Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([C:8]1[C:16]2[CH2:15][CH2:14][O:13][CH:12]([CH2:17][NH2:18])[C:11]=2[S:10][C:9]=1[NH2:19])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:20][O:21][C:22]1[CH:27]=[C:26]([O:28][CH3:29])[CH:25]=[CH:24][C:23]=1[N:30]=[C:31]=[O:32]>ClCCl>[C:1]([O:5][C:6]([C:8]1[C:16]2[CH2:15][CH2:14][O:13][CH:12]([CH2:17][NH:18][C:31]([NH:30][C:23]3[CH:24]=[CH:25][C:26]([O:28][CH3:29])=[CH:27][C:22]=3[O:21][CH3:20])=[O:32])[C:11]=2[S:10][C:9]=1[NH2:19])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)c1c(N)sc2c1CCOC2CN
Reactant: COc1ccc(N=C=O)c(OC)c1
Solvent: ClCCl
Product: COc1ccc(NC(=O)NCC2OCCc3c2sc(N)c3C(=O)OC(C)(C)C)c(OC)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 53.9 %

Procedure:
To a solution of 2-amino-7-aminomethyl-4,7-dihydro-5H-thieno[2,3-c]pyran-3-carboxylic acid tert-butyl ester (64 mg, 0.22 mmol) in dichloromethane (1 ml) was added 2,4-dimethoxyphenylisocyanate (40 mg, 0.22 mmol). The reaction mixture was stirred at room temperature for 18 h. The reaction mixture was concentrated in vacuo, diluted with ethyl acetate (30 ml), washed with saturated sodium carbonate (3×25 ml), brine (3×25 ml), dried (MgSO4), filtered and the solvent evaporated in vacuo. The residue was subjected to preparative thin layer chromatography (100% dichloromethane). Rf=0.8 was isolated and the solvent evaporated in vacuo which afforded 55 mg (53%) of 2-amino-7-(3-(2,4-dimethoxy-phenyl)ureidomethyl)-4,7-dihydro-5H-thieno[2,3-c]pyran-3-carboxylic acid tert-butyl ester as an oil.
Reaction SMILES: C(#N)C.C(Cl)(=O)C(Cl)=O.[F:10][C:11]1[C:19]([O:20][CH3:21])=[CH:18][CH:17]=[C:16]([F:22])[C:12]=1[C:13]([NH2:15])=O.C(N(CC)CC)C>CN(C=O)C>[F:10][C:11]1[C:19]([O:20][CH3:21])=[CH:18][CH:17]=[C:16]([F:22])[C:12]=1[C:13]#[N:15]
Reactant: COc1ccc(F)c(C(N)=O)c1F
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: CC#N
Solvent: CN(C)C=O
Product: COc1ccc(F)c(C#N)c1F
Temperature: 0 °C
Reaction time: 0.67 h
Yield: 65.7 %

Procedure:
To an ice cold solution of DMF (0.45 ml) and acetonitrile (10 ml) was added oxalyl chloride (0.41 g, 0.28 ml, 3.20 mmol) dropwise while maintaining the temperature to 0° C. The reaction mixture was stirred at 0° C. for 40 min followed by addition of a solution of 2,6-difluoro-3-methoxybenzamide (0.50 g, 2.70 mmol) in DMF (4.5 ml).The resulting reaction mixture was stirred at 0° C. 40 min and then allowed to come to room temperature. After completion of reaction (10 min, TLC monitoring), triethyl amine (0.57 g, 0.80 ml, 5.67 mmol) was added dropwise. The reaction mass was concentrated in vacuo followed by addition of water (100 ml) and extraction with ethyl acetate (3×100 ml). The combined organics was washed with water, brine, dried (Na2SO4), filtered and concentrated. The crude residue was purified over silica gel (60-120 M, 10% EtOAc-Hexane) to get the desired product (0.30 g, 66%) as a white solid.
Reaction SMILES: C(C1SC(COC2C(C3CN(C)CCC=3)=NSN=2)=CC=1)CC.C([C:28]1[S:32][C:31]([CH2:33][CH2:34][CH2:35][O:36][C:37]2[C:41]([C:42]3[CH2:43][N:44]([CH3:48])[CH2:45][CH2:46][CH:47]=3)=[N:40][S:39][N:38]=2)=[CH:30][CH:29]=1)CCCC.S1C=CC=C1CCCSC1C(C2CN(C)CCC=2)=NSN=1.S1C=CC=C1CSC1C(C2CN(C)CCC=2)=NSN=1.O1CCN(CCCSC2C(C3CN(C)CCC=3)=NSN=2)C1=O.S1CCN(C2C(C3CN(C)CCC=3)=NS(SCCC)N=2)C1=O>>[CH3:48][N:44]1[CH2:45][CH2:46][CH:47]=[C:42]([C:41]2[C:37]([O:36][CH2:35][CH2:34][CH2:33][C:31]3[S:32][CH:28]=[CH:29][CH:30]=3)=[N:38][S:39][N:40]=2)[CH2:43]1
Reactant: CCCCCc1ccc(CCCOc2nsnc2C2=CCCN(C)C2)s1
Agent: CCCS[SH]1N=C(C2=CCCN(C)C2)C(N2CCSC2=O)=N1
Agent: CCCc1ccc(COc2nsnc2C2=CCCN(C)C2)s1
Agent: CN1CCC=C(c2nsnc2SCCCN2CCOC2=O)C1
Product: CN1CCC=C(c2nsnc2OCCCc2cccs2)C1

