Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][C:6]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[Cl:14])=[O:7].[NH:15]1[CH2:20][CH2:19][CH:18]([C:21]2[CH:22]=[C:23]([NH:27][C:28](=[O:31])[CH2:29][CH3:30])[CH:24]=[CH:25][CH:26]=2)[CH2:17][CH2:16]1>>[Cl:14][C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=1[C:6](=[O:7])[CH2:5][CH2:4][CH2:3][CH2:2][N:15]1[CH2:20][CH2:19][CH:18]([C:21]2[CH:22]=[C:23]([NH:27][C:28](=[O:31])[CH2:29][CH3:30])[CH:24]=[CH:25][CH:26]=2)[CH2:17][CH2:16]1
Reactant: O=C(CCCCCl)c1ccccc1Cl
Reactant: CCC(=O)Nc1cccc(C2CCNCC2)c1
Product: CCC(=O)Nc1cccc(C2CCN(CCCCC(=O)c3ccccc3Cl)CC2)c1

Procedure:
Prepared by Procedure K and Scheme B1 using 5-chloro-1-(2-chlorophenyl)-1-pentanone and N-[3-(4-piperidinyl)phenyl]propanamide: ESMS m/e: 427.1 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([N:8]2[C:12]3=[N:13][CH:14]=[CH:15][CH:16]=[C:11]3[N:10]=[CH:9]2)[CH:5]=[CH:4][C:3]=1[CH2:17][C:18]([OH:20])=O.[CH:21]([N:24]1[CH2:29][CH2:28][N:27]([CH2:30][C:31]2[CH:36]=[CH:35][C:34]([NH2:37])=[CH:33][C:32]=2[C:38]([F:41])([F:40])[F:39])[CH2:26][CH2:25]1)([CH3:23])[CH3:22]>C(Cl)Cl.CO>[Cl:1][C:2]1[CH:7]=[C:6]([N:8]2[C:12]3=[N:13][CH:14]=[CH:15][CH:16]=[C:11]3[N:10]=[CH:9]2)[CH:5]=[CH:4][C:3]=1[CH2:17][C:18]([NH:37][C:34]1[CH:35]=[CH:36][C:31]([CH2:30][N:27]2[CH2:26][CH2:25][N:24]([CH:21]([CH3:23])[CH3:22])[CH2:29][CH2:28]2)=[C:32]([C:38]([F:41])([F:40])[F:39])[CH:33]=1)=[O:20]
Reactant: CC(C)N1CCN(Cc2ccc(N)cc2C(F)(F)F)CC1
Reactant: O=C(O)Cc1ccc(-n2cnc3cccnc32)cc1Cl
Solvent: CO
Solvent: ClCCl
Product: CC(C)N1CCN(Cc2ccc(NC(=O)Cc3ccc(-n4cnc5cccnc54)cc3Cl)cc2C(F)(F)F)CC1

