Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1[N:6]=[C:5](Cl)[C:4]2[N:8]=[CH:9][N:10]([C@@H:11]3[O:15][C@H:14]([CH2:16][OH:17])[C@@H:13]([OH:18])[C@H:12]3[OH:19])[C:3]=2[N:2]=1.[C:20]1([CH2:33][CH2:34][NH2:35])[C:32]2[CH2:31][C:30]3[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=3)[C:24]=2[CH:23]=[CH:22][CH:21]=1.C(N(CC)CC)C>C(O)C>[C:20]1([CH2:33][CH2:34][NH:35][C:5]2[C:4]3[N:8]=[CH:9][N:10]([C:3]=3[N:2]=[CH:1][N:6]=2)[C@@H:11]2[O:15][C@H:14]([CH2:16][OH:17])[C@@H:13]([OH:18])[C@H:12]2[OH:19])[C:32]2[CH2:31][C:30]3[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=3)[C:24]=2[CH:23]=[CH:22][CH:21]=1
Reactant: NCCc1cccc2c1Cc1ccccc1-2
Reactant: OC[C@H]1O[C@@H](n2cnc3c(Cl)ncnc32)[C@H](O)[C@@H]1O
Solvent: CCO
Solvent: CCN(CC)CC
Product: OC[C@H]1O[C@@H](n2cnc3c(NCCc4cccc5c4Cc4ccccc4-5)ncnc32)[C@H](O)[C@@H]1O
Yield: 98 %

Procedure:
A reaction mixture of 1.75 g of 6-chloropurine riboside, 1.78 g of fluorenylethylamine and 1.84 g of triethylamine is refluxed in 50 ml of ethanol under nitrogen for 20 hrs. Upon cooling, solid material crystallizes out. It is filtered and dried affording 2.75 g (95%) of N6 -fluorenylethyl adenosine having a melting point of 120°-123° C.
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[C:3]([C:6]1[CH:11]=[CH:10][C:9]([OH:12])=[CH:8][CH:7]=1)([CH3:5])[CH3:4].C(=O)([O-])[O-].[K+].[K+].Br[CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24]>CN(C)C=O>[F:1][C:2]([F:13])([F:14])[C:3]([C:6]1[CH:11]=[CH:10][C:9]([O:12][CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])=[CH:8][CH:7]=1)([CH3:5])[CH3:4]
Reactant: CC(C)(c1ccc(O)cc1)C(F)(F)F
Reactant: CCOC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)COc1ccc(C(C)(C)C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a mixture of 4-(2,2,2-trifluoro-1,1-dimethylethyl)phenol (408 mg, 2.0 mmol, WO 9708144A1) and potassium carbonate (552 mg, 4.0 mmol) in N,N-dimethylformamide (DMF) (30 ml) was added ethyl bromoacetate (334 mg, 2.0 mmol) and the mixture was stirred for 3 hours at ambient temperature. The reaction was partitioned with water and a 1:10 by volume mixture of ethylacetate/hexane, and the organic layer was separated and dried over sodium sulfate. After filtration to separate solvent and sodium sulfate, the solvent was removed under reduced pressure to give a residue, which was passed through a silica gel chromatography column and eluted with a 1:1 by volume mixture of ethyl acetate/hexane to furnish ethyl [4-(2,2,2-trifluoro-1,1-dimethylethyl)phenoxy]acetate. Then, ethyl [4-(2,2,2-trifluoro-1,1-dimethylethyl)phenoxy]acetate was treated with 2M aqueous sodium hydroxide (3.0 ml) and methanol (3.0 ml) for 2 hours at room temperature and was quenched with 2M aqueous hydrogen chloride to acidify the mixture adjusting to pH 1. Crude product was extracted with ethyl acetate, and then the organic layer was dried over magnesium sulfate. After filtration, solvent was evaporated under reduced pressure to give 345 mg (66% yield) of the title compound as a white solid.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:5]2[C:6](=[O:9])[CH2:7][O:8][C:4]=2[C:3]=1[CH2:12][N:13]1[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15][CH2:14]1.[F:26][C:27]([F:49])([F:48])[C:28]1[CH:33]=[CH:32][C:31]([S:34]([N:37]2[C:45]3[C:40](=[CH:41][CH:42]=[CH:43][CH:44]=3)[C:39]([CH:46]=O)=[CH:38]2)(=[O:36])=[O:35])=[CH:30][CH:29]=1.N1CCCCC1>CO>[OH:1][C:2]1[CH:11]=[CH:10][C:5]2[C:6](=[O:9])/[C:7](=[CH:46]/[C:39]3[C:40]4[C:45](=[CH:44][CH:43]=[CH:42][CH:41]=4)[N:37]([S:34]([C:31]4[CH:32]=[CH:33][C:28]([C:27]([F:49])([F:26])[F:48])=[CH:29][CH:30]=4)(=[O:36])=[O:35])[CH:38]=3)/[O:8][C:4]=2[C:3]=1[CH2:12][N:13]1[CH2:14][CH2:15][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:17][CH2:18]1
Reactant: O=Cc1cn(S(=O)(=O)c2ccc(C(F)(F)F)cc2)c2ccccc12
Reactant: CC(C)(C)OC(=O)N1CCN(Cc2c(O)ccc3c2OCC3=O)CC1
Solvent: C1CCNCC1
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCN(Cc2c(O)ccc3c2O/C(=C\c2cn(S(=O)(=O)c4ccc(C(F)(F)F)cc4)c4ccccc24)C3=O)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 77.1 %

