Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]1[C@@H:4]([C:5]([OH:7])=O)[NH:3][CH2:2]1.[CH3:8][C:9]1[CH:10]=[CH:11][CH:12]=[C:13]2[NH:19]C(=O)O[C:15](=[O:16])[C:14]=12>CS(C)=O>[CH3:8][C:9]1[C:14]2[C:15](=[O:16])[N:3]3[CH2:2][CH2:1][C@H:4]3[C:5](=[O:7])[NH:19][C:13]=2[CH:12]=[CH:11][CH:10]=1
Reactant: O=C(O)[C@@H]1CCN1
Reactant: Cc1cccc2[nH]c(=O)oc(=O)c12
Solvent: CS(C)=O
Product: Cc1cccc2c1C(=O)N1CC[C@H]1C(=O)N2

Procedure:
13.0 g (128.4 mmol) of L-azetidine-2-carboxylic acid and 22.7 g (128.4 mmol) of 6-methylisatoic acid anhydride in 150 ml of dimethyl sulphoxide are heated to 95° for 3 hours, evaporated to dryness in a high vacuum and the residue obtained is heated to 140° for 2.25 hours. By crystallization from ethyl acetate there is obtained (S)-1,10a-dihydro-5-methyl-2H-azeto[2,1-c][1,4]benzodiazepine-4,10(9H)-dione of melting point 159°-160°.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[NH:6][CH:5]=1.[F:13][C:14]1[CH:15]=[C:16]([CH:19]=[CH:20][C:21]=1[F:22])[CH:17]=O.C(O)(C(F)(F)F)=O>>[F:13][C:14]1[CH:15]=[C:16]([CH:17]2[C:5]3[NH:6][C:7]4[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=4)[C:4]=3[CH2:3][CH2:2][NH:1]2)[CH:19]=[CH:20][C:21]=1[F:22]
Reactant: NCCc1c[nH]c2ccccc12
Reactant: O=Cc1ccc(F)c(F)c1
Solvent: O=C(O)C(F)(F)F
Product: Fc1ccc(C2NCCc3c2[nH]c2ccccc32)cc1F
Yield: 81.9 %

Procedure:
This product was prepared using the same procedure as for Intermediate 1 with tryptamine (5.4 g, 33.5 mmol), 3,4-difluorobenzaldehyde (5.0 g, 1.05 equiv.) and TFA (5.2 mL, 2 equiv.) to give the title compound (7.8 g, 82%) as white crystals.
Reaction SMILES: [OH:1][C:2]1[C:7]2[C@@:8]3([OH:45])[C@@:21]([O:25][CH3:26])([C@H:22]([OH:24])[CH2:23][C:6]=2[CH:5]=[C:4]([CH3:46])[C:3]=1[C:47]([O:49][CH3:50])=[O:48])[C:20](=[O:27])[C:19]1[C:10](=[CH:11][C:12]2[C:13](=[O:43])[C:14]([NH:30][C@@H:31]4[C@H:36]([O:37][CH3:38])[C@H:35]([OH:39])[C@@H:34]([O:40][CH3:41])[C@H:33]([CH3:42])[O:32]4)=[CH:15][C:16](=[O:29])[C:17]=2[C:18]=1[OH:28])[C:9]3=[O:44].C(=O)([O-])[O-].[K+].[K+].Br[CH2:58][C:59]([O:61][CH3:62])=[O:60]>>[OH:24][C@H:22]1[C@:21]2([O:25][CH3:26])[C@@:8]([OH:45])([C:9](=[O:44])[C:10]3[C:19]([C:20]2=[O:27])=[C:18]([OH:28])[C:17]2[C:16](=[O:29])[CH:15]=[C:14]([NH:30][C@@H:31]4[C@H:36]([O:37][CH3:38])[C@H:35]([OH:39])[C@@H:34]([O:40][CH3:41])[C@H:33]([CH3:42])[O:32]4)[C:13](=[O:43])[C:12]=2[CH:11]=3)[C:7]2[C:2]([O:1][CH2:58][C:59]([O:61][CH3:62])=[O:60])=[C:3]([C:47]([O:49][CH3:50])=[O:48])[C:4]([CH3:46])=[CH:5][C:6]=2[CH2:23]1
Reactant: COC(=O)c1c(C)cc2c(c1O)[C@]1(O)C(=O)c3cc4c(c(O)c3C(=O)[C@]1(OC)[C@H](O)C2)C(=O)C=C(N[C@H]1O[C@@H](C)[C@H](OC)[C@@H](O)[C@H]1OC)C4=O
Reactant: COC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Product: COC(=O)COc1c(C(=O)OC)c(C)cc2c1[C@]1(O)C(=O)c3cc4c(c(O)c3C(=O)[C@]1(OC)[C@H](O)C2)C(=O)C=C(N[C@H]1O[C@@H](C)[C@H](OC)[C@@H](O)[C@H]1OC)C4=O
Yield: 18 %

