Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5](Cl)=[O:6].Cl.Cl.[CH3:13][N:14]1[C:18]2[C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][C:24]=3[O:25][C:26]3([CH2:31][CH2:30][NH:29][CH2:28][CH2:27]3)[C:17]=2[CH:16]=[N:15]1.C(N(CC)CC)C>CN(C=O)C>[CH3:13][N:14]1[C:18]2[C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][C:24]=3[O:25][C:26]3([CH2:31][CH2:30][N:29]([C:5]([C:4]4[CH:3]=[C:2]([CH3:1])[CH:10]=[CH:9][CH:8]=4)=[O:6])[CH2:28][CH2:27]3)[C:17]=2[CH:16]=[N:15]1
Reactant: Cc1cccc(C(=O)Cl)c1
Reactant: Cn1ncc2c1-c1ccccc1OC21CCNCC1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Cc1cccc(C(=O)N2CCC3(CC2)Oc2ccccc2-c2c3cnn2C)c1
Temperature: 50 °C
Reaction time: 8 h

Procedure:
3-Methylbenzoyl chloride (14 mg, 0.09 mmol) was added to a mixture of 1-methyl-1H-spiro[chromeno[4,3-c]pyrazole-4,4′-piperidine]dihydrochloride (30 mg, 0.09 mmol), triethylamine (64 μL, 0.46 mmol), and DMF (0.7 mL) at 25° C. The mixture was allowed to stir at 50° C. overnight before it was cooled to 25° C. The mixture was filtered and then purified by reverse phase-HPLC to give (1-methyl-1H-spiro[chromeno[4,3-c]pyrazole-4,4′-piperidine]-1′-yl)(m-tolyl)methanone. ESI-MS m/z calc. 373.2. found 374.2 (M+1)+. Retention time: 2.04 minutes (4 min run).
Reaction SMILES: [H-].[Na+].[CH3:3][N:4]1[CH2:10][CH:9]2[C:11](=O)[CH:6]([C@H:7]([CH3:14])[C@H:8]2[CH3:13])[CH2:5]1.[C:15]([O:18][CH2:19][CH3:20])(=[O:17])[CH3:16]>O1CCCC1>[CH3:3][N:4]1[CH2:10][CH:9]2[C:11](=[CH:16][C:15]([O:18][CH2:19][CH3:20])=[O:17])[CH:6]([C@H:7]([CH3:14])[C@H:8]2[CH3:13])[CH2:5]1
Reactant: CCOC(C)=O
Reactant: C[C@H]1C2CN(C)CC(C2=O)[C@@H]1C
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)C=C1C2CN(C)CC1[C@H](C)[C@H]2C
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
To a solution of 4.35 g of triethyl phosphonoacetate in tetrahydrofuran (50 ml) was added 0.85 g of sodium hydride (oily: 60-72%) under ice-cooling and the resulting mixture was stirred at 0° C. for 10 minutes. Then a solution of 2.7 g of the crude (6R*,7R*)-3,6,7-trimethyl-3-azabicyclo[3.2.1]octan-8-one in tetrahydrofuran (20 ml) was added thereto and the reaction mixture was heated under reflux for 1 hour. After adding ethyl acetate, the reaction mixture was washed with a saturated aqueous solution of sodium chloride and the organic layer was dried over anhydrous magnesium sulfate. After distilling off the solvent under reduced pressure, the residue was purified by silica gel column chromatography (eluted with n-hexane/ethyl acetate) to thereby give 1.6 g of the title compound as a pale yellow oily substance.
Reaction SMILES: C([O-])([O-])=O.[K+].[K+].[OH:7][C:8]1[CH:15]=[CH:14][CH:13]=[C:12]([OH:16])[C:9]=1[CH:10]=[O:11].Cl[CH2:18][C:19]1[CH2:20][CH2:21][N:22]([C:31](=[O:33])[CH3:32])[CH2:23][C:24]=1[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>CN(C=O)C.CCOC(C)=O>[C:31]([N:22]1[CH2:23][C:24]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[C:19]([CH2:18][O:7][C:8]2[CH:15]=[CH:14][CH:13]=[C:12]([OH:16])[C:9]=2[CH:10]=[O:11])[CH2:20][CH2:21]1)(=[O:33])[CH3:32]
Reactant: CC(=O)N1CCC(CCl)=C(c2ccccc2)C1
Reactant: O=Cc1c(O)cccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(=O)N1CCC(COc2cccc(O)c2C=O)=C(c2ccccc2)C1
Temperature: 50 °C
Yield: 34.6 %

