Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([F:11])=[CH:7][C:6]=1[F:12])=[O:4].[CH2:13]([O:20][CH2:21][CH2:22][SH:23])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C(=O)([O-])[O-].[K+].[K+]>CO>[CH2:13]([O:20][CH2:21][CH2:22][S:23][CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([F:11])=[CH:7][C:6]=1[F:12])=[O:4])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: SCCOCc1ccccc1
Reactant: O=C(CCl)c1ccc(F)cc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: O=C(CSCCOCc1ccccc1)c1ccc(F)cc1F
Yield: 80.1 %

Procedure:
Using 2-chloro-2',4'-difluoroacetophenone (4.5 g, 0.024 mol), 2-benzyloxyethanethiol (4.2 g, 0.025 mol), potassium carbonate (4.0 g, 0.029 mol) and methanol (50 ml), 2-(2-benzyloxyethyl)thio-2',4'-difluoroacetophenone (6.2 g, yield: 80.8%) was obtained as a colorless oil by similar procedures to Example 1.
Reaction SMILES: [Cl:1][C:2]1[CH:19]=[C:18]([N+:20]([O-:22])=[O:21])[CH:17]=[C:16]([Cl:23])[C:3]=1[O:4][C:5]1[CH:6]=[CH:7][C:8]([O:14][CH3:15])=[C:9]([S:11]([OH:13])=[O:12])[CH:10]=1.[OH-].[Na+].[CH:26]1([CH2:29]Br)[CH2:28][CH2:27]1>C(O)C>[Cl:1][C:2]1[CH:19]=[C:18]([N+:20]([O-:22])=[O:21])[CH:17]=[C:16]([Cl:23])[C:3]=1[O:4][C:5]1[CH:6]=[CH:7][C:8]([O:14][CH3:15])=[C:9]([S:11]([CH2:29][CH:26]2[CH2:28][CH2:27]2)(=[O:13])=[O:12])[CH:10]=1
Reactant: BrCC1CC1
Reactant: COc1ccc(Oc2c(Cl)cc([N+](=O)[O-])cc2Cl)cc1S(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: COc1ccc(Oc2c(Cl)cc([N+](=O)[O-])cc2Cl)cc1S(=O)(=O)CC1CC1
Temperature: 70 °C
Reaction time: 6 h
Yield: 14 %

Procedure:
To a solution of 5-(2,6-dichloro-4-nitro-phenoxy)-2-methoxy-benzenesulfinic acid (1.0 g, 2.64 mmol) in ethanol was added NaOH (116 mg, 2.89 mmol) and cyclopropylmethyl bromide (1.40 mL, 14.5 mmol). The resulting mixture was stirred at 70° C. for 6 h, then at 50° C. for 20 h and concentrated to dryness. The residue was dissolved in 1 N HCl (40 mL) and extracted with EtOAc (4×40 mL). The combined organic extracts were dried and concentrated. The residue was purified by preparative TLC (CH2Cl2: Hex=4:1) to give the title compound of Step C (160 mg) as a solid. MS (APCl−) Caic.: 431.0, Found: 430.2 (M−1).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([F:14])=[C:10]([Cl:15])[CH:9]=2)[C:5]([CH3:16])=[CH:4][N:3]=1.[CH3:17][N:18]([CH:26]1[CH2:31][CH2:30][N:29]([CH3:32])[CH2:28][CH2:27]1)[C:19]1[CH:24]=[CH:23][C:22]([NH2:25])=[CH:21][CH:20]=1>C(Cl)Cl.CO>[Cl:15][C:10]1[CH:9]=[C:8]([C:6]2[C:5]([CH3:16])=[CH:4][N:3]=[C:2]([NH:25][C:22]3[CH:21]=[CH:20][C:19]([N:18]([CH3:17])[CH:26]4[CH2:31][CH2:30][N:29]([CH3:32])[CH2:28][CH2:27]4)=[CH:24][CH:23]=3)[N:7]=2)[CH:13]=[CH:12][C:11]=1[F:14]
Reactant: Cc1cnc(Cl)nc1-c1ccc(F)c(Cl)c1
Reactant: CN1CCC(N(C)c2ccc(N)cc2)CC1
Solvent: CO
Solvent: ClCCl
Product: Cc1cnc(Nc2ccc(N(C)C3CCN(C)CC3)cc2)nc1-c1ccc(F)c(Cl)c1
Yield: 25 %

