Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[NH:8][C:9]2[C:10]([N:15]=1)=[N:11][CH:12]=[CH:13][CH:14]=2.CCCCCC.[H-].[Na+].Br[CH2:25][C:26]1[CH:43]=[CH:42][C:29]([C:30]([N:32]([CH:36]2[CH2:41][CH2:40][CH2:39][CH2:38][CH2:37]2)[CH:33]([CH3:35])[CH3:34])=[O:31])=[CH:28][C:27]=1[O:44][CH3:45]>CC(N(C)C)=O>[CH:36]1([N:32]([CH:33]([CH3:35])[CH3:34])[C:30](=[O:31])[C:29]2[CH:42]=[CH:43][C:26]([CH2:25][N:11]3[CH:12]=[CH:13][CH:14]=[C:9]4[N:8]=[C:7]([C:2]5[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=5)[N:15]=[C:10]34)=[C:27]([O:44][CH3:45])[CH:28]=2)[CH2:41][CH2:40][CH2:39][CH2:38][CH2:37]1
Reactant: COc1cc(C(=O)N(C(C)C)C2CCCCC2)ccc1CBr
Reactant: c1ccc(-c2nc3ncccc3[nH]2)nc1
Agent: [H-]
Agent: [Na+]
Solvent: CCCCCC
Solvent: CC(=O)N(C)C
Product: COc1cc(C(=O)N(C(C)C)C2CCCCC2)ccc1Cn1cccc2nc(-c3ccccn3)nc1-2
Temperature: 25 °C
Reaction time: 1 h
Yield: 72 %

Procedure:
2-(2-Pyridyl)-1H-imidazo(4,5-b)pyridine (1.1 g, 5.6 mmol) was added portionwise with stirring over 5 minutes to a suspension of hexane-washed NaH (150 mg, 6.16 mmol) in dimethylacetamide (15 ml) under Ar and stirred at room temperature for 1 hour. 4-Bromomethyl-3-methoxy-N-cyclohexyl-N-isopropylbenzamide (2.1 g, 5.6 mmol) was added portionwise over 30 minutes and the mixture was stirred overnight at 25° C. The solvent was removed at <50° C. in vacuo using an oil pump and the residue was chromatographed on silica gel with 95/5/1 CH2Cl2 /MeOH/NH4OH to give the titled product (1.95 g, 67%) as a glass. Anal. Calcd. for C29H33N5O2.H2O: C, 69.44; H, 7.03; N, 13.96. Found: C, 69.70; H, 7.16; N, 13.87.
Reaction SMILES: Cl[CH2:2][C:3]1[C:4]([CH2:19][CH2:20][O:21][CH3:22])=[N:5][C:6]([C:9]2[CH:14]=[CH:13][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:11][CH:10]=2)=[N:7][CH:8]=1.[CH2:23]([O:25][C:26](=[O:38])[CH2:27][N:28]1[C:36]2[C:31](=[CH:32][C:33]([OH:37])=[CH:34][CH:35]=2)[CH:30]=[CH:29]1)[CH3:24].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C.CCOCC>[CH2:23]([O:25][C:26](=[O:38])[CH2:27][N:28]1[C:36]2[C:31](=[CH:32][C:33]([O:37][CH2:2][C:3]3[C:4]([CH2:19][CH2:20][O:21][CH3:22])=[N:5][C:6]([C:9]4[CH:14]=[CH:13][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:11][CH:10]=4)=[N:7][CH:8]=3)=[CH:34][CH:35]=2)[CH:30]=[CH:29]1)[CH3:24]
Reactant: COCCc1nc(-c2ccc(C(F)(F)F)cc2)ncc1CCl
Reactant: CCOC(=O)Cn1ccc2cc(O)ccc21
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOCC
Solvent: CN(C)C=O
Product: CCOC(=O)Cn1ccc2cc(OCc3cnc(-c4ccc(C(F)(F)F)cc4)nc3CCOC)ccc21
Temperature: 25 °C
Reaction time: 3 h
Yield: 32.5 %

