Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([NH:7]C(=O)CCl)=[N:4][C:3]=1/[C:12](=[N:36]/[O:37][CH3:38])/[C:13]([NH:15][C@@H:16]1[C:34](=[O:35])[N:18]2[C:19]([C:31]([OH:33])=[O:32])=[C:20]([CH2:23][O:24][C:25](=[O:30])[CH2:26][C:27](=[O:29])[CH3:28])[CH2:21][S:22][C@H:17]12)=[O:14].CNC(=S)[S-].[Na+].C(OCC)(=O)C>O.O1CCCC1>[NH2:7][C:5]1[S:6][C:2]([Cl:1])=[C:3](/[C:12](=[N:36]/[O:37][CH3:38])/[C:13]([NH:15][C@@H:16]2[C:34](=[O:35])[N:18]3[C:19]([C:31]([OH:33])=[O:32])=[C:20]([CH2:23][O:24][C:25](=[O:30])[CH2:26][C:27](=[O:29])[CH3:28])[CH2:21][S:22][C@H:17]23)=[O:14])[N:4]=1
Reactant: CO/N=C(\C(=O)N[C@@H]1C(=O)N2C(C(=O)O)=C(COC(=O)CC(C)=O)CS[C@H]12)c1nc(NC(=O)CCl)sc1Cl
Agent: CNC(=S)[S-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: O
Product: CO/N=C(\C(=O)N[C@@H]1C(=O)N2C(C(=O)O)=C(COC(=O)CC(C)=O)CS[C@H]12)c1nc(N)sc1Cl
Temperature: 25 °C
Reaction time: 3 h
Yield: 88.7 %

Procedure:
In a mixture of 13 ml of water and 13 ml of tetrahydrofuran is dissolved 2.94 g of 7β-[2-(5-chloro-2-chloroacetamidothiazol-4-yl)-2(Z)-methoxyiminoacetamido]-3-(3-oxobutyryloxymethyl)-3-cephem-4-carboxylic acid. To the mixture is added 1.15 g of sodium N-methyldithiocarbamate in 3 portions with stirring at room temperature for 3 hours. Ethyl acetate is added to the reaction mixture and the ethyl acetate layer is separated and discarded. The aqueous layer is acidified with concentrated hydrochloric acid and extracted with 200 ml of methyl ethyl ketone. The extract is washed with aqueous sodium chloride solution and dried over anhydrous sodium sulfate. The solvent is then evaporated off to give 2.28 g of the above-identified compound.
Reaction SMILES: [N:1]1[CH:6]=[C:5]([CH3:7])[CH:4]=[C:3]([CH3:8])[CH:2]=1.[Li][CH3:10]>C1(C)C=CC=CC=1>[CH3:10][C:2]1[C:3]([CH3:8])=[CH:4][C:5]([CH3:7])=[CH:6][N:1]=1
Reactant: [Li]C
Reactant: Cc1cncc(C)c1
Solvent: Cc1ccccc1
Product: Cc1cnc(C)c(C)c1
Yield: 72.7 %

