Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][N:5]([CH:7]2[CH2:12][CH2:11][CH2:10][CH2:9][O:8]2)[CH:6]=1.C(=O)([O-])[O-].[Na+].[Na+].[N:19]1[CH:24]=[CH:23][C:22](B(O)O)=[CH:21][CH:20]=1>O1CCOCC1.O.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>[O:8]1[CH2:9][CH2:10][CH2:11][CH2:12][CH:7]1[N:5]1[CH:6]=[C:2]([C:22]2[CH:23]=[CH:24][N:19]=[CH:20][CH:21]=2)[CH:3]=[N:4]1
Reactant: OB(O)c1ccncc1
Reactant: Brc1cnn(C2CCCCO2)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: c1cc(-c2cnn(C3CCCCO3)c2)ccn1
Temperature: 80 °C
Yield: 68 %

Procedure:
A mixture of tetrakis(triphenylphosphine)palladium(0) (0.025 eq, 4.22 mmol), 4-bromo-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole (1 eq, 0.17 mol, synthesis described in US2009/203705), sodium carbonate (675 mL, 2.0 M solution in water, 1.35 mol) and 4-pyridine boronic acid (1.2 eq, 0.21 mol) in dioxane (2000 mL) was heated under argon 41 h at 80° C. After that time, the reaction mixture was diluted with water (50 mL) and the volatiles were reduced in vacuo to a quarter of the volume. The crude was extracted with ethyl acetate and the combined organic fractions were washed with brine, dried over MgSO4 and evaporated. The obtained crude material was purified by bulb-to-bulb distillation (bp 130-135° C. at 0.02 mm Hg) and 26.37 g (68%) 4-[1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl]pyridine were obtained as slightly yellow viscuous oil.
Reaction SMILES: C(C1SCCS1)CCCC.[S].C1(C)C=CC(S(O)(=O)=O)=CC=1.[H][H].CCCCCCSCCS.[CH3:35][O:36][Si:37]([O:47][CH3:48])([O:45][CH3:46])[CH2:38][CH2:39][CH:40]1[S:44][CH2:43][CH2:42][S:41]1>C1(C)C=CC=CC=1>[Si:37]([CH2:38][CH2:39][CH2:40][S:41][CH2:42][CH2:43][SH:44])([O:47][CH3:48])([O:36][CH3:35])[O:45][CH3:46]
Reactant: CO[Si](CCC1SCCS1)(OC)OC
Reactant: [H][H]
Agent: CCCCCC1SCCS1
Agent: CCCCCCSCCS
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: CO[Si](CCCSCCS)(OC)OC

Procedure:
Into a 300 ml rocking autoclave were charged 58.2 g (0.331 m) of 2-(n-pentyl)-1,3-dithiolane, 1.06 g of sulfur, 0.12 g of p-toluenesulfonic acid, and 1.87 g of cobalt polysulfide catalyst (added as a 43% slurry in toluene). The autoclave was pressurized with hydrogen and maintained between 1600 and 2200 psi while being heated to 250°. After cooling and venting, the crude product contained 57% of the hydrogenolysis product, CH3(CH2)5S(CH2)2SH, as determined by GC/MS. When this procedure is applied to the product of Example 1, the hydrogenolysis product, (MeO)3Si(CH2)3S(CH2)2SH, is obtained.
Reaction SMILES: [CH2:1]([O:3][C:4]([NH:6][N:7]=[CH:8][CH2:9][CH:10]1[CH2:12][CH2:11]1)=[O:5])[CH3:2]>CCO.[Pt]>[CH2:1]([O:3][C:4]([NH:6][NH:7][CH2:8][CH2:9][CH:10]1[CH2:11][CH2:12]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)NN=CCC1CC1
Agent: [Pt]
Solvent: CCO
Product: CCOC(=O)NNCCC1CC1
Temperature: 25 °C
Reaction time: 12 h
Yield: 91.3 %

