Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC([N:8]1[CH2:12][CH2:11][C@H:10]([O:13][Si:14]([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:16])[CH3:15])[C@H:9]1[C@@H:21]([NH:23][C:24]1[CH:29]=[CH:28][C:27]([C:30]#[N:31])=[C:26]([Cl:32])[C:25]=1[CH3:33])[CH3:22])=O)(C)(C)C.C1(C)C=CC=CC=1>C(O)(C(F)(F)F)=O.C(Cl)Cl>[Si:14]([O:13][C@H:10]1[CH2:11][CH2:12][NH:8][C@@H:9]1[C@@H:21]([NH:23][C:24]1[CH:29]=[CH:28][C:27]([C:30]#[N:31])=[C:26]([Cl:32])[C:25]=1[CH3:33])[CH3:22])([C:17]([CH3:19])([CH3:20])[CH3:18])([CH3:16])[CH3:15]
Reactant: Cc1c(N[C@@H](C)[C@@H]2[C@@H](O[Si](C)(C)C(C)(C)C)CCN2C(=O)OC(C)(C)C)ccc(C#N)c1Cl
Solvent: ClCCl
Solvent: Cc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: Cc1c(N[C@@H](C)[C@H]2NCC[C@@H]2O[Si](C)(C)C(C)(C)C)ccc(C#N)c1Cl
Temperature: 25 °C
Reaction time: 5 h
Yield: 56.4 %

Procedure:
Intermediate 61H (825 mg, 1.67 mmol) was dried azeotropically with toluene (2×). The residue was taken up in 15% TFA in CH2Cl2 (10 mL) and stirred at rt for 5 h. Toluene (10 mL) was added and solvent was removed under vacuum. The product was purified by reverse phase HPLC (Phenomenex Luna 30×100 mm S5 C18, 10 min. grad, 25 mL/min, 20-100% B solvent, A=10% MeOH/water+0.1% TFA, B=90% MeOH/Water+0.1% TFA, 4 injections). Solvent was reduced to ˜10% volume and the product was then extracted into EtOAc, washed with sat. aqueous NaHCO3, dried over MgSO4 and filtered. Solvents were removed to provide the title compound (371 mg): MS (ES) m/z 394.53 [M+H]+
Reaction SMILES: [CH2:1]([O:15][C:16]1[O:20][C:19]([C:21]([OH:23])=[O:22])=[CH:18][CH:17]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14].C(Cl)(=O)C(Cl)=O.[C:30]([OH:39])(=[O:38])[C:31]1[C:32](=[CH:34][CH:35]=[CH:36][CH:37]=1)O.CCN(CC)CC>C(Cl)Cl.CN(C)C=O.CCOC(C)=O>[CH2:1]([O:15][C:16]1[O:20][C:19]([C:21]([O:23][C:37]2[CH:36]=[CH:35][CH:34]=[CH:32][C:31]=2[C:30]([OH:39])=[O:38])=[O:22])=[CH:18][CH:17]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14]
Reactant: CCCCCCCCCCCCCCOc1ccc(C(=O)O)o1
Reactant: O=C(O)c1ccccc1O
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCCCCCCCCCCCCCOc1ccc(C(=O)Oc2ccccc2C(=O)O)o1
Temperature: 0 °C
Yield: 50.6 %

