Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:44])([F:43])[C:3]1[CH:4]=[C:5]([CH:40]=[CH:41][CH:42]=1)[CH2:6][NH:7][C:8]([C:10]1[CH:15]=[CH:14][N:13]=[C:12]([C:16]2[CH:21]=[C:20]([N:22]3[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]3)[CH:19]=[CH:18][C:17]=2[NH:28][C:29]([C:31]2[CH:32]=[C:33]([CH:37]=[CH:38][CH:39]=2)[C:34](O)=[O:35])=[O:30])[CH:11]=1)=[O:9].CN(CCN1CCOCC1)C(=O)C1C=CC=[C:50]([C:51]([NH:53][C:54]2C=CC(N3CCCCC3)=C[C:55]=2[C:66]2C=C(C(=O)NCC3C=CC=C(C(F)(F)F)C=3)C=[CH:68][N:67]=2)=[O:52])C=1.CC#N.N1CC[C@@H](NC(=O)C)C1>CN(C=O)C>[C:51]([NH:53][C@H:54]1[CH2:55][CH2:66][N:67]([C:34]([C:33]2[CH:32]=[C:31]([CH:39]=[CH:38][CH:37]=2)[C:29]([NH:28][C:17]2[CH:18]=[CH:19][C:20]([N:22]3[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]3)=[CH:21][C:16]=2[C:12]2[CH:11]=[C:10]([CH:15]=[CH:14][N:13]=2)[C:8]([NH:7][CH2:6][C:5]2[CH:40]=[CH:41][CH:42]=[C:3]([C:2]([F:1])([F:44])[F:43])[CH:4]=2)=[O:9])=[O:30])=[O:35])[CH2:68]1)(=[O:52])[CH3:50]
Reactant: CN(CCN1CCOCC1)C(=O)c1cccc(C(=O)Nc2ccc(N3CCCCC3)cc2-c2cc(C(=O)NCc3cccc(C(F)(F)F)c3)ccn2)c1
Reactant: O=C(O)c1cccc(C(=O)Nc2ccc(N3CCCCC3)cc2-c2cc(C(=O)NCc3cccc(C(F)(F)F)c3)ccn2)c1
Agent: CC(=O)N[C@@H]1CCNC1
Solvent: CN(C)C=O
Solvent: CC#N
Product: CC(=O)N[C@H]1CCN(C(=O)c2cccc(C(=O)Nc3ccc(N4CCCCC4)cc3-c3cc(C(=O)NCc4cccc(C(F)(F)F)c4)ccn3)c2)C1

Procedure:
This compound was prepared from 3-((2-(4-((3-(trifluoromethyl)benzyl)carbamoyl)pyridin-2-yl)-4-(piperidin-1-yl)phenyl)carbamoyl)-benzoic acid 4.1e using the procedure described for the preparation of N1-methyl-N1-(2-morpholinoethyl)-N3-(4-(piperidin-1-yl)-2-(4-((3-(trifluoromethyl)benzyl)carbamoyl)-pyridin-2-yl)phenyl)isophthalamide 4.8, except that CH3CN was substituted for DMF as the reaction solvent and (R)—N-(pyrrolidin-3-yl)acetamide was used as the amine component. 1H-NMR (300 MHz, CD3OD, ppm): δ 8.99 (d, J=6.0 Hz, 1H), 8.70 (d, J=9.6 Hz, 1H), 8.41 (s, 1H), 8.21 (d, J=6.0 Hz, 1H), 8.12 (d, J=7.8 Hz, 1H), 8.01 (s, 1H), 7.88˜7.78 (m, 2H), 7.72˜7.54 (m, 6H), 4.72 (s, 1H), 4.51˜4.28 (m, 1H), 3.91˜3.52 (m, 8H), 2.30˜4.79 (m, 11H). MS (ES, m/z): 713 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[CH:4][C:3]=1[C:9]([F:20])([F:19])[C:10]([F:18])([F:17])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.[Br:21]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[CH3:1][C:2]1[C:3]([C:9]([F:19])([F:20])[C:10]([F:17])([F:18])[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)=[CH:4][CH:5]=[CH:6][C:7]=1[CH2:8][Br:21]
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1cccc(C(F)(F)C(F)(F)c2ccccc2)c1C
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: Cc1c(CBr)cccc1C(F)(F)C(F)(F)c1ccccc1

Procedure:
A mixture of 4.0 g. (0.0142 mole) of 2,3-dimethyl-α,α,α',α'-tetrafluorobibenzyl, 2.52 g. (0.0142 mole) of N-bromosuccinimide, about 50 mg. of benzoyl peroxide, and 100 ml. of carbon tetrachloride is stirred at reflux for 21/2 hours. After cooling, the precipitate of succinimide is removed by filtration and the filtrate is evaporated to dryness under reduced pressure. The residual solid is recrystallized from petroleum ether to yield the white crystalline product, m.p. 67°-71°C. Repeated recrystallization from petroleum ether affords the analytical sample, m.p. 69°-71°C.
