Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([Br:4])[CH:2]=C.[CH:5](/[N:9]([CH2:14][CH:15]([CH3:17])[CH3:16])[CH2:10][CH:11]([CH3:13])[CH3:12])=[CH:6]\[CH2:7][CH3:8].[C:18](#N)C>>[Br-:4].[CH2:10]([N+:9]([CH2:14][CH:15]([CH3:16])[CH3:17])=[CH:5][CH:6]([CH2:1][CH3:2])[CH2:7][CH:8]=[CH2:18])[CH:11]([CH3:12])[CH3:13]
Reactant: C=CCBr
Reactant: CC/C=C/N(CC(C)C)CC(C)C
Reactant: CC#N
Product: C=CCC(C=[N+](CC(C)C)CC(C)C)CC
Product: [Br-]
Temperature: 60 °C
Reaction time: 15 h
Yield: 92 %

Procedure:
Allyl bromide (1.30 mL, 15 mmol) was added to a mixture of (E)-but-1-enyldiisobutylamine (1.83 g, 10 mmol) and acetonitrile (5.5 mL) at room temperature under a nitrogen atmosphere, and the mixture was then stirred at an external temperature of 60° C. for 15 hours. The reaction mixture was cooled to room temperature and then concentrated under reduced pressure to obtain the title compound (2.79 g, 92%) as a red purple solid.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([C@@H:11]([CH2:15][C@H:16]2[CH2:20][CH2:19][C:18](=[O:21])[CH2:17]2)[C:12]([OH:14])=O)=[CH:7][C:6]=1[CH3:22])(=[O:4])=[O:3].C(Cl)(=O)C(Cl)=O.[NH2:29][C:30]1[CH:34]=[CH:33][N:32]([CH2:35][CH2:36][CH2:37][OH:38])[N:31]=1.N1C(C)=CC=CC=1C>C(Cl)Cl.CN(C)C=O>[OH:38][CH2:37][CH2:36][CH2:35][N:32]1[CH:33]=[CH:34][C:30]([NH:29][C:12](=[O:14])[C@@H:11]([C:8]2[CH:9]=[CH:10][C:5]([S:2]([CH3:1])(=[O:4])=[O:3])=[C:6]([CH3:22])[CH:7]=2)[CH2:15][C@H:16]2[CH2:20][CH2:19][C:18](=[O:21])[CH2:17]2)=[N:31]1
Reactant: Nc1ccn(CCCO)n1
Reactant: Cc1cc([C@@H](C[C@H]2CCC(=O)C2)C(=O)O)ccc1S(C)(=O)=O
Agent: O=C(Cl)C(=O)Cl
Solvent: Cc1cccc(C)n1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: Cc1cc([C@@H](C[C@H]2CCC(=O)C2)C(=O)Nc2ccn(CCCO)n2)ccc1S(C)(=O)=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 82.7 %

