Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:11][CH2:12][NH:13][C:14](=[O:27])[C:15]([C:20]2[CH:25]=[CH:24][C:23]([CH3:26])=[CH:22][CH:21]=2)=[CH:16]N(C)C)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].Cl.[O:29]1CCCC1>O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:11][CH2:12][NH:13][C:14](=[O:27])[C:15]([C:20]2[CH:25]=[CH:24][C:23]([CH3:26])=[CH:22][CH:21]=2)=[CH:16][OH:29])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: C1CCOC1
Reactant: COc1ccc(CCNC(=O)C(=CN(C)C)c2ccc(C)cc2)cc1OC
Agent: Cl
Solvent: O
Product: COc1ccc(CCNC(=O)C(=CO)c2ccc(C)cc2)cc1OC
Temperature: 25 °C
Reaction time: 2 h

Procedure:
One gram (1.0 g) of crude N-[2-(3,4-dimethoxyphenyl)ethyl]-3-dimethylamino-2-(4-methylphenyl)acrylamide (2.7 mmol), 12 ml of 5% hydrochloric acid and 20 ml of tetrahydrofuran were mixed and stirred at room temperature for 2 hours. Water was added to the reaction mixture, which was followed by extracted with ethyl acetate twice, washed with saturated brine twice, dried over anhydrous magnesium sulfate and the solvent was distilled off under reduced pressure. The residue was washed with hexane and dried to give 0.76 g of N-[2-(3,4-dimethoxyphenyl)ethyl]-3-hydroxy-2-(4-methylphenyl)acrylamide.
Reaction SMILES: [Br:1][C:2]1[C:3]([Cl:23])=[CH:4][C:5]2[O:15][CH2:14][C:13]3[C:8](=[N:9][CH:10]=[CH:11][CH:12]=3)[C:7](=[C:16]3[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]3)[C:6]=2[CH:22]=1.[N+:24]1([O-])[CH:29]=[CH:28][C:27]([CH2:30][C:31](O)=[O:32])=[CH:26][CH:25]=1.C1C=CC2N([OH:44])N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.CN1CCOCC1>CN(C=O)C>[Br:1][C:2]1[C:3]([Cl:23])=[CH:4][C:5]2[O:15][CH2:14][C:13]3[C:8](=[N:9][CH:10]=[CH:11][CH:12]=3)[C:7](=[C:16]3[CH2:17][CH2:18][N+:19]([O-:44])([C:31](=[O:32])[CH2:30][C:27]4[CH:28]=[CH:29][N:24]=[CH:25][CH:26]=4)[CH2:20][CH2:21]3)[C:6]=2[CH:22]=1
Reactant: O=C(O)Cc1cc[n+]([O-])cc1
Reactant: On1nnc2ccccc21
Reactant: Clc1cc2c(cc1Br)C(=C1CCNCC1)c1ncccc1CO2
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: O=C(Cc1ccncc1)[N+]1([O-])CCC(=C2c3cc(Br)c(Cl)cc3OCc3cccnc32)CC1
Temperature: 20 °C
Reaction time: 8 h
Yield: 97.8 %

Procedure:
4-(9-Bromo-8-chloro-5,11-dihydro[1]benzoxepino[4,3-b]pyridin-11-ylidene)-piperidine (130 mg, 0.33 mmol), 4-pyridine-acetic acid 1-oxide (130 mg, 0.85 mmol), HOBT (120 mg, 0.89 mmol), and EDCl (160 mg, 0.83 mmol) were stirred at 0° C. in DMF (5 ml, anhydrous). N-Methyl-morpholine (0.5 ml, 4.53 mmol) was added, and the reaction mixture was stirred overnight at 20° C. The solvent was evaporated off, and the residue was extracted with methylene chloride (2×100 ml) and water (30 ml). The organic layer was separated and dried (MgSO4), filtered and evaporated, yielding an oil which was chromatographed on silica gel and eluted with 15%methanol/ethylacetate containing 2% ammonium hydroxide. The product was obtained as a white solid, 4-(9-bromo-8-chloro-5,11-dihydro[1]benzoxepino[4,3-b]pyridin-11-ylidene)-1-(4-pyridine-acetyl)piperidine N1-oxide (170 mg, 98%). MS (FAB, M+H)=526.
