Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][N:5]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH:6]=1.C(N([CH2:19][CH3:20])CC)C.[CH3:21]N(C=O)C>[Cu]I.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:21]([C:2]1[CH:3]=[N:4][N:5]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH:6]=1)#[C:19][CH3:20]
Reactant: CC(C)(C)OC(=O)n1cc(Br)cn1
Reactant: CCN(CC)CC
Reactant: CN(C)C=O
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Product: CC#Cc1cnn(C(=O)OC(C)(C)C)c1
Temperature: 70 °C

Procedure:
A sealable vial was charged with a solution of tert-butyl 4-bromo-1H-pyrazole-1-carboxylate (1 g, 4.05 mmol) and triethylamine (2.81 mL, 20.24 mmol) in DMF (6.75 mL). The solution was purged with nitrogen for 10 minutes. Copper (I) iodide (0.077 g, 0.405 mmol) and tetrakis(triphenylphosphine)palladium (0.234 g, 0.202 mmol) were added and 1-propyne was bubbled through the solution for 2 min. The reaction mixture was heated at 70° C. overnight. The reaction was poured into a 9:1 mixture of aqueous saturated ammonium chloride/ammonium hydroxide and the mixture was extracted with EtOAc. The combined organic extracts were washed with a 9:1 mixture of aqueous saturated ammonium chloride/ammonium hydroxide, aqueous lithium bromide solution, brine, and dried over sodium sulfate. The filtrate was concentrated in vacuo and the residue was purified by silica gel chromatography, eluting with 1:9 EtOAc in heptane, to provide tert-butyl 4-(prop-1-yn-1-yl)-1H-pyrazole-1-carboxylate, which was taken up in MeOH and treated with excess solid K2CO3 for 15 minutes. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure The crude material was partitioned between DCM and water. The layers were separated and the aqueous layer was extracted with DCM. The combined organic extracts were washed with brine and dried over sodium sulfate. The filtrate was concentrated in vacuo to afford 4-(prop-1-yn-1-yl)-1H-pyrazole. LC/MS (ESI−) m/z=107.0 (M+H).
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:16]=[CH:15][C:14]([OH:17])=[C:13](O)[CH:12]=2)=[CH:7][CH:6]=1)(=[O:4])=[O:3].[C:19](=[O:22])([O-])[O-].[K+].[K+].[I-].[CH4:26]>CC(CC)=O>[CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:16]=[CH:15][C:14]([O:17][CH3:26])=[C:13]([O:22][CH3:19])[CH:12]=2)=[CH:7][CH:6]=1)(=[O:4])=[O:3]
Reactant: C
Reactant: CS(=O)(=O)c1ccc(-c2ccc(O)c(O)c2)cc1
Reactant: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CCC(C)=O
Product: COc1ccc(-c2ccc(S(C)(=O)=O)cc2)cc1OC
Temperature: 100 °C
Yield: 60 %

