Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: COC([CH:5]1[C:10](=[O:11])[CH2:9][C:8](=[O:12])[CH2:7][CH:6]1[CH2:13][CH2:14][S:15][C:16]1[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=1)=O.C(=O)([O-])[O-].[Na+].[Na+]>O>[F:24][C:22]([F:23])([F:25])[C:19]1[CH:18]=[CH:17][C:16]([S:15][CH2:14][CH2:13][CH:6]2[CH2:7][C:8](=[O:12])[CH2:9][C:10](=[O:11])[CH2:5]2)=[CH:21][CH:20]=1
Reactant: COC(=O)C1C(=O)CC(=O)CC1CCSc1ccc(C(F)(F)F)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Product: O=C1CC(=O)CC(CCSc2ccc(C(F)(F)F)cc2)C1

Procedure:
2.00 Grams of 6-methoxycarbonyl-5-[2-(4-trifluoromethylphenylthio)ethyl]cyclohexane-1,3-dione was dissolved in 30 ml of water, and 1.6 g of sodium carbonate was added to the resulting solution which was then heated under reflux for 5 hours. After thoroughly cooling the reaction solution, the reaction solution was extracted with ether to remove impurities, and the aqueous layer was acidified with hydrochloric acid and extracted with ethyl acetate to separate the desired product. The ethyl acetate layer was dried over anhydrous magnesium sulfate, and after removing ethyl acetate, the resulting crystals were washed with hexane to obtain 1.5 g of 5-[2-(4-trifluoromethylphenylthio)ethyl]cyclohexane-1,3-dione.
Reaction SMILES: Cl.[NH:2]1[CH2:5][CH:4]([O:6][C:7]2[CH:12]=[CH:11][C:10]([N:13]3[CH:18]=[CH:17][C:16]4[N:19]=[C:20]([C:22]5[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][CH:23]=5)[S:21][C:15]=4[C:14]3=[O:29])=[CH:9][C:8]=2[O:30][CH3:31])[CH2:3]1.[C:32](O)(=O)C.C([BH3-])#N.[Na+].C=O.C([O-])(O)=O.[Na+]>CO.O>[Cl:28][C:25]1[CH:24]=[CH:23][C:22]([C:20]2[S:21][C:15]3[C:14](=[O:29])[N:13]([C:10]4[CH:11]=[CH:12][C:7]([O:6][CH:4]5[CH2:5][N:2]([CH3:32])[CH2:3]5)=[C:8]([O:30][CH3:31])[CH:9]=4)[CH:18]=[CH:17][C:16]=3[N:19]=2)=[CH:27][CH:26]=1
Reactant: COc1cc(-n2ccc3nc(-c4ccc(Cl)cc4)sc3c2=O)ccc1OC1CNC1
Reactant: CC(=O)O
Agent: C=O
Agent: Cl
Agent: O=C([O-])O
Solvent: O
Solvent: CO
Product: COc1cc(-n2ccc3nc(-c4ccc(Cl)cc4)sc3c2=O)ccc1OC1CN(C)C1
Temperature: 5 °C
Reaction time: 1 h
Yield: 28.3 %

Procedure:
Cool a mixture of 5-[4-(azetidin-3-yloxy)-3-methoxy-phenyl]-2-(4-chloro-phenyl)-5H-thiazolo[5,4-c]pyridin-4-one, hydrochloride salt (20 g, 42.0 mmol) in methanol (600 mL) to 15° C. Add acetic acid (12.1 mL, 211.6 mmol) and sodium cyanoborohydride (7 g, 111 mmol). Add formaldehyde (10.2 mL, 136.45 mmol, as a solution in water to the thick mixture and stir for 15 h at room temperature. Cool the mixture to 5° C., add saturated aqueous NaHCO3 (320 mL), and stir the mixture for one hour at room temperature. Extract the mixture with CHCl3 (3×1 L). Combine the organic solutions and wash with brine, then dry, filter, and concentrate. Dissolve the residue in CHCl3 (240 mL) and dilute with tert-butyl methyl ether (700 mL). Collect the precipitate by filtration and rinse the solids with additional tert-butyl methyl ether. Dry the solid under vacuum for 5 h at room temperature to obtain 5.4 g (81%) of the title compound. ES/MS m/z (35Cl) 454 [M+1]+.
Reaction SMILES: [C:1]1(=[O:7])[O:6][C:4](=[O:5])[CH2:3][CH2:2]1.[SH:8][C:9]1([CH2:19][CH2:20][OH:21])[CH:16]2[CH2:17][CH:12]3[CH2:13][CH:14]([CH2:18][CH:10]1[CH2:11]3)[CH2:15]2>C1(C)C=CC=CC=1>[SH:8][C:9]1([CH2:19][CH2:20][O:21][C:4]([CH2:3][CH2:2][C:1]([OH:6])=[O:7])=[O:5])[CH:16]2[CH2:17][CH:12]3[CH2:13][CH:14]([CH2:18][CH:10]1[CH2:11]3)[CH2:15]2
Reactant: O=C1CCC(=O)O1
Reactant: OCCC1(S)C2CC3CC(C2)CC1C3
Solvent: Cc1ccccc1
Product: O=C(O)CCC(=O)OCCC1(S)C2CC3CC(C2)CC1C3

