Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([SiH](CC)CC)C.[Br:8][C:9]1[N:14]=[C:13]([C:15]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)(O)[CH3:16])[CH:12]=[CH:11][CH:10]=1.FC(F)(F)C(O)=O>ClCCl>[Br:8][C:9]1[CH:10]=[CH:11][CH:12]=[C:13]([C:15]([C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)=[CH2:16])[N:14]=1
Reactant: CC(O)(c1ccccc1)c1cccc(Br)n1
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: C=C(c1ccccc1)c1cccc(Br)n1
Temperature: 5 °C
Reaction time: 96 h
Yield: 70 %

Procedure:
At 0° C. triethylsilane (1.09 g, 9.4 mmol, 1.3 equiv) was added to compound 7 (2.0 g, 7.2 mmol, 1.0 equiv) in dichloromethane (50 mL). Trifluoroacetic acid (4.1 g, 36.1 mmol, 5.0 equiv) was added dropwise while maintaining the temperature<5° C. The reaction was allowed to warm to room temperature at which point the solution became a yellowish-green color. The reaction was stirred for 96 hr, LC/MS and TLC indicated the reaction was incomplete. The reaction was then refluxed for an additional 18 hr, at this point LC/MS and TLC indicated the reaction was complete. The reaction was carefully quenched with saturated sodium bicarbonate (100 mL). The layers were separated, the organic layer was dried over sodium sulfate and absorbed onto silica gel (5 g) by concentration under reduced pressure. This material was purified on a silica gel column (30 g) by eluting with heptanes (150 mL), ethyl acetate (2%) in heptanes (200 mL) and ethyl acetate (5%) in heptanes (200 mL). The desired product was isolated pure in nearly 70% yield (1.3 g).
Reaction SMILES: [CH3:1][N:2]([CH3:19])[CH:3]=[N:4][S:5]([C:8]1[C:13]([O:14]C)=[CH:12][CH:11]=[CH:10][C:9]=1[N+:16]([O-:18])=[O:17])(=[O:7])=[O:6]>ClCCl>[CH3:1][N:2]([CH3:19])[CH:3]=[N:4][S:5]([C:8]1[C:13]([OH:14])=[CH:12][CH:11]=[CH:10][C:9]=1[N+:16]([O-:18])=[O:17])(=[O:6])=[O:7]
Reactant: COc1cccc([N+](=O)[O-])c1S(=O)(=O)N=CN(C)C
Solvent: ClCCl
Product: CN(C)C=NS(=O)(=O)c1c(O)cccc1[N+](=O)[O-]
Temperature: 25 °C

Procedure:
To a solution of N-[1-dimethylamino-methylidene]-2-nitro-6-methoxy-benzenesulfonamide (956 mg, 3.33 mmol) in dichloromethane (50 mL) BBr3 (0.64 mL, 6.64 mmol is added under stirring at room temperature. After stirring for 30 min the 4 mixture is diluted with CH2Cl2 and extracted twice with saturated brine. Drying of the organic phase with Na2SO4, evaporation of solvent, addition of hexanes to the residue, and filtration gives N-(1-dimethylamino-methylidene)-2-nitro-6-hydroxy-benzenesulfonamide.
Reaction SMILES: [F:1][C:2]([F:39])([C:27]1[CH:32]=[CH:31][C:30]([C:33]#[C:34][CH2:35][CH2:36][CH2:37][OH:38])=[CH:29][CH:28]=1)[O:3][C:4]1[CH:25]=[CH:24][C:7]([O:8][C:9]([F:23])([F:22])[C:10]2[CH:15]=[CH:14][C:13]([C:16]#[C:17][CH2:18][CH2:19][CH2:20][OH:21])=[CH:12][CH:11]=2)=[CH:6][C:5]=1[CH3:26]>C1COCC1>[F:22][C:9]([F:23])([C:10]1[CH:15]=[CH:14][C:13]([CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][OH:21])=[CH:12][CH:11]=1)[O:8][C:7]1[CH:24]=[CH:25][C:4]([O:3][C:2]([F:1])([F:39])[C:27]2[CH:28]=[CH:29][C:30]([CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][OH:38])=[CH:31][CH:32]=2)=[C:5]([CH3:26])[CH:6]=1
Reactant: Cc1cc(OC(F)(F)c2ccc(C#CCCCO)cc2)ccc1OC(F)(F)c1ccc(C#CCCCO)cc1
Solvent: C1CCOC1
Product: Cc1cc(OC(F)(F)c2ccc(CCCCCO)cc2)ccc1OC(F)(F)c1ccc(CCCCCO)cc1

