Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C.[C:35]1(=[O:48])[C:40]2[C:41]3[CH:47]=[CH:46][CH:45]=[CH:44][C:42]=3[S:43][C:39]=2[CH2:38][CH2:37][NH:36]1.[O-]P([O-])([O-])=O.[K+].[K+].[K+].Br[C:58]1[CH:59]=[N:60][CH:61]=[CH:62][C:63]=1[C:64]([F:67])([F:66])[F:65]>CCCCCC.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C(OCC)(=O)C.O1CCOCC1>[F:65][C:64]([F:67])([F:66])[C:63]1[CH:62]=[CH:61][N:60]=[CH:59][C:58]=1[N:36]1[CH2:37][CH2:38][C:39]2[S:43][C:42]3[CH:44]=[CH:45][CH:46]=[CH:47][C:41]=3[C:40]=2[C:35]1=[O:48]
Reactant: FC(F)(F)c1ccncc1Br
Reactant: O=C1NCCc2sc3ccccc3c21
Agent: [Pd]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Solvent: CCCCCC
Product: O=C1c2c(sc3ccccc23)CCN1c1cnccc1C(F)(F)F
Temperature: 120 °C
Yield: 8.2 %

Procedure:
X-Phos (35 mg, 0.0739 mmol) and Pd2(dba)3 (45 mg, 0.0492 mmol) were added to a previously degassed solution of 3,4-dihydro-2H-benzo[4,5]thieno[3,2-c]pyridin-1-one (I-9d: 100 mg, 0.4919 mmol), K3PO4 (313 mg, 1.4759 mmol) and 1,4-dioxane (5 mL) in a sealed tube. This was followed by the addition of 3-bromo-4-(trifluoromethyl)pyridine (134 mg, 0.5903 mmol) and the resulting reaction mass was heated at 120° C. for 48 hours. The reaction was monitored by TLC (50% ethyl acetate in hexane). The reaction mass was partitioned between water and ethylacetate. The organic layer was washed with water, brine solution, dried over Na2SO4 and concentrated to afford the crude product. Purification by column chromatography on silica gel (30% ethyl acetate in hexane), followed by preparative HPLC afforded 14 mg of the product (8.18% yield).
Reaction SMILES: C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[I:20]I.N1C=CN=C1.[C:27]([O:31][C:32](=[O:39])[NH:33][CH2:34][CH2:35][CH2:36][CH2:37]O)([CH3:30])([CH3:29])[CH3:28]>C(Cl)Cl>[C:27]([O:31][C:32](=[O:39])[NH:33][CH2:34][CH2:35][CH2:36][CH2:37][I:20])([CH3:30])([CH3:29])[CH3:28]
Reactant: II
Reactant: CC(C)(C)OC(=O)NCCCCO
Agent: c1c[nH]cn1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NCCCCI
Reaction time: 0.75 h

Procedure:
To a suspension of PPh3-resin (16.4 g, 21.1 mmol) in methylene chloride (150 mL) at 0° C. is added iodine (5.4 g, 21.2 mmol) and imidazole (1.66 g, 24.4 mmol) then stirring is continued at 0° C. for 45 min. To this is added (4-hydroxybutyl)-carbamic acid tert-butyl ester (2.0 g, 10.6 mmol) and the suspension is refluxed for 2 h. The suspension is filtered and the organic layer is washed with a saturated sodium bisulfite solution, water and brine, and dried over sodium sulfate. The solvent is removed under reduced pressure to afford the title compound as pale yellow liquid: 1H NMR (CDCl3) δ 4.51 (s, 1H), 3.21-3.17 (t, J=6.82 Hz, 2H), 3.16-3.11 (q, J=6.82 Hz, 2H), 1.88-1.81 (m, 2H), 1.62-1.55 (m, 2H), 1.43 (s, 9H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:4][C:3]=1[C:12]1[C:20]2[C:15](=[CH:16][C:17]([S:21]([N:24](CC3C=CC(OC)=CC=3OC)[C:25]3[S:29][N:28]=[CH:27][N:26]=3)(=[O:23])=[O:22])=[CH:18][CH:19]=2)[N:14]([CH3:41])[CH:13]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[C:6]([C:8]([F:10])([F:9])[F:11])[CH:5]=[CH:4][C:3]=1[C:12]1[C:20]2[C:15](=[CH:16][C:17]([S:21]([NH:24][C:25]3[S:29][N:28]=[CH:27][N:26]=3)(=[O:23])=[O:22])=[CH:18][CH:19]=2)[N:14]([CH3:41])[CH:13]=1
Reactant: COc1ccc(CN(c2ncns2)S(=O)(=O)c2ccc3c(-c4ccc(C(F)(F)F)cc4Cl)cn(C)c3c2)c(OC)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cn1cc(-c2ccc(C(F)(F)F)cc2Cl)c2ccc(S(=O)(=O)Nc3ncns3)cc21
Reaction time: 0.25 h
Yield: 105.7 %

