Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[C:25](=[O:26])[N:24]([CH:27]2[CH2:31][CH2:30][CH2:29][CH2:28]2)[C:5]2[N:6]=[C:7]([NH:10][C:11]3[CH:16]=[CH:15][C:14]([N:17]4[CH2:22][CH2:21][N:20]([CH3:23])[CH2:19][CH2:18]4)=[CH:13][N:12]=3)[N:8]=[CH:9][C:4]=2[C:3]=1[CH3:32].C1(C)C=CC=CC=1.C([Sn](CCCC)(CCCC)[C:45]([O:47][CH2:48][CH3:49])=[CH2:46])CCC>C(Cl)(Cl)Cl.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>[CH:27]1([N:24]2[C:5]3[N:6]=[C:7]([NH:10][C:11]4[CH:16]=[CH:15][C:14]([N:17]5[CH2:22][CH2:21][N:20]([CH3:23])[CH2:19][CH2:18]5)=[CH:13][N:12]=4)[N:8]=[CH:9][C:4]=3[C:3]([CH3:32])=[C:2]([C:45]([O:47][CH2:48][CH3:49])=[CH2:46])[C:25]2=[O:26])[CH2:28][CH2:29][CH2:30][CH2:31]1
Reactant: C=C(OCC)[Sn](CCCC)(CCCC)CCCC
Reactant: Cc1c(Br)c(=O)n(C2CCCC2)c2nc(Nc3ccc(N4CCN(C)CC4)cn3)ncc12
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Solvent: ClC(Cl)Cl
Product: C=C(OCC)c1c(C)c2cnc(Nc3ccc(N4CCN(C)CC4)cn3)nc2n(C2CCCC2)c1=O
Temperature: 110 °C
Reaction time: 12 h
Yield: 90.6 %

Procedure:
A 6-dram vial was charged with 6-bromo-8-cyclopentyl-5-methyl-2-[5-(4-methyl-piperazin-1-yl)-pyridin-2-ylamino]-8H-pyrido[2,3-d]pyrimidin-7-one (266 mg, 0.53 mmol) and tetrakis(triphenylphosphine)palladium(0) (61 mg, 0.053 mmol) and the atmosphere replaced with argon. Toluene (5 ml) was added followed by tributyl-(1-ethoxy-vinyl)-stannane (289 mg, 0.80 mmol). The vial was heated to 110° C. and stirred for 12 h. The reaction mixture was diluted with chloroform (25 ml) and adsorbed onto silica gel. Chromatographic purification on silica gel (chloroform/2-propanol+1% TEA gradient) gave the 8-cyclopentyl-6-(1-ethoxy-vinyl)-5-methyl-2-[5-(4-methyl-piperazin-1-yl)-pyridin-2-ylamino]-8H-pyrido[2,3-d]pyrimidin-7-one (237 mg, 0.48 mmol). MS (APCI+) 490 (M+1, 100).
Reaction SMILES: [NH2:1][C:2]1[C:10]2[C:5](=[N:6][CH:7]=[C:8]([Cl:25])[C:9]=2[N:11]2[CH2:16][CH2:15][CH2:14][C@@H:13]([NH:17][C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21])[CH2:12]2)[NH:4][CH:3]=1.[CH3:26][O:27][CH2:28][C:29](Cl)=[O:30].C(N(CC)CC)C.[Li+].[OH-]>CC#N.O.O.CN1C(=O)CCC1>[Cl:25][C:8]1[C:9]([N:11]2[CH2:16][CH2:15][CH2:14][C@@H:13]([NH:17][C:18](=[O:24])[O:19][C:20]([CH3:21])([CH3:22])[CH3:23])[CH2:12]2)=[C:10]2[C:2]([NH:1][C:29](=[O:30])[CH2:28][O:27][CH3:26])=[CH:3][NH:4][C:5]2=[N:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCCN(c2c(Cl)cnc3[nH]cc(N)c23)C1
Reactant: COCC(=O)Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CCN(CC)CC
Solvent: CC#N
Product: COCC(=O)Nc1c[nH]c2ncc(Cl)c(N3CCC[C@@H](NC(=O)OC(C)(C)C)C3)c12
Reaction time: 0.17 h
Yield: 77.2 %

