Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C:7]2[CH:12]=[CH:11][C:10]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)=[CH:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl-].[Al+3].[Cl-].[Cl-].[C:23](Cl)(=[O:33])[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32].Cl>C(Cl)Cl>[C:23]([C:4]1[CH:3]=[CH:2][C:1]([C:7]2[CH:12]=[CH:11][C:10]([C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=3)=[CH:9][CH:8]=2)=[CH:6][CH:5]=1)(=[O:33])[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32]
Reactant: CCCCCCCCCC(=O)Cl
Reactant: c1ccc(-c2ccc(-c3ccccc3)cc2)cc1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: CCCCCCCCCC(=O)c1ccc(-c2ccc(-c3ccccc3)cc2)cc1
Temperature: 0 °C
Yield: 71.4 %

Procedure:
A reaction vessel was charged with 5.7 g of p-terphenyl and 40 ml of methylene chloride. To this mixture was added 4 g of anhydrous aluminum chloride with stirring at 0° C. A solution of 5.2 g of decanoyl chloride in 10 ml of methylene chloride was added dropwise. After the dropwise addition, the mixture was stirred for 5 hours. The reaction liquid was poured into diluted hydrochloric acid and the mixture was stirred well. Insolubles were collected by filtration, washed and dried to obtain 6.8 g (71%) of 4-decanoyl-p-terphenyl.
Reaction SMILES: Cl[C:2]1[N:3]=[CH:4][C:5]2[N:11]([CH3:12])[C:10](=[O:13])[CH:9]([CH3:14])[CH2:8][N:7]([CH:15]3[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]3)[C:6]=2[N:21]=1.[CH3:22][O:23][C:24](=[O:34])[C:25]1[CH:30]=[CH:29][C:28]([NH2:31])=[C:27]([O:32][CH3:33])[CH:26]=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>CC(O)C>[CH3:22][O:23][C:24](=[O:34])[C:25]1[CH:30]=[CH:29][C:28]([NH:31][C:2]2[N:3]=[CH:4][C:5]3[N:11]([CH3:12])[C:10](=[O:13])[CH:9]([CH3:14])[CH2:8][N:7]([CH:15]4[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]4)[C:6]=3[N:21]=2)=[C:27]([O:32][CH3:33])[CH:26]=1
Reactant: COC(=O)c1ccc(N)c(OC)c1
Reactant: CC1CN(C2CCCCC2)c2nc(Cl)ncc2N(C)C1=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CC(C)O
Solvent: O
Product: COC(=O)c1ccc(Nc2ncc3c(n2)N(C2CCCCC2)CC(C)C(=O)N3C)c(OC)c1
Yield: 96.5 %

Procedure:
A solution of 0.10 g (0.00032 mole) of (rac)-2-chloro-9-cyclohexyl-5,7-dimethyl-5,7,8,9-tetrahydro-pyrimido[4,5-b][1,4]diazepin-6-one (VII-19), 0.060 g (0.00032 mole) of 4-amino-3-methoxy-benzoic acid methyl ester, 0.10 g (0.00049 mole) of p-toluene-sulfonic acid monohydrate and 4 mL of 2-propanol at 150 degrees for 1 hour in a microwave reactor. The reaction mixture was concentrated under reduced pressure. The residue was diluted with dichloromethane and washed twice with saturated sodium bicarbonate solution. The aqueous phase was extracted with dichloromethane and the combined organic phases were washed with brine, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography, eluting with dichloromethane-methanol (100:0-85:15%), to give 0.14 g of (rac)-4-(9-cyclohexyl-5,7-dimethyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-methoxy-benzoic acid methyl ester as white powder.
Reaction SMILES: I[C:2]1[C:10]2[C:5](=[CH:6][C:7]([C@H:11]3[C@@:13]4([C:21]5[C:16](=[CH:17][CH:18]=[C:19]([O:22][CH3:23])[CH:20]=5)[NH:15][C:14]4=[O:24])[CH2:12]3)=[CH:8][CH:9]=2)[NH:4][N:3]=1.[C:25]([O:28][CH:29]1[CH2:34][CH2:33][N:32]([C:35]2[CH:40]=[CH:39][C:38](B3OC(C)(C)C(C)(C)O3)=[CH:37][CH:36]=2)[CH2:31][CH2:30]1)(=[O:27])[CH3:26]>>[C:25]([O:28][CH:29]1[CH2:30][CH2:31][N:32]([C:35]2[CH:40]=[CH:39][C:38]([C:2]3[C:10]4[C:5](=[CH:6][C:7]([C@H:11]5[C@@:13]6([C:21]7[C:16](=[CH:17][CH:18]=[C:19]([O:22][CH3:23])[CH:20]=7)[NH:15][C:14]6=[O:24])[CH2:12]5)=[CH:8][CH:9]=4)[NH:4][N:3]=3)=[CH:37][CH:36]=2)[CH2:33][CH2:34]1)(=[O:27])[CH3:26]
Reactant: COc1ccc2c(c1)[C@]1(C[C@H]1c1ccc3c(I)n[nH]c3c1)C(=O)N2
Reactant: CC(=O)OC1CCN(c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)CC1
Product: COc1ccc2c(c1)[C@]1(C[C@H]1c1ccc3c(-c4ccc(N5CCC(OC(C)=O)CC5)cc4)n[nH]c3c1)C(=O)N2
Yield: 40.4 %

