Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(N(CC)CC)C.Cl[CH2:9][CH2:10][C:11]([S:13][CH2:14][CH:15]1[S:19][CH:18]([CH2:20][S:21][C:22](=[O:26])[CH2:23][CH2:24]Cl)[CH2:17][S:16]1)=[O:12].O.C1(C)C=CC=CC=1>CC(C)=O>[C:11]([S:13][CH2:14][CH:15]1[S:19][CH:18]([CH2:20][S:21][C:22](=[O:26])[CH:23]=[CH2:24])[CH2:17][S:16]1)(=[O:12])[CH:10]=[CH2:9]
Reactant: O=C(CCCl)SCC1CSC(CSC(=O)CCCl)S1
Solvent: CC(C)=O
Solvent: O
Solvent: CCN(CC)CC
Product: C=CC(=O)SCC1CSC(CSC(=O)C=C)S1
Yield: 72.8 %

Procedure:
Next, 40.0 g (0.39 mol) of triethylamine was added dropwise to a solution of 52.1 g of 2,4-bis(3-chloropropionylthiomethyl)-1,3-dithiolan prepared above and dissolved in 195 g of acetone at 2 to 50° C. in 1 hour. They were allowed to react at the same temperature for 1.5 hours, with stirring, to which 520 g of water was added. The resultant mixture was treated with 520 g of toluene to extract the reaction product. The extract organic phase (toluene solution) was washed with water until the aqueous phase turned neutral. Then, the organic phase was separated out, incorporated with 0.12 g of 4-methoxyphenol as a polymerization inhibitor, and distilled under a vacuum to be concentrated while removing toluene, to obtain a lightly yellowish, transparent liquid as the crude product. The crude product thus prepared was purified by silica gel column chromatography (developing solvent: hexane/ethyl acetate mixture), to obtain 24.6 g (0.10 mol) of 2,4-bis(acryloylthiomethyl)-1,3-dithiolan.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][N:4]=[CH:3][C:2]=1[N:7]1[CH2:12][CH2:11][N:10]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:9][CH2:8]1.[Br:20]N1C(=O)CCC1=O>C(Cl)(Cl)Cl>[Br:20][C:5]1[N:4]=[CH:3][C:2]([N:7]2[CH2:8][CH2:9][N:10]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:11][CH2:12]2)=[N:1][CH:6]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: CC(C)(C)OC(=O)N1CCN(c2cnccn2)CC1
Solvent: ClC(Cl)Cl
Product: CC(C)(C)OC(=O)N1CCN(c2cnc(Br)cn2)CC1
Yield: 54.4 %

Procedure:
Using similar reaction conditions as described in step i of intermediate 1, tert-butyl 4-(pyrazin-2-yl)piperazine-1-carboxylate (2 g, 7.5 mmol) was brominated with N-bromosuccinimide (1.46 g, 8.25 mmol) in chloroform (20 ml) to afford 1.4 g (54% yield) of the pure product. MS: m/z=343.1 (M+1).
Reaction SMILES: Cl[C:2](=[O:13])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][C:9]([O:11][CH3:12])=[O:10].[Br:14][C:15]1[CH:21]=[CH:20][C:18]([NH2:19])=[C:17]([N+:22]([O-:24])=[O:23])[CH:16]=1.C(N(CC)CC)C>CN(C=O)C.C(OCC)(=O)C>[Br:14][C:15]1[CH:21]=[CH:20][C:18]([NH:19][C:2](=[O:13])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][C:9]([O:11][CH3:12])=[O:10])=[C:17]([N+:22]([O-:24])=[O:23])[CH:16]=1
Reactant: COC(=O)CCCCCCC(=O)Cl
Reactant: Nc1ccc(Br)cc1[N+](=O)[O-]
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COC(=O)CCCCCCC(=O)Nc1ccc(Br)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 8 h
Yield: 81.2 %