Procedure:
3-(2-chloro-4-(trifluoromethyl)phenyl)-N-(2,4-dimethoxybenzyl)-1-methyl-N-(1,2,4-thiadiazol-5-yl)-1H-indole-6-sulfonamide (0.020 g, 0.032 mmol) was dissolved in 0.5 mL of DCM, and TFA (0.5 ml, 6.49 mmol) was added. The reaction was stirred for 15 minutes. The reaction was concentrated, dissolved in acetonitrile, and passed through a PEAX ion exchange column. The column was flushed several times with acetonitrile, then the product was liberated by flushing several times with an 1M HCl solution in 15% MeOH/EtOAc. The solution was concentrated to afford 3-(2-chloro-4-(trifluoromethyl)phenyl)-1-methyl-N-(1,2,4-thiadiazol-5-yl)-1H-indole-6-sulfonamide (0.016 g) as a tan solid. (M+H)+. 1H NMR (400 MHz, DMSO-d6) δ=8.43 (s, 7 H), 8.03 (s, 1 H), 8.01-7.97 (m, 2 H), 7.79 (d, J=1.1 Hz, 2 H), 7.67 (d, J=8.6 Hz, 4 H), 7.55 (dd, J=1.7, 8.5 Hz, 1 H), 3.98 (s, 3 H). m/z (ESI) 473.1 (M+H)+.
Reaction SMILES: [OH:1][C:2]12[CH2:11][CH:6]3[CH2:7][CH:8]([CH2:10][CH:4]([C:5]3=O)[CH2:3]1)[CH2:9]2.[NH2:13][CH2:14][C:15]([N:17]([CH:24]1[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:16].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(=O)C>CN(C=O)C.ClCCCl>[CH:24]1([N:17]([C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)[C:15](=[O:16])[CH2:14][NH:13][CH:5]2[CH:4]3[CH2:10][CH:8]4[CH2:9][C:2]([OH:1])([CH2:11][CH:6]2[CH2:7]4)[CH2:3]3)[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1
Reactant: O=C1C2CC3CC1CC(O)(C3)C2
Reactant: NCC(=O)N(c1ccccc1)C1CCCCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Solvent: CN(C)C=O
Solvent: CC(=O)O
Product: O=C(CNC1C2CC3CC1CC(O)(C3)C2)N(c1ccccc1)C1CCCCC1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 60 %

