Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][CH:2]([O:4][CH:5]1[CH2:10][CH:9]2[CH2:11][CH:6]1[CH2:7][CH:8]2[CH2:12][CH2:13][CH:14]=[O:15])[CH3:3].[BH4-].[Na+].C12(CCC=O)CC(CC1)CC2>C(O)(C)C>[CH3:3][CH:2]([O:4][CH:5]1[CH2:10][CH:9]2[CH2:11][CH:6]1[CH2:7][CH:8]2[CH2:12][CH2:13][CH2:14][OH:15])[CH3:1]
Reactant: CC(C)OC1CC2CC1CC2CCC=O
Agent: O=CCCC12CCC(CC1)C2
Agent: [BH4-]
Agent: [Na+]
Solvent: CC(C)O
Product: CC(C)OC1CC2CC1CC2CCCO

Procedure:
Into a 250 cc reaction flash equipped with stirrer, thermometer, reflux condensor and heating mantle is placed 28.7 grams (0.13 moles) of the reaction product of Example III containing the compounds having the structures: ##STR86## 9.6 grams (0.26 moles) of sodium borohydride and 50 ml of anhydrous isopropanol. The isopropanol and sodium borohydride are first mixed together and placed in the flask. The resulting composition is heated to reflux and then over a period of one hour the isopropoxinene norbornane propanal is added. The resulting reaction mass is refluxed for a period of three hours. The reaction mass is then washed to neutral and distilled on a micro vigreux column yielding the following fractions:
Reaction SMILES: [Br:1]Br.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Br:22][C:23]1[CH:47]=[CH:46][C:26]([CH2:27][N:28]2[C:36]3[C:31](=[CH:32][C:33]([O:37][CH3:38])=[CH:34][CH:35]=3)[C:30]([C:39]3([CH2:42][CH2:43]O)[CH2:41][CH2:40]3)=[C:29]2[CH3:45])=[CH:25][CH:24]=1>C(Cl)Cl>[Br:22][C:23]1[CH:47]=[CH:46][C:26]([CH2:27][N:28]2[C:36]3[C:31](=[CH:32][C:33]([O:37][CH3:38])=[CH:34][CH:35]=3)[C:30]([C:39]3([CH2:42][CH2:43][Br:1])[CH2:41][CH2:40]3)=[C:29]2[CH3:45])=[CH:25][CH:24]=1
Reactant: COc1ccc2c(c1)c(C1(CCO)CC1)c(C)n2Cc1ccc(Br)cc1
Reactant: BrBr
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: COc1ccc2c(c1)c(C1(CCBr)CC1)c(C)n2Cc1ccc(Br)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 45.2 %

Procedure:
Bromine (136 mg, 0.85 mmol) was added to a-78° C. solution of triphenylphosphine (244 rag, 0.93 mmol) in 4 mL CH2Cl2, and the mixture was stirred 0.5 h at 0° C. and 5 rain at r.t. before recooling to -5° C. The alcohol from Step 8 (319 mg, 0.77 mmol) was then slowly added as a 1 mL CH2Cl2 solution and the mixture was stirred 2 h at 0° C. The reaction mixture was partitioned between CH2Cl2 and saturated NaHCO3. The organic layer was dried over MgSO4, concentrated and the residue purified by flash chromatography (10% ethyl acetate in hexane) to give 166 mg of the title compound.
Reaction SMILES: Br[C:2]1[C:11]([F:12])=[C:10]([F:13])[C:9]([F:14])=[C:8]2[C:3]=1[C:4](=[O:23])[C:5]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:6][N:7]2[CH:15]1[CH2:17][CH2:16]1.C([Sn]([C:37]#[C:38][Si:39]([CH3:42])([CH3:41])[CH3:40])(CCCC)CCCC)CCC>C1(C)C=CC=CC=1>[CH:15]1([N:7]2[C:8]3[C:3](=[C:2]([C:37]#[C:38][Si:39]([CH3:42])([CH3:41])[CH3:40])[C:11]([F:12])=[C:10]([F:13])[C:9]=3[F:14])[C:4](=[O:23])[C:5]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:6]2)[CH2:17][CH2:16]1
Reactant: CCCC[Sn](C#C[Si](C)(C)C)(CCCC)CCCC
Reactant: CCOC(=O)c1cn(C2CC2)c2c(F)c(F)c(F)c(Br)c2c1=O
Solvent: Cc1ccccc1
Product: CCOC(=O)c1cn(C2CC2)c2c(F)c(F)c(F)c(C#C[Si](C)(C)C)c2c1=O