Procedure:
The title compound was synthesized according to the method described for example A45 except reacting a (1R*,2S*)-2-(3-iodo-1H-indazol-6-yl)-5′-methoxyspiro[cyclopropane-1,3′-indolin]-2′-one (76 mg, 0.18 mmol) with 1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)piperidin-4-yl acetate (67 mg, 0.19 mmol). Crude product was purified by flash chromatography using EtOAc/Hexanes (2:3 to 1:0) to give the title compound as a yellow solid (38 mg, 41%). MS ESI 523.3[M+H]+, calcd for [C31H30N4O4+H]+ 523.23.
Reaction SMILES: CS(Cl)(=O)=O.O[CH:7]([C@H:14]1[CH2:18][N:17]([C@@H:19]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH3:20])[C:16](=[O:27])[CH2:15]1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.C(O)(=O)CC(CC(O)=O)(C(O)=O)O.[N-:41]=[N+:42]=[N-:43].[Na+]>O.ClCCl.C(N(CC)CC)C>[N:41]([CH:7]([C@H:14]1[CH2:18][N:17]([C@@H:19]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH3:20])[C:16](=[O:27])[CH2:15]1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[N+:42]=[N-:43]
Reactant: C[C@H](c1ccccc1)N1C[C@H](C(O)c2ccccc2)CC1=O
Reactant: [N-]=[N+]=[N-]
Agent: CS(=O)(=O)Cl
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O
Product: C[C@H](c1ccccc1)N1C[C@H](C(N=[N+]=[N-])c2ccccc2)CC1=O
Reaction time: 1 h
Yield: 87.5 %

Procedure:
Under ice cooling, triethylamine (0.46 ml) and methanesulfonyl chloride (217 μl, 2.80 mmol) were added to a dichloromethane (10 ml) solution of 4-(R)-[1-hydroxy-1-phenylmethyl]-1-[1-(R)-phenylethyl]-2-pyrrolidone [F1] (738 mg, 2.50 mmol), followed by stirring at the same temperature for 1 hour. To the reaction solution was added 10% citric acid (20 ml) under ice cooling, and the mixture was extracted with chloroform (30 ml×2). After washing with saturated saline (100 ml), the organic layer was dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure, and the residue was dissolved in N,N-dimethylformamide (10 ml). Then, sodium azide (488 mg, 7.50 mmol) was added thereto, followed by stirring at 60° C. for 1.5 hours. After cooling on standing, water (50 ml) was added to the reaction solution and the resulting mixture was extracted with ethyl acetate (70 ml×3). The organic layer was washed with saturated saline (150 ml) and dried over anhydrous sodium sulfate. After removal of the solvent under reduced pressure, the residue was subjected to silica gel column chromatography. Elution with n-hexane/ethyl acetate (3/2) afforded the title compound (701 mg, 87%) as a colorless oil.
Reaction SMILES: [OH-].[Na+].C([O:5][C:6](=[O:21])[CH2:7][C:8]([NH:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[S:17](=[O:20])(=[O:19])[NH2:18])=O)C.Cl>O>[O:19]=[S:17]1(=[O:20])[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[NH:10][C:8]([CH2:7][C:6]([OH:5])=[O:21])=[N:18]1
Reactant: CCOC(=O)CC(=O)Nc1ccccc1S(N)(=O)=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=C(O)CC1=NS(=O)(=O)c2ccccc2N1
Temperature: 110 °C
Yield: 71.7 %

