Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[CH:6]=[CH:5][C:4]=1[S:11]([OH:14])(=[O:13])=[O:12].C(Cl)(Cl)Cl.[N+:19]([O-])([OH:21])=[O:20]>C(#N)C>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[C:6]([N+:19]([O-:21])=[O:20])=[CH:5][C:4]=1[S:11]([OH:14])(=[O:13])=[O:12]
Reactant: O=[N+]([O-])O
Reactant: COc1ccc(S(=O)(=O)O)c(OC)c1
Solvent: ClC(Cl)Cl
Solvent: CC#N
Product: COc1cc(OC)c(S(=O)(=O)O)cc1[N+](=O)[O-]

Procedure:
To a solution prepared by adding 90 g of 2,4-dimethoxybenzenesulfonic acid obtained in Step (1) above to 200 ml of chloroform, was added 225 ml of nitric acid (d=1.42) with stirring. The reaction mixture was stirred at 25° to 30° C. for 2 hours and 300 ml of acetonitrile was added thereto. The crystals thus-precipitated were collected by filtration and washed with 100 ml of acetonitrile.
Reaction SMILES: [OH:1][CH2:2][CH2:3][NH:4][NH2:5].[Cl:6][C:7]1[CH:12]=[CH:11][C:10]([S:13]([N:16]2[CH:21]3[CH2:22][CH2:23][CH2:24][CH:17]2[C:18](=[CH:26]O)[C:19](=O)[CH2:20]3)(=[O:15])=[O:14])=[CH:9][CH:8]=1>>[Cl:6][C:7]1[CH:8]=[CH:9][C:10]([S:13]([N:16]2[CH:21]3[CH2:22][CH2:23][CH2:24][CH:17]2[C:18]2[CH:26]=[N:5][N:4]([CH2:3][CH2:2][OH:1])[C:19]=2[CH2:20]3)(=[O:15])=[O:14])=[CH:11][CH:12]=1
Reactant: NNCCO
Reactant: O=C1CC2CCCC(C1=CO)N2S(=O)(=O)c1ccc(Cl)cc1
Product: O=S(=O)(c1ccc(Cl)cc1)N1C2CCCC1c1cnn(CCO)c1C2

Procedure:
Prepared as described in Example 5 using hydroxyethylhydrazine and 9-(4-chlorophenylsulfonyl)-2-(hydroxymethylene)-9-azabicyclo[3.3.1]nonan-3-one which was prepared as described in Example 34.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[S:9](Cl)(=[O:11])=[O:10])#[N:2].[CH2:13]([NH2:15])[CH3:14]>C1COCC1>[C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[S:9]([NH:15][CH2:13][CH3:14])(=[O:11])=[O:10])#[N:2]
Reactant: N#Cc1ccccc1S(=O)(=O)Cl
Reactant: CCN
Solvent: C1CCOC1
Product: CCNS(=O)(=O)c1ccccc1C#N
Reaction time: 0.5 h
Yield: 49.9 %

Procedure:
To 2-cyanobenzene-1-sulfonyl chloride (201 mg, 1.00 mmol) in THF (10 mL), a 2M THF solution of ethylamine (5.0 mL, 10.0 mmol) was added. After stirring for 30 min, the reaction was concentrated then purified via preparative HPLC eluting with MeOH/H2O/TFA to provide 2-cyano-N-ethylbenzenesulfonamide (105 mg). The product was dissolved in MeOH (8 mL), conc. HCl (70 mg) was added, and the whole was hydrogenated at 30 psi for 3 h. The reaction was filtered and dried (Na2SO4) to provide 201A (123 mg, 49%). LC-MS: 215.1 (M+H)+.
Reaction SMILES: [OH-].[Na+].[CH:3]1[CH:8]=[CH:7][C:6]([CH2:9][O:10][C:11]([CH2:13][CH:14]([NH2:18])[C:15]([OH:17])=[O:16])=[O:12])=[CH:5][CH:4]=1.[CH:19]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH:22]=[CH:21][C:20]=1[S:29](Cl)(=[O:31])=[O:30].Cl>O1CCOCC1>[CH:19]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH:22]=[CH:21][C:20]=1[S:29]([NH:18][C@@H:14]([C:15]([OH:17])=[O:16])[CH2:13][C:11]([O:10][CH2:9][C:6]1[CH:7]=[CH:8][CH:3]=[CH:4][CH:5]=1)=[O:12])(=[O:30])=[O:31]
Reactant: NC(CC(=O)OCc1ccccc1)C(=O)O
Reactant: O=S(=O)(Cl)c1ccc2ccccc2c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: O=C(C[C@@H](NS(=O)(=O)c1ccc2ccccc2c1)C(=O)O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 98.4 %