Procedure:
4′-methanesulfonyl-biphenyl-3,4-diol (30 mg) and potassium carbonate (38 mg) were dissolved in methylethylketone. Afterward, methane iodide (0.021 ml) was added and refluxed for 3 hours at 100° C. After filtering just potassium carbonate, the residue was separated through a silica gel attributed chromatography (an eluting agent: ethylacetate/n-hexane=1/4, v/v). As a result, the present compound (22 mg, productive yield 60%) was obtained.
Reaction SMILES: [NH2:1][C@:2]12[CH2:43][CH2:42][C@@H:41]([C:44]([CH3:46])=[CH2:45])[C@@H:3]1[C@@H:4]1[C@@:17]([CH3:20])([CH2:18][CH2:19]2)[C@@:16]2([CH3:21])[C@@H:7]([C@:8]3([CH3:40])[C@@H:13]([CH2:14][CH2:15]2)[C:12]([CH3:23])([CH3:22])[C:11]([C:24]2[CH2:29][CH2:28][C@H:27]([C:30]([O:32][CH2:33][C:34]4[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=4)=[O:31])[CH2:26][CH:25]=2)=[CH:10][CH2:9]3)[CH2:6][CH2:5]1.Cl[CH2:48][CH2:49][N:50]1[CH2:55][C@@H:54]2[CH2:56][C@H:51]1[CH2:52][S:53]2(=[O:58])=[O:57].P([O-])([O-])([O-])=O.[K+].[K+].[K+].[I-].[K+]>C(#N)C>[O:58]=[S:53]1(=[O:57])[CH2:52][C@@H:51]2[CH2:56][C@H:54]1[CH2:55][N:50]2[CH2:49][CH2:48][NH:1][C@:2]12[CH2:43][CH2:42][C@@H:41]([C:44]([CH3:46])=[CH2:45])[C@@H:3]1[C@@H:4]1[C@@:17]([CH3:20])([CH2:18][CH2:19]2)[C@@:16]2([CH3:21])[C@@H:7]([C@:8]3([CH3:40])[C@@H:13]([CH2:14][CH2:15]2)[C:12]([CH3:23])([CH3:22])[C:11]([C:24]2[CH2:29][CH2:28][C@H:27]([C:30]([O:32][CH2:33][C:34]4[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=4)=[O:31])[CH2:26][CH:25]=2)=[CH:10][CH2:9]3)[CH2:6][CH2:5]1
Reactant: O=S1(=O)C[C@@H]2C[C@H]1CN2CCCl
Reactant: C=C(C)[C@@H]1CC[C@]2(N)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(C6=CC[C@@H](C(=O)OCc7ccccc7)CC6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Agent: O=P([O-])([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC#N
Product: C=C(C)[C@@H]1CC[C@]2(NCCN3C[C@@H]4C[C@H]3CS4(=O)=O)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(C6=CC[C@@H](C(=O)OCc7ccccc7)CC6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Temperature: 120 °C
Yield: 39.2 %

Procedure:
A mixture of (S)-benzyl 4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-amino-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)cyclohex-3-enecarboxylate (10 mg, 0.016 mmol), (1S,4S)-5-(2-chloroethyl)-2-thia-5-azabicyclo[2.2.1]heptane 2,2-dioxide (3.36 mg, 0.016 mmol), potassium phosphate (17.01 mg, 0.080 mmol) and potassium iodide (5.32 mg, 0.032 mmol) in acetonitrile (1 mL) was heated up at 120° C. for 16 hours. The reaction mixture was then filtered and purified by HPLC to provide the desired product (5 mg, 39% yield) as a white solid. LCMS: m/e 797.8 (M+H)+, 2.31 min (method 5).
Reaction SMILES: Br[C:2]1[N:19]([CH2:20][C@H:21]2[CH2:26][CH2:25][C@H:24]([CH3:27])[CH2:23][CH2:22]2)[C:5]2[C:6]([C:12]3[CH:13]=[N:14][CH:15]=[C:16]([Cl:18])[CH:17]=3)=[N:7][C:8]([C:10]#[N:11])=[CH:9][C:4]=2[N:3]=1.[F:28][C:29]1[CH:35]=[CH:34][CH:33]=[CH:32][C:30]=1[NH2:31].C([O-])([O-])=O.[Cs+].[Cs+]>O1CCOCC1>[Cl:18][C:16]1[CH:17]=[C:12]([C:6]2[C:5]3[N:19]([CH2:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([CH3:27])[CH2:23][CH2:22]4)[C:2]([NH:31][C:30]4[CH:32]=[CH:33][CH:34]=[CH:35][C:29]=4[F:28])=[N:3][C:4]=3[CH:9]=[C:8]([C:10]#[N:11])[N:7]=2)[CH:13]=[N:14][CH:15]=1
Reactant: C[C@H]1CC[C@H](Cn2c(Br)nc3cc(C#N)nc(-c4cncc(Cl)c4)c32)CC1
Reactant: Nc1ccccc1F
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Product: C[C@H]1CC[C@H](Cn2c(Nc3ccccc3F)nc3cc(C#N)nc(-c4cncc(Cl)c4)c32)CC1
Temperature: 75 °C

