Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].[C:12]([NH:15][C:16]1[CH:21]=[CH:20][C:19]([SH:22])=[CH:18][CH:17]=1)(=[O:14])[CH3:13].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C.C(OCC)(=O)C>[Cl:8][C:6]1[CH:5]=[CH:4][C:3]([N+:9]([O-:11])=[O:10])=[C:2]([S:22][C:19]2[CH:18]=[CH:17][C:16]([NH:15][C:12](=[O:14])[CH3:13])=[CH:21][CH:20]=2)[CH:7]=1
Reactant: O=[N+]([O-])c1ccc(Cl)cc1Cl
Reactant: CC(=O)Nc1ccc(S)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(=O)Nc1ccc(Sc2cc(Cl)ccc2[N+](=O)[O-])cc1
Temperature: 100 °C

Procedure:
A mixture of 2,4-Dichloro nitro benzene (0.25 g, 1.3 mmol), 4-Acetamido thiophenol (0.26 g, 1.43 mmol) and cesium carbonate (0.466 g, 1.43 mmol) in DMF (3 mL) was heated 2.5 hr at 100° C. The mixture was cooled, diluted with ethyl acetate (100 mL) and the organic layer was washed with water and aqueous 10% sodium chloride solution, then, dried over anhydrous sodium sulfate. The drying agent was filtered and the solvent removed under vacuum. The residue is purified by silica gel column chromatography eluting with CH2Cl2/methanol leaving the title compound as a yellow solid (0.25 g, 63%).
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][C:3]=1[N+:10]([O-])=O.[Cl-].[NH4+]>CO.O.[Fe]>[NH2:10][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][C:2]=1[Cl:1])[CH:6]=[O:7]
Reactant: O=Cc1ccc(Cl)c([N+](=O)[O-])c1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CO
Product: Nc1cc(C=O)ccc1Cl
Temperature: 25 °C
Reaction time: 16 h
Yield: 55.6 %

Procedure:
To a solution of 4-chloro-3-nitrobenzaldehyde 1 (11.47 g, 62 mmol) in MeOH (230 mL) and water (85 mL) was added ammonium chloride (24.2 g, 452 mmol) and iron (18.4 g, 329 mmol). The reaction mixture was stirred at room temperature for 16 h, filtered, partially concentrated under reduced pressure, and diluted with EtOAc and water. The aqueous phase was extracted with EtOAc (3×) and the combined organic extracts were washed with brine (1×), dried over MgSO4, filtered, and concentrated in vacuo. The crude aniline was dissolved in CH2Cl2 (˜150 mL), diluted with hexanes (˜300 mL), and cooled to 0° C. The solid was collected by filtration and washed with hexanes to give 3-amino-4-chlorobenzaldehyde 2 (5.36 g, 56% yield) as a yellow solid. Mass spectrum: calculated for C7H5ClNO 155.0. found 156.1 (M++1).
Reaction SMILES: [Cl:1][C:2]1[CH:25]=[C:24]([Cl:26])[CH:23]=[CH:22][C:3]=1[C:4]([NH:6][C:7]1[C:8](Cl)=[N:9][CH:10]=[N:11][C:12]=1[NH:13][C:14]1[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=1)=O.C(O)(=[O:29])C>>[Cl:20][C:17]1[CH:18]=[CH:19][C:14]([N:13]2[C:4]([C:3]3[CH:22]=[CH:23][C:24]([Cl:26])=[CH:25][C:2]=3[Cl:1])=[N:6][C:7]3[C:12]2=[N:11][CH:10]=[N:9][C:8]=3[OH:29])=[CH:15][CH:16]=1
Reactant: CC(=O)O
Reactant: O=C(Nc1c(Cl)ncnc1Nc1ccc(Cl)cc1)c1ccc(Cl)cc1Cl
Product: Oc1ncnc2c1nc(-c1ccc(Cl)cc1Cl)n2-c1ccc(Cl)cc1
Temperature: 0 °C

