Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5](/[C:7](=[N:11]/[O:12][CH:13]([C:28]([O:30][CH:31]([C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)[C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)=[O:29])[C:14]2[CH:19]=[CH:18][C:17]([O:20][C:21](=[O:23])[CH3:22])=[C:16]([O:24][C:25](=[O:27])[CH3:26])[CH:15]=2)/[C:8](O)=[O:9])[N:6]=1.[C:44]1([CH:50]([O:57][C:58]([C:60]2[N:61]3[C@H:64]([S:65][CH2:66][C:67]=2[CH2:68][S:69][C:70]2[N:75]4[N:76]=[C:77]([C:79]([O:81][CH:82]([C:89]5[CH:94]=[CH:93][CH:92]=[CH:91][CH:90]=5)[C:83]5[CH:88]=[CH:87][CH:86]=[CH:85][CH:84]=5)=[O:80])[N:78]=[C:74]4[N:73]=[C:72]([CH3:95])[CH:71]=2)[C@H:63]([NH2:96])[C:62]3=[O:97])=[O:59])[C:51]2[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=2)[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1.C1(N=C=NC2CCCCC2)CCCCC1>ClCCl>[C:44]1([CH:50]([O:57][C:58]([C:60]2[N:61]3[C@H:64]([S:65][CH2:66][C:67]=2[CH2:68][S:69][C:70]2[N:75]4[N:76]=[C:77]([C:79]([O:81][CH:82]([C:89]5[CH:90]=[CH:91][CH:92]=[CH:93][CH:94]=5)[C:83]5[CH:84]=[CH:85][CH:86]=[CH:87][CH:88]=5)=[O:80])[N:78]=[C:74]4[N:73]=[C:72]([CH3:95])[CH:71]=2)[C@H:63]([NH:96][C:8](=[O:9])/[C:7](/[C:5]2[N:6]=[C:2]([NH2:1])[S:3][CH:4]=2)=[N:11]\[O:12][CH:13]([C:28]([O:30][CH:31]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)=[O:29])[C:14]2[CH:19]=[CH:18][C:17]([O:20][C:21](=[O:23])[CH3:22])=[C:16]([O:24][C:25](=[O:27])[CH3:26])[CH:15]=2)[C:62]3=[O:97])=[O:59])[C:51]2[CH:52]=[CH:53][CH:54]=[CH:55][CH:56]=2)[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1
Reactant: Cc1cc(SCC2=C(C(=O)OC(c3ccccc3)c3ccccc3)N3C(=O)[C@@H](N)[C@H]3SC2)n2nc(C(=O)OC(c3ccccc3)c3ccccc3)nc2n1
Reactant: CC(=O)Oc1ccc(C(O/N=C(\C(=O)O)c2csc(N)n2)C(=O)OC(c2ccccc2)c2ccccc2)cc1OC(C)=O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClCCl
Product: CC(=O)Oc1ccc(C(O/N=C(\C(=O)N[C@@H]2C(=O)N3C(C(=O)OC(c4ccccc4)c4ccccc4)=C(CSc4cc(C)nc5nc(C(=O)OC(c6ccccc6)c6ccccc6)nn45)CS[C@H]23)c2csc(N)n2)C(=O)OC(c2ccccc2)c2ccccc2)cc1OC(C)=O
Temperature: 25 °C
Yield: 72.1 %

