Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]=[C:4]([C:8]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([S:17]([NH:20][CH2:21][CH2:22][CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25])(=[O:19])=[O:18])=[CH:13][C:12]=2[CH3:29])=[O:9])[CH:3]=1.C(NC(C)C)(C)C.[CH:37]1([CH2:40][NH:41][CH:42]2[CH2:47][CH2:46][CH2:45][CH2:44][CH2:43]2)[CH2:39][CH2:38]1>C(O)C>[CH:42]1([N:41]([CH2:40][CH:37]2[CH2:38][CH2:39]2)[C:2]2[N:7]=[CH:6][N:5]=[C:4]([C:8]([NH:10][C:11]3[CH:16]=[CH:15][C:14]([S:17]([NH:20][CH2:21][CH2:22][CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25])(=[O:19])=[O:18])=[CH:13][C:12]=3[CH3:29])=[O:9])[CH:3]=2)[CH2:43][CH2:44][CH2:45][CH2:46][CH2:47]1
Reactant: CCOC(=O)CCCNS(=O)(=O)c1ccc(NC(=O)c2cc(Cl)ncn2)c(C)c1
Reactant: C1CCC(NCC2CC2)CC1
Solvent: CCO
Solvent: CC(C)NC(C)C
Product: CCOC(=O)CCCNS(=O)(=O)c1ccc(NC(=O)c2cc(N(CC3CC3)C3CCCCC3)ncn2)c(C)c1
Temperature: 160 °C

Procedure:
A solution of ethyl 4-(4-(6-chloropyrimidine-4-carboxamido)-3-methylphenylsulfonamido)butanoate (Intermediate 35, 123 mg; 0.31 mmol) and diisopropylamine (105.5 mL; 0.61 mmol) in ethanol (4 ml) was treated with N-(cyclopropylmethyl)cyclohexanamine (56.6 mg, 0.4 mmol). The mixture was heated to 160° C. in a microwave for 1 hour and the solvent removed in vacuo. The residue purified by column chromatography (silica) eluting with petroleum ether containing increasing amounts of EtOAc to give ethyl 4-(4-(6-(cyclohexyl(cyclopropylmethyl)amino)pyrimidine-4-carboxamido)-3-methylphenylsulfonamido)butanoate which was used directly without any further purification. The residue was dissolved in methanol (10 ml) and THF (10 ml) and treated with 5 N NaOH solution (1 ml). After stirring at RT for 5 hours the solvent was removed in vacuo. The residue was redissolved in water (10 ml) and acidified with concentrated HCl. The aqueous phase was extracted with EtOAc and the organic extracts passed through a hydrophobic frit and the solvent removed in vacuo. The residue was triturated with petroleum ether to yield the title compound as a white solid (120 mg, 73%).
Reaction SMILES: Cl.[CH3:2][N:3]([CH3:35])[C:4]1[CH:9]=[CH:8][C:7]([C:10](=[O:34])[CH2:11][CH2:12][CH2:13][N:14]2[CH2:19][CH2:18][CH:17]([C:20](O)([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[CH2:16][CH2:15]2)=[CH:6][CH:5]=1.Cl>C(O)C>[CH3:35][N:3]([CH3:2])[C:4]1[CH:9]=[CH:8][C:7]([C:10](=[O:34])[CH2:11][CH2:12][CH2:13][N:14]2[CH2:19][CH2:18][C:17](=[C:20]([C:27]3[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=3)[C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=3)[CH2:16][CH2:15]2)=[CH:6][CH:5]=1
Reactant: CN(C)c1ccc(C(=O)CCCN2CCC(C(O)(c3ccccc3)c3ccccc3)CC2)cc1
Agent: Cl
Solvent: CCO
Product: CN(C)c1ccc(C(=O)CCCN2CCC(=C(c3ccccc3)c3ccccc3)CC2)cc1

