Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([NH:8][CH:9]2[CH2:13][CH2:12][CH2:11][CH2:10]2)[N:5]2[N:14]=[C:15]([C:26]3[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[CH:28][CH:27]=3)[C:16]([C:17]3[CH:22]=[CH:21][N:20]=[C:19](S(C)=O)[N:18]=3)=[C:4]2[CH:3]=1.C(OCC)(=O)C.[CH:40]1([NH2:43])[CH2:42][CH2:41]1>>[Cl:1][C:2]1[CH:7]=[C:6]([NH:8][CH:9]2[CH2:13][CH2:12][CH2:11][CH2:10]2)[N:5]2[N:14]=[C:15]([C:26]3[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[CH:28][CH:27]=3)[C:16]([C:17]3[CH:22]=[CH:21][N:20]=[C:19]([NH:43][CH:40]4[CH2:42][CH2:41]4)[N:18]=3)=[C:4]2[CH:3]=1
Reactant: NC1CC1
Reactant: COc1ccc(-c2nn3c(NC4CCCC4)cc(Cl)cc3c2-c2ccnc(S(C)=O)n2)cc1
Solvent: CCOC(C)=O
Product: COc1ccc(-c2nn3c(NC4CCCC4)cc(Cl)cc3c2-c2ccnc(NC3CC3)n2)cc1
Temperature: 25 °C
Yield: 83 %

Procedure:
A solution of N-{5-chloro-2-(4-methoxyphenyl)-3-[2-(methylsulfinyl)-4-pyrimidinyl]pyrazolo[1,5-a]pyridin-7-yl}-N-cyclopentylamine (118 mg, 0.24 mmol) in cyclopropylamine (5 mL) was heated at 45° C. in a sealed tube for 5 hours. The reaction mixture was cooled to room temperature and ethyl acetate was added to the reaction mixture. The organic phase was washed with water, brine and dried over magnesium sulfate. Filtration and concentration followed by chromatography (7:3 hexanes:ethyl acetate) gave N-{4-[5-chloro-7-(cyclopentylamino)-2-(4-methoxyphenyl)pyrazolo[1,5-a]pyridin-3-yl]-2-pyrimidinyl}-N-cyclopropylamine (96 mg, 83%) as a yellow solid. 1H NMR (CDCl3) δ 8.10 (broad s, 1H), 8.00 (d, 1H), 7.55 (d, 2H), 6.98 (d, 2H), 6.33 (d, 1H), 6.09 (d, 1H), 5.98 (d, 1H), 5.68 (s, 1H), 3.93 (m, 1H), 3.86 (s, 3H), 2.84 (m, 1H), 2.10 (m, 2H), 1.78-1.65 (m, 6H), 0.90 (m, 2H), 0.63 (m, 2H). MS m/z 475 (M+1).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:14][CH2:15][C:16](=O)[CH2:17]C.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([CH:15]([CH2:16][CH3:17])[CH3:14])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: CCC(=O)CC
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Product: CCC(C)N1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 68.9 %

Procedure:
A mixture of piperazine-1-carboxylic acid tert-butyl ester (7.00 g), 3-pentanone (3.89 g), glacial acetic acid (2.22 mL) and sodium triacetoxyborohydride (11.95 g) in dichloromethane (DCM, 200 mL) was stirred for 18 h at room temperature. The reaction mixture was quenched with 1 N aqueous NaOH (80 mL) and stirred for 2.5 h at room temperature. Additional water (100 mL) was added, and the resulting mixture was extracted with DCM (3×100 mL). Extracts were combined and washed with water (2×100 mL), dried (Na2SO4), and concentrated under reduced pressure, yielding the title compound (6.28 g).
Reaction SMILES: Br[C:2]1[CH:17]=[CH:16][C:15]([NH:18][C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])=[CH:14][C:3]=1[CH2:4][N:5]([CH3:13])[C:6](=[O:12])[O:7][C:8]([CH3:11])([CH3:10])[CH3:9].CCN(CC)CC.[P:33]([O-:40])([O:37][CH2:38][CH3:39])[O:34][CH2:35][CH3:36]>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[C:22]([O:21][C:19]([NH:18][C:15]1[CH:16]=[CH:17][C:2]([P:33]([O:37][CH2:38][CH3:39])([O:34][CH2:35][CH3:36])=[O:40])=[C:3]([CH:14]=1)[CH2:4][N:5]([CH3:13])[C:6](=[O:12])[O:7][C:8]([CH3:11])([CH3:10])[CH3:9])=[O:20])([CH3:25])([CH3:24])[CH3:23]
Reactant: CCOP([O-])OCC
Reactant: CN(Cc1cc(NC(=O)OC(C)(C)C)ccc1Br)C(=O)OC(C)(C)C
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CCOP(=O)(OCC)c1ccc(NC(=O)OC(C)(C)C)cc1CN(C)C(=O)OC(C)(C)C
Temperature: 105 °C
Reaction time: 48 h
Yield: 53.3 %

