Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[C:3]([C@@H:12]([NH:22][C:23](=[O:29])[O:24][C:25]([CH3:28])([CH3:27])[CH3:26])[CH2:13][C:14]2[CH:19]=[C:18]([F:20])[CH:17]=[C:16]([F:21])[CH:15]=2)=[N:4][C:5](S(C)(=O)=O)=[N:6][CH:7]=1.[NH:30]1[CH:34]=[N:33][CH:32]=[N:31]1.C(N(CC)CC)C>CN(C=O)C>[Br:1][C:2]1[C:3]([C@@H:12]([NH:22][C:23](=[O:29])[O:24][C:25]([CH3:28])([CH3:27])[CH3:26])[CH2:13][C:14]2[CH:19]=[C:18]([F:20])[CH:17]=[C:16]([F:21])[CH:15]=2)=[N:4][C:5]([N:30]2[CH:34]=[N:33][CH:32]=[N:31]2)=[N:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1cc(F)cc(F)c1)c1nc(S(C)(=O)=O)ncc1Br
Reactant: c1nc[nH]n1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N[C@@H](Cc1cc(F)cc(F)c1)c1nc(-n2cncn2)ncc1Br
Temperature: 120 °C

Procedure:
In a microwave tube were charged with compound 23B (100 mg, 0.2 mmol), 1H-1,2,4-triazole (42 mg, 0.6 mmol), triethylamine (84 μL, 0.6 mmol) and DMF (0.6 mL, The mixture was heated up to 120° C. for 15 min in a Microwave Synthesizer. After cooled down, it was partitioned between ethyl acetate and 5% of LiCl aqueous solution. The organic layer was separated and concentrated. The residue was purified on silica gel chromatography eluting with ethyl acetate and hexanes to afford the title compound. MS (m/z) 481.21 [M+H]+.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([CH2:13][CH2:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=1)[C:10](O)=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH2:25][C:26]1[CH:27]=[N:28][C:29]2[C:34]([CH:35]=1)=[CH:33][CH:32]=[CH:31][CH:30]=2.C[N+]1(C2N=C(OC)N=C(OC)N=2)CCOCC1.[Cl-]>C(OCC)(=O)C>[N:28]1[C:29]2[C:34](=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH:35]=[C:26]([NH:25][C:10]([C@H:9]([NH:8][C:6](=[O:7])[O:5][C:1]([CH3:3])([CH3:2])[CH3:4])[CH2:13][CH2:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]([F:23])([F:24])[F:22])=[CH:17][CH:16]=2)=[O:11])[CH:27]=1
Reactant: Nc1cnc2ccccc2c1
Reactant: CC(C)(C)OC(=O)N[C@H](CCc1ccc(C(F)(F)F)cc1)C(=O)O
Agent: COc1nc(OC)nc([N+]2(C)CCOCC2)n1
Agent: [Cl-]
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N[C@H](CCc1ccc(C(F)(F)F)cc1)C(=O)Nc1cnc2ccccc2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 93 %

