Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][CH2:15][NH2:16])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH:17]1([NH:20][C:21]([C:23]2[C:31]3[CH:30]=[C:29]([C:32]4[C:37]([Br:38])=[CH:36][N:35]=[C:34](Cl)[N:33]=4)[S:28][C:27]=3[CH:26]=[CH:25][CH:24]=2)=[O:22])[CH2:19][CH2:18]1.C(N(C(C)C)CC)(C)C>O1CCOCC1>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][CH2:15][NH:16][C:34]2[N:33]=[C:32]([C:29]3[S:28][C:27]4[CH:26]=[CH:25][CH:24]=[C:23]([C:21](=[O:22])[NH:20][CH:17]5[CH2:18][CH2:19]5)[C:31]=4[CH:30]=3)[C:37]([Br:38])=[CH:36][N:35]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: O=C(NC1CC1)c1cccc2sc(-c3nc(Cl)ncc3Br)cc12
Reactant: CC(C)(C)OC(=O)N1CCC(CCN)CC1
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1CCC(CCNc2ncc(Br)c(-c3cc4c(C(=O)NC5CC5)cccc4s3)n2)CC1

Procedure:
4-(2-Aminoethyl)-piperidine-1-carboxylic acid tert-butyl ester (1.41 g, 6.18 mmol) is added to a stirred suspension of 2-(5-bromo-2-chloropyrimidin-4-yl)-benzo[b]thiophene-4-carboxylic acid cyclopropylamide (0.75 g, 2.1 mmol) and diisopropylethylamine (0.80 g, 6.2 mmol) in anhydrous 1,4-dioxane (15 mL) at room temperature under nitrogen. The resultant mixture is heated in an oil bath at 90° C. for 12 hours. At room temperature the mixture is concentrated and chromatographed on silica gel, eluting with 2 M NH3/CH3OH in dichloromethane: 1-10%, to give 4-{2-[5-bromo-4-(4-cyclopropylcarbamoyl-benzo[b]thiophen-2-yl)-pyrimidin-2-ylamino]-ethyl}-piperidine-1-carboxylic acid tert-butyl ester as a solid.
Reaction SMILES: [C:1]1([P:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)Cl)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:15]([NH:17][CH2:18][CH3:19])[CH3:16]>C1(C)C=CC=CC=1>[P:7]([N:17]([CH2:18][CH3:19])[CH2:15][CH3:16])([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CCNCC
Reactant: ClP(c1ccccc1)c1ccccc1
Solvent: Cc1ccccc1
Product: CCN(CC)P(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Diphenylchlorophosphine (2.0 mL, 2.38 g, 10.79 mmol) was added to a stirred solution of diethylamine (2.5 mL, 1.82 g, 24.9 mmol) in toluene (20 mL). The resulting white slurry was stirred overnight at ambient temperature and filtered. The filtered solid was washed with toluene (2×10 mL). The combined filtrate was reduced in volume by distillation in vacuum to approximately 20 mL and transferred to a graduated Schlenk tube equipped with a Yong valve. The volume of the solution was adjusted to 31.0 mL by addition of toluene to give 0.348 M solution of Ph2PNEt2. 31P{1H} NMR (toluene, 25° C.), δ: 51.0 (s).
Reaction SMILES: [O:1]=[C:2]1[CH2:7][CH2:6][N:5]([CH2:8][C:9]#[N:10])[CH2:4][CH2:3]1.[CH2:11](O)[CH2:12][OH:13].C(=O)([O-])O.[Na+]>C1(C)C=CC=CC=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>[CH2:11]1[CH2:12][O:13][C:2]2([CH2:7][CH2:6][N:5]([CH2:8][C:9]#[N:10])[CH2:4][CH2:3]2)[O:1]1
Reactant: OCCO
Reactant: N#CCN1CCC(=O)CC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Product: N#CCN1CCC2(CC1)OCCO2
Yield: 97.1 %

