Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:34])([O:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][P:26](=[O:33])([O:30]CC)[O:27]CC)[C:3]1[C:8]([F:9])=[C:7]([F:10])[C:6]([F:11])=[C:5]([F:12])[C:4]=1[F:13].Br[Si](C)(C)C.O>ClCCl.CO>[F:34][C:2]([F:1])([O:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][P:26](=[O:27])([OH:33])[OH:30])[C:3]1[C:8]([F:9])=[C:7]([F:10])[C:6]([F:11])=[C:5]([F:12])[C:4]=1[F:13]
Reactant: CCOP(=O)(CCCCCCCCCCCOC(F)(F)c1c(F)c(F)c(F)c(F)c1F)OCC
Agent: C[Si](C)(C)Br
Solvent: CO
Solvent: ClCCl
Solvent: O
Product: O=P(O)(O)CCCCCCCCCCCOC(F)(F)c1c(F)c(F)c(F)c(F)c1F
Reaction time: 8 h
Yield: 80.5 %

Procedure:
A solution of diethyl 11-(perfluorobenzyloxy)undecylphosphonate (0.63 g, 1.3 mmol) in 15 mL of dry dichloromethane and 0.7 mL (5.3 mmol) bromotrimethylsilane was made. The system was sealed with a greased stopper and allowed to stir overnight. Volatiles were removed under reduced pressure to produce a viscous, brown oil, which was dissolved in 25 mL of a 4:1 methanol:water solution and allowed to stir for six hours. After removal of solvent under reduced pressure an off white solid formed, which was recrystallized from a minimal amount of acetonitrile to afford white crystals of 11-(perfluorobenzyloxy)undecylphosphonic acid (0.49 g, 92%). 1H NMR (399.9 MHz, DMSO-d6) δ 4.55 (s, 2H), 3.42 (t, J=6.4 Hz, 2H), 1.49-1.44 (m, 6H), 1.34-1.18 (m, 14H). 13C{1H} NMR (100.5 MHz, DMSO-d6) δ 104.5, 69.9, 58.8, 30.1, 29.9, 28.9, 28.8, 28.8, 28.7, 28.1, 26.8, 25.4, 22.648 (d, J=4.8 Hz). 31P{1H} NMR (161.91 MHz, DMSO-d6): δ 27.63. 19F NMR (376.3 MHz, DMSO-d6): δ −141.86 (m, 2F), −152.95 (m, 1F), −160.88 (m, 2F), from trifluoro acetic acid. Analysis calculated (found): C 50.00 (50.16), H 6.06 (6.23), F 21.97 (21.79). Exact mass calculated (found) for [M−H]−, m/z: 432.1489 (432.1487).
Reaction SMILES: Cl.[CH:2]1([CH2:8][C@H:9]([C:11]([OH:13])=[O:12])[NH2:10])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1.Cl.C(=O)([O-])[O-].[K+].[K+].[CH2:21](O)[CH3:22]>O>[NH2:10][C@H:9]([CH2:8][CH:2]1[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1)[C:11]([O:13][CH2:21][CH3:22])=[O:12]
Reactant: CCO
Reactant: N[C@H](CC1CCCCC1)C(=O)O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: CCOC(=O)[C@H](N)CC1CCCCC1
Temperature: 80 °C

Procedure:
The process is performed as in Example 2, starting with 10 g of β-cyclohexyl-(D)-alanine hydrochloride in 96 cm3 of absolute ethanol, by treating it with a stream of dry hydrogen chloride at a temperature in the region of 0° C. for 20 minutes. After heating to about 80° C. for 4 days, followed by cooling to 0° C., the mixture is again treated with a stream of hydrogen chloride for 20 minutes, followed by heating to a temperature in the