Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:12])[C@H:5]([CH2:7][C:8]([O:10][CH3:11])=[O:9])[NH2:6].Cl.[C:14](Cl)(=[O:21])[C:15]1[CH:20]=[CH:19][N:18]=[CH:17][CH:16]=1.C(N(CC)CC)C>C(Cl)(Cl)Cl.O>[CH3:2][O:3][C:4](=[O:12])[C@H:5]([CH2:7][C:8]([O:10][CH3:11])=[O:9])[NH:6][C:14](=[O:21])[C:15]1[CH:20]=[CH:19][N:18]=[CH:17][CH:16]=1
Reactant: COC(=O)C[C@H](N)C(=O)OC
Reactant: O=C(Cl)c1ccncc1
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Solvent: O
Product: COC(=O)C[C@H](NC(=O)c1ccncc1)C(=O)OC
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a solution of L-aspartic acid dimethyl ester hydrochloride (2.0 g, 10 mmol) in chloroform (100 mL) was added isonicotinoyl chloride hydrochloride (1.8 g, 10 mmol) and triethylamine (3.0 mL, 21.5 mmol). The reaction mixture was refluxed for 2 h, and then stirred at room temperature for 24 h. The solution was filtered and the filtrate was evaporated to give a whitish oil. This residue was dissolved in 20 mL H2O, and was then extracted with ethyl acetate (2×100 mL). The organic phases were combined, washed with H2O (50 mL), and dried over Na2SO4. Removal of ethyl acetate gave a whitish oil, isonicotinoyl aspartic acid dimethyl ester. Electrospray MS: m/z=267 (M+1, [C12H14N2O5]+) 1H NMR (CDCl3): 2.91-3.17 (m, 2H, CH2), 3.69 (s, 3H, COOCH3), 3.78 (s, 3H, COOCH3), 4.99-5.05 (m, 1H, CH), 7.38-7.41 (d, 1H, NH), 7.62-7.65 (m, 2H, py), 7.82-7.84 (m, 2H, py).
Reaction SMILES: C(OC1N=NC(C#CC2C=CC(C(F)(F)F)=CN=2)=CC=1OCC1C=CC=CC=1)C1C=CC=CC=1.[CH2:35]([O:42][C:43]1[N:44]=[N:45][C:46]([C:57]#[CH:58])=[CH:47][C:48]=1[O:49][CH2:50][C:51]1[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=1)[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1.[Cl:59][C:60]1[CH:65]=[CH:64][C:63](I)=[CH:62][CH:61]=1>>[CH2:35]([O:42][C:43]1[N:44]=[N:45][C:46]([C:57]#[C:58][C:63]2[CH:64]=[CH:65][C:60]([Cl:59])=[CH:61][CH:62]=2)=[CH:47][C:48]=1[O:49][CH2:50][C:51]1[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=1)[C:36]1[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=1
Reactant: C#Cc1cc(OCc2ccccc2)c(OCc2ccccc2)nn1
Reactant: Clc1ccc(I)cc1
Agent: FC(F)(F)c1ccc(C#Cc2cc(OCc3ccccc3)c(OCc3ccccc3)nn2)nc1
Product: Clc1ccc(C#Cc2cc(OCc3ccccc3)c(OCc3ccccc3)nn2)cc1
Yield: 70 %

Procedure:
Prepared as described for 3,4-bis(benzyloxy)-6-{[5-(trifluoromethyl)pyridin-2-yl]ethynyl}pyridazine (Intermediate 6) from 3,4-bis(benzyloxy)-6-ethynylpyridazine (Intermediate 5) and 1-chloro-4-iodobenzene in 70% yield.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:12]=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]=1.[C:13]1([OH:19])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(=O)([O-])[O-].[K+].[K+].C(=O)([O-])[O-].[Cs+].[Cs+].[I-].[Na+]>CC(C)=O>[O:19]([CH2:2][C:3]1[CH:12]=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: ClCc1ccc2ccccc2n1
Reactant: Oc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Agent: [I-]
Solvent: CC(C)=O
Product: c1ccc(OCc2ccc3ccccc3n2)cc1
Temperature: 25 °C

