Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:22]=[CH:23][C:24]=1[F:25])[NH:5][C:6]1[C:15]2[C:10](=[CH:11][C:12](Cl)=[C:13]([N+:16]([O-:18])=[O:17])[CH:14]=2)[N:9]=[CH:8][C:7]=1[C:20]#[N:21].[CH3:26][N:27]1[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1.C1(C)C=CC=CC=1>CC(C)=O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:22]=[CH:23][C:24]=1[F:25])[NH:5][C:6]1[C:15]2[C:10](=[CH:11][C:12]([N:30]3[CH2:31][CH2:32][N:27]([CH3:26])[CH2:28][CH2:29]3)=[C:13]([N+:16]([O-:18])=[O:17])[CH:14]=2)[N:9]=[CH:8][C:7]=1[C:20]#[N:21]
Reactant: N#Cc1cnc2cc(Cl)c([N+](=O)[O-])cc2c1Nc1ccc(F)c(Cl)c1
Reactant: CN1CCNCC1
Solvent: Cc1ccccc1
Solvent: CC(C)=O
Product: CN1CCN(c2cc3ncc(C#N)c(Nc4ccc(F)c(Cl)c4)c3cc2[N+](=O)[O-])CC1

Procedure:
A stirred mixture of 4-(3-chloro-4-fluoroanilino)-7-chloro-6-nitro-3-quinolinecarbonitrile (1.88 g, 5.0 mmol), N-methylpiperazine (5 ml, 45 mmol), and 10 ml of toluene was refluxed for 45 m, evaporated to remove volatile matter, and stirred in water with potassium carbonate (2.75 g). The resulting solid was filtered, washed with water, and dried to give 2.26 g. An acetone solution was passed onto a pad of silica gel; elution with 50:2:1 acetone-MeOH-TEA and evaporation gave a red solid, mp 240-246°; ms 441.2 (M+H)+, 221.2 (M+2H)+2.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10]([OH:12])=O)=[CH:5][CH:4]=1.[NH2:13][C:14]1[CH:18]=[CH:17][S:16][C:15]=1[C:19]([O:21][CH3:22])=[O:20]>>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:9][C:10]([NH:13][C:14]2[CH:18]=[CH:17][S:16][C:15]=2[C:19]([O:21][CH3:22])=[O:20])=[O:12])=[CH:7][CH:8]=1
Reactant: COC(=O)c1sccc1N
Reactant: COc1ccc(CC(=O)O)cc1
Product: COC(=O)c1sccc1NC(=O)Cc1ccc(OC)cc1

Procedure:
The title compound was prepared from 2-(4-methoxyphenyl)acetic acid (3.18 g, 19.2 mmol) and methyl 3-aminothiophene-2-carboxylate (3.02 g, 19.2 mmol) according to protocol B. Retention time (min)=2.143, method [1], MS (ESI) 306.1 (M+H).
Reaction SMILES: [Si:1]([O:8][CH2:9][C:10]([C@H:12]1[N:15]([CH:16]([CH2:26][C:27]2[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[CH:29][CH:28]=2)[CH2:17][C:18]2[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=2)[C:14](=[O:35])[C@@H:13]1[C@H:36]([O:38][C:39]([O:41][CH2:42][C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1)=[O:40])[CH3:37])=[CH2:11])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].O.[H][H]>C(#N)C>[Si:1]([O:8][CH2:9][CH:10]([C@@H:12]1[N:15]([CH:16]([CH2:26][C:27]2[CH:28]=[CH:29][C:30]([O:33][CH3:34])=[CH:31][CH:32]=2)[CH2:17][C:18]2[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=2)[C:14](=[O:35])[C@@H:13]1[C@H:36]([O:38][C:39]([O:41][CH2:42][C:43]1[CH:44]=[CH:45][CH:46]=[CH:47][CH:48]=1)=[O:40])[CH3:37])[CH3:11])([C:4]([CH3:5])([CH3:6])[CH3:7])([CH3:3])[CH3:2]
Reactant: [H][H]
Reactant: C=C(CO[Si](C)(C)C(C)(C)C)[C@@H]1[C@@H]([C@@H](C)OC(=O)OCc2ccccc2)C(=O)N1C(Cc1ccc(OC)cc1)Cc1ccc(OC)cc1
Solvent: CC#N
Solvent: O
Product: COc1ccc(CC(Cc2ccc(OC)cc2)N2C(=O)[C@H]([C@@H](C)OC(=O)OCc3ccccc3)[C@@H]2C(C)CO[Si](C)(C)C(C)(C)C)cc1

