Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([CH2:7][NH:8][C:9]([N:11]2[C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=3[N:13]([CH2:20][CH3:21])[C:12]2=[O:22])=[O:10])[CH2:3][CH2:2]1.[CH3:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[O:30][CH2:31][CH:32]1[O:34][CH2:33]1>>[NH:1]1[CH2:6][CH2:5][CH:4]([CH2:7][NH:8][C:9]([N:11]2[C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=3[N:13]([CH:20]([CH3:23])[CH3:21])[C:12]2=[O:22])=[O:10])[CH2:3][CH2:2]1.[O:34]1[CH:32]([CH2:31][O:30][C:25]2[CH:24]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH2:33]1
Reactant: Cc1ccccc1OCC1CO1
Reactant: CCn1c(=O)n(C(=O)NCC2CCNCC2)c2ccccc21
Product: CC(C)n1c(=O)n(C(=O)NCC2CCNCC2)c2ccccc21
Product: c1ccc(OCC2CO2)cc1

Procedure:
The procedure given in Example 104 was followed using 3-ethyl-2-oxo-2,3-dihydro-benzimidazole-1-carboxylic acid (piperidin-4-ylmethyl)-amide and glycidyl 2-methylphenyl ether as a reactant, instead of 3-isopropyl-2-oxo-2,3-dihydro-benzimidazole-1-carboxylic acid (piperidin-4-ylmethyl)-amide and 1,2-epoxy-3-phenoxypropane, to give the title compound.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]([NH:10][C:11]2[CH:12]=[C:13]([CH:17]([NH:22][C:23]3[C:32]4[C:27](=[C:28]([C:33]([NH2:35])=[O:34])[CH:29]=[CH:30][CH:31]=4)[N:26]=[CH:25][N:24]=3)[CH2:18][N:19]([CH3:21])[CH3:20])[CH:14]=[CH:15][CH:16]=2)=[O:9])[CH:5]=[CH:4][N:3]=1.CC(O)(C)C.CS(C)=O.[NH:45]1[CH2:49][CH2:48][CH2:47][CH2:46]1>O>[CH3:20][N:19]([CH3:21])[CH2:18][CH:17]([NH:22][C:23]1[C:32]2[C:27](=[C:28]([C:33]([NH2:35])=[O:34])[CH:29]=[CH:30][CH:31]=2)[N:26]=[CH:25][N:24]=1)[C:13]1[CH:14]=[CH:15][CH:16]=[C:11]([NH:10][C:8]([C:6]2[CH:5]=[CH:4][N:3]=[C:2]([N:45]3[CH2:49][CH2:48][CH2:47][CH2:46]3)[CH:7]=2)=[O:9])[CH:12]=1
Reactant: C1CCNC1
Reactant: CN(C)CC(Nc1ncnc2c(C(N)=O)cccc12)c1cccc(NC(=O)c2ccnc(Cl)c2)c1
Solvent: CS(C)=O
Solvent: CC(C)(C)O
Solvent: O
Product: CN(C)CC(Nc1ncnc2c(C(N)=O)cccc12)c1cccc(NC(=O)c2ccnc(N3CCCC3)c2)c1
Temperature: 110 °C
Yield: 35.8 %