Procedure:
Solid sodium hydroxide (3.48 g, 87 mmol) was dissolved in water to make a saturated solution. The crude N-(2-sulfamoyl-phenyl)-malonamic acid ethyl ester was added into the sodium hydroxide solution. The reaction mixture was heated at 110° C. for 2.5 h, and then was cooled down to 25° C. The reaction mixture was acidified by slowly adding a 12.0M aqueous hydrochloric acid solution (9.67 g, 116 mmol) while cooling in an ice-water bath. The product precipitated and was collected by vacuum filtration. The solid was washed with cold water and dried under high vacuum to afford the crude product, (1,1-dioxo-1,4-dihydro-1λ6-benzo[1,2,4]thiadiazin-3-yl)-acetic acid (5 g, 20.8 mmol, 71.7% over two steps), as a white solid. 1H NMR (400 MHz, DMSO-d6) δ: 3.58 (2H, s), 7.31 (1H, d, J=8.0 Hz), 7.44 (1H, dd, J1=7.8 Hz, J2=7.8 Hz), 7.67 (1H, dd, J1=7.8 Hz, J2=7.8 Hz), 7.79 (1H, d, J=7.9 Hz), 12.18 (1H, bs), 13.03 (1H, bs). LC-MS (ESI) calcd for C9H8N2O4S 240.02, found 241.1 [M+H+].
Reaction SMILES: [C:1]([C:6]1([C:9]([OH:11])=O)[CH2:8][CH2:7]1)([O:3][CH2:4][CH3:5])=[O:2].ClC(OCC)=O.[NH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C(N(CC)CC)C>>[C:19]1([NH:18][C:9]([C:6]2([C:1]([O:3][CH2:4][CH3:5])=[O:2])[CH2:7][CH2:8]2)=[O:11])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: Nc1ccccc1
Reactant: CCOC(=O)C1(C(=O)O)CC1
Agent: CCOC(=O)Cl
Solvent: CCN(CC)CC
Product: CCOC(=O)C1(C(=O)Nc2ccccc2)CC1

Procedure:
1-Carboethoxycyclopropanecarboxylic acid (3.95 grams, 0.025 mole), ethyl chloroformate (2.71 grams, 0.025 mole) and aniline (2.33 grams, 0.025 mole) were reacted sequentially in the presence of triethylamine (2.53 grams, 0.025 mole) in a manner similar to that described for ethyl 1-(4-chloro-2-ethylphenylamlnocarbonyl)cyclopropanecarboxylate in Example XXXIII to give ethyl 1-(phenylaminocarbonyl)cyclopropanecarboxylate which was then hydrolyzed in a manner similar to that described in Example VII to give 2.42 grams (0.01 mole) of 1-(phenylaminocarbonyl)cyclopropanecarboxylic acid having a melting point of 178° C.-181° C. NMR analysis of the product indicated the following:
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([CH:8]([OH:10])[CH3:9])[CH:5]=[C:4]([F:11])[C:3]=1[C:12]1[S:13][CH:14]=[C:15]([C:17]([OH:19])=[O:18])[N:16]=1.FC1C=C(C(O)C)C=C(F)C=1.FC1C=C(C(O)C)C=C(F)C=1B1OC(C)(C)C(C)(C)O1.FC1C=C([C@H](O)C)C=C(F)C=1>>[F:1][C:2]1[CH:7]=[C:6]([C@H:8]([OH:10])[CH3:9])[CH:5]=[C:4]([F:11])[C:3]=1[C:12]1[S:13][CH:14]=[C:15]([C:17]([OH:19])=[O:18])[N:16]=1
Reactant: CC(O)c1cc(F)c(-c2nc(C(=O)O)cs2)c(F)c1
Agent: CC(O)c1cc(F)c(B2OC(C)(C)C(C)(C)O2)c(F)c1
Agent: CC(O)c1cc(F)cc(F)c1
Agent: C[C@@H](O)c1cc(F)cc(F)c1
Product: C[C@@H](O)c1cc(F)c(-c2nc(C(=O)O)cs2)c(F)c1