Procedure:
To a suspension of K2CO3 (40 mg, 0.28 mmol) and 2,6-dihydroxybenzaldehyde (40 mg, 0.28 mmol) in DMF (1 mL) was added a solution of 1-(4-(chloromethyl)-5-phenyl-3,6-dihydropyridin-1(2H)-yl)ethan-1-one (35 mg, 0.14 mmol) in DMF (1 mL), the mixture was heated at 50° C. for 3 h, cooled to room temperature, and was diluted with EtOAc, organic layer was separated and aqueous layer was extracted with EtOAc. EtOAc layers were combined, washed with Sat. NaHCO3, brine, dried over Na2SO4, and was concentrated to give crude oil, which was purified by column (DCM/MeOH=90:10) to give 2-((1-acetyl-5-phenyl-1,2,3,6-tetrahydropyridin-4-yl)methoxy)-6-hydroxybenzaldehyde (17 mg). 1H NMR (400 MHz, CDCl3, NMR shows rotamer exist, only one set of signal was reported) □ (ppm) 11.93 (s, 1H), 10.36 (s, 1H), 7.34 (m, 5H), 7.22 (m, 1H), 6.49 (d, J=8.8 Hz, 1H), 6.10 (d, J=8.8 Hz, 1H), 4.47 (s, 2H), 4.32 (s, 2H), 3.68 (t, J=6.0 Hz, 2H), 2.47 (m, 2H), 2.18 (s, 3H); MS (ESI) m/z 352.5 [M+H]+.
Reaction SMILES: FC(F)(F)C(O)=O.[CH3:8][C@@H:9]([O:13][C:14]1[NH:15][C:16]([NH2:25])=[C:17]2[C:21]([N:22]=1)=[N:20][C:19]([O:23][CH3:24])=[N:18]2)[CH2:10][CH2:11][CH3:12].Br[CH2:27][CH2:28][CH2:29][CH:30]1[CH2:35][CH2:34][CH2:33][CH2:32][O:31]1>>[CH3:8][C@@H:9]([O:13][C:14]1[N:22]=[C:21]2[C:17]([N:18]=[C:19]([O:23][CH3:24])[N:20]2[CH2:27][CH2:28][CH2:29][CH:30]2[CH2:35][CH2:34][CH2:33][CH2:32][O:31]2)=[C:16]([NH2:25])[N:15]=1)[CH2:10][CH2:11][CH3:12]
Reactant: CCC[C@@H](C)Oc1nc2nc(OC)nc-2c(N)[nH]1
Reactant: BrCCCC1CCCCO1
Solvent: O=C(O)C(F)(F)F
Product: CCC[C@@H](C)Oc1nc(N)c2nc(OC)n(CCCC3CCCCO3)c2n1

Procedure:
Prepared similarly to Intermediate 216 from 2-{[(1R)-1-methylbutyl]oxy}-8-(methyloxy)-1H-purin-6-amine trifluoroacetate and 2-(3-bromopropyl)tetrahydro-2H-pyran.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH:20]#[C:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27].[CH3:28][SiH:29]([CH3:36])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][N:31]=1.Cl>C(OCC)C>[CH3:28][Si:29]([CH3:36])([CH:20]=[CH:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][N:31]=1
Reactant: C#CCCCCCC
Reactant: C[SiH](C)c1ccccn1
Agent: Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOCC
Product: CCCCCCC=C[Si](C)(C)c1ccccn1
Temperature: 40 °C
Reaction time: 1 h
Yield: 90.5 %