Procedure:
A solution of tert-butyl 4-[(6-hydroxy-3-oxo-2,3-dihydrobenzofuran-7-yl)methyl]piperazine-1-carboxylate (0.0500 g, 0.144 mmol) obtained in Example A16, Step 1 in methanol (0.6 mL) was added with 1-[4-(trifluoromethyl)phenylsulfonyl]-1H-indole-3-carboxaldehyde (0.0509 g, 0.144 mmol) and piperidine (0.00123 g, 0.0144 mmol), and the mixture was stirred overnight at room temperature. The reaction mixture was added with methanol (1 mL), and the solid was suspended in methanol and thereby washed to obtain tert-butyl (Z)-4-([6-hydroxy-3-oxo-2-({1-[4-(trifluoromethyl)phenylsulfonyl]-1H-indol-3-yl}methylene)-2,3-dihydrobenzofuran-7-yl]methyl)piperazine-1-carboxylate (0.0759 g, 77%).
Reaction SMILES: [CH:1]1([C:4]2[C:5]3[CH:17]=[C:16]([C:18](O)=[O:19])[S:15][C:6]=3[N:7]([C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=3)[N:8]=2)[CH2:3][CH2:2]1.Cl.[NH:22]1[C:26]([C:27]2[CH:28]=[C:29]3[C:39](=[CH:40][CH:41]=2)[O:38][C:32]2([CH2:37][CH2:36][NH:35][CH2:34][CH2:33]2)[CH2:31][C:30]3=[O:42])=[N:25][N:24]=[N:23]1.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.Cl>O.CN(C=O)C>[CH:1]1([C:4]2[C:5]3[CH:17]=[C:16]([C:18]([N:35]4[CH2:36][CH2:37][C:32]5([CH2:31][C:30](=[O:42])[C:29]6[C:39](=[CH:40][CH:41]=[C:27]([C:26]7[NH:25][N:24]=[N:23][N:22]=7)[CH:28]=6)[O:38]5)[CH2:33][CH2:34]4)=[O:19])[S:15][C:6]=3[N:7]([C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=3)[N:8]=2)[CH2:2][CH2:3]1
Reactant: O=C1CC2(CCNCC2)Oc2ccc(-c3nnn[nH]3)cc21
Reactant: O=C(O)c1cc2c(C3CC3)nn(-c3ccccn3)c2s1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Product: O=C1CC2(CCN(C(=O)c3cc4c(C5CC5)nn(-c5ccccn5)c4s3)CC2)Oc2ccc(-c3nnn[nH]3)cc21
Temperature: 80 °C
Reaction time: 2 h

