Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(O)C.[CH3:4][C:5]1[S:9][C:8]([CH2:10][C:11]2[CH:12]=[C:13]([CH:16]=[CH:17][CH:18]=2)[CH:14]=[O:15])=[CH:7][CH:6]=1.[BH4-].[Na+]>O>[CH3:4][C:5]1[S:9][C:8]([CH2:10][C:11]2[CH:12]=[C:13]([CH2:14][OH:15])[CH:16]=[CH:17][CH:18]=2)=[CH:7][CH:6]=1
Reactant: Cc1ccc(Cc2cccc(C=O)c2)s1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: Cc1ccc(Cc2cccc(CO)c2)s1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 84.9 %

Procedure:
To a solution of ethanol (5.0 mL) and 3-(5-methyl-thiophen-2-ylmethyl)-benzaldehyde (350 mg) described in Manufacturing Example 52-2 was added sodium borohydride (120 mg), which was stirred for 10 minutes at room temperature. Water was added to the reaction solution, which was then extracted with ethyl acetate. The solvent was evaporated from the organic layer under a reduced pressure, and the residue was purified by silica gel chromatography (heptane:ethyl acetate=2:1) to obtain the titled compound (300 mg).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[C:18]([F:23])[CH:17]=1.[C:24]1([CH3:33])[C:25]([N:30]=[C:31]=[O:32])=[CH:26][CH:27]=[CH:28][CH:29]=1.CO>C(Cl)(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH:20][C:31]([NH:30][C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=2[CH3:33])=[O:32])=[C:18]([F:23])[CH:17]=1
Reactant: Cc1ccccc1N=C=O
Reactant: COc1cc2ncnc(Oc3ccc(N)c(F)c3)c2cc1OC
Solvent: ClC(Cl)Cl
Solvent: CO
Product: COc1cc2ncnc(Oc3ccc(NC(=O)Nc4ccccc4C)c(F)c3)c2cc1OC
Temperature: 60 °C
Reaction time: 8 h
Yield: 24 %

Procedure:
4-[(6,7-Dimethoxy-4-quinazolinyl)oxy]-2-fluoroaniline (50 mg) was dissolved in chloroform (3 ml), and o-toluyl isocyanate (30 μl) was then added to the solution. The mixture was stirred at 60° C. overnight. Methanol was added to the reaction solution, and the mixture was purified by HPLC by development with chloroform/methanol to give 17 mg (yield 24%) of the title compound.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[C:12]([NH:14][CH:15]1[CH2:20][CH2:19][CH2:18][CH:17]([C:21]([O:23][CH3:24])=[O:22])[CH2:16]1)=[O:13].Br[CH2:26]/[CH:27]=[CH:28]/[C:29]1[CH:34]=[CH:33][C:32]([O:35][CH2:36][CH2:37][CH2:38][CH2:39][O:40][C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)=[CH:31][CH:30]=1>>[CH3:24][O:23][C:21]([CH:17]1[CH2:18][CH2:19][CH2:20][CH:15]([NH:14][C:12]([C:3]2[CH:4]=[C:5]([CH:10]=[CH:11][C:2]=2[O:1][CH2:26]/[CH:27]=[CH:28]/[C:29]2[CH:34]=[CH:33][C:32]([O:35][CH2:36][CH2:37][CH2:38][CH2:39][O:40][C:41]3[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=3)=[CH:31][CH:30]=2)[C:6]([O:8][CH3:9])=[O:7])=[O:13])[CH2:16]1)=[O:22]
Reactant: BrC/C=C/c1ccc(OCCCCOc2ccccc2)cc1
Reactant: COC(=O)c1ccc(O)c(C(=O)NC2CCCC(C(=O)OC)C2)c1
Product: COC(=O)c1ccc(OC/C=C/c2ccc(OCCCCOc3ccccc3)cc2)c(C(=O)NC2CCCC(C(=O)OC)C2)c1

