Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:12]([C:22]3[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][CH:23]=3)([C:14]3[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=3)[OH:13])[CH:10]=2)[N:5]=[C:4]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])[CH:3]=1.[CH:34](/B(O)O)=[CH:35]\[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1.COC1C=CC=C(OC)C=1C1C=CC=CC=1P(C1CCCCC1)C1CCCCC1.[O-]P([O-])([O-])=O.[K+].[K+].[K+].O>C1COCC1.C(Cl)Cl.O.CC([O-])=O.CC([O-])=O.[Pd+2]>[C:30]([O:29][C:4]1[CH:3]=[C:2](/[CH:34]=[CH:35]/[C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:12]([C:22]3[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][CH:23]=3)([C:14]3[CH:15]=[CH:16][C:17]([O:20][CH3:21])=[CH:18][CH:19]=3)[OH:13])[CH:10]=2)[N:5]=1)([CH3:31])([CH3:33])[CH3:32]
Reactant: COc1ccc(C(O)(c2ccc(Cl)cc2)c2ccc3nc(OC(C)(C)C)cc(Br)c3c2)cc1
Reactant: OB(O)/C=C/c1ccccc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: COc1cccc(OC)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Solvent: C1CCOC1
Solvent: ClCCl
Solvent: O
Product: COc1ccc(C(O)(c2ccc(Cl)cc2)c2ccc3nc(OC(C)(C)C)cc(/C=C/c4ccccc4)c3c2)cc1
Temperature: 35 °C

Procedure:
A mixture of (4-bromo-2-(tert-butoxy)quinolin-6-yl)(4-chlorophenyl)(4-methoxyphenyl)methanol (107 mg, 0.203 mmol), (E)-styrylboronic acid (60 mg, 0.406 mmol), Pd(OAc)2 (4.56 mg, 0.0203 mmol), SPhos (16.7 mg, 0.0406 mmol) and K3PO4.H2O (86.2 mg, 0.406 mmol) in anhydrous THF (1 mL) was heated at 35° C. overnight. The reaction was diluted with DCM and water. The organics were washed with water and concentrated. The crude material was purified by silica column (40-55% EtOAc/hexanes) to yield (E)-(2-(tert-butoxy)-4-styrylquinolin-6-yl)(4-chlorophenyl)(4-methoxyphenyl)methanol.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]2[O:9][CH:10]=[CH:11][CH:12]=2)[C:5]([C:13]#[N:14])=[C:4](S(C)=O)[N:3]=1.[F:18][C:19]([F:29])([F:28])[C:20]1[CH:21]=[CH:22][C:23]([CH2:26][NH2:27])=[N:24][CH:25]=1>COCCOC>[NH2:1][C:2]1[N:7]=[C:6]([C:8]2[O:9][CH:10]=[CH:11][CH:12]=2)[C:5]([C:13]#[N:14])=[C:4]([NH:27][CH2:26][C:23]2[CH:22]=[CH:21][C:20]([C:19]([F:29])([F:18])[F:28])=[CH:25][N:24]=2)[N:3]=1
Reactant: NCc1ccc(C(F)(F)F)cn1
Reactant: CS(=O)c1nc(N)nc(-c2ccco2)c1C#N
Solvent: COCCOC
Product: N#Cc1c(NCc2ccc(C(F)(F)F)cn2)nc(N)nc1-c1ccco1