Procedure:
A suspension of 2,4-dichloro-N-[4-chloro-6-(4-chlorophenylamino)-pyrimidin-5-yl]-benzamide I-(1A-1)b (48 g, 0.11 mol) in acetic acid (1 l) was heated to reflux for 7 hours. The reaction mixture was cooled to 0° C., the product (colorless needles) was collected by vacuum filtration, and the solid was washed with additional acetic acid, ethyl acetate, and then ether. The product was dried overnight under high vacuum to afford the title compound I-(1A-1)c (32 g, 73%) as a colorless, fluffy solid. The mother liquor was concentrated under reduced pressure and the solid crystallized from methanol to provide additional material (16 g) as a colorless solid: mp 314–315° C.; +ESI MS (M+1) 391.3; 1H NMR: (400 MHz, CD3OD): δ 8.06 (s, 1H), 7.61 (d, J=8.3 Hz, 1H), 7.52 (d, J=2.1 Hz, 1H), 7.48–7.41 (m, 3H), 7.31 (d, J=8.7 Hz, 2H).
Reaction SMILES: Br[C:2]1[C:10]2[N:9]=[C:8]([CH3:11])[N:7]([CH:12]3[CH2:17][CH2:16][CH2:15][CH2:14][O:13]3)[C:6]=2[CH:5]=[C:4]([Cl:18])[CH:3]=1.[CH3:19][N:20]1C(=O)CCC1>[C-]#N.[C-]#N.[Zn+2].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>[Cl:18][C:4]1[CH:3]=[C:2]([C:19]#[N:20])[C:10]2[N:9]=[C:8]([CH3:11])[N:7]([CH:12]3[CH2:17][CH2:16][CH2:15][CH2:14][O:13]3)[C:6]=2[CH:5]=1
Reactant: CN1CCCC1=O
Reactant: Cc1nc2c(Br)cc(Cl)cc2n1C1CCCCO1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Agent: [Zn+2]
Product: Cc1nc2c(C#N)cc(Cl)cc2n1C1CCCCO1
Temperature: 90 °C
Reaction time: 3 h
Yield: 37.2 %

Procedure:
A mixture of 4-bromo-6-chloro-2-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-benzo[d]imidazole (3.2 g, 9.70 mmol), Zn(CN)2 (2.3 g, 19.40 mmol), and Pd(PPh3)4 (1.1 g, 0.97 mmol) in NMP (20 mL) was stirred at 90° C. for 3 h. The reaction mixture was filtered and the filtrate diluted with EtOAc (50 mL). The organic layer was washed with water (50 mL×3), dried (MgSO4), filtered and concentrated in vacuo. The residue was purified by SiO2 chromatography eluting with a DCM:MeOH gradient (0 to 6% MeOH) to afford 6-chloro-2-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-benzo[d]imidazole-4-carbonitrile as a white solid (1.0 g, 37.2%). MS (ESI): m/z=276.2 [M+1]+.
Reaction SMILES: [CH2:1]([OH:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].Cl[C:12]1[NH:17][C:16](=[O:18])[C:15]([F:19])=[CH:14][N:13]=1>C1(C)C=CC=CC=1>[CH2:1]([O:8][C:12]1[NH:17][C:16](=[O:18])[C:15]([F:19])=[CH:14][N:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OCc1ccccc1
Reactant: O=c1[nH]c(Cl)ncc1F
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: O=c1[nH]c(OCc2ccccc2)ncc1F
Yield: 78.2 %

Procedure:
A 100 ml quantity of benzyl alcohol and 7.2 g of sodium hydride are added to 100 ml of absolute toluene, and the mixture is refluxed for 1 hour. Subsequently 14.9 g of 2-chloro-5-fluoropyrimidin-4-one is added to the reaction mixture, and the resulting mixture is heated in a sealed tube at 140° to 150° C for 6 hours for reaction. The reaction mixture is further treated in the same manner as in Example 6 to give 17.2 g of white crystalline 2-benzyloxy-5-fluoropyrimidin-4-one in a yield of 78.2%, m.p. 146°-147° C.
Reaction SMILES: [C:1]([O:5][CH3:6])(=[O:4])[CH:2]=[CH2:3].[F:7][C:8]([F:19])([F:18])[C:9]([C:14]([F:17])([F:16])[F:15])([OH:13])[CH2:10]C=C>ClCCl>[F:7][C:8]([F:18])([F:19])[C:9]([OH:13])([C:14]([F:16])([F:15])[F:17])[CH2:10]/[CH:3]=[CH:2]/[C:1]([O:5][CH3:6])=[O:4]
Reactant: C=CCC(O)(C(F)(F)F)C(F)(F)F
Reactant: C=CC(=O)OC
Solvent: ClCCl
Product: COC(=O)/C=C/CC(O)(C(F)(F)F)C(F)(F)F
Yield: 65.3 %

