Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([OH:6])[CH2:2][C:3]#[C:4][CH3:5].C(N(CC)CC)C.Cl[SiH:15]([CH:19]([CH3:21])[CH3:20])[CH:16]([CH3:18])[CH3:17]>CN(C)C1C=CN=CC=1.CCCCCC>[CH:16]([SiH:15]([CH:19]([CH3:21])[CH3:20])[O:6][CH2:1][CH2:2][C:3]#[C:4][CH3:5])([CH3:18])[CH3:17]
Reactant: CC#CCCO
Reactant: CC(C)[SiH](Cl)C(C)C
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: CCCCCC
Product: CC#CCCO[SiH](C(C)C)C(C)C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a cold (0° C.) solution of 3-pentynol (5.880g, 70.0 mmol, 1.0 equiv), 4-dimethylaminopyridine (DMAP) (840 mg, 7.00 mmol, 0.10 equiv), and triethylamine (TEA) (9.80 ml, 71.0 mmol, 1.01 equiv) in 100 mL of dry hexane was added dropwise chlorodiisopropylsilane (11.0 g, 71.0 mmol, 1.01 equiv) over 20 minutes. The resulting white suspension was allowed to warm to room temperature and was stirred overnight. The reaction mixture was filtered through a short silica pad (10 g) and the solvent was then evaporated in vacuo to give a colorless liquid. Fractional distillation of this liquid afforded 11.2 g (81%) of A-7 as a colorless liquid. An analytical sample (0.48 g) was obtained by redistillation of a 0.50 g sample by Kugelrohr distillation.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:7](=[O:8])[O:6][CH2:5]2.C(N(CC)CC)C.[C:19](OC(=O)C)(=[O:21])[CH3:20].C(=O)([O-])O.[Na+]>O1CCCC1>[C:19]([NH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:7](=[O:8])[O:6][CH2:5]2)(=[O:21])[CH3:20]
Reactant: CC(=O)OC(C)=O
Reactant: Nc1ccc2c(c1)COC2=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(=O)Nc1ccc2c(c1)COC2=O
Temperature: 25 °C
Reaction time: 3 h
Yield: 97.1 %

Procedure:
In tetrahydrofuran (100 ml) was dissolved 5-aminophthalide (10 g, 67.05 mmol), and triethylamine (18.64 ml, 134 mmol) was added thereto. To the resulting mixture was added dropwise acetic anhydride (12.61 ml, 134 mmol) under ice-cooling, followed by stirring at room temperature for 3 hours. After addition of a 5% aqueous solution of sodium hydrogen carbonate, the precipitated white solid was separated by filtration, washed several times with water, and then dried to give 5-acetamidophthalide (12.45 g, 97%).
Reaction SMILES: [CH2:1]([N:8]1[C:12]([C:13]2[CH:14]=[CH:15][C:16]3[O:21][CH2:20][CH2:19][CH2:18][C:17]=3[CH:22]=2)=[CH:11][C:10]([C:23]([F:26])([F:25])[F:24])=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Br:27]N1C(=O)CCC1=O.O>C(#N)C>[CH2:1]([N:8]1[C:12]([C:13]2[CH:14]=[CH:15][C:16]3[O:21][CH2:20][CH2:19][CH2:18][C:17]=3[CH:22]=2)=[C:11]([Br:27])[C:10]([C:23]([F:26])([F:24])[F:25])=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: FC(F)(F)c1cc(-c2ccc3c(c2)CCCO3)n(Cc2ccccc2)n1
Solvent: CC#N
Solvent: O
Product: FC(F)(F)c1nn(Cc2ccccc2)c(-c2ccc3c(c2)CCCO3)c1Br
Yield: 63 %

