Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:14]2[C:9](=[CH:10][C:11]([Br:28])=[C:12]([CH2:15][C:16]3[C:25]4[C:20](=[CH:21][C:22]([O:26][CH3:27])=[CH:23][CH:24]=4)[CH2:19][CH2:18][N:17]=3)[CH:13]=2)[NH:8][C:7]=1[CH3:29])=[O:5])[CH3:2].N1C=CC=CC=1.[C:36](OC=O)(=[O:41])C(C)(C)C>C(Cl)Cl>[CH2:1]([O:3][C:4]([C:6]1[C:14]2[C:9](=[CH:10][C:11]([Br:28])=[C:12]([CH:15]=[C:16]3[C:25]4[C:20](=[CH:21][C:22]([O:26][CH3:27])=[CH:23][CH:24]=4)[CH2:19][CH2:18][N:17]3[CH:36]=[O:41])[CH:13]=2)[NH:8][C:7]=1[CH3:29])=[O:5])[CH3:2]
Reactant: CC(C)(C)C(=O)OC=O
Reactant: CCOC(=O)c1c(C)[nH]c2cc(Br)c(CC3=NCCc4cc(OC)ccc43)cc12
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCOC(=O)c1c(C)[nH]c2cc(Br)c(C=C3c4ccc(OC)cc4CCN3C=O)cc12
Temperature: 25 °C
Reaction time: 3 h
Yield: 59.8 %

Procedure:
To a solution of 6-bromo-5-(6-methoxy-3,4-dihydro-isoquinoline-1-ylmethyl)-2-methyl-1H-indole-3-carboxylic acid ethyl ester (2.03 g, 4.5 mmol) in CH2Cl2 (50 mL) is added pyridine (2.3 g, 30 mmol) and 3N formic pivalic anhydride (5 mL; 14.5 mmol) at 0° C., and the reaction is stirred at room temperature for 3 hours. CH2Cl2 (50 mL) is then added to the reaction mixture and the organic layer is washed with water (2×50 mL), IN HCl (50 mL), 1N NaOH (50 mL), and brine (50 mL). The solution is dried (Na2SO4), filtered, and concentrated in vacuo to give the desired product (1.3 g, 60%). MS: 483, 485 (M+1)+.
Reaction SMILES: C(O[CH:5]1[CH2:10][CH2:9][CH2:8][CH2:7][O:6]1)C#C.[CH2:11]([Li])[CH2:12][CH2:13][CH3:14]>CCCCCC.O1CCCC1>[CH3:14][C@:13]12[CH2:12][CH2:11][C@H:5]3[C@@H:5]([CH2:11][CH2:12][C:13]4[C@@H:10]3[CH2:9][CH2:8][CH2:7][CH:14]=4)[C@@H:10]1[CH2:9][CH2:8][C@@H:7]2[OH:6]
Reactant: C#CCOC1CCCCO1
Reactant: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: C[C@]12CC[C@H]3[C@@H](CCC4=CCCC[C@@H]43)[C@@H]1CC[C@@H]2O

Procedure:
As described under 3D, 460 mg of 7G is produced from 442 mg of 7F with 1.30 ml of 2-(2-propinyloxy)tetrahydro-2H-pyrane and 5.36 ml of a 15% solution of butyllithium in hexane in 70 ml of tetrahydrofuran.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[C:11]1[C:23]2[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[CH2:16][C:15]=2[C:14]([C:24]#[N:25])=[C:13]([N:26]2[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]2)[CH:12]=1.[H-].[Na+].C1C[O:37]CC1>>[CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[C:11]1[C:23]2[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[C:16](=[O:37])[C:15]=2[C:14]([C:24]#[N:25])=[C:13]([N:26]2[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]2)[CH:12]=1
Reactant: N#Cc1c(N2CCCCC2)cc(-c2ccc3ccccc3c2)c2c1Cc1ccccc1-2
Reactant: C1CCOC1
Agent: [H-]
Agent: [Na+]
Product: N#Cc1c(N2CCCCC2)cc(-c2ccc3ccccc3c2)c2c1C(=O)c1ccccc1-2
Temperature: 2.5 °C

