Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1[CH2:7][CH:6]([C:8]2[C:16]3[S:15][C:14]([NH2:17])=[N:13][C:12]=3[C:11]([O:18][CH3:19])=[CH:10][CH:9]=2)[CH2:5][O:4][CH2:3][CH2:2]1.Cl[C:21](OC1C=CC=CC=1)=[O:22].[O:30]1[C:34]2([CH2:39][CH2:38][NH:37][CH2:36][CH2:35]2)[O:33][CH2:32][CH2:31]1>>[O:4]1[CH2:5][CH:6]([C:8]2[C:16]3[S:15][C:14]([NH:17][C:21]([N:37]4[CH2:38][CH2:39][C:34]5([O:33][CH2:32][CH2:31][O:30]5)[CH2:35][CH2:36]4)=[O:22])=[N:13][C:12]=3[C:11]([O:18][CH3:19])=[CH:10][CH:9]=2)[CH2:7][O:1][CH2:2][CH2:3]1
Reactant: O=C(Cl)Oc1ccccc1
Reactant: C1CC2(CCN1)OCCO2
Reactant: COc1ccc(C2COCCOC2)c2sc(N)nc12
Product: COc1ccc(C2COCCOC2)c2sc(NC(=O)N3CCC4(CC3)OCCO4)nc12

Procedure:
Using 7-[1,4]dioxepan-6-yl-4-methoxy-benzothiazol-2-ylamine, phenyl chloroformate and 1,4-dioxa-8-aza-spiro[4,5]decane, the title compound was prepared as off-white powder. MS: m/e=450(M+H+).
Reaction SMILES: [C:1]([O:4][CH2:5][C:6](=O)[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][N:9]=1)(=[O:3])[CH3:2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C[Si]([N:42]=[N+:43]=[N-:44])(C)C>C1COCC1.CCOC(C)=O>[C:1]([O:4][CH2:5][C:6]1[N:7]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][N:9]=2)[N:44]=[N:43][N:42]=1)(=[O:3])[CH3:2]
Reactant: C[Si](C)(C)N=[N+]=[N-]
Reactant: CC(=O)OCC(=O)Nc1ccc(C(F)(F)F)cn1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(=O)OCc1nnnn1-c1ccc(C(F)(F)F)cn1
Reaction time: 0.5 h
Yield: 49.7 %

Procedure:
To a solution of 2-oxo-2-{[5-(trifluoromethyl)-2-pyridinyl]amino}ethyl acetate (Intermediate 56, 3.30 g, 12.6 mmol) in THF at 0° C. were added triphenylphosphine (8.24 g, 31.4 mmol) and diisopropyl azodicorboxylate (6.30 g, 31.2 mmol). The reaction mixture was stirred for 30 min and trimethylsilyl azide (3.60 g, 31.2 mmol) was added dropwise at room temperature. The reaction mixture was heated to reflux for 4 hr. The reaction mixture was diluted with EtOAc and washed with ice water, aq. NaHCO3 solution and saturated brine solution, dried over anhydrous Na2SO4, and concentrated under reduced pressure to afford the crude product. This was purified by column chromatography (60-120 mesh silica gel), eluting with 20% ethyl acetate/pet ether, to give the title compound (1.80 g) as a pale yellow liquid.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:31]=[CH:32][CH:33]=1)[O:5][C:6]1[C:7]2[C:21]([F:22])=[CH:20][N:19]([CH2:23][O:24][CH2:25][CH2:26][Si:27]([CH3:30])([CH3:29])[CH3:28])[C:8]=2[N:9]=[C:10]([NH:12][C:13]2[CH:17]=[CH:16][N:15]([CH3:18])[N:14]=2)[N:11]=1.[C:34](Cl)(=[O:37])[CH:35]=[CH2:36]>C(Cl)Cl>[F:22][C:21]1[C:7]2[C:6]([O:5][C:4]3[CH:3]=[C:2]([NH:1][C:34](=[O:37])[CH:35]=[CH2:36])[CH:33]=[CH:32][CH:31]=3)=[N:11][C:10]([NH:12][C:13]3[CH:17]=[CH:16][N:15]([CH3:18])[N:14]=3)=[N:9][C:8]=2[N:19]([CH2:23][O:24][CH2:25][CH2:26][Si:27]([CH3:28])([CH3:29])[CH3:30])[CH:20]=1
Reactant: Cn1ccc(Nc2nc(Oc3cccc(N)c3)c3c(F)cn(COCC[Si](C)(C)C)c3n2)n1
Reactant: C=CC(=O)Cl
Solvent: ClCCl
Product: C=CC(=O)Nc1cccc(Oc2nc(Nc3ccn(C)n3)nc3c2c(F)cn3COCC[Si](C)(C)C)c1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 55.9 %

