Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[C:8]([CH3:9])=[CH:7][C:5]([NH2:6])=[C:4]([O:10][CH3:11])[CH:3]=1.C(Cl)Cl.Cl[C:16]([O:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:17]>O>[CH3:1][C:2]1[C:8]([CH3:9])=[CH:7][C:5]([NH:6][C:16](=[O:17])[O:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[C:4]([O:10][CH3:11])[CH:3]=1
Reactant: COc1cc(C)c(C)cc1N
Reactant: O=C(Cl)Oc1ccccc1
Solvent: O
Solvent: ClCCl
Product: COc1cc(C)c(C)cc1NC(=O)Oc1ccccc1
Reaction time: 2 h
Yield: 98 %

Procedure:
To 4,5-dimethyl-2-methoxyaniline(4.50 g, 0.03 mol), methylene chloride(100 ml) was added and phenyl chloroformate(4.80 g, 0.03 mol) was added slowly. The resulting solution was stirred for 2 hrs and thereto water(150 ml) was added, and extracted with methylene chloride and purified by column chromatography to obtain the titled compound.
Reaction SMILES: OO.[C:3]1([N:9]2[C:14](=[O:15])[C:13]([Cl:16])=[C:12]([S:17][CH:18]3[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]3)[CH:11]=[N:10]2)[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.C(O)(=[O:26])C>O>[C:3]1([N:9]2[C:14](=[O:15])[C:13]([Cl:16])=[C:12]([S:17]([CH:18]3[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]3)=[O:26])[CH:11]=[N:10]2)[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: O=c1c(Cl)c(SC2CCCCC2)cnn1-c1ccccc1
Reactant: CC(=O)O
Agent: OO
Solvent: O
Product: O=c1c(Cl)c(S(=O)C2CCCCC2)cnn1-c1ccccc1
Reaction time: 12 h

Procedure:
5.1 parts by volume of 30% strength by weight hydrogen peroxide were added dropwise to a solution of 16 parts by weight of 1-phenyl-4-(cyclohexylthio)-5-chloropyridazin-6-one in 100 parts by volume of glacial acetic acid, and stirring was continued for 12 hours at 60° C. The reaction mixture was then stirred into 1,000 parts by volume of water, and the precipitate was filtered off under suction, washed with water and dried under reduced pressure. 16.3 parts by weight of 1-phenyl-4-(cyclohexyl-sulfinyl)-5-chloropyridazin-6-one of melting point 128°-130° C. were obtained (compound No.1).
Reaction SMILES: C(Cl)(Cl)Cl.C1(C)C=CC(S(O[CH2:15][CH:16]2[S:28][C:20]3=[N:21][C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=4[N:19]3[CH2:18][CH2:17]2)(=O)=O)=CC=1.[NH:30]1[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]1>O>[N:30]1([CH2:15][CH:16]2[S:28][C:20]3=[N:21][C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=4[N:19]3[CH2:18][CH2:17]2)[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]1
Reactant: Cc1ccc(S(=O)(=O)OCC2CCn3c(nc4ccccc43)S2)cc1
Reactant: C1CNCCN1
Solvent: ClC(Cl)Cl
Solvent: O
Product: c1ccc2c(c1)nc1n2CCC(CN2CCNCC2)S1
Yield: 51.9 %

Procedure:
To 30 ml of chloroform were dissolved 3 g of 3,4-dihydro-2-p-toluenesulfonyloxymethyl-2H-(1,3)-thiazino[3,2-a]benzimidazole and 10 g of piperazine. The resultant solution was refluxed for 18 hours. The reaction mixture was cooled, added with water and then extracted with chloroform, followed by washing the chloroform layer and dried over anhydrous magnesium sulfate. Chloroform was evaporated under reduced pressure and the residue was chromatographed on silica gel and eluted with chloroform to obtain 1.2 g (Yield: 51%) of the intended product, m.p. 151°-153° C.; IR νmaxKBr cm-1 : 3600-3000, 3100-2800, 1420; Anal. Calcd. for C15H20N4S: C, 62.47; L H, 6.99; N, 19.43; S, 11.11; Found: C, 62.41; H, 7.01; N, 19.70; S, 10.88.
Reaction SMILES: [NH2:1]/[C:2](/[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[C:3]1\[C:4](=[O:12])[C:5]2[CH:11]=[CH:10][CH:9]=[CH:8][C:6]=2[S:7]\1.I([O-])(=O)(=O)=[O:20].C([N+](CCCC)(CCCC)CCCC)CCC>ClCCl>[NH2:1]/[C:2](/[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[C:3]1\[C:4](=[O:12])[C:5]2[CH:11]=[CH:10][CH:9]=[CH:8][C:6]=2[S:7]\1=[O:20]
Reactant: N/C(=C1/Sc2ccccc2C1=O)c1ccccc1
Reactant: [O-][I+3]([O-])([O-])[O-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: ClCCl
Product: N/C(=C1\C(=O)c2ccccc2S1=O)c1ccccc1