Procedure:
An NMP (2 mL) solution of (R)-tert-butyl 1-(3-amino-5-chloro-1H-pyrrolo[2,3-b]pyridin-4-yl)piperidin-3-ylcarbamate (0.200 g, 0.547 mmol; Example 91, Step A), 2-methoxyacetyl chloride (0.302 mL, 3.28 mmol), and triethylamine (0.533 mL, 3.83 mmol) was stirred at room temperature for 1 hour. 3M aqueous LiOH (3 mL) was then added. The reaction was stirred for 10 minutes, poured into water, and extracted with DCM. The combined organic fractions were dried (MgSO4), filtered, and concentrated to give the crude product, which was purified by reverse phase chromatography (Biotage SP4, C-18 25M+, 5-95 CH3CN/water) to give (R)-tert-butyl 1-(5-chloro-3-(2-methoxyacetamido)-1H-pyrrolo[2,3-b]pyridin-4-yl)piperidin-3-ylcarbamate (0.185 g, 77% yield).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2OC(=O)[S:10][N:9]=2)=[CH:4][CH:3]=1.[C:14]([O:18][CH2:19][CH3:20])(=[O:17])[C:15]#[CH:16]>ClC1C=CC=CC=1Cl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:16]=[C:15]([C:14]([O:18][CH2:19][CH3:20])=[O:17])[S:10][N:9]=2)=[CH:4][CH:3]=1
Reactant: C#CC(=O)OCC
Reactant: O=c1oc(-c2ccc(F)cc2)ns1
Solvent: Clc1ccccc1Cl
Product: CCOC(=O)c1cc(-c2ccc(F)cc2)ns1
Temperature: 135 °C
Yield: 31.8 %

Procedure:
To a stirred solution of 5-(4-fluorophenyl)-1,3,4-oxathiazol-2-one (42.80 g, 217.1 mmol) in o-dichlorobenzene (600 mL) was added ethyl propiolate (66.0 mL, 651 mmol). The mixture was heated overnight at 135° C. and concentrated. The residual oil was purified by flash chromatography using a hexane/ethyl acetate gradient to afford ethyl 3-(4-fluorophenyl)isothiazole-5-carboxylate as a pale golden solid (17.35 g, 32%). The more polar, ethyl 3-(4-fluorophenyl)isothiazole-4-carboxylate isomer (generated in 57/43 ratio versus the desired product) was discarded.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]2[O:8][CH2:9][O:10][C:5]2=[CH:4][C:3]=1[C:11]1[O:12][CH2:13][C:14]([CH3:17])([CH3:16])[N:15]=1.[CH3:18][N:19]1[CH2:24][CH2:23][C:22](=[O:25])[CH2:21][CH2:20]1>>[CH3:16][C:14]1([CH3:17])[CH2:13][O:12][C:11]([C:3]2[CH:4]=[C:5]3[O:10][CH2:9][O:8][C:6]3=[CH:7][C:2]=2[C:22]2([OH:25])[CH2:23][CH2:24][N:19]([CH3:18])[CH2:20][CH2:21]2)=[N:15]1
Reactant: CN1CCC(=O)CC1
Reactant: CC1(C)COC(c2cc3c(cc2Br)OCO3)=N1
Product: CN1CCC(O)(c2cc3c(cc2C2=NC(C)(C)CO2)OCO3)CC1

Procedure:
Reaction of 2-(2-bromo-4,5-methylenedioxyphenyl)-4,4-dimethyl-2-oxazoline and 1methyl-4-piperidone by the method described in Example 1c provides 4-[2-(4,4-dimethyl-2-oxazolin-2-yl)-4,5-methylenedioxyphenyl]-4-hydroxy-1-methylpiperidine.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([F:11])=[CH:7][CH:6]=1)=O.[C:12]([NH2:16])(=[S:15])[CH2:13][CH3:14].O>C(O)C>[CH2:13]([C:12]1[S:15][CH:2]=[C:3]([C:5]2[CH:10]=[CH:9][C:8]([F:11])=[CH:7][CH:6]=2)[N:16]=1)[CH3:14]
Reactant: CCC(N)=S
Reactant: O=C(CBr)c1ccc(F)cc1
Solvent: CCO
Solvent: O
Product: CCc1nc(-c2ccc(F)cc2)cs1
Temperature: 25 °C