Procedure:
To a 10-mL microwave-rated vial with magnetic stir bar at r.t. was added 4-(1-{3-[(2-Chloro-pyridine-4-carbonyl)-amino]-phenyl}-2-dimethylamino-ethylamino)-quinazoline-8-carboxylic acid amide (0.045 g, 0.092 mmol, 1 eq.), t-BuOH (2 mL), DMSO (1 mL), and Pyrrolidine (0.076 mL, 0.92 mmol, 10 eq.). The vial was capped and heated under microwave conditions (50 W, 20 min. ramp, 110° C., STND, 1 hr. hold time) followed by addition of another aliquot of Pyrrolidine (0.1 mL) then microwaved (70 W, 20 min. ramp, 140° C., STND, 1 hr. hold time). Reaction was diluted with water (20 mL) and extracted with EtOAc (3×30 mL). The combined organics were washed with brine, dried (e.g., Na2SO4), filtered and concentrated. The resulting residue was purified via preparative HPLC afforded the desired compound as a white solid (17.3 mg, 36% yield) LCMS (ESI) 525 (M+H).
Reaction SMILES: [OH:1][C:2]1([C:9]2[S:13][C:12]([CH:14]([CH3:16])[CH3:15])=[N:11][CH:10]=2)[CH2:7][CH2:6][C:5](=O)[CH2:4][CH2:3]1.[NH:17]1[CH2:21][CH2:20][C@@H:19]([NH:22][C:23](=[O:29])[O:24][C:25]([CH3:28])([CH3:27])[CH3:26])[CH2:18]1>C(Cl)Cl.[Pd]>[OH:1][C:2]1([C:9]2[S:13][C:12]([CH:14]([CH3:16])[CH3:15])=[N:11][CH:10]=2)[CH2:7][CH2:6][CH:5]([N:17]2[CH2:21][CH2:20][C@@H:19]([NH:22][C:23](=[O:29])[O:24][C:25]([CH3:27])([CH3:26])[CH3:28])[CH2:18]2)[CH2:4][CH2:3]1
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCNC1
Reactant: CC(C)c1ncc(C2(O)CCC(=O)CC2)s1
Agent: [Pd]
Solvent: ClCCl
Product: CC(C)c1ncc(C2(O)CCC(N3CC[C@@H](NC(=O)OC(C)(C)C)C3)CC2)s1
Reaction time: 24 h
Yield: 75.7 %

Procedure:
To a Parr hydrogenation bottle was added 4-hydroxy-4-(2-isopropyl-1,3-thiazol-5-yl)cyclohexanone (0.50 g, 2.09 mmol) and tert-butyl (3R)-pyrrolidin-3-ylcarbamate (0.373 g, 2.0 mmol), dissolved in CH2Cl2 (20 mL), followed by the addition of 10% Pd/C (0.12 g). This mixture was hydrogenated at 35 psi for 24 hour. After the catalyst was filtered and washed with methanol, the filtrate was concentrated in vacuo and chromatographed using MeOH/EtOAc/Et3N (1:9:0.1) to give 0.62 g of title compound in 76% yield. MS (EI) calcd: (M+1)+=409.2; found: 410.2.
Reaction SMILES: [Br:1][C:2]1[S:3][CH:4]=[CH:5][N:6]=1.[CH2:7](Br)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>>[Br-:1].[Br:1][C:2]1[S:3][CH:4]=[CH:5][N+:6]=1[CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: BrCc1ccccc1
Reactant: Brc1nccs1
Product: Brc1scc[n+]1Cc1ccccc1
Product: [Br-]

Procedure:
The starting material was prepared by reaction of equimolar amounts of 2-bromothiazole and benzyl bromide at ambient temperature for 4 hours to give 2-bromo-3-benzylthiazolium bromide.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[C:4]([F:20])=[C:5]([O:10][C:11]2[CH:12]=[C:13]([CH:16]=[C:17](Br)[CH:18]=2)[C:14]#[N:15])[C:6]([Cl:9])=[CH:7][CH:8]=1.[CH2:21]([Sn](CCCC)(CCCC)CCCC)[CH:22]=[CH2:23]>CN(C=O)C.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[NH2:1][CH2:2][C:3]1[C:4]([F:20])=[C:5]([O:10][C:11]2[CH:12]=[C:13]([CH:16]=[C:17]([CH2:23][CH:22]=[CH2:21])[CH:18]=2)[C:14]#[N:15])[C:6]([Cl:9])=[CH:7][CH:8]=1
Reactant: N#Cc1cc(Br)cc(Oc2c(Cl)ccc(CN)c2F)c1
Reactant: C=CC[Sn](CCCC)(CCCC)CCCC
Agent: [Pd]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Product: C=CCc1cc(C#N)cc(Oc2c(Cl)ccc(CN)c2F)c1
Temperature: 160 °C
Yield: 54.3 %

