Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:34])=[C:4]([CH:31]=[CH:32][CH:33]=1)[CH2:5][NH:6][C:7]([C@@H:9]1[CH2:13][C@@H:12]([F:14])[CH2:11][N:10]1[C:15](=[O:30])[CH2:16][N:17]1[C:25]2[C:20](=[CH:21][C:22]([OH:26])=[CH:23][CH:24]=2)[C:19]([C:27](=[O:29])[CH3:28])=[CH:18]1)=[O:8].[OH-].[K+].I[CH3:38]>CS(C)=O>[Cl:1][C:2]1[C:3]([F:34])=[C:4]([CH:31]=[CH:32][CH:33]=1)[CH2:5][NH:6][C:7]([C@@H:9]1[CH2:13][C@@H:12]([F:14])[CH2:11][N:10]1[C:15](=[O:30])[CH2:16][N:17]1[C:25]2[C:20](=[CH:21][C:22]([O:26][CH3:38])=[CH:23][CH:24]=2)[C:19]([C:27](=[O:29])[CH3:28])=[CH:18]1)=[O:8]
Reactant: CI
Reactant: CC(=O)c1cn(CC(=O)N2C[C@H](F)C[C@H]2C(=O)NCc2cccc(Cl)c2F)c2ccc(O)cc12
Agent: [K+]
Agent: [OH-]
Solvent: CS(C)=O
Product: COc1ccc2c(c1)c(C(C)=O)cn2CC(=O)N1C[C@H](F)C[C@H]1C(=O)NCc1cccc(Cl)c1F
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
A solution of (2S,4R)-1-[2-(3-acetyl-5-hydroxy-indol-1-yl)-acetyl]-4-fluoro-pyrrolidine-2-carboxylic acid 3-chloro-2-fluoro-benzylamide Example 579 (28.0 mg, 0.057 mmol) in DMSO (2 mL) was treated with potassium hydroxide (15.0 mg, 0.257 mmol). The mixture was stirred at RT for 5 min, followed by addition of iodomethane (0.006 mL, 0.089 mmol) and stirring at RT for 60 h. The reaction mixture was partitioned between water and CH2Cl2 and the aqueous layer was extracted with CH2Cl2 (2×). The combined organics were washed with brine (3×), dried (phase separator) and concentrated under reduced pressure. The crude product was purified by preparative HPLC (Waters Sunfire, C18-ODB, 5 μm, 19×50 mm, flow: 20 mL/min, eluent: 5-100% CH3CN/H2O/20 min, 100% CH3CN/2 min, CH3CN and H2O containing 0.1% TFA) to afford after lyophilization of the purified fractions the title compound as a solid. MS (LC/MS): 504 [M+H]+, 526 [M+Na]+; tR (HPLC conditions k): 3.38 min.
Reaction SMILES: [NH2:1][C:2]1[C:3]([Br:12])=[C:4]([CH:9]=[CH:10][CH:11]=1)[C:5]([O:7][CH3:8])=[O:6].[C:13]1(=O)[CH2:17][CH2:16][CH2:15][CH2:14]1.C(O)(=O)C.C([BH3-])#N.[Na+]>CO>[Br:12][C:3]1[C:2]([NH:1][CH:13]2[CH2:17][CH2:16][CH2:15][CH2:14]2)=[CH:11][CH:10]=[CH:9][C:4]=1[C:5]([O:7][CH3:8])=[O:6]
Reactant: O=C1CCCC1
Reactant: COC(=O)c1cccc(N)c1Br
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: COC(=O)c1cccc(NC2CCCC2)c1Br
Temperature: 25 °C
Reaction time: 3 h
Yield: 36.1 %

Procedure:
To a stirred solution of methyl 3-amino-2-bromobenzoate (3 g, 13.0 mmol) and cyclopentanone (5.4 g, 64.28 mmol) in methanol (20 mL), acetic acid (1.56 g, 26 mmol) was added and reaction stirred at room temperature for 3 h. Then sodium cyanoborohydride (2 g, 31.7 mmol) was added and reaction stirred overnight. On completion, solvent was removed under reduced pressure and crude material purified by column chromatography to afford methyl 2-bromo-3-(cyclopentylamino)benzoate (1.4 g, 36%).
