Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[NH:3]1[CH:7]=[N:6][CH:5]=[N:4]1.[F:8][C:9]1[CH:14]=[C:13]([F:15])[CH:12]=[CH:11][C:10]=1[C@:16]1([O:36][CH2:35]1)[C@H:17]([N:19]1[CH:23]=[CH:22][N:21]([C:24]2[CH:29]=[CH:28][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:26][CH:25]=2)[C:20]1=[O:34])[CH3:18].O>CN(C)C=O.C(OCC)(=O)C>[F:8][C:9]1[CH:14]=[C:13]([F:15])[CH:12]=[CH:11][C:10]=1[C@:16]([OH:36])([CH2:35][N:3]1[CH:7]=[N:6][CH:5]=[N:4]1)[C@H:17]([N:19]1[CH:23]=[CH:22][N:21]([C:24]2[CH:29]=[CH:28][C:27]([C:30]([F:31])([F:33])[F:32])=[CH:26][CH:25]=2)[C:20]1=[O:34])[CH3:18]
Reactant: C[C@@H](n1ccn(-c2ccc(C(F)(F)F)cc2)c1=O)[C@@]1(c2ccc(F)cc2F)CO1
Reactant: c1nc[nH]n1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: C[C@@H](n1ccn(-c2ccc(C(F)(F)F)cc2)c1=O)[C@@](O)(Cn1cncn1)c1ccc(F)cc1F
Temperature: 25 °C
Yield: 82.8 %

Procedure:
60% Sodium hydride in oil (65 mg) was dispersed in 4 ml of dimethylformamide, and 118 mg of 1,2,4-triazole was added thereto with ice cooling. The resulting mixture was stirred at room temperature for ten minutes. The solution of 362 mg of 1-[(1R,2S)-2-(2,4-difluorophenyl)-2,3-epoxy-1-methylpropyl]-3-(4-trifluoromethylphenyl)-2(1H,3H)-imidazolone prepared hereinabove in 2 ml of dimethylformamide was added thereto and the resulting mixture was heated at 50° C. for five hours. After cooling, to the reaction solution was added 8 ml of cold water and 40 ml of ethyl acetate to fractionate and the aqueous layer was extracted with ethyl acetate twice. The ethyl acetate layers were combined, washed with water and a saturated aqueous solution of sodium chloride successively, dried over anhydrous magnesium sulfate and distilled off under reduced pressure. The residue was purified by silica gel chromatography (eluent: ethyl acetate/hexane=1/1 to 2/1 to ethyl acetate) to give 350 mg of 1-[(1R,2S)-2-(2,4-difluorophenyl)-2-hydroxy-1-methyl-3-(1H-1,2,4-triazol-1-yl)propyl]-3-(4-trifluoromethylphenyl)-2(1H,3H) -imidazolone as a colorless powder.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1C(Cl)=O.[F:11][C:12]1[CH:13]=[C:14]([OH:19])[CH:15]=[CH:16][C:17]=1[F:18].CN(C)[CH:22]=[O:23].N1C=CC=CC=1>O>[Br:1][C:2]1[CH:10]=[CH:9][C:8]([C:22]([O:19][C:14]2[CH:15]=[CH:16][C:17]([F:18])=[C:12]([F:11])[CH:13]=2)=[O:23])=[CH:7][CH:3]=1
Reactant: Oc1ccc(F)c(F)c1
Reactant: O=C(Cl)c1ccccc1Br
Reactant: CN(C)C=O
Solvent: c1ccncc1
Solvent: O
Product: O=C(Oc1ccc(F)c(F)c1)c1ccc(Br)cc1
Temperature: 70 °C

Procedure:
120 g of thionyl chloride was added to 100 g of 4-bromobenzoic acid and the mixture was heated at 90° C. While stirring for 6 hours. After the reaction, an excess amount of thionyl chloride was removed by evaporation. 85 g of bromobenzoic acid chloride was obtained by vacuum distillation at about 20 mmHg in a distillation temperature range of 190-200° C. The bromobenzoic acid chloride was added dropwise to a solution prepared from 50 g of 3,4-difluorophenol, 150 ml of dimethylformamide, and 31 g of pyridine over about one hour while stirring at a temperature below 30° C. The mixture was then heated to 70° C. and stirred for 10 hours, and poured into a 10-fold amount of water to produce crystals. The crystals were collected by filtration, washed with dilute HCl and then water, dried in vacuum at 40° C., and recrystallized from ethyl acetate to obtain 50 g or 3,4-difluorophenyl 4-bromobenzoate. To this were added 40 g of 4-propylcyclohexylphenylacetylene, 0.11 g of bis(triphenylphosphine)palladium(II) chloride, 0.12 g of copper iodide, 0.96 g of triphenylphosphine, and 400 ml of triethylamine, followed by stirring for 10 hours while heating at 90° C. After the reaction, the reaction product was poured into a 10-fold amount of water to produce crystals. The crystals were collected by filtration, washed with water, dried in vacuum at 40° C., and recrystallized from a mixed solvent of ethyl acetate and methanol to obtain 43 g of a compound of the following formula. This compound had a nematic liquid crystal phase, a C-N point (crystal-nematic phase transition temperature) of 104° C., and an N-I point of 235° C. The IR spectrum of this compound had peaks (cm−1) at 3030, 2921, 2217, 1735, 1518, 1246, 1178, 1145, and 1107.
