Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]2[CH:8]=[CH:9][S:10][C:5]2=[CH:4][CH:3]=1.C(NC(C)C)(C)C.[Li]CCCC.[Cl:23]N1C(=O)CCC1=O.[NH4+].[Cl-]>C1COCC1>[Cl:23][C:9]1[S:10][C:5]2[C:6](=[N:7][C:2]([CH3:1])=[CH:3][CH:4]=2)[CH:8]=1
Reactant: O=C1CCC(=O)N1Cl
Reactant: Cc1ccc2sccc2n1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: Cc1ccc2sc(Cl)cc2n1
Temperature: -78 °C
Reaction time: 0.33 h
Yield: 81.7 %

Procedure:
To a solution 5-methylthieno[3,2-b]pyridine (3.60 g, 24 mmol) and N,N-diisopropylamine (100 uL) in THF (80 mL) at -78° C. was added dropwise 16 mL of n-BuLi (1.6M, 25.6 mmol). The mixture was stirred at -78° C. for 20 min and then transfered via a cannula to a solution of N-chlorosuccinimide (4.5 g, 34 mmol) in THF (300 mL) at -10° C. The mixture was stirred at -10° C. for 30 min. Saturated NH4Cl solution was then added and the product was extracted with EtOAc, dried over MgSO4, and concentrated to an oil. Chromatography of the crude oil on silica gel (eluted with 15% EtOAc in hexane) yielded 3.60 g (81%) of the title compound.
Reaction SMILES: [CH2:1]([N:8]([CH2:12][C:13]1[C:18](Cl)=[N:17][C:16]([N:20]([CH2:22][CH:23]2[CH2:25][CH2:24]2)[CH3:21])=[CH:15][N:14]=1)[CH2:9][CH2:10][OH:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CC(C)([O-])C.[K+].O>CN(C=O)C>[CH2:1]([N:8]1[CH2:12][C:13]2[N:14]=[CH:15][C:16]([N:20]([CH2:22][CH:23]3[CH2:25][CH2:24]3)[CH3:21])=[N:17][C:18]=2[O:11][CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CN(CC1CC1)c1cnc(CN(CCO)Cc2ccccc2)c(Cl)n1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CN(CC1CC1)c1cnc2c(n1)OCCN(Cc1ccccc1)C2
Reaction time: 2.5 h
Yield: 80.1 %

Procedure:
To a solution of 2-[benzyl({3-chloro-5-[(cyclopropylmethyl)(methyl)amino]pyrazin-2-yl}methyl)amino]ethanol (0.50 g) in DMF (3 mL) was added potassium tert-butoxide (0.19 g) at 0° C., and the mixture was stirred for 2.5 hr. Water (10 mL) was added, and the mixture was extracted with ethyl acetate. The aqueous layer was extracted again with ethyl acetate. The combined organic layer was washed with water and saturated brine, dried over magnesium sulfate, and concentrated. The residue was purified by silica gel column chromatography (solvent gradient: 10-*40% ethyl acetate/hexane) to give the title compound (0.36 g, 79%) as a pale-yellow oil.
Reaction SMILES: [F:1][C:2]([F:35])([F:34])[CH2:3][NH:4][C:5]([NH:7][C:8]1[CH:9]=[C:10]([N:14]2[C:18]3[CH:19]=[CH:20][C:21]([C:23]4[CH:28]=[CH:27][C:26]([CH:29]([CH3:33])[C:30](O)=[O:31])=[CH:25][CH:24]=4)=[CH:22][C:17]=3[N:16]=[CH:15]2)[CH:11]=[CH:12][CH:13]=1)=[O:6].[CH:36]1([CH2:39][NH2:40])[CH2:38][CH2:37]1>>[CH:36]1([CH2:39][NH:40][C:30](=[O:31])[CH:29]([C:26]2[CH:25]=[CH:24][C:23]([C:21]3[CH:20]=[CH:19][C:18]4[N:14]([C:10]5[CH:11]=[CH:12][CH:13]=[C:8]([NH:7][C:5]([NH:4][CH2:3][C:2]([F:35])([F:34])[F:1])=[O:6])[CH:9]=5)[CH:15]=[N:16][C:17]=4[CH:22]=3)=[CH:28][CH:27]=2)[CH3:33])[CH2:38][CH2:37]1
Reactant: NCC1CC1
Reactant: CC(C(=O)O)c1ccc(-c2ccc3c(c2)ncn3-c2cccc(NC(=O)NCC(F)(F)F)c2)cc1
Product: CC(C(=O)NCC1CC1)c1ccc(-c2ccc3c(c2)ncn3-c2cccc(NC(=O)NCC(F)(F)F)c2)cc1