Procedure:
To a solution of (3S,4S)-4-(1-t-butyldimethylsilyloxymethylethenyl)-3-(1-(R)-benzyloxycarbonyloxyethyl)-1-di(p-anisyl)methyl-2-azetidinone (20 g) in acetonitrile (200 ml), there were added 5% platinium on activated carbon (4.0 g) and water (4 ml) under nitrogen atmosphere. The mixture was stirred at 10° C. in a hydrogen gas flow until 2.2 equivalents of hydrogen had been taken up. The catalyst was removed by filtration and washed with ethyl acetate. The filtrate and the washings were combined together and concentrated in vacuo to give (3S,4S)-4-(1-t-butyldimethylsilyloxymethylethyl)-3-(1-(R)-benzyloxycarbonyloxyethyl)-1-di-(p-anisyl)methyl-2-azetidinone as an oil.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH3:20][N:21]([CH3:25])[CH2:22][CH2:23][OH:24].[CH2:26]([O:30][C:31]1[CH:36]=[CH:35][C:34]([S:37]([N:40]([CH:42]([C:47]2[CH:52]=[CH:51][C:50](O)=[CH:49][CH:48]=2)[C:43]([O:45][CH3:46])=[O:44])[CH3:41])(=[O:39])=[O:38])=[CH:33][CH:32]=1)[C:27]#[C:28][CH3:29].N(C(OCC)=O)=NC(OCC)=O>C1COCC1>[CH3:46][O:45][C:43](=[O:44])[CH:42]([N:40]([S:37]([C:34]1[CH:35]=[CH:36][C:31]([O:30][CH2:26][C:27]#[C:28][CH3:29])=[CH:32][CH:33]=1)(=[O:38])=[O:39])[CH3:41])[C:47]1[CH:52]=[CH:51][C:50]([O:24][CH2:23][CH2:22][N:21]([CH3:25])[CH3:20])=[CH:49][CH:48]=1
Reactant: CC#CCOc1ccc(S(=O)(=O)N(C)C(C(=O)OC)c2ccc(O)cc2)cc1
Reactant: CN(C)CCO
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC#CCOc1ccc(S(=O)(=O)N(C)C(C(=O)OC)c2ccc(OCCN(C)C)cc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 52.2 %

Procedure:
To a solution of 0.390 g (1.489 mmol) of triphenylphosphine in 8 mL of THF was added 0.150 mL (1.489 mmol) of N,N-dimethylethanolamine followed by 0.400 g (0.993 mmol) of methyl [{[4-(2-butynyloxy)phenyl]sulfonyl}(methyl)amino](4-hydroxyphenyl)acetate (from Example 179) and 0.234 mL (1.489 mmol) of diethyl azodicarboxylate. The reaction was stirred overnight at room temperature and then concentrated in vacuo. The residue was chromatographed on silica gel eluting with ethyl acetate/hexanes (1:3) to give 0.246 g of methyl[{[4-(2-butynyloxy)phenyl]sulfonyl}(methyl)amino]{4-[2-(dimethylamino)ethoxy]phenyl}acetate as a white solid. Electrospray Mass Spec 475.2 (M+H)+
Reaction SMILES: [CH3:1][N:2]([CH3:14])[C:3]1[C:8]([C:9]#[N:10])=[C:7]([F:11])[C:6]([CH:12]=O)=[CH:5][CH:4]=1.[CH3:15][O:16][C:17]1[N:18]=[C:19]2[C:24](=[CH:25][CH:26]=1)[N:23]=[CH:22][CH:21]=[C:20]2[N:27]1[CH:35]=[C:34]2[C:29]([CH2:30][CH2:31][CH:32]([NH2:36])[CH2:33]2)=[N:28]1.[BH4-].[Na+]>CO.O>[CH3:1][N:2]([CH3:14])[C:3]1[C:8]([C:9]#[N:10])=[C:7]([F:11])[C:6]([CH2:12][NH:36][CH:32]2[CH2:31][CH2:30][C:29]3[C:34](=[CH:35][N:27]([C:20]4[C:19]5[C:24](=[CH:25][CH:26]=[C:17]([O:16][CH3:15])[N:18]=5)[N:23]=[CH:22][CH:21]=4)[N:28]=3)[CH2:33]2)=[CH:5][CH:4]=1
Reactant: CN(C)c1ccc(C=O)c(F)c1C#N
Reactant: COc1ccc2nccc(-n3cc4c(n3)CCC(N)C4)c2n1
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: COc1ccc2nccc(-n3cc4c(n3)CCC(NCc3ccc(N(C)C)c(C#N)c3F)C4)c2n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 43.7 %

