Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]2[CH:9]([NH:12][C:13]3[O:14][CH2:15][C:16]4[CH:22]=[C:21]([NH2:23])[CH:20]=[CH:19][C:17]=4[N:18]=3)[CH2:10][O:11][C:7]=2[CH:6]=[CH:5][CH:4]=1.[C:24]1([S:30](Cl)(=[O:32])=[O:31])[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>>[CH3:1][O:2][C:3]1[C:8]2[CH:9]([NH:12][C:13]3[O:14][CH2:15][C:16]4[CH:22]=[C:21]([NH:23][S:30]([C:24]5[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=5)(=[O:32])=[O:31])[CH:20]=[CH:19][C:17]=4[N:18]=3)[CH2:10][O:11][C:7]=2[CH:6]=[CH:5][CH:4]=1
Reactant: COc1cccc2c1C(NC1=Nc3ccc(N)cc3CO1)CO2
Reactant: O=S(=O)(Cl)c1ccccc1
Product: COc1cccc2c1C(NC1=Nc3ccc(NS(=O)(=O)c4ccccc4)cc3CO1)CO2
Yield: 55.1 %

Procedure:
Prepared from rac-N2-(4-methoxy-2,3-dihydro-benzofuran-3-yl)-4H-benzo[d][1,3]oxazine-2,6-diamine (Example 6) (150 mg, 0.482 mmol) and benzenesulfonyl chloride (94 mg, 0.53 mmol) according to the procedure described for Example 27. Obtained the title compound as a white solid (120 mg, 55%), MS (ISP) m/e=452.3 [(M+H)+].
Reaction SMILES: C[O:2][C:3]1[CH:12]=[C:11]([NH:13][C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][N:15]=2)[C:10]2[C:5](=[N:6][C:7]([C:24]3[C:29]([C:30]([F:33])([F:32])[F:31])=[CH:28][CH:27]=[CH:26][N:25]=3)=[CH:8][CH:9]=2)[N:4]=1.Cl>CCOCC.C(O)(C)C>[F:33][C:30]([F:31])([F:32])[C:29]1[C:24]([C:7]2[N:6]=[C:5]3[C:10]([C:11]([NH:13][C:14]4[CH:19]=[CH:18][C:17]([C:20]([F:21])([F:22])[F:23])=[CH:16][N:15]=4)=[CH:12][C:3]([OH:2])=[N:4]3)=[CH:9][CH:8]=2)=[N:25][CH:26]=[CH:27][CH:28]=1
Reactant: COc1cc(Nc2ccc(C(F)(F)F)cn2)c2ccc(-c3ncccc3C(F)(F)F)nc2n1
Agent: Cl
Solvent: CC(C)O
Solvent: CCOCC
Product: Oc1cc(Nc2ccc(C(F)(F)F)cn2)c2ccc(-c3ncccc3C(F)(F)F)nc2n1

Procedure:
Heat 2-methoxy-7-[3-(trifluoromethyl)pyridin-2-yl]-N-[5-(trifluoromethyl)pyridin-2-yl]-[1,8]naphthyridin-4-amine (128 mg), 1M hydrochloric acid in ether (0.25 mL) and isopropanol at 80° C. overnight. Cool and collect the precipitate by filtration to give the hydrochloride salt of the title compound.
Reaction SMILES: [Br:1][C:2]1[C:3]([CH3:11])=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([NH2:7])=O.C1COCC1.S(C)C.Cl>CO>[Br:1][C:2]1[C:3]([CH3:11])=[C:4]([CH2:5][NH2:7])[CH:8]=[CH:9][CH:10]=1
Reactant: Cc1c(Br)cccc1C(N)=O
Agent: Cl
Solvent: CO
Solvent: C1CCOC1
Solvent: CSC
Product: Cc1c(Br)cccc1CN
Temperature: 25 °C
Reaction time: 1 h
Yield: 84.1 %