Procedure:
The title compound is prepared as described in Example 1 but using (2-chloro-4-imidazo[4,5-b]pyridin-3-yl-phenyl)-acetic acid and 4-(4-isopropyl-piperazin-1-ylmethyl)-3-trifluoromethyl-phenylamine (see WO 03/099771). Title compound: ES-MS: 570.9 [M+H]+; single peak at tR=3.46 min (System 1); Rf=0.26 (CH2Cl2/MeOH+1% NH3aq, 9:1).
Reaction SMILES: C([O:5][C:6](=[O:30])/[CH:7]=[CH:8]/[C:9]1[CH:29]=[N:28][C:12]2[NH:13][C:14](=[O:27])[CH2:15][N:16]([CH2:18][CH2:19][CH2:20][N:21]3[CH2:26][CH2:25][O:24][CH2:23][CH2:22]3)[CH2:17][C:11]=2[CH:10]=1)(C)(C)C.C(O)(C(F)(F)F)=O.C(Cl)[Cl:39]>>[ClH:39].[N:21]1([CH2:20][CH2:19][CH2:18][N:16]2[CH2:17][C:11]3[CH:10]=[C:9](/[CH:8]=[CH:7]/[C:6]([OH:30])=[O:5])[CH:29]=[N:28][C:12]=3[NH:13][C:14](=[O:27])[CH2:15]2)[CH2:26][CH2:25][O:24][CH2:23][CH2:22]1
Reactant: ClCCl
Reactant: CC(C)(C)OC(=O)/C=C/c1cnc2c(c1)CN(CCCN1CCOCC1)CC(=O)N2
Solvent: O=C(O)C(F)(F)F
Product: Cl
Product: O=C(O)/C=C/c1cnc2c(c1)CN(CCCN1CCOCC1)CC(=O)N2
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of (E)-3-[4-(3-Morpholin-4-yl-propyl)-2-oxo-2,3,4,5-tetrahydro-1H-pyrido[2,3-e][1,4]diazepin-7-yl]acrylic acid tert-butyl ester (2.21 g, 5.30 mmol) in CH2Cl2 (20 mL) was treated with TFA (20 mL). After stirring at room temperature for 30 min, the solution was concentrated in vacuo. The resulting oil was treated with anhydrous HCl (50 mL of a 4.0 M solution in dioxane, 200 mmol) and the mixture was sonicated for 1.5 h. The mixture was diluted with Et2O (200 mL) and sonicated for 15 min. The solid was isolated by filtration, washed with Et2O, and dried under vacuum at 50° C. for 5 h to give the title compound (3.08 g, quantitative) as an off-white solid: 1H NMR (500 MHz, DMSO-d6) δ 11.23 (br s, 2H), 8.74 (s, 1H), 8.36 (s, 1H), 7.63 (d, J=15.9, 1H), 6.63 (d, J=16.0 Hz, 1H), 4.33 (br s, 2H), 3.90 (br s, 6H), 3.24 (m, 8H), 2.22 (br s, 2H); MS (ESI) m/e 361 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH:11]2[CH2:15][CH2:14][CH2:13][CH2:12]2)=[C:4](Cl)[N:3]=1.C(N[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=1)C.[CH2:26]([N:28](CC)CC)[CH3:27]>>[Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH:11]2[CH2:15][CH2:14][CH2:13][CH2:12]2)=[C:4]([NH:28][CH2:26][CH2:27][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=2)[N:3]=1
Reactant: Clc1nc(Cl)c2ncn(C3CCCC3)c2n1
Reactant: CCN(CC)CC
Reactant: CCNc1ccccn1
Product: Clc1nc(NCCc2ccccn2)c2ncn(C3CCCC3)c2n1

Procedure:
2-Chloro-6-[2-(2-pyridyl)ethylamino]-9-cyclopentylpurine is prepared from 2,6-dichloro-9-cyclopentylpurine, 2-(ethylamino)pyridine, and triethylamine essentially as described above in Example 1, Scheme A, step b.
Reaction SMILES: [C:1](Cl)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:10](#[N:12])C.[Cu]C#N.[C-]#N.[Na+]>C1(C)C(C)=CC=CC=1>[C:1]([C:10]#[N:12])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC#N
Reactant: O=C(Cl)c1ccccc1
Agent: N#C[Cu]
Agent: [C-]#N
Agent: [Na+]
Solvent: Cc1ccccc1C
Product: N#CC(=O)c1ccccc1
Temperature: 112 °C
Reaction time: 1.5 h
Yield: 93 %

Procedure:
There were present in a reaction vessel provided with a reflux condenser a mixture of 141 grams (1.0 mole) of benzoyl chloride and 25 ml of acetonitrile and the mixture was heated to 112° C. Then there were added in the course of 60 minutes a suspension of 9 grams of copper (I) cyanide (0.1 mole) and 44 grams of sodium cyanide (1.1 mole) in 79 ml of xylene. The sodium cyanide had 13% with a particle size below 0.1 mm, 41% with a particle size between 0.1 and 0.2 mm, 23% with a particle size between 0.2 and 0.4 mm and 23% with a particle size between 0.4 and 0.8 mm. The temperature of the mixture increased slowly to 128° C. during the addition of the suspension. Then the mixture was held at this temperature for a further 90 minutes and subsequently cooled to 18° C. The salt, chiefly sodium chloride, which separated was filtered off and washed with 25 ml xylene. The filtrate was distilled under reduced pressure. There were obtained 121 grams of pure benzoyl cyanide, corresponding to a yield of 93% based on the benzoyl chloride added. The benzoyl cyanide contained no benzoyl chloride. It had a boiling point of 115° to 117° C. at 45 mbar.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([Cl:12])=[CH:9][CH:10]=2)[N:5]=[CH:4][N:3]=1.[Cl:13][C:14]1[CH:21]=[CH:20][C:17]([NH:18][CH3:19])=[CH:16][CH:15]=1>C(O)C>[Cl:12][C:8]1[CH:7]=[C:6]2[C:11]([C:2]([N:18]([CH3:19])[C:17]3[CH:20]=[CH:21][C:14]([Cl:13])=[CH:15][CH:16]=3)=[N:3][CH:4]=[N:5]2)=[CH:10][CH:9]=1.[ClH:1]
Reactant: CNc1ccc(Cl)cc1
Reactant: Clc1ccc2c(Cl)ncnc2c1
Solvent: CCO
Product: CN(c1ccc(Cl)cc1)c1ncnc2cc(Cl)ccc12
Product: Cl

