Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.[CH:23]1([CH2:29][CH2:30][CH2:31][CH2:32][OH:33])[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1.C(OCC)C.[OH-].[Na+]>ClCCl>[CH:23]1([CH2:29][CH2:30][CH2:31][CH:32]=[O:33])[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1
Reactant: OCCCCC1CCCCC1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Solvent: ClCCl
Product: O=CCCCC1CCCCC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 90.5 %

Procedure:
Add Dess-Martin reagent (7.02 g, 16.6 mmol) to a stirred solution of 4-cyclohexyl-1-butanol (2.5 mL, 14.4 mmol) in anhydrous dichloromethane (120 mL). Stir for 3 h at room temperature under nitrogen. Add diethyl ether (200 mL) and 1N sodium hydroxide (150 mL) and stir for 10 minutes. Separate the layers and extract a second time with diethyl ether (100 mL). Combine the diethyl ether extracts, wash with 1N sodium hydroxide (100 mL), dry over magnesium sulfate, filter, and concentrate on a rotary evaporator to yield 2.01 g (90%) of 4-cyclohexyl-butyraldehyde: 1H NMR (CDCl3): 9.76 (s, 1H), 2.41-2.37 (m, 2H), 1.71-1.58 (m, 7H), 1.27-1.07 (m, 6H), 0.93-0.82 (m, 2H).
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:23])[CH2:10][C@@H:11]([C:20](O)=[O:21])[NH:12][C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CN1CCOCC1.C(OC(Cl)=O)C(C)C.[BH4-].[Na+]>COCCOC>[CH2:1]([O:8][C:9](=[O:23])[CH2:10][C@H:11]([NH:12][C:13]([O:15][C:16]([CH3:18])([CH3:17])[CH3:19])=[O:14])[CH2:20][OH:21])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)N[C@@H](CC(=O)OCc1ccccc1)C(=O)O
Agent: CC(C)COC(=O)Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CN1CCOCC1
Solvent: COCCOC
Product: CC(C)(C)OC(=O)N[C@H](CO)CC(=O)OCc1ccccc1
Temperature: -20 °C
Reaction time: 1 h

Procedure:
To a solution of Boc-L-aspartic acid-4-benzyl ester (100 g, 309 mmol) in DME (1.8 L) at −20° C. was added NMM (34 mL, 309 mmol) then dropwise iso-butylchloroformate (40 mL, 309 mmol) and the mixture was stirred at −20° C. for 20 min. The reaction mixture was filtered and the filtrate was cooled to −20° C. NaBH4 (17.5 g, 463 mmol) was added portionwise at −20° C. The mixture was allowed to warm and stirred at rt for 1 h. The mixture was quenched with a 20% citric acid solution and then extracted with AcOEt. The organic layer was washed with NaHCO3 solution, H2O and brine, dried (MgSO4), filtered and concentrated. The product was used without further purification for the next step.
Reaction SMILES: [CH2:1]([C:3]1[C:12]2[C:7](=[CH:8][C:9]([O:15][CH3:16])=[C:10]([O:13][CH3:14])[CH:11]=2)[CH:6]=[C:5]([OH:17])[N:4]=1)[CH3:2].[ClH:18].[Cl:19][CH2:20][C:21]1[C:22]([NH:33][CH2:34][CH2:35][CH3:36])=[N:23][C:24]2[C:29]([CH:30]=1)=[CH:28][C:27]([O:31][CH3:32])=[CH:26][CH:25]=2.[Li+].[OH-]>CC1C=CC(C(C)C)=CC=1.C(Cl)Cl>[ClH:19].[ClH:18].[CH2:1]([C:3]1[C:12]2[C:7](=[CH:8][C:9]([O:15][CH3:16])=[C:10]([O:13][CH3:14])[CH:11]=2)[C:6]([CH2:20][C:21]2[C:22]([NH:33][CH2:34][CH2:35][CH3:36])=[N:23][C:24]3[C:29]([CH:30]=2)=[CH:28][C:27]([O:31][CH3:32])=[CH:26][CH:25]=3)=[C:5]([OH:17])[N:4]=1)[CH3:2]
Reactant: CCCNc1nc2ccc(OC)cc2cc1CCl
Reactant: CCc1nc(O)cc2cc(OC)c(OC)cc12
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: ClCCl
Solvent: Cc1ccc(C(C)C)cc1
Product: CCCNc1nc2ccc(OC)cc2cc1Cc1c(O)nc(CC)c2cc(OC)c(OC)cc12
Temperature: 150 °C
Reaction time: 1 h
Yield: 10 %

