Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([CH2:8]O)[CH:3]=1.S(Cl)([Cl:12])=O>C(Cl)Cl>[Cl:12][CH2:8][C:4]1[CH:3]=[C:2]([CH3:1])[CH:7]=[CH:6][N:5]=1
Reactant: O=S(Cl)Cl
Reactant: Cc1ccnc(CO)c1
Solvent: ClCCl
Product: Cc1ccnc(CCl)c1
Yield: 72.1 %

Procedure:
A mixture solution of (4-methyl-pyridine-2-yl)-methanol (410 mg, 3.33 mmol) described in Manufacturing Example 11-1-3, thionyl chloride (0.49 mL, 6.66 mmol) and methylene chloride (10 mL) was stirred under reflux for 5 minutes. The reaction solution was allowed to room temperature and concentrated under a reduced pressure. The resulting residue was partitioned into diethyl ether and saturated sodium bicarbonate solution. The organic layer was purified by silica gel column chromatography (ethyl acetate) to obtain the title compound (340 mg, 72.1%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C@@H:9]2[C@@H:14]([O:15][CH2:16][C:17]3[CH:18]=[CH:19][C:20]4[O:25][CH2:24][CH2:23][N:22]([CH2:26][CH2:27][CH2:28][O:29][CH3:30])[C:21]=4[CH:31]=3)[CH2:13][N:12]([S:32]([C:35]3[CH:40]=[CH:39][C:38]([CH3:41])=[CH:37][CH:36]=3)(=[O:34])=[O:33])[C@@H:11]([CH2:42][CH2:43][NH:44][C:45](=[O:47])[CH3:46])[CH2:10]2)=[CH:5][CH:4]=1.[H-].[Na+].[CH3:50]I>CN(C)C=O.Cl>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C@@H:9]2[C@@H:14]([O:15][CH2:16][C:17]3[CH:18]=[CH:19][C:20]4[O:25][CH2:24][CH2:23][N:22]([CH2:26][CH2:27][CH2:28][O:29][CH3:30])[C:21]=4[CH:31]=3)[CH2:13][N:12]([S:32]([C:35]3[CH:40]=[CH:39][C:38]([CH3:41])=[CH:37][CH:36]=3)(=[O:33])=[O:34])[C@@H:11]([CH2:42][CH2:43][N:44]([CH3:50])[C:45](=[O:47])[CH3:46])[CH2:10]2)=[CH:7][CH:8]=1
Reactant: CI
Reactant: COCCCN1CCOc2ccc(CO[C@H]3CN(S(=O)(=O)c4ccc(C)cc4)[C@@H](CCNC(C)=O)C[C@@H]3c3ccc(OC)cc3)cc21
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COCCCN1CCOc2ccc(CO[C@H]3CN(S(=O)(=O)c4ccc(C)cc4)[C@@H](CCN(C)C(C)=O)C[C@@H]3c3ccc(OC)cc3)cc21
Reaction time: 1 h

Procedure:
To a solution of 82 mg of N-{2-[(2R,4R,5R)-4-(4-methoxy-phenyl)-5-[4-(3-methoxy-propyl)-3,4-dihydro-2H-benzo[1,4]oxazin-6-ylmethoxy]-1-(toluene-4-sulfonyl)-piperidin-2-yl]-ethyl}-acetamide (from example 25a) in 2.0 ml of N,N-dimethylformamide are added 59 mg of sodium hydride and 0.110 ml of methyl iodide at 0° C. The reaction mixture is stirred for 1 hour, diluted with 1N hydrochloric acid and extracted with tert-butyl methyl ether. The organic phases are combined, dried over sodium sulfate and concentrated under reduced pressure. The residue is purified by flash chromatography (SiO2 60 F) to afford the title compound as a yellow oil. Rf=0.49 (dichlormethane-methanol 10:1); Rt=4.83.
Reaction SMILES: [Cl:1][C:2]1[C:7]([N+:8]([O-])=O)=[C:6]([NH:11][CH2:12][CH:13]([CH3:15])[CH3:14])[CH:5]=[C:4]([CH3:16])[N:3]=1.[H][H]>[Pt].C1(C)C=CC=CC=1>[Cl:1][C:2]1[C:7]([NH2:8])=[C:6]([NH:11][CH2:12][CH:13]([CH3:14])[CH3:15])[CH:5]=[C:4]([CH3:16])[N:3]=1
Reactant: [H][H]
Reactant: Cc1cc(NCC(C)C)c([N+](=O)[O-])c(Cl)n1
Agent: [Pt]
Solvent: Cc1ccccc1
Product: Cc1cc(NCC(C)C)c(N)c(Cl)n1