Procedure:
A compound according to claim 1, wherein the compound is: 3-(3-[2-(1-Pyrrolidinyl)ethoxy]-1,2,5-thiadiazol-4-yl)-1,2,5,6-tetrahydro-1methylpyrid 3-(3-(3-(5-Methyl-2-thienyl)-1-propoxy)- 1,2,5-thiadiazol-4-yl)- 1,2,5,6-tetrahydro- 1-methylpyridine; 3-(3-( (5-Propyl-2-thienyl)methoxy)-1,2,5-thiadiazol-4-yl)-1,2,5,6-tetrahydro-1 methylpyridine; 3-(3-(3-(5-Pentyl-2-thienyl)-1-propoxy)-1,2,5-thiadiazol-4-yl)-1,2,5,6-tetrahydro-1-methylpyridine; 3-(3-(3-(2-Thienylthio)-1-propoxy)-1,2,5-thiadiazol-4-yl)-1,2,5,6-tetahydro-1-methylpyridine; 3-(3-(3-(2-Thienyl)-1-propylthio)-1,2,5-thiadiazol-4-yl)-1,2,5,6-tetrahydro-1methylpyridine; 3-(3-(2-Thienylmethylthio)-1,2,5-thiadiazol-4-yl)-1,2,5,6-tetrahydro- 1methylpyridine; 3-(3-(3-(2-Oxazolidinon-3-yl)-1-propylthio)-1,2,5-thiadiazol-4yl )-1,2,5,6-tetrahydro- 1-methylpyridine; 3-(3-(3-(2-Thiazolidinon-3-yl)-1-propylthio- 1,2,5-thiadiazol-4yl)-1,2,5,6-tetrahydro- 1-methylpyridine; 3-(3-(5-Pentyl-2-thienyl)methylthio-1,2,5-thiadiazol-4-yl)-1,2,5,6-tetrahydro-1-methylpyrid
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][CH:3]=1.[CH2:12]([OH:17])[CH2:13][CH2:14][C:15]#[CH:16]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[F:9][C:8]([F:11])([F:10])[C:5]1[CH:6]=[CH:7][C:2]([C:16]#[C:15][CH2:14][CH2:13][CH2:12][OH:17])=[CH:3][CH:4]=1
Reactant: FC(F)(F)c1ccc(I)cc1
Reactant: C#CCCCO
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Product: OCCCC#Cc1ccc(C(F)(F)F)cc1