Procedure:
To a sealed tube were added 2-bromo-4-(5-chloropyridin-3-yl)-3-((trans-4-methylcyclohexyl)methyl)-3H-imidazo[4,5-c]pyridine-6-carbonitrile (Preparative Example 3.1) (0.010 g, 0.045 mmol), 2-fluoroaniline (0.0050 g, 0.045 mmol), Cs2CO3 (0.022 g, 0.067 mmol), chloro[(4,5-bis(diphenylphosphino)-9,9-dimethylxanthene)-2-(2′-amino-1,1′-biphenyl)]palladium(11) (0.0050 g, 0.0056 mmol), and dioxane (0.5 mL). The reaction vessel was purged with argon, sealed and warmed to 75° C. for 8 hours with stirring. The reaction was cooled and diluted with dioxane (1.0 mL) and was passed through a syringe filter. The collected eluent was concentrated in vacuo to afford 4-(5-chloropyridin-3-yl)-2-((2-fluorophenyl)amino)-3-((trans-4-methylcyclohexyl)methyl)-3H-imidazo[4,5-c]pyridine-6-carbonitrile as a crude residue. MS ESI calc'd. for C26H24ClFN6 [M+H]+ 475. found 475.
Reaction SMILES: [CH:1]1([C:4]2[N:8]=[C:7]([CH:9]3[CH2:14][CH:13]([C:15]4[CH:20]=[CH:19][C:18]([O:21][C:22]([F:25])([F:24])[F:23])=[CH:17][CH:16]=4)[CH2:12][N:11]([C:26]([O:28]C4C=CC([N+]([O-])=O)=CC=4)=O)[CH2:10]3)[O:6][N:5]=2)[CH2:3][CH2:2]1.[NH:38]1[CH2:42][CH2:41][CH:40]([OH:43])[CH2:39]1>>[CH:1]1([C:4]2[N:8]=[C:7]([CH:9]3[CH2:14][CH:13]([C:15]4[CH:16]=[CH:17][C:18]([O:21][C:22]([F:25])([F:23])[F:24])=[CH:19][CH:20]=4)[CH2:12][N:11]([C:26]([N:38]4[CH2:42][CH2:41][CH:40]([OH:43])[CH2:39]4)=[O:28])[CH2:10]3)[O:6][N:5]=2)[CH2:3][CH2:2]1
Reactant: OC1CCNC1
Reactant: O=C(Oc1ccc([N+](=O)[O-])cc1)N1CC(c2ccc(OC(F)(F)F)cc2)CC(c2nc(C3CC3)no2)C1
Product: O=C(N1CCC(O)C1)N1CC(c2ccc(OC(F)(F)F)cc2)CC(c2nc(C3CC3)no2)C1

Procedure:
100 mg (0.19 mmol) of the compound from Example 176A and 50 mg (0.58 mmol) of 3-pyrrolidinol were reacted according to the General Method 6. Yield: 50 mg (53% of theory)
Reaction SMILES: [Br:1]Br.[Cl:3][C:4]1[S:8][C:7]([C:9]([OH:11])=[O:10])=[CH:6][CH:5]=1>CC(O)=O>[Br:1][C:5]1[CH:6]=[C:7]([C:9]([OH:11])=[O:10])[S:8][C:4]=1[Cl:3]
Reactant: O=C(O)c1ccc(Cl)s1
Reactant: BrBr
Solvent: CC(=O)O
Product: O=C(O)c1cc(Br)c(Cl)s1

Procedure:
A solution of bromine (634 uL, 12.3 mmol) in AcOH (2.5 mL) was added dropwise to 5-chloro-2-thiophenecarboxylic acid (2 g, 12.3 mmol) and FeCl3 (399 mg, 2.50 mmol) in AcOH (25 mL) at 25° C. The reaction mixture was warmed to reflux where additional bromine (634 uL, 12.3 mmol) and FeCl3 (399 mg, 2.50 mmol) were added. After 7d, the solution was poured onto ice and the precipitate was filtered and washed with water affording the title compound (3 g, quant.) as a yellow powder: LCMS (ES) m/z 242 (M+H)+.
Reaction SMILES: C1C=CC2N(O)[N:8]=[N:7]C=2C=1.[F:11][C:12]1[CH:13]=[C:14]([CH:22]=[CH:23][C:24]=1[F:25])[O:15][C:16]([CH3:21])([CH3:20])[C:17](O)=[O:18].C(OC(C)(C)C)(=O)NN.[Cl:35]CCl>>[ClH:35].[F:11][C:12]1[CH:13]=[C:14]([CH:22]=[CH:23][C:24]=1[F:25])[O:15][C:16]([CH3:21])([CH3:20])[C:17]([NH:7][NH2:8])=[O:18]
Reactant: CC(C)(Oc1ccc(F)c(F)c1)C(=O)O
Reactant: On1nnc2ccccc21
Reactant: ClCCl
Agent: CC(C)(C)OC(=O)NN
Product: CC(C)(Oc1ccc(F)c(F)c1)C(=O)NN
Product: Cl
Temperature: 25 °C
Reaction time: 1 h