Procedure:
From 2-amino-4-furan-2-yl-6-methanesulfinyl-pyrimidine-5-carbonitrile and C-(5-trifluoromethyl-pyridin-2-yl)-methylamine in DME. ES-MS m/e (%): 361 (M+H+, 100).
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]([C:10]2[C:15]([O:16][CH3:17])=[CH:14][CH:13]=[C:12]([F:18])[C:11]=2[F:19])=[O:9])=[CH:6][N:5]=[C:4]([NH:20][CH:21]2[CH2:26][CH2:25][N:24]([S:27]([CH2:30][CH2:31][CH2:32]Cl)(=[O:29])=[O:28])[CH2:23][CH2:22]2)[N:3]=1.[NH:34]1[CH2:39][CH2:38][O:37][CH2:36][CH2:35]1>>[NH2:1][C:2]1[C:7]([C:8]([C:10]2[C:15]([O:16][CH3:17])=[CH:14][CH:13]=[C:12]([F:18])[C:11]=2[F:19])=[O:9])=[CH:6][N:5]=[C:4]([NH:20][CH:21]2[CH2:26][CH2:25][N:24]([S:27]([CH2:30][CH2:31][CH2:32][N:34]3[CH2:39][CH2:38][O:37][CH2:36][CH2:35]3)(=[O:29])=[O:28])[CH2:23][CH2:22]2)[N:3]=1
Reactant: COc1ccc(F)c(F)c1C(=O)c1cnc(NC2CCN(S(=O)(=O)CCCCl)CC2)nc1N
Reactant: C1COCCN1
Product: COc1ccc(F)c(F)c1C(=O)c1cnc(NC2CCN(S(=O)(=O)CCCN3CCOCC3)CC2)nc1N

Procedure:
The compound was prepared from [4-amino-2-[1-(3-chloro-propane-1-sulfonyl)-piperidin-4-ylamino]-pyrimidin-5-yl]-(2,3-difluoro-6-methoxy-phenyl)-methanone (Example 226) and morpholine (Aldrich) in an analogous manner as described in Example 227. HR-MS (ES, m/z) calculated for C24H33N6O5SF2 [(M+H)+] 555.2196, observed 555.2199.
Reaction SMILES: [CH2:1]([O:8][C:9](Cl)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:12][CH2:13][C@@H:14]([C@H:16]([C@@H:18]([C@@H:20]([CH2:22][OH:23])[OH:21])[OH:19])[OH:17])[OH:15].[OH-].[Na+]>O>[CH2:1]([O:8][C:9]([NH:12][CH2:13][C@@H:14]([C@H:16]([C@@H:18]([C@@H:20]([CH2:22][OH:23])[OH:21])[OH:19])[OH:17])[OH:15])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Reactant: O=C(Cl)OCc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=C(NC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO)OCc1ccccc1

Procedure:
Benzyloxycarbonyl chloride was added dropwise to 3.7 kg of 1-amino-1-desoxy-D-glucitol (about 70% pure) in 7 liters of H2O, whilst stirring vigorously, and the pH was kept at 8-9 with 2 N sodium hydroxide solution. The batch was allowed to warm to 40°-50° C. during this operation. The batch was then further stirred overnight at room temperature and the precipitate was filtered off, washed with acetone and recrystallised from water.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]([N:10]2[CH2:15][CH2:14][N:13]([C:16]3[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][C:17]=3[CH3:23])[CH2:12][CH2:11]2)=[O:9])=[C:4]([S:24]([CH3:27])(=[O:26])=[O:25])[CH:3]=1.[OH:28][CH2:29][CH:30]1[NH:34][C:33](=[O:35])[CH2:32][CH2:31]1>>[CH3:23][C:17]1[CH:18]=[C:19]([CH3:22])[CH:20]=[CH:21][C:16]=1[N:13]1[CH2:14][CH2:15][N:10]([C:8]([C:5]2[CH:6]=[CH:7][C:2]([N:34]3[C@H:30]([CH2:29][OH:28])[CH2:31][CH2:32][C:33]3=[O:35])=[CH:3][C:4]=2[S:24]([CH3:27])(=[O:26])=[O:25])=[O:9])[CH2:11][CH2:12]1
Reactant: Cc1ccc(N2CCN(C(=O)c3ccc(Br)cc3S(C)(=O)=O)CC2)c(C)c1
Reactant: O=C1CCC(CO)N1
Product: Cc1ccc(N2CCN(C(=O)c3ccc(N4C(=O)CC[C@H]4CO)cc3S(C)(=O)=O)CC2)c(C)c1
Yield: 50.1 %

