Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([NH:11][C:12]([C:14]1[CH:19]=[CH:18][C:17]([N+:20]([O-])=O)=[CH:16][CH:15]=1)=[O:13])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10]>[Pd].C1COCC1>[CH2:1]([NH:11][C:12]([C:14]1[CH:19]=[CH:18][C:17]([NH2:20])=[CH:16][CH:15]=1)=[O:13])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10]
Reactant: CCCCCCCCCCNC(=O)c1ccc([N+](=O)[O-])cc1
Agent: [Pd]
Solvent: C1CCOC1
Product: CCCCCCCCCCNC(=O)c1ccc(N)cc1
Reaction time: 17 h
Yield: 94.7 %

Procedure:
A mixture of 8.05 g of 4-[(decylamino)carbonyl]nitrobenzene and 2.5 g of 10% palladium on carbon in 175 ml of THF was shaken under an initial hydrogen pressure of 54 psi in a Parr Hydrogenator for 17 hours. The catalyst was removed by filtration and the filtrate was concentrated to a solid which was triturated with hexane and filtered to give 6.88 g (95% yield, mp 117°-119°) of 4-[(decylamino)carbonyl]benzenamine. The structure was confirmed by the nmr spectrum.
Reaction SMILES: C([N:8]1[C:13]2[CH:14]=[C:15]([CH2:18][C:19]3[CH:24]=[C:23]([C@H:25]4[C@H:30]([O:31]CC5C=CC=CC=5)[C@@H:29]([O:39]CC5C=CC=CC=5)[C@H:28]([O:47]CC5C=CC=CC=5)[C@@H:27]([CH2:55][O:56]CC5C=CC=CC=5)[O:26]4)[CH:22]=[CH:21][C:20]=3[CH:64]3[CH2:66][CH2:65]3)[CH:16]=[CH:17][C:12]=2[O:11][CH2:10][CH2:9]1)C1C=CC=CC=1.Cl.CO>C1COCC1.[Pd]>[CH:64]1([C:20]2[CH:21]=[CH:22][C:23]([C@H:25]3[C@H:30]([OH:31])[C@@H:29]([OH:39])[C@H:28]([OH:47])[C@@H:27]([CH2:55][OH:56])[O:26]3)=[CH:24][C:19]=2[CH2:18][C:15]2[CH:16]=[CH:17][C:12]3[O:11][CH2:10][CH2:9][NH:8][C:13]=3[CH:14]=2)[CH2:66][CH2:65]1
Reactant: c1ccc(COC[C@H]2O[C@@H](c3ccc(C4CC4)c(Cc4ccc5c(c4)N(Cc4ccccc4)CCO5)c3)[C@H](OCc3ccccc3)[C@@H](OCc3ccccc3)[C@@H]2OCc2ccccc2)cc1
Agent: [Pd]
Agent: Cl
Solvent: CO
Solvent: C1CCOC1
Product: OC[C@H]1O[C@@H](c2ccc(C3CC3)c(Cc3ccc4c(c3)NCCO4)c2)[C@H](O)[C@@H](O)[C@@H]1O
Reaction time: 18 h
Yield: 16.6 %

Procedure:
To a solution of 4-benzyl-6-[2-cyclopropyl-5-((2S,3S,4R,5R,6R)-3,4,5-tris-benzyloxy-6-benzyloxymethyl-tetrahydro-pyran-2-yl)-benzyl]-3,4-dihydro-2H-benzo[1,4]oxazine (0.42 g, 0.4783 mmol) in THF (4.7 mL) was added 10% palladium on charcoal (80 mg), 0.1 mL conc. HCl followed by methanol (4.7 mL) and the mixture was stirred under hydrogen atmosphere for 18 h. The reaction mixture was filtered through a celite bed, washed with methanol and concentrated. The resulting residue was purified by preparative HPLC to furnish (2S,3R,4R,5S,6R)-2-[4-cyclopropyl-3-(3,4-dihydro-2H-benzo[1,4]oxazin-6-ylmethyl)-phenyl]-6-hydroxymethyl-tetrahydro-pyran-3,4,5-triol (34 mg).
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1B(O)O)([CH3:3])[CH3:2].Br[C:15]1[CH:20]=[CH:19][C:18]([C:21]2[N:22]=[CH:23][C:24]([NH2:27])=[N:25][CH:26]=2)=[C:17]([F:28])[CH:16]=1>>[F:28][C:17]1[CH:16]=[C:15]([C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[O:4][CH:1]([CH3:3])[CH3:2])[CH:20]=[CH:19][C:18]=1[C:21]1[N:22]=[CH:23][C:24]([NH2:27])=[N:25][CH:26]=1
Reactant: Nc1cnc(-c2ccc(Br)cc2F)cn1
Reactant: CC(C)Oc1ccccc1B(O)O
Product: CC(C)Oc1ccccc1-c1ccc(-c2cnc(N)cn2)c(F)c1