Procedure:
Preparation takes place in analogy to Example 22 from the (+)-B-enantiomer of methyl 4-hydroxy-3-({[3-(methoxycarbonyl)cyclohexyl]amino}carbonyl)benzoate (see Example IX, method 2) and 1-[(1E)-3-bromoprop-1-en-1-yl]-4-(4-phenoxybutoxy)benzene.
Reaction SMILES: [I:1][C:2]1[CH:3]=[CH:4][C:5]([NH2:11])=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8].[C:12](=O)([O-])[O-:13].[Na+].[Na+].O.C(Cl)(Cl)=O>C1(C)C=CC=CC=1>[I:1][C:2]1[CH:10]=[C:6]2[C:7]([O:9][C:12](=[O:13])[NH:11][C:5]2=[CH:4][CH:3]=1)=[O:8]
Reactant: Nc1ccc(I)cc1C(=O)O
Reactant: O=C([O-])[O-]
Agent: O=C(Cl)Cl
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Product: O=c1[nH]c2ccc(I)cc2c(=O)o1
Reaction time: 2 h
Yield: 84.1 %

Procedure:
To a mechanically stirred solution of 26.3 grams of 5-iodo-2-amino benzoic acid (0.1 mol), 10.6 grams of sodium carbonate (0.1 mol), and 250 mL water, cooled to 0° C., was slowly added, via an addition funnel, 80 mL of a 1.93M solution of phosgene in toluene. After 2 hours, the precipitated product was isolated by filtration. The solids were washed with 200 mL water, 300 mL of a 1:1 mixture ethanol and ether, 200 mL of ether, and dried under vacuum to yield 24.3 grams (84%) of 5-iodoisatoic anhydride (264°-268° C., decomposition).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:9]2[O:13][CH:12]=[N:11][C:10]=2[CH3:14])[CH:5]=[CH:6][C:7]=1[CH3:8].[Li+].C[Si]([N-][Si](C)(C)C)(C)C.[Cl:25]C(Cl)(Cl)C(Cl)(Cl)Cl>C1COCC1>[Cl:25][C:12]1[O:13][C:9]([C:4]2[CH:5]=[CH:6][C:7]([CH3:8])=[C:2]([F:1])[CH:3]=2)=[C:10]([CH3:14])[N:11]=1
Reactant: Cc1ccc(-c2ocnc2C)cc1F
Reactant: ClC(Cl)(Cl)C(Cl)(Cl)Cl
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: Cc1ccc(-c2oc(Cl)nc2C)cc1F
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 92.9 %

Procedure:
A solution of Example 30A (1.56 g, 8.16 mmol) in THF (36 mL) was cooled to −78° C., followed by dropwise addition of LiHMDS (1 M in THF, 10.2 mL, 10.2 mmol). The reaction was stirred 30 min and then hexachloroethane (3.86 g, 16.3 mmol) was added in one portion. The reaction was allowed to slowly warm to room temperature and stir over the weekend. The reaction was then quenched with 50 mL of 1:1 water:saturated aqueous NH4Cl solution, and extracted with Et2O (2×). The combined organic layer was dried with MgSO4, filtered, and concentrated in vacuo. The residue was chromatographed on silica gel (Analogix® SF40-80 g column) eluting with 7% EtOAc/hexanes to yield 1.71 g (93%) of the title compound. 1H NMR (300 MHz, DMSO-d6) δ 7.43 (dd, J=11.9, 4.4 1H), 7.35-7.29 (m, 2H), 2.34 (s, 3H), 2.27 (d, J=1.9, 3H). MS (DCI+) m/z 226 (M+H).
Reaction SMILES: [C:1]1([C:7]2[CH:12]=[C:11]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[N:10]=[C:9]([N:19]3[C:38]4[C:26](=[CH:27][C:28]5[C:29]([CH3:46])([CH3:45])[C:30]6[CH:31]=[C:32]([C:39]7[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=7)[CH:33]=[CH:34][C:35]=6[C:36]=5[CH:37]=4)[C:25]4[C:20]3=[CH:21][CH:22]=[CH:23][CH:24]=4)[N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1C(=O)N([Br:54])C(=O)C1.O>C(#N)C>[Br:54][C:23]1[CH:24]=[C:25]2[C:20]([N:19]([C:9]3[N:8]=[C:7]([C:1]4[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=4)[CH:12]=[C:11]([C:13]4[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=4)[N:10]=3)[C:38]3[C:26]2=[CH:27][C:28]2[C:29]([CH3:46])([CH3:45])[C:30]4[CH:31]=[C:32]([C:39]5[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=5)[CH:33]=[CH:34][C:35]=4[C:36]=2[CH:37]=3)=[CH:21][CH:22]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: CC1(C)c2cc(-c3ccccc3)ccc2-c2cc3c(cc21)c1ccccc1n3-c1nc(-c2ccccc2)cc(-c2ccccc2)n1
Solvent: CC#N
Solvent: O
Product: CC1(C)c2cc(-c3ccccc3)ccc2-c2cc3c(cc21)c1cc(Br)ccc1n3-c1nc(-c2ccccc2)cc(-c2ccccc2)n1
Reaction time: 4 h

