Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Si:1]([O:8][CH2:9][C:10]1[C:11](=[O:17])[NH:12][C:13](=[O:16])[NH:14][CH:15]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[CH2:18]([N:24]=[C:25]=[O:26])[CH2:19][CH2:20][CH2:21][CH2:22][CH3:23]>CN(C1C=CN=CC=1)C>[Si:1]([O:8][CH2:9][C:10]1[C:11](=[O:17])[NH:12][C:13](=[O:16])[N:14]([C:25]([NH:24][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])=[O:26])[CH:15]=1)([C:4]([CH3:7])([CH3:5])[CH3:6])([CH3:3])[CH3:2]
Reactant: CCCCCCN=C=O
Reactant: CC(C)(C)[Si](C)(C)OCc1c[nH]c(=O)[nH]c1=O
Agent: CN(C)c1ccncc1
Product: CCCCCCNC(=O)n1cc(CO[Si](C)(C)C(C)(C)C)c(=O)[nH]c1=O
Reaction time: 66 h
Yield: 73 %

Procedure:
The title compound: was obtained according to the procedure described for the synthesis of Example 1, starting from 5-[[tert-butyl(dimethyl)silyl]oxymethyl]-1H-pyrimidine-2,4-dione (0.28 g, 1.08 mmol); 2.2 equiv of DMAP and 2.2 equiv of hexyl isocyanate were used herein. The reaction was here stirred for 66 hrs, and the crude was purified by column chromatography using a Teledyne ISCO apparatus (cyclohexane:EtOAc 75:25) to afford the title compound (0.30 g, 73%) as a white solid. 1H NMR (400 MHz, CDCl3); δ 0.12 (s, 6H), 0.89 (t, J=6.9 Hz, 3H), 0.94 (s, 9H), 1.29-1.39 (m, 6H), 1.58-1.63 (m, 2H), 3.39 (td, J=7.1, 5.7 Hz, 2H), 4.52 (d, J=1.7 Hz, 2H), 828 (s, 1H), 8.47 (t, J=1.7 Hz, 1H), 9.06 (t, J=4.8 Hz, 1H). MS (ESI) m/z: 384 [M-H]+.
Reaction SMILES: [C:1]([C:6]1[CH:11]=[CH:10][C:9]([NH:12]C(=O)OC)=[CH:8][CH:7]=1)([CH2:4][CH3:5])([CH3:3])[CH3:2].NC1C=CC=CC=1.C[O-].[Na+]>CO>[C:1]([C:6]1[CH:7]=[CH:8][C:9]([NH2:12])=[CH:10][CH:11]=1)([CH2:4][CH3:5])([CH3:2])[CH3:3]
Reactant: CCC(C)(C)c1ccc(NC(=O)OC)cc1
Agent: C[O-]
Agent: [Na+]
Solvent: Nc1ccccc1
Solvent: CO
Product: CCC(C)(C)c1ccc(N)cc1
Temperature: 200 °C
Reaction time: 4 h
Yield: 83 %

Procedure:
A mixture of 110 parts of methyl N-(4-tert.-pentyl-phenyl)-carbamate, 400 parts of aniline, 400 parts of methanol and 0.2 part of sodium methylate is heated to 200° C. in an autoclave and kept at this temperature for 4 hours. The mixture is then subjected to fractional distillation under reduced pressure. 67 parts (83% of theory) of 4-tert.-pentylaniline, of boiling point 140°-142° C./16 mbar, are obtained.
Reaction SMILES: [C:1]([N:8]1[CH2:13][CH2:12][C:11]([CH3:24])([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([C:20](OC)=[O:21])[CH:15]=2)[CH:10]([CH3:25])[CH2:9]1)(=O)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].[H-].[Al+3].[Li+].[H-].[H-].[H-]>O1CCCC1>[CH2:1]([N:8]1[CH2:13][CH2:12][C:11]([CH3:24])([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([CH2:20][OH:21])[CH:15]=2)[CH:10]([CH3:25])[CH2:9]1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: CCCCCC(=O)N1CCC(C)(c2cccc(C(=O)OC)c2)C(C)C1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CCCCCCN1CCC(C)(c2cccc(CO)c2)C(C)C1
Temperature: 25 °C
Reaction time: 3 h
Yield: 43 %

