Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][CH:2]([CH3:5])[CH2:3]O.[CH3:6][C:7]1[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][C:8]=1[NH2:9].[I-].[K+].ClCCl>O>[CH3:6][C:7]1[CH:13]=[CH:12][C:11]([C:14]([F:15])([F:16])[F:17])=[CH:10][C:8]=1[NH:9][CH2:1][CH:2]([CH3:5])[CH3:3]
Reactant: Cc1ccc(C(F)(F)F)cc1N
Reactant: CC(C)CO
Agent: [I-]
Agent: [K+]
Solvent: O
Solvent: ClCCl
Product: Cc1ccc(C(F)(F)F)cc1NCC(C)C
Yield: 36.7 %

Procedure:
2-methyl-1-propanol (0.556 mL, 6.00 mmol), 2-methyl-5-(trifluoromethyl)aniline (525 mg, 3 mmol), potassium iodide (996 mg, 6.00 mmol) and [Cp*IrCl2]2 (33.1 mg, 0.030 mmol) were dissolved in water (2 mL). The resulting mixture was irradiated under microwaves (CEM microwave) at 170° C. for 1 hour. To the reaction mixture was added dichloromethane (5 mL) and the crude material was purified by mass directed autoprep (250 mg scale ×3, Method C, formic acid modifier). Relevant fractions were combined and evaporated to give 2-methyl-N-(2-methylpropyl)-5-(trifluoromethyl)aniline (260 mg, 1.102 mmol, 36.7% yield) as a dark yellow oil.
Reaction SMILES: Cl.[NH2:2][CH:3]1[CH2:8][CH2:7][N:6]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:5][CH2:4]1.Cl[C:17](=[O:23])[CH2:18][C:19]([O:21][CH3:22])=[O:20].CCN(C(C)C)C(C)C>C(Cl)Cl>[CH3:22][O:21][C:19](=[O:20])[CH2:18][C:17]([NH:2][CH:3]1[CH2:4][CH2:5][N:6]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:7][CH2:8]1)=[O:23]
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Reactant: COC(=O)CC(=O)Cl
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COC(=O)CC(=O)NC1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 77.1 %

Procedure:
The mixture of tert-butyl 4-aminopiperidine-1-carboxylate hydrochloride (512 mg, 2.16 mmol), methyl 3-chloro-3-oxopropanoate (232 μL, 2.16 mmol), and DIPEA (828 μL, 4.75 mmol) in DCM (20 mL) was stirred at room temperature overnight. The solvent was removed under reduced pressure and the residue was purified by flash chromatography (eluent EtOAc) to afford tert-butyl 4-(3-methoxy-3-oxopropanamido)piperidine-1-carboxylate as a white solid (500 mg, 78%). MS (m/z): 301.1 (M+H). This material (500 mg, 1.67 mmol) was dissolved in MeOH/THF/H2O (2 mL/2 mL/1 mL), and LiOH×H2O (280 mg, 6.75 mmol) was added to the solution. The reaction mixture was stirred for 2 hrs, the solvent was removed under reduced pressure and the residue was purified by flash chromatography (eluent CH3Cl/MeOH/AcOH) to afford the title compound 42 (300 mg, 63% yield) as yellowish syrup. MS (m/z): 287.1 (M+H).
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:4]=[N:5][CH:6]=[CH:7][C:8]2[C:9]=1[N:10]=[C:11]1[C:16]=2[CH:15]=[CH:14][CH:13]=[CH:12]1.C(N(C(C)C)CC)(C)C.[CH2:26](Br)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.C(=O)([O-])[O-].[K+].[K+]>C(Cl)(Cl)Cl.O>[CH2:26]([N:5]1[CH2:6][CH2:7][C:8]2[C:16]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[NH:10][C:9]=2[CH:3]([CH2:2][OH:1])[CH2:4]1)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: OCc1cnccc2c3ccccc3nc1-2
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCN(C(C)C)C(C)C
Solvent: ClC(Cl)Cl
Solvent: O
Product: OCC1CN(Cc2ccccc2)CCc2c1[nH]c1ccccc21
Yield: 77.6 %