Procedure:
To a solution of 4-(3-aminophenoxy)-5-fluoro-N-(1-methyl-1H-pyrazol-3-yl)-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-2-amine (197 mg, 0.42 mmol) in DCM (20 mL) was added acryloyl chloride (34 μL, 0.42 mmol) and the reaction was stirred at rt for 45 min. Additional acryloyl chloride (34 μL, 0.42 mmol) was added and after another 2 hrs a final charge of acryloyl chloride (34 μL, 0.42 mmol) was added. After 30 min, the reaction was complete and was partitioned between DCM (30 mL) and saturated aqueous NaHCO3 (10 mL). The organic layer was separated, dried over Na2SO4 and evaporated to dryness. Purification via flash chromatography eluting with a gradient of 0%-80% EtOAc in heptane afforded the title compound (123 mg, 56 yield) as a solid. 1H NMR (400 MHz, methanol-d4) δ ppm 7.64 (s, 1H) 7.57 (d, J=8.81 Hz, 1H) 7.41 (t, J=8.18 Hz, 1H) 7.27 (d, J=1.76 Hz, 1H) 7.01 (dd, J=8.18, 2.14 Hz, 1H) 6.89 (d, J=2.27 Hz, 1H) 6.30-6.48 (m, 3H) 5.76 (dd, J=9.44, 2.14 Hz, 1H) 5.48 (s, 2H) 3.71 (s, 3H) 3.58 (t, J=8.06 Hz, 2H) 0.90 (t, J=8.06 Hz, 2H) −0.08 (s, 9H). m/z (APCI+) for C25H30FN7O3Si 524.2 (M+H)+.
Reaction SMILES: [C:1]([OH:12])(=[O:11])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][C:8]([OH:10])=[O:9]>ClCCl>[C:1]([OH:12])(=[O:11])[CH2:2][CH2:3][CH:4]=[CH:5][CH2:6][CH2:7][C:8]([OH:10])=[O:9]
Reactant: O=C(O)CCCCCCC(=O)O
Solvent: ClCCl
Product: O=C(O)CCC=CCCC(=O)O
Yield: 71 %

Procedure:
Intramolecular cyclic diester of octane-1,8-dioic acid and 2-(3-diisopropylamino-1-phenylpropyl)-4-hydroxymethyl-phenol Grubbs catalyst (benzylidene-bis-(tricyclohexylphosphine)-dichlororuthenium, 16 mg, 0.002 mmol, 2 mol-%) was added to a solution of (±)-pent-4-enoic acid 2-(3-diisopropylamino-1-phenylpropyl)-4-(pent-4-enoyloxnymethyl)-phenyl ester (483 mg, 0.96 mmol) in dichloromethane (150 ml) and the mixture was refluxed for 96 hrs. under an atmosphere of nitrogen gas, after which all of the starting material was consumed as indicated by tlc. The mixture was filtered through a short pad of basic alumina, and the solvent was removed in vacuum. Flash chromatography (solvent system (4)) afforded the intermediate intramolecular cyclic diester of oct-4-ene-1,8-dioic acid and 2-(3-diisopropylamino)-1-(phenylpropyl)-4-hydroxymethyl-phenol (324 mg) as a colourless syrup (tlc: (4) Rf 0.68) in 71% yield, mixture of two geometrical isomers.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:40]=[CH:39][CH:38]=[CH:37][C:4]=1[CH2:5][NH:6][C:7]([C:9]1[N:13]([C:14]2[CH:15]=[C:16]([CH:30]=[CH:31][CH:32]=2)[CH2:17][N:18]([CH3:29])[CH2:19][CH2:20][NH:21][C:22](=[O:28])[O:23][C:24]([CH3:27])([CH3:26])[CH3:25])[N:12]=[C:11]([C:33]([F:36])([F:35])[F:34])[CH:10]=1)=[O:8].[CH3:41]OC1C=CC=CC=1CNC(C1N(C2C=C(C=CC=2)CNCCN(C)C(=O)OC(C)(C)C)N=C(C(F)(F)F)C=1)=O.COC1C=CC=CC=1CNC(C1N(C2C=CC=C(CNC)C=2)N=C(C(F)(F)F)C=1)=O>>[CH3:1][O:2][C:3]1[CH:40]=[CH:39][CH:38]=[CH:37][C:4]=1[CH2:5][NH:6][C:7]([C:9]1[N:13]([C:14]2[CH:15]=[C:16]([CH:30]=[CH:31][CH:32]=2)[CH2:17][N:18]([CH3:29])[CH2:19][CH2:20][N:21]([CH3:41])[C:22](=[O:28])[O:23][C:24]([CH3:27])([CH3:25])[CH3:26])[N:12]=[C:11]([C:33]([F:35])([F:34])[F:36])[CH:10]=1)=[O:8]
Reactant: COc1ccccc1CNC(=O)c1cc(C(F)(F)F)nn1-c1cccc(CN(C)CCNC(=O)OC(C)(C)C)c1
Reactant: COc1ccccc1CNC(=O)c1cc(C(F)(F)F)nn1-c1cccc(CNCCN(C)C(=O)OC(C)(C)C)c1
Agent: CNCc1cccc(-n2nc(C(F)(F)F)cc2C(=O)NCc2ccccc2OC)c1
Product: COc1ccccc1CNC(=O)c1cc(C(F)(F)F)nn1-c1cccc(CN(C)CCN(C)C(=O)OC(C)(C)C)c1

