Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1([C:7]([OH:9])=[O:8])[CH2:6][CH2:5][CH2:4][CH2:3]1.S(=O)(=O)(O)O.[CH2:15]=[C:16]([CH3:18])[CH3:17]>CCOCC>[Br:1][C:2]1([C:7]([O:9][C:16]([CH3:18])([CH3:17])[CH3:15])=[O:8])[CH2:6][CH2:5][CH2:4][CH2:3]1
Reactant: C=C(C)C
Reactant: O=C(O)C1(Br)CCCC1
Agent: O=S(=O)(O)O
Solvent: CCOCC
Product: CC(C)(C)OC(=O)C1(Br)CCCC1
Temperature: 25 °C
Reaction time: 20 h
Yield: 70 %

Procedure:
To a mixture of 1 -bromocyclopentanecarboxylic acid (36.99g) and anhydrous ether (35ml) in a 500ml pressure bottle, containing a magnetic stirrer-bar, was added concentrated sulphuric acid (3.5ml), followed by precondensed isobutene (150ml). The bottle was sealed, and stirred at ambient temperature for 20 hours. The bottle was then opened, excess isobutene was evaporated, and the residue in ether was washed with aqueous sodium bicarbonate solution and water, dried, and concentrated. The residue was distilled under reduced pressure to give the title ester (b.p. 66°-74°/0.5-2.0mm) (33.6g 70%); λmax (CHBr3) 1702cm-1 ; τ (CDCl3) 7.78, 8.20 (cyclopentane protons) and 8.54 (C(CH3)3).
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][N:5]=1)(=[O:3])[CH3:2].OO.C(OCC)(=[O:14])C.CCCCCC>C(O)(=O)C.CO>[C:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][N+:5]=1[O-:14])(=[O:3])[CH3:2]
Reactant: CC(=O)c1ccccn1
Reactant: CCOC(C)=O
Agent: OO
Solvent: CC(=O)O
Solvent: CO
Solvent: CCCCCC
Product: CC(=O)c1cccc[n+]1[O-]
Yield: 33 %

Procedure:
To a solution of 2-acetyl-pyridine (Aldrich, 0.3 mol) in 150 ml of glacial acetic acid was added with stirring 33 ml of 30% hydrogen peroxide (0.32 mol), and the mixture was allowed to react at 60° to 65° C. for 16 h. An additional 3.3 ml of 30% hydrogen peroxide was added, and the mixture was allowed to react at 70° C. for 2 h. After cooling, the water was removed by evaporation at reduced pressure to leave a crude liquid residue which was taken up in an equal volume of 50:50 ethyl acetate and hexane, and the components were separated by chromatography on 330 g of silica gel. Gradient elution starting with 50:50 ethyl acetate/hexane to 100% ethyl acetate and then to 5% methanol gave 13.48 g (33% yield) of 2-acetyl-pyridine-N-oxide. 1H NMR (CDCl3): 2.81 (s, 3H, CH3), 7.34 (m, 2H, H4 and H5), 7.71 (d, 1H, H3), and 8.22 ppm (d, 1H, H5); 13C NMR (CDCl3): 31.3 (CH3), 125.9, 127.4, 128.6, 141.2, and 195.7 ppm (C=0); mass spectrum (DCl) M+H=138 m/e; IRmax (film) 1686 cm-1 (C=0).
Reaction SMILES: Cl[CH2:2][S:3]([N:6]1[CH2:11][CH2:10][N:9]([CH2:12][C:13]2[CH:18]=[CH:17][C:16]([C:19]#[N:20])=[CH:15][CH:14]=2)[C:8](=[O:21])[CH2:7]1)(=[O:5])=[O:4].[Cl:22][C:23]1[CH:30]=[C:27]([CH:28]=O)[C:26]([OH:31])=[CH:25][CH:24]=1.C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>CN(C=O)C>[Cl:22][C:23]1[CH:24]=[CH:25][C:26]2[O:31][C:2]([S:3]([N:6]3[CH2:11][CH2:10][N:9]([CH2:12][C:13]4[CH:18]=[CH:17][C:16]([C:19]#[N:20])=[CH:15][CH:14]=4)[C:8](=[O:21])[CH2:7]3)(=[O:5])=[O:4])=[CH:28][C:27]=2[CH:30]=1
Reactant: O=Cc1cc(Cl)ccc1O
Reactant: N#Cc1ccc(CN2CCN(S(=O)(=O)CCl)CC2=O)cc1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Product: N#Cc1ccc(CN2CCN(S(=O)(=O)c3cc4cc(Cl)ccc4o3)CC2=O)cc1
Temperature: 80 °C
Reaction time: 48 h
Yield: 9.2 %

