Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([NH:20][C:21]1[S:22][CH:23]=[C:24](/[C:26](=[N:53]/[O:54][CH2:55][C:56]([O:58][CH:59]([C:66]2[CH:71]=[CH:70][CH:69]=[CH:68][CH:67]=2)[C:60]2[CH:65]=[CH:64][CH:63]=[CH:62][CH:61]=2)=[O:57])/[C:27]([NH:29][CH:30]2[C:51](=[O:52])[N:32]3[C:33]([C:39]([O:41][CH2:42][C:43]4[CH:48]=[CH:47][C:46]([O:49][CH3:50])=[CH:45][CH:44]=4)=[O:40])=[C:34]([CH2:37]Cl)[CH2:35][S:36][C@H:31]23)=[O:28])[N:25]=1)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[SH:72][C:73]1[S:74][C:75]2[C:76]([N:81]=1)=[N:77][CH:78]=[CH:79][CH:80]=2.SC1SC2C=CN=CC=2N=1>>[C:1]([NH:20][C:21]1[S:22][CH:23]=[C:24](/[C:26](=[N:53]/[O:54][CH2:55][C:56]([O:58][CH:59]([C:66]2[CH:71]=[CH:70][CH:69]=[CH:68][CH:67]=2)[C:60]2[CH:65]=[CH:64][CH:63]=[CH:62][CH:61]=2)=[O:57])/[C:27]([NH:29][CH:30]2[C:51](=[O:52])[N:32]3[C:33]([C:39]([O:41][CH2:42][C:43]4[CH:48]=[CH:47][C:46]([O:49][CH3:50])=[CH:45][CH:44]=4)=[O:40])=[C:34]([CH2:37][S:72][C:73]4[S:74][C:75]5[C:76]([N:81]=4)=[N:77][CH:78]=[CH:79][CH:80]=5)[CH2:35][S:36][C@H:31]23)=[O:28])[N:25]=1)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1ccc(COC(=O)C2=C(CCl)CS[C@@H]3C(NC(=O)/C(=N\OCC(=O)OC(c4ccccc4)c4ccccc4)c4csc(NC(c5ccccc5)(c5ccccc5)c5ccccc5)n4)C(=O)N23)cc1
Reactant: Sc1nc2ncccc2s1
Agent: Sc1nc2cnccc2s1
Product: COc1ccc(COC(=O)C2=C(CSc3nc4ncccc4s3)CS[C@@H]3C(NC(=O)/C(=N\OCC(=O)OC(c4ccccc4)c4ccccc4)c4csc(NC(c5ccccc5)(c5ccccc5)c5ccccc5)n4)C(=O)N23)cc1
Yield: 71.1 %

Procedure:
Using 301 mg of p-methoxybenzyl 7-{(Z)-2-(2-tritylaminothiazol-4-yl)-2-diphenylmethoxycarbonylmethoxyiminoacetamido}-3-chloromethyl-3-cephem-4-carboxylate and 60 mg of 2-mercaptothiazolo[4,5-b]pyridine in place of p-methoxybenzyl 7-{(Z)-2-(2-tritylaminothiazol-4-yl)-2-methoxyiminoacetamido}-3-chloromethyl-3-cephem-4-carboxylate and 2-mercaptothiazolo[4,5-c]pyridine, respectively, the reaction and purification were carried out in the same manner as in Example 1(a) to obtain 242 mg of the title compound in a yield of 71%.
Reaction SMILES: [NH2:1][C:2]1[C:7]([OH:8])=[C:6]([Br:9])[CH:5]=[CH:4][N:3]=1.[Cl:10]Cl>>[NH2:1][C:2]1[C:7]([OH:8])=[C:6]([Br:9])[C:5]([Cl:10])=[CH:4][N:3]=1
Reactant: ClCl
Reactant: Nc1nccc(Br)c1O
Product: Nc1ncc(Cl)c(Br)c1O

Procedure:
The procedure of Example I-12 is followed with 2-amino-4 -bromo-3-pyridinol and chlorine to give 2-amino- 4-bromo-5-chloro-3-pyridinol.
