Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([C:3]1[CH:10]=[C:7]([CH:8]=O)[C:6]([OH:11])=[CH:5][CH:4]=1)=[O:2].[F:12][C:13]([F:22])([F:21])/[CH:14]=[CH:15]/[C:16]([O:18][CH2:19][CH3:20])=[O:17].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH:1]([C:3]1[CH:4]=[CH:5][C:6]2[O:11][CH:14]([C:13]([F:12])([F:22])[F:21])[C:15]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:8][C:7]=2[CH:10]=1)=[O:2]
Reactant: CCOC(=O)/C=C/C(F)(F)F
Reactant: O=Cc1ccc(O)c(C=O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)C1=Cc2cc(C=O)ccc2OC1C(F)(F)F
Temperature: 60 °C

Procedure:
A 50 mL round bottom flask was charged with 5-formylsalicylaldehyde (3.21 g, 21.39 mmol), ethyl 4,4,4-trifluorocrotonate (3.50 mL, 3.96 g, 23.53 mmol), dimethylformamide (15 mL) and potassium carbonate (2.95 g, 21.39 mmol) and heated to 60° C. for 12 hours. Additional ethyl 4,4,4-trifluorocrotonate (3.50 mL, 3.96 g, 23.53 mmol) was added and the reaction heated for 16 hours at 75° C. After cooling to room temperature, the reaction was partitioned between H2O and diethyl ether. The organic phase was washed with saturated NaHCO3 solution, KHSO4 solution (0.25 M), brine, treated with decolorizing carbon (warmed gently). The resulting black suspension was dried over MgSO4, vacuum filtered through diatomaceous earth, and concentrated in vacuo yielding an orange crystalline mass. This material was recrystallized from hot hexanes yielding the ester (1.51 g, 24%) as orange crystals: mp 84.3–86.2° C. 1H NMR (acetone-d6/300 MHz) 9.96 (s, 1H), 8.06 (d, 1H, J=2 Hz), 8.02 (s, 1H), 7.99 (dd, 1H, J=8.5, 2.0 Hz), 7.24 (d, 1H, J=8.5 Hz), 5.99 (q, 1H, J=7.1 Hz), 4.43–4.25 (m, 2H), 1.34 (t, 3H, J=7.3 Hz). FABLRMS m/z 301 (M+H). EIHRMS m/z 300.0605 (M+, Calc'd 300.0609). Anal. Calc'd for C14H11F3O4: C, 56.01; H, 3.69. Found: C, 56.11; H, 3.73.
Reaction SMILES: [Li+].[CH3:2]C([N-]C(C)C)C.[CH:9]1[C:14]2[C:15]3[C:28](=O)[C:20]4S[C:22]5C=CC=[CH:24][C:23]=5[C:19]=4[C:18](=O)[C:16]=3SC=2C=CC=1.O>C1COCC1>[C:23]([C:19]1[CH:18]=[CH:16][C:15]([C:14]#[CH:9])=[CH:28][CH:20]=1)([CH3:22])([CH3:24])[CH3:2]
Reactant: CC(C)[N-]C(C)C
Reactant: O=C1c2sc3ccccc3c2C(=O)c2sc3ccccc3c21
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: C#Cc1ccc(C(C)(C)C)cc1
Temperature: 24.5 °C
Reaction time: 0.17 h

