Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][CH2:2][C@@H:3]1[CH2:7][N:6]([C:8]([C:10]2[NH:11][C:12]3[C:17]([CH:18]=2)=[CH:16][C:15](NC(C2NC4C(C=2)=CC=CC=4)=O)=[CH:14][CH:13]=3)=[O:9])[C:5]2[CH:31]=[C:32]([OH:39])[C:33]3[NH:34][CH:35]=[C:36]([CH3:38])[C:37]=3[C:4]1=2>N1C=CC=CC=1>[C:32]([O:39][C:32]1[C:33]2[NH:34][CH:35]=[C:36]([CH3:38])[C:37]=2[C:4]2[CH:3]([CH2:2][Cl:1])[CH2:7][N:6]([C:8]([C:10]3[NH:11][C:12]4[C:17]([CH:18]=3)=[CH:16][C:15]([N:11]3[C:12]5[C:17](=[CH:16][CH:15]=[CH:14][CH:13]=5)[CH:18]=[C:10]3[C:8]([NH2:6])=[O:9])=[CH:14][CH:13]=4)=[O:9])[C:5]=2[CH:31]=1)(=[O:39])[CH3:31]
Reactant: Cc1c[nH]c2c(O)cc3c(c12)[C@H](CCl)CN3C(=O)c1cc2cc(NC(=O)c3cc4ccccc4[nH]3)ccc2[nH]1
Solvent: c1ccncc1
Product: CC(=O)Oc1cc2c(c3c(C)c[nH]c13)C(CCl)CN2C(=O)c1cc2cc(-n3c(C(N)=O)cc4ccccc43)ccc2[nH]1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
15 mg (0.028 mmol) of (S)-N-[2-[[1-(chloromethyl)-1,6-dihydro-5-hydroxy-8-methylbenzo[1,2-b:4,3-b']dipyrrol-3(2H)-yl]carbonyl]-1H-indol-5-yl]-1H-Indole-2-carboxamide is dissolved in 2 ml of dry pyridine at 5° C., degassed with nitrogen and treated with 0.005 ml of acetyl chloride. After 30 min. at 5° C., the solution is warmed to room temperature, quenched with 1 ml of water, diluted with 50 ml of ethyl acetate, and washed with two 20 ml portions of 1:1 brine/1N hydrochloric acid, and then brine. The solution is dried with sodium sulfate, filtered, adsorbed on 1 g of Celite™, and flash chromatographed on 10 g of silica gel, eluting with 50% ethyl acetate in hexane to give in fractions (25 ml) 6-12 the title compound as a solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]1[CH2:11][CH:12]([CH2:16][C:17]([OH:19])=[O:18])[CH2:13][CH2:14][CH2:15][C:5]2=1.[H-].[Na+].Cl.Cl[CH2:24][C:25]1[CH:30]=[CH:29][C:28]([N:31]2[CH:35]=[CH:34][N:33]=[CH:32]2)=[CH:27][CH:26]=1.O>CN(C=O)C>[F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:24][C:25]1[CH:26]=[CH:27][C:28]([N:31]3[CH:35]=[CH:34][N:33]=[CH:32]3)=[CH:29][CH:30]=1)[C:6]1[CH2:11][CH:12]([CH2:16][C:17]([OH:19])=[O:18])[CH2:13][CH2:14][CH2:15][C:5]2=1
Reactant: ClCc1ccc(-n2ccnc2)cc1
Reactant: O=C(O)CC1CCCc2c([nH]c3ccc(F)cc23)C1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: O=C(O)CC1CCCc2c(n(Cc3ccc(-n4ccnc4)cc3)c3ccc(F)cc23)C1
Temperature: 0 °C
Reaction time: 1 h
Yield: 59.5 %

Procedure:
A solution of 122 mg of 2-fluoro- 5,6,7,8,9,10-hexahydrocyclohept[b]indole-7-acetic acid in 20 ml of dry DMF is cooled at 0° C., and treated with 102 mg of 55% NaH. The reaction mixture is stirred for 60 minutes at 0° C., then 160 mg of 1-[4-(chloro-methyl)phenyl]-1H-imidazole hydrochloride are added portionwise at 0° C. After stirring at room temperature for 16 hours the mixture is poured into water and washed with methylene chloride. The aqueous solution is neutralized with diluited HCl and extracted with methylene chloride. The organic layer is dried over sodium sulfate and evaporated to dryness. The residue, washed with acetone and dried, yields 116 mg of the title compound m.p. 237° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:7]=[CH:8][C:9]=1[CH3:10])[NH2:6].C([O-])(O)=O.[Na+].[C:16](Cl)(=[O:21])[C:17]([CH3:20])([CH3:19])[CH3:18]>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:7]=[CH:8][C:9]=1[CH3:10])[NH:6][C:16](=[O:21])[C:17]([CH3:20])([CH3:19])[CH3:18]
Reactant: COc1cc(N)ccc1C
Reactant: CC(C)(C)C(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: COc1cc(NC(=O)C(C)(C)C)ccc1C
Reaction time: 12 h

Procedure:
5.1 g (37 mmol) of 3-methoxy-4-methylaniline are dissolved in 70 ml of methylene chloride, and treated with 70 ml of satd. NaHCO3 solution and with 4.6 ml (37 mmol) of pivaloyl chloride. After stirring vigorously for 12 hours, the organic phase is separated off, washed with 1N hydrochloric acid and water, dried over magnesium sulphate and concentrated in vacuo. The product is obtained in crystalline form and is further processed without further purification.