Procedure:
A solution of 4-(naphthalen-2-yl)-2-(piperidin-1-yl)-9H-fluorene-1-carbonitrile (400 mg) in THF was added sodium hydride (32 mg) and was stirred at 0-5° C. for less than five minutes. After completion, the reaction solvent was evaporated under vacuum and the crude solid obtained was quenched with ice water and subsequently neutralized by dilute HCL. The precipitate thus obtained was filtered and purified on a silica gel column using ethyl acetate-hexane as eluent. Light red solid; mp 182-184° C.; ESIMS 415 (M++1); IR (KBr) 2213 (CN), 1695 cm−1 (CO).
Reaction SMILES: [N:1]1([C:7]2[N:8]=[C:9]([CH2:14][C:15]([O-:17])=O)[NH:10][C:11](=[O:13])[CH:12]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[Na+].[NH:19]1[C:27]2[CH:26]=[CH:25][CH:24]=[C:23]([OH:28])[C:22]=2[CH2:21][CH2:20]1.Cl.CN(C)CCCN=C=NCC>N1C=CC=CC=1.CN(C)C=O>[OH:28][C:23]1[CH:24]=[CH:25][CH:26]=[C:27]2[C:22]=1[CH2:21][CH2:20][N:19]2[C:15](=[O:17])[CH2:14][C:9]1[NH:10][C:11](=[O:13])[CH:12]=[C:7]([N:1]2[CH2:2][CH2:3][O:4][CH2:5][CH2:6]2)[N:8]=1
Reactant: Oc1cccc2c1CCN2
Reactant: O=C([O-])Cc1nc(N2CCOCC2)cc(=O)[nH]1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: [Na+]
Solvent: c1ccncc1
Solvent: CN(C)C=O
Product: O=C(Cc1nc(N2CCOCC2)cc(=O)[nH]1)N1CCc2c(O)cccc21
Yield: 57.6 %

Procedure:
The product is prepared according to the procedure described in example 5, using 261 mg of sodium [4-(morpholin-4-yl)-6-oxo-1,6-dihydropyrimidin-2-yl]acetate, 270 mg of 2,3-dihydro-1H-indol-4-ol, and 254 mg of N-[3-(dimethylamino)propyl]-N′-ethylcarbodiimide hydrochloride in a mixture of 0.16 ml of pyridine and 4 ml of N,N-dimethylformamide. 205 mg of 2-[2-(4-hydroxy-2,3-dihydro-1H-indol-1-yl)-2-oxoethyl]-6-(morpholin-4-yl)pyrimidin-4(3H)-one are obtained in the form of a pink solid, the characteristics of which are the following:
Reaction SMILES: [CH3:1][S:2]C1C=C(C=CC=1)N.[CH3:10][S:11][C:12]1[CH:13]=[C:14]([CH:23]=[CH:24][CH:25]=1)[NH:15][CH:16]=[C:17](C)[C:18]([O:20]C)=S.C([O-])(=O)C=C>>[CH3:1][S:2][CH:17]1[C:18](=[O:20])[C:23]2[C:14](=[CH:13][C:12]([S:11][CH3:10])=[CH:25][CH:24]=2)[N:15]=[CH:16]1
Reactant: COC(=S)C(C)=CNc1cccc(SC)c1
Reactant: CSc1cccc(N)c1
Agent: C=CC(=O)[O-]
Product: CSc1ccc2c(c1)N=CC(SC)C2=O