Procedure:
138 g (234.6 mmol) of 6-(4,6-diphenylpyrimidin-2-yl)-12,12-dimethyl-2-phenyl-6,12-dihydro-6-azaindeno[1,2-b]fluorene are initially introduced in 1000 ml of acetonitrile. A solution of 41.7 g (234.6 mmol) of NBS in 500 ml of CH3 CN is subsequently added dropwise at −15° C. with exclusion of light, and the mixture is allowed to come to room temperature and is stirred at this temperature for a further 4 h. 150 ml of water are subsequently added to the mixture, which is then extracted with CH2 Cl2. The organic phase is dried over MgSO4, and the solvents are removed in vacuo. The product is washed by stirring with hot hexane and filtered off with suction.
Reaction SMILES: Br[C:2]1[N:10]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[C:9]2[C:4](=[N:5][C:6]([O:18][CH3:19])=[CH:7][CH:8]=2)[C:3]=1[CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22].[CH2:26](C([Sn])=C(CCCC)CCCC)[CH2:27]CC>CN(C=O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH2:24]([O:23][C:21](=[O:22])[CH2:20][C:3]1[C:4]2=[N:5][C:6]([O:18][CH3:19])=[CH:7][CH:8]=[C:9]2[N:10]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[C:2]=1[CH:26]=[CH2:27])[CH3:25]
Reactant: CCCCC([Sn])=C(CCCC)CCCC
Reactant: CCOC(=O)Cc1c(Br)n(C(=O)OC(C)(C)C)c2ccc(OC)nc12
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Product: C=Cc1c(CC(=O)OCC)c2nc(OC)ccc2n1C(=O)OC(C)(C)C
Temperature: 85 °C
Yield: 66.6 %

Procedure:
Under a nitrogen atmosphere, tert-butyl 2-bromo-3-(2-ethoxy-2-oxoethyl)-5-methoxy-1H-pyrrolo[3,2-b]pyridine-1-carboxylate (207 mg, 0.5 mmol), tributylvinyl tin (175 μL, 0.6 mmol) and tetrakis(triphenylphosphine)palladium(0) (29 mg, 0.025 mmol) were combined in 10 mL of DMF, and the mixture was heated to 85° C. overnight. The reaction was allowed to cool to ambient temperature and was partitioned between ethyl acetate and water. The organic layer was separated and washed with 5% aqueous LiCl and brine. The organic layer was then dried over MgSO4, filtered and concentrated to afford crude product which was purified by RP HPLC eluting with acetonitrile and water to afford 120 mg of tert-butyl 3-(2-ethoxy-2-oxoethyl)-5-methoxy-2-vinyl-1H-pyrrolo[3,2-b]pyridine-1-carboxylate. MS (m/z): 361.2 [M+H]+; HPLC retention time 4.69 min (5-99% acetonitrile:water with 0.05% formic acid).
Reaction SMILES: [C:1]1([NH:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].Br.[NH2:17][C:18]1[N:19]=[C:20]([NH2:30])[C:21]2[CH:27]=[C:26]([CH2:28]Br)[CH:25]=[N:24][C:22]=2[N:23]=1>>[NH2:17][C:18]1[N:19]=[C:20]([NH2:30])[C:21]2[CH:27]=[C:26]([CH2:28][N:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[C:8]3[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=3)[CH:25]=[N:24][C:22]=2[N:23]=1
Reactant: c1ccc(Nc2ccccc2)cc1
Reactant: Nc1nc(N)c2cc(CBr)cnc2n1
Agent: Br
Agent: [H-]
Agent: [Na+]
Product: Nc1nc(N)c2cc(CN(c3ccccc3)c3ccccc3)cnc2n1

