Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:6]=[CH:7][C:8]([O:11][CH2:12][CH2:13][C@@H:14]2[CH2:16][C@@H:15]2[CH:17]2[CH2:22][CH2:21][N:20]([C:23]#[N:24])[CH2:19][CH2:18]2)=[N:9][CH:10]=1)(=[O:4])=[O:3].[OH:25][NH:26][C:27](=N)[CH2:28][O:29][CH3:30]>O1CCCC1.[Cl-].[Zn+2].[Cl-]>[CH3:30][O:29][CH2:28][C:27]1[N:24]=[C:23]([N:20]2[CH2:19][CH2:18][CH:17]([C@H:15]3[CH2:16][C@H:14]3[CH2:13][CH2:12][O:11][C:8]3[CH:7]=[CH:6][C:5]([S:2]([CH3:1])(=[O:3])=[O:4])=[CH:10][N:9]=3)[CH2:22][CH2:21]2)[O:25][N:26]=1
Reactant: CS(=O)(=O)c1ccc(OCC[C@@H]2C[C@@H]2C2CCN(C#N)CC2)nc1
Reactant: COCC(=N)NO
Agent: [Cl-]
Agent: [Zn+2]
Solvent: C1CCOC1
Product: COCc1noc(N2CCC([C@H]3C[C@H]3CCOc3ccc(S(C)(=O)=O)cn3)CC2)n1
Temperature: 25 °C

Procedure:
To a solution of 4-((1R,2S)-2-(2-(5-(methylsulfonyl)pyridin-2-yloxy)ethyl)cyclopropyl)piperidine-1-carbonitrile (Step A, Example 98; 80 mg, 0.23 mmol) and N-hydroxy-2-methoxyacetimidamide (38 mg, 0.37 mmol) in tetrahydrofuran (5 mL) was added zinc chloride (0.6 mL, 0.5 M in tetrahydrofuran, 0.3 mmol). The mixture was refluxed for 2 h, cooled to RT, and concentrated to dryness under reduced pressure. The residue was dissolved in 2 mL of 4N HCl ethanol and water (1:1). The solution was refluxed for 30 min, cooled to RT, and concentrated to dryness under reduced pressure. The residue was dissolved in methanol (5 mL), neutralized by the addition of excess potassium carbonate, mixed silica gel (2 g), and concentrated to dryness under reduced pressure. The residue was loaded on a silica gel column (10 g of silica gel) and eluted with a gradient of dichloromethane/CMA, 19:1, 500 mL; 4:1, 500 mL to provide the title compound as an off-white solid, 1H NMR (300 MHz, CDCl3) δ 8.72 (d, J=2.4 Hz, 1H), 8.03 (dd, J=2.5, 8.7 Hz, 1H), 6.85 (d, J=8.7 Hz, 1H), 4.50 (t, J=7.2 Hz, 2H), 4.38 (s, 2H), 4.25-4.10 (m, 2H), 3.46 (s, 3H), 3.15-2.95 (m, 2H), 3.08 (s, 3H), 2.20-2.05 (m, 1H), 1.95-1.80 (m, 2H), 1.60-1.40 (m, 3H), 1.20-0.85 (m, 2H), 0.80-0.55 (m, 2H), −0.08 (q, J=4.6 Hz, 1H). MS (ESI) m/z 437 [M+H]+. MP: 68-70° C. GPR119 Human EC50: 7 nM
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([P:8]([C:11](=[O:18])[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)(=O)[OH:9])=[C:4]([CH3:19])[C:3]=1[CH3:20].N1C=CC=CC=1.S(Cl)([Cl:29])=O>C1(C)C=CC=CC=1>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([P:8]([Cl:29])([C:11](=[O:18])[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[O:9])=[C:4]([CH3:19])[C:3]=1[CH3:20]
Reactant: Cc1ccc(P(=O)(O)C(=O)c2ccccc2)c(C)c1C
Reactant: O=S(Cl)Cl
Solvent: c1ccncc1
Solvent: Cc1ccccc1
Product: Cc1ccc(P(=O)(Cl)C(=O)c2ccccc2)c(C)c1C
Temperature: 0 °C