Procedure:
(R)-2-(4-Methanesulfonyl-3-methyl-phenyl)-3-((R)-3-oxo-cyclopentyl)-propionic acid (prepared in Example 122, 65 mg, 0.20 mmol) was dissolved in methylene chloride (2 mL) and N,N-dimethylformamide (two drops) at 25° C. under argon. To this solution was added dropwise a solution of oxalyl chloride in methylene chloride (2 M solution, 110 μL, 0.21 mmol) which produced gas evolution and it was then stirred at 25° C. for 30 minutes after which time it was concentrated in vacuo. The residue was then dissolved in methylene chloride (2 mL) and added dropwise into a solution of 3-(3-amino-pyrazol-1-yl)-propan-1-ol (prepared in Example 23, 29 mg, 0.20 mmol), 2,6-lutidine (46 μL, 0.40 mmol) and methylene chloride (2 mL) at 0° C. It was then allowed to warm to 25° C. and stirred for 1 h. After this time, the reaction was quenched with a small amount of methanol and diluted with methylene chloride and then concentrated with silica gel (2 g) in vacuo and purified on Biotage Flash chromatography system (40S column, silica gel, 80% ethyl acetate/hexanes to 10% methanol/ethyl acetate) to afford (R)—N-[1-(3-hydroxy-propyl)-1H-pyrazol-3-yl]-2-(4-methanesulfonyl-3-methyl-phenyl)-3-((R)-3-oxo-cyclopentyl)-propionamide (74 mg, 83%) as a colorless gum: [α]32589=−23.3° (c=0.15, methanol); ES-HRMS m/e calcd for C22H29N3O5S (M+H)+ 448.1901, observed 448.1901; 1H NMR (300 MHz, DMSO-d6) δ 1.50 (m, 1H, CH), 1.76-2.29 (m, 10H, 5×CH2), 2.62 (s, 3H, ArCH3), 3.18 (s, 3H, SO2CH3), 3.33 (m, 2H, OCH2), 3.90 (m, 1H, ArCHCO), 4.01 (t, J=6.9 Hz, 2H, NCH2), 4.56 (t, J=5.1 Hz, 1H, OH), 6.41 (d, J=2.2 Hz, 1H, Ar), 7.45 (brs, 1H, Ar), 7.46 (brd, 1H, Ar), 7.54 (d, J=2.2 Hz, 1H, Ar), 7.85 (d, Jo=8.6 Hz, 1H, Ar), 10.78 (s, 1H, NH).
Reaction SMILES: [Cl:1][C:2]1[CH:20]=[CH:19][C:5]([CH2:6][O:7][C:8]2[CH:9]=[CH:10][C:11]([NH:14]C(=O)OC)=[N:12][CH:13]=2)=[CH:4][CH:3]=1.C(Cl)(Cl)Cl.O>[OH-].[Na+].CO>[NH2:14][C:11]1[CH:10]=[CH:9][C:8]([O:7][CH2:6][C:5]2[CH:19]=[CH:20][C:2]([Cl:1])=[CH:3][CH:4]=2)=[CH:13][N:12]=1
Reactant: COC(=O)Nc1ccc(OCc2ccc(Cl)cc2)cn1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: ClC(Cl)Cl
Solvent: O
Product: Nc1ccc(OCc2ccc(Cl)cc2)cn1
Reaction time: 1 h

Procedure:
A slurry of methyl 5-(4-chlorobenzyloxy)-2-pyridylcarbamate (0.75 g, 2.6 mmol) in 10% sodium hydroxide (20 ml) and methanol (40 ml) is heated to 90° under nitrogen gas. After 1 hour, 10 ml of 10% sodium hydroxide and 10 ml of methanol are added. Heating is continued, and after 2 hours, 10 ml more of methanol is added. The reaction is heated under reflux overnight. The reaction is then rotoevaporated, and chloroform and water are added. The residue is extracted with chloroform (4X). The combined chloroform extracts are washed with water until neutral and with brine, dried over calcium sulfate, filtered and rotoevaporated to yield 2-amino-5-(4-chlorobenzyloxy)pyridine.
Reaction SMILES: [C:1]([N:9]1[CH2:14][CH2:13][N:12]([C:15]2[N:20]=[C:19]([O:21][CH3:22])[CH:18]=[CH:17][N:16]=2)[CH2:11][CH2:10]1)(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:32])=CC=1.C(OCC)C.O>C1(C)C=CC=CC=1>[C:1]([N:9]1[CH2:14][CH2:13][N:12]([C:15]2[N:20]=[C:19]([O:21][CH3:22])[CH:18]=[CH:17][N:16]=2)[CH2:11][CH2:10]1)(=[S:32])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: COc1ccnc(N2CCN(C(=O)c3ccccc3)CC2)n1
Solvent: Cc1ccccc1
Solvent: CCOCC
Solvent: O
Product: COc1ccnc(N2CCN(C(=S)c3ccccc3)CC2)n1
Temperature: 85 °C
Yield: 43.9 %

