Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[NH:10][C:9](=O)[N:8]([CH:13]1[CH2:16][CH2:15][CH2:14]1)[C:7]2=[O:17].P(Cl)(Cl)([Cl:20])=O.CCN(C(C)C)C(C)C.[OH-].[Na+]>O>[Br:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([Cl:20])[N:8]([CH:13]1[CH2:16][CH2:15][CH2:14]1)[C:7]2=[O:17]
Reactant: O=P(Cl)(Cl)Cl
Reactant: O=c1[nH]c2c(Br)cccc2c(=O)n1C1CCC1
Agent: [Na+]
Agent: [OH-]
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: O=c1c2cccc(Br)c2nc(Cl)n1C1CCC1
Temperature: 25 °C
Yield: 76.3 %

Procedure:
A solution of 8-bromo-3-cyclobutylquinazoline-2,4(1H,3H)-dione (2.33 g, 7.89 mmol), phosphorous oxychloride (Acros Organics, Geel, Belgium; 3.68 ml, 39.5 mmol), and DIPEA (5.50 ml, 31.6 mmol) was heated over a 130° C. oil bath for 5 h. The reaction mixture was then cooled to RT and poured onto ice, and the resulting mixture was diluted with water (250 mL) to provide a brown suspension. 10N aqueous NaOH was added to the vigorously stirred suspension (maintaining the reaction mixture at 0° C.) until a pH of 10 was achieved. The precipitated solid was collected by vacuum filtration, washed with water (3×20 mL), and dried in vacuo to provide 8-bromo-2-chloro-3-cyclobutylquinazolin-4(3H)-one (1.888 g, 6.02 mmol, 76% yield) as a tan solid: 1H NMR (400 MHz, CDCl3) δ ppm 8.16 (1H, dd, J=8.0, 1.4 Hz), 7.99 (1H, dd, J=7.8, 1.4 Hz), 7.32 (1H, t, J=7.8 Hz), 5.22 (1H, quin, J=8.8 Hz), 2.89-3.05 (2H, m), 2.43-2.56 (2H, m), 1.98 (1H, q, J=10.7 Hz), 1.74-1.90 (1H, m). m/z (ESI, +ve) 313.0/314.9/316.9 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:13]2[CH2:14][CH2:15][C:16](=[O:19])[NH:17][N:18]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][CH:10]1[O:12][CH2:11]1.[C:20]([NH2:24])([CH3:23])([CH3:22])[CH3:21]>>[ClH:1].[C:20]([NH:24][CH2:11][CH:10]([OH:12])[CH2:9][O:8][C:7]1[CH:6]=[CH:5][C:4]([C:13]2[CH2:14][CH2:15][C:16](=[O:19])[NH:17][N:18]=2)=[CH:3][C:2]=1[Cl:1])([CH3:23])([CH3:22])[CH3:21]
Reactant: CC(C)(C)N
Reactant: O=C1CCC(c2ccc(OCC3CO3)c(Cl)c2)=NN1
Product: CC(C)(C)NCC(O)COc1ccc(C2=NNC(=O)CC2)cc1Cl
Product: Cl

Procedure:
A stirred mixture of 6-[3-chloro-4-(2,3-epoxypropoxy)phenyl]-4,5-dihydro-3(2H)-pyridazinone (2.91 g, 0.01 mole) methanol (58 ml), and t-butylamine (6.6 ml, 0.06 mole) was heated under reflux for 90 minutes. Evaporation of the solution under reduced pressure gave a glassy solid, 3.79g. The hydrochloride (m.p. 229°-238°C decomposition) was recrystallised from ethanol-ether to give pure 6-[4-(3-t-butylamino-2-hydroxypropoxy)-3-chlorophenyl]-4,5-dihydro-3(2H)-pyridazinone hydrochloride m.p. 234°-238°C (decomposition).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([NH:9][CH2:10][CH2:11][C:12]2[CH:13]=[N:14][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:16][CH:17]=2)[CH:5]=[CH:6][C:7]=1[CH3:8].[C:22]([C:30](O)=[O:31])(=[O:29])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C>CN(C=O)C.CC(OC)(C)C>[CH3:1][C:2]1[CH:3]=[C:4]([N:9]([CH2:10][CH2:11][C:12]2[CH:13]=[N:14][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:16][CH:17]=2)[C:30](=[O:31])[C:22](=[O:29])[C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH:5]=[CH:6][C:7]=1[CH3:8]
Reactant: O=C(O)C(=O)c1ccccc1
Reactant: Cc1ccc(NCCc2ccc(C(F)(F)F)nc2)cc1C
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: COC(C)(C)C
Product: Cc1ccc(N(CCc2ccc(C(F)(F)F)nc2)C(=O)C(=O)c2ccccc2)cc1C
Temperature: 25 °C
Reaction time: 18 h
Yield: 53.4 %

