Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:17][C:18]2[C:19]3[C:26]4[CH2:27][CH2:28][N:29]([C:31](OC(C)(C)C)=[O:32])[CH2:30][C:25]=4[O:24][C:20]=3[N:21]=[CH:22][N:23]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([F:16])[CH:11]=1.Cl.O1CCOCC1.Cl.[CH3:46][N:47]([CH3:54])[CH2:48]/[CH:49]=[CH:50]/C(O)=O>CC(O)C>[Cl:1][C:2]1[CH:3]=[C:4]([NH:17][C:18]2[C:19]3[C:26]4[CH2:27][CH2:28][N:29]([C:31](=[O:32])/[CH:50]=[CH:49]/[CH2:48][N:47]([CH3:54])[CH3:46])[CH2:30][C:25]=4[O:24][C:20]=3[N:21]=[CH:22][N:23]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([F:16])[CH:11]=1
Reactant: CC(C)(C)OC(=O)N1CCc2c(oc3ncnc(Nc4ccc(OCc5cccc(F)c5)c(Cl)c4)c23)C1
Reactant: CN(C)C/C=C/C(=O)O
Agent: Cl
Solvent: CC(C)O
Solvent: C1COCCO1
Product: CN(C)C/C=C/C(=O)N1CCc2c(oc3ncnc(Nc4ccc(OCc5cccc(F)c5)c(Cl)c4)c23)C1
Temperature: 80 °C
Yield: 38.4 %

Procedure:
tert-Butyl 4-({3-chloro-4-[(3-fluorobenzyl)oxy]phenyl}amino)-5,8-dihydropyrido[4′,3′:4,5]furo-[2,3-d]pyrimidine-7(6H)-carboxylate from Example 86A (18 mg, 0.034 mmol) was dissolved in 2-propanol (1.0 mL) and treated with 4 M gaseous hydrogen chloride in dioxane (0.25 mL, 1.0 mmol). The mixture was heated to 80° C. for 2 h. Subsequently, the solvent was removed in vacuo. The residue was reacted in analogy to Example 89 with (2E)-4-(dimethylamino)but-2-enoic acid hydrochloride from Example 1A (8.0 mg, 0.048 mmol) to yield 7.0 mg (38%) of the title compound.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]2[CH2:10][C@H:9]2[NH:11][C:12](=[O:18])[O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[CH:4][CH:3]=1.[Br:19][C:20]1[CH:21]=[C:22]([CH:26]=[CH:27][CH:28]=1)[C:23](Cl)=[O:24].C(N(CC)CC)C.O>C(#N)C>[Br:19][C:20]1[CH:21]=[C:22]([C:23]([NH:1][C:2]2[CH:7]=[CH:6][C:5]([C@@H:8]3[CH2:10][C@H:9]3[NH:11][C:12](=[O:18])[O:13][C:14]([CH3:15])([CH3:17])[CH3:16])=[CH:4][CH:3]=2)=[O:24])[CH:26]=[CH:27][CH:28]=1
Reactant: O=C(Cl)c1cccc(Br)c1
Reactant: CC(C)(C)OC(=O)N[C@@H]1C[C@H]1c1ccc(N)cc1
Solvent: CC#N
Solvent: CCN(CC)CC
Solvent: O
Product: CC(C)(C)OC(=O)N[C@@H]1C[C@H]1c1ccc(NC(=O)c2cccc(Br)c2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of tert-butyl [trans-2-(4-aminophenyl)cyclopropyl]carbamate (300 mg) described in a document (J. Am. Chem. Soc., 2010, 132, 6827.) in acetonitrile (12 mL) were added 3-bromobenzoyl chloride (191 μL) and triethylamine (202 μL). The mixture was stirred at room temperature overnight and water was added. The mixture was extracted with ethyl acetate, and the extract was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give the title compound (407 mg).
Reaction SMILES: [CH:1](Br)([CH3:3])[CH3:2].[Br:5][C:6]1[CH:7]=[CH:8][C:9](=[O:12])[NH:10][CH:11]=1>>[Br:5][C:6]1[CH:7]=[CH:8][C:9]([O:12][CH:1]([CH3:3])[CH3:2])=[N:10][CH:11]=1
Reactant: CC(C)Br
Reactant: O=c1ccc(Br)c[nH]1
Product: CC(C)Oc1ccc(Br)cn1