Procedure:
In analogy to the procedure described in example 1 a], 1-iodo-4-trifluoromethyl-benzene was reacted with 4-pentyn-1-ol in the presence of Pd(PPh3)4 and cuprous iodide to give the title compound as yellow oil.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([CH3:10])[C:6]=1[C:7]([NH2:9])=[O:8].[I:11][C:12]1[CH:17]=[CH:16][C:15]([CH2:18][C:19](O)=[O:20])=[CH:14][CH:13]=1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C(Cl)Cl>[I:11][C:12]1[CH:17]=[CH:16][C:15]([CH2:18][C:19]([NH:1][C:2]2[S:3][CH:4]=[C:5]([CH3:10])[C:6]=2[C:7]([NH2:9])=[O:8])=[O:20])=[CH:14][CH:13]=1
Reactant: Cc1csc(N)c1C(N)=O
Reactant: O=C(O)Cc1ccc(I)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1csc(NC(=O)Cc2ccc(I)cc2)c1C(N)=O
Reaction time: 18 h

Procedure:
To a solution of 2-amino-4-methylthiophene-3-carboxamide (1 g, 6.4 mmol) and 2-(4-iodophenyl)acetic acid (1.83 g, 7.0 mmol) in methylene chloride (10 mL) was added Hunig's base (i.e., N,N-diisopropylethylamine) (30.1 mL, 18 mmol) and HATU (2.66 g, 7.0 mmol). The heterogeneous mixture was stirred for 18 h. The reaction was quenched by addition of saturated aqueous ammonium chloride solution and the biphasic mixture was extracted with additional methylene chloride. The organic layer was washed with brine, dried over sodium sulfate and concentrated under reduced pressure to provide a pale brown solid. LCMS method [2]: rt=2.02 min; M+Na 423.0. Material was used without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[OH:9].[CH3:10]OS(OC)(=O)=O.C([O-])([O-])=O.[K+].[K+].C(OCC)(=O)C>C1COCC1.O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[O:9][CH3:10]
Reactant: COS(=O)(=O)OC
Reactant: Cc1ccc(Cl)c(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COc1cc(C)ccc1Cl
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 2-chloro-5-methylphenol (14.2 g, 1 equiv), Me2SO4 (10.5 mL, 1.1 equiv) and K2CO3 (27.6 g, 2 equiv) in 150 mL of THF was stirred at rt overnight. Ethyl acetate and water were added and the organic layer was dried over sodium sulfate, filtered and evaporated to give 2-chloro-5-methylanisole as a crude product.
Reaction SMILES: S([CH2:5][CH2:6][C:7]#[CH:8])(C)(=O)=O.[Cl:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2([OH:22])[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]2)=[CH:12][CH:11]=1.C([O-])([O-])=O.[K+].[K+]>CC#N>[CH2:5]([N:19]1[CH2:18][CH2:17][C:16]([C:13]2[CH:14]=[CH:15][C:10]([Cl:9])=[CH:11][CH:12]=2)([OH:22])[CH2:21][CH2:20]1)[CH2:6][C:7]#[CH:8]
Reactant: OC1(c2ccc(Cl)cc2)CCNCC1
Reactant: C#CCCS(C)(=O)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: C#CCCN1CCC(O)(c2ccc(Cl)cc2)CC1
Yield: 87.2 %

Procedure:
A mixture of 1-mesylbut-3-yne (1.48 g, 10.0 mmol), 4-(4-chlorophenyl)-4-hydroxypiperidine (2.54 g, 12.0 mmol) and K2CO3 (4.14 g, 30.0 mmol) in CH3CN (25 mL) is refluxed for 12 hr. The mixture is filtered and washed with EtOAc (3×30 mL). The filtrate is evaporated in vacuo and is purified by flash chromatography to give the product as a colorless solid (2.30 g, 87%): mp 98-100° C.; 1H NMR (CDCl3) 1.55 (s, 1 H), 1.74 (m, 2 H), 1.99 (m, 1 H), 2.10 (m, 2 H), 2.42 (m, 4 H), 2.65 (m, 2 H), 2.79 (m, 2 H), 7.32 (d, J=7.2 Hz, 2 H), 7.42 (d, J=7.2 Hz, 2 H).
Reaction SMILES: [C:1]([NH2:9])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.I[C:11]1[CH:22]=[CH:21][C:14]([C:15]([O:17][CH2:18][CH:19]=[CH2:20])=[O:16])=[CH:13][CH:12]=1>>[CH2:18]([O:17][C:15]([C:14]1[CH:21]=[CH:22][C:11]([NH:9][C:1](=[O:8])[C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[CH:12][CH:13]=1)=[O:16])[CH:19]=[CH2:20]
Reactant: NC(=O)c1ccccc1
Reactant: C=CCOC(=O)c1ccc(I)cc1
Product: C=CCOC(=O)c1ccc(NC(=O)c2ccccc2)cc1
Yield: 90.9 %

