Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([OH:17])=[CH:14][CH:15]=2)[C:10]([C:18]([OH:20])=O)=[C:9]1[CH3:21])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.[F:36][C:37]1[CH:38]=[C:39]([CH:42]=[C:43]([F:45])[CH:44]=1)[CH2:40][NH2:41]>C(Cl)Cl.CN(C=O)C.CCOC(C)=O>[F:36][C:37]1[CH:38]=[C:39]([CH:42]=[C:43]([F:45])[CH:44]=1)[CH2:40][NH:41][C:18]([C:10]1[C:11]2[C:16](=[CH:15][CH:14]=[C:13]([OH:17])[CH:12]=2)[N:8]([CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[C:9]=1[CH3:21])=[O:20]
Reactant: Cc1c(C(=O)O)c2cc(O)ccc2n1Cc1ccccc1
Reactant: NCc1cc(F)cc(F)c1
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: Cc1c(C(=O)NCc2cc(F)cc(F)c2)c2cc(O)ccc2n1Cc1ccccc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 1-benzyl-5-hydroxy-2-methyl-1H-indole-3-carboxylic acid (Compound 2, 205 mg, 0.73 mmol) in CH2Cl2 (5 ml) and DMF (3 ml) was added EDC (211 mg, 1.1 mmol), HOBT (149 mg, 1.1 mmol) and 3,5-difluorobenzylamine (260 μl, 2.2 mmol). The mixture was stirred at room temperature for 16 h, diluted with EtOAc, and washed with 1M HCl, and brine, and dried over Na2SO4, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (30% to 50% EtOAc-hexanes) to yield 1-benzyl-5-hydroxy-2-methyl-1H-indole-3-carboxylic acid, 3,5-difluorobenzylamide (Compound 3) as a beige solid.
Reaction SMILES: [CH2:1]([OH:19])[CH2:2][O:3][CH2:4][CH2:5][O:6][CH2:7][CH2:8][O:9][CH2:10][CH2:11][O:12][CH2:13][CH2:14][O:15][CH2:16][CH2:17][OH:18].[CH2:20](Br)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>[OH-].[Na+].O>[CH2:20]([O:18][CH2:17][CH2:16][O:15][CH2:14][CH2:13][O:12][CH2:11][CH2:10][O:9][CH2:8][CH2:7][O:6][CH2:5][CH2:4][O:3][CH2:2][CH2:1][OH:19])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: OCCOCCOCCOCCOCCOCCO
Reactant: BrCc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: OCCOCCOCCOCCOCCOCCOCc1ccccc1
Temperature: 100 °C
Reaction time: 2 h

Procedure:
A mixture of hexaethylene glycol (Aldrich, 100 g) and benzyl bromide (Aldrich, 12 g) in aqueous sodium hydroxide (50% (w/w), 80 ml) was stirred at 100° C. (oil bath) under nitrogen for 2 h. The reaction mixture was then cooled to ambient temperature, diluted with water to a total volume of 500 ml, and extracted with diethyl ether (200 ml) to remove dibenzylated product. Sodium chloride (100 g) was added to the aqueous layer, which was extracted further with diethyl ether (6×100 ml). These ether extracts were combined, dried (sodium sulfate), and concentrated to give hexaethylene glycol monobenzyl ether as an oil (25 g, 20% based on glycol), 1H-NMR (CDCl3) δ: 7.30 (m, 5, 5 phenyl CH), 4.53 (s, 2, benzyl CH2), 3.69-3.54 (m, 22, 11 OCH2), 3.06 (br s, 3, OH and CH2O).
Reaction SMILES: [Br:1][CH2:2][CH2:3]Br.[CH3:5][C:6]1[CH:7]=[C:8]([CH:11]=[C:12]([CH3:15])[C:13]=1[OH:14])[CH:9]=[O:10].C(=O)([O-])[O-].[K+].[K+].[Cl-].[Na+]>CN(C=O)C.O>[Br:1][CH2:2][CH2:3][O:14][C:13]1[C:6]([CH3:5])=[CH:7][C:8]([CH:9]=[O:10])=[CH:11][C:12]=1[CH3:15]
Reactant: BrCCBr
Reactant: Cc1cc(C=O)cc(C)c1O
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1cc(C=O)cc(C)c1OCCBr
Temperature: 25 °C
Reaction time: 16 h
Yield: 106.3 %

