Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[N:3]=[CH:4][C:5]([C:8]([OH:10])=[O:9])=[N:6][CH:7]=1.[CH2:11](O)[CH3:12]>>[CH3:1][C:2]1[N:3]=[CH:4][C:5]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[N:6][CH:7]=1
Reactant: CCO
Reactant: Cc1cnc(C(=O)O)cn1
Product: CCOC(=O)c1cnc(C)cn1
Yield: 93 %

Procedure:
The reaction was carried out, under nitrogen, in a 2 L×4 neck flask equipped with a mechanical stirrer, water condenser (with gas inlet), and a thermocouple. The reactor was charged with 5-methylpyrazinecarboxylic acid (300.84 g), an acidic cation exchange resin (60.17 g), and ethanol (1004 g). The mixture was stirred at reflux for about 16 h after which the reaction was found to be complete by GC or GC/MS. The resin was removed by pressure filtration and rinsed with ethanol. The rinse was added to the alcohol solution of the ester. Evaporation of the solvent under reduced pressure gave 336.7 g (93%) of 5-methylpyrazinecarboxylic acid, ethyl ester that was suitable for use in the following examples. It was also possible to pass the material through a thin film evaporator at 125° C./3 mm. The material from this distillation was almost colorless and crystallizes at about 20° C.
Reaction SMILES: I[C:2]1[CH:12]=[CH:11][C:5]2[O:6][CH2:7][CH2:8][N:9]([CH3:10])[C:4]=2[CH:3]=1.[N:13]([O-])=O.[Na+]>C(O)(=O)C>[CH3:10][N:9]1[CH2:8][CH2:7][O:6][C:5]2[CH:11]=[CH:12][C:2]([NH2:13])=[CH:3][C:4]1=2
Reactant: O=N[O-]
Reactant: CN1CCOc2ccc(I)cc21
Agent: [Na+]
Solvent: CC(=O)O
Product: CN1CCOc2ccc(N)cc21
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
6-Iodo-4-methyl-3,4-dihydro-2H-benzo[b][1,4]oxazine [S12-5]. To solution of S12-4 (2.1 g, 12.8 mmol) in 50 mL of acetic acid cooled in ice bath was added NaNO2 (1.77 g, 26.9 mmol) slowly in portions. The resulting mixture was stirred at 0° C. for 10 min and was added KI (4.24 g, 38.4 mmol) in portions. The reaction mixture was stirred at 0° C. for 30 min, allowed to warm up to rt and stirred for 2 h. The resulting mixture was quenched with 100 mL of water, extracted with ethyl acetate (3×150 mL). The organic layer was combined, treated with Na2S2O3, washed with brine, dried over MgSO4 and purified by flash chromatography to give S12-5 (1.86 g, 53%) as a yellow solid. 1H NMR (CDCl3, 500 MHz) δ 6.64 (d, J=8.3 Hz, 1H), 6.56 (s, 1H), 6.48 (d, J=8.4 Hz, 1H), 4.25 (m, 2H), 3.24 (m, 2H), 2.85 (s, 3H); 13C NMR (CDCl3, 125 MHz) δ 138.1, 126.6, 120.5, 117.6, 111.9, 83.7, 64.8, 48.7, 36.5.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]([OH:9])=[O:8].[C:10]1(=[O:16])[O:15][C:13](=[O:14])[CH:12]=[CH:11]1.O>CN(C=O)C>[C:7]([CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][NH:1][C:10]([CH:11]=[CH:12][C:13]([OH:15])=[O:14])=[O:16])([OH:9])=[O:8]
Reactant: NCCCCCC(=O)O
Reactant: O=C1C=CC(=O)O1
Solvent: CN(C)C=O
Solvent: O
Product: O=C(O)C=CC(=O)NCCCCCC(=O)O
Temperature: 25 °C
Reaction time: 24 h