Procedure:
Using the methods described in Example 11 and Example 12, 3-methylthioaniline was converted to methyl 3-(3-methylthioanilino)-2-methylthioacrylate, m.p. 90°-92°. This acrylate was cyclised to give 3,7-bis(methylthio)4-quinolone, m.p. 197°-200°, containing the corresponding 5-methylthio isomer. This product was methylated with dimethyl sulphate in aqueous potassium hydroxide at room temperature to give a mixture of 1-methyl-3,7-bis (methylthio)-4-quinolone and 1-methyl-3,5-bis(methylthio)-4-quinolone. This mixture was separated by high pressure liquid chromatography to give 1-methyl-3,7-bis(methylthio)-4-quinolone, m.p. 154°-155° (from ethanol). Oxidation of this compound with 3-chloroper benzoic acid gave 1-methyl-3-methylsulphinyl-7-methylthio-4-quinolone, m.p. 196°-198° (from ethanol).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:22]2[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][CH:23]=2)[C:9]2[CH:10]=[C:11]3[C:16](=[C:17]([Br:19])[CH:18]=2)[N:15]=[C:14]([OH:20])[CH:13]=[C:12]3[Br:21])=[CH:4][CH:3]=1.[CH3:29]N(C)C=O.C([O-])([O-])=O.[Cs+].[Cs+].CI>O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:22]2[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][CH:23]=2)[C:9]2[CH:10]=[C:11]3[C:16](=[C:17]([Br:19])[CH:18]=2)[N:15]([CH3:29])[C:14](=[O:20])[CH:13]=[C:12]3[Br:21])=[CH:4][CH:3]=1
Reactant: Oc1cc(Br)c2cc(C(c3ccc(Cl)cc3)c3ccc(Cl)cc3)cc(Br)c2n1
Reactant: CN(C)C=O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CI
Product: Cn1c(=O)cc(Br)c2cc(C(c3ccc(Cl)cc3)c3ccc(Cl)cc3)cc(Br)c21
Temperature: 80 °C
Reaction time: 8 h

Procedure:
Into a 25-mL round-bottom flask, was placed 6-[bis(4-chlorophenyl)methyl]-4,8-dibromoquinolin-2-ol (360 mg, 0.67 mmol, 1.00 equip), N,N-dimethylformamide (15 mL), Cs2CO3 (654 mg, 2.01 mmol, 3.00 equip), and CH3I (190 mg, 1.34 mmol, 2.00 equip). The resulting solution was stirred overnight at 80° C. The resulting solution was diluted with water (80 mL). The solids were collected by filtration to yield 6-[bis(4-chlorophenyl)methyl]-4,8-dibromo-1-methyl-1,2-dihydroquinolin-2-one as a yellow solid. LCMS (ES, m/z) 552 [M+H]+
Reaction SMILES: [K+].[C:2]([C@@H:4]([CH2:14][CH:15]([CH3:17])[CH3:16])[CH:5]([C:9]([O:11]CC)=[O:10])[C:6]([O-])=[O:7])#[N:3].[H][H]>[Ni]>[CH2:14]([CH:4]1[CH2:2][NH:3][C:6](=[O:7])[C@H:5]1[C:9]([OH:11])=[O:10])[CH:15]([CH3:17])[CH3:16]
Reactant: CCOC(=O)C(C(=O)[O-])[C@@H](C#N)CC(C)C
Reactant: [H][H]
Agent: [Ni]
Agent: [K+]
Product: CC(C)CC1CNC(=O)[C@H]1C(=O)O

Procedure:
A vessel was charged with an aqueous solution containing (3S)-3-cyano-2-ethoxycarbonyl-5-methyl-hexanoic acid potassium salt (Formula 23, 411 L from Example 2). Raney Nickel (50% aq solution, Sigma-Aldrich) was added to the mixture, and hydrogen gas was introduced into the vessel over a 20 h period to maintain a pressure of 50 psig in the vessel headspace throughout reaction. The hydrogenation reaction was monitored by H2 uptake and HPLC analysis (C18 column, 4.6 mm×150 mm, detection at 200 nm) of the vessel contents. Following reaction, the aqueous mixture was filtered to remove the Raney Ni catalyst. The pH of the concentrated solution was adjusted to 3.0 using 37% HCl (about 14 L). The resulting solution was extracted three times with EtOAc (50% v/v). The combined organic layers were concentrated under vacuum to afford (S)-4-isobutyl-2-oxo-pyrrolidine-3-carboxylic acid (Formula 10). MS ink [M+H]+186.1130. 13C NMR (75 ppm, CDCl3) δ 175.67, 172.23, 54.09, 47.62, 43.69, 37.22, 26.31, 23.34, 22.54. Yield 40-42%; 97% ee.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([CH2:14][C:15]([O:17]CC)=[O:16])=[CH:10][N:9]=2)[CH:5]=[CH:4][N:3]=1.[OH-].[Na+].Cl>C1COCC1.O>[F:1][C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([CH2:14][C:15]([OH:17])=[O:16])=[CH:10][N:9]=2)[CH:5]=[CH:4][N:3]=1
Reactant: CCOC(=O)Cc1ccc(-c2ccnc(F)c2)nc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)Cc1ccc(-c2ccnc(F)c2)nc1
Temperature: 65 °C
Reaction time: 3 h