Procedure:
Following General Procedure: Method A using (6R,6aS,14aR)-methyl 1,6,8,14a-tetrahydroxy-11-((2S,3R,4R,5R,6S)-4-hydroxy-3,5-dimethoxy-6-methyltetrahydro-2H-pyran-2-ylamino)-6a-methoxy-3-methyl-7,9,12,14-tetraoxo-5,6,6a,7,9,12,14,14a-octahydrobenzo[a]tetracene-2-carboxylate (50 mg, 0.072 mmol), potassium carbonate (30 mg, 0.22 mmol) and methyl bromoacetate (20 μL, 0.22 mmol), the product was purified by preparative TLC (silica gel, 95:5 dichloromethane/methanol) and semi-preparative HPLC (45:55 acetonitrile/water with 0.05% TFA) to afford (6R,6aS,14aR)-methyl 6,8,14a-trihydroxy-11-((2S,3R,4R,5R,6S)-4-hydroxy-3,5-dimethoxy-6-methyltetrahydro-2H-pyran-2-ylamino)-6a-methoxy-1-(2-methoxy-2-oxoethoxy)-3-methyl-7,9,12,14-tetraoxo-5,6,6a,7,9,12,14,14a-octahydrobenzo[a]tetracene-2-carboxylate (10 mg, 20%) as a red solid: 1H NMR (500 MHz, CDCl3) δ 14.19 (s, 1H), 8.27 (s, 1H), 6.89 (d, J=9.0 Hz, 1H), 6.86 (s, 1H), 5.88 (s, 1H), 4.96 (d, J=6.6 Hz, 1H), 4.69 (d, J=8.7 Hz, 1H), 4.54 (d, J=15.1 Hz, 1H), 4.43 (d, J=15.1 Hz, 1H), 3.91 (br s, 3H), 3.79 (s, 3H), 3.76-3.67 (m, 3H), 3.73 (s, 3H), 3.64-3.55 (m, 1H), 3.60 (s, 3H), 3.39 (s, 3H), 3.36-3.29 (m, 3H), 3.13 (t, J=9.2 Hz, 1H), 2.60 (br s, 1H), 2.19 (s, 3H), 1.36 (d, J=6.2 Hz, 3H); MS (ESI+) m/z 770 (M+H); HPLC 96.4% (AUC), tR 15.46 min.
Reaction SMILES: F[C:2]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[C:7]2[C:3]=1[CH2:4][N:5]([CH3:15])[C:6]2=[O:14].C(=O)([O-])[O-].[K+].[K+].C(N(CC)CC)C.[C:29]([O:33][C:34]([N:36]1[CH2:41][CH2:40][NH:39][CH2:38][CH2:37]1)=[O:35])([CH3:32])([CH3:31])[CH3:30]>CS(C)=O.O>[C:29]([O:33][C:34]([N:36]1[CH2:41][CH2:40][N:39]([C:2]2[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[C:7]3[C:3]=2[CH2:4][N:5]([CH3:15])[C:6]3=[O:14])[CH2:38][CH2:37]1)=[O:35])([CH3:32])([CH3:30])[CH3:31]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: CN1Cc2c(F)ccc([N+](=O)[O-])c2C1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: CN1Cc2c(N3CCN(C(=O)OC(C)(C)C)CC3)ccc([N+](=O)[O-])c2C1=O
Temperature: 60 °C
Reaction time: 6 h
Yield: 75 %