Procedure:
The sub-title compound was prepared in accordance with Example 36(b) from isopropylbromide and 5-bromo-1H-pyridin-2-one.
Reaction SMILES: C1(C)C=CC(S(O[CH2:11][CH2:12][C:13]2[S:14][CH:15]=[CH:16][CH:17]=2)(=O)=O)=CC=1.[Cl:19][C:20]1[CH:27]=[CH:26][CH:25]=[CH:24][C:21]=1[CH2:22][NH2:23]>C(#N)C>[ClH:19].[Cl:19][C:20]1[CH:27]=[CH:26][CH:25]=[CH:24][C:21]=1[CH2:22][NH:23][CH2:11][CH2:12][C:13]1[S:14][CH:15]=[CH:16][CH:17]=1
Reactant: NCc1ccccc1Cl
Reactant: Cc1ccc(S(=O)(=O)OCCc2cccs2)cc1
Solvent: CC#N
Product: Cl
Product: Clc1ccccc1CNCCc1cccs1
Yield: 79.1 %

Procedure:
850 g (3 moles) 2-(2-thienyl)-ethyl paratoluene sulfonate and 850 g (6 moles) ortho-chlorobenzylamine are dissolved in 5.2 liters acetonitrile and the mixture is refluxed during 6.5 hours. After filtration, 630 g ortho-chlorobenzylamine paratoluene sulfonate are removed by filtration. The filtrate is concentrated and the residue is taken up into diisopropyl ether and 500 ml 2N sodium hydroxide. The organic phase is separated and is made acidic with 3N hydrochloric acid. The resulting hydrochloride precipitates out; it is collected by filtration, suction filtered and washed with acetone, to give 684 g (Yield: 78%) N-(2-chloro-benzyl)-2-(2-thienyl)-ethylamine hydrochloride.
Reaction SMILES: [H-].[Na+].[F:3][C:4]1[CH:5]=[C:6]([S:11]([N:14]2[CH2:18][CH2:17][CH2:16][CH:15]2[C:19]([NH:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[O:20])(=[O:13])=[O:12])[CH:7]=[CH:8][C:9]=1[CH3:10].Cl[CH2:29][N:30]1[C:34]2[CH:35]=[CH:36][CH:37]=[CH:38][C:33]=2[N:32]=[N:31]1>CN(C=O)C>[N:30]1([CH2:29][N:21]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:19]([CH:15]2[CH2:16][CH2:17][CH2:18][N:14]2[S:11]([C:6]2[CH:7]=[CH:8][C:9]([CH3:10])=[C:4]([F:3])[CH:5]=2)(=[O:13])=[O:12])=[O:20])[C:34]2[CH:35]=[CH:36][CH:37]=[CH:38][C:33]=2[N:32]=[N:31]1
Reactant: Cc1ccc(S(=O)(=O)N2CCCC2C(=O)Nc2ccccc2)cc1F
Reactant: ClCn1nnc2ccccc21
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1ccc(S(=O)(=O)N2CCCC2C(=O)N(Cn2nnc3ccccc32)c2ccccc2)cc1F
Reaction time: 1 h
Yield: 76 %

