Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][C:3]=1[CH:9]([N:16]([CH3:23])S(C(C)(C)C)=O)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>CCOC(C)=O.Cl>[Br:8][C:5]1[CH:6]=[CH:7][C:2]([NH2:1])=[C:3]([CH:9]([NH:16][CH3:23])[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:4]=1
Reactant: CN(C(c1ccccc1)c1cc(Br)ccc1N)S(=O)C(C)(C)C
Agent: Cl
Solvent: CCOC(C)=O
Product: CNC(c1ccccc1)c1cc(Br)ccc1N

Procedure:
To a solution of 2-Methyl-propane-2-sulfinic acid [(2-amino-5-bromo-phenyl)-phenyl-methyl]-methyl-amide (60 g, 152 mmol) in EtOAc/HCl (600 mL) is stirred at r.t. for 2 h. The mixture is concentrated and NaHCO3 is added to brought the PH>7, extracted with EtOAc. The organic layer is concentrated to give product. This is used in the next step without further purification.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][CH:6]=[CH:5]2.Br[C:13]1[CH:22]=[CH:21][C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:14]=1.CC(C)([O-])C.[Na+]>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C1(P(C2C=CC=CC=2)C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(C)C=CC=CC=1>[CH:19]1[C:20]2[C:15](=[CH:14][CH:13]=[CH:22][CH:21]=2)[CH:16]=[CH:17][C:18]=1[NH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][CH:6]=[CH:5]2
Reactant: Brc1ccc2ccccc2c1
Reactant: Nc1ccc2ncccc2c1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1
Product: c1ccc2cc(Nc3ccc4ncccc4c3)ccc2c1
Temperature: 25 °C
Yield: 72 %

Procedure:
To a flask equipped with a magnetic stirrer, reflux condensor, and nitrogen inlet was added 6-aminoquinoline (6.69 grams, 46.4 mmoles), 2-bromonapthalene (9.15 grams, 44.2 mmoles), tris(dibenzylideneacetone)dipalladium (0) (0.80 grams, 0.87 mmoles), rac-2,2′-bis(diphenylphosphino)-1,1′-binapthyl (1.10 grams, 1.77 mmoles), sodium tert-butoxide (8.49 grams, 88.3 mmoles) and anhydrous toluene (90 mL). The contents of the flask were refluxed for five hours; cooled to room temperature; and filtered through a pad of silica gel. The silica gel pad was then eluted with tetrahydrofuran (135 mL). The combined organic layers were concentrated in vacuo to yield a brown solid. The solid was recrystallized from ethanol to afford 8.6 grams of the desired product as a yellow solid. 1H NMR (DMSO-d6/D2O) δ 8.9 (d, 1H), 8.65 (d, 1H), 8.2 (d, 1H), 7.25-8.05 (m, 10H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:9]([S:10]([C:13]3[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=3)(=[O:12])=[O:11])[C:8](=[O:21])[N:7]([CH:22]([C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)[C:23]([NH:25][CH2:26][CH2:27][N:28]3[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]3)=[O:24])[C:6]=2[CH:40]=1.C=O.[C:43](O[BH-](OC(=O)C)OC(=O)C)(=O)C>C1COCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:9]([S:10]([C:13]3[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=3)(=[O:11])=[O:12])[C:8](=[O:21])[N:7]([CH:22]([C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)[C:23]([NH:25][CH2:26][CH2:27][N:28]3[CH2:29][CH2:30][N:31]([CH3:43])[CH2:32][CH2:33]3)=[O:24])[C:6]=2[CH:40]=1
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Reactant: COc1ccc(S(=O)(=O)n2c(=O)n(C(C(=O)NCCN3CCNCC3)c3ccccc3)c3cc(Cl)ccc32)cc1
Agent: C=O
Solvent: C1CCOC1
Product: COc1ccc(S(=O)(=O)n2c(=O)n(C(C(=O)NCCN3CCN(C)CC3)c3ccccc3)c3cc(Cl)ccc32)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 98.0 mg (0.17 mmol) 2-[6-chloro-3-(4-methoxybenzenesulfonyl)-2-oxo-2,3-dihydrobenzimidazol-1-yl]-2-phenyl-N-(2-piperazin-1-yl-ethyl)acetamide (Example 131) in 4 ml of THF was mixed with 5.54 mg (0.19 mmol) of paraformaldehyde and 170 mg of MP-triacetoxyborohydride resin (Argonaut, 2.55 mmol/g, 0.42 mmol) and shaken at room temperature overnight. The solid phase reagent was filtered off and washed with dichloromethane. The filtrate was concentrated under reduced pressure. The residue was purified by preparative RP-HPLC (mobile phase: gradient from 10% to 80% acetonitrile in water, 0.1% trifluoroacetic acid as modulator). Yield: 69.6 mg (69%) of colorless solid
Reaction SMILES: C[O:2][C:3]([C:5]1[N:6]=[C:7]([C:27]#[N:28])[C:8]2[C:13]([C:14]=1[OH:15])=[CH:12][CH:11]=[C:10]([O:16][C:17]1[CH:26]=[CH:25][C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[CH:18]=1)[CH:9]=2)=O.[NH2:29][CH2:30][C:31]([CH3:38])([CH3:37])[C:32]([O:34][CH2:35][CH3:36])=[O:33]>CCO>[CH2:35]([O:34][C:32](=[O:33])[C:31]([CH3:38])([CH3:37])[CH2:30][NH:29][C:3]([C:5]1[N:6]=[C:7]([C:27]#[N:28])[C:8]2[C:13]([C:14]=1[OH:15])=[CH:12][CH:11]=[C:10]([O:16][C:17]1[CH:26]=[CH:25][C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[CH:18]=1)[CH:9]=2)=[O:2])[CH3:36]
Reactant: COC(=O)c1nc(C#N)c2cc(Oc3ccc4ccccc4c3)ccc2c1O
Reactant: CCOC(=O)C(C)(C)CN
Solvent: CCO
Product: CCOC(=O)C(C)(C)CNC(=O)c1nc(C#N)c2cc(Oc3ccc4ccccc4c3)ccc2c1O