Procedure:
To a cooled (0° C.) and stirred suspension of 5-(tetradecyloxy)furan-2-carboxylic acid (0.324 g, 1 mmol) in 10 mL of CH2Cl2 was added oxalyl chloride (0.135 mL, 1.5 mmol) and 2 drops of N,N-dimethylformamide. Immediate effervescence was observed. The solution was allowed to warm to room temperature with continued stirring until such a time that gas evolution had ceased and all suspended solids had dissolved. The solution was then cooled to 0° C. once more and salicylic acid (0.180 g, 1.3 mmol) and Et3N (3 mL) were added to the rapidly stirred reaction. After stirring for 2 hrs, the reaction was diluted with EtOAc (100 mL) and the organic phase was washed with 1M HCl (2×100 mL) and brine (100 mL) and then dried and concentrated to give a white solid residue. The crude material was purified by flash chromatography eluting with 5-40% EtOAc in Hexanes with 1% AcOH. The resulting material was further purified by recrystallization from CH2Cl2 and hexanes to yield 0.225 g (57%) of the title compound as a white crystalline material. 1H NMR (300 MHz, CDCl3) δ: 8.08 (dd, 1H), 7.62 (dt, 1H), 7.32-7.38 (m, 2H), 7.24 (dd, 1H), 5.39 (d, 1H), 4.18 (t, 2H), 1.80 (p, 2H), 1.2-1.5 (m, 22H), 0.88 (t, 3H).
Reaction SMILES: [CH3:1][C:2]1[C:3](OS(C(F)(F)F)(=O)=O)=[CH:4][C:5]2[C:6]([CH3:14])([CH3:13])[CH2:7][CH:8]=[C:9]([CH3:12])[C:10]=2[CH:11]=1.C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1.C([O-])([O-])=O.[Cs+].[Cs+].[NH2:75][C:76]1[CH:86]=[CH:85][C:79]([C:80]([O:82][CH2:83][CH3:84])=[O:81])=[CH:78][CH:77]=1>CC([O-])=O.CC([O-])=O.[Pd+2].C1(C)C=CC=CC=1>[CH3:1][C:2]1[C:3]([NH:75][C:76]2[CH:77]=[CH:78][C:79]([C:80]([O:82][CH2:83][CH3:84])=[O:81])=[CH:85][CH:86]=2)=[CH:4][C:5]2[C:6]([CH3:14])([CH3:13])[CH2:7][CH:8]=[C:9]([CH3:12])[C:10]=2[CH:11]=1
Reactant: CCOC(=O)c1ccc(N)cc1
Reactant: CC1=CCC(C)(C)c2cc(OS(=O)(=O)C(F)(F)F)c(C)cc21
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Product: CCOC(=O)c1ccc(Nc2cc3c(cc2C)C(C)=CCC3(C)C)cc1
Temperature: 100 °C
Reaction time: 48 h
Yield: 81.1 %

Procedure:
General Procedure H A solution of trifluoromethanesulfonic acid 3,5,8,8-tetramethyl-7,8-dihydronaphthalen-2-yl ester (Compound 35, 0.41 g, 1.2 mmol), Pd(OAc)2 (0.027 g, 0.12 mmol), BINAP (0.11 g, 0.18 mmol), Cs2CO3 (0.56 g, 1.72 mmol), ethyl 4-aminobenzoate (0.25 g, 1.5 mmol) and 5 mL of toluene was flushed with argon for 10 min, then stirred at 100° C. in a sealed tube for 48 h. After the reaction mixture had been cooled to room temperature, the solvent was removed, and the residue was purified by flash column (hexane:ethyl acetate=4:1) to give 0.34 g (80%) of the title compound as a yellowish solid.
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH2:18][CH:19]3[C:25](=[O:26])[N:24]([CH2:27][C:28]([N:30]([CH:37]([CH3:39])[CH3:38])[C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=4)=[O:29])[C:23]4[CH:40]=[CH:41][CH:42]=[CH:43][C:22]=4[N:21]([C:44]4[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=4)[C:20]3=[O:50])=[N:7][N:8]2C(OC(C)(C)C)=O)=[CH:4][CH:3]=1.C(O)(C(F)(F)F)=O>C(Cl)(Cl)Cl>[F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH2:18][CH:19]3[C:25](=[O:26])[N:24]([CH2:27][C:28]([N:30]([CH:37]([CH3:39])[CH3:38])[C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=4)=[O:29])[C:23]4[CH:40]=[CH:41][CH:42]=[CH:43][C:22]=4[N:21]([C:44]4[CH:45]=[CH:46][CH:47]=[CH:48][CH:49]=4)[C:20]3=[O:50])=[N:7][NH:8]2)=[CH:4][CH:3]=1
Reactant: CC(C)N(C(=O)CN1C(=O)C(Cc2nn(C(=O)OC(C)(C)C)c3cc(F)ccc23)C(=O)N(c2ccccc2)c2ccccc21)c1ccccc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClC(Cl)Cl
Product: CC(C)N(C(=O)CN1C(=O)C(Cc2n[nH]c3cc(F)ccc23)C(=O)N(c2ccccc2)c2ccccc21)c1ccccc1
Reaction time: 6 h
Yield: 70.4 %

