Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[CH2:2][C:3]1[CH:4]=[C:5]([C:9]2[NH:26][C:12]3[N:13]=[CH:14][N:15]=[C:16]([NH:17][C@@H:18]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)[CH3:19])[C:11]=3[CH:10]=2)[CH:6]=[CH:7][CH:8]=1.[CH3:27][NH:28][CH3:29]>C(O)C>[NH3:13].[CH3:27][N:28]([CH2:2][C:3]1[CH:4]=[C:5]([C:9]2[NH:26][C:12]3[N:13]=[CH:14][N:15]=[C:16]([NH:17][C@@H:18]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)[CH3:19])[C:11]=3[CH:10]=2)[CH:6]=[CH:7][CH:8]=1)[CH3:29]
Reactant: C[C@@H](Nc1ncnc2[nH]c(-c3cccc(CCl)c3)cc12)c1ccccc1
Reactant: CNC
Solvent: CCO
Product: C[C@@H](Nc1ncnc2[nH]c(-c3cccc(CN(C)C)c3)cc12)c1ccccc1
Product: N
Yield: 1 %

Procedure:
A mixture of 240 mg (0.5 mmol) crude [6-(3-chloromethyl-phenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl]-((R)-1-phenyl-ethyl)-amine in 15 ml ethanol is treated with 0.8 ml (5 mmol) of a 33% solution of dimethylamine in ethanol (Fluka, Buchs, Switzerland) and then heated under reflux for 1 h. The clear solution is cooled and the solvent evaporated. The residue is purified with flash chromatography using dichloromethane/ethanol 95:5 and then dichloromethane/ethanol 9:1 plus 1% conc. ammonia to give the title compound; m.p. 108-110° C.; MS-ES+: (M+H)+=372.
Reaction SMILES: Cl[C:2]1[N:7]2[N:8]=[CH:9][N:10]=[C:6]2[C:5]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([N:18]3[CH2:23][CH2:22][N:21]([CH2:24][CH2:25][CH3:26])[CH2:20][CH2:19]3)=[CH:14][CH:13]=2)=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[C:33]([C:36]1[CH:41]=[CH:40][C:39](B(O)O)=[CH:38][CH:37]=1)(=[O:35])[NH2:34].O1CCOCC1>O>[CH2:24]([N:21]1[CH2:22][CH2:23][N:18]([C:15]2[CH:16]=[CH:17][C:12]([NH:11][C:5]3[C:6]4[N:7]([N:8]=[CH:9][N:10]=4)[C:2]([C:39]4[CH:40]=[CH:41][C:36]([C:33]([NH2:34])=[O:35])=[CH:37][CH:38]=4)=[CH:3][CH:4]=3)=[CH:13][CH:14]=2)[CH2:19][CH2:20]1)[CH2:25][CH3:26]
Reactant: NC(=O)c1ccc(B(O)O)cc1
Reactant: CCCN1CCN(c2ccc(Nc3ccc(Cl)n4ncnc34)cc2)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: CCCN1CCN(c2ccc(Nc3ccc(-c4ccc(C(N)=O)cc4)n4ncnc34)cc2)CC1
Temperature: 107.5 °C
Yield: 42.2 %

