Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([CH3:8])[C:5]([CH:9]([CH2:14][CH2:15][CH3:16])[C:10]([O:12][CH3:13])=[O:11])=[C:4]([C:17]2[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][CH:18]=2)[N:3]=1.[NH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2>O1CCOCC1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH3:8][C:6]1[C:5]([CH:9]([CH2:14][CH2:15][CH3:16])[C:10]([O:12][CH3:13])=[O:11])=[C:4]([C:17]2[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][CH:18]=2)[N:3]=[C:2]([NH:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[N:7]=1
Reactant: Nc1ccccc1
Reactant: CCCC(C(=O)OC)c1c(C)nc(Cl)nc1-c1ccc(C)cc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Solvent: C1COCCO1
Product: CCCC(C(=O)OC)c1c(C)nc(Nc2ccccc2)nc1-c1ccc(C)cc1
Yield: 49.6 %

Procedure:
Methyl 2-(2-chloro-4-methyl-6-p-tolylpyrimidin-5-yl)pentanoate (100 mg; 0.300 mmol), aniline (0.033 mL; 0.361 mmol), palladium acetate (2 mg, 0.009 mmol) and xantphos (10 mg; 0.018 mmol) were placed in a 2 mL reaction tube and dissolved in dioxane (1 mL), the tube was purged with argon, sealed and irradiated in a microwave oven at 160° C. for 15 min. The reaction mixture was partitioned between a saturated sodium chloride solution and dichloromethane, filtered over a phase separator filter (1PS) and concentrated under reduced pressure. The crude material was purified by flash chromatography on silica gel using a linear gradient of ethylacetate (5-40%) in heptane to yield 58 mg (39%) of the title compound as a colorless oil.
Reaction SMILES: [CH2:1]([N:3]1[CH:7]=[C:6]([CH:8]=O)[C:5]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][C:15]([O:18][CH2:19][C:20]3[N:21]=[C:22]([C:26]4[O:27][CH:28]=[CH:29][CH:30]=4)[O:23][C:24]=3[CH3:25])=[C:14]([O:31][CH3:32])[CH:13]=2)=[N:4]1)[CH3:2].C(OP([CH2:41][C:42]([O:44][CH2:45][CH3:46])=[O:43])(OCC)=O)C.CN(C)C=O.[H-].[Na+]>O>[CH2:1]([N:3]1[CH:7]=[C:6](/[CH:8]=[CH:41]/[C:42]([O:44][CH2:45][CH3:46])=[O:43])[C:5]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][C:15]([O:18][CH2:19][C:20]3[N:21]=[C:22]([C:26]4[O:27][CH:28]=[CH:29][CH:30]=4)[O:23][C:24]=3[CH3:25])=[C:14]([O:31][CH3:32])[CH:13]=2)=[N:4]1)[CH3:2]
Reactant: CCOC(=O)CP(=O)(OCC)OCC
Reactant: CCn1cc(C=O)c(OCc2ccc(OCc3nc(-c4ccco4)oc3C)c(OC)c2)n1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)/C=C/c1cn(CC)nc1OCc1ccc(OCc2nc(-c3ccco3)oc2C)c(OC)c1
Reaction time: 15 h
Yield: 87.9 %

Procedure:
To a mixture of 1-ethyl-3-[(4-{[2-(2-furyl)-5-methyl-1,3-oxazol-4-yl]methoxy}-3-methoxybenzyl)oxy]-1H-pyrazole-4-carbaldehyde (0.50 g), ethyl diethylphosphonoacetate (0.27 g) and N,N-dimethylformamide (10 mL) was added sodium hydride (60% in oil, 0.05 g) at room temperature, and the mixture was stirred at the same temperature for 15 hrs. Water was poured into the reaction mixture, and the precipitated crystals were collected by filtration to give ethyl (2E)-3-{1-ethyl-3-[(4-{[2-(2-furyl)-5-methyl-1,3-oxazol-4-yl]methoxy}-3-methoxybenzyl)oxy]-1H-pyrazol-4-yl}-2-propenoate as colorless crystals (0.51 g, yield 91%). Recrystallization from ethyl acetate-hexane gave colorless prism crystals. melting point: 149-150° C.
Reaction SMILES: C[O:2][C:3](=O)[CH:4]=[CH:5][C:6](=[C:11]([NH:13][CH2:14][C:15]1[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=1)[CH3:12])[C:7]([O:9][CH3:10])=[O:8].C[O-].[Na+].[Br:27]N1C(=O)CCC1=O>CO>[CH3:10][O:9][C:7]([C:6]1[CH:5]=[C:4]([Br:27])[C:3](=[O:2])[N:13]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=2)[C:11]=1[CH3:12])=[O:8]
Reactant: O=C1CCC(=O)N1Br
Reactant: COC(=O)C=CC(C(=O)OC)=C(C)NCc1ccc(OC)cc1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: COC(=O)c1cc(Br)c(=O)n(Cc2ccc(OC)cc2)c1C
Temperature: 25 °C
Yield: 60.9 %