Procedure:
To 1.0 ml of diethyl ether were added 10 mg (0.25 μmol) of bis(cyclooctadiene)platinum, 13 mg (0.50 μmol) of triphenylphosphine and 165 mg (1.5 mmol) of 1-octyne, and 69 mg (0.5 mmol) of dimethyl(2-pyridyl)silane was added dropwise thereto at room temperature over 1 hour. Further, the mixture was continued to be stirred for 6 hours at an inner temperature of 40° C., followed by the addition of 6 ml of 1N hydrochloric acid and 5 ml of diethyl ether. After the mixture was stirred for 30 minutes, it was left stand and separated into the organic and aqueous layers. The organic layer was extracted with five portions of 6 ml of 1N hydrochloric acid, and the resulting aqueous layers were combined together and turned basic with the addition of sodium hydroxide pellets. This aqueous layer was extracted with three portions of 10 ml of diethyl ether. The resulting organic layer was dried over magnesium sulfate and the solvent was evaporated off under reduced pressure to give 112 mg of dimethyl(1-octenyl)(2-pyridyl)silane. Yield: 90%
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][N:3]=1.Br.[NH2:12][C:13]1[CH:14]=[CH:15][C:16]([F:20])=[C:17]([OH:19])[CH:18]=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[F:20][C:16]1[CH:15]=[CH:14][C:13]([NH2:12])=[CH:18][C:17]=1[O:19][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][N:3]=1
Reactant: Nc1ccc(F)c(O)c1
Reactant: O=[N+]([O-])c1ccc(Cl)nc1
Agent: Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Nc1ccc(F)c(Oc2ccc([N+](=O)[O-])cn2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 87.5 %

Procedure:
A mixture of 2-chloro-5-nitropyridine (3.17 g, 20 mmol), 5-amino-2-fluorophenol hydrobromide (4.16 g, 20 mmol) and potassium carbonate (5.52 g, 40 mmol) in N,N-dimethylformamide (20 mL) was stirred at room temperature overnight. The reaction mixture was poured into water (200 mL), and the mixture was extracted with ethyl acetate (100 mL×2). The ethyl acetate layers were combined, and dried over anhydrous sodium sulfate. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate/hexane=0/100→50/50), and crystallized from diethyl ether to give the title compound (4.36 g, 88%) as an orange powder.
Reaction SMILES: [N:1]1[CH:2]=[CH:3][N:4]2[CH:9]=[CH:8][C:7]([C:10]3[CH:11]=[C:12]([CH:17]=[CH:18][CH:19]=3)[C:13]([NH:15][CH3:16])=[O:14])=[CH:6][C:5]=12.C1C(=O)N([Br:27])C(=O)C1>CN(C=O)C.CCOC(C)=O>[Br:27][C:3]1[N:4]2[CH:9]=[CH:8][C:7]([C:10]3[CH:11]=[C:12]([CH:17]=[CH:18][CH:19]=3)[C:13]([NH:15][CH3:16])=[O:14])=[CH:6][C:5]2=[N:1][CH:2]=1
Reactant: CNC(=O)c1cccc(-c2ccn3ccnc3c2)c1
Reactant: O=C1CCC(=O)N1Br
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CNC(=O)c1cccc(-c2ccn3c(Br)cnc3c2)c1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
3-Imidazo[1,2-a]pyridine-7-yl-N-methyl-benzamide (1 eq, 0.398 mmol, 100 mg) is dissolved in DMF (4 ml) at 0° C. and NBS (1.1 eq, 0.438 mmol, 77.9 mg) is added. The reaction mixture is stirred for 1 h at 0° C. and then is diluted with EtOAc. The reaction mixture is washed with NaHCO3 and brine, dried over MgSO4, filtered and evaporated. The product is purified by flash column chromatography eluting with 8:2 DCM/MeOH to afford 3-(3-bromo-imidazo[1,2-a]pyridin-7-yl)-N-methyl-benzamide as a brown solid; [M+H]+=331
Reaction SMILES: [C:1]1([S:7][C:8]([C:11]([S:14](F)(=[O:16])=[O:15])([F:13])[F:12])([F:10])[F:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:18]([NH2:25])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.Cl>ClCCCl>[CH2:18]([NH:25][S:14]([C:11]([F:13])([F:12])[C:8]([S:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)([F:10])[F:9])(=[O:16])=[O:15])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: NCc1ccccc1
Reactant: O=S(=O)(F)C(F)(F)C(F)(F)Sc1ccccc1
Agent: Cl
Solvent: ClCCCl
Product: O=S(=O)(NCc1ccccc1)C(F)(F)C(F)(F)Sc1ccccc1