Procedure:
A solution of succinic anhydride (10 mmol, 1.00 g) and 2-(2-sulfanyladamantan-2-yl)ethan-1-ol (2.214 g, 10.4 mmol) in toluene (30 mL) was heated at 70° C. for 16 hours. Removal of the solvent under vacuum provided a low-melting solid, 3.12 g, 10 mmol. 1H NMR (CDCl3, 300 MHz): δ4.44 (t, J=7.4 Hz, 2H), 2.68 (m, 2H), 2.63 (m, 2H), 2.43 (m, 2H), 2.25 (t, J=7.4 Hz, 2H), 2.11 (m, 2H), 1.88-1.62 (m, 10H); MS (CI/NH3) (m/e) 330 (M+NH4), 279 (M-SH), 195, 161.
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:14])[C@H:5]([CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[NH2:6].C([O-])(O)=O.[Na+].CC(O)=O.[S:24]1[CH:28]=[C:27]([CH:29]=O)[N:26]=[CH:25]1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C(Cl)Cl>[C:8]1([CH2:7][C@H:5]([NH:6][CH2:29][C:27]2[N:26]=[CH:25][S:24][CH:28]=2)[C:4]([O:3][CH3:2])=[O:14])[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: COC(=O)[C@@H](N)Cc1ccccc1
Reactant: O=Cc1cscn1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: O=C([O-])O
Solvent: ClCCl
Solvent: CC(=O)O
Product: COC(=O)[C@H](Cc1ccccc1)NCc1cscn1
Temperature: 25 °C
Reaction time: 3 h
Yield: 81.4 %

Procedure:
L-Phenylalanine methyl ester HCl 34.8.A (2.15 g, 10.0 mmol) was partitioned with DCM and saturated NaHCO3. The aqueous layer was extracted with DCM (2×). The organic layers were combined, dried with sodium sulfate, filtered, and concentrated. The residue was dissolved in DCM (30 ml) and AcOH (571 μL, 10 mmol), thiazole-4-carboxaldehyde 34.8.B (1.13 g, 10 mmol), and NaBH(OAc)3 (4.24 g, 20 mmol) were added and the reaction mixture was stirred at room temperature for 3 h. The reaction mixture was quenched with NaHCO3(sat) and extracted with DCM. The organic extracts were dried with sodium sulfate, filtered, and concentrated. The resulting residue was partially purified on a silica gel column (120 g, 0-8% MeOH:DCM) to yield 34.8.0 as a crude oil (2.25 g).
Reaction SMILES: C(OC1C2C(=CC=C(OC)C=2C)NC=1C)(=O)C.[Na].[CH2:19]([OH:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.C([CH:34]([C:38]1[C:46]2[C:41](=[CH:42][CH:43]=[C:44]([O:47][CH3:48])[CH:45]=2)[NH:40][C:39]=1[CH3:49])[C:35]([O-:37])=[O:36])C1C=CC=CC=1>>[C:19]([N:40]1[C:41]2[C:46](=[CH:45][C:44]([O:47][CH3:48])=[CH:43][CH:42]=2)[C:38]([CH2:34][C:35]([OH:37])=[O:36])=[C:39]1[CH3:49])(=[O:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: COc1ccc2[nH]c(C)c(C(Cc3ccccc3)C(=O)[O-])c2c1
Reactant: OCc1ccccc1
Agent: COc1ccc2[nH]c(C)c(OC(C)=O)c2c1C
Agent: [Na]
Product: COc1ccc2c(c1)c(CC(=O)O)c(C)n2C(=O)c1ccccc1

