Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:5]1[C:9]([CH2:10][C:11]2[CH:12]=[CH:13][C:14]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[C:23]3[NH:27][N:26]=[N:25][N:24]=3)=[N:15][CH:16]=2)=[N:8][C:7]([CH:28](O)[CH2:29][CH2:30][CH3:31])=[N:6]1)[CH2:2][CH2:3][CH3:4].C(N(S(F)(F)[F:39])CC)C>>[CH2:1]([N:5]1[C:9]([CH2:10][C:11]2[CH:12]=[CH:13][C:14]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[C:23]3[NH:27][N:26]=[N:25][N:24]=3)=[N:15][CH:16]=2)=[N:8][C:7]([CH:28]([F:39])[CH2:29][CH2:30][CH3:31])=[N:6]1)[CH2:2][CH2:3][CH3:4]
Reactant: CCN(CC)S(F)(F)F
Reactant: CCCCn1nc(C(O)CCC)nc1Cc1ccc(-c2ccccc2-c2nnn[nH]2)nc1
Product: CCCCn1nc(C(F)CCC)nc1Cc1ccc(-c2ccccc2-c2nnn[nH]2)nc1

Procedure:
Reaction of the compound of Example 10 with DAST (diethylaminosulfur trifluoride) gave 5-[2-[5-[[1-butyl-3-(1-fluorobutyl)-1H-1,2,4-triazol-5-yl]methyl]-2-pyridinyl]phenyl]-1H-tetrazole: NMR (CDCL3) δ 0.91 (t, J=7 Hz, 3H), 0.99 (t, J=7 Hz, 3H), 1.22-1.63 (m, 4H), 1.71-2.28 (m, 4H), 4.03 (t, J=7 Hz, 2H), 4.14 (s, 2H), 5.52 (ddd, J=48, 9, and 6 Hz, 1H), 7.23 (d, J=9 Hz, 1H), 7.38-7.50 (m, 3H), 7.69 (dd, J=9 and 2 Hz, 1H), 7.80-7.88 (m, 1H), 8.53 (d, J=2 Hz, 1H); MS(EC) m/e (rel intensity) 435(100); HRMS. Calc'd. for M+H: 435.2421. Found: 435.2459.
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]1[CH:18]=[CH:17][C:13]([C:14]([OH:16])=O)=[CH:12][CH:11]=1.[C:19]1([N:25]2[CH2:30][CH2:29][N:28]([CH2:31][CH2:32][NH2:33])[CH2:27][CH2:26]2)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.Cl.CN(C)CCCN=C=NCC.C(N(CC)CC)C>ClCCl>[NH3:1].[NH:3]1[C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=2[N:1]=[C:2]1[C:10]1[CH:11]=[CH:12][C:13]([C:14]([NH:33][CH2:32][CH2:31][N:28]2[CH2:29][CH2:30][N:25]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH2:26][CH2:27]2)=[O:16])=[CH:17][CH:18]=1
Reactant: O=C(O)c1ccc(-c2nc3ccccc3[nH]2)cc1
Reactant: NCCN1CCN(c2ccccc2)CC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: N
Product: O=C(NCCN1CCN(c2ccccc2)CC1)c1ccc(-c2nc3ccccc3[nH]2)cc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 73.9 %

Procedure:
A mixture of 4-(1H-benzimidazol-2-yl)benzoic acid (Example E) (0.50 g), 2-(4-phenylpiperazin-1-yl)ethylamine (0.77 g), 1-(3-dimethylaminopropyl)3-ethylcarbodiimide hydrochloride (0.44 g) and triethylamine (0.29 mL) in dichloromethane (20 mL) is stirred at room temperature for 2 days. The mixture is washed with water (50 mL), dried over MgSO4, filtered and evaporated. The residue is purified by MPLC on silica gel eluting with 100:8:1 dichloromethane: ethanol:0.880 aqueous ammonia to give 0.33 g of the title compound as a beige solid; mp 190°-192° C.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([O:13][CH3:14])[CH:11]=2)[CH2:6][CH2:5]1.C(N(CC)CC)C.[C:22](Cl)(=[O:24])[CH3:23].O>ClCCl>[C:22]([NH:1][CH2:2][CH2:3][CH:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([O:13][CH3:14])[CH:11]=2)[CH2:6][CH2:5]1)(=[O:24])[CH3:23]
Reactant: CC(=O)Cl
Reactant: COc1ccc2c(c1)C(CCN)CC2
Solvent: ClCCl
Solvent: O
Solvent: CCN(CC)CC
Product: COc1ccc2c(c1)C(CCNC(C)=O)CC2
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 69.7 %

