Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([NH:3][C:4]1[S:5][CH:6]=[C:7]([C:9](=[N:25][O:26][CH2:27][CH:28]([CH3:30])[CH3:29])[C:10]([NH:12][CH:13]2[C:23](=[O:24])[N:15]3[C:16]([C:20]([OH:22])=[O:21])=[CH:17][CH2:18][S:19][C@H:14]23)=[O:11])[N:8]=1)=O.Cl>CO>[NH2:3][C:4]1[S:5][CH:6]=[C:7]([C:9](=[N:25][O:26][CH2:27][CH:28]([CH3:30])[CH3:29])[C:10]([NH:12][CH:13]2[C:23](=[O:24])[N:15]3[C:16]([C:20]([OH:22])=[O:21])=[CH:17][CH2:18][S:19][C@H:14]23)=[O:11])[N:8]=1
Reactant: CC(C)CON=C(C(=O)NC1C(=O)N2C(C(=O)O)=CCS[C@H]12)c1csc(NC=O)n1
Agent: Cl
Solvent: CO
Product: CC(C)CON=C(C(=O)NC1C(=O)N2C(C(=O)O)=CCS[C@H]12)c1csc(N)n1
Yield: 62.4 %

Procedure:
7-[2-(2-formamidothiazol-4-yl)-2-iso-butoxyiminoacetamido]-3-cephem-4-carboxylic acid (syn isomer, 4.1 g.), conc. hydrochloric acid (3.65 g.) and methanol (61.5 ml.) were treated in a similar manner to that of Example 15(3) to give 7-[2-(2-aminothiazol-4-yl)-2-iso-butoxyiminoacetamido]-3-cephem-4-carboxylic acid (syn isomer, 2.4 g.).
Reaction SMILES: [C:1]([C:3]1[NH:7][C:6]([C:8]2[C:13]([Cl:14])=[CH:12][C:11]([C:15]([F:18])([F:17])[F:16])=[CH:10][C:9]=2[Cl:19])=[N:5][C:4]=1[C:20]([OH:22])=O)#[N:2].[F-].[K+].[CH2:25]([NH:27][CH2:28][CH3:29])[CH3:26]>COCCOCCOC.ClCCl>[CH2:25]([N:27]([CH2:28][CH3:29])[C:20]([C:4]1[N:5]=[C:6]([C:8]2[C:13]([Cl:14])=[CH:12][C:11]([C:15]([F:16])([F:18])[F:17])=[CH:10][C:9]=2[Cl:19])[NH:7][C:3]=1[C:1]#[N:2])=[O:22])[CH3:26]
Reactant: CCNCC
Reactant: N#Cc1[nH]c(-c2c(Cl)cc(C(F)(F)F)cc2Cl)nc1C(=O)O
Agent: [F-]
Agent: [K+]
Solvent: COCCOCCOC
Solvent: ClCCl
Product: CCN(CC)C(=O)c1nc(-c2c(Cl)cc(C(F)(F)F)cc2Cl)[nH]c1C#N
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 16 %

Procedure:
5-cyano-2-(2,6-dichloro-4-trifluoromethylphenyl)-imidazole-4-carboxylic acid (1.4 g, 0.004 mol) in 2-methoxyethyl ether (11 ml) whilst maintaining the temperature at about 0° C. Potassium fluoride (0.67 g, 0.0115 mol) was added and the mixture was stirred at 0° C. for 0.5 hours, and added slowly to a solution of diethylamine (8.8 g, 12.5 ml, 0.12 mol) in dichloromethane (75 ml) whilst maintaining the temperature in the range 0°-5° C. The mixture was stirred at 0°-5° C. for 1 hour and at room temperature for 0.5 hours. The mixture was washed with saturated aqueous sodium bicarbonate solution (50 ml), dried over anhydrous sodium sulphate and evaporated to dryness. The residue was purified by mplc on silica eluting with a mixture of ethyl acetate and dichloromethane (1:2) to give N,N-diethyl 5-cyano-2-(2,6-dichloro-4-trifluoromethylphenyl)imidazole-4-carboxamide (0.26 g) m.p. 195°- 197° C. as an off-white solid.
Reaction SMILES: [CH2:1]([C:5]1[CH:12]=[CH:11][C:8]([C:9]#[N:10])=[CH:7][CH:6]=1)[CH2:2][CH2:3][CH3:4]>C1COCC1>[CH2:1]([C:5]1[CH:6]=[CH:7][C:8]([CH2:9][NH2:10])=[CH:11][CH:12]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1ccc(C#N)cc1
Solvent: C1CCOC1
Product: CCCCc1ccc(CN)cc1
Temperature: 25 °C