Procedure:
The title compound 142 (103 mg, 0.179 mmol, 46% yield) was isolated as white foam following the procedure described for the synthesis of compound 59 (scheme 8, example 6, step 7), except using 141 (205 mg, 0.3855 mmol) in place of 58. LRMS (ESI): (calc.) 575.6; (found) 576.5 (MH)+.
Reaction SMILES: C(P(CCCC)CCCC)CCC.[CH2:14]([Li])[CH2:15][CH2:16][CH3:17].[C:19]1(=[O:24])[CH2:23][CH2:22][CH:21]=[CH:20]1.[CH:25](=[O:32])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.[Cl-].[NH4+]>CCOCC.O1CCCC1.CCCCCC>[CH2:14]([C:21]1[CH2:22][CH2:23][C:19](=[O:24])[C:20]=1[CH:25]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[OH:32])[CH2:15][CH2:16][CH3:17]
Reactant: O=C1C=CCC1
Reactant: O=Cc1ccccc1
Reactant: [Li]CCCC
Agent: CCCCP(CCCC)CCCC
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCCCCC
Solvent: CCOCC
Product: CCCCC1=C(C(O)c2ccccc2)C(=O)CC1
Temperature: -78 °C
Reaction time: 0.17 h
Yield: 83 %

Procedure:
Cuprous iodide (325 mg; 1.7 mmoles) was weighed into a 50 ml flask, and the inside atmosphere of the flask was purged with argon. Anhydrous ether (20 ml) was added, and then 687 mg (3.4 mmoles; 0.85 ml) of tri-n-butylphosphine was added at room temperature. The mixture was stirred for 10 minutes. It was then cooled to -78° C., and 1.14 ml (1.7 mmoles) of n-butyllithium (as a 1.49 M hexane solution) was slowly added dropwise. The mixture was stirred at -78° C. for 15 minutes, and 194 mg (1.7 mmoles) of a boron trifluoride-ether complex was added, followed by stirring for 5 minutes. Then, a solution of 123 mg (1.5 mmoles) of 2-cyclopentenone in 5 ml of anhydrous ether was slowly added dropwise. The mixture was stirred at -78° C. for 10 minutes, at -55° C. for 30 minutes, and then at -40° C. for 20 minutes. Anhydrous tetrahydrofuran (5 ml) was added, and then a solution of 212 mg (2 mmoles) of benzaldehyde in 10 ml of anhydrous tetrahydrofuran was added. The temperature of the mixture was gradually raised to room temperature, and the product was hydrolyzed with a saturated aqueous solution of ammonium chloride, and extracted with ether. The organic layer was dried over anhydrous sodium sulfate, and concentrated under reduced pressure by an evaporator. The crude product was subjected to silica gel column chromatography (10 g of ammonia-treated silica gel; benzene as an eluent) to afford 306 mg (yield 83%, a mixture of stereoisomers having different polarities) of the captioned compound.
Reaction SMILES: C(N(S(F)(F)F)CC)C.[CH3:10][O:11][C:12](=[O:28])[CH:13]([NH:16][C:17](=[O:27])[CH2:18][C:19]1[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=1)[CH2:14]O.C(Br)(Cl)(Cl)Cl.C1CCN2C(=NCCC2)CC1.C([O-])(O)=O.[Na+]>ClCCl>[CH3:10][O:11][C:12]([C:13]1[N:16]=[C:17]([CH2:18][C:19]2[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=2)[O:27][CH:14]=1)=[O:28]
Reactant: COC(=O)C(CO)NC(=O)Cc1ccc(OC)cc1
Agent: CCN(CC)S(F)(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)(Cl)Br
Solvent: C1CCC2=NCCCN2CC1
Solvent: ClCCl
Product: COC(=O)c1coc(Cc2ccc(OC)cc2)n1
Temperature: -78 °C
Reaction time: 1 h

