Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:5][P:6]([O:52]C(C)(C)C)([O:8][CH2:9][O:10][C:11](=[O:51])[C:12]1[CH:17]=[CH:16][C:15]([NH:18][C:19]([C@H:21]2[C@H:25]([C:26]3[CH:31]=[CH:30][CH:29]=[C:28]([Cl:32])[C:27]=3[F:33])[C@:24]([C:36]3[CH:41]=[CH:40][C:39]([Cl:42])=[CH:38][C:37]=3[F:43])([C:34]#[N:35])[C@H:23]([CH2:44][C:45]([CH3:48])([CH3:47])[CH3:46])[NH:22]2)=[O:20])=[C:14]([O:49][CH3:50])[CH:13]=1)=[O:7])(C)(C)C.[F:57][C:58]([F:63])([F:62])[C:59]([OH:61])=[O:60]>ClCCl>[F:57][C:58]([F:63])([F:62])[C:59]([OH:61])=[O:60].[P:6]([O:8][CH2:9][O:10][C:11](=[O:51])[C:12]1[CH:17]=[CH:16][C:15]([NH:18][C:19]([C@H:21]2[C@H:25]([C:26]3[CH:31]=[CH:30][CH:29]=[C:28]([Cl:32])[C:27]=3[F:33])[C@:24]([C:36]3[CH:41]=[CH:40][C:39]([Cl:42])=[CH:38][C:37]=3[F:43])([C:34]#[N:35])[C@H:23]([CH2:44][C:45]([CH3:46])([CH3:48])[CH3:47])[NH:22]2)=[O:20])=[C:14]([O:49][CH3:50])[CH:13]=1)([OH:52])([OH:7])=[O:5]
Reactant: COc1cc(C(=O)OCOP(=O)(OC(C)(C)C)OC(C)(C)C)ccc1NC(=O)[C@@H]1N[C@@H](CC(C)(C)C)[C@](C#N)(c2ccc(Cl)cc2F)[C@H]1c1cccc(Cl)c1F
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1cc(C(=O)OCOP(=O)(O)O)ccc1NC(=O)[C@@H]1N[C@@H](CC(C)(C)C)[C@](C#N)(c2ccc(Cl)cc2F)[C@H]1c1cccc(Cl)c1F

Procedure:
In a 25 mL pear-shaped flask, (di-tert-butoxyphosphoryloxy)methyl 4-((2R,3S,4R,5S)-3-(3-chloro-2-fluorophenyl)-4-(4-chloro-2-fluorophenyl)-4-cyano-5-neopentylpyrrolidine-2-carboxamido)-3-methoxybenzoate (20 mg, 23.8 μmmol, Example 2) was combined with dichloromethane (1 mL) to give a colorless solution which was cooled in an ice-water bath. After 5 min trifluoroacetic acid (744 mg, 0.5 mL, 6.53 mmol) was added over 8 min. The reaction mixture was concentrated and dried in vacuo overnight to give 4-{[(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carbonyl]-amino}-3-methoxy-benzoic acid phosphonooxymethyl ester, trifluoro-acetate salt, as off-white solids (19.5 mg, 97%).
Reaction SMILES: [C:1]([N:4]([CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[N+:25]([O-])=O)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[O:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)(=[O:3])[CH3:2].C(Cl)(Cl)Cl>CO.[Pt](=O)=O>[C:1]([N:4]([CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[NH2:25])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[O:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)N(Cc1ccccc1[N+](=O)[O-])c1ccccc1Oc1ccccc1
Agent: O=[Pt]=O
Solvent: ClC(Cl)Cl
Solvent: CO
Product: CC(=O)N(Cc1ccccc1N)c1ccccc1Oc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 93.8 %

Procedure:
In 80 ml of methanol was dissolved 8.00 g of N-acetyl-N-(2-nitrobenzyl)-2-phenoxyaniline synthesized in the same manner as in Example 3, and then 66 mg of platinum dioxide was added, followed by stirring under a hydrogen atmosphere at room temperature overnight. To the reaction mixture was added 40 ml of chloroform for dissolving the precipitate, and the catalyst was removed by filtration. The filtrate was concentrated under reduced pressure, and the residue was recrystallized from methanol to give 6.88 g of N-acetyl-N-(2-aminobenzyl)-2-phenoxyaniline.
