Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[NH:7][N:8]=[C:9]([C:11]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[O:12][SiH2:13][C:14]([CH3:17])([CH3:16])[CH3:15])[CH:10]=1)=[O:5])[CH3:2].Br[CH2:31][C:32]([NH:34][C:35]1[CH:40]=[CH:39][C:38]([Cl:41])=[CH:37][N:36]=1)=[O:33].O>CN(C=O)C>[CH2:1]([O:3][C:4]([C:6]1[CH:10]=[C:9]([C:11]([C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[O:12][SiH2:13][C:14]([CH3:17])([CH3:15])[CH3:16])[N:8]([CH2:31][C:32](=[O:33])[NH:34][C:35]2[CH:40]=[CH:39][C:38]([Cl:41])=[CH:37][N:36]=2)[N:7]=1)=[O:5])[CH3:2]
Reactant: O=C(CBr)Nc1ccc(Cl)cn1
Reactant: CCOC(=O)c1cc(C(O[SiH2]C(C)(C)C)(c2ccccc2)c2ccccc2)n[nH]1
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)c1cc(C(O[SiH2]C(C)(C)C)(c2ccccc2)c2ccccc2)n(CC(=O)Nc2ccc(Cl)cn2)n1
Reaction time: 3 h

Procedure:
To a solution of 5 g 5-(tert-Butyl-diphenyl-silanyloxymethyl)-2H-pyrazole-3-carboxylic acid ethyl ester in 10 ml DMF 4 g Cs2CO3 and 3 g 2-Bromo-N-(5-chloro-pyridin-2-yl)-acetamide were added and the mixture was stirred for 3 h. Then 10 ml of water were added and the mixture was extracted with ethyl acetate (2×50 ml). The combined organic layers were dried over MgSO4, filtered and concentrated under reduced pressure. Inspection of the TLC and HPLC/MS indicated that a 1:1 mixture of the desired product together with the regioisomeric 5-(tert-Butyl-diphenyl-silanyloxymethyl)-2-[(5-chloro-pyridin-2-ylcarbamoyl)-methyl]-2H-pyrazole-3-carboxylic acid ethyl ester was present. Purification of this mixture on silica gel eluting with a gradient on n-heptane/ethylacetate yielded the desired product as the faster eluting less polar isomer.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([O:8][CH2:9][C:10]#[C:11][CH2:12][CH3:13])[N:5]=[CH:4][N:3]=1.[F:14][C:15]([F:23])([F:22])[CH:16]1[CH2:21][CH2:20][CH2:19][NH:18][CH2:17]1>>[CH2:9]([O:8][C:6]1[N:5]=[CH:4][N:3]=[C:2]([N:18]2[CH2:19][CH2:20][CH2:21][CH:16]([C:15]([F:23])([F:22])[F:14])[CH2:17]2)[CH:7]=1)[C:10]#[C:11][CH2:12][CH3:13]
Reactant: CCC#CCOc1cc(Cl)ncn1
Reactant: FC(F)(F)C1CCCNC1
Product: CCC#CCOc1cc(N2CCCC(C(F)(F)F)C2)ncn1
Reaction time: 10 h
Yield: 47.1 %

Procedure:
0.2 g of 4-chloro-6-(2-pentynyloxy)pyrimidine and 0.23 g of 3-trifluoromethylpiperidine were mixed and left for 10 hours at room temperature. The reaction mixture was subjected to silica gel column chromatography to obtain 0.15 g of 6-(2-pentynyloxy)-4-(3-trifluoromethylpiperidino)pyrimidine (hereinafter, referred to as Compound (25)).
Reaction SMILES: C(OC([N:8]([CH2:21][CH:22]1[CH2:27][CH2:26][N:25]([CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][C:33]([OH:35])=[O:34])[CH2:24][CH:23]1[C:36]1[CH:41]=[CH:40][CH:39]=[C:38]([F:42])[CH:37]=1)[C@@H:9]([C:11]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:14]=[CH:13][CH:12]=1)[CH3:10])=O)(C)(C)C.[ClH:43].C(OCC)(=O)C>C(OCC)(=O)C>[ClH:43].[ClH:43].[F:42][C:38]1[CH:37]=[C:36]([CH:23]2[CH:22]([CH2:21][NH:8][C@@H:9]([C:11]3[C:20]4[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=4)[CH:14]=[CH:13][CH:12]=3)[CH3:10])[CH2:27][CH2:26][N:25]([CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][C:33]([OH:35])=[O:34])[CH2:24]2)[CH:41]=[CH:40][CH:39]=1
Reactant: C[C@H](c1cccc2ccccc12)N(CC1CCN(CCCCCC(=O)O)CC1c1cccc(F)c1)C(=O)OC(C)(C)C
Agent: Cl
Solvent: CCOC(C)=O
Product: C[C@@H](NCC1CCN(CCCCCC(=O)O)CC1c1cccc(F)c1)c1cccc2ccccc12
Reaction time: 2 h