Reaction SMILES: [CH3:1][C:2]1[N:10]=[C:9]([C:11]([F:14])([F:13])[F:12])[CH:8]=[CH:7][C:3]=1[C:4](Cl)=[O:5].[CH3:15][O:16][C:17]([C:19]1([O:28][CH3:29])[CH2:24][CH:23]([CH3:25])[C:22](=[O:26])[CH:21]=[C:20]1[OH:27])=[O:18].C(N(CC)CC)C.[C-]#N.[K+]>C(#N)C>[CH3:15][O:16][C:17]([C:19]1([O:28][CH3:29])[CH2:24][CH:23]([CH3:25])[C:22](=[O:26])[C:21]([C:4]([C:3]2[C:2]([CH3:1])=[N:10][C:9]([C:11]([F:14])([F:13])[F:12])=[CH:8][CH:7]=2)=[O:5])=[C:20]1[OH:27])=[O:18]
Reactant: COC(=O)C1(OC)CC(C)C(=O)C=C1O
Reactant: Cc1nc(C(F)(F)F)ccc1C(=O)Cl
Agent: [C-]#N
Agent: [K+]
Solvent: CC#N
Solvent: CCN(CC)CC
Product: COC(=O)C1(OC)CC(C)C(=O)C(C(=O)c2ccc(C(F)(F)F)nc2C)=C1O
Reaction time: 0.5 h

Procedure:
2.23 g of fresh 2-methyl-6-trifluoromethyl-nicotinoyl chloride are added to a mixture of 2.14 g of 2-hydroxy-1-methoxy-5-methyl-4-oxo-cyclohex-2-ene-carboxylic acid methyl ester and 2.02 g of triethylamine in 30 ml of acetonitrile. After about 30 minutes, 0.065 g of potassium cyanide is added and the batch is stirred for 18 hours. The batch is then extracted at pH 2 with water against ethyl acetate, dried over magnesium sulfate and concentrated by evaporation. By filtering over silica gel (mobile phase: ethyl acetate/methanol/triethylamine 85:10:5), pure 2-hydroxy-1-methoxy-5-methyl-3-(2-methyl-6-trifluoromethyl-pyridine-3-carbonyl)-4-oxo-cyclohex-2-enecarboxylic acid methyl ester is obtained in the form of a viscous oil.
Reaction SMILES: [F:1][C:2]1[C:3]([C:9]([O:11][CH2:12][CH3:13])=[O:10])=[N:4][CH:5]=[C:6](F)[CH:7]=1.[F:14][C:15]([F:18])(O)[CH3:16].C(=O)([O-])[O-:20].[K+].[K+]>C(#N)C>[F:14][CH:15]([F:18])[CH2:16][O:20][C:6]1[CH:7]=[C:2]([F:1])[C:3]([C:9]([O:11][CH2:12][CH3:13])=[O:10])=[N:4][CH:5]=1
Reactant: CC(O)(F)F
Reactant: CCOC(=O)c1ncc(F)cc1F
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCOC(=O)c1ncc(OCC(F)F)cc1F
Temperature: 25 °C
Reaction time: 48 h
Yield: 18.5 %

Procedure:
Ethyl 3,5-difluoropyridine-2-carboxylate (0.98 g, 5.24 mmol) is dissolved in acetonitrile (20 mL). Difluoroethanol (430 μL, 6.81 mmol) is added followed by potassium carbonate (1.83 g, 13.09 mmol). The solution is stirred at room temperature for 2 days then filtered and the filtrate is concentrated. The crude material is purified via silica gel chromatography eluting with a 0-25-50% ethyl acetate/hexanes gradient to give the title compound (242 mg, 18%). ES/MS (m/e): 250.0 (M+1).