Procedure:
Added to a solution of 1,2-dichloroethane (20 ml), containing the PhSCF2CF2SO2F (2.09 g, 7.2 mmol) obtained according to the method from example 3, was freshly distilled benzylamine (4 ml, 37 mmol). The mixture was stirred and heated at 50° C. for 20 h until the disappearance of PhSCF2CF2SO2F (monitored by TLC and 19F NMR/CDCl3). After returning to ambient temperature, an aqueous solution of HCl (10%) was added to the reaction medium. The aqueous and organic phases were separated and the aqueous phase was extracted with dichloromethane. The organic phases were combined and dried over MgSO4. After filtration and evaporation of the solvents, the residue was purified by chromatography over silica gel (pentane to pentane/AcOEt:4/1). The sulfonamide product was obtained in the form of a white solid (2.1 g, 77%).
Reaction SMILES: [CH2:1]([O:5][C:6]1[C:11]2[C:12]([O:15][CH2:16][CH:17]3[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]3)=[N:13][O:14][C:10]=2[CH:9]=[CH:8][CH:7]=1)[CH:2]([CH3:4])[CH3:3].[CH:23]([C@H:25]1[CH2:30][CH2:29][C@H:28]([C:31]([O:33][CH3:34])=[O:32])[CH2:27][CH2:26]1)=O.C(C1(C(OC)=O)CCCC1)=O>>[CH2:1]([O:5][C:6]1[C:11]2[C:12]([O:15][CH2:16][CH:17]3[CH2:22][CH2:21][N:20]([CH2:23][C@H:25]4[CH2:26][CH2:27][C@H:28]([C:31]([O:33][CH3:34])=[O:32])[CH2:29][CH2:30]4)[CH2:19][CH2:18]3)=[N:13][O:14][C:10]=2[CH:9]=[CH:8][CH:7]=1)[CH:2]([CH3:4])[CH3:3]
Reactant: CC(C)COc1cccc2onc(OCC3CCNCC3)c12
Reactant: COC(=O)[C@H]1CC[C@H](C=O)CC1
Agent: COC(=O)C1(C=O)CCCC1
Product: COC(=O)[C@H]1CC[C@H](CN2CCC(COc3noc4cccc(OCC(C)C)c34)CC2)CC1

Procedure:
The title compound was prepared according to the procedure described in Step 3 of EXAMPLE 2 using 4-isobutoxy-3-(piperidin-4-ylmethoxy)-1,2-benzisoxazole (EXAMPLE 10, Step 1) and methyl trans-4-formylcyclohexanecarboxylate (JP 49048639) instead of 3-(piperidin-4-ylmethoxy)-4-(2,2,2-trifluoroethoxy)-1,2-benzisoxazole and methyl 1-formylcyclopentanecarboxylate.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:16][C@@H:15]2[C@@H:10]([C@@H:11](OS(C(F)(F)F)(=O)=O)[CH2:12][CH2:13][C:14]2([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[F-:37].C([N+](CCCC)(CCCC)CCCC)CCC>FCF.O1CCCC1>[C:1]([O:5][C:6]([N:8]1[CH2:16][C@@H:15]2[C@@H:10]([C@H:11]([F:37])[CH2:12][CH2:13][C:14]2([C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH2:9]1)=[O:7])([CH3:2])([CH3:4])[CH3:3]
Reactant: [F-]
Reactant: CC(C)(C)OC(=O)N1C[C@@H]2[C@@H](OS(=O)(=O)C(F)(F)F)CCC(c3ccccc3)(c3ccccc3)[C@@H]2C1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: FCF
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1C[C@@H]2[C@H](F)CCC(c3ccccc3)(c3ccccc3)[C@@H]2C1
Temperature: 20 °C
Reaction time: 17 h