Procedure:
To a 250 mL 3 neck roundbottom flask with reflux condenser and Teflon-coated magnetic stir bar was added methyl acrylate (9.10 g, 105.7 mmol, 1.1 eq.), 1,1,1-trifluoro-2-trifluoromethyl-pent-4-ene-2-ol (20 g, 96.1 mmol, 1 eq.) and 100 mL of anhydrous dichloromethane. The solution was heated to reflux under nitrogen and 300 mg of the Hoveyda-Grubbs 2nd generation ruthenium metathesis catalyst (0.048 mmol, 0.005 eq.) was added in 4 portions over 4 hours. The reaction was heated an additional 12 hours after which the product was purified by vacuum distillation (65° C., 6 Torr) and column chromatography (silica gel, 80:20 hexane:ethyl acetate eluent) to afford 16.7 g of methyl 6,6,6-trifluoro-5-hydroxy-5-(trifluoromethyl)hex-2-enoate (I) as colorless liquid (E/Z=2.15:1) contaminated with a small amount (0.15 eq.) of 1,1,1,8,8,8-hexafluoro-2,7-di(trifluoromethyl)-oct-4-ene-2,7-diol (E/Z=6.7:1).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH2:8][C:9]2[CH:14]=[CH:13][C:12]([O:15][CH2:16][O:17][CH3:18])=[C:11]([CH:19]([CH3:21])[CH3:20])[CH:10]=2)[C:5]([CH3:22])=[CH:4][C:3]=1[OH:23].CN.[I:26]I>CCO.O>[CH3:1][C:2]1[CH:7]=[C:6]([CH2:8][C:9]2[CH:14]=[CH:13][C:12]([O:15][CH2:16][O:17][CH3:18])=[C:11]([CH:19]([CH3:20])[CH3:21])[CH:10]=2)[C:5]([CH3:22])=[C:4]([I:26])[C:3]=1[OH:23]
Reactant: II
Reactant: COCOc1ccc(Cc2cc(C)c(O)cc2C)cc1C(C)C
Agent: CN
Solvent: O
Solvent: CCO
Product: COCOc1ccc(Cc2cc(C)c(O)c(I)c2C)cc1C(C)C
Temperature: 0 °C
Reaction time: 2 h
Yield: 64 %

Procedure:
To a stirred solution of 2,5-dimethyl-4-(4′-methoxymethoxy-3′-iso-propylbenzyl)phenol (intermediate for the synthesis of compound 7-17; 0.35 g, 1.11 mmol) in EtOH (5.0 mL) and CH3NH2 40% in water (2.5 mL) was added iodine (0.34 g, 1.33 mmol) and KI (0.27 g 1.66 mmol) in H2O (3 mL) at 0° C. The reaction mixture was stirred at 0° C. for 2 h, quenched with brine (50 mL) and extracted with ethyl acetate (100 mL×2). The combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure. The crude product was purified by column chromatography on silica gel, eluting with ethyl acetate-hexanes (1:3) to afford 2,5-dimethyl-6-iodo-4-(4′-methoxymethoxy-3′-iso-propylbenzyl)phenol as a colorless oil (0.32 g, 64%): 1H NMR (300 MHz, CDCl3): δ 7.02 (d, J=2.4 Hz, 1H), 6.95 (d, J=8.7 Hz, 1H), 6.88 (s, 1H), 6.75 (dd, J=2.4, 8.4 Hz, 1H), 5.20 (s, 2H), 3.95 (s, 2H), 3.51 (s, 3H), 3.35-3.30 (m, 1H), 2.39 (s, 3H), 2.30 (s, 3H), 1.22 (d, J=6.9 Hz, 6H); TLC conditions: Uniplate silica gel, 250 microns; Mobile phase=hexanes-ethylacetate (9:1); Rf=0.6.
Reaction SMILES: [C:1]1([O:7][CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:9](Cl)(=[O:13])/[CH:10]=[CH:11]/[CH3:12].[Cl-].[Al+3].[Cl-].[Cl-]>ClCCl>[CH3:8][O:7][C:1]1[CH:6]=[CH:5][C:4]([C:9](=[O:13])/[CH:10]=[CH:11]/[CH3:12])=[CH:3][CH:2]=1
Reactant: C/C=C/C(=O)Cl
Reactant: COc1ccccc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: C/C=C/C(=O)c1ccc(OC)cc1