Procedure:
In another flame dried flask, a solution of 1-tert-butyl-4-ethynyl-benzene (3.56 g, 22.5 mmol) in THF (20 ml) is prepared, and the freshly prepared LDA is added to this solution within 10 minutes. The temperature is maintained in the range between 23-26° C. by cooling, and the solution is stirred for another 10 minutes at ambient temperature. Then dibenzo[d,d′]benzo[1,2-b;4,5-b′]dithiophene-6,12-dione (educt 1) (2.40 g, 7.5 mmol) is added as a solid, and the mixture heated to 50° C. and stirred for 52 hours at this temperature. The clear red solution is poured carefully into water (100 ml), and the product extracted with chloroform (80 ml). The aqueous layer is extracted again with chloroform (80 ml), and the combined organic layers are washed with brine and dried (sodium sulphate). Removal of the solvent leaves the crude product as light brown crystals. The crystals are refluxed in methanol (50 ml) (incompletely dissolved) and the mixture allowed to crystallise over night. The solid is then filtered off and washed with methanol thrice (7 ml each time) and dried in vacuo to give the product as beige crystals. 1H-NMR (CDCl3, 300 MHz) δ 1.29 (s, 9H, C(CH3)3); 3.09 (s, 1H, OH); 7.27, 7.36 (AA′BB′, 4H, Ph H); 7.43, 7.48 (2 “tr”, 1H each), 7.89 pp (d, J=6.5 Hz, 1H), 8.54 (d, J=8.2 Hz, 1H) benzothiophene H. 13C-NMR (CDCl3, 75 MHz) δ 31.47 (C(CH3)3); 35.17 (q, C(CH3)3); 64.79 (q, COH); 87.80, 88.69 (2 q, C≡C); 118.96 (q), 123.03, 124.84, 125.13, 125.77 (benzothiophene CH); 125.46, 131.76 (Ph CH); 130.90 (q), 136.15 (q), 140.37 (q), 144.11 (q), 152.48 (q).
Reaction SMILES: FC1C=CC(C[N:7]2C(=O)N(C3SC(C(O)=O)=C(C)N=3)C=N2)=CC=1.[Cl:24][C:25]1[CH:46]=[CH:45][C:28]([CH2:29][N:30]2[CH2:34][CH2:33][N:32]([C:35]3[S:36][C:37]([C:41](O)=[O:42])=[C:38]([CH3:40])[N:39]=3)[C:31]2=[O:44])=[CH:27][CH:26]=1>>[Cl:24][C:25]1[CH:46]=[CH:45][C:28]([CH2:29][N:30]2[CH2:34][CH2:33][N:32]([C:35]3[S:36][C:37]([C:41]([NH2:7])=[O:42])=[C:38]([CH3:40])[N:39]=3)[C:31]2=[O:44])=[CH:27][CH:26]=1
Reactant: Cc1nc(-n2cnn(Cc3ccc(F)cc3)c2=O)sc1C(=O)O
Reactant: Cc1nc(N2CCN(Cc3ccc(Cl)cc3)C2=O)sc1C(=O)O
Product: Cc1nc(N2CCN(Cc3ccc(Cl)cc3)C2=O)sc1C(N)=O

Procedure:
Following the procedure as described in Example 1, making variations as required to replace 2-(1-(4-fluorobenzyl)-5-oxo-1H-1,2,4-triazol-4(5H)-yl)-4-methyl-thiazole-5-carboxylic acid with 2-(3-(4-chlorobenzyl)-2-oxoimidazolidin-1-yl)-4-methylthiazole-5-carboxylic acid, the title compound was obtained as a colorless solid: mp >200° C.; 1H NMR (300 MHz, DMSO-d6) δ 7.46-7.37 (m, 6H), 4.47 (s, 2H), 4.03 (br s, 2H), 3.49-3.37 (m, 2H), 2.50 (s, 3H); MS (ES+) m/z 350.8 (M+1).
Reaction SMILES: [CH:1]1([O:6][C:7]2[CH:8]=[C:9]([CH:25]=[CH:26][C:27]=2[O:28][CH3:29])[CH2:10][N:11]2[C:19]3[N:18]=[C:17]([CH:20]([CH3:22])[CH3:21])[NH:16][C:15]=3[C:14](=O)[NH:13][C:12]2=[O:24])[CH2:5][CH2:4][CH2:3][CH2:2]1.P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:31].[OH-].[Na+]>N1C=CC=CC=1>[CH:1]1([O:6][C:7]2[CH:8]=[C:9]([CH:25]=[CH:26][C:27]=2[O:28][CH3:29])[CH2:10][N:11]2[C:19]3[N:18]=[C:17]([CH:20]([CH3:22])[CH3:21])[NH:16][C:15]=3[C:14](=[S:31])[NH:13][C:12]2=[O:24])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COc1ccc(Cn2c(=O)[nH]c(=O)c3[nH]c(C(C)C)nc32)cc1OC1CCCC1
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Agent: [Na+]
Agent: [OH-]
Solvent: c1ccncc1
Product: COc1ccc(Cn2c(=O)[nH]c(=S)c3[nH]c(C(C)C)nc32)cc1OC1CCCC1
Yield: 151 %

