Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([Mg]Cl)(C)C.[Cl:6][C:7]1[C:12]([O:13][Si](C)(C)C)=[C:11]([C:18]([O:20][Si](C)(C)C)=[CH2:19])[CH:10]=[CH:9][C:8]=1[O:25][CH2:26][C:27]1[CH:32]=[CH:31][C:30](I)=[CH:29][CH:28]=1.[H-].[Na+].[O:36]=[C:37]1[O:41][N:40]=[C:39]([C:42]2[CH:43]=[C:44]([CH:47]=[CH:48][CH:49]=2)[CH:45]=[O:46])[NH:38]1>O1CCCC1>[C:18]([C:11]1[CH:10]=[CH:9][C:8]([O:25][CH2:26][C:27]2[CH:32]=[CH:31][C:30]([CH:45]([OH:46])[C:44]3[CH:43]=[C:42]([C:39]4[NH:38][C:37](=[O:36])[O:41][N:40]=4)[CH:49]=[CH:48][CH:47]=3)=[CH:29][CH:28]=2)=[C:7]([Cl:6])[C:12]=1[OH:13])(=[O:20])[CH3:19]
Reactant: O=Cc1cccc(-c2noc(=O)[nH]2)c1
Reactant: C=C(O[Si](C)(C)C)c1ccc(OCc2ccc(I)cc2)c(Cl)c1O[Si](C)(C)C
Agent: CC(C)[Mg]Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(=O)c1ccc(OCc2ccc(C(O)c3cccc(-c4noc(=O)[nH]4)c3)cc2)c(Cl)c1O
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
Add isopropyl magnesium chloride (2M solution in tetrahydrofuran, 1.01 ml, 2.02 mmol) to a solution of 2-chloro-1-(4-iodo-benzyloxy)-3-trimethylsilanyloxy-4-(1-trimethylsilanyloxy-vinyl)-benzene (1.00 g, 1.83 mmol) in tetrahydrofuran (0.1M) at 0° C. After 15 minutes, warm to room temperature. After 1 hour, cool to −78° C. Add sodium hydride (60% dispersion, 80 mg, 2.01 mmol) to a solution of 3-(5-oxo-4,5-dihydro-[1,2,4]oxadiazol-3-yl)-benzaldehyde (348 mg, 1.83 mmol) in tetrahydrofuran (0.1M). Sonicate the solution for 5 minutes, then add it via syringe to the gringard reagent. After 30 minutes, warm the reaction to room temperature. Quench with 10% aq hydrochloric acid. Pour the reaction into brine and extract with 25% isopropyl alcohol:75% dichloromethane. Combine the organic layers, dry with sodium sulfate, filter, and concentrate under reduced pressure to give a residue. Purify the residue by flash chromatography eluting with 5% methanol:methylene chloride to yield the title product as a off white solid (389 mg, 46%): 1H NMR (DMSO-d6) δ 2.61 (s, 3H), 5.31 (s, 2H), 5.80 (d, 1H), 6.12 (d, 1H), 6.87 (d, 1H), 7.43 (m, 4H), 7.51 (t, 1H), 7.64 (tt, 2H), 7.90 (t, 1H), 7.91 (d, 1H), 12.96 (bs, 1H), 13.12 (s, 1H); MS (esi negative) m/z (rel intensity) 465 (100).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([CH:12]([N:21]([CH3:23])[CH3:22])[CH2:13][CH2:14][CH2:15][O:16][CH2:17][C:18](=[O:20])[CH3:19])[CH2:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[BH4-].[Na+].CC(O)C>O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2([CH:12]([N:21]([CH3:23])[CH3:22])[CH2:13][CH2:14][CH2:15][O:16][CH2:17][CH:18]([OH:20])[CH3:19])[CH2:9][CH2:10][CH2:11]2)=[CH:6][CH:7]=1
Reactant: CC(=O)COCCCC(N(C)C)C1(c2ccc(Cl)cc2)CCC1
Agent: [BH4-]
Agent: [Na+]
Solvent: CC(C)O
Solvent: O
Product: CC(O)COCCCC(N(C)C)C1(c2ccc(Cl)cc2)CCC1