Procedure:
This compound was prepared by using procedures analogous to those described for the synthesis of Example 14 starting from 2-(4-{1-[3-({[(2,2,2-trifluoro ethyl)amino]carbonyl}amino)phenyl]-1H-benzimidazol-5-yl}phenyl)propanoic acid (prepared by the procedure for Example 14, step 3) and cyclopropylmethylamine (Aldrich, Cat. No. 359521), LCMS (M+H)+: m/z=536.2.
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][C:13]=1[O:14][CH3:15])[C:10](=[CH:16][C:17]1[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[C:19]([O:25][CH3:26])[CH:18]=1)[NH:9][CH2:8][CH2:7]2.N1C=CC=CC=1.[CH:33]1([C:36](Cl)=[O:37])[CH2:35][CH2:34]1>O>[CH:33]1([C:36]([N:9]2[CH2:8][CH2:7][C:6]3[C:11](=[CH:12][C:13]([O:14][CH3:15])=[C:4]([O:3][CH3:2])[CH:5]=3)/[C:10]/2=[CH:16]/[C:17]2[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[C:19]([O:25][CH3:26])[CH:18]=2)=[O:37])[CH2:35][CH2:34]1
Reactant: O=C(Cl)C1CC1
Reactant: COc1ccc(C=C2NCCc3cc(OC)c(OC)cc32)cc1OC
Agent: Cl
Solvent: c1ccncc1
Solvent: O
Product: COc1ccc(/C=C2/c3cc(OC)c(OC)cc3CCN2C(=O)C2CC2)cc1OC

Procedure:
To a suspension of 6 parts of 3,4-dihydro-6,7-dimethoxy-1-[(3,4-dimethoxyphenyl)methylene]isoquinoline hydrochloride in 40 parts of pyridine is added 6 parts of cyclopropanecarbonyl chloride. The resultant mixture is stirred at room temperatures for 18 hours, then poured into 500 parts of water. The mixture thus obtained is extracted with chloroform. The chloroform extract is washed with 5% hydrochloric acid, dried over anhydrous sodium sulfate, and stripped of solvent by vacuum distillation. The residue is crystallized from a mixture of ethyl acetate and dichloromethane to give (Z)-2-cyclopropylcarbonyl-1,2,3,4-tetrahydro-6,7-dimethoxy-1-[(3,4-dimethoxyphenyl)methylene]isoquinoline melting at 148°-151°.
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1.C([Li])CCC.[CH:15](=[O:22])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>O1CCCC1>[S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[CH:15]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[OH:22]
Reactant: O=Cc1ccccc1
Reactant: c1ccc2scnc2c1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: OC(c1ccccc1)c1nc2ccccc2s1
Temperature: -20 °C
Reaction time: 0.25 h

Procedure:
A solution of benzothiazole (1.35 g) in tetrahydrofurane (10 mL) in a dried round bottom baloon is cooled at −70° C. A solution of butyl lithium (4.1 mL) is added and the mixture stirred for 15 minutes. Benzaldehyde (1.03 mL) diluted with tetrahydrofurane (10 mL) is then added. The mixture is stirred at −70° C. for 1 h, allowed to warm to −20° C. and quenched with saturated aqueous ammonium chloride solution. The mixture is extracted with ethyl acetate. Organic extracts are pooled, dried over magnesium sulfate and concentrated under reduced pressure. Trituration of the residue with diisopropyl oxyde affords benzothiazol-2-ylphenylmethanol.
Reaction SMILES: [CH2:1]([C:3]1[C:4]([NH2:9])=[N:5][CH:6]=[CH:7][CH:8]=1)[CH3:2].O1CCOCC1.[Br:16]N1C(=O)CCC1=O>O>[Br:16][C:7]1[CH:8]=[C:3]([CH2:1][CH3:2])[C:4]([NH2:9])=[N:5][CH:6]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: CCc1cccnc1N
Solvent: O
Solvent: C1COCCO1
Product: CCc1cc(Br)cnc1N
Reaction time: 1.5 h
Yield: 66.5 %

