Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:14]2[O:15][C:16]([CH3:19])([CH3:18])[O:17][C:13]=2[CH:12]=[C:11]([CH2:20]O)[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1(P([N:36]=[N+:37]=[N-:38])(C2C=CC=CC=2)=O)C=CC=CC=1.N12CCCN=C1CCCCC2>O1CCCC1>[N:36]([CH2:20][C:11]1[CH:10]=[C:9]([O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[C:14]2[O:15][C:16]([CH3:19])([CH3:18])[O:17][C:13]=2[CH:12]=1)=[N+:37]=[N-:38]
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Reactant: CC1(C)Oc2cc(CO)cc(OCc3ccccc3)c2O1
Solvent: C1CCOC1
Solvent: C1CCC2=NCCCN2CC1
Product: CC1(C)Oc2cc(CN=[N+]=[N-])cc(OCc3ccccc3)c2O1
Temperature: 25 °C

Procedure:
To a 0° C. mixture of (7-benzyloxy-2,2-dimethyl-benzo[1,3]dioxol-5-yl)-methanol (0.57 g, 2.0 mmol) and diphenylphosphoryl azide (0.52 mL, 2.4 mmol) in tetrahydrofuran (10 mL) is added 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU, 0.33 mL, 2.2 mmol). The mixture is allowed to warm to room temperature over the weekend and then quenched with the addition of water. The reaction mixture is extracted 3× with ethyl acetate, and the combined extracts were washed with 5% aqueous potassium hydrogen sulfate solution and saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, and then concentrated to give 6-azidomethyl-4-benzyloxy-2,2-dimethyl-benzo[1,3]dioxole, which is used in the next step without purification.
Reaction SMILES: N[C@@](C1C=CC2C(=CC=C(O[C@H]3CC[C@H](C(C)(C)C)CC3)C=2C2C=CC(OC(F)(F)F)=CC=2)C=1)(C)CO.[C:38]([C@H:42]1[CH2:47][CH2:46][C@H:45]([O:48][C:49]2[C:50]([F:66])=[C:51]3[C:56](=[CH:57][CH:58]=2)[CH:55]=[C:54]([C@:59]2([CH3:65])[CH2:63][O:62]C(=O)[NH:60]2)[CH:53]=[CH:52]3)[CH2:44][CH2:43]1)([CH3:41])([CH3:40])[CH3:39]>>[NH2:60][C@@:59]([C:54]1[CH:53]=[CH:52][C:51]2[C:56](=[CH:57][CH:58]=[C:49]([O:48][C@H:45]3[CH2:44][CH2:43][C@H:42]([C:38]([CH3:41])([CH3:40])[CH3:39])[CH2:47][CH2:46]3)[C:50]=2[F:66])[CH:55]=1)([CH3:65])[CH2:63][OH:62]
Reactant: CC(C)(C)[C@H]1CC[C@H](Oc2ccc3cc([C@]4(C)COC(=O)N4)ccc3c2F)CC1
Agent: CC(C)(C)[C@H]1CC[C@H](Oc2ccc3cc([C@@](C)(N)CO)ccc3c2-c2ccc(OC(F)(F)F)cc2)CC1
Product: CC(C)(C)[C@H]1CC[C@H](Oc2ccc3cc([C@@](C)(N)CO)ccc3c2F)CC1