Reaction SMILES: Br[C:2]1[C:11]2[C:6](=[C:7]([Cl:13])[CH:8]=[C:9]([OH:12])[CH:10]=2)[N:5]=[C:4]([C:14]2[CH:19]=[CH:18][C:17]([OH:20])=[C:16]([F:21])[CH:15]=2)[CH:3]=1.[C:22]([C:24]1[CH:29]=[CH:28][C:27](B(O)O)=[CH:26][CH:25]=1)#[N:23]>>[Cl:13][C:7]1[CH:8]=[C:9]([OH:12])[CH:10]=[C:11]2[C:6]=1[N:5]=[C:4]([C:14]1[CH:19]=[CH:18][C:17]([OH:20])=[C:16]([F:21])[CH:15]=1)[CH:3]=[C:2]2[C:27]1[CH:28]=[CH:29][C:24]([C:22]#[N:23])=[CH:25][CH:26]=1
Reactant: Oc1cc(Cl)c2nc(-c3ccc(O)c(F)c3)cc(Br)c2c1
Reactant: N#Cc1ccc(B(O)O)cc1
Product: N#Cc1ccc(-c2cc(-c3ccc(O)c(F)c3)nc3c(Cl)cc(O)cc23)cc1
Yield: 94 %

Procedure:
This compound was prepared from 45a using 4-cyanophenylboronic acid according to method P. Yellow solid; Yield: 94%; mp 324° C. (dec.); 1H-NMR (400 MHz, DMSO-d6) δ 6.93 (d, J=2.5 Hz, 1H), 7.09 (dd, J=8.8, 8.8 Hz, 1H), 7.54 (d, J=2.6 Hz, 1H), 7.81 (d, J=8.4 Hz, 2H), 8.03 (s, 1H), 8.04 (dd, J=8.5, 1.6 Hz, 1H), 8.09 (d, J=8.4 Hz, 2H), 8.17 (dd, J=12.9, 2.1 Hz, 1H), 10.32 (s, 2H); 19F-NMR (400 MHz, DMSO-d6) δ −136.43 (dd, J=13.0, 9.7 Hz); MS (ESI) m/z 389/391 ([M−H]−), 391/393 ([M+H]+); Anal. Calcd for C22H12ClFN2O2: C: 67.62, H: 3.09, N: 7.17. Found: C: 67.00, H: 3.74, N: 6.64.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.C([Li])CCC.[C:13](OCC)(=[O:19])[C:14]([O:16][CH2:17][CH3:18])=[O:15]>CCOCC.CCCCCC>[N:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[C:13]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[O:19]
Reactant: CCOC(=O)C(=O)OCC
Reactant: Brc1ccccn1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: CCOCC
Product: CCOC(=O)C(=O)c1ccccn1
Reaction time: 0.5 h

Procedure:
To a stirred solution of 20 mL (210 mmol) of 2-bromopyridine in 500 mL of dry ether at −78° C. under Ar was added 85 mL of a 2.5 M solution of n-butyllithium in hexane in a slow stream. After stirring in the cold for 30 min, the solution was transferred over a 5 min period via two cannula into a 0° C. stirred solution of 100 mL (736 mmol) of diethyl oxalate in 1.0 L of dry ether under Ar. After stirring for 2 h in the cold, the reaction mixture was washed with 600 mL of sat. NaHCO3, water, and brine. The solution was dried over MgSO4 and the solvents concentrated at reduced pressure to give a red oil that was purified by SiO2 chromatography (10×15 cm) using 1:4 to 35:65 EtOAc-hexanes. The product-containing fractions were concentrated at reduced pressure to afford 6-1 as a reddish oil: 1H NMR (CDCl3) δ 1.42 (t, 3H), 4.45-4.55 (m, 2H), 7.55-7.6 (m, 1H), 7.9-7.95 (m, 1H), 8.11 (d, 1H), 8.78 (d, 1H).