Procedure:
To a solution of methyl 8-chloro-8-oxooctanoate (229 mg, 1.11 mmol) in DMF at 0° C. was added a solution of 4-bromo-2-nitroaniline (200 mg, 0.922 mmol) and triethylamine (0.37 mL, 2.77 mmol) in DMF drop-wise. The reaction was stirred overnight at room temperature, diluted with ethyl acetate and washed with 1 N HCl, saturated sodium bicarbonate solution and brine. The separated organic layer was concentrated and purified by biotage column chromatography to give methyl 8-(4-bromo-2-nitrophenylamino)-8-oxooctanoate (290 mg)
Reaction SMILES: [F:1][C:2]1[CH:15]=[C:14]([CH2:16][CH2:17][N+:18]([O-:20])=O)[CH:13]=[CH:12][C:3]=1[O:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][N:7]=1.C[O-].[Li+].C(=O)(O)[O-].[Na+].[C:29]([C:31]1[C:32]([NH2:38])=[N:33][C:34]([NH2:37])=[CH:35][CH:36]=1)#[CH:30].C(N(CC)CC)C>[Ti](Cl)(Cl)(Cl)Cl.O.O1CCCC1.C(OCC)(=O)C.CO>[F:1][C:2]1[CH:15]=[C:14]([CH:13]=[CH:12][C:3]=1[O:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][N:7]=1)[CH2:16][C:17]1[CH:30]=[C:29]([C:31]2[C:32]([NH2:38])=[N:33][C:34]([NH2:37])=[CH:35][CH:36]=2)[O:20][N:18]=1
Reactant: O=[N+]([O-])CCc1ccc(OCc2ccccn2)c(F)c1
Reactant: C#Cc1ccc(N)nc1N
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: C[O-]
Agent: O=C([O-])O
Solvent: C1CCOC1
Solvent: O
Solvent: CCN(CC)CC
Product: Nc1ccc(-c2cc(Cc3ccc(OCc4ccccn4)c(F)c3)no2)c(N)n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 39.7 %

Procedure:
To a methanol (20.0 mL) solution of 2-(2-fluoro-4-(2-nitro-ethyl)-phenoxymethyl)-pyridine (500 mg, 1.81 mmol) described in Manufacturing Example 87-1-3 was added lithium methoxide (137 mg, 3.61 mmol) under nitrogen atmosphere, which was stirred for 30 minutes at room temperature. The reaction mixture was concentrated under a reduced pressure, and dichloromethane (15.0 mL) and anhydrous tetrahydrofuran (7.00 mL) were added to the residue. Titanium (IV) chloride (656 μL, 5.97 mmol) was added dropwise to the reaction mixture on a dry ice-ethanol bath (−78° C.), and which was stirred for 30 minutes at room temperature. Aqueous sodium bicarbonate and ethyl acetate were added to the reaction mixture on an ice bath (0° C.), which was filtered through a Celite pad. The organic layer of the filtrate was extracted with ethyl acetate, and this organic layer was washed with water and saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under a reduced pressure to obtain a crude product (300 mg). To a tetrahydrofuran (5.00 mL) solution of this crude product (150 mg) and 3-ethynyl-pyridin-2,6-diamine (30.0 mg, 0.225 mmol) described in Manufacturing Example 13-1-3 was added triethylamine (94.1 μL, 0.675 mmol) at room temperature, which was stirred for 1 hour at room temperature. Water was added to the reaction solution, which was extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride and dried over anhydrous magnesium sulfate, and the solvent was evaporated under a reduced pressure. The residue was purified by NH silica gel column chromatography (ethyl acetate:heptane=2:1→10:1) to obtain the title compound (35.0 mg, 39.7%).
Reaction SMILES: [O:1]1[CH:5]=[CH:4][C:3]([C:6]([OH:8])=O)=[CH:2]1.[NH2:9][C:10]1[CH:19]=[CH:18][C:17]2[C:12](=[N:13][C:14]([O:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[CH:15][CH:16]=2)[N:11]=1.C(#N)C>O>[O:20]([C:14]1[N:13]=[C:12]2[C:17]([CH:18]=[CH:19][C:10]([NH:9][C:6]([C:3]3[CH:4]=[CH:5][O:1][CH:2]=3)=[O:8])=[N:11]2)=[CH:16][CH:15]=1)[C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1
Reactant: Nc1ccc2ccc(Oc3ccccc3)nc2n1
Reactant: O=C(O)c1ccoc1
Solvent: O
Solvent: CC#N
Product: O=C(Nc1ccc2ccc(Oc3ccccc3)nc2n1)c1ccoc1
Temperature: 4 °C
Yield: 64.4 %

