Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][CH2:2][CH:3]([OH:6])[CH2:4][F:5].[Cl:7][C:8]1[CH:9]=[C:10]([CH:15]=[CH:16][C:17]=1O)[C:11]([O:13][CH3:14])=[O:12].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1.CCOC(C)=O>[Cl:7][C:8]1[CH:9]=[C:10]([CH:15]=[CH:16][C:17]=1[O:6][CH:3]([CH2:4][F:5])[CH2:2][F:1])[C:11]([O:13][CH3:14])=[O:12]
Reactant: OC(CF)CF
Reactant: COC(=O)c1ccc(O)c(Cl)c1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc(OC(CF)CF)c(Cl)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 131.9 %

Procedure:
To a solution of 1,3-difluoropropan-2-ol (2.57 g, 26.8 mmol) in THF (35 mL) was added methyl 3-chloro-4-hydroxybenzoate (2.00 g, 10.72 mmol), followed by triphenylphosphine (7.03 g, 26.8 mmol) and DIAD (5.21 mL, 26.8 mmol). The reaction was stirred overnight at room temperature, diluted with EtOAc and washed with brine. The organics were separated, washed with brine, dried over MgSO4, filtered, and concentrated. The residue was purified by silica gel chromatography to give the title compound (3.743 g) as a clear oil. LCMS m/z=265.1 [M+H]+.
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[C:3]1[CH:4]=[C:5]([N+:10]([O-:12])=[O:11])[CH:6]=[CH:7][C:8]=1Cl.[CH3:15][SH:16].[OH-].[Na+]>CS(C)=O.O>[F:1][C:2]([F:14])([F:13])[C:3]1[CH:4]=[C:5]([N+:10]([O-:12])=[O:11])[CH:6]=[CH:7][C:8]=1[S:16][CH3:15]
Reactant: CS
Reactant: O=[N+]([O-])c1ccc(Cl)c(C(F)(F)F)c1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CS(C)=O
Product: CSc1ccc([N+](=O)[O-])cc1C(F)(F)F
Temperature: 0 °C
Reaction time: 1 h
Yield: 94.9 %

Procedure:
To a stirred solution containing 45.1 g (0.20 mole) of 3-(trifluoromethyl)-4-chloronitrobenzene and 15 g (0.30 mole) of methyl mercaptan in 150 ml of DMSO was added dropwise at ambient temperature a solution containing 8.0 g (0.20 mole) of sodium hydroxide in 20 ml of water. This addition was exothermic to 60° C. After one hour, the reaction mixture was poured into ice water. The product was filtered and dried to give 45.0 g (95%) of yellow solid; m.p. 50° C.
Reaction SMILES: Cl[C:2]1[N:3]=[CH:4][C:5]2[N:11]([CH2:12][CH2:13][CH3:14])[C:10](=[O:15])[C:9]([F:17])([F:16])[CH2:8][N:7]([CH:18]3[CH2:22][CH2:21][CH2:20][CH2:19]3)[C:6]=2[N:23]=1.[NH2:24][C:25]1[CH:39]=[CH:38][C:28]([C:29]([NH:31][CH:32]2[CH2:37][CH2:36][O:35][CH2:34][CH2:33]2)=[O:30])=[CH:27][CH:26]=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>CC(O)C>[CH:18]1([N:7]2[CH2:8][C:9]([F:17])([F:16])[C:10](=[O:15])[N:11]([CH2:12][CH2:13][CH3:14])[C:5]3[CH:4]=[N:3][C:2]([NH:24][C:25]4[CH:26]=[CH:27][C:28]([C:29]([NH:31][CH:32]5[CH2:37][CH2:36][O:35][CH2:34][CH2:33]5)=[O:30])=[CH:38][CH:39]=4)=[N:23][C:6]2=3)[CH2:22][CH2:21][CH2:20][CH2:19]1
Reactant: CCCN1C(=O)C(F)(F)CN(C2CCCC2)c2nc(Cl)ncc21
Reactant: Nc1ccc(C(=O)NC2CCOCC2)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CC(C)O
Product: CCCN1C(=O)C(F)(F)CN(C2CCCC2)c2nc(Nc3ccc(C(=O)NC4CCOCC4)cc3)ncc21
Yield: 25.2 %