Procedure:
DAST (diethylaminosulfur trifluoride) was added to a cold (−78° C.) solution of 3-hydroxy-2-[2-(4-methoxy-phenyl)-acetylamino]-propanoic acid methyl ester (400 mg, 1.5 mmol) in dichloromethane (8 mL). After stirring for 1 h at −78° C., CCl3Br (149 μL, 1.5 mmol) and DBU (226 μL, 1.5 mmol) were added and the reaction was allowed to warm to 25° C. and stirred at this temperature for 12 h. The reaction was poured into saturated aqueous NaHCO3 and the biphasic mixture was extracted with DCM. The combined organic extracts were dried with MgSO4 and purified by column chromatography (hexanes:ethyl acetate from 25 to 100%). 2-(4-Methoxy-benzyl)-oxazole-4-carboxylic acid methyl ester was isolated as a white solid (80 mg, 21%). ESI-MS m/z calc. 247.5, found 248.2 (M+1)+. Retention time of 2.64 minutes. 1H NMR (400 MHz, CDCl3) δ 3.80 (s, 3H), 3.92 (s, 3H), 4.12 (s, 2H), 6.87 (d, J=8.0 Hz, 2H), 7.24 (d, J=8.0 Hz, 2H).
Reaction SMILES: [CH3:1][C@@:2]1([C:8]2[CH:17]=[CH:16][C:15]3[C:10](=[CH:11][CH:12]=[C:13]([O:18][CH:19]4[CH2:24][CH2:23][CH:22]([C:25]([F:28])([F:27])[F:26])[CH2:21][CH2:20]4)[CH:14]=3)[CH:9]=2)[CH2:6][O:5]C(=O)[NH:3]1.C(O)C.[OH2:32].[OH-:33].[Li+]>O>[NH2:3][C@@:2]([C:8]1[CH:17]=[CH:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13]([O:18][CH:19]3[CH2:24][CH2:23][CH:22]([C:25]([F:26])([F:27])[F:28])[CH2:21][CH2:20]3)[CH:14]=2)[CH:9]=1)([CH3:1])[CH2:6][OH:5].[C:22]([OH:33])([C:25]([F:28])([F:27])[F:26])=[O:32]
Reactant: O
Reactant: C[C@@]1(c2ccc3cc(OC4CCC(C(F)(F)F)CC4)ccc3c2)COC(=O)N1
Reactant: [OH-]
Agent: [Li+]
Solvent: CCO
Product: C[C@](N)(CO)c1ccc2cc(OC3CCC(C(F)(F)F)CC3)ccc2c1
Product: O=C(O)C(F)(F)F
Temperature: 80 °C