Reaction SMILES: [CH3:1][C:2]1[C:6]([CH3:7])=[C:5]([NH2:8])[O:4][N:3]=1.[H-].[Na+].[Cl:11][C:12]1[CH:31]=[CH:30][C:15]([CH2:16][C:17]2[S:21][C:20]3[CH:22]=[CH:23][CH:24]=[CH:25][C:19]=3[C:18]=2[S:26](Cl)(=[O:28])=[O:27])=[CH:14][CH:13]=1>C1COCC1>[CH3:1][C:2]1[C:6]([CH3:7])=[C:5]([NH:8][S:26]([C:18]2[C:19]3[CH:25]=[CH:24][CH:23]=[CH:22][C:20]=3[S:21][C:17]=2[CH2:16][C:15]2[CH:14]=[CH:13][C:12]([Cl:11])=[CH:31][CH:30]=2)(=[O:28])=[O:27])[O:4][N:3]=1
Reactant: Cc1noc(N)c1C
Reactant: O=S(=O)(Cl)c1c(Cc2ccc(Cl)cc2)sc2ccccc12
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1noc(NS(=O)(=O)c2c(Cc3ccc(Cl)cc3)sc3ccccc23)c1C

Procedure:
N-(3,4-dimethyl-5-isoxazolyl)-2-(4-chlorobenzyl)-benzo[b]thiophene-3-sulfonamide was prepared by the method of Example 41 with 3,4-dimethyl-5-aminoisoxazole (1.2 mmoles, 1.4 g), NaH (3.0 mmoles, 73 mg), 2-(4-chlorobenzyl)-benzo[b]thiophene-3-sulfonylchloride (1.4 mmoles, 0.50 g) and THF (8 ml). Flash chromatography (50% ethyl acetate/hexanes) followed by recrystallization from methanol and water provided 1.04 g (27%) of a yellow solid, m.p. 100-102° C.
Reaction SMILES: C[O:2][C:3](=[O:23])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH3:11])=[C:6]([O:12][CH2:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([C:21]#[N:22])[CH:16]=2)[CH:5]=1.[OH-].[Li+]>O1CCOCC1>[C:21]([C:17]1[CH:16]=[C:15]([CH2:14][CH2:13][O:12][C:6]2[CH:5]=[C:4]([CH:9]=[CH:8][C:7]=2[O:10][CH3:11])[C:3]([OH:23])=[O:2])[CH:20]=[CH:19][CH:18]=1)#[N:22]
Reactant: COC(=O)c1ccc(OC)c(OCCc2cccc(C#N)c2)c1
Agent: [Li+]
Agent: [OH-]
Solvent: C1COCCO1
Product: COc1ccc(C(=O)O)cc1OCCc1cccc(C#N)c1
Temperature: 60 °C
Reaction time: 0.5 h
Yield: 60.9 %

Procedure:
The compound of step 2 (274 mg, 0.883 mmol) was dissolved in dioxane (4.5 ml), lithium hydroxide (4.42 ml of a 1 M aqueous solution, 4.42 mmol) was added, and the mixture was stirred at 60° C. for 30 min. The mixture was partitioned between 2 N hydrochloric acid and EA, the aqueous phase extracted with EA, and the combined organic extracts were dried over sodium sulfate, filtered and evaporated to dryness. The residue was purified by preparative RP HPLC (water/ACN gradient) to give 160 mg of the title compound.