Procedure:
Using general procedure A, benzamide (150 mg, 1.24 mmol) was coupled with allyl 4-iodobenzoate (300 mg, 1.04 mmol). The crude product was purified by flash chromatography on silica gel (2×15 cm; hexane-ethyl acetate 3:1; 10 mL fractions). Fractions 8–15 provided 266 mg (91% yield) of the product as white crystals. 1H NMR (400 MHz, CDCl3): δ 8.14–8.09 (m, 2H), 8.00 (br s, 1H), 7.93–7.88 (m, 2H), 7.80–7.75 (m, 2H), 7.63–7.58 (m, 1H), 7.56–7.51 (m, 2H), 6.07 (ddt, J=17.2, 11.7, 5.6 Hz, 1H), 5.45 (dq, J=17.2, 1.4 Hz, 1H), 5.32 (dq, J=11.7, 1.4 Hz, 1H), 4.85 (dt, J=5.6, 1.4 Hz, 2H).
Reaction SMILES: [C:1](/[C:3](=[C:9](/[C:11]1[CH:16]=[CH:15][C:14]([N:17]2[CH2:22][CH2:21][N:20]([CH3:23])[CH2:19][CH2:18]2)=[CH:13][CH:12]=1)\[CH3:10])/[C:4]([O:6][CH2:7]C)=[O:5])#[N:2]>CO>[C:1]([CH:3]([CH:9]([C:11]1[CH:16]=[CH:15][C:14]([N:17]2[CH2:18][CH2:19][N:20]([CH3:23])[CH2:21][CH2:22]2)=[CH:13][CH:12]=1)[CH3:10])[C:4]([O:6][CH3:7])=[O:5])#[N:2]
Reactant: CCOC(=O)/C(C#N)=C(/C)c1ccc(N2CCN(C)CC2)cc1
Solvent: CO
Product: COC(=O)C(C#N)C(C)c1ccc(N2CCN(C)CC2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 57.7 %

Procedure:
(Z)-ethyl 2-cyano-3-(4-(4-methylpiperazin-1-yl)phenyl)but-2-enoate (700 mg, 2.30 mmol) was added to a stirred mixture of Mg metal (2.10 g, 89.4 mmol) in methanol (20 ml) at 0° C. and stirred for 2 h at room temperature (reaction was activated by Mg metal, so exothermic). Then the reaction mixture was quenched with 6N HCl (20 ml) up to a clear solution was obtained. The reaction mixture was washed with ethyl acetate (2×20 ml), basified with saturated sodium bicarbonate and extracted with DCM (3×50 ml). The combined organic layer was washed with water, brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to afford 400 mg (54%) of methyl 2-cyano-3-(4-(4-methylpiperazin-1-yl)phenyl)butanoate as a colorless liquid.
Reaction SMILES: [Cl:1][C:2]1[C:7]([F:8])=[CH:6][C:5](/[CH:9]=[CH:10]/[C:11]([O:13][CH2:14][CH3:15])=[O:12])=[C:4]([C@H:16]([O:18][CH2:19][C@H:20]([OH:36])[CH2:21][N:22]2[CH2:26][CH2:25][CH2:24][C@H:23]2[CH2:27][C:28]2[CH:33]=[CH:32][C:31]([CH3:34])=[C:30]([F:35])[CH:29]=2)[CH3:17])[CH:3]=1>C(O)C.[Rh]>[Cl:1][C:2]1[C:7]([F:8])=[CH:6][C:5]([CH2:9][CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])=[C:4]([C@H:16]([O:18][CH2:19][C@H:20]([OH:36])[CH2:21][N:22]2[CH2:26][CH2:25][CH2:24][C@H:23]2[CH2:27][C:28]2[CH:33]=[CH:32][C:31]([CH3:34])=[C:30]([F:35])[CH:29]=2)[CH3:17])[CH:3]=1
Reactant: CCOC(=O)/C=C/c1cc(F)c(Cl)cc1[C@@H](C)OC[C@H](O)CN1CCC[C@H]1Cc1ccc(C)c(F)c1
Agent: [Rh]
Solvent: CCO
Product: CCOC(=O)CCc1cc(F)c(Cl)cc1[C@@H](C)OC[C@H](O)CN1CCC[C@H]1Cc1ccc(C)c(F)c1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 97 %

