Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC([N:8]1[CH2:11][CH:10]([N:12]2[CH2:15][C:14]([F:17])([F:16])[CH2:13]2)[CH2:9]1)=O)(C)(C)C>C(Cl)Cl.C(O)(C(F)(F)F)=O>[F:16][C:14]1([F:17])[CH2:15][N:12]([CH:10]2[CH2:11][NH:8][CH2:9]2)[CH2:13]1
Reactant: CC(C)(C)OC(=O)N1CC(N2CC(F)(F)C2)C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: FC1(F)CN(C2CNC2)C1
Temperature: 25 °C
Reaction time: 3 h
Yield: 36.5 %

Procedure:
A 10 mL round-bottomed flask was charged with a solution of 3,3-difluoro-[1,3′]biazetidinyl-1′-carboxylic acid tert-butyl ester (0.15 g, 0.61 mmol) in DCM/TFA (3 mL/3 mL). The reaction mixture was stirred for 3 h at room temperature. The reaction mixture was loaded onto an Isolute® SCX-2 cartridge. The cartridge was washed with MeOH and the desired product was eluted using 2 M NH3 in MeOH to give 3,3-Difluoro-[1,3′]biazetidinyl as a colourless oil (0.033 g, 37%). 1H NMR (300 MHz, CDCl3): δ 3.73-3.55 (m, 8 H), 3.57-3.43 (m, 1 H), 2.77 (s, 1 H)
Reaction SMILES: C(O)(=O)C.[Br:5][C:6]1[S:10][C:9]([NH2:11])=[N:8][CH:7]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[CH:26]1([CH:29]=O)[CH2:28][CH2:27]1>C(Cl)Cl>[Br:5][C:6]1[S:10][C:9]([NH:11][CH2:29][CH:26]2[CH2:28][CH2:27]2)=[N:8][CH:7]=1
Reactant: Nc1ncc(Br)s1
Reactant: O=CC1CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Product: Brc1cnc(NCC2CC2)s1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 74.3 %

Procedure:
Add acetic acid (2 mL, 33.4 mmol) to a mixture of 5-bromo-thiazol-2-ylamine (1 g, 5.6 mmol), sodium triacetoxyborohydride (3.5 g, 16.7 mmol) and cyclopropane carboxaldehyde (820 mg, 11.7 mmol) at room temperature under a nitrogen atmosphere. Stir the resulting solution for 1.5 h at ambient temperature. Dilute the solution with DCM (50 mL) and wash with saturated aqueous NaHCO3 (80 mL). Dry the organic layer over Na2SO4, filter and concentrate in vacuo. Purify the residue by chromatography on silica gel (40 g) eluting with hexane/EtOAc (9:1 to 7:3 gradient) to obtain the title compound (970 mg, 75%). MS (ES+) m/z: 233.1 (M+).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[C:8]1[CH2:13][C:12]([CH3:15])([CH3:14])[CH2:11][CH:10]([N:16]2[C:24](=[O:25])[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[C:17]2=[O:26])[CH:9]=1.[H][H]>C(O)(=O)C.[Pd]>[NH2:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[CH:8]1[CH2:9][CH:10]([N:16]2[C:17](=[O:26])[C:18]3[C:23](=[CH:22][CH:21]=[CH:20][CH:19]=3)[C:24]2=[O:25])[CH2:11][C:12]([CH3:15])([CH3:14])[CH2:13]1
Reactant: [H][H]
Reactant: CC1(C)CC(c2ccncc2N)=CC(N2C(=O)c3ccccc3C2=O)C1
Agent: [Pd]
Solvent: CC(=O)O
Product: CC1(C)CC(c2ccncc2N)CC(N2C(=O)c3ccccc3C2=O)C1
Temperature: 45 °C
Yield: 53 %