Procedure:
0.56 g (1.9 mmol) of 2-(4-benzoyl-1-piperazinyl)-4-methoxypyrimidine are dissolved in 25 mL of dry toluene, and 0.46 g (1.14 mmol) of Lawesson's reagent (2,4-bis(4-methoxyphenyl)-1,32,4-dithiadiphosphaethano-2,4-disulphide) added. The mixture is heated to 80-90° C. for 16 hours. Ethyl ether is added, basic water is used to wash the residue and the organic extract is dried with NaSO4 and the solvent evaporated off under reduced pressure. The resulting crude residue is crystallised with ethyl ether-petroleum ether to give 160 mg (0.5 mmol) of 2-(4-thiobenzoyl-1-piperazinyl)-4-methoxypyrimidine. m.p.=125-129° C.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([O:8][C:9]2[C:15]([F:16])=[CH:14][C:12]([NH2:13])=[C:11]([F:17])[CH:10]=2)[CH:5]=[CH:4][N:3]=1.[CH3:18][N:19]1[CH:23]=[C:22](B2OC(C)(C)C(C)(C)O2)[CH:21]=[N:20]1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>CN(C=O)C.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>[F:17][C:11]1[CH:10]=[C:9]([O:8][C:6]2[CH:5]=[CH:4][N:3]=[C:2]([C:22]3[CH:21]=[N:20][N:19]([CH3:18])[CH:23]=3)[CH:7]=2)[C:15]([F:16])=[CH:14][C:12]=1[NH2:13]
Reactant: Nc1cc(F)c(Oc2ccnc(Cl)c2)cc1F
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cn1cc(-c2cc(Oc3cc(F)c(N)cc3F)ccn2)cn1
Temperature: 90 °C
Yield: 63 %

Procedure:
A solution of 4-(2-chloropyridin-4-yloxy)-2,5-difluoroaniline (450 mg, 1.76 mmol) and 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (400 mg, 1.9 mmol) in DMF (30 mL) was treated with tetrakis(triphenylphosphine)palladium(0) [Pd(PPh3)4](105 mg, 0.09 mmol) and an aqueous solution of potassium phosphate (2 M, 1.8 mL). The mixture was flushed with nitrogen for 10 min, and then heated at 90° C. overnight. After cooling to RT, the mixture was treated with water, extracted with EtOAc (4×) and the combined organics were washed with brine, dried (Na2SO4), concentrated under reduced pressure and purified by silica gel chromatography to give 2,5-difluoro-4-((2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yl)oxy)aniline (335 mg, 63% yield). 1H NMR (300 MHz, DMSO-d6): δ 8.35 (d, J=5.7 Hz, 1 H), 8.27 (s, 1 H), 7.98 (s, 1 H), 7.24-7.18 (m, 2 H), 6.75 (dd, J=1 2.3, 8.1 Hz, 1 H), 6.62 (dd, J=5.4, 2.1 Hz, 1 H), 5.53 (br s, 2 H), 3.87 (s, 3 H); MS (ESI): m/z 303.1 [M+1]+.
Reaction SMILES: C([Li])CCC.[CH3:6][P:7](=[O:14])([O:11][CH2:12][CH3:13])[O:8][CH2:9][CH3:10].[CH2:15]([O:22][C@H:23]1[C@H:28]([O:29][CH2:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[C@H:27]([O:37][CH2:38][C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)[C@H:26]([CH3:45])[O:25][C:24]1=[O:46])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>C1COCC1>[CH2:15]([O:22][C@H:23]1[C@H:28]([O:29][CH2:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[C@H:27]([O:37][CH2:38][C:39]2[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=2)[C@H:26]([CH3:45])[O:25][C@@:24]1([CH2:6][P:7](=[O:14])([O:11][CH2:12][CH3:13])[O:8][CH2:9][CH3:10])[OH:46])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: CCOP(C)(=O)OCC
Reactant: C[C@@H]1OC(=O)[C@@H](OCc2ccccc2)[C@H](OCc2ccccc2)[C@@H]1OCc1ccccc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCOP(=O)(C[C@@]1(O)O[C@@H](C)[C@@H](OCc2ccccc2)[C@@H](OCc2ccccc2)[C@@H]1OCc1ccccc1)OCC
Temperature: 25 °C
Reaction time: 1 h
Yield: 67.5 %