Reaction SMILES: CS(O[CH2:6][C:7]1[C:12]([CH3:13])=[C:11]([O:14][CH2:15][CH2:16][CH2:17][O:18][CH2:19][CH2:20][O:21][CH3:22])[CH:10]=[CH:9][N:8]=1)(=O)=O.[SH:23][C:24]1[NH:28][C:27]2[CH:29]=[CH:30][CH:31]=[CH:32][C:26]=2[N:25]=1.C(=O)([O-])O.[Na+]>C(O)C>[CH3:22][O:21][CH2:20][CH2:19][O:18][CH2:17][CH2:16][CH2:15][O:14][C:11]1[CH:10]=[CH:9][N:8]=[C:7]([CH2:6][S:23][C:24]2[NH:28][C:27]3[CH:29]=[CH:30][CH:31]=[CH:32][C:26]=3[N:25]=2)[C:12]=1[CH3:13]
Reactant: COCCOCCCOc1ccnc(COS(C)(=O)=O)c1C
Reactant: Sc1nc2ccccc2[nH]1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: COCCOCCCOc1ccnc(CSc2nc3ccccc3[nH]2)c1C
Temperature: 25 °C
Reaction time: 1 h
Yield: 70.1 %

Procedure:
A mixture comprising 1.9 g of crude [4-{3-(2-methoxyethoxy)propoxy}-3-methylpyridine-2-yl]methyl methanesulfonate, 0.83 g of 2-mercapto-1H-benzimidazole and 20 ml of ethanol was stirred at a room temperature for one hour, made basic with a saturated aqueous solution of sodium hydrogencarbonate and extracted with chloroform. The extract was dried over magnesium sulfate and distilled under a reduced pressure. The obtained residue was chromatographed over a silica gel column and eluted with ethyl acetate/n-hexane to obtain 1.5 g of an oily product.
Reaction SMILES: Cl.[NH2:2][C:3]1([C:6]#[N:7])[CH2:5][CH2:4]1.C(N(C(C)C)C(C)C)C.[Cl:17][C:18]1[CH:26]=[CH:25][C:24]([N:27]([CH3:44])[C:28]([C:30]2[N:34]([CH3:35])[N:33]=[C:32]([C:36]([F:39])([F:38])[F:37])[C:31]=2[C:40]([F:43])([F:42])[F:41])=[O:29])=[CH:23][C:19]=1[C:20](Cl)=[O:21]>ClCCl.C(OCC)(=O)C>[Cl:17][C:18]1[CH:26]=[CH:25][C:24]([N:27]([CH3:44])[C:28]([C:30]2[N:34]([CH3:35])[N:33]=[C:32]([C:36]([F:39])([F:37])[F:38])[C:31]=2[C:40]([F:41])([F:42])[F:43])=[O:29])=[CH:23][C:19]=1[C:20](=[O:21])[NH:2][C:3]1([C:6]#[N:7])[CH2:5][CH2:4]1
Reactant: N#CC1(N)CC1
Reactant: CN(C(=O)c1c(C(F)(F)F)c(C(F)(F)F)nn1C)c1ccc(Cl)c(C(=O)Cl)c1
Agent: Cl
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CN(C(=O)c1c(C(F)(F)F)c(C(F)(F)F)nn1C)c1ccc(Cl)c(C(=O)NC2(C#N)CC2)c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
