Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([NH:5][S:6]([C:9]1[C:10]([Cl:42])=[CH:11][C:12]([O:39][CH2:40][CH3:41])=[C:13]([C:15]2[N:16]([C:36](Cl)=[O:37])[C:17]([C:29]3[CH:34]=[CH:33][C:32]([Cl:35])=[CH:31][CH:30]=3)([CH3:28])[C:18]([C:21]3[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][CH:22]=3)([CH3:20])[N:19]=2)[CH:14]=1)(=[O:8])=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.Cl.Cl.[CH3:52][S:53]([CH2:56][CH2:57][CH2:58][N:59]1[CH2:64][CH2:63][NH:62][CH2:61][CH2:60]1)(=[O:55])=[O:54]>C(Cl)Cl>[Cl:27][C:24]1[CH:25]=[CH:26][C:21]([C@@:18]2([CH3:20])[C@:17]([C:29]3[CH:34]=[CH:33][C:32]([Cl:35])=[CH:31][CH:30]=3)([CH3:28])[N:16]([C:36]([N:62]3[CH2:61][CH2:60][N:59]([CH2:58][CH2:57][CH2:56][S:53]([CH3:52])(=[O:54])=[O:55])[CH2:64][CH2:63]3)=[O:37])[C:15]([C:13]3[C:12]([O:39][CH2:40][CH3:41])=[CH:11][C:10]([Cl:42])=[C:9]([S:6]([NH:5][C:1]([CH3:3])([CH3:2])[CH3:4])(=[O:8])=[O:7])[CH:14]=3)=[N:19]2)=[CH:22][CH:23]=1
Reactant: CS(=O)(=O)CCCN1CCNCC1
Reactant: CCOc1cc(Cl)c(S(=O)(=O)NC(C)(C)C)cc1C1=NC(C)(c2ccc(Cl)cc2)C(C)(c2ccc(Cl)cc2)N1C(=O)Cl
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOc1cc(Cl)c(S(=O)(=O)NC(C)(C)C)cc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCN(CCCS(C)(=O)=O)CC1

Procedure:
In a manner analogous to the method described in example 5, rac-(4S*,5R*)-2-(5-tert-butylsulfamoyl-4-chloro-2-ethoxy-phenyl)-4,5-bis-(4-chloro-phenyl)-4,5-dimethyl-4,5-dihydro-imidazole-1-carbonyl chloride (260 mg, 0.39 mmol, example 45) and triethylamine (350 mg, 3.34 mmol) in methylene chloride (10 mL) was treated with 1-(3-methanesulfonyl-propyl)-piperazine dihydrochloride (110 mg, 0.39 mmol, prepared as described in Fotouhi, N. et al. WO 2005110996) to give the title compound as a racemic mixture. The enantiomers were then separated by supercritical fluid chromatography (Berger Instrument Multi-Gram II, Daicel ChiralPak OD-H 3×25 cm, 35° C. at 100 bar, eluting with 30% methanol in carbon dioxide). HR-MS (ES, m/z) calculated for C38H49N5O6S2Cl3 [(M+H)+] 840.2185, observed 840.2179
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:15]2[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=2)[N:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)=[CH:4][CH:3]=1.[OH:22][C:23]1[C:24]([C:36]([CH3:39])([CH3:38])[CH3:37])=[CH:25][C:26]2[O:31][CH2:30][CH:29]([C:32](O)=[O:33])[O:28][C:27]=2[CH:35]=1>>[OH:22][C:23]1[C:24]([C:36]([CH3:39])([CH3:38])[CH3:37])=[CH:25][C:26]2[O:31][CH2:30][CH:29]([C:32]([N:12]3[CH2:11][CH2:10][N:9]([CH:8]([C:5]4[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=4)[C:15]4[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=4)[CH2:14][CH2:13]3)=[O:33])[O:28][C:27]=2[CH:35]=1
Reactant: Fc1ccc(C(c2ccc(F)cc2)N2CCNCC2)cc1
Reactant: CC(C)(C)c1cc2c(cc1O)OC(C(=O)O)CO2
Product: CC(C)(C)c1cc2c(cc1O)OC(C(=O)N1CCN(C(c3ccc(F)cc3)c3ccc(F)cc3)CC1)CO2
Yield: 72 %