Procedure:
A mixture of 1-{4-[1-(4-chlorophenyl)cyclobutyl]-4-dimethylaminobutoxy}propan-2-one (1.4 g prepared as described in Example 214) sodium borohydride (1.5 g) and propan-2-ol (30 ml) was heated under reflux for 4.25 hours. The mixture was cooled and poured into water. The aqueous mixture was extracted with ether. The extract was dried and evaporated to give a residue which was heated at 90°/20 mm to leave 1-{4-[1-(4-chlorophenyl)cyclobutyl]-4-dimethylaminobutoxy}propan-2-ol as an oil the boiling point which was not determined.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([OH:7])=[O:6].[C:11]([C:15]1[CH:16]=[C:17]([CH:21]=[C:22]([C:25]([CH3:28])([CH3:27])[CH3:26])[C:23]=1[OH:24])[C:18](Cl)=[O:19])([CH3:14])([CH3:13])[CH3:12]>COCCOC>[C:5]([C:4]1[CH:3]=[C:2]([NH:1][C:18](=[O:19])[C:17]2[CH:21]=[C:22]([C:25]([CH3:26])([CH3:27])[CH3:28])[C:23]([OH:24])=[C:15]([C:11]([CH3:14])([CH3:13])[CH3:12])[CH:16]=2)[CH:10]=[CH:9][CH:8]=1)([OH:7])=[O:6]
Reactant: Nc1cccc(C(=O)O)c1
Reactant: CC(C)(C)c1cc(C(=O)Cl)cc(C(C)(C)C)c1O
Solvent: COCCOC
Product: CC(C)(C)c1cc(C(=O)Nc2cccc(C(=O)O)c2)cc(C(C)(C)C)c1O
Temperature: 24 °C
Reaction time: 1 h
Yield: 50.9 %

Procedure:
A solution of 8.6 g (0.063 mole) of a m-aninobenzoic acid in 200 ml of 1,2-dimethoxyethane was mixed with a suspension of 8.0 g (0.0298 mole) of 3,5-di-t-butyl-4-hydroxybenzoyl chloride in 100 ml of 1,2-dimethoxyethane, and the mixture was stirred at 24° C. for one hour. The reaction mixture was then filtered. The filtrate was thereafter diluted with 300 ml of water and cooled to give the crude product as a white solid. This material was recrystallized from a mixture of ethanol and water to give 5.6 g of white solid N-(3-carboxyphenyl)-3,5-di-t-butyl-4-hydroxybenzamide, m.p. 279°-280° C. Analysis: Calculated for C22H27NO4 : %C, 71.5; %H, 7.4; %N, 3.8; Found: %C, 72.0; %H, 7.3; %N, 3.7.
Reaction SMILES: [O:1]=[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:11])[N:3]1[CH:12]1[CH2:17][CH2:16][CH:15]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH2:14][CH2:13]1.[Li+].[CH3:24]C([N-]C(C)C)C.CI>C1COCC1>[O:1]=[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:11])[N:3]1[CH:12]1[CH2:13][CH2:14][C:15]([CH3:24])([C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH2:16][CH2:17]1
Reactant: CC(C)[N-]C(C)C
Reactant: CCOC(=O)C1CCC(N2C(=O)c3ccccc3C2=O)CC1
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CI
Product: CCOC(=O)C1(C)CCC(N2C(=O)c3ccccc3C2=O)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 95.1 %

Procedure:
A solution of ethyl 4-(1,3-dioxoisoindolin-2-yl)cyclohexanecarboxylate (0.30 g, 1.00 mmol) in THF (10 mL) was cooled to −78° C. followed by dropwise addition of LDA (1.60 M in THF, 1.88 mL, 3.00 mmol) at −78° C. The mixture was stirred at the same temperature for 30 minutes followed by addition of MeI (0.311 mL, 5.00 mmol) at −78° C. The temperature of the reaction was slowly raised up to rt and left to stir overnight. The reaction was then cooled to 0° C. and quenched by dropwise addition of saturated NH4Cl solution (30 mL), extracted with EtOAc (3×50 mL) and the combined organics washed with brine, dried (Na2SO4), filtered and concentrated under reduced pressure to obtain the desired product as a viscous liquid (0.30 g, 97%). MS: 316.12 [M+H]+.
Reaction SMILES: [Cl:1][CH2:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][CH:11]=1)[C:6](Cl)=[O:7].C1(C)C(S(O)(=O)=O)=CC=CC=1.[NH2:23][CH2:24][CH2:25][C:26]([O:28][CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)=[O:27].C(N(CC)CC)C>>[Cl:1][CH2:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][CH:11]=1)[C:6]([NH:23][CH2:24][CH2:25][C:26]([O:28][CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)=[O:27])=[O:7]
Reactant: O=C(Cl)c1cccc(CCl)c1
Reactant: NCCC(=O)OCc1ccccc1
Agent: Cc1ccccc1S(=O)(=O)O
Solvent: CCN(CC)CC
Product: O=C(CCNC(=O)c1cccc(CCl)c1)OCc1ccccc1
Yield: 100.5 %