Procedure:
n-Butyllithium (2.5 M in hexanes, 0.64 mL, 1.59 mmol, commercially available from Sigma Aldrich) was added to a stirred solution of diethyl methylphosphonate (0.23 mL, 1.59 mmol, commercially available from Sigma Aldrich) in THF (1.5 mL) at −78° C. under an argon atmosphere. The mixture was stirred for 15 min before a solution of (3 S,4R,5R,6S)-3,4,5-tris(benzyloxy)-6-methyltetrahydro-2H-pyran-2-one (0.275 g, 0.636 mmol) in THF (1 mL) at −78° C. was added. The reaction mixture was removed from the cooling bath, and the mixture was allowed to warm to room temperature while stirring for 1 h. The reaction mixture was next concentrated in vacuo. The resulting oil was purified by silica gel chromatography (0 to 75% EtOAc/hexanes gradient) to give diethyl (((2S,3S,4R,5R,6S)-3,4,5-tris(benzyloxy)-2-hydroxy-6-methyltetrahydro-2H-pyran-2-yl)methyl)phosphonate as a colorless oil (0.251 g, 67.5% yield). 1H NMR (400 MHz, CDCl3): δ ppm 1.09 (d, J=6.65 Hz, 3 H) 1.26 (q, J=6.85 Hz, 6 H) 1.76 (dd, J=18.49, 15.16 Hz, 1 H) 2.33 (dd, J=17.41, 15.26 Hz, 1 H) 3.68 (br. d, J=1.60 Hz, 1 H) 3.72 (d, J=9.98 Hz, 1 H) 3.92-4.02 (m, 2 H) 4.06-4.17 (m, 4 H) 4.69 (dd, J=11.54, 4.11 Hz, 2H) 4.77 (dd, J=16.43, 11.74 Hz, 2 H) 4.99 (dd, J=11.54, 9.39 Hz, 2 H) 7.26-7.41 (m, 15 H).
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[N:10]=[C:11]1[NH:15][CH2:14][CH2:13][S:12]1)([CH3:3])[CH3:2].[C:16](=[S:18])=[S:17].[H-].[Na+].[CH3:21]I>O.CN(C)C=O>[CH:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[N:10]=[C:11]1[N:15]([C:16]([S:18][CH3:21])=[S:17])[CH2:14][CH2:13][S:12]1)([CH3:3])[CH3:2]
Reactant: S=C=S
Reactant: CI
Reactant: CC(C)c1ccccc1N=C1NCCS1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CSC(=S)N1CCSC1=Nc1ccccc1C(C)C
Reaction time: 0.5 h
Yield: 45.2 %

Procedure:
To a mixture of 2-(2-isopropylphenyl)imino-1,3-thiazolidine (0.22 g), carbon disulfide (0.09 g) and N,N-dimethylformamide (2 ml) was added under ice-cooling 60% sodium hydride (0.05 g). The mixture was stirred for 30 minutes. Methyliodide (0.17 g) was added thereto. The mixture was stirred at room temperature for 2 hours. To the mixture was added water (30 ml). The mixture was extracted with diethylether (60 ml), dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (n-hexane/ethyl acetate) to give 2-(2-isopropylphenyl)imino-3-(methylthio)thiocarbonyl-1,3-thiazolidine (0.14 g, yield: 45%) as colorless oil.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([O:12][CH3:13])[CH:11]=1)[C:5]([O:7][CH3:8])=[O:6].C([O-])([O-])=O.[K+].[K+].Br[CH2:21][CH2:22][O:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>CN(C=O)C.CCOC(C)=O>[CH2:24]([O:23][CH2:22][CH2:21][O:1][C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([O:12][CH3:13])[CH:11]=1)[C:5]([O:7][CH3:8])=[O:6])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: BrCCOCc1ccccc1
Reactant: COC(=O)c1cc(O)cc(OC)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC(=O)c1cc(OC)cc(OCCOCc2ccccc2)c1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 90 %