Procedure:
To a stirred solution of 1-ethyl-6,7-dimethoxyisoquinolin-3-ol SLA 28136 (250 mg, 1.07 mmol) in p-cymene (11 mL) in a 100 mL round-bottomed flask equipped with a magnetic stirrer was added 3-(chloromethyl)-6-methoxy-N-propylquinolin-2-amine hydrochloride SLA 28178 (323 mg, 1.07 mmol) at RT followed by a 2 N aq. LiOH solution (1.07 mL, 2.14 mmol) and the mixture was stirred at 150° C. for 1 h before addition of a new portion of SLA 28178 (323 mg, 1.07 mmol, done 3 times). After cooling to RT, the mixture was diluted with CH2Cl2:MeOH=9:1 (150 mL) and washed with brine (20 mL), dried over Na2SO4, filtered, and concentrated at 40° C. under vacuum. Purification by column chromatography (SiO2, eluent EtOAc:MeOH=100:0 to 92:8) followed by a second purification by column chromatography (SiO2, eluent CH2Cl2:MeOH=100:0 to 95:5) provided, after evaporation, 14.8 mg of 1-ethyl-6,7-dimethoxy-4-((6-methoxy-2-(propylamino)quinolin-3-yl)methyl)isoquinolin-3-ol as a brown solid. This free base was dissolved in CH2Cl2 (2 mL) in a 10 mL round-bottomed flask equipped with a magnetic stirrer before addition of a 0.49 M HCl solution in MeOH (0.26 mL). The reaction mixture was stirred for 5 min at RT then concentrated at 40° C. under vacuum, to afford 1-ethyl-6,7-dimethoxy-4-((6-methoxy-2-(propylamino)quinolin-3-yl)methyl)isoquinolin-3-ol dihydrochloride 42 as a yellow solid (6 mg, 10% yield).
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:8][C:9]([F:14])([F:13])[C:10]([OH:12])=[O:11].FC(F)(F)C(O)=O.[Cl:22][C:23]1[CH:24]=[N:25][C:26]2[NH:27][C:28]3[CH:29]=[N:30][CH:31]=[C:32]([CH:53]=3)[CH2:33][CH2:34][C:35]3[CH:43]=[C:39]([NH:40][C:41]=1[N:42]=2)[CH:38]=[CH:37][C:36]=3[NH:44][C:45](=[O:52])[CH2:46][C@@H:47]1[CH2:51][CH2:50][NH:49][CH2:48]1.[F:54][C:55]1[CH:60]=[CH:59][C:58]([N:61]=[C:62]=[O:63])=[CH:57][CH:56]=1>>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:8][C:9]([F:14])([F:13])[C:10]([OH:12])=[O:11].[Cl:22][C:23]1[CH:24]=[N:25][C:26]2[NH:27][C:28]3[CH:29]=[N:30][CH:31]=[C:32]([CH:53]=3)[CH2:33][CH2:34][C:35]3[CH:43]=[C:39]([NH:40][C:41]=1[N:42]=2)[CH:38]=[CH:37][C:36]=3[NH:44][C:45](=[O:52])[CH2:46][C@@H:47]1[CH2:51][CH2:50][N:49]([C:62]([NH:61][C:58]2[CH:59]=[CH:60][C:55]([F:54])=[CH:56][CH:57]=2)=[O:63])[CH2:48]1
Reactant: O=C(C[C@@H]1CCNC1)Nc1ccc2cc1CCc1cncc(c1)Nc1ncc(Cl)c(n1)N2
Reactant: O=C=Nc1ccc(F)cc1
Solvent: O=C(O)C(F)(F)F
Product: O=C(C[C@@H]1CCN(C(=O)Nc2ccc(F)cc2)C1)Nc1ccc2cc1CCc1cncc(c1)Nc1ncc(Cl)c(n1)N2
Yield: 79 %