Procedure:
(R)-2-amino-2-(6-(trans-4-tert-butylcyclohexyloxy)-5-fluoronaphthalen-2-yl)propan-1-ol was synthesized as per (R)-2-amino-2-(6-(trans-4-tert-butylcyclohexyloxy)-5-(4-(trifluoromethoxy)phenyl)naphthalen-2-yl)propan-1-ol (Example 221) in 34% yield using (R)-4-(6-(trans-4-tert-butylcyclohexyloxy)-5-fluoronaphthalen-2-yl)-4-methyloxazolidin-2-one as starting material. MS: m/z=357.34 [M−16]+. 1H NMR (MeOD) δ: 8.25 (d, J=9.0 Hz, 1H), 7.92 (d, J=2.0 Hz, 1H), 7.88 (d, J=9.0 Hz, 1H), 7.68 (dd, J=9.3, 2.3 Hz, 1H), 7.49 (d, J=9.3 Hz, 1H), 4.33-4.42 (m, 1H), 3.94 (d, J=11.5 Hz, 1H), 3.84 (d, J=11.5 Hz, 1H), 2.17-2.26 (m, 2H), 1.86-1.95 (m, 2H), 1.79 (s, 3H), 1.46-1.58 (m, 2H), 1.08-1.27 (m, 3H), 0.90 (s, 9H)
Reaction SMILES: [Cl:1][C:2]1[N:3]=[CH:4][NH:5][C:6]=1[Cl:7].[OH-].[K+].[Br:10][CH2:11][CH3:12].[K+].[Br-].Br[CH2:16][CH2:17][C:18]1[CH:27]=[CH:26][C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH:19]=1>C(#N)C>[Br-:10].[CH2:16]([N+:3]1[C:2]([Cl:1])=[C:6]([Cl:7])[N:5]([C:18]2([CH2:17][CH3:16])[CH:27]=[CH:26][C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[CH2:19]2)[CH:4]=1)[CH2:17][CH2:18][CH2:19][CH2:20][CH2:11][CH3:12]
Reactant: BrCCc1ccc2ccccc2c1
Reactant: CCBr
Reactant: Clc1nc[nH]c1Cl
Agent: [Br-]
Agent: [K+]
Agent: [OH-]
Solvent: CC#N
Product: CCCCCCC[n+]1cn(C2(CC)C=Cc3ccccc3C2)c(Cl)c1Cl
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
4,5-Dichloroimidazole (1.23 g, 9 mmol) will be dissolved into acetonitrile. Potassium hydroxide (0.61 g, 9.9 mmol) will be added and the mixture will be allowed to stir for 0.5 h. 1-bromethane (9 mmol) will be added and the solution will be allowed to reflux overnight. The solution will be filtered hot to remove a white precipitate (presumed to be KBr) and 2-(2-bromoethyl)naphthalene (9 mmol) will be added and the mixture will be returned to reflux overnight. The mixture will be allowed to cool to room temperature, and the volatiles will be removed en vacuo resulting in the product.
Reaction SMILES: Cl[CH2:2][C:3]1[C:4]([CH3:9])=[CH:5][CH:6]=[CH:7][CH:8]=1.[Na].[SH:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][N+:13]=1[O-:18]>>[CH3:9][C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=1[CH2:2][S:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][N+:13]=1[O-:18]
Reactant: Cc1ccccc1CCl
Reactant: [O-][n+]1ccccc1S
Agent: [Na]
Product: Cc1ccccc1CSc1cccc[n+]1[O-]
Yield: 85 %

Procedure:
The intermediate 2-(2-methylphenylmethylthio)pyridine N-oxide is prepared by the procedure described in Example 2 from α-chloro o-xylene and 2-mercaptopyridine N-oxide sodium salt. Melting point 134° -136° C. Yield 85% theory. Structure confirmed by IR and NMR.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([I:12])[CH:10]=2)[N:5]=[CH:4][C:3]=1[C:13]#[N:14].CCN(C(C)C)C(C)C.[CH3:24][C:25]([SH:28])([CH3:27])[CH3:26]>CN(C=O)C>[C:25]([S:28][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([I:12])[CH:10]=2)[N:5]=[CH:4][C:3]=1[C:13]#[N:14])([CH3:27])([CH3:26])[CH3:24]
Reactant: CC(C)(C)S
Reactant: N#Cc1cnc2ccc(I)cc2c1Cl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)Sc1c(C#N)cnc2ccc(I)cc12
Temperature: 25 °C
Reaction time: 4 h
Yield: 48.7 %