Procedure:
That compound is obtained in a yield of 72% starting from 1-[bis(4-fluorophenyl)methyl]piperazine and 7-hydroxy-6-tert-butyl-2,3-dihydro-1,4-benzodioxin-2-carboxylic acid.
Reaction SMILES: [C:1]([NH:9][C:10]1[CH:14]=[CH:13][S:12][C:11]=1[C:15]([O:17]C)=O)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH3:19]>CO.C1COCC1>[C:1]([NH:9][C:10]1[CH:14]=[CH:13][S:12][C:11]=1[C:15]([NH2:19])=[O:17])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)c1sccc1NC(=O)c1ccccc1
Reactant: N
Solvent: CO
Solvent: C1CCOC1
Product: NC(=O)c1sccc1NC(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 120 h
Yield: 89 %

Procedure:
To a stirred solution of 14.21 g (54.4 mmol) of crude methyl 3-(benzoylamino)-2-thiophenecarboxylate in 100 mL of methanol and 100 mL of THF was added 100 mL of concentrated aqueous ammonia. The mixture was stirred at room temperature for 5 days and an additional 100 mL of concentrated aqueous ammonia was added. After stirring for 5 more days the mixture was rotovapped to remove the bulk of the organic solvents and the residue was extracted with two 125 mL portions of ethyl acetate. The insoluble material was collected by filtration and combined with the residue from evaporating the ethyl acetate extracts to dryness to furnish 11.96 g (89%) of crude 3-(benzoylamino)-2-thiophenecarboxamide as a tan solid. 1H-NMR (d6-DMSO)δ7.55(3H,m), 7.7(1H, d), 7.95(2H,m), 8.18(1H,d).
Reaction SMILES: [C:1]1([CH2:7][S:8]([C:11]2[CH:12]=[C:13]3[C:17](=[CH:18][CH:19]=2)[NH:16][C:15](=[O:20])[CH2:14]3)(=[O:10])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:21][C:22]1[C:26]([CH2:27][C:28]([N:30]2[CH2:35][CH2:34][O:33][CH2:32][CH2:31]2)=[O:29])=[C:25]([CH3:36])[NH:24][C:23]=1[CH:37]=O.N1CCCCC1>C(O)C>[CH3:21][C:22]1[C:26]([CH2:27][C:28]([N:30]2[CH2:31][CH2:32][O:33][CH2:34][CH2:35]2)=[O:29])=[C:25]([CH3:36])[NH:24][C:23]=1/[CH:37]=[C:14]1\[C:15](=[O:20])[NH:16][C:17]2[C:13]\1=[CH:12][C:11]([S:8]([CH2:7][C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)(=[O:10])=[O:9])=[CH:19][CH:18]=2
Reactant: O=C1Cc2cc(S(=O)(=O)Cc3ccccc3)ccc2N1
Reactant: Cc1[nH]c(C=O)c(C)c1CC(=O)N1CCOCC1
Solvent: CCO
Solvent: C1CCNCC1
Product: Cc1[nH]c(/C=C2\C(=O)Nc3ccc(S(=O)(=O)Cc4ccccc4)cc32)c(C)c1CC(=O)N1CCOCC1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
A mixture of 5-phenylmethanesulfonyl-1,3-dihydro-indol-2-one (100 mg, 0.35 mmol), 3,5-dimethyl-4-(2-morpholin-4-yl-2-oxo-ethyl)-1H-pyrrole-2-carbaldehyde (166 mg, 0.68 mmol) and piperidine (0.5 eq.) in ethanol (2 mL) was stirred at rt for 48 hours. The reaction was concentrated and triturated with methanol to give the titled compound as a pale orange solid.
Reaction SMILES: C(N1C=CN=C1)(N1C=CN=C1)=O.[CH3:13][CH:14]([CH3:20])[CH2:15][CH2:16][C:17]([OH:19])=O.[NH2:21][C:22]1[C:23]([CH3:28])=[CH:24][CH:25]=[CH:26][CH:27]=1>ClCCl>[CH3:28][C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=1[NH:21][C:17](=[O:19])[CH2:16][CH2:15][CH:14]([CH3:13])[CH3:20]
Reactant: CC(C)CCC(=O)O
Reactant: Cc1ccccc1N
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: ClCCl
Product: Cc1ccccc1NC(=O)CCC(C)C