Procedure:
To a solution of 5-hydroxy-2-adamantanone (80 mg, 0.48 mmol) in a mixed solvent of 1,2-dichloroethane and DMF (6 mL and 0.5 mL, respectively) at room temperature was added compound 2-amino-N-cyclohexyl-N-phenylacetamide (92 mg, 0.40 mmol). The reaction mixture was stirred for 15 minutes before cooling to 0° C. Sodium triacetoxyborohydride (128 mg, 0.60 mmol) was slowly added, followed by addition of glacial acetic acid (22 μL, 0.40 mmol). The reaction mixture was allowed to warm to room temperature, and then stirred for 24 hours. Concentration under reduced pressure, and purification on silica gel (5% methanol/dichloromethane) afforded N-cyclohexyl-2-[(5-hydroxyadamantan-2-yl)amino]-N-phenylacetamide CVT-6441 (90 mg, 60% yield). (M+1)=383.24.
Reaction SMILES: [NH2:1][C:2]1[C:3]([F:19])=[CH:4][C:5]2[N:9]=[N:8][N:7]([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[O:16][CH3:17])[C:6]=2[CH:18]=1.[C:20]1(=O)[O:25][C:23](=[O:24])[C:22]2[CH2:26][CH2:27][CH2:28][CH2:29][C:21]1=2.O.C(OCC)(=O)C>C(O)(=O)C.C(Cl)Cl>[F:19][C:3]1[C:2]([N:1]2[C:20](=[O:25])[C:21]3[CH2:29][CH2:28][CH2:27][CH2:26][C:22]=3[C:23]2=[O:24])=[CH:18][C:6]2[N:7]([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[O:16][CH3:17])[N:8]=[N:9][C:5]=2[CH:4]=1
Reactant: O=C1OC(=O)C2=C1CCCC2
Reactant: COc1ccccc1-n1nnc2cc(F)c(N)cc21
Solvent: CC(=O)O
Solvent: O
Solvent: CCOC(C)=O
Product: COc1ccccc1-n1nnc2cc(F)c(N3C(=O)C4=C(CCCC4)C3=O)cc21
Temperature: 25 °C

Procedure:
A solution of 6-amino-5-fluoro-1-(o-methoxyphenyl)-1H-benzotriazole (5.10 g, 0.019 mol) and 3,4,5,6-tetrahydrophthalic anhydride (3.68 g, 0.024 mol) in acetic acid is refluxed for 6 hours, cooled to room temperature and poured into water. The resultant aqueous mixture is extracted with ethyl acetate. The organic extracts are combined, washed sequentially with water and brine, dried over anhydrous magnesium sulfate and concentrated in vacuo to obtain an orange oil. Flash column chromatography of the oil using silica gel and 2.5% to 5% ethyl acetate in methylene chloride solutions gives the title product as an orange solid, mp 83°-87° C.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12](B(O)O)=[CH:11][C:10]=1[F:18])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:19]([O:23][C:24](=[O:38])[CH2:25][S:26][C:27]1[NH:31][C:30]2[CH:32]=[C:33]([Cl:37])[C:34](I)=[CH:35][C:29]=2[N:28]=1)([CH3:22])([CH3:21])[CH3:20].C([O-])([O-])=O.[K+].[K+]>C1(C)C=CC=CC=1.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>[C:19]([O:23][C:24](=[O:38])[CH2:25][S:26][C:27]1[NH:31][C:30]2[CH:32]=[C:33]([Cl:37])[C:34]([C:12]3[CH:13]=[CH:14][C:9]([O:8][CH2:1][C:2]4[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=4)=[C:10]([F:18])[CH:11]=3)=[CH:35][C:29]=2[N:28]=1)([CH3:22])([CH3:20])[CH3:21]
Reactant: OB(O)c1ccc(OCc2ccccc2)c(F)c1
Reactant: CC(C)(C)OC(=O)CSc1nc2cc(I)c(Cl)cc2[nH]1
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: [K+]
Solvent: O
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)CSc1nc2cc(-c3ccc(OCc4ccccc4)c(F)c3)c(Cl)cc2[nH]1
Temperature: 80 °C
Reaction time: 14 h