Procedure:
3-Bromo-2-methylbenzamide (1.4 g) was dissolved with dry THF (15 mL) under nitrogen, then Me2S.BH3 (94%, 1.34 mL) was added slowly. After being stirred at room temperature for 1 h, the mixture was heated to 50° C. overnight. When the 3-bromo-2-methylbenzamide disappeared, methanol was added dropwise until there no more air bubble formed. 10 min later, 10% HCl was added dropwise, stirred for 1 h, and then solvent was removed. The white residue was recrystallized with iPrOH to obtain 1.1 g of the product. Yield: 35%. 1H NMR (400 MHz, DMSO-d6): δ 2.42 (s, 3 H), 4.09 (s, 2 H), 7.20 (t, J=7.8 Hz, 1 H), 7.44 (d, J1=8.0 Hz, 1 H), 7.63 (d, J1=7.6 Hz, 1 H), 8.49 (br, 3 H); 13C NMR (100 MHz, DMSO-d6): δ 18.8, 19.0, 46.1, 125.2, 127.4, 127.5, 129.0, 129.1, 132.1, 132.5, 134.7, 135.9, 136.1, 136.5; HPLC: retention time: 4.696 min; purity: 96.0%.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[C:4](S(C)(=O)=O)[C:5]2[N:10]=[C:9]([CH2:11][CH2:12][C:13]3[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=3)[S:8][C:6]=2[N:7]=1.C(N(C(C)C)CC)(C)C.Cl.[C:34]([CH:42]1[CH2:47][CH2:46][NH:45][CH2:44][CH2:43]1)(=[O:41])[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1>C(#N)C>[NH2:1][C:2]1[N:3]=[C:4]([N:45]2[CH2:46][CH2:47][CH:42]([C:34](=[O:41])[C:35]3[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=3)[CH2:43][CH2:44]2)[C:5]2[N:10]=[C:9]([CH2:11][CH2:12][C:13]3[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=3)[S:8][C:6]=2[N:7]=1
Reactant: CS(=O)(=O)c1nc(N)nc2sc(CCc3ccc(F)cc3)nc12
Reactant: O=C(c1ccccc1)C1CCNCC1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: Nc1nc(N2CCC(C(=O)c3ccccc3)CC2)c2nc(CCc3ccc(F)cc3)sc2n1
Temperature: 25 °C
Reaction time: 16 h
Yield: 91.3 %

Procedure:
To a solution of 5-amino-2-[2-(4-fluorophenyl)ethyl]-7-methanesulfonyl-thiazolo[5,4-d]pyrimidine (50 mg, 0.14 mmol) in acetonitrile (5 ml) was added diisopropylethylamine (0.45 mmol, 74 μL) and 4-benzoylpiperidine hydrogen chloride (0.15 mmol). The reaction mixture was stirred at room temperature for 16 hours whereupon the solvent was removed in vacuo. The resulting residue was purified by flash chromatography on silica, the mobile phase being a mixture of methanol and dichloromethane (in a ratio gradually ranging from 100% CH2Cl2 to 1% CH3OH in CH2Cl2), yielding the pure title compound (59 mg) which was characterized by its mass spectrum: MS m/z (%): 462 ([M+H]+, 100).
Reaction SMILES: [C:1](#[N:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:9][C:10]1[CH:16]=[CH:15][C:13]([NH2:14])=[CH:12][CH:11]=1>>[CH3:9][C:10]1[CH:16]=[CH:15][C:13]([NH:14][C:1]([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[NH:8])=[CH:12][CH:11]=1
Reactant: N#Cc1ccccc1
Reactant: Cc1ccc(N)cc1
Product: Cc1ccc(NC(=N)c2ccccc2)cc1
Yield: 55 %

Procedure:
The title compound was prepared from benzonitrile (0.96 g, 9 mmol) and 4-methylaniline (1 g, 9 mmol) by following the procedure described in preparation 10 (1.08 g, yield 55%, purity 98.42% by HPLC). 1H-NMR (CDCl3):δ 2.33 (s, 3H), 5 (bs, 2H, D2O exchangeable), 6.89-6.91 (d, 2H), 7.15-7.17 (d, 2H), 7.44-7.46 (m, 3H), 8 (bs, 2H). MS m/z:211.2 (M+).
Reaction SMILES: C[Al](C)C.[CH:5]1([NH2:8])[CH2:7][CH2:6]1.C[O:10][C:11](=O)[C:12]1[CH:17]=[CH:16][C:15]([O:18][CH2:19][C:20]2[C:21]([C:27]3[CH:32]=[CH:31][C:30]([F:33])=[C:29]([F:34])[CH:28]=3)=[N:22][O:23][C:24]=2[CH2:25][OH:26])=[N:14][CH:13]=1>O1CCOCC1>[CH:5]1([NH:8][C:11](=[O:10])[C:12]2[CH:17]=[CH:16][C:15]([O:18][CH2:19][C:20]3[C:21]([C:27]4[CH:32]=[CH:31][C:30]([F:33])=[C:29]([F:34])[CH:28]=4)=[N:22][O:23][C:24]=3[CH2:25][OH:26])=[N:14][CH:13]=2)[CH2:7][CH2:6]1
Reactant: COC(=O)c1ccc(OCc2c(-c3ccc(F)c(F)c3)noc2CO)nc1
Reactant: NC1CC1
Agent: C[Al](C)C
Solvent: C1COCCO1
Product: O=C(NC1CC1)c1ccc(OCc2c(-c3ccc(F)c(F)c3)noc2CO)nc1
Temperature: 50 °C
Reaction time: 1 h
Yield: 24.9 %