Procedure:
The title compound was prepared using methods analogous to those described in Example 369 3 using (2-isopropoxyphenyl)boronic acid and 5-(4-bromo-2-fluorophenyl)pyrazin-2-amine in Step B. MS (ESI): mass calcd. for C19H18FN3O, 323.14; m/z found, 324.1 [M+H]+. 1H NMR (400 MHz, CDCl3) δ 8.63-8.57 (m, 1H), 8.12 (d, J=1.4, 1H), 7.97-7.87 (m, 1H), 7.48-7.42 (m, 1.5H), 7.42-7.34 (m, 1.5H), 7.34-7.28 (m, 1H), 7.07-6.97 (m, 2H), 4.65 (s, 2H), 4.59-4.44 (m, 1H), 1.29 (d, J=6.1, 6H).
Reaction SMILES: [F-].C([N+](CCCC)(CCCC)CCCC)CCC.[F:19][C:20]([F:44])([F:43])[C:21]1[CH:22]=[C:23]([C:31](=[O:42])[C:32]2[CH:37]=[CH:36][C:35]([N+:38]([O-:40])=[O:39])=[C:34]([CH3:41])[CH:33]=2)[CH:24]=[C:25]([C:27]([F:30])([F:29])[F:28])[CH:26]=1.[F:45][C:46]([Si](C)(C)C)([F:48])[F:47]>O1CCCC1.C(OCC)(=O)C>[F:19][C:20]([F:43])([F:44])[C:21]1[CH:22]=[C:23]([C:31]([C:32]2[CH:37]=[CH:36][C:35]([N+:38]([O-:40])=[O:39])=[C:34]([CH3:41])[CH:33]=2)([OH:42])[C:46]([F:48])([F:47])[F:45])[CH:24]=[C:25]([C:27]([F:28])([F:30])[F:29])[CH:26]=1
Reactant: Cc1cc(C(=O)c2cc(C(F)(F)F)cc(C(F)(F)F)c2)ccc1[N+](=O)[O-]
Reactant: C[Si](C)(C)C(F)(F)F
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Cc1cc(C(O)(c2cc(C(F)(F)F)cc(C(F)(F)F)c2)C(F)(F)F)ccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 8 h
Yield: 48.2 %

Procedure:
A solution of 1M tetrabutylammonium fluoride in tetrahydrofuran (0.2 ml) was added to a solution of 3′,5′-bis-trifluoromethyl-3-methyl-4-nitrobenzophenone (1.4 g) and trifluoromethyltrimethyl-silane (1.0 g) in tetrahydrofuran (20 ml) in an ice bath and stirred at room temperature for 8 hours. The reaction solution was diluted with ethyl acetate and washed with water and a saturated salt solution. After drying over anhydrous magnesium sulfate, the solvent was distilled off. The residue was dissolved in tetrahydrofuran (20 ml) and, by adding 2N hydrochloric acid (2 ml), stirred at room temperature for 30 minutes. After diluting with ethyl acetate and washing with water and a saturated salt solution and after drying over anhydrous magnesium sulfate, the solvent was distilled off. Then the residue was purified by silica gel column chromatography to obtain 1-(3,5-bis-trifluoromethylphenyl)-2,2,2-trifluoro-1-(3-methyl-4-nitrophenyl)ethanol (0.8 g).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][C:9]2[CH:18]=[CH:17][C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[N:10]=2)=[CH:4][CH:3]=1.[Cl:19][C:20]1[CH:21]=[C:22]([N:27]=[C:28]=[S:29])[CH:23]=[CH:24][C:25]=1[Cl:26]>>[N:10]1[C:11]2[C:16](=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:17]=[CH:18][C:9]=1[S:8][C:5]1[CH:4]=[CH:3][C:2]([NH:1][C:28]([NH:27][C:22]2[CH:23]=[CH:24][C:25]([Cl:26])=[C:20]([Cl:19])[CH:21]=2)=[S:29])=[CH:7][CH:6]=1
Reactant: Nc1ccc(Sc2ccc3ccccc3n2)cc1
Reactant: S=C=Nc1ccc(Cl)c(Cl)c1
Product: S=C(Nc1ccc(Sc2ccc3ccccc3n2)cc1)Nc1ccc(Cl)c(Cl)c1

