Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1.[C:6]([C:8]1[CH:9]=[C:10]2[C:15](=[CH:16][C:17]=1[O:18][CH2:19][C@H:20]1[CH2:22][O:21]1)[N:14]=[CH:13][CH:12]=[C:11]2[O:23][C:24]1[CH:29]=[CH:28][C:27]([NH:30][C:31]([NH:33][CH:34]2[CH2:36][CH2:35]2)=[O:32])=[C:26]([CH3:37])[C:25]=1[CH3:38])#[N:7]>O1CCCC1>[C:6]([C:8]1[CH:9]=[C:10]2[C:15](=[CH:16][C:17]=1[O:18][CH2:19][C@H:20]([OH:21])[CH2:22][N:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1)[N:14]=[CH:13][CH:12]=[C:11]2[O:23][C:24]1[CH:29]=[CH:28][C:27]([NH:30][C:31]([NH:33][CH:34]2[CH2:36][CH2:35]2)=[O:32])=[C:26]([CH3:37])[C:25]=1[CH3:38])#[N:7]
Reactant: Cc1c(NC(=O)NC2CC2)ccc(Oc2ccnc3cc(OC[C@H]4CO4)c(C#N)cc23)c1C
Reactant: C1CCNC1
Solvent: C1CCOC1
Product: Cc1c(NC(=O)NC2CC2)ccc(Oc2ccnc3cc(OC[C@H](O)CN4CCCC4)c(C#N)cc23)c1C
Temperature: 60 °C

Procedure:
After adding tetrahydrofuran (2.0 ml) and pyrrolidine (0.20 ml) to N-(4-(6-cyano-7-((2R)-oxiran-2-yl)methoxy-quinolin-4-yloxy)-2,3-dimethylphenyl)-N′-cyclopropylurea (110 mg), the mixture was heated at 60° C. for 2 hours. After allowing the reaction solution to cool, the precipitated crystals were filtered out to obtain the title compound (18 mg) as light brown crystals.
Reaction SMILES: Cl.Cl[CH2:3][C:4]1([NH:9][CH:10]2[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]2)[CH2:8][CH2:7][CH2:6][CH2:5]1.[CH3:16][C:17]1[CH:22]=[C:21]([N+:23]([O-:25])=[O:24])[CH:20]=[CH:19][C:18]=1[N:26]=[C:27]=[O:28].CN1CCOCC1>ClCCCl>[CH:10]1([N:9]2[C:4]3([CH2:8][CH2:7][CH2:6][CH2:5]3)[CH2:3][O:28][C:27]2=[N:26][C:18]2[CH:19]=[CH:20][C:21]([N+:23]([O-:25])=[O:24])=[CH:22][C:17]=2[CH3:16])[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1
Reactant: ClCC1(NC2CCCCC2)CCCC1
Reactant: Cc1cc([N+](=O)[O-])ccc1N=C=O
Agent: Cl
Solvent: ClCCCl
Solvent: CN1CCOCC1
Product: Cc1cc([N+](=O)[O-])ccc1N=C1OCC2(CCCC2)N1C1CCCCC1
Temperature: 50 °C
Yield: 1.4 %

Procedure:
To a solution of 1-(chloromethyl)-1-(cyclohexylamino)cyclopentane HCl salt (Method B7b; 1.06 g, 4.2 mmol) and 2-methyl-4-nitrophenyl isocyanate (0.75 g, 4.2 mmol) in 1,2-dichloroethane (10 mL) was added N-methylmorpholine (0.92 mL, 8.4 mmol). The resulting mixture was heated to 50° C. for 18 h, then cooled to 20° C. and concentrated under reduced pressure. The residue was purified by chromatography (SiO2, gradient from hexane to 10% EtOAc/hex) to yield 1-cyclohexyl-2-(2-methyl-4-nitrophenylimino)-3-oxa-1-azaspiro[4.4]nonane (0.021 g, 1.4%): CI-MS m/z 358 ((M+H)+).
Reaction SMILES: [CH:1]1[C:14]2[C:13]([CH2:19][C:20](O)=[O:21])([CH2:15][C:16]([OH:18])=[O:17])[C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[O:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.O>C(OC(=O)C)(=O)C>[O:17]1[C:20](=[O:21])[CH2:19][C:13]2([C:12]3[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=3[O:6][C:5]3[C:14]2=[CH:1][CH:2]=[CH:3][CH:4]=3)[CH2:15][C:16]1=[O:18]
Reactant: O=C(O)CC1(CC(=O)O)c2ccccc2Oc2ccccc21
Solvent: O
Solvent: CC(=O)OC(C)=O
Product: O=C1CC2(CC(=O)O1)c1ccccc1Oc1ccccc12