Procedure:
A mixture of 3 g (0.0065 mole) of 4'-dimethylamino-4-[4-(α-hydroxy-α-phenylbenzyl)piperidino]butyrophenone hydrochloride, 150 ml of ethanol and 150 ml of 37% HCl was heated on a steam bath about 4 hours. The solvent and excess acid were removed. The remaining solid was recrystallized from methanol-butanone, converted to the free base, and recrystallized for benzene-hexane to give the desired product, M.P. 110°-112° C.
Reaction SMILES: [H-].[Na+].[OH:3][C:4]1[CH:13]=[C:12]2[C:7]([CH2:8][CH2:9][N:10]([C:15]3[CH:16]=[N:17][CH:18]=[CH:19][C:20]=3[CH3:21])[C:11]2=[O:14])=[CH:6][CH:5]=1.Cl[C:23]1[N:28]=[CH:27][C:26]([F:29])=[CH:25][N:24]=1.CO>CN(C=O)C.C(Cl)Cl>[F:29][C:26]1[CH:25]=[N:24][C:23]([O:3][C:4]2[CH:13]=[C:12]3[C:7]([CH2:8][CH2:9][N:10]([C:15]4[CH:16]=[N:17][CH:18]=[CH:19][C:20]=4[CH3:21])[C:11]3=[O:14])=[CH:6][CH:5]=2)=[N:28][CH:27]=1
Reactant: Fc1cnc(Cl)nc1
Reactant: Cc1ccncc1N1CCc2ccc(O)cc2C1=O
Agent: [H-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Solvent: CN(C)C=O
Product: Cc1ccncc1N1CCc2ccc(Oc3ncc(F)cn3)cc2C1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 10.4 %

Procedure:
60% NaH (13 mg, 0.33 mmol) was added to a stirred solution of 7-hydroxy-2-(4-methyl-pyridin-3-yl)-3,4-dihydro-2H-isoquinolin-1-one (27A: 70 mg, 0.275 mmol) in DMF (2 mL) at 0° C. The reaction mixture was stirred at room temperature for 1 hour. This was followed by the addition of 2-chloro-5-fluoro-pyrimidine (44 mg, 0.33 mmol) at 0° C. and stirring was continued for a further 1 hour at room temperature. The reaction was monitored by TLC (5% methanol in DCM). The reaction mixture was quenched with chilled water and extracted with ethylacetate. The organic layer was washed with brine solution, dried over Na2SO4 and concentrated. Purification by column chromatography on silica gel (2% methanol in DCM) afforded 10 mg of the product (10.4% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[C:12]([N:14]1[CH2:18][CH2:17][CH2:16][CH2:15]1)=[O:13])[N:8]=[CH:7][N:6]=[C:5]2[NH:19][CH:20]([C:26]1[N:30](C(OC(C)(C)C)=O)[C:29]2[CH:38]=[CH:39][C:40]([Cl:42])=[CH:41][C:28]=2[N:27]=1)[CH2:21][CH2:22][C:23](O)=[O:24].[NH:43]1[C:51]2[CH2:50][CH2:49][NH:48][CH2:47][C:46]=2[N:45]=[CH:44]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.FC(F)(F)C(O)=O>C(#N)C.O1CCCC1>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[C:12]([N:14]1[CH2:15][CH2:16][CH2:17][CH2:18]1)=[O:13])[N:8]=[CH:7][N:6]=[C:5]2[NH:19][CH:20]([C:26]1[NH:30][C:29]2[CH:38]=[CH:39][C:40]([Cl:42])=[CH:41][C:28]=2[N:27]=1)[CH2:21][CH2:22][C:23]([N:48]1[CH2:49][CH2:50][C:51]2[NH:43][CH:44]=[N:45][C:46]=2[CH2:47]1)=[O:24]
Reactant: CC(C)(C)OC(=O)n1c(C(CCC(=O)O)Nc2ncnc3cc(C(=O)N4CCCC4)c(Cl)cc23)nc2cc(Cl)ccc21
Reactant: c1nc2c([nH]1)CCNC2
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: O=C(O)C(F)(F)F
Solvent: CC#N
Solvent: C1CCOC1
Product: O=C(CCC(Nc1ncnc2cc(C(=O)N3CCCC3)c(Cl)cc12)c1nc2cc(Cl)ccc2[nH]1)N1CCc2[nH]cnc2C1

