Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: COC(=O)C1(CCC(C(O)=O)C1(C)C)C.Cl.C[O:18][C:19](=[O:40])[C@@H:20]([CH2:22][C:23]1[CH:28]=[CH:27][C:26](NC(=O)C2C(Cl)=CC=CC=2Cl)=[CH:25][CH:24]=1)[NH2:21]>>[NH2:21][C@@H:20]([C:19]([OH:40])=[O:18])[CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: COC(=O)[C@H](N)Cc1ccc(NC(=O)c2c(Cl)cccc2Cl)cc1
Agent: COC(=O)C1(C)CCC(C(=O)O)C1(C)C
Agent: Cl
Product: N[C@H](Cc1ccccc1)C(=O)O

Procedure:
The preparation follows that of Preparation 37-C-8. The starting materials are (1R-cis)-1,2,2-trimethylcyclopentane-1,3-dicarboxylic acid 3-methyl ester, 10-A, and 4-[(2,6-dichlorobenzoyl)amino]-D-phenylalanine methyl ester, hydrochloride salt, 37-B-2. Physical properties as follows: m.p.155-159° C.; 1H NMR(300 MHz, DMSO-d6). δ12.4(1H), 10.6(1H), 7.51(5H), 7.19(3H), 4.42(1H), 2.99(2H), 2.64(1H), 2.26(1H), 1.94(1H), 1.68(1H), 1.29(1H), 1.17(3H), 1.05(3H), 0.51(3H) MS−ESI (m/z): 533([M−H−]).
Reaction SMILES: [Cl:1][C:2]1[N:6]([CH2:7][C:8]([O:10]CC)=[O:9])[N:5]=[C:4]([C:13]([F:16])([F:15])[F:14])[CH:3]=1.[OH-].[Na+].Cl>O1CCCC1.O>[Cl:1][C:2]1[N:6]([CH2:7][C:8]([OH:10])=[O:9])[N:5]=[C:4]([C:13]([F:16])([F:14])[F:15])[CH:3]=1
Reactant: CCOC(=O)Cn1nc(C(F)(F)F)cc1Cl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)Cn1nc(C(F)(F)F)cc1Cl
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A solution of ethyl 5-chloro-3-(trifluoromethyl)-1H-pyrazole-1-acetate (i.e. the product of Example 10, Step D or D1) (218 mg, 0.85 mmol) in tetrahydrofuran (1 mL) was treated with a 50 wt. % aqueous solution of sodium hydroxide (0.2 mL) in water (0.6 mL). The reaction mixture was stirred at room temperature for 4 h. The reaction mixture was treated with concentrated aqueous hydrochloric acid to lower the pH to 1, and then extracted with ethyl acetate. The extract was dried (MgSO4) and concentrated under pressure to give 140 mg of the title compound. This compound was of sufficient purity to use in subsequent reactions.
Reaction SMILES: [CH3:1][C:2]1([CH3:17])[CH2:7][CH2:6][C:5]([CH3:9])([CH3:8])[CH2:4][C:3]1([O:12][Si](C)(C)C)[C:10]#[N:11].Cl>O1CCCC1>[OH:12][C:3]1([C:10]#[N:11])[CH2:4][C:5]([CH3:8])([CH3:9])[CH2:6][CH2:7][C:2]1([CH3:17])[CH3:1]
Reactant: CC1(C)CCC(C)(C)C(C#N)(O[Si](C)(C)C)C1
Agent: Cl
Solvent: C1CCOC1
Product: CC1(C)CCC(C)(C)C(O)(C#N)C1
Temperature: 44 °C
Reaction time: 5 h
Yield: 0.1 %