region of 80° C. for 20 hours. The reaction medium is concentrated under reduced pressure (5 kPa) at a temperature in the region of 40° C., and the residue obtained is dissolved in 200 cm3 of water, made alkaline by addition of 19 g of solid potassium carbonate. After evaporation, the resulting solid is taken up in 200 cm3 of ethanol at a temperature in the region of 80° C. The insoluble material is filtered off and the filtrate is evaporated under reduced pressure (5 kPa) at a temperature in the region of 40° C. The residue obtained is taken up in 130 cm3 of ethanol at room temperature. The insoluble material is filtered off and the filtrate is again evaporated under the same conditions as above. 4.8 g of ethyl (2R)-2-amino-3-cyclohexylpropionate are obtained in the form of a whitish paste. (Rf=0.80 in a 90/10 by volume mixture of ethanol/aqueous ammonia, on a Merck 60F254R silica plate)
Reaction SMILES: FC1(F)[CH2:7][CH2:6][N:5]([C:8]([C:10]2[NH:11][C:12]3[C:17]([CH:18]=2)=[CH:16][C:15]([O:19][CH:20]2[CH2:25][CH2:24][N:23]([CH:26]([CH3:28])[CH3:27])[CH2:22][CH2:21]2)=[CH:14][CH:13]=3)=[O:9])[CH2:4][CH2:3]1.Cl.FC1(F)CCNCC1.C(N1CCC([O:48]C2C=C3C(=CC=2)NC(C(O)=O)=C3)CC1)(C)C.N1CCOCC1>>[CH:26]([N:23]1[CH2:24][CH2:25][CH:20]([O:19][C:15]2[CH:16]=[C:17]3[C:12](=[CH:13][CH:14]=2)[NH:11][C:10]([C:8]([N:5]2[CH2:4][CH2:3][O:48][CH2:7][CH2:6]2)=[O:9])=[CH:18]3)[CH2:21][CH2:22]1)([CH3:28])[CH3:27]
Reactant: CC(C)N1CCC(Oc2ccc3[nH]c(C(=O)O)cc3c2)CC1
Reactant: CC(C)N1CCC(Oc2ccc3[nH]c(C(=O)N4CCC(F)(F)CC4)cc3c2)CC1
Agent: Cl
Agent: FC1(F)CCNCC1
Solvent: C1COCCN1
Product: CC(C)N1CCC(Oc2ccc3[nH]c(C(=O)N4CCOCC4)cc3c2)CC1

Procedure:
In analogy to the procedure described for the synthesis of intermediate 1, the title compound was synthesized from 5-(1-isopropyl-piperidin-4-yloxy)-1H-indole-2-carboxylic acid difluoropiperidine hydrochloride salt with one equivalent of lithium chloride (intermediate 1, step 3) and morpholine. The title compound was obtained in 60% yield as off-white solid. MS (m/e): 372.5 (MH+, 100%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[NH:7][C:6](=[O:13])/[C:5]/2=[CH:14]/OC.[CH3:17][O:18][C:19]1[CH:24]=[CH:23][C:22]([CH2:25][NH:26][CH3:27])=[CH:21][C:20]=1[OH:28]>O1CCCC1>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[NH:7][C:6](=[O:13])/[C:5]/2=[CH:14]\[N:26]([CH2:25][C:22]1[CH:23]=[CH:24][C:19]([O:18][CH3:17])=[C:20]([OH:28])[CH:21]=1)[CH3:27]
Reactant: CO/C=C1/C(=O)NC(=O)c2ccc(Br)cc21
Reactant: CNCc1ccc(OC)c(O)c1
Solvent: C1CCOC1
Product: COc1ccc(CN(C)/C=C2\C(=O)NC(=O)c3ccc(Br)cc32)cc1O
Yield: 94.9 %

Procedure:
(4E)-6-Bromo-4-(methoxymethylene)isoquinoline-1,3(2H,4H)-dione (0.15 g, 0.53 mmol) and 2-methoxy-5-methylaminomethyl-phenol (80 mg, 0.48 mmol) were stirred in tetrahydrofuran (10 mL) at room temperature. The reaction mixture is concentrated under reduced pressure. The solid material is then collected, washed with diethyl ether, water, and methanol, and then dried under vacuum to give (4Z)-6-bromo-4-{[(3-hydroxy-4-methoxybenzyl)(methyl)amino]methylene}isoquinoline-1,3(2H,4H)-dione as a yellow solid (0.19 g, 95%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=O)[CH2:9][C:10]2[CH:15]=[CH:14][N:13]=[CH:12][CH:11]=2)=[CH:4][CH:3]=1.[N:17]([O-])=[O:18].[Na+].C(O)(=[O:23])C>O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[N:17][OH:18])[C:9]([C:10]2[CH:15]=[CH:14][N:13]=[CH:12][CH:11]=2)=[O:23])=[CH:4][CH:3]=1
Reactant: CC(=O)O
Reactant: O=N[O-]
Reactant: O=C(Cc1ccncc1)c1ccc(F)cc1
Agent: [Na+]
Solvent: O
Product: O=C(C(=NO)c1ccc(F)cc1)c1ccncc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A solution of 1-(4-fluoro-phenyl)-2-pyridin-4-yl-ethanone (6.45 g, prepared according to the method described for Reference Example 11 in the specification of International Patent Application No. WO98/56788) in acetic acid (50 ml) was treated with a solution of sodium nitrite (4.14 g) in water (30 ml) at 10° C. The reaction mixture was stirred at room temperature for 16 hours then treated with water (150 ml) and then filtered to give the title compound as a white solid.
Reaction SMILES: [CH:1]1([Si:7]([CH3:10])([CH3:9])[CH3:8])[CH:6]=[CH:5][CH2:4][CH:3]=[CH:2]1.C[N+]1([O-])CC[O:15]CC1.[OH2:19].[O-]S([O-])=O.[Na+].[Na+]>C(Cl)Cl.O=[Os](=O)(=O)=O.CCOC(C)=O.C1CCCCC1>[CH3:8][Si:7]([C:1]1([OH:15])[CH2:6][CH:5]=[CH:4][CH2:3][CH:2]1[OH:19])([CH3:10])[CH3:9]
Reactant: C[N+]1([O-])CCOCC1
Reactant: O
Reactant: C[Si](C)(C)C1C=CCC=C1
Agent: O=[Os](=O)(=O)=O
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: C1CCCCC1
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: C[Si](C)(C)C1(O)CC=CCC1O
Yield: 54 %

Procedure:
The allylsilane of Example 25 (0.15 g, 1 mmol, 1 eq.) was added to a stirring solution of NMO.H2O (0.4 g, 3 mmol, 3 eq.) and OsO4 (20 μL, 0.05 mmol, 0.05 eq.) in DCM (50 mL) and the reaction stirred overnight at room temperature. Na2SO3 (0.1 g) was added and the organic layer was washed with H2O (50 mL) and brine (50 mL), dried over MgSO4 and the solvent removed in vacuo. Column chromatography (cyclohexane:EtOAc, 60:40, RF=0.25) furnished the product as a colourless oil (0.1 g, 0.54 mmol, 54% yield); 1H NMR (400 MHz, CDCl3) 5.56 (1H, m, H-3), 5.50 (1H, m, H-4), 3.94 (1H, m, H-7), 3.81 (1H, m, H-6), 2.35 (1H, m, H-5), 1.86 (1H, m, H-5′), 1.86 (1H, m, H-2), 0.07 (9H, s, H-1); 13C NMR (100 MHz, CDCl3) δ 125.19 (C-4), 120.82 (C-3), 70.39 (C-6), 68.30 (C-7), 35.73 (C-2), 30.16 (C-5), −2.42 (C-1); IR (neat, cm−1) 3423 (b, OH) 1640 (b, C═C) MS (ESI-, m/z) 185.25 [M−H+].