Procedure:
To a solution of 300 mg (0.91 mmol) 5-chloromethyl-4-(2-methoxy-ethyl)-2-(4-trifluoromethyl-phenyl)-pyrimidine and 199 mg (0.91 mmol) (5-hydroxy-indol-1-yl)-acetic acid ethyl ester in 5 ml DMF was added 443 mg (136 mmol) cesium carbonate. The reaction mixture was stirred at RT for 3 h and then taken up in ether, washed with 1N HCl and water. The crude product was purified by chromatography with AcOEt/heptane 1:4 to provide 152 mg of pure {5-[4-(2-methoxy-ethyl)-2-(4-trifluoromethyl-phenyl)-pyrimidin-5-ylmethoxy]-indol-1-yl}-acetic acid ethyl ester.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([C:14]#[N:15])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[N:16]([CH2:19][CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22])=[C:17]=[O:18]>O1CCOCC1>[C:14]([C:11]1[CH:12]=[CH:13][C:8]([C:5]2[CH:4]=[CH:3][C:2]([NH:1][C:17]([NH:16][CH2:19][CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22])=[O:18])=[CH:7][CH:6]=2)=[CH:9][CH:10]=1)#[N:15]
Reactant: N#Cc1ccc(-c2ccc(N)cc2)cc1
Reactant: CCOC(=O)CCN=C=O
Solvent: C1COCCO1
Product: CCOC(=O)CCNC(=O)Nc1ccc(-c2ccc(C#N)cc2)cc1

Procedure:
Prepared by reacting 4-amino-4'-cyano-biphenyl with ethyl 3-isocyanato-propionate in dioxane at 50° C.
Reaction SMILES: [C:1]1([CH3:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(O[O:13][C:14]([CH3:17])(C)C)(C)(C)C.[C]=O.[CH2:20]([OH:22])C>C(=[Rh])=O.CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2>[C:1]1([CH2:7][C:20]([O:13][CH2:14][CH3:17])=[O:22])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Cc1ccccc1
Reactant: CC(C)(C)OOC(C)(C)C
Reactant: CCO
Agent: O=C=[Rh]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: [C]=O
Product: CCOC(=O)Cc1ccccc1
Temperature: 120 °C
Reaction time: 16 h
Yield: 35.4 %

Procedure:
Toluene (1.38 g), ethanol (46 mg), di-tert-butyl peroxide (73 mg, 1 equivalent), carbonyl rhodium (0.9 mg, 1 mol %), and Xantphos (2.9 mg) were added into a reaction kettle, into which 10 atm carbon monoxide was introduced. The reaction was heated to 120° C., and stirred at this constant temperature for 16 h. After the reaction was completed, carbon monoxide was discharged, and 29 mg ethyl phenylacetate was obtained by column chromatography, in a yield of 36%. The ethyl phenylacetate obtained was dissolved in 1,4-dioxane. 6 N sodium hydroxide solution was added, and the reaction was heated to 60° C. After 2 h of reaction, the pH value was adjusted to 1 by adding 2 N hydrochloric acid. After removing the organic solvent under reduced pressure, 22 mg product phenylacetic acid was obtained by extraction with ethyl acetate, and the yield of hydrolysis was 91%.
Reaction SMILES: [CH2:1]([O:8][CH:9]1[CH2:14][CH2:13][C:12]([CH2:17][OH:18])([C:15]#[N:16])[CH2:11][CH2:10]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:19]1([CH3:29])[CH:24]=[CH:23][C:22]([S:25](Cl)(=[O:27])=[O:26])=[CH:21][CH:20]=1.C(N(CC)CC)C.CCOC(C)=O>C(Cl)Cl.CN(C1C=CN=CC=1)C>[CH3:29][C:19]1[CH:24]=[CH:23][C:22]([S:25]([O:18][CH2:17][C:12]2([C:15]#[N:16])[CH2:13][CH2:14][CH:9]([O:8][CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[CH2:10][CH2:11]2)(=[O:27])=[O:26])=[CH:21][CH:20]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: N#CC1(CO)CCC(OCc2ccccc2)CC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: Cc1ccc(S(=O)(=O)OCC2(C#N)CCC(OCc3ccccc3)CC2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 36 %