Procedure:
N′-(2-cyclopropylethylidene)hydrazinecarboxylic acid ethyl ester (4a) (1.5 g, 8.9 mmol) was dissolved in 35 mL EtOH and to this solution was added 5% Pt/C (0.2 g, 0.9 mol). The atmosphere in the flask was evacuated and replaced three times with H2. The reaction was stirred at room temperature for 12 h under a slightly positive pressure of H2, upon which it was filtered through neutral alumina and concentrated to afford 1.4 g (93%) of the desired product (La) as a clear colorless liquid. 1H-NMR (400 MHz, CDCl3): 4.18 (q, 2H, J=7.0 Hz); 3.00 (t, 2H, J=7.0 Hz) 1.42 (q, 2H, J=7.0 Hz); 1.29 (t, 3H, J=7.2 Hz); 0.73 (m, 1H); 0.1 (d, 2H); 0.47 (m, 2H); 0.08 (m, 2H) ppm.
Reaction SMILES: [OH:1][B:2]1[C:6]2[CH:7]=[CH:8][C:9]([O:11][C:12]3[CH:20]=[CH:19][C:15]([C:16](O)=[O:17])=[CH:14][CH:13]=3)=[CH:10][C:5]=2[CH2:4][O:3]1.C1N=C[N:23](C(N2C=NC=C2)=O)C=1.C(=O)([O-])[O-].[NH4+].[NH4+].O>CN(C=O)C>[OH:1][B:2]1[C:6]2[CH:7]=[CH:8][C:9]([O:11][C:12]3[CH:20]=[CH:19][C:15]([C:16]([NH2:23])=[O:17])=[CH:14][CH:13]=3)=[CH:10][C:5]=2[CH2:4][O:3]1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: O=C(O)c1ccc(Oc2ccc3c(c2)COB3O)cc1
Agent: O=C([O-])[O-]
Agent: [NH4+]
Solvent: O
Solvent: CN(C)C=O
Product: NC(=O)c1ccc(Oc2ccc3c(c2)COB3O)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a 40 mL scintillation vial containing 4-(1-hydroxy-1,3-dihydro-benzo[c][1,2]oxaborol-5-yloxy)-benzoic acid (77 mg, 0.28 mmol, 1.0 eq.) and CDI (101.3 mg, 0.62 mmol), 2.5 eq.) in DMF (3.0 mL) was added Ammonium carbonate (123.3 mg, 1.28 mmol, 4.5 eq.). The mixture was stirred at room temperature overnight. The mixture was treated with H2O (5 mL) and the layers were separated. The aqueous was extracted with EtOAc (2×5 mL), combined organic phase was washed with brine (10 mL), dried over MgSO4, filtered and the filtrate was concentrated under reduced pressure. The residue was applied to silica chromatography eluting with MeOH/DCM (0:100 to 10:90) to give 4-(1-hydroxy-1,3-dihydro-benzo[c][1,2]oxaborol-5-yloxy)-benzamide as a white solid. LCMS (m/z) 270 (M+H); 1H NMR (DMSO-d6) δ: 9.14 (s, 1H), 7.87-7.92 (m, 2H), 7.73 (d, J=7.8 Hz, 1H), 7.05 (d, J=8.8 Hz, 4H), 4.93 (s, 2H).
Reaction SMILES: C1(C2C=CC(C[NH:9][CH2:10][CH2:11][C:12]3[CH:17]=[CH:16][C:15](F)=[C:14](C(F)(F)F)[CH:13]=3)=CC=2)CC1.[CH3:25][C:26]1([CH3:37])[C:34]2[C:29](=[CH:30][C:31]([CH:35]=O)=[CH:32][CH:33]=2)[CH2:28][CH2:27]1.C(N)CC1C=CC=CC=1.[BH4-].[Na+]>>[CH3:25][C:26]1([CH3:37])[C:34]2[C:29](=[CH:30][C:31]([CH2:35][NH:9][CH2:10][CH2:11][C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[CH:32][CH:33]=2)[CH2:28][CH2:27]1
Reactant: CC1(C)CCc2cc(C=O)ccc21
Reactant: Fc1ccc(CCNCc2ccc(C3CC3)cc2)cc1C(F)(F)F
Agent: NCCc1ccccc1
Agent: [BH4-]
Agent: [Na+]
Product: CC1(C)CCc2cc(CNCCc3ccccc3)ccc21
Yield: 83 %