Procedure:
2.5 g of 4,7-dichloroquinazoline and 2.2 g of p-chloro-N-methylaniline were added to 10 ml of ethanol and then the mixture was heated. The mixture became a homogeneous solution which solidified soon after. After cooling, the solidified crystals were collected and recrystallized from ethanol to give the desired compound in the form of its hydrochloride (Compound No. 68). The crystals of hydrochloride were crushed and added to a dilute aqueous solution of sodium hydroxide, with stirring, to precipitate the free base. The precipitate was collected by filtration, washed with water and recrystallized from ethanol to give 2.4 g (yield 65%) of the desired Compound No. 67 in the form of colourless plates melting at 129°-131° C.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:20]([CH3:21])[C:11]3=[N:12][CH:13]=[C:14]([C:16]([F:19])([F:18])[F:17])[CH:15]=[C:10]3[N:9]=2)=[C:4]([S:22]([CH2:25][CH3:26])(=[O:24])=[O:23])[CH:3]=1.C([Sn](CCCC)(CCCC)[C:32]1[N:37]=[CH:36][CH:35]=[CH:34][N:33]=1)CCC.C1(C)C=CC=CC=1>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>[CH2:25]([S:22]([C:4]1[CH:3]=[C:2]([C:32]2[N:37]=[CH:36][CH:35]=[CH:34][N:33]=2)[CH:7]=[CH:6][C:5]=1[C:8]1[N:20]([CH3:21])[C:11]2=[N:12][CH:13]=[C:14]([C:16]([F:19])([F:18])[F:17])[CH:15]=[C:10]2[N:9]=1)(=[O:24])=[O:23])[CH3:26]
Reactant: CCCC[Sn](CCCC)(CCCC)c1ncccn1
Reactant: CCS(=O)(=O)c1cc(Br)ccc1-c1nc2cc(C(F)(F)F)cnc2n1C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: CCS(=O)(=O)c1cc(-c2ncccn2)ccc1-c1nc2cc(C(F)(F)F)cnc2n1C
Temperature: 25 °C
Yield: 100.2 %

Procedure:
A mixture of 2-(4-bromo-2-ethylsulfonylphenyl)-3-methyl-6-trifluoromethyl-3H-imidazo[4,5-b]pyridine (0.20 g), 2-tributylstannylpyrimidine (0.17 g), tetrakis(triphenylphosphine)palladium (27 mg) and toluene (5 ml) was heated at reflux under nitrogen atmosphere for 5.5 hours. After the mixture was cooled to room temperature, to the mixture, 2-tributylstannylpyrimidine (0.17 g) and tetrakis(triphenylphosphine)palladium (27 mg) were added, and stirred under reflux for further 8 hours. After the mixture was cooled to room temperature, water was poured thereinto, and extracted with ethyl acetate. The combined organic layer was dried over magnesium sulfate, and concentrated under reduced pressure. The resulting residue was subjected to silica gel column chromatography to give 0.20 g of 2-[2-ethylsulfonyl-4-(pyrimidine-2-yl)-phenyl)-3-methyl-6-trifluoromethyl-3H-imidazo[4,5-b]pyridine (hereinafter, Present Compound 333).
Reaction SMILES: [CH:1]12[NH:13][CH:5]([CH2:6][CH:7]([CH2:9][C:10]([OH:12])=[O:11])[CH2:8]1)[CH2:4][O:3][CH2:2]2.S(Cl)(Cl)(=O)=O.[CH3:19]O>>[CH3:19][O:11][C:10](=[O:12])[CH2:9][CH:7]1[CH2:6][CH:5]2[NH:13][CH:1]([CH2:2][O:3][CH2:4]2)[CH2:8]1
Reactant: CO
Reactant: O=C(O)CC1CC2COCC(C1)N2
Solvent: O=S(=O)(Cl)Cl
Product: COC(=O)CC1CC2COCC(C1)N2
Yield: 99 %