Procedure:
A mixture of 4-chloromethylsulfonyl-1-(4-cyanobenzyl)-2-piperazinone (3.20 g), 5-chlorosalicylaldehyde (2.29 g), potassium carbonate (1.48 g), potassium iodide (1.62 g) and DMF (80 ml) was stirred at 80° C. for 2 days. The reaction solution was concentrated under reduced pressure, and to the residue was added ethyl acetate. The mixture was washed with water and saturated brine, dried (MgSO4) and concentrated, and the residue was purified with silica gel column chromatography (hexane:ethyl acetate=1:1) to give colorless crystals of the title compound (384 mg).
Reaction SMILES: Br[CH2:2][C:3]1[N:13]([CH2:14][C:15]([CH3:18])([CH3:17])[CH3:16])[C:6]2[N:7]=[C:8]([C:11]#[N:12])[N:9]=[CH:10][C:5]=2[CH:4]=1.Cl.Cl.[CH3:21][N:22]([CH3:38])[CH2:23][CH2:24][O:25][C:26]1[CH:31]=[CH:30][C:29]([CH:32]2[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]2)=[CH:28][CH:27]=1.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH3:21][N:22]([CH3:38])[CH2:23][CH2:24][O:25][C:26]1[CH:31]=[CH:30][C:29]([CH:32]2[CH2:37][CH2:36][N:35]([CH2:2][C:3]3[N:13]([CH2:14][C:15]([CH3:18])([CH3:17])[CH3:16])[C:6]4[N:7]=[C:8]([C:11]#[N:12])[N:9]=[CH:10][C:5]=4[CH:4]=3)[CH2:34][CH2:33]2)=[CH:28][CH:27]=1
Reactant: CN(C)CCOc1ccc(C2CCNCC2)cc1
Reactant: CC(C)(C)Cn1c(CBr)cc2cnc(C#N)nc21
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CN(C)CCOc1ccc(C2CCN(Cc3cc4cnc(C#N)nc4n3CC(C)(C)C)CC2)cc1

Procedure:
0.22 g of 6-bromomethyl-7-(2,2-dimethyl-propyl)-7H-pyrrolo[2,3-d]pyrimidine-2-carbonitrile, 0.23 g of dimethyl-[2-(4-piperidin-4-yl-phenoxy)-ethyl]-amine bishydrochloride and 0.5 g of potassium carbonate were stirred in 2 ml acetone at 25° C. for 2 hours. The mixture was extracted with ethyl acetate/water, dried over sodium sulfate and evaporated to driness. After chromatography on silicagel using CH2Cl2/MeOH=90:10 6-{4-[4-(2-dimethylamino-ethoxy)-phenyl]-piperidin-1-ylmethyl}-7-(2,2-dimethyl-propyl)-7H-pyrrolo[2,3-d]pyrimidine-2-carbonitrile was obtained as yellow solid.
Reaction SMILES: [CH2:1]([N:8]1[CH:12]=[C:11]([C:13]2[CH:14]=[C:15]3[C:19](=[CH:20][CH:21]=2)[N:18](C(OC(C)(C)C)=O)[N:17]=[C:16]3[NH:29][C:30](=[O:33])[CH2:31]Br)[N:10]=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:34]([N:37]([CH:40]([CH3:42])C)CC)([CH3:36])C.N1CCCC1.FC(F)(F)C(O)=O>C(#N)C>[CH2:1]([N:8]1[CH:12]=[C:11]([C:13]2[CH:14]=[C:15]3[C:19](=[CH:20][CH:21]=2)[NH:18][N:17]=[C:16]3[NH:29][C:30](=[O:33])[CH2:31][N:37]2[CH2:34][CH2:36][CH2:42][CH2:40]2)[N:10]=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCN(C(C)C)C(C)C
Reactant: CC(C)(C)OC(=O)n1nc(NC(=O)CBr)c2cc(-c3cn(Cc4ccccc4)nn3)ccc21
Solvent: CC#N
Solvent: C1CCNC1
Solvent: O=C(O)C(F)(F)F
Product: O=C(CN1CCCC1)Nc1n[nH]c2ccc(-c3cn(Cc4ccccc4)nn3)cc12
Temperature: 60 °C