Procedure:
To a mixture of the product of Example 10d (3.8 g, 15.0 mol) in tetrahydrofuran (29 mL) was added 10% hydrochloric acid (75 mL) and the reaction was stirred at 44° C. for 5 hours. The reaction was concentrated under reduced pressure and the residue diluted with diethyl ether. The organic phase was washed with water (20 mL) and brine (20 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give the title compound as a colorless oil (2.22 g, Yield: 82%). 1H NMR (400 MHz, CDCl3) δ 2.21 (s, 1H), 1.87 (d, J=14.4 Hz, 1H), 1.72 (d, J=14.4 Hz, 1H), 1.66-1.60 (m, 1H), 1.42-1.34 (m, 3H), 1.17 (s, 3H), 1.06 (s, 3H), 1.05 (s, 3H), 1.04 (s, 3H) ppm.
Reaction SMILES: [CH2:1]([NH:8][C:9]1[C:10]2[C:15]([N:16]=[C:17]3[C:22]=1[CH:21]([OH:23])[CH2:20][CH2:19][CH2:18]3)=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)(O)[O-].[Na+].[Br:29][CH2:30][CH2:31]O>FC(F)(F)C(O)=O>[CH2:1]([NH:8][C:9]1[C:10]2[C:15]([N:16]=[C:17]3[C:22]=1[CH:21]([O:23][CH2:31][CH2:30][Br:29])[CH2:20][CH2:19][CH2:18]3)=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OCCBr
Reactant: OC1CCCc2nc3ccccc3c(NCc3ccccc3)c21
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Product: BrCCOC1CCCc2nc3ccccc3c(NCc3ccccc3)c21
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 71 %

Procedure:
To a suspension of 9-benzylamino-1,2,3,4-tetrahydroacridin-1ol (7.20 g) in 2-bromoethanol (45 ml) was added 40 drops of trifluoroacetic acid. The reaction mixture was stirred at ambient temperature for 20 mins, added to iced sodium bicarbonate solution, and the suspension was extracted with ethyl acetate. The combined organic extracts were washed with water, saturated sodium chloride solution, dried over anhydrous magnesium sulfate, filtered, and evaporated. The residue was purified by flash chromatography (ethyl acetate→1% triethylamine/ethyl acetate) to give 6.85 g (71%) of product. Recrystallization from cyclohexane gave the analytical sample, mp 89°-91° C.
Reaction SMILES: [Cl:1][C:2]1[CH:16]=[C:15]([Cl:17])[CH:14]=[CH:13][C:3]=1[CH2:4][N:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][C:6]1=[O:12].[H-].[Na+].[CH2:20](Br)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>CN(C=O)C>[CH2:20]([O:11][C:8]1[CH:9]=[CH:10][N:5]([CH2:4][C:3]2[CH:13]=[CH:14][C:15]([Cl:17])=[CH:16][C:2]=2[Cl:1])[C:6](=[O:12])[CH:7]=1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: BrCc1ccccc1
Reactant: O=c1cc(O)ccn1Cc1ccc(Cl)cc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=c1cc(OCc2ccccc2)ccn1Cc1ccc(Cl)cc1Cl

Procedure:
1-(2,4-dichloro-benzyl)-4-hydroxy-1H-pyridin-2-one synthesized in Example 14 was dissolved in DMF followed by adding NaH and benzyl bromide to obtain 4-benzyloxy-1-(2,4-dichloro-benzyl)-1H-pyridin-2-one and the titled compound in the ratio of 1:1.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:29]=[CH:28][C:6]([CH2:7][N:8]([C:23]2[S:24][CH:25]=[CH:26][N:27]=2)[S:9]([C:12]2[CH:13]=[CH:14][C:15]3[NH:20][CH2:19][CH:18]([CH3:21])[O:17][C:16]=3[CH:22]=2)(=[O:11])=[O:10])=[CH:5][CH:4]=1.F[C:31]1[CH:38]=[CH:37][C:36]([C:39]([F:42])([F:41])[F:40])=[CH:35][C:32]=1[C:33]#[N:34].C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C>[C:33]([C:32]1[CH:35]=[C:36]([C:39]([F:40])([F:41])[F:42])[CH:37]=[CH:38][C:31]=1[N:20]1[CH2:19][CH:18]([CH3:21])[O:17][C:16]2[CH:22]=[C:12]([S:9]([N:8]([CH2:7][C:6]3[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:29][CH:28]=3)[C:23]3[S:24][CH:25]=[CH:26][N:27]=3)(=[O:11])=[O:10])[CH:13]=[CH:14][C:15]1=2)#[N:34]
Reactant: COc1ccc(CN(c2nccs2)S(=O)(=O)c2ccc3c(c2)OC(C)CN3)cc1
Reactant: N#Cc1cc(C(F)(F)F)ccc1F
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: COc1ccc(CN(c2nccs2)S(=O)(=O)c2ccc3c(c2)OC(C)CN3c2ccc(C(F)(F)F)cc2C#N)cc1
Temperature: 90 °C
Reaction time: 2 h
Yield: 75 %