Procedure:
1.95 g of ethyl 5-bromo-1-cyclopropyl-6,7,8-trifluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylate, 2.7 g of tributylstannyl-trimethylsilyl-acetylene and 0.29 g of tetrakis-(triphenylphosphine)palladium(0) are refluxed for 4 hours in 20 ml of absolute toluene under a nitrogen atmosphere. The reaction mixture is filtered at room temperature; the solid is washed with a small amount of toluene and dried 1.6 g of the title compound are obtained (78% of theory).
Reaction SMILES: [F:1][C:2]([F:9])([F:8])[C:3](=[CH2:7])[C:4]([OH:6])=[O:5].[CH2:10]([N:17]([CH2:21][Si](C)(C)C)[CH2:18]OC)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.FC(F)(F)C(O)=O>C(Cl)Cl>[CH2:10]([N:17]1[CH2:18][CH2:7][C:3]([C:2]([F:9])([F:8])[F:1])([C:4]([OH:6])=[O:5])[CH2:21]1)[C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: C=C(C(=O)O)C(F)(F)F
Reactant: COCN(Cc1ccccc1)C[Si](C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(O)C1(C(F)(F)F)CCN(Cc2ccccc2)C1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A 2.48 g sample of 2-(trifluoromethyl)acrylic acid was dissolved in 40 mL of dry methylene chloride, and a solution of 4.75 g of N-benzyl-N-(methoxymethyl)-trimethylsilylmethylamine in 20 mL of dry methylene chloride was added dropwise under N2 at 0° C. To this mixture was added 2 mL of trifluoroacetic acid, and the mixture was stirred for 2 hours at room temperature. The product was removed by filtration, washed and dried to give the title product.
Reaction SMILES: Br[C:2]1[N:7]=[C:6]2[NH:8][C:9]([CH3:12])=[C:10]([CH3:11])[C:5]2=[CH:4][CH:3]=1.[Li]CCCC.CCCCCC.[CH3:24][S:25]SC>C1COCC1.O>[CH3:12][C:9]1[NH:8][C:6]2=[N:7][C:2]([S:25][CH3:24])=[CH:3][CH:4]=[C:5]2[C:10]=1[CH3:11]
Reactant: Cc1[nH]c2nc(Br)ccc2c1C
Reactant: CSSC
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CSc1ccc2c(C)c(C)[nH]c2n1
Reaction time: 0.08 h
Yield: 83.2 %

Procedure:
A deaerated solution of 6-bromo-2,3-dimethyl-pyrrolo [2,3-b]pyridine (225 mg, 1.0 mmol) in 25 ml dry THF was cooled to -78° C. and treated with 1.6M n-BuLi in hexane (1,5 ml, 2.4 mmol). The reaction mixture was brought to 0° C. and the lithiate trapped with dimethyl disulfide (444 μl, 5 mmol). After reacting for 5 min 1.5 ml H2O was added and the THF evaporated. The residue was taken up in 100 ml CH2Cl2 and washed with 50 ml 5% NaHCO3, 50 ml 2M HCl (reextracted twice with 25 ml CH2Cl2), and 50 ml 5% NaHCO3. The organic layer was dried over MgSO4 and evaporated leaving 160 mg (83%) pure 2,3-dimethyl-6-methylthio-pyrrolo[2,3-b]pyridine.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([N+:8]([O-])=O)[CH:5]=[CH:4][C:3]=1[N:11]1[CH:15]=[N:14][C:13]([CH3:16])=[N:12]1.C(N(CC)CC)C.[H][H]>O1CCCC1.[Pd]>[F:1][C:2]1[CH:7]=[C:6]([NH2:8])[CH:5]=[CH:4][C:3]=1[N:11]1[CH:15]=[N:14][C:13]([CH3:16])=[N:12]1
Reactant: Cc1ncn(-c2ccc([N+](=O)[O-])cc2F)n1
Reactant: [H][H]
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: Cc1ncn(-c2ccc(N)cc2F)n1
Yield: 73.2 %

