Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: N[C@@](C1C=CC2C(=CC=C(O[C@H]3CC[C@H](C(C)(C)C)CC3)C=2C2C=CC(OC(F)(F)F)=CC=2)C=1)(C)CO.[C:38]([C@H:42]1[CH2:47][CH2:46][C@H:45]([O:48][C:49]2[C:50]([F:66])=[C:51]3[C:56](=[CH:57][CH:58]=2)[CH:55]=[C:54]([C@:59]2([CH3:65])[CH2:63][O:62]C(=O)[NH:60]2)[CH:53]=[CH:52]3)[CH2:44][CH2:43]1)([CH3:41])([CH3:40])[CH3:39]>>[NH2:60][C@@:59]([C:54]1[CH:53]=[CH:52][C:51]2[C:56](=[CH:57][CH:58]=[C:49]([O:48][C@H:45]3[CH2:44][CH2:43][C@H:42]([C:38]([CH3:41])([CH3:40])[CH3:39])[CH2:47][CH2:46]3)[C:50]=2[F:66])[CH:55]=1)([CH3:65])[CH2:63][OH:62]
Reactant: CC(C)(C)[C@H]1CC[C@H](Oc2ccc3cc([C@]4(C)COC(=O)N4)ccc3c2F)CC1
Agent: CC(C)(C)[C@H]1CC[C@H](Oc2ccc3cc([C@@](C)(N)CO)ccc3c2-c2ccc(OC(F)(F)F)cc2)CC1
Product: CC(C)(C)[C@H]1CC[C@H](Oc2ccc3cc([C@@](C)(N)CO)ccc3c2F)CC1

Procedure:
(R)-2-amino-2-(6-(trans-4-tert-butylcyclohexyloxy)-5-fluoronaphthalen-2-yl)propan-1-ol was synthesized as per (R)-2-amino-2-(6-(trans-4-tert-butylcyclohexyloxy)-5-(4-(trifluoromethoxy)phenyl)naphthalen-2-yl)propan-1-ol (Example 221) in 34% yield using (R)-4-(6-(trans-4-tert-butylcyclohexyloxy)-5-fluoronaphthalen-2-yl)-4-methyloxazolidin-2-one as starting material. MS: m/z=357.34 [M-16]+. 1H NMR (MeOD) δ: 8.25 (d, J=9.0 Hz, 1H), 7.92 (d, J=2.0 Hz, 1H), 7.88 (d, J=9.0 Hz, 1H), 7.68 (dd, J=9.3, 2.3 Hz, 1H), 7.49 (d, J=9.3 Hz, 1H), 4.33-4.42 (m, 1H), 3.94 (d, J=11.5 Hz, 1H), 3.84 (d, J=11.5 Hz, 1H), 2.17-2.26 (m, 2H), 1.86-1.95 (m, 2H), 1.79 (s, 3H), 1.46-1.58 (m, 2H), 1.08-1.27 (m, 3H), 0.90 (s, 9H)
Reaction SMILES: [F:1][C:2]([F:52])([F:51])[C:3]1[CH:4]=[C:5]([C:13]([CH3:50])([CH3:49])[C:14]([N:16]([CH3:48])[C:17]2[C:18]([C:40]3[CH:45]=[CH:44][C:43]([F:46])=[CH:42][C:41]=3[CH3:47])=[CH:19][C:20]([C@@H:23]3[N:27](C(OC(C)(C)C)=O)[C@:26]([CH3:39])([C:35]([O:37][CH3:38])=[O:36])[CH2:25][CH2:24]3)=[N:21][CH:22]=2)=[O:15])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.C(O)(C(F)(F)F)=O>ClCCl>[F:52][C:2]([F:1])([F:51])[C:3]1[CH:4]=[C:5]([C:13]([CH3:49])([CH3:50])[C:14]([N:16]([CH3:48])[C:17]2[C:18]([C:40]3[CH:45]=[CH:44][C:43]([F:46])=[CH:42][C:41]=3[CH3:47])=[CH:19][C:20]([C@@H:23]3[NH:27][C@:26]([CH3:39])([C:35]([O:37][CH3:38])=[O:36])[CH2:25][CH2:24]3)=[N:21][CH:22]=2)=[O:15])[CH:6]=[C:7]([C:9]([F:11])([F:12])[F:10])[CH:8]=1
Reactant: COC(=O)[C@]1(C)CC[C@H](c2cc(-c3ccc(F)cc3C)c(N(C)C(=O)C(C)(C)c3cc(C(F)(F)F)cc(C(F)(F)F)c3)cn2)N1C(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)[C@]1(C)CC[C@H](c2cc(-c3ccc(F)cc3C)c(N(C)C(=O)C(C)(C)c3cc(C(F)(F)F)cc(C(F)(F)F)c3)cn2)N1
Temperature: 25 °C
Reaction time: 2 h
Yield: 97.1 %

