Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:4]1[N:17]([CH2:18][C:19]2[CH:24]=[CH:23][C:22]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[C:31]3[N:35]([C:36]([C:49]4[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=4)([C:43]4[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=4)[C:37]4[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=4)[N:34]=[N:33][N:32]=3)=[CH:21][CH:20]=2)[C:7]2[CH:8]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[NH:9][CH2:10][CH2:11][C:6]=2[N:5]=1)[CH2:2][CH3:3].C(=O)([O-])[O-].[K+].[K+].[CH2:61](Br)[C:62]1[CH:67]=[CH:66][CH:65]=[CH:64][CH:63]=1.CN(C)C=O>C(OCC)(=O)C>[CH2:61]([N:9]1[CH2:10][CH2:11][C:6]2[N:5]=[C:4]([CH2:1][CH2:2][CH3:3])[N:17]([CH2:18][C:19]3[CH:20]=[CH:21][C:22]([C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=4[C:31]4[N:35]([C:36]([C:43]5[CH:44]=[CH:45][CH:46]=[CH:47][CH:48]=5)([C:37]5[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=5)[C:49]5[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=5)[N:34]=[N:33][N:32]=4)=[CH:23][CH:24]=3)[C:7]=2[CH:8]1[C:12]([O:14][CH2:15][CH3:16])=[O:13])[C:62]1[CH:67]=[CH:66][CH:65]=[CH:64][CH:63]=1
Reactant: CCCc1nc2c(n1Cc1ccc(-c3ccccc3-c3nnnn3C(c3ccccc3)(c3ccccc3)c3ccccc3)cc1)C(C(=O)OCC)NCC2
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCCc1nc2c(n1Cc1ccc(-c3ccccc3-c3nnnn3C(c3ccccc3)(c3ccccc3)c3ccccc3)cc1)C(C(=O)OCC)N(Cc1ccccc1)CC2
Yield: 66.6 %

Procedure:
A mixture of ethyl 2-n-propyl-3-[2'-(1-trityl-1H-tetrazol-5-yl)biphenyl-4-yl]methyl-4,5,6,7-tetrahydroimidazo[4,5-c]pyridine-4-carboxylate (2.00 g), potassium carbonate (1.16 g), benzyl bromide (0.72 g) and dimethylformamide (10 ml) is stirred under ice-cooling for two hours. The mixture is diluted with ethyl acetate, and the solution is washed with water, dried and evaporated. The residue is purified by silica gel column chromatography (solvent; n-hexane/ethyl acetate) to give ethyl 5-benzyl-2-n-propyl-3-[2'-(1-trityl-1H-tetrazol-5-yl)biphenyl-4-yl]methyl-4,5,6,7-tetrahydroimidazo[4,5-c]pyridine-4-carboxylate (1.50 g) as a white foam.
Reaction SMILES: [NH2:1][CH2:2][CH:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)[CH3:4].C(N(CC)CC)C.[C:18](Cl)(=[O:25])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>C(Cl)(Cl)Cl>[C:5]1([CH:3]([CH3:4])[CH2:2][NH:1][C:18](=[O:25])[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: CC(CN)c1ccccc1
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CC(CNC(=O)c1ccccc1)c1ccccc1
Yield: 94.9 %

