Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8](Cl)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[CH3:12][N:13]1[CH2:18][CH2:17][CH:16]([C:19]2[C:27]3[C:22](=[CH:23][CH:24]=[C:25]([OH:28])[CH:26]=3)[NH:21][CH:20]=2)[CH2:15][CH2:14]1.[OH-].[Na+]>>[CH3:12][N:13]1[CH2:18][CH2:17][CH:16]([C:19]2[C:27]3[C:22](=[CH:23][CH:24]=[C:25]([O:28][S:8]([C:5]4[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=4)(=[O:10])=[O:9])[CH:26]=3)[NH:21][CH:20]=2)[CH2:15][CH2:14]1
Reactant: CN1CCC(c2c[nH]c3ccc(O)cc23)CC1
Reactant: O=S(=O)(Cl)c1ccc(Cl)cc1
Agent: [Na+]
Agent: [OH-]
Product: CN1CCC(c2c[nH]c3ccc(OS(=O)(=O)c4ccc(Cl)cc4)cc23)CC1
Yield: 97.8 %

Procedure:
By a method similar to Example 31, using 4-chlorobenzenesulfonyl chloride (242 mg, 1.15 mmol) and 3-(1-methylpiperidin-4-yl)-5-hydroxy-1H-indole (220 mg, 0.96 mmol), 0.2 N sodium hydroxide (5.5 mL, 1.1 mmol) gave 380 mg of a white solid. The crude product was recrystallized from ethyl acetate/hexanes to give 300 mg (78%) of the title compound as an off white powder: mp=182-183.5° C.; MS(m/e): 404 (M+); Calculated for C20H21ClN2O3S: C, 59.33; H, 5.23; N, 6.92. Found: C, 59.24; H, 5.22; N, 6.90.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(OC([N+](C(OC(C)C)=O)=[N-])=O)(C)C.[CH3:34][N:35]1[C:43]2[C:38](=[CH:39][C:40]([OH:44])=[CH:41][CH:42]=2)[C:37]([C:45]2[N:53]([S:54]([C:57]3[CH:62]=[CH:61][C:60]([CH3:63])=[CH:59][CH:58]=3)(=[O:56])=[O:55])[C:48]3=[N:49][CH:50]=[CH:51][CH:52]=[C:47]3[CH:46]=2)=[CH:36]1.[CH3:64][O:65][CH2:66][CH:67](O)[CH3:68]>C1(C)C=CC=CC=1>[CH3:64][O:65][CH2:66][CH:67]([CH3:68])[O:44][C:40]1[CH:39]=[C:38]2[C:43](=[CH:42][CH:41]=1)[N:35]([CH3:34])[CH:36]=[C:37]2[C:45]1[N:53]([S:54]([C:57]2[CH:62]=[CH:61][C:60]([CH3:63])=[CH:59][CH:58]=2)(=[O:56])=[O:55])[C:48]2=[N:49][CH:50]=[CH:51][CH:52]=[C:47]2[CH:46]=1
Reactant: COCC(C)O
Reactant: Cc1ccc(S(=O)(=O)n2c(-c3cn(C)c4ccc(O)cc34)cc3cccnc32)cc1
Agent: CC(C)OC(=O)[N+](=[N-])C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: COCC(C)Oc1ccc2c(c1)c(-c1cc3cccnc3n1S(=O)(=O)c1ccc(C)cc1)cn2C

Procedure:
A solution of triphenylphosphine (470 mg) and diisopropyldiazodicarboxylate (350 μl) in dry toluene (15 mL) was treated with 1-methyl-3-[1-(toluene-4-sulfonyl)-1H-pyrrolo[2,3-b]pyridin-2-yl]-1H-indol-5-ol [150 mg, Reference Example 14(a)] followed by 1-methoxy-2-propanol (150 μl). The resulting mixture was heated under reflux for 5 hours then cooled and then evaporated. The residue was subjected to flash chromatography on silica eluting with a mixture of ethyl acetate and pentane (1:1, v/v) to give the title compound (50 mg) as a clear oil. TLC: RF=0.65 (pentane/ethyl acetate: 1/1). MS: 480(MH+).