Reaction SMILES: [C:1]([OH:9])(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CCN(C(C)C)C(C)C.[NH2:41][C:42]1[NH:43][C:44]2[C:45]([N:63]=1)=[CH:46][C:47]1[C:48]([CH3:62])([CH3:61])[C:49](=[O:60])[N:50]([CH2:53][C:54](=[O:59])[C:55]([CH3:58])([CH3:57])[CH3:56])[C:51]=1[CH:52]=2>CN(C)C=O>[CH3:56][C:55]([CH3:58])([CH3:57])[C:54](=[O:59])[CH2:53][N:50]1[C:51]2[CH:52]=[C:44]3[NH:43][C:42]([NH:41][C:1](=[O:9])[C:2]4[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=4)=[N:63][C:45]3=[CH:46][C:47]=2[C:48]([CH3:61])([CH3:62])[C:49]1=[O:60]
Reactant: O=C(O)c1ccccc1
Reactant: CC(C)(C)C(=O)CN1C(=O)C(C)(C)c2cc3nc(N)[nH]c3cc21
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)C(=O)CN1C(=O)C(C)(C)c2cc3nc(NC(=O)c4ccccc4)[nH]c3cc21
Temperature: 25 °C
Reaction time: 18 h
Yield: 66.5 %

Procedure:
A solution of benzoic acid (85.5 mg), TBTU (225 mg; 0.70 mmol) and DIPEA (240 μl) in N,N-dimethylformamide (8 ml) is stirred at RT for 5 min. Afterwards D7 (210 mg) is added and the mixture is stirred at RT for 18 h. After evaporation of the solvent the crude material is purified by RP-MPLC eluted with MeCN/water to give the desired compound (186 mg).
Reaction SMILES: [CH3:1][N:2]([CH:22]1[CH2:27][CH2:26][N:25]([CH2:28][C:29]2[CH:34]=[CH:33][N:32]=[C:31]([C:35]3[CH:40]=[C:39]([O:41][CH3:42])[C:38]([O:43]C)=[C:37]([O:45][CH3:46])[CH:36]=3)[CH:30]=2)[CH2:24][CH2:23]1)[CH2:3][C:4]1[CH:9]=[CH:8][N:7]=[C:6]([C:10]2[CH:15]=[C:14]([O:16][CH3:17])[C:13]([O:18]C)=[C:12]([O:20][CH3:21])[CH:11]=2)[CH:5]=1.I[Si](C)(C)C.O.C(=O)([O-])O.[Na+].[Cl:58]CCl>C(OCC)(=O)C>[ClH:58].[ClH:58].[ClH:58].[ClH:58].[CH3:1][N:2]([CH:22]1[CH2:23][CH2:24][N:25]([CH2:28][C:29]2[CH:34]=[CH:33][N:32]=[C:31]([C:35]3[CH:36]=[C:37]([O:45][CH3:46])[C:38]([OH:43])=[C:39]([O:41][CH3:42])[CH:40]=3)[CH:30]=2)[CH2:26][CH2:27]1)[CH2:3][C:4]1[CH:9]=[CH:8][N:7]=[C:6]([C:10]2[CH:11]=[C:12]([O:20][CH3:21])[C:13]([OH:18])=[C:14]([O:16][CH3:17])[CH:15]=2)[CH:5]=1
Reactant: ClCCl
Reactant: COc1cc(-c2cc(CN3CCC(N(C)Cc4ccnc(-c5cc(OC)c(OC)c(OC)c5)c4)CC3)ccn2)cc(OC)c1OC
Agent: C[Si](C)(C)I
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Product: COc1cc(-c2cc(CN3CCC(N(C)Cc4ccnc(-c5cc(OC)c(O)c(OC)c5)c4)CC3)ccn2)cc(OC)c1O
Product: Cl
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To an ice-cooled solution of 4-[N-methyl-N-[[2-(3,4,5-trimethoxyphenyl)pyridin-4-yl]methyl]amino]-1-[[2-(3,4,5-trimethoxyphenyl)pyridin-4-yl]methyl]piperidine (100 mg) in dichloromethane (5 mL) was added iodotrimethylsilane (173 μL). The mixture was stirred at 0° C. for 2 hours and then at room temperature overnight. A small amount of water, ethyl acetate and saturated aqueous sodium hydrogencarbonate were added to the mixture at 0° C. and the organic layer was separated. The organic layer was washed with brine, dried over anhydrous magnesium sulfate and evaporated. The residue was applied to a preparative TLC using chloroform-ammonia saturated methanol (15:1) to give a free base of the title compound which was converted to a tetrahydrochloride by the conventional method.