Procedure:
3-{[3-(aminomethyl)-6-chloro-2-fluorophenyl]oxy}-5-bromobenzonitrile (0.300 g, 0.844 mmol), allyltributyl tin (0.414 mL, 1.350 mmol) and tetrakis(triphenylphosphine) palladium(0) (0.097 g, 0.084 mmol) were combined in DMF (7 mL), purged with nitrogen, and heated at 160° C. in a microwave reactor for 30 min. The reaction mixture was filtered through Celite, diluted with EtOAc, and washed four times with dilute aqueous NaHCO3. The organic phase was isolated, dried over MgSO4, filtered and concentrated to dryness. The residue was purified on 40 g silica gel eluted successively with EtOAc followed by 0 to 10% CH3OH/DCM to give 3-{[3-(aminomethyl)-6-chloro-2-fluorophenyl]oxy}-5-(2-propen-1-yl)benzonitrile (0.145 g, 0.458 mmol, 54.3% yield) as a clear oil. 1H NMR (400 MHz, DMSO-d6) δ ppm 7.45-7.53 (m, 2H), 7.42 (s, 1H), 7.22 (s, 1H), 7.13 (s, 1H), 5.87-6.00 (m, 1H), 5.04-5.14 (m, 2H), 3.76 (s, 2H), 3.41 (d, J=6.59 Hz, 2H), 2.18-2.46 (br. s., 2H). LC-MS (ES−) m/z 315.20, 317.08 [M−1]. LC-MS (ES+) m/z 317.31, 319.31 [M+H].
Reaction SMILES: [F:1][C:2]1[C:8]([F:9])=[CH:7][C:5]([NH2:6])=[C:4]([N+:10]([O-])=O)[CH:3]=1.[H][H].O.[C:16](O)(=O)[CH:17]=[O:18]>C(O)C.[Pd].O>[F:1][C:2]1[CH:3]=[C:4]2[C:5](=[CH:7][C:8]=1[F:9])[NH:6][C:17](=[O:18])[CH:16]=[N:10]2
Reactant: O=CC(=O)O
Reactant: Nc1cc(F)c(F)cc1[N+](=O)[O-]
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Solvent: O
Product: O=c1cnc2cc(F)c(F)cc2[nH]1
Reaction time: 2 h
Yield: 54.9 %

Procedure:
4,5-difluoro-2-nitroaniline (2.17 g, 12.5 mmol) was dissolved in 55 ml of ethanol and 250 mg of 10% palladium on carbon was added. The mixture was hydrogenated until the theoretical amount of hydrogen had been absorbed, using a low pressure hydrogenation apparatus. The catalyst was filtered off and the filtrate, containing 4,5-difluoro-o-phenylenediamine, was kept under a nitrogen atmosphere at 0° C. followed by addition of a solution of glyoxylic acid hydrate (1.28 g, 13.7 mmol) in water (3 ml). When the addition was complete the reaction temperature was allowed to reach room temperature during 2 h and 30 ml of water was added. The precipitate was filtered off and dissolved in 60 ml of 5% NaOH solution at 50° C. followed by addition of activated carbon. The mixture was filtered and the filtrate was acidified (pH=1) by addition of concentrated hydrochloric acid. The pinky precipitate was filtered off, washed with water and dried to afford 1.25 g (55 %) of 6,7-difluoroquinoxalin-2(1H)-one melting at 284°-85° C. 1H-NMR (DMSO-d6): 7.27 (m, 1H), 7.95 (m, 1H), 8.20 (s, 1H), 12.55 (s,1H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=O)=[CH:4][CH:3]=1.[CH2:17]([O:19][C:20]1[CH:21]=[C:22]([CH:25]=[C:26]([N+:29]([O-:31])=[O:30])[C:27]=1[OH:28])[CH:23]=O)[CH3:18].[NH2:32][C:33]([NH2:35])=[O:34].Cl>CCO.CO.CCOC(C)=O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:23]([C:22]3[CH:25]=[C:26]([N+:29]([O-:31])=[O:30])[C:27]([OH:28])=[C:20]([O:19][CH2:17][CH3:18])[CH:21]=3)[NH:32][C:33](=[O:34])[NH:35][C:9]=2[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[CH:4][CH:3]=1
Reactant: CCOc1cc(C=O)cc([N+](=O)[O-])c1O
Reactant: NC(N)=O
Reactant: O=C(Cc1ccc(Cl)cc1)c1ccccc1
Agent: Cl
Solvent: CO
Solvent: CCOC(C)=O
Solvent: CCO
Product: CCOc1cc(C2NC(=O)NC(c3ccccc3)=C2c2ccc(Cl)cc2)cc([N+](=O)[O-])c1O
Yield: 6.1 %