Procedure:
1-Cyano-4-hydroxy-7-(naphthalen-2-yloxy)-isoquinoline-3-carboxylic acid methyl ester (15 mg, 0.04 mmol) and ethyl 3-amino-2,2-dimethylpropanoate (24 mg, 0.16 mmol) in EtOH (3 mL) were heated at 150° C. in a microwave for 1.5 hours. The solvent was removed in vacuo and the residue oil was purified by flash chromatography (0-50% EtOAc/hexanes) to give the title compound in 18 mg. MS: (−) m/z 482.36 (M−1).
Reaction SMILES: [CH3:1][C:2]1([CH3:14])[C:11]2[C:6](=[CH:7][C:8](Br)=[CH:9][CH:10]=2)[NH:5][C:4](=[O:13])[CH2:3]1.C(N(CC)CC)C.CC1(C)C2C(=CC=C([C:33]#[C:34][Si:35]([CH3:38])([CH3:37])[CH3:36])C=2)NC(=O)C1>[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:1][C:2]1([CH3:14])[C:11]2[C:6](=[CH:7][C:8]([C:33]#[C:34][Si:35]([CH3:38])([CH3:37])[CH3:36])=[CH:9][CH:10]=2)[NH:5][C:4](=[O:13])[CH2:3]1
Reactant: CC1(C)CC(=O)Nc2cc(Br)ccc21
Reactant: CC1(C)CC(=O)Nc2ccc(C#C[Si](C)(C)C)cc21
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Product: CC1(C)CC(=O)Nc2cc(C#C[Si](C)(C)C)ccc21
Yield: 74 %