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[CH2:11][CH2:10][C@@H:9]([OH:12])[C@H:8]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH2:7]1)=[O:5])[CH3:2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:38]1([CH3:45])[C:43](O)=[CH:42][CH:41]=[CH:40][CH:39]=1.N(C(OCC)=O)=NC(OCC)=O>C1C=CC=CC=1>[CH2:1]([O:3][C:4]([N:6]1[CH2:11][CH2:10][C@H:9]([O:12][C:39]2[CH:40]=[CH:41][CH:42]=[CH:43][C:38]=2[CH3:45])[C@H:8]([C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)N1CC[C@@H](O)[C@H](c2ccccc2)C1
Reactant: Cc1ccccc1O
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: c1ccccc1
Product: CCOC(=O)N1CC[C@H](Oc2ccccc2C)[C@H](c2ccccc2)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture of 6.23 g of trans-1-ethoxycarbonyl-3-phenyl-4-piperidinol, 7.21 g of triphenylphosphine, 2.97 g of o-cresol and 250 ml of anhydrous benzene is added, dropwise at 5° C. under nitrogen over a 90 minute period, a solution of 4.79 g of diethyl azodicarboxylate in 250 ml of benzene. After the addition is complete the mixture is stirred overnight at room temperature. The solid is then filtered and washed with benzene and the filtrate concentrated in vacuo to an oil. The oil is triturated overnight in a stoppered flask with 250 ml of hexane. The hexane is decanted and the gummy solid is triturated with more hexane and the hexane solution is filtered. The hexane filtrate is washed with 10% aqueous sodium hydroxide solution (3×75 ml), 2 N hydrochloric acid (100 ml), water (100 ml), saturated sodium chloride solution (100 ml), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to a yellow gum. The gummy solid previously obtained is washed with ether. The ether filtrate is concentrated in vacuo and the residue is partitioned between 150 ml of hexane and 50 ml of 10% sodium hydroxide solution. The phases are separated. The hexane phase is washed with 10% sodium hydroxide solution, followed by 2 N hydrochloric acid solution (50 ml), water (100 ml), saturated sodium chloride solution (100 ml), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The resulting gum is combined with the previously obtained gum. Trituration of the gum with a 2:1 mixture of petroleum ether:ether affords a colorless solid. A second crop is obtained from the filtrate. Filtration through a silica gel plug using dichloromethane as solvent, followed by trituration with 2:1 /petroleum ether:ether solution and filtration affords product as a colorless solid, mp 119.5°-121° C.
Reaction SMILES: [Cl:1][C:2]1[C:7]2[C:8](=[O:22])[N:9]3[CH2:21][CH2:20][C@H:10]3[C:11]3[N:12]([CH:13]=[N:14][C:15]=3[C:16](=[N:18][OH:19])[NH2:17])[C:6]=2[CH:5]=[CH:4][CH:3]=1.[Cl:23][CH2:24][C:25](OC(=O)CCl)=O>CN(C)C=O>[Cl:1][C:2]1[C:7]2[C:8](=[O:22])[N:9]3[CH2:21][CH2:20][C@H:10]3[C:11]3[N:12]([CH:13]=[N:14][C:15]=3[C:16]3[N:17]=[C:25]([CH2:24][Cl:23])[O:19][N:18]=3)[C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: O=C(CCl)OC(=O)CCl
Reactant: NC(=NO)c1ncn2c1[C@@H]1CCN1C(=O)c1c(Cl)cccc1-2
Solvent: CN(C)C=O
Product: O=C1c2c(Cl)cccc2-n2cnc(-c3noc(CCl)n3)c2[C@@H]2CCN12
Yield: 74.2 %

Procedure:
