Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[CH:2]([F:4])[F:3].[O:5]=[CH:6][C:7]1[CH:15]=[CH:14][C:11]([O:12][CH3:13])=[C:9]([OH:10])[CH:8]=1.[OH-].[Na+]>[Cl-].C([N+](C)(C)C)C1C=CC=CC=1.O1CCOCC1>[F:3][CH:2]([F:4])[O:10][C:9]1[CH:8]=[C:7]([CH:15]=[CH:14][C:11]=1[O:12][CH3:13])[CH:6]=[O:5]
Reactant: COc1ccc(C=O)cc1O
Reactant: FC(F)Cl
Agent: C[N+](C)(C)Cc1ccccc1
Agent: [Cl-]
Agent: [Na+]
Solvent: C1COCCO1
Product: COc1ccc(C=O)cc1OC(F)F

Procedure:
With vigorous stirring, chlorodifluoromethane is introduced into a mixture of 200 g of isovanillin, 6.7 g of benzyltrimethylammonium chloride, 314 g of 50% strength aqueous sodium hydroxide solution and 2 l of dioxane for approximately 2 h. The mixture is subsequently partitioned between ice-water and ethyl acetate, the organic phase is separated off, the aqueous phase is extracted twice with ethyl acetate and the combined organic phases are dried over magnesium sulfate and concentrated under reduced pressure. To remove unreacted isovanillin, the oil is chromatographed over neutral silica gel using toluene. Evaporation of the eluate gives 249 g of 3-difluoromethoxy-4-methoxybenzaldehyde as an oil.
Reaction SMILES: [C:1]([O:5][C:6](=[O:19])[CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]#[N:16])=[CH:11][C:10]=1[C:17]#[CH:18])([CH3:4])([CH3:3])[CH3:2].I[C:21]1[CH:26]=[C:25]([S:27]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)(=[O:29])=[O:28])[CH:24]=[CH:23][C:22]=1[CH3:36]>>[C:1]([O:5][C:6](=[O:19])[CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]#[N:16])=[CH:11][C:10]=1[C:17]#[C:18][C:23]1[CH:24]=[C:25]([S:27]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)(=[O:29])=[O:28])[CH:26]=[CH:21][C:22]=1[CH3:36])([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1ccc(S(=O)(=O)c2ccccc2)cc1I
Reactant: C#Cc1cc(C#N)ccc1OCC(=O)OC(C)(C)C
Product: Cc1ccc(S(=O)(=O)c2ccccc2)cc1C#Cc1cc(C#N)ccc1OCC(=O)OC(C)(C)C
Yield: 89 %

Procedure:
Following the general method as outlined in Intermediate 79, starting from (4-cyano-2-ethynyl-phenoxy)-acetic acid tert-butyl ester (Intermediate 46) and 2-iodo-1-methyl-4-(phenylsulfonyl)benzene (Intermediate 114), the title compound was obtained as a brown sticky solid in 89% yield.
Reaction SMILES: [C:1]([N:4]([C:30]1[CH:35]=[CH:34][C:33]([Cl:36])=[CH:32][CH:31]=1)[C@H:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[N:8]([C:15]([C:17]2[CH:22]=[CH:21][C:20]([NH:23][CH2:24][CH2:25][C:26](O)=[O:27])=[CH:19][CH:18]=2)=[O:16])[C@@H:7]([CH3:29])[CH2:6]1)(=[O:3])[CH3:2].C1C=CC2N(O)N=[N:43]C=2C=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C.[Cl-].[NH4+]>CN(C=O)C.C(OCC)(=O)C>[C:1]([N:4]([C:30]1[CH:31]=[CH:32][C:33]([Cl:36])=[CH:34][CH:35]=1)[C@H:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[N:8]([C:15]([C:17]2[CH:18]=[CH:19][C:20]([NH:23][CH2:24][CH2:25][C:26]([NH2:43])=[O:27])=[CH:21][CH:22]=2)=[O:16])[C@@H:7]([CH3:29])[CH2:6]1)(=[O:3])[CH3:2]
Reactant: CC(=O)N(c1ccc(Cl)cc1)[C@@H]1C[C@H](C)N(C(=O)c2ccc(NCCC(=O)O)cc2)c2ccccc21
Reactant: On1nnc2ccccc21
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: [Cl-]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)N(c1ccc(Cl)cc1)[C@@H]1C[C@H](C)N(C(=O)c2ccc(NCCC(N)=O)cc2)c2ccccc21
Temperature: 25 °C
Reaction time: 18 h