Reaction SMILES: [C:1]([O:5][C:6](=[O:19])[NH:7][C@H:8]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C@@H:9]([OH:12])[CH2:10][OH:11])([CH3:4])([CH3:3])[CH3:2].[C:20]([Si:24]([CH3:27])([CH3:26])Cl)([CH3:23])([CH3:22])[CH3:21].N1C=CN=C1.ClCCl>C(OCC)(=O)C.O>[C:1]([O:5][C:6](=[O:19])[NH:7][C@H:8]([C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1)[C@@H:9]([OH:12])[CH2:10][O:11][Si:24]([C:20]([CH3:23])([CH3:22])[CH3:21])([CH3:27])[CH3:26])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: CC(C)(C)OC(=O)N[C@H](c1ccccc1)[C@@H](O)CO
Agent: c1c[nH]cn1
Solvent: O
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N[C@H](c1ccccc1)[C@@H](O)CO[Si](C)(C)C(C)(C)C
Reaction time: 2 h
Yield: 79.7 %

Procedure:
A mixture of 620 mg of tert-butyl[(1R,2R)-2,3-dihydroxy-1-phenylpropyl]carbamate, 0.37 g of tert-butyldimethylchlorosilane, 0.19 g of imidazole, and 9.3 ml of dichloromethane was stirred for 2 hours. To the reaction mixture were added water and ethyl acetate to carry out a layer separation operation. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography to obtain 705 mg of tert-butyl[(1R,2R)-3-{[tert-butyl(dimethyl)silyl]oxy}-2-hydroxy-1-phenylpropyl]carbamate.
Reaction SMILES: C([O-])(=O)C.[NH4+].[N+:6]([CH3:9])([O-:8])=[O:7].[CH2:10]([O:17][C:18]1[CH:19]=[C:20]([CH:23]=[CH:24][C:25]=1[O:26][CH2:27][CH2:28][CH2:29][O:30][CH3:31])[CH:21]=O)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>C(O)(=O)C>[CH2:10]([O:17][C:18]1[CH:19]=[C:20](/[CH:21]=[CH:9]/[N+:6]([O-:8])=[O:7])[CH:23]=[CH:24][C:25]=1[O:26][CH2:27][CH2:28][CH2:29][O:30][CH3:31])[C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: C[N+](=O)[O-]
Reactant: COCCCOc1ccc(C=O)cc1OCc1ccccc1
Agent: CC(=O)[O-]
Agent: [NH4+]
Solvent: CC(=O)O
Product: COCCCOc1ccc(/C=C/[N+](=O)[O-])cc1OCc1ccccc1
Temperature: 130 °C
Reaction time: 2 h

Procedure:
Ammonium acetate (6.10 g, 79.1 mmol) and nitromethane (8.93 mL, 165 mmol) were added to a solution of 3-(benzyloxy)-4-(3-methoxypropoxy)benzaldehyde described in Production Example 32-2 (19.8 g, 65.9 mmol) in acetic acid (52.8 mL) under nitrogen atmosphere at room temperature. The liquid mixture was stirred under a thermal condition of 130° C. for 2 hours. The reaction liquid was allowed to stand to cool to room temperature, then the precipitate was collected by filteration and washed with ethanol to quantitatively obtain the title compound.