Procedure:
1-(2-Fluoro-4-nitro-phenyl)-3-methyl-1H-[1,2,4]triazole (250 mg, 1.13 mmol) was dissolved in tetrahydrofurane (6 mL) and triethylamine (5 mL) and stirred for 2 hours with 10% palladium on carbon (55 mg) under 1.5 bar of hydrogen. The reaction mixture was filtered and the solvent was removed under reduced pressure to yield the title compound (159 mg, 73%) as a yellow solid MS ISP (m/e): 193.3 [(M+H)+]. 1H NMR (CDCl3, 300 MHz): δ (ppm)=8.31 (d, 1H), 7.45 (dd, 1H), 6.51 (m, 2H), 3.94 (s broad, 2H), 2.48 (s, 3H). Mp 122-125° C.
Reaction SMILES: [NH2:1][C:2]1[C:7]([N+:8]([O-])=O)=[CH:6][C:5]([Br:11])=[C:4]([O:12][CH2:13][CH3:14])[N:3]=1>[Ni].C1COCC1>[Br:11][C:5]1[CH:6]=[C:7]([NH2:8])[C:2]([NH2:1])=[N:3][C:4]=1[O:12][CH2:13][CH3:14]
Reactant: CCOc1nc(N)c([N+](=O)[O-])cc1Br
Agent: [Ni]
Solvent: C1CCOC1
Product: CCOc1nc(N)c(N)cc1Br

Procedure:
Prepared analogously to example 154d by hydrogenation of the product obtained in (842a) using Raney nickel in THF.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([C:8]#[N:9])[CH:5]=[CH:4][N:3]=1.P(OCC)(OCC)([S-])=[S:11].O1CCCC1.C(=O)(O)[O-].[Na+]>O>[NH2:1][C:2]1[CH:7]=[C:6]([C:8](=[S:11])[NH2:9])[CH:5]=[CH:4][N:3]=1
Reactant: N#Cc1ccnc(N)c1
Reactant: CCOP(=S)([S-])OCC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: NC(=S)c1ccnc(N)c1
Temperature: 60 °C
Reaction time: 4 h
Yield: 80.9 %

Procedure:
A mixture of 2-aminopyridine-4-carbonitrile (6.0 g, 50 mmol), O,O′-diethyl dithiophosphate (11 mL, 60 mmol), tetrahydrofuran (25 mL) and water (25 mL) was stirred at 60° C. for 4 hr. To the reaction mixture was added O,O′-diethyl dithiophosphate (2.8 mL, 15 mmol) and the mixture was stirred at 60° C. for 1 day. To the reaction mixture was added aqueous sodium bicarbonate solution, and the mixture was extracted with ethyl acetate. The combined organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate, and the insoluble material was filtered off. The filtrate was concentrated under reduced pressure, and the obtained residue was washed with diisopropyl ether to give the title compound (6.2 g, 81%) as a yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[N:13]=[C:12]([NH:14][C:15]3[N:20]=[CH:19][C:18]([CH2:21][C:22]([O:24]CC)=[O:23])=[CH:17][CH:16]=3)[CH:11]=[C:10]([CH:27]3[CH2:29][CH2:28]3)[N:9]=2)[CH:5]=[CH:6][CH:7]=1.O1CCOCC1.O.[OH-].[Li+].Cl>O>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[N:13]=[C:12]([NH:14][C:15]3[N:20]=[CH:19][C:18]([CH2:21][C:22]([OH:24])=[O:23])=[CH:17][CH:16]=3)[CH:11]=[C:10]([CH:27]3[CH2:29][CH2:28]3)[N:9]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)Cc1ccc(Nc2cc(C3CC3)nc(-c3cccc(Cl)c3)n2)nc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: O=C(O)Cc1ccc(Nc2cc(C3CC3)nc(-c3cccc(Cl)c3)n2)nc1
Temperature: 50 °C
Reaction time: 1.5 h
Yield: 105 %