Procedure:
2-(4-Aminophenylthio)quinoline (11.9 moles, 3.0 g) and 3,4-dichlorophenylisothiocyanate (11.9 mmoles, 2.42 g) were reacted according to procedure B to yield the title compound, 360 mg, 6.6%. Mass Spec (FD) 455. Calculated for C22H15Cl2N3S2 : C, 57.90 H, 3.31; N, 9.21. Found: C, 57.86; H, 3.53; N, 9.07. m.p. 125°-126°.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C@H:8]([NH:10][S:11]([CH2:14][CH3:15])(=[O:13])=[O:12])[CH3:9])[CH:5]=[N:6][CH:7]=1.[H-].[Na+].I[CH3:19]>C1COCC1.C(Cl)Cl>[Br:1][C:2]1[CH:3]=[C:4]([C@H:8]([N:10]([CH3:19])[S:11]([CH2:14][CH3:15])(=[O:12])=[O:13])[CH3:9])[CH:5]=[N:6][CH:7]=1
Reactant: CI
Reactant: CCS(=O)(=O)N[C@H](C)c1cncc(Br)c1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: ClCCl
Product: CCS(=O)(=O)N(C)[C@H](C)c1cncc(Br)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 61.9 %

Procedure:
To a vial is added ethanesulfonic acid [(R)-1-(5-bromo-pyridin-3-yl)-ethyl]-amide (180 mg, 0.61 mmol) in 3 ml of THF, followed by the addition of NaH (35 mg, 0.92 mmol). Then iodomethane (131 mg, 0.92 mmol) is added. The reaction mixture is stirred at room temperature for 18 hours. The reaction mixture is diluted with DCM, washed with water, brine, dried over anhydrous Na2SO4, filtered and concentrated to give the crude product. Purification by the flash column chromatography affords 116 mg of ethanesulfonic acid [(R)-1-(5-bromo-pyridin-3-yl)-ethyl]-methyl-amide.
Reaction SMILES: [Br:1][C:2]1[N:3]=[C:4]2[CH:11]=[C:10]([CH:12]3[CH2:14][CH2:13]3)[NH:9][C:5]2=[N:6][C:7]=1[Cl:8].C(=O)([O-])[O-].[K+].[K+].Br[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][C:28]([O:30][CH2:31][CH3:32])=[O:29].[Cl-].[NH4+]>CN(C=O)C>[CH2:31]([O:30][C:28](=[O:29])[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][N:9]1[C:5]2=[N:6][C:7]([Cl:8])=[C:2]([Br:1])[N:3]=[C:4]2[CH:11]=[C:10]1[CH:12]1[CH2:14][CH2:13]1)[CH3:32]
Reactant: CCOC(=O)CCCCCCBr
Reactant: Clc1nc2[nH]c(C3CC3)cc2nc1Br
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)CCCCCCn1c(C2CC2)cc2nc(Br)c(Cl)nc21
Reaction time: 0.08 h

Procedure:
2-Bromo-3-chloro-6-cyclopropyl-5H-pyrrolo[2,3-b]pyrazine (step 1) (1.0 g, 3.696 mmol) in DMF (10 ml), cooled to 0° C. and degassed with argon, was treated with potassium carbonate (1.53 g, 10.88 mmol) and stirred for 5 minutes. The reaction mixture was then treated with ethyl 7-bromoheptanoate (960 mg, 4.066 mmol) and stirred at room temperature for 16 hours. Saturated aqueous ammonium chloride solution was added slowly at 0° C. and the mixture was extracted with diethyl ether. The organic portion was dried (Na2SO4), and the solvent was removed under reduced pressure. Purification of the crude product by chromatography on neutral alumina eluting with 0-2% EtOAc in iso-hexane afforded the titled compound;
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([C:8]([CH3:11])([CH3:10])[CH3:9])[C:5]([OH:12])=[CH:4][C:3]=1[CH2:13][C:14]([O:16][CH3:17])=[O:15].[CH2:18](O)[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24]C.C[O-].[Na+].C(O)(=O)C>C1(C)C=CC=CC=1>[CH3:1][C:2]1[CH:7]=[C:6]([C:8]([CH3:11])([CH3:9])[CH3:10])[C:5]([OH:12])=[CH:4][C:3]=1[CH2:13][C:14]([O:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])=[O:15]
Reactant: COC(=O)Cc1cc(O)c(C(C)(C)C)cc1C
Reactant: CCCCCCCCO
Agent: C[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CC(=O)O
Product: CCCCCCCCOC(=O)Cc1cc(O)c(C(C)(C)C)cc1C
Temperature: 80 °C
Reaction time: 5 h
Yield: 88 %