Procedure:
Prepared analogously to Example 61 from 6-chloro-4-[1-(1-tert.-butyloxycarbonyl-5-chloro-1H-benzimidazol-2-yl)-3-hydroxycarbonyl-propyl-amino]-7-(pyrrolidin-1-yl-carbonyl)-quinazoline and 4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridine with TBTU in acetonitrile/tetrahydrofuran and subsequent reaction with trifluoroacetic acid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([N:12]([CH2:21][C:22]2[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=2)[C:13](=[O:20])[CH2:14][C:15]2[S:16][CH:17]=[CH:18][CH:19]=2)=[C:6]([CH:11]=1)[C:7](OC)=[O:8].CC(C)([O-])C.[K+].Cl>O1CCCC1>[Br:1][C:2]1[CH:11]=[C:6]2[C:5](=[CH:4][CH:3]=1)[N:12]([CH2:21][C:22]1[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=1)[C:13](=[O:20])[C:14]([C:15]1[S:16][CH:17]=[CH:18][CH:19]=1)=[C:7]2[OH:8]
Reactant: COC(=O)c1cc(Br)ccc1N(Cc1ccc(OC)cc1)C(=O)Cc1cccs1
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: C1CCOC1
Product: COc1ccc(Cn2c(=O)c(-c3cccs3)c(O)c3cc(Br)ccc32)cc1

Procedure:
Methyl 5-bromo-2-[(4-methoxybenzyl)(thiophen-2-ylacetyl)amino]benzoate (2.7 g, 5.7 mmol) was taken into tetrahydrofuran (0.50 M, 11 mL) and to this solution was added potassium tert-butoxide (1.3 g, 11 mmol) at room temp. The reaction was stirred for an hour. The crude reaction mixture was poured into 1 N HCl aq. (100 mL). The product was extracted with ethyl acetate (3×50 mL). The combined organic extractions were dried over magnesium sulfate, filtered, and concentrated in vacuo to yield 6-bromo-4-hydroxy-1-(4-methoxybenzyl)-3-(thiophen-2-yl)quinolin-2(1H)-one as a brown oil. Used without further purification. LCMS (M+H)=441.6.
Reaction SMILES: [CH2:1]([C:4]1(O)[CH2:9][C:8]([CH3:11])([CH3:10])[CH2:7][C:6]([CH3:13])([CH3:12])[CH2:5]1)[CH:2]=[CH2:3].[N:15]([Si](C)(C)C)=[N+:16]=[N-:17].B(F)(F)F.O>C1C=CC=CC=1>[CH2:1]([C:4]1([N:15]=[N+:16]=[N-:17])[CH2:9][C:8]([CH3:11])([CH3:10])[CH2:7][C:6]([CH3:13])([CH3:12])[CH2:5]1)[CH:2]=[CH2:3]
Reactant: C[Si](C)(C)N=[N+]=[N-]
Reactant: C=CCC1(O)CC(C)(C)CC(C)(C)C1
Agent: FB(F)F
Solvent: O
Solvent: c1ccccc1
Product: C=CCC1(N=[N+]=[N-])CC(C)(C)CC(C)(C)C1
Temperature: 5 °C
Reaction time: 6 h
Yield: 11.7 %

Procedure:
To a solution of cyclohexanol 8 (1.96 g, 10 mmol) in dry benzene (20 ml) under argon was added azidotrimethylsilane (12 mmol). To this cooled (5° C.) solution was slowly added BF3*OEt2 (12 mmol) via syringe within 20 min. The mixture was stirred for 6 h, then water was slowly added. The organic layer was separated and washed with saturated aqueous NaHCO3, and with brine, and dried over MgSO4. Filtration and evaporation of the solvent keeping the temperature below 25° C. gave an oil which was separated by column chromatography on silica gel (light petroleum ether). A fraction with Rf 0.85 (hexane) was collected. Evaporation of the solvent provided 9 as a colorless oil (0.26 g, 11.7%). 1H NMR (CDCl3, TMS): 0.89 (6H, s, 3,5-CH3eq); 0.90 (1H, d, 14 Hz, 4-CHax); 1.05 (2H, d, 14 Hz, 2,6-CHax); 1.18 (6H, s, 3,5-CH3ax); 1.37 (1H, d, 14 Hz, 4-CHeq); 1.60 (2H, d, 14 Hz, 2,6-CHeq), 2.29 (2H, d, 7 Hz, CH2C═); 4.95-5.25 (2H, m, ═CH2) and 5.65-6.15 ppm (1H, m, ═CH).
Reaction SMILES: [C:1]1([C:7]2[C:8](=[O:18])[O:9][C:10]3[C:15]([C:16]=2[OH:17])=[CH:14][CH:13]=[CH:12][CH:11]=3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(=O)([O-])[O-].[K+].[K+].[I-].[K+].[CH2:27]([N:29]([CH2:33][CH3:34])[CH2:30][CH2:31]Cl)[CH3:28]>C(C(C)=O)C(C)C>[CH2:27]([N:29]([CH2:33][CH3:34])[CH2:30][CH2:31][O:17][C:16]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[O:9][C:8](=[O:18])[C:7]=1[C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)[CH3:28]
Reactant: O=c1oc2ccccc2c(O)c1-c1ccccc1
Reactant: CCN(CC)CCCl
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC(=O)CC(C)C
Product: CCN(CC)CCOc1c(-c2ccccc2)c(=O)oc2ccccc12