Procedure:
2-Chloro-N-(2-methylpropyl)-6-methyl-3-nitropyridin-4-amine (5.00 g) from Part A, toluene (100 ml), and 5% platinum on carbon (3.5 g) were added to a Parr shaker and placed on a hydrogenator at a hydrogen pressure of 345 kPa for 4 hours. The reaction, monitored by HPLC, was complete, and the resulting reaction mixture was filtered through a fluted filter paper and then through a folded No.2 Whatman filter. The solvent was removed from the filtrate under reduced pressure, and the resulting oil (4.14 g) was carried on to the next step.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:10][CH:9]([C:11]([OH:13])=[O:12])[O:8][C:7]([CH:20]3[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]3)([CH:14]3[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]3)[C:6]=2[CH:26]=1.[C:27]1(C)C=CC(S(O)(=O)=O)=CC=1.C(=O)(O)[O-].[Na+]>CO>[CH3:27][O:12][C:11]([CH:9]1[O:8][C:7]([CH:20]2[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25]2)([CH:14]2[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]2)[C:6]2[CH:26]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]=2[O:10]1)=[O:13]
Reactant: O=C(O)C1Oc2ccc(Cl)cc2C(C2CCCCC2)(C2CCCCC2)O1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Product: COC(=O)C1Oc2ccc(Cl)cc2C(C2CCCCC2)(C2CCCCC2)O1
Temperature: 25 °C

Procedure:
A solution of 2 g 6-chloro-4,4-dicyclohexyl-4H-benzo[1,3]dioxine-2-carboxylic acid and 73 mg para-toluenesulfonic acid in 4 ml methanol was refluxed for 4 hours. After cooling to room temperature, 50 mg sodium bicarbonate was added and the solvent was removed in vacuo. The residue was dissolved in 10 ml EtOAc, washed with water and dried over Na2SO4. The solvent was removed in vacuo. Yield 1.3 g.
Reaction SMILES: [Cl:1][C:2]1[S:3][C:4]([S:7]([C:10]2[CH:15]=[CH:14][C:13](Cl)=[CH:12][CH:11]=2)(=[O:9])=[O:8])=[CH:5][CH:6]=1.[F:17]C1C=CC=CC=1>ClC1C=CC=CC=1>[Cl:1][C:2]1[S:3][C:4]([S:7]([C:10]2[CH:15]=[CH:14][C:13]([F:17])=[CH:12][CH:11]=2)(=[O:9])=[O:8])=[CH:5][CH:6]=1
Reactant: Fc1ccccc1
Reactant: O=S(=O)(c1ccc(Cl)cc1)c1ccc(Cl)s1
Solvent: Clc1ccccc1
Product: O=S(=O)(c1ccc(F)cc1)c1ccc(Cl)s1