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([C:17]([NH2:19])=[O:18])=[C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[C:13]([F:16])([F:15])[F:14])[N:6]=1.[CH3:20][O:21][CH:22]([O:33][CH3:34])[C:23]1[CH:28]=[CH:27][C:26]([N+:29]([O-:31])=[O:30])=[C:25](F)[CH:24]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C=O>[CH3:34][O:33][CH:22]([O:21][CH3:20])[C:23]1[CH:28]=[CH:27][C:26]([N+:29]([O-:31])=[O:30])=[C:25]([NH:1][C:2]2[S:3][C:4]([C:17]([NH2:19])=[O:18])=[C:5]([C:7]3[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=3[C:13]([F:16])([F:14])[F:15])[N:6]=2)[CH:24]=1
Reactant: NC(=O)c1sc(N)nc1-c1ccccc1C(F)(F)F
Reactant: COC(OC)c1ccc([N+](=O)[O-])c(F)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: COC(OC)c1ccc([N+](=O)[O-])c(Nc2nc(-c3ccccc3C(F)(F)F)c(C(N)=O)s2)c1
Temperature: 0 °C
Yield: 68.1 %

Procedure:
A mixture of 0.20 g (0.70 mmole) of 2-amino-4-(2-trifluoromethyl-phenyl)-thiazole-5-carboxylic acid amide (V.17), 0.18 g (0.84 mmole) of 4-dimethoxymethyl-2-fluoro-1-nitro-benzene (IV.2a) and 1.14 g (3.5 mmole) of cesium carbonate in 12 mL of dimethylformamide was heated to 60 degrees for 3 hours, then cooled. The mixture was poured into ice water, extracted three times with ethyl acetate. The combined organic layers were washed with water, brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. Purification by silica gel chromatography, eluting with hexanes-ethyl acetate (gradient 100:0-50:50) gave 0.23 g of 2-(5-dimethoxymethyl-2-nitro-phenylamino)-4-(2-trifluoromethyl-phenyl)-thiazole-5-carboxylic acid amide (VI.17a) as a yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C@@H:12]2[CH2:17][CH2:16][CH2:15][CH2:14][C@H:13]2[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[C:24](Cl)(=[O:26])[CH3:25].[Cl-].[Al+3].[Cl-].[Cl-]>ClCCl>[C:24]([C:21]1[CH:20]=[CH:19][C:18]([C@@H:13]2[CH2:14][CH2:15][CH2:16][CH2:17][C@H:12]2[NH:11][S:8]([C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)(=[O:10])=[O:9])=[CH:23][CH:22]=1)(=[O:26])[CH3:25]
Reactant: CC(=O)Cl
Reactant: O=S(=O)(N[C@@H]1CCCC[C@H]1c1ccccc1)c1ccc(Cl)cc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: CC(=O)c1ccc([C@@H]2CCCC[C@H]2NS(=O)(=O)c2ccc(Cl)cc2)cc1
Reaction time: 4 h
Yield: 42.5 %

Procedure:
To a mixture maintained at 0° C. of 4.0 g (12 mmoles) of trans-4-chloro-N-(2-phenylcyclohexyl)-benzenesulfonamide (prepared according to Das P. C. et al., Indian J. Chem. (1974), 12, 1139-40), 80 ml of anhydrous dichloromethane and 2.4 g (31 mmoles) of acetyl chloride, 5.3 g (40 mmoles) of aluminum chloride are added by fractions. After 4 hours at 0° C., the reaction mixture is thrown onto an ice-HCl mixture before being extracted with dichloromethane. The organic phase is washed with water to neutrality, dried over Na2SO4 and concentrated. The residue is purified by chromatography on a column of silica (eluant:hexane-ethyl acetate 4/1) to give 2 g of a colorless oil (yield:42.5%).