68.3 mg (0.58 mmol) of 1-aminocyclopropanecarbonitrile hydrochloride are initially charged in 5.0 ml of dichloromethane p.a., and 0.148 ml (0.86 mmol) of N-ethyldiisopropylamine and 156 mg of 2-chloro-5-(methyl{[1-methyl-3,4-bis(trifluoromethyl)-1H-pyrazol-5-yl]carbonyl}amino)benzoyl chloride (0.29 mmol) dissolved in 5.0 ml of dichloromethane p.a. are then added in succession. The reaction is stirred at room temperature for 16 hours. The reaction solution is diluted with 30 ml of ethyl acetate. The organic phase is washed twice with 1 N hydrochloric acid, once with 1 N aqueous sodium hydroxide solution and once with saturated sodium chloride solution. The organic phase is dried over magnesium sulphate and filtered and the solvent is removed on a rotary evaporator under reduced pressure.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].Cl.[N:8]1([CH2:14][C:15]2[CH:23]=[CH:22][C:18]([C:19](Cl)=[O:20])=[CH:17][CH:16]=2)[CH2:13][CH2:12][O:11][CH2:10][CH2:9]1.[NH2:24][C:25]1[C:26]2[CH:39]=[C:38]([C:40]([NH:42][N:43]([CH3:50])[C:44]3[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=3)=[O:41])[S:37][C:27]=2[N:28](C(OC(C)(C)C)=O)[N:29]=1>O1CCCC1>[CH3:50][N:43]([C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1)[NH:42][C:40]([C:38]1[S:37][C:27]2[NH:28][N:29]=[C:25]([NH:24][C:19](=[O:20])[C:18]3[CH:22]=[CH:23][C:15]([CH2:14][N:8]4[CH2:13][CH2:12][O:11][CH2:10][CH2:9]4)=[CH:16][CH:17]=3)[C:26]=2[CH:39]=1)=[O:41]
Reactant: O=C(Cl)c1ccc(CN2CCOCC2)cc1
Reactant: CN(NC(=O)c1cc2c(N)nn(C(=O)OC(C)(C)C)c2s1)c1ccccc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CN(NC(=O)c1cc2c(NC(=O)c3ccc(CN4CCOCC4)cc3)n[nH]c2s1)c1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 29.1 %

Procedure:
193 mg (1.39 mmol) of potassium carbonate, followed by 240 mg (0.87 mmol) of 4-morpholin-4-ylmethylbenzoyl chloride hydrochloride, are added to a solution of 0.27 g (0.70 mmol) of tert-butyl 3-amino-5-(N′-methyl-N′-phenylhydrazinocarbonyl)-thieno[2,3-c]pyrazole-1-carboxylate in 20 mL of tetrahydrofuran under argon. The reaction mixture is stirred at a temperature in the region of 25° C. for 2 hours, and then refluxed for 4 hours. The reaction mixture is then cooled to a temperature in the region of 25° C., and then treated with 40 mL of ice-cold water. The mixture is extracted successively with 60 mL, and then with twice 40 mL of ethyl acetate. The organic phases are combined, washed twice with 40 mL of saturated brine, dried over magnesium sulfate, filtered and then concentrated to dryness under vacuum (2 kPa) at a temperature in the region of 40° C. The residue is purified by chromatography on a cartridge of 25 g of silica gel (0.015-0.040 mm), eluting successively with pure dichloromethane, and then with