Procedure:
A mixture of 2-chloromethyl quinoline (0.05 mol), phenol (0.055 mol), finely powdered potassium carbonate (0.055 mol), cesium carbonate (0.005 mol) and sodium iodide (0.0025 mol) in acetone was refluxed for about 4 hours. The reaction mixture was cooled to room temperature and filtered and the filtrate was concentrated and dissolved in ether. The ether solution was washed thoroughly with lN NaOH solution, water and brine. After drying the ether solution over anhydrous magnesium sulfate, and filtering off the drying agent, the solvent was evaporated off to leave the crude product which was crystallized from hexane and ether to yield the desired compound as a light yellow solid, m.p. 79.5°-80.5° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[CH3:13])[C:9](OC1C=CC=CC=1)=[N:8][CH:7]=[CH:6]2.C([O-])(=O)C.[NH4+:25]>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[CH3:13])[C:9]([NH2:25])=[N:8][CH:7]=[CH:6]2
Reactant: COc1cc2ccnc(Oc3ccccc3)c2cc1C
Reactant: [NH4+]
Agent: CC(=O)[O-]
Product: COc1cc2ccnc(N)c2cc1C
Temperature: 170 °C
Reaction time: 5 h
Yield: 80 %

Procedure:
A mixture of the crude 6-methoxy-7-methyl-1-phenoxyisoquinoline (9 g, 33.96 mmol) and ammonium acetate (26 g) was melted with stirring at 170° C. for 5 h. The mixture was partitioned between aqueous sodium hydroxide (2 M) and ethyl acetate. The phases were separated and the organic phase extracted with dilute aqueous hydrochloric acid. The acidic aqueous phase was neutralized to pH 12 using sodium hydroxide (2M), extracted with ethyl acetate, dried (MgSO4) then dried in vacuo to give 6-methoxy-7-methylisoquinolin-1-ylamine (5.11 g, 27.18 mmol).
Reaction SMILES: [C:1]([NH:9][C:10]1[C:11]([N+:23]([O-:25])=[O:24])=[CH:12][C:13]2[O:18][C:17]([CH3:20])([CH3:19])[CH:16]3[O:21][CH:15]3[C:14]=2[CH:22]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:26]1[CH2:30][CH2:29][CH2:28][CH2:27]1>C(O)C>[C:1]([NH:9][C:10]1[C:11]([N+:23]([O-:25])=[O:24])=[CH:12][C:13]2[O:18][C:17]([CH3:20])([CH3:19])[C@@H:16]([OH:21])[C@H:15]([N:26]3[CH2:30][CH2:29][CH2:28][CH2:27]3)[C:14]=2[CH:22]=1)(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC1(C)Oc2cc([N+](=O)[O-])c(NC(=O)c3ccccc3)cc2C2OC21
Reactant: C1CCNC1
Solvent: CCO
Product: CC1(C)Oc2cc([N+](=O)[O-])c(NC(=O)c3ccccc3)cc2[C@@H](N2CCCC2)[C@@H]1O
Temperature: 25 °C
Yield: 23 %

Procedure:
A solution of an ethanol (5 mL) solution of a 6-(benzoylamino)-3,4-epoxy-3,4-dihydro-2,2-dimethyl-7-nitro-2H-1-benzopyran (II-1) (147 mg, 0.43 mmol) was added with a pyrrolidine (0.07 mL) and heated under reflux for two hours. After the mixture was cooled to room temperature, the mixture was concentrated and the obtained residue was purified through silica gel column chromatography (hexane:ethyl acetate=3:1) to obtain the intended product (40.3 mg, 23%) as a brown solid.
Reaction SMILES: C[O:2][C:3]([C:5]1[N:6]([CH2:22][CH3:23])[S:7](=[O:21])(=[O:20])[C:8]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH:13]=[CH:12][C:9]=2[C:10]=1[OH:11])=O.[NH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>C1(C)C(C)=CC=CC=1>[CH2:22]([N:6]1[C:5]([C:3]([NH:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[O:2])=[C:10]([OH:11])[C:9]2[CH:12]=[CH:13][C:14]3[C:19]([C:8]=2[S:7]1(=[O:21])=[O:20])=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH3:23]
Reactant: Nc1ccccc1
Reactant: CCN1C(C(=O)OC)=C(O)c2ccc3ccccc3c2S1(=O)=O
Solvent: Cc1ccccc1C
Product: CCN1C(C(=O)Nc2ccccc2)=C(O)c2ccc3ccccc3c2S1(=O)=O