Procedure:
To a solution of 168 mg of 6-[4-({(tert-butoxycarbonyl)[(1R)-1-(1-naphthyl)ethyl]amino}methyl)-3-(3-fluorophenyl)piperidin-1-yl]hexanoic acid in 2.0 mL of ethyl acetate was added 1.00 mL of a 4 M hydrogen chloride/ethyl acetate solution at room temperature, followed by stirring for 2 hours. The solvent was removed by distillation under reduced pressure. The residue was purified by reverse phase silica gel column chromatography (acetonitrile-0.001 M hydrochloric acid) to obtain 70 mg of 6-[3-(3-fluorophenyl)-4-({[(1R)-1-(1-naphthyl)ethyl]amino}methyl)piperidin-1-yl]hexanoic acid dihydrochloride as a pale yellow solid.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[CH:5][C:6]([C:9]([NH:11][C:12]2[CH:40]=[N:39][C:15]3[O:16][CH2:17][CH2:18][C@@H:19]4[C@@:24]([CH3:25])([C:14]=3[CH:13]=2)[N:23]=[C:22]([NH:26]C(=O)OC(C)(C)C)[C:21]2([CH2:36][CH2:35][CH2:34]2)[S:20]4(=[O:38])=[O:37])=[O:10])=[N:7][CH:8]=1)#[N:2].C(O)(C(F)(F)F)=O.C([O-])(O)=O.[Na+].[OH-].[Na+]>O>[NH2:26][C:22]1[C:21]2([CH2:34][CH2:35][CH2:36]2)[S:20](=[O:37])(=[O:38])[C@@H:19]2[CH2:18][CH2:17][O:16][C:15]3[N:39]=[CH:40][C:12]([NH:11][C:9](=[O:10])[C:6]4[CH:5]=[CH:4][C:3]([C:1]#[N:2])=[CH:8][N:7]=4)=[CH:13][C:14]=3[C@@:24]2([CH3:25])[N:23]=1
Reactant: CC(C)(C)OC(=O)NC1=N[C@]2(C)c3cc(NC(=O)c4ccc(C#N)cn4)cnc3OCC[C@H]2S(=O)(=O)C12CCC2
Agent: O=C([O-])O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: C[C@]12N=C(N)C3(CCC3)S(=O)(=O)[C@@H]1CCOc1ncc(NC(=O)c3ccc(C#N)cn3)cc12
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 32.6 %

Procedure:
To tert-butyl ((4a′R,11b′R)-10′-(5-cyanopicolinamido)-11b′-methyl-4′,4′-dioxido-4a′,5′,6′,11b′-tetrahydrospiro[cyclobutane-1,3′-pyrido[3′,2′:6,7]oxepino[4,5-b][1,4]thiazin]-2′-yl)carbamate was added TFA (0.015 ml, 0.197 mmol) and the resulting solution was stirred at rt for 15 min. The reaction mixture was poured into water and the pH was brought to >10 using sat. NaHCO3 and 5 N NaOH, then extracted with DCM. The combined organics were dried over Na2SO4, filtered, concentrated and purified by silica gel chromatography using a gradient 0-3% MeOH/DCM solvent system to afford a white solid as N-((4a′R,11b′R)-2′-amino-11b′-methyl-4′,4′-dioxido-4a′,5′,6′,11b′-tetrahydrospiro[cyclobutane-1,3′-pyrido[3′,2′:6,7]oxepino[4,5-b][1,4]thiazin]-10′-yl)-5-cyanopicolinamide (0.030 g, 0.064 mmol, 32.6% yield). MS m/z=466.9 (M+H).
Reaction SMILES: Cl[C:2]1[CH:7]=[N:6][CH:5]=[C:4]([Cl:8])[N:3]=1.Cl.[C:10]([O:14][C:15](=[O:19])[C@@H:16]([CH3:18])[NH2:17])([CH3:13])([CH3:12])[CH3:11].CS(C)=O.CCN(C(C)C)C(C)C>C(OCC)(=O)C>[Cl:8][C:4]1[N:3]=[C:2]([NH:17][C@H:16]([CH3:18])[C:15]([O:14][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:19])[CH:7]=[N:6][CH:5]=1
Reactant: Clc1cncc(Cl)n1
Reactant: C[C@@H](N)C(=O)OC(C)(C)C
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: C[C@@H](Nc1cncc(Cl)n1)C(=O)OC(C)(C)C
Temperature: 120 °C