Procedure:
7.6 gm (0.003 mol) of (E)-2-[(amino)phenylmethylene]-benzo[b]thiophen-3(2H)-one and 13.75 gm (0.03 mol) of tetrabutylammonium periodate (prepared from tetrabutylammonium hydrogen sulfate and sodium metaperiodate in water) in 50 ml of dichloromethane were refluxed for about 2 hours. After the end of the reaction, which was monitored by thin-layer chromatography, the mixture was allowed to cool and was then filtered through a column of silicagel (200 gm), finally using dichloromethane/ethyl acetate (97:3 v/v) as the eluant. By evaporating the appropriate fractions and subsequently recrystallizing the residue from ethanol, 5.8 gm (72% of theory) of pale yellow crystals, m.p. 246°-247° C. (decomposition), were obtained.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:11][C:12]([O:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:13])[CH2:6][CH2:5]2.[CH3:22][S:23](Cl)(=[O:25])=[O:24]>N1C=CC=CC=1>[CH3:22][S:23]([NH:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:11][C:12]([O:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:13])[CH2:6][CH2:5]2)(=[O:25])=[O:24]
Reactant: Nc1ccc2c(c1)CCN2CC(=O)OCc1ccccc1
Reactant: CS(=O)(=O)Cl
Solvent: c1ccncc1
Product: CS(=O)(=O)Nc1ccc2c(c1)CCN2CC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 72.6 %

Procedure:
To a solution of benzyl 2-(5-aminoindolin-1-yl)acetate (0.610 g, 2.161 mmol) in pyridine (15 ml), methanesulfonyl chloride (0.251 ml, 3.24 mmol) was added at 0° C. The mixture was allowed to warm to room temperature and stirred for 1 hour. The solvent was removed under vacuum and the residue was partitioned between DCM and water; the organic phase was washed with brine, dried over sodium sulfate and evaporated to dryness. The crude was purified by flash chromatography on silica gel column (petroleum ether:ethyl acetate=70:30 to 60:40) affording benzyl 2-(5-(methylsulfonamido)indolin-1-yl)acetate (0.565 g, 1.568 mmol, 73% yield). MS/ESI+ 361.0 [MH]+.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[CH:5][N:4]=[CH:3]1.C([Li])CCC.Cl[Si](CC)(CC)CC.[Cl:20][C:21]1[CH:47]=[CH:46][C:24]([C:25]([C:27]2[CH:28]=[C:29]3[C:34](=[CH:35][CH:36]=2)[N:33]([CH3:37])[C:32](=[O:38])[CH:31]=[C:30]3[C:39]2[CH:44]=[CH:43][CH:42]=[C:41]([Cl:45])[CH:40]=2)=[O:26])=[CH:23][CH:22]=1>O1CCCC1.CCCCCC>[OH:26][C:25]([C:24]1[CH:23]=[CH:22][C:21]([Cl:20])=[CH:47][CH:46]=1)([C:6]1[N:2]([CH3:1])[CH:3]=[N:4][CH:5]=1)[C:27]1[CH:28]=[C:29]2[C:34](=[CH:35][CH:36]=1)[N:33]([CH3:37])[C:32](=[O:38])[CH:31]=[C:30]2[C:39]1[CH:44]=[CH:43][CH:42]=[C:41]([Cl:45])[CH:40]=1
Reactant: Cn1ccnc1
Reactant: Cn1c(=O)cc(-c2cccc(Cl)c2)c2cc(C(=O)c3ccc(Cl)cc3)ccc21
Agent: CC[Si](Cl)(CC)CC
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: Cn1cncc1C(O)(c1ccc(Cl)cc1)c1ccc2c(c1)c(-c1cccc(Cl)c1)cc(=O)n2C

