Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.CN(C)CCCN=C=NCC.CN(C=O)C.[CH3:18][N:19]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[C:21]([CH3:28])=[C:20]1[C:29]([OH:31])=O.[NH2:32][C@H:33]([C:37]([NH:39][CH:40]([CH:49]([OH:52])[CH2:50][F:51])[CH2:41][C:42]([O:44][C:45]([CH3:48])([CH3:47])[CH3:46])=[O:43])=[O:38])[CH:34]([CH3:36])[CH3:35]>CN(C)C1C=CN=CC=1.C(Cl)Cl>[CH3:18][N:19]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[C:21]([CH3:28])=[C:20]1[C:29]([NH:32][C@H:33]([C:37]([NH:39][CH:40]([CH:49]([OH:52])[CH2:50][F:51])[CH2:41][C:42]([O:44][C:45]([CH3:46])([CH3:47])[CH3:48])=[O:43])=[O:38])[CH:34]([CH3:35])[CH3:36])=[O:31]
Reactant: CC(C)[C@H](N)C(=O)NC(CC(=O)OC(C)(C)C)C(O)CF
Reactant: Cc1c(C(=O)O)n(C)c2ccccc12
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: Cc1c(C(=O)N[C@H](C(=O)NC(CC(=O)OC(C)(C)C)C(O)CF)C(C)C)n(C)c2ccccc12
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 56.1 %

Procedure:
4-Dimethylaminopyridine (DMAP) (67 mg, 0.55 mmol) and 1-(3′-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDAC) (125 mg, 0.65 mmol) were added as solids to a DMF solution of 1,3-dimethylindole-2-carboxylic acid (95 mg, 0.5 mmol in 1 mL of DMF), and the resultant reaction mixture was stirred for 10 minutes under a nitrogen atmosphere at 0° C. A methylene chloride solution of N-(valinyl)-3-amino-4-hydroxy-5-fluoropentanoic acid, t-butyl ester (153 mg, 0.5 mmol in 1 mL of methylene chloride) was added and the resultant reaction mixture was first stirred for 1 hour at 0° C. and then for 4 hours at room temperature. The reaction mixture was partitioned between ethyl acetate and 5% KHSO4 solution and the aqueous solution was back-extracted with ethyl acetate. The combined ethyl acetate solutions were washed with 5% KHSO4 solution, saturated sodium bicarbonate solution (2×), and brine, dried over sodium sulfate, and concentrated to give a solid. The solid was triturated with ether/hexane to yield the title product as a white solid (134 mg, 56%). TLC: (ethyl acetate/hexanes, 2:1): Rf=0.42. 1H NMR (CDCl3): δ 7.59 (d, J=8.8, 1H), 7.37 (d, J=7.7, 1H), 7.29-7.24 (m, 1 H), 7.12-7.07 (m, 1H), 4.49-4.26 (m, 5H), 3.81-3.79 (m, 3H), 2.66-2.47 (m, 5H), 2.22-2.10 (m, 1 H), 1.45-1.41 (m, 9 H), 1.09-1.03 (m, 6 H).
Reaction SMILES: [C:1]([O:5][C:6](=[O:28])[C@H:7]([NH:20]C(OC(C)(C)C)=O)[CH2:8][N:9]1[C:13](=[O:14])[C:12]2=[CH:15][CH:16]=[CH:17][CH:18]=[C:11]2[C:10]1=[O:19])([CH3:4])([CH3:3])[CH3:2].Cl.CC(C(OC)=O)=C>O1CCOCC1>[C:1]([O:5][C:6](=[O:28])[C@H:7]([NH2:20])[CH2:8][N:9]1[C:10](=[O:19])[C:11]2=[CH:18][CH:17]=[CH:16][CH:15]=[C:12]2[C:13]1=[O:14])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N[C@H](CN1C(=O)c2ccccc2C1=O)C(=O)OC(C)(C)C
Agent: C=C(C)C(=O)OC
Agent: Cl
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)[C@H](N)CN1C(=O)c2ccccc2C1=O
Temperature: 80 °C
Yield: 90.1 %