Procedure:
A solution of xanthene 9,9-diacetic acid (0.8 g.) in acetic anhydride (3 ml.) is heated under reflux for 1 hour, cooled and poured into water. Extraction with ethyl acetate gives xanthene-9-spiro-4'-tetrahydropyran-2',6'-dione which is recrystallised from ethyl acetate-petroleum ether (b.p. 60°-80° C.), m.p. 188°-190° C.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([CH2:21][O:22][C:23]([C:25]3[S:26][C:27]([CH3:30])=[CH:28][CH:29]=3)=[O:24])=[C:10]3[C:15](=[CH:16][CH:17]=2)[NH:14][C:13]([CH3:19])([CH3:18])[CH:12]=[C:11]3[CH3:20])=[C:4]([O:31][CH3:32])[CH:3]=1.C(N(CC)CC)C.[C:40](Cl)(=[O:43])[O:41][CH3:42]>C(Cl)Cl>[CH3:32][O:31][C:4]1[CH:3]=[C:2]([O:1][C:40]([O:41][CH3:42])=[O:43])[CH:7]=[CH:6][C:5]=1[C:8]1[C:9]([CH2:21][O:22][C:23]([C:25]2[S:26][C:27]([CH3:30])=[CH:28][CH:29]=2)=[O:24])=[C:10]2[C:15](=[CH:16][CH:17]=1)[NH:14][C:13]([CH3:18])([CH3:19])[CH:12]=[C:11]2[CH3:20]
Reactant: COC(=O)Cl
Reactant: COc1cc(O)ccc1-c1ccc2c(c1COC(=O)c1ccc(C)s1)C(C)=CC(C)(C)N2
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)Oc1ccc(-c2ccc3c(c2COC(=O)c2ccc(C)s2)C(C)=CC(C)(C)N3)c(OC)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 74.9 %

Procedure:
6-(4-Hydroxy-2-methoxyphenyl)-5-(5-methylthiophen-2-ylcarbonyloxymethyl)-2,2,4-trimethyl-1,2-dihydroquinoline (Reference Compound No. 3-2, 31.7 mg, 0.0705 mmol) was dissolved in anhydrous methylene dichloride (1 mL), triethylamine (30 μL, 0.22 mmol) and methyl chlorocarbonate (10 μL, 0.13 mmol) were added thereto, and then the mixture was stirred at room temperature for 1 hour. The reaction mixture was purified by silica gel column chromatography (hexane-ethyl acetate) to give the titled compound (26.8 mg) as a pale yellow amorphous product. (Yield 79%)
Reaction SMILES: [NH2:1][C:2]1[CH:18]=[CH:17][C:5]([O:6][CH2:7][C:8]([O:10][CH2:11][CH2:12][Si:13]([CH3:16])([CH3:15])[CH3:14])=[O:9])=[CH:4][C:3]=1[O:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:34][C:35]([O:37][CH3:38])=[O:36].O>CN(C=O)C>[CH3:15][Si:13]([CH3:16])([CH3:14])[CH2:12][CH2:11][O:10][C:8](=[O:9])[CH2:7][O:6][C:5]1[CH:17]=[CH:18][C:2]([NH:1][CH2:34][C:35]([O:37][CH3:38])=[O:36])=[C:3]([O:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:4]=1
Reactant: C[Si](C)(C)CCOC(=O)COc1ccc(N)c(OCc2ccccc2)c1
Reactant: COC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)CNc1ccc(OCC(=O)OCC[Si](C)(C)C)cc1OCc1ccccc1
Temperature: 60 °C
Reaction time: 1 h