Procedure:
The procedure is similar to that described in Example 1, but starting with 3-furancarboxylic acid (7.5 g), N,N'-carbonyldiimidazole (10.9 g) and 2-amino-7-phenoxy-1,8-naphthyridine (11.9 g). The product produced by precipitation in water (13 g; m.p. approximately 90° C.) is dissolved in boiling acetonitrile (80 cc). After 2 hours' cooling at 4° C., the crystallised solid is separated by filtration, washed with acetonitrile (2×10 cc) and dried at 40° C. under reduced pressure (0.067 kPa). N-(7-Phenoxy-1,8-naphthyridin-2-yl)-3-furancarboxamide (10.7 g) is produced, m.p. 102° C.
Reaction SMILES: [O:1]1[CH2:5][CH2:4][O:3][CH:2]1[CH2:6][CH:7]1[CH2:12][C:11](=[O:13])[CH2:10][C:9](=[O:14])[CH2:8]1.C(Cl)(Cl)Cl.C1(C)C=CC=CC=1.C([O-])(=O)C.C([O-])(=O)C.C([O-])(=O)C.[Cl:38][C:39]1[CH:44]=[CH:43][C:42]([C:45]2[CH:50]=[CH:49][C:48]([CH3:51])=[C:47]([Pb+3])[CH:46]=2)=[CH:41][CH:40]=1>ClCCl>[Cl:38][C:39]1[CH:40]=[CH:41][C:42]([C:45]2[CH:50]=[CH:49][C:48]([CH3:51])=[C:47]([CH:10]3[C:11](=[O:13])[CH2:12][CH:7]([CH2:6][CH:2]4[O:3][CH2:4][CH2:5][O:1]4)[CH2:8][C:9]3=[O:14])[CH:46]=2)=[CH:43][CH:44]=1
Reactant: Cc1ccc(-c2ccc(Cl)cc2)cc1[Pb+3]
Reactant: O=C1CC(=O)CC(CC2OCCO2)C1
Agent: CC(=O)[O-]
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Solvent: Cc1ccccc1
Product: Cc1ccc(-c2ccc(Cl)cc2)cc1C1C(=O)CC(CC2OCCO2)CC1=O
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a solution of 5-[1,3]dioxolan-2-ylmethylcyclohexane-1,3-dione (1.43 g, 7.22 mmol) in a mixed solvent system of chloroform (72 ml) and toluene (18 ml) is added N,N-dimethylaminopyridine (4.40 g, 36.08 mmol) and the solution is stirred at room temperature for 10 minutes. To this mixture is then added 4′-chloro-4-methylbiphenyl-3-yllead triacetate (described in WO 2008/071405) (4.95 g, 7.91 mmol) in one portion, followed by heating at 80° C. for 2 hours. After cooling to room temperature the solution is diluted with dichloromethane (90 ml) and quenched with 1M hydrochloric acid (90 ml). The resulting precipitate is filtered through celite and the residue washed with additional dichloromethane (20 ml). The biphasic solution is separated and the organic layer further washed with 1M hydrochloric acid (45 ml). Organics are finally passed through a phase separator then concentrated in vacuo to afford the crude product as a yellow oil. After flash column chromatography on silica (7:1 ethyl acetate/hexane eluant) 2-(4′-chloro-4-methylbiphenyl-3-yl)-5-[1,3]dioxolan-2-ylmethylcyclohexane-1,3-dione is afforded as a cream solid.
Reaction SMILES: [OH:1][N:2]=[C:3](Cl)[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([O:10][C:11]([F:14])([F:13])[F:12])[CH:5]=1.[CH3:16][O:17][C:18](=[O:23])[CH2:19][C:20]([CH3:22])=O.C[O-].[Na+]>CO>[CH3:16][O:17][C:18]([C:19]1[C:3]([C:4]2[CH:9]=[CH:8][CH:7]=[C:6]([O:10][C:11]([F:14])([F:13])[F:12])[CH:5]=2)=[N:2][O:1][C:20]=1[CH3:22])=[O:23]
Reactant: COC(=O)CC(C)=O
Reactant: ON=C(Cl)c1cccc(OC(F)(F)F)c1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: COC(=O)c1c(-c2cccc(OC(F)(F)F)c2)noc1C
Yield: 67.8 %