Reaction SMILES: [C:1]1([CH:7]=[CH:8][CH2:9][N:10]2[C:16](=[O:17])[CH:15]3[CH2:18][CH2:19][CH2:20][CH:14]3[NH:13][C:12]3[CH:21]=[CH:22][CH:23]=[CH:24][C:11]2=3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1>CO.[C].[Pd]>[C:1]1([CH2:7][CH2:8][CH2:9][N:10]2[C:16](=[O:17])[CH:15]3[CH2:18][CH2:19][CH2:20][CH:14]3[NH:13][C:12]3[CH:21]=[CH:22][CH:23]=[CH:24][C:11]2=3)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C1C2CCCC2Nc2ccccc2N1CC=Cc1ccccc1
Agent: [Pd]
Solvent: CO
Product: O=C1C2CCCC2Nc2ccccc2N1CCCc1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 1097.3 %

Procedure:
To a solution of 9-(3-phenyl-2-propen-1-yl)-2,3,3a,4,9,10a-hexahydrobenzo[b]cyclopenta[e][1,4]diazepin-10(1H)-one (1.0 g, 3.1 mmol) in methanol (10 mL) was added 10% palladium-carbon (hydrous) (0.1 g). The mixture was stirred for 30 minutes at room temperature under hydrogen atmosphere. The catalyst was filtered off, and the filtrate was concentrated under reduced pressure. To the concentrate were added ethyl acetate and hexane. Insoluble material was filtered off, and the filtrate was concentrated, which was subjected to a silica-gel column chromatography (hexane-ethyl acetate 10:1) to afford the desired product (10.90 g, 90%) as an oily product.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[C:9]([Cl:14])=[N:10][CH:11]=[CH:12][CH:13]=2)[N:5]=[CH:4][N:3]=1.[CH3:15][NH2:16]>C(Cl)Cl.C1COCC1.CC(C)=O>[Cl:14][C:9]1[C:8]([C:6]2[N:5]=[CH:4][N:3]=[C:2]([CH2:15][NH2:16])[N:7]=2)=[CH:13][CH:12]=[CH:11][N:10]=1
Reactant: CN
Reactant: Clc1ncnc(-c2cccnc2Cl)n1
Solvent: ClCCl
Solvent: CC(C)=O
Solvent: C1CCOC1
Product: NCc1ncnc(-c2cccnc2Cl)n1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To 2-chloro-4-(2-chloro-pyridin-3-yl)-[1,3,5]triazine (10.0 g, 44.0 mmol) in 55 ml of methylene chloride was added methylamine (45 ml, 88.0 mmol) as a 2.0 M solution in THF at 0° C. After stirring at room temperature for 18 h, the mixture was diluted with acetone and filtered through a plug of silica gel and concentrated to yield the desired product. MS m/z=222 [M+H]+. Calc'd for C9H8ClN5: 221.65.