Procedure:
22.4 ml of 2N NaOH are added dropwise at 10° C. to a solution of 5 g of D-aspartic acid β-benzyl ester and 5.07 g of 2-naphthylsulphonyl chloride in 80 ml of dioxan cooled to IOOC. The reaction mixture is subsequently stirred at room temperature for 2 hours and then treated with 25 ml of 1N hydrochloric acid. After evaporation of the dioxan the residue is taken up in ethyl 30 acetate and washed with water. After drying and evaporation of the ethyl acetate phase there are obtained 9.1 g of 4-benzyl 1-hydrogen N-(2-naphthylsulfonyl)-D-aspartate, Rf=0.53 (ethyl acetate/glacial acetic acid 0.97:0.03).
Reaction SMILES: [OH:1][C:2]1[C:3]([CH3:18])=[C:4]([CH3:17])[C:5]2[O:9][C:8]([CH3:11])([CH3:10])[CH:7]([C:12]([OH:14])=[O:13])[C:6]=2[C:15]=1[CH3:16].[C:19](OC(=O)C)(=[O:21])[CH3:20].O.Cl>N1C=CC=CC=1>[C:19]([O:1][C:2]1[C:3]([CH3:18])=[C:4]([CH3:17])[C:5]2[O:9][C:8]([CH3:11])([CH3:10])[CH:7]([C:12]([OH:14])=[O:13])[C:6]=2[C:15]=1[CH3:16])(=[O:21])[CH3:20]
Reactant: Cc1c(C)c2c(c(C)c1O)C(C(=O)O)C(C)(C)O2
Reactant: CC(=O)OC(C)=O
Agent: Cl
Solvent: O
Solvent: c1ccncc1
Product: CC(=O)Oc1c(C)c(C)c2c(c1C)C(C(=O)O)C(C)(C)O2
Temperature: 25 °C
Reaction time: 24 h
Yield: 81 %

Procedure:
To a solution of 25.03 g (0.1M) of 2,3-dihydro-5-hydroxy-2,2,4,6,7-pentamethyl-1-benzofuran-3-carboxylic acid (described in Example 1) in 200 ml of pyridine is added 100 ml of acetic anhydride and the mixture is stirred at room temperature for 24 hours. Water and ice is added and the mixture is stirred at about 30° C. for 30 minutes. More ice and 450 ml of 6N hydrochloric acid is added and the resulting solid is collected, washed with water, and taken up in ethyl acetate. The solution is washed with 2N hydrochloric acid and water and is dried over anhydrous sodium sulfate. The residue obtained after filtration and evaporation of solvent is recrystallized from ethyl acetate to give 23.6 g (81%) of the title compound as racemate, m.p. 187°-8° C. Elemental analysis, UV, and 1H-NMR spectra confirm the structure.
Reaction SMILES: [CH2:1]([C:4]1[N:9]=[C:8]([CH3:10])[N:7]2[N:11]=[C:12]([SH:14])[N:13]=[C:6]2[C:5]=1[CH2:15][C:16]1[CH:21]=[CH:20][C:19]([N+:22]([O-:24])=[O:23])=[CH:18][CH:17]=1)[CH2:2][CH3:3].[CH3:25]I>C(Cl)(Cl)Cl.C(N(CC)CC)C>[CH2:1]([C:4]1[N:9]=[C:8]([CH3:10])[N:7]2[N:11]=[C:12]([S:14][CH3:25])[N:13]=[C:6]2[C:5]=1[CH2:15][C:16]1[CH:21]=[CH:20][C:19]([N+:22]([O-:24])=[O:23])=[CH:18][CH:17]=1)[CH2:2][CH3:3]
Reactant: CI
Reactant: CCCc1nc(C)n2nc(S)nc2c1Cc1ccc([N+](=O)[O-])cc1
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CCCc1nc(C)n2nc(SC)nc2c1Cc1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
5 g of 7-n-propyl-5-methyl-2-mercapto-8-(4-nitrobenzyl)-1,2,4-triazolo[1,5-c]pyrimidine, prepared in Example 37, are dissolved in 50 ml of chloroform and 2.2 ml of triethylamine. 1.5 ml of methyl iodide are added and the mixture is stirred at room temperature for 2 hours and then left overnight. The mixture is then washed with dilute sodium hydroxide solution and the organic phase is separated after settling has taken place, dried over magnesium sulphate and evaporated under vacuum to give a residue which crystallise in an ether/pentane mixture to yield 4 g of 7-n-propyl-5-methyl-2-methylmercapto-8-(4-nitrobenzyl)-1,2,4triazolo[1,5-c]pyrimidine in the form of crystals of melting point 130° C.
Reaction SMILES: [CH:1]1([N:4]2[C:9]3[N:10]=[C:11](S(C)=O)[N:12]=[CH:13][C:8]=3[CH:7]=[CH:6][C:5]2=[O:17])[CH2:3][CH2:2]1.[C:18]([O:22][C:23]([N:25]1[CH2:30][CH2:29][N:28]([C:31]2[CH:32]=[N:33][C:34]([NH2:37])=[CH:35][CH:36]=2)[CH2:27][CH2:26]1)=[O:24])([CH3:21])([CH3:20])[CH3:19]>C1(C)C=CC=CC=1>[C:18]([O:22][C:23]([N:25]1[CH2:30][CH2:29][N:28]([C:31]2[CH:32]=[N:33][C:34]([NH:37][C:11]3[N:12]=[CH:13][C:8]4[CH:7]=[CH:6][C:5](=[O:17])[N:4]([CH:1]5[CH2:3][CH2:2]5)[C:9]=4[N:10]=3)=[CH:35][CH:36]=2)[CH2:27][CH2:26]1)=[O:24])([CH3:21])([CH3:19])[CH3:20]
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(N)nc2)CC1
Reactant: CS(=O)c1ncc2ccc(=O)n(C3CC3)c2n1
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N1CCN(c2ccc(Nc3ncc4ccc(=O)n(C5CC5)c4n3)nc2)CC1
Temperature: 100 °C
Yield: 13.3 %