Procedure:
To a solution of 6-dimethylamino-2-fluoro-3-formyl-benzonitrile (69 mg, 0.36 mmol) in CH3OH (7 mL) was added 2-(6-methoxy-[1,5]naphthyridin-4-yl)-4,5,6,7-tetrahydro-2H-indazol-5-ylamine (11 mg, 0.34 mmol). The reaction mixture was stirred overnight at RT. NaBH4 (19 mg, 0.50 mmol) was then added and the suspension was stirred for 30 min at RT. The reaction mixture was diluted with a few drops of H2O, and the solvents were removed under reduced pressure. The crude material was purified by basic reverse phase to provide 70 mg (44%) of the title compound. MS (ESI): exact mass calculated for C26H26FN7O, 471.22; m/z found, 472.5 [M+H]+. 1H NMR (500 MHz, CDCl3): 9.09 (s, 1H), 8.75 (d, J=5.1, 1H), 8.26 (d, J=9.1, 1H), 8.14 (d, J=5.1, 1H), 7.38 (t, J=8.7, 1H), 7.18 (d, J=9.1, 1H), 6.58 (d, J=8.7, 1H), 4.75 (br s, 1H), 4.10 (s, 3H), 3.86 (s, 2H), 3.08 (s, 6H), 3.02-2.97 (m, 3H), 2.84-2.77 (m, 1H), 2.52 (dd, J=16.6, 9.9, 1H), 2.15-2.11 (m, 1H).
Reaction SMILES: C(OC([NH:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][NH:16][C:17]2[C:22]([Cl:23])=[CH:21][N:20]=[C:19]([Cl:24])[N:18]=2)=[CH:11][C:10]=1[CH2:25][CH2:26][C:27]1[CH:28]=[C:29]([NH:33]C(=O)OC(C)(C)C)[CH:30]=[N:31][CH:32]=1)=O)(C)(C)C.CO.[ClH:43]>O1CCOCC1>[ClH:23].[ClH:43].[ClH:23].[NH2:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][NH:16][C:17]2[C:22]([Cl:23])=[CH:21][N:20]=[C:19]([Cl:24])[N:18]=2)=[CH:11][C:10]=1[CH2:25][CH2:26][C:27]1[CH:32]=[N:31][CH:30]=[C:29]([NH2:33])[CH:28]=1
Reactant: CC(C)(C)OC(=O)Nc1cncc(CCc2cc(CNc3nc(Cl)ncc3Cl)ccc2NC(=O)OC(C)(C)C)c1
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: Nc1cncc(CCc2cc(CNc3nc(Cl)ncc3Cl)ccc2N)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 98 %