Procedure:
To a reaction vial (40 mL), is added 5-chloro-N-(4-(4-propylpiperazin-1-yl)phenyl)-[1,2,4]triazolo[1,5-a]pyridin-8-amine (55 mg, 0.15 mmol), potassium carbonate (104 mg, 0.75 mmol, 5 eq.), 4-carbamoylphenylboronic acid (50 mg, 0.30 mmol, 2 eq), PddppfCl2 (20 mg, 15%), dioxane (4.0 mL) and water (1.0 mL). The reaction mixture is degassed and filled with argon. The reaction is heated at 105-110° C. for 20 h. After cooling to rt, ethyl acetate (10 mL) is added to each reaction vial. The organic phase was filtered through a pat of celite and then is evaporated to give a dry residue that was purified by preparatory HPLC to give the title compound, 28.9 mg, yield 42.2%; LCMS-ESI (m/z): calcd for C26H29N7O, 455; [M+H]+ found, 456.
Reaction SMILES: [C:1]([O:5][C:6](=[O:18])[CH2:7][N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([OH:17])[CH:15]=2)[CH:10]=[CH:9]1)([CH3:4])([CH3:3])[CH3:2].[CH3:19][C:20]1[C:25]([CH2:26]O)=[CH:24][CH:23]=[C:22]([C:28]2[CH:33]=[CH:32][C:31]([C:34]([F:37])([F:36])[F:35])=[CH:30][CH:29]=2)[N:21]=1.C(P(CCCC)CCCC)CCC.CN(C)C(N=NC(N(C)C)=O)=O>O1CCCC1>[C:1]([O:5][C:6](=[O:18])[CH2:7][N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([O:17][CH2:26][C:25]3[C:20]([CH3:19])=[N:21][C:22]([C:28]4[CH:29]=[CH:30][C:31]([C:34]([F:37])([F:35])[F:36])=[CH:32][CH:33]=4)=[CH:23][CH:24]=3)[CH:15]=2)[CH:10]=[CH:9]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)Cn1ccc2ccc(O)cc21
Reactant: Cc1nc(-c2ccc(C(F)(F)F)cc2)ccc1CO
Agent: CCCCP(CCCC)CCCC
Agent: CN(C)C(=O)N=NC(=O)N(C)C
Solvent: C1CCOC1
Product: Cc1nc(-c2ccc(C(F)(F)F)cc2)ccc1COc1ccc2ccn(CC(=O)OC(C)(C)C)c2c1
Temperature: 0 °C
Reaction time: 14 h
Yield: 75 %

Procedure:
To an ice cold solution of (6-hydroxy-indol-1-yl)-acetic acid tert-butyl ester (70 mg, 0.28 mmol), [2-methyl-6-(4-trifluoromethyl-phenyl)-pyridin-3-yl]-methanol (76 mg, 0.28 mmol) and tributylphosphine (110 μl, 0.42 mmol) in tetrahydrofuran (4 ml) was added N,N,N′,N′-tetramethyl azodicarboxamide (73 mg, 0.42 mmol) under an argon atmosphere. The cooling bath was removed and stirring continued for 14 h. Filtration over celite and evaporation of the solvent under reduced pressure gave a yellow oil which was purified by column chromatography (silica gel, heptane/AcOEt) to give 105 mg (0.21 mmol, 75%) of the title compound as white crystals.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[C@@H:28](OS(C)(=O)=O)[CH2:27][CH2:26][C@@:9]32[O:13][CH2:12][C@H:11]([C:14]2[CH:19]=[C:18]([C:20]#[N:21])[CH:17]=[CH:16][C:15]=2[O:22][CH:23]([CH3:25])[CH3:24])[CH2:10]3)=[CH:4][CH:3]=1.[I-:34].[Na+].[CH3:36]C(C)=O>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C@@H:8]2[C@@H:28]([CH2:36][I:34])[CH2:27][CH2:26][C@@:9]32[O:13][CH2:12][C@H:11]([C:14]2[CH:19]=[C:18]([C:20]#[N:21])[CH:17]=[CH:16][C:15]=2[O:22][CH:23]([CH3:25])[CH3:24])[CH2:10]3)=[CH:6][CH:7]=1
Reactant: [I-]
Reactant: CC(C)=O
Reactant: CC(C)Oc1ccc(C#N)cc1[C@H]1CO[C@]2(CC[C@H](OS(C)(=O)=O)[C@@H]2c2ccc(F)cc2)C1
Agent: [Na+]
Product: CC(C)Oc1ccc(C#N)cc1[C@H]1CO[C@]2(CC[C@H](CI)[C@H]2c2ccc(F)cc2)C1