Procedure:
A 4 mL vial with a septum cap and a stirring bar was charged with 4-benzyloxy-3-fluoro-phenylboronic acid (14.8 mg, 0.060 mmol) and Pd(PPh3)4 (5.8 mg, 5 mol %) and was purged briefly with N2. A solution of (6-chloro-5-iodo-1H-benzoimidazol-2-ylsulfanyl)-acetic acid tert-butyl ester (Intermediate 4, 21.4 mg, 0.050 mmol) in toluene (200 uL) was added to the vial, followed by a solution K2CO3 (21.4 mg, 0.050 mmol) in water (100 uL). The resulting mixture was stirred at 80° C. for 14 h. The mixture was allowed to cool down to rt, and was partitioned with EtOAc (1 mL) and 10% aqueous AcOH (1 mL). The organic layer was separated evaporated to dryness in vacuo. LR-MS (API-ES) of the residue confirmed the presence of the title compound: calculated for C26H24ClFN2O3S 498.1, observed m/e 499.0 (M+H)+ (Rt 3.54 min). The crude product was used in the next step without further purification.
Reaction SMILES: Cl.[NH2:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([C:12]1[CH:17]=[CH:16][C:15]([NH:18][C:19]([N:21]([C:23]3[CH:28]=[CH:27][C:26]([Cl:29])=[C:25]([C:30]([F:33])([F:32])[F:31])[CH:24]=3)[OH:22])=[O:20])=[CH:14][CH:13]=1)[CH:7]=[CH:6]2.[C:34](Cl)(=[O:44])[CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH3:43]>>[Cl:29][C:26]1[CH:27]=[CH:28][C:23]([N:21]([OH:22])[C:19](=[O:20])[NH:18][C:15]2[CH:14]=[CH:13][C:12]([N:8]3[C:9]4[C:5](=[CH:4][C:3]([NH:2][C:34](=[O:44])[CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH3:43])=[CH:11][CH:10]=4)[CH:6]=[CH:7]3)=[CH:17][CH:16]=2)=[CH:24][C:25]=1[C:30]([F:33])([F:32])[F:31]
Reactant: Nc1ccc2c(ccn2-c2ccc(NC(=O)N(O)c3ccc(Cl)c(C(F)(F)F)c3)cc2)c1
Reactant: CCCCCCCCCC(=O)Cl
Agent: Cl
Product: CCCCCCCCCC(=O)Nc1ccc2c(ccn2-c2ccc(NC(=O)N(O)c3ccc(Cl)c(C(F)(F)F)c3)cc2)c1

Procedure:
The title compound can be synthesized from 1-[4-(5-aminoindol-1-yl)phenyl]-3-(4-chloro-3-(trifluoromethyl)phenyl)-3-hydroxyurea hydrochloride and n-decanoyl chloride by using the same techniques as in Example 41.
Reaction SMILES: [Br:1][C:2]1[C:3]([N:27]([CH3:31])[CH2:28][CH2:29][OH:30])=[C:4]2[C:10]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[O:17][CH3:18])=[CH:9][N:8](COCC[Si](C)(C)C)[C:5]2=[N:6][CH:7]=1>FC(F)(F)C(O)=O.ClCCl>[Br:1][C:2]1[C:3]([N:27]([CH3:31])[CH2:28][CH2:29][OH:30])=[C:4]2[C:10]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[O:17][CH3:18])=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1
Reactant: COc1ccccc1-c1cn(COCC[Si](C)(C)C)c2ncc(Br)c(N(C)CCO)c12
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1ccccc1-c1c[nH]c2ncc(Br)c(N(C)CCO)c12
Temperature: 23 °C
Reaction time: 1.5 h
Yield: 14.8 %

Procedure:
2-{[5-Bromo-3-(2-methoxy-phenyl)-1-(2-trimethylsilanyl-ethoxymethyl)-1H-pyrrolo[2,3-b]pyridin-4-yl]-methyl-amino}-ethanol (10 mg, 0.0197 mmol) was dissolved in a solution of trifluoroacetic acid (1 mL) and dichloromethane (1 mL) and stirred at 23° C. for 1.5 hours. The solvent was evaporated and the resulting oil was dissolved in 1 mL DMSO and 100 μL ethylenediamine and purified by mass triggered reverse phase HPLC to afford 2-{[5-Bromo-3-(2-methoxy-phenyl)-1H-pyrrolo[2,3-b]pyridin-4-yl]-methyl-amino}-ethanol (1.1 mg, 0.00266, 13% yield). 1H-NMR [500 MHz, d6-DMSO] δ: 8.14 (s, 1H), 7.31 (m, 1H), 7.27 (s, 1H) 7.21 (dd, 1H), 7.02 (d, 1H), 6.96, (td, 1H), 6.67, (s, 5H), 3.14 (t, 2H), 2.75 (s, 4H); MS [MH+] m/z: 376, 378.
Reaction SMILES: O[CH2:2][C:3]1[N:8]=[C:7]([NH:9][C:10]2[S:11][C:12]([C:15]#[N:16])=[CH:13][N:14]=2)[CH:6]=[CH:5][CH:4]=1.CN(C=O)C.O=P(Cl)(Cl)[Cl:24].C([O-])(O)=O.[Na+]>C(Cl)Cl.O>[Cl:24][CH2:2][C:3]1[N:8]=[C:7]([NH:9][C:10]2[S:11][C:12]([C:15]#[N:16])=[CH:13][N:14]=2)[CH:6]=[CH:5][CH:4]=1
Reactant: N#Cc1cnc(Nc2cccc(CO)n2)s1
Reactant: O=P(Cl)(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: O
Product: N#Cc1cnc(Nc2cccc(CCl)n2)s1