Procedure:
To a reaction vessel was added 2,6-dichloropyrazine (CA, 492 mg, 3.30 mmol), D-Alanine tert-butyl ester hydrochloride (Aldrich Chemical) (500 mg, 2.75 mmol), DMSO (3 mL) and DIPEA (1.923 mL, 11.01 mmol). The resulting solution was heated to 120° C. for 18 hrs. The reaction mixture was cooled and diluted with ethyl acetate (30 mL). The organic layer was washed with aqueous sodium hydrogen carbonate followed by aq. brine. The aqueous layers were back extracted with ethyl acetate and the combined organic layers dried with sodium sulfate, filtered and concentrated to give an oil. The residue was purified by silica gel chromatography on Biotage 50 g SNAP column, eluting with EtOAc/Hexane (10-60%) to give the product, I-9, as a yellow oil. (663 mg, 93%) LRMS (ESI) m/z 258.1 [(M+H)+; calcd for C11H16ClN3O2: 258.1].
Reaction SMILES: N[C:2]1[N:6]([CH2:7][C:8]2[CH:13]=[C:12]([C:14]([F:17])([F:16])[F:15])[CH:11]=[C:10]([C:18]([F:21])([F:20])[F:19])[CH:9]=2)[CH:5]=[N:4][C:3]=1[C:22]#[N:23].C(I)[I:25].N(OCCC(C)C)=O>>[F:19][C:18]([F:21])([F:20])[C:10]1[CH:9]=[C:8]([CH:13]=[C:12]([C:14]([F:17])([F:16])[F:15])[CH:11]=1)[CH2:7][N:6]1[C:2]([I:25])=[C:3]([C:22]#[N:23])[N:4]=[CH:5]1
Reactant: N#Cc1ncn(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)c1N
Reactant: ICI
Agent: CC(C)CCON=O
Product: N#Cc1ncn(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)c1I
Reaction time: 0.5 h

Procedure:
Combine 5-Amino-1-(3,5-bis-trifluoromethyl-benzyl)-1H-imidazole-4-carbonitrile (0.066 g, 0.20 mmol), CH2I2 (3 mL), and isoamyl nitrite (250 μL, 2 mmol) in a round bottom flask and stir the mixture at 100° C. After 30 min., remove from heat and concentrate. Purify by flash chromatography on silica gel to give the title compound. MS (ES) 443.9 (M−1); 1H NMR (300 MHz, CDCl3) δ 7.93 (s, 1H), 7.78 (s, 1H), 7.58 (s, 2H), 5.31 (s, 2H).
Reaction SMILES: [CH3:1][CH2:2][N:3]1[C:9]2[N:10]=[C:11]([CH3:14])[CH:12]=[CH:13][C:8]=2[C:6](=[O:7])[C:5]([C:15]([OH:17])=O)=[CH:4]1.ClCCl.C(OC(Cl)=O)(C)=C.[NH2:28][CH2:29][CH2:30][C:31]1[CH:36]=[CH:35][N:34]=[CH:33][CH:32]=1>C(N(CC)CC)C>[CH2:2]([N:3]1[C:9]2[C:8](=[CH:13][CH:12]=[C:11]([CH3:14])[N:10]=2)[C:6](=[O:7])[C:5]([C:15]([NH:28][CH2:29][CH2:30][C:31]2[CH:36]=[CH:35][N:34]=[CH:33][CH:32]=2)=[O:17])=[CH:4]1)[CH3:1]
Reactant: CCn1cc(C(=O)O)c(=O)c2ccc(C)nc21
Reactant: NCCc1ccncc1
Agent: C=C(C)OC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCn1cc(C(=O)NCCc2ccncc2)c(=O)c2ccc(C)nc21
Temperature: 0 °C
Reaction time: 1.5 h