Procedure:
400 mg of 2-[3-(6-Fluoro-1-tert-butoxycarbonyl-1H-indazol-3-ylmethyl)-2,4-dioxo-5-phenyl-2,3,4,5-tetrahydro-benzo[b][1,4]diazepin-1-yl)-N-isopropyl-N-phenyl-acetamide, prepared as in Intermediate 69, is dissolved in 10 mL of CHCl3 and 5 mL of TFA is added. The reaction mixture is stirred for 6 h and the solvents were removed in vacuo to afford 240 mg of the title compound: 1H NMR (400 MHz, DMSO-d6) δ7.82-6.88 (m, 18H), 4.77(m, 1H, J=6.8), 4.45 (d, 1H, J=16.8), 4.12 (m, 2H), 3.41 (m, 2H), 0.95 (t, 6H, J=6.8); low resolution MS (FAB) m/e 576 (MH+); Tr =10.31 min. (HPLC Column: Dynamax C-8 2 mL/min., 50-90% Acetonitrile in aqueous TFA (0.1% v/v) over 15 min.).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([OH:11])[CH:5]=[CH:6][C:7]=1[N+:8]([O-])=O.ClC1C=C(N)C=CC=1SC1N(C)C=CN=1>>[NH2:8][C:7]1[CH:6]=[CH:5][C:4]([OH:11])=[CH:3][C:2]=1[F:1]
Reactant: O=[N+]([O-])c1ccc(O)cc1F
Agent: Cn1ccnc1Sc1ccc(N)cc1Cl
Product: Nc1ccc(O)cc1F
Yield: 92.3 %

Procedure:
Compound 427A (1.49 g, 92%) was prepared from 3-fluoro-4-nitro-phenol (2.0 g, 12.7 mmol) by a route analogous to that used for the preparation of compound 426B. It is a yellow solid and has a retention time of 4.79 min (standard LC1 method, 8 min run). MS Found: (M+H)+=128.1
Reaction SMILES: [N+:1]([C:4]1[CH:58]=[CH:57][CH:56]=[CH:55][C:5]=1[CH2:6][O:7][C:8]([CH:10]([PH:36]([C:49]1[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=1)([C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1)[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)[N:11]1[CH:14]([CH2:15][C:16](O)=[O:17])[CH:13]([CH:19]([NH:21][C:22]([O:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=2[N+:32]([O-:34])=[O:33])=[O:23])[CH3:20])[C:12]1=[O:35])=[O:9])([O-:3])=[O:2].C(Cl)(=O)C([Cl:62])=O>C(Cl)Cl.CN(C=O)C>[N+:1]([C:4]1[CH:58]=[CH:57][CH:56]=[CH:55][C:5]=1[CH2:6][O:7][C:8]([CH:10]([PH:36]([C:49]1[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=1)([C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1)[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)[N:11]1[C@@H:14]([CH2:15][C:16]([Cl:62])=[O:17])[C@H:13]([CH:19]([NH:21][C:22]([O:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=2[N+:32]([O-:34])=[O:33])=[O:23])[CH3:20])[C:12]1=[O:35])=[O:9])([O-:3])=[O:2]
Reactant: CC(NC(=O)OCc1ccccc1[N+](=O)[O-])C1C(=O)N(C(C(=O)OCc2ccccc2[N+](=O)[O-])[PH](c2ccccc2)(c2ccccc2)c2ccccc2)C1CC(=O)O
Reactant: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CC(NC(=O)OCc1ccccc1[N+](=O)[O-])[C@@H]1C(=O)N(C(C(=O)OCc2ccccc2[N+](=O)[O-])[PH](c2ccccc2)(c2ccccc2)c2ccccc2)[C@H]1CC(=O)Cl
Reaction time: 0.08 h

