Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[S:3][C:4]([N+:7]([O-:9])=[O:8])=[CH:5][N:6]=1.CN(C)C=O.[C:15]1([C:21]2[NH:30][C:24]3[N:25]=[CH:26][N:27]=[C:28]([SH:29])[C:23]=3[CH:22]=2)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.N1C=CC=CC=1>O>[N+:7]([C:4]1[S:3][C:2]([S:29][C:28]2[C:23]3[CH:22]=[C:21]([C:15]4[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=4)[NH:30][C:24]=3[N:25]=[CH:26][N:27]=2)=[N:6][CH:5]=1)([O-:9])=[O:8]
Reactant: Sc1ncnc2[nH]c(-c3ccccc3)cc12
Reactant: O=[N+]([O-])c1cnc(Br)s1
Solvent: c1ccncc1
Solvent: CN(C)C=O
Solvent: O
Product: O=[N+]([O-])c1cnc(Sc2ncnc3[nH]c(-c4ccccc4)cc23)s1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
After adding 1.06 g of 2-bromo-5-nitrothiazole and 15 ml of dimethylformamide to 6-phenyl-7H-pyrrolo[2,3-d]pyrimidine-4-thiol, the mixture was stirred at room temperature for 3 hours, and then 0.45 ml of pyridine was added and the mixture was stirred overnight. Water was added, and the precipitated crystals were filtered out, blow-dried and dried under reduced pressure to obtain 1.20 g of the title compound.
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10](=[O:14])[C:11]([OH:13])=[O:12])=[CH:5][CH:4]=1.N12CCCN=C1CCCC[CH2:16]2.IC.Cl>CN(C)C=O>[CH3:1][S:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:9][C:10](=[O:14])[C:11]([O:13][CH3:16])=[O:12])=[CH:7][CH:8]=1
Reactant: C1CCC2=NCCCN2CC1
Reactant: CSc1ccc(CC(=O)C(=O)O)cc1
Agent: Cl
Solvent: CI
Solvent: CN(C)C=O
Product: COC(=O)C(=O)Cc1ccc(SC)cc1

Procedure:
3-(4-(Methylsulfanyl)phenyl)-2-oxopropanoic acid (16.2 g), N,N-dimethylformamide (81 ml) and 1,8-diazabicyclo[5.4.0]undec-7-ene (11.5 ml) were combined at 0° C. under nitrogen atmosphere. The mixture was stirred at the same temperature for an hour, and then iodomethane (9.59 ml) was added to the solution at the same temperature. The reaction mixture was stirred at room temperature for 4 hours, poured into 1N-hydrochloric acid, and extracted with ethyl acetate (twice). The combined organic layer was washed with saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and concentrated in vacuo. The residue was purified by flash column chromatography over silica gel with chloroform/ethyl acetate (30:1) as an eluent, and triturated with isopropyl ether/n-hexane to give methyl 3-(4-(methylsulfanyl)phenyl)-2-oxopropanoate (8.6 g) as a dark yellow solid.
Reaction SMILES: [Cl:1][C:2]1[C:14]([Cl:15])=[CH:13][CH:12]=[C:11]2[C:3]=1[C:4]1[CH2:5][CH2:6][CH2:7][C:8](=[O:26])[C:9]=1[N:10]2[S:16]([C:19]1[CH:25]=[CH:24][C:22]([CH3:23])=[CH:21][CH:20]=1)(=[O:18])=[O:17].[Li+].C[Si]([N-][Si](C)(C)C)(C)C.[F:37]NS(C1C=CC=CC=1)(=O)=O>C1COCC1>[Cl:1][C:2]1[C:14]([Cl:15])=[CH:13][CH:12]=[C:11]2[C:3]=1[C:4]1[CH2:5][CH2:6][CH:7]([F:37])[C:8](=[O:26])[C:9]=1[N:10]2[S:16]([C:19]1[CH:20]=[CH:21][C:22]([CH3:23])=[CH:24][CH:25]=1)(=[O:18])=[O:17]
Reactant: Cc1ccc(S(=O)(=O)n2c3c(c4c(Cl)c(Cl)ccc42)CCCC3=O)cc1
Reactant: O=S(=O)(NF)c1ccccc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: Cc1ccc(S(=O)(=O)n2c3c(c4c(Cl)c(Cl)ccc42)CCC(F)C3=O)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 33.5 %

