Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CCN(CC)CC.Br[CH2:9][CH2:10][CH2:11][CH2:12][C:13](Cl)=[O:14].[NH2:16][C:17]1[CH:22]=[CH:21][C:20]([B:23]2[O:31][C:28]([CH3:30])([CH3:29])[C:25]([CH3:27])([CH3:26])[O:24]2)=[CH:19][CH:18]=1.[H-].[Na+]>C(Cl)Cl.CN(C=O)C>[CH3:29][C:28]1([CH3:30])[C:25]([CH3:26])([CH3:27])[O:24][B:23]([C:20]2[CH:21]=[CH:22][C:17]([N:16]3[CH2:9][CH2:10][CH2:11][CH2:12][C:13]3=[O:14])=[CH:18][CH:19]=2)[O:31]1
Reactant: O=C(Cl)CCCCBr
Reactant: CC1(C)OB(c2ccc(N)cc2)OC1(C)C
Agent: [H-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC1(C)OB(c2ccc(N3CCCCC3=O)cc2)OC1(C)C
Temperature: 25 °C
Reaction time: 18.5 h
Yield: 36.1 %

Procedure:
Et3N (239 μL, 1.71 mmol) and 5-bromovaleroyl chloride (166 μL, 1.26 mmol) were added to a solution of 4-aminophenylboronic acid pinacol ester (250 mg, 1.14 mmol) in DCM (5 mL) at 0° C. After stirring the mixture for 18.5 hours at room temperature, the mixture was concentrated. The residue was diluted with EtOAc and washed with sat. NaHCO3 and brine. The organic layer was dried over anhydrous Na2SO4, and concentrated. The residue was diluted with DMF (5 mL) and NaH (55% in liquid paraffin, 62.2 mg, 1.43 mmol) at 0° C. After stirring the mixture for 21 hours at room temperature, the mixture was concentrated. The residue was diluted with 10% aqueous citric acid and extracted with DCM (3×). The combined organic layers were dried over anhydrous Na2SO4, and concentrated. The residue was purified by PTLC (EtOAc/hexane=1:1) to afford desired product (124 mg, 36.1%) as white solid. 1HNMR (CDCl3) 400 MHz δ: 7.86-7.81 (m, 2H), 7.30-7.24 (m, 2H), 3.70-3.60 (m, 2H), 2.61-2.51 (m, 2H), 2.00-1.87 (m, 4H), 1.33 (s, 12H).
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[N:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([N+:12]([O-:14])=[O:13])[CH:8]=2)[N:3]=1.[N+](C1C=CC(N)=C(N)C=1)([O-])=O.CC(C=O)=O.[BH4-].[Na+]>C(O)(=O)C.O>[CH3:1][CH:2]1[CH2:11][NH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([N+:12]([O-:14])=[O:13])[CH:8]=2)[NH:3]1
Reactant: Cc1cnc2cc([N+](=O)[O-])ccc2n1
Agent: CC(=O)C=O
Agent: Nc1ccc([N+](=O)[O-])cc1N
Agent: [BH4-]
Solvent: CC(=O)O
Solvent: O
Product: CC1CNc2cc([N+](=O)[O-])ccc2N1

Procedure:
1 g 2-methyl-6-nitroquinoxaline synthesized by the method described in Coll. Czech. Chem. Comm. 30, 3106 (1965) from 4-nitro-1,2-diaminobenzene by reaction with methyl glyoxal was dissolved in 30 ml acetic acid. Sodium borohydride was added to this solution in small portions at +5° C. until the starting compound could no longer be detected in the solution by thin-layer chromatography. The solution was then diluted with 200 ml water and extracted twice with chloroform. The organic phase was washed with water and dried. After concentration to dryness, the residue was dissolved in acetone and precipitated with hydrochloric acid. The yield amounted to 0.6 g (58% of the theoretical). The melting point of the 1,2,3,4-tetrahydro-2-methyl-6-nitroquinoxaline thus obtained was 178° C.