Procedure:
Using (4-bromo-2-methanesulfonylphenyl)[4-(2,4-dimethylphenyl)piperazin-1-yl]methanone (903 mg) described in Preparation Example 110 and 5-hydroxymethylpyrrolidin-2-one (230 mg) and by the reaction and treatment in the same manner as in Example 1, the title compound (486 mg) was obtained.
Reaction SMILES: [Na].[CH3:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]([C:15]([O:17]CC)=O)[C:10]([O:12]CC)=O)=[CH:5][CH:4]=1.[NH2:20][C:21]([NH2:23])=[O:22]>C(O)C>[CH3:2][C:3]1[CH:4]=[CH:5][C:6]([CH:9]2[C:10](=[O:12])[NH:23][C:21](=[O:22])[NH:20][C:15]2=[O:17])=[CH:7][CH:8]=1
Reactant: CCOC(=O)C(C(=O)OCC)c1ccc(C)cc1
Reactant: NC(N)=O
Agent: [Na]
Solvent: CCO
Product: Cc1ccc(C2C(=O)NC(=O)NC2=O)cc1

Procedure:
To a solution of sodium (184 mg) in 12 ml of ethanol are added 0.95 ml of diethyl 2-(4-methylphenyl)malonate and 360 mg of urea, then the mixture is refluxed for 3 hours. A white solid separates, which is filtered and redissolved in 4 ml of water. The solution is acidified to pH=1-2 by adding 6 N hydrochloric acid, A white solid separates, which is collected by filtration, washed with 15 ml of water and dried under vacuum. 619 mg of the product are obtained. m.p. 271° C.
Reaction SMILES: O=C1[CH:6]([C:7](=[O:17])[C:8]([F:16])([F:15])[CH2:9][CH2:10][C:11]([CH3:14])([CH3:13])[CH3:12])[CH2:5][CH2:4][O:3]1>Cl.C(O)(=O)C>[OH:3][CH2:4][CH2:5][CH2:6][C:7](=[O:17])[C:8]([F:16])([F:15])[CH2:9][CH2:10][C:11]([CH3:12])([CH3:13])[CH3:14]
Reactant: CC(C)(C)CCC(F)(F)C(=O)C1CCOC1=O
Agent: Cl
Solvent: CC(=O)O
Product: CC(C)(C)CCC(F)(F)C(=O)CCCO

Procedure:
A 10 mL one neck round bottom flask, fitted with argon inlet, magnetic stirrer, and reflux condenser was charged with 1.0 mL glacial acetic acid, 4 drops of concentrated HCl and 200 mg (0.81 mM) of 2,3,4,5-tetrahydro-2-oxo-3-(5,5-dimethyl-2,2-difluoro-1-oxohexyl)furan. The reaction mixture was heated at 110 C. overnight under a blanket of argon. The reaction was extracted with ethyl ether, and the ether was cross washed with water, dried (anhydrous MgSO4), and solvent removed under reduced pressure. The residue was chromatographed on a 10×60 mm silica gel column using a 9:1 hexane:ethyl acetate mixture to give a clear oil. nmr(CDCl3)--α0.95(s, 9H), 1.45(t, 2H), 2.00(m, 6H), 3.12(bs, 1H), 4.15(m, 1H)
Reaction SMILES: Cl[CH2:2][C:3]1[CH:4]=[C:5]([C:9]2[C:14]([F:15])=[CH:13][CH:12]=[C:11]([CH2:16][NH:17][C:18]([C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([C:26]([NH:28][CH2:29][C:30]4[C:31]([NH:43][CH:44]5[CH2:49][CH2:48][O:47][CH2:46][CH2:45]5)=[C:32]5[CH:40]=[N:39][N:38]([CH2:41][CH3:42])[C:33]5=[N:34][C:35]=4[CH2:36][CH3:37])=[O:27])[CH:21]=3)=[O:19])[CH:10]=2)[CH:6]=[CH:7][CH:8]=1.[CH2:50]([N:52]1[CH2:57][CH2:56][NH:55][CH2:54][CH2:53]1)[CH3:51]>C1COCC1>[CH2:41]([N:38]1[C:33]2=[N:34][C:35]([CH2:36][CH3:37])=[C:30]([CH2:29][NH:28][C:26]([C:22]3[CH:23]=[CH:24][CH:25]=[C:20]([C:18]([NH:17][CH2:16][C:11]4[CH:10]=[C:9]([C:5]5[CH:6]=[CH:7][CH:8]=[C:3]([CH2:2][N:55]6[CH2:56][CH2:57][N:52]([CH2:50][CH3:51])[CH2:53][CH2:54]6)[CH:4]=5)[C:14]([F:15])=[CH:13][CH:12]=4)=[O:19])[CH:21]=3)=[O:27])[C:31]([NH:43][CH:44]3[CH2:49][CH2:48][O:47][CH2:46][CH2:45]3)=[C:32]2[CH:40]=[N:39]1)[CH3:42]
Reactant: CCN1CCNCC1
Reactant: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC(=O)c1cccc(C(=O)NCc2ccc(F)c(-c3cccc(CCl)c3)c2)c1
Solvent: C1CCOC1
Product: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC(=O)c1cccc(C(=O)NCc2ccc(F)c(-c3cccc(CN4CCN(CC)CC4)c3)c2)c1