Procedure:
To a solution of (3,4-dimethyl-phenyl)-[2-(6-trifluoromethyl-pyridin-3-yl)-ethyl]-amine (172 mg, 0.58 mmol) in DMF (4 mL) was added under a nitrogen atmosphere at 0° C. benzoylformic acid (105 mg, 0.70 mmol), 2-(1H-benzotriazole-1-yl)-1,1,3,3-tetramethyl-uronium tetrafluoroborate (280 mg, 0.88 mmol) and N,N-diisopropyl ethyl amine (299 μl, 1.75 mmol). The resulting solution was stirred for 18 h at ambient temperature. It was diluted with TBME (15 mL) and washed with aqueous hydrochloric acid (1 M, 15 mL), water (15 mL), aqueous Na2CO3 (saturatedm, 15 mL) and brine (15 mL). The combined aqueous layers were extracted with TBME (15 mL) and the combined organic layers dried over sodium sulfate. Concentration and purification by chromatography (SiO2, heptane:ethyl acetate=95:5 to 60:40) afforded the title compound (132 mg, 53%) as a light brown oil. MS m/e: 427.2 [M+H]+.
Reaction SMILES: [S:1]1[CH2:6][CH2:5][C:4](=[O:7])[CH2:3][CH2:2]1.[Cl-].[CH3:9][N+:10](=[CH2:12])[CH3:11].C([Cl:16])(=O)C>C(#N)C>[ClH:16].[CH3:9][N:10]([CH2:12][CH:3]1[C:4](=[O:7])[CH2:5][CH2:6][S:1][CH2:2]1)[CH3:11]
Reactant: O=C1CCSCC1
Reactant: C=[N+](C)C
Reactant: CC(=O)Cl
Agent: [Cl-]
Solvent: CC#N
Product: CN(C)CC1CSCCC1=O
Product: Cl
Temperature: 60 °C
Reaction time: 0.75 h