Reaction SMILES: S([O:6][CH3:7])(OC)(=O)=O.CSC.[Cl:11][C:12]1[CH:17]=[CH:16][C:15]([CH2:18][C:19]([C:22]([C:24]2[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][CH:25]=2)=O)([CH3:21])[CH3:20])=[CH:14][CH:13]=1.C[O-].[Na+]>C(#N)C>[Cl:11][C:12]1[CH:13]=[CH:14][C:15]([C:18]2([C:19]([CH3:21])([CH3:20])[CH2:22][C:24]3[CH:25]=[CH:26][C:27]([Cl:30])=[CH:28][CH:29]=3)[CH2:7][O:6]2)=[CH:16][CH:17]=1
Reactant: COS(=O)(=O)OC
Reactant: CC(C)(Cc1ccc(Cl)cc1)C(=O)c1ccc(Cl)cc1
Agent: C[O-]
Agent: [Na+]
Solvent: CC#N
Solvent: CSC
Product: CC(C)(Cc1ccc(Cl)cc1)C1(c2ccc(Cl)cc2)CO1
Reaction time: 12 h
Yield: 85.1 %

Procedure:
A solution of 59.2 g (0.47 mol) of dimethyl sulphate and 32 g (0.517 mol) of dimethyl sulphide in 270 ml of acetonitrile is stirred for 5 days at room temperature. A solution of 81.5 g (0.2655 mol) of 4-chlorophenyl 4-chlorophenyl-tert.-butyl ketone in 80 ml of acetonitrile is then added dropwise at 20° to 25° C., in the course of approx. 2 hours 28.7 g (0.53 mol) of sodium methylate are added at the same temperature. The total reaction mixture is stirred for 12 hours and thereafter concentrated in vacuo. The residue is stirred overnight with a mixture of 200 ml of ethyl acetate and 150 ml of water. The organic phase is separated off, dried over sodium sulphate and concentrated in vacuo. 72.6 g (85.2% of theory) of crude 2-(4-chlorophenyl)-2-(4-chlorophenyl-tert.-butyl)-oxirane are obtained and this compound is directly reacted further. ##STR155## 85 g (0.466 mol) of 4-chlorophenyl isopropyl ketone, 31.3 g (0.56 mol) of potassium hydroxide and 5 g of tetrabutylammonium bromide in 120 ml of toluene are heated to the reflux temperature, and a solution of 75 g (0.466 mol) of 4-chlorobenzyl chloride in 60 ml of toluene is added dropwise. The reaction mixture is stirred under reflux for a further 12 hours, cooled, and washed with water, and the organic phase is dried over sodium sulphate and concentrated in vacuo. 81.5 g (60% of theory) of 4-chlorophenyl 4-chlorophenyl-tert.-butyl ketone of refractive index nD20 =1,5711 are obtained.
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:7]=[N:8][N:9]([C:17]([CH3:20])([CH3:19])[CH3:18])[C:10]=1[C:11]1[CH:15]=[C:14]([Cl:16])[O:13][N:12]=1)=[O:5])C.[OH-].[Li+]>C(O)C>[C:17]([N:9]1[C:10]([C:11]2[CH:15]=[C:14]([Cl:16])[O:13][N:12]=2)=[C:6]([C:4]([OH:5])=[O:3])[CH:7]=[N:8]1)([CH3:20])([CH3:18])[CH3:19]
Reactant: CCOC(=O)c1cnn(C(C)(C)C)c1-c1cc(Cl)on1
Agent: [Li+]
Agent: [OH-]
Solvent: CCO
Product: CC(C)(C)n1ncc(C(=O)O)c1-c1cc(Cl)on1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 79.7 %

Procedure:
A solution of 1-tert-butyl-5-(5-chloro-isoxazol-3-yl)-1H-pyrazole-4-carboxylic acid ethyl ester (55.3 mg, 0.18 mmol) in absolute ethanol (0.93 mL, 0.2M) was treated with a 2M aqueous lithium hydroxide solution (0.18 mL, 0.37 mmol). The reaction was stirred at 25° C. for 1.5 h and then was heated to 100° C. for 1 h. At this time, the reaction was allowed to cool to 25° C. and was stirred at 25° C. overnight. At this time, the reaction was concentrated in vacuo. The residue was treated with water followed by acidification to pH=1 with a 1N aqueous hydrochloric acid solution. The resulting precipitate that formed was collected by filtration, washed with water and hexanes and dried in vacuo to afford 1-tert-butyl-5-(5-chloro-isoxazol-3-yl)-1H-pyrazole-4-carboxylic acid (38.7 mg, 77%) as an off-white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([CH3:10])=[N+:5]([O-])[CH:6]=[CH:7][CH:8]=1.[C:11]([Si](C)(C)C)#[N:12].CN(C)C(Cl)=O>ClCCl>[C:11]([C:6]1[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[C:4]([CH3:10])[N:5]=1)#[N:12]