Procedure:
To a solution of methyl 3-hydroxy-5-methoxybenzoate (Chakraporty, T. K. and Reddy, G. V. J. Org. Chem, 57, 1992, 5462.) (3.3 g, 18.1 mmol) in dry DMF (30 mL) was added K2CO3 (6.3 g, 45.3 mmol) at room temperature. The reaction was stirred at room temperature for 10 minutes then ((2-bromoethoxy)methyl)benzene (3.4 mL, 21.7 mmol) was added and the mixture stirred at 160° C. for 2 hrs. The reaction was cooled down to room temperature and diluted with EtOAc, washed with water and brine, and dried over MgSO4, filtered and concentrated to give the crude product (90%) which was used in the next step without further purification.
Reaction SMILES: C[O:2][C:3](=O)[CH:4]([CH:9]([S:19][C:20]1[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=1)[C:10]1[C:15]([F:16])=[CH:14][CH:13]=[C:12]([F:17])[C:11]=1[F:18])[C:5](OC)=[O:6].CC(C[AlH]CC(C)C)C.O.C(OCC)(=O)C>C1COCC1>[Cl:26][C:23]1[CH:24]=[CH:25][C:20]([S:19][CH:9]([C:10]2[C:15]([F:16])=[CH:14][CH:13]=[C:12]([F:17])[C:11]=2[F:18])[CH:4]([CH2:5][OH:6])[CH2:3][OH:2])=[CH:21][CH:22]=1
Reactant: COC(=O)C(C(=O)OC)C(Sc1ccc(Cl)cc1)c1c(F)ccc(F)c1F
Agent: CC(C)C[AlH]CC(C)C
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: O
Product: OCC(CO)C(Sc1ccc(Cl)cc1)c1c(F)ccc(F)c1F
Temperature: 25 °C
Reaction time: 5 h

Procedure:
2-[(4-Chloro-phenylsulfanyl)-(2,3,6-trifluoro-phenyl)-methyl]-malonic acid dimethyl ester (Example 10, step 3, 11 g, 26.3 mmole) was dissolved in 200 mL THF and DIBAL-H (1M in hexane, 105 mL) was added. The reaction was stirred at room temperature for five hours. Additional DIBAL-H (M in hexane, 100 mL) was added and the reaction was stirred at 60° C. for three hours. 300 mL water and 300 mL EtOAc were added. The organic layer washed with 1N HCl solution (2×100 mL), brine (100 mL), dried over Na2SO4 and concentrated. The product was purified by column chromatography (EtOAc/hexane from 0/100 to 50/50 in 45 minutes). Yield: 6.2 g, 65%. 1H NMR (CDCl3 400 MHz) δ 7.28 (d, J=8.1 Hz, 2H), 7.20 (d, J=8.1 Hz, 2H), 7.00 (m, 1H), 6.75 (m, 1H), 4.85 (d, J=11.0 Hz, 1H), 4.36 (dd, J=7.3 and 3.7 Hz, 1H), 4.21 (dd, J=8.1 and 2.9 Hz, 1H), 3.85 (dd, J=8.8 and 2.9 Hz, 1H), 3.49 (m, 1H), 2.46 (m, 1H), 2.22 (br, 1H), 2.10 (br, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([CH:11]2[CH2:16][CH2:15][N:14](C(OC(C)(C)C)=O)[CH2:13][CH2:12]2)([OH:10])[CH3:9])=[CH:4][C:3]=1[C:24]([NH:26][CH2:27][C:28]12[CH2:37][CH:32]3[CH2:33][CH:34]([CH2:36][CH:30]([CH2:31]3)[CH2:29]1)[CH2:35]2)=[O:25].Cl>CO.O1CCOCC1>[ClH:1].[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([OH:10])([CH:11]2[CH2:12][CH2:13][NH:14][CH2:15][CH2:16]2)[CH3:9])=[CH:4][C:3]=1[C:24]([NH:26][CH2:27][C:28]12[CH2:29][CH:30]3[CH2:31][CH:32]([CH2:33][CH:34]([CH2:36]3)[CH2:35]1)[CH2:37]2)=[O:25]
Reactant: CC(C)(C)OC(=O)N1CCC(C(C)(O)c2ccc(Cl)c(C(=O)NCC34CC5CC(CC(C5)C3)C4)c2)CC1
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: CC(O)(c1ccc(Cl)c(C(=O)NCC23CC4CC(CC(C4)C2)C3)c1)C1CCNCC1
Yield: 123.4 %