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:21]=[CH:20][C:19]([NH2:22])=[CH:18][CH:17]=1.ClC(Cl)(O[C:27](=[O:33])OC(Cl)(Cl)Cl)Cl.[NH2:35][C:36]1[CH:37]=[C:38]([OH:42])[CH:39]=[CH:40][CH:41]=1.C(=O)([O-])O.[Na+]>C1(C)C=CC=CC=1.C(N(CC)CC)C>[OH:42][C:38]1[CH:37]=[C:36]([NH:35][C:27]([NH:22][C:19]2[CH:18]=[CH:17][C:16]([O:15][C:6]3[C:5]4[C:10](=[CH:11][C:12]([O:13][CH3:14])=[C:3]([O:2][CH3:1])[CH:4]=4)[N:9]=[CH:8][CH:7]=3)=[CH:21][CH:20]=2)=[O:33])[CH:41]=[CH:40][CH:39]=1
Reactant: COc1cc2nccc(Oc3ccc(N)cc3)c2cc1OC
Reactant: Nc1cccc(O)c1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: COc1cc2nccc(Oc3ccc(NC(=O)Nc4cccc(O)c4)cc3)c2cc1OC
Yield: 57.8 %

Procedure:
6,7-Dimethoxy-4-(4-aminophenoxy)quinoline (115 mg) was dissolved in toluene (12 ml) with heat, after the addition of triethylamine (2 ml), triphosgene (113 mg) was added, and the admixture was refluxed with heat for 2 minutes. 3-Aminophenol (73 mg) was added to the reaction mixture, and the admixture was refluxed with heat for 10 minutes. After the addition of aqueous sodium hydrogen carbonate, the reaction mixture was extracted with chloroform, and the organic layer was then washed with brine and dried with anhydrous sodium sulfate. The solvent was removed by reduced-pressure distillation, and the resulting residue was washed with chloroform and filtered to obtain 95 mg of the title compound (yield: 60%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[C:17]3[C:12](=[CH:13][CH:14]=[C:15]([C:18](O)([C:27]4[N:31]([CH3:32])[CH:30]=[N:29][CH:28]=4)[C:19]4[CH:26]=[CH:25][C:22]([C:23]#[N:24])=[CH:21][CH:20]=4)[CH:16]=3)[N:11]([CH3:34])[C:10](=[O:35])[CH:9]=2)[CH:5]=[CH:6][CH:7]=1.S(Cl)([Cl:38])=O>>[Cl:38][C:18]([C:15]1[CH:16]=[C:17]2[C:12](=[CH:13][CH:14]=1)[N:11]([CH3:34])[C:10](=[O:35])[CH:9]=[C:8]2[C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=1)([C:27]1[N:31]([CH3:32])[CH:30]=[N:29][CH:28]=1)[C:19]1[CH:20]=[CH:21][C:22]([C:23]#[N:24])=[CH:25][CH:26]=1
Reactant: Cn1cncc1C(O)(c1ccc(C#N)cc1)c1ccc2c(c1)c(-c1cccc(Cl)c1)cc(=O)n2C
Reactant: O=S(Cl)Cl
Product: Cn1cncc1C(Cl)(c1ccc(C#N)cc1)c1ccc2c(c1)c(-c1cccc(Cl)c1)cc(=O)n2C
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of (±)-4-[[4-(3-chlorophenyl)-1,2-dihydro-1-methyl-2-oxo-6-quinolinyl]hydroxy(1-methyl-1H-imidazol-5yl)methyl]benzonitrile (0.00121 mol), obtained in stage b), in thionyl chloride (6 ml) was stirred at room temperature for 2 hours. The solvent was evaporated. The residue was taken up in DCM. The solvent was evaporated till dryness, yielding 4-[chloro[4-(3-chlorophenyl)-1,2-dihydro-1-methyl-2-oxo-6-quinolinyl](1-methyl-1H-imidazol-5-yl)methyl]-benzonitrile. The product was used without further purification in the next reaction step
Reaction SMILES: [CH:1]1([NH:4][C:5]([C:7]2[N:8]=[N:9][N:10]([C:15]3[CH:20]=[CH:19][C:18]([NH:21][C:22](=[O:29])[CH2:23][C:24]([O:26]CC)=[O:25])=[CH:17][CH:16]=3)[C:11]=2[CH2:12][CH2:13][CH3:14])=[O:6])[CH2:3][CH2:2]1.C(=O)([O-])[O-].[Na+].[Na+].O>CO>[CH:1]1([NH:4][C:5]([C:7]2[N:8]=[N:9][N:10]([C:15]3[CH:16]=[CH:17][C:18]([NH:21][C:22](=[O:29])[CH2:23][C:24]([OH:26])=[O:25])=[CH:19][CH:20]=3)[C:11]=2[CH2:12][CH2:13][CH3:14])=[O:6])[CH2:2][CH2:3]1
