Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][NH2:9].[CH:10]1[N:15]=[C:14](Cl)[C:13]2[N:17]=[CH:18][N:19]([C@@H:20]3[O:24][C@H:23]([CH2:25][OH:26])[C@@H:22]([OH:27])[C@H:21]3[OH:28])[C:12]=2[N:11]=1.C(N(C(C)C)CC)(C)C>O1CCOCC1>[CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][NH:9][C:14]1[C:13]2[N:17]=[CH:18][N:19]([C:12]=2[N:11]=[CH:10][N:15]=1)[C@@H:20]1[O:24][C@H:23]([CH2:25][OH:26])[C@@H:22]([OH:27])[C@H:21]1[OH:28]
Reactant: Cc1ccccc1CN
Reactant: OC[C@H]1O[C@@H](n2cnc3c(Cl)ncnc32)[C@H](O)[C@@H]1O
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: Cc1ccccc1CNc1ncnc2c1ncn2[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O
Temperature: 60 °C

Procedure:
The title compound was prepared by reacting (2-methylphenyl)methylamine (1.51 g, 12.5 mmol) with 6-chloropurine riboside (2.87 g, 10.0 mmol) in dioxan (100 ml) in the presence of diisopropylethylamine (1.94 g, 15.0 mmol). The reaction mixture was heated at 60° C. for 6 h, cooled, filtered and evaporated. The residue was purified by flash chromatography, eluting initially with dichloromethane, and later increasing polarity to dichloromethanethanol (9:1), to provide the product (2.6 g, 70%) as a solid which was recrystallised from methanol to give N-[(2-methylphenyl)methyl]adenosine as white crystals (1.75 g, 47%), mp 161.5°-163.5° C., 1H NMR (DMSO-d6)δ 2.35 (3H, s, --CH3), 3.53-3.60 (1H, m, H-5'a), 3.65-3.72 (1H, m, H-5'b), 3.98 (1H, q, H-4'), 4.16 (1H, m, H-3'), 4.64 (1H, q, H-2'), 5.41 (1H, t, 5'-0H), 5.21, 5.48 (2H, 2d, 2'- and 3'-OH), 5.92 (1H, d, H-1'), 7.06-7.24 (4H, m, Ar--H), 8.20 and 8.40 (3H, s and br s, H-2, H-8 and N--H).
Reaction SMILES: [CH:1]12[CH2:7][CH:4]([CH:5]=[CH:6]1)[C:3](=[O:8])[NH:2]2.[C:9](OC=C)(=O)[CH3:10]>[Na+].[Na+].Cl[Pd+2](Cl)(Cl)Cl>[CH:9]([N:2]1[C:3](=[O:8])[CH:4]2[CH2:7][CH:1]1[CH:6]=[CH:5]2)=[CH2:10]
Reactant: C=COC(C)=O
Reactant: O=C1NC2C=CC1C2
Agent: Cl[Pd]Cl
Agent: [Na+]
Product: C=CN1C(=O)C2C=CC1C2

Procedure:
A solution of 2-azabicyclo[2.2.1]hept-5-en-3-one (0.5 g, 4.6 mmole) in vinyl acetate (3 ml, 33 mmole) with sodium tetrachloropalladate (15 mg, 0.05 mmole) was refluxed for 5 days. The product, Compound 6, was isolated by evaporation of the volatiles. Analysis by Gas Liquid Chromatography-Mass Spectrometry (GLC-MS) was consistent with the predicted molecular weight.
Reaction SMILES: [CH3:1][C:2]1([CH3:35])[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5](=[O:12])[N:4]([CH2:13][CH2:14][CH2:15][NH:16][CH2:17][CH2:18][CH2:19][N:20]2[C:29](=[O:30])[C:28]([CH3:32])([CH3:31])[C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[C:21]2=[O:33])[C:3]1=[O:34].[CH2:36](Br)[CH2:37][CH2:38][CH2:39][CH2:40][CH3:41].C([O-])(=O)/C=C/C([O-])=O>>[CH3:32][C:28]1([CH3:31])[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[C:21](=[O:33])[N:20]([CH2:19][CH2:18][CH2:17][N:16]([CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH3:41])[CH2:15][CH2:14][CH2:13][N:4]2[C:3](=[O:34])[C:2]([CH3:35])([CH3:1])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]2=[O:12])[C:29]1=[O:30]
Reactant: CC1(C)C(=O)N(CCCNCCCN2C(=O)c3ccccc3C(C)(C)C2=O)C(=O)c2ccccc21
Reactant: CCCCCCBr
Agent: O=C([O-])/C=C/C(=O)[O-]
Product: CCCCCCN(CCCN1C(=O)c2ccccc2C(C)(C)C1=O)CCCN1C(=O)c2ccccc2C(C)(C)C1=O