Procedure:
Following the procedure of Intermediate 109, replacing 1-(3,5-difluorophenyl)ethanol in step 1 (Intermediate 106) with (R)-1-(3,5-difluorophenyl)ethanol (commercial).
Reaction SMILES: [CH3:1][CH2:2][C@H:3]1[C@@H:16]([OH:17])[C@@H:15]2[C@H:10]([CH2:11][CH2:12][C@:13]3([CH3:28])[C@@H:20]([C@@H:21]([CH2:23][CH2:24][C:25]([OH:27])=[O:26])[CH3:22])[CH2:19][CH2:18][C@H:14]32)[C@:9]2([CH3:29])[C@H:4]1[CH2:5][C@H:6]([OH:30])[CH2:7][CH2:8]2.[CH3:31]C=O>>[CH3:31][O:26][C:25](=[O:27])[CH2:24][CH2:23][C@H:21]([C@@H:20]1[C@:13]2([CH3:28])[C@H:14]([C@H:15]3[C@H:10]([CH2:11][CH2:12]2)[C@:9]2([CH3:29])[C@@H:4]([CH2:5][C@H:6]([OH:30])[CH2:7][CH2:8]2)/[C:3](=[CH:2]/[CH3:1])/[C:16]3=[O:17])[CH2:18][CH2:19]1)[CH3:22]
Reactant: CC=O
Reactant: CC[C@H]1[C@@H](O)[C@@H]2[C@H](CC[C@]3(C)[C@@H]([C@H](C)CCC(=O)O)CC[C@@H]23)[C@@]2(C)CC[C@@H](O)C[C@@H]12
Product: C/C=C1\C(=O)[C@@H]2[C@H](CC[C@]3(C)[C@@H]([C@H](C)CCC(=O)OC)CC[C@@H]23)[C@@]2(C)CC[C@@H](O)C[C@@H]12

Procedure:
The present invention relates to a process for preparing obeticholic acid Form 1, comprising the steps of reacting 3α,7-ditrimethylsilyloxy-5β-chol-6-en-24-oic acid methyl ester with CH3CHO to form E- or E/Z-3α-hydroxy-6-ethylidene-7-keto-5β-cholan-24-oic acid methyl ester; reacting E- or E/Z-3α-hydroxy-6-ethylidene-7-keto-5β-cholan-24-oic acid methyl ester with NaOH to form E- or E/Z-3α-hydroxy-6-ethylidene-7-keto-5β-cholan-24-oic acid; reacting E- or E/Z-3α-hydroxy-6-ethylidene-7-keto-5β-cholan-24-oic acid with Pd/C and hydrogen gas to form 3α-hydroxy-6α-ethyl-7-keto-5β-cholan-24-oic acid; reacting 3α-hydroxy-6α-ethyl-7-keto-5β-cholan-24-oic acid with NaBH4 to form crystalline obeticholic acid, and converting crystalline obeticholic acid to obeticholic acid Form 1.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([N:12]2[CH2:17][CH2:16][C:15](=O)[CH2:14][CH2:13]2)[CH:6]=[CH:7][C:8]=1[N+:9]([O-:11])=[O:10].[CH3:19][NH:20][CH3:21].CC(O)=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl.O>[CH3:19][N:20]([CH3:21])[CH:15]1[CH2:16][CH2:17][N:12]([C:5]2[CH:6]=[CH:7][C:8]([N+:9]([O-:11])=[O:10])=[C:3]([O:2][CH3:1])[CH:4]=2)[CH2:13][CH2:14]1
Reactant: CNC
Reactant: COc1cc(N2CCC(=O)CC2)ccc1[N+](=O)[O-]
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: O
Solvent: ClCCCl
Solvent: CC(=O)O
Product: COc1cc(N2CCC(N(C)C)CC2)ccc1[N+](=O)[O-]
Yield: 87.6 %