Procedure:
To a solution of 3,5-lutidine (42.86, 0.400 mol) in toluene (240 ml) in a three-neck flask, under N2 atmosphere, was added dropwise MeLi [0.33M in ether, 1330 ml (0.44 mol), prepared from CH3I and Li or obtained from Aldrich]. The reaction was stirred and heated at 60°-80° C. for 6 h, after which time the ether was distilled off. The remaining solution was poured into water/crushed ice (200 ml), acidified with conc. HCl and extracted with ethyl acetate (2×100 ml). The aqueous solution then was basified with aq. NaOH and extracted with CH2Cl2 (3×100 ml). The CH2Cl2 extracts were combined, washed with sat. NaCl solution (1×50 ml), dried (MgSO4) and the solvent removed in vacuo. The residue was distilled under reduced pressure to give 2,3,5-trimethylpyridine (35.24 g, 72%) as a pale oil; bp 65°-71° C./11 mmHg. A solution of 2,3,5-trimethylpyridine (36.35 g, 0.30 mol) in AcOH (120 ml) was treated with 30% H2O (45 ml) and the mixture heated at 100° C. for 3 h. An additional aliquot of 30% H2O2 (15 ml) was added and the mixture was heated for an additional 10 h at 100° C. The reaction was cooled to rt, diluted with water (100 ml) and concentrated in vacuo. The residue again was diluted with water (200 ml), neutralized with KOH pellets and extracted with CH2Cl2 (3×100 ml). The extracts were combined, washed with sat. NaCl (1×50 ml), dried (MgSO4) and the solvent removed in vacuo to give 2,3,5-trimethylpyridine-N-oxide as a pale yellow solid, (50 g, quant.); mp 41°-42° C. (hexanes, colorless needles).
Reaction SMILES: C[O:2][C:3](=O)[CH2:4][CH2:5][C:6]1[CH:15]=[CH:14][C:13]2[C:8](=[CH:9][CH:10]=[C:11]([CH2:16][O:17][Si:18]([C:21]([CH3:24])([CH3:23])[CH3:22])([CH3:20])[CH3:19])[CH:12]=2)[CH:7]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].CO.C(C(C(C([O-])=O)O)O)([O-])=O.[Na+].[K+]>C1COCC1>[Si:18]([O:17][CH2:16][C:11]1[CH:12]=[C:13]2[C:8](=[CH:9][CH:10]=1)[CH:7]=[C:6]([CH2:5][CH2:4][CH2:3][OH:2])[CH:15]=[CH:14]2)([C:21]([CH3:24])([CH3:23])[CH3:22])([CH3:20])[CH3:19]
Reactant: COC(=O)CCc1ccc2cc(CO[Si](C)(C)C(C)(C)C)ccc2c1
Agent: O=C([O-])C(O)C(O)C(=O)[O-]
Agent: [Al+3]
Agent: [H-]
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)(C)[Si](C)(C)OCc1ccc2cc(CCCO)ccc2c1
Reaction time: 0.5 h
Yield: 109.3 %

Procedure:
The compound (2.62 g) obtained in Example 121-5 was dissolved in anhydrous THF (100 ml) and added with lithium aluminum hydride (555 mg) under ice-cooling, followed by stirring for 30 minutes under a nitrogen atmosphere. After completion of the reaction, the solution was added with methanol and then added with an aqueous potassium sodium tartrate solution, followed by stirring overnight. The solution was extracted with chloroform and the extract was washed with saturate saline solution. Then, the organic layer was dried with anhydrous sodium sulfate. The solvent was distilled off, thereby obtaining the subject compound (2.64 g) as a white solid.
Reaction SMILES: CN(C)[CH:3]=[N:4][C:5]1[S:6][C:7]([CH3:13])=[C:8]([Cl:12])[C:9]=1[C:10]#[N:11].C(O)=[O:16]>O>[Cl:12][C:8]1[C:9]([C:10]#[N:11])=[C:5]([NH:4][CH:3]=[O:16])[S:6][C:7]=1[CH3:13]
Reactant: Cc1sc(N=CN(C)C)c(C#N)c1Cl
Reactant: O=CO
Solvent: O
Product: Cc1sc(NC=O)c(C#N)c1Cl
Yield: 93 %

Procedure:
6.8 parts of N,N-dimethyl-N'-(4-chloro-3-cyano-5-methylthien-2-yl)-formamidine, 30 parts of formic acid and 30 parts of water are heated at the boil for 1 hour, and the precipitated product is filtered off under suction when the mixture is cooled, and washed with water and dried. 5.6 parts (93% of theory) of N-(4-chloro-3-cyano-5-methylthien-2-yl)-formamide are obtained.
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:7]=[N:8][N:9]([C:11]2[CH:16]=[C:15]([C:17](=[O:36])[NH:18][C:19]3[CH:24]=[C:23]([C:25]([CH3:28])([CH3:27])[CH3:26])[CH:22]=[C:21]([NH:29][S:30]([CH3:33])(=[O:32])=[O:31])[C:20]=3[O:34][CH3:35])[CH:14]=[CH:13][C:12]=2[CH3:37])[CH:10]=1)=[O:5])C.[OH-].[Na+].Cl>CO>[C:25]([C:23]1[CH:22]=[C:21]([NH:29][S:30]([CH3:33])(=[O:31])=[O:32])[C:20]([O:34][CH3:35])=[C:19]([NH:18][C:17]([C:15]2[CH:14]=[CH:13][C:12]([CH3:37])=[C:11]([N:9]3[CH:10]=[C:6]([C:4]([OH:5])=[O:3])[CH:7]=[N:8]3)[CH:16]=2)=[O:36])[CH:24]=1)([CH3:28])([CH3:26])[CH3:27]
Reactant: CCOC(=O)c1cnn(-c2cc(C(=O)Nc3cc(C(C)(C)C)cc(NS(C)(=O)=O)c3OC)ccc2C)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COc1c(NC(=O)c2ccc(C)c(-n3cc(C(=O)O)cn3)c2)cc(C(C)(C)C)cc1NS(C)(=O)=O
Reaction time: 2 h
Yield: 91.8 %