Procedure:
DMF (5 mL) and TEA (0.2 mL) were added to 3-cyclopropyl-1-pyridin-2-yl-1H-thieno[2,3-c]pyrazole-5-carboxylic acid (143 mg), 6-(tetrazol-5-yl)spiro[chroman-2,4′-piperidin]-4-one hydrochloride (177 mg), EDCI (119 mg) and HOBT (90 mg), heated at 80° C. and stirred for 2 hours. This was cooled to room temperature, iced water was added to it, and its pH was adjusted at 2.5 with 1 N HCl added thereto. The formed crystal was taken out through filtration, washed with water, washed with Et2O and dried in vacuum at 70° C. to obtain the title compound as a pale brown powder. 1H-NMR (400 MHz, DMSO-d6) δ: 8.54-8.51 (1H, br m), 8.43 (1H, d, J=2.2 Hz), 8.25 (1H, dd, J=8.3, 2.2 Hz), 8.03-7.97 (1H, m), 7.88 (1H, d, J=8.3 Hz), 7.51 (1H, s), 7.36-7.27 (2H, m), 4.24-4.14 (2H, br m), 3.4-3.6 (2H, br m), 3.00 (2H, s), 2.31-2.22 (1H, m), 2.10-2.02 (2H, br m), 1.93-1.81 (2H, br m), 1.11-1.04 (4H, m). MS [M+H]+=553.
Reaction SMILES: [Br:1][C:2]1[CH:19]=[CH:18][C:5]2[N:6]3[CH2:17][CH2:16][C:15]4[C:7]3=[C:8]([CH:12]=[CH:13][CH:14]=4)[C:9](=[O:11])[NH:10][C:4]=2[CH:3]=1.[H-].[Na+].O.[CH2:23](Br)[C:24]#[CH:25]>CN(C)C=O>[Br:1][C:2]1[CH:19]=[CH:18][C:5]2[N:6]3[CH2:17][CH2:16][C:15]4[C:7]3=[C:8]([CH:12]=[CH:13][CH:14]=4)[C:9](=[O:11])[N:10]([CH2:25][C:24]#[CH:23])[C:4]=2[CH:3]=1
Reactant: O=C1Nc2cc(Br)ccc2N2CCc3cccc1c32
Reactant: C#CCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: C#CCN1C(=O)c2cccc3c2N(CC3)c2ccc(Br)cc21
Reaction time: 0.5 h

Procedure:
A solution of 9-bromo-1,2-dihydrobenzo[b]pyrrolo[3,2,1-jk][1,4]benzodiazepin-6-one (8.0 gm, 25.4 mmoles) in dimethylformamide (DMF, 120 ml) was stirred with sodium hydride (50% oil suspension, 1.9 gm, 1.6 eq) at ~0° C. (water bath) for 1.5 hours. Propargyl bromide (80% wt in toluene, 7.5 gm, 2 eq) was charged in one portion. The mixture was stirred for 30 minutes. After the starting material was consumed (TLC, dichloromethane), the solution was diluted with dichloromethane, then washed with water (3×500 ml) and brine (2×500 ml). The solution was dried over MgSO4, and concentrated on a rotary evaporator to an oil.
Reaction SMILES: [C:1]([C:4]1(C(OC)=O)[CH2:9][CH2:8][CH:7]([C:10]([O:12][CH3:13])=[O:11])[CH2:6][CH2:5]1)(=[O:3])[CH3:2].Cl.O>CO>[C:1]([CH:4]1[CH2:9][CH2:8][CH:7]([C:10]([O:12][CH3:13])=[O:11])[CH2:6][CH2:5]1)(=[O:3])[CH3:2]
Reactant: COC(=O)C1CCC(C(C)=O)(C(=O)OC)CC1
Agent: Cl
Solvent: O
Solvent: CO
Product: COC(=O)C1CCC(C(C)=O)CC1

Procedure:
Dimethyl 1-acetylcyclohexane-1,4-dicarboxylate (23.3 g.) was added to a solution of concentrated hydrochloric acid (253 ml.) in methanol (126 ml.). After refluxing for 10 hours the reaction mixture was poured into water and then extracted with dichloromethane. The organic phase was then washed with saturated sodium bicarbonate solution and brine. After drying over anhydrous magnesium sulphate the solvent was removed under reduced pressure to give methyl 4-acetylcyclohexanecarboxylate as a colourless oil. This was purified by distillation (b.p. 138°-145°/14 mmHg). Nuclear Magnetic Resonance spectrum (NMR) was as follows: 3.60, 3H, s; 2.6-1.2, 13H, m.
Reaction SMILES: [Na].CO.[ClH:4].[NH2:5][C:6]([NH2:8])=[NH:7].[Cl:9][C:10]([C:12]1[C:20]2[C:15](=[CH:16][C:17]([O:21][CH3:22])=[CH:18][CH:19]=2)[N:14]([C:23]2[C:32]3[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=3)[N:26]=[CH:25][CH:24]=2)[CH:13]=1)=[O:11]>COCCOC>[ClH:9].[ClH:4].[NH:7]([C:10]([C:12]1[C:20]2[C:15](=[CH:16][C:17]([O:21][CH3:22])=[CH:18][CH:19]=2)[N:14]([C:23]2[C:32]3[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=3)[N:26]=[CH:25][CH:24]=2)[CH:13]=1)=[O:11])[C:6]([NH2:8])=[NH:5]
Reactant: COc1ccc2c(C(=O)Cl)cn(-c3ccnc4ccccc34)c2c1
Reactant: N=C(N)N
Agent: Cl
Agent: [Na]
Solvent: CO
Solvent: COCCOC
Product: COc1ccc2c(C(=O)NC(=N)N)cn(-c3ccnc4ccccc34)c2c1
Temperature: 22 °C
Reaction time: 1 h