Procedure:
2-(6-Hydroxymethyl-pyridin-2-ylamino)-thiazole-5-carbonitrile (0.300 g, 0.29 mmol) was stirred in 5 mL anh DCM under N2. Anhydrous DMF (0.100 mL, 1.29 mmol) and POCl3 (0.120 mL, 1.29 mmol) were added. After 15 h the reaction was diluted with water and the pH was adjusted to 9 with sat NaHCO3 (aq). The dCM was removed in vacuo and the precipitate which formed was filtered and washed with water to provide the titled compound. 1H NMR (DMSO-d6) δ 12.35 (s, 1H), 8.29 (s, 1H), 7.85 (t, 1H, J=7.8 Hz), 7.21 (d, 1H, 7.3 Hz), 7.11 (d, 1H, 8.2 Hz), 4.85 (s, 2H).
Reaction SMILES: [CH3:1][O:2][CH:3]([O:7][CH3:8])[CH2:4][NH:5][CH3:6].C1C=CC=CC=1.[Cl:15][C:16]1[CH:17]=[C:18]([CH:30]=[CH:31][C:32]=1[Cl:33])[O:19][CH:20]([C:22]1[S:26][C:25]([N:27]=[C:28]=[O:29])=[N:24][N:23]=1)[CH3:21]>CCCCCC>[Cl:15][C:16]1[CH:17]=[C:18]([CH:30]=[CH:31][C:32]=1[Cl:33])[O:19][CH:20]([C:22]1[S:26][C:25]([NH:27][C:28](=[O:29])[N:5]([CH3:6])[CH2:4][CH:3]([O:7][CH3:8])[O:2][CH3:1])=[N:24][N:23]=1)[CH3:21]
Reactant: CNCC(OC)OC
Reactant: CC(Oc1ccc(Cl)c(Cl)c1)c1nnc(N=C=O)s1
Solvent: CCCCCC
Solvent: c1ccccc1
Product: COC(CN(C)C(=O)Nc1nnc(C(C)Oc2ccc(Cl)c(Cl)c2)s1)OC
Yield: 68.1 %

Procedure:
3.3 grams (0.028 mole) of methylaminoacetaldehyde dimethylacetal was slowly added to a 50 milliliter benzene solution containing 9.0 grams (0.028 mole) of the 5-[1-(3,4-dichlorophenoxy)ethyl]-1,3,4-thiadiazol-2-yl isocyanate dimer (prepared above). The resulting solution was heated to reflux and hexane was added, crystals formed on cooling. The crystals were filtered off, and dried in a vacuum oven at 80° C. to give 8.3 grams of fluffy white crystals at 3-[5-[1-(3,4-dichlorophenoxy)ethyl]-1,3,4-thiadiazol-1-yl]-1-methyl-1-(2,2-dimethoxyethyl)urea. (Melting point 124°-127° C.).
Reaction SMILES: [CH2:1]([C:4]1[CH:9]=[CH:8][C:7]([CH:10]=[CH:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][C:17]([OH:19])=[O:18])=[CH:6][CH:5]=1)[CH2:2][CH3:3]>[Pd].[O-]S([O-])(=O)=O.[Ba+2]>[CH2:1]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][C:17]([OH:19])=[O:18])=[CH:6][CH:5]=1)[CH2:2][CH3:3]
Reactant: CCCc1ccc(C=CCCCCCC(=O)O)cc1
Agent: [Pd]
Agent: O=S(=O)([O-])[O-]
Agent: [Ba+2]
Product: CCCc1ccc(CCCCCCCC(=O)O)cc1
Yield: 95.3 %

