Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:14][CH2:13][CH2:12][C@@H:11]2[C:15]([OH:17])=O)=[CH:6][CH:5]=1)([O-:3])=[O:2].CN(C(ON1N=NC2[CH:29]=[CH:30][CH:31]=[N:32]C1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.CN>C(Cl)Cl>[CH:31]1([NH:32][C:15]([C@H:11]2[CH2:12][CH2:13][CH2:14][N:10]2[C:7]2[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:9][CH:8]=2)=[O:17])[CH2:29][CH2:30]1
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Reactant: O=C(O)[C@H]1CCCN1c1ccc([N+](=O)[O-])cc1
Agent: CN
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NC1CC1)[C@H]1CCCN1c1ccc([N+](=O)[O-])cc1
Reaction time: 1 h

Procedure:
To (R)-1-(4-nitro-phenyl)-pyrrolidine-2-carboxylic acid (Method 55; 1.8 g, 7.6 mmol) in DCM (50 ml) was added HATU (3.2 g, 8.4 mmol) and DIPEA (2.0 ml, 11.4 mmol). The reaction was stirred for 10 minutes before the addition of methylamine (0.84 g, 15 mmol); the reaction was stirred for 1 hour and then quenched with water (50 ml). The reaction was extracted with DCM (3×100 ml), dried and solvent removed in vacuo to yield a yellow gum. Purification was achieved via column chromatography eluting with 20% EtOAc/isohexane, 60% EtOAc/isohexane and finally 100% EtOAc. The title compound was obtained as a yellow solid (1.4 g, 74%). NMR (299.954 MHz, CDCl3) δ 8.13 (d, 2H), 6.55 (d, 2H), 6.06 (s, 1H), 4.14 (t, 1H), 3.70 (t, 1H), 3.38 (q, 1H), 2.75-2.66 (m, 1H), 2.36-2.29 (m, 2H), 2.17-1.95 (m, 2H), 0.82-0.73 (m, 2H), 0.46-0.35 (m, 2H); m/z 276.
Reaction SMILES: [CH3:1][NH:2][CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([O:10][C:11]([F:14])([F:13])[F:12])[C:5]=1[O:15][CH2:16][CH2:17][CH3:18].[C:19](Cl)(=[O:22])[CH:20]=[CH2:21].C(N(CC)CC)C>C(Cl)Cl>[CH3:1][N:2]([CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([O:10][C:11]([F:12])([F:13])[F:14])[C:5]=1[O:15][CH2:16][CH2:17][CH3:18])[C:19](=[O:22])[CH:20]=[CH2:21]
Reactant: CCCOc1c(CNC)cccc1OC(F)(F)F
Reactant: C=CC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C=CC(=O)N(C)Cc1cccc(OC(F)(F)F)c1OCCC
Reaction time: 0.08 h
Yield: 89.4 %

Procedure:
To a solution of methyl-(2-propoxy-3-trifluoromethoxybenzyl)amine (0.890 g, 3.35 mmol) in CH2Cl2 (30 mL) was added acryloyl chloride (0.30 mL, 3.6 mmol) drop-wise. After stirring for five minutes, triethylamine (0.51 mL, 3.6 mmol) was added. The solution was allowed to stir under N2 for 3 h. The solution was diluted with CH2Cl2 (30 mL), washed with H2O (3×50 mL) and brine (2×50 mL), dried (Na2SO4) filtered and concentrated to yield the title compound (0.95 g, 90%) as a yellow oil and as a mixture of amide rotamers: 1H NMR (500 MHz, CDCl3) δ 7.21-7.00 (m, 3H), 6.67-6.48 (m, 1H), 6.41-6.36 (m, 1H), 5.76-5.66 (m, 1H), 4.75-4.65 (m, 2H), 3.99-3.93 (m, 2H), 3.03 (s, 3H), 1.83-1.78 (m, 2H), 1.07-1.03 (m, 3H).
Reaction SMILES: [CH2:1]([NH2:4])[CH2:2][NH2:3].C[Al](C)C.CO[C:11](=O)[CH2:12][N:13]1[C:21]2[C:16](=[CH:17][C:18]([N:22]3[CH:27]=[CH:26][C:25]4[O:28][C:29]([C:31]5[CH:36]=[CH:35][C:34]([Cl:37])=[CH:33][CH:32]=5)=[CH:30][C:24]=4[C:23]3=[O:38])=[CH:19][CH:20]=2)[CH:15]=[N:14]1>C1(C)C=CC=CC=1.O>[Cl:37][C:34]1[CH:35]=[CH:36][C:31]([C:29]2[O:28][C:25]3[CH:26]=[CH:27][N:22]([C:18]4[CH:17]=[C:16]5[C:21](=[CH:20][CH:19]=4)[N:13]([CH2:12][C:11]4[NH:3][CH2:2][CH2:1][N:4]=4)[N:14]=[CH:15]5)[C:23](=[O:38])[C:24]=3[CH:30]=2)=[CH:32][CH:33]=1
Reactant: NCCN
Reactant: COC(=O)Cn1ncc2cc(-n3ccc4oc(-c5ccc(Cl)cc5)cc4c3=O)ccc21
Agent: C[Al](C)C
Solvent: Cc1ccccc1
Solvent: O
Product: O=c1c2cc(-c3ccc(Cl)cc3)oc2ccn1-c1ccc2c(cnn2CC2=NCCN2)c1
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 21.4 %

