Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([CH:7]([NH:20][C:21]2[CH:26]=[CH:25][C:24]([C:27]([N:29]([CH3:37])[CH2:30][CH2:31][C:32]([O:34]CC)=[O:33])=[O:28])=[CH:23][CH:22]=2)[C:8]2[O:9][C:10]3[CH:18]=[CH:17][C:16]([F:19])=[CH:15][C:11]=3[C:12]=2[O:13][CH3:14])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[OH-].[Na+]>C(O)C>[CH:1]1([CH:7]([NH:20][C:21]2[CH:22]=[CH:23][C:24]([C:27]([N:29]([CH3:37])[CH2:30][CH2:31][C:32]([OH:34])=[O:33])=[O:28])=[CH:25][CH:26]=2)[C:8]2[O:9][C:10]3[CH:18]=[CH:17][C:16]([F:19])=[CH:15][C:11]=3[C:12]=2[O:13][CH3:14])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CCOC(=O)CCN(C)C(=O)c1ccc(NC(c2oc3ccc(F)cc3c2OC)C2CCCCC2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: COc1c(C(Nc2ccc(C(=O)N(C)CCC(=O)O)cc2)C2CCCCC2)oc2ccc(F)cc12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 52.9 %

Procedure:
Ethyl 3-{[(4-{[cyclohexyl(5-fluoro-3-methoxy-1-benzofuran-2-yl)methyl]amino}phenyl)carbonyl](methyl)amino}propanoate (0.30 g) synthesized in the above-mentioned (4) was dissolved in ethanol (5 mL), 1N aqueous sodium hydroxide solution (1.0 mL) was added to the solution at room temperature, and the mixture was stirred at room temperature for 0.5 hr. Ethanol was evaporated under reduced pressure, and 1N hydrochloric acid (1.0 mL) was added to the residue. The precipitate was washed with water to give the title object compound (0.15 g, 52%) as a colorless solid.
Reaction SMILES: C(N(CC)C(=O)[O:5][C:6]1[CH:15]=[CH:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH:7]=1)C>C1COCC1>[CH:7]1[C:8]2[C:13](=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:14]=[CH:15][C:6]=1[OH:5]
Reactant: CCN(CC)C(=O)Oc1ccc2ccccc2c1
Solvent: C1CCOC1
Product: Oc1ccc2ccccc2c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 94.3 %

Procedure:
To a solution of naphthalen-2-yl diethylcarbamate (73.0 mg, 0.3 mmol) and Cp2ZrCl2 (265.8 mg, 0.9 mmol, 3 eq.) in THF (4 mL) at 0° C. was added 1 M THF solution of LiAlH(Ot-Bu)3 (0.9 mL, 0.9 mmol, 3 eq.). After addition, the resultant cloudy mixture was warmed to RT and stirred for 3 hours. The reaction was quenched by H2O. The procedures outlined in Example 1a regarding acidification, extraction, and purification were performed. Naphthalen-2-ol (40.8 mg, 95% yield) was obtained as a colorless solid. Its melting point was determined to be 120-121° C. (EtOAc/hexanes). NMR (400 MHz, CDCl3) δ ppm: 7.77 (m, 2H), 7.69 (d, J=8.23 Hz, 1H), 7.44 (td, J=7.52, 0.99 Hz, 1H), 7.34 (td, J=7.51, 0.98 Hz, 1H), 7.15 (d, J=2.33 Hz, 1H), 7.11 (dd, J=8.80, 2.51 Hz, 1H), 5.06 (brs, 1H). 13C NMR (101 MHz, CDCl3) δ ppm: 153.26, 134.55, 129.84, 128.93, 127.74, 126.51, 126.34, 123.61, 117.69, 109.48. The physical and spectral data were consistent with those reported by Morley et al. (see Morley, J. A.; Woolsey, N. F., J. Org. Chem. 1992, 57, 6487-95), who reported a melting point of 121-123° C.
Reaction SMILES: CC1(C)[O:6][C@H:5]([CH2:7][O:8][C:9]2[C:14]([CH3:15])=[CH:13][C:12]([C:16]3[N:20]=[C:19]([C:21]4[CH:26]=[C:25]([O:27][CH3:28])[N:24]=[C:23]([CH:29]([CH2:32][CH3:33])[CH2:30][CH3:31])[CH:22]=4)[O:18][N:17]=3)=[CH:11][C:10]=2[CH2:34][CH3:35])[CH2:4][O:3]1>Cl.O1CCOCC1>[CH2:34]([C:10]1[CH:11]=[C:12]([C:16]2[N:20]=[C:19]([C:21]3[CH:26]=[C:25]([O:27][CH3:28])[N:24]=[C:23]([CH:29]([CH2:32][CH3:33])[CH2:30][CH3:31])[CH:22]=3)[O:18][N:17]=2)[CH:13]=[C:14]([CH3:15])[C:9]=1[O:8][CH2:7][C@@H:5]([OH:6])[CH2:4][OH:3])[CH3:35]
Reactant: CCc1cc(-c2noc(-c3cc(OC)nc(C(CC)CC)c3)n2)cc(C)c1OC[C@@H]1COC(C)(C)O1
Agent: Cl
Solvent: C1COCCO1
Product: CCc1cc(-c2noc(-c3cc(OC)nc(C(CC)CC)c3)n2)cc(C)c1OC[C@@H](O)CO
Yield: 33.1 %