Procedure:
(R)-4-methyl-4-(6-(4-(trifluoromethyl)cyclohexyloxy)naphthalen-2-yl)oxazolidin-2-one (0.1442 g, 0.0003665 mol) was dissolved in ethanol (1.00 mL, 0.0171 mol) in a capped vial equipped with a magnetic stir bar. 4.2 M Lithium hydroxide, monohydrate in water (1.00 mL) was added and the mixture was heated overnight at 80° C. with stirring. TLC analysis showed that the reaction was complete. The mixture was concentrated to dryness under vacuum. Water (3 mL) and methylene chloride (3 mL) were added and the layers were separated (2×). The combined organic layers were concentrated under vacuum and purified by HPLC to give the title compound as a TFA salt in 0.0388 g (29% yield). MS: m/z=351.41 [M−NH2]+. 1H NMR (400 MHz, MeOD) δ 1.48-1.65 (m, 2H), 1.75-1.80 (m, 4H), 2.04-2.11 (m, 2H), 2.17-2.25 (m, 2H), 2.33 (d, J=11.04 Hz, 2H), 3.79-3.85 (m, 1H), 3.90-3.95 (m, 1H), 4.41-4.83 (m, 1H, 2:1 ratio), 7.16-7.27 (m, 1H, 2:1 ratio) 7.29-7.32 (m, 1H), 7.52 (dd, J=8.66, 2.13 Hz, 1H), 7.79-7.88 (m, 3H)
Reaction SMILES: [H-].[Na+].[N+:3]([C:6]1[CH:7]=[CH:8][C:9]2[N:13]=[C:12]([S:14]([NH:17][CH2:18][CH3:19])(=[O:16])=[O:15])[N:11]([CH2:20][CH3:21])[C:10]=2[CH:22]=1)([O-:5])=[O:4].[CH2:23](Br)[CH3:24].O>CN(C)C=O>[N+:3]([C:6]1[CH:7]=[CH:8][C:9]2[N:13]=[C:12]([S:14]([N:17]([CH2:23][CH3:24])[CH2:18][CH3:19])(=[O:16])=[O:15])[N:11]([CH2:20][CH3:21])[C:10]=2[CH:22]=1)([O-:5])=[O:4]
Reactant: CCBr
Reactant: CCNS(=O)(=O)c1nc2ccc([N+](=O)[O-])cc2n1CC
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCN(CC)S(=O)(=O)c1nc2ccc([N+](=O)[O-])cc2n1CC
Temperature: 40 °C
Reaction time: 1 h
Yield: 78.4 %

Procedure:
2.6 g (0.11 mol) of sodium hydride are added to a solution of 29.8 g (0.1 mol) of 6-nitro-1,N-diethyl-1H-benzimidazole-2-sulfonamide in 100 ml of dimethylformamide. The solution is stirred for one hour at 40° C., 10.8 g (0.1 mol) of ethyl bromide are added and the mixture is stirred for 12 hours at 50° C. It is poured into water and the product is filtered off and washed with water. The precipitate is recrystallized from ethanol to give 25.6 g (78%) of 6-nitro-1,N,N-triethyl-1H-benzimidazole-2-sulfonamide melting at 90°-1° C.
Reaction SMILES: [Na].[NH:2]1[C:6]([C:7]#[N:8])=[C:5]([C:9]#[N:10])[N:4]=[CH:3]1.[CH3:11][C:12]1[CH:19]=[CH:18][CH:17]=[CH:16][C:13]=1[CH2:14]Cl>C(O)C>[CH3:11][C:12]1[CH:19]=[CH:18][CH:17]=[CH:16][C:13]=1[CH2:14][N:2]1[C:6]([C:7]#[N:8])=[C:5]([C:9]#[N:10])[N:4]=[CH:3]1
Reactant: Cc1ccccc1CCl
Reactant: N#Cc1nc[nH]c1C#N
Agent: [Na]
Solvent: CCO
Product: Cc1ccccc1Cn1cnc(C#N)c1C#N

Procedure:
3.70 g of sodium are dissolved in 375 ml of ethanol and then 14.6 g of imidazole-4,5-dinitrile and 16.5 ml of o-methylbenzyl chloride are added and the whole is heated under reflux for 8 hours. The whole is concentrated to dryness by evaporation under reduced pressure and the residue is taken up in dichloromethane, washed in succession with water and with saturated sodium chloride solution, dried over sodium sulphate and concentrated to dryness by evaporation. The crude product is purified by chromatography on silica gel with toluene/ethyl acetate (5:1) and crystallised from ethyl acetate/hexane. 1-(o-methylbenzyl)-imidazole-4,5-dinitrile having a melting point of 80°-81° is obtained.
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([O:12][CH3:13])[CH:8]=2)[CH:3]=1.C[Sn](C)(C)[C:16]1[C:21]([N+:22]([O-:24])=[O:23])=[CH:20][C:19]2[O:25][CH2:26][O:27][C:18]=2[CH:17]=1>C1COCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH2:26]1[O:27][C:18]2[C:19](=[CH:20][C:21]([N+:22]([O-:24])=[O:23])=[C:16]([C:2]3[CH:3]=[C:4]4[C:9](=[CH:10][CH:11]=3)[CH:8]=[C:7]([O:12][CH3:13])[CH:6]=[CH:5]4)[CH:17]=2)[O:25]1
Reactant: COc1ccc2cc(Br)ccc2c1
Reactant: C[Sn](C)(C)c1cc2c(cc1[N+](=O)[O-])OCO2
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COc1ccc2cc(-c3cc4c(cc3[N+](=O)[O-])OCO4)ccc2c1
Reaction time: 0.5 h
Yield: 71 %