Procedure:
To an ice-cooled solution containing the product obtained in Step 1 (3.0 g) and (6R,7R)-7-amino-3-[(2- diphenylmethyloxycarbonyl-5-methyl-s-triazolo[1,5-a]- pyrimidin-7-yl)thiomethyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid diphenylmethyl ester (3.75 g) in dichloromethane (100 ml) was added dicyclohexylcarbodiimide (1.54 g), and the mixture was stirred at room temperature. After filtering off the insoluble matters, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography, giving 4.8 g of the objective compound.
Reaction SMILES: C(OC([N:8]1[CH2:12][CH2:11][CH2:10][CH:9]1[C:13]1[NH:14][C:15]([C:18]2[CH:27]=[CH:26][C:25]3[C:20](=[CH:21][CH:22]=[C:23]([C:28]4[CH:33]=[CH:32][C:31]([C:34]5[NH:35][C:36]([CH:39]6[CH2:43][CH2:42][CH2:41][N:40]6[C:44](=[O:57])[CH:45]([NH:52][C:53]([O:55][CH3:56])=[O:54])[C:46]6[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=6)=[N:37][CH:38]=5)=[CH:30][CH:29]=4)[CH:24]=3)[CH:19]=2)=[CH:16][N:17]=1)=O)(C)(C)C.Cl.[CH3:59][O:60][C:61]([NH:63][CH:64]([CH2:68][CH:69]1[CH2:74][CH2:73][O:72][CH2:71][CH2:70]1)[C:65]([OH:67])=O)=[O:62].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>C(Cl)Cl.CO>[CH3:59][O:60][C:61](=[O:62])[NH:63][CH:64]([CH2:68][CH:69]1[CH2:74][CH2:73][O:72][CH2:71][CH2:70]1)[C:65]([N:8]1[CH2:12][CH2:11][CH2:10][CH:9]1[C:13]1[NH:14][C:15]([C:18]2[CH:27]=[CH:26][C:25]3[C:20](=[CH:21][CH:22]=[C:23]([C:28]4[CH:29]=[CH:30][C:31]([C:34]5[NH:35][C:36]([CH:39]6[CH2:43][CH2:42][CH2:41][N:40]6[C:44](=[O:57])[CH:45]([NH:52][C:53]([O:55][CH3:56])=[O:54])[C:46]6[CH:47]=[CH:48][CH:49]=[CH:50][CH:51]=6)=[N:37][CH:38]=5)=[CH:32][CH:33]=4)[CH:24]=3)[CH:19]=2)=[CH:16][N:17]=1)=[O:67]
Reactant: COC(=O)NC(C(=O)N1CCCC1c1ncc(-c2ccc(-c3ccc4cc(-c5cnc(C6CCCN6C(=O)OC(C)(C)C)[nH]5)ccc4c3)cc2)[nH]1)c1ccccc1
Reactant: COC(=O)NC(CC1CCOCC1)C(=O)O
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: CO
Solvent: ClCCl
Product: COC(=O)NC(CC1CCOCC1)C(=O)N1CCCC1c1ncc(-c2ccc3cc(-c4ccc(-c5cnc(C6CCCN6C(=O)C(NC(=O)OC)c6ccccc6)[nH]5)cc4)ccc3c2)[nH]1
Temperature: 25 °C
Reaction time: 2 h
Yield: 18.2 %

Procedure:
To a solution of 2-{5-[6-(4-{2-[1-(2-Methoxycarbonylamino-2-phenyl-acetyl)-pyrrolidin-2-yl]-3H-imidazol-4-yl}-phenyl)-naphthalen-2-yl]-1H-imidazol-2-yl}-pyrrolidine-1-carboxylic acid tert-butyl ester (0.12 g, 0.15 mmol) in CH2Cl2 (1.5 mL) and MeOH (0.2 mL) was added HCl (in dioxanes, 4 M, 0.75 mL, 3.0 mmol). The solution was stirred at room temperature for 2 h and concentrated to dryness. The resulting solid was dissolved in DMF (1.5 mL). 2-Methoxycarbonylamino-3-(tetrahydro-pyran-4-yl)-propionic acid (0.05 g, 0.22 mmol), HATU (0.07 g, 0.19 mmol) and DIPEA (0.13 mL, 0.74 mmol) were added. The resulting solution was stirred at room temperature for 18 h. The solution was purified twice by preparative HPLC (Gemini, 15→40% MeCN in H2O (0.1% TFA)) and lyophilized to provide [2-(2-{5-[6-(4-{2-[1-(2-Methoxycarbonylamino-2-phenyl-acetyl)-pyrrolidin-2-yl]-3H-imidazol-4-yl}-phenyl)-naphthalen-2-yl]-1H-imidazol-2-yl}-pyrrolidin-1-yl)-2-oxo-1-(tetrahydro-pyran-4-ylmethyl)-ethyl]-carbamic acid methyl ester (0.024 g, 18%). LCMS-ESI+: calc'd for C50H54N8O7: 878.41 (M+); Found: 879.97 (M+H+).
Reaction SMILES: FC(F)(F)C(O)=O.C[N:9]([CH:11]=[C:12]([N:18]1[CH:22]=[CH:21][N:20]=[CH:19]1)[C:13]([O:15]CC)=O)C.[CH:23]1([N:27]2[CH2:32][CH2:31][N:30]([C:33]3[CH:38]=[C:37]([NH:39]N)[N:36]=[CH:35][N:34]=3)[CH2:29][CH2:28]2)[CH2:26][CH2:25][CH2:24]1>C(OCC)(=O)C>[CH:23]1([N:27]2[CH2:32][CH2:31][N:30]([C:33]3[N:34]=[CH:35][N:36]=[C:37]([N:39]4[C:13](=[O:15])[C:12]([N:18]5[CH:22]=[CH:21][N:20]=[CH:19]5)=[CH:11][NH:9]4)[CH:38]=3)[CH2:29][CH2:28]2)[CH2:24][CH2:25][CH2:26]1
Reactant: NNc1cc(N2CCN(C3CCC3)CC2)ncn1
Reactant: CCOC(=O)C(=CN(C)C)n1ccnc1
Solvent: O=C(O)C(F)(F)F
Solvent: CCOC(C)=O
Product: O=c1c(-n2ccnc2)c[nH]n1-c1cc(N2CCN(C3CCC3)CC2)ncn1
Temperature: 100 °C
Reaction time: 20 h