Procedure:
To a mixture of 2-(4-chlorophenyl)-1-phenylethanone (200 mg, 0.88 mmol), 3-ethoxy-4-hydroxy-5-nitrobenzaldehyde (200 mg, 0.95 mmol), and urea (156 mg, 2.65 mmol) in anhydrous EtOH (20 mL) was added concentrated HCl solution (0.1 mL), and the reaction mixture was refluxed for three days. When TLC (EtOAc:MeOH=10:1) showed that about 50% of starting materials were consumed, the reaction mixture was concentrated, and the residue was purified by column chromatography (EtOAc:MeOH=40:1) and preparative HPLC to afford Compound 27 as a yellow solid (25 mg, yield: 6.25%). 1H NMR (DMSO-d6 400 MHz TMS): δ 10.30 (s, 1H), 8.81 (s, 1H), 7.60 (s, 1H), 7.45 (s, 1H), 7.25-7.30 (m, 3H), 7.17-7.24 (m, 3H), 7.10 (d, J=8.8 Hz, 2H), 6.80 (d, J=8.4 Hz, 2H), 5.20 (d, J=2.8 Hz, 1H), 4.00-4.11 (m, 2H), 1.33 (t, J=6.8 Hz, 3H); MS (ESI): m/z 466.0 [M+1]+.
Reaction SMILES: [CH3:1][C:2]1[O:3][C:4]([CH2:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[C:5]([C:7](Cl)=[O:8])[N:6]=1.C(=S)=S.[Cl-].[Al+3].[Cl-].[Cl-]>C(OCC)(=O)C>[CH3:1][C:2]1[O:3][C:4]2[CH2:10][CH2:11][C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[C:7](=[O:8])[C:5]=2[N:6]=1
Reactant: Cc1nc(C(=O)Cl)c(CCc2ccccc2)o1
Agent: [Al+3]
Agent: [Cl-]
Solvent: S=C=S
Solvent: CCOC(C)=O
Product: Cc1nc2c(o1)CCc1ccccc1C2=O

Procedure:
1.0 g. of 2-methyl-5-phenethyl-4-oxazolecarbonyl chloride (obtainable by Step D, above) in 15 ml. of carbon disulfide, 2.5 g. of anhydrous aluminum chloride added, and the mixture refluxed for 1 hour. The mixture is then cooled, poured on to ice, and extracted twice with 10 ml. portions of chloroform. The extracts are combined, dried over anhydrous sodium sulfate and evaporated (under vacuum) to obtain a solid residue, which is recyrstallized from ethyl acetate to obtain the title compound, m.p. 174°-176°.
Reaction SMILES: [BH4-].[Na+].C(N)CN.[CH3:7][O:8][C:9](=[O:35])[CH2:10][CH2:11][CH2:12][C:13]#[C:14][CH2:15][N:16]1[C@@H:20]([CH2:21][O:22][C:23](=[O:33])[NH:24][CH2:25][CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH2:19][CH2:18][C:17]1=[O:34]>C(O)C.[Ni](Cl)Cl>[CH3:7][O:8][C:9](=[O:35])[CH2:10][CH2:11][CH2:12]/[CH:13]=[CH:14]\[CH2:15][N:16]1[C@@H:20]([CH2:21][O:22][C:23](=[O:33])[NH:24][CH2:25][CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH2:19][CH2:18][C:17]1=[O:34]
Reactant: COC(=O)CCCC#CCN1C(=O)CC[C@@H]1COC(=O)NCCc1ccccc1
Agent: Cl[Ni]Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: NCCN
Product: COC(=O)CCC/C=C\CN1C(=O)CC[C@@H]1COC(=O)NCCc1ccccc1
Reaction time: 0.25 h
Yield: 57.3 %