Procedure:
This monomer was synthesized as described in Example 3 for 2-chloro-5-(4'-chlorophenylsulfonyl) thiophene with 1.6 moles of fluorobenzene being substituted for chlorobenzene. The synthesis produced white crystals with a Tm =89.9° C.
Reaction SMILES: I[C:2]1[CH:3]=[C:4]([CH:8]([N:10]([O:22][CH3:23])[C:11]([C:13]2[C:14]([CH:19]([F:21])[F:20])=[N:15][N:16]([CH3:18])[CH:17]=2)=[O:12])[CH3:9])[CH:5]=[CH:6][CH:7]=1.[Cl:24][C:25]1[CH:30]=[CH:29][C:28](B(O)O)=[CH:27][CH:26]=1.C(=O)([O-])[O-].[K+].[K+]>C(O)C.O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[Cl:24][C:25]1[CH:30]=[CH:29][C:28]([C:2]2[CH:7]=[CH:6][CH:5]=[C:4]([CH:8]([N:10]([O:22][CH3:23])[C:11]([C:13]3[C:14]([CH:19]([F:21])[F:20])=[N:15][N:16]([CH3:18])[CH:17]=3)=[O:12])[CH3:9])[CH:3]=2)=[CH:27][CH:26]=1
Reactant: OB(O)c1ccc(Cl)cc1
Reactant: CON(C(=O)c1cn(C)nc1C(F)F)C(C)c1cccc(I)c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: O
Solvent: CCO
Product: CON(C(=O)c1cn(C)nc1C(F)F)C(C)c1cccc(-c2ccc(Cl)cc2)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 46.6 %

Procedure:
To a stirred solution of 3-difluoromethyl-1-methyl-1H-pyrazole-4-carboxylic acid [1-(3-iodo-phenyl)-ethyl]-methoxy-amide (0.2 g, 0.46 mmol), prepared as described in example P2, in a mixture of ethanol (12 ml) and water (4 ml) was added, 4-chloro-phenyl boronic acid (0.079 g, 0.5 mmol) followed by palladium acetate (0.052 g, 0.23 mmol) and potassium carbonate (0.19 g, 1.38 mmol). It was stirred for 18 hours at ambient temperature. Reaction mass was filtered on celite bed then diluted with water and extracted in ethyl acetate (3×60 ml), washed with water, brine and dried over anhydrous sodium sulfate. The crude mass was purified by column chromatography using 36% Ethyl acetate in hexane to yield 0.09 g (50% of theory) of 3-Difluoromethyl-1-methyl-1H-pyrazole-4-carboxylic acid [1-(4′ chloro-biphenyl-3-yl)-ethyl]-methoxy-amide in form of a resin.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3](O)=[O:4].[CH3:8][NH:9][CH:10]([OH:12])[CH3:11]>CC1C=CC(C)=CC=1>[CH3:8][N:9]([CH:10]([OH:12])[CH3:11])[C:3](=[O:4])[C:2]([F:7])([F:6])[F:1]
Reactant: O=C(O)C(F)(F)F
Reactant: CNC(C)O
Solvent: Cc1ccc(C)cc1
Product: CC(O)N(C)C(=O)C(F)(F)F
Reaction time: 8 h

Procedure:
Trifluoroacetic acid (10 ml; 129 mmol) was added to a stirred solution of N-methylaminoethanol (9.72 g; 129 mmol) in p-xylene (10 ml) at 0° C. The mixture was heated under reflux for 12 hours, then allowed to cool and stand at room temperature overnight. All the volatiles were removed and the product distilled under high vacuum to afford the product as a clear liquid. Yield 9.8 g (44%); b.p. 110° C./1 mm.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[N:9]([CH2:13][C:14]([F:17])([F:16])[F:15])[C:8](=[O:18])[CH2:7]2)(=[O:3])[CH3:2].[CH2:19](O)[CH2:20][OH:21].C1(C)C=CC(S(O)(=O)=O)=CC=1>C1C=CC=CC=1.C(OCC)(=O)C>[CH3:2][C:1]1([C:4]2[CH:5]=[C:6]3[C:10](=[CH:11][CH:12]=2)[N:9]([CH2:13][C:14]([F:15])([F:16])[F:17])[C:8](=[O:18])[CH2:7]3)[O:21][CH2:20][CH2:19][O:3]1
Reactant: CC(=O)c1ccc2c(c1)CC(=O)N2CC(F)(F)F
Reactant: OCCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCOC(C)=O
Solvent: c1ccccc1
Product: CC1(c2ccc3c(c2)CC(=O)N3CC(F)(F)F)OCCO1