Procedure:
A stirred solution of 1-hexanoyl-3,4-dimethyl-4-(3-methoxycarbonyl-phenyl)piperidine (Preparation 7, 80 mg, 0.23 mmol) in anhydrous tetrahydrofuran (1 mL) under nitrogen was treated with lithium aluminium hydride (1.0 M in ether, 0.70 mL, 0.70 mmol) and the mixture was stirred at room temperature for 3 hours. The reaction mixture was then quenched with water (7.5 mL) and extracted with ethyl acetate (7 mL). The phases were separated and the aqueous layer was further extracted with ethyl acetate (2×5 mL). The combined organics were dried (Na2SO4) and the solvent removed in vacuo to give the title compound as a pale oil (30 mg).
Reaction SMILES: C[O:2][C:3](=[O:15])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([O:10][S:11]([CH3:14])(=[O:13])=[O:12])[CH:5]=1.[OH-].[Na+]>C1COCC1.C(O)C>[CH3:14][S:11]([O:10][C:6]1[CH:5]=[C:4]([CH:9]=[CH:8][CH:7]=1)[C:3]([OH:15])=[O:2])(=[O:13])=[O:12]
Reactant: COC(=O)c1cccc(OS(C)(=O)=O)c1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: CS(=O)(=O)Oc1cccc(C(=O)O)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 97.7 %

Procedure:
The above prepared 3-methanesulfonyloxy-benzoic acid methyl ester (3.81 g, 16 mmol) was dissolved in 100 ml of THF/ethanol=1/1 and treated with 50 ml of aq. NaOH (1M, 3 eq.). The mixture was stirred for 2 h at ambient temperature and was then poured onto crashed ice/AcOEt/HCl dil.; the organic layer was washed with water, dried over sodium sulfate, and evaporated to dryness to leave 3.38 g of the title compound as white solid.
Reaction SMILES: [F:1][B-:2]([F:5])([F:4])[F:3].[C:6]1([C:12]2[CH:17]=[C:16]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH:15]=[C:14]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[O+]=2)[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[O:30]([C:37]1[CH:43]=[CH:42][C:40]([NH2:41])=[CH:39][CH:38]=1)[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>C(O)C>[F:1][B-:2]([F:5])([F:4])[F:3].[O:30]([C:37]1[CH:38]=[CH:39][C:40]([N+:41]2[C:14]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)=[CH:15][C:16]([C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=3)=[CH:17][C:12]=2[C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=2)=[CH:42][CH:43]=1)[C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1
Reactant: c1ccc(-c2cc(-c3ccccc3)[o+]c(-c3ccccc3)c2)cc1
Reactant: Nc1ccc(Oc2ccccc2)cc1
Agent: F[B-](F)(F)F
Solvent: CCO
Product: c1ccc(Oc2ccc(-[n+]3c(-c4ccccc4)cc(-c4ccccc4)cc3-c3ccccc3)cc2)cc1
Temperature: 25 °C
Yield: 95.8 %

Procedure:
A 1 L round-bottom flask equipped with a condenser was charged with 2,4,6-triphenyl-pyrylium tetrafluoroborate (50.0 g, 0.126 mole), 4-phenoxyaniline (25.7 g, 0.138 mole) and ethanol (400 mL). The resulting solution was magnetically stirred and refluxed under nitrogen atmosphere for 6 hours. The solution was cooled to room temperature, the condensation product precipitate out as cream color crystal. The crystal was collected by filtration and dried in vacuum oven (100° C.) to give the desired product (68 g, 95% yield). Mp=201.7 C
Reaction SMILES: [NH:1]([C:5]1[S:6][CH:7]=[C:8]([C:10](OCC)([O:13]CC)[CH2:11][Br:12])[N:9]=1)[C:2]([NH2:4])=[NH:3]>Br>[BrH:12].[Br:12][CH2:11][C:10]([C:8]1[N:9]=[C:5]([NH:1][C:2]([NH2:4])=[NH:3])[S:6][CH:7]=1)=[O:13]
Reactant: CCOC(CBr)(OCC)c1csc(NC(=N)N)n1
Agent: Br
Product: N=C(N)Nc1nc(C(=O)CBr)cs1
Temperature: 25 °C
Reaction time: 15 h
Yield: 209.7 %