Procedure:
A solution of 15 g. of methyl-(2-methyl-5-methoxy-3-indolyl) acetate and 0.2 g. of sodium in 60 ml. of benzyl alcohol is slowly fractionated over a period of 41/2 hours through a Vigreux column to remove methanol. The excess benzyl alcohol is then removed by distillation at 60° C. (2.5 mm.) to give a residue of 18.6 g. of benzyl-(2-methyl-5-methoxy-3-indolyl)-acetate.
Reaction SMILES: Cl.Cl.Cl.[N:4]1([CH2:9][C:10]2[CH:11]=[C:12]([CH:23]=[CH:24][CH:25]=2)[O:13][CH2:14][CH2:15][CH2:16][NH:17][C:18](=[NH:22])[C:19](=[NH:21])[NH2:20])[CH2:8][CH2:7][CH2:6][CH2:5]1.C(Cl)Cl.[S:29](N1C(=O)C2=CC=CC=C2C1=O)N1C(=O)C2=CC=CC=C2C1=O.Cl>C(O)CC.C(N(CC)CC)C>[NH2:21][C:19]1[C:18]([NH:17][CH2:16][CH2:15][CH2:14][O:13][C:12]2[CH:23]=[CH:24][CH:25]=[C:10]([CH2:9][N:4]3[CH2:8][CH2:7][CH2:6][CH2:5]3)[CH:11]=2)=[N:22][S:29][N:20]=1
Reactant: O=C1c2ccccc2C(=O)N1SN1C(=O)c2ccccc2C1=O
Reactant: N=C(N)C(=N)NCCCOc1cccc(CN2CCCC2)c1
Agent: Cl
Solvent: CCCO
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Nc1nsnc1NCCCOc1cccc(CN2CCCC2)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of N-[3-(3-pyrrolidinomethylphenoxy)propyl]-ethanediimidamide trihydrochloride (22.0 g; 53.0 mmoles) [prepared in Example 4, Step A], 200 ml of CH2Cl2 and 22 ml of triethylamine was treated with N,N'-thiobisphthalimide (DMF solvate) (21.2 g; 53.0 mmoles). After stirring at ambient temperature for one hour, the mixture was washed with 100 ml of 20% KOH, dried (MgSO4), filtered, diluted with 100 ml of toluene and concentrated. The product was treated with one equivalent of aqueous HCl in 1-propanol to give 13.2 g (67%) of the hydrochloride salt of the title compound, mp 135°-137° C.
Reaction SMILES: [C:1]([C:3]1[C@@H:8]([C:9]2[CH:14]=[CH:13][C:12]([C:15]#[N:16])=[CH:11][C:10]=2[S:17]([CH3:20])(=[O:19])=[O:18])[N:7]([C:21](OC2C=CC([N+]([O-])=O)=CC=2)=[O:22])[C:6](=[O:33])[N:5]([C:34]2[CH:39]=[CH:38][CH:37]=[C:36]([C:40]([F:43])([F:42])[F:41])[CH:35]=2)[C:4]=1[CH3:44])#[N:2].[NH:45]1[CH2:50][CH2:49][CH2:48][C@@H:47]([NH:51][C:52](=[O:58])[O:53][C:54]([CH3:57])([CH3:56])[CH3:55])[CH2:46]1>C(#N)C>[C:1]([C:3]1[C@@H:8]([C:9]2[CH:14]=[CH:13][C:12]([C:15]#[N:16])=[CH:11][C:10]=2[S:17]([CH3:20])(=[O:18])=[O:19])[N:7]([C:21]([N:45]2[CH2:50][CH2:49][CH2:48][C@@H:47]([NH:51][C:52](=[O:58])[O:53][C:54]([CH3:55])([CH3:57])[CH3:56])[CH2:46]2)=[O:22])[C:6](=[O:33])[N:5]([C:34]2[CH:39]=[CH:38][CH:37]=[C:36]([C:40]([F:42])([F:43])[F:41])[CH:35]=2)[C:4]=1[CH3:44])#[N:2]
Reactant: CC1=C(C#N)[C@@H](c2ccc(C#N)cc2S(C)(=O)=O)N(C(=O)Oc2ccc([N+](=O)[O-])cc2)C(=O)N1c1cccc(C(F)(F)F)c1
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCCNC1
Solvent: CC#N
Product: CC1=C(C#N)[C@@H](c2ccc(C#N)cc2S(C)(=O)=O)N(C(=O)N2CCC[C@@H](NC(=O)OC(C)(C)C)C2)C(=O)N1c1cccc(C(F)(F)F)c1