Procedure:
N-{[3′-(Chloromethyl)-6-fluoro-3-biphenylyl]methyl}-N′-{[1,6-diethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-5-yl]methyl}-1,3-benzenedicarboxamide (0.034 g, 0.05 mmol) and 1-ethylpiperazine (0.0285 g, 0.25 mmol) were combined in THF (1 mL) and microwaved at 150° C. for 1 h. The mixture was purified using a Gilson HPLC with a TFA system followed by passing the product though a quaternary ammonium hydroxide cartridge to give the free base, the title compound, as a tan solid. LC-MS m/z 760.8 (M+H)+, 1.55 min (ret time); mp 155-158° C. Analytical HPLC shows 95.7% purity, (ret time 10.098 min).
Reaction SMILES: Cl.[CH:2]([C@H:15]1[C@@H:20]([O:21][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([O:29][C:30]([F:33])([F:32])[F:31])[CH:24]=2)[CH2:19][CH2:18][NH:17][CH2:16]1)([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[C:34](O)(=[O:37])[CH2:35][CH3:36]>>[CH:2]([C@H:15]1[C@@H:20]([O:21][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([O:29][C:30]([F:33])([F:31])[F:32])[CH:24]=2)[CH2:19][CH2:18][N:17]([C:34](=[O:37])[CH2:35][CH3:36])[CH2:16]1)([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: CCC(=O)O
Reactant: FC(F)(F)Oc1cccc(CO[C@H]2CCNC[C@H]2C(c2ccccc2)c2ccccc2)c1
Agent: Cl
Product: CCC(=O)N1CC[C@H](OCc2cccc(OC(F)(F)F)c2)[C@H](C(c2ccccc2)c2ccccc2)C1

Procedure:
The compound (27.7 mg) obtained in Example 27 and propionic acid (9.0 μl) were reacted and treated in the same manner as in the method described in Example 33 to obtain the title compound.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH2:4]O.[P:10]([O:17]CC)([O:14][CH2:15][CH3:16])[O:11][CH2:12][CH3:13]>CC1C=CC=CC=1C>[OH:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH2:4][P:10](=[O:17])([O:14][CH2:15][CH3:16])[O:11][CH2:12][CH3:13]
Reactant: CCOP(OCC)OCC
Reactant: OCc1ccccc1O
Solvent: Cc1ccccc1C
Product: CCOP(=O)(Cc1ccccc1O)OCC
Reaction time: 1 h
Yield: 90 %

Procedure:
38.4 g of 2-hydroxybenzylalcohol from TOKYO KASEI KOGYO Co., Ltd. and 80 ml of o-xylene were put in a reaction reservoir having a mixer, a thermometer and a dropping funnel. Under a nitrogen stream, 62.8 g of triethyl phosphite were slowly dropped therein at 80° C., and the reaction therein is further performed for 1 hr at the same temperature. Then, the produced ethanol, o-xylene and unreacted triethyl phosphite were removed from the reaction by reduced-pressure distillation to prepare 66 g of 2-diethylhydroxybenzylphosphonate at a yield of 90%, having a boiling point of 120.0° C./1.5 mm Hg.
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][CH:8]=[CH:7]2.[CH3:13][CH:14]1[CH2:16][O:15]1.O>O1CCCC1.CCOCC>[CH3:3][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[N:9]([CH2:13][CH:14]([OH:15])[CH3:16])[CH:8]=[CH:7]2
Reactant: Cc1ccc2[nH]ccc2c1
Reactant: CC1CO1
Agent: [H-]
Agent: [Na+]
Solvent: CCOCC
Solvent: O
Solvent: C1CCOC1
Product: Cc1ccc2c(ccn2CC(C)O)c1
Reaction time: 1 h
Yield: 62.7 %