Reactant: CCCc1c(C(=O)NC2CC2)nnn1-c1ccc(NC(=O)CC(=O)OCC)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CCCc1c(C(=O)NC2CC2)nnn1-c1ccc(NC(=O)CC(=O)O)cc1
Yield: 89 %

Procedure:
A solution of ethyl 3-[(4-{4-[(cyclopropylamino)carbonyl]-5-propyl-1H-1,2,3-triazol-1-yl}phenyl)amino]-3-oxopropanoate obtained in Example 12 and sodium carbonate (0.80 g) in methanol (10 ml)—water (10 ml) was heated under reflux for 2 hr, and the reaction mixture was concentrated under reduced pressure. The concentrate was acidified with 1N hydrochloric acid and extracted with ethyl acetate. The extract was washed with saturated brine and dried over magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was washed with diethyl ether to give the title compound as a colorless powder (0.83 g, 89%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:17]([O:19][CH3:20])=[O:18])[C:5]2[C:6]([CH:15]=O)=[CH:7][N:8]([CH:11]([CH2:13][CH3:14])[CH3:12])[C:9]=2[CH:10]=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.S1(CCCC1)(=O)=O.C([BH3-])#N.[Na+]>CN(C=O)C.O>[Br:1][C:2]1[CH:3]=[C:4]([C:17]([O:19][CH3:20])=[O:18])[C:5]2[C:6]([CH3:15])=[CH:7][N:8]([CH:11]([CH2:13][CH3:14])[CH3:12])[C:9]=2[CH:10]=1
Reactant: CCC(C)n1cc(C=O)c2c(C(=O)OC)cc(Br)cc21
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Solvent: O=S1(=O)CCCC1
Product: CCC(C)n1cc(C)c2c(C(=O)OC)cc(Br)cc21
Temperature: 100 °C
Reaction time: 1 h
Yield: 54.5 %

Procedure:
To a stirred solution of methyl 6-bromo-1-sec-butyl-3-formyl-1H-indole-4-carboxylate (15 g, 44.6 mmol) in DMF (115 mL) was added p-toluenesulfonic acid mono hydrate (1.1 g, 5.8 mmol), p-toluenesulfonyl hydrazide (10.8 g, 58 mmol) followed by sulfolane (115 mL) at RT and the reaction mixture was stirred at 100° C. for 1 h. The reaction mixture was cooled to room temperature, treated with sodium cyanoborohydride (11.9 g, 178.5 mmol) portion wise over a period of 5 min and stirred at 100° C. for 2 h. The reaction mixture was cooled to room temperature and stirred at the same temperature for 16 h. The reaction mixture was diluted with water and extracted with 30% EtOAc: Pet ether. The organic layer was washed with cold water (100 mL), brine (100 mL) and dried over anhydrous Na2SO4 and concentrated under reduced pressure to afford crude, which was purified by column chromatography over silica gel (100-200 mesh) using 5% EtOAc: Pet ether as eluent to afford title compound methyl 6-bromo-1-sec-butyl-3-methyl-1H-indole-4-carboxylate (7.88 g, 54.6%) as pale yellow gum. 1H NMR (CDCl3, 400 MHz): δ 0.804-0.841 (t, J=7.4 Hz, 3H), 1.454-1.470 (d, J=6.4 Hz, 3H), 1.865-1.884 (m, 2H), 2.363 (s, 3H), 3.950 (s, 3H), 4.265-4.316 (m, 1H), 7.038 (s, 1H), 7.609 (d, J=1.2 Hz, 1H), 7.671 (d, J=2 Hz, 1H). MS (ES+): 324.19 [M+H] ion present.
