Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[NH:5][CH2:4][CH2:3][C:2]1=[O:12].[CH3:13][O:14][C:15]1[CH:16]=[C:17]([S:23](Cl)(=[O:25])=[O:24])[CH:18]=[CH:19][C:20]=1[O:21][CH3:22]>N1C=CC=CC=1.C(OCC)(=O)C>[CH3:13][O:14][C:15]1[CH:16]=[C:17]([S:23]([N:5]2[C:6]3[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=3[NH:1][C:2](=[O:12])[CH2:3][CH2:4]2)(=[O:24])=[O:25])[CH:18]=[CH:19][C:20]=1[O:21][CH3:22]
Reactant: O=C1CCNc2ccccc2N1
Reactant: COc1ccc(S(=O)(=O)Cl)cc1OC
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: COc1ccc(S(=O)(=O)N2CCC(=O)Nc3ccccc32)cc1OC
Temperature: 25 °C
Reaction time: 2 h
Yield: 85 %

Procedure:
To a solution of 1,3,4,5-tetrahydro-1,5-benzodiazepin-2(2H)-one (700 mg) in pyridine (10 ml) was added 3,4-dimethoxybenzenesulfonyl chloride (1.07 g) and the mixture was stirred at ambient temperature for 2 hours. The resulting mixture was diluted with ethyl acetate, and then the organic solution was washed successively with 0.5N hydrochloric acid, saturated aqueous sodium bicarbonate solution and brine. Drying, filtering and the removal of solvents afforded a crude product. The crude product was triturated with a mixture of diethyl ether and n-hexane (1:1) to give 5-(3,4-dimethoxybenzenesulfonyl)-1,3,4,5-tetrahydro-1,5-benzodiazepin-2(2H)-one (1.33 g) as a yellow powder.
Reaction SMILES: [C:1]([O:5][C:6](=[O:16])[NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([Cl:14])[C:9]=1[CH3:15])([CH3:4])([CH3:3])[CH3:2].C([Li])(CC)C.CON(C)[C:25](=[O:27])[CH3:26]>O1CCCC1>[C:1]([O:5][C:6](=[O:16])[NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([Cl:14])[C:9]=1[CH2:15][C:25](=[O:27])[CH3:26])([CH3:4])([CH3:3])[CH3:2]
Reactant: CON(C)C(C)=O
Reactant: Cc1c(Cl)cccc1NC(=O)OC(C)(C)C
Agent: [Li]C(C)CC
Solvent: C1CCOC1
Product: CC(=O)Cc1c(Cl)cccc1NC(=O)OC(C)(C)C
Temperature: -10 °C
Yield: 88.7 %

Procedure:
To a cold solution of (3-Chloro-2-methyl-phenyl)-carbamic acid tert-butyl ester (5.0 g, 20.7 mmol) in anhydrous tetrahydrofuran (100 ml) at −40° C. under N2, was added a solution of s-butyl lithium (40 ml, 52 mmol, 1.3 M in cyclohexane) dropwise and maintained the reaction temperature below −30° C. To the bright yellow solution at −50° C. was added a solution of N-methoxy N-methylacetamide (2.33 g, 22.6 mmol) in anhydrous tetrahydrofuran (40 ml) dropwise and maintained the reaction temperature between −50° C. to −40° C. The mixture was allowed to warm to −10° C. over a period of 35 minutes and was then partitioned between diethyl ether and 0.3 N hydrochloric acid solution. The organic extract was washed with water and brine, dried (anhydrous sodium sulfate), and concentrated under reduced pressure. The residue was purified by flash column chromatography over silica gel eluting with 20% ethyl acetate in hexane to give crude [3-Chloro-2-(2-oxo-propyl)-phenyl]-carbamic acid tert-butyl ester (5.21 g) as a colorless oil.
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][NH2:7])=[CH:4][CH:3]=1.[Br:10][CH2:11][CH2:12][CH2:13][CH2:14][C:15]1([C:28](Cl)=[O:29])[C:27]2[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=2[C:21]2[C:16]1=[CH:17][CH:18]=[CH:19][CH:20]=2>>[F:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][NH:7][C:28]([C:15]2([CH2:14][CH2:13][CH2:12][CH2:11][Br:10])[C:27]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[C:21]3[C:16]2=[CH:17][CH:18]=[CH:19][CH:20]=3)=[O:29])=[CH:4][CH:3]=1
Reactant: NCc1ccc(F)cc1
Reactant: O=C(Cl)C1(CCCCBr)c2ccccc2-c2ccccc21
Product: O=C(NCc1ccc(F)cc1)C1(CCCCBr)c2ccccc2-c2ccccc21