Procedure:
4-Nitrophenyl (6S)-5-cyano-6-[4-cyano-2-(methylsulfonyl)phenyl]-4-methyl-2-oxo-3-[3-(trifluoromethyl)phenyl]-3,6-dihydropyrimidine-1(2H)-carboxylate (Example 6A; 100 mg, 0.16 mmol) was dissolved in acetonitrile (1.25 ml), and tert-butyl (3R)-piperidin-3-ylcarbamate (96.1 mg, 0.48 mmol) was added with stirring. The mixture was stirred at RT overnight. The reaction mixture was then purified directly by preparative HPLC (column: Kromasil C18, 125 mm×20 mm, 5 μm; mobile phase A: water with 0.01% formic acid, mobile phase B: acetonitrile; gradient: 0 min 10% B→2 min 10% B→9 min 90% B→12 min 90% B→12.1 min 10% B→15 min 10% B; flow rate: 0.35 ml/min; UV detection: 254 nm). The product fractions were combined and concentrated under reduced pressure. This gave 81 mg (74% of theory) of the target compound.
Reaction SMILES: C(OC(=O)[NH:7][C@H:8]([C:13]([N:15]1[CH2:19][C:18]([F:21])([F:20])[C:17]([F:23])([F:22])[CH2:16]1)=[O:14])[C@@H:9]([CH3:12])[CH2:10][CH3:11])(C)(C)C.[ClH:25]>C(OCC)(=O)C>[ClH:25].[NH2:7][C@@H:8]([C@@H:9]([CH3:12])[CH2:10][CH3:11])[C:13]([N:15]1[CH2:19][C:18]([F:20])([F:21])[C:17]([F:23])([F:22])[CH2:16]1)=[O:14]
Reactant: CC[C@H](C)[C@H](NC(=O)OC(C)(C)C)C(=O)N1CC(F)(F)C(F)(F)C1
Agent: Cl
Solvent: CCOC(C)=O
Product: CC[C@H](C)[C@H](N)C(=O)N1CC(F)(F)C(F)(F)C1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
[(1S,2S)-2-Methyl-1-(3,3,4,4-tetrafluoro-pyrrolidine-1-carbonyl)-butyl]-carbamic acid tert-butyl ester (200 mg, 0.56 mmol) was dissolved in ethyl acetate (4 mL), cooled to about 0° C. and treated with gaseous hydrochloric acid for about 1 minute. After about 15 minutes at about 0° C. and about 30 minutes at room temperature, the mixture was concentrated to dryness and the solid was triturated with hexane, collected and dried under vacuum overnight (124 mg, 76%, melting point: greater than 250° C.).
Reaction SMILES: FC(F)(F)C([NH:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[C:12]1[C:21]2[C:20](=O)[C:19]3[CH:23]=[CH:24][CH:25]=[N:26][C:18]=3[C:17](=[O:27])[C:16]=2[N:15]=[CH:14][CH:13]=1)=O.FC(F)(F)C(O)=O>C(Cl)Cl>[CH:11]1[C:6]2=[N:5][C:20]3[C:19]4[C:18]([C:17](=[O:27])[C:16]5[C:21]=3[C:12]([CH:13]=[CH:14][N:15]=5)=[C:7]2[CH:8]=[CH:9][CH:10]=1)=[N:26][CH:25]=[CH:24][CH:23]=4
Reactant: O=C1c2ncccc2C(=O)c2c(-c3ccccc3NC(=O)C(F)(F)F)ccnc21
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C1c2ncccc2-c2nc3ccccc3c3ccnc1c23
Reaction time: 8 h

Procedure:
30 mg (0.0756 mmol) of the compound of Example 4 and 1 mL of trifluoroacetic acid in 2 mL of CH2Cl2 are refluxed for 3 hours. After evaporating off the solvent on a rotary evaporator, the residue is taken up in 2 mL of 1N NaOH and 2 mL of CHCl3 and the mixture is stirred overnight. After recovering the organic phase, the aqueous phase is extracted with CHCl3 (5 times 10 mL). After drying the organic phases over MgSO4 and evaporating off the solvent on a rotary evaporator, 17 mg of compound are obtained in the form of yellow-colored crystals.
Reaction SMILES: [NH2:1][C@@H:2]([CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][CH2:15][C:16]2[N:17]=[C:18]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[O:19][C:20]=2[CH3:21])=[CH:9][CH:8]=1)[C:3]([OH:5])=[O:4].C(O)(C(F)(F)F)=O.[CH:35]([O:38][C:39]1[CH:44]=[CH:43][C:42]([C:45](=[O:50])[CH2:46][C:47](=O)[CH3:48])=[CH:41][CH:40]=1)([CH3:37])[CH3:36]>>[CH:35]([O:38][C:39]1[CH:40]=[CH:41][C:42]([C:45](=[O:50])/[CH:46]=[C:47](\[NH:1][C@@H:2]([CH2:6][C:7]2[CH:12]=[CH:11][C:10]([O:13][CH2:14][CH2:15][C:16]3[N:17]=[C:18]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[O:19][C:20]=3[CH3:21])=[CH:9][CH:8]=2)[C:3]([OH:5])=[O:4])/[CH3:48])=[CH:43][CH:44]=1)([CH3:37])[CH3:36]
Reactant: CC(=O)CC(=O)c1ccc(OC(C)C)cc1
Reactant: Cc1oc(-c2ccccc2)nc1CCOc1ccc(C[C@H](N)C(=O)O)cc1
Solvent: O=C(O)C(F)(F)F
Product: C/C(=C/C(=O)c1ccc(OC(C)C)cc1)N[C@@H](Cc1ccc(OCCc2nc(-c3ccccc3)oc2C)cc1)C(=O)O