Procedure:
2.2398 g (8.8 mmol) of 4,4-dimethyl-2-oxo-1,2,3,4-tetrahydro-7-bromoquinoline (Compound 18), 371 mg (1.9 mmol) of CuI, 1.087 g (1.5 mmol) of Pd(PPh3)2Cl2, 35 ml (0.251 mol) of triethylamine and 4.0 ml (28.0 mmol) of trimethylacetylene were reacted substantially in accordance with the procedure used for the preparation of 4,4-dimethyl-2-oxo-1,2,3,4-tetrahydro-6-[(trimethylsilyl)ethynyl]quinoline (Compound 2) to give the title compound as pale orange solids (74%).
Reaction SMILES: [H-].[Na+].[CH2:3]([O:5][C:6]([C:8]1[N:12]=[CH:11][NH:10][N:9]=1)=[O:7])[CH3:4].[CH3:13][O:14][C:15](=[O:30])[C:16]1[CH:21]=[C:20](F)[C:19]([C:23]([F:26])([F:25])[F:24])=[CH:18][C:17]=1[N+:27]([O-:29])=[O:28].O>CN1CCCC1=O>[CH2:3]([O:5][C:6]([C:8]1[N:12]=[CH:11][N:10]([C:20]2[CH:21]=[C:16]([C:15]([O:14][CH3:13])=[O:30])[C:17]([N+:27]([O-:29])=[O:28])=[CH:18][C:19]=2[C:23]([F:24])([F:26])[F:25])[N:9]=1)=[O:7])[CH3:4]
Reactant: COC(=O)c1cc(F)c(C(F)(F)F)cc1[N+](=O)[O-]
Reactant: CCOC(=O)c1nc[nH]n1
Agent: [H-]
Agent: [Na+]
Solvent: CN1CCCC1=O
Solvent: O
Product: CCOC(=O)c1ncn(-c2cc(C(=O)OC)c([N+](=O)[O-])cc2C(F)(F)F)n1
Temperature: 2.5 °C
Reaction time: 1 h
Yield: 71.7 %

Procedure:
A solution of 613 mg (14.0 mmol) of sodium hydride in 10 ml of 1-methyl-2-pyrrolidinone is cooled to 0-5° C. and treated dropwise with a solution of 1.74 g (12.4 mmol) of 1H-[1,2,4]triazole-3-carboxylic acid ethyl ester in 10 ml of 1-methyl-2-pyrrolidinone over 8 minutes. The mixture is stirred for 1 hour at 0-5° C. and a solution of 3.00 g (11.2 mmol) of 5-fluoro-2-nitro4-trifluoromethyl-benzoic acid methyl ester in 10 ml of 1-methyl-2-pyrrolidinone is added. The mixture is allowed to warm slowly to room temperature and stirred for 18 hours under N2. It is poured into water and extracted with ethyl acetate. The organic phase is separated and dried over Na2SO4, filtered and concentrated in vacuo. The residue is purified by flash chromatography (SiO2, hexane/ethyl acetate 1:1) and the mixed fractions are recrystallized in toluene to provide overall 3.12 g (71%) of 1-(5-methoxycarbonyl-4-nitro-2-trifluoromethyl-phenyl)-1H-[1,2,4]triazole-3-carboxylic acid ethyl ester, m.p. 190-192° C.
Reaction SMILES: [OH:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([C:9]2[CH:14]=[CH:13][C:12]([C:15]([O:17][CH3:18])=[O:16])=[CH:11][CH:10]=2)=[CH:4][C:3]=1[CH3:19].[Cl:20][C:21]1[N:29]=[C:28]2[C:24]([N:25]=[CH:26][N:27]2[CH3:30])=[C:23](Cl)[N:22]=1.C([O-])([O-])=O.[K+].[K+]>COCCOC>[Cl:20][C:21]1[N:29]=[C:28]2[C:24]([N:25]=[CH:26][N:27]2[CH3:30])=[C:23]([O:1][C:2]2[C:3]([CH3:19])=[CH:4][C:5]([C:9]3[CH:14]=[CH:13][C:12]([C:15]([O:17][CH3:18])=[O:16])=[CH:11][CH:10]=3)=[CH:6][C:7]=2[CH3:8])[N:22]=1
Reactant: COC(=O)c1ccc(-c2cc(C)c(O)c(C)c2)cc1
Reactant: Cn1cnc2c(Cl)nc(Cl)nc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: COCCOC
Product: COC(=O)c1ccc(-c2cc(C)c(Oc3nc(Cl)nc4c3ncn4C)c(C)c2)cc1