Procedure:
A solution 1-benzyl-5-(3,4-dihydro-2H-1-benzopyran-6-yl)-3-(trifluoromethyl)-1H-pyrazole (49c) (260 mg, 0.73 mmol) and N-bromosuccinimide (157 mg, 0.88 mmol) in acetonitrile (5 mL) was refluxed for 45 minutes. Water (5 mL) was added, and the aqueous layer was extracted with dichloromethane (2×5 mL). The combined organics layers were dried over sodium sulfate and concentrated in vacuo. The residue was purified by preparative TLC (cyclohexane/ethyl acetate 100/0 to 90/10) to provide the 1-benzyl-4-bromo-5-(3,4-dihydro-2H-1-benzopyran-6-yl)-3-(trifluoromethyl)-1H-pyrazole (49d) (200 mg, 0.46 mmol, 63%).
Reaction SMILES: [OH:1][C:2]1[C:11]2[N:10]=[CH:9][CH:8]=[CH:7][C:6]=2[C:5]([CH:12]=[O:13])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:20]([O:22][C:23](=[O:26])[CH2:24]Br)[CH3:21]>CN(C=O)C.ClCCl>[CH2:20]([O:22][C:23](=[O:26])[CH2:24][O:1][C:2]1[CH:3]=[CH:4][C:5]([CH:12]=[O:13])=[C:6]2[C:11]=1[N:10]=[CH:9][CH:8]=[CH:7]2)[CH3:21]
Reactant: CCOC(=O)CBr
Reactant: O=Cc1ccc(O)c2ncccc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CCOC(=O)COc1ccc(C=O)c2cccnc12
Reaction time: 1 h
Yield: 74.8 %

Procedure:
To a solution of 8-hydroxyquinoline-5-carbaldehyde (170 mg, 0.98 mmol) in DMF (5 ml) were added anhydrous potassium carbonate (150 mg) and 2-bromoacetic acid ethyl ester (0.12 ml, 180 mg, 1.08 mmol) at room temperature and the stirring was continued for 1 h. Then the reaction mixture was diluted with dichloromethane, the organic layer was washed several times with water, dried over sodium sulfate and then evaporated under vacuum. The residue was chromatographed on silica gel with ethyl acetate/cyclohexane (9:1) as eluant; to give 190 mg (74.8% yield) of pure 2-(5-formylquinol-8-yloxy)acetic acid ethyl ester.
Reaction SMILES: [CH:1]1([NH:4][C@@H:5]2[CH2:10][CH2:9][N:8]([C:11]3[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][N:12]=3)[CH2:7][C@@H:6]2[F:21])[CH2:3][CH2:2]1.[F:22][C:23]1[CH:24]=[C:25]([CH:29]=[CH:30][C:31]=1[N:32]1[CH:36]=[N:35][N:34]=[N:33]1)[C:26](O)=[O:27]>>[CH:1]1([N:4]([C@@H:5]2[CH2:10][CH2:9][N:8]([C:11]3[CH:16]=[CH:15][C:14]([C:17]([F:18])([F:20])[F:19])=[CH:13][N:12]=3)[CH2:7][C@@H:6]2[F:21])[C:26](=[O:27])[C:25]2[CH:29]=[CH:30][C:31]([N:32]3[CH:36]=[N:35][N:34]=[N:33]3)=[C:23]([F:22])[CH:24]=2)[CH2:2][CH2:3]1
Reactant: F[C@H]1CN(c2ccc(C(F)(F)F)cn2)CC[C@H]1NC1CC1
Reactant: O=C(O)c1ccc(-n2cnnn2)c(F)c1
Product: O=C(c1ccc(-n2cnnn2)c(F)c1)N(C1CC1)[C@@H]1CCN(c2ccc(C(F)(F)F)cn2)C[C@@H]1F

Procedure:
The title compound is prepared from (3S,4R)-cyclopropyl-(3-fluoro-5′-trifluoromethyl-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-yl)-amine and 3-fluoro-4-tetrazol-1-yl-benzoic acid following a procedure analogous to that described in Example 107. LC (method 19): tR=4.39 min; Mass spectrum (ESI+): m/z=494 [M+H]+.
Reaction SMILES: [CH3:1][C:2]([CH3:18])=[CH:3][CH2:4][C:5]1[C:15](=[O:16])[C:14]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[C:7](=[O:8])[C:6]=1[OH:17]>S(=O)(=O)(O)O>[CH3:1][C:2]1([CH3:18])[O:16][C:15]2[C:14]3[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=3[C:7]([C:6](=[O:17])[C:5]=2[CH2:4][CH2:3]1)=[O:8]
Reactant: CC(C)=CCC1=C(O)C(=O)c2ccccc2C1=O
Agent: O=S(=O)(O)O
Product: CC1(C)CCC2=C(O1)c1ccccc1C(=O)C2=O
Temperature: 80 °C