Procedure:
To a solution of Example 305A (44 mg, 0.086 mmol) and diisopropylethylamine (0.015 mL, 0.086 mmol) in acetonitrile (1 mL) was added pyrrolidine (0.021 mL, 0.25 mmol) and the reaction mixture was heated at about 60° C. for about 15 minutes. The reaction mixture was cooled to ambient temperature and trifluoroacetic acid (1 mL) was added. The reaction mixture was heated at about 60° C. for about 48 hours. The reaction mixture was concentrated under reduced pressure, diluted with dichloromethane (20 mL) and washed with 15% aqueous sodium hydroxide solution (20 mL). The organic layer was separated, dried over magnesium sulfate, filtered and concentrated under reduced pressure. The crude material was purified by reverse-phase HPLC using acetonitrile/water (0.05 M ammonium acetate) gradient elution method to afford the title compound. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.58 (s, 1H), 8.24 (s, 1H), 7.81 (d, J=8.7 Hz, 1H), 7.50 (d, J=8.7 Hz, 1H), 7.27-7.45 (m, 5H), 5.64 (s, 2H), 3.35 (s, 2H), 2.65 (s, 4H), 1.76 (s, 4H). MS (ESI+) m/z 402 (M+H)+.
Reaction SMILES: [CH3:1][C:2]([CH3:17])([CH3:16])[C:3]([N:5]=[C:6](OCC)[CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])=O.O.[NH2:19][NH2:20]>CO>[C:2]([C:3]1[N:5]=[C:6]([CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])[NH:20][N:19]=1)([CH3:17])([CH3:16])[CH3:1]
Reactant: CCOC(=O)CC(=NC(=O)C(C)(C)C)OCC
Reactant: NN
Solvent: O
Solvent: CO
Product: CCOC(=O)Cc1nc(C(C)(C)C)n[nH]1
Reaction time: 24 h
Yield: 59.4 %

Procedure:
Ethyl 3-[(2,2-Dimethylpropanoyl)imino]-3-ethoxypropanoate (Preparation 117, 40 g, 0.165 mol) was dissolved in methanol (250 mL) and hydrazine hydrate (9.6 mL, 0.196 mol) was added at 0° C. The reaction mixture was stirred for 24 hours. The solvents concentrated in vacuo. The residue was dissolved in water (200 mL), and the solution was extracted with chloroform (3×100 mL). The combined organic extracts were dried over MgSO4 and evaporated to afford the title compound (20.7 g, 59%).
Reaction SMILES: C(Cl)CCl.[Cl:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[NH:12][C:13]1[C:22]([C:23](O)=[O:24])=[CH:21][C:20]2[C:15](=[CH:16][C:17]([O:26]C)=[CH:18][CH:19]=2)[N:14]=1.[CH:28]1[CH:29]=[CH:30][C:31]2N(O)N=[N:34][C:32]=2[CH:33]=1.NC1C=CC=CC=1>CN(C=O)C.C(Cl)Cl>[C:32]1([NH:34][C:23]([C:22]2[C:13]([NH:12][C:7]3[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=3[Cl:5])=[N:14][C:15]3[C:20]([CH:21]=2)=[CH:19][CH:18]=[C:17]([OH:26])[CH:16]=3)=[O:24])[CH:33]=[CH:28][CH:29]=[CH:30][CH:31]=1
Reactant: COc1ccc2cc(C(=O)O)c(Nc3ccccc3Cl)nc2c1
Reactant: On1nnc2ccccc21
Solvent: ClCCl
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: O=C(Nc1ccccc1)c1cc2ccc(O)cc2nc1Nc1ccccc1Cl
Reaction time: 1 h