Procedure:
A mixture of 9.5 g (28 mmol) of 2-guanidino-4-(2-bromo-1,1-diethoxyethyl)thiazole in 50 ml of 48% hydrobromic acid was stirred at room temperature for 15 hours. The mixture was evaporated to complete dryness to afford 10.1 g (100%) of 2-bromo-1-(2-guanidino-4-thiazolyl)ethanone hydrobromide mp 247° (dec). This material could be converted to the free base by triturating with saturated sodium bicarbonate, stirring for 15 minutes, filtering the solid, and drying it under vacuum. In this way, 3.0 g of the hydrobromide salt was converted to 1.7 g (88%) of the free base, mp 210° (dec); nmr (DMSO-d6 (δ): 7.84 (s, 1H); 6.92 (s, 4H); 4.78 (s, 2H).
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][CH:3]=[N:2]1.[H-].[Na+].[CH3:8][N:9]([CH3:14])[S:10](Cl)(=[O:12])=[O:11].C(=O)([O-])O.[Na+]>O1CCCC1>[CH3:8][N:9]([CH3:14])[S:10]([N:1]1[CH:5]=[CH:4][CH:3]=[N:2]1)(=[O:12])=[O:11]
Reactant: CN(C)S(=O)(=O)Cl
Reactant: c1cn[nH]c1
Agent: O=C([O-])O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CN(C)S(=O)(=O)n1cccn1
Reaction time: 0.33 h

Procedure:
Pyrazole (12 g) was dissolved in tetrahydrofuran (200 mL), sodium hydride (60% in oil, 8.46 g) was added at 0° C. with stirring under a nitrogen atmosphere. After 20 min, dimethylsulfamoyl chloride (17 mL) was added dropwise, and the mixture was further stirred at the same temperature for 1 hr, and at room temperature for 1 hr. The reaction mixture was poured into saturated aqueous sodium hydrogen carbonate (400 mL), the mixture was extracted with ethyl acetate (400 mL), and the extract was dried over anhydrous magnesium sulfate. Insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane), and the object fraction was concentrated under reduced pressure to give the title compound (25.3 g) as a colorless oil.
Reaction SMILES: Cl.Cl.[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[S:18][C:17]3[C:16](=[O:19])[N:15]([CH2:20][CH2:21][C:22]4[CH:34]=[CH:33][C:25]([CH2:26][N:27]([CH3:32])[CH2:28][C:29](O)=[O:30])=[CH:24][CH:23]=4)[CH:14]=[N:13][C:12]=3[CH:11]=2)=[CH:6][CH:5]=1.CN.[CH2:37]([N:39](CC)CC)C.O=C1N(P(Cl)(N2CCOC2=O)=O)CCO1>O1CCCC1.C(OCC)(=O)C.C(Cl)Cl>[Cl:3][C:4]1[CH:5]=[CH:6][C:7]([C:10]2[S:18][C:17]3[C:16](=[O:19])[N:15]([CH2:20][CH2:21][C:22]4[CH:23]=[CH:24][C:25]([CH2:26][N:27]([CH3:32])[CH2:28][C:29]([NH:39][CH3:37])=[O:30])=[CH:33][CH:34]=4)[CH:14]=[N:13][C:12]=3[CH:11]=2)=[CH:8][CH:9]=1
Reactant: CN(CC(=O)O)Cc1ccc(CCn2cnc3cc(-c4ccc(Cl)cc4)sc3c2=O)cc1
Reactant: CCN(CC)CC
Agent: CN
Agent: Cl
Agent: O=C1OCCN1P(=O)(Cl)N1CCOC1=O
Solvent: ClCCl
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CNC(=O)CN(C)Cc1ccc(CCn2cnc3cc(-c4ccc(Cl)cc4)sc3c2=O)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 22.5 %