Procedure:
An 250-mL round bottom flask was charged with ethyl 2-(6-((2-(3-chlorophenyl)-6-cyclopropylpyrimidin-4-yl)amino)pyridin-3-yl)acetate (0.417 g, 1.02 mmol), dioxane (20 ml) and water (10 ml). To this solution was then added lithium hydroxide monohydrate (0.214 g, 5.10 mmol). The resulting mixture was stirred at 50° C. for 1.5 h. The cooled reaction mixture was treated with 2N aqueous HCl until pH˜4 affording a solid. The solid was isolated by filtration and dried under reduced pressure at 55° C. to afford the title compound (0.408 g, 100%) as a white solid. MW=380.83. M.p.>260° C. 1H NMR (DMSO-d6, 500 MHz) δ 12.33 (br s, 1H), 10.41 (s, 1H), 8.32-8.24 (m, 3H), 7.80-7.70 (m, 2H), 7.60-7.52 (m, 3H), 3.62 (s, 2H), 2.10 (septet, J=4.5 Hz, 1H), 1.16-1.10 (m, 2H), 1.10-1.02 (m, 2H); ESI MS m/z 381 [M+H]+.
Reaction SMILES: [CH2:1]([O:4][C:5]1[CH:6]=[C:7]([CH2:15][CH2:16][NH2:17])[CH:8]=[CH:9][C:10]=1[O:11][CH2:12][CH2:13][CH3:14])[CH2:2][CH3:3].[CH2:18]([O:20][C:21]1[CH:22]=[C:23]([CH2:30][C:31](OCC)=[O:32])[CH:24]=[CH:25][C:26]=1[O:27][CH2:28][CH3:29])[CH3:19]>>[CH2:1]([O:4][C:5]1[CH:6]=[C:7]([CH2:15][CH2:16][NH:17][C:31](=[O:32])[CH2:30][C:23]2[CH:24]=[CH:25][C:26]([O:27][CH2:28][CH3:29])=[C:21]([O:20][CH2:18][CH3:19])[CH:22]=2)[CH:8]=[CH:9][C:10]=1[O:11][CH2:12][CH2:13][CH3:14])[CH2:2][CH3:3]
Reactant: CCCOc1ccc(CCN)cc1OCCC
Reactant: CCOC(=O)Cc1ccc(OCC)c(OCC)c1
Product: CCCOc1ccc(CCNC(=O)Cc2ccc(OCC)c(OCC)c2)cc1OCCC

Procedure:
N-[2-(3,4-di-n-propoxyphenyl)ethyl]-3,4-diethoxy-phenylacetamide was prepared from 2-(3,4-di-n-propoxyphenyl)ethylamine and ethyl 3,4-diethoxyphenylacetate using the process described in Example 1 (a).
Reaction SMILES: [CH3:1][C:2]1([CH3:29])[CH2:11][CH2:10][C:9]([CH3:13])([CH3:12])[C:8]2[CH:7]=[C:6]([C:14]([O:16][C:17]3[CH:27]=[CH:26][C:20]([C:21]([O:23][CH2:24][CH3:25])=[O:22])=[CH:19][C:18]=3C)=[O:15])[CH:5]=[CH:4][C:3]1=2.OC1C=CC(C(OCC)=O)=CC=1C>>[CH3:29][C:2]1([CH3:1])[CH2:11][CH2:10][C:9]([CH3:12])([CH3:13])[C:8]2[CH:7]=[C:6]([C:14]([O:16][C:17]3[CH:18]=[CH:19][C:20]([C:21]([O:23][CH2:24][CH3:25])=[O:22])=[CH:26][CH:27]=3)=[O:15])[CH:5]=[CH:4][C:3]1=2
Reactant: CCOC(=O)c1ccc(OC(=O)c2ccc3c(c2)C(C)(C)CCC3(C)C)c(C)c1
Agent: CCOC(=O)c1ccc(O)c(C)c1
Product: CCOC(=O)c1ccc(OC(=O)c2ccc3c(c2)C(C)(C)CCC3(C)C)cc1

