Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:15]=[CH:14][CH:13]=[CH:12][C:3]=1[CH2:4][N:5]1[CH2:10][CH2:9][C:8](=[O:11])[CH2:7][CH2:6]1.[OH-].[Na+].[C:18]1(C)C=CC=CC=1>S([O-])(O)(=O)=O.C([N+](CCCC)(CCCC)CCCC)CCC>[F:1][C:2]1[CH:15]=[CH:14][CH:13]=[CH:12][C:3]=1[CH2:4][N:5]1[CH2:10][CH2:9][C:8]2([O:11][CH2:18]2)[CH2:7][CH2:6]1
Reactant: O=C1CCN(Cc2ccccc2F)CC1
Reactant: Cc1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=S(=O)([O-])O
Agent: [Na+]
Product: Fc1ccccc1CN1CCC2(CC1)CO2
Temperature: 80 °C

Procedure:
68.95 g (0.333 mol) of 1-(2-fluorobenzyl)-4-piperidone crude product was added to a reaction bottle, and 290 mL of toluene was added. The reaction heated at 80° C. in an oil bath under stirring, and then to the reaction 83.00 g (0.377 mol) of trimethylsulfoxide iodide and 2.20 g (0.0065 mol) of tetrabutylammonium hydrogen sulfate was added in sequence. Then to the reaction 28.40 g (0.710 mol) sodium hydroxide dissolved in 90 mL of aqueous solution was added dropwise under stirring. After the addition, the reaction was stirred at 80° C. of bath temperature overnight. On the next day, the reaction was cooled, washed with water twice, extracted with a small amount of toluene, combined, and the solvent was recovered to obtain light yellow liquid, 54.70 g (74.2%), i.e., a crude target product. 1H-NMR (CDCl3, ppm) δ: 7.394 (1H, dt, J1=7.56 Hz, J2=1.68 Hz), 7.254 (1H, m), 7.118 (1H, ddd, J1=7.56 Hz, J2=1.12 Hz), 7.037 (1H, dtd, J1=8.96 Hz, J2=1.12 Hz), 3.562 (2H, d, J=1.12 Hz), 2.647 (2H, s), 2.637 (4H, m), 1.820 (2H, m), 1.569 (2H, m).
Reaction SMILES: Cl.[CH2:2]([NH:4][CH2:5][CH3:6])[CH3:3].[C:7]([C:9]1[CH:35]=[CH:34][C:12]([C:13]([NH:15][C:16]2[CH:17]=[CH:18][C:19]([CH3:33])=[C:20]([NH:22][C:23](=[O:32])[C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([CH2:30]Cl)[CH:25]=3)[CH:21]=2)=[O:14])=[CH:11][CH:10]=1)#[N:8].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[C:7]([C:9]1[CH:35]=[CH:34][C:12]([C:13]([NH:15][C:16]2[CH:17]=[CH:18][C:19]([CH3:33])=[C:20]([NH:22][C:23](=[O:32])[C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([CH2:30][N:4]([CH2:5][CH3:6])[CH2:2][CH3:3])[CH:25]=3)[CH:21]=2)=[O:14])=[CH:11][CH:10]=1)#[N:8]
Reactant: CCNCC
Reactant: Cc1ccc(NC(=O)c2ccc(C#N)cc2)cc1NC(=O)c1cccc(CCl)c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCN(CC)Cc1cccc(C(=O)Nc2cc(NC(=O)c3ccc(C#N)cc3)ccc2C)c1
Temperature: 55 °C
Yield: 55 %