Procedure:
The title compound was synthesized in analogy to (4-cyclopropylbenzyl)-[2-(4-fluoro-3-trifluoromethylphenyl)-ethyl]-amine (described in example S53) using 1,1-dimethylindan-5-carbaldehyde (prepared as described in example S100) (197 mg, 0.56 mmol), phenethylamine (67 mg, 0.56 mmol) and sodium borohydride (32 mg, 0.84 mmol). The desired product (129 mg, 83%) was isolated without further purification as a colorless oil. MS (ISP) 280.2 (M+H)+.
Reaction SMILES: [CH2:1]([N:8]1[CH2:17][C:16]2[NH:15][C:14](C)=[C:13]([C:19]([O:21][CH3:22])=[O:20])[CH:12]([C:23]3[CH:28]=[CH:27][C:26]([F:29])=[C:25]([Br:30])[CH:24]=3)[C:11]=2[C:10](=[O:31])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Br-].[Br-].[Br-].[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1>C(Cl)(Cl)Cl>[CH2:1]([N:8]1[CH2:17][C:16]2[NH:15][C:14]3[CH2:22][O:21][C:19](=[O:20])[C:13]=3[CH:12]([C:23]3[CH:28]=[CH:27][C:26]([F:29])=[C:25]([Br:30])[CH:24]=3)[C:11]=2[C:10](=[O:31])[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)C1=C(C)NC2=C(C(=O)CN(Cc3ccccc3)C2)C1c1ccc(F)c(Br)c1
Agent: [Br-]
Agent: c1cc[nH+]cc1
Solvent: ClC(Cl)Cl
Product: O=C1CN(Cc2ccccc2)CC2=C1C(c1ccc(F)c(Br)c1)C1=C(COC1=O)N2
Reaction time: 16 h
Yield: 71 %

Procedure:
A solution of the product from Example 39A (3.1 g, 6.3 mmol) in chloroform (50 mL) was cooled to 0° C., treated with 90% pyridinium tribromide (2.45 g, 6.9 mmol), warmed to abmient temperature, stirred for 16 hours and washed with water. The chloroform layer was isolated, dried (MgSO4), filtered, refluxed for 16 hours and cooled in an ice bath. The resulting precipitate was collected by filtration and dried to provide the title compound (2.1 g) as tan crystals.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:13]2[C:12]3[CH:14]=[CH:15][C:16]([N+:18]([O-])=O)=[CH:17][C:11]=3[CH2:10][O:9][CH2:8][C:7]=2[CH:6]=[C:5]([O:21][CH3:22])[C:4]=1[O:23][CH3:24]>C(OCC)(=O)C.[Pd]>[CH3:22][O:21][C:5]1[C:4]([O:23][CH3:24])=[C:3]([O:2][CH3:1])[C:13]2[C:12]3[CH:14]=[CH:15][C:16]([NH2:18])=[CH:17][C:11]=3[CH2:10][O:9][CH2:8][C:7]=2[CH:6]=1
Reactant: COc1cc2c(c(OC)c1OC)-c1ccc([N+](=O)[O-])cc1COC2
Agent: [Pd]
Solvent: CCOC(C)=O
Product: COc1cc2c(c(OC)c1OC)-c1ccc(N)cc1COC2
Reaction time: 24 h
Yield: 90 %

Procedure:
1,2,3-Trimethoxy-9-nitro-5,7-dihydrodibenzo[c,e]oxepine (Example 5, 85.4 mg, 0.258 mmol) in ethyl acetate (4 mL) containing palladium on charcoal (10% w/w; 7 mg) was stirred under a hydrogen balloon for 24 hours until TLC indicated the consumption of starting material. The mixture was passed through a plug of neutral alumina (0.5 cm depth in a Pasteur pipette) and concentrated in vacuo to afford the title compound as a yellow crystalline solid (70 mg, 91%); m.p. 145° C.; High Resolution Mass Spectrometry Found: M 301.1305 (C17H19NO4 requires 301.1314); νmax/cm−1 (thin film) 3461, 3361, 2938, 2852, 1607, 1482; NMR Spectrum δH (400 MHz, CDCl3) 3.66 (3H, s, OCH3), 3.78 (2H, br s, NH2), 3.91 (3H, s, OCH3), 3.94 (3H, s, OCH3), 4.03-4.18 (2H, br m, 5-H or 7-H), 4.30-4.44 (2H, br m, 5-H or 7-H), 6.74 (1H, s, 8-H), 6.745 (1H, d, J 2.5 Hz, 4-H), 6.77 (1H, dd, J 2.5, 8.2 Hz, 2-H), 7.52 (1H, d, J 8.2 Hz, 1-H); NMR Spectrum δC (100 MHz, CDCl3) 56.44, 61.12, 61.50, 68.11, 68.15, 109.08, 115.26, 116.12, 127.20, 127.47, 130.97, 131.34, 136.64, 143.09, 150.92, 152.79; m/z (ES) 301 (M, 20%); Rf (petroleum ether 60-80°—ethyl acetate 2:3) 0.32.
Reaction SMILES: [F:1][C:2]1[CH:3]=[N:4][C:5]2[CH:6]=[CH:7][C:8](=[O:30])[N:9]3[CH2:13][C:12]([CH2:15][N:16]4[CH2:21][CH2:20][CH:19]([NH:22]C(=O)OC(C)(C)C)[CH2:18][CH2:17]4)([F:14])[C:11]=1[C:10]=23.[ClH:31].O1CCOCC1>ClCCl.CO>[ClH:31].[ClH:31].[NH2:22][CH:19]1[CH2:18][CH2:17][N:16]([CH2:15][C:12]2([F:14])[C:11]3=[C:2]([F:1])[CH:3]=[N:4][C:5]4[CH:6]=[CH:7][C:8](=[O:30])[N:9]([C:10]=43)[CH2:13]2)[CH2:21][CH2:20]1
Reactant: CC(C)(C)OC(=O)NC1CCN(CC2(F)Cn3c(=O)ccc4ncc(F)c2c43)CC1
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Solvent: CO
Product: NC1CCN(CC2(F)Cn3c(=O)ccc4ncc(F)c2c43)CC1