Procedure:
The desired compound was prepared according to the procedure of Example D41 using N-[6-chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).1(9,13)]docosa-1(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-2-[(3S)-pyrrolidin-3-yl]acetamide tris(trifluoroacetate) and 1-fluoro-4-isocyanatobenzene as the starting materials in 79% yield. LCMS for C30H29ClFN8O2 (M+H)+: m/z=587.0.
Reaction SMILES: Cl.[Cl:2][C:3]1[S:18][C:6]2[C:7]3([CH2:17][CH2:16][NH:15][CH2:14][CH2:13]3)[O:8][CH2:9][C:10]([F:12])([F:11])[C:5]=2[CH:4]=1.[CH3:19][C:20]1[C:21]([N:26]2[CH:30]=[C:29]([CH:31]=O)[C:28]([C:33]([O-])=[O:34])=[N:27]2)=[N:22][CH:23]=[CH:24][CH:25]=1>>[Cl:2][C:3]1[S:18][C:6]2[C:7]3([O:8][CH2:9][C:10]([F:12])([F:11])[C:5]=2[CH:4]=1)[CH2:13][CH2:14][N:15]([CH2:31][C:29]1[C:28]([CH2:33][OH:34])=[N:27][N:26]([C:21]2[C:20]([CH3:19])=[CH:25][CH:24]=[CH:23][N:22]=2)[CH:30]=1)[CH2:16][CH2:17]3
Reactant: FC1(F)COC2(CCNCC2)c2sc(Cl)cc21
Reactant: Cc1cccnc1-n1cc(C=O)c(C(=O)[O-])n1
Agent: Cl
Product: Cc1cccnc1-n1cc(CN2CCC3(CC2)OCC(F)(F)c2cc(Cl)sc23)c(CO)n1
Yield: 14 %

Procedure:
The title compound is prepared essentially as described in Example 60 by using 2′-chloro-4′,4′-difluoro-4′,5′-dihydrospiro[piperidine-4,7′-thieno[2,3-c]pyran]hydrochloride and 1-(3-methylpyridin-2-yl)-4-formyl-pyrazole-3-carboxylate as starting materials in a 14% yield. MS (m/z): 481 (M+1).
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:7][CH2:6][C@H:5]([NH:8][C:9]([C:11]2[C:15]3[N:16]=[CH:17][N:18]=[C:19]([C:20]4[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][C:21]=4[O:28][CH2:29][CH2:30][O:31][CH3:32])[C:14]=3[NH:13][CH:12]=2)=[O:10])[CH2:4][CH2:3]1.[C:33](Cl)(=[O:35])[CH3:34]>>[C:33]([NH:1][C@@H:2]1[CH2:7][CH2:6][C@H:5]([NH:8][C:9]([C:11]2[C:15]3[N:16]=[CH:17][N:18]=[C:19]([C:20]4[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][C:21]=4[O:28][CH2:29][CH2:30][O:31][CH3:32])[C:14]=3[NH:13][CH:12]=2)=[O:10])[CH2:4][CH2:3]1)(=[O:35])[CH3:34]
Reactant: COCCOc1cc(OC)ccc1-c1ncnc2c(C(=O)N[C@H]3CC[C@@H](N)CC3)c[nH]c12
Reactant: CC(=O)Cl
Product: COCCOc1cc(OC)ccc1-c1ncnc2c(C(=O)N[C@H]3CC[C@@H](NC(C)=O)CC3)c[nH]c12

Procedure:
Starting from cis-4-[4-methoxy-2-(2-methoxy-ethoxy)-phenyl]-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylic acid (4-amino-cyclohexyl)-amide (example A183) and acetyl chloride the title compound was obtained as colorless solid.
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[C:18]3=[N:19][C:20]([Cl:31])=[N:21][C:22]([N:23]4[CH2:29][CH:28]5[O:30][CH:25]([CH2:26][CH2:27]5)[CH2:24]4)=[C:17]3[CH:16]=[N:15]2)[CH2:10][CH2:9]1)C1C=CC=CC=1.C(=O)([O-])[O-].[K+].[K+].Cl[C:39]([O:41][CH3:42])=[O:40]>ClCCCl>[CH:25]12[O:30][CH:28]([CH2:27][CH2:26]1)[CH2:29][N:23]([C:22]1[N:21]=[C:20]([Cl:31])[N:19]=[C:18]3[N:14]([CH:11]4[CH2:12][CH2:13][N:8]([C:39]([O:41][CH3:42])=[O:40])[CH2:9][CH2:10]4)[N:15]=[CH:16][C:17]=13)[CH2:24]2
Reactant: COC(=O)Cl
Reactant: Clc1nc(N2CC3CCC(C2)O3)c2cnn(C3CCN(Cc4ccccc4)CC3)c2n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCCl
Product: COC(=O)N1CCC(n2ncc3c(N4CC5CCC(C4)O5)nc(Cl)nc32)CC1
Temperature: 57.5 °C