Procedure:
A solution of 4-butylbenzonitrile (3.63 g, 22.8 mmol) in THF (10 mL) was placed in a three-neck round bottom flask equipped with a vigreux column and short-path distillation head. The solution was heated to reflux and BH3-methyl sulfide complex (2.0 M in THF, 15 mL, 30 mmol) was added dropwise over 15 minutes. Methyl sulfide was distilled off from the reaction mixture over 1 h and the solution was cooled to room temperature. Aqueous HCl (6N, 25 mL) was added slowly via an addition funnel and the mixture was heated at reflux for 30 minutes. The reaction was cooled to 0° C. and NaOH (7.0 g) was added portionwise. The aqueous solution was extracted with EtOAc (3×) and the organic solution was dried (MgSO4), filtered, and concentrated. The product (4.01 g) was used in the next step without further purification. 1H NMR (400 MHz, CDCl3) δ 7.34 (m, 2H), 7.24 (m, 2H), 4.04 (s, 2H), 2.62 (t, 2H), 1.58 (m, 2H), 1.34 (m, 2H), 0.92 (t, 3H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:20])[CH:4]([O:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([OH:12])=[CH:8][CH:7]=1.[CH3:21][S:22][C:23]1[CH:28]=[CH:27][C:26]([CH2:29][CH2:30]O)=[CH:25][CH:24]=1>>[CH3:1][O:2][C:3](=[O:20])[CH:4]([O:13][C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH2:30][CH2:29][C:26]2[CH:27]=[CH:28][C:23]([S:22][CH3:21])=[CH:24][CH:25]=2)=[CH:8][CH:7]=1
Reactant: COC(=O)C(Cc1ccc(O)cc1)Oc1ccccc1
Reactant: CSc1ccc(CCO)cc1
Product: COC(=O)C(Cc1ccc(OCCc2ccc(SC)cc2)cc1)Oc1ccccc1