Procedure:
The title compound was prepared according to synthesis procedure B described above from 2-chloro-4-(3-chloro-4-fluorophenyl)-5-methylpyrimidine and N1-methyl-N1-(1-methylpiperidin-4-yl)benzene-1,4-diamine in 25% yield (yellow solid) after flash chromatography (CH2Cl2/CH3OH 99:1 gradually increasing to 95:5). 1H NMR (400 MHz, CDCl3): δ 8.24 (s, 1H), 7.69 (dd, 1H, J=7.2, 1.7 Hz), 7.49 (m, 1H), 7.41 (d, 2H, J=8.9 Hz), 7.20 (d, 1H, 8.5 Hz), 6.79 (d, 2H, J=8.5 Hz), 3.49 (m, 1H), 3.00 (d, 2H, J=10.6 Hz), 2.74 (s, 3H), 2.34 (s, 3H), 2.21 (s, 3H), 2.11 (m, 2H), 1.89 (m, 2H), 1.72 (d, 2H, J=11.6 Hz); MS (ESI): 440.3 [M+H]+, 220.8 [M+2H]2+.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[CH:5]=[CH:4][N:3]=1.[CH3:9][O:10][C:11]1[C:16]([O:17][CH3:18])=[C:15]([O:19][CH3:20])[CH:14]=[CH:13][C:12]=1B(O)O.C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1.O>[Cl:1][C:2]1[N:7]=[C:6]([C:12]2[CH:13]=[CH:14][C:15]([O:19][CH3:20])=[C:16]([O:17][CH3:18])[C:11]=2[O:10][CH3:9])[CH:5]=[CH:4][N:3]=1
Reactant: Clc1ccnc(Cl)n1
Reactant: COc1ccc(B(O)O)c(OC)c1OC
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Product: COc1ccc(-c2ccnc(Cl)n2)c(OC)c1OC
Yield: 74.1 %

Procedure:
In a 250 mL round-bottomed flask, 1.49 grams (10 mmol) of 2,4-dichloropyrimidine was combined with 2,3,4-trimethoxyphenylboronic acid (2.12 g, 10 mmol), sodium carbonate (2.12 g, 2 equivalents), and 1.15 g (0.1 equivalents) of tetrakis-triphenylphosphinepalladium. Toluene (50 mL) and water (5 mL) were added. The reaction was allowed to reflux under nitrogen overnight. The reaction was diluted with toluene and water and the organic layer was separated, washed with brine, dried (Na2SO4), filtered, and concentrated to afford the crude pyrimidine 5. The compound was purified on silica gel using an eluent of 30% acetone/hexane to afford 2.08 g (74%) of the product 5 as a white solid.
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][CH:7]([C:10]([N:12]([CH2:21][CH2:22][CH2:23][N:24]2[CH2:29][CH2:28][CH:27]([NH:30]C(OC(C)(C)C)=O)[CH2:26][CH2:25]2)[C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[C:15]([Cl:20])[CH:14]=2)=[O:11])[CH2:6][CH2:5]1)(=[O:3])[CH3:2].Cl>CO.C(OCC)(=O)C>[C:1]([N:4]1[CH2:9][CH2:8][CH:7]([C:10]([N:12]([CH2:21][CH2:22][CH2:23][N:24]2[CH2:25][CH2:26][CH:27]([NH2:30])[CH2:28][CH2:29]2)[C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[C:15]([Cl:20])[CH:14]=2)=[O:11])[CH2:6][CH2:5]1)(=[O:3])[CH3:2]
Reactant: CC(=O)N1CCC(C(=O)N(CCCN2CCC(NC(=O)OC(C)(C)C)CC2)c2ccc(Cl)c(Cl)c2)CC1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CO
Product: CC(=O)N1CCC(C(=O)N(CCCN2CCC(N)CC2)c2ccc(Cl)c(Cl)c2)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 121.8 %