Procedure:
A solution of methyl 4′-hydroxy-3′,5′-dimethylbiphenyl-4-carboxylate (134 mg, 0.52 mmol), 2,6-dichloro-9-methyl-9H-purine (103 mg, 0.51 mmol), and K2CO3 (215 mg, 1.56 mmol) in DME (5 mL) was heated at 80° C. overnight. The desired product was precipitated with H2O and collected by filtration (186 mg). NMR (CDCl3): δ 8.12 (d, 2H), 8.01 (s, 1H), 7.70 (d, 2H), 7.40 (s, 2H), 3.97 (s, 3H), 3.93 (s, 3H), 2.24 (s, 6H).
Reaction SMILES: [CH2:1]([N:8]([CH2:10][CH2:11][C:12]1[C:20]2[C:15](=[CH:16][CH:17]=[C:18]([Cl:21])[CH:19]=2)[N:14]([C:22]2[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=2)[CH:13]=1)C)C1C=CC=CC=1.Cl[C:30]([O:32][CH3:33])=[O:31]>ClC(Cl)(Cl)C>[CH3:1][N:8]([CH2:10][CH2:11][C:12]1[C:20]2[C:15](=[CH:16][CH:17]=[C:18]([Cl:21])[CH:19]=2)[N:14]([C:22]2[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=2)[CH:13]=1)[C:30]([O:32][CH3:33])=[O:31]
Reactant: COC(=O)Cl
Reactant: CN(CCc1cn(-c2ccc(F)cc2)c2ccc(Cl)cc12)Cc1ccccc1
Solvent: CC(Cl)(Cl)Cl
Product: COC(=O)N(C)CCc1cn(-c2ccc(F)cc2)c2ccc(Cl)cc12
Yield: 130 %

Procedure:
A mixture of N-benzyl-N-methyl-2-[5-chloro-1-(4-fluorophenyl)-3-1H-indolyl]ethylamine (14a) (13.7 g, 0.026 mol), methyl chloroformate (2.9 g, 0.031), K2 CO3 (4.2 g, 0.031) and 1,1,1-trichloroethane (150 mL) was heated at reflux for 2 h and the precipitates was filtered off. Evaporation of the solvents afforded crude N-methyl-N-methoxycarbonyl-2-[5-chloro-1-(4-fluorophenyl)-3-1H-indolyl]ethylamine (12.2 g) as an oil. A mixture of the crude N-methoxycarbonyl-2-[5-chloro-1-(4-fluorophenyl)-3-1H-indolyl]ethylamine (12.2 g, 0.034) and 47% hydrobromic acid (150 mL) was heated at reflux for 14 h. The reaction mixture was poured into ice, made alkaline with concentrated NaOH and extracted with diethyl ether (2×200 mL). The combined organic phases were washed with brine and dried (Na2 SO4). Evaporation of the solvents afforded pure title compound as an oil (7.9 g, 52%) which was crystalized as its maleate from ethyl acetate: mp 171°-173° C. (ethyl acetate); 1H NMR (DMSO-d6) δ 2.65 (s, 3 H), 3.05-3.20 (m, 2 H), 3.20-3.30 (m, 2 H), 6.05 (s, 2 H), 7.20 (broad d, 1 H), 7.45 (t, 2 H), 7.50 (s, 1 H), 7.60 (dd, 2 H), 7.65 (s, 1 H), 7.80 (broad s, 1 H); MS (m/z) 303 (MH+), 237 (82) 236 (100). Anal. (C17H16FClN2.C4H4O4) C, H, N.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:8]2[C:13](=[O:14])[C:12]([CH2:15][CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[C:11]([C:23]3[CH:28]=[CH:27][C:26]([S:29](C)(=[O:31])=[O:30])=[CH:25][CH:24]=3)[CH:10]=[N:9]2)[CH:5]=[CH:6][CH:7]=1.[NH3:33]>O>[Cl:1][C:2]1[CH:3]=[C:4]([N:8]2[C:13](=[O:14])[C:12]([CH2:15][CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[C:11]([C:23]3[CH:28]=[CH:27][C:26]([S:29]([NH2:33])(=[O:31])=[O:30])=[CH:25][CH:24]=3)[CH:10]=[N:9]2)[CH:5]=[CH:6][CH:7]=1
Reactant: CS(=O)(=O)c1ccc(-c2cnn(-c3cccc(Cl)c3)c(=O)c2CCc2ccccc2)cc1
Reactant: N
Solvent: O
Product: NS(=O)(=O)c1ccc(-c2cnn(-c3cccc(Cl)c3)c(=O)c2CCc2ccccc2)cc1