Reaction SMILES: Cl.[NH2:2][NH:3][C:4]([NH2:6])=[O:5].[C:7]([O:12][CH2:13][CH3:14])(=[O:11])[C:8]([CH3:10])=O.C([O-])(=O)C.[Na+]>O>[CH2:13]([O:12][C:7](=[O:11])[C:8](=[N:2][NH:3][C:4](=[O:5])[NH2:6])[CH3:10])[CH3:14]
Reactant: CCOC(=O)C(C)=O
Reactant: NNC(N)=O
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Product: CCOC(=O)C(C)=NNC(N)=O
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
A 100 mL round bottomed flask is charged with semicarbazide hydrochloride (2 g, 17.93 mmol), ethyl pyruvate (11.8 mL) and sodium ethanoate (2.97 g). Then water (9 mL) is added. The mixture is stirred at room temperature for 90 minutes, then it is filtered and solids are washed with more water. White solid is dried under vacuum in an oven (40° C.) overnight. 2.66 g of ethyl-2-(carbamoylhydrazono)-propanoate is obtained pure. Phosphoryl chloride (3.28 mL) is added dropwise to dimethylformamide (7.13 mL) at 0° C. Cooling bath is removed to reach room temperature Then, the mixture is heated to 40° C. and ethyl-2-(carbamoylhydrazono)propanoate previously obtained (2.66 g, 15.36 mmol) is added in several portions over 15-20 min (gas evolution during the addition). When internal temperature is 55° C., heating bath is removed so internal temperature is maintained in the range 60-70° C. Then, the mixture is heated to 80° C. Almost no more gas evolution is observed once the reaction is stabilized at 80° C. The resulting suspension is stirred at 80° C. for 2 h. Reaction mixture is poured over ice/water (30 mL) mixture and stirred to get a suspension. 50% solution of sodium hydroxide is added dropwise until pH 10 is reached. The solution is stirred at 50° C. for 5 min. Solution is then cooled with ice/water bath and 35% aqueous solution of hydrochloric acid is added until pH 7. The mixture is extracted with ethyl acetate. Organic layer is decanted, dried over magnesium sulfate and solvent is evaporated under reduced pressure. The residue is triturated with hexane and some drops of dichloromethane to give 1.6 g of ethyl 4-formyl-1H-pyrazole-3-carboxylate that is used in the next step without further purification. MS (m/z): 169 (M+1).
Reaction SMILES: [F:1][C:2]([F:29])([F:28])[C:3]1[CH:12]=[C:11]2[C:6]([C:7]([NH:13][C:14]3[CH:27]=[CH:26][C:17]([C:18]([N:20]4[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]4)=[O:19])=[CH:16][CH:15]=3)=[CH:8][CH:9]=[N:10]2)=[CH:5][CH:4]=1.[Cl:30][C:31]1[CH:32]=[C:33]([N:37]=[C:38]=[O:39])[CH:34]=[CH:35][CH:36]=1>C(Cl)Cl>[Cl:30][C:31]1[CH:32]=[C:33]([NH:37][C:38]([N:23]2[CH2:24][CH2:25][N:20]([C:18](=[O:19])[C:17]3[CH:26]=[CH:27][C:14]([NH:13][C:7]4[C:6]5[C:11](=[CH:12][C:3]([C:2]([F:1])([F:28])[F:29])=[CH:4][CH:5]=5)[N:10]=[CH:9][CH:8]=4)=[CH:15][CH:16]=3)[CH2:21][CH2:22]2)=[O:39])[CH:34]=[CH:35][CH:36]=1
Reactant: O=C(c1ccc(Nc2ccnc3cc(C(F)(F)F)ccc23)cc1)N1CCNCC1
Reactant: O=C=Nc1cccc(Cl)c1
Solvent: ClCCl
Product: O=C(Nc1cccc(Cl)c1)N1CCN(C(=O)c2ccc(Nc3ccnc4cc(C(F)(F)F)ccc34)cc2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 90 %

Procedure:
To a suspension of 4-[4-[[7-(trifluoromethyl)-4-quinolinyl]amino]benzoyl]piperazine (2.0 g, 0.005 mol) in 15 ml of methylene chloride is added a solution of m-chlorophenyl isocyanate in 10 ml of methylene chloride at 0° C. under nitrogen. The resulting suspension is stirred for 1 hour at room temperature. The above mixture is then filtered and the white solid residue is washed with more methylene chloride and dried. This is recrystallized from methanol/methylene chloride to give 2.5 g (90%) of white crystalline 1-[[(3-chlorophenyl)amino]carbonyl]-4-[4-[[7-(trifluoromethyl)-4-quinolinyl]amino]benzoyl]piperazine of melting point 266°-268° C.