Procedure:
Ethyl 4-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthoyloxy)-3-methylbenzoate-Using ethyl 4-hydroxy-3-methylbenzoate, the title compound was synthesized as a white solid. PMR (CDCl3): δ 1.34 (6H, s), 1.36 (6H, s), 1.41 (3H, t, J~7.2 Hz), 1.74 (4H, s), 2.30 (3H, s), 4.39 (2H, t, J~7.2 Hz), 7.22 (1H, d, J~8.4 Hz), 7.47 (1H, d, J~8.3 Hz), 7.94-8.04 (3H, m), 8.19 (1H, d, J~1.7 Hz).
Reaction SMILES: [C:1]([Si:5]([CH3:29])([CH3:28])[O:6][C:7]1[CH:8]=[C:9]([CH:15]([OH:27])[C:16]2[CH:17]=[CH:18][C:19]([Cl:26])=[C:20]([S:22]([NH2:25])(=[O:24])=[O:23])[CH:21]=2)[CH:10]=[CH:11][C:12]=1[O:13][CH3:14])([CH3:4])([CH3:3])[CH3:2].CC(C)=O.OS(O)(=O)=O.O=[Cr](=O)=O>CC(C)=O>[C:1]([Si:5]([CH3:29])([CH3:28])[O:6][C:7]1[CH:8]=[C:9]([CH:10]=[CH:11][C:12]=1[O:13][CH3:14])[C:15]([C:16]1[CH:17]=[CH:18][C:19]([Cl:26])=[C:20]([S:22]([NH2:25])(=[O:23])=[O:24])[CH:21]=1)=[O:27])([CH3:4])([CH3:3])[CH3:2]
Reactant: COc1ccc(C(O)c2ccc(Cl)c(S(N)(=O)=O)c2)cc1O[Si](C)(C)C(C)(C)C
Agent: O=[Cr](=O)=O
Agent: O=S(=O)(O)O
Solvent: CC(C)=O
Product: COc1ccc(C(=O)c2ccc(Cl)c(S(N)(=O)=O)c2)cc1O[Si](C)(C)C(C)(C)C
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 49.5 %

Procedure:
To a solution of 5-{[3-(tert-butyl-dimethyl-silanyloxy)-4-methoxy-phenyl]-hydroxy-methyl}-2-chloro-benzenesulfonamide (0.57 g, 1.24 mmol) dissolved in acetone (100 mL) is added Jones reagent (3 M, 0.4 mL), and the reaction mixture is stirred at room temperature for 15 minutes. The reaction is quenched with water, and the aqueous layer is extracted with methylene chloride three times. The combined organic extracts are washed with saturated sodium bicarbonate solution, a saturated sodium chloride solution, dried with magnesium sulfate, and concentrated in vacuo. Recrystallization from methylene chloride/hexane provides 0.28 g (50%) of the title compound as a grey solid. 1H NMR (CDCl3): δ 8.23 (d, J=2 Hz, 1H), 7.80 (dd, J=8, 2 Hz, 1H), 7.50 (d, J=8 Hz, 1H), 7.20 (m, 2H), 6.70 (d, J=8 Hz, 1H), 5.00 (s, 2H), 3.70 (s, 3H), 0.90 (s, 9H), 0.05 (s, 6H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:12][CH3:13])=[C:6]([C:8]([CH3:11])(O)[CH3:9])[CH:7]=1.[CH2:14]([O:16][C:17](=[O:25])[C:18]([O:20][Si](C)(C)C)=[CH2:19])[CH3:15].[Sn](Cl)(Cl)(Cl)Cl.C(=O)([O-])[O-].[K+].[K+]>ClCCl>[CH2:14]([O:16][C:17](=[O:25])[C:18](=[O:19])[CH2:20][C:8]([C:6]1[CH:7]=[C:2]([Br:1])[CH:3]=[CH:4][C:5]=1[O:12][CH3:13])([CH3:11])[CH3:9])[CH3:15]
Reactant: COc1ccc(Br)cc1C(C)(C)O
Reactant: C=C(O[Si](C)(C)C)C(=O)OCC
Agent: Cl[Sn](Cl)(Cl)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Product: CCOC(=O)C(=O)CC(C)(C)c1cc(Br)ccc1OC
Reaction time: 0.33 h
Yield: 37.9 %