Procedure:
In a similar manner as described in Preparation Example 17, by using methanol (160 mL), N-hydroxy-3-(trifluoromethoxy)benzimidoylchloride (8.00 g, 33.39 mmol), methylacetoacetate (7.76 g, 66.78 mmol) and sodium methoxide (5.41 g, 100.17 mmol), a white solid required compound (6.82 g, 22.64 mmol, 68%) was obtained.
Reaction SMILES: ClC1C=C(S)C=CC=1.C(=O)([O-])[O-].[Na+].[Na+].[Cl:15][C:16]1[CH:17]=[C:18]([S:22][CH:23]2[CH2:28][CH2:27][CH2:26][N:25](S(C3C=CC(C)=CC=3)(=O)=O)[CH2:24]2)[CH:19]=[CH:20][CH:21]=1.C1(O)C=CC=CC=1.[BrH:46]>CN(C)C=O>[BrH:46].[Cl:15][C:16]1[CH:17]=[C:18]([S:22][CH:23]2[CH2:28][CH2:27][CH2:26][NH:25][CH2:24]2)[CH:19]=[CH:20][CH:21]=1
Reactant: Cc1ccc(S(=O)(=O)N2CCCC(Sc3cccc(Cl)c3)C2)cc1
Agent: Br
Agent: O=C([O-])[O-]
Agent: Sc1cccc(Cl)c1
Solvent: CN(C)C=O
Solvent: Oc1ccccc1
Product: Clc1cccc(SC2CCCNC2)c1
Temperature: 100 °C

Procedure:
A mixture of 25.2 g (0.175 mole) of m-chlorothiophenol, 48.26 g (0.118 mole) of 1-[(4-methylphenyl)sulfonyl]-3-piperidinol-4-methylphenylsulfonate ester and 56 g of sodium carbonate in 300 ml of dimethylformamide was heated at 100° C. for 22 hr. The mixture was cooled and quenched in excess 1M sodium hydroxide solution. The aqueous mixture was extracted with several portions of methylene chloride and the combined methylene chloride extracts were extracted with several portions of 1N sodium hydroxide solution and dried over magnesium sulfate. The solvent was removed in vacuo to give an oil which was shown by NMR, mass spectrum and TLC to be 3-[(3-chlorophenyl)thio]-1-[(4-methylphenyl)sulfonyl]piperidine. A mixture of the oil and excess phenol in 200 ml of 48% hydrobromic acid was refluxed for 1 hr and quenched in an ice-water mix. The mixture was made basic with sodium hydroxide and extracted with several portions of methylene chloride. The combined methylene chloride extracts were extracted with several portions of 1M sulfuric acid and the methylene chloride layer discarded. The combined acidic extracts were made basic with sodium hydroxide and the basic solution was extracted with several portions of methylene chloride. The aqueous layer was discarded. The combined methylene chloride extract was dried over magnesium sulfate and methylene chloride was removed in vacuo to give an oil, the free base of the title compound. The free base was reacted with hydrogen bromide using the solvent pair isopropanol-isopropyl ether for crystallization and recrystallization to obtain the hydrobromide salt, m.p. 117.5°-120° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:17]=[C:16]([C:18](=[O:29])[CH2:19][N:20]2[CH2:25][CH2:24][N:23]([CH:26]([CH3:28])[CH3:27])[CH2:22][CH2:21]2)[CH:15]=[C:14]2[C:9]=1[CH2:10][N:11](CC1C=CC(OC)=CC=1)[C:12](=[O:38])[N:13]2[C:30]1[C:35]([Cl:36])=[CH:34][CH:33]=[CH:32][C:31]=1[Cl:37]>FC(F)(F)C(O)=O>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:17]=[C:16]([C:18](=[O:29])[CH2:19][N:20]2[CH2:21][CH2:22][N:23]([CH:26]([CH3:28])[CH3:27])[CH2:24][CH2:25]2)[CH:15]=[C:14]2[C:9]=1[CH2:10][NH:11][C:12](=[O:38])[N:13]2[C:30]1[C:31]([Cl:37])=[CH:32][CH:33]=[CH:34][C:35]=1[Cl:36]
Reactant: COc1ccc(CN2Cc3c(-c4ccccc4Cl)cc(C(=O)CN4CCN(C(C)C)CC4)cc3N(c3c(Cl)cccc3Cl)C2=O)cc1
Solvent: O=C(O)C(F)(F)F
Product: CC(C)N1CCN(CC(=O)c2cc(-c3ccccc3Cl)c3c(c2)N(c2c(Cl)cccc2Cl)C(=O)NC3)CC1
Temperature: 70 °C