Procedure:
The title compound was prepared according to the method of Example 384, substituting 2-(3-chlorophenyl)-4-(phenethyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone (Example 372) in place of 2-benzyl-4-(4-fluorophenyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone (yield: 0.075 g, 17%). semi-solid; 1H NMR (300 MHz, DMSO d6) δ 2.80 (m, 4H), 3.29-3.42 (3H, obstructed by H2O), 6.96 (m, 2H), 7.14-7.28 (m, 3H), 7.46-7.68 (m, 7H), 7.78 (m, 1H), 7.92 (m, 2H), 8.01 (s, 1H). MS (DCI/NH3) m/z 466 (M+H)+, 483 (M+NH4)+. Anal. calc. for C24H20ClN2O3S.0.25 H2O: C, 61.27; H, 4.39; N, 8.93. Found: 61.18; H, 4.68; N, 8.58.
Reaction SMILES: [OH:1][N:2]=[C:3]([C:9](=[O:11])[CH3:10])[C:4]([O:6][CH2:7][CH3:8])=[O:5].C(=O)([O-])[O-].[K+].[K+].[CH2:18](Br)[CH2:19][CH2:20][CH2:21][CH3:22]>CN(C)C=O>[CH2:18]([O:1][N:2]=[C:3]([C:9](=[O:11])[CH3:10])[C:4]([O:6][CH2:7][CH3:8])=[O:5])[CH2:19][CH2:20][CH2:21][CH3:22]
Reactant: CCOC(=O)C(=NO)C(C)=O
Reactant: CCCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCCCON=C(C(C)=O)C(=O)OCC
Yield: 99.9 %

Procedure:
To a suspension of ethyl 2-hydroxyimino-3-oxobutyrate (syn isomer) (40 g.) and potassium carbonate (52 g.) in dimethylformamide (200 ml.) was added pentyl bromide (37.9 g.) with stirring, and the mixture was stirred for 1.5 hours at ambient temperature. The insoluble material was collected by filtration and washed with dimethylformamide. The filtrate and the washings were combined together and evaporated to dryness under reduced pressure. To the residue was added water and the mixture was extracted with chloroform. The extract was washed with a saturated aqueous solution of sodium chloride, dried over magnesium sulfate and concentrated under reduced pressure to give an oil of ethyl 2-pentyloxyimino-3-oxobutyrate (syn isomer) (57.5 g.).
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.[CH3:9][C:10]1[CH:11]=[C:12]([S:16]([Cl:19])(=[O:18])=[O:17])[CH:13]=[CH:14][CH:15]=1>C(Cl)(Cl)(Cl)Cl.CC(N=NC(C#N)(C)C)(C#N)C>[Br:1][CH2:9][C:10]1[CH:11]=[C:12]([S:16]([Cl:19])(=[O:18])=[O:17])[CH:13]=[CH:14][CH:15]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1cccc(S(=O)(=O)Cl)c1
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: O=S(=O)(Cl)c1cccc(CBr)c1
Yield: 37 %