Reaction SMILES: [Mn]([O-])(=O)(=O)=O.[K+].[C:7]([O:11][C:12]([NH:14][C@@:15]([CH2:21][C@@H:22]1[O:26][C:25]([CH3:28])([CH3:27])[NH:24][C@H:23]1[CH2:29][C@H:30]([CH2:34][C:35]1[CH:40]=[CH:39][C:38]([O:41][CH3:42])=[C:37]([O:43][CH2:44][CH2:45][CH2:46][O:47][CH3:48])[CH:36]=1)[CH:31]([CH3:33])[CH3:32])([CH:18]([CH3:20])[CH3:19])[CH:16]=[O:17])=[O:13])([CH3:10])([CH3:9])[CH3:8].S([O-])([O-])=[O:50].[Na+].[Na+].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.C1(C)C=CC=CC=1.O>[C:7]([O:11][C:12]([NH:14][C@@:15]([CH2:21][C@@H:22]1[O:26][C:25]([CH3:28])([CH3:27])[NH:24][C@H:23]1[CH2:29][C@H:30]([CH2:34][C:35]1[CH:40]=[CH:39][C:38]([O:41][CH3:42])=[C:37]([O:43][CH2:44][CH2:45][CH2:46][O:47][CH3:48])[CH:36]=1)[CH:31]([CH3:32])[CH3:33])([CH:18]([CH3:19])[CH3:20])[C:16]([OH:50])=[O:17])=[O:13])([CH3:8])([CH3:9])[CH3:10]
Reactant: O=S([O-])[O-]
Reactant: COCCCOc1cc(C[C@@H](C[C@@H]2NC(C)(C)O[C@H]2C[C@](C=O)(NC(=O)OC(C)(C)C)C(C)C)C(C)C)ccc1OC
Agent: O=[Mn](=O)(=O)[O-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: Cc1ccccc1
Solvent: O
Product: COCCCOc1cc(C[C@@H](C[C@@H]2NC(C)(C)O[C@H]2C[C@@](NC(=O)OC(C)(C)C)(C(=O)O)C(C)C)C(C)C)ccc1OC
Reaction time: 48 h

Procedure:
Water (470 ml), potassium permanganate (79.1 g) and tetrabutylammonium bromide (9.7 g) are added in succession at 0° C., with stirring, to a solution of N-(tert-butoxycarbonyl)amino-2(S)-{4(S)-[2(S)-[4-methoxy-3-(3-methoxypropoxy)-benzyl]-3-methyl-butyl]-2,2-dimethyloxazolidin-5(S)-ylmethyl}-3-methyl-butyraldehyde (53.0 g) in toluene (470 ml). The reaction mixture is stirred for 48 hours at 0°-5° C. and then, at 10% sodium sulfite solution (1.2 liters) and, after a further 30 minutes, 10% citric acid solution (1.95 liters) and water (1.2 liters) are added. The mixture is extracted with ethyl acetate (3×2.5 liters), and the organic phases are washed with water and saturated sodium chloride solution, dried over magnesium sulfate and concentrated. Purification of the crude product by FC (2.3 kg of silica gel, ethyl acetate/hexane 3:7) yields the pure title compound in the form of an oil (31.7 g): Rf (ethyl acetate/hexane 1:2)=0.21; Anal. C33H55NO8 (593.80): calc. C, 66.75; H, 9.34; N, 2.36; found C, 66.69; H, 9.39; N, 2.39.
Reaction SMILES: [CH2:1]([O:19][C:20]1[CH:29]=[CH:28][C:23]([C:24]([O:26]C)=[O:25])=[CH:22][CH:21]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].S(=O)(=O)(O)O>C(O)(=O)C>[CH2:1]([O:19][C:20]1[CH:21]=[CH:22][C:23]([C:24]([OH:26])=[O:25])=[CH:28][CH:29]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: CCCCCCCCCCCCCCCCCCOc1ccc(C(=O)OC)cc1
Agent: O=S(=O)(O)O
Solvent: CC(=O)O
Product: CCCCCCCCCCCCCCCCCCOc1ccc(C(=O)O)cc1
Reaction time: 0.67 h
Yield: 82.9 %

Procedure:
A mixture containing methyl 4-octadecyloxybenzoate (30 g) and acetic acid (10 ml) was warmed until a solution was obtained. To this solution was added concentrated sulfuric acid (3 ml), and the mixture heated to slowly distill off the methyl acetate. This distillation was carried out over a period of 40 minutes. The solution was then cooled just below the boiling point and stirred for an additional 30 minutes. The hot reaction mixture was poured onto cold water and the solid filtered and dried. The product was then slurried in methylene chloride (100 ml) then filtered. The solid was recrystallized from 2-butanone to give 4-octadecyloxybenzoic acid (24 g).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH3:12])[C:7](=[O:13])[CH2:6][CH2:5]2.[F:14][C:15]([F:26])([F:25])[C:16]1[CH:17]=[CH:18][C:19]([CH2:22][CH2:23][NH2:24])=[N:20][CH:21]=1>>[CH3:12][N:8]1[C:9]2[C:4](=[CH:3][C:2]([NH:24][CH2:23][CH2:22][C:19]3[CH:18]=[CH:17][C:16]([C:15]([F:26])([F:14])[F:25])=[CH:21][N:20]=3)=[CH:11][CH:10]=2)[CH2:5][CH2:6][C:7]1=[O:13]
Reactant: CN1C(=O)CCc2cc(Br)ccc21
Reactant: NCCc1ccc(C(F)(F)F)cn1
Product: CN1C(=O)CCc2cc(NCCc3ccc(C(F)(F)F)cn3)ccc21

Procedure:
In analogy to the procedure described for the synthesis example 71 (step 1), the title compound 1-methyl-6-[2-(5-trifluoromethyl-pyridin-2-yl)-ethylamino]-3,4-dihydro-1H-quinolin-2-one (MS m/e: 350.3 [M+H]+) was prepared from 6-bromo-1-methyl-3,4-dihydro-1H-quinolin-2-one instead of 6-bromo-2,3-dihydro-benzofuran and 2-(5-trifluoromethyl-pyridin-2-yl)-ethylamine instead of 2-(6-trifluoromethyl-pyridin-3-yl)-ethylamine.
Reaction SMILES: [C:1]1(=[O:7])[O:6][C:4](=[O:5])[CH:3]=[CH:2]1.[CH2:8](O)[CH2:9][CH2:10][CH2:11][OH:12]>>[C:4]1(=[O:5])[O:12][CH2:11][CH2:10][CH2:9][CH2:8][O:6][C:1](=[O:7])[CH:2]=[CH:3]1
Reactant: O=C1C=CC(=O)O1
Reactant: OCCCCO
Agent: O=C1/C=C\C(=O)OCCCCO1
Product: O=C1C=CC(=O)OCCCCO1
Reaction time: 12 h

Procedure:
A solution of 768 g (7.83 mol) of maleic anhydride (MA) in 1059 g (11.75 mol) of 1,4-butanediol was placed in the first reactor of a reactor cascade made of acid-resistant material, which cascade comprised 3 reactors connected in series each having a volume of 5 l and each being provided with a high-speed stirring system of conventional construction (turbine stirrer, speed: 800-1200/min) and a distillation column (10 theoretical plates), the solution was quickly heated while stirring to a reaction temperature of 105°-100° C. and the water of reaction which formed was distilled off. After a reaction time of 6 hours, the reaction mixture was transferred into the connected second reactor; there a further part of the water of reaction was distilled off at a reaction temperature of 110°-115° C. while stirring. After a reaction time of 4 hours, the reaction mixture was finally transferred into the connected third reactor; there the remainder of the water of reaction was removed under a pressure of 400 mbar and at a reaction temperature which was gradually increased from 115° to 125° C. After a further 2 hours (total of 12 hours), the esterification was ended. The oligomeric 1,4-butanediyl maleate obtained (1682 g) had a mean degree of oligomerization of n=3 (measured by gel permeation chromatography) and an acid number of 21 mg KOH/g of reaction mixture.