Procedure:
To a solution of (2R)-2-{[(tert-butoxy)carbonyl]amino}-4-[4-(trifluoromethyl)phenyl]butanoic acid V (0.97 g, 2.79 mmol) and 3-aminoquinoline VI (0.45 g, 3.10 mmol) in ethyl acetate (30 mL) was added DMT-MM (1.0 g, 3.63 mmol). After being stirred at r.t. overnight, the reaction was washed with water, 1N HCl, aq. sat. NaHCO3, water and dried over Na2SO4. The solvent was removed under reduced pressure to afford tert-butyl N-[(1R)-1-[(quinolin-3-yl)carbamoyl]-3-[4-(trifluoromethyl)phenyl]propyl]carbamate (1.23 g, 2.59 mmol, 93% yield). ESIMS found for C25H26F3N3O3 m/z 474 (M+H).
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[O:25]=[C:26]1[N:32]([CH:33]2[CH2:38][CH2:37][N:36]([C:39]([O:41][C@@H:42]([C:54]([OH:56])=O)[CH2:43][C:44]3[CH:49]=[C:48]([CH3:50])[C:47]([OH:51])=[C:46]([O:52][CH3:53])[CH:45]=3)=[O:40])[CH2:35][CH2:34]2)[CH2:31][CH2:30][C:29]2[CH:57]=[CH:58][CH:59]=[CH:60][C:28]=2[NH:27]1.C(N(C(C)C)C(C)C)C.[O:70]1[CH2:75][CH2:74][CH:73]([N:76]2[CH2:81][CH2:80][NH:79][CH2:78][CH2:77]2)[CH2:72][CH2:71]1>CN(C=O)C>[O:25]=[C:26]1[N:32]([CH:33]2[CH2:34][CH2:35][N:36]([C:39]([O:41][C@H:42]([CH2:43][C:44]3[CH:49]=[C:48]([CH3:50])[C:47]([OH:51])=[C:46]([O:52][CH3:53])[CH:45]=3)[C:54](=[O:56])[N:79]3[CH2:78][CH2:77][N:76]([CH:73]4[CH2:74][CH2:75][O:70][CH2:71][CH2:72]4)[CH2:81][CH2:80]3)=[O:40])[CH2:37][CH2:38]2)[CH2:31][CH2:30][C:29]2[CH:57]=[CH:58][CH:59]=[CH:60][C:28]=2[NH:27]1
Reactant: COc1cc(C[C@@H](OC(=O)N2CCC(N3CCc4ccccc4NC3=O)CC2)C(=O)O)cc(C)c1O
Reactant: C1CN(C2CCOCC2)CCN1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COc1cc(C[C@@H](OC(=O)N2CCC(N3CCc4ccccc4NC3=O)CC2)C(=O)N2CCN(C3CCOCC3)CC2)cc(C)c1O
Reaction time: 3 h

Procedure:
84 mg (0.22 mmol) HATU was added at RT under nitrogen to a solution of 100 mg (0.20 mmol) (R)-1-carboxy-2-(4-hydroxy-3-methoxy-5-methyl-phenyl)-ethyl 4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate, 10 μL (0.64 mmol) ethyldiisopropylamine and 59 mg (0.24 mmol) 1-(tetrahydropyran-4-yl)-piperazine (used as the bis-hydrochloride salt) in 5 mL DMF and the mixture was stirred for 3 h. The reaction mixture was evaporated down i.vac. at 50° C. and the crude product was purified by HPLC-MS; the fractions containing the product were combined and lyophilised.
Reaction SMILES: [CH:1]1[C:11]2[C:10]3[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=3[CH2:8][N:7]([C:16](=[NH:20])[O:17][CH2:18][CH3:19])[CH2:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.[CH2:21]1[O:32][C:31]2[CH:30]=[CH:29][C:25]([C:26](Cl)=[O:27])=[CH:24][C:23]=2[O:22]1>>[CH2:21]1[O:32][C:31]2[CH:30]=[CH:29][C:25]([C:26]([N:20]=[C:16]([N:7]3[CH2:6][C:5]4[CH:4]=[CH:3][CH:2]=[CH:1][C:11]=4[C:10]4[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=4[CH2:8]3)[O:17][CH2:18][CH3:19])=[O:27])=[CH:24][C:23]=2[O:22]1
Reactant: CCOC(=N)N1Cc2ccccc2-c2ccccc2C1
Reactant: O=C(Cl)c1ccc2c(c1)OCO2
Product: CCOC(=NC(=O)c1ccc2c(c1)OCO2)N1Cc2ccccc2-c2ccccc2C1

Procedure:
starting from ethyl 5,7-dihydro-6H-dibenz[c,e]azepine-6-carboximidate and 3,4-methylenedioxybenzoyl chloride, there is obtained ethyl N-(3,4-methylenedioxybenzoyl)-5,7-dihydro-6H-dibenz[c,e]azepine-6-carboximidate as a syrup, mass spectrum m/e: M+ 414 (5), 385 (7), 194 (100), 149 (33);
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[CH:6][C:5]([F:9])=[C:4]([F:10])[C:3]=1[CH2:11][O:12][CH:13]1[CH2:18][CH2:17][CH2:16][CH2:15][O:14]1.C([Li])CCC.CN(C)[CH:26]=[O:27].[Cl-].[Na+]>O1CCCC1.CCCCCC>[F:9][C:5]1[C:4]([F:10])=[C:3]([CH2:11][O:12][CH:13]2[CH2:18][CH2:17][CH2:16][CH2:15][O:14]2)[C:2]([F:1])=[C:7]([F:8])[C:6]=1[CH:26]=[O:27]
Reactant: Fc1cc(F)c(F)c(COC2CCCCO2)c1F
Reactant: CN(C)C=O
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCCCCC
Product: O=Cc1c(F)c(F)c(COC2CCCCO2)c(F)c1F
Temperature: -55 °C
Reaction time: 1 h