Procedure:
To a solution of 4-(benzyloxy)-1-(hydroxymethyl)cyclohexanecarbonitrile (crude 770 mg, 1.0 equiv) in DCM (7 mL) was added p-toluenesulfonyl chloride (898 mg, 1.5 equiv), triethylamine (1.44 mL, 3.3 equiv) and DMAP (38 mg, 0.1 equiv). The solution was stirred at room temperature overnight. It was concentrated to give the residue. EtOAc (120 mL) was added. The organic solution was washed with saturated NaHCO3 (30 mL), H2O (30 mL) and HCl (1.0 N, 30 mL), brine (30 mL), dried over anhydrous Na2SO4 and then concentrated to give yellow solid which was purified by CombiFlash (24 g silica gel column, EtOAc/Hexane: 0-30%) to afford 450 mg (yield 36%) of (4-(benzyloxy)-1-cyanocyclohexyl)methyl 4-methylbenzenesulfonate as a white solid.
Reaction SMILES: [CH2:1]([SH:17])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].[C:18]([O:22][CH2:23][CH3:24])(=[O:21])[CH:19]=[CH2:20]>C(N(CC)CC)C>[CH2:1]([S:17][CH2:20][CH2:19][C:18]([O:22][CH2:23][CH3:24])=[O:21])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: C=CC(=O)OCC
Reactant: CCCCCCCCCCCCCCCCS
Solvent: CCN(CC)CC
Product: CCCCCCCCCCCCCCCCSCCC(=O)OCC
Yield: 184.3 %

Procedure:
A solution of 15 g of hexadecylmercaptan, 3.0 g of ethyl acrylate and 2 ml of triethylamine is stirred at ambient temperature for 18 hours. The solvent is evaporated and the concentrate purified by high pressure liquid chromatography, to give 19.8 g of the desired product.
Reaction SMILES: [Br:1][C:2]1[C:7]([CH3:8])=[N:6][N:5]2[C:9]([C:13]3[S:17][C:16]([N:18]4[CH2:23][CH2:22][O:21][CH2:20][CH2:19]4)=[N:15][C:14]=3[CH3:24])=[C:10]([CH3:12])[N:11]=[C:4]2[C:3]=1[CH:25]([CH2:28][CH3:29])[CH2:26][CH3:27].[Li][CH2:31]CCC.CCCCCC.IC>CCOCC>[Br:1][C:2]1([CH3:31])[C:7]([CH3:8])=[N:6][N:5]2[CH:9]([C:13]3[S:17][C:16]([N:18]4[CH2:23][CH2:22][O:21][CH2:20][CH2:19]4)=[N:15][C:14]=3[CH3:24])[C:10]([CH3:12])=[N:11][C:4]2=[C:3]1[CH:25]([CH2:28][CH3:29])[CH2:26][CH3:27]
Reactant: [Li]CCCC
Reactant: CCC(CC)c1c(Br)c(C)nn2c(-c3sc(N4CCOCC4)nc3C)c(C)nc12
Solvent: CCCCCC
Solvent: CI
Solvent: CCOCC
Product: CCC(CC)C1=C2N=C(C)C(c3sc(N4CCOCC4)nc3C)N2N=C(C)C1(C)Br
Temperature: -78 °C
Reaction time: 0.33 h
Yield: 69 %

