Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].P(=O)([O-])O[C:5](CC)(CC)[C:6]#[N:7].[C:14]([O:18][C:19](=[O:28])[NH:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH:26]=O)([CH3:17])([CH3:16])[CH3:15].O>COCCOC>[C:14]([O:18][C:19](=[O:28])[NH:20][CH:21]([CH2:5][C:6]#[N:7])[CH2:22][CH2:23][CH2:24][CH:25]=[CH2:26])([CH3:17])([CH3:16])[CH3:15]
Reactant: CC(C)(C)OC(=O)NCCCCCC=O
Reactant: CCC(C#N)(CC)O[PH](=O)[O-]
Agent: [H-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: C=CCCCC(CC#N)NC(=O)OC(C)(C)C
Temperature: 20 °C

Procedure:
Sodium hydride (50% suspension in oil, 1.2 g, 0.025 mol) is placed in 100 ml of dry 1.2-dimethoxyethane. The slurry is cooled to 20° C. and diethylcyanomethyl phosphonate (4.43 g, 0.025 mol) is added dropwise with stirring. After the addition, the solution is stirred at room temperature for 1 hour until gas evolution has ceased. To the yellow solution, maintained below 25° C., is added dropwise t-butyl(5-formylpentyl)carbamate (5.38 g, 0.025 mol). The solution is stirred at room temperature for 1 hour and refluxed for 0.5 hour. A large excess of water is added and the product t-butyl-(7-cyanohepten-6-yl)carbamate (3.63 g, 61%) is extracted with ether.
Reaction SMILES: [CH3:1][O:2][C@H:3]1[C@@H:8]([CH3:9])[CH2:7][O:6][C@@H:5](/[CH:10]=[CH:11]/[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])[C@@H:4]1[NH2:19].[C:20]([O:24][C:25]([NH:27][CH2:28][C:29](O)=[O:30])=[O:26])([CH3:23])([CH3:22])[CH3:21].C1(N=C=NC2CCCCC2)CCCCC1>CN(C)C1C=CN=CC=1.ClCCl>[C:20]([O:24][C:25]([NH:27][CH2:28][C:29]([NH:19][C@@H:4]1[C@@H:3]([O:2][CH3:1])[C@@H:8]([CH3:9])[CH2:7][O:6][C@H:5]1/[CH:10]=[CH:11]/[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])=[O:30])=[O:26])([CH3:23])([CH3:22])[CH3:21]
Reactant: CCCCCCC/C=C/[C@@H]1OC[C@H](C)[C@H](OC)[C@H]1N
Reactant: CC(C)(C)OC(=O)NCC(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CCCCCCC/C=C/[C@@H]1OC[C@H](C)[C@H](OC)[C@H]1NC(=O)CNC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 76.5 %

Procedure:
A mixture of (2S,3R,4S,5S)-4-methoxy-5-methyl-2-[(E)-1-nonenyl]tetrahydro-2H-pyran-3-amine (5.2 mg), N-(tert-butoxycarbonyl)glycine (10.1 mg), 4-dimethylaminopyridine (7.0 mg), and dicyclohexylcarbodiimide (12.0 mg) in dichloromethane (0.5 ml) was stirred for 2 hours at room temperature. The reaction was quenched by addition of water. The mixture was extracted with dichloromethane, and the organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated. Purification of the residue by preparative thin layer chromatography (ethylacetate as an eluent) gave (2S,3R,4S,5S)-3-[[(tert-butoxycarbonylamino)acetyl]amino]-4-methoxy-5-methyl-2-[(E)-1-nonenyl]tetrahydro-2H-pyran (6.3 mg, y. 79%).
Reaction SMILES: [CH3:1][C:2]1[C:11]([N+:12]([O-:14])=[O:13])=[CH:10][CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].C1C(=O)N([Br:22])C(=O)C1.CC(N=NC(C#N)(C)C)(C#N)C>C(Cl)Cl>[Br:22][CH2:1][C:2]1[C:11]([N+:12]([O-:14])=[O:13])=[CH:10][CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5]
Reactant: O=C1CCC(=O)N1Br
Reactant: COC(=O)c1cccc([N+](=O)[O-])c1C
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClCCl
Product: COC(=O)c1cccc([N+](=O)[O-])c1CBr
Temperature: 60 °C
Reaction time: 20 h
Yield: 74.1 %