Procedure:
Carbonyldiimidazole (65 g) was mixed with 500 ml of dry dichloromethane in a 2-L round bottom flask and stirred magnetically. A solution of 4-methylvaleric acid in 200 ml of dichloromethane was added dropwise over 45 minutes and the mixture was stirred for another 1.25 hours. o-Toluidine (45 g) in 100 ml of dichloromethane was then added over about 20 minutes. After stirring for 2 hours the mixture was washed with water and then the solvent was stripped on a rotary evaporator. The residue was mixed with 150 ml of methanol and 75 ml of water and put in the freezer. Filtration of the precipitate, dilution of the filtrate with water and refiltration of the precipitate gave 75 g (94%) of vacuum dried N-(2-methylphenyl)-4-methylvaleramide which was used without further treatment in the next step.
Reaction SMILES: [OH:1][C:2]1[C:10]([CH2:11]/[CH:12]=[C:13](\[CH3:20])/[CH2:14][CH2:15][C:16]([O:18][CH3:19])=[O:17])=[C:9]([O:21][CH3:22])[C:8]([CH3:23])=[C:7]2[C:3]=1[C:4](=[O:24])[O:5][CH2:6]2.[Si:25](Cl)([C:28]([CH3:31])([CH3:30])[CH3:29])([CH3:27])[CH3:26].N1C=CN=C1.O>CN(C)C=O>[Si:25]([O:1][C:2]1[C:10]([CH2:11]/[CH:12]=[C:13](\[CH3:20])/[CH2:14][CH2:15][C:16]([O:18][CH3:19])=[O:17])=[C:9]([O:21][CH3:22])[C:8]([CH3:23])=[C:7]2[C:3]=1[C:4](=[O:24])[O:5][CH2:6]2)([C:28]([CH3:31])([CH3:30])[CH3:29])([CH3:27])[CH3:26]
Reactant: COC(=O)CC/C(C)=C/Cc1c(O)c2c(c(C)c1OC)COC2=O
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)CC/C(C)=C/Cc1c(OC)c(C)c2c(c1O[Si](C)(C)C(C)(C)C)C(=O)OC2
Temperature: 50 °C
Reaction time: 24 h

Procedure:
To methyl (E) 6-(1,3-dihydro-4-hydroxy-6-methoxy-7-methyl-3-oxoisobenzofuran-5-yl)-4-methyl-4-hexenoate (Tetrahedron, 28, 4395, 1972) (10.0 g) in dimethylformamide (75 ml) was added t-butyldimethylsilyl chloride (4.97 g) and imidazole (2.24 g). The mixture was heated at 50° C. for 1 hour, then left at room temperature for 24 hours, then poured into water and extracted with ethyl acetate. The extract was washed twice with water, dried over magnesium sulfate and evaporated under vacuum to give methyl (E) 6-(4-t-butyldimethylsilyloxy-1,3-dihydro-6-methoxy-7-methyl-3-oxoisobenzofuran-5-yl)-4-methyl-4-hexenoate as a beige solid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH:9]1[C:14]([OH:16])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.[C:18]1([CH2:24][CH2:25][CH2:26][CH:27]([NH2:37])[CH2:28][CH2:29][CH2:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C(N(C(C)C)CC)(C)C.C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F>C(Cl)Cl>[C:31]1([CH2:30][CH2:29][CH2:28][CH:27]([NH:37][C:14]([CH:9]2[CH2:10][CH2:11][CH2:12][CH2:13][N:8]2[C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])=[O:16])[CH2:26][CH2:25][CH2:24][C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1
Reactant: NC(CCCc1ccccc1)CCCc1ccccc1
Reactant: CC(C)(C)OC(=O)N1CCCCC1C(=O)O
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1CCCCC1C(=O)NC(CCCc1ccccc1)CCCc1ccccc1
Temperature: 25 °C
Reaction time: 17 h

