Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](O)=[N:7][N:6]=[CH:5]2.P(Cl)(Cl)([Cl:15])=O>>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8]([Cl:15])=[N:7][N:6]=[CH:5]2
Reactant: Oc1nncc2cc(Br)ccc12
Reactant: O=P(Cl)(Cl)Cl
Product: Clc1nncc2cc(Br)ccc12
Temperature: 105 °C
Reaction time: 3 h

Procedure:
A mixture of 6-bromophthalazin-1-ol (10.0 g, 44.4 mmol) in phosphorus oxychloride (104 mL, 1111 mmol) was heated at 105° C. in an oil bath for 3 h. After cooling to RT, the volatiles were removed by vacuum distillation. The residue was diluted with CH2Cl2 and treated with 10% Na2CO3 solution. After stirring for 3 h, the mixture was diluted with 10% Na2CO3 and extracted with CH2Cl2 (3×). The combined organic solution was dried over Na2SO4, filtered through a short pad of silica gel, eluted with EtOAc, and concentrated in vacuo to yield the title compound as a tan solid. MS (ESI, pos. ion) m/z: 242.9, 244.9 (M+1).
Reaction SMILES: C([Li])CCC.[F:6][C:7]1[C:12]([F:13])=[CH:11][CH:10]=[CH:9][C:8]=1[O:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22].[B:23](OC(C)C)([O:28]C(C)C)[O:24]C(C)C>>[F:13][C:12]1[C:7]([F:6])=[C:8]([O:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])[CH:9]=[CH:10][C:11]=1[B:23]([OH:28])[OH:24]
Reactant: CC(C)OB(OC(C)C)OC(C)C
Reactant: CCCCCCCCOc1cccc(F)c1F
Agent: [Li]CCCC
Product: CCCCCCCCOc1ccc(B(O)O)c(F)c1F

Procedure:
Quantities: n-butyllithium (10 cm3, 10.0M in hexanes, 0.1 mol), compound from Example 41 (23.4 g, 0.1 mol) and triisopropyl borate (37.6 g, 0.2 mol). The experimental procedure was as described in Example 28.
Reaction SMILES: [SH:1][C:2]1[CH:11]=[CH:10][CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].Br[CH:13]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[CH:14]([O:17][CH3:18])[O:15][CH3:16].C[O-].[Na+]>CO>[CH3:18][O:17][CH:14]([O:15][CH3:16])[CH:13]([S:1][C:2]1[CH:11]=[CH:10][CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5])[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: COC(OC)C(Br)c1ccccc1
Reactant: COC(=O)c1ccccc1S
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: COC(=O)c1ccccc1SC(c1ccccc1)C(OC)OC
Yield: 70 %

Procedure:
In each case 10 ml of methyl 2-mercaptobenzoate and 2-bromo-1,1-dimethoxy-2-phenylethane are refluxed overnight in 30 ml of methanol, with addition of 10 ml of NaOMe. After working up and purification by chromatography, 70% of viscous oil is obtained.
Reaction SMILES: [S:1](Cl)(=[O:4])(=[O:3])[NH2:2].[O:6]([CH:13]([CH3:16])[CH2:14][OH:15])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1>>[S:1]([O:15][CH2:14][CH:13]([O:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[CH3:16])(=[O:4])(=[O:3])[NH2:2]
Reactant: CC(CO)Oc1ccccc1
Reactant: NS(=O)(=O)Cl
Product: CC(COS(N)(=O)=O)Oc1ccccc1

Procedure:
The title compound was prepared by procedures of Example 33 from sulfamoyl chloride and 2-phenoxypropanol. The oil obtained was further purified as in Example 38 by chromatography and recrystallization to give the title compound as colorless, viscous oil in 35% yield.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][N:11]=1)[C:5]([O:7][CH3:8])=[O:6].[C:12]([Si:14]([CH3:17])([CH3:16])[CH3:15])#[CH:13].C(NC(C)C)(C)C>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.[Cu](I)I.C(#N)C>[CH3:15][Si:14]([C:12]#[C:13][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][N:11]=1)[C:5]([O:7][CH3:8])=[O:6])([CH3:17])[CH3:16]
Reactant: COC(=O)c1ccnc(Br)c1
Reactant: C#C[Si](C)(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: I[Cu]I
Solvent: CC#N
Solvent: CC(C)NC(C)C
Product: COC(=O)c1ccnc(C#C[Si](C)(C)C)c1
Temperature: 10 °C
Reaction time: 0.5 h
Yield: 81.9 %