Procedure:
To a solution of methyl 2-methyl-3-nitrobenzoate (5 g, 25.6 mmol) in dry DCM (20 mL) were added NBS (4.56 g, 25.6 mmol) and AIBN (0.421 g, 2.56 mmol) and the mixture was stirred at 60° C. After 20 h, additional AIBN (0.42 g) was added and the mixture continued to be stirred at 60° C. After 72 h, the mixture was filtered and concentrated. Purification by flash chromatography (100% hexanes to 10% EtOAC/hexanes) afforded 18 (5.2 g, 74%) as a light yellow solid. Rf=0.3 (9:1 hexanes:ethyl acetate). 1H NMR (400 MHz, CDCl3) δ 8.11 (dd, J=7.9, 1.4 Hz, 1H), 8.03-7.91 (m, 1H), 7.54 (dd, J=8.0 Hz, 8.0 Hz, 1H), 5.24-5.03 (s, 2H), 4.08-3.88 (s, 3H). MS (ESI) m/z calcd for C9H9BrNO4 [M+H]+ 275.1, found 275.5.
Reaction SMILES: CO[C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C@H:10]([C:17]2[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=2)[CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:5][CH:4]=1.C(S)C.[Al+3].[Cl-].[Cl-].[Cl-].C([O-])(O)=[O:31].[Na+]>C(Cl)Cl>[OH:31][C:7]1[CH:8]=[CH:3][CH:4]=[CH:5][C:6]=1[CH2:9][C@H:10]([C:17]1[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=1)[CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13]
Reactant: CCOC(=O)C[C@H](Cc1ccc(OC)cc1)c1cccnc1
Reactant: O=C([O-])O
Agent: [Al+3]
Agent: [Cl-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CCS
Product: CCOC(=O)C[C@H](Cc1ccccc1O)c1cccnc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 73 %

Procedure:
A solution of ethyl (S)-4-(4-methoxyphenyl)-3-(pyridin-3-yl)butanoate (9.25 g, 31 mmole) in CH2Cl2 (150 mL) was cooled to 0° C. Ethanethiol (11.5 mL, 155 mmole) was added, then AlCl3 (20.7 g, 155 mmole) was added portionwise. After 2 hr, the mixture was poured over ice, allowed to warm to RT, and neutralized with NaHCO3. The resulting suspension was filtered through celite® and the filter pad was washed with CH2Cl2. The layers were separated and the aqueous layer was extracted with CH2Cl2. The combined organic layers were dried (MgSO4) and concentrated. Flash chromatography on silica gel (1:1 EtOAc/hexanes) afforded the title compound (6.435 g, 73%) 1H NMR (400 MHz, CDCl3) δ 8.72, 8.41 (dd, J=4.9, 1.5 Hz, 1 H), 8.24 (narrow m, 1 H), 7.26 (dd, J=7.8, 4.9 Hz, 1 H). 6.78 (d, J=8.5 Hz, 2 H), 6.64 (d, J=8.5 Hz, 2 H), 4.03 (q, J=7.1 Hz, 2 H), 3.34-3.48 (m, 1 H), 2.92 (dd, J=13.7, 6.1 Hz, 1 H). 2.69-2.81 (m, 2 H), 2.64 (dd, J=15.6, 8.7 Hz, 1 H), 1.13 (t, J=7.1 Hz, 3 H); MS (ES) m/e 286 (M+H)+.
Reaction SMILES: [F:1][C:2]([F:35])([F:34])[C:3]1[CH:4]=[C:5]([CH:27]=[C:28]([C:30]([F:33])([F:32])[F:31])[CH:29]=1)[CH2:6][N:7]([CH2:14][C:15]1[CH:22]=[C:21]([C:23]([F:26])([F:25])[F:24])[CH:20]=[CH:19][C:16]=1[CH:17]=[O:18])[C:8]1[N:9]=[N:10][N:11]([CH3:13])[N:12]=1.[CH:36]1([Mg]Br)[CH2:41][CH2:40][CH2:39][CH2:38][CH2:37]1>C1COCC1>[F:33][C:30]([F:31])([F:32])[C:28]1[CH:27]=[C:5]([CH:4]=[C:3]([C:2]([F:1])([F:34])[F:35])[CH:29]=1)[CH2:6][N:7]([CH2:14][C:15]1[CH:22]=[C:21]([C:23]([F:26])([F:25])[F:24])[CH:20]=[CH:19][C:16]=1[CH:17]([CH:36]1[CH2:41][CH2:40][CH2:39][CH2:38][CH2:37]1)[OH:18])[C:8]1[N:9]=[N:10][N:11]([CH3:13])[N:12]=1
Reactant: Br[Mg]C1CCCCC1
Reactant: Cn1nnc(N(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)Cc2cc(C(F)(F)F)ccc2C=O)n1
Solvent: C1CCOC1
Product: Cn1nnc(N(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)Cc2cc(C(F)(F)F)ccc2C(O)C2CCCCC2)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 38.5 %