Procedure:
1-tert-Butoxycarbonyl-piperidine-2-carboxylic acid (3 g; 13.1 mmol) is dissolved in methylene chloride (100 mL) at ambient temperature. 1,7-Diphenyl-4-aminoheptane hydrochloride (1) (4.77 g; 15.7 mmol), diisopropylethylamine (7.3 mL; 41.9 mmol), and PyBOP (8.17 g; 15.7 mmol) are added sequentially. The mixture is stirred for 17 hours at ambient temperature then concentrated in vacuo at 40° C. The residue is purified via silica gel chromatography with gradient elution (10%→30% ethyl acetate in hexanes) affording the desired product as an oil. ESMS: MH− 479.4
Reaction SMILES: FC(F)(F)C(O)=O.[Cl:8][C:9]1[CH:10]=[C:11](/[CH:29]=[CH:30]/[C:31]([O:33]C(C)(C)C)=[O:32])[CH:12]=[CH:13][C:14]=1[C:15](=[C:23]1[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1)[C:16]1[CH:21]=[CH:20][C:19]([OH:22])=[CH:18][CH:17]=1>C(Cl)Cl>[Cl:8][C:9]1[CH:10]=[C:11](/[CH:29]=[CH:30]/[C:31]([OH:33])=[O:32])[CH:12]=[CH:13][C:14]=1[C:15](=[C:23]1[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1)[C:16]1[CH:21]=[CH:20][C:19]([OH:22])=[CH:18][CH:17]=1
Reactant: CC(C)(C)OC(=O)/C=C/c1ccc(C(=C2CCCCC2)c2ccc(O)cc2)c(Cl)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(O)/C=C/c1ccc(C(=C2CCCCC2)c2ccc(O)cc2)c(Cl)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 86.4 %

Procedure:
Trifluoroacetic acid (2.0 mL) was added dropwise to 73 (300 mg, 0.706 mmol) dissolved in CH2Cl2 (2 mL) at 0° C. The reaction mixture was stirred at RT for 3 h and the volatiles were removed under reduced pressure. The residue was chromatographed on silica gel (20:1 CH2Cl2:MeOH) to afford 225 mg (86%) of 74 as a yellow solid. 1H NMR (400 MHz, DMSO-d6): δ 1.53 (br s, 6H), 1.88 (br s, 2H), 2.20 (m, 2H), 6.54 (d, J=16.0 Hz, 1H), 6.65 (d, J=8.8 Hz, 2H), 6.92 (d, J=8.4 Hz, 2H), 7.23 (d, J=7.9 Hz, 1H), 7.52 (d, J=16.0 Hz, 1H), 7.59 (d, J=7.9 Hz, 1H). LRMS (ESI): m/z 370 (M+H)+.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[C:12]1[CH:21]=[C:20]([C:22]([F:25])([F:24])[F:23])[C:15]([C:16](OC)=O)=[CH:14][N:13]=1.[C-:26]#[N:27].[K+]>CO>[CH3:1][O:2][CH2:3][CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[C:12]1[N:13]=[CH:14][C:15]([CH2:16][C:26]#[N:27])=[C:20]([C:22]([F:25])([F:23])[F:24])[CH:21]=1
Reactant: COCCCc1ccccc1-c1cc(C(F)(F)F)c(C(=O)OC)cn1
Reactant: [C-]#N
Agent: [K+]
Solvent: CO
Product: COCCCc1ccccc1-c1cc(C(F)(F)F)c(CC#N)cn1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
A mixture of 5-(bromomethyl)-2-[2-(3-methoxypropyl)phenyl]-4-(trifluoromethyl)pyridine (1 eq.) from step 1 and KCN (5 eq.) in MeOH (0.08M) was stirred for 48 h at room temperature. The mixture was concentrated and purification by column chromatography on silica gel, eluting with Hex/EtOAc 30%, afforded the title desired material as an off-white solid.
Reaction SMILES: [O-]CC.[Na+].C(O)C.[CH2:8]([CH:15](C(C)=O)[C:16]([O:18][CH2:19][CH3:20])=[O:17])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[Br:24]N1C(=O)CCC1=O>>[Br:24][C:14]1[C:9]([CH2:8][CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: CCOC(=O)C(Cc1ccccc1)C(C)=O
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)CCc1ccccc1Br
Temperature: 22.5 °C
Reaction time: 0.5 h
Yield: 83.7 %