Procedure:
Add N-bromosuccinimide (9.34 g, 52.5 mmol) and AIBN (5 mg, 0.32 mmol) to a solution of 3-methyl-benzenesulfonyl chloride (10.0 g, 52.5 mmol) in carbon tetrachloride (52 mL), and heat the solution at reflux for 12 hours. Filter the mixture to remove solids and condense under reduced pressure to afford a thick oil. Purify by flash chromatography to yield the title compound as an off-white crystalline solid (5.24 g, 19.4 mmol): 1H NMR (CDCl3) δ 4.54 (s, 2H), 7.62 (m, 1H), 7.78 (m, 1H), 7.98 (m, 1H), 8.06 (m, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:28]([F:31])([F:30])[F:29])=[C:6]([CH:27]=1)[CH2:7][N:8]1[CH2:13][CH2:12][NH:11][C:10]2[N:14]=[CH:15][C:16]([C:18]3[CH:26]=[CH:25][C:21]([C:22]([OH:24])=O)=[CH:20][CH:19]=3)=[CH:17][C:9]1=2.[NH2:32][CH2:33][C:34]1[CH:39]=[CH:38][C:37]([C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)=[CH:36][CH:35]=1>>[C:37]1([C:40]2[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=2)[CH:36]=[CH:35][C:34]([CH2:33][NH:32][C:22](=[O:24])[C:21]2[CH:25]=[CH:26][C:18]([C:16]3[CH:15]=[N:14][C:10]4[NH:11][CH2:12][CH2:13][N:8]([CH2:7][C:6]5[CH:27]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]=5[C:28]([F:31])([F:29])[F:30])[C:9]=4[CH:17]=3)=[CH:19][CH:20]=2)=[CH:39][CH:38]=1
Reactant: O=C(O)c1ccc(-c2cnc3c(c2)N(Cc2cc(Cl)ccc2C(F)(F)F)CCN3)cc1
Reactant: NCc1ccc(-c2ccccc2)cc1
Product: O=C(NCc1ccc(-c2ccccc2)cc1)c1ccc(-c2cnc3c(c2)N(Cc2cc(Cl)ccc2C(F)(F)F)CCN3)cc1

Procedure:
4-{1-[5-chloro-2-(trifluoromethyl)benzyl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl}benzoic acid was reacted with 4-(aminomethyl)biphenyl as in General Procedure 10 to give the title compound. LCMS: m/z=613.00 (M+H+); retention time=1.07 minutes.
Reaction SMILES: [CH:1]1[C:6]([CH:7]=[O:8])=[CH:5][C:4]2[O:9][CH2:10][O:11][C:3]=2[CH:2]=1.O[C:13]1[CH:18]=[CH:17][C:16]([O:19][CH:20]([CH3:22])[CH3:21])=[CH:15][C:14]=1[C:23](=[O:29])[CH2:24][C:25]([O:27][CH3:28])=[O:26].N1CCCCC1.C(O)(=O)C>C1(C)C=CC=CC=1>[O:11]1[C:3]2[CH:2]=[CH:1][C:6]([CH:7]3[CH:24]([C:25]([O:27][CH3:28])=[O:26])[C:23](=[O:29])[C:14]4[C:13](=[CH:18][CH:17]=[C:16]([O:19][CH:20]([CH3:22])[CH3:21])[CH:15]=4)[O:8]3)=[CH:5][C:4]=2[O:9][CH2:10]1
Reactant: COC(=O)CC(=O)c1cc(OC(C)C)ccc1O
Reactant: O=Cc1ccc2c(c1)OCO2
Solvent: Cc1ccccc1
Solvent: CC(=O)O
Solvent: C1CCNCC1
Product: COC(=O)C1C(=O)c2cc(OC(C)C)ccc2OC1c1ccc2c(c1)OCO2
Temperature: 0 °C

Procedure:
A solution of piperonal (182.4 g, 1.22 mol) in toluene (1 L) was heated to reflux in a flask equipped with a Dean Stark dehydration apparatus to which a mixture of methyl 3-(2-hydroxy-5-isopropoxy-phenyl)-3-oxo-propionate (VIII-2) (151 g, 0.61 mol) synthesized by the method described in Reference Example 4, piperidine (1.55 g, 0,018 mol), acetic acid (3.65 g, 0.061 mol) in toluene (1.3 L) was added dropwise over a period of 1 h and the solution was refluxed for another 1 h. After cooling, the reaction mixture was poured into ice water (3 L) and extracted with toluene. The organic layer was washed with water, dried, and concentrated under reduced pressure. The residue was treated with Girard T reagent (143 g) in methanol (500 ml) and toluene (2 L) for 2 h. Brine (3.5 L) was added and the organic layer was separated and the aqueous layer was further extracted with toluene. The combined organic layers were washed with water, dried, and concentrated. The residue was subjected to a chromatographed on silica gel (toluene). During the elution, the products gradually cyclized to give compound (IV-2) (102 g, 44%) as an oil. The oil was clarified a keto-enol tautomeric mixture as shown by NMR. NMR(CDCl3):1.3 l(d, J=6.0), 1.32*(d, J=6.2), 3.67*(s), 3.76(s), 4.02*(d, J=12.0), 4.46(m), 4.53*(m), 5.55*(d, J=12.0), 5.91*(s), 6.00(s),6.10(s), 6.67-7.36(m) (* are signals derived from a major product)
Reaction SMILES: [Al+3].[Cl-].[Cl-].[Cl-].Cl[C:6]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[O:7].[F:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[S:20][CH3:21].C(OCC)(=O)C>C(Cl)(Cl)Cl.CCCCCC>[F:13][C:14]1[CH:19]=[C:18]([C:6](=[O:7])[C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH:17]=[CH:16][C:15]=1[S:20][CH3:21]
Reactant: CSc1ccccc1F
Reactant: CCOC(=O)C(=O)Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: CCCCCC
Solvent: CCOC(C)=O
Solvent: ClC(Cl)Cl
Product: CCOC(=O)C(=O)c1ccc(SC)c(F)c1
Reaction time: 0.62 h
Yield: 64.6 %