Procedure:
3-(4-Hydroxyphenyl)-2-phenoxypropanoic acid methyl ester was reacted with 2-(4-methylsulfanylphenyl)ethanol using the same methods as in Example 38(c) to give 3-{4-[2-(4-methylsulfanylphenyl)ethoxy]phenyl}-2-phenoxy-propanoic acid methyl ester.
Reaction SMILES: [C:1]([S:5]([CH2:8][C@@H:9]([CH2:38][C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)[C:10]([NH:12][C@@H:13]([CH2:32][C:33]1[N:34]=[CH:35][NH:36][CH:37]=1)[C:14]([NH:16][C@@H:17]([CH2:25][CH:26]1[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]1)[C@@H:18]([OH:24])[C@H:19]([CH:21]1[CH2:23][CH2:22]1)[OH:20])=[O:15])=[O:11])(=[O:7])=[O:6])([CH3:4])([CH3:3])[CH3:2].Br[CH2:46][C:47](=[CH2:53])[C:48]([O:50][CH2:51][CH3:52])=[O:49].C(N(CC)CC)C>C(Cl)Cl>[C:1]([S:5]([CH2:8][C@@H:9]([CH2:38][C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)[C:10]([NH:12][C@H:13]([C:14](=[O:15])[NH:16][C@@H:17]([CH2:25][CH:26]1[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]1)[C@@H:18]([OH:24])[C@H:19]([CH:21]1[CH2:22][CH2:23]1)[OH:20])[CH2:32][C:33]1[N:34]=[CH:35][N:36]([CH2:53][C:47](=[CH2:46])[C:48]([O:50][CH2:51][CH3:52])=[O:49])[CH:37]=1)=[O:11])(=[O:7])=[O:6])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)S(=O)(=O)C[C@@H](Cc1ccccc1)C(=O)N[C@@H](Cc1c[nH]cn1)C(=O)N[C@@H](CC1CCCCC1)[C@@H](O)[C@@H](O)C1CC1
Reactant: C=C(CBr)C(=O)OCC
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C=C(Cn1cnc(C[C@H](NC(=O)[C@H](Cc2ccccc2)CS(=O)(=O)C(C)(C)C)C(=O)N[C@@H](CC2CCCCC2)[C@@H](O)[C@@H](O)C2CC2)c1)C(=O)OCC
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A mixture of 100 mg (0.16 mmol) of (S)-α-[(S)-α-[(tert-butylsulphonyl)methyl]hydrocinnamamido]-N-[(1S,2R,3S)-1-(cyclohexylmethyl)-3-cyclopropyl-2,3-dihydroxypropyl]imidazole-4-propionamide, 46 mg (0.24 mmol) of ethyl 2-(bromomethyl)acrylate and 0.044 ml (0.32 mmol) of triethylamine in 3 ml of methylene chloride is stirred at room temperature under argon for 24 hours. Subsequently, the reaction mixture is evaporated and, for purification, the residue is chromatographed on 30 g of silica gel using a 14:1:0.1 mixture of methylene chloride, methanol and ammonia as the eluent. There are obtained mg of ethyl 4-[(S)-2-[(S)-α-[(tert-butylsulphonyl)methyl]hydrocinnamamido]-2-[[(1S,2R,3S)-1-(cyclohexylmethyl)-3-cyclopropyl-2,3-dihydroxypropyl]carbamoyl]ethyl]-α-methyleneimidazole-1-propionate as an amorphous solid; MS: 743 (M+H)+.
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[C:3]1[CH:12]=[CH:11][C:6]2[N:7]=[C:8]([NH2:10])[S:9][C:5]=2[CH:4]=1.C(N=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1.[C:36]([N:39]1[CH:43]([C:44]2[CH:45]=[CH:46][C:47]([O:55][CH3:56])=[C:48]([CH:54]=2)[O:49][CH2:50][C:51](O)=[O:52])[CH2:42][C:41]([C:57]2[CH:62]=[C:61]([O:63][CH3:64])[C:60]([O:65][CH3:66])=[C:59]([O:67][CH3:68])[CH:58]=2)=[N:40]1)(=[O:38])[CH3:37]>ClCCl.O>[F:14][C:2]([F:1])([F:13])[C:3]1[CH:12]=[CH:11][C:6]2[N:7]=[C:8]([NH:10][C:51](=[O:52])[CH2:50][O:49][C:48]3[CH:54]=[C:44]([CH:43]4[N:39]([C:36](=[O:38])[CH3:37])[N:40]=[C:41]([C:57]5[CH:62]=[C:61]([O:63][CH3:64])[C:60]([O:65][CH3:66])=[C:59]([O:67][CH3:68])[CH:58]=5)[CH2:42]4)[CH:45]=[CH:46][C:47]=3[O:55][CH3:56])[S:9][C:5]=2[CH:4]=1
Reactant: Nc1nc2ccc(C(F)(F)F)cc2s1
Reactant: COc1ccc(C2CC(c3cc(OC)c(OC)c(OC)c3)=NN2C(C)=O)cc1OCC(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: O
Product: COc1ccc(C2CC(c3cc(OC)c(OC)c(OC)c3)=NN2C(C)=O)cc1OCC(=O)Nc1nc2ccc(C(F)(F)F)cc2s1
Yield: 801.6 %

Procedure:
To a solution of 6-(trifluoromethyl)-2-aminobenzothiazole (218 mg, 1.0 mmol) in dichloromethane (20 mL) was added 1-Ethyl-3-(3-Dimethylaminopropyl)carbodiimide (EDC) (191 mg, 1.0 mmol) and 1-hydroxy-1,2,3-benzotriazole (HOBt) (13.5 mg, 0.1 mmol). Then added 2-{5-[1-acetyl-3-(3,4,5-trimethoxyphenyl)-4,5-dihydro-1H-5-pyrazolyl]-2-methoxyphenoxy}acetic acid (3) (458 mg, 0.1 mmol) and the reaction mixture was stirred at a temperature of 25° C. for 24 h and the reaction was monitored by TLC. Then to this water is added and extracted with dichloromethane. The solvent was evaporated under vacuum to afford the crude product. This was further purified by column chromatography using ethyl acetate and hexane as solvent system to obtain the pure product (10i) (528 mg, 80% yield).
Reaction SMILES: [C:1]1(/[C:7](/[C:13]2[CH:14]=[C:15]([CH3:19])[CH:16]=[CH:17][CH:18]=2)=[C:8]2/[CH2:9][NH:10][CH2:11][CH2:12]/2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H][H]>CO.[Pd]>[C:1]1([CH:7]([C:13]2[CH:14]=[C:15]([CH3:19])[CH:16]=[CH:17][CH:18]=2)[CH:8]2[CH2:12][CH2:11][NH:10][CH2:9]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: [H][H]
Reactant: Cc1cccc(/C(=C2/CCNC2)c2ccccc2)c1
Agent: [Pd]
Solvent: CO
Product: Cc1cccc(C(c2ccccc2)C2CCNC2)c1
Yield: 74.1 %