Procedure:
Anisole (0.3 mL), crotonoyl chloride (24 mg), and aluminium chloride (160 mg) were reacted in dichloromethane (1.5 mL) at from −50° C. to room temperature for 4 hours. The resultant was treated in the same manner as described in Example 1 to obtain the title compound (75 mg).
Reaction SMILES: [C:1]([C:6]1[C:7](=[O:24])[CH2:8][CH:9]([C:13]2[C:18]([CH3:19])=[CH:17][C:16]([CH3:20])=[C:15]([CH:21]=O)[C:14]=2[CH3:23])[CH2:10][C:11]=1[OH:12])(=[O:5])[CH2:2][CH2:3][CH3:4].Cl.[NH2:26]O>C(O)=O>[C:1]([C:6]1[C:7](=[O:24])[CH2:8][CH:9]([C:13]2[C:18]([CH3:19])=[CH:17][C:16]([CH3:20])=[C:15]([C:21]#[N:26])[C:14]=2[CH3:23])[CH2:10][C:11]=1[OH:12])(=[O:5])[CH2:2][CH2:3][CH3:4]
Reactant: CCCC(=O)C1=C(O)CC(c2c(C)cc(C)c(C=O)c2C)CC1=O
Reactant: NO
Agent: Cl
Solvent: O=CO
Product: CCCC(=O)C1=C(O)CC(c2c(C)cc(C)c(C#N)c2C)CC1=O
Temperature: 0 °C
Yield: 45.1 %

Procedure:
A solution of 2-butyryl-3-hydroxy-5-(3-formyl-2,4,6-trimethylphenyl)cyclohex-2-en-1-one (1.50 g) and hydroxylamine hydrochloride (0.35 g) in 98% formic acid (7 ml) was refluxed for an hour and then allowed to cool. The mixture was diluted with ice water and the precipitate collected. Purification by column chromatography over silica gel (eluant dichloromethane) gave 2-butyryl-3-hydroxy-5-(3-cyano-2,4,6-trimethylphenyl)cyclohex-2-en-1-one (0.67 g; 44%) as a pale yellow oil. Proton nuclear magnetic resonance spectrum (CDCl3 ; δ in ppm): 1.00 (3H, t); 1.68 (2H, m); 2.45 (6H, s); 2.60 (3H, s); 2.65-4.20 (7H, m); 7.42 (1H, s); 18.35 (1H, s).
Reaction SMILES: [CH2:1]([C:3]1[CH2:4][CH:5]2[CH:8]([CH:9]=1)[C:7]([CH2:14][C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])([CH2:10][N+:11]([O-])=O)[CH2:6]2)[CH3:2].[H][H]>[Ni].C(O)C>[NH2:11][CH2:10][C:7]1([CH2:14][C:15]([O:17][C:18]([CH3:19])([CH3:21])[CH3:20])=[O:16])[CH2:6][CH:5]2[CH:8]1[CH:9]=[C:3]([CH2:1][CH3:2])[CH2:4]2
Reactant: CCC1=CC2C(C1)CC2(CC(=O)OC(C)(C)C)C[N+](=O)[O-]
Reactant: [H][H]
Agent: [Ni]
Solvent: CCO
Product: CCC1=CC2C(C1)CC2(CN)CC(=O)OC(C)(C)C
Yield: 92 %

