Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C@@H:13]([CH2:14][O:15]CC2C=CC=CC=2)[CH2:12][O:11][C:10]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H][H]>[Pd].C(O)C>[C:1]([O:5][C:6]([N:8]1[C@@H:13]([CH:14]=[O:15])[CH2:12][O:11][C:10]([C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=2)([C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CC(c2ccccc2)(c2ccccc2)OC[C@@H]1COCc1ccccc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CC(c2ccccc2)(c2ccccc2)OC[C@@H]1C=O

Procedure:
To 10% palladium on carbon (2.1 g) in ethanol (50 mL) add (S)-5-benzyloxymethyl-2,2-diphenylmorpholine-4-carboxylic acid tert-butyl ester (3.29 g, 7.16 mmol) in ethanol (75 mL) and stir under 1 atmosphere of hydrogen gas at room temperature for 4 hours. Filter and concentrate to give the desired compound as a white solid. Dissolve the solid in dimethylsulfoxide (20 mL) and add triethylamine (1.30 g, 12.82 mmol), then pyridine sulfur trioxide complex (1.84 g, 11.55 mmol). Stir at room temperature 3 hours and dilute with 10% ethyl acetate/hexanes (˜150 mL). Wash with water, 1 N aqueous citric acid and saturated aqueous sodium chloride, dry (magnesium sulfate), filter and concentrate to give the desired compound as a white solid.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][NH:14][CH2:13][C@H:12]1[CH3:17])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:18]([O:25][C:26]1[CH:31]=[CH:30][C:29](Br)=[CH:28][CH:27]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C(=O)([O-])[O-].[Cs+].[Cs+].F[B-](F)(F)F.C(P(C(C)(C)C)C(C)(C)C)(C)(C)C>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C(OCC)(=O)C.O.C1(C)C=CC=CC=1>[CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][N:14]([C:29]2[CH:30]=[CH:31][C:26]([O:25][CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[CH:27][CH:28]=2)[CH2:13][C@H:12]1[CH3:17])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C[C@@H]1CNCCN1C(=O)OCc1ccccc1
Reactant: Brc1ccc(OCc2ccccc2)cc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)P(C(C)(C)C)C(C)(C)C
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Solvent: O
Product: C[C@@H]1CN(c2ccc(OCc3ccccc3)cc2)CCN1C(=O)OCc1ccccc1
Temperature: 95 °C
Reaction time: 48 h
Yield: 78.5 %

Procedure:
(R)-2-Methylpiperazine-1-carboxylic acid benzyl ester (4.42 g, 18.9 mmol), 1-benzyloxy-4-bromobenzene (5.95 g, 22.6 mmol), cesium carbonate (8.60 g, 26.4 mmol) and toluene (49 ml) were mixed, and the atmosphere was replaced with nitrogen. Palladium acetate (0.42 g, 1.9 mmol) and tri-tert-butylphosphine tetrafluoroborate (0.66 g, 2.3 mmol) were added thereto and stirred at 90 to 100° C. for 2 days. Water and ethyl acetate were added to the reaction mixture, the mixture was filtered through Celite to remove insoluble matter. The filtrate was separated into layers. The organic layer was washed with a saturated sodium chloride aqueous solution, dried over magnesium sulfate and concentrated. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=100:0→70:30) to afford the title compound as a brown oil (6.18 g, 79%).
Reaction SMILES: [C:1]1([C:7]2[N:12]=[C:11]3[CH2:13][CH2:14][CH2:15][N:16]([CH2:17][C:18]4[CH:19]=[C:20]([OH:24])[CH:21]=[CH:22][CH:23]=4)[C:10]3=[N:9][C:8]=2[C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:38][C:39]([O:41][CH2:42][CH3:43])=[O:40]>CC(C)=O>[C:1]1([C:7]2[N:12]=[C:11]3[CH2:13][CH2:14][CH2:15][N:16]([CH2:17][C:18]4[CH:19]=[C:20]([CH:21]=[CH:22][CH:23]=4)[O:24][CH2:38][C:39]([O:41][CH2:42][CH3:43])=[O:40])[C:10]3=[N:9][C:8]=2[C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: Oc1cccc(CN2CCCc3nc(-c4ccccc4)c(-c4ccccc4)nc32)c1
Reactant: CCOC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCOC(=O)COc1cccc(CN2CCCc3nc(-c4ccccc4)c(-c4ccccc4)nc32)c1
Temperature: 25 °C