Procedure:
A mixture of ethyl 2-(2′-fluoro-2,4′-bipyridin-5-yl)acetate 208-2 (93 mg, 0.36 mmol) and NaOH (57 mg, 1.43 mmol) in THF (0.5 mL) and water (0.5 mL) was stirred at 65° C. for 3 hours. After cooled down to room temperature, the mixture was treated with 3N HCl aqueous solution to adjust the pH around 3, and then stirred for 15 minutes. The resulting solution was evaporated to dryness and the remaining solid was extracted with 20% methanol in ethyl acetate. The organic portion was concentrated to give 2-(2′-fluoro-2,4′-bipyridin-5-yl)acetic acid 208-3 as pale white solid. MS m/z 233.1 (M+1).
Reaction SMILES: [NH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH2:2]1.[H-].[Na+].Cl[CH2:14][N:15]1[CH2:19][CH:18]([CH2:20][CH2:21][CH3:22])[CH2:17][C:16]1=[O:23].O>CN(C=O)C>[N:1]1([CH2:14][N:15]2[CH2:19][CH:18]([CH2:20][CH2:21][CH3:22])[CH2:17][C:16]2=[O:23])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH2:2]1
Reactant: CCCC1CC(=O)N(CCl)C1
Reactant: c1ccc2c(c1)CCCN2
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCC1CC(=O)N(CN2CCCc3ccccc32)C1
Temperature: 25 °C
Reaction time: 3 h
Yield: 28 %

Procedure:
To a solution of 1,2,3,4-tetrahydroquinoline x158 (400 mg, 3 mmol, 1 eq) in DMF (7 ml) maintained under argon is added NaH (60% in mineral oil; 120 mg, 3 mmol, 1 eq). The reaction mixture is stirred for three hour at room temperature, then a solution of 1-(chloromethyl)-4-propylpyrrolidin-2-one x63 in DMF (1 M, 3 ml, 3 mmol, 1 eq) is added. The reaction mixture is stirred for 20 hours at the same temperature. Water (70 ml) is added and the resulting mixture is extracted with ethyl acetate (30 ml). The organic phase is washed twice with water and dried over Na2SO4. After filtration and evaporation, the crude product is purified by two consecutive chromatographies on silicagel (CH2Cl2/MeOH gradient, then CH2Cl2). Pure 1-(3,4-dihydroquinolin-1(2H)-ylmethyl)-4-propylpyrrolidin-2-one 295 is obtained as syrup (231 mg).
Reaction SMILES: [CH:1]1[CH:6]=[CH:5][C:4]([NH:7][C:8]2[CH:13]=[CH:12][C:11]([NH2:14])=[CH:10][CH:9]=2)=[CH:3][CH:2]=1.C1(C)C=CC=CC=1.C(=O)([O-])O.[Na+].Cl[CH2:28][C:29]1[CH:36]=[CH:35][C:32]([CH:33]=[CH2:34])=[CH:31][CH:30]=1>O>[NH:7]([C:8]1[CH:13]=[CH:12][C:11]([NH:14][CH2:28][C:29]2[CH:36]=[CH:35][C:32]([CH:33]=[CH2:34])=[CH:31][CH:30]=2)=[CH:10][CH:9]=1)[C:4]1[CH:3]=[CH:2][CH:1]=[CH:6][CH:5]=1
Reactant: Nc1ccc(Nc2ccccc2)cc1
Reactant: C=Cc1ccc(CCl)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Product: C=Cc1ccc(CNc2ccc(Nc3ccccc3)cc2)cc1
Yield: 82.9 %