Procedure:
To a suspension of 4-fluoro-2-methyl-7-nitro-2,3-dihydro-isoindol-1-one (2.0 g, 8.52 mmol) and potassium carbonate (657.9 mg, 4.76 mmol), triethylamine (2.0 mL, 14.3 mmol) in dimethylsulfoxide (20 mL), piperazine-1-carboxylic acid tert-butyl ester (1.77 g, 9.52 mmol) is added and the mixture is stirred at 60° C. for 6 hours. The mixture is poured into iced water and the resulting brown solids are collected by filtration. The obtained solid is dried in vacuo at 50° C. to afford 4-(2-methyl-7-nitro-1-oxo-2,3-dihydro-1H-isoindol-4-yl)-piperazine-1-carboxylic acid tert-butyl ester as brown solid in 75% yield. Rf=0.25 (Hexane/AcOEt=1/1). 1H-NMR (400 MHz, CDCl3, δ, ppm): 1.50 (s, 9H), 3.13 (t, 4H), 3.20 (s, 3H), 3.61 (t, 4H), 4.37 (s, 2H), 7.04 (d, 1H), 7.78 (d, 1H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]([CH2:13][OH:14])=[C:11](/[CH:15]=[CH:16]/[C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[O:10][N:9]=2)=[CH:4][CH:3]=1.[CH2:23]([O:25][C:26]([C:28]1[CH:33]=[CH:32][C:31](O)=[CH:30][N:29]=1)=[O:27])[CH3:24].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>C1COCC1>[CH2:23]([O:25][C:26]([C:28]1[CH:33]=[CH:32][C:31]([O:14][CH2:13][C:12]2[C:8]([C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=3)=[N:9][O:10][C:11]=2/[CH:15]=[CH:16]/[C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)=[CH:30][N:29]=1)=[O:27])[CH3:24]
Reactant: CCOC(=O)c1ccc(O)cn1
Reactant: OCc1c(-c2ccc(F)cc2)noc1/C=C/c1ccccc1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCOC(=O)c1ccc(OCc2c(-c3ccc(F)cc3)noc2/C=C/c2ccccc2)cn1
Yield: 47.5 %

Procedure:
To a stirred solution of [3-(4-fluoro-phenyl)-5-((E)-styryl)-isoxazol-4-yl]-methanol (4.0 g, 13.5 mmol) and 5-hydroxy-pyridine-2-carboxylic acid ethyl ester (2.49 g, 14.9 mmol) in THF (130 mL) under argon was added triphenylphosphine (5.49 g, 20.31 mmol). Diethyl azodicarboxylate (9.3 mL, 20.31 mmol) was then added dropwise. After 3 h the reaction mixture was concentrated then purified by chromatography (silica, 10 to 40% ethyl actetate in heptane) afforded the title compound (2.85 g, 47%) as a white solid. MS: m/e=445.4 [M+H]+.
Reaction SMILES: [O:1]1C2=NC=CC=C2C=C1.[CH:10]([C:13]1([CH3:31])[C:17](=[S:18])[NH:16][C:15]([C:19]2[N:24]=[C:23]3S[CH:26]=[CH:27][C:22]3=[CH:21][C:20]=2[C:28]([OH:30])=[O:29])=[N:14]1)([CH3:12])[CH3:11]>>[CH:10]([C:13]1([CH3:31])[C:17](=[S:18])[NH:16][C:15]([C:19]2[N:24]=[C:23]3[O:1][CH:26]=[CH:27][C:22]3=[CH:21][C:20]=2[C:28]([OH:30])=[O:29])=[N:14]1)([CH3:12])[CH3:11]
Reactant: c1cnc2occc2c1
Reactant: CC(C)C1(C)N=C(c2nc3sccc3cc2C(=O)O)NC1=S
Product: CC(C)C1(C)N=C(c2nc3occc3cc2C(=O)O)NC1=S