Procedure:
EDC (633 mg, 3.3 mmol) was added to a solution of 2-(2-Chloro-phenylamino)-7-methoxy-quinoline-3-carboxylic acid (986 mg, 3.0 mmol), HOBt (446 mg, 3.3 mmol) and aniline (307 mg, 3.3 mmol) in DMF (5 ml) at room temperature. After stirring the mixture for 1 hr, CH2Cl2 was used to extract the reaction mixture, and washed with water, saturated brine and then dried with magnesium sulfate. The solvent was removed under reduced pressure to give yellow oil. The yellow oil was purified by chromatography on SCX column using MeOH as eluent. At last, 2-(2-Chloro-phenylamino)-7-hydroxy-quinoline-3-carboxylic acid phenylamide was obtained as yellow solid after recrystallization from CH2Cl2 and Hexane; 947 mg (78%).
Reaction SMILES: [OH-].[Na+].C([O:6][C:7]1[CH:31]=[CH:30][C:29]([O:32][CH2:33][CH3:34])=[CH:28][C:8]=1[C:9]([NH:11][C:12]1[CH:21]=[C:20]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH:19]=[CH:18][C:13]=1[C:14]([O:16]C)=[O:15])=[O:10])(=O)C.Cl>CO>[CH2:33]([O:32][C:29]1[CH:30]=[CH:31][C:7]([OH:6])=[C:8]([CH:28]=1)[C:9]([NH:11][C:12]1[CH:21]=[C:20]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH:19]=[CH:18][C:13]=1[C:14]([OH:16])=[O:15])=[O:10])[CH3:34]
Reactant: CCOc1ccc(OC(C)=O)c(C(=O)Nc2cc(-c3ccccc3)ccc2C(=O)OC)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCOc1ccc(O)c(C(=O)Nc2cc(-c3ccccc3)ccc2C(=O)O)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 77 %

Procedure:
Methanol (4 mL) and a 2 mol/L aqueous solution of sodium hydroxide (0.95 mL) were added to the obtained methyl 2-(2-acetoxy-5-ethoxybenzamido)-4-phenylbenzoate (0.082 g), followed by stirring at room temperature for 3 hours and 30 minutes and then heating to reflux for 30 minutes. The reaction mixture was cooled to room temperature and adjusted to a pH of 1.2 with 6 mol/L hydrochloric acid. The solid substance was collected by filtration to obtain 0.055 g of 2-(5-ethoxy-2-hydroxybenzamido)-4-phenylbenzoic acid as a white solid.
Reaction SMILES: [NH2:1][CH:2]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[CH2:3][CH2:4][OH:5].[Cl:12][C:13]1[CH:20]=[CH:19][C:16]([C:17]#[N:18])=[C:15](F)[CH:14]=1.C(N(C(C)C)CC)(C)C.C(OCC)C.CCCC(C)C>>[Cl:12][C:13]1[CH:20]=[CH:19][C:16]([C:17]#[N:18])=[C:15]([NH:1][CH:2]([C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=2)[CH2:3][CH2:4][OH:5])[CH:14]=1
Reactant: N#Cc1ccc(Cl)cc1F
Reactant: NC(CCO)c1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCCC(C)C
Solvent: CCOCC
Product: N#Cc1ccc(Cl)cc1NC(CCO)c1ccccc1
Temperature: 140 °C

Procedure:
A mixture of 3-amino-3-phenylpropanol (1 g, 6.6 mmol) and 4-chloro-2-fluorobenzonitrile (1 g, 6.4 mmol) in diisopropylethylamine (1.2 ml, 6.9 mmol) was heated at 140° C. for 5 h. The crude reaction mixture was cooled to room temperature and applied to a silica column. The title compound was isolated as a colourless solid (1.1 g, 58%) by elution with 20% diethyl ether/isohexane.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]2[NH:8][C:9](=[O:41])[C:10]3([CH:15]([C:16]4[CH:21]=[C:20]([Cl:22])[CH:19]=[CH:18][C:17]=4[O:23][C:24]([C:27](OCC)=[O:28])([CH3:26])[CH3:25])[CH2:14][C:13](=[O:32])[NH:12][CH:11]3[C:33]3[CH:38]=[C:37]([F:39])[CH:36]=[CH:35][C:34]=3[F:40])[C:5]2=[CH:4][CH:3]=1.[H-].[H-].[H-].[H-].[Li+].[Al+3]>C1COCC1>[Cl:1][C:2]1[CH:7]=[C:6]2[NH:8][C:9](=[O:41])[C:10]3([CH:15]([C:16]4[CH:21]=[C:20]([Cl:22])[CH:19]=[CH:18][C:17]=4[O:23][C:24]([CH3:25])([CH3:26])[CH2:27][OH:28])[CH2:14][C:13](=[O:32])[NH:12][CH:11]3[C:33]3[CH:38]=[C:37]([F:39])[CH:36]=[CH:35][C:34]=3[F:40])[C:5]2=[CH:4][CH:3]=1
Reactant: CCOC(=O)C(C)(C)Oc1ccc(Cl)cc1C1CC(=O)NC(c2cc(F)ccc2F)C12C(=O)Nc1cc(Cl)ccc12
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C)(CO)Oc1ccc(Cl)cc1C1CC(=O)NC(c2cc(F)ccc2F)C12C(=O)Nc1cc(Cl)ccc12
Yield: 3.2 %

