Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:17](=[O:18])[C:16]3[C:11](=[CH:12][C:13]([O:19][CH2:20][C:21]4[CH:22]=[C:23]([CH:30]=[CH:31][CH:32]=4)[C:24]([O:26][CH2:27][CH:28]=[CH2:29])=[O:25])=[CH:14][CH:15]=3)[O:10][CH:9]=2)=[CH:4][CH:3]=1.N1C=CC=CC=1.[CH3:39][S:40](Cl)(=[O:42])=[O:41]>C(Cl)Cl>[CH3:39][S:40]([NH:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:17](=[O:18])[C:16]3[C:11](=[CH:12][C:13]([O:19][CH2:20][C:21]4[CH:22]=[C:23]([CH:30]=[CH:31][CH:32]=4)[C:24]([O:26][CH2:27][CH:28]=[CH2:29])=[O:25])=[CH:14][CH:15]=3)[O:10][CH:9]=2)=[CH:6][CH:7]=1)(=[O:42])=[O:41]
Reactant: CS(=O)(=O)Cl
Reactant: C=CCOC(=O)c1cccc(COc2ccc3c(=O)c(-c4ccc(N)cc4)coc3c2)c1
Solvent: c1ccncc1
Solvent: ClCCl
Product: C=CCOC(=O)c1cccc(COc2ccc3c(=O)c(-c4ccc(NS(C)(=O)=O)cc4)coc3c2)c1
Temperature: 25 °C
Reaction time: 21 h

Procedure:
To a mixture of prop-2-enyl 3-{[3-(4-aminophenyl)-4-oxochromen-7-yloxy]methyl}benzoate, prepared as described in Example 7A, (169.5 mg, 0.397 mmol) and anhydrous pyridine (34.5 mg, 0.44 mmol) in dry methylene chloride (3 ml) at 0° C. was added methanesulfonyl chloride (68.1 mg, 0.60 mmol). The mixture was then stirred at room temperature for 21 hours, then mixed with silics gel and the solvent removed under reduced pressure. Flash chromatography of the silica gel mixture, eluting with methylene chloride/methanol (99.5/0.5) gave prop-2-enyl 3-[(3-{4-[(methylsulfonyl)amino]phenyl}-4-oxochromen-7-yloxy)methyl]benzoate as a white solid (160.9 mg). (ESI) m/z 506 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH2:14][CH2:13][N:12]([C:15]3[CH:20]=[CH:19][C:18]([NH:21][C:22](=[O:30])OC4C=CC=CC=4)=[CH:17][CH:16]=3)[CH2:11][CH2:10]2)=[CH:5][CH:4]=1.[CH3:31][CH:32]([NH:34][CH2:35][C:36](OCC)=[O:37])[CH3:33].O1CCOCC1>CN(C)C1C=CN=CC=1.O>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH2:10][CH2:11][N:12]([C:15]3[CH:16]=[CH:17][C:18]([N:21]4[C:36](=[O:37])[CH2:35][N:34]([CH:32]([CH3:33])[CH3:31])[C:22]4=[O:30])=[CH:19][CH:20]=3)[CH2:13][CH2:14]2)=[CH:5][CH:4]=1
Reactant: CCOC(=O)CNC(C)C
Reactant: COc1ccc(N2CCN(c3ccc(NC(=O)Oc4ccccc4)cc3)CC2)cc1
Agent: CN(C)c1ccncc1
Solvent: C1COCCO1
Solvent: O
Product: COc1ccc(N2CCN(c3ccc(N4C(=O)CN(C(C)C)C4=O)cc3)CC2)cc1
Yield: 73 %