Procedure:
Nalidixic acid (0.45 g) and dichloromethane (20 ml) were combined and cooled to 0° C. under nitrogen. Triethylamine (0.3 ml) was then added, followed by isopropenylchloro-formate (0.24 ml) and the whole stirred for 90 minutes. 4-(2-Aminoethyl)pyridine (0.26 ml) was then added and stirring continued for 20 h, after which time the reaction was concentrated onto silica and purified by flash chromatography to give the title compound as an off white solid.
Reaction SMILES: [C:1]1([C:7]2[C:8]3[CH:23]=[CH:22][CH:21]=[C:20]4[C:9]=3[N:10]([CH2:18][CH2:19]4)[C:11]3[CH:17]=[CH:16][CH:15]=[CH:14][C:12]=3[N:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[BH4-].[Na+].O>C(O)C>[C:1]1([CH:7]2[NH:13][C:12]3[CH:14]=[CH:15][CH:16]=[CH:17][C:11]=3[N:10]3[CH2:18][CH2:19][C:20]4=[CH:21][CH:22]=[CH:23][C:8]2=[C:9]34)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: c1ccc(C2=Nc3ccccc3N3CCc4cccc2c43)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: c1ccc(C2Nc3ccccc3N3CCc4cccc2c43)cc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A stirred mixture, under N2, of 23.0 g of 1,2-dihydro-6-phenylindolo[1,7-ab][1,5]benzodiazepine in 200 ml of absolute ethanol is cooled to 0°-5° C. Sodium borohydride is then added in small portions and at such a rate as to keep the reaction temperature less than 5° C., and to minimize foaming. About 3 g. are required to discharge the initial blue-purple color, and another 1 g. is added to insure complete reduction. The mixture is then stirred 1 hour at 0° C. and 1 hour at room temperature. Water is added, the product is filtered, washed repeatedly with water, and dried to give 6-phenyl-1,2,6,7-tetrahydroindolo[1,7-ab][1,5]benzodiazepine, m.p. 161°-164° C.
Reaction SMILES: CO[C:3]([CH:5]1[C:11](=[O:12])[C:10]2[CH:13]=[CH:14][C:15]([Cl:17])=[CH:16][C:9]=2[N:8]([CH2:18][CH2:19][CH2:20][CH3:21])[C:7](=[O:22])[CH2:6]1)=[O:4].[NH2:23][C:24]1[S:25][CH:26]=[CH:27][N:28]=1>C1(C)C=CC=CC=1>[Cl:17][C:15]1[CH:14]=[CH:13][C:10]2[C:11](=[O:12])[CH:5]([C:3](=[O:4])[NH:23][C:24]3[S:25][CH:26]=[CH:27][N:28]=3)[CH2:6][C:7](=[O:22])[N:8]([CH2:18][CH2:19][CH2:20][CH3:21])[C:9]=2[CH:16]=1
Reactant: CCCCN1C(=O)CC(C(=O)OC)C(=O)c2ccc(Cl)cc21
Reactant: Nc1nccs1
Solvent: Cc1ccccc1
Product: CCCCN1C(=O)CC(C(=O)Nc2nccs2)C(=O)c2ccc(Cl)cc21

