Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[CH2:11][Br:12])[C:5](O)=[O:6].[CH3:13][Si:14]([CH3:18])([CH3:17])[CH2:15][NH2:16].Cl.CN(C)CCCN=C=NCC.O>ClCCl>[Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[CH2:11][Br:12])[C:5]([NH:16][CH2:15][Si:14]([CH3:18])([CH3:17])[CH3:13])=[O:6]
Reactant: O=C(O)c1ccc(CBr)c(Br)c1
Reactant: C[Si](C)(C)CN
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: O
Solvent: ClCCl
Product: C[Si](C)(C)CNC(=O)c1ccc(CBr)c(Br)c1
Temperature: 25 °C
Reaction time: 5 h
Yield: 62 %

Procedure:
3-bromo-4-(bromomethyl)benzoic acid (5 g), 1-(trimethylsilyl)methylamine (1.76 g), N,N-dimethylaminopyridine (0.1 g) and N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (4.3 g) were dissolved in dichloromethane (30 ml), and stirred for 5 hours at room temperature. Water was added to the reaction mixture, and then organic layer was separated and dried over magnesium sulfate. After filtering the reaction mixture, the solvent was distilled off under reduced pressure, and the resulting mixture was purified by silica gel chromatography, to obtain 3-bromo-4-(bromomethyl)-N-[(trimethysilyl)methyl]benzamide (4 g).
Reaction SMILES: [ClH:1].[N+:2]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[O:15][C:14]([C:16]3[NH:17][CH:18]=[CH:19][N:20]=3)=[CH:13][CH:12]=2)=[CH:7][CH:6]=1)([O-])=O.[H][H]>[Pd].CO>[ClH:1].[NH2:2][C:5]1[CH:6]=[CH:7][C:8]([C:11]2[O:15][C:14]([C:16]3[NH:20][CH:19]=[CH:18][N:17]=3)=[CH:13][CH:12]=2)=[CH:9][CH:10]=1
Reactant: O=[N+]([O-])c1ccc(-c2ccc(-c3ncc[nH]3)o2)cc1
Reactant: [H][H]
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: Nc1ccc(-c2ccc(-c3ncc[nH]3)o2)cc1

Procedure:
A mixture of 17 g (0.057 mole) of the compound of Example I, 200 ml of CH3OH and 1 teaspoon of 5% Pd/C (50% H2O) was shaken on a Parr apparatus with the theoretical amount of hydrogen being absorbed. The mixture was heated to reflux and CH3OH added to dissolution. The catalyst was removed by filtration and the filtrate cooled and diluted with ether. The resulting solid was recrystallized from anhydrous methanol and dried at 110° to yield 7 g (46%). An analytical sample was prepared by drying a sample in the vacuum pistol at the temperature of refluxing dimethylformamide, m.p. 242°-245°.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[C:2]1[C:10]([NH:12][C:13]1[CH:18]=[CH:17][C:16]([CH2:19][C:20]([O:22]C(C)(C)C)=[O:21])=[CH:15][C:14]=1[O:27][CH3:28])=[O:11].C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[C:2]1[C:10]([NH:12][C:13]1[CH:18]=[CH:17][C:16]([CH2:19][C:20]([OH:22])=[O:21])=[CH:15][C:14]=1[O:27][CH3:28])=[O:11]
Reactant: COc1cc(CC(=O)OC(C)(C)C)ccc1NC(=O)c1cc2ccccc2[nH]1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1cc(CC(=O)O)ccc1NC(=O)c1cc2ccccc2[nH]1
Temperature: 25 °C
Reaction time: 1 h
Yield: 99.5 %

