Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][CH:5]=[N:6][CH:7]=1.[CH3:8][C:9]([CH3:11])=O.[H][H]>C(O)C.O=[Pt]=O>[CH:9]([NH:1][C:2]1[CH:3]=[N:4][CH:5]=[N:6][CH:7]=1)([CH3:11])[CH3:8]
Reactant: [H][H]
Reactant: CC(C)=O
Reactant: Nc1cncnc1
Agent: O=[Pt]=O
Solvent: CCO
Product: CC(C)Nc1cncnc1

Procedure:
A suspension of the 5-aminopyrimidine, and one twenty-fifth an equal mass of PtO2, and 1.1 equivalents acetone, in ethanol solvent, was shaken under 60 psi hydrogen gas for 24 h. At this time, TLC of an evaporated aliquot of the reaction mixture indicated complete conversion of the 5-aminopyrimidine. The Pt catalyst was removed by filtering the reaction mixture through Celite, and the 5-(N-isopropyl)aminopyrimidine was isolated by evaporation of the ethanol solvent. The crude product was used in subsequent chemical steps without purification.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH2:4][N:5]([CH:12]([CH3:14])[CH3:13])[C:6]2=[O:11].C1C(=O)N([Cl:22])C(=O)C1.O>CN(C=O)C>[NH2:1][C:2]1[CH:10]=[CH:9][C:8]([Cl:22])=[C:7]2[C:3]=1[CH2:4][N:5]([CH:12]([CH3:14])[CH3:13])[C:6]2=[O:11]
Reactant: CC(C)N1Cc2c(N)cccc2C1=O
Reactant: O=C1CCC(=O)N1Cl
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)N1Cc2c(N)ccc(Cl)c2C1=O
Yield: 29.7 %

Procedure:
A solution of 2.8 grams (0.015 mole) of 4-amino-2-(1-methylethyl)isoindolin-1-one and 2.0 grams (0.015 mole) of NCS in 80 mL of DMF was stirred at 25° C. for about 18 hours. The reaction mixture was then poured into water, and the mixture was extracted repeatedly with diethyl ether. The combined extracts were dried with magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure to a residue. The residue was purified by column chromatography on silica gel using mixtures of EtOAc and methylene chloride as eluants. The fractions containing product were combined and concentrated under reduced pressure, yielding about 1.0 gram of subject compound. The NMR spectrum was consistent with the proposed structure.
Reaction SMILES: Cl.[O:2]1CCO[CH2:4][CH2:3]1.[C:8]([O:12][C:13]([N:15]1[CH2:20][CH2:19][CH:18]([CH:21]([C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)[CH2:22][CH2:23][N:24]2[CH2:31][CH:30]3[CH:26]([CH2:27][N:28]([C:32]([C:34]4[C:35]([CH3:41])=[N:36][CH:37]=[N:38][C:39]=4[CH3:40])=[O:33])[CH2:29]3)[CH2:25]2)[CH2:17][CH2:16]1)=[O:14])(C)([CH3:10])[CH3:9].C1(O)CCC(O)C1>CC#N>[OH:2][CH:3]1[CH2:4][CH2:10][CH:8]([O:12][C:13]([N:15]2[CH2:20][CH2:19][CH:18]([CH:21]([C:42]3[CH:43]=[CH:44][CH:45]=[CH:46][CH:47]=3)[CH2:22][CH2:23][N:24]3[CH2:31][CH:30]4[CH:26]([CH2:27][N:28]([C:32]([C:34]5[C:35]([CH3:41])=[N:36][CH:37]=[N:38][C:39]=5[CH3:40])=[O:33])[CH2:29]4)[CH2:25]3)[CH2:17][CH2:16]2)=[O:14])[CH2:9]1
Reactant: Cc1ncnc(C)c1C(=O)N1CC2CN(CCC(c3ccccc3)C3CCN(C(=O)OC(C)(C)C)CC3)CC2C1
Reactant: C1COCCO1
Agent: Cl
Agent: OC1CCC(O)C1
Solvent: CC#N
Product: Cc1ncnc(C)c1C(=O)N1CC2CN(CCC(c3ccccc3)C3CCN(C(=O)OC4CCC(O)C4)CC3)CC2C1
Reaction time: 4 h