Procedure:
Tert-butyl-2(R)-[(tert-butoxycarbonyl)amino]-3-phthalimido-propionate (8.58 g, 21.8 mmol) was taken up in a anhydrous solution of hydrochloric acid in dioxane (100 ml, 4% wt/wt). The reaction flask was fitted with a rotovap trap, which was topped with a teflon stopper and the mixture was heated to 80° C. (use a plexiglass shield for safety). After 1.5 hours the material was cooled to ambient temperature and all volatiles removed on the rotary evaporator. The white solid was taken up in methylene chloride (100 ml) and transferred to a seperatory funnel. The solution was partitioned with an equal volume of aqueous sodium hydroxide (1.0 N) and the organic phase collected. This was subsequently shaken with brine solution (2×100 ml, consecutively) and the aqueous phases back extracted with methylene chloride (3×100 ml). The organic phases were combined, dried (MgSO4), filtered and condensed to provide tert-butyl-2(R)-amino-3-phthalimido-propionate (5.7 g) as a white powder.
Reaction SMILES: [CH2:1]([N:3]1[C:9]2[CH:10]=[CH:11][C:12]([C:14](=[N:16]O)[CH3:15])=[CH:13][C:8]=2[C:7]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[F:24])=[N:6][CH2:5][C:4]1=[O:25])[CH3:2].[H][H]>C(O)C.[Ni]>[NH2:16][CH:14]([C:12]1[CH:11]=[CH:10][C:9]2[N:3]([CH2:1][CH3:2])[C:4](=[O:25])[CH2:5][N:6]=[C:7]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[F:24])[C:8]=2[CH:13]=1)[CH3:15]
Reactant: CCN1C(=O)CN=C(c2ccccc2F)c2cc(C(C)=NO)ccc21
Reactant: [H][H]
Agent: [Ni]
Solvent: CCO
Product: CCN1C(=O)CN=C(c2ccccc2F)c2cc(C(C)N)ccc21

Procedure:
A solution of 1 g (2.95 mmol) of 1-ethyl-5-(o-fluorophenyl)-1,3-dihydro-7-[1-(hydroxyimino)ethyl]-2H-1,4-benzodiazepin-2-one in 150 ml of ethanol is stirred with 1.0 g of Raney-nickel paste for 21 hours in a hydrogen atmosphere at 50°. After filtration over Digalite and evaporation in vacuo, there is obtained 7-(1-aminoethyl)-1-ethyl-5-(o-fluorophenyl)-1,3-dihydro-2H-1,4-benzodiazepin-2-one of melting point 53°-55°.
Reaction SMILES: C([O:8][CH2:9][CH:10]1[C:14]2[NH:15][C:16]([C:18]3[CH:27]=[CH:26][CH:25]=[C:24]4[C:19]=3[N:20]=[C:21]([NH:29][C:30]3([CH3:33])[CH2:32][CH2:31]3)[C:22]([CH3:28])=[N:23]4)=[CH:17][C:13]=2[C:12](=[O:34])[NH:11]1)C1C=CC=CC=1.B(Cl)(Cl)Cl>C(Cl)Cl>[OH:8][CH2:9][CH:10]1[C:14]2[NH:15][C:16]([C:18]3[CH:27]=[CH:26][CH:25]=[C:24]4[C:19]=3[N:20]=[C:21]([NH:29][C:30]3([CH3:33])[CH2:31][CH2:32]3)[C:22]([CH3:28])=[N:23]4)=[CH:17][C:13]=2[C:12](=[O:34])[NH:11]1
Reactant: Cc1nc2cccc(-c3cc4c([nH]3)C(COCc3ccccc3)NC4=O)c2nc1NC1(C)CC1
Agent: ClB(Cl)Cl
Solvent: ClCCl
Product: Cc1nc2cccc(-c3cc4c([nH]3)C(CO)NC4=O)c2nc1NC1(C)CC1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a 50-mL round-bottomed flask was added 6-((benzyloxy)methyl)-2-(2-methyl-3-((1-methylcyclopropyl)amino)quinoxalin-5-yl)-5,6-dihydropyrrolo[3,4-b]pyrrol-4(1H)-one (364) (0.27 g, 0.63 mmol) and DCM (10 mL). The reaction mixture was cooled to −78° C. and under a N2 atmosphere boron trichloride (1.25 mL, 1.25 mmol, 1M in DCM) (Sigma-Aldrich Chemical Company, Inc.) was added dropwise. The reaction mixture was stirred at −78° C. for 30 min and at 0° C. for 30 min. The reaction was quenched by the addition of NaHCO3 (100 mg in MeOH, 3 mL) and the solvent was removed under vacuum. The crude material was absorbed onto a plug of silica gel and purified by chromatography through a Redi-Sep pre-packed silica gel column (12 g), eluting with a gradient of 2-8% MeOH in DCM to provide 6-(hydroxymethyl)-2-(2-methyl-3-((1-methylcyclopropyl)amino)quinoxalin-5-yl)-5,6-dihydropyrrolo[3,4-b]pyrrol-4(1H)-one (365) (50% ee) as a yellow solid. 1H NMR (400 MHz, DMSO-d6) δ 13.17 (s, 1H), 8.04 (dd, J=1.17, 7.63 Hz, 1H), 7.58-7.63 (m, 2H), 7.55 (s, 1H), 7.36 (t, J=7.82 Hz, 1H), 6.97 (d, J=1.17 Hz, 1H), 5.21 (t, J=5.28 Hz, 1H), 4.48 (dd, J=6.06, 8.02 Hz, 1H), 3.74 (td, J=5.21, 10.12 Hz, 1H), 3.20-3.28 (m, 1H), 2.92 (dt, J=2.93, 6.46 Hz, 1H), 2.51 (s, 3H), 1.00-1.13 (m, 1H), 0.86-0.96 (m, 1H), 0.75-0.85 (m, 1H), 0.44-0.55 (m, 1H). m/z (ESI, +ve) 350.3 (M+H)+.
Reaction SMILES: [C:1]([C:3]1[N:8]=[C:7]([C:9]2[CH:14]=[C:13]([C:15]3[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=3)[CH:12]=[C:11]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=3)[N:10]=2)[CH:6]=[CH:5][CH:4]=1)#[N:2]>C(O)(=O)C.[Pd]>[NH2:2][CH2:1][C:3]1[N:8]=[C:7]([C:9]2[CH:14]=[C:13]([C:15]3[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=3)[CH:12]=[C:11]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=3)[N:10]=2)[CH:6]=[CH:5][CH:4]=1
Reactant: COc1ccc(-c2cc(-c3ccccn3)nc(-c3cccc(C#N)n3)c2)cc1
Agent: [Pd]
Solvent: CC(=O)O
Product: COc1ccc(-c2cc(-c3ccccn3)nc(-c3cccc(CN)n3)c2)cc1

