Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[S:11][C:10]3[CH:12]=[CH:13][C:14]([CH3:16])=[CH:15][C:9]=3[CH2:8][C:7](=O)[C:6]=2[CH:18]=1.[Cl-:19].[Ca+2].[Cl-].Cl>C1C=CC=CC=1>[Cl:19][CH:7]1[C:6]2[CH:18]=[C:2]([F:1])[CH:3]=[CH:4][C:5]=2[S:11][C:10]2[CH:12]=[CH:13][C:14]([CH3:16])=[CH:15][C:9]=2[CH2:8]1
Reactant: [Cl-]
Reactant: Cc1ccc2c(c1)CC(=O)c1cc(F)ccc1S2
Agent: Cl
Agent: [Ca+2]
Solvent: c1ccccc1
Product: Cc1ccc2c(c1)CC(Cl)c1cc(F)ccc1S2
Reaction time: 8 h

Procedure:
103 G. of 8-fluoro-10,11-dihydro-2-methyl-dibenzo[b,f]thiepin-10-one, 500 ml. of benzene and 38.4 g. of finely pulverized calcium chloride are saturated with hydrochloric acid gas at 15° and stirred overnight. The residue is filtered, washed with benzene and evaporated under reduced pressure, whereby there is obtained 10 -chlor-8-fluoro-10,11-dihydro-2-methyl-dibenzo[b,f]-thiepin, having a melting point of 63°-64°.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][CH:6]=[C:5]2[CH2:12][N:13]1[C:21]([C:22]2[N:26]([CH3:27])[CH:25]=[C:24]([C:28](O)=[O:29])[CH:23]=2)=[C:20]2[C:15]([N:16]([CH2:34][CH:35]3[CH2:37][CH2:36]3)[C:17](=[O:33])[N:18]([CH3:32])[C:19]2=[O:31])=[N:14]1.Cl.[O:39]([NH2:41])[CH3:40].C(P(=O)(OCC)OCC)#N>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][CH:6]=[C:5]2[CH2:12][N:13]1[C:21]([C:22]2[N:26]([CH3:27])[CH:25]=[C:24]([C:28]([NH:41][O:39][CH3:40])=[O:29])[CH:23]=2)=[C:20]2[C:15]([N:16]([CH2:34][CH:35]3[CH2:36][CH2:37]3)[C:17](=[O:33])[N:18]([CH3:32])[C:19]2=[O:31])=[N:14]1
Reactant: CON
Reactant: Cn1cc(C(=O)O)cc1-c1c2c(=O)n(C)c(=O)n(CC3CC3)c2nn1Cc1ccnc2ccc(Cl)cc12
Agent: CCOP(=O)(C#N)OCC
Agent: Cl
Product: CONC(=O)c1cc(-c2c3c(=O)n(C)c(=O)n(CC4CC4)c3nn2Cc2ccnc3ccc(Cl)cc23)n(C)c1

Procedure:
This compound was synthesized by the reaction 5-[2-[(6-chloroquinolin-4-yl)methyl]-7-(cyclopropylmethyl)-5-methyl-4,6-dioxo-4,5,6,7-tetrahydro-2H-pyrazolo[3,4-d]pyrimidin-3-yl]-1-methyl-1H-pyrrole-3-carboxylic acid and methoxylamine hydrochloride using diethyl cyanophosphonate as a coupling reagent. Mass: 548.13 (M+H).
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([CH3:8])[N:5]=[C:4]([CH3:9])[CH:3]=1.C([Li])CCC.[CH2:15]([Sn:19](Cl)([CH2:24][CH2:25][CH2:26][CH3:27])[CH2:20][CH2:21][CH2:22][CH3:23])[CH2:16][CH2:17][CH3:18]>C(OCC)C>[CH3:8][C:6]1[CH:7]=[C:2]([Sn:19]([CH2:20][CH2:21][CH2:22][CH3:23])([CH2:24][CH2:25][CH2:26][CH3:27])[CH2:15][CH2:16][CH2:17][CH3:18])[CH:3]=[C:4]([CH3:9])[N:5]=1
Reactant: Cc1cc(Br)cc(C)n1
Reactant: CCCC[Sn](Cl)(CCCC)CCCC
Agent: [Li]CCCC
Solvent: CCOCC
Product: CCCC[Sn](CCCC)(CCCC)c1cc(C)nc(C)c1
Temperature: -60 °C
Reaction time: 0.25 h
Yield: 101.1 %