Procedure:
(2S,4R)-3-(4-{4-[Acetyl-(4-chloro-phenyl)-amino]-2-methyl-3,4-dihydro-2H-quinoline-1-carbonyl}-phenylamino)-propionamide was prepared from (2S,4R)-3-(4-{4-[acetyl(4-chloro-phenyl)-amino]-2-methyl-3,4-dihydro-2H-quinoline-1-carbonyl}-phenylamino)-propionic acid. The acid (0.060 g, 0.118 mmol) was dissolved in DMF (1.5 mL) at room temperature and HOBt (0.024 g, 0.177 mmol), HATU (0.068 g, 0.177 mol), and diisopropylethylamine (0.082 mL, 0.472 mmol) was added followed by ammonium chloride (0.014 g, 0.236 mmol) and stirred at room temperature for 18 h. The reaction was diluted with ethyl acetate, washed with 1N NaOH, 1N HCl and brine. The organics were dried over MgSO4, filtered and concentrated down. The crude residue was purified HPLC purification.
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].C(O[C:10]([O:12][CH:13]([O:15][C:16](=[O:32])[CH2:17][CH:18]([CH2:23][NH:24][C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:19][CH:20]([CH3:22])[CH3:21])[CH3:14])=[O:11])C.IC(O[C:37](=O)[CH:38](C)[CH3:39])C>CO.CC#N>[C:10]([O:12][CH:13]([O:15][C:16](=[O:32])[CH2:17][CH:18]([CH2:23][NH:24][C:25]([O:27][C:28]([CH3:29])([CH3:30])[CH3:31])=[O:26])[CH2:19][CH:20]([CH3:21])[CH3:22])[CH3:14])(=[O:11])[CH:38]([CH3:39])[CH3:37]
Reactant: CC(I)OC(=O)C(C)C
Reactant: CCOC(=O)OC(C)OC(=O)CC(CNC(=O)OC(C)(C)C)CC(C)C
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CO
Solvent: CC#N
Product: CC(C)CC(CNC(=O)OC(C)(C)C)CC(=O)OC(C)OC(=O)C(C)C
Temperature: 25 °C
Reaction time: 4 h
Yield: 27.2 %

Procedure:
Cesium carbonate (0.365 g, 1.12 mmol) was dissolved in methanol (5 mL) and S-form of compound 4 (0.500 g, 1.28 mmol) was added. The solution was stirred for 4 hours at room temperature and concentrated to dryness. The residue was diluted with CH3CN (7.5 mL), and compound 14 (0.945 g, 3.56 mmol) and CH3CN (5 mL) were then added. After stirring overnight at room temperature, the reaction solution was filtered and concentrated to give 1 g of the crude product, which was then purified by chromatography on a column of silica gel (70-230 mesh, elution: EA/Hexane=1:4). Compound 3-(tert-butoxycarbonylamino-methyl)-5-methyl-hexanoic acid 1-isobutyryloxy-ethyl ester 15 (0.13 g) was obtained with 27% yield. 1HNMR (CDCl3, 500 MHz) δ0.87-0.92 (m, 6H), 1.10-1.21 (m, 2H), 1.55 (d, J=5 Hz, 6H), 1.44 (s, 9H), 1.48 (d, J=5.5 Hz, 3H), 1.52-1.59 (m, 2H), 2.06-2.12 (m, 1H), 2.28-2.35 (m, 2H), 2.49-2.57 (m, 1H), 2.93-3.06 (m, 1H), 3.12-3.22 (m, 1H), 4.62-4.73 (m, 1H), 6.84 (q, J=5.5 Hz, 1H).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([N:14]([CH2:22][C:23](O)=[O:24])[C:15]2[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=2)(=[O:13])=[O:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH:26]1([NH:29][CH2:30][C:31]2[CH:36]=[CH:35][CH:34]=[C:33]([CH3:37])[CH:32]=2)[CH2:28][CH2:27]1>>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([N:14]([C:15]2[CH:16]=[CH:17][C:18]([CH3:21])=[CH:19][CH:20]=2)[CH2:22][C:23]([N:29]([CH:26]2[CH2:28][CH2:27]2)[CH2:30][C:31]2[CH:36]=[CH:35][CH:34]=[C:33]([CH3:37])[CH:32]=2)=[O:24])(=[O:13])=[O:12])=[CH:7][CH:6]=1)([CH3:3])([CH3:2])[CH3:4]
Reactant: Cc1cccc(CNC2CC2)c1
Reactant: Cc1ccc(N(CC(=O)O)S(=O)(=O)c2ccc(C(C)(C)C)cc2)cc1
Product: Cc1ccc(N(CC(=O)N(Cc2cccc(C)c2)C2CC2)S(=O)(=O)c2ccc(C(C)(C)C)cc2)cc1