Procedure:
WSC•monohydrochloride (7.84 g) and HOBt (4.25 g) were added to a solution of 2-(3,4-difluorophenoxy)-2-methylpropanoic acid (6.80 g) in dichloromethane (60 ml), followed by stirring at room temperature for one hour, tert-butyl carbazate (4.57 g) was added thereto, followed by stirring at room temperature for 14 hours. The reaction solution was concentrated under reduced pressure and ethyl acetate was then added thereto, the organic layer was washed with water, 0.5M hydrochloric acid, saturated aqueous sodium bicarbonate solution-water (1:1) and then saturated brine in this order, and then dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The resulting oil (10.2 g) was dissolved in ethyl acetate, 4M hydrogen chloride-ethyl acetate was added thereto, followed by stirring at room temperature for 5 hours, and then concentrated under reduced pressure. Ethyl acetate was added thereto, followed by stirring and collecting by filtration, to obtain, as a colorless solid, 2-(3,4-difluorophenoxy)-2-methylpropanohydrazide monohydrochloride (8.11 g).
Reaction SMILES: [C:1]([NH:4][C@@H:5]([CH3:16])[CH2:6][O:7][C:8]1[CH:12]=[C:11]([C:13]([OH:15])=O)[O:10][N:9]=1)(=[O:3])[CH3:2].[NH2:17][C:18]1[CH:23]=[CH:22][C:21]([O:24][CH2:25][CH:26]2[CH2:28][CH2:27]2)=[CH:20][C:19]=1[S:29][CH2:30][CH2:31][C:32]([O:34][CH2:35][CH:36]([CH2:41][CH3:42])[CH2:37][CH2:38][CH2:39][CH3:40])=[O:33]>>[C:1]([NH:4][C@@H:5]([CH3:16])[CH2:6][O:7][C:8]1[CH:12]=[C:11]([C:13]([NH:17][C:18]2[CH:23]=[CH:22][C:21]([O:24][CH2:25][CH:26]3[CH2:27][CH2:28]3)=[CH:20][C:19]=2[S:29][CH2:30][CH2:31][C:32]([O:34][CH2:35][CH:36]([CH2:41][CH3:42])[CH2:37][CH2:38][CH2:39][CH3:40])=[O:33])=[O:15])[O:10][N:9]=1)(=[O:3])[CH3:2]
Reactant: CCCCC(CC)COC(=O)CCSc1cc(OCC2CC2)ccc1N
Reactant: CC(=O)N[C@@H](C)COc1cc(C(=O)O)on1
Product: CCCCC(CC)COC(=O)CCSc1cc(OCC2CC2)ccc1NC(=O)c1cc(OC[C@H](C)NC(C)=O)no1

Procedure:
Using 3-{[(2S)-2-(acetylamino)propyl]oxy}isoxazole-5-carboxylic acid and 2-ethylhexyl 3-{[2-amino-5-(cyclopropylmethoxy)phenyl]sulfanyl}propanoate, and in the same manner as in Example 2, step C, the title compound was obtained.
Reaction SMILES: [Cl-:1].[NH3+:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]([C:9]1[CH:10]=[NH+:11][CH:12]=[CH:13][CH:14]=1)=O.[Cl-].[CH:16]([C:18]1[O:22][C:21]([C:23]2[CH:27]=[CH:26][S:25][C:24]=2[C:28]([O:30][CH3:31])=[O:29])=[CH:20][CH:19]=1)=O.Cl>C(O)(C)C>[ClH:1].[ClH:1].[N:11]1[CH:12]=[CH:13][CH:14]=[C:9]([C:7]2[C:6](=[CH:16][C:18]3[O:22][C:21]([C:23]4[CH:27]=[CH:26][S:25][C:24]=4[C:28]([O:30][CH3:31])=[O:29])=[CH:20][CH:19]=3)[CH2:5][CH2:4][CH2:3][N:2]=2)[CH:10]=1
Reactant: [NH3+]CCCCC(=O)c1ccc[nH+]c1
Reactant: COC(=O)c1sccc1-c1ccc(C=O)o1
Reactant: [Cl-]
Agent: Cl
Solvent: CC(C)O
Product: COC(=O)c1sccc1-c1ccc(C=C2CCCN=C2c2cccnc2)o1
Temperature: 80 °C
Reaction time: 8 h
Yield: 97.7 %

