Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.Cl[CH2:3][N:4]1[CH:8]=[N:7][CH:6]=[N:5]1.[F:9][C:10]([F:19])([F:18])[CH2:11][CH2:12][CH:13]([C:16]#[N:17])[C:14]#[N:15].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[N:4]1([CH2:3][C:13]([CH2:12][CH2:11][C:10]([F:9])([F:18])[F:19])([C:14]#[N:15])[C:16]#[N:17])[CH:8]=[N:7][CH:6]=[N:5]1
Reactant: N#CC(C#N)CCC(F)(F)F
Reactant: ClCn1cncn1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: N#CC(C#N)(CCC(F)(F)F)Cn1cncn1
Yield: 34.6 %

Procedure:
0.77 g of 1-(chloromethyl)-1H-1,2,4-triazole hydrochloride and 0.81 g of (3,3,3-trifluoropropyl) malononitrile were dissolved in 15 ml of N,N-dimethylformamide. 1.38 g of potassium carbonate was added to the solution under ice cooling with stirring, followed by stirring at room temperature for 7 hours. Water was added to the reaction mixture, and then extracted with MTBE. The organic layer was washed with water, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was recrystallized from hexane-MTBE to obtain 0.42 g of [(1H-1,2,4-triazole-1-yl)methyl](3,3,3-trifluoropropyl) malononitrile (referred as the compound of the present invention (27), hereinafter) shown by below formula.
Reaction SMILES: [C:1]([O:5][C:6](=[O:16])[C:7]1[CH:12]=[CH:11][C:10]([N:13]=[C:14]=[S:15])=[CH:9][CH:8]=1)([CH3:4])([CH3:3])[CH3:2].[OH-].[K+].[C:19]([CH2:21][C:22]([NH2:24])=[O:23])#[N:20].Cl>CN(C=O)C>[C:1]([O:5][C:6](=[O:16])[C:7]1[CH:8]=[CH:9][C:10]([NH:13][C:14](=[S:15])[CH:21]([C:22](=[O:23])[NH2:24])[C:19]#[N:20])=[CH:11][CH:12]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)c1ccc(N=C=S)cc1
Reactant: N#CCC(N)=O
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)c1ccc(NC(=S)C(C#N)C(N)=O)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 83.5 %

Procedure:
4-Isothiocyanato-benzoic acid t-butyl ester 2 (28.3 gm, 120.4 mmol) was taken into DMF (200 ml). To this KOH (6.74 gm, 120.4 mmol) and cyanoacetamide (10.21 gm, 120.4 mmol) were added. The reaction mixture was stirred at room temperature for 16 h. The reaction mixture was acidified with 1N HCl, the precipitate obtained was filtered, washed with water, and dried under vacuum, to provide 32.10 gm of 4-(2-Carbamoyl-2-cyano-thioacetylamino)-benzoic acid t-butyl ester 3.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[CH2:4][C:5]1[C:6]([CH3:11])=[N:7][NH:8][C:9]=1[CH3:10].[F:13][C:14]1[CH:21]=[C:20]([N+:22]([O-:24])=[O:23])[CH:19]=[CH:18][C:15]=1[CH2:16]Br.C([O-])([O-])=O.[K+].[K+]>C(#N)C>[CH3:1][O:2][C:3](=[O:12])[CH2:4][C:5]1[C:9]([CH3:10])=[N:8][N:7]([CH2:16][C:15]2[CH:18]=[CH:19][C:20]([N+:22]([O-:24])=[O:23])=[CH:21][C:14]=2[F:13])[C:6]=1[CH3:11]
Reactant: O=[N+]([O-])c1ccc(CBr)c(F)c1
Reactant: COC(=O)Cc1c(C)n[nH]c1C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COC(=O)Cc1c(C)nn(Cc2ccc([N+](=O)[O-])cc2F)c1C
Temperature: 60 °C
Reaction time: 48 h
Yield: 82.7 %