Reaction SMILES: O=[C:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][CH2:3]1.Cl.Cl.[NH2:17][CH2:18][CH2:19][C:20]1[N:24]=[CH:23][NH:22][CH:21]=1.[C:25](O[BH-](OC(=O)C)OC(=O)C)(=[O:27])C.[Na+].[OH-].[Na+]>ClCCCl>[O:27]=[C:25]1[N:24]2[CH:23]=[N:22][CH:21]=[C:20]2[CH2:19][CH2:18][N:17]1[CH:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][CH2:3]1
Reactant: NCCc1c[nH]cn1
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCCl
Product: CC(C)(C)OC(=O)N1CCC(N2CCc3cncn3C2=O)CC1
Yield: 74.7 %

Procedure:
To a solution of tert-butyl 4-oxo-1-piperidinecarboxylate (11 g) and histamine dihydrochloride (10 g) in 1,2-dichloroethane (300 ml) was added sodium triacetoxyborohydride (17 g), and mixed at room temperature for 15 hours. pH of the aqueous layer was adjusted to about 12 by adding a 1 N aqueous sodium hydroxide solution to the reaction solution, and then extracted with chloroform. The extract was dried over anhydrous magnesium sulfate, and then the solvent was distilled off under reduced pressure. The resulting yellow oil was dissolved in dichloromethane (300 ml), DBU (13 ml) and N,N′-carbonyldiimidazole (7.6 g) were added to the reaction solution, and mixed at room temperature for 15 hours. The reaction mixture was diluted with water and chloroform, and the organic layer was collected by separation, and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified with silica gel column (ethyl acetate:ethanol=5:1) to obtain the title compound as a colorless oil (13 g, 77%).
Reaction SMILES: S(=O)(=O)(O)[OH:2].[Cl:6][C:7]1[CH:8]=[C:9]([C:13]2(O)[C:21]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[N:15]3[CH2:22][CH2:23][CH2:24][N:25]=[C:14]23)[CH:10]=[CH:11][CH:12]=1.N.[C:28](#[N:30])[CH3:29]>>[C:28]([NH:30][C:13]1([C:9]2[CH:10]=[CH:11][CH:12]=[C:7]([Cl:6])[CH:8]=2)[C:21]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[N:15]2[CH2:22][CH2:23][CH2:24][N:25]=[C:14]12)(=[O:2])[CH3:29]
Reactant: O=S(=O)(O)O
Reactant: OC1(c2cccc(Cl)c2)C2=NCCCN2c2ccccc21
Reactant: CC#N
Agent: N
Product: CC(=O)NC1(c2cccc(Cl)c2)C2=NCCCN2c2ccccc21
Reaction time: 0.08 h

Procedure:
Concentrated sulphuric acid (12 ml) was added dropwise over 5 minutes to vigorously stirred acetonitrile (24 ml) at 0°-5°. The resulting colourless solution was treated in one portion with 10-(3-chlorophenyl)-2,3,4,10-tetrahydropyrimido[1,2-a]indol -10-ol (3.0 g). The mixture was immediately stirred and heated at 50°-60° whereupon solution occurred within 5 minutes. After 1 hour, the solution was poured onto ice (100 ml) and the mixture was basified with saturated aqueous ammonia (90 ml) and extracted with dichloromethane (3×60 ml). The extracts were dried (MgSO4) and evaporated in vacuo. The residue was triturated with ethyl acetate to give light brown crystals which were purified by flash chromatography (Al2O3, ethyl acetate), trituration with ethanol-ether (1:1), and washing with ether to give the title compound free base as a colourless powder.
