Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([C:30]([F:33])([F:32])[F:31])[CH:25]=2)[C:5]([C:21](O)=[O:22])=[N:6][C:7]=1[C:8]([N:10]1[CH2:15][CH2:14][CH:13]([N:16]2[CH2:20][CH2:19][CH2:18][CH2:17]2)[CH2:12][CH2:11]1)=[O:9].[CH2:34]([CH2:36][NH2:37])[OH:35].CCN(CC)CC.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[OH:35][CH2:34][CH2:36][NH:37][C:21]([C:5]1[C:4]([C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([C:30]([F:33])([F:32])[F:31])[CH:25]=2)=[CH:3][C:2]([CH3:1])=[C:7]([C:8]([N:10]2[CH2:15][CH2:14][CH:13]([N:16]3[CH2:17][CH2:18][CH2:19][CH2:20]3)[CH2:12][CH2:11]2)=[O:9])[N:6]=1)=[O:22]
Reactant: Cc1cc(-c2cccc(C(F)(F)F)c2)c(C(=O)O)nc1C(=O)N1CCC(N2CCCC2)CC1
Reactant: NCCO
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Cc1cc(-c2cccc(C(F)(F)F)c2)c(C(=O)NCCO)nc1C(=O)N1CCC(N2CCCC2)CC1

Procedure:
In analogy to the procedure described for the preparation of example 1, 5-methyl-6-(4-pyrrolidin-1-yl-piperidine-1-carbonyl)-3-(3-trifluoromethyl-phenyl)-pyridine-2-carboxylic acid (example 47) was reacted with ethanolamine, Et3N and HATU in DMF to give the title compound as light yellow solid. MS: 505.2 (MH+).
Reaction SMILES: [CH3:1][C@@:2]([S:43]([CH3:46])(=[O:45])=[O:44])([CH2:13][CH2:14][N:15]1[CH:20]=[CH:19][C:18]([C:21]2[CH:26]=[CH:25][C:24]([O:27][CH2:28][C@H:29]3[CH2:34][CH2:33][C@H:32]([O:35]C4CCCCO4)[CH2:31][CH2:30]3)=[CH:23][CH:22]=2)=[CH:17][C:16]1=[O:42])[C:3]([NH:5][O:6]C1CCCCO1)=[O:4].ONC(=O)[C@](C)(S(C)(=O)=O)CCN1C=CC(C2C=CC(OC[C@H]3CC[C@@H](O)CC3)=CC=2)=CC1=O>>[OH:6][NH:5][C:3](=[O:4])[C@:2]([CH3:1])([S:43]([CH3:46])(=[O:45])=[O:44])[CH2:13][CH2:14][N:15]1[CH:20]=[CH:19][C:18]([C:21]2[CH:26]=[CH:25][C:24]([O:27][CH2:28][C@H:29]3[CH2:30][CH2:31][C@H:32]([OH:35])[CH2:33][CH2:34]3)=[CH:23][CH:22]=2)=[CH:17][C:16]1=[O:42]
Reactant: C[C@@](CCn1ccc(-c2ccc(OC[C@H]3CC[C@H](OC4CCCCO4)CC3)cc2)cc1=O)(C(=O)NOC1CCCCO1)S(C)(=O)=O
Agent: C[C@@](CCn1ccc(-c2ccc(OC[C@H]3CC[C@@H](O)CC3)cc2)cc1=O)(C(=O)NO)S(C)(=O)=O
Product: C[C@@](CCn1ccc(-c2ccc(OC[C@H]3CC[C@H](O)CC3)cc2)cc1=O)(C(=O)NO)S(C)(=O)=O

