Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]([O:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[N+:12]([O-])=O)=[CH:3][Cl:4].[H][H].[O-][Si]([O-])=O.[Mg+2]>C(OCC)(=O)C.C(OCC)(=O)C.CCCCCC.[Pd]>[NH2:12][C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=1[O:5][C:2]([Cl:1])=[CH:3][Cl:4]
Reactant: O=[N+]([O-])c1ccccc1OC(Cl)=CCl
Reactant: [H][H]
Agent: [Pd]
Agent: O=[Si]([O-])[O-]
Agent: [Mg+2]
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: Nc1ccccc1OC(Cl)=CCl
Yield: 89.2 %

Procedure:
Two hundred and eighteen grams of 1,2-dichloro-1-(2-nitrophenoxy)ethene in ethyl acetate with 2.2 g of 10% palladium-on-charcoal was treated with 60 pounds per square inch gauge of hydrogen at 60° until there was no further uptake of hydrogen. The reaction mixture was filtered through Celite® and concentrated in vacuo to yield a brown oil. This oil was taken up in 20% ethyl acetate/hexane and passed through a column of Florisil® two times to yield 169.5 g of oil after evaporation of the solvent.
Reaction SMILES: [ClH:1].O[CH2:3][N:4]1[C:8](=[O:9])[C:7]2=[CH:10][CH:11]=[CH:12][CH:13]=[C:6]2[C:5]1=[O:14]>>[Cl:1][CH2:3][N:4]1[C:8](=[O:9])[C:7]2=[CH:10][CH:11]=[CH:12][CH:13]=[C:6]2[C:5]1=[O:14]
Reactant: O=C1c2ccccc2C(=O)N1CO
Reactant: Cl
Product: O=C1c2ccccc2C(=O)N1CCl

Procedure:
reacting said mixture at a temperature of from about 45° to about 75° C at a pressure of from about 0 psig to about 50 psig while intimately contacting said reacting mixture with anhydrous HCl at a rate of from approximately 15 to approximately 65 pounds HCl per hour per pound-mole of N-hydroxymethyl phthalimide used to form the mixture in step (a), to maintain the concentration of said aqueous HCl at 35 to 40 wt.%, to form N-chloromethyl phthalimide in an aqueous-organic mixture;
Reaction SMILES: [O:1]=[C:2]([NH:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([NH:20][C:21]([C:23]2[C:24]([NH:38][CH2:39][CH2:40][CH3:41])=[N:25][C:26]([NH:29][CH2:30][CH2:31][C:32]3[CH:37]=[CH:36][N:35]=[CH:34][CH:33]=3)=[N:27][CH:28]=2)=[O:22])[CH:15]=1)[C@@H:3]([NH:5]C(=O)OC(C)(C)C)[CH3:4]>C(Cl)(Cl)Cl.FC(F)(F)C(O)=O>[NH2:5][C@@H:3]([CH3:4])[C:2]([NH:13][C:14]1[CH:15]=[C:16]([NH:20][C:21]([C:23]2[C:24]([NH:38][CH2:39][CH2:40][CH3:41])=[N:25][C:26]([NH:29][CH2:30][CH2:31][C:32]3[CH:33]=[CH:34][N:35]=[CH:36][CH:37]=3)=[N:27][CH:28]=2)=[O:22])[CH:17]=[CH:18][CH:19]=1)=[O:1]
Reactant: CCCNc1nc(NCCc2ccncc2)ncc1C(=O)Nc1cccc(NC(=O)[C@H](C)NC(=O)OC(C)(C)C)c1
Solvent: ClC(Cl)Cl
Solvent: O=C(O)C(F)(F)F
Product: CCCNc1nc(NCCc2ccncc2)ncc1C(=O)Nc1cccc(NC(=O)[C@H](C)N)c1
Reaction time: 3 h
Yield: 66.6 %

