Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH:10]([NH:12][C:13](=[O:15])[CH3:14])[CH3:11])=[CH:4][CH:3]=1.[H-].[Na+].Cl[C:19]1[N:20]=[N:21][C:22]([O:25][CH:26]([CH3:28])[CH3:27])=[CH:23][CH:24]=1.C(OCC)(=O)C>CN1C(=O)CCC1.O>[CH:26]([O:25][C:22]1[N:21]=[N:20][C:19]([O:1][C:2]2[CH:3]=[CH:4][C:5]([CH2:8][CH2:9][CH:10]([NH:12][C:13](=[O:15])[CH3:14])[CH3:11])=[CH:6][CH:7]=2)=[CH:24][CH:23]=1)([CH3:28])[CH3:27]
Reactant: CC(=O)NC(C)CCc1ccc(O)cc1
Reactant: CC(C)Oc1ccc(Cl)nn1
Agent: [H-]
Agent: [Na+]
Solvent: CN1CCCC1=O
Solvent: CCOC(C)=O
Solvent: O
Product: CC(=O)NC(C)CCc1ccc(Oc2ccc(OC(C)C)nn2)cc1
Temperature: 150 °C
Reaction time: 0.25 h

Procedure:
N-[3-(4-Hydroxyphenyl)-1-methylpropyl]acetamide (311 mg, 1.5 mmol) was dissolved in 3 ml of NMP, admixed with sodium hydride (55% in oil) (120 mg, 3 mmol) and, after addition of 3-chloro-6-isopropoxypyridazine (259 mg, 1.5 mmol) stirred in a microwave reactor at 150° C. for 15 min. Following addition of ethyl acetate and water, the organic phase was separated off, concentrated and purified by preparative HPLC (PR18, acetonitrile/water 0.1% TFA). Yield: 40mg (8%), M+H+: 344.2.
Reaction SMILES: [CH3:1][C:2]1([CH3:10])[O:9][C:7](=[O:8])[CH2:6][C:4](=[O:5])[O:3]1.[CH2:11](OC(OCC)OCC)C.[F:21][C:22]1[CH:23]=[C:24]([CH:26]=[C:27]([F:29])[CH:28]=1)[NH2:25]>CCCCCC>[F:21][C:22]1[CH:23]=[C:24]([NH:25][CH:11]=[C:6]2[C:7](=[O:8])[O:9][C:2]([CH3:10])([CH3:1])[O:3][C:4]2=[O:5])[CH:26]=[C:27]([F:29])[CH:28]=1
Reactant: CC1(C)OC(=O)CC(=O)O1
Reactant: CCOC(OCC)OCC
Reactant: Nc1cc(F)cc(F)c1
Solvent: CCCCCC
Product: CC1(C)OC(=O)C(=CNc2cc(F)cc(F)c2)C(=O)O1
Temperature: 100 °C
Reaction time: 4 h

Procedure:
In a oven dried 2-neck RBF equipped with reflux condenser and inert atmosphere, meldrum's acid (30 g, 0.208 mole) was dissolved in triethylorthoformate (185 g, 1.25 mole) and the reaction mixture was refluxed at 100° C. under nitrogen for 1 h. On complete consumption of starting material (tic), 3,5-difluoroaniline (26.8 g, 0.208 mol) was added and the heating continued for 4 h. After completion of the reaction (tic), reaction mixture was brought to RT and diluted with hexane (300 ml) when yellow solid precipitated. The solid was filtered, washed thoroughly with hexane and dried to furnish the product.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([CH:10]([CH2:14][CH2:15][C:16](=[O:18])[CH3:17])[C:11]([O-:13])=[O:12])=O)=[CH:4][CH:3]=1.[C:19](O)(=O)[CH3:20].N1CCCCC1.CCOC(C)=O>C1(C)C=CC=CC=1>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:10]([C:11]([O:13][CH2:19][CH3:20])=[O:12])[CH2:14][CH2:15][C:16](=[O:18])[CH:17]=2)=[CH:4][CH:3]=1
Reactant: CC(=O)O
Reactant: CC(=O)CCC(C(=O)[O-])C(=O)c1ccc(C)cc1
Solvent: Cc1ccccc1
Solvent: C1CCNCC1
Solvent: CCOC(C)=O
Product: CCOC(=O)C1CCC(=O)C=C1c1ccc(C)cc1
Temperature: 25 °C
Yield: 587.5 %