Procedure:
36.8 g (0.2 mole) of p-aminodiphenylamine was added to 200 ml of toluene, and 16.8 g of sodium hydrogen carbonate and 30 ml of water was added. With stirring, 30.5 g (0.2 mole) of p-chloromethylstyrene was added dropwise to the mixture at 60° C. After the addition, the mixture was stirred at less than 60° C. for 4 hours. The resulting precipitate was separated, and washed with water to afford 49.8 g (yield 83%) of 4-anilino-N-(4-vinylbenzyl)aniline having a melting point of 143° C.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][C:9]([CH3:12])=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].C(N(CC)CC)C.[C:20](Cl)(=[O:25])[CH2:21][CH2:22][CH2:23][CH3:24]>C(Cl)Cl>[CH3:12][C:9]1[CH:10]=[CH:11][C:2]([NH:1][C:20](=[O:25])[CH2:21][CH2:22][CH2:23][CH3:24])=[C:3]([CH:8]=1)[C:4]([O:6][CH3:7])=[O:5]
Reactant: CCCCC(=O)Cl
Reactant: COC(=O)c1cc(C)ccc1N
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCCC(=O)Nc1ccc(C)cc1C(=O)OC
Yield: 104.7 %

Procedure:
To a solution of methyl 2-amino-5-methylbenzoate (8.1 g) and triethylamine (6.0 g) in methylene chloride (50 ml) was added dropwise, while stirring under ice-cooling, valeryl chloride (6.5 g). The reaction was allowed to stir for two hours, then the reaction mixture was washed with an aqueous solution of sodium carbonate, dilute hydrochloric acid and water, followed by drying. The solvent was evaporated to dryness to give a pale brown oil (12.8 g, 99%).
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][CH:8]=[CH:7]2.Br[CH2:14][C:15]([O:17]CC)=[O:16].O>CN(C=O)C>[Cl:3][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[N:9]([CH2:14][C:15]([OH:17])=[O:16])[CH:8]=[CH:7]2.[Cl:3][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][CH:8]=[CH:7]2
Reactant: CCOC(=O)CBr
Agent: Clc1ccc2[nH]ccc2c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: O=C(O)Cn1ccc2cc(Cl)ccc21
Reaction time: 0.5 h