Reaction SMILES: [C:1]1([S:7]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([N+:17]([O-:19])=[O:18])=[CH:13][CH:12]=2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].Br[CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25]>CN(C=O)C>[CH2:27]([O:26][C:24](=[O:25])[CH2:23][N:10]([C:11]1[CH:16]=[CH:15][C:14]([N+:17]([O-:19])=[O:18])=[CH:13][CH:12]=1)[S:7]([C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)(=[O:9])=[O:8])[CH3:28]
Reactant: CCOC(=O)CBr
Reactant: O=[N+]([O-])c1ccc(NS(=O)(=O)c2ccccc2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)CN(c1ccc([N+](=O)[O-])cc1)S(=O)(=O)c1ccccc1

Procedure:
A cold (0° C.) solution of N-phenylsulphonyl-4-nitroaniline (7.39 g, 30 mmol) in DMF (65 mL) was treated with sodium hydride (0.76 g, 32 mmol) portionwise over a period of 1.5 h. A solution of ethyl bromoacetate (4 mL) in DMF (10 mL) was added, and the resultant mixture stirred at RT overnight. The product mixture was concentrated under vacuum, and the residue dissolved in ethyl acetate. The organic extract was washed with brine, dried over magnesium sulfate, filtered and concentrated under vacuum. The residue was subjected to column chromatography on silica gel eluting with 0.5% methanol in chloroform. Collection and concentration of appropriate fractions provided N-4-nitrophenyl-N-phenylsulfonylglycine ethyl ester (4-8a) as a clear gum. ##STR41## Step 2: N-{4-[4-(4-tert-Butyloxycarbonylpiperazin-1-yl)phenylcarbonyl-amino]phenyl}-N-phenylsulfonylglycine ethyl ester (4-10a)
Reaction SMILES: [CH3:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[C:4]([CH3:11])[N:3]=1.[O:12]1CCOCC1>>[CH3:1][C:2]1[N:3]=[C:4]([CH:11]=[O:12])[CH:5]=[CH:6][C:7]=1[N+:8]([O-:10])=[O:9]
Reactant: Cc1ccc([N+](=O)[O-])c(C)n1
Reactant: C1COCCO1
Product: Cc1nc(C=O)ccc1[N+](=O)[O-]
Yield: 37.4 %

Procedure:
A solution of 2,6-dimethyl-3-nitropyridine (1.5 g, 9.85 mmol) and SeO2 (1.4 g, 12.81 mmol) in 1,4-dioxane (15 mL) was heated at reflux for 16 h. The reaction mixture was then filtered through Celite and the solvent was evaporated. The crude material obtained was purified by column chromatography (silica: 100-200 mesh, EtOAc:hexane 20-25%) to afford the title compound (0.61 g, 37.4%). δH (CDCl3) 10.09 (s, 1H), 8.39 (d, J=8.3 Hz, 1H), 7.97 (d, J=8.3 Hz, 1H), 2.94 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[CH:9]([C:20]1[C:28]2[C:23](=[C:24]([CH2:30][S:31][CH3:32])[CH:25]=[C:26]([F:29])[CH:27]=2)[NH:22][CH:21]=1)[CH:10]1C(=O)O[C:13](C)([CH3:17])[O:12][C:11]1=[O:19]>N1C=CC=CC=1.C(O)C.[Cu]>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[CH:9]([C:20]1[C:28]2[C:23](=[C:24]([CH2:30][S:31][CH3:32])[CH:25]=[C:26]([F:29])[CH:27]=2)[NH:22][CH:21]=1)[CH2:10][C:11]([O:12][CH2:13][CH3:17])=[O:19]
Reactant: CSCc1cc(F)cc2c(C(c3ccc(Cl)cc3Cl)C3C(=O)OC(C)(C)OC3=O)c[nH]c12
Agent: [Cu]
Solvent: CCO
Solvent: c1ccncc1