Procedure:
Into a 1,000 ml beaker containing sulfuric acid (300 ml), lapachol (30 g, 0.124 mol) was added in portions slowly over 5 minutes at room temperature while stirring vigorously. After addition, the dark mixture was stirred for an additional 30 min and then poured into ice water (800 g) with manual stirring in a 2,000 ml beaker. The mixture was transferred into a 2,000 ml separatory funnel and extracted twice with toluene (600 ml and 400 ml). The toluene phases were pooled and washed successively with 1% aqueous sodium chloride (800 ml), 1% aqueous sodium bicarbonate (400 ml) and 1% aqueous sodium chloride (800 ml), and then dried with sodium sulfate (50 g). After filtration, the filtrate was evaporated to dryness by Rotovap and then ethanol (300 ml) was added for co-evaporation to completely remove residual toluene. The residue was dissolved in 75% ethanol or absolute ethanol, preferably absolute ethanol (ethanol/water, 3:1, 300 ml) with heating in an 80° C. water bath, then was filtered and cooled to 4° C. slowly. Pure β-lapachone was isolated by filtration, then washed with cold 75% ethanol (4° C., 100 ml), dried under vacuum, packed under Argon atmosphere and stored at −20° C. in the dark.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:21]2[CH2:26][CH2:25][S:24](=[O:27])[CH2:23][CH2:22]2)[C:5]2[N:11]=[CH:10][N:9]=[C:8]([N:12]([CH3:20])[CH2:13][C:14]3[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=3)[C:6]=2[N:7]=1.[OH:28][CH2:29][CH2:30][NH2:31]>>[OH:28][CH2:29][CH2:30][NH:31][C:2]1[N:3]=[C:4]([N:21]2[CH2:22][CH2:23][S:24](=[O:27])[CH2:25][CH2:26]2)[C:5]2[N:11]=[CH:10][N:9]=[C:8]([N:12]([CH3:20])[CH2:13][C:14]3[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=3)[C:6]=2[N:7]=1
Reactant: NCCO
Reactant: CN(Cc1cccnc1)c1ncnc2c(N3CCS(=O)CC3)nc(Cl)nc12
Product: CN(Cc1cccnc1)c1ncnc2c(N3CCS(=O)CC3)nc(NCCO)nc12

Procedure:
This compound was prepared analogous to Example 2 from 2-chloro-8-[N-methyl-N-(3-picolyl)-amino]-4-(1-oxidothiomorpholino)-pyrimido[5,4-d]pyrimidine (melting point: 154°-156° C.) and 2-hydroxyethyl-amine.
Reaction SMILES: Cl[C:2]([C:4](=[C:10]([CH3:12])[CH3:11])[C:5]([O:7][CH2:8][CH3:9])=[O:6])=[O:3].[Br:13][C:14]1[CH:20]=[CH:19][C:17]([NH2:18])=[C:16]([CH3:21])[CH:15]=1.C(N(CC)CC)C>>[Br:13][C:14]1[CH:20]=[CH:19][C:17]([NH:18][C:2]([C:4](=[C:10]([CH3:12])[CH3:11])[C:5]([O:7][CH2:8][CH3:9])=[O:6])=[O:3])=[C:16]([CH3:21])[CH:15]=1
Reactant: CCOC(=O)C(C(=O)Cl)=C(C)C
Reactant: Cc1cc(Br)ccc1N
Solvent: CCN(CC)CC
Product: CCOC(=O)C(C(=O)Nc1ccc(Br)cc1C)=C(C)C
Yield: 30 %

Procedure:
In a manner similar to the procedure described in Example I, ethyl 2-chlorocarbonyl-3-methyl-2-butenoate (9.6 grams, 0.05 mole) prepared in Example XXV, 4-bromo-2-methylaniline (5.3 grams, 0.03 mole) and triethylamine (4.0 milliliters, 0.03 mole) were reacted to give 2.9 grams (0.009 mole) of ethyl 2-[(4-bromo-2-methylphenyl)aminocarbonyl]-3-methyl-2-butenoate as a white solid having a melting point of 116° C.-119° C. NMR analysis of the product indicated the following:
Reaction SMILES: [CH3:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[NH:4][N:3]=1.CCN(CC)CC.[O:18](C(OC(C)(C)C)=O)[C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=O>CC#N.CN(C1C=CN=CC=1)C>[C:22]([O:21][C:19]([N:4]1[C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[C:2]([CH3:1])=[N:3]1)=[O:18])([CH3:25])([CH3:24])[CH3:23]
Reactant: Cc1n[nH]c2ccccc12
Reactant: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Agent: CN(C)c1ccncc1
Solvent: CC#N
Solvent: CCN(CC)CC
Product: Cc1nn(C(=O)OC(C)(C)C)c2ccccc12
Temperature: 0 °C
Yield: 100 %

