Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:17])[C:4]1[CH:9]=[CH:8][C:7]([C:10]([NH:12][NH:13][C:14](=[O:16])[CH3:15])=O)=[CH:6][CH:5]=1>O=P(Cl)(Cl)Cl.O>[CH3:1][O:2][C:3](=[O:17])[C:4]1[CH:9]=[CH:8][C:7]([C:10]2[O:16][C:14]([CH3:15])=[N:13][N:12]=2)=[CH:6][CH:5]=1
Reactant: COC(=O)c1ccc(C(=O)NNC(C)=O)cc1
Solvent: O=P(Cl)(Cl)Cl
Solvent: O
Product: COC(=O)c1ccc(-c2nnc(C)o2)cc1
Yield: 75.92 %

Procedure:
Oxalyl chloride (1.05 g, 8.3 mmol) was added to a stirred solution of terephthalic acid monomethyl ester (1 g, 5.55 mmol) in DCM (12 mL) and stirring was continued at ambient temperature for 4 hr. The reaction mixture was concentrated under reduced pressure to afford the residue. The residue was dissolved in DCM (4 mL) and to the resulting solution was added, acetic acid hydrazide (490 mg, 6.66 mmol), Et3N (670 mg, 6.66 mmol) and stirring was continued at temperature overnight. The reaction mixture was diluted with water and extracted with ethylacetate, dried over sodium sulfate and concentrated under reduced pressure to afford 1 g (76.39% Yield) of 4-(N′-acetyl-hydrazinocarbonyl)-benzoic acid methyl ester. A stirred solution of 4-(N′-acetyl-hydrazinocarbonyl)-benzoic acid methyl ester (500 mg, 5.55 mmol) in POCl3 (12 mL) was heated at 100° C. for 3 hr. The reaction mixture was concentrated under reduced pressure to afford the residue. The residue was diluted with cold water, extracted with ethyl acetate, washed the organic layer with sodium bicarbonate solution, saturated brine solution and dried over sodium sulfate. The organic layer was concentrated under reduced pressure to 350 mg (75.92% Yield) of afford 4-(5-methyl-[1,3,4]oxadiazol-2-yl)-benzoic acid methyl ester. LiOH.H2O (330 mg, 8 mmol) was added to a solution of 4-(5-methyl-[1,3,4]oxadiazol-2-yl)-benzoic acid methyl ester (350 mg, 1.6 mmol) in the mixture of methanol (4 mL), THF (10 mL) and H2O (4 mL). The resulting reaction mixture was stirred at ambient temperature for 2 hrs. The reaction mixture was concentrated The residue was diluted with water, acidified with aqueous citric acid solution, extracted with ethyl acetate and dried over sodium sulfate. The organic layer was concentrated under reduced pressure to afford 280 mg (87.46% Yield) of 4-(5-methyl-[1,3,4]oxadiazol-2-yl)-benzoic acid.
Reaction SMILES: [C:1](Cl)(=O)C.[NH2:5][C:6]1[CH:7]=[C:8]([CH:12]=[C:13]([CH3:15])[N:14]=1)[C:9]([OH:11])=[O:10]>CO>[CH3:1][O:10][C:9](=[O:11])[C:8]1[CH:12]=[C:13]([CH3:15])[N:14]=[C:6]([NH2:5])[CH:7]=1
Reactant: CC(=O)Cl
Reactant: Cc1cc(C(=O)O)cc(N)n1
Solvent: CO
Product: COC(=O)c1cc(C)nc(N)c1
Temperature: 50 °C
Reaction time: 0.25 h