Procedure:
To a 0° C. solution of ethylenediamine (68 mL, 1.0 mmol) in toluene (0.36 mL) was slowly added trimethyl aluminium (0.50 mL, 10 M in toluene) over ten minutes. The solution was allowed to stir at 0° C. for 5 minutes; then a suspension of methyl-2-(5-(2-(4-chlorophenyl)-4-oxofuro[3,2-c]pyridin-5(4H)-yl)-1H-indazol-1-yl)acetate (0.22 g, 0.50 mmol) in toluene (7.27 mL) was added and the reaction mixture was heated to reflux. The reaction mixture was stirred at reflux for 18 h; then the reaction mixture was diluted with H2O (2 mL) and the solids were removed by filtration. The filtrate was extracted with CH2Cl2 (3×20 mL) and the extracts were dried (Na2SO4), filtered and concentrated. Purification by flash chromatography (silica gel, CH2Cl2/9:1 EtOH with NH4OH, 100:0 to 90:10) yielded the title compound (47.6 mg, 21%) as an off-white solid: 1H NMR (500 MHz, DMSO-d6) δ 8.15 (s, 1H), 7.91 (d, J=9.0 Hz, 1H), 7.83 (d, J=1.5 Hz, 1H), 7.74 (d, J=9.0 Hz, 1H), 7.69 (d, J=7.5 Hz, 1H), 7.64 (s, 1H), 7.57-7.55 (m, 2H), 7.42 (dd, J=9.0, 2.0 Hz, 2H), 6.89 (d, J=7.0 Hz, 1H), 5.21 (s, 2H) 3.51 (br s, 1H), 3.30 (s, 4H); ESI MS m/z 444 [M+H]+; HPLC (Method A) 95.7% (AUC), tR=15.8 min.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[CH:9]1[CH:18]([C:19]([NH:21][O:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][N:25]=2)=[O:20])[C:17]2[C:12](=[CH:13][CH:14]=[C:15]([N+:30]([O-])=O)[CH:16]=2)[C:11](=[O:33])[N:10]1[CH:34]1[CH2:39][CH2:38][CH2:37][CH2:36][CH:35]1[NH:40][S:41]([CH3:44])(=[O:43])=[O:42]>[Ni]>[NH2:30][C:15]1[CH:16]=[C:17]2[C:12](=[CH:13][CH:14]=1)[C:11](=[O:33])[N:10]([CH:34]1[CH2:39][CH2:38][CH2:37][CH2:36][CH:35]1[NH:40][S:41]([CH3:44])(=[O:43])=[O:42])[CH:9]([C:3]1[CH:4]=[CH:5][C:6]([Cl:8])=[CH:7][C:2]=1[Cl:1])[CH:18]2[C:19]([NH:21][O:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][N:25]=1)=[O:20]
Reactant: CS(=O)(=O)NC1CCCCC1N1C(=O)c2ccc([N+](=O)[O-])cc2C(C(=O)NOCc2ccccn2)C1c1ccc(Cl)cc1Cl
Agent: [Ni]
Product: CS(=O)(=O)NC1CCCCC1N1C(=O)c2ccc(N)cc2C(C(=O)NOCc2ccccn2)C1c1ccc(Cl)cc1Cl
Reaction time: 0.5 h
Yield: 62.8 %