Procedure:
Into a reaction flask were added tert-butyl {5-[2-(2-[(tert-butoxycarbonyl)amino]-5-{[(2,5-dichloropyrimidin-4-yl)amino]methyl}phenyl)ethyl]pyridin-3-yl}carbamate (0.44 g, 0.75 mmol), methanol (3 mL), and a solution of hydrogen chloride in 1,4-dioxane (5 mL, 4.0 M). The reaction mixture was stirred at rt overnight and concentrated under vacuum to give the desired product as a white powder (0.40 g, 98%). LCMS for C18H19Cl2N6 (M+H)+: m/z=389.0, 391.0.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH:9]2[CH2:14][CH2:13][CH2:12][CH2:11][O:10]2)=[CH:4][CH:3]=1.[CH3:15][Si:16]([C:19]#[CH:20])([CH3:18])[CH3:17]>C(NC(C)C)(C)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[O:10]1[CH2:11][CH2:12][CH2:13][CH2:14][CH:9]1[O:8][C:5]1[CH:6]=[CH:7][C:2]([C:20]#[C:19][Si:16]([CH3:18])([CH3:17])[CH3:15])=[CH:3][CH:4]=1
Reactant: C#C[Si](C)(C)C
Reactant: Ic1ccc(OC2CCCCO2)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CC(C)NC(C)C
Product: C[Si](C)(C)C#Cc1ccc(OC2CCCCO2)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a degassed solution of compound 1 (9.12 g, 30 mmol) in diisopropylamine (180 ml) under nitrogen, Pd(PPh3)2Cl2 (140 mg, 0.2 mmol) and CuI (78 mg, 0.4 mmol) were added. Then trimethylsilyl acetylene (3.3 g, 33 mmol) was added dropwise to this clear solution. The reaction mixture was stirred for 2 hours at room temperature. The salt formed during the reaction procedure was filtered off and washed well with ethyl acetate. The filtrate was evaporated to dryness and hydrolyzed with concentrated hydrochloric acid (5 ml), water (25 ml) and crushed ice (10 g), then extracted with ethyl acetate. The combined organic paste was washed with brine and dried with MgSO4. The solvent was removed in vacuo and the residue was purified by column chromatography (petroleum ether-ethyl acetate=9:1) to give a yellow oil of 2. Yield 7.9 g (96%); δH(CDCl3; 300 MHz): 7.39(d, J=8.7, 2H, Ar—H, 6.97(d, J=8.6, 2H, Ar—H), 5.41(t, J=3.1, 1H, OCHO), 3.84(m, 1H, THP), 3.59(m, 1H, THP), 1.86˜1.61(m, 6H, THP), 0.23(s, 9H, 3CH3).
Reaction SMILES: [CH2:1]([C:3]1[C:4](=[O:19])[NH:5][C:6](=[O:18])[NH:7][C:8]=1[O:9][C:10]1[CH:15]=[C:14]([CH3:16])[CH:13]=[C:12]([CH3:17])[CH:11]=1)[CH3:2].Cl[CH2:21][N:22]1[C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=2[N:24]=[N:23]1>>[N:22]1([CH2:21][N:7]2[C:8]([O:9][C:10]3[CH:11]=[C:12]([CH3:17])[CH:13]=[C:14]([CH3:16])[CH:15]=3)=[C:3]([CH2:1][CH3:2])[C:4](=[O:19])[NH:5][C:6]2=[O:18])[C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=2[N:24]=[N:23]1
Reactant: ClCn1nnc2ccccc21
Reactant: CCc1c(Oc2cc(C)cc(C)c2)[nH]c(=O)[nH]c1=O
Product: CCc1c(Oc2cc(C)cc(C)c2)n(Cn2nnc3ccccc32)c(=O)[nH]c1=O
Yield: 28.6 %

Procedure:
5-Ethyl-6-(3,5-dimethylphenoxy)-2,4-pyrimidinedione and 1-chloromethyl-1H-benzotriazole were reacted by the same way with the example 1 to obtain the titled compound (112 mg, yield: 28.6%).
Reaction SMILES: [O:1]([CH2:19][CH2:20][C:21]1([CH2:27][CH2:28][C:29]([CH2:35][OH:36])([CH2:32][CH2:33][OH:34])[CH2:30][OH:31])[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1)[Si:2]([C:15]([CH3:18])([CH3:17])[CH3:16])([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.C(O[C:41](=[O:43])[CH3:42])(=O)C>N1C=CC=CC=1>[C:19]([O:31][CH2:30][C:29]([CH2:28][CH2:27][C:21]1([CH2:20][CH2:19][O:1][Si:2]([C:15]([CH3:17])([CH3:18])[CH3:16])([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1)([CH2:32][CH2:33][O:34][C:41](=[O:43])[CH3:42])[CH2:35][O:36][C:30](=[O:31])[CH3:29])(=[O:1])[CH3:20]
Reactant: CC(=O)OC(C)=O
Reactant: CC(C)(C)[Si](OCCC1(CCC(CO)(CO)CCO)CCCCC1)(c1ccccc1)c1ccccc1
Solvent: c1ccncc1
Product: CC(=O)OCCC(CCC1(CCO[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)CCCCC1)(COC(C)=O)COC(C)=O
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 2-[2-[1-[2-(tert-butyldiphenylsiloxy)ethyl]cyclohexyl]ethyl]-2-hydroxymethylbutan-1,4-diol (300 mg) in pyridine (5.0 mL) was added acetic anhydride (5.0 mL) at room temperature. After stirring the solution at room temperature for 16 hours, it was concentrated under reduced pressure to give the title compound (340 mg).
Reaction SMILES: [CH2:1]([SH:7])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].[H-].[Na+].[Cl:10][C:11]1[C:16](Cl)=[N:15][CH:14]=[CH:13][N:12]=1>C1COCC1>[Cl:10][C:11]1[C:16]([S:7][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH3:6])=[N:15][CH:14]=[CH:13][N:12]=1
Reactant: Clc1nccnc1Cl
Reactant: CCCCCCS
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCCCCCSc1nccnc1Cl
Temperature: -5 °C
Reaction time: 0.5 h