Procedure:
A mixture of 2.40 g (11.0 mmol) of 2-bromo-1-(4-fluorophenyl)ethanone and 1.00 g (11.0 mmol) of thiopropanamide in 50 ml of ethanol is stirred under reflux for 2 h and at room temperature for 16 h. The reaction mixture is stirred into 200 ml of water and extracted with ethyl acetate (3×100 ml). The combined organic phases are washed with 50 ml of water, dried over MgSO4 and freed from the solvent under reduced pressure. This gives 2.05 g (87%) of the desired product; 1H-NMR(DMSO-d6) δ: 7.99 (m, 2H), 7.92 (s, 1H), 7.26 (m, 2H), 3.04 (q, 2H), 1.34 (t, 3H).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2=[CH:12][C:13]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[N:16]=[CH:15][CH:14]=1.[P:23](=O)([OH:26])([OH:25])[OH:24].O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O>>[P:23]([O:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2=[CH:12][C:13]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[N:16]=[CH:15][CH:14]=1)([OH:26])([OH:25])=[O:24]
Reactant: O=P(O)(O)O
Reactant: O=C1Nc2ccc(O)cc2C1=Cc1ccnc2ccccc12
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Product: O=C1Nc2ccc(OP(=O)(O)O)cc2C1=Cc1ccnc2ccccc12
Temperature: 60 °C
Yield: 50 %

Procedure:
A mixture of 5-hydroxy-3-(quinol-4-ylmethylene)-2-oxindole (2.883 g, 10 mmol) and phosphoric acid 85% (13 g) and phosphorous pentoxide (10 g) was heated for 2 h at 60° C. The usual work-up gave the title compound in about 50% yield.
Reaction SMILES: NC(N)=[S:3].[Cl:5][C:6]1[CH:23]=[CH:22][C:9]([CH2:10][N:11]2[CH2:17][CH2:16][CH2:15][N:14]([CH2:18][CH2:19][CH2:20]Cl)[CH2:13][CH2:12]2)=[CH:8][CH:7]=1.C(O)C.[OH-].[Na+]>O>[Cl:5][C:6]1[CH:23]=[CH:22][C:9]([CH2:10][N:11]2[CH2:17][CH2:16][CH2:15][N:14]([CH2:18][CH2:19][CH2:20][SH:3])[CH2:13][CH2:12]2)=[CH:8][CH:7]=1
Reactant: ClCCCN1CCCN(Cc2ccc(Cl)cc2)CC1
Reactant: NC(N)=S
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: SCCCN1CCCN(Cc2ccc(Cl)cc2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 39.1 %

Procedure:
4.1 g of thiourea were added to a mixture of 8.0 g of 1-(4-chlorobenzyl)-4-(3-chloropropyl)homopiperazine and 100 ml of reagent ethanol. The mixture was refluxed for 6 hours and then stirred overnight at room temperature. A solution of 5.0 g of sodium hydroxide in 30 ml of water was added, and the resulting solution was refluxed for 4 hours. The ethanol was removed in vacuo, and water was added to the residue. The product was extracted with methylene chloride, and the extract was dried (sodium sulfate) and concentrated to give 3.1 g (39% of theory) of 3-[4-(4-chlorobenzyl)homopiperazin-1-yl]propanethiol as a yellow oil.
Reaction SMILES: [NH2:1][C:2]1[C:3]2[N:10]=[C:9]([C:11]3[N:15]([CH3:16])[C:14]([SH:17])=[N:13][C:12]=3[C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[S:8][C:4]=2[N:5]=[CH:6][N:7]=1.Cl.[CH2:25]([N:27]([CH2:30]CCl)[CH2:28]C)[CH3:26].[OH-].[Na+]>>[CH3:28][N:27]([CH3:30])[CH2:25][CH2:26][S:17][C:14]1[N:15]([CH3:16])[C:11]([C:9]2[S:8][C:4]3[N:5]=[CH:6][N:7]=[C:2]([NH2:1])[C:3]=3[N:10]=2)=[C:12]([C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)[N:13]=1
Reactant: CCN(CC)CCCl
Reactant: Cn1c(S)nc(-c2ccccc2)c1-c1nc2c(N)ncnc2s1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: CN(C)CCSc1nc(-c2ccccc2)c(-c2nc3c(N)ncnc3s2)n1C
Temperature: 60 °C

