Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].[CH3:5][C:6]1[C:12]([F:13])=[CH:11][CH:10]=[CH:9][C:7]=1[NH2:8].C(N(CC)CC)C>C(Cl)Cl>[C:1]([NH:8][C:7]1[CH:9]=[CH:10][CH:11]=[C:12]([F:13])[C:6]=1[CH3:5])(=[O:3])[CH3:2]
Reactant: CC(=O)Cl
Reactant: Cc1c(N)cccc1F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)Nc1cccc(F)c1C
Temperature: 25 °C
Reaction time: 1 h
Yield: 91 %

Procedure:
1.98 ml (27.78 mmol) of acetyl chloride were added, with stirring, to a solution of 3.161 g (25.26 mmol of 2-methyl-3-fluoroaniline and 3.87 ml (27.78 mmol) of triethylamine in 50 ml of DCM at 0° C. The solution was allowed to warm up to ambient temperature and was stirred for 1 hour. The solution was washed with water (3 times 50 ml), the product was dried with MgSO4 and the solvent was removed under reduced pressure. After recrystallization from a mixture of mineral oil/ethyl acetate (EtOac), 3.844 g (91%) of the title compound were obtained in the form of white crystals.
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6]([OH:8])=O)[N:3]=[N:2]1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH3:42][O:43][C:44]([CH2:46][O:47][C:48](=[O:69])[C@@:49]([CH2:67][OH:68])([CH3:66])[CH2:50][C@H:51]([NH2:65])[CH2:52][C:53]1[CH:58]=[CH:57][C:56]([C:59]2[CH:64]=[CH:63][CH:62]=[CH:61][CH:60]=2)=[CH:55][CH:54]=1)=[O:45]>CN(C=O)C>[CH3:42][O:43][C:44]([CH2:46][O:47][C:48](=[O:69])[C@@:49]([CH2:67][OH:68])([CH3:66])[CH2:50][C@H:51]([NH:65][C:6]([C:4]1[NH:3][N:2]=[N:1][CH:5]=1)=[O:8])[CH2:52][C:53]1[CH:54]=[CH:55][C:56]([C:59]2[CH:64]=[CH:63][CH:62]=[CH:61][CH:60]=2)=[CH:57][CH:58]=1)=[O:45]
Reactant: O=C(O)c1c[nH]nn1
Reactant: COC(=O)COC(=O)[C@](C)(CO)C[C@H](N)Cc1ccc(-c2ccccc2)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)COC(=O)[C@](C)(CO)C[C@@H](Cc1ccc(-c2ccccc2)cc1)NC(=O)c1cnn[nH]1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 30.2 %

