Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:20])[CH2:4][C:5]1[C:14]([CH3:15])=[C:13]([C:16](Cl)=[O:17])[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([F:19])[CH:11]=2)[CH:6]=1.[C:21]([O:25][C:26]([N:28]1[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]1)=[O:27])([CH3:24])([CH3:23])[CH3:22].C(N(CC)CC)C>ClCCl>[C:21]([O:25][C:26]([N:28]1[CH2:33][CH2:32][N:31]([C:16]([C:13]2[C:12]3[C:7](=[CH:8][CH:9]=[C:10]([F:19])[CH:11]=3)[CH:6]=[C:5]([CH2:4][C:3]([O:2][CH3:1])=[O:20])[C:14]=2[CH3:15])=[O:17])[CH2:30][CH2:29]1)=[O:27])([CH3:24])([CH3:22])[CH3:23]
Reactant: COC(=O)Cc1cc2ccc(F)cc2c(C(=O)Cl)c1C
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)Cc1cc2ccc(F)cc2c(C(=O)N2CCN(C(=O)OC(C)(C)C)CC2)c1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 92.2 %

Procedure:
To a solution of (4-chlorocarbonyl-6-fluoro-3-methyl-naphthalen-2-yl)-acetic acid methyl ester (294 mg, 1.0 mmol) and piperazine-1-carboxylic acid tert-butyl ester (279 mg, 1.5 mmol) in dichloromethane was added triethylamine (458 μL, 3.3 mmol). The resulting mixture was stirred at room temperature overnight, and concentrated in vacuo. The residue was purified by column chromatography (gradient elution with 20-40% ethyl acetate in petroleum ether) to afford 4-(7-fluoro-3-methoxycarbonylmethyl-2-methyl-naphthalene-1-carbonyl)-piperazine-1-carboxylic acid tert-butyl ester (410 mg, 92%) as a white solid.
Reaction SMILES: [CH3:1][C:2]1[S:3][C:4]2[CH:10]=[C:9]([CH3:11])[CH:8]=[CH:7][C:5]=2[N:6]=1.[Br:12][CH2:13][CH2:14][OH:15]>C(OCC)(=O)C>[Br-:12].[OH:15][CH2:14][CH2:13][N+:6]1[C:5]2[CH:7]=[CH:8][C:9]([CH3:11])=[CH:10][C:4]=2[S:3][C:2]=1[CH3:1]
Reactant: OCCBr
Reactant: Cc1ccc2nc(C)sc2c1
Solvent: CCOC(C)=O
Product: Cc1ccc2c(c1)sc(C)[n+]2CCO
Product: [Br-]
Temperature: 120 °C
Reaction time: 1 h
Yield: 60.8 %

Procedure:
A solution of 2,6-dimethylbenzothiazole (13.0 g) and 2-bromoethanol (100 g) was stirred and heated in an oil bath to 120° C. for 96 hours. After cooling the reaction mixture to room temperature, adding ethyl acetate (150 ml) and stirring for 1 hour, the resultant solid was filtered and collected. The solid was then dissolved in methanol (150 ml) and charcoal (2 g) was added. The charcoal was removed by passing through a pad of Celite®. The solution was then concentrated to a small volume and triturated with acetone (200 ml). The solid was collected, washed with acetone (2×30 ml), ethyl acetate (2×30 ml) and dried in an oven under high vacuum at 50 C overnight to obtain 13.95 g (61%) of 4b.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:15]=[N:16][C:17]([NH:20][C:21]3[N:22]=[CH:23][C:24]4[CH:30]=[C:29]([CH2:31][C:32]5[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=5)[C:28](=[O:38])[N:27]([CH:39]5[CH2:43][CH2:42][CH2:41][CH2:40]5)[C:25]=4[N:26]=3)=[CH:18][CH:19]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.C(Cl)(Cl)[Cl:45]>>[ClH:45].[CH2:31]([C:29]1[C:28](=[O:38])[N:27]([CH:39]2[CH2:40][CH2:41][CH2:42][CH2:43]2)[C:25]2[N:26]=[C:21]([NH:20][C:17]3[CH:18]=[CH:19][C:14]([N:11]4[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]4)=[CH:15][N:16]=3)[N:22]=[CH:23][C:24]=2[CH:30]=1)[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(Nc3ncc4cc(Cc5ccccc5)c(=O)n(C5CCCC5)c4n3)nc2)CC1
Reactant: ClC(Cl)Cl
Product: Cl
Product: O=c1c(Cc2ccccc2)cc2cnc(Nc3ccc(N4CCNCC4)cn3)nc2n1C1CCCC1
Reaction time: 3 h