Procedure:
To a solution prepared by dissolving 360 mg of 3-ethylpyridine-2-amine (synthesized according to the method disclosed in International Publication WO2006/025567, page 142) in a mixed solvent of 12 mL of 1,4-dioxane and 4 mL of water, 553 mg of N-bromosuccinimide was added at 0° C., and the mixture was stirred for 1.5 hours at the same temperature. Water was added to the reaction solution, which was extracted with ethyl acetate. The organic layer thus obtained was washed with water and saturated brine in that order, and dried over anhydrous sodium sulfate. Thereafter, the insolubles were filtered and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: hexane/ethyl acetate=75/25), to obtain 394 mg of 5-bromo-3-ethylpyridine-2-amine [33-1] (hereinafter, referred to as the compound [33-1]).
Reaction SMILES: [CH3:1][C:2]([C:6]1[CH:11]=[CH:10][C:9]([C:12]2[O:13][CH:14]=[CH:15][CH:16]=2)=[CH:8][CH:7]=1)([CH3:5])[CH:3]=[CH2:4].C1C[O:20]CC1.[OH-].[Na+].OO>CCOCC>[O:13]1[CH:14]=[CH:15][CH:16]=[C:12]1[C:9]1[CH:10]=[CH:11][C:6]([C:2]([CH3:1])([CH3:5])[CH2:3][CH2:4][OH:20])=[CH:7][CH:8]=1
Reactant: C=CC(C)(C)c1ccc(-c2ccco2)cc1
Reactant: C1CCOC1
Agent: OO
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Product: CC(C)(CCO)c1ccc(-c2ccco2)cc1
Temperature: 20 °C
Reaction time: 1 h

Procedure:
To a cooled solution (0° C.) of 2-[4-(1,1-dimethyl-allyl)-phenyl]-furan (424 mg, 2 mmol) (reference example 51)in THF (4 mL) is added dropwise (1M)borane-THF complex (2.2 mL, 2.2 mmol) and the resulting mixture stirred for 1 hour. To the mixture is added 10% NaOH (1.5 mL) and 30 wt % H2O2 (1.5 mL) and stirred for 1 hour while allowing to warm to 20° C. The mixture is diluted with ether, washed with water and brine, dried over MgSO4 and concentrated. The residue is purified by flash chromatography (eluting with 25% ethyl acetate in hexanes) to give 341 mg of the title compound. 1H NMR (CDCl3) δ 1.34 (s, 6H), 1.40 (m, 1H), 1.94 (t, J=8 Hz, 2H), 3.48 (t, J=8 Hz, 2H), 6.45 (m, 1H), 6.60 (m, 1H), 7.35 (d, J=8 Hz, 2H), 7.44 (bs, 1H), 6.61 (d, J=8 Hz, 2H). MS (EI) m/z 230 (M+).
Reaction SMILES: [C:1]1(=[O:7])[CH2:6][CH2:5][CH2:4][CH:3]=[CH:2]1.[C:8]([O:16][CH2:17][CH3:18])(=[O:15])[CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11]>CC(O)(C)C>[CH2:17]([O:16][C:8]([CH:9]([C:10]([O:12][CH2:13][CH3:14])=[O:11])[C@@H:3]1[CH2:4][CH2:5][CH2:6][C:1](=[O:7])[CH2:2]1)=[O:15])[CH3:18]
Reactant: O=C1C=CCCC1
Reactant: CCOC(=O)CC(=O)OCC
Solvent: CC(C)(C)O
Product: CCOC(=O)C(C(=O)OCC)[C@@H]1CCCC(=O)C1
Temperature: 30 °C
Reaction time: 48 h
Yield: 79.8 %