Procedure:
5.00 g tetrahydrothiopyran-4-one were dissolved in 15 ml acetonitrile, and 4.03 g N,N-dimethyl-methylenammonium chloride, followed by 40 μl acetyl chloride, were added. After the mixture had been stirred at a bath temperature of 60° C. for 45 minutes, it was stirred at room temperature for 60 hours and the precipitate formed was filtered off with suction and dried. 8.17 g 3-dimethylaminomethyl-tetrahydrothiopyran-4-one hydrochloride with a melting point of 155-157° C. were obtained. The corresponding base was liberated from this with methylene chloride and sodium hydroxide solution (32 percent strength by weight).
Reaction SMILES: [H-].[Na+].[C:3]([O:7][C:8](=[O:18])[NH:9][C@H:10]([CH2:16][OH:17])[CH2:11][C:12]([CH3:15])([CH3:14])[CH3:13])([CH3:6])([CH3:5])[CH3:4].IC.[C:21]([O-])(O)=O.[Na+]>C1COCC1>[C:3]([O:7][C:8](=[O:18])[NH:9][C@H:10]([CH2:16][O:17][CH3:21])[CH2:11][C:12]([CH3:15])([CH3:14])[CH3:13])([CH3:6])([CH3:4])[CH3:5]
Reactant: O=C([O-])O
Reactant: CC(C)(C)C[C@@H](CO)NC(=O)OC(C)(C)C
Agent: [H-]
Agent: [Na+]
Solvent: CI
Solvent: C1CCOC1
Product: COC[C@H](CC(C)(C)C)NC(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a suspension of NaH (51.3 mg, 1.284 mmol) in THF (10 mL) cooled at 0° C. under Argon atmosphere was slowly added ((S)-1-hydroxymethyl-3,3-dimethyl-butyl)-carbamic acid tert-butyl ester (300 mg, 1.167 mmol). The mixture was stirred at 0° C. for 30 min and iodomethane (0.095 ml, 1.517 mmol) was added. The reaction mixture was allowed to reach RT and further stirred overnight. To complete the reaction, NaH (24 mg, 0.584 mmol) was again added at 0° C. followed 30 min later by the addition of iodomethane (36 μL, 0.584 mmol). The reaction mixture was stirred at RT for 6 h, then poured into a sat. aq. solution of NaHCO3 and extracted twice with CH2Cl2. The combined organic extracts were dried (Na2SO4), filtered and concentrated. The crude material was purified by flash chromatography on silica gel (c-hexane to c-hexane/EtOAc 8:2) to give the desired material as a white powder. 1H NMR (400 MHz, DMSO-d6) δ (ppm): 6.60 (m, 1H), 3.66 (m, 1H), 3.23 (s, 3H), 3.14 (m, 1H), 3.05 (m, 1H), 1.38 (s, 9H), 1.30 (m, 2H), 0.88 (s, 9H).
Reaction SMILES: [CH2:1]([C:5]1[N:6]([CH2:13][C:14]2[CH:19]=[CH:18][C:17]([C:20]3[C:21]([C:26]#[N:27])=[CH:22][CH:23]=[CH:24][CH:25]=3)=[CH:16][C:15]=2[F:28])[C:7](=[O:12])[CH:8]=[C:9]([CH3:11])[N:10]=1)[CH2:2][CH2:3][CH3:4].C([O-])(=O)C.[Na+].[Br:34]Br>C(O)(=O)C.C(OCC)(=O)C>[Br:34][C:8]1[C:7](=[O:12])[N:6]([CH2:13][C:14]2[CH:19]=[CH:18][C:17]([C:20]3[C:21]([C:26]#[N:27])=[CH:22][CH:23]=[CH:24][CH:25]=3)=[CH:16][C:15]=2[F:28])[C:5]([CH2:1][CH2:2][CH2:3][CH3:4])=[N:10][C:9]=1[CH3:11]
Reactant: BrBr
Reactant: CCCCc1nc(C)cc(=O)n1Cc1ccc(-c2ccccc2C#N)cc1F
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: CCCCc1nc(C)c(Br)c(=O)n1Cc1ccc(-c2ccccc2C#N)cc1F
Reaction time: 2 h
Yield: 60 %

Procedure:
To a solution of 4′-[(2-butyl-4-methyl-6-oxopyrimidin-1(6H)-yl)methyl]-3′-fluorobiphenyl-2-carbonitrile (1.48 g) and sodium acetate (0.36 g) in acetic acid (20 mL) was added bromine (0.22 mL), and the mixture was stirred for 2 hr. The reaction mixture was diluted with ethyl acetate, washed with saturated aqueous sodium hydrogen carbonate and saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography to give the title compound (1.07 g, 60%) as a colorless solid.
Reaction SMILES: [CH:1]1([NH:7][C:8]2[N:16]=[C:15](I)[N:14]=[C:13]3[C:9]=2[N:10]=[CH:11][N:12]3[C@@H:18]2[O:22][C@H:21]([C:23]([NH:25][CH2:26][CH3:27])=[O:24])[C@@H:20]([OH:28])[C@H:19]2[OH:29])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[N:30]1([CH2:36][CH2:37][NH2:38])[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]1.[C]=O.C1C[O:44][CH2:43]C1>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>[CH:1]1([NH:7][C:8]2[N:16]=[C:15]([C:43]([NH:38][CH2:37][CH2:36][N:30]3[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]3)=[O:44])[N:14]=[C:13]3[C:9]=2[N:10]=[CH:11][N:12]3[C@H:18]2[C@H:19]([OH:29])[C@H:20]([OH:28])[C@@H:21]([C:23]([NH:25][CH2:26][CH3:27])=[O:24])[O:22]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CCNC(=O)[C@H]1O[C@@H](n2cnc3c(NC4CCCCC4)nc(I)nc32)[C@H](O)[C@@H]1O
Reactant: NCCN1CCCCC1
Reactant: C1CCOC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C]=O
Product: CCNC(=O)[C@H]1O[C@@H](n2cnc3c(NC4CCCCC4)nc(C(=O)NCCN4CCCCC4)nc32)[C@H](O)[C@@H]1O
Yield: 58 %