Procedure:
The compound obtained in Example 193 (4.08 g, 7.34 mmol) was dissolved in methanol (20 mL). To the solution was added a solution of 4N-hydrogen chloride in ethyl acetate (40 mL), and the mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure, and to the concentrate was added diethyl ether. The resulting precipitates were collected by fltration, washed with diethyl ether, and dried under reduced pressure to give the titled compound (4.07 g) as white amorphous substance.
Reaction SMILES: Cl.[NH2:2][C@H:3]1[CH2:8][CH2:7][C@H:6]([NH:9][C:10]([C:12]2[C:16]3[N:17]=[CH:18][N:19]=[C:20]([C:21]4[CH:26]=[C:25]([CH3:27])[C:24]([F:28])=[CH:23][C:22]=4[O:29][CH2:30][CH:31]4[CH2:33][CH2:32]4)[C:15]=3[NH:14][C:13]=2[CH3:34])=[O:11])[CH2:5][CH2:4]1.[C:35](Cl)(=[O:38])[CH2:36][CH3:37]>>[CH:31]1([CH2:30][O:29][C:22]2[CH:23]=[C:24]([F:28])[C:25]([CH3:27])=[CH:26][C:21]=2[C:20]2[C:15]3[NH:14][C:13]([CH3:34])=[C:12]([C:10]([NH:9][C@H:6]4[CH2:7][CH2:8][C@H:3]([NH:2][C:35](=[O:38])[CH2:36][CH3:37])[CH2:4][CH2:5]4)=[O:11])[C:16]=3[N:17]=[CH:18][N:19]=2)[CH2:32][CH2:33]1
Reactant: CCC(=O)Cl
Reactant: Cc1cc(-c2ncnc3c(C(=O)N[C@H]4CC[C@H](N)CC4)c(C)[nH]c23)c(OCC2CC2)cc1F
Agent: Cl
Product: CCC(=O)N[C@H]1CC[C@H](NC(=O)c2c(C)[nH]c3c(-c4cc(C)c(F)cc4OCC4CC4)ncnc23)CC1

Procedure:
Starting from N-(trans-4-aminocyclohexyl)-4-[2-(cyclopropylmethoxy)-4-fluoro-5-methylphenyl]-6-methyl-5H-pyrrolo[3,2-d]pyrimidine-7-carboxamide hydrochloride (example D.f41) and commercially available propionyl chloride the title compound is obtained as colorless solid.
Reaction SMILES: Br[C:2]1[N:10]2[C:5]([C:6]([NH2:11])=[N:7][CH:8]=[N:9]2)=[CH:4][C:3]=1[CH2:12][CH2:13][CH2:14][N:15]1[CH2:19][CH2:18][CH2:17][CH2:16]1.CC1(C)C(C)(C)OB([C:28]2[CH2:33][CH2:32][N:31]([C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[CH2:30][CH:29]=2)O1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[NH2:11][C:6]1[C:5]2=[CH:4][C:3]([CH2:12][CH2:13][CH2:14][N:15]3[CH2:19][CH2:18][CH2:17][CH2:16]3)=[C:2]([C:28]3[CH2:33][CH2:32][N:31]([C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[CH2:30][CH:29]=3)[N:10]2[N:9]=[CH:8][N:7]=1
Reactant: Nc1ncnn2c(Br)c(CCCN3CCCC3)cc12
Reactant: CC(C)(C)OC(=O)N1CC=C(B2OC(C)(C)C(C)(C)O2)CC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)N1CC=C(c2c(CCCN3CCCC3)cc3c(N)ncnn23)CC1
Temperature: 90 °C
Yield: 73.7 %

Procedure:
To a solution of the compound (135 mg, 0.42 mmol) prepared in Example 13, tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5,6-dihydropyridine-1(2H)-carboxylate (194 mg, 0.63 mmol), potassium phosphate (2N, 1 mL, 2.0 mmol), Pd(PPh3)4 (11 mg, 0.01 mmol) in dioxane (3 mL) was deoxygenated by nitrogen gas for 5 minutes, and the reactor was sealed, heated at 90° C. for 20 hours. The mixture was concentrated, extracted with DCM and sodium hydroxide (1N). The organic layer was dried, concentrated, and the crude product was purified by prep TLC using 5% methanol in DCM (with 1% ammonium hydroxide) to obtain the title compound (132 mg) having the following physical data.
Reaction SMILES: C([O:3][C:4](=[O:33])/[C:5](/[F:32])=[C:6](\[CH3:31])/[CH:7]=[CH:8]/[C:9](/[F:30])=[C:10](\[C:13]1[C:22]([O:23][CH2:24][CH3:25])=[CH:21][C:20]2[C:19]([CH3:27])([CH3:26])[CH2:18][CH2:17][C:16]([CH3:29])([CH3:28])[C:15]=2[CH:14]=1)/[CH2:11][CH3:12])C.[OH-].[Na+]>CCO>[CH2:24]([O:23][C:22]1[C:13](/[C:10](/[CH2:11][CH3:12])=[C:9](/[F:30])\[CH:8]=[CH:7]\[C:6](\[CH3:31])=[C:5](/[F:32])\[C:4]([OH:33])=[O:3])=[CH:14][C:15]2[C:16]([CH3:28])([CH3:29])[CH2:17][CH2:18][C:19]([CH3:26])([CH3:27])[C:20]=2[CH:21]=1)[CH3:25]
Reactant: CCOC(=O)/C(F)=C(C)/C=C/C(F)=C(/CC)c1cc2c(cc1OCC)C(C)(C)CCC2(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCOc1cc2c(cc1/C(CC)=C(F)\C=C\C(C)=C(/F)C(=O)O)C(C)(C)CCC2(C)C

