Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:18]=[CH:17][CH:16]=[C:15]([CH3:19])[C:3]=1[C:4]([NH:6][CH:7]1[CH2:12][CH2:11][C:10](=[O:13])[NH:9][C:8]1=[O:14])=[O:5].[C:20]1(C)[CH:25]=[CH:24]C(S(O)(=O)=O)=[CH:22][CH:21]=1>CN(C=O)C>[CH2:21]([C:22]1[N:6]([CH:7]2[CH2:12][CH2:11][C:10](=[O:13])[NH:9][C:8]2=[O:14])[C:4](=[O:5])[C:3]2[C:2](=[CH:18][CH:17]=[CH:16][C:15]=2[CH3:19])[N:1]=1)[CH2:20][CH2:25][CH3:24]
Reactant: Cc1cccc(N)c1C(=O)NC1CCC(=O)NC1=O
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CN(C)C=O
Product: CCCCc1nc2cccc(C)c2c(=O)n1C1CCC(=O)NC1=O
Yield: 30.1 %

Procedure:
A solution of 2-amino-N-(2,6-dioxo-piperidin-3-yl)-6-methyl-benzamide (0.65 g, 2.5 mmol) and trimethyl orthopentionate (0.66 mL, 3.8 mmol) and p-toluenesulfonic acid (140 mg) in DMF (7 mL) was heated at 150° C. in a microwave oven for 20 minutes. The mixture was extracted with ethyl acetate (50 mL) and water (50 mL). The aqueous layer was extracted with ethyl acetate (50 mL). The combined organic layers was washed with water (50 mL), HCl (1N, 50 mL) and brine (50 mL). The solvent was removed in vacuo to give an oil, which was purified with column chromatography (Silica Gel, methanol/methylene chloride 0% gradient to 5% 15 min), and followed by reversed layer column chromatography (C-18, acetonitrile/water 0% gradient to 100% 15 min) to give 3-(2-butyl-5-methyl-4-oxo-4H-quinazolin-3-yl)-piperidine-2,6-dione as a white solid (80 mg, 10% yield): HPLC: Waters Symmetry C18, 5 μm, 3.9×150 mm, 1 mL/min, 240 nm, 10/90 grad 90/10 in 5 min CH3CN/0.1% H3PO4, 6.59 min (95.4%); mp: 190-192° C.; 1H NMR (DMSO-d6) δ 0.95 (t, J=8 Hz, 3H, CH3), 1.40-1.49 (m, 2H, CH2), 1.67-1.75 (m, 2H, CH2), 2.05-2.09 (m, 1H, CHH), 2.51-2.67 (m, 3H, CH2, CHH), 2.69 (s, 3H, CH3), 2.81-2.90 (m, 3H, CH2, CHH), 5.20 (dd, J=5, 11 Hz, 1H, NCH), 7.25 (d, J=7 Hz, 1H, Ar), 7.44 (d, J=8 Hz, 1H, Ar), 7.64 (t, J=8 Hz, 1H, Ar), 10.98 (s, 1H, NH); 13C NMR (DMSO-d6) δ 13.80, 21.11, 21.72, 22.48, 28.60, 30.50, 34.42, 55.41, 118.63, 124.98, 128.83, 133.70, 139.81, 148.25, 156.95, 161.17, 169.75, 172.65; LCMS: MH=328; Anal Calcd for C18H21N3O3: C, 66.04; H, 6.47; N, 12.84. Found: C, 65.87; H, 6.61; N, 12.89.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:9]([C:11]2[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=2)=[O:10])=[N:4][CH:5]=[C:6]([Cl:8])[CH:7]=1.[Cl:17][C:18]1[CH:23]=[CH:22][C:21]([S:24](Cl)(=[O:26])=[O:25])=[CH:20][C:19]=1[C:28]([F:31])([F:30])[F:29]>CN(C1C=CN=CC=1)C.N1C=CC=CC=1>[Cl:17][C:18]1[CH:23]=[CH:22][C:21]([S:24]([NH:1][C:2]2[C:3]([C:9]([C:11]3[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=3)=[O:10])=[N:4][CH:5]=[C:6]([Cl:8])[CH:7]=2)(=[O:25])=[O:26])=[CH:20][C:19]=1[C:28]([F:31])([F:29])[F:30]
Reactant: Nc1cc(Cl)cnc1C(=O)c1cccnc1
Reactant: O=S(=O)(Cl)c1ccc(Cl)c(C(F)(F)F)c1
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Product: O=C(c1cccnc1)c1ncc(Cl)cc1NS(=O)(=O)c1ccc(Cl)c(C(F)(F)F)c1