Procedure:
A mixture of 6-cyano-4'-(4-methoxyphenyl)-2,2':6',2"-terpyridine (4 mmol) and 480 mg of 10% Pd/C in 130 ml of acetic acid is hydrogenated (H2, 50 psi) at 45° C. for 22 hours. The reaction mixture is filtered and the solvent is stripped, the residue is triturated with methanol, filtered and dried to provide the desired product as the acetic acid salt.
Reaction SMILES: [N:1]12[CH2:8][CH2:7][CH:4]([CH2:5][CH2:6]1)[CH:3]([OH:9])[CH2:2]2.[CH3:10][O:11][C:12]1[CH:17]=[CH:16][C:15]([N:18]=[C:19]=[O:20])=[CH:14][CH:13]=1>>[N:1]12[CH2:8][CH2:7][CH:4]([CH2:5][CH2:6]1)[CH:3]([O:9][C:19](=[O:20])[NH:18][C:15]1[CH:14]=[CH:13][C:12]([O:11][CH3:10])=[CH:17][CH:16]=1)[CH2:2]2
Reactant: COc1ccc(N=C=O)cc1
Reactant: OC1CN2CCC1CC2
Product: COc1ccc(NC(=O)OC2CN3CCC2CC3)cc1
Yield: 43 %

Procedure:
3-Quinuclidinol and 4-methoxyphenyl isocyanate were used. The solid which precipitated from the reaction mixture was recrystallized from ethyl acetate to afford the title compound (43%) as a white solid: mp 159.5-160.5° C.; FAB LRMS m /z (relative intensity, %) 277 (MH+, 16), 110 (100).
Reaction SMILES: C1COCC1.[Cl:6][CH2:7][C:8]1[CH:16]=[CH:15][C:11]([C:12](Cl)=[O:13])=[CH:10][CH:9]=1.[C:17]([O:21][C:22]([N:24]1[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]1)=[O:23])([CH3:20])([CH3:19])[CH3:18]>C(N(CC)CC)C>[C:17]([O:21][C:22]([N:24]1[CH2:29][CH2:28][N:27]([C:12](=[O:13])[C:11]2[CH:15]=[CH:16][C:8]([CH2:7][Cl:6])=[CH:9][CH:10]=2)[CH2:26][CH2:25]1)=[O:23])([CH3:20])([CH3:18])[CH3:19]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: O=C(Cl)c1ccc(CCl)cc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCN(C(=O)c2ccc(CCl)cc2)CC1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 100 %