Procedure:
1,2-Dibromoethane (26 mL, 0.3 moles) was added to a mixture of 3,5-dimethyl-4-hydroxybenzaldehyde (4.57 g, 30 mmoles) and potassium carbonate (21 g, 150 mmoles) in DMF (90 ml) and the resulting mixture was stirred vigorously at room temperature for 16 hours. The mixture was poured into water (0.3 L), added saturated sodium chloride (200 mL) and extracted with ethyl acetate (2×200 mL). The combined organic phases were washed with saturated sodium chloride (300 mL), dried over MgSO4 and evaporated in vacuo to afford 8.2 g (95%) of 4-(2-bromoethoxy)-3,5-dimethylbenzaldehyde as an oil.
Reaction SMILES: [CH:1]1([C:6]2[C:7]([O:23]S(C3C=CC(C)=CC=3)(=O)=O)=[N:8][N:9]3[C:14]=2[C:13]([CH3:15])=[N:12][N:11]=[C:10]3[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[F:22])[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:34][N:35]1[C:39]([CH2:40]O)=[N:38][CH:37]=[N:36]1.[H-].[Na+].O>CN(C=O)C>[CH:1]1([C:6]2[C:7]([O:23][CH2:40][C:39]3[N:35]([CH3:34])[N:36]=[CH:37][N:38]=3)=[N:8][N:9]3[C:14]=2[C:13]([CH3:15])=[N:12][N:11]=[C:10]3[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[F:22])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: Cn1ncnc1CO
Reactant: Cc1ccc(S(=O)(=O)Oc2nn3c(-c4ccccc4F)nnc(C)c3c2C2CCCC2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1nnc(-c2ccccc2F)n2nc(OCc3ncnn3C)c(C3CCCC3)c12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To toluene-4-sulfonic acid 3-cyclopentyl-7-(2-fluorophenyl)-4-methylpyrazolo[1,5-d][1,2,4]triazin-2-yl ester (Example 3, step c; 230 mg, 0.494 mmol) and (2-methyl-2H-[1,2,4]triazol-3-yl)methanol (67 mg, 1.2 molar eq; prepared as described in EP-A-170073) in DMF (10 ml) was added sodium hydride (22 mg of a 60% dispersion in mineral oil; 1.2 molar eq) and the mixture was stirred at room temperature for 1 h. Water (90 ml) was added then the solution was extracted with diethyl ether (4×50 ml). The combined ether layers were washed with brine (1×100 ml), dried (Na2SO4), the solvent was removed in vacuo and the residue was purified by flash chromatography on silica gel eluting with 0 to 50% ethyl acetate in dichloromethane. 3-Cyclopentyl-7-(2-fluorophenyl)-4-methyl-2-(2-methyl-2H-[1,2,4]triazol-3-ylmethoxy)pyrazolo[1,5-d][1,2,4]triazine was isolated as a gum, which solidified upon trituration under diethyl ether/isohexane (77 mg, mp=123° C.). 1H NMR (360 MHz, CDCl3) δ 1.60-1.98 (8H, m), 2.88 (3H, s), 3.42 (1H, m), 3.73 (3H, s), 5.44 (2H, s), 7.22-7.37 (2H, m), 7.56-7.71 (2H, m), 7.85 (1H, s); MS (ES+) m/e 408 [MH]+. Anal. Found C, 61.64; H, 5.31; N, 23.77%. C21H22FN7O requires C, 61.90; H, 5.44; N, 24.06%.
Reaction SMILES: C([BH3-])#N.[Na+].[F:5][C:6]1[CH:7]=[CH:8][C:9]([O:22][CH3:23])=[C:10]2[C:15]=1[O:14][CH2:13][C@H:12]([NH:16][CH:17]([CH2:20][CH3:21])[CH2:18][CH3:19])[CH2:11]2.[CH:24](=O)[CH2:25][CH3:26].C(O)(=O)C>CO>[F:5][C:6]1[CH:7]=[CH:8][C:9]([O:22][CH3:23])=[C:10]2[C:15]=1[O:14][CH2:13][C@H:12]([N:16]([CH:17]([CH2:18][CH3:19])[CH2:20][CH3:21])[CH2:24][CH2:25][CH3:26])[CH2:11]2
Reactant: CCC(CC)N[C@H]1COc2c(F)ccc(OC)c2C1
Reactant: CCC=O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: CCCN(C(CC)CC)[C@H]1COc2c(F)ccc(OC)c2C1
Reaction time: 18 h
Yield: 94.4 %