Procedure:
To a solution of 1-(2-aminoethyl)-6-methoxyindan (0.80 g, 4.18 mmol) and triethylamine (0.44 g, 4.39 mmol) in dichloromethane (15 ml) was gradually added dropwise, under ice cooling, acetyl chloride (0.33 g, 4.18 mmol). The mixture was stirred for 10 minutes at room temperature. The reaction mixture was poured into water. The organic layer was subjected to extraction with chloroform. The extract solution was washed with 1N hydrochloric acid, a saturated aqueous solution of sodium hydrogencarbonate and brine, which was dried over anhydrous magnesium sulfate, followed by distilling off the solvent under reduced pressure. The residue was recrystallized from ethyl acetate/isopropyl ether to give the above-titled compound (yield 0.68 g, 70%).
Reaction SMILES: C([O:5][NH:6][C:7](=[O:34])[C@@H:8]([NH:26][C:27](=[O:33])[C@H:28]([CH:30]([CH3:32])[CH3:31])[NH2:29])[CH2:9][S:10]([C:13]1[CH:18]=[CH:17][C:16]([O:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[CH:15][CH:14]=1)(=[O:12])=[O:11])(C)(C)C.CO.C(Cl)[Cl:38]>ClCCCl>[ClH:38].[OH:5][NH:6][C:7](=[O:34])[C@@H:8]([NH:26][C:27](=[O:33])[C@H:28]([CH:30]([CH3:32])[CH3:31])[NH2:29])[CH2:9][S:10]([C:13]1[CH:14]=[CH:15][C:16]([O:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[CH:17][CH:18]=1)(=[O:11])=[O:12]
Reactant: ClCCl
Reactant: CC(C)[C@H](N)C(=O)N[C@@H](CS(=O)(=O)c1ccc(Oc2ccccc2)cc1)C(=O)NOC(C)(C)C
Solvent: ClCCCl
Solvent: CO
Product: CC(C)[C@H](N)C(=O)N[C@@H](CS(=O)(=O)c1ccc(Oc2ccccc2)cc1)C(=O)NO
Product: Cl
Reaction time: 24 h

Procedure:
A solution of (R)-N-tert-butoxy-2-valinamido-3-(4-phenoxyphenylsulfonyl)-propionamide (1.6 g) in 1,2-dichloroethane (50 ml) was cooled to -20° C. and bubbled for 15-20 minutes with hydrochloric acid gas in a pressure tube. The flask was then sealed and the mixture stirred for 24 hours. After cooling the tube was cautiously vented and its contents evaporated to yield a gum, which upon trituration with ethyl acetate gave a crude product as a white powder. This product was stirred overnight with 10% methanol/methylene chloride (20 ml) and filtered to remove impurities. This was repeated three times to give (R)-N-hydroxy-2-valinamido-3-(4-phenoxyphenylsulfonyl)-propionamide hydrochloride (760 mg), m.p. 214-217° C.
Reaction SMILES: [CH3:1][N:2]([CH2:4][CH2:5][CH2:6][NH:7][CH2:8][CH:9](O)[CH2:10][NH:11][CH2:12][CH2:13][CH2:14][N:15]([CH3:17])[CH3:16])[CH3:3].C(N([CH2:24][CH3:25])CC)C.[C:26](Cl)(=[O:38])[CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37]>C(Cl)Cl>[O:38]=[C:26]([N:7]([CH2:8][CH2:9][CH2:10][N:11]([C:26](=[O:38])[CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:24][CH3:25])[CH2:12][CH2:13][CH2:14][N:15]([CH3:17])[CH3:16])[CH2:6][CH2:5][CH2:4][N:2]([CH3:3])[CH3:1])[CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37]
Reactant: CCN(CC)CC
Reactant: CCCCCCCCCCCC(=O)Cl
Reactant: CN(C)CCCNCC(O)CNCCCN(C)C
Solvent: ClCCl
Product: CCCCCCCCCCCC(=O)N(CCCN(C)C)CCCN(CCCN(C)C)C(=O)CCCCCCCCCCC
Yield: 31.1 %