Procedure:
To a solution of 1-amino-2-phenylpropane (25.0 g, 0.185 mol) and triethylamine (18.2 g, 0.185 mol) in 150 mL of chloroform was added dropwise, a solution of benzoyl chloride (26.0 g, 0.185 mol) in 150 mL of chloroform under nitrogen. After completion of the addition, the reaction mixture was heated at reflux for 1 hour. The solution was then washed with water and the organic layer dried over magnesium sulfate. Removal of the solvent yielded 42.0 g (95%) of N-(2-phenylpropyl)benzamide as a white powder.
Reaction SMILES: Cl.[NH2:2][C:3]1[N:11]=[CH:10][N:9]=[C:8]2[C:4]=1[N:5]=[CH:6][N:7]2[C:12]1[CH:17]=[CH:16][C:15]([NH:18][C:19]([NH:21][C:22]2[CH:27]=[CH:26][C:25]([Cl:28])=[C:24]([C:29]([F:32])([F:31])[F:30])[CH:23]=2)=[O:20])=[CH:14][CH:13]=1.C(OC([NH:40][C@@H:41]([C:45](O)=O)[CH:42]([CH3:44])[CH3:43])=O)(C)(C)C>>[ClH:28].[NH2:40][C@H:41]([CH:42]([CH3:44])[CH3:43])[CH2:45][N-:2][C:3]1[N:11]=[CH:10][N:9]=[C:8]2[C:4]=1[N:5]=[CH:6][N:7]2[C:12]1[CH:13]=[CH:14][C:15]([NH:18][C:19]([NH:21][C:22]2[CH:27]=[CH:26][C:25]([Cl:28])=[C:24]([C:29]([F:31])([F:32])[F:30])[CH:23]=2)=[O:20])=[CH:16][CH:17]=1
Reactant: Nc1ncnc2c1ncn2-c1ccc(NC(=O)Nc2ccc(Cl)c(C(F)(F)F)c2)cc1
Reactant: CC(C)[C@@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: Cl
Product: CC(C)[C@@H](N)C[N-]c1ncnc2c1ncn2-c1ccc(NC(=O)Nc2ccc(Cl)c(C(F)(F)F)c2)cc1

Procedure:
The titled compound can be synthesized from 1-[4-(6-amino-purin-9-yl)phenyl]-3-(4-chloro-3-(trifluoromethyl)phenyl)urea hydrochloride and tert-butoxycarbonyl-D-valine by using the same method as in Example 96.
Reaction SMILES: [CH3:1][CH:2]([NH2:9])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[OH-].[Na+].O(C(C)C)C(C)C>>[CH3:1][C@@H:2]([NH2:9])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: CC(N)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)OC(C)C
Product: C[C@@H](N)c1ccccc1

Procedure:
A mixture of 1 part of (+)-α-methylbenzylamine salt with R-(+)-1 -(α-methylbenzyl)-5-imidazolecarboxylic acid and 6 parts of sodium hydroxide solution 1N is shaken in a closed tube till all solid enters solution (pH = ±11). The resulting solution is shaken five times for 1 minute, each time after the addition of 1.4 parts of 2,2'-oxybispropane. The organic phases are combined (the alkaline aqueous phase is set aside) and evaporated, yielding R-(+)-α-methylbenzylamine.
Reaction SMILES: [CH2:1]([N:3]1[C:8](=O)[NH:7][C:6]([CH3:10])=[N:5][S:4]1(=[O:12])=[O:11])[CH3:2].P(Cl)(Cl)([Cl:15])=O.P(Cl)(Cl)(Cl)(Cl)Cl>>[Cl:15][C:8]1[N:3]([CH2:1][CH3:2])[S:4](=[O:12])(=[O:11])[N:5]=[C:6]([CH3:10])[N:7]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: CCN1C(=O)NC(C)=NS1(=O)=O
Agent: ClP(Cl)(Cl)(Cl)Cl
Product: CCN1C(Cl)=NC(C)=NS1(=O)=O
Yield: 93 %

Procedure:
225 parts of 2-ethyl-5-methyl-2H-1,2,4,6-thiatriazin-3-one-1,1-dioxide were introduced into a mixture of 1,300 parts of phosphorus oxychloride and 292 parts of phosphorus pentachloride in the course of 2 minutes, while stirring. The reaction mixture was stirred under reflux for 7 hours and then concentrated under reduced pressure. The oil which remained was taken up in 350 parts of 1,2-dichloroethane and chromatographed over neutral alumina (activity I). The solution was then evaporated down, giving 230 parts (93% of theory) of 3-chloro-2-ethyl-5-methyl-2H-1,2,4,6-thiatriazine-1,1-dioxide of melting point 57°-59° C. (NMR (60 MHz, CDCl3): CH3 -C 2.3δ, N-CH2 3.68-4.03δ (q), CH3 -C 1.2-1.43δ (t)).
Reaction SMILES: Cl[C:2]1[C:7]([O:8][C:9]2[CH:14]=[C:13]([CH3:15])[C:12]([O:16][CH3:17])=[CH:11][C:10]=2[CH:18]([CH3:20])[CH3:19])=[CH:6][N:5]=[C:4]([NH2:21])[N:3]=1.C(Cl)Cl.[NH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>>[CH:18]([C:10]1[CH:11]=[C:12]([O:16][CH3:17])[C:13]([CH3:15])=[CH:14][C:9]=1[O:8][C:7]1[C:2]([NH:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[N:3][C:4]([NH2:21])=[N:5][CH:6]=1)([CH3:20])[CH3:19]
Reactant: COc1cc(C(C)C)c(Oc2cnc(N)nc2Cl)cc1C
Reactant: Nc1ccccc1
Solvent: ClCCl
Product: COc1cc(C(C)C)c(Oc2cnc(N)nc2Nc2ccccc2)cc1C
Temperature: 100 °C