Procedure:
A mixture of 5 parts of phenyl [4-[4-(4-methoxyphenyl)-1-piperazinyl]phenyl]carbamate, 3 parts of ethyl [(1-methylethyl)amino]acetate, 1 part of N,N-dimethyl-4-pyridinamine and 100 parts of 1,4-dioxane was stirred and refluxed overnight. The warm solution was saturated with water and allowed to cool. The solution was poured onto water and extracted with trichloromethane. The extract was washed with water, dried, filtered and evaporated. The residue was purified by filtration over silica gel using a mixture of trichloromethane and methanol (98:2 by volume) as eluent. The filtrate was evaporated and the residue was crystallized from methylbenzene, yielding 3.7 parts (73%) of 3-[4-[4-(4-methoxyphenyl)-1-piperazinyl]phenyl]-1-(1-methylethyl)-2,4-imidazolidinedione; mp. 193.7° C. (38).
Reaction SMILES: Cl.[CH:2]1([CH2:5][O:6][C:7]2[CH:12]=[CH:11][C:10]([CH3:13])=[CH:9][C:8]=2[C:14]2[C:15]3[NH:22][C:21]([CH3:23])=[C:20]([C:24]([NH:26][CH:27]4[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]4)=[O:25])[C:16]=3[N:17]=[CH:18][N:19]=2)[CH2:4][CH2:3]1.C([O:36][CH2:37][C:38](Cl)=[O:39])(=O)C>>[CH:2]1([CH2:5][O:6][C:7]2[CH:12]=[CH:11][C:10]([CH3:13])=[CH:9][C:8]=2[C:14]2[C:15]3[NH:22][C:21]([CH3:23])=[C:20]([C:24]([NH:26][CH:27]4[CH2:28][CH2:29][N:30]([C:37](=[O:36])[CH2:38][OH:39])[CH2:31][CH2:32]4)=[O:25])[C:16]=3[N:17]=[CH:18][N:19]=2)[CH2:4][CH2:3]1
Reactant: CC(=O)OCC(=O)Cl
Reactant: Cc1ccc(OCC2CC2)c(-c2ncnc3c(C(=O)NC4CCNCC4)c(C)[nH]c23)c1
Agent: Cl
Product: Cc1ccc(OCC2CC2)c(-c2ncnc3c(C(=O)NC4CCN(C(=O)CO)CC4)c(C)[nH]c23)c1

Procedure:
Starting from 4-[2-(cyclopropylmethoxy)-5-methylphenyl]-6-methyl-N-(piperidin-4-yl)-5H-pyrrolo[3,2-d]pyrimidine-7-carboxamide hydrochloride (example D.f28) and commercially available 2-chloro-2-oxoethyl acetate the title compound is obtained as colorless solid.
Reaction SMILES: C[O:2][C:3](=[O:28])[C:4]([NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([CH:14]2[C:23]([CH3:25])([CH3:24])[CH2:22][C:21]3[C:16](=[CH:17][CH:18]=[C:19]([C:26]#[N:27])[CH:20]=3)[NH:15]2)[CH:9]=1)([CH3:6])[CH3:5].Cl>O1CCCC1.[OH-].[Li+].O>[C:26]([C:19]1[CH:20]=[C:21]2[C:16](=[CH:17][CH:18]=1)[NH:15][CH:14]([C:10]1[CH:9]=[C:8]([NH:7][C:4]([CH3:6])([CH3:5])[C:3]([OH:28])=[O:2])[CH:13]=[CH:12][CH:11]=1)[C:23]([CH3:25])([CH3:24])[CH2:22]2)#[N:27]
Reactant: COC(=O)C(C)(C)Nc1cccc(C2Nc3ccc(C#N)cc3CC2(C)C)c1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(Nc1cccc(C2Nc3ccc(C#N)cc3CC2(C)C)c1)C(=O)O
Temperature: 25 °C
Reaction time: 36 h
Yield: 7.5 %

Procedure:
A mixture of 2-[3-(6-cyano-3,3-dimethyl-1,2,3,4-tetrahydro-quinolin-2-yl)-phenylamino]-2-methyl-propionic acid methyl ester (500 mg, 1.32 mmol) in tetrahydrofuran (30 mL), 2M lithium hydroxide in water (15 mL) was prepared. The reaction mixture was stirred at 25° C. for 36 h. The mixture was neutralized with a 3 N aqueous hydrochloric acid solution and extracted with ethyl acetate (2×100 mL), washed with water, dried over anhydrous sodium sulfate and then concentrated in vacuo. Purification by Waters automated flash system (column: Xterra 30 mm×100 mm, sample manager 2767, pump 2525, detector: ZQ mass and UV 2487, solvent system: acetonitrile and 0.1% formic acid in water) afforded 2-[3-(6-cyano-3,3-dimethyl-1,2,3,4-tetrahydro-quinolin-2-yl)-phenylamino]-2-methyl-propionic acid (36 mg, 7%) as a white solid: LC/MS m/e calcd for C22H25N3O2 (M+H)+: 364.46, observed: 364.1.
Reaction SMILES: [CH3:1][N:2]([CH3:10])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][NH2:9].[NH:11]1[C:19]2[C:14](=[CH:15][C:16]([NH:20][C:21]3[CH:26]=[CH:25][N:24]=[C:23]4[CH:27]=[C:28]([C:30]5[CH:37]=[CH:36][C:33]([CH:34]=O)=[CH:32][CH:31]=5)[S:29][C:22]=34)=[CH:17][CH:18]=2)[CH:13]=[CH:12]1>>[NH:11]1[C:19]2[C:14](=[CH:15][C:16]([NH:20][C:21]3[CH:26]=[CH:25][N:24]=[C:23]4[CH:27]=[C:28]([C:30]5[CH:37]=[CH:36][C:33]([CH2:34][NH:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][N:2]([CH3:10])[CH3:1])=[CH:32][CH:31]=5)[S:29][C:22]=34)=[CH:17][CH:18]=2)[CH:13]=[CH:12]1
Reactant: CN(C)CCCCCCN
Reactant: O=Cc1ccc(-c2cc3nccc(Nc4ccc5[nH]ccc5c4)c3s2)cc1
Product: CN(C)CCCCCCNCc1ccc(-c2cc3nccc(Nc4ccc5[nH]ccc5c4)c3s2)cc1