Reactant: C[Si](C)(C)C#N
Reactant: COc1ccc[n+]([O-])c1C
Agent: CN(C)C(=O)Cl
Solvent: ClCCl
Product: COc1ccc(C#N)nc1C
Temperature: 25 °C
Reaction time: 216 h
Yield: 11.8 %

Procedure:
To a solution obtained by dissolving 3-methoxy-2-methyl-pyridine-N-oxide (1.57 g, 11.3 mmol) in 30 ml of dichloromethane were added cyanotrimethylsilane (1.12 g, 11.3 mmol) and dimethylcarbamoyl chloride (1.21 g, 11.3 mmol), followed by stirring at room temperature for 9 days. The reaction solution was washed with 10% sodium carbonate aqueous solution and then with water. The organic layer was dried with sodium sulfate and concentrated to remove the solvent, by which 0.198 g (percent yield: 11.8%) of 2-cyano-5-methoxy-6-methylpyridine was obtained.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:24]2[CH2:29][CH2:28][O:27][CH2:26][CH2:25]2)[C:5]2[S:10][C:9]([CH2:11][N:12]3[CH2:17][CH2:16][N:15]([C:18](=[O:22])[C@@H:19]([OH:21])[CH3:20])[CH2:14][CH2:13]3)=[C:8]([CH3:23])[C:6]=2[N:7]=1.B(O)(O)[C:31]1[CH:36]=[CH:35][C:34]([O:37][CH3:38])=[N:33][CH:32]=1>>[OH:21][C@@H:19]([CH3:20])[C:18]([N:15]1[CH2:16][CH2:17][N:12]([CH2:11][C:9]2[S:10][C:5]3[C:4]([N:24]4[CH2:29][CH2:28][O:27][CH2:26][CH2:25]4)=[N:3][C:2]([C:31]4[CH:32]=[N:33][C:34]([O:37][CH3:38])=[CH:35][CH:36]=4)=[N:7][C:6]=3[C:8]=2[CH3:23])[CH2:13][CH2:14]1)=[O:22]
Reactant: COc1ccc(B(O)O)cn1
Reactant: Cc1c(CN2CCN(C(=O)[C@H](C)O)CC2)sc2c(N3CCOCC3)nc(Cl)nc12
Product: COc1ccc(-c2nc(N3CCOCC3)c3sc(CN4CCN(C(=O)[C@H](C)O)CC4)c(C)c3n2)cn1
Yield: 74 %

Procedure:
(S)-1-(4-((2-Chloro-7-methyl-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)piperazin-1-yl)-2-hydroxypropan-1-one (60 mg) was reacted with 35 mg of 6-methoxypyridin-3-yl-3-boronic acid via General Procedure A to give 51.7 mg of 204. MS (Q1) 513.3 (M)+.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:15]=[C:14]2[C:9]([C:10]([O:16][C:17]3[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][C:18]=3[C:24]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)=[O:25])=[CH:11][CH:12]=[N:13]2)=[CH:8][C:7]=1[O:32][CH3:33].[CH2:34]([NH:36][CH2:37][CH3:38])[CH3:35].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[CH2:34]([N:36]([CH2:37][CH3:38])[CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:15]=[C:14]2[C:9]([C:10]([O:16][C:17]3[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][C:18]=3[C:24]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)=[O:25])=[CH:11][CH:12]=[N:13]2)=[CH:8][C:7]=1[O:32][CH3:33])[CH3:35]
Reactant: COc1cc2c(Oc3ccc(C)cc3C(=O)c3ccccc3)ccnc2cc1OCCCCl
Reactant: CCNCC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCN(CC)CCCOc1cc2nccc(Oc3ccc(C)cc3C(=O)c3ccccc3)c2cc1OC
Temperature: 80 °C
Reaction time: 8 h
Yield: 35.4 %

Procedure:
(2-{[7-(3-Chloropropoxy)-6-methoxy-4-quinolyl]oxy}-5-methylphenyl)(phenyl)methanone (68 mg), diethylamine (30 mg), and potassium carbonate (95 mg) were suspended in N,N-dimethylformamide (3 ml), and the suspension was stirred at 80° C. overnight. The reaction solution was cooled to room temperature, water was then added to the reaction solution, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was then washed with water and saturated brine and was dried over anhydrous sodium sulfate. The solvent was removed therefrom by distillation under the reduced pressure, and the residue was purified by thin layer chromatography using methanol-chloroform to give the title compound (26 mg, yield 38%).