Procedure:
A mixture of 0.05 g (0.15 mmole) of 2-chloro-9-cyclopentyl-7,7-difluoro-5-propyl-5,7,8,9-tetrahydro-pyrimido[4,5-b][1,4]diazepin-6-one (VII-144), 0.04 g (0.17 mmole) of 4-amino-N-(tetrahydro-pyran-4-yl)-benzamide, 0.04 g (0.22 mmole) of p-toluenesulfonic acid monohydrate and 4.0 mL of 2-propanol was heated at 160 degrees for 2 hours in a microwave reactor. The cooled mixture was concentrated under reduced pressure. The residue was diluted with dichloromethane and washed twice with saturated aqueous sodium bicarbonate solution. The aqueous phases were extracted with dichloromethane, and the combined organic layers washed with brine, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with methanol-dichloromethane (gradient, 0:100-25:75), to give 0.020 g of 4-(9-cyclopentyl-7,7-difluoro-6-oxo-5-propyl-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-N-(tetrahydro-pyran-4-yl)-benzamide (I-149).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[C:9]([F:12])([F:11])[F:10].[C:13](OC(=O)C)(=[O:15])[CH3:14]>>[C:13]([NH:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[C:9]([F:12])([F:10])[F:11])(=[O:15])[CH3:14]
Reactant: CC(=O)OC(C)=O
Reactant: Nc1ccc(Cl)cc1C(F)(F)F
Product: CC(=O)Nc1ccc(Cl)cc1C(F)(F)F
Yield: 91.7 %

Procedure:
A solution of 2-amino-5-chlorobenzotrifluoride (1.01 g, 5.16 mmol, Aldrich) in acetic anhydride (5 mL) was stirred at room temperature for 12 h to produce white needle precipitate. It was filtered to give 1.123 g (91.7%) of 2-acetamido-5-chlorobenzotrifluoride. 1H NMR (CDCl3): δ 2.214 (S, 3H); 7.359 (br, 1H); 7.512 (d, 1H, J=9 Hz), 7.581 (s, 1H); 7.163 (d, 1H, J=8.4 Hz).
Reaction SMILES: C[N:2](C)[CH:3]=[C:4]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[N+:13]([O-:15])=[O:14])[CH:5]=O.[NH2:17]N>C(O)C>[N+:13]([C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=1[C:4]1[CH:3]=[N:2][NH:17][CH:5]=1)([O-:15])=[O:14]
Reactant: NN
Reactant: CN(C)C=C(C=O)c1ccccc1[N+](=O)[O-]
Solvent: CCO
Product: O=[N+]([O-])c1ccccc1-c1cn[nH]c1

Procedure:
3-Dimethylamino-2-(2-nitrophenyl)propenal (Maybridge) in ethanol was treated with hydrazine via syringe and heated to reflux for 16 hours. Concentration in vacuo afforded crude 4-(2-nitrophenyl)pyrazole, which was reduced as in Example 64 and coupled with CMI to give the fumaric acid salt of N-(4,5-dihydro-1H-imidazol-2-ylmethyl)-2-(1H-pyrazol-4-yl)aniline.
Reaction SMILES: [CH3:1][C:2]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)([CH3:5])[C:3]#N.[H-].C([Al+]CC(C)C)C(C)C.[OH2:22].Cl>CCCCCC>[CH3:1][C:2]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)([CH3:5])[CH:3]=[O:22]
Reactant: O
Reactant: CC(C)(C#N)c1ccccc1
Agent: CC(C)C[Al+]CC(C)C
Agent: Cl
Agent: [H-]
Solvent: CCCCCC
Product: CC(C)(C=O)c1ccccc1
Temperature: 10 °C
Reaction time: 0.25 h
Yield: 92.8 %