Procedure:
6-Aminocaproic acid (10.1 g, 81.6 mmol) was added to maleic anhydride (8.09 g, 82.6 mmol), in 100 mL of anhydrous DMF. The mixture was stirred at room temperature for 24 h and poured into 250 mL of water. White precipitate was filtered, washed with ether and dried (15 g, 86%). 1H NMR (DMSO-d6): δ 1.27-1.33 (2H, m), 1.45-1.54 (4H, m), 2.21 (2H, t, J=7.3), 3.18 (2H, q, J=6.7), 6.24 (1H, d, J=13.0), 6.42 (1H, d, J=12.5), 9.11 (1H, br s), 13.6 (1H, br).
Reaction SMILES: C(S[C:4]1[S:5][C:6](=[CH:10][C:11]2[CH:12]=[C:13]3[C:17](=[CH:18][CH:19]=2)[N:16]([CH2:20][C:21]2[CH:26]=[CH:25][C:24]([C:27]([OH:30])([CH3:29])[CH3:28])=[CH:23][C:22]=2[C:31]([F:34])([F:33])[F:32])[N:15]=[CH:14]3)[C:7](=[O:9])[N:8]=1)C.[CH3:35][C@@H:36]1[CH2:41][NH:40][CH2:39][C@H:38]([CH3:42])[NH:37]1>>[CH3:35][C@H:36]1[NH:37][C@@H:38]([CH3:42])[CH2:39][N:40]([C:4]2[S:5][C:6](=[CH:10][C:11]3[CH:12]=[C:13]4[C:17](=[CH:18][CH:19]=3)[N:16]([CH2:20][C:21]3[CH:26]=[CH:25][C:24]([C:27]([OH:30])([CH3:28])[CH3:29])=[CH:23][C:22]=3[C:31]([F:32])([F:33])[F:34])[N:15]=[CH:14]4)[C:7](=[O:9])[N:8]=2)[CH2:41]1
Reactant: C[C@@H]1CNC[C@H](C)N1
Reactant: CCSC1=NC(=O)C(=Cc2ccc3c(cnn3Cc3ccc(C(C)(C)O)cc3C(F)(F)F)c2)S1
Product: C[C@@H]1CN(C2=NC(=O)C(=Cc3ccc4c(cnn4Cc4ccc(C(C)(C)O)cc4C(F)(F)F)c3)S2)C[C@H](C)N1

Procedure:
2-((3R,5S)-3,5-Dimethylpiperazin-1-yl)-5-({1-[4-(1-hydroxy-1-methylethyl)-2-(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-1,3-thiazol-4(5H)-one was prepared from 2-Ethylsulfanyl-5-{1-[4-(1-hydroxy-1-methyl-ethyl)-2-trifluoromethyl-benzyl]-1H-indazol-5-ylmethylene}-thiazol-4-one and (2R,6S) 2,6-Dimethyl-piperazine following General Procedure C.
Reaction SMILES: [CH2:1]([O:3][CH2:4][CH2:5][O:6][C:7]1[CH:12]=[C:11]([CH3:13])[C:10]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([CH:20]=O)[CH:15]=2)=[C:9]([CH3:22])[CH:8]=1)[CH3:2].[NH2:23][C:24]1[CH:29]=[CH:28][C:27]([CH:30]2[CH2:32][CH:31]2[C:33]([O:35][CH2:36][CH3:37])=[O:34])=[C:26]([F:38])[CH:25]=1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[CH2:1]([O:3][CH2:4][CH2:5][O:6][C:7]1[CH:12]=[C:11]([CH3:13])[C:10]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([CH2:20][NH:23][C:24]3[CH:29]=[CH:28][C:27]([CH:30]4[CH2:32][CH:31]4[C:33]([O:35][CH2:36][CH3:37])=[O:34])=[C:26]([F:38])[CH:25]=3)[CH:15]=2)=[C:9]([CH3:22])[CH:8]=1)[CH3:2]
Reactant: CCOC(=O)C1CC1c1ccc(N)cc1F
Reactant: CCOCCOc1cc(C)c(-c2cccc(C=O)c2)c(C)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Solvent: CC(=O)O
Product: CCOCCOc1cc(C)c(-c2cccc(CNc3ccc(C4CC4C(=O)OCC)c(F)c3)c2)c(C)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 85.9 %