Procedure:
A solution of 5-acetyl-1-(2,2,2-trifluoro-ethyl)-1,3-dihydro-indol-2-one (1.04 g, 4.0 mmol), ethylene glycol (1.37 mL, 24 mmol) and p-toluenesulfonic acid (10 mg) in benzene (25 mL) was heated to reflux for 4 hours in a flask fitted with a Dean-Stark trap. The solution was diluted with ethyl acetate, washed with saturated sodium bicarbonate, water and brine, dried over magnesium sulfate and concentrated in vacuo to an oil which solidified upon standing (1.19 g, 98%, mp 87-89° C.).
Reaction SMILES: Br[CH2:2][C:3]1[C:4]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[C:5]([S:9]([NH2:12])(=[O:11])=[O:10])[CH:6]=[CH:7][CH:8]=1.[N-:18]=[N+:19]=[N-:20].[Na+]>C(O)C>[N:18]([CH2:2][C:3]1[C:4]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[C:5]([S:9]([NH2:12])(=[O:11])=[O:10])[CH:6]=[CH:7][CH:8]=1)=[N+:19]=[N-:20]
Reactant: [N-]=[N+]=[N-]
Reactant: CCOC(=O)c1c(CBr)cccc1S(N)(=O)=O
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)c1c(CN=[N+]=[N-])cccc1S(N)(=O)=O
Temperature: 25 °C

Procedure:
A solution of 1.64 g of 3-bromomethyl-2-carboethoxybenzenesulfonamide and 0.43 g of sodium azide in ethanol was heated to reflux for 3 hours. The resulting reaction mixture was cooled to room temperature and the ethanol was removed on the rotovap. The residue was partitioned between water and ethyl acetate. The organic phase was dried over magnesium sulfate, filtered and concentrated to give 1.32 g of a waxy solid.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[C:4]([Cl:9])[N:3]=1.[CH3:10][C:11]([CH3:14])([O-:13])[CH3:12].[K+]>O1CCCC1.C(OCC)(=O)C>[C:11]([O:13][C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[C:4]([Cl:9])[N:3]=1)([CH3:14])([CH3:12])[CH3:10]
Reactant: Clc1cc(I)cc(Cl)n1
Reactant: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(C)(C)Oc1cc(I)cc(Cl)n1

Procedure:
To a solution of 2,6 dichloro-4-iodo pyridine (1 g, 3.65 mmol) in 15 mL tetrahydrofuran was added 1M potassium tert-butoxide (4.02 mL, 4.02 mmol) and the solution heated at reflux for 2 hours. The mixture was diluted with ethyl acetate, washed with water and brine and dried over magnesium sulfate, filtered and concentrated. The crude material was used without further purification. MS (DCI) m/e 312.0 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([SH:8])=[CH:4][CH:3]=1.[CH3:9][CH:10]([OH:13])[C:11]#[CH:12].[OH-].[K+]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]/[CH:12]=[CH:11]\[CH:10]([OH:13])[CH3:9])=[CH:4][CH:3]=1
Reactant: C#CC(C)O
Reactant: Sc1ccc(Cl)cc1
Agent: [K+]
Agent: [OH-]
Product: CC(O)/C=C\Sc1ccc(Cl)cc1
Temperature: 100 °C

Procedure:
A mixture of 4.5 g (31.1 mmol) of p-chlorothiophenol, 3.7 g (4.2 ml; 37.3 mmol) of 3-butyn-2-ol and 150 mg of powdered potassium hydroxide is heated to 100° C for 20 minutes. The brown crude product is then chromatographed on silica gel (ethyl acetate/hexane). There is obtained pure rac-(Z)-4-[(p-chlorophenyl)thio]-3-buten-2-ol.
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]#[N:10])=[CH:5][CH:4]=1.[S:11]([O-:14])([O-:13])=[O:12].[Na+:15].[Na+].[Na+].[Cl-]>O>[C:9]([C:6]1[CH:7]=[CH:8][C:3]([CH2:2][S:11]([O-:14])(=[O:13])=[O:12])=[CH:4][CH:5]=1)#[N:10].[Na+:15]
Reactant: O=S([O-])[O-]
Reactant: N#Cc1ccc(CBr)cc1
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Product: N#Cc1ccc(CS(=O)(=O)[O-])cc1