31.7 g (100 mmol) of (S)-8-chloro-9-oxo-12,12a-dihydro-9H, 11H-azeto[2,1-c]imidazo[1,5-a][1,4]-benzodiazepine-1-carboxamidoxime were suspended in 200 ml of N,N-dimethylformamide and treated with 18.8 g (110 mmol) of chloroacetic anhydride. The reaction mixture was heated to 105° for 2 hours and evaporated. By chromatography of the residue on silica gel while eluting with chloroform/methanol 9/1 there were obtained 27.9 g (74%) of (S)-8-chloro-1-(5-chloromethyl-1,2,4-oxadiazol-3-yl)-12,12a-dihydro-9H,11H-azeto[2,1-c]-imidazo[1,5-a][1,4]benzodiazepin-9-one of m.p. 211°-212°.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4](OS(C(F)(F)F)(=O)=O)[CH:5]=[C:6]([Cl:23])[C:7]=1[CH2:8][N:9]1[CH2:13][CH2:12][CH:11]([N:14]2[CH2:19][CH2:18][C:17]([F:21])([F:20])[CH2:16][CH2:15]2)[C:10]1=[O:22].[C:32]1([C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)[CH:37]=[CH:36][C:35](B(O)O)=[CH:34][CH:33]=1.C(=O)([O-])[O-].[Na+].[Na+]>C1COCC1.C(OCC)(=O)C.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>[Cl:1][C:2]1[CH:3]=[C:4]([C:44]2[CH:45]=[CH:46][C:41]([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)=[CH:42][CH:43]=2)[CH:5]=[C:6]([Cl:23])[C:7]=1[CH2:8][N:9]1[CH2:13][CH2:12][CH:11]([N:14]2[CH2:19][CH2:18][C:17]([F:21])([F:20])[CH2:16][CH2:15]2)[C:10]1=[O:22]
Reactant: O=C1C(N2CCC(F)(F)CC2)CCN1Cc1c(Cl)cc(OS(=O)(=O)C(F)(F)F)cc1Cl
Reactant: OB(O)c1ccc(-c2ccccc2)cc1
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: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: O=C1C(N2CCC(F)(F)CC2)CCN1Cc1c(Cl)cc(-c2ccc(-c3ccccc3)cc2)cc1Cl
Temperature: 80 °C
Yield: 100.1 %

Procedure:
Purge with N2 a mixture of trifluoro-methanesulfonic acid 3,5-dichloro-4-[3-(4,4-difluoro-piperidin-1-yl)-2-oxo-pyrrolidin-1-ylmethyl]-phenyl ester (0.097 g, 0.19 mmol), 4-biphenylboronic acid (0.045 g, 0.23 mmol) in THF (5 mL), and 2M sodium carbonate (0.29 mL). Treat the reaction with Pd(PPh3)4 (0.011 g, 0.01 mmol) and heat to 80° C. for 1 hour under N2. Cool the reaction, dilute with ethyl acetate, and wash with water. Dry the organic layer with Na2SO4 and remove the solvent in vacuo to afford crude product. Purify on silica with 100% ethyl acetate to afford 0.098 g (100%) of the titled product. Rf=0.44 (100% ethyl acetate). MS (m/z): 515 (M+).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C@H:15]2[CH2:20][CH2:19][C@H:18]([NH2:21])[CH2:17][CH2:16]2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[O:22]1[CH2:31][CH:23]1[CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>CO>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([C@@H:15]2[CH2:20][CH2:19][C@H:18]([NH:21][CH2:31][CH:23]([OH:22])[CH2:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[CH2:17][CH2:16]2)=[CH:13][CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1.[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([C@H:15]2[CH2:20][CH2:19][C@H:18]([NH:21][CH2:31][CH:23]([OH:22])[CH2:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[CH2:17][CH2:16]2)=[CH:13][CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: c1ccc(CC2CO2)cc1
Reactant: N[C@H]1CC[C@H](c2ccc(OCc3ccccc3)cc2)CC1
Solvent: CO
Product: OC(CN[C@H]1CC[C@@H](c2ccc(OCc3ccccc3)cc2)CC1)Cc1ccccc1
Product: OC(CN[C@H]1CC[C@H](c2ccc(OCc3ccccc3)cc2)CC1)Cc1ccccc1
Reaction time: 48 h

Procedure:
A mixture of cis and trans 4-(4-benzyloxy-phenyl)-cyclohexyl-amine (preparation see under 43a, 1.0 g, 3.55 mmol), MeOH (100 ml) and 2,3-epoxypropyl-benzene (480 mg, 3.55 mmol) was refluxed for 3 days. Another portion of and 2,3-epoxypropyl-benzene (480 mg, 3.55 mmol) was added and stirring was continued for 2 days. The solvent was evaporated and the residue was purified by chromatography (SiO2, AcOEt-hexane 1:1) to give (RS)-1-[cis-4-(4-benzyloxy-phenyl)-cyclohexylamino]-3-phenyl-propan-2-ol (430 mg, colorless oil, MS: m/e=416.3 (M+H+)) and (RS)-1-[trans-4-(4-benzyloxy-phenyl)-cyclohexylamino]-3-phenyl-propan-2-ol (85 mg, white crystals, Mp. 137.5-138, MS: m/e=416.3 (M+H+)).