Procedure:
A solution of 2-(3-(3-aminopyridin-4-yl)-5,5-dimethylcyclohex-2-enyl)isoindoline-1,3-dione (1.0 eq) in acetic acid (0.1M) was purged with nitrogen for 10 min. Then 10% Pd/C (0.1 eq) was added. The reaction mixture was stirred at 45° C., 300 psi hydrogen atmosphere in a steel bomb overnight and at 65° C., 300 psi for 5 hours. Solids were removed by filtration over celite, then rinsed with EtOAc and MeOH. The filtrate was concentrated, diluted with EtOAc and washed 2× with sat. aq. 2M Na2CO3. The organic layer was dried with MgSO4, filtered, and concentrated. The residue was purified by column (5% methanol in 1:1 ethyl acetate and hexanes) to give 2-(5-(3-aminopyridin-4-yl)-3,3-dimethylcyclohexyl)isoindoline-1,3-dione (53%). LC/MS (m/z): MH+=350.3, Rt=0.78. The enantiomerically pure 2-((1R,5R)-5-(3-aminopyridin-4-yl)-3,3-dimethylcyclohexyl)isoindoline-1,3-dione and 2-((1S,5S)-5-(3-aminopyridin-4-yl)-3,3-dimethylcyclohexyl)isoindoline-1,3-dione were resolved by chiral HPLC (For analysis Rt=7.526 min and 13.105 min respectively; hexanes:ethanol=80:20 (v:v), Chiralcel OJ-H 100×4.6 mm at 1 mL/min. For preparative separation, hexanes:ethanol=80:20 (v:v), Chiralcel OJ-H (250×20 mm at 20 mL/min). 1H NMR (CDCl3): δ 8.04 (s, 1H), 8.00 (d, 1H), 7.82 (m, 2H), 7.71 (m, 2H), 7.06 (d, 1H), 4.54 (m, 1H), 3.71 (m, 2H), 2.89 (m, 1H), 2.23-2.44 (m, 2H), 1.90 (m, 1H), 1.20-1.60 (m, 3H), 1.18 (s, 3H), 1.07 (s, 3H).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:6][CH:7]=[CH:8][C:9]=1[S:10]([OH:13])(=O)=[O:11])=[O:4].S(Cl)([Cl:16])=O>>[CH3:1][O:2][C:3]([C:5]1[S:6][CH:7]=[CH:8][C:9]=1[S:10]([Cl:16])(=[O:13])=[O:11])=[O:4]
Reactant: O=S(Cl)Cl
Reactant: COC(=O)c1sccc1S(=O)(=O)O
Product: COC(=O)c1sccc1S(=O)(=O)Cl

Procedure:
7.4 G of crude 3-sulfothiophene-2-carboxylic acid methyl ester are dissolved in 50 ml. of thionyl chloride and boiled to reflux for 16 hours. The mixture is then evaporated to dryness in vacuo and the remaining bright-yellow oil is brought to crystallization with petroleum ether. There is obtained 3-chlorosulfonylthiophene-2-carboxylic acid methyl ester.
Reaction SMILES: [C:1]([N:5]1[C:9](=[O:10])[CH:8]=[C:7]([C:11]2[CH:16]=[CH:15][C:14]([CH2:17][CH:18]([NH:21][S:22]([C:25]3[CH:30]=[CH:29][CH:28]=[C:27]([C:31]([F:34])([F:33])[F:32])[CH:26]=3)(=[O:24])=[O:23])[C:19]#[N:20])=[CH:13][CH:12]=2)[S:6]1(=[O:36])=[O:35])([CH3:4])([CH3:3])[CH3:2].[ClH:37].[CH2:38]([OH:40])[CH3:39]>C(Cl)Cl>[ClH:37].[CH2:38]([O:40][C:19](=[NH:20])[CH:18]([NH:21][S:22]([C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([C:31]([F:34])([F:32])[F:33])[CH:26]=1)(=[O:24])=[O:23])[CH2:17][C:14]1[CH:13]=[CH:12][C:11]([C:7]2[S:6](=[O:35])(=[O:36])[N:5]([C:1]([CH3:4])([CH3:2])[CH3:3])[C:9](=[O:10])[CH:8]=2)=[CH:16][CH:15]=1)[CH3:39]
Reactant: CC(C)(C)N1C(=O)C=C(c2ccc(CC(C#N)NS(=O)(=O)c3cccc(C(F)(F)F)c3)cc2)S1(=O)=O
Reactant: CCO
Agent: Cl
Solvent: ClCCl
Product: CCOC(=N)C(Cc1ccc(C2=CC(=O)N(C(C)(C)C)S2(=O)=O)cc1)NS(=O)(=O)c1cccc(C(F)(F)F)c1