Procedure:
The methanesulfonate from Step B was dissolved in acetone (2 mL). Sodium iodide (25 mg, 0.167 mmol) was added, and the mixture was heated at reflux temperature until TLC indicated disappearance of starting material. The cooled reaction mixture was evaporated, the residue taken up in methylene chloride, washed with water, 10% sodium thiosulfate solution, saturated brine solution, dried (Na2SO4), and evaporated. The title compound was obtained pure by silica gel chromatography eluting with 15% diethyl ether/hexane; yield 35 mg.
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[C:11]([C:12]3[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][CH:13]=3)=[CH:10][C:9]([CH:22]([CH2:28][CH:29]([CH3:31])[CH3:30])[C:23]([O:25]CC)=[O:24])=[CH:8][C:7]=2[N+:32]([O-:34])=[O:33])[CH2:3][CH2:2]1.C1COCC1.O.[Li+].[OH-]>CO>[CH:1]1([CH2:4][O:5][C:6]2[C:11]([C:12]3[CH:13]=[CH:14][C:15]([C:18]([F:19])([F:21])[F:20])=[CH:16][CH:17]=3)=[CH:10][C:9]([CH:22]([CH2:28][CH:29]([CH3:30])[CH3:31])[C:23]([OH:25])=[O:24])=[CH:8][C:7]=2[N+:32]([O-:34])=[O:33])[CH2:2][CH2:3]1
Reactant: CCOC(=O)C(CC(C)C)c1cc(-c2ccc(C(F)(F)F)cc2)c(OCC2CC2)c([N+](=O)[O-])c1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)CC(C(=O)O)c1cc(-c2ccc(C(F)(F)F)cc2)c(OCC2CC2)c([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 74.5 %

Procedure:
Ethyl 2-(6-(cyclopropylmethoxy)-5-nitro-4′-(trifluoromethyl)biphenyl-3-yl)-4-methylpentanoate (100 mg, 0.208 mmol) was taken in a mixture of MeOH; THF:Water (30 ml, 10:10:2) and to it added LiOH (30 mg, 0.7 mmol). The reaction mixture was stirred at room temperature for 3 h. After completion of the reaction, it was poured into water (50 ml) and extracted with ethyl acetate (100 ml×2). The ethyl acetate layer was washed with 1N HCl, water and finally brine solution. The organic layer was then distilled off and the crude residue was purified by column chromatography using Ethyl acetate:hexane (1:1) as eluent provided 70 mg of 2-(6-(cyclopropylmethoxy)-5-nitro-4′-(trifluoromethyl)biphenyl-3-yl)-4-methylpentanoic acid. 1H NMR (CDCl3): δ 8.20 (s 1H), 7.40-7.20 (m, 5H), 3.60 (t, 1H), 3.45 (d, 2H), 1.95-2.00 (m, 1H), 1.75-1.80 (m, 1H), 1.45-1.50 (m, 1H), 1.00 (m, 6H), 0.35-0.25 (m, 5H). Mass: (452, M+1, 100%).
Reaction SMILES: [F:1][C:2]1[C:11]([CH:12]([N:14]2[C:18]3=[N:19][C:20]([C:23](=O)[CH3:24])=[CH:21][N:22]=[C:17]3[N:16]=[N:15]2)[CH3:13])=[C:10]([F:26])[CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2.Cl.[NH2:28][O:29][CH2:30][CH2:31][OH:32]>CO>[OH:32][CH2:31][CH2:30][O:29]/[N:28]=[C:23](/[C:20]1[N:19]=[C:18]2[N:14]([CH:12]([C:11]3[C:2]([F:1])=[C:3]4[C:8](=[CH:9][C:10]=3[F:26])[N:7]=[CH:6][CH:5]=[CH:4]4)[CH3:13])[N:15]=[N:16][C:17]2=[N:22][CH:21]=1)\[CH3:24]
Reactant: CC(=O)c1cnc2nnn(C(C)c3c(F)cc4ncccc4c3F)c2n1
Reactant: NOCCO
Agent: Cl
Solvent: CO
Product: C/C(=N\OCCO)c1cnc2nnn(C(C)c3c(F)cc4ncccc4c3F)c2n1
Temperature: 45 °C
Yield: 63.8 %