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:25])[N:10]([C@H:12]([C:14](=[O:24])[NH:15][C:16]1[C:17](=[O:23])[NH:18][C:19]([Br:22])=[CH:20][CH:21]=1)[CH3:13])[CH3:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[I-].[Li+].[F:28][C:29]1[CH:34]=[CH:33][C:32]([C:35]([C:37]2[CH:38]=[N:39][CH:40]=[C:41]([CH2:43]Cl)[CH:42]=2)=[O:36])=[CH:31][CH:30]=1.C(N(C(C)C)CC)(C)C>O(C(OC)C)C.C(OCC)(=O)C>[CH2:1]([O:8][C:9](=[O:25])[N:10]([C@H:12]([C:14](=[O:24])[NH:15][C:16]1[C:17](=[O:23])[N:18]([CH2:43][C:41]2[CH:40]=[N:39][CH:38]=[C:37]([C:35](=[O:36])[C:32]3[CH:33]=[CH:34][C:29]([F:28])=[CH:30][CH:31]=3)[CH:42]=2)[C:19]([Br:22])=[CH:20][CH:21]=1)[CH3:13])[CH3:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C[C@@H](C(=O)Nc1ccc(Br)[nH]c1=O)N(C)C(=O)OCc1ccccc1
Reactant: O=C(c1ccc(F)cc1)c1cncc(CCl)c1
Agent: COC(C)OC
Agent: [I-]
Agent: [Li+]
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: C[C@@H](C(=O)Nc1ccc(Br)n(Cc2cncc(C(=O)c3ccc(F)cc3)c2)c1=O)N(C)C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 61.6 %

Procedure:
To a solution of [(S)-1-(6-bromo-2-oxo-1,2-dihydro-pyridin-3-ylcarbamoyl)-ethyl]-methyl-carbamic acid benzyl ester (1C) (100 mg, 0.25 mmol) in dimethoxylethane (DME) (3 mL) at room temperature, is added lithium iodide (36 mg, 0.27 mmol) in one portion. After being stirred at room temperature for 5 minutes, to the reaction mixture, is added 4-fluoro-phenyl-(5-chloromethyl-pyridin-3-yl)-methanone (IF) (80 mg, 0.32 mmol) in one portion. After being stirred at room temperature for 5 minutes, to the reaction mixture, is added drop wise diisopropylethylamine (DIPEA) (0.09 mL, 0.50 mmol). The reaction mixture is stirred at 60□C for 6 hours. The reaction solution is diluted with ethyl acetate (EtOAc) (30 mL) and washed with 2×8 mL of water. After concentration, the crude product is purified by chromatography (heptanes 60%, EtOAc 40%) to give ((S)-1-{6-bromo-1-[5-(4-fluoro-benzoyl)-pyridin-3-ylmethyl]-2-oxo-1,2-dihydro-pyridin-3-ylcarbamoyl}-ethyl)-methyl-carbamic acid benzyl ester (1D) (95.7 mg, yield 63%) as light yellow solid, MS (ESI) m/e 621.2, 623.3 (M+H+).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[N:22]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=3[O:29][CH3:30])[C:21]3[C:20](=[O:31])[N:19]([CH2:32][C:33]([O:35]CC)=[O:34])[C:18](=[O:38])[N:17]([CH3:39])[C:16]=3[N:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+].Cl>C(O)C>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[N:22]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=3[O:29][CH3:30])[C:21]3[C:20](=[O:31])[N:19]([CH2:32][C:33]([OH:35])=[O:34])[C:18](=[O:38])[N:17]([CH3:39])[C:16]=3[N:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:3])([CH3:4])[CH3:2]
Reactant: CCOC(=O)Cn1c(=O)c2c(nc(N3CCN(C(=O)OC(C)(C)C)CC3)n2-c2ccccc2OC)n(C)c1=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: COc1ccccc1-n1c(N2CCN(C(=O)OC(C)(C)C)CC2)nc2c1c(=O)n(CC(=O)O)c(=O)n2C
Reaction time: 5 h
Yield: 35.2 %

Procedure:
4-[7-(2-Methoxyphenyl)-1-(ethoxycarbonylmethyl)-3-methyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl]piperazine-1-carboxylic acid tert-butyl ester (9 mg) was dissolved in ethanol (1 ml), and 5 N sodium hydroxide aqueous solution (0.1 ml) was added thereto. The reaction mixture was left standing at room temperature for 5 hours, and neutralized with 1 N hydrochloric acid. The reaction mixture was extracted with ethyl acetate, the organic layer was dried over anhydrous magnesium sulfate, and was filtered. The filtrate was concentrated under reduced pressure to give 3 mg of the title compound.