Procedure:
A solution of 12B (25 mg, 0.060 mmol), bis(tri-t-butylphosphine)palladium (0) (3.08 mg, 6.02 μmol), Et3N (0.042 mL, 0.301 mmol) and diethyl phosphite (0.039 mL, 0.301 mmol) in toluene (0.6 mL) was degassed with Ar by evacuating and filling (4×). The sealed vessel was stirred for 2 days at 105° C. The reaction mixture was concentrated and purified by column chromatography (0 to 30% EtOAc in hexanes) to yield 12C (15 mg, 0.032 mmol, 52.7% yield).
Reaction SMILES: [OH:1][C:2]1[C:11]2[CH2:10][CH2:9][CH2:8][CH2:7][C:6]=2[NH:5][C:4](=[O:12])[CH:3]=1.[N+:13]([O-])([OH:15])=[O:14].O>C(O)(=O)C>[OH:1][C:2]1[C:11]2[CH2:10][CH2:9][CH2:8][CH2:7][C:6]=2[NH:5][C:4](=[O:12])[C:3]=1[N+:13]([O-:15])=[O:14]
Reactant: O=c1cc(O)c2c([nH]1)CCCC2
Reactant: O=[N+]([O-])O
Solvent: CC(=O)O
Solvent: O
Product: O=c1[nH]c2c(c(O)c1[N+](=O)[O-])CCCC2

Procedure:
A solution of 4-hydroxy-5,6,7,8-tetrahydrocarbostyril (1.70g; 0.0103 mole) and concentrated nitric acid (2.5 ml; d 1.42), in glacial acetic acid (10 ml) was heated at 100° C till the oxides of nitrogen were evolved and rapidly cooled in ice. Water (40 ml) was added to the red solution to precipitate the yellow-orance 3-nitro derivative. After filtration, thorough washing with water and recrystallisation from acetic acid - ethanol the product had m.p. 241° (d).
Reaction SMILES: [C:1]([CH:3]1[CH2:7][CH2:6][N:5]([CH3:8])[CH2:4]1)#[N:2].[NH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1N.[NH4+].[OH-]>Cl>[CH3:8][N:5]1[CH2:6][CH2:7][CH:3]([C:1]2[NH:9][C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[N:2]=2)[CH2:4]1
Reactant: Nc1ccccc1N
Reactant: CN1CCC(C#N)C1
Agent: Cl
Agent: [NH4+]
Agent: [OH-]
Product: CN1CCC(c2nc3ccccc3[nH]2)C1
Temperature: 110 °C