Procedure:
2,14-Dimethyl-8-hydroxy-2,6,10,14-tetrazapentadecane (17 g, 0.067 mol) synthesized in accordance with the method described in DE2616411, triethylamine (13 g, 0.13 mol), and methylene chloride (200 ml) were placed in a 500-ml four-necked round flask, and the mixture was cooled on ice. Dodecanoylchloride (29 g, 0.13 mol) was added dropwise over 1 hour to the flask while the contents of the flask were stirred under nitrogen. The mixture was stirred for 24 more hours at room temperature. The solid which precipitated was removed by filtration, after which water was added for washing. Methylene chloride was removed from the organic phase under reduced pressure. The residue was purified by column chromatography (packed with Kieselgel 60 (product of Merck), eluent:chloroform/methanol=7:1 (v/v)) to obtain 12.3 g of 4,8-bis(1-oxododecyl)-1,11-di(dimethylamino)-4,8-diazaundecane. Yield: 30 wt %.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[N:5][CH:6]=[C:7]([CH2:9][N:10]2[CH2:14][CH2:13][CH2:12][CH2:11]2)[CH:8]=1)#[CH:2].[N:15]1([C:20]2[CH:21]=[C:22]([NH:30][C:31](=[O:40])[C:32]3[CH:37]=[CH:36][C:35]([CH3:38])=[C:34](I)[CH:33]=3)[CH:23]=[C:24]([C:26]([F:29])([F:28])[F:27])[CH:25]=2)[CH:19]=[CH:18][N:17]=[CH:16]1.C(N(C(C)C)CC)(C)C>CN(C=O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Cu]I>[N:15]1([C:20]2[CH:21]=[C:22]([NH:30][C:31](=[O:40])[C:32]3[CH:37]=[CH:36][C:35]([CH3:38])=[C:34]([C:2]#[C:1][C:3]4[CH:4]=[N:5][CH:6]=[C:7]([CH2:9][N:10]5[CH2:14][CH2:13][CH2:12][CH2:11]5)[CH:8]=4)[CH:33]=3)[CH:23]=[C:24]([C:26]([F:29])([F:28])[F:27])[CH:25]=2)[CH:19]=[CH:18][N:17]=[CH:16]1
Reactant: Cc1ccc(C(=O)Nc2cc(-n3ccnc3)cc(C(F)(F)F)c2)cc1I
Reactant: C#Cc1cncc(CN2CCCC2)c1
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1ccc(C(=O)Nc2cc(-n3ccnc3)cc(C(F)(F)F)c2)cc1C#Cc1cncc(CN2CCCC2)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 3-Ethynyl-5-(pyrrolidin-1-ylmethyl)pyridine (0.52 mmol), 0.245 g (0.52 mmol) of N-(3-(1H-imidazol-1-yl)-5-(trifluoromethyl)phenyl)-3-iodo-4-methylbenzamide (as prepared above), 0.030 g (0.026 mmol) of Pd(PPh3)4, 0.007 g (0.039 mmol) of CuI, and 0.14 mL (0.78 mmol) of diisopropylethylamine in 3.0 mL of DMF is stirred at ambient temperature overnight under an atmosphere of N2. The reaction mixture is concentrated and the crude product is purified by silica gel flash chromatography (eluted with 10% EtOAc/hexanes, then 100% EtOAc, then 10% MeOH/EtOAc) to provide the title product.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][N:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:8](=[O:15])[NH:7][C:6]1=[O:16].[C:17]1([CH:23]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[N:24]2[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]2)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[C:30]1([CH:23]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[N:24]2[CH2:25][CH2:26][N:27]([CH2:2][CH2:3][CH2:4][N:5]3[C:14]4[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=4)[C:8](=[O:15])[NH:7][C:6]3=[O:16])[CH2:28][CH2:29]2)[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1
Reactant: O=c1[nH]c(=O)n(CCCBr)c2ccccc12
Reactant: c1ccc(C(c2ccccc2)N2CCNCC2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: O=c1[nH]c(=O)n(CCCN2CCN(C(c3ccccc3)c3ccccc3)CC2)c2ccccc12
Temperature: 100 °C
Reaction time: 2.5 h
Yield: 47 %