Procedure:
A solution of (2S,3S,4R,5R)-5-[6-(cyclohexylamino)-2-iodo-9H-purin-9-yl]-N-ethyl-3,4-dihydroxytetrahydro-2-furancarboxamide (Preparation 31) (125 mg, 0.24 mmol), 2-(1-piperidinyl)ethylamine (0.14 ml, 0.96 mmol) and tetrakis(triphenylphosphine)palladium(0) (20 mg, 0.024 mmol) in THF (5 ml) was carbonylated at 60° C. and 345 KPa carbon monoxide for 18 hours. Solvent was evaporated under reduced pressure and the residue purified by column chromatography on silica gel eluting with dichloromethane:methanol:concentrated aqueous ammonia (95:5:1, by volume). After evaporation of appropriate fractions the residue was triturated with diethyl ether, filtered and dried to yield the target compound as a beige powder, (77 mg, 58%).
Reaction SMILES: [S-:1][C:2]#[N:3].[NH4+].Cl.[CH3:6][O:7][C:8]([C:10]1[CH:11]=[C:12]2[C:17](=[CH:18][CH:19]=1)[CH2:16][NH:15][CH2:14][CH2:13]2)=[O:9].C1COCC1>CCOC(C)=O>[NH2:3][C:2]([N:15]1[CH2:14][CH2:13][C:12]2[C:17](=[CH:18][CH:19]=[C:10]([C:8]([O:7][CH3:6])=[O:9])[CH:11]=2)[CH2:16]1)=[S:1]
Reactant: COC(=O)c1ccc2c(c1)CCNC2
Reactant: N#C[S-]
Agent: Cl
Agent: [NH4+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COC(=O)c1ccc2c(c1)CCN(C(N)=S)C2
Temperature: 100 °C
Yield: 100.1 %

Procedure:
A mixture of ammonium thiocyanate (0.105 g, 1.384 mmol), 6-methoxycarbonyl-1,2,3,4-tetrahydroisoquinoline hydrochloride (0.3 g, 1.3176 mmol) and THF (2 mL) was heated in a CEM microwave reactor for 1 h at 100° C. Upon cooling to room temperature, the reaction mixture was diluted with EtOAc, and washed with H2O, 1 N HCl, saturated aqueous NaHCO3 and brine respectively, dried over anhydrous MgSO4, and concentrated under reduced pressure to afford methyl 2-(aminocarbonothioyl)-1,2,3,4-tetrahydroisoquinoline-6-carboxylate (0.33 g, 47%) as a white solid. LCMS: (FA) ES+ 251.
Reaction SMILES: [CH2:1]1[CH2:5][NH+:4]([CH2:6][CH2:7]O)[CH2:3][CH2:2]1.C1C=C(C[C:16]([O-])=[O:17])C(NC2C(Cl)=CC=CC=2Cl)=CC=1.[CH3:28][O:29][C:30]1[N:35]=C(O)C=C(O)[N:31]=1.COC(=N)[NH2:41].C(OC)(=O)CC(OC)=O>>[CH3:28][O:29][C:30](=[NH:31])[NH2:35].[CH3:5][C:1]1[C:2]([CH2:16][OH:17])=[CH:3][N:4]=[C:6]([CH3:7])[N:41]=1
Reactant: O=C([O-])Cc1ccccc1Nc1c(Cl)cccc1Cl
Reactant: OCC[NH+]1CCCC1
Reactant: COc1nc(O)cc(O)n1
Agent: COC(=N)N
Solvent: COC(=O)CC(=O)OC
Product: Cc1ncc(CO)c(C)n1