Reaction SMILES: [N:1]1([C:7]2[CH:12]=[CH:11][C:10]([NH:13][C:14]([C:16]3[CH:17]=[C:18]([CH:27]=[CH:28][CH:29]=3)[CH2:19][S:20][CH2:21][CH2:22][C:23]([O:25]C)=[O:24])=[O:15])=[C:9]([C:30](=[O:48])[NH:31][C:32]3[CH:33]=[N:34][C:35]([C:38]4[CH:43]=[CH:42][CH:41]=[C:40]([C:44]([F:47])([F:46])[F:45])[CH:39]=4)=[N:36][CH:37]=3)[CH:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.O[Li].O.Cl>O1CCCC1.O>[N:1]1([C:7]2[CH:12]=[CH:11][C:10]([NH:13][C:14]([C:16]3[CH:17]=[C:18]([CH:27]=[CH:28][CH:29]=3)[CH2:19][S:20][CH2:21][CH2:22][C:23]([OH:25])=[O:24])=[O:15])=[C:9]([C:30](=[O:48])[NH:31][C:32]3[CH:37]=[N:36][C:35]([C:38]4[CH:43]=[CH:42][CH:41]=[C:40]([C:44]([F:47])([F:45])[F:46])[CH:39]=4)=[N:34][CH:33]=3)[CH:8]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: COC(=O)CCSCc1cccc(C(=O)Nc2ccc(N3CCCCC3)cc2C(=O)Nc2cnc(-c3cccc(C(F)(F)F)c3)nc2)c1
Agent: Cl
Agent: [Li]O
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)CCSCc1cccc(C(=O)Nc2ccc(N3CCCCC3)cc2C(=O)Nc2cnc(-c3cccc(C(F)(F)F)c3)nc2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 80.8 %

Procedure:
To methyl 3-(3-((4-(piperidin-1-yl)-2-((2-(3-(trifluoromethyl)phenyl)pyrimidin-5-yl)carbamoyl)phenyl)carbamoyl)-benzylthio)propanoate (280 mg, 0.41 mmol, 1.00 equiv) in tetrahydrofuran (8 mL) was added LiOH H2O (500 mg, 11.90 mmol, 25.00 equiv) in water (2 mL) and the resulting solution was stirred overnight at room temperature. The reaction progress was monitored by LCMS. The solution was adjusted to pH 5-6 with hydrochloric acid and then extracted with 2×20 mL of ethyl acetate. The organic layers were combined, dried over anhydrous sodium sulfate, and concentrated under vacuum until about 5 mL remained. The product was then precipitated with petroleum ether and the resulting solids were collected by filtration and washed with ether. This resulted in 0.22 g (80%) of product as a yellow to green solid. 1H-NMR (400 MHz, DMSO, ppm): δ 12.24 (s, 1H), 10.92 (s, 1H), 10.91 (s, 1H), 9.27 (s, 2H), 8.64 (m, 2H), 68.06 (d, 1H), 7.89 (d, 2H), 7.75-7.80 (m, 2H), 7.47-7.53 (m, 2H), 7.39 (s, 1H), 7.25 (d, 1H), 3.83 (s, 2H) 3.24 (m, 4H), 2.58 (t, 2H), 1.67 (m, 4H). 1.58 (m, 2H). MS (ES, m/z): 664 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:9])[C:7]=1Cl.[NH:10]1[CH2:15][CH2:14][CH:13]([CH2:16][OH:17])[CH2:12][CH2:11]1.C(N(CC)CC)C>CN1C(=O)CCC1>[Cl:9][C:6]1[CH:5]=[N:4][CH:3]=[C:2]([Cl:1])[C:7]=1[N:10]1[CH2:15][CH2:14][CH:13]([CH2:16][OH:17])[CH2:12][CH2:11]1