Procedure:
A solution of 1.37-C of Step 3 (87 mg, 0.16 mmol) in methylene chloride (5 mL) and ethanol (0.2 mL) was treated with HCl gas for 1 h. Additional methylene chloride was added during the reaction to replenish the amount which was evaporated during the bubbling of HCl. The reaction mixture was concentrated and used immediately in the next reaction.
Reaction SMILES: [O:1]1[CH2:5][CH2:4][C@H:3]([O:6][C:7]([O:9]N2C(=O)CCC2=O)=O)[CH2:2]1.Cl.Cl.[CH3:19][C:20]1[N:24]([CH:25]2[CH2:31][CH:30]3[N:32]([CH2:33][CH2:34][C:35]4([C:41]5[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=5)[CH2:40][CH2:39][NH:38][CH2:37][CH2:36]4)[CH:27]([CH2:28][CH2:29]3)[CH2:26]2)[C:23]2[CH:47]=[CH:48][CH:49]=[CH:50][C:22]=2[N:21]=1.C(N(CC)C(C)C)(C)C>C(#N)C>[CH3:19][C:20]1[N:24]([CH:25]2[CH2:31][C@H:30]3[N:32]([CH2:33][CH2:34][C:35]4([C:41]5[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=5)[CH2:36][CH2:37][N:38]([C:7]([O:6][C@H:3]5[CH2:4][CH2:5][O:1][CH2:2]5)=[O:9])[CH2:39][CH2:40]4)[C@H:27]([CH2:28][CH2:29]3)[CH2:26]2)[C:23]2[CH:47]=[CH:48][CH:49]=[CH:50][C:22]=2[N:21]=1
Reactant: O=C(O[C@H]1CCOC1)ON1C(=O)CCC1=O
Reactant: Cc1nc2ccccc2n1C1CC2CCC(C1)N2CCC1(c2ccccc2)CCNCC1
Agent: Cl
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: Cc1nc2ccccc2n1C1C[C@H]2CC[C@@H](C1)N2CCC1(c2ccccc2)CCN(C(=O)O[C@H]2CCOC2)CC1

Procedure:
A solution of 1-({[(3S)-tetrahydrofuran-3-yloxy]carbonyl}oxy)pyrrolidine-2,5-dione (U.S. Pat. No. 6,344,465) (55 mg, 0.24 mmol), amine dihydrochloride II (100 mg, 0.199 mmol) and N,N-diisopropylethylamine (0.14 mL, 0.80 mmol) in acetonitrile (3 mL) was stirred overnight at rt. The solvent was removed at reduced pressure and the remaining material was dissolved in dichloromethane, washed with saturated sodium bicarbonate solution and dried over magnesium sulfate. Filtration and evaporation of the dichloromethane solution provided the crude product which was purified by chromatography on silica gel eluting with 5% methanol/dichloromethane. Title compound in example 692 was obtained as a white hygroscopic powder (70 mg, 65%). 1H NMR (400 MHz, CDCl3) δ 7.66 (d, 1H, J=8 Hz), 7.37 (m, 2H), 7.30-7.20 (m, 4H), 7.16 (m, 2H), 5.25 (m, 1H), 4.61 (m, 1H), 3.85 (m, 4H), 3.73 (m, 2H), 3.22 (m, 4H), 2.58 (br s, 3H), 2.36 (m, 2H), 2.17 (m, 3H), 2.05-1.70 (m, 13H). HRMS C33H42N4O3 m/z 543.3335 (M+H)Cal., 543.3331 (M+H)Obs..
Reaction SMILES: C([O-])([O-])=O.[Cs+].[Cs+].Br[C:8]1[CH:9]=[C:10]([C:15]2[N:16]=[N:17][N:18]([CH:20]([CH3:22])[CH3:21])[CH:19]=2)[C:11]([NH2:14])=[N:12][CH:13]=1.[Cl:23][C:24]1[CH:25]=[C:26](B(O)O)[CH:27]=[C:28]([C:30]([N:32]2[CH2:37][CH2:36][O:35][CH2:34][CH2:33]2)=[O:31])[CH:29]=1>O1CCOCC1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[NH2:14][C:11]1[N:12]=[CH:13][C:8]([C:26]2[CH:27]=[C:28]([C:30]([N:32]3[CH2:33][CH2:34][O:35][CH2:36][CH2:37]3)=[O:31])[CH:29]=[C:24]([Cl:23])[CH:25]=2)=[CH:9][C:10]=1[C:15]1[N:16]=[N:17][N:18]([CH:20]([CH3:22])[CH3:21])[CH:19]=1
Reactant: CC(C)n1cc(-c2cc(Br)cnc2N)nn1
Reactant: O=C(c1cc(Cl)cc(B(O)O)c1)N1CCOCC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: C1COCCO1
Product: CC(C)n1cc(-c2cc(-c3cc(Cl)cc(C(=O)N4CCOCC4)c3)cnc2N)nn1
Temperature: 120 °C
Yield: 15.4 %