Procedure:
A THF (8 ml) solution of 4-chloromethylbenzoylchloride (5.3 g) was added dropwise at 0° C. to a THF (16 ml) solution of 1-tert-butoxycarbonylpiperazine (5.19 g) and triethylamine (2.82 g) and the solution was stirred at room temperature for 10 minutes. The reaction solution was concentrated and the obtained solid residue was washed with water and ethyl acetate, and dried to give a colorless solid of the title compound (9.44 g).
Reaction SMILES: CO[CH:3](OC)[CH2:4][CH:5](OC)OC.S(=O)(=O)(O)O.[NH:17]([C:19]1[N:23]([C:24]2[C:29]([Cl:30])=[CH:28][C:27]([C:31]([F:34])([F:33])[F:32])=[CH:26][C:25]=2[Cl:35])[N:22]=[CH:21][C:20]=1[S:36]([C:39]([F:42])([F:41])[F:40])(=[O:38])=[O:37])[NH2:18].C(=O)([O-])[O-].[Na+].[Na+]>C(O)C>[Cl:30][C:29]1[CH:28]=[C:27]([C:31]([F:32])([F:33])[F:34])[CH:26]=[C:25]([Cl:35])[C:24]=1[N:23]1[C:19]([N:17]2[CH:5]=[CH:4][CH:3]=[N:18]2)=[C:20]([S:36]([C:39]([F:42])([F:41])[F:40])(=[O:37])=[O:38])[CH:21]=[N:22]1
Reactant: COC(CC(OC)OC)OC
Reactant: NNc1c(S(=O)(=O)C(F)(F)F)cnn1-c1c(Cl)cc(C(F)(F)F)cc1Cl
Agent: O=C([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CCO
Product: O=S(=O)(c1cnn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)c1-n1cccn1)C(F)(F)F
Yield: 76.7 %

Procedure:
1.2 ml (0.0078 mole) of 1,1,3,3-tetramethoxypropane and 0.2 ml (0.0034 mole) of 96 percent strength sulphuric acid are added in sequence to 3 g (0.0068 mole) of 5-hydrazino-4-(trifluoromethylsulphonyl)-1-(2,6-dichloro-4-trifluoromethyl-phenyl)-pyrazole in 7 ml of ethanol at 20° C. to 25° C. The reaction mixture is heated at the reflux temperature for 2 hours, cooled, and neutralized with 0.36 g (0.0034 mole) of sodium carbonate, and the solvent is removed in vacuo. The residue is suspended in water, filtered, washed again with water and dried. 2.5 g (77% of theory) of 1-(2,6-dichloro-4-trifluoromethyl-phenyl)-5-(pyrazol-1-yl)-4-trifluoromethylsulphonyl-pyrazole of melting point 127° C. to 133° C. are obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:13]([CH2:23][C:24]2[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][CH:25]=2)[C:14]2[CH:15]=[C:16]([CH:20]=[CH:21][CH:22]=2)[C:17](O)=[O:18])[C:5]2[N:6]([C:8]([C:11]#[N:12])=[CH:9][N:10]=2)[N:7]=1.[CH3:32][NH:33][CH:34]1[CH2:38][CH2:37][N:36]([CH3:39])[CH2:35]1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([N:13]([CH2:23][C:24]2[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][CH:25]=2)[C:14]2[CH:15]=[C:16]([CH:20]=[CH:21][CH:22]=2)[C:17]([N:33]([CH3:32])[CH:34]2[CH2:38][CH2:37][N:36]([CH3:39])[CH2:35]2)=[O:18])[C:5]2[N:6]([C:8]([C:11]#[N:12])=[CH:9][N:10]=2)[N:7]=1
Reactant: COc1ccc(CN(c2cccc(C(=O)O)c2)c2cc(Cl)nn3c(C#N)cnc23)cc1
Reactant: CNC1CCN(C)C1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Product: COc1ccc(CN(c2cccc(C(=O)N(C)C3CCN(C)C3)c2)c2cc(Cl)nn3c(C#N)cnc23)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 55.2 %