Procedure:
Following General Procedure E and using (2Z,4E,6E)-7-(-3-ethoxy-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-naphthalen-2-yl)-2,6-difluoro-3-methyl-nona-2,4,6-trienoic acid ethyl ester (Compound 25, 81 mg, 0.18 mmol), 1M NaOH (0.53 mL), and EtOH (2 mL) at 40° C. for overnight followed by flash column chromatography on silica gel (10%→50% EtOAc-hexane), the title compound was obtained as a yellow solid (46 mg, 61%).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[C:19]([O:20][CH2:21][C:22]3[CH:27]=[CH:26][N:25]=[CH:24][CH:23]=3)=[CH:18][CH:17]=[CH:16][N:15]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.[F:28][C:29]([F:34])([F:33])[C:30]([OH:32])=[O:31]>ClCCl>[F:28][C:29]([F:34])([F:33])[C:30]([OH:32])=[O:31].[N:25]1[CH:26]=[CH:27][C:22]([CH2:21][O:20][C:19]2[C:14]([N:11]3[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]3)=[N:15][CH:16]=[CH:17][CH:18]=2)=[CH:23][CH:24]=1
Reactant: CC(C)(C)OC(=O)N1CCN(c2ncccc2OCc2ccncc2)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: c1cnc(N2CCNCC2)c(OCc2ccncc2)c1
Reaction time: 3 h

Procedure:
The crude 4-[3-(Pyridin-4-ylmethoxy)-pyridin-2-yl]piperazine-1-carboxylic acid tert-butyl ester (˜500 mg) was dissolved in 10 mL of 30% trifluoroacetic acid in dichloromethane. The reaction mixture was stirred for 3 hr and then the solvent was removed under vacuum. The impure material was used without purification.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[N:6][C:5]([Cl:8])=[C:4]2[NH:9][CH:10]=[CH:11][C:3]=12.[H-].[Na+].FC(F)(F)S(O[Si:20]([C:23]([CH3:26])([CH3:25])[CH3:24])([CH3:22])[CH3:21])(=O)=O>O1CCCC1>[Br:1][C:2]1[CH:7]=[N:6][C:5]([Cl:8])=[C:4]2[N:9]([Si:20]([C:23]([CH3:26])([CH3:25])[CH3:24])([CH3:22])[CH3:21])[CH:10]=[CH:11][C:3]=12
Reactant: CC(C)(C)[Si](C)(C)OS(=O)(=O)C(F)(F)F
Reactant: Clc1ncc(Br)c2cc[nH]c12
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)(C)[Si](C)(C)n1ccc2c(Br)cnc(Cl)c21
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 4-bromo-7-chloro-1H-pyrrolo[2,3-c]pyridine (1.64 g) in dry tetrahydrofuran (80 ml) at 0° C. under an atmosphere of nitrogen was added portionwise sodium hydride (60% dispersion in mineral oil, 625 mg). After addition, the solution was stirred at room temperature for 30 minutes. The solution was then recooled to 0° C. and a solution of tert-butyldimethylsilyl trifluoromethanesulphonate (3.75 g) in dry tetrahydrofuran (20 ml) was added dropwise. The solution was partitioned between ethyl acetate (100 ml) and water (100 ml) and washed with water until the pH of the aqueous was neutral. The organic layer was dried (MgSO4) and evaporated to give a brown oil. The residue was purified by Biotage chromatography over silica gel (10 g), eluting with 10% ethyl acetate/isohexane to give the title compound as a red oil. (1.63 g).
Reaction SMILES: C(OC([C:6]1[NH:7][CH:8]=[C:9]2[C:14]=1[CH:13]1[CH2:15][CH2:16][CH:10]2[CH:11]=[CH:12]1)=O)C.[OH-].[K+]>C(O)CO>[CH:6]1[NH:7][CH:8]=[C:9]2[C:14]=1[CH:13]1[CH2:15][CH2:16][CH:10]2[CH:11]=[CH:12]1
Reactant: CCOC(=O)c1[nH]cc2c1C1C=CC2CC1
Agent: [K+]
Agent: [OH-]
Solvent: OCCO
Product: C1=CC2CCC1c1c[nH]cc12
Temperature: 175 °C
Reaction time: 2 h
Yield: 70.3 %