Procedure:
A solution of 10.0 g of 4-oxo-1-piperidineacetonitrile, 22.6 g of ethylene glycol and 0.62 g of anhydrous p-toluenesulfonic acid in 100 ml of toluene was refluxed for 6 hours with Dean-stark dehydrating apparatus. After cooling, the reaction mixture was added with saturated aqueous sodium hydrogencarbonate solution and extracted with ethyl acetate. The extract was dried, and the solvent was evaporated to give a pale brown liquid. The resulting liquid was purified by alumina column chromatography using ethyl acetate—n-heptane (1:3) as an eluting solvent to give 12.8 g of a colorless liquid.
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[Cl:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][C:13]([C:15]2[CH:20]=[CH:19][C:18]([O:21]C)=[CH:17][CH:16]=2)=[O:14])=[CH:8][CH:7]=1.Cl.C(OCC)(=O)C>C1(C)C=CC=CC=1>[Cl:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][C:13]([C:15]2[CH:16]=[CH:17][C:18]([OH:21])=[CH:19][CH:20]=2)=[O:14])=[CH:8][CH:7]=1
Reactant: COc1ccc(C(=O)Cc2ccc(Cl)cc2)cc1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: O=C(Cc1ccc(Cl)cc1)c1ccc(O)cc1
Temperature: 60 °C
Reaction time: 2 h

Procedure:
Aluminum chloride (29.8 g, 0.223 mol) is added in small portions to a stirred solution of 2-(4-chlorophenyl)-1-(4-methoxyphenyl)ethanone (19.4 g, 0.074 mol) in toluene (300 ml). The mixture is heated to 60° C. and stirring is continued for 2 h. Dilute hydrochloric acid is added to the cooled mixture. Ethyl acetate is added to dissolve the product. The layers are separated and the aqueous phase is extracted with ethyl acetate. The combined organic phases are dried and the solvents are evaporated. The product is recrystallized from toluene. The yield is 17 g, 93%.
Reaction SMILES: C([N:4]1[C:12]2[C:7](=[CH:8][C:9]([N+:13]([O-:15])=[O:14])=[CH:10][CH:11]=2)[C:6](=[C:16](OCC)[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:5]1=[O:26])(=O)C.[C:27]([O:31][C:32]([NH:34][CH2:35][C:36]1[CH:42]=[CH:41][C:39]([NH2:40])=[CH:38][CH:37]=1)=[O:33])([CH3:30])([CH3:29])[CH3:28].[OH-].[Na+]>CN(C=O)C.CO>[C:27]([O:31][C:32]([NH:34][CH2:35][C:36]1[CH:42]=[CH:41][C:39]([NH:40]/[C:16](=[C:6]2\[C:5](=[O:26])[NH:4][C:12]3[C:7]\2=[CH:8][C:9]([N+:13]([O-:15])=[O:14])=[CH:10][CH:11]=3)/[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[CH:38][CH:37]=1)=[O:33])([CH3:30])([CH3:28])[CH3:29]
Reactant: CCOC(=C1C(=O)N(C(C)=O)c2ccc([N+](=O)[O-])cc21)c1ccccc1
Reactant: CC(C)(C)OC(=O)NCc1ccc(N)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NCc1ccc(N/C(=C2\C(=O)Nc3ccc([N+](=O)[O-])cc32)c2ccccc2)cc1

Procedure:
Prepared analogously to Example 82 from 1-acetyl-3-(1-ethoxy-1-phenyl-methylidene)-5-nitro-2-indolinone and 4-tert.butoxycarbonylaminomethyl-aniline in DMF and subsequent treatment with sodium hydroxide solution in methanol.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([C:10]2[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=2)[S:5][C:6]=1[N+:7]([O-:9])=[O:8].[CH3:16][S-:17].[Na+]>O1CCOCC1.C(OCC)(=O)C>[CH3:16][S:17][C:2]1[N:3]=[C:4]([C:10]2[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=2)[S:5][C:6]=1[N+:7]([O-:9])=[O:8]
Reactant: C[S-]
Reactant: O=[N+]([O-])c1sc(-c2cccnc2)nc1Cl
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: CSc1nc(-c2cccnc2)sc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 3 h
Yield: 68.3 %