Procedure:
A suspension of 4-chloro-5-(2-isopropyl-4-methoxy-5-methyl-phenoxy)-pyrimidin-2-ylamine (0.043 g, 0.14 mmol) in aniline (4 ml) was placed in a sealed tube and heated at 100° C. over night. Methylene chloride was added and insoluble solid was removed by filtration through celite. The combined methylene chloride filtrate was washed with water and dried over anhydrous sodium sulfate. After removal of the drying agent, the organic phase was concentrated under reduced pressure. The residue was purified with silica gel chromatography (2% methanol in methylene chloride) to yield a yellow oily residue, which was further purified with preparative TLC and HPLC (5 to 100% acetonitrile in water with 0.1% trifluoroacetic acid to yield 5-(2-Isopropyl-4-methoxy-5-methyl-phenoxy)-N*4*-phenyl-pyrimidine-2,4-diamine, M+H: 365.
Reaction SMILES: Br[CH:2]1[CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([CH3:13])[C:8]=2[O:11][CH3:12])[C:3]1=[O:14].[Na].[N+:16]([C:19]1[CH:24]=[CH:23][C:22]([OH:25])=[CH:21][CH:20]=1)([O-:18])=[O:17].O>CN(C)C=O>[CH3:12][O:11][C:8]1[C:7]([CH3:13])=[CH:6][CH:5]=[C:4]2[C:9]=1[CH2:10][CH:2]([O:25][C:22]1[CH:23]=[CH:24][C:19]([N+:16]([O-:18])=[O:17])=[CH:20][CH:21]=1)[C:3]2=[O:14]
Reactant: O=[N+]([O-])c1ccc(O)cc1
Reactant: COc1c(C)ccc2c1CC(Br)C2=O
Agent: [Na]
Solvent: O
Solvent: CN(C)C=O
Product: COc1c(C)ccc2c1CC(Oc1ccc([N+](=O)[O-])cc1)C2=O
Temperature: 26.5 °C
Reaction time: 2 h
Yield: 73.7 %

Procedure:
To a stirred solution of 2-Bromo-4-methoxy-5-methyl-indan-1-one (2.0 gm, 0.0078 mole) in Dimethylformamide (15 ml), added Sodium salt of 4-Nitrophenol (1.27 gm, 0.0078 mole) at 10-15° C. After 2 hours stirring at 25-28° C., reaction mixture was poured into water (50 ml). The separated solid was filtered, washed with hexane and dried under vacuum to give 1.8 gm of desired product as a solid
Reaction SMILES: [C:1]([C:3]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:4]=1[CH2:5][CH:6]([N:13]1[CH:17]=[CH:16][N:15]=[C:14]1[C:18]([O:20]CC)=O)[C:7]2=[O:12])#[N:2].[NH3:23]>CO>[C:1]([C:3]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:4]=1[CH2:5][CH:6]([N:13]1[CH:17]=[CH:16][N:15]=[C:14]1[C:18]([NH2:23])=[O:20])[C:7]2=[O:12])#[N:2]
Reactant: N
Reactant: CCOC(=O)c1nccn1C1Cc2c(C#N)cccc2C1=O
Solvent: CO
Product: N#Cc1cccc2c1CC(n1ccnc1C(N)=O)C2=O