Procedure:
A solution of HCl-dioxane (1 mL, 4.0 M) and 78a (35 mg, 0.064 mmol) was stirred at RT for 90 min. The solvent was removed, and the residue was dried in vacuo. Cyclopentane-1,3-diol (cis/trans, 9 μL, 0.096 mmol) was added to a solution of N,N′-disuccimidylcarbonate (30 mg, 0.12 mmol) and TEA (44 μL, 0.32 mmol) in MeCN (0.47 mL) and the solution was stirred for 4 h. A solution of the above residue from the Boc deprotection in MeCN was added and the reaction mixture was stirred for 3 h. The solvent was evaporated and the crude product was purified on a preparative TLC plate developed with a mixture of 45% DCM and 55% of DCM/MeOH/NH4OH (60/10/1) to afford 0.011 g (30%) of V-6.
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4](=[O:7])[O:5][CH:6]=1.[Cl-].[Al+3].[Cl-].[Cl-].[N:12]1([C:17]2[CH:25]=[CH:24][C:20]([C:21](Cl)=[O:22])=[CH:19][CH:18]=2)[CH:16]=[CH:15][N:14]=[CH:13]1>C(Cl)Cl>[N:12]1([C:17]2[CH:18]=[CH:19][C:20]([C:21]([C:6]3[O:5][C:4](=[O:7])[NH:3][C:2]=3[CH3:1])=[O:22])=[CH:24][CH:25]=2)[CH:16]=[CH:15][N:14]=[CH:13]1
Reactant: O=C(Cl)c1ccc(-n2ccnc2)cc1
Reactant: Cc1coc(=O)[nH]1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: Cc1[nH]c(=O)oc1C(=O)c1ccc(-n2ccnc2)cc1
Reaction time: 0.5 h

Procedure:
In 50 ml methylene chloride were placed 1.30 g (0.0132 mol) 4-methyl-2(3H)-oxazolone and 5.22 g (0.039 mol) aluminum chloride. The mixture was stirred 30 minutes and 2.72 g (0.0132 mol) 4-(1H-imidazol-1-yl)benzoyl chloride were added. The mixture was heated on the steam bath allowing the methylene chloride to evaporate, after which the residue was heated an additional 30 minutes. The residue was quenched with water and the water solution neutralized with sodium bicarbonate. The solution was evaporated to dryness and the residue was leached with hot methanol. Evaporation of the methanol provided the crude product which was purified by chromatography; m.p. 320°.
Reaction SMILES: [CH2:1]([CH:8]1[CH2:12][CH2:11][N:10]([S:13]([C:16]2[CH:20]=[N:19][NH:18][C:17]=2[NH2:21])(=[O:15])=[O:14])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.COCCO.FC(F)(F)C(O)=O.[CH3:34][C:35]([CH3:45])=[CH:36][C:37]([C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)=O>>[CH2:1]([CH:8]1[CH2:12][CH2:11][N:10]([S:13]([C:16]2[CH:20]=[N:19][N:18]3[C:35]([CH3:45])([CH3:34])[CH:36]=[C:37]([C:39]4[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=4)[NH:21][C:17]=23)(=[O:15])=[O:14])[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Nc1[nH]ncc1S(=O)(=O)N1CCC(Cc2ccccc2)C1
Reactant: CC(C)=CC(=O)c1ccccc1
Solvent: O=C(O)C(F)(F)F
Solvent: COCCO
Product: CC1(C)C=C(c2ccccc2)Nc2c(S(=O)(=O)N3CCC(Cc4ccccc4)C3)cnn21