Procedure:
To a solution of 4-chloro-5-nitro-2-(pyridin-3-yl)thiazole (500 mg, 2.07 mmol) in 1,4-dioxane (2 mL) was added in one portion solid sodium thiomethoxide (145 mg, 2.07 mmol). The orange-red mixture was stirred at room temperature for 3 hours. The mixture was diluted with ethyl acetate and rinsed with brine, dried over MgSO4 and concentrated in vacuo to give a yellow solid. This solid was purified by silica gel chromatography (ethyl acetate/hexanes) to give 4-(methylthio)-5-nitro-2-(pyridin-3-yl)thiazole (358 mg, 68%): 1H NMR (300 MHz, CDCl3) δ 9.21 (d, J=5.4 Hz, 1H), 8.79 (dd, J=4.8, 1.8 Hz, 1H), 8.24 (dt, J=7.8, 2.1 Hz, 1H), 7.46 (ddd, J=8.1, 4.8, 0.9 Hz, 1H), 2.81 (s, 3H); EIMS m/z 253.
Reaction SMILES: [C:1]([NH:5][CH2:6][CH:7]([OH:26])[CH2:8][O:9][C:10]1[CH:11]=[C:12]([C:19]2[CH2:20][CH2:21][C:22](=[O:25])[NH:23][N:24]=2)[CH:13]=[CH:14][C:15]=1[N+:16]([O-])=O)([CH3:4])([CH3:3])[CH3:2].C1CCCCC=1>C(O)C.[Pd]>[NH2:16][C:15]1[CH:14]=[CH:13][C:12]([C:19]2[CH2:20][CH2:21][C:22](=[O:25])[NH:23][N:24]=2)=[CH:11][C:10]=1[O:9][CH2:8][CH:7]([OH:26])[CH2:6][NH:5][C:1]([CH3:3])([CH3:2])[CH3:4]
Reactant: CC(C)(C)NCC(O)COc1cc(C2=NNC(=O)CC2)ccc1[N+](=O)[O-]
Agent: [Pd]
Solvent: C1=CCCCC1
Solvent: CCO
Product: CC(C)(C)NCC(O)COc1cc(C2=NNC(=O)CC2)ccc1N

Procedure:
A solution of 6-[3-(3-t-butylamino-2-hydroxypropoxy)-4-nitrophenyl]-4,5-dihydro-3(2H)-pyridazinone in ethanol was heated under reflux with palladium on charcoal and excess of cyclohexene for 18 hours. Evaporation of the filtered solution under reduced pressure gave 6-[4-amino-3-(3-t-butylamino-2-hydroxypropoxy)phenyl]-4,5-dihydro-3(2H)-pyridazinone.
Reaction SMILES: [CH2:1]([C@H:3]1[CH2:8][N:7]([CH3:9])[CH2:6][CH2:5][N:4]1[C:10]1[N:14]([CH3:15])[N:13]=[CH:12][C:11]=1[NH2:16])[CH3:2].C(OC([NH:24][C:25]1[S:29][C:28]([C:30]2[C:35]([F:36])=[CH:34][CH:33]=[CH:32][C:31]=2[F:37])=[N:27][C:26]=1[C:38](O)=[O:39])=O)(C)(C)C>>[NH2:24][C:25]1[S:29][C:28]([C:30]2[C:35]([F:36])=[CH:34][CH:33]=[CH:32][C:31]=2[F:37])=[N:27][C:26]=1[C:38]([NH:16][C:11]1[CH:12]=[N:13][N:14]([CH3:15])[C:10]=1[N:4]1[CH2:5][CH2:6][N:7]([CH3:9])[CH2:8][C@@H:3]1[CH2:1][CH3:2])=[O:39]
Reactant: CC(C)(C)OC(=O)Nc1sc(-c2c(F)cccc2F)nc1C(=O)O
Reactant: CC[C@H]1CN(C)CCN1c1c(N)cnn1C
Product: CC[C@H]1CN(C)CCN1c1c(NC(=O)c2nc(-c3c(F)cccc3F)sc2N)cnn1C