Reaction SMILES: [NH2:1][CH2:2][CH:3]([OH:5])[CH3:4].C([O-])([O-])=O.[K+].[K+].[CH3:12][C:13]([C:15](Cl)=[O:16])=[CH2:14]>C(#N)C.CO>[OH:5][CH:3]([CH3:4])[CH2:2][NH:1][C:15](=[O:16])[C:13]([CH3:14])=[CH2:12]
Reactant: CC(O)CN
Reactant: C=C(C)C(=O)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: CC#N
Product: C=C(C)C(=O)NCC(C)O
Temperature: 25 °C

Procedure:
3.75 g of 1-amino-2-propanol (0.05 mol) were placed in a three-necked flask, equipped with dropping funnel and gas inlet and gas outlet pipe, together with 30 ml of acetonitrile (anhydrous) and 13.79 g of K2CO3 (0.1 mol), and cooled to 0° C. in an ice bath. 6.18 g of methacryl chloride (0.06 mol), dissolved in 30 ml of acetonitrile, were added dropwise over 30 minutes with constant stirring and gentle passage of nitrogen. After stirring for a further 60 minutes with ice cooling, the mixture was allowed to warm to room temperature and was stirred for a further 30 minutes. The batch was filtered through a glass frit and the precipitate was discarded. The filtrate was concentrated in a rotary evaporator until a viscous oil was produced. This was dissolved in 30 ml of methanol and separated from any precipitate which appeared. The filtrate was again concentrated in a rotary evaporator and the residual amounts of the solvent were removed in a high vacuum. The yield was 6.66 g.
Reaction SMILES: [C:1]1([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:6]=[CH:5][C:4]([O:7][CH:8]([N:15]2[CH:19]=[N:18][CH:17]=[N:16]2)[CH:9]([OH:14])[C:10]([CH3:13])([CH3:12])[CH3:11])=[CH:3][CH:2]=1.[CH3:26][O:27][CH2:28][N:29]=[C:30]=[O:31].C(N(CC)CC)C.C([O-])(=O)CCCCCCCCCCC.C([O-])(=O)CCCCCCCCCCC.C([Sn+2]CCCC)CCC>O1CCCC1>[C:1]1([C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH:6]=[CH:5][C:4]([O:7][CH:8]([N:15]2[CH:19]=[N:18][CH:17]=[N:16]2)[CH:9]([O:14][C:30](=[O:31])[NH:29][CH2:28][O:27][CH3:26])[C:10]([CH3:13])([CH3:12])[CH3:11])=[CH:3][CH:2]=1
Reactant: CC(C)(C)C(O)C(Oc1ccc(-c2ccccc2)cc1)n1cncn1
Reactant: COCN=C=O
Agent: CCCCCCCCCCCC(=O)[O-]
Agent: CCCC[Sn+2]CCCC
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COCNC(=O)OC(C(Oc1ccc(-c2ccccc2)cc1)n1cncn1)C(C)(C)C
Yield: 82.9 %

Procedure:
505 g (1.5 moles) of 1-(4-biphenylyloxy)-3,3-dimethyl-1-(1,2,4-triazol-1-yl)-butan-2-ol (A form) and 140 g (1.6 moles) of methoxymethyl isocyanate were heated under reflux in 2.5 liters of tetrahydrofuran in the presence of 40 ml of triethylamine and 1 ml of dibutyl-tin dilaurate for 48 hours. Thereafter, the solvent was stripped off in vacuo and 3 liters of petroleum ether were added to the residue. The crystalline precipitate formed was extracted by stirring with 1.5 liters of diisopropyl ether. 528 g (82.5% of theory) of 1-(4-biphenylyloxy)-3,3-dimethyl-2-methoxymethylcarbamoyloxy-1-(1,2,4-triazol-1-yl)-butane (A form) of melting point 95°-98° C. were obtained.