Procedure:
Methyl 2-bromoisonicotinate (216 g, 1 mol), dry acetonitrile (1.7 L), ethynyl(trimethyl)silane (117 g, 1.2 mol), diisopropylamine (122 g, 1.2 mol), and dichlorobis(triphenylphosphine)palladium (36 g, 0.05 mol) were placed into a well dried three necked flask which was twice purged with a stream of nitrogen. The reaction mixture was stirred for 0.5 hours, cooled to 10° C., and copper iodide (19 g, 0.1 mol) was added under a stream of nitrogen. At 20° C., the reaction mixture became thick and black and an exotherm was observed which was followed by formation of a precipitate. After the addition of copper iodide, the reaction mixture was stirred for further 2 hours at ambient temperature. The precipitated residue was separated by filtration and twice washed with diethyl ether (800 mL). The filtrate was washed with saturated ammonium chloride (2×300 mL) and brine (2×300 mL). After drying over sodium sulfate, the solvent was evaporated. The residue was purified using a silica gel column, eluting with hexane followed by 5% ethyl acetate in petroleum ether to yield 191 g (82%) of methyl 2-((trimethylsilyl)ethynyl)isonicotinate.
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][N:5]([C:8]2[NH:12][C:11]3[CH:13]=[CH:14][CH:15]=[C:16]([C:17]([O:19][CH3:20])=[O:18])[C:10]=3[N:9]=2)[CH2:4][C@H:3]1[O:21][CH3:22].[Cl:23][C:24]1[N:25]=[C:26]([C:31](O)=[O:32])[NH:27][C:28]=1[CH2:29][CH3:30].CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1>CC(N(C)C)=O.C(OCC)(=O)C>[Cl:23][C:24]1[N:25]=[C:26]([C:31]([NH:1][C@H:2]2[CH2:7][CH2:6][N:5]([C:8]3[NH:12][C:11]4[CH:13]=[CH:14][CH:15]=[C:16]([C:17]([O:19][CH3:20])=[O:18])[C:10]=4[N:9]=3)[CH2:4][C@H:3]2[O:21][CH3:22])=[O:32])[NH:27][C:28]=1[CH2:29][CH3:30]
Reactant: CCc1[nH]c(C(=O)O)nc1Cl
Reactant: COC(=O)c1cccc2[nH]c(N3CC[C@H](N)[C@H](OC)C3)nc12
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCOC(C)=O
Solvent: CC(=O)N(C)C
Product: CCc1[nH]c(C(=O)N[C@H]2CCN(c3nc4c(C(=O)OC)cccc4[nH]3)C[C@H]2OC)nc1Cl
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Methyl cis(±)-2-(4-amino-3-methoxypiperidin-1-yl)-1H-benzimidazole-4-carboxylate obtained in Example (187c) (220 mg, 0.75 mmol) and 4-chloro-5-ethyl-1H-imidazole-2-carboxylic acid obtained in Example (1d) (130 mg, 0.75 mmol) were dissolved in DMA (5 ml). WSC hydrochloride (580 mg, 3 mmol) and HOBt (100 mg, 0.75 mmol) were added, and the mixture was stirred at room temperature overnight. The reaction solution was diluted with ethyl acetate, washed with water and brine, and dried over anhydrous sodium sulfate. Following concentration under reduced pressure, the residue was recrystallized from an ethyl acetate/hexane solvent to obtain the title compound as crystals.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](S(C)(=O)=O)[N:5]=[C:4]([NH:12][CH:13]([CH3:15])[CH3:14])[C:3]=1[C:16]1[C:21]([F:22])=[CH:20][CH:19]=[CH:18][C:17]=1[Cl:23].[C-:24]#[N:25].[K+]>C(#N)C>[Cl:1][C:2]1[C:3]([C:16]2[C:21]([F:22])=[CH:20][CH:19]=[CH:18][C:17]=2[Cl:23])=[C:4]([NH:12][CH:13]([CH3:15])[CH3:14])[N:5]=[C:6]([C:24]#[N:25])[N:7]=1
Reactant: CC(C)Nc1nc(S(C)(=O)=O)nc(Cl)c1-c1c(F)cccc1Cl
Reactant: [C-]#N
Agent: [K+]
Solvent: CC#N
Product: CC(C)Nc1nc(C#N)nc(Cl)c1-c1c(F)cccc1Cl
Yield: 71.3 %