Product: CCOC(=O)CC(c1ccc(Cl)cc1Cl)c1c[nH]c2c(CSC)cc(F)cc12

Procedure:
2.8 mg (0.05 mmol) of copper powder were added to 3.10 g of the compound from Example 18A with a purity of 68% (4.23 mmol) in 34 ml of pyridine and 8 ml of ethanol. The reaction mixture was heated under reflux for 1 h. It was concentrated, and the crude product was purified by preparative HPLC (RP18 column; mobile phase: acetonitrile/water gradient) to result in 1.52 g (82% of theory) of the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:10]=[C:11]([O:15][CH2:16][C:17]#[CH:18])[C:12]=1[O:13][CH3:14])[C:6]([O:8][CH3:9])=[O:7]>C(N(CC)C1C=CC=CC=1)C.C(Cl)Cl>[CH3:1][O:2][C:3]1[C:12]([O:13][CH3:14])=[C:11]2[O:15][CH2:16][CH:17]=[CH:18][C:10]2=[C:5]([C:6]([O:8][CH3:9])=[O:7])[CH:4]=1
Reactant: C#CCOc1cc(C(=O)OC)cc(OC)c1OC
Solvent: CCN(CC)c1ccccc1
Solvent: ClCCl
Product: COC(=O)c1cc(OC)c(OC)c2c1C=CCO2
Yield: 99.9 %

Procedure:
Methyl 3,4-dimethoxy-5-(2-propynyloxy)benzoate (390 g, 1.56 mol) in N,N-diethylaniline (0.4 L) was refluxed for 40 min. The solution was cooled and diluted with methylene chloride (2 L). The organic solution was extracted with 1N hydrochloric acid (5×1 L), dried (MgSO4) and concentrated to give title compound (390 g, 100%).
Reaction SMILES: Cl.[NH:2]1[CH2:10][CH2:9][CH2:8][C@H:3]1[C:4]([O:6][CH3:7])=[O:5].CCN(C(C)C)C(C)C.[Cl:20][C:21]1[CH:22]=[C:23]([S:28](Cl)(=[O:30])=[O:29])[CH:24]=[C:25]([Cl:27])[CH:26]=1>C(Cl)Cl>[Cl:27][C:25]1[CH:24]=[C:23]([S:28]([N:2]2[CH2:10][CH2:9][CH2:8][C@H:3]2[C:4]([O:6][CH3:7])=[O:5])(=[O:29])=[O:30])[CH:22]=[C:21]([Cl:20])[CH:26]=1
Reactant: COC(=O)[C@@H]1CCCN1
Reactant: O=S(=O)(Cl)c1cc(Cl)cc(Cl)c1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)[C@@H]1CCCN1S(=O)(=O)c1cc(Cl)cc(Cl)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture of (L)-proline, methyl ester hydrochloride (838 mg, 5.06 mmol) in CH2Cl2 (25 mL) at 0° C. were added DIPEA (2.64 mL, 15.2 mmol) and a solution of 3,5-dichlorobenzenesulfonyl chloride (1.49 g, 6.07 mmol) in CH2Cl2 (5 mL). The cooling bath was removed, and the mixture was stirred overnight at rt. It was then diluted with CH2Cl2, washed with 1N hydrochloric acid, saturated NaHCO3, saturated brine solution, dried over anhydrous Na2SO4, and rotoevaporated. The product was purified by flash column chromatography on silica gel eluted with 10% acetone in hexanes to yield N-(3,5-dichlorobenzenesulfonyl)-(L)-proline, methyl ester; yield 1.49 g.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:27]=[CH:26][C:7]([NH:8][CH:9]=[C:10]([C:24]#[N:25])[C:11]([NH:13][C:14]2[CH:19]=[C:18]([O:20][CH3:21])[C:17]([Cl:22])=[CH:16][C:15]=2[Cl:23])=O)=[CH:6][C:5]=1[F:28])[CH3:2].P(Cl)(Cl)(Cl)=O>C(#N)C.CO>[Cl:23][C:15]1[CH:16]=[C:17]([Cl:22])[C:18]([O:20][CH3:21])=[CH:19][C:14]=1[NH:13][C:11]1[C:26]2[C:7](=[CH:6][C:5]([F:28])=[C:4]([O:3][CH2:1][CH3:2])[CH:27]=2)[N:8]=[CH:9][C:10]=1[C:24]#[N:25]