Procedure:
Ethyl (2E)-3-{4-chloro-5-fluoro-2-[(1R)-1-({(2R)-3-[(2S)-2-(3-fluoro-4-methylbenzyl)pyrrolidin-1-yl]-2-hydroxypropyl}oxy)ethyl]phenyl}prop-2-enoate (320 mg, 0.61 mmol) which had been obtained in Example 156 (156a) was dissolved in ethanol (20 mL), added with rhodium/alumina (96 mg), and stirred at room temperature for 45 minutes under a hydrogen atmosphere. The reaction solution was filtered through Celite. The solvent was distilled off under reduced pressure. The residue was purified by basic silica gel column chromatography (n-hexane/ethyl acetate=1/1) to give the title compound as a colorless oily substance (310 mg, yield 97%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:16]3[C:11](=[N:12][CH:13]=[CH:14][CH:15]=3)[NH:10][C:9]=2[C:17]([NH2:19])=[O:18])=[CH:4][CH:3]=1.[F:20][C:21]1[C:26]([C:27]([F:30])([F:29])[F:28])=[CH:25][CH:24]=[CH:23][C:22]=1[N:31]=[C:32]=[O:33]>>[F:20][C:21]1[C:26]([C:27]([F:30])([F:29])[F:28])=[CH:25][CH:24]=[CH:23][C:22]=1[NH:31][C:32](=[O:33])[NH:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:16]3[C:11](=[N:12][CH:13]=[CH:14][CH:15]=3)[NH:10][C:9]=2[C:17]([NH2:19])=[O:18])=[CH:6][CH:7]=1
Reactant: NC(=O)c1[nH]c2ncccc2c1-c1ccc(N)cc1
Reactant: O=C=Nc1cccc(C(F)(F)F)c1F
Product: NC(=O)c1[nH]c2ncccc2c1-c1ccc(NC(=O)Nc2cccc(C(F)(F)F)c2F)cc1

Procedure:
79 mg of solid white 3-{4-[3-(2-fluoro-3-trifluoromethylphenyl)ureido]phenyl}-1H-pyrrolo[2,3-b]pyridine-2-carboxamide are prepared as described in Example 7 starting with 3-(4-aminophenyl)-1H-pyrrolo[2,3-b]pyridine-2-carboxamide and 2-fluoro-3-trifluoromethylphenyl isocyanate.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].F[C:8]1[CH:15]=[CH:14][C:11]([C:12]#[N:13])=[CH:10][CH:9]=1.[F:16][C:17]([F:25])([C:21]([F:24])([F:23])[F:22])[CH:18]([OH:20])[CH3:19]>CN(C=O)C.CCCCCC.CCOC(C)=O>[F:16][C:17]([CH:18]([O:20][C:8]1[CH:15]=[CH:14][C:11]([C:12]#[N:13])=[CH:10][CH:9]=1)[CH3:19])([F:25])[C:21]([F:24])([F:23])[F:22]
Reactant: CC(O)C(F)(F)C(F)(F)F
Reactant: N#Cc1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCCCCC
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(Oc1ccc(C#N)cc1)C(F)(F)C(F)(F)F
Temperature: 130 °C
Yield: 97.7 %