Procedure:
Raney nickel (96 mg, 0.16 w/w) and ethanol (200 μL) were added to tert-butyl [3-ethyl-6-(nitromethyl)bicyclo[3.2.0]hept-3-en-6-yl]acetate (59 mg, 85:15 diastereomeric mixture), and the mixture was stirred at room temperature for 12 hours under the hydrogen atmosphere. The Raney nickel was filtered off. Then, the solvent was distilled off to obtain the compound of interest as a brown oil substance (49 mg, yield: 92%, 85:15 diastereomeric mixture).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]1[CH:12]=[C:13]([C:15]([O:17]CC)=[O:16])[N:14]=[C:7]1[CH:6]=[CH:5]2.Cl>C(O)C.[OH-].[Na+].O>[OH2:16].[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]1[CH:12]=[C:13]([C:15]([OH:17])=[O:16])[N:14]=[C:7]1[CH:6]=[CH:5]2
Reactant: CCOC(=O)c1cn2c(ccc3cc(Cl)ccc32)n1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: O=C(O)c1cn2c(ccc3cc(Cl)ccc32)n1

Procedure:
820 mg of ethyl 7-chloroimidazo-[1,2-a]-quinoline-2-carboxylate in 25 ml of ethanol and 1 N sodium hydroxide solution was added thereto. The mixture obtained was heated on a steam bath for 30 minutes and then was diluted with 50 ml of water. The mixture was neutralized with 3.5 ml of 2 N hydrochloric acid and then cooled to obtain pale cream crystals of 7-chloroimidazo-[1,2-a]-quinoline-2-carboxylic acid monohydrate melting at 278°-279° C. The I.R. spectrum suggests that the compound exists at least partially in the zwitterionic form.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([SH:8])=[CH:4][CH:3]=1.Br[CH2:10][CH2:11][CH2:12][O:13][C:14]1[C:19]([Cl:20])=[CH:18][C:17]([O:21][CH2:22][CH:23]=[C:24]([Cl:26])[Cl:25])=[CH:16][C:15]=1[Cl:27].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][CH2:10][CH2:11][CH2:12][O:13][C:14]2[C:15]([Cl:27])=[CH:16][C:17]([O:21][CH2:22][CH:23]=[C:24]([Cl:26])[Cl:25])=[CH:18][C:19]=2[Cl:20])=[CH:4][CH:3]=1
Reactant: Sc1ccc(Cl)cc1
Reactant: ClC(Cl)=CCOc1cc(Cl)c(OCCCBr)c(Cl)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: ClC(Cl)=CCOc1cc(Cl)c(OCCCSc2ccc(Cl)cc2)c(Cl)c1
Temperature: 25 °C
Reaction time: 24 h
Yield: 80.7 %

Procedure:
A mixture of 0.47 g of 4-chlorothiophenol, 1.33 g of 1-(3-bromopropyloxy)-2,6-dichloro-4-(3,3-dichloro-2-propenyloxy)benzene, 0.49 g of potassium carbonate and 20 ml of N,N-dimethylformamide was stirred at room temperature for 24 hours. The reaction mixture was poured into ice-water, and extracted twice with 50 ml of diethyl ether. The combined ether layer was washed with water, dried with anhydrous magnesium sulfate, and concentrated to obtain a crude product. The crude product was subjected to silica gel chromatography, which afforded 1.24 g of 1-(3-(4-chlorophenylthio) propyloxy)-2,6-dichloro-4-(3,3-dichloro-2-propenyloxy)benzene (81% yield), nD26.0 1.6035.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([C:11]3([C:14]4[CH:15]=[C:16]5[C:21](=[CH:22][CH:23]=4)[N:20]=[CH:19][CH:18]=[CH:17]5)[CH2:13][CH2:12]3)=[N:9][N:10]=2)[N:7]=1.C([Sn](CCCC)(CCCC)[C:29]([O:31]CC)=[CH2:30])CCC>O1CCOCC1.CCOC(C)=O.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>[N:20]1[C:21]2[C:16](=[CH:15][C:14]([C:11]3([C:8]4[N:6]5[N:7]=[C:2]([C:29](=[O:31])[CH3:30])[CH:3]=[CH:4][C:5]5=[N:10][N:9]=4)[CH2:13][CH2:12]3)=[CH:23][CH:22]=2)[CH:17]=[CH:18][CH:19]=1
Reactant: C=C(OCC)[Sn](CCCC)(CCCC)CCCC
Reactant: Clc1ccc2nnc(C3(c4ccc5ncccc5c4)CC3)n2n1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: CC(=O)c1ccc2nnc(C3(c4ccc5ncccc5c4)CC3)n2n1
Temperature: 90 °C
Reaction time: 3 h