Procedure:
To 50 ml of MeOH is added drop wise acetyl chloride (3 ml) at room temperature. After 15 min, 2-amino-6-methylisonicotinic acid (2.3 g) is added and the mixture is stirred overnight at 50° C. After concentrating the solution, the resulting residue is suspended in acetone and then filtered and dried at 50° C. in vacuum, to yield 2-amino-6-methylisonicotinic acid methyl ester (4.1 g). HPLC: Rt=0.91 min (method D)
Reaction SMILES: [O:1]1[C:5]2([CH2:10][CH2:9][C:8](=[O:11])[CH2:7][CH2:6]2)[O:4][CH2:3][CH2:2]1.C[Si]([N-][Si](C)(C)C)(C)C.[Na+].[O:22](S(C(F)(F)F)(=O)=O)[S:23]([C:26]([F:29])([F:28])[F:27])(=O)=[O:24]>CCOCC>[F:27][C:26]([F:29])([F:28])[S:23]([O:11][C:8]1[CH2:7][CH2:6][C:5]2([O:4][CH2:3][CH2:2][O:1]2)[CH2:10][CH:9]=1)(=[O:24])=[O:22]
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Reactant: O=C1CCC2(CC1)OCCO2
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: CCOCC
Product: O=S(=O)(OC1=CCC2(CC1)OCCO2)C(F)(F)F
Temperature: -15 °C
Yield: 65 %

Procedure:
1,4-Dioxaspiro[4.5]decan-8-one (1.0 equiv) was dissolved in Ether (0.1 M and stirred at −15° C. then 1M NaHMDS (1.05 equiv.) was added and stirred for 70 min then Tf2O (1.05 equiv.) added and reaction allowed to slowly warm to rt. The mixture was stirred for 28 hr, washed with sat. aq. NaHCO3 and then water. Aqueous layers combined and extracted with ether. Organic layers combined, dried over MgSO4, filtered, and concentrated. The residue was purified by column (ethyl ether:hexanes=1:4) to give 1,4-dioxaspiro[4.5]dec-7-en-8-yl trifluoromethanesulfonate (65%). LC/MS (m/z): MH+=289.0, Rt=0.97. HPLC Rt=3.77.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]([N:10]2[CH2:15][CH2:14][N:13]([C:16]3[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][C:17]=3[CH3:23])[CH2:12][CH2:11]2)=[O:9])=[C:4]([N:24]2[CH2:28][CH2:27][CH2:26][S:25]2(=[O:30])=[O:29])[CH:3]=1.[O:31]=[C:32]1[NH:36][C@H:35]([CH2:37][O:38][C:39](=[O:46])[C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)[CH2:34][O:33]1>>[C:39]([O:38][CH2:37][C@@H:35]1[CH2:34][O:33][C:32](=[O:31])[N:36]1[C:2]1[CH:7]=[CH:6][C:5]([C:8]([N:10]2[CH2:15][CH2:14][N:13]([C:16]3[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][C:17]=3[CH3:23])[CH2:12][CH2:11]2)=[O:9])=[C:4]([N:24]2[CH2:28][CH2:27][CH2:26][S:25]2(=[O:30])=[O:29])[CH:3]=1)(=[O:46])[C:40]1[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=1
Reactant: Cc1ccc(N2CCN(C(=O)c3ccc(Br)cc3N3CCCS3(=O)=O)CC2)c(C)c1
Reactant: O=C1N[C@H](COC(=O)c2ccccc2)CO1
Product: Cc1ccc(N2CCN(C(=O)c3ccc(N4C(=O)OC[C@H]4COC(=O)c4ccccc4)cc3N3CCCS3(=O)=O)CC2)c(C)c1
Yield: 95.9 %

Procedure:
By reaction and treatment in the same manner as in Preparation Example 91 and using [4-bromo-2-(1,1-dioxoisothiazolidin-2-yl)phenyl][4-(2,4-dimethylphenyl)piperazin-1-yl]methanone (1.72 g) described in Preparation Example 181 and benzoic acid (R)-2-oxooxazolidin-4-ylmethyl ester (852 mg), the title compound (2.12 g) was obtained.
Reaction SMILES: [CH2:1]([C:5]1[C:9]([C:10](O)=[O:11])=[C:8](/[CH:13]=[CH:14]/[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[O:7][N:6]=1)[CH2:2][CH2:3][CH3:4].C(N(CC)CC)C.ClC(OCC)=O.[BH4-].[Na+]>C1COCC1.O>[CH2:1]([C:5]1[C:9]([CH2:10][OH:11])=[C:8](/[CH:13]=[CH:14]/[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[O:7][N:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1noc(/C=C/c2ccccc2)c1C(=O)O
Agent: CCOC(=O)Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: O
Product: CCCCc1noc(/C=C/c2ccccc2)c1CO
Temperature: 25 °C
Reaction time: 60 h
Yield: 103.9 %