Procedure:
Diethylamine hydrochloride (0.33 g) was added to a stirred mixture of N-[5-(4-cyanobenzamido)-2-methylphenyl]-3-chloromethylbenzamide (0.4 g), potassium carbonate (0.5 g) and acetone (6 ml) and the reaction mixture was stirred and heated to 55° C. for 16 hours. The reaction mixture was evaporated and the residue was triturated under water. The solid was isolated and dried under vacuum at 55° C. to give the title compound (0.24 g); NMR spectrum: (DMSOd6) 0.95 (t, 6H), 2.19 (s, 3H), 3.58 (s, 2H), 7.22 (d, 1H), 7.5 (m, 3H), 7.85 (m, 3H), 7.99 (d, 2H), 8.12 (d, 2H); Mass Spectrum: M−H− 439.
Reaction SMILES: [NH2:1][CH2:2][C:3]([NH:5][CH:6]([C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([F:20])[CH:15]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([F:13])[CH:8]=1)=[O:4].[Cl:21][C:22]1[C:30]([C:31]([F:34])([F:33])[F:32])=[CH:29][CH:28]=[CH:27][C:23]=1[C:24](O)=[O:25]>>[F:20][C:16]1[CH:15]=[C:14]([CH:6]([NH:5][C:3]([CH2:2][NH:1][C:24](=[O:25])[C:23]2[CH:27]=[CH:28][CH:29]=[C:30]([C:31]([F:32])([F:33])[F:34])[C:22]=2[Cl:21])=[O:4])[C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([F:13])[CH:8]=2)[CH:19]=[CH:18][CH:17]=1
Reactant: NCC(=O)NC(c1cccc(F)c1)c1cccc(F)c1
Reactant: O=C(O)c1cccc(C(F)(F)F)c1Cl
Product: O=C(CNC(=O)c1cccc(C(F)(F)F)c1Cl)NC(c1cccc(F)c1)c1cccc(F)c1

Procedure:
Prepared in analogy to example 1.12 from 2-amino-N-[bis-(3-fluoro-phenyl)-methyl]-acetamide (example 3.4) and 2-chloro-3-trifluoromethyl-benzoic acid.
Reaction SMILES: [C:1]1([C@H:7]([NH2:9])[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:10][C:11]1[N:20]=[CH:19][C:18]2[C:17](SC)=[N:16][CH:15]=[N:14][C:13]=2[CH:12]=1.O>C(Cl)(Cl)Cl>[NH2:10][C:11]1[N:20]=[CH:19][C:18]2[C:17]([NH:9][C@@H:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[CH3:8])=[N:16][CH:15]=[N:14][C:13]=2[CH:12]=1
Reactant: C[C@@H](N)c1ccccc1
Reactant: CSc1ncnc2cc(N)ncc12
Solvent: O
Solvent: ClC(Cl)Cl
Product: C[C@@H](Nc1ncnc2cc(N)ncc12)c1ccccc1
Temperature: 180 °C
Yield: 10.9 %

Procedure:
A mixture of [R]-1-phenylethylamine (0.072 mL, 0.55 mmol) and 7-amino-4-methylthiopyrido[4,3-d]pyrimidine (97 mg, 0.5 mmol) (described in a previous experimental) is heated at 180° C. under N2 for 1.5 hr. The reaction is then cooled to room temperature producing a precipitate. The mixture is added to water and CHCl3, sonicated and filtered. The phases are separated and the aqueous phase is extracted with CHCl3. The combined extracts are washed with water, saturated brine and dried (MgSO4). The solvent is removed under reduced pressure and the residue purified by using preparative tlc (5% MeOH/CHCl3) and recrystallization from CHCl3 to give 7-amino-4-([R]-1-phenylethylamino)pyrido[4,3-d]pyrimidine (14.5 mg, 11%), mp 231.8-232.1° C. 1H NMR (DMSO) δ 9.23 (1H, s), 8.50 (1H, d, J=8.0 Hz), 8.19 (1H, s), 7.41 (2H, d, J=7.0 Hz), 7.31 (2H, t, J=8.0 Hz, 7.21 (1H, tt, J=7.4, 1.2 Hz), 6.45 (2H, s), 6.33 (1H, s), 5.56 (1H, p, J=7.2 Hz), 1.55 (3H, d, J=7.0 Hz).
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6]2[CH:11]=[C:10]([C:12]#[N:13])[CH:9]=[CH:8][N:7]=2)[N:3]=[CH:2]1.Br[CH2:15][C:16]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH:19]=[CH:18][CH:17]=1>>[C:16]1([CH2:15][N:1]2[CH:5]=[C:4]([C:6]3[CH:11]=[C:10]([C:12]#[N:13])[CH:9]=[CH:8][N:7]=3)[N:3]=[CH:2]2)[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH:19]=[CH:18][CH:17]=1
Reactant: BrCc1cccc2ccccc12
Reactant: N#Cc1ccnc(-c2c[nH]cn2)c1
Product: N#Cc1ccnc(-c2cn(Cc3cccc4ccccc34)cn2)c1