Procedure:
A solution of 4-{3-[4-((R)-2,2-dimethyl-[1,3]dioxolan-4-ylmethoxy)-3-ethyl-5-methyl-phenyl]-[1,2,4]oxadiazol-5-yl}-2-(1-ethyl-propyl)-6-methoxy-pyridine (250 mg, 504 μmol) in 4 M HCl in dioxane (10 mL) is stirred at rt for 90 min before it is concentrated. The crude product is purified on prep. TLC plates using DCM containing 10% of methanol to give the title compound (76 mg) as a pale brownish solid; LC-MS: tR=1.12 min, [M+H]+=456.12; 1H NMR (CDCl3): δ0.85 (t, J=7.0 Hz, 6H), 1.33 (t, J=7.0 Hz, 3H), 1.70-1.89 (m, 4H), 2.42 (s, 3H), 2.61-2.71 (m, 1H), 2.78 (q, J=7.3 Hz, 2H), 3.82-4.00 (m, 4H), 4.04 (s, 3H), 4.14-4.21 (m, 1H), 7.34 (s, 1H), 7.46 (s, 1H), 7.86-7.91 (m, 2H).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[S:10][C:11]1[CH:19]=[CH:18][CH:17]=[CH:16][C:12]=1[C:13]([OH:15])=[O:14])([O-])=O>C(OCC)(=O)C.[Pd]>[NH2:1][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[S:10][C:11]1[CH:19]=[CH:18][CH:17]=[CH:16][C:12]=1[C:13]([OH:15])=[O:14]
Reactant: O=C(O)c1ccccc1Sc1ccccc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CCOC(C)=O
Product: Nc1ccccc1Sc1ccccc1C(=O)O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 2-((2-nitrophenyl)thio)benzoic acid, prepared as described in the previous step, (43.3 g, 0.157 mol) in ethyl acetate (500 mL) was added Pd/C (8 g). The reaction solution was stirred at room temperature overnight under hydrogen gas atmosphere. The mixture was filtered and concentrated to provide the title compound.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12](B(O)O)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1.[C:64]1(=[O:70])[CH2:69][CH2:68][CH2:67][CH:66]=[CH:65]1.C(=O)([O-])O.[Na+]>O1CCOCC1.O>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH:66]2[CH2:67][CH2:68][CH2:69][C:64](=[O:70])[CH2:65]2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C1C=CCCC1
Reactant: OB(O)c1ccc(OCc2ccccc2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Agent: c1ccc(P(c2ccccc2)c2ccc3ccccc3c2-c2c(P(c3ccccc3)c3ccccc3)ccc3ccccc23)cc1
Solvent: C1COCCO1
Solvent: O
Product: O=C1CCCC(c2ccc(OCc3ccccc3)cc2)C1
Yield: 23 %

