Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(O)(C(F)(F)F)=O.[CH:8]([C:12]1[N:17]=[C:16]2[O:18][C:19]([C:25]3[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=3)=[C:20]([C:21](=[O:24])[NH:22][CH3:23])[C:15]2=[CH:14][C:13]=1[C:32]1[CH:33]=[C:34]([CH:42]=[CH:43][CH:44]=1)[C:35]([O:37]C(C)(C)C)=[O:36])([CH2:10][CH3:11])[CH3:9]>C(Cl)Cl>[CH:8]([C:12]1[N:17]=[C:16]2[O:18][C:19]([C:25]3[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=3)=[C:20]([C:21](=[O:24])[NH:22][CH3:23])[C:15]2=[CH:14][C:13]=1[C:32]1[CH:33]=[C:34]([CH:42]=[CH:43][CH:44]=1)[C:35]([OH:37])=[O:36])([CH2:10][CH3:11])[CH3:9]
Reactant: CCC(C)c1nc2oc(-c3ccc(F)cc3)c(C(=O)NC)c2cc1-c1cccc(C(=O)OC(C)(C)C)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCC(C)c1nc2oc(-c3ccc(F)cc3)c(C(=O)NC)c2cc1-c1cccc(C(=O)O)c1
Reaction time: 2 h
Yield: 93.6 %

Procedure:
TFA (0.90 ml, 12 mmol) was added to a stirring solution of tert-butyl 3-(6-(sec-butyl)-2-(4-fluorophenyl)-3-(methylcarbamoyl)furo[2,3-b]pyridin-5-yl)benzoate (118 mg, 0.235 mmol) in DCM (2.3 ml) at rt. The reaction was allowed to stir for 2 h and then was concentrated to dryness azeotroping with toluene 2×. The resulting solid was triturated with DCM to give 3-(6-(sec-butyl)-2-(4-fluorophenyl)-3-(methylcarbamoyl)furo[2,3-b]pyridin-5-yl)benzoic acid (98 mg, 0.22 mmol, 93% yield) consistent by LCMS. LC-MS retention time: 1.84 min; m/z (MH+): 447. LC data was recorded on a Shimadzu LC-10AS liquid chromatograph equipped with a Phenomenex-Luna 3u C18 2.0×30 mm column using a SPD-10AV UV-Vis detector at a detector wave length of 220 nM. The elution conditions employed a flow rate of 1 mL/min, a gradient of 100% solvent A/0% solvent B to 0% solvent A/100% solvent B, a gradient time of 2 min, a hold time of 1 min, and an analysis time of 3 min where solvent A was 10% acetonitrile/90% H2O/0.1% trifluoroacetic acid and solvent B was 10% H2O/90% acetonitrile/0.1% trifluoroacetic acid. MS data was determined using a Micromass Platform for LC in electrospray mode.
Reaction SMILES: Br[C:2]1[C:3]([C:14]2[S:15][CH:16]=[C:17]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[N:18]=2)=[CH:4][C:5]([NH:8][C:9]([NH:11][CH2:12][CH3:13])=[O:10])=[N:6][CH:7]=1.CC1(C)C(C)(C)OB([C:33]2[CH:34]=[N:35][CH:36]=[C:37]([CH:43]=2)[C:38]([O:40][CH2:41][CH3:42])=[O:39])O1.C(=O)([O-])[O-].[Cs+].[Cs+]>>[CH2:12]([NH:11][C:9]([NH:8][C:5]1[N:6]=[CH:7][C:2]([C:33]2[CH:34]=[N:35][CH:36]=[C:37]([C:38]([O:40][CH2:41][CH3:42])=[O:39])[CH:43]=2)=[C:3]([C:14]2[S:15][CH:16]=[C:17]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[N:18]=2)[CH:4]=1)=[O:10])[CH3:13]
Reactant: CCOC(=O)c1cncc(B2OC(C)(C)C(C)(C)O2)c1
Reactant: CCNC(=O)Nc1cc(-c2nc(-c3ccccc3)cs2)c(Br)cn1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: CCNC(=O)Nc1cc(-c2nc(-c3ccccc3)cs2)c(-c2cncc(C(=O)OCC)c2)cn1
Temperature: 100 °C
Yield: 100.6 %