Reaction SMILES: [C:1]([NH2:5])(=[O:4])[CH:2]=[CH2:3].[CH2:6]([O:8][C:9](=[O:12])[CH:10]=[CH2:11])[CH3:7].[OH-:13].[Na+].[CH2:15]=O.C(O)C>O>[CH2:6]([O:8][C:9](=[O:12])[CH:10]=[CH2:11])[CH3:7].[CH2:3]([C:2](=[CH2:15])[C:1]([NH2:5])=[O:4])[OH:13]
Reactant: C=O
Reactant: C=CC(N)=O
Reactant: [OH-]
Agent: C=CC(=O)OCC
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: C=C(CO)C(N)=O
Temperature: 70 °C

Procedure:
400 g of an acrylamide-ethylacrylate 80-20 copolymer were dissolved in 1200ml of water; the pH was adjusted to 12-13 by adding NaOH; 400 ml of 40% formalin were added while heating to 70° C. for 2 hours; the pH waskept at 12-13 with further addition of NaOH. After cooling the solution waspoured into 15 liters of ethanol under good stirring, the separated polymerwas filtered, washed with acetone and dried at reduced pressure. Yield: 590g of water-soluble polymer. Analytical results: free CH2O: absent; total CH2O: 18.9%; [η]: 0.36 dl/g in NaNO3N at 30° C.
Reaction SMILES: [CH3:1][S:2]([N:5]1[CH2:10][CH2:9][N:8]([CH2:11][C:12]2[S:28][C:15]3[N:16]=[C:17](SC)[N:18]=[C:19]([N:20]4CCOCC4)[C:14]=3[CH:13]=2)[CH2:7][CH2:6]1)(=[O:4])=[O:3].[CH3:29][C:30]1[N:35]=[CH:34][C:33]([Sn](CCCC)(CCCC)CCCC)=[CH:32][N:31]=1.[C:49]([O:52][CH2:53][CH3:54])(=O)[CH3:50]>COCCOC.CSC.[Cu]Br.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>[CH3:29][C:30]1[N:31]=[CH:32][C:33]([CH:53]2[CH2:54][N:18]([C:17]3[N:20]=[CH:19][C:14]4[CH:13]=[C:12]([CH2:11][N:8]5[CH2:7][CH2:6][N:5]([S:2]([CH3:1])(=[O:4])=[O:3])[CH2:10][CH2:9]5)[S:28][C:15]=4[N:16]=3)[CH2:50][CH2:49][O:52]2)=[CH:34][N:35]=1
Reactant: CCCC[Sn](CCCC)(CCCC)c1cnc(C)nc1
Reactant: CCOC(C)=O
Reactant: CSc1nc(N2CCOCC2)c2cc(CN3CCN(S(C)(=O)=O)CC3)sc2n1
Agent: [Cu]Br
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CSC
Solvent: COCCOC
Product: Cc1ncc(C2CN(c3ncc4cc(CN5CCN(S(C)(=O)=O)CC5)sc4n3)CCO2)cn1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a solution of 6-(4-methanesulfonyl-piperazin-1-ylmethyl)-2-methylsulfanyl-4-morpholin-4-yl-thieno[2,3-d]pyrimidine (104 mg) in 1,2-dimethoxyethane (10 mL) was added 2-methyl-5-tributylstannanyl-pyrimidine (180 mg) (prepared as above) and copper(I)bromide-dimethyl sulfide (96 mg) and the reaction mixture was stirred at room temperature for 10 minutes. Tetrakis(triphenylphosphine)palladium (0) (14 mg) was then added and the reaction mixture was heated at reflux for 16 h. After cooling to room temperature, the mixture was diluted with ethyl acetate (20 mL) and washed with water (2×20 mL) and brine (2×20 mL). The organic phase was dried (MgSO4), reduced in vacuo and purified by column chromatography to give 304. NMR: (CDCl3) 2.67-2.70 (4H, m), 2.82 (3H, s, Me), 2.84 (3H, s, Me), 3.30-3.32 (4H, m), 3.85 (2H, s, CH2), 3.91-3.92 (4H, m), 3.98-4.01 (4H, m), 7.01 (1H, s, Ar) and 9.58 (2H, s, Ar). MS: (ESI+): MH+=490.14