Procedure:
To a solution of N-(4-methoxybenzyl)-2-methyl-N-(thiazol-2-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-sulfonamide (INTERMEDIATE AE) (1.3 g, 3.02 mmol) and 2-fluoro-5-(trifluoromethyl)benzonitrile in DMF (20 ml) was added Cs2CO3 (1.8 g, 5.56 mmol) at 25° C. and the reaction mixture was stirred at 90° C. for 2 h. The reaction mixture was poured into ice water and the resulting mixture was extracted with EtOAc. The layers were separated and the organic layer was washed with water, dried over sodium sulfate and concentrated. The resulting residue was purified by silica gel column chromatography using a gradient of 0-50% EtOAc in hexanes to afford 1.2 g of 4-(2-cyano-4-(trifluoromethyl)phenyl)-N-(4-methoxybenzyl)-2-methyl-N-(thiazol-2-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-sulfonamide as off white solid in 75% yield. 1H-NMR (400 MHz, DMSO): 6.44 (s, 1H), 8.12 (d, J=8.8 Hz, 1H), 7.76 (d, J=8.4 Hz, 1H), 7.75-7.77 (m, 1H), 7.43-7.44 (m, 1H), 7.19-7.25 (m, 4H), 6.78-6.86 (m, 3H), 5.02 (s, 2H), 4.37-4.42 (m, 1H), 3.89-3.92 (m, 1H), 3.70 (s, 3H), 3.55-3.61 (m, 1H), 1.35 (s, 3H); m/z (ESI, positive ion) 601.0 (M+H)
Reaction SMILES: [Na].[C:2]1([N:8]2[C:12]([SH:13])=[N:11][N:10]=[N:9]2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.I[CH2:15][C@H:16]1[CH2:36][CH2:35][C:18]2([O:22][C@H:21]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[C@@H:20]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[O:19]2)[CH2:17]1>CC(C)=O>[C:29]1([C@@H:20]2[C@@H:21]([C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=3)[O:22][C:18]3([CH2:35][CH2:36][C@H:16]([CH2:15][S:13][C:12]4[N:8]([C:2]5[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=5)[N:9]=[N:10][N:11]=4)[CH2:17]3)[O:19]2)[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: Sc1nnnn1-c1ccccc1
Reactant: IC[C@H]1CCC2(C1)O[C@H](c1ccccc1)[C@@H](c1ccccc1)O2
Agent: [Na]
Solvent: CC(C)=O
Product: c1ccc([C@H]2OC3(CC[C@H](CSc4nnnn4-c4ccccc4)C3)O[C@@H]2c2ccccc2)cc1
Temperature: 60 °C
Reaction time: 3 h
Yield: 73 %

Procedure:
1-Phenyl-1H-tetrazole-5-thiol sodium salt (25 g) was added to a solution of (2R,3R,7S)-7-(iodomethyl)-2,3-diphenyl-1,4-dioxaspiro[4.4]nonane (48.3 g, described in WO 2003095438) in acetone (500 mL), and the mixture was stirred at 60° C. for three hours. The solvent was evaporated from the reaction solution under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=4:1→1:1) to give 5-({[(2R,3R,7S)-2,3-diphenyl-1,4-dioxaspiro[4.4]non-7-yl]methyl}sulfanyl)-1-phenyl-1H-tetrazole (39.5 g) as a pale yellow oil.
Reaction SMILES: [BH4-].[Na+].[Cl:3][C:4]1[CH:17]=[CH:16][C:7]([C:8]([CH2:10][CH2:11][C:12]([O:14][CH3:15])=[O:13])=[O:9])=[CH:6][CH:5]=1>CO>[Cl:3][C:4]1[CH:5]=[CH:6][C:7]([CH:8]([OH:9])[CH2:10][CH2:11][C:12]([O:14][CH3:15])=[O:13])=[CH:16][CH:17]=1
Reactant: COC(=O)CCC(=O)c1ccc(Cl)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: COC(=O)CCC(O)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
Sodium borohydride (1.3 g, 35 mmol) was added portionwise to a stirred solution of methyl 3-(4-chlorobenzoyl)propionate (5.3 g, 23 mmol) in methanol (50 ml) at 0° C. The mixture was allowed to warm up to room temperature, stirred for 4 h and partitioned between 1M aqueous hydrochloric acid (100 ml) and DCM (150 ml). The organic layer was separated and the aqueous layer extracted with DCM 2×100 ml). The combined extracts were dried over anhydrous sodium sulphate, filtered and concentrated to give crude methyl 4-(4-chlorophenyl)-4-hydroxybutanoate which was dissolved in methanol (40 ml). Sodium hydride (80% dispersion in oil: 100 mg, 3 mmol) was added, the mixture stirred for 1 h, and partitioned between aqueous 1M hydrochloric acid (50 ml) and ethyl acetate (100 ml). The organic layer was separated and the aqueous layer extracted with ethyl acetate (100 ml). The combined organics were dried over anhydrous potassium carbonate, filtered and concentrated to give 5-(4-chlorophenyl)-gamma-butyrolactone (3.85 g, 83%) as a colourless oil.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6](O)[C:5]([CH2:9][CH2:10][C:11]#[N:12])=[C:4]([CH3:13])[N:3]=1.P(Cl)(Cl)([Cl:16])=O>>[NH2:1][C:2]1[N:7]=[C:6]([Cl:16])[C:5]([CH2:9][CH2:10][C:11]#[N:12])=[C:4]([CH3:13])[N:3]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: Cc1nc(N)nc(O)c1CCC#N
Product: Cc1nc(N)nc(Cl)c1CCC#N
Reaction time: 5 h
Yield: 48 %