Procedure:
Under an atmosphere of argon, 24.0 mg (0.04 mmol, S/C=50) of Ru[(S,S)-Tsdpen](p-cymene), 194 μL (2.0 mmol) of 2-cyclohexenone, 304 μL (2.0 mmol) of diethyl malonate, and 2 mL of 2-methyl-2-propanol were placed in a 20 mL Schlenk tube and stirred at 30° C. for 48 hours. This solution was purified by flash column chromatography (hexane/acetone=90/10, SiO2) to give 409 mg (80% yield) of the title compound. After this was converted into an ethylene ketal derivative as shown in Example 3, the optical purity was measured by HPLC (CHIRALCEL OD manufactured by Daicel Chemical Industries, Ltd., hexane: 2-propanol=97:3, flow rate 0.5 mL/min, detection at 210 nm) and it was found to be 61% ee.
Reaction SMILES: [NH2:1][C:2]([CH3:16])([CH3:15])[CH2:3][O:4][C:5]1[CH:13]=[C:9]([C:10]([NH2:12])=[O:11])[C:8]([OH:14])=[CH:7][CH:6]=1.[O:17]1[CH2:29][CH:18]1[CH2:19][O:20][C:21]1[CH:28]=[CH:27][CH:26]=[CH:25][C:22]=1[C:23]#[N:24]>O1CCOCC1>[C:10]([C:9]1[CH:13]=[C:5]([CH:6]=[CH:7][C:8]=1[OH:14])[O:4][CH2:3][C:2]([NH:1][CH2:29][CH:18]([OH:17])[CH2:19][O:20][C:21]1[CH:28]=[CH:27][CH:26]=[CH:25][C:22]=1[C:23]#[N:24])([CH3:16])[CH3:15])(=[O:11])[NH2:12]
Reactant: CC(C)(N)COc1ccc(O)c(C(N)=O)c1
Reactant: N#Cc1ccccc1OCC1CO1
Solvent: C1COCCO1
Product: CC(C)(COc1ccc(O)c(C(N)=O)c1)NCC(O)COc1ccccc1C#N

Procedure:
The solution of 2.24 g of 5-(2-amino-2-methylpropoxy)salicylamide in 30 ml of dioxan is refluxed for 7 hours after the addition of 2.3 g of 2-(2,3-epoxypropoxy)-benzonitrile, and then concentrated by evaporation. The residue is divided between 10 ml of 2N hydrochloric acid and 100 ml of ethyl acetate. The acidic aqueous phase is rendered alkaline with concentrated ammonia solution, the base is extracted with ethyl acetate and the solvent is evaporated off, whereupon an oil is obtained from which, by crystallisation from isopropanol and recrystallisation from ethyl acetate, 1-[2-(3-carbamoyl-4-hydroxyphenoxy)-1,1-dimethylethylamino]-3-(2-cyanophenoxy)propan-2-ol having a melting point of 125°-126° is obtained.
Reaction SMILES: CC(O[CH2:5][C:6]1[CH2:15][S:14][C@@H:9]2[C@H:10]([NH2:13])[C:11](=[O:12])[N:8]2[C:7]=1[C:16]([OH:18])=[O:17])=O.C(=O)(O)[O-].[Na+].[SH:24][C:25]1[N:26]2[CH:33]=[CH:32][CH:31]=[CH:30][C:27]2=[N:28][N:29]=1.Cl>O.CC(C)=O>[NH2:13][CH:10]1[C:11](=[O:12])[N:8]2[C:7]([C:16]([OH:18])=[O:17])=[C:6]([CH2:5][S:24][C:25]3[N:26]4[CH:33]=[CH:32][CH:31]=[CH:30][C:27]4=[N:28][N:29]=3)[CH2:15][S:14][C@H:9]12
Reactant: CC(=O)OCC1=C(C(=O)O)N2C(=O)[C@@H](N)[C@H]2SC1
Reactant: Sc1nnc2ccccn12
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CC(C)=O
Product: NC1C(=O)N2C(C(=O)O)=C(CSc3nnc4ccccn34)CS[C@H]12
Temperature: 50 °C
Reaction time: 0.17 h
Yield: 63.6 %

Procedure:
2.72 g (0.01 mol) of 7-aminocephalosporanic acid was suspended in 18 ml of water, and a suspension of 2.1 g (0.025 mol) of sodium bicarbonate in 20 ml of water was added dropwise thereto over a period of time of 10 minutes. The inside temperature of the reactor was then increased to 50° C., and a suspension of 1.81 g (0.0125 mol) of 3-mercaptopyrido[2,1-c]-s-triazole in 35 ml of acetone was added dropwise thereto over a period of time of 10 minutes. The resulting mixture was refluxed for 4 hours at a stable inside temperature of the reactor of 63° C. followed by ice cooling the mixture. After the inside temperature of the reactor reached 4° C., the mixture was adjusted to a pH of 3.6 with 6 N hydrochloric acid. One hour after the stirring, the precipitated crystals were filtered and dried over phosphorus pentoxide under reduced pressure to obtain 2.31 g (yield: 61%) of the tilted compound having a melting point (decomposition) of 173° to 175° C.
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]([C:7]([O:9][CH3:10])=[O:8])[NH:5][CH:6]=1.I[CH2:12][CH2:13][CH3:14]>>[CH2:12]([N:5]1[CH:6]=[C:2]([I:1])[CH:3]=[C:4]1[C:7]([O:9][CH3:10])=[O:8])[CH2:13][CH3:14]
Reactant: CCCI
Reactant: COC(=O)c1cc(I)c[nH]1
Product: CCCn1cc(I)cc1C(=O)OC
Yield: 64.7 %