Procedure:
Into a 200-ml four-necked flask, were charged 23.6 g of methyl (2-methyl-4-t-butyl-5-hydroxyphenyl)acetate, 13.0 g of octylalcohol and 0.5 g of sodium methoxide. The mixture was allowed to react at 120° C. for 2 hours, and then at 140° to 150° C. under a reduced pressure of 20 mmHg for 5 hours. During the course of this reaction, along with the progress of reaction 1.5 g of sodium methoxide was added in three equal portions. After completion of the reaction, the reaction mixture was cooled to 80° C., neutralized with glacial acetic acid, then dissolved in toluene, washed with water, dried over anhydrons sodium sulfate, and freed from the solvent under reduced pressure to obtain 29.4 g (88% yield) of viscous octyl 2-methyl-4-t-butyl-5-hydroxyphenylacetate.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([O:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:5]([NH:8][C:9]([NH2:11])=[S:10])=[N:6][CH:7]=1.Br[CH2:20][C:21](=O)[CH2:22][C:23]([O:29][CH3:30])([CH3:28])[C:24]([O:26][CH3:27])=[O:25]>C1COCC1>[Br:1][C:2]1[CH:3]=[C:4]([O:12][C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)[C:5]([NH:8][C:9]2[S:10][CH:20]=[C:21]([CH2:22][C:23]([O:29][CH3:30])([CH3:28])[C:24]([O:26][CH3:27])=[O:25])[N:11]=2)=[N:6][CH:7]=1
Reactant: NC(=S)Nc1ncc(Br)cc1Oc1ccccc1
Reactant: COC(=O)C(C)(CC(=O)CBr)OC
Solvent: C1CCOC1
Product: COC(=O)C(C)(Cc1csc(Nc2ncc(Br)cc2Oc2ccccc2)n1)OC
Temperature: 50 °C
Reaction time: 8 h
Yield: 65.8 %

Procedure:
In a 125 mL round-bottom flask, 1-(5-bromo-3-phenoxypyridin-2-yl)thiourea (0.50 g, 1.54 mmol) (prepared as described in Example 10, Steps A-D) and methyl 5-bromo-2-methoxy-2-methyl-4-oxopentanoate (0.586 g, 2.31 mmol) were dissolved in dry THF (25 mL), heated to 50° C. and agitated overnight. The solvent was evaporated and the residue was dissolved in chloroform and washed with diluted sodium bicarbonate solution twice, dried over magnesium sulfate, filtered and evaporated. The resulting solid was purified by chromatography on silica gel, eluted with 10-15% ethyl acetate/hexane to give the title compound (0.485 g, 65.7% yield) as yellow solid. 1H NMR (CDCl3) δ 1.46 (s, 3H), 3.12 (s, 2H), 3.34 (s, 3H), 3.73 (s, 3H), 6.58 (s, 1H), 7.06-7.45 (m, 6H), 8.11 (s, 1H), 8.64 (bs, 1H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]3[C:10](=[N:27][N:28]([CH2:30][C:31]([OH:33])=O)[CH:29]=3)[N:11]=[C:12]([C:20]3[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=3)[C:13]=2[C:14]2[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=2)=[CH:4][CH:3]=1.C1(N=C=NC2CCCCC2)CCCCC1.ON1C2C=CC=CC=2N=N1.[NH:59]1[CH2:64][CH2:63][O:62][CH2:61][CH2:60]1>CN(C=O)C.CCOC(C)=O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:9]3[C:10](=[N:27][N:28]([CH2:30][C:31]([N:59]4[CH2:64][CH2:63][O:62][CH2:61][CH2:60]4)=[O:33])[CH:29]=3)[N:11]=[C:12]([C:20]3[CH:21]=[CH:22][C:23]([F:26])=[CH:24][CH:25]=3)[C:13]=2[C:14]2[CH:15]=[CH:16][N:17]=[CH:18][CH:19]=2)=[CH:6][CH:7]=1
Reactant: C1COCCN1
Reactant: O=C(O)Cn1cc2c(-c3ccc(F)cc3)c(-c3ccncc3)c(-c3ccc(F)cc3)nc2n1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: On1nnc2ccccc21
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: O=C(Cn1cc2c(-c3ccc(F)cc3)c(-c3ccncc3)c(-c3ccc(F)cc3)nc2n1)N1CCOCC1
Reaction time: 0.25 h
Yield: 35.2 %