Procedure:
A 2 mL ethanol solution containing 0.079 g (0.247 mmol) of 3 was treated with 0.013 mL (0.27 mmol) of hydrazine monohydrate and heated to reflux for 5 h. The reaction was concentrated in vacuo to give crude 4-(3-benzylpyrrolidine-1-sulfonyl)-2H-pyrazol-3-ylamine. The crude pyrazole thus obtained was dissolved in 2 mL of 2-methoxyethanol containing 0.044 g (0.27 mmol) of 3-methyl-1-phenyl-but-2-en-1-one and 0.038 mL (0.49 mmol) of trifluoroacetic acid was added. The mixture was refluxed for three days then concentrated and purified by flash chromatography eluting with 60% hexanes/AcOEt to give 3-(3-benzylpyrrolidine-1-sulfonyl)-7,7-dimethyl-5-phenyl-4,7-dihydropyrazolo[1,5-a]pyrimidine that was found to be only 90% pure by HPLC analysis. This material was then dissolved in 1 mL of 1:1 THF:ethanol and 0.010 g of 10% palladium on carbon. The reaction vessel was capped with a rubber septum and charged with hydrogen via a balloon. After 90 min at room temperature, the catalyst was removed via filtration and the filtrate concentrated to an oil. Purification by flash chromatography eluting with 75% hexanes/AcOEt gave 0.024 g (20% from 3) of the title compound as a light yellow oil. 1H NMR (CDCl3) δ 1.55-1.66 (m, 7H), 1.94-2.03 (m, 1H), 2.08-2.16 (m, 2H), 2.37-2.50 (m, 1H), 2.58-2.70 (m, 2H), 2.90-2.97 (m, 1H), 3.18-3.27 (m, 1H), 3.31-3.42 (m, 2H), 4.53-4.60 (m, 1H), 5.71 (s, 1H), 7.11-7.14 (m, 2H), 7.19-7.23 (m, 1H), 7.26-7.40 (m, 7H), 7.53 (s, 1H). MS Calcd.: 450. Found: 451 (M+H).
Reaction SMILES: [C:1]([N:9]1[CH2:14][CH2:13][CH:12]([CH2:15][S:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH2:11][CH2:10]1)(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>C1COCC1>[CH2:1]([N:9]1[CH2:10][CH2:11][CH:12]([CH2:15][S:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH2:13][CH2:14]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(c1ccccc1)N1CCC(CSc2ccccc2)CC1
Solvent: C1CCOC1
Product: c1ccc(CN2CCC(CSc3ccccc3)CC2)cc1
Reaction time: 1.5 h
Yield: 77.3 %

Procedure:
40 ml (0.04 mol) of 1M BH3 in THF were added to a solution of 3.11 g (0.01 mol) of 1-benzoyl-4-thiophenoxymethyl-piperidine in 50 ml of THF. The mixture was boiled at reflux for 16 hrs. Then, 90 ml of 1N aqueous HCI were added and the mixture was stirred for 1.5 hrs. It was extracted with ether and concentrated and the residue was taken up in a mixture of 20 ml of glacial acetic acid and 20 ml of THF and boiled at reflux for 3 hrs. The solvents were distilled off and the residue was taken up in ethyl acetate, washed with saturated sodium carbonate solution and sodium chloride solution and dried over sodium sulfate. The solvent was removed and the residue was chromatographed on silica gel with ethyl acetate/hexane (1:9) as the eluent. 2.3 g (77%) of 1-benzyl-4-phenylsulfanylmethyl-piperidine were obtained as a colorless oil. MS: me/e=298 (C19H24NS+).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:30])[C:4]1[CH:9]=[C:8]([O:10][CH2:11][CH2:12][CH2:13][O:14][C:15]2[CH:20]=[CH:19][C:18]([O:21][CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)=[CH:17][CH:16]=2)[CH:7]=[C:6]([OH:29])[CH:5]=1.Br[CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH3:41].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH3:1][O:2][C:3](=[O:30])[C:4]1[CH:9]=[C:8]([O:10][CH2:11][CH2:12][CH2:13][O:14][C:15]2[CH:20]=[CH:19][C:18]([O:21][CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)=[CH:17][CH:16]=2)[CH:7]=[C:6]([O:29][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH3:41])[CH:5]=1
Reactant: COC(=O)c1cc(O)cc(OCCCOc2ccc(OCc3ccccc3)cc2)c1
Reactant: CCCCCCCCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCCCCCCCCOc1cc(OCCCOc2ccc(OCc3ccccc3)cc2)cc(C(=O)OC)c1
Reaction time: 24 h
Yield: 93 %