Procedure:
To a solution of 1-(1-(1-(5,7-difluoroquinolin-6-yl)ethyl)-1H-[1,2,3]triazolo[4,5-b]pyrazin-6-yl)ethanone (76.5 mg, 0.22 mmol) in MeOH (50 mL) was added 2-(aminooxy)ethanol hydrochloride (49.0 mg, 0.43 mol). The mixture was heated at 45° C. overnight. The solvent was removed under reduced pressure. The residue was purified by column chromatography with gradient (DCM/MeOH=10:1) to give the title compound as a white solid (58.0 mg, 62%). 1H-NMR (400 MHz, DMSO-d6) δ ppm 9.23 (s, 1H), 9.01 (dd, 1H), 8.52 (d, 1H), 7.74 (d, 1H), 7.63 (dd, 1H), 6.80 (q, 1H), 4.74 (t, 1H), 4.27 (t, 2H), 3.68 (m, 2H), 2.36 (d, 3H), 2.10 (s, 3H). LCMS (method A): [MH]+=414, tR=5.44 min.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][CH:11]=1)[CH:7]=O)([O-:3])=[O:2].[C:12]([O:18][CH2:19][CH2:20][N:21]1[CH2:26][CH2:25][N:24]([C:27]2[CH:32]=[CH:31][CH:30]=[C:29]([C:33]([F:36])([F:35])[F:34])[CH:28]=2)[CH2:23][CH2:22]1)(=[O:17])[CH2:13][C:14]([CH3:16])=O.[NH2:37]/[C:38](/[CH3:44])=[CH:39]\[C:40]([O:42][CH3:43])=[O:41]>C(O)(C)C>[CH3:44][C:38]1[NH:37][C:14]([CH3:16])=[C:13]([C:12]([O:18][CH2:19][CH2:20][N:21]2[CH2:22][CH2:23][N:24]([C:27]3[CH:32]=[CH:31][CH:30]=[C:29]([C:33]([F:36])([F:35])[F:34])[CH:28]=3)[CH2:25][CH2:26]2)=[O:17])[CH:7]([C:6]2[CH:9]=[CH:10][CH:11]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=2)[C:39]=1[C:40]([O:42][CH3:43])=[O:41]
Reactant: COC(=O)/C=C(/C)N
Reactant: CC(=O)CC(=O)OCCN1CCN(c2cccc(C(F)(F)F)c2)CC1
Reactant: O=Cc1cccc([N+](=O)[O-])c1
Solvent: CC(C)O
Product: COC(=O)C1=C(C)NC(C)=C(C(=O)OCCN2CCN(c3cccc(C(F)(F)F)c3)CC2)C1c1cccc([N+](=O)[O-])c1
Yield: 82.7 %

Procedure:
A mixture of m-nitrobenzaldehyde, 2-[4-(3-trifluoromethylphenyl)-1-piperazinyl]ethyl acetoacetate and methyl 3-aminocrotonate was worked up in isopropyl alcohol in the same manner as Example 1 to give methyl 2-[4-(3-trifluoromethylphenyl)-1-piperazinyl]ethyl 2,6-dimethyl-4-(3-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylate as a light yellow powder, m.p. 95°-87° C. (sintering). Yield 82.7%. IR(Nujol)cm-1 : 3345, 1695, 1645. NMR(CDCl3) δ: 2.34(6H,s, ##STR31## 3.64(3H,s,COOCH3), 4.21(2H,t,J=5.5,--COOCH2CH2 --), 5.11(1H,s,C(4) --H), 6.39(1H,s,NH).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8]([C:10]2[NH:14][C:13]3[CH:15]=[CH:16][CH:17]=[C:18]([N+:19]([O-])=O)[C:12]=3[N:11]=2)=[O:9])[CH2:4][CH2:3]1.[H][H]>C1COCC1.C(O)C.[Pd]>[NH2:19][C:18]1[C:12]2[N:11]=[C:10]([C:8]([N:5]3[CH2:4][CH2:3][N:2]([CH3:1])[CH2:7][CH2:6]3)=[O:9])[NH:14][C:13]=2[CH:15]=[CH:16][CH:17]=1
Reactant: CN1CCN(C(=O)c2nc3c([N+](=O)[O-])cccc3[nH]2)CC1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Solvent: C1CCOC1
Product: CN1CCN(C(=O)c2nc3c(N)cccc3[nH]2)CC1
Yield: 90.6 %