Procedure:
MeOH (120 mL) was added to a flask containing 4-[1-(4-methoxy-benzylamino)-ethylidene]-pent-2-enedioic acid dimethyl ester (5 g, 15.7 mmol). NaOMe solution (3.6 mL, 15.7 mmol, 4.375 M in MeOH) and N-bromosuccinimide (3.35 g, 18.8 mmol) were added, and the resulting mixture was refluxed for 1 h. After cooling to r.t., the solvent was evaporated in vacuo. The residue was partitioned between saturated NH4Cl and CH2Cl2. The aqueous layer was extracted with additional CH2Cl2 and the organic layers were combined, dried over MgSO4, and concentrated. The crude product was chromatographed (0-50% EtOAc/hexanes) to give 3.5 g of the title compound. MS: (+) m/z 388.14, 390.15 (M+Na, 79/81Br).
Reaction SMILES: [CH2:1]([N:3]([CH2:20][CH3:21])[C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([O:13][CH3:14])[CH:11]=2)[NH:6][C:5]=1[C:15](OCC)=[O:16])[CH3:2].[NH2-:22].[Li+].C(O)(=O)C.[ClH:28]>CCOCC>[ClH:28].[CH2:1]([N:3]([CH2:20][CH3:21])[C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([O:13][CH3:14])[CH:11]=2)[NH:6][C:5]=1[C:15]([NH2:22])=[O:16])[CH3:2]
Reactant: [NH2-]
Reactant: CCOC(=O)c1[nH]c2ccc(OC)cc2c1N(CC)CC
Agent: Cl
Agent: [Li+]
Solvent: CCOCC
Solvent: CC(=O)O
Product: CCN(CC)c1c(C(N)=O)[nH]c2ccc(OC)cc12
Yield: 36 %

Procedure:
Prepared from ethyl 3-(diethylamino)-5-methoxy-1H-indole-2-carboxylate (Unangst PC, et al., J. Heterocyclic Chem. 1987;24:817) and lithium amide by the procedure described in Example 18, with the exception that dilute acetic acid is substituted for 1.0N HCl during the wash of the ethyl acetate extracts. The crude product is purified by flash chromatography (silica gel, 30% ethyl acetate in dichloromethane elution) to give a foam. The foam is dissolved in ether and treated with gaseous HCl to provide the product salt in 36% yield after recrystallization from acetonitrile; mp 244° C.-dec.
Reaction SMILES: [C:1](O)(=O)C(O)=O.[Cl:7][C:8]1[CH:13]=[CH:12][C:11]([CH:14]([NH:17][CH2:18][CH2:19][CH2:20][N:21]2[CH:25]=[CH:24][N:23]=[CH:22]2)[CH2:15][CH3:16])=[CH:10][CH:9]=1.C=O>C(O)=O>[Cl:7][C:8]1[CH:13]=[CH:12][C:11]([CH:14]([N:17]([CH2:18][CH2:19][CH2:20][N:21]2[CH:25]=[CH:24][N:23]=[CH:22]2)[CH3:1])[CH2:15][CH3:16])=[CH:10][CH:9]=1
Reactant: O=C(O)C(=O)O
Reactant: CCC(NCCCn1ccnc1)c1ccc(Cl)cc1
Agent: C=O
Solvent: O=CO
Product: CCC(c1ccc(Cl)cc1)N(C)CCCn1ccnc1
Temperature: 95 °C