Reactant: OCC1CCNCC1
Reactant: Clc1cncc(Cl)c1Cl
Solvent: CCN(CC)CC
Solvent: CN1CCCC1=O
Product: OCC1CCN(c2c(Cl)cncc2Cl)CC1
Yield: 72.3 %

Procedure:
General procedure C was followed using 3,4,5-trichloropyridine (50 mg, 0.27 mmol), piperidin-4-ylmethanol (35 mg, 0.30 mmol), triethylamine (76 μL, 0.54 mmol) and NMP (1.5 mL). The crude product was purified by flash column chromatography on silica gel (hexane, EtOAc, 85:15) to furnish the title compound as white solid (51 mg, 71%), LC-MS (ESI, 3.5 min) Rt 2.49 min, m/z 261 (100%, [M+H]+); m/z (ESI) C11H15Cl2N2O requires 261.0556 found [M+H]+ 261.0558; HPLC Rt 6.68 min, 100%.
Reaction SMILES: [CH2:1]([C:4]1[NH:5][CH:6]=[CH:7][N:8]=1)[CH2:2][CH3:3].Br[CH:10]([CH3:16])[C:11]([O:13][CH2:14][CH3:15])=[O:12].C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[CH2:14]([O:13][C:11](=[O:12])[CH:10]([N:5]1[CH:6]=[CH:7][N:8]=[C:4]1[CH2:1][CH2:2][CH3:3])[CH3:16])[CH3:15]
Reactant: CCCc1ncc[nH]1
Reactant: CCOC(=O)C(C)Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCCc1nccn1C(C)C(=O)OCC

Procedure:
2-Propylimidazole (5.5 g), ethyl 2-bromopropionate (9.95 g) and potassium carbonate (12.4 g) were stirred in refluxing acetonitrile (100 ml) for 72 hours. The suspension was allowed to cool, filtered and the solvent removed under reduced pressure, yielding the title compound as an off-white foam, 9.2 g [88%].
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].C(O[C:12]([N:14]1[CH2:19][CH2:18][NH:17][C:16]([CH3:21])([CH3:20])[C:15]1=O)=O)(C)(C)C>C1COCC1>[CH3:12][N:14]1[CH2:19][CH2:18][NH:17][C:16]([CH3:21])([CH3:20])[CH2:15]1
Reactant: CC(C)(C)OC(=O)N1CCNC(C)(C)C1=O
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CN1CCNC(C)(C)C1
Temperature: 50 °C
Reaction time: 3 h
Yield: 71.9 %

Procedure:
LiAlH4 (1 M in THF, 32.5 mL, 32.5 mmol, 1.5 equiv) was added to a solution of 3,3-dimethyl-2-oxo-piperazine-1-carboxylic acid tert-butyl ester (Step 114.3) (4.95 g, 21.7 mmol) in THF (100 mL) at 50° C., under an argon atmosphere. The resulting mixture was stirred for 3 h at 50° C., cooled to 0° C., quenched by addition of acetone and concentrated. The residue was purified by silica gel column chromatography (DCM/MeOH/NH3aq, 94:5:1) to afford 2 g of the title compound as a yellow oil. Title compound: ESI-MS: 129.1.