Procedure:
A solution of 4.87 g of (3aR, 7S, 7aR)-2-t-butoxycarbonyl-4,4-diphenyl-7trifluoromethylsulphonyloxyperhydroisoindole in 150 cm3 of dry difluoromethane is treated with 22.6 cm3 of a 1M solution of tetrabutylammonium fluoride in tetrahydrofuran and then stirred for 17 hours at 20° C and concentrated to dryness under reduced pressure (2.7 kPa). The residue is chromatographed on a silica gel column (particle size 0.2-0.063 mm, diameter 4.5 cm, height 35 cm), eluting under a nitrogen pressure of 0.4 bar with a cyclohexane and ethyl acetate mixture (75/25) and collecting fractions of 20 cm3. Fractions 28 to 38 are pooled and concentrated to dryness under reduced pressure (2.7 kPa) to give 1.44 g of (3aR, 7R,7aR)-2-t-butoxycarbonyl-4,4-diphenyl-7-fluoroperhydroisoindole in the form of white crystals; melting point 200° C., [α]D20 =-225° C. (c=1, CHCl3).
Reaction SMILES: [Cl:1][C:2]1[CH:27]=[CH:26][CH:25]=[CH:24][C:3]=1[C:4]([NH:6][C:7]([NH:9][C:10]1[CH:15]=[N:14][C:13]([C:16]2[CH:21]=[CH:20][C:19]([Br:22])=[CH:18][CH:17]=2)=[C:12](Cl)[N:11]=1)=[O:8])=[O:5].N[C:29]1C=NC(C2C=CC(Br)=CC=2)=C(Cl)N=1.ClC1C=CC=CC=1C(N=C=O)=O>>[Cl:1][C:2]1[CH:27]=[CH:26][CH:25]=[CH:24][C:3]=1[C:4]([NH:6][C:7]([NH:9][C:10]1[CH:15]=[N:14][C:13]([C:16]2[CH:21]=[CH:20][C:19]([Br:22])=[CH:18][CH:17]=2)=[C:12]([CH3:29])[N:11]=1)=[O:8])=[O:5]
Reactant: O=C(NC(=O)c1ccccc1Cl)Nc1cnc(-c2ccc(Br)cc2)c(Cl)n1
Reactant: Nc1cnc(-c2ccc(Br)cc2)c(Cl)n1
Agent: O=C=NC(=O)c1ccccc1Cl
Product: Cc1nc(NC(=O)NC(=O)c2ccccc2Cl)cnc1-c1ccc(Br)cc1

Procedure:
1-(2-Chlorobenzoyl)-3-[5-(4-bromophenyl)-6-chloro-2-pyrazinyl]urea, weighing 1.4 g., and having a melting point of about 240°-242° C., from 0.9 g. of 2-amino-5-(4-bromophenyl)-6-chloropyrazine and 0.65 g. of 2-chlorobenzoylisocyanate.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9]([C:11]1[S:12][C:13]2[CH2:14][N:15]([C:20](=[O:29])COC3C=CC=CC=3)[CH2:16][CH2:17][C:18]=2[N:19]=1)=[O:10].[S:30](=[O:34])(=[O:33])([OH:32])[OH:31].[CH3:35][OH:36]>>[S:30]([OH:34])([OH:33])(=[O:32])=[O:31].[NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9]([C:11]1[S:12][C:13]2[CH2:14][N:15]([C:20]([O:36][CH2:35][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)=[O:29])[CH2:16][CH2:17][C:18]=2[N:19]=1)=[O:10]
Reactant: CO
Reactant: Nc1ccccc1NC(=O)c1nc2c(s1)CN(C(=O)COc1ccccc1)CC2
Agent: O=S(=O)(O)O
Product: Nc1ccccc1NC(=O)c1nc2c(s1)CN(C(=O)OCc1ccccc1)CC2
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A solution of N-(2-aminophenyl)-5-(phenoxyacetyl)-4,5,6,7-tetrahydro[1,3]thiazolo[5,4-c]-pyridine-2-carboxamide obtained in example 172 in methanol cooled to 0° C. A solution of sulphuric acid in methanol (1:1) was added slowly and stirred at room temperature for 3 hrs. White precipitated solid was filtered out and dried to afford title compound.
Reaction SMILES: [C:1]1([S:7]([N:10]2[C:14]3=[N:15][CH:16]=[C:17]([CH2:19][CH:20]([OH:23])[CH2:21][OH:22])[CH:18]=[C:13]3[CH:12]=[CH:11]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:24]1(C)[CH:29]=CC(S(O)(=O)=O)=C[CH:25]=1.COC(OC)(C)C>ClCCl>[C:1]1([S:7]([N:10]2[C:14]3=[N:15][CH:16]=[C:17]([CH2:19][CH:20]4[CH2:21][O:22][C:24]([CH3:29])([CH3:25])[O:23]4)[CH:18]=[C:13]3[CH:12]=[CH:11]2)(=[O:9])=[O:8])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=S(=O)(c1ccccc1)n1ccc2cc(CC(O)CO)cnc21
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Solvent: ClCCl
Solvent: COC(C)(C)OC
Product: CC1(C)OCC(Cc2cnc3c(ccn3S(=O)(=O)c3ccccc3)c2)O1
Yield: 810.9 %