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[C:4]([C:10]([F:13])([F:12])[F:11])[CH:3]=1.[CH2:14](O)[CH2:15][OH:16].CC1C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[F:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]2[O:16][CH2:15][CH2:14][O:7]2)=[C:4]([C:10]([F:11])([F:12])[F:13])[CH:3]=1
Reactant: O=Cc1ccc(F)cc1C(F)(F)F
Reactant: OCCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: Fc1ccc(C2OCCO2)c(C(F)(F)F)c1
Reaction time: 4 h
Yield: 51 %

Procedure:
To a solution of commercially available 4-fluoro-2-(trifluoromethyl)benzaldehyde (15 g, 78 mmol) in toluene (90 mL) was added ethylene glycol (21.77 mL, 390 mmol) and TsOH (0.743 g, 3.90 mmol). The mixture was then heated (under a Dean-Stark trap attached to a reflux condenser) in an oil bath at 140° C. for 4 h, about 1.4-1.5 mL of water was collected, which was close to the expected volume. TLC (20% EtOAc-hexane) showed a major, new more polar spot. The mixture is diluted with EtOAc (100 mL) and washed with water (50 mL). The organic phase is washed with water (1×50 mL) and brine (50 mL), dried over Na2SO4, filtered and concentrated. The residue was purified by silica gel column chromatography (330 g ISCO column) eluting with 0-10% EtOAc-hexane gradient. The cleanest fractions with product afforded 9.83 g (51% yield): MS (ESI): m/z 237 (M+H).
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[C:8]([NH:10][CH2:11][CH2:12][O:13][CH3:14])[C:5]([C:6]#[N:7])=[CH:4][N:3]=1.N1([C:20](N2C=NC=N2)=[O:21])C=NC=N1.[CH3:27][O:28][CH:29]([O:48][CH3:49])[C:30]1[C:39]([CH2:40][N:41]2[CH2:46][CH2:45][S:44][CH2:43][C:42]2=[O:47])=[CH:38][C:37]2[CH2:36][CH2:35][CH2:34][NH:33][C:32]=2[N:31]=1>CN(C=O)C>[C:6]([C:5]1[C:8]([NH:10][CH2:11][CH2:12][O:13][CH3:14])=[CH:9][C:2]([NH:1][C:20]([N:33]2[C:32]3[C:37](=[CH:38][C:39]([CH2:40][N:41]4[CH2:46][CH2:45][S:44][CH2:43][C:42]4=[O:47])=[C:30]([CH:29]([O:48][CH3:49])[O:28][CH3:27])[N:31]=3)[CH2:36][CH2:35][CH2:34]2)=[O:21])=[N:3][CH:4]=1)#[N:7]
Reactant: COCCNc1cc(N)ncc1C#N
Reactant: O=C(n1cncn1)n1cncn1
Reactant: COC(OC)c1nc2c(cc1CN1CCSCC1=O)CCCN2
Solvent: CN(C)C=O
Product: COCCNc1cc(NC(=O)N2CCCc3cc(CN4CCSCC4=O)c(C(OC)OC)nc32)ncc1C#N
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A solution of 6-amino-4-((2-methoxyethyl)amino)nicotinonitrile (intermediate 75, 478 mg, 2.46 mmol) in anhydrous DMF (4 ml) was added drop wise to a mixture of di(1H-1,2,4-triazol-1-yl)methanone (449 mg, 2.46 mmol) and DMF (4 ml) cooled at 0° C. After stirring for 60 minutes at 0° C. the reaction mixture was allowed to warm to room temperature and a solution of 4-((2-(dimethoxymethyl)-5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl)methyl)thiomorpholin-3-one (intermediate 208, 415 mg, 1.230 mmol) in DMF (4 ml) was added. The reaction mixture was stirred for approximately 24 h at room temperature, quenched by the addition