Procedure:
To a solution of (Z)-3-(phenyl(m-tolyl)methylene)pyrrolidine (4.0 g, 16.1 mmol) in methanol (40 mL) at room temperature was added 10% Pd/C (9.5 g) and the contents were hydrogenated at 50 psi hydrogen atmosphere and at room temperature for 12 h. The reaction mixture was filtered through celite bed and the bed was washed with methanol. The filtrate was concentrated under reduced pressure to afford 3.0 g of 3-(phenyl(m-tolyl)methyl)pyrrolidine.
Reaction SMILES: Br[C:2]1[C:3]([CH:8]=[O:9])=[N:4][CH:5]=[CH:6][CH:7]=1.[S:10]1[CH:14]=[CH:13][CH:12]=[C:11]1B(O)O.COCCOC.C([O-])([O-])=O.[Na+].[Na+]>C1COCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[S:10]1[CH:14]=[CH:13][CH:12]=[C:11]1[C:2]1[C:3]([CH:8]=[O:9])=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: OB(O)c1cccs1
Reactant: O=Cc1ncccc1Br
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: C1CCOC1
Product: O=Cc1ncccc1-c1cccs1
Temperature: 90 °C
Yield: 63.4 %

Procedure:
A stirred solution of 3-bromo-pyridine-2-carbaldehyde (126 mg, 0.675 mmol) and 2-thiopheneboronic acid (91.6 mg, 0.716 mmol) in a mixture of THF (0.75 mL), DME (2.0 mL) and 2M Na2CO3 (0.75 mL) was degassed with Ar for 15 minutes, after which Pd(PPh3)4 (39 mg, 0.034 mmol) was added and the heterogeneous mixture heated to 90° C. for 4 h. The reaction was quenched with brine (15 mL) and diluted with EtOAc (40 mL). The organic layer was separated, washed with brine (2×15 mL), dried (Na2SO4), filtered and concentrated in vacuo. Purification by flash chromatography on silica gel (Hexanes/EtOAc, 80:20) gave 3-thiophen-2-yl-pyridine-2-carbaldehyde (81 mg, 63%) as a yellow oil. 1H NMR (CDCl3) δ 7.13-7.22 (m, 2H), 7.48-7.57 (m, 2H), 7.92 (dd, 1H, J=7.9, 1.9 Hz), 8.82 (dd, 1H, J=6.0, 1.5 Hz), 10.23 (s, 1H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[C:9]1[S:13][N:12]=[C:11]([CH3:14])[C:10]=1[CH2:15][OH:16].[F:17][C:18]1[CH:19]=[C:20]([CH2:26][CH2:27][C:28]([O:30][CH2:31][CH3:32])=[O:29])[CH:21]=[C:22]([F:25])[C:23]=1O.C1CCN(C(N=NC(N2CCCCC2)=O)=O)CC1.P(CCCC)(CCCC)CCCC>C1(C)C=CC=CC=1>[F:17][C:18]1[CH:19]=[C:20]([CH2:26][CH2:27][C:28]([O:30][CH2:31][CH3:32])=[O:29])[CH:21]=[C:22]([F:25])[C:23]=1[O:16][CH2:15][C:10]1[C:11]([CH3:14])=[N:12][S:13][C:9]=1[C:3]1[CH:4]=[CH:5][C:6]([CH3:8])=[CH:7][C:2]=1[F:1]
Reactant: CCOC(=O)CCc1cc(F)c(O)c(F)c1
Reactant: Cc1ccc(-c2snc(C)c2CO)c(F)c1
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: Cc1ccccc1
Product: CCOC(=O)CCc1cc(F)c(OCc2c(C)nsc2-c2ccc(C)cc2F)c(F)c1
Temperature: 60 °C
Reaction time: 8 h