Procedure:
Tetrakis(triphenylphosphine)palladium (0) (120 mg) and cuprous bromide (20 mg) were added to a solution of 2-bromo-6-methoxynaphthalene (0.3 g, 1.27 mmol) and trimethyl(3,4-methylenedioxy-6-nitrophenyl)stannane, 62, (0.45 g, 1.37 mmol) in THF (30 mL) at room temperature and stirred for 0.5 h. The mixture was then refluxed under N2 for 16 h. After cooling, THF was evaporated and 50 mL ethyl acetate was added to the residue. The solution was washed with water. The organic layer was separated and passed through a Celite bed to remove suspended particles. The organic layer was then washed with brine, dried (anhydrous Na2SO4), and evaporated in vacuo. The residue was chromatographed using a 80:20 mixture of hexanes:ethyl acetate to give the desired product 45 (0.29 g) in 71% yield; mp 165-167° C.; IR (KBr) 2911, 1609, 1520, 1482, 1429, 1393, 1344, 1257, 1199 cm−1; 1H NMR (CDCl3) δ3.94 (3H, s), 6.14 (2H, s), 6.88 (1H, s), 7.16-7.21 (2H, m), 7.31 (1H, dd, J1=8.5, J2=1.9), 7.47 (1H, s), 7.67-7.77 (3H, m); 13C NMR δ55.89, 103.45, 105.92, 106.19, 111.69, 119.86, 126.90, 127.02, 127.55, 129.23, 130.09, 133.76, 133.85, 134.48, 143.38, 147.52, 151.47, 158.62; HRMS (EI) calcd for C18H13NO5 m/z: 323.0794; found: 323.0788.
Reaction SMILES: C[O:2][C:3]([C:5]1[S:9][C:8](/[CH:10]=[CH:11]/[C:12]2[C:13]([CH2:18][CH2:19][CH2:20][CH3:21])=[N:14][O:15][C:16]=2[CH3:17])=[N:7][C:6]=1[CH3:22])=[O:4].O.[OH-].[Li+].CO>C1COCC1.O>[CH2:18]([C:13]1[C:12](/[CH:11]=[CH:10]/[C:8]2[S:9][C:5]([C:3]([OH:4])=[O:2])=[C:6]([CH3:22])[N:7]=2)=[C:16]([CH3:17])[O:15][N:14]=1)[CH2:19][CH2:20][CH3:21]
Reactant: CCCCc1noc(C)c1/C=C/c1nc(C)c(C(=O)OC)s1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: CCCCc1noc(C)c1/C=C/c1nc(C)c(C(=O)O)s1
Temperature: 25 °C
Reaction time: 1 h
Yield: 90.3 %