Procedure:
4-[6-(6-Benzyl-8-cyclopentyl-7-oxo-7,8-dihydro-pyrido[2,3-d]pyrimidin-2-ylamino)-pyridin-3-yl]-piperazine-1-carboxylic acid tert-butyl ester (0.21 g, 0.36 mmol) prepared as in Example 23, was dissolved in 1:1 chloroform:methanol (15 ml), purged with anhydrous hydrogen chloride gas and stoppered for 3 hours. The mixture was poured into diethyl ether (50 ml) to give a precipitate which was filtered and dried in vacuo to provide 6-benzyl-8-cyclopentyl-2-(5-piperazin-1-yl-pyridin-2-ylamino)-8H-pyrido[2,3-d]pyrimidin-7-one hydrochloride (0.162 g). Analyses for C28H31N72.1.5 H2O.1.5HCl: Calc'd: C, 57.26; H, 6.09; N, 16.69, Cl (ionic), 9.05; H2O, 4.60. Found: C, 57.95; H, 6.23; N, 16.80; Cl (ionic), 9.87; H2O, 4.59.
Reaction SMILES: [CH3:1][N:2]([CH3:17])[C:3](=[S:16])[O:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([OH:11])[C:6]=1[C:12]([O:14][CH3:15])=[O:13].[H-].[Na+].I[CH3:21].O>CN(C)C=O>[CH3:17][N:2]([CH3:1])[C:3](=[S:16])[O:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([O:11][CH3:21])[C:6]=1[C:12]([O:14][CH3:15])=[O:13]
Reactant: CI
Reactant: COC(=O)c1c(O)cccc1OC(=S)N(C)C
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1c(OC)cccc1OC(=S)N(C)C
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A solution of O-2-carbomethoxy-3-hydroxyphenyl dimethylthiocarbamate (1.0 g, 3.9 mmol) in N,N-dimethylformamide (10 ml) was added dropwise with stirring to a suspension of sodium hydride (0.19 g, 3.9 mmol) in N,N-dimethylformamide (15 ml) cooled to 0° C. in an ice bath. The reaction mixture was stirred for 1 hour at room temperature. Iodomethane (0.26 ml, 4.3 mmol) was added, and stirring was continued for an additional 3 hours, at which time the mixture was poured into water. Extraction with diethyl ether followed by washing of the extracts with water (3×), saturated aqueous sodium chloride solution, drying (sodium sulfate), and evaporation gave a syrup that was triturated with methanol to afford O-2-carbomethoxy-3-methoxyphenyl dimethylthiocarbamate as a white crystalline solid; yield 0.80 g (76%). NMR (CDCl3, 60 MHz: δ3.30 (d, NME2) p.p.m.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][NH:16][C:17](=[O:49])[C@@H:18]([NH:25][C:26](=[O:48])[CH:27]([C:38](=[O:47])[NH:39][CH2:40][C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)[CH2:28][C:29]2[CH:34]=[CH:33][C:32]([C:35](=[NH:37])[NH2:36])=[CH:31][CH:30]=2)[CH:19]2[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]2)[CH2:10][CH2:9]1)=O)(C)(C)C.[F:50][C:51]([F:56])([F:55])[C:52]([OH:54])=[O:53].ClCCl>>[F:50][C:51]([F:56])([F:55])[C:52]([OH:54])=[O:53].[CH2:40]([NH:39][C:38](=[O:47])[CH:27]([CH2:28][C:29]1[CH:30]=[CH:31][C:32]([C:35](=[NH:36])[NH2:37])=[CH:33][CH:34]=1)[C:26]([NH:25][C@@H:18]([CH:19]1[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1)[C:17](=[O:49])[NH:16][CH2:15][CH2:14][N:11]1[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]1)=[O:48])[C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1
Reactant: CC(C)(C)OC(=O)N1CCN(CCNC(=O)[C@@H](NC(=O)C(Cc2ccc(C(=N)N)cc2)C(=O)NCc2ccccc2)C2CCCCC2)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: N=C(N)c1ccc(CC(C(=O)NCc2ccccc2)C(=O)N[C@H](C(=O)NCCN2CCNCC2)C2CCCCC2)cc1
Reaction time: 20 h