Procedure:
A mixture of 1.0 g (2.45 mmol) of 3-hydroxy-5-[3-[4-(phenylmethoxy)phenoxy]propoxy]benzoic acid methyl ester, 0.6 ml (2.69 mmol) of 1-bromodecane and 0.7 g (4.9 mmol) of potassium carbonate in 20 ml of DMF was stirred at 80° for 24 hours. The usual workup followed by recrystallization from ether-hexane gave 1.25 g (93% yield, mp 68°-70°) of 3-(decyloxy)-5-[3-[4-(phenylmethoxy) phenoxy]propoxy]benzoic acid methyl ester.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([S:8][CH3:9])[C:3]=1[CH3:10].C(Cl)(Cl)(Cl)Cl.C(#N)C.I([O-])(=O)(=O)=[O:20].[Na+].[OH2:25]>[Ru](Cl)(Cl)Cl>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([S:8]([CH3:9])(=[O:20])=[O:25])[C:3]=1[CH3:10]
Reactant: O
Reactant: CSc1cccc(Br)c1C
Reactant: [O-][I+3]([O-])([O-])[O-]
Agent: Cl[Ru](Cl)Cl
Agent: [Na+]
Solvent: CC#N
Solvent: ClC(Cl)(Cl)Cl
Product: Cc1c(Br)cccc1S(C)(=O)=O

Procedure:
Preparation according to preparation 4: 1-bromo-2-methyl-3-(methylthio)benzene (1.33 g), carbon tetrachloride (8 ml), acetonitrile (8 ml), water (16 ml), sodium periodate (3.9 g), ruthenium trichloride (1 mg). Yield: 1.6 g. MS m/z (rel. intensity, 70 eV) 250 (M+, 69), 248 (M+, 67), 169 (49), 90 (63), 89 (bp).
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][N:5]([C:8]2[N:13]=[C:12]([CH3:14])[N:11]([CH2:15][C:16]3[S:17][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:19][CH:20]=3)[C:10](=[O:25])[N:9]=2)[CH2:4][CH2:3]1.C(N(CC)CC)C.[CH3:33][S:34](Cl)(=[O:36])=[O:35]>ClCCl.O>[CH3:33][S:34]([O:1][CH:2]1[CH2:3][CH2:4][N:5]([C:8]2[N:13]=[C:12]([CH3:14])[N:11]([CH2:15][C:16]3[S:17][C:18]([C:21]([F:23])([F:22])[F:24])=[CH:19][CH:20]=3)[C:10](=[O:25])[N:9]=2)[CH2:6][CH2:7]1)(=[O:36])=[O:35]
Reactant: CS(=O)(=O)Cl
Reactant: Cc1nc(N2CCC(O)CC2)nc(=O)n1Cc1ccc(C(F)(F)F)s1
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O
Product: Cc1nc(N2CCC(OS(C)(=O)=O)CC2)nc(=O)n1Cc1ccc(C(F)(F)F)s1
Yield: 100.1 %

Procedure:
To a dichloromethane solution (2.0 mL) of 4-(4-hydroxypiperidin-1-yl)-6-methyl-1-{[5-(trifluoromethyl)thiophen-2-yl]methyl}-1,3,5-triazin-2(1H)-one (374 mg, 1.00 mmol) synthesized in Reference Synthesis Example 348 and triethylamine (557 μL, 4.00 mmol), methanesulfonyl chloride (155 μL, 2.00 mmol) was added dropwise at 0° C. and the resultant mixture was stirred at room temperature for 1 hour. After the reaction, water was added to the reaction solution and extraction from the resultant mixture with dichloromethane was performed. The obtained organic layer was dried over anhydrous sodium sulfate and thereafter concentrated under reduced pressure to obtain the title compound (453 mg, yield 100%).
Reaction SMILES: [C:1]([NH:18][NH2:19])([O:3][CH2:4][CH:5]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]2[C:6]1=[CH:7][CH:8]=[CH:9][CH:10]=2)=[O:2].Cl.C1N=CN([C:26](N2C=NC=C2)=[O:27])C=1.CCN(C(C)C)C(C)C.[NH2:42][C@H:43]([C:48]([O:50][C:51]([CH3:54])([CH3:53])[CH3:52])=[O:49])[CH2:44][CH:45]([CH3:47])[CH3:46].Cl>C1COCC1.CN(C=O)C>[NH:18]([C:1]([O:3][CH2:4][CH:5]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]2[C:6]1=[CH:7][CH:8]=[CH:9][CH:10]=2)=[O:2])[NH:19][C:26]([NH:42][C@H:43]([C:48]([O:50][C:51]([CH3:52])([CH3:54])[CH3:53])=[O:49])[CH2:44][CH:45]([CH3:47])[CH3:46])=[O:27]
Reactant: CC(C)C[C@H](N)C(=O)OC(C)(C)C
Reactant: NNC(=O)OCC1c2ccccc2-c2ccccc21
Reactant: O=C(n1ccnc1)n1ccnc1
Agent: Cl
Solvent: C1CCOC1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)C[C@H](NC(=O)NNC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)OC(C)(C)C
Temperature: 25 °C
Yield: 98.6 %