Procedure:
This compound was synthesized in a similar way as for I from 3-chloromethylbenzoyl chloride (3 mmol, 426 mL), benzyl 3-aminopropionate toluenesulfonic acid salt (3.2 mmol, 1.12 g) and triethylamine (7 mmol, 0.98 mL). Crystallization from ether-petroleum ether gave 1.0 g (100%) product. NMR (DMSO-d6): δ 8.62 (t, 1H); 7.88 (s, 1H); 7.78 (d, 1H); 7.46 (t, 1H); 7.32 (m, 5H); 5.10 (s, 2H); 4.80 (s, 2H); 3.52 (m, 2H); 3.65 (t, 2H).
Reaction SMILES: O1CCCC1.[Cl:6][C:7]1[CH:13]=[C:12]([Cl:14])[C:11]([F:15])=[CH:10][C:8]=1[NH2:9].[F:16][B-:17]([F:20])([F:19])[F:18].[H+].[N:22]([O-])=O.[Na+]>O>[F:16][B-:17]([F:20])([F:19])[F:18].[Cl:6][C:7]1[CH:13]=[C:12]([Cl:14])[C:11]([F:15])=[CH:10][C:8]=1[N+:9]#[N:22]
Reactant: Nc1cc(F)c(Cl)cc1Cl
Reactant: O=N[O-]
Agent: F[B-](F)(F)F
Agent: [H+]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: N#[N+]c1cc(F)c(Cl)cc1Cl

Procedure:
165 ml of tetrahydrofuran are added to 100 g of 2,4-dichloro-5-fluoroaniline at room temperature. To this solution are added 333 ml of tetrafluoroboric acid (50% strength) with cooling. 57.5 g of sodium nitrite in 117 ml of water are added to the reaction mixture cooled to 5°-10° C. in such a way that the internal temperature is 7°-13° C. After addition is completed, the 0° C. solution is filtered. The residue is washed with tetrahydrofuran and ice-cold water. 121 g of product remain.
Reaction SMILES: [O-]CC.[Na+].C1(C)C=CC=CC=1.C([O:14][C:15](=[O:32])[CH2:16][C:17]([C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([CH3:31])[N:26]=1)=[N:18][N:19]1[CH2:23][CH2:22][CH2:21][C:20]1=O)C.Cl>O>[CH3:31][C:27]1[N:26]=[C:25]([C:17]2[C:16]([C:15]([OH:14])=[O:32])=[C:23]3[CH2:22][CH2:21][CH2:20][N:19]3[N:18]=2)[CH:30]=[CH:29][CH:28]=1
Reactant: CCOC(=O)CC(=NN1CCCC1=O)c1cccc(C)n1
Agent: CC[O-]
Agent: Cl
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Product: Cc1cccc(-c2nn3c(c2C(=O)O)CCC3)n1
Temperature: 100 °C
Yield: 85.8 %