Procedure:
A solution of (3-amino-5-chloro-pyridin-2-yl)-pyridin-3-yl-methanone (26 mg, 0.11 mmol), 4-chloro-3-trifluoromethyl-benzenesulfonyl chloride (28 mg, 0.10 mmol), DMAP (7.3 mg, 0.06 mmol) in anhydrous pyridine (0.5 mL) was heated at 60° C. for 2 days. The reaction mixture was separated by preparative HPLC and pure product fractions were lyophilized to provide pure product as a solid. 1H NMR (400 MHz, CDCl3) δ 11.03 (s, 1H), 9.15 (s, 1H), 8.81-8.80 (m, 1H), 8.37 (d, J=2.0 Hz, 1H), 8.29-8.26 (m, 1H), 8.20-8.18 (m, 2H), 7.98 (dd, J=8.4, 2.8 Hz, 1H), 7.63 (d, J=8.4 Hz, 1H), 7.51-7.48 (m, 1H). Mass spectrum m/z: 476.0 (M+H).
Reaction SMILES: [NH2:1][C:2]1[C:10]2[C:5](=[N:6][CH:7]=[C:8]([C:11]3[O:12][CH:13]=[CH:14][CH:15]=3)[N:9]=2)[S:4][C:3]=1[C:16]([OH:18])=O.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.Cl.[NH2:53][C:54]1[CH:55]=[C:56]([NH:61][C:62](=[O:74])[C:63]2[CH:68]=[CH:67][CH:66]=[C:65]([C:69]([C:72]#[N:73])([CH3:71])[CH3:70])[CH:64]=2)[CH:57]=[CH:58][C:59]=1[CH3:60]>CN(C=O)C>[NH2:1][C:2]1[C:10]2[C:5](=[N:6][CH:7]=[C:8]([C:11]3[O:12][CH:13]=[CH:14][CH:15]=3)[N:9]=2)[S:4][C:3]=1[C:16]([NH:53][C:54]1[CH:55]=[C:56]([NH:61][C:62](=[O:74])[C:63]2[CH:68]=[CH:67][CH:66]=[C:65]([C:69]([C:72]#[N:73])([CH3:70])[CH3:71])[CH:64]=2)[CH:57]=[CH:58][C:59]=1[CH3:60])=[O:18]
Reactant: Nc1c(C(=O)O)sc2ncc(-c3ccco3)nc12
Reactant: Cc1ccc(NC(=O)c2cccc(C(C)(C)C#N)c2)cc1N
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1ccc(NC(=O)c2cccc(C(C)(C)C#N)c2)cc1NC(=O)c1sc2ncc(-c3ccco3)nc2c1N
Temperature: 80 °C
Reaction time: 8 h
Yield: 34.6 %