Procedure:
Fmoc-Phe,Fmoc-Orn(Mtt) was introduced into 4 g (0.55 mmol/g) of Rink Amide MBHA resin commercially available to prepare Fmoc-Orn(Mtt)-Phe-Rink Amide MBHA resin, and 50 mL of TFA/TIS/DCM (Jan. 5, 1994) was added to the resin, followed by shaking for 50 minutes. After the resin washed, 40 mL of DCM and 2.27 g of N-methyl-N,N′-bis-Boc-1-guanylpyrazole prepared in REFERENCE EXAMPLE 1 were added to the resin. DIEA was added to the mixture to adjust pH of the solution to 9. The mixture was shaken for 15 hours to give 4.74 g of Fmoc-Arg(Boc2,Me)Phe-Rink Amide MBHA resin. Separately, 145 mg of Fmoc-NHNH2HCl was suspended in 10 mL of THF. Under ice cooling, 89 mg of CDI and 87 mL of DIEA were added to the suspension, followed by stirring at room temperature for an hour. Under ice cooling, a solution of 224 mg of H-Leu-OBut HCl in 5 mL of DMF 5 mL was added to the mixture. While reverting to room temperature, the mixture was stirred for 18 hours. After the solvent was distilled off, the residue was dissolved in AcOEt and the solution washed with 1N HCl aq. solution, satd. NaHCO3 aq. solution and then satd. NaCl aq. solution. After drying over Na2SO4, the solvent was concentrated and the concentrate was purified by flash column chromatography to give 230 mg (yield 99%) of Fmoc-AzaGly-Leu-OBut. To 187 mg of the product, 10 mL of TFA/H2O (9/1) was added, followed by stirring for an hour. After the solvent was distilled off, the residue was dissolved in AcOEt and the solution washed with satd. NaCl aq. solution. After drying over Na2SO4, the solvent was concentrated and diethyl ether was added to give 143 mg of Fmoc-AzaGly-Leu-OH as the precipitate (yield 87%). The resulting Fmoc-AzaGly-Leu-OH, Trt-Phe was introduced into Fmoc-Arg(Boc2,Me)Phe-Rink Amide MBHA resin. To the thus prepared Trt-Phe-AzaGly-Leu-Arg(Boc2,Me)Phe-Rink Amide MBHA resin, 50 mL of TFA/TIS/DCM (Jan. 5, 1994) was added and the mixture was shaken for 50minutes. After the resin washed and neutralized, Fmoc-Ser(But) and then Fmoc-Asn(Trt) were introduced thereinto. Using 80.3 mg of the resulting Fmoc-Asn(Trt)Ser(But)Phe-AzaGly-LeuArg(Boc2,Me)Phe-Rink Amide MBHA resin, the peptide chain was extended to give 97.2 mg of H-D-Tyr(But)Asn(Trt)Trp(Boc)Asn(Trt)Ser(But)Phe-AzaGly-LeuArg(Boc2,Me)Phe-Rink Amide MBHA resin.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:15]3([C:23]4[C:18](=[N:19][CH:20]=[CH:21][CH:22]=4)[C:17]([NH2:24])=[N:16]3)[C:14]3[CH:13]=[C:12]([Cl:25])[N:11]=[C:10]([F:26])[C:9]=3[O:8][C:5]2=[CH:6][CH:7]=1.C(=O)=O>>[Br:1][C:2]1[CH:3]=[C:4]2[C@:15]3([C:23]4[C:18](=[N:19][CH:20]=[CH:21][CH:22]=4)[C:17]([NH2:24])=[N:16]3)[C:14]3[CH:13]=[C:12]([Cl:25])[N:11]=[C:10]([F:26])[C:9]=3[O:8][C:5]2=[CH:6][CH:7]=1
Reactant: NC1=NC2(c3cc(Br)ccc3Oc3c2cc(Cl)nc3F)c2cccnc21
Agent: O=C=O
Product: NC1=N[C@@]2(c3cc(Br)ccc3Oc3c2cc(Cl)nc3F)c2cccnc21