Procedure:
prepared by reaction of [(4-tert-butyl-benzenesulfonyl)-p-tolyl-amino]-acetic acid with cyclopropyl-(3-methyl-benzyl)-amine
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][CH2:11][N:10]([C@@H:13]([C:58]([CH3:61])([CH3:60])[CH3:59])[C:14]([NH:16][C@@H:17]([CH2:51][C:52]2[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=2)[C@@H:18]([O:47][CH2:48]SC)[CH2:19][C@@H:20]([NH:34][C:35](=[O:46])[C@H:36]([C:42]([CH3:45])([CH3:44])[CH3:43])[NH:37][C:38]([O:40][CH3:41])=[O:39])[CH2:21][C:22]2[CH:27]=[CH:26][C:25]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][N:29]=3)=[CH:24][CH:23]=2)=[O:15])[C:9]1=[O:62])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[CH3:64][N:65]([CH3:70])[CH2:66][C:67]([OH:69])=[O:68].IN1C(=O)CCC1=O.Cl>O1CCOCC1>[CH3:64][N:65]([CH2:66][C:67]([O:69][CH2:48][O:47][C@H:18]([C@@H:17]([NH:16][C:14](=[O:15])[C@@H:13]([N:10]1[CH2:11][CH2:12][N:8]([CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[C:9]1=[O:62])[C:58]([CH3:61])([CH3:60])[CH3:59])[CH2:51][C:52]1[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=1)[CH2:19][C@H:20]([CH2:21][C:22]1[CH:27]=[CH:26][C:25]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][N:29]=2)=[CH:24][CH:23]=1)[NH:34][C:35](=[O:46])[C@H:36]([C:42]([CH3:45])([CH3:43])[CH3:44])[NH:37][C:38](=[O:39])[O:40][CH3:41])=[O:68])[CH3:70]
Reactant: COC(=O)N[C@H](C(=O)N[C@@H](Cc1ccc(-c2ccccn2)cc1)C[C@H](OCSC)[C@H](Cc1ccccc1)NC(=O)[C@@H](N1CCN(Cc2ccccc2)C1=O)C(C)(C)C)C(C)(C)C
Reactant: CN(C)CC(=O)O
Agent: Cl
Agent: O=C1CCC(=O)N1I
Solvent: C1COCCO1
Product: COC(=O)N[C@H](C(=O)N[C@@H](Cc1ccc(-c2ccccn2)cc1)C[C@H](OCOC(=O)CN(C)C)[C@H](Cc1ccccc1)NC(=O)[C@@H](N1CCN(Cc2ccccc2)C1=O)C(C)(C)C)C(C)(C)C
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of the product from Example 195A (0.045 g, 0.052 mmol) in 1,2-dichloromethane (1.5 mL) were added molecular sieves (4 Å, 0.24 g), N,N-dimethylglycine hydrochloride (0.075 g, 0.537 mmol), followed by N-iodosuccinimide (0.013 g, 0.058 mmol), and the mixture was stirred at room temperature for 2 hours. The reaction was filtered through celite. The filtrate was diluted with ethyl acetate and was washed with a mixture of dilute NaHCO3 and Na2S2O3, dried over MgSO4, filtered and evaporated. The residue was dissolved in ether and 2 equivalents of 4 N HCl in dioxane were added. The crude product was purified by chromatography on silica gel eluting with a gradient starting with dichloromethane and ending with methanol to give the title compound as the bis hydrochloride salt (0.037 g, 77% yield). 1H NMR (300 MHz, DMSO-d6), δ ppm 0.87 (s, 9 H), 0.88 (s, 9 H), 1.60-1.73 (m, 2 H), 2.22 (s, 6 H), 2.29 (q, J=9.6 Hz, 1 H), 2.54-2.84 (m, 6 H), 2.93 (q, J=8.8 Hz, 1 H), 3.08-3.24 (m, 4 H), 3.53 (s, 3 H), 3.72-3.76 (m, 1 H), 3.87 (d, J=9.6 Hz, 1 H), 4.11-4.35 (m, 5 H), 5.26 (d, J=6.6 Hz, 1 H), 5.37 (d, J=6.6 Hz, 1 H), 6.78 (d, J=9.6 Hz, 1 H), 6.94-7.15 (m, 5 H), 7.22-7.40 (m, 8 H), 7.82-7.95 (m, 6 H), 8.63 (m, 1 H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[S:11](=[O:13])(=[O:12])[N:10]([CH2:14][CH2:15][CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:9](=O)[CH2:8][C:7]=2[CH:24]=1.Cl>C1COCC1>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[S:11](=[O:13])(=[O:12])[N:10]([CH2:14][CH2:15][CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH2:9][CH2:8][C:7]=2[CH:24]=1
Reactant: COc1ccc2c(c1)CC(=O)N(CCCc1ccccc1)S2(=O)=O
Agent: Cl
Solvent: C1CCOC1
Product: COc1ccc2c(c1)CCN(CCCc1ccccc1)S2(=O)=O