Procedure:
A mixture of 2-((4-methylphenyl)carbonyl)-5-oxohexanoate(4.19 g, 15.2 mmol), acetic acid(137 mg, 2.28 mmol) and piperidine(129 mg, 1.52 mmol) in toluene(10 ml) was refluxed for 9 hr. After cooling down to room temperature, AcOEt was added to the reaction mixture and washed with dil. HCl, water and brine, dried over MgSO4. After removal of the solvent, the residue was purified by column chromatography on silica gel with n-hexane-AcOEt to afford 3.46 g of ethyl 2-(4-methylphenyl)-4-oxocyclohex-2-enecarboxylate(y=88.0%) as a brown oil. 1H-NMR(ppm, 300 MHz, CDCl3) δ 7.41(2H, d, J=8.2 Hz), 7.21(2H, d, J=8.2 Hz), 5.47(1H, s), 4.11(2H, q, J=7.0 Hz), 3.96(1H, dd, J=4.8 and 4.8 Hz), 2.55-2.65(1H, m), 2.40-2.55(3H, m), 2.38(3H, s), 1.14(3H, t, J=7.0 Hz).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8]([OH:12])=[N:7][CH:6]=[CH:5]2.C([O-])(O)=O.[Na+].F[C:19](=[O:34])[C@H:20]([NH:26][C:27](=[O:33])[O:28][C:29]([CH3:32])([CH3:31])[CH3:30])[C:21]1[CH:25]=[CH:24][S:23][CH:22]=1>O.C(Cl)Cl>[OH:12][C:8]1[C:9]2[C:4](=[CH:3][C:2]([NH:1][C:19](=[O:34])[C@H:20]([NH:26][C:27](=[O:33])[O:28][C:29]([CH3:30])([CH3:32])[CH3:31])[C:21]3[CH:25]=[CH:24][S:23][CH:22]=3)=[CH:11][CH:10]=2)[CH:5]=[CH:6][N:7]=1
Reactant: Nc1ccc2c(O)nccc2c1
Reactant: CC(C)(C)OC(=O)N[C@@H](C(=O)F)c1ccsc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: CC(C)(C)OC(=O)N[C@@H](C(=O)Nc1ccc2c(O)nccc2c1)c1ccsc1
Reaction time: 4 h

Procedure:
To 6-aminoisoquinolin-1-ol in H2O was added NaHCO3 followed by a solution of (R)-tert-butyl 2-fluoro-2 oxo-1-(thiophen-3-yl)ethylcarbamate in CH2Cl2. The solution was stirred for 4 hours, extracted with EtOAc and NH4Cl(sat)/HCl(1N) and then with NaHCO3 (0.05%), dried (Na2SO4), filtered and evaporated. Column chromatography (SiO2, 5% MeOH, CH2Cl2) gave pure (R)-tert-butyl 2-(1-hydroxyisoquinolin-6-ylamino)-2-oxo-1-(thiophen-3-yl)ethylcarbamate (95% ee by Chiracel OD-RH)
Reaction SMILES: [CH:1]1([C:6]2[CH:11]=[C:10]([C:12]3[N:16]=[C:15]([C:17]4[CH:22]=[C:21]([CH3:23])[C:20]([OH:24])=[C:19]([CH2:25][CH3:26])[CH:18]=4)[O:14][N:13]=3)[CH:9]=[C:8]([O:27][CH3:28])[N:7]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:29]([C@@H:31]1[O:33][CH2:32]1)Cl>C(O)(C)C.[OH-].[Na+].CC(=O)OCC>[CH:1]1([C:6]2[CH:11]=[C:10]([C:12]3[N:16]=[C:15]([C:17]4[CH:22]=[C:21]([CH3:23])[C:20]([O:24][CH2:29][C@@H:31]5[CH2:32][O:33]5)=[C:19]([CH2:25][CH3:26])[CH:18]=4)[O:14][N:13]=3)[CH:9]=[C:8]([O:27][CH3:28])[N:7]=2)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: ClC[C@H]1CO1
Reactant: CCc1cc(-c2nc(-c3cc(OC)nc(C4CCCC4)c3)no2)cc(C)c1O
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CC(C)O
Product: CCc1cc(-c2nc(-c3cc(OC)nc(C4CCCC4)c3)no2)cc(C)c1OC[C@@H]1CO1
Temperature: 25 °C
Reaction time: 72 h
Yield: 55.8 %