Procedure:
A mixture of 8-cyclopropyl-2-methylsulfinyl-8H-pyrido[2,3-d]pyrimidin-7-one (388 mg, 1.56 mmol) and 4-(6-amino-pyridin-3-yl)-piperazine-1-carboxylic acid tert-butyl ester (462 mg, 2.0 mmol) in toluene (5 mL) was heated at 100° C. for 18 hours. It was cooled to room temperature and the solid was collected by filtration and washed with toluene and dried to give 4-[6-(8-cyclopropyl-7-oxo-7,8-dihydro-pyrido[2,3-d]pyrimidin-2-ylamino)-pyridin-3-yl]-piperazine-1-carboxylic acid tert-butyl ester (96 mg, 13%). 1H NMR δ (400 MHz, DMSO) 9.97 (s, 1H), 8.67 (s, 1H), 8.39 (d, J=9.3 Hz, 1H), 8.0 (d, J=2.95 Hz, 1H), 7.71 (d, J=9.3 Hz, 1H), 6.28 (d, J=9.3 Hz, 1H), 3.42 (br, 4H), 3.05 (br, 4H0, 2.80 (m, 1H), 1.37 (s, 9H), 1.20 (d, J=6.1 Hz, 2H), 0.76 (br, 2H).
Reaction SMILES: [CH3:1]C1C=CC(S(OCC2CC3C=C(F)C=C(C4C=CC=CC=4F)C=3O2)(=O)=O)=CC=1.[N-]=[N+]=[N-].[Na+].[N:34]([CH2:37][CH:38]1[CH2:42][C:41]2[CH:43]=[C:44]([F:54])[CH:45]=[C:46]([C:47]3[CH:52]=[CH:51][CH:50]=[CH:49][C:48]=3F)[C:40]=2[O:39]1)=[N+]=[N-].[N-]=[N+]=[N-]>[Pd]>[F:54][C:44]1[CH:45]=[C:46]([C:47]2[CH:52]=[CH:51][CH:50]=[CH:49][C:48]=2[CH3:1])[C:40]2[O:39][CH:38]([CH2:37][NH2:34])[CH2:42][C:41]=2[CH:43]=1
Reactant: [N-]=[N+]=NCC1Cc2cc(F)cc(-c3ccccc3F)c2O1
Reactant: Cc1ccc(S(=O)(=O)OCC2Cc3cc(F)cc(-c4ccccc4F)c3O2)cc1
Agent: [Pd]
Agent: [N-]=[N+]=[N-]
Agent: [Na+]
Product: Cc1ccccc1-c1cc(F)cc2c1OC(CN)C2
Yield: 77 %