Procedure:
3.59 g of 3-(3-cyclopentyloxy-4-methoxy-benzyl)-8-isopropyl-xanthine and 2.40 g of phosphorus pentasulfide were heated under reflux in 60 ml of pyridine for 8 hours. At −5° C., 11.9 ml of 2N NaOH were added slowly. The suspension was evaporated to dryness, the residue suspended in 100 ml of water, neutralized to pH 8, and the solid, collected, washed and dried to give the crude 6-thioxanthine (3.45 g). Purification by filtration chromatography (SiO2, 15g; chloroform) yielded a solid which was reprecipitated from NaOH by addition of HCl, to pH 6.5, collected, washed and dried to give the monohydrate of the title compound (3.38 g) as a white solid, mp 192-3° C.
Reaction SMILES: [NH2:1][C:2]([NH2:4])=[O:3].Cl.N=[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]1[CH:13]=[CH:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>C(O)(=O)C>[CH:10]1[CH:11]=[CH:12][C:7]2[N:1]([C:2]([NH2:4])=[O:3])[C:20]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[CH:14]=[CH:13][C:8]=2[CH:9]=1
Reactant: N=C1C=CC=CC1C=Cc1ccccc1
Reactant: NC(N)=O
Agent: Cl
Solvent: CC(=O)O
Product: NC(=O)N1c2ccccc2C=Cc2ccccc21
Temperature: 27.5 °C

Procedure:
To a suspension of urea (80 g, 1.333 mols) in acetic acid (100 ml), iminostilbene hydrochloride (20.5 g, 0.089 mols) was added under stirring at 25-30° C. The resulting reaction mixture was worked up according to the method of Example 1 to produce carbamazepine, which was identical to the product of Example 1.
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[C:7]([NH:9][C@@H:10]([CH2:13][O:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:11][OH:12])[C:6]([N+:22]([O-:24])=[O:23])=[CH:5][CH:4]=1.Cl[Si:26]([C:29]([CH3:32])([CH3:31])[CH3:30])([CH3:28])[CH3:27].N1C=CN=C1>CN(C=O)C>[CH3:30][C:29]([Si:26]([CH3:28])([CH3:27])[O:12][CH2:11][C@@H:10]([NH:9][C:7]1[C:6]([N+:22]([O-:24])=[O:23])=[CH:5][CH:4]=[C:3]([O:2][CH3:1])[N:8]=1)[CH2:13][O:14][CH2:15][C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1)([CH3:32])[CH3:31]
Reactant: COc1ccc([N+](=O)[O-])c(N[C@H](CO)COCc2ccccc2)n1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: COc1ccc([N+](=O)[O-])c(N[C@@H](COCc2ccccc2)CO[Si](C)(C)C(C)(C)C)n1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 85.4 %

Procedure:
To a solution of (2R)-2-{[6-(methyloxy)-3-nitro-2-pyridinyl]amino}-3-[(phenylmethyl)oxy]-1-propanol (675.8 g) in DMF (2.37 L) was added chloro(1,1-dimethylethyl)dimethylsilane (382.0 g) in portions. Then, imidazole (331.2 g) was added in portions and the mixture was stirred at room temperature for 1.5 h. The reaction mixture was evaporated and the resulting orange gum was partitioned between EtOAc (3 L) and H2O (3 L). The layers were separated and the aqueous was extracted with EtOAc (2.5+2 L). The organic layers were combined, dried over MgSO4 (˜500 g), filtered and evaporated to give an orange oil. The crude product was purified by column chromatography (10 kg silica, 9:1 heptane:EtOAc) to give N-((1S)-2-{[(1,1-dimethylethyl)(dimethyl)silyl]oxy}-1-{[(phenylmethyl)oxy]methyl}ethyl)-6-(methyloxy)-3-nitro-2-pyridinamine (774.7 g, 100%) as a bright yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([C:30]([F:33])([F:32])[F:31])[O:13][N:12]=[C:11]([C:14]3[C:23]4[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=4)[C:17]([C:24]4[O:25][C:26](=[O:29])[CH2:27][N:28]=4)=[CH:16][CH:15]=3)[CH2:10]2)[CH:5]=[C:6]([Cl:8])[CH:7]=1.[NH2:34][CH2:35][CH:36]1[CH2:38][CH2:37]1>CN(C)C=O.O>[CH:36]1([CH2:35][NH:34][C:26](=[O:29])[CH2:27][NH:28][C:24]([C:17]2[C:18]3[C:23](=[CH:22][CH:21]=[CH:20][CH:19]=3)[C:14]([C:11]3[CH2:10][C:9]([C:4]4[CH:5]=[C:6]([Cl:8])[CH:7]=[C:2]([Cl:1])[CH:3]=4)([C:30]([F:31])([F:33])[F:32])[O:13][N:12]=3)=[CH:15][CH:16]=2)=[O:25])[CH2:38][CH2:37]1
Reactant: NCC1CC1
Reactant: O=C1CN=C(c2ccc(C3=NOC(c4cc(Cl)cc(Cl)c4)(C(F)(F)F)C3)c3ccccc23)O1
Solvent: CN(C)C=O
Solvent: O
Product: O=C(CNC(=O)c1ccc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)c2ccccc12)NCC1CC1
Temperature: 150 °C