Procedure:
Sodiumcyanoborohydride (1.3 g, 20.7 mmol) was added during 10 min. to a stirred solution of (R)-8-fluoro-5-methoxy-3-(N-3-pentylamino)chroman (3.69 g, 13.8 mmol) and propionaldehyde (5 ml, 69.3 mmol) in 100 ml dry MeOH. The pH was adjusted with acetic acid to pH 6. The solution was stirred in room temp. for 18 hours and propionaldehyde (1 ml, 13.7 mmol) was added. After stirring at room temp. for 3.5 hours the solution was concentrated, and the residue was partitionated between 100 ml 2M NH3 and 200 ml ether. Extraction with 2×200 ml ether and drying of the combined organic layers (Na2SO4) gave after evaporation a crude product. Purification by flash chromatography on silica with hexane:acetone 20:1 gave 4.03 g of (R)-8-fluoro-5-methoxy-3-(N-3-pentyl-N-n-propylamino)chroman as an uncolored oil. [α]D22 -83° (c 1.08 in MeOH).
Reaction SMILES: [CH:1](NC(C)C)(C)C.C([Li])CCC.[CH3:13][C:14]([Si:17]([CH3:26])([CH3:25])[N:18]1[CH2:22][CH2:21][CH:20]([CH3:23])[C:19]1=[O:24])([CH3:16])[CH3:15].IC.[NH4+].[Cl-]>C1COCC1>[CH3:13][C:14]([Si:17]([CH3:26])([CH3:25])[N:18]1[CH2:22][CH2:21][C:20]([CH3:1])([CH3:23])[C:19]1=[O:24])([CH3:15])[CH3:16]
Reactant: CC(C)NC(C)C
Reactant: CC1CCN([Si](C)(C)C(C)(C)C)C1=O
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CI
Solvent: C1CCOC1
Product: CC1(C)CCN([Si](C)(C)C(C)(C)C)C1=O
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 81.7 %

Procedure:
In an oven-dried 1000 ml 3-neck flask fitted with septa and thermometer was charged with diisopropylamine (0.177 mol, 17.9 g) and 300 ml THF. The solution was cooled to 0° C. and n-Butyl lithium (0.193 mol, 77.1 ml of a 2.5M solution in hexanes) was added with stirring over 5 min. After 30 min, the reaction was cooled to −78° C. and a solution of 1-[(1,1-dimethylethyl)(dimethyl)silyl]-3-methyl-2-pyrrolidinone (0.161 mol, 34.3 g) in 80 ml THF was added dropwise keeping reaction temperature below −60° C. Once complete, the reaction was warmed to 20° C. After 1 hr, the reaction was cooled to −78° C. and a solution of Iodomethane (0.177 mol, 25.1 g) in 10 ml of THF was added dropwise over 10 min. The reaction was warmed to 20° C. and stirred for 16 hr, after which time 300 ml saturated NH4Cl was added. The aqueous phase was extracted with ethylacetate (2×150 ml), the organics were combined, dried over MgSO4, filtered and concentrated. The resulting crude oil was purified on 400 g silica (ethyl acetate/hexanes) to yield 29.9 g (82%) of 1-[(1,1-dimethylethyl)(dimethyl)silyl]-3,3-dimethyl-2-pyrrolidinone as a light yellow oil. LCMS (ESI+)=228 m/z (M+). 1H NMR (400 MHz CDCl3) δ 3.31-3.27 (t, 2H, J=6.68 Hz), 1.90-1.87 (t, 2H, J=6.79 Hz), 1.15 (s, 6H), 0.96 (s, 9H), 0.28 (s, 6H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1F)[CH:5]=[O:6].[F:11][C:12]1[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][CH:13]=1>>[F:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[O:18][C:15]1[CH:16]=[CH:17][C:12]([F:11])=[CH:13][CH:14]=1)[CH:5]=[O:6]
Reactant: Oc1ccc(F)cc1
Reactant: O=Cc1ccc(F)c(F)c1
Product: O=Cc1ccc(Oc2ccc(F)cc2)c(F)c1