Procedure:
A solution of 1.0 g (2.63 mmol) of sulfone 3 and 0.21 g (3.16 mmol) of potassium cyanide in acetonitrile was stirred at 20-25° C. for 5 days. The solvent was distilled off and the residue was digested with MTBE:ethyl acetate [EA] 9:1. Filtration and concentration of the filtrate gave 0.61 g of the title compound of m.p 186-188° C.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[NH:9][C:10](=[O:32])[CH2:11][N:12]1[CH2:17][CH2:16][N:15]([CH2:18][CH:19]([OH:31])[CH2:20]OC2CC3C(=CC=CC=3)C2)[CH2:14][CH2:13]1.[CH:33]1[C:42]2[C:37](=[CH:38][CH:39]=[CH:40][CH:41]=2)[CH:36]=[CH:35][C:34]=1[CH2:43][OH:44]>CC(O)C>[CH3:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([CH3:1])[C:3]=1[NH:9][C:10](=[O:32])[CH2:11][N:12]1[CH2:17][CH2:16][N:15]([CH2:18][CH:19]([OH:31])[CH2:20][O:44][CH2:43][C:34]2[CH:35]=[CH:36][C:37]3[C:42](=[CH:41][CH:40]=[CH:39][CH:38]=3)[CH:33]=2)[CH2:14][CH2:13]1
Reactant: Cc1cccc(C)c1NC(=O)CN1CCN(CC(O)COC2Cc3ccccc3C2)CC1
Reactant: OCc1ccc2ccccc2c1
Solvent: CC(C)O
Product: Cc1cccc(C)c1NC(=O)CN1CCN(CC(O)COCc2ccc3ccccc3c2)CC1

Procedure:
Compound 25 was prepared in a similar manner to compound 7, substituting the commercially available 2-naphthylmethanol for 2-propanol in part C. MS (M+1)=462.41
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12](/[CH:13]=[CH:14]/[C:15]3[CH:16]=[C:17]([C:21](O)=[O:22])[N:18]([CH3:20])[N:19]=3)=[C:11]([CH3:24])[O:10][N:9]=2)=[CH:4][CH:3]=1.[NH:25]1[CH2:30][CH2:29][O:28][CH2:27][CH2:26]1>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:12](/[CH:13]=[CH:14]/[C:15]3[CH:16]=[C:17]([C:21]([N:25]4[CH2:30][CH2:29][O:28][CH2:27][CH2:26]4)=[O:22])[N:18]([CH3:20])[N:19]=3)=[C:11]([CH3:24])[O:10][N:9]=2)=[CH:6][CH:7]=1
Reactant: C1COCCN1
Reactant: Cc1onc(-c2ccc(F)cc2)c1/C=C/c1cc(C(=O)O)n(C)n1
Product: Cc1onc(-c2ccc(F)cc2)c1/C=C/c1cc(C(=O)N2CCOCC2)n(C)n1
Yield: 25 %

Procedure:
As described for example 122, 5-{(E)-2-[3-(4-fluoro-phenyl)-5-methyl-isoxazol-4-yl]-vinyl}-2-methyl-2H-pyrazole-3-carboxylic acid was converted, using morpholine instead of isopropylamine, to the title compound (8.3 mg, 25%) which was obtained as a white solid. MS: m/e=397.2 [M+H]+.
Reaction SMILES: [O:1]1[CH2:27][CH:2]1[CH2:3][O:4][C:5]1[CH:14]=[C:13]2[C:8]([CH:9]([C:17]3[C:26]4[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=4)[CH:20]=[CH:19][CH:18]=3)[CH2:10][C:11]([CH3:16])([CH3:15])[O:12]2)=[CH:7][CH:6]=1.[CH3:28][NH:29][CH3:30]>C(O)C>[C:17]1([CH:9]2[C:8]3[C:13](=[CH:14][C:5]([O:4][CH2:3][CH:2]([OH:1])[CH2:27][N:29]([CH3:30])[CH3:28])=[CH:6][CH:7]=3)[O:12][C:11]([CH3:16])([CH3:15])[CH2:10]2)[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH:20]=[CH:19][CH:18]=1
Reactant: CC1(C)CC(c2cccc3ccccc23)c2ccc(OCC3CO3)cc2O1
Reactant: CNC
Solvent: CCO
Product: CN(C)CC(O)COc1ccc2c(c1)OC(C)(C)CC2c1cccc2ccccc12
Reaction time: 48 h