Procedure:
N,N-Bis-[3-(3,4-dihydro-4,4-dimethyl-1,3-dioxo-2(1H)-isoquinolyl)-propyl]-n-hexylamine was prepared analogous to Example 27 from 2.6 gm of N,N-bis-[3-(3,4-dihydro-4,4-dimethyl-1,3-dioxo-2(1H)-isoquinolyl)-propyl]-amine and 1 gm of n-hexyl bromide. M.p. of the fumarate: 137°-138° C; yield: 1.7 gm (50% of theory).
Reaction SMILES: [NH2:1]/[C:2](/[CH3:19])=[C:3](/[C:9](=[O:18])[NH:10][C:11]1[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=1)\[C:4]([O:6][CH2:7][CH3:8])=[O:5].[C:20](OCC)(OCC)(OCC)[CH3:21].C(OCC)(OCC)OCC>>[Cl:17][C:14]1[CH:13]=[CH:12][C:11]([N:10]2[C:9](=[O:18])[C:3]([C:4]([O:6][CH2:7][CH3:8])=[O:5])=[C:2]([CH3:19])[N:1]=[C:20]2[CH3:21])=[CH:16][CH:15]=1
Reactant: CCOC(=O)/C(C(=O)Nc1ccc(Cl)cc1)=C(/C)N
Reactant: CCOC(C)(OCC)OCC
Solvent: CCOC(OCC)OCC
Product: CCOC(=O)c1c(C)nc(C)n(-c2ccc(Cl)cc2)c1=O
Yield: 42 %

Procedure:
This compound is prepared in 42% yield from ethyl 3-amino-2-(4-chlorophenylcarbamoyl)crotonate in a manner analogous to Example 1 substituting triethyl orthoacetate for triethyl orthoformate.
Reaction SMILES: COC1C=CC(C[N:8]2[CH:12]=[C:11]([C:13]3[CH:18]=[CH:17][N:16]=[C:15]([O:19][C:20]4[CH:21]=[CH:22][C:23]([F:27])=[C:24]([NH2:26])[CH:25]=4)[N:14]=3)[CH:10]=[N:9]2)=CC=1.C(O)(C(F)(F)F)=O>ClCCl>[NH:8]1[CH:12]=[C:11]([C:13]2[CH:18]=[CH:17][N:16]=[C:15]([O:19][C:20]3[CH:21]=[CH:22][C:23]([F:27])=[C:24]([NH2:26])[CH:25]=3)[N:14]=2)[CH:10]=[N:9]1
Reactant: COc1ccc(Cn2cc(-c3ccnc(Oc4ccc(F)c(N)c4)n3)cn2)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Nc1cc(Oc2nccc(-c3cn[nH]c3)n2)ccc1F
Temperature: 25 °C
Reaction time: 12 h
Yield: 42.5 %

Procedure:
To a solution of 5-(4-(1-(4-methoxybenzyl)-1H-pyrazol-4-yl)pyrimidin-2-yloxy)-2-fluorobenzenamine (50 mg, 0.13 mmol) in dichloromethane (3 mL) was added TFA (0.3 mL) at 0° C. and the reaction stirred at RT for 12 h. The solvent was removed in vacuo, the residue was washed with ether and treated with saturated ammonia solution. The solid was collected via filtration and dried under vacuum to give 5-(4-(1H-pyrazol-4-yl)pyrimidin-2-yloxy)-2-fluorobenzenamine (15 mg, 43% yield). 1H NMR (300 MHz, MeOD) δ 8.44 (d, J=5.1 Hz, 1H), 8.23 (br s, 2H), 7.40 (d, J=5.4, 1 H), 7.02 (dd, J=10.8, 8.7 Hz, 1H), 6.73 (dd, J=2.7, 7.2 Hz, 1H), 6.50 (m, 1H); MS (ESI) m/z: 272.2 (M+H+).
Reaction SMILES: C[O:2][C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]=[C:5]([NH:13][C:14]([C:16]2[C:25](=[O:26])[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[NH:18][CH:17]=2)=[O:15])[CH:4]=1.B(Br)(Br)Br>C(Cl)Cl>[OH:2][C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]=[C:5]([NH:13][C:14]([C:16]2[C:25](=[O:26])[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[NH:18][CH:17]=2)=[O:15])[CH:4]=1
Reactant: COc1cc(NC(=O)c2c[nH]c3ccccc3c2=O)cc2ccccc12
Agent: BrB(Br)Br
Solvent: ClCCl
Product: O=C(Nc1cc(O)c2ccccc2c1)c1c[nH]c2ccccc2c1=O
Temperature: 25 °C