Procedure:
To 240 g of concentrated hydrochloric acid was added 43.2 g (0.39 mol) of 3-cyano-1-methylpyrrolidine (the temperature rose to 90° C.). After the temperature began to fall the solution was heated to 110° C. for 4 h. The solution was cooled to 60° C. and 42 g (0.39 mol) of 1,2-diaminobenzene in 250 mL of 1N hydrochloric acid was added. The solution was heated to reflux for 20 h. The cooled solution was made basic with concentrated NH4OH and the resulting crystals were collected by filtration. The product was chromatographed on a 7.5×36 cm silica column eluting with 1 gallon of 10% NH4OH-90% ethanol. The eluent was collected in 500-mL portions. The first 6 fractions were discarded and fractions 7-14 were collected and concentrated. The residue was recrystallized from ethyl acetate. Yield: 18 g (23%). A 5-g sample was recrystallized three times from ethyl acetate. Yield: 1.6 g, mp 189°-193° C.
Reaction SMILES: [F:1][C:2]([F:27])([F:26])[C:3]1[CH:4]=[C:5]([C:9]2[CH:14]=[CH:13][C:12]([C@@H:15]3[CH2:17][C@H:16]3[NH:18]C(=O)OC(C)(C)C)=[CH:11][CH:10]=2)[CH:6]=[CH:7][CH:8]=1.Cl.C([O-])([O-])=O.[Na+].[Na+]>C(OCC)C.O>[F:1][C:2]([F:26])([F:27])[C:3]1[CH:4]=[C:5]([C:9]2[CH:14]=[CH:13][C:12]([C@@H:15]3[CH2:17][C@H:16]3[NH2:18])=[CH:11][CH:10]=2)[CH:6]=[CH:7][CH:8]=1
Reactant: CC(C)(C)OC(=O)N[C@@H]1C[C@H]1c1ccc(-c2cccc(C(F)(F)F)c2)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CCOCC
Product: N[C@@H]1C[C@H]1c1ccc(-c2cccc(C(F)(F)F)c2)cc1
Reaction time: 1 h
Yield: 98 %

Procedure:
To a solution of tert-butyl(trans)-2-(3′-(trifluoromethyl)biphenyl-4-yl)cyclopropylcarbamate (5 g) in diethyl ether (50 mL) at 0° C., HCl in Diethyl ether (20 mL) was added and stirred for 1 h. After completion, the solvent was evaporated and residue was triturated with Et2O (20 mL) to give crude salt. The crude salt was dissolved in water (50 mL), basified with Na2CO3 solution, extracted with EtOAc (3×50 mL). The combined extracts were washed with water (50 mL), brine (50 mL), dried over anhydrous Na2SO4, filtered and evaporated to get crude (trans)-2-(3′-(trifluoromethyl)biphenyl-4-yl)cyclopropanamine (3.6 g, 98.09%) as a white solid
Reaction SMILES: [C-:1]#[N:2].[Na+].[CH3:4][O:5][C:6]1[CH:7]=[C:8]([CH2:12][CH2:13][CH2:14]I)[CH:9]=[CH:10][CH:11]=1.C(OCC)C>CS(C)=O>[CH3:4][O:5][C:6]1[CH:7]=[C:8]([CH2:12][CH2:13][CH2:14][C:1]#[N:2])[CH:9]=[CH:10][CH:11]=1
Reactant: [C-]#N
Reactant: COc1cccc(CCCI)c1
Agent: [Na+]
Solvent: CCOCC
Solvent: CS(C)=O
Product: COc1cccc(CCCC#N)c1
Temperature: 90 °C
Yield: 89.5 %

Procedure:
A magnetically stirred suspension of sodium cyanide (13.65 g, 265 mmol) in anhydrous methyl sulfoxide (65 mL) was treated dropwise with 3-(3-methoxyphenyl)propyl iodide (66.25 g, 240 mmol) at a rate sufficient to keep the temperature below 45° C. The suspension was heated at 90° C. for 1 h, cooled to room temperature, poured over ice (1000 g), treated with diethyl ether (500 mL), the layers separated, and the aqueous portion back-extracted with diethyl ether (2×300 mL). The combined organic extracts were washed with water (3×500 mL), 6N HCl (500 mL), brine (500 mL), dried (MgSO4), filtered, and concentrated in vacuo to a clear liquid. Kugelrohr distillation (0.1 torr, 120° C.) provided the desired product as a clear liquid (37.62 g, 89%): 1H NMR (CDCl3) δ 7.25 (t, J=8 Hz, 1H), 6.78-6.69 (m, 3H), 3.80 (s, 3H), 2.75 (t, J=8 Hz, 2H), 2.31 (t, J=8 Hz, 2H), 1.98 (quint, J=8 Hz, 2H).
Reaction SMILES: [O:1]([CH2:8][CH:9]1[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[CH2:16][CH2:17][CH2:18][Cl:19].C(N(CC)CC)C>O1CCCC1>[O:1]([CH2:8][CH:9]1[CH2:10][CH2:11][N:12]([CH2:16][CH2:17][CH2:18][Cl:19])[CH2:13][CH2:14]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: ClCCCBr
Reactant: c1ccc(OCC2CCNCC2)cc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: ClCCCN1CCC(COc2ccccc2)CC1
Yield: 83.6 %