Procedure:
A mixture consisting of 1.65 gm (5 millimols) of 2-ethyl-4-hydroxy-2H-naphtho[2,1-e]-1,2-thiazine-3-carboxylic acid methyl ester -1,1-dioxide, 0.56 gm (6 millimols) of aniline and 150 ml of anhydrous xylene was refluxed for 24 hours in a Soxhlet apparatus equippedwith a 4-A-molecular sieve. After cooling, 1.8 gm (90% of theory) of 2-ethyl-4-hydroxy-N-phenyl-2H-naphtho[2,1-e]-1,2-thiazine-3-carboxamide-1,1-dioxide, m.p. 245°-247° C (from xylene), crystallized out of the reaction mixture.
Reaction SMILES: [C:1]([C:3]([C:12]#[N:13])=[C:4]([NH:6][C:7](=[O:11])[N:8]([CH3:10])[CH3:9])[SH:5])#[N:2].[OH:14]O>O>[C:1]([C:3]1[C:12]([OH:14])=[N:13][S:5][C:4]=1[NH:6][C:7](=[O:11])[N:8]([CH3:10])[CH3:9])#[N:2]
Reactant: CN(C)C(=O)NC(S)=C(C#N)C#N
Reactant: OO
Solvent: O
Product: CN(C)C(=O)Nc1snc(O)c1C#N
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 3-(2,2-Dicyano-1-mercapto-vinyl)-1,1-dimethyl-urea (sodium salt)(30 g, 137 mmol) in water (300 mL) was treated at ambient temperature with hydrogen peroxide (14 mL of a 10 M solution). The reaction warmed and thickened with solid formation and so was treated with additional water (100 mL). The mixture was heated to reflux for 15 minutes, effecting complete dissolution and then cooled to ambient temperature. After 1 hour at ambient temperature, the mixture was concentrated to a constant weight (35 g, >100% due to water content) and was used immediately in the next step.
Reaction SMILES: [C:1]([CH2:3][C:4]1[C:12]2[C:7](=[N:8][CH:9]=[CH:10][CH:11]=2)[NH:6][CH:5]=1)#[N:2].S(Cl)([Cl:16])(=O)=O>C(O)(=O)C>[Cl:16][C:5]1[NH:6][C:7]2=[N:8][CH:9]=[CH:10][CH:11]=[C:12]2[C:4]=1[CH2:3][C:1]#[N:2]
Reactant: O=S(=O)(Cl)Cl
Reactant: N#CCc1c[nH]c2ncccc12
Solvent: CC(=O)O
Product: N#CCc1c(Cl)[nH]c2ncccc12
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
3-cyanomethylpyrrolo[2,3-b]pyridine (1,55 g, 0.098 mol) was treated in 5 ml acetic acid with an equimolecular amount of sulfurylchloride at 0° C. for 5 min. The mixture was allowed to warm to room temperature and was stirred 5 min. After evaporation the residue was dissolved in methylen chloride and was treated with bicarbonate. The organic layer was separated, dried over Na2SO4 and the solvent was removed under reduced pressure. Chromatography on silica gel eluting with ethyl acetate gave the desired product. (0,4 g 21%).
Reaction SMILES: CC(OC(/N=N/C(OC(C)C)=O)=O)C.[CH3:15][C@H:16]1[CH2:44][O:43][C@@:19]2([O:23][C@H:22]3[CH2:24][C@H:25]4[C@@H:30]5[CH2:31][CH2:32][C@@H:33]6[CH2:38][C@H:37]([OH:39])[CH2:36][CH2:35][C@:34]6([CH3:40])[C@H:29]5[CH2:28][CH2:27][C@:26]4([CH3:41])[C@H:21]3[C@@H:20]2[CH3:42])[CH2:18][CH2:17]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:64](O)(=[O:71])[C:65]1[CH:70]=[CH:69][CH:68]=[CH:67][CH:66]=1>C1COCC1>[CH3:15][CH:16]1[CH2:44][O:43][C:19]2([O:23][CH:22]3[CH2:24][CH:25]4[CH:30]5[CH2:31][CH2:32][CH:33]6[CH2:38][CH:37]([O:39][C:64]([C:65]7[CH:70]=[CH:69][CH:68]=[CH:67][CH:66]=7)=[O:71])[CH2:36][CH2:35][C:34]6([CH3:40])[CH:29]5[CH2:28][CH2:27][C:26]4([CH3:41])[CH:21]3[CH:20]2[CH3:42])[CH2:18][CH2:17]1
Reactant: C[C@@H]1CC[C@@]2(OC1)O[C@H]1C[C@H]3[C@@H]4CC[C@@H]5C[C@H](O)CC[C@]5(C)[C@H]4CC[C@]3(C)[C@H]1[C@@H]2C
Reactant: O=C(O)c1ccccc1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC1CCC2(OC1)OC1CC3C4CCC5CC(OC(=O)c6ccccc6)CCC5(C)C4CCC3(C)C1C2C
Temperature: 25 °C