Reaction SMILES: [CH3:1]C(C)([O-])C.[K+].[C:7]1([N:13]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:14]2[CH:21]=[CH:20][C:17]([CH:18]=O)=[CH:16][CH:15]=2)[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C1COCC1.ClCCl>[C:7]1([N:13]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:14]2[CH:21]=[CH:20][C:17]([CH:18]=[CH2:1])=[CH:16][CH:15]=2)[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: CC(C)(C)[O-]
Reactant: O=Cc1ccc(N(c2ccccc2)c2ccccc2)cc1
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Agent: [K+]
Solvent: ClCCl
Solvent: C1CCOC1
Product: C=Cc1ccc(N(c2ccccc2)c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 20 h
Yield: 85.9 %

Procedure:
19 g (53 mmol) of methyltriphenylphosphonium bromide [1779-49-3] are suspended in dried THF under protective gas, and 6 g (53 mmol) of potassium tert-butoxide are added in portions at 0° C.; an immediate colour change to orange occurs. 14 g (51.2 mmol) of N,N-diphenyl-p-aminobenzaldehyde [4181-05-9] are added to the reaction solution at 0° C. The mixture is warmed to room temperature and stirred for a further 20 h. The solvent is stripped off in vacuo, the residue is taken up in dichloromethane, the solution is extracted with water, dried over magnesium sulfate, filtered, and the solvent is stripped off in vacuo. The yellow oil obtained is chromatographed over silica gel, giving 12 g (44 mmol) (86%) of a white solid having a purity of 99.5%.
Reaction SMILES: S(Cl)(Cl)=O.[CH2:5]([C:9]1[NH:10][C:11]2[CH:17]=[C:16]([C:18]([OH:20])=O)[CH:15]=[CH:14][C:12]=2[N:13]=1)[CH2:6][CH2:7][CH3:8].[NH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1O.[OH-].[Na+]>CN1CCCC1=O>[CH2:5]([C:9]1[NH:10][C:11]2[CH:17]=[C:16]([C:18]3[O:20][C:23]4[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=4[N:21]=3)[CH:15]=[CH:14][C:12]=2[N:13]=1)[CH2:6][CH2:7][CH3:8]
Reactant: Nc1ccccc1O
Reactant: CCCCc1nc2ccc(C(=O)O)cc2[nH]1
Agent: [Na+]
Agent: [OH-]
Solvent: O=S(Cl)Cl
Solvent: CN1CCCC1=O
Product: CCCCc1nc2ccc(-c3nc4ccccc4o3)cc2[nH]1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
1.43 g (12 mMol) of thionyl chloride are added dropwise at 10° C. with stirring to a suspension of 2.52 g (10 mMol) of 2-n-butyl-benzimidazole-5-carboxylic acid in 15 ml of N-methylpyrrolidinone. The mixture is stirred for a further 15 minutes at ambient temperature, then 1.31 g (11 mMol) of 2-aminophenol are added and the mixture is heated to 140° C. for 2 hours. The mixture is then poured onto about 50 g of ice and 5 ml of 30% sodium hydroxide solution are added with stirring. The crude product precipitated is suction filtered and purified by column chromatography (300 g of silica gel; eluant:methylene chloride+3% ethanol).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[OH:11])[C:5]([OH:7])=O.C1N=CN([C:17](N2C=NC=C2)=[O:18])C=1.[BH4-].[Na+].Cl>C1COCC1.O>[OH:7][CH2:5][C:4]1[CH:8]=[CH:9][C:10]2[O:11][C:17](=[O:18])[NH:1][C:2]=2[CH:3]=1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: Nc1cc(C(=O)O)ccc1O