Procedure:
To a solution of 2-{[(3,5-bis-trifluoromethyl-benzyl)-(2-methyl-2H-tetrazol-5-yl)-amino]-methyl}-4-trifluoromethyl-benzaldehyde (244 mg, 0.48 mmoles) in THF (3 mL) at 0° C. was added cyclohexylmagnesium bromide (18% solution in THF, 0.6 mL, 0.57 mmoles) and the reaction was allow to warm to room temperature and stirred overnight. The reaction mixture was quenched with aqueous NH4Cl and extracted with ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate and concentrated in vacuo. The residue was purified over 25+S Biotage silica column (eluted with 0-30% ethyl acetate in hexane) to yield 110 mg (39%) of the title compound. 1H NMR (400 MHz, CDCl3) δ ppm 1.0 (m, 6H) 1.6 (m, 3H) 1.8 (m, 1H) 1.9 (d, J=12.4 Hz, 1H) 2.2 (s, 1H) 4.2 (s, 3H) 4.6 (d, J=7.5 Hz, 1H) 4.8 (m, 4H) 7.3 (s, 1H) 7.5 (m, 2H) 7.6 (s, 2H) 7.8 (s, 1H)). MS (ES+) Calc: 595.2, Found: 596.4 (M+1).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([O:18][C:19]3[C:28]4[C:23](=[CH:24][C:25]([O:31][CH3:32])=[C:26]([O:29][CH3:30])[CH:27]=4)[N:22]=[CH:21][CH:20]=3)=[CH:14][CH:13]=2)=S)[CH:5]=[CH:6][CH:7]=1.C1([N:39]=[C:40]=[N:41]C2CCCCC2)CCCCC1.C(N(C(C)C)CC)(C)C.N#CN>C(Cl)Cl.C1COCC1>[CH3:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([O:18][C:19]3[C:28]4[C:23](=[CH:24][C:25]([O:31][CH3:32])=[C:26]([O:29][CH3:30])[CH:27]=4)[N:22]=[CH:21][CH:20]=3)=[CH:14][CH:13]=2)=[N:41][C:40]#[N:39])[CH:5]=[CH:6][CH:7]=1
Reactant: C(=NC1CCCCC1)=NC1CCCCC1
Reactant: COc1cc2nccc(Oc3ccc(NC(=S)Nc4cccc(C)c4)cc3)c2cc1OC
Agent: N#CN
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: COc1cc2nccc(Oc3ccc(NC(=NC#N)Nc4cccc(C)c4)cc3)c2cc1OC
Temperature: 25 °C
Reaction time: 8 h
Yield: 103.7 %