Procedure:
To a solution of (3,5-dimethyl-1H-pyrazol-4-yl)-acetic acid methyl ester (10 g, 48.9 mmol) and 2-fluoro-4-nitrobenzyl bromide (11.5 g, 49.1 mmol) in acetonitrile (150 mL) is added K2CO3 (10.1 g, 73.3 mmol) and the mixture is stirred for 48 hours at 60° C. The solvent is removed by evaporation and the residue is dissolved in dichloromethane/water. After extraction with dichloromethane the organic layer is dried over Na2SO4 and evaporated under reduced pressure. The residue is purified by MPLC (cyclohexane/diethyl ether 7:3) to yield 13 g of [3,5-dimethyl-1-(2-fluoro-4-nitrobenzyl)-1H-pyrazol-4-yl]acetic acid methyl ester (ESI mass spectrum: [M+H]+=322; Retention time (HPLC): 0.85 min (method C)). b) To a solution of [3,5-dimethyl-1-(2-fluoro-4-nitro-benzyl)-1H-pyrazol-4-yl]acetic acid methyl ester (13 g, 40.4 mmol) in methanol (250 mL) is added Raney nickel (6 g) and the mixture is hydrogenated at 50 psi and 50° C. The catalyst is filtered off and the filtrate is concentrated under reduced pressure. The mixture is purified by crystallization in diisopropyl ether to yield 12.8 g of the title compound (ESI mass spectrum: [M+H]+=292; Retention time HPLC: 0.61 min (method C)).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([N+:10]([O-])=O)[CH:5]=[C:6]([CH3:9])[C:7]=1[F:8].[H][H]>CO.[C].[Pd]>[CH3:1][C:2]1[CH:3]=[C:4]([CH:5]=[C:6]([CH3:9])[C:7]=1[F:8])[NH2:10]
Reactant: [H][H]
Reactant: Cc1cc([N+](=O)[O-])cc(C)c1F
Agent: [Pd]
Solvent: CO
Product: Cc1cc(N)cc(C)c1F
Yield: 99.7 %

Procedure:
In 3 liters of methanol was dissolved 15 g of this 3,5-dimethyl-4-fluoro-1-nitrobenzene, and the resulting solution was treated with nitrogen to replace the air, after which 10 g of palladium carbon was added and catalytic reduction with hydrogen gas was carried out. After completion of the reaction, the insoluble materials were filtered off and the filtrate was concentrated to obtain 12.3 g of 3,5-dimethyl-4-fluoroaniline.
Reaction SMILES: [CH3:1][C:2]1([CH3:9])[CH2:6][C:5](=[O:7])[O:4][C:3]1=[O:8].[Cl:10][C:11]1[CH:12]=[C:13]2[C:17](=[CH:18][CH:19]=1)[NH:16][C:15]([CH3:20])=[CH:14]2.[Al+3].[Cl-].[Cl-].[Cl-]>ClCCCl>[Cl:10][C:11]1[CH:12]=[C:13]2[C:17](=[CH:18][CH:19]=1)[NH:16][C:15]([CH3:20])=[C:14]2[C:5](=[O:7])[CH2:6][C:2]([CH3:9])([CH3:1])[C:3]([OH:4])=[O:8]
Reactant: Cc1cc2cc(Cl)ccc2[nH]1
Reactant: CC1(C)CC(=O)OC1=O
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCCl
Product: Cc1[nH]c2ccc(Cl)cc2c1C(=O)CC(C)(C)C(=O)O

Procedure:
3,3-Dimethyl-dihydro-furan-2,5-dione (7.8 mmol, 1.0 g), 5-chloro-2-methylindole (13.8 mmol, 2.28 g), and AlCl3 (9.0 mmol, 1.2 g) were stirred in 100 mL DCE overnight at 65° C. The reaction was cooled and quenched with 10 mL water. The resultant precipitate was filtered and washed with a small amount of DCE giving 1.06 g of the sub-titled compound.
Reaction SMILES: [C:1]1([CH:7]2[CH2:10][NH:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:11]1([CH2:17][CH2:18][C:19](Cl)=[O:20])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C(N(CC)CC)C>ClCCl>[C:11]1([CH2:17][CH2:18][C:19]([N:9]2[CH2:10][CH:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[CH2:8]2)=[O:20])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: O=C(Cl)CCc1ccccc1
Reactant: c1ccc(C2CNC2)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(CCc1ccccc1)N1CC(c2ccccc2)C1
Temperature: 25 °C
Reaction time: 6 h
Yield: 79.3 %