Procedure:
To a 1M BH3 solution (300 mL, 30 mmol) @ 0° is added a solution of 6-methoxy-2-(3-phenylpropyl)-3-oxo-3,4-dihydro-2H-1,2-benzothiazine-1,1-dioxide (3.3 g, 9.6 mmol) in anhydrous THF (75 mL). After addition is complete the reaction mixture is brought to reflux for 2 hours. When the mixture has cooled to ambient temperature 6N HCl is carefully added until gas evolution ceases. The volatiles are removed in vacuo and the residue extracted with EtOAc (200 mL). The organic phase is washed with saturated NaCl solution (2×200 mL), dried over MgSO4 and concentrated in vacuo. The resulting material is chromatographed (silica gel, 1:2 EtOAc/hexanes) to afford 6-methoxy-2-(3-phenylpropyl)-3,4-dihydro-2H-1,2-benzothiazine-1,1-dioxide.
Reaction SMILES: Br[C:2]1[N:3]=[C:4]([C:9]2[N:10]=[N:11][N:12]([CH:14]([CH3:16])[CH3:15])[CH:13]=2)[C:5]([NH2:8])=[N:6][CH:7]=1.[CH3:17][N:18]1[C:26]2[C:21](=[CH:22][C:23](B(O)O)=[CH:24][CH:25]=2)[CH:20]=[CH:19]1.O.C([O-])([O-])=O.[Cs+].[Cs+]>O1CCOCC1.CCOC(C)=O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH:14]([N:12]1[CH:13]=[C:9]([C:4]2[C:5]([NH2:8])=[N:6][CH:7]=[C:2]([C:23]3[CH:22]=[C:21]4[C:26](=[CH:25][CH:24]=3)[N:18]([CH3:17])[CH:19]=[CH:20]4)[N:3]=2)[N:10]=[N:11]1)([CH3:16])[CH3:15]
Reactant: Cn1ccc2cc(B(O)O)ccc21
Reactant: CC(C)n1cc(-c2nc(Br)cnc2N)nn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Solvent: O
Product: CC(C)n1cc(-c2nc(-c3ccc4c(ccn4C)c3)cnc2N)nn1
Temperature: 100 °C
Reaction time: 16 h