Procedure:
In the same manner as described above for the furo[2,3-b]pyridine compound, 6-(4-isopropyl-4-methyl-5-thioxo-2-imidazolin-2-yl)-thieno[2,3-b]pyridine-5-carboxylic acid is prepared in 37% yield having a mp 242° C.
Reaction SMILES: [CH3:1][N:2]1[CH2:25][CH2:24][C:5]2[N:6]([CH2:14][C:15]3([C:18]4[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=4)[CH2:17][O:16]3)[C:7]3[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][C:12]=3[C:4]=2[CH2:3]1.[CH3:26][NH:27][CH3:28]>C1COCC1>[CH3:1][N:2]1[CH2:25][CH2:24][C:5]2[N:6]([CH2:14][C:15]([C:18]3[CH:19]=[CH:20][N:21]=[CH:22][CH:23]=3)([OH:16])[CH2:17][N:27]([CH3:28])[CH3:26])[C:7]3[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][C:12]=3[C:4]=2[CH2:3]1
Reactant: CNC
Reactant: Cc1ccc2c(c1)c1c(n2CC2(c3ccncc3)CO2)CCN(C)C1
Solvent: C1CCOC1
Product: Cc1ccc2c(c1)c1c(n2CC(O)(CN(C)C)c2ccncc2)CCN(C)C1
Temperature: 60 °C
Reaction time: 8 h

Procedure:
2,8-Dimethyl-5-((2-(pyridin-4-yl)oxiran-2-yl)methyl)-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (100 mg, 0.3 mmol) was added to 2M dimethyl amine solution in THF (5 mL) and the reaction mixture was allowed to stir at 60° C. overnight. The progress of reaction was monitored by LCMS. The solvent was removed under reduced pressure to obtain a crude oily product that was purified by reverse phase HPLC to afford 5 mg of 1-(2,8-dimethyl-3,4-dihydro-1H-pyrido[4,3-b]indol-5(2H)-yl)-3-(dimethylamino)-2-(pyridin-4-yl)propan-2-ol as the TFA salt. 1H NMR (CD3OD, TFA salt) δ (ppm): 8.58 (d, 2H), 7.81 (m, 2H), 7.18 (d, 1H), 7.05 (m, 1H), 6.91 (m, 1H), 4.63 (m, 1H), 4.51 (s, 2H), 4.27 (d, 1H), 4.18 (m, 2H), 3.58 (m, 2H), 3.48 (m, 1H), 3.1 (s, 6H), 2.89 (m, 1H), 2.8 (s, 3H), 2.35 (s, 3H). Separation by chiral HPLC provides enantiomers II-259a-b.
Reaction SMILES: [CH3:1][C:2]([CH3:13])([CH3:12])[C:3]([NH:5][C:6]1[CH:11]=[CH:10][N:9]=[CH:8][CH:7]=1)=[O:4].C([Li])CCC.CCCCCC.Cl.[C:26](=O)([O-])[O-:27].[K+].[K+]>O1CCCC1.CN(C)C=O>[CH:26]([C:7]1[CH:8]=[N:9][CH:10]=[CH:11][C:6]=1[NH:5][C:3](=[O:4])[C:2]([CH3:13])([CH3:12])[CH3:1])=[O:27]
Reactant: CC(C)(C)C(=O)Nc1ccncc1
Reactant: O=C([O-])[O-]
Agent: Cl
Agent: [K+]
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: CC(C)(C)C(=O)Nc1ccncc1C=O
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 52 %

Procedure:
2,2-Dimethyl-N-pyridin-4-yl-propionamide (5.60 g) was dissolved in tetrahydrofuran (70 ml) to prepare a solution which was then cooled to −78° C. A 1.57 M n-butyllithium/n-hexane solution (62 ml) was gradually added dropwise thereto, and the mixture was stirred at −78° C. for 15 min. The reaction solution was stirred at 0° C. for 4 hr and was then again cooled to −78° C. A solution of N,N-dimethylformamide (6.69 g) in tetrahydrofuran (7 ml) was gradually added dropwise thereto. The temperature of the reaction solution was raised to room temperature, the reaction solution was then poured into a mixture composed of ice (10 g) and 6 N hydrochloric acid (30 ml), and the mixture was stirred at room temperature for 15 min. The aqueous layer was neutralized with potassium carbonate powder and was extracted with diethyl ether. The diethyl ether layer was then washed with water and saturated brine and was dried over magnesium sulfate. The solvent was removed by distillation under the reduced pressure, and the residue was purified by column chromatography using acetone-chloroform to give N-(3-formyl-pyridin-4-yl)-2,2-dimethyl-propionamide (3.35 g, yield 52%).
Reaction SMILES: [CH2:1]([O:3][SiH:4]([O:8][CH2:9]C)[O:5][CH2:6]C)C.CO[SiH](OC)OC.C1(C)C=CC=CC=1.[NH2:25][CH2:26][CH2:27][CH2:28][Si](OC)(OC)OC>CC1C=CC(C)=CC=1>[CH2:26]([NH2:25])[CH:27]=[CH2:28].[CH3:1][O:3][SiH:4]([O:8][CH3:9])[O:5][CH3:6]
Reactant: CCO[SiH](OCC)OCC
Reactant: CO[Si](CCCN)(OC)OC
Agent: CO[SiH](OC)OC
Solvent: Cc1ccc(C)cc1
Solvent: Cc1ccccc1
Product: C=CCN