Procedure:
The title compound was prepared from 2-(1H-imidazol-4-yl)pyridine-4-carbonitrile (PREPARATION 4) and 1-(bromomethyl)naphthalene according to the procedure for the preparation of Example 43, part A using room temp. [M+H] Calc'd for C20H14N4, 311. Found, 311.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH2:8][NH:9][C:10]2[CH:18]=[CH:17][CH:16]=[C:12]([C:13]([OH:15])=O)[C:11]=2[C:19]([OH:21])=O)[O:5][C:6]=1[CH3:7].[O:22]=[C:23]1[CH:28]([N:29]2C(=O)C3C(=CC=CC=3NCCOC)C2=O)[CH2:27][CH2:26][C:25](=[O:45])[NH:24]1>>[CH3:1][C:2]1[CH:3]=[C:4]([CH2:8][NH:9][C:10]2[CH:18]=[CH:17][CH:16]=[C:12]3[C:11]=2[C:19](=[O:21])[N:29]([CH:28]2[CH2:27][CH2:26][C:25](=[O:45])[NH:24][C:23]2=[O:22])[C:13]3=[O:15])[O:5][C:6]=1[CH3:7]
Reactant: COCCNc1cccc2c1C(=O)N(C1CCC(=O)NC1=O)C2=O
Reactant: Cc1cc(CNc2cccc(C(=O)O)c2C(=O)O)oc1C
Product: Cc1cc(CNc2cccc3c2C(=O)N(C2CCC(=O)NC2=O)C3=O)oc1C
Yield: 22 %

Procedure:
3-[(4,5-Dimethyl-furan-2-ylmethyl)-amino]-phthalic acid (3 mmol) was treated in the same manner as described above for the synthesis of 2-(2,6-dioxo-piperidin-3-yl)-4-(2-methoxy-ethylamino)-isoindole-1,3-dione. The solid yellow residue was purified by preparative HPLC (Symmetry C18, isocratic, 40% acetonitrile/water) to give 0.25 g (22%) of product as a yellow solid: mp 127-129° C.; 1H NMR (DMSO-d6) δ 11.10 (s, 1H), 7.58 (dd, J=7.4 Hz and 8.4 Hz, 1H), 7.17 (d, J=8.6 Hz, 1H), 7.06 (d, J=7.1 Hz, 1H), 6.91 (t, J=6.1 Hz, 1H), 5.11 (s, 1H), 5.06 (dd, J=5.4 and 12.5 Hz, 1H), 4.45 (d, J=6.0 Hz, 2H), 2.97-2.82 (m, 1H), 2.63-2.44 (m, 2H), 2.13 (s, 3H), 2.08-1.99 (m, 1H), 1.85 (s, 3H); 13C NMR (DMSO-d6) δ 172.75, 170.02, 168.77, 167.21, 148.75, 146.18, 145.82, 136.05, 132.07, 117.57, 114.16, 110.94, 110.55, 109.61, 48.56, 38.94, 30.95, 22.10, 11.08, 9.50; Anal. Calcd. For C20H19N3O5: C, 62.99; H, 5.02; N, 11.02. Found: C, 62.75; H, 4.97; N, 10.72.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[CH2:9][CH2:10][OH:11].C(OI1(OC(=O)C)(OC(=O)C)C2C(=CC=CC=2)C(=O)O1)(=O)C.C([O-])(O)=O.[Na+].[O-]S([O-])(=S)=O.[Na+].[Na+]>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[CH2:9][CH:10]=[O:11]
Reactant: OCCc1c(Cl)cccc1Cl
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: O=C([O-])O
Agent: O=S([O-])([O-])=S
Solvent: ClCCl
Product: O=CCc1c(Cl)cccc1Cl
Yield: 70.5 %

Procedure:
To a solution of 2,6-dichlorophenylethylalcohol (2.0 g, 10.5 mmol) and CH2Cl2 (50 mL) was added acetic acid 1,1-diacetoxy-3-oxo-1λ5-ioda-2-oxa-indan-1-yl ester (Dess-Martin periodinane; 4.9 g, 11.5 mmol) at rt. After 30 min. the mixture was diluted with satd. aq. NaHCO3 (10 mL) and satd. aq. Na2S2O3 (10 mL) and was stirred at rt for 1 h. The mixture was extracted with CH2Cl2 (3×15 mL) and the combined organic layers were dried (MgSO4), concentrated, and purified by FCC to afford a colorless solid (1.4 g, 70%). 1H NMR (CDCl3): 9.76 (dd, J=2.24, 1.12 Hz, 1H), 7.38 (d, J=8.1 Hz, 2H), 7.25-7.20 (m, 1H), 4.14 (d, J=0.93 Hz, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[Cl:11])[C:7](=O)[CH2:6][CH2:5]2.C([O-])(=O)C.[NH4+].C([BH3-])#[N:19].[Na+]>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[Cl:11])[CH:7]([NH2:19])[CH2:6][CH2:5]2
Reactant: [BH3-]C#N
Reactant: O=C1CCc2cc(Cl)c(Cl)cc21
Agent: CC(=O)[O-]
Agent: [NH4+]
Agent: [Na+]
Product: NC1CCc2cc(Cl)c(Cl)cc21