Procedure:
A mixture of 5-(7-amino[1,3]thiazolo[5,4-d]pyrimidin-2-yl)-1-methyl-4-phenyl-1H-imidazole-2-thiol (Intermediate 47) (10 mg), N,N-diethyl-2-chloroethylamine hydrochloride (9 mg) and 2M NaOH (1 mL) was heated at 60° C. for 6 hours. After which the reaction mixture was cooled to ambient temperature and the title compound isolated by filtration as a yellow solid (6 mg, 50%);
Reaction SMILES: C(O)(=[O:3])C.[F:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[CH:12]=[C:13]([N+]([O-])=O)[CH2:14][CH3:15]>[Zn].C1(C)C=CC=CC=1>[F:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[CH2:12][C:13](=[O:3])[CH2:14][CH3:15]
Reactant: CCC(=Cc1ccccc1F)[N+](=O)[O-]
Reactant: CC(=O)O
Agent: [Zn]
Solvent: Cc1ccccc1
Product: CCC(=O)Cc1ccccc1F
Reaction time: 4 h

Procedure:
100 ml of 90% v/v aqueous acetic acid were added to 7.4 g of 1-(2-fluorophenyl)-2-nitro-1-butene [prepared as described in step (a) above], and then 12.11 g (190 mmole) of a zinc powder were added in portions to the resulting solution, whilst heating. The mixture was then heated under reflux, whilst stirring, for 4 hours. At the end of this time, the reaction mixture was left to stand overnight, and then the crystals which had precipitated were filtered off and washed with toluene. The filtrate was combined with the toluene washings, and the mixture was concentrated by evaporation under reduced pressure. The residue thus obtained was subjected to silica gel column chromatography, using toluene as the eluent, to give 1.85 g of the title compound as a pale brown oil.
Reaction SMILES: Br[C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([N+:10]([O-:12])=[O:11])[C:3]=1[C:4]#[N:5].[CH:13]1(B(O)O)[CH2:15][CH2:14]1.C1(P(C2CCCCC2)C2CCCCC2)CCCCC1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>C1(C)C=CC=CC=1.O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[N+:10]([C:6]1[CH:7]=[CH:8][CH:9]=[C:2]([CH:13]2[CH2:15][CH2:14]2)[C:3]=1[C:4]#[N:5])([O-:12])=[O:11]
Reactant: N#Cc1c(Br)cccc1[N+](=O)[O-]
Reactant: OB(O)C1CC1
Agent: [Pd+2]
Agent: C1CCC(P(C2CCCCC2)C2CCCCC2)CC1
Agent: CC(=O)[O-]
Solvent: Cc1ccccc1
Solvent: O
Product: N#Cc1c(C2CC2)cccc1[N+](=O)[O-]
Temperature: 100 °C
Yield: 109.9 %

Procedure:
2-Bromo-6-nitrobenzonitrile (0.56 g), cyclopropyl boronic acid (0.63 g), palladium (II) acetate (0.055 g), tricyclohexylphosphine (0.135 g) and potassium phosphate tribasic (2.36 g) were dissolved in a mixture of toluene (15 mL) and water (3 mL). The mixture was heated at 100° C. under nitrogen for 18 hours. The mixture was cooled and then partitioned between water and DCM. The organic solution was separated, dried with magnesium sulfate, filtered and the solvent was removed under vacuum. The residue was purified by flash chromatography on silica, eluting with a mixture of ethyl acetate and cyclohexane. The fractions containing the desired product were combined and evaporated to give the title compound as a light yellow solid (0.51 g).
Reaction SMILES: [NH2:1][C:2]1[NH:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][C:10]([N+:13]([O-:15])=[O:14])=[CH:9][CH:8]=2)[C:3]=1[C:16]#[N:17].C(O[CH:26](OCC1C=CC=CC=1)[N:27]([CH3:29])[CH3:28])C1C=CC=CC=1>C1(C)C=CC=CC=1>[N+:13]([C:10]1[CH:9]=[CH:8][C:7]([C:4]2[C:3]([C:16]#[N:17])=[C:2]([N:1]=[CH:26][N:27]([CH3:29])[CH3:28])[NH:6][N:5]=2)=[CH:12][CH:11]=1)([O-:15])=[O:14]
Reactant: CN(C)C(OCc1ccccc1)OCc1ccccc1
Reactant: N#Cc1c(-c2ccc([N+](=O)[O-])cc2)n[nH]c1N
Solvent: Cc1ccccc1
Product: CN(C)C=Nc1[nH]nc(-c2ccc([N+](=O)[O-])cc2)c1C#N