Procedure:
1,2,3-Triazole-4-carboxylic acid (14 mg, 124 μmol), DIPEA (86.3 μL, 496 μmol) and HATU (47.1 mg, 124 μmol) were combined in DMF (0.2 mL) and stirred for 5 minutes at room temperature. This was then combined with (2S,4R)-4-amino-5-biphenyl-4-yl-2-hydroxymethyl-2-methyl-pentanoic acid methoxycarbonylmethyl ester (47.8 mg, 124 μmol). The resulting mixture was stirred for 15 minutes and the reaction was quenched with AcOH. The product purified by preparative HPLC and lyophilized to yield the title compound (18 mg; purity 95%). MS m/z [M+H]+ calc'd for C25H28N4O6, 481.20. found 481.2.
Reaction SMILES: [CH:1]1(N=C=NC2CCCCC2)CCCC[CH2:2]1.[CH3:16][C:17]1[S:21][C:20]([C:22]([OH:24])=[O:23])=[CH:19][CH:18]=1.C(O)C.CN(C1C=CC=CN=1)C>ClCCl>[CH3:16][C:17]1[S:21][C:20]([C:22]([O:24][CH2:1][CH3:2])=[O:23])=[CH:19][CH:18]=1
Reactant: C(=NC1CCCCC1)=NC1CCCCC1
Reactant: Cc1ccc(C(=O)O)s1
Agent: CN(C)c1ccccn1
Solvent: ClCCl
Solvent: CCO
Product: CCOC(=O)c1ccc(C)s1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
To a stirred solution of 15.9 g (77.4 mmol) of 1,3-dicyclohexylcarbodiimide in 40 mL dichloromethane was added 10 g (70.3 mmol) of 5-methyl-2-thiophenecaboxylic acid and 4.85 g (105.5 mmol) of anhydrous ethanol. 0.86 g of dimethylaminopyridine was then added and the suspension stirred at room temperature for 20 hours. The resulting white precipitate was removed by filtration. The filtrate was washed with water, dried (MgSO4), filtered and concentrated under reduced pressure. The residue was purified by bulb-to-bulb distillation (bp=95° C. 3 mm Hg) to give the title compound as a clear, pale yellow oil.
Reaction SMILES: [Cl:1][C:2]1[CH:12]=[CH:11][C:10]([N:13]2[C:18](=[O:19])[C:17]3[CH2:20][S:21][CH2:22][C:16]=3[NH:15][C:14]2=[O:23])=[CH:9][C:3]=1[C:4]([O:6][CH2:7][CH3:8])=[O:5].[CH3:24]N(C)C=O>>[Cl:1][C:2]1[CH:12]=[CH:11][C:10]([N:13]2[C:18](=[O:19])[C:17]3[CH2:20][S:21][CH2:22][C:16]=3[N:15]([CH3:24])[C:14]2=[O:23])=[CH:9][C:3]=1[C:4]([O:6][CH2:7][CH3:8])=[O:5]
Reactant: CN(C)C=O
Reactant: CCOC(=O)c1cc(-n2c(=O)[nH]c3c(c2=O)CSC3)ccc1Cl
Product: CCOC(=O)c1cc(-n2c(=O)c3c(n(C)c2=O)CSC3)ccc1Cl

Procedure:
using ethyl 2-chloro-5-{1,2,5,7-tetrahydro-2,4-dioxo-thieno[3,4-d]pyrimidin-3(4H)-yl}-benzoate in dimethylformamide there is obtained ethyl 2-chloro-5-{1,2,5,7-tetrahydro-1-methyl-2,4-dioxo-thieno[3,4-d]pyrimidin-3(4H)-yl}-benzoate, m.p. 203°-206° C.,
Reaction SMILES: [F:1][CH:2]([F:15])[O:3][C:4]1[N:8]([CH3:9])[N:7]=[C:6]([C:10]([F:13])([F:12])[F:11])[C:5]=1[CH3:14].S(Cl)([Cl:19])(=O)=O.N(C(C)(C)C#N)=NC(C)(C)C#N.O>C(Cl)(Cl)(Cl)Cl>[Cl:19][CH2:14][C:5]1[C:6]([C:10]([F:13])([F:12])[F:11])=[N:7][N:8]([CH3:9])[C:4]=1[O:3][CH:2]([F:1])[F:15]
Reactant: Cc1c(C(F)(F)F)nn(C)c1OC(F)F
Reactant: O=S(=O)(Cl)Cl
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: O
Solvent: ClC(Cl)(Cl)Cl
Product: Cn1nc(C(F)(F)F)c(CCl)c1OC(F)F
Yield: 36.3 %