Procedure:
A mixture of 6-[1-(6-chloro-[1,2,4]triazolo[4,3-b]pyridazin-3-yl)-cyclopropyl]-quinoline (30 mg, 0.093 mmol), PdCl2(PPh3)2 (6.5 mg, 0.0093 mmol) and tributyl(1-ethoxyvinyl)stannane (67 mg, 0.186 mmol) in 3 mL of 1,4-dioxane was heated at 90° C. for 3 h under nitrogen. The reaction mixture was diluted with EtOAc, washed with aqueous KF. The organic layer was dried over Na2SO4, filtered and concentrated in vacuo. The residue was dissolved in HOAc and 3 N HCl, and the solution was stirred at rt for 3 h. The solvent was removed under reduced pressure and the residue was dissolved in DCM, washed with saturated aqueous NaHCO3 and brine. The organic layer was dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by flash chromatography on silica gel eluting with EtOAc/MeOH gradient to afford the title compound as a yellow solid. 1H-NMR (400 MHz, CDCl3) δ ppm 8.89 (dd, 1H), 8.13-8.04 (m, 3H), 7.93 (d, 1H), 7.87 (dd, 1H), 7.70 (d, 1H), 7.40 (dd, 1H), 2.51 (s, 3H), 1.92-1.89 (m, 2H), 1.73-1.69 (m, 2H). LCMS (method A): [MH]+=330, tR=4.18 min.
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:13][O:14][C:15]1[CH:16]=[C:17](/[CH:21]=[CH:22]/[CH:23]=O)[CH:18]=[CH:19][CH:20]=1.[C:25]([CH2:27]P(=O)(OCC)OCC)#[N:26]>>[CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)=[N:4][C:3]=1[CH2:13][O:14][C:15]1[CH:16]=[C:17](/[CH:21]=[CH:22]/[CH:23]=[CH:27]/[C:25]#[N:26])[CH:18]=[CH:19][CH:20]=1
Reactant: CCOP(=O)(CC#N)OCC
Reactant: Cc1oc(-c2ccccc2)nc1COc1cccc(/C=C/C=O)c1
Product: Cc1oc(-c2ccccc2)nc1COc1cccc(/C=C/C=C/C#N)c1

Procedure:
According to the method described for Reference Example 35, (E)-3-[3-(5-methyl-2-phenyl-4-oxazolylmethoxy)phenyl]-2-propen-1-al was allowed to react with diethyl cyanomethylphosphonate to give (E,E)-5-[3-(5-methyl-2-phenyl-4-oxazolylmethoxy)phenyl]-2,4-pentadienenitrile as an oily product.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10](=[N:18][C:19]#[N:20])OC2C=CC=CC=2)[CH:5]=[C:6]([Cl:8])[CH:7]=1.[CH3:21][CH:22]([CH3:26])[CH2:23][CH2:24][NH2:25].C(N(CC)CC)C>C(#N)C>[C:19]([NH:18][C:10]([NH:9][C:4]1[CH:5]=[C:6]([Cl:8])[CH:7]=[C:2]([Cl:1])[CH:3]=1)=[N:25][CH2:24][CH2:23][CH:22]([CH3:26])[CH3:21])#[N:20]
Reactant: N#CN=C(Nc1cc(Cl)cc(Cl)c1)Oc1ccccc1
Reactant: CC(C)CCN
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CC(C)CCN=C(NC#N)Nc1cc(Cl)cc(Cl)c1
Temperature: 85 °C
Reaction time: 16 h
Yield: 54.6 %