Procedure:
Cs2CO3 (682 mg, 2.10 mmol) was added to a solution of 5-bromo-3-(1-isopropyl-1H-[1,2,3]triazol-4-yl)-pyridin-2-ylamine (200 mg, 0.70 mmol) and (3-chloro-5-(morpholine-4-carbonyl)phenyl)boronic acid (210 mg, 0.78 mmol) in dioxane: water (8 mL: 4 mL) degassed the reaction mixture for 10 min with nitrogen. Then added Pd(PPh3)4 (40 mg, 0.035 mmol), degassed the reaction mixture for additional 10 min with nitrogen, the reaction mixture was heated to 120° C. in microwave for 1 h. The reaction mixture was diluted with water (50 mL) and extracted with ethyl acetate (2×30 mL). Combined organic layers was dried over Na2SO4 and concentrated under reduced pressure. Crude product was purified by silica (100-200 mesh) column eluted with 80-90% ethyl acetate in pet-ether to afford 46 mg (Yield: 47.0%) of the title compound as a pale yellow solid.
Reaction SMILES: Cl[CH:2]1[CH2:7][CH2:6][N:5]([CH3:8])[CH2:4][CH2:3]1.[Mg].[F:10][C:11]1[CH:24]=[CH:23][C:22]2[S:21][C:20]3[C:15](=[CH:16][CH:17]=[C:18]([F:25])[CH:19]=3)[C:14](=[O:26])[C:13]=2[CH:12]=1.[Cl-].[NH4+]>O1CCCC1>[F:10][C:11]1[CH:24]=[CH:23][C:22]2[S:21][C:20]3[C:15](=[CH:16][CH:17]=[C:18]([F:25])[CH:19]=3)[C:14]([CH:2]3[CH2:7][CH2:6][N:5]([CH3:8])[CH2:4][CH2:3]3)([OH:26])[C:13]=2[CH:12]=1
Reactant: CN1CCC(Cl)CC1
Reactant: O=c1c2ccc(F)cc2sc2ccc(F)cc12
Agent: [Cl-]
Agent: [Mg]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CN1CCC(C2(O)c3ccc(F)cc3Sc3ccc(F)cc32)CC1

Procedure:
The Grignard reagent prepared from 2.7 g. (0.02 mol) of 4-chloro-N-methylpiperidine and 0.5 g. (0.02 mol) of magnesium turnings in tetrahydrofuran is treated with 2.5 g. (0.01 mol) of 2,6-difluorothioxanthone at a rate to maintain slow reflux. The mixture is refluxed for six hours, hydrolyzed with saturated ammonium chloride solution and extracted with ether to yield 2,6-difluoro-9-(1-methyl-4-piperidyl)-thioxanthene-9-ol, m.p. 207°-209° C.
Reaction SMILES: [CH3:1][NH2:2].[C:3]([C:7]1[CH:23]=[CH:22][CH:21]=[CH:20][C:8]=1[O:9][C:10]1[C:15]([N+:16]([O-:18])=[O:17])=[CH:14][CH:13]=[C:12](Cl)[N:11]=1)([CH3:6])([CH3:5])[CH3:4].[Cl-]>O1CCOCC1.O>[C:3]([C:7]1[CH:23]=[CH:22][CH:21]=[CH:20][C:8]=1[O:9][C:10]1[N:11]=[C:12]([NH:2][CH3:1])[CH:13]=[CH:14][C:15]=1[N+:16]([O-:18])=[O:17])([CH3:6])([CH3:5])[CH3:4]
Reactant: CC(C)(C)c1ccccc1Oc1nc(Cl)ccc1[N+](=O)[O-]
Reactant: CN
Agent: [Cl-]
Solvent: C1COCCO1
Solvent: O
Product: CNc1ccc([N+](=O)[O-])c(Oc2ccccc2C(C)(C)C)n1
Temperature: 25 °C
Reaction time: 72 h
Yield: 61.2 %

Procedure:
Methylamine (280 μL, 0.56 mmol) was added into a solution of 136b (157 mg, 0.51 mmol) in 1,4-dioxane at 0° C. (1 mL) over 1 h and the resulting reaction mixture was stirred at rt. After 72 h, 40% of the starting chloride remained by HPLC. Another 1.1 eq of methylamine was added at −10° C. over 30 min. The reaction was allowed to warm to rt, stir for 30 min and was then diluted with water (1 mL) and extracted with ethyl acetate (3×1 mL). The combined organic layer was washed with brine (1 mL), dried over sodium sulfate, and concentrated to give a yellow oil. The oil was purified by SiO2 chromatography (12 g) using a gradient of ethyl acetate in hexanes to afford 136c (94 mg, 61% yield) as a yellow oil; HPLC purity 100%, 3.76 min (Method A); [M+H]+=302.24.
Reaction SMILES: [Cl:1][C:2]1[C:7]2[CH:8]=[C:9]([C:11](O)=[O:12])[O:10][C:6]=2[CH:5]=[C:4]([N+:14]([O-:16])=[O:15])[C:3]=1[O:17][CH3:18].Cl.[CH3:20][NH:21][CH3:22]>>[Cl:1][C:2]1[C:7]2[CH:8]=[C:9]([C:11]([N:21]([CH3:22])[CH3:20])=[O:12])[O:10][C:6]=2[CH:5]=[C:4]([N+:14]([O-:16])=[O:15])[C:3]=1[O:17][CH3:18]
Reactant: CNC
Reactant: COc1c([N+](=O)[O-])cc2oc(C(=O)O)cc2c1Cl
Agent: Cl
Product: COc1c([N+](=O)[O-])cc2oc(C(=O)N(C)C)cc2c1Cl
Yield: 66 %