Procedure:
N-(3-Methylphenyl)-N'-{4-[(6,7-dimethoxy-4-quinolyl)oxy]phenyl}thiourea (18 mg) obtained in Example 171, dicyclohexylcarbodiimide (35 mg) and a catalytic amount of diisopropylethyl amine were dissolved in methylene chloride (6 ml), to which a solution of cyanamide (23 mg) in THF (1 ml) was added, and the admixture was stirred at room temperature overnight. After removing the solvent by distillation, the resulting residue was purified by column chromatography on silica gel eluting with chloroform/methanol (100/1) to obtain 19 mg of the title compound (yield: 95%).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:13]2[N:12]=[C:11]([NH:14][CH2:15][CH:16]3[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]3)[NH:10][C:9]=2[CH:8]=[CH:7][CH:6]=1)=[O:4].[OH:22][C:23]1[C:30]([Cl:31])=[CH:29][C:28]([Cl:32])=[CH:27][C:24]=1[CH:25]=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].CO>CS(C)=O.C(O)(=O)C>[CH3:1][O:2][C:3]([C:5]1[C:13]2[N:12]=[C:11]([NH:14][CH2:15][CH:16]3[CH2:21][CH2:20][N:19]([CH2:25][C:24]4[CH:27]=[C:28]([Cl:32])[CH:29]=[C:30]([Cl:31])[C:23]=4[OH:22])[CH2:18][CH2:17]3)[NH:10][C:9]=2[CH:8]=[CH:7][CH:6]=1)=[O:4]
Reactant: COC(=O)c1cccc2[nH]c(NCC3CCNCC3)nc12
Reactant: O=Cc1cc(Cl)cc(Cl)c1O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CS(C)=O
Solvent: CO
Product: COC(=O)c1cccc2[nH]c(NCC3CCN(Cc4cc(Cl)cc(Cl)c4O)CC3)nc12
Temperature: 50 °C
Reaction time: 48 h

Procedure:
After dissolving 2-[(piperidin-4-ylmethyl)-amino]-1H-benzimidazole-4-carboxylic acid methyl ester (20 mg, 0.055 mmol) in dimethylsulfoxide-acetic acid (10:1), 2-hydroxy-3,5-dichlorobenzaldehyde (32.0 mg, 0.166 mmol) and sodium triacetoxyborohydride (35.0 mg, 0.166 mg) were added and the mixture was stirred at 50° C. for 2 days. Methanol (1 ml) was added to the reaction mixture, and then after stirring for 1 minute, it was purified by SCX solid phase extraction (Bond Elute SCX500MG). The product was further purified by preparative HPLC to obtain 2-{[1-(3,5-dichloro-2-hydroxy-benzyl)-piperidin-4-ylmethyl]-amino}-1H-benzimidazole-4-carboxylic acid methyl ester. The compound was identified by LC-MS.
Reaction SMILES: [Br:1][C:2]1[N:6]2[CH:7]=[CH:8][CH:9]=[C:10]([O:11][CH2:12][C:13]3[C:18]([Cl:19])=[CH:17][CH:16]=[C:15]([N:20]([C:22](=[O:25])[CH2:23][NH2:24])[CH3:21])[C:14]=3[Cl:26])[C:5]2=[N:4][C:3]=1[CH3:27].[C:28](O)(=[O:33])[CH2:29][CH2:30][CH:31]=[CH2:32].Cl.CN(C)CCCN=C=N.ON1C2C=CC=CC=2N=N1>O.CN(C)C=O>[Br:1][C:2]1[N:6]2[CH:7]=[CH:8][CH:9]=[C:10]([O:11][CH2:12][C:13]3[C:18]([Cl:19])=[CH:17][CH:16]=[C:15]([N:20]([C:22](=[O:25])[CH2:23][NH:24][C:28](=[O:33])[CH2:29][CH2:30][CH:31]=[CH2:32])[CH3:21])[C:14]=3[Cl:26])[C:5]2=[N:4][C:3]=1[CH3:27]
Reactant: C=CCCC(=O)O
Reactant: Cc1nc2c(OCc3c(Cl)ccc(N(C)C(=O)CN)c3Cl)cccn2c1Br
Agent: CN(C)CCCN=C=N
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Product: C=CCCC(=O)NCC(=O)N(C)c1ccc(Cl)c(COc2cccn3c(Br)c(C)nc23)c1Cl
Yield: 97.7 %