Procedure:
16 μl (23 mg, 0.2 mmol) of trifluoroacetic acid are added to a mixture of 211 mg (1.0 mmol) of the compound from Example 5A and 250 mg (1.0 mmol) of the compound from Example 9A in 4 ml of ethyl acetate, and the mixture is stirred at 100° C. for 20 h. The reaction mixture is concentrated under reduced pressure, more ethyl acetate and trifluoroacetic acid (the same amounts as above) are added and the mixture is stirred at 100° C. for 20 h. The reaction mixture is cooled to RT, and the precipitated solid is filtered off and washed with diethyl ether. The residue is pre-purified by column chromatography on silica gel (mobile phase dichloromethane/methanol/ammonia 10/2/0.2) and purified by preparative HPLC (RP 18 column; mobile phase: acetonitrile/water gradient). Yield: 137 mg (36% of theory)
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([CH:8]([O:11][CH3:12])[O:9][CH3:10])[CH:5]=[CH:4][C:3]=1[O:13][CH2:14][CH2:15][N:16]1[CH2:21][CH2:20][O:19][CH2:18][CH2:17]1.C([Li])CCC.[C:27](=[O:29])=[O:28]>C1COCC1>[CH3:10][O:9][CH:8]([O:11][CH3:12])[C:6]1[CH:5]=[CH:4][C:3]([O:13][CH2:14][CH2:15][N:16]2[CH2:21][CH2:20][O:19][CH2:18][CH2:17]2)=[C:2]([CH:7]=1)[C:27]([OH:29])=[O:28]
Reactant: COC(OC)c1ccc(OCCN2CCOCC2)c(Br)c1
Reactant: O=C=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COC(OC)c1ccc(OCCN2CCOCC2)c(C(=O)O)c1
Temperature: -78 °C
Reaction time: 0.08 h
Yield: 21 %

Procedure:
A solution of 1-bromo-5-dimethoxymethyl-2-(2-morpholinoethoxy)benzene (3.11 g, 8.63 mmol) obtained in Step 3 in THF (40.0 mL) was cooled to −78° C., to which n-butyllithium (1.60 mol/L, 20.0 mL, 32.0 mmol) was added dropwise for 3 minutes, followed by stirring at −78° C. for 5 minutes. The reaction mixture was added with dry ice and was stirred for 3 hours while warming to room temperature. The solvent of the reaction mixture was evaporated under reduced pressure. The residue was added with a 1 mol/L aqueous ammonium acetate solution (30 mL), was purified by HP-20 column chromatography (water, then acetonitrile/water=2/1), then crystallized from mixed solvent of ethyl acetate/hexane (1/1) to obtain 5-dimethoxymethyl-2-(2-morpholinoethoxy)benzoic acid (0.58 g, 21%).
Reaction SMILES: [CH3:1][N:2]([CH3:24])[CH2:3][CH2:4][CH2:5][NH:6][C:7]1[C:20]2[C:19](=[O:21])[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[S:12][C:11]=2[C:10]([CH:22]=O)=[CH:9][CH:8]=1.C(O)=O.[OH-].[Na+].[CH:30]([NH2:32])=[O:31]>O>[CH3:24][N:2]([CH3:1])[CH2:3][CH2:4][CH2:5][NH:6][C:7]1[C:20]2[C:19](=[O:21])[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[S:12][C:11]=2[C:10]([CH2:22][NH:32][CH:30]=[O:31])=[CH:9][CH:8]=1
Reactant: CN(C)CCCNc1ccc(C=O)c2sc3ccccc3c(=O)c12
Reactant: NC=O
Agent: [Na+]
Agent: [OH-]
Solvent: O=CO
Solvent: O
Product: CN(C)CCCNc1ccc(CNC=O)c2sc3ccccc3c(=O)c12
Reaction time: 8 h
Yield: 79.4 %