Procedure:
4-(2-{2-(S)-[2-(R,S)-Benzylcarbamoyl-3-(4-carbamimidoyl-phenyl)-propionylamino]-2-cyclohexyl-acetylamino}-ethyl)-piperazine-1-carboxylic acid tert-butyl ester (30 mg, 0.04 mmol, example 6b) was treated with a mixture of trifluoroacetic acid/dichloromethane (1/1, 0.5 ml) and stirred for 20 hours. The solvent was evaporated in vacuo and the residue lyophilized to give the desired product. mp.: 196° C. (dc), MS (FAB) m/z: 576.3 ((M+H)+, 100%).
Reaction SMILES: [C:1]([C:3]1[CH:29]=[CH:28][C:6]2[NH:7][C:8]([CH:10]([C:16]3[C:24]([O:25][CH3:26])=[CH:23][C:22]([CH3:27])=[C:21]4[C:17]=3[CH:18]=[CH:19][NH:20]4)[CH2:11][C:12](OC)=[O:13])=[N:9][C:5]=2[CH:4]=1)#[N:2].[BH4-].[Na+]>CO>[OH:13][CH2:12][CH2:11][CH:10]([C:8]1[NH:7][C:6]2[CH:28]=[CH:29][C:3]([C:1]#[N:2])=[CH:4][C:5]=2[N:9]=1)[C:16]1[C:24]([O:25][CH3:26])=[CH:23][C:22]([CH3:27])=[C:21]2[C:17]=1[CH:18]=[CH:19][NH:20]2
Reactant: COC(=O)CC(c1nc2cc(C#N)ccc2[nH]1)c1c(OC)cc(C)c2[nH]ccc12
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: COc1cc(C)c2[nH]ccc2c1C(CCO)c1nc2cc(C#N)ccc2[nH]1
Reaction time: 48 h

Procedure:
To a solution of (±)-methyl 3-(5-cyano-1H-benzo[d]imidazol-2-yl)-3-(5-methoxy-7-methyl-1H-indol-4-yl)propanoate (Example 145-C) (50 mg, 0.129 mmol) in MeOH (1.3 mL) was added NaBH4 (121 mg, 3.25 mmol) at 0° C. The reaction mixture was allowed to reach rt and stirred for 48 hrs. The reaction mixture was quenched with water at 0° C. and extracted with EtOAc (2×). The combined organic layers were passed through a phase separator and concentrated and absorbed onto silica to purify via FCC with DCM/MeOH (100/0 to 95/5) to obtain the title compound. 1H NMR (400 MHz, DMSO-d6) δ ppm 12.04-12.30 (m, 1H) 10.89 (br. s., 1H) 8.10 (s, 1H) 7.68-7.77 (m, 1H) 7.38-7.51 (m, 1H) 6.99-7.21 (m, 1H) 6.78 (s, 1H) 6.10 (br. s., 1H) 4.99 (t, J=7.33 Hz, 1H) 4.36-4.57 (m, 1H) 3.74 (s, 3H) 3.42 (td, J=11.56, 5.68 Hz, 2H) 2.77 (dd, J=13.39, 6.82 Hz, 1H) 2.44 (s, 3H) 2.11-2.23 (m, 1H). HRMS calcd. for C21H20N4O2 (M+H)+ 361.1651. found 361.1659.
Reaction SMILES: [NH:1]([C:9]([O:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:10])[C@H:2]([C:5]([NH:7]N)=[O:6])[CH2:3][OH:4].N(OCCC(C)C)=O.C(N(CC)CC)C.N[C@H:35]([C:40]([NH:42][CH2:43][C:44]([O:46][CH2:47][CH3:48])=[O:45])=[O:41])[CH2:36][CH:37]([CH3:39])[CH3:38]>CN(C)C=O>[NH:1]([C:9]([O:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:10])[C@H:2]([C:5]([NH:7][C@H:35]([C:40]([NH:42][CH2:43][C:44]([O:46][CH2:47][CH3:48])=[O:45])=[O:41])[CH2:36][CH:37]([CH3:39])[CH3:38])=[O:6])[CH2:3][OH:4]
Reactant: CCOC(=O)CNC(=O)[C@@H](N)CC(C)C
Reactant: NNC(=O)[C@H](CO)NC(=O)OCc1ccccc1
Agent: CC(C)CCON=O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCOC(=O)CNC(=O)[C@H](CC(C)C)NC(=O)[C@H](CO)NC(=O)OCc1ccccc1
Reaction time: 0.08 h