Procedure:
To a solution of 1-(1,1-dimethylethyl) 2-methyl (2S,5R)-5-[5-[{2-[3,5-bis(trifluoromethyl)phenyl]-2-methylpropanoyl}(methy)amino]-4-(4-fluoro-2-methylphenyl)-2-pyridinyl]-2-methyl-1,2-pyrrolidinedicarboxylate (Intermediate 8, 50 mg, 0.068 mmol) in dry Dichloromethane (3 ml) was added TFA (1 ml, 12.98 mmol) and the reaction mixture was stirred for 2 hours at rt. The solvent and the excess of TFA were evaporated and the residue was purified by SPE-SCX cartridge affording the title compound (42 mg, 0.066 mmol, 97% yield) as a white solid. HPLC: Rt 5.79 min. MS: m/z 640 [M+H]+ and 662 [M+Na]+.
Reaction SMILES: [Li]CCCC.[CH3:6][C:7]1[S:8][CH:9]=[CH:10][CH:11]=1.C([O:15][B:16](OC(C)C)[O:17]C(C)C)(C)C>C1COCC1.CCOCC>[CH3:6][C:7]1[S:8][C:9]([B:16]([OH:17])[OH:15])=[CH:10][CH:11]=1
Reactant: Cc1cccs1
Reactant: CC(C)OB(OC(C)C)OC(C)C
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCOCC
Product: Cc1ccc(B(O)O)s1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 88.8 %

Procedure:
n-BuLi (2.38 M, 16 ml) was slowly added to a solution of 2-methyl thiophene (3.0 g, 31 mmol) in THF (20 ml) at −78° C. The solution was kept at −78° C. For 10 min. then warmed to 0° C. for an additional 0.5 hr. The solution was then transferred by steel canula under nitrogen into a vessel containing triisopropylborate (6.3 g, 33 mmol) in ether (15 ml) at −78° C. The resulting milky white solution was stirred at −78° C. for 20 min. then at room temperature for 2 hours. The reaction was quenched by the addition of 10% aqueous HCl (5.0 ml) and the solution was extracted into ether. The combined ether extracts were extracted with 10 M NaOH (2×30 ml), the aqueous extracts were acidified with dilute HCl to pH 2 and extracted into ether (3×25 ml). The combined ether extracts were washed once with water (10 ml), once with brine (10 ml) and dried and evaporated to give 3.91 g 2-methylthiophene-5-boronic acid as a light brown solid. This was used in the next step with no further purification.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:20])[C:5]([C:8]1[CH:13]=[CH:12][C:11]([S:14]([CH:17]2[CH2:19][CH2:18]2)(=[O:16])=[O:15])=[CH:10][CH:9]=1)=[N+]=[N-])[CH3:2]>ClCCl.C(C1CCCCC1)=C>[CH2:1]([O:3][C:4]([C@:5]1([C:8]2[CH:13]=[CH:12][C:11]([S:14]([CH:17]3[CH2:19][CH2:18]3)(=[O:16])=[O:15])=[CH:10][CH:9]=2)[CH2:4][C@H:5]1[CH:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1)=[O:20])[CH3:2]
Reactant: CCOC(=O)C(=[N+]=[N-])c1ccc(S(=O)(=O)C2CC2)cc1
Agent: C=CC1CCCCC1
Solvent: ClCCl
Product: CCOC(=O)[C@]1(c2ccc(S(=O)(=O)C3CC3)cc2)C[C@H]1C1CCCCC1
Temperature: 40 °C
Reaction time: 1.5 h
Yield: 201.2 %