Procedure:
To the solution of 4-chloro-6-iodo-quinoline-3-carbonitrile (example 14c, 1.0 g, 3.18 mmol) in anhydrous DMF (1 mL) and DIEA (1.67 mL, 9.54 mmol) was added 2-methyl-2-propanethiol (0.72 ul, 6.4 mmol). The mixture was stirred at room temperature for 4 h. The reaction was extracted with methylene chloride (2×100 mL). The combined organic layers were successively washed with water (3×50 mL), dried over sodium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 70-230 mesh, 0%-50% ethyl acetate in hexanes in 30 min) afforded 4-tert-butylsulfanyl-6-iodo-quinoline-3-carbonitrile (0.57 g, 48%) as a white solid. LC-MS m/e 369 (MH+).
Reaction SMILES: [CH3:1][C:2]1[C:14]([CH3:15])=[CH:13][CH:12]=[CH:11][C:3]=1[O:4][C:5]([CH3:10])([CH3:9])[C:6]([OH:8])=O.CN(C=O)C.C(Cl)(=O)C(Cl)=O.[Cl-].[Al+3].[Cl-].[Cl-]>C1COCC1.O>[CH3:9][C:5]1([CH3:10])[C:6](=[O:8])[C:11]2[CH:12]=[CH:13][C:14]([CH3:15])=[C:2]([CH3:1])[C:3]=2[O:4]1
Reactant: Cc1cccc(OC(C)(C)C(=O)O)c1C
Agent: O=C(Cl)C(=O)Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: CN(C)C=O
Solvent: O
Solvent: C1CCOC1
Product: Cc1ccc2c(c1C)OC(C)(C)C2=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 71 %

Procedure:
To a solution of 2-(2,3-dimethylphenoxy)-2-methylpropionic acid obtained in Reference Example 36 (21.0 g, 101 mmol) in THF (200 mL) was added DMF (0.1 mL), and then to the mixture was added dropwise oxalyl chloride (10.6 mL, 121 mmol). The reaction solution was warmed to room temperature, stirred for 1 hour, and then concentrated under reduced pressure. The residue was dissolved in dichloromethane (200 mL), to which was added aluminum chloride (32.3 g, 242 mmol) at −70° C. or lower, and then warmed to room temperature over 12 hours. The reaction solution was added to water with ice-cooling and dichloromethane was distilled off under reduced pressure, which was extracted with ethyl acetate. The organic layer was washed with water, a saturated sodium hydrogen carbonate solution, water and a saturated brine, and then was dried over anhydrous sodium sulfate. The residue after distilling off the solvent under reduced pressure was crystallized from ethyl acetate-hexane to obtain 17.5 g (yield 71%) of the title compound. Melting point: 79-81° C. (methanol).
Reaction SMILES: [NH:1]1[CH2:4][CH:3]([C:5]([OH:7])=[O:6])[CH2:2]1.S(Cl)([Cl:10])=O.[CH3:12]O>>[ClH:10].[NH:1]1[CH2:4][CH:3]([C:5]([O:7][CH3:12])=[O:6])[CH2:2]1
Reactant: CO
Reactant: O=C(O)C1CNC1
Reactant: O=S(Cl)Cl
Product: COC(=O)C1CNC1
Product: Cl
Temperature: 5 °C

Procedure:
A stirred suspension of azetidine-3-carboxylic acid (2 g, 19.8 mmol) in MeOH (8 ml) was cooled to 5° C. in an ice-water bath. Thionyl chloride (4.3 ml, 59 mmol) was added dropwise at such a rate as to maintain reaction temperature below 30° C. A further portion of MeOH (8 ml) was added carefully and the mixture heated at 65° C. overnight. Evaporation of the solvent and co-evaporation with MeOH (2×20 ml) at reduced pressure provided the title compound as viscous brown oil that crystallized on standing (3.17 g, 100%). The material was used without purification.
Reaction SMILES: [Br:1][C:2]1[C:3]([N:20]2[CH2:25][CH2:24][N:23](C(NC3C=CC=CC=3)=O)[CH2:22][CH2:21]2)=[C:4]2[N:10]=[C:9]([C:11]3[CH:16]=[CH:15][C:14]([N:17]([CH3:19])C)=CC=3)[NH:8][C:5]2=[N:6][CH:7]=1.NC1C([N+]([O-])=O)=C(N2CCN([CH2:51][C:52]([NH:54][C:55]3[S:56][CH:57]=[CH:58][N:59]=3)=[O:53])CC2)C(Br)=CN=1.[O-]S(S([O-])=O)=O.[Na+].[Na+].N1C=CC=C(C=O)C=1>CN(C=O)C>[Br:1][C:2]1[C:3]([N:20]2[CH2:25][CH2:24][N:23]([CH2:51][C:52]([NH:54][C:55]3[S:56][CH:57]=[CH:58][N:59]=3)=[O:53])[CH2:22][CH2:21]2)=[C:4]2[N:10]=[C:9]([C:11]3[CH:19]=[N:17][CH:14]=[CH:15][CH:16]=3)[NH:8][C:5]2=[N:6][CH:7]=1
Reactant: CN(C)c1ccc(-c2nc3c(N4CCN(C(=O)Nc5ccccc5)CC4)c(Br)cnc3[nH]2)cc1
Reactant: Nc1ncc(Br)c(N2CCN(CC(=O)Nc3nccs3)CC2)c1[N+](=O)[O-]
Agent: O=Cc1cccnc1
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C(CN1CCN(c2c(Br)cnc3[nH]c(-c4cccnc4)nc23)CC1)Nc1nccs1
Reaction time: 16 h
Yield: 38 %