Procedure:
A solution of 7-amino-2-(furan-2-yl)thieno[2,3-b]pyrazine-6-carboxylic acid 59 (66 mg, 0.253 mmol), HATU (106 mg, 0.278 mmol) and DIPEA (0.104 mL, 0.632 mmol) in DMF (2 mL) was stirred at rt for 30 min. N-(3-amino-4-methylphenyl)-3-(2-cyanopropan-2-yl)benzamide hydrochloride 6 (83 mg, 0.253 mmol) was added and stirred overnight at 80° C. Quenched in 2N HCl solution, the resulting precipitate was collected and dried. Purification by HPLC gave the title compound 7-amino-N-(5-(3-(2-cyanopropan-2-yl)benzamido)-2-methylphenyl)-2-(furan-2-yl)thieno[2,3-b]pyrazine-6-carboxamide 60 (47 mg, 34%). NMR (400 MHz, DMSO-d6) 1.76 (s, 6H), 2.23 (s, 3H), 6.79 (dd, J=1.6 and 3.5 Hz, 1H), 7.01 (s, 2H), 7.27 (d, J=8.2 Hz, 1H), 7.46 (d, J=3.5 Hz, 1H), 7.60 (t, J=7.8 Hz, 2H), 7.75 (m, 1H), 7.82 (d, J=1.9 Hz, 1H), 7.95 (m, 1H), 8.01 (m, 1H), 8.05 (m, 1H), 9.16 (s, 1H), 9.48 (s, 1H), 10.33 (s, 1H). (m/z)=537 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[CH:5]2.C(N(CC)CC)C.[C:18](Cl)(=[O:25])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>C(Cl)Cl>[C:18]([N:7]1[C:8]2[C:4](=[CH:3][C:2]([CH3:1])=[CH:10][CH:9]=2)[CH:5]=[CH:6]1)(=[O:25])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: Cc1ccc2[nH]ccc2c1
Reactant: O=C(Cl)c1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1ccc2c(ccn2C(=O)c2ccccc2)c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 5-methylindole (1.0 g, 7.6 mmol) in 8.0 mL of CH2Cl2 was added N,N-dimethylamino pyridine (0.186 g, 1.52 mmol), 2.12 mL (15.24 mmol) of triethylamine and 0.97 mL (1.18 g, 8.39 mmol) of benzoyl chloride. The resulting solution was stirred for 16 hours at room temperature. The solution was diluted with 500 mL of CH2Cl2 and washed with 200 mL of saturated aqueous NaHCO3 and 200 mL of brine. The organic phase was dried over MgSO4, filtered, and concentrated to a yellow oil. The resultant oil was flash chromatographed eluting with 20% ethyl acetate in hexane yielding 1.73 g (96%) of the titled compound as a white powder.
Reaction SMILES: [N+:1]([C:4]1[CH:8]=[CH:7][NH:6][N:5]=1)([O-:3])=[O:2].[H-].[Na+].[CH2:11]([S:13](Cl)(=[O:15])=[O:14])[CH3:12]>CN(C)C=O.C(OCC)(=O)C>[CH2:11]([S:13]([N:6]1[CH:7]=[CH:8][C:4]([N+:1]([O-:3])=[O:2])=[N:5]1)(=[O:15])=[O:14])[CH3:12]
Reactant: O=[N+]([O-])c1cc[nH]n1
Reactant: CCS(=O)(=O)Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCS(=O)(=O)n1ccc([N+](=O)[O-])n1
Yield: 76.1 %

Procedure:
3-Nitro-1H-pyrazole (prepared in example 3, 100 mg, 0.89 mmol) was dissolved in anhydrous N,N-dimethylformamide (4 mL) and a 60% dispersion of sodium hydride in mineral oil (39 mg, 0.94 mmol) was added while stirring under nitrogen. After the effervescence ceased and the mixture was stirred for an additional 10 min, the ethanesulfonyl chloride (94 μL, 1.00 mmol) was added. The mixture was continued to stir under nitrogen for 16 h. The solution was diluted with ethyl acetate (50 mL), washed with water (2×20 mL), saturated aqueous brine solution (2×20 mL), dried over magnesium sulfate, filtered and concentrated in vacuo. Purification by ISCO flash column chromatography (Teledyne Isco RediSep Flash Column 10 g; 25% ethyl acetate/hexanes to 75% ethyl acetate/hexanes) afforded 1-ethanesulfonyl-3-nitro-1H-pyrazole (139 mg, 77%) as a clear, waxy solid: H1-NMR (400 MHz, CDCl3) δ 1.38 (2H, t, J=7.2 Hz), 3.68 (2H, qt, J=7.2 Hz), 7.05 (1H, d, J=2.8 Hz), 8.14 (1H, d, J=2.8 Hz).
Reaction SMILES: [CH:1]1([C:7]2[C:15]3[C:14](=[O:16])[NH:13][C:12]([C:17]4[CH:22]=[CH:21][C:20]([S:23](Cl)(=[O:25])=[O:24])=[CH:19][C:18]=4[O:27][CH3:28])=[N:11][C:10]=3[N:9]([CH2:29][CH3:30])[N:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[OH:31][CH:32]1[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]1>>[CH:1]1([C:7]2[C:15]3[C:14](=[O:16])[NH:13][C:12]([C:17]4[CH:22]=[CH:21][C:20]([S:23]([N:35]5[CH2:36][CH2:37][CH:32]([OH:31])[CH2:33][CH2:34]5)(=[O:25])=[O:24])=[CH:19][C:18]=4[O:27][CH3:28])=[N:11][C:10]=3[N:9]([CH2:29][CH3:30])[N:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CCn1nc(C2CCCCC2)c2c(=O)[nH]c(-c3ccc(S(=O)(=O)Cl)cc3OC)nc21
Reactant: OC1CCNCC1
Product: CCn1nc(C2CCCCC2)c2c(=O)[nH]c(-c3ccc(S(=O)(=O)N4CCC(O)CC4)cc3OC)nc21
Yield: 91 %