Procedure:
To a suspension of 2-[(E)-2-(3-butyl-5-methyl-isoxazol-4-yl)-vinyl]-4-methyl-thiazole-5-carboxylic acid methyl ester (150 mg, 0.47 mmol) in THF (1.5 mL) was added a solution of lithium hydroxide monohydrate (39 mg, 0.93 mmol) in water (1.5 mL) followed by methanol (1 mL) and the resulting mixture stirred at room temperature for 1 h. The mixture was then evaporated to half volume and then acidified to pH 4 with HCl (1 N) and cooled to 0° C. for 30 min. A solid precipitated and was filtered off and dried to afford the title compound (130 mg, 91%) which was obtained as a light yellow solid. MS: m/e=305.2 [M−H]−.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([C:11]([NH:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([F:23])([F:22])[F:21])[CH:15]=1)=[O:12])[CH:6]=[CH:5]2.OC1C=C2C(=CC=1)N(C(NC1C=CC=C(C(F)(F)F)C=1)=O)CC2.[OH-].[Na+].[Cl:49][C:50]1[N:55]=[C:54](Cl)[CH:53]=[CH:52][N:51]=1>CC(C)=O.O>[Cl:49][C:50]1[N:55]=[C:54]([O:1][C:2]2[CH:3]=[C:4]3[C:8](=[CH:9][CH:10]=2)[N:7]([C:11]([NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([F:23])([F:21])[F:22])[CH:15]=2)=[O:12])[CH:6]=[CH:5]3)[CH:53]=[CH:52][N:51]=1
Reactant: O=C(Nc1cccc(C(F)(F)F)c1)n1ccc2cc(O)ccc21
Reactant: Clc1ccnc(Cl)n1
Agent: O=C(Nc1cccc(C(F)(F)F)c1)N1CCc2cc(O)ccc21
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(C)=O
Product: O=C(Nc1cccc(C(F)(F)F)c1)n1ccc2cc(Oc3ccnc(Cl)n3)ccc21
Reaction time: 1.5 h

Procedure:
A mixture of 5-hydroxy-N-(3-(trifluoromethyl)phenyl)-1H-indole-1-carboxamide and 5-hydroxy-N-(3-(trifluoromethyl)phenyl)indoline-1-carboxamide (6:4) (3 g) is mixed with sodium hydroxide (0.45 g, 11.2 mmol) and 2,4-dichloropyrimidine (1.68 g, 11.2 mmol) in 50 mL of acetone and 50 mL of water at 0° C. and stirred for 1.5 h. Additional sodium hydroxide (0.075 g, 1.88 mmol) and (0.279 g, 1.88 mmol) are added. After additional 30 min stirring the reaction is concentrated, diluted with EtOAc, washed with water and brine before the organic layer is dried over sodium sulfate and concentrated. The residue is separated via FCC (5-50% EtOAc in heptane) to give 5-(2-chloropyrimidin-4-yloxy)-N-(3-(trifluoromethyl)phenyl)-1H-indole-1-carboxamide. 1H NMR (400 MHz, CDCl3) δ ppm 8.45 (d, J=5.7 Hz, 1H), 8.24 (d, J=9.0 Hz, 1H), 7.86 (s, 1H), 7.78 (d, J=8.2 Hz, 1H), 7.60 (d, J=3.7 Hz, 1H), 7.55 (t, J=8.0 Hz, 1H), 7.45-7.50 (m, 2H), 7.42 (d, J=2.1 Hz, 1H), 7.15 (dd, J=8.9, 2.3 Hz, 1H), 6.82 (d, J=5.7 Hz, 1H), 6.73 (dd, J=3.7, 0.6 Hz, 1H).
Reaction SMILES: [CH3:1][C:2]([CH2:4][C:5]([CH3:8])([CH3:7])[CH3:6])=[CH2:3].S(Cl)([Cl:11])=O.O>C(Cl)Cl>[Cl:11][C:2]([CH3:1])([CH2:4][C:5]([CH3:8])([CH3:7])[CH3:6])[CH3:3]
Reactant: O=S(Cl)Cl
Reactant: C=C(C)CC(C)(C)C
Solvent: O
Solvent: ClCCl
Product: CC(C)(C)CC(C)(C)Cl
Temperature: -30 °C
Yield: 85 %

Procedure:
15 ml of 2,4,4-trimethyl-pentene-1 are dissolved in 150 ml of CH2Cl2, cooled to -30° C. and mixed dropwise with a mixture of 10.3 ml of thionyl chloride and 5.4 ml of H2O. The mixture is then heated to 0° C. and washed after 2.5 hours with cold 1% aqueous K2CO3 solution, then with ice-cold water. The product is dried over MgSO4 and distilled off. Yield 85%; nD20 =1.4308; Bpt.10 mm 38° C.
Reaction SMILES: Cl.Cl.[NH2:3][NH2:4].C(O/[CH:8]=[CH:9]/[C:10](=O)[C:11]([F:14])([F:13])[F:12])C.C(OCC)(=O)C.CCCCCC>C(O)C>[F:12][C:11]([F:14])([F:13])[C:10]1[CH:9]=[CH:8][NH:4][N:3]=1
Reactant: CCO/C=C/C(=O)C(F)(F)F
Reactant: NN
Agent: Cl
Solvent: CCO
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: FC(F)(F)c1cc[nH]n1