Procedure:
Under inert atmosphere, to a stirred solution of NaH (5 mg, 0.13 mmol) in 0.20 ml anhydrous DMF at 0° C., was added a solution of parent compound 1-((3-fluoro-4-methylphenyl)sulfonyl)-N-phenylpyrrolidine-2-carboxamide (0.016 g, 0.04 mmol) in 0.20 ml anhydrous DMF. After 1 h at 0° C., a solution of 1-(chloromethyl)-1H-benzotriazole (0.022 g, 0.13 mmol) in 0.20 ml anhydrous DMF was added to the reaction mixture. This mixture was stirred for 16 h, and then solvent was completely removed. The crude was chromatographically purified over SiO2 using Hexane/AcOEt as the eluant, yielding 0.015 g (32%) of the desired product.
Reaction SMILES: Br[CH:2]([C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][CH:15]([O:17][C:18]2[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=2)[CH3:16])=[CH:9][CH:8]=1)[C:3]([O:5][CH3:6])=[O:4].[C:25]([C:29]1[CH:34]=[CH:33][C:32]([OH:35])=[CH:31][CH:30]=1)([CH3:28])([CH3:27])[CH3:26]>O1CCCC1>[C:25]([C:29]1[CH:30]=[CH:31][C:32]([O:35][CH:2]([C:7]2[CH:12]=[CH:11][C:10]([O:13][CH2:14][CH:15]([O:17][C:18]3[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=3)[CH3:16])=[CH:9][CH:8]=2)[C:3]([O:5][CH3:6])=[O:4])=[CH:33][CH:34]=1)([CH3:28])([CH3:26])[CH3:27]
Reactant: CC(C)(C)c1ccc(O)cc1
Reactant: COC(=O)C(Br)c1ccc(OCC(C)Oc2ccc(F)cc2)cc1
Solvent: C1CCOC1
Product: COC(=O)C(Oc1ccc(C(C)(C)C)cc1)c1ccc(OCC(C)Oc2ccc(F)cc2)cc1

Procedure:
As described in Example 71, methyl bromo{p-[2-(p-fluorophenoxy)propoxy]phenyl}acetate (0.017 mole) is reacted with 2.55 g of p-tert-butylphenol in 75 ml of tetrahydrofuran at 80° C. for 18 hrs to give the product as a gum.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[CH:4][CH:3]=1.[NH2:11][C:12]1[CH:26]=[CH:25][CH:24]=[CH:23][C:13]=1[CH2:14][CH2:15][CH:16]1[CH2:21][CH2:20][CH2:19][CH2:18][N:17]1[CH3:22]>>[Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH:11][C:12]2[CH:26]=[CH:25][CH:24]=[CH:23][C:13]=2[CH2:14][CH2:15][CH:16]2[CH2:21][CH2:20][CH2:19][CH2:18][N:17]2[CH3:22])=[O:7])=[CH:4][CH:3]=1
Reactant: O=C(Cl)c1ccc(Br)cc1
Reactant: CN1CCCCC1CCc1ccccc1N
Product: CN1CCCCC1CCc1ccccc1NC(=O)c1ccc(Br)cc1

Procedure:
Reaction of 4-bromobenzoyl chloride with 2-(o-aminophenethyl)-1-methylpiperidine according to the procedure of Example 114 affords 4-bromo-2'-[2-(1methyl-2-piperidyl)ethyl]benzanilide, m.p. 137.5° - 138.5° C. (corr.), from ethyl acetate.
Reaction SMILES: [Br:1][C:2]1[C:3]([CH3:16])=[C:4]([N:8]2[C:13](=[O:14])[CH:12]=[CH:11][NH:10][C:9]2=[O:15])[CH:5]=[CH:6][CH:7]=1.[F:17][C:18]1[CH:23]=[CH:22][C:21](B(O)O)=[CH:20][CH:19]=1.N1C=CC=CC=1>C(Cl)Cl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[Br:1][C:2]1[C:3]([CH3:16])=[C:4]([N:8]2[C:13](=[O:14])[CH:12]=[CH:11][N:10]([C:21]3[CH:22]=[CH:23][C:18]([F:17])=[CH:19][CH:20]=3)[C:9]2=[O:15])[CH:5]=[CH:6][CH:7]=1
Reactant: OB(O)c1ccc(F)cc1
Reactant: Cc1c(Br)cccc1-n1c(=O)cc[nH]c1=O
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: c1ccncc1
Solvent: ClCCl
Product: Cc1c(Br)cccc1-n1c(=O)ccn(-c2ccc(F)cc2)c1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 64.4 %