Procedure:
A stirred solution of 253C (500 mg, 1.152 mmol) in DMF (1 mL) was treated with N,1-dimethylpyrrolidin-3-amine (0.217 mL, 1.73 mmol), BOP (663 mg, 1.5 mmol) and TEA (0.32 mL, 2.30 mmol), and the reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was triturated with water, and the solid was collected by filtration and dried in vacuo to obtain 254A (337 mg, 0.636 mmol, 55.2% yield) as a light grey solid. HPLC: Rt=1.56 min. (PHENOMENEX® Luna 5 micron C18 4.6×30 mm, 0 to 100 B in 2 min. with 1 min. hold time, flow rate=5 mL/min., detection at 254 nm, Solvent A: 10% methanol/90% water/0.1% TFA; solvent B: 10% water/90% methanol/0.1% TFA). MS (ES): m/z=531.97 [M+H]+.
Reaction SMILES: C(O[C:9]([N:11]1[CH2:15][CH2:14][C@@H:13]([C:16]2([NH:19]C(OC(C)(C)C)=O)[CH2:18][CH2:17]2)[CH2:12]1)=O)C1C=CC=CC=1.C(N(CC)CC)C.[F:34][C:35]1[CH:36]=[C:37]2[C:42](=[CH:43]C=1F)[N:41]([C@@H:46]1[CH2:48][C@@H:47]1[F:49])[CH:40]=[C:39]([C:50]([OH:52])=[O:51])[C:38]2=[O:53].[OH-].[Na+]>CO.[C].[Pd]>[NH2:19][C:16]1([C@@H:13]2[CH2:14][CH2:15][N:11]([C:9]3[CH:43]=[C:42]4[C:37]([C:38](=[O:53])[C:39]([C:50]([OH:52])=[O:51])=[CH:40][N:41]4[C@@H:46]4[CH2:48][C@@H:47]4[F:49])=[CH:36][C:35]=3[F:34])[CH2:12]2)[CH2:17][CH2:18]1
Reactant: O=C(O)c1cn([C@@H]2C[C@@H]2F)c2cc(F)c(F)cc2c1=O
Reactant: CC(C)(C)OC(=O)NC1([C@@H]2CCN(C(=O)OCc3ccccc3)C2)CC1
Agent: [Pd]
Agent: [Na+]
Agent: [OH-]
Solvent: CCN(CC)CC
Solvent: CO
Product: NC1([C@@H]2CCN(c3cc4c(cc3F)c(=O)c(C(=O)O)cn4[C@@H]3C[C@@H]3F)C2)CC1
Reaction time: 2 h
Yield: 77 %

Procedure:
A 322 mg (0.89 mmol) portion of (3R)-1-benzyloxycarbonyl-3-(1-tert-butoxycarbonylaminocyclopropyl)pyrrolidine was dissolved in 10 ml of methanol to which was subsequently added 100 mg of 5% palladium-carbon to carry out 2 hours of hydrogenation under normal pressure with warming by an infrared lamp. After completion of the reaction, 5% palladium-carbon was removed by filtration and methanol was evaporated. The resulting residue was dissolved in 5 ml of acetonitrile to which were subsequently added 0.5 ml of triethylamine and 113 mg (0.4 mmol) of 6,7-difluoro-[(1R,2S)-2-fluorocyclopropyl]-1,4-dihydro-4-oxoquinoline-3-carboxylic acid, followed by 18 hours of heating under reflux. After completion of the reaction, the reaction solution was spontaneously cooled to collect the thus formed crystals by filtration. With cooling in an ice bath, to the thus obtained crystals was added dropwise 5 ml of concentrated hydrochloric acid, followed by 30 minutes of stirring at the same temperature. After completion of the reaction, the reaction solution was adjusted to pH 12 with sodium hydroxide aqueous solution and then to pH 7.4 with hydrochloric acid, followed by extraction with chloroform (50 ml×3). The organic layers were combined and dried on sodium sulfate, and then the solvent was evaporated. Thereafter, the resulting residue was recrystallized from liquid ammonia-ethanol to yield 120 mg (77%) of the title compound.
Reaction SMILES: B.C1COCC1.[CH:7]([O:10][CH2:11][C:12]1[N:17]=[CH:16][C:15]([C:18]#[N:19])=[CH:14][CH:13]=1)([CH3:9])[CH3:8]>Cl>[NH2:19][CH2:18][C:15]1[CH:16]=[N:17][C:12]([CH2:11][O:10][CH:7]([CH3:9])[CH3:8])=[CH:13][CH:14]=1
Reactant: CC(C)OCc1ccc(C#N)cn1
Agent: B
Agent: Cl
Solvent: C1CCOC1
Product: CC(C)OCc1ccc(CN)cn1
Temperature: 25 °C
Reaction time: 16 h
Yield: 46.4 %