Procedure:
13 g of 2-[(2,3,5,6-tetrafluorophenyl)-methoxy]-tetra hydropyran in 200 ml of tetrahydrofuran were cooled to -60 C. and 35.1 ml of butyllithium (1,6M) in hexane were added dropwise over the course of 30 minutes. The mixture was stirred for 1 hour at -55° C. and 5 ml of dimethylformamide dissolved in 10 ml of tetrahydrofuran were added over the course of 5 minutes. The mixture was stirred for 1/2hours at this temperature and 50 ml of a saturated aqueous sodium chloride solution were added. Extraction was carried out with isopropyl ether and the extract was dried and the solvents removed under reduced pressure to obtain 14.4 g of the expected product which was used as is in the following step.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][N:8]=[C:7]2[C:13](O)=[O:14])([O-])=O.[AlH4-].[Li+].O.[OH-].[Na+]>C1COCC1>[NH2:1][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][N:8]=[C:7]2[CH2:13][OH:14]
Reactant: O=C(O)c1n[nH]c2ccc([N+](=O)[O-])cc12
Agent: [AlH4-]
Agent: [Li+]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: Nc1ccc2[nH]nc(CO)c2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 19.9 %

Procedure:
5-nitro-1H-indazole-3-carboxylic acid (500 mg, 0.002 mol) was dissolved in 50 mL THF, added lithium tetrahydroaluminate (366 mg, 0.00964 mol) in 3 portions and stirred at room temperature overnight. 65 mg (15%). Water (366 μL), 15% NaOH solution (366 μL), and water (1.1 mL) were added cautiously and the mixtured was filtered. The filtrate was concentrated under vacuum to give the product (65 mg, 15%) as an oil. m/z=160.0.
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]([NH:10][C:11]2[CH:16]=[C:15]([O:17][CH3:18])[CH:14]=[C:13]([F:19])[CH:12]=2)=[O:9])=[C:6](Cl)[N:5]=[CH:4][N:3]=1.[NH3:21]>O1CCOCC1>[NH2:21][C:6]1[C:7]([C:8]([NH:10][C:11]2[CH:16]=[C:15]([O:17][CH3:18])[CH:14]=[C:13]([F:19])[CH:12]=2)=[O:9])=[C:2]([Cl:1])[N:3]=[CH:4][N:5]=1
Reactant: N
Reactant: COc1cc(F)cc(NC(=O)c2c(Cl)ncnc2Cl)c1
Solvent: C1COCCO1
Product: COc1cc(F)cc(NC(=O)c2c(N)ncnc2Cl)c1
Temperature: 0 °C
Reaction time: 8 h

Procedure:
4,6-Dichloro-N-(3-fluoro-5-methoxyphenyl)pyrimidine-5-carboxamide (800 mg, 1.42 mmol) was dissolved in dioxane (5 ml) and cooled in an ice bath. Ammonia solution (1 ml, 7N in MeOH) was added dropwise and the mixture was stirred at 0° C. for 6 h and overnight at room temperature. After evaporation of the solvent under reduced pressure, the residue (458 mg, 100%) was used in the next synthetic step without further purification.
Reaction SMILES: Br[C:2]1[CH:12]=[CH:11][C:10]([N+:13]([O-:15])=[O:14])=[CH:9][C:3]=1[NH:4][CH2:5][C:6]([CH3:8])=[CH2:7].C(N(CC)CC)C.C([O-])=O.[Na+].O>[N+](CCCC)(CCCC)(CCCC)CCCC.[Br-].CN(C=O)C.CC([O-])=O.CC([O-])=O.[Pd+2]>[CH3:7][C:6]1([CH3:8])[C:2]2[C:3](=[CH:9][C:10]([N+:13]([O-:15])=[O:14])=[CH:11][CH:12]=2)[NH:4][CH2:5]1
Reactant: C=C(C)CNc1cc([N+](=O)[O-])ccc1Br
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: O
Product: CC1(C)CNc2cc([N+](=O)[O-])ccc21
Temperature: 80 °C
Yield: 84.6 %