Procedure:
This was prepared using, the same procedure as for 4-(6-bromo-2-(4-(dimethylamino)phenyl)-3H-imidazo[4,5-b]pyridin-7-yl)-N-phenylpiperazine-1-carboxamide, but here using 2-(4-(2-amino-5-bromo-3-nitropyridin-4-yl)piperazin-1-yl)-N-(thiazol-2-yl)acetamide (50 mg, 0.11 mmol), DMF (1 mL), 1M Na2S2O4 (3 eq, 0.33 mmol, 0.33 mL) and 3-pyridinecarboxaldehyde (1.05 eq, 0.12 mmol, 0.011 mL). After 16 h, the DMF was removed in vacuo, the residue taken up in water (2 mL) and extracted with EtOAc (2×3 mL) and CH2Cl2 (2×3 mL). The combined extracts were dried (Na2SO4) and concentrated in vacuo to give the product (21 mg, 38%) as a pale brown solid; 1H-NMR (500 MHz, DMSO-d6) 3.30 (hidden by water-in-DMSO peak, 6H, NCH2CO and piperazine N(CH2)2), 3.89 (br s, 4H, piperazine N(CH2)2), 7.28 (br s, 1H, thiazole H-4 or H-5), 7.52 (d, J=3.5 Hz, 1H, thiazole H-4 or H-5), 7.60 (dd, J=7.9, 4.8 Hz, 1H, pyridine H-5), 8.32 (s, 1H, imidazo[4,5-b]pyridine H-5), 8.52 (d, br, J=8.0 Hz, 1H, pyridine H-4), 8.71 (d, br, J=4.7 Hz, 1H, pyridine H-6), 9.38 (s, 1H, pyridine H-2), 13.80 (s, br, 1H, imidazo[4,5-b]pyridine NH);
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([Br:8])[CH:5]=[CH:4][C:3]=1[OH:9].C[O:11]C(C)=C.C([Li])CCC.[C:20]([C:22]1[C:27]([O:28][Si](C)(C)C)=[CH:26][CH:25]=[CH:24][N:23]=1)#N>C(OCC)C>[Br:8][C:6]1[CH:5]=[CH:4][C:3]([OH:9])=[C:2]([CH:7]=1)[C:20]([C:22]1[C:27]([OH:28])=[CH:26][CH:25]=[CH:24][N:23]=1)=[O:11]
Reactant: Oc1ccc(Br)cc1Br
Reactant: C=C(C)OC
Reactant: C[Si](C)(C)Oc1cccnc1C#N
Agent: [Li]CCCC
Solvent: CCOCC
Product: O=C(c1cc(Br)ccc1O)c1ncccc1O
Temperature: -78 °C
Reaction time: 1 h