Procedure:
Add sodium ethoxide (90 g, 1.32 mol), toluene (5 L) and 3-(6-methyl-pyridin-2-yl)-3-(2-oxo-pyrrolidin-1-ylimino)-propionic acid ethyl ester (Preparation 1, Part B; 201 g, 0.661 mol) to a 22 L flask equipped with a mechanical stirrer, nitrogen inlet and a reflux condenser. Heat the mixture at 100° C. for 24 h then cool to room temperature. Add water (4 L) and adjust the pH to 4 with concentrated hydrochloric acid. Separate the organic layer and extract the aqueous portion with 10% isopropyl alcohol in chloroform is (3×4.5 L). Combine the organic layers, dry (sodium sulfate), filter, and concentrate in vacuo to yield the subtitled product (138 g, 86% yield) as a yellow solid in 78% purity by HPLC analysis. MS ES+ m/e 244 (M+1).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([SH:8])=[C:4]([CH3:9])[CH:3]=1.[O-]CC.[Na+].Br[CH2:15][CH:16]([O:20][CH2:21][CH3:22])[O:17][CH2:18][CH3:19]>CCO>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][CH2:15][CH:16]([O:20][CH2:21][CH3:22])[O:17][CH2:18][CH3:19])=[C:4]([CH3:9])[CH:3]=1
Reactant: CCOC(CBr)OCC
Reactant: Cc1cc(Br)ccc1S
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: CCOC(CSc1ccc(Br)cc1C)OCC
Temperature: 25 °C
Reaction time: 8 h
Yield: 88 %

Procedure:
To a solution of the thiocarbamic acid S-ester (34.7 g) in THF (500 mL) under an atmosphere of nitrogen was added a solution of KOH (17.8 g, 2.5 equiv) in MeOH (90 mL), the solution allowed to stir at room temperature for 5 hr and quenched by the addition of 1N HCl, extracted with EtOAc and the organic phase was washed with brine, dried over Na2SO4, filtered and concentrated to give 4-bromo-2-methyl benzenethiol which was used immediately. The thiol was added dropwise to a solution of sodium ethoxide (10.3 g, 1.2 equiv) in EtOH (600 mL), allowed to stir for 30 min before the dropwise addition of 2-bromo-1,1-diethoxyethane (23 mL, 1.2 equiv). The reaction mixture was heated at reflux for 4 hr, allowed to cool and stir at room temperature overnight, then quenched by the addition of water and concentrated. Water and EtOAc were added, the phases separated, and the aqueous phase was further extracted with EtOAc. The organic phase was dried over Na2SO4, filtered and concentrated. The crude product was purified by column chromatography (SiO2, 5% EtOAC in hexanes) to give 4-bromo-1-(2,2-diethoxyethylsulfanyl)-2-methylbenzene (38.4 g, 88% for 2 steps).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]([NH:13][C:14](=[O:18])OCC)=[N:11][C:10]2[C:5](=[CH:6][C:7]([CH3:20])=[C:8]([CH3:19])[CH:9]=2)[N:4]=1.[CH3:21][C:22]1[CH:23]=[C:24]([N:29]2[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]2)[CH:25]=[C:26]([CH3:28])[CH:27]=1>>[CH3:1][O:2][C:3]1[C:12]([NH:13][C:14]([N:32]2[CH2:33][CH2:34][N:29]([C:24]3[CH:25]=[C:26]([CH3:28])[CH:27]=[C:22]([CH3:21])[CH:23]=3)[CH2:30][CH2:31]2)=[O:18])=[N:11][C:10]2[C:5](=[CH:6][C:7]([CH3:20])=[C:8]([CH3:19])[CH:9]=2)[N:4]=1
Reactant: Cc1cc(C)cc(N2CCNCC2)c1
Reactant: CCOC(=O)Nc1nc2cc(C)c(C)cc2nc1OC
Product: COc1nc2cc(C)c(C)cc2nc1NC(=O)N1CCN(c2cc(C)cc(C)c2)CC1
Yield: 58 %

Procedure:
Ethyl N-(2-methoxy-6,7-dimethylquinoxalin-3-yl)carbamate and 1-(3,5-dimethylphenyl)piperazine were reacted by the same way with the example 183 to obtain the titled compound (yield, 58%). 1H NMR (300 MHz, CDCl3) δ 2.29-2.40 (m, 12H), 3.20-3.29 (m, 4H), 3.80-3.83 (m, 3H), 4.10 (s, 4H), 5.12 (br s, 1H), 6.59 (s, 3H), 7.36-7.60 (m, 2H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([O:9][CH3:10])[C:4]=1[O:11][C:12](=[O:14])[CH3:13].[I:15]I>C(Cl)(Cl)Cl.FC(F)(F)C([O-])=O.[Ag+]>[C:12]([O:11][C:4]1[C:3]([O:2][CH3:1])=[C:8]([I:15])[CH:7]=[CH:6][C:5]=1[O:9][CH3:10])(=[O:14])[CH3:13]
Reactant: II
Reactant: COc1cccc(OC)c1OC(C)=O
Agent: [Ag+]
Agent: O=C([O-])C(F)(F)F
Solvent: ClC(Cl)Cl
Product: COc1ccc(I)c(OC)c1OC(C)=O
Temperature: 0 °C
Reaction time: 1 h
Yield: 95.6 %