Procedure:
To a stirring solution of 30.3 g (0.23 mol) of 3-methylindazole, prepared as in Part A, in 300 mL of CH3CN is added 35.0 mL (0.25 mol, 1.1 equiv) of Et3N and 5.77 g (47.2 mmol, 0.2 equiv) of DMAP, and the mixture is cooled to 0° C. 60.5 g (0.28 mol, 1.2 equiv) of (BOC)2O in 200 mL CH3CN is added dropwise with stirring at 0° C. and the resultant reaction mixture stirred 3 h at RT. The solvent is removed in vacuo and the crude material partitioned between Et2O (300 mL) and H2O (100 mL). The pH is adjusted to 2.0 with 1N HCl, the organic phase separated, dried (MgSO4), filtered and concentrated in vacuo to an orange oil which is purified by filtration through a pad of silica gel using Hexane/EtOAc 4/1 as eluent. The filtrate is concentrated in vacuo to give 53.4 g of 1-tert-butoxycarbonyl-3-methylindazole as a white solid: 1H NMR (CDCl3, 300 MHz) δ8.15 (d, 1H, J=7.8), 7.67 (d, 1H, J=7.8), 7.56 (dd, 1H, J=7.3, 7.3), 7.35 (dd, 1H, J=7.3, 7.3), 2.62 (s, 3H), 1.77 (s, 9H); TLC Rf =0.66 (EtOAc/Hexane 1/2).
Reaction SMILES: [O:1]=[C:2]1[C:7](C(OCC)=O)=[CH:6][NH:5][N:4]2[CH:13]=[CH:14][CH:15]=[C:3]12.[Cl-].[Na+].O>CS(C)=O>[NH:5]1[CH:6]=[CH:7][C:2](=[O:1])[C:3]2=[CH:15][CH:14]=[CH:13][N:4]12
Reactant: CCOC(=O)c1c[nH]n2cccc2c1=O
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: O=c1cc[nH]n2cccc12

Procedure:
Ethyl 4-oxo-1,4-dihydropyrrolo[1,2-b]pyridazine-3-carboxylate (412 mg, 2.00 mmol), sodium chloride (200 mg), water (1 mL), and DMSO (1 mL) were heated at 150° C. for 3 hours. The solvent was concentrated in vacuo and the residue was purified using 0-50% EtOAc/Hexanes to provide pyrrolo[1,2-b]pyridazin-4(1H)-one. MS: Found M+H+=135.
Reaction SMILES: C([O:5][C:6](=[O:37])[CH2:7][C@@H:8]([CH2:35]O)[NH:9][C:10]([C@@H:12]1[CH2:17][CH2:16][CH2:15][N:14]([C:18](=[O:34])[CH2:19][CH2:20][CH:21]2[CH2:26][CH2:25][N:24](C(OC(C)(C)C)=O)[CH2:23][CH2:22]2)[CH2:13]1)=[O:11])(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[NH:24]1[CH2:23][CH2:22][CH:21]([CH2:20][CH2:19][C:18]([N:14]2[CH2:15][CH2:16][CH2:17][C@@H:12]([C:10]([NH:9][C@@H:8]3[CH2:35][O:37][C:6](=[O:5])[CH2:7]3)=[O:11])[CH2:13]2)=[O:34])[CH2:26][CH2:25]1
Reactant: CC(C)(C)OC(=O)C[C@@H](CO)NC(=O)[C@@H]1CCCN(C(=O)CCC2CCN(C(=O)OC(C)(C)C)CC2)C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C1C[C@H](NC(=O)[C@@H]2CCCN(C(=O)CCC3CCNCC3)C2)CO1
Reaction time: 1 h
Yield: 127.1 %