Procedure:
7-Bromo-3-chloro-1-fluorospiro[chromeno[2,3-c]pyridine-5,5′-pyrrolo[3,4-b]pyridin]-7′-amine subjected to chromatography using supercritical CO2 (additives 50% MeOH with 20 mM NH3) on a Chiralpak ADH column (21×250 mm, 5 μm) eluting at a flow rate 63 ml/min (100 bar pressure, 40° C. column temperature). The first peak (retention time=2.34 min) provided (R)-7-Bromo-3-chloro-1-fluorospiro[chromeno[2,3-c]pyridine-5,5′-pyrrolo[3,4-b]pyridin]-7′-amine (Example 17c-1; 99% ee), and the second peak (retention time=3.98 min) provided (S)-7-Bromo-3-chloro-1-fluorospiro[chromeno[2,3-c]pyridine-5,5′-pyrrolo[3,4-b]pyridin]-7′-amine (Example 17c-2; 99% ee).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:6]2[CH:7]=[CH:8][CH2:9][O:10][C:11]=2[C:12]([F:15])=[CH:13][CH:14]=1)=[O:4].[N:16]([O-:18])=[O:17].[Na+].II.S(S([O-])=O)([O-])(=O)=O.[Na+].[Na+]>C(OCC)(=O)C>[CH3:1][O:2][C:3]([C:5]1[C:6]2[CH:7]=[C:8]([N+:16]([O-:18])=[O:17])[CH2:9][O:10][C:11]=2[C:12]([F:15])=[CH:13][CH:14]=1)=[O:4]
Reactant: COC(=O)c1ccc(F)c2c1C=CCO2
Reactant: O=N[O-]
Agent: II
Agent: O=S([O-])S(=O)(=O)[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc(F)c2c1C=C([N+](=O)[O-])CO2
Temperature: 50 °C
Yield: 55 %

Procedure:
Into a reactor, equipped with mechanic stirrer and reflux condenser, 8-fluoro-2H-chromene-5-carboxylic acid methyl ester (6.6 g; 30 mmoles), sodium nitrite (6.2 g; 90 mmoles) and ethyl acetate (60 ml) were added at room temperature and under inert gas. The mixture was heated under stirring at 50° C., then iodine (2:6 g; 10 mmoles) and, slowly in 4 hours, Oxistrong 15® (7.4 ml) were added. At the end of the addition the reaction mixture was kept under stirring for a further hour, then cooled at 0° C. A 20% solution of sodium metabisulphite (about 25 ml) was added and the mixture was kept under stirring for 1 hour. After filtration the solid was washed with water (2×10 ml). The mother liquors were separated and, the previously filtered solid was added to the organic phase. The solvent was removed under reduced pressure and the semisolid residue was taken up with methanol (about 10 ml) and kept under stirring at 0° C. for 1 hour. After filtration and wash of the panel with methanol pre-cooled at 0° C. (3 ml), the resultant solid was dried in oven under vacuum at 40° C. overnight obtaining 8-fluoro-3-nitro-2H-chromene-5-carboxylic acid methyl ester (4.6 g; titre 92%; 55% yield). The mother liquors were evaporated to dryness obtaining an oil (2.7 g) containing 55% of 8-fluoro-3-nitro-2H-chromene-5-arboxylic acid methyl ester. Overall yield 75%.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([NH2:11])=[S:10])=[CH:4][CH:3]=1.[Cl:12][CH:13](Cl)[C:14](=O)[CH3:15].C(=O)([O-])O.[Na+]>O1CCOCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][C:9]2[S:10][CH:15]=[C:14]([CH2:13][Cl:12])[N:11]=2)=[CH:6][CH:7]=1
Reactant: NC(=S)Cc1ccc(Cl)cc1
Reactant: CC(=O)C(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Product: ClCc1csc(Cc2ccc(Cl)cc2)n1
Temperature: 70 °C
Reaction time: 72 h
Yield: 85.9 %