Procedure:
A mixture of 1-(3-bromopropyl)-2,4(1H,3H)-quinazolinedione (2.12 g), 1-diphenylmethylpiperazine (2.07 g), anhydrous potassium carbonate (3.1 g) and N,N-dimethylformamide (14 ml) was stirred for 2.5 hours at 100° C. After the reaction mixture was cooled to ambient temperature, to the mixture was added water and then stirred to give precipitates. The precipitates were collected by filtration and they were dissolved in hot chloroform containing a little quantity of methanol. The resultant solution was washed with saturated sodium chloride aqueous solution, dried over anhydrous sodium sulfate and concentrated in vacuo to give a crystal, which was washed enough with methanol and dried to give 1-[3-{4-(diphenylmethyl)piperazin-1-yl}propyl]-2,4(1H,3H)-quinazolinedione (1.6 g). This crystal was dissolved in 2N hydrochloric acid solution and then the solution was concentrated in vacuo to give a white crystal, which was washed with methanol, dissolved in water with warming and the solution was evaporated in vacuo. The resultant crystal was washed enough with methanol, to give 1-[3-{4-(diphenylmethyl)piperazin-1-yl}propyl]-2,4(1H,3H)-quinazolinedione.2HCl.0.7H2O (1.6 g).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([N:19]2[CH2:24][CH2:23][O:22][CH2:21][CH2:20]2)[C:5]2[N:10]=[C:9]([CH:11]=CC3C=CC=CC=3)[S:8][C:6]=2[N:7]=1.I(O)(=O)(=O)=[O:26]>C1COCC1.C(#N)C.O.[Ru](Cl)(Cl)Cl>[Cl:1][C:2]1[N:3]=[C:4]([N:19]2[CH2:24][CH2:23][O:22][CH2:21][CH2:20]2)[C:5]2[N:10]=[C:9]([CH:11]=[O:26])[S:8][C:6]=2[N:7]=1
Reactant: [O-][I+3]([O-])([O-])O
Reactant: Clc1nc(N2CCOCC2)c2nc(C=Cc3ccccc3)sc2n1
Agent: Cl[Ru](Cl)Cl
Solvent: O
Solvent: C1CCOC1
Solvent: CC#N
Product: O=Cc1nc2c(N3CCOCC3)nc(Cl)nc2s1
Temperature: 25 °C
Reaction time: 2 h
Yield: 41.2 %

Procedure:
To a suspension of 2-(5-chloro-7-morpholin-4-yl-thiazolo[5,4-d]pyrimidin-2-yl)-1-phenyl-ethanol (1.1 g, 2.9 mmol) in toluene (25 mL) was added p-toluenesulfonic acid (0.11 g, 0.58 mmol) and the resulting solution stirred at 120° C. for 24 h. The reaction mixture was concentrated in vacuo to give 5-chloro-7-morpholin-4-yl-2-styryl-thiazolo[5,4-d]pyrimidine as a crude yellow solid which was used without purification. To a suspension of 5-chloro-7-morpholin-4-yl-2-styryl-thiazolo[5,4-d]pyrimidine (2.9 mmol) in THF (9 mL), acetonitrile (9 mL) and H2O (3 mL) were added ruthenium(III) chloride (18 mg, 0.081 mmol) and periodic acid (1.3 g, 5.80 mmol). The resulting solution was stirred at RT for 2 h, then partitioned between EtOAc and an aqueous solution of sodium thiosulfate. The aqueous layer was isolated and extracted with EtOAc. The combined organic layers were washed with brine, dried (Na2SO4) and concentrated in vacuo. The resultant residue was purified by column chromatography to give the title compound as a yellow solid (0.34 g, 42%).
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][OH:5].C(C1C=CC=C(C(C)(C)C)N=1)(C)(C)C.FC(F)(F)S(OS(C(F)(F)F)(=O)=O)(=O)=O.O[CH2:36][C@H:37]1[CH2:42][CH2:41][C@H:40]([N:43]([CH3:57])[S:44]([C:47]2[CH:52]=[CH:51][C:50]([C:53]([F:56])([F:55])[F:54])=[CH:49][CH:48]=2)(=[O:46])=[O:45])[CH2:39][CH2:38]1>C(Cl)Cl.[N+](C)([O-])=O>[Br:1][CH2:2][CH2:3][CH2:4][O:5][CH2:36][C@H:37]1[CH2:38][CH2:39][C@H:40]([N:43]([CH3:57])[S:44]([C:47]2[CH:48]=[CH:49][C:50]([C:53]([F:56])([F:54])[F:55])=[CH:51][CH:52]=2)(=[O:45])=[O:46])[CH2:41][CH2:42]1
Reactant: OCCCBr
Reactant: CN([C@H]1CC[C@H](CO)CC1)S(=O)(=O)c1ccc(C(F)(F)F)cc1
Agent: CC(C)(C)c1cccc(C(C)(C)C)n1
Agent: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: C[N+](=O)[O-]
Solvent: ClCCl
Product: CN([C@H]1CC[C@H](COCCCBr)CC1)S(=O)(=O)c1ccc(C(F)(F)F)cc1
Temperature: 60 °C
Reaction time: 2.5 h