Procedure:
A solution of 1,1-dimethylethyl {1-[((4R/S)-3,4-difluoro-7-oxo-4,5-dihydro-7H-pyrrolo[3,2,1-de]-1,5-naphthyridin-4-yl)methyl]-4-piperidinyl}carbamate (98 mg, 0.23 mmol) in dichloromethane (2 ml) and methanol (1.5 ml), was treated with hydrochloric acid in 1,4-dioxane (4M, 3.5 ml, 14 mmol). After 1.5 hours the mixture was evaporated affording the product (82 mg).
Reaction SMILES: [CH:1]1([CH2:5][O:6][C:7]2[CH:15]=[CH:14][CH:13]=[C:12]3[C:8]=2[CH:9]=[C:10]([C:16]([OH:18])=[O:17])[NH:11]3)[CH2:4][CH2:3][CH2:2]1.[CH3:19][O:20][C:21]1[N:26]=[CH:25]C(CCO)=CC=1.C(OC(C1NC2C(C=1)=C(O)C=CC=2)=O)C>>[CH3:19][O:20][C:21]1[N:26]=[CH:25][C:4]([CH2:1][CH2:5][O:6][C:7]2[CH:15]=[CH:14][CH:13]=[C:12]3[C:8]=2[CH:9]=[C:10]([C:16]([OH:18])=[O:17])[NH:11]3)=[CH:3][CH:2]=1
Reactant: O=C(O)c1cc2c(OCC3CCC3)cccc2[nH]1
Reactant: COc1ccc(CCO)cn1
Agent: CCOC(=O)c1cc2c(O)cccc2[nH]1
Product: COc1ccc(CCOc2cccc3[nH]c(C(=O)O)cc23)cn1

Procedure:
4-[2-(6-Methoxy-pyridin-3-yl)-ethoxy]-1H-indole-2-carboxylic acid (16n) is synthesized analogous to 16a from 4-[2-(6-methoxy-pyridin-3-yl)-ethanol and 4-hydroxy-1H-indole-2-carboxylic acid ethyl ester.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH:15]=[CH:14][C:13](=[O:16])[NH:12][C:11]2=[O:17])=[CH:6][CH:5]=1)([O-:3])=[O:2].[OH-].[K+].Br[CH2:21][CH3:22]>CN(C)C(=O)C>[CH2:21]([N:12]1[C:13](=[O:16])[CH:14]=[CH:15][N:10]([C:7]2[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:9][CH:8]=2)[C:11]1=[O:17])[CH3:22]
Reactant: O=c1ccn(-c2ccc([N+](=O)[O-])cc2)c(=O)[nH]1
Reactant: CCBr
Agent: [K+]
Agent: [OH-]
Solvent: CC(=O)N(C)C
Product: CCn1c(=O)ccn(-c2ccc([N+](=O)[O-])cc2)c1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 65.6 %