Procedure:
A solution of 3-phenylazetidine (266 mg, 2 mmol) in dry dichloromethane (6 mL) is cooled in an ice bath, and 3-phenylpropionyl chloride (421.5 mg, 2.5 mmol, 1.25 eq) and triethylamine (417 μL, 3 mmol, 1.5 eq) are added. After stirring for 6 hours at room temperature the reaction mixture is diluted with dichloromethane (10 mL). The organic solution is subsequently washed with 1 M KHSO4, 5% NaHCO3 and brine. After drying over Na2SO4, dichloromethane is removed in vacuo and the crude material is purified by flash chromatography (silicagel, ethyl acetate/toluene 1:4). The fractions containing 3-phenyl-1-(3-phenylazetidin-1-yl)propan-1-one are collected and the solvent is removed in vacuo to give 421 mg of colorless oil.
Reaction SMILES: [NH:1]1[CH2:4][CH:3]([NH:5][C:6](=[O:12])[O:7][C:8]([CH3:11])([CH3:10])[CH3:9])[CH2:2]1.F[C:14]1[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][CH:15]=1>>[N+:20]([C:17]1[CH:18]=[CH:19][C:14]([N:1]2[CH2:4][CH:3]([NH:5][C:6](=[O:12])[O:7][C:8]([CH3:9])([CH3:11])[CH3:10])[CH2:2]2)=[CH:15][CH:16]=1)([O-:22])=[O:21]
Reactant: O=[N+]([O-])c1ccc(F)cc1
Reactant: CC(C)(C)OC(=O)NC1CNC1
Product: CC(C)(C)OC(=O)NC1CN(c2ccc([N+](=O)[O-])cc2)C1

Procedure:
tert-Butyl azetidin-3-ylcarbamate was reacted with 4-fluoronitrobenzene by method C. This resulted in the product with the molecular weight of 293.33 (C14H19N3O4); MS (ESI): 294 (M+H+).
Reaction SMILES: C([O-])(=O)C.[Na+].Cl[C:7]1[S:8][C:9](Cl)=[C:10]2[C:16]=1[C:15](=[O:17])[C:14]1=[CH:18][S:19][CH:20]=[C:13]1[C:12](=[O:21])[NH:11]2>CN1CCCC1=O.[Pd]>[CH:7]1[S:8][CH:9]=[C:10]2[C:16]=1[C:15](=[O:17])[C:14]1=[CH:18][S:19][CH:20]=[C:13]1[C:12](=[O:21])[NH:11]2
Reactant: O=c1[nH]c2c(Cl)sc(Cl)c2c(=O)c2cscc12
Agent: [Pd]
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CN1CCCC1=O
Product: O=c1[nH]c2cscc2c(=O)c2cscc12
Reaction time: 5 h

Procedure:
3.0 g of Pd/C (10%) and 15.0 g (183 millimoles) of finely powedered sodium acetate were added to 19.2 g (63.2 millimoles) of 1,3-dichloro-4,5-dihydrodithieno[3,4-b:3',4'-e]azepine-5,9-dione in 600 ml of 1-methylpyrrolid-2-one, and hydrogenation was carried out in a 2.5 l Rollhofer apparatus for 5 hours under a hydrogen pressure of 200 bar and at 80° C. Thereafter, the mixture was filtered under suction, the residue was washed with pyrrolidone and then H2O, the filtrate was poured onto 5 l of ice water, acidified with concentrated HCl and stirred for a further hour, after which the solid was filtered off under suction with thorough washing with H2O, and the crude product was dried. The yield was 12.6 g (85%) and the melting point 267°-270° C.
Reaction SMILES: [NH:1]([C:8]1[C:13]([CH2:14]OCC)=[CH:12][N:11]=[C:10]([NH:18][C:19]2[CH:24]=[CH:23][C:22]([O:25][CH2:26][CH:27]([OH:32])[CH2:28][N:29]([CH3:31])[CH3:30])=[CH:21][CH:20]=2)[N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:33][C:34]([NH2:36])=[O:35].Cl.C(OCC)C>O1CCOCC1>[NH:1]([C:8]1[C:13]([CH2:14][NH:33][C:34]([NH2:36])=[O:35])=[CH:12][N:11]=[C:10]([NH:18][C:19]2[CH:20]=[CH:21][C:22]([O:25][CH2:26][CH:27]([OH:32])[CH2:28][N:29]([CH3:31])[CH3:30])=[CH:23][CH:24]=2)[N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NC(N)=O
Reactant: CCOCc1cnc(Nc2ccc(OCC(O)CN(C)C)cc2)nc1Nc1ccccc1
Agent: Cl
Solvent: CCOCC
Solvent: C1COCCO1
Product: CN(C)CC(O)COc1ccc(Nc2ncc(CNC(N)=O)c(Nc3ccccc3)n2)cc1
Temperature: 100 °C
Yield: 27.7 %