Procedure:
A solution of 3-(1-benzenesulfonyl-pyrrolo[2,3-b]pyridine-5-yl)-propane-1,2-diol (1.67 g, 5.03 mmol), p-toluene sulfonic acid (96 mg, 0.5 mmol) and 2,2-dimethoxy-propane (3.1 mL, 25.2 mmol) in dichloromethane (20 mL) was stirred at 25° C. for 12 h. The solution was concentrated in vacuo. The residue was diluted with ethyl acetate, washed with a saturated aqueous sodium bicarbonate solution, brine, dried over anhydrous sodium sulfate and concentrated in vacuo. Purification by flash silica gel chromatography (silica gel from QingDao, 200-300 mesh, glass column from Shanghai SD company, 33% ethyl acetate/hexanes) afforded 1-benzenesulfonyl-5-(2,2-dimethyl-[1,3]dioxolan-4-ylmethyl)-1H-pyrrolo[2,3-b]pyridine (1.51 g, 81%) as a white solid: LC/MS m/e calcd for C19H20N2O4S [M+H]+ 373.45, observed 373.0.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[S:7]([NH2:10])(=[O:9])=[O:8].N1C=CC=C(S(N[C:21](=[O:47])[O:22][CH2:23][CH2:24][C:25]2[CH:30]=[CH:29][C:28]([N:31]3[C:35]4[CH:36]=[C:37]([Cl:44])[C:38]([C:40]([F:43])([F:42])[F:41])=[CH:39][C:34]=4[N:33]=[C:32]3[CH2:45][CH3:46])=[CH:27][CH:26]=2)(=O)=O)C=1>>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[S:7]([NH:10][C:21](=[O:47])[O:22][CH2:23][CH2:24][C:25]1[CH:26]=[CH:27][C:28]([N:31]2[C:35]3[CH:36]=[C:37]([Cl:44])[C:38]([C:40]([F:41])([F:43])[F:42])=[CH:39][C:34]=3[N:33]=[C:32]2[CH2:45][CH3:46])=[CH:29][CH:30]=1)(=[O:9])=[O:8]
Reactant: NS(=O)(=O)c1ccccn1
Reactant: CCc1nc2cc(C(F)(F)F)c(Cl)cc2n1-c1ccc(CCOC(=O)NS(=O)(=O)c2cccnc2)cc1
Product: CCc1nc2cc(C(F)(F)F)c(Cl)cc2n1-c1ccc(CCOC(=O)NS(=O)(=O)c2ccccn2)cc1