Procedure:
A mixture of 3 parts of 1-(4-nitrophenyl)-2,4(1H,3H)-pyrimidinedione, 1,4 parts of potassium hydroxide and 67.5 parts of N,N-dimethylacetamide was stirred for 1 hour at room temperature under nitrogen atmosphere. 1.52 Parts of bromoethane were added and stirring was continued overnight at room temperature. The reaction mixture was poured into 100 parts of ice water. The product was filtered off and stirred in methanol. The product was filtered off and dried in vacuo at 60° C., yielding 2.4 parts (65.6%) of 3-ethyl-1-(4-nitro-phenyl)-2,4(1H,3H)-pyrimidinedione; mp. 182.5° C. (int. 24).
Reaction SMILES: CN(C)C(C)(C)COC1C=CC(C=O)=CC=1.[CH3:17][N:18]([CH3:61])[C:19]([CH3:60])([CH3:59])[CH2:20][O:21][C:22]1[CH:58]=[CH:57][C:25]([CH2:26][CH2:27][CH2:28][NH:29][C:30]2[CH:35]=[C:34]([O:36][CH3:37])[C:33]([O:38][CH3:39])=[CH:32][C:31]=2[C@@H:40]2[CH2:49][CH2:48][C:47]3[CH:46]=[C:45]([O:50]C(=O)C(C)(C)C)[CH:44]=[CH:43][C:42]=3[CH2:41]2)=[CH:24][CH:23]=1>>[CH3:61][N:18]([CH3:17])[C:19]([CH3:59])([CH3:60])[CH2:20][O:21][C:22]1[CH:23]=[CH:24][C:25]([CH2:26][CH2:27][CH2:28][NH:29][C:30]2[CH:35]=[C:34]([O:36][CH3:37])[C:33]([O:38][CH3:39])=[CH:32][C:31]=2[C@@H:40]2[CH2:49][CH2:48][C:47]3[CH:46]=[C:45]([OH:50])[CH:44]=[CH:43][C:42]=3[CH2:41]2)=[CH:57][CH:58]=1
Reactant: COc1cc(NCCCc2ccc(OCC(C)(C)N(C)C)cc2)c([C@@H]2CCc3cc(OC(=O)C(C)(C)C)ccc3C2)cc1OC
Agent: CN(C)C(C)(C)COc1ccc(C=O)cc1
Product: COc1cc(NCCCc2ccc(OCC(C)(C)N(C)C)cc2)c([C@@H]2CCc3cc(O)ccc3C2)cc1OC

Procedure:
From (R)-6-(2-ethylamino-4,5-dimethoxyphenyl)-5,6,7,8-tetrahydronaphthalen-2-yl ester (20 mg) and 4-(2-dimethylamino-2-methylpropoxy)benzaldehyde (50 mg), synthesis was carried out according to an analogous synthetic method to Example 212. Synthesized from the total amount of the resulting pivalic acid (R)-6-{2-{[4-(2-dimethylamino-2-methylpropoxy)benzyl]ethylamino}-4,5-dimethoxyphenyl}-5,6,7,8-tetrahydronaphthalen-2-yl ester crude product according to an analogous synthetic method to Example 337 described below and purified by LC-MS, the title compound (21 mg) was obtained.
Reaction SMILES: Br[C:2]1[C:10]2[O:9][C:8]([C:11]3[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=3)=[N:7][C:6]=2[CH:5]=[C:4]([O:19][CH3:20])[CH:3]=1>CC(C)=O>[CH3:20][O:19][C:4]1[CH:3]=[C:2]([C:10]([OH:9])([CH3:2])[CH3:6])[C:10]2[O:9][C:8]([C:11]3[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=3)=[N:7][C:6]=2[CH:5]=1
Reactant: COc1ccc(-c2nc3cc(OC)cc(Br)c3o2)cc1
Solvent: CC(C)=O
Product: COc1ccc(-c2nc3cc(OC)cc(C(C)(C)O)c3o2)cc1