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][CH2:5][CH:4]([N:8]2[C:16](=[O:17])[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:9]2=[O:18])[CH2:3]1.C(OC(=O)C)=C>C1COCC1>[OH:1][C@@H:2]1[CH2:7][CH2:6][CH2:5][C@H:4]([N:8]2[C:9](=[O:18])[C:10]3[C:15](=[CH:14][CH:13]=[CH:12][CH:11]=3)[C:16]2=[O:17])[CH2:3]1
Reactant: O=C1c2ccccc2C(=O)N1C1CCCC(O)C1
Solvent: C=COC(C)=O
Solvent: C1CCOC1
Product: O=C1c2ccccc2C(=O)N1[C@H]1CCC[C@@H](O)C1
Temperature: 25 °C
Yield: 37.8 %

Procedure:
A solution of 2-(3-hydroxy-cyclohexyl)-isoindole-1,3-dione (240 g, 0.98 mol) and Lipase B (87 g) in THF (3000 mL) was stirred at room temperature under nitrogen for 1˜2 h. Then acetic acid vinyl ester (252 g, 2.88 mol) was added to the solution, and the reaction mixture was stirred at rt for 3˜5 h. Then the reaction mixture was filtered, and the filtrate was concentrated to give crude product. The crude product was purified on silica gel (eluting with petroleum ether/ethyl acetate=10:1) to give (1S,3R)-2-(3-hydroxy-cyclohexyl)-isoindole-1,3-dione (Rf=0.6, petroleum ether/ethyl acetate=3/1, 90 g, 0.37 mol, yield: 39%) as a white solid. 1H NMR (CD3OD, 400 MHz): δ ppm 7.82 (m, 4H), 4.16 (m, 1H), 3.63 (m, 1H), 2.13 (m, 2H), 1.98 (m, 2H), 1.89 (m, 1H), 1.68 (m, 1H), 1.46 (m, 1H), 1.31 (m, 1H).
Reaction SMILES: [OH:1][CH2:2][CH2:3][NH:4][S:5]([C:8]1[CH:17]=[CH:16][CH:15]=[C:14]([N+:18]([O-:20])=[O:19])[C:9]=1[C:10]([O:12]C)=O)(=[O:7])=[O:6].[CH3:21][NH:22][CH3:23].CC(C)([O-])C.[K+]>CO.C(O)(C)(C)C>[CH3:21][N:22]([CH3:23])[C:10](=[O:12])[C:9]1[C:14]([N+:18]([O-:20])=[O:19])=[CH:15][CH:16]=[CH:17][C:8]=1[S:5]([NH:4][CH2:3][CH2:2][OH:1])(=[O:6])=[O:7]
Reactant: CNC
Reactant: COC(=O)c1c([N+](=O)[O-])cccc1S(=O)(=O)NCCO
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CO
Solvent: CC(C)(C)O
Product: CN(C)C(=O)c1c([N+](=O)[O-])cccc1S(=O)(=O)NCCO
Reaction time: 96 h
Yield: 87.7 %

Procedure:
A solution of methyl 2-[N-(2-hydroxyethyl)aminosulfonyl]-6-nitrobenzoate (4.58 g, 15.1 mmol) in absolute MeOH (50 ml) was added to a solution of dimethylamine (6.8 g, 0.15 mol) and potassium tertbutoxide (0.68 ml of a 0.262 M soluton in tertbutanol) in absolute MeOH (100 ml). After stirring at 20-25° for 4 days, solvents were removed under reduced pressure. The residue was dissolved in EtOAc and washed with 0.5N HCl followed by a saturated aqueous NaCl solution. The EtOAc extract was dried (Na2SO4), filtered and concentrated to give 4.2 g (88%) of product.