Procedure:
A solution of 7 g (0.0324 mol) of 5-hydroxymethylazepino[4,5-b]indole, of 5.02 g (0.0388 mol) of diisopropylethylamine, and of 6.67 g (0.0388 mol) of benzyl bromide in 150 ml of chloroform is heated under reflux for 10 hours. The reaction mixture is then drowned in water and alkalified with a saturated aqueous solution of potassium carbonate. The organic phase is separated off and the aqueous phase is again extracted twice with 100 ml portions of chloroform. The organic phases are combined, washed with water, dried over magnesium sulphate, filtered and evaporated to dryness under vacuum. The residue, recrystallized from ether, yields 7.7 g of product.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[NH:13][C:12]([O:14][CH3:15])=[N:11][C:10]([CH3:16])=[C:9]2[C:17]([O:19][CH3:20])=[O:18])=[CH:4][CH:3]=1.Cl[C:22]([O:24][C:25]1[CH:30]=[CH:29][C:28]([N+:31]([O-:33])=[O:32])=[CH:27][CH:26]=1)=[O:23]>CN(C)C1C=CN=CC=1.C(Cl)Cl>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]2[N:13]([C:22]([O:24][C:25]3[CH:26]=[CH:27][C:28]([N+:31]([O-:33])=[O:32])=[CH:29][CH:30]=3)=[O:23])[C:12]([O:14][CH3:15])=[N:11][C:10]([CH3:16])=[C:9]2[C:17]([O:19][CH3:20])=[O:18])=[CH:6][CH:7]=1
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Reactant: COC(=O)C1=C(C)N=C(OC)NC1c1ccc(F)cc1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: COC(=O)C1=C(C)N=C(OC)N(C(=O)Oc2ccc([N+](=O)[O-])cc2)C1c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of methyl 6-(4-fluorophenyl)-2-methoxy-4-methyl-1,6-dihydro-5-pyrimidinecarboxylate (1.76 g, 6.34 mmol) and 4-dimethylaminopyridine (12.7 mmol, 1.55 g) in anhydrous CH2Cl2 (20.0 mL) was added solution of 4-nitrophenyl chloroformate (4.47 g, 22.2 mmol) in CH2Cl2 (20.0 mL) at 23° C. The reaction mixture was stirred for 2 hours at room temperature. The reaction mixture was diluted with CH2Cl2 (50 mL), washed with water, brine, dried over sodium sulfate and concentrated in vacuo. The residue was purified by flash column chromatography (hexanesiethyl acetate 4:1). The product was obtained as yellow syrup, which upon trituration with hexanes became a white powder (2.40 g, 84.3%). The crude product was used in next step without further purification.
Reaction SMILES: [N:1]1[CH:6]=[C:5]([C:7]([OH:9])=[O:8])[CH:4]=[CH:3][C:2]=1[C:10]([OH:12])=[O:11].[C:13]([O:23][CH3:24])(=[O:22])[CH:14]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)O>>[N:1]1[CH:6]=[C:5]([C:7]([O:9][CH:14]([C:13]([O:23][CH3:24])=[O:22])[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[O:8])[CH:4]=[CH:3][C:2]=1[C:10]([O:12][CH:14]([C:13]([O:23][CH3:24])=[O:22])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:11]
Reactant: O=C(O)c1ccc(C(=O)O)nc1
Reactant: COC(=O)C(O)c1ccccc1
Product: COC(=O)C(OC(=O)c1ccc(C(=O)OC(C(=O)OC)c2ccccc2)nc1)c1ccccc1