Procedure:
The title compound was prepared (as described above for the preparation of Example 2) from 435 mg (0.91 mmol) of Intermediate 45 (as the TFA salt) and 200 mg (0.91 mmol) of Intermediate 29 to yield 125 mg of Example 27 as a beige glassy solid: TLC (DCM/MeOH (4:1): Rf=0.50; 1H NMR (DMSO-d6, 400 MHz) δ11.29 (d, 1H, J=8.8), 7.88 (m, 2H), 7.70 (d, 2H, 8.8), 7.48 (m, 3H), 7.09 (d, 2H, J=8.0), 6.85 (d, 2H, J=8.8), 6.78 (d, 2H, J=8.0), 5.46 (s, 1H), 4.62 (septuplet, 1H, J=6.4), 4.12 (t, 2H, J=6.4), 4.0 (m, 1H), 3.14 (m, 2H), 2.87 (t, 2H; J=6.4), 2.70 (dd, 1H, J=13.2, 9.6), 2.31 (s, 3H), 1.61 (s, 3H), 1.21 (d, 6H, J=6.4); low resolution MS (ES+)m/e 569 (MH+).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:15]([NH:17][CH2:18][C:19]2[C:20](=[O:29])[NH:21][C:22]([CH3:28])=[CH:23][C:24]=2[CH2:25][CH2:26][CH3:27])=[O:16])[C:5]2[C:6]([CH3:14])=[N:7][N:8]([CH:11]([CH3:13])[CH3:12])[C:9]=2[CH:10]=1.[CH3:30][N:31]([CH3:41])[C:32]1[N:37]=[CH:36][C:35](B(O)O)=[CH:34][CH:33]=1>>[CH3:30][N:31]([CH3:41])[C:32]1[N:37]=[CH:36][C:35]([C:2]2[CH:3]=[C:4]([C:15]([NH:17][CH2:18][C:19]3[C:20](=[O:29])[NH:21][C:22]([CH3:28])=[CH:23][C:24]=3[CH2:25][CH2:26][CH3:27])=[O:16])[C:5]3[C:6]([CH3:14])=[N:7][N:8]([CH:11]([CH3:13])[CH3:12])[C:9]=3[CH:10]=2)=[CH:34][CH:33]=1
Reactant: CN(C)c1ccc(B(O)O)cn1
Reactant: CCCc1cc(C)[nH]c(=O)c1CNC(=O)c1cc(Br)cc2c1c(C)nn2C(C)C
Product: CCCc1cc(C)[nH]c(=O)c1CNC(=O)c1cc(-c2ccc(N(C)C)nc2)cc2c1c(C)nn2C(C)C