Reaction SMILES: [O:1]=[C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[C:13]2[CH:18]=[CH:17][C:16]([CH2:19][C:20]3[C:21](=[O:43])[N:22]([C@H:32]4[CH2:37][CH2:36][C@H:35]([O:38][CH2:39][C:40](=O)[CH3:41])[CH2:34][CH2:33]4)[C:23]4[N:24]([N:29]=[CH:30][N:31]=4)[C:25]=3[CH2:26][CH2:27][CH3:28])=[CH:15][CH:14]=2)[NH:3]1.Cl.[NH2:45][O:46][CH3:47].N1C=CC=CC=1.Cl>O.C(OCC)(=O)C>[CH3:47][O:46]/[N:45]=[C:40](\[CH3:41])/[CH2:39][O:38][C@H:35]1[CH2:34][CH2:33][C@H:32]([N:22]2[C:21](=[O:43])[C:20]([CH2:19][C:16]3[CH:17]=[CH:18][C:13]([C:8]4[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=4[C:4]4[NH:3][C:2](=[O:1])[O:6][N:5]=4)=[CH:14][CH:15]=3)=[C:25]([CH2:26][CH2:27][CH3:28])[N:24]3[N:29]=[CH:30][N:31]=[C:23]23)[CH2:37][CH2:36]1
Reactant: CON
Reactant: CCCc1c(Cc2ccc(-c3ccccc3-c3noc(=O)[nH]3)cc2)c(=O)n([C@H]2CC[C@H](OCC(C)=O)CC2)c2ncnn12
Agent: Cl
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Solvent: O
Product: CCCc1c(Cc2ccc(-c3ccccc3-c3noc(=O)[nH]3)cc2)c(=O)n([C@H]2CC[C@H](OC/C(C)=N/OC)CC2)c2ncnn12
Temperature: 80 °C
Reaction time: 16 h

Procedure:
A mixture of 6-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-4-[trans-4-(2-oxopropoxy)cyclohexyl]-7-propyl[1,2,4]triazolo[1,5-a]pyrimidin-5(4H)-one (0.095 g), (aminooxy)methane hydrochloride (0.041 g) and pyridine (5 mL) was stirred at 80° C. for 16 hr. Ethyl acetate and water were added to the reaction mixture, and the mixture was adjusted to pH 4 with 1 N hydrochloric acid. The ethyl acetate layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography to give the title compound as colorless crystals (0.07 g, 70%).
Reaction SMILES: OS(O)(=O)=O.[CH3:6][C:7]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)([CH3:21])[C:8]([CH:10]([C:16]([O:18]CC)=O)[C:11]([O:13][CH2:14][CH3:15])=[O:12])=[O:9]>CCOC(C)=O>[OH:18][C:16]1[C:23]2[C:22](=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:7]([CH3:21])([CH3:6])[C:8](=[O:9])[C:10]=1[C:11]([O:13][CH2:14][CH3:15])=[O:12]
Reactant: CCOC(=O)C(C(=O)OCC)C(=O)C(C)(C)c1ccccc1
Agent: O=S(=O)(O)O
Solvent: CCOC(C)=O
Product: CCOC(=O)C1=C(O)c2ccccc2C(C)(C)C1=O
Temperature: 0 °C
Reaction time: 2 h
Yield: 57.7 %

Procedure:
Concentrated H2SO4 (38.5 mL) was added dropwise via addition funnel to diethyl 2-(2-methyl-2-phenylpropanoyl)malonate (22.1 g, 72.1 mmol) cooled to 0° C. The reaction mixture was stirred for 2 hours at 0° C. and then poured into a flask containing ice, diluted with 400 mL of EtOAc, added to a separatory funnel, partitioned with water, washed 2 times with 100 mL of water, separated, dried over Na2SO4, and concentrated in vacuo to give the title compound (10.82 g) as a white amorphous solid after flash chromatography. MS (m/z)=261 (M+H)+.