Procedure:
To a solution of 11.5 g (50.0 mmol) of 5-difluoromethoxy-1,4-dimethyl-3-trifluoromethyl-1H-pyrazole in 50 ml of carbon tetrachloride were added 10.1 g (75.0 mmol) of sulfuryl chloride and 0.8 (5.0 mmol) of α,α′-azobisisobutyronitrile, followed by heating and refluxing under stirring. The reaction solution was externally irradiated with a light for 11 hours. After the completion of the reaction was confirmed, the reaction solution was poured into water and extracted with chloroform. The resulting organic layer was washed with water and saline, successively, and then dried over anhydrous magnesium sulfate. The solvent was removed by evaporation under reduced pressure and the residue was purified by silica gel column chromatography to obtain 4.8 g (purity: 83.4%, yield: 30.3%) of 4-chloromethyl-5-difluoromethoxy-1-methyl-3-trifluoromethyl-1H-pyrazole as a colorless transparent liquid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[CH:9]([CH3:15])[NH:8][CH2:7][CH2:6]2.C(N(CC)CC)C.[C:23]([O:26][C:27]1[CH:32]=[CH:31][C:30]([CH2:33][C:34](Cl)=[O:35])=[CH:29][CH:28]=1)(=[O:25])[CH3:24]>C(Cl)(Cl)Cl>[C:23]([O:26][C:27]1[CH:32]=[CH:31][C:30]([CH2:33][C:34]([N:8]2[CH2:7][CH2:6][C:5]3[C:10](=[CH:11][C:12]([O:13][CH3:14])=[C:3]([O:2][CH3:1])[CH:4]=3)[CH:9]2[CH3:15])=[O:35])=[CH:29][CH:28]=1)(=[O:25])[CH3:24]
Reactant: COc1cc2c(cc1OC)C(C)NCC2
Reactant: CC(=O)Oc1ccc(CC(=O)Cl)cc1
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: COc1cc2c(cc1OC)C(C)N(C(=O)Cc1ccc(OC(C)=O)cc1)CC2
Temperature: 25 °C
Reaction time: 16 h
Yield: 90.1 %

Procedure:
To a stirred solution of 1,2,3,4-tetrahydro-6,7-dimethoxy-1-methylisoquinoline (20.0 g, 0.097 m) and triethylamine (9.8 ml, 0.097 m) in chloroform (200 ml) under nitrogen was added dropwise a solution of 4-acetoxyphenylacetyl chloride (20.3 g, 0.097 m) in 50 ml chloroform and the mixture stirred at ambient temperature for 16 hours. The mixture was washed with 10% HCl (3×200 ml), water (200 ml), saturated sodium carbonate (3×150 ml) and water (200 ml) and the chloroform layer dried over MgSO4. Evaporation of the solvent afforded 33.0 g of N-(4-acetoxyphenylacetyl)-1,2,3,4-tetrahydro-6,7-dimethoxy-1-methylisoquinoline as a pale yellow oil (89% yield).
Reaction SMILES: [CH:1]1([C:4]2[CH:5]=[C:6]([NH2:9])[NH:7][N:8]=2)[CH2:3][CH2:2]1.[Cl:10][C:11]1[N:16]=[C:15](Cl)[N:14]=[C:13]([Cl:18])[N:12]=1>C1COCC1>[CH:1]1([C:4]2[CH:5]=[C:6]([NH:9][C:15]3[N:14]=[C:13]([Cl:18])[N:12]=[C:11]([Cl:10])[N:16]=3)[NH:7][N:8]=2)[CH2:3][CH2:2]1
Reactant: Clc1nc(Cl)nc(Cl)n1
Reactant: Nc1cc(C2CC2)n[nH]1
Solvent: C1CCOC1
Product: Clc1nc(Cl)nc(Nc2cc(C3CC3)n[nH]2)n1
Reaction time: 1 h
Yield: 50.4 %

Procedure:
A solution of 5-Cyclopropyl-2H-pyrazol-3-ylamine(334 mg, 2.71 mmol) in 2 ml of THF was added dropwise to a solution of 2,4,6-Trichloro-[1,3,5]triazine (500 mg, 2.71 mmol) in 5 ml of THF at room temperature. After 1 hour, the precipitate was collected to afford 370 mg (50.4% yield) of the desired product.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[CH3:9].[CH:10](=O)[C:11]1[C:12](=[CH:14][CH:15]=[CH:16][CH:17]=1)[OH:13].C(OCC)(=O)C>CCCCCC>[OH:13][C:12]1[CH:14]=[CH:15][CH:16]=[CH:17][C:11]=1[CH:10]=[N:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[CH3:9]
Reactant: Cc1cc(O)ccc1N
Reactant: O=Cc1ccccc1O
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: Cc1cc(O)ccc1N=Cc1ccccc1O
Temperature: 25 °C
Reaction time: 19 h
Yield: 93 %