Procedure:
Hexanethiol (4.7 g, 40 mmole) was added to a slurry of sodium hydride (0.96 g) in THF (60 ml), and the mixture stirred for 30 minutes. The slurry was cooled to -5° C. and a solution of 2,3-dichloropyrazine (6 g) added. The mixture was stirred for 1.5 hours, filtered and the filtrate evaporated. The residue was purified by column chromatography on silica gel using varying concentrations of methanol in chloroform. Fractions containing the desired product were evaporated, yielding 2-chloro-3-hexylsulfanyl pyrazine. as an oil.
Reaction SMILES: Cl[CH2:2][C:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[NH:5][CH:4]=1.[Cl:12][C:13]([Cl:18])([Cl:17])[C:14]([NH2:16])=[NH:15]>CCOCC>[NH:5]1[C:6]2[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=2)[C:3]([CH2:2][NH:16][C:14](=[NH:15])[C:13]([Cl:18])([Cl:17])[Cl:12])=[CH:4]1
Reactant: ClCc1c[nH]c2ccccc12
Reactant: N=C(N)C(Cl)(Cl)Cl
Solvent: CCOCC
Product: N=C(NCc1c[nH]c2ccccc12)C(Cl)(Cl)Cl

Procedure:
A solution of 8.3 g. (0.05 mole) of 3-(chloromethyl) indole in 30 ml. of ether is mixed with a solution of 8.1 g. (0.05 mole) of trichloroacetamidine, also in ether. The mixture is heated at reflux for 3 hours, and concentrated in vacuo to an oil. This is taken up in warm chloroform, filtered, and the chloroform extracts washed first with water and then with dilute hydrochloric acid. The aqueous layers are combined, made basic with a saturated aqueous solution of sodium bicarbonate and the product extracted with chloroform. The combined chloroform extracts are washed with water, dried over magnesium sulfate, filtered and concentrated in vacuo affording N-(3-indolylmethyl) trichloroacetamidine m.p. 135.5 to 138.5 after recrystallization from benzene/hexane.
Reaction SMILES: Cl[CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[C:11]1([NH:14][C:15]2[C:16](=[O:35])[N:17]([C:21]3[CH:22]=[C:23]([CH:30]=[C:31]([F:34])[C:32]=3[CH3:33])[C:24]([NH:26][CH:27]3[CH2:29][CH2:28]3)=[O:25])[CH:18]=[CH:19][N:20]=2)[CH2:13][CH2:12]1.[CH3:36][NH2:37]>O.O1CCOCC1>[CH:27]1([NH:26][C:24](=[O:25])[C:23]2[CH:22]=[C:21]([N:17]3[CH:18]=[CH:19][N:20]=[C:15]([NH:14][C:11]4([C:6]5[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=5[O:4][CH2:3][CH2:2][NH:37][CH3:36])[CH2:13][CH2:12]4)[C:16]3=[O:35])[C:32]([CH3:33])=[C:31]([F:34])[CH:30]=2)[CH2:29][CH2:28]1
Reactant: CN
Reactant: Cc1c(F)cc(C(=O)NC2CC2)cc1-n1ccnc(NC2(c3ccccc3OCCCl)CC2)c1=O
Solvent: O
Solvent: C1COCCO1
Product: CNCCOc1ccccc1C1(Nc2nccn(-c3cc(C(=O)NC4CC4)cc(F)c3C)c2=O)CC1