Procedure:
To a solution of 2-[4,6-bis(4-fluorophenyl)-5-(4-pyridyl)pyrazolo[3,4-b]pyridin-2-yl]acetic acid (0.05 g, 0.1 mmol, obtained in example 44) in DMF (1 mL), N,N′-dicyclohexylcarbodiimide (0.02 g, 0.1 mmol) and 1-hydroxybenzotriazole (0.02 g, 0.1 mmol) were added under argon atmosphere. The mixture was stirred for 15 min and morpholine (0.01 g, 0.1 mmol) was added. This was stirred at room temperature for 2 days. EtOAc was added and the mixture was filtered. The filtrate was washed with saturated NaHCO3. The organic phase was dried over Na2SO4 and concentrated to dryness. The crude product obtained was purified by chromatography on silica gel using EtOAc-MeOH mixtures of increasing polarity as eluent, to afford 18 mg of title compound (yield: 35%).
Reaction SMILES: [CH2:1]([N:3]([C:20](=O)[CH2:21][CH2:22][C:23]([CH3:26])([CH3:25])[CH3:24])[CH2:4][CH2:5][CH2:6][CH:7]([C:9]1[CH:14]=[CH:13][C:12]([NH:15][S:16]([CH3:19])(=[O:18])=[O:17])=[CH:11][CH:10]=1)[OH:8])[CH3:2].[H-].[H-].[H-].[H-].[Li+].[Al+3].C(C(C(C([O-])=O)O)O)([O-])=O.[Na+].[K+]>C1COCC1>[CH2:1]([N:3]([CH2:20][CH2:21][CH2:22][C:23]([CH3:24])([CH3:26])[CH3:25])[CH2:4][CH2:5][CH2:6][CH:7]([C:9]1[CH:10]=[CH:11][C:12]([NH:15][S:16]([CH3:19])(=[O:18])=[O:17])=[CH:13][CH:14]=1)[OH:8])[CH3:2]
Reactant: CCN(CCCC(O)c1ccc(NS(C)(=O)=O)cc1)C(=O)CCC(C)(C)C
Agent: O=C([O-])C(O)C(O)C(=O)[O-]
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Product: CCN(CCCC(O)c1ccc(NS(C)(=O)=O)cc1)CCCC(C)(C)C
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
A solution of the product from Step I (4.4 g, 0.0115 mol) in THF (46.4 ml) was added dropwise during 45 minutes, under nitrogen to a stirred, ice cold mixture of a 1M solution of LiAlH4 in THF (24.0 ml) and THF (24 ml). The mixture was kept in the ice bath for 45 minutes and then treated slowly with a saturated aqueous solution of potassium sodium tartrate (24.4 ml). This mixture was stirred for 30 minutes and extracted with EtOAc. The extracts were washed with water and brine, dried (MgSO4) and concentrated. The residue was chromatographed on silica gel with 5-10% MeOH--CHCl3. The product was dissolved in Et2O, washed with NaHCO3, dried (MgSO4) and concentrated to give 2.96 of the titled compound. The FAB mass spectrum had m/z 385 (M+H)+. Theory for C20H37N2O3S: 385.2525; measured.: 385.2546.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][C:12]([CH3:17])([CH3:16])[N+:13]([O-])=O.O.NN>C(O)C.[Ni]>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][C:12]([NH2:13])([CH3:16])[CH3:17]
Reactant: CC(C)(Cc1c[nH]c2ccc(Cl)cc12)[N+](=O)[O-]
Agent: [Ni]
Agent: NN
Solvent: O
Solvent: CCO
Product: CC(C)(N)Cc1c[nH]c2ccc(Cl)cc12
Temperature: 80 °C
Reaction time: 0.5 h
Yield: 77 %