Procedure:
3-(5-Ammoniopentanoyl)pyridinium chloride (99 mg, 0.39 mmol) and methyl 3-(5-formyl-2-furyl)thiophene-2-carboxylate (102 mg, 0.43 mmol) were combined in a reaction vessel and treated with isopropanol (6 mL). The reaction vessel was sealed and the reaction was heated to 80° C. with stirring overnight. The reaction was cooled to room temperature. The precipitate was recovered by vacuum filtration, then treated with saturated NaHCO3(aq) and extracted three times with EtOAc. The EtOAc extracts were washed with brine, combined, dried over Na2SO4, filtered, concentrated under reduced pressure, and eluted through a 20 gram column of silica gel with 99:1:0.1 CH2Cl2:MeOH:NH4OH (1 liter). The recovered material was dissolved into MeOH and treated with 2 eq. of 6 N HCl(aq). This solution was concentrated under reduced pressure and the recovered material was dissolved into hot isopropanol to re-crystallize. Crystals were recovered by vacuum filtration, washed with a 20 isopropanol in hexane solution, and then with ether, then dried under vacuum giving 86 mg (48%) of an orange solid. LC-MS: RT=5.25 min, [M+H]+=379.0.
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][OH:8].[C:9]1([CH2:15][CH2:16][C:17](O)=[O:18])[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>>[Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][O:8][C:17](=[O:18])[CH2:16][CH2:15][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: O=C(O)CCc1ccccc1
Reactant: OCCCCCCBr
Product: O=C(CCc1ccccc1)OCCCCCCBr
Yield: 85 %

Procedure:
From 6-bromo-1-hexanol and 3-phenylpropionic acid. Yield: 85% (oil).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[NH:10][CH:9]=2)[C:5]([Cl:17])=[CH:4][N:3]=1.[NH2:18][C:19]1[CH:24]=[CH:23][C:22]([N:25]2[CH2:30][CH2:29][CH:28]([NH2:31])[CH2:27][CH2:26]2)=[CH:21][C:20]=1[O:32][CH3:33].CC1C=CC(S(O)(=O)=O)=CC=1>C(O)CCCC>[NH2:31][CH:28]1[CH2:29][CH2:30][N:25]([C:22]2[CH:23]=[CH:24][C:19]([NH:18][C:2]3[N:7]=[C:6]([C:8]4[C:16]5[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=5)[NH:10][CH:9]=4)[C:5]([Cl:17])=[CH:4][N:3]=3)=[C:20]([O:32][CH3:33])[CH:21]=2)[CH2:26][CH2:27]1
Reactant: Clc1ncc(Cl)c(-c2c[nH]c3ccccc23)n1
Reactant: COc1cc(N2CCC(N)CC2)ccc1N
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCCCCO
Product: COc1cc(N2CCC(N)CC2)ccc1Nc1ncc(Cl)c(-c2c[nH]c3ccccc23)n1
Temperature: 140 °C
Reaction time: 72 h
Yield: 36.2 %