Procedure:
To a solution of 3-butyl-5-([E]-styryl)-isoxazole-4-carboxylic acid (7.0 g, 25.8 mmol) and triethylamine (3.8 mL, 27.0 mmol) in THF (30 mL) was added at 0° C. ethyl chloroformate (2.6 mL, 27.0 mmol). After 1 h the triethylamine hydrochloride salt was filtered off and washed with a small amount of THF. The filtrate was concentrated, the residue taken up in ethanol (70 mL) and added to a solution of sodium borohydride (2.4 g, 63.4 mmol) in water (35 mL) at 0° C. After stirring at room temperature for 2.5 days, the reaction was quenched with aqueous sodium hydroxide (1 M, 40 mL) and extracted twice with tert-butylmethylether. The combined phases were washed with brine, dried over sodium sulfate and filtered. The filtrate was concentrated to a yellow oil and purified by flash chromatography (silica, dichloromethane:methanol 100:0 to 97:3) to afford the title compound (6.9 g, 98%) as an orange oil. MS: m/e=258.1 [M+H]+.
Reaction SMILES: Br[C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.[C:10]([O:14][CH3:15])(=[O:13])[CH:11]=[CH2:12].C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.C(N(CC)CC)C>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.O.CC(N(C)C)=O>[CH:6]([C:5]1[CH:8]=[CH:9][C:2](/[CH:12]=[CH:11]/[C:10]([O:14][CH3:15])=[O:13])=[CH:3][CH:4]=1)=[O:7]
Reactant: O=Cc1ccc(Br)cc1
Reactant: C=CC(=O)OC
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: O
Solvent: CC(=O)N(C)C
Solvent: CCN(CC)CC
Product: COC(=O)/C=C/c1ccc(C=O)cc1
Temperature: 110 °C
Yield: 83 %

Procedure:
4-Bromobenzaldehyde (30 g, 162.15 mmol) and methyl acrylate (20.94 g, 243.22 mmol) were taken up in thoroughly degassed DMA (300 nil) and treated with tri-o-tolylphosphine (4.94 g. 16.21 mmol), palladium(II) acetate (1.820 g, 8.11 mmol) and triethylamine (45.2 ml, 324.29 mmol) and heated to 110° C. for 16 hours. The reaction appeared complete after this time. The reaction mixture was poured into water (4 L) and the resulting precipitate was filtered and dried. The solid was chromatographed on silica, eluting with 100% heptane to 30% EtOAc in heptane. Relevant fractions were combined and evaporated to dryness to afford a yellow solid product which was triturated with heptane, filtered and washed with cold heptane. The solid was dried to afford (E)-methyl 3-(4-formylphenyl)acrylate (25.6 g. 83%) as a yellow crystalline product. 1H NMR (400 MHz, DMSO, 30° C.) δ 3.75 (3H, s), 6.79 (1H, d), 7.72 (1H, d), 7.93 (4H, s), 10.03 (1H, s). No mass ion observed in LCMS.
Reaction SMILES: [OH:1][N:2]1[C:6](=[O:7])[C:5]2=[CH:8][CH:9]=[CH:10][CH:11]=[C:4]2[C:3]1=[O:12].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH3:32][O:33][C:34]1[CH:67]=[CH:66][C:37]([C:38]([O:53][CH2:54][CH2:55][O:56][CH2:57][CH2:58][O:59][CH2:60][CH2:61][O:62][CH2:63][CH2:64]O)([C:47]2[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=2)[C:39]2[CH:44]=[CH:43][C:42]([O:45][CH3:46])=[CH:41][CH:40]=2)=[CH:36][CH:35]=1.CCOC(/N=N/C(OCC)=O)=O>C1COCC1>[CH3:46][O:45][C:42]1[CH:41]=[CH:40][C:39]([C:38]([O:53][CH2:54][CH2:55][O:56][CH2:57][CH2:58][O:59][CH2:60][CH2:61][O:62][CH2:63][CH2:64][O:1][N:2]2[C:3](=[O:12])[C:4]3=[CH:11][CH:10]=[CH:9][CH:8]=[C:5]3[C:6]2=[O:7])([C:47]2[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=2)[C:37]2[CH:36]=[CH:35][C:34]([O:33][CH3:32])=[CH:67][CH:66]=2)=[CH:44][CH:43]=1
Reactant: COc1ccc(C(OCCOCCOCCOCCO)(c2ccccc2)c2ccc(OC)cc2)cc1
Reactant: O=C1c2ccccc2C(=O)N1O
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COc1ccc(C(OCCOCCOCCOCCON2C(=O)c3ccccc3C2=O)(c2ccccc2)c2ccc(OC)cc2)cc1
Reaction time: 8 h
Yield: 81.8 %