Procedure:
Add a solution of borane-THF complex (4.5 mL, 4.54 mmol, 1M solution in THF) to neat 6-(iso-propoxy)methyl-pyridine-3-carbonitrile (0.4 g, 2.27 mmol) and stir the mixture for 16 h at reflux. Cool to room temperature and stir for 48 h. Add 2N aqueous HCl (10 mL) until gas evolution stops and then concentrate in vacuo. Dissolve the crude mixture in methanol and filter through a SCX-2 column eluting with methanol followed by 3N ammonia in methanol to obtain the title compound (190 mg, 46%).
Reaction SMILES: [NH:1]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[CH2:5][CH2:4][CH2:3][CH2:2]1.[C:12]([C:14]1[CH:22]=[CH:21][C:17]([C:18](O)=[O:19])=[CH:16][C:15]=1[CH3:23])#[N:13].C(N(CC)CC)C>ClCCl.CN(C)C1C=CN=CC=1>[C:12]([C:14]1[CH:22]=[CH:21][C:17]([C:18]([N:1]2[C:7]3[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=3[CH2:5][CH2:4][CH2:3][CH2:2]2)=[O:19])=[CH:16][C:15]=1[CH3:23])#[N:13]
Reactant: c1ccc2c(c1)CCCCN2
Reactant: Cc1cc(C(=O)O)ccc1C#N
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1cc(C(=O)N2CCCCc3ccccc32)ccc1C#N

Procedure:
To a solution of 2,3,4,5-tetrahydro-1H-1-benzazepine (0.80 g, 5.44 mmol) in dichloromethane (40 ml) were added 4-cyano-3-methylbenzoic acid from example B (0.96 g, 5.95 mmol), triethylamine (0.76 g, 5.44 mmol), 4-(dimethylamino)pyridine (0.66 g, 5.44 mmol) and WSCDI (2.17 g, 10.88 mmol). The mixture was stirred at reflux for 18 h, cooled and evaporated in vacuo. The residue was partitioned between EtOAc and 1M KHSO4. The organic layer was washed with saturated sodium bicarbonate solution and brine, dried over MgSO4, and concentrated in vacuo. The residue was purified by flash chromatography on silica (eluant EtOAc:pet. ether 30:70); yield 1.10 g (70%).
Reaction SMILES: C([N:8]1[CH2:15][C@H:14]2[C@H:10]([CH2:11][C:12]([F:17])([F:16])[CH2:13]2)[C@H:9]1[CH2:18][N:19]1[C:27](=[O:28])[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[C:20]1=[O:29])C1C=CC=CC=1.C([O-])=O.[NH4+]>CO.[Pd]>[F:17][C:12]1([F:16])[CH2:11][C@H:10]2[C@H:14]([CH2:15][NH:8][C@@H:9]2[CH2:18][N:19]2[C:20](=[O:29])[C:21]3[C:26](=[CH:25][CH:24]=[CH:23][CH:22]=3)[C:27]2=[O:28])[CH2:13]1
Reactant: O=C1c2ccccc2C(=O)N1C[C@@H]1[C@H]2CC(F)(F)C[C@H]2CN1Cc1ccccc1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CO
Product: O=C1c2ccccc2C(=O)N1C[C@H]1NC[C@@H]2CC(F)(F)C[C@@H]21
Temperature: 25 °C
Yield: 59.8 %