Procedure:
To a solution of 500 mg of (3RS,4RS)-3-(2,4-dichlorophenyl)-2-{(1SR,2SR)-2-[(methylsulfonyl)amino]cyclohexyl}-6-nitro-1-oxo-N-(pyridin-2-ylmethoxy)-1,2,3,4-tetrahydroisoquinoline-4-carboxamide in 10 ml of methanol-dioxane (1:1) was added 500 mg of Raney nickel, followed by stirring for 30 minutes under a hydrogen atmosphere. The catalyst was removed by filtration and the solvent was concentrated under reduced pressure to obtain 300 mg of (3RS,4RS)-6-amino-3-(2,4-dichlorophenyl)-2-{(1SR,2SR)-2-[(methylsulfonyl)amino]cyclohexyl}-1-oxo-N-(pyridin-2-ylmethoxy)-1,2,3,4-tetrahydroisoquinoline-4-carboxamide as a black solid.
Reaction SMILES: [CH3:1][N:2]1[CH:7]2[CH2:8][CH2:9][CH:3]1[CH2:4][N:5]([C:10]1[N:15]=[N:14][C:13]([C:16]#[C:17][C:18]3[CH:23]=[CH:22][C:21]([NH2:24])=[CH:20][CH:19]=3)=[CH:12][CH:11]=1)[CH2:6]2.[CH2:25]([N:27]=[C:28]=[O:29])[CH3:26]>>[CH2:25]([NH:27][C:28]([NH:24][C:21]1[CH:20]=[CH:19][C:18]([C:17]#[C:16][C:13]2[N:14]=[N:15][C:10]([N:5]3[CH2:6][CH:7]4[N:2]([CH3:1])[CH:3]([CH2:9][CH2:8]4)[CH2:4]3)=[CH:11][CH:12]=2)=[CH:23][CH:22]=1)=[O:29])[CH3:26]
Reactant: CN1C2CCC1CN(c1ccc(C#Cc3ccc(N)cc3)nn1)C2
Reactant: CCN=C=O
Product: CCNC(=O)Nc1ccc(C#Cc2ccc(N3CC4CCC(C3)N4C)nn2)cc1

Procedure:
Was prepared according to Method F from 4-[6-(8-methyl-3,8-diaza-bicyclo[3.2.1]oct-3-yl)-pyridazin-3-ylethynyl]-phenylamine and ethylisocyanate. Mp 269° C. LC-ESI-HRMS of [M+H]+ shows 391.2253 Da. Calc. 391.224634 Da, dev. 1.7 ppm.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[C:9]([OH:11])[C:8]([OH:12])=[C:7]([CH3:13])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].Cl[C:15]([O:17][CH2:18][CH3:19])=[O:16]>>[C:15](=[O:16])([O:17][CH2:18][CH3:19])[O:11][C:9]1[CH:10]=[C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])[CH:6]=[C:7]([CH3:13])[C:8]=1[O:12][C:15](=[O:16])[O:17][CH2:18][CH3:19]
Reactant: CCOC(=O)Cl
Reactant: Cc1cc(C(C)(C)C)cc(O)c1O
Product: CCOC(=O)Oc1cc(C(C)(C)C)cc(C)c1OC(=O)OCC
Yield: 81.4 %

Procedure:
Prepared from 5-tert-butyl-3-methylbenzene-1,2-diol and ethyl chloroformate; purified by flash column chromatography on silica gel to yield a sticky colorless oil (81.4%); 1H NMR (500 MHz, CDCl3, ppm) δ 7.09-7.11 (m, 2H), 4.32 (q, 2H, J=9.0 Hz), 4.31 (q, 2H, J=9.0 Hz), 2.25 (s, 3H), 1.38 (t, 3H, J=9.0 Hz), 1.37 (t, 3H, J=9.0 Hz), 1.29 (s, 9H);
Reaction SMILES: [C:1]1([CH:7]2[CH2:12][CH2:11][CH2:10][N:9]([CH2:13][CH2:14][CH3:15])[CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[N+:16]([O-])([O-:18])=[O:17].[K+].OS(O)(=O)=O>>[N+:16]([C:4]1[CH:5]=[CH:6][C:1]([CH:7]2[CH2:12][CH2:11][CH2:10][N:9]([CH2:13][CH2:14][CH3:15])[CH2:8]2)=[CH:2][CH:3]=1)([O-:18])=[O:17]
Reactant: CCCN1CCCC(c2ccccc2)C1
Reactant: O=[N+]([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [K+]
Product: CCCN1CCCC(c2ccc([N+](=O)[O-])cc2)C1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 106.1 %