Procedure:
To a 2 L 4-necked round bottom flask that was equipped with an overhead stirrer, an addition funnel, a condenser and a temperature-probe, was added the solution of sodium ethoxide/ethanol (21% wt. %, 161.8 g) at 20-25° C. under nitrogen. Ethyl 2-benzylacetoacetate (103.1 g, 0.454 mole) was added dropwise. The resulting solution was stirred at 20-25° C. for 30 minutes. The reaction mixture was then cooled to −35° C. with a dry ice/acetone bath. N-Bromosuccinimide (NBS; 97.95 g, 0.545 mole) was added portion-wise over 30 minutes. After the addition was over, the reaction mixture was stirred at −35° C. for 1 hr before warming up to 20-25° C. and it was stirred for an additional 2 hrs. The reaction was then quenched with water (400 mL) and ethyl acetate (600 mL) was added. The layers were separated and the product was extracted from aqueous layer with ethyl acetate (400 mL×3). The combined organic layers was washed with saturated sodium bicarbonate twice (400 mL×2), water twice (400 mL×2) and brine (500 mL). After the removal of solvent, the product (crude, 132 g) was distilled under reduced pressure. Ethyl 2-bromo-3-benzenepropanoate (97.7 g) was obtained at yield 83.7%.
Reaction SMILES: F[C:2]1[CH:3]=[C:4]([C:26](=[O:28])[CH3:27])[CH:5]=[CH:6][C:7]=1[N:8]1[CH2:13][CH2:12][N:11]([C:14](=[O:25])[C:15]2[CH:20]=[C:19]([N+:21]([O-:23])=[O:22])[CH:18]=[CH:17][C:16]=2F)[CH2:10][CH2:9]1.[CH3:29][N:30]1[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]1.O>C1COCC1>[CH3:29][N:30]1[CH2:35][CH2:34][N:33]([C:16]2[CH:17]=[CH:18][C:19]([N+:21]([O-:23])=[O:22])=[CH:20][C:15]=2[C:14]([N:11]2[CH2:12][CH2:13][N:8]([C:7]3[CH:6]=[CH:5][C:4]([C:26](=[O:28])[CH3:27])=[CH:3][CH:2]=3)[CH2:9][CH2:10]2)=[O:25])[CH2:32][CH2:31]1
Reactant: CC(=O)c1ccc(N2CCN(C(=O)c3cc([N+](=O)[O-])ccc3F)CC2)c(F)c1
Reactant: CN1CCNCC1
Solvent: C1CCOC1
Solvent: O
Product: CC(=O)c1ccc(N2CCN(C(=O)c3cc([N+](=O)[O-])ccc3N3CCN(C)CC3)CC2)cc1
Temperature: 800 °C