Procedure:
To a solution of AlCl3 (9.2 g, 0.06 mol, 2 eq) in chloroform (50 mL) cooled at 0° C., ethyl (chlorocarbonyl)formate (7.3 g, 0.05 mol, 1.6 eq) was added drop wise and the reaction mixture was stirred for 30-45 min at the same temperature. (2-fluorophenyl)(methyl)sulfane (5 g, crude) was added at 0° C. and the reaction mixture was stirred for 4 h at room temperature. Progress of the reaction was monitored by TLC (5% ethyl acetate in n-hexane, Rf˜0.5). On completion of the reaction, crushed ice was added and the mixture was stirred for some time. The organic layer was separated and the aqueous layer was extracted with DCM (2×50 mL). The combined extract was washed with NaHCO3 solution, dried over sodium sulfate and concentrated under reduced pressure to yield ethyl 2-(3-fluoro-4-(methylthio)phenyl)-2-oxoacetate as an yellow colored liquid (5.5 g).
Reaction SMILES: [C:1]1([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([O:20]C(C)(C)C)=[O:19])[CH:13]=2)[C:2]([C:7]([O:9][CH2:10][CH3:11])=[O:8])=[CH:3][CH:4]=[CH:5][CH:6]=1.FC(F)(F)C(O)=O>C(Cl)Cl>[CH2:10]([O:9][C:7]([C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][C:1]=1[C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([OH:20])=[O:19])[CH:13]=1)=[O:8])[CH3:11]
Reactant: CCOC(=O)c1ccccc1-c1cccc(C(=O)OC(C)(C)C)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCOC(=O)c1ccccc1-c1cccc(C(=O)O)c1
Temperature: 25 °C
Reaction time: 5 h
Yield: 100.2 %

Procedure:
To a solution of 3′-tert-butyl 2-ethyl biphenyl-2,3′-dicarboxylate 55 (0.2 g, 0.613 mmol) in DCM (2 ml), trifluoroacetic acid (0.472 ml, 6.13 mmol) was added and stirred at rt for 5 h. It was then concentrated in vacuo, taken up in DCM and concentrated again (2×). The crude compound was then dried overnight on the vacuum pump to afford compound 56 (0.166 g, 100% yield) as a white solid.
Reaction SMILES: [C:1]12([C:11]3[CH:21]=[CH:20][C:14]([O:15][CH2:16][C:17](O)=[O:18])=[CH:13][CH:12]=3)[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.[CH3:22][O:23][C:24](=[O:36])[C:25]1[CH:34]=[C:33]([NH2:35])[CH:32]=[C:27]([C:28]([O:30][CH3:31])=[O:29])[CH:26]=1.Cl.C(N=C=N)C.ON1C2C=CC=CC=2N=N1>CN(C=O)C>[CH3:31][O:30][C:28](=[O:29])[C:27]1[CH:32]=[C:33]([NH:35][C:17](=[O:18])[CH2:16][O:15][C:14]2[CH:13]=[CH:12][C:11]([C:1]34[CH2:10][CH:5]5[CH2:4][CH:3]([CH2:9][CH:7]([CH2:6]5)[CH2:8]3)[CH2:2]4)=[CH:21][CH:20]=2)[CH:34]=[C:25]([C:24]([O:23][CH3:22])=[O:36])[CH:26]=1
Reactant: COC(=O)c1cc(N)cc(C(=O)OC)c1
Reactant: O=C(O)COc1ccc(C23CC4CC(CC(C4)C2)C3)cc1
Agent: CCN=C=N
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: COC(=O)c1cc(NC(=O)COc2ccc(C34CC5CC(CC(C5)C3)C4)cc2)cc(C(=O)OC)c1
Reaction time: 8 h
Yield: 81.9 %