Procedure:
The same reaction procedure as in Example 49 was performed, except that the compound obtained in Example 206 was used in place of the compound obtained in Example 48, and 4-hydroxypiperidine was used in place of N-methylpiperazine. In this manner, 155 mg (91%) of the captioned compound was obtained.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[C:9]([CH3:11])[CH:8]=[CH:7][C:6]=1[OH:12])([CH3:4])([CH3:3])[CH3:2].C1C[O:16][CH2:15]C1.C(N(CC)CC)C>C1(C)C=CC=CC=1>[C:1]([C:5]1[CH:10]=[C:9]([CH3:11])[CH:8]=[C:7]([CH:15]=[O:16])[C:6]=1[OH:12])([CH3:4])([CH3:3])[CH3:2]
Reactant: C1CCOC1
Reactant: Cc1ccc(O)c(C(C)(C)C)c1
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: Cc1cc(C=O)c(O)c(C(C)(C)C)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 65 %

Procedure:
2-tert-Butyl-4-methylphenol 9.68 g (58.93 mmol) and THF 100 ml were charged in a sufficiently dried 1 liter reactor purged with nitrogen, ethylmagnesium bromide 23.00 ml (an ether solution, 3.0N, 69.00 mmol) was added dropwise to the reactor at 0° C. in 30 minutes and after that, the resultant mixture was gradually heated to a room temperature and stirred for 1 hour at a room temperature. Toluene 100 ml was added, the resultant mixture was heated to 95° C., and the mixed solvents of the ether/THF were evaporated off to obtain a slightly opaque slurry. After the slurry was cooled to a room temperature, toluene 100 ml, p-formaldehyde 4.50 g (149.90 mmol) and triethylamine 12.50 ml (89.93 mmol) were added and the resultant mixture was stirred at 95° C. for 2 hour. After being cooled to a room temperature, the mixture was quenched with 300 ml of 1N hydrochloric acid and an organic layer was concentrated and purified by a silica gel column to obtain 3-tert-butyl-5-methylsalicylaldehyde 7.36 g (yield 65%).
Reaction SMILES: [N:1]1([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[C:9]2[CH:8]=[CH:7][CH:6]=[C:5]([C:10]([O:12]CC3C=CC=CC=3)=[O:11])[C:4]=2[CH:3]=[CH:2]1.[H][H]>[Pd].CO.O>[C:23]([O:22][C:20]([N:1]1[C:9]2[CH:8]=[CH:7][CH:6]=[C:5]([C:10]([OH:12])=[O:11])[C:4]=2[CH:3]=[CH:2]1)=[O:21])([CH3:26])([CH3:24])[CH3:25]
Reactant: CC(C)(C)OC(=O)n1ccc2c(C(=O)OCc3ccccc3)cccc21
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Solvent: O
Product: CC(C)(C)OC(=O)n1ccc2c(C(=O)O)cccc21
Yield: 61.2 %

Procedure:
The mixture of 4-benzyl 1-tert-butyl 1H-indole-1,4-dicarboxylate (6.37 g) and 10% palladium on carbon (964 mg) in MeOH (95.6 mL) and water (3.2 mL) was hydrogenated at 3.5 atm of hydrogen for 3.5 hours. The resulting mixture was filtered through a bed of celite and the filtrate was evaporated in vacuo. The residue was dissolved in chloroform (100 mL) and the solution was dried over anhydrous MgSO4, filtered and evaporated in vacuo. The residue was triturated with cold MeOH (20 mL) to give 1-(tert-butoxycarbonyl)-1H-indole-4-carboxylic acid (2.90 g) as a colorless crystals. The above filtrate was evaporated in vacuo and the residue was triturated with solvent (n-hexane:EtOAc=5:1, 12 mL) to afford 1-(tert-butoxycarbonyl)-1H-indole-4-carboxylic acid (1.31 g) as colorless crystals.
Reaction SMILES: [N:1]1([C:6]2[CH:11]=[CH:10][C:9]([N:12]3[CH:16]=[CH:15][NH:14][C:13]3=[O:17])=[CH:8][CH:7]=2)[CH:5]=[CH:4][N:3]=[N:2]1.CN1CCCC1=O.[H-].[Na+].[F:27][C:28]1[CH:33]=[C:32]([F:34])[CH:31]=[CH:30][C:29]=1[C@@:35]1([CH2:39][N:40]2[CH:44]=[N:43][CH:42]=[N:41]2)[C@H:37]([CH3:38])[O:36]1>C(OCC)(=O)C>[F:27][C:28]1[CH:33]=[C:32]([F:34])[CH:31]=[CH:30][C:29]=1[C@@:35]([OH:36])([CH2:39][N:40]1[CH:44]=[N:43][CH:42]=[N:41]1)[C@H:37]([N:14]1[CH:15]=[CH:16][N:12]([C:9]2[CH:10]=[CH:11][C:6]([N:1]3[CH:5]=[CH:4][N:3]=[N:2]3)=[CH:7][CH:8]=2)[C:13]1=[O:17])[CH3:38]
Reactant: C[C@@H]1O[C@@]1(Cn1cncn1)c1ccc(F)cc1F
Reactant: O=c1[nH]ccn1-c1ccc(-n2ccnn2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN1CCCC1=O
Product: C[C@@H](n1ccn(-c2ccc(-n3ccnn3)cc2)c1=O)[C@](O)(Cn1cncn1)c1ccc(F)cc1F
Temperature: 25 °C
Reaction time: 1 h
Yield: 38.1 %