Procedure:
Following the procedure for Example 110 starting from (S)-5-(2-ethyl-4-methylpiperazin-1-yl)-1-methyl-1H-pyrazol-4-amine and 5-(tert-butoxycarbonylamino)-2-(2,6-difluorophenyl)thiazole-4-carboxylic acid from Example 25 gave 176 as a lilac solid (53 mg, 31%). 1H NMR (400 MHz, CDCl3) δ 8.58 (s, 1H), 7.88 (s, 1H), 7.37-7.27 (m, 1H), 7.01 (t, J=8.8 Hz, 2H), 6.16 (s, 2H), 3.76 (s, 3H), 3.32 (t, J=11.3 Hz, 1H), 3.22 (t, J=9.3 Hz, 1H), 2.96 (t, J=12.9 Hz, 2H), 2.79 (d, J=11.0 Hz, 1H), 2.42-2.22 (m, 4H), 1.96 (t, J=10.2 Hz, 1H), 1.41-1.33 (m, 1H), 1.29-1.15 (m, 1H), 0.80 (t, J=7.5 Hz, 3H). LCMS (ES+) m/z 462 (M+1).
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]([N:11]2[C:19]3[CH2:18][CH2:17][C:16]4[CH:20]=[CH:21][CH:22]=[CH:23][C:15]=4[C:14]=3[CH:13]=[C:12]2[C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH:7]=[CH:8][C:9]=1[OH:10])([OH:3])=[O:2].Cl.[CH2:31](O)[CH3:32]>>[CH2:31]([O:2][C:1]([C:4]1[CH:5]=[C:6]([N:11]2[C:19]3[CH2:18][CH2:17][C:16]4[CH:20]=[CH:21][CH:22]=[CH:23][C:15]=4[C:14]=3[CH:13]=[C:12]2[C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH:7]=[CH:8][C:9]=1[OH:10])=[O:3])[CH3:32]
Reactant: CCO
Reactant: O=C(O)c1cc(-n2c(-c3ccccc3)cc3c2CCc2ccccc2-3)ccc1O
Agent: Cl
Product: CCOC(=O)c1cc(-n2c(-c3ccccc3)cc3c2CCc2ccccc2-3)ccc1O

Procedure:
A boiling solution of 7.5 g. (0.02 mole) of 3-(3-carboxy-4-hydroxyphenyl)-4,5-dihydro-2-phenylbenz[e]indole and 200 ml. of ethanol was saturated with hydrogen chloride, then heated under reflux for 26 hours and cooled. The solid which separated was collected and recrystallized from ethanol to provide 4.1 g. (51%) of off-white crystals, m.p. 134°-135°.
Reaction SMILES: [C:1]([N:4]1[C:12]2[C:7](=[CH:8][C:9]([Br:17])=[C:10]([S:13](Cl)(=[O:15])=[O:14])[CH:11]=2)[CH2:6][CH2:5]1)(=[O:3])[CH3:2].[CH2:18]([N:20](CC)CC)C.CN.O>C1COCC1>[CH3:18][NH:20][S:13]([C:10]1[CH:11]=[C:12]2[C:7]([CH2:6][CH2:5][N:4]2[C:1](=[O:3])[CH3:2])=[CH:8][C:9]=1[Br:17])(=[O:15])=[O:14]
Reactant: CC(=O)N1CCc2cc(Br)c(S(=O)(=O)Cl)cc21
Reactant: CCN(CC)CC
Agent: CN
Solvent: O
Solvent: C1CCOC1
Product: CNS(=O)(=O)c1cc2c(cc1Br)CCN2C(C)=O
Reaction time: 1.5 h
Yield: 82.5 %

Procedure:
To a slurry of 1-acetyl-5-bromo-2,3-dihydro-1H-indole-6-sulfonyl chloride (see Preparation 43) (0.40 g, 1.2 mmol) in THF (3.38 mL) was added triethylamine (0.660 mL, 4.73 mmol) and 40% methylamine in water (0.18 mL, 2.4 mmol). The reaction was heated to reflux and stirred for 1.5 h, then cooled and concentrated. The residue was slurried in hot MeOH and filtered under vacuum washing with MeOH. The solid was dried in vacuo at 40° C., to give 1-acetyl-5-bromo-2,3-dihydro-1H-indole-6-sulfonic acid methylamide (0.33 g, 85%) as a colourless solid. This product (320 mg, 1.0 mmol) was slurried in 1,4-dioxane (0.98 mL) and concentrated hydrochloric acid (0.72 mL), heated to 100° C. for 1.5 h, then cooled to ambient temperature solvent removed in vacuo. The pH was adjusted to 7 with 1 M aqueous NaOH and the resulting precipitate collected by vacuum filtration, washed with water and dried in vacuo at 40° C., to give the title compound (0.176 g, 62%) as a beige solid; MS: [M+H]+ 291
Reaction SMILES: [C:1]1([NH2:8])[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH2:7].Cl[C:10]1(Cl)[C:22]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[C:16]2[C:11]1=[CH:12][CH:13]=[CH:14][CH:15]=2>>[NH2:7][C:2]1[CH:3]=[C:4]([C:10]2([C:5]3[CH:4]=[CH:3][C:2]([NH2:7])=[C:1]([NH2:8])[CH:6]=3)[C:22]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[C:16]3[C:11]2=[CH:12][CH:13]=[CH:14][CH:15]=3)[CH:5]=[CH:6][C:1]=1[NH2:8]
Reactant: Nc1ccccc1N
Reactant: ClC1(Cl)c2ccccc2-c2ccccc21
Product: Nc1ccc(C2(c3ccc(N)c(N)c3)c3ccccc3-c3ccccc32)cc1N
Temperature: 105 °C
Reaction time: 4 h