Procedure:
Herein, in step 1, the intermediate 1-methyl imidazole in tetrahydrofuran, is mixed with a solution of n-butyllithium in a hexane solvent to which is added chlorotriethylsilane (triethylsilyl chloride), followed by a further addition of n-butyllithium in hexane, the resulting mixture being cooled to −78° C. before the addition of a solution of a compound of formula (I), i.e. 6-(4-chlorobenzoyl)-4-(3-chlorophenyl)-1-methyl-2(1H)-quinolinone in tetrahydrofuran. The reaction mixture is subsequently brought to room temperature, and then hydrolysed, extracted with ethyl acetate and the organic layer worked up to obtain a compound of formula (II), i.e. (±)-6-[hydroxy (4-chlorophenyl)(1-methyl-1H-imidazol-5-yl)methyl]-4-(3-chlorophenyl)-1-methyl-2(1H)-quinolinone.
Reaction SMILES: Cl[CH2:2][CH2:3][N:4]1[CH2:9][CH2:8][CH:7]([NH:10][C:11](=[O:20])[C:12]2[C:17]([Cl:18])=[CH:16][CH:15]=[CH:14][C:13]=2[Cl:19])[CH2:6][CH2:5]1.[CH3:21][C:22]1[CH:35]=[CH:34][C:25]([CH2:26][NH:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][N:29]=2)=[CH:24][CH:23]=1>>[Cl:19][C:13]1[CH:14]=[CH:15][CH:16]=[C:17]([Cl:18])[C:12]=1[C:11]([NH:10][CH:7]1[CH2:8][CH2:9][N:4]([CH2:3][CH2:2][N:27]([CH2:26][C:25]2[CH:24]=[CH:23][C:22]([CH3:21])=[CH:35][CH:34]=2)[C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][N:29]=2)[CH2:5][CH2:6]1)=[O:20]
Reactant: Cc1ccc(CNc2ccccn2)cc1
Reactant: O=C(NC1CCN(CCCl)CC1)c1c(Cl)cccc1Cl
Product: Cc1ccc(CN(CCN2CCC(NC(=O)c3c(Cl)cccc3Cl)CC2)c2ccccn2)cc1

Procedure:
The title compound is prepared in a manner similar to Example 11 using 1-(2-chloroethyl)-4-(2,6-dichlorobenzamido)piperidine and 2-(p-methylbenzyl)aminopyridine.
Reaction SMILES: Cl[C:2]1[CH:17]=[C:6]2[C:7]3[C:12]([CH2:13][CH2:14][N:5]2[C:4](=[O:18])[N:3]=1)=[CH:11][C:10]([O:15][CH3:16])=[CH:9][CH:8]=3.[CH3:19][C:20]1[CH:26]=[CH:25][CH:24]=[C:23]([CH3:27])[C:21]=1[NH2:22]>>[CH3:19][C:20]1[CH:26]=[CH:25][CH:24]=[C:23]([CH3:27])[C:21]=1[NH:22][C:2]1[CH:17]=[C:6]2[C:7]3[C:12]([CH2:13][CH2:14][N:5]2[C:4](=[O:18])[N:3]=1)=[CH:11][C:10]([O:15][CH3:16])=[CH:9][CH:8]=3
Reactant: Cc1cccc(C)c1N
Reactant: COc1ccc2c(c1)CCn1c-2cc(Cl)nc1=O
Product: COc1ccc2c(c1)CCn1c-2cc(Nc2c(C)cccc2C)nc1=O

Procedure:
The title compound was prepared from 2-chloro-9-methoxy-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one (4) and 2,6-dimethyl-aniline as in Example 1 d. 1H-NMR as two isomeric mixture (400 MHz, d6-DMSO) δ 8.96 and 8.87 (br, 1H), 7.75 and 7.29 (d, 1H), 7.23-6.80 (5H), 6.37 and 5.33 (br, 1H), 3.96 and 3.92 (t, 2H), 3.84 and 3.78 (s, 3H), 2.95 (t, 2H) and 2.18 and 2.16 (s, 6H); MS (ESI) (M+H)+ 348.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]([O:11][CH2:12][CH2:13][CH2:14][N:15]2[CH2:20][CH2:19][O:18][CH2:17][CH2:16]2)[C:8]([O:21][CH3:22])=[CH:7][C:3]=1[C:4]([NH2:6])=[O:5].[CH3:23]N(C=NC=[N+](C)C)C.[Cl-].C(O)(=O)C.C([O-])(=O)C.[Na+]>O1CCOCC1>[OH:5][C:4]1[C:3]2[C:2](=[CH:10][C:9]([O:11][CH2:12][CH2:13][CH2:14][N:15]3[CH2:20][CH2:19][O:18][CH2:17][CH2:16]3)=[C:8]([O:21][CH3:22])[CH:7]=2)[N:1]=[CH:23][N:6]=1
Reactant: COc1cc(C(N)=O)c(N)cc1OCCCN1CCOCC1
Reactant: CN(C)C=NC=[N+](C)C
Agent: CC(=O)[O-]
Agent: [Cl-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: C1COCCO1
Product: COc1cc2c(O)ncnc2cc1OCCCN1CCOCC1
Temperature: 25 °C
Yield: 77.7 %