Procedure:
5-Chloro-3-(2,2-dimethyl-2-nitroethyl)-1H-indole (13.5 g, 53.1 mmol), prepared as in Example 2, Step (b), was dissolved in ethanol (≈100 mL). An aqueous suspension of RANEY NICKEL® catalyst (5.0 mL) was added to the solution and the mixture was heated to 80° C. Hydrazine hydrate (10 mL, 321.1 mmol) in ethanol (≈30 mL) was added dropwise to the mixture which was then stirred for an additional 30 minutes. The mixture was filtered through celite and the filter cake was washed with methanol. The filtrate was concentrated by rotary evaporation to ≈75 mL. Crystallization upon addition of water gave [2-(5-chloro-1H-indol-3-yl)-1,1-dimethylethyl]amine (9.17 g, 40.9 mmol), m.p. 156°-158° C.
Reaction SMILES: [CH2:1]([N:3]1[CH2:16][CH2:15][C:6]2[NH:7][C:8]3[CH:9]=[CH:10][C:11]([CH3:14])=[CH:12][C:13]=3[C:5]=2[CH2:4]1)[CH3:2].[CH:17]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=1)=[CH2:18].[Na].FC(F)(F)C([O-])=O>C(O)C.[O-]S([O-])(=O)=O.[Cu+2]>[CH2:1]([N:3]1[CH2:16][CH2:15][C:6]2[N:7]([CH2:18][CH2:17][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=3)[C:8]3[CH:9]=[CH:10][C:11]([CH3:14])=[CH:12][C:13]=3[C:5]=2[CH2:4]1)[CH3:2]
Reactant: C=Cc1ccccn1
Reactant: CCN1CCc2[nH]c3ccc(C)cc3c2C1
Agent: [Cu+2]
Agent: O=C([O-])C(F)(F)F
Agent: O=S(=O)([O-])[O-]
Solvent: CCO
Product: CCN1CCc2c(c3cc(C)ccc3n2CCc2ccccn2)C1
Yield: 4.7 %

Procedure:
The title compound was prepared according to General Method 3. 2-Ethyl-2,3,4,5-tetrahydro-8-methyl-5-(2-(pyridin-2-yl)ethyl)-1H-pyrido[4,3-b]indole was prepared from 2-ethyl-2,3,4,5-tetrahydro-8-methyl-1H-pyrido[4,3-b]indole (See Example 6) (214 mg, 1 mmol), 2-vinylpyridine (0.25 ml, 2.3 mmol), sodium (15 mg, 0.65 g atom) and CuSO4 (10 mg, catalytic) in ethanol (2 mL) at 120° C. for 48 h to obtain 15 mg of 2-ethyl-2,3,4,5-tetrahydro-8-methyl-5-(2-(pyridin-2-yl)ethyl)-1H-pyrido[4,3-b]indole as a trifluoroacetate salt after purification on reverse-phase chromatography (C-18, 500 mm×50 mm, Mobile Phase A=0.05% TFA in water, B=0.05% TFA in acetonitrile, Gradient: 10% B to 80% B in 30 min, injection vol. 5 mL).
Reaction SMILES: [CH2:1]([OH:5])[CH2:2][CH2:3][CH3:4].C(=O)([O-])[O-].[Cs+].[Cs+].[Cl:12][C:13]1[C:14](F)=[CH:15][C:16]([F:26])=[C:17]([CH:25]=1)[C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19].Cl>CS(C)=O>[CH2:1]([O:5][C:14]1[C:13]([Cl:12])=[CH:25][C:17]([C:18]([O:20][C:21]([CH3:22])([CH3:23])[CH3:24])=[O:19])=[C:16]([F:26])[CH:15]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCO
Reactant: CC(C)(C)OC(=O)c1cc(Cl)c(F)cc1F
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CS(C)=O
Product: CCCCOc1cc(F)c(C(=O)OC(C)(C)C)cc1Cl
Temperature: 70 °C
Reaction time: 16 h
Yield: 84.4 %