Procedure:
In 1 ml of toluene, 57.3 mg (0.25 mmol) of 5-amino-3-(4-nitro-phenyl)-1H-pyrazole-4-carbonitrile and 79.3 μl of N,N-dimethylformamide dibenzylacetal are boiled overnight. Filtering of the suspension and washing with hexane yield N'-[3-(4-nitro-phenyl)-4-cyano-1H-pyrazol-5-yl]-N,N-dimethylformamidine; TLC: Rf =0.15 (ethyl acetate:hexane=2:1); TRet (Grad20-100)=8.8.
Reaction SMILES: [C:1]([O:5][C@@H:6]([C:10]1[C:31]([CH3:32])=[CH:30][C:13]2[N:14]=[C:15]([C:17]3[CH:18]=[C:19]4[C:23](=[CH:24]C=3)[N:22]([CH3:26])[N:21]=[C:20]4[CH:27]3[CH2:29]C3)[S:16][C:12]=2[C:11]=1[C:33]1[CH:38]=[CH:37][C:36]([Cl:39])=[CH:35][CH:34]=1)[C:7]([OH:9])=[O:8])([CH3:4])([CH3:3])[CH3:2].BrC1C=CC2C(=C(C)N(C)N=2)C=1>>[C:1]([O:5][C@@H:6]([C:10]1[C:31]([CH3:32])=[CH:30][C:13]2[N:14]=[C:15]([C:17]3[CH:29]=[CH:27][C:20]4[C:19](=[C:23]([CH3:24])[N:22]([CH3:26])[N:21]=4)[CH:18]=3)[S:16][C:12]=2[C:11]=1[C:33]1[CH:34]=[CH:35][C:36]([Cl:39])=[CH:37][CH:38]=1)[C:7]([OH:9])=[O:8])([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1cc2nc(-c3ccc4c(c3)c(C3CC3)nn4C)sc2c(-c2ccc(Cl)cc2)c1[C@H](OC(C)(C)C)C(=O)O
Agent: Cc1c2cc(Br)ccc2nn1C
Product: Cc1cc2nc(-c3ccc4nn(C)c(C)c4c3)sc2c(-c2ccc(Cl)cc2)c1[C@H](OC(C)(C)C)C(=O)O