Procedure:
N-hydroxyphthalimide (0.7 g, 4.3 mmol) and triphenyl-phosphine (1.1 g, 4.2 mmol) were added to a solution of 11-(4,4′-dimethoxytrityloxy)-3,6,9-trioxaundecanol (2.0 g, 4.0 mmol) in THF (60 mL). Diethylazodicarboxylate (DEAD, 0.7 mL, 3.6 mmol) was added dropwise and the stirring was continued overnight at ambient temperature. The reaction mixture was evaporated to an oil, applied onto a silica gel column, and eluted with a linear gradient from neat CH2Cl2 to a 97:3 (v/v) mixture of CH2Cl2 and MeOH. The purification was repeated to yield 2.1 g (80%) of the title compound.
Reaction SMILES: [N+](=[CH2:3])=[N-].[O:4]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[N:6]=[C:5]1[C:13]1[CH:18]=[CH:17][C:16]([CH2:19][C:20]([OH:22])=[O:21])=[CH:15][CH:14]=1>CCOCC>[O:4]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[N:6]=[C:5]1[C:13]1[CH:18]=[CH:17][C:16]([CH2:19][C:20]([O:22][CH3:3])=[O:21])=[CH:15][CH:14]=1
Reactant: C=[N+]=[N-]
Reactant: O=C(O)Cc1ccc(-c2nc3ccccc3o2)cc1
Solvent: CCOCC
Product: COC(=O)Cc1ccc(-c2nc3ccccc3o2)cc1
Reaction time: 1 h