Procedure:
In methylene chloride (20 ml) was dissolved tert-butyl (4-((2-indolylcarbonyl)amino)-3-methoxyphenyl)acetate (1.31 g, 3.44 mmol). To the resulting solution was added TFA (10 ml) at 0° C. After the reaction mixture was stirred at room temperature for 1 hour, the reaction mixture was distilled under reduced pressure to remove the solvent, whereby (4-((2-indolylcarbonyl)amino)-3-methoxyphenyl)acetic acid (1.11 g, 99%) was obtained as a brown solid.
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[CH:5][S:4][C:3]=1[C:7]([OH:9])=O.S(Cl)([Cl:12])=O.[NH:14]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[C:16](/[CH:23]=[CH:24]/[C:25]2[CH:30]=[CH:29][C:28]([N:31]3[CH2:36][CH2:35][O:34][CH2:33][CH2:32]3)=[CH:27][C:26]=2[NH2:37])=[N:15]1.C(N(CC)CC)C.Cl.C(O)C>CN(C=O)C>[ClH:12].[NH:14]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[C:16](/[CH:23]=[CH:24]/[C:25]2[CH:30]=[CH:29][C:28]([N:31]3[CH2:32][CH2:33][O:34][CH2:35][CH2:36]3)=[CH:27][C:26]=2[NH:37][C:7]([C:3]2[S:4][CH:5]=[CH:6][C:2]=2[CH3:1])=[O:9])=[N:15]1
Reactant: O=S(Cl)Cl
Reactant: Nc1cc(N2CCOCC2)ccc1/C=C/c1n[nH]c2ccccc12
Reactant: Cc1ccsc1C(=O)O
Agent: Cl
Solvent: CCO
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Cc1ccsc1C(=O)Nc1cc(N2CCOCC2)ccc1/C=C/c1n[nH]c2ccccc12
Reaction time: 1 h
Yield: 40.9 %

Procedure:
In a similar manner to Example 29, a free base of Compound 247 was synthesized from 3-methylthiophene-2-carboxylic acid (0.13 g, 0.94 mmol), thionyl chloride (0.10 mL, 1.4 mmol), DMF (few drops), (E)-2-[2-(1H-indazol-3-yl)vinyl]-5-(morpholin-4-yl)phenylamine (0.10 g, 0.31 mmol) obtained in Step 2 of Example 246 and triethylamine (0.13 mL, 0.94 mmol). Further, said free base was added with 1 mol/L hydrogen chloride-ethanol solution (2.0 mL), stirred for 1 hour and then the reaction mixture was concentrated. The residue was triturated in acetone to obtain Compound 247 (61 mg, 44%).
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5]1[N:10]2[C:11](=[O:18])[CH:12]([NH2:17])[CH2:13][CH:14]=[CH:15][CH2:16][CH:9]2[CH2:8][CH2:7][CH2:6]1)=[O:4].CCN(CC)CC.[C:26](Cl)(=[O:33])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>C1COCC1>[CH3:1][O:2][C:3]([C@H:5]1[N:10]2[C:11](=[O:18])[C@@H:12]([NH:17][C:26](=[O:33])[C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[CH2:13][CH:14]=[CH:15][CH2:16][C@H:9]2[CH2:8][CH2:7][CH2:6]1)=[O:4]
Reactant: O=C(Cl)c1ccccc1
Reactant: COC(=O)C1CCCC2CC=CCC(N)C(=O)N21
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COC(=O)[C@@H]1CCC[C@@H]2CC=CC[C@H](NC(=O)c3ccccc3)C(=O)N21
Reaction time: 0.08 h