Procedure:
Following the procedure of Example 1, 5,6-dichloro-1-indanone was reacted with ammonium acetate and sodium cyanoborohydride to yield 5,6-dichloro-1-aminoindane; yield = 670 mg. The crystalline compound was treated with 360 mg. of maleic acid in 25 ml. of isopropanol. The maleate salt crystallized and was separated by filtration. Recrystallization of the salt from a 1:3 isopropanol/ethyl acetate solvent mixture yielded 650 mg. of 5,6-dichloro-1-aminoindane maleate melting at 167°-170° C.
Reaction SMILES: [OH:1][C:2]1[CH:6]=[C:5]([C:7]([F:10])([F:9])[F:8])[S:4][C:3]=1[CH2:11][N:12]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[C:14]2([C:24]3=[CH:25][C:26]4[O:30][CH2:29][O:28][C:27]=4[CH:31]=[C:23]3[O:22][CH2:21]2)[C:13]1=[O:32].[OH-].[Na+].I[CH3:36]>CN(C)C=O>[CH3:36][O:1][C:2]1[CH:6]=[C:5]([C:7]([F:8])([F:9])[F:10])[S:4][C:3]=1[CH2:11][N:12]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[C:14]2([C:24]3=[CH:25][C:26]4[O:30][CH2:29][O:28][C:27]=4[CH:31]=[C:23]3[O:22][CH2:21]2)[C:13]1=[O:32]
Reactant: CI
Reactant: O=C1N(Cc2sc(C(F)(F)F)cc2O)c2ccccc2C12COc1cc3c(cc12)OCO3
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: COc1cc(C(F)(F)F)sc1CN1C(=O)C2(COc3cc4c(cc32)OCO4)c2ccccc21
Temperature: 25 °C
Reaction time: 16 h
Yield: 80.9 %

Procedure:
A mixture of 1′-{[3-hydroxy-5-(trifluoromethyl)-2-thienyl]methyl}spiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one (0.18 g, 0.39 mmol), NaOH (0.08 g, 1.96 mmol) and iodomethane (0.17 g, 1.18 mmol) in anhydrous N,N-dimethylformamide (2.00 mL) was stirred at ambient temperature for 16 h. The reaction was quenched by addition of saturated ammonium chloride (10.0 mL) and extracted with ethyl acetate (3×50.0 mL). The combined organic layers was washed with water (3×20.0 mL), brine (20.0 mL), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated in vacuo to dryness. The colorless solid was triturated with ether to give the title compound (0.15 g, 81%): mp 178-180° C.; 1H NMR (300 MHz, DMSO-d6) δ 7.71 (s, 1H), 7.30 (dt, 1H), 7.15 (d, 1H), 7.07-7.02 (m, 2H), 6.68 (s, 1H), 6.08 (s, 1H), 5.89 (d, 2H), 4.95 (ABq, 2H), 4.70 (ABq, 2H), 3.90 (s, 3H); 13C NMR (75 MHz, DMSO-d6) δ 177.0, 155.8, 154.9, 148.9, 142.2, 141.8, 132.1, 129.4, 125.7, 124.3, 123.8, 120.4, 120.3, 120.0, 119.5, 109.4, 103.2, 102.0, 93.9, 80.1, 59.9, 57.9, 34.9; MS (ES+) m/z 476.3 (M+1).
Reaction SMILES: [Br:1][C:2]1[C:7]2[C:8](=[O:20])[N:9]([CH3:19])[CH2:10][C:11]3[N:12]([CH:13]=[N:14][C:15]=3[C:16](O)=[O:17])[C:6]=2[CH:5]=[CH:4][CH:3]=1.C(N1C=CN=C1)([N:23]1C=CN=C1)=O.N>CN(C)C=O.O>[Br:1][C:2]1[C:7]2[C:8](=[O:20])[N:9]([CH3:19])[CH2:10][C:11]3[N:12]([CH:13]=[N:14][C:15]=3[C:16]([NH2:23])=[O:17])[C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: CN1Cc2c(C(=O)O)ncn2-c2cccc(Br)c2C1=O
Reactant: O=C(n1ccnc1)n1ccnc1
Agent: N
Solvent: O
Solvent: CN(C)C=O
Product: CN1Cc2c(C(N)=O)ncn2-c2cccc(Br)c2C1=O
Reaction time: 0.5 h
Yield: 87 %