Procedure:
2.48 Grams of Z-Ser-NHNH2 was dissolved in 20 ml of dimethylformamide and 4.89 ml of N-hydrochloric acid/dioxane, after cooled the reaction mixture to -15° C., then 1.31 ml of isoamyl nitrite was added thereto and stirred for 5 minutes. Then 4.11 ml of triethylamine was added to the reaction mixture to neutralize the mixture. This reaction mixture was added into 10 ml of a dimethylformamide solution containing the above-mentioned H-Leu-Gly-OC2H5 and 1.24 ml of triethylamine and stirred at 4° C. for 20 hours. After removal of dimethylformamide by distillation, the residue thus obtained was extracted with ethyl acetate, and the extract was washed with 1N-citric acid and a saturated aqueous solution of sodium chloride in this order, then the extract was dried with anhydrous magnesium sulfate. After removal of ethyl acetate, reprecipitated from ethyl acetate to obtain 2.64 g of Z-Ser-Leu-Gly-OC2H5.
Reaction SMILES: [Cl-].O[NH3+:3].[C:4](=[O:7])([O-])[OH:5].[Na+].CS(C)=O.[CH2:13]([C:15]1[N:16]([C:40]2[CH:45]=[CH:44][C:43]([O:46][C@@H:47]3[CH2:52][CH2:51][CH2:50][CH2:49][C@H:48]3[OH:53])=[CH:42][CH:41]=2)[C:17](=[O:39])[C:18]([CH2:24][C:25]2[CH:30]=[CH:29][C:28]([C:31]3[C:32]([C:37]#[N:38])=[CH:33][CH:34]=[CH:35][CH:36]=3)=[CH:27][CH:26]=2)=[C:19]([CH2:21][CH2:22][CH3:23])[N:20]=1)[CH3:14]>O>[CH2:13]([C:15]1[N:16]([C:40]2[CH:45]=[CH:44][C:43]([O:46][C@@H:47]3[CH2:52][CH2:51][CH2:50][CH2:49][C@H:48]3[OH:53])=[CH:42][CH:41]=2)[C:17](=[O:39])[C:18]([CH2:24][C:25]2[CH:26]=[CH:27][C:28]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=3[C:37]3[NH:3][C:4](=[O:7])[O:5][N:38]=3)=[CH:29][CH:30]=2)=[C:19]([CH2:21][CH2:22][CH3:23])[N:20]=1)[CH3:14]
Reactant: O=C([O-])O
Reactant: CCCc1nc(CC)n(-c2ccc(O[C@@H]3CCCC[C@H]3O)cc2)c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Reactant: [NH3+]O
Agent: [Cl-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: CCCc1nc(CC)n(-c2ccc(O[C@@H]3CCCC[C@H]3O)cc2)c(=O)c1Cc1ccc(-c2ccccc2-c2noc(=O)[nH]2)cc1
Temperature: 40 °C
Reaction time: 0.5 h
Yield: 54.6 %

Procedure:
A mixture of hydroxylammonium chloride (1.6 g), sodium hydrogen carbonate (2.3 g) and dimethyl sulfoxide (8 mL) was stirred at 40° C. for 30 min, 4′-{[2-ethyl-1-(4-{[(1R,2R)-2-hydroxycyclohexyl]oxy}phenyl)-6-oxo-4-propyl-1,6-dihydropyrimidin-5-yl]methyl}biphenyl-2-carbonitrile (0.76 g) was added, and the mixture was stirred at 90° C. for 24 hr. The mixture was allowed to cool to room temperature, water was added to the reaction mixture, and the precipitated solid was collected by filtration. The obtained solid was dissolved in ethyl acetate. The solution was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated and the residue was dissolved in tetrahydrofuran (10 mL). N,N′-carbonyldiimidazole (0.22 g) and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.21 mL) were added, and the mixture was stirred at room temperature for 30 min. The reaction mixture was diluted with ethyl acetate, washed with 1 M hydrochloric acid and then with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography to give the title compound as a colorless solid (0.46 g, 55%).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH:7]=[CH:8][C:9]([OH:11])=O)[CH:2]=1.C(Cl)(=O)C(Cl)=O.[O:18]=[C:19]1[C:23]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[C:22]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[C:21](=[O:36])[N:20]1[CH2:37][CH2:38][CH2:39][NH2:40].Cl>>[O:18]=[C:19]1[C:23]([C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)=[C:22]([C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=2)[C:21](=[O:36])[N:20]1[CH2:37][CH2:38][CH2:39][NH:40][C:9](=[O:11])[CH:8]=[CH:7][C:3]1[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=1
Reactant: O=C(O)C=Cc1cccnc1
Reactant: NCCCN1C(=O)C(c2ccccc2)=C(c2ccccc2)C1=O
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Product: O=C(C=Cc1cccnc1)NCCCN1C(=O)C(c2ccccc2)=C(c2ccccc2)C1=O