Procedure:
Add potassium carbonate (27.4 g, 198 mmol) to a mixture of 4-fluorobenzonitrile (8 g, 66 mmol) and (±)-3,3,4,4,4-pentafluoro-2-butanol (17.2 g, 105 mmol) in anhydrous DMF (60 mL). Heat the mixture in a sealed flask for 4 h at 130° C. Cool the reaction to ambient temperature, dilute with hexane/EtOAc (1:1, 350 mL) and wash with aqueous 5% sodium chloride (3×100 mL). Collect the organic layer, dry over Na2SO4, filter and concentrate in vacuo to obtain the desired intermediate (17.1 g, 98%). GC-MS m/z: 432 (M+).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3](/[CH:10]=[CH:11]/[C:12]([C:14]2[CH:19]=[C:18]([O:20][CH3:21])[C:17]([O:22][CH3:23])=[C:16]([O:24][CH3:25])[CH:15]=2)=[O:13])=[CH:2]1.[CH2:26](Br)[CH3:27].[H-].[Na+]>CN(C)C=O.O1CCCC1>[CH2:26]([N:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3](/[CH:10]=[CH:11]/[C:12]([C:14]2[CH:19]=[C:18]([O:20][CH3:21])[C:17]([O:22][CH3:23])=[C:16]([O:24][CH3:25])[CH:15]=2)=[O:13])=[CH:2]1)[CH3:27]
Reactant: COc1cc(C(=O)/C=C/c2c[nH]c3ccccc23)cc(OC)c1OC
Reactant: CCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: CCn1cc(/C=C/C(=O)c2cc(OC)c(OC)c(OC)c2)c2ccccc21
Temperature: 25 °C
Reaction time: 3 h
Yield: 84.1 %

Procedure:
Compound 1 (1.69 g) obtained in Example 1 was dissolved in a mixed solvent of N,N-dimethylformamide (12.5 ml) and tetrahydrofuran (12.5 ml), and ethyl bromide (817.3 mg) and sodium hydride (300 mg, 60% mineral oil dispersion) were added thereto, followed by stirring at room temperature for 3 hours. Ice was added to the reaction solution, and the mixture was subjected to partitioning between ethyl acetate and water. The organic layer was dried over magnesium sulfate and concentrated under reduced pressure, and the residue was recrystallized from 2-propanol to give Compound 3 (1.54 g).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[C:19]([CH:20]3[CH2:23][N:22]([C:24]4[CH:33]=[CH:32][C:31]5[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=5)[N:25]=4)[CH2:21]3)=[N:18][CH:17]=[CH:16][N:15]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.[ClH:34].CO>>[ClH:34].[NH:8]1[CH2:13][CH2:12][CH:11]([C:14]2[C:19]([CH:20]3[CH2:21][N:22]([C:24]4[CH:33]=[CH:32][C:31]5[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=5)[N:25]=4)[CH2:23]3)=[N:18][CH:17]=[CH:16][N:15]=2)[CH2:10][CH2:9]1
Reactant: CC(C)(C)OC(=O)N1CCC(c2nccnc2C2CN(c3ccc4ccccc4n3)C2)CC1
Agent: Cl
Solvent: CO
Product: c1ccc2nc(N3CC(c4nccnc4C4CCNCC4)C3)ccc2c1
Yield: 98.9 %

Procedure:
A solution of 4-[3-(1-quinolin-2-yl-azetidin-3-yl)-pyrazin-2-yl]-piperidine-1-carboxylic acid tert-butyl ester (53) (346 mg, 0.78 mmol) in 4N HCl/MeOH (20 mL) was stirred at RT for 30 min. The reaction mixture was concentrated to give the product (54) (294 mg, 0.77 mmol, yield 98.9%).
Reaction SMILES: [OH:1][CH:2]([C:22]([F:37])([F:36])[CH2:23][C:24]([N:26]([CH:28]([NH:30][CH2:31][CH2:32][CH:33]([CH3:35])[CH3:34])[CH3:29])[CH3:27])=[O:25])[CH:3]([NH:8][C:9](=[O:21])[C@H:10]([CH:18]([CH3:20])[CH3:19])[NH:11][C:12](=[O:17])[CH2:13][CH:14]([CH3:16])[CH3:15])[CH2:4][CH:5]([CH3:7])[CH3:6].C(Cl)(=O)C(Cl)=O.CS(C)=O.CCN(CC)CC>C(Cl)Cl.CCOC(C)=O>[O:1]=[C:2]([C:22]([F:36])([F:37])[CH2:23][C:24]([N:26]([CH:28]([NH:30][CH2:31][CH2:32][CH:33]([CH3:35])[CH3:34])[CH3:29])[CH3:27])=[O:25])[CH:3]([NH:8][C:9](=[O:21])[C@H:10]([CH:18]([CH3:19])[CH3:20])[NH:11][C:12](=[O:17])[CH2:13][CH:14]([CH3:15])[CH3:16])[CH2:4][CH:5]([CH3:7])[CH3:6]
Reactant: CC(C)CCNC(C)N(C)C(=O)CC(F)(F)C(O)C(CC(C)C)NC(=O)[C@@H](NC(=O)CC(C)C)C(C)C
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: CC(C)CCNC(C)N(C)C(=O)CC(F)(F)C(=O)C(CC(C)C)NC(=O)[C@@H](NC(=O)CC(C)C)C(C)C