Procedure:
The title compound (300 mg, 83%) was prepared from (2R)-2-methyl-2-(methylsulfonyl)-4-[2-oxo-4-(4-{[trans-4-(tetrahydro-2H-pyran-2-yloxy)cyclohexyl]methoxy}phenyl)pyridin-1 (2H)-yl]-N-(tetrahydro-2H-pyran-2-yloxy)butanamide (480 mg, 0.726 mmol) by a procedure analogous to that described for (2R)—N-hydroxy-4-[4-{4-[(cis-4-hydroxycyclohexyl)methoxy]phenyl}-2-oxopyridin-1(2H)-yl]-2-methyl-2-(methylsulfonyl)butanamide Example 8, Step F. LCMS m/z 493.7 (M+1)1H NMR (400 MHz, DMSO-d6) δ ppm 0.92-1.23 (m, 4H) 1.54 (s, 3H) 1.58-1.72 (m, 1H) 1.81 (br. s., 4H) 2.06-2.21 (m, 1H) 2.41 (s, 1H) 3.08 (s, 3H) 3.25-3.41 (m, 1H) 3.74 (br. s., 1H) 3.80 (d, J=6.44 Hz, 2H) 3.98-4.17 (m, 1H) 6.48-6.71 (m, 2H) 6.85-7.06 (m, 2H) 7.52-7.78 (m, 3H) 11.15 (s, 1H)
Reaction SMILES: [CH3:1][O:2][C:3](=[O:14])[C:4]1[CH:9]=[CH:8][C:7]([CH3:10])=[C:6]([N+:11]([O-])=O)[CH:5]=1.CCOC(C)=O>CO.[Pd]>[CH3:1][O:2][C:3](=[O:14])[C:4]1[CH:9]=[CH:8][C:7]([CH3:10])=[C:6]([NH2:11])[CH:5]=1
Reactant: COC(=O)c1ccc(C)c([N+](=O)[O-])c1
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CO
Product: COC(=O)c1ccc(C)c(N)c1
Reaction time: 1 h
Yield: 100 %

Procedure:
The ester from above (29.37 g, 150 mmol) was added to a 2L Parr hydrogenation flask and dissolved in anhydrous MeOH (200 mL) plus EtOAc (25 mL). The solution was then treated with 10% Pd/C (2.25 g, 50% wet) and fitted to a hydrogenator apparatus. After purging the flask 3 times with hydrogen gas, the mixture was shaken for 1 hour at 30 psi. The flask was then removed, and filtered through a celite pad washing with MeOH. The solvent was then removed under reduced pressure to afford 3-amino-4-methyl-benzoic acid methyl ester as a white solid (25.0 g, 100%). 1H NMR (CDCl3) δ 2.21 (s, 3H), 3.70 (br s, 2H, NH2), 3.88 (s, 3H), 7.10 (d, 1H, J=7.5 Hz), 7.35 (s, 1H), 7.37 (d, 1H, J=8.4 Hz).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]2[N:7]([CH2:11][C:12]([C:15]3[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=3)(O)[CH3:13])[C:6]3[CH2:23][CH2:24][N:25]([CH3:27])[CH2:26][C:5]=3[C:4]=2[CH:3]=1.S(=O)(=O)(O)O>O>[Cl:1][C:2]1[CH:10]=[CH:9][C:8]2[N:7](/[CH:11]=[C:12](/[C:15]3[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=3)\[CH3:13])[C:6]3[CH2:23][CH2:24][N:25]([CH3:27])[CH2:26][C:5]=3[C:4]=2[CH:3]=1.[Cl:1][C:2]1[CH:10]=[CH:9][C:8]2[N:7]([CH2:11][C:12]([C:15]3[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=3)=[CH2:13])[C:6]3[CH2:23][CH2:24][N:25]([CH3:27])[CH2:26][C:5]=3[C:4]=2[CH:3]=1
Reactant: COc1ccc(C(C)(O)Cn2c3c(c4cc(Cl)ccc42)CN(C)CC3)cc1
Agent: O=S(=O)(O)O
Solvent: O
Product: C=C(Cn1c2c(c3cc(Cl)ccc31)CN(C)CC2)c1ccc(OC)cc1
Product: COc1ccc(/C(C)=C/n2c3c(c4cc(Cl)ccc42)CN(C)CC3)cc1
Temperature: 7.5 °C