Procedure:
A 22 L flask was charged with 740 g of 4-bromo-2,6-lutidine and 10.0 L of diethyl ether and cooled to -60° C. in a Dry Ice/acetone bath under nitrogen. A solution of 4.0 moles of n-butyllithium was added dropwise over 1 hour maintaining a temperature below -58° C. to form an orange-yellow precipitate. After continued stirring in the cold for 15 minutes, 1280 g of tributyltin chloride was added over 2 hours at a temperature of -60° to -57° C. to form a solution. The reaction was stirred cold for 45 minutes before it was slowly (2 hours) warmed to 20° C. A portion of Super-Cel (100 g) was added and the reaction mixture was filtered to remove the precipitated lithium chloride. The cake was washed with diethyl ether (2×500 ml). After concentration to dryness a total of 1575 g (99.7% yield) of product was obtained which was used without further purification.
Reaction SMILES: C(=O)(O)[O-].[Na+].[NH2:6][C:7]1[CH:15]=[CH:14][CH:13]=[C:12]([CH3:16])[C:8]=1[C:9]([OH:11])=[O:10].[CH3:17][C:18]1[O:22][C:21]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[N:20][C:19]=1[CH2:29][O:30][C:31]1[CH:36]=[CH:35][C:34]([S:37](Cl)(=[O:39])=[O:38])=[CH:33][CH:32]=1>C1COCC1.O>[CH3:16][C:12]1[CH:13]=[CH:14][CH:15]=[C:7]([NH:6][S:37]([C:34]2[CH:35]=[CH:36][C:31]([O:30][CH2:29][C:19]3[N:20]=[C:21]([C:23]4[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=4)[O:22][C:18]=3[CH3:17])=[CH:32][CH:33]=2)(=[O:38])=[O:39])[C:8]=1[C:9]([OH:11])=[O:10]
Reactant: Cc1oc(-c2ccccc2)nc1COc1ccc(S(=O)(=O)Cl)cc1
Reactant: Cc1cccc(N)c1C(=O)O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: Cc1cccc(NS(=O)(=O)c2ccc(OCc3nc(-c4ccccc4)oc3C)cc2)c1C(=O)O
Temperature: 60 °C

Procedure:
Sodium bicarbonate (159 mg, 1.89 mmol) and 2-amino-6-methylbenzoic acid (95.5 mg, 0.63 mmol) are dissolved in a mixture of 1 mL of THF and 1.5 mL of water and heated to 60° C. A solution of the title C compound, 4-(5-methyl-2-phenyl-oxazol-4-ylmethoxy)-benzenesulfonyl chloride (200 mg, 0.55 mmol) in 1 mL of THF is then added dropwise. The mixture is heated for an additional 2 h at 60° C., after which most of the THF is removed by passing a stream of nitrogen gas over the solution. The residue is partitioned between EtOAc and 1 N aqueous HCl. The organic phase is dried over anhydrous magnesium sulfate, filtered, and concentrated under vacuum to give crude product which is purified by chromatography on silica gel with an EtOAc (15%)-hexane (85%) mixture (containing 0.5% formic acid) as the eluent to give 2-methyl-6-[4-(5-methyl-2-phenyl-oxazol-4-ylmethoxy)-benzenesulfonylamino]-benzoic acid as a white solid: m.p. 167-170° C.; ESI-MS 479 [M+1]+.
Reaction SMILES: CS(O[CH2:6][C@H:7]1[CH2:11][CH2:10][N:9]([C:12]2[C:21]3[C:16](=[N:17][CH:18]=[CH:19][N:20]=3)[CH:15]=[C:14]([C:22]3[CH:27]=[CH:26][C:25]([N:28]4[CH2:33][CH2:32][O:31][CH2:30][CH2:29]4)=[CH:24][CH:23]=3)[N:13]=2)[CH2:8]1)(=O)=O.[CH3:34][NH2:35]>>[CH3:34][NH:35][CH2:6][C@H:7]1[CH2:11][CH2:10][N:9]([C:12]2[C:21]3[C:16](=[N:17][CH:18]=[CH:19][N:20]=3)[CH:15]=[C:14]([C:22]3[CH:23]=[CH:24][C:25]([N:28]4[CH2:33][CH2:32][O:31][CH2:30][CH2:29]4)=[CH:26][CH:27]=3)[N:13]=2)[CH2:8]1
Reactant: CS(=O)(=O)OC[C@H]1CCN(c2nc(-c3ccc(N4CCOCC4)cc3)cc3nccnc23)C1
Reactant: CN
Product: CNC[C@H]1CCN(c2nc(-c3ccc(N4CCOCC4)cc3)cc3nccnc23)C1