Procedure:
0.87 g (38 mmol) of sodium is added at a temperature in the region of 22° C. under an argon atmosphere to 60 cm3 of methanol. After complete dissolution, 3.6 g (37.5 mmol) of guanidine hydrochloride are added. After stirring at a temperature in the region of 22° C. for 1 hour, the reaction mixture is concentrated to dryness under reduced pressure (2.7 kPa) to give a residue which is suspended in 60 cm3 of 1,2-dimethoxyethane. 2.4 g (7.13 mmol) of 3-chlorocarbonyl-6-methoxy-1-(quinol-4-yl)-1H-indole are subsequently added at a temperature in the region of 22° C. under an argon atmosphere. After stirring at reflux for 18 hours, the reaction mixture is concentrated to dryness under reduced pressure (2.7 kPa) to give a residue which is triturated in 100 cm3 of water. The suspension is filtered and dried to give a beige-coloured powder which is purified by silica gel chromatography [eluent: dichloromethane/methanol (85/15 by volume)]. After concentrating the fractions under reduced pressure (2.7 kPa), 1.7 g of a beige-coloured foam are obtained, which foam is triturated in 60 cm3 of N hydrochloric acid to provide, after filtration, 1.86 g of 3-guanidinocarbonyl-6-methoxy-1-(quinol-4-yl)-1H-indole dihydrochloride in the form of yellow crystals melting at a temperature of greater than 260° C. Mass spectrum (EI): m/e 359 (M+·), m/e 301. IR spectrum (KBr): 3356, 2587, 1694, 1630, 1595, 1542, 1495, 1441, 1261, 1232, 1192, 823 and 763 cm−1.
Reaction SMILES: [O:1]=[C:2]1[NH:7][C:6]2[CH:8]=[C:9]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[S:10][C:5]=2[C:4](=[O:17])[N:3]1[CH:18]1[CH2:23][CH2:22][N:21]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:20][CH2:19]1.Cl[CH2:32][C:33]1[O:37][N:36]=[C:35]([CH2:38][O:39][CH3:40])[N:34]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.CCOC(C)=O>[CH3:40][O:39][CH2:38][C:35]1[N:34]=[C:33]([CH2:32][N:7]2[C:6]3[CH:8]=[C:9]([C:11]4[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=4)[S:10][C:5]=3[C:4](=[O:17])[N:3]([CH:18]3[CH2:23][CH2:22][N:21]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:20][CH2:19]3)[C:2]2=[O:1])[O:37][N:36]=1
Reactant: COCc1noc(CCl)n1
Reactant: CC(C)(C)OC(=O)N1CCC(n2c(=O)[nH]c3cc(-c4ccccc4)sc3c2=O)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COCc1noc(Cn2c(=O)n(C3CCN(C(=O)OC(C)(C)C)CC3)c(=O)c3sc(-c4ccccc4)cc32)n1