Procedure:
1-(8-Chloro-1,2,3,4-tetrahydro-2-methylpyrido[4,3-b]indol-5-yl)-2-(4-methoxyphenyl)propan-2-ol (1 equiv.) is heated to 55° C. with sulfuric acid in water for 2.5 h. The reaction mixture is cooled to 5-10° C. and neutralized by dropwise addition of satd. aq. sodium hydrogen carbonate solution followed by extraction with EtOAc. The combined organic extract is washed with water, then brine, dried over sodium sulfate and evaporated under vacuum to obtain 8-chloro-2,3,4,5-tetrahydro-5-((E)-2-(4-methoxyphenyl)prop-1-enyl)-2-methyl-1H-pyrido[4,3-b]indole and 8-chloro-2,3,4,5-tetrahydro-5-(2-(4-methoxyphenyl)allyl)-2-methyl-1H-pyrido[4,3-b]indole, which are separated by HPLC.
Reaction SMILES: O[C:2]([CH3:14])([CH3:13])[C:3]([C:5]1[CH:10]=[CH:9][C:8]([S:11]C)=CC=1)=O.[F:15][C:16]1[CH:17]=[C:18]([CH2:22][C:23]([OH:25])=[O:24])[CH:19]=[CH:20][CH:21]=1.[CH2:26]1CCN2C(=NCCC2)CC1>CN(C1C=CN=CC=1)C.C(Cl)Cl>[CH3:14][C:2]1([CH3:13])[O:24][C:23](=[O:25])[C:22]([C:18]2[CH:19]=[CH:20][CH:21]=[C:16]([F:15])[CH:17]=2)=[C:3]1[C:5]1[S:11][CH:8]=[C:9]([CH3:26])[CH:10]=1
Reactant: CSc1ccc(C(=O)C(C)(C)O)cc1
Reactant: C1CCC2=NCCCN2CC1
Reactant: O=C(O)Cc1cccc(F)c1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: Cc1csc(C2=C(c3cccc(F)c3)C(=O)OC2(C)C)c1
Reaction time: 16 h
Yield: 173.9 %

Procedure:
To a room temperature solution of 2-hydroxy-2-methyl-1-(4-methylthiophenyl)-propan-1-one (WO 95/00501, 20.0 g, 95.1 mmol), 3-fluorophenylacetic acid (29.3 g, 190 mmol) and DMAP (1.16 g, 9.5 mmol) in 500 mL of CH2Cl2 was added CMC (80.5 g, 190.2 mmol). The resulting mixture was stirred for 16 h under nitrogen. DBU (46 mL, 301 mmol) was then added, and the mixture stirred for 1.5 h. The reaction was quenched with 1M HCl, and the organic phase was washed with saturated aqueous NaHCO3 and brine. The CH2Cl2 layer wa filtered through cotton and concentrated to give 50 g of the title compound, which was used in Step 2 without further purification.
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[CH:6][C:3]=1[C:4]#[N:5].[CH3:13][CH2:14][O:15][C:16]([CH2:18][SH:19])=[O:17].CCN(CC)CC>CS(C)=O>[NH2:5][C:4]1[C:3]2[CH:6]=[C:7]([N+:10]([O-:12])=[O:11])[CH:8]=[CH:9][C:2]=2[S:19][C:18]=1[C:16]([O:15][CH2:14][CH3:13])=[O:17]
Reactant: N#Cc1cc([N+](=O)[O-])ccc1F
Reactant: CCOC(=O)CS
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: CCOC(=O)c1sc2ccc([N+](=O)[O-])cc2c1N
Yield: 100.5 %

Procedure:
2-Fluoro-5-nitrobenzonitrile (1.664 g, 10 mmol), ethyl thioglycollate (1.21 g, 10 mmol) and NEt3 (3.06 g, 30 mmol) are stirred in DMSO (5 mL) at 100° C. under N2 for h h. The deep orange-red reaction mixture is poured onto ice-water (50 mL), and the solid is collected by suction filtration, rinsed with water, and dried in a vacuum oven at 60° C. to give ethyl 3-amino-5-nitrobenzothiophene-2-carboxylate (2.675 g, 100%) as a bright orange solid. 1H NMR (DMSO) δ9.23 (1H, d, J=2.1 Hz), 8.28 (1H, dd, J=2.3, 8.9 Hz), 8.10 (1H, d, J=9.0 Hz), 7.45 (2H, brs), 4.29 (2H, q, J=7.1 Hz), 1.30 (3H, t, J=7.1 Hz).
Reaction SMILES: [C:1]1(O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH:8]1C(C(CBr)=O)=[CH:12][CH:11]=[C:10]([Cl:18])[CH:9]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:25]([CH2:28][O:29]C)[O:26][CH3:27]>>[Cl:18][C:10]1[CH:11]=[CH:12][C:27]([O:26][CH2:25][C:28]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)=[O:29])=[CH:8][CH:9]=1
Reactant: COCCOC
Reactant: Oc1ccccc1
Reactant: O=C(CBr)c1ccc(Cl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: O=C(COc1ccc(Cl)cc1)c1ccccc1