Procedure:
The mixture of (S)-(1-(7-(4-morpholinophenyl)pyrido[4,3-b]pyrazin-5-yl)pyrrolidin-3-yl)methyl methanesulfonate (100 mg, 0.21 mmol) and MeNH2 solution (33% in water, 5 mL) was refluxed overnight, concentrated, and purified by chromatography to give the title compound. MS (m/z): 405 (M+H)+
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][C:7]([NH:9][CH:10]1[C:35](=[O:36])[N:12]2[CH:13]([C:19]([O:21][CH:22]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)=[O:20])[C:14]([CH:17]=[O:18])=[CH:15][S:16][C@H:11]12)=[O:8].[CH2:37](O)[CH2:38][OH:39].O.C1(C)C(S(O)(=O)=O)=CC=CC=1>C1C=CC=CC=1>[S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][C:7]([NH:9][CH:10]1[C:35](=[O:36])[N:12]2[CH:13]([C:19]([O:21][CH:22]([C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=3)[C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)=[O:20])[C:14]([CH:17]3[O:39][CH2:38][CH2:37][O:18]3)=[CH:15][S:16][C@H:11]12)=[O:8]
Reactant: O=CC1=CS[C@@H]2C(NC(=O)Cc3cccs3)C(=O)N2C1C(=O)OC(c1ccccc1)c1ccccc1
Reactant: OCCO
Agent: Cc1ccccc1S(=O)(=O)O
Solvent: O
Solvent: c1ccccc1
Product: O=C(Cc1cccs1)NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)C(C3OCCO3)=CS[C@H]12

Procedure:
Benzhydryl 7-(2-thienylacetamido)-3-formyl-2-cephem-4-carboxylate (21.5 g., 41.5 mmol.) was combined with 11.6 ml. of ethylene glycol (0.2 mole) and toluenesulfonic acid monohydrate (0.197 g., 1.04 mmol.) in 500 ml. benzene. The mixture was refluxed for 10 hours using a Dean-Stark trap (1.5 ml. water collected), cooled, and evaporated in vacuo to dryness. The product was taken up in ethyl acetate and washed successively with sodium bicarbonate solution (2X), water (2X) and sodium chloride solution and subsequently dried over Na2SO4. Evaporation in vacuo to dryness gave a product which was chromatographed on 40 g. of silica gel using a benzene-ethyl acetate gradient. Crystallization of the purified product from methylene chloride-hexane gave benzhydryl 7(2-thienylacetamido)-3-(1,3-dioxolan-2-yl)-2-cephem-4-carboxylate as colorless needles (15.07 g., 64.2%): mp 142°-143°; ir (CHCl3) 1780 cm-1 (β-lactam C = 0); nmr (CDCl3) 3.3-3.9 (m, 4, --CH2 --CH2 --), 3.83 (s, 2, side chain CH2), 5.10 (d, 1, J = 4.0 Hz, C6 -H), 5.17 (s, 1, acetal CH), 5.21 (s, 1, C4 -H) and 5.45 ppm (q, 1, J = 4.0 and 8.0 Hz, C7 -H).
Reaction SMILES: [CH3:1][C:2]1[NH:6][C:5]2[C:7](=[O:10])[CH2:8][CH2:9][C:4]=2[C:3]=1[C:11]([OH:13])=O.C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl.[NH:28]1[CH2:32][CH2:31][CH2:30][C@H:29]1[CH2:33][N:34]1[CH2:38][CH2:37][CH2:36][CH2:35]1>CN(C=O)C>[CH3:1][C:2]1[NH:6][C:5]2[C:7](=[O:10])[CH2:8][CH2:9][C:4]=2[C:3]=1[C:11]([N:28]1[CH2:32][CH2:31][CH2:30][C@H:29]1[CH2:33][N:34]1[CH2:38][CH2:37][CH2:36][CH2:35]1)=[O:13]
Reactant: C1CN[C@H](CN2CCCC2)C1
Reactant: Cc1[nH]c2c(c1C(=O)O)CCC2=O
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: Cc1[nH]c2c(c1C(=O)N1CCC[C@H]1CN1CCCC1)CCC2=O
Reaction time: 0.33 h
Yield: 80.8 %