Procedure:
A solution containing crude 7-amino-6-oxo-1,3,4,6,7,8,11,11a-octahydro-2H-pyrido[1,2-a]azocine-4-carboxylic acid methyl ester, 42, (50 mg, 0.2 mmol) and Et3N (0.56 mL, 4.0 mmol) in 5 mL THF is treated with excess benzoyl chloride (0.23 mL, 2.0 mmol) and stirred for 5 minutes. The reaction is quenched with MeOH and concentrated. The crude residue obtained is purified by preparative reverse phase HPLC (CH3CN/H2O) to yield 45 mg of desired product. 1H NMR (CDCl3) δ 7.92 (d, J=5.9 Hz, 1H), 7.87 (d, J=7.7 Hz, 2H), 7.57–7.42 (m, 3H), 5.70 (m, 2H), 5.30 (m, 1H), 5.18 (m, 1H), 4.63 (m, 1H), 3.74 (s, 3H), 3.12 (m, 1H), 2.67 (m, 1H), 2.52 (m, 1H), 2.29 (m, 2H), 1.90–1.60 (m, 5H); 13C NMR δ 172.8, 172.3, 166.4, 134.4, 131.8, 129.9, 128.8(2C), 127.3(2C), 125.0, 52.3, 51.8, 51.4, 50.8, 35.4, 34.2, 29.7, 26.4, 15.7.
Reaction SMILES: ClC1N=C2C(N=CN2C2CC(N3C=C(C)C=N3)C([OH:22])C2O)=C(NCC(C2C=CC=CC=2)C2C=CC=CC=2)N=1.C(OC(=O)[O:43][C@H:44]1[CH2:48][C@@H:47]([N:49]2[CH:57]=[N:56][C:55]3[C:50]2=[N:51][C:52]([Cl:76])=[N:53][C:54]=3[NH:58][CH:59]([C:68]2[CH:73]=[CH:72][C:71]([O:74][CH3:75])=[CH:70][CH:69]=2)[C:60]2[CH:65]=[CH:64][C:63]([O:66][CH3:67])=[CH:62][CH:61]=2)[CH:46]=[CH:45]1)C.CC1C=NNC=1.[C:84]([SiH2:88][O:89][C:90]([C:102]1[CH:107]=[CH:106][CH:105]=[CH:104][CH:103]=1)([C:96]1[CH:101]=[CH:100][CH:99]=[CH:98][CH:97]=1)[C:91]1[CH:92]=[N:93][NH:94][CH:95]=1)([CH3:87])([CH3:86])[CH3:85]>>[CH3:75][O:74][C:71]1[CH:70]=[CH:69][C:68]([CH:59]([NH:58][C:54]2[N:53]=[C:52]([Cl:76])[N:51]=[C:50]3[C:55]=2[N:56]=[CH:57][N:49]3[C@@H:47]2[CH2:46][C@H:45]([N:94]3[CH:95]=[C:91]([C:90]([C:102]4[CH:107]=[CH:106][CH:105]=[CH:104][CH:103]=4)([C:96]4[CH:97]=[CH:98][CH:99]=[CH:100][CH:101]=4)[O:89][SiH2:88][C:84]([CH3:87])([CH3:85])[CH3:86])[CH:92]=[N:93]3)[C@@H:44]([OH:43])[C@H:48]2[OH:22])[C:60]2[CH:65]=[CH:64][C:63]([O:66][CH3:67])=[CH:62][CH:61]=2)=[CH:73][CH:72]=1
Reactant: Cc1cnn(C2CC(n3cnc4c(NCC(c5ccccc5)c5ccccc5)nc(Cl)nc43)C(O)C2O)c1
Reactant: CCOC(=O)O[C@@H]1C=C[C@H](n2cnc3c(NC(c4ccc(OC)cc4)c4ccc(OC)cc4)nc(Cl)nc32)C1
Reactant: CC(C)(C)[SiH2]OC(c1ccccc1)(c1ccccc1)c1cn[nH]c1
Agent: Cc1cn[nH]c1
Product: COc1ccc(C(Nc2nc(Cl)nc3c2ncn3[C@@H]2C[C@H](n3cc(C(O[SiH2]C(C)(C)C)(c4ccccc4)c4ccccc4)cn3)[C@@H](O)[C@H]2O)c2ccc(OC)cc2)cc1

Procedure:
The title compound is prepared by an analogous procedure to 1R,2S,3R,5S)-3-[2-Chloro-6-(2,2-diphenyl-ethylamino)-purin-9-yl]-5-(4-methyl-pyrazol-1-yl)-cyclopentane-1,2-diol (Intermediate BA1) by replacing Carbonic acid (1S,4R)-4-[2-chloro-6-(2,2-diphenyl-ethylamino)-purin-9-yl]-cyclopent-2-enyl ester ethyl ester (Intermediate AA) in step 1 with Carbonic acid (1S,4R)-4-(6-{[bis-(4-methoxy-phenyl)-methyl]-amino}-2-chloro-purin-9-yl)-cyclopent-2-enyl ester ethyl ester (Intermediate AB) and by replacing 4-methylpyrazole with 4-(tert-Butyl-diphenyl-silanyloxymethyl)-1H-pyrazole. 1H nmr (CDCl3, 400 MHz); 7.70 (m, 4H), 7.50-7.20 (m, 13H), 6.85 (m, 4H), 6.60 (s, 1H), 5.60 (s, 1H), 4.80 (m, 1H), 4.70 (m, 4H), 4.30 (m, 1H), 3.80 (s, 6H), 3.00 (m, 1H), 2.70 (m, 1H), 1.10 (s, 9H).
Reaction SMILES: [CH3:1][CH2:2][O:3][C:4]([C:6]1[CH:11]([C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:17]=2[Cl:18])[C:10]([C:19]([O:21][CH3:22])=[O:20])=[C:9]([CH3:23])[NH:8][C:7]=1[CH2:24][O:25][CH2:26][CH2:27][NH2:28])=[O:5].[O:29]=[C:30]1[O:34][C@H:33]([C:35]([OH:37])=[O:36])[CH2:32][CH2:31]1>C(OCC)(=O)C>[CH3:1][CH2:2][O:3][C:4]([C:6]1[CH:11]([C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:17]=2[Cl:18])[C:10]([C:19]([O:21][CH3:22])=[O:20])=[C:9]([CH3:23])[NH:8][C:7]=1[CH2:24][O:25][CH2:26][CH2:27][NH2:28])=[O:5].[O:29]=[C:30]1[O:34][C@H:33]([C:35]([O-:37])=[O:36])[CH2:32][CH2:31]1
Reactant: O=C1CC[C@@H](C(=O)O)O1
Agent: CCOC(=O)C1=C(COCCN)NC(C)=C(C(=O)OC)C1c1ccccc1Cl
Solvent: CCOC(C)=O
Product: O=C1CC[C@@H](C(=O)[O-])O1