Procedure:
A mixture of 2-[4-[5-(3,5-dichlorophenyl)-4,5-dihydro-5-(trifluoromethyl)-3-isoxazolyl]-1-naphthalenyl]-5(4H)-oxazolone (i.e. the title product of Step A) (50 mg) and (aminomethyl)cyclopropane (0.1 mL) in N,N-dimethylformamide (1 mL) was irradiated with microwave radiation to maintain a temperature around 150° C. for 30 minutes. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was washed with brine, dried with anhydrous sodium sulfate, and concentrated. The residue was purified by column chromatography on silica gel using hexanes/ethyl acetate (3:2 to 3:7) as eluent to afford the title compound, a compound of the present invention, as a pale yellow solid (47 mg, 82% yield).
Reaction SMILES: Cl[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2([NH:12][C:13](=[O:15])[CH3:14])[CH2:11][CH2:10]2)=[CH:5][CH:4]=1.[N:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[N:22]1[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1>>[N:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[N:22]1[CH2:23][CH2:24][N:25]([CH2:2][C:3]2[CH:8]=[CH:7][C:6]([C:9]3([NH:12][C:13](=[O:15])[CH3:14])[CH2:11][CH2:10]3)=[CH:5][CH:4]=2)[CH2:26][CH2:27]1
Reactant: c1ccc(N2CCNCC2)nc1
Reactant: CC(=O)NC1(c2ccc(CCl)cc2)CC1
Product: CC(=O)NC1(c2ccc(CN3CCN(c4ccccn4)CC3)cc2)CC1

Procedure:
By similar reaction and treatment to that in Example 1(5) using N-(1-(4-chloromethylphenyl)cyclopropyl)acetamide obtained in Example 71(1) instead of N-(4-chloromethylphenylmethyl)acetamide and 1-(2-pyridyl)piperazine instead of phenylpiperazine, the title compound was obtained as white crystals, m.p.=145-147° C.
Reaction SMILES: [CH:1]12[N:8]([C:9]([C:11]3[C:16]([O:17][CH3:18])=[CH:15][CH:14]=[CH:13][C:12]=3[O:19][CH3:20])=[O:10])[CH2:7][CH:6]1[CH2:5][CH2:4][NH:3][CH2:2]2.[C:21]1([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)C=CC=C[C:22]=1[C:27]([N:29]1C2C(CCNC2)[CH2:30]1)=O.ClC1C=CC=CC=1C1N=CC=C[N:51]=1.ClC1C=NC2C(=CC=CC=2)N=1>>[CH3:18][O:17][C:16]1[CH:15]=[CH:14][CH:13]=[C:12]([O:19][CH3:20])[C:11]=1[C:9]([N:8]1[CH:1]2[CH:6]([CH2:5][CH2:4][N:3]([C:30]3[N:51]=[C:21]([C:37]4[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=4)[CH:22]=[CH:27][N:29]=3)[CH2:2]2)[CH2:7]1)=[O:10]
Reactant: Clc1ccccc1-c1ncccn1
Reactant: O=C(c1ccccc1-c1ccccc1)N1CC2CCNCC21
Reactant: COc1cccc(OC)c1C(=O)N1CC2CCNCC21
Agent: Clc1cnc2ccccc2n1
Product: COc1cccc(OC)c1C(=O)N1CC2CCN(c3nccc(-c4ccccc4)n3)CC21