Procedure:
To a mixture of 1-[4-(1H-1,2,3-triazol-1-yl)phenyl]-2(1H,3H)-imidazolone (2.72 g) and 1-methyl-2-pyrrolidone (100 ml) was added sodium hydride (70% in oil, 0.40 g), and the mixture was stirred at room temperature for 1 hour. (2R,3S)-2-(2,4-Difluorophenyl)-3-methyl-2-(1H-1,2,4-triazol-1-yl)methyloxirane (2.51 g) was added thereto, and the mixture was stirred at 100° C. for 8 hours under an argon atmosphere. After cooling, the reaction solution was diluted with ethyl acetate (400 ml), and washed with water (100 ml), 1N-hydrochloric acid (100 ml×2) and a saturated aqueous solution of sodium chloride (50 ml) successively. The ethyl acetate layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel chromatography (eluent:ethyl acetate to ethyl acetate/acetone=5/1) and recrystallized from ethyl acetate-diisopropyl ether to give 1-[(1R,2R)-2-(2,4-difluorophenyl)-2-hydroxy-1-methyl-3-(1H-1,2,4-triazol -1-yl)propyl]-3-[4-(1H-1,2,3-triazol-1-yl)phenyl]-2(1H,3H) -imidazolone (Compound 11; 1.82 g) as a pale yellow crystalline powder.
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:10]=[C:9]([NH:11][CH2:12][CH2:13][C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)[N:8]=[C:7](Cl)[N:6]=1)=[O:4].[CH3:23][O-:24].[Na+]>CO>[CH3:23][O:24][C:7]1[N:6]=[C:5]([C:3]([OH:2])=[O:4])[CH:10]=[C:9]([NH:11][CH2:12][CH2:13][C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)[N:8]=1
Reactant: C[O-]
Reactant: COC(=O)c1cc(NCCc2ccc(OC)cc2)nc(Cl)n1
Agent: [Na+]
Solvent: CO
Product: COc1ccc(CCNc2cc(C(=O)O)nc(OC)n2)cc1
Reaction time: 5 h
Yield: 64 %