Procedure:
Amlodipine (10 g, 0.025 mole) was dissolved in ethyl acetate (100 ml) with stirring. The solution was adjusted to 3° C. and slowly added with (S)-tetrahydro-5-oxo-2-furancarboxylic acid (3.69 g, 0.028 mole) prepared according to Korean Pat. Publication No. 0159540 to obtain a clear solution. This reaction was stirred at 3° C. for 20 hour to produce precipitates. They were filtered off and washed with ethyl acetate (50 ml), followed by drying at 40° C. under vacuum to give 12.4 g of the title compound (Yield 92.0%).
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][N:3]=1.[C:16]([C:18]1[CH:19]=[C:20]([CH:22]=[CH:23][CH:24]=1)[NH2:21])#[CH:17]>C(O)(C)C>[ClH:1].[CH3:13][O:12][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][C:8]=1[O:14][CH3:15])[N:5]=[CH:4][N:3]=[C:2]2[NH:21][C:20]1[CH:22]=[CH:23][CH:24]=[C:18]([C:16]#[CH:17])[CH:19]=1
Reactant: C#Cc1cccc(N)c1
Reactant: COc1cc2ncnc(Cl)c2cc1OC
Solvent: CC(C)O
Product: C#Cc1cccc(Nc2ncnc3cc(OC)c(OC)cc23)c1
Product: Cl

Procedure:
4-Chloro-6,7-dimethoxyquinazoline (250 mg, 1.12 mmol) and 3-ethynyl-aniline (137 mg, 1.17 mmol) were refluxed in 10 mL of isopropyl alcohol for 0.5 hour, cooled and filtered to afford solid title product which was washed with 10 mL of isopropyl alcohol and dried in vacuo, at 70° C., 338 mg (99%); mp 269°-270° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[CH2:14][CH2:13][N:12]3[C:7](=[C:8]([CH2:22][NH:23][CH2:24][C:25]#[N:26])[CH:9]=[C:10]([C:16]4[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=4)[C:11]3=[O:15])[C:6]=2[CH:27]=1.[CH:28](O)=[O:29].C(OC(=O)C)(=O)C>O1CCCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[CH2:14][CH2:13][N:12]3[C:7](=[C:8]([CH2:22][N:23]([CH2:24][C:25]#[N:26])[CH:28]=[O:29])[CH:9]=[C:10]([C:16]4[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=4)[C:11]3=[O:15])[C:6]=2[CH:27]=1
Reactant: O=CO
Reactant: N#CCNCc1cc(-c2ccccc2)c(=O)n2c1-c1cc(Cl)ccc1CC2
Solvent: C1CCOC1
Solvent: CC(=O)OC(C)=O
Product: N#CCN(C=O)Cc1cc(-c2ccccc2)c(=O)n2c1-c1cc(Cl)ccc1CC2
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
A suspension of 0.376 g of [[(10-chloro-6,7-dihydro-4-oxo-3-phenyl-4H-benzo[a]quinolizine-1-yl)methyl]amino]acetonitrile in 10 ml of tetrahydrofuran was treated with 0.1 ml of formic acid-acetic acid anhydride and the clear yellow solution which formed after a short time was stirred at room temPerature for 45 minutes. After evaporation the residue was taken up in chloroform, washed with 10 percent potassium bicarbonate solution and saturated sodium chloride solution, dried over magnesium sulfate, concentrated and purified by chromatography on silica gel with toluene/dioxane (9:1). N-[(10-Chloro-6,7-dihydro-4-oxo-3-phenyl-4H-benzo[a]quinolizine-1-yl)methyl]-N-(cyanomethyl)formamide formed a yellow resin.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([OH:9])=[C:5]([N+:10]([O-:12])=[O:11])[CH:4]=1.C1(O)C=CC=CC=1.[CH3:20][O:21][C:22](=[O:26])[CH:23](Br)[CH3:24]>>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([O:9][CH:23]([CH3:24])[C:22]([O:21][CH3:20])=[O:26])=[C:5]([N+:10]([O-:12])=[O:11])[CH:4]=1
Reactant: COc1ccc(O)c([N+](=O)[O-])c1
Reactant: COC(=O)C(C)Br
Solvent: Oc1ccccc1
Product: COC(=O)C(C)Oc1ccc(OC)cc1[N+](=O)[O-]
Yield: 70.9 %