Procedure:
A mixture of 4′-(2-ethoxyethoxy)-2′,6′-dimethyl-3-biphenylcarbaldehyde (0.313 g, 1.05 mmol), ethyl 2-(4-amino-2-fluorophenyl)cyclopropanecarboxylate (0.234 g, 1.05 mmol), acetic acid (0.126 g, 2.10 mmol) and 1,2-dichloroethane (5 mL) was stirred under a nitrogen atmosphere at room temperature for 3 hr. Sodium triacetoxyborohydride (0.445 g, 2.10 mmol) was added to the reaction mixture by small portions, and the mixture was stirred for 3.5 hr. The reaction mixture was concentrated under reduced pressure. Water was added to the residue, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:hexane=5:95-30:70) to give the title compound (0.456 g, yield 86%) as a yellow oil.
Reaction SMILES: [CH3:1][O:2][CH2:3][O:4][C:5]1[CH:6]=[C:7]([CH2:15][OH:16])[CH:8]=[C:9]([O:11][CH2:12][O:13][CH3:14])[CH:10]=1.[Br:17]N1C(=O)CCC1=O.O>CN(C)C=O>[Br:17][C:6]1[C:5]([O:4][CH2:3][O:2][CH3:1])=[CH:10][C:9]([O:11][CH2:12][O:13][CH3:14])=[CH:8][C:7]=1[CH2:15][OH:16]
Reactant: O=C1CCC(=O)N1Br
Reactant: COCOc1cc(CO)cc(OCOC)c1
Solvent: CN(C)C=O
Solvent: O
Product: COCOc1cc(CO)c(Br)c(OCOC)c1
Temperature: 25 °C
Reaction time: 5 h
Yield: 69.4 %

Procedure:
The above-obtained 3,5-bis(methoxymethoxy)phenylmethanol (5.3 g, 23 mmol) was dissolved in N,N-dimethylformamide (20 mL) and obtained solution was added with N-bromosuccinimide (4.3 g, 24 mmol) followed by stirring at a room temperature for 5 hours. The reaction mixture was added with water and extracted with chloroform 3 times. The organic layers were combined, washed with saturated brine, dried over anhydrous sodium sulfate and then the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=9/1 to 5/1 to 2/1) to obtain [2-bromo-3,5-bis(methoxymethoxy)phenyl]methanol (4.9 g, 69%).
Reaction SMILES: [NH2:1][C:2]1[C:3]([F:27])=[CH:4][C:5]([Cl:26])=[C:6]([C:8]2[C:9](=[O:25])[N:10]([CH2:23][CH3:24])[C:11]3[C:16]([CH:17]=2)=[CH:15][N:14]=[C:13]([NH:18][CH2:19][CH2:20][S:21][CH3:22])[CH:12]=3)[CH:7]=1.[C:28]1([N:34]=[C:35]=[O:36])[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>C(Cl)Cl>[Cl:26][C:5]1[C:6]([C:8]2[C:9](=[O:25])[N:10]([CH2:23][CH3:24])[C:11]3[C:16]([CH:17]=2)=[CH:15][N:14]=[C:13]([NH:18][CH2:19][CH2:20][S:21][CH3:22])[CH:12]=3)=[CH:7][C:2]([NH:1][C:35]([NH:34][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)=[O:36])=[C:3]([F:27])[CH:4]=1
Reactant: CCn1c(=O)c(-c2cc(N)c(F)cc2Cl)cc2cnc(NCCSC)cc21
Reactant: O=C=Nc1ccccc1
Solvent: ClCCl
Product: CCn1c(=O)c(-c2cc(NC(=O)Nc3ccccc3)c(F)cc2Cl)cc2cnc(NCCSC)cc21
Reaction time: 8 h
Yield: 38.4 %