Reaction SMILES: N(C([O:10][CH2:11][CH3:12])=O)=NC(OCC)=O.[NH:13]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)C[C:14]1=O.CO.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1COCC1>[CH3:14][N:13]1[C:21]2[C:20](=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:12][C:11]1=[O:10]
Reactant: O=C1Cc2ccccc2N1
Reactant: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CO
Product: CN1C(=O)Cc2ccccc21
Yield: 58.9 %

Procedure:
Add diethyl azodicarboxylate (DEAD, 8.0 g, 44.9 mmol) dropwise to a solution of indolin-2-one (4.0 g, 30.0 mmol), methanol (1.4 g, 44.9 mmol) and triphenylphosphine (12.0 g, 44.9 mmol) in THF (40 mL) at 0° C., stir the reaction at room temperature overnight. Concentrate under reduced pressure, purify the resulting residue with flash chromatography (silica gel, EtOAc:PE=1:3) to afford the title compound (2.6 g, 59.1%). MS: (M+1): 148.2.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[CH:5][C:6]([CH:12]2[C:21]3[C:20](=[O:22])[CH2:19][CH2:18][CH2:17][C:16]=3[N:15]([C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([C:29]([F:32])([F:31])[F:30])[CH:24]=3)[C:14](=[O:33])[N:13]2[CH3:34])=[C:7]([CH:11]=1)[C:8](O)=[O:9])#[N:2].C(N1C=CN=C1)(N1C=CN=C1)=O.[BH4-].[Na+].C(O)(=O)C>C1COCC1.O>[OH:9][CH2:8][C:7]1[CH:11]=[C:3]([CH:4]=[CH:5][C:6]=1[CH:12]1[C:21]2[C:20](=[O:22])[CH2:19][CH2:18][CH2:17][C:16]=2[N:15]([C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([C:29]([F:32])([F:30])[F:31])[CH:24]=2)[C:14](=[O:33])[N:13]1[CH3:34])[C:1]#[N:2]
Reactant: CN1C(=O)N(c2cccc(C(F)(F)F)c2)C2=C(C(=O)CCC2)C1c1ccc(C#N)cc1C(=O)O
Agent: O=C(n1ccnc1)n1ccnc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Solvent: C1CCOC1
Product: CN1C(=O)N(c2cccc(C(F)(F)F)c2)C2=C(C(=O)CCC2)C1c1ccc(C#N)cc1CO
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a mixture of 5-cyano-2-[3-methyl-2,5-dioxo-1-(3-trifluoromethyl-phenyl)-1,2,3,4,5,6,7,8-octahydro-quinazolin-4-yl]-benzoic acid (INTERMEDIATE 25, 710 mg, 1.51 mmol) in THF (11.2 mL) is added 1,1′-carbonyldiimidazole (270 mg, 1.66 mol) and the reaction mixture is stirred 90 min at room temp. The reaction mixture is cooled to 5° C. and a solution of sodium borohydride (85 mg, 2.27 mmol) in water (1.4 mL) is added dropwise. After stirring at room temp. for 3 h, the reaction mixture is acidified with dilute aqueous acetic acid, diluted with water and extracted with ethyl acetate. The organic phase is washed with water, dried over MgSO4 and concentrated under reduced pressure. The crude product is purified by reversed phase HPLC. Yield: 420 mg; ESI mass spectrum [M+H]+=456; Retention time HPLC: 0.62 min (X012_S02).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[NH:8][C:9]3[C:14]([CH:15]=2)=[CH:13][C:12]([C:16]#[N:17])=[CH:11][CH:10]=3)[CH:2]=1.C[Si]([N-][Si](C)(C)C)(C)C.[K+].C1(C)C=CC=CC=1.[C:35]([O:41][CH2:42]Cl)(=[O:40])[C:36]([CH3:39])([CH3:38])[CH3:37].C(=O)(O)[O-].[Na+]>C1COCC1>[C:16]([C:12]1[CH:13]=[C:14]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH2:42][O:41][C:35](=[O:40])[C:36]([CH3:39])([CH3:38])[CH3:37])[C:7]([C:3]1[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=1)=[CH:15]2)#[N:17]