Procedure:
4-Chloro-5-methoxy-N,N-dimethyl-6-nitrobenzofuran-2-carboxamide was prepared by the procedure described in Example 1, step 2 starting from 4-chloro-5-methoxy-6-nitrobenzofuran-2-carboxylic acid (1.17 g, 4.31 mmol) an dimethylamine hydrochloride (386 mg, 4.74 mmol). Purification via silica gel column chromatography (20-100% ethyl acetate/isohexane) gave 4-chloro-5-methoxy-N,N-dimethyl-6-nitrobenzofuran-2-carboxamide as a orange solid (850 mg, 66%).
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:13][CH2:14][O:15][C:16]1[CH:21]=[CH:20][C:19](/[CH:22]=[CH:23]/[CH:24]=[CH:25]/[CH:26]=O)=[CH:18][CH:17]=1.[O:28]1[CH2:32][C:31](=[O:33])[NH:30][C:29]1=[O:34]>>[CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)=[N:4][C:3]=1[CH2:13][CH2:14][O:15][C:16]1[CH:17]=[CH:18][C:19]([CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=[C:32]2[O:28][C:29](=[O:34])[NH:30][C:31]2=[O:33])=[CH:20][CH:21]=1
Reactant: O=C1COC(=O)N1
Reactant: Cc1oc(-c2ccccc2)nc1CCOc1ccc(/C=C/C=C/C=O)cc1
Product: Cc1oc(-c2ccccc2)nc1CCOc1ccc(C=CC=CC=C2OC(=O)NC2=O)cc1
Yield: 31 %

Procedure:
In substantially the same manner as in Example 1, (E,E)-5-[4-[2-(5-methyl-2-phenyl-4-oxazolyl)ethoxy]phenyl]-2,4-pentadien-1-al was allowed to react with 2,4-oxazolidinedione to give 5-[5-[4-[2-(5-methyl-2-phenyl-4-oxazolyl)ethoxy]phenyl]-2,4-pentadienylidene]-2,4-oxazolidinedione. The yield was 31%. Recrystallization from dichloromethane-methanol gave yellow needles, m.p.209°-211° C.
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]1[C:11]([NH:15][CH2:16][CH2:17][C:18]#N)=[N:12][O:13][N:14]=1.[H-].[H-].[H-].[H-].[Li+].[Al+3].C1C[O:29]CC1>>[NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]1[C:11]([NH:15][CH2:16][CH2:17][CH2:18][OH:29])=[N:12][O:13][N:14]=1
Reactant: C1CCOC1
Reactant: N#CCCNc1nonc1-c1nc2ccccc2[nH]1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Product: OCCCNc1nonc1-c1nc2ccccc2[nH]1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A solution of 4-(1H-benzimidazol-2-yl)-furazan-3-yl-N-(2-cyanoethyl)-amine (0.272 g, 0.947 mmol, Example 6a) in THF (5 ml) is added dropwise at 0° C. to an efficiently stirred suspension of LiAlH4 (0.054 g, 1.42 mmol) in THF (5 ml). After stirring for 16 hours at room temperature the mixture is quenched by careful addition of aqueous saturated solution of sodium sulphate. The suspension is filtered and the filtrate evaporated to dryness. Crystallization by addition of hexane yields the title compound in pure form. 1H-NMR (400 MHz, d6-DMSO): 13.6 (s, 1H); 7.66 (m, 2H); 7.31 (m, 2H); 6.92 (t, 1H); 4.61 (m, 1H); 3.51 (m, 2H); 3.39 (m, 2H); 1.81 (m, 2H).
Reaction SMILES: [NH2:1][CH2:2][C:3]1[C:8](=[O:9])[NH:7][C:6]2[CH2:10][CH2:11][CH2:12][C:5]=2[C:4]=1C.[O:14]([C:21]1[CH:29]=[CH:28][C:24]([C:25](O)=[O:26])=[CH:23][CH:22]=1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl>CN(C=O)C>[O:9]=[C:8]1[NH:7][C:6]2[CH2:10][CH2:11][CH2:12][C:5]=2[CH:4]=[C:3]1[CH2:2][NH:1][C:25](=[O:26])[C:24]1[CH:23]=[CH:22][C:21]([O:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[CH:29][CH:28]=1
Reactant: O=C(O)c1ccc(Oc2ccccc2)cc1
Reactant: Cc1c2c([nH]c(=O)c1CN)CCC2
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: O=C(NCc1cc2c([nH]c1=O)CCC2)c1ccc(Oc2ccccc2)cc1
Yield: 56.8 %