Procedure:
A mixture of 2-methyl-6-oxo-1,4,5,6-tetrahydro-cyclopenta[b]pyrrole-3-carboxylic acid (Example B, 3.58 g, 20 mmol), HOBt (2.7 g, 20 mmol) and EDC (5.74 g, 30 mmol) in dry DMF (50 mL) was stirred at 0° C. to room temperature for 20 min. Then (S)-(+)-1-(2-pyrrolidinylmethyl)pyrrolidine (24 mmol) was added and stirring was continued for 48 hours. The solvent was removed under reduced pressure and the residue was dissolved in EtOAc, washed with sat. Na2CO3, dried, concentrated and purified on a silica gel column to give 5.1 g (81%) of the titled compound as a yellowish foam.
Reaction SMILES: S(Cl)([Cl:3])=O.[CH3:5][S:6]([C:9]1[C:17]([S:18]([CH3:21])(=[O:20])=[O:19])=[CH:16][C:12]([C:13](O)=[O:14])=[C:11]([CH3:22])[CH:10]=1)(=[O:8])=[O:7]>CN(C=O)C>[CH3:5][S:6]([C:9]1[C:17]([S:18]([CH3:21])(=[O:20])=[O:19])=[CH:16][C:12]([C:13]([Cl:3])=[O:14])=[C:11]([CH3:22])[CH:10]=1)(=[O:8])=[O:7]
Reactant: O=S(Cl)Cl
Reactant: Cc1cc(S(C)(=O)=O)c(S(C)(=O)=O)cc1C(=O)O
Solvent: CN(C)C=O
Product: Cc1cc(S(C)(=O)=O)c(S(C)(=O)=O)cc1C(=O)Cl

Procedure:
15 l of thionyl chloride are initially introduced at 40°, and 50 ml of DMF are added. 3.8 kg of 4,5-bismethanesulfonyl-2-methylbenzoic acid are slowly introduced with stirring, and the mixture is then stirred at the boiling point for 1 hour. After cooling, the excess SOCl2 is removed, and the residue is codistilled a number of times with 5 l of toluene, giving 4, 5-bismethanesulfonyl-2-methylbenzoyl chloride, which is reacted further as the crude product.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]([C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([N+:27]([O-])=O)[CH:22]=2)[NH:10][CH:11]([C:13]2[CH:18]=[C:17]([F:19])[CH:16]=[C:15]([F:20])[CH:14]=2)[CH3:12])=[CH:5][CH:4]=1.[BH4-].[Na+]>CO.O.O.O.O.O.O.[Ni](Cl)Cl>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]([NH:10][CH:11]([C:13]2[CH:14]=[C:15]([F:20])[CH:16]=[C:17]([F:19])[CH:18]=2)[CH3:12])[C:21]2[CH:22]=[C:23]([NH2:27])[CH:24]=[CH:25][CH:26]=2)=[CH:5][CH:4]=1
Reactant: COc1ccc(C(NC(C)c2cc(F)cc(F)c2)c2cccc([N+](=O)[O-])c2)cc1
Agent: Cl[Ni]Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: COc1ccc(C(NC(C)c2cc(F)cc(F)c2)c2cccc(N)c2)cc1
Yield: 91.4 %

Procedure:
In a similar manner to that described in Example (1b), a solution of N-[(4-methoxyphenyl)-(3-nitrophenyl)methyl]-N-[1-(3,5-difluorophenyl)ethyl]amine (2.65 g) [prepared as described in step (a) above] in methanol (50 ml), nickel chloride hexahydrate (3.16 g) and sodium borohydride (1.0 g) were reacted, to afford the title compound (2.24 g) as a pale orange oil.
Reaction SMILES: [F:1][C:2]([F:22])([F:21])[C:3]1[CH:4]=[C:5]([CH:18]=[CH:19][CH:20]=1)[O:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][CH2:14][C:15](=[NH:17])[NH2:16])=[CH:9][CH:8]=1.[OH:23][CH:24]=[C:25]([CH2:30][C:31]1[CH:32]=[N:33][C:34]([O:37][CH3:38])=[N:35][CH:36]=1)[C:26](OC)=O.C([O-])(=O)C.[K+]>C1(C)C=CC=CC=1>[CH3:38][O:37][C:34]1[N:33]=[CH:32][C:31]([CH2:30][C:25]2[C:24](=[O:23])[N:17]=[C:15]([CH2:14][CH2:13][C:10]3[CH:9]=[CH:8][C:7]([O:6][C:5]4[CH:18]=[CH:19][CH:20]=[C:3]([C:2]([F:21])([F:22])[F:1])[CH:4]=4)=[CH:12][CH:11]=3)[NH:16][CH:26]=2)=[CH:36][N:35]=1
Reactant: N=C(N)CCc1ccc(Oc2cccc(C(F)(F)F)c2)cc1
Reactant: COC(=O)C(=CO)Cc1cnc(OC)nc1
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: COc1ncc(Cc2c[nH]c(CCc3ccc(Oc4cccc(C(F)(F)F)c4)cc3)nc2=O)cn1
Yield: 64.3 %