Procedure:
Prepared analogously to Example 1 from 4-fluoro-benzylamine and 9-(4-bromo-butyl)-9H-fluorene-9-carboxylic acid chloride.
Reaction SMILES: C(N)C1C=CC=CC=1.[NH2:9][CH2:10][C:11]1[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=1.[F:17][C:18]1[CH:43]=[CH:42][C:21]([O:22][CH2:23][CH2:24][N:25]([CH3:41])[C:26]2[N:31]=[C:30]([C:32]3[S:33][C:34]([C:38](O)=[O:39])=[C:35]([CH3:37])[N:36]=3)[CH:29]=[N:28][CH:27]=2)=[CH:20][CH:19]=1>>[N:13]1[CH:14]=[CH:15][CH:16]=[C:11]([CH2:10][NH:9][C:38]([C:34]2[S:33][C:32]([C:30]3[CH:29]=[N:28][CH:27]=[C:26]([N:25]([CH2:24][CH2:23][O:22][C:21]4[CH:20]=[CH:19][C:18]([F:17])=[CH:43][CH:42]=4)[CH3:41])[N:31]=3)=[N:36][C:35]=2[CH3:37])=[O:39])[CH:12]=1
Reactant: NCc1cccnc1
Reactant: Cc1nc(-c2cncc(N(C)CCOc3ccc(F)cc3)n2)sc1C(=O)O
Solvent: NCc1ccccc1
Product: Cc1nc(-c2cncc(N(C)CCOc3ccc(F)cc3)n2)sc1C(=O)NCc1cccnc1
Yield: 85 %

Procedure:
Following the procedure described in Example 1 (Part A), making variations as required to replace benzylamine with 3-(aminomethyl)-pyridine to react with 2-(6-{[2-(4-fluoro-phenoxy)-ethyl]-methyl-amino}-pyrazin-2-yl)-4-methyl-thiazole-5-carboxylic acid, the title compound was obtained in 85% yield. 1H NMR (400 MHz, CD2Cl2) δ 8.51 (s, 1H), 8.47-8.62 (m, 2H), 8.12 (s, 1H), 7.67-7.73 (m, 1H), 7.25-7.30 (m, 1H), 6.90-6.96 (m, 2H), 6.78-6.84 (m, 2H), 6.31 (bs, 1H), 4.59 (d, J=4.0 Hz, 2H), 4.16-4.21 (m, 2H), 3.95-4.01 (m, 2H), 3.23 (s, 3H), 2.70 (s, 3H); MS (ES+) m/z 479.2 (M+1), Rt=1.36 min.
Reaction SMILES: C1CCN2C(=NCCC2)CC1.[C:12]1([CH2:18][CH2:19][CH:20]=[O:21])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.[N:22]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[O:23]>ClCCl>[OH:23][N:22]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[C:20](=[O:21])[CH2:19][CH2:18][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: O=CCCc1ccccc1
Reactant: O=Nc1ccccc1
Solvent: C1CCC2=NCCCN2CC1
Solvent: ClCCl
Product: O=C(CCc1ccccc1)N(O)c1ccccc1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
DBU (15 mg, 0.1 mmol) was added under argon to a solution of 3-phenylpropanal (134 mg, 1 mmol), nitrosobenzene (107 mg, 1 mmol) and catalyst (36.4 mg, 0.1 mmol) in dichloromethane (5 mL). The reaction mixture was stirred at room temperature for 10 min. The solvent was removed under vacuum, and the residue was purified by flash silica gel column chromatography using hexane and ethyl acetate as the eluents.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([CH:9]2[CH2:13][CH2:12][CH2:11][CH2:10]2)[CH:3]=1.C(N(CC)CC)C.Cl[C:22]([O:24][CH3:25])=[O:23]>CN(C1C=CN=CC=1)C.ClCCl>[C:22](=[O:23])([O:24][CH3:25])[O:8][C:5]1[CH:6]=[CH:7][C:2]([Br:1])=[CH:3][C:4]=1[CH:9]1[CH2:13][CH2:12][CH2:11][CH2:10]1
Reactant: COC(=O)Cl
Reactant: Oc1ccc(Br)cc1C1CCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)Oc1ccc(Br)cc1C1CCCC1
Temperature: 25 °C
Yield: 84.6 %