Procedure:
To a solution of 4-[1-[4chloro-3-[[(tricyclo[3.3.1.13,7]dec-1-ylmethyl)amino]carbonyl]phenyl]-1-hydroxyethyl]-1-piperidinecarboxylic acid, 1,1-dimethylethyl ester (0.07 g, Example 77a) in methanol (3 ml) was added 4N hydrochloric acid solution in dioxane (1 ml). After 14 h the solvents were removed under reduced pressure and the residue was triturated with diethyl ether to give the title compound as a white powder (0.038 g).
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[C:3]1[CH:10]=[CH:9][C:6]([CH:7]=O)=[CH:5][CH:4]=1.[CH3:13][C:14](=[O:19])[CH2:15][C:16](=[O:18])[CH3:17].O>FC(F)(F)C(O)=O>[F:1][C:2]([F:12])([F:11])[C:3]1[CH:10]=[CH:9][C:6]([CH:7]=[C:15]([C:14](=[O:19])[CH3:13])[C:16](=[O:18])[CH3:17])=[CH:5][CH:4]=1
Reactant: O=Cc1ccc(C(F)(F)F)cc1
Reactant: CC(=O)CC(C)=O
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: CC(=O)C(=Cc1ccc(C(F)(F)F)cc1)C(C)=O
Temperature: 20 °C

Procedure:
4-Trifluoromethylbenzaldehyde (8,7 g) was condenced with 2,4-pentanedione (5,01 g in trifluoroacetic acid (10 ml) thionylchloride (4 ml) and catalytic amount of water (0,05 ml) were added at room temperature. The solution was stirred over right at 20° C. The solvent was evaporated and the residue was destilled in vacuo, bp 110° C./1,5 mbar. The crude product was crystallized from a mixture of ether-petroleum ether (1:1), mp 46°-48° C., yield 3,8 g (30 %).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:10])[CH2:5][CH2:6][C:7]([OH:9])=O)[CH3:2].C(Cl)(=O)C(Cl)=O.[C:17]([C:21]1[CH:31]=[CH:30][CH:29]=[CH:28][C:22]=1[O:23][CH:24]1[CH2:27][NH:26][CH2:25]1)([CH3:20])([CH3:19])[CH3:18].C(N(CC)CC)C>C1COCC1.CN(C=O)C>[C:17]([C:21]1[CH:31]=[CH:30][CH:29]=[CH:28][C:22]=1[O:23][CH:24]1[CH2:25][N:26]([C:7](=[O:9])[CH2:6][CH2:5][C:4]([O:3][CH2:1][CH3:2])=[O:10])[CH2:27]1)([CH3:20])([CH3:18])[CH3:19]
Reactant: CCOC(=O)CCC(=O)O
Reactant: CC(C)(C)c1ccccc1OC1CNC1
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCOC(=O)CCC(=O)N1CC(Oc2ccccc2C(C)(C)C)C1
Temperature: 25 °C
Yield: 90 %