Procedure:
A mixture of the compound (70 mg) obtained in Example 30, 2N methylamine in tetrahydrofuran solution (0.65 ml), triethylamine (59 mg), bis(2-oxo-3-oxazolidinyl)phosphinoyl chloride (39 mg) and methylene chloride (5 ml) was stirred overnight at room temperature. The reaction mixture was diluted with ethyl acetate, washed with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated is under reduced pressure. The residue was purified by column chromatography [developing solvent:ethyl acetate-methanol (10:1, volume ratio)] and recrystallized from ethyl acetate-hexane (1:1, volume ratio) to give the title compound (14 mg) as a colorless powder.
Reaction SMILES: [C:1]([O:5][CH3:6])(=[O:4])[CH:2]=[CH2:3].[C:7]([O:11][CH3:12])(=[O:10])[CH2:8][SH:9].N1CCCCC1.C([O-])(=O)C=C>C(Cl)(Cl)Cl>[CH3:12][O:11][C:7]([CH2:8][S:9][CH2:3][CH2:2][C:1]([O:5][CH3:6])=[O:4])=[O:10]
Reactant: COC(=O)CS
Reactant: C=CC(=O)OC
Agent: C=CC(=O)[O-]
Solvent: C1CCNCC1
Solvent: ClC(Cl)Cl
Product: COC(=O)CCSCC(=O)OC
Temperature: 25 °C
Reaction time: 1 h
Yield: 99.3 %

Procedure:
Methyl acrylate (4.25 g, 49.5 mmol) was added dropwise over 20 min to a stirred solution of methyl thioglycolate (5 g, 47.16 mmol) and piperidine (0.10 mL) at rt. When about half of the acrylate had been introduced, more piperidine (0.10 mL) was added. After completion of the addition of the acrylate, the reaction mixture was stirred for 1 h at rt. The mixture was diluted with 100 mL of chloroform. The chloroform layer was washed with water, brine and dried over Na2SO4. The solution was filtered and evaporated the solvent to give the product as an oil (9 g, 100%).
Reaction SMILES: [Cl:1][C:2]1[CH:28]=[CH:27][C:5]2[N:6]3[C:10]([CH2:11][NH:12][CH2:13][C:4]=2[CH:3]=1)=[N:9][N:8]=[C:7]3[C@H:14]1[CH2:19][CH2:18][C@H:17]([C:20]2[C:25]([F:26])=[CH:24][CH:23]=[CH:22][N:21]=2)[CH2:16][CH2:15]1.[CH3:29][C:30]([CH3:32])=O.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(N(C(C)C)C(C)C)C>ClCCCl.CO>[Cl:1][C:2]1[CH:28]=[CH:27][C:5]2[N:6]3[C:10]([CH2:11][N:12]([CH:30]([CH3:32])[CH3:29])[CH2:13][C:4]=2[CH:3]=1)=[N:9][N:8]=[C:7]3[C@H:14]1[CH2:19][CH2:18][C@H:17]([C:20]2[C:25]([F:26])=[CH:24][CH:23]=[CH:22][N:21]=2)[CH2:16][CH2:15]1
Reactant: Fc1cccnc1[C@H]1CC[C@H](c2nnc3n2-c2ccc(Cl)cc2CNC3)CC1
Reactant: CC(C)=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Solvent: CC(=O)O
Solvent: CO
Product: CC(C)N1Cc2cc(Cl)ccc2-n2c(nnc2[C@H]2CC[C@H](c3ncccc3F)CC2)C1
Reaction time: 20 h

Procedure:
After stirring a solution of trans-8-chloro-1-[4-(3-fluoro-pyridin-2-yl)-cyclohexyl]-5,6-dihydro-4H-2,3,5,10b-tetraaza-benzo[e]azulene (50.0 mg, 0.126 mmol), acetone (0.019 ml, 0.251 mmol) and acetic acid (0.014 ml, 0.25 mmol) in 1,2-dichloroethane (1.3 ml) at room temperature for 5 h, sodium triacetoxyborohydride (58.6 mg, 0.276 mmol) was added. Stirring for further 20 h was followed by quenching with methanol (1 ml) and N-ethyldiisopropylamine (0.044 ml, 0.25 mmol). The reaction mixture was stirred for 30 minutes and concentrated in vacuo. Preparative RP-HPLC with water (0.05% formic acid)/methanol as eluent gave the title compound (40 mg, 72%) as white solid. MS m/e: 440 ([M+H]+)
Reaction SMILES: [O:1]=[C:2]1[N:6]([CH2:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=2)[C@H:5]([C:14]([OH:16])=O)[CH2:4][CH2:3]1.Cl.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1.[Cl:39][C:40]1[C:45]([C:46]([F:49])([F:48])[F:47])=[CH:44][CH:43]=[CH:42][C:41]=1[CH2:50][NH2:51]>ClCCl>[Cl:39][C:40]1[C:45]([C:46]([F:48])([F:49])[F:47])=[CH:44][CH:43]=[CH:42][C:41]=1[CH2:50][NH:51][C:14](=[O:16])[C@@H:5]1[CH2:4][CH2:3][C:2](=[O:1])[N:6]1[CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=1
Reactant: NCc1cccc(C(F)(F)F)c1Cl
Reactant: O=C(O)[C@@H]1CCC(=O)N1Cc1ccccn1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Product: O=C(NCc1cccc(C(F)(F)F)c1Cl)[C@@H]1CCC(=O)N1Cc1ccccn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 63.9 %