Reaction SMILES: I[C:2]1[C:10]2[C:5](=[N:6][CH:7]=[N:8][C:9]=2[NH2:11])[N:4]([C@H:12]2[CH2:17][CH2:16][C@@H:15]([N:18]3[CH2:23][CH2:22][N:21]([CH3:24])[CH2:20][CH2:19]3)[CH2:14][CH2:13]2)[N:3]=1.[F:25][C:26]1[CH:31]=[C:30](B2OC(C)(C)C(C)(C)O2)[CH:29]=[CH:28][C:27]=1[NH:41][C:42]1[O:43][C:44]2[CH:50]=[CH:49][CH:48]=[CH:47][C:45]=2[N:46]=1.O.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.O.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[NH2:11][C:9]1[N:8]=[CH:7][N:6]=[C:5]2[N:4]([C@H:12]3[CH2:17][CH2:16][C@@H:15]([N:18]4[CH2:23][CH2:22][N:21]([CH3:24])[CH2:20][CH2:19]4)[CH2:14][CH2:13]3)[N:3]=[C:2]([C:30]3[CH:29]=[CH:28][C:27]([NH:41][C:42]4[O:43][C:44]5[CH:50]=[CH:49][CH:48]=[CH:47][C:45]=5[N:46]=4)=[C:26]([F:25])[CH:31]=3)[C:10]=12
Reactant: CC1(C)OB(c2ccc(Nc3nc4ccccc4o3)c(F)c2)OC1(C)C
Reactant: CN1CCN([C@H]2CC[C@@H](n3nc(I)c4c(N)ncnc43)CC2)CC1
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: CN1CCN([C@H]2CC[C@@H](n3nc(-c4ccc(Nc5nc6ccccc6o5)c(F)c4)c4c(N)ncnc43)CC2)CC1
Temperature: 83 °C
Reaction time: 19 h
Yield: 25 %

Procedure:
To a solution of cis-3-iodo-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-4-amine (0.150 g, 0.340 mmol) in ethylene glycol dimethyl ether (3 mL) and water (1.5 mL) under nitrogen was added N2-[2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-1,3-benzoxazol-2-amine (0.151 g, 0.425 mmol), tetrakis(triphenylphosphine) palladium (0) (0.020 mg, 0.017 mmol), and sodium carbonate monohydrate (0.105 mg, 0.850 mmol). The solution was stirred at 83° C. for 19 h. The resulting yellow mixture was concentrated in vacuo to give a yellow oil. Purification by preparative RP-HPLC (25 to 100% CH3CN in 0.1 N aqueous ammonium acetate over 20 min at 21 mL/min using a 8 m Hypersil HS C18, 250×21 mm column, tr=5.7-8.1 min.) afforded cis-N2-(4-{4-amino-1-[4-(4-methylpiperazino)-cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-3-yl}-2-fluorophenyl)-1,3-benzoxazol-2-amine as an off-white solid (0.046 g, 25%): 1H NMR (DMSO-d6, 400 MHz) δ 10.65 (s, 1H), 8.49 (m, 1H), 8.25 (s, 1H), 7.53 (d, 2H), 7.48 (d, 2H), 7.26 (t, 1H), 7.20 (t, 1H), 4.80 (m, 1H), 3.51-2.50 (m, 11H), 2.33-2.32 (m, 4H), 2.09-2.06 (m, 2H), 1.80-1.40 (m, 3H); RP-HPLC (25 to 100% CH3CN in 0.1 N aqueous ammonium acetate over 10 min at 1 mL/min using a Hypersil HS C18, 250×4.6 mm column) tr=6.95 min., 99%; m/z 542 (MH+).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([N+:15]([O-])=O)[C:10]=2[S:18][CH2:19][C@@H:20]([C:29]([OH:31])=[O:30])[NH:21][O:22][C:23](=[O:28])[C:24]([CH3:27])([CH3:26])[CH3:25])[CH:6]=[CH:7][CH:8]=1)#[N:2]>[Pd].CO>[NH2:15][C:11]1[C:10]([S:18][CH2:19][C@@H:20]([C:29]([OH:31])=[O:30])[NH:21][O:22][C:23](=[O:28])[C:24]([CH3:25])([CH3:26])[CH3:27])=[C:9]([C:5]2[CH:6]=[CH:7][CH:8]=[C:3]([C:1]#[N:2])[CH:4]=2)[CH:14]=[CH:13][CH:12]=1
Reactant: CC(C)(C)C(=O)ON[C@@H](CSc1c(-c2cccc(C#N)c2)cccc1[N+](=O)[O-])C(=O)O
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)C(=O)ON[C@@H](CSc1c(N)cccc1-c1cccc(C#N)c1)C(=O)O
Yield: 91.5 %

Procedure:
410 mg of 43 (0.925 mmol), 41 mg of Pd/C (10%) and 20 mL of MeOH are hydrogenated at 7 bar for 10 hours at 20° C. in an autoclave. After filtering off the catalyst through Celite, the solvent is evaporated off to give 350 mg of expected product 44, which product is used directly in the following step.