Procedure:
3-[3-[[1-[2-(2-chloroethoxy)phenyl]cyclopropyl]amino]-2-oxo-1(2H)-pyrazinyl]-N-cyclopropyl-5-fluoro-4-methyl-benzamide (Example 259d 0.5 g) and 40% methylamine in water (0.697 mL) were heated at 100° C. in dioxane (8 mL) in a sealed tube for 24 h. Purification of the cooled solution by preparative HPLC (Xbridge column—acetonitrile/0.2% ammonia mobile phase) gave the title compound (270 mg).
Reaction SMILES: [OH:1][C@:2]1([CH3:23])[CH2:7][CH2:6][C@@H:5]([NH:8][C:9]2[C:14]([C:15]#[N:16])=[CH:13][N:12]=[C:11](S(C)(=O)=O)[N:10]=2)[CH2:4][C:3]1([CH3:22])[CH3:21].[F:24][C:25]([F:37])([CH3:36])[CH2:26][O:27][C:28]1[C:33]([CH2:34][NH2:35])=[CH:32][N:31]=[CH:30][N:29]=1.CCN(C(C)C)C(C)C>C1COCC1>[F:37][C:25]([F:24])([CH3:36])[CH2:26][O:27][C:28]1[C:33]([CH2:34][NH:35][C:11]2[N:10]=[C:9]([NH:8][C@@H:5]3[CH2:6][CH2:7][C@:2]([OH:1])([CH3:23])[C:3]([CH3:22])([CH3:21])[CH2:4]3)[C:14]([C:15]#[N:16])=[CH:13][N:12]=2)=[CH:32][N:31]=[CH:30][N:29]=1
Reactant: CC1(C)C[C@H](Nc2nc(S(C)(=O)=O)ncc2C#N)CC[C@@]1(C)O
Reactant: CC(F)(F)COc1ncncc1CN
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CC(F)(F)COc1ncncc1CNc1ncc(C#N)c(N[C@@H]2CC[C@@](C)(O)C(C)(C)C2)n1
Temperature: 100 °C
Reaction time: 2 h
Yield: 30.1 %

Procedure:
To a solution of 4-(((1R,4R)-4-hydroxy-3,3,4-trimethylcyclohexyl)amino)-2-(methylsulfonyl)pyrimidine-5-carbonitrile (90 mg, crude) in THF (2.8 mL) was added (4-(2,2-difluoropropoxyl)pyrimidin-5-yl)methanamine (50 mg, 0.246 mmol) and DIEA (100 mg, 0.738 mmol). The resulting mixture was stirred at 100° C. in a microwave reactor for 2 h. The solvent was evaporated and the residue was purified via standard methods to afford the title compound (34.2 mg, 0.074 mmol, 30% yield). 1H NMR (400 MHz, CD3OD) δ (ppm) 8.70 (s, 1H), 8.34-8.32 (m, 1H), 8.13 (s, 1H), 4.70 (t, J=12.0 Hz, 1H), 4.64-4.59 (m, 2H), 4.18-4.15 (m, 1H), 1.81-1.74 (m, 3H), 1.68-1.41 (m, 6H), 1.32-1.30 (s, 3H), 0.92-0.85 (s, 6H). MS (ESI) m/z 462.2 [M+H]+.
Reaction SMILES: C[O:2][C:3]([C:5]1[CH2:6][N:7]([CH2:11][CH2:12][O:13][CH:14]=[C:15]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:8][CH2:9][CH:10]=1)=[O:4].[OH-].[Na+].O.[ClH:31]>C(O)C>[ClH:31].[C:22]1([C:15]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[CH:14][O:13][CH2:12][CH2:11][N:7]2[CH2:8][CH2:9][CH:10]=[C:5]([C:3]([OH:4])=[O:2])[CH2:6]2)[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1
Reactant: COC(=O)C1=CCCN(CCOC=C(c2ccccc2)c2ccccc2)C1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: O=C(O)C1=CCCN(CCOC=C(c2ccccc2)c2ccccc2)C1
Reaction time: 2.5 h