Procedure:
To a solution of 1-[3-(methyloxy)-4-nitrophenyl]-4-piperidinone (Example 57, step B; 1.41 g, 5.6 mmol) in 50 mL 1,2-dichloroethane was added a solution of dimethylamine (2M in THF, 5.6 mL, 11.2 mmol), HOAc (1.3 mL, 22.4 mmol) and sodium triacetoxyborohydride (1.78 g, 8.4 mmol). When TLC indicated the reaction to be complete, the solution was diluted with H2O and extracted with DCM. The aqueous phase was brought to pH>7 with the addition of saturated NaHCO3. This was extracted twice with DCM and EtOAc. The combined organic phases were dried over MgSO4 and concentrated to give 1.37 g (88%) of the desired product. 1H NMR (400 MHz, DMSO-d6) δ 7.84 (d, J=9.6 Hz, 1H), 6.54 (dd, J=9.4 and 2.2 Hz, 1H), 6.46 (d, J=2.0 Hz, 1H), 3.99 (d, J=13.2 Hz, 1H), 3.87 (s, 3H), 2.96-2.89 (m, 2H), 2.35-2.30 (m, 1H), 2.15 (s, 6H), 1.79 (d, J=11.6 Hz, 2H), 1.42-1.32 (m, 2H).
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[C:15]([Br:16])=[C:10]3[CH2:11][CH2:12][CH2:13][CH2:14][N:9]3[N:8]=2)[N:5]=[CH:4][CH:3]=1.C(OC(=O)C)(=O)C.[N+:24]([O-])([OH:26])=[O:25]>C(O)(=O)C>[NH2:1][C:2]1[N:6]([C:7]2[C:15]([Br:16])=[C:10]3[CH2:11][CH2:12][CH2:13][CH2:14][N:9]3[N:8]=2)[N:5]=[CH:4][C:3]=1[N+:24]([O-:26])=[O:25]
Reactant: Nc1ccnn1-c1nn2c(c1Br)CCCC2
Reactant: O=[N+]([O-])O
Solvent: CC(=O)OC(C)=O
Solvent: CC(=O)O
Product: Nc1c([N+](=O)[O-])cnn1-c1nn2c(c1Br)CCCC2
Temperature: 25 °C
Reaction time: 5 h

Procedure:
3.6 g (12.7 mmol) 5-Amino-1-(3-bromo-4,5,6,7-tetrahydro-pyrazolo[1,5-a]pyridin-2-yl)pyrazole was suspended in 15 ml acetic acid and treated with 1.23 ml (13.0 mmol) acetic anhydride. The mixture was stirred for 5 hours at room temperature. 1.5 ml (15.9 mmol) acetic anhydride was added and then, with ice-bath cooling, 0.66 ml (15.5 mmol) fuming nitric acid was added, dropwise. After stirring for 12 hours at room temperature, the mixture was concentrated. The residue was dissolved in 30 ml ethanol and treated with 11.2 ml concentrated hydrochloric acid. After heating for 3 hours under reflux, the mixture was concentrated and the residue taken up in water and ethyl acetate. It was made basic with 2N aqueous sodium hydroxide and the organic phase separated. The aqueous phase was extracted twice with ethyl acetate. The combined organic phases were washed once with water and once with saturated aqueous sodium chloride. The organic phase was dried and concentrated. The residue was recrystallised from ethyl acetate.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH2:13][C@@H:14]([CH2:19][C:20]([O:22][CH3:23])=[O:21])[C:15]([O:17]C)=O)[C:5]([CH2:11]Cl)=[C:6]2[C:10]=1[NH:9][N:8]=[CH:7]2.C(=O)([O-])[O-].[K+].[K+].[NH2:30][CH2:31][CH:32]1[CH2:34][CH2:33]1>C(#N)C>[CH3:23][O:22][C:20](=[O:21])[CH2:19][C@H:14]1[C:15](=[O:17])[N:30]([CH2:31][CH:32]2[CH2:34][CH2:33]2)[CH2:11][C:5]2[C:6]3[CH:7]=[N:8][NH:9][C:10]=3[C:2]([Br:1])=[CH:3][C:4]=2[CH2:13]1
Reactant: COC(=O)C[C@H](Cc1cc(Br)c2[nH]ncc2c1CCl)C(=O)OC
Reactant: NCC1CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COC(=O)C[C@@H]1Cc2cc(Br)c3[nH]ncc3c2CN(CC2CC2)C1=O
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 64 %