Procedure:
9.8 g of 1-(5-bromo-2-methoxyphenyl)-1-methylethanol and 15.24 g of 2-(trimethylsilyloxy)-acrylic acid ethyl ester in 150 ml of dichloromethane are mixed at −70° C. with 5.6 ml of tin tetrachloride. After 20 minutes at −70° C., the solution is poured onto a semi-saturated potassium carbonate solution and mixed with dichloromethane. The dichloromethane phase is washed with potassium carbonate solution, 1 M hydrochloric acid and water, dried (Na2SO4) and concentrated by evaporation. After bulb tube distillation, 5.2 g of 4-(5-bromo-2-methoxyphenyl)-4-methyl-2-oxopentanoic acid-ethyl ester is obtained. Boiling point: 160° C./0.04 hPa.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][CH:3]=[CH:2]1.[H-].[Na+].Br[CH2:9][C:10]1[CH:11]=[C:12]([CH:17]=[CH:18][CH:19]=1)[C:13]([O:15][CH3:16])=[O:14].O>CN(C)C=O>[N:1]1([CH2:9][C:10]2[CH:11]=[C:12]([CH:17]=[CH:18][CH:19]=2)[C:13]([O:15][CH3:16])=[O:14])[CH:5]=[CH:4][CH:3]=[CH:2]1
Reactant: c1cc[nH]c1
Reactant: COC(=O)c1cccc(CBr)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1cccc(Cn2cccc2)c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To the mixture of pyrrole (2.3 ml) and 60% sodium hydride (1.3 g) in N,N-dimethylformamide (50 ml) was added methyl 3-(bromomethyl)benzoate (5.0 g) under ice-cooling and the mixture was stirred for 3 hours at ambient temperature. The reaction mixture was poured into water and extracted with ethyl acetate. The extract layer was washed with water, dried over magnesium sulfate and evaporated to give methyl 3-(pyrrol-1-yl)methylbenzoate (4.14 g) as an oil.
Reaction SMILES: Cl[C:2]1[C:3]2[CH:11]=[C:10]([CH:12]3[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]3)[S:9][C:4]=2[N:5]=[C:6]([CH3:8])[N:7]=1.CN(C=O)C.[CH2:23]([O:25]/[CH:26]=[CH:27]/B1OC(C)(C)C(C)(C)O1)[CH3:24].[O-]P([O-])([O-])=O.[K+].[K+].[K+]>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.O>[CH:12]1([C:10]2[S:9][C:4]3[N:5]=[C:6]([CH3:8])[N:7]=[C:2](/[CH:24]=[CH:23]/[O:25][CH2:26][CH3:27])[C:3]=3[CH:11]=2)[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1
Reactant: Cc1nc(Cl)c2cc(C3CCCCC3)sc2n1
Reactant: CCO/C=C/B1OC(C)(C)C(C)(C)O1
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: O
Solvent: CN(C)C=O
Product: CCO/C=C/c1nc(C)nc2sc(C3CCCCC3)cc12
Temperature: 85 °C
Reaction time: 2 h
Yield: 78.1 %