Procedure:
7-(2,3-Epoxypropoxy)-2,2-dimethyl-4-(1-napthyl)chroman (3.15 g., 0.0088 moles) was dissolved in a solution of dimethylamine in ethanol (20 ml., ~40%) and left to stand at room temperature for 48 hours. Removal of solvent gave the title compound as a dark coloured oil which was converted to the succinate salt. Recrystallization from acetone gave a white solid (1.72g., 49%) m.p. 123-125° C.
Reaction SMILES: [CH:1]([S:3]([C:6]1[CH:7]=[CH:8][C:9]([O:35][CH3:36])=[C:10]([S:12]([NH:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[NH:22][S:23]([C:26]2[S:30][C:29]3[CH:31]=[CH:32][CH:33]=[CH:34][C:28]=3[CH:27]=2)(=[O:25])=[O:24])(=[O:14])=[O:13])[CH:11]=1)(=[O:5])=[O:4])=[CH2:2].C[N:38]1[CH2:43][CH2:42]N[CH2:40][CH2:39]1>C1COCC1.C(Cl)Cl>[CH3:36][O:35][C:9]1[CH:8]=[CH:7][C:6]([S:3]([CH2:1][CH2:2][N:38]2[CH2:43][CH2:42][CH2:40][CH2:39]2)(=[O:4])=[O:5])=[CH:11][C:10]=1[S:12]([NH:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[NH:22][S:23]([C:26]1[S:30][C:29]2[CH:31]=[CH:32][CH:33]=[CH:34][C:28]=2[CH:27]=1)(=[O:25])=[O:24])(=[O:13])=[O:14]
Reactant: CN1CCNCC1
Reactant: C=CS(=O)(=O)c1ccc(OC)c(S(=O)(=O)Nc2ccccc2NS(=O)(=O)c2cc3ccccc3s2)c1
Solvent: C1CCOC1
Solvent: ClCCl
Product: COc1ccc(S(=O)(=O)CCN2CCCC2)cc1S(=O)(=O)Nc1ccccc1NS(=O)(=O)c1cc2ccccc2s1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of benzo[b]thiophene-2-sulfonic acid [2-(5-ethenesulfonyl-2-methoxybenzenesulfonylamino)phenyl] amide (0.2 mmol, prepared as in Example 19) in dry THF (2 mL) was added 0.2 mL of 1-methylpiperazine. The resulting reaction mixture was stirred at room temperature for 1 h. The reaction mixture was diluted with DCM (10 mL) and washed with saturated sodium chloride aqueous solution (25 mL). The organic phase was dried over anhydrous sodium sulfate and concentrated under vacuum. The residue obtained was purified by flash column chromatography eluting with EtOAc then DCM/methanol/AcOH (100:2:1 to 100:10:2) to furnish 118 mg of benzo[b]thiophene-2-sulfonic acid {2-[2-methoxy-5-(2-pyrrolidin-1-yl-ethanesulfonyl)-benzenesulfonylamino]-phenyl}-amide. LC: Tr 0.84 min; MS: 666.0 (M+1)+.
Reaction SMILES: [Li].[CH3:2][O:3][C:4](=[O:9])[CH:5]=[C:6]([CH3:8])[CH3:7].[N+:10]([CH:13]=[C:14]([CH3:17])[CH:15]=[CH2:16])([O-:12])=[O:11]>C1COCC1>[CH3:2][O:3][C:4](=[O:9])[CH:5]=[C:6]([CH3:8])[CH2:7][CH2:16][CH:15]=[C:14]([CH3:17])[CH2:13][N+:10]([O-:12])=[O:11]
Reactant: COC(=O)C=C(C)C
Reactant: C=CC(C)=C[N+](=O)[O-]
Agent: [Li]
Solvent: C1CCOC1
Product: COC(=O)C=C(C)CCC=C(C)C[N+](=O)[O-]