Reactant: N#Cc1ccc2[nH]c(-c3cccnc3)cc2c1
Reactant: CC(C)(C)C(=O)OCCl
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: O=C([O-])O
Agent: [K+]
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: CC(C)(C)C(=O)OCn1c(-c2cccnc2)cc2cc(C#N)ccc21
Reaction time: 0.5 h

Procedure:
To a solution of 2-pyridin-3-yl-1H-indole-5-carbonitrile (Example 8, 210 mg, 1.37 mmol) in THF (20 mL) at room temperature is added 0.5 M KHMDS in toluene (4.1 mL, 2.05 mmol). After 30 min, chloromethyl pivalate (510 mg, 3.08 mmol) is added. The mixture is stirred under N2 for 1 h. Saturated aqueous sodium bicarbonate (0.5 mL) is added to quench the reaction. Silica gel is added to the mixture and the solvents are removed in vacuo. The residue is purified by silica gel flash chromatography (ethyl acetate-heptane, 0:1 to 1:0). Further purification by HPLC using an Xbridge RP18 with a gradient of 0.1% aqueous ammonium hydroxide in acetonitrile gives 2,2-dimethyl-propionic acid 5-cyano-2-pyridin-3-yl-indol-1-ylmethyl ester as a white solid. 1H NMR (400 MHz, CDCl3) δ ppm 1.20 (s, 9H), 6.08 (s, 2H), 6.77 (s, 1H), 7.49 (ddd, J=7.8, 4.8, 0.8 Hz, 1H), 7.56 (dd, J=8.6, 1.8 Hz, 1H), 7.68 (d, J=8.6 Hz, 1H), 7.94 (ddd, J=7.9, 2.0 Hz, 1H), 8.01 (dd, J=1.5, 0.5 Hz, 1H), 8.75 (dd, J=4.8, 1.8 Hz, 1H), 8.87 (d, J=1.5 Hz, 1H). HRMS (ESI) m/z 334.1566 [(M+H)+ Calcd for C20H20N3O2: 334.1556].
Reaction SMILES: [BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].[Cl:15][C:16]1[C:17]([CH:42]=O)=[C:18]([C:26]2[CH:27]=[CH:28][C:29]([C:32]([NH:34][CH2:35][CH2:36][C:37]([O:39][CH2:40][CH3:41])=[O:38])=[O:33])=[N:30][CH:31]=2)[CH:19]=[C:20]([C:22]([F:25])([F:24])[F:23])[CH:21]=1.[Cl:44][C:45]1[CH:50]=[CH:49][C:48]([C:51]2[CH:56]=[CH:55][C:54]([NH2:57])=[CH:53][C:52]=2[CH3:58])=[CH:47][CH:46]=1.CC(O)=O>CCOC(C)=O.C([O-])([O-])=O.[K+].[K+].ClCCCl>[Cl:15][C:16]1[C:17]([CH2:42][NH:57][C:54]2[CH:55]=[CH:56][C:51]([C:48]3[CH:49]=[CH:50][C:45]([Cl:44])=[CH:46][CH:47]=3)=[C:52]([CH3:58])[CH:53]=2)=[C:18]([C:26]2[CH:27]=[CH:28][C:29]([C:32]([NH:34][CH2:35][CH2:36][C:37]([O:39][CH2:40][CH3:41])=[O:38])=[O:33])=[N:30][CH:31]=2)[CH:19]=[C:20]([C:22]([F:23])([F:24])[F:25])[CH:21]=1
Reactant: CCOC(=O)CCNC(=O)c1ccc(-c2cc(C(F)(F)F)cc(Cl)c2C=O)cn1
Reactant: Cc1cc(N)ccc1-c1ccc(Cl)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: ClCCCl
Solvent: CC(=O)O
Product: CCOC(=O)CCNC(=O)c1ccc(-c2cc(C(F)(F)F)cc(Cl)c2CNc2ccc(-c3ccc(Cl)cc3)c(C)c2)cn1
Temperature: 25 °C

Procedure:
Solid NaBH(OAc)3 (2.6 g, 12.1 mmol) was added to a DCE solution (16 mL) of ethyl 3-(5-(3-chloro-2-formyl-5-(trifluoromethyl)phenyl)picolinamido)propanoate (2.6 g, 6.1 mmol) and 4′-chloro-2-methyl-[1,1′-biphenyl]-4-amine (1.6 g, 7.3 mmol), and AcOH (1.4 mL, 1.2 mmol) and the resulting mixture was stirred at room temperature. After 2 h additional NaBH(OAc)3 (2.6 g, 12.1 mmol) was added. After 4 h the resulting mixture was diluted with EtOAc and 2M aqueous K2CO3 and the layers were separated. The aqueous phase was added was extracted with EtOAc and the combined organics were dried (Na2SO4), concentrated and purified via column chromatography to yield the title compound.