Procedure:
N-[5-bromo-4-(4-phenyl-1,3-thiazol-2-yl)pyridin-2-yl]-N′-ethylurea (Intermediate 69, 0.17 g, 0.42 mmol), ethyl 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)nicotinate (0.14 g, 0.51 mmol), tetrakis triphenyl phosphine palladium (0.024 g, 0.02 mmol), and cesium carbonate (0.165 g, 0.51 mmol) were combined in a microwave vial and degassed with nitrogen. 1,4-dioxane:water (4:1, 2.5 mL) was added to the mixture and the reaction mixture was heated to 100° C. for 60 minutes. The reaction mixture was partitioned between water and ethyl acetate and the layers separated. The organic layer was washed with saturated NaHCO3, water, and brine, then dried over magnesium sulfate. The organic layer was concentrated to form a precipitate, and the resulting solids were filtered and then washed with acetonitrile followed by chloroform to yield 200 mg of the title compound as an off-white solid. LC/MS (ES+)[(M+H)+]: 474 for C25H23N5O3S. 1H NMR (300 MHz, CHCl3): 1.28 (t, 3H), 1.39 (t, 3H), 3.44-3.49 (m, 2H), 4.41 (q, 2H), 7.31-7.39 (m, 2H), 7.52 (s, 1H), 7.62 (d, 2H), 8.17 (s, 1H), 8.28 (t, 1H), 8.32 (t, 1H), 8.4 (s, 1H), 8.71 (d, 1H), 8.73 (d, 1H), 9.23 (d, 1H), 9.27 (s, 1H).
Reaction SMILES: II.Br[CH2:4][CH2:5][CH:6]([O:9][CH3:10])[O:7][CH3:8].[Br:11][C:12]1[CH:13]=[C:14]([CH:21]=[CH:22][N:23]=1)[C:15](N(OC)C)=[O:16].[NH4+].[Cl-]>C1COCC1.O>[Br:11][C:12]1[CH:13]=[C:14]([C:15](=[O:16])[CH2:4][CH2:5][CH:6]([O:9][CH3:10])[O:7][CH3:8])[CH:21]=[CH:22][N:23]=1
Reactant: COC(CCBr)OC
Reactant: CON(C)C(=O)c1ccnc(Br)c1
Agent: II
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: O
Product: COC(CCC(=O)c1ccnc(Br)c1)OC
Temperature: 25 °C
Reaction time: 2 h
Yield: 82.3 %

Procedure:
To a suspension of Mg (3.67 g, 153.01 mmol) in THF (40 mL) is added cat. Iodine, followed by a solution of 3-bromo-1,1-dimethoxy-propane (21.47 g, 117.30 mmol) in THF (40 mL). The mixture is stirred at room temperature for 2 h. Then the fresh prepared Grignard reagent is cooled down in an ice bath, and added to a solution of 2-bromo-N-methoxy-N-methyl-isonicotinamide (12.50 g, 51.00 mmol) in THF (50 mL) at 0° C. The mixture is warmed up to room temperature and stirred at this temperature for 2 h. Then the reaction mixture is cooled in an ice bath, sat. NH4Cl and water are added and the mixture is extracted with EtOAc. The combined organic layers are washed with brine, dried over Na2SO4, filtered and concentrated down. The crude product is purified by flash chromatography on silica gel (EtOAc/Hexane: 10%) to give 1-(2-Bromo-pyridin-4-yl)-4,4-dimethyoxy-butane-1-one (12.1 g, 82%) as a pale yellow oil. M/Z=288.14
Reaction SMILES: [C:1]1([CH:7]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[N:8]2[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][NH:16][C:17]3[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:19][C:18]=3[N+:27]([O-])=O)[CH2:10][CH2:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H][H]>[Ni].CO>[C:30]1([CH:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[N:8]2[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][NH:16][C:17]3[C:18]([NH2:27])=[CH:19][C:20]([C:23]([F:26])([F:24])[F:25])=[CH:21][CH:22]=3)[CH2:10][CH2:9]2)[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1
Reactant: O=[N+]([O-])c1cc(C(F)(F)F)ccc1NCCN1CCN(C(c2ccccc2)c2ccccc2)CC1
Reactant: [H][H]
Agent: [Ni]
Solvent: CO
Product: Nc1cc(C(F)(F)F)ccc1NCCN1CCN(C(c2ccccc2)c2ccccc2)CC1