Procedure:
This compound was synthesized from 8-(p-propylphenyl)-7-octenoic acid (1.30 g, 5 mmol) and Pd/BaSO4 (130 mg) by a hydrogenation reaction. Crystallization (petroleum ether) afforded the product (1.25 g, 95%) as white crystals (mp 42°-43° C.). IR: 3400-2500, 1705 cm-1 ; 1H-NMR: 0.95 (t, 3H), 1.45 (m, 12H), 2.50 (m, 6H), 7.05 (s, 4H), 11.40 (bs, 1H). Anal. Calcd. for C17H26O2 : C, 77.82, H, 9.99%; Found: C, 77.75, H, 10.04%.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:9]=[C:10]2[C:14]3=[C:15]([O:17][CH2:18][CH2:19][N:13]3[C@H:12]3[CH2:20][CH2:21][N:22](C(OC(C)(C)C)=O)[CH2:23][C@@H:11]23)[CH:16]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:9]=[C:10]2[C:14]3=[C:15]([O:17][CH2:18][CH2:19][N:13]3[C@H:12]3[CH2:20][CH2:21][N:22]=[CH:23][C@H:11]23)[CH:16]=1
Reactant: CC(C)(C)OC(=O)N1CC[C@H]2[C@@H](C1)c1cc(-c3ccccc3Cl)cc3c1N2CCO3
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Clc1ccccc1-c1cc2c3c(c1)[C@H]1C=NCC[C@@H]1N3CCO2
Reaction time: 3 h
Yield: 95 %

Procedure:
To a solution of tert-butyl(6bR,10aS)-5-(2-chlorophenyl)-1,2,6b,9,10,10a-hexahydro[1,4]oxazino[2,3,4-hi]pyrido[4,3-b]indole-8(7H)-carboxylate in CH2Cl2 (2.4 mL) was added TFA (0.6 mL) and the reaction mixture was stirred for 3 h. The reaction mixture was concentrated in vacuo, diluted with CH2Cl2 (100 mL), washed with NaHCO3 (100 mL) and brine (100 mL), dried over MgSO4 and concentrated in vacuo to afford the title compound (130 mg, 95%) as a light yellow oil. 1H NMR (CDCl3) δ1.78-1.99 (m, 2H), 2.11 (br-s, 1H), 2.76-2.95 (m, 4H), 3.09-3.20 (m, 2H), 2.32-2.39 (m, 1H), 2.41-2.46 (m, 1H), 4.44-4.52 (m, 2H), 6.76 (dd, 1H, J=1.5, 13.2 Hz), 7.19-7.36 (m, 4H), 7.42 (dd, 1H, J=1.4, 7.7 Hz) ppm.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=1.C(=O)(O)[O-].[Na+].Cl[C:17]([O:19][CH2:20][CH3:21])=[O:18]>Cl>[CH2:20]([O:19][C:17]([NH:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=1)=[O:18])[CH3:21]
Reactant: Nc1ccc(C(=O)O)cc1
Reactant: CCOC(=O)Cl
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: CCOC(=O)Nc1ccc(C(=O)O)cc1
Temperature: 5 °C
Reaction time: 0.5 h

Procedure:
A mixture composed of 4-aminobenzoic acid (10 g), 1N aqueous sodium bicarbonate solution (365 cc) and ethyl chloroformate (7 cc) is left stirring for 30 minutes at 5° C. 2.5N hydrochloric acid (150 cc) is then added to the reaction mixture. The precipitate formed is separated by filtration, washed with water (3×200 cc) and dried at 40° C. under reduced pressure (0.07 kPa). 4-(Ethoxycarbonylamino)benzoic acid (13.8 g), m.p. 207° C., is obtained.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([N+:20]([O-])=O)[CH:15]=3)[N:9]=2)[CH:5]=[C:4]([C:23]2[CH:28]=[CH:27][C:26]([C:29]([F:32])([F:31])[F:30])=[CH:25][CH:24]=2)[CH:3]=1.[H][H]>C1COCC1.CCO.[Pd]>[CH3:1][C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]3[CH:15]=[C:16]([NH2:20])[CH:17]=[CH:18][CH:19]=3)[N:9]=2)[CH:5]=[C:4]([C:23]2[CH:28]=[CH:27][C:26]([C:29]([F:31])([F:30])[F:32])=[CH:25][CH:24]=2)[CH:3]=1
Reactant: [H][H]
Reactant: Cc1cc(-c2ccc(C(F)(F)F)cc2)cc(-c2cccc(-c3cccc([N+](=O)[O-])c3)n2)n1
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CCO
Product: Cc1cc(-c2ccc(C(F)(F)F)cc2)cc(-c2cccc(-c3cccc(N)c3)n2)n1
Yield: 80.5 %