Procedure:
Treatment of (±)-[5-fluoro-7-(2-fluorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl 4-methylbenzenesulfonate (1.84 g, 4.42 mmol) with sodium azide (1.15 g, 17.67 mmol) generally according to the procedure described for Intermediate 98 afforded (±)-2-(azidomethyl)-5-fluoro-7-(2-fluorophenyl)-2,3-dihydro-1-benzofuran. Treatment of the azide with palladium on carbon (0.111 g, 10 wt. %) generally according to the procedure described for Example 1 provided 1.02 g (77%) of (±)-1-[5-fluoro-7-(2-methylphenyl)-2,3-dihydro-1-benzofuran-2-yl]methanamine as a white solid, hydrochloride salt. mp 240-247° C. (dec); Anal. calcd. for C15H13F2NOHCl: C, 60.51; H, 4.74; N, 4.7. Found: C, 60.33; H, 4.69; N, 4.4.
Reaction SMILES: C1[CH:5]2[CH:6]3[CH:10]=[CH:9][CH:8]([CH:4]2[CH:3]=C1)[CH2:7]3.C([OH:14])C=C>>[CH:8]12[CH2:7][CH:6]([CH:10]=[CH:9]1)[CH2:5][CH:4]2[CH2:3][OH:14]
Reactant: C1=CC2C3C=CC(C3)C2C1
Reactant: C=CCO
Product: OCC1CC2C=CC1C2
Temperature: 190 °C
Reaction time: 3.5 h
Yield: 67 %

Procedure:
132 g (1 mol) of dicyclopentadiene and 116.2 g (2 mol) of allyl alcohol were placed into a 300 ml high-pressure reactor and stirred at 190° C. for 3 to 4 hours. The resulting solution was distilled at 80° C. under vacuum to give 5-norbornene-2-methanol. (Yield: 67%, 166 g)
Reaction SMILES: Cl[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([O:9][CH3:10])=[CH:5][CH:4]=1.[N-:11]=[N+:12]=[N-:13].[Na+]>C(#N)C>[N:11]([CH2:2][C:3]1[CH:8]=[CH:7][C:6]([O:9][CH3:10])=[CH:5][CH:4]=1)=[N+:12]=[N-:13]
Reactant: COc1ccc(CCl)cc1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CC#N
Product: COc1ccc(CN=[N+]=[N-])cc1

Procedure:
A mixture of 1-(chloromethyl)-4-methoxybenzene (20.0 g, 128 mmol) and sodium azide (12.5 g, 192 mmol) in acetonitrile (255 mL) was refluxed for 5 h under N2 atmosphere. The mixture was filtered and concentrated in vacuo. The residue was diluted in DCM, washed with H2O and brine, dried over Na2SO4 and concentrated in vacuo to afford crude 1-(azidomethyl)-4-methoxybenzene. The residue was used for the next reaction without further purification.
Reaction SMILES: [NH2:1][C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][CH:3]=1.CS(O[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)(=O)=O>CN(C)P(N(C)C)(N(C)C)=O>[C:24]1([CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][NH:1][C:2]2[CH:3]=[CH:4][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:11][CH:12]=2)[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: CS(=O)(=O)OCCCCCCc1ccccc1
Reactant: CCOC(=O)c1ccc(N)cc1
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: CCOC(=O)c1ccc(NCCCCCCc2ccccc2)cc1

Procedure:
A solution of 34.9 g. of ethyl p-aminobenzoate, 26.9 g. of 6-phenylhexanol O-methanesulfonate (prepared as described in Example 47) and 200 ml. of hexamethylphosphoramide is heated at 110° C. in an oil bath for 20 hours. The mixture is cooled, diluted with 100 ml. of water and filtered. The solid is washed with 60 ml. of ethanol-water (1:1) to give crude ethyl 4-(6-phenylhexylamino)benzoate. Purification gives the product as crystals, m.p. 69.5°-72.5° C.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[S:10][C:11]1[CH:17]=[CH:16][C:15](=O)[C:14]([O:19]C)=[CH:13][CH:12]=1)([OH:3])=[O:2].[NH3:21]>CO>[NH2:21][C:15]1[C:14](=[O:19])[CH:13]=[CH:12][C:11]([S:10][C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[C:1]([OH:3])=[O:2])=[CH:17][CH:16]=1
Reactant: COc1ccc(Sc2ccccc2C(=O)O)ccc1=O
Reactant: N
Solvent: CO
Product: Nc1ccc(Sc2ccccc2C(=O)O)ccc1=O
Temperature: 80 °C