Procedure:
A solution of 1-[[3-(dimethylamino)propyl]amino]-9-oxothioxanthen-4-carboxaldehyde (3.6 g; 10.57 mmol) in 50 mL of formamide containing 3.6 g of formic acid was refluxed for 1.5 h and then was allowed to stand at room temperature overnight. The reaction mixture was diluted with water (400 ml), basified with 3 mL of 5N NaOH solution, stirred rapidly for 30 rain, and the precipitated solid was filtered, washed with water, and dried, yielding 3.1 g (79%) of N-[[1-[[3-(dimethylamino)propyl]amino]-9-oxothioxanthen-4-yl]methyl]formamide (Formula I: R1 =R2 =Me; Q=CH2NHCHO; R8 =H; n=3), as a yellow powder.
Reaction SMILES: CC1C=CC(S([NH:11][CH:12]2[CH:17]=[CH:16][C:15]([O:18][C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([N+:25]([O-:27])=[O:26])[CH:20]=3)=[CH:14][N:13]2[CH2:28][C:29]([NH2:31])=O)(=O)=O)=CC=1.FC(F)(F)C(OC(=O)C(F)(F)F)=O>ClCCl>[N+:25]([C:21]1[CH:20]=[C:19]([CH:24]=[CH:23][CH:22]=1)[O:18][C:15]1[CH:16]=[CH:17][C:12]2[N:13]([CH:28]=[C:29]([NH2:31])[N:11]=2)[CH:14]=1)([O-:27])=[O:26]
Reactant: Cc1ccc(S(=O)(=O)NC2C=CC(Oc3cccc([N+](=O)[O-])c3)=CN2CC(N)=O)cc1
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: ClCCl
Product: Nc1cn2cc(Oc3cccc([N+](=O)[O-])c3)ccc2n1
Temperature: 25 °C
Reaction time: 5 h
Yield: 48.9 %

Procedure:
A mixture of 2-[2-{[(4-methylphenyl)sulfonyl]amino}-5-(3-nitrophenoxy)pyridin-1(2H)-yl]acetamide (4.70 g, 10.6 mmol), trifluoroacetic anhydride (30 mL) and dichloromethane (40 mL) was stirred at room temperature for 5 hr. The reaction solution was concentrated under reduced pressure, saturated aqueous sodium hydrogen carbonate solution was added to the residue and the mixture was extracted with ethyl acetate (×3). The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and filtrated. The filtrate was concentrated under reduced pressure, 8N aqueous sodium hydroxide solution (10 mL) and ethanol (30 mL) were added to the residue and the mixture was stirred at room temperature for 15 hr. The reaction mixture was diluted with water and extracted with ethyl acetate (×3). The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and filtrated. The filtrate was concentrated under reduced pressure, and the residue was purified by column chromatography (silica gel, ethyl acetate) to give the title compound (1.40 g, 49%) as a white solid.
Reaction SMILES: [Cl-].[K+].C([Al](CCCCCCCC)CCCCCCCC)CCCCCCC.C[Si](Cl)(Cl)Cl.[CH3:33][Si:34](CCCCCCCC)([CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH3:50])[CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH3:42].[Cl-].[Na+]>>[CH3:33][SiH:34]([CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH3:42])[CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH3:50]
Reactant: CCCCCCCC[Si](C)(CCCCCCCC)CCCCCCCC
Agent: CCCCCCCC[Al](CCCCCCCC)CCCCCCCC
Agent: C[Si](Cl)(Cl)Cl
Agent: [Cl-]
Product: CCCCCCCC[SiH](C)CCCCCCCC