Procedure:
50 mg of N-{5-[7-Bromo-8-(1-ethyl-propyl)-2,6-dimethyl-imidazo[1,2-b]pyridazin-3-yl]-4-methyl-thiazol-2-yl}-morpholine (0.1 mmol) is dissolved in 4 ml of Et2O and cooled to −78° C. 0.09 ml of n-BuLi 1.6M in hexane (0.15 mmol) is added at −78° C. and stirred at −78° C. for 20 min. 43 mg of iodomethane (0.3 mmol) is added to the mixture and stirred at −78° C. and allowed to come to room temperature overnight. The reaction is quenched with sat. NH4Cl and extracted with Et2O. The separated organic layer is dried over Na2SO4 and evaporated. The crude product is applied onto a silica-gel chromatography column (Hexane:AcOEt=3:1) to give 29.6 mg of the title compound. Yield 69%. mass spectrum (m/e): 414 (M+1). 1H NMR (CDCl3): δ 3.87 (t, J=4.6 Hz, 4H), 3.56 (t, J=4.6 Hz, 4H), 3.35 (m, 1H), 2.54 (s, 3H), 2.43 (s, 3H), 2.35 (s, 3H), 2.20 (s, 3H), 2.01 (m, 4H), 0.88 (m, 6H).
Reaction SMILES: [CH2:1]([C:8]1[C:9](=[O:18])[NH:10][C:11]([S:15][CH2:16][CH3:17])=[N:12][C:13]=1[CH3:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[CH2:20][C:21]1[CH:26]=[CH:25][C:24]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=2[C:33]2[N:37]=[C:36](C(Cl)(Cl)Cl)[O:35][N:34]=2)=[CH:23][CH:22]=1.C(=O)([O-])[O-:43].[Cs+].[Cs+]>CN(C)C=O.C(OCC)(=O)C>[CH2:1]([C:8]1[C:9](=[O:18])[N:10]([CH2:20][C:21]2[CH:26]=[CH:25][C:24]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=3[C:33]3[NH:37][C:36](=[O:43])[O:35][N:34]=3)=[CH:23][CH:22]=2)[C:11]([S:15][CH2:16][CH3:17])=[N:12][C:13]=1[CH3:14])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: ClC(Cl)(Cl)c1nc(-c2ccccc2-c2ccc(CBr)cc2)no1
Reactant: CCSc1nc(C)c(Cc2ccccc2)c(=O)[nH]1
Reactant: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCSc1nc(C)c(Cc2ccccc2)c(=O)n1Cc1ccc(-c2ccccc2-c2noc(=O)[nH]2)cc1
Reaction time: 12 h
Yield: 5.8 %

Procedure:
To a solution of 5-benzyl-2-(ethylthio)-6-methylpyrimidin-4(3H)-one (0.22 g) and 3-[4′-(bromomethyl)biphenyl-2-yl]-5-(trichloromethyl)-1,2,4-oxadiazole (0.44 g) in N,N-dimethylformamide (5 mL) was added cesium carbonate (0.36 g), and the mixture was stirred for 12 hr. The reaction mixture was diluted with ethyl acetate, washed with 1 M hydrochloric acid and saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The residue was dissolved in tetrahydrofuran-ethanol (1:1, 4 mL), 1 M sodium hydroxide (2 mL) was added and the mixture was stirred for 30 min. The reaction mixture was weakly acidified with 1 M hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography to give the title compound (0.025 g, 6%) as a colorless solid.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([CH2:7][N:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10]3([C:20]4=[CH:21][C:22]5[O:26][CH2:25][O:24][C:23]=5[CH:27]=[C:19]4[O:18][CH2:17]3)[C:9]2=[O:28])[CH2:3][CH2:2]1.C=O.[C:31](O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[Cl:45]C(Cl)C>ClCCl>[ClH:45].[CH3:31][N:1]1[CH2:6][CH2:5][CH:4]([CH2:7][N:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10]3([C:20]4=[CH:21][C:22]5[O:26][CH2:25][O:24][C:23]=5[CH:27]=[C:19]4[O:18][CH2:17]3)[C:9]2=[O:28])[CH2:3][CH2:2]1
Reactant: O=C1N(CC2CCNCC2)c2ccccc2C12COc1cc3c(cc12)OCO3
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Reactant: CC(Cl)Cl
Agent: C=O
Agent: [Na+]
Solvent: ClCCl
Product: CN1CCC(CN2C(=O)C3(COc4cc5c(cc43)OCO5)c3ccccc32)CC1
Product: Cl
Temperature: 25 °C
Reaction time: 20 h
Yield: 20 %