Procedure:
To a 500 milliliter round bottom flask equipped with a water condenser, magnetic stirrer and drying tube was added 12.32 grams (0.10 mole) of 4-amino-3-methylphenol, 12.21 grams (0.10 mole) of salicylaldehyde and 250 milliliters of ethyl acetate. The resulting reaction mixture was stirred for 19 hours at room temperature and ambient pressure. After the stirring period, the reaction mixture was washed twice with saturated brine solution and decolorized with activated charcoal. The reaction mixture was then dried over magnesium sulfate, filtered and concentrated under reduced pressure to give a yellow oil which solidified on standing. The resulting solidified material was slurried in hexane, collected by filtration and dried to yield 21.12 grams (0.093 moles) of 4-(2-hydroxybenzylideneamino)-3-methylphenol in the form of a yellow solid having a melting point of 95°-97° C.
Reaction SMILES: Cl[C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[C@H:11]1[CH2:14][C@H:13]([NH:15][C:16]2[N:25]=[CH:24][C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[N:17]=2)[CH2:12]1.[CH3:26][O:27][C:28]([C:30]1[CH:35]=[CH:34][C:33](B(O)O)=[CH:32][CH:31]=1)=[O:29].C(=O)([O-])[O-].[Cs+].[Cs+]>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>[N:17]1[C:18]2[C:23](=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:24]=[N:25][C:16]=1[NH:15][C@H:13]1[CH2:14][C@H:11]([N:6]2[CH:5]=[N:4][C:3]3[C:7]2=[N:8][CH:9]=[N:10][C:2]=3[C:33]2[CH:34]=[CH:35][C:30]([C:28]([O:27][CH3:26])=[O:29])=[CH:31][CH:32]=2)[CH2:12]1
Reactant: COC(=O)c1ccc(B(O)O)cc1
Reactant: Clc1ncnc2c1ncn2[C@H]1C[C@H](Nc2ncc3ccccc3n2)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: [Cs+]
Solvent: O
Solvent: C1COCCO1
Product: COC(=O)c1ccc(-c2ncnc3c2ncn3[C@H]2C[C@H](Nc3ncc4ccccc4n3)C2)cc1
Temperature: 120 °C

Procedure:
N-(Trans-3-(6-chloro-9H-purin-9-yl)cyclobutyl)quinazolin-2-amine (example 21, 0.110 g, 0.313 mmol), tetrakis(triphenylphosphine)palladium (0.018 g, 0.016 mmol), (4-methoxycarbonylphenyl)boronic acid (0.073 g, 0.406 mmol), and cesium carbonate (0.357 g, 1.094 mmol) were suspended in a mixture of dioxane (1.25 mL) and water (0.15 mL) and heated in the microwave to 120° C. for 25 minutes. The crude was partitioned between ethyl acetate (200 mL) and water (200 mL). The organic phase was dried with magnesium sulfate and evaporated to dryness under reduced pressure. Purification using silica chromatography (0-3% methanol in dichloromethane gradient) gave the desired methyl 4-(9-(trans-3-(quinazolin-2-ylamino)cyclobutyl)-9H-purin-6-yl)benzoate (0.0531 g, 0.118 mmol, 37.6% yield). M+1: 452.1. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 2.89 (ddd, J=13.60, 8.51, 4.89 Hz, 2 H) 3.15-3.33 (m, 2 H) 3.98 (s, 3 H) 4.89-5.00 (m, 1 H) 5.44 (quin, J=7.34 Hz, 1 H) 7.30-7.35 (m, 1 H) 7.65 (d, J=8.41 Hz, 1 H) 7.69-7.81 (m, 2 H) 8.24 (d, J=8.41 Hz, 2 H) 8.45 (s, 1 H) 8.84 (d, J=8.41 Hz, 2 H) 9.01-9.14 (m, 2 H).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]2[C:10](=[CH:11][C:12]=1[CH3:13])[C:8](=[O:9])[CH:7]=[CH:6][C:5]2=[O:14].[Br:15]Br.C([O-])(=O)C.[Na+].O>C(O)(=O)C>[Br:15][C:6]1[C:5]([C:4]2[C:10]([C:8](=[O:9])[CH:7]=1)=[CH:11][C:12]([CH3:13])=[C:2]([CH3:1])[CH:3]=2)=[O:14]
Reactant: Cc1cc2c(cc1C)C(=O)C=CC2=O
Reactant: BrBr
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: Cc1cc2c(cc1C)C(=O)C(Br)=CC2=O
Reaction time: 2 h