Procedure:
A mixture of 7.5 parts of 4-(diphenylmethyl)-N-[2-nitro-4-(trifluoromethyl)phenyl]-1-piperazineethanamine in 200 parts of methanol is hydrogenated at normal pressure and at room temperature with 5 parts of Ra/Ni. After the calculated amount of hydrogen is taken up, the catalyst is filtered off and the filtrate is evaporated, yielding N1 -{2-[4-(diphenylmethyl)-1-piperazinyl]ethyl}-4-(trifluoromethyl)-1,2-benzenediamine as an oily residue.
Reaction SMILES: [N:1]([CH:4]1[CH2:9][C:8]([CH3:11])([CH3:10])[CH2:7][C:6]([CH3:12])=[CH:5]1)=[N+]=[N-].[ClH:13].C(C1(N)CC(C)(C)CC(C)(C)C1)C=C>>[ClH:13].[CH3:12][C:6]1[CH2:7][C:8]([CH3:11])([CH3:10])[CH2:9][CH:4]([NH2:1])[CH:5]=1
Reactant: CC1=CC(N=[N+]=[N-])CC(C)(C)C1
Agent: C=CCC1(N)CC(C)(C)CC(C)(C)C1
Agent: Cl
Product: CC1=CC(N)CC(C)(C)C1
Yield: 57 %

Procedure:
Prepared from azide 34 according to the procedure for compound 11 (Example 3, c). Amine hydrochloride 35 obtained as a colorless solid in 57% yield. 1H NMR (CDCl3, TMS): 0.89 and 1.03 (total 6H, both s, 5,5-CH3); 1.25-2.15 (4H, m, 4,6-CH2); 1.72 (3H, s, 3-CH3); 3.88 (1H, m, 1-CH); 5.41 (1H, s, C═CH) and 8.40 ppm (3H, br s, NH3+).
Reaction SMILES: Cl[CH:2]1[CH2:7][CH2:6][CH:5]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[C:4]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:3]1.C(O[K])(C)(C)C.O.Cl>C(O)(C)(C)C>[C:13]1([C:4]2[CH:3]=[CH:2][CH2:7][CH2:6][C:5]=2[C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: CCOC(=O)C1CCC(Cl)C=C1c1ccccc1
Agent: CC(C)(C)O[K]
Agent: Cl
Solvent: O
Solvent: CC(C)(C)O
Product: CCOC(=O)C1=C(c2ccccc2)C=CCC1
Reaction time: 1 h
Yield: 75.3 %

Procedure:
To a stirred solution of ethyl 4-chloro-2-phenylcyclohex-2-enecarboxylate (110 mg, 0.407 mmol) in tert-BuOH(2 ml), tert-BuOK(93 mg, 0.832 mmol) was added by portion on a water bath. After stirring for 1hr. at room temperature, water was added to the reaction mixture, and it was acidified with dil. HCl aq. and extracted with AcOEt. The organic layer was washed with brine and dried over MgSO4. After removal of the solvent, the residue was purified by column chromatography on silica gel with n-hexane-AcOEt to afford 70 mg of ethyl 2-phenylcyclohexa-1,3-dienecarboxylate (y=74.0%) as a pale yellow oil. 1H-NMR(ppm, 300 MHz, CDCl3) δ 7.14-7.39(5H, m), 6.03-6.24(2H, m), 3.94(2H, q, J=6.9 Hz), 2.55-2.65(2H, m), 2.26-2.35(2H, m), 0.90(3H, t, J=6.9 Hz).
Reaction SMILES: [CH3:1][O:2][CH2:3][C@@H:4]([NH:6][C:7]([C:9]1[C:17]2[C:12](=[N:13][CH:14]=[C:15]([C:18]3[C:26]4[C:21](=[CH:22][C:23]([F:27])=[CH:24][CH:25]=4)[NH:20][N:19]=3)[N:16]=2)[N:11]([CH2:28][O:29][CH2:30][CH2:31][Si:32]([CH3:35])([CH3:34])[CH3:33])[CH:10]=1)=[O:8])[CH3:5].[H-].[Na+].Cl.Cl[CH2:40][C:41]1[CH:42]=[CH:43][C:44]([N:47]2[CH2:52][CH2:51][O:50][CH2:49][CH2:48]2)=[N:45][CH:46]=1>CN(C=O)C>[CH3:1][O:2][CH2:3][C@@H:4]([NH:6][C:7]([C:9]1[C:17]2[C:12](=[N:13][CH:14]=[C:15]([C:18]3[C:26]4[C:21](=[CH:22][C:23]([F:27])=[CH:24][CH:25]=4)[N:20]([CH2:40][C:41]4[CH:46]=[N:45][C:44]([N:47]5[CH2:52][CH2:51][O:50][CH2:49][CH2:48]5)=[CH:43][CH:42]=4)[N:19]=3)[N:16]=2)[N:11]([CH2:28][O:29][CH2:30][CH2:31][Si:32]([CH3:33])([CH3:35])[CH3:34])[CH:10]=1)=[O:8])[CH3:5]
Reactant: ClCc1ccc(N2CCOCC2)nc1
Reactant: COC[C@H](C)NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(-c3n[nH]c4cc(F)ccc34)nc12
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC[C@H](C)NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(-c3nn(Cc4ccc(N5CCOCC5)nc4)c4cc(F)ccc34)nc12
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 53.7 %