Procedure:
Following the basic procedure of Example 7(d), by reacting 1.96 g (7.8 mmol) of methyl 4-iodo-2-pyrrolecarboxylate with 940 μl (9.6 mmol) of 3-iodopropane, 1.48 g (64%) of methyl N-propyl-4-iodo-2-pyrrolecarboxylate was obtained in the form of a slightly yellow oil.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][C:4]2([CH2:11][CH2:10][C:9]3[CH:12]=[CH:13][CH:14]=[CH:15][C:8]=3[O:7]2)[CH2:3][CH2:2]1.[CH3:16][C:17]([CH3:43])([O:19][C:20]([NH:22][C:23]([CH3:42])([CH3:41])[C:24]([NH:26][C@H:27]([CH2:31][C:32]1[C:40]2[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=2)[NH:34][CH:33]=1)[C:28](O)=[O:29])=[O:25])=[O:21])[CH3:18]>>[N:1]1([C:28]([C@H:27]([NH:26][C:24](=[O:25])[C:23]([NH:22][C:20]([O:19][C:17]([CH3:43])([CH3:18])[CH3:16])=[O:21])([CH3:42])[CH3:41])[CH2:31][C:32]2[C:40]3[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=3)[NH:34][CH:33]=2)=[O:29])[CH2:6][CH2:5][C:4]2([CH2:11][CH2:10][C:9]3[CH:12]=[CH:13][CH:14]=[CH:15][C:8]=3[O:7]2)[CH2:3][CH2:2]1
Reactant: c1ccc2c(c1)CCC1(CCNCC1)O2
Reactant: CC(C)(C)OC(=O)NC(C)(C)C(=O)N[C@H](Cc1c[nH]c2ccccc12)C(=O)O
Product: CC(C)(C)OC(=O)NC(C)(C)C(=O)N[C@H](Cc1c[nH]c2ccccc12)C(=O)N1CCC2(CCc3ccccc3O2)CC1

Procedure:
This intermediate was prepared from the product of Step A and α(R)-[[2-[[(1,1-dimethylethoxy)carbonyl]amino]-2,2-dimethyl-1-oxoethyl]amino]-1H-indole-3-propanoic acid following standard peptide coupling methods.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([CH2:8][N:9]2[C:17]3[C:12](=[C:13]([N+:18]([O-])=O)[CH:14]=[CH:15][CH:16]=3)[C:11]([CH:21]=[CH2:22])=[N:10]2)[CH:5]=[CH:4][CH:3]=1>CCO.C(Cl)Cl.[OH-].[Pd+2].[OH-]>[CH2:21]([C:11]1[C:12]2[C:13]([NH2:18])=[CH:14][CH:15]=[CH:16][C:17]=2[N:9]([CH2:8][C:6]2[CH:5]=[CH:4][CH:3]=[C:2]([CH3:1])[N:7]=2)[N:10]=1)[CH3:22]
Reactant: C=Cc1nn(Cc2cccc(C)n2)c2cccc([N+](=O)[O-])c12
Agent: [Pd+2]
Agent: [OH-]
Solvent: ClCCl
Solvent: CCO
Product: CCc1nn(Cc2cccc(C)n2)c2cccc(N)c12
Reaction time: 2 h
Yield: 87.8 %