Procedure:
1-[(4-Cyano-1-oxoindan-2-yl)]imidazole-2-carboxamide can be obtained in the following way: a solution of 1.5 g of ethyl 1-[(4-cyano-1-oxoindan-2-yl)]imidazole-2-carboxylate in 130 ml of methanol is kept saturated for one hour at a temperature in the region of 20° C. with a stream of gaseous ammonia. The reaction mixture is then concentrated to dryness under reduced pressure (15 mm Hg; 2 kPa) at 50° C. 1.2 g of 1-[(4-cyano-1-oxoindan-2-yl)]imidazole-2-carboxamide are thus obtained, which product melts at 216° C.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:13]=[C:12]2[C:8]([CH:9]=[CH:10][NH:11]2)=[CH:7][CH:6]=1)=[O:4].[CH:14]1([CH2:20]Br)[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1.[H-].[Na+]>CN(C=O)C.O.C(OCC)(=O)C>[CH3:1][O:2][C:3]([C:5]1[CH:13]=[C:12]2[C:8]([CH:9]=[CH:10][N:11]2[CH2:20][CH:14]2[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]2)=[CH:7][CH:6]=1)=[O:4]
Reactant: COC(=O)c1ccc2cc[nH]c2c1
Reactant: BrCC1CCCCC1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc2ccn(CC3CCCCC3)c2c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 73.7 %

Procedure:
To a solution of commercially available 1H-indole-6-carboxylic acid methyl ester (0.35 g, 2.0 mmol) and cyclohexylmethyl bromide (0.31 mL, 2.2 mmol) in DMF (2 mL) was added sodium hydride (92 mg, 2.3 mmol). After stirring at room temperature for 3 hr, the solution was diluted with water (25 mL) and ethyl acetate (75 mL), the organic layer was washed again with dilute NaHCO3 (25 mL) and then brine (25 mL). The organic layer was dried over Na2SO4, filtered and concentrated. The remaining residue was subjected to flash chromatography (ethyl acetate/hexane, 1:24) to provide 1-cyclohexylmethyl-1H-indole-6-carboxylic acid methyl ester as a white solid (0.40 g, 74% yield). 1H NMR (400 MHz, DMSO) δ 8.10 (s, 1H), 7.62 (m, 2H), 7.58 (d, 1H, J=3.1 Hz), 6.52 (d, 1H, J=3.1 Hz), 4.10 (d, 2H, J=7.4 Hz), 3.85 (s, 3H), 1.77 (m, 1H), 1.65-1.57 (m 3H), 1.46 (m, 2H), 1.19 (m, 3H), 0.98 (m, 2H).
Reaction SMILES: [C:1]1([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH:6]=[CH:5][C:4]([CH2:7][N:8]2[C:17]3[CH2:16][CH2:15][CH2:14][CH:13]([OH:18])[C:12]=3[C:11](=[O:19])[C:10]([C:20]([O:22][CH2:23][CH3:24])=[O:21])=[CH:9]2)=[CH:3][CH:2]=1.[H-].[Na+].[CH3:33]I.O>CN(C)C=O>[C:1]1([C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH:2]=[CH:3][C:4]([CH2:7][N:8]2[C:17]3[CH2:16][CH2:15][CH2:14][CH:13]([O:18][CH3:33])[C:12]=3[C:11](=[O:19])[C:10]([C:20]([O:22][CH2:23][CH3:24])=[O:21])=[CH:9]2)=[CH:5][CH:6]=1
Reactant: CI
Reactant: CCOC(=O)c1cn(Cc2ccc(-c3ccccc3)cc2)c2c(c1=O)C(O)CCC2
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)c1cn(Cc2ccc(-c3ccccc3)cc2)c2c(c1=O)C(OC)CCC2
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
Racemic ethyl 1-(biphenyl-4-ylmethyl)-5-hydroxy-4-oxo-1,4,5,6,7,8-hexahydroquinoline-3-carboxylate (Example 17, 174 mg, 0.431 mmol) was dissolved in degassed N,N-dimethylformamide (2 mL), cooled to 0° C. under an atmosphere of nitrogen and treated with sodium hydride (19 mg, 0.47 mmol, 60% dispersion in mineral oil, 1.1 equiv) and then methyl iodide (0.096 mL, 1.55 mmol, 3.6 equiv). After stirring for 15 min, the mixture was warmed to ambient temperature and stirred for an additional 1 hr. The reaction mixture was poured into water and extracted three times with ethyl acetate. The combined ethyl acetate extracts were washed once with water and brine, dried with sodium sulfate, filtered and concentrated in vacuo to provide racemic ethyl 1-(biphenyl-4-ylmethyl)-5-methoxy-4-oxo-1,4,5,6,7,8-hexahydroquinoline-3-carboxylate.
Reaction SMILES: C([O:8][C:9]1[CH:10]=[C:11]([CH:18]=[CH:19][CH:20]=1)[C:12]([N:14]([O:16][CH3:17])[CH3:15])=[O:13])C1C=CC=CC=1>O1CCCC1>[OH:8][C:9]1[CH:10]=[C:11]([CH:18]=[CH:19][CH:20]=1)[C:12]([N:14]([O:16][CH3:17])[CH3:15])=[O:13]
Reactant: CON(C)C(=O)c1cccc(OCc2ccccc2)c1
Solvent: C1CCOC1
Product: CON(C)C(=O)c1cccc(O)c1
Reaction time: 2 h
Yield: 98.4 %