Procedure:
A mixture of 2-amino-5-methoxy-4-(3-morpholinopropoxy)benzamide (4.57 g, 12.25 mmol) and Gold's reagent (2.6 g, 15.89 mmol) in dioxane (35 ml) was heated at reflux for 5 hours. Acetic acid (0.55 ml) and sodium acetate (1.0 g) were added to the reaction mixture which was heated for a further 3 hours. The mixture was cooled to ambient temperature and the volatiles removed by evaporation. The residue was adjusted to pH7 with 2M sodium hydroxide and then purified on a Diaion (trade mark of Mitsubishi) HP20SS resin column, eluting with methanol (gradient of 0 to 60%) in water. Concentration of the fractions by evaporation gave a precipitate which was collected by filtration and dried under vacuum over phosphorus pentoxide to give 4-hydroxy-6-methoxy-7-(3-morpholinopropoxy)quinazoline (3.04 g, 78%) as a white solid.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([O:11][C:12]2[CH:19]=[CH:18][C:15]([CH:16]=[O:17])=[CH:14][CH:13]=2)[CH:5]=[CH:6][C:7]=1[N+:8]([O-:10])=[O:9].C1(C)C=CC(S(O)(=O)=O)=CC=1.[CH2:31](O)[CH2:32][OH:33]>C1(C)C=CC=CC=1.C(OC(=O)C)C>[CH3:1][C:2]1[CH:3]=[C:4]([O:11][C:12]2[CH:19]=[CH:18][C:15]([CH:16]3[O:33][CH2:32][CH2:31][O:17]3)=[CH:14][CH:13]=2)[CH:5]=[CH:6][C:7]=1[N+:8]([O-:10])=[O:9]
Reactant: Cc1cc(Oc2ccc(C=O)cc2)ccc1[N+](=O)[O-]
Reactant: OCCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: Cc1cc(Oc2ccc(C3OCCO3)cc2)ccc1[N+](=O)[O-]
Temperature: 25 °C
Yield: 98 %

Procedure:
4-[(3-Methyl-4-nitrophenyl)oxy]benzaldehyde (1.72 g, 6.4 mmol), p-toluenesulfonic acid (120 mg, 0.64 mmol), and ethylene glycol (1.7 mL, 32 mmol) were heated to reflux in 70 mL toluene for 16 hours in a round bottom flask equipped with a Dean-Stark trap. The reaction mixture was cooled to room temperature, diluted with ethylacetate and extracted with 1N NaOH. The organic layer was dried over MgSO4, filtered and concentrated to afford 1.89 g crude 2-{4-[(3-methyl-4-nitrophenyl)oxy]phenyl}-1,3-dioxolane, which was used without further purification.
Reaction SMILES: [CH3:1][NH:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.I[CH2:10][CH2:11][OH:12].C(N(C(C)C)CC)(C)C>C(#N)C>[CH3:1][N:2]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1)[CH2:10][CH2:11][OH:12]
Reactant: OCCI
Reactant: CNc1ccccc1
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: CN(CCO)c1ccccc1
Yield: 60 %