Procedure:
The title compound was prepared in a manner analogous to Example 1, substituting substituting the trifluoro acetic acid salt of (3,8-diaza-bicyclo[4.2.0]oct-8-yl)-(2,6-dimethoxy-phenyl)-methanone (Intermediate 4) for biphenyl-2-yl-(3,8-diaza-bicyclo[4.2.0]oct-8-yl)-methanone and 2-chloro phenyl pyrimidine for 2-chloro quinoxaline. MS (ESI) mass calcd. for C25H26N4O3, 430.20; m/z found, 431.3 [M+H]+. 1H NMR (CDCl3): 8.64 (d, J=5.3, 0.75H), 8.42 (d, J=5.2, 0.25H), 8.11-8.00 (m, 2H), 7.65 (d, J=5.3, 0.75H), 7.58-7.37 (m, 4H), 7.23-7.11 (m, 0.75H), 6.95 (d, J=5.2, 0.75H), 6.54 (d, J=8.4, 0.75H), 5.33-4.76 (m, 0.5H), 4.60-4.20 (m, 1.5H), 4.09-3.04 (m, 9H), 3.00-2.72 (m, 1H), 2.25-1.80 (m, 2H), 1.75-1.60 (m, 2H).
Reaction SMILES: Cl[CH2:2][C:3]([NH:5][C:6]1[CH:15]=[CH:14][C:9]2[NH:10][C:11](=[O:13])[O:12][C:8]=2[CH:7]=1)=[O:4].[CH2:16]([CH:23]1[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>O>[CH2:16]([CH:23]1[CH2:28][CH2:27][N:26]([CH2:2][C:3]([NH:5][C:6]2[CH:15]=[CH:14][C:9]3[NH:10][C:11](=[O:13])[O:12][C:8]=3[CH:7]=2)=[O:4])[CH2:25][CH2:24]1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: c1ccc(CC2CCNCC2)cc1
Reactant: O=C(CCl)Nc1ccc2[nH]c(=O)oc2c1
Solvent: O
Product: O=C(CN1CCC(Cc2ccccc2)CC1)Nc1ccc2[nH]c(=O)oc2c1

Procedure:
The title compound is prepared from 2-chloro-N-(2-oxo-2,3-dihydro-benzoxazol-6-yl)-acetamide (Example 142a) and 4-benzyl-piperidine according to the method described in Example 142b. Melting Point: 210-212° C. (water)
Reaction SMILES: [Br:1][C:2]1[C:3]([CH3:10])=[C:4]([CH:8]=O)[CH:5]=[N:6][CH:7]=1.[CH2:11]([S:13]([NH2:16])(=[O:15])=[O:14])[CH3:12].[BH4-].[Na+]>CO>[Br:1][C:2]1[C:3]([CH3:10])=[C:4]([CH2:8][NH:16][S:13]([CH2:11][CH3:12])(=[O:15])=[O:14])[CH:5]=[N:6][CH:7]=1
Reactant: CCS(N)(=O)=O
Reactant: Cc1c(Br)cncc1C=O
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CCS(=O)(=O)NCc1cncc(Br)c1C

Procedure:
In analogy to the procedure described for the preparation of intermediate A-11, 5-bromo-4-methyl-pyridine-3-carbaldehyde has been reacted first with ethanesulfonamide, followed by reduction of the thus formed imine with NaBH4 in MeOH to give the title compound as an off-white solid. MS: 293.1 and 295.3 (M+H+).
Reaction SMILES: O[N:2]1[C:10]2[C:5](=[N:6][C:7]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[C:8]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH:9]=2)[CH:4]=[CH:3]1.[H-].[Na+].C(Br)C=C.[O:27]1C[CH2:30][CH2:29][CH2:28]1>>[CH2:19]([O:18][C:16]([C:7]1[NH:6][C:5]2=[CH:4][C:3]([O:27][CH2:28][CH:29]=[CH2:30])=[N:2][C:10]2=[CH:9][C:8]=1[C:11]([O:13][CH2:14][CH3:15])=[O:12])=[O:17])[CH3:20]
Reactant: C1CCOC1
Reactant: CCOC(=O)c1cc2c(ccn2O)nc1C(=O)OCC
Agent: [H-]
Agent: [Na+]
Solvent: C=CCBr
Product: C=CCOc1cc2[nH]c(C(=O)OCC)c(C(=O)OCC)cc-2n1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 89 %