of MeOH. The residue was diluted with EtOAc and water, filtered to remove insoluble byproducts. Phases were separated and the aqueous layer was washed with EtOAc (2×). The organic layers were combined, washed with water, dried using Na2SO4, filtered and evaporated. The crude product was purified using silica gel column chromatography eluting with a gradient of MeOH (0-3%) in DCM, followed by an additional purification with a gradient of MeOH (0-2%) in DCM. Fractions containing the product were combined and evaporated to yield the title compound as a white solid. (UPLC-MS 3) tR 0.98 min, ESI-MS 556.4 [M+H]+. 1H NMR (600 MHz, CDCl3) δ 13.77 (s, 1H), 8.17 (s, 1H), 7.48 (s, 1H), 7.45 (s, 1H), 5.52-5.37 (m, 1H), 4.82 (s, 2H), 3.98-3.93 (m, 2H), 3.59-3.55 (m, 2H), 3.55-3.50 (m, 2H), 3.47-3.39 (m, 8H), 3.36-3.30 (m, 5H), 2.77 (t, 2H), 2.74-2.70 (m, 2H), 1.96-1.89 (m, 2H).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[C:11](OC(=O)C)(=O)[CH3:12]>>[CH3:11][C:12]1[O:5][C:4](=[O:6])[C:3]2[CH:7]=[CH:8][CH:9]=[CH:10][C:2]=2[N:1]=1
Reactant: CC(=O)OC(C)=O
Reactant: Nc1ccccc1C(=O)O
Product: Cc1nc2ccccc2c(=O)o1

Procedure:
A solution of 2-aminobenzoic acid (300mg, 1.46 mmol) in acetic anhydride (2 mL) was heated to 130° C. for 16 hours. The mixture was concentrated under reduced pressure. The residue was chromatographed on silica gel eluting with 20% ethyl acetate in hexanes to provide the title compound. 1H NMR (300 MHz, CDCl3) δ ppm 2.44-2.52 (m, 3H), 7.44-7.60 (m, 2H), 7.76-7.87 (m, 1H), 8.20 (dd, J=7.97, 1.53 Hz, 1H); MS (DCI/NH3) m/z 162 (M+H)+.
Reaction SMILES: [CH2:1](Br)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[OH:10][C:11]1[CH:19]=[CH:18][C:14]([C:15]([OH:17])=[O:16])=[CH:13][CH:12]=1.C(=O)([O-])[O-].[K+].[K+].Cl>CN(C)C=O.O.C(OCC)C>[CH2:1]([O:10][C:11]1[CH:19]=[CH:18][C:14]([C:15]([OH:17])=[O:16])=[CH:13][CH:12]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: O=C(O)c1ccc(O)cc1
Reactant: CCCCCCCCBr
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOCC
Solvent: CN(C)C=O
Solvent: O
Product: CCCCCCCCOc1ccc(C(=O)O)cc1
Yield: 71.4 %

Procedure:
A solution of octylbromide (4.19 g), 4-hydroxybenzoic acid (3 g) and potassium carbonate (3 g) in dimethylformamide (100 ml) was stirred at 130° C. for two hours. The solution was poured in water and neutralized with dilute aqueous hydrochloric acid solution. Diethylether was added to effect extraction. After the extracted layer was distilled to remove the solvent, the residue was added to a solution of sodium hydroxide (3.3 g), water (10 ml) and ethanol (50 ml). The solution obtained was refluxed for about a day and neutralized with dilute aqueous hydrochloric acid solution. The solution was distilled to remove the solvent and concentrated. The solid obtained was collected and recrystallized from water/ethanol to obtain the titled compound (3.88 g).