Procedure:
X=N; W=CH2; Z=non-linked hydrogens on each phenyl group; Z=CH2; m=n=0) is prepared similarly as disclosed in Example 1 above by using N,N-diphenylamine (1.3 g, 0.77 mmol), NaH (50 mg, 2.1 mmol), and 2,4-diamino-6-bromomethylpyrido[2,3-d]pyrimidine hydrobromide (100 mg, 0.3 mmol). The product can be purified by chromatography.
Reaction SMILES: [S:1]1[C:5]([S:6]([Cl:9])(=[O:8])=[O:7])=[CH:4][C:3]2[CH:10]=[CH:11][CH:12]=[CH:13][C:2]1=2.[N+:14]([O-])([OH:16])=[O:15]>ClCCl>[N+:14]([C:4]1[C:3]2[CH:10]=[CH:11][CH:12]=[CH:13][C:2]=2[S:1][C:5]=1[S:6]([Cl:9])(=[O:8])=[O:7])([O-:16])=[O:15]
Reactant: O=S(=O)(Cl)c1cc2ccccc2s1
Reactant: O=[N+]([O-])O
Solvent: ClCCl
Product: O=[N+]([O-])c1c(S(=O)(=O)Cl)sc2ccccc12
Temperature: 25 °C

Procedure:
To a solution of benzo[b]thiophene-2-sulfonyl chloride (1.165 g, 5 mmol) in 25 mL of dichloromethane was added 3.6 mL of concentrated nitric acid (≧22.05 mol/L) dropwise, the resulting mixture was refluxed overnight and cooled to room temperature before it was poured into 20 gram of crushed ice. The organic layer was separated and the aqueous layer was extracted by 220 mL 2 dichloromethane. The organic layers were combined and dried over MgSO4. Solvent was then removed by rotary evaporator. The crude product was purified by flash column chromatography with an eluent of hexane, followed by a gradient eluent of hexane/ethyl acetate (6/1-3/1) to afford 0.58 g of product (mixture of 65% of 4-nitro-benzo[b]thiophene-2-sulfonyl chloride and 35% of 7-nitro-benzo[b]thiophene-2-sulfonyl chloride).
Reaction SMILES: CS[C:3]([S:14][CH3:15])=[C:4]1[C:9](=[O:10])[O:8][C:7]([CH3:12])([CH3:11])[O:6][C:5]1=[O:13].[CH3:16][O:17][C:18]1[CH:19]=[C:20]([CH:22]=[CH:23][C:24]=1[O:25][CH3:26])[NH2:21]>CCO>[CH3:16][O:17][C:18]1[CH:19]=[C:20]([NH:21][C:3]([S:14][CH3:15])=[C:4]2[C:9](=[O:10])[O:8][C:7]([CH3:12])([CH3:11])[O:6][C:5]2=[O:13])[CH:22]=[CH:23][C:24]=1[O:25][CH3:26]
Reactant: COc1ccc(N)cc1OC
Reactant: CSC(SC)=C1C(=O)OC(C)(C)OC1=O
Solvent: CCO
Product: COc1ccc(NC(SC)=C2C(=O)OC(C)(C)OC2=O)cc1OC
Yield: 83 %