Procedure:
To a solution of N-(4-methoxy-2-naphthyl)-4-oxo-1H-quinoline-3-carboxamide (73 mg, 0.21 mmol) in DCM (4 mL) was added BBr3 (1.1 mL, 11.64 mmol) dropwise at −78° C. After the addition was complete the cooling bath was removed and the resulting reaction mixture was warmed to room temperature and then was heated to 50° C. for 2 h, cooled to −10° C. and quenched with saturated solution of NaHCO3. The aqueous layer was extracted with DCM and the combined organic layer was dried over MgSO4, filtered and concentrated in vacuo. The residue was purified via reverse phase HPLC to get N-(4-hydroxy-2-naphthyl)-4-oxo-1H-quinoline-3-carboxamide. LC/MS: m/z 331 (M+H)+ at 1.47 min (10%-99% CH3CN (0.035% TFA)/H2O (0.05% TFA)).
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:14](=[O:15])[N:13]([CH3:16])[CH:12]=[C:11](B(O)O)[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[C:21]1[N:26]=[C:25]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH:24]=[CH:23][N:22]=1.[F-].[K+]>O1CCOCC1.CC(C)([P](C(C)(C)C)([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)C(C)(C)C)C>[CH2:1]([O:8][C:9]1[C:14](=[O:15])[N:13]([CH3:16])[CH:12]=[C:11]([C:21]2[N:26]=[C:25]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[CH:24]=[CH:23][N:22]=2)[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Clc1nccc(-c2ccccc2)n1
Reactant: Cn1cc(B(O)O)cc(OCc2ccccc2)c1=O
Agent: CC(C)(C)[P]([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)(C(C)(C)C)C(C)(C)C
Agent: [F-]
Agent: [K+]
Solvent: C1COCCO1
Product: Cn1cc(-c2nccc(-c3ccccc3)n2)cc(OCc2ccccc2)c1=O
Temperature: 60 °C
Reaction time: 22 h
Yield: 49 %

Procedure:
A mixture of [5-(benzyloxy)-1-methyl-6-oxo-1,6-dihydropyridin-3-yl]boronic acid (30 mg, 0.116 mmol), 2-chloro-4-phenylpyrimidine (23.2 mg, 0.122 mmol), bis(tri-t-butylphosphine)palladium(0) (5.9 mg, 0.012 mmol) and potassium fluoride (24 mg, 0.405 mmol) in dioxane (1.5 mL) was stirred at 60° C. for 22 h, cooled to room temperature and filtered through a plug of silica gel (washed with EtOAc). Combined filtrate and washings were concentrated. Purification by preparative HPLC (5-55% CH3CN/H2O over 20 min, 0.05% added TFA) afforded 21 mg 3-(benzyloxy)-1-methyl-5-(4-phenylpyrimidin-2-yl)pyridin-2(1H)-one (49%) as a yellow solid. LC/MS (M+H)+ 370.3.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:33])[CH:5]([C:7]1[C:12]([F:13])=[CH:11][CH:10]=[C:9]([O:14][Si:15]([C:28]([CH3:31])([CH3:30])[CH3:29])([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:8]=1[F:32])[OH:6])[CH3:2].I[CH2:35][CH3:36]>>[CH2:1]([O:3][C:4](=[O:33])[CH:5]([C:7]1[C:12]([F:13])=[CH:11][CH:10]=[C:9]([O:14][Si:15]([C:28]([CH3:29])([CH3:31])[CH3:30])([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:8]=1[F:32])[O:6][CH2:35][CH3:36])[CH3:2]
Reactant: CCI
Reactant: CCOC(=O)C(O)c1c(F)ccc(O[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)c1F
Product: CCOC(=O)C(OCC)c1c(F)ccc(O[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)c1F
Temperature: 90 °C
Reaction time: 68 h
Yield: 83.3 %