Procedure:
[4-(Benzyloxy)phenyl]boronic acid (2 g, 8.77 mmol) was dissolved in dioxane/water (50 mL/5 mL) and Rh(acac)(C2H4)2 (68 mg, 0.26 mmol) and racemic BINAP (164 mg, 0.26 mmol) were added. The mixture was degassed 3 times and put under a nitrogen atmosphere. Cyclohexenone (1.02 mL, 10.52 mmol) was added to the yellow solution and the mixture heated at reflux overnight. The reaction mixture was cooled, saturated aqueous sodium hydrogen carbonate solution (50 mL) added, then extracted with EtOAc (2×100 mL). The organic extracts were washed with water (100 mL) and dried. Volatile material was removed by evaporation and purification by chromatography gave the title compound (565 mg, 23%) as a solid; 1H NMR δ1.65-1.69 (1H, m), 1.78-1.93 (2H, m), 1.99-2.04 (1H, m), 2.22-2.35 (2H, m), 2.39-2.43 (1H, m), 2.65 (1H, m), 2.90-2.96 (1H, m), 5.08 (2H, s), 6.96 (2H, d), 7.20 (2H, d), 7.31-7.45 (5H, m); MS m/e MH+ 281.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:21]=[CH:22][CH:23]=1)[O:5][C:6]1[N:11]=[C:10]2[S:12][C:13]([NH:15][C:16]([CH:18]3[CH2:20][CH2:19]3)=[O:17])=[N:14][C:9]2=[CH:8][CH:7]=1.[CH3:24][N:25]1[CH:29]=[CH:28][N:27]=[C:26]1[C:30](O)=[O:31].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C>O.CN(C)C=O>[CH:18]1([C:16]([NH:15][C:13]2[S:12][C:10]3[C:9]([N:14]=2)=[CH:8][CH:7]=[C:6]([O:5][C:4]2[CH:3]=[C:2]([NH:1][C:30]([C:26]4[N:25]([CH3:24])[CH:29]=[CH:28][N:27]=4)=[O:31])[CH:23]=[CH:22][CH:21]=2)[N:11]=3)=[O:17])[CH2:20][CH2:19]1
Reactant: Nc1cccc(Oc2ccc3nc(NC(=O)C4CC4)sc3n2)c1
Reactant: Cn1ccnc1C(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: Cn1ccnc1C(=O)Nc1cccc(Oc2ccc3nc(NC(=O)C4CC4)sc3n2)c1
Temperature: 25 °C
Reaction time: 15 h
Yield: 65.3 %

Procedure:
A mixture of N-[5-(3-aminophenoxy)[1,3]thiazolo[5,4-b]pyridin-2-yl]cyclopropanecarboxamide (175 mg, 0.536 mmol), 1-methyl-1H-imidazole-2-carboxylic acid (101 mg, 0.804 mmol), HATU (367 mg, 0.965 mmol), N,N-diisopropylethylamine (420 μL, 2.41 mmol) and N,N-dimethylformamide (5 mL) was stirred at room temperature for 15 hr. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate and filtrated. The filtrate was concentrated under reduced pressure, and the residue was purified by column chromatography (silica gel, hexane/ethyl acetate=50/50→0/100) and recrystallized from ethyl acetate-tetrahydrofuran to give the title compound (152 mg, 65%) as a white solid.
Reaction SMILES: Br[C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4]1([CH2:26][O:25][C:24]3[CH:27]=[C:28]4[C:32](=[CH:33][C:23]1=3)[CH2:31][CH2:30][O:29]4)[C:5](=[O:22])[N:6]2[CH2:11][C:12]([NH:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[F:21])=[O:13].BrC1C=CC=C2C=1C1(C3=CC4OCOC=4C=C3OC1)C(=O)N2CCCCC.[N:61]1[CH:66]=[C:65](B(O)O)[CH:64]=[N:63][CH:62]=1.CN(C)C1N=CC(B(O)O)=CC=1>>[F:21][C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=1[NH:14][C:12](=[O:13])[CH2:11][N:6]1[C:7]2[C:3](=[C:2]([C:65]3[CH:66]=[N:61][CH:62]=[N:63][CH:64]=3)[CH:10]=[CH:9][CH:8]=2)[C:4]2([CH2:26][O:25][C:24]3[CH:27]=[C:28]4[C:32](=[CH:33][C:23]2=3)[CH2:31][CH2:30][O:29]4)[C:5]1=[O:22]
Reactant: OB(O)c1cncnc1
Reactant: O=C(CN1C(=O)C2(COc3cc4c(cc32)CCO4)c2c(Br)cccc21)Nc1ccccc1F
Agent: CCCCCN1C(=O)C2(COc3cc4c(cc32)OCO4)c2c(Br)cccc21
Agent: CN(C)c1ccc(B(O)O)cn1
Product: O=C(CN1C(=O)C2(COc3cc4c(cc32)CCO4)c2c(-c3cncnc3)cccc21)Nc1ccccc1F