Procedure:
To N-(3,5-Dichlorophenyl)-N'-cyano-O-phenylisourea (0.98 mmol, 300 mg) in dry acetonitrile (2 ml), 3-methylbutylamine (2.16 mmol, 0.255 ml) and triethylamine (1.08 mmol, 0.150 ml) were added. The reaction mixture was stirred for 16 h at 85° C. under nitrogen. The precipitated material was filtered off and recrystallized from ethyl acetate to give the title compound (160 mg, 54%) as white crystals. Mp 146.5-1451.5° C.; 1H-NMR (CDCl3): δ 0.94 (d, 6H), 1.43 (q, 2H), 1.6 (m, 1H), 3.31 (q, 2H), 4.9 (br, 1H), 7.18 (br s, 2H), 7.29 (br s, 1H), 7.5 ppm (br, 1H); MA calc for C13H16Cl2N4 : C, 52.19%; H, 5.39%; N, 18.73%. Found: C, 52.23%; H, 5.51%; N, 18.60%.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([NH:8][CH:9]2[CH2:11][CH2:10]2)[N:5]2[N:12]=[CH:13][C:14]([CH:15]=[O:16])=[C:4]2[N:3]=1.Cl[C:18]([O:20][CH3:21])=[O:19].CCN(C(C)C)C(C)C>O1CCCC1>[CH:9]1([NH:8][C:6]2[N:5]3[N:12]=[CH:13][C:14]([CH:15]=[O:16])=[C:4]3[N:3]=[C:2]([NH:1][C:18](=[O:19])[O:20][CH3:21])[CH:7]=2)[CH2:11][CH2:10]1
Reactant: COC(=O)Cl
Reactant: Nc1cc(NC2CC2)n2ncc(C=O)c2n1
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)Nc1cc(NC2CC2)n2ncc(C=O)c2n1
Temperature: 60 °C

Procedure:
To 5-amino-7-(cyclopropylamino)pyrazolo[1,5-a]pyrimidine-3-carbaldehyde (50 mg, 0.23 mmol) in 1.0 mL tetrahydrofuran was added methyl chloroformate (35 ul, 0.46 mmol) and DIEA (39 ul). The reaction mixture was heated at 60° C. for one hour. The reaction was partitioned between ethyl acetate/water. The organic layer was collected, dried over sodium sulfate, and concentrated under high vacuum to yield methyl 7-(cyclopropylamino)-3-formylpyrazolo[1,5-a]pyrimidin-5-ylcarbamate. The crude product was taken to next step without further purification. LCMS (M+1=276)
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[CH2:10][C:9](=[O:12])[CH2:8][CH2:7]2.[BH4-].[Na+].O>CO>[NH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[CH2:10][CH:9]([OH:12])[CH2:8][CH2:7]2
Reactant: Nc1cccc2c1CC(=O)CC2
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: Nc1cccc2c1CC(O)CC2
Reaction time: 1 h
Yield: 71.3 %

Procedure:
Next, to 8-amino-3,4-dihydronaphthalen-2(1H)-one (0.050 g, 0.318 mmol) in methanol (10 mL) was added sodium borohydride (0.030 g, 0.175 mmol) at 0° C., and the mixture was stirred for 1 hour. The mixture was poured into water, and the product was extracted with ethylacetate. The organic layer was dried over Na2SO4, filtered, and concentrated under reduced pressure to afford 8-amino-1,2,3,4-tetrahydronaphthalen-2-ol (0.037 g, 71% yield).
Reaction SMILES: Cl[C:2]1[CH:10]=[CH:9][C:8]([S:11]([CH3:14])(=[O:13])=[O:12])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[CH:15]([OH:18])([CH3:17])[CH3:16]>CCN(CC)CC>[CH:15]([O:18][C:2]1[CH:10]=[CH:9][C:8]([S:11]([CH3:14])(=[O:13])=[O:12])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5])([CH3:17])[CH3:16]
Reactant: CC(C)O
Reactant: CS(=O)(=O)c1ccc(Cl)c(C(=O)O)c1
Solvent: CCN(CC)CC
Product: CC(C)Oc1ccc(S(C)(=O)=O)cc1C(=O)O
Temperature: 120 °C