Procedure:
n-[1-(4-Chlorophenyl)propyl]-3-(imidazol-1-yl)propylamine (13.9 g, free base of Example 30) was added in portions to formic acid (11.75 g, 98-100%) at 0° C. Formaldehyde (9.6 g, 37%) was added and the mixture heated at 95° C. for 6 hours. Work-up as described in Example 90 gave N-[1-(4-chlorophenyl)propyl]-3-(imidazol-1-yl)-N-methylpropylamine as an oil which was not distilled.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]([OH:8])=O.C1CCC(N=C=NC2CCCCC2)CC1.[N:24]1([CH2:30][C:31]2[CH:32]=[C:33]([CH:46]=[CH:47][CH:48]=2)[O:34][CH2:35][CH2:36][CH2:37][NH:38][C:39](=[O:45])[CH2:40][S:41][CH2:42][CH2:43][NH2:44])[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1>ClCCl>[N:24]1([CH2:30][C:31]2[CH:32]=[C:33]([CH:46]=[CH:47][CH:48]=2)[O:34][CH2:35][CH2:36][CH2:37][NH:38][C:39](=[O:45])[CH2:40][S:41][CH2:42][CH2:43][NH:44][C:6]([C:2]2[O:1][CH:5]=[CH:4][CH:3]=2)=[O:8])[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1
Reactant: NCCSCC(=O)NCCCOc1cccc(CN2CCCCC2)c1
Reactant: O=C(O)c1ccco1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClCCl
Product: O=C(CSCCNC(=O)c1ccco1)NCCCOc1cccc(CN2CCCCC2)c1
Reaction time: 0.5 h
Yield: 26.1 %

Procedure:
There was dissolved 1.12 g of 2-furancarboxylic acid in 50 ml of dichloromethane and added 2.06 g (0.01 mol) of DCC under cooling with ice and the mixture was stirred for 30 minutes. Thereto was added 3.65 g (0.01 mol) of N-[3-[3-(piperidinomethyl)phenoxy]propyl]-2-(2-aminoethylthio)acetamide and the mixture was stirred for 18 hours at room temperature. The precipitate was filtrated off, and the filtrate was washed with water and dried over Glauber's salt. Then the solvent was removed under reduced pressure and the residue was purified by silica gel column chromatography (chloroform:methanol=10:1) to give 1.2 g of the titled compound as crystals.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6](Cl)[CH:5]=[C:4]([C:9]([F:12])([F:11])[F:10])[N:3]=1.[CH3:13][O-:14].[Na+]>C(O)C>[NH2:1][C:2]1[N:7]=[C:6]([O:14][CH3:13])[CH:5]=[C:4]([C:9]([F:12])([F:11])[F:10])[N:3]=1
Reactant: C[O-]
Reactant: Nc1nc(Cl)cc(C(F)(F)F)n1
Agent: [Na+]
Solvent: CCO
Product: COc1cc(C(F)(F)F)nc(N)n1

Procedure:
2-Amino-4-ethoxy-6-trifluoromethylpyrimidine of melting point 114°-116° C. was obtained in a similar manner by reacting 2-amino-4-chloro-6-trifluoromethylpyrimidine with sodium methylate in ethanol.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:13])[C:5]1[CH:10]=[C:9]([F:11])[CH:8]=[C:7](Br)[CH:6]=1)[CH3:2].C1(P(C2C=CC=CC=2)C2C3OC4C(=CC=CC=4P(C4C=CC=CC=4)C4C=CC=CC=4)C(C)(C)C=3C=CC=2)C=CC=CC=1.[CH3:56][O:57][C:58]1[CH:65]=[CH:64][C:61]([CH2:62][SH:63])=[CH:60][CH:59]=1.CCN(C(C)C)C(C)C>O1CCOCC1.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]>[CH2:1]([O:3][C:4](=[O:13])[C:5]1[CH:6]=[C:7]([S:63][CH2:62][C:61]2[CH:64]=[CH:65][C:58]([O:57][CH3:56])=[CH:59][CH:60]=2)[CH:8]=[C:9]([F:11])[CH:10]=1)[CH3:2]
Reactant: CCOC(=O)c1cc(F)cc(Br)c1
Reactant: COc1ccc(CS)cc1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: CCOC(=O)c1cc(F)cc(SCc2ccc(OC)cc2)c1
Temperature: 90 °C
Reaction time: 2 h