Procedure:
A mixture comprising 3-((2,3-diphenyl-7,8-dihydropyrido[3,2-b]pyrazin-5(6H)-yl)methyl)phenol (140 mg, 0.356 mmol), potassium carbonate (98 mg, 0.712 mmol) and ethyl 2-bromoacetate (119 mg, 0.712 mmol) in acetone (3 ml) was heated at reflux overnight. The suspension was cooled to room temperature and filtered. The filtrate was evaporated to dryness and the residue was purified by chromatography on silica eluting with EtOAc/iso-hexane to afford the title compound.
Reaction SMILES: I[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]([C:12]([F:15])([F:14])[F:13])[C:6]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:5]2.[CH3:21][N:22](C)C=O>[C-]#N.[Zn+2].[C-]#N.C(OCC)(=O)C>[C:21]([C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]([C:12]([F:15])([F:14])[F:13])[C:6]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:5]2)#[N:22]
Reactant: CN(C)C=O
Reactant: CCOC(=O)C1=Cc2cc(I)ccc2NC1C(F)(F)F
Agent: [C-]#N
Agent: [Zn+2]
Solvent: CCOC(C)=O
Product: CCOC(=O)C1=Cc2cc(C#N)ccc2NC1C(F)(F)F
Temperature: 80 °C
Yield: 48 %

Procedure:
N,N-Dimethylformamide (5 mL) was degassed with nitrogen for thirty minutes in a three neck round bottom flask equipped with a condenser, temperature monitoring, nitrogen purge and heating mantle. Ethyl 6-iodo-1,2-dihydro-2-(trifluoromethyl)-3-quinolinecarboxylate (Example 158) (0.522 g, 1.32 mmol) and zinc cyanide (0.102 g, 0.792 mmol) were added to the N,N-dimethylformamide and stirred vigorously for ten minutes. Tetrakis(triphenyl-phosphine)palladium(0) (0.068 g, 0.53 mmol) was added and the contents gently warmed to 80° C. for 2 hours under a nitrogen atmosphere. Ethyl acetate (20 mL) was added, followed by extraction with aqueous 2 N ammonium hydroxide (2×10 mL), water (2×10 mL), saturated ammonium chloride (2×10 mL), dried over sodium sulfate and solvent removed in vacuo to yield a yellow solid. The product was purified by flash chromatography (silica gel, ethyl acetate-hexanes, 3:1) to yield, upon concentration of the appropriate fractions, ethyl 6-cyano-1,2-dihydro-2-(trifluoromethyl)-3-quinolinecarboxylate as a yellow solid (188 mg, 48%): mp 211-212° C. 1H NMR (CDCl3 /300 MHz) 7.68 (s, 1H), 7.43 (m, 2H), 6.69 (d, 1H, J=8.3 Hz), 5.22 (m, 1H), 4.98 (br s, 1H), 1.30 (m, 2H), 1.36 (t, 3H, J=7.1 Hz). EIHRMS m/z 314.1147 (M+NH4+, Calc'd 314.1116). Anal. Calc'd for C14H11F3N2O2 : C, 56.76; H, 3.74; N, 9.46. Found: C, 56.44; H, 4.03; N, 9.29.
Reaction SMILES: C([O:5][C:6](=[O:20])[CH2:7][N:8]1[CH2:13][CH2:12][NH:11][C@@H:10]([CH2:14][C:15]([O:17][CH3:18])=[O:16])[C:9]1=[O:19])(C)(C)C.[CH3:21][O:22][C:23]1[CH:48]=[CH:47][C:26]([CH2:27][CH:28]([CH2:32][C:33](=[O:46])[N:34]2[CH2:39][CH2:38][N:37]([C:40]3[CH:45]=[CH:44][N:43]=[CH:42][CH:41]=3)[CH2:36][CH2:35]2)[C:29](O)=[O:30])=[CH:25][CH:24]=1.Cl.C(N=C=NCCCN(C)C)C>C(#N)C>[CH3:21][O:22][C:23]1[CH:24]=[CH:25][C:26]([CH2:27][C@@H:28]([CH2:32][C:33](=[O:46])[N:34]2[CH2:35][CH2:36][N:37]([C:40]3[CH:41]=[CH:42][N:43]=[CH:44][CH:45]=3)[CH2:38][CH2:39]2)[C:29]([N:11]2[CH2:12][CH2:13][N:8]([CH2:7][C:6]([OH:5])=[O:20])[C:9](=[O:19])[CH:10]2[CH2:14][C:15]([O:17][CH3:18])=[O:16])=[O:30])=[CH:47][CH:48]=1
Reactant: COc1ccc(CC(CC(=O)N2CCN(c3ccncc3)CC2)C(=O)O)cc1
Reactant: COC(=O)C[C@@H]1NCCN(CC(=O)OC(C)(C)C)C1=O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CC#N
Product: COC(=O)CC1C(=O)N(CC(=O)O)CCN1C(=O)[C@H](CC(=O)N1CCN(c2ccncc2)CC1)Cc1ccc(OC)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 58.5 %