Procedure:
A solution of 6,7-dimethyl naphtho-1,4-quinone (20.0 g.; 0.107 mole) in glacial acetic acid (250 ml) was stirred during the dropwise addition of bromine (5.6 ml; 17.2 g; 0.107 mole) in acetic acid (10 ml.) at 15° C. and allowed to stir at this temperature for a further 2 hours. Anhydrous sodium acetate (20 g) was added and the mixture stirred at 100° C. for 11/2 hours after an initial half hour period at room temperature; cooled, poured into water (2.5 l) and the yellow bromo product filtered off. It had m.p. (ethanol, chloroform) 156°-159° C. (Found; C, 53.47; H, 3.39; Br, 30.23; C12H9BrO2 requires; C, 54.36; H, 3.42; Br, 30.14%):
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[C:11]1(=[O:17])[O:16][C:14](=[O:15])[CH2:13][CH2:12]1.[Al+3].[Cl-].[Cl-].[Cl-]>>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]([CH2:12][CH2:13][C:14]([OH:16])=[O:15])=[O:17])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: O=C1CCC(=O)O1
Reactant: CC(C)(C)c1ccccc1
Agent: [Al+3]
Agent: [Cl-]
Product: CC(C)(C)c1ccc(C(=O)CCC(=O)O)cc1
Yield: 68 %

Procedure:
tert-Butylbenzene 10e (99%, 4.3 eq) was reacted with succinic anhydride (99%, 1 eq) and AlCl3 (95%, 2 eq) for 120 h according to the general procedure. Extractive purification of the crude product afforded white crystals of 11e in 68% yield. 1H-NMR: 7.93 (d, 2H Ar--H); 7.48 (d, 2H, Ar--H); 3.30 (t, 2H, CH2CH2COOH); 2.81 (t, 2H, CH2CH2COOH); 1.34 (s, 9H, CH3).
Reaction SMILES: Br[C:2]1[O:6][C:5]([C:7]2[CH:14]=[CH:13][C:10]([C:11]#[N:12])=[CH:9][N:8]=2)=[CH:4][CH:3]=1.[Br-].[C:16]([C:18]1[CH:25]=[CH:24][C:21]([CH2:22][Zn+])=[CH:20][CH:19]=1)#[N:17]>O1CCCC1.ClCCl.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Pd]>[C:16]([C:18]1[CH:25]=[CH:24][C:21]([CH2:22][C:2]2[O:6][C:5]([C:7]3[CH:14]=[CH:13][C:10]([C:11]#[N:12])=[CH:9][N:8]=3)=[CH:4][CH:3]=2)=[CH:20][CH:19]=1)#[N:17]
Reactant: N#Cc1ccc(C[Zn+])cc1
Reactant: N#Cc1ccc(-c2ccc(Br)o2)nc1
Agent: [Pd]
Agent: [Br-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: ClCCl
Product: N#Cc1ccc(Cc2ccc(-c3ccc(C#N)cn3)o2)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 48 %