Procedure:
To a solution of vinylcyclohexane (300 mL, 2.72 mol) in 150 mL of anhydrous dichloromethane maintained at 25-30° C. under an inert atmosphere is added a solution of tetrakis[N-phthaloyl-(R)-tert-leucinato]dirhodium bis(ethylacetate) adduct (120 mg, 84 μmol) in vinylcyclohexane (40 mL) dropwise, while portions of (4-cyclopropanesulfonyl-phenyl)-diazo-acetic acid ethyl ester (169.40 g, 575.5 mmol) are added. The addition rates are adjusted to maintain an internal temperature of 40° C. The addition is complete after approximately 1.5 hours, and the reaction mixture is stirred for an additional 2 hours at 30° C. Volatiles are then removed under vacuum to afford crude (1R,2S)-2-cyclohexyl-1-(4-cyclopropanesulfonyl-phenyl)-cyclopropanecarboxylic acid ethyl ester as a viscous brown oil (218 g, 579 mmol) which is dissolved in 1.1 L of methanol to afford a yellow-brown solution, to which a 5 N aqueous sodium hydroxide solution (500 mL, 2.5 mmol) is added slowly. The resulting slurry is then stirred at 50° C. for 1 hour, during which time a solution forms. Methanol is removed under vacuum, and 1 L of ethylacetate is added. The resulting mixture is acidified by the addition of approximately 550 mL of 5% aqueous hydrochloric acid, and the two layers are separated. The aqueous layer is then extracted with two 500 mL portions of ethyl acetate. The organic phases are combined, washed with 500 mL of saturated aqueous sodium chloride solution, dried over magnesium sulfate, filtered, and concentrated to afford a moist pale yellow solid. This material is then dissolved in 1 L of methanol. Water (1 L) is then added to the stirred solution over the course of 1.5 hours. The resulting slurry is stirred at room temperature for 30 minutes, and then filtered. The filter pad is washed with 1:1 methanol/water, and dried to afford the title compound as pale yellow crystals (166 g). MS exact mass calculated 349.14735; found 349.14679 (Agilent 1100 LC-TOF using electrospray ionization); [α]D20=−31°.
Reaction SMILES: [Cl-].[Cl-].C([Al+2])C.[CH3:6][C:7]1([CH3:16])[CH2:12][CH2:11][CH2:10][CH:9]([CH:13]([OH:15])[CH3:14])[CH2:8]1.[CH3:17][C:18]1([O:21][CH2:20]1)[CH3:19]>C1(C)C=CC=CC=1.C1CCCCC1>[CH3:16][C:7]1([CH3:6])[CH2:12][CH2:11][CH2:10][CH:9]([CH:13]([O:15][C:18]([CH3:19])([CH3:17])[CH2:20][OH:21])[CH3:14])[CH2:8]1
Reactant: CC(O)C1CCCC(C)(C)C1
Reactant: CC1(C)CO1
Agent: CC[Al+2]
Agent: [Cl-]
Solvent: Cc1ccccc1
Solvent: C1CCCCC1
Product: CC(OC(C)(C)CO)C1CCCC(C)(C)C1
Temperature: 25 °C
Reaction time: 15 h
Yield: 37.6 %

Procedure:
At 0° C. under an atmosphere of nitrogen, 178 ml (321 mmol) of a 1.8 M solution of ethyl aluminium dichloride in toluene was slowly added to a stirred solution of 100 g (641 mmol) of 1-(3′,3′-dimethylcyclohexyl)ethanol and 55.4 g (769 mmol) of isobutylenoxide in 500 ml of cyclohexane. After complete addition, the cooling bath was removed, the reaction mixture was allowed to warm to room temperature, and stirring was continued at this temperature for 15 h. The reaction mixture was then poured into 1 L of brine, acidified with concentrated phosphoric acid, and thrice extracted with ether. The combined organic extracts were washed with brine and water, dried with sodium sulphate, and concentrated on a rotary evaporator. Distillation of the crude material (136 g) provided at 78-85° C./0.3 mbar 55.1 g (38%) of pure 2-[1′-(3″,3″-dimethylcyclohexyl)-ethoxy]-2-methylpropan-1-ol, while 60.4 g of starting material were recovered.
Reaction SMILES: [CH3:1][C:2]1([CH2:8][S:9]([CH2:12][CH:13]([OH:18])[CH:14]([OH:17])[CH2:15][OH:16])(=[O:11])=[O:10])[CH2:6][O:5][C:4](=[O:7])[NH:3]1.C(O[Cl:24])(C)(C)C>CO>[Cl:24][N:3]1[C:2]([CH3:1])([CH2:8][S:9]([CH2:12][CH:13]([OH:18])[CH:14]([OH:17])[CH2:15][OH:16])(=[O:11])=[O:10])[CH2:6][O:5][C:4]1=[O:7]
Reactant: CC1(CS(=O)(=O)CC(O)C(O)CO)COC(=O)N1
Reactant: CC(C)(C)OCl
Solvent: CO
Product: CC1(CS(=O)(=O)CC(O)C(O)CO)COC(=O)N1Cl
Reaction time: 2 h