Procedure:
A mixture of 3-bromo-8-[2,6-dichloro-3-(N-glycyl-N-methylamino)benzyloxy]-2-methylimidazo[1,2-a]pyridine (150 mg), 4-pentenoic acid (33 mg), N-ethyl-N,-(3-dimethylaminopropyl)carbodiimide hydrochloride (77 mg), 1-hydroxybenzotriazole (64 mg) and N,N-dimethylformamide (1.5 ml) was stirred for 2 hours at ambient temperature. Water was added thereto, and the mixture was extracted with methylene chloride three times. The organic layers were combined, washed with water four times and brine, dried over magnesium sulfate and concentrated in vacuo. The residue was purified by silica gel column chromatography (methylene chloride:methanol =30:1, V/V) to give 3-bromo-8-[2,6-dichloro-3-[N-(4-pentenoylglycyl)-N-methylamino]benzyloxy]-2-methylimidazo[1,2-a]pyridine (172 mg).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([C:8]#[C:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[CH:16]([CH3:20])[C:17]([NH2:19])=[O:18])[C:5]([CH3:21])=[CH:4][N:3]=1.CO>CN(C=O)C.CCOC(C)=O.O=[Pt]=O>[Cl:1][C:2]1[N:7]=[C:6]([CH2:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[CH:16]([CH3:20])[C:17]([NH2:19])=[O:18])[C:5]([CH3:21])=[CH:4][N:3]=1
Reactant: Cc1cnc(Cl)nc1C#Cc1ccccc1C(C)C(N)=O
Agent: O=[Pt]=O
Solvent: CCOC(C)=O
Solvent: CO
Solvent: CN(C)C=O
Product: Cc1cnc(Cl)nc1CCc1ccccc1C(C)C(N)=O
Reaction time: 72 h

Procedure:
A solution of 2-(2-((2-chloro-5-methylpyrimidin-4-yl)ethynyl)phenyl)propanamide A48 (2.08 g, 6.95 mmol) in DMF (110 mL) and MeOH (10 mL) was stirred with PtO2 (0.395 g, 1.74 mmol) under an atmosphere of H2 for 16 hours at room temperature. An extra portion of PtO2 (0.189 g, 0.832 mmol) was added and stirring was continued under H2 for 72 hours at room temperature. The mixture was diluted with EtOAc (200 mL) and filtered through Celite. The volatiles were removed in vacuo and the residue was purified by column chromatography (Biotage Isolera, 120 g SiO2 cartridge, 10-100% EtOAc in petroleum benzine 40-60° C.) to give the title compound A49 as a white solid (1.51 g, 72%). LCMS-D: rt 3.15 min; m/z 304 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[C:22](C(O)=O)=[C:5]2[S:6][CH:7]=[C:8]([C:9]3[C:14]([O:15][CH3:16])=[CH:13][C:12]([CH2:17][O:18][CH3:19])=[CH:11][C:10]=3[O:20][CH3:21])[N:4]2[N:3]=1.Cl>O1CCOCC1>[Br:1][C:2]1[CH:22]=[C:5]2[S:6][CH:7]=[C:8]([C:9]3[C:10]([O:20][CH3:21])=[CH:11][C:12]([CH2:17][O:18][CH3:19])=[CH:13][C:14]=3[O:15][CH3:16])[N:4]2[N:3]=1
Reactant: COCc1cc(OC)c(-c2csc3c(C(=O)O)c(Br)nn23)c(OC)c1
Agent: Cl
Solvent: C1COCCO1
Product: COCc1cc(OC)c(-c2csc3cc(Br)nn23)c(OC)c1
Yield: 25 %

Procedure:
To a 1,4-dioxane (90.0 mL) solution of 6-bromo-3-[2,6-dimethoxy-4-(methoxymethyl)phenyl]pyrazolo[5,1-b][1,3]thiazole-7-carboxylic acid (5.00 g, 11.7 mmol) was added concentrated hydrochloric acid (14.9 mL) and the mixture was heated to reflux for 13 hours. After the reaction was completed, the solvent was distilled off under reduced pressure, water (50 mL) was added to the residue, and the precipitated solid was subjected to suction filtration and dried to obtain the title compound (1.12 g, 2.92 mmol).
Reaction SMILES: [CH:1]1([NH:7][C:8](=O)[C:9]2[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][CH:10]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.S(Cl)([Cl:19])=O>>[CH:1]1([N:7]=[C:8]([Cl:19])[C:9]2[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][CH:10]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=S(Cl)Cl
Reactant: O=C(NC1CCCCC1)c1ccc(Cl)cc1
Product: ClC(=NC1CCCCC1)c1ccc(Cl)cc1
Reaction time: 1.75 h