Procedure:
To an ice-cooled suspension of acetic acid 2,6-dimethoxy-phenyl ester (1.0 g, 5.1 mmol) and silver trifluoroacetate (5.1 mmol) in CHCl3 (16 ml) was added iodine (1.3 g, 5.1 mmol) and the reaction stirred for 1 hour. The crude mixture was filtered through celite to remove the precipitated silver iodide and the filtrate was washed with 10% Na2S2O3 (aq). An emulsion was formed and the mixture was again passed through celite and the filtrate washed with brine, dried over MgSO4 and concentrated under reduced pressure to give the product as a tan solid (1.57 g, 96%). 1H-NMR (300 MHz, CDCl3) δ 7.55 (d, J=8.9 Hz, 1H), 6.54 (d, J=8.9 Hz, 1H), 3.80 (s, 6H), 2.33 (s, 3H).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([CH2:7][CH2:8][O:9][C:10]2[CH:11]=[C:12]([NH:16][C:17]3[CH:22]=[CH:21][N:20]4[N:23]=[CH:24][C:25]([CH:26]=O)=[C:19]4[N:18]=3)[CH:13]=[CH:14][CH:15]=2)[CH2:3][CH2:2]1.[NH:28]1[CH2:34][C:32](=[O:33])[NH:31][C:29]1=[O:30].N1CCCCC1>CCO>[O:1]1[CH2:6][CH2:5][N:4]([CH2:7][CH2:8][O:9][C:10]2[CH:11]=[C:12]([NH:16][C:17]3[CH:22]=[CH:21][N:20]4[N:23]=[CH:24][C:25]([CH:26]=[C:34]5[NH:28][C:29](=[O:30])[NH:31][C:32]5=[O:33])=[C:19]4[N:18]=3)[CH:13]=[CH:14][CH:15]=2)[CH2:3][CH2:2]1
Reactant: O=Cc1cnn2ccc(Nc3cccc(OCCN4CCOCC4)c3)nc12
Reactant: O=C1CNC(=O)N1
Solvent: CCO
Solvent: C1CCNCC1
Product: O=C1NC(=O)C(=Cc2cnn3ccc(Nc4cccc(OCCN5CCOCC5)c4)nc23)N1
Temperature: 70 °C

Procedure:
To 5-(3-(2-morpholinoethoxy)phenylamino)pyrazolo[1,5-a]pyrimidine-3-carbaldehyde (81 mg, 0.221 mmol) in EtOH was added hydantoin (27 mg, 0.270 mmol) and piperidine (22 μL, 0.221 mmol). The mixture was heated at 70° C. for 48 hr. The solution was then purified by HPLC to yield 5-((5-(3-(2-morpholinoethoxy)phenylamino)pyrazolo[1,5-a]pyrimidin-3-yl)methylene)imidazolidine-2,4-dione. LCMS (M+1=450)
Reaction SMILES: [Cl:1][C:2]1[CH:31]=[CH:30][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([CH:16]=[C:17]4[S:21][C:20]([N:22]5[CH2:28][CH2:27][CH2:26][NH:25][CH2:24][CH2:23]5)=[N:19][C:18]4=[O:29])=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:32]([F:35])([F:34])[F:33])[CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:43][CH2:44][F:45]>C(#N)C>[Cl:1][C:2]1[CH:31]=[CH:30][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([CH:16]=[C:17]4[S:21][C:20]([N:22]5[CH2:28][CH2:27][CH2:26][N:25]([CH2:43][CH2:44][F:45])[CH2:24][CH2:23]5)=[N:19][C:18]4=[O:29])=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:32]([F:35])([F:34])[F:33])[CH:3]=1
Reactant: FCCBr
Reactant: O=C1N=C(N2CCCNCC2)SC1=Cc1ccc2c(cnn2Cc2ccc(Cl)cc2C(F)(F)F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: O=C1N=C(N2CCCN(CCF)CC2)SC1=Cc1ccc2c(cnn2Cc2ccc(Cl)cc2C(F)(F)F)c1
Temperature: 70 °C
Reaction time: 18 h
Yield: 100.1 %