Procedure:
11.9 g. (0.05 mol) of 3-phenyl-4-hydroxy-coumarin, 8.3 g. (0.06 mol) of anhydrous potassium carbonate and 200 ml. of methyl isobutyl ketone are placed in a dry reactor. The mixture is brought while stirring for 1 hour to 70° C. 0.5 g. of potassium iodide is then added, followed by dropwise addition of a solution of 8.8 g. (0.065 mol) of 2-diethylamino-1-chlorethane in 20 ml. of methyl isobutyl ketone.
Reaction SMILES: [C:1]1([CH:7]([CH2:25][CH3:26])[C:8]([O:10][C:11]2[CH:16]=[CH:15][C:14]([S:17][CH2:18][C:19]([C:22]([OH:24])=[O:23])([CH3:21])[CH3:20])=[CH:13][CH:12]=2)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH:27]O>C(O)(=O)C>[C:1]1([CH:7]([CH2:25][CH3:26])[C:8]([O:10][C:11]2[CH:16]=[CH:15][C:14]([S:17]([CH2:18][C:19]([C:22]([OH:24])=[O:23])([CH3:20])[CH3:21])=[O:27])=[CH:13][CH:12]=2)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CCC(C(=O)Oc1ccc(SCC(C)(C)C(=O)O)cc1)c1ccccc1
Reactant: OO
Solvent: CC(=O)O
Product: CCC(C(=O)Oc1ccc(S(=O)CC(C)(C)C(=O)O)cc1)c1ccccc1

Procedure:
To a solution of 4-(2'-carboxy-2'-methylpropylmercapto)phenyl 2-phenylbutyrate (745 mg, 2 mmol) in 1 mL of glacial acetic acid was added 0.25 mL of 30% H2O2. Additional 0.25 mL aliquots of 30% H2O2 were added at one-half hour intervals until TLC indicated complete consumption of the starting material. The reaction was quenched with 20 mL of H2O, extracted with Et2O (2×25 mL), dried over anhydrous MgSO4 and evaporated to give the sulfoxide containing a residual amount of acetic acid. The residue was suspended in 20 mL of H2O, the mixture was shell frozen and lyophilized to give 506 mg (65%) of the pure product sulfoxide. 1H NMR (CDCl3) δ1.00 (t, 3H, J=7.4 Hz), 1.42 (s, 3H), 1.54 (s, 3H), 1.85-1.99 (m, 1H), 2.16-2.31 (m, 1H), 3.07 (s, 2H), 3.72 (t, 1H, J=7.6 Hz), 7.17 (d, 2H, J=8.7 Hz), 7.32-7.40 (ArH, 5H), 7.70 (d, 2H, J=8.7 Hz), 11.17 (br s, --OH); 13C NMR (CDCl3) δ 11.83, 24.54, 25.71, 26.39, 41.73, 53.26, 68.81, 122.75, 125.60, 127.73, 128.10, 128.98, 138.30, 141.34, 153.11, 172.49, 180.33.
Reaction SMILES: Br[CH:2]([CH3:5])[CH:3]=O.[NH2:6][C:7]1[CH:12]=[CH:11][C:10]([N+:13]([O-:15])=[O:14])=[CH:9][N:8]=1>C(OCC)(=O)C>[CH3:5][C:2]1[N:8]2[CH:9]=[C:10]([N+:13]([O-:15])=[O:14])[CH:11]=[CH:12][C:7]2=[N:6][CH:3]=1
Reactant: CC(Br)C=O
Reactant: Nc1ccc([N+](=O)[O-])cn1
Solvent: CCOC(C)=O
Product: Cc1cnc2ccc([N+](=O)[O-])cn12