Procedure:
2-(6-Fluoro-1H-indazol-3-yl)-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid ((S)-2-methoxy-1-methyl-ethyl)-amide (80 mg, 0.16 mmol) was combined with DMF (8 mL) at 0° C. to give a yellow solution. Sodium hydride (60% in mineral oil, 19 mg, 0.48 mmol) was added and the reaction was stirred at 0° C. for 10 min. 4-(5-(Chloromethyl)pyridin-2-yl)morpholine hydrochloride (60 mg, 0.24 mmol) was added and the reaction mixture was stirred at 0° C. for 30 min then warmed to room temperature and stirred for 2 h. The reaction mixture was quenched with 5 mL of brine and 10 mL of water and extracted with ethyl acetate (2×30 mL). The combined organic layers were washed with water and brine then dried and concentrated in vacuo. The crude material was purified by silica gel chromatography (0-10% methanol in dichloromethane) to afford 58 mg (53%) of 2-[6-fluoro-1-(6-morpholin-4-yl-pyridin-3-ylmethyl)-1H-indazol-3-yl]-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid ((S)-2-methoxy-1-methyl-ethyl)-amide as a foaming solid. MS: (M+H)+=675.
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[CH:11]=[C:10]([F:12])[CH:9]=[CH:8][C:7]=2[C:13]2[C:14]3[NH:21][CH:20]=[C:19]([C:22]([OH:24])=O)[C:15]=3[N:16]=[CH:17][N:18]=2)[CH2:3][CH2:2]1.[C:25]([O:29][C:30](=[O:39])[NH:31][C@H:32]1[CH2:37][CH2:36][C@@H:35]([NH2:38])[CH2:34][CH2:33]1)([CH3:28])([CH3:27])[CH3:26]>>[C:25]([O:29][C:30](=[O:39])[NH:31][C@H:32]1[CH2:33][CH2:34][C@@H:35]([NH:38][C:22]([C:19]2[C:15]3[N:16]=[CH:17][N:18]=[C:13]([C:7]4[CH:8]=[CH:9][C:10]([F:12])=[CH:11][C:6]=4[O:5][CH2:4][CH:1]4[CH2:2][CH2:3]4)[C:14]=3[NH:21][CH:20]=2)=[O:24])[CH2:36][CH2:37]1)([CH3:28])([CH3:26])[CH3:27]
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@@H](N)CC1
Reactant: O=C(O)c1c[nH]c2c(-c3ccc(F)cc3OCC3CC3)ncnc12
Product: CC(C)(C)OC(=O)N[C@H]1CC[C@@H](NC(=O)c2c[nH]c3c(-c4ccc(F)cc4OCC4CC4)ncnc23)CC1

Procedure:
Starting from 4-(2-cyclopropylmethoxy-4-fluoro-phenyl)-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylic acid (example A76) and cis-(4-amino-cyclohexyl)-carbamic acid tert-butyl ester the title compound is obtained as colorless solid.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][O:5][CH2:6][CH2:7][O:8][CH2:9][CH2:10][O:11][CH2:12][CH2:13][CH2:14][NH:15][C:16]1[CH:21]=[CH:20][C:19]([N+:22]([O-])=O)=[CH:18][CH:17]=1.[ClH:25]>CO>[ClH:25].[NH2:1][CH2:2][CH2:3][CH2:4][O:5][CH2:6][CH2:7][O:8][CH2:9][CH2:10][O:11][CH2:12][CH2:13][CH2:14][NH:15][C:16]1[CH:21]=[CH:20][C:19]([NH2:22])=[CH:18][CH:17]=1
Reactant: NCCCOCCOCCOCCCNc1ccc([N+](=O)[O-])cc1
Agent: Cl
Solvent: CO
Product: NCCCOCCOCCOCCCNc1ccc(N)cc1