Procedure:
Trimethylaluminium solution (2 M in toluene, 0.8 mL, 1.60 mmol) was added to a solution of cyclopropylamine (62.0 mg, 1.06 mmol) in dioxane (5 mL). The mixture was stirred for 1 h at 50° C. Then a solution of 6-[3-(3,4-difluoro-phenyl)-5-hydroxymethyl-isoxazol-4-ylmethoxy]-nicotinic acid methyl ester (100 mg, 0.27 mmol) in dioxane (5 mL) was added. The reaction mixture was stirred overnight at 85° C. The dioxane was removed by distillation. The remaining material was purified by chromatography (silica, ethyl acetate:heptane=8:2 to 1:0) to afford the title compound (27 mg, 25%) as a colourless oil. MS: m/e=402.3 [M+H]+.
Reaction SMILES: [OH:1][C:2]1[C:3]([C:14](=[O:16])[CH3:15])=[CH:4][C:5]2[CH2:6][CH2:7][CH2:8][C:9]([CH3:13])([CH3:12])[C:10]=2[CH:11]=1.[Br:17]N1C(=O)CCC1=O>CN(C)C=O.O>[Br:17][C:11]1[C:10]2[C:9]([CH3:12])([CH3:13])[CH2:8][CH2:7][CH2:6][C:5]=2[CH:4]=[C:3]([C:14](=[O:16])[CH3:15])[C:2]=1[OH:1]
Reactant: CC(=O)c1cc2c(cc1O)C(C)(C)CCC2
Reactant: O=C1CCC(=O)N1Br
Solvent: O
Solvent: CN(C)C=O
Product: CC(=O)c1cc2c(c(Br)c1O)C(C)(C)CCC2
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 1-(3-hydroxy-5,5-dimethyl-5,6,7,8-tetrahydro-naphthalen-2-yl)-ethanone (Compound A-88, 13.3 g, 61 mmol) in N,N-dimethylformamide (120 mL) was added N-bromosuccinimide (10.9 mg, 61 mmol). The mixture was stirred at room temperature for 16 h. The mixture was then diluted with water and extracted with diethyl ether. The combined ethereal layers were washed with water, brine, dried (Na2SO4), filtered and concentrated in vacuo. Recrystallization from diethyl ether and flash column chromatography (silica gel, 5% ethyl acetate in hexane) afforded the title compound as a yellow solid.
Reaction SMILES: [CH:1]1([NH:7][C:8]2[N:9]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[N:10]=[C:11]3[C:16]=2[CH:15]=[CH:14][CH:13]=[CH:12]3)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:23][O:24][C:25](=[O:36])[C:26]1[CH:31]=[CH:30][C:29]([N:32]=[C:33]=[O:34])=[C:28]([Cl:35])[CH:27]=1>C1(C)C=CC=CC=1>[CH3:23][O:24][C:25](=[O:36])[C:26]1[CH:31]=[CH:30][C:29]([NH:32][C:33]([N:7]([CH:1]2[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)[C:8]2[N:9]([C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)[N:10]=[C:11]3[C:16]=2[CH:15]=[CH:14][CH:13]=[CH:12]3)=[O:34])=[C:28]([Cl:35])[CH:27]=1
Reactant: COC(=O)c1ccc(N=C=O)c(Cl)c1
Reactant: c1ccc(-n2nc3ccccc3c2NC2CCCCC2)cc1
Solvent: Cc1ccccc1
Product: COC(=O)c1ccc(NC(=O)N(c2c3ccccc3nn2-c2ccccc2)C2CCCCC2)c(Cl)c1