Procedure:
95% Ethanol (1.0 mL) was added to a slowly stirred mixture of nickel (II) chloride (86 mg, 0.66 mmol) and sodium borohydride (12 mg, 0.33 mmol) under nitrogen. The mixture immediately turned black. After 15 min, ethylenediamine (70 μL, 1.04 mmol) was added. After an additional 15 min, a solution of alkyne 13 (53 mg, 0.13 mmol) in 95% ethanol (1.0 mL) was added. The flask was evacuated and refilled with hydrogen (3×), and the reaction mixture was stirred vigorously under a balloon of hydrogen for 22 h. The mixture was then filtered through celite, washing with MeOH (5 mL) and the filtrate was concentrated in vacuo. Purification of the residue by flash column chromatography on silica (100% CH2Cl2→50% EtOAc/CH2Cl2, gradient) afforded 30 mg (56%) of the title compound (15).
Reaction SMILES: [NH2:1][CH:2]1[N:8]=[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:6]2[CH:15]=[CH:16][CH:17]=[CH:18][C:5]=2[N:4]([CH2:19][C:20]([F:23])([F:22])[F:21])[C:3]1=[O:24].C(N(CC)CC)C.FC(F)(F)[C:34](O)=[O:35].[C:39]1([CH:45]2[CH2:49][N:48]([CH:50]3[CH2:55][CH2:54][NH:53][CH2:52][CH2:51]3)[C:47](=[O:56])[NH:46]2)[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1>O1CCCC1.CS(C)=O>[O:24]=[C:3]1[C@H:2]([NH:1][C:34]([N:53]2[CH2:52][CH2:51][CH:50]([N:48]3[CH2:49][CH:45]([C:39]4[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=4)[NH:46][C:47]3=[O:56])[CH2:55][CH2:54]2)=[O:35])[N:8]=[C:7]([C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:6]2[CH:15]=[CH:16][CH:17]=[CH:18][C:5]=2[N:4]1[CH2:19][C:20]([F:21])([F:23])[F:22]
Reactant: O=C1NC(c2ccccc2)CN1C1CCNCC1
Reactant: O=C(O)C(F)(F)F
Reactant: NC1N=C(c2ccccc2)c2ccccc2N(CC(F)(F)F)C1=O
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=C(N[C@@H]1N=C(c2ccccc2)c2ccccc2N(CC(F)(F)F)C1=O)N1CCC(N2CC(c3ccccc3)NC2=O)CC1
Temperature: 0 °C
Reaction time: 1 h
Yield: 51 %

Procedure:
3-Amino-2-oxo-5-phenyl-1-(2,2,2-trifluoroethyl)-2,3-dihydro-1H-1,4-benzodiazepine (20.0 mg, 0.06 mmol) and p-nitrophenylchloroformate (12.1 mg, 0.06 mmol) were dissolved in tetrahydrofuran (0.5 mL) under argon, and cooled to 0° C. Triethylamine (8.4 uL, 0.06 mmol) was added and the reaction stirred for 1 h, followed by addition of more triethylamine (21 uL) and 4-phenyl-1-piperidin-4-ylimidazolidin-2-one trifluoroacetic acid salt (21.6 mg, 0.06 mmol), in dimethylsulfoxide (0.5 mL). The reaction was warmed to room temperature and stirred overnight. The crude product was purified by reverse phase HPLC (C-18, 5% to 95% 0.1% trifluoroacetic acid/acetonitrile in 0.1% aqueous trifluoroacetic acid gradient elution) to give the title compound (18.5 mg). MS 605.2459 (M+1)
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH:21]([C:22]([OH:24])=[O:23])[CH2:20][C:19]2[CH:18]=[C:17]3[C:12]([O:13][C@@H:14]([C:26]4[CH:31]=[CH:30][C:29]([O:32][CH2:33][C:34]5[CH:39]=[CH:38][C:37]([Cl:40])=[C:36]([Cl:41])[CH:35]=5)=[CH:28][CH:27]=4)[C:15](=[O:25])[NH:16]3)=[CH:11][C:10]=2[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:42](Cl)[CH2:43]Cl>C(Cl)Cl.CN(C1C=CN=CC=1)C>[CH:10]([C@@H:19]1[CH2:20][CH2:21][C@@H:42]([CH3:43])[CH2:17][C@H:18]1[O:23][C:22]([C@@H:21]1[CH2:20][C:19]2[CH:18]=[C:17]3[C:12]([O:13][C@@H:14]([C:26]4[CH:31]=[CH:30][C:29]([O:32][CH2:33][C:34]5[CH:39]=[CH:38][C:37]([Cl:40])=[C:36]([Cl:41])[CH:35]=5)=[CH:28][CH:27]=4)[C:15](=[O:25])[NH:16]3)=[CH:11][C:10]=2[CH2:9][N:8]1[C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])=[O:24])([CH3:11])[CH3:9]
Reactant: CC(C)(C)OC(=O)N1Cc2cc3c(cc2CC1C(=O)O)NC(=O)[C@H](c1ccc(OCc2ccc(Cl)c(Cl)c2)cc1)O3
Reactant: ClCCCl
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CC(C)[C@@H]1CC[C@@H](C)C[C@H]1OC(=O)[C@@H]1Cc2cc3c(cc2CN1C(=O)OC(C)(C)C)O[C@@H](c1ccc(OCc2ccc(Cl)c(Cl)c2)cc1)C(=O)N3
Temperature: 25 °C
Reaction time: 6 h