Reaction SMILES: [OH:1][CH:2]([CH3:15])[C:3]([O:5][CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[CH:9][CH:8]=1)=[O:4].[C:16]([NH:26][C@H:27]([C:31](O)=[O:32])[CH:28]([CH3:30])[CH3:29])([O:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[O:17].C1CCC(N=C=NC2CCCCC2)CC1>CN(C1C=CN=CC=1)C.ClCCl>[C:16]([NH:26][C@H:27]([C:31]([O:1][CH:2]([CH3:15])[C:3]([O:5][CH2:6][C:7]1[CH:8]=[CH:9][C:10]([O:13][CH3:14])=[CH:11][CH:12]=1)=[O:4])=[O:32])[CH:28]([CH3:30])[CH3:29])([O:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[O:17]
Reactant: COc1ccc(COC(=O)C(C)O)cc1
Reactant: CC(C)[C@H](NC(=O)OCc1ccccc1)C(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: COc1ccc(COC(=O)C(C)OC(=O)[C@@H](NC(=O)OCc2ccccc2)C(C)C)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 4-methoxybenzyl 2-hydroxypropionate (4.2 g, 20 mmole), N-CBZ-L-valine (5.02 g, 20 mmole) and DMAP (0.24 g, 2 mmole) in 100 ml dichloromethane was added a solution of DCC (4.54 g, 22 mmole) and the mixture was stirred overnight at room temperature. The mixture was cooled to 5° C. and the urethane was filtered. The filtrate was evaporated and the product was isolated by silica gel column chromatography. Yield: 7.9 g
Reaction SMILES: Cl.[CH2:2]([O:4][CH2:5][CH2:6][N:7]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[N:9]=[C:8]1[N:16]1[CH2:22][CH2:21][CH2:20][N:19]([CH2:23][CH2:24][C:25]2([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[CH2:29][CH2:28][NH:27][CH2:26]2)[CH2:18][CH2:17]1)[CH3:3].[CH3:36][O:37][C:38]1[CH:46]=[CH:45][C:44]([N:47]2[C:51]([C:52]([F:55])([F:54])[F:53])=[N:50][N:49]=[N:48]2)=[CH:43][C:39]=1[C:40](O)=[O:41]>>[CH3:36][O:37][C:38]1[CH:46]=[CH:45][C:44]([N:47]2[C:51]([C:52]([F:55])([F:53])[F:54])=[N:50][N:49]=[N:48]2)=[CH:43][C:39]=1[C:40]([N:27]1[CH2:28][CH2:29][C:25]([CH2:24][CH2:23][N:19]2[CH2:20][CH2:21][CH2:22][N:16]([C:8]3[N:7]([CH2:6][CH2:5][O:4][CH2:2][CH3:3])[C:11]4[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=4[N:9]=3)[CH2:17][CH2:18]2)([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[CH2:26]1)=[O:41]
Reactant: CCOCCn1c(N2CCCN(CCC3(c4ccccc4)CCNC3)CC2)nc2ccccc21
Reactant: COc1ccc(-n2nnnc2C(F)(F)F)cc1C(=O)O
Agent: Cl
Product: CCOCCn1c(N2CCCN(CCC3(c4ccccc4)CCN(C(=O)c4cc(-n5nnnc5C(F)(F)F)ccc4OC)C3)CC2)nc2ccccc21

Procedure:
Prepare by the method of Example 51.1 using 3-(2-(4-(1-(2-ethoxyethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-phenylpyrrolidine hydrochloric acid salt (prepared from (−)-3-phenyl-3-(2-hydroxyethyl)pyrrolidine(R,R)-di-p-anisoyltartaric acid salt) and 2-methoxy-5-(5-trifluoromethyl-1H-tetrazol-1-yl)benzoic acid to give the title compound.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C@@H:10](O)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O.COC(=O)/C=C/C1C=CC(O)=CC=1>C1COCC1>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](O)C1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: COC(=O)/C=C/c1ccc(O)cc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCCC1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To a solution of 4-hydroxycinnamic acid (0.407 g, 2.48 mmol) in EtOAc, a solution of diazomethane in Et2O was added until the yellow color persisted. Excess diazomethane was quenched by the addition of AcOH and the reaction mixture was evaporated to dryness. The residue was dissolved in EtOAc and washed with 10% aqueous HCl, saturated NaHCO3 and brine. The organic layer was dried over anhydrous MgSO4 and evaporated to dryness. The residue was purified by flash column chromatography, using a gradient from 10%-20% EtOAc in hexane, to give E-3-(4-hydroxyphenyl)acrylic acid methyl ester as a white solid (0.362 g). To a solution of (R)-3-hydroxypyrrolidine-1-carboxylic acid tert-butyl ester (0.215 g, 1.15 mmol) in THF at 0° C., triphenylphosphine (0.316 g, 1.21 mmol), diisopropyl azodicarboxylate (236 μL, 1.21 mmol) and E-3-(4-hydroxy-phenyl)-acrylic acid methyl ester (0.215 g, 1.21 mmol) were added. The reaction mixture was stirred for 2 h at 0° C., followed by 4 h at room temperature and then the solvent was evaporated in vacuo. The residue was purified by flash column chromatography, using 20%-30% EtOAc in hexane, to give crude (S)-3-[4-(E)-2-methoxycarbonylvinyl)phenoxy]pyrrolidine-1-carboxylic acid tert-butyl ester as a yellow solid.