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: O=c1[nH]c2cc(CO)ccc2o1
Temperature: 25 °C
Reaction time: 1 h
Yield: 54 %

Procedure:
To a solution of 2.06 g of 3-amino-4-hydroxybenzoic acid in 20.6 ml of THF was added 4.81 g of CDI, followed by stirring at room temperature for 1 hour. The reaction mixture was added dropwise to a mixed liquid of 3.06 g of sodium borohydride in 20.6 ml of THF and 8.26 ml of water, cooled to 0° C., which had been separately prepared, followed by stirring overnight. 1 M hydrochloric acid was added thereto, followed by extracting with ethyl acetate, and washing with a saturated aqueous sodium chloride solution. The organic layer was dried over anhydrous magnesium sulfate and then concentrated under reduced pressure to obtain 1.2 g of 5-(hydroxymethyl)-1,3-benzoxazol-2(3H)-one.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:6]([S:21]([CH3:24])(=[O:23])=[O:22])=[CH:7][C:8]2[N:12]3[CH2:13][CH2:14][NH:15][C@H:16]([CH:17]([CH3:19])[CH3:18])[C:11]3=[N:10][C:9]=2[CH:20]=1)=[O:4].Cl[C:26]1[N:31]=[C:30]([C:32]([F:35])([F:34])[F:33])[C:29]([C:36]([OH:39])([CH3:38])[CH3:37])=[CH:28][N:27]=1.CCN(C(C)C)C(C)C>O1CCOCC1>[CH3:1][O:2][C:3]([C:5]1[C:6]([S:21]([CH3:24])(=[O:22])=[O:23])=[CH:7][C:8]2[N:12]3[CH2:13][CH2:14][N:15]([C:26]4[N:31]=[C:30]([C:32]([F:33])([F:34])[F:35])[C:29]([C:36]([OH:39])([CH3:37])[CH3:38])=[CH:28][N:27]=4)[C@H:16]([CH:17]([CH3:19])[CH3:18])[C:11]3=[N:10][C:9]=2[CH:20]=1)=[O:4]
Reactant: COC(=O)c1cc2nc3n(c2cc1S(C)(=O)=O)CCN[C@@H]3C(C)C
Reactant: CC(C)(O)c1cnc(Cl)nc1C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: COC(=O)c1cc2nc3n(c2cc1S(C)(=O)=O)CCN(c1ncc(C(C)(C)O)c(C(F)(F)F)n1)[C@@H]3C(C)C
Temperature: 165 °C
Reaction time: 21 h
Yield: 61.7 %

Procedure:
(R)-methyl-1-isopropyl-7-(methylsulfonyl)-1,2,3,4-tetrahydrobenzo[4,5]imidazo[1,2-a]pyrazine-8-carboxylate (224 mg, 0.639 mmol) and 2-(2-chloro-4-(trifluoromethyl)pyrimidin-5-yl)propan-2-ol (192 mg, 0.799 mmol) were combined in a small vial and azeotroped with benzene to remove any residual water. A mixture of dioxane (1 mL) and iPr2NEt (0.22 mL, 1.28 mmol) was degassed with N2 for 10 minutes. This mixture was then added to the reaction vial and sealed with a Teflon® coated cap which was then wrapped with Teflon® tape. The resulting suspension was then placed in a 165° C. silicone oil bath at which point the mixture became homogeneous. The resulting solution stirred at 165° C. for 21 h. After the solvents were removed by rotovap, the mixture was purified using ISCO FCC, eluting with 50% EtOAc in Hexanes to obtain 219 mg of (R)-methyl-2-(5-(2-hydroxypropan-2-yl)-4-(trifluoromethyl)pyrimidin-2-yl)-1-isopropyl-7-(methylsulfonyl)-1,2,3,4-tetrahydrobenzo[4,5]imidazo[1,2-a]pyrazine-8-carboxylate as a white solid (62% yield, 40% ee).