Procedure:
To a solution of 5-bromo-3-(1-isopropyl-1H-[1,2,3]triazol-4-yl)-pyrazin-2-ylamine (750 mg, 2.65 mmol) and N-methylindole-5-boronic acid (556 mg, 3.18 mmol) in 1,4-dioxane (15.0 mL)/water (5.0 mL) was added Cs2CO3 (1.29 g, 3.97 mmol) at room temperature. The reaction mixture was purged with argon for 30 min. Then Pd(PPh3)4 (153 mg, 0.13 mmol) was added and allowed to stir at 100° C. for 16 h. The reaction mixture was cooled to RT, diluted with EtOAc (20 mL) and washed with water (20 mL). The organic layer was washed with brine solution (20 mL), dried over anhydrous Na2SO4 and solvent was evaporated under reduced pressure to afford crude product. The crude compound was purified by column using 100-200 mesh silica gel. The column was eluted with 70-80% EtOAc in Hexane to afford the title compound as a yellow solid.
Reaction SMILES: [Cl:1][C:2]1[C:11]([CH2:12][C:13]2[CH:18]=[CH:17][C:16](S(C)(=O)=O)=[CH:15][CH:14]=2)=[C:10]([Cl:23])[C:9]2[C:4](=[C:5]([CH3:32])[CH:6]=[C:7]([C:24]([C:26]3[N:30]([CH3:31])[CH:29]=[N:28][CH:27]=3)=[O:25])[CH:8]=2)[N:3]=1.[F:33][C:34]([F:50])([F:49])C1C=C(C=CC=1)CC(C(O)=O)C(O)=O>O=P(Cl)(Cl)Cl>[Cl:1][C:2]1[C:11]([CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([C:34]([F:50])([F:49])[F:33])[CH:14]=2)=[C:10]([Cl:23])[C:9]2[C:4](=[C:5]([CH3:32])[CH:6]=[C:7]([C:24]([C:26]3[N:30]([CH3:31])[CH:29]=[N:28][CH:27]=3)=[O:25])[CH:8]=2)[N:3]=1
Reactant: O=C(O)C(Cc1cccc(C(F)(F)F)c1)C(=O)O
Reactant: Cc1cc(C(=O)c2cncn2C)cc2c(Cl)c(Cc3ccc(S(C)(=O)=O)cc3)c(Cl)nc12
Solvent: O=P(Cl)(Cl)Cl
Product: Cc1cc(C(=O)c2cncn2C)cc2c(Cl)c(Cc3cccc(C(F)(F)F)c3)c(Cl)nc12
Temperature: 105 °C

Procedure:
A heterogeneous mixture of (4-amino-3-methylphenyl)(1-methyl-1H-imidazol-5-yl)methanone (1.3 g, 6.04 mmol, Intermediate 13: step c), 2-(3-(trifluoromethyl)benzyl)malonic acid (2.06 g, 7.85 mmol, Intermediate 15: step b) and POCl3 (10 mL) was heated at 105° C. for 4 hours. The mixture was cooled to room temperature and concentrated to remove excess POCl3. Ice water was then added and the mixture treated with aqueous NH4OH (kept adding ice during addition) to a basic pH 8-9. The aqueous mixture was extracted with EtOAc (2×). The EtOAc extracts were dried over Na2SO4, evaporated in vacuo and chromatographed (DCM/EtOAc, gradient) to provide the title compound as an off-white solid.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]2[CH2:17][CH2:16][C@@:10]3([NH:14][C:13](=[O:15])[O:12][CH2:11]3)[CH2:9]2)=[CH:4][CH:3]=1.[CH2:18](O)[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)(C)C)=O)=NC(OC(C)(C)C)=O>C1COCC1>[CH2:18]([O:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]2[CH2:17][CH2:16][C@@:10]3([NH:14][C:13](=[O:15])[O:12][CH2:11]3)[CH2:9]2)=[CH:4][CH:3]=1)[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25]
Reactant: CCCCCCCCO
Reactant: O=C1N[C@@]2(CC[C@@H](c3ccc(O)cc3)C2)CO1
Agent: CC(C)(C)OC(=O)N=NC(=O)OC(C)(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCCCCCCCOc1ccc([C@@H]2CC[C@]3(COC(=O)N3)C2)cc1
Temperature: 25 °C
Yield: 60.6 %