Procedure:
To a room temperature, degassed solution of 3-Bromo-5-fluoro-benzoic acid ethyl ester (4.0 g, 16.2 mmol) in dioxane (100 mL) was added 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (0.48 g, 0.82 mmol), 4-methoxy-benzylmercaptan (2.26 mL, 16.2 mmol), DIEA (5.6 mL, 32.4 mmol), and tris(dibenzylideneacetone)dipalladium(0) (0.37 g, 0.41 mmol). The resulting mixture was warmed to 90° C. and stirred for 2 hrs, then cooled to room temperature. The mixture was subjected to standard aqueous workup, and the crude residue was filtered through a pad of silica gel to afford the title compound.
Reaction SMILES: [OH:1][CH:2]([C:5]1[N:10]=[C:9]([C:11](=O)[CH2:12]Br)[CH:8]=[CH:7][CH:6]=1)[CH2:3][OH:4].[CH2:15]([O:17][C:18]1[CH:19]=[C:20]([CH:24]=[CH:25][C:26]=1[O:27][CH2:28][CH3:29])[C:21]([NH2:23])=[S:22])[CH3:16]>>[CH2:15]([O:17][C:18]1[CH:19]=[C:20]([C:21]2[S:22][CH:12]=[C:11]([C:9]3[CH:8]=[CH:7][CH:6]=[C:5]([CH:2]([OH:1])[CH2:3][OH:4])[N:10]=3)[N:23]=2)[CH:24]=[CH:25][C:26]=1[O:27][CH2:28][CH3:29])[CH3:16]
Reactant: CCOc1ccc(C(N)=S)cc1OCC
Reactant: O=C(CBr)c1cccc(C(O)CO)n1
Product: CCOc1ccc(-c2nc(-c3cccc(C(O)CO)n3)cs2)cc1OCC

Procedure:
A reaction was conducted in the same manner as in Example 1, by using 6-(1,2-dihydroxyethyl)-2-(α-bromoacetyl)pyridine and 3,4-diethoxythiobenzamide, to obtain 2-(3,4-diethoxyphenyl)-4-[6-(1,2-dihydroxyethyl)-2-pyridyl]thiazole.
Reaction SMILES: [Na].CO.[CH:4]1[C:9]([CH:10]=[O:11])=[CH:8][C:7]2[O:12][CH2:13][O:14][C:6]=2[CH:5]=1.[N+:15]([CH:18]([CH3:20])[CH3:19])([O-:17])=[O:16]>C(O)(=O)C>[CH2:13]1[O:14][C:6]2[CH:5]=[CH:4][C:9]([CH:10]([OH:11])[C:18]([CH3:20])([N+:15]([O-:17])=[O:16])[CH3:19])=[CH:8][C:7]=2[O:12]1
Reactant: O=Cc1ccc2c(c1)OCO2
Reactant: CC(C)[N+](=O)[O-]
Agent: [Na]
Solvent: CC(=O)O
Solvent: CO
Product: CC(C)(C(O)c1ccc2c(c1)OCO2)[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 1 h
Yield: 18.8 %

