Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@@H:12]([CH2:16][S:17][CH2:18][C@H:19]([O:35][C:36](=[O:48])[NH:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH3:47])[CH2:20][O:21][C:22](=[O:34])[NH:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33])[C:13](O)=[O:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[NH2:82][CH2:83][CH2:84][O:85][CH2:86][CH2:87][O:88][CH2:89][CH2:90][O:91][CH2:92][CH2:93][C:94]([O:96][C:97]([CH3:100])([CH3:99])[CH3:98])=[O:95]>C(Cl)Cl>[CH2:1]([O:8][C:9]([NH:11][C@@H:12]([CH2:16][S:17][CH2:18][C@H:19]([O:35][C:36](=[O:48])[NH:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH3:47])[CH2:20][O:21][C:22](=[O:34])[NH:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33])[C:13](=[O:14])[NH:82][CH2:83][CH2:84][O:85][CH2:86][CH2:87][O:88][CH2:89][CH2:90][O:91][CH2:92][CH2:93][C:94]([O:96][C:97]([CH3:100])([CH3:99])[CH3:98])=[O:95])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)CCOCCOCCOCCN
Reactant: CCCCCCCCCCNC(=O)OC[C@H](CSC[C@H](NC(=O)OCc1ccccc1)C(=O)O)OC(=O)NCCCCCCCCCC
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCCCCCCCCCNC(=O)OC[C@H](CSC[C@H](NC(=O)OCc1ccccc1)C(=O)NCCOCCOCCOCCC(=O)OC(C)(C)C)OC(=O)NCCCCCCCCCC
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of (R)-2-(benzyloxycarbonylamino)-3-((R)-2,3-bis(decylcarbamoyloxy)propylthio)propanoic acid (15, 1 eq) and HBTU (1.2 eq) in DCM (0.06 M) was added DIEA (2.4 eq), followed by tert-butyl 3-(2-(2-(2-aminoethoxy)ethoxy)ethoxy)propanoate (1.2 eq). The reaction was stirred at room temperature for 4 hours. The crude mixture was purified by flash chromatography on a COMBIFLASH® system (ISCO) using a gradient of 0-100% EtOAc/Hex to afford the title compound as an off-white solid.
Reaction SMILES: [C:1]([OH:9])(=[O:8])[C:2]1[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=1.S(=O)(=O)(O)O.[C:15](=O)([O-])[O-].[Na+].[Na+]>CO>[C:1]([O:9][CH3:15])(=[O:8])[C:2]1[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=1
Reactant: O=C([O-])[O-]
Reactant: O=C(O)c1ccncc1
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CO
Product: COC(=O)c1ccncc1
Temperature: 0 °C
Reaction time: 8 h
Yield: 71.8 %

Procedure:
A suspension of 100 g of isonicotinic acid (0.812 mol) in 250 ml of methanol was stirred and cooled to 10°. To this mixture was added dropwise 125 ml of sulfuric acid during 15 min. keeping the temperature below 20°. The reaction mixture was allowed to come to room temperature and then heated under reflux for 4.5 hr. After standing overnight it was poured onto 1 kg of ice and made alkaline with 235 g of sodium carbonate. The solid was filtered off, washed with water and with ether, and discarded. The filtrate was extracted with 3×300 ml of ether. The combined organic extracts were washed with water and with brine, dried over sodium sulfate, and concentrated in vacuo to leave 80 g (65%) of crude product as a pale oil.
Reaction SMILES: [C:1]([CH2:8][C:9](=[O:19])[CH:10]([NH2:18])[CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[CH3:20][Mg]Br>C(Cl)Cl>[C:1]([CH2:8][C:9]([CH3:20])([OH:19])[CH:10]([NH2:18])[CH2:11][C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2]
Reactant: C[Mg]Br
Reactant: CC(C)(C)OC(=O)CC(=O)C(N)Cc1ccccc1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)CC(C)(O)C(N)Cc1ccccc1
Temperature: 25 °C
Reaction time: 14 h