Reaction SMILES: [CH3:1][CH:2]([CH3:9])N=C=NC(C)C.FF.[C:12]([O:15][CH:16]([CH3:20])[CH2:17][O:18]C)(=[O:14])[CH3:13]>>[C:17]1(=[O:18])[CH2:16][CH2:20][CH2:9][CH2:2][CH2:1]1.[C:12]1(=[O:14])[O:15][CH2:16][CH2:20][CH2:13]1
Reactant: COCC(C)OC(C)=O
Reactant: CC(C)N=C=NC(C)C
Agent: FF
Product: O=C1CCCCC1
Product: O=C1CCCO1

Procedure:
To 2 g of the resin obtained in Synthesis Example 2, 0.01 g of a surfactant (manufactured by DIC Corporation, product name: MEGAFAC [trade name] R-30, composed of a fluorine-based surfactant) was added. The resultant mixture was dissolved in 3.5 g of propylene glycol monomethyl ether acetate, 18.4 g of cyclohexanone, and 1.2 g of γ-butyrolactone to obtain a solution. Subsequently, the solution was filtered using a polyethylene microfilter with a pore diameter of 0.2 μm to prepare a solution of the organic underlayer film forming composition for use in a lithography process with a multilayer film.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=1.[OH-:11].[Na+].[CH:13](Cl)(Cl)Cl.Cl>O>[CH:13]([C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][C:2]=1[OH:1])[C:6]([OH:8])=[O:7])=[O:11]
Reactant: ClC(Cl)Cl
Reactant: [OH-]
Reactant: O=C(O)c1ccc(O)cc1
Agent: Cl
Agent: [Na+]
Solvent: O
Product: O=Cc1cc(C(=O)O)ccc1O
Temperature: 25 °C
Reaction time: 8 h
Yield: 23 %

Procedure:
140 g (1.01 mol) of 4-hydroxybenzoic acid were added to a hot solution of 250 g (6.25 mol) of sodium hydroxide in 500 mL H2O. 150 mL of CHCl3 were cautiously added to the hot solution, and after the foaming had ceased, the reaction mixture was stirred overnight at room temperature. The reaction mixture was then diluted to 4 L with H2O, acidified to pH 1 by addition of about 300 mL of concentrated HCl, and extracted two times with 2 L and then three times with 1 L ethyl ether. The ether extracts were combined and a solution of 750 g sodium bisulfite in 3 L H2O was added. This mixture was stirred thoroughly for 2 minutes, then the layers were separated and the aqueous layer was extracted two times with 500 ml ethyl ether. The aqueous layer was acidified by slow addition of a solution of 230 mL concentrated H2SO4 in 230 mL H2O. Vigorous SO2 evolution was noted. The solution was then heated on a steam bath, and a stream of N2 was blown through the hot solution for about 15 minutes until a large amount of crystals formed. The mixture was allowed to stand at room temperature overnight, then cooled to -10° C. for 1/20 hour, then filtered. The crystals were washed two times with H2O and then dried under vacuum to yield 38.46 g of the title product as a tan powder. 23% yield.