Procedure:
(S)-3-[4-(3,4-Dichloro-benzyloxy)-phenyl]-2-oxo-1,2,3,5,7,8-hexahydro-4-oxa-1,6-diaza-anthracene-6,7-dicarboxylic acid 6-tert-butyl ester (8.0 g, 13.3 mmol) was suspended in 30 mL DCM and 1R-2S-5R (−)-menthol (26.6 mmol), EDC (26.6 mmol) and DMAP (cat.) added. The mixture was stirred at r.t. for 6 h and the mixture was diluted with DCM. The organic layer was washed with water and brine, dried over sodium sulfate and concentrated. The residue purified over silica with hexanes-EtOAc gradient (0% EtOAc to 30%) to provide (3S,7S)-3-[4-(3,4-Dichloro-benzyloxy)-phenyl]-2-oxo-1,2,3,5,7,8-hexahydro-4-oxa-1,6-diaza-anthracene-6,7-dicarboxylic acid 6-tert-butyl ester 7-((1R,2S,5R)-2-isopropyl-5-methyl-cyclohexyl) ester (2.4 g, 1H NMR (400 MHz, CDCl3): 8.2 (m, 1H), 7.5 (m, 1H), 7.42 (d, 1H), 7.35 (m, 2H), 7.25 (m, 1H), 6.9 (m, 2H), 6.7 (m, 1H), 6.6 (s, 1H), 5.55 (m, 1H), 4.8-5.1 (m, 1H), 5.0 (s, 2H), 4.3-4.6 (m, 3H), 3.1 (m, 2H), 1.8 (m, 1H), 1.6 (m, 3H), 1.5 (d, 9H), 1.3 (m, 2H), 0.7-1.0 (m, 9H), 0.4 (m, 3H).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:10]=[C:11]([N+:13]([O-:15])=[O:14])[CH:12]=1)[C:7]([OH:9])=[O:8])([O-:3])=[O:2].C(=O)([O-])O.[Na+].[I-].[Na+].Cl[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][OH:30]>CN1CCCC1=O.O>[N+:1]([C:4]1[CH:5]=[C:6]([CH:10]=[C:11]([N+:13]([O-:15])=[O:14])[CH:12]=1)[C:7]([O:9][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][OH:30])=[O:8])([O-:3])=[O:2]
Reactant: OCCCCCCCl
Reactant: O=C(O)c1cc([N+](=O)[O-])cc([N+](=O)[O-])c1
Agent: O=C([O-])O
Agent: [I-]
Agent: [Na+]
Solvent: CN1CCCC1=O
Solvent: O
Product: O=C(OCCCCCCO)c1cc([N+](=O)[O-])cc([N+](=O)[O-])c1
Temperature: 50 °C
Yield: 89 %

Procedure:
357.7 g (1.68 mol) of 3,5-dinitrobenzoic acid are suspended in 750 ml of 1-methyl-2-pyrrolidone. The suspension is stirred up to 50° C. 386.4 g (4.60 mol) of sodium hydrogen carbonate are added and the mixture was heated up to 90° C. 22.50 g (0.150 mol) of sodium iodide and 204.0 ml (1.53 mol) of 6-chlorohexanol are added to the reaction mixture which is heated to 100° C. for 1 h. After 1 h of reaction, the reaction is complete and the orange suspension is thrown on 21 of ice and 11 of water. The product is filtrated, washed water and dried at 50° C. under vacuum for 24 h to give 425.0 g of 6-hydroxyhexyl 3,5-dinitrobenzoate as a rose powder.
Reaction SMILES: [Cl:1][C:2]1[CH:25]=[CH:24][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:11](=[O:23])[C:12]3[S:19][C:18]([CH2:20]Cl)=[C:17]([CH3:22])[C:13]=3[N:14]([CH3:16])[CH:15]=2)=[O:9])=[CH:4][CH:3]=1.CN[CH2:28][P:29]([C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)(=[O:31])[OH:30].C(=O)([O-])[O-].[K+].[K+].[CH3:44][N:45](C=O)C>O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:11](=[O:23])[C:12]3[S:19][C:18]([CH2:20][N:45]([O:30][P:29]([CH3:28])([C:32]4[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=4)=[O:31])[CH3:44])=[C:17]([CH3:22])[C:13]=3[N:14]([CH3:16])[CH:15]=2)=[O:9])=[CH:24][CH:25]=1
Reactant: CN(C)C=O
Reactant: CNCP(=O)(O)c1ccccc1
Reactant: Cc1c(CCl)sc2c(=O)c(C(=O)NCc3ccc(Cl)cc3)cn(C)c12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: Cc1c(CN(C)OP(C)(=O)c2ccccc2)sc2c(=O)c(C(=O)NCc3ccc(Cl)cc3)cn(C)c12
Temperature: 60 °C
Reaction time: 0.5 h