Procedure:
Grignard Addition A solution of Boc-3-amino-4-phenyl-2-butanone (0.5 g, 1.9 mmol) in 100 mL methylene chloride was cooled to −78° C. and treated with methyl magnesium bromide (1.39 mL of a 3.0M solution, 4.2 mmol). The reaction was warmed to ambient temperature and stirred for 14 hours. The reaction was charged with additional methyl magnesium bromide (1.39 mL of a 3.0 M solution, 4.2 mmol) and stirred at ambient temperature for 5 hours. The reaction was quenched with ammonium chloride solution and partitioned between water and ethyl acetate. The organics were washed with water (3×), brine, dried over sodium sulfate, filtered and evaporated in vactio. Purification by flash column chromatography (20-35% ethyl acetate/hexanes) gave Boc-3-amino-2-methyl-4-phenylbutan-2-ol as a white solid: 1H NMR (400 MHz, CDCl3) δ 7.25 (m, 5H), 4.52 (m, 1H), 3.69 (m, 1H), 3.09 (dd, J=14.1, 3.3 Hz, 1H), 2.61 (t, J=12.0 Hz, 1H), 2.39 (s, 1H), 1.30 (m, 15H). Step B: Deprotection
Reaction SMILES: [O:1]1[C@H:3]2[CH2:4][C@H:5]3[C@:20]([CH3:22])([CH2:21][C@@H:2]12)[C@@H:19]1[C@H:8]([C@H:9]2[C@:16]([CH3:23])([CH2:17][CH2:18]1)[C:12]([C:13](=[O:15])[CH3:14])=[CH:11][CH2:10]2)[CH2:7][CH2:6]3.Cl.O.C(Cl)(Cl)[Cl:27]>C(Cl)Cl>[Cl:27][C@H:2]1[CH2:21][C@@:20]2([CH3:22])[C@@H:5]([CH2:6][CH2:7][C@@H:8]3[C@@H:19]2[CH2:18][CH2:17][C@@:16]2([CH3:23])[C@H:9]3[CH2:10][CH:11]=[C:12]2[C:13](=[O:15])[CH3:14])[CH2:4][C@@H:3]1[OH:1]
Reactant: ClC(Cl)Cl
Reactant: CC(=O)C1=CC[C@H]2[C@@H]3CC[C@H]4C[C@@H]5O[C@@H]5C[C@]4(C)[C@H]3CC[C@]12C
Agent: Cl
Solvent: O
Solvent: ClCCl
Product: CC(=O)C1=CC[C@H]2[C@@H]3CC[C@H]4C[C@H](O)[C@@H](Cl)C[C@]4(C)[C@H]3CC[C@]12C
Reaction time: 0.33 h

Procedure:
2α,3α-Epoxy-5α-pregn-16-en-20-one (500 mg.) was dissolved in methylene chloride (15 ml.) and concentrated hydrochloric acid (12 ml.) was added. The mixture was shaken for 20 minutes, and then poured into water (100 ml.) and chloroform (100 ml.). The organic layer was separated, washed well with water, dried over sodium sulphate and evaporated to an oil. Recrystallisation from ethyl acetate gave title compound (447 mg.) as colourless crystals, m.p. 246°-252° , [α]D (c, 1.10)+ 65.8° , λmax. (EtOH) 239 nm (ε 8770).
Reaction SMILES: [Br:1][C:2]1[C:10]2[NH:9][C:8]3[CH2:11][CH2:12][N:13](C(OCC)=O)[CH2:14][C:7]=3[C:6]=2[C:5]([Br:20])=[CH:4][CH:3]=1.[OH-].[K+]>C(O)C.O>[Br:1][C:2]1[C:10]2[NH:9][C:8]3[CH2:11][CH2:12][NH:13][CH2:14][C:7]=3[C:6]=2[C:5]([Br:20])=[CH:4][CH:3]=1
Reactant: CCOC(=O)N1CCc2[nH]c3c(Br)ccc(Br)c3c2C1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: Brc1ccc(Br)c2c3c([nH]c12)CCNC3
Temperature: 95 °C
Yield: 95.7 %