Procedure:
A solution 5-[1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-[1,4]diazepan-1-yl-thiazol-4-one (0.016 g, 0.03 mmol) in acetonitrile (1.5 mL) was treated with potassium carbonate (0.022 g, 0.15 mmol) and 1-bromo-2-fluoro-ethane (0.04 g, 0.3 mmol). Reaction mixture was stirred at 70° C. for 18 hours and the solvent evaporated in vacuo. The residue was partitioned between dichloromethane and water. The dichloromethane layer was washed with brine, dried over Na2SO4, filtered, and the solvent evaporated in vacuo to yield a crude solid. The crude solid was purified via flash chromatography (5% methanol in dichloromethane) to yield the title compound (17 mg, 100%).
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:6]=[CH:7][C:8]([C:11]2[N:12]=[C:13](O)[C:14]3[C:19]([CH:20]=2)=[CH:18][C:17]([O:21][CH3:22])=[CH:16][CH:15]=3)=[N:9][CH:10]=1)([CH3:3])[CH3:2].O=P(Cl)(Cl)[Cl:26]>>[Cl:26][C:13]1[C:14]2[C:19](=[CH:18][C:17]([O:21][CH3:22])=[CH:16][CH:15]=2)[CH:20]=[C:11]([C:8]2[CH:7]=[CH:6][C:5]([O:4][CH:1]([CH3:3])[CH3:2])=[CH:10][N:9]=2)[N:12]=1
Reactant: COc1ccc2c(O)nc(-c3ccc(OC(C)C)cn3)cc2c1
Reactant: O=P(Cl)(Cl)Cl
Product: COc1ccc2c(Cl)nc(-c3ccc(OC(C)C)cn3)cc2c1

Procedure:
A solution of 3-(5-isopropoxypyridin-2-yl)-6-methoxyisoquinolin-1-ol (4 g, 12.89 mmol) in POCl3 (20 mL) was refluxed for 2 hs. After concentration, the residue was taken into the mixture of DCM and 4N NaOH solution. The organic phase was collected and dried over sodium sulfate, filtered, then concentrated under vacuum. The crude material was purified by silica gel chromatography using CH2Cl2 as eluent to give 3.4 g of the desired product 1-chloro-3-(5-isopropoxypyridin-2-yl)-6-methoxyisoquinoline as a solid. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 8.49 (s, 1H), 8.39 (d, J=8.8 Hz, 1H), 8.33 (d, J=2.5 Hz, 1H), 8.19 (d, J=9.1 Hz, 1H), 7.29 (dd, J=8.8, 3.0 Hz, 1H), 7.23 (dd, J=6.8, 2.5 Hz, 1H), 7.16 (d, J=2.3 Hz, 1H), 4.65 (spt, J=6.0 Hz, 1H), 3.94 (s, 3H), 1.38 (d, J=6.3 Hz, 6H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:21](=[O:22])[N:20]([CH3:23])[C:11]3[N:12]([CH3:19])[C:13]4[C:18]([C:10]=3[CH:9]=2)=[CH:17][CH:16]=[CH:15][CH:14]=4)=[CH:4][CH:3]=1.[C:24](Cl)(=[O:27])[CH2:25][CH3:26]>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:21](=[O:22])[N:20]([CH3:23])[C:11]3[N:12]([CH3:19])[C:13]4[C:18]([C:10]=3[CH:9]=2)=[CH:17][C:16]([C:24](=[O:27])[CH2:25][CH3:26])=[CH:15][CH:14]=4)=[CH:6][CH:7]=1
Reactant: Cn1c(=O)c(-c2ccc(F)cc2)cc2c3ccccc3n(C)c21
Reactant: CCC(=O)Cl
Product: CCC(=O)c1ccc2c(c1)c1cc(-c3ccc(F)cc3)c(=O)n(C)c1n2C