Procedure:
To a solution of 1′-(piperidin-4-ylmethyl)spiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one (0.19 g, 0.50 mmol) in dichloroethane (5.00 mL) was added formaldehyde (0.10 mL, 33% solution, 0.03 g, 1.10 mmol) and sodium triacetoxyborohydride (0.30 g, 1.40 mmol). After stirring at ambient temperature for 20 hours, the reaction mixture was diluted with of dichloromethane (20.0 mL) and washed with water (2×20.0 mL). The organic layer was dried over sodium sulfate and filtered. The filtrate was concentrated in vacuo to dryness. The residue was subjected to column chromatography and the product was dissolved in dichloromethane (5.00 mL) and excess of HCl in ether was added. The precipitate was filtered to give the title compound in 20% yield: MS (ES+) m/z 393.3 (M+1).
Reaction SMILES: [CH3:1][C:2]1([CH3:10])[CH2:7][CH2:6][C:5](=[O:8])[CH2:4][C:3]1=[O:9].C([O-])(=O)C.C([O-])(=O)C.C([O-])(=O)C.[Br:23][C:24]1[CH:25]=[CH:26][C:27]([CH2:31][CH3:32])=[C:28]([Pb+3])[CH:29]=1.CN(C1C=CC=CN=1)C.Cl>ClCCl.C1(C)C=CC=CC=1.C(Cl)(Cl)Cl>[Br:23][C:24]1[CH:29]=[CH:28][C:27]([CH2:31][CH3:32])=[C:26]([CH:4]2[C:3](=[O:9])[C:2]([CH3:10])([CH3:1])[CH2:7][CH2:6][C:5]2=[O:8])[CH:25]=1
Reactant: CC1(C)CCC(=O)CC1=O
Reactant: CCc1ccc(Br)cc1[Pb+3]
Agent: CC(=O)[O-]
Agent: CN(C)c1ccccn1
Agent: Cl
Solvent: Cc1ccccc1
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Product: CCc1ccc(Br)cc1C1C(=O)CCC(C)(C)C1=O
Temperature: 80 °C
Yield: 46.6 %

Procedure:
To a mixture of 4,4-dimethylcyclohexane-1,3-dione (6.28 g, 45 mmol), 5-bromo-2-ethylphenyl lead triacetate (28 g, 49 mmol) and dimethylaminopyridine (27.4 g, 0.22 mol) under nitrogen are added anhydrous chloroform (300 ml) and toluene (75 ml). The reaction mixture is heated at 80° C. for 2 hours and then allowed to cool to room temperature overnight. 2M Aqueous hydrochloric acid (750 ml) and dichloromethane (500 ml) are added and the mixture is filtered through diatomaceous earth, washing through with more dichloromethane (250 ml). The two layers are separated and the aqueous phase is extracted with dichloromethane (500 ml). The organic layers are combined and washed with 2M aqueous hydrochloric acid (1000 ml) and then brine (1000 ml), dried over anhydrous magnesium sulfate, filtered and the filtrate is evaporated under reduced pressure. The residue is purified by preparative normal phase chromatography to give 2-(5-bromo-2-ethylphenyl)-4,4-dimethylcyclohexane-1,3-dione (6.78 g).
Reaction SMILES: C([Li])CCC.CC(C)=O.C(=O)=O.[Cl:13][C:14]1[C:19]([Cl:20])=[CH:18][CH:17]=[CH:16][C:15]=1[CH:21]1[C:26]([C:27]([O:29][CH3:30])=[O:28])=[C:25]([CH3:31])[NH:24][C:23]([CH2:32][O:33][CH2:34][C:35]#[CH:36])=[C:22]1[C:37]([O:39][CH2:40][CH3:41])=[O:38].[CH:42](=[O:49])[C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1>CCCCCC.O1CCCC1>[Cl:13][C:14]1[C:19]([Cl:20])=[CH:18][CH:17]=[CH:16][C:15]=1[CH:21]1[C:26]([C:27]([O:29][CH3:30])=[O:28])=[C:25]([CH3:31])[NH:24][C:23]([CH2:32][O:33][CH2:34][C:35]#[C:36][CH:42]([OH:49])[C:43]2[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=2)=[C:22]1[C:37]([O:39][CH2:40][CH3:41])=[O:38]
Reactant: C#CCOCC1=C(C(=O)OCC)C(c2cccc(Cl)c2Cl)C(C(=O)OC)=C(C)N1
Reactant: O=Cc1ccccc1
Agent: O=C=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)=O
Solvent: CCCCCC
Product: CCOC(=O)C1=C(COCC#CC(O)c2ccccc2)NC(C)=C(C(=O)OC)C1c1cccc(Cl)c1Cl
Reaction time: 2 h
Yield: 21.9 %