Procedure:
A solution of 5-[(2-carboxyphenyl)thio]-2-methoxy-2,4,6-cycloheptatrien-1-one (1.0 g, prepared from 5-chloro-2-methoxy-2,4,6-cycloheptatrien-1-one and 2-mercaptobenzoic acid) in methanol (30 ml) at -25° C. is saturated with ammonia gas. The solution is heated in a pressure bottle at 80° C. for 8 hours and cooled to -70° C. The bottle is opened and the solvent is evaporated to give 2-amino-5-[(2-carboxyphenyl)thio]-2,4,6-cycloheptatrien-1-one.
Reaction SMILES: [OH:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([NH:8][C:9]2[CH:17]=[C:16]([N:18]3[C:26]4[CH2:25][C:24]([CH3:28])([CH3:27])[CH2:23][C:22](=[O:29])[C:21]=4[C:20]([CH3:30])=[CH:19]3)[CH:15]=[CH:14][C:10]=2[C:11]([NH2:13])=[O:12])[CH2:4][CH2:3]1.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>C(Cl)Cl>[O:1]=[C:2]1[CH2:3][CH2:4][CH:5]([NH:8][C:9]2[CH:17]=[C:16]([N:18]3[C:26]4[CH2:25][C:24]([CH3:27])([CH3:28])[CH2:23][C:22](=[O:29])[C:21]=4[C:20]([CH3:30])=[CH:19]3)[CH:15]=[CH:14][C:10]=2[C:11]([NH2:13])=[O:12])[CH2:6][CH2:7]1
Reactant: Cc1cn(-c2ccc(C(N)=O)c(N[C@H]3CC[C@H](O)CC3)c2)c2c1C(=O)CC(C)(C)C2
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: ClCCl
Product: Cc1cn(-c2ccc(C(N)=O)c(NC3CCC(=O)CC3)c2)c2c1C(=O)CC(C)(C)C2
Temperature: 25 °C
Reaction time: 1 h

Procedure:
The title compound of Example 3 [2-(4-Hydroxycyclohexylamino)-4-(3,6,6-trimethyl-4-oxo-4,5,6,7-tetrahydroindol-1-yl)-benzamide] (150 mg, 0.366 mmol) and Dess-Martin periodinane (0.366 mmol) were dissolved in anhydrous CH2Cl2 and stirred at room temperature for one hour. The reaction mixture was concentrated and the title compound was isolated as a white solid (36.2 mg, 24% yield) after purification by column chromatography eluting with EtOAc-MeOH. LCMS m/z: (M+H)=408.3.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([O:15][CH2:16][C:17]#[CH:18])=[CH:11][CH:10]=2)[C:5]([F:19])=[CH:4][N:3]=1.[NH2:20][S:21]([C:24]1[CH:25]=[C:26]([CH:28]=[CH:29][C:30]=1[CH3:31])[NH2:27])(=[O:23])=[O:22].FC(F)(F)C(O)=O.CC(O)C>Cl>[NH2:20][S:21]([C:24]1[CH:25]=[C:26]([NH:27][C:2]2[N:7]=[C:6]([NH:8][C:9]3[CH:14]=[CH:13][C:12]([O:15][CH2:16][C:17]#[CH:18])=[CH:11][CH:10]=3)[C:5]([F:19])=[CH:4][N:3]=2)[CH:28]=[CH:29][C:30]=1[CH3:31])(=[O:22])=[O:23]
Reactant: Cc1ccc(N)cc1S(N)(=O)=O
Reactant: C#CCOc1ccc(Nc2nc(Cl)ncc2F)cc1
Agent: Cl
Solvent: CC(C)O
Solvent: O=C(O)C(F)(F)F
Product: C#CCOc1ccc(Nc2nc(Nc3ccc(C)c(S(N)(=O)=O)c3)ncc2F)cc1
Temperature: 100 °C