Procedure:
To a suspension of NaH 60% dispersion in oil (1.52 g, 38 mmol) in DMF (50 mL) at r.t. there was added, in portions, 5-chloroindole (5.0 g, 33 mol) and the mixture was stirred for 30 minutes. There was added ethyl bromoacetate (7.44 g, 44 mmol) and the mixture was stirred for a further 5 hours. H2O (200 mL) was added and the mixture was extracted with Et2O. These extracts were washed with H2O, dried over MgSO4 and evaporated to a crude oily residue. Chromatography on silica gel, eluting with 5% EtOAc in toluene, afforded the ethyl ester of the title compound contaminated with some 5-chloroindole. This mixture was dissolved in EtOH (100 mL) and 2.5N aqueous NaOH was added (50 mL). The mixture was stirred at r.t. for 2 hours, then concentrated to a small volume. This residue was partitioned between H2O and Et2O, and by acidification of the aqueous fraction with 6N aqueous HCl, the title compound precipitated. The precipitate was filtered, washed with H2O and air-dried to afford the pure title product as a cream-colored solid.
Reaction SMILES: C[O-].[Na+].[O:4]=[C:5]1[C:13]2[S:12][C:11]([NH:14][C:15](=[O:17])[CH3:16])=[N:10][C:9]=2[CH2:8][CH2:7][CH2:6]1.[CH:18](OCC)=[O:19].Cl>CN(C)C=O.C1C=CC=CC=1>[CH:18]([CH:6]1[CH2:7][CH2:8][C:9]2[N:10]=[C:11]([NH:14][C:15](=[O:17])[CH3:16])[S:12][C:13]=2[C:5]1=[O:4])=[O:19]
Reactant: CC(=O)Nc1nc2c(s1)C(=O)CCC2
Reactant: CCOC=O
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: c1ccccc1
Product: CC(=O)Nc1nc2c(s1)C(=O)C(C=O)CC2
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
20 g (0.37 mol) sodium methoxide are suspended in 50 mL dimethylformamide, a suspension of 21 g (0.1 mol) N-(7-oxo-4,5,6,7-tetrahydro-benzothiazol-2-yl)-acetamide in 100 mL dimethylformamide is added dropwise. The mixture is stirred for 15 minutes, then cooled to 0° C. A mixture of 29.9 mL (0.37 mol) ethyl formate and 60 mL benzene is added dropwise and the reaction mixture is diluted with another 100 mL benzene. A precipitate gradually settles out and stirring is continued at 0° C. for 3.5 hours. The suspension is hydrolysed with 370 mL 1 molar hydrochloric acid, the solid precipitated is suction filtered. The two phases of the mother liquor are separated, the aqueous phase is extracted with dichloromethane. The resulting organic phase is dried and evaporated to dryness. The solid and the residue from the extraction are recrystallised from acetonitrile. Yield: 20 g
Reaction SMILES: [CH3:1][CH:2]([CH3:31])[CH2:3][CH:4]([C:22]1[CH:30]=[CH:29][C:25]([C:26]([OH:28])=O)=[CH:24][N:23]=1)[NH:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][CH:13]=2)=[CH:8][CH:7]=1.C(N1C=CN=C1)(N1C=CN=C1)=O.C(N(CC)C(C)C)(C)C.[NH:53]1[C:57]([CH2:58][NH2:59])=[N:56][N:55]=[N:54]1>CN(C)C=O.[Cl-].[NH4+]>[NH:53]1[C:57]([CH2:58][NH:59][C:26](=[O:28])[C:25]2[CH:29]=[CH:30][C:22]([CH:4]([NH:5][C:6]3[CH:7]=[CH:8][C:9]([C:12]4[CH:17]=[CH:16][C:15]([C:18]([F:20])([F:21])[F:19])=[CH:14][CH:13]=4)=[CH:10][CH:11]=3)[CH2:3][CH:2]([CH3:1])[CH3:31])=[N:23][CH:24]=2)=[N:56][N:55]=[N:54]1
Reactant: NCc1nnn[nH]1
Reactant: CC(C)CC(Nc1ccc(-c2ccc(C(F)(F)F)cc2)cc1)c1ccc(C(=O)O)cn1
Agent: O=C(n1ccnc1)n1ccnc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)CC(Nc1ccc(-c2ccc(C(F)(F)F)cc2)cc1)c1ccc(C(=O)NCc2nnn[nH]2)cn1
Temperature: 80 °C
Reaction time: 8 h
Yield: 13.2 %

Procedure:
To a solution of 6-(3-methyl-1-(4′-(trifluoromethyl)biphenyl-4-ylamino) butyl)nicotinic acid (0.100 g, 0.233 mmol) in N,N-dimethylformamide (3.0 mL) was added 1,1′-carbonyldiimidazole (75.6 mg, 0.466 mmol) and N,N-diisopropylethylamine (181 mg, 1.40 mmol). The reaction was stirred for 30 minutes at 80° C. (1H-tetrazol-5-yl)methanamine (80.2 mg, 0.466 mmol) was added and the reaction continued to stir at 80° C. overnight. The reaction was diluted with saturated ammonium chloride and extracted with ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate, filtered and concentrated. Purification by preparative HPLC (column: Boston Analytics Symmetrix ODS-H 150×30 mm, 5 μm; modifier: formic acid 0.225%; gradient: 10 to 80% MeCN in water) gave N-((1H-tetrazol-5-yl)methyl)-6-(3-methyl-1-(4′-(trifluoromethyl)biphenyl-4-ylamino)butyl)nicotinamide (15.7 mg, 13%) as a light yellow solid. 1H NMR (400 MHz, CD3OD, δ): 9.35 (m, 1H), 8.98 (s, 1H), 8.15 (d, 1H), 7.72 (d, 4H), 7.50 (d, 1H), 7.35 (d, 2H), 6.64 (m, 3H), 4.75 (d, 2H), 4.55 (m, 1H), 1.75 (m, 2H), 1.55 (m, 1H), 0.95 (d, 3H), 0.85 (d, 3H). MS (M+1): 510.4.
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][C@@H:5]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])[CH2:4][C@H:3]1[CH:16]([CH3:18])[CH3:17].[NH:19]([C:24]([O:26][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)=[O:25])[CH2:20][C:21](O)=[O:22].CN1CCOCC1.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>[CH2:27]([O:26][C:24]([NH:19][CH2:20][C:21]([NH:1][C@H:2]1[CH2:7][CH2:6][C@@H:5]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:12])([CH3:13])[CH3:14])[CH2:4][C@H:3]1[CH:16]([CH3:18])[CH3:17])=[O:22])=[O:25])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: O=C(O)CNC(=O)OCc1ccccc1
Reactant: CC(C)[C@@H]1C[C@H](NC(=O)OC(C)(C)C)CC[C@@H]1N
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: CC(C)[C@@H]1C[C@H](NC(=O)OC(C)(C)C)CC[C@@H]1NC(=O)CNC(=O)OCc1ccccc1
Temperature: 0 °C
Reaction time: 12 h
Yield: 58 %