Procedure:
N-methylaniline (5 mls, 0.05 mol) was reacted with 2-Iodoethanol (3.599 mls, 0.05 mol) and diisopropylethylamine (8.039 mls, 0.05 mol) in ACN at 70° C. for 16 hours. The solvent was evaporated and the residue was purified by silica gel column chromatography with hexane/EtOAc to provide the compound as a yellow orange oil, 2a (4.48 g, 0.03 mol, 64.5% yield). 1H NMR (400 MHz, Chloroform-d) δ 7.27-7.15 (m, 2H), 6.81-6.67 (m, 3H), 3.74 (t, J=5.8 Hz, 2H), 3.42 (t, J=5.8 Hz, 2H), 2.92 (s, 3H).
Reaction SMILES: BrC1C(N2CCN(C(NC3C=CC=CC=3)=O)CC2)=C2N=C(C3C=CC(N(C)C)=CC=3)NC2=NC=1.[Br:35][C:36]1[C:37]([N:46]2[CH2:51][CH2:50][N:49]([CH2:52][C:53]3[CH:54]=[N:55][CH:56]=[CH:57][CH:58]=3)[CH2:48][CH2:47]2)=[C:38]([N+:43]([O-])=O)[C:39]([NH2:42])=[N:40][CH:41]=1.[O-]S(S([O-])=O)=O.[Na+].[Na+].[N:67]1([CH2:72][C:73]2[CH:80]=[CH:79][C:76]([CH:77]=O)=[CH:75][CH:74]=2)[CH:71]=[CH:70][CH:69]=[N:68]1>C(O)C.CN(C=O)C>[N:67]1([CH2:72][C:73]2[CH:80]=[CH:79][C:76]([C:77]3[NH:42][C:39]4=[N:40][CH:41]=[C:36]([Br:35])[C:37]([N:46]5[CH2:51][CH2:50][N:49]([CH2:52][C:53]6[CH:54]=[N:55][CH:56]=[CH:57][CH:58]=6)[CH2:48][CH2:47]5)=[C:38]4[N:43]=3)=[CH:75][CH:74]=2)[CH:71]=[CH:70][CH:69]=[N:68]1
Reactant: O=Cc1ccc(Cn2cccn2)cc1
Reactant: Nc1ncc(Br)c(N2CCN(Cc3cccnc3)CC2)c1[N+](=O)[O-]
Agent: CN(C)c1ccc(-c2nc3c(N4CCN(C(=O)Nc5ccccc5)CC4)c(Br)cnc3[nH]2)cc1
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCO
Product: Brc1cnc2[nH]c(-c3ccc(Cn4cccn4)cc3)nc2c1N1CCN(Cc2cccnc2)CC1
Reaction time: 6 h
Yield: 40.7 %

Procedure:
This was prepared using the same procedure as for 4-(6-bromo-2-(4-(dimethylamino)phenyl)-3H-imidazo[4,5-b]pyridin-7-yl)-N-phenylpiperazine-1-carboxamide, but here using 5-bromo-3-nitro-4-(4-(pyridin-3-ylmethyl)piperazin-1-yl)pyridin-2-amine (20 mg, 0.051 mmol), DMF (0.15 mL), ethanol (0.85 mL), 1M Na2S2O4 (3 eq, 0.15 mmol, 0.15 mL) and 4-(1H-pyrazol-1-ylmethyl)benzaldehyde (1.1 eq, 0.056 mmol, 11 mg). After 6 h, concentration in vacuo and purification by preparative tlc (CH2Cl2-MeOH, 95:5) gave the product (11 mg, 41%) as a colourless solid; δH (500 MHz, DMSO-d6) 2.62 (s, br, 4H, piperazine N(CH2)2), 3.61 (s, 2H, CH2), 3.66 (s, br, 4H, piperazine N(CH2)2), 5.41 (s, 2H, PhCH2), 6.30 (t, J=2.0 Hz, pyrazole H-4), 7.34 (d, J=8.2 Hz, 2H, phenyl H-3 & H-5), 7.39 (dd, J=7.8, 4.8 Hz, 1H, pyridine H-5), 7.49 (d, J=1.8 Hz, 1H, pyrazole H-3 or H-5), 7.78 (dt, J=7.8, 1.7 Hz, 1H, pyridine H-4), 7.86 (d, J=2.2 Hz, 1H, pyrazole H-3 or H-5), 8.14 (d, J=8.2 Hz, 2H, phenyl H-2 & H-6), 8.23 (s, 1H, imidazo[4,5-b]pyridine H-5), 8.49 (dd, J=4.7, 1.7 Hz, 1H, pyridine H-6), 8.56 (d, J=1.6 Hz, 1H, pyridine H-2), 13.49 (s, br, 1H, imidazo[4,5-b]pyridine NH);
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.[C:9]([C:11]1[C:16]2[N:17]=[C:18]([C:20]([N:22]([CH3:24])[CH3:23])=[O:21])[O:19][C:15]=2[C:14]([F:25])=[C:13]([C:26]([O:28]CC)=[CH2:27])[C:12]=1[CH3:31])#[N:10]>O1CCCC1.O>[Br:1][CH2:28][C:26]([C:13]1[C:12]([CH3:31])=[C:11]([C:9]#[N:10])[C:16]2[N:17]=[C:18]([C:20]([N:22]([CH3:24])[CH3:23])=[O:21])[O:19][C:15]=2[C:14]=1[F:25])=[O:27]
Reactant: O=C1CCC(=O)N1Br
Reactant: C=C(OCC)c1c(C)c(C#N)c2nc(C(=O)N(C)C)oc2c1F
Solvent: O
Solvent: C1CCOC1
Product: Cc1c(C(=O)CBr)c(F)c2oc(C(=O)N(C)C)nc2c1C#N
Reaction time: 0.33 h