Procedure:
The title compound was prepared in the same manner as described for example 67 from 6-bromo-3-methyl-1-(1-methylethyl)-N-[(6-methyl-2-oxo-4-propyl-1,2-dihydro-3-pyridinyl)methyl]-1H-indazole-4-carboxamide (0.079 g, 0.172 mmol) and [6-(dimethylamino)-3-pyridinyl]boronic acid (0.034 g, 0.206 mmol). The product was triturated from EtOAc spiked with DCM, and dried in a hi-vacuum oven for 4 h. The title compound was collected as a white solid (49 mg, 56%); 1H NMR (400 MHz, DMSO-d6) δ ppm 0.93 (t, J=7.33 Hz, 3H), 1.45 (d, J=6.57 Hz, 6H), 1.51-1.64 (m, 2H), 2.12 (s, 3H), 2.42 (s, 3H), 2.52-2.59 (m, 2H), 3.08 (s, 6H), 4.38 (d, J=5.05 Hz, 2H), 4.96-5.09 (m, 1H), 5.90 (s, 1H), 6.75 (d, J=9.09 Hz, 1H), 7.31 (d, J=1.26 Hz, 1H) 7.86 (d, J=1.26 Hz, 1H), 7.96 (dd, J=8.97, 2.65 Hz, 1H), 8.40 (t, J=4.93 Hz, 1H), 8.55 (d, J=2.27 Hz, 1H) 11.50 (s, 1H); LCMS (ES+) m/z: 501.1.
Reaction SMILES: [CH2:1](Br)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=2)=[CH:12][CH:11]=1.[BH4-].[Na+]>CC(C)=O>[F:9][C:10]1[CH:11]=[CH:12][C:13]([C:16]2[CH2:21][CH2:20][N:19]([CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[CH2:18][CH:17]=2)=[CH:14][CH:15]=1
Reactant: Fc1ccc(-c2ccncc2)cc1
Reactant: BrCc1ccccc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CC(C)=O
Product: Fc1ccc(C2=CCN(Cc3ccccc3)CC2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 78.2 %

Procedure:
Benzyl bromide (52.4 mL, 441 mmol) was added to a solution of 4-(4-fluorophenyl)pyridine (Description 9, 50.87 g, 294 mmol) in acetone (500 mL) and mixture was heated under reflux for 3 days. The mixture was cooled to room temperature and the solid was collected, washed with acetone and diethyl ether and dried in vacuo. The solid was dissolved in methanol (400 mL) and water (100 mL), cooled to 0° C. and sodium borohydride (20.6 g, 542 mmol) was added in portions. The mixture was stirred at room temperature for 1 hour, then heated under reflux for 18 hours. The mixture was cooled and the solvent was evaporated under reduced pressure. Dichloromethane (300 mL) and water (200 mL) were added and the layers were separated. The organic layer was dried (MgSO4) and the solvent was evaporated under reduced pressure to give the title compound as a light brown oil (61.5 g, 78%). m/z (ES+) 268 (M+1).
Reaction SMILES: Cl.Cl.[O:3]1[C:8]2=[CH:9][CH:10]=[CH:11][C:7]2=[C:6]([CH:12]2[CH2:17][CH2:16][CH2:15][CH2:14][N:13]2[CH2:18][CH2:19][C@H:20]2[CH2:25][CH2:24][C@H:23]([NH2:26])[CH2:22][CH2:21]2)[CH:5]=[CH:4]1.[CH3:27][O:28][CH2:29][CH2:30][C:31](O)=[O:32]>>[O:3]1[C:8]2=[CH:9][CH:10]=[CH:11][C:7]2=[C:6]([CH:12]2[CH2:17][CH2:16][CH2:15][CH2:14][N:13]2[CH2:18][CH2:19][C@H:20]2[CH2:21][CH2:22][C@H:23]([NH:26][C:31](=[O:32])[CH2:30][CH2:29][O:28][CH3:27])[CH2:24][CH2:25]2)[CH:5]=[CH:4]1
Reactant: COCCC(=O)O
Reactant: N[C@H]1CC[C@H](CCN2CCCCC2c2ccoc3cccc2-3)CC1
Agent: Cl
Product: COCCC(=O)N[C@H]1CC[C@H](CCN2CCCCC2c2ccoc3cccc2-3)CC1

Procedure:
The title compound, off-white solid (74 mg, 72%), MS (ISP) m/z=413.4 [(M+H)+], mp 154° C., was prepared in accordance with the general method of example 1 from trans-4-[2-(4-benzofuran-4-yl-piperidin-1-yl)-ethyl]-cyclohexyl-amine dihydrochloride (intermediate A) (100 mg, 0.25 mmol) and 3-methoxypropionic acid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]3[CH:21]=[CH:20][C:19](=[O:22])[N:18]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=4[F:29])[C:10]=3[N:11]=[C:12](S(C)(=O)=O)[N:13]=2)=[C:4]([CH3:30])[CH:3]=1.[NH2:31][CH:32]1[CH2:37][CH2:36][O:35][CH2:34][CH2:33]1>C1COCC1>[O:35]1[CH2:36][CH2:37][CH:32]([NH:31][C:12]2[N:13]=[C:8]([C:5]3[CH:6]=[CH:7][C:2]([F:1])=[CH:3][C:4]=3[CH3:30])[C:9]3[CH:21]=[CH:20][C:19](=[O:22])[N:18]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=4[F:29])[C:10]=3[N:11]=2)[CH2:33][CH2:34]1
Reactant: NC1CCOCC1
Reactant: Cc1cc(F)ccc1-c1nc(S(C)(=O)=O)nc2c1ccc(=O)n2-c1ccccc1F
Solvent: C1CCOC1
Product: Cc1cc(F)ccc1-c1nc(NC2CCOCC2)nc2c1ccc(=O)n2-c1ccccc1F
Reaction time: 18 h