Procedure:
7.7 g of sodium are added to 220 ml of anhydrous methanol, and 50 g of piperonal and 90 g of 2-nitropropane are added thereto. The mixture is stirred at room temperature for one hour, and then refluxed for 4 hours. After cooling, the reaction mixture is poured into ice-water containing 21 g of acetic acid, and then extracted with ether. The extract is washed with a saturated sodium chloride solution, a saturated sodium bisulfite solution and a saturated sodium chloride solution, successively. The washed extract is dried and then evaporated to remove solvent. 15 g of 1-(3,4-methylenedioxyphenyl)-2-methyl-2-nitropropanol are thereby obtained as a crude oil.
Reaction SMILES: Cl[C:2]1[N:11]=[C:10]([O:12]COCCOC)[C:9]2[C:4](=[CH:5][C:6]([Cl:19])=[CH:7][CH:8]=2)[N:3]=1.[NH:20]1[CH:24]=[C:23]([C:25]([O:27][CH2:28][CH3:29])=[O:26])[CH:22]=[N:21]1.C([O-])([O-])=O.[Cs+].[Cs+].CN(C=O)C>Cl>[CH2:28]([O:27][C:25]([C:23]1[CH:24]=[N:20][N:21]([C:2]2[NH:11][C:10](=[O:12])[C:9]3[C:4](=[CH:5][C:6]([Cl:19])=[CH:7][CH:8]=3)[N:3]=2)[CH:22]=1)=[O:26])[CH3:29]
Reactant: COCCOCOc1nc(Cl)nc2cc(Cl)ccc12
Reactant: CCOC(=O)c1cn[nH]c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1cnn(-c2nc3cc(Cl)ccc3c(=O)[nH]2)c1
Temperature: 120 °C
Yield: 49.9 %

Procedure:
A mixture of 2,7-dichloro-4-(2-methoxy-ethoxymethoxy)-quinazoline (0.68 g, 2.2 mmol), ethyl pyrazole-4-carboxylate (0.34 g, 2.4 mmol), Cs2CO3 (1.2 g, 3.6 mmol) and anhydrous DMF (10 mL) was heated to 120° C. for 20 min, and then was cooled to 0° C. The mixture was carefully diluted with 1 M aq. HCl (30 mL). The mixture was allowed to warm to rt and the precipitate was collected by filtration to provide the titled compound (0.35 g, 50%). MS (Cl): mass calcd. for C14H11ClN4O3, 318.7; m/z found, 317.0 [M−H]−. 1H NMR (400 MHz, DMSO-d6): 13.04 (br s, 1H), 8.99 (s, 1H), 8.32 (s, 1H), 8.11 (d, J=8.5 Hz, 1H), 7.75 (s, 1H), 7.54 (dd, J=8.5, 2.1 Hz, 1H), 4.30 (q, J=7.1 Hz, 2H), 1.33 (t, J=7.1 Hz, 3H).
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@@H:12]([CH2:20][S:21][CH2:22][C@H:23]([O:37][C:38](=[O:48])[NH:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH3:47])[CH2:24][O:25][C:26](=[O:36])[NH:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH3:35])[C:13]([O:15]C(C)(C)C)=[O:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>C(O)(C(F)(F)F)=O.C(Cl)Cl>[CH2:1]([O:8][C:9]([NH:11][C@@H:12]([CH2:20][S:21][CH2:22][C@H:23]([O:37][C:38](=[O:48])[NH:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH3:47])[CH2:24][O:25][C:26](=[O:36])[NH:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH3:35])[C:13]([OH:15])=[O:14])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCCCCCCCNC(=O)OC[C@H](CSC[C@H](NC(=O)OCc1ccccc1)C(=O)OC(C)(C)C)OC(=O)NCCCCCCCC
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCCCCCCCNC(=O)OC[C@H](CSC[C@H](NC(=O)OCc1ccccc1)C(=O)O)OC(=O)NCCCCCCCC

Procedure:
A solution of (R)-tert-butyl 2-(benzyloxycarbonylamino)-3-((R)-2,3-bis(octylcarbamoyloxy)propylthio)propanoate in 30% TFA in DCM (0.3 M) was stirred at room temperature until complete deprotection of the tert-butyl group (4 hours). The reaction was diluted with DCM and concentrated with a stream of nitrogen. The reaction mixture was then diluted in MTBE and washed once with 1M citric acid (adjusted to pH3). The organic layer was dried over anhydrous Na2SO4 and concentrated en vaccuo. The resulting waxy solid was used without further purification.
Reaction SMILES: [N:1]1([CH2:7][CH2:8][NH:9][C:10]([NH2:12])=[S:11])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.Br[CH:14]([CH:20]([CH3:22])[CH3:21])[C:15](OCC)=[O:16]>>[CH:20]([CH:14]1[S:11][C:10]([NH:9][CH2:8][CH2:7][N:1]2[CH2:2][CH2:3][O:4][CH2:5][CH2:6]2)=[N:12][C:15]1=[O:16])([CH3:22])[CH3:21]
Reactant: NC(=S)NCCN1CCOCC1
Reactant: CCOC(=O)C(Br)C(C)C
Product: CC(C)C1SC(NCCN2CCOCC2)=NC1=O