Procedure:
A solution of 3-(2,5-dichloropyrimidin-4-yl)-1H-indole (5.28 g, 20 mmol), 1-(4-amino-3-methoxyphenyl)piperidin-4-amine (4.43 g, 20.00 mmol), and tosic acid (5.71 g, 30.00 mmol) in n-pentanol (40.0 ml) was placed in a round-bottomed flask. The solution was heated at 140° C., and stirred at that temperature for three days. The solvent was removed by concentration in vacuo, and to the residue was added sat. NaHCO3 solution and dichloromethane. The mixture was filtered and the obtained solid was dissolved in a mixture of THF and methanol and pre-absorbed on silica gel (120 g). The mixture was loaded onto silica gel column and eluted with 10% MeOH, 1% NH4OH in DCM. The collected fractions were concentrated, and the residue was triturated in diethyl ether. The collected solid after filtration was triturated in ethanol. Filtration afforded the title compound (3.25 g, 36.2% yield).
Reaction SMILES: C(O[C:6](=O)[N:7]([CH:9]([C:11]1[N:12](C2CCCCO2)[C:13]2[C:18]([N:19]=1)=[C:17]([N:20]1[CH2:25][CH2:24][O:23][CH2:22][CH2:21]1)[N:16]=[C:15]([Cl:26])[N:14]=2)[CH3:10])C)(C)(C)C.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>CO>[Cl:26][C:15]1[N:14]=[C:13]2[C:18]([N:19]=[C:11]([CH:9]([NH:7][CH3:6])[CH3:10])[NH:12]2)=[C:17]([N:20]2[CH2:21][CH2:22][O:23][CH2:24][CH2:25]2)[N:16]=1
Reactant: CC(c1nc2c(N3CCOCC3)nc(Cl)nc2n1C1CCCCO1)N(C)C(=O)OC(C)(C)C
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CO
Solvent: O
Product: CNC(C)c1nc2c(N3CCOCC3)nc(Cl)nc2[nH]1
Temperature: 25 °C
Reaction time: 3 h
Yield: 97 %

Procedure:
A mixture of {1-[2-chloro-6-morpholin-4-yl-9-(tetrahydro-pyran-2-yl)-9H-purin-8-yl]-ethyl}-methyl-carbamic acid tert-butyl ester (316 mg, 0.66 mmol) and p-toluenesulfonic acid monohydrate (30 mg) in methanol was stirred at room temperature for 3 h, then allowed to stand for 56h. The reaction mixture was concentrated in vacuo to a small volume, then DCM (3 mL) and trifluoroacetic acid (3 mL) were added and the reaction mixture was stirred for 4.75 h at RT. Another portion of trifluoroacetic acid (3 mL) was added and stirring was continued for 2 h. The mixture was concentrated in vacuo and the resulting residue was triturated three times with diethyl ether. The resulting solid was partitioned between a 10% solution of methanol in DCM and aqueous sodium bicarbonate. The phases were separated, and the aqueous phase was extracted four times with a 10% solution of methanol in DCM. The combined organic fractions were dried (Na2SO4), filtered and concentrated in vacuo to give [1-(2-Chloro-6-morpholin-4-yl-9H-purin-8-yl)-ethyl]-methyl-amine (0.19 g, 97%). LCMS RT=1.68 min, [M+H]+=297
Reaction SMILES: [C:1]([CH2:7][C:8]#[N:9])(=O)[C:2]([CH3:5])([CH3:4])[CH3:3].[C:10]1([NH:16][NH2:17])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C(O)(=O)C>C(O)C>[NH2:9][C:8]1[N:16]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[N:17]=[C:1]([C:2]([CH3:5])([CH3:4])[CH3:3])[CH:7]=1
Reactant: CC(C)(C)C(=O)CC#N
Reactant: NNc1ccccc1
Solvent: CCO
Solvent: CC(=O)O
Product: CC(C)(C)c1cc(N)n(-c2ccccc2)n1
Temperature: 0 °C