Procedure:
A suspension of 1-(1-benzyl-piperidin-4-yl)-6-chloro-4-(8-oxa-3-aza-bicyclo[3.2.1]oct-3-yl)-1H-pyrazolo[3,4-d]pyrimidine (1.0 g, 2.3 mmol) and potassium carbonate (0.94 g, 6.8 mmol) in 1,2-dichloroethane (15 mL) was treated with methyl chloroformate (0.53 mL, 6.8 mmol) and then heated for two hours in a 55-60° C. oil bath. The mixture was filtered through a pad of diatomaceous earth, eluting with dichloromethane. The filtrate was concentrated to dryness under reduced pressure to furnish methyl 4-(4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-6-chloro-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidine-1-carboxylate. MS (ES+): 407.5, 409.6 (M+H)+
Reaction SMILES: [NH2:1][C:2]([CH:5]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[OH:6])([CH3:4])[CH3:3].[C:13]1([CH2:19][CH:20]=O)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C1C=CC=CC=1>O>[CH3:3][C:2]([CH:5]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[OH:6])([NH:1][CH2:20][CH2:19][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[CH3:4]
Reactant: CC(C)(N)C(O)c1ccccc1
Reactant: O=CCc1ccccc1
Solvent: c1ccccc1
Solvent: O
Product: CC(C)(NCCc1ccccc1)C(O)c1ccccc1
Reaction time: 20 h

Procedure:
A solution of 6.6 g. (0.03 mole) of α-(1-amino-1-methylethyl)benzenemethanol and 4.8 g. (0.03 mole) of phenylacetaldehyde in 75 ml. benzene is refluxed for 1 hour while 0.7 ml. of water separates in a Dean-Stark trap. The infrared absorption spectrum showed absence of the C=O function and the presence of a C=N function at 1650 cm-1. The solvent is removed in vacuo. The residue of the imino derivative was taken up with 60 ml. of methanol and 1.6 g. of KBH4 is added with stirring at 20°-25° C. After 20 hours, the solution is evaporated in vacuo. The residue is taken up with cold water, and the resulting crystalline product (6.8 g., 85% crude yield, m.p. 103°-104° C.) is collected by filtration. Recrystallization from methanol gives pure α-{1-methyl-1-[(2-phenylethyl)amino]-ethyl}benzenemethanol as white crystals, m.p. 105°-106° C.
Reaction SMILES: C([Li])CCC.[Cl:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([C:13]([F:16])([F:15])[F:14])[N:8]=1.[I:17]I.S([O-])([O-])=O.[Na+].[Na+]>O1CCCC1.CCCCCC>[Cl:6][C:7]1[C:12]([I:17])=[CH:11][CH:10]=[C:9]([C:13]([F:14])([F:15])[F:16])[N:8]=1
Reactant: FC(F)(F)c1cccc(Cl)n1
Reactant: II
Agent: O=S([O-])[O-]
Agent: [Li]CCCC
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCCCCC
Product: FC(F)(F)c1ccc(I)c(Cl)n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 44.3 %

Procedure:
A hexane solution of n-butyl lithium (3.8 mL) was added to a tetrahydrofuran (10 mL) solution of 2,2,6,6-tetramethylpyrrolidine (0.93 mL) at −78° C. The reaction mixture was stirred at the same temperature for 30 minutes. A tetrahydrofuran (5 mL) solution of 2-chloro-6-trifluoromethylpyridine (1.0 g) was added dropwise to the reaction mixture, and the solution was further stirred at −78° C. for 30 minutes. A tetrahydrofuran (5 mL) solution of iodine (1.54 g) was added to the solution, and the temperature of the solution was increased to the room temperature. An aqueous sodium sulfite solution was added to the solution, and the solution was extracted with diethyl ether. The organic layer was sequentially washed with an aqueous sodium sulfite solution, an aqueous sodium hydrogencarbonate solution, and a saturated brine and then dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (eluate; n-hexane:ethyl acetate=100:0 to 95:5). The title compound (750 mg) was obtained as pale yellow oil.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]2[C:9]([C:10](=[O:22])[C:11]3[CH:16]=[CH:15][C:14]([CH:17]=[CH:18][C:19]([OH:21])=[O:20])=[CH:13][CH:12]=3)=[C:8]([C:23]3[CH:28]=[CH:27][C:26]([OH:29])=[CH:25][CH:24]=3)[S:7][C:6]=2[CH:30]=1>CCO.CCOC(C)=O.[Pd]>[OH:1][C:2]1[CH:3]=[CH:4][C:5]2[C:9]([C:10](=[O:22])[C:11]3[CH:12]=[CH:13][C:14]([CH2:17][CH2:18][C:19]([OH:21])=[O:20])=[CH:15][CH:16]=3)=[C:8]([C:23]3[CH:24]=[CH:25][C:26]([OH:29])=[CH:27][CH:28]=3)[S:7][C:6]=2[CH:30]=1
Reactant: O=C(O)C=Cc1ccc(C(=O)c2c(-c3ccc(O)cc3)sc3cc(O)ccc23)cc1
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CCO
Product: O=C(O)CCc1ccc(C(=O)c2c(-c3ccc(O)cc3)sc3cc(O)ccc23)cc1
Yield: 72.7 %