Procedure:
To a solution of (4-methyl-piperazin-1-yl)-(4-nitro-1H-benzoimidazol-2-yl)-methanone (640 mg, 2.21 mmol) in 1:1 THF/ethanol (10 mL, with a few drops of ethyl acetate) was added 10% palladium on carbon (640 mg). The reaction mixture was placed under 1 atm hydrogen for 72 h. The resulting mixture was filtered through diatomaceous earth, and the filtrate was concentrated under reduced pressure. The crude product was purified on silica gel (40 g; 0-10% methanol/CH2Cl2) to afford 519 mg (91%) of the title compound. MS (ESI): mass calculated for C13H17N5O, 259.31; m/z found, 260.3 [M+H]+. 1H NMR (400 MHz, CDCl3): 12.21-11.36 (s, 1H), 7.12 (t, J=7.8 Hz, 1H), 6.94-6.83 (m, 1H), 6.53 (d, J=7.8 Hz, 1H), 4.82-4.78 (m, 2H), 4.43-4.40 (m, 2H), 3.94-3.92 (m, 2H), 2.56-2.54 (m, 4H), 2.35 (s, 3H).
Reaction SMILES: N[C@@H:2]1[CH2:15][CH2:14][C@:13]2([O:16][CH3:17])[C@:4]34[CH2:20][CH2:19][N:18]([CH3:21])[C@@H:12]2[CH2:11][C:10]2[CH:9]=[CH:8][C:7]([OH:22])=[C:6]([O:23][C@@H:3]13)[C:5]4=2.[C:24]([O:28][C:29]([NH:31][C:32](=[N:35][C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])SC)=[O:30])([CH3:27])([CH3:26])[CH3:25].C([N:45](C(C)C)C(C)C)C>CN(C)C=O.[N+]([O-])([O-])=O.[Ag+]>[O:23]1[C@@H:3]2[C@@:4]34[CH2:20][CH2:19][N:18]([CH3:21])[C@@H:12]([C@:13]3([O:16][CH3:17])[CH2:14][CH2:15][C@H:2]2[N:35]([C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])[C:32]([NH:31][C:29]([O:28][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:30])=[NH:45])[CH2:11][C:10]2=[C:5]4[C:6]1=[C:7]([OH:22])[CH:8]=[CH:9]2
Reactant: CCN(C(C)C)C(C)C
Reactant: CSC(=NC(=O)OC(C)(C)C)NC(=O)OC(C)(C)C
Reactant: CO[C@@]12CC[C@@H](N)[C@@H]3Oc4c(O)ccc5c4[C@@]31CCN(C)[C@@H]2C5
Agent: [Ag+]
Agent: O=[N+]([O-])[O-]
Solvent: CN(C)C=O
Product: CO[C@@]12CC[C@@H](N(C(=N)NC(=O)OC(C)(C)C)C(=O)OC(C)(C)C)[C@@H]3Oc4c(O)ccc5c4[C@@]31CCN(C)[C@@H]2C5
Reaction time: 4 h
Yield: 88 %

Procedure:
A solution of Compound 15 (0.94 g, 2.97 mmol), N,N′-bis-(tert.-butoxycarbonyl)-S-methylisothiourea (0.92 g, 3.17 mmol) and N-ethyldiisopropylamine (0.58 ml, 3.33 mmol) in absolute N,N-dimethylformamide (40 ml) was mixed with silver nitrate (0.54 g, 3.18 mmol) and the mixture stirred for 4 hours. Then the silver mercaptane was filtered off through Celite and washed afterwards with CH2Cl2 (4×50 ml). The filtrate was washed with H2O (10×150 ml) and saturated NaCl solution (2×150 ml), dried (Na2SO4) and evaporated. In this way 1.46 g of a yellow foam resin was obtained which was purified through MPLC (p=5 bar, silica gel 60, CH2Cl2/MeOH/conc. ammonia 95:4, 5:0.5). Yield: 0.77 g (46%) of green foam resin: 1H-NMR (CDCl3): δ 11.49 (s, br, NH—COO(CH3)3); 8.59 (d, J=8.0, C(6)-NH—); 6.71 (d, J=8.4, 1 arom. H); 6.56 (d, J=8.4, 1 arom. H); 4.41 (d, J=7.2, H—C(5)); 3.22 (s, CH3O—C(14)); 2.38 (s, CH3N); 1.51 (s, C(CH3)3), 1.47 (s, C(CH3)3).
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[CH:6][C:3]=1[CH:4]=O.[CH3:13][NH2:14].[BH4-].[Na+].[CH:17]1[CH:22]=[CH:21][C:20]([CH2:23][O:24][C:25](Cl)=[O:26])=[CH:19][CH:18]=1>CO>[Cl:1][C:2]1[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[CH:6][C:3]=1[CH2:4][N:14]([CH3:13])[C:25](=[O:26])[O:24][CH2:23][C:20]1[CH:21]=[CH:22][CH:17]=[CH:18][CH:19]=1
Reactant: CN
Reactant: O=C(Cl)OCc1ccccc1
Reactant: O=Cc1cc([N+](=O)[O-])ccc1Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CN(Cc1cc([N+](=O)[O-])ccc1Cl)C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 82.1 %