Procedure:
A suspension of 0.26 g of sodium hydride dispersion in 35 ml of tetrahydrofuran was treated with 0.95 g of 5-methylindole at 0° and stirred at this temperature for 1 hour. After the addition of 1 ml of (RS)-methyloxirane the reaction mixture was stirred at room temperature for 48 hours and subsequently treated with water. The mixture was diluted with ether, washed with water and with saturated sodium chloride solution and the organic phase was dried over sodium sulfate. After removal of the solvent the residue was chromatographed over 30 g of silica gel with toluene-ethyl acetate (19:1). There was obtained 0.86 g (62.7%) of (RS)-1-(5-methyl-indol-1-yl)-propan-2-ol as a yellow oil.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]([O:11][CH3:12])=[O:10].[N:13]([O:15][C:16](C)(C)C)=O.[K].CI>C(O)(C)(C)C.C(O)(C)C.O>[CH3:16][O:15][N:13]=[C:8]([C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[CH3:1])[C:9]([O:11][CH3:12])=[O:10]
Reactant: CC(C)(C)ON=O
Reactant: COC(=O)Cc1ccccc1C
Agent: [K]
Solvent: CI
Solvent: O
Solvent: CC(C)O
Product: CON=C(C(=O)OC)c1ccccc1C
Temperature: 70 °C

Procedure:
A mixture of 200 g (1.22 mol) of methyl 2-methylphenylacetate and 377 g (3.66 mol) of tert.-butyl nitrite in 400 ml of tert.-butanol is added rapidly to 150 g (1.34 mol) of potassium tert.-butylate in 1500 ml of anhydrous tert.-butanol, the reaction temperature increasing to 70° C. After a few minutes, the potassium salt which forms begins to precipitate, and the reaction solution becomes difficult to stir. The mixture is stirred for a further one hour, and 261 g (1.84 mol) of methyl iodide are added in one portion. The potassium salt slowly dissolves, and microcrystalline potassium iodide precipitates. The mixture is stirred at room temperature overnight and evaporated, the residue is taken up in methyl tert.-butyl ether/H2O, and the solution is washed several times with H2O, dried over sodium sulfate and re-evaporated. The residue obtained is dissolved in warm isopropanol. H2O is added until the turbidity has just disappeared, and the product is then allowed to crystallize out at 0° C. 114 g (45%, m.p. =65°-66° C.) of product are obtained.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[NH:9][S:10]([CH:13]1[C:18]([C:19]([O:21][CH2:22][C:23]([O:25]C(C)(C)C)=[O:24])=[O:20])=[CH:17][CH2:16][CH2:15][CH2:14]1)(=[O:12])=[O:11].Cl>C(OCC)(=O)C>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[NH:9][S:10]([CH:13]1[C:18]([C:19]([O:21][CH2:22][C:23]([OH:25])=[O:24])=[O:20])=[CH:17][CH2:16][CH2:15][CH2:14]1)(=[O:12])=[O:11]
Reactant: CC(C)(C)OC(=O)COC(=O)C1=CCCCC1S(=O)(=O)Nc1ccc(F)cc1F
Agent: Cl
Solvent: CCOC(C)=O
Product: O=C(O)COC(=O)C1=CCCCC1S(=O)(=O)Nc1ccc(F)cc1F
Temperature: 25 °C
Reaction time: 70 h
Yield: 35.9 %