Procedure:
A solution of 2-bromo-N-(2-methyl-2-propenyl)-5-nitroaniline (100 mg, 0.369 mmol), Pd(OAc)2 (2 mg, 0.0073 mol), Bu4NBr (119 mg, 0.369 mmol) and triethylamine (129 mL, 0.922 mmol) in 1 mL of dry DMF under argon atmosphere was heated at 80° C. for 1 h. Then sodium formate (25 mg, 0.369 mmol) was added to the reaction mixture with continued heating at 80° C. for 20 h. Water (2 mL) was added and the mixture was extracted with ethyl acetate (2×5 mL), dried (Na2SO4) and concentrated in vacuo to an oil that was subjected to flash column chromatography (silica gel, hexanes/ethyl acetate, 8:2) to give 60 mg (80%) of 3,3-dimethyl-6-nitroindoline. Data for 3,3-dimethyl-6-nitroindoline: 1H NMR (400 MHz, CDCl3) 7.60 (dd, J=8.2, 2.0, 1H), 7.35 (d, J=2.0, 1H), 7.08 (d, J=8.2, 1H), 3.98 (bs, 1H), 3.41 (bs, 2H), 1.33 (s, 6H).
Reaction SMILES: [F:1][C:2]1[CH:38]=[CH:37][CH:36]=[CH:35][C:3]=1[CH2:4][O:5][C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[CH:12]=[C:11]([CH2:16][N:17]1[CH:21]=[C:20]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[C:19]([CH2:28][CH2:29][C:30]([O:32]CC)=[O:31])=[CH:18]1)[CH:10]=[CH:9]2.[OH-].[Na+].O1CCCC1.Cl>C(O)C>[F:1][C:2]1[CH:38]=[CH:37][CH:36]=[CH:35][C:3]=1[CH2:4][O:5][C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[CH:12]=[C:11]([CH2:16][N:17]1[CH:21]=[C:20]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[C:19]([CH2:28][CH2:29][C:30]([OH:32])=[O:31])=[CH:18]1)[CH:10]=[CH:9]2
Reactant: CCOC(=O)CCc1cn(Cc2ccc3cc(OCc4ccccc4F)ccc3c2)cc1-c1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: O=C(O)CCc1cn(Cc2ccc3cc(OCc4ccccc4F)ccc3c2)cc1-c1ccccc1
Temperature: 25 °C
Reaction time: 7 h
Yield: 76.3 %

Procedure:
A mixture of ethyl 3-[1-[6-(2-fluorobenzyloxy)-2-naphthylmethyl]-4-phenyl-3-pyrrolyl]propionate (401 mg), 1N aqueous sodium hydroxide solution (2 ml), tetrahydrofuran (4 ml) and ethanol (4 ml) was stirred at room temperature for 7 hours, and 1N hydrochloric acid (2 ml) was added to the mixture, which was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated aqueous sodium chloride solution, dried (MgSO4), then concentrated. The colorless crystals obtained were collected by filtration to yield 3-[1-[6-(2-fluorobenzyloxy)-2-naphthylmethyl]-4-phenyl-3-pyrrolyl]propionic acid (289 mg, yield: 76%). This was recrystallized from ethanol-hexane. Melting point: 143–144° C.
Reaction SMILES: [C:1]([C:3]1[C:7]([CH3:8])=[N:6][N:5]([CH3:9])[C:4]=1[NH:10][C:11](=O)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[F:18])#[N:2].[OH:20]O.Cl>[OH-].[Na+]>[F:18][C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=1[C:11]1[NH:2][C:1](=[O:20])[C:3]2[C:7]([CH3:8])=[N:6][N:5]([CH3:9])[C:4]=2[N:10]=1
Reactant: Cc1nn(C)c(NC(=O)c2ccccc2F)c1C#N
Reactant: OO
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: Cc1nn(C)c2nc(-c3ccccc3F)[nH]c(=O)c12
Temperature: 90 °C
Yield: 67 %