Reaction SMILES: Cl[C:2]1[CH:7]=[N:6][CH:5]=[C:4]([Cl:8])[N:3]=1.[NH2:9][CH:10]1[CH2:15][CH2:14][N:13]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:12][CH2:11]1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C>[Cl:8][C:4]1[N:3]=[C:2]([NH:9][CH:10]2[CH2:11][CH2:12][N:13]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:14][CH2:15]2)[CH:7]=[N:6][CH:5]=1
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Reactant: Clc1cncc(Cl)n1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(Nc2cncc(Cl)n2)CC1
Temperature: 100 °C
Reaction time: 4 h

Procedure:
To a stirred solution of 2,6-dichloropyrazine (5.0 g, 34 mmol) and 4-amino-1-boc-piperidine (6.7 g, 34 mmol) in DMF (67 mL) was added cesium carbonate (22 g, 67 mmol). The reaction mixture was stirred at 100° C. After 4 h, the reaction was quenched with saturated aqueous sodium bicarbonate (100 mL) and extracted with EtOAc (3×100 mL). The combined organic layers were dried over magnesium sulfate, filtered and concentrated. The crude residue was purified by silica gel chromatography (EtOAc/Hexanes gradient) to afford tert-butyl 4-[(6-chloropyrazin-2-yl)amino]piperidine-1-carboxylate as a yellow solid. LRMS (ESI) calculated for C14H21ClN4O2 [M+Na]+, 335.1; found 335.1.
Reaction SMILES: Cl.[NH2:2][CH2:3][CH2:4][NH:5][C:6](=[O:15])[O:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[CH:16]([N:19]([CH:30]([CH3:32])[CH3:31])[CH2:20][CH2:21][NH:22][C:23](N1C=CN=C1)=[O:24])([CH3:18])[CH3:17].C(N(CC)CC)C>ClCCl>[CH:30]([N:19]([CH:16]([CH3:18])[CH3:17])[CH2:20][CH2:21][NH:22][C:23]([NH:2][CH2:3][CH2:4][NH:5][C:6](=[O:15])[O:7][CH2:8][C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1)=[O:24])([CH3:32])[CH3:31]
Reactant: CC(C)N(CCNC(=O)n1ccnc1)C(C)C
Reactant: NCCNC(=O)OCc1ccccc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)N(CCNC(=O)NCCNC(=O)OCc1ccccc1)C(C)C
Temperature: 25 °C
Yield: 109.6 %

Procedure:
A solution of benzyl 2-aminoethylcarbamate hydrochloride (4.33 g, 18.8 mmol), N-[2-(diisopropylamino)ethyl]-1H-imidazole-1-carboxamide (Preparation 19) (3.73 g, 15.64 mmol) and triethylamine (2.62 ml, 18.8 mmol) in dichloromethane (100 ml) was heated under reflux for 14 hours. The solution was allowed to cool to room temperature and then washed with water (20 ml). The aqueous layer was separated and extracted with more dichloromethane (20 ml). The combined organic layers were dried over anhydrous magnesium sulfate and solvent evaporated under reduced pressure to give the title compound as a yellow oil (6.25 g).