Procedure:
1-[5-(5-tert-butyl-3-methanesulfonylamino-2-methoxy-phenylcarbamoyl)-2-methyl-phenyl]-1H-pyrazole-4-carboxylic acid ethyl ester (Example 2) (900 mg) was suspended in MeOH (7 mL). A solution of 10% sodium hydroxide (33 mL) was added and the reaction stirred 2 h. The solution was acidified with concentrated HCl to a pH of 4 resulting in a suspension. The suspension was cooled in an ice bath and the solids collected by vacuum filtration. The solids were washed with water, dried under vacuum over P2O5 at 50° C. to provide 1-[5-(5-tert-butyl-3-methanesulfonylamino-2-methoxy-phenylcarbamoyl)-2-methyl-phenyl]-1H-pyrazole-4-carboxylic acid (782 mg, 91%) as a white solid.
Reaction SMILES: [N+:1]([C:4]1[CH:28]=[CH:27][C:7]([O:8][CH2:9][C:10]([CH3:26])([CH3:25])[CH:11]([O:15][C:16]2[CH:21]=[CH:20][C:19]([N+:22]([O-])=O)=[CH:18][CH:17]=2)[CH:12]([CH3:14])[CH3:13])=[CH:6][CH:5]=1)([O-])=O>CN(C=O)C.[Ni]>[NH2:1][C:4]1[CH:5]=[CH:6][C:7]([O:8][CH2:9][C:10]([CH3:26])([CH3:25])[CH:11]([O:15][C:16]2[CH:17]=[CH:18][C:19]([NH2:22])=[CH:20][CH:21]=2)[CH:12]([CH3:14])[CH3:13])=[CH:27][CH:28]=1
Reactant: CC(C)C(Oc1ccc([N+](=O)[O-])cc1)C(C)(C)COc1ccc([N+](=O)[O-])cc1
Agent: [Ni]
Solvent: CN(C)C=O
Product: CC(C)C(Oc1ccc(N)cc1)C(C)(C)COc1ccc(N)cc1

Procedure:
250 g 1,3-bis-(4-nitrophenoxy)-2,2,4-trimethyl-pentane were hydrogenated as in Example 10 in 1300 ml DMF in the presence of 39 g Raney nickel.
Reaction SMILES: C([O:8][C:9]1[CH:18]=[C:17]2[C:12]([C:13]([O:19][C:20]3[CH:21]=[C:22]([CH:24]=[CH:25][CH:26]=3)[NH2:23])=[N:14][CH:15]=[N:16]2)=[CH:11][C:10]=1[O:27][CH3:28])C1C=CC=CC=1.[H][H]>C(O)C.[Pd]>[NH2:23][C:22]1[CH:21]=[C:20]([CH:26]=[CH:25][CH:24]=1)[O:19][C:13]1[C:12]2[C:17](=[CH:18][C:9]([OH:8])=[C:10]([O:27][CH3:28])[CH:11]=2)[N:16]=[CH:15][N:14]=1
Reactant: COc1cc2c(Oc3cccc(N)c3)ncnc2cc1OCc1ccccc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: COc1cc2c(Oc3cccc(N)c3)ncnc2cc1O
Yield: 44 %