Reaction SMILES: [C:1]1([C:7](=O)[CH2:8][CH2:9][CH:10]=[CH2:11])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH:13]1([Mg]Cl)[CH:17]=[CH:16][CH:15]=[CH:14]1.[Cl-].[NH4+].Cl>O.C1COCC1>[C:1]1([C:7]([CH2:8][CH2:9][CH:10]=[CH2:11])=[C:13]2[CH:17]=[CH:16][CH:15]=[CH:14]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: C=CCCC(=O)c1ccccc1
Reactant: Cl[Mg]C1C=CC=C1
Agent: Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: C1CCOC1
Product: C=CCCC(=C1C=CC=C1)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A 1 L round bottomed flask was charged with 1-phenyl-4-penten-1-one (49.1 g, 307 mmol), THF (200 mL), and a stir bar, and cooled in an ice bath. Cyclopentadienyl magnesium chloride (330 mL of approximately 1 M solution in THF, 330 mmol) was added dropwise over 1 hour. The pale red solution was stirred overnight while warming to room temperature. The solution was then refluxed for 4.5 hours, during which time the red color intensified. After being stirred overnight at room temperature again, the solution was acidified by first adding 5.5 g of ammonium chloride in 100 mL of water, and then adding 50 mL of 1 M HCl. The product was extracted with pentane, and the pentane extracts were collected, washed with water, and dried over sodium sulfate. Elution through silica with heptane and concentration under vacuum afforded 38.6 g (55% isolated and purified yield) of the product 6-phenyl-6-(3-butenyl)fulvene as a red oil.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[C:11]#[N:12].[K].[C:14]1([SH:20])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C1(S)C=CC=CC=1.[OH-].[K+]>CO.CN(C)C=O>[C:14]1([S:20][C:2]2[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=2[C:11]#[N:12])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: Sc1ccccc1
Reactant: N#Cc1cc([N+](=O)[O-])ccc1Cl
Agent: [K+]
Agent: [K]
Agent: [OH-]
Solvent: CO
Solvent: CN(C)C=O
Product: N#Cc1cc([N+](=O)[O-])ccc1Sc1ccccc1
Temperature: 105 °C
Reaction time: 2.5 h

Procedure:
4-Chloro-3-cyanonitrobenzene (12.5 g, 6.84 mmol) was added portionwise to a stirred N,N-dimethylformamide (50 mL) solution of thiophenol potassium salt [prepared by adding thiophenol (7.1 mL, 6.9 mmol) to a solution of potassium hydroxide (3.84 g, 6.84 mmol) in methanol followed by removal of the methanol in vacuo]. After stirring at 105° C. for 2.5 hours the mixture was poured into ice-water, filtered, the collected solid washed with water, dissolved in 300 mL of refluxing ethanol (charcoal), filtered, treated with 35 mL of water and refrigerated. The resulting pale yellow solid weighed 13.3 g (76%), mp 82°-84° C. 1H-NMR (250 MHz, CDCl3): 6.93 (d, 1H, J=9.0 Hz, aromatic), 7.51-7.62 (m, 5H, aromatic), 8.12(dd, 1H, J=9.2, 2.5 Hz, aromatic), 8.46 (d, 1H, J=2.5 Hz, aromatic). MS (CI, CH4): 257(M+1).