Procedure:
Tert-butyl(1R,3S,4S)-4-amino-3-isopropylcyclohexylcarbamate (780 mg) dissolved in DMF (10 mL) and cooled to 0° C. prior to the addition of N-Cbz-Gly-OH (1.14 g), 4-methylmorpholine (1.2 mL), and BOP (2.42 g). The reaction was stirred for 12 h at rt and then partitioned between EtOAc and 1N HCl solution. The organic phases were combined, washed with saturated NaHCO3 and brine, dried (MgSO4), filtered, and concentrated in vacuo. The residue was purified by flash chromatography to afford tert-butyl (1R,3S,4S)-4-(2-benzyloxycarbonylaminoacetamido)-3-isopropylcyclohexylcarbamate (790 mg). MS found: (M+H)+=448.4.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([Br:23])[C:10]=1[O:11][C:12]1[CH:17]=[CH:16][C:15]([O:18]C)=[C:14]([CH:20]([CH3:22])[CH3:21])[CH:13]=1)[C:5]([OH:7])=O.[N+:24]([C:27]1[CH:28]=[C:29]([S:33]([NH2:36])(=[O:35])=[O:34])[CH:30]=[CH:31][CH:32]=1)([O-:26])=[O:25]>>[Br:23][C:9]1[CH:8]=[C:4]([CH:3]=[C:2]([Br:1])[C:10]=1[O:11][C:12]1[CH:17]=[CH:16][C:15]([OH:18])=[C:14]([CH:20]([CH3:22])[CH3:21])[CH:13]=1)[C:5]([C:28]1[C:27]([N+:24]([O-:26])=[O:25])=[CH:32][CH:31]=[CH:30][C:29]=1[S:33]([NH2:36])(=[O:34])=[O:35])=[O:7]
Reactant: COc1ccc(Oc2c(Br)cc(C(=O)O)cc2Br)cc1C(C)C
Reactant: NS(=O)(=O)c1cccc([N+](=O)[O-])c1
Product: CC(C)c1cc(Oc2c(Br)cc(C(=O)c3c([N+](=O)[O-])cccc3S(N)(=O)=O)cc2Br)ccc1O
Yield: 32.6 %

Procedure:
3,5-Dibromo-4-(4-methoxy-3-isopropylphenoxy)benzoic acid (0.035 mmol) was coupled with 3-nitrobenzenesulphonamide (0.175 mmol) using the method described in Example 58. Purification on HPLC of the residue gave 7 mg (33%) of the title compound.
Reaction SMILES: [OH:1][C:2]([CH3:16])([CH3:15])[CH2:3][O:4][C:5]1[C:12]([CH3:13])=[CH:11][C:8]([C:9]#[N:10])=[CH:7][C:6]=1[CH3:14].N1C=CN=C1.[Si:22](Cl)([C:25]([CH3:28])([CH3:27])[CH3:26])([CH3:24])[CH3:23].O>CN(C=O)C>[Si:22]([O:1][C:2]([CH3:16])([CH3:15])[CH2:3][O:4][C:5]1[C:12]([CH3:13])=[CH:11][C:8]([C:9]#[N:10])=[CH:7][C:6]=1[CH3:14])([C:25]([CH3:28])([CH3:27])[CH3:26])([CH3:24])[CH3:23]
Reactant: Cc1cc(C#N)cc(C)c1OCC(C)(C)O
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: O
Solvent: CN(C)C=O
Product: Cc1cc(C#N)cc(C)c1OCC(C)(C)O[Si](C)(C)C(C)(C)C
Temperature: 25 °C
Reaction time: 72 h
Yield: 50.9 %