Procedure:
The title compound was prepared from N,N-dimethyl-hexane-1,6-diamine and 4-[7-(1H-indol-5-ylamino)-thieno[3,2-b]pyridin-2-yl]-benzaldehyde by a procedure analogous to example 17. LC-MS: 498 (MH+); HPLC RT: 3.93 minutes.
Reaction SMILES: Cl[C:2]1[C:11]2[N:12]=[C:13]([CH2:21][CH2:22][CH3:23])[N:14]([CH2:15][C:16]3([OH:20])[CH2:19][CH2:18][CH2:17]3)[C:10]=2[C:9]2[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=2[N:3]=1.[NH3:24]>CO>[NH2:24][C:2]1[C:11]2[N:12]=[C:13]([CH2:21][CH2:22][CH3:23])[N:14]([CH2:15][C:16]3([OH:20])[CH2:19][CH2:18][CH2:17]3)[C:10]=2[C:9]2[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=2[N:3]=1
Reactant: CCCc1nc2c(Cl)nc3ccccc3c2n1CC1(O)CCC1
Reactant: N
Solvent: CO
Product: CCCc1nc2c(N)nc3ccccc3c2n1CC1(O)CCC1
Temperature: 150 °C

Procedure:
1-[(4-Chloro-2-propyl-1H-imidazo[4,5-c]quinolin-1-yl)methyl]cyclobutanol (1.56 g) was combined with a solution of ammonia in methanol (23 mL). The mixture was heated at 150° C. in a pressure vessel for 2 days. A portion of the solvent was removed under vacuum and then the mixture was diluted with additional methanol. A solid was isolated by filtration, washed with methanol, triturated with acetonitrile, and then dried. The material was suspended in water (70 mL). Concentrated hydrochloric acid (1.4 mL) was added and the mixture was heated at 90° C. for 30 minutes. The hot solution was neutralized with solid sodium bicarbonate. The solution was allowed to cool to ambient temperature. A precipitate was isolated by filtration, washed well with water, and then dried to provide 1-[(4-amino-2-propyl-1H-imidazo[4,5-c]quinolin-1-yl)methyl]cyclobutanol as a white powder, mp 228.0-229.0° C. Anal. Calcd for C18H22N4O C, 69.65; H, 7.14; N, 18.05; Found: C, 69.36; H, 7.24; N, 18.03.
Reaction SMILES: [CH3:1][C:2]1([CH3:16])[C:6]([CH3:8])([CH3:7])[O:5][B:4]([C:9]2[CH:10]=[CH:11][C:12]([NH2:15])=[N:13][CH:14]=2)[O:3]1.Br[CH2:18][C:19]([C:21]1[CH:26]=[CH:25][C:24]([F:27])=[CH:23][C:22]=1[F:28])=O>>[F:28][C:22]1[CH:23]=[C:24]([F:27])[CH:25]=[CH:26][C:21]=1[C:19]1[N:15]=[C:12]2[CH:11]=[CH:10][C:9]([B:4]3[O:3][C:2]([CH3:16])([CH3:1])[C:6]([CH3:7])([CH3:8])[O:5]3)=[CH:14][N:13]2[CH:18]=1
Reactant: O=C(CBr)c1ccc(F)cc1F
Reactant: CC1(C)OB(c2ccc(N)nc2)OC1(C)C
Product: CC1(C)OB(c2ccc3nc(-c4ccc(F)cc4F)cn3c2)OC1(C)C