Procedure:
To a mixture of 2-trimethylsilanylethyl (4-amino-3-benzyloxyphenoxy)acetate (4.56 g, 12.2 mmol) and potassium carbonate (3.37 g, 24.4 mmol) in DMF (25 mL) is added methyl bromoacetate (1.87 g, 12.2 mmol). The mixture is stirred at 60° C. for 1 h then is allowed to cool to RT. It is poured into water and extracted with EtOAc and the organic phase is washed with water (1×), brine (5×), and dried over Na2SO4. The solvent is removed under reduced pressure to afford the title compound which is used directly in the next step.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][C:17]([OH:19])=O)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CN1CCOCC1.[C:51]([O:55][C:56](=[O:77])[NH:57][C@H:58]([CH2:64][NH:65][C:66]([C:68]1[C:73]([NH2:74])=[N:72][C:71]([NH2:75])=[C:70]([Cl:76])[N:69]=1)=[O:67])[CH2:59][CH2:60][CH2:61][CH2:62][NH2:63])([CH3:54])([CH3:53])[CH3:52]>CN(C=O)C>[C:51]([O:55][C:56](=[O:77])[NH:57][C@H:58]([CH2:64][NH:65][C:66]([C:68]1[C:73]([NH2:74])=[N:72][C:71]([NH2:75])=[C:70]([Cl:76])[N:69]=1)=[O:67])[CH2:59][CH2:60][CH2:61][CH2:62][NH:63][C:17](=[O:19])[CH2:16][CH2:15][C:12]1[CH:11]=[CH:10][C:9]([O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[CH:14][CH:13]=1)([CH3:54])([CH3:52])[CH3:53]
Reactant: O=C(O)CCc1ccc(OCc2ccccc2)cc1
Reactant: CC(C)(C)OC(=O)N[C@@H](CCCCN)CNC(=O)c1nc(Cl)c(N)nc1N
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: CC(C)(C)OC(=O)N[C@@H](CCCCNC(=O)CCc1ccc(OCc2ccccc2)cc1)CNC(=O)c1nc(Cl)c(N)nc1N
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 3-(4-benzyloxyphenyl)propionic acid (0.19 g, 0.74 mmol) and HATU (0.29 g, 0.75 mmol) in DMF (10 mL) is added N-methylmorpholine (0.32 mL, 2.91 mmol) followed by ((S)-5-amino-1-{[(3,5-diamino-6-chloro-pyrazine-2-carbonyl)-amino]-methyl}-pentyl)-carbamic acid tert-butyl ester (Intermediate B) (0.30 g, 0.75 mmol). The resulting mixture is stirred at RT for 16 h. The solvent is removed in vacuo and the residue is purified by column chromatography (basic alumina, 2% MeOH in DCM) to afford the title compound as yellow solid. [M-Boc+H]+ 540.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]([Cl:11])=[O:10].[S:12](=[O:15])(=[O:14])=[O:13]>ClCCl.ClC(Cl)C>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]([S:12]([OH:15])(=[O:14])=[O:13])[C:9]([Cl:11])=[O:10]
Reactant: O=C(Cl)Cc1ccccc1F
Reactant: O=S(=O)=O
Solvent: ClCCl
Solvent: CC(Cl)Cl
Product: O=C(Cl)C(c1ccccc1F)S(=O)(=O)O
Temperature: 25 °C

Procedure:
A solution of 2-(2-fluorophenyl)acetyl chloride (1.73 g, 10 mmole) in dichloromethane (20 ml) was treated with a suspension of sulphur trioxide--dioxane complex (15 mmole) in dichloroethane at 0° C. This mixture was stirred at room temperature for eighteen hours and evaporated to a yellow gum. νmax. (CHCl3) 1805 cm-1.
Reaction SMILES: C([O:4][CH2:5][C:6]1[N:7]=[C:8]([Br:12])[S:9][C:10]=1[CH3:11])(=O)C.[OH-].[Na+].Cl>C(O)C.O1CCCC1>[Br:12][C:8]1[S:9][C:10]([CH3:11])=[C:6]([CH2:5][OH:4])[N:7]=1
Reactant: CC(=O)OCc1nc(Br)sc1C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: Cc1sc(Br)nc1CO
Temperature: 25 °C
Reaction time: 8 h
Yield: 59.1 %