Procedure:
A mixture of 2.13 mmol 2-chloro-5-methanesulfonyl-benzoic acid, 0.64 mmol Cu(I)Br in 5 ml NEt3 and 25 ml isopropanol was heated to 120° C. for 16 h in a sealed tube. The volatiles were removed under vacuum and the residue was taken up in 70 ml 1N HCl. Extraction with ethyl acetate drying of the combined organic fractions and evaporation yielded a residue which was purified by reversed phase preparative HPLC eluting with an acetonitrile/water gradient. Evaporation of the product fractions yielded the title compound.
Reaction SMILES: [Cl:1][C:2]1[C:7]([OH:8])=[C:6](I)[CH:5]=[C:4]([CH:10]([OH:12])[CH3:11])[N:3]=1.[CH:13]([Sn](C=C)(C=C)C=C)=[CH2:14].C(OCC)(=O)C>CN(C)C=O.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>[Cl:1][C:2]1[C:7]([OH:8])=[C:6]([CH:13]=[CH2:14])[CH:5]=[C:4]([CH:10]([OH:12])[CH3:11])[N:3]=1
Reactant: C=C[Sn](C=C)(C=C)C=C
Reactant: CC(O)c1cc(I)c(O)c(Cl)n1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: C=Cc1cc(C(C)O)nc(Cl)c1O
Temperature: 50 °C
Yield: 70.1 %

Procedure:
A solution of 2-chloro-3-hydroxy-4-iodo-6-(1-hydroxyethyl)-pyridine (3.6 g, 12 mmol) in 36 mL of N,N-dimethylformamide is treated with bis(triphenylphosphine)-palladium dichloride (632 mg, 0.9 mmol) and tetravinyltin (2.7 mL, 15 mmol) and heated at 50° C. for 24 h and at room temperature for 40 h. The mixture is poured into 300 mL of ethyl acetate, filtered through a celite pad and the filtrate is washed with 4×50 mL of saturated sodium chloride. The organics are concentrated in vacuo and the crude material is chromatographed over 150 g of silica gel (230-400 mesh), eluting with 25% ethyl acetate/hexanes to provide 1.68 g (70%) of 2-chloro-3-hydroxy-4-vinyl-6-(1-hydroxyethyl)-pyridine.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:16]2[CH2:21][CH2:20][O:19][CH2:18][CH2:17]2)[C:5]2[S:10][C:9]([C:11]3[N:12]=[CH:13][S:14][CH:15]=3)=[N:8][C:6]=2[N:7]=1.C(=O)([O-])[O-].[Na+].[Na+].[C:28](#[N:30])[CH3:29]>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>[O:19]1[CH2:20][CH2:21][N:16]([C:4]2[C:5]3[S:10][C:9]([C:11]4[N:12]=[CH:13][S:14][CH:15]=4)=[N:8][C:6]=3[N:7]=[C:2]([C:29]3[CH:28]=[N:30][C:2]([NH2:7])=[N:3][CH:4]=3)[N:3]=2)[CH2:17][CH2:18]1
Reactant: CC#N
Reactant: Clc1nc(N2CCOCC2)c2sc(-c3cscn3)nc2n1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: Nc1ncc(-c2nc(N3CCOCC3)c3sc(-c4cscn4)nc3n2)cn1

Procedure:
5-Chloro-7-morpholino-2-(thiazol-4-yl)thiazolo[4,5-d]pyrimidine, 5-pyrimidine-2-amine boronic acid (1.2 eq), and trans-dichlorobis(triphenylphosphine)palladium(II) (0.1 eq) were slurried with equal parts 1M sodium carbonate (3 eq) and acetonitrile. The solution was microwaved at 130° C. for 15 minutes. Acetonitrile was added and the solution was filtered. The resulting organic layer was purified by reverse phase silica gel chromatography to give the product 138. MS data: (ESI+): MH+ 399.