Procedure:
A solution of (5R,7R)-7-(4-hydroxy-phenyl)-3-oxa-1-aza-spiro[4.4]nonan-2-one (75 mg, 0.32 mmol), octanol (55.6 μL, 0.35 mmol) and resin bound triphenylphosphine (343 mg, 2 mmol/g, 0.70 mmol) in THF (4.0 mL) was cooled to about 0° C. and di-tert-butyl azodicarboxylate (80.5 mg, 0.35 mmol) was added dropwise. The reaction was allowed to warm up to room temperature for about 3 hours, then the resin was filtered off and washed with DCM (10 mL). The filtrates were combined and concentrated. The crude product was purified on silica gel using a gradient of 30% to 60% EtOAc in heptane. Pure fractions were combined and concentrated to yield 67.0 mg (61%) of (5R,7R)-7-(4-octyloxy-phenyl)-3-oxa-1-aza-spiro[4.4]nonan-2-one as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:20]=[CH:21][C:22]=1[F:23])[C:5]([N:7]1[CH:16](C(O)=O)[CH2:15][C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH2:8]1)=O.[C:24]([C:30]([O:32][CH3:33])=[O:31])#[C:25][C:26]([O:28][CH3:29])=[O:27]>C(OC(=O)C)(=O)C>[CH3:29][O:28][C:26]([C:25]1[C:24]([C:30]([O:32][CH3:33])=[O:31])=[C:5]([C:4]2[CH:20]=[CH:21][C:22]([F:23])=[C:2]([F:1])[CH:3]=2)[N:7]2[C:16]=1[CH2:15][C:14]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[CH2:8]2)=[O:27]
Reactant: COC(=O)C#CC(=O)OC
Reactant: O=C(O)C1Cc2ccccc2CN1C(=O)c1ccc(F)c(F)c1
Solvent: CC(=O)OC(C)=O
Product: COC(=O)c1c(C(=O)OC)c(-c2ccc(F)c(F)c2)n2c1Cc1ccccc1C2
Temperature: 65 °C
Yield: 78.9 %

Procedure:
A mixture of 2-(3,4-difluorobenzoyl)-1,2,3,4-tetrahydro-isoquinoline-3-carboxylic acid (11.10 g, 35 mmol) and dimethyl acetylenedicarboxylate (7.39 g, 52 mmol) in acetic anhydride (70 mL) was heated at 60-70° C. for 15 min. The reaction mixture was then cooled and evaporated in vacuo to dryness. The solid residue was recrystallized from ethanol to give 3-(3,4-difluorophenyl)-5,10-dihydropyrrolo[1,2-b]isoquinoline-1,2-dicarboxylic acid dimethyl ester 10.97 g, (78.6%); mp 142-144° C.; 1H NMR (DMSO-d6) δ 3.61 (3H, s, Me), 3.77 (3H, s, Me), 4.31 (2H, s, CH2), 5.00 (2H, s, CH2), 7.21-7.27 (1H, m, ArH), 7.29-7.35 (3H, m, 3×ArH), 7.37-7.43 (1H, m, ArH), 7.50-7.65 (2H, m, 2×ArH); m/z 397.00 (M+H)+ Anal. Calcld. for C22H17F2NO4: C, 66.50; H, 4.31; N, 3.52. Found: C, 66.65; H, 4.51; N, 3.47.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([C:10]2[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=2)[C:5]([C:17]#[N:18])=[C:4]([S:19][CH2:20][CH2:21][NH2:22])[N:3]=1.[O-:23][C:24]#[N:25].[K+]>Cl.CO>[NH2:1][C:2]1[N:3]=[C:4]([S:19][CH2:20][CH2:21][NH:22][C:24]([NH2:25])=[O:23])[C:5]([C:17]#[N:18])=[C:6]([C:10]2[CH:11]=[CH:12][C:13]([OH:16])=[CH:14][CH:15]=2)[C:7]=1[C:8]#[N:9]
Reactant: N#C[O-]
Reactant: N#Cc1c(N)nc(SCCN)c(C#N)c1-c1ccc(O)cc1
Agent: Cl
Agent: [K+]
Solvent: CO
Product: N#Cc1c(N)nc(SCCNC(N)=O)c(C#N)c1-c1ccc(O)cc1
Temperature: 50 °C
Reaction time: 10 h