Procedure:
A mixture of 40.5 g. (0.43 mole) of phenol, 100 g. (0.428 mole) of 4-chloro-α-bromoacetophenone, 100 g. (0.725 mole) of potassium carbonate and 500 ml. of glyme is heated to its reflux temperature and maintained at reflux for about 6 hours. The reaction mixture is evaporated to remove the solvent. The residue is diluted with water and diethyl ether, and the layers are separated. The ether layer is washed with water and saturated sodium chloride solution and dried over magnesium sulfate. The ether solution is evaporated to provide a dark oil gradually solidifies on cooling. The solid is recrystallized from ethanol to provide 4-chloro-α-phenoxyacetophenone, m.p. 81°-86° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=2)[O:9][CH2:10][CH2:11]Br)=[CH:4][CH:3]=1.[CH3:20][O:21][C:22]1[CH:23]=[C:24]([CH:30]2[CH2:34][CH2:33][NH:32][CH2:31]2)[CH:25]=[C:26]([O:28][CH3:29])[CH:27]=1.C(=O)([O-])[O-].[K+].[K+]>C(Cl)(Cl)Cl.CO>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=2)[O:9][CH2:10][CH2:11][N:32]2[CH2:33][CH2:34][CH:30]([C:24]3[CH:25]=[C:26]([O:28][CH3:29])[CH:27]=[C:22]([O:21][CH3:20])[CH:23]=3)[CH2:31]2)=[CH:4][CH:3]=1
Reactant: COc1cc(OC)cc(C2CCNC2)c1
Reactant: Fc1ccc(C(OCCBr)c2ccc(F)cc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClC(Cl)Cl
Solvent: CO
Product: COc1cc(OC)cc(C2CCN(CCOC(c3ccc(F)cc3)c3ccc(F)cc3)C2)c1
Yield: 46.5 %

Procedure:
Proceeding as in Example 9, using 14.8 g (45 mmole) of 1-[bis(4-fluorophenyl)methoxy]-2-bromoethane, 9.4 g (45 mmole) of 3-(3,5-dimethoxyphenyl)pyrrolidine and 12 g (86 mmole) of potassium carbonate, there was obtained after silica gel column chromatography (eluent chloroform-methanol, 9/1), 9.5 g (yield: 46%) of 1-[2-[bis(4-fluorophenyl)methoxy]ethyl]-3-(3,5-dimethoxy phenyl)pyrrolidine.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][C:8]([OH:10])=O.[CH2:11]([C@@H:18]1[NH:23][CH2:22][CH2:21][N:20]([C:24]2[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[C:26]([O:32][CH:33]([CH3:35])[CH3:34])[CH:25]=2)[CH2:19]1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>>[CH2:11]([C@H:18]1[CH2:19][N:20]([C:24]2[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[C:26]([O:32][CH:33]([CH3:35])[CH3:34])[CH:25]=2)[CH2:21][CH2:22][N:23]1[C:8](=[O:10])[CH2:7][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=1)[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: O=C(O)Cc1ccccn1
Reactant: COc1ccc(N2CCN[C@@H](Cc3ccccc3)C2)cc1OC(C)C
Product: COc1ccc(N2CCN(C(=O)Cc3ccccn3)[C@@H](Cc3ccccc3)C2)cc1OC(C)C