Procedure:
Using 4-methoxy-2-nitrophenol as the phenol and methyl-2-bromopropanoate as the alkylating agent in the general procedure for alkylation of substituted-2-nitrophenols gives the title compound as a light yellow solid (5.35 g, 70.9% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.50 (d, J=6.82 Hz, 3H) 3.67 (s, 3H) 3.78 (s, 3H) 5.12 (q, J=6.65 Hz, 1H) 7.15-7.27 (m, 2H) 7.39-7.49 (m, 1H). ESI-MS: m/z 256.1 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:12][CH2:13][CH2:14][O:15][CH3:16])=[CH:9][CH:10]=2)[N:5]=[N:4][CH:3]=1.[F:17][C:18]1[CH:24]=[C:23]([CH3:25])[C:22]([OH:26])=[CH:21][C:19]=1[NH2:20].Cl>CC(O)CCC>[ClH:1].[F:17][C:18]1[CH:24]=[C:23]([CH3:25])[C:22]([OH:26])=[CH:21][C:19]=1[NH:20][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:12][CH2:13][CH2:14][O:15][CH3:16])=[CH:9][CH:10]=2)[N:5]=[N:4][CH:3]=1
Reactant: COCCOc1ccc2c(Cl)cnnc2c1
Reactant: Cc1cc(F)c(N)cc1O
Agent: Cl
Solvent: CCCC(C)O
Product: COCCOc1ccc2c(Nc3cc(O)c(C)cc3F)cnnc2c1
Yield: 83.8 %

Procedure:
A solution of 4-chloro-7-(2-methoxyethoxy)cinnoline (156 mg, 0.65 mmol) and 2-fluoro-5-hydroxy-4-methylaniline (111 mg, 0.78 mmol), (prepared as described for the starting material in Example 11), in 2-pentanol (8 ml) and 5M isopropanolic hydrogen chloride (1 ml) was heated at 120° C. for 2.5 hours. The solid was filtered off, washed with isopropanol and then ether and dried under vacuum to give 4-(2-fluoro-5-hydroxy-4-methylanilino)-7-(2-methoxyethoxy)cinnoline hydrochloride (207 mg, 84%).
Reaction SMILES: [C:1]([O:4][C@@H:5]1[C@@H:11]([O:12][C:13](=[O:15])[CH3:14])[C@H:10]([O:16][C:17](=[O:19])[CH3:18])[C@@H:9]([CH2:20][O:21][C:22](=[O:24])[CH3:23])[S:8][CH:6]1[OH:7])(=[O:3])[CH3:2].[CH2:25]([C:27]1[CH:41]=[CH:40][C:30]([CH2:31][C:32]2[C:38](O)=[CH:37][CH:36]=[CH:35][C:33]=2[OH:34])=[CH:29][CH:28]=1)[CH3:26].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>C1(C)C=CC=CC=1>[C:1]([O:4][C@@H:5]1[C@@H:11]([O:12][C:13](=[O:15])[CH3:14])[C@H:10]([O:16][C:17](=[O:19])[CH3:18])[C@@H:9]([CH2:20][O:21][C:22](=[O:24])[CH3:23])[S:8][C@H:6]1[O:7][C:38]1[CH:37]=[CH:36][CH:35]=[C:33]([OH:34])[C:32]=1[CH2:31][C:30]1[CH:29]=[CH:28][C:27]([CH2:25][CH3:26])=[CH:41][CH:40]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)OC[C@H]1SC(O)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Reactant: CCc1ccc(Cc2c(O)cccc2O)cc1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: CCc1ccc(Cc2c(O)cccc2O[C@@H]2S[C@H](COC(C)=O)[C@@H](OC(C)=O)[C@H](OC(C)=O)[C@H]2OC(C)=O)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 16.6 %