Reaction SMILES: [O:1]1[C:5]2([CH2:10][CH2:9][CH:8]([CH:11]=[O:12])[CH2:7][CH2:6]2)[O:4][CH2:3][CH2:2]1.[CH:13]([Mg]Br)=[CH2:14]>C1COCC1>[O:1]1[C:5]2([CH2:10][CH2:9][CH:8]([CH:11]([OH:12])[CH:13]=[CH2:14])[CH2:7][CH2:6]2)[O:4][CH2:3][CH2:2]1
Reactant: C=C[Mg]Br
Reactant: O=CC1CCC2(CC1)OCCO2
Solvent: C1CCOC1
Product: C=CC(O)C1CCC2(CC1)OCCO2
Temperature: -78 °C
Reaction time: 8 h

Procedure:
To a solution of 1,4-dioxaspiro[4.5]decane-8-carbaldehyde (860 mg, 5.05 mmol, prepared as described in Pearson, et al. in J. Org. Chem. 1997, 62(16), 5284-5292) in THF (6 mL) cooled to −78° C. under argon was added a vinylmagnesium bromide (20 mL, 20 mmol, 1 M in THF) dropwise. After the complete addition, the reaction mixture was allowed to reach room temperature overnight. It was then re-cooled to −78° C. and quenched with saturated NaHCO3 solution and warmed to room temperature. After extraction with ether, the organic layer was concentrated in vacuo and the residue purified by flash chromatography (silica gel, 0-100% ether/hexanes) to afford the product.
Reaction SMILES: [OH-].[Na+].C1COCC1.[Cl:8][C:9]1[CH:14]=[C:13]([NH:15][CH2:16][C:17]2[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:19][C:18]=2[C:27]2[CH:32]=[CH:31][C:30]([C:33]([O:35]C)=[O:34])=[CH:29][C:28]=2[CH3:37])[CH:12]=[CH:11][C:10]=1[C:38]1[CH:43]=[CH:42][C:41]([Cl:44])=[CH:40][C:39]=1[CH3:45]>CO>[Cl:8][C:9]1[CH:14]=[C:13]([NH:15][CH2:16][C:17]2[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:19][C:18]=2[C:27]2[CH:32]=[CH:31][C:30]([C:33]([OH:35])=[O:34])=[CH:29][C:28]=2[CH3:37])[CH:12]=[CH:11][C:10]=1[C:38]1[CH:43]=[CH:42][C:41]([Cl:44])=[CH:40][C:39]=1[CH3:45]
Reactant: COC(=O)c1ccc(-c2cc(C(F)(F)F)ccc2CNc2ccc(-c3ccc(Cl)cc3C)c(Cl)c2)c(C)c1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: Cc1cc(Cl)ccc1-c1ccc(NCc2ccc(C(F)(F)F)cc2-c2ccc(C(=O)O)cc2C)cc1Cl
Temperature: 25 °C

Procedure:
A 3M aqueous solution of NaOH (0.26 mL, 0.79 mmol) was added to a THF (2 mL) and MeOH (1 mL) solution of methyl 2′-(((2,4′-dichloro-2′-methyl-[1,1′-biphenyl]-4-yl)amino)methyl)-2-methyl-5′-(trifluoromethyl)-[1,1′-biphenyl]-4-carboxylate (340 mg, 0.61 mmol) and the resulting homogeneous mixture was stirred at room temperature. After 16 h the resulting mixture was concentrated in vacuo, suspended in water, and acidified with 2 M HCl. The resulting precipitate was filtered off, dried in vacuo, and the resulting residue was used in the next step without further purification.