Procedure:
One method taught in the art for making the 2-methoxy analog of DHEP is disclosed by S. Basterfield and E. C. Powell in Canadian Journal of Research, vol. 1, pp. 261-272 (1929). In this article, Basterfield and Powell describe the synthesis of a number of 2-alkoxypyrimidine derivatives, including 2-methoxy-4,6-dihydroxypyrimidine (DHMP). DHMP is prepared by condensing O-methylisourea with dimethyl malonate. Although a 75% of theoretical yield is reported in the article, the theoretical yield requires consumption of 2 equivalents of O-methylisourea to form 1 equivalent of the O-methylisourea salt of DHMP. Thus, the reported 75% yield means that 0.75 moles of DHMP salt are formed for every 2 moles of O-methylisourea utilized. The O-methylisourea is prepared by first preparing and isolating the hydrochloride salt of O-methylisourea, then neutralizing this salt with potassium hydroxide in ether to form neutral O-methylisourea, which is apparently isolated as well. At page 262 of their article, Basterfield and Powell reference the unpublished observations of Stieglitz and Basterfield, who found that O-ethylisourea can be condensed with dimethyl malonate in the absence of a base and of a solvent to obtain the O-ethylisourea salt of 2-ethoxybarbituric acid, i.e., a salt of DHEP.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]([NH:8][CH:9]2[CH2:14][C:13]([CH3:16])([CH3:15])[NH:12][C:11]([CH3:18])([CH3:17])[CH2:10]2)[N:3]=1.C([Si](C)(C)[O:24][CH:25]([C:40]1[S:41][CH:42]=[CH:43][CH:44]=1)[C:26]([F:39])([F:38])[C:27]([O:30][Si](C(C)(C)C)(C)C)([CH3:29])[CH3:28])(C)(C)C.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C1COCC1>[F:39][C:26]([F:38])([C:27]([CH3:28])([OH:30])[CH3:29])[CH:25]([C:40]1[S:41][C:42]([C:2]2[CH:7]=[CH:6][N:5]=[C:4]([NH:8][CH:9]3[CH2:14][C:13]([CH3:16])([CH3:15])[NH:12][C:11]([CH3:18])([CH3:17])[CH2:10]3)[N:3]=2)=[CH:43][CH:44]=1)[OH:24]
Reactant: CC(C)(O[Si](C)(C)C(C)(C)C)C(F)(F)C(O[Si](C)(C)C(C)(C)C)c1cccs1
Reactant: CC1(C)CC(Nc2nccc(Cl)n2)CC(C)(C)N1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: CC1(C)CC(Nc2nccc(-c3ccc(C(O)C(F)(F)C(C)(C)O)s3)n2)CC(C)(C)N1

Procedure:
The title compound was prepared analogous to Method C, starting from (4-chloro-pyrimidin-2-yl)-(2,2,6,6-tetramethyl-piperidin-4-yl)-amine and 2-[1,3-Bis-(tert-butyl-dimethyl-silanyloxy)-2,2-difluoro-3-methyl-butyl]-thiophene (prepared from 2,2-Difluoro-3-hydroxy-3-thiophen-2-yl-propionic acid ethyl ester by treatment with MeMgBr (Step A of Method A) and TBDMS protection), followed by TBDMS cleavage with TBAF in THF.
Reaction SMILES: [N:1]1([CH2:6][CH2:7][N:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([NH2:17])[CH:15]=3)[CH:10]=[N:9]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[C:18]1([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[CH:23]=[CH:22][C:21]([C:24](=[O:30])[CH2:25][CH2:26][C:27](O)=[O:28])=[CH:20][CH:19]=1>>[C:18]1([C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=2)[CH:23]=[CH:22][C:21]([C:24](=[O:30])[CH2:25][CH2:26][C:27]([NH:17][C:14]2[CH:15]=[C:16]3[C:11]([CH:10]=[N:9][N:8]3[CH2:7][CH2:6][N:1]3[CH2:5][CH2:4][CH2:3][CH2:2]3)=[CH:12][CH:13]=2)=[O:28])=[CH:20][CH:19]=1
Reactant: O=C(O)CCC(=O)c1ccc(-c2ccccc2)cc1
Reactant: Nc1ccc2cnn(CCN3CCCC3)c2c1
Product: O=C(CCC(=O)c1ccc(-c2ccccc2)cc1)Nc1ccc2cnn(CCN3CCCC3)c2c1