Procedure:
The title compound was prepared by a procedure similar to that described for D4 starting from 3,4-difluorobenzaldehyde and 4-fluorophenol.
Reaction SMILES: Cl.Cl.[CH3:3][C@H:4]1[C:12]2[C:11]([N:13]3[CH2:18][CH2:17][NH:16][CH2:15][C@@H:14]3[CH3:19])=[N:10][CH:9]=[N:8][C:7]=2[CH2:6][CH2:5]1.C(N(CC)CC)C.[C:27]([O:31][C:32]([NH:34][C@H:35]([CH2:39][C:40]1[CH:45]=[CH:44][C:43]([Cl:46])=[CH:42][CH:41]=1)[C:36](O)=[O:37])=[O:33])([CH3:30])([CH3:29])[CH3:28].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C(Cl)Cl>[Cl:46][C:43]1[CH:44]=[CH:45][C:40]([CH2:39][C@@H:35]([NH:34][C:32](=[O:33])[O:31][C:27]([CH3:29])([CH3:28])[CH3:30])[C:36]([N:16]2[CH2:17][CH2:18][N:13]([C:11]3[C:12]4[C@H:4]([CH3:3])[CH2:5][CH2:6][C:7]=4[N:8]=[CH:9][N:10]=3)[C@@H:14]([CH3:19])[CH2:15]2)=[O:37])=[CH:41][CH:42]=1
Reactant: CC(C)(C)OC(=O)N[C@H](Cc1ccc(Cl)cc1)C(=O)O
Reactant: C[C@@H]1CCc2ncnc(N3CCNC[C@@H]3C)c21
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C[C@@H]1CCc2ncnc(N3CCN(C(=O)[C@@H](Cc4ccc(Cl)cc4)NC(=O)OC(C)(C)C)C[C@@H]3C)c21
Temperature: 25 °C
Reaction time: 1 h
Yield: 83.4 %

Procedure:
To a solution of (R)-5-methyl-4-((S)-2-methylpiperazin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine dihydrochloride (32 mg, 0.14 mmol) in DCM (5 mL) were added triethylamine (1 mL), (R)-2-(tert-butoxycarbonylamino)-3-(4-chlorophenyl)propanoic acid (41 mg, 0.14 mmol) and HBTU (52 mg, 0.14 mmol). The mixture was stirred at room temperature for 1 hour. The solvent was removed and the residue was purified by silica gel chromatography, eluting with ethyl acetate to afford tert-butyl (R)-3-(4-chlorophenyl)-1-((S)-3-methyl-4-((R)-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)-1-oxopropan-2-ylcarbamate (60 mg, 88%). 1H NMR (CDCl3, 400 MHz) δ 8.44 (s, 1H), 7.23-7.01 (m, 4H), 5.40-5.15 (m, 1H), 4.85-4.60 (m, 1H), 4.46-4.30 (m, 1H), 4.20-4.00 (m, 1H), 3.82-3.60 (m, 1H), 3.40 (m, 1H), 3.00-2.70 (m, 2H), 2.28 (m, 1H), 1.70 (m, 1H), 1.40 (s, 9H), 1.30-0.98 (m, 6H). MS (APCI+) [M+H] +514.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[CH:4][C:3]=1[O:11][CH3:12].[CH2:13]1[C@H:22]2[C@H:17]([CH2:18][CH2:19][C:20]3[CH:26]=[CH:25][CH:24]=[CH:23][C:21]=32)[NH:16][CH2:15][CH2:14]1.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1>>[NH2:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([N:16]2[C@@H:17]3[C@@H:22]([C:21]4[CH:23]=[CH:24][CH:25]=[CH:26][C:20]=4[CH2:19][CH2:18]3)[CH2:13][CH2:14][CH2:15]2)=[O:8])=[CH:4][C:3]=1[O:11][CH3:12]
Reactant: c1ccc2c(c1)CC[C@@H]1NCCC[C@H]21
Reactant: COc1cc(C(=O)O)ccc1N
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Product: COc1cc(C(=O)N2CCC[C@@H]3c4ccccc4CC[C@@H]32)ccc1N
Yield: 64 %