Procedure:
6-hydroxy-3-[4-(2-carboxyvinyl)benzoyl]-2-(4-hydroxyphenyl)benzo[b]thiophene (310 mg, 0.74 mmol) was dissolved in 50 mL of a 1:1 mixture of EtOH and EtOAc. This solution was hydrogenated at 40 psi in the presence of 10% Pd/C (200 mg). When the reaction was judged complete by TLC analysis, the mixture was filtered through Celite to remove the catalyst. The filtrated was concentrated in vacuo to a yellow oil that was triturated from hexanes/EtOAc. Filtration provided 225 mg (72%) of 6-hydroxy-3-[4-(2-carboxyethyl)benzoyl]-2-(4-hydroxyphenyl)benzo[b]thiophene as a yellow solid. mp 244-248° C. 1H NMR (DMSO-d6) δ12.15 (bs, 1H), 9.74 (s, 1H), 9.68 (s, 1H), 7.56 (d, J=8.1 Hz, 2H), 7.30 (d, J=2.0 Hz, 1H), 7.23-7.19 (m, 3H), 7.12 (d, J=8.5 Hz, 2H), 6.82 (dd, J=9.0, 2.0 Hz, 1H), 6.62 (d, J=8.5 Hz, 2H), 2.77 (t, J=7.0 Hz, 2H), 2.45 (t, J=7.0 Hz, 2). FD mass spec: 418. Anal. Calcd. for C24H18O5S.20 H20: C, 68.89; H, 4.34. Found: C, 68.35; H, 4.72.
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7](=[O:12])[CH2:6]2)[CH3:2].C([OH:15])C.[OH-].[K+]>O>[CH2:1]([C:3]1[CH:11]=[CH:10][C:9]([NH2:8])=[C:5]([CH2:6][C:7]([OH:12])=[O:15])[CH:4]=1)[CH3:2]
Reactant: CCO
Reactant: CCc1ccc2c(c1)CC(=O)N2
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: CCc1ccc(N)c(CC(=O)O)c1

Procedure:
5-Ethyloxindole (˜54 g, ˜335 mmol), ethanol (750 ml), water (150 ml) and potassium hydroxide (65 g, 1.62 mol) are combined and heated at reflux for 3 days. The mixture is allowed to cool and then filtered through a bed of Celite. The filtrate is concentrated under reduced pressure, water is added and the pH adjusted to 6.5. The precipitate is filtered off, washed with water and dried in an oven overnight to yield 5-ethyl-2-aminophenylacetic acid.
Reaction SMILES: Cl.[F:2][C:3]([F:14])([F:13])[O:4][C:5]1[CH:10]=[CH:9][C:8]([NH:11]N)=[CH:7][CH:6]=1.[C:15]([OH:22])(=[O:21])[CH2:16][CH2:17][C:18]([CH3:20])=O.S(=O)(=O)(O)O>O>[CH3:20][C:18]1[NH:11][C:8]2[C:9]([C:17]=1[CH2:16][C:15]([OH:22])=[O:21])=[CH:10][C:5]([O:4][C:3]([F:14])([F:13])[F:2])=[CH:6][CH:7]=2
Reactant: CC(=O)CCC(=O)O
Reactant: NNc1ccc(OC(F)(F)F)cc1
Agent: Cl
Agent: O=S(=O)(O)O
Solvent: O
Product: Cc1[nH]c2ccc(OC(F)(F)F)cc2c1CC(=O)O
Temperature: 80 °C
Reaction time: 6 h
Yield: 33.5 %