Procedure:
Commercially available 5-(bis-methylsulfanyl-methylene)-2,2-dimethyl-[1,3]dioxane-4,6-dione (3.5 g, 14 mmol) and 3,4-dimethoxyaniline (2.2 g, 14 mmol) were reflux in EtOH (20 mL) for 2 hours. The EtOH was removed under reduced pressure and EtOAc was added to the residue. The product was filtered and washed with cold EtOAc (3×). 5-[(3,4-dimethoxy-phenylamino)-methylsulfanyl-methylene]-2,2-dimethyl-[1,3]dioxane-4,6-dione was obtained as a white solid (1.7 g, 47% yield) and used without further purification. LCMS: m/z 352 (M−H)−.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([S:8][CH3:9])[N:5]=[C:4]2[NH:10][N:11]=[C:12]([CH3:13])[C:3]=12.[CH:14]([S:17][C:18]1[CH:24]=[CH:23][CH:22]=[CH:21][C:19]=1[NH2:20])([CH3:16])[CH3:15]>C(O)(C)C>[CH:14]([S:17][C:18]1[CH:24]=[CH:23][CH:22]=[CH:21][C:19]=1[NH:20][C:2]1[N:7]=[C:6]([S:8][CH3:9])[N:5]=[C:4]2[NH:10][N:11]=[C:12]([CH3:13])[C:3]=12)([CH3:16])[CH3:15]
Reactant: CC(C)Sc1ccccc1N
Reactant: CSc1nc(Cl)c2c(C)n[nH]c2n1
Solvent: CC(C)O
Product: CSc1nc(Nc2ccccc2SC(C)C)c2c(C)n[nH]c2n1
Temperature: 25 °C

Procedure:
A mixture of 4-chloro-3-methyl-6-methylmercaptopyrazolo[3,4-d]pyrimidine (A-3) (1.21 g, 5.63 mmol) and 2-(isopropylthio)aniline (A-4) (1.42 g, 8.50 mmol) in isopropanol (56 mL) was stirred at reflux for 3 h. After cooling down to ambient temperature, TEA (0.78 mL, 5.66 mmol) was added to the mixture, and the solution was again heated to reflux for 0.5 h. After cooling down to ambient temperature, the mixture was filtered to give the title compound (A-5) as white solid (1.30 g, 3.77 mmol). MS-ESI (m/z): 346 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[CH:15]=[C:14](Cl)[N:13]=[CH:12][N:11]=2)[CH:5]=[CH:6][C:7]=1[F:8].[CH3:17][O:18][C:19]1[CH:25]=[CH:24][C:23]([N+:26]([O-])=O)=[CH:22][C:20]=1[NH2:21]>>[NH2:26][C:23]1[CH:24]=[CH:25][C:19]([O:18][CH3:17])=[C:20]([NH:21][C:14]2[CH:15]=[C:10]([NH:9][C:4]3[CH:5]=[CH:6][C:7]([F:8])=[C:2]([Cl:1])[CH:3]=3)[N:11]=[CH:12][N:13]=2)[CH:22]=1
Reactant: Fc1ccc(Nc2cc(Cl)ncn2)cc1Cl
Reactant: COc1ccc([N+](=O)[O-])cc1N
Product: COc1ccc(N)cc1Nc1cc(Nc2ccc(F)c(Cl)c2)ncn1

Procedure:
In a manner substantially similar to that described above 4-(3-chloro-4-fluorophenylamino)-6-chloropyrimidine and 2-methoxy-5-nitroaniline gave N-(5-amino-2-methoxyphenyl)-N′-(3-chloro-4-fluorophenyl)pyrimidine-4,6-diamine. (Int-G) MS (m/z): 360/362 (M+1).
Reaction SMILES: [OH:1][C:2]1[C:10]([OH:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[CH2:12](I)[CH2:13][CH3:14].[OH-].[K+].C>C(O)C.O>[CH2:12]([O:11][C:10]1[CH:9]=[CH:8][CH:7]=[C:3]([C:4]([OH:6])=[O:5])[C:2]=1[OH:1])[CH2:13][CH3:14]
Reactant: CCCI
Reactant: O=C(O)c1cccc(O)c1O
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CCCOc1cccc(C(=O)O)c1O
Yield: 65 %