Procedure:
To a solution of t-butyl [6-[N-(2,4-difluorophenyl)sulfamoyl]-1-cyclohexen-1-yl]carbonyloxyacetate (Compound 59, 80 mg) obtained in Example 56 in ethyl acetate (4 ml), a 4N solution of hydrogen chloride in ethyl acetate (5 ml) was added with ice-cooling and the mixture was stirred at room temperature for 70 hours. The reaction mixture was evaporated under reduced pressure to dryness and the residue was purified by ODS column chromatography (eluent: methanol/water=3/2) to yield [6-[N-(2,4-difluorophenyl)sulfamoyl]-1-cyclohexen-1-yl]carbonyloxyacetic acid (Compound 60, 25 mg) as white powdery crystals.
Reaction SMILES: C([N:3](CC)CC)C.CS(Cl)(=O)=O.[CH2:13]([O:20][CH2:21][CH2:22][O:23][CH2:24][CH2:25][O:26][CH2:27][CH2:28][O:29][CH2:30][CH2:31][O:32][CH2:33][CH2:34][O:35][CH2:36][CH2:37][OH:38])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>C(Cl)Cl>[CH2:13]([O:20][CH:21]([NH2:3])[CH2:22][O:23][CH2:24][CH2:25][O:26][CH2:27][CH2:28][O:29][CH2:30][CH2:31][O:32][CH2:33][CH2:34][O:35][CH2:36][CH2:37][OH:38])[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: OCCOCCOCCOCCOCCOCCOCc1ccccc1
Reactant: CCN(CC)CC
Agent: CS(=O)(=O)Cl
Solvent: ClCCl
Product: NC(COCCOCCOCCOCCOCCO)OCc1ccccc1
Reaction time: 0.5 h
Yield: 54.8 %

Procedure:
Triethylamine (1.45 mL, 10.74 mmol) and methanesulfonyl chloride (0.48 mL, 5.9 mmol) were added to a solution of hexaethyleneglycol monobenzyl ether (2.0 g, 5.37 mmol) in methylene chloride (30 mL) at 0° C. and the solution was stirred for 30 min at ice bath temperature. The reaction mixture was filtered and concentrated to an oil which was dissolved in 30% ammonium hydroxide solution (50 mL). The reaction mixture was heated at reflux for 3 days and concentrated. Residual water was removed by evaporation from toluene and the crude material was slurried with THF and filtered. The filtrate was concentrated at reduced pressure to provide the title compound as an amber oil (1.14 g, 57% yield). 1H-NMR (300 MHz DMSO-d6) δ: 7.77 (br s, 2H), 7.40-7.10 (m, 5H), 4.48 (s, 2H), 3.61-3.48 (m, 24H).
Reaction SMILES: [CH2:1]([N:3]([CH2:6][C:7]1[N:12]=[C:11]2[S:13][C:14]3[CH2:15][NH:16][CH2:17][CH2:18][C:19]=3[C:10]2=[C:9]([C:20]2[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[C:22]([O:28][CH3:29])[CH:21]=2)[C:8]=1[C:30]([O:32][CH2:33][CH3:34])=[O:31])[CH2:4][CH3:5])[CH3:2].[C:35](Cl)(=[O:37])[CH3:36].C(N(CC)CC)C.O1CCCC1>O>[C:35]([N:16]1[CH2:17][CH2:18][C:19]2[C:10]3[C:11]([S:13][C:14]=2[CH2:15]1)=[N:12][C:7]([CH2:6][N:3]([CH2:1][CH3:2])[CH2:4][CH3:5])=[C:8]([C:30]([O:32][CH2:33][CH3:34])=[O:31])[C:9]=3[C:20]1[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[C:22]([O:28][CH3:29])[CH:21]=1)(=[O:37])[CH3:36]
Reactant: CCOC(=O)c1c(CN(CC)CC)nc2sc3c(c2c1-c1ccc(OC)c(OC)c1)CCNC3
Reactant: CC(=O)Cl
Solvent: O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCOC(=O)c1c(CN(CC)CC)nc2sc3c(c2c1-c1ccc(OC)c(OC)c1)CCN(C(C)=O)C3
Reaction time: 3 h
Yield: 51.1 %