Procedure:
A light-resistant reaction vessel equipped with a reflux condenser was charged with the ethyl-4,7-dihydro-4,7-ethano-2H-isoindole-1-carboxylate (1.95 g, 9.6 mmol) obtained in Step 2, 100 ml of ethylene glycol and 2.0 g of potassium hydroxide. The vessel was then purged with nitrogen, and the mixture was stirred for 2 hours at 175° C. The reaction mixture was then cooled to room temperature, and poured into ice water. The resulting solution was extracted with chloroform, the extract was washed with saturated saline and the obtained organic layer was dried over anhydrous sodium sulfate. Concentration of the solution under reduced pressure then gave 4,7-dihydro-4,7-ethano-2H-isoindole (0.98 g, yield 70.4%).
Reaction SMILES: [C:1]([NH:4][CH2:5][CH2:6][C:7]1[CH:8]=[CH:9][CH:10]=[C:11]2[C:16]=1[CH:15]=[C:14]([O:17][CH2:18][CH2:19][CH2:20][CH2:21][C:22](OC)=[O:23])[CH:13]=[CH:12]2)(=[O:3])[CH3:2].[H-].[Al+3].[Li+].[H-].[H-].[H-].Cl>O1CCCC1>[OH:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][O:17][C:14]1[CH:15]=[C:16]2[C:11]([CH:10]=[CH:9][CH:8]=[C:7]2[CH2:6][CH2:5][NH:4][C:1](=[O:3])[CH3:2])=[CH:12][CH:13]=1
Reactant: COC(=O)CCCCOc1ccc2cccc(CCNC(C)=O)c2c1
Agent: Cl
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Product: CC(=O)NCCc1cccc2ccc(OCCCCCO)cc12
Temperature: 25 °C
Reaction time: 6 h

Procedure:
In a 100 ml round-bottomed flask, dissolve the compound obtained in Step A (3.42 g, 10 mmol) in 50 ml of anhydrous tetrahydrofuran. Add lithium aluminium hydride (379.5 mg; 10 mmol) in small portions. Stir at room temperature for 6 hours. Hydrolyse the reaction mixture with 100 ml of an aqueous 1M hydrochloric acid solution. Extract the aqueous phase 3 times with dichloromethane. Dry the organic phase over magnesium sulphate and evaporate under reduced pressure. Use the resulting oil directly in the following Step.
Reaction SMILES: [O:1]=[C:2]1[N:6]([C@@H:7]2[CH2:12][CH2:11][N:10]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:9][C@H:8]2[OH:20])[C:5](=[O:21])[CH2:4][S:3]1.[Cl:22][C:23]1[CH:40]=[CH:39][C:26]([CH2:27][N:28]2[C:36]3[C:31](=[CH:32][C:33]([CH:37]=O)=[CH:34][CH:35]=3)[CH:30]=[N:29]2)=[C:25]([C:41]([F:44])([F:43])[F:42])[CH:24]=1>>[C:16]([O:15][C:13]([N:10]1[CH2:11][CH2:12][CH:7]([N:6]2[C:5](=[O:21])/[C:4](=[CH:37]/[C:33]3[CH:32]=[C:31]4[C:36](=[CH:35][CH:34]=3)[N:28]([CH2:27][C:26]3[CH:39]=[CH:40][C:23]([Cl:22])=[CH:24][C:25]=3[C:41]([F:44])([F:42])[F:43])[N:29]=[CH:30]4)/[S:3][C:2]2=[O:1])[CH:8]([OH:20])[CH2:9]1)=[O:14])([CH3:17])([CH3:18])[CH3:19]
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](N2C(=O)CSC2=O)[C@H](O)C1
Reactant: O=Cc1ccc2c(cnn2Cc2ccc(Cl)cc2C(F)(F)F)c1
Product: CC(C)(C)OC(=O)N1CCC(N2C(=O)S/C(=C\c3ccc4c(cnn4Cc4ccc(Cl)cc4C(F)(F)F)c3)C2=O)C(O)C1