Procedure:
To the lithium salt of methylsenecioate in THF at -70° was added an equimolar amount of 1-nitro-2-methyl-1,3-butadiene. Quenching in ice, followed by ether extraction yielded a crude product which was purified by Kugelrohr distillation and chromatography. The product had the appearance of a yellowish colored liquid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]([CH2:17][CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH2:10][CH2:11][C:12]([O:14]CC)=O)=[CH:5][CH:4]=1.[O-]CC.[Na+]>C1(C)C(C)=CC=CC=1.C(O)C>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([N:9]2[CH2:10][CH2:11][C:12](=[O:14])[CH:18]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH2:17]2)=[CH:7][CH:8]=1
Reactant: CCOC(=O)CCN(CCC(=O)OCC)c1ccc(OC)cc1
Agent: CC[O-]
Agent: [Na+]
Solvent: Cc1ccccc1C
Solvent: CCO
Product: CCOC(=O)C1CN(c2ccc(OC)cc2)CCC1=O
Temperature: 110 °C

Procedure:
32.3 g of diethyl 3,3'-[(4-methoxyphenyl)-imino]dipropionate in 40 ml of xylene were added under argon to a freshly prepared solution of sodium ethoxide in absolute ethanol (2.3 g of sodium in 55 ml of ethanol). The mixture was heated slowly to about 110° C., by which means the ethanol was distilled off. Thereafter, the mixture was heated for a further 2 hours. The mixture was cooled to room temperature and poured on to ice. After neutralization with concentrated hydrochloric acid, the mixture was extracted with ether. The extract was washed three times with water, dried over sodium sulfate and evaporated. The product was chromatographed on silica gel with hexane/ethyl acetate (9:1) and yielded ethyl 1-(p-methoxyphenyl)-4-oxo-3-piperidinecarboxylate as a yellow oil.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[S:10][C:11]2[CH:17]=[C:16]([O:18][S:19]([C:22]3[CH:27]=[CH:26][C:25](F)=[CH:24][CH:23]=3)(=[O:21])=[O:20])[CH:15]=[CH:14][C:12]=2[N:13]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:29]([NH2:33])[CH:30]([CH3:32])[CH3:31].C(=O)([O-])[O-].[Cs+].[Cs+].O>CS(C)=O>[C:1]([O:5][C:6]([NH:8][C:9]1[S:10][C:11]2[CH:17]=[C:16]([O:18][S:19]([C:22]3[CH:27]=[CH:26][C:25]([NH:33][CH2:29][CH:30]([CH3:32])[CH3:31])=[CH:24][CH:23]=3)(=[O:21])=[O:20])[CH:15]=[CH:14][C:12]=2[N:13]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)Nc1nc2ccc(OS(=O)(=O)c3ccc(F)cc3)cc2s1
Reactant: CC(C)CN
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CS(C)=O
Product: CC(C)CNc1ccc(S(=O)(=O)Oc2ccc3nc(NC(=O)OC(C)(C)C)sc3c2)cc1
Yield: 79.4 %

Procedure:
A solution of 4-fluorobenzenesulfonic acid 2-tert-butoxycarbonylamino-benzothiazol-6-yl ester (intermediate 15) (1 g, 2.32 mmol), isobutylamine (517 mg, 7.07 mmol) and cesium carbonate (845 mg, 2.59 mmol) in 12 ml of DMSO is stirred at 80° C. overnight. 60 ml of water are added to the reaction medium. The mixture is extracted with ethyl acetate. The organic phase is washed with water and with saturated sodium chloride solution, dried over magnesium sulfate and then evaporated to dryness. The residue is washed with ethyl ether to give 880 mg of 4-isobutylaminobenzenesulfonic acid 2-tert-butoxycarbonylaminobenzothiazol-6-yl ester (beige-colored solid) in a yield of 80%.
Reaction SMILES: [NH2:1][CH:2]1[C:8](=[O:9])[NH:7][C:6]2[CH:10]=[CH:11][CH:12]=[CH:13][C:5]=2[NH:4][C:3]1=[O:14].[C:15](Cl)(=[O:19])[CH2:16][CH2:17][CH3:18]>>[O:9]=[C:8]1[NH:7][C:6]2[CH:10]=[CH:11][CH:12]=[CH:13][C:5]=2[NH:4][C:3](=[O:14])[CH:2]1[NH:1][C:15](=[O:19])[CH2:16][CH2:17][CH3:18]
Reactant: CCCC(=O)Cl
Reactant: NC1C(=O)Nc2ccccc2NC1=O
Product: CCCC(=O)NC1C(=O)Nc2ccccc2NC1=O
Yield: 76.2 %