Procedure:
To ice cooled 3-phenyl-1-propyl-piperidine (4.6 g, 19.73 mmol) and KNO3 (2.254 g, 22.29 mmol) was added concentrated H2SO4. The reaction mixture was allowed to warm to room temperature and stirred for another 30 minutes. To the reaction mixture was added cautiously ice and subsequently the pH was adjusted to 9-10. The aqueous phase was extracted several times with ethyl acetate. The organic phases was dried over magnesium sulfate, filtered, and evaporated to dryness to yield the crude product (5.2 g, 81% purity).
Reaction SMILES: [OH:1][CH2:2][CH2:3][C:4]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:5]=1[CH2:6][C:7](=[O:13])[NH:8]2.[CH3:14][C:15]1[C:19]([C:20]([N:22]2[CH2:27][CH2:26][N:25]([CH3:28])[CH2:24][CH2:23]2)=[O:21])=[C:18]([CH3:29])[NH:17][C:16]=1[CH:30]=O>>[CH3:14][C:15]1[C:19]([C:20]([N:22]2[CH2:23][CH2:24][N:25]([CH3:28])[CH2:26][CH2:27]2)=[O:21])=[C:18]([CH3:29])[NH:17][C:16]=1[CH:30]=[C:6]1[C:5]2[C:9](=[CH:10][CH:11]=[CH:12][C:4]=2[CH2:3][CH2:2][OH:1])[NH:8][C:7]1=[O:13]
Reactant: Cc1[nH]c(C=O)c(C)c1C(=O)N1CCN(C)CC1
Reactant: O=C1Cc2c(CCO)cccc2N1
Product: Cc1[nH]c(C=C2C(=O)Nc3cccc(CCO)c32)c(C)c1C(=O)N1CCN(C)CC1
Yield: 55 %

Procedure:
4-(2-Hydroxyethyl)-1,3-dihydroindol-2-one (71 mg, 0.4 mmol) was condensed with 3,5-dimethyl-4-(4-methyl-piperazine-1-carbonyl)-1H-pyrrole-2-carbaldehyde to give 90 mg (55%) of the title compound as an orange solid.
Reaction SMILES: [CH3:1][C:2]1([CH3:40])[CH2:6][CH2:5][CH:4]([CH3:7])[CH:3]1[O:8][C:9](=[O:39])[C@@H:10]([CH2:37][OH:38])[NH:11][C:12](=[O:36])[C@H:13]([CH:25](CC1C=CC=CC=1)[C:26](=[O:28])[OH:27])[NH:14]C(OCC1C=CC=CC=1)=O>CO.[Pd]>[CH3:40][C:2]1([CH3:1])[CH2:6][CH2:5][CH:4]([CH3:7])[CH:3]1[O:8][C:9](=[O:39])[C@@H:10]([CH2:37][OH:38])[NH:11][C:12](=[O:36])[C@H:13]([CH2:25][C:26](=[O:27])[OH:28])[NH2:14]
Reactant: CC1CCC(C)(C)C1OC(=O)[C@@H](CO)NC(=O)[C@@H](NC(=O)OCc1ccccc1)C(Cc1ccccc1)C(=O)O
Agent: [Pd]
Solvent: CO
Product: CC1CCC(C)(C)C1OC(=O)[C@@H](CO)NC(=O)[C@@H](N)CC(=O)O