Procedure:
The above-named compound was prepared from N1 -(2-Hydroxy-3,3-difluoro-1-isobutyl-4[[1-(isoamylamino)ethyl]-methylamino]carbonylbutyl)-N2 -isovaleryl valinamide by the procedure described in example 7. Proportions: Oxalylchloride (0.176 mmol, 0.0224 mg) in 0.5 ml CH2Cl2, 0.0275 mg (0.352 mmol) DMSO, 90 mg of alcohol in 1.5 ml CH2Cl2 (at -55° C.) 0.081 g Et3N (0.8 mmol). Flash chromatography (EtOAc) gave 0.02 g of above-named compound.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][OH:5].[Cl:6][C:7]1[C:12]([N+:13]([O-:15])=[O:14])=[C:11](Cl)[C:10]([CH3:17])=[C:9]([CH3:18])[N:8]=1.C(N(CC)CC)C>CN(C=O)C>[Cl:6][C:7]1[C:12]([N+:13]([O-:15])=[O:14])=[C:11]([NH:1][CH2:2][CH2:3][CH2:4][OH:5])[C:10]([CH3:17])=[C:9]([CH3:18])[N:8]=1
Reactant: NCCCO
Reactant: Cc1nc(Cl)c([N+](=O)[O-])c(Cl)c1C
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Cc1nc(Cl)c([N+](=O)[O-])c(NCCCO)c1C
Reaction time: 16 h
Yield: 52.9 %

Procedure:
3-Amino-1-propanol (6.92 mL, 90.5 mmol) was added dropwise to a stirred solution of 2,4-dichloro-5,6-dimethyl-3-nitropyridine (20.0 g, 90.5 mmol) and triethylamine (18.9 mL, 136 mmol) in DMF (300 mL) at room temperature. After 16 hours, the solvent was removed under reduced pressure and the resulting oil was partitioned between ethyl acetate (450 mL) and water (50 mL). The layers were separated and the organic layer was washed with water (3×50 mL). The combined aqueous layers were back-extracted with ethyl acetate (2×30 mL). The combined organic layers were dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The resulting orange solid was triturated with hexanes/ethyl acetate (2:1) and was isolated by filtration to yield 12.43 g of 3-[(2-chloro-5,6-dimethyl-3-nitropyridin-4-yl)amino]propan-1-ol as a yellow solid.
Reaction SMILES: [CH:1]1([CH2:6][C:7]([NH:9][C:10]2[CH:19]=[C:18]3[C:13]([CH2:14][CH2:15][CH2:16][C:17]3=[O:20])=[CH:12][CH:11]=2)=[O:8])[CH2:5][CH2:4][CH2:3][CH2:2]1.[Br:21]Br.C(Cl)(Cl)(Cl)Cl.C(OCC)(=O)C>Cl.C(Cl)Cl>[Br:21][CH:16]1[CH2:15][CH2:14][C:13]2[C:18](=[CH:19][C:10]([NH:9][C:7](=[O:8])[CH2:6][CH:1]3[CH2:2][CH2:3][CH2:4][CH2:5]3)=[CH:11][CH:12]=2)[C:17]1=[O:20]
Reactant: BrBr
Reactant: O=C(CC1CCCC1)Nc1ccc2c(c1)C(=O)CCC2
Agent: Cl
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: ClC(Cl)(Cl)Cl
Product: O=C(CC1CCCC1)Nc1ccc2c(c1)C(=O)C(Br)CC2
Reaction time: 3 h
Yield: 95 %