Procedure:
A mixture of 3-(2-amino-4-hydroxy-6-methylpyrimidine-5-yl)propanenitrile (2 g, 11.2 mmol) and phosphorous oxychloride (13 ml) was kept at 90° C. for 5 hours. The procedure according to pro-treatment of Reference-example 6 was carried out to give the object compound (1.06 g, 48%).
Reaction SMILES: OO.[OH:3][CH:4]1[CH2:9][C:8]([CH3:11])([CH3:10])[N:7]([OH:12])[C:6]([CH3:14])([CH3:13])[CH2:5]1.[CH3:15]S(C)=O>CCCCCCC.C(OCC)(=O)C>[CH3:15][O:12][N:7]1[C:8]([CH3:10])([CH3:11])[CH2:9][CH:4]([OH:3])[CH2:5][C:6]1([CH3:14])[CH3:13]
Reactant: CC1(C)CC(O)CC(C)(C)N1O
Reactant: CS(C)=O
Agent: OO
Solvent: CCOC(C)=O
Solvent: CCCCCCC
Product: CON1C(C)(C)CC(O)CC1(C)C
Reaction time: 0.5 h
Yield: 60 %

Procedure:
A solution of 9.1 g (80 mmol) of 30% aqueous hydrogen peroxide is added dropwise, under nitrogen, over a 30-minute period to a mixture of 10.0 g (58.1 mmol) of 4-hydroxy-1-oxyl-2,2,6,6-tetramethylpiperidine, 17.8 g (64.0 mmol) of ferrous sulfate heptahydrate, and 100 ml of dimethyl sulfoxide which is initially at 23° C. The reaction temperature reaches 65° C. during the addition. After the peroxide is all added, the reaction mixture is stirred for 30 minutes. During this time, the temperature falls to 35° C. The reaction mixture is partitioned between methylene chloride (150 ml) and water (100 ml). The organic layer is dried over anhydrous magnesium sulfate and concentrated at reduced pressure to obtain a yellow liquid. Purification by flash chromatography on silica gel (10:1 heptane/ethyl acetate, then 4:1 heptane/ethyl acetate) affords 6.5 g (60% yield) of the title compound.
Reaction SMILES: FC1C=CC(CN2C(=O)N(C3SC(C(O)=O)=C(C)C=3)C=N2)=CC=1.[CH3:24][C:25]1[CH:29]=[C:28]([N:30]2[C:34](=[O:35])[N:33]([CH2:36][C:37]3[CH:42]=[CH:41][C:40]([S:43]([CH3:46])(=[O:45])=[O:44])=[CH:39][CH:38]=3)[N:32]=[CH:31]2)[S:27][C:26]=1[C:47]([OH:49])=O.[NH2:50][CH2:51][C:52]1[CH:53]=[N:54][CH:55]=[CH:56][CH:57]=1>>[CH3:24][C:25]1[CH:29]=[C:28]([N:30]2[C:34](=[O:35])[N:33]([CH2:36][C:37]3[CH:38]=[CH:39][C:40]([S:43]([CH3:46])(=[O:45])=[O:44])=[CH:41][CH:42]=3)[N:32]=[CH:31]2)[S:27][C:26]=1[C:47]([NH:50][CH2:51][C:52]1[CH:53]=[N:54][CH:55]=[CH:56][CH:57]=1)=[O:49]
Reactant: Cc1cc(-n2cnn(Cc3ccc(S(C)(=O)=O)cc3)c2=O)sc1C(=O)O
Reactant: NCc1cccnc1
Agent: Cc1cc(-n2cnn(Cc3ccc(F)cc3)c2=O)sc1C(=O)O
Product: Cc1cc(-n2cnn(Cc3ccc(S(C)(=O)=O)cc3)c2=O)sc1C(=O)NCc1cccnc1
Yield: 61 %