Procedure:
Using the method of Example 53, using 3-amino-1H-1,5-benzodiazepine-2,4-(3H, 5H)-dione (4.0 g, 20.9 mmol), butyryl chloride (2.45 g, 23.0 mmol) and overnight at RT gives the title compound (4.16 g, yield 76%); 1H NMR (300 MHz, DMSO-d6): δ 10.70 (s, 2H), 8.21 (d, 1H, J=7.8 Hz), 7.24-7.15 (m, 4H), 4.74 (d, 1H, J=7.5 Hz), 2.24 (t, 2H, J=7.2 Hz), 1.51-1.43 (m, 2H), 0.83 (t, 3H, J=7.5 Hz).
Reaction SMILES: [F:1][C:2]([F:30])([C:16]1[CH:17]=[C:18]2[C:23](=[CH:24][CH:25]=1)[C:22]([CH3:27])([CH3:26])[CH2:21][CH2:20][C:19]2([CH3:29])[CH3:28])[C:3]([NH:5][C:6]1[CH:15]=[CH:14][C:9]([C:10]([O:12]C)=[O:11])=[CH:8][CH:7]=1)=[O:4].O.[OH-].[Na+]>CO>[F:1][C:2]([F:30])([C:16]1[CH:17]=[C:18]2[C:23](=[CH:24][CH:25]=1)[C:22]([CH3:26])([CH3:27])[CH2:21][CH2:20][C:19]2([CH3:29])[CH3:28])[C:3]([NH:5][C:6]1[CH:7]=[CH:8][C:9]([C:10]([OH:12])=[O:11])=[CH:14][CH:15]=1)=[O:4]
Reactant: COC(=O)c1ccc(NC(=O)C(F)(F)c2ccc3c(c2)C(C)(C)CCC3(C)C)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CC1(C)CCC(C)(C)c2cc(C(F)(F)C(=O)Nc3ccc(C(=O)O)cc3)ccc21
Temperature: 70 °C
Reaction time: 1 h
Yield: 35 %

Procedure:
4-[2,2-Difluoro-2-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-naphthalen-2-yl)-acetylamino]-benzoic acid methyl ester 17 (500 mg, 1.20 mmol) was dissolved in methanol (33.5 mL). Water (3.35 mL) and NaOH (270 mg, 4.81 mmol) were successively added at RT. The mixture was stirred at 70° C. for 1 h. The mixture was evaporated in vacuo and dissolved in water (100 ml) and extracted with diethyl ether (2×50 mL). The aqueous layer was acidified by HCl (1M) to about pH=1 and extracted with diethyl ether (2×100 mL), the organic layer was dried over MgSO4, filtered and evaporated. 4-(2,2-Difluoro-2-(1,2,3,4-tetrahydro-1,1,4,4-tetramethylnaphthalen-6-yl)acetamido)benzoic acid 18 was obtained (169 mg, 35% yield) as a beige solid.
Reaction SMILES: C(OC(=O)[NH:7][C@H:8]([CH2:13][N:14]([C:26]1[CH:31]=[CH:30][C:29]([C:32]2[CH:37]=[CH:36][C:35]([CH2:38][CH2:39][CH3:40])=[CH:34][CH:33]=2)=[CH:28][CH:27]=1)[C:15]([CH:17]1[CH2:19][CH:18]1[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=1)=[O:16])[C@@H:9]([CH3:12])[CH2:10][CH3:11])(C)(C)C.ClCCl.Cl>O1CCOCC1>[NH2:7][C@@H:8]([C@@H:9]([CH3:12])[CH2:10][CH3:11])[CH2:13][N:14]([C:26]1[CH:27]=[CH:28][C:29]([C:32]2[CH:37]=[CH:36][C:35]([CH2:38][CH2:39][CH3:40])=[CH:34][CH:33]=2)=[CH:30][CH:31]=1)[C:15]([C@@H:17]1[CH2:19][C@H:18]1[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=1)=[O:16]
Reactant: CCCc1ccc(-c2ccc(N(C[C@@H](NC(=O)OC(C)(C)C)[C@@H](C)CC)C(=O)C3CC3c3ccccn3)cc2)cc1
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: CCCc1ccc(-c2ccc(N(C[C@@H](N)[C@@H](C)CC)C(=O)[C@@H]3C[C@H]3c3ccccn3)cc2)cc1
Temperature: 25 °C
Yield: 99.3 %