Procedure:
In a manner similar to the method described in Example 231, racemic (2′R,3S,4′R)-6-chloro-4′-[5-chloro-2-(1-ethoxycarbonyl-1-methyl-ethoxy)-phenyl]-2′-(2,5-difluoro phenyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione (200 mg, 0.33 mmol) was reacted with LiAlH4 (63 mg, 1.66 mmol) in THF and the crude product was purified by Prep-HPLC to give title compound as a white solid (6 mg).
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][C:5]([CH2:6][NH:7][NH2:8])=[CH:4][C:3]=1[Cl:11].C([O:14][C:15](=O)[CH:16]=[C:17]([NH2:21])OCC)C.C1(C)C=CC(S(O)(=O)=O)=CC=1>C(O)C>[NH2:21][C:17]1[NH:8][N:7]([CH2:6][C:5]2[CH:9]=[CH:10][C:2]([CH3:1])=[C:3]([Cl:11])[CH:4]=2)[C:15](=[O:14])[CH:16]=1
Reactant: CCOC(=O)C=C(N)OCC
Reactant: Cc1ccc(CNN)cc1Cl
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCO
Product: Cc1ccc(Cn2[nH]c(N)cc2=O)cc1Cl
Reaction time: 2 h

Procedure:
50 g of 4-methyl-3-chlorobenzylhydrazine were added dropwise, under nitrogen, to a solution of 46.7 g of β-amino-β-ethoxyacrylic acid ethyl ester and 1.5 g of p-toluenesulphonic acid in 200 ml of ethanol. After stirring for a further 2 hours, the compound identified above precipitated. It was filtered off and recrystallised from ethanol. Melting point: 130°-131°, 35 g (50%).
Reaction SMILES: [S:1]1[CH:5]=[C:4]([C:6]([O:8]CC)=O)[C:3]([C:11]([O:13]CC)=O)=[CH:2]1.[O-][CH2:17]C.[Na+].C(OCC)(=O)C.S(=O)(=O)(O)O>O>[CH:5]1[S:1][CH:2]=[C:3]2[C:11](=[O:13])[CH2:17][C:6](=[O:8])[C:4]=12
Reactant: CCOC(=O)c1cscc1C(=O)OCC
Reactant: CC[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Product: O=C1CC(=O)c2cscc21

Procedure:
In a dry 3-neck flask with an argon inlet and a water condenser, diethyl thiophene-3,4-dicarboxylate (3.7 g, 16.2 mmol) is mixed with sodium ethoxide (1.1 g, 16.2 mmol). After heating to 100° C. ethyl acetate (1.4 g, 16.2 mmol) is added through syringe pump over one hour. The mixture was further heated for a few hours. The residue was redissolved in water at 70° C. and concentrated sulfuric acid is added (1 mL). The mixture is heated at this temperature for one hour to ensure complete decarboxylation.
Reaction SMILES: [C:1]([N:5]1[C:9]2[N:10]=[CH:11][N:12]=[CH:13][C:8]=2[C:7]([C:14]([C:16]2[CH:17]=[N:18][CH:19]=[C:20]([NH:22][CH3:23])[CH:21]=2)=[O:15])=[CH:6]1)([CH3:4])([CH3:3])[CH3:2].[Cl:24][C:25]1[CH:30]=[CH:29][C:28]([CH2:31][C:32]([OH:34])=O)=[CH:27][CH:26]=1>>[C:1]([N:5]1[C:9]2[N:10]=[CH:11][N:12]=[CH:13][C:8]=2[C:7]([C:14]([C:16]2[CH:21]=[C:20]([N:22]([CH3:23])[C:32](=[O:34])[CH2:31][C:28]3[CH:27]=[CH:26][C:25]([Cl:24])=[CH:30][CH:29]=3)[CH:19]=[N:18][CH:17]=2)=[O:15])=[CH:6]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: O=C(O)Cc1ccc(Cl)cc1
Reactant: CNc1cncc(C(=O)c2cn(C(C)(C)C)c3ncncc23)c1
Product: CN(C(=O)Cc1ccc(Cl)cc1)c1cncc(C(=O)c2cn(C(C)(C)C)c3ncncc23)c1