Procedure:
A stirred mixture of 3-(7-(benzyloxy)-6-methoxyquinazolin-4-yloxy)aniline from the previous step (2.52 g, 6.76 mmol) and palladium (10% wt on activated carbon) (200 mg) in ethanol (100 mL), under 1 atmosphere of hydrogen gas, was heated at 50° C. for 45 mins. The reaction mixture was filtered through a celite plug and concentrated under reduced pressure. The residue was purified via silica gel chromatography eluting with 1% to 10% methanol in dichloromethane to afford 4-(3-aminophenoxy)-6-methoxyquinazolin-7-ol as a colorless solid (840 mg, 44%). 1H NMR (300 MHz, DMSO-d6) δ 10.73 (brs, 1H), 8.47 (s, 1H), 7.50 (s, 1H), 7.21 (s, 1H), 7.08 (m, 1H), 6.35-6.50 (m, 3H), 5.28 (brs, 2H), 3.97 (s, 3H); LC-MS (ESI) m/z 284 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:12]2[CH2:13][CH2:14][N:15]([CH2:18][CH2:19][C:20]([F:23])([F:22])[F:21])[CH2:16][CH:17]=2)[CH:6]=[CH:7][C:8]=1[N+:9]([O-])=O>C(O)C.C(O)(=O)C.[Pt](=O)=O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:12]2[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][C:20]([F:23])([F:21])[F:22])[CH2:14][CH2:13]2)[CH:6]=[CH:7][C:8]=1[NH2:9]
Reactant: COc1cc(C2=CCN(CCC(F)(F)F)CC2)ccc1[N+](=O)[O-]
Agent: O=[Pt]=O
Solvent: CC(=O)O
Solvent: CCO
Product: COc1cc(C2CCN(CCC(F)(F)F)CC2)ccc1N
Temperature: 25 °C
Reaction time: 4 h
Yield: 99.2 %

Procedure:
1.65 g (5.0 mmol) of the product prepared in step 16.2 are placed in 120 mL of an ethanol/acetic acid mixture (v/v=1/1) in a hydrogenation autoclave, and 0.150 g of platinum (IV) oxide is added, under an inert atmosphere. The mixture is stirred under a hydrogen pressure of 4 bar at room temperature for 4 hours. After filtering through thin glass fibre paper and evaporating to dryness under reduced pressure, the oily residue is taken up in chloroform and washed with aqueous 1N NaOH solution. The organic phase is dried over Na2SO4, filtered and concentrated under vacuum. 1.5 g of the expected product are obtained in the form of a brown oil, which is used as obtained in the following step. Crude yield=quantitative.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:5]2[C:6](=[O:9])[CH2:7][O:8][C:4]=2[C:3]=1[CH2:12][N:13]1[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15][CH2:14]1.[Cl:26][C:27]1[CH:28]=[C:29]2[C:33](=[CH:34][CH:35]=1)[NH:32][N:31]=[C:30]2[CH:36]=O.N1CCCCC1>CO>[OH:1][C:2]1[CH:11]=[CH:10][C:5]2[C:6](=[O:9])/[C:7](=[CH:36]/[C:30]3[C:29]4[C:33](=[CH:34][CH:35]=[C:27]([Cl:26])[CH:28]=4)[NH:32][N:31]=3)/[O:8][C:4]=2[C:3]=1[CH2:12][N:13]1[CH2:14][CH2:15][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:17][CH2:18]1
Reactant: CC(C)(C)OC(=O)N1CCN(Cc2c(O)ccc3c2OCC3=O)CC1
Reactant: O=Cc1n[nH]c2ccc(Cl)cc12
Solvent: CO
Solvent: C1CCNCC1
Product: CC(C)(C)OC(=O)N1CCN(Cc2c(O)ccc3c2O/C(=C\c2n[nH]c4ccc(Cl)cc24)C3=O)CC1
Temperature: 60 °C
Reaction time: 3 h
Yield: 51.1 %