Procedure:
By carrying out the procedure as in stage 4.1, starting from 4.76 g of 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-ylamine and 5.09 g of 2-bromo-1-(2,4-difluorophenyl)ethanone, 4.84 g of compound are obtained.
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH2:7]1)=[O:5])[CH3:2].[H][H].C(OC(N1C[C@H]2[C@H](CCCC2)C1)=O)C>[C].[Rh].C(O)C>[CH2:1]([O:3][C:4]([N:6]1[CH2:7][C@H:8]2[C@@H:13]([CH2:12][CH2:11][CH2:10][CH2:9]2)[CH2:14]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)N1Cc2ccccc2C1
Reactant: [H][H]
Agent: [Rh]
Agent: CCOC(=O)N1C[C@H]2CCCC[C@H]2C1
Solvent: CCO
Product: CCOC(=O)N1C[C@@H]2CCCC[C@H]2C1
Yield: 0.6 %

Procedure:
In a 3-liter GL autoclave fitted with a electromagnetic stirrer are added 207 g of N-ethoxycarbonylisoindoline, 793 g of ethylalcohol and 20 g of 5% rhodium-carbon catalyst (50% water-containing). The reaction mixture is subjected to a hydrogen-pressure of 25 kg/cm2 and a temperature of 130° C. After a 10 hour hydrogen introduction, the drop in the rate of the hydrogen-absorption is observed, at this point the introduction of hydrogen is ceased to terminate the reaction. After the termination of reaction, the catalyst is filtered out from the reacted solution. By the result of the capillary chromatographic analysis, the yield of cis-hexahydro-N-ethoxycarbonylisoindoline is 95.3%. In addition, 0.6% of trans-hexahydro-N-ethoxycarbonylisoindoline is formed.
Reaction SMILES: [NH:1]([C:13]([O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:14])[C@H:2]([C:10]([OH:12])=O)[C@@H:3]([CH3:9])[O:4][C:5]([CH3:8])([CH3:7])[CH3:6].CN1CCOCC1.C(OC(Cl)=O)C(C)C.[NH:38]1[CH2:49][CH2:48][CH2:47][C@H:39]1[C:40]([O:42][C:43]([CH3:46])([CH3:45])[CH3:44])=[O:41]>O1CCCC1>[NH:1]([C:13]([O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:14])[C@H:2]([C:10]([N:38]1[CH2:49][CH2:48][CH2:47][C@H:39]1[C:40]([O:42][C:43]([CH3:45])([CH3:46])[CH3:44])=[O:41])=[O:12])[C@@H:3]([CH3:9])[O:4][C:5]([CH3:6])([CH3:7])[CH3:8]
Reactant: CC(C)(C)OC(=O)[C@@H]1CCCN1
Reactant: C[C@@H](OC(C)(C)C)[C@H](NC(=O)OCc1ccccc1)C(=O)O
Agent: CC(C)COC(=O)Cl
Solvent: C1CCOC1
Solvent: CN1CCOCC1
Product: C[C@@H](OC(C)(C)C)[C@H](NC(=O)OCc1ccccc1)C(=O)N1CCC[C@H]1C(=O)OC(C)(C)C
Reaction time: 0.33 h