Procedure:
A mixture of 2-chloro-6-[2-(4-methoxy-phenyl)-ethylamino]-pyrimidine-4-carboxylic acid methyl ester [650 mg, 2.02 mmol, Intermediate (55)] 5M sodium methoxide in MeOH (20 mL, 10.1 mmol), in MeOH (10 mL) is heated to reflux and stirred for 5 hours. The heating is turned off and the mixture is stirred for 15 hours at room temperature and concentrated by rotary evaporator to remove the solvent. The solid is dissolved in water and the solution is acidified to pH 2 with the addition of 1N hydrochloric acid. Extracted three times with 75 mL EtOAc and concentrated the combined organic extracts to afford 2-methoxy-6-[2-(4-methoxy-phenyl)-ethylamino]-pyrimidine-4-carboxylic acid [390 mg, 64%, Intermediate (56)] as a solid. LCMS: RT=1.99 minutes, MS: 304 (M+H).
Reaction SMILES: C(C1N=C(N2CCC(F)(F)C2)[C:8]2[N:13]=[N:12][N:11]([CH2:14]C)[C:9]=2[N:10]=1)(C)(C)C.[C:23]([C:27]1[N:28]=[C:29]([N:36]2[CH2:40][C:39]([F:42])([F:41])[C:38]([F:44])([F:43])[CH2:37]2)[C:30]2[N:35]=[N:34][NH:33][C:31]=2[N:32]=1)([CH3:26])([CH3:25])[CH3:24].ClCC1N(C)N=NN=1>>[C:23]([C:27]1[N:28]=[C:29]([N:36]2[CH2:40][C:39]([F:41])([F:42])[C:38]([F:43])([F:44])[CH2:37]2)[C:30]2[N:35]=[N:34][N:33]([CH2:8][C:9]3[N:11]([CH3:14])[N:12]=[N:13][N:10]=3)[C:31]=2[N:32]=1)([CH3:26])([CH3:24])[CH3:25]
Reactant: CCn1nnc2c(N3CCC(F)(F)C3)nc(C(C)(C)C)nc21
Reactant: CC(C)(C)c1nc(N2CC(F)(F)C(F)(F)C2)c2nn[nH]c2n1
Agent: Cn1nnnc1CCl
Product: Cn1nnnc1Cn1nnc2c(N3CC(F)(F)C(F)(F)C3)nc(C(C)(C)C)nc21

Procedure:
In analogy to the procedure described for the synthesis of 5-tert-butyl-7-(3,3-difluoropyrrolidin-1-yl)-3-ethyl-3H-[1,2,3]triazolo[4,5-d]pyrimidine (example 61), the title compound was prepared from 5-tert-Butyl-7-(3,3,4,4-tetrafluoro-pyrrolidin-1-yl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine and 5-(chloromethyl)-1-methyl-1H-tetrazole and isolated as yellow solid. MS (m/e): 415.3 (MH+).
Reaction SMILES: [ClH:1].[NH2:2][C:3]1[CH:4]=[C:5]([CH:14]=[CH:15][C:16]=1[OH:17])[CH:6]([OH:13])[CH2:7][NH:8][C:9]([CH3:12])([CH3:11])[CH3:10].[CH3:18][O:19][C:20]1[CH:27]=[CH:26][C:23]([CH:24]=O)=[CH:22][CH:21]=1.CO>O=[Pt]=O.O>[ClH:1].[CH3:18][O:19][C:20]1[CH:27]=[CH:26][C:23]([CH2:24][NH:2][C:3]2[CH:4]=[C:5]([CH:14]=[CH:15][C:16]=2[OH:17])[CH:6]([OH:13])[CH2:7][NH:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[CH:22][CH:21]=1
Reactant: COc1ccc(C=O)cc1
Reactant: CC(C)(C)NCC(O)c1ccc(O)c(N)c1
Agent: O=[Pt]=O
Agent: Cl
Solvent: O
Solvent: CO
Product: COc1ccc(CNc2cc(C(O)CNC(C)(C)C)ccc2O)cc1

Procedure:
A mixture of 3-amino-4-hydroxy-α-(tert.butylaminomethyl)-benzylalcohol hydrochloride (6.53 g, 0.025 mole), p-methoxybenzaldehyde (3.4 g, 0.025 mole), PtO2 (180 mg), and methanol (125 ml) was placed in a hydrogenation apparatus and hydrogenated at normal pressure (20 - 30 cm H2O superatmospheric) for one hour and 50 minutes. During this period of time, the calculated amount of hydrogen was absorbed, and the hydrogenation was interrupted by supplying argon. The platinum catalyst was filtered off with continued supply of argon, but in spite of this, the filtrate quickly became dark due to oxidation. The filtrate was immediately evaporated in vacuum at 40° - 50° C. The residue which was a light brown foam (9.53 g), was recrystallized twice by precipitation from ethanol/ether (1:1). The yield of the analytical pure 3-(4-methoxybenzylamino)-4-hydroxy-α-(tert.butylaminomethyl)benzylalcohol hydrochloride was 5.2 g (55%), m.p. 196.6° - 197.8° C.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([NH2:10])[C:5]=1[NH2:11])([O-:3])=[O:2].[I:12][C:13]1[CH:18]=[CH:17][N:16]=[C:15]([O:19][CH3:20])[C:14]=1[CH:21]=O.[S]>>[I:12][C:13]1[CH:18]=[CH:17][N:16]=[C:15]([O:19][CH3:20])[C:14]=1[C:21]1[NH:11][C:5]2[C:4]([N+:1]([O-:3])=[O:2])=[CH:9][CH:8]=[CH:7][C:6]=2[N:10]=1
Reactant: Nc1cccc([N+](=O)[O-])c1N
Reactant: COc1nccc(I)c1C=O
Agent: [S]
Product: COc1nccc(I)c1-c1nc2cccc([N+](=O)[O-])c2[nH]1
Yield: 101 %