Procedure:
A mixture of (RS)-[3-(tert-butyl-diphenyl-silanyloxy)-2,6-difluoro-phenyl]-hydroxy-acetic acid ethyl ester (70.8 g), Ag2O (69.7 g) and iodoethane (117 g) in Tol (700 ml) was stirred 68 h at 90° C. After filtration and evaporation of the solvent the product was separated from the remaining starting material by MPLC (Hept to Hept/AcOEt 1:9). The procedure was repeated with the recovered starting material. 62.5 g (83%) of (RS)-[3-(tert-butyl-diphenyl-silanyloxy)-2,6-difluoro-phenyl]-ethoxy-acetic acid ethyl ester were obtained. Light yellow oil. MS 498.3 (1, M+); 441.1 (73, [M−tBu]+); 425.2 (33, [M-COOEt]+).
Reaction SMILES: [C:1]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1OS(C)(=O)=O)=[CH:13][CH:12]=[N:11][C:10]=2[O:21][CH3:22])(=[O:5])[CH2:2][CH2:3][CH3:4].[NH2:23][C:24]1[C:25]([CH3:30])=[CH:26][CH:27]=[CH:28][CH:29]=1>C(#N)C>[C:1]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1[NH:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[CH3:30])=[CH:13][CH:12]=[N:11][C:10]=2[O:21][CH3:22])(=[O:5])[CH2:2][CH2:3][CH3:4]
Reactant: Cc1ccccc1N
Reactant: CCCC(=O)c1cnc2c(OC)nccc2c1OS(C)(=O)=O
Solvent: CC#N
Product: CCCC(=O)c1cnc2c(OC)nccc2c1Nc1ccccc1C
Yield: 56 %

Procedure:
3-Butyryl-4-methanesulfonyloxy-8-methoxy-1,7-naphthyridine (259 mg) and o-toluidine (0.17 ml) were dissolved into 7 ml of acetonitrile, and the solution was extracted with chloroform, and the organic phase was washed with water and then saturated sodium bicarbonate. After drying, and concentration under reduced pressure, the resulting residue was subjected to silica gel column chromatography using a mixture of hexane:ethyl acetate (1:1) as an eluant to give yellow titled compound (150 mg, 56%).
Reaction SMILES: [Na].[F:2][C:3]1[CH:4]=[CH:5][C:6](Br)=[C:7]([CH:11]=1)[C:8]([OH:10])=[O:9].[K].[NH3:14]>[OH-].[K+]>[F:2][C:3]1[CH:11]=[C:7]([C:8]([OH:10])=[O:9])[C:6]([NH2:14])=[CH:5][CH:4]=1
Reactant: O=C(O)c1cc(F)ccc1Br
Reactant: N
Agent: [K+]
Agent: [K]
Agent: [Na]
Product: Nc1ccc(F)cc1C(=O)O

Procedure:
If the sodium salt solution of 5-fluoro-2-bromobenzoic acid is replaced by aliquot parts of the potassium or ammonium salt solution, prepared by dissolving 219 parts of 5-fluoro-2-bromobenzoic acid in 256.1 parts of 21.9% strength aqueous potassium hydroxide or, respectively, 217 parts of 7.9% aqueous ammonia solution and used as the metering medium in a procedure otherwise identical to that indicated, then 5-fluoroanthranilic acid is obtained in identical yield and quality.
Reaction SMILES: [C:1]1([CH:7]([C:9]2[CH:17]=[C:16]3[C:12]([C:13]([CH:26]=[CH:27][C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)=[N:14][N:15]3[CH2:18][O:19][CH2:20][CH2:21][Si:22]([CH3:25])([CH3:24])[CH3:23])=[CH:11][CH:10]=2)[OH:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>ClCCl.CCCCCC>[C:1]1([C:7]([C:9]2[CH:17]=[C:16]3[C:12]([C:13]([CH:26]=[CH:27][C:28]4[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=4)=[N:14][N:15]3[CH2:18][O:19][CH2:20][CH2:21][Si:22]([CH3:25])([CH3:24])[CH3:23])=[CH:11][CH:10]=2)=[O:8])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: C[Si](C)(C)CCOCn1nc(C=Cc2ccccc2)c2ccc(C(O)c3ccccc3)cc21
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: ClCCl
Solvent: CCCCCC
Product: C[Si](C)(C)CCOCn1nc(C=Cc2ccccc2)c2ccc(C(=O)c3ccccc3)cc21
Temperature: 23 °C
Reaction time: 1 h
Yield: 79.2 %