Procedure:
Analogously to Example 1, 10 g of pyridine-2,5-dicarboxylic acid are converted into the acid chloride and this is reacted with 19.9 g of methyl (±)-mandelate. After extraction, working up is carried out by chromatography over silica gel with a mixture of toluene and ethyl acetate as the mobile phase.
Reaction SMILES: Cl.[O:2]1[C:10]2[CH2:9][CH2:8][NH:7][CH2:6][C:5]=2[CH:4]=[CH:3]1.[CH2:11]([O:18][C:19]1[CH:24]=[CH:23][C:22]([CH2:25][C:26](O)=[O:27])=[CH:21][C:20]=1[O:29][CH3:30])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(N(CC)CC)C.C(P(=O)(OCC)OCC)#N>ClCCl.O>[CH2:11]([O:18][C:19]1[CH:24]=[CH:23][C:22]([CH2:25][C:26]([N:7]2[CH2:8][CH2:9][C:10]3[O:2][CH:3]=[CH:4][C:5]=3[CH2:6]2)=[O:27])=[CH:21][C:20]=1[O:29][CH3:30])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: c1cc2c(o1)CCNC2
Reactant: COc1cc(CC(=O)O)ccc1OCc1ccccc1
Agent: CCOP(=O)(C#N)OCC
Agent: Cl
Solvent: ClCCl
Solvent: O
Solvent: CCN(CC)CC
Product: COc1cc(CC(=O)N2CCc3occc3C2)ccc1OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 0.160 g (1.000 mmol) of 4,5,6,7-tetrahydrofuro[3,2-c]pyridine hydrochloride, 0.33 g (1.2 mmol) of 4-benzyloxy-3-methoxyphenylacetic acid and 0.55 ml (4.0 mmol) of triethylamine in 30 ml of dichloromethane, 0.24 g (1.5 mmol) of diethyl cyanophosphonate was added dropwise under ice-cooling, followed by overnight stirring at room temperature. The reaction mixture was poured into water and extracted with dichloromethane 2 times. The combined organic layer was washed with water and dried over anhydrous sodium sulfate; the solvent was distilled off under reduced pressure. The resulting crude product was purified by silica gel column chromatography (hexane/ethyl acetate=3/1 to 2/1) to yield the desired product.
Reaction SMILES: CO[C:3](=[O:22])[CH:4]([C:11]1[CH:16]=[CH:15][C:14]([S:17]([CH3:20])(=[O:19])=[O:18])=[C:13]([Cl:21])[CH:12]=1)[CH2:5][CH:6]1[CH2:10][CH2:9][CH2:8][CH2:7]1.C(OC(=O)C(C1C=CC(S(C)(=O)=O)=C(Cl)C=1)CC1CCCC1)C.[CH3:46][NH:47][C:48]([NH2:50])=[O:49].CO>C[O-].[Mg+2].C[O-]>[Cl:21][C:13]1[CH:12]=[C:11]([CH:4]([CH2:5][CH:6]2[CH2:7][CH2:8][CH2:9][CH2:10]2)[C:3]([NH:50][C:48]([NH:47][CH3:46])=[O:49])=[O:22])[CH:16]=[CH:15][C:14]=1[S:17]([CH3:20])(=[O:18])=[O:19]
Reactant: CNC(N)=O
Reactant: COC(=O)C(CC1CCCC1)c1ccc(S(C)(=O)=O)c(Cl)c1
Agent: CCOC(=O)C(CC1CCCC1)c1ccc(S(C)(=O)=O)c(Cl)c1
Agent: C[O-]
Agent: [Mg+2]
Solvent: CO
Product: CNC(=O)NC(=O)C(CC1CCCC1)c1ccc(S(C)(=O)=O)c(Cl)c1
Yield: 19 %

Procedure:
A solution of 2-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-propionic acid methyl ester and 2-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-propionic acid ethyl ester (268 mg) and methyl urea (110 mg, 1.5 mmol) in magnesium methoxide in methanol (7.4 wt %, 1.6 mL, 1.1 mmol) was heated to 100° C. for 8 h. At this time, the reaction was concentrated in vacuo. The residue was then dissolved in ethyl acetate (50 mL), filtered through a plug of silica gel, and washed with ethyl acetate (100 mL). The filtrate was concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230-400 mesh, 60/40 hexanes/ethyl acetate) afforded 1-[2-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-propionyl]-3-methyl-urea (55 mg, 19% yield) as a white foam: FAB-HRMS m/e calcd for C17H23ClN2O4S (M+H)+387.1145, found 387.1156.
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]([CH:8]([C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=2)[NH:9][CH:10]=O)[CH:5]=[CH:4][CH:3]=1>O=P(Cl)(Cl)Cl>[Br:1][C:2]1[N:7]2[CH:10]=[N:9][C:8]([C:12]3[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=3)=[C:6]2[CH:5]=[CH:4][CH:3]=1
Reactant: O=CNC(c1ccc(F)cc1)c1cccc(Br)n1
Solvent: O=P(Cl)(Cl)Cl
Product: Fc1ccc(-c2ncn3c(Br)cccc23)cc1
Reaction time: 1 h