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][C:9]([CH:11]=O)=[CH:10][C:5]=2[O:4][CH2:3]C1.[CH2:13]([N:17]1[C:21]([CH2:22][NH:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[C:27]([O:31][CH2:32][CH3:33])[CH:26]=2)=[C:20]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[NH:19][CH:18]1[I:40])[CH2:14][CH2:15][CH3:16].[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>ClCCCl.C(O)(=O)C>[O:1]1[C:6]2[CH:7]=[CH:8][C:9]([CH2:11][N:23]([CH2:22][C:21]3[N:17]([CH2:13][CH2:14][CH2:15][CH3:16])[CH:18]([I:40])[NH:19][C:20]=3[C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)[CH2:24][C:25]3[CH:30]=[CH:29][CH:28]=[C:27]([O:31][CH2:32][CH3:33])[CH:26]=3)=[CH:10][C:5]=2[O:4][CH2:3]1
Reactant: O=Cc1ccc2c(c1)OCCO2
Reactant: CCCCN1C(CNCc2cccc(OCC)c2)=C(c2ccccc2)NC1I
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Solvent: CC(=O)O
Product: CCCCN1C(CN(Cc2cccc(OCC)c2)Cc2ccc3c(c2)OCO3)=C(c2ccccc2)NC1I
Temperature: 25 °C
Reaction time: 2 h

Procedure:
2,3-Dihydro-benzo[1,4]dioxine-6-carbaldehyde (503 mg) is added to a solution of (1-butyl-2-iodo-4-phenyl-3H-imidazol-5-ylmethyl)-(3-ethoxy-benzyl)-amine (750 mg) in 10 mL of 1,2-dichlorethane followed by the addition of 10 drops of acetyl alcohol. The resulting mixture is stirred at room temperature for 2 hours. 2 Equivalents of NaBH(OAc)3 are added and the stirring is continued overnight. The reaction is quenched with 10 mL water. The organic phase is collected, washed with water and brine, and dried over Na2SO4. Concentration and purification via flash chromatography provides benzo[1,3]dioxol-5-ylmethyl-(1-butyl-2-iodo-4-phenyl-3H-imidazol-5-ylmethyl)-(3-ethoxy-benzyl)-amine (compound 4).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[C:4]([CH3:9])[C:3]=1[NH:10][C:11]1[C:16]([NH2:17])=[CH:15][CH:14]=[CH:13][N:12]=1.C([O-])(O)=O.[Na+].Br[C:24]#[N:25]>C(O)C>[CH3:9][C:4]1[CH:5]=[C:6]([CH3:8])[CH:7]=[C:2]([CH3:1])[C:3]=1[N:10]1[C:11]2=[N:12][CH:13]=[CH:14][CH:15]=[C:16]2[N:17]=[C:24]1[NH2:25]
Reactant: Cc1cc(C)c(Nc2ncccc2N)c(C)c1
Reactant: N#CBr
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: Cc1cc(C)c(-n2c(N)nc3cccnc32)c(C)c1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a mixture of N2-(2,4,6-Trimethyl-phenyl)-pyridine-2,3-diamine (3.05 g, 13.4 mmol), NaHCO3 (2.03 g, 24.1 mmol) in ethanol (40 mL) at 0° C., was added a solution of BrCN (2.55 g, 24.1 mmol) in ethanol (6 mL). The resulting mixture was stirred at 0° C. For 1 h, room temperature for 8 h, and then 80° C. For 8 h. Ethanol was removed in vacuo and the residue was taken up into a separatory funnel with methylene chloride (100 mL). The mixture was washed sequentially with IN NaOH, water and brine, then the organic layer was dried over Na2SO4. After removing solvents, a brown solid was obtained. By LC-MS, the solid was a mixture of the desired product and the unreacted starting material in a ratio of 4:1 in favor of the desired product. Mass spec.: 253.17 (MH+).