Procedure:
A mixture of 28.6 g (0.15 mole) of 4-phenoxymethyl-piperidine, 23.5 g (0.15 mole) of 1-bromo-3-chloropropane, 40.4 g (0.4 mole) of triethylamine and 150 ml of tetrahydrofuran is heated under reflux for 5 hours. After cooling, the reaction mixture is filtered, the filtrate is evaporated in a vacuum, the residue is extracted with diethyl ether and the extract is evaporated. There are obtained 33.6 g (84% of theory) of crude 3-(4-phenoxymethylpiperidino)-propyl chloride in the form of an oil which can be further used in this form. The pure compound is obtained by distillation and boils at 180°-183° C./0.4 mm Hg.
Reaction SMILES: [CH:1](/[C@H:6]1[CH2:11][CH2:10][C@H:9]([C:12]([OH:14])=[O:13])[CH2:8][CH2:7]1)=[CH:2]\[CH2:3][CH2:4][CH3:5].[CH2:15]([O:17][C:18]1[CH:23]=[CH:22][C:21](O)=[CH:20][CH:19]=1)[CH3:16].C1(N=C=NC2CCCCC2)CCCCC1>CN(C)C1C=CN=CC=1.C(Cl)Cl.C(OCC)C>[CH2:15]([O:17][C:18]1[CH:23]=[CH:22][C:21]([O:13][C:12]([C@H:9]2[CH2:8][CH2:7][C@H:6](/[CH:1]=[CH:2]/[CH2:3][CH2:4][CH3:5])[CH2:11][CH2:10]2)=[O:14])=[CH:20][CH:19]=1)[CH3:16]
Reactant: CCOc1ccc(O)cc1
Reactant: CCC/C=C/[C@H]1CC[C@H](C(=O)O)CC1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: CCOCC
Solvent: ClCCl
Product: CCC/C=C/[C@H]1CC[C@H](C(=O)Oc2ccc(OCC)cc2)CC1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
A mixture of 800 mg of trans-4-(trans-1-pentenyl)cyclohexanecarboxylic acid, 675.64 mg of p-ethoxyphenol, 1.01 g of dicyclohexylcarbodiimide and 49.79 mg of 4-(dimethylamino)pyridine was suspended in 14.5 ml of methylene chloride and stirred at room temperature for 20 hours. The mixture was subsequently diluted with diethyl ether, the precipitated urea was filtered off and the filtrate was concentrated. The residue was taken up in hexane and washed with dilute hydrochloric acid, sodium hydrogen carbonate solution and water. The aqueous phases were back-extracted twice with hexane. The organic phases were dried over magnesium sulphate and evaporated. Low-pressure chromatography of the resulting residue on silica gel with ethyl acetate/petroleum ether (vol. 3:97) gave 1.080 g (83.8%) of trans-4-(trans-1-pentenyl)cyclohexanecarboxylic acid p-ethoxyphenyl ester. After recrystallization from 40 ml of hexane, there were finally obtained 880 mg of product in the form of transparent crystals; m.p. (C--N) 57.2° C., cl.p. (N--I) 93.1° C.