Procedure:
1.5 g of nitro derivative (19) prepared above and about 100 ml of methanol were introduced into a 200 ml autoclave (hydrogenator) equipped with a magnetic stirrer. The solution obtained was degassed with nitrogen. 0.4 g of palladium-on-charcoal (5% humidity, comprising 50% water) was added thereto. The reaction mixture was stirred, while flushing once with hydrogen, and hydrogen was then introduced to a pressure of about 5 bar. After reaction for 4 hours, the reactor was flushed with nitrogen and the reaction mixture was filtered quickly through Celite under a gentle pressure of nitrogen. The filtrate was recovered in a pre-cooled solution of methanol comprising about 3 equivalents of hydrogen chloride gas. It was rinsed several times with methanol under a stream of nitrogen. The solution thus obtained was concentrated and was then treated with ether. The product obtained, in the form of a pale pink paste, was stirred and then rinsed several times with acetonitrile and ether under nitrogen. 1.6 g of expected product (20) were isolated in the form of a slightly pink white powder.
Reaction SMILES: O1C=CB=N1.[Cl:6][C:7]1[CH:16]=[C:15]2[C:10]([CH:11]=[CH:12][C:13]([CH:17]=[CH:18][C:19]3[CH:20]=[C:21]([C:25](=[O:38])[CH2:26][CH2:27][C:28]4[CH:37]=[CH:36][CH:35]=[CH:34][C:29]=4[C:30]([O:32][CH3:33])=[O:31])[CH:22]=[CH:23][CH:24]=3)=[N:14]2)=[CH:9][CH:8]=1.B.C1COCC1>C1COCC1>[Cl:6][C:7]1[CH:16]=[C:15]2[C:10]([CH:11]=[CH:12][C:13]([CH:17]=[CH:18][C:19]3[CH:20]=[C:21]([C@H:25]([OH:38])[CH2:26][CH2:27][C:28]4[CH:37]=[CH:36][CH:35]=[CH:34][C:29]=4[C:30]([O:32][CH3:33])=[O:31])[CH:22]=[CH:23][CH:24]=3)=[N:14]2)=[CH:9][CH:8]=1
Reactant: COC(=O)c1ccccc1CCC(=O)c1cccc(C=Cc2ccc3ccc(Cl)cc3n2)c1
Agent: B
Agent: b1ccon1
Solvent: C1CCOC1
Product: COC(=O)c1ccccc1CC[C@@H](O)c1cccc(C=Cc2ccc3ccc(Cl)cc3n2)c1
Temperature: -5 °C

Procedure:
At -20° C., a solution of (S)-tetrahydro-1-methyl-3,3-diphenyl-1H,3H-pyrrolo(1,2-c) (1,3,2,) oxazaborole.borane complex (J. Am. Chem. Soc., 104, 5551-5553 (1987) 6.34 g, 21.8 mmol) in anhydrous THF (20 ml) was added dropwise to a solution of the ketone of Step 2 (33.1 g, 72.6 mmol) in THF (300 mL). Then, 1.0M BH3.THF (108 ml) was added slowly and the reaction mixture was slowly warmed up to -5° C. within 3-4 hours. The mixture was added to an ice cold 25% NH4OAc solution. The product was extracted into hot EtOAc, dried over Na2So4, concentrated to dryness and co-evaporated twice with toluene. It was dissolved in hot toluene and filtered through silica (~400 ml) with toluene and EtOAc:toluene 10:90 and 15:85. The product was finally recrystallized as a hydrate from toluene containing 4 mL H2O. [α ]D : +29.5° (c=1.82, CHCl3).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][C:10]=1[N:11]1[CH:15]=[C:14]([CH3:16])[N:13]=[CH:12]1)[CH:6]=O.[C:17](=O)([O-])[O-].[K+].[K+].P(=O)([O-])OC(=[N+]=[N-])C(=O)C(C)C>CO>[C:6]([C:5]1[CH:8]=[CH:9][C:10]([N:11]2[CH:15]=[C:14]([CH3:16])[N:13]=[CH:12]2)=[C:3]([O:2][CH3:1])[CH:4]=1)#[CH:17]
Reactant: O=C([O-])[O-]
Reactant: COc1cc(C=O)ccc1-n1cnc(C)c1
Agent: CC(C)C(=O)C(=[N+]=[N-])O[PH](=O)[O-]
Agent: [K+]
Solvent: CO
Product: C#Cc1ccc(-n2cnc(C)c2)c(OC)c1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 87.1 %