Reaction SMILES: CN(C)C=O.[N+:6]([C:9]1[N:10]=[C:11](SC2C=CC=CC=2[N+]([O-])=O)[N:12]([CH2:14][C@:15]([OH:40])([CH3:39])[CH2:16][N:17]2[CH2:22][CH2:21][N:20]([C:23]([O:25][CH2:26][CH:27]=[CH:28][C:29]3[CH:34]=[CH:33][C:32]([C:35]([F:38])([F:37])[F:36])=[CH:31][CH:30]=3)=[O:24])[CH2:19][CH2:18]2)[CH:13]=1)([O-:8])=[O:7].CC(C)([O-])C.[Na+].O>C(OCC)(=O)C>[CH3:39][C@@:15]1([CH2:16][N:17]2[CH2:18][CH2:19][N:20]([C:23]([O:25][CH2:26][CH:27]=[CH:28][C:29]3[CH:34]=[CH:33][C:32]([C:35]([F:36])([F:38])[F:37])=[CH:31][CH:30]=3)=[O:24])[CH2:21][CH2:22]2)[O:40][C:11]2=[N:10][C:9]([N+:6]([O-:8])=[O:7])=[CH:13][N:12]2[CH2:14]1
Reactant: C[C@](O)(CN1CCN(C(=O)OCC=Cc2ccc(C(F)(F)F)cc2)CC1)Cn1cc([N+](=O)[O-])nc1Sc1ccccc1[N+](=O)[O-]
Agent: CC(C)(C)[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: C[C@]1(CN2CCN(C(=O)OCC=Cc3ccc(C(F)(F)F)cc3)CC2)Cn2cc([N+](=O)[O-])nc2O1
Reaction time: 0.5 h
Yield: 56.1 %

Procedure:
To N,N-dimethylformamide (0.9 ml) solution of 3-(4-trifluoromethylphenyl)-2-propenyl (S)-4-{3-[4-nitro-2-(2-nitrophenylthio)imidazol-1-yl]-2-hydroxy-2-methylpropyl}piperazin-1-carboxylate (89 mg) was added sodium tert-butoxide (16 mg) at 0° C., and stirred at the same temperature for 30 minutes. To the reaction mixture was added water and ethyl acetate, the organic layer was taken by separation. The ethyl acetate layer was washed with an aqueous solution of 5% potassium carbonate, water, and an aqueous solution being saturated with sodium chloride, then dried over anhydrous sodium sulfate. The residue obtained by removal of the solvent by distillation was purified by use of a thin layer chromatography (eluent: dichloromethane/ethyl acetate/methanol=15/15/1), there was obtained 3-(4-trifluoromethylphenyl)-2-propenyl (S)-4-[(2-methyl-6-nitro-2,3-dihydroimidazo-[2,1-b]oxazol-2-yl)methyl]piperazin-1-carboxylate (38 mg, yield: 59%) as pale yellow amorphous product.
Reaction SMILES: O1CCCC1.[CH3:6][C:7]1[CH:12]=[CH:11][N:10]=[C:9]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][C:18]([CH2:21][C:22](Cl)=[N:23][OH:24])=[CH:17][CH:16]=2)[CH:8]=1.[C:26]([C:28]1[C:29]([NH2:35])=[N:30][C:31]([NH2:34])=[CH:32][CH:33]=1)#[CH:27].C(N(CC)CC)C>O>[CH3:6][C:7]1[CH:12]=[CH:11][N:10]=[C:9]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][C:18]([CH2:21][C:22]3[CH:27]=[C:26]([C:28]4[C:29]([NH2:35])=[N:30][C:31]([NH2:34])=[CH:32][CH:33]=4)[O:24][N:23]=3)=[CH:17][CH:16]=2)[CH:8]=1
Reactant: Cc1ccnc(OCc2ccc(CC(Cl)=NO)cc2)c1
Reactant: C#Cc1ccc(N)nc1N
Solvent: O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: Cc1ccnc(OCc2ccc(Cc3cc(-c4ccc(N)nc4N)on3)cc2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 42.7 %

Procedure:
To a tetrahydrofuran (5.00 mL) solution of (4-(4-methyl-pyridin-2-yloxymethyl)-phenyl)-acetohydroximoyl chloride (130 mg, 0.447 mmol) described in Manufacturing Example 43-1-5 and 3-ethynyl-pyridin-2,6-diamine (30.0 mg, 0.226 mmol) described in Manufacturing Example 13-1-3 was added triethylamine (126 μL, 0.903 mmol) at room temperature, which was stirred for 1 hour at room temperature. Water was added to the reaction solution at room temperature, which was extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride and dried over anhydrous magnesium sulfate, and the solvent was evaporated under a reduced pressure. The residue was purified by NH silica gel column chromatography (ethyl acetate:heptane=2:1) to obtain the title compound (37.4 mg, 42.7%).