Procedure:
N-(4-Cyano-2,5-dimethyl-2H-pyrazol-3-yl)-2-fluoro-benzamide (5.0 g, 19.36 mmole) was suspended in 38 ml 1M sodium hydroxide and heated to 90° C. for 3 hours followed by addition of 30% hydrogen peroxide (10 ml) and further heating overnight. The reaction mixture was cooled to room temperature and acidified with dilute hydrochloric acid. The product was isolated by filtration, washed with water, and dried overnight under vacuum to obtain 3.39 g of product. (Yield 67%).
Reaction SMILES: FC1C=CC=CC=1S(F)(=O)=O.[F:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[S:19]([C:22]([F:25])([F:24])[F:23])(=[O:21])=[O:20].C[Si](C(F)(F)F)(C)C.CN([S+](N(C)C)N(C)C)C.C[Si-](F)(F)(C)C.[Cl:50][S:51](O)(=[O:53])=[O:52]>C(COC)OC.C1(C)C=CC=CC=1.ClCCl.O1CCCC1>[F:12][C:13]1[CH:18]=[CH:17][C:16]([S:51]([Cl:50])(=[O:53])=[O:52])=[CH:15][C:14]=1[S:19]([C:22]([F:23])([F:24])[F:25])(=[O:20])=[O:21]
Reactant: O=S(=O)(c1ccccc1F)C(F)(F)F
Reactant: O=S(=O)(O)Cl
Agent: CN(C)[S+](N(C)C)N(C)C
Agent: C[Si-](C)(C)(F)F
Agent: C[Si](C)(C)C(F)(F)F
Solvent: ClCCl
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: O=S(=O)(Cl)c1ccc(F)c(S(=O)(=O)C(F)(F)F)c1

Procedure:
Scheme 2 shows two routes used to make 4-(((1R)-3-morpholin-4-yl-1-((phenylthio)methyl)propyl)amino)-3-((trifluoromethyl)sulfonyl)benzenesulfonamide (17). One route involves reacting commercially available 2-fluorobenzenesulfonyl chloride (11) with TBAF (tetra-n-butylammonium fluoride) to provide 2-fluorobenzenesulfonyl fluoride (12). The reaction is typically performed below room temperature in a solvent such as but not limited to tetrahydrofuran. 2-Fluorobenzenesulfonyl fluoride (12) can be converted to 1-fluoro-2-((trifluoromethyl)sulfonyl)benzene (13) by reaction with Ruppert's reagent (CH3SiCF3) catalyzed by (((CH3)2N)3S)+(F2Si(CH3)3)−, also known as TASF. The reaction is typically performed at about room temperature in a solvent such as but not limited to tetrahydrofuran, dichloromethane, toluene, dimethoxyethane, or mixtures thereof. 1-Fluoro-2-((trifluoromethyl)sulfonyl)benzene (13) can be reacted with chlorosulfonic acid to provide 4-fluoro-3-((trifluoromethyl)sulfonyl)benzenesulfonyl chloride (14). The reaction is typically performed at an elevated temperature before cooling for the addition of SO2Cl2, used to quench the chlorosulfonic acid. 4-Fluoro-3- ((trifluoromethyl)sulfonyl)benzenesulfonamide (15) can be prepared from 4-fluoro-3-((trifluoromethyl)sulfonyl)benzenesulfonyl chloride (14) by reacting the latter with aqueous ammonium hydroxide. The reaction is typically performed in a solvent such as acetonitrile, tetrahydrofuran, ethyl acetate, isopropyl alcohol, isopropyl acetate, dimethoxyethane, dichloromethane, toluene, or mixtures thereof. (1R)-3-morpholin-4-yl-1-((phenylthio)methyl)propylamine (16), prepared as described in U.S. Pat. No. 7,390,799 B2, can be reacted with 4-fluoro-3-((trifluoromethyl)sulfonyl)benzenesulfonamide (15) in the presence of a base such as but not limited to triethylamine, to provide 4-(((1R)-3-morpholin-4-yl-1-((phenylthio)methyl)propyl)amino)-3-((trifluoromethyl)sulfonyl)benzenesulfonamide (17). The reaction is typically performed at elevated temperatures in a solvent such as but not limited to ethyl acetate.
Reaction SMILES: [CH:1]1([C:4]([OH:6])=O)[CH2:3][CH2:2]1.[CH3:7][NH:8][C@H:9]1[CH2:28][N:13]2[C:14]3[C:19]([C:20]([CH2:21][C:22]([O:24]CCC)=[O:23])=[C:12]2[CH2:11][CH2:10]1)=[CH:18][CH:17]=[CH:16][CH:15]=3>>[CH:1]1([C:4]([N:8]([CH3:7])[C@H:9]2[CH2:28][N:13]3[C:14]4[C:19]([C:20]([CH2:21][C:22]([OH:24])=[O:23])=[C:12]3[CH2:11][CH2:10]2)=[CH:18][CH:17]=[CH:16][CH:15]=4)=[O:6])[CH2:3][CH2:2]1
Reactant: O=C(O)C1CC1
Reactant: CCCOC(=O)Cc1c2n(c3ccccc13)C[C@H](NC)CC2
Product: CN(C(=O)C1CC1)[C@@H]1CCc2c(CC(=O)O)c3ccccc3n2C1