Procedure:
Next, at room temperature, N-bromosuccinimide (2.10 g, 11.8 mmol) was added to a tetrahydrofuran/water (178 ml/11 ml) mixed solution of the obtained 4-cyano-6-[1-(ethoxy)ethenyl]-7-fluoro-N,N,5-trimethyl-1,3-benzoxazole-2-carboxamide (3.56 g, 11.2 mmol), and stirred for 20 minutes. The solvent was evaporated away under reduced pressure, and the resulting residue was dissolved in ethyl acetate, and the solution was washed with water.
Reaction SMILES: [CH2:1]([C:4]1[N:5]([CH2:17][C:18]2([OH:24])[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]2)[C:6]2[C:15]3[N:14]=[CH:13][CH:12]=[CH:11][C:10]=3[N:9]=[CH:8][C:7]=2[N:16]=1)[CH2:2][CH3:3].ClC1C=CC=C(C(OO)=O)C=1.[OH-].[NH4+:37].C1(C)C=CC(S(Cl)(=O)=O)=CC=1>C(Cl)(Cl)Cl>[NH2:37][C:8]1[C:7]2[N:16]=[C:4]([CH2:1][CH2:2][CH3:3])[N:5]([CH2:17][C:18]3([OH:24])[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23]3)[C:6]=2[C:15]2[N:14]=[CH:13][CH:12]=[CH:11][C:10]=2[N:9]=1
Reactant: CCCc1nc2cnc3cccnc3c2n1CC1(O)CCCCC1
Reactant: [NH4+]
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: O=C(OO)c1cccc(Cl)c1
Agent: [OH-]
Solvent: ClC(Cl)Cl
Product: CCCc1nc2c(N)nc3cccnc3c2n1CC1(O)CCCCC1
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 38 %

Procedure:
To a solution of 1-[(2-propyl-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl)methyl]cyclohexanol (1.43 g, 4.41 mmol) in chloroform (20 mL) at rt was added m-chloroperbenzoic acid (m-CPBA, 70%, 2.17 g, 8.82 mmol). After 1.5 h, the solution was was cooled to 0° C. and concentrated ammonium hydroxide (5 mL) was added. After 3 min, p-toluenesulfonyl chloride (TsCl, 0.920 g, 4.85 mmol) was added in portions. After 1 h, the reaction mixture was filtered and the filter cake was washed with chloroform. The filtrate was washed with saturated aqueous sodium bicarbonate (50 mL) and dried over Na2SO4, filtered, and concentrated under reduced pressure to yield an orange foam which was purified twice by HPFC (silica gel, gradient elution with 0-25% CMA/CHCl3 where CMA is a solution comprised of 80% CHCl3, 18% MeOH, and 2% conc. NH4OH; followed by 0-30% CMA/CHCl3). The appropriate fractions were concentrated and triturated with acetonitrile. The solid was isolated by filtration and dried at 100° C. under vacuum to yield 1-[(4-amino-2-propyl-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl)methyl]cyclohexanol (567 mg, 38%) as a white powder, mp 209.0-211.0° C. Anal. Calcd for C19H25N5O .0.2H2O C, 66.35; H, 7.47; N, 20.36; Found: C, 66.62; H, 7.34; N, 20.05.
Reaction SMILES: [CH3:1][SH:2].[Na].F[C:5]1[CH:6]=[CH:7][C:8]([N+:14]([O-:16])=[O:15])=[C:9]([CH:13]=1)[C:10]([OH:12])=[O:11].C(O)C.Cl>O>[CH3:1][S:2][C:5]1[CH:6]=[CH:7][C:8]([N+:14]([O-:16])=[O:15])=[C:9]([CH:13]=1)[C:10]([OH:12])=[O:11]
Reactant: O=C(O)c1cc(F)ccc1[N+](=O)[O-]
Reactant: CS
Agent: Cl
Agent: [Na]
Solvent: CCO
Solvent: O
Product: CSc1ccc([N+](=O)[O-])c(C(=O)O)c1
Reaction time: 48 h