Procedure:
5-{4-[(4-{Difluoro-[4-(5-hydroxypent-1-ynyl)phenyl]methoxy}-3-methylphenoxy)difluoromethyl]phenyl}pent-4-yn-1-ol is hydrogenated to completion on palladium/active carbon catalyst in THF. The catalyst is filtered off, and the filtrate is evaporated in vacuo, giving 5-{4-[(4-{difluoro-[4-(5-hydroxypentyl)phenyl]methoxy}-2-methylphenoxy)difluoromethyl]phenyl}-pentan-1-ol, which is sufficiently pure for further reactions.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][N:11]([C:14]3[N:19]=[C:18]([CH3:20])[NH:17][C:16](=[O:21])[C:15]=3[N+:22]([O-:24])=[O:23])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.Cl[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][OH:32].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:9][CH2:10][N:11]([C:14]3[N:19]=[C:18]([CH3:20])[N:17]=[C:16]([O:21][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][OH:32])[C:15]=3[N+:22]([O-:24])=[O:23])[CH2:12][CH2:13]2)=[CH:4][CH:3]=1
Reactant: Cc1nc(N2CCN(c3ccc(F)cc3)CC2)c([N+](=O)[O-])c(=O)[nH]1
Reactant: OCCCCCCCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1nc(OCCCCCCO)c([N+](=O)[O-])c(N2CCN(c3ccc(F)cc3)CC2)n1

Procedure:
In analogy to the procedure described in example 8, the 6-[4-(4-fluoro-phenyl)-piperazin-1-yl]-2-methyl-5-nitro-3H-pyrimidin-4-one (example 1) was treated with 6-chloro-1-hexanol and potassium carbonate in N,N-dimethylformamide at 120° C. to yield the 6-{6-[4-(4-fluoro-phenyl)-piperazin-1-yl]-2-methyl-5-nitro-pyrimidin-4-yloxy}-hexan-1-ol as a yellow amorphous solid; MS: [M+H]+=434.
Reaction SMILES: Cl[C:2]1[C:3]([C:11]([CH:14]2[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]2)=[N:12][OH:13])=[C:4]2[CH:10]=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.CC(C)([O-])C.[K+]>CS(C)=O>[CH:14]1([C:11]2[C:3]3=[C:4]4[CH:10]=[CH:9][NH:8][C:5]4=[N:6][CH:7]=[C:2]3[O:13][N:12]=2)[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1
Reactant: ON=C(c1c(Cl)cnc2[nH]ccc12)C1CCCCC1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: c1cc2c(ncc3onc(C4CCCCC4)c32)[nH]1
Temperature: 125 °C
Yield: 45 %

Procedure:
A mixture of (5-chloro-1H-pyrrolo[2,3-b]pyridin-4-yl)(cyclohexyl)methanone oxime (0.19 g, 0.70 mmol) and potassium tert-butoxide (0.16 g, 1.4 mmol) in DMSO (6 mL) was heated in a Biotage microwave at about 125° C. for about 30 min. The solvent was removed under reduced pressure and the crude product was purified by silica gel chromatography (0-30% EtOAc in heptane gradient as the eluent to afford 1-cyclohexyl-6H-isoxazolo[4,5-d]pyrrolo[2,3-b]pyridine as a white solid (0.076 g, 46%): LC/MS (Table 2, Method d) Rt=2.50 min; m/z: 242 (M+H)+.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([C:10]2[N:11]=[C:12]([NH:15][C:16](=[O:26])[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][C:23]([OH:25])=[O:24])[S:13][CH:14]=2)[CH:7]=[CH:8][CH:9]=1)([O-])=O.COC(=O)CCCCCCC(NC1SC=C(C2C=CC=C(N)C=2)N=1)=O>>[NH2:1][C:4]1[CH:5]=[C:6]([C:10]2[N:11]=[C:12]([NH:15][C:16](=[O:26])[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][C:23]([OH:25])=[O:24])[S:13][CH:14]=2)[CH:7]=[CH:8][CH:9]=1
Reactant: O=C(O)CCCCCCC(=O)Nc1nc(-c2cccc([N+](=O)[O-])c2)cs1
Agent: COC(=O)CCCCCCC(=O)Nc1nc(-c2cccc(N)c2)cs1
Product: Nc1cccc(-c2csc(NC(=O)CCCCCCC(=O)O)n2)c1