Reaction SMILES: C[C:2]1(C)[S:7][CH2:6][CH2:5][N:4](S(C2C=CC(OCC#CCCOC3CCCCO3)=CC=2)(=O)=O)[CH:3]1[C:30]([OH:32])=O.O[N:35]1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.NO>CN(C=O)C.C(OCC)(=O)C>[NH:4]1[CH2:5][CH2:6][S:7][CH2:2][CH:3]1[C:30]([NH2:35])=[O:32]
Reactant: CC1(C)SCCN(S(=O)(=O)c2ccc(OCC#CCCOC3CCCCO3)cc2)C1C(=O)O
Reactant: On1nnc2ccccc21
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: NO
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: NC(=O)C1CSCCN1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 0.28 g (0.56 mmol) of 2,2-dimethyl-4-[(4-{[5-(tetrahydro-2H-pyran-2-yloxy)-2-pentynyl]oxy}phenyl)sulfonyl]-3-thiomorpholine carboxylic acid and 0.091 g (0.675 mmol) of 1-hydroxybenzotriazole in 2.5 mL of DMF was added 0.151 g (0.788 mmol) of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride and stirred at room temperature for 1 h. Then 0.173 mL (2.8 mmol) of 50% aqueous hydroxylamine was added and the reaction was stirred for 18 h. The resulting mixture was diluted with ethyl acetate, washed with water, brine, dried over MgSO4, filtered and concentrated in vacuo. The residue was chromatographed on silica gel eluting with 5% methanol/dichloromethane. The product was triturated with ether to provide 0.024 g (8%) of N-hydroxy-2,2-dimethyl-4-[(4-{[5-tetrahydro-2H-pyran-2-yloxy)-2-pentynyl]oxy}phenyl)sulfonyl]-3-thiomorpholine carboxamide as a white solid.
Reaction SMILES: Cl.[Cl:2][CH2:3][C:4]1[CH:5]=[C:6]([CH:8]=[CH:9][CH:10]=1)[NH2:7].C(N(CC)CC)C.[CH3:18][S:19](Cl)(=[O:21])=[O:20]>O1CCCC1>[Cl:2][CH2:3][C:4]1[CH:5]=[C:6]([NH:7][S:19]([CH3:18])(=[O:21])=[O:20])[CH:8]=[CH:9][CH:10]=1
Reactant: Nc1cccc(CCl)c1
Reactant: CS(=O)(=O)Cl
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CS(=O)(=O)Nc1cccc(CCl)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
873 mg (4.903 mmol) of 3-(chloromethyl)aniline hydrochloride (Example 89A) were initially charged in 4 ml of tetrahydrofuran, and 2.48 g (24.514 mmol) of triethylamine were added. A solution of 421 mg (3.677 mmol) of methanesulfonyl chloride in 3 ml of tetrahydrofuran was slowly added dropwise, and the reaction solution was stirred at RT for 2 h. The reaction solution was concentrated using a rotary evaporator and the residue was purified by preparative HPLC (Chromasil, water/acetonitrile).