Procedure:
5-oxo-1-(2-pyridinylmethyl)proline (0.220 g, 1 mmol, prepared as described below), N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (0.384 g, 2 mmol), and 1-hydroxybenzotriazole (0.308 g, 2 mmol) were stirred together in dichloromethane (10 ml) at room temperature for 30 minutes. The mixture was then treated with {[2-chloro-3-(trifluoromethyl)phenyl]methyl}amine (0.314 g, 1.5 mmol) and the mixture was stirred overnight at room temperature. The mixture was concentrated and partitioned between ethyl acetate and saturated aqueous sodium hydrogen carbonate solution. The aqueous layer was separated and extracted with ethyl acetate and then the combined ethyl acetate fractions were washed with 3 portions of water and then with saturated aqueous sodium chloride solution. Drying over sodium sulphate and concentration gave a solid residue which was purified by mass-directed automated HPLC to give N-{[2-chloro-3-(trifluoromethyl)phenyl]methyl}-5-oxo-1-(2-pyridinylmethyl)prolinamide (0.263 g) as a buff-coloured solid.
Reaction SMILES: Br[C:2]1[N:3]=[C:4]([C:7]2[CH:16]=[C:15]([OH:17])[C:14]3[C:9](=[C:10]([Cl:20])[C:11]([O:18][CH3:19])=[CH:12][CH:13]=3)[N:8]=2)[S:5][CH:6]=1.O.C[C:23]([N:25](C)C)=O>[Zn].[C-]#N.[C-]#N.[Zn+2].C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.[Fe+2]>[Cl:20][C:10]1[C:11]([O:18][CH3:19])=[CH:12][CH:13]=[C:14]2[C:9]=1[N:8]=[C:7]([C:4]1[S:5][CH:6]=[C:2]([C:23]#[N:25])[N:3]=1)[CH:16]=[C:15]2[OH:17]
Reactant: COc1ccc2c(O)cc(-c3nc(Br)cs3)nc2c1Cl
Reactant: CC(=O)N(C)C
Agent: [Fe+2]
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: O
Product: COc1ccc2c(O)cc(-c3nc(C#N)cs3)nc2c1Cl
Yield: 81 %