Procedure:
To a solution of N-[(R)-1-{3-(1-tert-butoxycarbonyl-4-piperidyl)propionyl}-3-piperidylcarbonyl]-3(S)-hydroxymethyl-β-alanine tert-butyl ester (0.2 g) in dichloromethane (3 ml) was added trifluoroacetic acid (3 ml) at ambient temperature. After stirring for 1 hour, the mixture was evaporated in vacuo. The residue was dissolved in water and freeze-dried to give (S)-4-[(R)-1-{3-(4-piperidyl)propionyl}-3-piperidylcarbonylamino]-1,2,3,4-tetrahydro-2-furanone (0.17 g) as a pale yellow oil.
Reaction SMILES: [CH3:1][N:2](C)[CH:3]=[CH:4][C:5]([C:7]1[CH:8]=[C:9]([CH:14]=[CH:15][CH:16]=1)[C:10]([O:12][CH3:13])=[O:11])=O.CC(O)=O.C(N)=[NH:23].C[O-].[Na+]>CO>[N:2]1[CH:3]=[CH:4][C:5]([C:7]2[CH:8]=[C:9]([CH:14]=[CH:15][CH:16]=2)[C:10]([O:12][CH3:13])=[O:11])=[N:23][CH:1]=1
Reactant: COC(=O)c1cccc(C(=O)C=CN(C)C)c1
Reactant: N=CN
Agent: C[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: COC(=O)c1cccc(-c2ccncn2)c1
Yield: 62.2 %

Procedure:
The mixture of methyl 3-(3-dimethylaminopropenoyl)benzoate (1.4 g), formamidine-acetate (2.8 g) and 28% methanolic sodium methoxide (5.2 ml) in methanol (38 ml) was heated under reflux for 64 hours under stirring. The solvent was removed by concentration and to the residue was added water. The mixture was adjusted to pH 9 with 20% aqueous potassium carbonate solution and the mixture was extracted with ethyl acetate. The extract layer was washed with brine, dried over magnesium sulfate and evaporated in vacuo. The residue was triturated with the solution of diisopropyl ether and n-hexane and the precipitate was collected by filtration to give methyl 3-(pyrimidin-4-yl)benzoate (0.8 g).
Reaction SMILES: [CH3:1][CH2:2][CH:3]([C:7]1[C:12]2[N:13]([CH3:17])[C:14](=O)[NH:15][C:11]=2[CH:10]=[CH:9][N:8]=1)[CH2:4][CH2:5][CH3:6].[Cl:18]C1N(C)C2C(C(CCC)CCC)=CC=CC=2N=1>>[Cl:18][C:14]1[N:13]([CH3:17])[C:12]2[C:7]([CH:3]([CH2:4][CH2:5][CH3:6])[CH2:2][CH3:1])=[N:8][CH:9]=[CH:10][C:11]=2[N:15]=1
Reactant: CCCC(CCC)c1cccc2nc(Cl)n(C)c12
Reactant: CCCC(CC)c1nccc2[nH]c(=O)n(C)c12
Product: CCCC(CC)c1nccc2nc(Cl)n(C)c12

Procedure:
Prepared from 4-(hexan-3-yl)-3-methyl-1H-imidazo[4,5-c]pyridin-2(3H)-one according to the method described previously for 2-chloro-1-methyl-7-(1-propylbutyl)-1H-benzimidazole in 68% isolated yield.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[O:7][C:8]2[CH:15]=[CH:14][CH:13]=[C:12]([O:16][CH2:17][CH2:18][CH2:19]Br)[C:9]=2[C:10]=1[CH3:11])=[O:5])[CH3:2].[N:21]1[CH:26]=[CH:25][CH:24]=[C:23]([CH2:27][NH2:28])[CH:22]=1>C(O)C.C(OCC)(=O)C>[CH2:1]([O:3][C:4]([C:6]1[O:7][C:8]2[CH:15]=[CH:14][CH:13]=[C:12]([O:16][CH2:17][CH2:18][CH2:19][NH:28][CH2:27][C:23]3[CH:22]=[N:21][CH:26]=[CH:25][CH:24]=3)[C:9]=2[C:10]=1[CH3:11])=[O:5])[CH3:2]
Reactant: NCc1cccnc1
Reactant: CCOC(=O)c1oc2cccc(OCCCBr)c2c1C
Solvent: CCOC(C)=O
Solvent: CCO
Product: CCOC(=O)c1oc2cccc(OCCCNCc3cccnc3)c2c1C
Temperature: 50 °C