Procedure:
A solution of ((1S,2S)-1-{[(4′-propyl-biphenyl-4-yl)-(2-pyridin-2-yl-cyclopropanecarbonyl)-amino]-methyl}-2-methyl-butyl)-carbamic acid tert-butyl ester (48 mg, 0.084 mmol) and dichloromethane (4 mL) was treated with a solution of HCl in dioxane (4 N, 0.5 mL) and the resulting reaction mixture was maintained at room temperature for 12 h. The reaction was then concentrated to dryness to afford (1R,2R)-2-pyridin-2-yl-cyclopropanecarboxylic acid ((2S,3S)-2-amino-3-methyl-pentyl)-(4′-propyl-biphenyl-4-yl)-amide (38 mg, 95% yield) as a white solid: 1H NMR (400 MHz, MeOD) δ 8.31 (d, J=5.1 Hz, 1H), 7.86-7.95 (m, 1H), 7.57 (d, J=8.1 Hz, 2H), 7.33-7.43 (m, 5H), 7.30 (d, J=8.1 Hz, 1H), 7.17 (d, J=8.1 Hz, 2H), 4.21 (dd, J=14.9, 9.1 Hz, 1H), 3.65 (d, J=14.9 Hz, 1H), 3.23-3.29 (m, 1H), 2.64-2.73 (m, 1H), 2.53 (t, J=7.6 Hz, 2H), 1.96-2.05 (m, 1H), 1.70-1.78 (m, 1H), 1.61-1.70 (m, 1H), 1.57 (dd, J=15.2, 7.6 Hz, 2H), 1.43-1.51 (m, 1H), 1.22-1.36 (m, 1H), 1.05-1.17 (m, 1H), 0.82-0.90 (m, 6H), 0.75 (t, J=7.3 Hz, 3H); LRMS (ESI) m/e 456.3 [(M+H)+, calcd for C30H38N3O 456.3].
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[C:3]1[CH:4]=[C:5]([NH:9][C:10]2[CH:18]=[CH:17][CH:16]=[CH:15][C:11]=2[C:12]([OH:14])=[O:13])[CH:6]=[CH:7][CH:8]=1.S(=O)(=O)(O)O.[CH3:26]O>>[F:1][C:2]([F:19])([F:20])[C:3]1[CH:4]=[C:5]([NH:9][C:10]2[CH:18]=[CH:17][CH:16]=[CH:15][C:11]=2[C:12]([O:14][CH3:26])=[O:13])[CH:6]=[CH:7][CH:8]=1
Reactant: CO
Reactant: O=C(O)c1ccccc1Nc1cccc(C(F)(F)F)c1
Agent: O=S(=O)(O)O
Product: COC(=O)c1ccccc1Nc1cccc(C(F)(F)F)c1
Yield: 71 %

Procedure:
Reaction of 2-[[3-(trifluoromethyl)phenyl]amino]benzoic acid with methanol and sulfuric acid according to the procedure of Example 26 gives a 71% yield of 2-[[3-(trifluoromethyl)phenyl]amino]benzoic acid, methyl ester as a colorless oil.
Reaction SMILES: [C:1]([OH:7])([C:3]([F:6])([F:5])[F:4])=[O:2].C(OC([N:15]1[CH2:20][CH2:19][N:18]([C:21](=[O:38])[CH2:22][NH:23][C:24]([C:26]2[CH:31]=[CH:30][C:29]([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)=[CH:28][CH:27]=2)=[O:25])[CH2:17][CH2:16]1)=O)(C)(C)C>C(Cl)Cl>[OH:7][C:1]([C:3]([F:6])([F:5])[F:4])=[O:2].[O:38]=[C:21]([N:18]1[CH2:19][CH2:20][NH:15][CH2:16][CH2:17]1)[CH2:22][NH:23][C:24]([C:26]1[CH:27]=[CH:28][C:29]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)=[CH:30][CH:31]=1)=[O:25]
Reactant: CC(C)(C)OC(=O)N1CCN(C(=O)CNC(=O)c2ccc(-c3ccccc3)cc2)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(NCC(=O)N1CCNCC1)c1ccc(-c2ccccc2)cc1
Reaction time: 3 h
Yield: 94.8 %