Procedure:
A stirred mixture of 150 mg (0.39 mmol) 1-{3-fluoro-4-[4-(2-fluoro-5-nitro-benzoyl)-piperazin-1-yl]-phenyl}-ethanone, 200 mg (2.0 mmol) 1-methylpiperazine in 4 ml THF was heated to 800° C. for 1 h. Water was added to the reaction mixture, the precipitate isolated, dried and purified by flash-chromatography on silica gel with heptane/AcOEt as eluent. The title compound was obtained as a light yellow powder, MS (m/e): 471.2 (MH+, 100%).
Reaction SMILES: C([O-])([O-])=O.[K+].[K+].Cl[CH2:8][CH2:9][CH2:10][C:11]1[N:15]([C:16]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[N:14]=[N:13][N:12]=1.[Cl:35][C:36]1[CH:37]=[C:38]([OH:57])[CH:39]=[CH:40][C:41]=1[CH:42]([CH3:56])[C:43]([C:49]1[CH:54]=[CH:53][N:52]=[C:51]([Cl:55])[CH:50]=1)([OH:48])[C:44]([F:47])([F:46])[F:45].O>CN1CCCC1=O>[Cl:55][C:51]1[CH:50]=[C:49]([C:43]([OH:48])([CH:42]([C:41]2[CH:40]=[CH:39][C:38]([O:57][CH2:8][CH2:9][CH2:10][C:11]3[N:15]([C:16]([C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)([C:23]4[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=4)[C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=4)[N:14]=[N:13][N:12]=3)=[CH:37][C:36]=2[Cl:35])[CH3:56])[C:44]([F:47])([F:46])[F:45])[CH:54]=[CH:53][N:52]=1
Reactant: ClCCCc1nnnn1C(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CC(c1ccc(O)cc1Cl)C(O)(c1ccnc(Cl)c1)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN1CCCC1=O
Solvent: O
Product: CC(c1ccc(OCCCc2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1Cl)C(O)(c1ccnc(Cl)c1)C(F)(F)F
Temperature: 60 °C
Yield: 51.5 %

Procedure:
To a suspension of K2CO3 (93 mg), KI (90 mg) in N-methyl-2-pyrrolidone (0.5 mL) were added 5-(3-chloropropyl)-1-(triphenylmethyl)-1H-tetrazole (137 mg, CAS 823797-34-8, preparation see Bosmans et al., WO2005003124 A1, page 23) and 3-chloro-4-[2-(2-chloro-pyridin-4-yl)-3,3,3-trifluoro-2-hydroxy-1-methyl-propyl]-phenol (99 mg, Example 133). The mixture was heated to 60° C. for 20 hours and TLC confirmed almost complete conversion. The mixture was allowed to cool and poured into water. The aqueous layer was extracted with ethyl acetate and the organic extracts were washed with brine, dried and evaporated. The residue was purified by flash chromatography (silica gel, gradient of ethyl acetate in heptane) to give the title compound as a colorless solid (100 mg). MS (neg. ion, m/e)=716.2 ((M−H)−).
Reaction SMILES: [Si:1]([O:8][C@H:9]1[CH2:31][CH2:30][C@@:29]2([CH3:32])[C@@H:11]([CH2:12][CH2:13][C:14]3[C:15]4[C@:25]([CH3:33])([CH2:26][CH2:27][C:28]=32)[C@@H:18]([C@H:19]([CH3:24])[CH2:20][CH2:21][CH2:22][OH:23])[CH2:17][CH:16]=4)[C:10]1([CH3:35])[CH3:34])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[C:36]1([CH3:46])[CH:41]=[CH:40][C:39]([S:42](Cl)(=[O:44])=[O:43])=[CH:38][CH:37]=1>N1C=CC=CC=1>[Si:1]([O:8][C@H:9]1[CH2:31][CH2:30][C@@:29]2([CH3:32])[C@@H:11]([CH2:12][CH2:13][C:14]3[C:15]4[C@:25]([CH3:33])([CH2:26][CH2:27][C:28]=32)[C@@H:18]([C@H:19]([CH3:24])[CH2:20][CH2:21][CH2:22][O:23][S:42]([C:39]2[CH:40]=[CH:41][C:36]([CH3:46])=[CH:37][CH:38]=2)(=[O:44])=[O:43])[CH2:17][CH:16]=4)[C:10]1([CH3:34])[CH3:35])([C:4]([CH3:7])([CH3:5])[CH3:6])([CH3:3])[CH3:2]
Reactant: C[C@H](CCCO)[C@H]1CC=C2C3=C(CC[C@@]21C)[C@@]1(C)CC[C@H](O[Si](C)(C)C(C)(C)C)C(C)(C)[C@@H]1CC3
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)OCCC[C@@H](C)[C@H]2CC=C3C4=C(CC[C@@]32C)[C@@]2(C)CC[C@H](O[Si](C)(C)C(C)(C)C)C(C)(C)[C@@H]2CC4)cc1
Temperature: 5 °C
Reaction time: 5 h
Yield: 57.5 %