Procedure:
To 1-((6-methylpyridin-2-yl)methyl)-4-nitro-3-vinyl-1H-indazole (28.2 g, 95.8 mmol, Example 5, step C) in EtOH/DCM (300 mL/10 mL) was added palladium hydroxide (15 g, 20% wt). The reaction was purged with N2 and charged with hydrogen to 45 psi. The reaction was recharged during the reaction to 45 psi 4-5 times for the first 30 minutes. After 2 hours, the reaction was stopped, filtered through Celite, and the filter pad was washed with MeOH/DCM/Et3N (1 L, 10:1:1). The filtrate was concentrated and silica gel chromatography (EtOAc/hexanes 1:3) to provide the desired product (22.4 g).
Reaction SMILES: [NH2:1][C:2]1[C:24]([Cl:25])=[CH:23][C:5]([C:6]([NH:8][CH2:9][CH:10]2[O:15][CH2:14][CH2:13][N:12](CC3C=CC=CC=3)[CH2:11]2)=[O:7])=[C:4]([O:26][CH3:27])[CH:3]=1.C(O)C>[Pd].C(O)(=O)C>[NH2:1][C:2]1[C:24]([Cl:25])=[CH:23][C:5]([C:6]([NH:8][CH2:9][CH:10]2[O:15][CH2:14][CH2:13][NH:12][CH2:11]2)=[O:7])=[C:4]([O:26][CH3:27])[CH:3]=1
Reactant: COc1cc(N)c(Cl)cc1C(=O)NCC1CN(Cc2ccccc2)CCO1
Agent: [Pd]
Solvent: CC(=O)O
Solvent: CCO
Product: COc1cc(N)c(Cl)cc1C(=O)NCC1CNCCO1
Yield: 98.8 %

Procedure:
A mixture of 4-amino-N-[(4-benzyl-2-morpholinyl)methyl]-5-chloro-2-methoxybenzamide (5.0 g), ethanol (100 ml), and acetic acid (20 ml) is hydrogenated over 10% palladium on carbon (0.5 g) at 25° C. After the calculated amount of hydrogen is absorbed, the catalyst is filtered off. The filtrate is evaporated under reduced pressure to give the title compound (3.8 g).
Reaction SMILES: [O:1]=[C:2]([NH:17][C@@H:18]1[CH2:22][CH2:21][N:20]([CH:23]2[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]2)[CH2:19]1)[CH2:3][NH:4][C:5](=[O:16])[C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([C:12]([F:15])([F:14])[F:13])[CH:7]=1.C(N(CC)CC)C.[C:36](Cl)(=[O:46])[O:37][CH2:38][C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][C:40]=1[Cl:45]>C(Cl)Cl>[F:13][C:12]([F:15])([F:14])[C:8]1[CH:7]=[C:6]([CH:11]=[CH:10][CH:9]=1)[C:5]([NH:4][CH2:3][C:2]([NH:17][C@@H:18]1[CH2:22][CH2:21][N:20]([CH:23]2[CH2:24][CH2:25][N:26]([C:36]([O:37][CH2:38][C:39]3[CH:44]=[CH:43][CH:42]=[CH:41][C:40]=3[Cl:45])=[O:46])[CH2:27][CH2:28]2)[CH2:19]1)=[O:1])=[O:16]
Reactant: O=C(Cl)OCc1ccccc1Cl
Reactant: O=C(CNC(=O)c1cccc(C(F)(F)F)c1)N[C@@H]1CCN(C2CCNCC2)C1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(CNC(=O)c1cccc(C(F)(F)F)c1)N[C@@H]1CCN(C2CCN(C(=O)OCc3ccccc3Cl)CC2)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 38.6 %