Procedure:
Prepared by the method outlined for Example 189 using pyridine-2-yl-acetic acid and 3(S)-benzyl-1-(3-(1-methylethoxy)-4-methoxy-phenyl)-piperazine (Example 9, Compound 97) as starting materials. Product as an oil (30 mg, 68%). LC/MS (Method B) 2.45 min, [M+1]+ 460. Potency class B.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:10][CH:9]1[CH2:21]O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:23]1(=[O:33])[NH:27][C:26](=[O:28])[C:25]2=[CH:29][CH:30]=[CH:31][CH:32]=[C:24]12.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>O1CCCC1.C1(C)C=CC=CC=1>[CH2:1]([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:10][CH:9]1[CH2:21][N:27]1[C:23](=[O:33])[C:24]2[C:25](=[CH:29][CH:30]=[CH:31][CH:32]=2)[C:26]1=[O:28])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C1NC(=O)c2ccccc21
Reactant: OCC1CN(Cc2ccccc2)CCN1Cc1ccccc1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: O=C1c2ccccc2C(=O)N1CC1CN(Cc2ccccc2)CCN1Cc1ccccc1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
To a solution of 1,4-dibenzyl-2-(hydroxymethyl)piperazine (1.51 g), phthalimide (0.790 g) and triphenylphosphine (1.40 g) in tetrahydrofuran (20 ml) was added a 40% toluene solution (2.34 ml) of diethyl azodicarboxylate under ice cooling. The resulting mixture was stirred at room temperature for 6 hours. Furthermore, 1,4-dibenzyl-2-(hydroxymethyl)piperazine (0.87 g), phthalimide (0.486 g), triphenylphosphine (0.81 g) and tetrahydrofuran (5 ml) were added to the reaction mixture, followed by the addition of a 40% toluene solution (1.34 ml) of diethyl azodicarboxylate under ice cooling. The resulting mixture was stirred at room temperature for 18.5 hours. Phthalimide (0.405 g) and a 40% toluene solution (1.10 ml) of diethyl azodicarboxylate were added under ice cooling, followed by stirring at room temperature for 20 hours. The solvent was distilled off under reduced pressure. The residue was subjected to column chromatography twice (3% methanol—methylene chloride for the first time and ethyl acetate/hexane=1/3 for the second time) using as a carrier silica gel, whereby a crude product was obtained. The crude product was crystallized from hexane - methylene chloride, collected by filtration and washed with hexane, whereby the title compound (0.243 g) was obtained as colorless powder.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([S:9][CH2:10][CH:11]([C:18](=[O:30])[N:19]([CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])[CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])[CH2:12][CH2:13][C:14]([O:16][CH3:17])=[O:15])[CH:5]=[CH:6][C:7]=1[Cl:8].ClC1C=CC=C(C(OO)=[O:39])C=1.S([O-])([O-])=O.[Na+].[Na+]>ClCCl>[Cl:1][C:2]1[CH:3]=[C:4]([S:9]([CH2:10][CH:11]([C:18](=[O:30])[N:19]([CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])[CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])[CH2:12][CH2:13][C:14]([O:16][CH3:17])=[O:15])=[O:39])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CCCCCN(CCCCC)C(=O)C(CCC(=O)OC)CSc1ccc(Cl)c(Cl)c1
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Product: CCCCCN(CCCCC)C(=O)C(CCC(=O)OC)CS(=O)c1ccc(Cl)c(Cl)c1
Temperature: -78 °C
Yield: 45.2 %