Procedure:
Utilizing the apparatus of Examples 1-5, 100 millimoles of potassium chloride, 100 millimoles of tri-n-octylaluminum, and 98 millimoles of methyltrichlorosilane were reacted at 180° C. for 4 hours. The analyses utilized in Examples 1-5 revealed that only 8.3% mole percent methyltrioctylsilane was produced as compared with 63-66 mole percent methyltrioctylsilane that was produced using comparable conditions but adding sodium chloride (compare Examples 8 and 9 from Table II). The major product, methyldioctylsilane was produced in a 47.2 weight percent yield. Product was identified by characteristic infrared Si--H found at 2100 cm-1 ; independent synthesis by reaction of methyldichlorosilane with two equivalents of n-octyl-magnesium bromide; and conversion under hydrosilylation conditions with octene to methyltrioctylsilane. This clearly demonstrates a different mode of action for sodium chloride versus potassium chloride.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([NH:8][CH2:9][C:10]2[N:15]=[C:14]([N:16]3[CH2:20][CH2:19][CH2:18][C:17]3=[O:21])[CH:13]=[CH:12][CH:11]=2)[C:5]([NH2:22])=[C:4]([Cl:23])[N:3]=1.[N:24]([O-])=O.[Na+]>C(O)(=O)C.CCO.O>[NH2:1][C:2]1[N:3]=[C:4]([Cl:23])[C:5]2[N:22]=[N:24][N:8]([CH2:9][C:10]3[N:15]=[C:14]([N:16]4[CH2:20][CH2:19][CH2:18][C:17]4=[O:21])[CH:13]=[CH:12][CH:11]=3)[C:6]=2[N:7]=1
Reactant: Nc1nc(Cl)c(N)c(NCc2cccc(N3CCCC3=O)n2)n1
Reactant: O=N[O-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Solvent: CC(=O)O
Product: Nc1nc(Cl)c2nnn(Cc3cccc(N4CCCC4=O)n3)c2n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 77 %

Procedure:
A suspension of 1-{6-[(2,5-diamino-6-chloro-pyrimidin-4-ylamino)methyl]pyridin-2-yl}pyrrolidin-2-one (2.10 g, 6.29 mmol) in glacial acetic acid (6 mL) and EtOH (24 mL) at 0° C. was treated with a solution of sodium nitrite (0.564 g, 8.17 mmol) in water (1.5 mL), stirred for 2 h, warmed to room temperature and the resulting precipitate filtered and dried to give the title compound (1.67 g, 77%) as an off-white solid; LC-MS retention time 1.99 min, (M+H)+ 345.
Reaction SMILES: [Br:1][C:2]1[CH:9]=[C:8]([CH3:10])[C:5]([CH:6]=[O:7])=[C:4]([O:11][CH3:12])[CH:3]=1.Cl([O-])=[O:14].[Na+].P(O)(O)([O-])=O.[Na+].CC(=CC)C>C(O)(C)(C)C.O>[Br:1][C:2]1[CH:9]=[C:8]([CH3:10])[C:5]([C:6]([OH:14])=[O:7])=[C:4]([O:11][CH3:12])[CH:3]=1
Reactant: [O-][Cl+][O-]
Reactant: COc1cc(Br)cc(C)c1C=O
Agent: CC=C(C)C
Agent: O=P([O-])(O)O
Agent: [Na+]
Solvent: O
Solvent: CC(C)(C)O
Product: COc1cc(Br)cc(C)c1C(=O)O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 89.7 %

Procedure:
To a suspension of 4-bromo-2-methoxy-6-methyl-benzaldehyde (1.25 g, 5.45 mmol) in tert-butanol (21.7 ml) is added a solution of sodium chlorite (0.98 g, 10.9 mmol) and monosodium phosphate (4.25 g, 27.3 mmol) in water (11 ml). To the solution is added 2-methyl-2-butene (4.63 ml, 43.7 mmol). The resulting homogeneous solution is stirred at RT for 30 min. After completion of the reaction, the solvent is evaporated and the residue is diluted with water and acidified with 1 M hydrochloric acid to pH=1 and extracted with methyl tert-butyl ether (3×40 ml). The combined organic layers are extracted with 1 M sodium hydroxide solution which is further acidified with 6 M hydrochloric acid and extracted with ethyl acetate (3×50 ml). The organic layer is washed with brine (40 ml), dried over sodium sulfate and concentrated to yield 4-bromo-2-methoxy-6-methyl-benzoic acid (1.2 g, 4.89 mmol, 90%).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:18]=[CH:17][CH:16]=[C:15]2[C:10]=1[CH2:11][CH2:12][CH2:13][CH:14]2[C:19](O)=[O:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:22][N:23]([CH3:41])[C:24]1[CH:29]=[CH:28][C:27]([CH2:30][NH:31][C:32]2[CH:33]=[N:34][C:35]([CH:38]([CH3:40])[CH3:39])=[CH:36][CH:37]=2)=[CH:26][CH:25]=1>>[CH2:1]([O:8][C:9]1[CH:18]=[CH:17][CH:16]=[C:15]2[C:10]=1[CH2:11][CH2:12][CH2:13][CH:14]2[C:19]([N:31]([CH2:30][C:27]1[CH:26]=[CH:25][C:24]([N:23]([CH3:41])[CH3:22])=[CH:29][CH:28]=1)[C:32]1[CH:33]=[N:34][C:35]([CH:38]([CH3:39])[CH3:40])=[CH:36][CH:37]=1)=[O:20])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)C1CCCc2c(OCc3ccccc3)cccc21
Reactant: CC(C)c1ccc(NCc2ccc(N(C)C)cc2)cn1
Product: CC(C)c1ccc(N(Cc2ccc(N(C)C)cc2)C(=O)C2CCCc3c(OCc4ccccc4)cccc32)cn1
Yield: 41.3 %