Procedure:
To a solution of 100 g (0.37 mol) B4 in 750 ml tetrahydrofurane 10 g Pd/C (10%) were added and the mixture was hydrogenated at atmospheric pressure for 2 hours. The catalyst was filtered off and the filtrate was evaporated to yield 66.0 g B5 (98%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:24])[CH2:4][N:5]([S:14]([C:17]1[S:18][CH:19]=[CH:20][C:21]=1[CH:22]=O)(=[O:16])=[O:15])[C:6]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[CH:8][CH:7]=1.C1CCN2C(=NCCC2)CC1>C(OCC)(=O)C>[CH3:13][O:12][C:9]1[CH:10]=[CH:11][C:6]([N:5]2[C:4]([C:3]([O:2][CH3:1])=[O:24])=[CH:22][C:21]3[CH:20]=[CH:19][S:18][C:17]=3[S:14]2(=[O:16])=[O:15])=[CH:7][CH:8]=1
Reactant: COC(=O)CN(c1ccc(OC)cc1)S(=O)(=O)c1sccc1C=O
Solvent: C1CCC2=NCCCN2CC1
Solvent: CCOC(C)=O
Product: COC(=O)C1=Cc2ccsc2S(=O)(=O)N1c1ccc(OC)cc1
Temperature: 25 °C
Yield: 54.9 %

Procedure:
A mixture of the product from Step B (3.67 g, 9.95 mmol), DBU (1.0 mL) and molecular sieves (1.5 g) in ethyl acetate (100 mL) was heated at reflux temperature for 4 h, cooled to room temperature, washed with 2N HCl (50 mL) and brine (50 mL), and dried (MgSO4). Evaporation of the solvent provided the desired ester (1.92 g) as an oil which was used without further purification.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][N:6]=[C:5]2[CH3:11].CC(C)([O-])C.[K+].[CH3:18][O:19][C:20]1[CH:27]=[CH:26][C:23]([CH2:24]Cl)=[CH:22][CH:21]=1.C(OCC)(=O)C>C1COCC1>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:24][C:23]1[CH:26]=[CH:27][C:20]([O:19][CH3:18])=[CH:21][CH:22]=1)[N:6]=[C:5]2[CH3:11]
Reactant: COc1ccc(CCl)cc1
Reactant: Cc1n[nH]c2ccc(Br)cc12
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COc1ccc(Cn2nc(C)c3cc(Br)ccc32)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 98.3 %