Procedure:
Compound 21 was prepared using the methodology described for the preparation of compound 18, by substituting compound 14 with compound 20. Yield (0.276 g, 79.8%). 1H NMR (300 MHz, CDCl3) δ 7.21 (1H, t, J=7.7 Hz), 7.07 (1H, d, J=8.2 Hz), 6.99 (2H, s), 6.69 (1H, d, J=7.8 Hz), 2.49 (2H, t, J=7.3 Hz), 2.40 (2H, t, J=7.1 Hz), 1.78 (2H, brs), 1.69 (2H, t, J=6.7 Hz), 1.50-1.35 (4H, m). 13C NMR (75 MHz, CDCl3) δ 179.6, 172.2, 160.8, 149.7, 147.1, 135.0, 130.2, 117.3, 115.6, 113.5, 108.1, 36.7, 34.4, 29.1, 28.9, 25.5, 24.9.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([CH2:8][CH3:9])[N:5]=[C:4]([NH2:10])[N:3]=1.C1C(=O)N([I:18])C(=O)C1.[O-]S([O-])(=S)=O.[Na+].[Na+].C([O-])(O)=O.[Na+]>C(O)(=O)C>[Cl:1][C:2]1[C:7]([I:18])=[C:6]([CH2:8][CH3:9])[N:5]=[C:4]([NH2:10])[N:3]=1
Reactant: O=C1CCC(=O)N1I
Reactant: CCc1cc(Cl)nc(N)n1
Agent: O=C([O-])O
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: CC(=O)O
Product: CCc1nc(N)nc(Cl)c1I
Temperature: 25 °C

Procedure:
25.0 g (159 mmol) 4-Chloro-6-ethyl-pyrimidin-2-ylamine in 1.0 L acetic acid is cooled to 0° C. and 36.0 g (159 mmol) NIS is added in one portion. The reaction mixture is stirred at RT until conversion of the starting material is completed (18 h). An aqueous solution of 5% Na2S2O3 and 10% NaHCO3 is added until the mixture decolorizes. The formed precipitate is filtered off, taken up with water and the suspension stirred at RT for 60 minutes. The product is filtered off, washed with diethyl ether and dried in vacuo at 40° C. Yield: 40.3 g (90%). 1H NMR (DMSO-d6) δ: 7.2 (s, 2H), 2.7 (quart., 2H), 1.1 (tripl., 3H). HPLC-MS: tR=1.62 min , (M+H)+=284.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:20])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][NH:11][C:12]1[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=1.C(N(CC)CC)C.[F:28][C:29]1[CH:37]=[CH:36][C:32]([C:33](Cl)=[O:34])=[CH:31][CH:30]=1>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3](=[O:20])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][N:11]([C:12]1[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=1)[C:33](=[O:34])[C:32]1[CH:36]=[CH:37][C:29]([F:28])=[CH:30][CH:31]=1
Reactant: O=C(Cl)c1ccc(F)cc1
Reactant: COC(=O)CCCCCCCNc1ccc(OC)cc1
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: COC(=O)CCCCCCCN(C(=O)c1ccc(F)cc1)c1ccc(OC)cc1

Procedure:
As described in example 3(b), the reaction is carried out with 5.6 g (20 mmol) of 8-(4-methoxyphenylamino)-caprylic acid methyl ester, 5 g (50 mmol) of triethylamine, 150 cc. of toluene and 4 g (25 mmol) of 4-fluorobenzoic acid chloride. Reaction time: 5 hours, reaction temperature: 25° C. The crude product is used in the next reaction step without further purification.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[N:6][CH:7]=[CH:8][C:9]=1[CH2:10][CH2:11][OH:12])([O-])=O>CO.[H][H].[Pd]>[NH2:1][C:4]1[CH:5]=[N:6][CH:7]=[CH:8][C:9]=1[CH2:10][CH2:11][OH:12]
Reactant: O=[N+]([O-])c1cnccc1CCO
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: Nc1cnccc1CCO
Yield: 79.1 %