Procedure:
Example 1 was repeated except that the 41 grams of triethoxy silane was replaced with 30.6 grams of trimethoxy silane (0.25 mole) and toluene was used as a solvent instead of p-xylene, with other conditions remaining the same. After the completion of the reaction, the reaction mixture was subjected to gas chromatography analysis. It was found that gamma-aminopropyl trimethoxy silane was obtained in a yield of 70% on an allylamine basis, while the yield of beta-amminopropyl trimethoxy silane was 0.9% on an a trimethoxy silane basis.
Reaction SMILES: C(C1N=C(N2CCOCC2)C2N=NN(CC3C=CC=CC=3Cl)C=2N=1)(C)(C)C.[C:28]([C:32]1[N:33]=[C:34](Cl)[C:35]2[N:40]=[N:39][N:38]([CH2:41][C:42]3[CH:47]=[CH:46][CH:45]=[CH:44][C:43]=3[Cl:48])[C:36]=2[N:37]=1)([CH3:31])([CH3:30])[CH3:29].C(O)(=O)C(O)=O.[CH2:56]1[C:59]2([CH2:63][CH2:62][NH:61][CH2:60]2)[CH2:58][O:57]1>>[C:28]([C:32]1[N:33]=[C:34]([N:61]2[CH2:62][CH2:63][C:59]3([CH2:56][O:57][CH2:58]3)[CH2:60]2)[C:35]2[N:40]=[N:39][N:38]([CH2:41][C:42]3[CH:47]=[CH:46][CH:45]=[CH:44][C:43]=3[Cl:48])[C:36]=2[N:37]=1)([CH3:31])([CH3:30])[CH3:29]
Reactant: C1CC2(CN1)COC2
Reactant: CC(C)(C)c1nc(Cl)c2nnn(Cc3ccccc3Cl)c2n1
Agent: CC(C)(C)c1nc(N2CCOCC2)c2nnn(Cc3ccccc3Cl)c2n1
Agent: O=C(O)C(=O)O
Product: CC(C)(C)c1nc(N2CCC3(COC3)C2)c2nnn(Cc3ccccc3Cl)c2n1

Procedure:
In analogy to the procedure described for the synthesis of 5-tert-butyl-3-(2-chloro-benzyl)-7-morpholin-4-yl-3H-[1,2,3]triazolo[4,5-d]pyrimidine (example 1, step c), the title compound was prepared from 5-tert-butyl-7-chloro-3-(2-chlorobenzyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine and 2-oxa-6-azaspiro[3.4]octane oxalate and isolated as colorless gum (2.6 mg, 13%). MS(m/e): 413.4 (MH+).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].F[C:19]1[CH:24]=[C:23]([N:25]2[C:30](=[O:31])[CH:29]=[C:28]([C:32]([F:35])([F:34])[F:33])[N:27]([CH3:36])[C:26]2=[O:37])[C:22]([F:38])=[CH:21][C:20]=1[N+:39]([O-:41])=[O:40]>CN(C)C=O>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([O:15][C:19]2[CH:24]=[C:23]([N:25]3[C:30](=[O:31])[CH:29]=[C:28]([C:32]([F:34])([F:35])[F:33])[N:27]([CH3:36])[C:26]3=[O:37])[C:22]([F:38])=[CH:21][C:20]=2[N+:39]([O-:41])=[O:40])=[CH:13][CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cn1c(C(F)(F)F)cc(=O)n(-c2cc(F)c([N+](=O)[O-])cc2F)c1=O
Reactant: Oc1ccc(OCc2ccccc2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cn1c(C(F)(F)F)cc(=O)n(-c2cc(Oc3ccc(OCc4ccccc4)cc3)c([N+](=O)[O-])cc2F)c1=O
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 44.1 %