Procedure:
2-Chloro-5-fluoro-N4-[4-(prop-2-ynyloxy)phenyl]-4-pyrimidineamine (0.514 g, 1.85 mmol), 3-(aminosulfonyl)-4-methylaniline (0.689 g, 3.70 mmol), and trifluoroacetic acid (0.186 mL, 2.41 mmol) were combined with iPrOH (6.0 mL) in a sealed vial and heated at 100° C. for 3 h. The reaction mixture was cooled to room temperature and diluted with 1N HCl (80 mL). N2-(3-Aminosulfonyl-4-methylphenyl)-5-fluoro-N4-[4-(prop-2-ynyloxy)phenyl]-2,4-pyrimidinediamine (VI-53) was isolated as a white solid by suction filtration (0.703 g). 1H NMR (DMSO-d6): δ 10.08 (bs, 2H), 8.19 (d, J=4.5 Hz, 1H), 7.89 (s, 1H), 7.74 (dd, J=2.4 and 8.4 Hz, 1H), 7.58 (d, J=8.7 Hz, 2H), 7.32 (bs, 2H), 7.23 (d, J=8.4 Hz, 1H), 6.97 (d, J=8.4 Hz, 2H), 4.79 (d, J=2.1 Hz, 2H), 3.59-3.55 (m, 1H), 2.53 (s, 3H); LCMS: purity: 97%; MS (m/e): 428 (MH+).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[Br:7][CH2:8][CH2:9][CH2:10]Br.[OH:12][C:13]1[CH:22]=[CH:21][C:20]2[CH2:19][CH2:18][CH2:17][CH2:16][C:15]=2[C:14]=1[N+:23]([O-:25])=[O:24]>CN(C)C=O>[N+:23]([C:14]1[C:15]2[CH2:16][CH2:17][CH2:18][CH2:19][C:20]=2[CH:21]=[CH:22][C:13]=1[O:12][CH2:10][CH2:9][CH2:8][Br:7])([O-:25])=[O:24]
Reactant: BrCCCBr
Reactant: O=[N+]([O-])c1c(O)ccc2c1CCCC2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1c(OCCCBr)ccc2c1CCCC2
Temperature: 70 °C
Reaction time: 4 h
Yield: 67.9 %

Procedure:
N,N-dimethylformamide (180 ml), potassium carbonate (37.8 g, 0.273 mol), and 1,3-dibromopropane (93 ml, 0.916 mol) were added to 2-hydroxy-5,6,7,8-tetrahydro-1-nitronaphthalene (17.6 g, 0.091 mol) and the mixture was stirred at 70° C. for 4 hours. The precipitated salts were removed by filtration, and then the solvent was evaporated and the residue was extracted with ethyl acetate. The extract was washed with saturated brine and dried over anhydrous magnesium sulfate, and then the solvent was evaporated. The residue was purified by silica gel chromatography (Wako Gell C-300: 500 g, eluent: ethyl acetate/hexane=1/20) to give 5,6,7,8-tetrahydro-1-nitro-2-(3-bromopropoxy)naphthalene (19.4 g).
Reaction SMILES: C([Li])CCC.C(NC(C)C)(C)C.[F:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([F:20])[C:15]=1[C:21]1[N:22]=[N:23][C:24]([CH3:27])=[CH:25][N:26]=1.[Cl:28][C:29]1[CH:36]=[CH:35][C:32]([CH:33]=[O:34])=[CH:31][CH:30]=1>O1CCCC1>[Cl:28][C:29]1[CH:36]=[CH:35][C:32]([CH:33]([OH:34])[CH2:27][C:24]2[N:23]=[N:22][C:21]([C:15]3[C:14]([F:13])=[CH:19][CH:18]=[CH:17][C:16]=3[F:20])=[N:26][CH:25]=2)=[CH:31][CH:30]=1
Reactant: Cc1cnc(-c2c(F)cccc2F)nn1
Reactant: O=Cc1ccc(Cl)cc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: OC(Cc1cnc(-c2c(F)cccc2F)nn1)c1ccc(Cl)cc1
Temperature: -50 °C
Reaction time: 2 h