Reaction SMILES: N[C@H:2]([C:7]([OH:9])=[O:8])[C@H:3]([CH2:5][CH3:6])[CH3:4].N([O-])=O.[Na+].[BrH:14]>>[Br:14][C@@H:2]([C@@H:3]([CH3:4])[CH2:5][CH3:6])[C:7]([OH:9])=[O:8]
Reactant: CC[C@H](C)[C@H](N)C(=O)O
Reactant: Br
Agent: O=N[O-]
Agent: [Na+]
Product: CC[C@H](C)[C@H](Br)C(=O)O
Temperature: 25 °C
Reaction time: 8 h
Yield: 55 %

Procedure:
To a cooled (0° C.) solution of L-Isoleucine (66 g) dissolved in HBr (6N, 500 ml) was added dropwise a solution of sodium nitrite (35 g in 100 ml water). The reaction was stirred overnight at room temperature and then extracted with EtOAc (3×150 ml). The combined organic extracts washed with 10% sodium bisulfit solution, water, saturated brine, dried over MgSO4, filtered and concentrated. The product a yellowish oil (53.9 g) was obtained in 55% yield. (The product can be purified by distillation and crystallization from PE). (see FIG. 6)
Reaction SMILES: [C:1]1([C@H:11]([NH:13][C@H:14]2[CH2:18][CH2:17][C@@H:16]([C:19]3[CH:24]=[CH:23][C:22]([N+:25]([O-])=O)=[CH:21][CH:20]=3)[CH2:15]2)[CH3:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[H][H]>C(OCC)(=O)C.[C].[Pd]>[C:1]1([C@H:11]([NH:13][C@H:14]2[CH2:18][CH2:17][C@@H:16]([C:19]3[CH:20]=[CH:21][C:22]([NH2:25])=[CH:23][CH:24]=3)[CH2:15]2)[CH3:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: C[C@@H](N[C@H]1CC[C@@H](c2ccc([N+](=O)[O-])cc2)C1)c1cccc2ccccc12
Reactant: [H][H]
Agent: [Pd]
Solvent: CCOC(C)=O
Product: C[C@@H](N[C@H]1CC[C@@H](c2ccc(N)cc2)C1)c1cccc2ccccc12
Yield: 99.4 %

Procedure:
(1S,3R)-N-[(1R)-1-(Naphthalen-1-yl)ethyl]-3-(4-nitrophenyl)cyclopentanamine 0.99 g (2.71 mmol) was dissolved in 2 mL of ethyl acetate, followed by addition of 0.20 g of 10% palladium-carbon catalyst, and the mixture was subjected to catalytic hydrogen reduction for 1.5 hours at room temperature. The reaction solution was filtered, and the filtrate was concentrated to give the title compound (0.89 g, 97%).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][N:6]=[CH:5][CH:4]=1)#[N:2].[F:9][C:10]1[CH:16]=[CH:15][C:13]([NH2:14])=[CH:12][CH:11]=1>>[F:9][C:10]1[CH:16]=[CH:15][C:13]([NH:14][C:1]([C:3]2[CH:8]=[CH:7][N:6]=[CH:5][CH:4]=2)=[NH:2])=[CH:12][CH:11]=1
Reactant: N#Cc1ccncc1
Reactant: Nc1ccc(F)cc1
Product: N=C(Nc1ccc(F)cc1)c1ccncc1

Procedure:
The title compound was prepared from 4-cyanopyridine (0.94 g, 9 mmol) and 4-fluoroaniline (1 g, 9 mmol) by following the procedure described in preparation 10 (1.1 g, yield 56.5%).
Reaction SMILES: C1(C)C=CC=CC=1.N1CCCCC1.[CH3:14][O:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[C:22]1[CH:23]=[C:24]([C:31]2[CH:38]=[CH:37][C:34]([CH:35]=O)=[CH:33][CH:32]=2)[CH:25]=[C:26]2[O:30][CH2:29][O:28][C:27]=12.[S:39]1[CH2:43][C:42](=[O:44])[NH:41][C:40]1=[O:45]>C(O)(=O)C>[CH3:14][O:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[C:22]1[CH:23]=[C:24]([C:31]2[CH:32]=[CH:33][C:34]([CH:35]=[C:43]3[S:39][C:40](=[O:45])[NH:41][C:42]3=[O:44])=[CH:37][CH:38]=2)[CH:25]=[C:26]2[O:30][CH2:29][O:28][C:27]=12