Procedure:
To a solution of butanol (0.07 g, 0.99 mmol) in anhydrous dimethylsulfoxide (2 mL) were added cesium carbonate (0.59 g, 1.81 mmol) and tert-butyl 5-chloro-2,4-difluorobenzoate (0.22 g, 0.90 mmol) and the reaction mixture was stirred at 70° C. for 16 hours. The reaction mixture was cooled down to room temperature and acidified to pH=1 with 5% aqueous hydrochloric acid solution and extracted with ethyl acetate (2×15 mL). The combined organic layers were washed with brine (15 mL); dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. Purification of the residue by column chromatography (0 to 10% ethyl acetate in hexanes) afforded the title compound (0.23 g, 72%); MS (ES+) m/z 303.2, 305.2 (M+1).
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([CH2:8][CH2:9][CH2:10][N:11]([C@H:25]2[CH2:30][CH2:29][C@H:28]([CH3:31])[CH2:27][CH2:26]2)[C:12](=[O:24])[NH:13][C:14]2[S:15][C:16]([S:19][CH2:20][C:21]([OH:23])=[O:22])=[CH:17][N:18]=2)[CH:5]=[CH:6][CH:7]=1.[F:32][C:33]([F:46])([F:45])C1C=C(CCC(O)=O)C=CC=1.C(OC(=O)CSC1SC(N)=NC=1)C>>[CH3:31][C@H:28]1[CH2:29][CH2:30][C@H:25]([N:11]([CH2:10][CH2:9][CH2:8][C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([C:33]([F:46])([F:45])[F:32])[CH:3]=2)[C:12](=[O:24])[NH:13][C:14]2[S:15][C:16]([S:19][CH2:20][C:21]([OH:23])=[O:22])=[CH:17][N:18]=2)[CH2:26][CH2:27]1
Reactant: C[C@H]1CC[C@H](N(CCCc2cccc(Cl)c2)C(=O)Nc2ncc(SCC(=O)O)s2)CC1
Reactant: O=C(O)CCc1cccc(C(F)(F)F)c1
Agent: CCOC(=O)CSc1cnc(N)s1
Product: C[C@H]1CC[C@H](N(CCCc2cccc(C(F)(F)F)c2)C(=O)Nc2ncc(SCC(=O)O)s2)CC1

Procedure:
The compound was prepared following an analogous procedure to the one described for the synthesis of {2-[-3-[3-(3-Chloro-phenyl)-propyl]-3-(trans-4-methyl -cyclohexyl)-ureido]-thiazol-5-ylsulfanyl}-acetic acid using 3-(3-trifluoromethyl-phenyl) -propionic acid and (2-aminothiazol-5-ylsulfanyl) acetic acid ethyl ester.
Reaction SMILES: Cl.C([O:9][C:10](=[O:29])[C@H:11]([CH3:28])[CH2:12][C@H:13]([NH2:27])[CH2:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[CH:17][CH:16]=1)C1C=CC=CC=1.[C:30]([O:33][C@@H:34]1[C:38](=[O:39])[O:37][C:36](=[O:40])[C@H:35]1[O:41][C:42](=[O:44])[CH3:43])(=[O:32])[CH3:31].C(Cl)Cl.N1C=CC=CC=1.CO>C(OCC)(=O)C.[Pd]>[C:18]1([C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH:17]=[CH:16][C:15]([CH2:14][C@@H:13]([NH:27][C:38](=[O:39])[C@@H:34]([O:33][C:30](=[O:32])[CH3:31])[C@H:35]([O:41][C:42](=[O:44])[CH3:43])[C:36]([OH:37])=[O:40])[CH2:12][C@@H:11]([CH3:28])[C:10]([OH:29])=[O:9])=[CH:20][CH:19]=1
Reactant: C[C@H](C[C@H](N)Cc1ccc(-c2ccccc2)cc1)C(=O)OCc1ccccc1
Reactant: CC(=O)O[C@@H]1C(=O)OC(=O)[C@H]1OC(C)=O
Agent: [Pd]
Agent: Cl
Solvent: ClCCl
Solvent: c1ccncc1
Solvent: CO
Product: CC(=O)O[C@H](C(=O)O)[C@H](OC(C)=O)C(=O)N[C@H](Cc1ccc(-c2ccccc2)cc1)C[C@@H](C)C(=O)O