Procedure:
According to the procedure for Example 49, 1-(2-pyrrolidin-1-yl-ethyl)-1H-indazol-6-ylamine and 4-biphenyl-4-yl-4-oxo-butyric acid were processed to provide the title compound. 1H NMR (500 MHz, DMSO-d6) δ ppm 1.80 (m, 2 H), 1.97 (m, 2 H), 2.83 (t, J=6.10 Hz, 2 H), 3.02 (m, 2 H), 3.41 (t, J=6.26 Hz, 2 H), 3.50 (m, 2 H), 3.69 (m, 2 H), 4.66 (t, J=6.26 Hz, 2 H), 7.11 (m, 1 H), 7.45 (m, 1 H), 7.52 (m, 2 H), 7.72 (m, 1 H), 7.77 (m, 2 H), 7.86 (m, 2 H), 8.10 (m, 3 H), 8.29 (s, 1 H), 9.56 (br s, N H); MS (DCI/NH3) m/z 467 (M+H)+.
Reaction SMILES: FC(F)(F)C(O)=O.[CH3:8][C@@H:9]([O:13][C:14]1[NH:15][C:16]([NH2:25])=[C:17]2[C:21]([N:22]=1)=[N:20][C:19]([O:23][CH3:24])=[N:18]2)[CH2:10][CH2:11][CH3:12].Br[CH2:27][CH2:28][CH2:29][CH:30]1[CH2:35][CH2:34][O:33][C:32]([CH3:37])([CH3:36])[CH2:31]1>>[CH3:36][C:32]1([CH3:37])[CH2:31][CH:30]([CH2:29][CH2:28][CH2:27][N:20]2[C:19]([O:23][CH3:24])=[N:18][C:17]3[C:21]2=[N:22][C:14]([O:13][C@H:9]([CH3:8])[CH2:10][CH2:11][CH3:12])=[N:15][C:16]=3[NH2:25])[CH2:35][CH2:34][O:33]1
Reactant: CC1(C)CC(CCCBr)CCO1
Reactant: CCC[C@@H](C)Oc1nc2nc(OC)nc-2c(N)[nH]1
Solvent: O=C(O)C(F)(F)F
Product: CCC[C@@H](C)Oc1nc(N)c2nc(OC)n(CCCC3CCOC(C)(C)C3)c2n1

Procedure:
Prepared similarly to Intermediate 223 from 2-{[(1R)-1-methylbutyl]oxy}-8-(methyloxy)-1H-purin-6-amine trifluoroacetate and 4-(3-bromopropyl)-2,2-dimethyltetrahydro-2H-pyran but conducting the alkylation over 1 hour at 60° C.
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[C:11](=[N:12][C:13](Cl)=[CH:14][CH:15]=2)[CH:10]=[C:9]1[C:18]1[S:19][CH:20]=[CH:21][N:22]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:23]([C:32](OC(C)(C)C)=O)[NH:24]C(OC(C)(C)C)=O.[C:39]([O-])([O-])=O.[Cs+].[Cs+]>C1(C)C=CC=CC=1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C(C(C)C)=CC(C(C)C)=CC=2C(C)C)CCCCC1.NC1C=CC=CC=1C1C=CC=CC=1[Pd]Cl>[CH2:1]([N:8]1[C:16]2[CH:15]=[CH:14][C:13]3[N:12]([C:32]([CH3:39])=[N:23][N:24]=3)[C:11]=2[CH:10]=[C:9]1[C:18]1[S:19][CH:20]=[CH:21][N:22]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C([O-])[O-]
Reactant: Clc1ccc2c(cc(-c3nccs3)n2Cc2ccccc2)n1
Reactant: CC(C)(C)OC(=O)NNC(=O)OC(C)(C)C
Agent: Nc1ccccc1-c1ccccc1[Pd]Cl
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: [Cs+]
Solvent: Cc1ccccc1
Product: Cc1nnc2ccc3c(cc(-c4nccs4)n3Cc3ccccc3)n12
Temperature: 110 °C