Reactant: CCOc1ccc(NC=C(C#N)C(=O)Nc2cc(OC)c(Cl)cc2Cl)cc1F
Solvent: CC#N
Solvent: O=P(Cl)(Cl)Cl
Solvent: CO
Product: CCOc1cc2c(Nc3cc(OC)c(Cl)cc3Cl)c(C#N)cnc2cc1F
Reaction time: 0.5 h
Yield: 36.6 %

Procedure:
A suspension of 4-ethoxy-3-fluoroanilino-N-(2,4-dichloro-5-methoxyphenyl)-2-cyano-2-propenamide (6.28 9, 14.8 mmol) in 54 mL of acetonitrile and 2.0 mL of methanol was heated to reflux and phosphorous oxychloride (8.3 mL, 88.8 mmol) was added dropwise. The mixture was heated at reflux for 17 hours. The resultant solution was concentrated in vacuo and acetonitrile was added to the residue. The solid was collected by filtration, washed with acetonitrile. The solid was suspended in tetrahydrofuran and neutralized with concentrated ammonium hydroxide. After stirring for 30 minutes, water was added and the mixture was stirred for 1 hour. The solid was collected by filtration, washed with water, followed by 1:1 diethyl ether and hexane. The light yellow solid was dried in vacuo to provide 2.2 g (37%) of 4-[(2,4-dichloro-5-methoxyphenyl)amino]-6-ethoxy-7-fluoro-3-quinolinecarbonitrile, mp 185-187° C.; 1H NMR (400 MHz, DMSO-d6) δ 1.95 (t, J=7 Hz, 3H), 3.87 (s, 3H), 4.29 (q, J=7 Hz, 2H), 7.39 (s, 1H), 7.66-7.81 (m, 2H), 8.09 (d, J=9 Hz, 1H), 8.49 (s, 1H), 9.80 (s, 1H); MS (ES) m/z 406.1, 408.2 (M+H)+
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[CH2:7]([O:14][C:15]1[CH:22]=[CH:21][C:18]([C:19]#[N:20])=[CH:17][C:16]=1[O:23][CH2:24][CH2:25][CH2:26][CH2:27][O:28][CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.C(O)C.S([O-])([O-])(=O)=O.[Na+].[Na+]>O1CCCC1.O>[CH2:7]([O:14][C:15]1[CH:22]=[CH:21][C:18]([CH2:19][NH2:20])=[CH:17][C:16]=1[O:23][CH2:24][CH2:25][CH2:26][CH2:27][O:28][CH2:29][C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1)[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: N#Cc1ccc(OCc2ccccc2)c(OCCCCOCc2ccccc2)c1
Agent: O=S(=O)([O-])[O-]
Agent: [Al+3]
Agent: [H-]
Solvent: CCO
Solvent: C1CCOC1
Solvent: O
Product: NCc1ccc(OCc2ccccc2)c(OCCCCOCc2ccccc2)c1
Temperature: 60 °C
Reaction time: 2 h
Yield: 41.9 %

Procedure:
Lithium aluminium hydride (2.6 g) was suspended in tetrahydrofuran (30 mL), and to the mixture was added dropwise a solution of 4-benzyloxy-3-(4-benzyloxybutoxy)benzonitrile (5.9 g) in tetrahydrofuran (30 mL) under ice-cooling. The mixture was stirred at 60° C. for 2 hours. After the mixture was cooled in an ice bath, ethanol and water were successively added dropwise to the reaction mixture. To the reaction mixture was added anhydrous sodium sulfate, and the insoluble material was removed by filtration through celite. The filtrate was concentrated under reduced pressure, and the obtained residue was purified by column chromatography on aminopropylated silica gel (eluent: ethyl acetate/hexane=1/5) to give the title compound (2.5 g).