dichloromethane/methanol mixtures (99/1 by volume, and then 98.5/1.5, 98/2 and finally 97/3) at a flow rate of 10 mL/min. The fractions containing the expected product are combined and then concentrated to dryness under reduced pressure (0.6 kPa) at a temperature in the region of 30° C. 0.1 g of N-[5-(N′-methyl-N′-phenylhydrazinocarbonyl)-1H-thieno[2,3-c]pyrazol-3-yl]-4-morpholin-4-ylmethylbenzamide is thus obtained in the form of an off-white solid melting at 190° C.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[N:11][N:12]([C:15]3[CH:23]=[CH:22][C:18]([C:19](O)=[O:20])=[CH:17][N:16]=3)[C:13]=2[OH:14])=[C:5]([CH3:24])[CH:4]=1)#[N:2].Cl.Cl.[CH3:27][C@H:28]1[CH2:33][NH:32][CH2:31][CH2:30][N:29]1[CH2:34][CH2:35][CH3:36]>>[OH:14][C:13]1[N:12]([C:15]2[CH:23]=[CH:22][C:18]([C:19]([N:32]3[CH2:31][CH2:30][N:29]([CH2:34][CH2:35][CH3:36])[C@@H:28]([CH3:27])[CH2:33]3)=[O:20])=[CH:17][N:16]=2)[N:11]=[CH:10][C:9]=1[C:6]1[CH:7]=[CH:8][C:3]([C:1]#[N:2])=[CH:4][C:5]=1[CH3:24]
Reactant: CCCN1CCNC[C@@H]1C
Reactant: Cc1cc(C#N)ccc1-c1cnn(-c2ccc(C(=O)O)cn2)c1O
Agent: Cl
Product: CCCN1CCN(C(=O)c2ccc(-n3ncc(-c4ccc(C#N)cc4C)c3O)nc2)C[C@@H]1C

Procedure:
The title compound was prepared in a manner similar to Example 112 using 6-(4-(4-cyano-2-methylphenyl)-5-hydroxy-1H-pyrazol-1-yl)nicotinic acid and (S)-2-methyl-1-propylpiperazine dihydrochloride. 1H NMR (500 MHz, DMSO-d6) δ ppm 0.86 (t, J=7.32 Hz, 3H) 0.90-1.15 (m, 3H) 1.35-1.56 (m, 2H) 2.31-2.41 (m, 2H) 2.43 (s, 3H) 2.58-2.73 (m, 2H) 2.81-3.01 (m, 1H) 3.02-3.17 (m, 2H) 3.44-3.65 (m, 1H) 4.02 (br. s., 1H) 7.62 (dd, J=8.05, 1.71 Hz, 1H) 7.69 (d, J=0.98 Hz, 1H) 7.86 (d, J=7.81 Hz, 1H) 8.03 (dd, J=8.54, 2.20 Hz, 1H) 8.08 (s, 1H) 8.41 (d, J=8.30 Hz, 1H) 8.52 (d, J=1.95 Hz, 1H); ESI-MS m/z [M+H]+ 445.3.
Reaction SMILES: [CH3:1][C:2]1[C:9]([N+:10]([O-])=O)=[CH:8][CH:7]=[CH:6][C:3]=1[CH2:4][OH:5]>C(O)C.[Pd].[C]>[NH2:10][C:9]1[C:2]([CH3:1])=[C:3]([CH:6]=[CH:7][CH:8]=1)[CH2:4][OH:5]
Reactant: Cc1c(CO)cccc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CCO
Product: Cc1c(N)cccc1CO
Yield: 87 %

Procedure:
A solution of 203 g of 2-methyl-3-nitrobenzyl alcohol in 1000 ml of ethanol is hydrogenated in the presence of 5 g of 10% strength Pd/carbon at from 30 to 35° C. The catalyst is filtered off, the solution is evaporated down and the resulting solid is dried. 145 g of 3-amino-2-methylbenzyl alcohol (mp. 104°-108° C.) are obtained.