Procedure:
Into a 25-mL round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed [5-(2-fluoro-4-methylphenyl)-3-methyl-1,2-thiazol-4-yl]methanol (100 mg, 0.42 mmol, 1.00 equiv), ethyl 3-(3,5-difluoro-4-hydroxyphenyl)propanoate (146 mg, 0.63 mmol, 1.50 equiv), ADDP (221.6 mg, 0.89 mmol, 2.10 equiv), Bu3P (128 mg, 0.63 mmol, 1.5 equiv), toluene (10 mL). The resulting solution was stirred overnight at 60° C. The resulting mixture was concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1:5). This resulted in 150 mg (79%) of ethyl 3-(3,5-difluoro-4-[[5-(2-fluoro-4-methylphenyl)-3-methyl-1,2-thiazol-4-yl]methoxy]phenyl) propanoate as colorless oil.
Reaction SMILES: NC1C=CC(C2N=C(N([C:15]3[CH:25]=[CH:24][C:18]([C:19]([O:21]CC)=O)=[CH:17][CH:16]=3)C)SC=2)=CC=1>O1CCCC1>[CH:15]1([C:15]2[CH:16]=[CH:17][C:18]([CH:19]=[O:21])=[CH:24][CH:25]=2)[CH2:25][CH2:24][CH2:18][CH2:17][CH2:16]1
Reactant: CCOC(=O)c1ccc(N(C)c2nc(-c3ccc(N)cc3)cs2)cc1
Solvent: C1CCOC1
Product: O=Cc1ccc(C2CCCCC2)cc1
Temperature: 25 °C
Yield: 219.4 %

Procedure:
Under a nitrogen stream, tetrahydrofuran (306 ml, 6.0 v/w) was added to ethyl 4-(N-(4-(4-aminophenyl)-2-thiazolyl)-N-methylamino)benzoate (51.0 g, 0.144 mol) obtained in Example 3(3). With stirring at room temperature, a solution of 4-cyclohexylbenzaldehyde (30.0 g, 0.158 mol) obtained in Production Example 1(2) in tetrahydrofuran (153 ml, 3.0 v/w) was added. The mixture was washed with tetrahydrofuran (51 ml, 1.0 v/w) and stirred at room temperature for 30 min. With stirring under ice-cooling, sodium triacetoxyborohydride (46.0 g, 0.216 mol) and acetic acid (12.4 ml, 0.216 mol) were added, and the mixture was stirred at room temperature for 1.5 hr. With stirring under ice-cooling, saturated aqueous sodium hydrogen carbonate (510 ml, 10.0 v/w) was added carefully. After stirring at room temperature for 1 hr., the mixture was extracted with ethyl acetate (408 ml) and the organic layer was washed successively with distilled water (255 ml) and saturated brine (255 ml), and dried over magnesium sulfate (50 g). After filtration and solvent evaporation, isopropyl alcohol (510 ml, 10.0 v/w) was added to the obtained orange solid, and the mixture was stirred at 60° C. for 1 hr. After stirring under ice-cooling for 1 hr., the resulting crystal were collected by filtration, and washed with isopropyl alcohol (102 ml) and tert-butylmethyl ether (102 ml) and dried in vacuo to give the title compound (58.0 g, yield 77.0%) as a pale-yellow solid.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][CH2:9][CH2:10][CH2:11][OH:12])[C:5]([C:13]2[S:14][CH:15]=[CH:16][CH:17]=2)=[CH:4][N:3]=1.[NH2:18][C:19]1[CH:24]=[CH:23][C:22]([S:25]([CH3:33])(=[N:27][C:28]([O:30][CH2:31][CH3:32])=[O:29])=[O:26])=[CH:21][CH:20]=1>>[CH2:31]([O:30][C:28]([N:27]=[S:25]([C:22]1[CH:21]=[CH:20][C:19]([NH:18][C:2]2[N:7]=[C:6]([NH:8][CH2:9][CH2:10][CH2:11][OH:12])[C:5]([C:13]3[S:14][CH:15]=[CH:16][CH:17]=3)=[CH:4][N:3]=2)=[CH:24][CH:23]=1)([CH3:33])=[O:26])=[O:29])[CH3:32]
Reactant: OCCCNc1nc(Cl)ncc1-c1cccs1
Reactant: CCOC(=O)N=S(C)(=O)c1ccc(N)cc1
Product: CCOC(=O)N=S(C)(=O)c1ccc(Nc2ncc(-c3cccs3)c(NCCCO)n2)cc1
Yield: 29 %