Procedure:
250 g of the acid from Example 2 were suspended in 670 ml of toluene and dissolved with 102.6 g of pyridine. 1546 g of thionyl chloride were added dropwise to the reaction mixture at 60° C. over the course of 1 hour. After a post-reaction time of 3 hours, the red-brown emulsion was cooled to 0° C., and the rust-brown crystals were filtered off. The solution which remained was evaporated under reduced pressure.
Reaction SMILES: [Si:1]([O:8][CH2:9][C:10]1[NH:11][C:12]2[CH:17]=[CH:16][N:15]=[CH:14][C:13]=2[N:18]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[H-].[Na+].[CH3:21]I>CN(C)C=O>[Si:1]([O:8][CH2:9][C:10]1[N:11]([CH3:21])[C:12]2[CH:17]=[CH:16][N:15]=[CH:14][C:13]=2[N:18]=1)([C:4]([CH3:7])([CH3:5])[CH3:6])([CH3:2])[CH3:3]
Reactant: CI
Reactant: CC(C)(C)[Si](C)(C)OCc1nc2cnccc2[nH]1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cn1c(CO[Si](C)(C)C(C)(C)C)nc2cnccc21

Procedure:
A procedure similar to that described in Preparation 59 was repeated, except that 7.4 g of 2-t-butyldimethylsilyloxymethyl-1H-imidazo[4,5-c]pyridine (prepared as described in Preparation 71), 1.23 g of sodium hydride (as a 55% by weight dispersion. in mineral oil), 2.0 ml of methyl iodide and 200 ml of dimethylformamide were used, to give the title compound as a crude product. This crude product was purified by column chromatography through silica gel, using a 10:1 by volume mixture of ethyl acetate and methanol as the eluent, to give 3.30 g of the title compound, melting at 93°-95° C.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[NH:7][C:8]2[C:13]([CH:14]=1)=[CH:12][CH:11]=[C:10]([CH3:15])[C:9]=2[Br:16])=[O:5])[CH3:2].[C:17]([O:21][C:22]([N:24]1[CH2:28][C@H:27]([CH3:29])OS1(=O)=O)=[O:23])([CH3:20])([CH3:19])[CH3:18]>>[CH2:1]([O:3][C:4]([C:6]1[N:7]([C@H:27]([CH3:29])[CH2:28][NH:24][C:22]([O:21][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:23])[C:8]2[C:13]([CH:14]=1)=[CH:12][CH:11]=[C:10]([CH3:15])[C:9]=2[Br:16])=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cc2ccc(C)c(Br)c2[nH]1
Reactant: C[C@H]1CN(C(=O)OC(C)(C)C)S(=O)(=O)O1
Product: CCOC(=O)c1cc2ccc(C)c(Br)c2n1[C@H](C)CNC(=O)OC(C)(C)C

Procedure:
The title compound, ISP-MS: m/e=439.1 and 441.3 (M+), was prepared in accordance with the general method of example 12b) from 7-bromo-6-methyl-1H-indole-2-carboxylic acid ethyl ester and (S)-5-methyl-2,2-dioxo-[1,2,3]oxathiazolidine-3-carboxylic acid tert-butyl ester.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][C:5]([O:7][CH3:8])=[O:6].C(=O)([O-])[O-].[Cs+].[Cs+].CN(C=O)C.[CH3:20][O:21][C:22](=[O:43])[C:23]1[CH:28]=[C:27]([CH3:29])[C:26]([O:30][C:31]([F:34])([F:33])[F:32])=[CH:25][C:24]=1[NH:35][C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37]>C(OCC)(=O)C>[CH3:20][O:21][C:22](=[O:43])[C:23]1[CH:28]=[C:27]([CH3:29])[C:26]([O:30][C:31]([F:34])([F:32])[F:33])=[CH:25][C:24]=1[N:35]([C:36]([O:38][C:39]([CH3:40])([CH3:42])[CH3:41])=[O:37])[CH2:2][CH2:3][CH2:4][C:5]([O:7][CH3:8])=[O:6]
Reactant: COC(=O)CCCBr
Reactant: COC(=O)c1cc(C)c(OC(F)(F)F)cc1NC(=O)OC(C)(C)C
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC(=O)CCCN(C(=O)OC(C)(C)C)c1cc(OC(F)(F)F)c(C)cc1C(=O)OC
Temperature: 60 °C
Reaction time: 5 h
Yield: 61.2 %