Procedure:
24.9 g (74.1 mmol) of 7-bromo-5-methyl-6-oxo-5,6-dihydro-4H-imidazo[1,5-a][1,4]benzodiazepine-3-carboxylic acid were suspended in 100 ml of N,N-dimethylformamide, treated at room temperature with 14.3 g (89 mmol) of 1,1'-carbonyldiimidazole and stirred at 70° for 30 minutes. 50 ml of 25% ammonia were added dropwise at 25°-30°. The reaction mixture was diluted with 200 ml of water and cooled to 0°, and the crystallizate was filtered off under suction and dried. There were obtained 21.6 g (86%) of 7-bromo-5-methyl-6-oxo-5,6-dihydro-4H-imidazo[1,5-a][1,4]benzodiazepine-3-carboxamide of m.p. 278°-279°.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:29])[C:4](=[CH:9][NH:10][C:11]1[C:20]2[C:15](=[CH:16][CH:17]=[C:18]([NH:21][C:22](=[O:28])[CH:23]([CH2:26][CH3:27])[CH2:24][CH3:25])[CH:19]=2)[N:14]=[CH:13][N:12]=1)[C:5](OC)=[O:6].C1(OC2C=CC=CC=2)C=CC=CC=1>CCCCCC>[O:6]=[C:5]1[N:12]2[CH:13]=[N:14][C:15]3[CH:16]=[CH:17][C:18]([NH:21][C:22](=[O:28])[CH:23]([CH2:26][CH3:27])[CH2:24][CH3:25])=[CH:19][C:20]=3[C:11]2=[N:10][CH:9]=[C:4]1[C:3]([O:2][CH3:1])=[O:29]
Reactant: CCC(CC)C(=O)Nc1ccc2ncnc(NC=C(C(=O)OC)C(=O)OC)c2c1
Solvent: CCCCCC
Solvent: c1ccc(Oc2ccccc2)cc1
Product: CCC(CC)C(=O)Nc1ccc2ncn3c(=O)c(C(=O)OC)cnc3c2c1
Temperature: 255 °C
Yield: 78.1 %

Procedure:
A mixture of dimethyl[[6-(2-ethylbutyramido)-4-quinazolinylamino]methylene]propanedioate (5.3 g) and diphenyl ether (32 ml) was heated at 255° C. for 15 minutes and cooled to ambient temperature. Hexane was added to the reaction mixture. The resulting crystals were filtered off, washed with hexane and dried. The crude crystals were dissolved in a mixture of chloroform and methanol (10:1) under heating. Insoluble materials were removed by filtration. The filtrate was concentrated under reduced pressure to give crystals, which were recrystallized from a mixture of chloroform and hexane to give methyl 4-oxo-10-(2-ethylbutyramido)-4H-pyrimido[1,2-C]quinazoline-3-carboxylate (3.81 g).
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]1[CH:9]=[C:8]([C:10]2[O:14][N:13]=[C:12]([C:15]3[CH:16]=[C:17]([CH:21]=[CH:22][CH:23]=3)[C:18](Cl)=[O:19])[N:11]=2)[CH:7]=[CH:6][C:5]=1[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[CH3:30].Cl.[NH2:32][CH2:33][CH2:34][CH2:35][C:36]([O:38][CH3:39])=[O:37]>>[CH3:1][O:2][CH2:3][C:4]1[CH:9]=[C:8]([C:10]2[O:14][N:13]=[C:12]([C:15]3[CH:16]=[C:17]([CH:21]=[CH:22][CH:23]=3)[C:18]([NH:32][CH2:33][CH2:34][CH2:35][C:36]([O:38][CH3:39])=[O:37])=[O:19])[N:11]=2)[CH:7]=[CH:6][C:5]=1[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[CH3:30]
Reactant: COCc1cc(-c2nc(-c3cccc(C(=O)Cl)c3)no2)ccc1-c1ccccc1C
Reactant: COC(=O)CCCN
Agent: Cl
Product: COCc1cc(-c2nc(-c3cccc(C(=O)NCCCC(=O)OC)c3)no2)ccc1-c1ccccc1C