Reaction SMILES: [F:1][C:2]1[CH:8]=[C:7]([F:9])[CH:6]=[CH:5][C:3]=1[NH2:4].C(=O)([O-])[O-].[K+].[K+].[CH2:16](Br)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>CN(C)C=O>[CH2:16]([N:4]([CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:3]1[CH:5]=[CH:6][C:7]([F:9])=[CH:8][C:2]=1[F:1])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: BrCc1ccccc1
Reactant: Nc1ccc(F)cc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Fc1ccc(N(Cc2ccccc2)Cc2ccccc2)c(F)c1

Procedure:
To 2,4-difluoroaniline (40.0 g, 0.31 mol) in N,N-dimethylformamide (400 mL) were added potassium carbonate (120 g, 0.92 mol, 3 eq) and benzyl bromide (112 mL, 0.71 mmol, 2.3 eq). The reaction was stirred with mechanical stirring at room temperature overnight. In order to quench the benzyl bromide in excess, NH4OH (90 mL) was added and the reaction was stirred overnight. The mixture was filtered and DMF was evaporated under reduced pressure. Ethyl acetate was added and the organic layer was washed with water and brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure and the oily crude was crystallized in methanol, obtaining after drying 71 g of dibenzyl-(2,4-difluoro-phenyl)-amine as a white solid (74%)
Reaction SMILES: C(C([NH:10][C:11]1[CH:30]=[CH:29][C:14]([CH2:15][N:16]2[CH2:21][CH2:20][C:19](=[O:22])[C:18](=[C:23]3[S:27][CH:26]=[CH:25][S:24]3)[C:17]2=[O:28])=[CH:13][CH:12]=1)=O)C1C=CC=CC=1.[BrH:31].C(O)(=O)C.CCOCC>C(O)(=O)C>[BrH:31].[NH2:10][C:11]1[CH:30]=[CH:29][C:14]([CH2:15][N:16]2[CH2:21][CH2:20][C:19](=[O:22])[C:18](=[C:23]3[S:24][CH:25]=[CH:26][S:27]3)[C:17]2=[O:28])=[CH:13][CH:12]=1
Reactant: O=C(Cc1ccccc1)Nc1ccc(CN2CCC(=O)C(=C3SC=CS3)C2=O)cc1
Agent: Br
Solvent: CCOCC
Solvent: CC(=O)O
Product: Nc1ccc(CN2CCC(=O)C(=C3SC=CS3)C2=O)cc1
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 79.3 %

Procedure:
1-(p-(N-Benzylcarbonylamino)benzyl)-3-(1,3-dithiol-2-ylidene)-2,4-dioxopiperidine (100 mg) is dissolved in acetic acid (2 ml), and a 25% HBr-acetic acid solution (0.5 ml) is added thereto. The mixture is stirred at room temperature for 40 minutes, and then at 40°-50° C. for one hour. After cooling the mixture, ether is added to the mixture. The precipitated crystals are collected by filtration, and recrystallized from a mixture of methanol and ether to give 1-(p-aminobenzyl)-3-(1,3-dithiol-2-ylidene)-2,4-dioxopiperidine hydrobromide (70 mg, 79.3%) as pale yellow needles, m.p. 210°-214° C. (decomp.).
Reaction SMILES: [NH2:1][C:2]1[C:3]([F:22])=[CH:4][C:5]([F:21])=[C:6]([C@:8]2([CH3:20])[C:14]([F:16])([F:15])[C:13]([CH3:18])([CH3:17])[O:12][CH2:11][C:10](=[S:19])[NH:9]2)[CH:7]=1.[Cl:23][C:24]1[CH:25]=[CH:26][C:27]([C:30](O)=[O:31])=[N:28][CH:29]=1>>[Cl:23][C:24]1[CH:25]=[CH:26][C:27]([C:30]([NH:1][C:2]2[CH:7]=[C:6]([C@:8]3([CH3:20])[C:14]([F:15])([F:16])[C:13]([CH3:17])([CH3:18])[O:12][CH2:11][C:10](=[S:19])[NH:9]3)[C:5]([F:21])=[CH:4][C:3]=2[F:22])=[O:31])=[N:28][CH:29]=1
Reactant: O=C(O)c1ccc(Cl)cn1
Reactant: CC1(C)OCC(=S)N[C@](C)(c2cc(N)c(F)cc2F)C1(F)F
Product: CC1(C)OCC(=S)N[C@](C)(c2cc(NC(=O)c3ccc(Cl)cn3)c(F)cc2F)C1(F)F
Yield: 91 %

Procedure:
The compound was prepared in an analogous manner as described for intermediate B14A from (R)-5-(5-amino-2,4-difluorophenyl)-6,6-difluoro-5,7,7-trimethyl-[1,4]oxazepane-3-thione (intermediate A17C) (70 mg, 0.208 mmol) and commercially available 5-chloro-pyridine-2-carboxylic acid [CAS No. 86873-60-1] (49 mg, 0.312 mmol). The compound was obtained as a white solid (90 mg, 91%). MS (ISP): m/z=476.1 [(M+H)+] and 478.1 [(M+2+H)+].