Procedure:
A mixture of the above prepared 6-methyl-6′-(3-nitro-phenyl)-4-(4-trifluoromethylphenyl)-[2,2′]bipyridinyl (3.4 g, 7.81 mmol) in THF-EtOH 1:1 (100 mL) and 10% palladium on carbon (1 mol %) was hydrogenated (1 bar hydrogen) at 23° C. for 2 h. The catalyst was filtered off, washed with EtOH and the filtrate was completely evaporated totally to leave a crude product, which was purified by silica gel column chromatography with heptane/EtOAc, followed by trituration with diethyl ether to give the title compound as a white solid (2.55 g, 80%). MS (ISP) 406.3 [(M+H)+]; mp 167° C.
Reaction SMILES: C(OC(=O)C)(=O)C.[CH:8]([OH:10])=O.[Cl:11][C:12]1[C:24]([Cl:25])=[CH:23][CH:22]=[CH:21][C:13]=1[C:14]([NH:16][CH2:17][CH2:18][NH:19][OH:20])=[O:15]>N1C=CC=CC=1>[Cl:11][C:12]1[C:24]([Cl:25])=[CH:23][CH:22]=[CH:21][C:13]=1[C:14]([NH:16][CH2:17][CH2:18][N:19]([CH:8]=[O:10])[OH:20])=[O:15]
Reactant: O=CO
Reactant: O=C(NCCNO)c1cccc(Cl)c1Cl
Solvent: c1ccncc1
Solvent: CC(=O)OC(C)=O
Product: O=CN(O)CCNC(=O)c1cccc(Cl)c1Cl
Temperature: 0 °C
Reaction time: 2.5 h
Yield: 15 %

Procedure:
A mixture of acetic anhydride (5 mL) and formic acid (2.5 mL) was allowed to stand at 55° C. for 2.5 h. After cooling to 0° C., the resulting mixed anhydride was added to a solution of 2,3-dichloro-N-(2-hydroxyamino-ethyl)-benzamide (10.5 g, 42 mmol) in pyridine (50 mL) at 0° C. under an argon atmosphere. The reaction mixture was stirred for 2 h and the pyridine was removed in vacuo. The residue was chased three times with water and three times with MeOH. The residue was partitioned between cold brine/1N HCl and dichloromethane/MeOH (9:1). The aqueous layer was extracted (10×100 mL) with dichloromethane/MeOH (9:1). The combined organic extracts were dried (Na2SO4) and were concentrated. Purification by preparative reverse-phase HPLC provided the title compound (1.8 g, 15%) as a white solid. 1H NMR* (400 MHz, CD3OD): δ 8.35 (s, 0.5H); 7.95 (s, 0.5H); 7.60 (m, 1H); 7.35 (m, 2H); 3.79 (m, 1H); 3.73 (m, 1H); 3.62 (m, 2H). * 1:1 mixture of rotamers. ESMS: M+H=277.
Reaction SMILES: C([O:3][C:4](=O)[CH2:5][C:6]([C@H:8]1[CH2:13][CH2:12][N:11]([C:14]([O:16][CH3:17])=[O:15])[C@@H:10]([CH2:18][C:19]2[CH:24]=[C:23]([C:25]([F:28])([F:27])[F:26])[CH:22]=[C:21]([F:29])[CH:20]=2)[CH2:9]1)=[O:7])C.[OH-].[Na+].[NH2:33]O.Cl>CO.O>[F:29][C:21]1[CH:20]=[C:19]([CH:24]=[C:23]([C:25]([F:28])([F:27])[F:26])[CH:22]=1)[CH2:18][C@H:10]1[CH2:9][C@@H:8]([C:6]2[O:7][NH:33][C:4](=[O:3])[CH:5]=2)[CH2:13][CH2:12][N:11]1[C:14]([O:16][CH3:17])=[O:15]
Reactant: CCOC(=O)CC(=O)[C@H]1CCN(C(=O)OC)[C@@H](Cc2cc(F)cc(C(F)(F)F)c2)C1
Reactant: NO
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: COC(=O)N1CC[C@H](c2cc(=O)[nH]o2)C[C@@H]1Cc1cc(F)cc(C(F)(F)F)c1
Temperature: -40 °C
Reaction time: 0.33 h
Yield: 65 %