Procedure:
To a solution of (3-oxa-9-aza-bicyclo[3.3.1]non-7-yl)-acetic acid (200 mg, 0.9 mmol) in 10 mL of methanol was added dropwise sulfuryl chloride (0.3 mL, 1.8 mmol) under ice cooling. After the mixture was refluxed for 3 hours, it was concentrated in vacuo. The residue was extracted with ethyl acetate (20 mL×2). The organic layer was washed with saturated aqueous sodium bicarbonate solution (20 mL×2), and then dried over anhydrous sodium sulfate and then concentrated in vacuo to afford (3-oxa-9-aza-bicyclo[3.3.1]non-7-yl)-acetic acid methyl ester (Compound AG) as colorless oil (179 mg, 99%) which was used directly in next step without further purification. MS: calc'd (MH+) 200, measured (MH+) 200.
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH3:11])=[N+:4]([O-])[CH:5]=[CH:6][C:7]=1[O:8][CH3:9].[C:12]([O:15]C(=O)C)(=[O:14])[CH3:13]>>[C:12]([O:15][CH2:11][C:3]1[C:2]([Cl:1])=[C:7]([O:8][CH3:9])[CH:6]=[CH:5][N:4]=1)(=[O:14])[CH3:13]
Reactant: COc1cc[n+]([O-])c(C)c1Cl
Reactant: CC(=O)OC(C)=O
Product: COc1ccnc(COC(C)=O)c1Cl
Temperature: 25 °C

Procedure:
The above 3-chloro-4-methoxy-2-methylpyridin-1-oxide (890 mg) was dissolved in acetic anhydride (12 mL), and the resulting solution was then heated under reflux for 30 minutes. After leaving to cool to room temperature, the reaction solution was concentrated under reduced pressure, and the residue was then purified by silica gel chromatography (hexane-ethyl acetate), so as to obtain the title compound (576 mg) as an oily substance.
Reaction SMILES: Br[C:2]1[CH:14]=[CH:13][C:5]2[NH:6][C:7](=[O:12])[O:8][C:9]([CH3:11])([CH3:10])[C:4]=2[CH:3]=1.[Cl:15][C:16]1[CH:21]=[CH:20][C:19](B(O)O)=[CH:18][CH:17]=1>>[Cl:15][C:16]1[CH:21]=[CH:20][C:19]([C:2]2[CH:14]=[CH:13][C:5]3[NH:6][C:7](=[O:12])[O:8][C:9]([CH3:11])([CH3:10])[C:4]=3[CH:3]=2)=[CH:18][CH:17]=1
Reactant: CC1(C)OC(=O)Nc2ccc(Br)cc21
Reactant: OB(O)c1ccc(Cl)cc1
Product: CC1(C)OC(=O)Nc2ccc(-c3ccc(Cl)cc3)cc21

Procedure:
Prepared according to Procedure A from 6-bromo-4,4-dimethyl-1,4-dihydro-benzo[d][1,3]oxazin-2-one and 4-chlorophenyl boronic acid. White solid: mp 255-257° C.; 1H-NMR (DMSO-d6) δ10.3 (s, 1H), 7.7 (d, 2H, J=8.52 Hz), 7.55 (m, 2H), 7.5 (d, 2H, J=8.52 Hz), 6.96 (d, 1H, J=8.52 Hz), 1.7 (s, 6H); MS (ESI) m/z 288 ([M+H]+, 70%); Anal. Calc. For C16H14ClNO2: C, 66.79; H, 4.90; N, 4.87. Found: C, 66.34; H, 4.76; N, 4.75
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([N+:11]([O-:13])=[O:12])[C:9]=1[OH:10])[CH:5]=O.[CH3:14][N:15]([CH3:21])[C:16](=[O:20])[CH2:17][C:18]#[N:19].C(O)(=O)C.N1CCCCC1>C(O)C>[CH3:14][N:15]([CH3:21])[C:16](=[O:20])[C:17]([C:18]#[N:19])=[CH:5][C:4]1[CH:7]=[C:8]([N+:11]([O-:13])=[O:12])[C:9]([OH:10])=[C:2]([OH:1])[CH:3]=1
Reactant: CN(C)C(=O)CC#N
Reactant: O=Cc1cc(O)c(O)c([N+](=O)[O-])c1
Solvent: CC(=O)O
Solvent: C1CCNCC1
Solvent: CCO
Product: CN(C)C(=O)C(C#N)=Cc1cc(O)c(O)c([N+](=O)[O-])c1