Procedure:
A mixture of 4-trifluoromethoxyphenylhydrazine hydrochloride (1 g), levulinic acid (1.3 g) and 10% aqueous sulfuric acid (20 ml) was stirred for 6 hours under a nitrogen atmosphere at 80° C. The reaction mixture was allowed to cool, water was added, and then extraction was performed with ethyl acetate and the organic layer was concentrated under reduced pressure. Saturated sodium bicarbonate water was added to the obtained residue and vigorously stirred therewith, and then dichloromethane was added and the mixture was again vigorously stirred. The aqueous layer was collected, rendered acidic with concentrated aqueous hydrochloric acid, and then extracted with ethyl acetate. The organic layer was dried over sodium sulfate and concentrated under reduced pressure, to obtain 0.40 g of the title compound as a colorless powder (31% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][C:6]([N+:9]([O-:11])=[O:10])=[CH:5][C:3]=1[NH2:4].[C:12](Cl)(=[O:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>>[Cl:1][C:2]1[CH:8]=[CH:7][C:6]([N+:9]([O-:11])=[O:10])=[CH:5][C:3]=1[NH:4][C:12](=[O:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: Nc1cc([N+](=O)[O-])ccc1Cl
Product: O=C(Nc1cc([N+](=O)[O-])ccc1Cl)c1ccccc1

Procedure:
2-chloro-5-nitroaniline (Aldrich), (10.0 mmol) was used in general procedure 1 with benzoyl chloride (12.2 mmol). The product was purified by silica gel chromatography (40% EtOAc/Hex) to give N-(2-chloro-5-nitrophenyl)benzamide as a tan solid. MS (Q1) 276.1 (M)+
Reaction SMILES: [H-].[Na+].[OH:3][C:4]1[CH:5]=[N:6][CH:7]=[C:8]([CH:11]=1)[C:9]#[N:10].[F:12][C:13]1[CH:14]=[C:15]([CH:18]=[C:19]([F:21])[CH:20]=1)[CH2:16]Br.C(OCC)(=O)C>CC(N(C)C)=O>[F:12][C:13]1[CH:14]=[C:15]([CH:18]=[C:19]([F:21])[CH:20]=1)[CH2:16][O:3][C:4]1[CH:5]=[N:6][CH:7]=[C:8]([CH:11]=1)[C:9]#[N:10]
Reactant: N#Cc1cncc(O)c1
Reactant: Fc1cc(F)cc(CBr)c1
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Solvent: CCOC(C)=O
Product: N#Cc1cncc(OCc2cc(F)cc(F)c2)c1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 68 %

Procedure:
876 mg (2 eq) of sodium hydride is added gradually at 0° C. under nitrogen to a solution of 865 mg of 5-hydroxynicotinonitrile (7.2 mmol) in 15 mL of dimethylacetamide. The mixture is stirred 10 min at 0° C. before adding 2.24 g (1.5 aq) of 3,5-difluorobenzyl bromide. The mixture is placed under stirring for 2.5 additional hours before being diluted in an ethyl acetate fraction and being washed with aqueous fractions. The organic phases are isolated, dried and concentrated. The solid residue obtained is recrystallized in methanol to yield 1.1 g (68% of 5-(3,5-difluorobenzyloxy)nicotinonitrile in the form of a beige powder.
Reaction SMILES: C(OC([NH:8][C@H:9]1[CH2:14][CH2:13][CH2:12][N:11]([CH2:15][C:16]([O:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[O:17])[C:10]1=[O:26])=O)(C)(C)C.Cl.C(Cl)[Cl:29].[NH4+].[OH-]>C(OCC)(=O)C.CO>[ClH:29].[NH2:8][C@H:9]1[CH2:14][CH2:13][CH2:12][N:11]([CH2:15][C:16]([O:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[O:17])[C:10]1=[O:26]
Reactant: CC(C)(C)OC(=O)N[C@H]1CCCN(CC(=O)OCc2ccccc2)C1=O
Reactant: ClCCl
Agent: Cl
Agent: [NH4+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CO
Product: N[C@H]1CCCN(CC(=O)OCc2ccccc2)C1=O
Reaction time: 3 h