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:38])[NH:10][CH2:11][C:12]1[CH:37]=[CH:36][C:15]2[CH:16]=[C:17]([C:19]([NH:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[NH:28]C(OC(C)(C)C)=O)=[O:20])[S:18][C:14]=2[CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:28][C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=1[NH:21][C:19]([C:17]1[S:18][C:14]2[CH:13]=[C:12]([CH2:11][NH:10][C:9](=[O:38])[O:8][CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[CH:37]=[CH:36][C:15]=2[CH:16]=1)=[O:20]
Reactant: CC(C)(C)OC(=O)Nc1ccccc1NC(=O)c1cc2ccc(CNC(=O)OCc3ccccc3)cc2s1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Nc1ccccc1NC(=O)c1cc2ccc(CNC(=O)OCc3ccccc3)cc2s1
Reaction time: 2 h

Procedure:
To a solution of benzyl({2-[({2-[(tert-butoxycarbonyl)amino]phenyl}amino)carbonyl]-1-benzothien-6-yl}methyl)carbamate (85 mg, 0.16 mmol) in CH2Cl2 (4 mL) was added TFA (2 mL). The reaction mixture was stirred for 2 h, the solvent was removed. The residue was triturated with CH2Cl2 and sat. NaHCO3, and the resultant solid was filtered yielding the desired product. 1H NMR (DMSO-d6, 600 MHz) δ 10.05 (br s, 1H), 8.23 (s, 1H), 7.87 (m, 2H), 7.80 (s, 1H), 7.32-7.29 (m, 4H), 7.27 (m, 1H), 7.17 (br d, J=6.8 Hz, 1H), 7.02 (dd, J=6.8, 6.8 Hz, 1H), 6.87 (br d, J=6.8 Hz, 1H), 6.75 (br s, 1H), 5.00 (s, 2H), 4.29 (d, J=6.2 Hz, 2H). MS: cal'd 432 (MH+), exp 432 (MH+).
Reaction SMILES: C(OC([N:8]1[CH2:12][C@H:11]([S:13][CH2:14][C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=2)[CH2:10][C@H:9]1[C:23]([NH:25][N:26]([CH3:37])[S:27]([C:30]1[CH:35]=[CH:34][C:33]([CH3:36])=[CH:32][CH:31]=1)(=[O:29])=[O:28])=[O:24])=O)(C)(C)C.[C:38]([OH:44])([C:40]([F:43])([F:42])[F:41])=[O:39]>C(Cl)Cl>[CH3:37][N:26]([S:27]([C:30]1[CH:31]=[CH:32][C:33]([CH3:36])=[CH:34][CH:35]=1)(=[O:29])=[O:28])[NH:25][C:23]([C@@H:9]1[CH2:10][C@@H:11]([S:13][CH2:14][C:15]2[CH:16]=[CH:17][C:18]([O:21][CH3:22])=[CH:19][CH:20]=2)[CH2:12][NH:8]1)=[O:24].[C:38]([OH:44])([C:40]([F:43])([F:42])[F:41])=[O:39]
Reactant: COc1ccc(CS[C@@H]2C[C@@H](C(=O)NN(C)S(=O)(=O)c3ccc(C)cc3)N(C(=O)OC(C)(C)C)C2)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1ccc(CS[C@H]2CN[C@H](C(=O)NN(C)S(=O)(=O)c3ccc(C)cc3)C2)cc1

Procedure:
(step 5) 2.37 g (4.3 mmol) (2S,4R)-2-[N′-Methyl-N′-(4-methyl-phenylsulfonyl)-hydrazinocarbonyl]-4-(4-methoxy-benzylsulfanyl)-pyrrolidine-1-carboxylic acid 1-tert-butyl ester in 10 ml CH2Cl2 were treated with 4 ml TFA at 0° C. and kept in the freezer over night. The solvent was evaporated, the crude material was dissolved and evaporated with toluene (2×) and hexane (3×) yielding (2S,4R)-2-[N′-Methyl-N′-(4-methyl-phenylsulfonyl)-hydrazinocarbonyl]-4-(4-methoxy-benzylsulfanyl)-pyrrolidine as TFA salt as crude product, which was subjected to the following reaction without further purification.