Procedure:
To a solution of 3-(5-amino-2-chloro-4-fluorophenyl)-1-ethyl-7-(2-(methylthio)ethylamino)-1,6-naphthyridin-2(1H)-one (400 mg, 0.99 mmol) in DCM (20 mL) was added phenyl isocyanate (200 mg, 1.68 mmol) and the mixture was stirred overnight. The reaction mixture was quenched with MeOH and concentrated under reduced pressure. The residue was washed with Et2O to give 1-(4-chloro-5-(1-ethyl-7-(2-(methylthio)ethylamino)-2-oxo-1,2-dihydro-1,6-naphthyridin-3-yl)-2-fluorophenyl)-3-phenylurea (200 mg, 39% yield).
Reaction SMILES: [CH3:1][N:2]([CH3:9])[C:3](=[O:8])[C:4]([O:6][CH3:7])=[O:5].[CH2:10]([CH:12]([CH2:15][CH2:16][CH2:17][CH3:18])CO)[CH3:11].S(=O)(=O)(O)O>CO>[CH3:1][N:2]([CH3:9])[C:3](=[O:8])[C:4]([O:6][CH2:7][CH:12]([CH2:10][CH3:11])[CH2:15][CH2:16][CH2:17][CH3:18])=[O:5]
Reactant: CCCCC(CC)CO
Reactant: COC(=O)C(=O)N(C)C
Agent: O=S(=O)(O)O
Solvent: CO
Product: CCCCC(CC)COC(=O)C(=O)N(C)C
Temperature: 80 °C

Procedure:
In a 1,000 mL reactor, are mixed at 20-25° C., methyl 2-(dimethylamino)-2-oxoacetate (compound 1) (390 g, 2.98 mol), 2-ethyl-hexan-1-ol (464 g, 3.5 mol) and 98% sulfuric acid (66 g, 0.67 mol). The temperature of the mixture is brought to and maintained at 80° C. for 24 hours. The progression of the reaction is tracked by gas chromatography analysis. At the end of the reaction, the methanol formed is removed from the reaction medium by distillation under reduced vacuum (Pmin=150 mbars) and an aqueous solution of sodium hydrogencarbonate is then added to the reaction medium so that the final pH is 7. The organic phase is separated from the aqueous phase. The latter is counter-extracted with 500 mL of dichloromethane. The organic phases are collected and then the reaction medium is concentrated in order to remove the dichloromethane. To the residue, are added 5 g of potassium carbonate and the thereby obtained medium is then distilled under partial vacuum (Tbp 150° C., P<1 mbar). The expected product is obtained with a purity of more than 98% (578 g).
Reaction SMILES: [C:1]1([S:7]([OH:10])(=[O:9])=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>>[C:11]1([S:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)(=[O:9])=[O:10])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: O=S(=O)(O)c1ccccc1
Reactant: c1ccccc1
Product: O=S(=O)(c1ccccc1)c1ccccc1
Yield: 40 %

Procedure:
A 158 g (1.0 mole) quantity of benzenesulfonic acid, 94 g (1.2 moles) of benzene and 5 g of 12-tungstophosphoric acid (H3PW12O40.29H2O) were refluxed with heating and stirring to undergo reaction for 30 minutes. The reaction mixture was analyzed by highperformance liquid chromatography, which showed that the conversion of benzenesulfonic acid was 30%. To the reaction mixture was added the same amount (10 g) of polyphosphoric acid as in Example 15. The mixture was refluxed for 5.5 hours. The same treatment as in Example 15 was followed, giving 87 g of diphenylsulfone in a yield of 40%.
Reaction SMILES: [CH3:1][Si](C=[N+]=[N-])(C)C.[Br:8][C:9]1[CH:14]=[CH:13][C:12]([NH:15][C:16]2[C:21]([C:22]([OH:24])=[O:23])=[CH:20][N:19]=[C:18]([Cl:25])[C:17]=2[Cl:26])=[C:11]([Cl:27])[CH:10]=1>>[CH3:1][O:23][C:22](=[O:24])[C:21]1[C:16]([NH:15][C:12]2[CH:13]=[CH:14][C:9]([Br:8])=[CH:10][C:11]=2[Cl:27])=[C:17]([Cl:26])[C:18]([Cl:25])=[N:19][CH:20]=1
Reactant: O=C(O)c1cnc(Cl)c(Cl)c1Nc1ccc(Br)cc1Cl
Reactant: C[Si](C)(C)C=[N+]=[N-]
Product: COC(=O)c1cnc(Cl)c(Cl)c1Nc1ccc(Br)cc1Cl