Procedure:
To a solution of 6.3 g of Z-Thr(tBu)-OH and 2.34 ml of N-methylmorpholine in 100 ml of tetrahydrofuran are added at -17°C 3.0 ml of chloroformic acid-isobutylester, the batch stirred for 20 minutes at this temperature, then reacted with 6.7 g of H-Pro-OtBu in 100 ml of tetrahydrofuran. The batch is allowed to stand at room temperature overnight, then filtered, the filtrate evaporated to dryness under vacuum, the residue dissolved in ethyl acetate and extracted several times with dilute aqueous citric acid solution, dilute aqueous sodium carbonate solution, and saturated sodium chloride solution. The resulting oily compound shows in the thin-layer chromatogram on silica gel:
Reaction SMILES: [C:1]1([C:7]2[CH:8]=[C:9]([C:13]3[N:22]=[C:21]([NH:23][C:24]4[CH:25]=[C:26]5[C:30](=[CH:31][CH:32]=4)[N:29](C([O-])=O)[N:28]=[CH:27]5)[C:20]4[C:15](=[CH:16][C:17]([O:47][CH3:48])=[C:18]([O:36][CH2:37][CH2:38][N:39]5[CH2:45][CH2:44][CH2:43][N:42]([CH3:46])[CH2:41][CH2:40]5)[CH:19]=4)[N:14]=3)[CH:10]=[CH:11][CH:12]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl>C(Cl)Cl.O1CCOCC1>[C:1]1([C:7]2[CH:8]=[C:9]([C:13]3[N:22]=[C:21]([NH:23][C:24]4[CH:25]=[C:26]5[C:30](=[CH:31][CH:32]=4)[NH:29][N:28]=[CH:27]5)[C:20]4[C:15](=[CH:16][C:17]([O:47][CH3:48])=[C:18]([O:36][CH2:37][CH2:38][N:39]5[CH2:45][CH2:44][CH2:43][N:42]([CH3:46])[CH2:41][CH2:40]5)[CH:19]=4)[N:14]=3)[CH:10]=[CH:11][CH:12]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: COc1cc2nc(-c3cccc(-c4ccccc4)c3)nc(Nc3ccc4c(cnn4C(=O)[O-])c3)c2cc1OCCN1CCCN(C)CC1
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: COc1cc2nc(-c3cccc(-c4ccccc4)c3)nc(Nc3ccc4[nH]ncc4c3)c2cc1OCCN1CCCN(C)CC1
Temperature: 25 °C
Reaction time: 5 h
Yield: 26 %

Procedure:
To a solution of 5-(2-[(3-phenyl)phenyl)-7-methoxy-6-(2-(4-methyl-1,4-diazepan-1-yl)ethoxy)quinazolin-4-ylamino)-1H-indazole-1-carboxylate in CH2Cl2 (2 mL) was added HCl as a 4.0 M solution in 1,4 dioxane (8 mL) and the reaction was stirred at RT for 5 h. The volatiles were removed in vacuo and the crude product was washed with hexane and dried under vacuum to yield 2-[(3-phenyl)phenyl)-N-(1H-indazol-5-yl)-7-methoxy-6-(2-(4-methyl-1,4-diazepan-1-yl)ethoxy)quinazolin-4-amine (0.063 g, 0.105 mmole, 26% over 2 steps). MS 600.4 (M+1). HPLC retention time 5.01 mins.
Reaction SMILES: [OH:1][C@H:2]([CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])[CH2:3][C:4]([O:6]C)=[O:5].[C:19]([Si:23]([CH3:26])([CH3:25])Cl)([CH3:22])([CH3:21])[CH3:20].C(N(CC)CC)C.Cl.C(N(CC)CC)C>CN(C)C1C=CN=CC=1.C(Cl)Cl.C([Si](C)(C)Cl)(C)(C)C>[CH3:20][C:19]([Si:23]([CH3:26])([CH3:25])[O:1][C@H:2]([CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])[CH2:3][C:4]([OH:6])=[O:5])([CH3:22])[CH3:21]
Reactant: CCCCCCCCCCC[C@@H](O)CC(=O)OC
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCCCCCCCCC[C@H](CC(=O)O)O[Si](C)(C)C(C)(C)C
Temperature: 25 °C
Reaction time: 30 h
Yield: 103.5 %

Procedure:
50 g of methyl (R)-3-hydroxytetradecanoate, 35 g of t-butyldimethylchlorosilane, 6.1 g of 4-dimethylaminopyridine and 29.4 g of triethylamine were dissolved in 200 ml of methylene chloride and stirred at room temperature for 30 hours as well as under reflux for 16 hours. Thereupon, a further 2 g of t-butyldimethylchlorosilane were added. After a further 24 hours under reflux the precipitated triethylamine hydrochloride salt was filtered off, washed with ether and the filtrate was concentrated. The residue was dissolved in ether and washed in sequence with water, 0.5M citric acid, again with water and saturated sodium chloride solution, dried, concentrated and subsequently freed from volatile material at 5° C. in a high vacuum for 5 hours. There were obtained 71.8 g of (R)-3-[(1,1-dimethylethyl)dimethylsilyloxy]tetradecanoic acid, IR (cm-1): 1745, 1254, 895, 776.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([OH:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:14]=[C:13]([C:15]2[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][C:16]=2[CH3:22])[N:12]=[C:11]([C:23]2[CH:28]=[CH:27][C:26]([CH3:29])=[CH:25][C:24]=2[CH3:30])[N:10]=1.[CH2:31]([O:35][CH2:36][CH2:37][CH2:38][CH3:39])[CH:32]1[O:34][CH2:33]1.CN(C)CC1C=CC=CC=1>C1(C)C(C)=CC=CC=1>[OH:1][C:2]1[CH:7]=[C:6]([O:8][CH2:33][CH:32]([OH:34])[CH2:31][O:35][CH2:36][CH2:37][CH2:38][CH3:39])[CH:5]=[CH:4][C:3]=1[C:9]1[N:10]=[C:11]([C:23]2[CH:28]=[CH:27][C:26]([CH3:29])=[CH:25][C:24]=2[CH3:30])[N:12]=[C:13]([C:15]2[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][C:16]=2[CH3:22])[N:14]=1
Reactant: Cc1ccc(-c2nc(-c3ccc(C)cc3C)nc(-c3ccc(O)cc3O)n2)c(C)c1
Reactant: CCCCOCC1CO1
Agent: CN(C)Cc1ccccc1
Solvent: Cc1ccccc1C
Product: CCCCOCC(O)COc1ccc(-c2nc(-c3ccc(C)cc3C)nc(-c3ccc(C)cc3C)n2)c(O)c1
Yield: 86 %