Procedure:
2.5 mL of 15% sodium methylmercaptan aqueous solution was added to the mixture of 11.0 g (5.40 mmol) of 5-fluoro-2-nitrobenzoic acid and 5 mL of ethanol and stirred for 2 days. Then, 10 mL of water was added and pH thereof was adjusted to become 1 by concentrated hydrochloric acid. After filtering out the precipitated compound, it was washed with water, ether and hexane and dried to obtain a crude material of 5-methylthio-2-nitrobenzoic acid. 3 mL of thionyl chloride was added to the obtained crude material and stirred for 5 hours. The thionyl chloride was removed to obtain the title compound.
Reaction SMILES: CON(C)[C:4]([C:6]1[N:7]=[CH:8][N:9]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([C:17]3[C:18]([O:25][CH3:26])=[N:19][C:20]([O:23][CH3:24])=[N:21][CH:22]=3)[CH:12]=2)[CH:10]=1)=[O:5].Br[C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([F:35])[CH:30]=1>>[CH3:24][O:23][C:20]1[N:19]=[C:18]([O:25][CH3:26])[C:17]([C:13]2[CH:12]=[C:11]([N:9]3[CH:10]=[C:6]([C:4]([C:29]4[CH:34]=[CH:33][CH:32]=[C:31]([F:35])[CH:30]=4)=[O:5])[N:7]=[CH:8]3)[CH:16]=[CH:15][CH:14]=2)=[CH:22][N:21]=1
Reactant: Fc1cccc(Br)c1
Reactant: COc1ncc(-c2cccc(-n3cnc(C(=O)N(C)OC)c3)c2)c(OC)n1
Product: COc1ncc(-c2cccc(-n3cnc(C(=O)c4cccc(F)c4)c3)c2)c(OC)n1

Procedure:
This compound is prepared by method C using compound 12m and 1-bromo-3-fluorobenzene
Reaction SMILES: [F:1][CH:2]([F:17])[O:3][C:4]1[CH:9]=[CH:8][C:7]([CH:10]([CH:14]([CH3:16])[CH3:15])[C:11]([OH:13])=[O:12])=[CH:6][CH:5]=1.[N+](C1C=CC(C(O)C(N(C)C)CO)=CC=1)([O-])=O>C(O)C>[F:1][CH:2]([F:17])[O:3][C:4]1[CH:5]=[CH:6][C:7]([C@H:10]([CH:14]([CH3:15])[CH3:16])[C:11]([OH:13])=[O:12])=[CH:8][CH:9]=1
Reactant: CC(C)C(C(=O)O)c1ccc(OC(F)F)cc1
Agent: CN(C)C(CO)C(O)c1ccc([N+](=O)[O-])cc1
Solvent: CCO
Product: CC(C)[C@H](C(=O)O)c1ccc(OC(F)F)cc1
Temperature: 25 °C
Yield: 43 %

Procedure:
Dissolve 50 g (0.2 mole) of 2-(4-difluoromethoxyphenyl)-3-methylbutyric acid in 150 g of ethyl alcohol and to this solution is added 0.2 mol of resolving agent 1-(4-nitrophenyl)-2-dimethylamino-1,3-propanediol. Heat the solution with stirring under reflux for 8 hours, then cool, filter, and transfer the resulting solids to 73 g of 10% hydrochloric acid. Heat the mixture with stirring at 30° C. for 2 hours and then allow the mixture to cool to room temperature. The resulting mixture is extracted with benzene 2-3 times, and the solvent benzene is then removed by distillation to give 21 g (yield: 42%) of (S)-2-(4-difluoromethoxyphenyl)-3-methylbutyric acid.
Reaction SMILES: [C:1]([Si:5]([CH3:28])([CH3:27])[O:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]([C:18]2[S:22][C:21]([CH2:23][OH:24])=[C:20]([CH3:25])[CH:19]=2)([CH2:16][CH3:17])[CH2:14][CH3:15])=[CH:9][C:8]=1[CH3:26])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[C:36]1([CH3:46])[CH:41]=[CH:40][C:39]([S:42](Cl)(=[O:44])=[O:43])=[CH:38][CH:37]=1>CCOCC>[C:1]([Si:5]([CH3:28])([CH3:27])[O:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]([C:18]2[S:22][C:21]([CH2:23][O:24][S:42]([C:39]3[CH:40]=[CH:41][C:36]([CH3:46])=[CH:37][CH:38]=3)(=[O:44])=[O:43])=[C:20]([CH3:25])[CH:19]=2)([CH2:16][CH3:17])[CH2:14][CH3:15])=[CH:9][C:8]=1[CH3:26])([CH3:2])([CH3:4])[CH3:3]
Reactant: CCC(CC)(c1ccc(O[Si](C)(C)C(C)(C)C)c(C)c1)c1cc(C)c(CO)s1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: CCOCC
Solvent: CCN(CC)CC
Product: CCC(CC)(c1ccc(O[Si](C)(C)C(C)(C)C)c(C)c1)c1cc(C)c(COS(=O)(=O)c2ccc(C)cc2)s1
Reaction time: 8 h
Yield: 54 %