Procedure:
A solution of tert-butyl 4-[1-(6-hydroxy-3-oxo-2,3-dihydrobenzofuran-7-yl)methyl]piperazine-1-carboxylate (0.100 g, 0.287 mmol) in methanol (1.2 mL) was added with 5-chloro-1H-indazole-3-carbaldehyde (0.0518 g, 0.287 mmol), and piperidine (0.00244 g, 0.0287 mmol) at room temperature, and the mixture was stirred at 60° C. for 3 hours. The reaction mixture was added with methanol (4 mL), suspended in methanol and thereby washed, and then the solid was collected by filtration to obtain tert-butyl (Z)-4-({6-hydroxy-3-oxo-2-[(5-chloro-1H-indazol-3-yl)methylene]-2,3-dihydrobenzofuran-7-yl}methyl)piperazine-1-carboxylate (0.0750 g, 51%).
Reaction SMILES: [C:1](O)(=O)[C:2]1[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=1.[Cl:10][C:11]1[CH:16]=[CH:15][C:14]([NH2:17])=[C:13]([NH2:18])[CH:12]=1.[NH4+].[OH-]>>[Cl:10][C:11]1[CH:16]=[CH:15][C:14]2[N:17]=[C:1]([C:2]3[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=3)[NH:18][C:13]=2[CH:12]=1
Reactant: Nc1ccc(Cl)cc1N
Reactant: O=C(O)c1ccncc1
Agent: [NH4+]
Agent: [OH-]
Product: Clc1ccc2nc(-c3ccncc3)[nH]c2c1
Yield: 49.1 %

Procedure:
To a mixture of isonicotinic acid (4.9 g., 0.04 mol) and 4-chloro-o-phenylenediamine (5.8 g., 0.041 mol) was added polylphosphoric acid (20 ml.). The mixture was heated to 200° and maintained at this temperature for 45 min. After cooling, the reaction mixture was poured onto ice and the solution made basic with conc. NH4OH. The resulting yellow solid was removed by filtration, dissolved in isopropanol, filtered and the filtrate concentrated to a solid. After recrystallization from EtOH-H2O, 4.5 g. of 5-chloro-2-(4-pyridyl)benzimidazole (49.1%) was obtained; m.p. 306-307.
Reaction SMILES: [NH:1]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[C@H:2]([C:5]([OH:7])=O)[CH2:3][NH2:4].Cl.[NH2:16][C@H:17]([C:25]([O:27][CH3:28])=[O:26])[CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.CCOC(OC(OCC)=O)=O.CCN(C(C)C)C(C)C>C(Cl)Cl.C(OCC)(=O)C>[NH:1]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[C@H:2]([C:5]([NH:16][C@H:17]([C:25]([O:27][CH3:28])=[O:26])[CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:7])[CH2:3][NH2:4]
Reactant: CC(C)(C)OC(=O)N[C@@H](CN)C(=O)O
Reactant: COC(=O)[C@@H](N)Cc1ccccc1
Agent: CCOC(=O)OC(=O)OCC
Agent: Cl
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)[C@H](Cc1ccccc1)NC(=O)[C@H](CN)NC(=O)OC(C)(C)C
Reaction time: 16 h

Procedure:
To a room temperature suspension of Boc-Dap-OH (6.31 g, 22 mmol) in anhydrous CH2Cl2 (100 mL) was added HCl×Phe-OMe (5.2 g, 24.2 mmol), DEPC (6.7 mL, 44 mmol) and DIEA (11.5 mL, 65.9 mmol). This reaction mixture was stirred for 16 h, diluted with ethyl acetate (500 mL) and washed sequentially with 0.1 M HCl (2×300 mL), H2O (300 mL), saturated NaHCO3 (2×300 mL) and H2O (300 mL). The organic layer was dried over anhydrous MgSO4, filtered and concentrated in vacuo. This crude oil was purified by silica gel flash column chromatography using a 20-100% ethyl acetate/hexanes gradient. Boc-Dap-Phe-OMe was obtained as white foam (8.85 g, 19.7 mmol, 90% yield).
Reaction SMILES: [CH3:1][C:2]1([CH3:15])[CH2:11][C:10]2[C:5](=[CH:6][C:7]([CH3:14])=[C:8]([OH:13])[C:9]=2[CH3:12])[CH:4]=[N:3]1>CCO.[Ni]>[CH3:1][C:2]1([CH3:15])[CH2:11][C:10]2[C:5](=[CH:6][C:7]([CH3:14])=[C:8]([OH:13])[C:9]=2[CH3:12])[CH2:4][NH:3]1
Reactant: Cc1cc2c(c(C)c1O)CC(C)(C)N=C2
Agent: [Ni]
Solvent: CCO
Product: Cc1cc2c(c(C)c1O)CC(C)(C)NC2