Procedure:
Following the procedure as described in EXAMPLE 4, and making non-critical variations using 2-(4′-bromo-2′-oxo-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-1′(2′H)-yl)-N-(2-fluorophenyl)acetamide to replace 4′-bromo-1′-pentylspiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one, and pyrimidine-5-boronic acid to replace [6-(dimethylamino)pyridin-3-yl]boronic acid, the title compound was obtained (53%) as a colorless solid: mp 229-230° C.; 1H NMR (300 MHz, CDCl3) δ 9.10 (s, 1H), 8.26-8.15 (m, 3H), 7.98 (s, 1H), 7.41 (t, 1H), 7.15-7.05 (m, 4H), 6.89 (d, 1H), 6.68 (s, 1H), 6.06 (s, 1H), 4.81-4.76 (m, 2H), 4.59-4.42 (m, 4H), 3.00 (t, 2H); 13C NMR (75 MHz, CDCl3) 178.2, 164.4, 162.5, 161.0, 157.0, 155.8, 141.8, 132.6, 131.1, 129.4, 125.8, 125.5, 125.4, 125.2, 125.1, 124.7, 121.9, 120.6, 119.9, 118.7, 115.1, 114.8, 109.5, 93.4, 79.0, 72.4, 57.8, 44.9, 28.9; MS (ES+) m/z 509.5 (M+1).
Reaction SMILES: [CH2:1]([NH:4][CH2:5][CH:6]=[CH2:7])[CH:2]=[CH2:3].[F:8][C:9]([F:27])([F:26])[C:10]1[CH:11]=[C:12]([CH:23]=[CH:24][CH:25]=1)[O:13][C:14]1[N:22]=[CH:21][CH:20]=[CH:19][C:15]=1[C:16](Cl)=[O:17]>C1C=CC=CC=1>[F:8][C:9]([F:27])([F:26])[C:10]1[CH:11]=[C:12]([CH:23]=[CH:24][CH:25]=1)[O:13][C:14]1[N:22]=[CH:21][CH:20]=[CH:19][C:15]=1[C:16]([N:4]([CH2:5][CH:6]=[CH2:7])[CH2:1][CH:2]=[CH2:3])=[O:17]
Reactant: O=C(Cl)c1cccnc1Oc1cccc(C(F)(F)F)c1
Reactant: C=CCNCC=C
Solvent: c1ccccc1
Product: C=CCN(CC=C)C(=O)c1cccnc1Oc1cccc(C(F)(F)F)c1

Procedure:
In the same manner as in Example 1(a), 1.6 grams (0.016 mole) diallylamine and 2.5 grams (0.008 mole) 2-(3-trifluoromethylphenoxy)nicotinoyl chloride were mixed in 100 milliliters benzene to yield 1.6 grams (55.2% of theoretical yield) of the desired product, nD30 1.5003. The structure of this compound was confirmed by mass spectrometry.
Reaction SMILES: [OH:1][N:2]=[C:3]([NH2:16])[CH2:4][C:5]1[CH:14]=[CH:13][C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]=1[CH3:15].[S:17](Cl)(Cl)=[O:18]>C1(C)C=CC=CC=1>[CH3:15][C:6]1[C:7]2[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=2)[CH:13]=[CH:14][C:5]=1[CH2:4][C:3]1[NH:16][S:17](=[O:18])[O:1][N:2]=1
Reactant: O=S(Cl)Cl
Reactant: Cc1c(CC(N)=NO)ccc2ccccc12
Solvent: Cc1ccccc1
Product: Cc1c(CC2=NOS(=O)N2)ccc2ccccc12
Temperature: 80 °C
Yield: 55.7 %

