)no1
Yield: 43 %

Procedure:
The title compound was prepared as described in Example 57B by using 1-(5-tert-butylisoxazol-3-yl)-3-(3-(6-(3-chloropropoxy)-7-methoxyquinazolin-4-ylthio)phenyl)urea from the previous step (230 mg, 0.45 mmol), thiomorpholine 1,1-dioxide (182 mg, 1.35 mmol), tetrabutylammonium iodide (166 mg, 0.45 mmol) and N,N′-diisopropylethylamine (160 μL, 0.89 mmol) in N,N′-dimethylformamide (3 mL) to afford 1-(5-tert-Butyl-isoxazol-3-yl)-3-(3-{6-[3-(1,1-dioxo-thiomorpholin-4-yl)-propoxy]-quinazolin-4-ylsulfanyl}-phenyl)-urea (117 mg, 43%) as solid. 1H NMR (300 MHz, DMSO-d6) δ 9.61 (s, 1H), 9.03 (s, 1H), 8.75 (s, 1H), 7.94-7.86 (m, 2H), 7.68 (d, 1H), 7.51-7.41 (m, 3H), 7.30 (d, 1H), 6.49 (s, 1H), 4.26-4.23 (m, 2H), 3.11 (bs, 4H), 2.95 (bs, 4H), 2.71-2.67 (m, 2H), 2.00-1.96 (m, 2H), 1.27 (s,m 9H); LC-MS (ESI) m/z 611 (M+H)+.
Reaction SMILES: [CH:1]1([CH2:5][O:6][C:7]2[CH:15]=[CH:14][CH:13]=[C:12]3[C:8]=2[CH:9]=[C:10]([C:16]([OH:18])=O)[NH:11]3)[CH2:4][CH2:3][CH2:2]1.[NH2:19][CH:20]1[CH2:25][CH2:24][C:23]([CH2:27][CH2:28][N:29]2[CH2:34][CH2:33][C@H:32]([OH:35])[C@@H:31]([CH3:36])[CH2:30]2)([OH:26])[CH2:22][CH2:21]1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F>CN(C=O)C>[OH:26][C:23]1([CH2:27][CH2:28][N:29]2[CH2:34][CH2:33][C@H:32]([OH:35])[C@@H:31]([CH3:36])[CH2:30]2)[CH2:24][CH2:25][CH:20]([NH:19][C:16]([C:10]2[NH:11][C:12]3[C:8]([CH:9]=2)=[C:7]([O:6][CH2:5][CH:1]2[CH2:2][CH2:3][CH2:4]2)[CH:15]=[CH:14][CH:13]=3)=[O:18])[CH2:21][CH2:22]1
Reactant: C[C@H]1CN(CCC2(O)CCC(N)CC2)CC[C@@H]1O
Reactant: O=C(O)c1cc2c(OCC3CCC3)cccc2[nH]1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: C[C@H]1CN(CCC2(O)CCC(NC(=O)c3cc4c(OCC5CCC5)cccc4[nH]3)CC2)CC[C@@H]1O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of 4-cyclobutylmethoxy-1H-indole-2-carboxylic acid (16a) (140 mg, 0.383 mmol), (3S,4S)-1-[2-(4-amino-1-hydroxy-cyclohexyl)-ethyl]-3-methyl-piperidin-4-ol (14) (103 mg, 0.421 mmol) and DIEA (0.263 ml, 1.532 mmol) in 5 ml of DMF is treated with solid TBTU (139 mg, 0.421 mmol). The mixture is stirred for 2 h at rt and then evaporated. The crude residue is dissolved in EtOAc and extracted with 1M-HCl. The aqueous layer is separated, its pH adjusted to 14 and extracted 3-times with DCM. The organic layers are dried over sodium sulphate and evaporated. The crude product is then purified by chromatography on silicagel using methanol and DCM (saturated with ammonia) from 1:99 to 5:95.
Reaction SMILES: [BrH:1].[OH:2][C:3]1[C:12]([CH2:13][CH:14]=[CH2:15])=[C:11]([NH:16][C:17]([CH3:19])=[O:18])[CH:10]=[CH:9][C:4]=1[C:5]([O:7][CH3:8])=[O:6]>[Hg].O>[OH:2][C:3]1[C:12]([CH2:13][CH2:14][CH2:15][Br:1])=[C:11]([NH:16][C:17]([CH3:19])=[O:18])[CH:10]=[CH:9][C:4]=1[C:5]([O:7][CH3:8])=[O:6]
Reactant: C=CCc1c(NC(C)=O)ccc(C(=O)OC)c1O
Reactant: Br
Agent: [Hg]
Solvent: O
Product: COC(=O)c1ccc(NC(C)=O)c(CCCBr)c1O
Reaction time: 4 h