Procedure:
4-Anilino-5-(ethoxymethyl)-2-{4-[2-hydroxy-3-(N,N-dimethylamino)propoxy]anilino}pyrimidine (Example 86, 70 mg, 0.16 mmol) was dissolved in 1,4-dioxane (2 ml). Urea (12 mg, 0.19 mmol) and ethereal hydrogen chloride (1.0M; 0.19 ml, 0.19 mmol) were added, and the suspension was heated at 100° C. for 20 hours. Diethyl ether (20 ml) was added, and the precipitated solid collected by filtration. The solid was dissolved in 10% methanol solution in DCM (3 ml), and loaded on a Varian Mega Bond Elut column. The column was eluted with 0-2.5% methanol solution in DCM containing 0.5% aqueous ammonia solution. Concentration of the appropriate fractions and trituration of the residue with diethyl ether gave the product as a white crystalline solid (20 mg, 28%). NMR: 2.18 (s, 6H), 2.2-2.45 (m, 2H), 3.75-3.9 (m, 3H), 4.07 (d, 2H), 4.74 (br d, 1H), 5.85 (s, 2H), 6.62 (t, 1H), 6.80 (d, 2H), 6.98 (t, 1H), 7.27 (dd, 2H), 7.54 (d, 2H), 7.77 (d, 2H), 7.88 (s, 1H), 8.88 (s, 1H), 9.88 (s, 1H); MS (MH+): 452.4.
Reaction SMILES: [CH:1]([C:3]1[CH:8]=[C:7]([C@@H:9]([NH:12][C:13]([C:15]2[C:16]3[CH:23]=[N:22][N:21]([C:24]4[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=4)[C:17]=3[CH:18]=[N:19][CH:20]=2)=[O:14])[CH2:10][CH3:11])[CH:6]=[CH:5][N:4]=1)=C.N1C(C)=CC=CC=1C.C([OH:43])(C)(C)C.I([O-])(=O)(=O)=O.[Na+]>O1CCOCC1.O.CCOC(C)=O.[Os](=O)(=O)(=O)=O>[CH:1]([C:3]1[CH:8]=[C:7]([C@@H:9]([NH:12][C:13]([C:15]2[C:16]3[CH:23]=[N:22][N:21]([C:24]4[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=4)[C:17]=3[CH:18]=[N:19][CH:20]=2)=[O:14])[CH2:10][CH3:11])[CH:6]=[CH:5][N:4]=1)=[O:43]
Reactant: CC(C)(C)O
Reactant: C=Cc1cc([C@H](CC)NC(=O)c2cncc3c2cnn3-c2ccc(F)cc2)ccn1
Agent: O=[Os](=O)(=O)=O
Agent: [Na+]
Agent: [O-][I+3]([O-])([O-])[O-]
Solvent: O
Solvent: C1COCCO1
Solvent: Cc1cccc(C)n1
Product: CC[C@H](NC(=O)c1cncc2c1cnn2-c1ccc(F)cc1)c1ccnc(C=O)c1
Reaction time: 5 h