Procedure:
A suspension of N'-hydroxy-2-(1-methylnaphthalenyl)ethanimidamide (2.8 g, 13.1 mmol) in toluene (250 mL) was heated to 80° C. until all of the solid had dissolved. Thionyl chloride (1.86 g, 15.7 mmol) was added dropwise to the above solution under a stream of nitrogen, and a white precipitate was formed. The mixture was heated to reflux for 15 minutes, during which the precipitate dissolved to give an orange solution. The hot solution was filtered to remove trace solids and the filtrate was concentrated in vacuo to give a yellow solid. Recrystallization from toluene gave the desired product (1.90 g, 56%) as a light yellow solid, m.p. 118°-119° C. (dec.).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]([N:10]2[CH2:15][CH2:14][CH:13]([N:16]3[CH2:20][CH2:19][CH2:18][CH2:17]3)[CH2:12][CH2:11]2)=[O:9])[C:5]([CH3:21])=[CH:4][C:3]=1[C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([C:28]([F:31])([F:30])[F:29])[CH:23]=1.[CH3:32][O:33][C:34]1[CH:41]=[CH:40][C:37]([CH2:38][NH2:39])=[CH:36][CH:35]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>C1(C)C=CC=CC=1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C1(P(C2C=CC=CC=2)C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH3:32][O:33][C:34]1[CH:41]=[CH:40][C:37]([CH2:38][NH:39][C:2]2[N:7]=[C:6]([C:8]([N:10]3[CH2:15][CH2:14][CH:13]([N:16]4[CH2:20][CH2:19][CH2:18][CH2:17]4)[CH2:12][CH2:11]3)=[O:9])[C:5]([CH3:21])=[CH:4][C:3]=2[C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([C:28]([F:31])([F:30])[F:29])[CH:23]=2)=[CH:36][CH:35]=1
Reactant: COc1ccc(CN)cc1
Reactant: Cc1cc(-c2cccc(C(F)(F)F)c2)c(Cl)nc1C(=O)N1CCC(N2CCCC2)CC1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Product: COc1ccc(CNc2nc(C(=O)N3CCC(N4CCCC4)CC3)c(C)cc2-c2cccc(C(F)(F)F)c2)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 80.8 %

Procedure:
A suspension of 1.25 g (2.8 mmol) of [6-chloro-3-methyl-5-(3-trifluoromethyl-phenyl)-pyridin-2-yl]-(4-pyrrolidin-1-yl-piperidin-1-yl)-methanone (example 3), 0.069 g (0.1 mmol) of [rac]-2,2′-bis(diphenylphosphino)-1,1′-binaphthyl, 0.025 g (0.1 mmol) of palladium(II) acetate and 0.40 g (2.9 mmol) of 4-methoxy-benzylamine in 30 ml of toluene was stirred at RT; 1.08 g (3.3 mmol) of cesium carbonate was added and the reaction mixture subsequently heated up to reflux. After 18 hours, it was cooled down to RT, poured into crashed ice and extracted twice with EtOAc; the organic phases were washed with water, dried over magnesium sulfate, filtered and evaporated. The residue was purified by flash column chromatography (CH2Cl2/MeOH 1:0 to 9:1) to give 1.25 g (82%) of the title compound as light yellow solid. MS: 553.3 (MH+).
Reaction SMILES: FC(F)(F)C([NH:5][C:6]1[N:7]=[C:8]2[CH:13]=[CH:12][C:11]([C:14](=[O:21])[C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)=[CH:10][N:9]2[C:22]=1[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[C:29]([F:32])([F:31])[F:30])=O>CC(=O)OCC>[NH2:5][C:6]1[N:7]=[C:8]2[CH:13]=[CH:12][C:11]([C:14](=[O:21])[C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=3)=[CH:10][N:9]2[C:22]=1[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[C:29]([F:32])([F:30])[F:31]
Reactant: O=C(c1ccccc1)c1ccc2nc(NC(=O)C(F)(F)F)c(-c3ccccc3C(F)(F)F)n2c1
Solvent: CCOC(C)=O
Product: Nc1nc2ccc(C(=O)c3ccccc3)cn2c1-c1ccccc1C(F)(F)F