Procedure:
To a solution of the compound of Example 38 (4.00 g, 0.0110 mole) in 10 mL of ethyl acetate at room temperature was added 5N HCl in ethyl acetate (50 mL, freshly prepared, 0.25 mole) in one portion. The solution was stirred for 3 hrs, solvent was evaporated, CH2Cl2 was added and the solvents were reevaporated. The residue was pumped at <1 mm Hg on a vacuum pump for 24 hours to afford 3.37 g (~Quantitative crude yield) of product as a colorless foam. TLC (silica gel; CH2Cl2, methanol, conc. NH4OH: 27:3:1): Rf=0.32.
Reaction SMILES: [CH:1]1([CH2:6][CH:7]([N:11]2[C:16](=[O:17])[CH:15]=[C:14]([O:18][CH3:19])[CH:13]=[N:12]2)[C:8]([OH:10])=O)[CH2:5][CH2:4][CH2:3][CH2:2]1.[B-](F)(F)(F)F.CN(C(ON1C(=O)CCC1=O)=[N+](C)C)C.C(N(CC)C(C)C)(C)C.[S:49]1[CH:53]=[CH:52][N:51]=[C:50]1[NH2:54]>C(Cl)Cl>[CH:1]1([CH2:6][CH:7]([N:11]2[C:16](=[O:17])[CH:15]=[C:14]([O:18][CH3:19])[CH:13]=[N:12]2)[C:8]([NH:54][C:50]2[S:49][CH:53]=[CH:52][N:51]=2)=[O:10])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: Nc1nccs1
Reactant: COc1cnn(C(CC2CCCC2)C(=O)O)c(=O)c1
Agent: CN(C)C(ON1C(=O)CCC1=O)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COc1cnn(C(CC2CCCC2)C(=O)Nc2nccs2)c(=O)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 32.1 %

Procedure:
A solution of 3-cyclopentyl-2-(4-methoxy-6-oxo-6H-pyridazin-1-yl)-propionic acid (100 mg, 0.37 mmol) in methylene chloride (2.08 mL, 0.18M) at 25° C. was treated with N,N,N′,N′-tetramethyl-O—(N-succinimidyl)uronium tetrafluoroborate (135.6 mg, 0.45 mmol) and N,N-diisopropylethylamine (0.196 mL, 1.12 mmol). The resulting solution was stirred at 25° C. for 2 h. After this time, the reaction was treated with thiazol-2-ylamine (49 mg, 0.48 mmol). The resulting solution was stirred at 25° C. for 1 d. After this time, the reaction was partitioned between water (75 mL) and methylene chloride (3×75 mL). The combined organics were dried over sodium sulfate, filtered and concentrated in vacuo. Silica gel column chromatography (ISCO, 40 g, 1% methanol/methylene chloride) afforded 3-cyclopentyl-2-(4-methoxy-6-oxo-6H-pyridazin-1-yl)-N-thiazol-2-yl-propionamide as a white solid (41.4 mg, 32%); ES+-HRMS m/e calcd for C16H20N4O3S [M+H+] 349.1329, found 349.1328. 1H-NMR (300 MHz, DMSO-d6) δ ppm 0.98-7.78 (m, 9H), 1.95 (m, 1H), 2.27 (m, 1H), 3.82 (s, 3H), 5.54 (dd, J=4.5, J=10.6 Hz, 1H), 6.32 (d, Jm=2.7 Hz, 1H), 7.23 (d, J=3.6 Hz, 1H), 7.48 (d, J=3.6 Hz, 1H), 7.88 (d, Jm=2.7 Hz, 1H), 12.53 (s, 1H).
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([NH:10][C@H:11]([C:13]2[CH:25]=[CH:24][C:16]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])=[CH:15][CH:14]=2)[CH3:12])=[O:9])=[CH:6][C:5]([Cl:26])=[CH:4][N:3]=1.[CH3:27][S:28][C:29]1[CH:30]=[C:31]([OH:35])[CH:32]=[CH:33][CH:34]=1>>[Cl:26][C:5]1[CH:6]=[C:7]([C:8]([NH:10][C@H:11]([C:13]2[CH:25]=[CH:24][C:16]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])=[CH:15][CH:14]=2)[CH3:12])=[O:9])[C:2]([O:35][C:31]2[CH:32]=[CH:33][CH:34]=[C:29]([S:28][CH3:27])[CH:30]=2)=[N:3][CH:4]=1
Reactant: C[C@H](NC(=O)c1cc(Cl)cnc1Cl)c1ccc(C(=O)OC(C)(C)C)cc1
Reactant: CSc1cccc(O)c1
Product: CSc1cccc(Oc2ncc(Cl)cc2C(=O)N[C@@H](C)c2ccc(C(=O)OC(C)(C)C)cc2)c1