Procedure:
A solution of diisopropylazodicarboxylate (0.81 g, 4.0 mmol) in dry THF (2 ml) was added to a stirred solution of epismilagenin (0.83 g, 2.0 mmol), triphenylphosphine (1.05 g, 4.0 mmol) and benzoic acid (0.49 g, 4.0 mmol) in dry THF (20 ml). The mixture was stirred at room temperature and monitored by TLC. After 2 h all the starting material had been consumed. The solvent was removed in vacuo, the residual syrup dissolved in ether (30 ml) and the solution washed with aqueous saturated sodium hydrogen carbonate (25 ml). The organic layer was dried over MgSO4 and passed down a short silica pad, the pad being washed with ether. The combined washings and filtrate were concentrated in vacuo to afford smilagenin benzoate as a white solid.
Reaction SMILES: [CH:1]1[C:11]2[C:10]3[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=3[CH2:8][N:7]([C:16](=[NH:20])[O:17][CH2:18][CH3:19])[CH2:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.[CH:21]1([C:24](Cl)=[O:25])[CH2:23][CH2:22]1>>[CH:21]1([C:24]([N:20]=[C:16]([N:7]2[CH2:6][C:5]3[CH:4]=[CH:3][CH:2]=[CH:1][C:11]=3[C:10]3[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=3[CH2:8]2)[O:17][CH2:18][CH3:19])=[O:25])[CH2:23][CH2:22]1
Reactant: CCOC(=N)N1Cc2ccccc2-c2ccccc2C1
Reactant: O=C(Cl)C1CC1
Product: CCOC(=NC(=O)C1CC1)N1Cc2ccccc2-c2ccccc2C1

Procedure:
starting from ethyl 5,7-dihydro-6H-dibenz[c,e]-azepine-6-carboximidate and cyclopropanecarboxylic acid chloride, there is obtained ethyl N-cyclopropylcarbonyl-5,7-dihydro-6H-dibenz[c,e]azepine-6-carboximidate, m.p. 97°-99° C.;
Reaction SMILES: [C:1]([C:4]1[CH:23]=[CH:22][C:7]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([C:15]3[CH2:20][N:19]([CH3:21])[CH2:18][CH2:17][CH:16]=3)[CH:10]=2)=[C:6]([N+:24]([O-])=O)[CH:5]=1)(=[O:3])[CH3:2].[CH2:27](O)C>[Pd]>[C:1]([C:4]1[CH:23]=[CH:22][C:7]2[N:8]([C:9]3[CH:14]=[CH:13][CH:12]=[C:11]([CH:15]4[CH2:16][CH2:17][CH2:18][N:19]([CH3:21])[CH2:20]4)[CH:10]=3)[CH:27]=[N:24][C:6]=2[CH:5]=1)(=[O:3])[CH3:2]
Reactant: CCO
Reactant: CC(=O)c1ccc(Nc2cccc(C3=CCCN(C)C3)c2)c([N+](=O)[O-])c1
Agent: [Pd]
Product: CC(=O)c1ccc2c(c1)ncn2-c1cccc(C2CCCN(C)C2)c1
Temperature: 80 °C
Yield: 50 %