Procedure:
To a solution of diazomethane in 75 ml. of ether is added, portionwise, as a solid, 1.0 gm. of 4-(benzoxazol-2-yl)phenylacetic acid. Nitrogen is evolved and after 1 hour the excess diazomethane is consumed by adding acetic acid. The reaction mixture is filtered and the filtrate concentrated to give a yellow solid. Recrystallization from methanol gives methyl 4-(benzoxazol-2-yl)phenylacetate, m.p. 109°-112°C.
Reaction SMILES: [Cl:1][C:2]1[CH:39]=[CH:38][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([O:16][CH2:17][C:18]4[CH:27]=[CH:26][C:25]5[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=5)[N:19]=4)=[CH:13][CH:14]=3)[CH:9]=[C:8]2[CH2:28][C:29]([CH2:36][CH3:37])([CH2:34][CH3:35])[C:30]([O:32][CH3:33])=[O:31])=[CH:4][CH:3]=1.[Al+3].[Cl-].[Cl-].[Cl-].[C:44]([CH2:48][C:49](Cl)=[O:50])([CH3:47])([CH3:46])[CH3:45]>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([O:16][CH2:17][C:18]4[CH:27]=[CH:26][C:25]5[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=5)[N:19]=4)=[CH:13][CH:14]=3)[C:9]([C:49](=[O:50])[CH2:48][C:44]([CH3:47])([CH3:46])[CH3:45])=[C:8]2[CH2:28][C:29]([CH2:34][CH3:35])([CH2:36][CH3:37])[C:30]([O:32][CH3:33])=[O:31])=[CH:38][CH:39]=1
Reactant: CCC(CC)(Cc1cc2cc(OCc3ccc4ccccc4n3)ccc2n1Cc1ccc(Cl)cc1)C(=O)OC
Reactant: CC(C)(C)CC(=O)Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: CCC(CC)(Cc1c(C(=O)CC(C)(C)C)c2cc(OCc3ccc4ccccc4n3)ccc2n1Cc1ccc(Cl)cc1)C(=O)OC
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
To a cold solution (0° C.) of methyl 3-[N-(4-chlorobenzyl)-5-(quinolin-2-ylmethoxy)indol-2-yl]-2,2-diethylpropanoate (from Step D) (177 mg, 0.33 mmol) in CH2Cl2 (3 mL) was added AlCl3 (220 mg, 1.65 mmol) followed by t-butylacetyl chloride (82 μL, 0.66 mmol). The reaction was stirred at 0° C. for 20 minutes and then quenched with 30 mL of 0.5N Na, K tartrate solution, and extracted with 3×30 mL of EtOAc. The organic layers were combined and dried over MgSO4. Filtration and concentration gave an oily residue which was purified by flash chromatography (eluant: EtOAc-hexane 17:83) to give the title compound.
Reaction SMILES: [C:1]([NH:8][C@@H:9]([CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[C@@H:10]([OH:27])[CH2:11][C@@H:12]([CH2:16][C:17]1[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[C:19]([O:25][CH3:26])[CH:18]=1)[C:13]([OH:15])=[O:14])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[C:35]([Si:39]([CH3:42])([CH3:41])Cl)([CH3:38])([CH3:37])[CH3:36].N1C=CN=C1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.O.C1COCC1.CO>[C:1]([NH:8][C@@H:9]([CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[C@@H:10]([O:27][Si:39]([C:35]([CH3:38])([CH3:37])[CH3:36])([CH3:42])[CH3:41])[CH2:11][C@@H:12]([CH2:16][C:17]1[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[C:19]([O:25][CH3:26])[CH:18]=1)[C:13]([OH:15])=[O:14])([O:3][C:4]([CH3:6])([CH3:7])[CH3:5])=[O:2]
Reactant: COc1ccc(C[C@H](C[C@H](O)[C@H](Cc2ccccc2)NC(=O)OC(C)(C)C)C(=O)O)cc1OC
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: O
Solvent: C1CCOC1
Product: COc1ccc(C[C@H](C[C@H](O[Si](C)(C)C(C)(C)C)[C@H](Cc2ccccc2)NC(=O)OC(C)(C)C)C(=O)O)cc1OC

Procedure:
In analogy with Example 44e), 804 mg of 5(S)-(Boc-amino)-4(S)-hydroxy-6-phenyl-2(R)-[(3,4-dimethoxyphenyl)methyl]hexanoic acid in 5.94 ml of DMF are silylated with 1.162 g of tert-butyldimethylchlorosilane and 946.6 mg of imidazole. The silyl ester in the crude product is cleaved at RT in 2 h in a mixture consisting of 19.61 ml of methanol, 7.56 ml of THF, 7.56 ml of water and 1.334 g of potassium carbonate. The title compound is purified by being chromatographed twice on silica gel (eluents: D, C, J and B). TLC Rf (C)=0.27. MS M+ =557.
Reaction SMILES: [N:1]1([CH2:7][CH2:8][CH2:9][O:10][C:11]2[CH:16]=[CH:15][C:14]([N:17]3[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]3)=[CH:13][CH:12]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[Cl:23][C:24]1[CH:25]=[C:26](Br)[CH:27]=[CH:28][C:29]=1[Cl:30].CC(C)([O-])C.[Na+].C1(P(C2C=CC=CC=2)C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1(C)C=CC=CC=1.C(OCC)(=O)C>[Cl:23][C:24]1[CH:25]=[C:26]([N:20]2[CH2:19][CH2:18][N:17]([C:14]3[CH:15]=[CH:16][C:11]([O:10][CH2:9][CH2:8][CH2:7][N:1]4[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]4)=[CH:12][CH:13]=3)[CH2:22][CH2:21]2)[CH:27]=[CH:28][C:29]=1[Cl:30]
Reactant: c1cc(N2CCNCC2)ccc1OCCCN1CCCCC1
Reactant: Clc1ccc(Br)cc1Cl
Agent: CC(C)(C)[O-]
Agent: [Na+]
Agent: c1ccc(P(c2ccccc2)c2ccc3ccccc3c2-c2c(P(c3ccccc3)c3ccccc3)ccc3ccccc23)cc1
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: Clc1ccc(N2CCN(c3ccc(OCCCN4CCCCC4)cc3)CC2)cc1Cl
Temperature: 25 °C