Procedure:
[following a procedure of Belostotskii, Anatoly M.; Hassner, Alfred. Synthetic methods. 41. Etherification of hydroxysteroids via triflates. Tetrahedron Lett. (1994), 35(28), 5075-6.]. A solution of 0.175 ml (2 mmol) 3-bromo-1-propanol and 0.48 ml 2,6-di-tert-butylpyridine in 1 ml CH2Cl2 was treated at 0° C. with a solution of 0.35 ml (2.1 mmol) trifluoromethansulfonic anhydride in 0.5 ml CH2Cl2. After 2.5 h at 0° C., the violet solution was evaporated, dissolved in 1 ml nitromethane and treated with a solution of 0.375 g (1 mmol) trans-N-(4-Hydroxymethyl-cyclohexyl)-N-methyl-4-trifluoromethyl-benzenesulfonamide and 0.45 ml (2 mmol) 2,6-di-tert-butylpyridine in 3 ml nitromethane (during 3 min). The reaction was heated (60° C.) for 3.5 h and then extracted with aqueous 10% KHSO4/EtOAc (3×). The organic phases were washed with aqueous saturated NaHCO3, aqueous 10% NaCl, dried over Na2SO4 and evaporated. Purification by flash-chromatography on silica gel (hexane/EtOAc 9:1) yielded 0.3 g (64%) of trans-N-[4-(3-Bromo-propoxymethyl)-cyclohexyl]-N-methyl-4-trifluoromethyl-benzenesulfonamide, MS: 452 (M−F, 1Br).
Reaction SMILES: Cl.Cl[CH2:3][C:4]1[C:5]([NH2:11])=[N:6][C:7]([CH3:10])=[N:8][CH:9]=1.Cl.[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]2[CH:21]=[C:22]3[C:27](=[CH:28][CH:29]=2)[CH2:26][NH:25][CH2:24][CH2:23]3)=[CH:16][CH:15]=1.C(N(CC)CC)C>CN(C)C=O>[Cl:13][C:14]1[CH:15]=[CH:16][C:17]([C:20]2[CH:21]=[C:22]3[C:27](=[CH:28][CH:29]=2)[CH2:26][N:25]([CH2:3][C:4]2[C:5]([NH2:11])=[N:6][C:7]([CH3:10])=[N:8][CH:9]=2)[CH2:24][CH2:23]3)=[CH:18][CH:19]=1
Reactant: Cc1ncc(CCl)c(N)n1
Reactant: Clc1ccc(-c2ccc3c(c2)CCNC3)cc1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Cc1ncc(CN2CCc3cc(-c4ccc(Cl)cc4)ccc3C2)c(N)n1
Temperature: 25 °C
Reaction time: 66 h
Yield: 75.5 %