Procedure:
3-Nitro-benzene-1,2-diamine (0.153 g, 1.0 mmol), 4-Iodo-2-methoxy-pyridine-3-carbaldehyde (0.263 g, 1.0 mmol) and sulfur (0.032 g, 1.0 mmol) were heated at 160° for 60 min. The resulting slurry was purred on ice water (100 ml). Precipitates were collected by filtration and dried in vacuum to yield the desired product (0.40 g, quant.) which was used without any further purification.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:20])[C@@H:5]([OH:19])[CH2:6][C:7]([C:9]1[CH:18]=[CH:17][C:16]2[C:11](=CC=CC=2)[CH:10]=1)=[O:8])[CH3:2].[CH3:21]CCCCC.CC(O)C>>[CH2:1]([O:3][C:4](=[O:20])[C@@H:5]([OH:19])[CH:6]([CH3:21])[C:7](=[O:8])[C:9]1[CH:10]=[CH:11][CH:16]=[CH:17][CH:18]=1)[CH3:2]
Reactant: CCCCCC
Reactant: CCOC(=O)[C@@H](O)CC(=O)c1ccc2ccccc2c1
Solvent: CC(C)O
Product: CCOC(=O)[C@@H](O)C(C)C(=O)c1ccccc1

Procedure:
1H NMR syn (CDCl3) δ=1.26 (t, 3H, J=7.0 Hz), 1.29 (d, 3H, J=7.0 Hz), 3.28 (br, (1H), 3.93 (dq, 1H, J=4.2, 7.0 Hz), 4.25 (q, 2H, J=7.0 Hz), 4.58 (d, 1H, J=4.2 Hz), 7.40-7.65 (m, 3H), 7.90-8.05 (m, 2H); anti (CDCl3) δ=1.20 (t, 3H, J=7.1 Hz), 1.36 (d, 3H, J=7.3 Hz), 3.61 (d, 1H, J=8.3 Hz), 3.98 (dq, 1H, J=4.6, 7.1 Hz), 4.10-4.25 (m, 2H), 4.39 (dd, 1H, J=4.6, 8.3 Hz), 7.40-7.65 (m, 3H); 13C NMR syn (CDCl3) δ=12.1, 14.0, 44.3, 61.9. 71.6, 128.4, 128.7, 133.3, 135.7, 173.1, 201.6; anti (CDCl3) δ=14.0, 14.1, 44.0, 61.5, 73.1, 128.3, 128.7, 133.4, 135.9, 173.1; IR (neat) syn 3480, 3063, 2978, 2936, 1734, 1678, 1596, 1579, 1449, 1369, 1217, 1133, 1062, 1023, 1001, 975, 952, 862, 794, 708; anti 3481, 3059, 2981, 2941, 1738, 1685, 1588, 1454, 1372, 1255, 1209, 1144, 1092, 1024, 973, 701 cm−1; HRMS (FAB); Exact mass calcd for C13H17O4 [M+H]+, 237.1127. Found 237.1118.; HPLC, Daicel Chiralcel AS+ADH+AD, hexane/iPrOH=4/1, flow rate=0.5 mL/min: tR=46.7 min (2S, 3S), tR=50.6 min (2R, 3R), tR=54.3 min (2S, 3R), tR=61.9 min (2R, 3S).
Reaction SMILES: C(O[C:9]([NH:11][CH2:12][CH2:13][CH2:14][CH2:15][N:16]1[C:21]2[CH:22]=[C:23]([CH2:26][O:27][CH:28]3[CH:33]([C:34]4[CH:39]=[CH:38][C:37]([O:40][CH2:41][CH2:42][CH2:43][O:44][CH2:45][C:46]5[CH:51]=[CH:50][CH:49]=[CH:48][C:47]=5[O:52][CH3:53])=[CH:36][CH:35]=4)[CH2:32][CH2:31][N:30]([C:54]([O:56][CH2:57][C:58]4[CH:63]=[CH:62][CH:61]=[CH:60][CH:59]=4)=[O:55])[CH2:29]3)[CH:24]=[CH:25][C:20]=2[O:19][CH2:18][C:17]1=[O:64])=O)C1C=CC=CC=1.[H-].[Na+].CI.[C:69](=[O:72])([O-:71])O.[Na+]>CN(C)C=O>[CH2:26]([O:71][C:69]([CH2:9][NH:11][CH2:12][CH2:13][CH2:14][CH2:15][N:16]1[C:21]2[CH:22]=[C:23]([CH2:26][O:27][CH:28]3[CH:33]([C:34]4[CH:39]=[CH:38][C:37]([O:40][CH2:41][CH2:42][CH2:43][O:44][CH2:45][C:46]5[CH:51]=[CH:50][CH:49]=[CH:48][C:47]=5[O:52][CH3:53])=[CH:36][CH:35]=4)[CH2:32][CH2:31][N:30]([C:54]([O:56][CH2:57][C:58]4[CH:63]=[CH:62][CH:61]=[CH:60][CH:59]=4)=[O:55])[CH2:29]3)[CH:24]=[CH:25][C:20]=2[O:19][CH2:18][C:17]1=[O:64])=[O:72])[C:23]1[CH:24]=[CH:25][CH:20]=[CH:21][CH:22]=1
Reactant: COc1ccccc1COCCCOc1ccc(C2CCN(C(=O)OCc3ccccc3)CC2OCc2ccc3c(c2)N(CCCCNC(=O)OCc2ccccc2)C(=O)CO3)cc1
Reactant: O=C([O-])O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CI
Product: COc1ccccc1COCCCOc1ccc(C2CCN(C(=O)OCc3ccccc3)CC2OCc2ccc3c(c2)N(CCCCNCC(=O)OCc2ccccc2)C(=O)CO3)cc1
Reaction time: 1 h