Procedure:
Batch size: 3.4 g (23.1 mmol) 3-(3-pyridyl)-acrylic acid, 5.3 g (42,0 mmol) oxalyl chloride, 4.2 g (42.0 mmol) TEA and 7.2 g (21.0 mmol) 3-(2,5-dioxo-3,4-diphenyl-2,5-dihydropyrrol-1-yl)-propylamine•hydrochloride.
Reaction SMILES: Cl.[NH:2]1[C:7]2[N:8]=[CH:9][CH:10]=[CH:11][C:6]=2[C:5]2([CH2:16][CH2:15][NH:14][CH2:13][CH2:12]2)[O:4][C:3]1=[O:17].Cl[C:19]1[N:24]=[CH:23][N:22]=[C:21]([O:25][C:26]2[CH:27]=[C:28]([CH3:38])[C:29]3[N:33]=[C:32]([CH2:34][O:35][CH3:36])[NH:31][C:30]=3[CH:37]=2)[CH:20]=1.CCN(C(C)C)C(C)C>CN(C=O)C>[CH3:36][O:35][CH2:34][C:32]1[NH:31][C:30]2[CH:37]=[C:26]([O:25][C:21]3[N:22]=[CH:23][N:24]=[C:19]([N:14]4[CH2:13][CH2:12][C:5]5([O:4][C:3](=[O:17])[NH:2][C:7]6[N:8]=[CH:9][CH:10]=[CH:11][C:6]5=6)[CH2:16][CH2:15]4)[CH:20]=3)[CH:27]=[C:28]([CH3:38])[C:29]=2[N:33]=1
Reactant: COCc1nc2c(C)cc(Oc3cc(Cl)ncn3)cc2[nH]1
Reactant: O=C1Nc2ncccc2C2(CCNCC2)O1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COCc1nc2c(C)cc(Oc3cc(N4CCC5(CC4)OC(=O)Nc4ncccc45)ncn3)cc2[nH]1

Procedure:
49 mg (0.19 mmol) spiro[piperidin-4,4′-pyrido[2,3-d][1,3]oxazin]-2′(1′H)-one hydrochloride, 50 mg (0.16 mmol) 6-(6-chloropyrimidin-4-yloxy)-2-(methoxymethyl)-4-methyl-1H-benzo-[d]imidazole and 0.10 mL (0.57 mmol) DIPEA in 2.0 mL DMF were stirred at 40° C. over the weekend. The reaction mixture was purified by preparative HPLC-MS. The fractions containing product were partially evaporated down i.vac. and neutralised with 4M sodium hydroxide solution. The precipitate formed was suction filtered, washed and dried.
Reaction SMILES: [CH2:1]([NH:11][C:12](=[O:22])[CH:13]=[CH:14][C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([NH2:21])[CH:16]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].[C:23]1(=[O:29])[O:28][C:26](=[O:27])[CH:25]=[CH:24]1>C1C=CC=CC=1>[CH2:1]([NH:11][C:12](=[O:22])[CH:13]=[CH:14][C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([NH:21][C:23](=[O:29])/[CH:24]=[CH:25]\[C:26]([OH:28])=[O:27])[CH:16]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10]
Reactant: O=C1C=CC(=O)O1
Reactant: CCCCCCCCCCNC(=O)C=Cc1cccc(N)c1
Solvent: c1ccccc1
Product: CCCCCCCCCCNC(=O)C=Cc1cccc(NC(=O)/C=C\C(=O)O)c1