Procedure:
2-(3-Nitropyridin-4-yl)ethanol (15) (WO 2006136562) (2.00 g, 11.89 mmol) in MeOH (150 mL) was passed through a Thales H-cube at 2.0 mL·min−1 using Pd/C Cat-Cart (55 mm) in controlled mode at 30° C., 30 bar. Analysis by LC-MS showed a significant amount of starting material was still present. The solution was passed through the H-cube a second time at 2.0 mL·min−1 in full hydrogen mode at RT, and again at 2.0 mL·min−1 in full hydrogen mode at 40° C. Evaporation of the volatiles gave 2-(3-Aminopyridin-4-yl)ethanol (16) as a purple oil (1.30 g, 81%): m/z 139 (M+H)+ (ES+).
Reaction SMILES: [N:1]([CH:4]([C:7]1[N:8]=[C:9]2[CH:23]=[CH:22][CH:21]=[C:20]([CH3:24])[N:10]2[C:11](=[O:19])[C:12]=1[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[CH2:5][CH3:6])=[N+]=[N-].CP(C)C.C(Cl)Cl>O1CCCC1.O>[NH2:1][CH:4]([C:7]1[N:8]=[C:9]2[CH:23]=[CH:22][CH:21]=[C:20]([CH3:24])[N:10]2[C:11](=[O:19])[C:12]=1[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1)[CH2:5][CH3:6]
Reactant: CCC(N=[N+]=[N-])c1nc2cccc(C)n2c(=O)c1-c1ccccc1
Agent: CP(C)C
Solvent: ClCCl
Solvent: C1CCOC1
Solvent: O
Product: CCC(N)c1nc2cccc(C)n2c(=O)c1-c1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a stirred solution of 2-(1-azidopropyl)-6-methyl-3-phenyl-4H-pyrido[1,2-a]pyrimidin-4-one (0.030 g, 0.094 mmol) in tetrahydrofuran (0.24 mL) and water (0.06 mL) was added 1.0 M of trimethylphosphine in tetrahydrofuran (0.11 mL) at room temperature and the mixture was stirred at room temperature for 1 hour. To the mixture was added methylene chloride and the mixture was washed with brine, dried over magnesium sulfate, and evaporated to dryness under reduced pressure. The crude residue was used directly in next step. LCMS calculated for C18H20N3O (M+H)+: m/z=294.2. Found: 294.3.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:6]([CH:25]([CH3:27])[CH3:26])=[N:7][C:8]2[C:13]([C:14]=1OS(C(F)(F)F)(=O)=O)=[CH:12][C:11]([Cl:23])=[CH:10][C:9]=2[Cl:24])=[O:4].[CH:28]([C:31]1[CH:32]=[C:33](B(O)O)[CH:34]=[CH:35][CH:36]=1)([CH3:30])[CH3:29]>>[CH3:1][O:2][C:3]([C:5]1[C:6]([CH:25]([CH3:27])[CH3:26])=[N:7][C:8]2[C:13]([C:14]=1[C:35]1[CH:34]=[CH:33][CH:32]=[C:31]([CH:28]([CH3:30])[CH3:29])[CH:36]=1)=[CH:12][C:11]([Cl:23])=[CH:10][C:9]=2[Cl:24])=[O:4]
Reactant: CC(C)c1cccc(B(O)O)c1
Reactant: COC(=O)c1c(C(C)C)nc2c(Cl)cc(Cl)cc2c1OS(=O)(=O)C(F)(F)F
Product: COC(=O)c1c(C(C)C)nc2c(Cl)cc(Cl)cc2c1-c1cccc(C(C)C)c1

Procedure:
The title compound was prepared in analogy to example 72 step C from 6,8-dichloro-2-isopropyl-4-trifluoromethanesulfonyloxy-quinoline-3-carboxylic acid methyl ester (prepared as described in example 72 step B) and 3-isopropylphenylboronic acid. Colorless semisolid. MS (ESI): 416.1 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[C:3]2[N:4]([C:39]([CH3:42])=[N:40][N:41]=2)[C:5]2[CH:10]=[C:9]([CH3:11])[N:8]([CH2:12][C:13]3[CH:18]=[C:17]([Cl:19])[CH:16]=[C:15]([CH2:20][O:21][Si](C(C)(C)C)(C4C=CC=CC=4)C4C=CC=CC=4)[CH:14]=3)[C:6]=2[CH:7]=1.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C1COCC1.O>[Br:1][C:2]1[C:3]2[N:4]([C:39]([CH3:42])=[N:40][N:41]=2)[C:5]2[CH:10]=[C:9]([CH3:11])[N:8]([CH2:12][C:13]3[CH:14]=[C:15]([CH2:20][OH:21])[CH:16]=[C:17]([Cl:19])[CH:18]=3)[C:6]=2[CH:7]=1
Reactant: Cc1cc2c(cc(Br)c3nnc(C)n32)n1Cc1cc(Cl)cc(CO[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: O
Solvent: C1CCOC1
Product: Cc1cc2c(cc(Br)c3nnc(C)n32)n1Cc1cc(Cl)cc(CO)c1