Procedure:
5-(2-Chlorophenyl)-1-(2,6-dichlorophenyl)-7-[(4-isopropylpiperazin-1-yl)acetyl]-3-(4-methoxybenzyl)-3,4-dihydroquinazolin-2(1H)-one (36 mg, 0.052 mmol) was dissolved in trifluoroacetic acid (0.8 mL), and this mixture was heated at 70° C. for 30 min. After cooling it down, trifluoroacetic acid was removed by co-evaporation with toluene to give crude product. This was purified by preparative thin layer chromatography using 5% 2M NH3 in MeOH/CH2Cl2 as an eluent to give the title compound. 1H NMR (CDCl3, 500 MHz): δ 7.54-7.29 (m, 8H); 6.94 (s, 1H); 5.44 (s, 1H); 4.47 (d, J=15.6 Hz, 1H); 4.29 (d, J=15.6 Hz, 1H); 3.54 (Abq, J=4.1, 14.9 Hz, 2H); 2.62 (m, 1H); 2.48 (brs, 8H); 1.03 (2 s, 6H). Mass spectrum (ESI): 571.2 (M+1).
Reaction SMILES: CC1C=CC(S(O[CH2:12][C@H:13]2[CH2:26][O:25][C:16]3[CH:17]=[CH:18][C:19]4[N:20]=[C:21]([CH3:24])[O:22][C:23]=4[C:15]=3[O:14]2)(=O)=O)=CC=1.[NH:27]1[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]1.C(O)(=O)/C=C/C(O)=O>C(O)C>[CH3:24][C:21]1[O:22][C:23]2=[C:15]3[C:16](=[CH:17][CH:18]=[C:19]2[N:20]=1)[O:25][CH2:26][CH:13]([CH2:12][N:27]1[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]1)[O:14]3
Reactant: C1CCNCC1
Reactant: Cc1ccc(S(=O)(=O)OC[C@H]2COc3ccc4nc(C)oc4c3O2)cc1
Agent: O=C(O)/C=C/C(=O)O
Solvent: CCO
Product: Cc1nc2ccc3c(c2o1)OC(CN1CCCCC1)CO3
Temperature: 80 °C