Procedure:
A stirred mixture of N-[(6-bromopyridin-2-yl)-(4-fluorophenyl)-methyl]-formamide (6.4 g, 21 mmol) in POCl3 (41 mL) is warmed at reflux. After 1 hour, the reaction mixture is cautiously quenched by a slow addition to saturated aqueous NaHCO3 and the mixture is extracted into EtOAc (3×200 mL). The combined organic layers are dried over Na2SO4 and concentrated. The crude material is purified by silica gel chromatography eluting with 30% EtOAc in hexanes to afford 5-bromo-1-(4-fluorophenyl)-imidazo[1,5-a]pyridine.
Reaction SMILES: Cl[C:2]([C:5]1[CH:6]=[C:7]([CH:29]=[C:30]([OH:32])[CH:31]=1)[CH2:8][NH:9][CH2:10][C@@H:11]([OH:28])[C@@H:12]([NH:20]C(=O)OC(C)(C)C)[CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([CH3:4])[CH3:3].FC(F)(F)C(O)=O>C(Cl)Cl>[NH2:20][C@@H:12]([CH2:13][C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)[C@H:11]([OH:28])[CH2:10][NH:9][CH2:8][C:7]1[CH:29]=[C:30]([OH:32])[CH:31]=[C:5]([C:2]([CH3:4])=[CH2:3])[CH:6]=1
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)[C@H](O)CNCc1cc(O)cc(C(C)(C)Cl)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: C=C(C)c1cc(O)cc(CNC[C@@H](O)[C@@H](N)Cc2ccccc2)c1

Procedure:
A solution of 27.5 mg of tert-butyl (2S,3R)-4-(3-(2-chloropropan-2-yl)-5-hydroxybenzylamino)-3-hydroxy-1-phenylbutan-2-ylcarbamate and 0.8 mL of trifluoroacetic acid in 2 mL of CH2Cl2 was stirred at r.t. for 1 h and then concentrated. The 3-(((2R,3S)-3-amino-2-hydroxy-4-phenylbutylamino)methyl)-5-(prop-1-en-2-yl)phenol amine salt was used in the next reaction without further purification.
Reaction SMILES: [NH:1]([C:13]([O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:14])[C@H:2]([C@H:7]([CH2:9][C:10]([OH:12])=O)[OH:8])[CH2:3][CH:4]([CH3:6])[CH3:5].[NH2:23][C@H:24]([C:29]([NH:31][C@H:32]([C:39]([NH:41][C@H:42]([C:55]([O:57][CH3:58])=[O:56])[CH2:43][CH2:44][CH2:45][CH2:46][NH:47][C:48]([O:50][C:51]([CH3:54])([CH3:53])[CH3:52])=[O:49])=[O:40])[CH2:33][C:34]1[N:38]=[CH:37][NH:36][CH:35]=1)=[O:30])[C@H:25]([CH2:27][CH3:28])[CH3:26].C1C=CC2N(O)N=NC=2C=1.C1CCC(N=C=NC2CCCCC2)CC1>CN(C=O)C.O>[NH:1]([C:13]([O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:14])[C@H:2]([C@H:7]([CH2:9][C:10]([NH:23][C@H:24]([C:29]([NH:31][C@H:32]([C:39]([NH:41][C@H:42]([C:55]([O:57][CH3:58])=[O:56])[CH2:43][CH2:44][CH2:45][CH2:46][NH:47][C:48]([O:50][C:51]([CH3:52])([CH3:53])[CH3:54])=[O:49])=[O:40])[CH2:33][C:34]1[N:38]=[CH:37][NH:36][CH:35]=1)=[O:30])[C@H:25]([CH2:27][CH3:28])[CH3:26])=[O:12])[OH:8])[CH2:3][CH:4]([CH3:5])[CH3:6]
Reactant: CC[C@H](C)[C@H](N)C(=O)N[C@@H](Cc1c[nH]cn1)C(=O)N[C@@H](CCCCNC(=O)OC(C)(C)C)C(=O)OC
Reactant: CC(C)C[C@H](NC(=O)OCc1ccccc1)[C@@H](O)CC(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Product: CC[C@H](C)[C@H](NC(=O)C[C@H](O)[C@H](CC(C)C)NC(=O)OCc1ccccc1)C(=O)N[C@@H](Cc1c[nH]cn1)C(=O)N[C@@H](CCCCNC(=O)OC(C)(C)C)C(=O)OC
Reaction time: 20 h