Procedure:
By the reaction and treatment in the same manner as in Example 12 using 5-benzyloxy-1,2,3,4-tetrahydronaphthalene-1-carboxylic acid (0.5 g) and [(4-dimethylaminophenyl)methyl](6-isopropylpyridin-3-yl)amine (0.48 g) as starting materials, 5-benzyloxy-N-[(4-dimethylaminophenyl)methyl]-N-(6-isopropylpyridin-3-yl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide (0.39 g) was obtained.
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[Br:6][C:7]1[N:8]([C:17]2[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[C:20]([CH:27]3[CH2:29][CH2:28]3)=[CH:19][CH:18]=2)[C:9]([S:12][CH2:13][C:14]([OH:16])=[O:15])=[N:10][N:11]=1.[OH:30][CH:31]1[O:37][C@H:36]([C@@H:38]([CH2:40]O)[OH:39])[C@H:34]([OH:35])[C@H:32]1[OH:33]>N1C=CC=CC=1>[Br:6][C:7]1[N:8]([C:17]2[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[C:20]([CH:27]3[CH2:29][CH2:28]3)=[CH:19][CH:18]=2)[C:9]([S:12][CH2:13][C:14]([O:16][CH2:40][CH:38]([OH:39])[CH:36]2[CH:34]([OH:35])[CH:32]([OH:33])[CH:31]([OH:30])[O:37]2)=[O:15])=[N:10][N:11]=1
Reactant: O=C(O)CSc1nnc(Br)n1-c1ccc(C2CC2)c2ccccc12
Reactant: OC[C@@H](O)[C@H]1OC(O)[C@H](O)[C@H]1O
Solvent: c1ccncc1
Solvent: O=P(Cl)(Cl)Cl
Product: O=C(CSc1nnc(Br)n1-c1ccc(C2CC2)c2ccccc12)OCC(O)C1OC(O)C(O)C1O
Temperature: 0 °C
Reaction time: 1 h

Procedure:
Phosphorus oxychloride (2.4 mmol) is added dropwise over 5 mins to a solution of 2-(5-bromo-4-(1-cyclopropylnaphthalen-4-yl)-4H-1,2,4-triazol-3-ylthio)acetic acid (810 mg, 2.0 mmol) in pyridine (20 mL) at 0° C. The mixture is stirred at 0° C. for a further 1 hour and then 1,2-O-isopropilydene-□-D-glucofuranose (440 mg, 2.0 mmol) dissolved in pyridine (5 mL) is added dropwise over 5 mins. The mixture is stirred at 0° C. for a further 3 hours and 1 hour at 20° C. and then quenched by addition of water (1 mL). Volatile solvents are removed in vacuo and DCM (200 mL) added. The organic phase is washed with water (1×50 mL), saturated sodium carbonate solution (1×50 mL) and brine (1×50 mL), dried over Na2SO4 and concentrated to dryness. Ethanol and water are added to produce a solid which is collected by filtration. Additional product is recovered by extraction of the filtrate with DCM. Combined product is concentrated, dried and purified by column chromatography (acetone/DCM eluent). The combined solids are dissolved in acetic acid (25 mL) and water (5 mL) mixture, heated at 60° C. for 3 hours. Volatile solvents are removed in vacuo. Ethanol and water are added to produce a solid which is collected by filtration.
Reaction SMILES: F[C:2]1[CH:41]=[CH:40][C:5]([C:6]([NH:8][C@](C2C=CC(F)=C(OC)C=2)(C2C=C(OC(F)(F)C(F)F)C=C(F)C=2)CC2C=CC=CC=2)=[O:7])=[CH:4][C:3]=1[C:42]([F:45])([F:44])[F:43].B(Br)(Br)Br>C(Cl)Cl>[F:43][C:42]([F:44])([F:45])[C:3]1[CH:4]=[C:5]([CH:40]=[CH:41][CH:2]=1)[C:6]([NH2:8])=[O:7]
Reactant: COc1cc([C@@](Cc2ccccc2)(NC(=O)c2ccc(F)c(C(F)(F)F)c2)c2cc(F)cc(OC(F)(F)C(F)F)c2)ccc1F
Agent: BrB(Br)Br
Solvent: ClCCl
Product: NC(=O)c1cccc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 100 %