Procedure:
The process is carried out as indicated in preparation 1.1E above, with compound from Example 63A, 3-(4-fluorophenyl)-1,9-dimethyl-1,9-dihydropyrido[2,3-b]indol-2-one and propionyl chloride
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH2:10][C@H:11]1[CH2:14][C@H:13](CS([O-])(=O)=O)[CH2:12]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N:20]1[C:28]([NH2:29])=[C:27]2[C:23]([N:24]=[CH:25][NH:26]2)=[N:22][CH:21]=1.C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C>[CH2:1]([O:8][CH2:9][CH2:10][C@@H:11]1[CH2:12][C@H:13]([N:24]2[CH:25]=[N:26][C:27]3[C:23]2=[N:22][CH:21]=[N:20][C:28]=3[NH2:29])[CH2:14]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Nc1ncnc2nc[nH]c12
Reactant: O=S(=O)([O-])C[C@H]1C[C@H](CCOCc2ccccc2)C1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: Nc1ncnc2c1ncn2[C@H]1C[C@@H](CCOCc2ccccc2)C1
Temperature: 120 °C
Yield: 42.2 %

Procedure:
In a 25 mL three-neck flask with trans-3-(benzyloxyethyl)cyclobutyl-mesylate (0.50 g, 1.76 mmol), adenine (0.35 g, 2.59 mmol) and Cs2CO3 (0.86 g, 2.64 mmol) inside, dry DMF 8 mL was added under argon. Then began to heat to 120° C. and after 24 hr, the solvent was removed and directly applied to silica gel flash chromatography to give 0.24 g (43%) the desired product. 1H NMR (CDCl3, 300 MHz): δ 1.84-1.92 (m, 2H), 2.16-2.46 (m, 3H), 2.68-2.80 (m, 2H), 3.48-3.52 (t, J=6.3, 2H), 4.51 (s, 2H), 4.80-4.92 (m, 1H), 7.88 (s, 1H), 8.35 (s, 1H). MS (FAB): expected for C18H21N5O (M+H)+ 324.39. Found 324.18195. IR (neat) νmax 3398, 2927, 2862, 1718, 1453, 1315, 1276, 1113, 1071, 1027, 738, 714, 698.
Reaction SMILES: [C:1]([O:5][C:6](/[C:8](=[CH:13]\[C:14]1[CH:19]=[CH:18][C:17]([Cl:20])=[C:16]([F:21])[CH:15]=1)/[C:9]([O:11][CH3:12])=[O:10])=[O:7])([CH3:4])([CH3:3])[CH3:2].CO>CCOC(C)=O>[C:1]([O:5][C:6]([C@H:8]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([Cl:20])=[C:16]([F:21])[CH:15]=1)[C:9]([O:11][CH3:12])=[O:10])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)/C(=C/c1ccc(Cl)c(F)c1)C(=O)OC(C)(C)C
Solvent: CO
Solvent: CCOC(C)=O
Product: COC(=O)[C@@H](Cc1ccc(Cl)c(F)c1)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 12 h
Yield: 755.2 %

Procedure:
(Z)-methyl 2-(tert-butoxycarbonyl)-3-(4-chloro-3-fluorophenyl)acrylate (200 mg) and ca. Rh—(R,R)-[Et-DuPhos(COD)]OTf (4 mg) in 1:1 MeOH:EtOAc (3 mL; degassed 1 h with N2 prior to use) was dissolved in 8 Argonaut Endeavor™ reaction tubes. The reaction mixtures were put on the Endeavor™ under 40 psi H2 and stirred for 12 hours at room temperature. All of the reaction mixtures were then combined and concentrated to give (R)-methyl 2-(tert-butoxycarbonyl)-3-(4-chloro-3-fluorophenyl)propanoate (1.52 g, 94.4% yield) as a pale yellow solid, which was used without further purification in next step.
Reaction SMILES: [CH2:1]([C@H:8]1[CH2:13][N:12]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[C:16]([O:22][CH:23]3[CH2:27][CH2:26][CH2:25][CH2:24]3)[CH:15]=2)[CH2:11][CH2:10][N:9]1[CH2:28][C:29](O)=[O:30])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:32]1([N:38]=C=NC2CCCCC2)CCCCC1.C1COCC1.CN>C(Cl)Cl.CN(C)C1C=CN=CC=1>[CH2:1]([C@H:8]1[CH2:13][N:12]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[C:16]([O:22][CH:23]3[CH2:27][CH2:26][CH2:25][CH2:24]3)[CH:15]=2)[CH2:11][CH2:10][N:9]1[CH2:28][C:29]([NH:38][CH3:32])=[O:30])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1ccc(N2CCN(CC(=O)O)[C@@H](Cc3ccccc3)C2)cc1OC1CCCC1
Reactant: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN
Agent: CN(C)c1ccncc1
Solvent: C1CCOC1
Solvent: ClCCl
Product: CNC(=O)CN1CCN(c2ccc(OC)c(OC3CCCC3)c2)C[C@@H]1Cc1ccccc1
Reaction time: 16 h
Yield: 29.3 %