Procedure:
Imine 38 (1.00 g, 4.93 mmol) is hydrogenated (50 psi H2) over RaNi (spatula scoop, washed 3×with water and 3×with EtOH) in EtOH (20 mL) for 2 h at rt. Filtration of the reaction mixture through filter aid and evaporation of the solvent gives the amine as a light yellow solid (MW=205.3) which is used without further purification. Yield: 0.90 g (89%) . 1H NMR (CDCl3) 6.68 (s, 1), 3.95 (s, 2), 3.62 (br s, 2), 2.45 (s, 2), 2.21 (s, 3), 2.08 (s, 3), 1.20 (s, 6); 13C NMR (CDCl3) 150.43, 131.39, 125.87, 125.12, 122.19, 121.16, 48.85, 43.93, 38.98, 27.89, 16.01, 10.97.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH:12]=[C:11]([C:14]2[C:22]3[S:21][C:20]([NH:23][C:24](=[O:32])[C:25]4[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=4)=[N:19][C:18]=3[C:17]([O:33][CH3:34])=[CH:16][CH:15]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.[ClH:35].CO>>[ClH:35].[F:31][C:28]1[CH:27]=[CH:26][C:25]([C:24]([NH:23][C:20]2[S:21][C:22]3[C:14]([C:11]4[CH2:12][CH2:13][NH:8][CH2:9][CH:10]=4)=[CH:15][CH:16]=[C:17]([O:33][CH3:34])[C:18]=3[N:19]=2)=[O:32])=[CH:30][CH:29]=1
Reactant: COc1ccc(C2=CCN(C(=O)OC(C)(C)C)CC2)c2sc(NC(=O)c3ccc(F)cc3)nc12
Agent: Cl
Solvent: CO
Product: COc1ccc(C2=CCNCC2)c2sc(NC(=O)c3ccc(F)cc3)nc12
Yield: 92 %

Procedure:
0.20 g (0.52 mMol) 4-[2-(4-fluoro-benzoylamino)-4-methoxy-benzothiazol-7-yl]-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester were dissolved in 5 ml 2.5 M HCl/MeOH and heated to reflux for 1.5 h. The reaction mixture was concentrated in vacuo and taken up in 4 ml isopropanol. The suspension formed was filtered and the material on the filter was washed with diethyl ether and dried in vacuo. One obtained 200 mg (92%) 4-fluoro-N-[4-methoxy-7-(1,2,3,6-tetrahydro-pyridin-4-yl)-benzothiazol-2-yl]-benzamide hydrochloride (1:1) as an off-white solid. F.p.: 268-275° C.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([N:8]([CH:20]2[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]2)[CH2:9][C:10]([F:19])([F:18])[C:11](=[O:17])C(OCC)=O)[C:5]([N+:26]([O-])=O)=[CH:4][N:3]=1.Cl>C(O)(=O)C.[Fe]>[Cl:1][C:2]1[N:3]=[CH:4][C:5]2[NH:26][C:11](=[O:17])[C:10]([F:19])([F:18])[CH2:9][N:8]([CH:20]3[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]3)[C:6]=2[N:7]=1
Reactant: CCOC(=O)C(=O)C(F)(F)CN(c1nc(Cl)ncc1[N+](=O)[O-])C1CCCCC1
Agent: [Fe]
Agent: Cl
Solvent: CC(=O)O
Product: O=C1Nc2cnc(Cl)nc2N(C2CCCCC2)CC1(F)F
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 60.4 %