Procedure:
Hydrazine dihydrochloride (225 g, 2.14 mol) in ethanol (1400 mL) was stirred well. TEA (185.4 mL, 1.34 mol) was added drop wise for 45 min at ambient temperature. Then (E)-4-ethoxy-1,1,1-trifluorobut-3-en-2-one (225 g, crude) was added drop wise at room temperature and the overall reaction mixture was refluxed overnight. Progress of the reaction was monitored by TLC (20% ethyl acetate/hexane, Rf˜0.4). On completion of the reaction, ethanol was distilled off completely, residue was taken in ice water (500 mL) and the product extracted with ethyl acetate (2×400 mL). Combined extract was washed with ice water (300 mL), dried over sodium sulfate and concentrated under reduced pressure to yield 3-(trifluoromethyl)-1H-pyrazole as a off white solid (175 g, crude).
Reaction SMILES: COC(=O)[CH2:4][NH:5][CH2:6][C:7]([NH:10][C:11]([O:13]C(C)(C)C)=O)([CH3:9])[CH3:8].C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:8][C:7]1([CH3:9])[NH:10][C:11](=[O:13])[CH2:4][NH:5][CH2:6]1
Reactant: COC(=O)CNCC(C)(C)NC(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC1(C)CNCC(=O)N1
Temperature: 25 °C
Yield: 44.8 %

Procedure:
A mixture of (2-tert-butoxycarbonylamino-2-methyl-propylamino)-acetic acid methyl ester (compound N; 26.5 g) in DCM (800 mL) was stirred at ambient temperature, TFA (180 mL) was added drop-wise. The mixture was stirred at 30-40° C. for 5 h before it was concentrated in vacuo. The residue was partitioned between dissolved toluene and water. The organic layer was dried over Na2SO4, filtered, and concentrated in vacuo. The residual solid was dissolved in a mixture of ethanol (400 mL) and methanol (90 mL). K2CO3 (207 g) was added and the mixture was refluxed overnight. The mixture was cooled to room temperature. DCM (2500 mL) was added, and the mixture was stirred for 1 hour at ambient temperature. The solid was filtered off, and the filtrate was concentrated in vacuo to afford 6,6-dimethyl-piperazin-2-one (Compound I; 5.85 g) as a white solid sufficiently pure for the next step.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:17]=[C:18]2[C:23](=[CH:24][CH:25]=1)[C:22]([NH2:26])=[CH:21][CH:20]=[CH:19]2.C([O-])(O)=O.[Na+].[F:32][C:33]1[CH:41]=[CH:40][CH:39]=[CH:38][C:34]=1[C:35](Cl)=[O:36].C(Cl)(Cl)Cl>C(Cl)Cl.O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:17]=[C:18]2[C:23](=[CH:24][CH:25]=1)[C:22]([NH:26][C:35](=[O:36])[C:34]1[CH:38]=[CH:39][CH:40]=[CH:41][C:33]=1[F:32])=[CH:21][CH:20]=[CH:19]2
Reactant: O=C(Cl)c1ccccc1F
Reactant: COc1cc2nccc(Oc3ccc4c(N)cccc4c3)c2cc1OC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Product: COc1cc2nccc(Oc3ccc4c(NC(=O)c5ccccc5F)cccc4c3)c2cc1OC
Temperature: 25 °C
Reaction time: 20 h

Procedure:
To a solution of 6-(6,7-dimethoxy-quinolin-4-yloxy)-naphthalen-1-ylamine (Step a, 50 mg, 0.14 mmol) and NaHCO3 (38 mg, 0.45 mmol) in CH2Cl2 (1 mL), 2-fluorobenzoyl chloride (18 mL, 0.15 mmol) was added. The reaction was stirred at RT for 20 h. The mixture was taken up into CHCl3 and water, washed with brine, dried with Na2SO4, filtered and concentrated in vacuo. The title compound was purified by column chromatography using 0-100% of a 90:10:1 (CH2Cl2:MeOH:NH4OH) solution as the eluant. M+H 469.1, Calc'd for C28H21FN2O4-468.49.