Procedure:
To a mixture of (4-adamantan-1-yl-phenoxy)-acetic acid (143.2 mg, 0.50 mmol), 5-aminoisophthalic acid dimethyl ester (156.9 mg, 0.75 mmol), N-3-dimethylaminopropyl)-N′-ethyl carbodiimide HCl (EDC) (143.8 mg, 0.75 mmol) and 1-hydroxybenzotriazole (HOBt) (101.4 mg, 0.75 mmol) in DMF (5 mL) was added N,N-disopropylethylamine, redistilled (DIPEA) (0.13 mL, 0.75 mmol). The mixture was stirred overnight, and then partitioned between ethyl acetate and 10% HCl. The organic phase washed with brine, dried (MgSO4 anh), and concentrated. The residue was purified by silica gel flash column chromatography (n-Hexane:Ethyl acetate:MeOH=9:3:1) to give 5-[2-(4-Adamantan-1-yl-phenoxy)-acetylamino]-isophthalic acid dimethyl ester as a light yellow solid (195.6 mg, 81.92% yield).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][NH2:7].[C:8](N)(=[O:15])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>>[NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][NH:7][C:8](=[O:15])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: NCCCCCN
Reactant: NC(=O)c1ccccc1
Product: NCCCCCNC(=O)c1ccccc1
Yield: 70.6 %

Procedure:
Under an argon atmosphere, 1,5-diaminopentane (25 g, 0.24 mol) and benzamide (9.9 g, 0.081 mol) were combined and heated at reflux overnight. The reaction mixture was concentrated under vacuum to remove the excess diamine. The residue was distilled at about 210° C. at 12 torr (16×102 pascals) to provide 11.8 g of N-(5-aminopentyl)benzamide as a colorless oil.
Reaction SMILES: N[C@H](C(O)=O)C.[C:7]([C@@H:10]([NH:14][C@H:15]([C:17]([OH:19])=O)[CH3:16])[CH2:11][CH2:12][CH3:13])(=[O:9])[NH2:8].Cl.[CH2:21]([O:29][C:30]([C@@H:32]1[CH:37]2[CH2:38][CH2:39][CH:34]([CH2:35][CH2:36]2)[NH:33]1)=[O:31])[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28]>>[CH2:21]([O:29][C:30]([C@@H:32]1[CH:37]2[CH2:38][CH2:39][CH:34]([CH2:35][CH2:36]2)[N:33]1[C:17](=[O:19])[C@@H:15]([NH:14][C@H:10]([C:7](=[O:9])[NH2:8])[CH2:11][CH2:12][CH3:13])[CH3:16])=[O:31])[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28]
Reactant: CCC[C@H](N[C@@H](C)C(=O)O)C(N)=O
Reactant: CCCCCCCCOC(=O)[C@H]1NC2CCC1CC2
Agent: C[C@H](N)C(=O)O
Agent: Cl
Product: CCCCCCCCOC(=O)[C@@H]1C2CCC(CC2)N1C(=O)[C@H](C)N[C@@H](CCC)C(N)=O
Yield: 21 %

Procedure:
Using the procedure described in Example 1, but replacing (S)-N-(S)-1-(ethoxycarbonyl)butyl]alanine by (S)-N-[(S)-1-carbamoylbutyl]alanine described in stage A of Example 3, and (3S)-3-carbamoyl-2-azobicyclo[2.2.2]-octane by (3S)-2-azabicyclo[2.2.2]octane-3-carboxylic acid n-octyl ester hydrochloride obtained in stage A (neutralized beforehand with triethylamine), the expected product is obtained from the product being purified by chromatography on silica gel (elution solvent: dichloromethane/ethanol, 95:5).