Procedure:
900 mg of Z-Sta-OH (for manufacture see stage 1.12), 1.24 g of H-Ile-His-Lys(Boc)-OMe and 560 mg of HOBt×H2O are dissolved in 13 ml of DMF. After the addition of 600 mg of DCCI, the whole is left to stand at room temperature for 20 hours, then the DCH which has crystallised out is filtered off and the filtrate is concentrated to dryness. The greasy residue is triturated at 0° with 30 ml of diisopropyl ether, the solvent is decanted and the residue is dried. Purification is carried out by Craig partitioning in the system methanol/buffer/ethylene chloride/chloroform (10:3:8:4; buffer=14.3 ml of glacial acetic acid and 9.6 g of ammonium acetate in 1000 ml of H2O) over 700 stages. The thin layer chromatographically pure fractions (K=0.5) are combined, strongly concentrated and lyophilised. To remove acetic acid, the product is dissolved and reprecipitated from 5% strength methanolic NaHCO3 solution, yielding Z-Sta-Ile-His-Lys(Boc)-OMe in the form of amorphous powder; Rf (B)=0.8; Rf (I)=0.56.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH:3]([CH2:7][NH:8][C:9]([C:11]2[C:15]3[N:16]=[CH:17][N:18]=[C:19]([C:20]4[C:28]5[O:27][CH2:26][O:25][C:24]=5[CH:23]=[CH:22][C:21]=4[O:29][CH2:30][CH:31]4[CH2:33][CH2:32]4)[C:14]=3[NH:13][CH:12]=2)=[O:10])[CH2:2]1.[CH:34](OC(=O)C)=[O:35]>>[CH:34]([N:1]1[CH2:6][CH2:5][O:4][CH:3]([CH2:7][NH:8][C:9]([C:11]2[C:15]3[N:16]=[CH:17][N:18]=[C:19]([C:20]4[C:28]5[O:27][CH2:26][O:25][C:24]=5[CH:23]=[CH:22][C:21]=4[O:29][CH2:30][CH:31]4[CH2:32][CH2:33]4)[C:14]=3[NH:13][CH:12]=2)=[O:10])[CH2:2]1)=[O:35]
Reactant: CC(=O)OC=O
Reactant: O=C(NCC1CNCCO1)c1c[nH]c2c(-c3c(OCC4CC4)ccc4c3OCO4)ncnc12
Product: O=CN1CCOC(CNC(=O)c2c[nH]c3c(-c4c(OCC5CC5)ccc5c4OCO5)ncnc23)C1

Procedure:
Starting from 4-(5-Cyclopropylmethoxy-benzo[1,3]dioxol-4-yl)-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylic acid (morpholin-2-ylmethyl)-amide (example A147) and acetic formic anhydride the title compound is obtained as colorless solid.
Reaction SMILES: [CH3:1][N:2]1[CH2:27][CH2:26][C:5]2[N:6]([CH2:14][C:15]([C:18]3[CH:19]=[CH:20][C:21]([C:24]#[N:25])=[N:22][CH:23]=3)([OH:17])[CH3:16])[C:7]3[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][C:12]=3[C:4]=2[CH2:3]1.[OH-:28].[K+]>C(O)(C)(C)C.[Cl-].[Na+].O>[CH3:1][N:2]1[CH2:27][CH2:26][C:5]2[N:6]([CH2:14][C:15]([C:18]3[CH:19]=[CH:20][C:21]([C:24]([NH2:25])=[O:28])=[N:22][CH:23]=3)([OH:17])[CH3:16])[C:7]3[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][C:12]=3[C:4]=2[CH2:3]1
Reactant: [OH-]
Reactant: Cc1ccc2c(c1)c1c(n2CC(C)(O)c2ccc(C#N)nc2)CCN(C)C1
Agent: [Cl-]
Agent: [K+]
Agent: [Na+]
Solvent: CC(C)(C)O
Solvent: O
Product: Cc1ccc2c(c1)c1c(n2CC(C)(O)c2ccc(C(N)=O)nc2)CCN(C)C1
Temperature: 80 °C