Procedure:
A mixture of the compound obtained in Example 5A (2.00 g), acetyl chloride (0.19 g), triethylamine (0.37 ml) and tetrahydrofuran (10 ml) was stirred under ice cooling conditions for 3 hours. The reaction mixture was poured over water and extracted with ethyl acetate. The ethyl acetate layer was washed with water and dried (MgSO4), after which the solvent was distilled off. The residue was subjected to silica gel column chromatography and eluted with chloroform-methanol (100:1, v/v) to yield ethyl 7-acetyl-2-(N,N-diethylaminomethyl)-4-(3,4-dimethoxyphenyl)-5,6,7,8-tetrahydrothieno[2,3-b:5,4-c']dipyridine-3-carboxylate (for structural formula, see below) (0.65 g, 60%) as an amorphous solid having a melting point of 72 to 75° C.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:6]([C:7]([NH2:9])=[O:8])[C:5]([NH2:11])=[CH:4][CH:3]=1.[C:12](Cl)(Cl)=[O:13]>O1CCCC1>[Cl:1][C:2]1[CH:10]=[C:6]2[C:5](=[CH:4][CH:3]=1)[NH:11][C:12](=[O:13])[NH:9][C:7]2=[O:8]
Reactant: NC(=O)c1cc(Cl)ccc1N
Reactant: O=C(Cl)Cl
Solvent: C1CCOC1
Product: O=c1[nH]c(=O)c2cc(Cl)ccc2[nH]1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of 5-chloroanthranilamide (3.4 g)in tetrahydrofuran (50 mL) was added phosgene (16 mL, 1.93M solution in toluene) via an addition funnel. The reaction mixture was stirred at room temperature for 4 hours and then heated to reflux for another two hours. The reaction mixture was concentrated to a total volume about 10 mL. After cooling, the title compound (3.72 g) having the following physical data, was collected by filtration and dried in vacuum.
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[CH:7]=[C:8]3[C:38](=[CH:39][CH:40]=2)[C:16]2[N:17](COCC[Si](C)(C)C)[C:18]([C:20]4[C:27]([C:28]#[N:29])=[CH:26][CH:25]=[CH:24][C:21]=4[C:22]#[N:23])=[N:19][C:15]=2[C:14]2[CH:13]=[CH:12][C:11]([CH2:41][C:42]([OH:45])([CH3:44])[CH3:43])=[CH:10][C:9]3=2)[CH2:3][CH2:2]1.O>CCCC[N+](CCCC)(CCCC)CCCC.[F-]>[CH:1]1([CH2:4][O:5][C:6]2[CH:7]=[C:8]3[C:38](=[CH:39][CH:40]=2)[C:16]2[NH:17][C:18]([C:20]4[C:27]([C:28]#[N:29])=[CH:26][CH:25]=[CH:24][C:21]=4[C:22]#[N:23])=[N:19][C:15]=2[C:14]2[CH:13]=[CH:12][C:11]([CH2:41][C:42]([OH:45])([CH3:43])[CH3:44])=[CH:10][C:9]3=2)[CH2:3][CH2:2]1
Reactant: CC(C)(O)Cc1ccc2c(c1)c1cc(OCC3CC3)ccc1c1c2nc(-c2c(C#N)cccc2C#N)n1COCC[Si](C)(C)C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: O
Product: CC(C)(O)Cc1ccc2c(c1)c1cc(OCC3CC3)ccc1c1[nH]c(-c3c(C#N)cccc3C#N)nc21
Yield: 36 %

Procedure:
Crude 2-(9-(cyclopropylmethoxy)-6-(2-hydroxy-2-methylpropyl)-1-{[2-(trimethyl silyl)ethoxy]methyl}-1H-phenanthro[9,10-d]imidazol-2-yl)isophthalonitrile (1.37 mmol) from Step 6 above was dissolved in TBAF (1 M in THF, 10 mL) and the mixture heated at reflux for 1.5 h. Water was added, and the aqueous layer extracted with ethyl acetate. The organic layer was dried over MgSO4, filtered and concentrated. The material was purified by flash chromatography on silica (70% ethyl acetate in hexanes) to afford 2-[9-(cyclopropylmethoxy)-6-(2-hydroxy-2-methylpropyl)-1H-phenanthro[9,10-d]imidazol-2-yl]isophthalonitrile (240 mg).
Reaction SMILES: [C:1]([C:5]1[C:19]([O:20]CC(C)=C)=[CH:18][C:8]2[CH2:9][C:10]3([O:17][C:7]=2[CH:6]=1)[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]3)([CH3:4])([CH3:3])[CH3:2]>CN(C)C1C=CC=CC=1>[C:1]([C:5]1[C:19]([OH:20])=[C:18]([CH2:3][C:1]([CH3:4])=[CH2:2])[C:8]2[CH2:9][C:10]3([O:17][C:7]=2[CH:6]=1)[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]3)([CH3:2])([CH3:3])[CH3:4]
Reactant: C=C(C)COc1cc2c(cc1C(C)(C)C)OC1(CCCCCC1)C2
Solvent: CN(C)c1ccccc1
Product: C=C(C)Cc1c(O)c(C(C)(C)C)cc2c1CC1(CCCCCC1)O2
Yield: 179.8 %