Procedure:
To a solution of 2-chloro-5-nitrobenzaldehyde (5 g, 26.9 mmol) in MeOH (100 mL), was added methylamine (33% in EtOH) (14.82 mL, 29.6 mmol). The mixture was stirred at rt for 1 h, cooled to 0° C. and treated with NaBH4 (1.223 g, 32.3 mmol). The mixture was stirred at rt for 30 min, then was concentrated. The residue was dissolved in THF (50 mL), treated with water (20 mL) and sat. NaHCO3 (20 mL). After stirring for 10 min, Cbz-Cl (4.62 mL, 32.3 mmol) was added dropwise. The mixture was stirred at rt over night. THF was removed under reduced pressure. The mixture was extracted with EtOAc (2×). The organic phase was washed with brine, dried (Na2SO4) and concentrated. The crude product was purified by flash chromatography (loaded in chloroform onto a 120 g column and eluted with a gradient from 0 to 50% ethyl acetate/hexanes) to give 6A (7.39 g, 22.08 mmol, 82% yield) as a white solid. MS (ESI) m/z: 335.1 [M+1]+; 1H NMR (400 MHz, chloroform-d) δ ppm 7.97-8.13 (m, 2H) 7.55 (d, J=7.53 Hz, 1H) 7.27-7.45 (m, 5H) 5.11-5.26 (m, 2H) 4.58-4.72 (m, 2H) 3.03 (br. s., 3H), 3:2 rotamers.
Reaction SMILES: [CH:1]1([SH:7])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(O)C.[OH-].[Na+].Br[CH:14]1[CH2:22][C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[C:15]1=[O:23]>CCOCC.O>[CH:1]1([S:7][CH:14]2[CH2:22][C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[C:15]2=[O:23])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: SC1CCCCC1
Reactant: O=C1c2ccccc2CC1Br
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Solvent: CCOCC
Product: O=C1c2ccccc2CC1SC1CCCCC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 20.6 %

Procedure:
After 5.5 g of cyclohexylmercaptan was dissolved into 50 ml of ethanol, 1.97 g of sodium hydroxide was added thereto and refluxed under heating. After the complete dissolving of the sodium hydroxide, the solution was cooled on standing. After 10 g of 2-bromo-1-indanone (available from Aldrich Corporation) dissolved in 10 ml of ether was added dropwise to the cooled solution and stirred for three hours at room temperature, the reaction mixture was poured into 300 ml of cold water. After 200 ml of ether was added thereto for extracting an organic phase, the ether layer was sequentially washed with an aqueous sodium chloride solution and water. After the ether layer was dried with magnesium sulfate, the ether was evaporated under vacuum. The residue was isolated and purified through a silica gel column (elute: hexane/ethyl acetate=9/1) to provide 2.4 g of 2-(cyclohexylthio)-1-indanone (yield: 23%). Then, 2 g of the 2-(cyclohexylthio)-1-indanone was dissolved into 6 ml of nitromethane, and 10.7 g of methyl iodide was added thereto and stirred at room temperature. After an hour, 40 ml of nitromethane dissolving 2.09 g of silver trifluoromethanesulfonate was added dropwise thereto. After the stirring for 18 hours at room temperature, precipitated silver iodide was filtrated and a filtrate was concentrated to about one-third under vacuum. After the residue was added dropwise to 250 ml of ether, a precipitated sulfonium salt was filtered. The precipitated sulfonium salt was recrystalized from ethyl acetate-ethanol to provide 2.42 g of the sulfonium salt having the above structure (yield: 73%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[C:9](=[CH:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])[NH:8][CH2:7][CH2:6]2.[CH3:21][C:22]1[CH:23]=[C:24]([CH:27]=[C:28]([CH3:31])[C:29]=1[OH:30])[CH:25]=O.[N+]([CH2:35][CH3:36])([O-])=O.N1CCCCC1>C(O)C.C(O)(C)C.C(O)(C)C>[OH:30][C:29]1[C:22]([CH3:21])=[CH:23][C:24]([C:25]2[C:15]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[C:9]3[C:10]4[C:5](=[CH:4][C:3]([O:2][CH3:1])=[C:12]([O:13][CH3:14])[CH:11]=4)[CH2:6][CH2:7][N:8]3[C:35]=2[CH3:36])=[CH:27][C:28]=1[CH3:31]
Reactant: Cc1cc(C=O)cc(C)c1O
Reactant: CC[N+](=O)[O-]
Reactant: CCOC(=O)C=C1NCCc2cc(OC)c(OC)cc21
Solvent: CC(C)O
Solvent: CCO
Solvent: C1CCNCC1
Product: CCOC(=O)c1c(-c2cc(C)c(O)c(C)c2)c(C)n2c1-c1cc(OC)c(OC)cc1CC2
Temperature: 80 °C
Reaction time: 8 h