Procedure:
4-Bromo-6-[3-({[tert-butyl(diphenyl)silyl]oxy}methyl)-5-chlorobenzyl]-1,7-dimethyl-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyridine (2.1 g, 3.2 mmol, from Step 3) in THF (30 mL) was treated with 1.0 M TBAF in THF (6.4 mL, 6.4 mmol, Aldrich) for 1 hour. The reaction mixture was diluted with water and extracted with three portions of EtOAc. The combined organic extracts were washed with brine, dried over sodium sulfate, filtered and concentrated. The product was purified by flash chromatography, eluting with a gradient from 0-10% MeOH. Yield: (0.722 g, 54% over the two steps).
Reaction SMILES: [CH3:1][N:2]([CH3:6])[C:3](Cl)=[S:4].[C:7]([C:9]1[CH:25]=[CH:24][C:12]2[CH2:13][CH2:14][N:15]([C:18](=[O:23])[C:19]([F:22])([F:21])[F:20])[CH2:16][CH2:17][C:11]=2[C:10]=1[OH:26])#[N:8].C(N(CC)CC)C>CN(C1C=CN=CC=1)C.O1CCOCC1.CCOC(C)=O>[C:7]([C:9]1[CH:25]=[CH:24][C:12]2[CH2:13][CH2:14][N:15]([C:18](=[O:23])[C:19]([F:22])([F:20])[F:21])[CH2:16][CH2:17][C:11]=2[C:10]=1[O:26][C:3](=[S:4])[N:2]([CH3:6])[CH3:1])#[N:8]
Reactant: CN(C)C(=S)Cl
Reactant: N#Cc1ccc2c(c1O)CCN(C(=O)C(F)(F)F)CC2
Agent: CN(C)c1ccncc1
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: CN(C)C(=S)Oc1c(C#N)ccc2c1CCN(C(=O)C(F)(F)F)CC2
Temperature: 120 °C
Reaction time: 48 h
Yield: 80.3 %

Procedure:
Add dimethylthiocarbamoyl chloride (197 mg, 1.58 mmol) to a stirred solution of 7-cyano-6-hydroxy-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine (150 mg, 0.53 mmol), DMAP (6 mg, 0.05 mmol) and dry triethylamine (300 μL) in dry 1,4-dioxane (5 mL) under an atmosphere of nitrogen and heat at 120° C. for 6 h. Cool and continue stirring for 2 days at ambient temperature. Dilute with EtOAc, wash with 1N aqueous HCl, water, saturated aqueous Na2CO3 and brine. Dry over MgSO4 then concentrate in vacuo. Purify by chromatography on silica gel eluting with EtOAc:heptane (0:1 to 3:10) to give the desired intermediate as a white solid (158 mg, 81%).
Reaction SMILES: Br[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([O:12][CH3:13])=[N:4][CH:3]=1.[C:14]([C:16]1[CH:17]=[C:18](B(O)O)[CH:19]=[CH:20][CH:21]=1)#[N:15].C(=O)([O-])[O-].[Na+].[Na+]>C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Pd].C1(C)C=CC=CC=1>[C:14]([C:16]1[CH:21]=[C:20]([C:2]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]([O:12][CH3:13])=[N:4][CH:3]=2)[CH:19]=[CH:18][CH:17]=1)#[N:15]
Reactant: COc1ncc(Br)c2ccccc12
Reactant: N#Cc1cccc(B(O)O)c1
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: COc1ncc(-c2cccc(C#N)c2)c2ccccc12
Yield: 16.3 %