Procedure:
A solution of 4-methyl-4-((2,3,4-trihydroxybutylsulfonyl)methyl)oxazolidin-2-one (990 mg, 3.49 mmol) in methanol (5 ml) was cooled to 0° C. and tert-butylhypochlorite (400 ul, 3.35 mmol) was added drop-wise. The solution was stirred for 2 hours, concentrated in vacuo, and the residue purified by flash chromatography (5% to 20% methanol in dichloromethane) to afford the title compound as a mixture of diastereomers (364.5 mg, 1.147 mmol, 33%). 1H NMR (D2O, 400 MHz) δ 1.50 (s, 3H), 3.3-4.3 (m, 7H), 4.4-4.5 (m, 1H), 4.9-5.0 (m, 1H); LRMS (ESI/APCI) m/z 318 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([O:14][CH3:15])[CH:12]=2)[NH:7][CH:6]=1)=[O:4].[CH2:16](Br)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>>[CH3:1][O:2][C:3]([C:5]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([O:14][CH3:15])[CH:12]=2)[N:7]([CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:6]=1)=[O:4]
Reactant: BrCc1ccccc1
Reactant: COC(=O)c1c[nH]c2ccc(OC)cc12
Product: COC(=O)c1cn(Cc2ccccc2)c2ccc(OC)cc12

Procedure:
Prepare by a method similar to Example 48 using 5-methoxy-1H-indole-3-carboxylic acid methyl ester and benzyl bromide.
Reaction SMILES: [Cl:1][C:2]1[CH:12]=[CH:11][CH:10]=[CH:9][C:3]=1[CH:4]=[CH:5][C:6]([OH:8])=[O:7].O=P(Cl)(Cl)Cl.[CH3:18]O>>[CH3:18][O:7][C:6](=[O:8])/[CH:5]=[CH:4]/[C:3]1[CH:9]=[CH:10][CH:11]=[CH:12][C:2]=1[Cl:1]
Reactant: O=C(O)C=Cc1ccccc1Cl
Reactant: CO
Solvent: O=P(Cl)(Cl)Cl
Product: COC(=O)/C=C/c1ccccc1Cl
Temperature: 25 °C

Procedure:
To a 250 ml round-bottomed flask, 2-Chlorocinnamic acid (25 g, 136.9 mmol) and MeOH(56 ml) were added. POCl3 (1.27 ml, 13.6 mmol) was added dropwise. The reaction mixture was stirred under reflux for 3˜4 h. The reaction mixture was cooled to room temperature, quenched with 1N NaOH solution. The mixture was extracted by EtOAc and washed with H2O. The aqueous layer was further extracted with EtOAc. The combined organic layer was dried over anhydrous magnesium sulfate (MgSO4), filtered and concentrated under vacuum. (26.98 g, 85˜97%)
Reaction SMILES: C1C=CC=CC=1.[CH3:7][C:8]([NH2:16])([CH3:15])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[Br:17][CH:18]([CH:22]([CH3:24])[CH3:23])[C:19](Cl)=[O:20]>C(N(CC)CC)C>[CH3:7][C:8]([NH:16][C:19](=[O:20])[CH:18]([Br:17])[CH:22]([CH3:24])[CH3:23])([CH3:15])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: CC(C)C(Br)C(=O)Cl
Reactant: CC(C)(N)c1ccccc1
Solvent: c1ccccc1
Solvent: CCN(CC)CC
Product: CC(C)C(Br)C(=O)NC(C)(C)c1ccccc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 85.1 %