Procedure:
The title compound is prepared from 4-amino-3-methoxy-benzoic acid and cis-1,2,3,4,4a,5,6,10b-octahydro-benzo[f]quinoline following a procedure analogous to that described in Example 1 [2-(7-aza-1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexa-fluorophosphate is used]. Yield: 64% of theory; LC (method 4): tR=1.84 min; Mass spectrum (ESI+): m/z=337 [M+H]+.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[C:19]([C:20]#[N:21])=[CH:18][C:17](Br)=[CH:16][N:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:23]B(O)O.[F-].[K+].O1CCCC1>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C1(P(C2CCCCC2)C2C=CC=CC=2C2C(OC)=CC=CC=2OC)CCCCC1.O>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[C:19]([C:20]#[N:21])=[CH:18][C:17]([CH3:23])=[CH:16][N:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CB(O)O
Reactant: CC(C)(C)OC(=O)N1CCN(c2ncc(Br)cc2C#N)CC1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: COc1cccc(OC)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Solvent: O
Solvent: C1CCOC1
Product: Cc1cnc(N2CCN(C(=O)OC(C)(C)C)CC2)c(C#N)c1
Yield: 108.7 %

Procedure:
Under a nitrogen stream, to a mixture of 4-(5-bromo-3-cyanopyridin-2-yl)piperazine-1-carboxylic acid tert-butyl ester (1.52 g) described in Preparation Example 105, methylboronic acid (0.50 g), palladium(II) acetate (46 mg), 2-dicyclohexylphosphino-2′,6′-dimethoxybiphenyl (0.17 g) and potassium fluoride (0.96 g) was added tetrahydrofuran (40 mL), and the mixture was stirred with heating under reflux for 8 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and the solvent was evaporated. The obtained residue was purified by silica gel column chromatography (hexane:ethyl acetate) to give the title compound (1.36 g).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][O:15][C:16]2[CH:25]=[C:24]3[C:19]([C:20]([O:26][C:27]4[CH:28]=[C:29]5[C:33](=[CH:34][CH:35]=4)[NH:32][C:31]([CH3:36])=[CH:30]5)=[N:21][CH:22]=[N:23]3)=[CH:18][CH:17]=2)[CH2:10][CH2:9]1)=O)(C)(C)C>C(Cl)Cl.C(O)(C(F)(F)F)=O>[CH3:36][C:31]1[NH:32][C:33]2[C:29]([CH:30]=1)=[CH:28][C:27]([O:26][C:20]1[C:19]3[C:24](=[CH:25][C:16]([O:15][CH2:14][CH:11]4[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]4)=[CH:17][CH:18]=3)[N:23]=[CH:22][N:21]=1)=[CH:35][CH:34]=2
Reactant: Cc1cc2cc(Oc3ncnc4cc(OCC5CCN(C(=O)OC(C)(C)C)CC5)ccc34)ccc2[nH]1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc2cc(Oc3ncnc4cc(OCC5CCNCC5)ccc34)ccc2[nH]1
Temperature: 25 °C
Reaction time: 1 h
Yield: 66.4 %