Procedure:
2,4-Dibromophenol (25.7 g) and 2-methoxypropene (10 ml) were stirred for one hour at room temperature. To the mixture was added diethyl ether (300 ml). The mixture was cooled at -78° C. under atmosphere of argon. Then, to the resultant mixture, a 1.6M solution of n-butyl lithium haxane solution (70 ml) was added dropwise. The mixture was stirred for one hour while maintaining the temperature. Then, 2-cyano-3-trimethylsilyloxy pyridine (19.1 g) was added dropwise to the reaction mixture. The cooling bath was then removed, and the reaction mixture was stirred for 3 hours while warming the reaction system to room temperature. Then, methanol (10 ml) was added to the reaction system, and the mixture was stirred for several minutes, followed by distilling off the solvent under reduced pressure. To the residue were added methanol (50 ml), THF (tetrahydrofuran) (15 ml) and 2N HCl (60 ml), and the mixture was stirred for 2 hours at room temperature. The resultant mixture was neutralized with sodium hydrogencarbonate, followed by extraction with ethyl acetate. The organic layer was dried (anhydrous magnesium sulfate), then the solvent was distilled off under reduced pressure. The residue was subjected to a silica gel column chromatography, eluting with ethyl acetate/hexane, followed by purification to give 2-(5-bromo-2-hydroxybenzoyl)-3-hydroxypyridine (19.9 g) (Compound A-1). Physical properties and spectrum data of the compound are shown in Table 1 and Table 3.
Reaction SMILES: [NH2:1][C:2]1[C:10]([Br:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4](O)=[O:5].C([N:14]=C=NCCCN(C)C)C.[Cl-].[NH4+].C(N(C(C)C)CC)(C)C>CN(C=O)C>[NH2:1][C:2]1[C:10]([Br:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([NH2:14])=[O:5]
Reactant: CCN=C=NCCCN(C)C
Reactant: Nc1c(Br)cccc1C(=O)O
Agent: [Cl-]
Agent: [NH4+]
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: NC(=O)c1cccc(Br)c1N
Reaction time: 6 h
Yield: 84.9 %

Procedure:
To 2-amino-3-bromobenzoic acid (0.5 g, 2.3 mmol) in DMF (5 mL) at rt were added hydroxybenzatriazole (0.46 g, 3.0 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (0.53 g, 2.8 mmol), ammonium chloride (0.5 g, 9.7 mmol), and diisopropylethylamine (1.7 ml, 9.7 mmol). The mixture was purged with N2 and stirred for 6 h. The mixture was poured into water and extracted with EtOAc (3×50 mL). The combined extracts were washed with brine (2×20 mL), dried over MgSO4, filtered, and concentrated under reduced pressure. The residue was treated with DCM (10 mL) resulting in a precipitate which was collected by filtration and dried to afford 2-amino-3-bromobenzamide as a pale pink solid (0.42 g, 84%). LCMS (ESI) m/z 215/217 (M+H)+
Reaction SMILES: [F:1][C:2]1[CH:15]=[CH:14][CH:13]=[C:12]([F:16])[C:3]=1[C:4]([NH:6][C:7]1[CH:11]=[CH:10][NH:9][N:8]=1)=[O:5].C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[C:27]1([CH2:33][O:34][C:35]2[CH:40]=[CH:39][C:38]([Cl:41])=[C:37]([CH2:42]Br)[CH:36]=2)[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>C1COCC1>[Cl:41][C:38]1[CH:39]=[CH:40][C:35]([O:34][CH2:33][C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)=[CH:36][C:37]=1[CH2:42][N:9]1[CH:10]=[CH:11][C:7]([NH:6][C:4](=[O:5])[C:3]2[C:12]([F:16])=[CH:13][CH:14]=[CH:15][C:2]=2[F:1])=[N:8]1
Reactant: Clc1ccc(OCc2ccccc2)cc1CBr
Reactant: O=C(Nc1cc[nH]n1)c1c(F)cccc1F
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: O=C(Nc1ccn(Cc2cc(OCc3ccccc3)ccc2Cl)n1)c1c(F)cccc1F
Reaction time: 0.5 h
Yield: 64.1 %