Procedure:
The title compound was prepared according to the procedure described in step 2 of Example 243 from 2-pyridinesulfonamide (Naito, T.; et al., Chem. Pharm. Bull., 1955, 3, 38) and 2-[4-(2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridin-3-yl)phenyl]ethylcarbamate (step 1 of Example 243).
Reaction SMILES: Cl[C:2]1[N:6]([CH3:7])[C:5]2[CH:8]=[CH:9][CH:10]=[CH:11][C:4]=2[N:3]=1.[CH2:12]([N:14]1[C:22]2[C:17](=[N:18][CH:19]=[C:20]([C:23]#[N:24])[CH:21]=2)[N:16]([C:25]2[CH:30]=[CH:29][C:28]([OH:31])=[CH:27][CH:26]=2)[C:15]1=[O:32])[CH3:13].[H-].[Na+]>CN(C=O)C.CO>[CH2:12]([N:14]1[C:22]2[C:17](=[N:18][CH:19]=[C:20]([C:23]#[N:24])[CH:21]=2)[N:16]([C:25]2[CH:30]=[CH:29][C:28]([O:31][C:2]3[N:6]([CH3:7])[C:5]4[CH:8]=[CH:9][CH:10]=[CH:11][C:4]=4[N:3]=3)=[CH:27][CH:26]=2)[C:15]1=[O:32])[CH3:13]
Reactant: Cn1c(Cl)nc2ccccc21
Reactant: CCn1c(=O)n(-c2ccc(O)cc2)c2ncc(C#N)cc21
Agent: [H-]
Agent: [Na+]
Solvent: CO
Solvent: CN(C)C=O
Product: CCn1c(=O)n(-c2ccc(Oc3nc4ccccc4n3C)cc2)c2ncc(C#N)cc21
Temperature: 180 °C
Yield: 13.5 %

Procedure:
2-Chloro-1-methyl-1H-benzimidazole (15 mg) was added to a solution of 1-ethyl-3-(4-hydroxyphenyl)-2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridine-6-carbonitrile (25.5 mg) and sodium hydride (4.0 mg) in DMF (1.0 mL) at room temperature. The mixture was heated at 180° C. for 30 min under microwave irradiation. The reaction mixture was diluted with MeOH and concentrated in vacuo. The residue was purified by column chromatography (NH silica gel, eluted with 0%-30% EtOAc in hexane) to give 1-ethyl-3-{4-[(1-methyl-1H-benzimidazol-2-yl)oxy]phenyl}-2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridine-6-carbonitrile (5 mg) as white crystals.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][CH:10]2[NH:14][N:13]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[C:12](=O)[CH2:11]2)=[CH:5][CH:4]=1.P(Cl)(Cl)([Cl:24])=O>O>[Cl:24][C:11]1[C:10]([NH:9][C:6]2[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)=[N:14][N:13]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:12]=1
Reactant: COc1ccc(NC2CC(=O)N(c3ccccc3)N2)cc1
Reactant: O=P(Cl)(Cl)Cl
Solvent: O
Product: COc1ccc(Nc2nn(-c3ccccc3)cc2Cl)cc1

Procedure:
A mixture of 5-(4-methoxyphenylamino)-2-phenylpyrazolidin-3-one (2.81 g) and excess phosphorous oxychloride (4 ml) was heated on a steam bath at 100° for 1 hour. Water was added and the aqueous phase extracted with dichloromethane. The organic phase was dried over magnesium sulphate, filtered and evaporated to dryness, and the title compound was obtained as a colourless solid (1.5 g), mp 119°-121° by recrystallisation from cyclohexane.
Reaction SMILES: [Cl-].[Cl-].[Cl-].[Al+3].[C:5](Cl)(=[O:11])[CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].[S:13]([N:23]1[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH:25]=[CH:24]1)([C:16]1[CH:22]=[CH:21][C:19]([CH3:20])=[CH:18][CH:17]=1)(=[O:15])=[O:14]>ClCCl>[C:5]([C:25]1[C:26]2[C:31](=[CH:30][CH:29]=[CH:28][CH:27]=2)[N:23]([S:13]([C:16]2[CH:22]=[CH:21][C:19]([CH3:20])=[CH:18][CH:17]=2)(=[O:15])=[O:14])[CH:24]=1)(=[O:11])[CH2:6][CH2:7][CH2:8][CH2:9][CH3:10]
Reactant: CCCCCC(=O)Cl
Reactant: Cc1ccc(S(=O)(=O)n2ccc3ccccc32)cc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: CCCCCC(=O)c1cn(S(=O)(=O)c2ccc(C)cc2)c2ccccc12
Temperature: 5 °C
Reaction time: 0.17 h
Yield: 78.4 %