Procedure:
To a solution of 5-bromo-3-methylindazole 104 (0.2 g, 0.948 mmol) in anhydrous THF (3 mL), cooled in ice bath, was added potassium t-butoxide (0.127 g, 1.13 mmol) and 4-methoxybenzyl chloride (0.14 mL, 1.04 mmol). The reaction mixture was allowed to warmed to room temperature and was stirred for 16 hours. Ethyl acetate (100 mL) was added and the organic layer was washed with saturated ammonium chloride solution, water and brine. The organic layer was dried over sodium sulfate. The organic solvent was evaporated under reduced pressure. The crude product was purified by flash column chromatography to yield the desired 5-bromo-N-(4-methoxybenzyl)-3-methylindazole 105 (0.29 g, 0.932 mmol) as a mixture of the 1H- and 2H-indazole regioisomers.
Reaction SMILES: B(Br)(Br)Br.C[O:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]#[C:14][C:15]2[S:19][C:18]([C:20]#[N:21])=[CH:17][CH:16]=2)=[CH:9][CH:8]=1.O>ClCCl>[OH:6][C:7]1[CH:8]=[CH:9][C:10]([C:13]#[C:14][C:15]2[S:19][C:18]([C:20]#[N:21])=[CH:17][CH:16]=2)=[CH:11][CH:12]=1
Reactant: COc1ccc(C#Cc2ccc(C#N)s2)cc1
Agent: BrB(Br)Br
Solvent: O
Solvent: ClCCl
Product: N#Cc1ccc(C#Cc2ccc(O)cc2)s1
Reaction time: 8 h
Yield: 63.7 %

Procedure:
A 1M solution of boron tribromide in dichloromethane (75 cm3) is added dropwise to a solution of 1-(4-methoxyphenyl)-2-(2-cyanothiophen-5-yl)acetylene (3.0 g) and dichloromethane (100 cm3) at 0° C. under an atmosphere of nitrogen. The reaction solution is stirred overnight and water (100 cm3) added. The organic layer is separated off and the aqueous layer extracted with dichloromethane (2×100 cm3). The combined organic layers are washed with brine (2×100 cm3) and then dried (MgSO4), filtered and evaporated down. The residue is purified by column chromatography on silica gel using a 9:1 hexane/ethyi acetate mixture as eluent and recrystallisation from ethanol to yield 1.8 g of g 1-(4-hydroxyphenyl)-2-(2-cyanothiophen-5-yl)acetylene.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([SH:10])=[CH:6][CH:5]=1)([O-:3])=[O:2].[Hg](C#N)C#N.[C:16]([O:19][C@@H:20]1[C@@H:25]([O:26][C:27](=[O:29])[CH3:28])[C@H:24]([O:30][C:31](=[O:33])[CH3:32])[CH2:23][S:22][C@@H:21]1Br)(=[O:18])[CH3:17]>>[C:16]([O:19][C@@H:20]1[C@@H:25]([O:26][C:27](=[O:29])[CH3:28])[C@H:24]([O:30][C:31](=[O:33])[CH3:32])[CH2:23][S:22][C@H:21]1[S:10][C:7]1[CH:8]=[CH:9][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=1)(=[O:18])[CH3:17]
Reactant: O=[N+]([O-])c1ccc(S)cc1
Reactant: CC(=O)O[C@@H]1[C@@H](OC(C)=O)[C@@H](Br)SC[C@H]1OC(C)=O
Agent: N#C[Hg]C#N
Product: CC(=O)O[C@@H]1[C@@H](OC(C)=O)[C@H](Sc2ccc([N+](=O)[O-])cc2)SC[C@H]1OC(C)=O
Yield: 66 %

Procedure:
If the procedure described in Preparation I is followed starting from 6 g (38.10-3 mol) of 4-nitrobenzenethiol, 10.7 g (42.10-3 mol) of mercuric cyanide, Hg(CN)2, and 15.1 g (42.10-3 mol) of 2,3,4-tri-O-acetyl-5-thio-α-D-xylopyranosyl bromide, 10.8 g (yield: 66%) of the expected product are obtained.
Reaction SMILES: [CH2:1]1[C:6](=[O:7])[O:5][CH2:4][C:2]1=O.[Cl:8][C:9]1[N:14]=[CH:13][C:12]([CH2:15][NH:16][CH3:17])=[CH:11][C:10]=1[F:18]>C(O)(=O)C>[Cl:8][C:9]1[N:14]=[CH:13][C:12]([CH2:15][N:16]([CH3:17])[C:2]2[CH2:4][O:5][C:6](=[O:7])[CH:1]=2)=[CH:11][C:10]=1[F:18]
Reactant: O=C1COC(=O)C1
Reactant: CNCc1cnc(Cl)c(F)c1
Solvent: CC(=O)O
Product: CN(Cc1cnc(Cl)c(F)c1)C1=CC(=O)OC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 51.9 %