Procedure:
A solution of [(S)-2-Benzyl-4-(3-cyclopentyloxy-4-methoxy-phenyl)-piperazin-1-yl]-acetic acid (21.2 mg, 0.05 mmol) in CH2Cl2 (0.5 mL) at 0° C. was treated with catalytic 4-dimethylaminopyridine (DMAP) (˜1 mg) and N,N′-dicyclohexylcarbodiimide (DCC) (11.3 mg, 0.055 mmol) followed 5 min later by a 2 M THF solution of methylamine (30 μL, 0.06 mmol). The reaction mixture was stirred for 16 h, evaporated, and purified by silica gel flash chromatography with 50% EtOAc/hexane, then 100% EtOAc, then 5% MeOH/EtOAc as eluant to afford the title compound as an oil (6.4 mg, 29%). LC/MS (Method A) 5.09 min, [M+1]+ 438.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[C:18]([NH:20][S:21]([C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([O:30][CH:31]([F:33])[F:32])[CH:25]=3)(=[O:23])=[O:22])[CH:17]=[CH:16][C:15]=2[O:34][CH3:35])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[F:38][CH2:39][CH2:40][CH2:41]Br>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[C:18]([N:20]([S:21]([C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([O:30][CH:31]([F:32])[F:33])[CH:25]=3)(=[O:23])=[O:22])[CH2:41][CH2:40][CH2:39][F:38])[CH:17]=[CH:16][C:15]=2[O:34][CH3:35])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: FCCCBr
Reactant: COc1ccc(NS(=O)(=O)c2cccc(OC(F)F)c2)cc1N1CCN(C(=O)OC(C)(C)C)CC1
Agent: [H-]
Agent: [Na+]
Product: COc1ccc(N(CCCF)S(=O)(=O)c2cccc(OC(F)F)c2)cc1N1CCN(C(=O)OC(C)(C)C)CC1

Procedure:
The compound was prepared by analogy to the methods described for Preparation Example 2 and Example 1 from 4-{5-[(3-difluoromethoxybenzenesulfonyl)-amino]-2-methoxy-phenyl}-piperazine-1-carboxylic acid tert-butyl ester, which was reacted with sodium hydride and 3-fluoro-1-bromopropane to yield 4-{5-[(3-difluoromethoxy-benzenesulfonyl)-(3-fluoropropyl)amino]-2-methoxy-phenyl}-piperazine-1-carboxylic acid tert-butyl ester, which was deprotected to yield the title compound.
Reaction SMILES: O=[C:2]([CH3:9])[CH2:3][CH2:4][CH2:5][C:6]([OH:8])=O.[NH2:10][C:11]1[CH:12]=[C:13]([C:15]([CH3:19])=[CH:16][C:17]=1[CH3:18])[NH2:14]>CO.[Ni]>[NH2:10][C:11]1[CH:12]=[C:13]([N:14]2[CH:2]([CH3:9])[CH2:3][CH2:4][CH2:5][C:6]2=[O:8])[C:15]([CH3:19])=[CH:16][C:17]=1[CH3:18]
Reactant: CC(=O)CCCC(=O)O
Reactant: Cc1cc(C)c(N)cc1N
Agent: [Ni]
Solvent: CO
Product: Cc1cc(C)c(N2C(=O)CCCC2C)cc1N

Procedure:
A solution of 65 g (0.5 mol) of 5-oxo-caproic acid and 70 g (0.51 mol) of 3-amino-4,6-dimethylaniline in 300 ml of methanol is hydrogenated at 130°-140° in the presence of Raney nickel. Yield: 110 g.