Procedure:
To a solution of 2,6-difluoro-N-1H-pyrazol-3-ylbenzamide (for as preparation see Intermediate 9) (0.790 g, 3.54 mmol) in THF (30 ml) was added 1.0 M lithium bis(trimethylsilyl)amide in THF (3.54 ml, 3.54 mmol). The reaction mixture was stirred for 30 min. To the reaction mixture was added 3-(bromomethyl)-4-chlorophenyl phenylmethyl ether (1.11 g, 3.56 mmol) in THF (10 ml). The reaction was stirred overnight, under nitrogen at ambient temperature. The solvent was evaporated in vacuo. The residue was partitioned between ethyl acetate (100 ml) and water (70 ml). The phases were separated and the organic phase washed with brine (70 ml). The phases were separated and the organic phase was evaporated in vacuo. The sample was loaded in dichloromethane and purified on silica (2×100 g) using 0-100% ethyl acetate-cyclohexane. The appropriate fractions were combined and evaporated in vacuo to give the title compound as an off-white gum (1.03 g);
Reaction SMILES: [C:1]([CH:3]([CH:7]1[C:11]([Cl:12])=[C:10](Cl)C(=O)O1)[C:4]([NH2:6])=[O:5])#[N:2].[NH2:15][C@@H:16]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH2:18][CH2:17]1>>[ClH:12].[Cl:12][C:11]1[CH:7]=[C:3]([C:4]([NH2:6])=[O:5])[C:1](=[NH:2])[N:15]([C@@H:16]2[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[CH2:18][CH2:17]2)[CH:10]=1
Reactant: N#CC(C(N)=O)C1OC(=O)C(Cl)=C1Cl
Reactant: N[C@H]1CCc2ccccc21
Product: Cl
Product: N=c1c(C(N)=O)cc(Cl)cn1[C@H]1CCc2ccccc21

Procedure:
According to the method of Example 168, 2-cyano-2-(3,4-dichloro-5-oxo-2,5-dihydrofuran-2-yl)acetamide was reacted with (S)-(+)-aminoindane to give the title compound.
Reaction SMILES: C(O[C:6]([N:8]1[CH2:12][C:11](=[N:13][O:14][CH3:15])[CH2:10][C@H:9]1[C:16]([OH:18])=[O:17])=[O:7])(C)(C)C.[C:19]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[C:27]1[CH:32]=[CH:31][C:30](C(O)=O)=[CH:29][CH:28]=1)#[N:20].[CH3:36]O>>[C:19]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[C:27]1[CH:32]=[CH:31][C:30]([C:6]([N:8]2[CH2:12][C:11](=[N:13][O:14][CH3:15])[CH2:10][C@H:9]2[C:16]([O:18][CH3:36])=[O:17])=[O:7])=[CH:29][CH:28]=1)#[N:20]
Reactant: N#Cc1ccccc1-c1ccc(C(=O)O)cc1
Reactant: CO
Reactant: CON=C1C[C@@H](C(=O)O)N(C(=O)OC(C)(C)C)C1
Product: CON=C1C[C@@H](C(=O)OC)N(C(=O)c2ccc(-c3ccccc3C#N)cc2)C1

Procedure:
Following the general method as outlined in Example 11, starting from (2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarboxylic acid, 2′-cyano[1,1′-biphenyl]-4-carboxylic acid, and methanol, the title compound was isolated as a mixture of two isomers in 91.6% purity by HPLC.
Reaction SMILES: [CH3:1][C:2]1[O:3][C:4]([C:8]2[CH:13]=[CH:12][C:11]([NH2:14])=[CH:10][CH:9]=2)=[C:5]([CH3:7])[N:6]=1.C([N:23]=[C:24]=[S:25])(=O)C1C=CC=CC=1.C(=O)([O-])[O-].[K+].[K+]>O1CCCC1.O>[CH3:1][C:2]1[O:3][C:4]([C:8]2[CH:13]=[CH:12][C:11]([NH:14][C:24]([NH2:23])=[S:25])=[CH:10][CH:9]=2)=[C:5]([CH3:7])[N:6]=1
Reactant: O=C(N=C=S)c1ccccc1
Reactant: Cc1nc(C)c(-c2ccc(N)cc2)o1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: Cc1nc(C)c(-c2ccc(NC(N)=S)cc2)o1
Temperature: 25 °C
Reaction time: 2 h
Yield: 67.9 %