Procedure:
Add methyl 4-bromobutyrate (1.1 g, 6.0 mmol) and cesium carbonate (3.9 g, 12.0 mmol) to a DMF solution of 2-(tert-butoxycarbonylamino)-5-methyl-4-trifluoromethoxy-benzoic acid methyl ester (1.4 g, 4.0 mmol) under nitrogen. After stirring at 60° C. for 5 hours, the reaction mixture is cooled to room temperature and diluted with ethyl acetate (150 mL). Wash the organics with water (2×150 mL) followed by brine (100 mL), dry over sodium sulfate, and filter. Remove the solvent under vacuum and chromatograph the crude product over silica gel using ethyl acetate/hexane (5-30%) to elute. This provides the title compound (1.1 g, 61%) as an oil: H NMR (CDCl3, 400 MHz) δ 1.28 (s, 6H), 1.49 (s, 3H), 1.91 (m, 2H), 2.33 (m, 5H), 3.39 (m, 1H), 3.63 (s, 3H), 3.77 (m, 1H), 3.86 (bs, 3H), 7.06 (m, 1H), 7.80 (m, 1H). MS (ES+): 350 (M+H-100).
Reaction SMILES: [CH2:1]([O:13][CH:14]([CH3:18])[C:15](O)=[O:16])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].S(Cl)([Cl:21])=O>>[CH2:1]([O:13][CH:14]([CH3:18])[C:15]([Cl:21])=[O:16])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: O=S(Cl)Cl
Reactant: CCCCCCCCCCCCOC(C)C(=O)O
Product: CCCCCCCCCCCCOC(C)C(=O)Cl

Procedure:
10 ml of thionyl chloride was added to 2.0 g of α-dodecyloxypropionicacid, and the mixture was refluxed under heat for 2 hours. Excess of thionyl chloride was distilled off to obtain α-dodecyloxypropionic acid chloride. 20 ml of dry pyridine was added thereto, and 5.0 g of 4,4'-dihydroxybiphenyl was further added dropwise. After the addition, themixture was refluxed under heat for 3 hours, charged into ice water, and extracted with benzene. The extract was purified with a silica gel column chromatography to obtain 4-hydroxy-4'-α-dodecyloxypropanoyloxybiphenyl.
Reaction SMILES: C([N:4]1[C:12]2[C:7](=[C:8]([O:13][CH2:14][CH2:15][Cl:16])[CH:9]=[CH:10][CH:11]=2)[CH:6]=[N:5]1)(=O)C.Cl>CO>[Cl:16][CH2:15][CH2:14][O:13][C:8]1[CH:9]=[CH:10][CH:11]=[C:12]2[C:7]=1[CH:6]=[N:5][NH:4]2
Reactant: CC(=O)n1ncc2c(OCCCl)cccc21
Agent: Cl
Solvent: CO
Product: ClCCOc1cccc2[nH]ncc12
Temperature: 65 °C
Yield: 96.9 %

Procedure:
A stirred solution of 1-acetyl-4-(2-chloroethoxy)-indazole (1.50 g, 6.3 mmol) in methanol is treated with hydrochloric acid (6.3 ml, 1.0 M HCl in Et2O, 6.3 mmol) at room temperature, heated at 65° C. under nitrogen for 18 hr, cooled to room temperature and concentrated in vacuo. The resultant residue is neutralized with 1N NaOH (6.0 ml) and diluted with H2O and ethyl acetate. The phases are separated and the aqueous phase is extracted with ethyl acetate. The combined organic phases are washed with water and saturated NaCl, dried over Na2SO4 and concentrated in vacuo to afford the title product (1.2 g) as a yellow solid, identified by NMR and mass spectral analyses.
Reaction SMILES: FC(F)(F)C(O)=O.[CH3:8][O:9][C:10]1[CH:11]=[C:12]([CH:37]=[C:38]([O:40][CH3:41])[CH:39]=1)[CH2:13][CH2:14][C:15]1[CH:19]=[C:18]([NH:20][C:21](=[O:29])[C:22]2[CH:27]=[CH:26][C:25]([I:28])=[CH:24][CH:23]=2)[N:17](C(OC(C)(C)C)=O)[N:16]=1>C(Cl)Cl>[CH3:8][O:9][C:10]1[CH:11]=[C:12]([CH2:13][CH2:14][C:15]2[CH:19]=[C:18]([NH:20][C:21](=[O:29])[C:22]3[CH:23]=[CH:24][C:25]([I:28])=[CH:26][CH:27]=3)[NH:17][N:16]=2)[CH:37]=[C:38]([O:40][CH3:41])[CH:39]=1
Reactant: COc1cc(CCc2cc(NC(=O)c3ccc(I)cc3)n(C(=O)OC(C)(C)C)n2)cc(OC)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1cc(CCc2cc(NC(=O)c3ccc(I)cc3)[nH]n2)cc(OC)c1
Reaction time: 24 h
Yield: 24.3 %