Procedure:
To a solution of 2-methyl-2-phenylpropanenitrile (290 g, 2.00 mol) in hexane (2000 mL) at 0° C. under N2 is added diisobutylaluminum hydride (DIBAL-H) (2600 mL, 1M in hexane) over a period of 80 minutes. The reaction mixture is stirred at 6-14° C. for 15 minutes, then allowed to warm to room temperature and stirred for 4 hours. The reaction mixture is cooled to 0° C. and H2O (50 mL) is added slowly during 1 hour. Aqueous HCl (900 mL, 15%) is then added slowly to maintain a gentle reflux. The reaction mixture is stirred for 17 hours and the organic phase is separated. The aqueous layer is extracted with ethyl acetate (400 mL) and the combined organic layers are washed with water (300 mL), brine (300 mL) and dried over Na2SO4. The organic extracts are filtered and concentrated to give 2-methyl-2-phenylpropanal as an oil (275 g, 92.8% yield, 98.2% by HPLC area).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([OH:11])[C:7]([OH:10])=[CH:8][CH:9]=1)([O-:3])=[O:2].Cl[C:13]([F:19])([F:18])C(OC)=O.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C>[F:18][CH:13]([F:19])[O:10][C:7]1[CH:8]=[CH:9][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][C:6]=1[OH:11]
Reactant: COC(=O)C(F)(F)Cl
Reactant: O=[N+]([O-])c1ccc(O)c(O)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccc(OC(F)F)c(O)c1
Yield: 27 %

Procedure:
A solution of 4-nitrobenzene-1,2-diol (4.18 g, 27.1 mmol), methyl chlorodifluoroacetate (3.0 mL, 28.5 mmol) and cesium carbonate (11.05 g, 33.9 mmol) in DMF (75 mL) was heated at 90° C. for 24 h. The reaction was cooled, evaporated and diluted with ethyl acetate. Product was extracted twice into 1N NaOH, the combined aqueous phase was acidified, extracted with ethyl acetate (twice) and the organic layers were washed with water (twice) and brine, dried (sodium sulfate) and evaporated. Purification by flash chromatography (SiO2) eluted with 2:8 ethyl acetate:hexanes provided 2-difluoromethoxy-5-nitro-phenol (1.50 g, 27% yield) as a bright yellow solid. 1H-NMR (DMSO-d6, 500 MHz) 10.9 (s, 1H), 7.76 (d, 1H), 7.73 (dd, 1H), 7.36 (d, 1H), 7.28 (t, 1H) ppm; MS (FIA) 204.1 (M−H); HPLC (Method A) 3.307 min.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4](=[O:16])[N:5]([CH2:12][C:13]([OH:15])=O)[C:6]2=[O:11].[N:17]1([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]1.CCN=C=NCCCN(C)C.Cl.ON1C2C=CC=CC=2N=N1.C(N(CC)CC)C>ClCCl>[NH2:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4](=[O:16])[N:5]([CH2:12][C:13]([N:20]1[CH2:19][CH2:18][N:17]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:22][CH2:21]1)=[O:15])[C:6]2=[O:11]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: Nc1cccc2c1C(=O)N(CC(=O)O)C2=O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCN(C(=O)CN2C(=O)c3cccc(N)c3C2=O)CC1

Procedure:
2 g (9.08 mmol) of (4-amino-1,3dioxo-1,3-dihydro-2H-isoindol-2-yl)acetic acid, 1.692 g (9.08 mmol) of tert-butyl 1-piperazinecarboxylate, 1.916 g (10 mmol) of N-(3-dimethylaminopropyl)-N-ethylcarbodiimide hydrochloride, 1.35 g (10 mmol) of 1-hydroxy-1H-benzotriazole and 3.8 ml (27 mmol) of triethylamine are stirred in 200 ml of dichloromethane at RT overnight. The reaction mixture is then washed with sat. aqu. NaHCO3 solution, dried over MgSO4, filtered and concentrated. The crude product (3.05 g) can be used without further purification for the next step or, if required, be chromatographed on silica gel (CH2Cl2/EtOH=1/0 to 2/1+0.1% conc. aqueous ammonia solution) for purification.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:10]=[CH:11][CH:12]=1)[CH2:5][S:6](Cl)(=[O:8])=[O:7].[CH3:13][O:14][C:15]1[CH:22]=[C:21]([O:23][CH3:24])[CH:20]=[CH:19][C:16]=1[CH2:17][NH2:18]>ClCCl>[Br:1][C:2]1[CH:3]=[C:4]([CH2:5][S:6]([NH:18][CH2:17][C:16]2[CH:19]=[CH:20][C:21]([O:23][CH3:24])=[CH:22][C:15]=2[O:14][CH3:13])(=[O:8])=[O:7])[CH:10]=[CH:11][CH:12]=1
Reactant: COc1ccc(CN)c(OC)c1
Reactant: O=S(=O)(Cl)Cc1cccc(Br)c1
Solvent: ClCCl
Product: COc1ccc(CNS(=O)(=O)Cc2cccc(Br)c2)c(OC)c1
Reaction time: 1 h