Procedure:
In a pyrex vial 3-(aminomethyl)-4-methyl-6,7-dihydro-1H-cyclopenta[b]pyridin-2(5H)-one (35 mg, 0.21 mmol), 4-phenoxybenzoic acid (50 mg, 0.23 mmol), HOBT (36 mg, 0.23 mmol) and DMF (1.5 mL) were cooled to 0° C. EDC (45 mg, 0.23 mmol) was then added in one portion and the cold bath was removed. The reaction was mixed at ambient temperature overnight then diluted with MeOH (2 mL) and water (1 mL), filtered through a PTFE screen and purified by reverse-phase HPLC 10-95% gradient of MeCN in water (0.1% TFA). The product fractions were lyophilized to produce N-((2-oxo-2,5,6,7-tetrahydro-1H-cyclopenta[b]pyridin-3-yl)methyl)-4-phenoxybenzamide as a white solid (43 mg, 56%). 1H NMR (400 MHz, DMSO-d6) δ 8.70 (t, J=5.71 Hz, 1H), 7.87-7.96 (m, 2H), 7.38-7.47 (m, 2H), 7.15-7.23 (m, 2H), 7.05-7.11 (m, 2H), 6.99-7.05 (m, 2H), 4.19 (d, J=5.61 Hz, 2H), 2.69 (t, J=7.48 Hz, 2H), 2.58 (t, J=7.17 Hz, 2H), 1.98 (quin, J=7.43 Hz, 1H). LRMS (M+H+) m/z: calcd 361.15. found 361.2.
Reaction SMILES: [CH3:1][NH:2][CH3:3].[C:4]([O:8][CH2:9][CH2:10][N:11]([CH3:13])[CH3:12])(=[O:7])[CH:5]=[CH2:6]>>[CH3:1][N:2]([CH2:6][CH2:5][C:4]([O:8][CH2:9][CH2:10][N:11]([CH3:13])[CH3:12])=[O:7])[CH3:3]
Reactant: C=CC(=O)OCCN(C)C
Reactant: CNC
Product: CN(C)CCOC(=O)CCN(C)C
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
Anhydrous dimethylamine (19.8 grams) was added dropwise to 2-(N,N-dimethylamino)ethyl acrylate (31.5 grams) in a magnetically-stirred, ice-cooled reaction vessel at such a rate that the temperature did not exceed 40° C. The addition of dimethylamine was complete in about 10 minutes. After allowing the reaction mixture to stir overnight at room temperature, it was subjected to reduced pressure (about 20 mm. Hg) to remove unreacted dimethylamine. Gas-liquid chromatographic analysis indicated that the residue product was 96.5 percent pure. The structure of the product, ##STR20## was verified spectroscopically (nuclear magnetic resonance and infrared) and by elemental analysis. Anal. Calc'd. for C9H20N2O2 : C, 57.4; H, 10.6; N, 14.9. Found: C, 57.3; H, 10.5; N, 14.8. This product is designated herein as Amine Catalyst X.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([OH:8])[CH:5]=[CH:6][CH:7]=1.O[C@@H:10]([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[CH2:11][N:12]1[CH2:17][CH2:16][CH:15]([C:18]2[CH:19]=[C:20]([NH:24][C:25](=[O:29])[CH:26]([CH3:28])[CH3:27])[CH:21]=[CH:22][CH:23]=2)[CH2:14][CH2:13]1>>[Cl:1][C:2]1[CH:3]=[C:4]([CH:5]=[CH:6][CH:7]=1)[O:8][C@H:10]([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[CH2:11][N:12]1[CH2:17][CH2:16][CH:15]([C:18]2[CH:19]=[C:20]([NH:24][C:25](=[O:29])[CH:26]([CH3:28])[CH3:27])[CH:21]=[CH:22][CH:23]=2)[CH2:14][CH2:13]1
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(C[C@@H](O)c3ccccc3)CC2)c1
Reactant: Oc1cccc(Cl)c1
Product: CC(C)C(=O)Nc1cccc(C2CCN(C[C@H](Oc3cccc(Cl)c3)c3ccccc3)CC2)c1