Procedure:
In analogy to the procedure described in example 1.2, cyclohexyl-(2-phenyl-2H-indazol-3-yl)-amine (example 1.1) was reacted with 3-chloro-4-isocyanato-benzoic acid methyl ester (example 9.1) in toluene for 4 days under reflux conditions to give the title compound as white solid. MS: m/e=503.0 [M+H+].
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:8]2[O:12][C:11]([C:13]([O:15]C)=[O:14])=[CH:10][CH:9]=2)[CH:5]=[CH:6][CH:7]=1.[OH-].[Na+]>C(O)C>[OH:1][C:2]1[CH:3]=[C:4]([C:8]2[O:12][C:11]([C:13]([OH:15])=[O:14])=[CH:10][CH:9]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)c1ccc(-c2cccc(O)c2)o1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)c1ccc(-c2cccc(O)c2)o1
Yield: 37.4 %

Procedure:
A solution of methyl 5-(3-hydroxyphenyl)furan-2-carboxylate (500 mg) in ethanol (11 mL) was treated with aqueous 3 mol/L sodium hydroxide (3.8 mL) at room temperature and refluxed for three hours. The reaction was brought to room temperature and concentrated. The residue was dissolved in water and brought to pH 2 via the addition of 1 N hydrochloric acid. The precipitated beige solids were collected by filtration to obtain the title compound (175 mg) having the following physical data.
Reaction SMILES: [CH2:1]([C:3]1[N:4]=[C:5]2[C:10]([CH3:11])=[CH:9][N:8](CC3C=CC(C4C=CC=CC=4C4N(C(C5C=CC=CC=5)(C5C=CC=CC=5)C5C=CC=CC=5)N=NN=4)=CC=3)[N:6]2[N:7]=1)[CH3:2].[CH2:49]([C:51]1[N:52]([CH2:60][C:61]2[CH:66]=[CH:65][C:64]([C:67]3[CH:72]=[CH:71][CH:70]=[CH:69][C:68]=3[C:73]3[N:77]([C:78]([C:91]4[CH:96]=[CH:95][CH:94]=[CH:93][CH:92]=4)([C:85]4[CH:90]=[CH:89][CH:88]=[CH:87][CH:86]=4)[C:79]4[CH:84]=[CH:83][CH:82]=[CH:81][CH:80]=4)[N:76]=[N:75][N:74]=3)=[CH:63][CH:62]=2)[C:53]2[N:54]([N:56]=[CH:57][C:58]=2[CH3:59])[N:55]=1)[CH3:50]>>[CH2:49]([C:51]1[N:52]([CH2:60][C:61]2[CH:62]=[CH:63][C:64]([C:67]3[CH:72]=[CH:71][CH:70]=[CH:69][C:68]=3[C:73]3[N:77]([C:78]([C:79]4[CH:84]=[CH:83][CH:82]=[CH:81][CH:80]=4)([C:91]4[CH:92]=[CH:93][CH:94]=[CH:95][CH:96]=4)[C:85]4[CH:86]=[CH:87][CH:88]=[CH:89][CH:90]=4)[N:76]=[N:75][N:74]=3)=[CH:65][CH:66]=2)[C:53]2[N:54]([N:56]=[CH:57][C:58]=2[CH3:59])[N:55]=1)[CH3:50].[CH2:1]([C:3]1[NH:4][C:5]2[N:6]([N:8]=[CH:9][C:10]=2[CH3:11])[N:7]=1)[CH3:2]
Reactant: CCc1nc2c(C)cn(Cc3ccc(-c4ccccc4-c4nnnn4C(c4ccccc4)(c4ccccc4)c4ccccc4)cc3)n2n1
Agent: CCc1nn2ncc(C)c2n1Cc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Product: CCc1nn2ncc(C)c2[nH]1

Procedure:
In the same manner as described in Example 38, 1.5 g of 2-ethyl-7-methyl-5-[[2'-(N-triphenylmethyl-tetrazol-5-yl)biphenyl-4-yl]methyl]-5H-pyrazolo[1,5-b][1,2,4]triazole (compound 44a) and 330 mg of 2-ethyl-7-methyl-1-[[2'-(N-triphenylmethyl-tetrazol-5-yl)biphenyl-4-yl]methyl]-1H-pyrazolo[1,5-b][1,2,4]triazole (compound 44b) were obtained from 500 mg of 2-ethyl-7-methyl-1H-pyrazolo[1,5-b][1,2,4]triazole.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH:4]([CH:7]=O)[CH2:3][CH2:2]1.[CH3:9][C:10]([CH:12]=[CH2:13])=[O:11].S(=O)(=O)(O)O.O>C1(C)C=CC=CC=1.C(OCC)(=O)C>[CH2:5]1[C:4]2([CH2:7][CH2:9][C:10](=[O:11])[CH:12]=[CH:13]2)[CH2:3][CH2:2][O:1][CH2:6]1
Reactant: C=CC(C)=O
Reactant: O=CC1CCOCC1
Agent: O=S(=O)(O)O
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Solvent: O
Product: O=C1C=CC2(CCOCC2)CC1
Reaction time: 3 h