Reaction SMILES: [C:1]([O:5][C:6](=[O:19])[NH:7][C@@H:8]([C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([Cl:17])[C:12]=1[F:18])[CH2:9][OH:10])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[S:27](Cl)([CH3:30])(=[O:29])=[O:28]>C(Cl)Cl>[C:1]([O:5][C:6]([NH:7][C@@H:8]([C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([Cl:17])[C:12]=1[F:18])[CH2:9][O:10][S:27]([CH3:30])(=[O:29])=[O:28])=[O:19])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N[C@H](CO)c1cccc(Cl)c1F
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N[C@H](COS(C)(=O)=O)c1cccc(Cl)c1F
Temperature: 0 °C
Reaction time: 1.5 h

Procedure:
To a solution of [(S)-1-(3-chloro-2-fluoro-phenyl)-2-hydroxy-ethyl]-carbamic acid tert-butyl ester (550 mg, 1.9 mmol) and triethylamine (0.29 mL, 2.09 mmol) in CH2Cl2 (5.5 mL) cooled at −10° C. was added under nitrogen atmosphere mesylchloride (0.16 mL, 2.09 mmol) and the reaction mixture was stirred at 0° C. for 1.5 h. The reaction mixture was quenched with ice and water then extracted twice with EtOAc. The combined organic layers were washed with water, dried (Na2SO4), filtered and concentrated. The crude material was used without purification in the next step. MS (UPLC/MS): 412.3/414.3 [M+HCOO]−; tR (HPLC conditions a): 3.66 min.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([CH3:13])([CH3:12])[CH2:9][CH:10]=[O:11])=[C:4]([O:14][CH3:15])[CH:3]=1.C[Si](C)(C)[C:18]([F:21])([F:20])[F:19].[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1.O>[F:19][C:18]([F:21])([F:20])[CH:10]([OH:11])[CH2:9][C:8]([C:5]1[CH:6]=[CH:7][C:2]([F:1])=[CH:3][C:4]=1[O:14][CH3:15])([CH3:12])[CH3:13]
Reactant: COc1cc(F)ccc1C(C)(C)CC=O
Reactant: C[Si](C)(C)C(F)(F)F
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: O
Product: COc1cc(F)ccc1C(C)(C)CC(O)C(F)(F)F
Reaction time: 0.5 h

Procedure:
To 1.89 g (8.99 mmol) of 3-(4-fluoro-2-methoxyphenyl)-3-methylbutyraldehyde was added 25 mL (12.5 mmol) of a 0.5 M solution of trimethyl(trifluoromethyl)silane in tetrahydrofuran and 2 mL (2 mmol) of a 1 M solution of tetrabutylammonium fluoride in tetrahydrofuran was added over a 2 minute period. The mixture stirred for 30 minutes and then an additional 8 mL (8 mmol) of a 1 M solution of tetrabutylammonium fluoride in tetrahydrofuran was added. The mixture was then diluted with water and extracted with three 25 mL portions of EtOAc. The combined organic layers were washed with three 20 mL portions of 1 N aqueous HCl, three 20 mL portions of brine, three 20 mL portions of saturated aqueous sodium bicarbonate, dried over magnesium sulfate, filtered, and concentrated to afford 2.78 g of 1,1,1-trifluoro-4-(4-fluoro-2-methoxyphenyl)-4-methylpentan-2-ol as an oil. The oil was dried under high vacuum to a constant weight of 2.36 g (93%) and was used without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:9][C:8](=[O:10])[N:7]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[C:6]=2[CH:17]=1.[H-].[Na+].Br[CH2:21][CH2:22][CH2:23][Cl:24]>CN(C)C=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:9]([CH2:21][CH2:22][CH2:23][Cl:24])[C:8](=[O:10])[N:7]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[C:6]=2[CH:17]=1
Reactant: O=c1[nH]c2ccc(Cl)cc2n1-c1ccccc1