Procedure:
A mixture of 4-[3-(2-cyclopentyl-6-methoxy-pyridin-4-yl)-[1,2,4]oxadiazol-5-yl]-2-ethyl-6-methyl-phenol (150 mg, 395 μmol) and (R)-epichlorohydrine (366 mg, 3.95 mmol) in isopropanol (4 mL) and 3 N aq. NaOH (1 mL) is stirred at rt for 72 h. The mixture is diluted with EA (50 mL), washed with 1 M aq. NaOH solution (20 mL) followed by brine (20 mL), dried over MgSO4, filtered and concentrated. The crude product is purified on prep. TLC plates using heptane:EA 1:1 to give 2-cyclopentyl-4-[5-((S)-3-ethyl-5-methyl-4-oxiranylmethoxy-phenyl)-[1,2,4]oxadiazol-3-yl]-6-methoxy-pyridine (96 mg) as a pale yellow oil; LC-MS**: tR=1.02 min, [M+H]+=436.18.
Reaction SMILES: [I:1][C:2]1[CH:22]=[CH:21][C:5]2[S:6][C:7]3[CH:20]=[CH:19][CH:18]=[CH:17][C:8]=3[CH:9]([N:11]3[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]3)[CH2:10][C:4]=2[CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[I-].[K+].Cl[CH2:32][CH2:33][N:34]1[CH2:38][CH2:37][O:36][C:35]1=[O:39]>C(Cl)(Cl)Cl.O.C1(C)C=CC=CC=1>[I:1][C:2]1[CH:22]=[CH:21][C:5]2[S:6][C:7]3[CH:20]=[CH:19][CH:18]=[CH:17][C:8]=3[CH:9]([N:11]3[CH2:12][CH2:13][N:14]([CH2:32][CH2:33][N:34]4[CH2:38][CH2:37][O:36][C:35]4=[O:39])[CH2:15][CH2:16]3)[CH2:10][C:4]=2[CH:3]=1
Reactant: O=C1OCCN1CCCl
Reactant: Ic1ccc2c(c1)CC(N1CCNCC1)c1ccccc1S2
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: ClC(Cl)Cl
Solvent: Cc1ccccc1
Solvent: O
Product: O=C1OCCN1CCN1CCN(C2Cc3cc(I)ccc3Sc3ccccc32)CC1

Procedure:
5.9 g of 1-(10,11-dihydro-2-iodo-dibenzo[b,f]thiepin- 10-yl)-piperazine are treated, together with 3.3 g of powdered potassium carbonate, 0.07 g of potassium iodide and 40 ml of toluene, with 4.35 g of N-(β-chloroethyl)-oxazolidinone and the mixture is heated under reflux for 27 hours. The mixture is then poured on to water and diluted with chloroform. The organic phase is extracted with 2-N hydrochloric acid. The aqueous phase is made alkaline with sodium hydroxide and extracted with chloroform. The organic phase is dried over magnesium sulphate and concentrated under reduced pressure. The residue is chromatographed over aluminum oxide. There is obtained 3-[2-[4-(10,11-dihydro-2-iodo-dibenzo[b,f]thiepin- 10-yl)-1-piperazinyl]-ethyl]-2-oxazolidinone which is converted into the maleate by treatment with maleic acid. The maleate melts at 176° - 177°C.
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]([CH3:26])=[C:5]([C:20]([O:22][CH:23]([CH3:25])[CH3:24])=[O:21])[CH:6]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([NH:18][OH:19])[CH:13]=2)[C:7]=1[C:8]([O:10][CH3:11])=[O:9].[S:27]1[CH:31]=[CH:30][CH:29]=[C:28]1[CH:32]=O>>[CH3:1][C:2]1[NH:3][C:4]([CH3:26])=[C:5]([C:20]([O:22][CH:23]([CH3:24])[CH3:25])=[O:21])[CH:6]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([N:18](=[O:19])=[CH:32][C:28]3[S:27][CH:31]=[CH:30][CH:29]=3)[CH:13]=2)[C:7]=1[C:8]([O:10][CH3:11])=[O:9]
Reactant: COC(=O)C1=C(C)NC(C)=C(C(=O)OC(C)C)C1c1cccc(NO)c1
Reactant: O=Cc1cccs1
Agent: COC(=O)C1=C(C)NC(C)=C(C(=O)OC(C)C)C1c1cccc(/[N+]([O-])=C/c2cccs2)c1
Product: COC(=O)C1=C(C)NC(C)=C(C(=O)OC(C)C)C1c1cccc([N+]([O-])=Cc2cccs2)c1