Procedure:
Synthesis was performed from N-(2-morpholin-4-ylethyl)thiourea and ethyl 2-bromo-3-methylbutanoate according to Method C.
Reaction SMILES: [CH2:1]([OH:6])[CH2:2][CH2:3][CH2:4][OH:5].C(N(C(C)C)CC)(C)C.[C:16]([Si:20](Cl)([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)([CH3:19])([CH3:18])[CH3:17].N#N>ClCCl>[C:16]([Si:20]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)([C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1)[O:5][CH2:4][CH2:3][CH2:2][CH2:1][OH:6])([CH3:19])([CH3:17])[CH3:18]
Reactant: OCCCCO
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Agent: N#N
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)[Si](OCCCCO)(c1ccccc1)c1ccccc1
Yield: 172.5 %

Procedure:
To a solution of 1,4-butanediol (5 g, 55 mol) in dichlormethane (10 mL) containing diisopropylethylamine (10 mL) was added tert-butylchlorodiphenylsilane (5 mL, 18 mmol) dropwise under N2 atmosphere at 18° C. over 2 h. The resultant solution was stirred at room temperature for 4 hours and concentrated under reduced pressure. Purification by column chromatography with hexane/ethyl acetate (1/1) gave 4-(tert-butyl-diphenyl-silanyloxy)-butan-1-ol (10.2 g, 85% yield) as colorless oil: 1H NMR (400 MHz, CDCl3) δ 7.62-7.71 (4H, m); 7.32-7.43 (6H, m), 3.63-3.69 (4H, m), 1.83 (1H, br s), 1.59-1.71 (4H, m), 1.03 (9H, s).
Reaction SMILES: [Br:1][C:2]1[C:3]([CH3:8])=[N:4][O:5][C:6]=1[NH2:7].[H-].[Na+].[CH3:11][O:12][C:13]1[CH:14]=[C:15]([CH:30]=[CH:31][C:32]=1[O:33][CH3:34])[CH2:16][C:17]1[S:21][C:20]2[CH:22]=[CH:23][CH:24]=[CH:25][C:19]=2[C:18]=1[S:26](Cl)(=[O:28])=[O:27]>C1COCC1>[Br:1][C:2]1[C:3]([CH3:8])=[N:4][O:5][C:6]=1[NH:7][S:26]([C:18]1[C:19]2[CH:25]=[CH:24][CH:23]=[CH:22][C:20]=2[S:21][C:17]=1[CH2:16][C:15]1[CH:30]=[CH:31][C:32]([O:33][CH3:34])=[C:13]([O:12][CH3:11])[CH:14]=1)(=[O:27])=[O:28]
Reactant: Cc1noc(N)c1Br
Reactant: COc1ccc(Cc2sc3ccccc3c2S(=O)(=O)Cl)cc1OC
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1ccc(Cc2sc3ccccc3c2S(=O)(=O)Nc2onc(C)c2Br)cc1OC