Procedure:
To a mixed solution of the compound (1.2 g, 4.8 mmol) obtained in Example 80c in ethanol/tetrahydrofuran (v/v=1/1, 4 mL) was added 2N aqueous sodium hydroxide solution (4.8 mL, 9.6 mmol), and the mixture was stirred at room temperature overnight. The reaction mixture was neutralized with 1N hydrochloric acid, and the mixture was extracted with ethyl acetate. The obtained organic layer was washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The resulting crude title compound was purified by column chromatography (hexane-hexane/ethyl acetate=50/50) to give the title compound (590 mg, 59%) as a colorless solid.
Reaction SMILES: [CH2:1]([Mg]Br)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].Br[C:14]1[C:18](Br)=[CH:17][S:16][CH:15]=1.O>C(OCC)C.Cl[Ni]1(Cl)[P](C2C=CC=CC=2)(C2C=CC=CC=2)CCC[P]1(C1C=CC=CC=1)C1C=CC=CC=1>[CH2:1]([C:14]1[C:18]([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10])=[CH:17][S:16][CH:15]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10]
Reactant: CCCCCCCCCC[Mg]Br
Reactant: Brc1cscc1Br
Agent: Cl[Ni]1(Cl)[P](c2ccccc2)(c2ccccc2)CCC[P]1(c1ccccc1)c1ccccc1
Solvent: CCOCC
Solvent: O
Product: CCCCCCCCCCc1cscc1CCCCCCCCCC
Yield: 76 %

Procedure:
Decylmagnesium bromide (140 mmol) was added dropwise at 0° C. to a mixture solution of 3,4-dibromothiophene (50 mmol) and [1,3-bis(diphenylphosphino)propane]dichloronickel(II) (0.3 mmol) in 100 mL of dry diethyl ether. The resulting mixture was heated and refluxed for 6 hours. The reaction mixture was combined with water, and extracted with diethyl ether. The extract solution was dried over magnesium sulfate, and the solvent was evaporated therefrom to obtain a crude product. The crude product was purified by silica gel column chromatography and by distillation to obtain the intended product (38 mmol) in a 76% yield.
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[CH:11]=[CH:10][C:9]([CH2:12][CH3:13])=[CH:8][C:7]=2[C:14]2[C:15]3[N:22]([CH2:23][O:24][CH2:25][CH2:26][Si:27]([CH3:30])([CH3:29])[CH3:28])[C:21]([CH3:31])=[C:20]([C:32](O)=[O:33])[C:16]=3[N:17]=[CH:18][N:19]=2)[CH2:3][CH2:2]1.[NH2:35][CH:36]1[CH2:41][CH2:40][N:39]([C:42]([O:44][C:45]([CH3:48])([CH3:47])[CH3:46])=[O:43])[CH2:38][CH2:37]1>>[CH:1]1([CH2:4][O:5][C:6]2[CH:11]=[CH:10][C:9]([CH2:12][CH3:13])=[CH:8][C:7]=2[C:14]2[C:15]3[N:22]([CH2:23][O:24][CH2:25][CH2:26][Si:27]([CH3:28])([CH3:29])[CH3:30])[C:21]([CH3:31])=[C:20]([C:32]([NH:35][CH:36]4[CH2:37][CH2:38][N:39]([C:42]([O:44][C:45]([CH3:48])([CH3:47])[CH3:46])=[O:43])[CH2:40][CH2:41]4)=[O:33])[C:16]=3[N:17]=[CH:18][N:19]=2)[CH2:2][CH2:3]1
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Reactant: CCc1ccc(OCC2CC2)c(-c2ncnc3c(C(=O)O)c(C)n(COCC[Si](C)(C)C)c23)c1
Product: CCc1ccc(OCC2CC2)c(-c2ncnc3c(C(=O)NC4CCN(C(=O)OC(C)(C)C)CC4)c(C)n(COCC[Si](C)(C)C)c23)c1