Procedure:
Pivaloyl acetonitrile (30.0 g; 0.24 mole) and ethanol (200 ml) were placed into a 500 ml round bottom flask. Phenylhydrazine (23.6 ml; 0.24 mole) was added with stirring followed by acetic acid (13.8 ml). The reaction was refluxed for 5 hours. Part of the ethanol was stripped off and the residue was poured into ice water. The product was filtered off and washed with water. The solid was dissolved in hot ethanol (100 ml), diluted with water, stirred, filtered, and washed with water. The yield of solid, m.p. 65°-7° C. was 46.3 g (90%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][C:12]([C:15]([O:17]C)=[O:16])=[CH:11][C:10]=2[CH3:19])=[CH:5][C:4]=1[C:20]1[CH:25]=[CH:24][C:23]([C:26]([F:29])([F:28])[F:27])=[CH:22][C:21]=1[CH2:30][N:31]1[C@@H:35]([CH3:36])[C@@H:34]([C:37]2[CH:42]=[CH:41][N:40]=[C:39]([CH3:43])[CH:38]=2)[O:33][C:32]1=[O:44].[Li+].[OH-].Cl>O1CCOCC1.O>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][C:12]([C:15]([OH:17])=[O:16])=[CH:11][C:10]=2[CH3:19])=[CH:5][C:4]=1[C:20]1[CH:25]=[CH:24][C:23]([C:26]([F:28])([F:29])[F:27])=[CH:22][C:21]=1[CH2:30][N:31]1[C@@H:35]([CH3:36])[C@@H:34]([C:37]2[CH:42]=[CH:41][N:40]=[C:39]([CH3:43])[CH:38]=2)[O:33][C:32]1=[O:44]
Reactant: COC(=O)c1ccc(-c2ccc(OC)c(-c3ccc(C(F)(F)F)cc3CN3C(=O)O[C@H](c4ccnc(C)c4)[C@@H]3C)c2)c(C)c1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: COc1ccc(-c2ccc(C(=O)O)cc2C)cc1-c1ccc(C(F)(F)F)cc1CN1C(=O)O[C@H](c2ccnc(C)c2)[C@@H]1C
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of methyl 4′-methoxy-2-methyl-2″-{[(4S,5R)-4-methyl-5-(2-methylpyridin-4-yl)-2-oxo-1,3-oxazolidin-3-yl]methyl}-4″-(trifluoromethyl)-1,1′:3′,1″-terphenyl-4-carboxylate (30.1 mg, 0.050 mmol) in 1,4-dioxane (1.5 mL) and water (1.5 mL) was added 1M aqueous LiOH (0.498 mL, 0.498 mmol). The mixture was stirred at room temperature for 4 h. The mixture was acidified with 1N HCl. The aqueous layer was extracted with EtOAc (3×). The combined organic layers were dried (Na2SO4), filtered and the solvent was evaporated in vacuo. The crude material was purified by preparative HPLC reverse phase (C-18), eluting with MeCN/water. The fractions were collected and lyophilized to give 4′-methoxy-2-methyl-2″-{[(4S,5R)-4-methyl-5-(2-methylpyridin-4-yl)-2-oxo-1,3-oxazolidin-3-yl]-methyl}-4″-(trifluoromethyl)-1,1′:3′,1″-terphenyl-4-carboxylic acid. LCMS calc.=591.2; found=591.1 (M+1)+. 1H NMR (500 MHz, CDCl3, 1:1 mixture of atropisomers) δ 8.83 (s, 1 H); 8.02 (s, 1 H); 7.94 (t, J=10.0 Hz, 1 H); 7.72 (s, 0.5 H); 7.69 (t, J=6.0 Hz, 1 H); 7.64 (s, 0.5 H); 7.49-7.43 (m, 3 H); 7.40 (d, J=5.2 Hz, 0.5 H); 7.35 (d, J=5.4 Hz, 0.5 H); 7.31 (m, 1 H); 7.16 (dd, J=2.1, 6.0 Hz, 1H); 7.12 (t, J=8.8 Hz, 1 H); 5.56 (d, J=8.1 Hz, 0.5 H); 5.26 (d, J=8.2 Hz, 0.5H); 4.94 (dd, J=8.7, 15.7 Hz, 1H); 4.77 (br s, 1 H); 4.20 (d, J=15.8 Hz, 0.5 H); 4.00 (d, J=15.7 Hz, 0.5 H); 3.90 (s, 1.5 H); 3.89 (s, 1.5 H); 3.89-3.81 (m, 1 H); 2.82 (s, 1.5 H); 2.81 (s, 1.5 H); 2.41 (s, 1.5 H); 2.36 (s, 1.5 H); 0.62 (d, J=6.5 Hz, 1.5 H); 0.49 (d, J=6.5 Hz, 1.5 H).
Reaction SMILES: [CH:1]1([S:4]([NH:7][C:8]([C@@:10]2([NH:15]C(=O)OC(C)(C)C)[CH2:12][C@H:11]2[CH:13]=[CH2:14])=[O:9])(=[O:6])=[O:5])[CH2:3][CH2:2]1.C([Cl:26])(=O)C>CO>[ClH:26].[NH2:15][C@:10]1([C:8]([NH:7][S:4]([CH:1]2[CH2:3][CH2:2]2)(=[O:6])=[O:5])=[O:9])[CH2:12][C@H:11]1[CH:13]=[CH2:14]
Reactant: C=C[C@@H]1C[C@]1(NC(=O)OC(C)(C)C)C(=O)NS(=O)(=O)C1CC1
Reactant: CC(=O)Cl
Solvent: CO
Product: C=C[C@@H]1C[C@]1(N)C(=O)NS(=O)(=O)C1CC1
Product: Cl
Temperature: 50 °C
Yield: 103 %