Procedure:
3β-tert-Butyldimethylsilyloxy-4,4-dimethyl-5α-chola-8,14-dien-24-ol (4.0 g) is dissolved in 80 ml of dry pyridine at 0° C. 3.04 g of p-toluenesulphonyl chloride is added and the mixture is stirred at 5° C. for 20 hours and at room temperature for 5 hours. After aqueous work-up and crystallisation from methanol, 3.01 g of 3β-tert-butyldimethylsilyloxy-4,4-dimethyl-24-p-toluenesulphonyloxy-5α-chola-8,14-diene is obtained.
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][C:11](=[O:14])[C:10]([CH3:16])([CH3:15])[CH2:9]1)C1C=CC=CC=1.[C:17](=[O:28])([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])OC(C)(C)C.C(=O)([O-])[O-].[Na+].[Na+]>C(OCC)(=O)C.C(O)C.[Pd]>[C:17]([N:8]1[CH2:13][CH2:12][C:11](=[O:14])[C:10]([CH3:16])([CH3:15])[CH2:9]1)([O:23][C:24]([CH3:25])([CH3:26])[CH3:27])=[O:28]
Reactant: CC1(C)CN(Cc2ccccc2)CCC1=O
Reactant: CC(C)(C)OC(=O)OC(C)(C)C
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCC(=O)C(C)(C)C1
Reaction time: 1 h
Yield: 90.6 %

Procedure:
To a solution of 1-benzyl-3,3-dimethylpiperidin-4-one (0.217 g, 1.00 mmol, 1.0 eq) in ethyl acetate-ethanol (1:1, 10 mL) was added palladium on carbon (approximately 0.100 g). The reaction was purged with nitrogen followed by hydrogen and stirred under an atmosphere of hydrogen for 1 hour. The reaction was purged with nitrogen and di-tert-butyl carbonate (0.327 g, 1.50 mmol, 1.5 eq) and sodium carbonate (0.212 g, 2.00 mmol, 2.0 eq) were added. The solution was stirred at room temperature for 1.5 hours and the reaction filtered through Celite®, eluting with EtOAc (4×20 mL). The filtrate was concentrated under reduced pressure. MPLC (15→50% EtOAc-hexane) yielded the title compound (0.206 g, 91%) as a white solid; 1H nmr (CDCl3) δ 3.69 (2H, dd, J 6.5, 6.0 Hz, pipH-6), 3.40 (2H, s, pipH-2), 2.46 (2H, t, J 6.5 Hz, pipH-5), 1.46 (9H, s, C(CH3)3), 1.08 (6H, s, 2×CH3); 13C nmr (CDCl3) δ 177.2, 154.7, 80.1, 54.9, 46.5, 43.4, 37.6, 28.3, 22.4; m/z 172 [M+H—C4H8]+.
Reaction SMILES: [I:1]Cl.[CH3:3][C:4]1[CH:10]=[CH:9][C:7]([NH2:8])=[CH:6][C:5]=1[C:11]([F:14])([F:13])[F:12].C(=O)(O)[O-].[Na+]>ClCCl.CO.S(S([O-])=O)([O-])(=O)=O.[Na+].[Na+]>[I:1][C:9]1[CH:10]=[C:4]([CH3:3])[C:5]([C:11]([F:12])([F:13])[F:14])=[CH:6][C:7]=1[NH2:8]
Reactant: ClI
Reactant: Cc1ccc(N)cc1C(F)(F)F
Agent: O=C([O-])O
Agent: O=S([O-])S(=O)(=O)[O-]
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Product: Cc1cc(I)c(N)cc1C(F)(F)F
Reaction time: 3 h
Yield: 103.1 %