Procedure:
2,3,4,6-Tetra-O-acetyl-5-thio-D-glucopyranose (1.29 g, 3.54 mmol), 2-(4-ethylbenzyl)resorcinol (2.42 g, 10.6 mmol), triphenylphosphine (1.86 g, 7.09 mmol) and toluene (13 mL) were mixed, and to the resulting mixture, diisopropyl azodicarboxylate (40% in toluene, 3.58 g) was then slowly added dropwise in ice. After stirring at room temperature for 24 hours, the reaction mixture was concentrated and the resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate=65:35–50:50) to give a crude product of 3-hydroxy-2-(4-ethylbenzyl)phenyl 2,3,4,6-tetra-O-acetyl-5-thio-β-D-glucopyranoside (338 mg). To a mixture of this crude product (338 mg) and pyridine (2 mL), acetic anhydride (0.5 mL) was added at room temperature. After stirring at room temperature for 20 hours, water was added to the reaction mixture, which was then extracted with ethyl acetate. The organic phase was washed with saturated aqueous sodium chloride and then dried over anhydrous magnesium sulfate. After the solvent was distilled off under reduced pressure, the resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate=2:1) to give the titled compound (134 mg, 6%) as a light-yellow gum.
Reaction SMILES: [F:1][CH:2]([F:37])[C:3]1[N:7]([C:8]2[N:13]=[C:12]([N:14]3[CH2:19][CH2:18][O:17][CH2:16][CH2:15]3)[N:11]=[C:10]([N:20]3[CH2:25][CH2:24][N:23]([S:26]([CH:29]=[CH2:30])(=[O:28])=[O:27])[CH2:22][CH2:21]3)[N:9]=2)[C:6]2[CH:31]=[CH:32][CH:33]=[C:34]([O:35][CH3:36])[C:5]=2[N:4]=1.[NH:38]1[CH2:43][CH2:42][S:41][CH2:40][CH2:39]1>C1COCC1>[F:37][CH:2]([F:1])[C:3]1[N:7]([C:8]2[N:13]=[C:12]([N:14]3[CH2:15][CH2:16][O:17][CH2:18][CH2:19]3)[N:11]=[C:10]([N:20]3[CH2:21][CH2:22][N:23]([S:26]([CH2:29][CH2:30][N:38]4[CH2:43][CH2:42][S:41][CH2:40][CH2:39]4)(=[O:28])=[O:27])[CH2:24][CH2:25]3)[N:9]=2)[C:6]2[CH:31]=[CH:32][CH:33]=[C:34]([O:35][CH3:36])[C:5]=2[N:4]=1
Reactant: C=CS(=O)(=O)N1CCN(c2nc(N3CCOCC3)nc(-n3c(C(F)F)nc4c(OC)cccc43)n2)CC1
Reactant: C1CSCCN1
Solvent: C1CCOC1
Product: COc1cccc2c1nc(C(F)F)n2-c1nc(N2CCOCC2)nc(N2CCN(S(=O)(=O)CCN3CCSCC3)CC2)n1
Temperature: 25 °C
Reaction time: 72 h
Yield: 84 %