Procedure:
Into a three-necked 100 mL round-bottomed flask is placed o-phenylene diamine (26 g). The flask is then equipped with a drying tube, magnetic stirbar, thermometer, powder addition funnel, and nitrogen inlet. The o-phenylene diamine is then stirred and heated to 105° C. and solid 9,9-dichlorofluorene is added to the melt. An immediate reaction occur s as evidenced by a color change to dark brown, formation of a copious precipitate and an increase in temperature to 110°-120° C. The temperature is then increased to 130° C. and held there for 4 hours during which time the mixture becomes more liquid. The reaction is then allowed to cool and the excess o-phenylenediamine is removed by pouring the reaction mixture into ethanol and filtering. The resulting dark brown solid is recrystallized from toluene to yield 9,9-bis(3,4-diaminophenyl)fluorene. HNMR (DMSO): delta 4.97 (bs, 8H, NH2), 6.07-6.11 (m, 2H), 6.31-6.42 (m, 4H), 7.17-7.33 (m, 6H), 7.76-7.79 (m, 2H). C-13 NMR (DMSO) (ppm): 152.55, 139.7 1,136.29, 134.37, 132.64, 127.56, 127.17, 126.40, 120.37, 118.36, 117.69, 115.63, 115.11, 64.4 (quaternary carbon) where s=singlet, m=multiplet, and bs=broad singlet.
Reaction SMILES: Cl[C:2]([O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:3].[Cl:11][C:12]1[CH:17]=[CH:16][C:15]([S:18]([C:21]([C:24]2[CH:29]=[C:28]([N:30]3[CH2:35][CH2:34][O:33][CH2:32][C@@H:31]3[CH3:36])[N:27]=[C:26]([C:37]3[CH:43]=[CH:42][C:40]([NH2:41])=[CH:39][CH:38]=3)[N:25]=2)([CH3:23])[CH3:22])(=[O:20])=[O:19])=[CH:14][CH:13]=1.C(=O)([O-])O.[Na+]>O1CCOCC1.C(OCC)(=O)C>[Cl:11][C:12]1[CH:17]=[CH:16][C:15]([S:18]([C:21]([C:24]2[CH:29]=[C:28]([N:30]3[CH2:35][CH2:34][O:33][CH2:32][C@@H:31]3[CH3:36])[N:27]=[C:26]([C:37]3[CH:38]=[CH:39][C:40]([NH:41][C:2](=[O:3])[O:4][C:5]4[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=4)=[CH:42][CH:43]=3)[N:25]=2)([CH3:22])[CH3:23])(=[O:19])=[O:20])=[CH:14][CH:13]=1
Reactant: C[C@H]1COCCN1c1cc(C(C)(C)S(=O)(=O)c2ccc(Cl)cc2)nc(-c2ccc(N)cc2)n1
Reactant: O=C(Cl)Oc1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: C[C@H]1COCCN1c1cc(C(C)(C)S(=O)(=O)c2ccc(Cl)cc2)nc(-c2ccc(NC(=O)Oc3ccccc3)cc2)n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 85 %

Procedure:
Phenyl chloroformate (0.256 mL, 2.04 mmol) was added dropwise to 4-[4-[2-(4-chlorophenyl)sulfonylpropan-2-yl]-6-[(3S)-3-methylmorpholin-4-yl]pyrimidin-2-yl]aniline (850 mg, 1.85 mmol) and sodium hydrogencarbonate (233 mg, 2.78 mmol) in dioxane (20 mL) at RT. The resulting suspension was stirred at RT for 2 hours. The reaction mixture was diluted with ethyl acetate (100 mL) and washed with water (2×100 mL) and saturated brine (50 mL). The organic layer was dried (MgSO4), filtered and evaporated. The crude product was purified by flash silica chromatography, elution gradient 30 to 50% ethyl acetate in isohexane. Pure fractions were evaporated to dryness to afford the desired material as a white solid (955 mg).
Reaction SMILES: [CH2:1]1[O:21][C:4]2=[CH:5][C:6]3[O:11][CH:10]=[C:9]([C:12]4[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][CH:13]=4)[C:8](=[O:19])[C:7]=3[CH:20]=[C:3]2[O:2]1.C([O-])([O-])=O.[K+].[K+].Br[CH2:29][CH2:30][O:31][C:32](=[O:36])[CH2:33][CH2:34][CH3:35].O>CN(C)C=O>[CH2:1]1[O:21][C:4]2=[CH:5][C:6]3[O:11][CH:10]=[C:9]([C:12]4[CH:13]=[CH:14][C:15]([O:18][CH:33]([C:32]([O:31][CH2:30][CH3:29])=[O:36])[CH2:34][CH3:35])=[CH:16][CH:17]=4)[C:8](=[O:19])[C:7]=3[CH:20]=[C:3]2[O:2]1
Reactant: O=c1c(-c2ccc(O)cc2)coc2cc3c(cc12)OCO3
Reactant: CCCC(=O)OCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)C(CC)Oc1ccc(-c2coc3cc4c(cc3c2=O)OCO4)cc1