Procedure:
(S)-dimethyl 2-((7-bromo-4-(chloromethyl)-1H-indazol-5-yl)methyl)succinate (630 mg, 1.6 mmol) was dissolved in acetonitrile (5 mL). Potassium carbonate (560 mg, 4.1 mmol) was added to the mixture followed by (aminomethyl)cyclopropane (700 μL, 8.1 mmol). Mixture was heated to reflux and held with stirring for 1.5 hours. Mixture was cooled to room temperature. Mixture was filtered. Filtrate was concentrated by roto-vap. Residue was dissolved in a mixture of toluene (10 mL) and acetic acid (1 mL). Mixture was heated to reflux and held with stirring for 18 hours. Mixture was concentrated by roto-vap. Silica gel chromatography (ethyl acetate-hexanes) afforded the title compound as tan solid in 64% yield. MS m/e (M+H)+=406.0, 408.0.
Reaction SMILES: [CH:1]([C:3]1[CH:8]=[CH:7][N:6]=[C:5]([CH2:9][O:10][C:11]([C@@H:13]2[CH2:18][CH2:17][CH2:16][N:15]([C:19](=[O:51])[C@@H:20]([NH:36][C:37](=[O:50])[C@@H:38]([NH:42][C:43](OC(C)(C)C)=[O:44])[CH:39]([CH3:41])[CH3:40])[CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([O:28][Si:29]([C:32]([CH3:35])([CH3:34])[CH3:33])([CH3:31])[CH3:30])[CH:23]=3)[NH:14]2)=[O:12])[CH:4]=1)=[CH2:2].FC(F)(F)S(O[Si](C)(C)C)(=O)=O.C(N(CC)C(C)C)(C)C>ClCCl>[CH:1]([C:3]1[CH:8]=[CH:7][N:6]=[C:5]([CH2:9][O:10][C:11]([C@@H:13]2[CH2:18][CH2:17][CH2:16][N:15]([C:19](=[O:51])[C@@H:20]([NH:36][C:37](=[O:50])[C@@H:38]([NH:42][CH:43]=[O:44])[CH:39]([CH3:41])[CH3:40])[CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([O:28][Si:29]([C:32]([CH3:33])([CH3:34])[CH3:35])([CH3:31])[CH3:30])[CH:23]=3)[NH:14]2)=[O:12])[CH:4]=1)=[CH2:2]
Reactant: C=Cc1ccnc(COC(=O)[C@@H]2CCCN(C(=O)[C@H](Cc3cccc(O[Si](C)(C)C(C)(C)C)c3)NC(=O)[C@@H](NC(=O)OC(C)(C)C)C(C)C)N2)c1
Agent: C[Si](C)(C)OS(=O)(=O)C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: C=Cc1ccnc(COC(=O)[C@@H]2CCCN(C(=O)[C@H](Cc3cccc(O[Si](C)(C)C(C)(C)C)c3)NC(=O)[C@@H](NC=O)C(C)C)N2)c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 100 %