Procedure:
Tris(dibenzylidineacetone) di palladium (0) (5 mol %; 23 mg) was added to a mixture of 1-[4-(3-piperidin-1-yl-propoxy)-phenyl]-piperazine (D11) (150 mg; 0.49 mmol), 3,4-dichloro bromo benzene (160 mg; 1.2 eq), sodium tert-butoxide (71 mg; 1.1 eq) and racemic 2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (7.5 mol %; 24 mg) in dry toluene (3 ml). The resulting mixture was heated at reflux under argon for 18 hours. The reaction was allowed to cool to room temperature and diluted with ethyl acetate (10 ml). The resulting solids were removed by filtration and the filtrate evaporated in vacuo. The residue was purified by column chromatography on silica eluting with 3% methanol in dichloromethane to afford the title compound as a buff solid (45 mg)
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.[F:10][C:11]([F:20])([F:19])[C:12]1[CH:13]=[C:14]([OH:18])[CH:15]=[N:16][CH:17]=1>>[F:20][C:11]([F:10])([F:19])[C:12]1[CH:13]=[C:14]([O:18][C:2]2[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=2)[CH:15]=[N:16][CH:17]=1
Reactant: Oc1cncc(C(F)(F)F)c1
Reactant: O=Cc1ccc(F)cc1
Product: O=Cc1ccc(Oc2cncc(C(F)(F)F)c2)cc1

Procedure:
The title compound was prepared by a procedure similar to that described for D4 starting from 4-fluorobenzaldehyde and 5-(trifluoromethyl)pyridin-3-ol
Reaction SMILES: [OH-].[NH4+:2].Cl[C:4]1[C:9]([I:10])=[CH:8][N:7]=[C:6]([C:11]([F:14])([F:13])[F:12])[CH:5]=1>CS(C)=O.[Cl-].[Na+].O>[I:10][C:9]1[C:4]([NH2:2])=[CH:5][C:6]([C:11]([F:14])([F:13])[F:12])=[N:7][CH:8]=1
Reactant: [NH4+]
Reactant: FC(F)(F)c1cc(Cl)c(I)cn1
Agent: [Cl-]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CS(C)=O
Product: Nc1cc(C(F)(F)F)ncc1I
Temperature: 110 °C

Procedure:
Concentrated aqueous ammonium hydroxide (10 mL) was added to a solution of 4-chloro-5-iodo-2-(trifluoromethyl)pyridine (4.11 g, 13.3 mmol) in DMSO in a glass pressure tube. The tube was sealed and placed in an oil bath pre-heated to 110° C. for 48 h. The resulting solution was diluted with brine, extracted with ethyl acetate, dried (Na2SO4), filtered and concentrated under vacuum to give 5-iodo-2-(trifluoromethyl)pyridin-4-amine. Retention time (min)=1.584, method [1], MS (ESI) 289.0 (M+H).
Reaction SMILES: [F:1][CH:2]([F:11])[O:3][C:4]1[CH:9]=[CH:8][C:7](I)=[CH:6][CH:5]=1.C([Mg]Cl)(C)C.[B:17](OC)([O:20]C)[O:18]C>>[F:1][CH:2]([F:11])[O:3][C:4]1[CH:9]=[CH:8][C:7]([B:17]([OH:20])[OH:18])=[CH:6][CH:5]=1
Reactant: FC(F)Oc1ccc(I)cc1
Reactant: COB(OC)OC
Agent: CC(C)[Mg]Cl
Product: OB(O)c1ccc(OC(F)F)cc1