Procedure:
A mixture of 2-(difluoromethyl)-4-methoxy-1-{4-(4-morpholinyl)-6-[4-(vinylsulfonyl)-1-piperazinyl]-1,3,5-triazin-2-yl}-1H-benzimidazole (Example 3) (180 mg, 0.335 mmol), thiomorpholine (0.17 mL, 1.68 mmol) in THF (50 mL) was stirred at room temperature for 3 days and then at reflux for 3 hrs. The solvent was removed under vacuum and the residue was dissolved in dioxane (30 mL) and additional thiomorpholine (0.17 mL, 1.68 mmol) was added. The reaction mixture was refluxed for 2 days. The solvent was removed under vacuum and the residue diluted with water. The resulting precipitate was filtered, washed with water and dissolved in CH2Cl2. The solution was dried (Na2SO4) and solvent removed under vacuum. Chromatography on silica, eluting with CH2Cl2/MeOH (98:2), followed by recrystallization from CH2Cl2/hexane gave 180 mg (84% yield) of 2-(difluoromethyl)-4-methoxy-1-[4-(4-morpholinyl)-6-(4-{[2-(4-thiomorpholinyl)ethyl]sulfonyl}-1-piperazinyl)-1,3,5-triazin-2-yl]-1H-benzimidazole: mp (CH2Cl2/hexane) 210-212° C.; 1H NMR (CDCl3) δ 7.86 (dd, J=8.3, 0.5 Hz, 1H), 7.43 (t, JHF=53.5 Hz, 1H), 7.36 (t, J=8.2 Hz, 1H), 6.82 (d, J=7.7 Hz, 1H), 4.05 (s, 3H), 4.00 (br s, 4H), 3.89 (br s, 4H), 3.79 (m, 4H), 3.38 (t, J=5.1 Hz, 4H), 3.11 (dd, J=8.3, 6.1 Hz, 2H), 2.87 (dd, J=8.3, 6.1 Hz, 2H), 2.73 (dd, J=6.1, 3.8 Hz, 4H), 2.63 (m, 4H); Anal. Calcd. for C26H35F2N9O4S2.0.5H2O: C, 48.1; H, 5.6; N, 19.4. Found: C, 48.2; H, 5.4; N, 19.3%.
Reaction SMILES: S(Cl)([Cl:3])=O.CN(C)C=O.[Br:10][C:11]1[CH:20]=[C:19]2[C:14]([N:15]=[CH:16][C:17](=O)[NH:18]2)=[CH:13][CH:12]=1>C1(C)C=CC=CC=1>[Br:10][C:11]1[CH:20]=[C:19]2[C:14]([N:15]=[CH:16][C:17]([Cl:3])=[N:18]2)=[CH:13][CH:12]=1
Reactant: O=c1cnc2ccc(Br)cc2[nH]1
Reactant: O=S(Cl)Cl
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: Clc1cnc2ccc(Br)cc2n1
Temperature: 80 °C
Reaction time: 17 h
Yield: 74.6 %

Procedure:
Thionyl chloride (407.5 mL; 5.59 mol), then N,N-dimethylformamide (34.6 mL; 0.45 mol) were added dropwise to a mixture of 7-bromo-2(1H)-quinoxalinone (500 g; 2.24 mol) in toluene (7.61 L). The reaction mixture was stirred at 80° C. for 17 hours then cooled to 35° C. and poured cautiously onto water. The bi-phasic mixture was stirred for 30 minutes and then decanted. The organic layer was evaporated to dryness and the residue crystallized in methyl-tert-butyl ether, filtered and the precipitate washed with methyl-tert-butyl ether and dried to give 407 g (74.7%) of 7-bromo-2-chloro-quinoxaline. Filtrate was evaporated and re-crystallized in methyl-tert-butyl ether to provide a second fraction of 72 g (13.2%) of 7-bromo-2-chloro-quinoxaline.
Reaction SMILES: C1(C2C=CC=CC=2)C=CC=CC=1.IC1C=CC2OCOC=2C=1.[CH3:23][O:24][C:25]1[CH:30]=[CH:29][C:28]([C:31]2[CH:36]=[CH:35][C:34](OC)=[CH:33][CH:32]=2)=[CH:27][CH:26]=1>>[CH3:23][O:24][C:25]1[CH:30]=[CH:29][C:28]([C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=2)=[CH:27][CH:26]=1
Reactant: COc1ccc(-c2ccc(OC)cc2)cc1
Agent: Ic1ccc2c(c1)OCO2
Solvent: c1ccc(-c2ccccc2)cc1
Product: COc1ccc(-c2ccccc2)cc1
Temperature: 60 °C