Procedure:
Into a solution of methyl 5-(3,4-dichlorophenylthio)-4-(N,N-dipentylcarbamoyl)pentanoate (5.12 g) in dry dichloromethane (100 ml) were added portions of m-chloroperbenzoic acid (70%, 2.65 g) with stirring at -78° C. After stirring at -78° C. for 2 hours, sodium sulfite was added. The reaction mixture was washed with a saturated sodium bicarbonate solution and water, dried over MgSO4, and concentrated in vacuo. The residue was purified by flash column chromatography on silica by eluting with dichloromethane/diethyl ether/hexane (1:1:2) to give 2.39 g of methyl 5-(3,4-dichlorophenylsulfinyl)-4-(N,N-dipentylcarbamoyl)pentanoate (diastereomer A) in a early fraction and 2.47 g of diastereomer B in a later fraction.
Reaction SMILES: C[Si](C)(C)N[Si](C)(C)C.[OH:10][C@H:11]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[C@H:12]([N:14]([CH3:26])[C:15](=[O:25])[CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([S:23][CH3:24])[CH:18]=1)[CH3:13].C(OC(=O)NC1C=CC=C(CN2C=CC(NC(=O)[C@@H](C3C=CC(S(C)(=O)=O)=C(Cl)C=3)[CH2:55][CH:56]3[CH2:60][CH2:59][CH2:58][CH2:57]3)=N2)C=1)(C)(C)C.O>O1CCCC1>[CH:56]1([CH2:55][C@H:16]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([S:23][CH3:24])[CH:18]=2)[C:15]([N:14]([C@H:12]([CH3:13])[C@H:11]([OH:10])[C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH3:26])=[O:25])[CH2:60][CH2:59][CH2:58][CH2:57]1
Reactant: CC(C)(C)OC(=O)Nc1cccc(Cn2ccc(NC(=O)[C@H](CC3CCCC3)c3ccc(S(C)(=O)=O)c(Cl)c3)n2)c1
Reactant: CSc1cccc(CC(=O)N(C)[C@H](C)[C@H](O)c2ccccc2)c1
Agent: C[Si](C)(C)N[Si](C)(C)C
Solvent: O
Solvent: C1CCOC1
Product: CSc1cccc([C@@H](CC2CCCC2)C(=O)N(C)[C@H](C)[C@H](O)c2ccccc2)c1
Temperature: -20 °C
Reaction time: 0.5 h
Yield: 58 %

Procedure:
To a solution of 1,1,1,3,3,3-Hexamethyldisilazane (1.81 g, 11.19 mmol) in tetrahydrofuran (15 mL) cooled to −20° C. under nitrogen was added n-butylithium (6.4 mL of a 1.6 M solution, 10.21 mmol) slowly keeping the temperature at −20° C. for 30 min. N-((1R,2R)-2-hydroxy-1-methyl-2-phenyl-ethyl)-N-methyl-2-(3-methylsulfanyl-phenyl)-acetamide (1.60 g, 4.86 mmol) in tetrahydrofuran (15 mL) was added slowly to the reaction maintaining the temperature at −20° C. After the addition was complete the reaction was warmed to 0° C. and stirred for 30 min. A solution of 2,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (1.31 g, 10.21 mmol) and iodomethylcyclopentane (prepared in PCT WO2004/052869 A1 Example 1, 1.23 g, 5.84 mmol) were added to the reaction at 0° C. and stirring continued for 3 h. The reaction was poured into water (60 mL) and extracted with ethyl acetate. The ethyl acetate fractions were washed with water, 2 N aqueous hydrochloric acid solution, saturated sodium bicarbonate and saturated sodium chloride solution and then dried over magnesium sulfate. Filtration and concentration afforded the crude product which was purified by ISCO flash column chromatography (Teledyne Isco RediSep Flash Column 40 g; 0% ethyl acetate/hexanes to 50% ethyl acetate/hexanes) to yield (R)-3-cyclopentyl-N-((1R,2R)-2-hydroxy-1-methyl-2-phenyl-ethyl)-N-methyl-2-(3-methylsulfanyl-phenyl)-propionamide (1.16 g, 58%) as a clear sticky solid.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][N:8]=[CH:9]2)=[CH:4][CH:3]=1.Br[CH:13]([CH2:23][CH3:24])[C:14]([NH:16][C:17]([CH3:22])([CH3:21])[C:18]#[C:19][CH3:20])=[O:15]>>[CH:9]1[C:10]2[C:5](=[CH:4][CH:3]=[C:2]([O:1][CH:13]([CH2:23][CH3:24])[C:14]([NH:16][C:17]([CH3:22])([CH3:21])[C:18]#[C:19][CH3:20])=[O:15])[CH:11]=2)[CH:6]=[CH:7][N:8]=1
Reactant: Oc1ccc2ccncc2c1
Reactant: CC#CC(C)(C)NC(=O)C(Br)CC
Product: CC#CC(C)(C)NC(=O)C(CC)Oc1ccc2ccncc2c1