Procedure:
4-(3-bromo-propoxy)-3-methyl-benzofuran-2-carboxylic acid ethyl ester (Example 5-a: 180 mg) and 3-picolylamine (500 μl) were dissolved in ethanol (2 ml) and heated at 50° C. for 16 hours. The reaction mixture was dissolved in ethyl acetate and washed with saturated ammonium chloride solution and water. The organic solvent was dried over anhydrous sodium sulfate and evaporated to dryness. The residue was purified by silica gel column chromatography (dichloromethane-MeOH) to afford 3-methyl-4-{3-[(pyridin-3-ylmethyl)-amino]-propoxy}-benzofuran-2-carboxylic acid ethyl ester (150 mg) as a colorless oil. EI-MS: m/z 368 (M+); 1H-NMR (CDCl3): δ 1.44 (3H, t, J=7 Hz), 2.07 (2H, quintet, J=6.5 Hz), 2.67 (3H, s), 2.89 (2H, t, J=7 Hz), 3.84 (2H, s), 4.17 (2H, t, J=6 Hz), 4.44 (2H, q, J=7 Hz), 6.62 (1H, d, 8 Hz), 7.12 (1H, d, J=8 Hz), 7.21 (1H, dd, J1=8 Hz, J2=5 Hz), 7.30 (1H, t, J=8 Hz), 7.66 (1H, dd, J1=8 Hz, J2=2 Hz), 8.49 (1H, dd, J1=5 Hz, J2=2 Hz), 8.57 (1H, d, J=2 Hz).
Reaction SMILES: [CH:1]1([C:6]2[CH:7]=[C:8]([CH:12]=[CH:13][C:14]=2[O:15][CH3:16])[C:9]([OH:11])=O)[CH2:5][CH2:4][CH2:3][CH2:2]1.C(Cl)(=O)C(Cl)=O.[Sn](Cl)(Cl)(Cl)Cl.[CH2:28]([C:35]1[O:36][C:37]([CH3:41])=[C:38]([CH3:40])[CH:39]=1)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>CN(C)C=O.C(Cl)Cl>[CH2:28]([C:35]1[O:36][C:37]([CH3:41])=[C:38]([CH3:40])[C:39]=1[C:9]([C:8]1[CH:12]=[CH:13][C:14]([O:15][CH3:16])=[C:6]([CH:1]2[CH2:2][CH2:3][CH2:4][CH2:5]2)[CH:7]=1)=[O:11])[C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1
Reactant: Cc1cc(Cc2ccccc2)oc1C
Reactant: COc1ccc(C(=O)O)cc1C1CCCC1
Agent: Cl[Sn](Cl)(Cl)Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: COc1ccc(C(=O)c2c(Cc3ccccc3)oc(C)c2C)cc1C1CCCC1

Procedure:
The title compound was prepared according to the procedure in Example 5, step 2 using 3-cyclopentyl-p-anisic acid (10.0 g, 45.5 mmol, RN-59216-82-9), oxalyl chloride (4.4 mL, 50.6 mmol), N,N-dimethylformamide (2 drops), tin (IV) chloride (15.8 mL, 49.6 mmol) and 2-benzyl-4,5-dimethyl-furan (10.1 g, 54.3 mmol) in CH2Cl2 to give 18.8 g (crude) of the title compound. 1H NMR (DMSO-d6) consistent.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[S:10][CH:11]=[C:12]([C:14]([OH:16])=[O:15])[N:13]=2)=[CH:4][C:3]=1[O:17][CH3:18].[Cl:19][C:20]1[CH:28]=[C:27]([Cl:29])[CH:26]=[CH:25][C:21]=1[C:22](Cl)=[O:23].C(=O)([O-])[O-].[K+].[K+]>C1COCC1>[Cl:19][C:20]1[CH:28]=[C:27]([Cl:29])[CH:26]=[CH:25][C:21]=1[C:22]([N:8]([C:5]1[CH:6]=[CH:7][C:2]([Cl:1])=[C:3]([O:17][CH3:18])[CH:4]=1)[C:9]1[S:10][CH:11]=[C:12]([C:14]([OH:16])=[O:15])[N:13]=1)=[O:23]
Reactant: O=C(Cl)c1ccc(Cl)cc1Cl
Reactant: COc1cc(Nc2nc(C(=O)O)cs2)ccc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: COc1cc(N(C(=O)c2ccc(Cl)cc2Cl)c2nc(C(=O)O)cs2)ccc1Cl
Temperature: 50 °C
Reaction time: 18 h
Yield: 74.5 %