Procedure:
A stirred mixture of 4-bromo-1-methoxyisoquinoline (1.19 g, 4.72 mmol), 3-cyanophenylboronic acid (1.04 g, 7.08 mmol), palladium tetrakis(triphenylphosphine) (0.33 g. 0.28 mmol), 2 m aq sodium carbonate (4.72 mmol) and toluene (30 mL) is heated 42 hr at reflux under a nitrogen atmosphere. After cooling, the solvent is removed and the residue is purified by chromatography eluting with cyclohexane-2.5 to 6% ethyl acetate. Product containing fractions are combined and concentrated to afford 4-(3-cyanophenyl)-1-methoxyisoquinoline (200 mg, 15.5% yield). LC/MS: MS m/e=275 (M+H); RT 4.38; 1H NMR (δ ppm): 8.22 (1H, d), 7.98 (1H, d), 7.83 (1H, s); 7.78 (1H, t), 7.65 (2H, m), 7.58 (1H, t), 7.18 (1H, d); 4.11 (3H, s), 2.23 (3H, s).
Reaction SMILES: [Cl:1][C:2]1[C:10]([Cl:11])=[CH:9][C:8]([Cl:12])=[C:4]([C:5](O)=[O:6])[C:3]=1[C:13]([OH:15])=O.[CH3:16][NH2:17]>C(O)(=O)C>[Cl:1][C:2]1[C:10]([Cl:11])=[CH:9][C:8]([Cl:12])=[C:4]2[C:5]([N:17]([CH3:16])[C:13](=[O:15])[C:3]=12)=[O:6]
Reactant: CN
Reactant: O=C(O)c1c(Cl)cc(Cl)c(Cl)c1C(=O)O
Solvent: CC(=O)O
Product: CN1C(=O)c2c(Cl)cc(Cl)c(Cl)c2C1=O
Temperature: 93 °C
Reaction time: 5 h
Yield: 65.1 %

Procedure:
A mixture of 3,4,6-trichlorophthalic acid (25.01 g, 92.8 mmol) and glacial acetic acid (100 mL) was charged to a 250 mL 3-neck flask, equipped with a dry-ice condenser, thermometer, gas sparger and magnetic stirrer and maintained under an atmosphere of dry nitrogen. The mixture was heated and maintained at 50°-54° C. while methylamine (12 g, 0.4 mol) was introduced over a period of 1.5 hours. Following the addition of the methylamine, the reaction mixture was heated to 93° C. and maintained thereat for about 5 hours, then cooled to room temperature and filtered. The filter cake was washed with cold water and vacuum dried (0.2 mmHg) for 24 hours to yield 15.97 g of 3,4,6-trichloro-N-methylphthalimide as a white powder (m.p. 166°-167.5° C.).
Reaction SMILES: CN(C)C1C=CC=CC=1.[CH:10]1([CH2:15][OH:16])[CH2:14][CH2:13][CH2:12][CH2:11]1.[C:17](Cl)([Cl:19])=[O:18].C1(C)C=CC=CC=1>>[Cl:19][C:17]([O:16][CH2:15][CH:10]1[CH2:14][CH2:13][CH2:12][CH2:11]1)=[O:18]
Reactant: OCC1CCCC1
Reactant: O=C(Cl)Cl
Solvent: CN(C)c1ccccc1
Solvent: Cc1ccccc1
Product: O=C(Cl)OCC1CCCC1
Reaction time: 0.5 h
Yield: 81 %

Procedure:
A mixture of 24.2 g (0.20 mole) N,N-dimethylaniline and 20.3 g (0.20 mole) of cyclopentylmethanol was slowly added to a 20% solution of phosgene in toluene (104 ml, 0.20 mole) cooled to -5° to +5° C. After the addition the reaction mixture was allowed to attain room temperature and was kept at room temperature for 30 min. The precipitate was filtered off and the solvent was evaporated. Distillation in vacuo gave 26.3 g (81%) of cyclopentylmethyl chloroformate. Bp17-20 82°-84° C., nD21 1.4541. Analysis for C7H11ClO2. Found (calculated): Cl 21.37 (21.80). IR (neat) cm-1 : 1790 (CO).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:13]([S:14]([N:17]([C:27]([O:29][CH2:30][CH:31]([CH3:33])[CH3:32])=[O:28])[C:18]3[C:23]([O:24][CH3:25])=[N:22][C:21]([CH3:26])=[CH:20][N:19]=3)(=[O:16])=[O:15])=[CH:12][CH:11]=[CH:10][N:9]=2)=[CH:4][CH:3]=1.Br[CH:35]([CH3:40])[C:36]([O:38][CH3:39])=[O:37].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH2:30]([O:29][C:27]([N:17]([C:18]1[C:23]([O:24][CH3:25])=[N:22][C:21]([CH3:26])=[CH:20][N:19]=1)[S:14]([C:13]1[C:8]([C:5]2[CH:6]=[CH:7][C:2]([O:1][CH:35]([C:36]([O:38][CH3:39])=[O:37])[CH3:40])=[CH:3][CH:4]=2)=[N:9][CH:10]=[CH:11][CH:12]=1)(=[O:16])=[O:15])=[O:28])[CH:31]([CH3:33])[CH3:32]
Reactant: COc1nc(C)cnc1N(C(=O)OCC(C)C)S(=O)(=O)c1cccnc1-c1ccc(O)cc1
Reactant: COC(=O)C(C)Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COC(=O)C(C)Oc1ccc(-c2ncccc2S(=O)(=O)N(C(=O)OCC(C)C)c2ncc(C)nc2OC)cc1
Yield: 57.3 %