Procedure:
3-Methoxy-4-(4-methyl-imidazol-1-yl)-benzaldehyde (2.00 g, 9.25 mmol) and anhydrous potassium carbonate (2.56 g, 18.5 mmol) were placed in a 250-mL flask and placed on high vacuum for 10 minutes. Under nitrogen, anhydrous MeOH (60 ml) was added via syringe. To the yellowish suspension was added dimethyl(1-diazo-2-oxopropyl) phosphonate (2.132 g, 11.10 mmol). The reaction was stirred at room temperature for 22 h. The reaction was quenched with aqueous sodium hydrogen carbonate (5%, 100 mL), and the mixture was diluted with diethyl ether (250 mL). The combined organic fractions were washed with brine (saturated, 2×100 mL), dried over MgSO4, filtered and evaporated. The residue was dried on high vacuum to give the title compound as a yellow solid (1.71 g, 87%). The product was pure enough by LCMS and NMR and not further purified.
Reaction SMILES: C([O:3][C:4]([C:6]1([NH:15][S:16]([C:19]2[CH:24]=[CH:23][C:22]([O:25][CH2:26][C:27]3[C:36]4[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=4)[N:30]=[C:29]([CH3:37])[CH:28]=3)=[CH:21][CH:20]=2)(=[O:18])=[O:17])[CH2:11][CH2:10][N:9]([C:12](=[O:14])[CH3:13])[CH2:8][CH2:7]1)=[O:5])C.Cl>O1CCOCC1>[C:12]([N:9]1[CH2:8][CH2:7][C:6]([NH:15][S:16]([C:19]2[CH:20]=[CH:21][C:22]([O:25][CH2:26][C:27]3[C:36]4[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=4)[N:30]=[C:29]([CH3:37])[CH:28]=3)=[CH:23][CH:24]=2)(=[O:18])=[O:17])([C:4]([OH:5])=[O:3])[CH2:11][CH2:10]1)(=[O:14])[CH3:13]
Reactant: CCOC(=O)C1(NS(=O)(=O)c2ccc(OCc3cc(C)nc4ccccc34)cc2)CCN(C(C)=O)CC1
Agent: Cl
Solvent: C1COCCO1
Product: CC(=O)N1CCC(NS(=O)(=O)c2ccc(OCc3cc(C)nc4ccccc34)cc2)(C(=O)O)CC1
Temperature: 60 °C
Yield: 5.3 %

Procedure:
To a solution of 1-acetyl-4-[4-(2-methyl-quinolin-4-ylmethoxy)-benzenesulfonylamino]-piperidine-4-carboxylic acid ethyl ester (0.4 g, 7.6 mmol) in 1,4-dioxane (4 mL) was added concentrated HCl (4 mL). The reaction was heated to 60° C. for 19 h. The solvent was then removed in vacuo and the residue was purified by reverse phase HPLC (Gilson) on a Phenomex C-18 semi-prep column eluting an acetonitrile:water gradient, to afford 1-acetyl-4-[4-(2-methyl-quinolin-4-ylmethoxy)-benzenesulfonyl amino]-piperidine-4-carboxylic acid as an amorphous white solid (0.2 g, 63.1%). MS: 498 (M+H)+.
Reaction SMILES: O[C:2]1[CH:7]=[C:6]([CH2:8][CH2:9][CH2:10][O:11][CH3:12])[N:5]=[C:4]([N:13]2[CH2:17][CH2:16][CH2:15][CH:14]2[C:18]2[O:22][N:21]=[C:20]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=3)[CH:19]=2)[N:3]=1.[NH2:29][C:30]1[CH:34]=[C:33]([CH3:35])[NH:32][N:31]=1>>[CH3:12][O:11][CH2:10][CH2:9][CH2:8][C:6]1[N:5]=[C:4]([N:13]2[CH2:17][CH2:16][CH2:15][CH:14]2[C:18]2[O:22][N:21]=[C:20]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=3)[CH:19]=2)[N:3]=[C:2]([NH:29][C:30]2[CH:34]=[C:33]([CH3:35])[NH:32][N:31]=2)[CH:7]=1
Reactant: COCCCc1cc(O)nc(N2CCCC2c2cc(-c3ccccn3)no2)n1
Reactant: Cc1cc(N)n[nH]1
Product: COCCCc1cc(Nc2cc(C)[nH]n2)nc(N2CCCC2c2cc(-c3ccccn3)no2)n1