Reactant: COc1ccccc1-c1cc(-c2ccc(C=O)cc2)cc2c1OCO2
Reactant: O=C1CSC(=O)N1
Solvent: CC(=O)O
Solvent: Cc1ccccc1
Solvent: C1CCNCC1
Product: COc1ccccc1-c1cc(-c2ccc(C=C3SC(=O)NC3=O)cc2)cc2c1OCO2
Temperature: 25 °C
Yield: 58.8 %

Procedure:
A solution of toluene (10 mL), piperidine (10 μL), acetic acid (10 μL), 4-[3-(2-methoxyphenyl)-4,5-methylenedioxyphenyl]benzaldehyde (0.164 g, 0.493 mmol) and 2,4-thiazolidinedione (0.0578 g, 0.493 mmol) was heated at reflux overnight under an argon atmosphere. The reaction mixture was cooled to room temperature, and the resulting crystalline compound was filtered, washed with ethanol. The yellow solid was dried under high vacuum to afford 0.125 g (59%) of 4-[3-(2-methoxyphenyl)-4,5-methylenedioxyphenyl]-benzylidene-2,4-thiazolidinedione, mp 227–228° C. (dec.). 1H NMR (300 MHz; DMSO-d6): 3.77 (s, 3H), 6.05 (s, 2H), 7.12 (t, J=7.5 Hz, 1H), 7.12 (d, J=8.7 Hz, 1H), 7.23 (s, 1H), 7.30 (s, 1H), 7.33–7.43 (m, 2H), 7.63 (d, J=7.8 Hz, 2H), 7.80 (d, J=7.8 Hz, 2H), 7.81 (s, 1H), 12.5–12.7 (brs, 1H). 13C NMR (75 MHz; DMSO-d6): 56.3, 56.4, 101.9, 106.6, 112.4, 120.8, 121.0, 123.0, 123.6, 124.7, 127.8, 130.2, 131.3, 131.4, 132.0, 132.2, 133.1, 142.2, 145.9, 148.7, 157.1, 168.0, 168.4.
Reaction SMILES: C(N(CC)CC)C.[CH3:8][N:9]1[CH2:14][CH2:13][C@@H:12]([C:15]2[C:20]([O:21][CH3:22])=[CH:19][C:18]([O:23][CH3:24])=[CH:17][C:16]=2[O:25][CH3:26])[C@H:11]([OH:27])[CH2:10]1.CS(Cl)(=O)=O.C([O-])(O)=O.[Na+].[C:38]([O-])(=[O:40])[CH3:39].[Na+]>C(Cl)Cl.C(O)(C)C>[CH3:8][N:9]1[CH2:14][CH2:13][C@@H:12]([C:15]2[C:16]([O:25][CH3:26])=[CH:17][C:18]([O:23][CH3:24])=[CH:19][C:20]=2[O:21][CH3:22])[C@@H:10]1[CH2:11][O:27][C:38](=[O:40])[CH3:39]
Reactant: CC(=O)[O-]
Reactant: COc1cc(OC)c([C@@H]2CCN(C)C[C@H]2O)c(OC)c1
Agent: CS(=O)(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1cc(OC)c([C@@H]2CCN(C)[C@H]2COC(C)=O)c(OC)c1
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
Distilled triethyl amine (344 mL, 2.49 mol) was added slowly to a solution of compound of example 2 (350 g, 1.25 mol) in dry CH2Cl2 (2.5 L). To the reaction mixture methanesulfonyl chloride (122 mL, 171.1 g, 1.49 mol) was added with stirring, at 0° C., under an atmosphere of N2 and over a period of 20 min. The reaction mixture was further stirred for 1 h at 0° C. It was poured over saturated aqueous NaHCO3 solution (1.5 L). The organic layer was separated, washed with brine, dried (anhydrousNa2SO4) and concentrated to obtained a residue. This was dissolved in distilled isopropyl alcohol (1.5 L), anhydrous sodium acetate (408 g, 4.97 mmol) was added and the reaction mixture was refluxed for 1 h. It was cooled to room temperature. Sodium acetate was filtered off and washed with CHCl3. The filtrate was concentrated to obtain the title compound, which was purified using a silica gel column and 60% EtOAc+petroleum ether 60-80° C. as eluant.