Procedure:
The title compound was prepared using analogous procedures described in Example 2 (Method B) from cyclopropanecarboxylic acid and propyl [(7R)-7-(methylamino)-6,7,8,9-tetrahydropyrido[1,2-a]indol-10-yl]acetate. MS (+ESI) m/z: 327.
Reaction SMILES: C([O:8][N:9]1[C:15](=[O:16])[N:14]2[CH2:17][C@H:10]1[CH2:11][CH2:12][C@H:13]2[C:18]1[O:22][N:21]=[C:20]([C:23]([O:25][CH2:26][CH3:27])=[O:24])[N:19]=1)C1C=CC=CC=1>CO.C1COCC1.[Pd]>[OH:8][N:9]1[C:15](=[O:16])[N:14]2[CH2:17][C@H:10]1[CH2:11][CH2:12][C@H:13]2[C:18]1[O:22][N:21]=[C:20]([C:23]([O:25][CH2:26][CH3:27])=[O:24])[N:19]=1
Reactant: CCOC(=O)c1noc([C@@H]2CC[C@@H]3CN2C(=O)N3OCc2ccccc2)n1
Agent: [Pd]
Solvent: CO
Solvent: C1CCOC1
Product: CCOC(=O)c1noc([C@@H]2CC[C@@H]3CN2C(=O)N3O)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 34.7 %