Procedure:
Trimethylsilyldiazomethane (2.0 M solution in hexanes, 37 mL, 74 mmol) was added slowly to a suspension of 4-(4-bromo-2-chloro-phenylamino)-5,6-dichloro-nicotinic acid (25) (14.67 g, 37 mmol). After the addition was complete the resulting slurry was diluted with hexanes (600 mL) and the solids isolated by filtration washing with hexanes. The desired product was isolated as an off-white solid (10.06 g). The hexanes washes were concentrated and the solids passed through a plug of silica gel eluting with dichloromethane. Concentration of the product-containing fractions provided an additional 3.83 g desired product (26) for a total of 13.89 g (91%). MS (APCI+) m/z 409, 411, 413 (M+; Cl, Br pattern) detected.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][CH:9]=2)[N:5]=[CH:4][N:3]=1.[CH3:18][C:19]1[CH:28]=[N:27][C:26]2[C:25]([OH:29])=[CH:24][CH:23]=[CH:22][C:21]=2[N:20]=1.[H-].[Na+]>CN(C=O)C>[CH3:18][C:19]1[CH:28]=[N:27][C:26]2[C:21](=[CH:22][CH:23]=[CH:24][C:25]=2[O:29][C:2]2[CH:7]=[C:6]([C:8]3[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][CH:9]=3)[N:5]=[CH:4][N:3]=2)[N:20]=1
Reactant: Cc1cnc2c(O)cccc2n1
Reactant: FC(F)(F)c1ccc(-c2cc(Cl)ncn2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1cnc2c(Oc3cc(-c4ccc(C(F)(F)F)cc4)ncn3)cccc2n1

Procedure:
The title compound was prepared analogous to the procedure in Example 29 using 4-chloro-6-(4-trifluoromethyl-phenyl)-pyrimidine, (Example 2(a), Method A), (0.20 g, 0.77 mmol), 2-methyl-quinoxalin-5-ol (0.14 g, 0.85 mmol, J. Med. Chem, 1988, 41, 4062.) DMF (3 mL), and a 60% dispersion of sodium hydride in mineral oil (0.040 g, 1.0 mmol, Aldrich). Purification by flash chromatography (0→75% EtOAc/hexanes) gave the title compound as an ivory powder. Mp: 135-141° C., MS (ESI, pos. ion) m/z: 383 (M+1).
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([C:8]2[CH:13]=[CH:12][C:11]([S:14]([N:17]([CH3:19])[CH3:18])(=[O:16])=[O:15])=[CH:10][CH:9]=2)=[C:5]([CH3:7])[N:6]=1.[N:20]([CH2:23][CH2:24][C:25]([O:27][CH2:28][CH3:29])=[O:26])=[C:21]=[O:22]>>[CH2:28]([O:27][C:25](=[O:26])[CH2:24][CH2:23][NH:20][C:21]([NH:1][C:2]1[S:3][C:4]([C:8]2[CH:9]=[CH:10][C:11]([S:14](=[O:15])(=[O:16])[N:17]([CH3:18])[CH3:19])=[CH:12][CH:13]=2)=[C:5]([CH3:7])[N:6]=1)=[O:22])[CH3:29]
Reactant: CCOC(=O)CCN=C=O
Reactant: Cc1nc(N)sc1-c1ccc(S(=O)(=O)N(C)C)cc1
Product: CCOC(=O)CCNC(=O)Nc1nc(C)c(-c2ccc(S(=O)(=O)N(C)C)cc2)s1

Procedure:
Using 4-(2-amino-4-methyl-thiazol-5-yl)-N,N-dimethyl-benzenesulfonamide (Example 24a) (0.083 g, 0.28 mmol) and replacing ethyl isocyanatoacetate with ethyl 3-isocyanatopropionate (0.05 ml, 0.34 mmol) in the above reaction affords the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[C:5]([O:10][CH2:11][O:12][CH2:13][CH2:14][Si:15]([CH3:18])([CH3:17])[CH3:16])=[CH:4][C:3]=1[CH2:19][OH:20].[OH-].[K+].I[CH2:24][CH3:25]>CS(C)=O.O>[Br:1][C:2]1[C:3]([CH2:19][O:20][CH2:24][CH3:25])=[CH:4][C:5]([O:10][CH2:11][O:12][CH2:13][CH2:14][Si:15]([CH3:16])([CH3:18])[CH3:17])=[C:6]([O:8][CH3:9])[CH:7]=1
Reactant: CCI
Reactant: COc1cc(Br)c(CO)cc1OCOCC[Si](C)(C)C
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CS(C)=O
Product: CCOCc1cc(OCOCC[Si](C)(C)C)c(OC)cc1Br
Reaction time: 16 h
Yield: 92 %