Procedure:
A solution of (2R,4S)-4-amino-5-biphenyl-4-yl-2-methyl-pentanoic acid benzyl ester hydrochloride (100 mg, 0.287 mmol) and acetic acid (3S,4S)-4-acetoxy-2,5-dioxo-tetrahydro-furan-3-yl ester (0.431 mmol) in 1:1 methylene chloride/pyridine (1.4 mL) is stirred at room temperature for 24 hours. The solvents are removed under reduced pressure and obtained residue is used directly in the subsequent hydrolysis reaction. Next, a solution of the benzyl ester in ethyl acetate is hydrogenated at 1 atm over 10% Pd/C for 18 hours. Methanol is added and the catalyst is filtered through Celite. The Solvent is removed under reduced pressure and the residue is purified by preparative HPLC using a gradient of 10-100% MeCN/water (0.1% TFA). The proper fractions are lyophilized to furnish (2R,4S)-5-biphenyl-4-yl-4-((2S,3S)-2,3-diacetoxy-3-carboxy-propionylamino)-2-methyl-pentanoic acid. HPLC Retention time 0.95 minutes (condition A); MS 500.3 (M+1); 1H NMR (400 MHz, DMSO-d6) δ ppm 1.09 (d, J=7.20Hz, 3H), 1.45 (m, 1H), 1.82 (m, 1H), 2.39 (m, 1H), 2.70 (d, J=6.82Hz, 2H), 4.01 (m, 1H), 5.38 (m, 2H), 7.19 (d, J=8.21Hz, 2H), 7.34 (t, 1H), 7.45 (t, 2H), 7.53 (d, J=8.21Hz, 2H), 7.64 (d, J=7.20Hz, 2H), 8.00 (d, J=8.72Hz, 1H).
Reaction SMILES: [C@H:1]12[CH2:7][C@H:4]([CH2:5][CH2:6]1)[CH2:3][C@H:2]2[NH:8][C:9]1[N:14]=[C:13]([C:15]([F:18])([F:17])[F:16])[C:12]([C:19](O)=[O:20])=[CH:11][N:10]=1.CN1CCOCC1.ClC(OCC(C)C)=O>COCCOC>[C@H:1]12[CH2:7][C@H:4]([CH2:5][CH2:6]1)[CH2:3][C@H:2]2[NH:8][C:9]1[N:14]=[C:13]([C:15]([F:18])([F:16])[F:17])[C:12]([CH2:19][OH:20])=[CH:11][N:10]=1
Reactant: O=C(O)c1cnc(N[C@@H]2C[C@H]3CC[C@@H]2C3)nc1C(F)(F)F
Agent: CC(C)COC(=O)Cl
Solvent: CN1CCOCC1
Solvent: COCCOC
Product: OCc1cnc(N[C@@H]2C[C@H]3CC[C@@H]2C3)nc1C(F)(F)F
Temperature: -10 °C
Reaction time: 1 h
Yield: 55.1 %

Procedure:
A mixture of rac-2-[(1R,2R,4S)-bicyclo[2.2.1]hept-2-ylamino]-4-(trifluoromethyl)pyrimidine-5-carboxylic acid (2.0 g), 4-methyl morpholine (1.1 mL) and 1,2-dimethoxyethane (40 mL) was cooled to −10° C., isobutyl chloroformate (1.1 mL) was added thereto, and the mixture was stirred at the same temperature for 1 hour. The insoluble materials in the reaction mixture were filtered and washed with 1,2-dimethoxyethane. The filtrate was cooled to −60° C. and a solution of sodium borohydride (377 mg) in water (4.0 mL) was added thereto, followed by stirring as it is for 1 hour. To the reaction mixture was added water, followed by extraction with ethyl acetate. The organic layer was washed with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and then the residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate=10:90 to 20:80) to obtain rac-{2-[(1R,2R,4S)-bicyclo[2.2.1]hept-2-ylamino]-4-(trifluoromethyl)pyrimidin-5-yl}methanol (1.05 g) as a colorless oily substance.
Reaction SMILES: CN(C=O)C.[Cl:6][C:7]1[N:17]=[CH:16][C:10]2[N:11]=[CH:12][NH:13][C:14](=O)[C:9]=2[CH:8]=1.S(Cl)([Cl:20])=O>C1(C)C=CC=CC=1>[Cl:20][C:14]1[C:9]2[CH:8]=[C:7]([Cl:6])[N:17]=[CH:16][C:10]=2[N:11]=[CH:12][N:13]=1
Reactant: O=c1[nH]cnc2cnc(Cl)cc12
Reactant: O=S(Cl)Cl
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: Clc1cc2c(Cl)ncnc2cn1
Reaction time: 1 h

Procedure:
DMF (0.1 ml) was added to 6-chloro-3H-pyrido[3,4-d]pyrimidin-4-one (1.82 g, 10 mmol) followed by dropwise addition of thionyl chloride (10 ml). The flask was fitted with a condenser and a drying tube and the contents heated to reflux for 20 minutes whereupon the solids dissolved. The heating was continued for a further 1 h and then cooled. Toluene was added to wash the sides of the flask and the solvents were evaporated in vacuo. Azeotroping with toluene was repeated twice and the crude so obtained was taken through to the next step.