Procedure:
A stirred suspension of copper(II) acetate (0.543 g, 2.99 mmol), 3-(3-bromo-2-methylphenyl)pyrimidine-2,4(1H,3H)-dione (0.42 g, 1.49 mmol), (4-fluorophenyl) boronic acid (0.418 g, 2.99 mmol), and activated molecular sieves (750 mg) in dry DCM (25 mL) was treated with pyridine (0.363 mL, 4.48 mmol) and stirred at room temperature overnight. The mixture was diluted with DCM, filtered through CELITE®, and the solids were washed with DCM and THF. The combined filtrates were washed with water, dried and concentrated. The residue was purified by column chromatography on silica gel (40 g), eluting with EtOAc-hexanes (gradient from 20-40%), to give 3-(3-bromo-2-methylphenyl)-1-(4-fluorophenyl)pyrimidine-2,4(1H,3H)-dione as a yellow glassy solid (0.36 g, 43% yield). Mass spectrum m/z 375, 377 (M+H)+. 1H NMR (400 MHz, DMSO-d6) δ 7.91 (d, J=7.9 Hz, 1H), 7.68 (dd, J=7.9, 1.3 Hz, 1H), 7.60-7.51 (m, 2H), 7.40-7.22 (m, 4H), 5.95 (d, J=7.9 Hz, 1H), 2.21-2.12 (m, 3H).
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[O:3][C:4]1[CH:10]=[CH:9][C:7]([NH2:8])=[CH:6][CH:5]=1.[CH:13]([C:15]1[N:16]=[CH:17][NH:18][CH:19]=1)=O.[BH4-].[Na+].O>CO>[N:18]1[CH:19]=[C:15]([CH2:13][NH:8][C:7]2[CH:9]=[CH:10][C:4]([O:3][C:2]([F:11])([F:12])[F:1])=[CH:5][CH:6]=2)[NH:16][CH:17]=1
Reactant: Nc1ccc(OC(F)(F)F)cc1
Reactant: O=Cc1c[nH]cn1
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: FC(F)(F)Oc1ccc(NCc2cnc[nH]2)cc1
Temperature: 60 °C
Reaction time: 8 h
Yield: 77.8 %

Procedure:
To a solution of 4-trifluoromethoxyaniline (0.89 g, 5 mmol) in methanol (5 ml) was added 4-formylimidazole (0.48 g, 5 mmol). After stirring the mixture overnight at 60° C. the solution was cooled and sodium borohydride (0.28 g, 7.5 mmol) were added. The reaction mixture was stirred at room temperature for 4 hours. Then water was added and the mixture was extracted with ethyl acetate. The organic layer was separated, washed with water, dried over magnesium sulfate and evaporated. The residue was purified by column filtration (heptane/ethyl acetate=1:1) to yield a light yellow liquid (1.0 g, 78%); MS (ISP): 258.1 ((M+H)+.).
Reaction SMILES: [OH:1][CH:2]([CH2:6][CH2:7][S:8][CH3:9])[C:3]([OH:5])=[O:4].C.[CH2:11](O)[CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].S([O-])(O)(=O)=O.[Na+]>O.C1(C)C=CC=CC=1>[OH:1][CH:2]([CH2:6][CH2:7][S:8][CH3:9])[C:3]([O:5][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])=[O:4]
Reactant: CCCCCCO
Reactant: CSCCC(O)C(=O)O
Agent: O=S(=O)([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Product: CCCCCCOC(=O)C(O)CCSC
Temperature: 25 °C