Procedure:
The compound 262 (286 mg, 1 eq.) in degazed dimethylacetamide (10 mL), and Zn (4.5 mg, 0.09 eq.), Zn(CN)2 (84 mg, 0.6 eq.), Pd2dba3 (21 mg, 0.03 eq.), and dppf (26 mg, 0.06 eq.) were heated at 110° C. under microwaves for 30 min. Then, water was added, the precipitate filtered and dissolved in ethyl acetate, dried, and concentrated under vacuum. The residue was purified by chromatography on a silica gel to give compound 263 as a yellow solid in 81% yield. 1H NMR (CDCl3, 400 MHz) δ (ppm) 4.07 (s, 3H), 6.79 (br s, 1H), 7.08 (d, J=9.11 Hz, 1H), 8.19 (s, 1H), 8.28 (d, J=9.11 Hz, 1H), 9.74 (br s, 1H); MS (ESI, EI+): m/z=318.15 (MH+).
Reaction SMILES: [C:1]([O:5][C:6](=[O:34])[NH:7][C:8]1[CH:13]=[C:12]([CH3:14])[C:11]([CH2:15][NH:16][C:17]([C:19]2[CH:20]=[N:21][N:22]([CH2:24][C:25]3[CH:30]=[CH:29][C:28]([CH2:31]O)=[CH:27][CH:26]=3)[CH:23]=2)=[O:18])=[C:10]([CH3:33])[N:9]=1)([CH3:4])([CH3:3])[CH3:2].C[Si]([Cl:39])(C)C.CS(C)=O.C([O-])(O)=O.[Na+]>>[C:1]([O:5][C:6](=[O:34])[NH:7][C:8]1[CH:13]=[C:12]([CH3:14])[C:11]([CH2:15][NH:16][C:17]([C:19]2[CH:20]=[N:21][N:22]([CH2:24][C:25]3[CH:30]=[CH:29][C:28]([CH2:31][Cl:39])=[CH:27][CH:26]=3)[CH:23]=2)=[O:18])=[C:10]([CH3:33])[N:9]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1cc(NC(=O)OC(C)(C)C)nc(C)c1CNC(=O)c1cnn(Cc2ccc(CO)cc2)c1
Reactant: C[Si](C)(C)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CS(C)=O
Product: Cc1cc(NC(=O)OC(C)(C)C)nc(C)c1CNC(=O)c1cnn(Cc2ccc(CCl)cc2)c1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
A mixture of [5-({[1-(4-Hydroxymethyl-benzyl)-1H-pyrazole-4-carbonyl]-amino}-methyl)-4,6-dimethyl-pyridin-2-yl]-carbamic acid tert-butyl ester (100 mg, 0.2 mmol, for preparation see step D, example 16), trimethylsilyl chloride (47 mg, 0.4 mmol) and DMSO (4 mg, 0.06 mmol) was stirred at RT for 10 min. Aq. NaHCO3-solution was added and the mixture was extracted with ethyl acetate. The organic layer was dried over MgSO4 and concentrated in vacuo to yield the title compound which was used in the next step without further purification. LCMS (method A) RtA=1.598 min; [M+H]+=484.0.
Reaction SMILES: [ClH:1].Cl.F[C:4]1C=C(C2(O)CCCCC2CCN2CCN(C)CC2)C=CC=1OCC1C=CC(C(F)(F)F)=CC=1.Cl.Cl.[F:40][C:41]1[CH:42]=[C:43]([CH:59]([C:67]2([OH:73])[CH2:72][CH2:71][CH2:70][CH2:69][CH2:68]2)[CH2:60][N:61]2[CH2:66][CH2:65][NH:64][CH2:63][CH2:62]2)[CH:44]=[CH:45][C:46]=1[O:47][CH2:48][C:49]1[CH:54]=[CH:53][C:52]([C:55]([F:58])([F:57])[F:56])=[CH:51][CH:50]=1>>[ClH:1].[ClH:1].[F:40][C:41]1[CH:42]=[C:43]([CH:59]([C:67]2([OH:73])[CH2:72][CH2:71][CH2:70][CH2:69][CH2:68]2)[CH2:60][N:61]2[CH2:62][CH2:63][N:64]([CH3:4])[CH2:65][CH2:66]2)[CH:44]=[CH:45][C:46]=1[O:47][CH2:48][C:49]1[CH:50]=[CH:51][C:52]([C:55]([F:57])([F:58])[F:56])=[CH:53][CH:54]=1
Reactant: OC1(C(CN2CCNCC2)c2ccc(OCc3ccc(C(F)(F)F)cc3)c(F)c2)CCCCC1
Reactant: CN1CCN(CCC2CCCCC2(O)c2ccc(OCc3ccc(C(F)(F)F)cc3)c(F)c2)CC1
Agent: Cl
Product: CN1CCN(CC(c2ccc(OCc3ccc(C(F)(F)F)cc3)c(F)c2)C2(O)CCCCC2)CC1