Procedure:
N-Cyclohexyl 4-chlorobenzamide (12.8 g, 53.9 mmole) and thionyl chloride (43.14 g, 363 mmole) were heated at reflux with stirring for 1.75 hours. Excess thionyl chloride was removed by distillation. The title compound was isolated by distillation (b.p. 130° C. at ~15 mm Hg) to yield 7.4 g (54%) of a clear colorless liquid which crystallized upon cooling.
Reaction SMILES: [NH2:1][C:2]1[C:3]2[N:10]([CH2:11][O:12][CH:13]([CH2:24][O:25]C(=O)C3C=CC=CC=3)[CH2:14][O:15]C(=O)C3C=CC=CC=3)[CH:9]=[P:8][C:4]=2[N:5]=[CH:6][N:7]=1.N>>[NH2:1][C:2]1[C:3]2[N:10]([CH2:11][O:12][CH:13]([CH2:14][OH:15])[CH2:24][OH:25])[CH:9]=[P:8][C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: Nc1ncnc2pcn(COC(COC(=O)c3ccccc3)COC(=O)c3ccccc3)c12
Agent: N
Product: Nc1ncnc2pcn(COC(CO)CO)c12
Temperature: 25 °C
Reaction time: 20 h
Yield: 78.1 %

Procedure:
A mixture of 7-amino-1-[(1,3-dibenzoyloxy-2-propoxy)methyl]-1,3-azaphospholo[4,5-d]pyrimidine (compound 21, R=CH2OCH(CH2OBz)2, 0.65 g, 1.4 mmol) and methanolic ammonia (125 mL, saturated at 0° C.) was stirred at room temperature for 20 h. The solvent was evaporated under reduced pressure. The solid thus obtained was triturated with cold methanol (5 mL) and the product was collected by filtration. To the filtrate silica gel was added and the solvent was evaporated. The dry powder was loaded on top of a silica gel column (2×8 cm). The column was flash eluted with dichloromethane containing 0-25% methanol to give 0.28 g (78%) of the title compound, mp 180-182° C. Ir (KBr): ν695 (=P-C), 1215 (-P=CH), and 3060, 3300, 3380 and 3500 (NH2, OH) cm-1. Uv (pH 1): λmax254 nm (ε19,000), 282 (12,100), and 314 (4000); (MeOH): λmax266 nm (ε24,700), and 336 (24,000); (pH 11): 266 nm (ε27,650), and 340 (1900). 31 p nmr (DMSO-d6): δ 65.02. 1H nmr (DMSO-d6): δ 3.43 (m, 3 H, CH, CH2), 3.53 (m, 2 H, CH2), 4.63 (br s, 2 H, 2OH), 5.68 (s, 2 H, CH2), 8.23 (s, 2 H, NH2), 8.53 (d, I H, C5H), and 8.82 (d, 1 H, J =58.5 Hz, C2H ). Anal. Calcd. for C9H13N4O3P: C, 42.19; H, 5.11; N, 21.87. Found: C,42.37; H, 5.12; N, 21.66.
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]1[C@H:8]([CH3:9])[CH2:7][CH2:6][CH2:5][N:4]1[C:10]([C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([F:18])[C:13]=1[N:19]1[N:23]=[CH:22][CH:21]=[N:20]1)=[O:11].Br[C:25]1[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][N:26]=1>>[Cl:31][C:28]1[CH:29]=[CH:30][C:25]([NH:1][CH2:2][C@@H:3]2[C@H:8]([CH3:9])[CH2:7][CH2:6][CH2:5][N:4]2[C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([F:18])[C:13]=2[N:19]2[N:23]=[CH:22][CH:21]=[N:20]2)=[O:11])=[N:26][CH:27]=1
Reactant: Clc1ccc(Br)nc1
Reactant: C[C@@H]1CCCN(C(=O)c2cccc(F)c2-n2nccn2)[C@@H]1CN
Product: C[C@@H]1CCCN(C(=O)c2cccc(F)c2-n2nccn2)[C@@H]1CNc1ccc(Cl)cn1