Procedure:
The crude benzyl alcohol was stirred with a solution of potassium hydroxide (800 mg, 14.4 mmol) in DMSO (8 mL). Iodoethane (580 mL, 7.2 mmol) was added, and the reaction stirred for 16 h before it was diluted with H2O (30 mL) and extracted with ether (2×30 mL). Organics were washed with brine (20 mL), dried (Na2SO4) and concentrated in vacuo. Purification by silica gel chromatography (15% EtOAc/hexanes) gave 1.30 g (92%) of the title compound as a clear oil. 1H NMR (300 MHz, CDCl3) δ 7.29 (s, 1H), 7.03 (s, 1H), 5.26 (s, 2H), 4.48 (s, 2H), 3.85 (s, 3H), 3.79 (t, 2H, J=8.4 Hz), 3.58 (q, 2H, J=6.9 Hz), 1.26 (t, 3H, J=6.9 Hz), 0.95 (t, 2H, J=8.4 Hz), −0.01 (s, 9H).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:7][O:8][C:9]1[CH:10]=[C:11]([CH:36]=[CH:37][CH:38]=1)[CH2:12][N:13]([CH:33]([CH3:35])[CH3:34])[C:14]([C:16]1[C:17]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=2[F:32])=[N:18][C:19](S(C)(=O)=O)=[N:20][CH:21]=1)=[O:15]>C1COCC1>[CH3:7][O:8][C:9]1[CH:10]=[C:11]([CH:36]=[CH:37][CH:38]=1)[CH2:12][N:13]([CH:33]([CH3:35])[CH3:34])[C:14]([C:16]1[C:17]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=2[F:32])=[N:18][C:19]([N:1]2[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)=[N:20][CH:21]=1)=[O:15]
Reactant: COc1cccc(CN(C(=O)c2cnc(S(C)(=O)=O)nc2-c2ccccc2F)C(C)C)c1
Reactant: C1CCNCC1
Solvent: C1CCOC1
Product: COc1cccc(CN(C(=O)c2cnc(N3CCCCC3)nc2-c2ccccc2F)C(C)C)c1
Temperature: 80 °C

Procedure:
Piperidine (0.0054 g, 0.064 mmol) was added to a stirred solution of N-(3-methoxybenzyl)-4-(2-fluorophenyl)-N-isopropyl-2-(methylsulfonyl)pyrimidine-5-carboxamide (0.015 g, 0.032 mmol) in THF (1 mL) and the mixture was heated at 80° C. for 1 h. The solvent was removed under reduced pressure, and the product was purified by preparative HPLC (5-80% CH3CN/0.05% TFA gradient over 15 min) to give N-(3-methoxybenzyl)-4-(2-fluorophenyl)-N-isopropyl-2-(piperdin-1-yl)pyrimidine-5-carboxamide Compound No. 20 (0.012 g, 81%).
Reaction SMILES: C[Si](Cl)(C)C.[BH4-].[Li+].[NH2:8][CH:9]([CH2:13][C:14]([F:17])([F:16])[F:15])[C:10](O)=[O:11]>C1COCC1>[NH2:8][CH:9]([CH2:13][C:14]([F:17])([F:16])[F:15])[CH2:10][OH:11]
Reactant: NC(CC(F)(F)F)C(=O)O
Agent: C[Si](C)(C)Cl
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Product: NC(CO)CC(F)(F)F
Reaction time: 0.08 h
Yield: 6.8 %