Procedure:
The product of Example 59 (200 mg, 0.47 mmol) and 4-aminotetra-hydropyran (102 mg, 1 mmol) were combined in THF (10 mL) and stirred under Ar at 23° for 18 h. The solvents were removed in vacuo, and the residue was flash chromatographed with 0-15% EtOAc/CH2Cl2. Recrystallization from CH2Cl2/hexane gave the title compound as a light-yellow crystalline solid. mp 211-212°, LC MS m/z=449 (MH+) Retention time=2.21 min.
Reaction SMILES: [C:1]([C:3]1[C:4](=[O:13])[NH:5][C:6]2[C:11]([CH:12]=1)=[CH:10][CH:9]=[CH:8][CH:7]=2)#[N:2].[Cl-].[NH4+].[N-:16]=[N+:17]=[N-:18].[Na+].Cl>CN(C)C=O.O>[NH:16]1[C:1]([C:3]2[C:4](=[O:13])[NH:5][C:6]3[C:11]([CH:12]=2)=[CH:10][CH:9]=[CH:8][CH:7]=3)=[N:2][N:18]=[N:17]1
Reactant: [N-]=[N+]=[N-]
Reactant: N#Cc1cc2ccccc2[nH]c1=O
Agent: Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: CN(C)C=O
Solvent: O
Product: O=c1[nH]c2ccccc2cc1-c1nnn[nH]1
Temperature: 120 °C

Procedure:
A mixture of 5.0 g of 3-cyano-2(1H)-quinolinone, 1.9 g of ammonium chloride and 2.4 g of sodium azide in 50 ml of dimethylformamide was heated at 120° C for 16 hours. The mixture was then poured into 250 ml of water and the resulting mixture was acidified to pH 2 with concentrated hydrochloric acid. The solid which formed was separated by filtration and dried. It was then dissolved in aqueous sodium hydroxide and the aqueous solution was washed with methylene chloride and filtered and the filtrate was acidified with hydrochloric acid. The light tan solid which formed was separated by filtration and dried to give 3-(IH-tetrazol-5-yl)-2(1H)-quinolinone 1/9 hydrate melting at about 301°-303° C. with decomposition.
Reaction SMILES: [F:1][C:2]([F:35])([F:34])[C:3]1[CH:4]=[N:5][N:6]([C:8]2[N:13]=[CH:12][C:11]([NH:14][CH:15]([C:19]3[CH:33]=[CH:32][C:22]([C:23]([NH:25][CH2:26][CH2:27][C:28]([O:30]C)=[O:29])=[O:24])=[CH:21][CH:20]=3)[CH2:16][CH2:17][CH3:18])=[CH:10][N:9]=2)[CH:7]=1.C(=O)=O>>[F:35][C:2]([F:1])([F:34])[C:3]1[CH:4]=[N:5][N:6]([C:8]2[N:13]=[CH:12][C:11]([NH:14][CH:15]([C:19]3[CH:33]=[CH:32][C:22]([C:23]([NH:25][CH2:26][CH2:27][C:28]([OH:30])=[O:29])=[O:24])=[CH:21][CH:20]=3)[CH2:16][CH2:17][CH3:18])=[CH:10][N:9]=2)[CH:7]=1
Reactant: CCCC(Nc1cnc(-n2cc(C(F)(F)F)cn2)nc1)c1ccc(C(=O)NCCC(=O)OC)cc1
Agent: O=C=O
Product: CCCC(Nc1cnc(-n2cc(C(F)(F)F)cn2)nc1)c1ccc(C(=O)NCCC(=O)O)cc1