Procedure:
The title compound was prepared according to the procedure described in step 2 of Example 45 from tert-butyl 4-((1S)-1-{[(2,5-dichloropyridin-3-yl)carbonyl]amino}ethyl)benzoate (step 1 of Example 45) and 3-(methylthio)phenol (J. Amer. Chem. Soc. 1957, 79, 717): 1H-NMR (CDCl3) δ 8.55 (1H, d, J=2.7 Hz), 8.15 (1H, d, J=2.7 Hz), 8.13–8.10 (1H, m), 7.97–7.94 (2H, m), 7.41–7.34 (3H, m), 7.20–7.16 (1H, m), 7.03–7.01 (1H, m), 6.93–6.89 (1H, m), 5.41–5.31 (1H, m), 2.50 (3H, s), 1.60–1.57 (12H, m); MS (ESI) m/z 499 (M+H)+, 497 (M−H)−.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:9]2[CH2:14][N:13]([C:15]([N:17]3[CH2:22][CH2:21][CH:20]([OH:23])[CH2:19][CH2:18]3)=[O:16])[CH2:12][CH:11]([C:24](O)=[O:25])[CH2:10]2)[CH:5]=[CH:6][C:7]=1[CH3:8].O[N:28]=[C:29]([NH2:34])[CH2:30][CH2:31][O:32][CH3:33]>>[CH3:1][C:2]1[CH:3]=[C:4]([CH:9]2[CH2:10][CH:11]([C:24]3[O:25][N:34]=[C:29]([CH2:30][CH2:31][O:32][CH3:33])[N:28]=3)[CH2:12][N:13]([C:15]([N:17]3[CH2:18][CH2:19][CH:20]([OH:23])[CH2:21][CH2:22]3)=[O:16])[CH2:14]2)[CH:5]=[CH:6][C:7]=1[CH3:8]
Reactant: Cc1ccc(C2CC(C(=O)O)CN(C(=O)N3CCC(O)CC3)C2)cc1C
Reactant: COCCC(N)=NO
Product: COCCc1noc(C2CC(c3ccc(C)c(C)c3)CN(C(=O)N3CCC(O)CC3)C2)n1

Procedure:
200 mg (0.54 mmol) of the compound from Example 128A and 128 mg (0.81 mmol) of N′-hydroxy-3-methoxypropanimidamide were reacted according to the General Method 2. Yield: 138 mg (56% of theory)
Reaction SMILES: [NH2:1][C:2]1[C:16]([CH2:17][NH:18][CH:19]2[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]2)=[CH:15][C:5]([C:6]([O:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13]Cl)=[O:7])=[CH:4][C:3]=1[Br:25].[Cl:26][C:27]1[CH:32]=[CH:31][CH:30]=[C:29]([Cl:33])[C:28]=1[NH:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=1[CH2:41][C:42]([O-:44])=[O:43].[Na+]>>[NH2:1][C:2]1[C:16]([CH2:17][NH:18][CH:19]2[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]2)=[CH:15][C:5]([C:6]([O:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][O:44][C:42](=[O:43])[CH2:41][C:36]2[CH:37]=[CH:38][CH:39]=[CH:40][C:35]=2[NH:34][C:28]2[C:27]([Cl:26])=[CH:32][CH:31]=[CH:30][C:29]=2[Cl:33])=[O:7])=[CH:4][C:3]=1[Br:25]
Reactant: Nc1c(Br)cc(C(=O)OCCCCCCl)cc1CNC1CCCCC1
Reactant: O=C([O-])Cc1ccccc1Nc1c(Cl)cccc1Cl
Agent: [Na+]
Product: Nc1c(Br)cc(C(=O)OCCCCCOC(=O)Cc2ccccc2Nc2c(Cl)cccc2Cl)cc1CNC1CCCCC1

Procedure:
This compound was prepared from 5-(4-amino-3-bromo-5-cyclohexylaminomethyl-benzoyloxy)-n-pentyl chloride and sodium 2-[(2,6-dichlorophenyl)-amino]-phenylacetate analogous to Example 8.