Reaction SMILES: CB1N2CCC[C@@H]2C(C2C=CC=CC=2)(C2C=CC=CC=2)O1.[F:22][C:23]1[CH:28]=[CH:27][C:26]([N:29]2[C@H:32]([C:33]3[CH:38]=[CH:37][C:36]([O:39][CH2:40][C:41]4[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=4)=[CH:35][CH:34]=3)[C@@H:31]([CH2:47][CH2:48][C:49]([C:51]3[CH:56]=[CH:55][C:54]([F:57])=[CH:53][CH:52]=3)=[O:50])[C:30]2=[O:58])=[CH:25][CH:24]=1.[BH4-].CSC.Cl>C1COCC1.CO>[F:22][C:23]1[CH:24]=[CH:25][C:26]([N:29]2[C@H:32]([C:33]3[CH:34]=[CH:35][C:36]([O:39][CH2:40][C:41]4[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=4)=[CH:37][CH:38]=3)[C@@H:31]([CH2:47][CH2:48][C@@H:49]([C:51]3[CH:56]=[CH:55][C:54]([F:57])=[CH:53][CH:52]=3)[OH:50])[C:30]2=[O:58])=[CH:27][CH:28]=1
Reactant: O=C(CC[C@H]1C(=O)N(c2ccc(F)cc2)[C@@H]1c1ccc(OCc2ccccc2)cc1)c1ccc(F)cc1
Agent: CB1OC(c2ccccc2)(c2ccccc2)[C@H]2CCCN12
Agent: Cl
Agent: [BH4-]
Solvent: CSC
Solvent: C1CCOC1
Solvent: CO
Product: O=C1[C@H](CC[C@H](O)c2ccc(F)cc2)[C@@H](c2ccc(OCc3ccccc3)cc2)N1c1ccc(F)cc1
Temperature: -20 °C
Reaction time: 0.08 h

Procedure:
Add (R)-tetrahydro-1-methyl-3,3-diphenyl-1H,3H-pyrrolo[1,2-c]-[1,3,2]oxazaborole (120 mg, 0.43 mmol) to 1-(4-fluorophenyl)-3(R)-(3-(4-fluorophenyl)-3-oxopropyl)-4(S)-(4-benzyloxyphenyl)-2-azetidinone (0.95 g, 1.91 mmol) in THF (3 mL) and cool to -20° C. After 5 min., add borohydride-dimethylsulfide complex (2M in THF, 0.85 mL, 1.7 mmol) dropwise over 0.5 h. After a total of 1.5 h, add CH3OH followed by HCl (1N) and extract the reaction mixture with EtOAc to obtain 1-(4-fluorophenyl)-3(R)-(3(S)-(4-fluorophenyl)-3-hydroxypropyl)-4(S)-(4-benzyloxyphenyl)-2-azetidinone.