Procedure:
A solution of (S)-1-{(S)-2-((S)-2-tert-butoxycarbonylamino-3-methyl-butyrylamino)-3-[3-(tert-butyl-dimethyl-silanyloxy)-phenyl]-propionyl}-hexahydro-pyridazine-3-carboxylic acid 4-vinyl-pyridin-2-ylmethyl ester (377 mg, 0.52 mmol) in dichloromethane (10 mL) was stirred at 0° C. under nitrogen. Trimethylsilyl trifluoromethanesulfonate (173 mg, 0.14 mL, 0.78 mmol) was added and the reaction mixture was stirred at 0° C. for 1 hour. N,N-Diisopropylethylamine (268 mg, 0.36 mL, 2.08 mmol) was added and the reaction mixture was warmed to room temperature. The solvent was evaporated to afford (S)-1-[(S)-3-[3-(tert-butyl-dimethyl-silanyloxy)-phenyl]-2-((S)-2-formylamino-3-methyl-butyrylamino)-propionyl]-hexahydro-pyridazine-3-carboxylic acid 4-vinyl-pyridin-2-ylmethyl ester (0.52 mmol), which was used crude in the next step. LCMS (m/z) 624 [M+H], Tr=4.30 min.
Reaction SMILES: N([O-])=O.[Na+].[Br:5][C:6]1[CH:12]=[CH:11][C:9](N)=[C:8]([F:13])[C:7]=1[C:14]([F:17])([F:16])[F:15].[ClH:18]>S(=O)(=O)(O)O.C(O)(=O)C.O.[Cu]Cl>[Br:5][C:6]1[C:7]([C:14]([F:17])([F:16])[F:15])=[C:8]([F:13])[C:9]([Cl:18])=[CH:11][CH:12]=1
Reactant: Cl
Reactant: Nc1ccc(Br)c(C(F)(F)F)c1F
Agent: Cl[Cu]
Agent: O=N[O-]
Agent: O=S(=O)(O)O
Solvent: O
Solvent: CC(=O)O
Product: Fc1c(Cl)ccc(Br)c1C(F)(F)F

Procedure:
A solution of sodium nitrite (7.3 g) in concentrated sulphuric acid was added to a stirred cooled solution of 4-bromo-2-fluoro-3-trifluoromethylaniline (27.4 g) in glacial acetic acid while maintaining the temperature below 15° C. The mixture was stirred at 10°-15° C. for one and a half hours then poured into a mixture of copper (I) chloride (10.5 g) in hydrochloric acid (5M). The mixture was stirred for one and a half hours then diluted with water, extracted with ether, washed with aqueous sodium hydroxide solution (2M), water, dried (MgSO4) and filtered. The filtrate was evaporated to dryness and the residue was distilled to give 6-bromo-3-chloro-2-fluorobenzotrifluoride (8.3 g) as a yellow oil b.p. 44°-45° C./2 mbar.
Reaction SMILES: [NH2:1][C:2](=[O:30])[C:3]([C:5]1[C:13]2[C:8](=[C:9]3[CH2:21][CH2:20][CH2:19][C:10]3=[CH:11][C:12]=2[O:14][CH2:15][C:16]([OH:18])=O)[N:7]([CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:6]=1[CH3:29])=[O:4].C(N(C(C)C)CC)(C)C.[C:40]1([S:46]([NH2:49])(=[O:48])=[O:47])[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1.Cl.CN(C)CCCN=C=NCC.Cl>C(Cl)Cl.C(OCC)(=O)C>[C:40]1([S:46]([NH:49][C:16](=[O:18])[CH2:15][O:14][C:12]2[CH:11]=[C:10]3[C:9]([CH2:21][CH2:20][CH2:19]3)=[C:8]3[C:13]=2[C:5]([C:3](=[O:4])[C:2]([NH2:1])=[O:30])=[C:6]([CH3:29])[N:7]3[CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)(=[O:48])=[O:47])[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1
Reactant: NS(=O)(=O)c1ccccc1
Reactant: Cc1c(C(=O)C(N)=O)c2c(OCC(=O)O)cc3c(c2n1Cc1ccccc1)CCC3
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: Cc1c(C(=O)C(N)=O)c2c(OCC(=O)NS(=O)(=O)c3ccccc3)cc3c(c2n1Cc1ccccc1)CCC3
Temperature: 25 °C
Reaction time: 18 h
Yield: 9.2 %