Reaction SMILES: [H-].[Na+].[CH3:3][N:4]1[CH2:9][CH2:8][C@H:7]([OH:10])[C@H:6]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH2:5]1.[H][H].F[C:20]1[CH:27]=[CH:26][C:23]([C:24]#[N:25])=[CH:22][CH:21]=1>CN(C=O)C.O>[C:24]([C:23]1[CH:26]=[CH:27][C:20]([O:10][C@H:7]2[CH2:8][CH2:9][N:4]([CH3:3])[CH2:5][C@H:6]2[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[CH:21][CH:22]=1)#[N:25]
Reactant: N#Cc1ccc(F)cc1
Reactant: CN1CC[C@H](O)[C@H](c2ccccc2)C1
Reactant: [H][H]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CN1CC[C@H](Oc2ccc(C#N)cc2)[C@H](c2ccccc2)C1
Temperature: 80 °C
Reaction time: 18 h

Procedure:
A mixture of 0.31 g of sodium hydride, 2.48 g of cis-1-methyl-3-phenyl-4-piperidinol of Example 22 and 20 ml of dry DMF is slowly heated to 80° C. When hydrogen evolution is no longer observed, the mixture is cooled to 3° C. and a solution of 1.73 g of p-fluorobenzonitrile in 10 ml of DMF is added. The mixture is stirred for 18 hours at room temperature under nitrogen, poured into 100 ml of distilled water, and extracted with chloroform. The chloroform extracts are dried over anhydrous Na2SO4 and concentrated in vacuo to an oil containing DMF. This oil is partitioned between saturated aqueous NaCl solution and ether. The aqueous phase is extracted with ether, and the ether extracts are then washed with water and dried over anhydrous Na2SO4. Concentration in vacuo affords an oil which crystallizes while under high vacuum. This material is chromatographed on silica gel, using 25% methanol/acetone solution to obtain cis-4-(4-cyanophenoxy)-1-methyl-3-phenylpiperidine, m.p. s 138°, 139°-141° C.
Reaction SMILES: Cl[CH:2](P(=O)(OCC)OCC)[C:3]1[CH:12]=[CH:11][C:10]2[C:9]([CH3:14])([CH3:13])[CH2:8][CH2:7][C:6]([CH3:16])([CH3:15])[C:5]=2[CH:4]=1.[C:25]([C:28]1[CH:35]=[CH:34][C:31]([CH:32]=O)=[CH:30][CH:29]=1)([OH:27])=[O:26].S(=O)(=O)(O)O>CS(C)=O>[CH3:13][C:9]1([CH3:14])[CH2:8][CH2:7][C:6]([CH3:16])([CH3:15])[C:5]2[CH:4]=[C:3]([C:2]#[C:32][C:31]3[CH:34]=[CH:35][C:28]([C:25]([OH:27])=[O:26])=[CH:29][CH:30]=3)[CH:12]=[CH:11][C:10]1=2
Reactant: O=Cc1ccc(C(=O)O)cc1
Reactant: CCOP(=O)(OCC)C(Cl)c1ccc2c(c1)C(C)(C)CCC2(C)C
Agent: O=S(=O)(O)O
Solvent: CS(C)=O
Product: CC1(C)CCC(C)(C)c2cc(C#Cc3ccc(C(=O)O)cc3)ccc21
Temperature: 0 °C
Reaction time: 1 h
Yield: 70.3 %

Procedure:
22.6 g (0.06 mole) of diethyl 1-chloro-1-(5,6,7,8-tetrahydro-5,5,8,8-tetramethylnaphth-2-yl)-methylphosphonate (about 85% strength) and 9 g of 4-carboxybenzaldehyde in 190 ml of dry dimethyl sulfoxide were initially taken. 21 g (0.185 mole) of potassium tert.-butylate in 65 ml of dimethyl sulfoxide were added dropwise to the stirred mixture at room temperature. Stirring was continued for 1 hour, after which the reaction mixture was poured onto 1 liter of ice water and acidified with 20% strength sulfuric acid. The resulting precipitate was filtered off under suction, washed with water and recrystallized from isopropanol to give 14 g (70%) of the title compound. Carrying out recrystallization twice more gave 6 g of pure material of melting point 263°-264° C.