Procedure:
Trifluoroacetic acid (3.85 mL, 50.02 mmol) was added in one portion to tert-butyl 3-(3,5-dimethoxyphenethyl)-5-(4-iodobenzamido)-1H-pyrazole-1-carboxylate (288 mg, 0.5 mmol) in DCM (10 mL) at room temperature. The resulting solution was stirred for 24 h. The reaction mixture was evaporated to dryness and redissolved in MeOH (5 mL). The crude product was purified by ion exchange chromatography, using a SCX column. The desired product was eluted from the column using 3.5M NH3/Methanol and pure fractions were evaporated to dryness to afford a tan solid. The solid was triturated with DCM to give the title compound (58.0 mg, 24.3%) as a white solid; 1H NMR (399.9 MHz, DMSO-d6) δ 2.88 (4H, s), 3.73 (6H, s), 6.33 (1H, t), 6.42 (2H, d), 6.47 (1H, s), 7.77 (2H, d), 7.87 (2H, d), 10.73 (1H, s), 12.17 (1H, s).
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[S:10][C:9]([CH2:11][OH:12])=[CH:8][C:6]=2[N:7]=1.[H-].[Na+].[CH3:21]I>CN(C=O)C>[Cl:1][C:2]1[N:3]=[C:4]([N:13]2[CH2:14][CH2:15][O:16][CH2:17][CH2:18]2)[C:5]2[S:10][C:9]([CH2:11][O:12][CH3:21])=[CH:8][C:6]=2[N:7]=1
Reactant: OCc1cc2nc(Cl)nc(N3CCOCC3)c2s1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COCc1cc2nc(Cl)nc(N3CCOCC3)c2s1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a solution of (2-chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidin-6-yl)-methanol (300 mg) in DMF (10 mL) at 0° C. was added sodium hydride (46 mg). The mixture was stirred for 1 h at 0° C. and then methyliodide (0.07 mL) was added. The reaction mixture was stirred at room temperature for 16 h and then quenched with water (20 mL) and extracted into ethyl acetate (2×20 mL). The combined organics were washed with aqueous brine solution (2×20 mL), dried (MgSO4) and concentrated to give 2-chloro-6-methoxymethyl-4-morpholin-4-yl-thieno[3,2-d]pyrimidine as a yellow solid (92 mg).
Reaction SMILES: [CH2:1]([CH:3]([C:6]1[N:11]2[N:12]=[C:13]([CH3:22])[C:14]([C:15]3[S:19][C:18](Cl)=[N:17][C:16]=3[Cl:21])=[C:10]2[N:9]=[C:8]([CH3:23])[CH:7]=1)[CH2:4][CH3:5])[CH3:2].CC(O)C.[NH:28]1[CH2:33][CH2:32][O:31][CH2:30][CH2:29]1>O>[CH2:1]([CH:3]([C:6]1[N:11]2[N:12]=[C:13]([CH3:22])[C:14]([C:15]3[S:19][C:18]([N:28]4[CH2:33][CH2:32][O:31][CH2:30][CH2:29]4)=[N:17][C:16]=3[Cl:21])=[C:10]2[N:9]=[C:8]([CH3:23])[CH:7]=1)[CH2:4][CH3:5])[CH3:2]
Reactant: C1COCCN1
Reactant: CCC(CC)c1cc(C)nc2c(-c3sc(Cl)nc3Cl)c(C)nn12
Solvent: O
Solvent: CC(C)O
Product: CCC(CC)c1cc(C)nc2c(-c3sc(N4CCOCC4)nc3Cl)c(C)nn12
Temperature: 20 °C
Reaction time: 0.08 h
Yield: 94.1 %