Procedure:
A mixture of 500 mg (1.8 mmol) of ethyl (6,7-dimethoxy-3,4-dihydro-1(2H)-isoquinolinylidene)-ethanoate (Example III.1), 558 mg (3.61 mmol) of 3,5-dimethyl-4-hydroxybenzaldehyde, 281 mg (3.61 mmol) of nitroethane and 61.4 mg (0.72 mmol) of piperidine in 10 mL of an ethanol/isopropanol 1:1 mixture was stirred at 80° C. overnight. 40 mL of isopropanol were added, the mixture was cooled to 0° C., and the resulting precipitate was filtered off. The solid was washed with ethanol and dried in vacuo to give the title compound as a white solid which was readily recrystallized from ethyl acetate to furnish white needles.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7](O)=[N:8][C:9]([S:13][CH3:14])=[N:10][C:11]=1[CH3:12])=[O:5])[CH3:2].C(N(CC)C(C)C)(C)C.O.O=P(Cl)(Cl)[Cl:28]>C(Cl)Cl.C([O-])(O)=O.[Na+]>[Cl:28][C:7]1[C:6]([C:4]([O:3][CH2:1][CH3:2])=[O:5])=[C:11]([CH3:12])[N:10]=[C:9]([S:13][CH3:14])[N:8]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: CCOC(=O)c1c(C)nc(SC)nc1O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)c1c(C)nc(SC)nc1Cl
Reaction time: 2 h
Yield: 96 %

Procedure:
A 100 mL round-bottomed flask was charged with ethyl-4-hydroxy-6-methyl-2-(methylthio)pyrimidine-5-carboxylate (6.49 g, 28.4 mmol) in 14 mL POCl3. To the solution was added N,N-diisopropylethylamine (1.2 mL), the reaction mixture was stirred at 80˜90° C. for 2 hours. The mixture was condensed under reduced pressure yielding the dark brown residue. To the residue was added iced water, then diluted with DCM, and saturated aqueous NaHCO3 solution. The separated organic layer was dried over MgSO4. The solvent was removed by a rotavapor providing dark brown oily product (6.76 g, 96%). MS m/z: 246.9 (M+H)+, 248.9 (isotope).
Reaction SMILES: Br[CH2:2][C:3]1[N:10]=[C:9]([Cl:11])[CH:8]=[C:7]([Cl:12])[C:4]=1[C:5]#[N:6].[CH3:13][OH:14]>F[B-](F)(F)F.[Ag+]>[Cl:12][C:7]1[C:4]([C:5]#[N:6])=[C:3]([CH2:2][O:14][CH3:13])[N:10]=[C:9]([Cl:11])[CH:8]=1
Reactant: CO
Reactant: N#Cc1c(Cl)cc(Cl)nc1CBr
Agent: [Ag+]
Agent: F[B-](F)(F)F
Product: COCc1nc(Cl)cc(Cl)c1C#N
Temperature: 50 °C
Reaction time: 17 h