Procedure:
While cooling with ice, 9.90 g of 3-bromobenzylsulfonyl chloride were initially charged in 120 ml of dichloromethane, and a solution of 11.55 ml of 2,4-dimethoxybenzylamine in 60 ml of dichloromethane was added dropwise within 15 minutes. The reaction mixture was allowed to come to room temperature and stirred for 1 hour. Subsequently, the mixture was washed with 50 ml of water, with 100 ml of 1 N aqueous hydrochloric acid, with 100 ml of saturated aqueous sodium hydrogencarbonate solution and finally once more with 100 ml of water. The organic phase was dried over MgSO4 and concentrated by rotary evaporation. The residue (14.30 g) was used in the next reaction without further purification.
Reaction SMILES: [CH2:1]([N:3]1[C:12]2[C:7](=[CH:8][C:9]3[O:15][CH2:14][O:13][C:10]=3[CH:11]=2)[C:6](=[O:16])[C:5]([C:17]([OH:19])=[O:18])=[N:4]1)[CH3:2].[N+:20]([O-])([O-:22])=[O:21].[K+]>S(=O)(=O)(O)O>[CH2:1]([N:3]1[C:12]2[C:7](=[C:8]([N+:20]([O-:22])=[O:21])[C:9]3[O:15][CH2:14][O:13][C:10]=3[CH:11]=2)[C:6](=[O:16])[C:5]([C:17]([OH:19])=[O:18])=[N:4]1)[CH3:2]
Reactant: CCn1nc(C(=O)O)c(=O)c2cc3c(cc21)OCO3
Reactant: O=[N+]([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [K+]
Product: CCn1nc(C(=O)O)c(=O)c2c([N+](=O)[O-])c3c(cc21)OCO3
Temperature: 10 °C
Reaction time: 12 h
Yield: 75.1 %

Procedure:
To a solution of 1-ethyl-4-oxo-1,4-dihydro-[1,3]dioxolo[4,5-g]cinnoline-3-carboxylic acid (5 g, 19.07 mmol) in sulfuric acid (15 mL) cooled to 0° C. was added potassium nitrate (2.121 g, 20.97 mmol) in small portions to maintain temperature bellow 10° C. with ice water. The mixture was stirred at 10° C. for 1 h and at room temperature for 12 h, and was then poured into ice cold water (200 ml). The mixture was filtered, the solid was washed with water and ethanol to afford 1-ethyl-5-nitro-4-oxo-1,4-dihydro-[1,3]dioxolo[4,5-g]cinnoline-3-carboxylic acid (4.4 g, 14.32 mmol, 75% yield). LCMS: (M+H)+: 308.2
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:25]#[N:26])=[C:6]([C:8]2[C:13]([O:14][CH3:15])=[CH:12][N:11]([CH2:16][C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[C:10](=[O:24])[CH:9]=2)[CH:7]=1.FC(F)(F)S(O[CH2:33][C:34]1([C:38]([F:41])([F:40])[F:39])[CH2:37][CH2:36][CH2:35]1)(=O)=O>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:25]#[N:26])=[C:6]([C:8]2[C:13]([O:14][CH3:15])=[CH:12][N:11]([CH:16]([CH2:33][C:34]3([C:38]([F:41])([F:40])[F:39])[CH2:37][CH2:36][CH2:35]3)[C:17]([O:19][C:20]([CH3:21])([CH3:22])[CH3:23])=[O:18])[C:10](=[O:24])[CH:9]=2)[CH:7]=1
Reactant: O=S(=O)(OCC1(C(F)(F)F)CCC1)C(F)(F)F
Reactant: COc1cn(CC(=O)OC(C)(C)C)c(=O)cc1-c1cc(Cl)ccc1C#N
Product: COc1cn(C(CC2(C(F)(F)F)CCC2)C(=O)OC(C)(C)C)c(=O)cc1-c1cc(Cl)ccc1C#N