Procedure:
A suspension of 1.69 g (0.0087 mol) of 5-chloromethyl-2-methyl-pyrimidin-4-ylamine hydrochloride in 95 ml of dimethylformamide was treated with 2.035 g (0.00726 mol) of 6-(4-chlorophenyl)-1,2,3,4-tetrahydro-isoquinoline hydrochloride and 3.35 ml (0.0;24 mol) of triethylamine and stirred at room temperature under argon for 66 hours. The mixture was completely freed from the solvents. The residue was partitioned between dichloromethane and water. 16 ml of a 1N aqueous sodium hydroxide solution were added dropwise thereto, the mixture was extracted and chromatographed over silica gel with ethyl acetate/isopropyl alcohol 9:1 as the eluent and digested in diethyl ether. 2.0 g (63%) of 5-[6-(4-chlorophenyl)-3,4-dihydro-1H-isoquinolin-2-ylmethyl]-2-methyl-pyrimidin-4-ylamine were obtained as a white solid. An analytical sample was recrystallized from ethyl acetate and gave white crystals; m.p. 205°-208°.
Reaction SMILES: [F:1][C:2]([F:22])([F:21])[C:3]([C:9]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:12]([NH2:19])=[C:11]([CH3:20])[CH:10]=1)([OH:8])[C:4]([F:7])([F:6])[F:5].[CH3:23][S:24](Cl)(=[O:26])=[O:25]>N1C=CC=CC=1>[F:1][C:2]([F:21])([F:22])[C:3]([C:9]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:12]([NH:19][S:24]([CH3:23])(=[O:26])=[O:25])=[C:11]([CH3:20])[CH:10]=1)([OH:8])[C:4]([F:6])([F:5])[F:7]
Reactant: Cc1cc(C(O)(C(F)(F)F)C(F)(F)F)c2ccccc2c1N
Reactant: CS(=O)(=O)Cl
Solvent: c1ccncc1
Product: Cc1cc(C(O)(C(F)(F)F)C(F)(F)F)c2ccccc2c1NS(C)(=O)=O
Reaction time: 2 h

Procedure:
To 3.23 g (10 mmole) 4-(hexafluoro-2-hydroxy-2-propyl)-2-methyl-1-naphthylamine in 25 ml pyridine add 1.25 g (11 mmole) methanesulfonyl chloride. After 2 hours, pour onto water and extract with Et2O. Wash with 1N HCl, and then extract with 1N NaOH. Acidify with concentrated HCl, extract with Et2O, dry and concentrate. Recrystallize from Et2O-hexane to obtain the product; m.p. 174° C.
Reaction SMILES: [H-].[Na+].[C:3]1([CH2:9][CH2:10][CH:11]([C:17]([CH3:19])=[O:18])[C:12](OCC)=[O:13])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.C([Li])CCC.[C:25]([C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)(=[O:32])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>C1COCC1.O>[OH:18][C:17]1[CH2:19][C:25]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[O:32][C:12](=[O:13])[C:11]=1[CH2:10][CH2:9][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: CCOC(=O)C(CCc1ccccc1)C(C)=O
Reactant: O=C(c1ccccc1)c1ccccc1
Agent: [H-]
Agent: [Li]CCCC
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: O=C1OC(c2ccccc2)(c2ccccc2)CC(O)=C1CCc1ccccc1
Temperature: 0 °C