Procedure:
A mixture of α-bromo-p-tolunitrile (24.5 g; 125 mmol) and sodium sulfite (17.0 g; 135 mmol) in 50 ml of water was heated to reflux and refluxed for 18 hours. The mixture was poured, while still hot, into 100 ml of saturated aqueous NaCl. The resulting heavy white precipitate was thoroughly chilled, collected by suction filtration, and washed with two portions of saturated aqueous NaCl and three portions of Et2O. After drying in vacuo over CaSO4, the sodium p-cyanophenylmethylsulfonate was obtained in essentially quantitative yield.
Reaction SMILES: I[C:2]1[CH:7]=[C:6]([N:8]2[CH2:13][CH2:12][N:11]([CH3:14])[CH2:10][CH2:9]2)[N:5]=[CH:4][C:3]=1[NH:15][C:16](=[O:21])[C:17]([CH3:20])([CH3:19])[CH3:18].C(=O)([O-])[O-].[Na+].[Na+].[C:28]1([CH3:37])[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1B(O)O>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.C1(C)C=CC=CC=1>[CH3:18][C:17]([CH3:20])([CH3:19])[C:16]([NH:15][C:3]1[CH:4]=[N:5][C:6]([N:8]2[CH2:13][CH2:12][N:11]([CH3:14])[CH2:10][CH2:9]2)=[CH:7][C:2]=1[C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][C:28]=1[CH3:37])=[O:21]
Reactant: CN1CCN(c2cc(I)c(NC(=O)C(C)(C)C)cn2)CC1
Reactant: Cc1ccccc1B(O)O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: Cc1ccccc1-c1cc(N2CCN(C)CC2)ncc1NC(=O)C(C)(C)C
Temperature: 80 °C

Procedure:
A mixture of 54 g (134 mmol) N-[4-iodo-6-(4-methyl-piperazin-1-yl)-pyridin-3-yl]-2,2-dimethyl-propionamide, 420 ml toluene, 150 ml 2 N sodium carbonate solution, 4.63 g (3.9 mmol) tetrakis(triphenylphosphine)palladium(0) and 20.16 g (147 mmol) o-tolylboronic acid was heated under argon at 80° C. for 12 h. After cooling to room temperature, the aqueous phase was separated and washed twice with toluene. The combined organic layers were washed with 50 ml brine, dried (sodium sulfate), evaporated and dried in vacuo to yield 49 g (quantitative) of the title compound as a brown oil.
Reaction SMILES: Cl[C:2]1[C:3]2[NH:10][C:9]([C:11]3[O:12][CH:13]=[CH:14][CH:15]=3)=[CH:8][C:4]=2[N:5]=[CH:6][N:7]=1.[Cl:16][C:17]1[CH:18]=[C:19]([CH:21]=[CH:22][C:23]=1[O:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][N:27]=1)[NH2:20].CN1CCCC1=O.C(=O)([O-])O.[Na+]>O>[Cl:16][C:17]1[CH:18]=[C:19]([NH:20][C:2]2[C:3]3[NH:10][C:9]([C:11]4[O:12][CH:13]=[CH:14][CH:15]=4)=[CH:8][C:4]=3[N:5]=[CH:6][N:7]=2)[CH:21]=[CH:22][C:23]=1[O:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][N:27]=1
Reactant: Clc1ncnc2cc(-c3ccco3)[nH]c12
Reactant: Nc1ccc(OCc2ccccn2)c(Cl)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN1CCCC1=O
Solvent: O
Product: Clc1cc(Nc2ncnc3cc(-c4ccco4)[nH]c23)ccc1OCc1ccccn1
Temperature: 140 °C
Reaction time: 2 h
Yield: 46.6 %