Procedure:
The stirred solution of 0.351 g of benzyl 3-[4-(4-benzyloxycarbonylaminobutyl)-3-oxo-3,4-dihydro-2H-benzo[1,4]oxazin-6-ylmethoxy]-4-{4-[3-(2-methoxybenzyloxy)propoxy]phenyl}piperidine-1-carboxylate and 8 ml of N,N-dimethylformamide is admixed at 0° C. with 0.031 g of sodium hydride (60% dispersion). After 1 hour, 0.144 ml of methyl iodide is added and the mixture is kept at 75° C. over 18 hours. The mixture is cooled, poured onto aqueous 1M sodium hydrogencarbonate solution (40 ml) and extracted with ethyl acetate (2×40 ml). The organic phases are washed with brine (40 ml), dried over sodium sulphate, filtered and concentrated by evaporation. The title compound is obtained as a slightly yellowish oil from the residue by means of flash chromatography (SiO2 60F). Rf=0.17 (1:1 EtOAc-heptane); Rt=6.18.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([N+:14]([O-:16])=[O:15])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.CC(C)([O-])C.[K+].[CH:23](Cl)([Cl:25])[Cl:24]>CN(C=O)C.C1COCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:13]=[CH:12][C:11]([N+:14]([O-:16])=[O:15])=[C:10]([CH:23]([Cl:25])[Cl:24])[CH:9]=2)=[CH:6][CH:7]=1
Reactant: O=[N+]([O-])c1ccc(-c2ccc(Cl)cc2)cc1
Reactant: ClC(Cl)Cl
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccc(-c2ccc(Cl)cc2)cc1C(Cl)Cl
Temperature: -73 °C
Reaction time: 0.02 h
Yield: 63 %

Procedure:
4′-Chloro-4-nitro-biphenyl [J. Amer. Chem. Soc; 68; 1946; 404] (2.74 g, 11.7 mmol) was dissolved in DMF (20 ml) and THF (6 ml), then potassium t-butoxide 5.26 g (47 mmol) was added. The stirred mixture was cooled to −73° C. then a solution of chloroform in THF (6 ml) was slowly introduced, maintaining this temperature. After a further 1 minute, the reaction was quenched with acetic acid (5 ml). The mixture was poured into water (200 ml) and extracted with dichloromethane. The crude product was purified by flash chromatography on silica (using dichloromethane-hexane as eluents) to give 4′-chloro-3-(1,1-dichloro-methyl)-4-nitro-biphenyl in 63% yield;