Procedure:
Starting materials: 4-hydroxy-6-(3-methoxypropyl)-2-[2-{3-(pyrid-2-yl)isoxazol-5-yl}pyrrolidin-1-yl]pyrimidine (Method 33) and 3-amino-5-methyl-1H-pyrazole.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([N:9]([CH2:15][CH:16]2[CH2:18][CH2:17]2)[C@H:10]([C:12]([OH:14])=O)[CH3:11])=[CH:5][C:4]=1[C:19]([F:22])([F:21])[F:20])#[N:2].[NH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([N:9]([CH2:15][CH:16]2[CH2:17][CH2:18]2)[C@H:10]([C:12]([NH:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[O:14])[CH3:11])=[CH:5][C:4]=1[C:19]([F:21])([F:22])[F:20])#[N:2]
Reactant: Nc1ccccc1
Reactant: C[C@@H](C(=O)O)N(CC1CC1)c1ccc(C#N)c(C(F)(F)F)c1
Product: C[C@@H](C(=O)Nc1ccccc1)N(CC1CC1)c1ccc(C#N)c(C(F)(F)F)c1

Procedure:
Synthesized as described for Example 91C using N-[4-cyano-3-(trifluoromethyl)phenyl]-N-(cyclopropylmethyl)alanine and aniline: 1H NMR (400 MHz, CDCl3) δ 8.20 (s, 1H), 7.51 (d, J=8.9 Hz, 1H), 7.45 (d, J=7.9 Hz, 2H), 7.30 (t, J=7.7 Hz, 2H), 7.16 (d, J=2.4 Hz, 1H), 7.11 (t, J=7.5 Hz, 1H), 6.93 (dd, J=8.9, 2.7 Hz, 1H), 4.47 (q, J=7.0 Hz, 1H), 3.37 (m, 2H), 1.56 (d, J=6.9 Hz, 3H), 1.12 (m, 1H), 0.69 (m, 2H), 0.37 (m, 2H).
Reaction SMILES: [CH:1]1[CH:6]=[CH:5][C:4]([NH:7][C:8]2[CH:13]=[CH:12][C:11]([N:14]=NC3C=CC=CC=3)=[CH:10][CH:9]=2)=[CH:3][CH:2]=1.C1(O)CCCCC1.CC(C)([O-])C.[K+]>>[CH:1]1[CH:2]=[CH:3][C:4]([NH:7][C:8]2[CH:13]=[CH:12][C:11]([NH2:14])=[CH:10][CH:9]=2)=[CH:5][CH:6]=1.[NH2:7][C:4]1[CH:5]=[CH:6][CH:1]=[CH:2][CH:3]=1
Reactant: c1ccc(N=Nc2ccc(Nc3ccccc3)cc2)cc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: OC1CCCCC1
Product: Nc1ccc(Nc2ccccc2)cc1
Product: Nc1ccccc1

Procedure:
A solution of 4-(phenylazo)diphenylamine (0.273 g), cyclohexanol (5 g) and potassium t-butoxide (1 g) was heated at reflux under nitrogen for 4 hours. Analysis of the reaction mixture by HPLC indicated all of the 4-(phenyazo)-diphenylamine was consumed. 4-aminodiphenylamine and aniline were produced in 99% yield based on 4-(phenylazo)diphenylamine charged.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=2)=[CH:5][C:6]=1[C:7]([O:9]CC)=O.[C:19](#[N:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.Cl>O1CCOCC1>[F:18][C:15]1[CH:14]=[CH:13][C:12]([C:4]2[S:3][C:2]3[N:1]=[C:19]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)[NH:26][C:7](=[O:9])[C:6]=3[CH:5]=2)=[CH:17][CH:16]=1
Reactant: CCOC(=O)c1cc(-c2ccc(F)cc2)sc1N
Reactant: N#Cc1ccccc1
Agent: Cl
Solvent: C1COCCO1
Product: O=c1[nH]c(-c2ccccc2)nc2sc(-c3ccc(F)cc3)cc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 82.7 %