Procedure:
The same procedure as E38 from a mixture of 3-(4-(3-(trifluoromethyl) phenoxy)phenyl)propanimidamide (200 mg, 0.580 mmol), methyl 3-hydroxy-2-((2-methoxypyrimidin-5-yl)methyl)acrylate (130 mg, 0.580 mmol) and potassium acetate (171 mg, 1.740 mmol) in toluene (10 mL) to afford the title compound (180 mg, 61.1% yield) as a yellow solid. LCMS: rt=8.88 min, [M+H+]=483.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][C@@H:12]([CH3:14])[NH:11][CH2:10][C@@H:9]1[CH3:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[O:16]1[CH2:21][CH2:20][C:19](=O)[CH2:18][CH2:17]1.[BH3-]C#N.[Na+].[N-]=C=O>C1COCC1.CCO>[CH2:1]([N:8]1[CH2:13][C@@H:12]([CH3:14])[N:11]([CH:19]2[CH2:20][CH2:21][O:16][CH2:17][CH2:18]2)[CH2:10][C@@H:9]1[CH3:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C[C@@H]1CN(Cc2ccccc2)[C@@H](C)CN1
Reactant: O=C1CCOCC1
Agent: [BH3-]C#N
Agent: [N-]=C=O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCO
Product: C[C@@H]1CN(Cc2ccccc2)[C@@H](C)CN1C1CCOCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 83.8 %

Procedure:
To a mixture of (2S,5R)-1-benzyl-2,5-dimethylpiperazine (11.0 g, 53.8 mmol) and of tetrahydro-4H-pyran-4-one (5.39 g, 53.8 mmol) at 0° C. was added Ti(IV) isopropoxide (19.2 mL, 67.3 mmol). The resulting mixture was stirred at rt overnight and an orange suspension was obtained. To the suspension was added EtOH (25 mL) and NaCNBH3 (4.27 g, 64.6 mmol, 1.20 eq). The resulting mixture was stirred at rt for 24 h. The reaction mixture was then quenched with water (5.0 mL) and a yellow solid was generated. The suspension was diluted with EtOAc (400 mL) and filtered. The filtrate was concentrated under reduced pressure. The residue was again diluted with EtOAc (500 mL), dried over Na2SO4, and filtered. The filtrate was collected and concentrated under reduced pressure to afford a yellow oil. The oil was diluted in THF (400 mL) and PS-isocyanate was added to remove secondary amine. The suspension was filtered and the filtrate concentrated. The residue was purified by column chromatography using 50:5:1 CHCl3/MeOH/Et3N to afford the desired compound as yellow oil (13.0 g, 84%)
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[C:5](OC(=O)C)(=[O:7])[CH3:6].ClC(Cl)C.[C:16]([C:18]1[CH:19]=[CH:20][C:21]2[CH2:27][CH2:26][C:25]3[CH:28]=[CH:29][CH:30]=[CH:31][C:24]=3[S:23][C:22]=2[CH:32]=1)#[N:17]>>[C:5]([C:29]1[CH:30]=[CH:31][C:24]2[S:23][C:22]3[CH:32]=[C:18]([C:16]#[N:17])[CH:19]=[CH:20][C:21]=3[CH2:27][CH2:26][C:25]=2[CH:28]=1)(=[O:7])[CH3:6]
Reactant: CC(=O)OC(C)=O
Reactant: N#Cc1ccc2c(c1)Sc1ccccc1CC2
Agent: [Al+3]
Agent: [Cl-]
Solvent: CC(Cl)Cl
Product: CC(=O)c1ccc2c(c1)CCc1ccc(C#N)cc1S2
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
Add 125.5 g. (0.94 mole) of aluminum chloride and 47.9 g. (0.47 mole) of acetic anhydride to 1.01 of dichloroethane. Stir at room temperature for 10 minutes. Add 14 g. (0.058 mole) of 3-cyano-10,11-dihydrodibenzo[b,f]thiepin in portions. Stir at room temperature for 4 hours. Pour the reaction mixture over ice and extract into ethyl acetate. Wash with water, dry over sodium sulfate, filter and evaporate to dryness to obtain the title product. (m.p. 138°-141° C.)
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[N:5]=[C:4]([NH:14][CH2:15][C:16]([N:18]([CH3:25])[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[O:17])[CH:3]=1.[Cl:26]N1C(=O)CCC1=O>C(O)(=O)C>[Cl:26][C:3]1[C:4]([NH:14][CH2:15][C:16]([N:18]([CH3:25])[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[O:17])=[N:5][C:6]([C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)=[N:7][C:2]=1[CH3:1]
Reactant: O=C1CCC(=O)N1Cl
Reactant: Cc1cc(NCC(=O)N(C)c2ccccc2)nc(-c2ccccc2)n1
Solvent: CC(=O)O
Product: Cc1nc(-c2ccccc2)nc(NCC(=O)N(C)c2ccccc2)c1Cl
Temperature: 90 °C
Reaction time: 3 h
Yield: 99.7 %