Procedure:
383 mg (1.02 mmol) of tert-butyl [4-(5-chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]acetate in the presence of 1.23 ml (1.23 mmol, 1.2 eq.) of bis(trimethylsilyl)lithium amide (1M in THF) and 780 mg (purity 60%, 1.64 mmol, 1.6 eq.) of [1-(trifluoromethyl)cyclobutyl]methyl trifluoromethanesulphonate were reacted according to General Method 7B. Yield: 119 mg (purity 91%, 21% of theory)
Reaction SMILES: [CH3:1][O:2][C:3](/[CH:5]=[CH:6]/[C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][CH:8]=1)=[O:4].Cl[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][OH:21].C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>CN1C(=O)CCC1.O>[CH3:1][O:2][C:3](=[O:4])[CH:5]=[CH:6][C:7]1[CH:8]=[CH:9][C:10]([O:13][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][OH:21])=[CH:11][CH:12]=1
Reactant: OCCCCCCCl
Reactant: COC(=O)/C=C/c1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: O
Solvent: CN1CCCC1=O
Product: COC(=O)C=Cc1ccc(OCCCCCCO)cc1
Temperature: 90 °C
Reaction time: 32 h
Yield: 71.9 %

Procedure:
Methyl 4-hydroxy cinnamate (40 g, 225 mmol) was dissolved in 300 ml of NMP. 6-Chlorohexanol (269 mmol, 36.8 g), anhydrous potassium carbonate (37.2 g, 269 mmol) and a catalytic amount of potassium iodide were added. The batch was stirred at 90° C. for 32 hours. Water was added to the cooled solution, which was subsequently extracted with 3×200 mls of ethyl acetate. The combined organics were washed with 10% KOH (2×100 mls), brine solution and then dried over magnesium sulfate. The concentrated product was then recrystallized from a 1:1 mixture of ethyl acetate/hexane to give 45 g (72% yield) of an off-white solid.
Reaction SMILES: [OH-].[Na+].C[O:4][C:5](=[O:25])[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]1[NH:13][C:14]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[O:23][CH3:24])=[CH:15][N:16]=1.Cl>O.CO>[CH3:24][O:23][C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=1[C:14]1[NH:13][C:12]([CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][C:5]([OH:25])=[O:4])=[N:16][CH:15]=1
Reactant: COC(=O)CCCCCCc1ncc(-c2ccccc2OC)[nH]1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: COc1ccccc1-c1cnc(CCCCCCC(=O)O)[nH]1
Temperature: 40 °C
Yield: 76.3 %