Procedure:
The title compound was prepared following procedure described in example 121 starting from 3-{5-[2-(methoxymethyl)-2′-methylbiphenyl-4-yl]-1,2,4-oxadiazol-3-yl}benzoyl chloride and methyl 4-aminobutyrate hydrochloride (55.01 mg; 0.36 mmol) The title compound was obtained as a sticky foam (85 mg, 71%). 1H NMR: (DMSO-d6, 300 MHz) δ 8.53 (brs, 1H), 8.43 (brs, 1H), 8.32 (m, 1H), 8.17 (m, 1H), 8 (m, 1H), 7.60 (t, J=7.8 Hz, 1H), 7.34-7.22 (m, 4H), 7.12 (m, 1H), 6.65 (m, 1H), 4.22 (s, 2H), 3.69 (s, 3H), 3.56 (m, 2H), 3.32 (s, 3H), 2.48 (t, J=7 Hz, 1H), 2.07 (s, 3H), 2.01 (m, 2H). LC/MS (Method B): 500.2 (M+H)+ 498.3 (M−H)−. HPLC (Method A) Rt: 5.68 min (purity: 99.2%).
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][C:11]2([C:21]3[C:16](=[CH:17][CH:18]=[CH:19][C:20]=3[CH2:22][NH:23]C(=O)OC(C)(C)C)[N:15]([C:31]3[C:32]4[CH:39]([CH:40]([CH3:42])[CH3:41])[CH2:38][CH2:37][C:33]=4[N:34]=[CH:35][N:36]=3)[CH2:14]2)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[ClH:43]>C(Cl)Cl.O1CCOCC1>[ClH:43].[ClH:43].[ClH:43].[CH2:1]([N:8]1[CH2:13][CH2:12][C:11]2([C:21]3[C:16](=[CH:17][CH:18]=[CH:19][C:20]=3[CH2:22][NH2:23])[N:15]([C:31]3[C:32]4[CH:39]([CH:40]([CH3:42])[CH3:41])[CH2:38][CH2:37][C:33]=4[N:34]=[CH:35][N:36]=3)[CH2:14]2)[CH2:10][CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)C1CCc2ncnc(N3CC4(CCN(Cc5ccccc5)CC4)c4c(CNC(=O)OC(C)(C)C)cccc43)c21
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: CC(C)C1CCc2ncnc(N3CC4(CCN(Cc5ccccc5)CC4)c4c(CN)cccc43)c21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of tert-butyl (1′-benzyl-1-(5-isopropyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)spiro[indoline-3,4′-piperidine]-4-yl)methylcarbamate (1.00 g, 1.76 mmol) in DCM (8 mL) was treated with 4N HCl in dioxane (2 mL). The reaction was stirred at room temperature for 1 hour and concentrated under reduced pressure to yield (1′-benzyl-1-(5-isopropyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)spiro[indoline-3,4′-piperidine]-4-yl)methanamine trihydrochloride. LCMS (APCI+) m/z 468.2 [M+H]+; Rt=3.42 min.
Reaction SMILES: [F:1][C:2]1[CH:23]=[CH:22][C:5]([CH2:6][CH2:7][N:8]2[C:16]3[C:11](=[CH:12][C:13]([Cl:17])=[CH:14][CH:15]=3)[C:10]([CH2:18][CH2:19][NH:20][CH3:21])=[CH:9]2)=[CH:4][CH:3]=1.[C:24](O)(C(F)(F)F)=O.C=O>C(#N)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][CH2:7][N:8]2[C:16]3[C:11](=[CH:12][C:13]([Cl:17])=[CH:14][CH:15]=3)[C:10]3[CH2:18][CH2:19][N:20]([CH3:24])[CH2:21][C:9]2=3)=[CH:22][CH:23]=1
Reactant: CNCCc1cn(CCc2ccc(F)cc2)c2ccc(Cl)cc12
Reactant: O=C(O)C(F)(F)F
Agent: C=O
Solvent: CC#N
Product: CN1CCc2c(n(CCc3ccc(F)cc3)c3ccc(Cl)cc23)C1
Temperature: 25 °C
Reaction time: 0.29 h