Procedure:
To a suspension of (S)-(3-methoxycarbonylmethyl-2-oxopiperazin-1-yl)acetic acid tert-butyl ester (0.29 g) and 2-(4-methoxybenzyl)-4-oxo-4-(4-pyridin-4-ylpiperazin-1-yl)butanoic acid (0.385 g) produced in Reference Example 9 in acetonitrile (30 ml) was added 1-ethyl-3-(3-di-methylaminopropyl)carbodiimide hydrochloride (0.4 g) and the suspension was stirred for 24 hours at room temperature. The reaction mixture was concentrated under reduced pressure and purified by means of a silica gel column chromatography (acetonitrile:methanol=7:3). To the produced ester derivative was added trifluoroacetic acid (6 ml) and the solution was stirred for 2 hours at room temperature. The reaction mixture was concentrated under reduced pressure and the concentrate was purified by means of CHP-20 column chromatography (H2O→20% acetonitrile aqueous solution). The objected fraction was concentrated and subjected to lyophilization to give the titled compound (0.35 g) as a white amorphous powdery product.
Reaction SMILES: [CH2:1]([C:4]1[N:5]=[C:6]([Cl:15])[C:7]2[C:12]([C:13]=1[OH:14])=[CH:11][CH:10]=[CH:9][CH:8]=2)[CH:2]=[CH2:3].B1C2CCCC1CCC2.[OH-:25].[Na+].OO>O1CCCC1>[Cl:15][C:6]1[C:7]2[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:13]([OH:14])=[C:4]([CH2:1][CH2:2][CH2:3][OH:25])[N:5]=1
Reactant: C=CCc1nc(Cl)c2ccccc2c1O
Reactant: [OH-]
Agent: B1C2CCCC1CCC2
Agent: OO
Agent: [Na+]
Solvent: C1CCOC1
Product: OCCCc1nc(Cl)c2ccccc2c1O
Reaction time: 8 h
Yield: 71.7 %

Procedure:
To a stirred solution of 3-allyl-1-chloroisoquinolin-4-ol (670 mg, 3.05 mmol) in dry tetrahydrofuran (5 mL) at room temperature was added 0.5 M in THF solution of 9-BBN (18.30 mL, 9.15 mmol) and the mixture was stirred for overnight. 3N NaOH (9.15 mL, 27.5 mmol) and H2O2 (2.83 mL, 30.5 mmol) were then added to the mixture. The mixture was stirred for 45 min before quenching with sat. NaCl solution. 1 N HCl was then added to the solution to adjust PH<7. The reaction was extracted with EtOAc. The organic layer was washed with brine, dried and concentrated to afford a yellow oil that was purified by silica gel chromatography using 20-40% EtOAc/hexane to obtain 1-chloro-3-(3-hydroxypropyl)isoquinolin-4-ol (520 mg, 70%) as product. MS: MS m/z 238.0 (M++1).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)([O-])=O>[Pd].CO>[C:5]1([C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:4]([NH2:1])=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: O=[N+]([O-])c1ccccc1-c1ccccc1
Agent: [Pd]
Solvent: CO
Product: Nc1ccccc1-c1ccccc1
Reaction time: 12 h