Procedure:
In an analogous manner to Example 24, 1-{1-(3-fluoro-4-{[4-(trifluoromethyl)benzyl]oxy}phenyl)-2-(4-methylpiperazin-1-ylethyl]cyclohexanol dihydrochloride was prepared from 1-[1-(3-fluoro-4-{[4-(trifluoromethyl)benzyl]oxy}phenyl)-2-piperazin-1-ylethyl]cyclohexanol dihydrochloride (See Example 415). MS (ESI) m/z 495; HRMS: calcd for C27H34F4N2O2+H+, 495.26292; found (ESI, [M+H]+), 495.2659.
Reaction SMILES: [C:1]1(=[O:22])[N:5]([CH:6]([C:12]([O:14]CC)=O)[C:7]([O:9][CH2:10][CH3:11])=[O:8])[C:4](=[O:17])[C:3]2=[CH:18][CH:19]=[CH:20][CH:21]=[C:2]12.[Cl:23][C:24]1[CH:30]=[C:29]([S:31]([CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH3:45])(=[O:33])=[O:32])[CH:28]=[CH:27][C:25]=1[NH2:26]>C1(C)C(C)=CC=CC=1>[Cl:23][C:24]1[CH:30]=[C:29]([S:31]([CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH3:45])(=[O:32])=[O:33])[CH:28]=[CH:27][C:25]=1[NH:26][C:12](=[O:14])[CH:6]([N:5]1[C:4](=[O:17])[C:3]2=[CH:18][CH:19]=[CH:20][CH:21]=[C:2]2[C:1]1=[O:22])[C:7]([O:9][CH2:10][CH3:11])=[O:8]
Reactant: CCCCCCCCCCCCS(=O)(=O)c1ccc(N)c(Cl)c1
Reactant: CCOC(=O)C(C(=O)OCC)N1C(=O)c2ccccc2C1=O
Solvent: Cc1ccccc1C
Product: CCCCCCCCCCCCS(=O)(=O)c1ccc(NC(=O)C(C(=O)OCC)N2C(=O)c3ccccc3C2=O)c(Cl)c1

Procedure:
Diethyl 2-phthalimidomalonate (obtained from Aldrich Chemical Company Limited) (9.8 g, 32.0 mmol) and 2-chloro-4-dodecylsulphonylaniline (11.5 g, 32.0 mmol) were added to xylene (250 ml) and refluxed under a Dean and Stark trap for 96 hr. The distillate was periodically removed and the main bulk of solvent replenished as necessary. Removal of the xylene solvent under reduced pressure afforded a light brown oil which was purified by column chromatography using a 4:1 mixture of 60-80° C. petroleum ether:ethyl acetate and silica gel. The product, coupler (C13), was obtained as a white solid which was slurried with a little petroleum ether, filtered and dried in air, 13.6 g, 67%.
Reaction SMILES: C([O:4][C@H:5]1[CH2:22][CH2:21][C@@:20]2([CH3:23])[C@@H:7]([CH2:8][CH2:9][C@:10]3([CH3:40])[C@@H:19]2[CH2:18][CH2:17][C@H:16]2[C@@:11]3([CH3:39])[CH2:12][CH2:13][C@@:14]3(/[CH:31]=[C:32](\[CH3:38])/[C:33]([O:35]CC)=[O:34])[CH2:26][C:25](=[O:27])[C:24]([CH:28]([CH3:30])[CH3:29])=[C:15]32)[C:6]1([CH3:42])[CH3:41])(=O)C.[OH-].[Na+]>C1COCC1.CO.O>[OH:4][C@H:5]1[CH2:22][CH2:21][C@@:20]2([CH3:23])[C@@H:7]([CH2:8][CH2:9][C@:10]3([CH3:40])[C@@H:19]2[CH2:18][CH2:17][C@H:16]2[C@@:11]3([CH3:39])[CH2:12][CH2:13][C@@:14]3(/[CH:31]=[C:32](\[CH3:38])/[C:33]([OH:35])=[O:34])[CH2:26][C:25](=[O:27])[C:24]([CH:28]([CH3:30])[CH3:29])=[C:15]32)[C:6]1([CH3:42])[CH3:41]
Reactant: CCOC(=O)/C(C)=C/[C@@]12CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC[C@H](OC(C)=O)C(C)(C)[C@@H]5CC[C@]43C)C1=C(C(C)C)C(=O)C2
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: C/C(=C\[C@@]12CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC[C@H](O)C(C)(C)[C@@H]5CC[C@]43C)C1=C(C(C)C)C(=O)C2)C(=O)O
Temperature: 20 °C
Reaction time: 2 h
Yield: 74 %