Procedure:
To a solution of 4-acetyl-N-[3-(1-methyl-1,2,3,6-tetrahydropyrid-5-yl)phenyl]-2-nitroaniline (6, Ex. 12a) (1 g, 3 mmol) in ethanol (50 ml) was added a catalytic amount of palladium on charcoal and the mixture was hydrogenated at ambient pressure over night. The reaction mixture was filtered through celite and the filtrate was concentrated under reduced pressure. To this concentrate formic acid (10 ml) was added and the resulting solution was stirred at 80° C. over night. Excess formic acid was removed by evaporation. The residue was dissolved in water and rendered alkaline by addition of solid sodium carbonate. Extraction with ethyl acetate and treatment of the extract with activated carbon in ethanol afforded 5-acetyl-1-[3-(1-methylpiperidin-3-yl)phenyl]-benzimidazole (9) (0.5 g, 50%) as an oil. m/e 333.
Reaction SMILES: C(S([NH:7][CH:8]([C:13]1([CH3:17])[CH2:16][O:15][CH2:14]1)[C:9]([NH2:12])=[N:10][OH:11])=O)(C)(C)C.CO[C:20](OC)(N(C)C)[CH3:21].Cl.O1CCOCC1>C(O)(C)C.C(OCC)(=O)C>[CH3:20][C:21]1[O:11][N:10]=[C:9]([CH:8]([C:13]2([CH3:17])[CH2:14][O:15][CH2:16]2)[NH2:7])[N:12]=1
Reactant: CC1(C(NS(=O)C(C)(C)C)C(N)=NO)COC1
Reactant: COC(C)(OC)N(C)C
Agent: Cl
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Solvent: CC(C)O
Product: Cc1nc(C(N)C2(C)COC2)no1
Temperature: 25 °C
Reaction time: 8 h
Yield: 20.1 %

Procedure:
To a solution of 2-(tert-butylsulfinylamino)-N′-hydroxy-2-(3-methyloxetan-3-yl)acetamidine (example 254a, 0.25 g, 949 μmol) in isopropanol (5.00 ml) was added 1,1-dimethoxy-N,N-dimethylethanamine (506 mg, 3.8 mmol) and the reaction mixture was stirred at room temperature overnight. A solution of 4M hydrochloric acid in dioxane (1.19 ml, 4.75 mmol) was added to the reaction mixture cooled down to 0° C. and the reaction was stirred at 0° C. for 2 hours. The reaction mixture was diluted with ethyl acetate and extracted with a 2M aqueous solution of sodium carbonate. The organic phase was collected and the aqueous phase was back-extracted with ethyl acetate. The combined organic phases were dried over sodium sulfate and evaporated down to dryness. The crude material was purified by flash chromatography on silica eluting with a dichloromethane-methanol gradient to yield the title compound (35 mg, 20%) as a yellow oil which was not totally pure and was used without any further purification. MS (ESI, m/z): 184.1 (M+H+).
Reaction SMILES: [C:1]([O:5][P:6]([O:13][CH2:14][CH2:15][NH:16]C(=O)OCC1C=CC=CC=1)([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7])([CH3:4])([CH3:3])[CH3:2]>CO.[Pd]>[P:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])([O:8][C:9]([CH3:10])([CH3:12])[CH3:11])([O:13][CH2:14][CH2:15][NH2:16])=[O:7]
Reactant: CC(C)(C)OP(=O)(OCCNC(=O)OCc1ccccc1)OC(C)(C)C
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)OP(=O)(OCCN)OC(C)(C)C
Yield: 79 %