Procedure:
24.80 g (248 mmol) of tetronic acid are added slowly to 41.40 g (225.3 mmol) of N-[(6-chloro-5-fluoropyridin-3-yl)methyl]methanamine (III-1) in 64 ml of acetic acid, and the mixture is stirred at room temperature for about 16 hours. The reaction mixture is concentrated under reduced pressure, the residue is taken up in ethyl acetate and the mixture is washed successively twice with 1 N aqueous hydrochloric acid, twice with 1 N aqueous sodium hydroxide solution and saturated sodium chloride solution and dried over sodium sulphate. Concentration of the organic phase under reduced pressure and purification of the residue by recrystallization from ethyl acetate gives 30.0 g (52% of theory) of 4-[[(6-chloro-5-fluoropyridin-3-yl)methyl](methyl)amino]furan-2(5H)-one.
Reaction SMILES: [CH:1]([N:4]=[N+:5]=[N-:6])([CH3:3])[CH3:2].[F:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]#[CH:15])=[CH:10][CH:9]=1>>[F:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[N:6]=[N:5][N:4]([CH:1]([CH3:3])[CH3:2])[CH:15]=2)=[CH:10][CH:9]=1
Reactant: CC(C)N=[N+]=[N-]
Reactant: C#Cc1ccc(F)cc1
Product: CC(C)n1cc(-c2ccc(F)cc2)nn1

Procedure:
A mixture of isopropylazide [G. A. Olah, D. J. Donovan, J. Org. Chem., 43, 860, (1978)] (54.5 g; 640.3 mmol) and 4-fluorophenylacetylene [J. B. Lambert et al., J. Am. Chem. Soc., 107, 5443, (1985)] (39 g; 325.1 mmol) was heated at 70° C. for 41 hours. The excess of isopropylazide was distilled off an the resultant crude compound was purified by chromatography on silica gel (230-400 mesh), eluent methylene chloride:acetone=39:1, giving the title compound (m.p. 54°-55° C.).
Reaction SMILES: [Cl:1][S:2]([OH:5])(=O)=[O:3].[NH2:6][C:7]1[NH:16][C:15](=[O:17])[C:14]2[C:13]3[CH:18]=[CH:19][CH:20]=[CH:21][C:12]=3[CH2:11][CH2:10][C:9]=2[N:8]=1>>[NH2:6][C:7]1[NH:16][C:15](=[O:17])[C:14]2[C:13]3[CH:18]=[CH:19][C:20]([S:2]([Cl:1])(=[O:5])=[O:3])=[CH:21][C:12]=3[CH2:11][CH2:10][C:9]=2[N:8]=1
Reactant: O=S(=O)(O)Cl
Reactant: Nc1nc2c(c(=O)[nH]1)-c1ccccc1CC2
Product: Nc1nc2c(c(=O)[nH]1)-c1ccc(S(=O)(=O)Cl)cc1CC2
Reaction time: 0.33 h