Procedure:
To a solution of (S)-tert-butyl (1-oxo-1-((3-(4-(propylamino)-2-((2-(pyridin-4-yl)ethyl)amino)pyrimidine-5-carboxamido)phenyl)amino)propan-2-yl)carbamate (A5, 137 mg) in chloroform (2 mL), trifluoroacetic acid (2 mL) was added at room temperature, and the mixture was stirred at the same temperature for 3 hours. The solvent was evaporated under reduced pressure, and to the obtained residue, saturated aqueous sodium hydrogencarbonate and ethyl acetate were added. The organic layer was separated, and the aqueous layer was extracted with ethyl acetate. The organic layer and the extract were combined, washed with saturated aqueous sodium chloride, and then dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. To the obtained residue, ethyl acetate was added, and the solid matter was taken by filtration, and dried under reduced pressure to obtain (S)—N-(3-(2-aminopropanamido)phenyl)-4-(propylamino)-2-((2-(pyridin-4-yl)ethyl)amino)pyrimidine-5-carboxamide (A6, 75 mg) as white solid.
Reaction SMILES: [CH3:1][C:2]([NH:4][CH2:5][CH2:6][CH2:7][CH2:8][C@H:9]([NH:13][C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[C:10]([OH:12])=[O:11])=[O:3].C[N:22]1CCOCC1.C(OC(Cl)=O)C(C)C.N[C:37]1[CH:47]=[CH:46][C:40]2[N:41]=[C:42]([C:44]#[N:45])[S:43][C:39]=2[CH:38]=1>C1COCC1>[NH:13]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[C@H:9]([C:10]([OH:12])=[O:11])[CH2:8][CH2:7][CH2:6][CH2:5][NH:4][C:2]([CH3:1])=[O:3].[NH2:22][C:46]1[C:40]2[N:41]=[C:42]([C:44]#[N:45])[S:43][C:39]=2[CH:38]=[CH:37][CH:47]=1
Reactant: CN1CCOCC1
Reactant: N#Cc1nc2ccc(N)cc2s1
Agent: CC(=O)NCCCC[C@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: CC(C)COC(=O)Cl
Solvent: C1CCOC1
Product: N#Cc1nc2c(N)cccc2s1
Temperature: 0 °C
Reaction time: 8 h

Procedure:
To a stirred solution of Boc-Lys-(Ac)—OH (20.5 g, 71 mmol) in dry THF (410 mL), N-methylmorpholine (7.8 mL, 71 mmol) was added under an atmosphere of N2. The reaction vessel was cooled to 4° C. for 20 minutes, at which time isobutylchloroformate (9.3 mL, 71 mmol) was added drop-wise. The reaction was allowed to stir in an ice bath for approximately 60 minutes, at which time 6-amino-2-cyanobenzothiazole (10 g, 57 mM) was added. The reaction was allowed to stir for approximately 30 minutes in the ice bath, removed, and the reaction mixture allowed to reach room temperature overnight. The reaction was then filtered through a Buchner funnel, and the filtrate concentrated to a solid foam. This solid foam was dissolved in dichloromethane (1 L) and washed 2× with NaHCO3 (sat. aq., 300 mL). The organic phase was dried over Na2SO4, filtered, and concentrated to provide a solid foam. This solid foam was then purified by silica gel chromatography with a gradient of heptane/ethyl acetate (EtOAc) (40% EtOAc to 100% EtOAc step gradient over 80 minutes) to provide 24.7 g of Boc-Lys(Ac)-aminocyanobenzothiazole as a foamy solid.
Reaction SMILES: [CH:1]1([N:4]2[CH:8]=[N:7][N:6]=[C:5]2[C:9]2[CH:14]=[CH:13][N:12]=[CH:11][CH:10]=2)[CH2:3][CH2:2]1.[CH2:15]=[O:16]>>[CH:1]1([N:4]2[C:5]([C:9]3[CH:10]=[CH:11][N:12]=[CH:13][CH:14]=3)=[N:6][N:7]=[C:8]2[CH2:15][OH:16])[CH2:3][CH2:2]1
Reactant: c1cc(-c2nncn2C2CC2)ccn1
Reactant: C=O
Product: OCc1nnc(-c2ccncc2)n1C1CC1
Temperature: 135 °C
Yield: 85 %