Procedure:
In the reaction of 3-(2-chloro-5-(2-thienyl)pyrimidine-4-ylamino)propanol (154 mg, 0.57 mmol) with (RS)—S-(4-aminophenyl)-N-(ethoxycarbonyl)-S-methyl-sulfoximide (127 mg, 0.53 mmol) according to procedure 5b, the desired product is obtained in 29% yield (80 mg) after chromatographic purification (silica gel, hexane/ethyl acetate (50%-100% ethyl acetate)) and subsequent purification by HPLC.
Reaction SMILES: [CH3:1][N:2]([CH3:6])[C:3](Cl)=[O:4].N1C=CC=CC=1.[CH3:13][N:14]([CH3:22])[C:15](=[O:21])[NH:16][C:17](=[NH:20])[S:18][CH3:19]>C(Cl)Cl>[CH3:1][N:2]([CH3:6])[C:3]([N:20]=[C:17]([S:18][CH3:19])[NH:16][C:15]([N:14]([CH3:22])[CH3:13])=[O:21])=[O:4]
Reactant: CN(C)C(=O)Cl
Reactant: CSC(=N)NC(=O)N(C)C
Solvent: c1ccncc1
Solvent: ClCCl
Product: CSC(=NC(=O)N(C)C)NC(=O)N(C)C
Temperature: 25 °C

Procedure:
5.4 Parts of dimethylcarbamoyl chloride is combined with 10 parts pyridine and stirred until the temperature returns to 25° C. 8.0 Parts methyl 4,4-dimethylthioallophanimidate (a compound of formula II), in 50 parts methylene chloride is added in one portion. The mixture is refluxed overnight, then cooled to give a white solid. The solid is removed and the organic layer is extracted with 200 parts water at pH 3, dried and evaporated to give 5 parts methyl N-dimethylcarbamoyl-4,4-dimethylthioallophanimidate (a compound of formula I), m.p. 115.5°-117.5° C.
Reaction SMILES: [CH2:1]([N:4]1[C:9](=[O:10])[CH:8]=[C:7]2[S:11][CH2:12][CH2:13][N:6]2[C:5]1=[O:14])[CH2:2][CH3:3].S(=O)(=O)(O)O.[N+:20]([O-])([OH:22])=[O:21]>>[N+:20]([C:8]1[C:9](=[O:10])[N:4]([CH2:1][CH2:2][CH3:3])[C:5](=[O:14])[N:6]2[CH2:13][CH2:12][S:11][C:7]=12)([O-:22])=[O:21]
Reactant: O=[N+]([O-])O
Reactant: CCCn1c(=O)cc2n(c1=O)CCS2
Agent: O=S(=O)(O)O
Product: CCCn1c(=O)c([N+](=O)[O-])c2n(c1=O)CCS2
Yield: 85 %

Procedure:
6-Propyl-2,3-dihydro-5H-thiazolo[3,2-c]pyrimidine-5,7-(6H)-dione (2.12 g) was added to concentrated sulfuric acid (5.2 ml) little by little under ice cooling, and then, fuming nitric acid (1.8 ml) was added dropwise thereto with stirring. The mixture was stirred under ice cooling for 1 hour. The reaction temperature was kept under 5° C. for this period. The reaction solution was poured on ice water, and the resulting crystals were collected by filtration and recrystallization from ethanol-ethyl acetate to give pale yellow needles (2.0 g, 85%).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH:9]1[C:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[C:13]([CH2:20]Br)[NH:12][C:11]([C:22]2[S:23][CH:24]=[CH:25][N:26]=2)=[N:10]1.[CH3:27][C:28]1([CH3:37])[O:33][CH2:32][CH2:31][NH:30][C@@H:29]1[C:34]([OH:36])=[O:35].C(=O)([O-])[O-].[K+].[K+]>C(O)C>[Br:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH:9]1[N:10]=[C:11]([C:22]2[S:23][CH:24]=[CH:25][N:26]=2)[NH:12][C:13]([CH2:20][N:30]2[CH2:31][CH2:32][O:33][C:28]([CH3:27])([CH3:37])[C@H:29]2[C:34]([OH:36])=[O:35])=[C:14]1[C:15]([O:17][CH2:18][CH3:19])=[O:16]
Reactant: CC1(C)OCCN[C@@H]1C(=O)O
Reactant: CCOC(=O)C1=C(CBr)NC(c2nccs2)=NC1c1ccc(F)cc1Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: CCOC(=O)C1=C(CN2CCOC(C)(C)[C@H]2C(=O)O)NC(c2nccs2)=NC1c1ccc(F)cc1Br
Temperature: 25 °C
Reaction time: 16 h
Yield: 65.2 %