Reaction SMILES: [NH2:1][CH2:2][CH2:3][S:4][CH2:5][C:6]1[C:11]([O:12][CH3:13])=[CH:10][CH:9]=[CH:8][N:7]=1.CN.[C:16]([NH:24][C:25](N)=[NH:26])(=O)C1C=CC=CC=1.Cl>C(O)C>[CH3:16][NH:24][C:25]([NH:1][CH2:2][CH2:3][S:4][CH2:5][C:6]1[C:11]([O:12][CH3:13])=[CH:10][CH:9]=[CH:8][N:7]=1)=[NH:26]
Reactant: N=C(N)NC(=O)c1ccccc1
Reactant: COc1cccnc1CSCCN
Agent: CN
Agent: Cl
Solvent: CCO
Product: CNC(=N)NCCSCc1ncccc1OC
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 2-[2-aminoethylthiomethyl]-3-methoxypyridine in ethanol is added to a stirred solution of N-benzoyl dimethyldithioimidocarbonate in ethanol and the mixture is stirred overnight at room temperature. The purified product is treated with methylamine in ethanol and the resultant benzoylguanidine is hydrolysed by refluxing with aqueous hydrochloric acid to give N-methyl-N'-[2-(3-methoxy-2-pyridylmethylthio)ethyl]guanidine.
Reaction SMILES: [CH2:1]([O:3][CH:4]([O:8][CH2:9][CH3:10])[CH2:5][CH2:6][NH2:7])[CH3:2].C(N(C(C)C)CC)(C)C.[Cl:20][CH2:21][CH2:22][CH2:23][CH2:24][C:25](Cl)=[O:26].OS([O-])(=O)=O.[Na+]>C(Cl)Cl>[CH2:1]([O:3][CH:4]([O:8][CH2:9][CH3:10])[CH2:5][CH2:6][NH:7][C:25](=[O:26])[CH2:24][CH2:23][CH2:22][CH2:21][Cl:20])[CH3:2]
Reactant: O=C(Cl)CCCCCl
Reactant: CCOC(CCN)OCC
Agent: O=S(=O)([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(CCNC(=O)CCCCCl)OCC

Procedure:
A solution of [3,3-bis(ethyloxy)propyl]amine (9.02 g, 61 mmol) and diisopropylethylamine (13.3 mL, 76.4 mmol) in CH2Cl2 (50 mL) was added dropwise to a cooled (0° C.) solution of 5-chloropentanoyl chloride (10.35 g, 61 mmol) in CH2Cl2 (50 mL) over 2 h. After addition was complete the mixture was treated with 1N NaHSO4 (75 mL) and separated the layers in a separatory funnel. Back extracted the aqueous with CH2Cl2 then combined the organics, washed them with brine, dried them over MgSO4, filtered, and concentrated in vacuo. The resulting oil was chromatographed on silica gel using a gradient between 50 and 100% EtOAC in Hexanes over 100 min. Collected, combined, and concentrated in vacuo pure fractions to provide the desired product as a yellow viscous oil: 1H NMR (300 MHz, DMSO-d6) δ ppm 1.10 (t, J=7.09 Hz, 6 H), 1.44-1.55 (m, 2 H), 1.59-1.75 (m, 4 H), 2.04 (t, J=7.23 Hz, 2 H), 3.01-3.08 (m, 2 H), 3.41 (dq, J=9.55, 7.07 Hz, 2 H), 3.50-3.64 (m, 4 H), 4.48 (t, J=5.69 Hz, 1 H), 7.74 (t, J=4.98 Hz, 1 H); ES+ MS: 288 (M+Na+).