Procedure:
A 1.6M solution of n-butyllithium in hexane (3.4 ml) was added dropwise over 15 minutes to a stirred, cooled (acetone/cardice bath) solution of 1-{[4-(2,3-dichlorophenyl)-3-ethoxycarbonyl-5-methoxycarbonyl-6-methyl-1,4-dihydropyrid-2-yl]methoxy}prop-2-yne (1.10 g) in tetrahydrofuran (25 ml) and the mixture stirred at -70° for 2 hours. The mixture was then allowed to warm up to between -35° and -40°, stirred at that temperature for 2 hours, treated dropwise with a solution of benzaldehyde (0.16 g) in tetrahydrofuran (5 ml) over 5 minutes and then stirred at between -10° and -15° for one hour and at room temperature for 14 hours. The reaction mixture was partitioned between ethyl acetate and water and the organic layer washed with water, dried over Na2SO4 and evaporated. The residue was triturated with diethyl ether and the resulting solid collected, washed with diethyl ether and dried to give the title compound (0.18 g), m.p. 160°-164°.
Reaction SMILES: [CH3:1][N:2]1[C:6]([NH:7][C:8]([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)[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[C:5]([CH2:27][CH2:28]C(O)=O)[CH:4]=[N:3]1.C([N:34](CC)CC)C.Cl[C:40]([O:42][CH2:43]C)=[O:41].[N-]=[N+]=[N-].[Na+]>O1CCCC1.O>[CH3:1][N:2]1[C:6]([NH:7][C:8]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[C:5]([CH2:27][CH2:28][NH:34][C:40](=[O:41])[O:42][CH3:43])[CH:4]=[N:3]1
Reactant: CCN(CC)CC
Reactant: CCOC(=O)Cl
Reactant: Cn1ncc(CCC(=O)O)c1NC(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)NCCc1cnn(C)c1NC(c1ccccc1)(c1ccccc1)c1ccccc1
Reaction time: 0.33 h
Yield: 101.2 %

Procedure:
To a solution of 3-(1-methyl-5-triphenylmethylaminopyrazol-4-yl)propionic acid (14.4 g, 35 mmol) and triethylamine (4.9 ml, 35 mmol) in tetrahydrofuran (150 ml) was added ethyl chloroformate (3.4 ml, 35 mmol) followed by stirring for 20 minutes under ice-cooling. To the reaction mixture was added a solution of sodium azide (2.3 g, 35 mmol) in water (30 ml) under ice-cooling. The mixture was stirred under ice-cooling for 20 minutes and then at room temperature for 20 minutes. To the reaction mixture was added ice-cold water, and the mixture was extracted with ethyl acetate. The extract was washed with saturated aqueous sodium hydrogencarbonate solution, dried over anhydrous magnesium sulfate, and filtered. To the filtrate was added methanol, and the mixed solution was concentrated in vacuo. To the residue was added methanol (150 ml), and the mixture was stirred under reflux for 1.5 hours. The reaction mixture was concentrated in vacuo to give methyl N-[2-(1-methyl-5-triphenylmethylaminopyrazol-4-yl)ethyl]carbamate (15.6 g) as a colorless solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([N+]([O-])=O)[CH:5]=[C:4]([Cl:11])[N:3]=1.[Cl:12][C:13]1[CH:18]=[C:17]([S:19][CH3:20])[C:16]([Cl:21])=[CH:15][C:14]=1[OH:22].C([O-])([O-])=O.[K+].[K+].O>CC(C)=O>[Cl:1][C:2]1[CH:7]=[C:6]([O:22][C:14]2[CH:15]=[C:16]([Cl:21])[C:17]([S:19][CH3:20])=[CH:18][C:13]=2[Cl:12])[CH:5]=[C:4]([Cl:11])[N:3]=1
Reactant: O=[N+]([O-])c1cc(Cl)nc(Cl)c1
Reactant: CSc1cc(Cl)c(O)cc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC(C)=O
Product: CSc1cc(Cl)c(Oc2cc(Cl)nc(Cl)c2)cc1Cl
Reaction time: 3 h