Procedure:
The reaction of hydroxylamine 82 (0.71 g, 2 mmol) with 2-thiophenecarboxaldehyde (64) (0.224 g, 2 mmol) afforded after workup, a light yellow oil. The crude product was purified by flash chromatography with 1:1 ethyl acetate/petroleum ether as the eluant to obtain 0.64 g (1.41 mmol, 71%) of 87 as a light yellow oil. The oil crystallized from ether/pentane to yield yellow crystalline solid: mp 106°-109° C.; IR (CH2Cl2) 3440, 2940, 1695, 1620, 1555, 1470, 1375, 1300, 1215, 1100 cm-1 ; 1H NMR (CDCl3) δ 1.10 (d, J=6.2 Hz, 3H), 1.22 (d, J=6.2 Hz, 3H), 2.27 (s, 6H), 3.61 (s, 3H), 4.94 (septet, J=6.2 Hz, 1H), 5.06 (s, 1H), 6.98 (s, 1H), 7.17-7.77 (m, 7H), 8.44 (s, 1H); 13C NMR (CDCl3) δ 19.87, 22.49, 22.74, 40.59, 51.54, 67.68, 103.30, 104.00, 119.18, 121.52, 127.64, 128,95, 129.76, 130.60, 130.66, 131.78, 133.49, 145.64, 146.13, 147.07, 150.57, 167.62, 168.64. Anal. Calcd for C24H26N2O5S: C, 63.43; H, 5.72. Found: C, 63.26; H, 5.72.
Reaction SMILES: ON=[CH:3][C:4]([NH:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[N+:13]([O-:15])=[O:14])=[O:5].S(=O)(=O)(O)[OH:17]>>[N+:13]([C:8]1[CH:9]=[CH:10][CH:11]=[C:12]2[C:7]=1[NH:6][C:4](=[O:5])[C:3]2=[O:17])([O-:15])=[O:14]
Reactant: O=C(C=NO)Nc1ccccc1[N+](=O)[O-]
Reactant: O=S(=O)(O)O
Product: O=C1Nc2c(cccc2[N+](=O)[O-])C1=O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
2-Hydroxyimino-N-(2-nitro-phenyl)-acetamide (15 g, 72 mmol) was carefully added in small portions over a period of 30 min to a stirred solution of conc. sulphuric acid (45 mL) which was preheated to 90° C. The reaction mixture was stirred for another 2 h at the same temperature then cooled to room temperature, poured into crushed ice. The precipitated products were collected by filtrations, washed with water and dried in a vacuum oven to get 9 g (65%) of brick red colour powder.
Reaction SMILES: CC(C)([O-])C.[K+].[F:7][C:8]1[C:18]([F:19])=[C:17]([F:20])[CH:16]=[CH:15][C:9]=1[NH:10][C@@H:11]([CH3:14])[CH2:12][OH:13].C(O[CH:24]=[C:25]([C:31]([O:33][CH2:34][CH3:35])=[O:32])[C:26]([O:28][CH2:29][CH3:30])=[O:27])C>CN(C=O)C>[F:7][C:8]1[C:18]([F:19])=[C:17]([F:20])[CH:16]=[CH:15][C:9]=1[N:10]([CH:24]=[C:25]([C:26]([O:28][CH2:29][CH3:30])=[O:27])[C:31]([O:33][CH2:34][CH3:35])=[O:32])[C@@H:11]([CH3:14])[CH2:12][OH:13]
Reactant: CCOC=C(C(=O)OCC)C(=O)OCC
Reactant: C[C@@H](CO)Nc1ccc(F)c(F)c1F
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)C(=CN(c1ccc(F)c(F)c1F)[C@@H](C)CO)C(=O)OCC
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 75 %

Procedure:
Potassium tertiary-butoxide (62 mg) was added to DMF (2 ml) and cooled to 0° C. Then a solution of the compound (100 mg) obtained in Example 51 in DMF (200 μl) was dropped therein to. After stirring for 15 minutes, diethyl ethoxymethylenemalonate was dropped therein to and the resultant mixture was stirred for 8 hours at room temperature. After treating in a conventional manner, it was subjected to silica gel column chromatography to thereby give 137 mg (75%) of the title compound as a colorless solid. The 1H-NMR and IR spectral data of this product was identical with those of the compound obtained in Example 63.
Reaction SMILES: Cl[CH2:2][CH2:3][C:4]([C:6]1[CH:11]=[CH:10][C:9]([CH2:12][C:13]([O:15]CC)=[O:14])=[CH:8][CH:7]=1)=[O:5]>S(=O)(=O)(O)O>[O:5]=[C:4]1[C:6]2[C:7](=[CH:8][C:9]([CH2:12][C:13]([OH:15])=[O:14])=[CH:10][CH:11]=2)[CH2:2][CH2:3]1
Reactant: CCOC(=O)Cc1ccc(C(=O)CCCl)cc1
Agent: O=S(=O)(O)O
Product: O=C(O)Cc1ccc2c(c1)CCC2=O
Temperature: 20 °C
Yield: 58.4 %