Procedure:
5.00 g (43.8 mmol) tetrahydropyran-4-carboxaldehyde and 3.56 ml (43.9 mmol) methylvinylketone were boiled in 70 ml of toluene with 0.07 ml conc. sulphuric acid using a water separator. After 3 h another 3.56 ml methylvinylketone were added and the mixture was boiled for a further 3 h. After cooling the reaction mixture was taken up in ethyl acetate, washed with water, dried and concentrated by rotary evaporation.
Reaction SMILES: [C:1]([C:3]1[C:8]([O:9][CH:10]2[CH2:14][CH2:13][CH2:12][CH2:11]2)=[C:7]([O:15][CH3:16])[C:6]([O:17][CH3:18])=[CH:5][C:4]=1[N+:19]([O-])=O)#[N:2].ClCCl.N>CO>[C:1]([C:3]1[C:8]([O:9][CH:10]2[CH2:14][CH2:13][CH2:12][CH2:11]2)=[C:7]([O:15][CH3:16])[C:6]([O:17][CH3:18])=[CH:5][C:4]=1[NH2:19])#[N:2]
Reactant: COc1cc([N+](=O)[O-])c(C#N)c(OC2CCCC2)c1OC
Agent: N
Solvent: ClCCl
Solvent: CO
Product: COc1cc(N)c(C#N)c(OC2CCCC2)c1OC

Procedure:
The subtitle compound was prepared from 2-cyano-3-cyclopentyloxy-4,5-dimethoxynitrobenzene following the procedure described in Example 10(f) and was obtained as a cream coloured solid (66%). Rf 0.79 (dichloromethane:methanol:0.880 aqueous ammonia, 92:7:1, v/v). 1H-NMR (CDCl3): δ=1.57 (2H, m), 1.70 (2H, m), 1.90 (4H, m), 3.68 (3H, s), 3.82 (3H, s), 5.10 (1H, m), 5.98 (1H, s).
Reaction SMILES: [Cl:1][C:2]1[CH:20]=[CH:19][C:5]2[O:6][C:7]3[CH:18]=[CH:17][CH:16]=[CH:15][C:8]=3[CH2:9][N:10]([C:11]([NH:13][NH2:14])=[O:12])[C:4]=2[CH:3]=1.CN(C1C=CC=CN=1)C.[Br:30][CH2:31][C:32](Br)=[O:33].CCOC(C)=O>CN(C=O)C.[Cl-].[Na+].O>[Br:30][CH2:31][C:32]([NH:14][NH:13][C:11]([N:10]1[CH2:9][C:8]2[CH:15]=[CH:16][CH:17]=[CH:18][C:7]=2[O:6][C:5]2[CH:19]=[CH:20][C:2]([Cl:1])=[CH:3][C:4]1=2)=[O:12])=[O:33]
Reactant: O=C(Br)CBr
Reactant: NNC(=O)N1Cc2ccccc2Oc2ccc(Cl)cc21
Agent: CN(C)c1ccccn1
Agent: [Cl-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O
Product: O=C(CBr)NNC(=O)N1Cc2ccccc2Oc2ccc(Cl)cc21
Reaction time: 16 h