Procedure:
N-(4-bromo-3-methyl-5-isoxazolyl)-2-(3,4-dimethoxy-benzyl)-benzo[b]thiophene-3-sulfonamide was prepared in the same manner as described in Example 41. Reaction of 4-bromo-3-methyl-5-aminoisoxazole (1.0 mmoles, 0.18 g), NaH (2.5 mmoles, 60 mg), and 2-(3,4-dimethoxybenzyl)benzo[b]thiophene-3-sulfonylchloride (1.2 mmoles, 0.44 g) in THF (6 ml), after recrystallization from chloroform and hexanes, yielded 0.42 g (80%) of a brown solid, m.p. 151-153° C.
Reaction SMILES: [O:1]([CH2:8][CH2:9][S:10][CH2:11][C:12]1[CH:13]=[C:14]([C:18]2[CH:23]=[CH:22][C:21]([C:24](O)=[O:25])=[CH:20][CH:19]=2)[CH:15]=[CH:16][CH:17]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:27][N:28]([CH3:32])[CH2:29][CH2:30][NH2:31]>C1COCC1>[CH3:27][N:28]([CH3:32])[CH2:29][CH2:30][NH:31][C:24]([C:21]1[CH:22]=[CH:23][C:18]([C:14]2[CH:15]=[CH:16][CH:17]=[C:12]([CH2:11][S:10][CH2:9][CH2:8][O:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[CH:13]=2)=[CH:19][CH:20]=1)=[O:25]
Reactant: CN(C)CCN
Reactant: O=C(O)c1ccc(-c2cccc(CSCCOc3ccccc3)c2)cc1
Solvent: C1CCOC1
Product: CN(C)CCNC(=O)c1ccc(-c2cccc(CSCCOc3ccccc3)c2)cc1

Procedure:
3′-(2-Phenoxy-ethylsulfanylmethyl)-biphenyl-4-carboxylic acid (2-dimethylamino-ethyl)-amide was synthesized as described for 41-(2-phenoxy-ethylsulfanylmethyl)-biphenyl-3-carboxylic acid (3-dimethylamino-propyl)-amide. 3′-(2-Phenoxy-ethylsulfanylmethyl)-biphenyl-4-carboxylic acid (0.80 g, 2.19 mmol, 1 eq.) in anhydrous THF was treated with 1,1-carbonyldiimidazole (0.36 g, 2.23 mmol, 1.02 eq.) and N,N-dimethylethylenediamine (0.23 g, 2.63 mmol, 1.2 eq.). When complete, the reaction was worked up as described leaving a yellow oil that later solidified.
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][CH:11]([N:14]([CH2:25][CH3:26])[C:15]2[C:20]([CH:21]=[C:22]([CH3:24])[CH3:23])=[CH:19][CH:18]=[CH:17][N:16]=2)[CH2:10][CH2:9]1)C1C=CC=CC=1.C1N=CN(C(N2C=NC=C2)=O)C=1.[NH:39]1[CH:43]=[CH:42][CH:41]=[C:40]1[C:44]([OH:46])=O>[OH-].[OH-].[Pd+2]>[NH:39]1[CH:43]=[CH:42][CH:41]=[C:40]1[C:44]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]([CH2:25][CH3:26])[C:15]2[C:20]([CH2:21][CH:22]([CH3:23])[CH3:24])=[CH:19][CH:18]=[CH:17][N:16]=2)[CH2:10][CH2:9]1)=[O:46]
Reactant: CCN(c1ncccc1C=C(C)C)C1CCN(Cc2ccccc2)CC1
Reactant: O=C(O)c1ccc[nH]1
Agent: [Pd+2]
Agent: O=C(n1ccnc1)n1ccnc1
Agent: [OH-]
Product: CCN(c1ncccc1CC(C)C)C1CCN(C(=O)c2ccc[nH]2)CC1

Procedure:
Following the general procedure of EXAMPLE 20 and making non-critical variations but starting with 1-benzyl-4-[N-ethyl-N-(3-(2-methyl-1-propenyl)-2-pyridinyl)amino]piperidine (XXII, EXAMPLE 17, 0.67 g, 1.92 mmol), Pearlman's catalyst (0.1 g), CDI (0.31 g, 1.92 mmol) and pyrrole-2-carboxylic acid (0.213 g, 1.92 mmol), the title compound is obtained, HRMS Calcd. for C21H30N4O=354.2419, found=354.2413.
Reaction SMILES: F[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[F:11])[NH:7][CH:6]=[C:5]2[C:12]1[CH:13]=[N:14][N:15](CC2CCNCC2)[CH:16]=1.[OH-].[Na+]>CO.O>[F:11][C:10]1[CH:9]=[C:8]2[C:4]([C:5]([C:12]3[CH:16]=[N:15][NH:14][CH:13]=3)=[CH:6][NH:7]2)=[CH:3][CH:2]=1
Reactant: Fc1cc2[nH]cc(-c3cnn(CC4CCNCC4)c3)c2cc1F
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: Fc1ccc2c(-c3cn[nH]c3)c[nH]c2c1
Temperature: 85 °C
Reaction time: 4 h
Yield: 35.9 %