Procedure:
Into a 200 ml four necked flask, there were charged benzene (100 ml), α,α-dimethylbenzylamine (9 g) and triethylamine (7.4 g), and α-bromo-isovaleryl chloride (13.3 g) was dropwise added thereto while stirring at room temperature. Stirring was continued for 3 hours. The reaction mixture was washed with water to remove triethylamine hydrochloride. After the benzene layer was dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure. The obtained residue was recrystallized from ethanol to give 16.9 g of N-(α,α-dimethylbenzyl)-α-bromo-isovaleramide. M.P., 128°-129.5° C.
Reaction SMILES: N1(/[C:6](/[CH3:13])=[CH:7]\[C:8]([O:10][CH2:11][CH3:12])=[O:9])CCCC1.[N+:14]([CH2:17][CH3:18])([O-:16])=O.C(N(CC)CC)C.P(Cl)(Cl)(Cl)=O>C(Cl)(Cl)Cl>[C:8]([C:7]1[C:17]([CH3:18])=[N:14][O:16][C:6]=1[CH3:13])([O:10][CH2:11][CH3:12])=[O:9]
Reactant: CCOC(=O)/C=C(/C)N1CCCC1
Reactant: CC[N+](=O)[O-]
Solvent: O=P(Cl)(Cl)Cl
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CCOC(=O)c1c(C)noc1C
Reaction time: 8 h

Procedure:
A solution of the ethyl β-pyrrolidinocrotonate (427 g. = 2.33 moles), 190 ml. (182 g., 2.43 mole) of nitroethane and 1300 ml. of triethylamine in 1200 ml. of anhydrous chloroform was cooled in an ice bath under nitrogen. A solution of 235 ml. (393 g. = 2.56 mole) of phosphorous oxychloride in 400 ml. of chloroform was added at such a rate that the temperature did not rise above 15°. During the addition, which took place over a three-hour period, a viscous orange precipitate formed. This suspension was then stirred under nitrogen overnight. As much solvent as possible was removed at reduced pressure and the resulting red-brown paste was diluted with water and extracted with ether. The ether solutions were washed sequentially with water, 3N hydrochloric acid, water, 5 percent sodium hydroxide solution and water, and were dried over anhydrous sodium sulfate. Solvent removal at reduced pressure gave a dark oil which was distilled through a short Vigreux column to give 4-carboethoxy-3,5-dimethyl-isoxazole as a slightly cloudy, colorless liquid of b.p. 100° /11mm.
Reaction SMILES: C[C@H]1O[C@H]([O:8][CH:9]2[C@@H:14]([OH:15])[C@@H:13]([OH:16])[CH:12]([OH:17])[C@H:11]([OH:18])[C@H:10]2[OH:19])[C@@H](N)C[C@@H]1N=C(N)C(O)=O.Cl.FC(F)(F)C(O)=O.[Mn]([O-])(=O)(=O)=O.[K+].C[C@H]1O[C@H](O[C@@H]2[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)[C@H]2O)[C@@H](N)C[C@@H]1NC(C(O)=O)=N>O.C(O)(=O)C>[CH:9]1([OH:8])[CH:10]([OH:19])[CH:11]([OH:18])[CH:12]([OH:17])[CH:13]([OH:16])[CH:14]1[OH:15]
Reactant: C[C@H]1O[C@H](OC2[C@@H](O)[C@@H](O)C(O)[C@H](O)[C@H]2O)[C@@H](N)C[C@@H]1N=C(N)C(=O)O
Agent: O=[Mn](=O)(=O)[O-]
Agent: C[C@H]1O[C@H](O[C@H]2[C@H](O)[C@@H](O)[C@@H](O)[C@H](O)[C@@H]2O)[C@@H](N)C[C@@H]1NC(=N)C(=O)O
Agent: Cl
Solvent: CC(=O)O
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: OC1C(O)C(O)C(O)C(O)C1O
Temperature: 75 °C
Yield: 20 %

Procedure:
Kasugamycin hydrochloride (1 g) and 2N trifluoroacetic acid (5 mL) were combined and heated 4 h at 75° C., after which time silica gel TLC (solvent-butanol:acetic acid:water, 2:1:1; Visualization with potassium permanganate stain showed kasugamycin was still present. The solution was concentrated in vacuo. The hydrolysis product was purified in the usual manner using ion exchange resins and charcoal. D-chiro-inositol was obtained in 20% yield.
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[C:17]([Cl:19])[CH:16]=[CH:15][C:3]=1[CH2:4][NH:5][C:6]([N:8]1[C:11]2([CH2:14][NH:13][CH2:12]2)[CH2:10][CH2:9]1)=[O:7].C(N(CC)CC)C.[Cl:27][C:28]1[CH:33]=[CH:32][C:31]([S:34](Cl)(=[O:36])=[O:35])=[CH:30][CH:29]=1>ClCCl>[Cl:27][C:28]1[CH:33]=[CH:32][C:31]([S:34]([N:13]2[CH2:12][C:11]3([N:8]([C:6]([NH:5][CH2:4][C:3]4[CH:15]=[CH:16][C:17]([Cl:19])=[CH:18][C:2]=4[Cl:1])=[O:7])[CH2:9][CH2:10]3)[CH2:14]2)(=[O:36])=[O:35])=[CH:30][CH:29]=1
Reactant: O=C(NCc1ccc(Cl)cc1Cl)N1CCC12CNC2
Reactant: O=S(=O)(Cl)c1ccc(Cl)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(NCc1ccc(Cl)cc1Cl)N1CCC12CN(S(=O)(=O)c1ccc(Cl)cc1)C2
Temperature: 25 °C
Yield: 85 %