Procedure:
The title compound was prepared according to the procedure of Example 43, Step a, from 7-bromo-5-methoxy-2-(4-methoxyphenyl)-1,3-benzoxazole, employing acetone as the electrophile, to give a white solid (78% yield, m.p. 149° C.); MS m/e 314 (M+H)+.
Reaction SMILES: [CH3:1][S:2][C:3]1[N:8]=[C:7](Cl)[C:6]([N+:10]([O-:12])=[O:11])=[C:5]([Cl:13])[N:4]=1.[CH2:14]([O:21][C:22]1[CH:27]=[CH:26][C:25]([C:28]#[N:29])=[CH:24][C:23]=1[OH:30])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>>[CH3:1][S:2][C:3]1[N:4]=[C:5]([Cl:13])[C:6]([N+:10]([O-:12])=[O:11])=[C:7]([O:30][C:23]2[CH:24]=[C:25]([C:28]#[N:29])[CH:26]=[CH:27][C:22]=2[O:21][CH2:14][C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)[N:8]=1
Reactant: N#Cc1ccc(OCc2ccccc2)c(O)c1
Reactant: CSc1nc(Cl)c([N+](=O)[O-])c(Cl)n1
Product: CSc1nc(Cl)c([N+](=O)[O-])c(Oc2cc(C#N)ccc2OCc2ccccc2)n1

Procedure:
In a similar manner, 2-methylthio-4,6-dichloro-5-nitropyrimidine, a compound of formula (A), was treated with 2-benzyloxy-5-cyanophenol to yield 2-methylthio-4-chloro-5-nitro-6-(2-benzyloxy-5-cyanophenoxy)pyrimidine, a compound of formula (K).
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([CH2:17][OH:18])[N:8]([C:10]2[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][CH:11]=2)[N:9]=1)([CH3:4])([CH3:3])[CH3:2].C(Cl)Cl.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>O>[C:1]([C:5]1[CH:6]=[C:7]([CH:17]=[O:18])[N:8]([C:10]2[CH:11]=[CH:12][C:13]([CH3:16])=[CH:14][CH:15]=2)[N:9]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: Cc1ccc(-n2nc(C(C)(C)C)cc2CO)cc1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: ClCCl
Solvent: O
Product: Cc1ccc(-n2nc(C(C)(C)C)cc2C=O)cc1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 98.3 %

Procedure:
To a scintillation vial containing (5-tert-Butyl-2-p-tolyl-2H-pyrazol-3-yl)-methanol (0.515 g, 2.1 mmol) was added 15 mL DCM followed by the addition of Dess-Martin periodinane (1.1 g, 2.52 mmol). The reaction mixture was allowed to stir at room temperature for 20 minutes and poured into a separatory funnel containing 30 mL water. The layers separated and the aqueous layer extracted twice more with 50 mL DCM. The combined organic layers were washed with Brine, dried over MgSO4 and concentrated under vacuum to afford the crude aldehyde. The crude material was purified by flash chromatography (0-50% EtOAc:Hexanes, silica gel) to yield the desired product as a clear oil (0.5 g, 97%). Expected mass=242. Observed mass=243.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([N:10]([CH2:32][CH:33]([CH3:35])[CH3:34])[C@H:11]2[CH2:16][C@@H:15]([C:17]([N:19]3[CH2:24][CH2:23][O:22][CH2:21][CH2:20]3)=[O:18])[CH2:14][N:13](C(OC(C)(C)C)=O)[CH2:12]2)=[O:9])=[CH:6][CH:5]=[C:4]([C:36]([F:39])([F:38])[F:37])[N:3]=1.C(N(C(C)C)CC)(C)C.[CH3:49][O:50][CH2:51][CH2:52][CH2:53][NH2:54]>CC(O)C>[CH3:49][O:50][CH2:51][CH2:52][CH2:53][NH:54][C:2]1[C:7]([C:8]([N:10]([CH2:32][CH:33]([CH3:34])[CH3:35])[C@H:11]2[CH2:16][C@@H:15]([C:17]([N:19]3[CH2:20][CH2:21][O:22][CH2:23][CH2:24]3)=[O:18])[CH2:14][NH:13][CH2:12]2)=[O:9])=[CH:6][CH:5]=[C:4]([C:36]([F:38])([F:37])[F:39])[N:3]=1
Reactant: COCCCN
Reactant: CC(C)CN(C(=O)c1ccc(C(F)(F)F)nc1Cl)[C@H]1C[C@@H](C(=O)N2CCOCC2)CN(C(=O)OC(C)(C)C)C1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)O
Product: COCCCNc1nc(C(F)(F)F)ccc1C(=O)N(CC(C)C)[C@@H]1CNC[C@H](C(=O)N2CCOCC2)C1
Temperature: 80 °C
Reaction time: 15 h