Procedure:
Activated palladium on carbon (10% w/w, 0.25 g) was added to a solution of the nitro 2 (1.70 g, 8.53 mmol) in anhydrous methanol (100 mL). The reaction flask was purged thrice with H2 (g), pressurized to 5 bar with H2 (g), and mechanically shaken in a Parr hydrogenator for 12 hours. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure to yield the amine 3 as a yellow oil (1.44 g, quant.) that was used immediately in the next step.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:11](=[O:12])[N:10]([CH:13]([CH3:15])[CH3:14])[C:8](=[O:9])[C:7]2=[CH:16][CH:17]=1)([O-])=O.[H][H]>N.O[V](=O)=O.[O-2].[O-2].[Ti+4].[Pd].O>[NH2:1][C:4]1[CH:5]=[C:6]2[C:11](=[O:12])[N:10]([CH:13]([CH3:15])[CH3:14])[C:8](=[O:9])[C:7]2=[CH:16][CH:17]=1
Reactant: [H][H]
Reactant: CC(C)N1C(=O)c2ccc([N+](=O)[O-])cc2C1=O
Agent: O=[V](=O)O
Agent: [Pd]
Agent: [Ti+4]
Solvent: O
Product: CC(C)N1C(=O)c2ccc(N)cc2C1=O
Temperature: 65 °C
Reaction time: 71 h
Yield: 59.8 %

Procedure:
0.001 g of ammonium vanadate and 0.5 g of titanium dioxide extrudate containing 1% by weight of metallic palladium and having a particle size of 3 mm (from Johnson Matthey) are added to a suspension consisting of 50 ml of water and 2.3 g of 4-nitro-N-isopropylphthalimide. After displacing the air with nitrogen, the latter is replaced by hydrogen at atmospheric pressure and the suspension is stirred at 65° C. for 71 hours. During this time, 102% of the theoretical amount of hydrogen, based on the 4-nitro-N-isopropylphthalimide, is absorbed. The resulting suspension is then sieved through a sieve having a mesh width of 1 mm. The material remaining on the sieve is washed with 50 ml of water and the combined aqueous phases are then filtered through a paper filter and washed with 1000 ml of water. Drying at 80° C. under reduced pressure (125 mbar) gives 1.2 g (57%) of 4-amino-N-isopropylphthalimide.
Reaction SMILES: Cl[CH2:2][CH2:3][C:4]([C:10]1[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=1)([OH:9])[CH2:5][CH2:6][CH:7]=[CH2:8].[F:17][CH:18]([F:31])[O:19][C:20]1[CH:25]=[CH:24][C:23]([C@@H:26]([N:28]=[C:29]=[O:30])[CH3:27])=[CH:22][CH:21]=1>>[CH2:5]([C:4]1([C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=2)[O:9][C:29](=[O:30])[N:28]([C@H:26]([C:23]2[CH:24]=[CH:25][C:20]([O:19][CH:18]([F:17])[F:31])=[CH:21][CH:22]=2)[CH3:27])[CH2:2][CH2:3]1)[CH2:6][CH:7]=[CH2:8]
Reactant: C[C@H](N=C=O)c1ccc(OC(F)F)cc1
Reactant: C=CCCC(O)(CCCl)c1ccc(F)cc1
Product: C=CCCC1(c2ccc(F)cc2)CCN([C@@H](C)c2ccc(OC(F)F)cc2)C(=O)O1

Procedure:
6-(but-3-enyl)-3-((S)-1-(4-(difluoromethoxy)phenyl)ethyl)-6-(4-fluorophenyl)-1,3-oxazinan-2-one was prepared from 1-chloro-3-(4-fluorophenyl)hept-6-en-3-ol and (S)-1-(difluoromethoxy)-4-(1-isocyanatoethyl)benzene following a procedure analogous to that described in Example 110 Step 2. Two isomers were isolated.
Reaction SMILES: [NH2:1][CH2:2][CH:3]1[CH2:8][CH2:7][N:6]([C:9]2[C:14]([NH:15][C:16](=[O:24])[C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([Cl:23])[CH:18]=3)=[CH:13][C:12]([S:25]([CH3:28])(=[O:27])=[O:26])=[CH:11][N:10]=2)[CH2:5][CH2:4]1.C(=O)([O-])[O-].[Na+].[Na+].[C:35]1([N:41]=[C:42]=[O:43])[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1>C(#N)C>[Cl:23][C:19]1[CH:18]=[C:17]([CH:22]=[CH:21][CH:20]=1)[C:16]([NH:15][C:14]1[C:9]([N:6]2[CH2:5][CH2:4][CH:3]([CH2:2][NH:1][C:42]([NH:41][C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)=[O:43])[CH2:8][CH2:7]2)=[N:10][CH:11]=[C:12]([S:25]([CH3:28])(=[O:26])=[O:27])[CH:13]=1)=[O:24]
Reactant: CS(=O)(=O)c1cnc(N2CCC(CN)CC2)c(NC(=O)c2cccc(Cl)c2)c1
Reactant: O=C=Nc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Product: CS(=O)(=O)c1cnc(N2CCC(CNC(=O)Nc3ccccc3)CC2)c(NC(=O)c2cccc(Cl)c2)c1
Temperature: 25 °C
Reaction time: 6 h
Yield: 0 %