Procedure:
A solution of 225 (1.17 g, 3.02 mmol) in MeOH (30 mL) with Pd/C (5%, 0.21 g) was hydrogenated at 50 psi for 2.5 h. The mixture was filtered through Celite, washing with MeOH, and the filtrate was evaporated. The residue was dissolved in CH2Cl and the solution was filtered once more, then evaporated to give 2-aminoethyl di(tert-butyl) phosphate (226) (604 mg, 79%) as a colourless oil: 1H NMR [CDCl3] δ 4.01-3.94 (m, 2H), 2.96-2.90 (m, 2H), 1.58 (br s, 2H), 1.49 (s, 18H). HRMS (FAB) calcd. for C10H25NO4P (MH+) m/z 254.1521, found 254.1519.
Reaction SMILES: [F:1][C:2]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[C:13]([O:15][CH3:16])[CH:12]=[CH:11][N:10]=2)=[CH:5][C:3]=1[NH2:4].[C:17]([O:21][C:22]([NH:24][C:25]([NH:27][C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])=S)=[O:23])([CH3:20])([CH3:19])[CH3:18].C(N(C(C)C)CC)(C)C.[I-].C[N+]1C=CC=CC=1Cl>ClCCl>[C:31]([O:30][C:28]([NH:27][C:25]([NH:24][C:22]([O:21][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:23])=[N:4][C:3]1[CH:5]=[C:6]([C:9]2[CH:14]=[C:13]([O:15][CH3:16])[CH:12]=[CH:11][N:10]=2)[CH:7]=[CH:8][C:2]=1[F:1])=[O:29])([CH3:34])([CH3:33])[CH3:32]
Reactant: CC(C)(C)OC(=O)NC(=S)NC(=O)OC(C)(C)C
Reactant: COc1ccnc(-c2ccc(F)c(N)c2)c1
Agent: C[n+]1ccccc1Cl
Agent: [I-]
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccnc(-c2ccc(F)c(N=C(NC(=O)OC(C)(C)C)NC(=O)OC(C)(C)C)c2)c1
Reaction time: 18 h
Yield: 67.5 %