Procedure:
(8R)-2-Methyl-7,8-dihydro[1,4]dioxino[2,3-g][1,3]benzoxazol-8-ylmethyl 4-methylbenzenesulfonate (0.38 g, 1 mmole) and piperidine 15 ml were combined and heated at 80° C. under nitrogen for 4 hours. After completion, piperidine was removed under vacuum and the residue was partitioned between ethyl acetate and saturated aqueous sodium bicarbonate. The organic phase was washed with brine, dried over magnesium sulfate and concentrated in vacuum. The crude oil was column chromatographed on silica gel using first methylene chloride to remove impurities and then 1% methanol/methylene chloride to elute the (S)-enantiomer of the title compound. This was recrystallized from ethanol with the addition of one equivalent of fumaric acid to give 0.24 g of white solid, m.p. 109-112° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:9]2[N:14]3[N:15]=[C:16]([CH3:18])[CH:17]=[C:13]3[NH:12][C:11](=O)[CH:10]=2)[CH:5]=[C:6]([F:8])[CH:7]=1.N1C=CC=CC=1.O=P(Cl)(Cl)[Cl:28]>>[Cl:28][C:11]1[CH:10]=[C:9]([C:4]2[CH:3]=[C:2]([F:1])[CH:7]=[C:6]([F:8])[CH:5]=2)[N:14]2[N:15]=[C:16]([CH3:18])[CH:17]=[C:13]2[N:12]=1
Reactant: Cc1cc2[nH]c(=O)cc(-c3cc(F)cc(F)c3)n2n1
Reactant: O=P(Cl)(Cl)Cl
Solvent: c1ccncc1
Product: Cc1cc2nc(Cl)cc(-c3cc(F)cc(F)c3)n2n1
Temperature: 100 °C

Procedure:
7-(3,5-Difluorophenyl)-2-methylpyrazolo[1,5-a]pyrimidin-5(4H)-one (521 mg) is dissolved in POCl3 (15 mL) and pyridine (0.2 mL) and stirred overnight while heating at 100° C. After cooling to room temperature, the reaction solvent is removed by distillation under reduced pressure. The remainder is extracted with ethyl acetate and water. The extracted organic layer is washed with 1 M NaHCO3 aqueous solution and brine and dehydrated with anhydrous MgSO4. The dehydrated organic layer is distilled under reduced pressure and purified by column chromatography to yield the target compound (327 mg). 1H NMR (CDCl3, 300 MHz) δ 7.63 (m, 2H), 7.02 (m, 1H), 6.82 (m, 1H), 6.52 (m, 1H), 2.52 (s, 3H).
Reaction SMILES: [S:1]([O:8][CH2:9][C:10]([O:12][CH3:13])=[O:11])([C:4]([F:7])([F:6])[F:5])(=[O:3])=[O:2].[CH2:14]([CH:18](O)C([O-])=O)[CH2:15]CC>>[S:1]([O:8][CH2:9][C:10]([O:12][CH2:13][CH2:15][CH2:14][CH3:18])=[O:11])([C:4]([F:6])([F:7])[F:5])(=[O:3])=[O:2]
Reactant: CCCCC(O)C(=O)[O-]
Reactant: COC(=O)COS(=O)(=O)C(F)(F)F
Product: CCCCOC(=O)COS(=O)(=O)C(F)(F)F

Procedure:
Prepared in the same way as described for TfO-CH2COOMe starting with butylglycolate.
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][NH:3][C:2]1=[O:6].[H-].[Na+].Br[CH2:10][CH2:11][O:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>CN(C=O)C.O>[CH2:13]([O:12][CH2:11][CH2:10][N:1]1[CH2:5][CH2:4][NH:3][C:2]1=[O:6])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: BrCCOCc1ccccc1
Reactant: O=C1NCCN1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: O=C1NCCN1CCOCc1ccccc1

Procedure:
To a solution of imidazolidin-2-one (500 mg) in DMF (5.0 mL) was added a sodium hydride 60% dispersion in mineral oil (232 mg) under ice-cooling, and the mixture was stirred under ice-cooling for 20 min. ((2-Bromoethoxy)methyl)benzene (0.83 mL) was added to the reaction mixture, and the mixture was stirred overnight at room temperature. The reaction mixture was diluted with water, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (methanol/ethyl acetate) to give the title compound (388 mg).
Reaction SMILES: [CH2:1]([C:7]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[N:9]([CH3:16])[CH:8]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].[Cl-].C[Al+]C.[CH3:21][O:22][C:23](=[O:30])[CH2:24][CH2:25][CH2:26][C:27](Cl)=[O:28].[Cl-].[NH4+]>C(Cl)Cl.CCCCCC.C(OCC)(=O)C>[CH3:21][O:22][C:23](=[O:30])[CH2:24][CH2:25][CH2:26][C:27]([C:8]1[N:9]([CH3:16])[C:10]2[C:15]([C:7]=1[CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH3:6])=[CH:14][CH:13]=[CH:12][CH:11]=2)=[O:28]
Reactant: CCCCCCc1cn(C)c2ccccc12
Reactant: COC(=O)CCCC(=O)Cl
Agent: C[Al+]C
Agent: [Cl-]
Agent: [NH4+]
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: CCCCCCc1c(C(=O)CCCC(=O)OC)n(C)c2ccccc12
Reaction time: 0.5 h