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7]2[CH:8]=[C:9]([NH:13][C:14]([NH:16][CH2:17][C@@H:18]3[CH2:23][CH2:22][CH2:21][CH2:20][C@H:19]3[NH:24][CH2:25][CH2:26][CH2:27][C:28]3[CH:33]=[CH:32][C:31]([F:34])=[CH:30][CH:29]=3)=[O:15])[CH:10]=[CH:11][CH:12]=2)=[N:5][N:4]=[N:3]1.C=O.[C:37]([BH3-])#N.[Na+]>C(Cl)Cl.C1COCC1>[CH3:1][N:2]1[C:6]([C:7]2[CH:8]=[C:9]([NH:13][C:14]([NH:16][CH2:17][C@@H:18]3[CH2:23][CH2:22][CH2:21][CH2:20][C@H:19]3[N:24]([CH2:25][CH2:26][CH2:27][C:28]3[CH:29]=[CH:30][C:31]([F:34])=[CH:32][CH:33]=3)[CH3:37])=[O:15])[CH:10]=[CH:11][CH:12]=2)=[N:5][N:4]=[N:3]1
Reactant: [BH3-]C#N
Reactant: Cn1nnnc1-c1cccc(NC(=O)NC[C@@H]2CCCC[C@H]2NCCCc2ccc(F)cc2)c1
Agent: C=O
Agent: [Na+]
Solvent: ClCCl
Solvent: C1CCOC1
Product: CN(CCCc1ccc(F)cc1)[C@@H]1CCCC[C@H]1CNC(=O)Nc1cccc(-c2nnnn2C)c1
Reaction time: 0.25 h

Procedure:
To a solution of N-[3-(1-methyl-tetrazol-5-yl)phenyl]-N′-[(1S,2R)-2-[3-(4-fluorophenyl)propylamino]-cyclohexylmethyl]urea (98 mg), the product of Step g of Example 31, in 4 mL of CH2Cl2 was added a solution of formaldehyde in THF (excess), and the mixture was stirred for 15 minutes. Then excess amount of sodium cyanoborohydride was added, and the mixture was continued to stir for 5 hrs at room temperature. After quenching the reaction with saturated Na2CO3, it was extracted with CH2Cl2. The extract was washed with water, dried over MgSO4 and evaporated to give an oily residue. It was purified by column chromatography (silica gel, 0.6:5.494 cNH4OH/CH3OH/CH2Cl2) to give pure N-[3-(1-methyl-tetrazol-5-yl)phenyl]-N′-[(1S,2R)-2-[N-methyl-3-(4-fluorophenyl)propylamino]-cyclohexylmethyl]urea.
Reaction SMILES: O=[C:2]([C:8]1[CH:13]=[CH:12][C:11]([S:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[CH:10][CH:9]=1)[CH2:3][CH2:4][C:5]([OH:7])=[O:6]>Cl>[C:15]1([S:14][C:11]2[CH:10]=[CH:9][C:8]([CH2:2][CH2:3][CH2:4][C:5]([OH:7])=[O:6])=[CH:13][CH:12]=2)[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: O=C(O)CCC(=O)c1ccc(Sc2ccccc2)cc1
Agent: Cl
Product: O=C(O)CCCc1ccc(Sc2ccccc2)cc1
Reaction time: 0.08 h
Yield: 81.1 %

Procedure:
Powdered Zinc (66 g) was washed with 2% HCl, added to a solution of HgCl2 (6 g) in 50 mL of 6M HCl. This mixture was shaken vigorously for 5 minutes, and excess liquid was decanted. The mixture was then added to a mechanically stirred suspension of 4-oxo-4-(4-phenylsulfanyl-phenyl)-butyric acid (6.5 g, 22.7 mmol) in 450 mL of 6M HCl, and the reaction mixture was stirred at room temperature for 5 days. The mixture was then decanted to remove excess HCl, and quenched by addition of 250 mL water. The aqueous mixture was extracted three times with 100 mL of EtOAc, and the combined organic layers were dried under reduced pressure to yield 5.0 g (18.4 mmol, 81%) of 4-(4-phenylsulfanyl-phenyl)-butyric acid as a crude solid. MS: 273 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:36][CH:37]([F:39])[F:38])=[C:6]([C:8]2[C:12]([NH:13][C:14]([C:16]3[CH:17]=[N:18][N:19]4[CH:24]=[CH:23][CH:22]=[N:21][C:20]=34)=[O:15])=[CH:11][N:10]([CH2:25][C:26]([N:28]3[CH2:35][C@@H:34]4[C@@H:30]([CH2:31][NH:32][CH2:33]4)[CH2:29]3)=[O:27])[N:9]=2)[CH:7]=1.[CH:40]1([CH:43]=O)[CH2:42][CH2:41]1.[BH4-].[Na+].CO>FC(F)(F)CO>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:36][CH:37]([F:39])[F:38])=[C:6]([C:8]2[C:12]([NH:13][C:14]([C:16]3[CH:17]=[N:18][N:19]4[CH:24]=[CH:23][CH:22]=[N:21][C:20]=34)=[O:15])=[CH:11][N:10]([CH2:25][C:26]([N:28]3[CH2:29][C@@H:30]4[C@@H:34]([CH2:33][N:32]([CH2:43][CH:40]5[CH2:42][CH2:41]5)[CH2:31]4)[CH2:35]3)=[O:27])[N:9]=2)[CH:7]=1