Procedure:
To an ice-cold stirred solution of 4-ethoxy-4-oxobutanoic acid (0.42 g, 2.56 mmol) and DMF (0.03 ml) in THF (15 mL) was added oxalyl chloride (0.35 g, 2.72 mmol). After 1 h the reaction mixture was concentrated under reduced pressure. The resulting residue was dissolved in THF (5.0 mL) and the solution was added to an ice-cold solution of 3-(2-tert-butylphenoxy)azetidine (0.35 g, 1.70 mmol) and triethylamine (0.31 g, 3.06 mmol) in THF (30.0 ml) and the resulting reaction mixture was warmed to room temperature. After 16 h the reaction mixture was filtered, the filtrate was partitioned between ethyl acetate and water and separated. The organic layer was washed with 10% sodium bicarbonate, saturated sodium chloride, dried (Na2SO4), filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography (silica gel, 50:50 heptane/ethyl acetate) to provide ethyl 4-(3-(2-tert-butylphenoxy)azetidin-1-yl)-4-oxobutanoate (0.51 g, 90%) as a colorless oil.
Reaction SMILES: Br[C:2]1[N:6]2[CH2:7][CH2:8][N:9]([C:11]([C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([C:19]([F:22])([F:21])[F:20])[C:14]=3[Cl:23])=[O:12])[CH2:10][C:5]2=[N:4][N:3]=1.C(=O)([O-])[O-].[Na+].[Na+].[C:30]1(B(O)O)[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>COCCOC.O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[Cl:23][C:14]1[C:15]([C:19]([F:22])([F:21])[F:20])=[CH:16][CH:17]=[CH:18][C:13]=1[C:11]([N:9]1[CH2:8][CH2:7][N:6]2[C:2]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)=[N:3][N:4]=[C:5]2[CH2:10]1)=[O:12]
Reactant: OB(O)c1ccccc1
Reactant: O=C(c1cccc(C(F)(F)F)c1Cl)N1CCn2c(Br)nnc2C1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: O=C(c1cccc(C(F)(F)F)c1Cl)N1CCn2c(nnc2-c2ccccc2)C1

Procedure:
To 3-bromo-7-{[2-chloro-3-(trifluoromethyl)phenyl]carbonyl}-5,6,7,8-tetrahydro[1,2,4]triazolo[4,3-a]pyrazine (0.150 g, 0.366 mmol, e.g. see Example 1 for methods of preparation) in 1,2-dimethoxyethane (DME) (3 mL) was added aqueous sodium carbonate solution (1.9 mL, 1 M) followed by phenylboronic acid (0.067 g, 0.549 mmol, commercially available e.g. from Sigma-Aldrich or Strem Chemicals) and dichlorobis(triphenylphosphine)palladium(II) (0.013 g, 0.018 mmol). The reaction mixture was heated at reflux for 7 hours. The mixture was diluted with water (10 mL) and extracted with ethyl acetate (twice). The combined organic fractions were dried, filtered and evaporated. An attempt to purify the crude material on silica gel chromatography using methanol in Dichloromethane (0-20%) as eluent was unsuccessful. The residue was then purified using mass-directed automated (preparative) HPLC (MDAP) to give 7-{[2-chloro-3-(trifluoromethyl)phenyl]carbonyl}-3-phenyl-5,6,7,8-tetrahydro[1,2,4]triazolo[4,3-a]pyrazine (0.076 g) as a white solid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][CH2:15][CH2:16][CH2:17][N:18]2C(=O)C3C(=CC=CC=3)C2=O)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].O.NN>C(O)C>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][CH2:15][CH2:16][CH2:17][NH2:18])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCC(CCCCN2C(=O)c3ccccc3C2=O)CC1
Agent: NN
Solvent: CCO
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC(CCCCN)CC1
Temperature: 50 °C
Reaction time: 3 h