Procedure:
To a solution of 6-fluoro-1-(phenylsulfonyl)-3-(1H-pyrazol-4-yl)-1H-indole (Intermediate 5; 183 mg; 0.54 mmol) in MeOH (20 mL) was added a solution of NaOH (142 mg; 3.55 mmol) in water (1 mL). The reaction mixture was stirred at 85° C. for 4 h, concentrated, diluted with H2O (5 mL), and extracted with Et2O (10 mL×3). The combined organic layers were washed with water (10 mL×2), brine (10 mL), dried over anhydrous Na2SO4, filtered, and concentrated. The crude product was purified by preparative HPLC. 39 mg (36%) of the title compound was obtained as a white solid.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[OH:12].[Br:13]NC(=O)CCC(N)=O>ClCCl.CN(C)C=O>[NH2:1][C:2]1[C:3]([OH:12])=[CH:4][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:10][C:11]=1[Br:13]
Reactant: COC(=O)c1ccc(N)c(O)c1
Reactant: NC(=O)CCC(=O)NBr
Solvent: ClCCl
Solvent: CN(C)C=O
Product: COC(=O)c1cc(O)c(N)c(Br)c1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 32.5 %

Procedure:
To a solution of methyl 4-amino-3-hydroxybenzoate (2.5 g, 15.0 mmol) in dichloromethane (71 mL) and N,N-dimethylformamide (3.6 mL) was added N-bromosuccinamide (2.93 g, 16.5 mmol). The mixture was stirred at ambient temperature. After 15 min, the mixture was quenched with sat. sodium sulfite. Hydrochloric acid (1.0 M) was added and the mixture was extracted with dichloromethane (3×). The combined organic layer was washed with brine, dried over magnesium sulfate, filtered and concentrated. Purification by silica gel chromatography (100% hexanes→100% ethyl acetate) gave the title compound (1.2 g). LC-MS [M]=246.0.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]=[CH:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:4][C:3]=1[N+:16]([O-])=O.[H][H]>[Pd].C(O)C>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)=[CH:4][C:3]=1[NH2:16]
Reactant: [H][H]
Reactant: Cc1ccc(C=Cc2ccccc2)cc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CCO
Product: Cc1ccc(CCc2ccccc2)cc1N

Procedure:
A mixture of the product from Example 241A (0.166 g, 0.694 mmol) and 10% palladium on charcoal (18.4 mg, 0.025 eq), in ethanol (10 mL) was stirred under one atmosphere of hydrogen for 16 hours. The reaction mixture was then filtered through Celite and the solvent evaporated under reduced pressure to provide the title compound as a slightly red oil (0.141 g, 96% yield).
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10]([N+:27]([O-])=O)=[C:11]([CH2:19][C:20](=O)[C:21]([O:23][CH2:24][CH3:25])=[O:22])[C:12]([C:15]([F:18])([F:17])[F:16])=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>[Cl-].[Ti+4].[Cl-].[Cl-].[Cl-].C(O)C>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]([F:18])([F:17])[F:16])=[C:11]2[C:10]=1[NH:27][C:20]([C:21]([O:23][CH2:24][CH3:25])=[O:22])=[CH:19]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)C(=O)Cc1c(C(F)(F)F)ccc(OCc2ccccc2)c1[N+](=O)[O-]
Agent: [Ti+4]
Agent: [Cl-]
Solvent: CCO
Product: CCOC(=O)c1cc2c(C(F)(F)F)ccc(OCc3ccccc3)c2[nH]1

Procedure:
The reaction was carried out in a manner similar to Reference Example 12 c) except for using 10.9 g (26.7 mmol) of ethyl (3-benzyloxy-6-trifluoromethyl-2-nitrophenyl)pyruvate, 165 g (213 mol) of 20% titanium chloride aqueous solution and 100 ml of ethanol. Ethyl 7-benzyloxy-4-trifluoromethyl-2-indolecarboxylate was thus obtained in the yield of 8.00 g (82.6%).