Procedure:
A mixture of 1.71 g of 4-benzyloxyphenol and 4.0 ml of N,N-dimethylformamide was added dropwise into a mixture of 0.34 g of sodium hydride and 8.5 ml of N,N-dimethylformamide while cooling with ice, and the mixture was stirred for 20 minutes. A mixture of 3.0 g of 2,5-difluoro-4-[3-methyl-2,6-dioxo-4-(trifluoromethyl)-1,2,3,6-tetrahydropyrimidin-1-yl]nitrobenzene (described later, produced in Intermediate Production Example 4) and 7.0 ml of N,N-dimethylformamide was added dropwise at the same temperature, and stirred for 1 hour. This reaction solution was poured into ice water, and extracted with ethyl acetate. The organic layer was washed once with IN hydrochloric acid and once with saturated saline and dried over anhydrous magnesium sulfate, and concentrated. The residue was subjected to silica gel column chromatography to obtain 2.0 g of 2-(4-benzyloxyphenoxy)-5-fluoro-4-[3-methyl-2,6-dioxo-4-(trifluoromethyl)-1,2,3,6-tetrahydropyrimidin-1-yl]nitrobenzene.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]([CH3:11])[C:5]([C:6]([OH:8])=[O:7])=[C:4]([CH3:12])[CH:3]=1.C(Cl)CCl.C1C=CC2N([OH:26])N=NC=2C=1.[CH3:27][CH2:28][N:29]([CH:33](C)C)C(C)C>>[CH2:28]([NH:29][C:33]([NH:1][C:2]1[CH:10]=[C:9]([CH3:11])[C:5]([C:6]([OH:8])=[O:7])=[C:4]([CH3:12])[CH:3]=1)=[O:26])[CH3:27]
Reactant: On1nnc2ccccc21
Reactant: Cc1cc(N)cc(C)c1C(=O)O
Reactant: CCN(C(C)C)C(C)C
Solvent: ClCCCl
Product: CCNC(=O)Nc1cc(C)c(C(=O)O)c(C)c1

Procedure:
8AA: The tri-hydrochloride salt of the product of Example 8. step 3 (2 g, 4.3 mmol) and 4-amino-2,6-dimethyl benzoic acid (710 mg, 4.3 mmol) (see preparation below) were subjected to the standard coupling conditions (EDC/HOBT/iPr2NEt). Purification via flash chromatography (2/1 hexanes/acetone, SiO2) gave 1.16 g (52%) of 8AA as a yellow foam.
Reaction SMILES: ClC1C([C:8](O)=[O:9])=C(C2C=CC=CC=2)C(C)=CN=1.[F:18][C:19]([F:37])([F:36])[C:20]1[CH:21]=[C:22]([CH:29]=[C:30]([C:32]([F:35])([F:34])[F:33])[CH:31]=1)[CH2:23][NH:24][CH2:25]CCO>>[F:35][C:32]([F:34])([F:33])[C:30]1[CH:29]=[C:22]([CH:21]=[C:20]([C:19]([F:37])([F:36])[F:18])[CH:31]=1)[CH2:23][NH:24][CH2:25][CH2:8][OH:9]
Reactant: Cc1cnc(Cl)c(C(=O)O)c1-c1ccccc1
Reactant: OCCCNCc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Product: OCCNCc1cc(C(F)(F)F)cc(C(F)(F)F)c1