Reaction SMILES: [CH3:1][N:2]([CH3:17])[C:3]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:4]=1[CH:5]=[CH:6][CH:7]=[C:8]2[S:13](Cl)(=[O:15])=[O:14].Cl.[C:19]([O:23][C:24](=[O:34])[C@@H:25]1[CH2:29][CH2:28][CH2:27][N:26]1[C:30](=[O:33])[CH2:31][NH2:32])([CH3:22])([CH3:21])[CH3:20].C(N(CC)CC)C>O1CCCC1.C(OCC)(=O)C>[C:19]([O:23][C:24](=[O:34])[C@@H:25]1[CH2:29][CH2:28][CH2:27][N:26]1[C:30](=[O:33])[CH2:31][NH:32][S:13]([C:8]1[C:9]2[C:4](=[C:3]([N:2]([CH3:17])[CH3:1])[CH:12]=[CH:11][CH:10]=2)[CH:5]=[CH:6][CH:7]=1)(=[O:15])=[O:14])([CH3:22])([CH3:20])[CH3:21]
Reactant: CN(C)c1cccc2c(S(=O)(=O)Cl)cccc12
Reactant: CC(C)(C)OC(=O)[C@@H]1CCCN1C(=O)CN
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CN(C)c1cccc2c(S(=O)(=O)NCC(=O)N3CCC[C@H]3C(=O)OC(C)(C)C)cccc12
Temperature: 25 °C
Reaction time: 4 h
Yield: 87.3 %

Procedure:
5-Dimethylamino-l-naphthalenesulfonyl chloride (5.10 g, 18.9 mmol) was added in portions to a well-stirred solution of glycyl-L-proline tert-butyl ester hydrochloride (5.00 g, 18.9 mmol) and triethylamine (5.20 mL, 37.8 mmol) in dry tetrahydrofuran (175 mL). The mixture was stirred at room temperature for 4 hours before it was diluted with ethyl acetate and washed successively with saturated sodium bicarbonate solution and brine. Following drying and solvent evaporation, the residue was chromatographed on silica gel (gradient elution with first 40% ethyl acetate in hexanes followed by 50% ethyl acetate in hexanes) and furnished 7.62 g (87%) of the title compound as a fluorescent green foam, m.p. 60°-67° C.; 1H NMR (CDCl3) δ 8.51 (dd, J=8.5, 3.3 Hz, 1H), 8.30 (d, J=8.7 Hz, 1H), 8.21-8.16 (m, 1H), 7.58-7.43 (m, 2H), 7.15 (d, J=7.4 Hz, 1H), 5.85-5.79 (m, 1H), 4.27-4.23 (m, 1H), 3.76-3.62 (m, 2H), 3.48-3.21 (m, 2H), 2.84 (s, 6H), 2.10-1.75 (m, 4H), 1.33 and 1.32 (2s, 9H); 13C NMR (CDCl3) ppm 170.84, 170.45, 165.84, 165.46, 152.04, 134.31, 134.16, 130.79, 130.16, 130.12, 129.87, 129.52, 129.47, 128.77, 123.23, 123.17, 119.22, 119.13, 115.59, 83.00, 81.82, 59.99, 59.38, 46.97, 45.98, 45.64, 44.69, 44.58, 31.41, 29.13, 28.05, 27.96, 24.49, 23.80, 22.36; IR (KBr, cm-1) 3266, 2978, 2942, 2876, 2834, 1736, 1658, 1456, 1440, 1370, 1330, 1148, 792, 626, 574; MS m/z (MH+) calcd 461.1984, obsd 461.1982.
Reaction SMILES: C(O[C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]#[N:22])=[CH:17][CH:16]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O.[C:30]1(=O)[CH2:33]C[CH2:31]1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl.C(Cl)CCl>[CH:6]1([N:8]2[CH2:9][CH2:10][CH:11]([O:14][C:15]3[CH:16]=[CH:17][C:18]([C:21]#[N:22])=[CH:19][CH:20]=3)[CH2:12][CH2:13]2)[CH2:33][CH2:30][CH2:31]1
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2ccc(C#N)cc2)CC1
Reactant: O=C1CCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCCl
Product: N#Cc1ccc(OC2CCN(C3CCC3)CC2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 60.5 %

Procedure:
To a stirred solution of 4-(4-Cyano phenoxy)piperidine-1-carboxylic acid tert-butyl ester (21.25 g, 0.0704 moles) in dichloromethane (300 mL) was added trifluoroacetic acid (81.4 g, 0.714 moles) and stirred the reaction mass overnight at room temperature. After completion of reaction, solvent was evaporated under vacuum and the residue, thus obtained, was basified with 10% caustic lye solution. The reaction mass was extracted with ethyl acetate twice, the combined organic layer was dried over sodium sulphate and evaporated under reduced pressure. The crude product, thus obtained, was treated with cyclobutanone (5.18 g, 0.074 moles), acetic acid (4.89 g, 0.0815 moles) in ethylene dichloride (100 mL), and stirred for 4 hours at room temperature. Sodium triacetoxyborohydride (35.06 g, 0.165 moles) was added to the reaction mass in a single lot and the mixture was stirred at room temperature for 2 hours. The reaction mixture was quenched in water and basified with lye solution. The layers were separated and the aqueous layer was extracted with dichloromethane twice. The combined organic layers were dried over sodium sulfate, concentrated under vacuum and the residual mass was further purified by flash chromatography (dichloromethane: triethylamine, 9.5:0.5) to obtain the title compound 10.92 g (Yield: 60.5%).