Procedure:
To an icebath-cooled stirring solution of 5.79 g (20 mmol) of 8-chlorodibenz[b,f][1,4]oxazepine-10(11H)-carboxylic acid, hydrazide (1), prepared as described above in Example 1, 3.1 mL (22 mmol) of TEA, and 0.16 g (1 mmol) of dimethylaminopyridine in 50 mL of DMF was added 4.44 g (22 mmol) of bromoacetyl bromide. After 16 hours of stirring, the reaction mixture was added to 250 mL of brine and 250 mL of EtOAc. The resulting layers were separated, and the organic layer was washed with 4×250 mL of brine. The organic layer was then dried and chromatographed. The yield of 8-chlorodibenz[b,f][1,4]oxazepine-10(11H)-carboxylic acid, 2-(bromoacetyl) hydrazide (19) was 3.75 g (45%). The product was employed immediately in the manner described in Example 20 below.
Reaction SMILES: [I-].C1([P+](C2C=CC=CC=2)(C2C=CC=CC=2)[CH2:9][CH:10]2[CH2:15][CH2:14][O:13][CH2:12][CH2:11]2)C=CC=CC=1.C[Si](C)(C)[N-][Si](C)(C)C.[Li+].[CH3:38][S:39][C:40]1[CH:41]=[CH:42][C:43]([C:46](=O)[C:47]([O:49][CH2:50][CH3:51])=[O:48])=[N:44][CH:45]=1.[Cl-].[NH4+]>O1CCCC1>[CH3:38][S:39][C:40]1[CH:41]=[CH:42][C:43]([C:46](=[CH:9][CH:10]2[CH2:11][CH2:12][O:13][CH2:14][CH2:15]2)[C:47]([O:49][CH2:50][CH3:51])=[O:48])=[N:44][CH:45]=1
Reactant: c1ccc([P+](CC2CCOCC2)(c2ccccc2)c2ccccc2)cc1
Reactant: CCOC(=O)C(=O)c1ccc(SC)cn1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Cl-]
Agent: [I-]
Solvent: C1CCOC1
Product: CCOC(=O)C(=CC1CCOCC1)c1ccc(SC)cn1
Temperature: 15 °C
Reaction time: 2 h
Yield: 86.1 %

Procedure:
To a solution of triphenyl(tetrahydro-2H-pyran-4-ylmethyl)phosphonium iodide (5.11 g) in dry tetrahydrofuran (20 mL) was added lithium hexamethyldisilazide (1.1M tetrahydrofuran solution, 9.1 mL), and the mixture was stirred at 15° C. for 2 hr. To the reaction mixture was added a solution of ethyl [5-(methylsulfanyl)pyridin-2-yl](oxo)acetate (2.05 g) in dry tetrahydrofuran (20 mL), and the mixture was stirred at room temperature for 16 hr. A saturated aqueous ammonium chloride solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography, and the title compound (2.41 g, yield 86%) was obtained as yellow amorphous crystals from a fraction eluted with ethyl acetate-hexane (1:2, volume ratio).
Reaction SMILES: [CH:1]1([N:6]2[C:11]3[N:12]=[C:13](S(C)=O)[N:14]=[CH:15][C:10]=3[CH:9]=[C:8]([F:19])[C:7]2=[O:20])[CH2:5][CH2:4][CH2:3][CH2:2]1.[C:21]([O:25][C:26]([N:28]1[CH2:33][CH2:32][N:31]([C:34]2[CH:35]=[N:36][C:37]([NH2:40])=[CH:38][CH:39]=2)[CH2:30][CH2:29]1)=[O:27])([CH3:24])([CH3:23])[CH3:22]>C1(C)C=CC=CC=1>[C:21]([O:25][C:26]([N:28]1[CH2:33][CH2:32][N:31]([C:34]2[CH:35]=[N:36][C:37]([NH:40][C:13]3[N:14]=[CH:15][C:10]4[CH:9]=[C:8]([F:19])[C:7](=[O:20])[N:6]([CH:1]5[CH2:5][CH2:4][CH2:3][CH2:2]5)[C:11]=4[N:12]=3)=[CH:38][CH:39]=2)[CH2:30][CH2:29]1)=[O:27])([CH3:24])([CH3:22])[CH3:23]
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(N)nc2)CC1
Reactant: CS(=O)c1ncc2cc(F)c(=O)n(C3CCCC3)c2n1
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N1CCN(c2ccc(Nc3ncc4cc(F)c(=O)n(C5CCCC5)c4n3)nc2)CC1
Temperature: 98 °C
Yield: 25.5 %