Procedure:
A stirred mixture of 0.907 g. of N-decyl-3-(3-aminophenyl)propenamide and 25 ml. of benzene was heated on a steam bath until a solution was obtained. To this solution was then added 0.358 g. of maleic anhydride in one portion. In about 30 seconds a solid precipitated. The mixture was allowed to cool and then the solid was recovered by filtration. The solid was recrystallized from acetic acid, to give 1.1 g. (92% yeild) of the title compound, melting point 187°-188° C. The IR spectrum (KBr disc) showed absorptions at 3279, 2899, 1724, 1653, 1626, 1587 and 1563 cm-1. The NMR spectrum (in DMSO-d6) showed absorptions at 0.91 (m, 3H), 1.24 (s, 16H), 3.18 (m, 2H), 6.50 (m, 4H), 7.42 (m, 4H), 8.11 (m, 2H) and 10.50 (s, 1H) ppm.
Reaction SMILES: [C:1]([O:6][CH:7]([O:9][C:10]([NH:12][CH2:13][CH:14]([CH2:26][CH:27]([CH3:29])[CH3:28])[CH2:15][C:16]([O:18]CC1C=CC=CC=1)=[O:17])=[O:11])[CH3:8])(=[O:5])[CH:2]([CH3:4])[CH3:3]>C(O)C.[Pd]>[C:1]([O:6][CH:7]([O:9][C:10]([NH:12][CH2:13][CH:14]([CH2:26][CH:27]([CH3:29])[CH3:28])[CH2:15][C:16]([OH:18])=[O:17])=[O:11])[CH3:8])(=[O:5])[CH:2]([CH3:4])[CH3:3]
Reactant: CC(C)CC(CNC(=O)OC(C)OC(=O)C(C)C)CC(=O)OCc1ccccc1
Agent: [Pd]
Solvent: CCO
Product: CC(C)CC(CNC(=O)OC(C)OC(=O)C(C)C)CC(=O)O
Reaction time: 0.5 h

Procedure:
A solution of (41) (270 mg, 0.663 mmol) in ethanol (20 mL) was stirred with 10% Pd on carbon (11 mg) in a 50 mL round-bottomed flask under an atmosphere of hydrogen gas (balloon). The reaction was judged complete in 30 min. (monitoring by TLC and LC/MS). The mixture was filtered through a pad of Celite, and the solvent removed in vacuo to afford the title compound (33) as a mixture of two diastereomers (177 mg, 84%). 1H-NMR (CDCl3, 400 MHz): δ 0.89 (m, 6H), 1.16 (m, 8H), 1.46 (d, 3H), 1.66 (m, 1H), 2.11–2.36 (m, 3H), 2.52 (m, 1H), 3.11 (m, 1H), 3.27 (m, 1H), 5.08 (t, 1H), 6.77 (m, 11H). MS (ESI) m/z 316.20 (M−H−).
Reaction SMILES: Br[C:2]1[CH:15]=[C:14]2[C:5]([CH:6]3[CH:11]([CH:12]([C:16]4[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=4)[CH2:13]2)[CH2:10][CH2:9][CH2:8][CH2:7]3)=[CH:4][C:3]=1[O:24][CH3:25].C[Li].[Li][C:29](C)(C)C.CI>>[CH3:25][O:24][C:3]1[CH:4]=[C:5]2[C:14](=[CH:15][C:2]=1[CH3:29])[CH2:13][CH:12]([C:16]1[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=1)[CH:11]1[CH:6]2[CH2:7][CH2:8][CH2:9][CH2:10]1
Reactant: COc1ccc(C2Cc3cc(Br)c(OC)cc3C3CCCCC23)cc1
Reactant: [Li]C(C)(C)C
Agent: [Li]C
Solvent: CI
Product: COc1ccc(C2Cc3cc(C)c(OC)cc3C3CCCCC23)cc1
Reaction time: 1 h
Yield: 100 %