Procedure:
To a solution of ethyl 2-amino-5-(4-fluorophenyl)thiophene-3-carboxylate (0.2 g, 0.75 mmol) and benzonitrile (0.23 g, 2.26 mmol) in dioxane (4 ml) was added 4M HCl in dioxane (4 ml). The mixture was stirred at room temperature overnight. The precipitate was filtered off, washed with diethyl ether and dried. The solid was redissolved in DMF and the mixture was heated at 100° C. for 3 hours. The solvents were removed under reduced pressure. The residue was diluted with water and the solid was filtered off, washed with water and dried. The crude residue was purified by flash chromatography on silica gel (CH2Cl2/MeOH 60:1) to yield the title compound as a white solid (0.20 g, 82%).
Reaction SMILES: [CH2:1]([C@H:4]1[CH2:9][CH2:8][C@H:7]([C@H:10]2[CH2:15][CH2:14][C@H:13]([CH:16]=[CH:17][C:18]3[CH:23]=[CH:22][C:21]([F:24])=[C:20]([F:25])[CH:19]=3)[CH2:12][CH2:11]2)[CH2:6][CH2:5]1)[CH2:2][CH3:3]>C(OCC)(=O)C.[Pd]>[CH2:1]([C@H:4]1[CH2:5][CH2:6][C@H:7]([C@H:10]2[CH2:15][CH2:14][C@H:13]([CH2:16][CH2:17][C:18]3[CH:23]=[CH:22][C:21]([F:24])=[C:20]([F:25])[CH:19]=3)[CH2:12][CH2:11]2)[CH2:8][CH2:9]1)[CH2:2][CH3:3]
Reactant: CCC[C@H]1CC[C@H]([C@H]2CC[C@H](C=Cc3ccc(F)c(F)c3)CC2)CC1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CCC[C@H]1CC[C@H]([C@H]2CC[C@H](CCc3ccc(F)c(F)c3)CC2)CC1

Procedure:
Next, the above 2-[trans-4-(trans-4-propylcyclohexyl)cyclohexyl]-1-(3,4-difluorophenyl)ethene (1Og) was dissolved in ethyl acetate (100 ml), followed by subjecting the solution to catalytic hydrogenation at 20° C. by means of 5%-Pd/C catalyst (0.5 g) till absorption of hydrogen ceased, removing the catalyst after completion of the reaction, distilling off ethyl acetate and recrystallizing a remaining oily substance from ethanol to obtain the objective 2-[trans-4-(trans-4-propylcyclohexyl)cyclohexyl]-1-(3,4-difluorophenyl)ethane (8 g). This product had a broad mesomorphic range, and C-S point: 18.4° C., S-N point: 49.5° C. and N-I point: 118.3° C.
Reaction SMILES: S(Cl)([Cl:3])=O.[CH3:5][N:6]([CH2:8][CH:9]1[CH2:17][C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]1([C:19]1[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=1)O)[CH3:7]>>[ClH:3].[CH3:5][N:6]([CH3:7])[CH2:8][C:9]1[CH2:17][C:16]2[C:11]([C:10]=1[C:19]1[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=1)=[CH:12][CH:13]=[CH:14][CH:15]=2
Reactant: CN(C)CC1Cc2ccccc2C1(O)c1cccnc1
Reactant: O=S(Cl)Cl
Product: CN(C)CC1=C(c2cccnc2)c2ccccc2C1
Product: Cl
Temperature: 65 °C

Procedure:
2.6 ml of thionyl chloride were added dropwise, with the pronounced evolution of gas, to 2.17 g of 2-dimethylaminomethyl-1-pyridin-3-yl-indan-1-ol (mixture of the diastereoisomers), and the mixture was heated for 2.5 hours at 65° C., with stirring, and then concentrated in a water-jet pump. After cooling, first water and then 1 M sodium carbonate solution were added, and extraction was then carried out with tetrahydrofuran/ethyl acetate; the combined extracts were dried over magnesium sulfate, filtered and concentrated. The resulting crude product (1.4 g) was dissolved in about 17 ml of absolute ethanol and converted into the corresponding hydrochloride with water and chlorotrimethylsilane. The resulting solid was filtered off with suction, washed with a small amount of absolute ethanol and dried at 120° C. in vacuo (about 50 mbar). 1.74 g of dimethyl-(3-pyridin-3-yl-1H-inden-2-ylmethyl)-amine hydrochloride having a melting point of from 156° C. to 159° C. were obtained.