Procedure:
2-Chloro-5-methyl-4-phenyl-3-pyridinecarboxylic acid was used in place of 2-chloro-4-phenyl-3-pyridinecarboxylic acid in Step 2 in Reference Example 12, reacted with N-[3,5-bis(trifluoromethyl)benzyl]-N-(3-hydroxypropyl)amine that had been obtained in Step 1 in Reference Example 23, in place of N-[3,5-bis(trifluoromethyl)benzyl]-N-(2-hydroxyethyl)amine, and treated in the same manner as in Step 2 in Reference Example 12, to obtain the entitled compound as a pale yellow oil. NMR(200 MHz, CDCl3) ppm: 1.10-1.80(2H,m), 2.06(3H×1/2,s), 2.08(3H×1/2,s), 2.80-3.30(3H,m), 3.35-3.70(1H,m), 4.08(1H×1/2,d,J=16.4 Hz), 4.39(1H×1/2,d,J=15.0 Hz), 4.47(1H×1/2,d,J=16.4 Hz), 4.70(1H×1/2,d,J=15.0 Hz), 6.90-7.62(7H,m), 7.72(1H×1/2,s), 7.77(1H×1/2,s), 8.28(1H×1/2,s), 8.31(1H×1/2,s).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C@:8]12[CH2:17][CH2:16][C@H:15](O)[CH2:14][C@H:13]1[CH2:12][S:11][C:10]([NH:19][C:20](=[O:26])[O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[N:9]2.[F:27]C(F)(S(F)(=O)=O)C(F)(F)C(F)(F)C(F)(F)F.C(N(CC)CC)C>C1COCC1>[F:27][C@@H:15]1[CH2:16][CH2:17][C@:8]2([C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=3[F:1])[N:9]=[C:10]([NH:19][C:20](=[O:26])[O:21][C:22]([CH3:25])([CH3:24])[CH3:23])[S:11][CH2:12][C@@H:13]2[CH2:14]1
Reactant: O=S(=O)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Reactant: CC(C)(C)OC(=O)NC1=N[C@@]2(c3ccccc3F)CC[C@H](O)C[C@H]2CS1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)NC1=N[C@@]2(c3ccccc3F)CC[C@@H](F)C[C@H]2CS1
Temperature: 50 °C
Reaction time: 16 h

Procedure:
tert-Butyl(±)-[(4aR*,6S*,8aS*)-8a-(2-fluorophenyl)-6-hydroxy-4a,5,6,7,8,8a-hexahydro-4H-benzo[d][1,3]thiazin-2-yl]carbamate obtained in Preparation Example 63-(4) (1.5 g) was dissolved in THF. Then, perfluorobutanesulfonyl fluoride (1.36 mL, specific gravity: 1.682 g/cm3), a triethylamine-trihydrofluoric acid complex (1.23 mL, specific gravity: 0.989 g/cm3) and triethylamine (3.15 mL, specific gravity: 0.73 g/cm3) were sequentially added at room temperature. After completion of the addition, the mixture was stirred for 16 hours. The mixture was heated to 50° C. and further stirred for 24 hours. Perfluorobutanesulfonyl fluoride (0.68 mL), a triethylamine-trihydrofluoric acid complex (0.62 mL) and triethylamine (1.58 mL) were further sequentially added to the mixture, followed by further stirring with heating under reflux for eight hours. The reaction solution was cooled to room temperature and concentrated under reduced pressure. Then, the residue was purified by silica gel column chromatography to obtain the title compound (106 mg).
Reaction SMILES: [C:1]1([CH2:17]O)[C:14]2[C:15]3=[C:16]4[C:11](=[CH:12][CH:13]=2)[CH:10]=[CH:9][CH:8]=[C:7]4[CH:6]=[CH:5][C:4]3=[CH:3][CH:2]=1.P(Br)(Br)[Br:20].CCOCC.O>C1C=CC=CC=1>[Br:20][CH2:17][C:1]1[C:14]2[C:15]3=[C:16]4[C:11](=[CH:12][CH:13]=2)[CH:10]=[CH:9][CH:8]=[C:7]4[CH:6]=[CH:5][C:4]3=[CH:3][CH:2]=1
Reactant: OCc1ccc2ccc3cccc4ccc1c2c34
Reactant: BrP(Br)Br
Solvent: c1ccccc1
Solvent: CCOCC
Solvent: O
Product: BrCc1ccc2ccc3cccc4ccc1c2c34
Reaction time: 2 h
Yield: 236.4 %