Procedure:
In a departure from the procedure described above the compound is prepared from 4-difluoromethoxy-1-iodo-benzene using iPrMgCl to generate the arylmetal compound and trapping this intermediate with trimethyl borate.
Reaction SMILES: C1O[C:4]2([C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[CH2:6][C:5]32[CH2:17][CH2:16][C:15](=[O:18])[CH2:14][CH2:13]3)OC1.O.NN.[OH-].[K+].[CH2:25](O)[CH2:26][OH:27]>>[CH2:25]1[O:18][C:15]2([CH2:14][CH2:13][C:5]3([CH2:4][C:12]4[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=4)[CH2:6]3)[CH2:17][CH2:16]2)[O:27][CH2:26]1
Reactant: OCCO
Reactant: O=C1CCC2(CC1)Cc1ccccc1C21OCCO1
Agent: NN
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: c1ccc2c(c1)CC1(CCC3(CC1)OCCO3)C2
Yield: 85 %

Procedure:
A mixture of 5g. (0.0194 M) of spiro(cyclohexane 1,2'-indan)-1',4-dione 4-ethylene ketal [9](prepared as in Example 16B), 2.6ml. of hydrazine hydrate and 3.76 g. of potassium hydroxide in 50 ml. of ethylene glycol is heated at reflux for about 1.5 hours. Material is then removed by distillation to bring the pot temperature to 200° C. After about 5 hours of additional heating at reflux, the mixture is allowed to cool and diluted with water. The precipitated solid is collected on a filter, dried and recrystallized from petroleum ether to give 4 g. (85% yield) of spiro(cyclohexane-1,2'-indan)-4-one ethylene ketal [10], having a melting point of 70° to 74° C.
Reaction SMILES: [C:1]([CH2:3][C@H:4]1[CH2:15][CH2:14][C:13]2[S:12][C:11]3[N:10]=[CH:9][N:8]=[C:7]([O:16][CH:17]4[CH2:22][CH2:21][C:20]([NH:24][C:25](=[O:31])[O:26][C:27]([CH3:30])([CH3:29])[CH3:28])([CH3:23])[CH2:19][CH2:18]4)[C:6]=3[C:5]1=2)#[N:2].[H-].[Na+].[CH3:34]I>CN(C=O)C>[C:1]([CH2:3][C@H:4]1[CH2:15][CH2:14][C:13]2[S:12][C:11]3[N:10]=[CH:9][N:8]=[C:7]([O:16][CH:17]4[CH2:18][CH2:19][C:20]([N:24]([CH3:34])[C:25](=[O:31])[O:26][C:27]([CH3:30])([CH3:29])[CH3:28])([CH3:23])[CH2:21][CH2:22]4)[C:6]=3[C:5]1=2)#[N:2]
Reactant: CC1(NC(=O)OC(C)(C)C)CCC(Oc2ncnc3sc4c(c23)[C@@H](CC#N)CC4)CC1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN(C(=O)OC(C)(C)C)C1(C)CCC(Oc2ncnc3sc4c(c23)[C@@H](CC#N)CC4)CC1
Reaction time: 0.5 h
Yield: 76.2 %

Procedure:
To a 50-mL round-bottom flask containing a solution of tert-butyl N-(4-[[(3R)-3-(cyanomethyl)-7-thia-9,11-diazatricyclo[6.4.0.0[2,6]]dodeca-1(8),2(6),9,11-tetraen-12-yl]oxy]-1-methylcyclohexyl)carbamate (100 mg, 0.23 mmol, 1.00 equiv) in distilled DMF (3 mL) was added sodium hydride (60% dispersion in mineral oil 37 mg, 0.93 mmol, 4.09 equiv) at 0° C. The resulting solution was stirred for 0.5 h at this temperature. Then CH3I (321 mg, 2.26 mmol, 1.00 equiv) was added and the resulting solution was allowed to react, with stirring, for an additional 2 h at 30° C. The reaction was then quenched with saturated aqueous NH4Cl and extracted with 3×30 mL of ethyl acetate. The combined organic layers were washed with brine, dried over sodium sulfate and concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1:2) to give tert-butyl N-(4-[[(3R)-3-(cyanomethyl)-7-thia-9,11-diazatricyclo[6.4.0.0[2,6]]dodeca-1(8),2(6),9,11-tetraen-12-yl]oxy]-1-methylcyclohexyl)-N-methylcarbamate (80 mg, 78%) as a white solid.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.C(N(C(C)C)CC)(C)C.Cl[C:17]1[O:18][C:19]2[C:20](=[C:22]([C:34]#[N:35])[C:23]([CH3:33])=[C:24]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[C:25]=2[F:26])[N:21]=1>ClCCl>[F:26][C:25]1[C:24]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[C:23]([CH3:33])[C:22]([C:34]#[N:35])=[C:20]2[C:19]=1[O:18][C:17]([N:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1)=[N:21]2
Reactant: Cc1c(-c2ccccc2)c(F)c2oc(Cl)nc2c1C#N
Reactant: C1COCCN1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1c(-c2ccccc2)c(F)c2oc(N3CCOCC3)nc2c1C#N
Temperature: 25 °C
Reaction time: 2 h
Yield: 99.1 %