Reactant: O=CC1CC1
Reactant: O=C(Nc1cn(CC(=O)N2C[C@H]3CNC[C@H]3C2)nc1-c1cc(Cl)ccc1OC(F)F)c1cnn2cccnc12
Agent: [BH4-]
Agent: [Na+]
Solvent: OCC(F)(F)F
Solvent: CO
Product: O=C(Nc1cn(CC(=O)N2C[C@H]3CN(CC4CC4)C[C@H]3C2)nc1-c1cc(Cl)ccc1OC(F)F)c1cnn2cccnc12
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a solution of cis-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid {3-(5-chloro-2-difluoromethoxyphenyl)-1-[2-(hexahydropyrrolo[3,4-c]pyrrol-2-yl)-2-oxoethyl]-1H-pyrazol-4-yl}amide (100 mg, 0.18 mmol) in 2,2,2-trifluoroethanol (3 mL) was added cyclopropanecarbaldehyde (67 μL, 0.90 mmol). After stirring at room temperature for 15 minutes, sodium borohydride (21 mg, 0.54 mmol) was added and the reaction was heated at 90° C. for 2 hours. MeOH was added to quench the reaction and the mixture was loaded onto an SCX-2 cartridge which had been conditioned with MeOH. After flushing with MeOH, the product was eluted with 2M ammonia in MeOH. Evaporation gave a crude product which was purified by HPLC (Method 1). The pure fractions loaded onto an SCX-2 cartridge which had been conditioned with MeOH. After flushing with MeOH, the product was eluted with 2M ammonia in MeOH. Evaporation gave the title compound as a free base which was crystallised from MeOH/Et2O and obtained as a yellow solid (55 mg, 50%). LCMS (Method 5) [M+H]+=611.1, RT=3.02 min. 1H NMR (400 MHz, DMSO-d6) δ: (ppm) 10.94-10.88 (m, 1H), 9.57-9.55 (m, 1H), 8.95-8.92 (m, 1H), 8.38-8.35 (m, 1H), 8.29-8.28 (m, 1H), 7.65-7.61 (m, 1H), 7.56-7.54 (m, 1H), 7.47 (d, 1H, J=8.9 Hz), 7.45-7.07 (m, 1H), 7.08 (d, 1H, J=1.9 Hz), 7.02-6.99 (m, 1H), 5.24-5.07 (m, 2H), 3.86-3.52 (m, 5H), 3.52-3.22 (m, 2H), 3.17-3.11 (m, 1H), 3.07-3.00 (m, 2H), 3.00-2.79 (m, 1H), 1.27-1.01 (m, 1H), 0.63-0.56 (m, 2H), 0.42-0.34 (m, 2H).
Reaction SMILES: C(OC(N1C=CN(C)C(=O)C1)=O)C1C=CC=CC=1.BrC1C=CC=CN=1.CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.C(=O)([O-])[O-].[Cs+].[Cs+].C(OC([N:84]1[CH2:89][CH2:88][N:87]([C:90]2[CH:95]=[CH:94][CH:93]=[CH:92][N:91]=2)[C:86](=[O:96])[CH2:85]1)=O)C1C=CC=CC=1>O1CCOCC1.ClCCl.[OH-].[OH-].[Pd+2].C(O)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[N:91]1[CH:92]=[CH:93][CH:94]=[CH:95][C:90]=1[N:87]1[CH2:88][CH2:89][NH:84][CH2:85][C:86]1=[O:96]
Reactant: O=C(OCc1ccccc1)N1CCN(c2ccccn2)C(=O)C1
Agent: [Pd+2]
Agent: Brc1ccccn1
Agent: CC(=O)[O-]
Solvent: C1COCCO1
Solvent: CCO
Solvent: ClCCl
Product: O=C1CNCCN1c1ccccn1
Temperature: 110 °C
Reaction time: 1 h

Procedure:
A mixture of 4-benzyloxycarbonyl-1-methyl-pyrazin-2(1H)-one (3.0 g, 12.8 mmol), 2-bromopyridine (2.02 g, 12.8 mmol), palladium acetate (0.29 g, 1.28 mmol), xantphos (1.11 g, 1.92 mmol), cesium carbonate (6.26 g, 19.2 mmol) in anhydrous dioxane (13 mL) in a sealed vessel was heated in an oil bath at 110° C. for 6 hrs. The resultant reaction mixture was cooled to room temperature, diluted with dichloromethane, filtered, and concentrated under vacuum. The residual solid was subjected to column chromatography on silica gel eluting with a ethyl acetate-hexane gradient. Concentration of appropriate fractions provide the pyridine intermediate. A mixture of 4-benzyloxycarbonyl-1-pyridin-2-ylpiperazin-2-one (1.50 g, 4.94 mmol) and Pearlmans catalyst (0.7 g) in ethanol (50 mL) was stirred under an atmosphere of hydrogen (1 atm) at room temperature for one hour. The product mixture was filtered through a pad of Celite, and concentrated under vacuum to provide the titled compound.