Procedure:
To a solution of 5,6-dichloro-9-tosyl-2,3,4,9-tetrahydro-1H-carbazol-1-one (300 mg, 0.7 mmol) in anhydrous THF (10 mL), cooled to −78° C., LiHMDS (1.47 mL, 1.4 mmol, 1M solution in THF) was added slowly. The reaction mixture was slowly warmed to 0° C. and stirred for an additional 30 min. while maintaining the temperature at 0° C. The reaction mixture was then cooled to −78° C. and N-fluoro benzene sulfonamide (0.22 g, 0.9 mmol), dissolved in THF (3 mL), was added dropwise. The reaction mixture was slowly warmed to 0° C. and stirred for 15 min during which time the reaction was complete. The reaction was quenched with saturated NH4Cl and extracted with EtOAc (3×25 mL). The combined organic extracts were dried over Na2SO4 and concentrated under reduced pressure to give the crude compound which was purified by column chromatography [EtOAc-hexane (1:9) as eluant] to give the title compound (100 mg, 32%). 1H NMR (500 MHz, CDCl3, δ in ppm) 8.27 (d, J=9.5 Hz, 1H), 8.07 (d, J=8.5 Hz, 2H), 7.59 (d, J=9.5 Hz, 1H), 7.35 (d, J=8.5 Hz, 2H), 5.30-5.13 (m, 1H), 3.71-3.66 (m, 1H), 3.35-3.28 (m, 1H), 2.58-2.55 (m, 1H), 2.43 (s, 3H), 2.40-2.38 (m, 1H)
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]2[O:6][CH2:7][O:8][C:4]=2[C:3]=1[NH:11][C:12]1[C:20]2[C:19]3[CH2:21][NH:22][CH2:23][CH2:24][C:18]=3[NH:17][C:16]=2[N:15]=[CH:14][CH:13]=1.CCN(C(C)C)C(C)C.[CH:34]1([C:37](Cl)=[O:38])[CH2:36][CH2:35]1>ClCCCl>[Cl:1][C:2]1[CH:10]=[CH:9][C:5]2[O:6][CH2:7][O:8][C:4]=2[C:3]=1[NH:11][C:12]1[C:20]2[C:19]3[CH2:21][N:22]([C:37]([CH:34]4[CH2:36][CH2:35]4)=[O:38])[CH2:23][CH2:24][C:18]=3[NH:17][C:16]=2[N:15]=[CH:14][CH:13]=1
Reactant: Clc1ccc2c(c1Nc1ccnc3[nH]c4c(c13)CNCC4)OCO2
Reactant: O=C(Cl)C1CC1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCCl
Product: O=C(C1CC1)N1CCc2[nH]c3nccc(Nc4c(Cl)ccc5c4OCO5)c3c2C1
Temperature: 25 °C
Yield: 35.3 %

Procedure:
(5-Chloro-benzo[1,3]-dioxol-4-yl)-(6,7,8,9-tetrahydro-5H-dipyrido[2,3-b;3′,4′-d]pyrrol-4-yl)-amine (100 mg, 0.29 mmol) and DIEA (0.15 mL, 0.88 mmol) were dissolved in 1,2-dichloroethane (2 mL) and stirred at room temperature. Cyclopropanecarbonyl chloride (0.03 mL, 0.35 mmol) was added dropwise, and the reaction was stirred for 1 h at room temperature. The reaction was concentrated. The crude material was dissolved in DMSO (3 mL) and filtered. The filtrate was purified directly via prep-LC-MS to provide 68 (42 mg, 35% yield) as a white fluffy solid. LC-MS (M+H=411, obsd.=411).
Reaction SMILES: C([Li])CCC.CCCCCC.Br[C:13]1[C:14]([O:23][CH3:24])=[N:15][CH:16]=[N:17][C:18]=1[C:19]([F:22])([F:21])[F:20].[CH:25](OCC)=[O:26]>O1CCCC1.O>[CH3:24][O:23][C:14]1[C:13]([CH:25]=[O:26])=[C:18]([C:19]([F:22])([F:21])[F:20])[N:17]=[CH:16][N:15]=1
Reactant: CCOC=O
Reactant: COc1ncnc(C(F)(F)F)c1Br
Agent: [Li]CCCC
Solvent: O
Solvent: CCCCCC
Solvent: C1CCOC1
Product: COc1ncnc(C(F)(F)F)c1C=O
Reaction time: 0.5 h
Yield: 15.8 %