Reaction SMILES: [Cl:1][C:2]1[C:3]([N+:20]([O-:22])=[O:21])=[CH:4][C:5]([CH3:19])=[C:6]([CH:18]=1)[O:7][C:8]1[CH:13]=[CH:12][N:11]=[C:10]2[NH:14][N:15]=[C:16]([I:17])[C:9]=12.CN(C=O)C.C([O-])([O-])=O.[K+].[K+].Cl[CH2:35][C:36]1[CH:41]=[CH:40][C:39]([O:42][CH3:43])=[CH:38][CH:37]=1>O>[CH3:43][O:42][C:39]1[CH:40]=[CH:41][C:36]([CH2:35][N:14]2[C:10]3=[N:11][CH:12]=[CH:13][C:8]([O:7][C:6]4[CH:18]=[C:2]([Cl:1])[C:3]([N+:20]([O-:22])=[O:21])=[CH:4][C:5]=4[CH3:19])=[C:9]3[C:16]([I:17])=[N:15]2)=[CH:37][CH:38]=1
Reactant: COc1ccc(CCl)cc1
Reactant: Cc1cc([N+](=O)[O-])c(Cl)cc1Oc1ccnc2[nH]nc(I)c12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc(Cn2nc(I)c3c(Oc4cc(Cl)c([N+](=O)[O-])cc4C)ccnc32)cc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
4-(5-Chloro-2-methyl-4-nitrophenoxy)-3-iodo-1H-pyrazolo[3,4-b]pyridine (26.5 g, 61.5 mmol) was dissolved in stirring DMF (100 mL). K2CO3 (17.0 g, 123 mmol) and 1-(chloromethyl)-4-methoxybenzene (10.1 ml, 73.9 mmol) were added and the reaction mixture was stirred at ambient temperature under N2 for 18 hours. The mixture was diluted with water, and then the water was decanted. The gum washed a second time with water, and the water decanted. The residue was partitioned between EtOAc (250 mL) and brine (100 mL). The phases were separated, and the organic phase was dried (Na2SO4), filtered, and concentrated. The resulting solid was triturated with diethyl ether (100 mL), and the yellow powder (27.3 g, 80%) filtered. The product was a 9:1 mixture of pyrazole regioisomers as determined by 1H NMR: (400 MHz, CDCl3, major regioisomer reported) δ 8.43 (d, J=5 Hz, 1H), 7.95 (s, 1H), 7.38 (d, J=9 Hz, 2H), 7.19 (s, 1H), 6.84 (d, J=9 Hz, 2H), 6.35 (d, J=5 Hz, 1H), 5.64 (s, 2H), 3.77 (s, 3H), 2.36 (s, 3H).
Reaction SMILES: Cl.[NH2:2][C@H:3]1[CH2:8][CH2:7][C@H:6]([NH:9][C:10]([C:12]2[C:16]3[N:17]=[CH:18][N:19]=[C:20]([C:21]4[CH:26]=[C:25]([CH:27]([F:29])[F:28])[CH:24]=[CH:23][C:22]=4[O:30][CH2:31][CH:32]4[CH2:34][CH2:33]4)[C:15]=3[NH:14][C:13]=2[CH3:35])=[O:11])[CH2:5][C@@H:4]1[CH3:36].[CH3:37][O:38][CH2:39][C:40](Cl)=[O:41]>>[CH:32]1([CH2:31][O:30][C:22]2[CH:23]=[CH:24][C:25]([CH:27]([F:29])[F:28])=[CH:26][C:21]=2[C:20]2[C:15]3[NH:14][C:13]([CH3:35])=[C:12]([C:10]([NH:9][C@H:6]4[CH2:7][CH2:8][C@H:3]([NH:2][C:40](=[O:41])[CH2:39][O:38][CH3:37])[C@@H:4]([CH3:36])[CH2:5]4)=[O:11])[C:16]=3[N:17]=[CH:18][N:19]=2)[CH2:34][CH2:33]1
Reactant: COCC(=O)Cl
Reactant: Cc1[nH]c2c(-c3cc(C(F)F)ccc3OCC3CC3)ncnc2c1C(=O)N[C@H]1CC[C@H](N)[C@@H](C)C1
Agent: Cl
Product: COCC(=O)N[C@H]1CC[C@H](NC(=O)c2c(C)[nH]c3c(-c4cc(C(F)F)ccc4OCC4CC4)ncnc23)C[C@@H]1C