Procedure:
To a solution of 4-(2-hydroxy-2-methylpropoxy)-3,5-dimethyl benzonitrile (2.90 g, 13.2 mmol) in anhydrous DMF (20 mL) was added imidazole (2.7 g, 40 mmol) and tert-butyldimethylsilylchloride (2.19 g, 14.6 mmol). The reaction mixture was stirred at room temperature under nitrogen for 3 d. Water (200 mL) was added and the mixture was extracted with ethyl acetate (200 mL). The organic layer was washed with water (2×100 mL) and brine (100 mL), and dried over anhydrous Na2SO4. The solvent was removed under reduced pressure and the crude compound was purified by column chromatography to give 4-[2-(tert-butyldimethylsilanyloxy)-2-methylpropoxy]-3,5-dimethylbenzonitrile (2.24 g, 54%). N-Butyl lithium (6.2 mL, 6.6 mmol, 1.6 M solution in hexanes) was added to a solution of 2,4-dimethoxy-6-N-dimethylbenzamide (0.9 g, 4.3 mmol) in anhydrous THF (10 mL) drop-wise at −10° C. over a period of 10 min under nitrogen. The stirring was continued at 0° C. for 1 h. The reaction mixture was cooled to −50° C. A solution of 4-[2-(tert-butyldimethylsilanyloxy)-2-methylpropoxy]-3,5-dimethylbenzonitrile (1.58 g, 4.73 mmol) in anhydrous THF (5 mL) was quickly added. The cooling bath was removed and the reaction mixture was allowed to warm to room temperature. The stirring was continued at room temperature for 1 h. An aqueous ammonium chloride solution (10 mL) was added followed by ethyl acetate (100 mL). The organic layer was separated, washed with water (10 mL) and dried (Na2SO4). The solvent was removed under reduced pressure and the crude compound was purified by column chromatography (silica gel 230-400 mesh; 0-5% methanol in CH2Cl2 as eluent) to give 3-{4-[2-(tert-butyldimethylsilanyloxy)-2-methylpropoxy]-3,5-dimethylphenyl}-6,8-dimethoxy-2H-isoquinolin-1-one (0.82 g, 37%), as a white solid.
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[C:7]([C:12]([F:15])([F:14])[F:13])[CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([CH2:16][CH:17]([CH3:19])[CH3:18])[C:3]=1[C:20](O)=[O:21].[NH2:23][C:24]1[S:25][CH:26]=[CH:27][N:28]=1.C1(N=C=NC2CCCCC2)CCCCC1>CN(C)C=O>[S:25]1[CH:26]=[CH:27][N:28]=[C:24]1[NH:23][C:20]([C:3]1[C:4]([CH2:16][CH:17]([CH3:19])[CH3:18])=[N:5][C:6]2[C:11]([C:2]=1[OH:1])=[CH:10][CH:9]=[CH:8][C:7]=2[C:12]([F:14])([F:15])[F:13])=[O:21]
Reactant: Nc1nccs1
Reactant: CC(C)Cc1nc2c(C(F)(F)F)cccc2c(O)c1C(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: CN(C)C=O
Product: CC(C)Cc1nc2c(C(F)(F)F)cccc2c(O)c1C(=O)Nc1nccs1
Yield: 31.9 %

Procedure:
Using the procedure of Step F of Example 6, 10.02 g of the product of Step E and 3.2 g of 2-aminothiazole were reacted in the presence of dicyclohexylcarbodiimide in dimethylformamide to obtain 4.03 g of N-(2-thiazolyl)-4-hydroxy-2-(2-methylpropyl)-8-trifluoromethyl-quinoline-3-carboxamide in the form of colorless crystals melting at 170°-171° C after crystallization from isopropanol.