Procedure:
30.0 ml of n-butyllithium (a 1.6 moles/liter n-hexane solution, 48.0 mmoles) was gradually added, at −65 to −60° C., to a solution of 10.3 g (40.0 mmoles) of 5-bromo-4-methoxy-6-trifluoromethylpyrimidine dissolved in 100 ml of tetrahydrofuran. The mixture was stirred for 30 minutes. Thereto was added 3.6 g (48.0 mmoles) of ethyl formate at the same temperature. The resulting mixture was stirred at the same temperature for 3 hours to give rise to a reaction. The reaction mixture was poured into water, followed by extraction with ethyl acetate. The resulting organic layer was washed with water and an aqueous sodium chloride solution in this order and then dried over anhydrous magnesium sulfate. The resulting solution was subjected to vacuum distillation to remove the solvent contained therein. The residue was purified by silica gel column chromatography to obtain 1.3 g (yield: 15.8%) of 4-methoxy-6-trifluoromethylpyrimidine-5-carboaldehyde.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:29]([OH:32])CO)[C:5]([CH2:21][O:22][CH:23]2[CH2:28][CH2:27][CH2:26][CH2:25][O:24]2)=[C:6]2[C:10]=1[N:9]([S:11]([C:14]1[CH:20]=[CH:19][C:17]([CH3:18])=[CH:16][CH:15]=1)(=[O:13])=[O:12])[CH:8]=[CH:7]2.O>C1COCC1.CCOC(C)=O>[CH3:1][C:2]1[CH:3]=[C:4]([CH:29]=[O:32])[C:5]([CH2:21][O:22][CH:23]2[CH2:28][CH2:27][CH2:26][CH2:25][O:24]2)=[C:6]2[C:10]=1[N:9]([S:11]([C:14]1[CH:15]=[CH:16][C:17]([CH3:18])=[CH:19][CH:20]=1)(=[O:13])=[O:12])[CH:8]=[CH:7]2
Reactant: Cc1ccc(S(=O)(=O)n2ccc3c(COC4CCCCO4)c(C(O)CO)cc(C)c32)cc1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: O
Product: Cc1ccc(S(=O)(=O)n2ccc3c(COC4CCCCO4)c(C=O)cc(C)c32)cc1
Temperature: 0 °C
Reaction time: 1.25 h

Procedure:
To a suspension of (±)-1-(7-methyl-4-(((tetrahydro-2H-pyran-2-yl)oxy)methyl)-1-tosyl-1H-indol-5-yl)ethane-1,2-diol (238 mg, 0.52 mmol) in THF (5 mL)/H2O (1 mL) was added NaIO4 (443 mg, 2.1 mmol) at 0° C., and then the mixture was stirred at 0° C. for 1.25 h. The reaction mixture was diluted with EtOAc. The bi-layer was partitioned. The organic phase was washed with half satd. Na2S2O3, H2O and brine, dried over Na2SO4, and then filtered. Concentration of the filtrate gave the title compound with no need of any further purification. 1H NMR (400 MHz, DMSO-d6) δ 10.35 (s, 1H), 8.02 (d, J=4.04 Hz, 1H), 7.68 (d, J=8.59 Hz, 2H), 7.55 (s, 1H), 7.43 (d, J=8.59 Hz, 2H), 7.20 (d, J=4.04 Hz, 1H), 5.27 (d, J=11.62 Hz, 1H), 5.09 (d, J=11.62 Hz, 1H), 4.69-4.76 (m, 1H), 3.68-3.81 (m, 1H), 3.37-3.51 (m, 1H), 2.52 (s, 3H), 2.36 (s, 3H), 1.53-1.70 (m, 2H), 1.32-1.53 (m, 4H).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]=[C:11]=[O:12])=[CH:6][CH:5]=1)([O-:3])=[O:2].[NH:13]1[CH2:18][CH:17]=[CH:16][CH2:15][CH2:14]1>CN(C=O)C>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([NH:10][C:11]([N:13]2[CH2:18][CH2:17][CH:16]=[CH:15][CH2:14]2)=[O:12])=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: O=C=Nc1ccc([N+](=O)[O-])cc1
Reactant: C1=CCNCC1
Solvent: CN(C)C=O
Product: O=C(Nc1ccc([N+](=O)[O-])cc1)N1CC=CCC1
Yield: 69.6 %