Reactant: ClCCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=c1n(CCCCl)c2ccc(Cl)cc2n1-c1ccccc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a stirred solution of 7 parts of 6-chloro-1,3-dihydro-1-phenyl-2H-benzimidazol-2-one in 67.5 parts of N,N-dimethylformamide is added portionwise 1 part of a sodium hydride dispersion 78%. After stirring for 2 hours at room temperature, there are added dropwise (slowly) 4.75 parts of 1-bromo-3-chloropropane. Upon completion, stirring is continued first for two hours at room temperature and further for one hour at 60° C. The reaction mixture is poured onto water and the product is extracted with methylbenzene. The extract is dried, filtered and evaporated. The residue is purified by column-chromatography over silica gel using a mixture of trichloromethane and 5% of methanol as eluent. The pure fractions are collected and the eluent is evaporated, yielding 5-chloro-1-(3-chloropropyl)-1,3-dihydro-3-phenyl-2H-benzimidazol-2-one as a residue.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[CH3:6][O:7][C:8]1[CH:49]=[CH:48][C:11]([CH2:12][N:13]([CH2:39][C:40]2[CH:45]=[CH:44][C:43]([O:46][CH3:47])=[CH:42][CH:41]=2)[C:14]2[N:19]=[C:18]([CH3:20])[N:17]=[C:16]([C:21]3[CH:22]=[C:23]([CH:36]([OH:38])[CH3:37])[CH:24]=[N:25][C:26]=3[NH:27][C:28]3[CH:29]=[N:30][C:31]([O:34][CH3:35])=[CH:32][CH:33]=3)[N:15]=2)=[CH:10][CH:9]=1.C(N(CC)CC)C>C(Cl)Cl>[CH3:1][S:2]([O:38][CH:36]([C:23]1[CH:24]=[N:25][C:26]([NH:27][C:28]2[CH:29]=[N:30][C:31]([O:34][CH3:35])=[CH:32][CH:33]=2)=[C:21]([C:16]2[N:15]=[C:14]([N:13]([CH2:12][C:11]3[CH:10]=[CH:9][C:8]([O:7][CH3:6])=[CH:49][CH:48]=3)[CH2:39][C:40]3[CH:41]=[CH:42][C:43]([O:46][CH3:47])=[CH:44][CH:45]=3)[N:19]=[C:18]([CH3:20])[N:17]=2)[CH:22]=1)[CH3:37])(=[O:4])=[O:3]
Reactant: CS(=O)(=O)Cl
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)c2nc(C)nc(-c3cc(C(C)O)cnc3Nc3ccc(OC)nc3)n2)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1ccc(CN(Cc2ccc(OC)cc2)c2nc(C)nc(-c3cc(C(C)OS(C)(=O)=O)cnc3Nc3ccc(OC)nc3)n2)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 95 %

Procedure:
Methanesulfonyl chloride (0.164 mL, 2.119 mmol) was added to a solution of 1-(5-(4-(bis(4-methoxybenzyl)amino)-6-methyl-1,3,5-triazin-2-yl)-6-(6-methoxypyridin-3-ylamino)pyridin-3-yl)ethanol (331.1 mg, 0.558 mmol) and triethylamine (0.350 mL, 2.510 mmol) in CH2Cl2 (7.5 mL) at 0° C., and the resulting mixture was stirred at 0° C. for 30 min. The reaction mixture was then partitioned between CH2Cl2 (40 mL) and water (30 mL). The organic layer was separated, and the aqueous layer was extracted with CH2Cl2 (30 mL). The combined organic extracts were dried over sodium sulfate, filtered, and concentrated in vacuo to provide 1-(5-(4-(bis(4-methoxybenzyl)amino)-6-methyl-1,3,5-triazin-2-yl)-6-(6-methoxypyridin-3-ylamino)pyridin-3-yl)ethyl methanesulfonate (356.1 mg, 0.530 mmol, 95% yield) as a yellow-brown solid, which was used directly in Step 3.
Reaction SMILES: [CH2:1]([O:3][C@@H:4]1[C@H:9]([NH:10][C:11](=[O:17])[O:12][C:13]([CH3:16])([CH3:15])[CH3:14])[CH:8]=[C:7]([C:18]2[CH:23]=[CH:22][N:21]=[CH:20][C:19]=2[N+:24]([O-])=O)[CH2:6][C@@H:5]1[CH3:27])[CH3:2]>CCCCCCC.CCO>[C:11](=[O:12])([O-:17])[NH2:10].[NH2:24][C:19]1[CH:20]=[N:21][CH:22]=[CH:23][C:18]=1[C@H:7]1[CH2:8][C@@H:9]([NH:10][C:11](=[O:17])[O:12][C:13]([CH3:14])([CH3:15])[CH3:16])[C@@H:4]([O:3][CH2:1][CH3:2])[C@@H:5]([CH3:27])[CH2:6]1
Reactant: CCO[C@H]1[C@@H](C)CC(c2ccncc2[N+](=O)[O-])=C[C@H]1NC(=O)OC(C)(C)C
Solvent: CCCCCCC
Solvent: CCO
Product: CCO[C@H]1[C@@H](C)C[C@@H](c2ccncc2N)C[C@H]1NC(=O)OC(C)(C)C
Product: NC(=O)[O-]
Yield: 33 %
Yield: 28 %

Procedure:
Method 6 was followed using (+/−)-tert-butyl (1R,5S,6S)-6-ethoxy-5-methyl-3-(3-nitropyridin-4-yl)cyclohex-2-enylcarbamate with Chiral HPLC (Heptane/EtOH=90/10, 20 mL/min, IC column) to yield tert-butyl a 1S,2R,3R,5S)-5-(3-aminopyridin-4-yl)-2-ethoxy-3-methylcyclohexyl)carbamate (33% yield, 99% ee) and tert-butyl ((1R,2S,3S,5R)-5-(3-aminopyridin-4-yl)-2-ethoxy-3-methylcyclohexyl)carbamate (28% yield, 99% ee). LC/MS (m/z)=350.2 (MH+), Rt=0.72 min.