Procedure:
To 0.028 g (0.066 mmol) of N-(4-aminomethyl-5′-methanesulfonyl-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-3′-yl)-3-chloro-benzamide in a mixture of acetonitrile (0.5 mL) and saturated aqueous sodium carbonate (0.5 mL) is added 0.0086 mL (0.11 mmol) of phenylisocyanate. The mixture is stirred at room temperature for 6 hours then concentrated under reduced pressure. The residue is diluted with water causing a gummy solid to form. The aqueous phase is decanted off and the solid is rinsed and decanted with water and then dried. The residue is purified by preparative thin layer chromatography to give 0.016 mg (44%) of the title compound (110) as a clear resin. [M+H]+=542.7.
Reaction SMILES: Cl.C(OC([N:9]1[CH2:14][CH2:13][C@@H:12]([O:15][C:16]2[CH:21]=[C:20]([F:22])[CH:19]=[CH:18][C:17]=2[C:23]([N:25]2[CH2:39][C:28]3=[C:29]4[N:34]([N:35]=[C:27]3[CH2:26]2)[C:33]([CH3:36])=[C:32]([Cl:37])[C:31]([CH3:38])=[N:30]4)=[O:24])[CH2:11][C@@H:10]1[C:40]([F:43])([F:42])[F:41])=O)(C)(C)C.[OH-].[Na+]>O1CCOCC1>[Cl:37][C:32]1[C:31]([CH3:38])=[N:30][C:29]2[N:34]([N:35]=[C:27]3[CH2:26][N:25]([C:23]([C:17]4[CH:18]=[CH:19][C:20]([F:22])=[CH:21][C:16]=4[O:15][C@@H:12]4[CH2:13][CH2:14][NH:9][C@@H:10]([C:40]([F:41])([F:43])[F:42])[CH2:11]4)=[O:24])[CH2:39][C:28]3=2)[C:33]=1[CH3:36]
Reactant: Cc1nc2c3c(nn2c(C)c1Cl)CN(C(=O)c1ccc(F)cc1O[C@@H]1CCN(C(=O)OC(C)(C)C)[C@@H](C(F)(F)F)C1)C3
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: Cc1nc2c3c(nn2c(C)c1Cl)CN(C(=O)c1ccc(F)cc1O[C@@H]1CCN[C@@H](C(F)(F)F)C1)C3
Temperature: 25 °C
Reaction time: 16 h
Yield: 35 %