Procedure:
To a magnetically stirred solution of 0.1 mole 2,2,5-trimethylcyclopentyl-D-serinate in 100 ml dry DMF at 0° C. under an argon atmosphere is added 1 equivalent of N-Cbz-L-aspartic acid β-benzyl ester followed by addition of 1 equivalent each of Cu(II) chloride and dicyclohexylcarbodiimide. After 18 hours the mixture is poured into 200 ml 0.1 NHCl and extracted with 300 ml ethyl acetate which is successively washed with saturated NaHCO3, H2O, and dried over MgSO4. Filtration and evaporation yields N-Cbz-β-benzyl-L-aspartyl-D-serine 2,2,5-trimethylcyclopentyl ester. 2 g N-Cbz-βbenzyl-L-aspartyl-D-serine 2,2,5-trimethylcyclopentyl ester in 50 ml dry CH3OH is hydrogenated in a Paar apparatus over 5% Pd/C. Upon completion of the reaction, the mixture is filtered through Celite and concentrated to dryness to yield the final product.
Reaction SMILES: [Si:1]([O:8][CH2:9][C:10]1[C:15]([O:16][CH3:17])=[CH:14][C:13]([NH:18][C:19](=[O:22])[CH:20]=[CH2:21])=[C:12]([Cl:23])[CH:11]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[OH:24][C:25]([C:42]1[S:43][CH:44]=[CH:45][CH:46]=1)([C:37]1[S:38][CH:39]=[CH:40][CH:41]=1)[C:26]([O:28][C@H:29]1[CH2:34][CH2:33][C@H:32]([NH:35][CH3:36])[CH2:31][CH2:30]1)=[O:27]>C(Cl)Cl>[OH:24][C:25]([C:37]1[S:38][CH:39]=[CH:40][CH:41]=1)([C:42]1[S:43][CH:44]=[CH:45][CH:46]=1)[C:26]([O:28][C@H:29]1[CH2:30][CH2:31][C@H:32]([N:35]([CH2:21][CH2:20][C:19]([NH:18][C:13]2[CH:14]=[C:15]([O:16][CH3:17])[C:10]([CH2:9][O:8][Si:1]([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2])=[CH:11][C:12]=2[Cl:23])=[O:22])[CH3:36])[CH2:33][CH2:34]1)=[O:27]
Reactant: C=CC(=O)Nc1cc(OC)c(CO[Si](C)(C)C(C)(C)C)cc1Cl
Reactant: CN[C@H]1CC[C@H](OC(=O)C(O)(c2cccs2)c2cccs2)CC1
Solvent: ClCCl
Product: COc1cc(NC(=O)CCN(C)[C@H]2CC[C@H](OC(=O)C(O)(c3cccs3)c3cccs3)CC2)c(Cl)cc1CO[Si](C)(C)C(C)(C)C
Temperature: 75 °C
Reaction time: 64 h

Procedure:
A mixture of N-[4-({[tert-butyl(dimethyl)silyl]oxy}methyl)-2-chloro-5-methoxyphenyl]-acrylamide (intermediate 40; 0.9 g, 0.002 mol) and trans-4-(methylamino)cyclohexyl hydroxy(di-2-thienyl)acetate (intermediate 5; 0.7 g, 0.002 mol) in methylene chloride (20 mL) was stirred at 75° C. in a closed vessel for 64 hours. The solvent was evaporated and the crude obtained was purified by column chromatography with silica gel, eluting with chloroform/methanol (from 50/1 to 25/1) to give the title compound as a white-yellow solid (49%).
Reaction SMILES: [CH:1]([NH:3][NH2:4])=O.[C:5]([O:9][C:10]([N:12]1[CH2:18][C:17]2[CH:19]=[C:20]([Cl:23])[CH:21]=[CH:22][C:16]=2[NH:15][C:14](=S)[CH2:13]1)=[O:11])([CH3:8])([CH3:7])[CH3:6]>O1CCOCC1>[C:5]([O:9][C:10]([N:12]1[CH2:13][C:14]2[N:15]([CH:1]=[N:3][N:4]=2)[C:16]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][C:17]=2[CH2:18]1)=[O:11])([CH3:8])([CH3:6])[CH3:7]
Reactant: NNC=O
Reactant: CC(C)(C)OC(=O)N1CC(=S)Nc2ccc(Cl)cc2C1
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)N1Cc2cc(Cl)ccc2-n2cnnc2C1
Temperature: 90 °C
Reaction time: 8 h
Yield: 75.1 %

Procedure:
Formylhydrazine (10.7 g, 160 mmol) was added over a period of 4 hours to a solution of 7-chloro-2-thioxo-1,2,3,5-tetrahydro-benzo[e][1,4]diazepine-4-carboxylic acid tert-butyl ester (10.0 g, 32.0 mmol) in dioxane (200 ml) at 90° C. The reaction mixture was stirred at 90° C. overnight, then evaporated. The residue was purified by chromatography (300 g silica gel, heptane: ethyl acetate, 8:2 to 0:1) to yield 7.71 g (75%) 8-chloro-4H,6H-2,3,5,10b-tetraaza-benzo[e]azulene-5-carboxylic acid tert-butyl ester as white solid. MS m/e: 379 ([M+CH3COO−])
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([C:8]([OH:10])=[O:9])[CH:5]=[CH:4][CH:3]=1.CO.[CH2:13](Cl)CCl>C(Cl)Cl.CN(C)C1C=CN=CC=1>[CH3:13][O:9][C:8]([C:6]1[CH:5]=[CH:4][CH:3]=[C:2]([CH3:1])[N:7]=1)=[O:10]
Reactant: ClCCCl
Reactant: Cc1cccc(C(=O)O)n1
Agent: CN(C)c1ccncc1
Solvent: CO
Solvent: ClCCl
Product: COC(=O)c1cccc(C)n1
Temperature: 0 °C
Reaction time: 6 h