Procedure:
A mixture of 2-(4-hydroxyphenyl)-N-(isobutoxycarbonyl)-N-(3-methoxy-5-methylpyrazin-2-yl)pyridine-3-sulphonamide (0.472 g), methyl 2-bromopropionate (217 mg) and potassium carbonate (166 mg) in acetone (20 ml) was heated under reflux for 15 hours. Volatile material was removed by evaporation and water (25 ml) was added to the residue. The mixture was extracted with ethyl acetate (25 ml) and the extracts were washed with 2M sodium hydroxide solution (10 ml) and water (20 ml). The solution was dried (MgSO4) and the solvent was removed by evaporation. The residue was purified by flash chromatography, eluting with ethyl acetate/hexane (1:1 v/v), to give N-(isobutoxycarbonyl)-2-(4-[1-(methoxycarbonyl)ethoxy]phenyl)-N-(3-methoxy-5-methylpyrazin-2-yl)pyridine-3-sulphonamide (0.32 g); 1H NMR (DMSO-d6): 0.6 (d, 6H), 1.5-1.7 (m, 4H), 2.5 (s, 3H), 3.7 (s, 3H), 3.8 (d, 2H), 4.0 (s, 3H), 5.1 (q, 1H), 6.95 (d, 2H), 7.5 (d, 2H), 7.7-7.8 (m, 1H), 8.2 (s, 1H), 8.85 (d, 1H), 8.9 (d, 1H).
Reaction SMILES: C([O:3][C:4](=O)[CH2:5][N:6]1[CH:15]=[C:14]2[C:8]([CH2:9][N:10]=[C:11]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[C:12]3[CH:19]=[C:18]([Cl:20])[CH:17]=[CH:16][C:13]=32)=[N:7]1)C.[NH3:28]>>[Cl:20][C:18]1[CH:17]=[CH:16][C:13]2[C:14]3[C:8](=[N:7][N:6]([CH2:5][C:4]([NH2:28])=[O:3])[CH:15]=3)[CH2:9][N:10]=[C:11]([C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=3)[C:12]=2[CH:19]=1
Reactant: N
Reactant: CCOC(=O)Cn1cc2c(n1)CN=C(c1ccccc1)c1cc(Cl)ccc1-2
Product: NC(=O)Cn1cc2c(n1)CN=C(c1ccccc1)c1cc(Cl)ccc1-2

Procedure:
Heating a mixture of 0.8 g (2.1 mmol) of 8-chloro-6-phenyl-2H,4H-pyrazolo[3,4-d][2]benzazepine-2-acetic acid ethyl ester and 20 ml of methanolic ammonia (ca. 20%, v/v) in an autoclave on the steam bath for 20 hr gave after crystallization from ethyl acetate/ether colorless crystals with mp 236°-238°. The analytical sample was recrystallized from ethyl acetate/methylene chloride/ether.
Reaction SMILES: [F:1][C:2]([F:26])([F:25])[CH:3]([CH2:8][N:9]1[CH2:14][CH2:13][CH2:12][CH:11]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([C:21]([F:24])([F:23])[F:22])[CH:16]=2)[CH2:10]1)[CH2:4][C:5](O)=O.[Cl:27][C:28]1[CH:37]=[CH:36][C:31]([C:32]([NH:34][NH2:35])=[O:33])=[CH:30][CH:29]=1.O=P(Cl)(Cl)Cl.C([O-])([O-])=O.[Na+].[Na+].Cl>CCOCC.CCCCCC.O1CCOCC1>[ClH:27].[Cl:27][C:28]1[CH:37]=[CH:36][C:31]([C:32]2[O:33][C:5]([CH2:4][CH:3]([C:2]([F:26])([F:1])[F:25])[CH2:8][N:9]3[CH2:14][CH2:13][CH2:12][CH:11]([C:15]4[CH:20]=[CH:19][CH:18]=[C:17]([C:21]([F:22])([F:23])[F:24])[CH:16]=4)[CH2:10]3)=[N:35][N:34]=2)=[CH:30][CH:29]=1
Reactant: O=C(O)CC(CN1CCCC(c2cccc(C(F)(F)F)c2)C1)C(F)(F)F
Reactant: NNC(=O)c1ccc(Cl)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCCCCC
Solvent: C1COCCO1
Solvent: CCOCC
Product: FC(F)(F)c1cccc(C2CCCN(CC(Cc3nnc(-c4ccc(Cl)cc4)o3)C(F)(F)F)C2)c1
Temperature: 110 °C
Yield: 111 %