Reaction SMILES: [NH2:1][C@@H:2]([C:13]1[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[C:15]([F:23])[CH:14]=1)[CH2:3][CH2:4][NH:5][C:6](=[O:12])[O:7][C:8]([CH3:11])([CH3:10])[CH3:9].O1C[CH2:28][CH:27]([NH:30][C:31]2[N:32]=[CH:33][C:34]3[CH2:40][CH2:39][NH:38][CH2:37][C:35]=3[N:36]=2)[CH2:26]C1.Cl.ClC1C=C(C(C2[O:56][CH:55]=NC=2)N)C=CC=1Cl>>[F:23][C:15]1[CH:14]=[C:13]([C@H:2]([NH:1][C:55]([N:38]2[CH2:39][CH2:40][C:34]3[CH:33]=[N:32][C:31]([NH:30][CH:27]([CH3:26])[CH3:28])=[N:36][C:35]=3[CH2:37]2)=[O:56])[CH2:3][CH2:4][NH:5][C:6](=[O:12])[O:7][C:8]([CH3:11])([CH3:9])[CH3:10])[CH:18]=[CH:17][C:16]=1[C:19]([F:20])([F:21])[F:22]
Reactant: CC(C)(C)OC(=O)NCC[C@@H](N)c1ccc(C(F)(F)F)c(F)c1
Reactant: NC(c1ccc(Cl)c(Cl)c1)c1cnco1
Reactant: c1nc(NC2CCOCC2)nc2c1CCNC2
Agent: Cl
Product: CC(C)Nc1ncc2c(n1)CN(C(=O)N[C@H](CCNC(=O)OC(C)(C)C)c1ccc(C(F)(F)F)c(F)c1)CC2
Yield: 39 %

Procedure:
Condensation of 290 and 72 was carried out in accord with the procedure described in step 6 of example 1 except 290 was used in place of 28 and 72 was used in place of 22. The crude product was purified by SiO2 chromatography eluting with DCM/MeOH gradient (500:8 to 500:15) to afford 0.090 g (39.0%) of (R)-tert-butyl 3-(3-fluoro-4-(trifluoromethyl)phenyl)-3-(2-(isopropylamino)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine-7-carboxamido)propylcarbamate (292).
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]=1[CH2:13][O:14][C:15]1[N:16]=[CH:17][C:18]([C:21]([OH:23])=O)=[N:19][CH:20]=1.F[B-](F)(F)F.[N:29]1(OC(N(C)C)=[N+](C)C)[C:33]2[CH:34]=[CH:35][CH:36]=CC=2N=N1.C(N(CC)C(C)C)(C)C.NCC1CC1>CN(C=O)C.O>[CH:34]1([CH2:33][NH:29][C:21]([C:18]2[CH:17]=[N:16][C:15]([O:14][CH2:13][C:3]3[C:4]([C:7]4[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=4)=[N:5][O:6][C:2]=3[CH3:1])=[CH:20][N:19]=2)=[O:23])[CH2:36][CH2:35]1
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Reactant: Cc1onc(-c2ccccc2)c1COc1cnc(C(=O)O)cn1
Agent: F[B-](F)(F)F
Agent: NCC1CC1
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1onc(-c2ccccc2)c1COc1cnc(C(=O)NCC2CC2)cn1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 5-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-pyrazine-2-carboxylic acid (150 mg, 0.48 mmol) in DMF (2 mL) were added 2-(1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium tetrafluoroborate (170 mg, 0.55 mmol), N,N-diisopropyl ethyl amine (410 μL, 2.4 mmol) and aminomethylcyclopropane (41 mg, 0.58 mmol). The resulting reaction mixture was stirred for 30 min at room temperature and diluted with water. The mixture was then extracted with ethyl acetate and the combined organic layers washed with aqueous sodium carbonate (saturated) and dried over sodium sulfate. Concentration and purification by chromatography (SiO2, heptane:ethyl acetate=90:10 to 60:40) (117 mg, 67%) which was obtained as an off-white solid. MS: m/e=365.3 [M+H]+.