Procedure:
A mixture of 5-(1-(2,8-dimethyl-3,4-dihydro-1H-pyrido[4,3-b]indol-5(2H)-yl)-2-hydroxypropan-2-yl)picolinonitrile (300 mg, 0.833 mmol), crushed KOH (140 mg, 2.499 mmol) in 12 mL tert-butanol was heated at 80° C. for 2 h. The reaction was monitored by TLC. The reaction mixture was allowed to cool at RT, diluted with brine (30 mL) and extracted with ethyl acetate (2×100 mL). The combined organic layer was washed with water (3×100 mL), dried over anhydrous sodium sulfate and concentrated to obtain the crude product, which was purified by Preparative HPLC followed by chiral HPLC to obtain 5-(1-(1,2,3,4-tetrahydro-2,8-dimethylpyrido[4,3-b]indol-5-yl)-2-hydroxypropan-2-yl)pyridine-2-carboxamide. 1H NMR (CDCl3, freebase) δ (ppm): 8.49 (s, 1H), 8.04 (d, 1H), 7.86 (d, 1H), 7.66 (s, 1H), 7.01 (s, 1H), 6.85 (s, 1H), 6.78 bs (NH), 5.48 s (OH), 4.16 (dd, 2H), 3.44 (q, 2H), 2.9 (m, 2H), 2.7 (m, 2H), 2.45 (s, 3H), 2.35 (s, 3H), 2.35 (s, 3H), 1.6 (s, 3H). Separation by chiral HPLC provided enantiomers II-136a-b.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6](I)[CH:5]=[CH:4][N:3]=1.[Cl:9][C:10]1[CH:17]=[CH:16][C:13]([CH2:14][OH:15])=[CH:12][CH:11]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>C1(C)C=CC=CC=1.[Cu]I>[Cl:1][C:2]1[CH:7]=[C:6]([O:15][CH2:14][C:13]2[CH:16]=[CH:17][C:10]([Cl:9])=[CH:11][CH:12]=2)[CH:5]=[CH:4][N:3]=1
Reactant: OCc1ccc(Cl)cc1
Reactant: Clc1cc(I)ccn1
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: Cc1ccccc1
Product: Clc1ccc(COc2ccnc(Cl)c2)cc1
Temperature: 105 °C
Yield: 56.2 %

Procedure:
A mixture of 2-chloro-4-iodopyridine (5.0 g, 21 mmol), 4-chlorobenzyl alcohol (3.3 g, 23 mmol), cesium carbonate (8.9 g, 27 mmol), CuI (4.0 g, 21 mmol) and phenanthronine (0.76 g, 4.2 mmol) in toluene (20.0 mL) was purged with nitrogen for 10 min. The reaction mixture was heated at 105° C. overnight and then cooled and diluted with EtOAc. The resulting solution was washed with brine, passed through a pad of celite and concentrated under reduced pressure. The resulting residue was purified by flash column chromatography (hexanes/EtOAc 100% to 70%) to give the title compound (3.0 g, 56%): 1H NMR (500 MHz, CDCl3) δ 8.21 (d, J=6.0 Hz, 1H), 7.39 (d, J=8.5 Hz, 2H), 7.32 (d, J=8.5 Hz, 2H), 6.90 (d, J=2.0 Hz, 1H), 6.80 (dd, J=6.0, 2.0 Hz, 1H), 4.07 (s, 2H).
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([S:9]([NH:12][C:13]2[C:22]([NH:23][C:24]3[CH:29]=[C:28]([O:30][CH3:31])[CH:27]=[C:26]([O:32][CH3:33])[C:25]=3[O:34][CH2:35][CH2:36][CH2:37][OH:38])=[N:21][C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[N:14]=2)(=[O:11])=[O:10])=[CH:5][CH:4]=1.[C:39](O)(=[O:41])[CH3:40].O>CN(C=O)C>[OH:38][CH2:37][CH2:36][CH2:35][O:34][C:25]1[C:26]([O:32][CH3:33])=[CH:27][C:28]([O:30][CH3:31])=[CH:29][C:24]=1[NH:23][C:22]1[C:13]([NH:12][S:9]([C:6]2[CH:7]=[CH:8][C:3]([CH2:2][NH:1][C:39](=[O:41])[CH3:40])=[CH:4][CH:5]=2)(=[O:11])=[O:10])=[N:14][C:15]2[C:20]([N:21]=1)=[CH:19][CH:18]=[CH:17][CH:16]=2
Reactant: COc1cc(Nc2nc3ccccc3nc2NS(=O)(=O)c2ccc(CN)cc2)c(OCCCO)c(OC)c1
Reactant: CC(=O)O
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc(Nc2nc3ccccc3nc2NS(=O)(=O)c2ccc(CNC(C)=O)cc2)c(OCCCO)c(OC)c1
Yield: 41 %