Procedure:
4-(4-cyclopropyl-4H-[1,2,4]triazol-3-yl)-pyridine (6.85 g, 36.8 mmol) was mixed with 37% formaldehyde (30 mL) in a sealed vial and heated at 135° C. o.n. The reaction mixture was concentrated with silica gel and then mixed with MeOH. The mixture was filtered and washed with MeOH. The filtrate was concentrated with silica gel again and loaded on a flash column and eluted with 10% MeOH (2 M NH3) in DCM to give the title compound (6.8 g, 85%). 1H-NMR(DMSO-d6): 8.75(d, 2H), 7.84 (d, 2H), 5.63 (t, 1H), 4.72 (d, 2H), 3.66 (m, 1H), 1.04 (m, 2H), 0.73 (m, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][CH:9]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:10](O)=O)=[CH:4][CH:3]=1.O=S(Cl)Cl.[NH:23]1[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]2[S:8][C:9]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)=[C:10]([N:23]3[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]3)[C:4]=2[CH:3]=1
Reactant: O=C(O)C(Sc1ccc(Cl)cc1)c1ccccc1
Reactant: C1CCNCC1
Solvent: O=S(Cl)Cl
Product: Clc1ccc2sc(-c3ccccc3)c(N3CCCCC3)c2c1

Procedure:
20 g (72 mmole) of α-(4-chlorophenylthio)-phenylacetic acid and 20 milliliters (280 mmole) of SOCl2 are refluxed for 3 hours. After the excess SOCl2 has been removed, the crude acid chloride is dissolved in 100 milliliters of dioxan and, with stirring the cooling, 21.2 milliliters (290 mmole) of piperidine are added dropwise. After dilution in water, the mixture is extracted with CH2Cl2. By evaporating the organic phase dried over Na2SO4, 22.6 g (91% theory) of the piperidinium salt of α-(4-chlorophenylthio)-phenylacetic acid are obtained: colourless rods, mp 125°-126° (benzene/petroleum ether).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][CH:9]=2)[N:5]=[CH:4][N:3]=1.[CH3:18][C:19]1[CH:20]=[N:21][C:22]2[CH:23]=[CH:24][CH:25]=[C:26]([OH:29])[C:27]=2[N:28]=1.[H-].[Na+]>CN(C=O)C>[CH3:18][C:19]1[CH:20]=[N:21][C:22]2[C:27](=[C:26]([O:29][C:2]3[CH:7]=[C:6]([C:8]4[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][CH:9]=4)[N:5]=[CH:4][N:3]=3)[CH:25]=[CH:24][CH:23]=2)[N:28]=1
Reactant: FC(F)(F)c1ccc(-c2cc(Cl)ncn2)cc1
Reactant: Cc1cnc2cccc(O)c2n1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1cnc2cccc(Oc3cc(-c4ccc(C(F)(F)F)cc4)ncn3)c2n1
Temperature: 60 °C

Procedure:
To a mixture of 4-chloro-6-(4-trifluoromethyl-phenyl)-pyrimidine, (Example 2(a), Method A), (0.20 g, 0.77 mmol) and 3-methyl-quinoxalin-5-ol (0.14 g, 0.85 mmol, prepared according to J. Med. Chem. 1988, 41, 4062-4079.) in DMF (3 mL) was added sodium hydride (0.040 g, 1.0 mmol, 60% dispersion in mineral oil, Aldrich). The reaction was heated at 60° C. for 24 h, allowed to cool to room temperature and partitioned between EtOAc and H2O. The aqueous layer was extracted with EtOAc (4 x). The combined organic layers were dried over MgSO4, filtered and the solvent was removed in vacuum. The residue was purified by flash chromatography (0→75% EtOAc/hexanes) to give the title compound as an ivory powder. Mp: 139-141° C., MS (ESI, pos. ion) m/z: 383 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([OH:11])=O)=[CH:4][CH:3]=1.C1(B(O)O)C=CC=CC=1.B(O)(O)O.[NH2:25][CH2:26][CH:27]([OH:29])[CH3:28]>O.C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][C:9]([NH:25][CH2:26][CH:27]([OH:29])[CH3:28])=[O:11])=[CH:6][CH:7]=1
Reactant: CC(O)CN
Reactant: O=C(O)Cc1ccc(Cl)cc1
Agent: OB(O)O
Agent: OB(O)c1ccccc1
Solvent: Cc1ccccc1
Solvent: O
Product: CC(O)CNC(=O)Cc1ccc(Cl)cc1
Temperature: 40 °C
Reaction time: 10 h
Yield: 92.9 %