Procedure:
900 mg (5 mmol) of 4-nitrophenylisocyanate is dissolved, under an argon atmosphere, in a 100 ml three-necked flask in 17 ml of dry DMF. 0.45 ml (5 mmol) of 1,2,3,6-tetrahydropyridine is added to this solution in one go, and agitation is maintained for 15 hours. The reaction mixture is then concentrated to dryness under vacuum and the evaporation residue placed on a silica gel column. After elution with a heptane/ethyl acetate mixture: 4/6, the pure fractions are collected and concentrated under reduced pressure in order to produce 860 mg (70%) of a bright yellow powder. Melting point: 169-170° C.
Reaction SMILES: [N:1]1([CH2:7][CH2:8][CH2:9][O:10][C:11]2[CH:16]=[CH:15][C:14](C3(C(O)=O)C=CC=CC3)=[CH:13][CH:12]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[C:26](Cl)(=[O:30])[C:27](Cl)=O.C(Cl)(Cl)Cl.[NH:36]1[CH2:41][CH2:40][CH2:39][CH2:38][CH2:37]1>ClCCl.CN(C)C=O>[N:36]1([C:26]([C:27]2[CH:6]=[CH:5][C:4]([C:14]3[CH:15]=[CH:16][C:11]([O:10][CH2:9][CH2:8][CH2:7][N:1]4[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]4)=[CH:12][CH:13]=3)=[CH:3][CH:2]=2)=[O:30])[CH2:41][CH2:40][CH2:39][CH2:38][CH2:37]1
Reactant: O=C(O)C1(c2ccc(OCCCN3CCCCC3)cc2)C=CC=CC1
Reactant: O=C(Cl)C(=O)Cl
Reactant: C1CCNCC1
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: ClC(Cl)Cl
Product: O=C(c1ccc(-c2ccc(OCCCN3CCCCC3)cc2)cc1)N1CCCCC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 4′-(3-piperidinopropoxy)biphenyl-1-carboxylic acid (0.9 g) in dichloromethane (10 mL) containing one drop of N,N-dimethylformamide is added oxalyl chloride (285 μL). The suspension is stirred for one hour at room temperature, then chloroform (20 mL) and a drop of N,N-dimethylformamide are added. and the mixture is stirred for three hours at room temperature. Piperidine (1.6 mL) is then added and the mixture is stirred for an half hour at room temperature, washed with water, dried over magnesium sulfate and concentrated under reduced pressure. The product thus obtained is purified by chromatography over silica gel with a gradient dichloromethane/methanol from 100/0 to 90/10. Fraction containing the expected product are pooled, concentrated under reduced pressure to give 620 mg of 1-(3-{[4′-(piperidinocarbonyl)biphenyl-4-yl]oxy}propyl)-piperidine as white crystals melting at 122° C.
Reaction SMILES: C1C=CC=CC=1.[CH3:7][C:8]1([CH3:14])[NH:12][CH2:11][CH:10]([CH3:13])[O:9]1.C(N(CC)CC)C.[Cl:22][CH:23]([Cl:27])[C:24](Cl)=[O:25]>O>[CH3:7][C:8]1([CH3:14])[N:12]([C:24](=[O:25])[CH:23]([Cl:27])[Cl:22])[CH2:11][CH:10]([CH3:13])[O:9]1
Reactant: O=C(Cl)C(Cl)Cl
Reactant: CC1CNC(C)(C)O1
Solvent: c1ccccc1
Solvent: O
Solvent: CCN(CC)CC
Product: CC1CN(C(=O)C(Cl)Cl)C(C)(C)O1