Procedure:
Continuing with Scheme 7, a solution of 2 (996 mg, 4 mmol) in tetrahydrofuran (25 mL) was added palladium tetrakis(triphenyl-phosphine) (228 mg) and p-cyanobenzyl zinc bromide (12 mL, 0.5 M in THF, 6 mmol). The reaction mixture was stirred 24 h at room temperature. The mixture was diluted with dichloromethane, washed with saturated NH4Cl and the organic layer was dried over anhydrous Na2SO4. After filtration and on concentration the residue was purified by chromatography (SiO2), hexanes (100–40%)/EtOAc (0–60%), to afford 35 in 48% yield, mp 204–206° C. 1H nmr (DMSO-d6); δ 4.23 (s, 2H), 6.46 (d, J=3.3 Hz, 1H), 7.27 (d, J=3.3 Hz, 1H), 7.51 (d, J=8.1 Hz, 2H), 7.77 (d, J=8.1 Hz, 2H), 7.79 (d, J=8.4 Hz, 1H), 8.25 (dd, J=8.4 Hz, 1.8 Hz, 1H), 8.92 (d, J=1.8 Hz, 1H). 13C nmr; δ 156.3, 152.6, 150.9, 150.6, 143.2, 140.5, 132.4, 129.6, 118.6, 117.5, 117.1, 113.5, 110.3, 109.5, 106.0, 33.5.
Reaction SMILES: [CH2:1]([O:3][C:4](/[CH:6]=[C:7]1\[CH2:8][N:9]([C:14]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:10][CH2:11][CH:12]\1[OH:13])=[O:5])[CH3:2].[Si:33](Cl)([C:36]([CH3:39])([CH3:38])[CH3:37])([CH3:35])[CH3:34].N1C=CN=C1>CN(C)C=O.CN(C)C1C=CN=CC=1.C(OCC)(=O)C>[Si:33]([O:13][CH:12]1[CH2:11][CH2:10][N:9]([C:14]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)([C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)[C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH2:8]/[C:7]/1=[CH:6]\[C:4]([O:3][CH2:1][CH3:2])=[O:5])([C:36]([CH3:39])([CH3:38])[CH3:37])([CH3:35])[CH3:34]
Reactant: CCOC(=O)/C=C1\CN(C(c2ccccc2)(c2ccccc2)c2ccccc2)CCC1O
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: CN(C)c1ccncc1
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOC(=O)/C=C1\CN(C(c2ccccc2)(c2ccccc2)c2ccccc2)CCC1O[Si](C)(C)C(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 86.3 %

Procedure:
To a solution of (E)-3-[(ethoxycarbonyl)methylidene]-1-(triphenylmethyl)piperidin-4-ol (14.97 g) in N,N-dimethylformamide (130 ml) were added successively t-butyldimethylsilyl chloride (6.86 g), 1H-imidazole (3.34 g) and 4-dimethylaminopyridine (0.43 g) under ice-cooling, and the resulting mixture was stirred at room temperature overnight. The reaction mixture was diluted with ethyl acetate and washed with saturated aqueous sodium chloride solution. The organic layer was dried over anhydrous sodium sulfate. The solvent was removed, and the residue was purified by chromatography on a silica gel column using a mixed solvent of ethyl acetate and hexane (1:19) as the eluent to afford the title compound (16.38 g, yield: 86%) as a colourless amorphous solid.
Reaction SMILES: [C:1](Cl)(Cl)=[O:2].[CH2:5]([O:7][Si:8]([O:16][CH2:17][CH3:18])([O:13][CH2:14][CH3:15])[CH2:9][CH2:10][CH2:11][NH2:12])[CH3:6].CN(C)C1C=CC=CC=1>C1(C)C=CC=CC=1>[CH2:14]([O:13][Si:8]([O:16][CH2:17][CH3:18])([O:7][CH2:5][CH3:6])[CH2:9][CH2:10][CH2:11][N:12]=[C:1]=[O:2])[CH3:15]
Reactant: CCO[Si](CCCN)(OCC)OCC
Reactant: O=C(Cl)Cl
Solvent: CN(C)c1ccccc1
Solvent: Cc1ccccc1
Product: CCO[Si](CCCN=C=O)(OCC)OCC
Yield: 80.2 %