Procedure:
To a solution of tert-butyl 1-(2,4-dichlorobenzylcarbamoyl)-1,6-diazaspiro[3.3]heptane-6-carboxylate (440 mg, 1.10 mmol) in dichloromethane (7 mL) was added TFA (593 μl, 7.7 mmol). After being stirred 2 h at ambient temperature, the reaction mixture was concentrated under reduced pressure. The residue was partitioned in toluene (10 mL) and then concentrated; this procedure was repeated twice to give the free amine (468 mg), which was used without further purification in the next step. To a solution of the previously obtained N-(2,4-dichlorobenzyl)-1,6-diazaspiro[3.3]heptane-1-carboxamide in dichloromethane (12 mL) was added at 0° C. triethylamine (217 μl, 1.56 mmol) followed by 4-chlorobenzene-1-sulfonyl chloride (329 mg, 1.56 mmol). The reaction mixture was left to warm to ambient temperature overnight, and was then diluted with dichloromethane (10 mL) and quenched with water (10 mL). The aqueous phase was extracted with dichloromethane and the combined organic phases were washed with brine, dried over sodium sulfate and were concentrated under reduced pressure. Purification by chromatography (SiO2; heptane:ethyl acetate 1:4) afforded the title compound (445 mg, 85%) as a colorless solid. HRMS (EI): 473.0134 (exact mass calculated for C19H18Cl3N3O3S ([M]+)=473.0134).
Reaction SMILES: [CH3:1][N:2]=[C:3]=[O:4].[C:5]([NH:8][NH:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)(=[O:7])[CH3:6]>C(N(CC)CC)C.ClCCl>[C:5]([NH:8][N:9]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:3]([NH:2][CH3:1])=[O:4])(=[O:7])[CH3:6]
Reactant: CC(=O)NNc1ccccc1
Reactant: CN=C=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CNC(=O)N(NC(C)=O)c1ccccc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A 5.7-g (0.1-mol) sample of methyl isocyanate was added dropwise to a solution of 15.0 g (0.1 mol) 1-acetyl-2-phenyl-hydrazine and 2 drops triethylamine in 200 ml dichloromethane. The resulting reaction mixture was stirred for 2 hours at about 25° C., refluxed for about 16 hours and evaporated under reduced pressure to give 21 g of crude 1-acetyl-2-phenyl-4-methyl semicarbazide, as a yellow solid.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([C:11]2[NH:30][C:14]3[C:15]([Cl:29])=[N:16][C:17]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=4[C:25]([F:28])([F:27])[F:26])=[CH:18][C:13]=3[N:12]=2)[N:8]([CH3:10])[N:9]=1)([CH3:4])([CH3:3])[CH3:2].C(Cl)[Cl:32]>CO>[C:1]([C:5]1[C:6]([Cl:32])=[C:7]([C:11]2[NH:30][C:14]3[C:15]([Cl:29])=[N:16][C:17]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=4[C:25]([F:27])([F:28])[F:26])=[CH:18][C:13]=3[N:12]=2)[N:8]([CH3:10])[N:9]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: Cn1nc(C(C)(C)C)cc1-c1nc2cc(-c3ccccc3C(F)(F)F)nc(Cl)c2[nH]1
Reactant: ClCCl
Solvent: CO
Product: Cn1nc(C(C)(C)C)c(Cl)c1-c1nc2cc(-c3ccccc3C(F)(F)F)nc(Cl)c2[nH]1
Temperature: 25 °C
Reaction time: 14 h