Procedure:
Starting from N-[(1S*,3S*,4S*)-4-amino-3-methylcyclohexyl]-4-[2-(cyclopropylmethoxy)-5-(difluoromethyl)phenyl]-6-methyl-5H-pyrrolo[3,2-d]pyrimidine-7-carboxamide hydrochloride (example D.f65) and commercially available methoxy-acetyl chloride the title compound is obtained as colorless solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1([CH2:13][N:14]2[CH:18]=[N:17][CH:16]=[N:15]2)[CH:11]([CH3:12])[O:10]1.[SH:19]CCC(OC)=O.C[O-].[Na+].CO.Cl>O.CO>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]([OH:10])([CH:11]([SH:19])[CH3:12])[CH2:13][N:14]1[CH:18]=[N:17][CH:16]=[N:15]1
Reactant: CC1OC1(Cn1cncn1)c1ccc(F)cc1F
Reactant: COC(=O)CCS
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CC(S)C(O)(Cn1cncn1)c1ccc(F)cc1F

Procedure:
A methanol (2.0 ml) solution containing (2RS,3RS)-2-(2,4-difluorophenyl)-3-methyl-2-(1H-1,2,4-triazol-1-ylmethyl)oxirane (0.05 g), methyl 3-mercaptopropionate (0.11 ml) and a 28% sodium methylate-methanol solution (0.14 ml) was refluxed for 1.0 hour. The reaction mixture was cooled, to which was added water (10 ml). The mixture was neutralized with 1N aqueous solution of hydrochloric acid, followed by extraction with methylene chloride (5.0 ml×twice). The extract solution was dried over anhydrous sodium sulfate, then the solvent was distilled off. The residue was subjected to a silica gel chromatography (2.5 cm×5 cm), followed by elution with ethyl acetate-hexane (1:2). The object fraction was concentrated, to which was added ethyl acetate to give (2RS,3RS)-2-(2,4-difluorophenyl)-3-mercapto-1-[(1H)-1,2,4-triazol-1-yl]-2-butanol (0.030 g) as colorless needles.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][N:3]=1.[H-].[Na+].[CH2:11](Br)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.O>CN(C=O)C>[CH2:11]([O:8][C:5]1[CH:6]=[CH:7][C:2]([Br:1])=[N:3][CH:4]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: BrCc1ccccc1
Reactant: Oc1ccc(Br)nc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Brc1ccc(OCc2ccccc2)cn1
Reaction time: 24 h
Yield: 80 %

Procedure:
2-Bromo-5-hydroxypyridine (3 mmol) is dissolved in DMF (2.5 ml) and NaH (1.4 eq., 60% suspension in liquid paraffin) is added. After 30 min benzylbromide (1.1 eq.) is added and the reaction solution is stirred 24 hours. The reaction solution is pored into water and extracted with methyltert.-butyl ether. The combined organic layers are dried over Na2SO4 and the solvent is removed in vacuo. 5-Benzyloxy-2-bromo-pyridine is obtained after column chromatography as brown oil in a yield of 80%. HPLC (method C): 2.01 min; LC-MS (method A): 1.97 min, 264.00 (MH+).
Reaction SMILES: Cl[CH2:2][C:3]([N:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH2:7][CH2:6]1)=[O:4].[NH:14]1[CH2:19][CH2:18][O:17][CH:16]([CH2:20][OH:21])[CH2:15]1.C(N(CC)CC)C>C(#N)C>[OH:21][CH2:20][C@@H:16]1[CH2:15][N:14]([CH2:2][C:3]([N:5]2[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[CH2:7][CH2:6]2)=[O:4])[CH2:19][CH2:18][O:17]1
Reactant: O=C(CCl)N1CCc2ccccc21
Reactant: OCC1CNCCO1
Solvent: CC#N
Solvent: CCN(CC)CC
Product: O=C(CN1CCO[C@H](CO)C1)N1CCc2ccccc21
Yield: 79 %

Procedure:
A microwave vial was charged with 1-(chloroacetyl)-indoline (compound 47; 390 mg, 2.00 mmol), hydroxymethylmorpholine (compound 54; 280 mg, 2.39 mmol), triethylamine (0.55 ml, 4.00 mmol) and acetonitrile (2 ml). The vial was sealed and irradiated for 30 min at 100° C. The crude mixture was purified by flash column chromatography (silica, DCM/MeOH 1:0 to 92:8). The product was obtained as a white solid (435 mg; yield 79%).
Reaction SMILES: [CH3:1][CH:2]([CH2:4][CH2:5][CH2:6][C@H:7]([C@@H:9]1[C@:27]2([CH3:28])[C@H:12]([C@H:13]3[C@H:24]([CH2:25][CH2:26]2)[C@:22]2([CH3:23])[C:16]([CH2:17][C@H:18]([CH2:20][CH2:21]2)O)=[CH:15][CH2:14]3)[CH2:11][CH2:10]1)[CH3:8])[CH3:3].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O.C1(P([N:76]=[N+:77]=[N-:78])(C2C=CC=CC=2)=O)C=CC=CC=1>O1CCCC1>[N:76]([C@@H:18]1[CH2:20][CH2:21][C@@:22]2([CH3:23])[C:16](=[CH:15][CH2:14][C@@H:13]3[C@@H:24]2[CH2:25][CH2:26][C@@:27]2([CH3:28])[C@H:12]3[CH2:11][CH2:10][C@@H:9]2[C@H:7]([CH3:8])[CH2:6][CH2:5][CH2:4][CH:2]([CH3:3])[CH3:1])[CH2:17]1)=[N+:77]=[N-:78]
Reactant: CC(C)CCC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3CC=C4C[C@@H](O)CC[C@]4(C)[C@H]3CC[C@]12C
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)CCC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3CC=C4C[C@H](N=[N+]=[N-])CC[C@]4(C)[C@H]3CC[C@]12C
Reaction time: 24 h
Yield: 67 %