Procedure:
6,7-Methylenedioxy-3-(4-hydroxyphenyl)-4H-1-benzopyran-4-one [cp. Nippon Kagaku Zasshi 85, 793 (1964), Agr. Biol. Chem. (Tokyo) 32, 740 (1968) and Angew. Chem. 93, 129 (1981)] (2.0 g) is dissolved in dimethylformamide (15 ml) and K2CO3 (2.8 g) is added to the solution. While stirring, 2-bromoethylbutyrate (2.7 g) is dropped into the mixture. The content of the reaction flask is refluxed for 30 min. After cooling, water (50 ml) is added and the mixture is extracted with chloroform (3×30 ml), the extract washed with water (3×15 ml) and dried over Na2SO4. Chloroform is removed under reduced pressure and the residue is recrystallized from methanol. The product is dried in vacuo to constant weight to yield 6,7-methylenedioxy-3-[4-(1-ethoxycarbonyl-1-propyloxy)-phenyl]-4H-1-benzopyran-4-one, m.p. 119°-121°.
Reaction SMILES: [CH2:1]([C:9]1[N:13]=[C:12]([C:14]2[CH:21]=[CH:20][C:17]([CH:18]=O)=[CH:16][CH:15]=2)[O:11][N:10]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[Cl:22][C:23]1[CH:24]=[C:25]([CH2:29][CH2:30][NH2:31])[CH:26]=[CH:27][CH:28]=1>>[Cl:22][C:23]1[CH:24]=[C:25]([CH2:29][CH2:30][NH:31][CH2:18][C:17]2[CH:20]=[CH:21][C:14]([C:12]3[O:11][N:10]=[C:9]([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8])[N:13]=3)=[CH:15][CH:16]=2)[CH:26]=[CH:27][CH:28]=1
Reactant: NCCc1cccc(Cl)c1
Reactant: CCCCCCCCc1noc(-c2ccc(C=O)cc2)n1
Product: CCCCCCCCc1noc(-c2ccc(CNCCc3cccc(Cl)c3)cc2)n1
Yield: 76 %

Procedure:
The same procedure as employed in the preparation of Example 226 (step a) but using 4-(3-octyl-1,2,4-oxadiazol-5-yl)benzaldehyde and [2-(3-chlorophenyl)ethyl]amine gave the title compound as a colorless oil (76%). 1H NMR (CDCl3, 300 MHz) δ 8.06 (d, J=8.3 Hz, 2H), 7.44 (d, J=8.3 Hz, 2H), 7.23-7.00 (m, 4H), 3.88 (s, 2H), 2.95-2.68 (m, 6H), 1.75-1.65 (m, 2H), 1.41-1.20 (m, 10H), 0.87 (t, J=7.1 Hz, 3H). M+(LC/MS(ESI)): 426.4. HPLC (Condition A), Rt: 4.35 min (HPLC purity: 99.6%).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].I[CH:8]([CH3:10])[CH3:9].[Br:11][C:12]1[CH:17]=[CH:16][C:15]([OH:18])=[C:14]([CH2:19][CH3:20])[CH:13]=1>CN(C=O)C>[Br:11][C:12]1[CH:17]=[CH:16][C:15]([O:18][CH:8]([CH3:10])[CH3:9])=[C:14]([CH2:19][CH3:20])[CH:13]=1
Reactant: CC(C)I
Reactant: CCc1cc(Br)ccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCc1cc(Br)ccc1OC(C)C
Temperature: 60 °C
Yield: 74 %