Procedure:
The title compound was prepared following the same general protocol as described for Example A44 using ((2S,3R)-2-(aminomethyl)-3-methylpiperidin-1-yl)(3-fluoro-2-(2H-1,2,3-triazol-2-yl)phenyl)methanone and 2-bromo-5-chloropyridine. ESI-MS (m/z): 429 [M+1]+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:30]=[CH:31][CH:32]=1)[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][C:11]([CH2:15][OH:16])=[CH:12][CH:13]=2)[C:8]([S:17]([C:20]2[C:29]3[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=3)[CH:23]=[CH:22][CH:21]=2)(=[O:19])=[O:18])=[N:7]1.C(N(C(C)C)CC)(C)C.FC(F)(F)S(OS(C(F)(F)F)(=O)=O)(=O)=O.[Cl:57][CH2:58][CH2:59]O>C(Cl)Cl.O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:30]=[CH:31][CH:32]=1)[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][C:11]([CH2:15][O:16][CH2:59][CH2:58][Cl:57])=[CH:12][CH:13]=2)[C:8]([S:17]([C:20]2[C:29]3[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=3)[CH:23]=[CH:22][CH:21]=2)(=[O:19])=[O:18])=[N:7]1
Reactant: OCCCl
Reactant: O=S(=O)(c1cccc2ccccc12)c1nn(Cc2cccc(Cl)c2)c2ccc(CO)cc12
Agent: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=S(=O)(c1cccc2ccccc12)c1nn(Cc2cccc(Cl)c2)c2ccc(COCCCl)cc12
Temperature: -20 °C
Reaction time: 12 h
Yield: 40 %

Procedure:
[1-(3-Chlorobenzyl)-3-(1-naphthylsulfonyl)-1H-indazol-5-yl]-methanol (0.18 g, 0.4 mmol) and diisopropyl ethyl amine (1 mmol) in methylene chloride were treated at −20° C. with trifluoromethanesulfonic anhydride (0.14 g, 0.5 mmol). After stirring for 30 min an excess of 2-chloroethanol (2 mmol) was added and the mixture stirred for additional 2 hrs at −20° C. and at room temperature for 12 hrs. The reaction mixture was diluted with water, extracted with ethyl acetate and after evaporation of solvent, chromatographed on silica gel using 40% ethyl acetate/hexane as an eluent to afford the target material (0.08 g, 0.16 mmoles).
Reaction SMILES: [CH2:1]([N:3]([CH2:30][CH3:31])[CH2:4][CH2:5][CH2:6][NH:7][C:8](=[O:29])[CH2:9][N:10]1[C:14]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[C:13]([C:21]2[CH:26]=[CH:25][C:24]([O:27]C)=[CH:23][CH:22]=2)[CH:12]=[N:11]1)[CH3:2].[Na].C(S)CC.[S-]CCC.Cl>CN(C=O)C.C(Cl)Cl>[CH2:30]([N:3]([CH2:1][CH3:2])[CH2:4][CH2:5][CH2:6][NH:7][C:8](=[O:29])[CH2:9][N:10]1[C:14]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[C:13]([C:21]2[CH:26]=[CH:25][C:24]([OH:27])=[CH:23][CH:22]=2)[CH:12]=[N:11]1)[CH3:31]
Reactant: CCN(CC)CCCNC(=O)Cn1ncc(-c2ccc(OC)cc2)c1-c1ccccc1
Agent: CCCS
Agent: CCC[S-]
Agent: Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CCN(CC)CCCNC(=O)Cn1ncc(-c2ccc(O)cc2)c1-c1ccccc1
Yield: 99 %

Procedure:
A solution of 14 g (00.33 mol) of N-[3-(diethylamino)propyl]-4-(4-methoxyphenyl)-5-phenyl-1H-pyrazole-1-acetamide of example 34 and 0.16 mol of the sodium salt of 1 propanethiol in 375 mL of DMF was heated at 155°-160° C. for 2 hours. The reaction was chilled and the excess thiopropoxide was neutralized with ethanolic HCl. The DMF solution was stripped under vacuum at 30°, dissolved in methylene dichloride, and washed with aqueous sodium carbonate, then water, and finally brine. The methylene chloride was dried over sodium sulfate and the solvent removed in vacuo to yield 13.4 g of gummy product. Seven grams of the gummy product was chromatographed on a silica gel column eluted with methanol/isopropylamine/chloroform (2:3:95) to yield 5.1 g of purified product. The residue was taken up in isopropyl acetate, washed twice with water, washed once with brine, and dried over sodium sulfate. The isopropyl acetate was evaporated in vacuo, but removal of the last traces of isopropyl acetate required extensive drying under high vacuum to yield 2.5 g of product as a glass.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:13]([CH3:14])=[CH:12][N:11]=[C:10]([F:15])[CH:9]=2)=[CH:4][CH:3]=1.[Br:16]N1C(=O)CCC1=O.N(C(C)(C)C#N)=NC(C)(C)C#N>C(Cl)(Cl)(Cl)Cl>[Br:16][CH2:14][C:13]1[C:8]([C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=2)=[CH:9][C:10]([F:15])=[N:11][CH:12]=1
Reactant: Cc1cnc(F)cc1-c1ccc(Cl)cc1
Reactant: O=C1CCC(=O)N1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: Fc1cc(-c2ccc(Cl)cc2)c(CBr)cn1