Procedure:
The title compound was prepared according to the method described for Example 1 using (7-tert-Butyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-(5-methylamino-pyridin-3-yl)-methanone (Preparation 187) and (4-chloro-phenyl)-acetic acid to afford the title compound as off white solid in 45% yield, 21 mg.
Reaction SMILES: C[O:2][C:3](=[O:67])[C@@H:4]([NH:20][C:21]([CH:23]1[CH2:36][C:35]2[CH:34]=[C:33]3[C:28]([O:29][C@@H:30]([C:38]4[CH:43]=[CH:42][C:41]([O:44][CH2:45][C:46]5[CH:51]=[CH:50][C:49]([Cl:52])=[C:48]([Cl:53])[CH:47]=5)=[CH:40][CH:39]=4)[C:31](=[O:37])[NH:32]3)=[CH:27][C:26]=2[CH2:25][N:24]1[S:54]([C:57]1[S:61][C:60]([NH:62]C(=O)C)=[N:59][C:58]=1[CH3:66])(=[O:56])=[O:55])=[O:22])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:17]=[CH:16][C:15]([C:18]#[N:19])=[CH:14][CH:13]=2)=[CH:8][CH:7]=1.COC(=O)[C@@H](NC(C1CC2C=C3C(O[C@@H](C4C=CC(OCC5C=CC(Cl)=C(Cl)C=5)=CC=4)C(=O)N3)=CC=2CN1S(C1SC(N)=NC=1C)(=O)=O)=O)CC1C=CC(C2C=CC(C#N)=CC=2)=CC=1>>[NH2:62][C:60]1[S:61][C:57]([S:54]([N:24]2[CH:23]([C:21]([NH:20][C@@H:4]([CH2:5][C:6]3[CH:7]=[CH:8][C:9]([C:12]4[CH:13]=[CH:14][C:15]([C:18]#[N:19])=[CH:16][CH:17]=4)=[CH:10][CH:11]=3)[C:3]([OH:67])=[O:2])=[O:22])[CH2:36][C:35]3[CH:34]=[C:33]4[C:28]([O:29][C@@H:30]([C:38]5[CH:43]=[CH:42][C:41]([O:44][CH2:45][C:46]6[CH:51]=[CH:50][C:49]([Cl:52])=[C:48]([Cl:53])[CH:47]=6)=[CH:40][CH:39]=5)[C:31](=[O:37])[NH:32]4)=[CH:27][C:26]=3[CH2:25]2)(=[O:56])=[O:55])=[C:58]([CH3:66])[N:59]=1
Reactant: COC(=O)[C@H](Cc1ccc(-c2ccc(C#N)cc2)cc1)NC(=O)C1Cc2cc3c(cc2CN1S(=O)(=O)c1sc(NC(C)=O)nc1C)O[C@@H](c1ccc(OCc2ccc(Cl)c(Cl)c2)cc1)C(=O)N3
Agent: COC(=O)[C@H](Cc1ccc(-c2ccc(C#N)cc2)cc1)NC(=O)C1Cc2cc3c(cc2CN1S(=O)(=O)c1sc(N)nc1C)O[C@@H](c1ccc(OCc2ccc(Cl)c(Cl)c2)cc1)C(=O)N3
Product: Cc1nc(N)sc1S(=O)(=O)N1Cc2cc3c(cc2CC1C(=O)N[C@@H](Cc1ccc(-c2ccc(C#N)cc2)cc1)C(=O)O)NC(=O)[C@H](c1ccc(OCc2ccc(Cl)c(Cl)c2)cc1)O3