Procedure:
Alternatively, the title compound could be prepared as follows. A suspension of 0.25 g (6.2 mmol) of sodium hydride in 5 mL of dry THF was cooled to 0° C. under nitrogen and treated with a solution of 1.40 g (6.0 mmol) of ethyl 2-(2-phenylethyl)acetoacetate in THF (2 mL). The solution was stirred at 0° C. for ten minutes, treated with 4.3 mL of 1.4 M n-butyllithium, and stirred for another fifteen minutes. A solution of 0.55 g (3.0 mmol) of benzophenone in THF (3 mL) was added all at once, and the reaction mixture was stirred at room temperature for two hours. Water (75 mL) was added, and the mixture was stirred overnight at room temperature. The solution was washed with ether. The aqueous layer was acidified to pH 2 with 6 N HCl and extracted with ethyl acetate; the extract was washed with brine, dried over magnesium sulfate, and concentrated. The residue was triturated with ether:hexane 1:1, and the solids were filtered and dried to give the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([N:11]2[C@H:20]([C:21]([OH:23])=O)[CH2:19][C:18]3[C:13](=[CH:14][C:15]([O:26][CH3:27])=[C:16]([O:24][CH3:25])[CH:17]=3)[CH2:12]2)=[O:10])=[CH:4][CH:3]=1.[N:28]1([N:33]=[C:34]2[CH:39]=[CH:38][C:37]([NH2:40])=[CH:36][CH2:35]2)[CH2:32][CH2:31][CH2:30][CH2:29]1.C(Cl)CCl>CN(C=O)C.O>[N:28]1([N:33]=[C:34]2[CH:35]=[CH:36][C:37]([NH:40][C:21]([C@@H:20]3[CH2:19][C:18]4[C:13](=[CH:14][C:15]([O:26][CH3:27])=[C:16]([O:24][CH3:25])[CH:17]=4)[CH2:12][N:11]3[C:9]([NH:8][C:5]3[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=3)=[O:10])=[O:23])=[CH:38][CH2:39]2)[CH2:29][CH2:30][CH2:31][CH2:32]1
Reactant: COc1cc2c(cc1OC)CN(C(=O)Nc1ccc(Cl)cc1)[C@H](C(=O)O)C2
Reactant: NC1=CCC(=NN2CCCC2)C=C1
Solvent: CN(C)C=O
Solvent: O
Solvent: ClCCCl
Product: COc1cc2c(cc1OC)CN(C(=O)Nc1ccc(Cl)cc1)[C@H](C(=O)NC1=CCC(=NN3CCCC3)C=C1)C2
Temperature: 25 °C
Reaction time: 2 h
Yield: 82.5 %

Procedure:
To a solution of (3S)-2N-(4-chlorophenylaminocarbonyl)-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid (100 mg, 0.26 mmol) and 4-(pyrrolidinylimino)phenylamine (97 mg, 0.51 mmol) in DMF (4 mL) and H2O (1 mL) at room temperature, EDC (196 mg, 1.02 mmol) was added. The mixture was stirred at room temperature for 2 h. It was concentrated in vacuo. The residue was purified by HPLC to give the titled compound as a powder (118 mg). MS 562.2 and 564.2 (M+H, Cl pattern).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([S:18](=[O:24])(=[O:23])[NH:19][C:20](=[O:22])[CH3:21])[C:10]=1[O:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:5]([OH:7])=[O:6].[CH:25](=O)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.[H][H]>[Pt]=O.C(O)(=O)C>[C:20]([NH:19][S:18]([C:9]1[C:10]([O:11][C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)=[C:2]([NH:1][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH:3]=[C:4]([CH:8]=1)[C:5]([OH:7])=[O:6])(=[O:24])=[O:23])(=[O:22])[CH3:21]
Reactant: [H][H]
Reactant: CC(=O)NS(=O)(=O)c1cc(C(=O)O)cc(N)c1Oc1ccccc1
Reactant: O=Cc1ccccc1
Agent: O=[Pt]
Solvent: CC(=O)O
Product: CC(=O)NS(=O)(=O)c1cc(C(=O)O)cc(NCc2ccccc2)c1Oc1ccccc1
Temperature: 25 °C

Procedure:
A mixture of 3-amino-5-acetylsulphamyl-4-phenoxy-benzoic acid (1 g), benzaldehyde (0.3 g), and acetic acid (40 ml) was heated on a steam bath for 2 hours. After cooling to room temperature, platinum oxide catalyst (0.035 mg) was added, and the reaction mixture was hydrogenated at room temperature and at 1.1 atmospheres hydrogen pressure. After the hydrogen uptake had become negligible, the catalyst was removed by filtration, and the filtrate evaporated in vacuo. After several recrystallizations of the residue from aqueous ethanol, and after drying in vacuo at 76° C, the compound was obtained with a melting point of 241°-243° C. The compound crystallized as a hemi-hydrate.
Reaction SMILES: [S:1]1[C:5]2[CH2:6][CH2:7][CH2:8][CH2:9][C:4]=2[NH:3][C:2]1=[O:10].C(=O)([O-])[O-].[K+].[K+].[P:17](Cl)([O:22][CH2:23][CH3:24])([O:19][CH2:20][CH3:21])=[S:18]>CC(C)=O>[CH2:20]([O:19][P:17]([O:10][C:2]1[S:1][C:5]2[CH2:6][CH2:7][CH2:8][CH2:9][C:4]=2[N:3]=1)([O:22][CH2:23][CH3:24])=[S:18])[CH3:21]
Reactant: CCOP(=S)(Cl)OCC
Reactant: O=c1[nH]c2c(s1)CCCC2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCOP(=S)(OCC)Oc1nc2c(s1)CCCC2
Temperature: 25 °C
Reaction time: 24 h
Yield: 59.5 %