Procedure:
Following the procedure as described in Example 31, making variations as required to replace 5-(1-(4-fluorobenzyl)-5-oxo-1H-1,2,4-triazol-4(5H)-yl)-3-methylthiophene-2-carboxylic acid with 3-methyl-5-(1-(4-(methylsulfonyl)benzyl)-5-oxo-1H-1,2,4-triazol-4(5H)-yl)thiophene-2-carboxylic acid to react with 3-(aminomethyl)pyridine, the title compound was obtained as a colorless solid in 61% yield: mp 208-210° C.; 1H NMR (300 MHz, DMSO-d6) δ 8.75 (s, 1H), 8.64 (t, J=5.6 Hz, 1H), 8.54 (s, 1H), 8.46 (d, J=4.4 Hz, 1H), 7.92 (d, J=8.1 Hz, 2H), 7.72 (d, J=7.7 Hz, 1H), 7.56 (d, J=8.1 Hz, 2H), 7.36 (dd, J=7.7, 4.4 Hz, 1H), 7.22 (s, 1H), 5.11 (s, 2H), 4.43 (d, J=5.6 Hz, 2H), 3.21 (s, 3H), 2.43 (s, 3H); 13C NMR (75 MHz, DMSO-d6) δ 162.1, 150.0, 148.8, 148.0, 142.0, 140.1, 138.6, 135.0, 134.9, 134.3, 134.1, 128.4, 127.3, 125.6, 123.4, 119.4, 47.9, 43.4, 40.4, 15.6; MS (ES+) m/z 484.4 (M+1).
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[C:7]([N:10]3[CH2:14][CH2:13][N:12]([C:15]4[CH:16]=[N:17][CH:18]=[CH:19][C:20]=4Cl)[C:11]3=[O:22])[CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1.[CH3:23][O-:24].[Na+].CO>O1CCOCC1.C(Cl)(Cl)Cl>[S:1]1[C:5]2[CH:6]=[C:7]([N:10]3[CH2:14][CH2:13][N:12]([C:15]4[CH:16]=[N:17][CH:18]=[CH:19][C:20]=4[O:24][CH3:23])[C:11]3=[O:22])[CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1
Reactant: O=C1N(c2ccc3ncsc3c2)CCN1c1cnccc1Cl
Reactant: C[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: CO
Solvent: ClC(Cl)Cl
Product: COc1ccncc1N1CCN(c2ccc3ncsc3c2)C1=O
Yield: 32.4 %

Procedure:
1-Benzothiazol-6-yl-3-(4-chloro-pyridin-3-yl)-imidazolidin-2-one (84A: 50 mg, 0.1515 mmol) was added dropwise to a solution of sodium methoxide (0.122 g, 2.259 mmol) in 1,4-dioxane (15 mL) over a period of 5 minutes. The resulting mixture was refluxed for 10 hours. The reaction was monitored by TLC (10% MeOH in CHCl3). The reaction mixture was partitioned between ice water and ethylacetate. The organic layer was dried over Na2SO4 and concentrated. Purification by preparative HPLC afforded 16 mg of the product (31.66% yield).
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]1[C@H:8]([CH3:9])[CH2:7][CH2:6][CH2:5][N:4]1[C:10]([C:12]1[C:17]([N:18]2[N:22]=[CH:21][CH:20]=[N:19]2)=[CH:16][CH:15]=[C:14]([CH3:23])[N:13]=1)=[O:11].Cl[C:25]1[N:30]=[CH:29][C:28]([C:31]([F:34])([F:33])[F:32])=[CH:27][N:26]=1>>[CH3:9][C@@H:8]1[CH2:7][CH2:6][CH2:5][N:4]([C:10]([C:12]2[C:17]([N:18]3[N:22]=[CH:21][CH:20]=[N:19]3)=[CH:16][CH:15]=[C:14]([CH3:23])[N:13]=2)=[O:11])[C@@H:3]1[CH2:2][NH:1][C:25]1[N:30]=[CH:29][C:28]([C:31]([F:34])([F:33])[F:32])=[CH:27][N:26]=1
Reactant: Cc1ccc(-n2nccn2)c(C(=O)N2CCC[C@@H](C)[C@H]2CN)n1
Reactant: FC(F)(F)c1cnc(Cl)nc1
Product: Cc1ccc(-n2nccn2)c(C(=O)N2CCC[C@@H](C)[C@H]2CNc2ncc(C(F)(F)F)cn2)n1