Procedure:
A mixture of ethyl 4-(2-bromo-4-fluorophenyl)-6-(bromomethyl)-2-(thiazol-2-yl)-1,4-dihydropyrimidine-5-carboxylate (7.7 g, 15.3 mmol), (S)-2,2-dimethylmorpholine-3-carboxylic acid (2.44 g, 15.3 mmol) and potassium carbonate (4.23 g, 30.6 mmol) in anhydrous ethanol (154 mL) was stirred at 25° C. for 16 hours. The reaction mixture was filtered and the filtrate was concentrated in vacuo. The residue was purified by a silica gel column chromatography (DCM/MeOH (V/V)=25/1) to give the title compound as a yellow solid (5.8 g, 65%). The compound was characterized by the following spectroscopic data:
Reaction SMILES: Br[C:2]1[C:10]2[O:9][CH2:8][CH:7]([C:11]3[CH:16]=[CH:15][C:14]([CH:17]([CH3:19])[CH3:18])=[CH:13][CH:12]=3)[C:6]=2[C:5]([CH3:20])=[C:4]([NH:21][C:22](=[O:28])[CH2:23][C:24]([CH3:27])([CH3:26])[CH3:25])[C:3]=1[CH3:29].[CH2:30]([O:32][C:33]([C:35]1[CH:36]=[C:37](B(O)O)[CH:38]=[CH:39][CH:40]=1)=[O:34])[CH3:31]>>[CH3:25][C:24]([CH3:27])([CH3:26])[CH2:23][C:22]([NH:21][C:4]1[C:3]([CH3:29])=[C:2]([C:39]2[CH:40]=[C:35]([CH:36]=[CH:37][CH:38]=2)[C:33]([O:32][CH2:30][CH3:31])=[O:34])[C:10]2[O:9][CH2:8][CH:7]([C:11]3[CH:16]=[CH:15][C:14]([CH:17]([CH3:19])[CH3:18])=[CH:13][CH:12]=3)[C:6]=2[C:5]=1[CH3:20])=[O:28]
Reactant: CCOC(=O)c1cccc(B(O)O)c1
Reactant: Cc1c(Br)c2c(c(C)c1NC(=O)CC(C)(C)C)C(c1ccc(C(C)C)cc1)CO2
Product: CCOC(=O)c1cccc(-c2c(C)c(NC(=O)CC(C)(C)C)c(C)c3c2OCC3c2ccc(C(C)C)cc2)c1
Yield: 63 %

Procedure:
Using N-(7-bromo-3-(4-isopropylphenyl)-4,6-dimethyl-2,3-dihydro-1-benzofuran-5-yl)-3,3-dimethylbutanamide obtained in Example 35 and 3-(ethoxycarbonyl)phenylboronic acid, the title compound was obtained in the same manner as in Example 107. Yield: 63%. Melting point: 175-177° C. (ethyl acetate-hexane).
Reaction SMILES: S(Cl)([Cl:3])=O.[S:5]1[CH:9]=[CH:8][CH:7]=[C:6]1[C:10]([C:12]1[CH:13]=[C:14]([CH:18](O)[CH3:19])[CH:15]=[CH:16][CH:17]=1)=[O:11]>C1C=CC=CC=1>[S:5]1[CH:9]=[CH:8][CH:7]=[C:6]1[C:10]([C:12]1[CH:13]=[C:14]([CH:18]([Cl:3])[CH3:19])[CH:15]=[CH:16][CH:17]=1)=[O:11]
Reactant: O=S(Cl)Cl
Reactant: CC(O)c1cccc(C(=O)c2cccs2)c1
Solvent: c1ccccc1
Product: CC(Cl)c1cccc(C(=O)c2cccs2)c1
Reaction time: 1 h