Reaction SMILES: [CH2:1]([C:4]1[CH:16]=[CH:15][CH:14]=[CH:13][C:5]=1[O:6][CH:7]([CH2:11][CH3:12])[C:8]([OH:10])=[O:9])[CH:2]=[CH2:3].[Si:17]([O:24][C@H:25]1[CH2:34][C@H:33](O)[C@H:32]2[C:27]([CH:28]=[CH:29][C@H:30]([CH3:53])[C@@H:31]2[CH2:36][CH2:37][C@H:38]2[O:43][C:42](=[O:44])[CH2:41][C@H:40]([O:45][Si:46]([C:49]([CH3:52])([CH3:51])[CH3:50])([CH3:48])[CH3:47])[CH2:39]2)=[CH:26]1)([C:20]([CH3:23])([CH3:22])[CH3:21])([CH3:19])[CH3:18]>>[Si:17]([O:24][C@H:25]1[CH2:34][C@H:33]([O:9][C:8](=[O:10])[CH:7]([O:6][C:5]2[CH:13]=[CH:14][CH:15]=[CH:16][C:4]=2[CH2:1][CH:2]=[CH2:3])[CH2:11][CH3:12])[C@H:32]2[C:27]([CH:28]=[CH:29][C@H:30]([CH3:53])[C@@H:31]2[CH2:36][CH2:37][C@H:38]2[O:43][C:42](=[O:44])[CH2:41][C@H:40]([O:45][Si:46]([C:49]([CH3:52])([CH3:51])[CH3:50])([CH3:47])[CH3:48])[CH2:39]2)=[CH:26]1)([C:20]([CH3:21])([CH3:22])[CH3:23])([CH3:19])[CH3:18]
Reactant: C=CCc1ccccc1OC(CC)C(=O)O
Reactant: C[C@H]1C=CC2=C[C@@H](O[Si](C)(C)C(C)(C)C)C[C@H](O)[C@@H]2[C@H]1CC[C@@H]1C[C@@H](O[Si](C)(C)C(C)(C)C)CC(=O)O1
Product: C=CCc1ccccc1OC(CC)C(=O)O[C@H]1C[C@H](O[Si](C)(C)C(C)(C)C)C=C2C=C[C@H](C)[C@H](CC[C@@H]3C[C@@H](O[Si](C)(C)C(C)(C)C)CC(=O)O3)[C@H]21
Yield: 95.1 %

Procedure:
A procedure similar to that described in Example 1, above, was followed, but using 0.80 g of (2RS)-2-(2-allylphenoxy)butyric acid and 1.0 g of (4R,6R)-6-{(1S,2S,6S,8S,8aR)-2-[1,2,6,7,8,8a-hexahydro-6-t-butyldimethylsilyloxy-8-hydroxy-2-methyl-1-naphthyl]ethyl}tetrahydro-4-t-butyldimethylsilyloxy-2H-pyran-2-one [prepared as described in Example B, above], to give 1.30 g of the title compound as a colorless foam.