Procedure:
Starting from 4-[2-(cyclopropylmethoxy)-5-ethylphenyl]-6-methyl-5-{[2-(trimethylsilyl)ethoxy]methyl}-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylic acid (example D.c14) and commercially available tert-butyl 4-amino-piperidine-1-carboxylate the title compound is obtained as pale yellow viscous oil.
Reaction SMILES: C[O:2][C:3](=[O:28])[C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:15]=[CH:14][N:13]=[C:12]([CH2:16][CH3:17])[C:11]=2[C:18]#[C:19][C:20]2[CH:21]=[N:22][C:23]([NH2:26])=[CH:24][CH:25]=2)=[CH:6][C:5]=1[Cl:27].[Li+].[OH-]>C1COCC1.O>[NH2:26][C:23]1[N:22]=[CH:21][C:20]([C:19]#[C:18][C:11]2[C:12]([CH2:16][CH3:17])=[N:13][CH:14]=[CH:15][C:10]=2[C:7]2[CH:8]=[CH:9][C:4]([C:3]([OH:28])=[O:2])=[C:5]([Cl:27])[CH:6]=2)=[CH:25][CH:24]=1
Reactant: CCc1nccc(-c2ccc(C(=O)OC)c(Cl)c2)c1C#Cc1ccc(N)nc1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CCc1nccc(-c2ccc(C(=O)O)c(Cl)c2)c1C#Cc1ccc(N)nc1

Procedure:
The title compound is synthesized according to general procedure GP4 starting from 1.1 g (2.8 mmol) 4-[3-(6-Amino-pyridin-3-ylethynyl)-2-ethyl-pyridin-4-yl]-2-chloro-benzoic acid methyl ester (A-39) using 134 mg (5.6 mmoL) LiOH in a mixture of 100 mL THF and 20 mL water. After completion of the reaction, THF is removed under reduced pressure, the aqueous solution is acidified with 1N HCl to pH ˜1 before the pH is adjusted to 6 with saturated aqueous NaHCO3 solution. The precipitated product is collected by filtration, washed with water and methanol. Yield: 760 mg (72%).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([CH2:14][C:15]([OH:17])=O)=[CH:10][CH:9]=2)[CH:5]=[CH:4][N:3]=1.[C:18]1([C:24]2[CH:25]=[CH:26][C:27]([NH2:30])=[N:28][CH:29]=2)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C>CN(C=O)C>[CH3:1][C:2]1[CH:7]=[C:6]([C:8]2[CH:9]=[CH:10][C:11]([CH2:14][C:15]([NH:30][C:27]3[CH:26]=[CH:25][C:24]([C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)=[CH:29][N:28]=3)=[O:17])=[CH:12][CH:13]=2)[CH:5]=[CH:4][N:3]=1
Reactant: Nc1ccc(-c2ccccc2)cn1
Reactant: Cc1cc(-c2ccc(CC(=O)O)cc2)ccn1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1cc(-c2ccc(CC(=O)Nc3ccc(-c4ccccc4)cn3)cc2)ccn1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of 2-(4-(2-methylpyridin-4-yl)phenyl)acetic acid 26-3 (50 mg, 0.2 mmol), 5-phenylpyridin-2-amine (41 mg, 0.24 mmol) and O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumhexafluorophosphate (HATU) (114 mg, 0.3 mmol) in 1.5 mL DMF was added N,N-diisopropylethylamine (DIEA, 104 μL, 0.6 mmol) at room temperature. The mixture was stirred at room temperature for 2 hours. The solvent was removed by rotary evaporation. The crude product was purified by reverse phase HPLC to give 2-(4-(2-methylpyridin-4-yl)phenyl)-N-(5-phenylpyridin-2-yl)acetamide 26 as white solid. MS m/z 380.17 (M+1); 1H NMR 400 MHz (DMSO-d6) δ 10.84(s, 1H), 8.60(d, 1H, J=2.4 Hz), 8.42(d, 1H, J=6.4 Hz), 8.10(d, 1H, J=8.8 Hz), 8.04(dd, 1H, J1=8.8 Hz, J2=2.4 Hz), 7.70(m, 2H), 7.65(m, 2H), 7.51(m, 1H), 7.44(m, 5H), 7.33(m, 1H), 3.76(s, 2H), 2.46(s, 3H).
Reaction SMILES: [C@@H:1]1([N:9]2[CH:17]=[C:15]([CH3:16])[C:13](=[O:14])[NH:12][C:10]2=[O:11])[O:8][C@H:5]([CH2:6][OH:7])[C@@H:3]([OH:4])[CH2:2]1.N1C=CC=CC=1.[CH3:24][S:25](Cl)(=[O:27])=[O:26]>O>[CH3:24][S:25]([O:4][C@@H:3]1[C@@H:5]([CH2:6][O:7][S:25]([CH3:24])(=[O:27])=[O:26])[O:8][C@@H:1]([N:9]2[CH:17]=[C:15]([CH3:16])[C:13](=[O:14])[NH:12][C:10]2=[O:11])[CH2:2]1)(=[O:27])=[O:26]
Reactant: CS(=O)(=O)Cl
Reactant: Cc1cn([C@H]2C[C@H](O)[C@@H](CO)O2)c(=O)[nH]c1=O
Solvent: c1ccncc1
Solvent: O
Product: Cc1cn([C@H]2C[C@H](OS(C)(=O)=O)[C@@H](COS(C)(=O)=O)O2)c(=O)[nH]c1=O
Temperature: 0 °C
Reaction time: 18 h
Yield: 81.2 %