Procedure:
Operations similar to Production Example 1-(2) were conducted using 2-bromopropionaldehyde and 2-amino-5-nitropyridine. The solid whereupon obtained was suspended in ethyl acetate, and washed with saturated aqueous sodium hydrogencarbonate solution to provide the title compound as yellow solid.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:22])[CH2:4][C:5]1[CH:10]=[C:9](B2OC(C)(C)C(C)(C)O2)[CH:8]=[CH:7][C:6]=1[O:20][CH3:21].[CH2:23]([O:30][C:31](=[O:47])[N:32]([CH2:35][C:36]1[CH:41]=[C:40]([C:42]([F:45])([F:44])[F:43])[CH:39]=[CH:38][C:37]=1Br)[CH2:33][CH3:34])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>>[CH3:1][O:2][C:3](=[O:22])[CH2:4][C:5]1[CH:10]=[C:9]([C:37]2[CH:38]=[CH:39][C:40]([C:42]([F:43])([F:44])[F:45])=[CH:41][C:36]=2[CH2:35][N:32]([C:31]([O:30][CH2:23][C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)=[O:47])[CH2:33][CH3:34])[CH:8]=[CH:7][C:6]=1[O:20][CH3:21]
Reactant: COC(=O)Cc1cc(B2OC(C)(C)C(C)(C)O2)ccc1OC
Reactant: CCN(Cc1cc(C(F)(F)F)ccc1Br)C(=O)OCc1ccccc1
Product: CCN(Cc1cc(C(F)(F)F)ccc1-c1ccc(OC)c(CC(=O)OC)c1)C(=O)OCc1ccccc1

Procedure:
Prepared according to the procedure described in Example 1, Step 4, using the following starting materials: [2-methoxy-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-acetic acid methyl ester and (2-bromo-5-trifluoromethyl-benzyl)-ethyl-carbamic acid benzyl ester.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([C:14]([NH2:16])=[O:15])=[C:5]([C:7]2[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][CH:8]=2)[N:6]=1.[CH3:17][O:18][CH:19]([O:30][CH3:31])[C:20]1[CH:25]=[CH:24][C:23]([N+:26]([O-:28])=[O:27])=[C:22](F)[CH:21]=1.C(=O)([O-])[O-].[Cs+].[Cs+].CN(C)C=O>C(OCC)(=O)C.O>[Cl:13][C:10]1[CH:9]=[CH:8][C:7]([C:5]2[N:6]=[C:2]([NH:1][C:22]3[CH:21]=[C:20]([CH:19]([O:30][CH3:31])[O:18][CH3:17])[CH:25]=[CH:24][C:23]=3[N+:26]([O-:28])=[O:27])[S:3][C:4]=2[C:14]([NH2:16])=[O:15])=[CH:12][CH:11]=1
Reactant: COC(OC)c1ccc([N+](=O)[O-])c(F)c1
Reactant: NC(=O)c1sc(N)nc1-c1ccc(Cl)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O
Product: COC(OC)c1ccc([N+](=O)[O-])c(Nc2nc(-c3ccc(Cl)cc3)c(C(N)=O)s2)c1
Yield: 34.9 %

Procedure:
A mixture of 0.89 g (3.51 mmole) of 2-amino-4-(4-chloro-phenyl)-thiazole-5-carboxylic acid amide (V.18), 0.91 g (4.21 mmole) of 4-dimethoxymethyl-2-fluoro-1-nitrobenzene, 5.70 g (17.55 mmole) of cesium carbonate (5.70 g, 17.55 mmole) and 10 mL of dimethylformamide was heated at 70 degrees for 2 days. The reaction mixture was diluted with ethyl acetate and water. The precipitate was collected by filtration, washed with water and dried under vacuum to give 0.55 g of 4-(4-chloro-phenyl)-2-(5-dimethoxymethyl-2-nitro-phenylamino)-thiazole-5-carboxylic acid amide (VI.19a).
Reaction SMILES: Cl[S:2]([C:5]1[CH:6]=[C:7]([CH:11]=[CH:12][C:13]=1[O:14][CH3:15])[C:8]([OH:10])=[O:9])(=O)=O.[Sn](Cl)Cl>C(O)(=O)C.Cl>[C:8]([C:7]1[CH:11]=[CH:12][C:13]([O:14][CH3:15])=[C:5]([S:2][S:2][C:5]2[CH:6]=[C:7]([CH:11]=[CH:12][C:13]=2[O:14][CH3:15])[C:8]([OH:10])=[O:9])[CH:6]=1)([OH:10])=[O:9]
Reactant: COc1ccc(C(=O)O)cc1S(=O)(=O)Cl
Agent: Cl
Agent: Cl[Sn]Cl
Solvent: CC(=O)O
Product: COc1ccc(C(=O)O)cc1SSc1cc(C(=O)O)ccc1OC
Temperature: 40 °C
Reaction time: 2 h
Yield: 99.7 %