Procedure:
The title compound was prepared following the same general protocol as described for Example A1, using ((2S,3R)-2-(aminomethyl)-3-methylpiperidin-1-yl)(6-methyl-3-(2H-1,2,3-triazol-2-yl)pyridin-2-yl)methanone and 2-chloro-5-trifluoromethylpyrimidine. ESI-MS (m/z): 461 [M+1]+.
Reaction SMILES: [CH:1]([C:4]1[CH:5]=[C:6]([CH:9]=[C:10]([CH:14]([CH3:16])[CH3:15])[C:11]=1[O:12][CH3:13])[CH:7]=O)([CH3:3])[CH3:2].[NH2:17][C:18]1[CH:19]=[C:20]2[C:24](=[CH:25][CH:26]=1)[NH:23][C:22](=[O:27])[CH2:21]2>>[NH2:17][C:18]1[CH:19]=[C:20]2[C:24](=[CH:25][CH:26]=1)[NH:23][C:22](=[O:27])[C:21]2=[CH:7][C:6]1[CH:5]=[C:4]([CH:1]([CH3:3])[CH3:2])[C:11]([O:12][CH3:13])=[C:10]([CH:14]([CH3:16])[CH3:15])[CH:9]=1
Reactant: COc1c(C(C)C)cc(C=O)cc1C(C)C
Reactant: Nc1ccc2c(c1)CC(=O)N2
Product: COc1c(C(C)C)cc(C=C2C(=O)Nc3ccc(N)cc32)cc1C(C)C

Procedure:
3,5-Diisopropyl-4-methoxybenzaldehyde was condensed with 5-amino-2-oxindole to give 0.3 g of 5-Amino-3-(3,5-diisopropyl-4-methoxybenzylidene)-1,3-dihydroindol-2-one as a yellow-orange solid.
Reaction SMILES: S(=O)(=O)(O)O.[N+:6]([O-:9])(O)=[O:7].[Cl:10][C:11]1[N:12]=[N:13][C:14]([N:17]2[C:21]([CH3:22])=[CH:20][C:19]([CH3:23])=[N:18]2)=[CH:15][CH:16]=1>O>[Cl:10][C:11]1[N:12]=[N:13][C:14]([N:17]2[C:21]([CH3:22])=[C:20]([N+:6]([O-:9])=[O:7])[C:19]([CH3:23])=[N:18]2)=[CH:15][CH:16]=1
Reactant: Cc1cc(C)n(-c2ccc(Cl)nn2)n1
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Solvent: O
Product: Cc1nn(-c2ccc(Cl)nn2)c(C)c1[N+](=O)[O-]
Reaction time: 8 h

Procedure:
To a mixture of 230 ml of concentrated sulphuric acid and 230 ml of 100% nitric acid, 26 g of 3-chloro-6-(3,5-dimethyl-1-pyrazolyl)-pyridazine are added portionwise, under stirring at a temperature between 0° C. and 5° C., then the mixture is stirred at room temperature for 2 hours, poured into 1 liter of water and set aside overnight in the refrigerator. The separated crystals are filtered, washed with water and dried. Yield: 26.7 g (84.5%); m.p. 164°-167° C.
Reaction SMILES: [O:1]([CH2:9][C:10]1([CH2:18][N:19]2[CH:23]=[CH:22][N:21]=[C:20]2[N+:24]([O-:26])=[O:25])[CH2:15][O:14][C:13]([CH3:17])([CH3:16])[O:12][CH2:11]1)[Si](C(C)(C)C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>>[CH3:16][C:13]1([CH3:17])[O:12][CH2:11][C:10]([CH2:9][OH:1])([CH2:18][N:19]2[CH:23]=[CH:22][N:21]=[C:20]2[N+:24]([O-:26])=[O:25])[CH2:15][O:14]1
Reactant: CC1(C)OCC(CO[Si](C)(C)C(C)(C)C)(Cn2ccnc2[N+](=O)[O-])CO1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Product: CC1(C)OCC(CO)(Cn2ccnc2[N+](=O)[O-])CO1