Procedure:
To a solution of (R)-4-fluoro-N-(1-(4-fluoro-3-methoxyphenyl)-1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)-2-phenylethyl)-3-(trifluoromethyl)benzamide, prepared as described in Procedure 3, 59a-f, 6 and 7, (2.8 g, 4.43 mmol) in CH2Cl2 (15 mL) was added BBr3 (12 mL, 12 mmol). The resulting mixture was stirred at room temperature for 2 h and quenched by addition of ice. The reaction mixture was diluted with EtOAc and washed with sat. NaHCO3, sat. NaCl, dried over Na2SO4, filtered and concentrated to afford (R)-4-fluoro-N-(1-(4-fluoro-3-hydroxyphenyl)-1-(3-fluoro-5-(1,1,2,2)-tetrafluoro ethoxy)phenyl)-2-phenylethyl)-3-(trifluoromethyl)benzamide (Example 264) as clear oil (2.9 g, 100% yield). LCMS: RT=4.176 min [M+H] 632.2 (4 min Phenomenex Luna C18 column, 4.6×50 mm eluting with 10-90% MeOH/H2O over 4 minutes containing 0.1% TFA; 4 mL/min, monitoring at 220 nm).
Reaction SMILES: P(Cl)(Cl)(Cl)=O.CC(OC([N:13]1[CH:22]([C:23]([N:25]2[CH2:29][CH2:28][CH2:27][CH:26]2[C:30]([NH2:32])=O)=[O:24])[CH2:21][C:20]2[C:15](=[CH:16][C:17]([O:35][CH3:36])=[C:18]([O:33][CH3:34])[CH:19]=2)[CH2:14]1)=O)(C)C.N1C=CN=C1>N1C=CC=CC=1>[CH3:34][O:33][C:18]1[CH:19]=[C:20]2[C:15](=[CH:16][C:17]=1[O:35][CH3:36])[CH2:14][NH:13][CH:22]([C:23]([N:25]1[CH2:29][CH2:28][CH2:27][CH:26]1[C:30]#[N:32])=[O:24])[CH2:21]2
Reactant: COc1cc2c(cc1OC)CN(C(=O)OC(C)(C)C)C(C(=O)N1CCCC1C(N)=O)C2
Agent: c1c[nH]cn1
Solvent: c1ccncc1
Solvent: O=P(Cl)(Cl)Cl
Product: COc1cc2c(cc1OC)CC(C(=O)N1CCCC1C#N)NC2
Reaction time: 1.75 h
Yield: 108.3 %

Procedure:
Phosphorus oxychloride (239 mg, 0.15 mL, 1.56 mmol) was added to a solution of the title D compound of Example 6, 3-(2-aminocarbonyl-1-pyrrolidinyl)carbonyl-3,4-dihydro-6,7-dimethoxy-2(1H)-isoquinolinecarboxylic acid 2-(1,1-dimethylethyl) ester (259 mg, 0.6 mmol; diastereomer B) and imidazole (53 mg, 0.78 mmol) in pyridine (6 mL) at −45° C. The reaction was stirred for 1.75 hours, then allowed to stand at 8° C. overnight, after which the mixture was concentrated under vacuum. The residue was purified by flash chromatography on silica gel using 2% methanol in methylene chloride as eluent to give 205 mg of the title compound as a yellowish white solid.
Reaction SMILES: ClC1C=CC=C(C(OO)=[O:9])C=1.[O:12]1[CH2:17][CH2:16][N:15]([C:18]2[CH:23]=[CH:22][N:21]=[C:20]([CH2:24][S:25][C:26]3[NH:30][C:29]4[CH:31]=[CH:32][C:33]([O:35][CH3:36])=[CH:34][C:28]=4[N:27]=3)[C:19]=2[Cl:37])[CH2:14][CH2:13]1.N>ClCCl>[O:12]1[CH2:13][CH2:14][N:15]([C:18]2[CH:23]=[CH:22][N:21]=[C:20]([CH2:24][S:25]([C:26]3[NH:30][C:29]4[CH:31]=[CH:32][C:33]([O:35][CH3:36])=[CH:34][C:28]=4[N:27]=3)=[O:9])[C:19]=2[Cl:37])[CH2:16][CH2:17]1
Reactant: COc1ccc2[nH]c(SCc3nccc(N4CCOCC4)c3Cl)nc2c1
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: N
Solvent: ClCCl
Product: COc1ccc2[nH]c(S(=O)Cc3nccc(N4CCOCC4)c3Cl)nc2c1
Reaction time: 1 h