Procedure:
To a suspension of (1S,2S,5R)-2-(3-benzyl-7,7-difluoro-3-azabicyclo[3.3.0]oct-2-ylmethyl)-isoindole-1,3-dione (1.73 g), Pd—C 10% (1.7 g) in dry MeOH (146 mL) was added ammonium formate (1.38 g). The reaction mixture was stirred at reflux for 16 h, cooled to RT and filtered over a pad of celite. The filtrate was concentrated in vacuo, partitioned between DCM/water. The aqueous phase was concentrated to yield 0.8 g (60%) of the title compound as a white solid
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]2[N:13]=[CH:12][C:11]([C:14]([OH:16])=O)=[CH:10][N:9]=2)[CH:5]=[CH:6][CH:7]=1.O[N:18]1[C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=2N=N1.C1CCC(N=C=NC2CCCCC2)CC1.NC1C=CC=CC=1.C(O)C(N)(CO)CO>CN(C=O)C>[C:22]1([NH:18][C:14]([C:11]2[CH:12]=[N:13][C:8]([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[CH:3]=3)=[N:9][CH:10]=2)=[O:16])[CH:23]=[CH:24][CH:25]=[CH:26][CH:21]=1
Reactant: On1nnc2ccccc21
Reactant: O=C(O)c1cnc(-c2cccc(F)c2)nc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: NC(CO)(CO)CO
Solvent: CN(C)C=O
Solvent: Nc1ccccc1
Product: O=C(Nc1ccccc1)c1cnc(-c2cccc(F)c2)nc1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
A mixture of 2-(3-fluoro-phenyl)-pyrimidine-5-carboxylic acid (107 mg, 0.49 mmol, prepared according to the general procedure described in Example 2, steps 1 and 2), 1-hydroxybenzotriazole (75 mg, 0.56 mmol) and PS-DCC (511 mg, 1.28 mmol/g, 0.65 mmol) in DMF (8 mL) is shaken at room temperature for 15 min. Aniline (30.4 mg, 0.33 mmol) is added. The mixture is shaken at room temperature for 18 hours. PS-trisamine (392 mg, 3.75 mmol/g, 1.47 mmol) is added and the mixture is continually shaken at room temperature for 18 hours. The solid is filtered and washed with EtOAc. The filtrate is concentrated to afford 2-(3-fluoro-phenyl)-pyrimidine-5-carboxylic acid phenylamide as a solid in quantitative yield. MS: 294 (M+H).
Reaction SMILES: [OH:1][CH:2]([CH2:10][O:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])[CH2:3][N:4]1[CH2:9][CH2:8][NH:7][CH2:6][CH2:5]1.[CH3:28][O:29][C:30]1[CH:37]=[CH:36][C:33]([CH2:34]Cl)=[CH:32][CH:31]=1>>[CH3:28][O:29][C:30]1[CH:37]=[CH:36][C:33]([CH2:34][N:7]2[CH2:8][CH2:9][N:4]([CH2:3][CH:2]([OH:1])[CH2:10][O:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])[CH2:5][CH2:6]2)=[CH:32][CH:31]=1
Reactant: CCCCCCCCCCCCCCCCOCC(O)CN1CCNCC1
Reactant: COc1ccc(CCl)cc1
Product: CCCCCCCCCCCCCCCCOCC(O)CN1CCN(Cc2ccc(OC)cc2)CC1

Procedure:
Following the procedure of Example 5, 1-(2-hydroxy-3-n-hexadecyloxypropyl)-piperazine was reacted with 4-methoxybenzyl chloride to form 1-(4-methoxybenzyl)-4-(2-hydroxy-3-n-hexadecyloxypropyl)-piperazine, mp 233°-245° C.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][CH:5]([C:8]2(O)[C:21]3[CH:20]=[C:19]([C:22]([F:25])([F:24])[F:23])[CH:18]=[CH:17][C:16]=3[O:15][C:14]3[C:9]2=[CH:10][CH:11]=[CH:12][CH:13]=3)[CH2:4][CH2:3]1.S(C1C=CC=CC=1C(OC(=O)C1C=CC=CC=1S(O)(=O)=O)=O)(O)(=O)=O.C(O)(=O)CC.[OH-].[Na+]>O>[CH3:1][N:2]1[CH2:3][CH2:4][C:5](=[C:8]2[C:21]3[CH:20]=[C:19]([C:22]([F:25])([F:23])[F:24])[CH:18]=[CH:17][C:16]=3[O:15][C:14]3[C:9]2=[CH:10][CH:11]=[CH:12][CH:13]=3)[CH2:6][CH2:7]1
Reactant: CN1CCC(C2(O)c3ccccc3Oc3ccc(C(F)(F)F)cc32)CC1
Agent: O=C(OC(=O)c1ccccc1S(=O)(=O)O)c1ccccc1S(=O)(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: CCC(=O)O
Solvent: O
Product: CN1CCC(=C2c3ccccc3Oc3ccc(C(F)(F)F)cc32)CC1
Temperature: 100 °C