Procedure:
The mixture of 3.8 g of 8-chloro-1-n-butyl-2,3,4,5-tetrahydro-1-benzazepine-2,5-dione-4-carboxylic acid methyl ester, 1.17 g of 2-aminothiazole and 70 ml of toluene is distilled for 20 hours so that after collecting 25 ml of toluene each, this amount is returned to the reaction mixture. It is finally concentrated to a small volume, the resulting suspension cooled with ice, filtered and the residue recrystallized from chloroform-acetonitrile, to yield the 8-chloro-1-n-butyl-4-(2-thiazolylcarbamoyl)-2,3,4,5-tetrahydro-1-benzazepine-2,5-dione melting at 238° to 240°.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][N:3]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Na+].Cl[C:19]1[N:24]=[C:23]([N:25]2[CH2:30][CH2:29][O:28][CH2:27][CH2:26]2)[N:22]=[C:21]([N:31]2[C:35]3[CH:36]=[CH:37][CH:38]=[C:39]([O:40][CH3:41])[C:34]=3[N:33]=[C:32]2[CH:42]([F:44])[F:43])[N:20]=1.C(O)(=O)C>C1COCC1.O>[F:44][CH:42]([F:43])[C:32]1[N:31]([C:21]2[N:22]=[C:23]([N:25]3[CH2:30][CH2:29][O:28][CH2:27][CH2:26]3)[N:24]=[C:19]([NH:1][C:2]3[CH:7]=[CH:6][N:5]=[CH:4][N:3]=3)[N:20]=2)[C:35]2[CH:36]=[CH:37][CH:38]=[C:39]([O:40][CH3:41])[C:34]=2[N:33]=1
Reactant: COc1cccc2c1nc(C(F)F)n2-c1nc(Cl)nc(N2CCOCC2)n1
Reactant: Nc1ccncn1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: COc1cccc2c1nc(C(F)F)n2-c1nc(Nc2ccncn2)nc(N2CCOCC2)n1
Reaction time: 0.17 h
Yield: 15.7 %

Procedure:
To 0.225 g (2.37 mmol) of 4-aminopyrimidine in THF (3 mL) was added 1.30 mL of NaHMDS (2 M solution in THF) and the mixture was stirred for 10 min. A solution of 0.320 g (0.81 mmol) of 1-[4-chloro-6-(4-morpholinyl)-1,3,5-triazin-2-yl]-2-(difluoromethyl)-4-methoxy-1H-benzimidazole in THF (5 mL) was added and the resulting mixture was stirred for 1 hr. The reaction mixture was neutralized with acetic acid, diluted with water and extracted with EtOAc. The organic layer was washed with water, and aq. NH3, and dried. Removal of the solvent, followed by chromatography on silica, eluting first with hexanes-EtOAc (1:1), then CH2Cl2/EtOAc (1:1) to CH2Cl2/EtOAc (1:3) gave a white powder. Recrystallization from EtOH/CH2Cl2 gave 0.058 g (16% yield) of 4-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-6-(4-morpholinyl)-N-(4-pyrimidinyl)-1,3,5-triazin-2-amine: mp 234-236° C.; 1H NMR (CDCl3) δ8.91 (d, J=1.0 Hz, 1H), 8.65 (d, J=5.8 Hz, 1H), 8.23 (dd, J=5.8, 1.3 Hz, 1H), 7.99 (s, 1H), 7.93 (dd, J=8.3, 0.5 Hz, 1H), 7.47 (t, JHF=53.4 Hz, 1H), 7.38 (t, J=8.2 Hz, 1H), 6.85 (d, J=7.8 Hz, 1H), 4.06 (s, 3H), 3.97-3.96 (m, 4H), 3.86-3.84 (m, 4H); Anal. Calcd. for C20H19F2N9O20.31H2O: C, 52.1; H, 4.3; N, 27.3. Found: C, 51.7; H, 4.15; N, 27.3%.
Reaction SMILES: [CH3:1][O:2][CH2:3][O:4][C:5]1[C:22]([OH:23])=[CH:21][C@H:20]2[C:7](=[CH:8][CH2:9][C@@H:10]3[C@@H:19]2[CH2:18][CH2:17][C@@:15]2([CH3:16])[C@H:11]3[CH2:12][CH2:13][C@@H:14]2[O:24][CH2:25][O:26][CH3:27])[CH:6]=1.C(=O)([O-])[O-].[K+].[K+].I[CH2:35][CH3:36]>C(O)C>[CH3:1][O:2][CH2:3][O:4][C:5]1[C:22]([O:23][CH2:35][CH3:36])=[CH:21][C@H:20]2[C:7](=[CH:8][CH2:9][C@@H:10]3[C@@H:19]2[CH2:18][CH2:17][C@@:15]2([CH3:16])[C@H:11]3[CH2:12][CH2:13][C@@H:14]2[O:24][CH2:25][O:26][CH3:27])[CH:6]=1
Reactant: COCOC1=CC2=CC[C@@H]3[C@H](CC[C@]4(C)[C@@H](OCOC)CC[C@@H]34)[C@H]2C=C1O
Reactant: CCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: CCOC1=C[C@H]2C(=CC[C@@H]3[C@@H]2CC[C@]2(C)[C@@H](OCOC)CC[C@@H]32)C=C1OCOC
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 92.9 %