Procedure:
45 g (179.5 mmol) of 3-chlorosulfonyl-4-methoxy-benzoic acid were suspended in 200 ml of acetic acid and warmed to 40° C. Then a solution of 85.1 g (448.8 mmol) tin(II) chloride in 100 ml of hydrochloric acid was added within 15 min and the mixture was stirred for 2 h under reflux. The hot solution was added dropwise to 2000 ml of ice/water. The formed precipitate was collected by suction, washed with water and dried. 32.8 g of the title compound were obtained.
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[C:11](=[C:12](Br)[CH:13]=[CH:14][CH:15]=2)[CH:10]=[CH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:18][C:19]([F:30])([F:29])[C:20]1[CH:25]=[CH:24][C:23](B(O)O)=[CH:22][CH:21]=1.ClCCl.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1.O.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.Cl[Pd]Cl.[Fe+2]>[CH2:1]([N:8]1[C:16]2[C:11](=[C:12]([C:23]3[CH:24]=[CH:25][C:20]([C:19]([F:30])([F:29])[F:18])=[CH:21][CH:22]=3)[CH:13]=[CH:14][CH:15]=2)[CH:10]=[CH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Brc1cccc2c1ccn2Cc1ccccc1
Reactant: OB(O)c1ccc(C(F)(F)F)cc1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: ClCCl
Solvent: C1COCCO1
Solvent: O
Product: FC(F)(F)c1ccc(-c2cccc3c2ccn3Cc2ccccc2)cc1
Yield: 49.1 %

Procedure:
1-Benzyl-4-[4-(trifluoromethyl)phenyl]-1H-indole was prepared by coupling of 1-benzyl-4-bromo-1H-indole (0.428 g, 1.50 mmol), and 4-trifluoromethylphenylboronic acid (0.374 g, 1.97 mmol), using [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium (II) complex with dichloromethane (1:1) (0.0638 g, 0.0781 mmol), and potassium carbonate (0.416 g, 3.01 mmol) in dioxane (15 mL) and water (1.5 mL) following the procedure described in Step 1 of Example 11. Purification by flash chromatography (Biotage apparatus) using hexane as an eluant yielded the title compound as a yellow gum (0.259 g, 49%). 1HNMR (300 MHz, DMSO-d6): δ 7.8-7.95 (m, 4H), 7.65 (d, 1H, J=3 Hz), 7.55 (d, 1H, J=7.5 Hz), 7.15-7.35 (m, 7H), 6.65 (d, 1H, J=3 Hz), and 5.5 ppm (s, 2H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:11][CH2:12][C:13](=O)[CH3:14])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].C([NH2:18])=O.[OH-].[Na+]>O>[NH2:18][CH:13]([CH2:12][CH2:11][C:5]1[CH:6]=[CH:7][C:8]([O:9][CH3:10])=[C:3]([O:2][CH3:1])[CH:4]=1)[CH3:14]
Reactant: NC=O
Reactant: COc1ccc(CCC(C)=O)cc1OC
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: COc1ccc(CCC(C)N)cc1OC
Temperature: 210 °C

Procedure:
A mixture of 41.4 g of 4-(3,4-dimethoxy-phenyl)-2-butanone and 41.9 ml of formamide is heated at 210° C. for 20 hours, cooled to ambient, 104 ml of 10N sodium hydroxide is added and the reaction mixture heated at reflux temperature for 24 hours. The reaction is cooled, added to 200 ml of water and extracted with diethyl ether. The diethyl ether solution is washed with 10% hydrochloric acid. The aqueous layer is made basic and extracted with diethyl ether. The organic layer is dried, filtered and evaporated in vacuo. The residue is purified by chromatography (silica gel: chloroform/hexane/ethyl acetate to 5% methyl alcohol/chrloroform) to give 5.72 g of racemic 2 -amino-4 -(3,4-dimethoxyphenyl)butane.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([O:14][CH2:15][CH3:16])[C:11]([C:17]([F:20])([F:19])[F:18])=[CH:10][C:9]=1[NH:21][C:22](=[O:43])[CH2:23][C:24](=O)[C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([C:31]2[CH:36]=[CH:35][N:34]=[C:33]([N:37]3[CH2:41][CH2:40][CH2:39][CH2:38]3)[CH:32]=2)[CH:26]=1)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH2:15]([O:14][C:12]1[C:11]([C:17]([F:20])([F:18])[F:19])=[CH:10][C:9]2[NH:21][C:22](=[O:43])[CH2:23][C:24]([C:25]3[CH:30]=[CH:29][CH:28]=[C:27]([C:31]4[CH:36]=[CH:35][N:34]=[C:33]([N:37]5[CH2:38][CH2:39][CH2:40][CH2:41]5)[CH:32]=4)[CH:26]=3)=[N:7][C:8]=2[CH:13]=1)[CH3:16]
Reactant: CCOc1cc(NC(=O)OC(C)(C)C)c(NC(=O)CC(=O)c2cccc(-c3ccnc(N4CCCC4)c3)c2)cc1C(F)(F)F
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCOc1cc2c(cc1C(F)(F)F)NC(=O)CC(c1cccc(-c3ccnc(N4CCCC4)c3)c1)=N2