Procedure:
According to GP1 tert-butyl 4-(2,4-dioxo-6-phenyl-1,4-dihydrothieno[3,2-d]pyrimidin-3(2H)-yl)piperidine-1-carboxylate (6.41 g; compound B50) is reacted with 5-(chloromethyl)-3-(methoxymethyl)-1,2,4-oxadiazole (2.44 g; compound D14) in the presence of potassium carbonate (2.07 g) in DMF (45 ml). Using WU1 a solid is obtained which is dissolved in EtOAc (400 ml) at 65° C. The solvent is removed in vacuo to a volume of 40 ml at 40° C. To this solution 20 ml of diethyl ether is added at RT and the resulting suspension is filtered off and the filter cake is washed with little amounts of EtOAc and diethyl ether. The solid is dried in vacuo at 60° C. for 1 h to give the title compound.
Reaction SMILES: O1C2C=CC=CC=2N=C1O[CH2:11][C:12]1[C:13](=[O:22])[N:14]([CH2:18][CH2:19][CH2:20][CH3:21])[CH:15]=[CH:16][CH:17]=1.S(Cl)([Cl:25])=O>C(Cl)Cl>[CH2:18]([N:14]1[CH:15]=[CH:16][CH:17]=[C:12]([CH2:11][Cl:25])[C:13]1=[O:22])[CH2:19][CH2:20][CH3:21]
Reactant: O=S(Cl)Cl
Reactant: CCCCn1cccc(COc2nc3ccccc3o2)c1=O
Solvent: ClCCl
Product: CCCCn1cccc(CCl)c1=O
Reaction time: 1 h

Procedure:
To a solution of 3-(benzoxazol-2-yloxymethyl)-1-butyl-2-pyridone (7-008-03) (169 mg) in methylene chloride (4.0 mL) was added thionyl chloride (122 mg) at room temperature. After stirring for 1 h, the solvent was removed to 1-butyl-3-chloromethyl-2-pyridone (7-008-04) as an oil.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([C:14]([N:16]2[CH2:21][CH2:20][N:19]([S:22]([C:25]3[CH:34]=[CH:33][C:32]4[C:27](=[CH:28][CH:29]=[C:30]([Cl:35])[CH:31]=4)[CH:26]=3)(=[O:24])=[O:23])[CH2:18][CH2:17]2)=[O:15])[CH2:10][CH2:9]1)=O)(C)(C)C>FC(F)(F)C(O)=O>[Cl:35][C:30]1[CH:31]=[C:32]2[C:27](=[CH:28][CH:29]=1)[CH:26]=[C:25]([S:22]([N:19]1[CH2:18][CH2:17][N:16]([C:14]([CH:11]3[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]3)=[O:15])[CH2:21][CH2:20]1)(=[O:23])=[O:24])[CH:34]=[CH:33]2
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)N2CCN(S(=O)(=O)c3ccc4cc(Cl)ccc4c3)CC2)CC1
Solvent: O=C(O)C(F)(F)F
Product: O=C(C1CCNCC1)N1CCN(S(=O)(=O)c2ccc3cc(Cl)ccc3c2)CC1
Reaction time: 1 h
Yield: 89.7 %

Procedure:
1-(t-Butoxycarbonyl)4-(1-(6-chloronaphth-2-ylsulphonyl)piperazin-4-ylcarbonyl)piperidine (28 g) was added in portions with stirring to trifluoroacetic acid (100 ml). The mixture was stirred for one hour. The trifluoroacetic acid was removed by evaporation. Aqueous 2M sodium hydroxide solution (150 ml) was added to the residue and the mixture extracted with dichloromethane (500 ml). The dichloromethane extract was washed with aqueous 2M sodium hydroxide solution (2×50 ml), water (2×100 ml), dried (MgSO4) and evaporated to give a solid which was recrystallised from a mixture of ethyl acetate/hexane to give 4-(1-(6-chloronaphth-2-ylsulphonyl)piperazin-4-ylcarbonyl)piperidine (20.31 g);
Reaction SMILES: [CH:1]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:2]=1[C:3]1[N:13]3[O:14][CH2:15][CH2:16][CH2:17][CH2:18][C:12]3=[N:11][C:4]=1[CH:5]=[N:6]2.ClC1C=C(C=CC=1)C(OO)=[O:24]>ClCCl>[CH:1]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:2]=1[C:3]1[N:13]3[O:14][CH2:15][CH2:16][CH2:17][CH2:18][C:12]3=[N:11][C:4]=1[CH:5]=[N+:6]2[O-:24]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: c1ccc2c(c1)ncc1nc3n(c12)OCCCC3
Solvent: ClCCl
Product: [O-][n+]1cc2nc3n(c2c2ccccc21)OCCCC3
Reaction time: 0.67 h
Yield: 89.6 %