Procedure:
Subsequently, the obtained 5-(t-butyldimethylsiloxymethyl)-2,2-dimethyl-5-[(2-nitro-1H-imidazol-1-yl)methyl]-1,3-dioxane is reacted with tetra-n-butylammonium fluoride in an organic solvent by for example a method of E. J. Corey et al. (Journal of American Chemical Society, 1972, 94, p. 6190) and purified, to give 2,2-dimethyl-5-hydroxymethyl-5-[(2-nitro-1H-imidazol-1-yl)methyl]-1,3-dioxane (FIG. 1, Step 4).
Reaction SMILES: O([CH2:9][CH:10]([CH2:16][CH2:17][CH3:18])[CH2:11][CH2:12][CH2:13][CH2:14][CH3:15])S(C(F)(F)F)(=O)=O.[CH3:19][C:20]1[CH:21]=[N:22][CH:23]=[C:24]([CH3:47])[C:25]=1[C:26]1[C:31]([CH3:32])=[CH:30][C:29]([CH:33]=[CH:34][C:35]2[CH:40]=[CH:39][C:38]([CH:41]([C:44]#[N:45])[C:42]#[N:43])=[CH:37][CH:36]=2)=[CH:28][C:27]=1[CH3:46].C[O-].[Na+]>C(Cl)Cl.CO>[CH3:19][C:20]1[C:25](=[C:26]2[C:27]([CH3:46])=[CH:28][C:29](=[CH:33][CH:34]=[C:35]3[CH:40]=[CH:39][C:38](=[C:41]([C:42]#[N:43])[C:44]#[N:45])[CH:37]=[CH:36]3)[CH:30]=[C:31]2[CH3:32])[C:24]([CH3:47])=[CH:23][N:22]([CH2:9][CH:10]([CH2:16][CH2:17][CH3:18])[CH2:11][CH2:12][CH2:13][CH2:14][CH3:15])[CH:21]=1
Reactant: Cc1cncc(C)c1-c1c(C)cc(C=Cc2ccc(C(C#N)C#N)cc2)cc1C
Reactant: CCCCCC(CCC)COS(=O)(=O)C(F)(F)F
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Product: CCCCCC(CCC)CN1C=C(C)C(=c2c(C)cc(=CC=c3ccc(=C(C#N)C#N)cc3)cc2C)C(C)=C1
Temperature: 25 °C
Reaction time: 4 h
Yield: 65.7 %