Procedure:
At −20° C., 1.5 ml of n-butyllithium (1.6M in hexane) are added to 202 mg of diisopropylamine in 6 ml of tetrahydrofuran. After 15 min. the reaction mixture is cooled to −50° C. and 0.414 g of 3-(2,6-difluorophenyl)-6-methyl-[1,2,4]triazine in 2 ml of tetrahydrofuran is added dropwise. After 20 min. the mixture is cooled to −70° C., 0.281 g of 4-chlorobenzaldehyde in 3 ml of tetrahydrofuran is added dropwise and the mixture is then stirred at −70° C. for 2 h. The reaction mixture is then poured into ice-water and extracted with ethyl acetate; the organic phase is concentrated and the residue is purified by means of flash chromatography. In this way 1-(4-chlorophenyl)-2-[3-(2,6-difluorophenyl)-[1,2,4]triazin-6-yl]-ethanol is obtained in the form of a light-brown resin. After recrystallisation from diethyl ether/hexane, 1-(4-chlorophenyl)-2-[3-(2,6-difluorophenyl)-[1,2,4]triazin-6-yl]-ethanol is obtained in the form of beige crystals having a melting point of 98-102° C.
Reaction SMILES: S(=O)(=O)(O)O.[CH3:6][C:7]1[NH:12][C:11](=[O:13])[C:10]([C:14]#[N:15])=[CH:9][C:8]=1[C:16]1[N:17]=[C:18]([CH3:21])[S:19][CH:20]=1.[OH-:22].[NH4+]>>[CH3:6][C:7]1[NH:12][C:11](=[O:13])[C:10]([C:14]([NH2:15])=[O:22])=[CH:9][C:8]=1[C:16]1[N:17]=[C:18]([CH3:21])[S:19][CH:20]=1
Reactant: Cc1nc(-c2cc(C#N)c(=O)[nH]c2C)cs1
Reactant: [OH-]
Agent: O=S(=O)(O)O
Agent: [NH4+]
Product: Cc1nc(-c2cc(C(N)=O)c(=O)[nH]c2C)cs1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
C-3. 1,2-Dihydro-6-methyl-5-(2-methyl-4-thiazolyl)-2-oxo-3-pyridinecarboxamide--To an ice cold stirred 150 ml portion of concentrated sulfuric acid was added over a 5 minute period 64.2 g of finely powdered 1,2-dihydro-6-methyl-5-(2-methyl-4-thiazolyl)-2-oxo-3-pyridinecarbonitrile and the resulting mixture was stirred in an ice bath for 30 minutes and then allowed to stand at room temperature overnight. The reaction mixture was poured onto ice (800 ml beaker half filled) and then neutralized by adding aqueous ammonium hydroxide solution. The tan solid that separated was collected, washed with water, recrystallized from dimethylformamide and dried in an oven at 90° C. for 2 days to produce 59.2 g of 1,2-dihydro-6-methyl-5-(2-methyl-4-thiazolyl)-2-oxo-3-pyridinecarboxamide, m.p. >300° C. with decomposition.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][CH:11](/[C:14](=[N:19]\[S@@:20]([C:22]([CH3:25])([CH3:24])[CH3:23])=[O:21])/[CH2:15][CH2:16][CH:17]=[CH2:18])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Al]([C:31]#[N:32])(CC)CC.CC(O)C>C1COCC1>[CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([C@@:14]([NH:19][S@@:20]([C:22]([CH3:25])([CH3:24])[CH3:23])=[O:21])([C:31]#[N:32])[CH2:15][CH2:16][CH:17]=[CH2:18])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C=CCC/C(=N/[S@](=O)C(C)(C)C)C1CCN(Cc2ccccc2)CC1
Reactant: CC[Al](C#N)CC
Solvent: C1CCOC1
Solvent: CC(C)O
Product: C=CCC[C@@](C#N)(N[S@](=O)C(C)(C)C)C1CCN(Cc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 67.6 %