Procedure:
To a solution of phenyl-{3-styryl-1-[2-(trimethyl-silanyl)-ethoxymethyl)-1H-indazol-6-yl }-methanol (68 mg, 0.15 mmol) in dichloromethane (3 mL) at 23° C. under n atmosphere of argon was added periodinane (Dess-Martin reagent) (190 mg, 0.45 mol). The resulting mixture was stirred at 23° C. for 1 hour. The solution was then diluted with hexane (3 mL) then filtered through Celite and concentrated under reduced pressure to a solid. The crude mixture was purified by silica gel chromatography (eluting with hexane:EtOAc 9:1) to give phenyl-{3-styryl-1-[2-(trimethyl-silanyl)-ethoxymethyl]-1H-indazol-6-yl}-methanone (54 mg, 79% yield). Rfsm=0.41, Rfp=0.63 (7:3 hexane:EtOAc); FTIR (thin film) 3059, 2952, 2894, 1659, 1474, 1448, 1307, 1249, 1078, 836, 649 cm−1. MS (ESI) [M+H]/z Calc'd 455, found 455.
Reaction SMILES: Cl.Cl.[O:3]1[C:8]2=[CH:9][CH:10]=[CH:11][C:7]2=[CH:6][C:5]([CH:12]2[CH2:17][CH2:16][CH2:15][CH2:14][N:13]2[CH2:18][CH2:19][C@H:20]2[CH2:25][CH2:24][C@H:23]([NH2:26])[CH2:22][CH2:21]2)=[CH:4]1.[O:27]1[C:31]2[CH:32]=[CH:33][C:34]([C:36](O)=[O:37])=[CH:35][C:30]=2[O:29][CH2:28]1>>[O:3]1[C:8]2=[CH:9][CH:10]=[CH:11][C:7]2=[CH:6][C:5]([CH:12]2[CH2:17][CH2:16][CH2:15][CH2:14][N:13]2[CH2:18][CH2:19][C@H:20]2[CH2:21][CH2:22][C@H:23]([NH:26][C:36]([C:34]3[CH:33]=[CH:32][C:31]4[O:27][CH2:28][O:29][C:30]=4[CH:35]=3)=[O:37])[CH2:24][CH2:25]2)=[CH:4]1
Reactant: O=C(O)c1ccc2c(c1)OCO2
Reactant: N[C@H]1CC[C@H](CCN2CCCCC2c2coc3cccc-3c2)CC1
Agent: Cl
Product: O=C(N[C@H]1CC[C@H](CCN2CCCCC2c2coc3cccc-3c2)CC1)c1ccc2c(c1)OCO2

Procedure:
The title compound, off-white solid (97 mg, 82%), MS (ISP) m/z=475.3 [(M+H)+], mp 198° C., was prepared in accordance with the general method of example 1 from trans-4-[2-(4-benzofuran-3-yl-piperidin-1-yl)-ethyl]-cyclohexylamine dihydrochloride (intermediate A) (100 mg, 0.25 mmol) and benzo[1,3]dioxole-5-carboxylic acid.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([C:8]2[O:9][C:10]([CH3:13])=[CH:11][CH:12]=2)[CH:5]=[CH:4][C:3]=1[C:14]1[CH:19]=[CH:18][C:17]([C:20]([OH:22])=O)=[CH:16][CH:15]=1.[CH3:23][N:24]1[CH2:29][CH2:28][C:27]2([C:40]3[C:32](=[CH:33][C:34]4[CH2:35][CH2:36][NH:37][C:38]=4[CH:39]=3)[O:31][CH2:30]2)[CH2:26][CH2:25]1>>[CH3:13][C:10]1[O:9][C:8]([C:6]2[CH:5]=[CH:4][C:3]([C:14]3[CH:15]=[CH:16][C:17]([C:20]([N:37]4[C:38]5[CH:39]=[C:40]6[C:27]7([CH2:30][O:31][C:32]6=[CH:33][C:34]=5[CH2:35][CH2:36]4)[CH2:28][CH2:29][N:24]([CH3:23])[CH2:25][CH2:26]7)=[O:22])=[CH:18][CH:19]=3)=[C:2]([CH3:1])[CH:7]=2)=[CH:12][CH:11]=1
Reactant: Cc1ccc(-c2ccc(-c3ccc(C(=O)O)cc3)c(C)c2)o1
Reactant: CN1CCC2(CC1)COc1cc3c(cc12)NCC3
Product: Cc1ccc(-c2ccc(-c3ccc(C(=O)N4CCc5cc6c(cc54)C4(CCN(C)CC4)CO6)cc3)c(C)c2)o1