Procedure:
A 3 liter, 3 necked round-bottomed flask was equipped with an overhead stirrer and paddle, a 500 mL dropping funnel and a Claisen adapter containing a drying tube and a thermometer. Thymidine (200 g, 0.82M) and pyridine (750 mL) were added to the flask. The mixture was stirred and warmed with a water bath (20 mins) to give a clear solution. The solution was then cooled in an ice bath to 0°-3° C. and the dropping funnel was charged with methanesulfonyl chloride (206.5 g, 1.08M). The methanesulfonyl chloride was then added dropwise over 40 minutes with no noticeable exotherm. The solution was stirred at 0° C. for 1 hr and then stored at 5° C. for 18 hr. The light brown mixture was then poured onto rapidly stirred water (3 L) containing ice (approx. 500 g). The desired product crystallised immediately. After stirring for 0.5 hr, the product was collected by filtration and washed several times with water (3×100mL). The white solid was then dried under vacuum overnight (crude weight, 322 g, 98% yield). The product was recrystallised from hot acetone to give 267 g of a white solid (81% yield), mp 169°-171° C. (lit. 170°-171° C.) 1H NMR (360 MHz, d6 -DMSO) 11.40 (s, 1H, NH), 7.50 (s, 1H, H-6), 6.21 (t, 1H, H-1'), 5.29 (m, 1H, H-3'), 4.45 (m, 2H, H-5'), 4.35 (m, 1H, H-4'), 3.31 (s, 6H, SO2CH3), 2.50 (m, 2H, H-2'), 1.78 (s, 3H, CH3). Analysis (C12H18N2O9S2) C, H, N.
Reaction SMILES: [C:1]1([N:7]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:8]2[CH:13]=[CH:12][C:11](B(O)O)=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Br:23][C:24]1[CH:25]=[CH:26][C:27](I)=[N:28][CH:29]=1.C([O-])([O-])=O.[Na+].[Na+].O>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O1CCCC1>[Br:23][C:24]1[CH:25]=[CH:26][C:27]([C:11]2[CH:12]=[CH:13][C:8]([N:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[CH:9][CH:10]=2)=[N:28][CH:29]=1
Reactant: Brc1ccc(I)nc1
Reactant: OB(O)c1ccc(N(c2ccccc2)c2ccccc2)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: Brc1ccc(-c2ccc(N(c3ccccc3)c3ccccc3)cc2)nc1
Temperature: 80 °C
Yield: 98.2 %