Procedure:
To a solution of 2-propyl-1-heptanol (0.81 g, 5.1 mmol) in dry CH2Cl2 (15 mL) was added dropwise a solution of trifluoromethanesulfonic anhydride (1.77 g, 6.10 mmol) in the same solvent (5 mL). After stirring at room temperature for 20 min, the reaction mixture was poured into ice (40 mL), and neutralized with saturated aqueous NaHCO3 solution. The organic layer was separated, washed with water, dried over anhydrous Na2SO4, filtered, and concentrated in vacuo to give nearly pure 2-propyl-1-heptyl triflate as purple liquid (1.40 g, 94.1%). Next, 2-propyl-1-heptyl triflate (0.319 g, 1.10 mmol) was added dropwise to a solution of 19 (0.377 g, 1.00 mmol) in dry CH2Cl2 (20 mL). The reaction mixture was stirred at room temperature for 4 h. A solution of sodium methoxide in methanol (2.4 mL, 0.5 M) was then added dropwise to the resulting solution of pyridinium salt 20. The color of the mixture immediately changed from yellow to red. After stirring at room temperature for 10 min, the solvent was removed under reduced pressure. The resulting purple solid was then partitioned between water (50 L) and CH2Cl2 (50 mL). The organic layer was separated, dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. The crude product was purified by flash chromatography on silica gel eluting with 4:100 methnol: CH2Cl2, to give 0.340 g (65.7%) of the title compound as purple solid: mp 161-162° C.; NMR (400 MHz, DMSO-d6): δ 9.039 (s, 2H), 7.418 (s, 2H), 7.286 (d, 2H, J=8.0 Hz), 7.145 (d, 1H, J=16.4 Hz), 6.919 (d, 1H, J=16.4 Hz), 6.739 (d, 2H, J=7.6 Hz), 4.453 (m, 2H, J=5.2 Hz), 2.125 (m, 1H), 2.074 (s, 6H), 1.859 (s, 6H), 1.319-1.219 (m, 12H), 0.849 (m, 6H); 13C NMR (125 MHz, DMSO-d6): δ 157.523, 142.592, 141.882, 138.688, 136.859, 133.320, 131.364, 129.981, 126.942, 125.704, 125.468, 121.582, 118.070, 64.195, 38.546, 32.695, 31.366, 30.156, 29.419, 25.061, 21.894, 19.010, 18.855, 16.581, 14.215, 13.942; MS (high resolution, EI): m/z 517.3451 [M+]; calcd, 517.3457; Anal. Calcd. for C36H43N3.1/3H2O: C, 82.56; H, 8.40; N, 8.02. Found; C, 82.59; H, 8.11; N, 8.36.
Reaction SMILES: [CH3:1][Si:2](Cl)([CH3:7])[C:3]([CH3:6])([CH3:5])[CH3:4].[Br:9][C:10]1[C:15]([O:16][CH2:17][CH2:18][OH:19])=[CH:14][CH:13]=[CH:12][N:11]=1.N1C=CN=C1>CN(C=O)C.[OH-].[Na+]>[Br:9][C:10]1[C:15]([O:16][CH2:17][CH2:18][O:19][Si:2]([C:3]([CH3:6])([CH3:5])[CH3:4])([CH3:7])[CH3:1])=[CH:14][CH:13]=[CH:12][N:11]=1
Reactant: OCCOc1cccnc1Br
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: [Na+]
Agent: [OH-]
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)OCCOc1cccnc1Br
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of dimethyl-t-butylsilyl chloride (11.1 g, 74 mmol) in DMF (30 mL) was added to a suspension of 2-bromo-3-(2-hydroxyethoxy)pyridine (15.3 g, 70 mmol; obtained in Example 191, Step 1) and imidazole (10.0 g, 147 mmol) in DMF (30 mL). The reaction mixture was stirred at ambient temperature for 2 h, diluted with 0.5 M aqueous NaOH (0.7 L), and extracted twice with toluene. The combined organic phases were washed once with water, dried (MgSO4), and concentrated. The resulting oil was treated with a mixture of petroleum ether and ethyl acetate (95:5; 50 mL) and an analytical sample of white crystals was collected. The remaining crystals were mixed with the filtrate, the solvent was evaporated and the resulting crude product was used directly in the next step. Solid; yield 18.3 g (78%); mp 81° C. Anal. (C13H22BrNO2Si) C, H, N.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[C:7]1([C:13]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[N:14]2[CH2:19][CH2:18][CH2:17][N:16]3[N:20]=[CH:21][C:22]([C:23]#[N:24])=[C:15]23)[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[F-].[K+].O>O1CCCC1>[C:31]1([C:13]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)([C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)[N:14]2[CH2:19][CH2:18][CH2:17][N:16]3[N:20]=[CH:21][C:22]([CH2:23][NH2:24])=[C:15]23)[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1
Reactant: N#Cc1cnn2c1N(C(c1ccccc1)(c1ccccc1)c1ccccc1)CCC2
Agent: [Al+3]
Agent: [F-]
Agent: [H-]
Solvent: O
Solvent: C1CCOC1
Product: NCc1cnn2c1N(C(c1ccccc1)(c1ccccc1)c1ccccc1)CCC2
Temperature: 65 °C
Reaction time: 16 h
Yield: 97.8 %

Procedure:
To a suspension of lithium aluminum hydride (2.7 g) in tetrahydrofuran (150 ml) was added 4-triphenylmethyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidine-3-carbonitrile (8.5 g) under ice-cooling. The mixture was stirred at 65° C. for 16 hours. After cooling on an ice bath, potassium fluoride (16.5 g) and water (5 ml) were added to the reaction mixture. The insoluble materials were removed by filtration. The filtrate was concentrated in vacuo to give 1-(4-triphenylmethyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidin-3-yl)methylamine (8.4 g) as a solid.