Procedure:
The title compound was prepared by General Method 4. 2-(1-(4-fluorophenethyl)-5-chloro-1H-indol-3-yl)-N-methylethanamine (600 mg) was dissolved in acetonitrile (10 mL) containing 5% TFA and the reaction mixture was heated to reflux. 37% aqueous formaldehyde (0.17 mL) was added and the reflux was continued for 15-20 min. The reaction mixture was cooled to 25° C., concentrated under reduced pressure and partitioned between ethyl acetate and satd. Aqueous NaHCO3. The organic layer was dried over sodium sulfate, evaporated under reduced pressure and the residue was purified by silica gel chromatography (eluent 6% methanol-chloroform) to obtain 170 mg of product. The free base was converted into its HCl salt by treatment of HCL-ether. 1H NMR (CDCl3) δ 13.1 (s, 1H), 7.25-7.1 (m, 3H), 6.8 (m, 2H), 6.7 (m, 2H), 4.4 (m, 1H), 4.2 (m, 1H), 3.9 (m, 1H), 3.4 (m, 1H), 3.2-3.0 (m, 3H), 2.8 (m, 3H), 2.6 (s, 3H). MS m/z observed 343. HPLC RT 5.16 min.
Reaction SMILES: C([O:8][C:9]1[C:10](=[O:16])[N:11]([CH3:15])[CH:12]=[CH:13][CH:14]=1)C1C=CC=CC=1.[H][H]>[Pd].CO>[OH:8][C:9]1[C:10](=[O:16])[N:11]([CH3:15])[CH:12]=[CH:13][CH:14]=1
Reactant: [H][H]
Reactant: Cn1cccc(OCc2ccccc2)c1=O
Agent: [Pd]
Solvent: CO
Product: Cn1cccc(O)c1=O

Procedure:
A mixture of 3-(benzyloxy)-1-methyl-1H-pyridin-2-one (23 g, 106.85 mmol) and 10% palladium on carbon (2.3 g) in methanol (250 mL) was stirred under 1 atmosphere of hydrogen for 5 hr at room temperature. The catalyst was removed by filtration. The filtrate was concentrated in vacuo to give the title compound (12 g (90%) as a purple solid: 1H NMR (400 MHz, DMSO) delta 8.96 (s, 1H), 7.15-7.13 (m, 1H), 6.70-6.68 (m, 1H), 6.07 (t, J=7.0 Hz, 1H), 3.47 (s, 3H).
Reaction SMILES: [CH3:1][O:2][C:3]([C@@H:5]1[CH2:9][C@H:8]([N:10]=[N+]=[N-])[CH2:7][N:6]1[C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])=[O:4]>CO.[Pd]>[CH3:1][O:2][C:3]([C@@H:5]1[CH2:9][C@H:8]([NH2:10])[CH2:7][N:6]1[C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])=[O:4]
Reactant: COC(=O)[C@@H]1C[C@H](N=[N+]=[N-])CN1C(=O)OC(C)(C)C
Agent: [Pd]
Solvent: CO
Product: COC(=O)[C@@H]1C[C@H](N)CN1C(=O)OC(C)(C)C
Yield: 96.8 %

Procedure:
(2S,4S)-4-azidopyrrolidine-1,2-dicarboxylic acid 1-t-butyl ester 2-methyl ester (8.5 g, 31 mmol) and Pd/C (10% w/w, 2.0 g) were stirred in MeOH (150 mL) at room temperature under an atmosphere of hydrogen for 48 hours. The mixture was filtered and the filtrate evaporated to afford the title compound (7.34 g, 30 mmol), which was used without further purification. MS m/z: [M+H]+ calcd for C11H20N2O4, 244.3. found 245.3.
Reaction SMILES: [C:1]([C:3]1[CH:12]=[C:11]2[C:6]([CH2:7][CH2:8][CH:9]([N:13]([CH2:33][CH2:34][CH3:35])[CH2:14][CH2:15][CH2:16][CH2:17][NH:18][C:19](=[O:32])[C:20]3[CH:25]=[CH:24][C:23]([C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)=[CH:22][CH:21]=3)[CH2:10]2)=[CH:5][CH:4]=1)#[N:2].OO.O.C(=O)([O-])[O-:40].[K+].[K+]>CS(C)=O>[C:26]1([C:23]2[CH:24]=[CH:25][C:20]([C:19]([NH:18][CH2:17][CH2:16][CH2:15][CH2:14][N:13]([CH2:33][CH2:34][CH3:35])[CH:9]3[CH2:10][C:11]4[CH:12]=[C:3]([C:1]([NH2:2])=[O:40])[CH:4]=[CH:5][C:6]=4[CH2:7][CH2:8]3)=[O:32])=[CH:21][CH:22]=2)[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: O=C([O-])[O-]
Reactant: CCCN(CCCCNC(=O)c1ccc(-c2ccccc2)cc1)C1CCc2ccc(C#N)cc2C1
Agent: OO
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: CCCN(CCCCNC(=O)c1ccc(-c2ccccc2)cc1)C1CCc2ccc(C(N)=O)cc2C1
Temperature: 25 °C
Reaction time: 6 h
Yield: 82.3 %