Procedure:
1-(o-nitrobenzyloxycarbonyltriphenylphosphoranylmethyl)-3-(1-o-nitrobenzyloxycarbonylaminoethyl)-4-(carboxymethyl)-2-azetidinone (0.1320 g from the previous step) is dissolved in 5 ml CH2Cl2 and cooled to 0° under N2. Oxalyl chloride (0.040 ml, 0.44 mmole) is added dropwise over 5 minutes and then 1 drop of DMF is added. The mixture is stirred at 0° for 5 minutes and then at 25° C. for another 15 minutes. The solvent and excess oxalyl chloride are evaporated under reduced pressure. The residue is then desired acid chloride which is used without purification in the next step.
Reaction SMILES: [CH3:1][N:2]1[C:6]([CH3:7])=[C:5]([CH:8]=O)[CH:4]=[N:3]1.[C:10]([S:14]([NH2:16])=[O:15])([CH3:13])([CH3:12])[CH3:11]>C1COCC1.[Cl-].[Na+].O>[CH3:1][N:2]1[C:6]([CH3:7])=[C:5](/[CH:8]=[N:16]/[S:14]([C:10]([CH3:13])([CH3:12])[CH3:11])=[O:15])[CH:4]=[N:3]1
Reactant: CC(C)(C)S(N)=O
Reactant: Cc1c(C=O)cnn1C
Agent: [Cl-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: Cc1c(/C=N/S(=O)C(C)(C)C)cnn1C
Temperature: 25 °C
Yield: 97 %

Procedure:
A mixture of 1,5-dimethyl-1H-pyrazole-4-carbaldehyde (Zhumal Obshchei Khimii 1980, 50, 2370-5, 2.0 g, 16.1 mmol), tert-butylsulfinamide (2.05 g, 16.9 mmol), and Ti(OEt)4 (6.76 ml, 32.2 mmol) in THF (32 ml) was heated under reflux for 18 h under nitrogen. After being cooled to rt, the mixture was poured into brine (32 ml) with stirring. The resulting suspension was filtered through a plug of Celite, and the filter cake was washed with EtOAc. The filtrate was transferred to a separation funnel, and organic layer was washed with brine. Then the aqueous layer was washed with EtOAc and the combined organic extracts were dried over Na2SO4, and concentrated in vacuo. The crude material was purified by silica gel chromatography (CH2Cl2:MeOH=50:1-30:1) to give the desired product as a white solid (3.55 g, 97% yield). 1H NMR (300 MHz, CDCl3) δ 1.23 (9H, s), 2.52 (3H, s), 3.83 (3H, s), 7.81 (1H, s), 8.49 (1H, s). MS (ESI) m/z 228 (M+H)+
Reaction SMILES: S(O)(O)(=O)=O.[CH3:6][N:7]1[C:11]([NH2:12])=[C:10]([NH2:13])[CH:9]=[N:8]1.[CH2:14]([O:21][C:22]([NH:24][C@@H:25]([CH2:29][CH2:30][CH2:31][NH:32][C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[C:26](O)=[O:27])=[O:23])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C(N(CC)CC)C.Cl.CN(C)CCCN=C=NCC>C(Cl)(Cl)Cl>[NH2:12][C:11]1[N:7]([CH3:6])[N:8]=[CH:9][C:10]=1[NH:13][C:26]([C@@H:25]([NH:24][C:22](=[O:23])[O:21][CH2:14][C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1)[CH2:29][CH2:30][CH2:31][NH:32][C:33](=[O:34])[O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:27]
Reactant: CC(C)(C)OC(=O)NCCC[C@H](NC(=O)OCc1ccccc1)C(=O)O
Reactant: Cn1ncc(N)c1N
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: O=S(=O)(O)O
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: Cn1ncc(NC(=O)[C@H](CCCNC(=O)OC(C)(C)C)NC(=O)OCc2ccccc2)c1N
Temperature: 25 °C
Reaction time: 15 h