Procedure:
(S)-2-({(S)-6-(2-Acetylamino-4-methyl-thiazole-5-sulfonyl)-3-[4-(3,4-dichloro-benzyloxy)-phenyl]-2-oxo-2,3,5,6,7,8-hexahydro-1H-4-oxa-1,6-diaza-anthracene-7-carbonyl}-amino)-3-(4′-cyano-biphenyl-4-yl)-propionic acid methyl ester (more polar diastereomer, 100 mg) was converted to (S)-2-({(S)-6-(2-amino-4-methyl-thiazole-5-sulfonyl)-3-[4-(3,4-dichloro-benzyloxy)-phenyl]-2-oxo-2,3,5,6,7,8-hexahydro-1H-4-oxa-1,6-diaza-anthracene-7-carbonyl}-amino)-3-(4′-cyano-biphenyl-4-yl)-propionic acid methyl ester (LC-MS m/z 941) following the general procedure P. This ester on hydrolysis using general procedure B furnished title compound (more polar diastereomer, 70 mg). LC-MS (m/z): 923.
Reaction SMILES: [CH3:1][NH:2][C:3]1[CH:8]=[C:7]([CH3:9])[CH:6]=[CH:5][C:4]=1[N+:10]([O-])=O.C([O-])=O.[NH4+]>C1COCC1.CO.[Pd]>[CH3:9][C:7]1[CH:8]=[C:3]([NH:2][CH3:1])[C:4]([NH2:10])=[CH:5][CH:6]=1
Reactant: CNc1cc(C)ccc1[N+](=O)[O-]
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CO
Solvent: C1CCOC1
Product: CNc1cc(C)ccc1N
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a solution of methyl-(5-methyl-2-nitro-phenyl)-amine (2.47 g, 14.9 mmol), ammonium formate (15 g, 237.9 mmol) in THF (7 mL) and MeOH (35 mL) at room temperature was added 10% Pd/C (650 mg) and the resuitng mixture was stirred at room temperature for 10 min. The resulting mixture was then filtered over CELITE® and concentrated in vacuo. The resulting residue was diluted with CH2Cl2, washed with H2O and the organic layer dried over Na2SO4, filtered, and concentrated in vacuo. The resultant residue was purified by flash column chromatography (SiO2), eluting with a hexanes-EtOAc gradient to yield 4,N2-dimethyl-benzene-1,2-diamine
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[C:2]1[CH2:6][C:7]1[CH:13]=[CH:12][C:10]([NH2:11])=[CH:9][CH:8]=1.[CH:14](O)=[O:15].O>C1(C)C=CC=CC=1>[NH:1]1[CH:5]=[CH:4][N:3]=[C:2]1[CH2:6][C:7]1[CH:13]=[CH:12][C:10]([NH:11][CH:14]=[O:15])=[CH:9][CH:8]=1
Reactant: O=CO
Reactant: Nc1ccc(Cc2ncc[nH]2)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: O=CNc1ccc(Cc2ncc[nH]2)cc1

Procedure:
In a 200 ml round-bottom flask is placed a solution of 8.0 g of p-(1-imidazolylmethyl)aniline prepared as described in Reference Example 3, and 30 ml of formic acid in 80 ml of toluene. The flask was fitted with a water separator, and the solution was refluxed for 4 hours. After concentration under reduced pressure, the residual solid was recrystallized from ethanol-diethyl ether to give 6.4 g of p-(1-imidazolylmethyl)-N-formylaniline as colorless prisms. M.P.: 121°-123° C. To a suspension of 0.48 g of 50% sodium hydride in 50 ml of dry dimethylformamide was added 2.01 g of the formylaniline and mixture was heated to 100° C. A solution of 1.81 g of ethyl α-bromopropionate in 30 ml of dry dimethylformamide was added to the mixture and the reaction mixture was heated at 100° C. for 16 hours. After removal of the solvent under reduced pressure, 50 ml of dichloromethane was added to the residue, and the solution was washed with water and dried over anhydrous magnesium sulfate. The solvent was evaporated and the residue was chromatographed on silica gel using dichloromethane-ethanol (20:1 by volume) to give 1.58 g of N-formyl-N-[p-(1-imidazolylmethyl)phenyl]alanine ethyl ester as a pale brown oil. Then, a solution of 1.58 g of the resulting ester and 5 ml of concentrated hydrochloric acid in 50 ml of ethanol was stirred for 40 hours at room temperature. After concentration under reduced pressure, the residual solid was recrystallized from ethanol-diethyl ether to give 1.18 g of N-[p-(1-imidazolylmethyl)phenyl]alanine ethyl ester dihydrochloride as pale yellow crystals. M.P.: 154°-159° C.
Reaction SMILES: C(OC(=O)[NH:10][C@@H:11]([CH3:25])[CH2:12][NH:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][C:21]([F:24])([F:23])[F:22])=[CH:16][CH:15]=1)C1C=CC=CC=1>C(O)C.[Pd]>[F:22][C:21]([F:23])([F:24])[O:20][C:17]1[CH:16]=[CH:15][C:14]([NH:13][CH2:12][C@@H:11]([NH2:10])[CH3:25])=[CH:19][CH:18]=1
Reactant: C[C@@H](CNc1ccc(OC(F)(F)F)cc1)NC(=O)OCc1ccccc1
Agent: [Pd]
Solvent: CCO
Product: C[C@H](N)CNc1ccc(OC(F)(F)F)cc1
Reaction time: 8 h
Yield: 72 %