Reaction SMILES: Cl.[NH2:2][CH2:3][CH:4]([C:9]1[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][CH:10]=1)[C:5]([O:7][CH3:8])=[O:6].C1COCC1.CCN(C(C)C)C(C)C.O([CH2:38][C:39]([F:42])([F:41])[F:40])S(C(F)(F)F)(=O)=O>CN(C=O)C>[Cl:15][C:12]1[CH:11]=[CH:10][C:9]([CH:4]([CH2:3][NH:2][CH2:38][C:39]([F:42])([F:41])[F:40])[C:5]([O:7][CH3:8])=[O:6])=[CH:14][CH:13]=1
Reactant: O=S(=O)(OCC(F)(F)F)C(F)(F)F
Reactant: COC(=O)C(CN)c1ccc(Cl)cc1
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COC(=O)C(CNCC(F)(F)F)c1ccc(Cl)cc1
Reaction time: 20 h
Yield: 92.4 %

Procedure:
A solution of methyl 3-amino-2-(4-chlorophenyl)propanoate hydrochloride (215 mg, 0.86 mmol) in 1:1 THF:DMF (3.0 mL) was treated with DIEA (389 uL, 2.23 mmol) at room temperature. Trifluoroethyl triflate (299 mg, 1.29 mmol) was added to the mixture, and the reaction was stirred for 20 hours to completion. The mixture was partitioned between ethyl acetate and diluted NaHCO3 solution. The aqueous portion was extracted twice, and the combined organic portions were washed with water (3×). The organic portion was washed with brine, separated, dried over MgSO4, filtered, and concentrated in vacuo. The residue was purified by chromatography (silica gel eluted with 4:1 hexanes:ethyl acetate, Rf=0.18) to afford the pure methyl 2-(4-chlorophenyl)-3-(2,2,2-trifluoroethylamino)propanoate (235 mg, 93%) as a colorless oil. LCMS (APCI+) m/z 296.0 [M+H]+.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[S:15][CH:16]=[C:17]([C:19](O)=[O:20])[CH:18]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH:53]1[CH:62]2[CH:57]([CH2:58][CH2:59][CH2:60][CH2:61]2)[CH2:56][CH2:55][CH2:54]1>C(#N)C>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][CH:11]([C:14]2[S:15][CH:16]=[C:17]([C:19]([N:53]3[C@@H:62]4[C@@H:57]([CH2:58][CH2:59][CH2:60][CH2:61]4)[CH2:56][CH2:55][CH2:54]3)=[O:20])[CH:18]=2)[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: C1CCC2NCCCC2C1
Reactant: CC(C)(C)OC(=O)N1CCC(c2cc(C(=O)O)cs2)CC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCC(c2cc(C(=O)N3CCC[C@@H]4CCCC[C@@H]43)cs2)CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 101.1 %

Procedure:
4-(4-Carboxy-thiophen-2-yl)-piperidine-1-carboxylic acid t-butyl ester (0.1 g, 0.32 mmol) was dissolved in acetonitrile (2 mL). Triethylamine (0.96 mmol), HATU (0.35 mmol) and decahydroquinoline (3:2 mixture of cis/trans-isomers; 2.5 mmol) were added and the reaction stirred at room temperature for 3 hours. The solvent was evaporated and the residue product was purified by flash chromatography on silica, eluting with 0-50% ethyl acetate in cyclohexane. The fractions containing the desired product were concentrated under vacuum to give the title compound (0.14 g). 1H NMR (400 MHz, CHCl3-d): δ 7.2 (s, 1H), 6.85 (s, 1H), 4.7 (m, 1H), 4.2 (m, 2H), 3.7 (m, 1H), 3.1-2.7 (m, 4H), 2.0-1.4 (m, 26H).