Procedure:
In a similar procedure to Example 1, 7-hydroxyisoquinoline (commercially available) and 2-bromo-N-(4-methylpent-2-yn-4-yl) butyramide were reacted to give 2-(7-isoquinolinyloxy)-N-(4-methylpent-2-yn-4-yl) butyramide (Compound No. 2 of Table 39) as a colourless solid, m.p. 149-50° C.
Reaction SMILES: Cl[C:2]1[C:3]2[CH:11]=[CH:10][C:9]([Cl:12])=[N:8][C:4]=2[N:5]=[CH:6][N:7]=1.[NH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>C1COCC1.CC(O)C>[Cl:12][C:9]1[CH:10]=[CH:11][C:3]2[C:2]([NH:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)=[N:7][CH:6]=[N:5][C:4]=2[N:8]=1
Reactant: Nc1ccccc1
Reactant: Clc1ccc2c(Cl)ncnc2n1
Solvent: CC(C)O
Solvent: C1CCOC1
Product: Clc1ccc2c(Nc3ccccc3)ncnc2n1
Reaction time: 48 h

Procedure:
A solution of Example 140D (0.5 g, 2.5 mmol), and aniline (0.23 mL, 2.5 mmol) in THF (25 mL) and 2-propanol (2.5 mL) was stirred at 0° C. for 1 h then at room temperature for 2 days. The THF was evaporated off and the residue was taken into ethyl acetate (75 ml), washed with water (50 ml) and brine (50 ml). The ethyl acetate was evaporated off and the residue was purified by flash column chromatography on silica gel, eluting with 1:1 ethyl acetate/hexane. Recovered 0.15 g of product (23%). MS (ESI) m/z 390 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:23]=[CH:22][C:21]([CH2:24][C:25]2[C:34]3[CH2:33][CH2:32][CH2:31][CH2:30][C:29]=3[C:28](=[O:35])[NH:27][N:26]=2)=[CH:20][C:3]=1[C:4]([N:6]1[CH2:12][CH2:11][CH2:10][N:9](C(OC(C)(C)C)=O)[CH2:8][CH2:7]1)=[O:5].FC(F)(F)C(O)=O.C(#N)C>ClCCl>[N:6]1([C:4]([C:3]2[CH:20]=[C:21]([CH:22]=[CH:23][C:2]=2[F:1])[CH2:24][C:25]2[C:34]3[CH2:33][CH2:32][CH2:31][CH2:30][C:29]=3[C:28](=[O:35])[NH:27][N:26]=2)=[O:5])[CH2:12][CH2:11][CH2:10][NH:9][CH2:8][CH2:7]1
Reactant: CC(C)(C)OC(=O)N1CCCN(C(=O)c2cc(Cc3n[nH]c(=O)c4c3CCCC4)ccc2F)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: CC#N
Product: O=C(c1cc(Cc2n[nH]c(=O)c3c2CCCC3)ccc1F)N1CCCNCC1
Temperature: 25 °C