Procedure:
31.1 mg (0.1 mmol) of 2-amino-6-[(2-aminoethyl)sulfanyl]-4-(4-hydroxyphenyl)-3,5-pyridinedicarbonitrile are suspended in 0.91 ml of 1N HCl, and 8.1 mg (0.1 mmol) of potassium cyanate are added. After the addition of a few drops of methanol, the mixture is stirred at 50° C. for a total of 10 hours. The crystals are filtered off with suction and washed with water and ether.
Reaction SMILES: [Si:1]([O:18][CH2:19][C:20]1[C:21]([N:34]2[CH2:39][C@H:38]([CH3:40])[O:37][C@H:36]([CH3:41])[CH2:35]2)=[C:22]([F:33])[C:23]2[O:27][N:26]=[C:25]([C:28]([NH:30][NH2:31])=[O:29])[C:24]=2[CH:32]=1)([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N1([C:47](N2C=CN=C2)=[O:48])C=CN=C1.CCN(C(C)C)C(C)C>C1COCC1.C(OCC)(=O)C>[Si:1]([O:18][CH2:19][C:20]1[C:21]([N:34]2[CH2:35][C@H:36]([CH3:41])[O:37][C@H:38]([CH3:40])[CH2:39]2)=[C:22]([F:33])[C:23]2[O:27][N:26]=[C:25]([C:28]3[O:29][C:47](=[O:48])[NH:31][N:30]=3)[C:24]=2[CH:32]=1)([C:14]([CH3:15])([CH3:16])[CH3:17])([C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: C[C@@H]1CN(c2c(CO[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)cc3c(C(=O)NN)noc3c2F)C[C@H](C)O1
Reactant: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: C[C@@H]1CN(c2c(CO[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)cc3c(-c4n[nH]c(=O)o4)noc3c2F)C[C@H](C)O1
Yield: 96.6 %

Procedure:
5-((tert-Butyldiphenylsilyloxy)methyl)-6-((2R,6S)-2,6-dimethylmorpholino)-7-fluorobenzo[d]isoxazole-3-carbohydrazide (Intermediate 207, 490 mg, 0.85 mmol) and di(1H-imidazol-1-yl)methanone (207 mg, 1.27 mmol) were dissolved in 8 ml of THF and was treated with DIEA (297 μl, 1.70 mmol) at room temperature for 16 hours. Reaction diluted with ethyl acetate and quenched with aq. Ammonium chloride solution. Organic layer was separated and washed with water, dried over sodium sulfate and concentrated to give 5-(5-((tert-butyldiphenylsilyloxy)methyl)-6-((2R,6S)-2,6-dimethylmorpholino)-7-fluorobenzo[d]isoxazol-3-yl)-1,3,4-oxadiazol-2(3H)-one (495 mg, 97%)
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7](=[O:22])[C:8]2[C:13]([C:14]=1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[CH:12][CH:11]=[C:10]([OH:21])[CH:9]=2)=[O:5])[CH3:2].C(=O)([O-])[O-].[K+].[K+].[I-].[Na+].Br[CH2:32][CH2:33][CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1>CN(C)C=O>[CH2:1]([O:3][C:4]([C:6]1[C:7](=[O:22])[C:8]2[C:13]([C:14]=1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[CH:12][CH:11]=[C:10]([O:21][CH2:32][CH2:33][CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)[CH:9]=2)=[O:5])[CH3:2]
Reactant: CCOC(=O)C1=C(c2ccccc2)c2ccc(O)cc2C1=O
Reactant: BrCCCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)C1=C(c2ccccc2)c2ccc(OCCCc3ccccc3)cc2C1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 84.6 %