Procedure:
(1-Oxoindan-5-yl)acetic acid can be obtained in the following way: a solution of 50.9 g of ethyl [4-(3-chloro-1-oxopropyl)phenyl]acetate in 950 ml of 95% sulphuric acid is heated for 1 hour at 100° C. The reaction mixture is cooled to a temperature in the region of 20° C. and then poured into 4 liters of ice-cold water. The mixture is extracted three times with 1.5 liter of dichloromethane. The organic phase is washed three times with 1 liter of water, then dried over magnesium sulphate and evaporated under reduced pressure. 22.2 g of (1-oxoindan-5-yl)acetic acid are thus obtained in the form of a cream solid melting at 141° C. (1H NMR spectrum in CDCl3, T=300K, δ in ppm: 2.70 (2H, m, COCH2), 3.12 (2H, t, J=5 Hz, CH2), 3.68 (2H, s, CH2), 7.27 (1H, d, J=7 Hz, arom. CH), 7.45 (1H, s, arom. CH), 7.76 (1H, d, J=7 Hz, arom. CH)).
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10]Br.[CH:12]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH:15]=[CH:14][N:13]=1>>[Br-:1].[Br-:1].[CH2:2]([N+:13]1[CH:14]=[CH:15][C:16]2[C:21](=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:12]=1)[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][N+:13]1[CH:14]=[CH:15][C:16]2[C:21](=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:12]=1
Reactant: BrCCCCCCCCCBr
Reactant: c1ccc2cnccc2c1
Product: [Br-]
Product: c1ccc2c[n+](CCCCCCCCC[n+]3ccc4ccccc4c3)ccc2c1
Temperature: 65 °C
Yield: 92 %

Procedure:
1,9-Dibromononane (mmol) was added to a solution (30 mL) of isoquinoline, and the solution heated for 24 hours at 65° C. The resulting precipitate was filtered, and the product washed five times with dry diethyl ether. The resulting purple solid was isolated in a 92% yield. 1H NMR (300 MHz, DMSO-D6) δ 10.17 (1H, d, C1-H), 8.85 (1H, d, C3-H), 8.62 (1H, d, C8-H), 8.49 (1H, d, C4-H), 8.36 (2H, d, C7-H), 8.26 (2H, t, C5-H), 8.08 (1H, t, C6-H), 4.72 (2H, t, C′1-CH2), 2.02 (2H, m, C′2-CH2), 1.78 (1H, m, C′3-CH2), 1.19-1.50 (4H, m, C′3-5-CH2).
Reaction SMILES: Cl.Cl.[CH3:3][NH:4][NH:5][CH3:6].C(=O)([O-])[O-].[K+].[K+].[Br:13][C:14]1[CH:15]=[C:16]([C:26]2[O:31][C:30](=[O:32])[C:29]3[CH:33]=[C:34]([Cl:38])[CH:35]=[C:36]([CH3:37])[C:28]=3[N:27]=2)[N:17]([C:19]2[C:24]([Cl:25])=[CH:23][CH:22]=[CH:21][N:20]=2)[CH:18]=1>O.CN(C)C=O>[Br:13][C:14]1[CH:15]=[C:16]([C:26]([NH:27][C:28]2[C:36]([CH3:37])=[CH:35][C:34]([Cl:38])=[CH:33][C:29]=2[C:30]([N:4]([CH3:3])[NH:5][CH3:6])=[O:32])=[O:31])[N:17]([C:19]2[C:24]([Cl:25])=[CH:23][CH:22]=[CH:21][N:20]=2)[CH:18]=1
Reactant: CNNC
Reactant: Cc1cc(Cl)cc2c(=O)oc(-c3cc(Br)cn3-c3ncccc3Cl)nc12
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CNN(C)C(=O)c1cc(Cl)cc(C)c1NC(=O)c1cc(Br)cn1-c1ncccc1Cl
Temperature: 25 °C
Reaction time: 6 h
Yield: 23.3 %