Procedure:
To a 4 neck 1 L round bottom flask fitted with a reflux condenser, dean stark trap, thermocouple, and mechanical overhead stirrer was added 2-hydroxy-4-(methylthio)butanoic acid (100 g, 666 mmol, obtained for example by stirring Alimet over activated charcoal, filtering and concentrating in a rotovap), 1-hexanol (125.4 mL, 999 mmol), sodium hydrogen sulfate (1.60 g, 13.32 mmol), and toluene (500 mL). The reaction was heated to reflux with removal of water (20 mL) during the course of about 5.5 hours and the reaction was monitored by GC analysis. The reaction was cooled to room temperature overnight and the organic layer was washed with saturated NaHCO3 (1×250 mL), DI water (1×250 mL) and brine (2×250 mL), dried over sodium sulfate, filtered and evaporated to give a brown oil (253.3 g). The oil was purified by kugelrohr distillation at 100° C. and 0.1 Torr vacuum to give a colorless oil (100.0 g, 64.1%). m/z 257 (MNa+).
Reaction SMILES: FC(F)(F)C(O)=O.N[C@H]1C(=O)NC2C=CC=CC=2O[C@H]1C.[Cl:22][C:23]1[CH:24]=[C:25]2[C:29](=[CH:30][CH:31]=1)[NH:28][C:27]([C:32]([NH:34][C@@H:35]1[C:41](=[O:42])[NH:40][C:39]3[CH:43]=[CH:44][CH:45]=[CH:46][C:38]=3[O:37][C@H:36]1[CH3:47])=[O:33])=[CH:26]2.FC(F)(F)C(O)=O.N[C@@H]1C(=O)NC2C=CC=CC=2O[C@H]1C>>[Cl:22][C:23]1[CH:24]=[C:25]2[C:29](=[CH:30][CH:31]=1)[NH:28][C:27]([C:32]([NH:34][C@H:35]1[C:41](=[O:42])[NH:40][C:39]3[CH:43]=[CH:44][CH:45]=[CH:46][C:38]=3[O:37][C@H:36]1[CH3:47])=[O:33])=[CH:26]2
Reactant: C[C@@H]1Oc2ccccc2NC(=O)[C@H]1NC(=O)c1cc2cc(Cl)ccc2[nH]1
Agent: C[C@@H]1Oc2ccccc2NC(=O)[C@@H]1N
Agent: C[C@@H]1Oc2ccccc2NC(=O)[C@H]1N
Solvent: O=C(O)C(F)(F)F
Product: C[C@@H]1Oc2ccccc2NC(=O)[C@@H]1NC(=O)c1cc2cc(Cl)ccc2[nH]1

Procedure:
The title compound was prepared from (2S,3R)-3-amino-2-methyl-2,3-dihydro-1,5-benzoxazepin-4 (5H)-one trifluoroacetate salt by the procedures described for the preparation of (2S,3S)-3-(5-chloroindole-2-carbonylamino)-2-methyl-2,3-dihydro-1,5-benzoxazepin-4(5H)-one (Example 22) from (2S,3S)-3-amino-2-methyl-2,3-dihydro-1,5-benzoxazepin-4 (5H)-one trifluoroacetate salt. HPLC/MS [M+H]+, 370.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([I:11])=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8].S(=O)(=O)(O)O.[CH3:17]O>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([I:11])=[C:6]([CH:10]=1)[C:7]([O:9][CH3:17])=[O:8]
Reactant: O=C(O)c1cc(Br)ccc1I
Reactant: CO
Agent: O=S(=O)(O)O
Product: COC(=O)c1cc(Br)ccc1I
Temperature: 20 °C
Yield: 90 %