Procedure:
7-(1-ethyl-propyl)-3-(2,4-dichloro-thiazol-5-yl)-2,5-dimethyl-pyrazolo[1,5-a]pyrimidine (11.64 mmoles) is charged into a 100 mL 3-necked round bottomed flask followed by addition of 2-propanol (16 mL, 3.72 volumes). The yellowish brown slurry is stirred at about 20° C. for 5 min. Then morpholine (3.3 g, 37.84 mmoles) is added over 2-5 minutes. Contents are refluxed for 6 hr. The slurry is cooled to 25° C. 2-Propanol (32 mL, 7.44 volumes) and water (8.6 mL, 2.0 volumes) are added and the mixture warmed to 70-75° C., filtered and concentrated to ˜9 volumes at atmospheric pressure. The clear solution is gradually cooled to 55° C., seeded with 0.06 g of crystalline 7-(1-ethyl-propyl)-3-(4-chloro-2-morpholin-4-yl-thiazol-5-yl)-2,5-dimethyl-pyrazolo[1,5-a]pyrimidine slurried in 0.5 mL 2-propanol, rinsed with additional 0.5 mL 2-propanol and added to crystallization flask. The slurry is cooled to 0-5° C., maintained for 1 hr., filtered and the product rinsed with 2-propanol (9 mL, 2.1 volumes). Suctioned dried under vacuum at 60° C. to afford 4.6 g of dry 7-(1-ethyl-propyl)-3-(4-chloro-2-morpholin-4-yl-thiazol-5-yl)-2,5-dimethyl-pyrazolo[1,5-a]pyrimidine (88.8% yield, purity by HPLC assay is 99.88%). MS (ES)=420 (M+1).
Reaction SMILES: [NH2:1][C@H:2]([C:4]([N:6]1[CH2:20][CH2:19][CH2:18][C@H:7]1[C:8]([N:10]1[CH2:17][CH2:16][CH2:15][C@H:11]1[C:12]([OH:14])=[O:13])=[O:9])=[O:5])[CH3:3].[C:21]1([N:27]=[C:28]=[O:29])[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>[OH-].[Na+]>[C:21]1([NH:27][C:28]([NH:1][C@H:2]([C:4]([N:6]2[CH2:20][CH2:19][CH2:18][C@H:7]2[C:8]([N:10]2[CH2:17][CH2:16][CH2:15][C@H:11]2[C:12]([OH:14])=[O:13])=[O:9])=[O:5])[CH3:3])=[O:29])[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: C[C@H](N)C(=O)N1CCC[C@H]1C(=O)N1CCC[C@H]1C(=O)O
Reactant: O=C=Nc1ccccc1
Agent: [Na+]
Agent: [OH-]
Product: C[C@H](NC(=O)Nc1ccccc1)C(=O)N1CCC[C@H]1C(=O)N1CCC[C@H]1C(=O)O
Yield: 58.7 %

Procedure:
L-alanyl-L-prolyl-L-proline (3.00 g, 10.6 m mole) was dissolved in 1N aqueous sodium hydroxide (10.6 ml, 10.6 m mole), and phenylisocyanate (1.89 g, 15.9 m mole) was gradually added thereto while stirring and coating with ice. After that, the reaction solution was stirred overnight at room temperature. The pH value of the solution was about 7 and white crystals were given in the solution. The solution was adjusted to pH 12 with 1N aqueous sodium hydroxide and the insoluble matters were filtered off. The filtrate was washed with two 50 ml portions of ether and 6N hydrochloric acid was added thereto to adjust the pH value to 1.0. The solution was extracted with two 100 ml portions of ethyl acetate in order to separate the products. The ethyl acetate layer was washed with 10% aqueous sodium chloride, dried over anhydrous sodium sufate, and concentrated under reduced pressure. To the thus concentrated matter with crystals, ether was added to effect further crystallization. The crystals were obtained by filtration and dried to give N-phenylcarbamoyl-L-alanyl-L-prolyl-L-proline (2.50 g).
Reaction SMILES: [CH3:1][N:2]([CH3:11])[CH2:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[Li].N>C(O)C>[CH3:11][N:2]([CH3:1])[CH2:3][CH2:4][C:5]1[CH2:10][CH:9]=[CH:8][CH2:7][CH:6]=1
Reactant: CN(C)CCc1ccccc1
Agent: N
Agent: [Li]
Solvent: CCO
Product: CN(C)CCC1=CCC=CC1