Procedure:
8-Cyclopentyl-6-fluoro-2-methanesulfinyl-8H-pyrido[2,3-d]pyrimidin-7-one (2.0 g, 6.77 mmol, prepared accoring to Example 16) and 5 4-(6-Amino-pyridin-3-yl)-piperazine-1-carboxylic acid tert-butyl ester (6.0 g, 21 mmol) were added to toluene (8 ml) and heated to 98° C. for 18 hours. The mixture was filtered, washed with toluene and the solid suspended in diethyl ether. The mixture was filtered and the solid was dissolved in chloroform, washed with 1 N citric acid, brine and dried over anhydrous magnesium sulfate. The crude product was triturated with diethyl ether and dried in vacuo to provide 4-[6-(8-cyclopentyl-6-fluoro-7-oxo-7,8-dihydro-pyrido[2,3-d]pyrimidin-2-ylamino)-pyridin-3-yl]-piperazine-1-carboxylic acid tert-butyl ester as a solid (0.88 g, 25%). MS (APCI) M++1: Calc'd, 510.3. Found 510.2.
Reaction SMILES: [CH:1]([NH:3][C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([N+:10]([O-:12])=[O:11])[CH:5]=1)=[O:2].C(=O)([O-])[O-].[K+].[K+].Br[CH:20]([C:22](=[O:24])[CH3:23])[CH3:21]>CN(C)C=O.C(OCC)(=O)C>[CH3:21][CH:20]([N:3]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([N+:10]([O-:12])=[O:11])[CH:5]=1)[CH:1]=[O:2])[C:22](=[O:24])[CH3:23]
Reactant: CC(=O)C(C)Br
Reactant: O=CNc1cccc([N+](=O)[O-])c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(=O)C(C)N(C=O)c1cccc([N+](=O)[O-])c1
Reaction time: 72 h
Yield: 99.9 %

Procedure:
To a suspension of N-formyl-3-nitroaniline (831 mg) and potassium carbonate (830 mg) in N,N-dimethylformamide (5 ml) was added 2-bromo-3-butanone (906 mg), and the mixture was stirred for 72 hours. The mixture was diluted with ethyl acetate and washed with water and brine. The mixture was dried over magnesium sulfate and evaporated to give N-(1-methyl-2-oxo-propyl)-N-(3-nitrophenyl)formamide (1.18 g, 100%).
Reaction SMILES: [CH3:1][N:2]([CH:12]1[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1)[C:3]1[S:4][C:5]([C:8]([F:11])([F:10])[F:9])=[N:6][N:7]=1.[F:18][C:19]1[CH:20]=[C:21]([CH:24]=[CH:25][CH:26]=1)[CH2:22]Br.C(N(C(C)C)CC)(C)C>C(#N)C.ClCCl>[F:18][C:19]1[CH:20]=[C:21]([CH:24]=[CH:25][CH:26]=1)[CH2:22][N:15]1[CH2:16][CH2:17][CH:12]([N:2]([CH3:1])[C:3]2[S:4][C:5]([C:8]([F:11])([F:9])[F:10])=[N:6][N:7]=2)[CH2:13][CH2:14]1
Reactant: CN(c1nnc(C(F)(F)F)s1)C1CCNCC1
Reactant: Fc1cccc(CBr)c1
Solvent: CC#N
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CN(c1nnc(C(F)(F)F)s1)C1CCN(Cc2cccc(F)c2)CC1
Temperature: 100 °C
Reaction time: 0.08 h
Yield: 87.2 %

Procedure:
A mixture of methyl-piperidin-4-yl-(5-trifluoromethyl-[1,3,4]thiadiazol-2-yl)-amine (D2) (0.050 g, 0.19 mmol), 3-fluorobenzyl bromide (0.030 ml, 0.24 mmol) and diisopropylethylamine (0.050 ml, 0.28 mmol) in acetonitrile (3 ml) was stirred at 100° C. for 5 min., under microwave irradiation. After cooling to room temperature, the reaction mixture was diluted with dichloromethane and extracted with a 10% solution of ammonium chloride (25 ml). The organic layer was separated, dried (Na2SO4) and the solvent evaporated in vacuo. The crude product was purified by flash column chromatography (silica gel; 0-1.5% ammonia in methanol (7M)/dichloromethane) to yield E2 (0.062 g, 88%) as a solid. C16H18F4N4S requires 374. Found 375 (MH+).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([S:9]([N:12]2[C:16]([C:17]3[C:18]([F:23])=[N:19][CH:20]=[CH:21][CH:22]=3)=[CH:15][C:14]([CH2:24][N:25](C)[C:26](=O)OC(C)(C)C)=[CH:13]2)(=[O:11])=[O:10])[CH:5]=[CH:6][C:7]=1[F:8].C(OCC)(=O)C.[ClH:40]>C(O)C>[ClH:40].[F:1][C:2]1[CH:3]=[C:4]([S:9]([N:12]2[C:16]([C:17]3[C:18]([F:23])=[N:19][CH:20]=[CH:21][CH:22]=3)=[CH:15][C:14]([CH2:24][NH:25][CH3:26])=[CH:13]2)(=[O:11])=[O:10])[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: CN(Cc1cc(-c2cccnc2F)n(S(=O)(=O)c2ccc(F)c(F)c2)c1)C(=O)OC(C)(C)C
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CCO
Product: CNCc1cc(-c2cccnc2F)n(S(=O)(=O)c2ccc(F)c(F)c2)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 52 %