Reaction SMILES: [OH-].[Na+].C([O:5][C:6]([C:8]1[CH:9]=[N:10][N:11]([CH3:31])[C:12]=1[C:13](=[O:30])[NH:14][C:15]1[CH:20]=[CH:19][N:18]2[CH:21]=[C:22]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[N:23]=[C:17]2[N:16]=1)=[O:7])C.O.Cl>C1COCC1.C(O)C>[CH3:31][N:11]1[C:12]([C:13](=[O:30])[NH:14][C:15]2[CH:20]=[CH:19][N:18]3[CH:21]=[C:22]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)[N:23]=[C:17]3[N:16]=2)=[C:8]([C:6]([OH:7])=[O:5])[CH:9]=[N:10]1
Reactant: CCOC(=O)c1cnn(C)c1C(=O)Nc1ccn2cc(-c3ccccc3)nc2n1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Solvent: O
Product: Cn1ncc(C(=O)O)c1C(=O)Nc1ccn2cc(-c3ccccc3)nc2n1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
NaOH (3N, 6.9 ml) was added to a solution of 1-methyl-5-(2-phenyl-imidazo[1,2-a]pyrimidin-7-ylcarbamoyl)-1H-pyrazole-4-carboxylic acid ethyl ester (2.70 g, 6.9 mmol) in THF/ethanol=1:1 (40 ml), an the mixture was stirred at RT overnight. Water (10 ml) and HCl (conc., approx. 3 ml) were added to the cooled (0° C.) mixture, until the mixture had a pH of 3. The suspension was stirred for 15 min, and filtered. The precipitate was washed with a small amount of water, and dried under vacuum. The thus obtained product (910 mg, 36%) was used in the next step without further purification. MS (m/e)=361.3 [M−H+].
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1F)[CH:5]=[O:6].[Cl:11][C:12]1[CH:13]=[C:14]([OH:19])[CH:15]=[CH:16][C:17]=1[Cl:18]>>[Cl:11][C:12]1[CH:13]=[C:14]([CH:15]=[CH:16][C:17]=1[Cl:18])[O:19][C:9]1[CH:8]=[CH:7][C:4]([CH:5]=[O:6])=[CH:3][C:2]=1[F:1]
Reactant: O=Cc1ccc(F)c(F)c1
Reactant: Oc1ccc(Cl)c(Cl)c1
Product: O=Cc1ccc(Oc2ccc(Cl)c(Cl)c2)c(F)c1

Procedure:
The title compound was prepared by a procedure similar to that described for D4 starting from 3,4-difluorobenzaldehyde and 3,4-dichlorophenol.
Reaction SMILES: C(N(CC)C(C)C)(C)C.[C:10]1([CH2:16][O:17][C:18]([NH:20][C:21]2([C:27]([NH:29][C@H:30]([CH2:34][OH:35])[CH:31]([CH3:33])[CH3:32])=[O:28])[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]2)=[O:19])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>CS(C)=O.C(Cl)Cl>[C:10]1([CH2:16][O:17][C:18]([NH:20][C:21]2([C:27]([NH:29][C@H:30]([CH:34]=[O:35])[CH:31]([CH3:33])[CH3:32])=[O:28])[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]2)=[O:19])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: CC(C)[C@@H](CO)NC(=O)C1(NC(=O)OCc2ccccc2)CCCCC1
Solvent: ClCCl
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)[C@@H](C=O)NC(=O)C1(NC(=O)OCc2ccccc2)CCCCC1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 76.9 %

Procedure:
Under an argon gas atmosphere, 1.22 g (9.44 mmol) of N,N-diisopropylethylamine was added dropwise to a solution of 1.50 g (9.44 mmol) of sulfur trioxide-pyridine complex in 10 ml of anhydrous dimethyl sulfoxide and 5 ml of anhydrous methylene chloride under ice-cooling, and the mixture was stirred for 15 minutes. Further, under ice-cooling, a solution of 570 mg (1.57 mmol) of N-[[1-[[(phenylmethoxy)carbonyl]amino]cyclohexyl]carbonyl]-L-valinol in 3 ml of anhydrous dimethyl sulfoxide was added to the reaction solution, and the mixture was stirred at the same temperature for 2 hours. The reaction solution was poured to ice-water and extracted with ethyl acetate twice. After the organic layer was washed with a 10% aqueous citric acid solution, a saturated aqueous sodium hydrogencarbonate solution and then saturated brine and dried with anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure. 20 ml of diisopropyl ether was added to the residue, and the mixture was stirred at room temperature for 18 hours. The obtained crystal was collected by filtration to obtain 435 mg (77%) of the title compound.