Procedure:
Prepared by Procedure B and Scheme B1 using 3-chlorophenol and N-(3-{1-[(2S)-2-hydroxy-2-phenylethyl]-4-piperidinyl}phenyl)-2-methylpropanamide: ESMS m/e: 478.5 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:25]=[CH:24][CH:23]=[C:22]([F:26])[C:3]=1[O:4][C:5]1[CH:6]=[N:7][N:8]([CH:12]([CH2:16][CH:17]([CH2:20][CH3:21])[CH2:18][CH3:19])[C:13](O)=[O:14])[C:9](=[O:11])[CH:10]=1.[CH3:27][C:28]1([CH3:40])[O:32][C@H:31]([CH2:33][N:34]2[CH:38]=[CH:37][C:36]([NH2:39])=[N:35]2)[CH2:30][O:29]1>>[CH3:27][C:28]1([CH3:40])[O:32][C@H:31]([CH2:33][N:34]2[CH:38]=[CH:37][C:36]([NH:39][C:13](=[O:14])[CH:12]([N:8]3[C:9](=[O:11])[CH:10]=[C:5]([O:4][C:3]4[C:2]([F:1])=[CH:25][CH:24]=[CH:23][C:22]=4[F:26])[CH:6]=[N:7]3)[CH2:16][CH:17]([CH2:20][CH3:21])[CH2:18][CH3:19])=[N:35]2)[CH2:30][O:29]1
Reactant: CCC(CC)CC(C(=O)O)n1ncc(Oc2c(F)cccc2F)cc1=O
Reactant: CC1(C)OC[C@@H](Cn2ccc(N)n2)O1
Product: CCC(CC)CC(C(=O)Nc1ccn(C[C@@H]2COC(C)(C)O2)n1)n1ncc(Oc2c(F)cccc2F)cc1=O

Procedure:
Using the method described in Example 49, 2-[4-(2,6-difluoro-phenoxy)-6-oxo-6H-pyridazin-1-yl]-4-ethyl-hexanoic acid (Intermediate 31) and 1-((R)-2,2-dimethyl-[1,3]dioxolan-4-ylmethyl)-1H-pyrazol-3-ylamine (Intermediate 4) afforded 2-[4-(2,6-difluoro-phenoxy)-6-oxo-6H-pyridazin-1-yl]-4-ethyl-hexanoic acid [1-((R)-2,2-dimethyl-[1,3]dioxolan-4-ylmethyl)-1H-pyrazol-3-yl]-amide as a viscous oil as a mixture of diastereomers. 1H NMR (300 MHz, CDCl3) δ ppm 0.79-0.93 (m, 6H), 1.12 (br s, 1H), 1.20-1.54 (m, 4H), 1.34 (s, 3H), 1.38 (s, 3H), 2.02-2.19 (m, 1H), 2.19-2.34 (m, 1H), 3.68-3.77 (m, 1H), 4.04 (dd, J=8.6, 6.5 Hz, 1H), 4.10 (d, J=5.4 Hz, 2H), 4.32-4.47 (m, 1H), 5.66 (dd, J=9.1, 6.0 Hz, 1H), 6.00 (br s, 1H), 6.68 (s, 1H), 7.01-7.14 (m, 2H), 7.28-7.37 (m, 2H), 8.01 (d, J=2.7 Hz, 1H), 8.59 (br s, 1H).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([CH:11]([CH3:13])[CH3:12])=[N:9][N:10]=2)[CH:7]=1.C([Mg]Cl)(C)C.CN(C)[CH:21]=[O:22]>O1CCCC1>[CH:11]([C:8]1[N:6]2[CH:7]=[C:2]([CH:21]=[O:22])[CH:3]=[CH:4][C:5]2=[N:10][N:9]=1)([CH3:13])[CH3:12]
Reactant: CN(C)C=O
Reactant: CC(C)c1nnc2ccc(Br)cn12
Agent: CC(C)[Mg]Cl
Solvent: C1CCOC1
Product: CC(C)c1nnc2ccc(C=O)cn12
Temperature: 50 °C
Reaction time: 0.17 h