Procedure:
1-Benzyl-5-chloro-2-(1,3-thiazol-2-yl)-1H-pyrrolo[3,2-b]pyridine (30 mg, 0.092 mmol, from Step 1), di-tert-butyl hydrazine-1,2-dicarboxylate (26 mg, 0.11 mmol) and Cs2CO3 (30 mg, 0.092 mmol) were combined in toluene (2.8 mL) and dicyclohexyl(2′,4′,6′-triisopropylbiphenyl-2-yl)phosphine-(2′-aminobiphenyl-2-yl)(chloro)palladium (1:1) (7.2 mg, 0.0092 mmol) was added. The mixture was degassed by a stream of nitrogen through the solution for 10 minutes. The reaction was heated to 110° C. overnight. The intermediate di-tert-butyl 1-[1-benzyl-2-(1,3-thiazol-2-yl)-1H-pyrrolo[3,2-b]pyridin-5-yl]hydrazine-1,2-dicarboxylate was purified via preparative HPLC-MS (C18 eluting with a gradient of MeCN and H2O containing 0.15% NH4OH) and was isolated in the amount of 20 mg after evaporation of eluent. The resulting residue was dissolved in acetic acid (1.9 mL) and heated in the microwave to a temperature of 165° C. for 5 minutes. AcOH was removed in vacuo and the residue was reconstituted and purified via preparative HPLC-MS (C18 eluting with a gradient of MeCN and H2O containing 0.15% NH4OH). Yield: (4.6 mg, 14%).
Reaction SMILES: Cl.Cl.[CH2:3]([O:5][CH2:6][CH2:7][N:8]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[N:10]=[C:9]1[N:17]1[CH2:23][CH2:22][CH2:21][N:20]([CH2:24][CH2:25][C@:26]2([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[CH2:30][CH2:29][NH:28][CH2:27]2)[CH2:19][CH2:18]1)[CH3:4].[CH3:37][O:38][C:39]1[CH:47]=[CH:46][C:45]([O:48][CH2:49][CH2:50][O:51][CH3:52])=[CH:44][C:40]=1[C:41](O)=[O:42].CN(C)CCCN=C=NCC.O.ON1C2C=CC=CC=2N=N1>ClCCl>[CH2:3]([O:5][CH2:6][CH2:7][N:8]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[N:10]=[C:9]1[N:17]1[CH2:23][CH2:22][CH2:21][N:20]([CH2:24][CH2:25][C@:26]2([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[CH2:30][CH2:29][N:28]([C:41]([C:40]3[CH:44]=[C:45]([O:48][CH2:49][CH2:50][O:51][CH3:52])[CH:46]=[CH:47][C:39]=3[O:38][CH3:37])=[O:42])[CH2:27]2)[CH2:19][CH2:18]1)[CH3:4]
Reactant: CCOCCn1c(N2CCCN(CC[C@]3(c4ccccc4)CCNC3)CC2)nc2ccccc21
Reactant: COCCOc1ccc(OC)c(C(=O)O)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: O
Product: CCOCCn1c(N2CCCN(CC[C@]3(c4ccccc4)CCN(C(=O)c4cc(OCCOC)ccc4OC)C3)CC2)nc2ccccc21
Yield: 79.6 %