Procedure:
Add a solution of sodium hydroxide (1.85 g, 46 mmol) in water (40 mL) to a solution of 7-[5-(2-methoxyphenyl)-1H-imidazol-2-yl]heptanoic acid methyl ester (5.84 g, 18.5 mmol) in methanol (30 mL) at room temperature under nitrogen and heat the mixture at 40° C. for 4.5 hours. Cool the mixture and treat with 1 N HCl (46 mL) and heat at reflux for 30 minutes. Collect the precipitate, wash with water (3×30 mL), and dry under reduced pressure for 12 hours. Triturate the solid with methylene chloride (50 mL) at reflux for 40 min and collect by filtration to provide 7-[5-(2-methoxyphenyl)-1H-imidazol-2-yl]heptanoic acid (4.27 g, 77%). APCI mass spectrum m/z 301 [C17H22N2O3—H]−.
Reaction SMILES: [CH3:1][N:2]1[C:7](=[O:8])[C:6]2=[C:9]([NH:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[N:10]([CH2:12][C:13]3[CH:18]=[CH:17][C:16]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=4)=[CH:15][CH:14]=3)[N:11]=[C:5]2[N:4]([CH2:32][CH:33]2[CH2:37][CH2:36][CH2:35][NH:34]2)[C:3]1=[O:38].C=O.[BH3-][C:42]#N.[Na+]>CO>[CH3:1][N:2]1[C:7](=[O:8])[C:6]2=[C:9]([NH:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[N:10]([CH2:12][C:13]3[CH:18]=[CH:17][C:16]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=4)=[CH:15][CH:14]=3)[N:11]=[C:5]2[N:4]([CH2:32][CH:33]2[CH2:37][CH2:36][CH2:35][N:34]2[CH3:42])[C:3]1=[O:38]
Reactant: Cn1c(=O)c2c(Nc3ccccc3)n(Cc3ccc(-c4ccccn4)cc3)nc2n(CC2CCCN2)c1=O
Reactant: [BH3-]C#N
Agent: C=O
Agent: [Na+]
Solvent: CO
Product: CN1CCCC1Cn1c(=O)n(C)c(=O)c2c(Nc3ccccc3)n(Cc3ccc(-c4ccccn4)cc3)nc21
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
5-methyl-3-(phenylamino)-2-(4-(pyridin-2-yl)benzyl)-7-(pyrrolidin-2-ylmethyl)-2H-pyrazolo[3,4-d]pyrimidine-4,6(5H,7H)-dione is dissolved in CH3OH (200 μL), and then 37% formaldehyde (2.3 μL) is added at room temperature. After 5 min, NaBH3CN (1.8 mg, 0.028 mmol) in CH3OH (100 μL) is added. The reaction mixture is stirred at r.t. for 30 min. The mixture is purified by HPLC to give pure product as white solids. MS (ESI) m/z 522.3 [M+H]+.
Reaction SMILES: [NH2:1][C:2]([NH2:4])=[S:3].C([O-])(=O)C.[Na+].Br[CH2:11][C:12]([C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([N+:20]([O-:22])=[O:21])[CH:15]=1)=O>C(O)C>[N+:20]([C:16]1[CH:15]=[C:14]([C:12]2[N:1]=[C:2]([NH2:4])[S:3][CH:11]=2)[CH:19]=[CH:18][CH:17]=1)([O-:22])=[O:21]
Reactant: NC(N)=S
Reactant: O=C(CBr)c1cccc([N+](=O)[O-])c1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CCO
Product: Nc1nc(-c2cccc([N+](=O)[O-])c2)cs1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Thiourea (0.31 g, 4.1 mmol) and sodium acetate (0.44 g, 5.3 mmol) were combined in 30 mL of dry ethanol. To this suspension was added 2-bromo-1-(3-nitro-phenyl)-ethanone (1.0 g, 4.1 mmol). Reaction mixture was stirred at room temperature overnight. Reaction mixture was evaporated to dryness to yield 4-(3-nitro-phenyl)-thiazol-2-ylamine, which was used in the next step without any further purification. MS: 222.0 (M+H+).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N:8]#[C:9][NH2:10].Cl>O1CCOCC1>[C:2]1([NH:1][C:9]([NH2:10])=[NH:8])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: N#CN
Reactant: Nc1ccccc1
Agent: Cl
Solvent: C1COCCO1
Product: N=C(N)Nc1ccccc1
Temperature: 60 °C