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]([O:7][C:8]([CH2:10][P:11]([O:15][CH3:16])([O:13][CH3:14])=[O:12])=[O:9])([CH3:6])[CH3:5].[CH2:17]([O:24][C:25]1[CH:32]=[CH:31][C:28]([CH2:29]Br)=[CH:27][CH:26]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.[Cl-].[NH4+]>O1CCCC1>[CH2:17]([O:24][C:25]1[CH:26]=[CH:27][C:28]([CH2:29][CH:10]([P:11]([O:15][CH3:16])([O:13][CH3:14])=[O:12])[C:8]([O:7][C:4]([CH3:3])([CH3:5])[CH3:6])=[O:9])=[CH:31][CH:32]=1)[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: BrCc1ccc(OCc2ccccc2)cc1
Reactant: COP(=O)(CC(=O)OC(C)(C)C)OC
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: COP(=O)(OC)C(Cc1ccc(OCc2ccccc2)cc1)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 20 %

Procedure:
To a suspension of 1.71 g sodium hydride (50% in oil, 35.7 mmol) in anhydrous tetrahydrofuran (100 mL) was added a solution of 8.0 g tert-butyl P,P-dimethylphosphonoacetate (35.7 mmol) in anhydrous tetrahydrofuran (25 mL) at room temperature, and the resulting mixture was stirred for 1 h at room temperature. Subsequently, a solution of 4.95 g 4-benzyloxybenzyl bromide (17.8 mmol; prepared according to Helv. Chim. Acta, 2002, 85, 3422) in tetrahydrofuran (25 mL) was added, and the mixture was stirred at room temperature overnight. Saturated aqueous ammonium chloride (50 mL) was then added, the mixture was stirred for another 20 minutes at room temperature, and extracted with ethyl acetate. The organic layer was dried over magnesium sulfate and evaporated. Column chromatography over silica gel (2.5→50% ethyl acetate in hexane) gave 1.48 g (20% yield based on 4-benzyloxybenzyl bromide) of the target compound.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([C:8]2[NH:16][C:15]3[C:14](=[O:17])[N:13]([CH2:18][CH2:19][CH3:20])[C:12](=[O:21])[NH:11][C:10]=3[N:9]=2)=[CH:4][CH:3]=1.[F:22][C:23]([F:33])([F:32])[C:24]1[CH:25]=[C:26]([CH:29]=[CH:30][CH:31]=1)[CH2:27][NH2:28]>>[CH2:18]([N:13]1[C:14](=[O:17])[C:15]2[NH:16][C:8]([C:5]3[CH:6]=[N:7][C:2]([NH:28][CH2:27][C:26]4[CH:29]=[CH:30][CH:31]=[C:24]([C:23]([F:22])([F:32])[F:33])[CH:25]=4)=[CH:3][CH:4]=3)=[N:9][C:10]=2[NH:11][C:12]1=[O:21])[CH2:19][CH3:20]
Reactant: CCCn1c(=O)[nH]c2nc(-c3ccc(Cl)nc3)[nH]c2c1=O
Reactant: NCc1cccc(C(F)(F)F)c1
Product: CCCn1c(=O)[nH]c2nc(-c3ccc(NCc4cccc(C(F)(F)F)c4)nc3)[nH]c2c1=O
Temperature: 200 °C
Reaction time: 48 h

Procedure:
A mixture of 8-(6-Chloro-pyridin-3-yl)-1-propyl-3,7-dihydro-purine-2,6-dione (0.5 g, 1.6 mmol) and 3-Trifluoromethyl-benzylamine (3 ml) was stirred in sealed tube for 48 hours at 200° C. Reaction mixture was cooled and filtered, washed with ethanol to get 1-Propyl-8-[6-(3-trifluoromethyl-benzylamino)-pyridin-3-yl]-3,7-dihydro-purine-2,6-dione as off white solid (0.61 g, 84%).