Procedure:
A mixture of 5.0 g (17 mmol) 2-(4-chloro-3-methoxy-phenylamino)-thiazole-4-carboxylic acid, 9.2 g (44 mmol) 2,4-dichloro-benzoyl chloride and 2.45 g (17.7 mmol) potassium carbonate in 250 mL THF was stirred at 50° C. for 18 h. After evaporation of the volatiles the residue was partitioned between water and ethyl acetate. Organic phases were pooled, dried with MgSO4 and the solvent was removed in vacuo. Crystallisation from n-heptane/ethyl acetate yielded 5.8 g (72%) of the title compound.
Reaction SMILES: [CH3:1][N:2]1[C:6](=O)[C@H:5]([O:8][CH3:9])[CH2:4][C@H:3]1[CH2:10][O:11][C:12]1[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=1.CO>C1COCC1>[CH3:9][O:8][CH:5]1[CH2:6][N:2]([CH3:1])[C@H:3]([CH2:10][O:11][C:12]2[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=2)[CH2:4]1
Reactant: CO[C@@H]1C[C@@H](COc2cccnc2)N(C)C1=O
Solvent: C1CCOC1
Solvent: CO
Product: COC1C[C@@H](COc2cccnc2)N(C)C1

Procedure:
To the compound from step 47a above, dissolved in 4 mL of THF, was added 3.39 mL of BH3 and the mixture was heated at reflux for 2 hours. Methanol was added to the reaction mixture and evaporated The residue was dissolved in anhydrous ethanol. Cesium fluoride was added, and the resultant solution was stirred under reflux for 16 hr. Evaporation of the solvent provided a white solid which was purified on a silica gel column. MS (DCI/NH3) m/e: 223 (M+H)+. 1H NMR (CDCl3, 300 MHz) δ: 8.34 (m, 1H), 8.23 (t, J=3 Hz, 1H), 7.22 (m, 1H), 3.93-4.10 (m, 3H), 3.44-3.54 (m, 1H), 3.32 (s, 3H), 3.03-2.87 (m, 1H), 2.51 (s, 3H), 2.44-2.33 (m, 1H), 2.11-1.92 (m, 2H).
Reaction SMILES: [CH3:1][C:2]([CH3:15])([CH3:14])[CH2:3][N:4]1[C:8]2[CH:9]=[CH:10][C:11]([NH2:13])=[CH:12][C:7]=2[N:6]=[N:5]1.[Br-:16].[Br-].[Br-].[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1>C(Cl)(Cl)Cl>[Br:16][C:12]1[C:7]2[N:6]=[N:5][N:4]([CH2:3][C:2]([CH3:15])([CH3:14])[CH3:1])[C:8]=2[CH:9]=[CH:10][C:11]=1[NH2:13]
Reactant: CC(C)(C)Cn1nnc2cc(N)ccc21
Reactant: [Br-]
Agent: c1cc[nH+]cc1
Solvent: ClC(Cl)Cl
Product: CC(C)(C)Cn1nnc2c(Br)c(N)ccc21
Temperature: 25 °C

Procedure:
1-(2,2-Dimethylpropyl)-1H-1,2,3-benzotriazol-5-amine (3.52 g, 17.23 mmol, 1.0 equiv.) was dissolved in chloroform (172 ml) and treated with pyridinium tribromide (5.51 g, 17.23 mmol, 1.0 equiv.). The mixture was stirred at room temperature until LCMS showed almost only product was observed. The mixture was filtered and the solid was washed with hexane, which was dissolved in diethyl ether/ethyl acetate and neutralized with saturated aqueous sodium bicarbonate. The organic extracts were dried with magnesium sulfate, filtered and concentrated in vacuo, providing the titled compound as a pale white solid. 1H NMR (500 MHz, CD3OD) 7.30 (d, 1H, J=8.8 Hz), 7.07 (sb, 3H), 7.02 (d, 1H, J=8.8 Hz), 4.34 (s, 2H), 1.03 (s, 9H) ppm. LRMS m/z (M+H) 283.0 and 285.0 (intensity ratio ˜1:1) found, 283.1 and 285.1 required.
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][C:6]([N+:9]([O-:11])=[O:10])=[CH:5][C:3]=1[NH2:4].[Cl:12][C:13]1[CH:14]=[C:15]([CH:19]=[CH:20][CH:21]=1)[C:16](Cl)=[O:17]>>[Cl:12][C:13]1[CH:14]=[C:15]([CH:19]=[CH:20][CH:21]=1)[C:16]([NH:4][C:3]1[CH:5]=[C:6]([N+:9]([O-:11])=[O:10])[CH:7]=[CH:8][C:2]=1[Cl:1])=[O:17]
Reactant: Nc1cc([N+](=O)[O-])ccc1Cl
Reactant: O=C(Cl)c1cccc(Cl)c1
Product: O=C(Nc1cc([N+](=O)[O-])ccc1Cl)c1cccc(Cl)c1