Procedure:
A 4M solution of HCl in 1,4-dioxane (0.47 mL; 1.87 mmol; 10 eq.) was added to a solution of trans-4-[2-(6-chloro-5,7-dimethyl-1H,3H-2,4,7a,8-tetraaza-cyclopenta[a]indene-2-carbonyl)-5-fluoro-phenoxy]-2-trifluoromethyl-piperidine-1-carboxylic acid tert-butyl ester (115 mg; 0.19 mmol; 1 eq.) in 1,4-dioxane (5 mL) and the reaction mixture was stirred at room temperature for 16 hours. 5M NaOH was added and the mixture extracted with DCM (3×). The combined organics were washed with brine, dried over sodium sulfate and concentrated in vacuo. The residue was dissolved in ACN/water and freeze-dried to afford the title compound (34 mg, 35%) as a yellow solid. 1H NMR (CDCl3) δ 7.45-7.29 (m, 1H), 6.91-6.74 (m, 1H), 6.74-6.60 (m, 1H), 5.12-4.91 (m, 2H), 4.84-4.53 (m, 3H), 3.56-3.29 (m, 1H), 3.07-2.79 (m, 5H), 2.78-2.55 (m, 3H), 2.22-1.99 (m, 1H), 1.99-1.86 (m, 1H), 1.86-1.56 (m, 3H). HPLC (max plot) 92.5%, Rt 3.10 min. UPLC/MS: (MS+) 512.3 ([M+H]+).
Reaction SMILES: COC1C=CC=C(OC)C=1C(N[C@H]1CCC[C@@H]1[NH:13][C:14]1C=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][N:15]=1)=O.Cl.[NH2:31][C@H:32]1[CH2:36][CH2:35][CH2:34][C@@H:33]1[NH:37][C:38](=[O:50])[C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][C:40]=1[N:45]1[N:49]=[CH:48][CH:47]=[N:46]1.ClC1N=CC(C(F)(F)F)=CN=1>>[N:49]1[N:45]([C:40]2[CH:41]=[CH:42][CH:43]=[CH:44][C:39]=2[C:38]([NH:37][C@H:33]2[CH2:34][CH2:35][CH2:36][C@@H:32]2[NH:31][C:14]2[N:13]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][N:15]=2)=[O:50])[N:46]=[CH:47][CH:48]=1
Reactant: COc1cccc(OC)c1C(=O)N[C@H]1CCC[C@@H]1Nc1ccc(C(F)(F)F)cn1
Reactant: N[C@H]1CCC[C@@H]1NC(=O)c1ccccc1-n1nccn1
Agent: Cl
Agent: FC(F)(F)c1cnc(Cl)nc1
Product: O=C(N[C@H]1CCC[C@@H]1Nc1ncc(C(F)(F)F)cn1)c1ccccc1-n1nccn1

Procedure:
Prepared according to the procedure for 2,6-dimethoxy-N-[(1S,2S)-2-{[5-(trifluoromethyl)pyridin-2-yl]amino}cyclopentyl]benzamide (Example 1) from N-[(1S,2S)-2-amino cyclopentyl]-2-(2H-1,2,3-triazol-2-yl)benzamide hydrochloride (Intermediate 4; 100 mg, 0.325 mmol) and 2-chloro-5-(trifluoromethyl)pyrimidine (CAS number 69034-12-4; 59.3 mg, 0.325 mmol). The crude reaction was filtered through cotton wool before being purified by reverse phase preparative HPLC (eluted with acetonitrile/water containing 0.1% ammonia) to afford the title compound.
Reaction SMILES: [CH2:1]([C:8]1[C:13]([C:14]#[C:15][C@:16]2([OH:24])[CH:21]3[CH2:22][CH2:23][N:18]([CH2:19][CH2:20]3)[CH2:17]2)=[CH:12][CH:11]=[C:10]([N:25]2[CH2:29][C@@H:28]([O:30][CH3:31])[C@H:27]([OH:32])[CH2:26]2)[N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>CO.[H][H].[Pt](=O)=O>[CH2:1]([C:8]1[C:13]([CH2:14][CH2:15][C@:16]2([OH:24])[CH:21]3[CH2:20][CH2:19][N:18]([CH2:23][CH2:22]3)[CH2:17]2)=[CH:12][CH:11]=[C:10]([N:25]2[CH2:29][C@@H:28]([O:30][CH3:31])[C@H:27]([OH:32])[CH2:26]2)[N:9]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: [H][H]
Reactant: CO[C@@H]1CN(c2ccc(C#C[C@@]3(O)CN4CCC3CC4)c(Cc3ccccc3)n2)C[C@H]1O
Agent: O=[Pt]=O
Solvent: CO
Product: CO[C@@H]1CN(c2ccc(CC[C@@]3(O)CN4CCC3CC4)c(Cc3ccccc3)n2)C[C@H]1O