Procedure:
45 g. (0.3 moles) of the dimethylphenethylamine is reduced by treatment with 16 g. of lithium (2.3 g. atom) in 1.5 l. of ammonia and 250 ml. of ethanol according to the procedure of Example 1(a) to yield crude 1-[2-(dimethylamino)ethyl]-1,4-cyclohexadiene.
Reaction SMILES: [I:1][C:2]1[C:3]([C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([N+:13]([O-:15])=[O:14])[CH:8]=2)=[N:4][NH:5][CH:6]=1.[C:16](=[O:19])([O-])[O-].[Cs+].[Cs+].[Cl-].O>CN(C)C=O>[I:1][C:2]1[C:3]([C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([N+:13]([O-:15])=[O:14])[CH:8]=2)=[N:4][N:5]([CH2:3][C:7]2[CH:12]=[CH:11][C:10]([O:19][CH3:16])=[CH:9][CH:8]=2)[CH:6]=1
Reactant: O=[N+]([O-])c1cccc(-c2n[nH]cc2I)c1
Reactant: O=C([O-])[O-]
Agent: [Cl-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc(Cn2cc(I)c(-c3cccc([N+](=O)[O-])c3)n2)cc1
Temperature: 70 °C
Reaction time: 5 h

Procedure:
2 g (6.3 mmol) of 4-iodo-3-(3-nitrophenyl)-1H-pyrazole were dissolved in 20 ml of dry dimethylformamide and 2.46 g (7.5 mmol) of cesium carbonate and 0.85 ml (6.3 mmol) of p-methoxybemzyl chloride were added successively. The reaction mixture was heated at 70° C. under stirring for 5 hours. Water was then added and the product extracted with dichloromethane. The organic phase was dried over sodium sulphate and the solvent evaporated under reduced pressure. 2.4 g (86%) of the title compound crystallized from a mixture diethylether-diisopropylether.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([C:8](Cl)=[O:9])[CH:3]=1.C(N(C(C)C)C(C)C)C.[C:20]([N:27]1[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1)([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21]>ClCCl>[C:23]([O:22][C:20]([N:27]1[CH2:32][CH2:31][N:30]([C:8]([C:4]2[CH:3]=[C:2]([Cl:1])[CH:7]=[CH:6][N:5]=2)=[O:9])[CH2:29][CH2:28]1)=[O:21])([CH3:26])([CH3:24])[CH3:25]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: O=C(Cl)c1cc(Cl)ccn1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCN(C(=O)c2cc(Cl)ccn2)CC1
Temperature: 25 °C
Reaction time: 12 h
Yield: 51.3 %

Procedure:
To a dichloromethane solution (4 ml) of 4-chloropicolinic acid chloride (175 mg, 0.994 mmol), N-ethyldiisopropylamine (346 μl, 1.99 mol) and N-Boc-piperazine (278 mg, 1.49 mmol) were added, followed by stirring at room temperature for 12 hours. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (dichloromethane/methanol=60/1), to obtain 4-(4-chloro-pyridine-2-carbonyl)-piperazine-1-carboxylic acid tert-butyl ester (166 mg, 51%).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:7]1[CH:11]=[C:10]([NH:12][C:13](=[O:21])OC2C=CC=CC=2)[N:9]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[N:8]=1)([CH3:6])[CH3:5])[CH3:2].[CH3:28][O:29][C:30]1[CH:31]=[C:32]2[C:37](=[CH:38][C:39]=1[O:40][CH3:41])[N:36]=[CH:35][N:34]=[C:33]2[O:42][C:43]1[CH:44]=[C:45]([CH:47]=[CH:48][CH:49]=1)[NH2:46].C(N(CC)C(C)C)(C)C>C1COCC1>[CH3:28][O:29][C:30]1[CH:31]=[C:32]2[C:37](=[CH:38][C:39]=1[O:40][CH3:41])[N:36]=[CH:35][N:34]=[C:33]2[O:42][C:43]1[CH:44]=[C:45]([NH:46][C:13]([NH:12][C:10]2[N:9]([C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=3)[N:8]=[C:7]([C:4]([O:3][CH2:1][CH3:2])([CH3:5])[CH3:6])[CH:11]=2)=[O:21])[CH:47]=[CH:48][CH:49]=1
Reactant: COc1cc2ncnc(Oc3cccc(N)c3)c2cc1OC
Reactant: CCOC(C)(C)c1cc(NC(=O)Oc2ccccc2)n(-c2ccccc2)n1
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(C)(C)c1cc(NC(=O)Nc2cccc(Oc3ncnc4cc(OC)c(OC)cc34)c2)n(-c2ccccc2)n1
Temperature: 50 °C
Yield: 60.2 %