Procedure:
To a solution of 7-cyano-N-(4-(4-phenylbenzoylamino)butyl)-2-(R,S)-propylamino-1,2,3,4-tetrahydronaphthalene (0.983 g, 2.11 mmol) in dimethyl sulfoxide (4 ml) at 15° C. was added a solution of hydrogen peroxide in water (27.5% w/v; 0.26 ml; 2.12 mmol) followed by anhydrous potassium carbonate (0.42 g, 3.06 mmol). The mixture was stirred for 6 h at room temperature, then poured into water (100 ml) and the resulting solid filtered off to give the title compound (0.84 g, 82%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]([C:11]1[CH:16]=[CH:15][N:14]=[CH:13][CH:12]=1)=O.Cl.O([NH2:20])C>FC(F)(F)C(O)=O.[Pd]>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][CH:9]([NH2:20])[C:11]1[CH:16]=[CH:15][N:14]=[CH:13][CH:12]=1
Reactant: CON
Reactant: O=C(Cc1ccccc1F)c1ccncc1
Agent: [Pd]
Agent: Cl
Solvent: O=C(O)C(F)(F)F
Product: NC(Cc1ccccc1F)c1ccncc1
Reaction time: 14 h

Procedure:
The intermediate oxime was prepared from 2-(2-fluoro-phenyl)-1-pyridin-4-yl-ethanone (crude) and methoxylamine hydrochloride (6.50 g, 77.83 mmol) according to the protocol described in general procedure B. The oxime was then dissolved in trifluoroacetic acid (30.00 mL) and Pd/C (0.80 g) was added. The reaction mixture was hydrogenated under 50 psi for 14 hours, then filtered and concentrated. The residue was basified with 5M sodium hydroxide and extracted with methylene chloride. The combined organic phases were dried over potassium carbonate and concentrated to yield the title compound. Spectroscopic data: 1H NMR (300 MHz, DMSO-d6) δ ppm 2.83-3.00 (m, 2 H) 4.11 (t, J=7.33 Hz, 1 H) 7.34-7.48 (m, 2 H) 7.75 (dd, J=20.96, 11.58 Hz, 2 H) 8.45-8.52 (m, 1 H) 8.53-8.58 (m, J=6.45 Hz, 2 H) 8.79-8.80 (m, 1 H).
Reaction SMILES: [C:1]([O:5][OH:6])([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+].[C:9]1([CH3:23])[CH:14]=[CH:13][C:12]([O:15][C:16]([CH2:18][CH2:19][C:20](Cl)=[O:21])=[O:17])=[CH:11][CH:10]=1.O=O>CCOCC>[C:20]([O:6][O:5][C:1]([CH3:4])([CH3:3])[CH3:2])(=[O:21])[CH2:19][CH2:18][C:16]([O:15][C:12]1[CH:11]=[CH:10][C:9]([CH3:23])=[CH:14][CH:13]=1)=[O:17]
Reactant: CC(C)(C)OO
Reactant: Cc1ccc(OC(=O)CCC(=O)Cl)cc1
Agent: O=O
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Product: Cc1ccc(OC(=O)CCC(=O)OOC(C)(C)C)cc1
Reaction time: 3 h
Yield: 92.8 %

Procedure:
To a vigorously stirred solution of 15.6 g. (0.143 mole) of 82.0% t-butyl hydroperoxide and 57.0 g (0.143 mole) of aqueous 10% sodium hydroxide at 5°-10° C was added slowly 24.6 g. (0.109 mole) of 3-(p-tolyloxycarbonyl)propionyl chloride (prepared from p-tolyl 3-carboxypropionate and thionyl chloride) in 50 ml. of diethyl ether. The reaction mixture was then stirred at 5°-10° C for three hours, after which additional ether was added to the mixture and the resulting ether solution was washed, first with 10% sodium hydroxide solution, and finally with water until the solution was neutral. After drying over anhydrous MgSO4 and removal of the ether in vacuo 28.2 g. (theory, 30.4 g.) of white solid, m.p. 72°-77° C, was obtained. The assay according to "active oxygen" content was 100% and the corrected yield was 92.8%.