Procedure:
2'-Methyl-4'-(5-methylfuran-2-yl)biphenyl-4-carboxylic acid (D119) (160 mg, 0.55 mmol) and 1'-methyl-2,3,6,7-tetrahydrospiro[furo[2,3-f]indole-3,4'-piperidine] (D8, 134 mg, 0.55 mmol) were converted to the title compound using the method outlined in Example 29, as an off-white foam (176 mg, 62%).
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:8]=[C:7]([OH:9])[C:6]([C:10]2[CH:14]=[CH:13][O:12][CH:11]=2)=[CH:5][N:4]=1.[I:15][C:16]1[CH:17]=[C:18]2[C:23](=[CH:24][CH:25]=1)[C:22](=[O:26])[NH:21][C:20](=[O:27])/[C:19]/2=[CH:28]/OC>CN(C)C=O>[O:12]1[CH:13]=[CH:14][C:10]([C:6]2[C:7]([OH:9])=[CH:8][C:3]([CH2:2][NH:1]/[CH:28]=[C:19]3\[C:20](=[O:27])[NH:21][C:22](=[O:26])[C:23]4[C:18]\3=[CH:17][C:16]([I:15])=[CH:25][CH:24]=4)=[N:4][CH:5]=2)=[CH:11]1
Reactant: NCc1cc(O)c(-c2ccoc2)cn1
Reactant: CO/C=C1/C(=O)NC(=O)c2ccc(I)cc21
Solvent: CN(C)C=O
Product: O=C1NC(=O)c2ccc(I)cc2/C1=C/NCc1cc(O)c(-c2ccoc2)cn1
Temperature: 25 °C
Reaction time: 6 h
Yield: 67.8 %

Procedure:
An amount of 64 mg (0.33 mmol) of 2-aminomethyl-5-furan-3-yl-pyridin-4-ol, is slurried in N,N-dimethylformamide (3 mL), followed by the addition of 110 mg (0.33 mmol) of (4E)-6-iodo-4-(methoxymethylene)isoquinoline-1,3(2H,4H)-dione. After the mixture is stirred at room temperature for 6 hours, the solid is filtered and washed several times with N,N-dimethylformamide, then ether and dried to give 109 mg of the title compound as a light beige solid (67% yield); mp 213-228° C. dec,
Reaction SMILES: [NH2:1][C@H:2]([C:4]([N:6]1[CH2:20][C@@H:19]([S:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH2:18][C@H:7]1[C:8]([O:10]CC1C=CC=CC=1)=[O:9])=[O:5])[CH3:3].[H][H]>[Pd].C(O)C>[NH2:1][C@H:2]([C:4]([N:6]1[CH2:20][C@@H:19]([S:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH2:18][C@H:7]1[C:8]([OH:10])=[O:9])=[O:5])[CH3:3]
Reactant: [H][H]
Reactant: C[C@H](N)C(=O)N1C[C@@H](Sc2ccccc2)C[C@H]1C(=O)OCc1ccccc1
Agent: [Pd]
Solvent: CCO
Product: C[C@H](N)C(=O)N1C[C@@H](Sc2ccccc2)C[C@H]1C(=O)O