Procedure:
113.0 g (292 mmol) 2-[4-(1-tert-butoxycarbonylpiperidin-4-yl)-butyl]-isoindol-1,3-dione are dissolved in 600 ml ethanol, added to 29.3 g (585 mmol) hydrazine hydrate and heated to boiling for three hours. After cooling the solution, the mixture is filtered and the filtrate is concentrated under vacuum. The residue is dispersed in the heat (ca. 50° C.) between 500 ml toluene and 500 ml 10% sodium hydroxide solution. The organic phase is washed once with 50 ml 10% sodium hydroxide solution and twice, each with 50 ml water. The solvent is removed under vacuum and the residue is dried at 70° C. under high-vacuum and processed further without additional purification. Yield of colorless oil: 64.0 g (85%).
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH:17]3[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]3)=[CH:7][N:8]2[CH2:11][C:12]2[O:13][CH:14]=[CH:15][CH:16]=2)=[CH:4][CH:3]=1.C[O:24][C:25](=[O:36])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[O:32][CH2:33][CH2:34]Cl>>[F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH:17]3[CH2:18][CH2:19][N:20]([CH2:34][CH2:33][O:32][C:27]4[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=4[C:25]([OH:36])=[O:24])[CH2:21][CH2:22]3)=[CH:7][N:8]2[CH2:11][C:12]2[O:13][CH:14]=[CH:15][CH:16]=2)=[CH:4][CH:3]=1
Reactant: Fc1ccc2c(C3CCNCC3)cn(Cc3ccco3)c2c1
Reactant: COC(=O)c1ccccc1OCCCl
Product: O=C(O)c1ccccc1OCCN1CCC(c2cn(Cc3ccco3)c3cc(F)ccc23)CC1

Procedure:
This compound was prepared following the procedure described in example 13 (part E) starting with 2 g (6.5 mmol) of 6-fluoro-1-furan-2-ylmethyl-3-piperidin-4-yl-1H-indole and 1.5 g (7.1 mmol) of 2-(2-chloro-ethoxy)-benzoic acid methyl ester. After standard work-up and purification by flash chromatography over silica gel, 0.9 g (30% of yield) of the expected acid were obtained.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)[C:5]2[N:10]=[C:9]([CH:11]=O)[S:8][C:6]=2[N:7]=1.[NH:19]1[CH2:24][CH2:23][CH:22]([C:25]([OH:28])([CH3:27])[CH3:26])[CH2:21][CH2:20]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[Cl:1][C:2]1[N:3]=[C:4]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)[C:5]2[N:10]=[C:9]([CH2:11][N:19]3[CH2:24][CH2:23][CH:22]([C:25]([OH:28])([CH3:27])[CH3:26])[CH2:21][CH2:20]3)[S:8][C:6]=2[N:7]=1
Reactant: CC(C)(O)C1CCNCC1
Reactant: O=Cc1nc2c(N3CCOCC3)nc(Cl)nc2s1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Product: CC(C)(O)C1CCN(Cc2nc3c(N4CCOCC4)nc(Cl)nc3s2)CC1
Reaction time: 90 h
Yield: 67.3 %

Procedure:
A mixture of 5-chloro-7-morpholin-4-yl-thiazolo[5,4-d]pyrimidine-2-carbaldehyde (5.11 g, 17.9 mmol), 2-piperidin-4-ylpropan-2-ol (3.08 g, 21.5 mmol) and 4 Å powdered molecular sieves (9 g) in DCE (85 mL) was stirred at room temperature for 1.5 h before the addition of sodium triacetoxyborohydride (7.61 g, 35.9 mmol). The reaction mixture was stirred for 90 h then filtered through celite, washing the celite bed with DCM. The organic phase was washed with brine and concentrated in vacuo. The resulting residue was purified by column chromatography (Si—PCC, EtOAc:DCM, 0-100%) affording 2-[1-(5-Chloro-7-morpholin-4-ylthiazolo[5,4-d]pyrimidin-2-ylmethyl)piperidin-4-yl]propan-2-ol as an orange solid (4.96 g, 67%). LCMS (Method A): RT 2.77 min [M+H]+ 412.2