Procedure:
Compound 130 (1 g) was suspended in methanol (2.5 mL). A solution of acetyl chloride (3 eq.) in methanol was added to the suspension. The reaction mixture was heated at 50° C. for 3 hrs. The reaction mixture was concentrated at 45-50° C. and co-evaporated with DCM to give compound 131 (833 mg) as a white foam in 103% yield due to DCM.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[N:10]([CH3:25])[C:11]1[CH:20]=[CH:19][C:18]2[C:17]([CH3:22])([CH3:21])[CH2:16][CH2:15][C:14]([CH3:24])([CH3:23])[C:13]=2[CH:12]=1)[C:5]#[N:6].[CH3:26][O:27][C:28](=[O:38])[C:29]1[CH:37]=[CH:36][C:32]([C:33](O)=O)=[CH:31][CH:30]=1.O=P(Cl)(Cl)Cl.Cl>O.C1(C)C=CC=CC=1>[CH3:26][O:27][C:28](=[O:38])[C:29]1[CH:37]=[CH:36][C:32]([C:33]2[C:20]3=[CH:19][C:18]4[C:17]([CH3:21])([CH3:22])[CH2:16][CH2:15][C:14]([CH3:24])([CH3:23])[C:13]=4[CH:12]=[C:11]3[N:10]([CH3:25])[C:9]3[CH:8]=[CH:7][C:4]([C:5]#[N:6])=[CH:3][C:2]=3[N:1]=2)=[CH:31][CH:30]=1
Reactant: COC(=O)c1ccc(C(=O)O)cc1
Reactant: CN(c1ccc2c(c1)C(C)(C)CCC2(C)C)c1ccc(C#N)cc1N
Agent: Cl
Solvent: Cc1ccccc1
Solvent: O
Solvent: O=P(Cl)(Cl)Cl
Product: COC(=O)c1ccc(C2=Nc3cc(C#N)ccc3N(C)c3cc4c(cc32)C(C)(C)CCC4(C)C)cc1
Temperature: 80 °C

Procedure:
A mixture of 3-amino-4-[methyl-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)amino]benzonitrile (32) (R4=CH3, 30.0 mmol), terephthalic acid monomethyl ester (30.0 mmol), POCl3 (69.0 mmol), and toluene (200 mL) is heated at 80° C. for 3 days. After cooling, the reaction mixture is treated with 1 N HCl (100 mL) and H2O (100 mL) and extracted with EtOAc. The organic layer is dried over MgSO4 and evaporated in vacuo. The residue is purified by flash column chromatography (hexane:EtOAc=5:1) to give (33) (R4=CH3, Z=H).
Reaction SMILES: C([NH:4][N:5]1[CH2:10][C:9]([CH3:11])=[N:8][NH:7][C:6]1=[O:12])(=O)C.Cl.C([O-])(=O)C.[Na+]>CO>[NH2:4][N:5]1[CH2:10][C:9]([CH3:11])=[N:8][NH:7][C:6]1=[O:12]
Reactant: CC(=O)NN1CC(C)=NNC1=O
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: CC1=NNC(=O)N(N)C1
Temperature: 50 °C
Reaction time: 4 h

Procedure:
A mixture of 85 g of 4-acetylamino-6-methyl-3-oxo-2,3,4,5-tetrahydro- 1,2,4-triazine, 63 ml of hydrochloric acid (37%) and 250 ml of methanol is stirred for 4 hours at 50° C. After cooling to 15° C., 82 g of sodium acetate are added, the mixture is stirred for a further 15 minutes, and the solvent is removed by evaporation. The residue is taken up in 100 ml of ethanol, and the solvent is removed again in vacuo. The residue is taken up in 1200 ml of acetonitrile, undissolved salt precipitates are filtered off, the filtrate is evaporated to dryness, the residue is caused to crystallize by adding 50 ml of acetic acid ethyl ester at ambient temperature, and the crystals are filtered off and dried yielding 54.6 g (85% of the theoretical amount) of the title compound having a melting point of 113°-118° C.