Procedure:
To a solution of ethyl 5-((2S,5R)-6-(benzyloxy)-7-oxo-1,6-diazabicyclo[3.2.1]octan-2-yl)-1,2,4-oxadiazole-3-carboxylate (323 mg, 0.867 mmol) in MeOH (6.0 mL) and THF (3.0 mL) was added 10% Pd/C (18.46 mg, 0.017 mmol). The reaction mixture was stirred under hydrogen balloon at rt for 1 h. The reaction mixture was then filtered and concentrated. The residue was purified by silica gel column chromatography (0 to 5% MeOH/DCM) to afford ethyl 5-((2S,5R)-6-hydroxy-7-oxo-1,6-diazabicyclo[3.2.1]octan-2-yl)-1,2,4-oxadiazole-3-carboxylate (85 mg, 35%).
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][N:6]([C:8]2[N:13]=[C:12]([CH3:14])[CH:11]=[C:10]([NH:15][C:16]3[NH:20][N:19]=[CH:18][CH:17]=3)[N:9]=2)[CH2:5][C@@H:4]([C:21]([O:23][CH3:24])=[O:22])[CH2:3]1.[C:25](=O)([O:36][C@@H:37]([CH3:42])[C:38]([F:41])([F:40])[F:39])[O:26]C1C=CC([N+]([O-])=O)=CC=1>C(Cl)(Cl)Cl.CCN(C(C)C)C(C)C>[CH3:14][C:12]1[CH:11]=[C:10]([NH:15][C:16]2[NH:20][N:19]=[CH:18][CH:17]=2)[N:9]=[C:8]([N:6]2[CH2:7][C@H:2]([NH:1][C:25]([O:36][C@@H:37]([CH3:42])[C:38]([F:41])([F:40])[F:39])=[O:26])[CH2:3][C@H:4]([C:21]([O:23][CH3:24])=[O:22])[CH2:5]2)[N:13]=1
Reactant: COC(=O)[C@H]1C[C@@H](N)CN(c2nc(C)cc(Nc3ccn[nH]3)n2)C1
Reactant: C[C@H](OC(=O)Oc1ccc([N+](=O)[O-])cc1)C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClC(Cl)Cl
Product: COC(=O)[C@H]1C[C@@H](NC(=O)O[C@@H](C)C(F)(F)F)CN(c2nc(C)cc(Nc3ccn[nH]3)n2)C1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
The crude methyl cis-5-amino-1-[4-methyl-6-(1H-pyrazol-5-ylamino)pyrimidin-2-yl]piperidine-3-carboxylate prepared in Step 4 of Example 6 was dissolved into CHCl3 (6 ml). To the solution was added the solution of 4-nitrophenyl (2S)-1,1,1-trifluoropropan-2-yl carbonate (203.3 mg) in CHCl3 and DIEA (125.0 μl). After stirring at room temperature for 2 hours, the mixture was concentrated in vacuo. The residue was dissolved into EtOAc, poured into 1 M aqueous solution of NaOH and extracted with EtOAc. The extract was washed with saturated aqueous solution of NaHCO3, dried over MgSO4 and concentrated to give the crude methyl cis-1-[4-methyl-6-(1H-pyrazol-5-ylamino)pyrimidin-2-yl]-5-[({[(2S)-1,1,1-trifluoropropan-2-yl]oxy}carbonyl)amino]piperidine-3-carboxylate as a pale orange amorphous form.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]([C:17]([O:19][CH3:20])=[O:18])([C:14](O)=[O:15])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[Cl:45][C:46]1[CH:53]=[CH:52][CH:51]=[CH:50][C:47]=1[CH2:48][NH2:49].CCN(C(C)C)C(C)C>CN(C=O)C>[Cl:45][C:46]1[CH:53]=[CH:52][CH:51]=[CH:50][C:47]=1[CH2:48][NH:49][C:14]([C:11]1([C:17]([O:19][CH3:20])=[O:18])[CH2:12][CH2:13][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[CH2:9][CH2:10]1)=[O:15]
Reactant: NCc1ccccc1Cl
Reactant: COC(=O)C1(C(=O)O)CCN(C(=O)OC(C)(C)C)CC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)C1(C(=O)NCc2ccccc2Cl)CCN(C(=O)OC(C)(C)C)CC1
Reaction time: 3 h
Yield: 51.6 %

Procedure:
To a solution of 1-(tert-butoxycarbonyl)-4-(methoxycarbonyl)piperidine-4-carboxylic acid (3.7 g, 13.2 mmol) in DMF (30 mL) were added HATU (6.0 g, 15.8 mmol, 1.2 equiv.), 2-chlorobenzylamine (1.9 mL, 15.8 mmol, 1.2 equiv.) and DIEA (228 μL, 1.31 mmol, 0.1 equiv.). The reaction mixture was stirred for 3 h and purified on RP-HPLC using a mixture of acetonitrile and H2O to give 1-tert-butyl 4-methyl 4-(2-chlorobenzylcarbamoyl)piperidine-1,4-dicarboxylate (2.8 g, 52%). LRMS (M+H+-Boc) m/z 311.0.
Reaction SMILES: FC(F)(F)C(O)=O.C(OC(=O)[NH:14][CH:15]([CH:24]1[CH2:29][CH2:28][CH:27]([OH:30])[CH2:26][CH2:25]1)[C:16]1[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=1)(C)(C)C.Cl.O>ClCCl.C(#N)C>[NH2:14][CH:15]([C:16]1[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=1)[CH:24]1[CH2:29][CH2:28][CH:27]([OH:30])[CH2:26][CH2:25]1
Reactant: COc1ccc(C(NC(=O)OC(C)(C)C)C2CCC(O)CC2)cc1
Agent: Cl
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: COc1ccc(C(N)C2CCC(O)CC2)cc1
Reaction time: 2 h
Yield: 117.1 %