Procedure:
A suspension of ethyl 6,9-dibromo-3,4-dihydro-1H-pyrido[4,3-b]indole-2(5H)-carboxylate (2.70 g, 6.72 mmol) in ethanol (25 mL) was treated with a solution of potassium hydroxide (15.07 g, 269 mmol) in water (15 mL) and ethanol (50 mL). The dark brown mixture was bubbled with nitrogen with sonication for 1 min. The mixture was then heated under nitrogen to 90-100° C. for 44 h, then at reflux for 23 h more. The solution was cooled to room temperature and concentrated under vacuum. The residual aqueous sludge was diluted with water (about 100 mL), stirred and intermittently sonicated for 1 h, and the precipitate was collected by filtration, washed thoroughly with water and dried under vacuum to provide the desired product as a light reddish-brown powder (2.123 g, 96% yield). LCMS (M+H+) m/z 329, 331, 333).
Reaction SMILES: CN(C=O)C.C(Cl)(=O)C(Cl)=O.[F:12][CH:13]([F:25])[CH:14]([C:16]1[N:17]([CH3:24])[CH:18]=[CH:19][C:20](=[O:23])[C:21]=1[OH:22])O>C(#N)C>[F:25][CH:13]([F:12])[CH2:14][C:16]1[N:17]([CH3:24])[CH:18]=[CH:19][C:20](=[O:23])[C:21]=1[OH:22]
Reactant: Cn1ccc(=O)c(O)c1C(O)C(F)F
Agent: O=C(Cl)C(=O)Cl
Solvent: CC#N
Solvent: CN(C)C=O
Product: Cn1ccc(=O)c(O)c1CC(F)F
Reaction time: 2 h
Yield: 24 %

Procedure:
To 10 mL of acetonitrile at ice-water bath was added DMF (0.14 mL, 1.8 mmol) followed by oxalyl chloride (0.15 mL, 1.8 mmol) dropwise. To this resulting suspension was added 2-(2,2-difluoro-1-hydroxyethyl)-3-hydroxy-1-methylpyridin-4(1H)-one (0.30 g, 1.5 mmol) in one portion, and the resulting mixture was stirred for 2 h. A solid was collected by filtration, and it was dissolved in 150 mL of acetonitrile. To this resulting solution was added Pd/C (10%, wet, 0.20 g, 66.7% w/w), and the mixture was subjected to hydrogenation under 40 psi hydrogen pressure for 2 h. The catalyst was filtered off, and the filtrate was evaporated to dryness. The residue was dissolved in de-ionized water, and the pH was adjusted to 5-6 using a 6N NaOH solution. The precipitate was collected via suction filtration to afford the crude product (100 mg) as an off-white solid. The crude was further purified by Biotage using reversed phase C18 cartridge to afford the title compound, Apo7080 (66 mg) as white solid. Yield=24%; 1H NMR (400 MHz, CD3OD) δ (ppm): 7.65 (d, J=7.2 Hz, 1H), 6.41 (d, J=7.2 Hz, 1H), 6.19 (tt, J=56.5, 4.7 Hz, 1H), 3.83 (s, 3H), 3.51 (dt, 3J=15.9 Hz, 2J=4.6 Hz, 2H); MS m/z 190 [M+1]+, 188 (100%).
Reaction SMILES: [CH3:1][CH:2]([CH3:28])[CH2:3][C:4]([C:6]1[CH:25]=[CH:24][C:9]2[O:10][C:11]3[C:20]([O:21][CH3:22])=[CH:19][C:18]([CH3:23])=[CH:17][C:12]=3[CH2:13][O:14][C:15](=[O:16])[C:8]=2[C:7]=1[O:26][CH3:27])=[O:5].[BH4-].[Na+]>O1CCCC1.O>[OH:5][CH:4]([C:6]1[CH:25]=[CH:24][C:9]2[O:10][C:11]3[C:20]([O:21][CH3:22])=[CH:19][C:18]([CH3:23])=[CH:17][C:12]=3[CH2:13][O:14][C:15](=[O:16])[C:8]=2[C:7]=1[O:26][CH3:27])[CH2:3][CH:2]([CH3:28])[CH3:1]
Reactant: COc1cc(C)cc2c1Oc1ccc(C(=O)CC(C)C)c(OC)c1C(=O)OC2
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: COc1cc(C)cc2c1Oc1ccc(C(O)CC(C)C)c(OC)c1C(=O)OC2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
158 g (0.41 mmol) of 3-(3-methyl-1-butanonyl)-4,11-dimethoxy-9-methyl-7H-dibenzo[b,g][1,5]dioxocin-5-one are dissolved in 2 ml of tetrahydrofuran and 0.1 ml of water. 23 mg (0.61 mmol) of sodium borohydride are added to the solution and the mixture is stirred overnight at room temperature. Excess sodium borohydride is destroyed by addition of a few drops of acetic acid. The mixture is concentrated in vacuo, the residue is taken up in dichloromethane and the solution is washed with water. The organic phase is dried over magnesium sulphate, concentrated and purified by column chromatography on silica gel using petroleum ether/diethyl ether 1:1.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[C:13](I)[CH:12]=[CH:11][C:10]=1[N:16]1[S:20](=[O:22])(=[O:21])[NH:19][C:18](=[O:23])[CH2:17]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:24][C:25]([CH3:30])=[CH:26]B(O)O.C([O-])([O-])=O.[Na+].[Na+]>COCCOC>[CH2:1]([O:8][C:9]1[CH:14]=[C:13]([CH:24]=[C:25]([CH3:30])[CH3:26])[CH:12]=[CH:11][C:10]=1[N:16]1[S:20](=[O:22])(=[O:21])[NH:19][C:18](=[O:23])[CH2:17]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C1CN(c2ccc(I)cc2OCc2ccccc2)S(=O)(=O)N1
Reactant: CC(C)=CB(O)O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: CC(C)=Cc1ccc(N2CC(=O)NS2(=O)=O)c(OCc2ccccc2)c1
Temperature: 12 °C