Procedure:
At −78° C., combine 7-Bromo-6-methoxy-10-(4-methoxy-phenyl)-1,2,3,4,4a,9,10,10a-octahydro-phenanthrene (chiral) (0.027 g, 0.067 mmol), and CH3Li (0.09 ml, 1.6M), then add t-BuLi (0.1 ml, 1.7M). After 30 minutes add CH3I (0.04 ml, 0.61 mmol) and remove cooling. After 1 hour at r.t., add ammonium chloride solution solution and ethyl acetate. Wash organic layer with water, dry over anhydrous sodium sulfate, remove solvent in vacuo to yield the titled compound (0.026 g, 100%). 1H NMR (CDCl3):): 7.27 (d, J=8.8 Hz, 2H), 6.99 (s, 1H), 6.93 (d, J=8.8 HZ, 2H), 6.89 (s, 1H), 3.87 (s, 3H), 3.86 (s, 3H), 3.2 (m, 2H), 2.85 (dd, J=4 and 11, 1H), 2.48 (d, J=14 Hz, 1H), 2.06 (m, 1H), 1.8-0.8 (m, 8H).
Reaction SMILES: [N+:1]([CH2:4][CH2:5][CH2:6][CH3:7])([O-])=[O:2].C1(N=C=O)C=CC=CC=1.[C:17]([C:19]12[CH2:26][CH2:25][CH2:24][N:23]1[CH2:22][CH2:21][CH2:20]2)#[CH:18]>C1C=CC=CC=1>[CH2:5]([C:4]1[CH:18]=[C:17]([C:19]23[CH2:26][CH2:25][CH2:24][N:23]2[CH2:22][CH2:21][CH2:20]3)[O:2][N:1]=1)[CH2:6][CH3:7]
Reactant: C#CC12CCCN1CCC2
Reactant: CCCC[N+](=O)[O-]
Solvent: O=C=Nc1ccccc1
Solvent: c1ccccc1
Product: CCCc1cc(C23CCCN2CCC3)on1
Temperature: 25 °C
Reaction time: 1 h
Yield: 53.4 %

Procedure:
Nitrobutane (0.705 mL, 6.66 mmol) and phenylisocyanate (1.50 mL, 13.3 mmol) were dissolved in benzene (13.5 mL) and added to a flask containing 7a-ethynyl-hexahydro-1H-pyrrolizine (450 mg, 3.33 mmol, from step 13a). The solution was stirred at ambient temperature for 1 hour and at reflux for 5 hours. The mixture was cooled, filtered, concentrated and diluted with EtOAc. The solution was extracted with 6N HCl. The aqueous phase was made basic with 15% NaOH and extracted with methylene chloride. The organic extracts were combined, dried (MgSO4) and concentrated. The residue was residue was chromatographed (silica gel; CHCl3 /MeOH, 98:2) to afford an amber oil (392 mg, 53%). 1H NMR (CDCl3, 300 MHz) δ0.97 (t, J=7.5 Hz, 3H), 1.61-1.92 (m, 8H), 2.15-2.26 (m, 2H), 2.55-2.69 (m, 4H), 3.13-3.20 (m, 2H), 5.96 (s, 1H); MS (CI/NH3) m/z: 221 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[F:13])[C:3]=1[C:14]([OH:16])=O.Cl.C(N=C=NCCCN(C)C)C.OC1C2N=NNC=2C=CC=1.[N:39]1([C:45]2[CH:50]=[CH:49][C:48]([OH:51])=[CH:47][CH:46]=2)[CH2:44][CH2:43][NH:42][CH2:41][CH2:40]1>>[NH2:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[F:13])[C:3]=1[C:14]([N:42]1[CH2:41][CH2:40][N:39]([C:45]2[CH:46]=[CH:47][C:48]([OH:51])=[CH:49][CH:50]=2)[CH2:44][CH2:43]1)=[O:16]
Reactant: Oc1ccc(N2CCNCC2)cc1
Reactant: Nc1onc(-c2ccccc2F)c1C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: Oc1cccc2[nH]nnc12
Product: Nc1onc(-c2ccccc2F)c1C(=O)N1CCN(c2ccc(O)cc2)CC1
Yield: 58.7 %