Procedure:
2277 g of 66% hydrobromic acid and 308 g of methyl 2-hydroxy-3-allyl-4-acetaminobenzoate were introduced into a 3-liter round-bottomed flask equipped with a leakproof stirrer, a thermometer and a safety tube containing mercury so that a pressure of approximately 2 cm of mercury is created in the apparatus. The mixture was stirred for 4 hours and then allowed to stand overnight. 5 liters of water were then added. The precipitate formed was drained, washed with water and dried at 50° C.
Reaction SMILES: [C:1]([OH:10])(=O)[C@@H:2]([C@H:4]([C:6](O)=[O:7])[OH:5])[OH:3].[CH2:11]([NH2:18])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C1(C)C(C)=CC=CC=1>O>[CH2:11]([N:18]1[C:6](=[O:7])[C@H:4]([OH:5])[C@@H:2]([OH:3])[C:1]1=[O:10])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: NCc1ccccc1
Reactant: O=C(O)[C@H](O)[C@@H](O)C(=O)O
Solvent: O
Solvent: Cc1ccccc1C
Product: O=C1[C@H](O)[C@@H](O)C(=O)N1Cc1ccccc1

Procedure:
L-Tartaric acid (30 g) and benzylamine (22 mL) were added to xylene (150 mL), and the mixture was heated under reflux at 150° C. for 3 hours while water was removed with Dean-Stark apparatus. After the reaction mixture was left to cool overnight, the resultant crystals were collected by filtration, and were washed with acetone. The thus-obtained crude product was recrystallized from ethanol, to thereby give the title compound (23.2 g).
Reaction SMILES: [OH-:1].[Na+].[C:3]([O:7][C:8]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[C:16]1[CH:21]=[CH:20][C:19]([CH2:22][N:23]2[C:27]([C:28]#[N:29])=[C:26]([CH:30]([OH:33])[CH2:31][CH3:32])[N:25]=[C:24]2[CH2:34][CH2:35][CH2:36][CH3:37])=[CH:18][CH:17]=1)=[O:9])([CH3:6])([CH3:5])[CH3:4]>C(O)C>[C:3]([O:7][C:8]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[C:16]1[CH:21]=[CH:20][C:19]([CH2:22][N:23]2[C:27]([C:28]([NH2:29])=[O:1])=[C:26]([CH:30]([OH:33])[CH2:31][CH3:32])[N:25]=[C:24]2[CH2:34][CH2:35][CH2:36][CH3:37])=[CH:18][CH:17]=1)=[O:9])([CH3:6])([CH3:5])[CH3:4]
Reactant: CCCCc1nc(C(O)CC)c(C#N)n1Cc1ccc(-c2ccccc2C(=O)OC(C)(C)C)cc1
Reactant: [OH-]
Agent: [Na+]
Solvent: CCO
Product: CCCCc1nc(C(O)CC)c(C(N)=O)n1Cc1ccc(-c2ccccc2C(=O)OC(C)(C)C)cc1