Procedure:
A solution containing 1.83 g of 3,4-dihydroxy-5-nitrobenz-aldehyde, 1.2 g of N,N-dimethylcyanoacetamide and catalytic amount of piperidine acetate in 40 ml of dry ethanol was refluxed over night. Yield 1.1 g (40%), m.p. 183°-185° C.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([NH:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:5]=[CH:6][CH:7]=1.[CH:16]([P:19](Cl)(Cl)=[O:20])([CH3:18])[CH3:17]>>[CH:16]([P:19]1(=[O:20])[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[CH2:9][N:8]1[C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([CH3:1])[CH:3]=1)([CH3:18])[CH3:17]
Reactant: CC(C)P(=O)(Cl)Cl
Reactant: Cc1cccc(NCc2ccccc2)c1
Product: Cc1cccc(N2Cc3ccccc3P2(=O)C(C)C)c1
Yield: 20 %

Procedure:
The procedure of Example 1 was employed utilizing N-(3-methylphenyl)-N-benzylamine and isopropyl phosphonic dichloride. The crude product produced as a result of the chromatographic separation was distilled at 150° C. and 0.8 mm to yield a pale yellow glass. The yellow glass was crystallized from methylcyclohexane to yield 1-isopropyl-2-(3-methylphenyl)-2,3-dihydro-1H-2,1-benzazaphosphole-1-oxide (3.5 g, 20% yield) as a white crystalline solid having a melting point of 112°-113° C. and the following analysis:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[CH:12]=[CH:11][N:10]([CH2:13][CH2:14][CH2:15][Cl:16])[C:9](=[O:17])[CH2:8][C:7]=2[C:18]=1[O:19][CH3:20].[CH3:21][NH:22][CH2:23][CH2:24][C:25]1[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[C:27]([O:33][CH3:34])[CH:26]=1>>[ClH:16].[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[CH:12]=[CH:11][N:10]([CH2:13][CH2:14][CH2:15][N:22]([CH3:21])[CH2:23][CH2:24][C:25]3[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[C:27]([O:33][CH3:34])[CH:26]=3)[C:9](=[O:17])[CH2:8][C:7]=2[C:18]=1[O:19][CH3:20]
Reactant: COc1ccc2c(c1OC)CC(=O)N(CCCCl)C=C2
Reactant: CNCCc1ccc(OC)c(OC)c1
Product: COc1ccc(CCN(C)CCCN2C=Cc3ccc(OC)c(OC)c3CC2=O)cc1OC
Product: Cl

Procedure:
This compound was prepared analogous to Example 1(b) by reacting 1-(8,9-dimethoxy-1,3-dihydro-2H-3-benzazepin-2on-3yl)-3-chloro-propane with N-methyl-N-[2-(3,4-dimethoxy-phenyl)-ethyl]-amine.
Reaction SMILES: [H-].[Na+].[CH2:3](P(=O)(O)O)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[CH3:14][O:15][C:16]1[CH:17]=[C:18]2[C:23](=[CH:24][C:25]=1[O:26][CH3:27])[N:22]=[CH:21][CH:20]=[C:19]2[O:28][C:29]1[CH:36]=[CH:35][C:34]([O:37][CH3:38])=[CH:33][C:30]=1[CH:31]=O.O>O1CCCC1>[CH3:14][O:15][C:16]1[CH:17]=[C:18]2[C:23](=[CH:24][C:25]=1[O:26][CH3:27])[N:22]=[CH:21][CH:20]=[C:19]2[O:28][C:29]1[CH:36]=[CH:35][C:34]([O:37][CH3:38])=[CH:33][C:30]=1/[CH:31]=[CH:3]/[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: O=P(O)(O)Cc1ccccc1
Reactant: COc1ccc(Oc2ccnc3cc(OC)c(OC)cc23)c(C=O)c1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: COc1ccc(Oc2ccnc3cc(OC)c(OC)cc23)c(/C=C/c2ccccc2)c1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 82.1 %