Procedure:
To a suspension of 1-methyl-1H-pyrazole-4,5-diamine sulfate (2.10 g), (2S)-2-[(benzyloxycarbonyl)amino]-5-[(tert-butoxycarbonyl)amino]pentanoic acid (3.66 g) and triethylamine (3.04 g) in chloroform (50 ml) was added N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (1.91 g), and the mixture was stirred at room temperature for 15 hours. The reaction mixture was washed successively with 10% aqueous citric acid solution, brine and saturated aqueous sodium hydrogencarbonate solution. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give a crude product of 1-benzyl 4-tert-butyl {(1S)-1-[(5-amino-1-methyl-1H-pyrazol-4-yl)carbamoyl]tetramethylene}biscarbamate as an oil. The crude product was used directly in the next step without further purification.
Reaction SMILES: [Na].Cl.[C:3]([NH2:9])(=[NH:8])[CH2:4][CH2:5][CH2:6][CH3:7].[C:10]1([CH3:19])[CH:15]=[CH:14][C:13]([N:16]=[C:17]=[O:18])=[CH:12][CH:11]=1>CC(C)=O>[C:10]1([CH3:19])[CH:15]=[CH:14][C:13]([NH:16][C:17]([NH:8][C:3](=[NH:9])[CH2:4][CH2:5][CH2:6][CH3:7])=[O:18])=[CH:12][CH:11]=1
Reactant: CCCCC(=N)N
Reactant: Cc1ccc(N=C=O)cc1
Agent: Cl
Agent: [Na]
Solvent: CC(C)=O
Product: CCCCC(=N)NC(=O)Nc1ccc(C)cc1

Procedure:
Following a procedure similar to that described in Example 23 but using 2.3 g. sodium in 300 ml. dry acetone, 13.6 g. valeramidine hydrochloride and 13.3 g. 4-tolyl isocyanate in 100 ml. dry acetone, there was obtained after recrystallization from acetonitrile 10.6 g. 1-(4-tolyl)-3-(pentanimidoyl)urea hydrochloride; m.p. 159°-160°C.
Reaction SMILES: CO[C:3]1[C:4]([N+:34]([O-:36])=[O:35])=[C:5]([C:15]2[C:20]([N+:21]([O-:23])=[O:22])=[CH:19][C:18]([N+:24]([O-:26])=[O:25])=[C:17]([NH:27][CH2:28][CH2:29][OH:30])[C:16]=2[N+:31]([O-:33])=[O:32])[C:6]([N+:12]([O-:14])=[O:13])=[CH:7][C:8]=1[N+:9]([O-:11])=[O:10].[NH3:37]>CO>[NH2:37][C:7]1[C:6]([N+:12]([O-:14])=[O:13])=[C:5]([C:15]2[C:20]([N+:21]([O-:23])=[O:22])=[CH:19][C:18]([N+:24]([O-:26])=[O:25])=[C:17]([NH:27][CH2:28][CH2:29][OH:30])[C:16]=2[N+:31]([O-:33])=[O:32])[C:4]([N+:34]([O-:36])=[O:35])=[CH:3][C:8]=1[N+:9]([O-:11])=[O:10]
Reactant: COc1c([N+](=O)[O-])cc([N+](=O)[O-])c(-c2c([N+](=O)[O-])cc([N+](=O)[O-])c(NCCO)c2[N+](=O)[O-])c1[N+](=O)[O-]
Reactant: N
Solvent: CO
Product: Nc1c([N+](=O)[O-])cc([N+](=O)[O-])c(-c2c([N+](=O)[O-])cc([N+](=O)[O-])c(NCCO)c2[N+](=O)[O-])c1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A mixture of 0.55 g (0.0011 mole) of 3-methoxy-3'-(2-hydroxyethylamino)-2,2',4,4',6,6'-hexanitrobiphenyl and 10 ml of methanol was stirred in an ice bath while a solution of gaseous ammonia in methanol was added until the mixture remained basic to damp pH paper. The mixture was then kept basic with ammonia as it was stirred at room temperature for 3 hours. After standing overnight, the insoluble yellow solid product 3-amino-3'-(2-hydroxyethylamino)-2,2',4,4',6,6'-hexanitrobiphenyl was removed to give 0.45 g (85%), mp 246° C. dec; 1H NMR (acetone-d6 +D2O): 3.28 (t, 2H), 3.90 (t, 2H), 9.50 (overlapping s, 2H).
Reaction SMILES: [OH-].[K+].[Cl:3][C:4]1[CH:26]=[CH:25][CH:24]=[CH:23][C:5]=1[C:6]([NH:8][CH:9]1[C:18]2[C:13](=[CH:14][CH:15]=[C:16]([C:19]([O:21]C)=[O:20])[CH:17]=2)[O:12][CH2:11][CH2:10]1)=[O:7]>C(O)C.O>[Cl:3][C:4]1[CH:26]=[CH:25][CH:24]=[CH:23][C:5]=1[C:6]([NH:8][CH:9]1[C:18]2[C:13](=[CH:14][CH:15]=[C:16]([C:19]([OH:21])=[O:20])[CH:17]=2)[O:12][CH2:11][CH2:10]1)=[O:7]
Reactant: COC(=O)c1ccc2c(c1)C(NC(=O)c1ccccc1Cl)CCO2
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: O=C(O)c1ccc2c(c1)C(NC(=O)c1ccccc1Cl)CCO2
Temperature: 25 °C
Reaction time: 16 h
Yield: 85 %