Procedure:
prepared in a similar manner as the preparation of (S)-2-tert-butoxy-2-(7-(4-chlorophenyl)-2-(3-cyclopropyl-1-methyl-1H-indazol-5-yl)-5-methylbenzo[d]thiazol-6-yl)acetic acid except using 5-bromo-2,3-dimethyl-2H-indazole instead of 5-bromo-3-cyclopropyl-1-methyl-1H-indazole. LCMS-ESI+: calc'd for C29H28ClN3O3S: 534.2, 536.2 (M+H+); Found: 534.2, 536.2 (M+H+). 1H NMR (400 MHz, CD3OD): δ 8.37 (s, 1H), 7.99 (dd, J=9.1, 1.7 Hz, 1H), 7.82 (s, 1H), 7.76-7.66 (m, 1H), 7.66-7.50 (m, J=9.1, 4.8 Hz, 4H), 5.26 (s, 1H), 4.12 (s, 3H), 2.71 (s, 3H), 2.62 (s, 3H), 0.99 (s, 9H).
Reaction SMILES: [CH:1]1([C:4]2[N:5]=[CH:6][C:7]([O:10][C@H:11]3[CH2:22][N:14]4[CH2:15][CH2:16][N:17]([C:19](Cl)=[O:20])[CH2:18][C@@H:13]4[CH2:12]3)=[N:8][CH:9]=2)[CH2:3][CH2:2]1.[F:23][C:24]([F:34])([F:33])[O:25][C:26]1[CH:27]=[C:28]([OH:32])[CH:29]=[CH:30][CH:31]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH:1]1([C:4]2[N:5]=[CH:6][C:7]([O:10][C@H:11]3[CH2:22][N:14]4[CH2:15][CH2:16][N:17]([C:19]([O:32][C:28]5[CH:29]=[CH:30][CH:31]=[C:26]([O:25][C:24]([F:23])([F:33])[F:34])[CH:27]=5)=[O:20])[CH2:18][C@@H:13]4[CH2:12]3)=[N:8][CH:9]=2)[CH2:3][CH2:2]1
Reactant: Oc1cccc(OC(F)(F)F)c1
Reactant: O=C(Cl)N1CCN2C[C@H](Oc3cnc(C4CC4)cn3)C[C@H]2C1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=C(Oc1cccc(OC(F)(F)F)c1)N1CCN2C[C@H](Oc3cnc(C4CC4)cn3)C[C@H]2C1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of the product from Example 114A (26 mg, 0.081 mmol) and 3-(trifluoromethoxy)phenol (14 mg, 0.081 mmol) in anhydrous N,N-dimethylformamide (0.8 mL) was added potassium carbonate (17 mg, 0.12 mmol), and the resulting mixture was stirred at ambient temperature for 16 hours. The mixture was partitioned between ethyl acetate and water, and the organic extract was dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The crude product was purified by column chromatography on silica gel using a solvent gradient of 0-60% ethyl acetate in hexanes to give the title compound. 1H NMR (300 MHz, CDCl3) δ ppm 0.89-1.01 (m, 4 H), 1.83-2.09 (m, 3 H), 2.30-2.59 (m, 3 H), 2.60-2.93 (m, 1 H), 2.97-3.38 (m, 2 H), 3.76 (dd, J=9.9, 6.7 Hz, 1 H), 4.15-4.29 (m, 1 H), 4.30-4.45 (m, 1 H), 5.38 (q, J=5.8 Hz, 1 H), 7.00-7.13 (m, 3 H), 7.37 (t, J=8.1 Hz, 1 H), 7.95 (d, J=1.2 Hz, 1 H), 8.04 (d, J=1.2 Hz, 1 H); MS (ESI) m/z 465.0 (M+H)+.
Reaction SMILES: [ClH:1].[OH:2][NH:3][C:4]([C:6]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:7]=1[CH2:8][CH2:9][C:10]2=[N:15]O)=[NH:5].N[N:18]1[CH:22]=[C:21]([C:23]2[CH:32]=[CH:31][C:30]3[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=3)[CH:24]=2)[N:20]=[C:19]1[NH2:33]>C(O)(C)C>[ClH:1].[ClH:1].[OH:2][NH:3][C:4]([C:6]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:7]=1[CH2:8][CH2:9][C:10]2=[N:15][N:18]1[CH:22]=[C:21]([C:23]2[CH:32]=[CH:31][C:30]3[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=3)[CH:24]=2)[N:20]=[C:19]1[NH2:33])=[NH:5]
Reactant: N=C(NO)c1cccc2c1CCC2=NO
Reactant: Nc1nc(-c2ccc3ccccc3c2)cn1N
Agent: Cl
Solvent: CC(C)O
Product: N=C(NO)c1cccc2c1CCC2=Nn1cc(-c2ccc3ccccc3c2)nc1N
Temperature: 120 °C
Reaction time: 24 h

Procedure:
7 ml of concentrated hydrochloric acid are added, with stirring, to a mixture of 2.01 g (9.8 mmol) of 4-(N-hydroxyarnidino)-2,3-dihydro-1H-inden-1-one oxime, 2.2 g (9.8 mmol) of 1,2-diamino-4-(2-naphthyl)-imidazole (see J. Heterocycl. Chem. 11, 327-329 (1974)) and 25 ml of isopropanol, and the mixture is stirred at 120° C. for 24 hours. The mixture is cooled to 20° C., filtered and washed with isopropanol, and the filtration product is taken up in 60 ml of methylene chloride. The suspension is stirred at room temperature for 15 hours and is then filtered, and the crystallizate is washed with methylene chloride. In that manner there is obtained the title compound, m.p. 265°-270° C., 1H-NMR (DMSO/D2O): δ=8.32 (s, 1H); 8.29 (d, 1H); 8.19 (s, 1H); 8.04 (d, 1H); 7.88-7.98 (m, 3H); 7.81 (d, 1H); 7.53-7.68 (m, 3H); 3.38 (s, 4H).
Reaction SMILES: [C@H:1]1([NH:10][C:11]2[CH:20]=[CH:19][C:18]3[C:13](=[CH:14][CH:15]=[CH:16][C:17]=3[N+:21]([O-])=O)[N:12]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1.[H][H]>C(O)C.[Pd]>[C@H:1]1([NH:10][C:11]2[CH:20]=[CH:19][C:18]3[C:17]([NH2:21])=[CH:16][CH:15]=[CH:14][C:13]=3[N:12]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1
Reactant: [H][H]
Reactant: O=[N+]([O-])c1cccc2nc(N[C@@H]3CCc4ccccc43)ccc12
Agent: [Pd]
Solvent: CCO
Product: Nc1cccc2nc(N[C@@H]3CCc4ccccc43)ccc12