Procedure:
Diethyl 1-hydroxypyrrolo[3,2-b]pyridine-5,6-dicarboxylate (6.2 g, 0.022 mol)is dissolved in (200 mL) dry tetrahydrofuran and cooled to 0° C. under nitrogen. Sodium hydride (0.77 g, 0.033 mol) is added in portions over ten minutes and the reaction is stirred for 30 minutes at 0° C. Allyl bromide (2.01 mL, 0.024 mol) is added all at once to the suspension and the mixture allowed to warm to room temperature and then stirred for 16 hours. The mixture is filtered and the filtrate concentrated in vacuo. The resulting oil is chromatographed using 4:1 hexanes/ethyl acetate and then increasing the polarity to 2:1 hexanes/ethyl acetate to give the product as a yellow oil in 89% yield.
Reaction SMILES: C(OC([N:8]1[CH:12]=[C:11]([CH2:13][CH2:14][O:15][C:16]2[CH:25]=[CH:24][C:23]3[C:22](=[O:26])[CH2:21][CH2:20][CH2:19][C:18]=3[CH:17]=2)[N:10]=[CH:9]1)=O)(C)(C)C.[CH:27](=O)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>[OH-].[K+].CCO>[CH:27](=[C:21]1[CH2:20][CH2:19][C:18]2[C:23](=[CH:24][CH:25]=[C:16]([O:15][CH2:14][CH2:13][C:11]3[N:10]=[CH:9][NH:8][CH:12]=3)[CH:17]=2)[C:22]1=[O:26])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: O=Cc1ccccc1
Reactant: CC(C)(C)OC(=O)n1cnc(CCOc2ccc3c(c2)CCCC3=O)c1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: O=C1C(=Cc2ccccc2)CCc2cc(OCCc3c[nH]cn3)ccc21
Yield: 47.8 %

Procedure:
According to the method of Example 6, the product of Step 1 (0.271 g, 0.76 mmol) was reacted with benzaldehyde (0.121 g, 1.14 mmol) in 5 mL of 4% KOH in EtOH for 3 hours at room temperature to afford 0.125 g (46%) of the title compound as a foam which solidified on standing to give a yellow solid, mp 53-56° C.: CI-MS m/e 345 (M++1).
Reaction SMILES: ClC1C=C(C=CC=1Cl)CN(C)C(=O)C=C1C(=O)OC(C)(C)O1.C=O.[NH2:25][CH2:26][CH2:27][NH:28][C:29](=[O:38])[CH2:30][CH2:31][N:32]1[CH2:37][CH2:36][O:35][CH2:34][CH2:33]1.[Cl:39][C:40]1[CH:41]=[C:42]([CH:65]=[CH:66][C:67]=1[Cl:68])[CH2:43][N:44]([CH3:64])[C:45]([C:47]1[CH2:51]N(CCC(NCCC(O)=O)=O)[C:49](=[O:62])[C:48]=1[OH:63])=[O:46]>>[Cl:39][C:40]1[CH:41]=[C:42]([CH:65]=[CH:66][C:67]=1[Cl:68])[CH2:43][N:44]([CH3:64])[C:45]([C:47]1[CH2:51][N:25]([CH2:26][CH2:27][NH:28][C:29](=[O:38])[CH2:30][CH2:31][N:32]2[CH2:33][CH2:34][O:35][CH2:36][CH2:37]2)[C:49](=[O:62])[C:48]=1[OH:63])=[O:46]
Reactant: CN(Cc1ccc(Cl)c(Cl)c1)C(=O)C1=C(O)C(=O)N(CCC(=O)NCCC(=O)O)C1
Reactant: NCCNC(=O)CCN1CCOCC1
Agent: C=O
Agent: CN(Cc1ccc(Cl)c(Cl)c1)C(=O)C=C1OC(C)(C)OC1=O
Product: CN(Cc1ccc(Cl)c(Cl)c1)C(=O)C1=C(O)C(=O)N(CCNC(=O)CCN2CCOCC2)C1

Procedure:
N-(3,4-Dichloro-benzyl)-2-(2,2-dimethyl-5-oxo-[1,3]dioxolan-4-ylidene)-N-methyl-acetamide (Compound 37-A) was treated with paraformaldehyde and N-(2-amino-ethyl)-3-morpholin-4-yl-propionamide as described in the preparation of Compound 37. The desired product was isolated as a white solid (0.0134 g, 5% yield). 1H NMR (300 MHz, CDCl3) δ: 2.41 (m, 2H), 2.64 (bs, 2H), 2.72 (bs, 2H), 2.98 (m, 2H), 3.03 (s, 3H), 3.51 (t, J=5.6 Hz, 2H), 3.63 (t, J=5.2 Hz, 2H), 3.78 (m, 4H), 4.35 (s, 2H), 4.59 (s, 2H), 7.11 (d, J=8.1 Hz, 1H), 7.35–7.44 (m, 3H), 8.27 (t, 1H). HRMS (M+H) calcd for C22H28N4Cl2O5: 497.13585. found: 497.1377.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[C:10]2[C:6]([C:7](C(=O)C(N)=O)=[C:8]([CH3:19])[N:9]2CC2C=CC=CC=2)=[CH:5][CH:4]=1.C(OC(NC1C=C(OC)C=CC=1CC(=O)C)=O)(C)(C)C>>[CH3:1][O:2][C:3]1[CH:11]=[C:10]2[C:6]([CH:7]=[C:8]([CH3:19])[NH:9]2)=[CH:5][CH:4]=1
Reactant: COc1ccc2c(C(=O)C(N)=O)c(C)n(Cc3ccccc3)c2c1
Agent: COc1ccc(CC(C)=O)c(NC(=O)OC(C)(C)C)c1
Product: COc1ccc2cc(C)[nH]c2c1
Yield: 61 %