Procedure:
23.8 g (0.06 mol) of 2-(2,4-dihydroxyphenyl)-4,6-bis-(2,4-dimethylphenyl) 1,3,5-triazine (prepared as described in U.S. Pat. No. 3,244,708 Example 16) are suspended in 300 ml of xylene. 12.1 g (0.09 mol) of 97% butyl glycidyl ether and 0.75 g (0.006 mol) of dimethylbenzylamine are added to this suspension, and the mixture is heated to reflux temperature. After a reaction time of 5 hours the clear, brownish solution is cooled and clarified by filtration through 100 g of silica gel. The yellow solution is evaporated and the residue is recrystallized from hexaneltoluene. This gives 27.3 g of pale yellow crystals of 2-[2-hydroxy4(3-butoxy-2-hydroxypropyloxy)-phenyl]4,6-bis(2,4-dimethylphenyl)-1,3,5-triazin (=86% yield). Melting point: 80-83° C. (Compound 1).
Reaction SMILES: [NH2:1][C:2]1[C:3]([NH:10][CH2:11][C:12]([CH3:15])([OH:14])[CH3:13])=[N:4][C:5]([CH3:9])=[N:6][C:7]=1[Cl:8].[Cl:16][C:17]1[CH:24]=[CH:23][CH:22]=[CH:21][C:18]=1[CH:19]=O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C(C1C(=O)C(Cl)=C(Cl)C(=O)C=1C#N)#N>C1(C)C=CC=CC=1.ClCCl>[Cl:8][C:7]1[N:6]=[C:5]([CH3:9])[N:4]=[C:3]2[C:2]=1[N:1]=[C:19]([C:18]1[CH:21]=[CH:22][CH:23]=[CH:24][C:17]=1[Cl:16])[N:10]2[CH2:11][C:12]([CH3:15])([OH:14])[CH3:13]
Reactant: O=Cc1ccccc1Cl
Reactant: Cc1nc(Cl)c(N)c(NCC(C)(C)O)n1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: Cc1nc(Cl)c2nc(-c3ccccc3Cl)n(CC(C)(C)O)c2n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 56.9 %

Procedure:
Heat a mixture of 1-(5-amino-6-chloro-2-methylpyrimidin-4-ylamino)-2-methylpropan-2-ol (0.5 g, 0.002 mol), 2-chlorobenzaldehyde (0.6 g, 0.004 mol), p-toluene sulfonic acid (0.1 g) and molecular sieves (1.0 g) in toluene (25 mL) to 130° C. for 16 h. Remove the molecular sieves by filtration through diatomaceous earth, and concentrate the filtrate under reduced pressure to give a residue. Dissolve the residue in dry dichloromethane (5 mL) and add DDQ (0.47 g, 0.002 mol) at 0° C. Stir the reaction mixture at room temperature for 2 h. Dilute the reaction mixture with dichloromethane, wash with 1 N sodium hydroxide solution, water, and brine. Dry the organic layer over anhydrous sodium sulfate, filter, and concentrate to give a residue. Purify the residue on a silica gel column eluting with methanol:dichloromethane (2:98) to give the title compound (0.4 g). ES/MS m/z 351 (M+1).
Reaction SMILES: [C:1]1([S:7]([C:10]2[CH:15]=[CH:14][C:13]([CH2:16][CH2:17][CH:18]=[O:19])=[C:12]([Br:20])[CH:11]=2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:21][Si:22]([CH2:25][Mg]Cl)([CH3:24])[CH3:23]>C1COCC1>[C:1]1([S:7]([C:10]2[CH:15]=[CH:14][C:13]([CH2:16][CH2:17][CH:18]([OH:19])[CH2:21][Si:22]([CH3:25])([CH3:24])[CH3:23])=[C:12]([Br:20])[CH:11]=2)(=[O:8])=[O:9])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=CCCc1ccc(S(=O)(=O)c2ccccc2)cc1Br
Reactant: C[Si](C)(C)C[Mg]Cl
Solvent: C1CCOC1
Product: C[Si](C)(C)CC(O)CCc1ccc(S(=O)(=O)c2ccccc2)cc1Br
Reaction time: 3 h
Yield: 77 %