Procedure:
To a solution of (5-{1-[4-(tert-butyl-dimethyl-silanyloxy)-3-methyl-phenyl]-1-ethyl-propyl}-3-methyl-thiophen-2-yl)-methanol (1.0 g, 2.39 mmol) in Et2O (5 ml) is added triethyl amine (666 μl, 4.78 mmol). The mixture is added to a solution of p-toluenesulfonyl chloride (501 mg, 2.62 mmol) in Et2O (5 ml) and stirred overnight. The reaction is filtered, concentrated and chromatographed (12 g SiO2, 5% EtOAc/Hex) to yield the title compound (740 mg, 55%).
Reaction SMILES: [Cl:1][C:2]1[C:3](OC)=[N:4][C:5]([O:8][CH3:9])=[N:6][CH:7]=1.O.[NH2:13][NH2:14].O>CO>[Cl:1][C:2]1[C:3]([NH:13][NH2:14])=[N:4][C:5]([O:8][CH3:9])=[N:6][CH:7]=1
Reactant: NN
Reactant: COc1ncc(Cl)c(OC)n1
Solvent: O
Solvent: CO
Product: COc1ncc(Cl)c(NN)n1
Reaction time: 8 h

Procedure:
A solution containing 0.35 g (2.0 mmol) of 5-chloro-2,4-dimethoxypyrimidine and 0.35 g (7.0 mmol) of hydrazine hydrate in 2.9 g of methanol was heated at reflux with stirring for 8 hours. The mixture was then cooled causing a precipitate to form. Water was added until the precipitation appeared to be complete and the precipitate was then recovered by vacuum filtration and allowed to air dry overnight to obtain 0.23 g (66 percent of theory) of the title compound as a white solid. The product melted at 172°-173° C. after changing crystalline form from needles to cube-like shapes in a phenomenon that appeared to involve sublimation.
Reaction SMILES: [Na]N([Si](C)(C)C)[Si](C)(C)C.[I:11][C:12]1[C:13]2[C:14](=[CH:18][NH:19][N:20]=2)[N:15]=[CH:16][CH:17]=1.[CH:21]1(B(O)O)[CH2:23][CH2:22]1>CN(C)C1C=CN=CC=1.C1(C)C=CC=CC=1.C(O[Cu]OC(=O)C)(=O)C>[CH:21]1([N:19]2[CH:18]=[C:14]3[N:15]=[CH:16][CH:17]=[C:12]([I:11])[C:13]3=[N:20]2)[CH2:23][CH2:22]1
Reactant: Ic1ccnc2c[nH]nc12
Reactant: OB(O)C1CC1
Agent: CC(=O)O[Cu]OC(C)=O
Agent: CN(C)c1ccncc1
Agent: C[Si](C)(C)N([Na])[Si](C)(C)C
Solvent: Cc1ccccc1
Product: Ic1ccnc2cn(C3CC3)nc12
Temperature: 95 °C

Procedure:
N-Sodiohexamethyldisilazane (3.40 mL, 2.041 mmol), N,N-dimethylpyridin-4-amine (748 mg, 6.12 mmol), 7-iodo-2H-pyrazolo[4,3-b]pyridine (500 mg, 2.041 mmol), diacetoxycopper (371 mg, 2.041 mmol) and cyclopropylboronic acid (351 mg, 4.08 mmol) were combined in toluene (15 mL) and sparged with air. The mixture was heated at 95° C. overnight. The mixture was then cooled and poured into saturated NH4Cl solution and extracted with EtOAc (2×). The combined organic layers were dried over Na2SO4 and concentrated to give a residue which was purified on silica column chromatography eluted with EtOAc/hexanes (0-97%) using a step gradient and then to 98% EtOAc to give 2-cyclopropyl-7-iodo-2H-pyrazolo[4,3-b]pyridine. Other fractions were combined and purified on a second silica column chromatography eluted with EtOAc/hexanes (0-50%) using a step gradient and then to 90% EtOAc to give 1-cyclopropyl-7-iodo-1H-pyrazolo[4,3-b]pyridine. MS [M+H] found 286.1.