Procedure:
Sodium hydride (60 wt % oil, 52 mg) was dissolved in anhydrous tetrahydrofuran (1 ml), and a solution (0.5 ml) of benzylphosphonic acid (114 mg) in tetrahydrofuran was added dropwise to the solution at 0° C. under an argon atmosphere. The mixture was stirred at 0° C. for 30 min, and a solution (0.5 ml) of 2-[(6,7-dimethoxy-4-quinolyl)oxy]-5-methoxybenzaldehyde (100 mg) in tetrahydrofuran was then added dropwise thereto. The reaction mixture was stirred at room temperature for one hr, and water (1 ml) was then added dropwise thereto to stop the reaction. The mixture was extracted with ethyl acetate, and 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 chromatography on silica gel using ethyl acetate-hexane for development to give the title compound (100 mg, yield 80%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:18])[C:4]([C:8](=[O:17])[C:9]1[CH:14]=[CH:13][C:12]([CH3:15])=[C:11]([CH3:16])[CH:10]=1)=[CH:5]OC.[NH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([CH3:26])[N:21]=1>>[CH3:1][O:2][C:3](=[O:18])[C:4]([C:8](=[O:17])[C:9]1[CH:14]=[CH:13][C:12]([CH3:15])=[C:11]([CH3:16])[CH:10]=1)=[CH:5][NH:19][C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([CH3:26])[N:21]=1
Reactant: Cc1cccc(N)n1
Reactant: COC=C(C(=O)OC)C(=O)c1ccc(C)c(C)c1
Product: COC(=O)C(=CNc1cccc(C)n1)C(=O)c1ccc(C)c(C)c1
Yield: 171.8 %

Procedure:
Experimental conditions analogous to those described for Step 1 of Example 1 were used with 0.50 g (2.01 mmol) of the crude 2-(3,4-Dimethyl-benzoyl)-3-methoxy-acrylic acid methyl ester and 0.22 g (2.01 mmol) of 2-amino-6-picoline to yield 1.12 g of 2-(3,4-Dimethyl-benzoyl)-3-(6-methyl-pyridin-2-ylamino)-acrylic acid methyl ester as brown crystalline solid.
Reaction SMILES: ClC1C=C(C(F)(F)F)C=C(Cl)C=1C1N(C)N=C(SC)C=1.[Cl:21][C:22]1[CH:27]=[C:26]([C:28]([F:31])([F:30])[F:29])[CH:25]=[C:24]([Cl:32])[C:23]=1[C:33]1[N:37]([CH3:38])[N:36]=[C:35]([S:39]([CH3:41])=[O:40])[CH:34]=1.ClC1C=CC=C(C(OO)=[O:50])C=1.S([O-])([O-])=O.[Na+].[Na+]>C(Cl)(Cl)Cl>[Cl:32][C:24]1[CH:25]=[C:26]([C:28]([F:31])([F:29])[F:30])[CH:27]=[C:22]([Cl:21])[C:23]=1[C:33]1[N:37]([CH3:38])[N:36]=[C:35]([S:39]([CH3:41])(=[O:50])=[O:40])[CH:34]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: Cn1nc(S(C)=O)cc1-c1c(Cl)cc(C(F)(F)F)cc1Cl
Agent: CSc1cc(-c2c(Cl)cc(C(F)(F)F)cc2Cl)n(C)n1
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: Cn1nc(S(C)(=O)=O)cc1-c1c(Cl)cc(C(F)(F)F)cc1Cl
Reaction time: 8 h