Procedure:
Quantities of 19.3 gm (0.1 mol) of 2,6-dichloro-4-nitropyridine and 23.1 gm (0.11 mol) of 2,5-dichloro-4-methylmercaptophenol were dissolved in 100 ml of acetone, 13.8 gm (0.1 mol) of K2CO3 were added, and the resulting mixture was stirred for 3 hours under reflux. It was then stirred into 500 ml of water, and the precipitate formed was recovered by suction filtration.
Reaction SMILES: [C:1]([CH2:9][C:10](=[O:12])[CH3:11])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:13]([C:19]1[CH:26]=[CH:25][C:22]([CH:23]=O)=[CH:21][CH:20]=1)[CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]>N1CCCCC1.C(OCC)C>[CH2:13]([C:19]1[CH:26]=[CH:25][C:22](/[CH:23]=[C:9](/[C:10](=[O:12])[CH3:11])\[C:1]([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[O:8])=[CH:21][CH:20]=1)[CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: CC(=O)CC(=O)c1ccccc1
Reactant: CCCCCCc1ccc(C=O)cc1
Solvent: CCOCC
Solvent: C1CCNCC1
Product: CCCCCCc1ccc(/C=C(/C(C)=O)C(=O)c2ccccc2)cc1
Reaction time: 48 h

Procedure:
Benzoylacetone (0.65g, 0.004 moles), parahexylbenzaldehyde (0.76g, 0.004 moles) and piperidine (3 drops) were stirred in ethyl ether (10ml) for 20 hrs. An additional 200mg benzoylacetone was added and the solution stirred for 48 hrs. The solution was concentrated to an oil with a gentle stream of Nitrogen. The product was purified by silica gel chromatography. The structure assignment was supported by NMR, infrared and uv spectra and elemental analysis (334.5).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([F:30])[C:5]([C:24]2[N:28]=[C:27]([CH3:29])[O:26][N:25]=2)=[C:6]([C:8]2[CH:23]=[CH:22][C:11]3[CH:12]([NH:15][C:16]([C:18]4([NH2:21])[CH2:20][CH2:19]4)=[O:17])[CH2:13][O:14][C:10]=3[CH:9]=2)[CH:7]=1.[CH3:31][O:32][C:33]1[CH:37]=[C:36]([C:38](O)=[O:39])[O:35][N:34]=1>>[Cl:1][C:2]1[CH:3]=[C:4]([F:30])[C:5]([C:24]2[N:28]=[C:27]([CH3:29])[O:26][N:25]=2)=[C:6]([C:8]2[CH:23]=[CH:22][C:11]3[CH:12]([NH:15][C:16]([C:18]4([NH:21][C:38]([C:36]5[O:35][N:34]=[C:33]([O:32][CH3:31])[CH:37]=5)=[O:39])[CH2:20][CH2:19]4)=[O:17])[CH2:13][O:14][C:10]=3[CH:9]=2)[CH:7]=1
Reactant: Cc1nc(-c2c(F)cc(Cl)cc2-c2ccc3c(c2)OCC3NC(=O)C2(N)CC2)no1
Reactant: COc1cc(C(=O)O)on1
Product: COc1cc(C(=O)NC2(C(=O)NC3COc4cc(-c5cc(Cl)cc(F)c5-c5noc(C)n5)ccc43)CC2)on1