Procedure:
To a solution of 2-(4-chlorophenyl)thioacetamide (3.51 g) in 1,4-dioxane (20 mL) were added dichloroacetone (2.64 g) and sodium hydrogen carbonate (1.75 g) at room temperature, and the mixture was stirred for 3 days. Insoluble material was removed by filtration, thionyl chloride (1.52 mL) was added to the filtrate, and the mixture was heated at 70° C. for 30 min. The reaction mixture was adjusted to pH=8-9 by the addition of saturated aqueous sodium hydrogen carbonate solution, and extracted with ethyl acetate/hexane (1/1)(100 mL×2). The organic layer was washed with saturated brine, and concentrated under reduced pressure to give the title compound (4.19 g) as a pale-yellow solid.
Reaction SMILES: [Na].[C:2]([C:5]1[N:6]=[C:7]([CH2:11][C:12]([O:14]CC)=[O:13])[NH:8][C:9]=1[OH:10])(=[O:4])[NH2:3]>CO>[C:2]([C:5]1[N:6]=[C:7]([CH2:11][C:12]([OH:14])=[O:13])[NH:8][C:9]=1[OH:10])(=[O:4])[NH2:3]
Reactant: CCOC(=O)Cc1nc(C(N)=O)c(O)[nH]1
Agent: [Na]
Solvent: CO
Product: NC(=O)c1nc(CC(=O)O)[nH]c1O
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 82.2 %

Procedure:
To 300 ml of anhydrous methanol was added 0.92 g of sodium and then 4.26 g of ethyl 4-carbamoyl-5-hydroxy-1H-imidazole-2-acetate was added thereto under ice-cooling. 5 minutes thereafter, the mixture was warmed to a room temperature and stirred for 15 minutes. The resulting mixture was concentrated under vacuum and the residue was dissolved into 100 ml of water. After addition of 120 ml of 1 N aqueous hydrochloric acid, the precipitated crystals were collected, washed with ethanol and diisopropyl ether, and dried to give 3.04 g of 4-carbamoyl-5-hydroxy-1H-imidazole-2-acetic acid, m.p. 299° C. (decomposition). Yield: 82.2%.
Reaction SMILES: C[O:2][C:3](=[O:24])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH2:10][N:11]2[CH:15]=[C:14]([C:16]3[CH:21]=[CH:20][C:19]([C:22]#[N:23])=[CH:18][CH:17]=3)[N:13]=[N:12]2)[CH:5]=1>CO.O>[C:22]([C:19]1[CH:18]=[CH:17][C:16]([C:14]2[N:13]=[N:12][N:11]([CH2:10][C:6]3[CH:5]=[C:4]([CH:9]=[CH:8][CH:7]=3)[C:3]([OH:24])=[O:2])[CH:15]=2)=[CH:21][CH:20]=1)#[N:23]
Reactant: COC(=O)c1cccc(Cn2cc(-c3ccc(C#N)cc3)nn2)c1
Solvent: CO
Solvent: O
Product: N#Cc1ccc(-c2cn(Cc3cccc(C(=O)O)c3)nn2)cc1
Temperature: 25 °C
Reaction time: 72 h
Yield: 92.4 %