Procedure:
To a stirred, cold (0° C.), dark brown solution of 0.48 g of 6-bromo-3-isopropyl-[1,2,4]triazolo[4,3-a]pyridine in 5 mL of tetrahydrofuran was added slowly 1.3 mL of 2 M isopropylmagnesium chloride in tetrahydrofuran. After 30 minutes N,N-dimethylformamide was added; the ice bath was removed, and the mixture was heated to 50° C. for 150 minutes. The mixture was cooled to 22° C., diluted with 1 M hydrochloric acid, and stirred for 10 minutes. The mixture was made basic with saturated aqueous sodium carbonate, and extracted with ethyl acetate (3×). The combined extracts were washed with brine (2×), dried (sodium sulfate), filtered, and the filtrate was concentrated to give a light yellow solid which was crystallized (ethyl acetate, hexanes, and methanol) to give 0.19 g of 3-isopropyl-[1,2,4]triazolo[4,3-a]pyridine-6-carbaldehyde as a faint yellow solid.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][C@H:6]([NH:17][C:18](=[O:33])[C:19]1[CH:24]=[CH:23][C:22]([C:25]([N:27]2[CH2:31][CH2:30][CH2:29][CH2:28]2)=[O:26])=[C:21]([CH3:32])[CH:20]=1)[C:7]1[NH:11][C:10]2[CH:12]=[CH:13][C:14]([Cl:16])=[CH:15][C:9]=2[N:8]=1.C(N(C(C)C)CC)(C)C.[O:43]=[C:44]1[NH:48][CH2:47][CH:46]([C:49](O)=[O:50])[CH2:45]1>CS(C)=O>[Cl:16][C:14]1[CH:13]=[CH:12][C:10]2[NH:11][C:7]([C@@H:6]([NH:17][C:18](=[O:33])[C:19]3[CH:24]=[CH:23][C:22]([C:25]([N:27]4[CH2:28][CH2:29][CH2:30][CH2:31]4)=[O:26])=[C:21]([CH3:32])[CH:20]=3)[CH2:5][CH2:4][CH2:3][CH2:2][NH:1][C:49]([CH:46]3[CH2:45][C:44](=[O:43])[NH:48][CH2:47]3)=[O:50])=[N:8][C:9]=2[CH:15]=1
Reactant: Cc1cc(C(=O)N[C@@H](CCCCN)c2nc3cc(Cl)ccc3[nH]2)ccc1C(=O)N1CCCC1
Reactant: O=C1CC(C(=O)O)CN1
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Product: Cc1cc(C(=O)N[C@@H](CCCCNC(=O)C2CNC(=O)C2)c2nc3cc(Cl)ccc3[nH]2)ccc1C(=O)N1CCCC1

Procedure:
Prepared analogously to Example 1d from N-[(1S)-5-amino-1-(5-chloro-1H-benzimidazol-2-yl)pentyl]-3-methyl-4-(pyrrolidin-1-ylcarbonyl)benzamide, PFTU, diisopropylethylamine, and 5-oxopyrrolidine-3-carboxylic acid in dimethylsulfoxide. HPLC-MS results: retention time: 2.04 minutes; C30H35ClN6O4 (579.10); mass spectrum: (M−H)−=578.
Reaction SMILES: [NH2:1][C:2]1[CH:21]=[CH:20][CH:19]=[CH:18][C:3]=1[C:4]([NH:6][CH2:7][CH2:8][CH2:9][CH2:10][S:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=1)=[O:5].[C:22](N1C=CN=C1)(N1C=CN=C1)=[O:23]>O1CCCC1>[N:13]1[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=1[S:11][CH2:10][CH2:9][CH2:8][CH2:7][N:6]1[C:4](=[O:5])[C:3]2[C:2](=[CH:21][CH:20]=[CH:19][CH:18]=2)[NH:1][C:22]1=[O:23]
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: Nc1ccccc1C(=O)NCCCCSc1ccccn1
Solvent: C1CCOC1
Product: O=c1[nH]c2ccccc2c(=O)n1CCCCSc1ccccn1
Temperature: 25 °C
Reaction time: 16 h
Yield: 68.6 %

Procedure:
Under nitrogen atmosphere, to a solution of 452 mg (1.5 mmol) of 2-[4-(2-aminobenzoylamino)butylthio]pyridine in 20 ml of tetrahydrofuran, 486 mg (3.0 mmol) of 1,1'-carbonyldiimidazole was added, and the mixture was stirred at room temperature for 16 hours. The solvent was distilled off and the residue was dissolved in chloroform. The solution was washed with water and dried. The solvent was distilled off and the residue was recrystallized from chloroform/ether to give 337 mg of the desired product (68.8% yield, white crystals).