Procedure:
The title compound was prepared from (5-ethoxy-2-{3-oxo-3-[3-(2-pyrrolidin-1-yl-pyridin-4-yl)-phenyl]-propionylamino}-4-trifluoromethyl-phenyl)-carbamic acid tert-butyl ester (Example M292) (337 mg, 0.55 mmol) by treatment with TFA in CH2Cl2 according to the general procedure N. Obtained as a yellow solid (142 mg, 52%).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:19])[C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([O:11][C:12]2[CH:13]=[N:14][C:15]([OH:18])=[CH:16][CH:17]=2)[CH:6]=1)[CH3:2].[Cl:20][C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([Cl:27])[C:22]=1[C:28]1[C:32]([CH2:33]O)=[C:31]([CH:35]([CH3:37])[CH3:36])[O:30][N:29]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1C=CC=CC=1>[CH2:1]([O:3][C:4](=[O:19])[C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([O:11][C:12]2[CH:13]=[N:14][C:15]([O:18][CH2:33][C:32]3[C:28]([C:22]4[C:21]([Cl:20])=[CH:26][CH:25]=[CH:24][C:23]=4[Cl:27])=[N:29][O:30][C:31]=3[CH:35]([CH3:37])[CH3:36])=[CH:16][CH:17]=2)[CH:6]=1)[CH3:2]
Reactant: CC(C)c1onc(-c2c(Cl)cccc2Cl)c1CO
Reactant: CCOC(=O)c1cccc(Oc2ccc(O)nc2)c1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: c1ccccc1
Product: CCOC(=O)c1cccc(Oc2ccc(OCc3c(-c4c(Cl)cccc4Cl)noc3C(C)C)nc2)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 41.1 %

Procedure:
To a suspension of 3-(6-hydroxy-pyridin-3-yloxy)-benzoic acid ethyl ester (0.20 g, 0.77 mmol), [3-(2,6-dichloro-phenyl)-5-isopropyl-isoxazol-4-yl]-methanol (0.22 g, 0.77 mmol), triphenylphosphine (0.242 g, 0.92 mmol) in benzene (10 ml) was added dropwise diisopropyldiazenedicarboxylate (0.202 g, 1.00 mmol). The reaction mixture was stirred at room temperature for 4 h and concentrated under reduced pressure. The resulting residue was further purified by column chromatography using silica (eluent hexanes-ethyl acetate 5:1) to give 0.167 g (41%) of 3-{6-[3-(2,6-dichloro-phenyl)-5-isopropyl-isoxazol-4-ylmethoxy]-pyridin-3-yloxy}-benzoic acid ethyl ester as colorless oil.
Reaction SMILES: C([O-])CC[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].[Na+].[CH2:13]([OH:23])CCCCCCCCC.C(OCCOCCOCCOCCO)CCC>>[CH2:9]([CH:8]([CH2:7][CH2:6][CH2:5][CH3:4])[CH2:13][OH:23])[CH3:10]
Reactant: CCCCCCCCCCO
Reactant: CCCCCCCCCC[O-]
Agent: CCCCOCCOCCOCCOCCO
Agent: [Na+]
Product: CCCCC(CC)CO
Temperature: 25 °C