Procedure:
A mixture of N-(4-chlorobenzyl)-2-(chloromethyl)-3,4-dimethyl-7-oxo-4,7-dihydrothieno[3,2-b]pyridine-6-carboxamide (25 mg, 0.063 mmol), 1-(methylamino)methyl(phenyl)phosphinic acid (R. Tyka, Synthesis 1984, 218) (24 mg, 0.0.13 mmol) and potassium carbonate (35 mg, 0.25 mmol) in dry DMF (1.0 mL) and water (0.25 mL) was stirred at 60° C. for 30 minutes, going to a solution. HPLC analysis indicated reaction was complete. The solvent was removed in vacuo, and the resulting white solid was washed with methylene chloride. The solid was dissolved in water (5 mL) and brought to pH 7 with 1.0 M aqueous HCl. After standing in a 0° C. refrigerator overnight, the mixture was filtered, and the collected solid was washed with cold water. Drying in vacuo left the title compound as a white powder (23 mg).
Reaction SMILES: [CH:1]([CH:3]=O)=[O:2].[CH2:5]([NH:7][N:8]=[CH:9][C:10](=[O:12])[CH3:11])[CH3:6]>O>[CH2:5]([N:7]1[CH:11]=[C:10]([OH:12])[C:9]([C:1](=[O:2])[CH3:3])=[N:8]1)[CH3:6]
Reactant: CCNN=CC(C)=O
Reactant: O=CC=O
Solvent: O
Product: CCn1cc(O)c(C(C)=O)n1
Temperature: 25 °C
Yield: 87.6 %

Procedure:
A 40% aqueous solution of glyoxal (2.3 g, 1.8 mL, 16 mmol) was added to a solution of 2-oxopropanal ethylhydrazone (1.83 g, 16 mmol) in water (90 mL). The mixture was heated at reflux for 1 hour. The reaction was cooled to room temperature and extracted with CH2Cl2 (4×). The combined organic extracts were dried over Na2SO4, filtered and concentrated to afford 1-(1-ethyl-4-hydroxy-1H-pyrazol-3-yl)ethanone as a yellow oil (2.16 g, 87%).
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7]2[CH:12]=[CH:11][N:10]=[CH:9][CH:8]=2)=[N:5][NH:4][C:3]1=[S:13].I[CH3:15]>[OH-].[Na+].C(O)C>[CH3:1][N:2]1[C:3]([S:13][CH3:15])=[N:4][N:5]=[C:6]1[C:7]1[CH:12]=[CH:11][N:10]=[CH:9][CH:8]=1
Reactant: Cn1c(-c2ccncc2)n[nH]c1=S
Reactant: CI
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CSc1nnc(-c2ccncc2)n1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 93.2 %