Procedure:
To a solution of 2-[[3-(2-amino-1,2-dioxoethyl)-2-methyl-1-benzyl-1,6,7,8-tetrahydrocyclopent[g]indol-4-yl]oxy]acetic acid (83 mg, 0.20 mmol) in methylene chloride (3 mL) was added diisopropylethylamine (0.1 mL, 0.6 mmol), 4-N,N-dimethylaminopyridine (24 mg, 0.20 mmol), benzenesulfonamide (31 mg, 0.20 mmol), and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (58 mg, 0.37 mmol). The mixture was stirred at room temperature for 18 h. Additional portions of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (29 mg), diisopropylethylamine (51 μL), and benzenesulfonamide (16 mg) were added and the resulting mixture stirred for 5 h. The mixture was poured into 1 N hydrochloric acid and extracted three times with methylene chloride. The combined methylene chloride extracts were washed once with water, once with saturated aqueous sodium chloride solution, dried (sodium sulfate), filtered, and concentrated in vacuo. Chromatography (silica gel, 7% methanol/93% chloroform) of the residue provided a solid that was slurried in hot ethyl acetate. Collection of the resulting solid via vacuum filtration provided 10 mg (9%) of the title compound as a yellow solid. 1H NMR (CDCl3) δ 10.95 (s, 1H), 7.91 (d, J=7.7 Hz, 2H), 7.55 (t, J=7.4 Hz, 1H), 7.38 (t, J=7.7 Hz, 2H), 7.20-7.35 (m, 4H), 6.91 (d, J=7.0 Hz, 2H), 6.21 (s, 1H), 5.84 (bs, 1H), 5.48 (s, 2H), 4.55 (s, 2H), 2.98 (t, J=7.3 Hz, 2H), 2.71 (t, J=7.7 Hz, 2H), 2.48 (s, 3H), 2.01 (quintet, J=7.7 Hz, 2H).
Reaction SMILES: Br[C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=[O:5].[CH3:10][Si:11]([C:14]#[CH:15])([CH3:13])[CH3:12].C(N(CC)CC)C.C(OCC)(=O)C>O1CCCC1.CCCCCC.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>[CH3:10][Si:11]([CH3:13])([CH3:12])[C:14]#[C:15][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=[O:5]
Reactant: O=Cc1ccccc1Br
Reactant: C#C[Si](C)(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: CCCCCC
Product: C[Si](C)(C)C#Cc1ccccc1C=O
Temperature: 25 °C
Reaction time: 16 h
Yield: 82.3 %

Procedure:
A solution of 2-bromo-benzaldehyde (20.0 g, 108.1 mmol) in anhydrous tetrahydrofuran (200 mL) was degassed with argon for 30 minutes at room temperature. To the above solution was added bis(triphenylphosphine)palladium(II) chloride (Pd(PPh3)2Cl2) (3.79 g, 5.4 mmol) and the mixture was degassed again for an additional 15 minutes. To the reaction mixture were added trimethylsilanyl acetylene (33.97 mL, 216.2 mmol), copper(I) iodide (1.0 g, 5.4 mmol) and triethylamine (29.5 mL, 216.2 mmol), and the mixture was stirred for 16 hours at room temperature. Tetrahydrofuran was removed in vacuo. To the residue was added water (100 mL), and the resulting mixture was extracted with ethyl acetate (3×100 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to give a black colored crude product. Flash chromatography (silica gel, 100-200 mesh, 2-5% ethyl acetate in hexane) afforded 2-trimethylsilanylethynyl-benzaldehyde (18.0 g, 82%) as a brown colored solid. MS (ESI+) cald. for C12H14OSi [(M+H)+] 202, obsd. 203.
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[CH:4]=[C:5]([CH:7]=[CH:8][CH:9]=1)[NH2:6].[N+:12]([C:15]1[CH:23]=[CH:22][C:18]([C:19](O)=[O:20])=[CH:17][CH:16]=1)([O-:14])=[O:13]>>[N+:12]([C:15]1[CH:16]=[CH:17][C:18]([C:19]([NH:6][C:5]2[CH:7]=[CH:8][CH:9]=[C:3]([C:2]([F:10])([F:11])[F:1])[CH:4]=2)=[O:20])=[CH:22][CH:23]=1)([O-:14])=[O:13]
Reactant: O=C(O)c1ccc([N+](=O)[O-])cc1
Reactant: Nc1cccc(C(F)(F)F)c1
Product: O=C(Nc1cccc(C(F)(F)F)c1)c1ccc([N+](=O)[O-])cc1
Yield: 79.9 %

Procedure:
Using 3-trifluoromethylaniline (1.77 g, 11.0 mmol) and 4-nitrobenzoic acid (1.67 g, 10.0 mmol), the procedure of Reference Example 16 was repeated to obtain 2.48 g (80.0%) of the title compound in the form of colorless powder.