Procedure:
Eighteen milliliters of a benzene solution containing 4.6 g. of 2,2,5-trimethyl oxazolidine was added to 25 ml. of benzene and 4.5 g. of triethylamine. Five and nine-tenths grams of dichloroacetyl chloride was added dropwise with stirring and cooling in an ice bath. When reaction was complete the mixture was poured into water and the benzene layer separated, dried over anhydrous magnesium sulfate and the benzene removed under vacuum. Yield was 7.7 g. of an oil, nD30 = 1.4950.
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:13][CH2:14][O:15][C:16]1[CH:22]=[CH:21][C:19](N)=[CH:18][CH:17]=1.[BrH:23].N([O-])=O.[Na+].[C:28]([O:32][CH2:33][CH3:34])(=[O:31])[CH:29]=[CH2:30]>CC(C)=O.CO.O>[Br:23][CH:29]([CH2:30][C:19]1[CH:21]=[CH:22][C:16]([O:15][CH2:14][CH2:13][C:3]2[N:4]=[C:5]([C:7]3[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=3)[O:6][C:2]=2[CH3:1])=[CH:17][CH:18]=1)[C:28]([O:32][CH2:33][CH3:34])=[O:31]
Reactant: C=CC(=O)OCC
Reactant: Br
Reactant: Cc1oc(-c2ccccc2)nc1CCOc1ccc(N)cc1
Agent: O=N[O-]
Agent: [Na+]
Solvent: CC(C)=O
Solvent: CO
Solvent: O
Product: CCOC(=O)C(Br)Cc1ccc(OCCc2nc(-c3ccccc3)oc2C)cc1
Temperature: 38 °C
Reaction time: 1 h

Procedure:
To a solution of 4-[2-(5-methyl-2-phenyl-4-oxazolyl)ethoxy]aniline (U.S. Pat. No. 4,725,610) (3.7 g, 12.6 mmol) in acetone (50 ml) and methanol (50 ml), cooled to 0° C., was added 48% hydrobromic acid (6.2 ml, 54 mmol), and after 5 minutes a solution of sodium nitrite (1.0 g, 15 mmol) in water (5 ml), dropwise, keeping the temperature below 5° C. After 15 minutes ethyl acrylate (8.6 ml, 79 mmol) was added dropwise, the mixture was warmed to 38° C. and cuprous oxide (0.42 g, 2.9 mmol) was added. The solution was stirred 1 hour at 40° C., then concentrated, diluted with aqueous ammonia and extracted with ethyl acetate (3×30 ml). The combined extracts were washed with water (2×), brine, dried over magnesium sulfate and concentrated. The product, ethyl alpha-bromo-4-[2-(5 -methyl-2-phenyl-4-oxazolyl)ethoxy]benzenepropanoate, was isolated by flash chromatography (hexane/ethyl acetate, 4:1) as a yellow oil (1.17 g).
Reaction SMILES: C(O[C:6](=[O:38])[NH:7][CH2:8][CH2:9][NH:10][C:11]([C:13]1[C:14]([OH:37])=[C:15]2[C:20](=[CH:21][N:22]=1)[N:19]([CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[C:18](=[O:30])[C:17]([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)=[CH:16]2)=[O:12])(C)(C)C.FC(F)(F)C(O)=O.[CH2:46]([N:48](CC)CC)[CH3:47].C(N=C=O)C.Cl>C(Cl)Cl.CCOC(C)=O>[CH2:46]([NH:48][C:6](=[O:38])[NH:7][CH2:8][CH2:9][NH:10][C:11]([C:13]1[C:14]([OH:37])=[C:15]2[C:20](=[CH:21][N:22]=1)[N:19]([CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[C:18](=[O:30])[C:17]([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)=[CH:16]2)=[O:12])[CH3:47]
Reactant: CCN(CC)CC
Reactant: CC(C)(C)OC(=O)NCCNC(=O)c1ncc2c(cc(-c3ccccc3)c(=O)n2Cc2ccccc2)c1O
Agent: CCN=C=O
Agent: Cl
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CCNC(=O)NCCNC(=O)c1ncc2c(cc(-c3ccccc3)c(=O)n2Cc2ccccc2)c1O
Reaction time: 2 h
Yield: 71.5 %