Procedure:
A solution of 2-(5-tert-butyl-2-methyl-2H-pyrazol-3-yl)-4-chloro-6-(2-trifluoromethyl-phenyl)-3H-imidazo[4,5-c]pyridine (101 mg, 0.232 mmol, Compound #74 freebase prepared according to Example 16, STEPS A, B and C) in DCM (2 mL) was treated with SO2Cl2 (28.3 μL, 0.348 mmol) and the resulting mixture was stirred at room temperature for 14 h. The resulting mixture was then diluted with MeOH (3 mL) and the solvent was removed under reduced pressure. The residue was chromatographed on a 25-g SiO2 pre-packed column eluting with 0:1-3:7 EtOAc/hexanes to yield 2-(5-tert-butyl-4-chloro-2-methyl-2H-pyrazol-3-yl)-4-chloro-6-(2-trifluoromethyl-phenyl)-3H-imidazo[4,5-c]pyridine. 1H-NMR (400 MHz, CD3OD) δ: 7.84 (d, J=7.8 Hz, 1H), 7.69-7.76 (m, 1H), 7.68 (s, 1H), 7.62-7.67 (m, 1H), 7.59 (d, J=7.6 Hz, 1H), 4.14 (s, 3H), 1.45 (s, 9H). Mass Spectrum (LCMS, ESI pos.): Calculated for C21H18Cl2F3N5: 468.1 (M+H); Measured: 468.1.
Reaction SMILES: [CH:1]([S:4][C:5]1[CH:6]=[C:7]([C:15]2[CH:20]=[CH:19][C:18]([CH2:21][C:22]([CH3:31])([NH:24]C(=O)C(F)(F)F)[CH3:23])=[CH:17][CH:16]=2)[CH:8]=[CH:9][C:10]=1[C:11](OC)=[O:12])([CH3:3])[CH3:2].[OH-].[Na+].[CH2:34]([OH:36])[CH3:35]>>[NH2:24][C:22]([CH3:23])([CH3:31])[CH2:21][C:18]1[CH:17]=[CH:16][C:15]([C:7]2[CH:8]=[CH:9][C:10]([C:11]([O:36][CH2:34][CH3:35])=[O:12])=[C:5]([S:4][CH:1]([CH3:3])[CH3:2])[CH:6]=2)=[CH:20][CH:19]=1
Reactant: CCO
Reactant: COC(=O)c1ccc(-c2ccc(CC(C)(C)NC(=O)C(F)(F)F)cc2)cc1SC(C)C
Agent: [Na+]
Agent: [OH-]
Product: CCOC(=O)c1ccc(-c2ccc(CC(C)(C)N)cc2)cc1SC(C)C

Procedure:
To a solution of methyl 3-(isopropylthio)-4′-[2-methyl-2-[(trifluoroacetyl)amino]propyl]-4-biphenylcarboxylate (810 mg) in ethanol was added sodium hydroxide aqueous solution (1M, 9 ml) at room temperature and stirred under reflux for 4 hours. The resultant mixture was evaporated. The residue was dissolved with hydrogen chloride solution in ethanol (5.5M, 12 ml) and stirred at room temperature overnight. The resultant mixture was evaporated and dried to give ethyl 4′-(2-amino-2-methylpropyl)-3-(isopropylthio)-4-biphenylcarboxylate (384 mg).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3](/[CH:10]=[CH:11]/[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[N:18]2[CH:22]=[CH:21][C:20]([CH:23]=[O:24])=[CH:19]2)=[N:2]1.[BH4-].[Na+].O>CO>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3](/[CH:10]=[CH:11]/[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[N:18]2[CH:22]=[CH:21][C:20]([CH2:23][OH:24])=[CH:19]2)=[N:2]1
Reactant: O=Cc1ccn(-c2ccccc2/C=C/c2n[nH]c3ccccc23)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: OCc1ccn(-c2ccccc2/C=C/c2n[nH]c3ccccc23)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 45.6 %