Procedure:
20 ml of a 1N aqueous solution of sodium hydroxide were added to a solution of 368 mg of 1-[(2'-t-butoxycarbonylbiphenyl-4-yl)methyl]-2-butyl-4-(1-hydroxypropyl)imidazole-5-carbonitrile [prepared as described in step (b) above] dissolved in 20 ml of ethanol, and the resulting mixture was heated under reflux for 6 hours. At the end of this time, the reaction mixture was worked up in a similar manner to that described in Example 45(c), to afford 316 mg of the title compound as an amorphous solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[CH2:13][CH2:12][N:11]([C:14](=[NH:27])[CH2:15][N:16]2[C:20]([CH3:21])=[CH:19][CH:18]=[C:17]2[C:22]([O:24]CC)=O)[CH2:10][CH2:9]1.C(N(CC)C(C)C)(C)C>O1CCCC1>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[CH2:9][CH2:10][N:11]([C:14]2[NH:27][C:22](=[O:24])[C:17]3[N:16]([C:20]([CH3:21])=[CH:19][CH:18]=3)[CH:15]=2)[CH2:12][CH2:13]1
Reactant: CCOC(=O)c1ccc(C)n1CC(=N)N1CCN(c2ccccc2F)CC1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: Cc1ccc2c(=O)[nH]c(N3CCN(c4ccccc4F)CC3)cn12
Temperature: 150 °C
Yield: 88.1 %

Procedure:
A mixture of ethyl 1-(2-(4-(2-fluorophenyl)piperazin-1-yl)-2-iminoethyl)-5-methyl-1H-pyrrole-2-carboxylate (150 mg, 0.4 mmol) and N,N-diisopropylethylamine (1.41 mL, 8 mmol) in tetrahydrofuran (4 mL) was heated at 150° C. in a microwave reactor for 3 h. At this time, the solution was cooled to room temperature. The resulting precipitate was collected by filtration, washed with minimal ethyl acetate and air dried to afford 3-[4-(2-fluoro-phenyl)-piperazin-1-yl]-6-methyl-2H-pyrrolo[1,2-a]pyrazin-1-one (115 mg, 87.5%) as a white solid. 1H NMR (300 MHz, DMSO-d6) δ ppm 10.55 (s, 1H), 7.21-7.06 (m, 3H), 7.05-6.96 (m, 1H), 6.73 (d, 1H), 6.53 (s, 1H), 6.26 (d, 1H), 3.15 (s, 8H), 2.26 (s, 3H). LC-MS calcd. for C18H20FN4O [(M+H)+] 327, obsd. 326.9.
Reaction SMILES: FC(F)(F)C(O)=O.[Cl:8][C:9]1[CH:14]=[C:13]2[NH:15][C:16](=[O:38])[C:17]3([CH:21]([C:22]4[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[C:23]=4[F:29])[CH:20]([C:30](O)=[O:31])[NH:19][CH:18]3[CH2:33][C:34]([CH3:37])([CH3:36])[CH3:35])[C:12]2=[CH:11][CH:10]=1.C(N(C(C)C)CC)(C)C.C1(P(Cl)(C2C=CC=CC=2)=O)C=CC=CC=1.[NH2:63][C:64]1[CH:69]=[CH:68][C:67]([C:70](=[O:80])[CH2:71][O:72][Si:73]([C:76]([CH3:79])([CH3:78])[CH3:77])([CH3:75])[CH3:74])=[CH:66][CH:65]=1>>[C:76]([Si:73]([CH3:75])([CH3:74])[O:72][CH2:71][C:70]([C:67]1[CH:68]=[CH:69][C:64]([NH:63][C:30]([CH:20]2[NH:19][CH:18]([CH2:33][C:34]([CH3:37])([CH3:35])[CH3:36])[C:17]3([C:12]4[C:13](=[CH:14][C:9]([Cl:8])=[CH:10][CH:11]=4)[NH:15][C:16]3=[O:38])[CH:21]2[C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[C:23]=2[F:29])=[O:31])=[CH:65][CH:66]=1)=[O:80])([CH3:79])([CH3:78])[CH3:77]
Reactant: CC(C)(C)[Si](C)(C)OCC(=O)c1ccc(N)cc1
Reactant: CC(C)(C)CC1NC(C(=O)O)C(c2cccc(Cl)c2F)C12C(=O)Nc1cc(Cl)ccc12
Agent: O=P(Cl)(c1ccccc1)c1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(C)CC1NC(C(=O)Nc2ccc(C(=O)CO[Si](C)(C)C(C)(C)C)cc2)C(c2cccc(Cl)c2F)C12C(=O)Nc1cc(Cl)ccc12
Yield: 26.5 %