Procedure:
A mixture of 4-(diphenylamino)phenylboronic acid (7.00 g, 24.2 mmol), 5-bromo-2-iodopyridine (7.56 g, 26.6 mmol), tetrakis(triphenylphosphine)palladium(0) (1.40 g, 1.21 mmol), Na2CO3 (9.18 g, 86.6 mmol), H2O (84 mL) and tetrahydrofuran (THF) (140 mL) was degassed with argon for about 1.5 h. while stirring. The stirring reaction mixture was then maintained under argon at 80° C. for about 19 h. Upon confirming consumption of the starting material by thin layer chromatography (TLC) (SiO2, 19:1 hexanes-EtOAc), the reaction was cooled to RT and poured over EtOAc (500 mL). The organics were then washed with saturated sodium bicarbonate (NaHCO3, H2O) and brine, dried over MgSO4, filtered and concentrated in vacuo. The crude product was then purified via flash chromatography (SiO2, 2:1 hexanes-dichloromethane) to afford Compound 23 (9.54 g, 98% yield) as a light yellow, crystalline solid.
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([C:7]([O:9][CH2:10][CH3:11])=[O:8])=[CH:4][CH:3]=1.S(=O)(=O)(O)O.[N+:17]([O-])([OH:19])=[O:18]>>[Cl:1][C:2]1[S:6][C:5]([C:7]([O:9][CH2:10][CH3:11])=[O:8])=[CH:4][C:3]=1[N+:17]([O-:19])=[O:18]
Reactant: O=[N+]([O-])O
Reactant: CCOC(=O)c1ccc(Cl)s1
Agent: O=S(=O)(O)O
Product: CCOC(=O)c1cc([N+](=O)[O-])c(Cl)s1
Temperature: 25 °C
Yield: 67.1 %

Procedure:
Ethyl 5-chlorothiophene-2-carboxylate (2.7 g, 14.1 mmol) was added in portions to concentrated sulfuric acid (5 mL) and the stirred solution was cooled to below 0° C. with a methanol/ice bath. Fuming nitric acid (1.78 g, 1.2 mL, 28.3 mmol) was added slowly, keeping the temperature below 0° C. throughout the addition. On completion of addition the stirred mixture was removed from the cold bath and warmed to ambient temperature for 2 hours. The reaction was quenched by addition to ice/water (100 mL) resulting in formation of a sticky solid. The product was extracted into dichloromethane (2×100 mL). The combined organic extracts were dried (MgSO4), filtered and the solvent was removed to afford an orange oil. The crude material was purified by silica gel chromatography using a 95:5 mixture of hexane and ethyl acetate as eluent to afford the title product as a solid (2.23 g, 67% yield). 1H NMR (CDCl3) δ: 8.14 (1H, s), 4.37 (2H, q, J=7.11 Hz), 1.37 (3H, t, J=7.11 Hz).
Reaction SMILES: Cl.[NH2:2][C@@H:3]1[CH2:8][CH2:7][C@H:6]([C:9]([N:11]2[CH2:16][CH2:15][N:14]([S:17]([C:20]3[CH:29]=[CH:28][C:27]4[C:22](=[CH:23][CH:24]=[C:25]([Cl:30])[CH:26]=4)[CH:21]=3)(=[O:19])=[O:18])[CH2:13][CH2:12]2)=[O:10])[CH2:5][CH2:4]1.Cl.[C:32](N1C=CC=N1)(=[NH:34])[NH2:33].C(N(CC)CC)C>CO>[ClH:30].[Cl:30][C:25]1[CH:26]=[C:27]2[C:22](=[CH:23][CH:24]=1)[CH:21]=[C:20]([S:17]([N:14]1[CH2:13][CH2:12][N:11]([C:9]([C@H:6]3[CH2:7][CH2:8][C@@H:3]([NH:2][C:32]([NH2:34])=[NH:33])[CH2:4][CH2:5]3)=[O:10])[CH2:16][CH2:15]1)(=[O:18])=[O:19])[CH:29]=[CH:28]2
Reactant: N[C@H]1CC[C@@H](C(=O)N2CCN(S(=O)(=O)c3ccc4cc(Cl)ccc4c3)CC2)CC1
Reactant: N=C(N)n1cccn1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CO
Product: N=C(N)N[C@H]1CC[C@@H](C(=O)N2CCN(S(=O)(=O)c3ccc4cc(Cl)ccc4c3)CC2)CC1
Yield: 161.6 %