Procedure:
Using the procedure described in Example 159B, phenyl 3-(2-ethoxypropan-2-yl)-1-phenyl-1H-pyrazol-5-ylcarbamate (0.115 g, 0.33 mmol), 3-(6,7-dimethoxyquinazolin-4-yloxy)aniline from Example 113A (0.098 g, 0.33 mmol), and N,N-diisopropylethylamine (0.8 mL) in THF (6 mL) were heated at 50° C. for 5 hours, to afford 1-[3-(6,7-dimethoxyquinazolin-4-yloxy)phenyl]-3-[3-(2-ethoxypropan-2-yl)-1-phenyl-1H-pyrazol-5-yl]urea as solid (0.113 g, 60%). 1H NMR (300 MHz, DMSO-d6) δ 9.25 (br, 1H), 8.55 (s, 1H), 8.54 (s, 1H), 7.54 (m, 6H), 7.39 (m, 3H), 7.18 (d, 1H), 6.93 (d, 1H), 6.41 (s, 1H), 3.77 (s, 3H), 3.98 (s, 3H), 3.25 (q, 2H), 1.45 (s, 6H), 1.03 (t, 3H); LC-MS (ESI) m/z 523 (M−OEt)+.
Reaction SMILES: Br[CH2:2][C:3]1[C:8]([CH3:9])=[N:7][C:6]([CH3:10])=[C:5]([CH3:11])[N:4]=1.[OH:12][C:13]1[CH:23]=[CH:22][C:16]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:15][CH:14]=1.C(=O)([O-])[O-].[K+].[K+].CN(C=O)C>O>[CH2:20]([O:19][C:17](=[O:18])[C:16]1[CH:22]=[CH:23][C:13]([O:12][CH2:2][C:3]2[C:8]([CH3:9])=[N:7][C:6]([CH3:10])=[C:5]([CH3:11])[N:4]=2)=[CH:14][CH:15]=1)[CH3:21]
Reactant: Cc1nc(C)c(CBr)nc1C
Reactant: CCOC(=O)c1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)c1ccc(OCc2nc(C)c(C)nc2C)cc1
Temperature: 85 °C
Yield: 63.3 %

Procedure:
Adding 2-bromomethyl-3,5,6-trimethylpyrazine (0.86 g, 0.0040 mol), ethyl p-hydroxybenzoate (0.948 g, 0.0057 mol), anhydrous potassium carbonate (1.38 g, 0.0103 mol), and DMF (60 mL) into a 100 mL three-necked bottle in turn, heating to 85° C. with oil bath, stirring to react for 12 hours, TLC [V(cyclohexane):V(ethyl acetate)=3:1 as developing agent] detecting shows that reaction is complete, (Rf of raw material=0.5, Rf of product=0.4), and the reaction solution appears yellow, filtering to obtain yellow filtrate, adding 30 mL water, extracting with chloroform (3×30 mL), incorporating the chloroform layer and wishing with water (2×20 mL), drying with anhydrous sodium sulfate, recycling chloroform under reduced pressure to obtain a light yellow oily matter, separating with a silica column, wherein eluant is V(cyclohexane):V(ethyl acetate)=3:1, collecting product, rotating distilling to obtain light yellow solid, recrystallizing with anhydrous alcohol to obtain 0.76 g 4-((3,5,6-trimethylpyrazine-2-yl)methoxyl)benzoic acid ethyl ester, a yield is 63.3%, m.p. 75.0-75.7° C.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([S:10](Cl)(=[O:12])=[O:11])[CH:7]=[CH:8][CH:9]=1)([O-])=O.[CH3:14][N:15]1[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]1>>[CH3:14][N:15]1[CH2:20][CH2:19][N:18]([S:10]([C:6]2[CH:5]=[C:4]([NH2:1])[CH:9]=[CH:8][CH:7]=2)(=[O:12])=[O:11])[CH2:17][CH2:16]1
Reactant: CN1CCNCC1
Reactant: O=[N+]([O-])c1cccc(S(=O)(=O)Cl)c1
Product: CN1CCN(S(=O)(=O)c2cccc(N)c2)CC1