Procedure:
1-(2-((2,2-Diphenylethenyl)oxy)ethyl)-1,2,5,6-tetrahydro3-pyridinecarboxylic acid methyl ester (4.33 g, 0.0115 mol, prepared similarly to the method described in Example 70) was dissolved in ethanol (50 ml) and 10 N sodium hydroxide solution (11.5 ml) was introduced, followed by water (5 ml). The solution was stirred at room tempeature for 2.5 h and stored at 4° C. for 18 h. 2 N hydrochloric acid solution was added until the pH 2, and the mixture was extracted with dichloromethane (3×60 ml). The combined extracts was dried (MgSO4) and evaporated to give a foam (4.24 g) which was crystallized from 2-propanol to provide the compound (2.32 g, 52%) as a white solid.
Reaction SMILES: C(OC(=O)O[C@H:6]1[CH2:10][C@@H:9]([N:11]2[CH:19]=[N:18][C:17]3[C:12]2=[N:13][C:14]([Cl:38])=[N:15][C:16]=3[NH:20][CH:21]([C:30]2[CH:35]=[CH:34][C:33]([O:36][CH3:37])=[CH:32][CH:31]=2)[C:22]2[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=2)[CH:8]=[CH:7]1)C.[NH:40]([C:48]([O:50][C:51]([CH3:54])([CH3:53])[CH3:52])=[O:49])[C:41]([O:43][C:44]([CH3:47])([CH3:46])[CH3:45])=[O:42].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>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>[CH3:29][O:28][C:25]1[CH:24]=[CH:23][C:22]([CH:21]([NH:20][C:16]2[N:15]=[C:14]([Cl:38])[N:13]=[C:12]3[C:17]=2[N:18]=[CH:19][N:11]3[C@@H:9]2[CH2:10][C@H:6]([N:40]([C:41]([O:43][C:44]([CH3:47])([CH3:46])[CH3:45])=[O:42])[C:48]([O:50][C:51]([CH3:52])([CH3:53])[CH3:54])=[O:49])[CH:7]=[CH:8]2)[C:30]2[CH:31]=[CH:32][C:33]([O:36][CH3:37])=[CH:34][CH:35]=2)=[CH:27][CH:26]=1
Reactant: CC(C)(C)OC(=O)NC(=O)OC(C)(C)C
Reactant: CCOC(=O)O[C@@H]1C=C[C@H](n2cnc3c(NC(c4ccc(OC)cc4)c4ccc(OC)cc4)nc(Cl)nc32)C1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: COc1ccc(C(Nc2nc(Cl)nc3c2ncn3[C@H]2C=C[C@@H](N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)C2)c2ccc(OC)cc2)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Carbonic acid (1S,4R)-4-(6-{[bis-(4-methoxy-phenyl)-methyl]-amino}-2-chloro-purin-9-yl)-cyclopent-2-enyl ester ethyl ester (2.00 g, 3.64 mmol), di-t-butyl iminodicarboxylate (0.87 g, 4.00 mmol) and triphenylphosphine (0.14 g, 0.55 mmol) are placed in an oven-dried flask under an atmosphere of argon. Dry deoxygenated THF (20 ml) is added followed by tetrakis(triphenylphosphine)palladium(0) (0.21 g, 0.18 mmol) and the mixture is stirred at room temperature. The reaction is shown to be complete by LCMS after 3 hours. The solvent is removed in vacuo and the title compound is obtained after purification by flash column chromatography (silica, iso-hexane/ethyl acetate 4:1). 1H nmr (CDCl3, 400 MHz); 8.20 (s, 1H), 7.25 (d, 4H), 6.85 (d, 4H), 6.60 (m, 1H), 6.35 (m, 1H), 6.10 (m, 1H), 5.80 (m, 1H), 5.65 (m, 1H), 5.35 (m, 1H), 3.80 (s, 6H), 3.15 (m, 1H), 2.10 (m, 1H), 1.55 (s, 18H).
Reaction SMILES: [CH:1]([C:3]1[N:4]([CH2:12][CH2:13][C:14]([O:16]C)=[O:15])[C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2)=[O:2].[Li+].[OH-].Cl>O1CCOCC1>[CH:1]([C:3]1[N:4]([CH2:12][CH2:13][C:14]([OH:16])=[O:15])[C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2)=[O:2]
Reactant: COC(=O)CCn1c(C=O)cc2ccccc21
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1COCCO1
Product: O=Cc1cc2ccccc2n1CCC(=O)O
Reaction time: 1 h