Procedure:
2-(4-Chlorophenyl)acetic acid (1.9 kg, 11.1 mol, 1.00 eq), toluene (1 L), phenylboronic acid (67 g, 549 mmo, 0.049 eq.), and boric acid (68 g, 1.10 mol. 0.099 eq) where charged to a 20 L jacketed reactor in the specified order. After the resulting mixture had been heated with stirring to 40° C., 1-amino-2-propanol (908 g, 12.09 mol, 1.085 eq) and toluene (1 L) were added. The reaction mixture was then heated to reflux while the water coproduct was removed in a Dean-Stark trap. Refluxing and water removal were continued until conversion of 2-(4-chlorophenyl)acetic acid exceeded 98%. Such conversion is usually achieved with 8-12 hours of refluxing. Water coproduct removed in the Dean-Stark trap totaled 265 mL (14.72 mol). After the reaction mixture had been cooled to 60-70° C., 5 wt % aqueous sodium bicarbonate (2 L) was added slowly while the reaction mixture was maintained at 60-70° C. Water (10 mL) was then added slowly while the stirred reaction mixture was maintained at ≧50° C. The diluted reaction mixture was cooled to 30° C. and stirred at that temperature for 30 minutes. The resulting solid precipitate was filtered and vacuum dried for 48 hours at 50° C. to provide 2-(4-chlorophenyl)-N-(2-hydroxypropyl)acetamide (2.356 kg, 92.9% yield not corrected for purity, 90.12% purity by HPLC peak area).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.[Br:8][C:9]1[O:13][C:12]([CH:14]=O)=[CH:11][CH:10]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C([O-])([O-])=O.[Na+].[Na+]>C(Cl)Cl>[Br:8][C:9]1[O:13][C:12]([CH2:14][N:5]2[CH2:6][CH2:7][N:2]([CH3:1])[CH2:3][CH2:4]2)=[CH:11][CH:10]=1
Reactant: O=Cc1ccc(Br)o1
Reactant: CN1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Product: CN1CCN(Cc2ccc(Br)o2)CC1
Reaction time: 0.5 h
Yield: 52.4 %

Procedure:
A round-bottomed flask was charged with 1-methylpiperazine (2.02 mL, 18.2 mmol), 5-bromofuran-2-carbaldehyde (3.03 g, 17.3 mmol), and CH2Cl2 (30 mL). The reaction mixture was stirred for 30 minutes, and then sodium triacetoxy borohydride (4.77 g, 22.5 mmol) was added slowly over five minutes. The reaction mixture was stirred at room temperature for 4 hours, then poured into Na2CO3 (100 mL) and extracted with CH2Cl2 (2×100 mL). The combined organic layers were dried over sodium sulfate, filtered and concentrated to provide the product (2.35 g, 50%) as an orange solid. LRMS (esi pos) m/e 260 (M+1).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH2:25][C@@H:26]3[CH2:30][CH2:29][CH2:28][N:27]3[C:31](=[O:35])[CH2:32][C:33]#[N:34])[N:9]=[C:10]([C:11]3[CH:16]=[CH:15][C:14]([O:17][C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)=[CH:13][C:12]=3[F:24])[C:3]=12.[CH3:36][C:37]1([CH:41]=O)[CH2:40][O:39][CH2:38]1.N1CCCCC1>C(O)C>[NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH2:25][C@@H:26]3[CH2:30][CH2:29][CH2:28][N:27]3[C:31]([C:32](=[CH:36][C:37]3([CH3:41])[CH2:40][O:39][CH2:38]3)[C:33]#[N:34])=[O:35])[N:9]=[C:10]([C:11]3[CH:16]=[CH:15][C:14]([O:17][C:18]4[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=4)=[CH:13][C:12]=3[F:24])[C:3]=12
Reactant: CC1(C=O)COC1
Reactant: N#CCC(=O)N1CCC[C@H]1Cn1nc(-c2ccc(Oc3ccccc3)cc2F)c2c(N)ncnc21
Solvent: CCO
Solvent: C1CCNCC1
Product: CC1(C=C(C#N)C(=O)N2CCC[C@H]2Cn2nc(-c3ccc(Oc4ccccc4)cc3F)c3c(N)ncnc32)COC1
Reaction time: 3 h