Procedure:
The 2-trifluoroacetamido-3-(2-trifluoromethylphenyl)-6-benzoyl-imidazo[1,2-a]pyridine (6.22 g, 13.0 mmol) was converted to product in a manner substantially analogous to Example 67 to yield 4.25 g. (85.5%). EA, MS(FD).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][N:3]=[C:2]1[C:6]1[N:11]=[C:10]([CH2:12][OH:13])[CH:9]=[CH:8][CH:7]=1>C(Cl)Cl.O=[Mn]=O>[S:1]1[CH:5]=[CH:4][N:3]=[C:2]1[C:6]1[N:11]=[C:10]([CH:12]=[O:13])[CH:9]=[CH:8][CH:7]=1
Reactant: OCc1cccc(-c2nccs2)n1
Agent: O=[Mn]=O
Solvent: ClCCl
Product: O=Cc1cccc(-c2nccs2)n1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of (6-(thiazol-2-yl)pyridin-2-yl)methanol (171 mg; 0.89 mmol) in anh. DCM (6 ml) was treated with MnO2 (1.164 g; 13.38 mmol), and the resulting mixture was stirred at rt, under nitrogen, for 2 h. The resulting reaction mixture was then filtered over celite, and the separated solids were washed with DCM. The filtrate was concentrated to dryness under reduced pressure giving 6-(thiazol-2-yl)picolinaldehyde as a yellow solid. LC-MS (conditions A): tR=0.62 min.; [M+H]+: 191.08 g/mol.
Reaction SMILES: [NH:1]1[CH2:8][CH2:7][CH2:6][C@H:2]1[C:3]([OH:5])=[O:4].[OH-].[K+].[CH2:11](Cl)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.Cl>C(O)(C)C>[CH2:11]([N:1]1[CH2:8][CH2:7][CH2:6][C@H:2]1[C:3]([OH:5])=[O:4])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: O=C(O)[C@@H]1CCCN1
Reactant: ClCc1ccccc1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CC(C)O
Product: O=C(O)[C@@H]1CCCN1Cc1ccccc1

Procedure:
A solution of 10 g of L-proline and KOH (10 g) in 120 mL isopropanol was stirred at 40° C., then benzyl chloride (13.5 mL) was added dropwise. The reaction mixture was stirred for 6 additional hours, then neutralized with concentrated HCl to a pH of 5-6. The reaction mixture was extracted with CH2Cl2 (3×70 mL), the combined organic layers were washed with brine, dried over anhydrous magnesium sulfate, the solids were removed by filtration and the solvents of the filtrate were removed under reduced pressure. The residue was treated with acetone to afford N-benzyl proline (15 g).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[C:9]([F:12])([F:11])[F:10].F[C:14]1[CH:21]=[CH:20][C:19]([CH:22]=[O:23])=[CH:18][C:15]=1[C:16]#[N:17].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.CC(=O)OCC>[F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:14]2[CH:21]=[CH:20][C:19]([CH:22]=[O:23])=[CH:18][C:15]=2[C:16]#[N:17])=[CH:4][C:3]=1[C:9]([F:10])([F:11])[F:12]
Reactant: N#Cc1cc(C=O)ccc1F
Reactant: Oc1ccc(F)c(C(F)(F)F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: N#Cc1cc(C=O)ccc1Oc1ccc(F)c(C(F)(F)F)c1
Temperature: 130 °C
Yield: 101.4 %

Procedure:
A mixture of 4-fluoro-3-(trifluoromethyl)phenol (1 g, 5.55 mmol), 2-fluoro-5-formylbenzonitrile (0.828 g, 5.55 mmol) and K2CO3 (0.921 g, 6.66 mmol) in DMF (10 mL) was heated with a microwave condition at 130° C. for 2 h. The solution was diluted with EA and washed with water twice, dried over Na2SO4 and concentrated in vacuo to afford the title compound (1.74 g, 101% yield) as a brown oil. LCMS: rt=3.38 min, [M+H+]=310
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([C:17]4([C:22]5[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=5)[CH2:19][CH:18]4[CH2:20][NH2:21])=[CH:14][CH:15]=3)[CH:10]=[N:9]2)=[CH:4][CH:3]=1.[F:28][C:29]([F:35])([F:34])[CH2:30][C:31](O)=[O:32]>>[F:28][C:29]([F:35])([F:34])[CH2:30][C:31]([NH:21][CH2:20][CH:18]1[CH2:19][C:17]1([C:13]1[CH:12]=[C:11]2[C:16](=[CH:15][CH:14]=1)[N:8]([C:5]1[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=1)[N:9]=[CH:10]2)[C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1)=[O:32]
Reactant: O=C(O)CC(F)(F)F
Reactant: NCC1CC1(c1ccccc1)c1ccc2c(cnn2-c2ccc(F)cc2)c1
Product: O=C(CC(F)(F)F)NCC1CC1(c1ccccc1)c1ccc2c(cnn2-c2ccc(F)cc2)c1
Yield: 85.6 %