Procedure:
A solution of 8,9,10,11-tetrahydro[1,2]oxazepino[2′,3′:1,2]imidazo[4,5-c]quinoline (0.1449 g, 0.605 mmol) in 6 mL of dichloromethane was treated with 3-chloroperoxybenzoic acid (0.30 g, 57-86% purity). After stirring for 40 minutes, the reaction mixture was diluted with dichloromethane, washed successively with dilute aqueous K2CO3, H2O, and brine, dried over Na2SO4, and concentrated under reduced pressure to give 0.1384 g of 8,9,10,11-tetrahydro[1,2]oxazepino[2′,3′:1,2]imidazo[4,5-c]quinoline 5-oxide as a tan solid.
Reaction SMILES: [C:1]1([CH:8]=[CH:7][C:5]([OH:6])=[CH:4][CH:3]=1)[OH:2].[CH3:9][C:10](O)([CH2:13][CH2:14][CH2:15][CH:16]([CH3:18])[CH3:17])[CH2:11][CH3:12].S(=O)(=O)(O)O>CO>[CH2:11]([C:10]([C:3]1[CH:4]=[C:5]([OH:6])[C:7]([C:10]([CH3:9])([CH2:11][CH3:12])[CH2:13][CH2:14][CH2:15][CH:16]([CH3:18])[CH3:17])=[CH:8][C:1]=1[OH:2])([CH3:9])[CH2:13][CH2:14][CH2:15][CH:16]([CH3:18])[CH3:17])[CH3:12]
Reactant: Oc1ccc(O)cc1
Reactant: CCC(C)(O)CCCC(C)C
Agent: O=S(=O)(O)O
Solvent: CO
Product: CCC(C)(CCCC(C)C)c1cc(O)c(C(C)(CC)CCCC(C)C)cc1O
Temperature: 0 °C
Yield: 33.8 %

Procedure:
55 g of hydroquinone and 71.5 g of 3,7-dimethyloctan-3-ol were dissolved in 100 ml of methanol. Then, 50 ml of concentrated sulfuric acid (36 N) was added dropwise thereto under stirring and cooling so as to maintain the temperature at 40° C. or less. Subsequently, the reaction mixture was maintained at 50° to 55° C. for 4 hours. The resulting reaction mixture was added to ice-water, and extracted with 500 ml benzene. The benzene layer was washed with water and, after drying over anhydrous sodium sulfate, benzene and unreacted 3,7-dimethyloctan-3-ol were distilled off under reduced pressure. The residual oil was chromatographed on silica gel using benzene as a developing solvent. Thus, 29.8 g of 2,5-bis(1-ethyl-1,5-dimethylhexyl)hydroquinone (the same compound as obtained in Synthesis Example 1) was first eluted, and then 15.1 g of 2-(1-ethyl-1,5-dimethylhexyl)hydroquinone was eluted.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([NH:21][C:22]2[CH:27]=[C:26]([CH3:28])[C:25](=[O:29])[N:24]([CH3:30])[CH:23]=2)[C:9]2[N:10]([CH:18]3[CH2:20][CH2:19]3)[CH:11]=[CH:12][C:13]=2[C:14]([O:16]C)=[O:15])=[CH:4][CH:3]=1.[OH-].[Na+]>C1COCC1.CO>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]([NH:21][C:22]2[CH:27]=[C:26]([CH3:28])[C:25](=[O:29])[N:24]([CH3:30])[CH:23]=2)[C:9]2[N:10]([CH:18]3[CH2:19][CH2:20]3)[CH:11]=[CH:12][C:13]=2[C:14]([OH:16])=[O:15])=[CH:6][CH:7]=1
Reactant: COC(=O)c1ccn(C2CC2)c1C(Nc1cc(C)c(=O)n(C)c1)c1ccc(Cl)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: Cc1cc(NC(c2ccc(Cl)cc2)c2c(C(=O)O)ccn2C2CC2)cn(C)c1=O
Temperature: 70 °C
Reaction time: 2 h
Yield: 93.9 %