Procedure:
To a slurry of 3-[(2S)-2-[[4-amino-3-(2-fluoro-4-phenoxy-phenyl)pyrazolo[3,4-d]pyrimidin-1-yl]methyl]pyrrolidin-1-yl]-3-oxo-propanenitrile (74.mg, 0.16 mmol) in ethanol (3 mL) was added 3-methyloxetane-3-carbaldehyde (78.54 mg, 0.78 mmol) and then piperidine (0.02 mL, 0.16 mmol) and the mixture heated to 80° C. with stirring. After 3 h, the mixture was cooled and partitioned between ethyl acetate and water. The organic phase was washed with brine, dried over sodium sulfate, and the filtered. Solvents were removed to afford an oil which was purified by column chromatography (gradient from neat methylene chloride to 95-5 methylene chloride:MeOH). The pure fractions were concentrated, then taken up in acetonitrile/water, frozen and lyophilized to afford 2-[(25)-2-[[4-amino-3-(2-fluoro-4-phenoxy-phenyl)pyrazolo[3,4-d]pyrimidin-1-yl]methyl]pyrrolidine-1-carbonyl]-3-(3-methyloxetan-3-yl)prop-2-enenitrile as a colorless solid weighing 14 mg.
Reaction SMILES: CS([O:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][O:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)(=O)=O.[C:20](O)(=[O:27])[C:21]1[CH:26]=[CH:25][CH:24]=[N:23][CH:22]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.C(OCC)(=O)C>[C:20]([O:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][O:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)(=[O:27])[C:21]1[CH:26]=[CH:25][CH:24]=[N:23][CH:22]=1
Reactant: CS(=O)(=O)OCCCCCCCOc1ccccc1
Reactant: O=C(O)c1cccnc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: O=C(OCCCCCCCOc1ccccc1)c1cccnc1
Temperature: 52.5 °C
Yield: 80.3 %