Procedure:
To a mixture of 0.29 g of N,N′-dimethylhydrazine dihydrochloride, 1 ml of water, 0.31 g of potassium carbonate and 10 ml of N,N-dimethylformamide was added 1.0 g of 2-[4-bromo-1-(3-chloro-2-pyridinyl)-1H-pyrrol-2-yl]-6-chloro-8-methyl-4H-3,1-benzoxazine-4-one. The resulting mixture was stirred at room temperature for 6 hours. Water was poured into the reaction mixture, and the mixture was extracted with ethyl acetate three times. The organic layers were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting residue was subjected to silica gel chromatography to obtain 0.26 g of 4-bromo-N-[4-chloro-2-(N,N′-dimethylhydrazinocarbonyl)-6-methylphenyl]-1-(3-chloro-2-pyridinyl)-1H-pyrrole-2-carboxamide of the formula:
Reaction SMILES: [C:1]([O:5][C@@H:6]([C:10]1[C:19]([CH3:20])=[CH:18][C:17]2[C:12](=[CH:13][CH:14]=[C:15]([C:21]3[CH:26]=CC=[CH:23][N:22]=3)[CH:16]=2)[C:11]=1[C:27]1[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][CH:28]=1)[C:7]([OH:9])=[O:8])([CH3:4])([CH3:3])[CH3:2].C([Sn](CCCC)(CCCC)[C:39]1C=CC=C[N:40]=1)CCC>>[C:1]([O:5][C@@H:6]([C:10]1[C:19]([CH3:20])=[CH:18][C:17]2[C:12](=[CH:13][CH:14]=[C:15]([C:21]3[N:22]([CH3:23])[CH:39]=[N:40][CH:26]=3)[CH:16]=2)[C:11]=1[C:27]1[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][CH:28]=1)[C:7]([OH:9])=[O:8])([CH3:2])([CH3:3])[CH3:4]
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccccn1
Reactant: Cc1cc2cc(-c3ccccn3)ccc2c(-c2ccc(Cl)cc2)c1[C@H](OC(C)(C)C)C(=O)O
Product: Cc1cc2cc(-c3cncn3C)ccc2c(-c2ccc(Cl)cc2)c1[C@H](OC(C)(C)C)C(=O)O

Procedure:
(S)-2-tert-Butoxy-2-(1-(4-chlorophenyl)-3-methyl-6-(1-methyl-1H-imidazol-5-yl)naphthalen-2-yl)acetic acid (65) was prepared in a similar fashion to compound 63 with the substitution of 1-methyl-5-(tributylstannyl)-1H-imidazole for 2-(tributylstannyl)pyridine in step 1. The title compound (0.026 g) was isolated as an amorphous white powder. LCMS-ESI+ (m/z): [M+H]+ calcd for C27H28ClN2O3: 463.98; found: 463.81. 1H-NMR: 400 MHz, (CD3CN) δ: 8.54 (s, 1H); 7.99 (s, 1H); 7.84 (s, 1H): 7.62-7.50 (m, 3H); 7.45-7.32 (m, 3H), 5.24 (s, 1H); 3.80 (s, 3H); 2.60 (s, 3H); 0.99 (s, 9H).
Reaction SMILES: [Br:1][C:2]1[C:3]([CH3:11])=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][N:6]=[CH:5]2.C(=O)([O-])[O-].[Cs+].[Cs+].[C:18]([N:25]1[CH2:30][CH2:29][CH:28]([CH2:31]Br)[CH2:27][CH2:26]1)([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19]>CN(C=O)C.C(OCC)(=O)C>[Br:1][C:2]1[CH:10]=[CH:9][C:8]2[C:4](=[CH:5][N:6]([CH2:31][CH:28]3[CH2:29][CH2:30][N:25]([C:18]([O:20][C:21]([CH3:22])([CH3:24])[CH3:23])=[O:19])[CH2:26][CH2:27]3)[N:7]=2)[C:3]=1[CH3:11]
Reactant: CC(C)(C)OC(=O)N1CCC(CBr)CC1
Reactant: Cc1c(Br)ccc2[nH]ncc12
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Cc1c(Br)ccc2nn(CC3CCN(C(=O)OC(C)(C)C)CC3)cc12
Temperature: 60 °C
Reaction time: 8 h