Procedure:
2,3-Dihydroxybenzoic acid (6.16 g) and propyl iodide (6.8 g) were added to a mixture of aqueous potassium hydroxide solution (20 ml, 25% w/v), water (50 ml) and ethanol (50 ml) and the mixture was stirred and heated at reflux for 5 hours. A further quantity of propyl iodide (17 g) was then added and the mixture was again heated at reflux for 4 hours, small quantities of solid potassium hydroxide being added meanwhile in order to keep the pH at about 10. Decolourizing charcoal was then carefully added, the mixture was filtered hot and the filtrate was acidified to pH 1 by treatment with concentrated hydrochloric acid. The resulting solid was filtered off and dissolved in aqueous ammonia solution (2N), and the solution was treated with decolourizing charcoal, filtered, and the filtrate was acidified to pH 1 by treatment with hydrochloric acid to give 3-propoxysalicylic acid (5.1 g), m.p. 114°-118° C.
Reaction SMILES: [CH:1](=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:9][CH:10]1[CH2:15][CH2:14][N:13]([C:16](=[O:28])[C:17]2[CH:22]=[CH:21][C:20]([N:23]3[CH:27]=[N:26][CH:25]=[N:24]3)=[CH:19][CH:18]=2)[CH2:12][CH2:11]1.[BH4-].[Na+]>CO>[CH2:1]([NH:9][CH:10]1[CH2:11][CH2:12][N:13]([C:16](=[O:28])[C:17]2[CH:18]=[CH:19][C:20]([N:23]3[CH:27]=[N:26][CH:25]=[N:24]3)=[CH:21][CH:22]=2)[CH2:14][CH2:15]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NC1CCN(C(=O)c2ccc(-n3cncn3)cc2)CC1
Reactant: O=Cc1ccccc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: O=C(c1ccc(-n2cncn2)cc1)N1CCC(NCc2ccccc2)CC1
Reaction time: 1 h

Procedure:
11.1 ml of benzaldehyde and 10 g of Molecular Sieve 3A were added to 50 ml of a solution of 2.97 g of 4-amino-1-[4-(1,2,4-triazol-1-yl)benzoyl]piperidine in methanol. The mixture was refluxed by heating, for 150 minutes. Thereto was added 4.97 g of sodium borohydride in small portions, under ice-cooling. The mixture was stirred for 1 hour under ice-cooling. The Molecular Sieve 3A was removed by filtration and the filtrate was subjected to distillation to remove the solvent. To the residue was added water. The mixture was made acidic with hydrochloric acid and then washed with ethyl acetate. The aqueous layer was made alkaline with an aqueous sodium hydroxide solution, under ice-cooling, followed by extraction with methylene chloride. The extract was washed with water, dried with anhydrous magnesium sulfate, and concentrated. The residue was purified by silica gel column chromatography (eluant: methylene chloride/methanol=50/1), followed by recrystallization from methylene chloride-ethyl acetate to obtain 2.92 g of 4-benzylamino-1-[4-(1,2,4-triazol-1-yl)benzoyl]piperidine as a white powder.
Reaction SMILES: C(#N)C.N1C=CC=CC=1.F.[CH2:11]([C:16]1[CH2:30][C@@H:29]([O:31][Si](C(C)(C)C)(C)C)[C@H:28](/[CH:39]=[CH:40]/[C@@H:41]([O:49][Si](C(C)(C)C)(C)C)[CH2:42][C@H:43]([CH3:48])[CH2:44][CH2:45][CH2:46][CH3:47])[C:17]=1[S:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][C:24]([O:26][CH3:27])=[O:25])[CH2:12][CH2:13][CH2:14][CH3:15]>N1C=CC=CC=1>[CH2:11]([C:16]1[CH2:30][C@@H:29]([OH:31])[C@H:28](/[CH:39]=[CH:40]/[C@@H:41]([OH:49])[CH2:42][C@H:43]([CH3:48])[CH2:44][CH2:45][CH2:46][CH3:47])[C:17]=1[S:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][C:24]([O:26][CH3:27])=[O:25])[CH2:12][CH2:13][CH2:14][CH3:15]
Reactant: CCCCCC1=C(SCCCCCC(=O)OC)[C@@H](/C=C/[C@H](C[C@H](C)CCCC)O[Si](C)(C)C(C)(C)C)[C@H](O[Si](C)(C)C(C)(C)C)C1
Agent: F
Solvent: c1ccncc1
Solvent: CC#N
Product: CCCCCC1=C(SCCCCCC(=O)OC)[C@@H](/C=C/[C@@H](O)C[C@H](C)CCCC)[C@H](O)C1
Reaction time: 15 h
Yield: 51.2 %