Procedure:
Dehydration of the xanthene-9-ol (88.2 g., 0.24 m.) is accomplished by refluxing with 88.1 g. (0.48 m.) of sulfobenzoic anhydride and 1.2 1. of propionic acid for two hours. The reaction mixture is heated in vacuo at 100° C. and the residual syrup is dissolved in water and made strongly basic with 40% sodium hydroxide solution. Extraction with ether gives 1-methyl-4-(2-trifluoromethyl-9-xanthenylidene)-piperidine, m.p. 82°-83° C.
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH3:8])=[C:6]([O:9][CH2:10][CH2:11][CH2:12][S:13]([CH3:16])(=[O:15])=[O:14])[C:5]([CH3:17])=[C:4]([CH3:18])[C:3]=1[C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([CH2:25][O:26][C:27]2[CH:40]=[CH:39][C:30]3[C@H:31]([CH2:34][C:35]([O:37]C)=[O:36])[CH2:32][O:33][C:29]=3[CH:28]=2)[CH:20]=1.CO.[OH-].[Na+].Cl>O.O1CCCC1>[CH3:1][C:2]1[C:7]([CH3:8])=[C:6]([O:9][CH2:10][CH2:11][CH2:12][S:13]([CH3:16])(=[O:15])=[O:14])[C:5]([CH3:17])=[C:4]([CH3:18])[C:3]=1[C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([CH2:25][O:26][C:27]2[CH:40]=[CH:39][C:30]3[C@H:31]([CH2:34][C:35]([OH:37])=[O:36])[CH2:32][O:33][C:29]=3[CH:28]=2)[CH:20]=1
Reactant: COC(=O)C[C@@H]1COc2cc(OCc3cccc(-c4c(C)c(C)c(OCCCS(C)(=O)=O)c(C)c4C)c3)ccc21
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: Cc1c(C)c(-c2cccc(COc3ccc4c(c3)OC[C@H]4CC(=O)O)c2)c(C)c(C)c1OCCCS(C)(=O)=O
Temperature: 50 °C
Reaction time: 2 h
Yield: 93.6 %

Procedure:
To a solution of methyl [(3S)-6-({2′,3′,5′,6′-tetramethyl-4′-[3-(methylsulfonyl)propoxy]biphenyl-3-yl}methoxy)-2,3-dihydro-1-benzofuran-3-yl]acetate (0.457 g, 0.806 mmol) in a mixed solvent of methanol (2 mL) and tetrahydrofuran (4 mL) was added 2 M aqueous sodium hydroxide solution (1 mL), and the mixture was stirred at 50° C. for 2 hr. The reaction mixture was diluted with water, acidified with 1 M hydrochloric acid, and extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The precipitated crystals were recrystallized from heptane-ethyl acetate to give the title compound (0.417 g, yield 94%) as colorless crystals.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[N:10][C:11]=1[CH2:12]O)[N:8]=[C:7]([C:14]([F:17])([F:16])[F:15])[C:6]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:5]2.C(N(S(F)(F)[F:29])CC)C>>[F:1][C:2]1[CH:3]=[C:4]2[C:9](=[N:10][C:11]=1[CH2:12][F:29])[N:8]=[C:7]([C:14]([F:17])([F:16])[F:15])[C:6]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:5]2
Reactant: CCOC(=O)c1cc2cc(F)c(CO)nc2nc1C(F)(F)F
Reactant: CCN(CC)S(F)(F)F
Product: CCOC(=O)c1cc2cc(F)c(CF)nc2nc1C(F)(F)F

Procedure:
In a similar procedure to Example 12, Stage 3, ethyl 6-fluoro-7-hydroxymethyl-2-trifluoromethyl-[1,8]-naphthyridine-3-carboxylate was reacted with N,N-diethylaminosulfur trifluoride to give the required product. as a pale brown solid, 1H NMR (CDCl3) δ: 8.74 (1H, s), 8.03 (1H, d), 5.83 (2H, double doublet), 4.51 (1H, q), 1.45 (3H, t).