Procedure:
A solution of 2-(bromomethyl)-4,6-dichloronicotinonitrile (378.9 mg, 1.425 mmol) in MeOH (5.0 ml) was charged with silver(I) tetrafluoroborate (360 mg, 1.849 mmol) and stirred at 50° C. for 17 hr. LCMS showed conversion to the desired mass. The mixture was concentrated in vacuo and purified via flash chromatography (15-60% Et2O/Hexane) to provide 4,6-dichloro-2-(methoxymethyl)nicotinonitrile. MS ESI calc'd for C8H7C12N2O [M+H]+ 217. found 217.
Reaction SMILES: C(OC(=O)[NH:10][CH:11]1[CH2:23][C:22]2[C:21]3[C:16](=[CH:17][CH:18]=[C:19]([O:24][C:25]([F:28])([F:27])[F:26])[CH:20]=3)[N:15]([CH2:29][C:30]3[CH:35]=[CH:34][CH:33]=[C:32]([F:36])[N:31]=3)[C:14]=2[CH2:13][CH2:12]1)C1C=CC=CC=1.[H][H]>CCO.C1COCC1.[Pd]>[F:36][C:32]1[N:31]=[C:30]([CH2:29][N:15]2[C:14]3[CH2:13][CH2:12][CH:11]([NH2:10])[CH2:23][C:22]=3[C:21]3[C:16]2=[CH:17][CH:18]=[C:19]([O:24][C:25]([F:28])([F:26])[F:27])[CH:20]=3)[CH:35]=[CH:34][CH:33]=1
Reactant: [H][H]
Reactant: O=C(NC1CCc2c(c3cc(OC(F)(F)F)ccc3n2Cc2cccc(F)n2)C1)OCc1ccccc1
Agent: [Pd]
Solvent: CCO
Solvent: C1CCOC1
Product: NC1CCc2c(c3cc(OC(F)(F)F)ccc3n2Cc2cccc(F)n2)C1
Yield: 117.5 %

Procedure:
Dissolve [9-(6-fluoro-pyridin-2-ylmethyl)-6-trifluoromethoxy-2,3,4,9-tetrahydro-1H-carbazol-3-yl]-carbamic acid benzyl ester (Preparation 45) (2.73 g, 5.32. mmol) in EtOH (100 mL) and THF (50 mL). Add 10% Pd/C (200 mg) and stir at room temperature under a balloon of hydrogen for 18 h. Filter the reaction through a pad of Celite®, rinse the pad with THF (50 mL), and concentrate the filtrate in vacuo to afford 2.37 g (90%) of the title compound as a dark brown oil. MS (ES): m/z 380 (M+1); HPLC (Method A): Rt=1.76 min (89%).
Reaction SMILES: [C:1]1([CH:7]([O:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[O:19][CH3:20])[CH:8]([OH:11])[CH2:9][NH2:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[Na+].[Cl:23][CH2:24][C:25](Cl)=[O:26]>C(Cl)Cl.O>[Cl:23][CH2:24][C:25]([NH:10][CH2:9][CH:8]([OH:11])[CH:7]([C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)[O:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[O:19][CH3:20])=[O:26]
Reactant: O=C(Cl)CCl
Reactant: COc1ccccc1OC(c1ccccc1)C(O)CN
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O
Product: COc1ccccc1OC(c1ccccc1)C(O)CNC(=O)CCl
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 99.9 %

Procedure:
A mixture of 2.73 g of 3-phenyl-2-hydroxy-3-(2-methoxy-phenoxy)-propylamine in 50 ml of methylene chloride and 0.56 g of NaOH in 15 ml of water was stirred at 0° C. Under vigorous stirring dropwise addition was made to the mixture over 30 minutes, again at 0° C., of 1.58 g of chloroacetyl chloride in 2 ml of methylene chloride. After the addition, the stirring was continued at 0° C. for 30 minutes. The layers were separated and the aqueous phase extracted with CH2Cl2. The organic extracts were combined and washed with water, dried over Na2SO4 and evaporated to dryness. There was obtained 3.49 g of N-chloroacetyl-2-hydroxy-3-phenyl-3-(2-methoxy-phenoxy)propylamine (oil). Yield 100%.