Procedure:
A solution of 3,17β-bis(methoxymethoxy)estra-1,3,5-triene-2-ol (Z. Wang and Cushman, Synzthetic Commun. 28:4431-4437 (1998)) (11.3 g, 27.8 mmol) in anhydrous ethanol (225 ml) containing anhydrous potassium carbonate (38.4 g, 280 mmol) was stirred at room temperature under argon for 10 min. Iodoethane (43.7 g, 280 mmol) was introduced to the reaction mixture. The resulting mixture was stirred at gentle reflux. After 4 hr, another portion of iodoethane (10.92 g, 70 mmol) was introduced and the reflux was continued for another 10 hr. The reaction mixture was cooled to room temperature and filtered. The solid was washed with ether (100 ml), and the filtrates were combined and evaporated to dryness. Chromatography of the residue (silica gel 230-400 mesh, ethyl acetate:hexane 1:7 by volume) gave the pure 2 (10.45 g, 92%) as a colorless oil: 1H NMR (CDCl3) δ6.85 (s, 2 H), 5.18 (s, 2 H), 4.66 (ABq, J=6.6 Hz, Δν=3.4 Hz, 2 H), 4.08 (q, J=7.0 Hz, 2 H), 3.61 (t, J=8.5 Hz, 1 H), 3.52 (s, 3 H), 3.38 (s, 3 H), 2.79 (m, 2 H), 2.30-1.20 (m, 13 H), 0.82 (s, 3 H); CIMS (isobutane) m/z (rel intensity) 405 (MH+, 39), 343 (100). Anal. Calcd. for C24H37O5: C, 71.26; H, 8.97. Found: C, 71.48; H, 9.14.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[C:5]#[N:6].[CH3:10][O-:11].[Na+]>CO.O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[C:5](=[NH:6])[O:11][CH3:10]
Reactant: N#Cc1cccc(Cl)c1
Reactant: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: COC(=N)c1cccc(Cl)c1
Temperature: 25 °C
Reaction time: 48 h
Yield: 471.7 %

Procedure:
To a solution of 3-chlorobenzonitrile (4.0 g, 29.1 mmol) in methanol (30 mL) was added sodium methoxide (0.16 g, 2.9 mmol). The mixture stirred at rt for 2 d, diluted with water, and extracted with methylene chloride. The combined organic layer was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The residue was purified by column chromatography (silica, hexanes/ethyl acetate) to afford the title compound (2.32 g, 47%) as a clear oil. MW=169.61. 1H NMR (CDCl3, 500 MHz) δ 7.85 (s, 1H), 7.70 (s, 1H), 7.57 (s, 1H), 7.46-7.42 (m, 1H), 7.35 (t, J=7.9 Hz, 1H), 3.94 (s, 3H); APCI MS m/z 170 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](O)=[C:7]([S:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=3)(=[O:14])=[O:13])[CH:8]=[N:9]2)=[CH:4][CH:3]=1.O(Cl)[Cl:24].[P+5].[Na]>O>[Cl:21][C:18]1[CH:19]=[CH:20][C:15]([S:12]([C:7]2[CH:8]=[N:9][C:10]3[C:5]([C:6]=2[Cl:24])=[CH:4][CH:3]=[C:2]([Cl:1])[CH:11]=3)(=[O:14])=[O:13])=[CH:16][CH:17]=1
Reactant: O=S(=O)(c1ccc(Cl)cc1)c1cnc2cc(Cl)ccc2c1O
Reactant: ClOCl
Agent: [Na]
Agent: [P+5]
Solvent: O
Product: O=S(=O)(c1ccc(Cl)cc1)c1cnc2cc(Cl)ccc2c1Cl
Yield: 85 %