Procedure:
A suspension of 7-(1-tert-butoxycarbonylpiperidin-4-ylmethoxy)-4-(2-methylindol-5-yloxy)quinazoline (150 mg, 0.31 mmol), (prepared as described in Example 90), in methylene chloride (2 ml) and TFA (1.5 ml) was stirred for 1 hour at ambient temperature. After removal of the volatiles under vacuum the residue was azeotroped with toluene. The residue was partitioned between methylene chloride and water and the aqueous layer was adjusted to pH11. The organic layer was separated, washed with brine, dried (MgSO4), and evaporated. The residue was triturated with ether, filtered, washed with ether and dried under vacuum to give 4-(2-methylindol-5-yloxy)-7-(piperidin-4-ylmethoxy)quinazoline (80 mg, 67%).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][CH3:12])(=[O:10])=[O:9])=[CH:4][C:3]=1[C:13]([N:15]1[CH2:20][CH2:19][N:18]([C:21]2[CH:26]=[CH:25][C:24]([C:27]([F:30])([F:29])[F:28])=[CH:23][CH:22]=2)[CH2:17][CH2:16]1)=[O:14].[C:31]1(B(O)O)[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1.[F-].[K+]>O1CCOCC1.C(OCC)(=O)C.[Pd].C(P(C(C)(C)C)C(C)(C)C)(C)(C)C.C(P(C(C)(C)C)C(C)(C)C)(C)(C)C>[CH3:12][NH:11][S:8]([C:5]1[CH:6]=[CH:7][C:2]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)=[C:3]([C:13]([N:15]2[CH2:20][CH2:19][N:18]([C:21]3[CH:22]=[CH:23][C:24]([C:27]([F:28])([F:30])[F:29])=[CH:25][CH:26]=3)[CH2:17][CH2:16]2)=[O:14])[CH:4]=1)(=[O:9])=[O:10]
Reactant: CNS(=O)(=O)c1ccc(Cl)c(C(=O)N2CCN(c3ccc(C(F)(F)F)cc3)CC2)c1
Reactant: OB(O)c1ccccc1
Agent: [Pd]
Agent: CC(C)(C)P(C(C)(C)C)C(C)(C)C
Agent: [F-]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: CNS(=O)(=O)c1ccc(-c2ccccc2)c(C(=O)N2CCN(c3ccc(C(F)(F)F)cc3)CC2)c1
Temperature: 90 °C
Reaction time: 19 h
Yield: 22.6 %

Procedure:
To a solution of 4-Chloro-N-methyl-3-[4-(4-trifluoromethyl-phenyl)-piperazine-1-carbonyl]-benzenesulfonamide (Example M; 30 mg, 0.065 mmol) in dioxane (2 ml) was added phenylboronic acid (12 mg, 0.098 mmol) followed by potassium fluoride (12 mg) and bis(tri-t-butylphosphine) palladium. The reaction mixture was then stirred for 19 hours at 90° C. After such time were added again (every 24 hours) the same amounts of phenylboronic acid, potassium fluoride, and bis(tri-t-butylphosphine) palladium After 3 days, the reaction mixture was diluted with ethyl acetate, filtered and concentrated in vacuo. The residue was purified by preparative HPLC (MeCN, H20+0.005 N HCOOH) to yield the title compound (7.4 mg). (M+H+: 504.4.)
Reaction SMILES: [CH3:1][CH:2]([CH2:7][CH2:8][CH:9]=[C:10]([CH3:12])[CH3:11])[CH2:3][C:4]([OH:6])=[O:5]>C(Cl)(Cl)Cl>[CH3:1][C:2]([CH2:7][CH2:8][CH:9]=[C:10]([CH3:12])[CH3:11])=[CH:3][C:4]([OH:6])=[O:5]
Reactant: CC(C)=CCCC(C)CC(=O)O
Solvent: ClC(Cl)Cl
Product: CC(C)=CCCC(C)=CC(=O)O