Procedure:
A mixture of 2-(6-methyl-2-phenyl-4-pyrimidinylamino)-N-methyl-N-phenylacetamide (1.0 g) obtained in Example 88, N-chlorosuccinimide (0.44 g) and acetic acid (15 ml) is heated with stirring at 90° C. for three hours, and the reaction mixture is concentrated under reduced pressure. To the residue is added ice-water (30 ml) with stirring, and the precipitates are collected by filtration, washed with water, and recrystallized from isopropanol to give the desired compound (1.1 g), m.p. 154-155° C.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:14]=[CH:15][CH:16]=1)[NH:7][C:8](=[O:13])[CH2:9][CH2:10][CH2:11][CH3:12])([O-])=O.O>[Fe].C(O)C>[NH2:1][C:4]1[CH:5]=[C:6]([CH:14]=[CH:15][CH:16]=1)[NH:7][C:8](=[O:13])[CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: CCCCC(=O)Nc1cccc([N+](=O)[O-])c1
Agent: [Fe]
Solvent: O
Solvent: CCO
Product: CCCCC(=O)Nc1cccc(N)c1
Reaction time: 0.5 h
Yield: 98.3 %

Procedure:
A mixture of 177.6 g of m-nitrovaleranilide, 160 ml of water, 8 ml of 22° Be hydrochloric acid and 640 ml of 95% ethanol was refluxed and 480 g of iron powder were added with stirring over 30 minutes. Reflux was continued for 30 minutes with stirring and the mixture was filtered. The filtrate was concentrated to dryness under reduced pressure and the residue was chromatographed over silica gel. Elution with an 8- 2 methylene chloride-acetone mixture gave 151 g of m-aminovaleranilide with a specific rotation nD20 = 1.541.
Reaction SMILES: [C:1]([N:9]=[C:10]=[S:11])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N+:12](=[CH2:14])=[N-:13]>CCOCC>[C:1]([NH:9][C:10]1[S:11][N:13]=[N:12][CH:14]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(N=C=S)c1ccccc1
Reactant: C=[N+]=[N-]
Solvent: CCOCC
Product: O=C(Nc1cnns1)c1ccccc1
Reaction time: 1 h
Yield: 36.6 %