Procedure:
5 g of 5-bromo-4-methyl-1H-indazole was dissolved in 110 ml DMF and treated with 11.5 g of caesium carbonate and 7.9 g of N-Boc-4-(bromomethyl)piperidine. The mixture was stirred for 3 hrs at 60° C. and overnight at RT. The reaction mixture was next diluted with ethyl acetate, and the organic phase was washed twice with water, dried over sodium sulphate, filtered and concentrated. The residue was purified chromatographically on the Biotage SP4 via a 65i-Si column Gradient: hexane/ethyl acetate 0-100%. Yield: 3.53 g of the title compound.
Reaction SMILES: C[O:2][C:3](=O)[C:4]([C:25]([F:28])([F:27])[F:26])=[C:5]([C:12]1[CH:17]=[CH:16][C:15]([O:18][CH:19]2[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]2)=[CH:14][CH:13]=1)[C:6](=O)[CH2:7][CH2:8][CH2:9][CH3:10].O.[NH2:31][NH2:32]>C(O)(=O)C>[CH2:7]([C:6]1[C:5]([C:12]2[CH:17]=[CH:16][C:15]([O:18][CH:19]3[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]3)=[CH:14][CH:13]=2)=[C:4]([C:25]([F:28])([F:27])[F:26])[C:3](=[O:2])[NH:31][N:32]=1)[CH2:8][CH2:9][CH3:10]
Reactant: NN
Reactant: CCCCC(=O)C(=C(C(=O)OC)C(F)(F)F)c1ccc(OC2CCCCC2)cc1
Solvent: CC(=O)O
Solvent: O
Product: CCCCc1n[nH]c(=O)c(C(F)(F)F)c1-c1ccc(OC2CCCCC2)cc1
Temperature: 100 °C
Yield: 119.3 %

Procedure:
To a stirred solution of 3-(4-cyclohexyloxy-phenyl)-4-oxo-2-trifluoromethyl-oct-2-enoic acid methyl ester (3.40 mmol, 1.4 g) in glacial acetic acid (3 mL) was added hydrazine hydrate (61.7 mmol, 3 mL) and the reaction was heated at 100° C. for 12 h. After cooling, the volatiles were under reduced pressure to give 1.6 g of crude 6-butyl-5-(4-cyclohexyloxy-phenyl)-4-trifluoromethyl-2H-pyridazin-3-one. The ketone was treated with phosphorous oxychloride (21.8 mmol, 2.0 mL) and heated at 90° C. for 1 hour with stirring. The reaction mixture was cooled to room temperature and the volatiles were removed under reduced pressure. The residue was dissolved in ethyl acetate (30 mL) and shaken with water (30 mL). The layers were separated and the organic layer was washed with saturated NaHCO3 (2×30 mL), brine (30 mL), dried (Na2SO4) filtered and concentrated under reduced pressure. The residue was purified on a 40 g SiO2 cartridge eluting with ethyl acetate/hexanes gradient to afford 3-butyl-6-chloro-4-(4-cyclohexyloxy-phenyl)-5-trifluoromethyl-pyridazine (0.65 g).
Reaction SMILES: [F:1][C:2]([F:42])([F:41])[C:3]1[CH:4]=[C:5]([C@H:13]([N:15]([CH3:40])[C:16]([N:18]2[CH2:31][CH2:30][C@:21]3([NH:25][C@H:24]([C:26]([O:28]C)=O)[CH2:23][CH2:22]3)[CH2:20][C@@H:19]2[C:32]2[CH:37]=[CH:36][C:35]([F:38])=[CH:34][C:33]=2[CH3:39])=[O:17])[CH3:14])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.CCOC(C)=O.C(Cl)Cl.[NH3:52]>CO>[F:10][C:9]([F:12])([F:11])[C:7]1[CH:6]=[C:5]([C@H:13]([N:15]([CH3:40])[C:16]([N:18]2[CH2:31][CH2:30][C@:21]3([NH:25][C@H:24]([C:26]([NH2:52])=[O:28])[CH2:23][CH2:22]3)[CH2:20][C@@H:19]2[C:32]2[CH:37]=[CH:36][C:35]([F:38])=[CH:34][C:33]=2[CH3:39])=[O:17])[CH3:14])[CH:4]=[C:3]([C:2]([F:1])([F:41])[F:42])[CH:8]=1
Reactant: COC(=O)[C@@H]1CC[C@@]2(CCN(C(=O)N(C)[C@H](C)c3cc(C(F)(F)F)cc(C(F)(F)F)c3)[C@@H](c3ccc(F)cc3C)C2)N1
Reactant: N
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: CO
Product: Cc1cc(F)ccc1[C@H]1C[C@]2(CC[C@@H](C(N)=O)N2)CCN1C(=O)N(C)[C@H](C)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Yield: 96 %