Procedure:
Following the procedure of Example 8, with the exception of using a substrate/catalyst ratio of 15, the hydrogenation of 3,7-dimethylocta-2,6-dienoic acid (E/Z≃7) was carried out at -23° C. under 130 psig of H2. The reaction was stopped after one week and there was obtained 1.41g. (94% yield) of a mixture of 65% 3,7-dimethyloct-6-enoic acid and 35% 3,7-dimethylocta-2,6-dienoic acid. The rotation of this mixture was [α]D25 +4.59° (c. 5.04, CHCl3) and of the methyl ester was [α]D25 +3.05° (c. 5.08, CHCl3). The nmr of the ester showed a 6:1 ratio of R to S enantiomers in the 3,7-dimethyloct-6-enoic acid. The optical purity calculated from the rotation of the acid is 69%, and the enantiomeric excess determined from the nmr of the ester is 71%.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([C:8]2[CH:9]=[C:10]3[C:16]([C:17]4[CH:18]=[N:19][N:20]([CH2:22][CH2:23][C:24]5[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=5)[CH:21]=4)=[CH:15][NH:14][C:11]3=[N:12][CH:13]=2)[CH:5]=[CH:4][C:3]=1[CH:30]1[CH2:35][CH2:34][N:33](C(OC(C)(C)C)=O)[CH2:32][CH2:31]1>CO.Cl.O1CCOCC1>[F:1][C:2]1[CH:7]=[C:6]([C:8]2[CH:9]=[C:10]3[C:16]([C:17]4[CH:18]=[N:19][N:20]([CH2:22][CH2:23][C:24]5[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=5)[CH:21]=4)=[CH:15][NH:14][C:11]3=[N:12][CH:13]=2)[CH:5]=[CH:4][C:3]=1[CH:30]1[CH2:31][CH2:32][NH:33][CH2:34][CH2:35]1
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(-c3cnc4[nH]cc(-c5cnn(CCc6ccccc6)c5)c4c3)cc2F)CC1
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: Fc1cc(-c2cnc3[nH]cc(-c4cnn(CCc5ccccc5)c4)c3c2)ccc1C1CCNCC1
Yield: 12.1 %

Procedure:
Using similar reaction conditions as described in step-ii of example-7, tert-butyl 4-(2-fluoro-4-(3-(1-phenethyl-1H-pyrazol-4-yl)-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)piperidine-1-carboxylate (82 mg, 0.145 mmol) was deprotected in methanol/HCl in dioxane (5/5 mL) to afford 8.2 mg (12.2% yield) of the titled compound after purification by preparative TLC using 8% methanol in chloroform as eluent. 1H NMR (CD3OD, 300 MHz): δ 8.448-8.442 (d, 1H), 8.098-8.091 (d, 1H), 7.839-7.837 (d, 1H), 7.73 (s, 1H), 7.54 (s, 1H), 7.48-7.38 (m, 3H), 7.26-7.12 (m, 5H), 7.44-7.41 (t, 2H), 3.37-3.31 (m, 1H), 3.19-3.15 (t, 3H), 3.03-2.93 (td, 2H), 1.97-1.88 (m, 5H). MS: m/z=466.5 (M+1), HPLC: 98.63% in method A.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([OH:8])=[N:6][CH:7]=1.Br[CH2:10][C:11](=[O:16])[C:12]([CH3:15])([CH3:14])[CH3:13]>CCCCCC.C(=O)([O-])[O-].[Ag+2]>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:8][CH2:10][C:11](=[O:16])[C:12]([CH3:15])([CH3:14])[CH3:13])=[N:6][CH:7]=1
Reactant: CC(C)(C)C(=O)CBr
Reactant: Oc1ccc(Cl)cn1
Agent: [Ag+2]
Agent: O=C([O-])[O-]
Solvent: CCCCCC
Product: CC(C)(C)C(=O)COc1ccc(Cl)cn1
Yield: 46.1 %