Procedure:
This reaction can also be conveniently carried out without removal of excess bis(pinacolato)diboron when this reagent is used in near stoichiometric molar ratio for the synthesis of the arylboronic acid ester. Thus, reacting 267 mgs (1.05 mmol) of bis(pinacolato)diboron, 25 mg of PdCl2(dppf).CH2Cl2, 416 mg (3.0 mmol) K2CO3 and 234 mg (1.0 mmol) 4-iodoanisole in 5 ml methanol at 25° C. for 16 h gave (by gc analysis) a 94% yield of the required ester (with 1.4% dimer) which was converted to the biphenyl by addition of 1-iodo-3,4-methylenedioxybenzene (excess, 315 mg, 1.27 mmol) and warming the mixture to 60° C. for 12 h. The ratio of 4,4′-dimethoxybiphenyl:4,4′-bis(1,3-benzodioxole) to asymmetric biaryl was 1:1.2:19. Some 4-methoxybiphenyl is also formed in the coupling reaction, presumably from the coupling of phenyl groups stemming from the catalyst phosphine ligand and the 4-methoxyphenyl from the boronic acid ester.
Reaction SMILES: [CH3:1]I.[H-].[Na+].[CH:5]([C:8]1[C:13]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[C:12]([C:19]2[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=2)[C:11]([CH2:26][OH:27])=[C:10]([CH:28]([CH3:30])[CH3:29])[N:9]=1)([CH3:7])[CH3:6].O>O1CCCC1>[CH:5]([C:8]1[C:13]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[C:12]([C:19]2[CH:20]=[CH:21][C:22]([F:25])=[CH:23][CH:24]=2)[C:11]([CH2:26][O:27][CH3:1])=[C:10]([CH:28]([CH3:29])[CH3:30])[N:9]=1)([CH3:7])[CH3:6]
Reactant: CCOC(=O)c1c(C(C)C)nc(C(C)C)c(CO)c1-c1ccc(F)cc1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CCOC(=O)c1c(C(C)C)nc(C(C)C)c(COC)c1-c1ccc(F)cc1
Reaction time: 2 h

Procedure:
0.57 ml (9.2 mmol)of methyl iodide and, at -50° C., 327 mg (10.9 mmol) of 80% strength sodium hydride are added under a nitrogen atmosphere to 3 g (8.4 mmol) of the compound from Example 4 in 100 ml of dry tetrahydrofuran. The mixture is stirred for 2 hours and the temperature is allowed to rise to 25° C. in the course of this. Water is cautiously added to the mixture and it is extracted several times using ether, and the organic phase is dried over sodium sulphate and concentrated in vacuo.
Reaction SMILES: Br[C:2]1[C:3](=[O:19])[C:4]2[C:9]([C:10]=1[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[CH:8][C:7]([O:17][CH3:18])=[CH:6][CH:5]=2.O1CCN(CCOC2C=C3C(C(C4C=CC=CC=4)=C(Br)C3=O)=CC=2)CC1.[F:46][C:47]1[CH:48]=[C:49](B(O)O)[CH:50]=[CH:51][C:52]=1[CH3:53]>>[F:46][C:47]1[CH:48]=[C:49]([C:2]2[C:3](=[O:19])[C:4]3[C:9]([C:10]=2[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[CH:8][C:7]([O:17][CH3:18])=[CH:6][CH:5]=3)[CH:50]=[CH:51][C:52]=1[CH3:53]
Reactant: Cc1ccc(B(O)O)cc1F
Reactant: COc1ccc2c(c1)C(c1ccccc1)=C(Br)C2=O
Agent: O=C1C(Br)=C(c2ccccc2)c2ccc(OCCN3CCOCC3)cc21
Product: COc1ccc2c(c1)C(c1ccccc1)=C(c1ccc(C)c(F)c1)C2=O
Reaction time: 0.17 h
Yield: 65 %

Procedure:
The procedure of Step 7 of Example 1 was repeated except for using 2-bromo-5-methoxy-3-phenyl-1H-inden-1-one obtained in Step 4 of Example 129 as a starting material instead of 6-(2-morpholinoethoxy)-2-bromo-3-phenyl-1H-inden-1-one, 3-fluoro-4-methylphenylboronic acid instead of 3-pyridinylboronic acid, and being stirred for 10 min to obtain the title compound (65%).