Procedure:
[1-(S)-Methyl-2-(4-trifluoromethoxy-phenylamino)-ethyl]-carbamic acid benzyl ester (23.9 mmol) was dissolved in ethanol (200 mL) then placed under nitrogen. 10% Palladium on carbon was added (0.5 g) and the mixture was stirred under hydrogen (atmospheric pressure) overnight. When reaction was complete, the mixture was filtered through celite. The celite was washed with ethanol (5×50 ml) then evaporated in vacuo to give a brown oil (4.03 g, 17.21 mmol, 72% yield over 3 steps).
Reaction SMILES: Br[CH2:2][C:3]1[O:4][C:5](=[O:8])[O:6][CH:7]=1.[C:9]1([SH:15])[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.C(N(CC)CC)C>ClCCl>[C:9]1([S:15][CH2:2][C:3]2[O:4][C:5](=[O:8])[O:6][CH:7]=2)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: O=c1occ(CBr)o1
Reactant: Sc1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=c1occ(CSc2ccccc2)o1
Temperature: 25 °C
Reaction time: 1 h
Yield: 60.2 %

Procedure:
In 30 ml of dichloromethane was dissolved 1.0 g of 4-bromomethyl-1,3-dioxol-2-one, and 0.7 g of benzenethiol was added. Then, 0.6 g of triethylamine was added, and the mixture was stirred at room temperature for 1 hour. After the reaction, the solvent was evaporated under reduced pressure. The residue was dissolved in ethyl acetate. The isoluble materials were separated by filtration, and the residue was evaporated under reduced pressure. The residue was subjected to medium-pressure silica gel column chromatography as in Example 1 except that the column was eluted with a mixture of chloroform and n-hexane (2/1, v/v). The eluate was concentrated under reduced pressure to give 0.7 g of the captioned compound as a colorless liquid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[N:9]=[CH:8][N:7]([CH2:10][C:11]([OH:13])=O)[C:6]=2[C:14]=1[F:15].Cl.[NH2:17][CH2:18][C:19]1[CH:24]=[CH:23][C:22]([C:25]([CH3:29])([CH3:28])[C:26]#[N:27])=[C:21]([F:30])[CH:20]=1.CCN(CC)CC.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[C:26]([C:25]([C:22]1[CH:23]=[CH:24][C:19]([CH2:18][NH:17][C:11](=[O:13])[CH2:10][N:7]2[C:6]3[C:14]([F:15])=[C:2]([F:1])[CH:3]=[CH:4][C:5]=3[N:9]=[CH:8]2)=[CH:20][C:21]=1[F:30])([CH3:29])[CH3:28])#[N:27]
Reactant: CC(C)(C#N)c1ccc(CN)cc1F
Reactant: O=C(O)Cn1cnc2ccc(F)c(F)c21
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(C)(C#N)c1ccc(CNC(=O)Cn2cnc3ccc(F)c(F)c32)cc1F

Procedure:
N-[4-(1-Cyano-1-methylethyl)-3-fluorobenzyl]-2-(6,7-difluoro-1H-benzimidazol-1-yl)acetamide is synthesized according to example 14 with (6,7-difluoro-1H-benzimidazol-1-yl)acetic acid (150 mg, 0.707 mmol) prepared according to scheme 2, 2-[4-(aminomethyl)-2-fluorophenyl]-2-methylpropanenitrile hydrochloride (194 mg, 0.848 mmol) prepared according to scheme 8, Et3N (237 μL, 1.70 mmol) and HATU (323 mg, 0.848 mmol) in DMF (3.0 mL). The product is purified by HPLC: Gilson prep pumps, Flow rate: 30 ml/min, Column: Gemini (50 21.2×50 mm, Mobile phase: A=water (0.075% TFA) B=MeCN (0.075% TFA). Yield=25 mg as TFA salt, 0.05 mmol, 7%). 1H NMR (400 MHz, DMSO-D6) δ ppm 1.74-1.87 (m, 6H), 4.43 (d, J=5.66 Hz, 2H), 5.22 (s, 2H), 7.19-7.40 (m, 2H), 7.45-7.61 (m, 2H), 8.34 (s, 1H), 8.91-9.04 (m, 1H). MS [M+H], calcd: 387.1. found: 387.0.