Procedure:
In a manner similar to the method described in Example 5, rac-(2′S,3′R,4′S,5′R)-6-chloro-4′-(3-chloro-2-fluoro-phenyl)-2′-(2,2-dimethyl-propyl)-2-oxo-1,2-dihydro-spiro[indole-3,3′-pyrrolidine]-5′-carboxylic acid trifluoroacetic acid prepared in Example 4 (0.3 g, 0.53 mmol), was reacted with diisopropylethylamine (0.28 g, 2.1 mmol), diphenylphosphinic chloride (0.38 g, 1.6 mmol), then reacted with 1-(4-amino-phenyl)-2-(tert-butyl-dimethyl-silanyloxy)-ethanone (0.21 g, 0.8 mmol) to give rac-(2′S,3′R,4′S,5′R)-6-chloro-4′-(3-chloro-2-fluoro-phenyl)-2′-(2,2-dimethyl-propyl)-2-oxo-1,2-dihydro-spiro[indole-3,3′-pyrrolidine]-5′-carboxylic acid {4-[2-(tert-butyl-dimethyl-silanyloxy)-acetyl]-phenyl}-amide as a yellow foam (Yield 0.1 g, 26%).
Reaction SMILES: Cl[CH2:2][C:3]([CH3:5])=[CH2:4].[C:6](=[O:9])([O-])[O-:7].[K+].[K+].[CH2:12](O)[CH3:13]>CC([O-])=O.CC([O-])=O.[Pd+2]>[CH2:12]([O:7][C:6](=[O:9])[CH2:2][C:3]([CH3:5])=[CH2:4])[CH3:13]
Reactant: O=C([O-])[O-]
Reactant: C=C(C)CCl
Reactant: CCO
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: [K+]
Product: C=C(C)CC(=O)OCC
Temperature: 10 °C
Reaction time: 0.5 h

Procedure:
An oven dried Fisher-Porter bottle was charged with 3-chloro-2-methyl propene (15.7 g, 173.4 mmol), potassium carbonate (13.0 g, 93.5 mmol), and ethanol (13.0 mL). The bottle was capped with a pressure head and the system was degassed on the vacuum line. The bottle was opened under an atmosphere of nitrogen and Pd(OAc)2 (0.6 g, 2.67 mmol) was added. The system was capped and evacuated. The system was pressurized with carbon monoxide to 30 psi and the reactants were stirred at 10° C. After 30 minutes, the reaction mixture was stirred at room temperature for 2.5 hours. The system was then opened. The reaction mixture was diluted with ether (100 mL), and filtered. The yellow colored filtrate was concentrated under reduced pressure and the residue was purified by silica gel flash chromatography using 10% EtOAc in hexane to afford ethyl-3-methyl-3-butenoate (9.0 g) as a yellow liquid. 1H-NMR and mass spectral data were consistent with the structure.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]2[C:8]([CH:11]3[CH2:16][CH2:15][N:14]([CH2:17][CH2:18][CH2:19][CH3:20])[CH2:13][CH2:12]3)=[CH:9][NH:10][C:5]2=[CH:4][CH:3]=1.[F:21][C:22]1[CH:30]=[CH:29][C:25]([C:26](Cl)=[O:27])=[CH:24][CH:23]=1>>[F:21][C:22]1[CH:30]=[CH:29][C:25]([C:26]([NH:1][C:2]2[N:7]=[C:6]3[C:8]([CH:11]4[CH2:16][CH2:15][N:14]([CH2:17][CH2:18][CH2:19][CH3:20])[CH2:13][CH2:12]4)=[CH:9][NH:10][C:5]3=[CH:4][CH:3]=2)=[O:27])=[CH:24][CH:23]=1
Reactant: CCCCN1CCC(c2c[nH]c3ccc(N)nc23)CC1
Reactant: O=C(Cl)c1ccc(F)cc1
Product: CCCCN1CCC(c2c[nH]c3ccc(NC(=O)c4ccc(F)cc4)nc23)CC1
Yield: 355.6 %

Procedure:
Beginning with 0.15 gm (0.55 mMol) 5-amino-3-(1-BUTYLPIPERIDIN-4-yl)pyrrolo[3,2-b]pyridine and 0.079 mL (0.067 mMol) 4-fluorobenzoyl chloride, 0.094 gm (43%) of the title compound were prepared as an ivory foam essentially by the procedure described in Example 4. An analytical sample was crystallized from aqueous ethanol.