Procedure:
To a solution of tert-butyl (3S,5R)-3-[{[2-chloro-6-(trifluoromethyl)pyridin-3-yl]carbonyl}(2-methylpropyl)amino]-5-(morpholin-4-ylcarbonyl)piperidine-1-carboxylate (40 mg) and diisopropylethylamine (37 μl) in 2-propanol (3 ml) was added 3-methoxypropylamine (23 μl) and the mixture was stirred at 80° C. for 15 hr. The reaction mixture was concentrated under reduced pressure, saturated aqueous sodium hydrogen carbonate was added, and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained residue was dissolved in methanol (2 ml), 4 M hydrogen chloride-ethyl acetate (2 ml) was added, and the mixture was stirred at room temperature for 15 hr. The reaction mixture was concentrated under reduced pressure, and the residue was subjected to reversed-phase preparative HPLC. Aqueous sodium hydrogen carbonate was added to the object fraction, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure to give the object compound (8.8 mg).
Reaction SMILES: [F:1][C:2]([F:22])([F:21])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[C:11]3[C:15](=[CH:16][CH:17]=2)[NH:14][CH:13]=[C:12]3[CH2:18][C:19]#[N:20])=[CH:5][CH:4]=1.[H-].[Na+].I[CH3:26]>C1COCC1>[CH3:26][N:14]1[C:15]2[C:11](=[CH:10][C:9]([C:6]3[CH:7]=[CH:8][C:3]([C:2]([F:21])([F:1])[F:22])=[CH:4][CH:5]=3)=[CH:17][CH:16]=2)[C:12]([CH2:18][C:19]#[N:20])=[CH:13]1
Reactant: N#CCc1c[nH]c2ccc(-c3ccc(C(F)(F)F)cc3)cc12
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cn1cc(CC#N)c2cc(-c3ccc(C(F)(F)F)cc3)ccc21

Procedure:
[1-Methyl-5-(4-trifluoromethyl-phenyl)-1H-indol-3-yl]-acetonitrile was prepared from [5-(4-trifluoromethyl-phenyl)-1H-indol-3-yl]-acetonitrile (0.377 g, 126 mmol), sodium hydride (0.117 g, 2.93 mmol of a 60% dispersion on mineral oil), iodomethane (0.17 mL, 2.8 mmol) and THF (10 mL) according to the procedure described in Step 2 of Example 1. Purification by flash chromatography using 5-15% ethyl acetate in hexane as an eluant affored the title compound as a yellow semi-solid (0.237 g, 60%), 1HNMR (300 MHz, DMSO-d6): δ 8.0 (s, 1H), 7.9 (d, 2H, J=7.7 Hz), 7.8 (d, 2H, J=7.7 Hz), 7.6 (s, 2H), 7.45 (s, 1H) 4.15 (s, 2H) and 3.8 ppm (s, 3H).
Reaction SMILES: C([O:3][C:4]([C:6]1([CH3:35])[CH2:11][CH2:10][N:9]([C:12]2[N:17]=[CH:16][C:15]([C:18]3[CH:19]=[C:20]([CH2:33][CH3:34])[C:21]4[S:25][C:24]([NH:26][C:27]([NH:29][CH2:30][CH3:31])=[O:28])=[N:23][C:22]=4[CH:32]=3)=[CH:14][N:13]=2)[CH2:8][CH2:7]1)=[O:5])C.[OH-].[Na+].Cl>CCO>[CH2:33]([C:20]1[C:21]2[S:25][C:24]([NH:26][C:27]([NH:29][CH2:30][CH3:31])=[O:28])=[N:23][C:22]=2[CH:32]=[C:18]([C:15]2[CH:14]=[N:13][C:12]([N:9]3[CH2:10][CH2:11][C:6]([CH3:35])([C:4]([OH:5])=[O:3])[CH2:7][CH2:8]3)=[N:17][CH:16]=2)[CH:19]=1)[CH3:34]
Reactant: CCNC(=O)Nc1nc2cc(-c3cnc(N4CCC(C)(C(=O)OCC)CC4)nc3)cc(CC)c2s1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCNC(=O)Nc1nc2cc(-c3cnc(N4CCC(C)(C(=O)O)CC4)nc3)cc(CC)c2s1
Temperature: 70 °C
Reaction time: 8 h
Yield: 11.2 %