Procedure:
A mixture of 5-(2-benzyloxy-4-iodophenyl)-1,1-dioxo-1,2,5-thiadiazolidin-3-one (150 mg, 0.338 mmol) and 2,2-dimethylethenylboronic acid (67 mg, 0.670 mmol), resin-bound PPh3Pd (519 mg, 0.069 mmol) and Na2CO3 (0.338 mL, 2M) in DME (3 mL) is heated in a microwave apparatus at 12° C. for 20 min. The mixture is filtered through Celite, washed with MeCN and concentrated. The residue is purified by reverse phase chromatography using a gradient of 10-60% EtOH/H2O as eluent to afford the title compound: (M−1)−=371.
Reaction SMILES: C(=O)([O-])[OH:2].[Na+].[CH2:6]([NH:13][C:14](=[O:28])[CH2:15][C:16]1[CH:17]=[C:18]2[C:23](=[CH:24][CH:25]=1)[O:22][C:21]([CH3:27])([CH3:26])[CH:20]=[CH:19]2)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.C1C=C(Cl)C=C(C(OO)=O)C=1>ClCCl>[CH2:6]([NH:13][C:14](=[O:28])[CH2:15][C:16]1[CH:25]=[CH:24][C:23]2[O:22][C:21]([CH3:26])([CH3:27])[CH:20]3[O:2][CH:19]3[C:18]=2[CH:17]=1)[C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1
Reactant: O=C([O-])O
Reactant: CC1(C)C=Cc2cc(CC(=O)NCc3ccccc3)ccc2O1
Agent: O=C(OO)c1cccc(Cl)c1
Agent: [Na+]
Solvent: ClCCl
Product: CC1(C)Oc2ccc(CC(=O)NCc3ccccc3)cc2C2OC21
Temperature: 25 °C
Reaction time: 18 h