Procedure:
A 10.00 g sample (43.1 mmol) of 1-Pyrenemethanol was dissolved in 250 mL of benzene with slight heating. The mixture was returned to room temperature and 1.63 mL (4.24 g, 17.24 mmol) of phosphorus tribromide were slowly added. The mixture was brought to reflux and stirred for 2 h. The mixture was returned to room temperature, and poured into a separatory funnel containing 500 mL 3:2 Et2O:H2O. The organic fraction was washed twice with 100 mL H2O and dried over anhydrous Na2SO4. Solvent was removed under reduced pressure to yield 1-(bromomethyl)pyrene (12.030 g, 95.0%) as a dark yellow powder. TLC (SiO2, 1:1 Hexane:EtOAc) Rƒ=0.95. Mp=270° C. (dec) 1H NMR (CDCl3), δ 5.28 (s, 2H), 8.0-8.3 (m, 9H from pyrene). 13C NMR (CDCl3), δ32.643, 123.258-132.374 16 pks from pyrene.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([NH2:15])[CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH2:7]1)=[O:5])[CH3:2].[Cl:16][C:17]1[C:18]([OH:28])=[C:19]([S:24](Cl)(=[O:26])=[O:25])[CH:20]=[C:21]([Cl:23])[CH:22]=1.CCN(C(C)C)C(C)C>C(Cl)Cl>[CH2:1]([O:3][C:4]([C:6]1([NH:15][S:24]([C:19]2[CH:20]=[C:21]([Cl:23])[CH:22]=[C:17]([Cl:16])[C:18]=2[OH:28])(=[O:25])=[O:26])[CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)C1(N)Cc2ccccc2C1
Reactant: O=S(=O)(Cl)c1cc(Cl)cc(Cl)c1O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCOC(=O)C1(NS(=O)(=O)c2cc(Cl)cc(Cl)c2O)Cc2ccccc2C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 27.4 %

Procedure:
To a solution of 2-amino-indan-2-carboxylic acid ethyl ester (3.14 g, 15.3 mmol) and 3,5-dichloro-2-hydroxy-benzenesulfonyl chloride (1 g, 3.82 mmol) in anhydrous DCM (dichloromethane, 20 mL) is added DIPEA (631 μL, 3.82 mmol). The resulting solution is stirred at RT for 1 hour. The reaction solution is diluted in DCM (50 mL) and washed with water (1×5 mL) and brine (2×5 mL). The organic layer is dried over anhydrous Na2SO4 and concentrated in vacuo. The residue is purified by HPLC to give a pure product (30) as white solid (450 mg, 27%).
Reaction SMILES: [CH3:1][C:2]1[N:29]=[C:5]2[NH:6][C:7](=[O:28])[C:8]([CH2:13][C:14]3[CH:19]=[CH:18][C:17]([C:20]4[C:21]([C:26]#[N:27])=[CH:22][CH:23]=[CH:24][CH:25]=4)=[CH:16][CH:15]=3)=[C:9]([CH2:10][CH2:11][CH3:12])[N:4]2[N:3]=1.[CH2:30]([C:32]1[N:37]=[CH:36][C:35]([CH2:38]O)=[CH:34][CH:33]=1)[CH3:31].C(P(CCCC)CCCC)CCC.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O>C1COCC1.C(OCC)(=O)C>[CH2:30]([C:32]1[N:37]=[CH:36][C:35]([CH2:38][N:6]2[C:7](=[O:28])[C:8]([CH2:13][C:14]3[CH:19]=[CH:18][C:17]([C:20]4[C:21]([C:26]#[N:27])=[CH:22][CH:23]=[CH:24][CH:25]=4)=[CH:16][CH:15]=3)=[C:9]([CH2:10][CH2:11][CH3:12])[N:4]3[N:3]=[C:2]([CH3:1])[N:29]=[C:5]23)=[CH:34][CH:33]=1)[CH3:31]
Reactant: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)[nH]c2nc(C)nn12
Reactant: CCc1ccc(CO)cn1
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n(Cc2ccc(CC)nc2)c2nc(C)nn12
Temperature: 25 °C
Reaction time: 8 h
Yield: 25.5 %

Procedure:
To a solution of 4′-[(2-methyl-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)methyl]biphenyl-2-carbonitrile (1.5 g), (6-ethylpyridin-3-yl)methanol (0.46 g) and tributylphosphine (1.1 mL) in THF (50 mL) was added 1,1′-(azodicarbonyl)dipiperidine (0.88 g) at 0° C., and the mixture was stirred at room temperature overnight. The reaction mixture was diluted with ethyl acetate, washed with 5% aqueous potassium hydrogensulfate solution and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography to give the title compound as a colorless solid (0.43 g, 49%).