Procedure:
To a solution of EXAMPLE 5A (330 mg) in dichloromethane (8 mL) at 0° C. was added trifluoroacetic acid (8 mL). The solution was warmed to ambient temperature, and acetonitrile was added. The mixture was concentrated. The concentrate was purified by HPLC (Zorbax® C-18 ODS packing material [Agilent Technologies, Santa Clara, Calif.], 0-100% acetonitrile/water with 0.1% trifluoroacetic acid). The product was dissolved in methanol/dichloromethane and treated with 1M hydrochloric acid in diethyl ether and filtered to give the title compound as the hydrochloride salt. 1H NMR (CD3OD) δ 1.70-1.76 (m, 4H), 2.02-2.11 (m, 2H), 2.52 (d, J=27.5 Hz, 4H), 3.32-3.36 (m, 2H), 3.40-3.46 (m, 2H), 3.51 (t, J=6.1 Hz, 2H), 3.95-4.01 (m, 2H), 4.06 (s, 2H), 7.19 (t, J=9.0 Hz, 1H), 7.29-7.34 (m, 1H), 7.36-7.41 (m, 1H).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[N:11]3[C:12]([CH3:15])=[N:13][N:14]=[C:10]3[C@H:9]([CH3:16])[CH2:8][N:7]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)[C:6]=2[CH:24]=1.[CH3:25][N:26]1[CH:31]=[C:30](B2OC(C)(C)C(C)(C)O2)[CH:29]=[CH:28][C:27]1=[O:41].C(=O)([O-])[O-].[Cs+].[Cs+].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(O)C>[Cl:23][C:20]1[CH:19]=[CH:18][C:17]([N:7]2[CH2:8][C@@H:9]([CH3:16])[C:10]3=[N:14][N:13]=[C:12]([CH3:15])[N:11]3[C:5]3[CH:4]=[CH:3][C:2]([C:30]4[CH:29]=[CH:28][C:27](=[O:41])[N:26]([CH3:25])[CH:31]=4)=[CH:24][C:6]2=3)=[CH:22][CH:21]=1
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)ccc1=O
Reactant: Cc1nnc2n1-c1ccc(Br)cc1N(c1ccc(Cl)cc1)C[C@H]2C
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: Cc1ccccc1
Solvent: O
Solvent: CCO
Product: Cc1nnc2n1-c1ccc(-c3ccc(=O)n(C)c3)cc1N(c1ccc(Cl)cc1)C[C@H]2C
Temperature: 100 °C
Reaction time: 16 h
Yield: 34.7 %

Procedure:
To a mixture of (R)-8-bromo-6-(4-chlorophenyl)-1,4-dimethyl-5,6-dihydro-4H-benzo[b][1,2,4]triazolo[4,3-d][1,4]diazepine (40.2 mg, 0.1 mmol), 1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2(1H)-one (44.2 mg, 0.2 mmol), tetrakis(triphenylphosphine)palladium(0) (12 mg, 0.01 mmol), cesium carbonate (98 mg, 0.3 mmol), toluene (2 mL), ethanol (1 mL) and water (3 drops) was stirred at 100° C. for 16 hours. The mixture was diluted with water (10 mL) and extracted with ethyl acetate (3*20 mL). The combined organic layers were washed with water (3*20 mL), brine (3*20 mL), dried over anhydrous sodium sulfate and filtered. The solvent was evaporated in vacuum, and then the residue was purified by column chromatography (silica gel, dichloromethane/methanol=15:1) to give (R)-5-(6-(4-chlorophenyl)-1,4-dimethyl-5,6-dihydro-4H-benzo[b][1,2,4]triazolo[4,3-d][1,4]diazepin-8-yl)-1-methylpyridin-2(1H)-one as a white solid (15 mg, 34.9%).
Reaction SMILES: Br[C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][C:5]([NH:12][C:13](=[O:15])[CH3:14])=[C:4]([F:16])[CH:3]=1.[C:17]([Cu])#[N:18].CCOC(C)=O>CN(C=O)C>[C:17]([C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][C:5]([NH:12][C:13](=[O:15])[CH3:14])=[C:4]([F:16])[CH:3]=1)#[N:18]
Reactant: N#C[Cu]
Reactant: CC(=O)Nc1cc(C(F)(F)F)c(Br)cc1F
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(=O)Nc1cc(C(F)(F)F)c(C#N)cc1F
Temperature: 150 °C
Yield: 56.9 %

Procedure:
A mixture of compound 23 (300 mg, 1 mmol), CuCN (355 mg, 4 mmol) in DMF (6 mL) was heated at 150° C. under N2 overnight. The reaction mixture was cooled to room temperature and then poured into ice water. EtOAc was added and the insoluble solid was filtered off (rinsed with EtOAc). The organic layer was separated, and the aqueous layer was extracted with EtOAc. The combined organic layers were washed with aq.NaHCO3 and brine, dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified with silica gel chromatography (PE:EtOAc=4:1) to afford the title compound 24 (140 mg, 28%) as a white solid. 1H NMR (400 MHz, CDCl3) δ8.99 (d, 1H, J=7.2 Hz), 7.55 (d, 1H, J=10.0 Hz), 2.92 (s, 3H).