Procedure:
{2-[(1-Benzyl-5-hydroxy-2-oxo-3-phenyl-1,2-dihydro-[1,7]naphthyridine-6-carbonyl)-amino]ethyl}-carbamic acid tert-butyl ester (25 mg, 0.049 mmol) was dissolved in CH2Cl2 (2 mL). Trifluoroacetic acid (1 mL) was added, and the mixture was stirred for 2 h. Solvent and excess TFA was removed by evaporation, and to the residue were added CH2Cl2 (3 mL), triethylamine (0.068 mL, 0.49 mmol), and ethyl isocyanate (17 mg, 0.24 mmol). The resulting mixture was stirred overnight. EtOAc (50 mL) and 0.1 M HCl (20 mL) were added, and the aqueous layer was extracted with additional EtOAc. The organic layers were combined, dried over MgSO4 and concentrated. The crude product was purified by silica gel chromatography (0-8% MeOH/CH2Cl2) to give 17 mg of the title compound as a pale yellow solid. MS: (+) m/z 486.39 (M+1).
Reaction SMILES: FC(F)(F)C(O)=O.[Cl:8][C:9]1[N:14]=[N:13][C:12]([NH:15][NH2:16])=[C:11]([CH2:17][CH3:18])[C:10]=1[CH3:19].[N:20]#[C:21]Br.C(=O)([O-])[O-].[K+].[K+]>CCO.O>[Cl:8][C:9]1[C:10]([CH3:19])=[C:11]([CH2:17][CH3:18])[C:12]2[N:13]([C:21]([NH2:20])=[N:16][N:15]=2)[N:14]=1
Reactant: N#CBr
Reactant: CCc1c(NN)nnc(Cl)c1C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: CCc1c(C)c(Cl)nn2c(N)nnc12
Reaction time: 8 h
Yield: 112.8 %

Procedure:
(6-Chloro-4-ethyl-5-methylpyridazin-3-yl)hydrazine trifluoroacetic acid salt (W3.008; 340 mg) was initially charged in a mixture of EtOH (12 ml) and water (2 ml) at RT while stirring. Thereafter, cyanogen bromide (240 mg), dissolved in 3 ml of EtOH and 1 ml of water, was cautiously added dropwise and the mixture was stirred for 8 h. After standing overnight, 0.5 eq. of cyanogen bromide solution was added and the mixture was stirred again at RT for 4.5 h and then at 55° C. for 2 h. After standing overnight, the solvent was drawn off and the residue was admixed with water. Once it had been alkalized with saturated potassium carbonate solution, the mixture was extracted three times with dichloromethane. The combined organic phases were dried over sodium sulfate and, after the desiccant had been filtered off, dried under reduced pressure. 270 mg of the title compound were obtained.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:18])[C:4]1[CH:9]=[C:8]([O:10][CH3:11])[C:7]([O:12][CH3:13])=[CH:6][C:5]=1[S:14](Cl)(=[O:16])=[O:15].C(N(CC)CC)C.[NH2:26][CH2:27][C:28]([O:30][CH3:31])=[O:29]>C(Cl)Cl.C(OCC)(=O)C.Cl>[CH3:1][O:2][C:3](=[O:18])[C:4]1[CH:9]=[C:8]([O:10][CH3:11])[C:7]([O:12][CH3:13])=[CH:6][C:5]=1[S:14](=[O:16])(=[O:15])[NH:26][CH2:27][C:28]([O:30][CH3:31])=[O:29]
Reactant: COC(=O)c1cc(OC)c(OC)cc1S(=O)(=O)Cl
Reactant: COC(=O)CN
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: COC(=O)CNS(=O)(=O)c1cc(OC)c(OC)cc1C(=O)OC
Reaction time: 2 h
Yield: 78 %