Procedure:
100 mg of 4-aminomethyl-N-{3-[2-(3-hydroxypropoxy)-3,5-dimethoxyphenylamino]-quinoxalin-2-yl}benzenesulfonamide (content 82%), 37 mg of DAPECI and 8.7 l of acetic acid in 1 ml of DMF are stirred at RT overnight in a screw-cap vial. The reaction solution is poured into water, and the deposited precipitate is filtered off with suction. Purification by preparative HPLC on silica gel RP18 (acetonitrile, water) gives a total of 39 mg of N-(4-{3-[2-(3-hydroxypropoxy)-3,5-dimethoxyphenylamino]quinoxalin-2-ylsulfamoyl}benzyl)acetamide (yield 41%); MS-FAB (M+H+)=582.2; Rf (polar method): 2.19 min.
Reaction SMILES: [CH3:1][C:2]1([CH2:8][O:9][C:10]([NH:12][C:13]2[C:14](=[O:39])[N:15]([CH2:25][C:26]([NH:28][CH:29]([CH:36]([CH3:38])[CH3:37])[C:30](=[O:35])[C:31]([F:34])([F:33])[F:32])=[O:27])[C:16]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[CH:17][CH:18]=2)=[O:11])[CH2:7][O:6]C[O:4][CH2:3]1.B(Cl)(Cl)Cl>C(Cl)Cl>[OH:6][CH2:7][C:2]([CH2:3][OH:4])([CH3:1])[CH2:8][O:9][C:10]([NH:12][C:13]1[C:14](=[O:39])[N:15]([CH2:25][C:26]([NH:28][CH:29]([CH:36]([CH3:38])[CH3:37])[C:30](=[O:35])[C:31]([F:33])([F:34])[F:32])=[O:27])[C:16]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[CH:17][CH:18]=1)=[O:11]
Reactant: CC(C)C(NC(=O)Cn1c(-c2ccccc2)ccc(NC(=O)OCC2(C)COCOC2)c1=O)C(=O)C(F)(F)F
Agent: ClB(Cl)Cl
Solvent: ClCCl
Product: CC(C)C(NC(=O)Cn1c(-c2ccccc2)ccc(NC(=O)OCC(C)(CO)CO)c1=O)C(=O)C(F)(F)F
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 73 %