Procedure:
Potassium carbonate (3.1 g, 22.4 mmol) followed by 2-iodopropane (0.75 mL, 7.5 mmol) were added to a solution of 4-bromo-2-ethyl-phenol (1.5 g, 7.5 mmol) in DMF (10 mL). The mixture was heated at 60° C. for 20 hours and then partitioned between 1N HCl and EtOAc. The organic layers were washed with saturated NaHCO3, brine, dried over Na2SO4 and concentrated. The crude yellow oil was purified by flash column chromatography (hexanes) to give the desired product (1.35 g, 75%). 1H NMR (400 MHz, CDCl3): δ 1.16 (t, J=7.6 Hz, 3 H), 1.32 (d, J=6.1 Hz, 6 H), 2.58 (q, J=7.6 Hz, 2 H), 4.49 (m, 1 H), 6.70 (d, J=8.6 Hz, 1 H), 7.23 (m, 2 H).
Reaction SMILES: CON(C)[C:4]([C:6]1[C:15](=[O:16])[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[N:8]([CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([Br:24])[N:19]=2)[CH:7]=1)=[O:5].I[C:27]1[CH:28]=[CH:29][C:30]([C:33]([F:36])([F:35])[F:34])=[N:31][CH:32]=1.C([Mg]Cl)(C)C>C1COCC1>[Br:24][C:20]1[N:19]=[C:18]([CH2:17][N:8]2[C:9]3[C:14](=[CH:13][CH:12]=[CH:11][CH:10]=3)[C:15](=[O:16])[C:6]([C:4]([C:27]3[CH:32]=[N:31][C:30]([C:33]([F:36])([F:35])[F:34])=[CH:29][CH:28]=3)=[O:5])=[CH:7]2)[CH:23]=[CH:22][CH:21]=1
Reactant: CON(C)C(=O)c1cn(Cc2cccc(Br)n2)c2ccccc2c1=O
Reactant: FC(F)(F)c1ccc(I)cn1
Agent: CC(C)[Mg]Cl
Solvent: C1CCOC1
Product: O=C(c1ccc(C(F)(F)F)nc1)c1cn(Cc2cccc(Br)n2)c2ccccc2c1=O

Procedure:
Experimental conditions analogous to those described for Step 6 of Example 60 from 120 mg (0.30 mmol) of 1-(6-bromo-pyridin-2-ylmethyl)-4-oxo-1,4-dihydro-quinoline-3-carboxylic acid methoxy-methyl-amide in 1 mL THF and 179 mg (0.66 mmol) of 5-iodo-2-trifluoromethyl-pyridine in 1 mL THF with 0.34 mL 2M isopropylmagnesium chloride. Yield: 76 mg of a white powder. LC-MSD, m/z for C22H13BrF3N3O2 [M+H]+=488.0, 490.0; HPLC retention time: 2.5 min.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:4]=[C:5]([C:9]2[C:14]([CH3:15])=[CH:13][C:12]([OH:16])=[CH:11][C:10]=2[CH3:17])[CH:6]=[CH:7][CH:8]=1.[CH2:18]([S:20][CH2:21][CH2:22]Cl)[CH3:19].C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>CN(C)C=O.O>[CH2:18]([S:20][CH2:21][CH2:22][O:16][C:12]1[CH:11]=[C:10]([CH3:17])[C:9]([C:5]2[CH:6]=[CH:7][CH:8]=[C:3]([CH2:2][OH:1])[CH:4]=2)=[C:14]([CH3:15])[CH:13]=1)[CH3:19]
Reactant: CCSCCCl
Reactant: Cc1cc(O)cc(C)c1-c1cccc(CO)c1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCSCCOc1cc(C)c(-c2cccc(CO)c2)c(C)c1
Temperature: 95 °C
Reaction time: 24 h
Yield: 47 %