Procedure:
7-Chloro-3-(4-chloro-benzenesulfonyl)-4-hydroxyquinoline (4.25 g, 12 mmol) in phosphorus(V) oxychloride (5.6 ml, 60 mmol) was refluxed for 3 h. The reaction mixture was poured into water (50 ml) and was alkalized with 5M sodium hydroxyde solution. After cooling the precipitate was filtered and washed with water to obtain 3.8 g of the title compound in 85.0% yield.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[C:11]([O:15][C:16]([N:18]1[CH2:23][CH2:22][N:21]([CH2:24][CH:25]([OH:42])[CH2:26][N:27]2[C:39]3[CH:38]=[CH:37][C:36]([Br:40])=[CH:35][C:34]=3[C:33]3[C:28]2=[CH:29][CH:30]=[C:31]([Br:41])[CH:32]=3)[CH2:20][CH2:19]1)=[O:17])([CH3:14])([CH3:13])[CH3:12].CCOCC.CO>C(Cl)Cl>[C:11]([O:15][C:16]([N:18]1[CH2:19][CH2:20][N:21]([CH2:24][C:25](=[O:42])[CH2:26][N:27]2[C:39]3[CH:38]=[CH:37][C:36]([Br:40])=[CH:35][C:34]=3[C:33]3[C:28]2=[CH:29][CH:30]=[C:31]([Br:41])[CH:32]=3)[CH2:22][CH2:23]1)=[O:17])([CH3:14])([CH3:12])[CH3:13]
Reactant: CC(C)(C)OC(=O)N1CCN(CC(O)Cn2c3ccc(Br)cc3c3cc(Br)ccc32)CC1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CO
Solvent: CCOCC
Product: CC(C)(C)OC(=O)N1CCN(CC(=O)Cn2c3ccc(Br)cc3c3cc(Br)ccc32)CC1
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 80.7 %

Procedure:
At −78° C. a solution of oxalyl chloride (200 μL, 2.34 mmol) in anhydrous DCM (20 mL) is treated with anhydrous DMSO (310 μL, 4.37 mmol). After 15 min of stirring at −78° C., a solution of Example 4 (1.0 g, 1.76 mmol) in anhydrous DCM (5 mL) is added dropwise. The resulting mixture is allowed to stir for 40 min at −78° C. and TEA (1250 μL) is added neat. After 10 min the reaction mixture is allowed to warm up to −30° C. After 1 hour of stirring at −30° C. the reaction mixture is quenched with water (50 mL). Extraction with DCM (3×100 mL), drying over MgSO4 and evaporation under reduced pressure gives a yellow oil. Flash chromatography on a 4×21 cm2 SiO2 column using Et2O/MeOH (100/1) mixture then (100/3) as eluant gives the title compound as a pale yellow foam (0.804 g, 1.42 mmol) in a 81% yield.
Reaction SMILES: C([NH:4][C:5]1[CH:6]=[C:7]([S:13](Cl)(=[O:15])=[O:14])[CH:8]=[CH:9][C:10]=1[O:11][CH3:12])(=O)C.[N:17]#[C:18][NH2:19].[OH-].[Na+].Cl>O>[CH3:12][O:11][C:10]1[CH:9]=[CH:8][C:7]([S:13]([NH:19][C:18]#[N:17])(=[O:15])=[O:14])=[CH:6][C:5]=1[NH2:4]
Reactant: N#CN
Reactant: COc1ccc(S(=O)(=O)Cl)cc1NC(C)=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: COc1ccc(S(=O)(=O)NC#N)cc1N
Temperature: 10 °C

Procedure:
132 parts of 3-acetylamino-4-methoxybenzenesulfonyl chloride and 25 parts of cyanamide are suspended in 400 parts of water at 0° C. and reacted with one another at a temperature of about 20° C. while a pH between 9 and 11 is maintained. Then 130 parts by volume of 33% strength aqueous sodium hydroxide solution are added and the acetylamino group is hydrolyzed at 100° C. in the course of an hour. The batch is then cooled down to 10° C. and brought to pH 2 with hydrochloric acid and the precipitated 2-methoxy-5-cyanamidosulfonylaniline is isolated.
Reaction SMILES: [C@@H:1]1(N2C=CC(=O)NC2=O)[O:9][C@H:6]([CH2:7][OH:8])[C@@H:4]([OH:5])[C@H:2]1[OH:3].[NH:18]([C:25]1[CH:30]=[CH:29][N:28]=[C:27]2[NH:31][CH:32]=[N:33][C:26]=12)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.[OH-].[K+]>>[NH:18]([C:25]1[CH:30]=[CH:29][N:28]=[C:27]2[N:31]([C@@H:1]3[O:9][C@H:6]([CH2:7][OH:8])[C@@H:4]([OH:5])[C@H:2]3[OH:3])[CH:32]=[N:33][C:26]=12)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: c1ccc(Nc2ccnc3[nH]cnc23)cc1
Reactant: O=c1ccn([C@@H]2O[C@H](CO)[C@@H](O)[C@H]2O)c(=O)[nH]1
Agent: [K+]
Agent: [OH-]
Product: OC[C@H]1O[C@@H](n2cnc3c(Nc4ccccc4)ccnc32)[C@H](O)[C@@H]1O
Yield: 90.9 %