Procedure:
Add 5-bromo-2-iodobenzoic acid (1998 g, 6.11 mol) portion wise to a 20° C. solution of sulfuric acid (100 mL) in methanol (13 L). Heat the suspension to reflux for 24 hours, then cool to 20° C. and remove the solvent under reduced pressure. Pour the residue into a 1:1 mixture of methyl-tert-butyl ether and ice water (20 L) and separate the phases. Extract the aqueous phase with methyl-tert-butyl ether (1.5 L), combine the organic phases and wash with aqueous 0.2 M NaOH (5 L), wash with saturated aqueous sodium chloride, dry over sodium sulfate, filter, and evaporate under reduced pressure. Dissolve the crude product in 40-45° C. petroleum ether (10 L), filter through a pad of diatomaceous earth and evaporate under reduced pressure. Dissolve the residue in petroleum ether (5 L) and cool to −50° C., filter the first crop solids, wash the solid with ice cold petroleum ether. Evaporate the mother liquor, redissolve the solid in petroleum ether (1 L), cool to −50° C., and filter a second crop. Combine first and second crops and dry in open air to provide the title compound as a yellow solid (1880 g, 90%).
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:9]=[CH:8][C:7]([NH:10][NH2:11])=[CH:6][CH:5]=1.C(N(CC)CC)C.[OH:19][C:20]1([C:30]#[C:31][C:32]([C:34]2[CH:39]=[CH:38][C:37]([CH3:40])=[CH:36][CH:35]=2)=O)[CH2:29][CH2:28][C:23]2([O:27][CH2:26][CH2:25][O:24]2)[CH2:22][CH2:21]1>C(O)C>[CH3:2][O:3][C:4]1[CH:9]=[CH:8][C:7]([N:10]2[C:32]([C:34]3[CH:35]=[CH:36][C:37]([CH3:40])=[CH:38][CH:39]=3)=[CH:31][C:30]([C:20]3([OH:19])[CH2:29][CH2:28][C:23]4([O:24][CH2:25][CH2:26][O:27]4)[CH2:22][CH2:21]3)=[N:11]2)=[CH:6][CH:5]=1
Reactant: COc1ccc(NN)cc1
Reactant: Cc1ccc(C(=O)C#CC2(O)CCC3(CC2)OCCO3)cc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCO
Product: COc1ccc(-n2nc(C3(O)CCC4(CC3)OCCO4)cc2-c2ccc(C)cc2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 91.4 %

Procedure:
To a solution of 4-methoxyphenylhydrazine hydrochloride (7.35 g, 42.1 mmol) in ethanol (76.6 mL), triethylamine (5.87 mL, 42.1 mmol) was added dropwise, and the obtained solution was stirred at room temperature for 30 minutes. To the reaction solution, a solution of 3-(8-hydroxy-1,4-dioxaspiro[4.5]decan-8-yl)-1-(p-tolyl)-2-propyn-1-one (Reference Example 15) (11.5 g, 38.3 mmol) in ethanol (76.6 mL) was added dropwise, and the obtained solution was stirred at room temperature for 15 hours. Thereafter, the reaction solution was concentrated under reduced pressure. Water was added to the residue and the resultant was extracted with ethyl acetate. The organic layer was washed with 1 M hydrochloric acid, distilled water and brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by flash chromatography (silica gel, n-hexane/ethyl acetate) to obtain the captioned compound (14.7 g, 35.0 mmol, 91%) as an amorphous product.
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:14][N:15]1[C:23]2[C:18](=[CH:19][C:20]([C:24]([OH:33])([C:29]([F:32])([F:31])[F:30])[C:25]([F:28])([F:27])[F:26])=[CH:21][CH:22]=2)[CH:17]=[C:16]1[CH3:34].[CH3:35][N:36]([CH3:40])[C:37](Cl)=[O:38].CCOCC.Cl>N1C=CC=CC=1>[CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:8]=[CH:9][C:10]([O:13][C:37](=[O:38])[N:36]([CH3:40])[CH3:35])=[CH:11][CH:12]=2)=[N:4][C:3]=1[CH2:14][N:15]1[C:23]2[C:18](=[CH:19][C:20]([C:24]([OH:33])([C:25]([F:26])([F:27])[F:28])[C:29]([F:32])([F:31])[F:30])=[CH:21][CH:22]=2)[CH:17]=[C:16]1[CH3:34]
Reactant: Cc1oc(-c2ccc(O)cc2)nc1Cn1c(C)cc2cc(C(O)(C(F)(F)F)C(F)(F)F)ccc21
Reactant: CN(C)C(=O)Cl
Agent: Cl
Solvent: c1ccncc1
Solvent: CCOCC
Product: Cc1oc(-c2ccc(OC(=O)N(C)C)cc2)nc1Cn1c(C)cc2cc(C(O)(C(F)(F)F)C(F)(F)F)ccc21
Temperature: 60 °C
Reaction time: 2 h
Yield: 65.8 %