Procedure:
To a mixture of 4-chloro-6-cyclohexyl-2-methylthieno[2,3-d]pyrimidine (1.0 g) and DMF (40 mL) were added (E)-1-ethoxyethene-2-boronic acid pinacol ester (900 mg) and K3PO4 (4.3 g), and Pd(PPh3)4 (500 mg) was added thereto under an argon atmosphere, followed by heating and stirring at 85° C. for 2 hours. To the reaction mixture was added water, followed by extraction with EtOAc. The organic layer was washed with brine, dried over Na2SO4, then concentrated under reduced pressure, and purified by silica gel column (hexane/EtOAc) to obtain 6-cyclohexyl-4-[(E)-2-ethoxyvinyl]-2-methylthieno[2,3-d]pyrimidine (885 mg).
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([C:7]2[N:11]([CH2:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[F:19])[C:10](=[O:20])[NH:9][CH:8]=2)=[CH:4][CH:3]=1.Cl[CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24].C(=O)([O-])[O-].[K+].[K+]>C(#N)C.C(OCC)(=O)C>[CH2:26]([O:25][C:23](=[O:24])[CH2:22][N:9]1[CH:8]=[C:7]([C:5]2[S:6][C:2]([Cl:1])=[CH:3][CH:4]=2)[N:11]([CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[F:19])[C:10]1=[O:20])[CH3:27]
Reactant: CCOC(=O)CCl
Reactant: O=c1[nH]cc(-c2ccc(Cl)s2)n1Cc1ccccc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CC#N
Product: CCOC(=O)Cn1cc(-c2ccc(Cl)s2)n(Cc2ccccc2F)c1=O

Procedure:
650 mg (2.15 mmol) of 5-(5-chloro-2-thienyl)-1-(2-fluorobenzyl)-1,3-dihydro-2H-imidazol-2-one from Example 236A, 516 mg (4.21 mmol) of ethyl chloroacetate and 582 mg (4.21 mmol) of potassium carbonate are stirred in 12 ml acetonitrile for 7 hrs at 80° C. The reaction solution is diluted with ethyl acetate and washed three times with saturated sodium chloride solution. The organic phase is dried over sodium sulphate. After filtration from the drying agent, the filtrate is concentrated in vacuo. After purification by flash chromatography over silica gel (eluent: cyclohexane/ethyl acetate first 5:1, then 1:1), 610 mg (74% of theory) of the target compound are obtained.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH3:9])[C:6]([S:10]([N:13]([CH2:15][C:16]2[O:20][CH:19]=[C:18]([C:21](O)=[O:22])[CH:17]=2)[CH3:14])(=[O:12])=[O:11])=[C:5]([CH3:24])[CH:4]=1.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C.Cl.Cl.[CH3:57][O:58][CH:59]1[CH2:62][N:61]([CH2:63][C:64]2[CH:69]=[CH:68][C:67]([CH2:70][NH:71][CH3:72])=[CH:66][CH:65]=2)[CH2:60]1>C(Cl)Cl>[CH3:57][O:58][CH:59]1[CH2:62][N:61]([CH2:63][C:64]2[CH:69]=[CH:68][C:67]([CH2:70][N:71]([CH3:72])[C:21]([C:18]3[CH:17]=[C:16]([CH2:15][N:13]([S:10]([C:6]4[C:5]([CH3:24])=[CH:4][C:3]([O:2][CH3:1])=[CH:8][C:7]=4[CH3:9])(=[O:12])=[O:11])[CH3:14])[O:20][CH:19]=3)=[O:22])=[CH:66][CH:65]=2)[CH2:60]1
Reactant: COc1cc(C)c(S(=O)(=O)N(C)Cc2cc(C(=O)O)co2)c(C)c1
Reactant: CNCc1ccc(CN2CC(OC)C2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COc1cc(C)c(S(=O)(=O)N(C)Cc2cc(C(=O)N(C)Cc3ccc(CN4CC(OC)C4)cc3)co2)c(C)c1

Procedure:
The title compound was prepared according to general procedure BH using 5-({[(4-methoxy-2,6-dimethylphenyl)sulfonyl](methyl)amino}methyl)furan-3-carboxylic acid (40 mg, 0.11 mmol), EDCI (29 mg, 0.15 mmol), HOBt (22 mg, 0.16 mmol), DIPEA (0.04 mL, 0.22 mmol), 1-{4-[(3-methoxyazetidin-1-yl)methyl]phenyl}-N-methylmethanamine dihydro chloride (35 mg, 0.13 mmol) and DCM (5 mL).
Reaction SMILES: [C:1]1([C:6]([CH2:8][C:9]#[N:10])=O)[S:5][CH:4]=[CH:3][CH:2]=1.Cl.[NH2:12][OH:13].C([O-])(=O)C.[Na+]>C(Cl)Cl.CO>[S:5]1[CH:4]=[CH:3][CH:2]=[C:1]1[C:6]1[CH:8]=[C:9]([NH2:10])[O:13][N:12]=1
Reactant: NO
Reactant: N#CCC(=O)c1cccs1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Product: Nc1cc(-c2cccs2)no1
Temperature: 40 °C