Procedure:
A mixture of 4-chloro-6-(2-furyl)-5H-pyrrolo[3,2-d]pyrimidine (80 mg), 3-chloro-4-(pyridin-2-ylmethoxy)aniline (94 mg) and 1-methyl-2-pyrrolidinone (2.5 mL) was stirred at 140° C. for 2 hrs, poured into water (10 mL) and adjusted to pH 8 with saturated aqueous sodium hydrogen carbonate. The mixture was extracted with ethyl acetate (30 mL×2). The organic layers were combined and dried over anhydrous magnesium sulfate. After concentration under reduced pressure, the residue was subjected to silica gel column chromatography (eluent, hexane:ethyl acetate=1:1→0:1). The object fraction was concentrated under reduced pressure. Chloroform-diisopropyl ether was added to the residue, and the solid was collected by filtration and dried under reduced pressure at 60° C. to give the title compound (71 mg).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([C:11]=1[NH:12][CH2:13][C:14]([CH3:21])([CH3:20])[C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:9][CH:8]=[CH:7][CH:6]=2.[C:22](OCC)(OCC)(OCC)[CH2:23][CH3:24].C(OC)(OC)(OC)CCC.C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1>>[CH2:23]([C:24]1[N:12]([CH2:13][C:14]([CH3:20])([CH3:21])[C:15]([O:17][CH2:18][CH3:19])=[O:16])[C:11]2[C:10]3[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=3[N:4]=[CH:3][C:2]=2[N:1]=1)[CH3:22]
Reactant: CCOC(=O)C(C)(C)CNc1c(N)cnc2ccccc12
Reactant: CCOC(CC)(OCC)OCC
Agent: CCCC(OC)(OC)OC
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Product: CCOC(=O)C(C)(C)Cn1c(CC)nc2cnc3ccccc3c21
Temperature: 25 °C

Procedure:
Ethyl 3-[(3-aminoquinolin-4-yl)amino]-2,2-dimethylpropanoate (see Example 26 Parts A through D, 3.6 g, 12 mmol) was treated according to a modification of the method described in Part B of Example 8 using triethyl orthopropionate in lieu of trimethyl orthobutyrate. Prior to the addition of triethyl orthopropionate (4.0 mL, 20 mmol) and pyridinium p-toluenesulfonate (0.030 g), the reaction was heated at reflux for 15 minutes. After the reaction was heated at reflux for three hours, it was concentrated under reduced pressure and found to be incomplete by 1H NMR. The oil was dissolved in toluene (100 mL), and concentrated sulfuric acid (one drop) was added. The reaction was heated at reflux for two hours and allowed to cool. Triethylamine (5 mL) was added, and the reaction was heated at reflux for two hours, allowed to cool to ambient temperature, washed with saturated aqueous sodium bicarbonate (2×35 mL), dried over potassium carbonate, filtered, and concentrated to provide 3.6 g of ethyl 3-(2-ethyl-1H-imidazo[4,5-c]quinolin-1-yl)-2,2-dimethylpropanoate as an oil.
Reaction SMILES: [C:1]12([C:11]3[CH:20]=[C:19]4[C:14]([CH:15]=[CH:16][C:17]([Br:21])=[CH:18]4)=[CH:13][C:12]=3[OH:22])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.[F:23][C:24]1[CH:31]=[CH:30][C:27]([CH2:28]Br)=[CH:26][CH:25]=1>>[C:1]12([C:11]3[CH:20]=[C:19]4[C:14]([CH:15]=[CH:16][C:17]([Br:21])=[CH:18]4)=[CH:13][C:12]=3[O:22][CH2:28][C:27]3[CH:30]=[CH:31][C:24]([F:23])=[CH:25][CH:26]=3)[CH2:8][CH:7]3[CH2:9][CH:3]([CH2:4][CH:5]([CH2:6]3)[CH2:10]1)[CH2:2]2
Reactant: Fc1ccc(CBr)cc1
Reactant: Oc1cc2ccc(Br)cc2cc1C12CC3CC(CC(C3)C1)C2
Product: Fc1ccc(COc2cc3ccc(Br)cc3cc2C23CC4CC(CC(C4)C2)C3)cc1
Yield: 85.9 %