Procedure:
To a suspension of 2-fluoro-5-(4-methoxypyridin-2-yl)aniline (174 mg), N,N′-bis(tert-butoxycarbonyl)thiourea (265 mg) and diisopropylethylamine (0.417 ml) in dichloromethane (10 ml) was added 1-methyl-2-chloropyridinium iodide (266 mg), and the mixture was stirred for 18 hours. The mixture was diluted with dichloromethane, washed with water and brine, dried over magnesium sulfate and evaporated under reduced pressure. The residue was purified by column chromatography (silica gel 30 g, n-hexane:ethyl acetate=3:1) to give N,N′-bis(tert-butoxycarbonyl)-N″-(2-fluoro-5-(4-methoxypyridin-2-yl)phenyl)guanidine (248 mg).
Reaction SMILES: [Cl:1]N1C(=O)CCC1=O.[F:9][C:10]1[CH:15]=[C:14]([N+:16]([O-:18])=[O:17])[CH:13]=[CH:12][C:11]=1[NH:19][C:20]1[C:21]2[CH:28]=[CH:27][NH:26][C:22]=2[N:23]=[CH:24][CH:25]=1.C(=O)(O)[O-].[Na+]>C1COCC1>[Cl:1][C:28]1[C:21]2[C:20]([NH:19][C:11]3[CH:12]=[CH:13][C:14]([N+:16]([O-:18])=[O:17])=[CH:15][C:10]=3[F:9])=[CH:25][CH:24]=[N:23][C:22]=2[NH:26][CH:27]=1
Reactant: O=C1CCC(=O)N1Cl
Reactant: O=[N+]([O-])c1ccc(Nc2ccnc3[nH]ccc23)c(F)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: O=[N+]([O-])c1ccc(Nc2ccnc3[nH]cc(Cl)c23)c(F)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
108 mg (810 μmol) of N-chlorosuccinimide are added to a solution of 200 mg (730 μmol) of N-(2-fluoro-4-nitrophenyl)-1H-pyrrolo[2,3-b]pyridine-4-amine in 5 ml of THF, and the mixture is stirred at RT overnight. To bring the reaction to completion, another 49 mg (365 μmol) of N-chlorosuccinimide are added, and the mixture is stirred for another night. Saturated sodium bicarbonate solution is then added to the reaction mixture, and the mixture is extracted with ethyl acetate. The organic phases are washed with saturated sodium chloride solution and then dried with magnesium sulfate, and the solvent is removed under reduced pressure. Purification by column chromatography on silica gel (mobile phase: gradient cyclohexane/ethyl acetate 1:1 to ethyl acetate 100%) and preparative RP-HPLC affords the title compound.
Reaction SMILES: C([O:4][C@@H:5]1[C@@H:10]([O:11]C(=O)C)[C@H:9]([O:15]C(=O)C)[C@@H:8]([CH2:19][O:20]C(=O)C)[O:7][C@H:6]1[O:24][C:25]1[C:29]([CH2:30][C:31]2[CH:36]=[CH:35][C:34]([O:37][CH2:38][CH2:39][CH2:40][NH2:41])=[CH:33][CH:32]=2)=[C:28]([CH:42]([CH3:44])[CH3:43])[NH:27][N:26]=1)(=O)C.C[O-].[Na+]>CO>[NH2:41][CH2:40][CH2:39][CH2:38][O:37][C:34]1[CH:33]=[CH:32][C:31]([CH2:30][C:29]2[C:25]([O:24][C@@H:6]3[O:7][C@H:8]([CH2:19][OH:20])[C@@H:9]([OH:15])[C@H:10]([OH:11])[C@H:5]3[OH:4])=[N:26][NH:27][C:28]=2[CH:42]([CH3:44])[CH3:43])=[CH:36][CH:35]=1
Reactant: CC(=O)OC[C@H]1O[C@@H](Oc2n[nH]c(C(C)C)c2Cc2ccc(OCCCN)cc2)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: CC(C)c1[nH]nc(O[C@@H]2O[C@H](CO)[C@@H](O)[C@H](O)[C@H]2O)c1Cc1ccc(OCCCN)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 78.2 %

Procedure:
To a solution of 3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-4-{[4-(3-aminopropoxy)phenyl]methyl}-5-isopropyl-1H-pyrazole (0.1 g) in methanol (2 mL) was added sodium methoxide (28% methanol solution, 0.062 mL), and the mixture was stirred at room temperature for 30 minutes. The reaction mixture was concentrated under reduced pressure, and the residue was purified by solid phase extraction on ODS (washing solvent: distilled water, eluent: methanol) to give the title compound (57 mg).
Reaction SMILES: [F:1][C:2]1[CH:30]=[CH:29][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([S:16]([CH3:19])(=[O:18])=[O:17])=[CH:13][CH:14]=3)[CH:9]=[C:8]2[C:20]2[CH:25]=[CH:24][C:23]([C:26]([OH:28])=O)=[CH:22][N:21]=2)=[CH:4][CH:3]=1.[CH3:31][NH2:32].CO>O1CCCC1>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([S:16]([CH3:19])(=[O:17])=[O:18])=[CH:13][CH:14]=3)[CH:9]=[C:8]2[C:20]2[CH:25]=[CH:24][C:23]([C:26]([NH:32][CH3:31])=[O:28])=[CH:22][N:21]=2)=[CH:29][CH:30]=1
Reactant: CN
Reactant: CS(=O)(=O)c1ccc2c(c1)cc(-c1ccc(C(=O)O)cn1)n2Cc1ccc(F)cc1
Solvent: C1CCOC1
Solvent: CO
Product: CNC(=O)c1ccc(-c2cc3cc(S(C)(=O)=O)ccc3n2Cc2ccc(F)cc2)nc1
Temperature: 22.5 °C
Reaction time: 0.17 h