Procedure:
TFA (3.6 mL) was added to a stirred solution of 4-{2-[(biphenyl-4-carbonyl)-amino]-acetyl}-piperazine-1-carboxylicacid tert-butyl ester (1.7 g, 4.01 mmol) in DCM (18 mL) at 0-4° C. and the resulting mixture was stirred at this temperature for 3 hrs. The reaction mixture was concentrated to afford 1.67 g (94.8% yield) of biphenyl-4-carboxylic acid (2-oxo-2-piperazin-1-yl-ethyl)-amide TFA salt. LC-MS purity: 85.4%,
Reaction SMILES: [H-].[Na+].[C:3]([O:7][C:8](=[O:16])/[CH:9]=[CH:10]/[C:11]1[CH:15]=[CH:14][NH:13][CH:12]=1)([CH3:6])([CH3:5])[CH3:4].[Br:17][CH2:18][C:19]1[CH:24]=[CH:23][C:22]([S:25](Cl)(=[O:27])=[O:26])=[CH:21][CH:20]=1.O>C1COCC1>[C:3]([O:7][C:8](=[O:16])/[CH:9]=[CH:10]/[C:11]1[CH:15]=[CH:14][N:13]([S:25]([C:22]2[CH:21]=[CH:20][C:19]([CH2:18][Br:17])=[CH:24][CH:23]=2)(=[O:26])=[O:27])[CH:12]=1)([CH3:6])([CH3:4])[CH3:5]
Reactant: CC(C)(C)OC(=O)/C=C/c1cc[nH]c1
Reactant: O=S(=O)(Cl)c1ccc(CBr)cc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)/C=C/c1ccn(S(=O)(=O)c2ccc(CBr)cc2)c1
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
4.25 g of sodium hydride (60% strength) are suspended in 300 ml of THF under nitrogen at −30° C. 9.78 g of (E)-3-(1H-pyrrol-3-yl)-acrylic acid tert-butyl ester (compound D1) are added to the suspension and warmed slowly to room temperature during 55 min. Afterwards it is recooled to −30° C. and it is added 13.98 g of 4-(bromomethyl)-benzenesulphonylchloride and stirred for 45 min. Then it is warmed to room temperature and stirred for 2 hour. After cooling to 0-5° C. water is added. Then the mixture is extracted with ethyl acetate and the organic phase is dried over sodium sulfate. The organic phase is evaporated under vacuum. The crude product is purified by silica gel flash chromatography using a gradient of hexane and ethyl acetate from 9:1-7:1.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]=[C:9]=[O:10].[CH2:11]([O:13][C:14]([C:16]1([CH2:21][O:22][C:23]2[CH:28]=[CH:27][C:26]([C:29]3[CH:34]=[CH:33][C:32]([F:35])=[CH:31][CH:30]=3)=[CH:25][CH:24]=2)[CH2:20][CH2:19][NH:18][CH2:17]1)=[O:15])[CH3:12]>>[CH2:11]([O:13][C:14]([C:16]1([CH2:21][O:22][C:23]2[CH:28]=[CH:27][C:26]([C:29]3[CH:30]=[CH:31][C:32]([F:35])=[CH:33][CH:34]=3)=[CH:25][CH:24]=2)[CH2:20][CH2:19][N:18]([C:9](=[O:10])[NH:8][C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[F:1])[CH2:17]1)=[O:15])[CH3:12]
Reactant: CCOC(=O)C1(COc2ccc(-c3ccc(F)cc3)cc2)CCNC1
Reactant: O=C=Nc1ccccc1F
Product: CCOC(=O)C1(COc2ccc(-c3ccc(F)cc3)cc2)CCN(C(=O)Nc2ccccc2F)C1

Procedure:
The title compound was prepared according to the method described for Preparation 71 using 2-fluoro phenyl isocyanate and 3-(4′-fluoro-biphenyl-4-yloxymethyl)-pyrrolidine-3-carboxylic acid ethyl ester (Preparation 65) to afford the racemate as a colourless liquid (230 mg, 82%)