Procedure:
Aluminium trichloride (6.01 g, 45.2 mmol), is suspended in dichloromethane (80 cm3), under nitrogen. A solution of hexanoyl chloride (5a) (6.62 g, 49.2 mmol) in dichloromethane (20 cm3) is added slowly to the stirred mixture at ambient temperature. After the addition is complete, the mixture is stirred for a further 10 minutes. The reaction mixture is cooled to 5° C. 1-tosylindole (4) (45.2 mmol, 12.24 g) in dichloromethane (20 cm3) is added to the mixture while the temperature is maintained at 5° C. After two hours stirring at room temperature the reaction mixture is treated with ice water, extracted with dichloromethane and dried over magnesium sulphate. Evaporation of the solvent gives a thick oil, which crystallises in the presence of methanol and dichloromethane to yield colourless crystals of 3-hexanoyl-1-tosylindole (6a) (13.07 g, 35.42 mmol, 78%), m.p. 91-93° C.
Reaction SMILES: C1(C)C=CC(S(O[CH2:11][C@H:12]2[O:16][C@@H:15]([N:17]3[CH:25]=[C:23]([CH3:24])[C:21](=[O:22])[NH:20][C:18]3=[O:19])[CH2:14][C@@H:13]2[OH:26])(=O)=O)=CC=1.[CH3:28][NH2:29].[K+].[Br-]>O>[CH3:28][NH:29][CH2:11][C@H:12]1[O:16][C@@H:15]([N:17]2[CH:25]=[C:23]([CH3:24])[C:21](=[O:22])[NH:20][C:18]2=[O:19])[CH2:14][C@@H:13]1[OH:26]
Reactant: Cc1ccc(S(=O)(=O)OC[C@H]2O[C@@H](n3cc(C)c(=O)[nH]c3=O)C[C@@H]2O)cc1
Reactant: CN
Agent: [Br-]
Agent: [K+]
Solvent: O
Product: CNC[C@H]1O[C@@H](n2cc(C)c(=O)[nH]c2=O)C[C@@H]1O
Reaction time: 72 h

Procedure:
5'-O-(p-toluenesulfonyl)thymidine (19.8 g, 50 mmol) was placed in a pressure vessel into which monomethylamine (250 g) was condensed. The vessel was sealed and allowed to stand at room temperature for 3 days. The vessel was cooled, opened, and the monomethylamine allowed to evaporate. The remaining contents of the vessel were removed by rinsing with water. The aqueous solution was passed through a column (6.5×20 cm) of AG50Wx8 ion-exchange resin (H+ form). The column was washed with water until the washings were neutral. The product was then eluted with 1N aqueous ammonium hydroxide. The eluent was stripped down and the resulting solid chromatographed on a column (6.5×20 cm) of silica gel with methylene chloride/methanol/concentrated aqueous ammonium hydroxide (85:13:2) as the eluting solvent. The product containing fractions were stripped down, then taken up in water and lyophilized. The product was a pale-yellow, amorphous solid (8.81 g, 69%). A satisfactory combustion analysis could not be obtained for this material.) [α]D25 (c=1.0 in water): +25.9 deg. ir (KBr): cm-1 1693, 1472, 1273, 1076. NMR (DMSO-d6): δ 1.790 (d, 3H), 2.051 (ddd, 13.4, 6.3, 3.5 hz, 1H), 2.142 (dt, 13.4, 6.9 hz, 1H), 2.314 (s, 3H), 2.658 (d, 5.5 hz, 2H), 3.775 (td, 5.3, 3.2 hz, 1H), 4.171 (dt, 6.3, 3.2 hz, 1H), 6.134 (t, 6.9 hz, 1H) and d7.639 (s, 1H).