Procedure:
A mixture of methyl 2-((4-chlorophenyl)((1,5-dimethyl-6-oxo-1,6-dihydropyridin-3-yl)amino)methyl)-1-cyclopropyl-1H-pyrrole-3-carboxylate (Step 240.4) (2.2 g, 5.17 mmol) and 2M NaOH (20.7 mL, 41.3 mmol) in THF (20 mL) and MeOH (20 mL) was stirred at 70° C. for 2 hr and concentrated. The aqueous residue was acidified with 2N HCl to pH 5, and extracted twice with EtOAc. The combined organic extracts were washed with brine, dried (Na2SO4), and concentrated to afford the title compound (2 g, 89% yield) as a red foam. tR: 0.94 min (LC-MS 6); ESI-MS: 412.2 [M+H]+ (LC-MS 6).
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[C:7]([OH:10])[CH:8]=[CH:9][C:4]=2[CH:3]=[CH:2]1.[Cl:11][C:12]1[CH:13]=[C:14]([C:19]([F:22])([F:21])[F:20])[CH:15]=[CH:16][C:17]=1F.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C.C(OCC)(=O)C>[Cl:11][C:12]1[CH:13]=[C:14]([C:19]([F:20])([F:21])[F:22])[CH:15]=[CH:16][C:17]=1[O:10][C:7]1[CH:8]=[CH:9][C:4]2[CH:3]=[CH:2][O:1][C:5]=2[CH:6]=1
Reactant: Oc1ccc2ccoc2c1
Reactant: Fc1ccc(C(F)(F)F)cc1Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: FC(F)(F)c1ccc(Oc2ccc3ccoc3c2)c(Cl)c1
Temperature: 80 °C

Procedure:
To a stirred solution of 1-benzofuran-6-ol (418.5 mg, 3.1 mmol) in 6 ml of DMF was added 3-Chloro-4-fluorobenzotrifluoride (681.4 mg, 3.4 mmol) and cesium carbonate (1.5 g, 4.7 mmol). The reaction mixture was heated at 80° C. for 2 hours. After cooling to room temperature, it was diluted with ethyl acetate, washed with water (2×) and brine, dried over magnesium sulfate, filtered and concentrated. The crude product was purified on a silica gel column, eluting with ethyl acetate (0-30%) in hexane. The final product was collected as colorless oil. 1H NMR (CDCl3, δ ppm): 6.8 (s, 1H), 7.0 (two d, 2H), 7.2 (s, 1H), 7.4 (d, 1H), 7.6 (d, 1H), 7.7 (s, 1H), 7.8 (s, 1H).
Reaction SMILES: [CH3:1][N:2]([CH2:19][CH:20]([O:23][CH3:24])[O:21][CH3:22])[C:3]1[C:8]([N+:9]([O-:11])=[O:10])=[CH:7][C:6]([C:12]([F:15])([F:14])[F:13])=[CH:5][C:4]=1[N+:16]([O-:18])=[O:17].C(O)CO.C1(C)C=CC(S(O)(=O)=O)=CC=1>C(OCC)(=O)C>[CH3:1][N:2]([CH2:19][CH:20]1[O:23][CH2:24][CH2:22][O:21]1)[C:3]1[C:8]([N+:9]([O-:11])=[O:10])=[CH:7][C:6]([C:12]([F:14])([F:15])[F:13])=[CH:5][C:4]=1[N+:16]([O-:18])=[O:17]
Reactant: COC(CN(C)c1c([N+](=O)[O-])cc(C(F)(F)F)cc1[N+](=O)[O-])OC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: OCCO
Solvent: CCOC(C)=O
Product: CN(CC1OCCO1)c1c([N+](=O)[O-])cc(C(F)(F)F)cc1[N+](=O)[O-]
Temperature: 120 °C
Reaction time: 1 h

Procedure:
N-Methyl-N-(2,2-dimethoxyethyl)-2,6-dinitro-4-trifluoromethylaniline (3.2 grams; 0.0915 mole), ethylene glycol 0.57 grams; 0.0915 mole), para-toluenesulfonic acid (200 mg) and ethyl acetate were charged into a glass reaction vessel equipped with a stirrer, heating mantle, reflux condenser and thermometer. The reaction mixture was heated at 120° C. with stirring for one hour. After this time the mixture was cooled to room temperature and washed with aqueous sodium bicarbonate. The washed solution was dried over anhydrous sodium sulfate, filtered and stripped of solvent leaving a solid residue. The residue was recrystallized from hexane to yield the desired N-methyl-N-1,3-dioxolan-2-ylmethyl-2,6-dinitro-4-trifluoromethylaniline as a yellow crystalline solid melting at 83° C.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=O)[CH2:9][S:10]([CH3:12])=[O:11].[NH3:14]>>[NH:14]=[C:8]([C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[OH:1])[CH2:9][S:10]([CH3:12])=[O:11]
Reactant: CS(=O)CC(=O)c1ccccc1O
Reactant: N
Product: CS(=O)CC(=N)c1ccccc1O
Yield: 79 %