Procedure:
A solution of 7-(phenyloxy)-1-heptyl methanesulfonate (0.2 g, 0.699 mmol) and nicotinic acid (0.173 g, 1.41 mmol) in anhydrous dimethyl formamide (15 mL) was placed in a 25 mL round bottomed flask. Potassium carbonate (0.097 g, 0.702 mmol) was added to this solution and the reaction mixture was heated at 50-55° C. using an oil bath for a period of 16 hours. It was then allowed to attain room temperature diluted with ethyl acetate (40 mL) and quenched with saturated NH4Cl containing ice (20 mL). The organic layer was separated and the aqueous layer was extracted with ethyl acetate (3×10 mL). The combined organic layer was washed with saturated NaHCO3 (3×10 mL), water (2×10 mL) and brine (2×10 mL). The organic layer was dried over Na2SO4. Removal of solvent from the dried extract under reduced pressure afforded the product 7-(phenyloxy)-1-heptyl nicotinate (0.176 g, 80.4%). The product ester from step C was analyzed yielding the following confirmatory data: 1H-NMR (CDCl3) δ 1.38-1.62 (m, 6H), 1.76-1.92 (m, 4H), 3.95 (t, 2H, J=6.45 Hz), 4.35 (t, 2H, J=6.64 Hz), 6.85-6.98 (m, 3H), 7.22-7.38 (m, 2H), 7.38 (dd, 1H, J1=7.93 Hz, J2=4.93 Hz), 8.29 (dt, 1H, J1=7.91 Hz, J2=1.92 Hz), 8.77 (dd, 1H, J1=4.83 Hz, J2=1.70 Hz) and 9.23 (d, 1H, J=2.00 Hz), 13C-NMR (CDCl3) δ 25.8, 25.9, 28.5, 28.9, 29.1, 65.4, 67.6, 114.3, 120.4, 123.2, 126.2, 129.3, 136.9, 150.8, 153.2, 158.9 and 165.2; IR (neat): 1712 cm−1; MS (ES+): 314 (M+1); Anal. Calcd. for C19H23NO3: C, 72.80; H, 7.40 and N, 4.47. Found: C, 72.94; H, 7.54 and N, 4.51.
Reaction SMILES: [Na].[CH:2]12[CH2:10][CH:6]([CH2:7][CH2:8][CH2:9]1)[CH2:5][C:4](=[N:11]O)[CH2:3]2>C1(C)C=CC=CC=1.CC(O)C>[CH:2]12[CH2:10][CH:6]([CH2:7][CH2:8][CH2:9]1)[CH2:5][CH:4]([NH2:11])[CH2:3]2
Reactant: ON=C1CC2CCCC(C1)C2
Agent: [Na]
Solvent: Cc1ccccc1
Solvent: CC(C)O
Product: NC1CC2CCCC(C1)C2
Temperature: 25 °C

Procedure:
Under a nitrogen atmosphere, to a refluxing suspension of sodium (2.401 g, 104 mmol) in toluene (20 mL) at a temperature of about 115° C. was added dropwise over 30 min bicyclo[3.3.1]nonan-3-one oxime (QS, 1.60 g, 10.44 mmol) in 2-propanol (8 mL). The mixture was stirred at reflux for 2 hr. After addition of the oxime solution is completed, 2-propanol (3 mL) was added dropwise. The reaction mixture was heated to reflux until all of the Na was consumed followed by cooling to a temperature of about 25° C. The reaction mixture was then quenched by the addition of H2O (20 mL). The organic layer was separated, and washed twice with 1N HCl (30 mL each). The acidic solution was made alkaline by the addition of 2N NaOH (50 mL), and extracted thrice with Et2O (50 mL each). The organic layers were combined and washed with saturated NaCl (50 mL). The organic layer was dried over Na2SO4, filtered and concentrated in vacuo to give of bicyclo[3.3.1]non-3-ylamine QA. This compound was used in the next step without purification in 2-propanol solution.
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]1[N:8]2[C:9]3[CH:15]=[C:14]([CH3:16])[NH:13][C:10]=3[CH:11]=[CH:12][C:7]2=[N:6][N:5]=1.[CH3:17][CH2:18][O:19][C:20]([CH:22](Br)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)=[O:21]>CN(C=O)C.CCOC(C)=O.O>[CH3:3][C:4]1[N:8]2[C:9]3[CH:15]=[C:14]([CH3:16])[N:13]([CH:22]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)[C:20]([O:19][CH2:18][CH3:17])=[O:21])[C:10]=3[CH:11]=[CH:12][C:7]2=[N:6][N:5]=1
Reactant: CCOC(=O)C(Br)c1ccccc1
Reactant: Cc1cc2c(ccc3nnc(C)n32)[nH]1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)C(c1ccccc1)n1c(C)cc2c1ccc1nnc(C)n12
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
Sodium hydride (110 mg, 2.7 mmol, 60% in mineral oil) was added to a solution of 1,7-dimethyl-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyridine (0.500 g, 2.68 mmol, from Example 2, Step 5) in DMF (50 mL). After 15 minutes, a solution of ethyl-alpha-bromophenyl acetate (0.70 mL, 4.0 mmol, Aldrich) in DMF (10 mL) was added dropwise. The mixture was stirred for 15 minutes at room temperature and then was poured into pH 7 buffer and diluted with EtOAc and water. The layers were separated and the aqueous was extracted again with EtOAc. The combined organic extracts were washed with water, then brine, dried over sodium sulfate, filtered and concentrated. The product was purified by flash chromatography, eluting with a gradient from 5-10% MeOH in DCM (187 mg, 20%).
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].CN(C)C=O.[S:10]1(=[O:19])[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=2[N:12]=[CH:11]1.[C:20](Cl)(=[O:22])[CH3:21]>>[C:20]([C:16]1[CH:17]=[CH:18][C:13]2[N:12]=[CH:11][S:10](=[O:19])[C:14]=2[CH:15]=1)(=[O:22])[CH3:21]
Reactant: O=S1C=Nc2ccccc21
Reactant: CC(=O)Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: CN(C)C=O
Product: CC(=O)c1ccc2c(c1)S(=O)C=N2