Procedure:
A solution of 1-(4-fluorophenyl)-1H-pyrazolo[3,4-c]pyridine-4-carboxylic acid [(S)-1-(2-vinyl-pyridin-4-yl)-propyl]-amide (200 mg, 0.5 mmol) in dioxane (10 mL) and water (3.3 mL) was treated with 2,6-lutidine (116 μL, 1 mmol), 2.5% osmium tetroxide in tert-butanol (125 μL, 0.01 mmol), and sodium periodate (426 mg, 2 mmol). After 5 hours, the reaction mixture was diluted with water (5 mL) and EtOAc (20 mL) and filtered. The organic layer was separated and washed with brine, dried over MgSO4, filtered and concentrated. The mixture was purified by silica gel chromatography eluting with a gradient of 0-100% EtOAc in heptane to afford 1-(4-fluorophenyl)-1H-pyrazolo[3,4-c]pyridine-4-carboxylic acid [(S)-1-(2-formyl-pyridin-4-yl)-propyl]-amide as a white solid.
Reaction SMILES: [CH2:1]([O:4][C:5]1[CH:6]=[C:7]([CH:27]=[C:28]([CH3:30])[CH:29]=1)[O:8][C:9]1[CH:26]=[CH:25][C:12]([CH2:13][NH:14][C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([N+:21]([O-:23])=[O:22])[C:16]=2[CH3:24])=[CH:11][CH:10]=1)[CH:2]=[CH2:3].[F:31][C:32]1[CH:39]=[C:38]([F:40])[CH:37]=[CH:36][C:33]=1[CH2:34]Br>>[CH2:1]([O:4][C:5]1[CH:6]=[C:7]([CH:27]=[C:28]([CH3:30])[CH:29]=1)[O:8][C:9]1[CH:26]=[CH:25][C:12]([CH2:13][N:14]([CH2:34][C:33]2[CH:36]=[CH:37][C:38]([F:40])=[CH:39][C:32]=2[F:31])[C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([N+:21]([O-:23])=[O:22])[C:16]=2[CH3:24])=[CH:11][CH:10]=1)[CH:2]=[CH2:3]
Reactant: Fc1ccc(CBr)c(F)c1
Reactant: C=CCOc1cc(C)cc(Oc2ccc(CNc3cccc([N+](=O)[O-])c3C)cc2)c1
Product: C=CCOc1cc(C)cc(Oc2ccc(CN(Cc3ccc(F)cc3F)c3cccc([N+](=O)[O-])c3C)cc2)c1

Procedure:
The product from Example 89C and 2,4-difluorobenzyl bromide were processed as described in Example 6B to provide the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][N:6]=[C:5]([CH2:9][CH2:10][CH3:11])[CH:4]=1.[CH3:12][O:13][C:14]1[CH:23]=[CH:22][C:17]([C:18](=O)[CH2:19]Br)=[CH:16][CH:15]=1>>[CH2:10]([C:9]1[C:18]([C:17]2[CH:22]=[CH:23][C:14]([O:13][CH3:12])=[CH:15][CH:16]=2)=[CH:19][N:6]2[C:5]=1[CH:4]=[C:3]([O:2][CH3:1])[CH:8]=[CH:7]2)[CH3:11]
Reactant: CCCc1cc(OC)ccn1
Reactant: COc1ccc(C(=O)CBr)cc1
Product: CCc1c(-c2ccc(OC)cc2)cn2ccc(OC)cc12
Yield: 86 %

Procedure:
4-Methoxy-2-n-propylpyridine was reacted with 4-methoxyphenacylbromide by the general synthetic principle outlined in example 23, step 5, to afford 1-ethyl-7-methoxy-2-(4-methoxyphenyl)indolizine in 86% yield. M.p. 101-103° C. 1H-NMR (DMSO-d6, 200 MHz) δ: 1.10 (t, 3H); 2.77 (q, 2H); 3.77 (s, 3H); 3.80 (s, 3H); 6.23 (dd, 1H); 6.65 (d, 1H); 7.00 (d, 2H); 7.35 (s, 1H); 7.38 (d, 2H); 8.06 (d, 1H). Analysis: Calculated for C18H19N1O2 : C, 76.84; H, 6.81; N, 4.98%. Found: C, 76.73; H, 6.94; N, 4.80%.
Reaction SMILES: [N+](=[C:3]([C:17](=[O:28])[C@@H:18]([C@@H:20]1[C@@H:23]([C@H:24]([OH:26])[CH3:25])[C:22](=[O:27])[NH:21]1)[CH3:19])[C:4]([O:6][CH2:7][C:8]1[CH:13]=[CH:12][C:11]([N+:14]([O-:16])=[O:15])=[CH:10][CH:9]=1)=[O:5])=[N-]>ClCCCl.C([O-])(=O)C.[Rh+2].C([O-])(=O)C>[OH:26][C@@H:24]([C@H:23]1[C:22](=[O:27])[N:21]2[C@@H:20]1[C@@H:18]([CH3:19])[C:17](=[O:28])[CH:3]2[C:4]([O:6][CH2:7][C:8]1[CH:13]=[CH:12][C:11]([N+:14]([O-:16])=[O:15])=[CH:10][CH:9]=1)=[O:5])[CH3:25]
Reactant: C[C@@H](O)[C@H]1C(=O)N[C@@H]1[C@@H](C)C(=O)C(=[N+]=[N-])C(=O)OCc1ccc([N+](=O)[O-])cc1
Agent: [Rh+2]
Agent: CC(=O)[O-]
Solvent: ClCCCl
Product: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)C(=O)[C@H](C)[C@H]12