Procedure:
In analogy to the procedure described for the preparation of intermediate A-1 [B], 1-amino-cyclopropanecarboxylic acid{(rac)-6-[5-chloro-3-fluoro-2-(5-methyl-[1,2,4]oxadiazol-3-yl)-phenyl]-2,3-dihydro-benzofuran-3-yl}-amide (example 45) has been coupled with 3-methoxy-isoxazole-5-carboxylic acid to yield the title compound as light yellow oil. MS: 554.1 (MH+, 1Cl).
Reaction SMILES: [CH:1]([NH:4][CH:5]([CH3:7])[CH3:6])(C)C.C([Li])CCC.CCCCCC.[Br:19][C:20]1[CH:28]=[CH:27][C:26]2C(=CN(C)[N:25]=2)[C:21]=1[C:30]([O:32][CH3:33])=[O:31].IC>O1CCCC1.[Cl-].[NH4+]>[Br:19][C:20]1[CH:28]=[CH:27][C:26]2[C:6](=[C:5]([CH3:7])[N:4]([CH3:1])[N:25]=2)[C:21]=1[C:30]([O:32][CH3:33])=[O:31]
Reactant: CC(C)NC(C)C
Reactant: COC(=O)c1c(Br)ccc2nn(C)cc12
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CCCCCC
Solvent: C1CCOC1
Solvent: CI
Product: COC(=O)c1c(Br)ccc2nn(C)c(C)c12
Reaction time: 0.5 h
Yield: 51.9 %

Procedure:
To a solution of diisopropylamine (1.38 mL, 9.73 mmol) in tetrahydrofuran (25 mL) was added 1.6M butyllithium/hexane solution (5.62 mL, 8.99 mmol) at −78° C., and the mixture was stirred for 30 min. A solution of methyl 5-bromo-2-methyl-2H-indazole-4-carboxylate (2.00 g, 7.49 mmol) in tetrahydrofuran (50 mL) was added and, after stirring for 30 min, iodomethane (933 μL, 15.0 mmol) was added. After stirring for 30 min, the reaction solution was diluted with saturated aqueous ammonium chloride solution. The solvent was evaporated under reduced pressure. The residue was diluted with ethyl acetate, washed with water and saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate/hexane=20/80→50/50) to give the title compound (1.10 g, yield 52%).
Reaction SMILES: Cl[C:2]1[C:3]2[C:10]([S:11][CH3:12])=[CH:9][NH:8][C:4]=2[N:5]=[CH:6][N:7]=1.[NH2:13][C:14]1[CH:15]=[C:16]([C:20]#[CH:21])[CH:17]=[CH:18][CH:19]=1>CO>[C:20]([C:16]1[CH:15]=[C:14]([NH:13][C:2]2[C:3]3[C:10]([S:11][CH3:12])=[CH:9][NH:8][C:4]=3[N:5]=[CH:6][N:7]=2)[CH:19]=[CH:18][CH:17]=1)#[CH:21]
Reactant: C#Cc1cccc(N)c1
Reactant: CSc1c[nH]c2ncnc(Cl)c12
Solvent: CO
Product: C#Cc1cccc(Nc2ncnc3[nH]cc(SC)c23)c1
Temperature: 125 °C
Yield: 27.1 %

Procedure:
To 4-chloro-5-methylsulfanyl-7H-pyrrolo[2,3-d]pyrimidine (150 mg, 0.75 mmol) in dry methanol (2 ml) was added m-aminophenyl acetylene (110 mg, 0.90 mmol). The solution was heated in a sealed pressure tube at 125° C. for 5.5 hours. The reaction mixture was cooled to ambient temperature, filtered with a small amount of methanol and dried in vacuo to afford the title compound as a tan powder (57 mg, 27%). TS-MS: 281 (MH+); anal. RP18-HPLC RT:4.74 min.