Procedure:
A mixture of aniline (11 mmol), cyanamide (420 mg, 10 mmol), and HCl (3 mL of 4N in dioxane, 12 mmol) in 1,4-dioxane (10 mL) was heated in a sealed tube at 60° C. overnight. The reaction was concentrated in vacuo and the residue partitioned between NaOH (2N) and dichloromethane. The organic layer was dried over Na2SO4 and concentrated in vacuo to afford N-phenyl-guanidine.
Reaction SMILES: C[O:2][C:3](=O)[CH2:4][C:5]1[C:9]2[CH:10]=[C:11]([CH2:14][N:15]([CH3:17])[CH3:16])[CH:12]=[CH:13][C:8]=2[O:7][CH:6]=1.[NH3:19]>CO>[CH3:16][N:15]([CH2:14][C:11]1[CH:12]=[CH:13][C:8]2[O:7][CH:6]=[C:5]([CH2:4][C:3]([NH2:19])=[O:2])[C:9]=2[CH:10]=1)[CH3:17]
Reactant: N
Reactant: COC(=O)Cc1coc2ccc(CN(C)C)cc12
Solvent: CO
Product: CN(C)Cc1ccc2occ(CC(N)=O)c2c1
Temperature: 60 °C
Reaction time: 48 h
Yield: 100 %

Procedure:
A solution of (5-dimethylaminomethyl-benzofuran-3-yl)-acetic acid methyl ester (170 mg, 0.69 mmol) in a mixture of methanol (15 mL) and liquid ammonia (15 mL) is stirred for 2 days in an autoclave at 60° C. After careful evaporation of the ammonia, the remaining solvent is evaporated in vacuo to afford the title compound as a yellow oil (160 mg, 0.69 mmol, 100%). MS (ES+): 233 (M(C13H16N2O2)+H)+.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N+:8]([O-])=O.C(N(CC)C1C=CC=CC=1)C.[CH3:22][C:23]1[CH:24]=[C:25]([CH:29]=[CH:30][CH:31]=1)[C:26](Cl)=O>C1(C)C=CC=CC=1>[CH3:22][C:23]1[CH:24]=[C:25]([C:26]2[NH:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=3[N:8]=2)[CH:29]=[CH:30][CH:31]=1
Reactant: Cc1cccc(C(=O)Cl)c1
Reactant: Nc1ccccc1[N+](=O)[O-]
Solvent: Cc1ccccc1
Solvent: CCN(CC)c1ccccc1
Product: Cc1cccc(-c2nc3ccccc3[nH]2)c1
Temperature: 100 °C

Procedure:
The intermediate 2-(3-methylphenyl)-benzimidazole was prepared by first mixing reacting 1-amino-2-nitrobenzene (8.50 g, 61.54 mmol) with toluene (180 ml) and heating to 100° C. To this mixture was then added 20 ml of N,N-diethylaniline and the reaction vessel was placed under a nitrogen atmosphere. To this solution was then added 3-methylbenzoyl chloride (24 ml, 132 mmol) and this mixture was then stirred overnight.
Reaction SMILES: [NH:1]1[CH2:7][CH2:6][CH2:5][C@H:2]1[CH2:3][OH:4].[OH-].[K+].[F:10][C:11]1[CH:16]=[C:15]([N+:17]([O-:19])=[O:18])[CH:14]=[C:13](F)[C:12]=1F>CS(C)=O.O>[F:10][C:11]1[C:12]2[N:1]3[CH2:7][CH2:6][CH2:5][CH:2]3[CH2:3][O:4][C:13]=2[CH:14]=[C:15]([N+:17]([O-:19])=[O:18])[CH:16]=1
Reactant: OC[C@@H]1CCCN1
Reactant: O=[N+]([O-])c1cc(F)c(F)c(F)c1
Agent: [K+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: O
Product: O=[N+]([O-])c1cc(F)c2c(c1)OCC1CCCN21
Temperature: 65 °C
Yield: 92.9 %

Procedure:
To a suspension of prolinol (2.74 g, 27.11 mmol) and KOH (3.17 g, 56.47 mmol) in DMSO (30 mL) was added 1,2,3-trifluoro-5-nitrobenzene (4.00 g, 22.59 mmol) at rt. The reaction mixture was heated at 65° C. for 4 h. The mixture was diluted with water (150 mL) and extracted with CH2Cl2 (100 mL×2). The combined organic phases were dried over anhydrous Na2SO4 and concentrated in vacuo to give the title compound as a yellow solid (5.00 g, 93%).
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[S:10][C:11]1[CH:12]=[C:13]([CH:16]=[CH:17][C:18]=1[OH:19])[CH:14]=O)([OH:3])=[O:2].Cl.[NH2:21]O.C([O-])=O.[Na+].O>C(O)=O>[C:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[S:10][C:11]1[CH:12]=[C:13]([CH:16]=[CH:17][C:18]=1[OH:19])[C:14]#[N:21])([OH:3])=[O:2]
Reactant: NO
Reactant: O=Cc1ccc(O)c(Sc2ccccc2C(=O)O)c1
Agent: Cl
Agent: O=C[O-]
Agent: [Na+]
Solvent: O=CO
Solvent: O
Product: N#Cc1ccc(O)c(Sc2ccccc2C(=O)O)c1