Procedure:
To a solution of N-(2-oxo-2-{[(3R)-1-piperidin-4-ylpyrrolidin-3-yl]amino}ethyl)-3-(trifluoromethyl)benzamide (50 mg, 0.16 mmol) in CH2Cl2 (5 mL) was added triethylamine (24 mg, 0.24 mmol) followed by 2-chlorobenzyl carbonochloridate (49 uL, 0.24 mmol). The mixture was stirred at room temperature overnight. The reaction mixture was concentrated under reduced pressure, then to the slurry was added NaHCO3 (sat. aq., 10 mL) and ethyl acetate (10 mL). The aqueous layer was separated and the organic layer was washed with brine (10 mL). The organic layer was dried over Na2SO4, filtered and concentrated. The resulting crude product was subjected to flash chromatography (15% MeOH, 1% NH4OH in EtOAc) to afford 2-Chlorobenzyl 4-{(3R)-3-[({[3-(trifluoromethyl)benzoyl]amino}acetyl)amino]pyrrolidin-1-yl}piperidine-1-carboxylate (35 mg, 38%) as a white solid. 1H-NMR (CDCl3) δ: 1.30-1.43 (m, 2H), 1.56-1.64 (m, 1H), 1.69-1.74 (b, 2H), 2.14-2.35 (m, 3H), 2.56-2.68 (m, 2H), 2.86-2.88 (m, 3H), 4.01-4.06 (m, 4H), 4.40-4.42 (m, 1H), 5.16 (s, 2H), 6.50 (d, J=7.5 Hz, 2H), 7.18-7.22 (m, 4H), 7.30-7.34 (r, 2H), 7.50 (t, J=8.1 Hz, 1H), 7.70 (d, J=7.5 Hz, 1H), 7.94 (d, J=7.5 Hz, 1H), 8.03 (s, 1H). MS m/z: 567 (M+1).
Reaction SMILES: [C:1]([O:9][CH:10]1[C:18]2[C:13](=[CH:14][CH:15]=[C:16]([CH3:19])[CH:17]=2)[N:12]([CH2:20][CH3:21])[C:11]1=[O:22])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:23]C1C=C2C(=CC=1)N(CCC)C(=O)C2=O>>[C:1]([O:9][CH:10]1[C:18]2[C:13](=[CH:14][CH:15]=[C:16]([CH3:19])[CH:17]=2)[N:12]([CH2:20][CH2:21][CH3:23])[C:11]1=[O:22])(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCCN1C(=O)C(=O)c2cc(C)ccc21
Reactant: CCN1C(=O)C(OC(=O)c2ccccc2)c2cc(C)ccc21
Product: CCCN1C(=O)C(OC(=O)c2ccccc2)c2cc(C)ccc21

Procedure:
Was made in an analogous fashion to 1-ethyl-5-methyl-2-oxoindolin-3-yl benzoate using 5-methyl-1-propylindoline-2,3-dione. 1H NMR δ 8.13 (dd, 2H), 7.60 (t, 1H), 7.46 (dd, 2H), 7.27 (s, 1H), 7.17 (dd, 1H), 6.80 (d, 1H), 6.19 (s, 1H), 3.74 (m, 2H), 2.33 (s, 3H), 1.80 (m, 2H), 1.04 (t, 3H).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:16]=[CH:17][CH:18]=1)[O:12][CH2:13][CH2:14][OH:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[S:19](Cl)(=[O:22])(=[O:21])[NH2:20].C(N(CC)CC)C>C(#N)C>[C:2]1([CH2:1][O:8][C:9]2[CH:10]=[C:11]([CH:16]=[CH:17][CH:18]=2)[O:12][CH2:13][CH2:14][O:15][S:19](=[O:22])(=[O:21])[NH2:20])[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: OCCOc1cccc(OCc2ccccc2)c1
Reactant: NS(=O)(=O)Cl
Solvent: CC#N
Solvent: CCN(CC)CC
Product: NS(=O)(=O)OCCOc1cccc(OCc2ccccc2)c1
Yield: 44.3 %

Procedure:
This compound was prepared according to the procedure used in Example 101. Thus, a mixture of 14.7 g (0.06 mole) of 2-(3-benzyloxyphenoxy)ethanol, 17 ml (0.066 mole) of sulfamoyl chloride (3.9M solution in acetonitrile) and 7.0 g (0.069 mole) of triethylamine in 150 ml of acetonitrile gave a viscous, oily residue. The oil was triturated with benzene-petroleum ether (30°-60° C.) and the solid was collected by filtration. The solid was recrystallized from chloroform to yield 8.6 g (44%) of a white solid, mp 107°-109° C.
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7](Cl)=[O:8])=[CH:5][C:4]([CH3:10])=[N:3]1.[NH2:11][C:12]1[CH:13]=[C:14]([CH:31]=[CH:32][C:33]=1[Cl:34])[O:15][C:16]1[CH:17]=[CH:18][C:19]2[N:20]([N:22]=[C:23]([NH:25][C:26]([CH:28]3[CH2:30][CH2:29]3)=[O:27])[N:24]=2)[CH:21]=1>CN(C)C(=O)C>[Cl:34][C:33]1[CH:32]=[CH:31][C:14]([O:15][C:16]2[CH:17]=[CH:18][C:19]3[N:20]([N:22]=[C:23]([NH:25][C:26]([CH:28]4[CH2:30][CH2:29]4)=[O:27])[N:24]=3)[CH:21]=2)=[CH:13][C:12]=1[NH:11][C:7]([C:6]1[N:2]([CH3:1])[N:3]=[C:4]([CH3:10])[CH:5]=1)=[O:8]
Reactant: Nc1cc(Oc2ccc3nc(NC(=O)C4CC4)nn3c2)ccc1Cl
Reactant: Cc1cc(C(=O)Cl)n(C)n1
Solvent: CC(=O)N(C)C
Product: Cc1cc(C(=O)Nc2cc(Oc3ccc4nc(NC(=O)C5CC5)nn4c3)ccc2Cl)n(C)n1
Yield: 40 %