Procedure:
In a similar manner as described in Example 1, by using dimethylformimide (15 mL), 5-amino-3-(2-fluorophenyl)isoxazol-4-carboxylic acid (409 mg, 1.84 mmol), 1-ethyl-3-(dimethylaminopropyl)carbodiimide hydrochloride (388 mg, 2.02 mmol), hydroxybenzotriazole (299 mg, 2.21 mmol) and 4-(piperazine-1-yl)phenol (328 mg, 1.84 mmol), a white solid required compound (412 mg, 1.08 mmol, 59%) was obtained.
Reaction SMILES: C(OC([NH:8][CH2:9][C:10]1[O:14][N:13]=[C:12]([C:15]2[S:19][C:18]([CH2:20][N:21]3[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]3)=[CH:17][CH:16]=2)[N:11]=1)=O)(C)(C)C.[ClH:28].O1CCOCC1>>[ClH:28].[ClH:28].[NH2:8][CH2:9][C:10]1[O:14][N:13]=[C:12]([C:15]2[S:19][C:18]([CH2:20][N:21]3[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]3)=[CH:17][CH:16]=2)[N:11]=1
Reactant: CC(C)(C)OC(=O)NCc1nc(-c2ccc(CN3CCCCCC3)s2)no1
Agent: Cl
Solvent: C1COCCO1
Product: NCc1nc(-c2ccc(CN3CCCCCC3)s2)no1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
1.1 g of 1-[5-(5-t-butoxycarbonylaminomethyl-1,2,4-oxadiazol-3-yl)-2-thenyl]hexahydro-1H-azepine was dissolved in 30 ml of 4 N hydrochloric acid-1,4-dioxane solution, and the solution was stirred at room temperature for 30 minutes. The reaction solution was concentrated under a reduced pressure, and the resulting residue was recrystallized from ethyl acetate to give 966 mg of the title compound.
Reaction SMILES: [CH:1]1[C:14]2[C:5](=[N:6][C:7]3[C:12]([CH:13]=2)=[CH:11][CH:10]=[CH:9][CH:8]=3)[C:4]([C:15]([O:17]C)=O)=[CH:3][CH:2]=1.[CH3:19][N:20]([CH3:24])[CH2:21][CH2:22][NH2:23].N#N>C(O)CC>[CH3:19][N:20]([CH3:24])[CH2:21][CH2:22][NH:23][C:15]([C:4]1[C:5]2[C:14](=[CH:13][C:12]3[C:7]([N:6]=2)=[CH:8][CH:9]=[CH:10][CH:11]=3)[CH:1]=[CH:2][CH:3]=1)=[O:17]
Reactant: CN(C)CCN
Reactant: COC(=O)c1cccc2cc3ccccc3nc12
Agent: N#N
Solvent: CCCO
Product: CN(C)CCNC(=O)c1cccc2cc3ccccc3nc12
Yield: 64.9 %

Procedure:
A solution of methyl acridine 4-carboxylate (1.83 g, 7.72 mmol) and N,N-dimethylethylenediamine (3.40 g, 38.6 mmol) in n-propanol (80 ml) was flushed with N2, and the mixture was heated at reflux for three days under N2. Solvent was then removed under reduced pressure, and the residue was partitioned between CH2Cl2 (100 ml) and 1M Na2CO3 (100 ml). The organic layer was evaporated and the residue chromatographed on alumina, eluting with CH2Cl2 /MeOH (199:1) to give N-[2-(dimethylamino)ethyl]acridine-4-carboxamide (DACA) (1.47 g, 61%), mp (dihydrochloride salt from MeOH/EtOAc) 162-165° C.
Reaction SMILES: C1C2C(=CC=CC=2)CCC1.[C:11]1([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2S)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>>[C:11]1([C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: Sc1ccccc1-c1ccccc1
Solvent: c1ccc2c(c1)CCCC2
Product: c1ccc(-c2ccccc2)cc1
Temperature: 375 °C

Procedure:
A volume of 1.5 ml of a tetralin solution containing 0.1 M of 2-phenylthiopheol was placed into 3 ml stainless-steel mini-bomb inside a dry-box. The mini-bomb was heated at 375° C. in an oven for a certain period of time and the content analyzed by GC/MS. Results in Table 1 below indicate desulfurization of 2-phenylthiophenol, giving biphenyl as the major product.
Reaction SMILES: [Na].O[CH:3]=[C:4]1[CH2:8][CH2:7][O:6][C:5]1=[O:9].[C:10]1([C@@H:16]([NH2:18])[CH3:17])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>>[C:10]1([C@@H:16]([NH:18][CH:3]=[C:4]2[CH2:8][CH2:7][O:6][C:5]2=[O:9])[CH3:17])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: O=C1OCCC1=CO
Reactant: C[C@H](N)c1ccccc1
Agent: [Na]
Product: C[C@H](NC=C1CCOC1=O)c1ccccc1
Yield: 72.9 %

Procedure:
Using 3-hydroxymethylenedihydrofuran-2-one sodium salt (50 mmol) and (S)-1-phenylethylamine (55 mmol) and proceeding according to the abovementioned method A1, (S)-3-(1-phenylethylamino)methylenedihydrofuran-2-one (7.92 g, efficiency: 73%) is produced in the form of a white powder.