Procedure:
KOH (1 mol/1 aq) (2 eq.) was added to a suspension of methyl 4-(2-chlorobenzamido)chroman-6-carboxylate (B-11) (2.227 mmol, 1 eq.) in a mixture of ethanol (13 ml) and water (4.5 ml). The reaction mixture was stirred at room temperature for 16 h. Ethanol was removed in vacuo and the aqueous residue was diluted with diethyl ether (20 ml) and water (20 ml). The phases were separated and the aqueous phase was acidified with 1N HCl to pH 3. The white precipitate was filtered out, washed with aqueous HCl solution and diethyl ether and finally dried in vacuo to obtain the desired product (E-11). Yield: 85%
Reaction SMILES: Br[C@H:2]([C@H:7]([CH2:9]Br)[OH:8])[C:3]([O:5][CH3:6])=[O:4].[C:11]([O-:14])(=[O:13])[CH3:12].[K+]>CN(C)C=O.C(OCC)(=O)C.[I-].[K+]>[C:11]([O:14][CH2:9][C@@H:7]1[O:8][C@@H:2]1[C:3]([O:5][CH3:6])=[O:4])(=[O:13])[CH3:12]
Reactant: CC(=O)[O-]
Reactant: COC(=O)[C@H](Br)[C@@H](O)CBr
Agent: [I-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COC(=O)[C@H]1O[C@H]1COC(C)=O
Temperature: 52.5 °C
Reaction time: 8 h
Yield: 99.3 %

Procedure:
The general procedure of Manchand, et. al. (Manchand, et al., 1988) is employed. Methyl 2,4-dibromo-2,4-dideoxy-L-threonate (131 g, 474 mmol) is added to a stirred solution of potassium acetate (102 g, 1.04 mol) and potassium iodide (3.94 g, 23.8 mmol) in dimethyl formamide (500 mL). This mixture is stirred under nitrogen gas at 50-55° C. for 4 hours and overnight at room temperature. The reaction mixture is diluted with ethyl acetate (1 L) and filtered. The filter cake is washed with ethyl acetate (250 mL). The combined ethyl acetate portion is washed with saturated sodium bicarbonate solution (500 mL) and saturated brine (2×500 mL) and dried over magnesium sulfate. The solvent is removed to yield the title compound as a dark oil (82.0 g, 99% theoretical yield).
Reaction SMILES: Cl.[CH3:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][NH2:10])=[CH:5][CH:4]=1.C(=O)([O-])[O-].[K+].[K+].[C:17](OC(=O)C)(=[O:19])[CH3:18]>C(OC(C)C)(=O)C.O>[CH3:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][NH:10][C:17](=[O:19])[CH3:18])=[CH:5][CH:4]=1
Reactant: CC(=O)OC(C)=O
Reactant: Cc1ccc(NN)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC(=O)OC(C)C
Product: CC(=O)NNc1ccc(C)cc1
Temperature: 57.5 °C