Procedure:
To a round-bottomed flask (5 ml) was added 4,4,4-trifluoro-3-((3-(3-(trifluoromethyl)phenyl)-piperidin-1-yl)methyl)butanoic acid (50 mg, 130 μmol), 4-chlorobenzohydrazide (22.3 mg, 130 μmol,) and POCl3 (1.64 g, 1 mL, 10.7 mmol). The reaction mixture was heated to reflux at 110° C. for 4 hr. The crude reaction mixture was allowed to cool to room temperature, poured into ice/water and made basic with a saturated solution of Na2CO3. The reaction mixture was extracted with ethyl acetate, washed with brine and H2O, dried over MgSO4, filtered and concentrated. The resultant residue was purified on a silica column (100% CH2Cl2 to 40% ethyl acetate/CH2Cl2 eluent) to give an oil. The oil was dissolved in ether/hexane, treated with 4N HCl in dioxane (0.2 ml) and concentrated to afford 40 mg (56%) of 1-{2-[5-(4-chloro-phenyl)-[1,3,4]oxadiazol-2-ylmethyl]-3,3,3-trifluoro-propyl}-3-(3-trifluoromethyl-phenyl)-piperidine hydrochloride as a white solid. MH+=518.
Reaction SMILES: [C:1]([OH:6])(=[O:5])[C:2]([OH:4])=[O:3].C(O)(=O)C(O)=O.[NH2:13][CH:14]1[CH2:19][CH2:18][N:17]([CH2:20][CH2:21][NH:22][C:23]([C:25]2[C:33]3[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=3)[N:27]([CH:34]([CH3:36])[CH3:35])[N:26]=2)=[O:24])[CH2:16][CH2:15]1.[F:37][C:38]1[CH:43]=[CH:42][C:41]([N:44]=[C:45]=[O:46])=[CH:40][CH:39]=1>O1CCCC1>[C:1]([OH:6])(=[O:5])[C:2]([OH:4])=[O:3].[F:37][C:38]1[CH:43]=[CH:42][C:41]([NH:44][C:45]([NH:13][CH:14]2[CH2:15][CH2:16][N:17]([CH2:20][CH2:21][NH:22][C:23]([C:25]3[C:33]4[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=4)[N:27]([CH:34]([CH3:36])[CH3:35])[N:26]=3)=[O:24])[CH2:18][CH2:19]2)=[O:46])=[CH:40][CH:39]=1
Reactant: O=C=Nc1ccc(F)cc1
Reactant: CC(C)n1nc(C(=O)NCCN2CCC(N)CC2)c2ccccc21
Agent: O=C(O)C(=O)O
Solvent: C1CCOC1
Product: CC(C)n1nc(C(=O)NCCN2CCC(NC(=O)Nc3ccc(F)cc3)CC2)c2ccccc21
Temperature: 10 °C
Reaction time: 1.5 h

Procedure:
The product from Example 23, as the free base (0.330 g, 1 mmol) was stirred in 8 mL tetrahydrofuran and cooled in an ice bath to 10° C. To the mixture was added dropwise 4-fluorophenyl isocyanate (0.11 mL, 1 mmol) and the resulting mixture was stirred 1.5 h at room temperature and filtered, and the filtrate was evaporated to an oil. Crystallization as the oxalate salt from ethyl acetate/methanol provided 0.147 g colorless crystals. Mp 158° C. Mass spectrum, m+ =466. Anal (C27H33 FN6O6) theory C, 58.27; H, 5.98; N, 15.10; found C, 58.48; H, 6.23; N, 14.94.