Procedure:
5.5 parts of thionyl chloride is added dropwise to a stirred solution of 9.5 parts of α-hydroxy-α-methyl-m-tolyl 2-thienyl ketone in 40 parts of benzene while keeping the temperature below 20° C. Upon completion, stirring is continued for one hour at room temperature and for one additional hour at 30°-35° C. The reaction mixture is evaporated in vacuo. The residue is taken up in toluene and the latter is evaporated again. The residue is distilled, yielding α-chloro-α-methyl-m-tolyl 2-thienyl ketone; bp. 168°-178° C at 0.7 mm pressure.
Reaction SMILES: C([O-])(O)=O.[Na+].[CH3:6][O:7][C:8]1[CH:9]=[C:10]([NH:16][C:17]([NH2:19])=[NH:18])[CH:11]=[CH:12][C:13]=1[O:14][CH3:15].[Cl:20][C:21]1[CH:22]=[CH:23][C:24]2[C:30](=O)[C:29](=[CH:32]N(C)C)[CH2:28][C:27](=[O:36])[N:26]([CH2:37][CH2:38][CH2:39][N:40]3[C:48](=[O:49])[C:47]4[C:42](=[CH:43][CH:44]=[CH:45][CH:46]=4)[C:41]3=[O:50])[C:25]=2[CH:51]=1>>[Cl:20][C:21]1[CH:22]=[CH:23][C:24]2[C:30]3[N:18]=[C:17]([NH:16][C:10]4[CH:11]=[CH:12][C:13]([O:14][CH3:15])=[C:8]([O:7][CH3:6])[CH:9]=4)[N:19]=[CH:32][C:29]=3[CH2:28][C:27](=[O:36])[N:26]([CH2:37][CH2:38][CH2:39][N:40]3[C:41](=[O:50])[C:42]4[C:47](=[CH:46][CH:45]=[CH:44][CH:43]=4)[C:48]3=[O:49])[C:25]=2[CH:51]=1
Reactant: CN(C)C=C1CC(=O)N(CCCN2C(=O)c3ccccc3C2=O)c2cc(Cl)ccc2C1=O
Reactant: COc1ccc(NC(=N)N)cc1OC
Agent: O=C([O-])O
Agent: [Na+]
Product: COc1ccc(Nc2ncc3c(n2)-c2ccc(Cl)cc2N(CCCN2C(=O)c4ccccc4C2=O)C(=O)C3)cc1OC

Procedure:
In a manner similar to that described for method I (NaHCO3 used instead of K2CO3), 1-(3,4-dimethoxyphenyl)guanidine and 8-chloro-4-((dimethylamino)-methylene)-1-(3-(1,3-dioxoisoindolin-2-yl)propyl)-3,4-dihydro-1H-benzo[b]azepine-2,5-dione (I-40-b) were converted to I-40-c and carried on crude: MS m/z=584 (M+H).
Reaction SMILES: N(C(OCC)=O)=NC(OCC)=O.[OH:13][C:14]1[C:15]([CH2:25][S:26]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)(=[O:28])=[O:27])=[C:16]2[C:21](=[CH:22][CH:23]=1)[C:20](=[O:24])[CH2:19][CH2:18][CH2:17]2.[N:35]1([CH2:40][CH:41](O)[CH2:42][CH2:43][CH2:44][CH3:45])[CH:39]=[CH:38][N:37]=[CH:36]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O1CCCC1>[N:35]1([CH2:40][CH:41]([O:13][C:14]2[C:15]([CH2:25][S:26]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)(=[O:28])=[O:27])=[C:16]3[C:21](=[CH:22][CH:23]=2)[C:20](=[O:24])[CH2:19][CH2:18][CH2:17]3)[CH2:42][CH2:43][CH2:44][CH3:45])[CH:39]=[CH:38][N:37]=[CH:36]1
Reactant: O=C1CCCc2c1ccc(O)c2CS(=O)(=O)c1ccccc1
Reactant: CCCCC(O)Cn1ccnc1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCCCC(Cn1ccnc1)Oc1ccc2c(c1CS(=O)(=O)c1ccccc1)CCCC2=O
Reaction time: 120 h
Yield: 62 %

Procedure:
Diethyl azodicarboxylate (0.16 mL, 0.99 mmol) was added over 10 min to a mixture of 6-Hydroxy-5-[(phenylsulfonyl)methyl]-3,4-dihydro-1(2H)-naphthalenone (300 mg, 0.99 mmol), 1-(1H-imidazol-1-yl)-2-hexanol (166 mg, 1.08 mmol), triphenylphosphine (259 mg, 0.99 mmol) and tetrahydrofuran (2 mL) under nitrogen. The resulting mixture was stirred for 5 d, whereupon it was concentrated and the residue was purified by dry-flash column chromatography (SiO2, 1-9% 2-propanol-dichloromethane) to give 6-{[1-(1H-imidazol-1-ylmethyl)pentyl]oxy}-5-[(phenylsulfonyl)methyl]-3,4-dihydro-1(2H)-naphthalenone as a colorless foam, 283 mg, 62% yield. NMR spectrum was consistent with structure. MS EI: M+• 466.1919 (M+• 466.1926).