Procedure:
A solution of 25 mg (0.052 mmol) 4-{5-methyl-4-[2-methyl-5-(2,2,2-trifluoro-1-hydroxy-1-trifluoromethyl-ethyl)-indol-1-ylmethyl]-oxazol-2-yl}-phenol (example 99) in 1 mL of pyridine was treated with 28 mg (0.26 mmol) of dimethyl carbamoylchloride and stirred at 60° C. for 2 hours. Et2O and aqueous HCl were added and the phases separated. The aqueous phase was extracted with Et2O and the combined organic phases dried over Na2SO4. Evaporation of the solvent and column chromatography on silica gel with n-heptane/EtOAc 1:1 yielded 19 mg (66%) of dimethyl-carbamic acid 4-{5-methyl-4-[2-methyl-5-(2,2,2-trifluoro-1-hydroxy-1-trifluoromethyl-ethyl)-indol-1-ylmethyl]-oxazol-2-yl}-phenyl ester, light yellow solid, MS: 556 (MH+).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([N+:8]([O-])=O)[CH:5]=[CH:4][C:3]=1[O:11][CH2:12][CH:13]1[CH2:15][CH2:14]1.[Cl-].[NH4+].O.C(O)C>C1COCC1.[Fe]>[Br:1][C:2]1[CH:7]=[C:6]([CH:5]=[CH:4][C:3]=1[O:11][CH2:12][CH:13]1[CH2:14][CH2:15]1)[NH2:8]
Reactant: O=[N+]([O-])c1ccc(OCC2CC2)c(Br)c1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCO
Solvent: O
Product: Nc1ccc(OCC2CC2)c(Br)c1
Yield: 99.4 %

Procedure:
A mixture of 2-bromo-1-(cyclopropylmethoxy)-4-nitrobenzene (1.07 g, 3.9 mmol), ammonium chloride (421 mg, 7.8 mmol), and iron powder (1.1 g, 20 mmol) suspended in THF (6.5 mL), water (2.5 mL) and ethanol (6.5 mL) was heated to 95° C. using microwave irradiation (normal) for 3 h. The crude reaction mixture was filtered through a short plug of celite; the celite plug was washed with MeOH (˜10 mL). The resulting filtrate was concentrated in vacuo. The resulting residue was diluted with EtOAc (50 ml) and washed with saturated bicarbonate solution (aq), dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo to afford the title compound, (939 mg, 90%). The material was carried forward without any further purification. LCMS (M+H)+=242.
Reaction SMILES: Br[C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][CH:3]=1.C(O[C:12](=[O:20])[CH2:13][C:14]([C:16]([F:19])([F:18])[F:17])=O)C.[C:21]1([CH3:27])[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>>[C:22]1([C:2]2[CH:8]=[C:7]3[C:5](=[CH:4][CH:3]=2)[NH:6][C:12](=[O:20])[CH:13]=[C:14]3[C:16]([F:17])([F:18])[F:19])[CH2:23][CH2:24][CH2:25][CH2:26][CH2:21][CH:27]=1
Reactant: CCOC(=O)CC(=O)C(F)(F)F
Reactant: Nc1ccc(Br)cc1
Reactant: Cc1ccccc1
Product: O=c1cc(C(F)(F)F)c2cc(C3=CCCCCC3)ccc2[nH]1