Procedure:
(2-(1-(4-Fluorophenyl)-1H-indazol-5-yl)-2-phenylcyclopropyl)methanamine (71 mg, 0.15 mmol) was coupled with 3,3,3-trifluoropropanoic acid (38 mg, 0.2 mmol) using General Coupling Method A to give 60 mg (86% yield) of 3,3,3-trifluoro-N-((2-(1-(4-fluorophenyl)-1H-indazol-5-yl)-2-phenylcyclopropyl)methyl) propanamide. MS found: (M+H)+=468.
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([C@H:10]2[CH2:15][CH2:14][C@H:13]([CH:16]3[CH2:21][CH2:20][CH:19]([CH:22]=[O:23])[CH2:18][CH2:17]3)[CH2:12][CH2:11]2)=[CH:6][C:5]=1[F:24].CO.[OH-].[Na+].O>C(Cl)Cl.C(N(CC)CC)C>[CH3:1][O:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([C@H:10]2[CH2:11][CH2:12][C@H:13]([C@H:16]3[CH2:21][CH2:20][C@H:19]([CH:22]=[O:23])[CH2:18][CH2:17]3)[CH2:14][CH2:15]2)=[CH:6][C:5]=1[F:24]
Reactant: COCc1ccc([C@H]2CC[C@H](C3CCC(C=O)CC3)CC2)cc1F
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCN(CC)CC
Solvent: CO
Product: COCc1ccc([C@H]2CC[C@H]([C@H]3CC[C@H](C=O)CC3)CC2)cc1F
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of 1.11 g of 4-[trans-4-(4-formylcyclohexyl)-cyclohexyl]-2-fluorobenzyl methyl ether (cis/trans=4:1) in 1.5 ml of methylene chloride was treated in succession with a few drops of triethylamine, 12 ml of methanol and 0.45 ml of 20 percent sodium hydroxide solution and stirred at room temperature for 30 minutes. Then, the reaction mixture was poured into 50 ml of water and extracted with methylene chloride. The organic phase was dried over sodium carbonate, filtered and the filtrate was evaporated. Crystallization from hexane gave 0.53 of pure 4-[trans-4-(trans-4-formylcyclohexyl)cyclohexyl]-2-fluorobenzyl methyl ether, m.p. 52°-54° C.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][OH:4].[CH:5]1([C:8]2[N:13]=[C:12]([C:14]([NH:16][C:17]3[CH:25]=[N:24][CH:23]=[CH:22][C:18]=3[C:19](O)=[O:20])=[O:15])[C:11]([NH:26][C:27]3[CH:28]=[N:29][CH:30]=[N:31][CH:32]=3)=[CH:10][CH:9]=2)[CH2:7][CH2:6]1>>[OH:4][CH2:3][CH2:2][NH:1][C:19]([C:18]1[CH:22]=[CH:23][N:24]=[CH:25][C:17]=1[NH:16][C:14]([C:12]1[C:11]([NH:26][C:27]2[CH:28]=[N:29][CH:30]=[N:31][CH:32]=2)=[CH:10][CH:9]=[C:8]([CH:5]2[CH2:7][CH2:6]2)[N:13]=1)=[O:15])=[O:20]
Reactant: NCCO
Reactant: O=C(O)c1ccncc1NC(=O)c1nc(C2CC2)ccc1Nc1cncnc1
Product: O=C(NCCO)c1ccncc1NC(=O)c1nc(C2CC2)ccc1Nc1cncnc1
Yield: 36 %

Procedure:
According to the general method described in step 3 of example 53, reaction of 2-aminoethanol with 3-{[6-cyclopropyl-3-(pyrimidin-5-ylamino)-pyridine-2-carbonyl]-amino}-isonicotinic acid provided the title compound (36%) as amorphous yellow solid.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C@H:10]([NH:12][C:13](=[O:19])[O:14][C:15]([CH3:18])([CH3:17])[CH3:16])[CH3:11])=[CH:6][CH:5]=1)([O-])=O>CO.[Pd]>[NH2:1][C:4]1[CH:9]=[CH:8][C:7]([C@H:10]([NH:12][C:13](=[O:19])[O:14][C:15]([CH3:18])([CH3:17])[CH3:16])[CH3:11])=[CH:6][CH:5]=1
Reactant: C[C@@H](NC(=O)OC(C)(C)C)c1ccc([N+](=O)[O-])cc1
Agent: [Pd]
Solvent: CO
Product: C[C@@H](NC(=O)OC(C)(C)C)c1ccc(N)cc1
Yield: 78 %