Procedure:
The title compound was prepared following the procedure of intermediate Example 2 with to 3-Nitro-benzenesulfonyl chloride (4.4 g, 20 mmol) and N-methyl-piperazine (2.2 ml 20 mmol) as an off white solid (3.6 g, 70%). MS (ESI) m/z=256 [M+H]+.
Reaction SMILES: CC(C)[CH2:3][O:4]CC1OC1.N1CCCC1.C[CH:16]([CH3:28])[CH2:17][O:18][CH2:19][CH:20]([OH:27])[CH2:21][N:22]1[CH2:26][CH2:25][CH2:24][CH2:23]1>C(O)C>[CH3:3][O:4][CH:16]([CH3:28])[CH2:17][O:18][CH2:19][CH:20]([OH:27])[CH2:21][N:22]1[CH2:23][CH2:24][CH2:25][CH2:26]1
Reactant: CC(C)COCC(O)CN1CCCC1
Reactant: CC(C)COCC1CO1
Solvent: CCO
Solvent: C1CCNC1
Product: COC(C)COCC(O)CN1CCCC1
Reaction time: 1 h

Procedure:
20 g. 1-(2-Methylpropoxy)-2,3-epoxypropane are dissolved in 40 ml. ethanol and the solution is warmed to 55° C. Subsequently, in the course of an hour and while stirring, there is added dropwise a solution of 13 g. pyrrolidine in 25 ml. ethanol. The temperature should thereby not increase above 70° C. After completion of the addition, stirring is continued for 1 hour at 70° C., the reaction mixture is then evaporated and the residue is distilled in a vacuum. There are obtained 35 g. 3-(2-methylpropoxy)-1-pyrrolidinopropan-2-ol; b.p. 134° C./14 mm.Hg.
Reaction SMILES: I/[CH:2]=[CH:3]\[CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[I-].[Li+].C([Li])CCC.Cl[SiH:17]([CH:21]([CH3:23])[CH3:22])[CH:18]([CH3:20])[CH3:19]>>[CH:2]([SiH:17]([CH:21]([CH3:23])[CH3:22])[CH:18]([CH3:20])[CH3:19])=[CH:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: CC(C)[SiH](Cl)C(C)C
Reactant: CCCCC/C=C\I
Agent: [I-]
Agent: [Li+]
Agent: [Li]CCCC
Product: CCCCCC=C[SiH](C(C)C)C(C)C
Yield: 95 %

Procedure:
To investigate the influence of the non-transferable groups on the silicon atom (and illustrate an alternative entry to the silanol precurors) di(isopropyl(silanols (E)-52 and (Z)-52 (Scheme 6) were prepared. Catalytic (H2PtCl6) hydrosilylation of 1-heptyne with chlorodi(isopropyl)silane followed by alkaline hydrolysis provided (E)-52 in 78% yield (25). The stereoisomer (Z)-52, was produced by a high yielding four-step synthesis starting from (Z)-1-iodo-1-heptene. Lithium-iodide exchange with n-butyllithium, followed by the addition of chlorodi(isopropyl)silane formed the intermediate (1-heptenyl)di(isopropyl)silane in 95% yield. Oxidation with chlorine (0.9 M solution in CCl4), followed by mild hydrolysis produced (Z)-52 in 90% yield over two steps.