Procedure:
6-Methoxy-2-methyl-1-(phenylmethyl)-1H-indole-3-glyoxylic acid amide. Using the method in Example 9, Part C, 13.7 g 49 mmol) of 1-[2-(tert-butoxycarbonylamino)-4-methoxyphenyl]-2-propanone was reacted with 20 mL of trifluoroacetic and the product chromatographed on silica eluting with 20% EtOAc/hexane. There was obtained 4.8 g (61% yield) of crude 6-methoxy-2-methyl-1H-indole. By the method in Example 6, Part A, this maternal (30 mmol) was treated with 1.2 g (30 mmol) of 60% NaH/mineral oil and 3.6 mL of benzyl bromide in DHF to give after chromatography on silica (eluting with 25% EtOAc/hexane) 4.77 g (63% yield) of 6-methoxy-2-methyl-1-(phenylmethyl)-1H-indole. By the method in Example 16, Part C, 1.97 g (8 mmol) of 6-methoxy-2-methyl-1-(phenylmethyl)-1H-indole was reacted with 0.73 mL (8.4 mmol) of oxalyl chloride and then ammonia to give 0.875 g (24% yield) of 6-methoxy-2-methyl-1-(phenylmethyl)-1H-indole-3-glyoxylic acid amide from EtOAc, mp, 230°-234° C.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)=[N:7][C:6]=2[CH:16]=1.C1C(=O)N([Br:24])C(=O)C1>C(Cl)(Cl)(Cl)Cl>[Br:24][CH2:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)=[N:7][C:6]=2[CH:16]=1
Reactant: Cc1ccc2oc(-c3ccccc3)nc2c1
Reactant: O=C1CCC(=O)N1Br
Solvent: ClC(Cl)(Cl)Cl
Product: BrCc1ccc2oc(-c3ccccc3)nc2c1
Yield: 70.6 %

Procedure:
5-methyl-2-phenylbenzoxazole 55 (1.23 g, 5.8 mmol) and NBS (1.17 g, 6.5 mmol) were dissolved in carbon tetrachloride (20 ml). The mixture was evacuated and flushed with argon. AIBN (ca. 5 mg) was added and the mixture heated at reflux and irradiated with a sun lamp for 3 hrs. The solvent was evaporated under reduced pressure and the residue purified by chromatography to yield 1.18 g of 5-bromomethyl-2-phenylbenzoxazole 56.
Reaction SMILES: Br[CH2:2][C:3]#[N:4].[CH2:5]([C:12]1[CH:39]=[C:38]([Cl:40])[CH:37]=[CH:36][C:13]=1[O:14][CH2:15][CH2:16][CH2:17][NH:18][CH:19]([C:28]1[CH:33]=[CH:32][C:31]([O:34][CH3:35])=[CH:30][CH:29]=1)[C:20]1[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.C(N(C(C)C)CC)(C)C.C([O-])(O)=O.[Na+]>O1CCOCC1.CCOC(C)=O>[CH2:5]([C:12]1[CH:39]=[C:38]([Cl:40])[CH:37]=[CH:36][C:13]=1[O:14][CH2:15][CH2:16][CH2:17][N:18]([CH2:2][C:3]#[N:4])[CH:19]([C:20]1[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=1)[C:28]1[CH:29]=[CH:30][C:31]([O:34][CH3:35])=[CH:32][CH:33]=1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: COc1ccc(C(NCCCOc2ccc(Cl)cc2Cc2ccccc2)c2ccc(OC)cc2)cc1
Reactant: N#CCBr
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: COc1ccc(C(c2ccc(OC)cc2)N(CC#N)CCCOc2ccc(Cl)cc2Cc2ccccc2)cc1
Temperature: 90 °C
Yield: 96.7 %