Procedure:
Cis-methyl 4-(3-ethoxy-3-oxopropanoyl)-2-(3-fluoro-5-(trifluoromethyl)benzyl)piperidine-1-carboxylate (2.52 g, 5.81 mmol) was dissolved in MeOH (20 mL) and cooled to −40° C. Sodium hydroxide (0.246 g, 6.15 mmol) dissolved in water (2.2 mL) was added over 1 min and the resulting solution was stirred at −40° C. for 20 min. Then hydroxylamine (50% by weight in water, 0.38 mL, 6.20 mmol) was added over 1 min and stirring continued at −40° C. for 2 h 20 min. The reaction mixture was then transferred into a prewarmed (80° C.) solution of 6 M hydrogen chloride (40 mL, 240.00 mmol) and the mixture was continued to be stirred at 80° C. for 1 h. Then cooled to room temperature. Methanol was evaporated, then water was added. Extracted three times with DCM. Combined organic layers dried over MgSO4 and evaporated. The compound was purified by preparative HPLC in 3 injections on a XBridge C18 column (10 μm 250×50 ID mm) using a gradient of 0-35% Acetonitrile in H2O/MeCN/NH3 95/5/0.2 buffer over 25 minutes with a flow of 100 mL/min. Cis-methyl 2-(3-fluoro-5-(trifluoromethyl)benzyl)-4-(3-oxo-2,3-dihydroisoxazol-5-yl)piperidine-1-carboxylate (1.52 g, 65%) was isolated as a colorless foam. 1H NMR (600 MHz, cdcl3) δ 1.87-2.10 (m, 4H), 2.61-2.67 (m, 1H), 2.80-2.87 (m, 1H), 2.97-3.04 (m, 1H), 3.13-3.21 (m, 1H), 3.60 (s, 3H), 3.96-4.04 (m, 1H), 4.26-4.32 (m, 1H), 5.74 (s, 1H), 7.00 (d, 1H), 7.11-7.16 (m, 2H). MS m/z 403 (M+H)+
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[N:5]=[C:4]([C:12]2[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=2)[N:3]=1.[NH2:18][C:19]1[C:20]([O:27][CH3:28])=[N:21][C:22]([O:25][CH3:26])=[CH:23][CH:24]=1>>[CH3:28][O:27][C:20]1[C:19]([NH:18][C:2]2[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[N:5]=[C:4]([C:12]3[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=3)[N:3]=2)=[CH:24][CH:23]=[C:22]([O:25][CH3:26])[N:21]=1
Reactant: FC(F)(F)c1cc(Cl)nc(-c2cccnc2)n1
Reactant: COc1ccc(N)c(OC)n1
Product: COc1ccc(Nc2cc(C(F)(F)F)nc(-c3cccnc3)n2)c(OC)n1

Procedure:
The title compound was prepared from 4-chloro-2-(3-pyridinyl)-6-trifluoromethylpyrimidine (50 mg, 0.192 mmol) and 3-amino-2,6-dimethoxypyridine (44 mg, 0.288 mmol) similar to Example 180 and was isolated as a yellow solid (15 mg, 20%). 1H NMR (CDCl3): 9.62 (brs, 1H), 8.72-8.67 (m, 2H), 7.42 (dd, J=8.1, 5.4 Hz, 1H), 7.09 (s, 1H), 6.75 (s, 1H), 6.43 (d, J=8.7 Hz, 1H), 4.08 (s, 3H), 4.02 (s, 3H).