Procedure:
In a round bottom flask compound ethyl 4-((2-chloro-5-nitropyrimidin-4-yl)(cyclohexyl)amino)-3,3-difluoro-2-oxobutanoate (11.85 g, 31.35 mmol) was dissolved in acetic acid (30 mL), and added iron powder (3.51 g, 62.7 mmol) to it. Then cooled the round bottom flask to 0° C. in an ice bath. After 10 min, added conc.HCl (12 mL) dropwise using addition funnel and continued the reaction at 60° C. on a preheated oil bath until starting material disappear. It was then concentrated in vacuo, diluted with EtOAc, basified with 10% NaOH solution at 0° C. The whole was filtered through celite, washed with EtOAc. The filtrate was then separated. The organic layer was dried over Na2SO4. The solution was concentrated in vacuo followed by precipitation from ether to afford the desired compound (6.0 g, 62% yield) as yellow solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 0.96-1.85 (m, 10H) 4.02 (t, J=11.37 Hz, 2H) 4.47 (m, 1H) 8.11 (s, 1H) 11.02 (br. s., 1H). [M+H] calc'd for C13H15ClF2N4O, 317. found 317.
Reaction SMILES: [C:1]1([CH:7]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:8][C:9]2[NH:10][CH2:11][CH2:12][N:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:20]([O:22]C=O)C>>[CH:20]([N:13]1[CH2:12][CH2:11][N:10]=[C:9]1[CH2:8][CH:7]([C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)=[O:22]
Reactant: CCOC=O
Reactant: c1ccc(C(CC2=NCCN2)c2ccccc2)cc1
Product: O=CN1CCN=C1CC(c1ccccc1)c1ccccc1

Procedure:
a mixture of 2.5 g of 2-(2,2-diphenyl ethyl)-2-imidazoline and 50 ml of ethylformate was refluxed for 5 hours. After the reaction, unreacted ethylformate was removed by distillation. The resulting residue was subjected to silica gel column chromatography and eluted with methylene chloride. The solvent was removed by distillation from the eluate to give 1.2 g of 1-formyl-2-(2,2-diphenyl ethyl)-2-imidazoline having a melting point of 105° to 107° C.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)=[CH:6][CH:5]=1)([O-])=O.Br[CH2:17][CH2:18][CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21].C(=O)([O-])[O-].[K+].[K+]>CN1CCCC1=O>[NH2:1][C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:15][CH2:14][N:13]([CH2:17][CH2:18][CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH2:12][CH2:11]2)=[CH:6][CH:5]=1
Reactant: CCOC(=O)CCCBr
Reactant: O=[N+]([O-])c1ccc(N2CCNCC2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN1CCCC1=O
Product: CCOC(=O)CCCN1CCN(c2ccc(N)cc2)CC1

Procedure:
1-(4-Nitrophenyl)piperazine and ethyl 4-bromobutanoate were allowed to undergo the reaction under heating in 1-methyl-2-pyrrolidone in the presence of potassium carbonate. The resulting compound was subjected to catalytic hydrogenation in the same manner as shown in Reference Example 3 to obtain ethyl 4-[4-(4-aminophenyl)-piperazin-1-yl]butanoate. F: 264.
Reaction SMILES: [C:1]([OH:6])(=[O:5])/[CH:2]=[CH:3]/[CH3:4].[C:7]1([CH3:17])[CH:12]=[CH:11][C:10](S(O)(=O)=O)=[CH:9][CH:8]=1>>[CH:10]1([CH:9]([O:5][C:1](=[O:6])[CH:2]=[CH:3][CH3:4])[CH3:8])[CH2:11][CH2:12][CH2:7][CH2:17]1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: C/C=C/C(=O)O
Product: CC=CC(=O)OC(C)C1CCCC1

Procedure:
Cyclopentene reacted with carbon monoxide (CO) and hydrogen (H2) in the presence of a Wilkinson's catalyst to provide cyclopentanecarboxaldehyde, which then reacted with methylmagnesium chloride (MeMgCl) to provide 1-cyclopentylethanol, which further reacted with crotonic acid in the presence of p-toluenesulfonic acid (pTSA) to afford product but-2-enoic acid 1-cyclopentyl-ethyl ester.
Reaction SMILES: [CH3:1][N:2]([CH2:4][C:5]1[CH:10]=[CH:9][C:8]([C@H:11]2[CH2:16][CH2:15][C@H:14]([OH:17])[CH2:13][CH2:12]2)=[CH:7][CH:6]=1)[CH3:3].C(N(CC)CC)C.[Cl:25][C:26]1[CH:34]=[CH:33][C:29]([C:30](Cl)=[O:31])=[CH:28][CH:27]=1.[OH-].[Na+]>C(Cl)Cl.O>[Cl:25][C:26]1[CH:34]=[CH:33][C:29]([C:30]([O:17][C@H:14]2[CH2:15][CH2:16][C@H:11]([C:8]3[CH:9]=[CH:10][C:5]([CH2:4][N:2]([CH3:1])[CH3:3])=[CH:6][CH:7]=3)[CH2:12][CH2:13]2)=[O:31])=[CH:28][CH:27]=1
Reactant: O=C(Cl)c1ccc(Cl)cc1
Reactant: CN(C)Cc1ccc([C@H]2CC[C@H](O)CC2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClCCl
Product: CN(C)Cc1ccc([C@H]2CC[C@H](OC(=O)c3ccc(Cl)cc3)CC2)cc1