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:27]2[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][CH:28]=2)[C:9]2[CH:10]=[C:11]3[C:16](=[CH:17][CH:18]=2)[NH:15][C:14](=[O:19])[CH:13]=[C:12]3[NH:20][CH:21]2[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]2)=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].Cl[CH2:41][C:42]([O:44][C:45]([CH3:48])([CH3:47])[CH3:46])=[O:43]>CC(C)=O.ClCCl>[Cl:33][C:30]1[CH:29]=[CH:28][C:27]([CH:8]([C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)[C:9]2[CH:10]=[C:11]3[C:16](=[CH:17][CH:18]=2)[NH:15][C:14](=[O:19])[CH:13]=[C:12]3[NH:20][CH:21]2[CH2:22][CH2:23][N:24]([CH2:41][C:42]([O:44][C:45]([CH3:48])([CH3:47])[CH3:46])=[O:43])[CH2:25][CH2:26]2)=[CH:32][CH:31]=1
Reactant: CC(C)(C)OC(=O)CCl
Reactant: O=c1cc(NC2CCNCC2)c2cc(C(c3ccc(Cl)cc3)c3ccc(Cl)cc3)ccc2[nH]1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: ClCCl
Solvent: CC(C)=O
Product: CC(C)(C)OC(=O)CN1CCC(Nc2cc(=O)[nH]c3ccc(C(c4ccc(Cl)cc4)c4ccc(Cl)cc4)cc23)CC1
Temperature: 40 °C
Reaction time: 16 h

Procedure:
To a mixture of 6-(bis(4-chlorophenyl)methyl)-4-(piperidin-4-ylamino)quinolin-2(1H)-one (0.1 g 0.209 mmol) and cesium carbonate (80 mg; 0.245 mmol) in acetone (2 mL) was added a solution of chloroacetic acid, 1,1-dimethylethyl ester (0.04 mL; 0.279 mmol) in dichloromethane (0.1 mL) by syringe. The reaction mixture was stirred at 40° C. in a sand bath for 16 h, cooled to room temperature and concentrated. The reaction was diluted with DCM and water. The organics were concentrated and purified by ISCO (0-10% MeOH/DCM) to yield tert-butyl 2-(4-((6-(bis(4-chlorophenyl)methyl)-2-oxo-1,2-dihydroquinolin-4-yl)amino)piperidin-1-yl)acetate.
Reaction SMILES: [Cl:1][C:2]1[C:7]2[O:8][C:9]3[C:18]([CH3:19])=[CH:17][C:16]([C:20]([OH:22])=[O:21])=[CH:15][C:10]=3[S:11](=[O:14])(=[O:13])[CH2:12][C:6]=2[CH:5]=[C:4]([S:23](Cl)(=[O:25])=[O:24])[CH:3]=1.[CH3:27][N:28]1[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]1.O>C(OCC)(=O)C>[Cl:1][C:2]1[C:7]2[O:8][C:9]3[C:18]([CH3:19])=[CH:17][C:16]([C:20]([OH:22])=[O:21])=[CH:15][C:10]=3[S:11](=[O:14])(=[O:13])[CH2:12][C:6]=2[CH:5]=[C:4]([S:23]([N:31]2[CH2:32][CH2:33][N:28]([CH3:27])[CH2:29][CH2:30]2)(=[O:25])=[O:24])[CH:3]=1
Reactant: CN1CCNCC1
Reactant: Cc1cc(C(=O)O)cc2c1Oc1c(Cl)cc(S(=O)(=O)Cl)cc1CS2(=O)=O
Solvent: O
Solvent: CCOC(C)=O
Product: Cc1cc(C(=O)O)cc2c1Oc1c(Cl)cc(S(=O)(=O)N3CCN(C)CC3)cc1CS2(=O)=O

Procedure:
A mixture of Example 49j (0.2 g, 0.45 mmol) and 1-methyl-piperazine (0.08 mL, 0.9 mmol) in dry ethyl acetate was stirred overnight at 25° C., treated with water and extracted with ethyl acetate. The organic layer was washed with dil aqueous HCl (10%, 50 mL), water, brine, concentrated and purified using flash chromatography (silica gel, methanol/chloroform) to obtain the title compound. Yield: 0.180 g, (80%) 1H NMR (DMSO-d6): δ 2.20 (s, 3H, CH3), 2.30 (s, 4H, CH2), 2.80 (s, 3H, CH3), 3.00 (s, 4H, CH2), 5.40 (s, 2H, CH2), 8.00 (s, 1H, Ar), 8.10 (s, 1H, Ar), 8.20 (s, 2H, Ar). MS: m/e (ES+) 501 (M+).