Procedure:
To a suspension of 6-methyl-pyridine-2-carboxylic acid (10 g, 72.9 mmol) in methylene chloride (200 mL) cooled to 0° C. is added methanol (10 mL), 4-dimethylaminopyridine (11.6 g, 94.8 mmol), and EDC (18.2 g, 94.8 mmol). The mixture is stirred at room temperature for 6 h, washed with water and brine, and dried over sodium sulfate. The mixture is filtered and concentrated in vacuo. The residue is chromatographed on SiO2 (50% ethyl acetate/hexanes) to yield the title compound, 9.66 g (92%), as a colorless liquid.
Reaction SMILES: [F:1][C:2]1[C:15]([F:16])=[C:14](F)[C:13]([F:18])=[CH:12][C:3]=1[C:4]([CH2:6][C:7]([O:9][CH2:10][CH3:11])=[O:8])=[O:5].[CH2:19]([O:21][C:22]([N:24]([CH2:26][CH:27]1[O:32][CH2:31][CH2:30][NH:29][CH2:28]1)[CH3:25])=[O:23])[CH3:20].C(=O)([O-])O.[Na+]>C(#N)C>[CH2:19]([O:21][C:22]([N:24]([CH2:26][CH:27]1[CH2:28][N:29]([C:14]2[C:13]([F:18])=[CH:12][C:3]([C:4]([CH2:6][C:7]([O:9][CH2:10][CH3:11])=[O:8])=[O:5])=[C:2]([F:1])[C:15]=2[F:16])[CH2:30][CH2:31][O:32]1)[CH3:25])=[O:23])[CH3:20]
Reactant: CCOC(=O)CC(=O)c1cc(F)c(F)c(F)c1F
Reactant: CCOC(=O)N(C)CC1CNCCO1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Product: CCOC(=O)CC(=O)c1cc(F)c(N2CCOC(CN(C)C(=O)OCC)C2)c(F)c1F
Yield: 72.7 %

Procedure:
A suspension of 26.4 g of ethyl 2,3,4,5-tetrafluorobenzoylacetate, 18.7 g of 2-(N-ethoxycarbonyl-N-methylaminomethyl)morpholine and 8.4 g of sodium hydrogen carbonate in 130 ml of acetonitrile is refluxed for 7 hours. The reaction mixture is concentrated under reduced pressure, to the obtained residue is added 100 ml of chloroform and the solution is washed with water. After drying over anhydrous magnesium sulfate, the chloroform is distilled off under reduced pressure and the residue is purified by chromatography on silica gel to give 30.0 g of ethyl 4-[2-(N-ethoxycarbonyl-N-methylaminomethyl)morpholino]-2,3,5-trifluorobenzoylacetate in 67% yield, as an oily substance.
Reaction SMILES: S(Cl)([Cl:3])=O.[CH3:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([CH3:12])[C:7]=1[N:13]([CH2:17][CH:18](O)[CH3:19])[C:14](=[O:16])[CH3:15]>C1C=CC=CC=1>[CH3:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([CH3:12])[C:7]=1[N:13]([CH2:17][CH:18]([Cl:3])[CH3:19])[C:14](=[O:16])[CH3:15]
Reactant: CC(=O)N(CC(C)O)c1c(C)cccc1C
Reactant: O=S(Cl)Cl
Solvent: c1ccccc1
Product: CC(=O)N(CC(C)Cl)c1c(C)cccc1C
Yield: 81.9 %

Procedure:
6.5 ml (10.76 g, 90.4 mmoles) of thionyl chloride are added dropwise, within 20 minutes, to a solution of 20 g (90.4 mmoles) of 1[N-(2,6-dimethylphenyl)-acetamido]-2-propanol in 200 ml of benzene, and the mixture is boiled until the gas evolution ceases (for about 0.25 hours). The mixture is cooled, the solvent is evaporated under reduced pressure, and the oily residue is distilled under reduced pressure. 17.75 g (81.9%) of 1-[N-(2,6-dimethylphenyl)-acetamido]-2-chloro-propane are obtained; b.p.: 138°-140° C./93.3 Pa, m.p.: 41°-42° C.
Reaction SMILES: [CH2:1]([O:3][CH:4]([O:34][CH2:35][CH3:36])[C:5]1[CH:10]=[CH:9][C:8]([CH:11]2[CH:20]([C:21]3[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=3)[C:19](=O)[C:18]3[C:17]([C:29]([O:31]CC)=O)=[CH:16][CH:15]=[CH:14][C:13]=3[NH:12]2)=[CH:7][CH:6]=1)[CH3:2].O.[NH2:38][NH2:39]>CO>[CH2:1]([O:3][CH:4]([O:34][CH2:35][CH3:36])[C:5]1[CH:6]=[CH:7][C:8]([CH:11]2[NH:12][C:13]3[C:18]4[C:19](=[N:38][NH:39][C:29](=[O:31])[C:17]=4[CH:16]=[CH:15][CH:14]=3)[CH:20]2[C:21]2[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=2)=[CH:9][CH:10]=1)[CH3:2]
Reactant: CCOC(=O)c1cccc2c1C(=O)C(c1ccc(F)cc1)C(c1ccc(C(OCC)OCC)cc1)N2
Reactant: NN
Solvent: CO
Solvent: O
Product: CCOC(OCC)c1ccc(C2Nc3cccc4c(=O)[nH]nc(c34)C2c2ccc(F)cc2)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 76 %