Procedure:
The title compound was prepared by a method analogous to that described in Step C of Example 109, using Isomer 2 of methyl 3-(4-(1-(2-(4-(trifluoromethyl)-1H-pyrazol-1-yl)pyrimidin-5-ylamino)butyl)benzamido)propanoate. 1H NMR (400 MHz, CD3OD, δ): 8.73 (s, 1H), 7.97 (s, 2H), 7.89 (s, 1H), 7.68 (d, J=8.4 Hz, 2H), 7.38 (d, J=8.4 Hz, 2H), 4.40 (t, J=6.8 Hz, 1H), 3.50 (t, J=6.8 Hz, 2H), 2.52 (t, J=6.4 Hz, 2H), 1.67-1.82 (m, 2H), 1.20-1.50 (m, 2H), 0.87 (t, J=7.2 Hz, 3H). MS (M+1) 477.2. Chiral SFC: Chiralpak AD-3, 4.6×150 mm, 3 μm. Modifier: 0.05% DEA. Gradient: 95% CO2/5% methanol linear to 60% CO2/40% methanol over 16.0 minutes. Flow rate: 2.5 mL/min. Retention time: 7.69 minutes, 99.8% ee (Isomer 1).
Reaction SMILES: Cl[CH2:2][C:3]([CH:5]1[O:11][CH:10]2[CH:7]([C:8](=[O:26])[N:9]2[C:12](=[C:23]([CH3:25])[CH3:24])[C:13]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[O:14])[N:6]1[C:27]([O:29][CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)=[O:28])=[O:4]>C(Cl)Cl.C(O)(=O)C.[Zn]>[C:3]([CH:5]1[O:11][CH:10]2[CH:7]([C:8](=[O:26])[N:9]2[C:12](=[C:23]([CH3:25])[CH3:24])[C:13]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[O:14])[N:6]1[C:27]([O:29][CH2:30][C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1)=[O:28])(=[O:4])[CH3:2]
Reactant: CC(C)=C(C(=O)OCc1ccccc1)N1C(=O)C2C1OC(C(=O)CCl)N2C(=O)OCc1ccccc1
Agent: [Zn]
Solvent: ClCCl
Solvent: CC(=O)O
Product: CC(=O)C1OC2C(C(=O)N2C(C(=O)OCc2ccccc2)=C(C)C)N1C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 92.8 %

Procedure:
To a solution of 433 mg of benzyl α-(3ξ-chloroacetyl-2-carbobenzoxy-7-oxo-4-oxa-2,6-diazabicyclo[3.2.0]heptan-6-yl)-α-isopropylideneacetate dissolved in a mixture of 4 ml of methylene chloride and 4 ml of acetic acid is added 450 mg of zinc powder, and the mixture stirred at room temperature for 1 hour. The reaction mixture is filtrated and the filtrate diluted with water and extracted with methylene chloride. The extract is washed with water, dried and evaporated to yield 375 mg of benzyl α-(3ξ-acetyl-2-carbobenzoxy-7-oxo-4-oxa-2,6-diazabicyclo[3.2.0]heptan-6-yl)-α-isopropylideneacetate as an oily material in 98% yield.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([CH2:8][CH:9]([CH3:11])[CH3:10])[CH:5]=[CH:4][C:3]=1[C:12]1[C:13]([S:18]([NH:21][C:22]2[O:26][N:25]=[C:24]([CH3:27])[C:23]=2[CH3:28])(=[O:20])=[O:19])=[CH:14][CH:15]=[CH:16][CH:17]=1.[CH3:29][N:30]=[C:31]=[O:32]>C(Cl)Cl>[CH3:27][C:24]1[C:23]([CH3:28])=[C:22]([NH:21][S:18]([C:13]2[C:12]([C:3]3[CH:4]=[CH:5][C:6]([CH2:8][CH:9]([CH3:11])[CH3:10])=[CH:7][C:2]=3[NH:1][C:31]([NH:30][CH3:29])=[O:32])=[CH:17][CH:16]=[CH:15][CH:14]=2)(=[O:20])=[O:19])[O:26][N:25]=1
Reactant: CN=C=O
Reactant: Cc1noc(NS(=O)(=O)c2ccccc2-c2ccc(CC(C)C)cc2N)c1C
Solvent: ClCCl
Product: CNC(=O)Nc1cc(CC(C)C)ccc1-c1ccccc1S(=O)(=O)Nc1onc(C)c1C
Temperature: 25 °C
Reaction time: 3 h
Yield: 104 %

Procedure:
To a solution of the compound of Example 32 (50 mg, 0.12 mmol) in 1.3 mL of methylene chloride at 0° C., methyl isocyanate (71 mg, 1.2 mmol) was added. The reaction was stirred at room temperature for 3 hours and concentrated. The residue was crystallized from methylene chloride/hexanes to afford 57 mg (100%) of the title compound as a white crystalline solid, m.p. 172-174° C.