Procedure:
Following the basic procedure of Example 11, by reacting 1.1 g (3 mmol) of 7-(1-adamantyl)-6-hydroxy-2-bromonaphthalene with 420 μl (3,3 mmol) of 4-fluorobenzyl bromide, 1.2 g (86%) of the expected compound was obtained in the form of a colorless oil.
Reaction SMILES: S(O[CH2:6][CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][CH:10]=1)(=O)(=O)C.C(=O)([O-])[O-].[Na+].[Na+].[I-].[Na+].[N+:25]([C:28]1[CH:41]=[CH:40][C:31]([C:32]([O:34][C@H:35]2[CH2:39][CH2:38][NH:37][CH2:36]2)=[O:33])=[CH:30][CH:29]=1)([O-:27])=[O:26]>C(#N)C>[N+:25]([C:28]1[CH:41]=[CH:40][C:31]([C:32]([O:34][C@H:35]2[CH2:39][CH2:38][N:37]([CH2:6][CH2:7][CH2:8][C:9]3[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][CH:10]=3)[CH2:36]2)=[O:33])=[CH:30][CH:29]=1)([O-:27])=[O:26]
Reactant: COc1ccc(CCCOS(C)(=O)=O)cc1
Reactant: O=C(O[C@H]1CCNC1)c1ccc([N+](=O)[O-])cc1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [Na+]
Solvent: CC#N
Product: COc1ccc(CCCN2CC[C@H](OC(=O)c3ccc([N+](=O)[O-])cc3)C2)cc1
Temperature: 90 °C

Procedure:
3-(4-Methoxyphenyl)propyl mesylate (732 mg, 3.00 mmol), sodium carbonate (320 mg, 3.00 mmol) and sodium iodide (30 mg, 0.20 mmol) were added to a solution of (S)-3-(4-nitrobenzoyloxy)pyrrolidine (472 mg, 2.00 mmol) in acetonitrile (25 ml), and they were heated under reflux at 90° C. for 6 hours. The solvent was evaporated under reduced pressure. The obtained residue was subjected to silica gel column chromatography. The product was eluted with hexane and ethyl acetate (10:1) and then with a mixture of the same solvents (1:1). The appropriate fractions were combined, and the solvent was evaporated under reduced pressure to obtain (S)-3-(4-nitrobenzoyloxy)-1-[3-(4-methoxyphenyl)propyl]pyrrolidine in the form of a light yellow oil (507 mg, 66%).
Reaction SMILES: CC[O-].[Na+].[CH:5](=O)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[CH2:13]([O:15][C:16](=[O:23])[CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH3:14].Cl>C(O)C>[CH2:13]([O:15][C:16](=[O:23])[C:17](=[CH:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH3:14]
Reactant: CCOC(=O)CC(=O)OCC
Reactant: O=Cc1ccccc1
Agent: CC[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)C(=Cc1ccccc1)C(=O)OCC
Temperature: 25 °C

Procedure:
To a solution of 12.8 g sodium ethylate in 140 ml of ethanol, 10.0 g of benzaldehyde and 17.4 g of Malonic acid diethyl ester dissolved in 35 ml ethanol was added drop-wise over 1 h at 50° C. Then, the reaction mixture was heated to reflux for 12 h. After cooling to RT half of the solvent was evaporated under reduced pressure and diluted with 200 ml of water. The remaining reaction mixture was acidified to pH 1 by addition of concentrated hydrochloric acid and then extracted with ethyl acetate. The organic phase was dried over MgSO4 and the solvents were removed under reduced pressure. The crude product was pure enough for the next reaction step.
Reaction SMILES: [Cl:1][C:2]1[C:15]([F:16])=[C:14]([F:17])[C:13]([Cl:18])=[C:12]([F:19])[C:3]=1[C:4]([CH2:6][C:7]([O:9][CH2:10][CH3:11])=[O:8])=[O:5].[CH:20](OCC)(OCC)[O:21][CH2:22][CH3:23].C(OC(=O)C)(=O)C>>[Cl:1][C:2]1[C:15]([F:16])=[C:14]([F:17])[C:13]([Cl:18])=[C:12]([F:19])[C:3]=1[C:4]([C:6](=[CH:20][O:21][CH2:22][CH3:23])[C:7]([O:9][CH2:10][CH3:11])=[O:8])=[O:5]
Reactant: CCOC(=O)CC(=O)c1c(F)c(Cl)c(F)c(F)c1Cl
Reactant: CCOC(OCC)OCC
Solvent: CC(=O)OC(C)=O
Product: CCOC=C(C(=O)OCC)C(=O)c1c(F)c(Cl)c(F)c(F)c1Cl
Temperature: 150 °C