Procedure:
To a solution of (E)-ethyl 3-((3aS,5aR,5bR,7aR,9S,11aR,11bR,13aS)-9-acetoxy-1-isopropyl-5a,5b,8,8,11a-pentamethyl-2-oxo-3,3a,4,5,5a,5b,6,7,7a,8,9,10,11,11a,11b,12,13,13a-octadecahydro-2H-cyclopenta[a]chrysen-3a-yl)-2-methylacrylate (2.0 g, 3.44 mmol) in THF (12 mL), MeOH (8 mL) and water (4 mL) was added sodium hydroxide (5.51 g, 138 mmol). The reaction mixture was stirred at 20° C. for 2 hrs. The reaction mixture was evaporated to dryness and the pH was adjusted to 5 with saturated NH4CI. The solid is solved into DCM (50 mL), washed with water, dried over Na2SO4 and concentrated to yield the (E)-3-((3aS,5aR,5bR,7aR,9S,11aR,11bR,13aS)-9-hydroxy-1-isopropyl-5a,5b,8,8,11a-pentamethyl-2-oxo-3,3a,4,5,5a,5b,6,7,7a,8,9,10,11,11a,11b,12,13,13a-octadecahydro-2H-cyclopenta[a]chrysen-3a-yl)-2-methylacrylic acid (1.3 g, 54.8%) as a yellow solid.
Reaction SMILES: C([CH:5]([C:18]1[C:19](Cl)=[N:20][CH:21]=[CH:22][CH:23]=1)[C:6](O[SiH3])([NH:12][CH:13](C)C)[C:7]([O:9][CH2:10][CH3:11])=[O:8])(C)(C)C.N12CCCC1=NCCC2.[Cl-]>CN(C)C=O>[CH3:13][N:12]1[C:19]2[C:18](=[CH:23][CH:22]=[CH:21][N:20]=2)[CH:5]=[C:6]1[C:7]([O:9][CH2:10][CH3:11])=[O:8]
Reactant: CCOC(=O)C(NC(C)C)(O[SiH3])C(c1cccnc1Cl)C(C)(C)C
Agent: C1CN=C2CCCN2C1
Agent: [Cl-]
Solvent: CN(C)C=O
Product: CCOC(=O)c1cc2cccnc2n1C
Yield: 27.6 %

Procedure:
A solution of 994 mg of ethyl 3-t-butyldimethyl-silyloxy-3-(2-chloropyridin-3-yl)-2-methylaminopropionate (prepared as described in Preparation 79) and 393 mg of 1,5-diazabicyclo[4.3.0]non-5-ene in 5 ml of dimethylformamide was stirred at 150° C. for 5 hours. At the end of this time, the reaction mixture was poured into a saturated aqueous solution of amnmonium chloride, after which it was extracted with ethyl acetate. The extract was washed with an aqueous solution of sodium chloride and dried over anhydrous sodium sulfate, after which the solvent was removed by distillation under reduced pressure. The residue was purified by column chromatography through silica gel, using a gradient elution method, with mixtures of hexane and ethyl acetate in ratios ranging from 9:1 to 5:1 by volume as the eluent, to give 150 mg of the title compound having Rf=0.40 (on silica gel thin layer chromatography using a 3:1 by volume mixture of hexane and ethyl acetate as the developing solvent).
Reaction SMILES: [C:1]([NH:4][C:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][C:12]=2[Cl:14])[N:7](C(OCC)=O)[C:6]=1[C:20](=[O:27])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)(=[O:3])[CH3:2].[K+].[Br-]>C(OCC)(=O)C.CCCCCC>[C:1]([NH:4][C:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][C:12]=2[Cl:14])[NH:7][C:6]=1[C:20](=[O:27])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)(=[O:3])[CH3:2]
Reactant: CCOC(=O)n1c(C(=O)c2ccccc2)c(NC(C)=O)c2c(Cl)cccc21
Agent: [Br-]
Agent: [K+]
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: CC(=O)Nc1c(C(=O)c2ccccc2)[nH]c2cccc(Cl)c12

Procedure:
The title compound was prepared according to the procedure described in step 2 of Example 2 (Method A) from 3-acetylamino-2-benzoyl-4-chloro-1-(ethoxycarbonyl)indole (step 3). m.p.: 221-222° C. (ethyl acetate/hexane) 1H-NMR (CDCl3) δ: 9.12 (1H, br s), 7.82 (2H, d, J=7 Hz), 7.60-7.20 (6H, m), 7.12 (1H, d, J=7 Hz), 1.79 (3H, s) IR (KBr) ν: 3400, 3150, 1670, 1630, 1507, 1270, 780, 730 cm−1