Procedure:
A mixture of 6.2 g of 2,3,4,5,6,7-hexahydrobenzothiazoline-2-one, 8.4 g of potassium carbonate and 300 ml of acetone was refluxed for 1 hour and after the addition of 11.4 g of O,O-diethyl chlorothiophosphate thereto, the mixture was refluxed for another hour. The mixture was stirred at room temperature for 24 hours and was filtered to remove mineral salts. The filtrate was concentrated to dryness by distillation under reduced pressure and the residue was chromatographed over silica gel. Elution with an 8-2 cyclohexane-ethyl acetate mixture yielded 7.3 g of 2-(diethoxythiophosphoryloxy)-4,5,6,7-tetrahydrobenzothiazole having a refractive index of nD22 = 1.532.
Reaction SMILES: Cl[C:2]1[C:12]2[CH2:11][CH2:10][N:9]([C:13]3[C:18]([C:19]([F:22])([F:21])[F:20])=[CH:17][CH:16]=[CH:15][N:14]=3)[CH2:8][CH2:7][C:6]=2[N:5]=[C:4]([N:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)[N:3]=1.[C:29]([C:33]1[CH:39]=[CH:38][C:36]([NH2:37])=[CH:35][CH:34]=1)([CH3:32])([CH3:31])[CH3:30]>CCCCO.CO>[C:29]([C:33]1[CH:34]=[CH:35][C:36]([NH:37][C:2]2[C:12]3[CH2:11][CH2:10][N:9]([C:13]4[C:18]([C:19]([F:21])([F:22])[F:20])=[CH:17][CH:16]=[CH:15][N:14]=4)[CH2:8][CH2:7][C:6]=3[N:5]=[C:4]([N:23]3[CH2:28][CH2:27][O:26][CH2:25][CH2:24]3)[N:3]=2)=[CH:38][CH:39]=1)([CH3:32])([CH3:30])[CH3:31]
Reactant: CC(C)(C)c1ccc(N)cc1
Reactant: FC(F)(F)c1cccnc1N1CCc2nc(N3CCOCC3)nc(Cl)c2CC1
Solvent: CO
Solvent: CCCCO
Product: CC(C)(C)c1ccc(Nc2nc(N3CCOCC3)nc3c2CCN(c2ncccc2C(F)(F)F)CC3)cc1
Temperature: 180 °C
Yield: 92.6 %

Procedure:
To a solution of 4-chloro-2-morpholin-4-yl-7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepine (30 mg, 0.08 mmol) in n-BuOH (2 mL) was added 4-tert-butylaniline (23 μL, 0.15 mmol). The mixture was heated in the microwave at 180° C. for 90 min, then was cooled to rt, diluted with MeOH, and filtered through quaternary amine resin, carbonate form (500 mg). The filtrate was concentrated and the residue was purified (FCC) to give the title compound (39 mg, 99%). MS (ESI): mass calcd. for C28H33F3N6O, 526.27; m/z found, 527.2 [M+H]+. 1H NMR (CDCl3): 8.40-8.37 (m, 1H), 7.87 (d, J=1.8 Hz, 1H), 7.48-7.43 (m, 2H), 7.37-7.31 (m, 2H), 6.96-6.89 (m, 1H), 6.35 (s, 1H), 3.80-3.70 (m, 8H), 3.64-3.54 (m, 4H), 3.11-3.04 (m, 2H), 2.88-2.82 (m, 2H), 1.33 (s, 9H).