Procedure:
To a solution of tert-butyl ({1-[(3,4-difluorophenyl)sulfonyl]-5-(2-fluoropyridin-3-yl)-1H-pyrrol-3-yl}methyl)methylcarbamate (468 mg) in ethanol (2 mL) was added 4 mol/L hydrogen chloride-ethyl acetate solution (2 mL), and the mixture was stirred at room temperature for 3 hr. The solvent was concentrated under reduced pressure, and the residue was recrystallized from ethanol to give the title compound (yield 210 mg, 52%).
Reaction SMILES: [CH3:1][C:2]1[NH:7][C:6](=O)[C:5]([N+:9]([O-:11])=[O:10])=[C:4]([NH:12][CH:13]([CH2:17][CH2:18][CH3:19])[CH2:14][CH2:15][CH3:16])[CH:3]=1.O=P(Cl)(Cl)[Cl:22]>>[Cl:22][C:6]1[C:5]([N+:9]([O-:11])=[O:10])=[C:4]([NH:12][CH:13]([CH2:17][CH2:18][CH3:19])[CH2:14][CH2:15][CH3:16])[CH:3]=[C:2]([CH3:1])[N:7]=1
Reactant: CCCC(CCC)Nc1cc(C)[nH]c(=O)c1[N+](=O)[O-]
Reactant: O=P(Cl)(Cl)Cl
Product: CCCC(CCC)Nc1cc(C)nc(Cl)c1[N+](=O)[O-]
Temperature: 0 °C

Procedure:
6-Methyl-3-nitro-4-(1-propylbutylamino)pyridone (3.7 g, 13.84 mmol), was treated with POCl3 (14 mL) at 25° C. for 20 h. Then it was poured into ice/water (200 mL) and extracted with EtOAc (300 mL). The EtOAc was washed with water, brine, dried (MgSO4) and stripped in vacuo. The residue was chromatographed on silica gel (20% EtOAc/hexanes eluting solvent) to give the product (3.3 g).
Reaction SMILES: C([C:4]([C@H:6]([C@@H:8]([C@@H:10]([N:13]=[N+:14]=[N-:15])[CH2:11][OH:12])[OH:9])[OH:7])=[O:5])C=C.O>CO.[Pd](Cl)Cl>[N:13]([C@@H:10]([CH2:11][OH:12])[C@@H:8]([OH:9])[C@H:6]([OH:7])[CH:4]=[O:5])=[N+:14]=[N-:15]
Reactant: C=CCC(=O)[C@@H](O)[C@H](O)[C@H](CO)N=[N+]=[N-]
Agent: Cl[Pd]Cl
Solvent: O
Solvent: CO
Product: [N-]=[N+]=N[C@@H](CO)[C@@H](O)[C@H](O)C=O
Temperature: 25 °C
Reaction time: 24 h
Yield: 61.7 %

Procedure:
1-allyl-4-azido-4-deoxy-L-xylose 36 (496 mg, 2.3 mmol) was dissolved in 99:1 methanol:water (10 mL), followed by the addition of palladium (II) chloride (81.7 mg, 0.46 mmol). The reaction mixture was stirred for 24 h at room temperature, and then filtered through a pad of Celite® with methanol wash (100 mL). The combined filtrates were purified by silica gel flash chromatography (DCM to 9:1 DCM:MeOH) to give of 37 as a yellow oil (249 mg, 1.42 mmol, 62%).
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[CH:4][CH:3]=1.[NH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C1C=CC=CC=1.C(O)(=O)C>O>[F:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[N:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[CH:4][CH:3]=1
Reactant: O=Cc1ccc(F)cc1
Reactant: Nc1ccccc1
Solvent: O
Solvent: c1ccccc1
Solvent: CC(=O)O
Product: Fc1ccc(C=Nc2ccccc2)cc1

Procedure:
To 4-fluorobenzaldehyde (24.8 g, 0.200 mol) and aniline (18.6 g, 0.200 mol) was added benzene (200 mL) and acetic acid (0.7 mL) and the mixture is heated under reflux until all the water (3.6 mL) was azeotropically removed. The solvent is evaporated and the residual oil upon cooling and stirring crystallized. The white mass was then recrystallize as needles (28 g, 70%): mp 39°-40° C. (PE) (lit.1 mp 40° C.).