Procedure:
In 150 ml of toluene was dissolved 9.9 g of carbonyl chloride, and a solution of 22.1 g of γ-triethoxysilylpropylamine and 27.9 g of N,N-dimethylaniline in 50 ml of toluene was dropped into the above solution at -5° C. to -10° C. over a period of 3 hours to effect reaction. After the reaction, the crystal of N,N-dimethylaniline chloride was removed by filtration and the filtrate was subjected to distillation to recover toluene, whereby 19.8 g of γ-triethoxysilylpropyl isocyanate was obtained as a fraction having a boiling point of 88° C. to 91° C. under 4.5 mmHg.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[CH:10][C:11]([C:14](=O)[CH2:15][CH2:16][C:17]([F:20])([F:19])[F:18])=[N:12][CH:13]=2)=[CH:4][CH:3]=1.Cl.[CH3:23][O:24][NH2:25].N1C=CC=CC=1>O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[CH:10][C:11]([C:14](=[N:25][O:24][CH3:23])[CH2:15][CH2:16][C:17]([F:20])([F:19])[F:18])=[N:12][CH:13]=2)=[CH:4][CH:3]=1
Reactant: O=C(CCC(F)(F)F)c1ccc(-c2ccc(Cl)cc2)cn1
Reactant: CON
Agent: Cl
Solvent: O
Solvent: c1ccncc1
Product: CON=C(CCC(F)(F)F)c1ccc(-c2ccc(Cl)cc2)cn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 93.9 %

Procedure:
A mixture of 1-(5-(4-chlorophenyl)pyridin-2-yl)-4,4,4-trifluorobutan-1-one (821.7 mg), O-methylhydroxylamine hydrochloride (656 mg) and pyridine (5.239 mL) was stirred at room temperature overnight, and water was added. The mixture was extracted with ethyl acetate, and the extract was washed with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (842.7 mg).
Reaction SMILES: [F:1][C:2]1[CH:16]=[CH:15][C:5]2[C:6]([CH:9]3[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]3)=[N:7][O:8][C:4]=2[CH:3]=1.C([O-])([O-])=O.[K+].[K+].[Br:23][CH2:24][CH2:25][CH2:26][CH2:27]Br>C(#N)C>[F:1][C:2]1[CH:16]=[CH:15][C:5]2[C:6]([CH:9]3[CH2:10][CH2:11][N:12]([CH2:27][CH2:26][CH2:25][CH2:24][Br:23])[CH2:13][CH2:14]3)=[N:7][O:8][C:4]=2[CH:3]=1
Reactant: BrCCCCBr
Reactant: Fc1ccc2c(C3CCNCC3)noc2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: Fc1ccc2c(C3CCN(CCCCBr)CC3)noc2c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 6-fluoro-3-(4-piperidinyl)-1,2-benzisoxazole (12 g, 55 mmol), K2CO3 (13 g) and 1,4-dibromobutane (20 g, 9.3 mmol, 1.7 eq) in acetonitrile (300 ml) was stirred at room temperature overnight. The inorganic material was filtered. The solution was concentrated to ˜80 ml, when crystals crashed out. The product was filtered to yield 14.16 g (73%), m.p.=243°-245° C.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([CH2:9][CH2:10][CH3:11])[C:3]=1[CH2:12][OH:13].O.C1(C)C=CC(S(O)(=O)=O)=CC=1.[O:26]1[CH:31]=[CH:30][CH2:29][CH2:28][CH2:27]1.O>ClCCl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([CH2:9][CH2:10][CH3:11])[C:3]=1[CH2:12][O:13][CH:27]1[CH2:28][CH2:29][CH2:30][CH2:31][O:26]1
Reactant: CCCc1c(O)ccc(Br)c1CO
Reactant: C1=COCCC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: ClCCl
Solvent: O
Product: CCCc1c(O)ccc(Br)c1COC1CCCCO1
Reaction time: 5 h
Yield: 69.6 %