Procedure:
To a solution of 4-nitrobenzyl (4R)-2-diazo-4-[(2R,3S)-3-{(1R)-1-hydroxyethyl}-4-oxoazetidin-2-yl]-3-oxopentanoate (0.72 g) in 1,2-dichloroethane (15 ml) was added rhodium(II) acetate (2 mg) under reflux. The mixture was refluxed for 30 minutes under nitrogen atmosphere, cooled and then concentrated under reduced pressure to give 4-nitrobenzyl (4R,5R,6S)-6-[(1R)-1-hydroxyethyl]-4-methyl-3,7-dioxo-1-azabicyclo[3.2.0]-heptane-2-carboxylate. The compound obtained above was dissolved in acetonitrile (15 ml) and N,N-diisopropyl-N-ethylamine (0.39 ml). Diphenyl phosphorochloridate (0.40 ml) was added thereto at -10°~-5° C. in a nitrogen stream, followed by stirring at -10°~-5° C. for 30 minutes. To the solution were added N,N-diisopropyl-Nethylamine (0.39 ml) and a solution of (2S,4S)-4-mercapto-1-(4-nitrobenzyloxycarbonyl)-2-[(2-ureidoethyl)oxymethyl]pyrrolidine (0.73 g) in acetonitrile (3 ml) at -20° C. successively. The mixture was stirred at the same temperature for 30 minutes and then at 0°-10° C. for 3 hours. The mixture was poured into ethyl acetate (150 ml) and water (100 ml). The organic layer was dried over magnesium sulfate and concentrated under reduced pressure to give a syrup. The syrup was subjected to a column chromatography on silica gel (20 g) eluting with a mixture of acetone and dichloromethane (1:1 V/V) to give 4-nitrobenzyl (4R,5S,6S)-6-[(1R)-1-hydroxyethyl]-4-methyl-3-[(2S,4S)-1-(4-nitrobenzyloxycarbonyl- 2-{(2-ureidoethyl)oxymethyl}pyrrolidin-4-yl]thio-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate (0.75 g).
Reaction SMILES: [CH2:1]([O:4][C:5]1[C:10]([Cl:11])=[CH:9][C:8]([N+:12]([O-:14])=[O:13])=[C:7](Cl)[CH:6]=1)[CH:2]=[CH2:3].[N-:16]=[N+]=[N-].[Na+].[N-]=[N+]=[N-].[BH4-].[Na+]>CN(C=O)C>[N+:12]([C:8]1[CH:9]=[C:10]([Cl:11])[C:5]([O:4][CH2:1][CH:2]=[CH2:3])=[CH:6][C:7]=1[NH2:16])([O-:14])=[O:13]
Reactant: C=CCOc1cc(Cl)c([N+](=O)[O-])cc1Cl
Reactant: [N-]=[N+]=[N-]
Agent: [BH4-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C=CCOc1cc(N)c([N+](=O)[O-])cc1Cl
Temperature: 0 °C
Yield: 82.7 %

Procedure:
The product of step (b) (66.1 g, 267 mmol) was dissolved in 600 ml DMF at ambient temperature. Sodium azide (19.1 g, 267 mmol) was added and the mixture allowed to stir over a 4-day weekend, after which another 2 g (30.8 mmol) of the azide were added. Sodium borohydride (2.77 g, 73.5 mmol) was added in small portions while cooling in an ice bath. The mixture was stirred over night and then another 0.85 g (0.015 m) of sodium borohydride were added portionwise to the cold mixture. When the reaction appeared complete, the mixture was poured over ice water, the product filtered and dried to yield 50.5 g of 2-nitro-4-chloro-5-allyloxyaniline.
Reaction SMILES: C[O:2][C:3](=[O:30])[CH2:4][O:5][C:6]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:7]=1[C:8]([C:25](=[O:29])[C:26]([NH2:28])=[O:27])=[C:9]([CH:22]1[CH2:24][CH2:23]1)[N:10]2[CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>[OH-].[Na+].CO>[NH2:28][C:26](=[O:27])[C:25]([C:8]1[C:7]2[C:11](=[CH:12][CH:13]=[CH:14][C:6]=2[O:5][CH2:4][C:3]([OH:30])=[O:2])[N:10]([CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:9]=1[CH:22]1[CH2:24][CH2:23]1)=[O:29]
Reactant: COC(=O)COc1cccc2c1c(C(=O)C(N)=O)c(C1CC1)n2Cc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: NC(=O)C(=O)c1c(C2CC2)n(Cc2ccccc2)c2cccc(OCC(=O)O)c12
Yield: 79.8 %