Procedure:
To a solution of 2-Chlorosulfonyl-4,5-dimethoxy-benzoic acid methyl ester (0.100 g, 0.339 mmol) in methylene chloride (5 mL) was added triethylamine (0.28 mL, 2.012 mmol) and methyl glycinate.HCl (0.128 g, 1.02 mmol). The mixture was stirred for 2 hours and then diluted with ethyl acetate (50 mL) and 1N HCl (50 mL). The organic fraction was washed with brine and dried over MgSO4. Crystallization from methylene chloride hexane affords the title compound (0.092 g, 78%);
Reaction SMILES: [F:1][C@H:2]1[C@@H:7]([NH:8]C(=O)OCC2C=CC=CC=2)[CH2:6][CH2:5][N:4]([CH2:19][CH:20]2[C:24]3=[C:25]([F:33])[CH:26]=[N:27][C:28]4[CH:29]=[CH:30][C:31](=[O:32])[N:22]([C:23]=43)[CH2:21]2)[CH2:3]1.O1CCOCC1>C(O)C.[Pd]>[NH2:8][C@H:7]1[CH2:6][CH2:5][N:4]([CH2:19][CH:20]2[C:24]3=[C:25]([F:33])[CH:26]=[N:27][C:28]4[CH:29]=[CH:30][C:31](=[O:32])[N:22]([C:23]=43)[CH2:21]2)[CH2:3][C@H:2]1[F:1]
Reactant: O=C(N[C@H]1CCN(CC2Cn3c(=O)ccc4ncc(F)c2c43)C[C@H]1F)OCc1ccccc1
Agent: [Pd]
Solvent: C1COCCO1
Solvent: CCO
Product: N[C@H]1CCN(CC2Cn3c(=O)ccc4ncc(F)c2c43)C[C@H]1F
Reaction time: 5 h
Yield: 86.8 %

Procedure:
A solution of racemic phenylmethyl {cis-3-fluoro-1-[(3-fluoro-7-oxo-4,5-dihydro-7H-pyrrolo[3,2,1-de]-1,5-naphthyridin-4-yl)methyl]-4-piperidinyl}carbamate (1.218 g) in ethanol (20 ml)/1,4-dioxane (5 ml) was treated with 10% Pd/C (600 mg) and stirred under hydrogen at atmospheric pressure for 5 hours. After filtration through kieselguhr, the filtrate was evaporated and the residue chromatographed on silica gel, eluting with dichloromethane/methanol/0.88 aqueous ammonia, to give the desired compound (745 mg, 86%).
Reaction SMILES: Cl[C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[C@@H:11]1[O:15][C@H:14]([CH2:16][OH:17])[CH2:13][C@@H:12]1[F:18].[NH3:19]>>[NH2:19][C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[C@@H:11]1[O:15][C@H:14]([CH2:16][OH:17])[CH2:13][C@@H:12]1[F:18]
Reactant: OC[C@@H]1C[C@H](F)[C@H](n2cnc3c(Cl)ncnc32)O1
Reactant: N
Product: Nc1ncnc2c1ncn2[C@@H]1O[C@H](CO)C[C@@H]1F

Procedure:
A solution of 6-chloro-9-(2,3-dideoxy-2-fluoro-β-D-arabinofuranosyl)-9H-purine (16 mg, 0.059 mmol) in saturated methanolic ammonia (5 ml) was sealed in a glass tube under an atmosphere of ammonia.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:14]2[CH:15]=[C:16]([CH2:18][C:19]([OH:21])=O)[S:17][C:13]=2[N:12]2[C:22]([CH3:25])=[N:23][N:24]=[C:11]2[CH2:10][N:9]=1.C(N1C=CN=C1)(N1C=CN=C1)=O.[NH:38]1[CH2:43][CH2:42][O:41][CH2:40][CH2:39]1>O1CCCC1>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:14]2[CH:15]=[C:16]([CH2:18][C:19]([N:38]3[CH2:43][CH2:42][O:41][CH2:40][CH2:39]3)=[O:21])[S:17][C:13]=2[N:12]2[C:22]([CH3:25])=[N:23][N:24]=[C:11]2[CH2:10][N:9]=1
Reactant: Cc1nnc2n1-c1sc(CC(=O)O)cc1C(c1ccccc1Cl)=NC2
Reactant: C1COCCN1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: Cc1nnc2n1-c1sc(CC(=O)N3CCOCC3)cc1C(c1ccccc1Cl)=NC2
Temperature: 25 °C
Reaction time: 8 h
Yield: 39.4 %