Procedure:
Trifluoroacetic acid (0.31 mL) was added to a solution of [(4-hydroxy-cyclohexyl)-(4-methoxy-phenyl)-methyl]-carbamic acid tert-butyl ester (34, 101 mg) in dichloromethane (6 mL). After stirring for 2 hours, 2M hydrochloric acid (3 mL) was added. Evaporation gave crude product as a colourless solid. Water and acetonitrile were added and the mixture was concentrated and then freeze dried to give 83 mg of 4-[amino-(4-methoxy-phenyl)-methyl]-cyclohexanol (35) as the hydrochloride salt. Rt=0.71 min (Method 5). Detected mass: 219.2 (M—NH2+).
Reaction SMILES: [I:1][C:2](=[CH:4][CH2:5][C@H:6]([C:15]1[CH:16]=[C:17]2[C:22](=[CH:23][CH:24]=1)[N:21]=[CH:20][CH:19]=[CH:18]2)[O:7][Si](CC)(CC)CC)[CH3:3]>C(O)(=O)C.C1COCC1.O>[I:1][C:2](=[CH:4][CH2:5][C@H:6]([C:15]1[CH:16]=[C:17]2[C:22](=[CH:23][CH:24]=1)[N:21]=[CH:20][CH:19]=[CH:18]2)[OH:7])[CH3:3]
Reactant: CC[Si](CC)(CC)O[C@H](CC=C(C)I)c1ccc2ncccc2c1
Solvent: CC(=O)O
Solvent: O
Solvent: C1CCOC1
Product: CC(I)=CC[C@@H](O)c1ccc2ncccc2c1

Procedure:
A solution of (5R)-2-iodo-5-(6-quinolyl)-5-(triethylsilyloxy)-2-pentene (2.26 g) in 50 mL of 3:1:1 acetic acid/THF/water is stirred at ambient temperature for 8 hours, then concentrated. The residue is dissolved in ethyl acetate, washed sequentially with sat. NaHCO3 and brine, then dried over MgSO4, filtered, and evaporated. The product is purified by SiO2 chromatography.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11](=[O:14])[CH:10]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]>C(O)C.[Pt]=O>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([OH:14])[CH:10]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCOC(=O)C1CN(C(=O)OC(C)(C)C)CCC1=O
Agent: O=[Pt]
Solvent: CCO
Product: CCOC(=O)C1CN(C(=O)OC(C)(C)C)CCC1O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
In 60 ml of ethanol, 6.1 g of 1-tert-butoxycarbonyl-3-ethoxycarbonyl-4-piperidone was dissolved, and subsequently, 100 mg of platinum oxide was added thereto, followed by stirring for 2 hours at room temperature under a hydrogen atmosphere. After the platinum oxide was filtered off using celite, the filtrate was concentrated under reduced pressure to yield crude 1-tert-butoxycarbonyl-3-ethoxycarbonyl-4-hydroxypiperidine. The obtained crude 1-tert-butoxycarbonyl-3-ethoxycarbonyl-4-hydroxypiperidine was dissolved in 100 ml of chloroform, and subsequently, 11.4 g of triethylamine and 0.55 g of 4-dimethylaminopyridine were added thereto. Methanesulfonyl chloride in an amount of 6.2 g was added dropwise thereto with ice-cooling. The reaction mixture was stirred for 5.5 hours at room temperature. The reaction mixture was washed successively with a saturated aqueous solution of sodium hydrogencarbonate and saturated brine, and subsequently, was dried over anhydrous sodium sulfate. After the desiccant was filtered off, the filtrate was concentrated under reduced pressure to yield crude 1-tert-butoxycarbonyl-3-ethoxycarbonylpiperidin-4-yl methanesulfonate. The obtained crude 1-tert-butoxycarbonyl-3-ethoxycarbonylpiperidin-4-yl methanesulfonate was dissolved in 50 ml of benzene, and 3.4 g of 1,8-diazabicyclo[5.4.0]-7-undecene was added thereto, followed by heating under reflux for 30 minutes. After the reaction mixture was cooled to room temperature, it was washed with a 5% aqueous solution of potassium hydrogensulfate and saturated brine, and was then dried over anhydrous sodium sulfate. After the desiccant was filtered off, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate=10:1 to 6:1) to yield 5.3 g of 1-tert-butoxycarbonyl-5-ethoxycarbonyl-1,2,3,6-tetrahydropyridine as an oil.