Procedure:
Cholesterol (7.76 mmol, 3.0 g) and triphenylphosphine (7.76 mmol, 2.04 g) were dissolved in 77.6 mL of anhydrous tetrahydrofuran. Diisopropyl azodicarboxylate (7.76 mmol, 1.5 mL) was then added dropwise. After stirring the orange mixture for a few minutes, diphenylphosphoryl azide (7.76 mmol, 1.68 mL) was added dropwise. After 24 hours, the pale yellow reaction mixture was concentrated. Purification by silica gel chromatography (100% hexanes) afforded 3α-azidocholest-5-ene (2.14 g, 67%) as a white solid. mp 110-112° C.; TLC Rf=0.87 (20% ethyl acetate/hexanes); IR (thin film) 2946, 2914, 2845, 2083 cm−1; 1H NMR (300 MHz, CDCl3) δ 5.42-5.40 (m, 1H), 3.89 (t, 1H, J=2.9 Hz), 2.58-2.49 (m, 1H), 2.23-2.16 (m, 1H), 2.16-1.93 (m, 2H), 1.89-1.05 (m, 24H), 1.02 (s, 3H), 0.93 (d, 3H, J=6.5 Hz), 0.88 (d, 6H, J=6.6 Hz), 0.69 (s, 3H).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([C:15]2[S:16][C:17]([CH2:20]Cl)=[CH:18][CH:19]=2)[CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH2:7]1)=[O:5])[CH3:2].[CH:22]1([C:25]2[NH:26][C:27]3[C:28]([N:35]=2)=[N:29][C:30]([CH3:34])=[CH:31][C:32]=3[CH3:33])[CH2:24][CH2:23]1>>[CH2:1]([O:3][C:4]([C:6]1([C:15]2[S:16][C:17]([CH2:20][N:35]3[C:28]4=[N:29][C:30]([CH3:34])=[CH:31][C:32]([CH3:33])=[C:27]4[N:26]=[C:25]3[CH:22]3[CH2:24][CH2:23]3)=[CH:18][CH:19]=2)[CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)C1(c2ccc(CCl)s2)Cc2ccccc2C1
Reactant: Cc1cc(C)c2[nH]c(C3CC3)nc2n1
Product: CCOC(=O)C1(c2ccc(Cn3c(C4CC4)nc4c(C)cc(C)nc43)s2)Cc2ccccc2C1

Procedure:
The product of Example 6, Step 4, above (26), was alkylated as described in Example 1, Step 5, using 2-cyclopropyl-5,7-dimethylimidazo[4,5-b]pyridine (13) to obtain the title compound (29).
Reaction SMILES: [CH2:1]([NH:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C@H:10]1[CH2:19][CH2:18][C:17]2[CH:16]=[C:15]([O:20]C(=O)C(C)(C)C)[CH:14]=[CH:13][C:12]=2[CH2:11]1)[CH3:2].[CH:27]([C:29]1[CH:47]=[CH:46][C:32]([O:33][CH2:34][C:35]([NH:38]C(=O)OC(C)(C)C)([CH3:37])[CH3:36])=[CH:31][CH:30]=1)=O>>[NH2:38][C:35]([CH3:36])([CH3:37])[CH2:34][O:33][C:32]1[CH:31]=[CH:30][C:29]([CH2:27][CH2:2][CH2:1][NH:3][C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=2[C@H:10]2[CH2:19][CH2:18][C:17]3[CH:16]=[C:15]([OH:20])[CH:14]=[CH:13][C:12]=3[CH2:11]2)=[CH:47][CH:46]=1
Reactant: CCNc1ccccc1[C@H]1CCc2cc(OC(=O)C(C)(C)C)ccc2C1
Reactant: CC(C)(COc1ccc(C=O)cc1)NC(=O)OC(C)(C)C
Product: CC(C)(N)COc1ccc(CCCNc2ccccc2[C@H]2CCc3cc(O)ccc3C2)cc1
Yield: 52.7 %