Procedure:
(R)-Indan-1-yl-(5-nitro-quinolin-2-yl)-amine (2.66 g, 8.7 mmol) was dissolved in 420 mL ethanol. Palladium on charcoal (10%, 463 mg, 0.4 mmol) was added and the reaction mixture war hydrogenated with a hydrogen balloon overnight. The palladium was filtered off and the solvent was evaporated. The title compound was obtained as a brown solid (2.29 g, 95%), MS: m/e=276.3 (M+H+).
Reaction SMILES: [CH2:1]([O:3][C:4]1[N:9]=[C:8]2[N:10]([CH2:14][CH3:15])[N:11]=[C:12]([CH3:13])[C:7]2=[N:6][C:5]=1[C:16]([OH:18])=O)[CH3:2].S(Cl)([Cl:21])=O>>[CH2:1]([O:3][C:4]1[N:9]=[C:8]2[N:10]([CH2:14][CH3:15])[N:11]=[C:12]([CH3:13])[C:7]2=[N:6][C:5]=1[C:16]([Cl:21])=[O:18])[CH3:2]
Reactant: CCOc1nc2c(nc1C(=O)O)c(C)nn2CC
Reactant: O=S(Cl)Cl
Product: CCOc1nc2c(nc1C(=O)Cl)c(C)nn2CC

Procedure:
22.7 g. of 6-ethoxy-1-ethyl-3-methyl-1H-pyrazolo-[3,4-b]pyrazine-5-carboxylic acid (0.09 mol.) and 250 ml. of thionyl chloride are heated at reflux temperature for two hours. After vacuum removal of excess thionyl chloride, the residual 6-ethoxy-1-ethyl-3-methyl-1H-pyrazolo[3,4-b]pyrazine-5-carbonyl chloride is recrystallized from hexane, yield 20.5 g. (85%), m.p. 109°-111°.
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[C:3]1[CH:14]=[CH:13][C:6]([CH2:7][CH:8]([C:11]#[N:12])[C:9]#[N:10])=[CH:5][CH:4]=1.C(=O)([O-])[O-].[Cs+].[Cs+].FC(F)(F)S(O[CH2:29][C:30]([F:36])([F:35])[C:31]([F:34])([F:33])[F:32])(=O)=O>CN(C)C=O>[F:35][C:30]([F:36])([C:31]([F:34])([F:33])[F:32])[CH2:29][C:8]([CH2:7][C:6]1[CH:5]=[CH:4][C:3]([C:2]([F:15])([F:16])[F:1])=[CH:14][CH:13]=1)([C:11]#[N:12])[C:9]#[N:10]
Reactant: O=S(=O)(OCC(F)(F)C(F)(F)F)C(F)(F)F
Reactant: N#CC(C#N)Cc1ccc(C(F)(F)F)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: N#CC(C#N)(Cc1ccc(C(F)(F)F)cc1)CC(F)(F)C(F)(F)F
Yield: 25.2 %

Procedure:
Using 0.50 g of (4-(trifluoromethyl)benzyl)malononitrile, 5 ml of N,N-dimethylformamide, 363 mg of cesium carbonate, and 0.63 g of 2,2,3,3,3-pentafluoropropyl trifluoromethanesulfonate, and according to the process described in the Production Example 1, there was obtained 0.20 g of 2-(2,2,3,3,3-pentafluoropropyl)-2-(4-(trifluoromethyl)benzyl)malononitrile (the present compound (76)).
Reaction SMILES: [Cl:1][C:2]1[CH:17]=[CH:16][CH:15]=[C:14]([Cl:18])[C:3]=1[C:4]([NH:6][CH:7]([CH2:11][CH:12]=[CH2:13])[C:8]([OH:10])=[O:9])=[O:5].S(Cl)(Cl)=O.O.[C:24](=O)([O-])O.[Na+]>CO>[CH3:24][O:9][C:8](=[O:10])[CH:7]([NH:6][C:4](=[O:5])[C:3]1[C:2]([Cl:1])=[CH:17][CH:16]=[CH:15][C:14]=1[Cl:18])[CH2:11][CH:12]=[CH2:13]
Reactant: O=C([O-])O
Reactant: C=CCC(NC(=O)c1c(Cl)cccc1Cl)C(=O)O
Agent: [Na+]
Solvent: O
Solvent: O=S(Cl)Cl
Solvent: CO
Product: C=CCC(NC(=O)c1c(Cl)cccc1Cl)C(=O)OC
Temperature: 25 °C
Reaction time: 5.5 h