Procedure:
A solution of 1-(cis-4-aminocyclohexane-1-ylcarbonyl)-4-(6-chloronaphthalene-2-sulfonyl)piperazine hydrochloride (100 mg), 1-amidinopyrazole hydrochloride (47 mg) and triethylamine (100 mg) in methanol (10 ml)was stirred at room temperature for 1 day. The reaction solution was concentrated, and to the residue was added dichloromethane. The mixture was washed with 1 N sodium hydroxide aqueous solution, dried and concentrated. The residue was dissolved in ethyl acetate and transformed into hydrochloride with hydrochloric acid to give a colorless solid of the title compound (88 mg).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([CH3:8])[CH:5]=[C:4](Cl)[N:3]=1.[CH3:10][NH:11][CH3:12]>C(O)C>[NH2:1][C:2]1[N:7]=[C:6]([CH3:8])[CH:5]=[C:4]([N:11]([CH3:12])[CH3:10])[N:3]=1
Reactant: CNC
Reactant: Cc1cc(Cl)nc(N)n1
Solvent: CCO
Product: Cc1cc(N(C)C)nc(N)n1

Procedure:
2-Amino-4-methyl-6-chloropyrimidine (52 g, 0.36 mole) is heated at 160° C. for 18 hours with ethanol and an equimolar amount of dimethylamine in a pressure vessel. The reaction mixture is evaporated in vacuo taken up in 200 ml. of water containg 50 ml. 10 N sodium hydroxide and 300 ml. of methylene chloride. The mixture is extracted with methylene chloride and the organic layer dried and evaporated to dryness in vacuo affording 46 g of 2-amino-4-methyl-6-dimethylaminopyrimidine with a melting point of 172°-174° C.
Reaction SMILES: [O:1]=[CH:2][C:3]1[CH:11]=[CH:10][C:8]([OH:9])=[C:5]([O:6][CH3:7])[CH:4]=1.Br[CH2:13][C:14]([O:16][CH3:17])=[O:15].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[CH3:7][O:6][C:5]1[CH:4]=[C:3]([CH:11]=[CH:10][C:8]=1[O:9][CH2:13][C:14]([O:16][CH3:17])=[O:15])[CH:2]=[O:1]
Reactant: COc1cc(C=O)ccc1O
Reactant: COC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)COc1ccc(C=O)cc1OC
Yield: 77 %

Procedure:
Vanillin was alkylated with methyl bromoacetate in DMF in the presence of K2CO3 in the usual way to give a colorless solid (77%). mp 91°-93 ° C. IR(KBr) cm-1 1760, 1682. 1H NMR(300 MHz, CDCl3): 9.86 (s, 1H), 7.44-7.40 (m, 2H), 6.86 (d, 1H, J=8 Hz), 4.79 (s, 2H), 3.95 (s, 3H), 3.80 (s, 3H). Anal. Calc'd for C11H12O5 : C, 58.92; H, 5.41; Found: C, 59.02; H, 5.26.
Reaction SMILES: [CH:1]([C:3]1[N:8]=[CH:7][C:6]([C:9]#[N:10])=[CH:5][CH:4]=1)=[CH2:2].BrN1C(=[O:17])CCC1=O.[OH-].[Na+]>O.CC(O)(C)C>[O:17]1[CH2:2][CH:1]1[C:3]1[N:8]=[CH:7][C:6]([C:9]#[N:10])=[CH:5][CH:4]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: C=Cc1ccc(C#N)cn1
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)(C)O
Solvent: O
Product: N#Cc1ccc(C2CO2)nc1
Temperature: 40 °C
Reaction time: 1 h

Procedure:
A solution of 6-ethenylpyridine-3-carbonitrile (0.742 g, 5.70 mmol) in a 2:1 ratio of H2O:t-BuOH (30 mL) was treated with N-bromosuccinimide in portions over 5 minutes (1.07 g, 5.99 mmol) and stirred at 40° C. for 1 hour. After cooling to 5° C., the reaction was basified with drop wise addition of solution of sodium hydroxide (0.684 g in 5 mL of H2O, 17.1 mmol) and stirred for another 1 hour. The reaction mixture was poured into H2O (10 mL) and extracted with EtOAc (2×50 mL). The combined organic layers were washed with saturated aqueous NaCl (1×30 mL) and dried over MgSO4. Evaporation of the solvent and purification over SiO2 (0-30% EtOAc/hexanes as eluent) provided 6-(oxiran-2-yl) pyridine-3-carbonitrile.