Procedure:
To a solution of ice-cooled acetonitrile (1 mL) and pyridine (0.1 mL) was added hydrogen fluoride-pyridine (0.1 mL). To this solution was added methyl (11R,12S,13E,15S,17R)-9-pentyl-11,15-bis(tert-butyldimethylsiloxy)-17,20-dimethyl-7-thiaprosta-8,13-dienoate (71 mg, 0.10 mmol) in pyridine (0.1 mL). The ice bath was removed and the solution was agitated for 15 hours while returning it to room temperature. The reaction solution was poured into a mixture of ethyl acetate and saturated aqueous sodium hydrogencarbonate. The desired product was extracted from this mixed solution with ethyl acetate. The extract was washed with brine, then dried over anhydrous sodium sulfate. The solution was concentrated under reduced pressure, then was purified by silica gel column chromotography (30 to 50% ethyl acetate/hexane) to obtain methyl (11R,12S,13E,15S,17R)-9-pentyl-11,15-dihydroxy-17,20-dimethyl-7-thiaprosta-8,13-dienoate (24 mg, 50%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:17]=[C:18]2[C:23](=[CH:24][CH:25]=1)[C:22]([C:26]([OH:28])=O)=[CH:21][CH:20]=[CH:19]2.Cl.CN(C)CCCN=C=NCC.C1C=NC2N(O)N=NC=2C=1.[CH3:51][N:52]([CH3:56])[CH2:53][CH2:54][NH2:55].CCN(C(C)C)C(C)C>CN(C=O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:17]=[C:18]2[C:23](=[CH:24][CH:25]=1)[C:22]([C:26]([NH:55][CH2:54][CH2:53][N:52]([CH3:56])[CH3:51])=[O:28])=[CH:21][CH:20]=[CH:19]2
Reactant: CN(C)CCN
Reactant: COc1cc2nccc(Oc3ccc4c(C(=O)O)cccc4c3)c2cc1OC
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc2nccc(Oc3ccc4c(C(=O)NCCN(C)C)cccc4c3)c2cc1OC
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
6-(6,7-Dimethoxyquinolin-4-yloxy)-1-naphthoic acid (80 mg, 0.213 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (61 mg, 0.32 mmol) and HOAT (29 mg, 0.213 mmol) were added to a reaction tube, then dissolved in DMF (0.6 mL). A solution of N,N-dimethylethylenediamine (23 mg, 0.256 mmol) in DMF (0.6 mL) was added to the reaction, followed by Hunig's base (75 mg, 0.581 mmol). The mixture became yellow and clear within 15 min and was stirred at RT for 16 h. The mixture was concentrated under vacuum. The remaining yellow oil was purified by silica gel chromatography (2% to 3% 7N NH3 in MeOH in CH2Cl2) to afford 6-((6,7-bis(methoxy)-4-quinolinyl)oxy)-N-(2-(dimethylamino)ethyl)-1-naphthalenecarboxamide as a white solid. MS (ESI, pos. ion) m/z: 446.1 (M+1). Calc'd for C226H27N3O4-445.52.
Reaction SMILES: C(O)=O.[C:4]([N:7]([CH:17]1[CH2:22][CH2:21][N:20]([C:23]([NH:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33])=[O:24])[CH2:19][CH2:18]1)[C:8]1[CH:13]=[CH:12][C:11]([CH2:14][CH2:15][NH2:16])=[CH:10][CH:9]=1)(=[O:6])[CH3:5].C([O:41][C:42]1[CH:52]=[CH:51][C:45]([O:46][CH2:47][C@@H:48]2[CH2:50][O:49]2)=[CH:44][CH:43]=1)C1C=CC=CC=1>>[CH2:26]([NH:25][C:23]([N:20]1[CH2:19][CH2:18][CH:17]([N:7]([C:4](=[O:6])[CH3:5])[C:8]2[CH:13]=[CH:12][C:11]([CH2:14][CH2:15][NH:16][CH2:50][C@H:48]([OH:49])[CH2:47][O:46][C:45]3[CH:51]=[CH:52][C:42]([OH:41])=[CH:43][CH:44]=3)=[CH:10][CH:9]=2)[CH2:22][CH2:21]1)=[O:24])[CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33]
Reactant: CCCCCCCCNC(=O)N1CCC(N(C(C)=O)c2ccc(CCN)cc2)CC1
Reactant: c1ccc(COc2ccc(OC[C@@H]3CO3)cc2)cc1
Solvent: O=CO
Product: CCCCCCCCNC(=O)N1CCC(N(C(C)=O)c2ccc(CCNC[C@H](O)COc3ccc(O)cc3)cc2)CC1
Yield: 28.3 %