Procedure:
Compound 167 (38 mg, 0.16 mmol) was dissolved in methanol (2.0 mL) and added with sodium borohydride (12 mg, 0.32 mmol) followed by stirring at room temperature for 4 hours. The reaction mixture was added with water, extracted with ethyl acetate and the organic layer was concentrated. Then, the residue was triturated in ethyl acetate to obtain Compound 168 (23 mg, 45%).
Reaction SMILES: [O:1]=[S:2]1(=[O:26])[C:7]2[CH:8]=[C:9]([O:12][C:13]3[CH:14]=[C:15]([C:19](=[N:21][OH:22])[NH2:20])[CH:16]=[CH:17][CH:18]=3)[CH:10]=[CH:11][C:6]=2[N:5]2[CH2:23][CH2:24][CH2:25][C:4]2=[N:3]1.N1C=CC=CC=1.[S:33](Cl)(Cl)=[O:34]>C1COCC1.C(Cl)Cl>[O:34]=[S:33]1[NH:20][C:19]([C:15]2[CH:14]=[C:13]([CH:18]=[CH:17][CH:16]=2)[O:12][C:9]2[CH:10]=[CH:11][C:6]3[N:5]4[CH2:23][CH2:24][CH2:25][C:4]4=[N:3][S:2](=[O:1])(=[O:26])[C:7]=3[CH:8]=2)=[N:21][O:22]1
Reactant: NC(=NO)c1cccc(Oc2ccc3c(c2)S(=O)(=O)N=C2CCCN23)c1
Reactant: O=S(Cl)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Solvent: C1CCOC1
Product: O=S1NC(c2cccc(Oc3ccc4c(c3)S(=O)(=O)N=C3CCCN34)c2)=NO1
Reaction time: 0.5 h

Procedure:
To a suspension, cooled to 0° C., of the product obtained in Step A of Example 13 (250 mg, 0.67 mmol) in 15 ml of THF there are added 109 μl (1.34 mmol) of pyridine and then, dropwise, 72 μl (1.01 mmol) of thionyl chloride dissolved in 3 ml of CH2Cl2. Stirring is carried out at 0° C. for 30 minutes and the mixture is allowed to come back to ambient temperature whilst stirring for a further hour. Evaporation to dryness is carried out and the residue is made more solid by triturating it in water. The precipitate is filtered off to yield the title product.
Reaction SMILES: [CH:1]1([C:4]2[CH:5]=[CH:6][C:7]([C:15]([OH:17])=O)=[N:8][C:9]=2[O:10][CH2:11][CH:12]2[CH2:14][CH2:13]2)[CH2:3][CH2:2]1.Cl.[NH2:19][C:20]([C:23]1[O:27][N:26]=[C:25]([NH2:28])[N:24]=1)([CH3:22])[CH3:21]>>[NH2:28][C:25]1[N:24]=[C:23]([C:20]([NH:19][C:15]([C:7]2[CH:6]=[CH:5][C:4]([CH:1]3[CH2:2][CH2:3]3)=[C:9]([O:10][CH2:11][CH:12]3[CH2:13][CH2:14]3)[N:8]=2)=[O:17])([CH3:22])[CH3:21])[O:27][N:26]=1
Reactant: O=C(O)c1ccc(C2CC2)c(OCC2CC2)n1
Reactant: CC(C)(N)c1nc(N)no1
Agent: Cl
Product: CC(C)(NC(=O)c1ccc(C2CC2)c(OCC2CC2)n1)c1nc(N)no1

Procedure:
The title compound was synthesized in analogy to Example 1, using 5-cyclopropyl-6-cyclopropylmethyloxy-pyridine-2-carboxylic acid (Example 42a) and 5-(1-amino-1-methyl-ethyl)-[1,2,4]oxadiazol-3-ylamine hydrochloride (1:1) (Example 309 b) as starting materials, LC-MS (UV peak area/ESI) 100%, 358.1872 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[C:3](Cl)=[N:4][C:5]([Cl:8])=[N:6][CH:7]=1.C(N(CC)CC)C.[NH2:17][C@@H:18]([CH2:20][OH:21])[CH3:19]>C(#N)C>[Br:1][C:2]1[C:3]([NH:17][C@H:18]([CH3:19])[CH2:20][OH:21])=[N:4][C:5]([Cl:8])=[N:6][CH:7]=1
Reactant: C[C@@H](N)CO
Reactant: Clc1ncc(Br)c(Cl)n1
Solvent: CCN(CC)CC
Solvent: CC#N
Product: C[C@H](CO)Nc1nc(Cl)ncc1Br
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 22.8 g (100 mmol) of 5-bromo-2,4-dichloropyrimidine in 100 ml of acetonitrile is mixed at 0° C. first with 17.0 ml (125 mmol) of triethylamine and then with 9.4 g (125 mmol) of D-alaninol. The batch is stirred overnight at room temperature. The precipitate that is formed is suctioned off, washed with water, and completely dried. 21.5 g (81 mmol, corresponding to 81% of theory) of the product is obtained.