Procedure:
980 ml of a saturated aqueous sodium hydrogen carbonate solution was added to a solution of 28 g of the N-benzyl-2-(2,2-dimethyl-2H-chromen-6-yl)acetamide obtained above in 480 ml dichloromethane. A total of 44.1 g MCPBA in three 14.7 g portions was added to this receiving solution at 5 min. intervals, and the mixture was stirred for 18 hours at room temperature. The organic phase was separated, extracted once with 200 ml of a saturated aqueous sodium hydrogen carbonate solution, and the organic phase was then substantially completely evaporated at reduced pressure. 35 g N-benzyl-2-(2,2-dimethyl-1a,7b-dihydro-2H-oxireno[c]chromen-6-yl)acetamide was obtained as crude oil, which was used without further purification or characterization for the subsequent reaction.
Reaction SMILES: [NH:1]1[C:5]([C:6]2[CH:11]=[CH:10][C:9]([N:12]3[CH2:17][CH2:16][C:15](=O)[CH2:14][CH2:13]3)=[CH:8][CH:7]=2)=[N:4][N:3]=[N:2]1.[NH2:19][CH2:20][C@@H:21]([C:23]1[CH:24]=[CH:25][C:26]([OH:34])=[C:27]([NH:29][S:30]([CH3:33])(=[O:32])=[O:31])[CH:28]=1)[OH:22]>>[OH:34][C:26]1[CH:25]=[CH:24][C:23]([CH:21]([OH:22])[CH2:20][NH:19][CH:15]2[CH2:16][CH2:17][N:12]([C:9]3[CH:10]=[CH:11][C:6]([C:5]4[NH:4][N:3]=[N:2][N:1]=4)=[CH:7][CH:8]=3)[CH2:13][CH2:14]2)=[CH:28][C:27]=1[NH:29][S:30]([CH3:33])(=[O:32])=[O:31]
Reactant: O=C1CCN(c2ccc(-c3nnn[nH]3)cc2)CC1
Reactant: CS(=O)(=O)Nc1cc([C@@H](O)CN)ccc1O
Product: CS(=O)(=O)Nc1cc(C(O)CNC2CCN(c3ccc(-c4nnn[nH]4)cc3)CC2)ccc1O

Procedure:
The title compound was prepared from 1-[4-(1H-tetrazol-5-yl)-phenyl]-piperidin-4-one (which was obtained in Example 47) and N-[5-((1R)-2-amino-1-hydroxy-ethyl)-2-hydroxy-phenyl]-methanesulfonamide (which was obtained in Example 10) according to the procedure of Example 73 as a white solid; mp>175° C. (decomposed); 1H NMR (300 MHz, DMSO-d6) δ 1.40–1.65 (m, 2 H), 1.90–2.10 (m, 2 H), 2.70–3.10 (m, 5 H), 2.95 (s, 3 H), 3.70–3.85 (m, 2 H), 4.69 (dd, J=9.3, 3.0 Hz, 1 H), 6.89 (d, J=8.3 Hz, 1 H), 6.97 (d, J=8.9 Hz, 2 H), 7.06 (dd, J=8.3, 2.0 Hz, 1 H), 7.24 (d, J=2.0 Hz, 1 H), 7.80 (d, J=8.9 Hz, 2 H); MS (ES) m/z: 474.1 (MH+); HRMS Calcd. for C21H28N7O4S (MH+): 474.1918. Found: 474.1912.
Reaction SMILES: CC(C[AlH]CC(C)C)C.C(Cl)Cl.C([O:15][C:16]([C:18]1[N:19]=[C:20]2[CH2:25][N:24]([CH2:26][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[CH2:23][CH2:22][N:21]2[CH:33]=1)=O)C>C1(C)C=CC=CC=1>[CH2:26]([N:24]1[CH2:23][CH2:22][N:21]2[CH:33]=[C:18]([CH:16]=[O:15])[N:19]=[C:20]2[CH2:25]1)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: CCOC(=O)c1cn2c(n1)CN(Cc1ccccc1)CC2
Agent: CC(C)C[AlH]CC(C)C
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: O=Cc1cn2c(n1)CN(Cc1ccccc1)CC2
Reaction time: 1.5 h