Procedure:
Add LiOH monohydrate (0.10 g, 2.40 mmol) to a suspension of 3-[4-(4-cyano-phenyl)-[1,2,3]triazol-1-ylmethyl]-benzoic acid methyl ester (0.50 g, 1.60 mmol) in 15 mL of a 4:1 MeOH-water mixture and stir at room temperature for 3 days. Concentrate the mixture to remove most of the MeOH, dilute with additional H2O and neutralize by the addition of 1N aqueous HCl. Isolate the resulting solid by filtration and dry to afford 0.45 g, 94% yield of 3-[4-(4-Cyano-phenyl)-[1,2,3]triazol-1-ylmethyl]-benzoic acid.
Reaction SMILES: [OH:1][NH:2][C:3](=[NH:14])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([S:10](=[O:13])(=[O:12])[NH2:11])[CH:5]=1.[F:15][CH:16]([F:36])[C:17]1[N:22]=[C:21]([C:23](O)=O)[N:20]=[C:19]([C:26]2[CH:31]=[CH:30][C:29]([C:32]([F:35])([F:34])[F:33])=[CH:28][CH:27]=2)[CH:18]=1>>[F:36][CH:16]([F:15])[C:17]1[CH:18]=[C:19]([C:26]2[CH:27]=[CH:28][C:29]([C:32]([F:35])([F:34])[F:33])=[CH:30][CH:31]=2)[N:20]=[C:21]([C:23]2[O:1][N:2]=[C:3]([C:4]3[CH:5]=[C:6]([S:10]([NH2:11])(=[O:12])=[O:13])[CH:7]=[CH:8][CH:9]=3)[N:14]=2)[N:22]=1
Reactant: O=C(O)c1nc(-c2ccc(C(F)(F)F)cc2)cc(C(F)F)n1
Reactant: N=C(NO)c1cccc(S(N)(=O)=O)c1
Product: NS(=O)(=O)c1cccc(-c2noc(-c3nc(-c4ccc(C(F)(F)F)cc4)cc(C(F)F)n3)n2)c1

Procedure:
The title compound was prepared from N-hydroxy-3-sulfamoyl-benzamidine [CAS-No. 9000-88-7] (0.16 g, 0.75 mmol) and 6-difluoromethyl-4-(4-trifluoromethyl-phenyl)-pyrimidine-2-carboxylic acid (example D.3) (0.16 g, 0.5 mmol) according to the general procedure V. Obtained as a white solid (0.12 g, 49%). MS (ISP) 498.3 [(M+H)+]; mp 217.5° C.
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[C:3]1[CH:11]=[C:10]([C:12]([F:15])([F:14])[F:13])[CH:9]=[CH:8][C:4]=1[C:5]([OH:7])=O.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C.Cl.Cl.[CH3:42][NH:43][C:44]1=[N:45][C:46](=[O:56])[S:47]/[C:48]/1=[CH:49]\[CH:50]1[CH2:55][CH2:54][NH:53][CH2:52][CH2:51]1>CN(C)C=O.O.C(N(CC)CC)C>[F:16][C:2]([F:1])([F:17])[C:3]1[CH:11]=[C:10]([C:12]([F:15])([F:14])[F:13])[CH:9]=[CH:8][C:4]=1[C:5]([N:53]1[CH2:54][CH2:55][CH:50](/[CH:49]=[C:48]2/[C:44]([NH:43][CH3:42])=[N:45][C:46](=[O:56])[S:47]/2)[CH2:51][CH2:52]1)=[O:7]
Reactant: O=C(O)c1ccc(C(F)(F)F)cc1C(F)(F)F
Reactant: CNC1=NC(=O)S/C1=C\C1CCNCC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CNC1=NC(=O)S/C1=C\C1CCN(C(=O)c2ccc(C(F)(F)F)cc2C(F)(F)F)CC1
Reaction time: 0.08 h
Yield: 56.8 %

Procedure:
To a solution of 2,4-bis(trifluoromethyl)benzoic acid (83 mg) in N,N-dimethylformamide (6 mL) were added 1-hydroxybenzotriazole (123 mg) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (154 mg), and the mixture was stirred for 5 min under ice-cooling. To the reaction mixture were added triethylamine (0.2 mL) and (5Z)-4-(methylamino)-5-(piperidin-4-ylmethylidene)-1,3-thiazol-2(5H)-one dihydrochloride (200 mg) under ice-cooling, and the mixture was stirred at room temperature overnight. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate) and recrystallized from ethyl acetate/pentane to give the title compound (85 mg).