Procedure:
A mixture of 2-thenoylacetonitrile (1 g, 6.6 mmol), hydroxylamine hydrochloride (1.38 g, 19.8 mmol) and sodium acetate (2.17 g, 26.5 mmol) in DCM (20 ml) and MeOH (20 ml) was heated at 40° C. overnight, cooled to rt and concentrated. The residue was partitioned between EtOAc and water, the organic layer was washed with water, brine, dried over magnesium sulfate and concentrated to give a brown solid 1-4. 1H NMR (400 MHz, CDCl3) δ 7.38 (m, 2H), 7.08 (m, 1H), 5.40 (s, 1H), 4.49 (bs, 21-1); ESI+ MS [M+H]+ C7H7N2OS=167.1.
Reaction SMILES: C(N(CC)CC)C.[C:8](Cl)([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[NH2:28][CH2:29][C:30]1[O:31][CH2:32][CH2:33][CH2:34][CH:35]=1>ClCCl>[C:8]([NH:28][CH2:29][C:30]1[O:31][CH2:32][CH2:33][CH2:34][CH:35]=1)([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: NCC1=CCCCO1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C1=C(CNC(c2ccccc2)(c2ccccc2)c2ccccc2)OCCC1
Temperature: 25 °C
Reaction time: 11 h

Procedure:
Triethylamine (37.7 mL, 270 mmol) and trityl chloride (41.4 g, 149 mmol) were sequentially added to a solution of the crude 2-aminomethyl-5,6-dihydro-4H-pyran (about 193 mmol) in dichloromethane (500 mL), and the mixture was stirred at room temperature for 11 hours. The reaction solution was diluted with dichloromethane (500 mL), washed with water (2×500 mL) and brine (500 mL), and then dried over anhydrous sodium sulfate and filtered. The solvent was evaporated under reduced pressure. Then, the residue was purified by silica gel column chromatography (ethyl acetate:hexane=5:95→10:90) to give 22.2 g (four steps, 32%) of the title compound as a colorless transparent gummy solid.
Reaction SMILES: [F:1][C:2]1[N:10]=[CH:9][C:8]([CH3:11])=[CH:7][C:3]=1[C:4](O)=[O:5].Cl.[CH3:13][NH:14][O:15][CH3:16].C(N(C(C)C)CC)(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F>ClCCl>[F:1][C:2]1[N:10]=[CH:9][C:8]([CH3:11])=[CH:7][C:3]=1[C:4]([N:14]([O:15][CH3:16])[CH3:13])=[O:5]
Reactant: Cc1cnc(F)c(C(=O)O)c1
Reactant: CNOC
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CON(C)C(=O)c1cc(C)cnc1F
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 86.9 %

Procedure:
To a solution of 2-fluoro-5-methylnicotinic acid (4.9 g, 31.6 mmol), N,O-dimethylhydroxylamine hydrochloride (4.01 g, 41.08 mmol), diisopropylethylamine (12.6 ml, 72.68 mmol) in dichloromethane (150 ml) at 0° C. was added TBTU (11.16 g, 34.76 mmol) portionwise over 30 minutes. The solution was stirred at 0° C. for a further 10 minutes then, at room temperature for 18 hours. The reaction mixture was washed with a 10 wt % solution of citric acid and brine. The organic layer was dried over magnesium sulfate, filtered and concentrated in vacuo. The residue was purified on silica gel by flash column chromatography (ISCO Companion□, 80 g column, 0-20% EtOAc/Petrol) to afford the title compound as a colourless solid (5.44 g, 87% yield).