Procedure:
(5Z)-4-{5-[1-(4-chloro-2-trifluoromethylbenzyl)-1H-indazol-5-ylmethylene]-2,4-dioxothiazolidin-3-yl}-3-hydroxypiperidine-1-carboxylic acid tert-butyl ester was prepared from 1,1-dimethylethyl trans-4-(2,4-dioxo-1,3-thiazolidin-3-yl)-3-hydroxypiperidine-1-carboxylate (from Example 270) and [4-chloro-2-(trifluoromethyl)benzyl]-1H-indazol-5-carbaldehyde (from Example 1) following General Procedure F1.
Reaction SMILES: [C:1]([C:4]1[CH:13]([C:14]2[CH:21]=[CH:20][C:17]([C:18]#[N:19])=[CH:16][C:15]=2[C:22]([F:25])([F:24])[F:23])[C:12]2[C:11](=[O:26])[NH:10][CH:9]=[CH:8][C:7]=2[NH:6][C:5]=1[CH3:27])(=[O:3])[CH3:2].ClCCl.F[B-](F)(F)F.[CH2:36]([O+](CC)CC)[CH3:37].CO>O>[C:1]([C:4]1[CH:13]([C:14]2[CH:21]=[CH:20][C:17]([C:18]#[N:19])=[CH:16][C:15]=2[C:22]([F:25])([F:24])[F:23])[C:12]2[C:7](=[CH:8][CH:9]=[N:10][C:11]=2[O:26][CH2:36][CH3:37])[NH:6][C:5]=1[CH3:27])(=[O:3])[CH3:2]
Reactant: CC(=O)C1=C(C)Nc2cc[nH]c(=O)c2C1c1ccc(C#N)cc1C(F)(F)F
Reactant: CC[O+](CC)CC
Agent: F[B-](F)(F)F
Solvent: O
Solvent: ClCCl
Solvent: CO
Product: CCOc1nccc2c1C(c1ccc(C#N)cc1C(F)(F)F)C(C(C)=O)=C(C)N2
Reaction time: 2 h

Procedure:
50 mg (0.134 mmol) of 4-(3-acetyl-2-methyl-5-oxo-1,4,5,6-tetrahydro-1,6-naphthyridin-4-yl)-3-(trifluoromethyl)benzonitrile are dissolved under an argon atmosphere in 5 ml of abs. dichloromethane, and 50.9 mg (0.268 mmol) of triethyloxonium tetrafluoroborate are added. After a reaction time of two hours at room temperature (reaction checked by HPLC), the mixture is mixed with 5 ml of methanol and 0.5 ml of water and again stirred for 2 h. It is then diluted with 20 ml of water and extracted three times with dichloromethane. The combined organic phases are dried with sodium sulfate, and the solvent is removed in a rotary evaporator. The residue is purified by preparative HPLC (eluent: acetonitrile/water with 0.1% formic acid, gradient 20:80→95:5). 23 mg (42.8% of theory) of the title compound are obtained.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][N:6]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[NH:8][C:7]1=[O:15].Cl.[F:17][C:18]1[CH:23]=[CH:22][C:21]([C:24]([CH:26]2[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]2)=[O:25])=[CH:20][CH:19]=1.C(=O)([O-])[O-].[Na+].[Na+].[I-].[K+]>O.CC(C)CC(=O)C>[F:17][C:18]1[CH:19]=[CH:20][C:21]([C:24]([CH:26]2[CH2:31][CH2:30][N:29]([CH2:2][CH2:3][CH2:4][CH2:5][N:6]3[C:10]4[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=4[NH:8][C:7]3=[O:15])[CH2:28][CH2:27]2)=[O:25])=[CH:22][CH:23]=1
Reactant: O=C(c1ccc(F)cc1)C1CCNCC1
Reactant: O=c1[nH]c2ccccc2n1CCCCCl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [I-]
Solvent: O
Solvent: CC(=O)CC(C)C
Product: O=C(c1ccc(F)cc1)C1CCN(CCCCn2c(=O)[nH]c3ccccc32)CC1
Yield: 30 %