Procedure:
To a solution of 3-hexyl-1-methyl-1H-indole in methylene chloride at 0° C. was added dimethyl aluminum chloride solution in hexane. The reaction mixture was stirred for 30 minutes. To this solution 4-chlorocarbonyl-butyric acid methyl ester was added at 0 ° C. and the reaction mixture was stirred for 3 hours. The reaction was treated with saturated ammonium chloride and ethyl acetate. The product was purified by column chromatography.
Reaction SMILES: [C:1]1([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]([OH:14])=[O:13].[Cl:21][C:22]1[CH:30]=[CH:29][C:25]([C:26](Cl)=[O:27])=[CH:24][CH:23]=1.Cl>[OH-].[Na+]>[Cl:21][C:22]1[CH:30]=[CH:29][C:25]([C:26]([N:7]([CH2:8][CH2:9][CH2:10][CH2:11][C:12]([OH:14])=[O:13])[C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][C:1]=2[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[O:27])=[CH:24][CH:23]=1
Reactant: O=C(O)CCCCNc1ccccc1-c1ccccc1
Reactant: O=C(Cl)c1ccc(Cl)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: O=C(O)CCCCN(C(=O)c1ccc(Cl)cc1)c1ccccc1-c1ccccc1

Procedure:
5.4 g of 5-[N-(biphenyl-2-yl)amino]valeric acid is dissolved in 40 ml of 0.2 N caustic soda solution. Into the resulting clear solution (while vigorously stirring and constantly controlling the pH) 3.5 g of p-chlorobenzoyl chloride is added, drop by drop, while concurrently adding dilute caustic soda solution in order to maintain the pH at between 7 and 8. After the addition of acid chloride is complete, the solution is stirred for a further 30 minutes at pH 8 and then acidified to pH 3 with dilute hydrochloric acid. The precipitate, which is oily at first crystallizes after a time. It is filtered off and recrystallized from isopropyl alcohol to obtain 7.6 g (93% of thoery) of 5-[p-chloro-N-(biphenyl-2-yl)benzamido]valeric acid, MP 170° to 173°, which is identical with the compound obtained by the procedure of Example 53.
Reaction SMILES: [C:1]([NH:5][C:6]([C:8]1[C:12]2=[N:13][C:14]([C:17]3[C:25]4[C:20](=[CH:21][CH:22]=[C:23]([O:26][CH:27]([F:29])[F:28])[CH:24]=4)[N:19]([CH2:30][CH2:31][C:32](=[O:34])[CH3:33])[N:18]=3)=[CH:15][N:16]=[C:11]2[N:10]([C:35]([C:48]2[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=2)([C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)[C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[CH:9]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[BH4-].[Na+].[NH4+].[Cl-]>CO>[C:1]([NH:5][C:6]([C:8]1[C:12]2=[N:13][C:14]([C:17]3[C:25]4[C:20](=[CH:21][CH:22]=[C:23]([O:26][CH:27]([F:28])[F:29])[CH:24]=4)[N:19]([CH2:30][CH2:31][CH:32]([OH:34])[CH3:33])[N:18]=3)=[CH:15][N:16]=[C:11]2[N:10]([C:35]([C:42]2[CH:43]=[CH:44][CH:45]=[CH:46][CH:47]=2)([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[C:48]2[CH:49]=[CH:50][CH:51]=[CH:52][CH:53]=2)[CH:9]=1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(=O)CCn1nc(-c2cnc3c(n2)c(C(=O)NC(C)(C)C)cn3C(c2ccccc2)(c2ccccc2)c2ccccc2)c2cc(OC(F)F)ccc21
Agent: [BH4-]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CO
Product: CC(O)CCn1nc(-c2cnc3c(n2)c(C(=O)NC(C)(C)C)cn3C(c2ccccc2)(c2ccccc2)c2ccccc2)c2cc(OC(F)F)ccc21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of N-tert-butyl-2-(5-(difluoromethoxy)-1-(3-oxobutyl)-1H-indazol-3-yl)-5-trityl-5H-pyrrolo[3,2-b]pyrazine-7-carboxamide (0.156 mmol) in MeOH (5 mL) was added NaBH4 (30 mg, 0.78 mmol) at 0° C. The mixture was warmed at room temperature and stirred for 1 hour. Aqueous NH4Cl solution was added to the mixture and product extracted with EtOAc (3×10 mL). The combined organic layers were washed with brine and dried over Na2SO4. After filtration and concentration, the crude product was used in the next step without purification. MS: (M+H)+=715.
Reaction SMILES: [CH2:1]([NH:3][CH2:4][CH3:5])[CH3:2].C(=O)([O-])[O-].[Na+].[Na+].[CH2:12]([C:16]1[CH2:17][C:18]2[C:23]([C:24]=1Br)=[CH:22][C:21]1[O:26][CH2:27][O:28][C:20]=1[CH:19]=2)[CH2:13][CH2:14][CH3:15].C(=O)([O-])O.[Na+]>CS(C)=O>[CH2:12]([C:16]1[CH2:17][C:18]2[C:23]([C:24]=1[N:3]([CH2:4][CH3:5])[CH2:1][CH3:2])=[CH:22][C:21]1[O:26][CH2:27][O:28][C:20]=1[CH:19]=2)[CH2:13][CH2:14][CH3:15]
Reactant: CCNCC
Reactant: CCCCC1=C(Br)c2cc3c(cc2C1)OCO3
Agent: O=C([O-])O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CS(C)=O
Product: CCCCC1=C(N(CC)CC)c2cc3c(cc2C1)OCO3
Reaction time: 5 h
Yield: 65 %