Procedure:
With cooling with ice, morpholine (36 μl, 0.413 mmol) and diisopropylethylamine (140 μl, 0.825 mmol) were added to a dichloromethane (3 ml) solution of 2-chloro-7-fluoro-5-methyl-6-phenylbenzoxazole-4-carbonitrile (I-130) (99 mg, 0.344 mmol), followed by stirring at room temperature for 2 hours. The reaction liquid was concentrated under reduced pressure, then the resulting residue was purified by silica gel column chromatography (eluent, n-hexane:ethyl acetate=2:1, v/v) to obtain the entitled compound (115 mg, 99%) as a white solid.
Reaction SMILES: [CH3:1][N:2]1[C:7](=[O:8])[CH:6]=[C:5]([NH:9][C:10]2[CH:15]=[CH:14][C:13]([Cl:16])=[C:12]([Cl:17])[C:11]=2[Cl:18])[C:4]([C:19]([OH:21])=O)=[CH:3]1.C(Cl)(=O)C(Cl)=O.[NH3:28].O1CCOCC1>C(Cl)Cl.CN(C=O)C>[CH3:1][N:2]1[C:7](=[O:8])[CH:6]=[C:5]([NH:9][C:10]2[CH:15]=[CH:14][C:13]([Cl:16])=[C:12]([Cl:17])[C:11]=2[Cl:18])[C:4]([C:19]([NH2:28])=[O:21])=[CH:3]1
Reactant: N
Reactant: Cn1cc(C(=O)O)c(Nc2ccc(Cl)c(Cl)c2Cl)cc1=O
Agent: O=C(Cl)C(=O)Cl
Solvent: C1COCCO1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: Cn1cc(C(N)=O)c(Nc2ccc(Cl)c(Cl)c2Cl)cc1=O
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
The product of Example 65, 1-methyl-6-oxo-4-(2,3,4-trichloro-phenylamino)-1,6-dihydro-pyridine-3-carboxylic acid (0.4 g, 1.15 mmol) was dissolved in DCM (20 mL). Added one drop of DMF and then oxalyl chloride (0.11 mL, 1.27 mmol) was added. Reaction was stirred at rt for 1.5 hours. Then 0.5 N NH3/dioxane (10 mL) was added and stirred for 72 hours. The solvent was removed in vacuum. Ethyl acetate was added and washed with sat. NaHCO3 soln. Filtered solid and dried in vacuum oven 1 hour. Tried to recrystalize using hexanes (5 mL) and EtOAc (30 mL) but never dissolved. Solvent removed in vacuum and took the residue up in ethyl acetate (10 mL)/MeOH (2 mL). Still did not dissolve. Cooled, filtered and dried in vacuum oven overnight at 60° C. Obtained white solid (210.0 mg, 52.7% y.). MS (APCI+) 347,349 [M+H]; HPLC 2.954 m. 94.68%; C13H10Cl3N3O2; CHN Calc. C)45.05% H)2.91% N)12.12% found C)27.56% H)1.29% N)3.96%; NMR (400 MHz, DMSO-d6) δ 13.36 (s, 1H), 8.11 (s, 1H), 7.55 (d, J=9.0 Hz, 1H), 7.51 (d, J=9.0 Hz, 1H), 5.67 (s, 1H), 3.31 (s, 3H).