Procedure:
To a mixture of 7-cyclopentylacetamido-1-tetralone (1.02 g) in ethereal HCl (0.2 ml) and methylene chloride (20 ml) was added a solution of bromine (0.19 ml) in a mixture of ethereal HCl (10 drops) and carbon tetrachloride (1 ml). The reaction was stirred for 3 h and ethyl acetate (60 ml) was added. The mixture was washed (saturated sodium bicarbonate, water, brine), dried (MgSO4), and evaporated. The residue was recrystallized from methylene chloride and petroleum ether to give 2-bromo-7-cyclopentylacetamido-1-tetralone (1.23 g, 95%) as a colorless solid; mp 162.5°-164.0° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]1[C:15]2[CH:16]=[N:17][S:18][C:14]=2[CH:13]=[CH:12][C:11]=1[C:19]([OH:21])=O.CCN(C(C)C)C(C)C.[CH:31]([O:33][CH2:34][CH2:35][O:36][NH2:37])=[CH2:32].C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C>C1COCC1>[CH:31]([O:33][CH2:34][CH2:35][O:36][NH:37][C:19]([C:11]1[CH:12]=[CH:13][C:14]2[S:18][N:17]=[CH:16][C:15]=2[C:10]=1[NH:9][C:3]1[CH:4]=[CH:5][C:6]([I:8])=[CH:7][C:2]=1[F:1])=[O:21])=[CH2:32]
Reactant: C=COCCON
Reactant: O=C(O)c1ccc2sncc2c1Nc1ccc(I)cc1F
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: C=COCCONC(=O)c1ccc2sncc2c1Nc1ccc(I)cc1F
Temperature: 25 °C
Reaction time: 18 h
Yield: 89.1 %

Procedure:
To a solution of 4-(2-fluoro-4-iodo-phenylamino)-benzo[d]isothiazole-5-carboxylic acid (240 mg, 0.58 mmol) in THF (6 mL) was added DIPEA (396 μL, 2.34 mmol), O-(2-vinyloxy-ethyl)-hydroxylamine (119 mg, 1.15 mmol), HOBt (156 mg, 1.15 mmol) and EDCI (221 mg, 1.15 mmol) before the reaction mixture was stirred at room temperature for 18 hours. The reaction mixture was concentrated in vacuo and the resultant residue was partitioned between ethyl acetate and water. The organic extract was washed with aqueous saturated sodium bicarbonate solution then water, dried (Na2SO4) and concentrated in vacuo. The resultant residue was subjected to flash chromatography (Si—SPE, gradient 0-10% methanol in DCM) to yield the title compound (258 mg, 89%). LCMS (Method B): RT=3.83 min, [M+H]+=500.
Reaction SMILES: [NH:1]1[CH:8]=[N:7][C:5]([NH2:6])=[N:4][C:2]1=[O:3].C(O[C@@H:13]1[O:35][C@H:34]([CH2:36][O:37][C:38](=[O:45])[C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)[C@@H:24]([O:25][C:26](=[O:33])[C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C@H:14]1[O:15][C:16](=[O:23])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)(=O)C.Cl[Sn](Cl)(Cl)Cl.ClC(Cl)C>>[C:16]([O:15][C@@H:14]1[C@H:24]([O:25][C:26](=[O:33])[C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C@@H:34]([CH2:36][O:37][C:38](=[O:45])[C:39]2[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=2)[O:35][C@H:13]1[N:1]1[CH:8]=[N:7][C:5]([NH2:6])=[N:4][C:2]1=[O:3])(=[O:23])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: Nc1nc[nH]c(=O)n1
Reactant: CC(=O)O[C@@H]1O[C@H](COC(=O)c2ccccc2)[C@@H](OC(=O)c2ccccc2)[C@H]1OC(=O)c1ccccc1
Agent: Cl[Sn](Cl)(Cl)Cl
Solvent: CC(Cl)Cl
Product: Nc1ncn([C@@H]2O[C@H](COC(=O)c3ccccc3)[C@@H](OC(=O)c3ccccc3)[C@H]2OC(=O)c2ccccc2)c(=O)n1

Procedure:
U.S. Pat. No. 3,819,780 discloses a process which involves reacting a bis-silyl compound of 5-Azacytosine with 1-O-acetyl-2,3,5-tri-O-benzoyl-beta-D-ribofuranose in the presence of SnCl4 and absolute dichloroethane to give 5-azacytidine tribenzoate, which is further reacted with methanolic ammonia to give 5-azacytidine.