Procedure:
A solution of trimethylsilyl chloride (1.38 g, 12.73 mmol) was added to a solution of lithium borohydride (3.2 mL, 2.0 M in THF) and THF (5 mL) at 25° C. After stirring 5 min, 2-amino-4,4,4-trifluoro-butyric acid (0.50 g, 3. 18 mmol) was added portionwise over a 5 min period. The reaction was allowed to stir 48 h. The reaction was quenched by cautious addition of MeOH (5 mL) dropwise. The solvent was evaporated and the residue treated with potassium hydroxide (KOH) solution (20%, 6 mL). The aqueous phase was extracted using dichloromethane, 3 times (10 mL each). The organic phases were combined and dried over anhydrous sodium sulfate. After filtration the solvent was evaporated to afford the 2-amino-4,4,4-trifluoro-butan-1-ol as an oil (0.174 g, 38%). This oil was used directly in the next reaction without further purification.
Reaction SMILES: [ClH:1].[C:2]([C@H:6]1[C@@H:12]([O:13]CC2C=CC=CC=2)[CH2:11][C@H:10]2[N:21]([CH3:22])[C@@H:7]1[CH2:8][CH2:9]2)([O:4]C)=[O:3]>Cl>[OH:13][C@H:12]1[CH2:11][C@H:10]2[N:21]([CH3:22])[C@H:7]([CH2:8][CH2:9]2)[C@H:6]1[C:2]([O-:4])=[O:3].[ClH:1]
Reactant: COC(=O)[C@H]1[C@@H](OCc2ccccc2)C[C@@H]2CC[C@H]1N2C
Agent: Cl
Product: CN1[C@H]2CC[C@@H]1[C@@H](C(=O)[O-])[C@@H](O)C2

Procedure:
(1R,2R,3S)-2-Carbomethoxy-3-benzoxytropane, hydrochloride (100 g, 0.29 mol) was refluxed in 1000 ml 1M hydrochloric acid for 18 hours and the solution was ice cooled. Benzoic acid was collected by filtration and the filtrate was concentrated in vacuo. Trituration of the residue with ethanol and filtration yielded (1R,2R,3S)-3-hydroxytropane-2-carboxylate, hydrochloride as a white crystalline compound which without further purification was dried and refluxed in phosphorous oxychloride (50 ml) for two hours. The solution was concentrated in vacuo and absolute methanol (150 ml) was addition of a sodium hydroxide solution (10M, approximately 100 ml) and was extracted 5 times with diethyl ether. The combined organic phase was dried and concentrated in vacuo yielding oil, which was distilled in vacuo (70°-74° C., 1 mBar) yielding the title compound as clear oil.
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[Cl:5][C:6]1[CH:14]=[CH:13][C:9]([C:10](Cl)=[O:11])=[CH:8][CH:7]=1.[NH:15]1[CH:19]=[CH:18][CH:17]=[C:16]1[CH2:20][C:21]#[N:22].Cl>C(Cl)Cl>[Cl:5][C:6]1[CH:14]=[CH:13][C:9]([C:10]([C:19]2[NH:15][C:16]([CH2:20][C:21]#[N:22])=[CH:17][CH:18]=2)=[O:11])=[CH:8][CH:7]=1
Reactant: O=C(Cl)c1ccc(Cl)cc1
Reactant: N#CCc1ccc[nH]1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: N#CCc1ccc(C(=O)c2ccc(Cl)cc2)[nH]1
Temperature: 0 °C

Procedure:
To a chilled suspension of 26.80 g. (0.2 mole) of aluminum chloride in 110 ml. of methylene chloride is added dropwise 35 g. (0.2 mole) of p-chlorobenzoyl chloride. The mixture is added dropwise to a solution of 21.22 g. (0.2 mole) of pyrrole-2-acetonitrile in 125 ml. methylene chloride which is cooled externally with an ammonium chloride ice bath. After addition is complete, the reaction mixture is stirred for ten minutes at 0°C. and then poured into ice acidified with dilute hydrochloric acid. A solid precipitate, 5-(p-chlorobenzoyl)-pyrrole-2-acetonitrile, which is filtered off, washed with hot methanol and dried, m.p. 203°-205°C.
Reaction SMILES: Cl.[F:2][C:3]1[CH:11]=[C:10]2[C:6]([C:7]([C:21]3[CH:22]=[N:23][N:24]([CH:26]4[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]4)[CH:25]=3)=[CH:8][N:9]2[S:12]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)(=[O:14])=[O:13])=[CH:5][CH:4]=1.CCN(CC)CC.[C:39](Cl)(=[O:41])[CH3:40]>C(Cl)Cl>[F:2][C:3]1[CH:11]=[C:10]2[C:6]([C:7]([C:21]3[CH:22]=[N:23][N:24]([CH:26]4[CH2:31][CH2:30][N:29]([C:39](=[O:41])[CH3:40])[CH2:28][CH2:27]4)[CH:25]=3)=[CH:8][N:9]2[S:12]([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)(=[O:13])=[O:14])=[CH:5][CH:4]=1
Reactant: CC(=O)Cl
Reactant: O=S(=O)(c1ccccc1)n1cc(-c2cnn(C3CCNCC3)c2)c2ccc(F)cc21
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)N1CCC(n2cc(-c3cn(S(=O)(=O)c4ccccc4)c4cc(F)ccc34)cn2)CC1
Reaction time: 1 h
Yield: 87.2 %