Procedure:
A solution of 2'-hydroxy-2-(methylsulfinyl)acetophenone (23.5 g, 0.12 mole) in liquid ammonia (450 ml) was stirred at -33° for 9 hrs. The ammonia was allowed to evaporate. The residue was recrystallized from methanol to give yellow crystals (18.5 g, 79%), mp 194°-195°.
Reaction SMILES: C[O:2][C:3](=O)[CH2:4][C:5]1[N:9]2[CH:10]=[C:11]([CH3:14])[CH:12]=[CH:13][C:8]2=[N:7][C:6]=1[C:15]1[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=1.[S:23]1[C:27](C(Cl)=O)=[CH:26][C:25]2[CH:31]=[CH:32][CH:33]=[CH:34][C:24]1=2>>[S:23]1[C:27]([C:3](=[O:2])[CH2:4][C:5]2[N:9]3[CH:10]=[C:11]([CH3:14])[CH:12]=[CH:13][C:8]3=[N:7][C:6]=2[C:15]2[CH:16]=[CH:17][C:18]([CH3:21])=[CH:19][CH:20]=2)=[CH:26][C:25]2[CH:31]=[CH:32][CH:33]=[CH:34][C:24]1=2
Reactant: O=C(Cl)c1cc2ccccc2s1
Reactant: COC(=O)Cc1c(-c2ccc(C)cc2)nc2ccc(C)cn12
Product: Cc1ccc(-c2nc3ccc(C)cn3c2CC(=O)c2cc3ccccc3s2)cc1

Procedure:
Prepared from (6-methyl-2-p-tolyl-imidazo[1,2-a]pyridin-3-yl)-acetic acid methyl ester 35a and benzo[b]thiophene-2-carbonyl chloride using the procedure of Method C described above. 1H NMR (400 MHz, CDCl3) 2.31 (s, 3H), 2.42 (s, 3H), 4.68 (s, 2H), 7.04 (d, J=9.1 Hz, 1H), 7.29 (d, J=7.7 Hz, 2H), 7.37 (t, J=7.7 Hz, 1H), 7.44 (5.8 Hz, 1H), 7.56 (m, 3H), 7.70 (m, 2H), 7.83 (m, 2H). Mass spectrum (m/e) 397 (M+).
Reaction SMILES: Cl.[NH:2]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][C:11]([N:13]([CH3:15])[CH3:14])=[O:12])=[CH:6][CH:5]=1)N.[O:16]=[C:17]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[C:19](=[O:26])[N:18]1[CH2:27][CH2:28][CH2:29][CH:30]=O.C(OCC)(=O)C>C(O)(=O)C>[O:16]=[C:17]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[C:19](=[O:26])[N:18]1[CH2:27][CH2:28][C:29]1[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([CH2:10][C:11]([N:13]([CH3:15])[CH3:14])=[O:12])[CH:8]=2)[NH:2][CH:30]=1
Reactant: O=CCCCN1C(=O)c2ccccc2C1=O
Reactant: CN(C)C(=O)Cc1ccc(NN)cc1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: CN(C)C(=O)Cc1ccc2[nH]cc(CCN3C(=O)c4ccccc4C3=O)c2c1

Procedure:
A mixture of 2-(4-hydrazinophenyl)-N,N-dimethylacetamide hydrochloride (0.875 g, contains 0.00315 mol) and 4-(1,3-dihydro-1,3-dioxo-2H-isoindol-2-yl)butanal, diethyl acetal (0.873 g) was heated under reflux in 25% aqueous acetic acid (100 ml) for 30 min. The mixture was poured into ethyl acetate (150 ml) and the aqueous phase was separated. This was washed with ethyl acetate (150 ml) and the organic extracts were combined. The yellow solution was washed successively with water (150 ml) 8% sodium bicarbonate solution (150 ml) and finally water (150 ml). Evaporation of the dried (Na2SO4) solvent gave a yellow solid which crystallised from propan-2-ol to give the title compound as a pale yellow powder (0.91 g) m.p. 193°-4° C.