Procedure:
To a solution of 4-(2,4-dimethyl-oxazol-5-yl)-phenylamine (470 mg, 2.5 mmol, CAS 100060-02-41) in tetrahydrofurane (20 mL) was added benzoyl isothiocyanate (449 mg, 2.8 mmol). The reaction was stirred at room temperature for 2 hours. The solvent was removed under reduced pressure and the residue was suspended in methanol (30 mL). Potassium carbonate (1036 mg, 7.5 mmol) dissolved in water (15 mL) was added drop wise to the suspension. The reaction was stirred at room temperature over night. The resulting solution was evaporated and the residue was stirred with water. The precipitate was filtered off, washed twice with water and twice with diethyl ether. The residue was dissolved in tetrahydrofurane and the solvent was removed under reduced pressure to yield the title compound as an off-white solid (420 mg, 68%). MS ISP (m/e): 248.1 (100) [(M+H)+]. 1H NMR (DMSO-D6, 300 MHz): δ (ppm)=9.80 (s, 1H, NH), 7.55 (d, 2H), 7.50 (d, 2H), 2.41 (s, 3H), 2.29 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:25]=[CH:24][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12](/[CH:16]=[C:17]4/[C:18](=[O:23])[NH:19][C:20](=[O:22])[S:21]/4)=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:26]([F:29])([F:28])[F:27])[CH:3]=1.[CH3:30]O>>[Cl:1][C:2]1[CH:25]=[CH:24][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12](/[CH:16]=[C:17]4/[C:18](=[O:23])[N:19]([CH3:30])[C:20](=[O:22])[S:21]/4)=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:26]([F:27])([F:29])[F:28])[CH:3]=1
Reactant: O=C1NC(=O)/C(=C/c2ccc3c(cnn3Cc3ccc(Cl)cc3C(F)(F)F)c2)S1
Reactant: CO
Product: CN1C(=O)S/C(=C\c2ccc3c(cnn3Cc3ccc(Cl)cc3C(F)(F)F)c2)C1=O

Procedure:
(5Z)-5-({1-[4-Chloro-2-(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-3-methyl-1,3-thiazolidine-2,4-dione was prepared from [(5Z)-5-({1-[4-chloro-2-(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-2,4-dioxo-1,3-thiazolidine (from Example 1) and methyl alcohol following General Procedure J.
Reaction SMILES: [CH2:1]([O:8][C:9]([C:11]([CH3:23])([CH3:22])[CH2:12][O:13][C:14]1[CH:21]=[CH:20][C:17]([CH:18]=[O:19])=[CH:16][CH:15]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[BH4-].[Na+].Cl>O1CCCC1>[CH2:1]([O:8][C:9]([C:11]([CH3:23])([CH3:22])[CH2:12][O:13][C:14]1[CH:15]=[CH:16][C:17]([CH2:18][OH:19])=[CH:20][CH:21]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(COc1ccc(C=O)cc1)C(=O)OCc1ccccc1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)(COc1ccc(CO)cc1)C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 97.3 %

Procedure:
To a solution of 4-(2-benzyloxycarbonyl-2-methylpropoxy)benzaldehyde (0.97 g) in tetrahydrofuran (20 mL) was added sodium borohydride (59 mg), and the mixture was stirred at room temperature for 3 hours. The reaction mixture was poured into 0.5 mol/L hydrochloric acid, and the resulting mixture was extracted with diethyl ether. The organic layer was washed with water and brine successively, and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure, and the residue was purified by column chromatography on silica gel (eluent: n-hexane/ethyl acetate=6/1-3/2) to give the title compound (0.95 g).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:11]2[CH:16]=[CH:15][C:14]([N+:17]([O-:19])=[O:18])=[CH:13][CH:12]=2)[CH:5]=[CH:6][C:7]=1[C:8]([OH:10])=O.C(Cl)(=O)C(Cl)=O.Cl.[CH3:27][O:28][C:29](=[O:35])[C@H:30]([CH:32]([CH3:34])[CH3:33])[NH2:31].C(N(CC)CC)C>C(Cl)Cl.CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([C:11]2[CH:16]=[CH:15][C:14]([N+:17]([O-:19])=[O:18])=[CH:13][CH:12]=2)[CH:5]=[CH:6][C:7]=1[C:8]([NH:31][C@H:30]([C:29]([O:28][CH3:27])=[O:35])[CH:32]([CH3:34])[CH3:33])=[O:10]
Reactant: COC(=O)[C@@H](N)C(C)C
Reactant: O=C(O)c1ccc(-c2ccc([N+](=O)[O-])cc2)cc1Cl
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CN(C)C=O
Product: COC(=O)[C@@H](NC(=O)c1ccc(-c2ccc([N+](=O)[O-])cc2)cc1Cl)C(C)C
Temperature: 50 °C
Reaction time: 0.75 h