Procedure:
To a stirred solution of benzoylisothiocyanate (50.6 g., 310 mmoles) in commercial anhydrous ether (400 ml.), maintained at 0° and in a nitrogen atmosphere, was added dropwise with vigorous stirring, 0.685 N ethereal diazomethane (453 ml., 310 mmoles). When the addition was completed, the mixture was stirred for 1 hour at 0°, the solid was collected by filtration and dried in vacuo. The melting point of the crude material (23.3 g.) thus obtained was observed somewhere in the region 232° to 257°. Goerdler reported m.p. 267° for the pure material. A small second crop (2.1 g.) was obtained by evaporation of the mother liquor in vacuo. The total yield was therefore 40%.
Reaction SMILES: [NH2:1][N:2]1[CH2:6][C:5](=[O:7])[N:4]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([OH:16])=[O:15])[CH:9]=2)[C:3]1=[S:17].[CH3:18][C:19]1[CH:20]=[C:21]([N:26]2[C:30]([OH:31])=[C:29]([CH:32]=O)[C:28]([CH3:34])=[N:27]2)[CH:22]=[CH:23][C:24]=1[CH3:25].C(O)C>CO>[C:14]([C:10]1[CH:9]=[C:8]([N:4]2[C:5](=[O:7])[CH2:6][N:2]([N:1]=[CH:32][C:29]3[C:28]([CH3:34])=[N:27][N:26]([C:21]4[CH:22]=[CH:23][C:24]([CH3:25])=[C:19]([CH3:18])[CH:20]=4)[C:30]=3[OH:31])[C:3]2=[S:17])[CH:13]=[CH:12][CH:11]=1)([OH:16])=[O:15]
Reactant: NN1CC(=O)N(c2cccc(C(=O)O)c2)C1=S
Reactant: Cc1ccc(-n2nc(C)c(C=O)c2O)cc1C
Solvent: CCO
Solvent: CO
Product: Cc1ccc(-n2nc(C)c(C=NN3CC(=O)N(c4cccc(C(=O)O)c4)C3=S)c2O)cc1C
Yield: 78.7 %

Procedure:
50 mg (0.2 mmol) of the 1-amino-3-(3-carboxyphenyl)-2-thioxoimidazolidin-4-one synthesized above in 1) and 55 mg (0.22 mmol) of the 1-(3,4-dimethylphenyl)-5-hydroxy-3-methyl-1H-pyrazole-4-carbaldehyde synthesized in 1) of Reference Synthetic Example 1 were stirred in a liquid mixture of 10 ml of ethanol and 5 ml of methanol at room temperature for 96 hours. The resulting insoluble was collected by filtration to obtain 73 mg of the desired product as a yellow solid (yield 72%).
Reaction SMILES: [NH2:1][C:2]1[N:13]=[C:12]([Cl:14])[CH:11]=[CH:10][C:3]=1[C:4](N(OC)C)=[O:5].[Cl:15][C:16]1[C:17]([F:25])=[CH:18][C:19](I)=[C:20]([O:22][CH3:23])[CH:21]=1>>[NH2:1][C:2]1[C:3]([C:4]([C:19]2[CH:18]=[C:17]([F:25])[C:16]([Cl:15])=[CH:21][C:20]=2[O:22][CH3:23])=[O:5])=[CH:10][CH:11]=[C:12]([Cl:14])[N:13]=1
Reactant: CON(C)C(=O)c1ccc(Cl)nc1N
Reactant: COc1cc(Cl)c(F)cc1I
Product: COc1cc(Cl)c(F)cc1C(=O)c1ccc(Cl)nc1N