Procedure:
2-chloro-5-nitroaniline (Aldrich, 25.7 mmol) was used in general procedure 1 with 3-chlorobenzoyl chloride (26.5 mmol). The product was purified by silica gel chromatography (40% EtOAc/Hex) to give 3-chloro-N-(2-chloro-5-nitrophenyl)benzamide as a brown solid. MS (Q1) 294.0 (M)+
Reaction SMILES: Cl.Cl[CH2:3][N:4]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[N:5]1.[F:15][C:16]([F:25])([F:24])[CH2:17][CH2:18][CH:19]([C:22]#[N:23])[C:20]#[N:21].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[C:9]1([C:6]2[CH:7]=[CH:8][N:4]([CH2:3][C:19]([CH2:18][CH2:17][C:16]([F:15])([F:24])[F:25])([C:20]#[N:21])[C:22]#[N:23])[N:5]=2)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: N#CC(C#N)CCC(F)(F)F
Reactant: ClCn1ccc(-c2ccccc2)n1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: N#CC(C#N)(CCC(F)(F)F)Cn1ccc(-c2ccccc2)n1
Yield: 23.7 %

Procedure:
2.01 g of 1-(chloromethyl)-3-phenyl-1H-pyrazole hydrochloride and 1.42 g of (3,3,3-trifluoropropyl) malononitrile were dissolved in 27 ml of N,N-dimethylformamide. 2.43 g of potassium carbonate was added to the solution under ice cooling with stirring, followed by stirring at room temperature for overnight. Water was added to the reaction mixture, and then extracted with MTBE. The organic layer was washed with water, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to obtain 0.66 g of [(3-phenyl-1H-pyrazole-1-yl)methyl](3,3,3-trifluoropropyl)malononitrile (referred as the compound of the present invention (10), hereinafter) shown by below formula.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([N+:8]([O-])=O)[C:3]=1[CH2:11][CH2:12][N:13]([CH2:15][C:16]([OH:18])=O)[CH3:14].[H][H].C1(N=C=NC2CCCCC2)CCCCC1>CO.[Pt]>[Cl:1][C:2]1[C:3]2[CH2:11][CH2:12][N:13]([CH3:14])[CH2:15][C:16](=[O:18])[NH:8][C:4]=2[CH:5]=[CH:6][CH:7]=1
Reactant: [H][H]
Reactant: CN(CCc1c(Cl)cccc1[N+](=O)[O-])CC(=O)O
Agent: [Pt]
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: CO
Product: CN1CCc2c(Cl)cccc2NC(=O)C1
Temperature: 0 °C
Reaction time: 48 h

Procedure:
{[2-(2-chloro-6-nitro-phenyl)-ethyl]-methyl-amino}-acetic acid (12 g, approximately 0.049 molE, not quite pure) in methanol (250 mL) containing platinum on sulfided carbon (5 wt. %, 1.2 g) was hydrogenated at room temperature and a hydrogen pressure of 50 psi overnight. The catalyst was removed by filtration through Celite and the filtrate was evaporated to dryness in vacuo. The residue was dissolved in pyridine (1.5 L) and the solution was cooled to 0° C., and 1,3-dicyclohexylcarbodiimide (20.0 g, 0.097 mole) was added. The reaction mixture was allowed to warm up to room temperature and stirred at room temperature for 48 hours. The solvent was removed and the residue was slurried with 10% hydrochloric acid and filtered. The filtrate was extracted with ether, the aqueous phase was made basic with sodium carbonate and then extracted with dichloromethane. The extract was dried over sodium sulfate and evaporated in vacuo. Purification by flash column chromatography (silica gel, methylene chloride) provided 4.0 g of the title compound as a white solid. 1H NMR (CDCl3): 7.50 δ (broad, 1H); 7.30 δ (d, 1H); 7.20 δ (s, 1H); 7.00 δ (d, 1H); 3.18 δ (s, 2H); 2.80 δ (broad s, 4H); 2.40 δ (s, 3H). MS(ES) m/z 225 ([M+H]+).