Procedure:
Bromoacetonitrile (0.575 mL, 8.25 mmol) is added to a stirred solution of [3-(2-benzyl-4-chloro-phenoxy)-propyl]-[bis-(4-methoxy-phenyl)-methyl]-amine (2.76 g, 5.50 mmol) and diisopropylethylamine (1.44 mL, 8.25 mmol) in anhydrous 1,4-dioxane (20 mL) at ambient temperature under nitrogen. The mixture is heated at 90° C. for 4 hours. At ambient temperature, EtOAc (100 mL) and half-saturated aqueous NaHCO3 solution (100 mL) are added to the mixture. The organic layer is separated, dried over MgSO4, filtered and concentrated. The crude product is chromatographed on silica (gradient 5-16% EtOAc in hexane) to give 2.88 g (5.32 mmol, 97% yield) of the title compound as oil. ESIMS: m/z 541 [(M+H)+, 35Cl], 543 [(M+H)+, 37Cl]. Analysis for C33H33ClN2O3: calcd: C, 73.25; H, 6.15; N, 5.18; found: C, 73.05; H, 6.28; N, 5.02.
Reaction SMILES: [CH2:1]1[C:3]2([CH2:8][CH2:7][CH2:6][C:5](=[O:9])[CH2:4]2)[CH2:2]1.[Li+].[CH3:11][Si]([N-][Si](C)(C)C)(C)C.IC>C1COCC1>[CH3:11][CH:6]1[CH2:7][CH2:8][C:3]2([CH2:2][CH2:1]2)[CH2:4][C:5]1=[O:9]
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Reactant: O=C1CCCC2(CC2)C1
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CI
Product: CC1CCC2(CC2)CC1=O
Temperature: -75 °C
Reaction time: 1 h
Yield: 35 %

Procedure:
Spiro[2.5]octan-5-one (2.4 g, 19.32 mmol) was dissolved in THF (100 mL) and cooled to −75° C. At that temperature LHMDS 1M in THF (24 mL, 24 mmol) was added dropwise over 15 minutes. The resulting pale yellow solution was stirred 1 hour at −75° C. Iodomethane (1.3 mL, 21.26 mmol) was added and stirring was continued at −75° C. for another hour before letting the mixture warm up to RT. The reaction was quenched by addition of saturated aqueous NH4Cl. The layers were separated and the aqueous layer was extracted with Et2O. The combined organic layers were washed with brine, dried (Na2SO4), filtered and evaporated. The remaining yellow oil was purified by SiO2 chromatography (330 g SiO2, hexanes/EtOAc 0 to 3% EtOAc) to give 0.93 g of racemic 6-methyl-spiro[2.5]octan-5-one as a colorless liquid (35% yield).
Reaction SMILES: O[C:2]1[CH2:7][CH2:6][C:5]([CH3:9])([CH3:8])[CH2:4][C:3]=1[C:10]([O-])=O.[ClH:13].[N:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[C:20](=[NH:22])[NH2:21]>>[Cl:13][C:10]1[C:3]2[CH2:4][C:5]([CH3:9])([CH3:8])[CH2:6][CH2:7][C:2]=2[N:21]=[C:20]([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][N:14]=2)[N:22]=1
Reactant: Cl
Reactant: CC1(C)CCC(O)=C(C(=O)[O-])C1
Reactant: N=C(N)c1ccccn1
Product: CC1(C)CCc2nc(-c3ccccn3)nc(Cl)c2C1

Procedure:
Synthesized according to the method of reagent preparation 8 by using 2-hydroxy-5,5-dimethylcyclohex-1-enecarboxylate and picolinimidamide hydrochloride in step 2. MS (ES) for C15H16ClN3: 274 (MH+).
Reaction SMILES: [N:1]12[CH2:16][CH:5]([C:6](=[C:8]([C:14]#[N:15])[C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH2:7]1)[CH2:4][CH2:3][CH2:2]2.[H][H]>[Pd].C(O)C>[N:1]12[CH2:16][CH:5]([CH:6]([CH:8]([C:14]#[N:15])[C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH2:7]1)[CH2:4][CH2:3][CH2:2]2
Reactant: [H][H]
Reactant: CCOC(=O)C(C#N)=C1CN2CCCC1C2
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)C(C#N)C1CN2CCCC1C2

Procedure:
A solution of ethyl (1-azabicyclo[3.2.1]octan-6-ylidene)cyanoacetate (41 g, 0.19 mol) in abs. ethanol (500 ml) was treated with 10% palladium on carbon (5 g) and hydrogen in a Parr shaker at 30 psi for 5 h. Filtration and evaporation gave the title compound in 36 g yield.