Procedure:
To a solution containing 0.5 mol of anhydrous aluminium chloride in 0.20 mol of dimethylformamide is added 0.05 mol of benzothiazolinone, then, slowly and with agitation, 0.06 mol of acetyl chloride.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([N:10]2[CH2:15][CH2:14][C@:13]([CH2:22][CH2:23][CH2:24][OH:25])([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[O:12][C:11]2=[O:26])[CH3:9])=[CH:4][CH:3]=1.Br[C:28]1[CH:33]=[CH:32][C:31]([F:34])=[CH:30][N:29]=1>>[F:34][C:31]1[CH:32]=[CH:33][C:28]([C:2]2[CH:3]=[CH:4][C:5]([C@@H:8]([N:10]3[CH2:15][CH2:14][C@:13]([CH2:22][CH2:23][CH2:24][OH:25])([C:16]4[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=4)[O:12][C:11]3=[O:26])[CH3:9])=[CH:6][CH:7]=2)=[N:29][CH:30]=1
Reactant: C[C@@H](c1ccc(Br)cc1)N1CC[C@](CCCO)(c2ccccc2)OC1=O
Reactant: Fc1ccc(Br)nc1
Product: C[C@@H](c1ccc(-c2ccc(F)cn2)cc1)N1CC[C@](CCCO)(c2ccccc2)OC1=O

Procedure:
The title compound was prepared from (R)-3-((S)-1-(4-bromophenyl)ethyl)-6-(3-hydroxypropyl)-6-phenyl-1,3-oxazinan-2-one following procedures analogous to those described in Example 313 Steps 3 and 4 using 2-bromo-5-fluoropyridine in Step 4. LC-MS Method 2 tR=1.197, m/z=435.1; 1H NMR (CDCl3) 1.21-1.37 (m, 2H), 1.48 (d, 3H), 1.81-1.95 (m, 2H), 2.18 (m, 1H), 2.20-2.31 (m, 2H), 2.85 (m, 1H), 3.52 (t, 2H), 5.65 (m, 1H), 6.95 (d, 2H), 7.22 (m, 3H), 7.28 (m, 2H), 7.40 (m, 1H), 7.58 (m, 3H), 8.42 (d, 1H).
Reaction SMILES: C([O:3][C:4](=[O:27])[C:5]1[CH:10]=[CH:9][C:8]([C:11]#[C:12][C:13]2[CH:22]=[CH:21][C:20]3[C:19](=[O:23])[CH2:18][CH2:17][C:16]([CH3:25])([CH3:24])[C:15]=3[CH:14]=2)=[CH:7][C:6]=1[F:26])C.ClCCl.C1(N)CC1.C([BH3-])#N.[Na+]>CCCCCC.C(OCC)(=O)C.C(O)(=O)C.C(#N)C>[F:26][C:6]1[CH:7]=[C:8]([C:11]#[C:12][C:13]2[CH:22]=[CH:21][C:20]3[C:19](=[O:23])[CH2:18][CH2:17][C:16]([CH3:25])([CH3:24])[C:15]=3[CH:14]=2)[CH:9]=[CH:10][C:5]=1[C:4]([OH:27])=[O:3]
Reactant: CCOC(=O)c1ccc(C#Cc2ccc3c(c2)C(C)(C)CCC3=O)cc1F
Agent: NC1CC1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: CC#N
Product: CC1(C)CCC(=O)c2ccc(C#Cc3ccc(C(=O)O)c(F)c3)cc21