Procedure:
104.8 g of 1-(4-methylphenyl)hydrazine hydrochloride are suspended in 525 ml of isopropyl acetate, a solution of 104.8 g of potassium carbonate in 300 ml of water is added and then the mixture is stirred until the solid has disappeared. 77.4 g of acetic anhydride are added while maintaining the temperature below 20° C. and then the mixture is left stirring at 20° C. A precipitate is observed to form, which precipitate disappears when the mixture is heated at approximately 55-60° C. The organic phase is washed twice with 200 ml of water and is then cooled at 0-5° C. overnight. The product formed is recovered by filtration and is then washed twice with 100 ml of MTBE.
Reaction SMILES: C[C:2](CC(OC)(C)C)=[O:3].O=O.[C:12]([N:16]=[N:17][C:18]([O:24][OH:25])([CH2:20][CH:21]([CH3:23])[CH3:22])[CH3:19])([CH3:15])([CH3:14])[CH3:13]>>[C:12]([N:16]=[N:17][C:18]([O:24][OH:25])([CH2:20][C:21]([O:3][CH3:2])([CH3:22])[CH3:23])[CH3:19])([CH3:13])([CH3:15])[CH3:14]
Reactant: CC(C)CC(C)(N=NC(C)(C)C)OO
Reactant: COC(C)(C)CC(C)=O
Agent: O=O
Product: COC(C)(C)CC(C)(N=NC(C)(C)C)OO
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A solution of 60 grams of the t-butylhydrazone of pentoxone (4-methoxy-4-methyl-pentanone-2) in 60 grams of odorless mineral spirits was oxidized by passing oxygen through the solution as in Example II. The oxidation was initiated at 30° C by adding 2 drops of a 50% solution of 2-t-butylazo-2-hydroperoxy-4-methylpentane. The oxidation was 1/2 complete after 50 minutes at 30° C. The temperature was lowered to 20° C. and an additional 1 hour was required before the oxidation was complete. It was then cooled to 0° C. by circulating ice water through the jacket and weighed into a cold poly bottle and stored at -30° C. or below. The yield was 126 g (97% of theory). The solution is not sensitive to shock.
Reaction SMILES: [O:1]=[C:2]1[NH:8][C:7]2[CH:9]=[CH:10][CH:11]=[CH:12][C:6]=2[N:5]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH2:4][CH2:3]1.[H-].[Na+].[CH3:21][O:22][CH2:23]Cl>O1CCCC1>[CH3:21][O:22][CH2:23][N:8]1[C:7]2[CH:9]=[CH:10][CH:11]=[CH:12][C:6]=2[N:5]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH2:4][CH2:3][C:2]1=[O:1]
Reactant: O=C1CCN(c2ccccc2)c2ccccc2N1
Reactant: COCCl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COCN1C(=O)CCN(c2ccccc2)c2ccccc21
Temperature: 0 °C
Reaction time: 1 h
Yield: 99 %

Procedure:
In an argon stream, 2-oxo-5-phenyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepine (40.4 g) was added to 60% sodium hydride (8.84 g) suspended in absolute tetrahydrofuran (500 ml) at 0° C. The mixture was stirred for one hour at 0° C., and chloromethyl methyl ether (20.5 g) was added thereto, followed by stirring for two hours and 30 minutes at room temperature. The reaction mixture was concentrated under reduced pressure, and ice-water was added thereto, followed by extraction with chloroform. The organic layer was washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, to thereby obtain 47.4 g of the title compound as a yellow oil (yield: 98.8%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([CH2:11][C:12]2[CH:17]=[C:16]([F:18])[CH:15]=[CH:14][C:13]=2[F:19])(=[O:10])=[O:9])=[CH:4][CH:3]=1.[C:20]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])(=[O:23])[CH:21]=[CH2:22].CCCCCC>CN(C)C=O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([CH:11]([C:12]2[CH:17]=[C:16]([F:18])[CH:15]=[CH:14][C:13]=2[F:19])[CH2:22][CH2:21][C:20]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: O=S(=O)(Cc1cc(F)ccc1F)c1ccc(Cl)cc1
Reactant: C=CC(=O)OC(C)(C)C
Solvent: CCCCCC
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)CCC(c1cc(F)ccc1F)S(=O)(=O)c1ccc(Cl)cc1
Yield: 98.8 %