Procedure:
The title compound was prepared from 2-Amino-6-chloro-N-methoxy-N-methyl-nicotinamide (Example 3) and 5-chloro-4-fluoro-2-iodoanisole (prepared as described in Step A above) using the procedure described in Example 7. HRMS, observed: 312.9943, Calcd for (M−H)+: 312.9947.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[C:12]3[CH:13]=[N:14][C:15]([CH3:18])=[C:16]([OH:17])[C:11]=3[CH2:10][O:9]2)=[CH:4][CH:3]=1.[H-].[Na+].[C:21](=O)([O:37]C(Cl)C)[O:22][CH2:23][C@@H:24]1[CH2:28][CH2:27][CH2:26][N:25]1/[N+:29](/[O-:36])=[N:30]/[O:31][CH2:32][CH2:33][CH2:34][CH3:35]>CN(C=O)C>[C:21](=[O:37])([O:17][C:16]1[C:11]2[CH2:10][O:9][C@@H:8]([C:5]3[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=3)[C:12]=2[CH:13]=[N:14][C:15]=1[CH3:18])[O:22][CH2:23][C@@H:24]1[CH2:28][CH2:27][CH2:26][N:25]1/[N+:29](/[O-:36])=[N:30]\[O:31][CH2:32][CH2:33][CH2:34][CH3:35]
Reactant: CCCCO/N=[N+](\[O-])N1CCC[C@H]1COC(=O)OC(C)Cl
Reactant: Cc1ncc2c(c1O)CO[C@H]2c1ccc(Cl)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCCO/N=[N+](/[O-])N1CCC[C@H]1COC(=O)Oc1c(C)ncc2c1CO[C@H]2c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a solution of (3S)-3-(4-chlorophenyl)-6-methyl-1,3-dihydrofuro[3,4-c]pyridine-7-ol (900 mg, 3.44 mmol) in DMF (10 mL) at 0° C. was added sodium hydride (206 mg, 5.16 mmol) and, in 10 minutes, followed by addition of {(2S)-1-[(Z)-butoxy-NNO-azoxy]pyrrolidin-2-yl}methyl 1-chloroethyl carbonate (1.3 g, 4.02 mmol). After stirring at rt for 3 h, the mixture was partitioned between Et2O (50 mL) and water (50 mL). The organic layer was washed with brine (3×50 mL), dried over MgSO4, and concentrated. The residue was purified by flash chromatography (Biotage 25+M) using 30-50% EtOAc/hexane gradient, affording the title compound: 1H NMR (500 MHz, CDCl3) δ 8.08 (s, 1H), 7.37-7.27 (m, 4H), 6.21 (s, 1H), 5.29-5.13 (m, 2H), 4.49 (m, 1H), 4.40 (m, 1H), 4.35 (m, 1H), 4.20 (m, 2H), 3.65 (m, 1H), 3.57 (m, 1H), 2.52 (s, 3H), 2.20 (m, 1H), 2.05 (m, 2H), 1.90 (m, 1H), 1.75 (m, 2H), 1.42 (m, 2H), 0.94 (m, 3H).
Reaction SMILES: [C:1]([CH:3]([CH2:8][C:9]([C:11]1[CH:16]=[CH:15][C:14]([CH:17]2[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]2)=[CH:13][CH:12]=1)=O)[C:4]([O:6][CH3:7])=[O:5])#[N:2].O1CCOCC1.[ClH:29]>>[Cl:29][C:1]1[NH:2][C:9]([C:11]2[CH:16]=[CH:15][C:14]([CH:17]3[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]3)=[CH:13][CH:12]=2)=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5]
Reactant: COC(=O)C(C#N)CC(=O)c1ccc(C2CCCCC2)cc1
Reactant: Cl
Solvent: C1COCCO1
Product: COC(=O)c1cc(-c2ccc(C3CCCCC3)cc2)[nH]c1Cl
Temperature: 25 °C
Reaction time: 8 h

Procedure:
14% Hydrogen chloride-1,4-dioxane solution (50 mL) was added to methyl 2-cyano-4-(4-cyclohexylphenyl)-4-oxobutanoate (12.1 g) and the mixture was stirred at room temperature for 8 hr and concentrated under reduced pressure. The residue was dissolved in ethyl acetate, washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was crystallized from diisopropyl ether and collected by filtration to give a nearly 1:1 mixture (3.41 g) of the title compound and methyl 2-amino-5-(4-cyclohexylphenyl)-3-furoate. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate=7:2) to give the title compound as crystals (yield 0.64 g, 5%).
Reaction SMILES: [OH-].[Na+].[CH:3]([C:6]1([C:12]([O:14][CH3:15])=[O:13])[CH2:10][CH2:9][CH2:8][C:7]1=[O:11])([CH3:5])[CH3:4].[Cl:16][C:17]1[CH:24]=[CH:23][C:20]([CH:21]=O)=[CH:19][CH:18]=1.Cl>O.CO>[Cl:16][C:17]1[CH:24]=[CH:23][C:20]([CH:21]=[C:8]2[CH2:9][CH2:10][C:6]([CH:3]([CH3:5])[CH3:4])([C:12]([O:14][CH3:15])=[O:13])[C:7]2=[O:11])=[CH:19][CH:18]=1
Reactant: COC(=O)C1(C(C)C)CCCC1=O
Reactant: O=Cc1ccc(Cl)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: COC(=O)C1(C(C)C)CCC(=Cc2ccc(Cl)cc2)C1=O

Procedure:
To a solution of 4 g of sodium hydroxide in 1000 ml of water were added 21 g of methyl 1-isopropyl-2-oxocylopentanecarboxylate (prepared in Reference Example 2 hereinafter) and a solution of 16 g of 4-chlorobenzaldehyde in 1000 ml of methanol, and the mixture was stirred for 5 hours at room temperature. The reaction mixture was neutralized with diluted hydrochloric acid and the precipitate was collected by filtration. Product 33.6 g (yield, 96.2%)