Procedure:
To a solution of 3-(4-benzenesulfonyl-2-bromo-phenyl)-propionaldehyde (4.77 g, 13.5 mmol) in THF (40 mL) was added trimethylsilylmethylmagnesium chloride (1M in Et2O, 27.3 mL) at −78° C. under Argon atmosphere. The reaction was allowed to reach 0° C. and was stirred for 3 hours, then quenched by addition of buffer pH=2 KHSO4/Na2SO4 (10%) at 0° C. The mixture was extracted 3 times with EtOAc and the combined extracts were washed with brine, dried over Na2SO4, filtered and evaporated in vacuo. The residue was purified via flash chromatography (hexane/EtOAc, 8/2) to afford 4-(4-benzenesulfonyl-2-bromo-phenyl)-1-trimethylsilanyl-butan-2-ol (4.60 g, 77% yield).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:16])[C:4]1[CH:12]=[C:11]([N+:13]([O-:15])=[O:14])[CH:10]=[C:6]([C:7](O)=[O:8])[CH:5]=1.[ClH:17]>S(Cl)(Cl)=O>[CH3:1][O:2][C:3](=[O:16])[C:4]1[CH:12]=[C:11]([N+:13]([O-:15])=[O:14])[CH:10]=[C:6]([C:7]([Cl:17])=[O:8])[CH:5]=1
Reactant: Cl
Reactant: COC(=O)c1cc(C(=O)O)cc([N+](=O)[O-])c1
Solvent: O=S(Cl)Cl
Product: COC(=O)c1cc(C(=O)Cl)cc([N+](=O)[O-])c1

Procedure:
A suspension of 5-nitro-isophtalic acid mono methyl ester (22.52 g, 100.0 mmol) in thionyl chloride (50 ml) was heated to reflux for 6 hours (until the production of SO2 and HCl-gas ceased). The excess of thionyl chloride was removed under reduced pressure, the residue was dissolved in DCM and the product was precipitated by addition of hexane to give a white solid. Yield: 24.10 g (99%).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[N:10]([CH3:17])[CH:9]=2)[C:5]([Cl:18])=[CH:4][N:3]=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.[F:31][C:32]1[C:38]([N+:39]([O-:41])=[O:40])=[CH:37][C:35]([NH2:36])=[C:34]([O:42][CH3:43])[CH:33]=1>CC(O)CCC>[Cl:18][C:5]1[C:6]([C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[N:10]([CH3:17])[CH:9]=2)=[N:7][C:2]([NH:36][C:35]2[CH:37]=[C:38]([N+:39]([O-:41])=[O:40])[C:32]([F:31])=[CH:33][C:34]=2[O:42][CH3:43])=[N:3][CH:4]=1
Reactant: Cn1cc(-c2nc(Cl)ncc2Cl)c2ccccc21
Reactant: COc1cc(F)c([N+](=O)[O-])cc1N
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCCC(C)O
Solvent: O
Product: COc1cc(F)c([N+](=O)[O-])cc1Nc1ncc(Cl)c(-c2cn(C)c3ccccc23)n1
Temperature: 125 °C
Yield: 72.2 %