Reaction SMILES: [NH2:1][C:2]1[CH:38]=[CH:37][C:5]([CH:6]=[CH:7][C:8]([NH:10][CH2:11][C:12]([N:14]([C:16]2[C:17]([Cl:36])=[C:18]([C:32]([Cl:35])=[CH:33][CH:34]=2)[CH2:19][O:20][C:21]2[CH:22]=[CH:23][CH:24]=[C:25]3[C:30]=2[N:29]=[C:28]([CH3:31])[CH:27]=[CH:26]3)[CH3:15])=[O:13])=[O:9])=[CH:4][C:3]=1[CH3:39].C(N(CC)CC)C.[CH3:47][S:48](Cl)(=[O:50])=[O:49]>ClCCl>[Cl:36][C:17]1[C:16]([N:14]([C:12](=[O:13])[CH2:11][NH:10][C:8](=[O:9])[CH:7]=[CH:6][C:5]2[CH:37]=[CH:38][C:2]([NH:1][S:48]([CH3:47])(=[O:50])=[O:49])=[C:3]([CH3:39])[CH:4]=2)[CH3:15])=[CH:34][CH:33]=[C:32]([Cl:35])[C:18]=1[CH2:19][O:20][C:21]1[CH:22]=[CH:23][CH:24]=[C:25]2[C:30]=1[N:29]=[C:28]([CH3:31])[CH:27]=[CH:26]2
Reactant: Cc1ccc2cccc(OCc3c(Cl)ccc(N(C)C(=O)CNC(=O)C=Cc4ccc(N)c(C)c4)c3Cl)c2n1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1ccc2cccc(OCc3c(Cl)ccc(N(C)C(=O)CNC(=O)C=Cc4ccc(NS(C)(=O)=O)c(C)c4)c3Cl)c2n1
Reaction time: 1 h

Procedure:
To a solution of 8-[3-[N-(4-amino-3-methylcinnamoylglycyl)-N-methylamino]-2,6-dichlorobenzyloxy]-2-methylquinoline (200 mg) and triethylamine (35.9 mg) in dichloromethane was dropwise added methanesulfonyl chloride (0.03 ml) at 0° C. under nitrogen atmosphere, and the mixture was stirred for 1 hour at the same temperature. Methanesulfonyl chloride (0.03 ml) and triethylamine (36 mg) were further added thereto, and the mixture was stirred for 1 hour at the same temperature. The solvent was removed in vacuo, and the residue was dissolved in methanol. To the solution was added 1N sodium hydroxide solution (0.5 ml), and the mixture was stirred for 3 hours at ambient temperature and concentrated. To the residue were added dichloromethane and water, the organic layer was washed with water, saturated sodium bicarbonate solution and brine, dried and concentrated in vacuo. The residue was purified by preparative thin-layer chromatography (dichloromethane:methanol=15:1, V/V) to give 8-[2,6-dichloro-3-[N-(4-methanesulfonamido-3-methylcinnamoylglycyl)-N-methylamino]benzyloxy]-2-methylquinoline (185 mg) as an amorphous powder.
Reaction SMILES: [F:1][C:2]([F:35])([F:34])[C:3]1[CH:4]=[C:5]([CH:27]=[C:28]([C:30]([F:33])([F:32])[F:31])[CH:29]=1)[C:6]([N:8]1[CH2:26][CH2:25][C:11]2([N:15]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[CH3:22])[C:14](=[O:23])[NH:13][C:12]2=[O:24])[CH2:10][CH2:9]1)=[O:7].O[CH2:37][CH2:38][N:39]1[CH2:44][CH2:43][O:42][CH2:41][CH2:40]1>>[F:35][C:2]([F:1])([F:34])[C:3]1[CH:4]=[C:5]([CH:27]=[C:28]([C:30]([F:33])([F:32])[F:31])[CH:29]=1)[C:6]([N:8]1[CH2:26][CH2:25][C:11]2([N:15]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[CH3:22])[C:14](=[O:23])[N:13]([CH2:37][CH2:38][N:39]3[CH2:44][CH2:43][O:42][CH2:41][CH2:40]3)[C:12]2=[O:24])[CH2:10][CH2:9]1)=[O:7]
Reactant: OCCN1CCOCC1
Reactant: Cc1ccccc1N1C(=O)NC(=O)C12CCN(C(=O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1)CC2
Product: Cc1ccccc1N1C(=O)N(CCN2CCOCC2)C(=O)C12CCN(C(=O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1)CC2

Procedure:
The title compound, MS: m/e=613.1 (M+), was prepared in accordance with the general method of example 121 from 8-(3,5-bis-trifluoromethyl-benzoyl)-1-o-tolyl-1,3,8-triaza-spiro[4.5]decane-2,4-dione and N-(2-hydroxyethyl)morpholine.