Procedure:
To a solution containing 300 mg of diethylamine and 430 mg of sodium carbonate in 6 ml of dimethylsulfoxide, 600 mg of 2-n-butyl-3-bromo-5,6-methylenedioxyindene was added at room temperature. The reaction mixture was stirred for 5 hours. After completion of the reaction, the reaction mixture was added with a saturated aqueous solution of sodium hydrogencarbonate and then extracted with ether. The ethereal layer was washed with water, dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (eluent: a 10:1 mixture of n-hexane and ether) to give 380 mg of an oily substance (yield: 65%).
Reaction SMILES: [CH:1]1([C:4]2[O:5][C:6]3[C:7](=[C:9]([C:17]#[N:18])[C:10]([CH3:16])=[C:11]([CH:14]=[CH2:15])[C:12]=3[F:13])[N:8]=2)[CH2:3][CH2:2]1.[H][H]>C(OCC)(=O)C.[C].[Pd]>[CH:1]1([C:4]2[O:5][C:6]3[C:7](=[C:9]([C:17]#[N:18])[C:10]([CH3:16])=[C:11]([CH2:14][CH3:15])[C:12]=3[F:13])[N:8]=2)[CH2:3][CH2:2]1
Reactant: C=Cc1c(C)c(C#N)c2nc(C3CC3)oc2c1F
Reactant: [H][H]
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CCc1c(C)c(C#N)c2nc(C3CC3)oc2c1F
Yield: 95.8 %

Procedure:
2-Cyclopropyl-7-fluoro-5-methyl-6 vinyl-1,3-benzoxazole-4-carbonitrile (I-180) (114 mg, 0.47 mmol) was dissolved in ethyl acetate (2.5 ml), then at room temperature, 10% palladium-carbon (23 mg) was added. The suspension was stirred at the same temperature under atmospheric pressure of hydrogen for 16 hours. The catalyst was separated by filtration with washing with ethyl acetate, and the filtrate was concentrated under reduced pressure. The residue was purified by preparative TLC (eluent, ethyl acetate:hexane=1:2) to obtain the entitled compound (110 mg, 96%) as a white solid.