Procedure:
To a solution of 3′-(hydroxymethyl)-2,6-dimethylbiphenyl-4-ol (1.83 g, 8.00 mmol) and 2-chloroethyl ethyl sulfide (1.07 mL, 12.0 mmol) in N,N-dimethylformamide (15 mL) were added potassium carbonate (1.33 g, 9.60 mmol) and potassium iodide (0.132 g, 0.800 mmol), and the mixture was stirred at 95° C. for 24 hr under nitrogen atmosphere. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed successively with 1 M aqueous sodium hydroxide solution and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:hexane=10:90-50:50) to give the title compound (1.19 g, yield 47%) as a colorless oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:31]2[C:40]3[C:35](=[CH:36][C:37]([F:42])=[C:38]([F:41])[CH:39]=3)[N:34]=[CH:33][CH:32]=2)[C@@H:9]([C:13]2[CH:30]=[CH:29][C:16]([C:17]([NH:19][CH2:20][CH2:21][C:22]([O:24]C(C)(C)C)=[O:23])=[O:18])=[CH:15][CH:14]=2)[CH2:10][CH2:11][CH3:12])=[CH:4][CH:3]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:31]2[C:40]3[C:35](=[CH:36][C:37]([F:42])=[C:38]([F:41])[CH:39]=3)[N:34]=[CH:33][CH:32]=2)[C@@H:9]([C:13]2[CH:14]=[CH:15][C:16]([C:17]([NH:19][CH2:20][CH2:21][C:22]([OH:24])=[O:23])=[O:18])=[CH:29][CH:30]=2)[CH2:10][CH2:11][CH3:12])=[CH:4][CH:3]=1
Reactant: CCC[C@H](c1ccc(C(=O)NCCC(=O)OC(C)(C)C)cc1)C(c1ccc(Cl)cc1)c1ccnc2cc(F)c(F)cc12
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCC[C@H](c1ccc(C(=O)NCCC(=O)O)cc1)C(c1ccc(Cl)cc1)c1ccnc2cc(F)c(F)cc12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of the slower-eluting isomer of tert-butyl N-(4-{(1S)-1-[(4-chlorophenyl)(6,7-difluoroquinolin-4-yl)methyl]butyl}benzoyl)-β-alaninate from Step G (34 mg, 0.058 mmol) in CH2Cl2 (2.0 mL) was treated with TFA (1.0 mL). After stirring at room temperature overnight, the solution was concentrated. The residue was purified by preparative reverse phase HPLC, eluting with acetonitrile/water+0.1% formic acid. Following lyophilization, this afforded the title compound as a fluffy, white solid: 1H NMR (500 MHz, CDCl3): δ 8.95 (s, 1H); 8.10-8.01 (m, 2H); 7.85 (d, J=5.0 Hz, 1H); 7.53 (d, J=7.8 Hz, 2H); 7.38 (d, J=8.4 Hz, 2H); 7.34 (d, J=8.4 Hz, 2H); 7.21 (d, J=7.8 Hz, 2H); 6.97 (s, 1H); 4.93 (d, J=11.4 Hz, 1H); 3.65-3.54 (m, 3H); 2.56 (t, J=5.5 Hz, 2H); 1.65-1.53 (m, 2H); 1.13-0.97 (m, 2H); 0.75 (t, J=7.2 Hz, 3H); LC4: 2.26 min. (M+H) 537.
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[CH:4]=[C:5]([N:9]=[C:10]=[S:11])[CH:6]=[CH:7][CH:8]=1.[NH2:14][CH2:15][C:16]1[C:21]([CH3:22])=[CH:20][CH:19]=[CH:18][C:17]=1[NH2:23]>C(OCC)(=O)C>[NH2:23][C:17]1[CH:18]=[CH:19][CH:20]=[C:21]([CH3:22])[C:16]=1[CH2:15][NH:14][C:10]([NH:9][C:5]1[CH:6]=[CH:7][CH:8]=[C:3]([C:2]([F:12])([F:1])[F:13])[CH:4]=1)=[S:11]
Reactant: Cc1cccc(N)c1CN
Reactant: FC(F)(F)c1cccc(N=C=S)c1
Solvent: CCOC(C)=O
Product: Cc1cccc(N)c1CNC(=S)Nc1cccc(C(F)(F)F)c1
Temperature: 80 °C
Reaction time: 8 h
Yield: 13.4 %

Procedure:
3-(Trifluoromethyl)phenyl isothiocyanate (224 mg, 1.10 mmol) was added to a solution of 2-aminomethyl-3-methyl-phenylamine (150 mg, 1.10 mmol) in ethyl acetate (3 ml); the reaction mixture was shaken at 80° C. overnight in a screw-cap vial. For workup, more ethyl acetate was added, the mixture was washed with water and brine, and dried (Na2SO4). After evaporation of the solvent under reduced pressure, the title compound (50 mg, 13%) was obtained by purification of the residue (silica gel, heptan/ethyl acetate=100:0-80:20).