Reaction SMILES: [NH:1]([C:8]1[CH:9]=[C:10]([CH:25]=[CH:26][CH:27]=1)[CH2:11][O:12][C:13]1[CH:18]=[CH:17][C:16]([CH2:19][CH2:20][C:21]([O:23]C)=[O:22])=[CH:15][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[CH2:30](Br)[CH2:31][CH3:32].[I-].[Na+]>CN(C)C=O.C(OCC)(=O)C>[C:2]1([N:1]([CH2:30][CH2:31][CH3:32])[C:8]2[CH:9]=[C:10]([CH:25]=[CH:26][CH:27]=2)[CH2:11][O:12][C:13]2[CH:14]=[CH:15][C:16]([CH2:19][CH2:20][C:21]([OH:23])=[O:22])=[CH:17][CH:18]=2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCCBr
Reactant: COC(=O)CCc1ccc(OCc2cccc(Nc3ccccc3)c2)cc1
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCCN(c1ccccc1)c1cccc(COc2ccc(CCC(=O)O)cc2)c1
Temperature: 0 °C
Yield: 48.7 %

Procedure:
To a solution of methyl 3-[4-[(3-anilinobenzyl)oxy]phenyl]propanoate (0.20 g, 0.58 mmol) in N,N-dimethylformamide (4 mL) was added 60% sodium hydride (0.035 g, 0.86 mmol) with stirring at 0° C., and the mixture was stirred at the same temperature for 10 min. n-Propylbromide (0.063 mL, 0.69 mmol) and sodium iodide (0.10 g, 0.69 mmol) were added to this mixture with stirring at 0° C., and the mixture was stirred at room temperature for 16 hrs. The reaction mixture was diluted with ethyl acetate, washed with water and saturated brine, dried, and concentrated under reduced pressure. Then the residue was dissolved in a mixed solution of methanol (3 mL) and tetrahydrofuran (6 mL), 1N aqueous sodium hydroxide solution (1.5 mL) was added, and the mixture was stirred at room temperature for 1 hr. The reaction mixture was adjusted to pH 3 with 1N hydrochloric acid, separated and extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=4/1-1/2) to give the title compound (0.11 g, yield 47%) as colorless crystals. MS (APCI−): 388 (M−H).
Reaction SMILES: [I:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[CH:4][CH:3]=1.IC1C=CC(C(O)=O)=CC=1.S(Cl)(Cl)=O.[CH2:25]([C:29]1[O:30][C:31]2[CH:37]=[CH:36][C:35]([NH:38][S:39]([CH3:42])(=[O:41])=[O:40])=[CH:34][C:32]=2[CH:33]=1)[CH2:26][CH2:27][CH3:28]>ClCCl>[CH2:25]([C:29]1[O:30][C:31]2[CH:37]=[CH:36][C:35]([NH:38][S:39]([CH3:42])(=[O:40])=[O:41])=[CH:34][C:32]=2[C:33]=1[C:6](=[O:7])[C:5]1[CH:9]=[CH:10][C:2]([I:1])=[CH:3][CH:4]=1)[CH2:26][CH2:27][CH3:28]
Reactant: CCCCc1cc2cc(NS(C)(=O)=O)ccc2o1
Reactant: O=C(Cl)c1ccc(I)cc1
Agent: O=C(O)c1ccc(I)cc1
Solvent: ClCCl
Solvent: O=S(Cl)Cl
Product: CCCCc1oc2ccc(NS(C)(=O)=O)cc2c1C(=O)c1ccc(I)cc1

Procedure:
6.12 g of 4-iodobenzoyl chloride—prepared by reacting 4-iodobenzoic acid with thionyl chloride—and 5.42 g of 2-butyl-5-methanesulfonamido-benzofuran (IV) were dissolved in 30 ml of dichloromethane. The reaction was performed according to Example 10.
Reaction SMILES: [Br:1][C:2]1[C:3](Cl)=[N:4][C:5]([Cl:8])=[N:6][CH:7]=1.[CH3:10][NH2:11]>CO.C(O)C>[Br:1][C:2]1[C:3]([NH:11][CH3:10])=[N:4][C:5]([Cl:8])=[N:6][CH:7]=1
Reactant: Clc1ncc(Br)c(Cl)n1
Reactant: CN
Solvent: CCO
Solvent: CO
Product: CNc1nc(Cl)ncc1Br
Temperature: 25 °C
Yield: 39 %

Procedure:
To a cooled (0° C.) solution of 5-bromo-2,4-dichloropyrimidine (5.0 g, 22 mmol) in methanol (42 mL) was added dropwise a 33 wt % solution of methylamine in ethanol (3.3 mL). The reaction was allowed to warm to room temperature. The reaction was then concentrated. The crude product was purified by column chromatography (0-10% methanol in DCM) to give 5-bromo-2-chloro-N-methylpyrimidin-4-amine (1.8 g, 39%). 1H-NMR (DMSO): δ 8.22 (s, 1H), 7.75 (s, 1H), 2.85 (d, J=3.9, 3H).