Procedure:
3-Chloro-4′-nitrobiphenyl-4-carboxylic acid (0.31 g, 1.12 mmol) was dissolved in methylene chloride (10 mL), and then oxalyl chloride (0.15 mL, 1.7 mmol) was added, followed by one drop of DMF. The resulting mixture was stirred at 50° C. for 45 min and then concentrated under reduced pressure. The residue was dissolved in methylene chloride (5 mL) and added dropwise to an ice-cold mixture of L-valine methyl ester hydrochloride (0.22 g, 1.3 mmol), methylene chloride (10 mL), and triethylamine (0.62 mL, 4.5 mmol). The resulting solution was stirred at rt for 18 h and then concentrated under reduced pressure. The residue was taken up in EtOAc, passed through a plug of silica gel, and concentrated under reduced pressure. This yielded 0.305 g (70%) of the title compound. LC/MS m/z 390.9 (MH+), retention time 3.30 min. 1H NMR (400 MHz, CD2Cl2) δ 1.06 (dd, 6H), 2.32-2.39 (m, 1H), 3.80 (s, 3H), 4.71-4.78 (m, 1H), 6.33 (d, 1H), 6.76 (d, 2H), 7.58-7.80 (m, 5H), 8.35 (d, 2H).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]([C:6]([OH:8])=O)=[CH:2]1.[N+]([O-])(O)=O.[O:13]([CH2:17][CH2:18][NH2:19])[N+:14]([O-:16])=[O:15].C(OC(C)C)(C)C>>[O:13]([CH2:17][CH2:18][NH:19][C:6]([C:3]1[CH:4]=[CH:5][S:1][CH:2]=1)=[O:8])[N+:14]([O-:16])=[O:15]
Reactant: O=C(O)c1ccsc1
Reactant: NCCO[N+](=O)[O-]
Solvent: O=[N+]([O-])O
Solvent: CC(C)OC(C)C
Product: O=C(NCCO[N+](=O)[O-])c1ccsc1
Yield: 35.2 %

Procedure:
Following a similar treatment to that in Example 2 and using 0.55 g of 3-thiophenecarboxylic acid and 0.60 g of nitroxyethylamine nitrate, 0.27 g of the title compound was obtained as colorless plates (solvent for recrystallization; diisopropyl ether).
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([C:7]2[CH:12]=[CH:11][C:10]([C:13]([CH3:16])([CH3:15])[CH3:14])=[CH:9][CH:8]=2)=[N:5][N:6]=1.[C:17](OC1C(Cl)=CC(Cl)=CC=1Cl)(=[O:22])[CH2:18][C:19]([O-])=[O:20]>C1C=CC(C2C=CC=CC=2)=CC=1.C1C=CC(OC2C=CC=CC=2)=CC=1>[C:13]([C:10]1[CH:11]=[CH:12][C:7]([C:4]2[S:3][C:2]3=[N:1][C:17]([OH:22])=[CH:18][C:19](=[O:20])[N:6]3[N:5]=2)=[CH:8][CH:9]=1)([CH3:16])([CH3:15])[CH3:14]
Reactant: O=C([O-])CC(=O)Oc1c(Cl)cc(Cl)cc1Cl
Reactant: CC(C)(C)c1ccc(-c2nnc(N)s2)cc1
Solvent: c1ccc(-c2ccccc2)cc1
Solvent: c1ccc(Oc2ccccc2)cc1
Product: CC(C)(C)c1ccc(-c2nn3c(=O)cc(O)nc3s2)cc1
Yield: 96.6 %

Procedure:
A mixture of 9.3 g of 2-amino-5-(4-tert-butylphenyl)-1,3,4-thiadiazole, 20 g of 2,4,6-trichlorophenyl malonate and 50 ml of Dowtherm A was heated at a temperature of 120° to 130° C. for 2 hours. After allowing the mixture to cool, the precipitate was separated by filtration, washed successively with isopropanol and diethyl ether to obtain 11.6 g of 2-(4-tert-butylphenyl)-7-hydroxy-5H-[1,3,4]thiadiazolo[3,2-a]pyrimidin-5-one as a colorless, crystalline powder having a melting point of 265° to 268° C. (decomposition).