Procedure:
Synthesized from pivalic acid (S)-6-(2-ethylaminophenyl)-5,6,7,8-tetrahydronaphthalen-2-yl ester (30 mg) and tert-butyl [2-(4-formylphenoxy)-1,1-dimethylethyl]carbamate (125 mg) according to an analogous synthetic method to Example 238 and purified by LC-MS, the title compound (20 mg) was obtained.
Reaction SMILES: [Br:1][C:2]1[S:3][C:4]([CH:7]=[O:8])=[CH:5][N:6]=1.[CH3:9][Mg+].[Br-]>C1COCC1.CCOCC>[Br:1][C:2]1[S:3][C:4]([CH:7]([OH:8])[CH3:9])=[CH:5][N:6]=1
Reactant: O=Cc1cnc(Br)s1
Reactant: C[Mg+]
Agent: [Br-]
Solvent: CCOCC
Solvent: C1CCOC1
Product: CC(O)c1cnc(Br)s1
Reaction time: 0.5 h

Procedure:
To a 0° C. solution of 2-bromo-5-formylthiazole (100.6 mg, 0.524 mmol) in THF (5 mL) was added MeMgBr (175 μL of a 3M solution in Et2O, 0.524 mmol). After 30 minutes, additional MeMgBr (50 μL of a 3M solution in Et2O, 0.150 mmol) was added. After 30 more minutes, the reaction was quenched by pouring into saturated NH4Cl (20 mL). The mixture was extracted with EtOAc (50 mL) and the organic layer was washed with water and brine (25 mL each). The organic layer was dried over Na2SO4, filtered, and concentrated. Purification of the residue by flash chromatography (0 to 80% EtOAc/hexanes) afforded 1-(2-bromo-1,3-thiazol-5-yl)ethanol. Rf=0.13 (25% EtOAc/hexanes). LCMS=210.0 (M+1)+. 1H NMR (CDCl3, 500 MHz) δ 7.40 (s, 1H), 5.12 (q, J=6.4 Hz, 1H), 1.59 (d, J=6.4 Hz, 3H).
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][C:8](=[O:12])[NH:9]2)=[CH:4][CH:3]=1.[Br:13][CH2:14][CH:15]1[CH2:20][CH2:19][CH:18]([CH2:21]Br)[CH2:17][CH2:16]1.C([O-])([O-])=O.[K+].[K+]>CCO.O>[Br:13][CH2:14][CH:15]1[CH2:20][CH2:19][CH:18]([CH2:21][O:1][C:2]2[CH:11]=[C:10]3[C:5]([CH2:6][CH2:7][C:8](=[O:12])[NH:9]3)=[CH:4][CH:3]=2)[CH2:17][CH2:16]1
Reactant: BrCC1CCC(CBr)CC1
Reactant: O=C1CCc2ccc(O)cc2N1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: O
Product: O=C1CCc2ccc(OCC3CCC(CBr)CC3)cc2N1
Yield: 30.8 %

Procedure:
A mixture of 7-hydroxy-3,4-dihydroquinolin-2(1H)-one (196 mg, 1.2 mmol), 1,4-bis(bromomethyl)cyclohexane (972 mg, 3.6 mmol) and anhydrous K2CO3 (166 mg, 1.2 mmol) was dissolved in EtOH and the solution was heated to reflux overnight. The solution was diluted with water and extracted with EtOAc. The combined organic layers were washed with saturated aq NaHCO3, brine, dried over anhydrous Na2SO4, concentrated in vacuo and purified by flash chromatography on silica gel column to give 7-((4-(bromomethyl)cyclohexyl)methoxy)-3,4-dihydroquinolin-2(1H)-one (intermediate 49) (130 mg, 30%) as a white solid.