Procedure:
4-[Acetyl-4-(2-aminoethyl)anilino]-N-octyl-1-piperidinecarboxamide formate (0.25 g, 0.59 mmol) was reacted with (2S)-2-{[4-(benzyloxy)phenoxy]methyl}oxirane (0.137 g, 0.53 mmol) according to Procedure G to give the title compound (eluant: 20:1 chloroform-methanol) (0.1 g, 0.15 mmol).
Reaction SMILES: [CH2:1]([C:4]1([C:14]([OH:16])=O)[S:11](=[O:13])(=[O:12])[C:7]2[S:8][CH:9]=[CH:10][C:6]=2[CH2:5]1)[CH:2]=[CH2:3].CN([P+](O[N:28]1N=N[C:30]2C=CC=C[C:29]1=2)(N(C)C)N(C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[CH2:29]([NH:28][C:14]([C:4]1([CH2:1][CH:2]=[CH2:3])[S:11](=[O:12])(=[O:13])[C:7]2[S:8][CH:9]=[CH:10][C:6]=2[CH2:5]1)=[O:16])[CH3:30]
Reactant: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Reactant: C=CCC1(C(=O)O)Cc2ccsc2S1(=O)=O
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Product: C=CCC1(C(=O)NCC)Cc2ccsc2S1(=O)=O
Reaction time: 1.5 h
Yield: 81.4 %

Procedure:
A solution of 2-allyl-2,3-dihydrothieno[2,3-b]thiophene-2-carboxylic acid-1,1-dioxide (8 g, 0.031 mol) and BOP reagent (17.8 g, 0.041 mol) in degassed DMF (150 mL) was cooled to 0° C. under nitrogen. Ethylamine was bubbled into the stirred reaction mixture until the solution was quite basic. After 1.5 hours, the DMF was removed in vacuo and the residue partitioned between ethyl acetate and 6N HCl. The aqueous phase was extracted a total of four times with ethyl acetate and the combined extracts washed with saturated sodium bicarbonate, brine, then dried over magnesium sulfate. Filtration and solvent removal gave the title compound as an oil (7.2 g).
Reaction SMILES: [C:1](Cl)(=[O:4])[CH:2]=[CH2:3].[CH:6]1([O:12][N:13]2[C:18]([CH3:20])([CH3:19])[CH2:17][CH:16]([OH:21])[CH2:15][C:14]2([CH3:23])[CH3:22])[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1.C(N(CC)CC)C>C(Cl)Cl>[CH:6]1([O:12][N:13]2[C:14]([CH3:23])([CH3:22])[CH2:15][CH:16]([O:21][C:1](=[O:4])[CH:2]=[CH2:3])[CH2:17][C:18]2([CH3:19])[CH3:20])[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11]1
Reactant: C=CC(=O)Cl
Reactant: CC1(C)CC(O)CC(C)(C)N1OC1CCCCC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C=CC(=O)OC1CC(C)(C)N(OC2CCCCC2)C(C)(C)C1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of 1.6 ml of acryloyl chloride in 20 ml of methylene chloride is added to a stirred solution of 5.11 grams of 1-cyclohexyloxy-2,2,6,6-tetramethylpiperidin-4-ol and 3.10 ml of triethylamine in 20 ml of methylene chloride at 0° C. After stirring at room temperature for 2 hours, the solvent is removed under reduced pressure. The residue is then purified by liquid chromatography to afford the title compound as a white solid with a melting point of 49°-52° C.