Procedure:
A mixture of 3-(2,5-dichloropyrimidin-4-yl)-1-methylindole (Intermediate 88, 1281 mg, 4.60 mmol), p-toluene sulphonic acid monohydrate (964 mg, 5.07 mmol) and 4-fluoro-2-s methoxy-5-nitroaniline (Intermediate 23, 900 mg, 4.84 mmol) in 2-pentanol (50 mL) was heated at 125° C. for 18 h. A precipitate formed from the solution upon cooling. The precipitate was collected by filtration, washed with CH3OH (10 mL) and diethyl ether (20 mL) and dried on the filter to give the title compound (1.42 g, 72%) as a tan solid, which was used without further purification; 1H NMR: 3.91 (3H, s), 3.96 (3H, s), 7.05 (1H, t), 7.23-7.3 (1H, m), 7.39 (1H, d), 7.53 (1H, d), 8.33 (1H, d), 8.47 (1H, s), 8.58 (1H, s), 8.65 (1H, d), 8.76 (1H, s); m/z: ES+ MH+ 428.10.
Reaction SMILES: [I-].ClC1C=CC=C[N+]=1C.[Br:10][C:11]1[CH:28]=[CH:27][C:14]([C:15]([NH:17][C:18]2[CH:26]=[CH:25][C:21]([C:22]([OH:24])=O)=[CH:20][N:19]=2)=[O:16])=[CH:13][N:12]=1.[NH2:29][C:30]1[CH:35]=[CH:34][C:33]([Br:36])=[CH:32][N:31]=1.CCN(C(C)C)C(C)C>C1COCC1>[Br:10][C:11]1[CH:28]=[CH:27][C:14]([C:15]([NH:17][C:18]2[CH:26]=[CH:25][C:21]([C:22](=[O:24])[NH:29][C:30]3[CH:35]=[CH:34][C:33]([Br:36])=[CH:32][N:31]=3)=[CH:20][N:19]=2)=[O:16])=[CH:13][N:12]=1
Reactant: Nc1ccc(Br)cn1
Reactant: O=C(O)c1ccc(NC(=O)c2ccc(Br)nc2)nc1
Agent: C[n+]1ccccc1Cl
Agent: [I-]
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Nc1ccc(C(=O)Nc2ccc(Br)cn2)cn1)c1ccc(Br)nc1
Temperature: 25 °C
Reaction time: 96 h
Yield: 13.5 %

Procedure:
2-chloro-1-methylpyridinium iodide (2.37 g, 18.6 mmol) was added to a suspension of 6-(6-bromonicotinamido)nicotinic acid 4 (2 g, 6.21 mmol) and 2-amino-5-bromopyridine 5 (1.07 g, 6.21 mmol) in THF (100 ml), followed by DIPEA (2.4 g, 18.6 mmol). The reaction mixture was stirred for 4 days at RT. The suspension was filtered off and washed with water (25 ml). The filtrate was concentrated, diluted in chloroform, washed with water and brine, and then dried over Na2SO4. The product precipitated during evaporation and was dried under vacuum to give 6-bromo-N-(5-(5-bromopyridin-2-ylcarbamoyl)pyridin-2-yl)nicotinamide 6 as a yellow solid (400 mg, 14%). Mp. 245-247° C.
Reaction SMILES: C[Si](C)(C)[NH:3][Si:4]([CH3:7])([CH3:6])[CH3:5].[SH:10][C:11]1N[N:14]=[N:13][CH:12]=1.S1(C2C(=CC=CC=2)C(=O)N1)(=O)=O.N.OS(O)(=O)=O>ClCCl.C(OCC)(=O)C>[CH3:7][Si:4]([CH3:5])([CH3:6])[N:3]1[C:11]([S:10][Si:4]([CH3:7])([CH3:6])[CH3:5])=[CH:12][N:13]=[N:14]1
Reactant: Sc1cnn[nH]1
Reactant: C[Si](C)(C)N[Si](C)(C)C
Agent: N
Agent: O=C1NS(=O)(=O)c2ccccc21
Agent: O=S(=O)(O)O
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: C[Si](C)(C)Sc1cnnn1[Si](C)(C)C
Yield: 96 %

Procedure:
1.52 ml of hexamethyldisilazane (7.3 mmoles) were added to a refluxing mixture of 0.49 (4.86 mmoles) of 5-mercapto-1,2,3-(1H)-triazole, 5 mg (0.207 mmole) of saccharin, 10 ml of ethyl acetate and 15 ml of dichloromethane and the ammonia evolved was titrated with 1 N H2SO4 by the method described in Example 1A. It was found that 2 equivalents (4.9 mmoles) were evolved after refluxing for 30 minutes. Volatile materials were evaporated in vacuo to obtain 1.19 g (96%) of 1-trimethylsilyl-5-trimethylsilylthio-1,2,3-triazole NMR Spectrum was taken in carbon tetrachloride solution: Δ0.31 (9H); 0.48 (9H); 7.46 (1H).