Procedure:
Reflux 91.3 g of the aldehyde of Step D, 27.4 g of hydroxylamine hydrochloride and 41.9 g of sodium formate in 900 ml of formic acid (98-100%) for 11/4 hours. Cool the mixture and pour into 21/2 liters of cold water. Separate the precipitate, wash with water and dry in vacuo at 75° C. (Yield: 82 g).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:14](=[O:16])[CH3:15])[CH:5]=[CH:6][C:7]=1[N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1.[Cl:17][C:18]1[CH:26]=[CH:25][C:24]([N:27]2[CH:31]=[N:30][N:29]=[N:28]2)=[CH:23][C:19]=1[C:20](O)=[O:21]>>[Cl:17][C:18]1[CH:26]=[CH:25][C:24]([N:27]2[CH:31]=[N:30][N:29]=[N:28]2)=[CH:23][C:19]=1[C:20]([N:11]1[CH2:12][CH2:13][N:8]([C:7]2[CH:6]=[CH:5][C:4]([C:14](=[O:16])[CH3:15])=[CH:3][C:2]=2[F:1])[CH2:9][CH2:10]1)=[O:21]
Reactant: O=C(O)c1cc(-n2cnnn2)ccc1Cl
Reactant: CC(=O)c1ccc(N2CCNCC2)c(F)c1
Product: CC(=O)c1ccc(N2CCN(C(=O)c3cc(-n4cnnn4)ccc3Cl)CC2)c(F)c1

Procedure:
The title compound was prepared according to the procedure E described for example 2 from 1-(3-Fluoro-4-piperazin-1-yl-phenyl)-ethanone and 2-Chloro-5-tetrazol-1-yl-benzoic acid (CAS: 190270-10-1; commercial) (50%, white solid, M+H: 429.2)
Reaction SMILES: C([N:8]1[CH2:12][CH2:11][C@H:10]([NH:13][C:14](=[O:25])[C@@H:15]([NH:17][C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH3:16])[CH2:9]1)C1C=CC=CC=1.O.[H][H]>CO.[OH-].[OH-].[Pd+2]>[C:21]([O:20][C:18]([NH:17][C@@H:15]([CH3:16])[C:14]([NH:13][C@H:10]1[CH2:11][CH2:12][NH:8][CH2:9]1)=[O:25])=[O:19])([CH3:24])([CH3:22])[CH3:23]
Reactant: C[C@H](NC(=O)OC(C)(C)C)C(=O)N[C@H]1CCN(Cc2ccccc2)C1
Reactant: [H][H]
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: C[C@H](NC(=O)OC(C)(C)C)C(=O)N[C@H]1CCNC1
Yield: 92.6 %

Procedure:
1 Benzyl-3-(S)-[2-(S)-(tert-butoxycarbonylamino)propionylamino]pyrrolidine (21.3 g) was dissolved in methanol (250 mL), and hydrogenated over 20% palladium hydroxide on charcoal, 50% water wet (5.0 g) at 50 psig and 25° to 40° C. until the uptake of hydrogen ceased. The reaction was then filtered through celite to remove the catalyst and the residue rinsed with methanol (100 mL) and the combined filtrates concentrated under vacuum to give 3-(S)-[2-(S)-(tert-butoxycarbonylamino)propionylamino]pyrrolidine (14.6 g) as a colorless oil which crystallized on standing: HPLC: 99% S,S isomer. A portion was recrystallized from methyl tert-butyl ether: mp 137°-138° C.