Procedure:
To a solution of 4-bromo-3-(hydroxymethyl)-2-propylphenol (1.04 g, 4.24 mmol) in dichloromethane (50 mL), p-toluenesulfonic acid-hydrate (81 mg, 0.424 mmol) and 3,4-dihydro-2H-pyrane (535 mg, 6.36 mmol) were added at room temperature. The mixture was stirred at same temperature for 5 hours. The reaction solution was added with water and extracted with chloroform. Subsequently, the organic layer was washed with saturated saline, dried using anhydrous sodium sulfate, and concentrated in vacuum. The residue was purified by silica-gel column chromatography (hexane/ethyl acetate) and the title compound (972 mg, 70%) was obtained as colorless oil.
Reaction SMILES: [C:1]1([S:7]([N:10]2[C:14]3=[N:15][CH:16]=[CH:17][CH:18]=[C:13]3[CH:12]=[C:11]2[C:19](OS(C2C=CC(C)=CC=2)(=O)=O)=[CH:20][CH:21]2[CH2:25][CH2:24][CH2:23][CH2:22]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:37][CH:38]([S:40]([C:43]1[CH:48]=[CH:47][C:46](B(O)O)=[CH:45][CH:44]=1)(=[O:42])=[O:41])[CH3:39].C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1.C(OCC)(=O)C.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>[C:1]1([S:7]([N:10]2[C:14]3=[N:15][CH:16]=[CH:17][CH:18]=[C:13]3[CH:12]=[C:11]2[C:19]([C:46]2[CH:47]=[CH:48][C:43]([S:40]([CH:38]([CH3:39])[CH3:37])(=[O:42])=[O:41])=[CH:44][CH:45]=2)=[CH:20][CH:21]2[CH2:25][CH2:24][CH2:23][CH2:22]2)(=[O:9])=[O:8])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CC(C)S(=O)(=O)c1ccc(B(O)O)cc1
Reactant: Cc1ccc(S(=O)(=O)OC(=CC2CCCC2)c2cc3cccnc3n2S(=O)(=O)c2ccccc2)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: CC(C)S(=O)(=O)c1ccc(C(=CC2CCCC2)c2cc3cccnc3n2S(=O)(=O)c2ccccc2)cc1
Yield: 86.8 %

Procedure:
To a mixture of toluene-4-sulfonic acid-1-(1-benzenesulfonyl-1H-pyrrolo[2,3-b]pyridin-2-yl)-2-cyclopentyl-vinyl ester (prepared as in Example 43, 0.15 g, 0.28 mmol), 4-(propane-2-sulfonyl)phenyl boronic acid (0.12 g, 0.72 mmol) and dichlorobis(triphenylphosphine)palladium (II) (21 mg, 0.03 mmol) in dioxane (3 mL) was added an aqueous sodium carbonate solution (2 M, 0.36 mL). The resulting mixture was subjected to microwave irradiation for 2 h at 100° C. The mixture was diluted with ethyl acetate (100 mL), washed with a saturated aqueous sodium bicarbonate solution (2×30 mL), brine, dried over anhydrous sodium sulfate and then concentrated in vacuo. Purification by flash silica gel chromatography (silica gel from QingDao, 200-300 mesh, glass column from Shanghai SD company, 25% ethyl acetate/hexanes) afforded 1-benzenesulfonyl-2-{2-cyclopentyl-1-[4-(propane-2-sulfonyl)-phenyl]-vinyl}-1H-pyrrolo[2,3-b]pyridine (130 mg, 84%) as a white solid: LC/MS m/e calcd for C29H30N2O4S2 [M+H]+ 535.70, observed 535.4.
Reaction SMILES: [CH:1]1([N:7]([CH:18]2[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]2)[C:8]([NH:10][C:11]2[S:12][CH:13]=[C:14]([CH:16]=O)[N:15]=2)=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[NH:24]1[CH2:29][CH2:28][O:27][CH2:26][CH2:25]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>>[CH:18]1([N:7]([CH:1]2[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)[C:8]([NH:10][C:11]2[S:12][CH:13]=[C:14]([CH2:16][N:24]3[CH2:29][CH2:28][O:27][CH2:26][CH2:25]3)[N:15]=2)=[O:9])[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23]1
Reactant: C1COCCN1
Reactant: O=Cc1csc(NC(=O)N(C2CCCCC2)C2CCCCC2)n1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Product: O=C(Nc1nc(CN2CCOCC2)cs1)N(C1CCCCC1)C1CCCCC1
Yield: 30 %

Procedure:
1,1-Dicyclohexyl-3-(4-morpholin-4-ylmethyl-thiazol-2-yl)-urea was prepared in 30% yield (30 mg) as described in general procedure A from 1,1-dicyclohexyl-3-(4-formyl-thiazol-2-yl)-urea (101 mg, 0.3 mmol) and morpholine (30 uL, 0.3 mmol) using sodium triacetoxyborohydride as the reducing reagent.