Procedure:
Here, [4-(2-chlorophenyl)-9-methyl-6H-thieno[3,2-f][1,2,4]-triazolo[4,3-a][1,4]diazepin-2-yl]-methane carboxylic acid (20 g, 0.054 mol), tetrahydrofuran (500 ml) and 1,1'-carbonyldiimidazole (10 g) are stirred for 1 hour at ambient temperature and the solution, now clear, is mixed with morpholine (0.06 mol, 5.2 g). After stirring overnight at ambient temperature, evaporation, taking up in methylene chloride, washing with sodium bicarbonate solution and filtering through a column of SiO2, the title compound (9.4 g), m.p. 143°-144° C., is obtained by recrystallization from ethyl acetate.
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[C:8]([CH:10]([CH3:12])[CH3:11])[CH:7]=[C:6]([CH:13]([CH3:15])[CH3:14])[C:5]=1[S:16](Cl)(=[O:18])=[O:17])([CH3:3])[CH3:2].[NH2:20][C:21]1[CH:26]=[CH:25][C:24]([S:27]([CH:30]=[CH:31][C:32]#[N:33])(=[O:29])=[O:28])=[CH:23][CH:22]=1.N1C=CC=CC=1>O1CCOCC1>[CH:1]([C:4]1[CH:9]=[C:8]([CH:10]([CH3:12])[CH3:11])[CH:7]=[C:6]([CH:13]([CH3:15])[CH3:14])[C:5]=1[S:16]([NH:20][C:21]1[CH:22]=[CH:23][C:24]([S:27]([CH:30]=[CH:31][C:32]#[N:33])(=[O:29])=[O:28])=[CH:25][CH:26]=1)(=[O:18])=[O:17])([CH3:3])[CH3:2]
Reactant: CC(C)c1cc(C(C)C)c(S(=O)(=O)Cl)c(C(C)C)c1
Reactant: N#CC=CS(=O)(=O)c1ccc(N)cc1
Solvent: C1COCCO1
Solvent: c1ccncc1
Product: CC(C)c1cc(C(C)C)c(S(=O)(=O)Nc2ccc(S(=O)(=O)C=CC#N)cc2)c(C(C)C)c1

Procedure:
a solution of 9.1 g (0.03 mol) of 2,4,6-tri-isopropylbenzenesulfonyl chloride in 50 ml dioxane is added at room temperature to a solution of 6.3 g (0.03 mol) of 3-(4-aminobenzenesulfonyl)acrylonitrile in 150 ml dioxane, the dioxane solution additionally containing 3 ml (0.03 mol) of pyridine. After 8 hours the reaction mixture is filtered and evaporated and a tannish solid consisting of 3-[4-(2,4,6-tri-isopropylbenzenesulfonamido)benzenesulfonyl]acrylonitrile is obtained: ##SPC19##
Reaction SMILES: [CH:1]1([NH:5][C:6]2[C:7]3[CH:31]=[CH:30][NH:29][C:8]=3[N:9]=[C:10]([NH:12][C:13]3[CH:18]=[CH:17][C:16](S(N4CCC(O)CC4)(=O)=O)=[CH:15][CH:14]=3)[N:11]=2)[CH2:4][CH2:3][CH2:2]1.[CH2:32]([O:39][CH2:40][C:41]([N:43](C)[C:44]1C=CC(N)=CC=1)=[O:42])[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1>>[CH2:32]([O:39][CH2:40][C:41]([N:43]([C:16]1[CH:17]=[CH:18][C:13]([NH:12][C:10]2[N:11]=[C:6]([NH:5][CH:1]3[CH2:2][CH2:3][CH2:4]3)[C:7]3[CH:31]=[CH:30][NH:29][C:8]=3[N:9]=2)=[CH:14][CH:15]=1)[CH3:44])=[O:42])[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1
Reactant: O=S(=O)(c1ccc(Nc2nc(NC3CCC3)c3cc[nH]c3n2)cc1)N1CCC(O)CC1
Reactant: CN(C(=O)COCc1ccccc1)c1ccc(N)cc1
Product: CN(C(=O)COCc1ccccc1)c1ccc(Nc2nc(NC3CCC3)c3cc[nH]c3n2)cc1

Procedure:
According to the general procedure for synthesis of 1-(4-(4-(cyclobutylamino)-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)phenylsulfonyl)piperidin-4-ol, 2-benzoxy-N-methyl-N-(4-aminophenyl)acetamide and 2-Chloro-N-cylclobutyl-7H-pyrrolo[2,3-d]pyrimidin-4-amine gave 2-benzyloxy N-(4-(4-(cyclobutylamino)-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)phenyl)-N-methylacetamide (MS calcd for C26H28N6O2 456.2. found [MH] 457.0).