Procedure:
A mixture of 1-(4-fluorobenzyl)-2-(5-carboxypyridin-2-yl)-5-methanesulfonylindole (20 mg), N,N′-carbonyldiimidazole (10 mg) and tetrahydrofuran (1 ml) was stirred at 15 to 30° C. for 10 minutes under nitrogen atmosphere, followed by addition of a 40% methylamine/methanol solution (0.1 ml), and the mixture was further stirred at 15 to 30° C. for 10 minutes. The reaction solution was then concentrated under reduced pressure. The resulting residue was subjected to silica gel column chromatography (hexane:ethyl acetate=1:5) to obtain 13 mg of the desired product.
Reaction SMILES: [O:1]1[CH2:5][CH2:4][O:3][CH:2]1[C:6]1[CH:13]=[CH:12][C:9]([C:10]#[N:11])=[CH:8][CH:7]=1.[SH2:14]>N1C=CC=CC=1.O>[O:1]1[CH2:5][CH2:4][O:3][CH:2]1[C:6]1[CH:13]=[CH:12][C:9]([C:10](=[S:14])[NH2:11])=[CH:8][CH:7]=1
Reactant: N#Cc1ccc(C2OCCO2)cc1
Reactant: S
Solvent: c1ccncc1
Solvent: O
Product: NC(=S)c1ccc(C2OCCO2)cc1
Temperature: 25 °C
Yield: 86 %

Procedure:
To a solution of 4-(1,3-dioxolan-2-yl)benzonitrile (2 g, 0.01 mol) in dry pyridine (50 mL) and TEA (5.75 g, 0.057 mol) was passed H2S gas (freshly generated) for 1 h with stirring at RT. The reaction mixture was diluted with water (100 mL), extracted with diethyl ether (100 mL), washed with brine (50 mL) and dried. The solvent was removed under vacuum and the crude product was purified by column chromatography over silica gel (PetEther/EtOAc, 3/7) to give 4-(1,3-dioxolan-2-yl)benzenecarbothioamide (1.9 g, 86%) as yellow solid. TLC (PetEther/EtOAc 3/7), Rf=0.35
Reaction SMILES: [CH3:1][CH:2]1[CH2:6][CH2:5][CH2:4][NH:3]1.Cl[CH2:8][CH2:9][CH2:10][O:11][C:12]1[CH:17]=[CH:16][C:15]([I:18])=[CH:14][CH:13]=1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C.[I-].[Na+]>[I:18][C:15]1[CH:16]=[CH:17][C:12]([O:11][CH2:10][CH2:9][CH2:8][N:3]2[CH2:4][CH2:5][CH2:6][CH:2]2[CH3:1])=[CH:13][CH:14]=1
Reactant: CC1CCCN1
Reactant: ClCCCOc1ccc(I)cc1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC#N
Product: CC1CCCN1CCCOc1ccc(I)cc1
Yield: 90.4 %

Procedure:
2-methylpyrrolidine a4 (2 g, 23 mmol, 2 eq) is added into a suspension of 1-(3-chloropropoxy)-4-iodobenzene a3 (3.48 g, 11.7 mmol, 1 eq), potassium carbonate (3.24 g, 23 mmol, 2 eq) and sodium iodide (0.035 g, 0.23 mmol, 0.02 eq) in acetonitrile (120 ml), and the mixture is heated at reflux overnight. The solvent is then removed in vacuo, and the residue is dissolved in ethyl acetate. The organic layer is washed twice with a saturated solution of aqueous sodium hydrogenocarbonate, dried over magnesium sulfate, and concentrated in vacuo to give 3.65 g of a yellow oil. This oil is purified by chromatography over silicagel (dichloromethane/methanol/ammonia:98/2/0.2) to afford 2.57 g of 1-[3-(4-iodophenoxy)propyl]-2-methylpyrrolidine a5 as a yellow oil.