Procedure:
Following general procedure G and using 2-fluoro-4-(8,8-dimethyl-5-oxo-5,6,7,8-tetrahydro-naphthalene-2-ylethynyl)-benzoic acid ethyl ester (Compound 9, 0.132 g, 0.3 mmol), dichloromethane (4 mL), acetonitrile(2 mL), cyclopropyl amine(1 mL, 14.45 mmol), acetic acid (1 mL)and sodium cyanoborohydride (0.18 g, 2.86 mmol) followed by flash column chromatography over silica gel (230-400 mesh) using 16-20% ethyl acetate in hexane as the eluent, the title compound was obtained as a pale yellow oil (0.1 g, 82%).
Reaction SMILES: Cl.Cl[CH2:3][CH2:4][N:5]([CH2:8][CH3:9])[CH2:6][CH3:7].[OH:10][CH2:11][C:12]1[C:18]2[N:19]([CH3:26])[C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][C:25]=3[C:17]=2[CH:16]=[CH:15][NH:14][CH:13]=1>>[CH2:6]([N:5]([CH2:4][CH2:3][N:14]1[CH2:15][CH2:16][C:17]2[C:25]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[N:19]([CH3:26])[C:18]=2[CH:12]([CH2:11][OH:10])[CH2:13]1)[CH2:8][CH3:9])[CH3:7]
Reactant: Cn1c2c(c3ccccc31)C=CNC=C2CO
Reactant: CCN(CC)CCCl
Agent: Cl
Product: CCN(CC)CCN1CCc2c(n(C)c3ccccc23)C(CO)C1

Procedure:
In accordance with the procedure described in example 18, the condensation of 1-chloro-2-diethylaminoethane hydrochloride with 5-hydroxymethyl-6-methylazepino[4,5-b]indole yields the product.
Reaction SMILES: [CH:1]([C:3]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:12]([O:14][CH3:15])=[O:13])[CH:10]=2)[NH:5][CH:4]=1)=O.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>CN(C=O)C.C(OCC)(=O)C>[CH3:1][C:3]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:12]([O:14][CH3:15])=[O:13])[CH:10]=2)[NH:5][CH:4]=1
Reactant: COC(=O)c1ccc2[nH]cc(C=O)c2c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc2[nH]cc(C)c2c1
Temperature: 100 °C
Yield: 59.1 %

Procedure:
To a solution of the methyl 3-formyl-1H-indole-5-carboxylate (893 mg, 4.4 mmol) in DMF (20 mL) was added the p-toluenesulfonic acid monohydrate (125 mg, 0.7 mmol) and the p-toluenesulfonyl hydrazide (982 mg, 5.3 mmol). The solution has been heated for 20 min at 100° C. The resulting mixture was diluted with ethyl acetate, washed with brine, dried over MgSO4 and concentrated. The crude product is dissolved in THF (40 mL) and NaBH3 CN (1.1 g, 17.6 mmol) was added. The solution has been heated for 8 h at 75° C. The resulting mixture was diluted with ethyl acetate, washed with a solution of 0.5 N HCl, a saturated solution of NaHCO3 and brine, dried over MgSO4 and concentrated. The crude product was purified by flash chromatography (Hexane/AcOEt, from 0 to 30%) to yield a white powder (500 mg, 2.6 mmol, 60%). ESI-MS (m/z): 190 [M+H]+.