Procedure:
To a solution of 0.2 g of 5-(2,6-dichloro-4-trifluoromethylphenyl)-1-methyl-3-methylsulfenylpyrazole (compound 40) in 20 ml of anhydrous chloroform was slowly added 0.3 g of 70% m-chloroperbenzoic acid at room temperature, followed by stirring overnight. The reaction mixture was poured into 10% aqueous sodium sulfite solution, and the organic layer was separated off, washed with 5% aqueous sodium hydroxide solution and brine and dried over anhydrous magnesium sulfate. The solvent was thereafter distilled of under reduced pressure to give 0.3 g of the desired compound in the form of white crystals (quantitative crude yield).
Reaction SMILES: C(OC([N:8]1[C:12]2=[C:13]([Cl:24])[N:14]=[CH:15][C:16]([C:17](=[O:23])[NH:18][CH2:19][CH:20]3[CH2:22][CH2:21]3)=[C:11]2[C:10]([CH3:25])=[CH:9]1)=O)(C)(C)C.[CH3:26][OH:27]>>[ClH:24].[CH:20]1([CH2:19][NH:18][C:17]([C:16]2[C:11]3[C:10]([CH3:25])=[CH:9][NH:8][C:12]=3[C:13]([N:8]3[CH2:9][CH2:10][O:27][CH2:26][CH2:12]3)=[N:14][CH:15]=2)=[O:23])[CH2:21][CH2:22]1
Reactant: Cc1cn(C(=O)OC(C)(C)C)c2c(Cl)ncc(C(=O)NCC3CC3)c12
Reactant: CO
Product: Cc1c[nH]c2c(N3CCOCC3)ncc(C(=O)NCC3CC3)c12
Product: Cl

Procedure:
Prepared in a similar manner to Example 11 (c) from 7-chloro-4-(cyclopropylmethyl-carbamoyl)-3-methyl-pyrrolo[2,3-c]pyridine-1-carboxylic acid tert-butyl ester. The solid mass was dissolved in the minimum of methanol and absorbed onto silica gel. The residue was purified by Biotage chromatography as described in Example 6 afford the title compound (14 mg).
Reaction SMILES: [C:1]([C:3]([C:16](=[O:32])[N:17]([CH2:28]C1CC1)[C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([C:24]([F:27])([F:26])[F:25])[CH:19]=1)=[CH:4][NH:5][C:6](=[NH:15])[N:7]1[CH2:11][C:10](C)([CH3:12])[NH:9][C:8]1=[O:14])#[N:2].[C:33](O)(=O)[C:34](O)=O.[C:39](O)(=O)C>>[CH3:28][N:17]([C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([C:24]([F:25])([F:26])[F:27])[CH:19]=1)[C:16]([C:3]1[C:1]([NH2:2])=[N:15][C:6]([N:7]2[CH2:11][C:10]([CH2:12][CH3:39])([CH2:33][CH3:34])[NH:9][C:8]2=[O:14])=[N:5][CH:4]=1)=[O:32]
Reactant: CC(=O)O
Reactant: O=C(O)C(=O)O
Reactant: CC1(C)CN(C(=N)NC=C(C#N)C(=O)N(CC2CC2)c2cccc(C(F)(F)F)c2)C(=O)N1
Product: CCC1(CC)CN(c2ncc(C(=O)N(C)c3cccc(C(F)(F)F)c3)c(N)n2)C(=O)N1
Reaction time: 2.5 h
Yield: 64.6 %

Procedure:
A mixture of 2.80 g (6.41 mmol) of a compound II (R1, R2 =C2H5 ; R3, R5, R6 =H; R4 =CH3), 210 mg of anhydrous oxalic acid and 4.75 ml of glacial acetic acid was stirred at 70° for 2.5 hours, a solution being produced after 20 min. It was then evaporated in vacuo. The residue was taken up in 70 ml of CH2Cl2 and extracted three times in succession with 20 ml of N NaOH each time and then twice with 20 ml of water each time. The CH2Cl2 solution was dried with MgSO4, filtered and evaporated in vacuo. The residue was taken up in about 15 ml of ether, whereupon crystallization occurred. The crystalline product was filtered off with suction and washed with ether and dried in vacuo at 100° for 17 hours. 1.81 g (=64.6% yield) of pure 4-amino-2-(4,4-diethyl-2-oxo-1-imidazolidinyl)pyrimidine-5-carboxylic acid N-methyl-N-(3-trifluoromethylphenyl)amide were obtained, melting point 185°-187°. C20H23F3N6O2 (436.45) Calculated: C 55.04 H 5.31 N 19.26% Found: C 54.8 H 5.2 N 19.2
Reaction SMILES: [CH2:1]1[C@@H:6](O)[C@@H:5]([OH:8])[C@H:4]([OH:9])[CH2:3][C@@:2]1([C:11]([OH:13])=[O:12])[OH:10].CN(C=O)C.C1C=CC=CC=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>CCOC(C)=O>[OH:10][C:2]12[CH2:1][CH:6]([O:13][C:11]1=[O:12])[CH:5]([OH:8])[CH:4]([OH:9])[CH2:3]2
Reactant: O=C(O)[C@]1(O)C[C@@H](O)[C@@H](O)[C@H](O)C1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CN(C)C=O
Solvent: c1ccccc1
Solvent: CCOC(C)=O
Product: O=C1OC2CC1(O)CC(O)C2O
Temperature: 25 °C
Yield: 77.3 %