Procedure:
To a solution of 6-fluoro-1-(phenylsulfonyl)-3-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)-1H-indole hydrochloride (Intermediate 17; 290 mg), Et3N (0.23 mL; 1.65 mmol) in DCM (20 mL) was added acetyl chloride (87 mg; 1.1 mmol) dropwise under nitrogen. The reaction mixture was stirred for 1 h and concentrated to afford 256 mg (100%) of the title compound as a white solid, which was used directly without further purification.
Reaction SMILES: C[O:2][C:3](=[O:27])[CH2:4][O:5][C:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([Br:15])[CH:13]=2)[N:8]([S:16]([C:19]2[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=2)(=[O:18])=[O:17])[CH:7]=1.[OH-].[Li+].C(OCC)(=O)C.Cl>C1COCC1>[Br:15][C:12]1[CH:13]=[C:14]2[C:9](=[CH:10][CH:11]=1)[N:8]([S:16]([C:19]1[CH:20]=[CH:21][C:22]([O:25][CH3:26])=[CH:23][CH:24]=1)(=[O:17])=[O:18])[CH:7]=[C:6]2[O:5][CH2:4][C:3]([OH:27])=[O:2]
Reactant: COC(=O)COc1cn(S(=O)(=O)c2ccc(OC)cc2)c2ccc(Br)cc12
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COc1ccc(S(=O)(=O)n2cc(OCC(=O)O)c3cc(Br)ccc32)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 90 %

Procedure:
[5-Bromo-1-(4-methoxy-benzenesulfonyl)-1H-indol-3-yloxy]-acetic acid methyl ester (22, 32.0 mg, 0.007 mmol) was dissolved in THF (1.50 mL) and 1M lithium hydroxide (0.4 mL) was added to this solution. After stirring for 30 min at 25° C., ethyl acetate was added and the mixture was acidified with 1M hydrochloric acid. The organic layer was dried over magnesium sulfate, filtered and concentrated at reduced pressure to obtain a white solid (23, 28 mg, 90% yield). MS(ESI) [M−H+]−=438.0; 440.0.
Reaction SMILES: Br[CH2:2][C:3](=[O:9])[C:4]([CH3:8])([CH3:7])[CH2:5][F:6].[Cl:10][C:11]1[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=1.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[Cl:10][C:11]1[CH:16]=[CH:15][C:14]([O:17][CH2:2][C:3](=[O:9])[C:4]([CH3:8])([CH3:7])[CH2:5][F:6])=[CH:13][CH:12]=1
Reactant: Oc1ccc(Cl)cc1
Reactant: CC(C)(CF)C(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CC(C)(CF)C(=O)COc1ccc(Cl)cc1
Temperature: 20 °C
Reaction time: 2 h
Yield: 90.5 %

Procedure:
157 g (0.79 mol) of 1-bromo-3,3-dimethyl-4-fluoro-2-butanone were added dropwise to a stirred mixture of 102 g (0.79 mol) of p-chlorophenol and 110 g (0.79 mol) of powered potassium carbonate in 500 ml of acetone at 20° to 30° C., while cooling. The mixture was subsequently stirred at 20° C. for 2 hours, the inorganic salt was filtered off and the filtrate was concentrated. The residue was distilled under a high vacuum. 175 g (90% of theory) of 1-(4-chlorophenoxy)-3,3-dimethyl-4-fluoro-2-butanone of boiling point 112° to 119° C./0.05 mm Hg were obtained. ##STR15##