Procedure:
1.01 M solution of DIBAL in toluene (1 mL+0.2 mL+0.3 mL) was added to the dry CH2Cl2 (5 mL) solution of 7-benzyl-5,6,7,8-tetrahydroimidazo[1,2-a]pyrazine-2-carboxylic acid ethyl ester (283 mg) under a nitrogen atmosphere at −78° C. and stirred for 1.5 h. The mixture was quenched with 1 M HCl (5 mL). The reaction mixture was filtered through a pad of Celite. The filtrate was washed with 50% K2CO3 aq. and the aqueous layer was extracted with CH2Cl2. The combined organic layer was dried (K2CO3) and filtered. The filtrate was concentrated under reduced pressure. The residue was applied to silica gel column chromatography, then the column was eluted with CHCl3-acetone (9/1˜4/1) and CHCl3-MeOH (19/1). The titled compound was obtained as colorless crystals (148 mg, 61%).
Reaction SMILES: [C:1](=[O:13])([O:10][CH2:11][CH3:12])[O:2][CH2:3][CH2:4][N:5]([C:7](Cl)=[O:8])[CH3:6].C(=O)(OCCN(C([N:25]1[C:33]2[C:28](=[N:29][C:30]([O:34][CH3:35])=[CH:31][CH:32]=2)[N:27]=[C:26]1[S:36]([CH2:38][C:39]1[C:44]([CH3:45])=[C:43]([O:46][CH3:47])[C:42]([CH3:48])=[CH:41][N:40]=1)=[O:37])=O)C)OCC>CN(C)C1C=CN=CC=1.C(N(CC)CC)C>[C:1](=[O:13])([O:2][CH2:3][CH2:4][N:5]([C:7]([N:27]1[C:28]2=[N:29][C:30]([O:34][CH3:35])=[CH:31][CH:32]=[C:33]2[N:25]=[C:26]1[S:36]([CH2:38][C:39]1[C:44]([CH3:45])=[C:43]([O:46][CH3:47])[C:42]([CH3:48])=[CH:41][N:40]=1)=[O:37])=[O:8])[CH3:6])[O:10][CH2:11][CH3:12]
Reactant: CCOC(=O)OCCN(C)C(=O)n1c(S(=O)Cc2ncc(C)c(OC)c2C)nc2nc(OC)ccc21
Reactant: CCOC(=O)OCCN(C)C(=O)Cl
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Product: CCOC(=O)OCCN(C)C(=O)n1c(S(=O)Cc2ncc(C)c(OC)c2C)nc2ccc(OC)nc21
Temperature: 50 °C
Reaction time: 18 h

Procedure:
To a solution of (+)-enantiomer (0.10 g) in tetrahydrofuran (5 mL), which was obtained by optically resolving 5-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridyl)methyl]sulfinyl]-1H-imidazo[4,5-b]pyridine synthesized by a method described in JP-A 63-146882 with preparative HPLC, were added 2-[(chlorocarbonyl)(methyl)amino]ethyl ethyl carbonate (0.081 g) obtained in Reference Synthetic Example 34, triethylamine (0.080 mL) and 4-dimethylaminopyridine (0.007 g), and stirred at 50° C. for 18 hrs. The reaction solution was concentrated under reduced pressure, and to the residue was added water (30 mL), and extracted with ethyl acetate (50 mL). The ethyl acetate layer was washed with saturated brine (30 mL), and dried over anhydrous sodium sulfate. After concentrating under reduced pressure, the residue was purified with basic silica gel column chromatography (eluted with ethyl acetate:hexane=2:1) to give a mixture of 2:1 of title compound and (+)-ethyl 2-[[[5-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridyl)methyl]sulfinyl]-1H-imidazo[4,5-b]pyridin-1-yl]carbonyl](methyl)amino]ethyl carbonate as colorless oil (0.115 g).
Reaction SMILES: [CH3:1][C@H:2]1[NH:7][CH2:6][CH2:5][N:4]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:3]1.CCN(C(C)C)C(C)C.[F:24][C:25]([F:37])([F:36])[C:26]1[CH:31]=[CH:30][C:29]([S:32](Cl)(=[O:34])=[O:33])=[CH:28][CH:27]=1.Cl>C(Cl)Cl>[CH3:1][C@H:2]1[N:7]([S:32]([C:29]2[CH:28]=[CH:27][C:26]([C:25]([F:24])([F:36])[F:37])=[CH:31][CH:30]=2)(=[O:34])=[O:33])[CH2:6][CH2:5][N:4]([C:8]([O:10][C:11]([CH3:13])([CH3:12])[CH3:14])=[O:9])[CH2:3]1
Reactant: C[C@@H]1CN(C(=O)OC(C)(C)C)CCN1
Reactant: O=S(=O)(Cl)c1ccc(C(F)(F)F)cc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: C[C@@H]1CN(C(=O)OC(C)(C)C)CCN1S(=O)(=O)c1ccc(C(F)(F)F)cc1
Yield: 110.8 %