Procedure:
Compound 2 was synthesized from Compound 1 as follows. To a solution of Compound 1 (306 mg, 1.32 mmol) dissolved in dioxane (18 mL) was added LiOH (2 M aqueous solution, 992 μL, 1.98 mmol, 1.5 equiv). After 1 h, hydrochloric acid (1 M aqueous solution) was added dropwise to give a solution with pH=5. The solution was concentrated and the resulting pale brown oil was dissolved in ethyl acetate (20 mL) and washed with acetic acid (5% aqueous solution, 10 mL), water (10 mL), and brine (10 mL). The organic layer was dried over sodium sulfate, filtered, and concentrated to a pale brown oil. Purification by silica gel chromatography (5-50% ethyl acetate in hexanes with 0.1% acetic acid) yielded the product as a pale yellow solid (290 mg, 1.34 mmol, quantitative). 1H NMR (400 MHz, CDCl3) δ 9.89 (s, 1H), 7.76 (dt, J=8.1, 0.9 Hz, 1H), 7.53 (dd, J=8.6, 0.9 Hz, 1H), 7.48-7.43 (m, 1H), 7.33 (d, J=0.8 Hz, 1H), 7.21 (ddd, J=8.0, 6.9, 1.0 Hz, 1H), 4.85 (t, J=7.2 Hz, 2H), 2.91 (t, J=7.2 Hz, 2H). 13C NMR (101 MHz, CDCl3) δ 182.65, 176.96, 140.12, 135.02, 127.33, 126.42, 123.53, 121.27, 118.76, 110.55, 40.19, 34.82. HRMS (ESI) calcd for C12H10NO3 [M−H]−: 216.0666. found: 216.0665.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([C:24]#[C:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[CH:8][C:9]=1[N:10]1[CH:15]([CH:16]2[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]2)[CH2:14][CH2:13][C@H:12](Br)[C:11]1=[O:23])=[O:4].[N-:30]=[N+:31]=[N-:32].[Na+]>CN(C=O)C>[CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([C:24]#[C:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[CH:8][C:9]=1[N:10]1[CH:15]([CH:16]2[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]2)[CH2:14][CH2:13][C@H:12]([N:30]=[N+:31]=[N-:32])[C:11]1=[O:23])=[O:4]
Reactant: COC(=O)c1sc(C#CC(C)(C)C)cc1N1C(=O)[C@@H](Br)CCC1C1CCCCC1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)c1sc(C#CC(C)(C)C)cc1N1C(=O)[C@@H](N=[N+]=[N-])CCC1C1CCCCC1
Temperature: 65 °C
Reaction time: 18 h
Yield: 59.3 %

Procedure:
To the solution of 3-((S)-3-bromo-6-cyclohexyl-2-oxo-piperidin-1-yl)-5-(3,3-dimethyl-but-1-ynyl)-thiophene-2-carboxylic acid methyl ester (78 mg, 0.16 mmol, 1 equiv.) in DMF (1.0 mL) was added NaN3 (12 mg, 0.19 mmol, 1.2 equiv) and the resulting mixture was stirred at 65° C. for 18 hours. The solvent was then removed under vacuum. The residue was purified by silica gel column chromatography (EtOAc/Heptane, 10%˜60%) to give product 42 mg (yield 56%). MS: 442 [M+H+].
Reaction SMILES: [CH3:1][O:2][C:3]([N:5]1[C@@H:13]2[C@@H:8]([C@@:9]([OH:23])([C:14]#[C:15][C:16]3[CH:17]=[C:18]([CH3:22])[CH:19]=[CH:20][CH:21]=3)[CH2:10][CH2:11][CH2:12]2)[CH2:7][CH2:6]1)=[O:4].[O:24]=[C:25]([N:31]1[CH2:35][CH2:34][CH2:33][CH2:32]1)[CH2:26][CH2:27][C:28](O)=[O:29]>>[CH3:1][O:2][C:3]([N:5]1[C@H:13]2[C@H:8]([C@:9]([O:23][C:28](=[O:29])[CH2:27][CH2:26][C:25](=[O:24])[N:31]3[CH2:35][CH2:34][CH2:33][CH2:32]3)([C:14]#[C:15][C:16]3[CH:17]=[C:18]([CH3:22])[CH:19]=[CH:20][CH:21]=3)[CH2:10][CH2:11][CH2:12]2)[CH2:7][CH2:6]1)=[O:4]
Reactant: COC(=O)N1CC[C@H]2[C@@H]1CCC[C@]2(O)C#Cc1cccc(C)c1
Reactant: O=C(O)CCC(=O)N1CCCC1
Product: COC(=O)N1CC[C@@H]2[C@H]1CCC[C@]2(C#Cc1cccc(C)c1)OC(=O)CCC(=O)N1CCCC1

Procedure:
Synthesis in analogy to the General Method 1 starting from (3aS,4R,7aS)-4-hydroxy-4-m-tolylethynyl-octahydro-indole-1-carboxylic acid methyl ester and 4-oxo-4-(pyrrolidin-1-yl)-butanoic acid to yield (3aR,4S,7aR)-4-(4-oxo-4-pyrrolidin-1-yl-butyryloxy)-4-m-tolylethynyl-octahydro-indole-1-carboxylic acid methyl ester. MS [M+H]=467; RT=2.88 min; UPLC Method II