Procedure:
180 mg of the target compound was obtained using 200 mg of (3R)-3-[2-benzyl-6-[(3R,4R)-3-hydroxy-4-methoxypyrrolidine-1-yl]-3-pyridyl]ethynyl-3-quinuclidinol (Example 10) in 2 ml of methanol at normal pressure in a hydrogen atmosphere wherein 10 mg of platinum (IV) oxide was used as a catalyst to carry out catalytic reduction.
Reaction SMILES: [NH2:1][C:2]1[C:6]2[C:7]([Br:13])=[C:8]([O:11][CH3:12])[CH:9]=[CH:10][C:5]=2[O:4][C:3]=1[C:14](=[O:28])[CH:15]=[CH:16][C:17]1[N:18]=[C:19]([NH:22][C:23](=[O:27])[CH:24]([CH3:26])[CH3:25])[S:20][CH:21]=1.CC#N.CC(O)=O.OP(O)(O)=O>[Cl-].[Cl-].[Zn+2].O>[Br:13][C:7]1[C:6]2[C:2]3[NH:1][CH:16]([C:17]4[N:18]=[C:19]([NH:22][C:23](=[O:27])[CH:24]([CH3:26])[CH3:25])[S:20][CH:21]=4)[CH2:15][C:14](=[O:28])[C:3]=3[O:4][C:5]=2[CH:10]=[CH:9][C:8]=1[O:11][CH3:12]
Reactant: COc1ccc2oc(C(=O)C=Cc3csc(NC(=O)C(C)C)n3)c(N)c2c1Br
Agent: O=P(O)(O)O
Agent: [Cl-]
Agent: [Zn+2]
Solvent: O
Solvent: CC#N
Solvent: CC(=O)O
Product: COc1ccc2oc3c(c2c1Br)NC(c1csc(NC(=O)C(C)C)n1)CC3=O
Temperature: 90 °C
Yield: 55.1 %

Procedure:
A mixture of 16A (2 g, 4.3 mmol), ZnCl2 (6 g), MeCN (10 mL), AcOH (2 mL) and H3PO4 (2 mL) was heated to 90° C. and reacted overnight. TLC monitored the reaction. After the reaction completed, the reaction mixture was added dropwise into water, extracted with ethyl acetate and concentrated to give 16B (1.1 g, 55% yield).
Reaction SMILES: [OH:1][N:2]1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C.[CH2:23]([O:30][C:31]1[CH:36]=[CH:35][C:34]([S:37]([NH:40][CH2:41][C@H:42]([N:46]2[CH2:51][CH2:50][N:49]([S:52]([CH3:55])(=[O:54])=[O:53])[CH2:48][CH2:47]2)[C:43](O)=[O:44])(=[O:39])=[O:38])=[CH:33][CH:32]=1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.[Si](ON)(C(C)(C)C)(C)C.C(=O)([O-])O.[Na+]>CN(C)C=O.O>[CH2:23]([O:30][C:31]1[CH:32]=[CH:33][C:34]([S:37]([NH:40][CH2:41][C@H:42]([N:46]2[CH2:51][CH2:50][N:49]([S:52]([CH3:55])(=[O:54])=[O:53])[CH2:48][CH2:47]2)[C:43]([NH:2][OH:1])=[O:44])(=[O:38])=[O:39])=[CH:35][CH:36]=1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: On1nnc2ccccc21
Reactant: CS(=O)(=O)N1CCN([C@@H](CNS(=O)(=O)c2ccc(OCc3ccccc3)cc2)C(=O)O)CC1
Agent: CC(C)(C)[Si](C)(C)ON
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CN(C)C=O
Solvent: O
Product: CS(=O)(=O)N1CCN([C@@H](CNS(=O)(=O)c2ccc(OCc3ccccc3)cc2)C(=O)NO)CC1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
224 mg (1.7 mmol) of 1-hydroxybenzotriazole and 318 mg (1.7 mmol) of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride are added successively to 750 mg (1.5 mmol) of (S)-3-(4-benzyloxybenzenesulfonylamino)-2-(4-methanesulfonylpiperazin-1-yl)propanoic acid in 20 ml of dimethylformamide. After stirring at ambient temperature for 20 min, a solution of 244 mg (1.7 mmol) of O-tert-butyldimethylsilylhydroxylamine in 3 ml of dimethylformamide is added. The reaction medium is then stirred at ambient temperature for 18 h and then 2 ml of a saturated aqueous solution of sodium hydrogen carbonate and finally 2 ml of water are added. After extraction with ethyl acetate, the organic phase is washed with a saturated aqueous solution of sodium hydrogen carbonate, dried over magnesium sulfate, filtered and concentrated. The crude residue obtained is taken up in 15 ml of ethyl acetate, heated to 70° C. and then brought back to ambient temperature, filtered and dried under vacuum.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([C:11]([OH:13])=[O:12])[CH:5]=[C:6]2[C:10]=1[NH:9][N:8]=[CH:7]2.[Cl:14]N1C(=O)CCC1=O.S([O-])([O-])(=O)=S.[Na+].[Na+].Cl>CC#N.O>[Cl:14][C:7]1[C:6]2[C:10](=[C:2]([CH3:1])[CH:3]=[C:4]([C:11]([OH:13])=[O:12])[CH:5]=2)[NH:9][N:8]=1
Reactant: Cc1cc(C(=O)O)cc2cn[nH]c12
Reactant: O=C1CCC(=O)N1Cl
Agent: Cl
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: CC#N
Solvent: O
Product: Cc1cc(C(=O)O)cc2c(Cl)n[nH]c12
Yield: 97.8 %