Procedure:
Chlorosulfonic acid (25 ml, Aldrich), cooled to 5° C. in ice, was stirred during its addition to 3-amino-1,2,5,6-tetrahydro-1-oxo-benzo[f]quinazoline (5 g, 0.025 mole) contained in a beaker immersed in an ice bath. The solution was removed from the ice bath, stirred for a further 20 min, then poured onto ice (1000 g). The solid product was removed by filtration, washed with water, and dried under high vacuum at room temperature. The sulfonyl chloride was used without further purification.
Reaction SMILES: F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.[Si]([O:32][CH2:33][CH2:34][C:35]1[C:36]([F:53])=[C:37]([CH:50]=[CH:51][CH:52]=1)[CH2:38][N:39]1[CH2:49][CH2:48][C:42]2([O:47][CH2:46][CH2:45][NH:44][CH2:43]2)[CH2:41][CH2:40]1)(C(C)(C)C)(C)C.[CH:54]([C:57]1[N:62]=[C:61]([C:63](O)=[O:64])[CH:60]=[CH:59][CH:58]=1)([CH3:56])[CH3:55].C(N(CC)CC)C>CN(C=O)C>[F:53][C:36]1[C:35]([CH2:34][CH2:33][OH:32])=[CH:52][CH:51]=[CH:50][C:37]=1[CH2:38][N:39]1[CH2:40][CH2:41][C:42]2([O:47][CH2:46][CH2:45][N:44]([C:63]([C:61]3[CH:60]=[CH:59][CH:58]=[C:57]([CH:54]([CH3:56])[CH3:55])[N:62]=3)=[O:64])[CH2:43]2)[CH2:48][CH2:49]1
Reactant: CC(C)c1cccc(C(=O)O)n1
Reactant: CC(C)(C)[Si](C)(C)OCCc1cccc(CN2CCC3(CC2)CNCCO3)c1F
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(C)c1cccc(C(=O)N2CCOC3(CCN(Cc4cccc(CCO)c4F)CC3)C2)n1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
O-(7-Azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (0.20 g) was added to a solution of 9-(3-(2-(tert-butyldimethylsilyloxy)ethyl)-2-fluorobenzyl)-1-oxa-4,9-diazaspiro[5.5]undecane (example 78, step d) (0.17 g), 6-isopropylpicolinic acid (example 85, step d) (0.07 g) and triethylamine (0.22 mL) in DMF (7 mL) at 0° C. The resulting yellow solution was allowed to warm to RT and was stirred for 2 h. The mixture was partitioned between ethyl acetate (100 mL) and brine (100 mL). The organic phase was separated, washed with brine (2×100 mL), dried over sodium sulphate, filtered and the solvent evaporated. The residue was dissolved in THF (10 mL) and a solution of TBAF in THF (1M, 0.8 mL) was added. The resulting mixture was stirred for 2 h and the solvent evaporated. Purification was by silica gel chromatography eluting with 47.5:47.5:5 isohexane:ethyl acetate:triethylamine to 95:5 ethyl acetate:triethylamine gradient. The fractions containing product were combined, toluene (50 mL) was added and the solvent evaporated under reduced pressure to give the subtitled compound as a clear gum. Yield 0.2 g.
Reaction SMILES: [F:1][C:2]([F:32])([F:31])[CH2:3][O:4][C:5]1[CH:6]=[C:7]([C:15]2[CH:20]=[C:19]([C:21]([F:24])([F:23])[F:22])[N:18]3[N:25]=[CH:26][C:27]([C:28](O)=O)=[C:17]3[N:16]=2)[CH:8]=[CH:9][C:10]=1[C:11]([F:14])([F:13])[F:12].[NH2:33][C:34]1[CH:43]=[CH:42][C:37]([C:38]([NH:40][OH:41])=[NH:39])=[CH:36][N:35]=1>>[F:32][C:2]([F:1])([F:31])[CH2:3][O:4][C:5]1[CH:6]=[C:7]([C:15]2[CH:20]=[C:19]([C:21]([F:22])([F:23])[F:24])[N:18]3[N:25]=[CH:26][C:27]([C:28]4[O:41][N:40]=[C:38]([C:37]5[CH:42]=[CH:43][C:34]([NH2:33])=[N:35][CH:36]=5)[N:39]=4)=[C:17]3[N:16]=2)[CH:8]=[CH:9][C:10]=1[C:11]([F:12])([F:13])[F:14]
Reactant: O=C(O)c1cnn2c(C(F)(F)F)cc(-c3ccc(C(F)(F)F)c(OCC(F)(F)F)c3)nc12
Reactant: N=C(NO)c1ccc(N)nc1
Product: Nc1ccc(-c2noc(-c3cnn4c(C(F)(F)F)cc(-c5ccc(C(F)(F)F)c(OCC(F)(F)F)c5)nc34)n2)cn1

Procedure:
The title compound was prepared from 5-[3-(2,2,2-trifluoro-ethoxy)-4-trifluoromethyl-phenyl]-7-trifluoromethyl-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (example C.10) (237 mg, 0.5 mmol) and 6-amino-N-hydroxy-nicotinamidine (example B.4) (114 mg, 0.75 mmol) according to general procedure II. Obtained after flash chromatography on silica gel (ethyl acetate/heptane) and further purification by crystallization (dichloromethane/hexane) as a yellow solid (129 mg, 44%). MS (ISP) 590.3 [(M+H)+]; mp 284° C.