Procedure:
A mixture of 220 mg (0.54 mmol) of [[3-(2-amino-1,2-dioxoethyl)-2-cyclopropyl-1-(phenylmethyl)-1H-indol-4-yl]oxy]acetic acid methyl ester in 5 mL of 1N NaOH and 15 mL of MeOH was heated to maintain reflux for 0.67 hours, concentrated at reduced pressure and the residue taken up in EtOAc/water. The aqueous layer was separated, made acidic with 1N HCl to pH 2-3 and EtOAc added. A precipitate formed and was separated to give 169 mg (80% yield) of [[3-(2-amino-1,2-dioxoethyl)-2-cyclopropyl-1-(phenylmethyl)-1H-indol-4-yl]oxy]acetic acid, mp, 246-249° C.
Reaction SMILES: Cl.[CH3:2][NH:3][CH3:4].C[Al](C)C.[Cl:9][C:10]1[CH:11]=[C:12]([C:16]2[C:29]([CH3:30])=[C:28]([C:31]#[N:32])[C:19]3[N:20]=[C:21]([C:23]([O:25]CC)=O)[O:22][C:18]=3[C:17]=2[F:33])[CH:13]=[CH:14][CH:15]=1.Cl>ClCCl>[Cl:9][C:10]1[CH:11]=[C:12]([C:16]2[C:29]([CH3:30])=[C:28]([C:31]#[N:32])[C:19]3[N:20]=[C:21]([C:23]([N:3]([CH3:4])[CH3:2])=[O:25])[O:22][C:18]=3[C:17]=2[F:33])[CH:13]=[CH:14][CH:15]=1
Reactant: CCOC(=O)c1nc2c(C#N)c(C)c(-c3cccc(Cl)c3)c(F)c2o1
Reactant: CNC
Agent: C[Al](C)C
Agent: Cl
Solvent: ClCCl
Product: Cc1c(-c2cccc(Cl)c2)c(F)c2oc(C(=O)N(C)C)nc2c1C#N
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 79.8 %

Procedure:
Dimethylamine hydrochloride (1.406 g, 17.27 mmol) was suspended in dichloromethane (20 ml), and under nitrogen atmosphere at 0° C., trimethylaluminium (1.03 M n-hexane solution) (16.8 ml, 17.27 mmol) was gradually dropwise added. After stirring at room temperature for 30 minutes, a dichloromethane (20 ml) solution of ethyl 6-(3-chlorophenyl)-4-cyano-7-fluoro-5-methyl-1,3-benzoxazole-2-carboxylate (I-310) (2.065 g, 5.75 mmol) was dropwise added at 0° C. The solution was stirred for 21 hours with gradually heating up to room temperature, then at 0° C., aqueous 1 N hydrochloric acid solution (50 ml) was dropwise added, taking 15 minutes. After stirring at the same temperature for 30 minutes, the reaction liquid was extracted three times with dichloromethane. The organic layers were combined, washed with saturated brine, then dried over anhydrous sodium sulfate. The insoluble matter was separated by filtration, the solvent was evaporated away, and the resulting residue was purified by middle-pressure liquid chromatography (eluent, chloroform:acetone=99:1, v/v) to obtain the entitled compound (1.641 g, 80%) as a pale yellow solid.
Reaction SMILES: [BH4-].[Na+].[F:3][C:4]1[CH:9]=[CH:8][C:7]([C:10](=[O:29])[CH:11]([CH2:17][C:18]2[CH:23]=[CH:22][C:21]([C:24]([F:27])([F:26])[F:25])=[C:20]([F:28])[CH:19]=2)[C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:6][CH:5]=1.Cl>C(OCC)C.[Cl-].[Zn+2].[Cl-]>[F:3][C:4]1[CH:5]=[CH:6][C:7]([CH:10]([OH:29])[CH:11]([CH2:17][C:18]2[CH:23]=[CH:22][C:21]([C:24]([F:26])([F:27])[F:25])=[C:20]([F:28])[CH:19]=2)[C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:8][CH:9]=1
Reactant: CCOC(=O)C(Cc1ccc(C(F)(F)F)c(F)c1)C(=O)c1ccc(F)cc1
Agent: Cl
Agent: [BH4-]
Agent: [Cl-]
Solvent: CCOCC
Product: CCOC(=O)C(Cc1ccc(C(F)(F)F)c(F)c1)C(O)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 99.4 %