Procedure:
In the same manner as in Example 24 and using 1,3-dimethyl-1H-pyrazole-5-carbonyl chloride (89.2 mg, 0.562 mmol), N,N-dimethylacetamide (5 mL) and N-[6-(3-amino-4-chlorophenoxy)[1,2,4]triazolo[1,5-a]pyridin-2-yl]cyclopropanecarboxamide (170 mg, 0.495 mmol) as starting materials, the title compound (92.2 mg, 40%) was obtained as a white solid.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10]2[C:23](=[O:24])[N:22]([CH2:25][C:26]3[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=3)[CH2:21][CH:20]([C:33]([O:35][CH3:36])=[O:34])[C:11]=2[N:12]2[CH2:17][CH2:16][N:15]([CH3:18])[C:14](=[O:19])[C:13]=12)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>C1(C)C=CC=CC=1.C(Cl)(Cl)Cl.[O-2].[Mn+4].[O-2]>[CH2:1]([O:8][C:9]1[C:10]2[C:23](=[O:24])[N:22]([CH2:25][C:26]3[CH:27]=[CH:28][C:29]([F:32])=[CH:30][CH:31]=3)[CH:21]=[C:20]([C:33]([O:35][CH3:36])=[O:34])[C:11]=2[N:12]2[CH2:17][CH2:16][N:15]([CH3:18])[C:14](=[O:19])[C:13]=12)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)C1CN(Cc2ccc(F)cc2)C(=O)c2c(OCc3ccccc3)c3n(c21)CCN(C)C3=O
Agent: [Mn+4]
Agent: [O-2]
Solvent: Cc1ccccc1
Solvent: ClC(Cl)Cl
Product: COC(=O)c1cn(Cc2ccc(F)cc2)c(=O)c2c(OCc3ccccc3)c3n(c12)CCN(C)C3=O
Temperature: 80 °C

Procedure:
A mixture of methyl 10-(benzyloxy)-2-(4-fluorobenzyl)-8-methyl-1,9-dioxo-1,2,3,4,6,7,8,9-octahydropyrido[3′,4′:4,5]pyrrolo[1,2-a]-pyrazine-4-carboxylate (0.4 g, 0.81 mmol) and manganese(IV) oxide (0.21 g, 2.44 mmol) in toluene (10 mL) was heated in a sealed tube in an oil bath 80° C. overnight. The reaction mixture was cooled to rt, diluted with chloroform (100 mL) and filtered through a pad of Celite. The filtrate was concentrated under vacuum. The filtrate was subjected to column chromatography on silica gel eluting with ethyl acetate. Collection and concentration of appropriate fractions provided the titled compound.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8]([C:12]([OH:14])=[O:13])=[CH:7][CH:6]=[CH:5]2.Cl[C:16]1[CH:21]=[CH:20][N:19]=[C:18]([C:22]([NH2:24])=[O:23])[CH:17]=1>>[C:22]([C:18]1[CH:17]=[C:16]([O:1][C:2]2[CH:3]=[C:4]3[C:9](=[CH:10][CH:11]=2)[C:8]([C:12]([OH:14])=[O:13])=[CH:7][CH:6]=[CH:5]3)[CH:21]=[CH:20][N:19]=1)(=[O:23])[NH2:24]
Reactant: O=C(O)c1cccc2cc(O)ccc12
Reactant: NC(=O)c1cc(Cl)ccn1
Product: NC(=O)c1cc(Oc2ccc3c(C(=O)O)cccc3c2)ccn1

Procedure:
6-Hydroxy-1-napthoic acid (2.5 g, 13 mmol) was reacted with 4-chloropicolinamide (WO 02/085857)(2.6 g, 15 mmol) under the conditions of Example 421 Step a to give the title compound as a brown solid. MS (ESI, pos. ion) m/z: 309.2 (M+1). Mass Calc'd for C17H12N2O4: 308.29.