Procedure:
A solution of C1 (1.0 g, 3.8 mmol) in MeOH (20 mL) was charged to a Parr reactor, and the contents of the reactor were treated with 10% Pd/C (800 mg, 0.376 mmol). The contents of the reactor were then hydrogenated at 45 Psi hydrogen pressure and 25° C. for 4 hours. The contents of the reactor were filtered through Celite® and washed with DCM. The combined filtrates were concentrated to provide C2 as a sticky orange residue. Yield: 690 mg, 78% yield. GC-MS=236. 1H NMR (500 MHz, d6-DMSO) δ: 7.07 (d, 1H), 6.88 (d, 2H), 6.43 (d, 2H), 4.85 (s, 2H), 4.40 (m, 1H), 1.31 (s, 9H), 1.18 (d, 3H).
Reaction SMILES: [C:1]([C:3]1[C:4](=[O:21])[NH:5][N:6]=[C:7]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:8]=1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)#[N:2].[CH2:22]([S:24]([CH:27]=[CH2:28])(=[O:26])=[O:25])[CH3:23]>N1C=CC=CC=1>[CH2:22]([S:24]([CH2:27][CH2:28][N:5]1[C:4](=[O:21])[C:3]([C:1]#[N:2])=[C:8]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:7]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[N:6]1)(=[O:26])=[O:25])[CH3:23]
Reactant: N#Cc1c(-c2ccccc2)c(-c2ccccc2)n[nH]c1=O
Reactant: C=CS(=O)(=O)CC
Solvent: c1ccncc1
Product: CCS(=O)(=O)CCn1nc(-c2ccccc2)c(-c2ccccc2)c(C#N)c1=O
Yield: 72.7 %

Procedure:
8.0 grams (0.0175 mole) of the product of Example 1 was reacted with 2.1 grams of ethyl-vinyl sulfone in 60 mls of pyridine. This solution was heated on a steam bath for 2 hours, cooled and the solvent distilled at reduced pressure. The residual oil was taken up in ethyl alcohol. 5.0 grams (72% yield) of a solid precipitated and was filtered, washed with petroleum ether and air dried. The infrared spectrum showed the nitrile band at 4.5μ, the carbonyl band at 6.0μ, the SO2 band at 8.7μ.
Reaction SMILES: [NH:1]1[CH2:4][CH2:3][CH2:2]1.C[O:6][C:7]([C:9]1[C:13]([NH:14][C:15]([C:17]2[C:22]([NH:23][C:24]3[CH:25]=[N:26][CH:27]=[N:28][CH:29]=3)=[CH:21][CH:20]=[C:19]([CH:30]3[CH2:32][CH2:31]3)[N:18]=2)=[O:16])=[CH:12][N:11]([CH3:33])[N:10]=1)=O>>[N:1]1([C:7]([C:9]2[C:13]([NH:14][C:15]([C:17]3[C:22]([NH:23][C:24]4[CH:25]=[N:26][CH:27]=[N:28][CH:29]=4)=[CH:21][CH:20]=[C:19]([CH:30]4[CH2:32][CH2:31]4)[N:18]=3)=[O:16])=[CH:12][N:11]([CH3:33])[N:10]=2)=[O:6])[CH2:4][CH2:3][CH2:2]1
Reactant: C1CNC1
Reactant: COC(=O)c1nn(C)cc1NC(=O)c1nc(C2CC2)ccc1Nc1cncnc1
Product: Cn1cc(NC(=O)c2nc(C3CC3)ccc2Nc2cncnc2)c(C(=O)N2CCC2)n1
Yield: 14 %

Procedure:
According to the general method described in step 5 of example 27, reaction of azetidine with 4-{[6-cyclopropyl-3-(pyrimidin-5-ylamino)-pyridine-2-carbonyl]-amino}-1-methyl-1H-pyrazole-3-carboxylic acid methyl ester provided the title compound (14%) as amorphous yellow solid.