Procedure:
To a solution of zinc chloride (7.06 g, 51.8 mmol) in diethyl ether (100 ml) was added sodium borohydride (3.92 g, 103.5 mmol) and the mixture was stirred at room temperature for 30 min. The insoluble material was filtered off. To the filtrate was added a solution of ethyl 3-(4-fluorophenyl)-2-((3-fluoro-4-(trifluoromethyl)phenyl)methyl)-3-oxopropionate (10 g, 25.9 mmol) in diethyl ether (50 ml) and the mixture was stirred at room temperature for 30 min. 1N Hydrochloric acid was added to the reaction solution under ice-cooling for quenching, water (200 ml) was added, and the mixture was extracted with ethyl acetate (300 ml×2). The extract was ashed with water and saturated brine, dried over anhydrous magnesium sulfate and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate) to give ethyl (2RS,3RS)-3-(4-fluorophenyl)-2-((3-fluoro-4-(trifluoromethyl)phenyl)methyl)-3-hydroxypropionate (10.0 g, 99%) as a colorless oil.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7](=O)[CH2:8][C:9]([O:11]CC)=O)=[CH:3][CH:2]=1.Cl.Cl.[NH2:17][CH:18]1[NH:23][CH2:22][CH:21]=[CH:20][NH:19]1.C(=O)([O-])[O-].[K+].[K+]>C(O)C>[N:1]1[CH:2]=[CH:3][C:4]([C:7]2[N:17]=[C:18]3[NH:23][CH2:22][CH2:21][CH2:20][N:19]3[C:9](=[O:11])[CH:8]=2)=[CH:5][CH:6]=1
Reactant: NC1NC=CCN1
Reactant: CCOC(=O)CC(=O)c1ccncc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: O=c1cc(-c2ccncc2)nc2n1CCCN2
Yield: 75.4 %

Procedure:
A mixture of 8.98 g (46.5 mmol) of ethyl 3-(4-pyridyl)-3-oxopropionate and 8.0 g (46.5 mmol) of 2-amino tetrahydropyrimidine dihydrochloride (prepared according to J. Org. Chem. 1955, 20, 829.) and 19.3 g (139.5 mmol) of potassium carbonate in 60 ml of ethanol was heated at reflux temperature during 18 h. The cooled solution was evaporated to removed solvent and the residue was treated with water and extracted with dichloromethane. The extracts were dried and evaporated to give 8.0 g (75%) of product as a white powder. Mp: 219° C.
Reaction SMILES: [F:1][C:2]1[CH:17]=[CH:16][C:5]2[C:6]3[N:7]([C:11](I)=[C:12]([I:14])[N:13]=3)[CH2:8][CH2:9][O:10][C:4]=2[CH:3]=1.O1CCCC1.C[Mg]Br>CCOCC.[Cl-].[NH4+]>[F:1][C:2]1[CH:17]=[CH:16][C:5]2[C:6]3[N:7]([CH:11]=[C:12]([I:14])[N:13]=3)[CH2:8][CH2:9][O:10][C:4]=2[CH:3]=1
Reactant: Fc1ccc2c(c1)OCCn1c-2nc(I)c1I
Agent: C[Mg]Br
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCOCC
Product: Fc1ccc2c(c1)OCCn1cc(I)nc1-2
Temperature: -78 °C
Reaction time: 4 h
Yield: 87.8 %

Procedure:
9-fluoro-2,3-diiodo-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine (1.24 g, 2.74 mmol) was dissolved in tetrahydrofuran (25 mL, 310 mmol) and cooled to −78° C. in a dry ice/acetone bath. Added 3.0 Methylmagnesium bromide in ether (1.37 mL and allowed the reaction to warm up to −40° C. and stir for 4 hours. Complete by LCMS. Diluted with 100 mL of saturated ammonium chloride and extracted with ethyl acetate. Dried over magnesium sulfate, concentrated in vacuo and purified by flash chromatography on the ISCO 0-40% ethyl acetate in hexanes to give 9-fluoro-2-iodo-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine (0.794 g, 88% yield)