Procedure:
To a solution of 2-[3-(5-methyl-1,3-dioxacyclohex-5-ylmethoxy-carbonylamino)-2-oxo-6-phenyl-1,2-dihydro-1-pyridyl]-N-(3,3,3-trifluoro-1-isopropyl-2-oxopropyl)acetamide (0.35 g) in methylene chloride (6 mL), cooled to 0° C. , was added dropwise 1.27 mL of a 10M methylene chloride solution of boron trichloride, and the reaction mixture allowed to warm to room temperature over 30 min. The reaction mixture was quenched by pouring into 25 mL of a 15% aqueous sodium chloride solution and stirring 15 min. Ethyl acetate (10 mL) was added, and the organic phase washed with brine, dried (MgSO4) and evaporated. Chromatography, using as eluant methylene chloride:methanol (20:1), followed by overnight vacuum-drying (50° C. at 27 Pa) yielded the title compound as a white solid (0.25 g); mp 94°-97° C. (dec); TLC: Rf =0.11, dichloromethane:methanol (95:5); 300 MHz NMR: 0.80 (s,3), 0.85 (s,3), 2.15 (m,1), 3.32 (2d,4), 3.98 (s,2), 4.4-4.6 (m,4), 4.65 (t,]), 6.25 (dd,1), 7.43 (m,5), 7.90 (d,1), 8.40 (d,1), 8.75 (d,1); IR(KBr): 3400 (broad), 2980, 1700, 1650, 1600, 1525, 1215 cm-1 ; MS: m/z=542(M+1).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([S:12]([CH3:15])(=[O:14])=[O:13])=[C:5]2[NH:16][C@H:17]1[CH2:22][CH2:21][C@H:20]([CH2:23][N:24]([CH3:26])[CH3:25])[CH2:19][CH2:18]1.[Cl:27][C:28]1[CH:33]=[C:32](B2OC(C)(C)C(C)(C)O2)[CH:31]=[C:30]([F:43])[C:29]=1[OH:44].C1(N)C(F)=C(F)C(F)=C(N)C=1F.Cl.Cl>>[ClH:1].[ClH:27].[Cl:27][C:28]1[CH:33]=[C:32]([C:2]2[N:3]=[C:4]3[C:9](=[CH:10][CH:11]=2)[N:8]=[CH:7][C:6]([S:12]([CH3:15])(=[O:13])=[O:14])=[C:5]3[NH:16][C@H:17]2[CH2:22][CH2:21][C@H:20]([CH2:23][N:24]([CH3:25])[CH3:26])[CH2:19][CH2:18]2)[CH:31]=[C:30]([F:43])[C:29]=1[OH:44]
Reactant: CN(C)C[C@H]1CC[C@H](Nc2c(S(C)(=O)=O)cnc3ccc(Cl)nc23)CC1
Reactant: CC1(C)OB(c2cc(F)c(O)c(Cl)c2)OC1(C)C
Agent: Cl
Agent: Nc1c(F)c(N)c(F)c(F)c1F
Product: CN(C)C[C@H]1CC[C@H](Nc2c(S(C)(=O)=O)cnc3ccc(-c4cc(F)c(O)c(Cl)c4)nc23)CC1

Procedure:
Following general procedure II, 6-chloro-N-{trans-4-[(dimethylamino)methyl]-cyclohexyl}-3-(methylsulfonyl)-1,5-naphthyridin-4-amine (61 mg, 0.15 mmol) was reacted with 2-chloro-6-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (63 mg, 0.23 mmol) followed by formation of the dihydrochloride salt to afford the desired product (52 mg, 59%) as a light yellow solid: 1H NMR (500 MHz, CD3OD) δ 8.90 (s, 1H), 8.50 (d, J=8.9 Hz, 1H), 8.35 (d, J=9.0 Hz, 1H), 8.04 (t, J=1.8 Hz, 1H), 7.90 (dd, J=11.5, 2.2 Hz, 1H), 5.77-5.67 (m, 1H), 3.38 (s, 3H), 3.09 (d, J=6.6 Hz, 2H), 2.94 (s, 6H), 2.51-2.44 (m, 2H), 2.08-1.97 (m, 3H), 1.76-1.64 (m, 2H), 1.46-1.34 (m, 2H). ESI MS m/z 507 [M+H]+; HPLC 99.0% (AUC), tR=9.81 min.
Reaction SMILES: C(OC([NH:11][C@H:12]1[CH2:17][CH2:16][N:15]([C:18]2[CH:19]=[C:20]([CH:25]=[CH:26][CH:27]=2)[C:21]([O:23][CH3:24])=[O:22])[CH2:14][C@H:13]1[O:28][CH2:29][CH3:30])=O)C1C=CC=CC=1>[C].[Pd]>[NH2:11][C@H:12]1[CH2:17][CH2:16][N:15]([C:18]2[CH:19]=[C:20]([CH:25]=[CH:26][CH:27]=2)[C:21]([O:23][CH3:24])=[O:22])[CH2:14][C@H:13]1[O:28][CH2:29][CH3:30]
Reactant: CCO[C@@H]1CN(c2cccc(C(=O)OC)c2)CC[C@@H]1NC(=O)OCc1ccccc1
Agent: [Pd]
Product: CCO[C@@H]1CN(c2cccc(C(=O)OC)c2)CC[C@@H]1N
Yield: 22.7 %

Procedure:
The same operation as in Example (160c) was performed using methyl cis(±)-3-(4-{[(benzyloxy)carbonyl]amino}-3-ethoxypiperidin-1-yl)benzoate obtained in Example (48c) (155 mg, 0.38 mmol) and a 10% palladium-carbon catalyst (200 mg), to obtain 24 mg of the title compound as a pale yellow oily substance. The resulting compound was used for the next reaction without purification.