Procedure:
6-Hydroxy-1-oxo-3-phenyl-1H-indene-2-carboxylic acid ethyl ester (2 g, 6.79 mmol) prepared in Preparation Example 2, potassium carbonate (1.40 g, 10.19 mmol) and sodium iodide (0.2 g, 1.39 mmol) were dissolved in N,N-dimethyl formamide, and 1-bromo-3-phenyl propane (2.066 ml, 13.592 mmol) was added thereto, followed by stirring for 8 hrs at room temperature. The resulting mixture washed with saturated ammonium chloride and extracted with ethyl acetate. The organic layer was separated, dried over anhydrous MgSO4, and concentrated under a reduced pressure. Then, the resulting residue was purified by flash chromatography to obtain 2.37 g of the titled compound (yield: 85%) as a dark red solid.
Reaction SMILES: C([N:4]1[CH2:9][CH2:8][CH:7]([C:10](=O)[C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][C:12]=2F)[CH2:6][CH2:5]1)(=O)C.O.[NH2:21][NH2:22]>C(O)CCC>[Cl:17][C:14]1[CH:13]=[C:12]2[C:11]([C:10]([CH:7]3[CH2:8][CH2:9][NH:4][CH2:5][CH2:6]3)=[N:21][NH:22]2)=[CH:16][CH:15]=1
Reactant: CC(=O)N1CCC(C(=O)c2ccc(Cl)cc2F)CC1
Reactant: NN
Solvent: CCCCO
Solvent: O
Product: Clc1ccc2c(C3CCNCC3)n[nH]c2c1
Yield: 20 %

Procedure:
A solution of 18.0 g of 1-acetyl-4-(4-chloro-2-fluorobenzoyl)piperidine, 130 ml of n-butanol and 51 ml of hydrazine monohydrate was stirred under reflux for 48 hrs. Most of the n-butanol was evaporated in vacuo and the residue was diluted with water. The aqueous mixture was extracted with ethyl acetate, and the extract was washed with water, dried over anhydrous magnesium sulfate and concentrated. The residue was recrystallized from acetonitrile to yield 3.0 g (20%) of product. This product was combined with a 1.3 g sample from another experiment and the combined samples (4.3 g) were recrystallized from acetonitrile to yield the analytical sample, mp 174°-176° C.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([C:10]2[NH:11][CH:12]=[CH:13][C:14]=2[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=O)=[CH:6][CH:5]=[CH:4][N:3]=1.O.[NH2:22][NH2:23]>C(O)C>[C:15]1([C:14]2[CH:13]=[CH:12][NH:11][C:10]=2[C:8]2[C:7]3[C:2](=[N:3][CH:4]=[CH:5][CH:6]=3)[NH:23][N:22]=2)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: NN
Reactant: O=C(c1cccnc1Cl)c1[nH]ccc1-c1ccccc1
Solvent: O
Solvent: CCO
Product: c1ccc(-c2cc[nH]c2-c2n[nH]c3ncccc23)cc1
Temperature: 90 °C
Yield: 56 %

Procedure:
A mixture of (2-chloro-pyridin-3-yl)-(3-phenyl-1H-pyrrol-2-yl)-methanone (150 mg, 0.53 mmol) from above and hydrazine hydrate (0.5 mL) in ethanol (6 mL) was heated at 90° C. for 24 hours. The reaction was concentrated, the residue was triturated with DCM, filtered to give 77 mg (56%) of the titled compound.
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[CH:8]=[C:7]([OH:9])[CH:6]=[CH:5][N:4]=1.[F:12][C:13]1[CH:14]=[C:15]([CH:18]=[C:19]([F:22])[C:20]=1F)[CH:16]=[O:17]>>[F:12][C:13]1[CH:14]=[C:15]([CH:18]=[C:19]([F:22])[C:20]=1[O:9][C:7]1[CH:6]=[CH:5][N:4]=[C:3]([C:2]([F:1])([F:10])[F:11])[CH:8]=1)[CH:16]=[O:17]
Reactant: O=Cc1cc(F)c(F)c(F)c1
Reactant: Oc1ccnc(C(F)(F)F)c1
Product: O=Cc1cc(F)c(Oc2ccnc(C(F)(F)F)c2)c(F)c1

Procedure:
The title compound was prepared by a procedure similar to that described for D30 starting from 2-(trifluoromethyl)pyridin-4-ol and 3,4,5-trifluorobenzaldehyde.