Procedure:
A mixture of 4 parts of 1-(4-chlorobutyl)-1,3-dihydro-2H-benzimidazol-2-one, 4 parts of (4-fluorophenyl) (4-piperidinyl) methanone hydrochloride, 10 parts of sodium carbonate, 0.2 parts of potassium iodide and 80 parts of 4-methyl-2-pentanone is stirred and refluxed overnight. After cooling, water is added and the layers are separated. The organic phase is dried, filtered and evaporated. The solid residue is purified by column-chromatography over silica gel using a mixture of trichloromethane and 10% of methanol as eluent. The pure fractions are collected and the eluent is evaporated. The residue is crystallized from 4-methyl-2-pentanone, yielding 2 parts (30%) of 1-{4-[4-(4-fluorobenzoyl)-1-piperidinyl]butyl} -1,3-dihydro-2H-benzimidazol-2-one; mp. 176.5° C.
Reaction SMILES: [CH2:1]([CH2:9][SiH](Cl)Cl)[CH2:2]C1C=CC=CC=1.ClS(O)(=O)=O.[Cl:18][S:19]([C:22]1[CH:33]=[CH:32][C:25]([CH2:26][CH2:27][CH2:28][SiH:29]([Cl:31])Cl)=[CH:24][CH:23]=1)(=[O:21])=[O:20].C([Mg]Cl)C=C>>[Cl:18][S:19]([C:22]1[CH:23]=[CH:24][C:25]([CH2:26][CH2:27][CH2:28][SiH:29]([CH2:9][CH:1]=[CH2:2])[Cl:31])=[CH:32][CH:33]=1)(=[O:20])=[O:21]
Reactant: Cl[SiH](Cl)CCCc1ccccc1
Reactant: O=S(=O)(Cl)c1ccc(CCC[SiH](Cl)Cl)cc1
Agent: C=CC[Mg]Cl
Agent: O=S(=O)(O)Cl
Product: C=CC[SiH](Cl)CCCc1ccc(S(=O)(=O)Cl)cc1

Procedure:
Phenethylmethyldichlorosilane (Gelest, Inc., Tullytown, Pa., USA) is chlorosulfonated with chlorosulfonic acid as described in Chem. Abstr. 103 P71494v. This yields [4-(chlorosulfonyl)phenethyl] methyldichlorosilane which is reacted with allyl-magnesium chloride to form [4-(chlorosulfonyl)phenethyl] methyl allylchlorosilane. This product is reacted with octadecyl methylchlorosilane (boiling point of 175° to 177°/0.5 mm, from reaction of octadecylmagnesium bromide with methyldichlorosilane) under chloroplatinic acid catalysis to form 1-(octadecyl methylchlorosilyl)-3-{methyl [4-(chlorosulfonyl)phenethyl] chlorosilyl}propane. This material is reacted with dimethylamine to form 1-(octadecyl methyl dimethylaminosilyl)-3-{methyl [4-(chlorosulfonyl)-phenethyl] dimethylaminosilyl}propane.
Reaction SMILES: [CH3:1][CH:2]([CH2:6][CH2:7][CH3:8])[C:3](Cl)=[O:4].[CH2:9]([O:11][C:12]#[CH:13])[CH3:10].C(N(CC)CC)C>CCOCC>[CH2:12]([O:11][C:9]1[C:2]([CH3:1])([CH2:6][CH2:7][CH3:8])[C:3](=[O:4])[CH:10]=1)[CH3:13]
Reactant: C#COCC
Reactant: CCCC(C)C(=O)Cl
Solvent: CCOCC
Solvent: CCN(CC)CC
Product: CCCC1(C)C(=O)C=C1OCC
Yield: 77 %