Procedure:
In a 100-mL flask a solution of 4-bromoaniline (20 g, 116 mmol) and ethyl-4,4,4-trifluoroacetoacetate (25.5 mL, 175 mmol, 1.5 equiv) in toluene (5 mL) is heated to reflux for 5 h, cooled and excess solvent removed to provide N-(4-bromophenyl)-4,4,4-trifluoroacetoacetamide (Structure 15 of Scheme XX). The crude reaction mixture is then dissolved in CH2Cl2 (40 mL) and water (10 mL) and then treated with N-fluorobenzenesulfonimide (1.1 equiv) at room temperature overnight. The reaction mixture is then diluted with water (30 mL) and partitioned. The aqueous layer is extracted with CH2Cl2 (3×75 mL), the combined organic layers are then washed with sat NaHCO3 (25 mL), saturated NH4Cl (2×25 mL), water (25 mL), Brine (25 mL), dried (MgSO4), filtered and concentrated to afford N-(4-bromophenyl)-2,4,4,4-tetrafluoroacetoacetamide (Structure 15a of Scheme XX). The crude product was then dissolved in concentrated H2SO4 (10 mL) and heated to 80° C. for 3-4 h, cooled to room temperature, and poured over NaOH pellets/ice. The cold aqueous solution was then filtered, the white precipitate was then redissolved in EtOAc (200 mL), washed with water (2×20 mL), Brine (25 mL), dried (MgSO4), filtered and concentrated to yield Compound 634 as a white powder: 1H NMR (400 MHz, DMSO-d6) 12.92 (bs, 1H), 7.83 (dd, J=8.0, 1.2, 1H), 7.77 (s, 1H), 7.41 (d, J=7.9, 1H).
Reaction SMILES: [CH:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1B(O)O)=[O:2].Br[C:13]1[CH:17]=[CH:16][O:15][CH:14]=1.C(=O)([O-])[O-].[Na+].[Na+]>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C(#N)C>[O:15]1[CH:16]=[CH:17][C:13]([C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=2[CH:1]=[O:2])=[CH:14]1
Reactant: Brc1ccoc1
Reactant: O=Cc1ccccc1B(O)O
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Product: O=Cc1ccccc1-c1ccoc1
Temperature: 150 °C
Yield: 31.9 %

Procedure:
A microwave vial (20 ml) was charged with 2-formylphenylboronic acid (298 mg, 2.0 mmol), 3-bromo-furan (350 mg, 2.4 mmol) and 8 ml of acetonitrile. To this mixture was added 4 ml of aqueous sodium carbonate (1M), followed by 100 mg of dichlorobis-(triphenylphosphine)-palladium(II). The reaction vessel was sealed and heated at 150° C. for 5 minutes with microwave irradiation. After cooling, the reaction mixture was extracted with ethylacetate. The organic layer was evaporated to provide crude material which was purified by ISCO to give 110 mg of 2-furan-3-yl-benzaldehyde (30% yield).
Reaction SMILES: [CH2:1]([Mg])[CH3:2].[F:4][C:5]1[CH:29]=[CH:28][C:8]([CH2:9][CH2:10][N:11]2[CH2:16][CH2:15][CH:14]([N:17]3[C:25]4[C:20](=[CH:21][CH:22]=[C:23]([CH:26]=[O:27])[CH:24]=4)[CH2:19][CH2:18]3)[CH2:13][CH2:12]2)=[CH:7][CH:6]=1.[Cl-].[NH4+].C(OCC)(=O)C>CCOCC.O1CCCC1>[F:4][C:5]1[CH:29]=[CH:28][C:8]([CH2:9][CH2:10][N:11]2[CH2:12][CH2:13][CH:14]([N:17]3[C:25]4[C:20](=[CH:21][CH:22]=[C:23]([CH:26]([OH:27])[CH2:1][CH3:2])[CH:24]=4)[CH2:19][CH2:18]3)[CH2:15][CH2:16]2)=[CH:7][CH:6]=1
Reactant: O=Cc1ccc2c(c1)N(C1CCN(CCc3ccc(F)cc3)CC1)CC2
Reactant: CC[Mg]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOCC
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCC(O)c1ccc2c(c1)N(C1CCN(CCc3ccc(F)cc3)CC1)CC2
Temperature: 25 °C
Yield: 66 %

Procedure:
A 3 M solution (1.4 ml) of ethylmagnesium in ether was added dropwise at −78° C. into a solution of 1-[1-(4-fluorophenethyl)piperidin-4-yl]-6-formylindoline (1.0 g) in tetrahydrofuran (30 ml) and the resultant mixture was allowed to warm to room temperature. Then a saturated aqueous solution of ammonium chloride and ethyl acetate were added to the reaction solution and the layers were separated. The organic layer was washed with brine and dried over magnesium sulfate. After removing the solvent, the residue was purified by NH-silica gel column chromatography (hexane/ethyl acetate system) to give the title compound (710 mg) as a colorless oil (yield: 66%).