Procedure:
In a 200 ml round-bottom flask fitted with a stirring bar, reflux condenser, Dean-Stark trap, and argon inlet, 5 g of quinic acid (1, 26 mmol) was placed and 10 mL of dry DMF was added via syringe and the slurry stirred at room temperature. Next, benzene 60 mL and p-toluenesulfonic acid 0.5 g were added, and the slurry was heated to reflux for 26 h. TLC was used confirm the completion of reaction. A 1:1 mixture of EtOAc and 16eptanes (100 mL) was added to the cooled reaction mixture. The mixture was stirred for 1 h at room temperature and filtered. The collected solid was again stirred with a 1:1 mixture of EtOAc and 17eptanes (100 mL) for 1 hr at room temperature and filtered. Tituration was repeated one more time with a 1:1 mixture of EtOAc and 17eptanes (100 mL) and the precipitate collected to give 3.5 g of Lactone 2 (78% yield). Mp: 192-193° C., Rf 0.25 (EtOAc); MS: [M-H]−: 171; 1H NMR (300 MHz, DMSO) δ 1.72 (t, J=1.6 Hz, 1H), 1.82-1.88 (m, 1H), 2.07-2.13 (m, 1H), 2.25 (d, J=1.1 Hz, 1H), 3.49 (ddd, J=11.4, 6.3, 5.7 Hz, 1H), 3.82 (t, J=4.5 Hz, 1H), 4.61 (t, J=5.1 Hz, 1H), 4.816 (d, J=6.0 Hz, 1H), 5.23 (d, J=4.5 Hz, 1H), 5.89 (s, 1H).
Reaction SMILES: [Cl:1][C:2]1[C:10]([C:11]([F:14])([F:13])[F:12])=[CH:9][C:5]([C:6](=S)[NH2:7])=[CH:4][C:3]=1[C:15]([F:18])([F:17])[F:16].O.[NH2:20][NH2:21].[CH:22](O)=O.C([O-])(O)=O.[Na+]>CN(C=O)C>[Cl:1][C:2]1[C:10]([C:11]([F:14])([F:13])[F:12])=[CH:9][C:5]([C:6]2[N:7]=[CH:22][NH:21][N:20]=2)=[CH:4][C:3]=1[C:15]([F:18])([F:17])[F:16]
Reactant: O=CO
Reactant: NC(=S)c1cc(C(F)(F)F)c(Cl)c(C(F)(F)F)c1
Reactant: NN
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: FC(F)(F)c1cc(-c2nc[nH]n2)cc(C(F)(F)F)c1Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 36 %

Procedure:
A solution of 4-chloro-3,5-bis(trifluoromethyl)benzothioamide (1 g) in DMF (10 mL) was treated with hydrazine hydrate (0.32 g, 2.0 eq.) and the reaction mixture was stirred at room temperature for 1 h before adding formic acid (3 mL). The reaction mixture was refluxed at 90° C. for 3 h then cooled to room temperature, poured into aqueous saturated NaHCO3 (slowly, maintaining temperature 25-30° C.) and extracted with EtOAc (3×100 mL). The combined organic extracts were washed with brine (3×50 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure (25° C., 20 mmHg) to afford 1.5 g of crude compound. Purification by column chromatography (eluting with 40% EtOAc in hexane) afforded 0.50 g of desired compound (yield: 36%).