Procedure:
Add a solution of iodine monochloride (27.8 g, 171 mmol) in dichloromethane (180 mL) to a solution of 4-methyl-3-trifluoromethylaniline (25.0 g, 143 mmol) and sodium bicarbonate (14.4 g, 171 mmol) in methanol (180 mL) and dichloromethane (730 mL) at room temperature under nitrogen. Stir the mixture for 3 h and dilute the cooled mixture with aqueous sodium metabisulfite (500 mL). Collect the organic phase, and extract the aqueous phase with methylene chloride (200 mL). Wash the combined organic extracts with brine (250 mL), dry over anhydrous sodium sulfate and filter. Remove the solvent under reduced pressure to provide a brown oil, which crystallizes upon standing to afford the title compound as brown needles (44.4 g, >99%), which is used in the next step without purification. APCI MS m/z 302 (M+H)+.
Reaction SMILES: [OH-].[Na+].[CH:3]1([C:9]2[C:10]3[CH:11]=[CH:12][C:13]([C:29]([O:31]C)=[O:30])=[CH:14][C:15]=3[N:16]3[CH2:22][CH:21]([CH2:23][OH:24])[CH2:20][C:19]4[CH:25]=[CH:26][CH:27]=[CH:28][C:18]=4[C:17]=23)[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1.Cl>CO.O1CCCC1>[CH:3]1([C:9]2[C:10]3[CH:11]=[CH:12][C:13]([C:29]([OH:31])=[O:30])=[CH:14][C:15]=3[N:16]3[CH2:22][CH:21]([CH2:23][OH:24])[CH2:20][C:19]4[CH:25]=[CH:26][CH:27]=[CH:28][C:18]=4[C:17]=23)[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]1
Reactant: COC(=O)c1ccc2c(C3CCCCC3)c3n(c2c1)CC(CO)Cc1ccccc1-3
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)c1ccc2c(C3CCCCC3)c3n(c2c1)CC(CO)Cc1ccccc1-3
Temperature: 100 °C
Yield: 69.4 %

Procedure:
Sodium hydroxide (0.2 mL of 1 N, 0.2 mmol) was added to a solution of methyl (±)-13-cyclohexyl-6,7-dihydro-6-hydroxymethyl-5H-indolo[2,1-a][2]benzazepine-10-carboxylate (15.0 mg, 0.037 mmol) in methanol (0.5 mL) and tetrahydrofuran (0.5 mL) in a microwave vial. The vial was sealed and the contents heated at 100° C. for 10 min in a microwave apparatus. The solution was acidified with dilute hydrochloric acid to precipitate the crude acid. The solid was collected and purified on the Shimadzu preparative liquid chromatograph. The product containing fraction was concentrated on a Speed Vac® to leave the titled compound as a white solid (10.0 mg, 69%). ESI-MS m/z 390 (MH+); 1H NMR (500 MHz, MeOD) δ 1.19–1.34 (m, 1 H) 1.36–1.56 (m, 2 H) 1.63 (m, 1 H) 1.74–1.87 (m, 2 H) 1.91–2.21 (m, 5 H) 2.37–2.60 (m, 1 H) 2.74 (m, 1 H) 2.97 (m, 1 H) 3.36 (m, 1 H) 3.47–3.67 (m, 2 H) 4.59 (m, 1 H) 7.38–7.50 (m, 4 H) 7.72 (m, 1 H) 7.88 (m, 1 H) 8.18 (m, 1 H).
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:11]=1[NH:10][CH:9]=[CH:8]2)[CH3:2].[Cl-].[CH3:13][O:14][C:15]1[CH:27]=[CH:26][CH:25]=[CH:24][C:16]=1[CH:17]=[N+:18]1[CH2:23][CH2:22][O:21][CH2:20][CH2:19]1>>[CH2:1]([C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:11]=1[NH:10][CH:9]=[C:8]2[CH:17]([C:16]1[CH:24]=[CH:25][CH:26]=[CH:27][C:15]=1[O:14][CH3:13])[N:18]1[CH2:23][CH2:22][O:21][CH2:20][CH2:19]1)[CH3:2]
Reactant: CCc1cccc2cc[nH]c12
Reactant: COc1ccccc1C=[N+]1CCOCC1
Agent: [Cl-]
Product: CCc1cccc2c(C(c3ccccc3OC)N3CCOCC3)c[nH]c12

Procedure:
The preparation was carried out in accordance with general synthesis instructions 4 from 7-ethyl-1H-indole and 4-(2-methoxy-benzylidene)-morpholin-4-ium chloride.