Procedure:
1-{5-[7-Ethyl-2-(3-ethyl-ureido)-benzothiazol-5-yl]-pyrimidin-2-yl}-4-methyl-piperidine-4-carboxylic acid ethyl ester (19 mg) was dissolved in EtOH (1 mL) and 1 M aq NaOH (1 mL) added. The mixture was stirred at 70° C. overnight. The mixture was cooled to rt and acidified to pH 3 with 1 M HCl (aq) then concentrated in vacuo and the residue suspended (sonication) in ˜10% MeOH in DCM. The mixture was filtered through a syringe filter (20 micron) and the filtrate concentrated in vacuo. A cream solid was obtained (54 mg) and purified by preperative HPLC (Gilson, 40s-70-100% water/MeCN+0.1% formic acid). The relevant fractions were combined and concentrated in vacuo slightly then freeze-dried to give Compound 37 (2 mg) as a white solid. 1H NMR (CDCl3+CD3OD): δ 1.21 (3H, t, J=7.2 Hz), 1.25 (3H, s), 1.35 (3H, t, J=7.6 Hz), 1.45 (2H, m), 2.17 (2H, br d, J=13.6 Hz), 2.85 (2H, q, J=7.6 Hz), 3.32-3.41 (4H, m), 4.31 (2H, br dt, J=13.8 and 4.0 Hz), 7.14 (1H, s), 7.54 (1H, s), 8.54 (1H, s), 8.54 (1H, s). m/z: 469 [M+H]+.
Reaction SMILES: [F:1][C:2]([F:47])([F:46])[C:3]1[CH:4]=[C:5]([CH:39]=[C:40]([C:42]([F:45])([F:44])[F:43])[CH:41]=1)[CH2:6][N:7]([C:27]1[N:32]=[CH:31][C:30]([C:33]2[CH:34]=[N:35][N:36]([CH3:38])[CH:37]=2)=[CH:29][N:28]=1)[C@@H:8]1[CH2:12][N:11]([C:13]2[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][C:14]=2[CH:15]=[O:16])[C@H:10]([CH2:25][CH3:26])[CH2:9]1.[CH3:48][Mg+].[Br-].[NH4+].[Cl-]>C1COCC1>[F:47][C:2]([F:46])([F:1])[C:3]1[CH:4]=[C:5]([CH:39]=[C:40]([C:42]([F:45])([F:44])[F:43])[CH:41]=1)[CH2:6][N:7]([C:27]1[N:28]=[CH:29][C:30]([C:33]2[CH:34]=[N:35][N:36]([CH3:38])[CH:37]=2)=[CH:31][N:32]=1)[C@@H:8]1[CH2:12][N:11]([C:13]2[CH:20]=[CH:19][C:18]([C:21]([F:22])([F:23])[F:24])=[CH:17][C:14]=2[CH:15]([OH:16])[CH3:48])[C@H:10]([CH2:25][CH3:26])[CH2:9]1
Reactant: C[Mg+]
Reactant: CC[C@@H]1C[C@H](N(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)c2ncc(-c3cnn(C)c3)cn2)CN1c1ccc(C(F)(F)F)cc1C=O
Agent: [Br-]
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CC[C@@H]1C[C@H](N(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)c2ncc(-c3cnn(C)c3)cn2)CN1c1ccc(C(F)(F)F)cc1C(C)O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a mixture of 2-((2R,4S)-4-{(3,5-bis-trifluoromethyl-benzyl)-[5-(1-methyl-1H-pyrazol-4-yl)-pyrimidin-2-yl]-amino}-2-ethyl-pyrrolidin-1-yl)-5-trifluoromethyl-benzaldehyde (120 mg, 0.17 mmol) in THF (3 mL) is added MeMgBr (0.24 mL, 0.23 mmol) in THF solution (0.97M). The reaction mixture is stirred at room temperature for 0.5 hour. After addition of saturated NH4Cl aq., the mixture is extracted with EtOAc. The combined organic layer is dried over MgSO4 then concentrated under reduced pressure to give 1-[2-((2R,4S)-4-{(3,5-bis-trifluoromethyl-benzyl)-[5-(1-methyl-1H-pyrazol-4-yl)-pyrimidin-2-yl]-amino}-2-ethyl-pyrrolidin-1-yl)-5-trifluoromethyl-phenyl]-ethanol as a colorless oil (122 mg, quant.). ESI-MS m/z: 687 [M+1]+, Retention time 2.05 min (condition A).