Procedure:
The crude compound ethyl 2-(4-(diethoxymethyl)phenyl)-3-(4-fluorophenyl)-4-oxo-1,2,3,4-tetrahydroquinoline-5-carboxylate (4.2 g, 8.54 mmol) and hydrazine monohydrate (5 mL) were added in methanol (60 mL) and the mixture was stirred at room temperature for 16 hr. The resulting mixture was concentrated under reduced pressure to a volume of 40 mL and then filtered to obtain the crude title compound (3.0 g, yield 76%). LC-MS (ESI) m/z: 460 (M+1)+.
Reaction SMILES: [ClH:1].Cl.[N+:3]([C:6]1[CH:18]=[CH:17][C:9]([CH2:10][N:11]2[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]2)=[CH:8][CH:7]=1)([O-:5])=[O:4].[Cl:19][CH2:20][C:21]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)=[O:22].C([O-])([O-])=O.[K+].[K+]>>[ClH:19].[ClH:1].[N+:3]([C:6]1[CH:18]=[CH:17][C:9]([CH2:10][N:11]2[CH2:16][CH2:15][N:14]([CH2:20][C:21]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)=[O:22])[CH2:13][CH2:12]2)=[CH:8][CH:7]=1)([O-:5])=[O:4]
Reactant: O=[N+]([O-])c1ccc(CN2CCNCC2)cc1
Reactant: O=C(CCl)c1ccccc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Product: O=C(CN1CCN(Cc2ccc([N+](=O)[O-])cc2)CC1)c1ccccc1
Yield: 75 %

Procedure:
A mixture of N-(4-nitrobenzyl)piperazine dihydrochloride (10 g, 34 mmol), 2-chloro-1-phenylethanone (5.80 g, 37 mmol) and anhydrous K2CO3 (16.5 g, 119 mmol) was treated according to general preparation 2 to give 10.51 g of N1-(4-nitrobenzyl)-N4-phenacyl piperazine dihydrochloride (A), yield 75%, mp 236-8° C.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][N:5]2[C:8](=[O:15])[N:9]([CH2:11][CH:12]([CH3:14])[CH3:13])[N:10]=[C:4]2[C:3]=1I.[CH3:17][C:18]1[CH:23]=[CH:22][C:21](B(O)O)=[CH:20][CH:19]=1.C([O-])([O-])=O.[K+].[K+]>O1CCOCC1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Br:1][C:2]1[CH:7]=[CH:6][N:5]2[C:8](=[O:15])[N:9]([CH2:11][CH:12]([CH3:14])[CH3:13])[N:10]=[C:4]2[C:3]=1[C:21]1[CH:22]=[CH:23][C:18]([CH3:17])=[CH:19][CH:20]=1
Reactant: CC(C)Cn1nc2c(I)c(Br)ccn2c1=O
Reactant: Cc1ccc(B(O)O)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: Cc1ccc(-c2c(Br)ccn3c(=O)n(CC(C)C)nc23)cc1
Temperature: 100 °C
Reaction time: 15 h
Yield: 34.4 %