Procedure:
To a solution of 5.0 grams of 1-(L-alanyl)-4-(S)-(phenylthio)-L-proline, phenylmethyl ester in 200 ml. of aqueous ethanol there is added 1 gram of freshly prepared palladium black and the mixture is hydrogenated at 50 psi of hydrogen. The reaction mixture is filtered and concentrated under reduced pressure to yield the desired (S)-1-(L-alanyl)-4-(phenylthio)-L-proline.
Reaction SMILES: [C:1]1(O)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[NH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([CH3:19])[CH:14]=1.P(OCCCC)(OCCCC)OCCCC>>[CH3:19][C:15]1[CH:14]=[C:13]([NH:12][C:1]2[C:10]3[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=3)[CH:4]=[CH:3][CH:2]=2)[CH:18]=[CH:17][CH:16]=1
Reactant: Oc1cccc2ccccc12
Reactant: Cc1cccc(N)c1
Agent: CCCCOP(OCCCC)OCCCC
Product: Cc1cccc(Nc2cccc3ccccc23)c1
Yield: 88 %

Procedure:
216 parts of α-naphthol, 214 parts of m-toluidine and 10 parts of tributyl phosphite are mixed. The reaction is carried out using the method described in Example 17. After removing 24 parts of water, the reaction has ended. After distilling off excess m-toluidine 309 parts of N-m-tolyl-α-naphthylamine, corresponding to a yield of 88% of theory, are obtained at a boiling point of 203° - 206° C/5 mm Hg.
Reaction SMILES: Br[C:2]1[CH:6]=[C:5]([C:7]([CH3:10])([CH3:9])[CH3:8])[S:4][C:3]=1[C:11]1[S:12][C:13]([C:16]2[S:17][C:18]([C:21]([CH3:24])([CH3:23])[CH3:22])=[CH:19][CH:20]=2)=[CH:14][CH:15]=1.C(=O)=O.CC(C)=O.[Li]CCCC.[F:37][C:38]1([F:49])[C:42]([F:43])=[C:41](F)[C:40]([F:46])([F:45])[C:39]1([F:48])[F:47].Cl>C(OCC)C.CO.O>[C:7]([C:5]1[S:4][C:3]([C:11]2[S:12][C:13]([C:16]3[S:17][C:18]([C:21]([CH3:24])([CH3:23])[CH3:22])=[CH:19][CH:20]=3)=[CH:14][CH:15]=2)=[C:2]([C:41]2[C:40]([F:46])([F:45])[C:39]([F:47])([F:48])[C:38]([F:37])([F:49])[C:42]=2[F:43])[CH:6]=1)([CH3:10])([CH3:9])[CH3:8]
Reactant: CC(C)(C)c1ccc(-c2ccc(-c3sc(C(C)(C)C)cc3Br)s2)s1
Reactant: FC1=C(F)C(F)(F)C(F)(F)C1(F)F
Agent: Cl
Agent: O=C=O
Agent: [Li]CCCC
Solvent: CO
Solvent: O
Solvent: CC(C)=O
Product: CC(C)(C)c1ccc(-c2ccc(-c3sc(C(C)(C)C)cc3C3=C(F)C(F)(F)C(F)(F)C3(F)F)s2)s1
Temperature: -45 °C
Reaction time: 0.33 h