Procedure:
The title compound was prepared using a modification of the method of Wasserman, H. H. et al [J. Org. Chem, 38, 1451-1455, (1973)]; to a solution of 2-methyl pentanoyl chloride (3.91 ml) and ethyl ethynylether (5 g, 40% solution in hexanes, 28.6 mmol) in Et2O (35 ml) at room temperature was added triethylamine (9.9 ml), with stirring. The reaction was warmed to 50° and stirred for 72 h prior to cooling and filtration. The filtrate was concentrated in vacuo and the residual oil chromatographed (SiO2; hexanes 80:EtOAc 20) to give the title compound as a colourless oil (3.71 g, 17.9 mmol, 77%). δH (CDCl3, 300K), 4.84 (1H, s), 4.24-3.98 (2H, m), 2.04 (3H, s), 1.56-1.43 (4H, m), 1.30-1.26 (3H, m), 0.91 (3H, t, J 7.3 Hz). m/z (ES+, 70V) 178.1 (MH+).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[C:8]([O:10][C:11]([F:14])([F:13])[F:12])[CH:7]=[CH:6][C:5]=1[OH:15])([O-])=O.S([O-])([O-])(=O)=S.[Na+].[Na+]>C(O)C.O>[NH2:1][C:4]1[CH:9]=[C:8]([O:10][C:11]([F:12])([F:13])[F:14])[CH:7]=[CH:6][C:5]=1[OH:15]
Reactant: O=[N+]([O-])c1cc(OC(F)(F)F)ccc1O
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: Nc1cc(OC(F)(F)F)ccc1O
Temperature: 80 °C
Reaction time: 1 h
Yield: 56.2 %

Procedure:
To a mixture of 2-nitro-4-(trifluoromethoxy)phenol (2 g, 0.0089 mol) in ethanol (50 mL) and water (25 mL) was added sodium thiosulfate (6.2 g, 0.0356 mol) at room temperature. The heterogeneous mixture was stirred at 80° C. under an atmosphere of nitrogen for 1 hour. The reaction mixture was cooled to room temperature, and ethanol was removed under reduced pressure. The aqueous layer was extracted with ethyl acetate (3×70 mL), and the organic layer was washed with brine and dried under sodium sulfate. The solvent was removed under reduced pressure to give yellow solid of 2-amino-4-(trifluoromethoxy)phenol (0.9 g, 0.005 mol). TLC (methanol/dichloromethane=5:95) Rf 0.29 MS: MH+: 194
Reaction SMILES: [CH2:1]([S:3]([N:6]1[CH2:11][CH2:10][CH:9]([C:12]2[C:20]3[C:15](=[C:16]([C:30]([NH2:32])=[O:31])[CH:17]=[C:18](B4OC(C)(C)C(C)(C)O4)[CH:19]=3)[NH:14][CH:13]=2)[CH2:8][CH2:7]1)(=[O:5])=[O:4])[CH3:2].C(=O)([O-])[O-].[Na+].[Na+].Br[C:40]1[CH:41]=[N:42][N:43]([CH2:45][CH2:46][Cl:47])[CH:44]=1>O1CCOCC1.O.CCOC(C)=O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:47][CH2:46][CH2:45][N:43]1[CH:44]=[C:40]([C:18]2[CH:19]=[C:20]3[C:15](=[C:16]([C:30]([NH2:32])=[O:31])[CH:17]=2)[NH:14][CH:13]=[C:12]3[CH:9]2[CH2:10][CH2:11][N:6]([S:3]([CH2:1][CH3:2])(=[O:5])=[O:4])[CH2:7][CH2:8]2)[CH:41]=[N:42]1
Reactant: ClCCn1cc(Br)cn1
Reactant: CCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(B4OC(C)(C)C(C)(C)O4)cc23)CC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Solvent: O
Product: CCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(-c4cnn(CCCl)c4)cc23)CC1
Temperature: 120 °C
Yield: 23.9 %

Procedure:
To a solution of 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indole-7-carboxamide (40 mg, 0.090 mmol) in dioxane (750 μL) and H2O (250 μL) was added sodium carbonate (53 mg, 0.50 mmol), and 4-bromo-1-(2-chloroethyl)-1H-pyrazole (26 mg, 0.126 mmol). The reaction mixture was flushed under Argon for 10 min before addition of tetrakis(triphenylphosphine)palladium (0) (5 mg, 0.004 mmol). The reaction was heated in a microwave at 120° C. for 20 min. It was then diluted with EtOAc (10 mL), filtered thru celite, followed by an aqueous work-up. The compound was purified by Gilson Preparatory HPLC to give 10 mg of 5-[1-(2-chloroethyl)-1H-pyrazol-4-yl]-3-[1-(ethylsulfonyl)-4-piperidinyl]-1H-indole-7-carboxamide (24%).