Procedure:
A solution of (R,Z)—N-(1-(1-benzylpiperidin-4-yl)pent-4-enylidene)-2-methylpropane-2-sulfinamide (2.74 g, 7.6 mmol) in THF (130 mL, 0.06 M) was cooled to −78° C. Separately, a 1 M solution of Et2AlCN (11.4 mmol, 11.4 mL) was dissolved in THF (20 mL) and cooled to −78° C. iPrOH (0.64 mL, 8.26 mmol) was added dropwise and the solution was warmed to RT over 20 min, then added dropwise to the sulfinamide solution. The reaction was allowed to warm gradually to RT and stirred overnight. The reaction was quenched with saturated aqueous ammonium chloride (50 mL) and filtered through Celite. The Celite pad was washed with ethyl acetate (3×) and the combined organics were washed saturated aqueous sodium chloride, dried over MgSO4, and concentrated in vacuo. The residue was chromatographed on silica gel (1-9% methanol in dichloromethane and again with 2-5% methanol in ethyl acetate) to afford the desired product (1.99 g, 67%) along with its undesired diastereoisomer (0.46 g, 15%). Rf 0.26 (10% MeOH/CH2Cl2). 1H NMR (CDCl3, 300 MHz) δ 7.31-7.25 (m, 5H), 5.83-5.78 (m, 1H), 5.13-5.03 (m, 2H), 3.51 (d, J=1.5 Hz, 2H), 3.41 (s, 1H), 3.00 (d, J=11.0 Hz, 2H), 2.34-2.29 (m, 2H), 2.05-1.83 (m, 6H), 1.60-1.44 (m, 3H), 1.25 (s, 9H). ESI MS found for C22H33N3OS m/z [388.4 (M+1)].
Reaction SMILES: [Cl:1][C:2]1[CH:6]=[CH:5][S:4][C:3]=1[C:7]1[N:8]=[C:9]([NH2:12])[S:10][CH:11]=1.[Br:13][C:14]1[C:19]([F:20])=[CH:18][C:17]([S:21](Cl)(=[O:23])=[O:22])=[C:16]([F:25])[CH:15]=1>>[Br:13][C:14]1[C:19]([F:20])=[CH:18][C:17]([S:21]([NH:12][C:9]2[S:10][CH:11]=[C:7]([C:3]3[S:4][CH:5]=[CH:6][C:2]=3[Cl:1])[N:8]=2)(=[O:22])=[O:23])=[C:16]([F:25])[CH:15]=1
Reactant: O=S(=O)(Cl)c1cc(F)c(Br)cc1F
Reactant: Nc1nc(-c2sccc2Cl)cs1
Product: O=S(=O)(Nc1nc(-c2sccc2Cl)cs1)c1cc(F)c(Br)cc1F

Procedure:
The title compound was prepared 4-(3-chloro-2-thienyl)-1,3-thiazol-2-amine (59 mg) and 4-bromo-2,5-difluorobenzenesulfonyl chloride (79 mg) as described in the synthetic METHOD B to give a white solid (22.3 mg) with purity >90%: MS (pos) m/z 471.2, 473.2.
Reaction SMILES: Cl.C([SiH2][O:7][C:8](C)(C)[C:9]1[CH:14]=[CH:13][C:12]([NH:15][C:16]([C:18]2[CH:19]=[N:20][N:21]3[CH:26]=[CH:25][CH:24]=[N:23][C:22]=23)=[O:17])=[C:11]([O:27][CH3:28])[CH:10]=1)(C)(C)C.O.[OH-].[Na+]>ClCCl>[OH:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([NH:15][C:16]([C:18]2[CH:19]=[N:20][N:21]3[CH:26]=[CH:25][CH:24]=[N:23][C:22]=23)=[O:17])=[C:11]([O:27][CH3:28])[CH:10]=1
Reactant: COc1cc(C(C)(C)O[SiH2]C(C)(C)C)ccc1NC(=O)c1cnn2cccnc12
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: ClCCl
Product: COc1cc(CO)ccc1NC(=O)c1cnn2cccnc12
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of hydrochloric acid (1 M in Et2O, 3 mL) was added to a solution of pyrazolo[1,5-a]pyrimidine-3-carboxylic acid [4-(tert-butyl-dimethyl-silanyloxymethyl)-2-methoxy-phenyl]-amide (150 mg, 0.364 mmol) in dichloromethane (20 mL) and the resulting mixture was stirred at room temperature for 2 hours. Ice and water were then added and the pH of the mixture was neutralized by addition of an aqueous solution of sodium hydroxide (5%). The resulting mixture was extracted 3 times with dichloromethane. The combined organic extracts were washed with brine, dried over anhydrous sodium sulfate, filtered and evaporated under reduced pressure. The crude residue was purified by flash chromatography and by preparative TLC to give a yellow solid which was washed with water, methanol, dichloromethane, hexane and diethyl ether to give after drying pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (4-hydroxymethyl-2-methoxy-phenyl)-amide as a light yellow solid. MS=299 [M+H]+.