Procedure:
In a flame-dried, 1 L rbf, 3-bromo-5,5″-di-t-butyl-2,2′:5′,2″-terthiophene (112, 4 g, 9.10 mmol) was dissolved in anhydrous diethyl ether (400 mL) and cooled to −48° C. (dry ice/acetone). n-BuLi (2.5 M in hexanes, 1.5 mL, 3.82 mmol) was added dropwise over a period of 5 minutes. The resulting yellow solution was allowed to stir for 20 minutes, then octafluorocyclopentene (0.24 mL, 1.82 mmol) was added in one portion. The reaction mixture warmed to −45° C. The reaction mixture was allowed to mix and slowly warm to 5° C., and then was poured into water (300 mL) and mixed well, then acidified with 10% HCl (100 mL). The aqueous phase was separated and extracted with EtOAc (2×100 mL). The combined organics were washed with water (500 mL), dried over MgSO4, filtered and solvent removed by rotary evaporation. The resulting dark orange oil was redissolved in chloroform and dry-loaded onto silica gel. Flash chromatography (hexanes) afforded a yellow oil, which was sonicated in methanol, filtered and air dried to afford 113 as a bright yellow, powdery solid (3.62 g, 72%).
Reaction SMILES: [Cl:1][C:2]1[CH:36]=[C:35]([F:37])[CH:34]=[CH:33][C:3]=1[CH2:4][NH:5][C:6](=[O:32])[N:7]([C@H:9]([CH2:17][O:18][C:19](=[O:31])[NH:20][C:21]1[N:22]=[CH:23][C:24]2[C:29]([CH:30]=1)=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH2:10][CH2:11][CH2:12][C:13](OC)=[O:14])[CH3:8].[Li+].[BH4-]>CO.C1COCC1>[CH:23]1[C:24]2[C:29](=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH:30]=[C:21]([NH:20][C:19](=[O:31])[O:18][CH2:17][C@@H:9]([N:7]([CH3:8])[C:6]([NH:5][CH2:4][C:3]2[CH:33]=[CH:34][C:35]([F:37])=[CH:36][C:2]=2[Cl:1])=[O:32])[CH2:10][CH2:11][CH2:12][CH2:13][OH:14])[N:22]=1
Reactant: COC(=O)CCC[C@@H](COC(=O)Nc1cc2ccccc2cn1)N(C)C(=O)NCc1ccc(F)cc1Cl
Agent: [BH4-]
Agent: [Li+]
Solvent: CO
Solvent: C1CCOC1
Product: CN(C(=O)NCc1ccc(F)cc1Cl)[C@@H](CCCCO)COC(=O)Nc1cc2ccccc2cn1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of (S)-methyl 5-(3-(2-chloro-4-fluorobenzyl)-1-methylureido)-6-(isoquinolin-3-ylcarbamoyloxy)hexanoate (80 mg, 0.15 mmol) in MeOH (1 mL) and THF (1 mL) was added LiBH4 (2 M in THF, 0.3 mL, 4 equiv.) dropwise. The reaction was stirred at RT for 2 h. The reaction was quenched with saturated NH4Cl (5 mL). The mixture was extracted with EtOAc (10 mL). The organic layer was concentrated. The resulting residue was purified on RP-HPLC using a mixture of acetonitrile and H2O to give (S)-2-(3-(2-chloro-4-fluorobenzyl)-1-methylureido)-6-hydroxyhexyl isoquinolin-3-ylcarbamate as a white solid 10 (40 mg, 53%). LRMS (M+H+) m/z 503.5.
Reaction SMILES: [CH:1]1([N:7]2[C:11]([CH2:12][CH2:13][CH2:14][O:15][C:16]3[CH:17]=[C:18]4[C:23](=[CH:24][CH:25]=3)[NH:22][C:21](=[O:26])[CH2:20][CH2:19]4)=[N:10][N:9]=[N:8]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(C1C(=O)C(Cl)=C(Cl)C(=O)C=1C#N)#N.O1CCOCC1>C(Cl)(Cl)Cl>[CH:1]1([N:7]2[C:11]([CH2:12][CH2:13][CH2:14][O:15][C:16]3[CH:17]=[C:18]4[C:23](=[CH:24][CH:25]=3)[NH:22][C:21](=[O:26])[CH:20]=[CH:19]4)=[N:10][N:9]=[N:8]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C1CCc2cc(OCCCc3nnnn3C3CCCCC3)ccc2N1
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Solvent: C1COCCO1
Solvent: ClC(Cl)Cl
Product: O=c1ccc2cc(OCCCc3nnnn3C3CCCCC3)ccc2[nH]1

Procedure:
3.2 Grams of 6-[3-(1-cyclohexyltetrazol-5-yl)propoxy]-3,4-dihydrocarbostyril and 3.4 g of 90% DDQ are added to 100 ml of dioxane and this mixture is refluxed for9.5 hours and then cooled. After the reaction is completed, the solvent is distilled off and the residue obtained is dissolved in chloroform and the organic layer is washed with aqueous saturated NaHCO3 solution, and with water then dried with Na2SO4 and treated with an activatedcharcoal. After the solvent is removed by distillation, the resultant residue is refined by silica gel column chromatography [silica gel: Wakogel C-200; eluent:chloroform:methanol=10:1 (V/V)] and the crude crystals are recrystallized from chloroform to obtain 1.1 g of 6-[3-(1-cyclohexyltetrazol-5-yl)propoxy]carbostyril in the form of colorless needle-like crystals. Melting point: 211°-212° C.