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][CH:9]=2)=[CH:6][C:5]([C:18]2([C:22]([O:24]CC)=[O:23])[CH2:21][CH2:20][CH2:19]2)=[CH:4][C:3]=1[O:27][CH2:28][C:29]([F:32])([F:31])[F:30].[Li+].[OH-]>CO.C1COCC1.O>[Cl:1][C:2]1[C:7]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][CH:9]=2)=[CH:6][C:5]([C:18]2([C:22]([OH:24])=[O:23])[CH2:21][CH2:20][CH2:19]2)=[CH:4][C:3]=1[O:27][CH2:28][C:29]([F:30])([F:31])[F:32]
Reactant: CCOC(=O)C1(c2cc(OCC(F)(F)F)c(Cl)c(-c3ccc(C(F)(F)F)cc3)c2)CCC1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)C1(c2cc(OCC(F)(F)F)c(Cl)c(-c3ccc(C(F)(F)F)cc3)c2)CCC1
Temperature: 25 °C
Reaction time: 5 h
Yield: 79.6 %

Procedure:
Ethyl 1-(6-chloro-5-(2,2,2-trifluoroethoxy)-4′-(trifluoromethyl)biphenyl-3-yl)cyclobutanecarboxylate (0.1 g) dissolved in MeOH/THF/H2O (10 mL/10 mL/5 mL) and 70 mg LiOH added. The reaction mixture was stirred at room temperature for 5 h and concentrated under reduced pressure. Water (10 mL) was added and the reaction mixture was extracted with EtOAc (3×10 mL). The combined organic phases were dried over MgSO4, filtered and evaporated under reduced pressure. Purification by column chromatography over silica gel (hexane/EtOAc 9:1) gave 1-(6-chloro-5-(2,2,2-trifluoroethoxy)-4′-(trifluoromethyl)biphenyl-3-yl)cyclobutanecarboxylic acid (75 mg) of the product as a white solid. 1H-NMR (500 MHz, CDCl3): 7.74 (d, 2H), 7.53 (d, 2H), 6.99 (s, 1H), 6.97 (s, 1H), 4.43 (q, 2H), 2.88 (m, 2H), 2.54 (m, 2H), 2.15 (m, 1H), 1.93 (m, 1H)
Reaction SMILES: [N:1]1([C:6]([C:8]2[C:13]([OH:14])=[CH:12][CH:11]=[CH:10][N:9]=2)=[O:7])[CH2:5][CH2:4][CH2:3][CH2:2]1.FC(F)(F)C(O)=O.[H][H]>C(O)(=O)C.O=[Pt]=O>[N:1]1([C:6]([CH:8]2[CH:13]([OH:14])[CH2:12][CH2:11][CH2:10][NH:9]2)=[O:7])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: [H][H]
Reactant: O=C(c1ncccc1O)N1CCCC1
Agent: O=[Pt]=O
Solvent: O=C(O)C(F)(F)F
Solvent: CC(=O)O
Product: O=C(C1NCCCC1O)N1CCCC1
Yield: 82.4 %

Procedure:
10 g (0.052 moles) of 2-(pyrrolidin-1-yl)carbonyl-3-hydroxy pyridine, dissolved in 100 ml of acetic acid and 8 mml of trifluoroacetic acid, were hydrogenated at 40 psi over 1 g of PtO2 at room temperature, until the theoretical amount of hydrogen was consumed. The catalyst was filtered off and the filtrate evaporated in vacuo. The residue was taken up in 20% NaOH and extracted with CH2Cl2, which was dried and evaporated in vacuo to dryness. 8.5 g of the title compound were obtained as a 80/20 diastereoisomeric mixture, which was used for the subsequent step without further purification.