Procedure:
To a solution of 1,1-dimethylethyl (3R)-3-methyl-1-piperazinecarboxylate (1.5 g, 7.49 mmol, supplier Aldrich) in DCM (30 ml) was added DIPEA (1.962 ml, 11.23 mmol) and then portionwise addition of 4-(trifluoromethyl)benzenesulfonyl chloride (2.2 g, 8.99 mmol) at room temperature. The resultant mixture was stirred under an atmosphere of Ar for 2 hours before addition of 1M HCl solution (75 ml) and DCM (75 ml). The layers were separated and the aqueous layer was then re-extracted with DCM (75 ml), the organic layers were combined and washed with saturated brine solution (100 ml). The organic layers were then separated, dried (MgSO4) and concentrated to dryness giving the title compound (3.39 g).
Reaction SMILES: [CH3:1][O:2][CH:3]([C:13]([OH:15])=[O:14])[NH:4][C:5](=[O:12])[CH2:6][C:7]1[S:8][CH:9]=[CH:10][CH:11]=1.C(N(CC)CC)C.Cl[C:24]([O:26][CH2:27][CH:28]([CH3:30])[CH3:29])=[O:25]>C(Cl)Cl>[C:24](=[O:25])([O:26][CH2:27][CH:28]([CH3:30])[CH3:29])[O:14][C:13](=[O:15])[CH:3]([O:2][CH3:1])[NH:4][C:5](=[O:12])[CH2:6][C:7]1[S:8][CH:9]=[CH:10][CH:11]=1
Reactant: CC(C)COC(=O)Cl
Reactant: COC(NC(=O)Cc1cccs1)C(=O)O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(NC(=O)Cc1cccs1)C(=O)OC(=O)OCC(C)C

Procedure:
One millimole of α-methoxy-N-(2-thienylacetyl)glycine in 10 ml methylene chloride at 0° is treated successively with one millimole each of triethylamine and isobutyl chloroformate, forming α-methoxy-N-(2-thienylacetyl)glycyl i-butyl carbonate. To this solution at -78° is added p-methoxybenzyl-5-N,N-di(p-methoxybenzyl)aminocarbonyloxymethyl 6H-1,3-thiazine-4-carboxylate, and then a second millimole of triethylamine. The reaction mixture is allowed to warm to room temperature over one hour, and kept at 25° one hour. The mixture is then washed successively with aqueous pH 2 buffer, water, and aqueous bicarbonate, dried with MgSO4, filtered and evaporated, affording p-methoxybenzyl 7-methoxy-7-(2-thienylacetamido)-3-N,N-di(p-methoxybenzyl)aminocarbonyloxymethyl decephalosporanate, which may be purified if desired by chromatography on silica gel, eluting with 4:1 chloroformethyl acetate.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[S:10][C:11]([C:14]([O:16]CC)=[O:15])=[CH:12][N:13]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH-].[K+].Cl>CCO.O>[C:1]([O:5][C:6]([NH:8][C:9]1[S:10][C:11]([C:14]([OH:16])=[O:15])=[CH:12][N:13]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOC(=O)c1cnc(NC(=O)OC(C)(C)C)s1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CC(C)(C)OC(=O)Nc1ncc(C(=O)O)s1
Yield: 85.6 %

Procedure:
A solution of ethyl 2-(tert-butoxycarbonylamino)thiazole-5-carboxylate (5 g, 18.36 mmol) and KOH (10.3 g, 184 mmol) in EtOH/H2O (1:1) (60 mL) was stirred at RT for 12 hrs. The solution was acidified with 1N HCl and the precipitate was filtered and dried, yielding 2-(tert-butoxycarbonylamino)thiazole-5-carboxylic acid (3.84 g, 86%) as a white solid.
Reaction SMILES: [CH2:1]([Mg]Br)[CH3:2].[CH3:5][CH:6]1[CH:11]=[C:10]([CH3:12])[CH2:9][CH2:8][CH:7]1[CH:13]=[O:14]>O1CCCC1>[CH3:5][CH:6]1[CH:11]=[C:10]([CH3:12])[CH2:9][CH2:8][CH:7]1[CH:13]([OH:14])[CH2:1][CH3:2]
Reactant: CC[Mg]Br
Reactant: CC1=CC(C)C(C=O)CC1
Solvent: C1CCOC1
Product: CCC(O)C1CCC(C)=CC1C
Temperature: 0 °C