Procedure:
Stir a mixture of 1-(2-ethoxy-ethyl)-2-{4-[2-((S)-3-phenyl-pyrrolidin-3-yl)-ethyl]-[1,4]diazepan-1-yl}-1H-benzoimidazole dihydrochloride (0.32 g, 0.6 mmol, Preparation 12.1), 2-methoxy-5-(2-methoxy-ethoxy)-benzoic acid (0.16 g, 0.72 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (0.14 g, 0.72 mmol), 1-hydroxybenzotriazole hydrate (0.097 g, 0.72 mmol), diisopropyoethylamine (0.2 mL, 1.2 mmol) and dichloromethane (20 mL) overnight at room temperature. Dilute the reaction mixture with dichloromethane, wash with saturated brine, dry (MgSO4) the organic phase, filter and concentrate the filtrate in vacuo. Purify the residue by column chromatography on silica gel eluting sequentially with ethyl acetate, 5% methanol in dichloromethane and 10% methanol in dichloromethane. Concentrate the appropriate fractions to afford 0.32 g of the title compound, Rf=0.46 (silica gel, 10% methanol in dichloromethane). The compound may be converted to the dihydrochloride salt by methods well known in the art.
Reaction SMILES: [CH2:1]([OH:6])[CH2:2][CH2:3][CH2:4][OH:5].C(N(CC)CC)C.[C:14]([Si:18](Cl)([CH3:20])[CH3:19])([CH3:17])([CH3:16])[CH3:15]>C(Cl)Cl>[Si:18]([O:5][CH2:4][CH2:3][CH2:2][CH2:1][OH:6])([C:14]([CH3:17])([CH3:16])[CH3:15])([CH3:20])[CH3:19]
Reactant: OCCCCO
Reactant: CC(C)(C)[Si](C)(C)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)[Si](C)(C)OCCCCO
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a solution of butane-1,4-diol (180.0 g, 2.0 mol), triethylamine (242.4 g, 2.4 mol) in DCM (1500 mL) was dropwised tert-butylchlorodimethylsilane (306 g, 2.03 mol) in 500 mL DCM, the mixture was stirred for about 1 hr at 0° C., then was warmed at RT for overnight. the reaction was washed with water (500 mL×3) and brine (500×3 mL), dried over Na2SO4 and concentrated to give the desired compound of 4-(tert-butyl dimethylsilyl oxy) butan-1-ol
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:9]=[CH:8][C:7]([CH3:10])=[CH:6][C:4]=1[NH2:5].[Br:11]N1C(=O)CCC1=O>CN(C=O)C.[Cl-].[Na+].O>[Br:11][C:8]1[C:7]([CH3:10])=[CH:6][C:4]([NH2:5])=[C:3]([O:2][CH3:1])[CH:9]=1
Reactant: COc1ccc(C)cc1N
Reactant: O=C1CCC(=O)N1Br
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1cc(Br)c(C)cc1N
Temperature: 25 °C
Reaction time: 18 h
Yield: 86.3 %

Procedure:
To a cooled (0° C.) solution of 2-methoxy-5-methylaniline (500 mg, 3.64 mmol) in DMF (5 mL) was added slowly, over 10 minutes, a solution of N-bromosuccinimide (662 mg, 3.72 mmol) in DMF (2.5 mL). The reaction mixture was stirred for 18 hours, whilst slowly warming to room temperature. The reaction mixture was diluted with brine (25 mL) and extracted with EtOAc (25 mL). The organic layer was dried (MgSO4) and concentrated in vacuo. The residue was purified by silica gel column chromatography eluting with 0-20% EtOAc in cyclohexane to give the title compound (679 mg, 86%). 1H NMR (500 MHz, CDCl3): δ 6.93 (s, 1H), 6.62 (d, J=0.5 Hz, 1H), 3.83 (s, 3H), 3.73 (br s, 2H), 2.26 (s, 3H).
Reaction SMILES: Cl.[CH:2]([C:5]1[CH:6]=[C:7]([NH:11]N)[CH:8]=[CH:9][CH:10]=1)([CH3:4])[CH3:3].[CH3:13][N:14]1[CH2:19][CH2:18][C:17](=O)[CH2:16][CH2:15]1>S(=O)(=O)(O)O.O1CCOCC1>[CH:2]([C:5]1[CH:10]=[CH:9][C:8]2[C:16]3[CH2:15][N:14]([CH3:13])[CH2:19][CH2:18][C:17]=3[NH:11][C:7]=2[CH:6]=1)([CH3:4])[CH3:3]
Reactant: CN1CCC(=O)CC1
Reactant: CC(C)c1cccc(NN)c1
Agent: Cl
Agent: O=S(=O)(O)O
Solvent: C1COCCO1
Product: CC(C)c1ccc2c3c([nH]c2c1)CCN(C)C3
Temperature: 25 °C
Yield: 18 %

Procedure:
A solution of (3-isopropylphenyl)hydrazine hydrochloride (5 g, 0.0267 mol) and 1-methyl-4-piperidone (3.3 mL, 0.0267 mol) in 7% sulfuric acid in dioxane (100 mL) was heated at 80° C. for 1 h. After completion, the reaction mixture was cooled to RT and the organic layer decanted. The residue was basified with 10% sodium hydroxide solution and extracted with EtOAc (3×100 mL). The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure affording crude material, which was purified by silica gel column chromatography (6% MeOH:DCM) to yield 7-isopropyl-2-methyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (1.1 g, 18% yield).