Procedure:
A solution of m-chloroperbenzoic acid (1.61 g) in dichloromethane (75 ml) was added dropwise to a stirred solution of 2 -(4 -morpholino-3 -chloro-2 -pyridylmethylthio)-5 -methoxy- (1H)-benzimidazole (3.35 g) in dichloromethane (150 ml) cooled to -35°. After 1 hour, ammonia was passed through the solution for 5 minutes and the precipitate filtered off. The solution was evaporated under reduced pressure and the residue chromatographed (silica gel, 2 % CHCl3 /MEOH-NH3 ) to give an oil which was crystallised from ethanol to give 2 -(4 -morpholino-3 -chloro-2 -pyridylmethylsulphinyl)-5 -methoxy-(1H)-benzimidazole. (2.6 g).
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:25]2[CH2:30][CH2:29][S:28](=[O:31])[CH2:27][CH2:26]2)[C:5]2[N:11]=[CH:10][N:9]=[C:8]([NH:12][CH2:13][CH2:14][C:15]3[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[C:17]([O:23][CH3:24])[CH:16]=3)[C:6]=2[N:7]=1.[OH:32][CH2:33][CH2:34][NH2:35]>>[CH3:24][O:23][C:17]1[CH:16]=[C:15]([CH:20]=[CH:19][C:18]=1[O:21][CH3:22])[CH2:14][CH2:13][NH:12][C:8]1[C:6]2[N:7]=[C:2]([NH:35][CH2:34][CH2:33][OH:32])[N:3]=[C:4]([N:25]3[CH2:30][CH2:29][S:28](=[O:31])[CH2:27][CH2:26]3)[C:5]=2[N:11]=[CH:10][N:9]=1
Reactant: COc1ccc(CCNc2ncnc3c(N4CCS(=O)CC4)nc(Cl)nc23)cc1OC
Reactant: NCCO
Product: COc1ccc(CCNc2ncnc3c(N4CCS(=O)CC4)nc(NCCO)nc23)cc1OC

Procedure:
This compound was prepared analogous to Example 2 from 2-chloro-8-(3,4-dimethoxyphenethyl-amino)-4-(1-oxidothiomorpholino)-pyrimido[5,4-d]pyrimidine (melting point: 214°-216° C.) and 2-hydroxyethyl-amine.
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][NH:3][C:2]1=[O:6].C([O-])([O-])=O.[K+].[K+].[Cl:13][C:14]1[CH:21]=[C:20]([Cl:22])[CH:19]=[CH:18][C:15]=1[CH2:16]Cl.O>CS(C)=O>[Cl:13][C:14]1[CH:21]=[C:20]([Cl:22])[CH:19]=[CH:18][C:15]=1[CH2:16][N:1]1[CH2:5][CH2:4][NH:3][C:2]1=[O:6]
Reactant: ClCc1ccc(Cl)cc1Cl
Reactant: O=C1NCCN1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: O=C1NCCN1Cc1ccc(Cl)cc1Cl
Reaction time: 0.3 h
Yield: 77 %

Procedure:
A 21.5 g (0.25 mole) portion of 2-imidazolidinone in 200 ml of dimethylsulfoxide was treated with 34.5 g (0.25 mole) of K2CO3, 20 g (0.12 mole) of KI and 48.9 g (0.25 mole) of 2,4-dichlorobenzyl chloride. The reaction mixture was heated with stirring to 105° over 0.3 hours, held at 105° for 1.8 hours, and poured with rapid stirring into 1.5 l of water. The aqueous mixture was extracted with 1.3 l of chloroform. The chloroform extract was washed with 580 ml of water, dried over MgSO4 overnight and filtered. The filtrate was concentrated under reduced pressure leaving 47 g (77%) of a light yellow oil. The oil was crystallized with 125 ml of ether, filtered, air dried, and dried to a constant weight at 60° to give 19 g (31%) of a white solid, m.p. 116°-118°.