Procedure:
To a solution of 4-Methyl-5-pyridin-4-yl-2,4-dihydro-[1,2,4]triazole-3-thione (1000 mg, 5.20 mmol) in 1M sodium hydroxide (10 mL), added a solution of iodomethane (0.52 mL, 8.32 mmol) in ethanol (3 mL). Stirred at RT overnight. Extracted into 200 mL dichloromethane and washed with brine (50 mL). Dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to yield title compound (1.00 g, 94% yield). 1H-NMR (CDCl3) δ (ppm): 8.81 (d, 2H), 7.62 (d, 2H), 3.68 (s, 3H), 2.82 (s, 3H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:31]=[CH:30][C:6]([CH2:7][S:8][C@@H:9]2[CH2:13][N:12]([C:14]([O:16][CH2:17][C:18]3[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[CH:20][CH:19]=3)=[O:15])[C@H:11]([C:27](O)=[O:28])[CH2:10]2)=[CH:5][CH:4]=1.Cl.Cl.[N:34]1([CH:39]2[CH2:42][NH:41][CH2:40]2)[CH:38]=[CH:37][N:36]=[CH:35]1.C(N(C(C)C)CC)(C)C>C(#N)C.CO>[N:34]1([CH:39]2[CH2:42][N:41]([C:27]([C@@H:11]3[CH2:10][C@H:9]([S:8][CH2:7][C:6]4[CH:30]=[CH:31][C:3]([O:2][CH3:1])=[CH:4][CH:5]=4)[CH2:13][N:12]3[C:14]([O:16][CH2:17][C:18]3[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[CH:20][CH:19]=3)=[O:15])=[O:28])[CH2:40]2)[CH:38]=[CH:37][N:36]=[CH:35]1
Reactant: COc1ccc(CS[C@H]2C[C@@H](C(=O)O)N(C(=O)OCc3ccc([N+](=O)[O-])cc3)C2)cc1
Reactant: c1cn(C2CNC2)cn1
Agent: Cl
Solvent: CO
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(CS[C@H]2C[C@@H](C(=O)N3CC(n4ccnc4)C3)N(C(=O)OCc3ccc([N+](=O)[O-])cc3)C2)cc1
Temperature: 40 °C
Reaction time: 1 h
Yield: 85.2 %

Procedure:
3.80 g of (2S, 4S)-4-(4-methoxybenzylthio)-1-(4-nitrobenzyloxycarbonyl)-2-pyrrolidinecarboxylic acid were dissolved in 40 ml of dry acetonitrile. 1.65 g of N,N'-carbonyldiimidazole were added to the resulting solution, and the mixture was stirred at 40° C. for 1 hour. A solution of 2.00 g of 3-(1-imidazolyl)azetidine dihydrochloride [prepared as described in step (b) above] and 2.90 g of diisopropylethylamine dissolved in a mixture of 30 ml of dry acetonitrile and 5 ml of methanol was then added at room temperature to the reaction mixture, after which the mixture was stirred at the same temperature for 1 hour. At the end of this time, the reaction mixture was concentrated by evaporation under reduced pressure, and the residue was diluted with ethyl acetate. The diluted solution was washed with water and with an aqueous solution of sodium chloride, in that order. The ethyl acetate layer was separated, dried over anhydrous magnesium sulfate and concentrated by evaporation under reduced pressure. The resulting residue was subjected to silica gel chromatography to obtain 4.00 g of the title compound, as a powder, from the fraction obtained by elution with an 85:15 by volume mixture of ethyl acetate and methanol.
Reaction SMILES: [CH3:1][C:2]1[CH:8]=[C:7]([F:9])[CH:6]=[CH:5][C:3]=1[NH2:4].[CH3:10][C:11]1[C:12]([Cl:28])=[N:13][C:14]([N:18]2[CH2:27][CH2:26][C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[CH2:19]2)=[N:15][C:16]=1[CH3:17]>CN(C)C=O>[ClH:28].[CH3:10][C:11]1[C:12]([NH:4][C:3]2[CH:5]=[CH:6][C:7]([F:9])=[CH:8][C:2]=2[CH3:1])=[N:13][C:14]([N:18]2[CH2:27][CH2:26][C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[CH2:19]2)=[N:15][C:16]=1[CH3:17]
Reactant: Cc1nc(N2CCc3ccccc3C2)nc(Cl)c1C
Reactant: Cc1cc(F)ccc1N
Solvent: CN(C)C=O
Product: Cc1cc(F)ccc1Nc1nc(N2CCc3ccccc3C2)nc(C)c1C
Product: Cl
Yield: 30.1 %

Procedure:
After 2-methyl-4-fluoroaniline(0.3 ml, 2.7 mmol) was added to a mixture solution of (5,6-dimethyl-2-(1,2,3,4-tetrahydroisoquinolin-2-yl)-4-chloropyrimidine(0.30 g, 1.0 mmol) and dimethylformamide(10 ml), 0.12 g of the titled compound was obtained in accordance with the same procedure as in Step 4 of Example 57.