Procedure:
A reaction flask was charged with ethylmagnesium bromide solution (CH3CH2MgBr) (3 M, 2.4 L) in tetrahydrofuran (THF) and cooled to 0° C. 2,4-Dimethyl-cyclohex-3-enecarbaldehyde (905 g) was added slowly while the temperature was kept at 0° C. The reaction mixture was stirred for an additional hour and then quenched with hydrochloric acid (HCl). The reaction mixture was washed with sodium carbonate (Na2CO3) and brine. Further distillation provided 1-(2,4 -dimethyl-cyclohex-3-enyl)-propan-1-ol (1.021 Kg).
Reaction SMILES: [NH2:1][C:2]([CH3:20])([CH3:19])[C:3]([NH:5][C:6]1[S:7][CH:8]=[CH:9][C:10]=1[C:11](=O)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:4].C(O)(=O)C>C(O)C>[CH3:19][C:2]1([CH3:20])[C:3](=[O:4])[NH:5][C:6]2[S:7][CH:8]=[CH:9][C:10]=2[C:11]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[N:1]1
Reactant: CC(C)(N)C(=O)Nc1sccc1C(=O)c1ccccc1
Solvent: CC(=O)O
Solvent: CCO
Product: CC1(C)N=C(c2ccccc2)c2ccsc2NC1=O
Yield: 48 %

Procedure:
55 mg of the compound of Example 2 was boiled in ethanol containing acetic acid at reflux. The cyclised title compound was obtained in 48% yield.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([CH2:17][C:18]3[CH:23]=[CH:22][C:21]([CH2:24][C:25]4[CH:30]=[CH:29][C:28]([CH2:31][C:32]5[CH:37]=[CH:36][C:35]([N+:38]([O-])=O)=[CH:34][CH:33]=5)=[CH:27][CH:26]=4)=[CH:20][CH:19]=3)=[CH:13][CH:12]=2)=[CH:6][CH:5]=1)([O-])=O.O.[H][H]>O1CCCC1.[Pd]>[NH2:1][C:4]1[CH:9]=[CH:8][C:7]([CH2:10][C:11]2[CH:12]=[CH:13][C:14]([CH2:17][C:18]3[CH:23]=[CH:22][C:21]([CH2:24][C:25]4[CH:30]=[CH:29][C:28]([CH2:31][C:32]5[CH:33]=[CH:34][C:35]([NH2:38])=[CH:36][CH:37]=5)=[CH:27][CH:26]=4)=[CH:20][CH:19]=3)=[CH:15][CH:16]=2)=[CH:6][CH:5]=1
Reactant: [H][H]
Reactant: O=[N+]([O-])c1ccc(Cc2ccc(Cc3ccc(Cc4ccc(Cc5ccc([N+](=O)[O-])cc5)cc4)cc3)cc2)cc1
Agent: [Pd]
Solvent: O
Solvent: C1CCOC1
Product: Nc1ccc(Cc2ccc(Cc3ccc(Cc4ccc(Cc5ccc(N)cc5)cc4)cc3)cc2)cc1

Procedure:
In a 1-liter three-necked flask equipped with a stirring device and a nitrogen substituting device, 25.00 g of 1,4-bis(4-(4-nitrophenylmethyl)phenylmethyl)benzene was dissolved in 400 milliliters of tetrahydrofuran, 2.5 g of a Pd-C catalyst (a 5% product, containing 55.9% of water) was added and contacted with hydrogen gas while cooled with water at a normal pressure and then stirred. By recrystallizing the concentrate from a tetrahydrofuran solvent, 21.13 g of a diamino compound according to the invention, that is, 1,4-bis(4-(4-aminophenylmethyl)phenylmethyl)benzene was obtained. Melting point was from 177.9° to 179.7° C.