Procedure:
0.89 g of 6-t-butyl-5-(2-methyl-2-propenyloxy)-2,3-dihydrobenzofuran-2-spiro-1′-cycloheptane was dissolved in 3 ml of dimethylaniline and the solution was treated in the same manner as in Example 8-2) to give 0.80 g of 6-t-butyl-5-hydroxy-4-(2-methyl-2-propenyl)-2,3-dihydrobenzofuran-2-spiro-1′-cycloheptane as a colorless oil (yield 90%).
Reaction SMILES: [N+:1]([C:4]1[CH:13]=[CH:12][C:11]([C:14]([OH:16])=[O:15])=[C:10]2[C:5]=1[CH:6]=[CH:7][CH:8]=[N:9]2)([O-:3])=[O:2].IC.[C:19](=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[CH3:19][O:15][C:14]([C:11]1[CH:12]=[CH:13][C:4]([N+:1]([O-:3])=[O:2])=[C:5]2[C:10]=1[N:9]=[CH:8][CH:7]=[CH:6]2)=[O:16]
Reactant: O=C([O-])[O-]
Reactant: O=C(O)c1ccc([N+](=O)[O-])c2cccnc12
Agent: [K+]
Solvent: CI
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1ccc([N+](=O)[O-])c2cccnc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 78.3 %

Procedure:
To a stirred solution of 300 mg (1.375 mmol) of 5-nitroquinoline-8-carboxilic acid (Breckenridge, J. G. Et al., Canadian J. of Research Sect. B; 1947, 25, 49) in DMF (6 mL), 546 mg (3.850 mmol) of iodomethane and 190 mg (1.375 mmol) of potassium carbonate were added. The resulting mixture was stirred at room temperature for one hour. Water (10 mL) was added and the product collected by filtration. The residue was washed with water and dried to yield the title compound (250 mg, 78.4%).
Reaction SMILES: [Al+3].[Cl-].[Cl-].[Cl-].[H-].[H-].[H-].[H-].[Li+].[Al+3].[CH3:11][O:12][CH:13]1[CH2:18][CH2:17][CH:16]([OH:19])[CH2:15][CH2:14]1>CCOCC>[CH3:11][O:12][C@@H:13]1[CH2:18][CH2:17][C@H:16]([OH:19])[CH2:15][CH2:14]1
Reactant: COC1CCC(O)CC1
Agent: [Al+3]
Agent: [Cl-]
Agent: [H-]
Solvent: CCOCC
Product: CO[C@H]1CC[C@@H](O)CC1

Procedure:
Following the procedure of J. Org. Chem., 28 1923 (1963), 13.35 g of AlCl3 and 125 ml of ether were stirred under N2. 25 ml of 1M LiAlH4 in ether were added by syringe to the solution. Next, 13 g of 4-methoxycyclohexanol in 50 ml of ether were added to the stirred mixture over a 30 minute period. The mixture was then allowed to settle. The supernate was removed. The solid remaining was washed three times with 25, 50 and 50 ml portions of ether. The solid precipitate was filtered and the filter cake thoroughly washed with ether. (The filtrate, and washings contained trans-4-methoxycyclohexanol). The dried precipitate (19.17 g) was slurried in 100 ml of ether. 100 ml of 10% sulfuric acid were slowly added thereto (30 minutes). The cis isomer obtained from the decompositions of the AlCl2 complex was in the ether layer which was separated. The separated layer was washed successively with 100 ml water, 50 ml saturated aqueous sodium bicarbonate and 50 ml of brine. The ethereal solution was dried and the ether evaporated to yield 1.7 g of cis-4-methoxycyclohexanol. An additional 4 g were obtained from the water layer.