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]([OH:32])[C@@H:4]([NH:12][C:13](=[O:31])[C@@H:14]([N:18]1[CH2:22][CH2:21][N:20]([CH2:23][C:24]2[N:25]=[C:26]([CH3:29])[S:27][CH:28]=2)[C:19]1=[O:30])[CH:15]([CH3:17])[CH3:16])[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.C1C=CC=CC=1.[O:39]([C:44]([N:46]1[CH2:52][CH2:51][CH2:50][C@H:47]1[CH:48]=O)=[O:45])[C:40]([CH3:43])([CH3:42])[CH3:41].[BH4-].[Na+]>C(O)C>[OH:32][C@@H:3]([C@@H:4]([NH:12][C:13](=[O:31])[C@@H:14]([N:18]1[CH2:22][CH2:21][N:20]([CH2:23][C:24]2[N:25]=[C:26]([CH3:29])[S:27][CH:28]=2)[C:19]1=[O:30])[CH:15]([CH3:17])[CH3:16])[CH2:5][C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1)[CH2:2][NH:1][CH2:48][CH:47]1[CH2:50][CH2:51][CH2:52][N:46]1[C:44]([O:39][C:40]([CH3:41])([CH3:43])[CH3:42])=[O:45]
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1C=O
Reactant: Cc1nc(CN2CCN([C@H](C(=O)N[C@@H](Cc3ccccc3)[C@H](O)CN)C(C)C)C2=O)cs1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: c1ccccc1
Product: Cc1nc(CN2CCN([C@H](C(=O)N[C@@H](Cc3ccccc3)[C@H](O)CNCC3CCCN3C(=O)OC(C)(C)C)C(C)C)C2=O)cs1
Temperature: 70 °C
Reaction time: 1 h
Yield: 103 %

Procedure:
A solution of the product of Example 274C (59 mg) in ethanol:benzene (1 mL, 1:1) was treated with N-t-butoxylcarbonyl-(L)-prolinal (26 mg, 1 equivalent), stirred at 70° C. for 1 hour, cooled at 25° C., treated with NaBH4 (14 mg, 3 equivalents) at 25° C. and stirred for 16 hours. The mixture was quenched with saturated NH4Cl and partitioned between water and ethyl acetate. The organic layer was separated, dried over MgSO4, filtered and concentrated to give 85 mg of the crude title compound.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][C:10]1[N:11]([CH2:37][CH:38]([CH3:40])[CH3:39])[C:12](=[O:36])[C:13]2[C:18]([C:19]=1[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[CH:17][C:16]([C:26]1[S:27][CH:28]=[C:29]([C:31]([O:33]CC)=[O:32])[N:30]=1)=[CH:15][CH:14]=2)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(O)C.[OH-].[Na+].Cl>O1CCCC1.O>[C:1]([O:5][C:6]([NH:8][CH2:9][C:10]1[N:11]([CH2:37][CH:38]([CH3:40])[CH3:39])[C:12](=[O:36])[C:13]2[C:18]([C:19]=1[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[CH:17][C:16]([C:26]1[S:27][CH:28]=[C:29]([C:31]([OH:33])=[O:32])[N:30]=1)=[CH:15][CH:14]=2)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCOC(=O)c1csc(-c2ccc3c(=O)n(CC(C)C)c(CNC(=O)OC(C)(C)C)c(-c4ccccc4)c3c2)n1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Solvent: C1CCOC1
Product: CC(C)Cn1c(CNC(=O)OC(C)(C)C)c(-c2ccccc2)c2cc(-c3nc(C(=O)O)cs3)ccc2c1=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 95.6 %

Procedure:
To a solution of ethyl 2-[3-[[(tert-butoxycarbonyl)amino]methyl]-2-isobutyl-1-oxo-4-phenyl-1,2-dihydro-6-isoquinolinyl]-1,3-thiazole-4-carboxylate (1.12 g, 2 mmol) in tetrahydrofuran (10 ml)-ethanol (10 ml) was added 1N sodium hydroxide (4 ml) and the mixture was stirred at room temperature for 2 h. The reaction mixture was poured into water, acidified with 1N hydrochloric acid and extracted with ethyl acetate. The extract was washed with brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The obtained crystals were recrystallized from ethyl acetate-diisopropyl ether to give 2-[3-[[(tert-butoxycarbonyl)amino]methyl]-2-isobutyl-1-oxo-4-phenyl-1,2-dihydro-6-isoquinolinyl]-1,3-thiazole-4-carboxylic acid (1.02 g, 96.2%) as crystals.