Procedure:
In a sealed tube a solution of Methyl (2S,5S,7R)-8-{[{(1R)-1-[3,5-bis(trifluoromethyl)phenyl]ethyl}(methyl)amino]carbonyl}-7-(4-fluoro-2-methylphenyl)-1,8-diazaspiro[4.5]decane-2-carboxylate (Intermediate 13, 24.1 mg, 0.04 mmol) in 7N Ammonia in MeOH (5 mL, 35.0 mmol) was stirred at 25° C. for 1 day. The solvent was evaporated to dryness and the crude was purified twice by silica cartridges (2 g) (1st time: with EtOAc and then 97.5:2.5 DCM/0.5 M NH3 in MeOH and 2nd time: from 98.75:1.25 to 95:5 DCM/0.5 M NH3 in MeOH) to give the title compound (22.5 mg, 0.038 mmol, 96% yield) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 7.92-8.05 (m, 1H) 7.61-7.77 (m, 2H) 7.21-7.27 (m, 1H) 7.13-7.19 (m, 1H) 6.87-6.97 (m, 2H) 6.73-6.83 (m, 1H) 5.25-5.37 (m, 1H) 4.08-4.20 (m, 1H) 3.44-3.55 (m, 1H) 3.26-3.38 (m, 1H) 2.57-2.85 (m, 4H) 2.26-2.36 (m, 3H) 1.98-2.16 (m, 1H) 1.41-1.82 (m, 10H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12](/[CH:13]=[CH:14]/[C:15]3[CH:16]=[C:17]([C:20]([OH:22])=O)[NH:18][N:19]=3)=[C:11]([CH3:23])[O:10][N:9]=2)=[CH:4][CH:3]=1.[CH:24]([NH2:27])([CH3:26])[CH3:25]>>[CH:24]([NH:27][C:20]([C:17]1[NH:18][N:19]=[C:15](/[CH:14]=[CH:13]/[C:12]2[C:8]([C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=3)=[N:9][O:10][C:11]=2[CH3:23])[CH:16]=1)=[O:22])([CH3:26])[CH3:25]
Reactant: CC(C)N
Reactant: Cc1onc(-c2ccc(F)cc2)c1/C=C/c1cc(C(=O)O)[nH]n1
Product: Cc1onc(-c2ccc(F)cc2)c1/C=C/c1cc(C(=O)NC(C)C)[nH]n1
Yield: 53 %

Procedure:
As described for example 132, 5-{(E)-2-[3-(4-fluoro-phenyl)-5-methyl-isoxazol-4-yl]-vinyl}-2H-pyrazole-3-carboxylic acid was converted, using isopropylamine instead of morpholine, to the title compound (28 mg, 53%) which was obtained as an off white solid. MS: m/e=355.2 [M+H]+.
Reaction SMILES: B.C1COCC1.[Cl:7][C:8]1[CH:17]=[C:16]([N:18]([CH2:25][CH:26]2[CH2:28][CH2:27]2)[C:19](=O)[C:20]([F:23])([F:22])[F:21])[CH:15]=[CH:14][C:9]=1[C:10](OC)=[O:11]>ClCCl.O>[Cl:7][C:8]1[CH:17]=[C:16]([N:18]([CH2:25][CH:26]2[CH2:28][CH2:27]2)[CH2:19][C:20]([F:22])([F:23])[F:21])[CH:15]=[CH:14][C:9]=1[CH2:10][OH:11]
Reactant: COC(=O)c1ccc(N(CC2CC2)C(=O)C(F)(F)F)cc1Cl
Agent: B
Solvent: C1CCOC1
Solvent: O
Solvent: ClCCl
Product: OCc1ccc(N(CC2CC2)CC(F)(F)F)cc1Cl
Temperature: 25 °C

Procedure:
Borane-THF complex (1.0M solution in THF, 13.7 ml) was added under ice-cooling to a solution of methyl 2-chloro-4-[cyclopropylmethyl(2,2,2-trifluoroacetyl)amino]benzoate (500 mg) in dichloromethane (10 ml). The reaction mixture was then refluxed overnight. After cooling to room temperature, the mixture was diluted with water and extracted with ethyl acetate. The organic layer was washed with brine and dried over anhydrous sodium sulfate.