Procedure:
To a suspension of 7-methyl-1H-indazole-5-carboxylic acid (180 mg, 1.01 mmol) in CH3CN (10 mL) was added N-chlorosuccinimide (150 mg, 1.12 mmol). The mixture was heated at reflux overnight before concentration. The solid was suspended in water and aqueous sodium thiosulfate solution, acidified with 1 N HCl and the solids were isolated by filtration. The solids were then washed with water and dried to provide the title compound as a tan solid (208 mg, 98%).
Reaction SMILES: [CH2:1]([C:3]1[C:4]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[C:5]([O:15][C:16]2[CH:21]=[CH:20][C:19](/[CH:22]=[CH:23]/[C:24]([OH:26])=[O:25])=[CH:18][CH:17]=2)[C:6]2[C:11]([CH:12]=1)=[CH:10][C:9]([O:13]C)=[CH:8][CH:7]=2)[CH3:2].B(Br)(Br)Br>C(Cl)Cl>[CH2:1]([C:3]1[C:4]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[C:5]([O:15][C:16]2[CH:21]=[CH:20][C:19](/[CH:22]=[CH:23]/[C:24]([OH:26])=[O:25])=[CH:18][CH:17]=2)[C:6]2[C:11]([CH:12]=1)=[CH:10][C:9]([OH:13])=[CH:8][CH:7]=2)[CH3:2]
Reactant: CCc1cc2cc(OC)ccc2c(Oc2ccc(/C=C/C(=O)O)cc2)c1-c1ccccc1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: CCc1cc2cc(O)ccc2c(Oc2ccc(/C=C/C(=O)O)cc2)c1-c1ccccc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 62.4 %

Procedure:
To a solution of (2E)-3-(4-{[3-ethyl-6-(methyloxy)-2-phenyl-1-naphthalenyl]oxy}phenyl)-2-propenoic acid (60) (104 mg, 0.25 mmol) in reagent grade CH2Cl2 (10 mL) at −10° C. was added BBr3 (1 M in CH2Cl2, 0.74 mL, 0.74 mmol) dropwise. The mixture was then stirred at −5° C. to 0° C. for 2 h, poured into ice water and extracted with EtOAc. The combined organic extract was washed with brine, dried over Na2SO4, filtered, and the filtrate was concentrated to give the crude product as reddish brown oil. The crude product was purified by reverse phase preparation HPLC on Agilent 1100 (30% CH3CN in H2O to 100% CH3CN) to give 64 mg (64%) of the title compound (61) as light beige solid. mp 188-190° C. 1H NMR (400 MHz, CH3OH-d4): δ 1.07 (t, J=7.5 Hz, 3H), 2.55 (q, J=7.5 Hz, 2H), 6.26 (d, J=16.0 Hz, 1H), 6.56 (d, J=8.8 Hz, 2H), 6.96 (dd, J1=9.2 Hz, J2=2.4 Hz, 1H), 7.10-7.16 (m, 3H), 7.18-7.28 (m, 3H), 7.34 (d, J=8.8 Hz, 2H), 7.52 (d, J=16.0 Hz, 1H), 7.53 (s, 1H), 7.59 (d, J=8.9 Hz, 1H). LCMS (ESI): m/z 411 (M+H)+, m/z 409 (M−H)−. HRMS (EI) Calcd for C27H22O4: 411.1596 (M+•). Found: 411.1596.