Procedure:
In N,N-dimethylformamide (4 ml) was dissolved the 2-[(4-chlorophenyl)sulfonylmethyl]-1,4-difluorobenzene (101 mg, 0.333 mmol) obtained in Example 5. After addition thereto of t-butyl acrylate (146 μl, 1.00 mmol) and 1,8-diazabicyclo[5,4,0]undece-7-en (151 μl, 1.00 mmol), stirring was conducted at room temperature for 1 week. The reaction mixture was then concentated. The residue thus obtained was subjected to flash chromatoraphy on a silica gel column, and the fraction obtained from the hexane:ethyl acetate=4:1 eluate was concentrated, whereby the title compound (142 mg, 0.329 mmol, 99%) was obtained as a colorless oil.
Reaction SMILES: [C:1]([CH:3]([CH:7]1[C:11]([Cl:12])=[C:10](Cl)C(=O)O1)[C:4]([NH2:6])=[O:5])#[N:2].Cl.[F:16][C:17]1[CH:22]=[CH:21][C:20]([CH2:23][NH2:24])=[C:19]([S:25]([CH3:28])(=[O:27])=[O:26])[CH:18]=1.C(=O)([O-])[O-].[K+].[K+].[OH-].[Na+]>C(O)C>[ClH:12].[Cl:12][C:11]1[CH:7]=[C:3]([C:4]([NH2:6])=[O:5])[C:1](=[NH:2])[N:24]([CH2:23][C:20]2[CH:21]=[CH:22][C:17]([F:16])=[CH:18][C:19]=2[S:25]([CH3:28])(=[O:27])=[O:26])[CH:10]=1
Reactant: N#CC(C(N)=O)C1OC(=O)C(Cl)=C1Cl
Reactant: CS(=O)(=O)c1cc(F)ccc1CN
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: CS(=O)(=O)c1cc(F)ccc1Cn1cc(Cl)cc(C(N)=O)c1=N
Yield: 48.5 %

Procedure:
A mixture of 2-cyano-2-(3,4-dichloro-5-oxo-2,5-dihydrofuran-2-yl)acetamide (3.0 g), 1-[4-fluoro-2-(methylsulfonyl)phenyl]methanamine hydrochloride (3.67 g) and potassium carbonate (5.29 g) was stirred in ethanol (50 ml) at 85° C. for 24 hr. The reaction mixture was treated with 1N sodium hydroxide solution, and extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by basic silica gel column chromatography (ethyl acetate:hexane=4:1). The obtained yellow solid was dissolved in methanol, and 4N hydrogen chloride-ethyl acetate solution (4 ml) was added. The mixture was crystallized from methanol-ethyl acetate, and the precipitated crystals were collected by filtration, and recrystallized to give the title compound (1.22 g).
Reaction SMILES: [CH3:1][C:2](=[CH2:5])[CH2:3][NH2:4].[CH3:6][C:7]1([CH3:16])[CH2:12][C:11](=O)[CH2:10][C:9]([CH3:15])([CH3:14])[NH:8]1>C1(C)C=CC=CC=1>[CH3:6][C:7]1([CH3:16])[CH2:12][C:11](=[N:4][CH2:3][C:2]([CH3:1])=[CH2:5])[CH2:10][C:9]([CH3:15])([CH3:14])[NH:8]1
Reactant: CC1(C)CC(=O)CC(C)(C)N1
Reactant: C=C(C)CN
Solvent: Cc1ccccc1
Product: C=C(C)CN=C1CC(C)(C)NC(C)(C)C1
Temperature: 25 °C
Yield: 82.8 %

Procedure:
400 g of 2-methylallylamine are dissolved in 400 ml of toluene in a 2.5 liter sulfonating flask, and 450 g of microfilter are added. A solution of 700 g of 2,2,6,6-tetramethyl-4-piperidone in 300 ml of toluene is then added dropwise in such a manner that the reaction temperature is kept at 30°-35° C. After the addition is completed, stirring is maintained for 6 hours at room temperature. The mixture is filtered off from the microfilter, and the solvent is removed in a rotary evaporator. Distillation of the residue yields 778 g of N-(2,2,6,6-tetramethyl-4- piperidylidene)-2-methylallylamine, corresponding to 83% of theory, in the form of a colourless liquid having a boiling point of 63° C. at 40 Pa.