Procedure:
A solution of 1.0 g (0.0043 mol) of trans-4-(4-dimethylaminomethylphenyl)-cyclohexanol and 0.6 ml of triethylamine in 50 ml of methylene chloride is combined, dropwise, with 0.75 g (0.0043 mol) of 4-chlorobenzoylchloride, with stirring, and refluxed for 3 hours. After cooling, 50 ml of water are added, the mixture is adjusted to pH 12-13 with sodium hydroxide solution, the methylene chloride phase is separated off and the aqueous phase is extracted once more with methylene chloride. The combined organic phases are dried over sodium sulphate and evaporated down in vacuo. The solid residue is purified by column chromatography (aluminium oxide neutral, activity stage III, ICN; petroleum ether/ethyl acetate=40:1). White crystals are obtained with a melting point of 94°-95° C.
Reaction SMILES: C([Li])CCC.[F:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH2:17][CH2:16][CH2:15][C:14]=2[C:18]2[CH:23]=[CH:22][C:21]([S:24](C)(=[O:26])=[O:25])=[CH:20][CH:19]=2)=[CH:9][CH:8]=1.ClC[Si](C)(C)C.[F-].C([N+:39](CCCC)(CCCC)CCCC)CCC.CC([O-])=O.[Na+].NOS(O)(=O)=O>C(OCC)(=O)C.O.O1CCCC1>[F:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH2:17][CH2:16][CH2:15][C:14]=2[C:18]2[CH:23]=[CH:22][C:21]([S:24]([NH2:39])(=[O:26])=[O:25])=[CH:20][CH:19]=2)=[CH:9][CH:8]=1
Reactant: CS(=O)(=O)c1ccc(C2=C(c3ccc(F)cc3)CCC2)cc1
Reactant: CCCC[N+](CCCC)(CCCC)CCCC
Agent: CC(=O)[O-]
Agent: C[Si](C)(C)CCl
Agent: NOS(=O)(=O)O
Solvent: C1CCOC1
Solvent: O
Solvent: CCOC(C)=O
Product: NS(=O)(=O)c1ccc(C2=C(c3ccc(F)cc3)CCC2)cc1
Temperature: 25 °C
Reaction time: 6 h
Yield: 84 %

Procedure:
n-Butyllithium (0.54 mL, 1.34 mmol, 2.49M) was added dropwise via syringe to 1-[2-(4-fluorophenyl)cyclopenten-1-yl]-4-(methylsulfonyl)benzene (prepared as described in U.S. Pat. No. 5,344,991) (0.352 g, 1.11 mmol) and dry tetrahydrofuran (THF) (3.5 mL) cooled in an ice-bath. The resulting orange solution was stirred for 1 hour in the ice-bath and (chloromethyl)trimethylsilane (235 μL, 1.68 mmol) was added in one portion via syringe. The ice-bath was removed and the reaction mixture was stirred for 6 hours at room temperature. Tetrabutylammonium fluoride (6.0 mL, 6.00 mmol, 1M in THF) was added in one portion via syringe, and the resulting mixture was heated to reflux for 45 minutes, then cooled to room temperature. To the reaction mixture was added sequentially NaOAc (0.501 g, 6.11 mmol), water (15.0 mL), and H2NOSO3H (0.712 g, 6.30 mmol) and the reaction was stirred overnight at room temperature. The reaction mixture was diluted with ethyl acetate (20.0 mL), the layers were separated, and the organic layer was washed with saturated NaHCO3 (2×10 mL), water (10.0 mL), and brine (10.0 mL) then dried over MgSO4. The solution was filtered, the solvents removed under reduced pressure, the crude product was purified by silica gel chromatography to afford 0.294 g (84%) of product as a white solid.