Reaction SMILES: [H-].[Na+].[C:3]([C:5]1[CH:10]=[CH:9][C:8]([CH2:11][CH2:12][NH:13][C:14](=O)OCC2C=CC=CC=2)=[CH:7][CH:6]=1)#[N:4].CI>O1CCCC1>[CH3:14][NH:13][CH2:12][CH2:11][C:8]1[CH:7]=[CH:6][C:5]([C:3]#[N:4])=[CH:10][CH:9]=1
Reactant: N#Cc1ccc(CCNC(=O)OCc2ccccc2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CI
Solvent: C1CCOC1
Product: CNCCc1ccc(C#N)cc1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
With ice bath cooling, 0.43 g (17.03 mmol) of sodium hydride (95%) was added to a solution of 3.183 g (11.36 mmol) of benzyl [2-(4-cyanophenyl)ethyl]carbamate in 70 ml of tetrahydrofuran. The mixture was stirred for a further 5 minutes with cooling and at room temperature for 10 minutes. 1.06 ml (17.03 mmol) of methyl iodide were then added to the reaction mixture, which was subsequently stirred at room temperature overnight. With ice bath cooling, the mixture was then quenched with water and extracted with ethyl acetate. The organic extracts were washed with saturated sodium chloride solution, dried over sodium sulphate and evaporated to dryness. The product obtained in this manner was reacted further without additional purification.
Reaction SMILES: O=[N+]([O-])[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[Ce+4].[NH4+].[NH4+].C(#N)C.[CH2:31]([O:33][C:34]([C:36]1([CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][CH2:58][CH2:59][C:60]([N:62]2[CH2:67][CH2:66][O:65][CH2:64][CH2:63]2)=[O:61])[CH2:44][C:43]2[C:38](=[C:39]([O:51]C)[C:40]([O:49][CH3:50])=[C:41]([O:47][CH3:48])[C:42]=2[O:45]C)[CH2:37]1)=[O:35])[CH3:32]>O>[CH2:31]([O:33][C:34]([C:36]1([CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][CH2:58][CH2:59][C:60]([N:62]2[CH2:63][CH2:64][O:65][CH2:66][CH2:67]2)=[O:61])[CH2:37][C:38]2[C:39](=[O:51])[C:40]([O:49][CH3:50])=[C:41]([O:47][CH3:48])[C:42](=[O:45])[C:43]=2[CH2:44]1)=[O:35])[CH3:32]
Reactant: CCOC(=O)C1(CCCCCCCC(=O)N2CCOCC2)Cc2c(c(OC)c(OC)c(OC)c2OC)C1
Agent: O=[N+]([O-])[O-]
Agent: [Ce+4]
Agent: [NH4+]
Solvent: CC#N
Solvent: O
Product: CCOC(=O)C1(CCCCCCCC(=O)N2CCOCC2)CC2=C(C1)C(=O)C(OC)=C(OC)C2=O
Reaction time: 0.25 h
Yield: 57.4 %

Procedure:
A water (1.2 ml) solution of CAN (323 mg, 0.590 mmols) was dropwise added to an acetonitrile (2.5 ml) solution of N-[8-(2-ethoxycarbonyl-4,5,6,7-tetramethoxyindan-2-yl)octanoyl]morpholine (123 mg, 0.236 mmols) with cooling with ice and stirring was continued for 15 minutes. Water was added to the reaction mixture, which was then extracted with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution and then dried. The solvent was evaporated out in vacuo and the resulting crude product was purified by silica gel column chromatography (hexane:ethyl acetate=2:1 to 1:1) to obtain the entitled compound (66.6 mg) as an oil.