Procedure:
Allylglycine (10.11 g) was dissolved in a mixed solvent of 2N aqueous sodium hydroxide solution (176 ml) and dioxane (175 ml), and 2,6-dichlorobenzoyl chloride (15.10 ml) was added dropwise thereto, followed by stirring the resulting mixture at room temperature for 10 hours. After concentrating the reaction solution to remove dioxane, water (150 ml) was added thereto and the resulting solution was washed with ether. Aqueous layer was acidified by adding 3N hydrochloric acid in small portions thereto, and extracted 3 times with ethyl acetate. Organic layers were washed with saturated brine and dried over anhydrous sodium sulfate. After removing anhydrous sodium sulfate by filtration, the filtrate was concentrated. The residue was recrystallized from hexane/ethyl acetate mixed solvent to obtain 2-(2,6-dichlorobenzamido)pent-4-enoic acid (23.48 g). (2) Under an argon atmosphere, a solution of 2-(2,6-dichlorobenzamido)pent-4-enoic acid (23.48 g) in methanol (250 ml) was cooled to 0° C. Thionyl chloride (10.70 ml) was added dropwise to the solution while keeping the reaction temperature not higher than 10° C., and thereafter the resulting mixture was stirred at room temperature for 5.5 hours. Water was added to the reaction solution, and sodium hydrogen carbonate was added thereto in small portions to neutralize it. After concentrating the reaction solution to remove methanol, aqueous layer was extracted twice with ethyl acetate. Organic layers were washed 3 times with water and once with saturated brine, and dried over anhydrous sodium sulfate. After removing anhydrous sodium sulfate by filtration, the filtrate was concentrated. The residue was recrystallized from hexane/ethyl acetate mixed solvent to obtain 2-(2,6-dichlorobenzamido)pent-4-enoic acid methyl ester (21.70 g). NMR (H1, CDCl3): δ 2.55-2.61 (1H, m), 2.68-2.75 (1H, m), 3.72 (3H, s), 4.88 (1H, td, J=7.8, 5.4 Hz), 5.06-5.13 (2H, m), 5.64-5.74 (1H, m), 6.33 (1H, brd, J=7.1 Hz), 7.17-7.26 (3H, m)
Reaction SMILES: C1(C)C=CC(S(O)(=O)=O)=CC=1.[Cl:12][C:13]1[CH:31]=[C:30]([Cl:32])[C:29]([F:33])=[CH:28][C:14]=1[C:15]([CH:17](C(OCC)=O)[C:18]([O:20][CH2:21][CH3:22])=[O:19])=[O:16]>O>[Cl:12][C:13]1[CH:31]=[C:30]([Cl:32])[C:29]([F:33])=[CH:28][C:14]=1[C:15]([CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])=[O:16]
Reactant: CCOC(=O)C(C(=O)OCC)C(=O)c1cc(F)c(Cl)cc1Cl
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Product: CCOC(=O)CC(=O)c1cc(F)c(Cl)cc1Cl
Yield: 78.6 %

Procedure:
0.15 g of p-toluenesulphonic acid is added to an emulsion of 34.9 g of crude diethyl 2,4-dichloro-5-fluoro-benzoyl-malonate in 50 ml of water. The mixture is heated at the boiling point for 3 hours, while stirring well, the cooled emulsion is extracted several times with methylene chloride, the combined methylene chloride solutions are washed once with saturated sodium chloride solution and dried with sodium sulphate and the solvent is distilled off in vacuo. Fractionation of the residue under a fine vacuum gives 21.8 g of ethyl 2,4-dichloro-5-fluoro-benzoylacetate of boiling point 127°-142° C./0.09 mbar.