Procedure:
Uridine (50 mmoles, 12.3 g) and 7-anilino-3H-imidazo[4,5-b]pyridine (33 mmole, 7.0 g), were suspended in 65 mL of 7.6 mM KxHxPO4, pH 8.0. After stirring, the pH of this suspension was adjusted from pH 6.6 to 7.4 with potassium hydroxide. The enzyme catalysts purified from Escherichia coli, purine nucleoside phosphorylase (13,000 I.U.) and uridine phosphorylase (335 I.U.) (Krenitsky et al., Biochemistry, 20, 3615, 1981 and U.S. Pat. No. 4,381,344) were then added and the suspension stirred at 38° C. for 5 days. The reaction mixture was filtered. The solids were washed with water and suspended in 250 mL of methanol, brought to a boil, and filtered while hot. The filtrate was dried and extracted with water at room temperature. The product in the washed solids was further purified by several recrystallizations from boiling water. Analytically pure 7-anilino-3-β-D-ribofuranosyl-3H-imidazo[4,5-b]pyridine (30 mmole, 10.46 g), m.p. 189° C. was obtained representing a yield of 91% with respect to the amount of 7-anilino-3H-imidazo[4,5-b]pyridine base used.
Reaction SMILES: CN(C)/[CH:3]=[CH:4]/[C:5]([C:7]1[CH:17]=[CH:16][C:10]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:9][CH:8]=1)=O.C(=O)([O-])[O-].[K+].[K+].[C:25]([NH:28][C:29]1[CH:37]=[CH:36][C:32]([C:33]([NH2:35])=[O:34])=[CH:31][CH:30]=1)(=[NH:27])[NH2:26]>CCOCC>[C:33]([C:32]1[CH:36]=[CH:37][C:29]([NH:28][C:25]2[N:26]=[C:5]([C:7]3[CH:17]=[CH:16][C:10]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:9][CH:8]=3)[CH:4]=[CH:3][N:27]=2)=[CH:30][CH:31]=1)(=[O:34])[NH2:35]
Reactant: CCOC(=O)c1ccc(C(=O)/C=C/N(C)C)cc1
Reactant: N=C(N)Nc1ccc(C(N)=O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOCC
Product: CCOC(=O)c1ccc(-c2ccnc(Nc3ccc(C(N)=O)cc3)n2)cc1
Yield: 46 %

Procedure:
A mixture of ethyl 4-acetylbenzoate (3.00 g, 15.62 mmol) and N,N-dimethylformamide dimethyl acetal (6.2 g, 52.10 mmol) was refluxed for 18 hours, cooled and concentrated to give ethyl 4-[(2E)-3-(dimethylamino)prop-2-enoyl]benzoate quantitatively. A solution of ethyl 4-[(2E)-3-(dimethylamino)prop-2-enoyl]benzoate, potassium carbonate (3.55 g, 25.74 mmol), and 4-(amidinoamino)benzamide (3.10 g, 12.87 mmol) in ETOH (120 mL) was refluxed for 18 hours. The mixture was cooled, filtered, and washed with ETOH, water, then ether respectively to give ethyl 4-{2-[(4-carbamoylphenyl)amino]pyrimidin-4-yl}benzoate (2.60 g, 46% yield). This compound was refluxed for 2 hours in ETOH (30 mL), water (20 mL), and NaOH (0.640 g, 16 mmol). The reaction mixture was cooled, acidified to pH 3, and filtered to give 1.00 gram (42% yield) of the titled compound. HPLC/ES-MS (20-100% acetonitrile): R.T. 4.7 min.(Method A); (m/z) 335 [M+1]+.