Procedure:
A mixture of 12.96 grams (g) (0.1 mole) of 5-chloro-2-hydroxypyridine, 17.9 g (0.1 mole) of 1-bromo-3,3-dimethyl-2-butanone, and 15 g (0.054 mole) of silver carbonate in hexane was stirred and heated at reflux temperature for 48 hours. The reaction mixture was filtered, and the solvent removed by evaporation. The residue was dissolved in methylene chloride and filtered through silica gel. Evaporation of the solvent gave 10.5 g (46 percent (%) yield) of 1-(5-chloro-2-pyridinyloxy)-3,3-dimethyl-2-butanone. A sample recrystallized from pentane had a melting point of 68°-69.5° C.
Reaction SMILES: Cl.Cl.[NH:3]1[CH2:7][CH2:6][CH2:5][NH:4]1.CO[C:10](=[O:30])[CH:11]([O:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[CH3:29])[C:12]([C:14]1[CH:19]=[CH:18][N:17]=[C:16]([S:20][CH3:21])[N:15]=1)=O>N1C=CC=CC=1>[CH3:21][S:20][C:16]1[N:15]=[C:14]([C:12]2[N:4]3[CH2:5][CH2:6][CH2:7][N:3]3[C:10](=[O:30])[C:11]=2[O:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[CH3:29])[CH:19]=[CH:18][N:17]=1
Reactant: COC(=O)C(Oc1ccccc1C)C(=O)c1ccnc(SC)n1
Reactant: C1CNNC1
Agent: Cl
Solvent: c1ccncc1
Product: CSc1nccc(-c2c(Oc3ccccc3C)c(=O)n3n2CCC3)n1
Temperature: 110 °C
Yield: 10 %

Procedure:
To a solution of pyrazolidine-bishydrochloride (1.7 g, 11.6 mmol) in pyridine (30 mL) was added 3-(2-Methylsulfanyl-pyrimidin-4-yl)-3-oxo-2-ortho-tolyloxy-propionic acid methyl ester, 1, (2.0 g, 5.78 mmol). The reaction mixture is heated to 110° C. for 18 h. The solvent is removed in vacuo and the resulting residue is purified by silica gel chromatography (10% MeOH/EtOAc, followed by 20% MeOH/EtOAc) to afford 220 mg (10%) of the desired product as a yellow solid. 1H NMR (300 MHz, CDCl3) δ 8.56 (d, J=5.4 Hz, 1H), 7.57 (d, J=5.4 Hz, 1H), 7.23 (d, J=7.5 Hz, 1H), 7.10 (dd, J=7.5, 7.5 Hz, 1H), 6.96 (dd, J=7.5, 7.5 Hz, 1H), 6.82 (d, J=7.5 Hz, 1H), 4.22 (t, J=6.6 Hz, 2H), 4.05 (t, J=6.9 Hz, 2H), 2.72 (dddd, J=6.9, 6.9, 6.9, 6.9 Hz, 2H), 2.62 (s, 3H), 2.48 (s, 3H); ESI+ MS: m/z (rel intensity) 355.0 (100, M++H).
Reaction SMILES: C(O)CCCCCCCO.C(Br)C1C=CC=CC=1.C(OCCCCCCCCO)C1C=CC=CC=1.C(OCCCCCCCC(O)=O)C1C=CC=CC=1.Cl.Cl.[CH2:56]([O:63][C:64](=[O:72])[CH2:65][C@@H:66](N)[CH2:67][N:68]([CH3:70])[CH3:69])[C:57]1[CH:62]=[CH:61][CH:60]=[CH:59][CH:58]=1>>[CH2:56]([O:63][C:64](=[O:72])[CH2:65][CH2:66][CH2:67][N:68]([CH3:69])[CH3:70])[C:57]1[CH:62]=[CH:61][CH:60]=[CH:59][CH:58]=1
Reactant: CN(C)C[C@H](N)CC(=O)OCc1ccccc1
Agent: BrCc1ccccc1
Agent: Cl
Agent: O=C(O)CCCCCCCOCc1ccccc1
Product: CN(C)CCCC(=O)OCc1ccccc1

Procedure:
The title compound, m/e=377.6 ([M−H]−), was produced in analogy with example 1, steps 1 to 4. Thus, 1,8-octanediol was alkylated in step 1 with benzyl bromide, leading to 8-benzyloxy-octan-1-ol, which was oxidized in step 2 to 8-benzyloxy-octanoic acid. This was coupled in step 3 with (R)-3-amino-4-dimethylamino-butyric acid benzyl ester dihydrochloride to produce (R)-3-[8-benzyloxy)-octanoylamino]-4-dimethylamino-butyric acid benzyl ester, which was hydrogenated in step 4.