Procedure:
A mixture of 31.5 g (0.1 mol) of ethyl (2,5-dichloro-3,4,6-trifluorobenzoyl)-acetate, 22.2 g (0.15 mol) of triethyl orthoformate and 25.5 g (0.25 mol) of acetic anhydride is heated under reflux for 2 hours (heating bath temperature of 150° C.). Low-boiling constituents are distilled off first under a waterpump vacuum and then under a high vacuum up to a bottom temperature of 130° C. The residue is used further as crude product.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][N:11]([NH2:14])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:15][C:16]1[NH:17][CH:18]=[C:19]([CH:21]=O)[N:20]=1>CO>[CH2:1]([N:8]1[CH2:9][CH2:10][N:11](/[N:14]=[CH:21]/[C:19]2[N:20]=[C:16]([CH3:15])[NH:17][CH:18]=2)[CH2:12][CH2:13]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: NN1CCN(Cc2ccccc2)CC1
Reactant: Cc1nc(C=O)c[nH]1
Solvent: CO
Product: Cc1nc(/C=N/N2CCN(Cc3ccccc3)CC2)c[nH]1
Temperature: 25 °C
Yield: 87.7 %

Procedure:
4-Benzyl-1-piperazinamine (K. L. Rinehart Jr et al. Bioorg. Chem., 6, 341 (1977); 10 g) and 2-methylimidazole-4-carbaldehyde (5.8 g) were suspended in methanol (200 ml), and the reaction mixture was heated under reflux for 3 hours. The reaction solution was cooled to room temperature, and then the solvent was distilled off under reduced pressure. To the residue was added diethyl ether, and the deposited precipitate was collected by filtration to obtain the title compound as a pale brown solid (13 g, 90%).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:11]2[O:10][C:9]([CH3:13])([CH3:12])[CH2:8][C:7]=2[C:6]([CH3:14])=[C:5]([N:15]2[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]2)[C:4]=1[CH3:21].Br[C:23]1[CH:28]=[CH:27][C:26]([O:29][CH:30]([F:32])[F:31])=[CH:25][CH:24]=1>>[F:31][CH:30]([F:32])[O:29][C:26]1[CH:27]=[CH:28][C:23]([N:18]2[CH2:19][CH2:20][N:15]([C:5]3[C:4]([CH3:21])=[C:3]([O:2][CH3:1])[C:11]4[O:10][C:9]([CH3:13])([CH3:12])[CH2:8][C:7]=4[C:6]=3[CH3:14])[CH2:16][CH2:17]2)=[CH:24][CH:25]=1
Reactant: COc1c(C)c(N2CCNCC2)c(C)c2c1OC(C)(C)C2
Reactant: FC(F)Oc1ccc(Br)cc1
Product: COc1c(C)c(N2CCN(c3ccc(OC(F)F)cc3)CC2)c(C)c2c1OC(C)(C)C2
Yield: 2 %

Procedure:
By using 1-(7-methoxy-2,2,4,6-tetramethyl-2,3-dihydro-1-benzofuran-5-yl)piperazine (436 mg, 1.50 mmol) synthesized in Reference example 96 and 1-bromo-4-(difluoromethoxy)benzene (524 mg, 2.25 mmol), the reaction was carried out in the same manner as Reference example 59 to synthesize the title compound 12.9 mg (yield 1%). Melting point was 151 to 152° C. (hexane).