Procedure:
A mixture of EXAMPLE 307A (1.2 g), N-bromosuccinimide (1.06 g) and AIBN (azobisisobutyronitrile) (0.178 g) in CCl4 (30 mL) was heated under reflux for 6 hours. After cooling, the solid was filtered off The filtrate was concentrated and loaded onto a silica gel column eluting with 3% ethyl acetate in hexanes to give the title compound.
Reaction SMILES: C(O[C:6](=[O:27])/[CH:7]=[CH:8]/[C:9]1[CH:14]=[CH:13][C:12](/[CH:15]=[CH:16]/[C:17]([C:19]2[CH:24]=[CH:23][C:22]([CH2:25][OH:26])=[CH:21][CH:20]=2)=[O:18])=[CH:11][N:10]=1)(C)(C)C.C(O)(C(F)(F)F)=O.[OH-].[K+].Cl.CCOCC.C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl.[NH2:57][O:58][CH:59]1[CH2:64][CH2:63][CH2:62][CH2:61][O:60]1>C(Cl)Cl.CCO.O.CN(C=O)C>[OH:26][CH2:25][C:22]1[CH:21]=[CH:20][C:19]([C:17](=[O:18])/[CH:16]=[CH:15]/[C:12]2[CH:13]=[CH:14][C:9](/[CH:8]=[CH:7]/[C:6]([NH:57][O:58][CH:59]3[CH2:64][CH2:63][CH2:62][CH2:61][O:60]3)=[O:27])=[N:10][CH:11]=2)=[CH:24][CH:23]=1
Reactant: NOC1CCCCO1
Reactant: CC(C)(C)OC(=O)/C=C/c1ccc(/C=C/C(=O)c2ccc(CO)cc2)cn1
Agent: Cl
Agent: On1nnc2ccccc21
Agent: [K+]
Solvent: CCO
Solvent: CN(C)C=O
Solvent: O
Product: O=C(/C=C/c1ccc(/C=C/C(=O)c2ccc(CO)cc2)cn1)NOC1CCCCO1
Temperature: 25 °C
Reaction time: 8 h
Yield: 29.3 %

Procedure:
A solution of (E)-3-{5-[(E)-3-(4-hydroxymethyl-phenyl)-3-oxo-propenyl]-pyridin-2-yl}-acrylic acid tert-butyl ester (700 mg, 1.92 mmol) and TFA (2.9 ml) in DCM (10 ml) was stirred at room temperature for 3 h and then the solvent was evaporated in vacuo. The resulting yellow solid was treated with a solution of KOH (240 mg, 4.28 mmol) in EtOH (30 ml) for 30 min. The mixture was acidified with HCl/Et2O and the solid was filtered with a buchner funnel. The powder was dissolved in DCM (10 ml), DMF (10 ml) and TEA (1.1 ml, 7.76 mmol), HOBT (524 mg, 3.88 mmol), EDC (741 mg, 3.88 mmol) and NH2OTHP (227 mg, 1.94 mmol) were added. The solution was stirred at room temperature overnight and then diluted with water and extracted twice with DCM. The organic layer was washed with water, dried over Na2SO4 and evaporated in vacuo. The crude reaction mixture was purified by column chromatography (eluent: DCM/MeOH/NH4OH 95:5:0.1) to give 230 mg of (E)-3-{5-[(E)-3-(4-hydroxymethyl-phenyl)-3-oxo-propenyl]-pyridin-2-yl}-N-(tetrahydro-pyran-2-yloxy)-acrylamide.