Procedure:
To a stirring, degassed mixture of 7-bromo-8-iodo-2-isobutyl-[1,2,4]triazolo[4,3-a]pyridin-3(2H)-one (0.1 g, 0.25 mmol), 4-methylphenylboronic acid (0.04 g, 0.28 mmol), and tetrakis(triphenylphosphine)palladium (15 mg, 0.013 mmol) in dioxane (2.0 mL) at 20° C. was added K2CO3 (0.04 g, 0.28 mmol) in water (0.6 mL). The resulting reaction mixture was stirred at 100° C. for 15 h under argon. Analysis by HPLC/MS indicated that starting material had been consumed. The reaction mixture was brought to room temperature and was concentrated under reduced pressure. The crude product was purified by reverse phase preparative HPLC (acetonitrile-water-TFA) to isolate 31 mg of the title compound as a yellow oil. MS: [M+H]+=360.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][CH:9]([C:12]1[S:13][CH:14]=[CH:15][C:16]=1[CH3:17])[NH:10][CH3:11].CO[C:20](OC)(OC)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>C(O)(=O)C>[CH3:11][N:10]1[CH:9]([C:12]2[S:13][CH:14]=[CH:15][C:16]=2[CH3:17])[CH2:8][C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[N:1]=[C:20]1[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: CNC(Cc1ccccc1N)c1sccc1C
Reactant: COC(OC)(OC)c1ccccc1
Solvent: CC(=O)O
Product: Cc1ccsc1C1Cc2ccccc2N=C(c2ccccc2)N1C
Yield: 91.4 %

Procedure:
A stirred solution of 2.19 g of 2-amino-N-methyl-α-(3-methyl-2-thienyl)benzeneethanamine and 9.88 g of trimethyl orthobenzoate was treated rapidly with 2.4 ml of glacial acetic acid, and heated under reflux for 8 hours. The solution was concentrated at 75° C. on a rotary evaporator (vacuum pump) to a syrup. The syrup was then partioned between 10% hydrochloric acid solution (50 ml) and ether. The aqueous phase was extracted again with ether, basified with 10% sodium hydroxide solution (60 ml) and extracted with dichloromethane (2×100 ml). The combined organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated to an oil. The oil was purified by preparative HPLC (Water's Associates Prep LC/System 500A, silica gel, sample applied in dichloromethane, 2% triethylamine in methanol as the eluent). Concentration of the appropriate fractions yielded 2.70 g of 4,5-dihydro-3-methyl-4-(3-methyl-2-thienyl)-2-phenyl-3H-1,3-benzodiazepine as an oil.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[NH:10][N:9]=[C:8]2[CH:14]=O)(=[O:4])=[O:3].[CH3:16][O:17][C:18]1[CH:27]=[CH:26][C:21]2[C:22](=[O:25])[CH2:23][O:24][C:20]=2[C:19]=1[CH2:28][N:29]1[CH2:34][CH2:33][N:32]([C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[CH2:31][CH2:30]1.N1CCCCC1>CO>[CH3:16][O:17][C:18]1[CH:27]=[CH:26][C:21]2[C:22](=[O:25])/[C:23](=[CH:14]/[C:8]3[C:7]4[C:11](=[CH:12][CH:13]=[C:5]([S:2]([CH3:1])(=[O:3])=[O:4])[CH:6]=4)[NH:10][N:9]=3)/[O:24][C:20]=2[C:19]=1[CH2:28][N:29]1[CH2:30][CH2:31][N:32]([C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[CH2:33][CH2:34]1
Reactant: CS(=O)(=O)c1ccc2[nH]nc(C=O)c2c1
Reactant: COc1ccc2c(c1CN1CCN(C(=O)OC(C)(C)C)CC1)OCC2=O
Solvent: CO
Solvent: C1CCNCC1
Product: COc1ccc2c(c1CN1CCN(C(=O)OC(C)(C)C)CC1)O/C(=C\c1n[nH]c3ccc(S(C)(=O)=O)cc13)C2=O
Temperature: 60 °C
Reaction time: 2 h
Yield: 47.2 %

Procedure:
A solution of 5-(methylsulfonyl)-1H-indazole-3-carboxaldehyde (0.0392 g, 0.175 mmol) in methanol (0.7 mL) was added with tert-butyl 4-[(6-methoxy-3-oxo-2,3-dihydrobenzofuran-7-yl)methyl]piperazine-1-carboxylate (0.0915 g, 0.252 mmol) synthesized in the same manner as that of Example B42, Step 5, and piperidine (0.00149 g, 0.0175 mmol), and the mixture was stirred at 60° C. for 2 hours. The reaction mixture was concentrated, and the resulting residue was purified by silica gel column chromatography (chloroform/methanol) to obtain tert-butyl (Z)-4-[(6-methoxy-2-{[5-(methylsulfonyl)-1H-indazol-3-yl]methylene}-3-oxo-2,3-dihydrobenzofuran-7-yl)methyl]piperazine-1-carboxylate (0.0470 g, 47%).