Procedure:
250.4 g of sodium decanolate (sodium salt of decanol) and 27.7 g of 1-decanol are treated at 200° C. with 113 g of tetraethylene glycol monobutyl ether. A clear solution has formed within 10 minutes. 142 g of high-naphthene neutral oil is added at 140° C., and the mixture is cooled to room temperature with stirring. The mixture which can be poured easily at 25° C. has the composition:
Reaction SMILES: [CH:1](=[N:8][NH:9][C:10]1[CH:19]=[CH:18][CH:17]=[CH:16][C:11]=1[C:12]([O:14][CH3:15])=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[CH:21]([C:27]([O-])=[O:28])[C:22]([O:24][CH2:25][CH3:26])=[O:23]>C1(C)C=CC=CC=1>[CH:1](=[N:8][N:9]([C:10]1[CH:19]=[CH:18][CH:17]=[CH:16][C:11]=1[C:12]([O:14][CH3:15])=[O:13])[C:27](=[O:28])[CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)c1ccccc1NN=Cc1ccccc1
Reactant: CCOC(=O)C(Cl)C(=O)[O-]
Solvent: Cc1ccccc1
Product: CCOC(=O)CC(=O)N(N=Cc1ccccc1)c1ccccc1C(=O)OC
Temperature: 25 °C
Yield: 67.4 %

Procedure:
Methyl 2-[2-benzylidenehydrazino]benzoate (5.29 g, 20.81 mmol) in toluene (80 mL) was reacted with ethyl chloromalonate (2.68 mL, 25.0 mmol) at reflux for 4 hours. The reaction mixture was cooled to 25° C. and concentrated under vacuum. The residue was triturated with diethyl ether and hexanes (3:1) to give methyl 2-[2-benzylidene-1-(3-ethoxy-3-oxopropanoyl)hydrazino]benzoate (5.17 g, 70%). MS (DCI) m/z 355 (M+H)+. 1H NMR (300 MHz, DMSO-d6) ppm 3.32 (s, 2 H) 3.69 (s, 3 H) 3.73 (s, 3 H) 7.16 (s, 1 H) 7.32 (dd, J=7.72, 1.10 Hz, 1 H) 7.40 (m, 3 H) 7.63 (m, 2 H) 7.70 (td, J=7.63, 1.29 Hz, 1 H) 7.85 (td, J=7.72, 1.47 Hz, 1 H) 8.10 (dd, J=7.72, 1.47 Hz, 1 H).
Reaction SMILES: [Br:1][C:2]([F:22])([F:21])[C:3]([F:20])([F:19])[O:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([O:11][C:12]([F:18])([F:17])[C:13]([F:16])([F:15])[Br:14])[CH:6]=1.[Cl:23][S:24](O)(=[O:26])=[O:25].Cl>C(Cl)(Cl)Cl>[Br:1][C:2]([F:21])([F:22])[C:3]([F:19])([F:20])[O:4][C:5]1[CH:6]=[C:7]([O:11][C:12]([F:17])([F:18])[C:13]([F:15])([F:16])[Br:14])[CH:8]=[CH:9][C:10]=1[S:24]([Cl:23])(=[O:26])=[O:25]
Reactant: O=S(=O)(O)Cl
Reactant: FC(F)(Br)C(F)(F)Oc1cccc(OC(F)(F)C(F)(F)Br)c1
Agent: Cl
Solvent: ClC(Cl)Cl
Product: O=S(=O)(Cl)c1ccc(OC(F)(F)C(F)(F)Br)cc1OC(F)(F)C(F)(F)Br
Temperature: 25 °C
Reaction time: 1 h
Yield: 88.6 %

Procedure:
In a 250 mL of round-bottom flask resting in an ice-bath were placed 23.35 g (0.05 mol) of this 1,3-di(2-bromotetrafluoroethoxy)benzene and 100 mL of chloroform. Then 116 g of chlorosulfonic acid was added dropwise into the solution. After the initial evolution of hydrogen chloride had subsided, the mixture was brought to room temperature. The reaction mixture was stirred at room temperature for 1 hour, then heated at 35° C. for another day. The contents of the flask were poured into a 1L beaker filled with crushed ice. The chloroform layer was separated and washed with ice cold water to neutral. The organic layer was dried over sodium sulfate. After the removal of the solid materials by filtration, the chloroform was evaporated off completely. The crude product was purified by distillation under the reduced pressure to collect the fraction boiling at 127-129° C./10−2 torr. A total of 25.1 g (0.0443 mol) of 2,4-bis(2-bromotetrafluoroethoxy)benzenesulfonyl chloride was obtained in 88.7% yield. The quantity of hydrogen by-product was below 3%.