Procedure:
4-Bromo-2-cyclopentylphenol (10.0 g, 41.47 mmol) and DMAP (253 mg, 2.07 mmol) was dissolved in dichloromethane (50 mL) and triethylamine (11.6 mL, 82.94 mmol), cooled to 0° C. and treated with methyl chloroformate (4.8 mL, 62.20 mmol). The reaction was allowed to warm to room temperature over 2 h. The reaction was quenched with water, the layers separated, and the aqueous layer re-extracted with dichloromethane. The combined organic extracts were dried over Na2SO4, filtered and concentrated in vacuo to yield an oil that was purified by silica gel chromatography (20% ethyl acetate/hexane) to yield 4-bromo-2-cyclopentylphenyl methyl carbonate (10.5 g, 85% yield). 1H NMR (400.0 MHz, DMSO-d6) δ 7.52 (d, J=2.4 Hz, 1H), 7.44 (dd, J=2.4, 8.6 Hz, 1H), 7.22-7.17 (m, 1H), 3.84 (s, 3H), 3.07-2.98 (m, 1H), 1.95-1.88 (m, 2H), 1.79-1.71 (m, 2H), 1.66-1.46 (m, 4H).
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[OH:9].[CH2:10](Br)[CH:11]=[CH2:12].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH2:12]([O:9][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]([Cl:8])[C:2]=1[Cl:1])[CH:11]=[CH2:10]
Reactant: C=CCBr
Reactant: Oc1cccc(Cl)c1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: C=CCOc1cccc(Cl)c1Cl
Temperature: 0 °C

Procedure:
A mixture of 2,3-dichlorophenol (35.5 g., 0.22 mole), allyl bromide (29.4 g., 0.24 mole) and potassium carbonate (33 g., 0.24 mole) in dimethylformamide (200 ml.) is vigorously stirred and heated at 55°-60° C. for one hour, poured into ice water, extracted with ether, washed with water and dried over magnesium sulfate. Evaporation of the ether leaves 2,3-dichlorophenyl allyl ether which is subjected to a Claisen rearrangement by heating at 250° C. for ten minutes. Distillation gives 36 g. of 2,3-dichloro-6-allylphenol which boils at 132°-4°/13 mm.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:9]2[CH2:13][C@H:12]([CH2:14][NH:15][C:16](=[O:18])[CH3:17])[O:11][C:10]2=[O:19])[CH:5]=[CH:6][C:7]=1I.[Si:20]([O:27][CH2:28][C@@H:29]1[O:33][C:32](=[O:34])[N:31]([C:35]2[CH:40]=[CH:39][C:38]([Sn](C)(C)C)=[C:37]([F:45])[CH:36]=2)[CH2:30]1)([C:23]([CH3:26])([CH3:25])[CH3:24])([CH3:22])[CH3:21]>>[Si:20]([O:27][CH2:28][C@@H:29]1[O:33][C:32](=[O:34])[N:31]([C:35]2[CH:40]=[CH:39][C:38]([C:7]3[CH:6]=[CH:5][C:4]([N:9]4[CH2:13][C@H:12]([CH2:14][NH:15][C:16](=[O:18])[CH3:17])[O:11][C:10]4=[O:19])=[CH:3][C:2]=3[F:1])=[C:37]([F:45])[CH:36]=2)[CH2:30]1)([C:23]([CH3:26])([CH3:24])[CH3:25])([CH3:22])[CH3:21]
Reactant: CC(C)(C)[Si](C)(C)OC[C@H]1CN(c2ccc([Sn](C)(C)C)c(F)c2)C(=O)O1
Reactant: CC(=O)NC[C@H]1CN(c2ccc(I)c(F)c2)C(=O)O1
Product: CC(=O)NC[C@H]1CN(c2ccc(-c3ccc(N4C[C@H](CO[Si](C)(C)C(C)(C)C)OC4=O)cc3F)c(F)c2)C(=O)O1
Yield: 57.7 %

Procedure:
Using essentially the same procedure as Example 28, but starting from N-{[(5S)-3-(3-fluoro-4-iodophenyl)-2-oxo-1,3-oxazolidin-5-yl]methyl}acetamide (0.38 g, 1.00 mM) and adding (5R)-5-({[tert-butyl(dimethyl)silyl]oxy}methyl)-3-[3-fluoro-4-(trimethylstannyl)phenyl]-1,3-oxazolidin-2-one (0.73 g, 1.50 mM) gave the title compound as a light yellow solid (0.334 g).
Reaction SMILES: CC1(C)[N:6]2[C:7](=[O:13])[C:8](=[C:10]([CH3:12])[CH3:11])[CH2:9][C@@H:5]2[CH2:4][O:3]1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>CO>[OH:3][CH2:4][C@@H:5]1[NH:6][C:7](=[O:13])[C:8](=[C:10]([CH3:12])[CH3:11])[CH2:9]1
Reactant: CC(C)=C1C[C@@H]2COC(C)(C)N2C1=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CO
Product: CC(C)=C1C[C@H](CO)NC1=O
Temperature: 60 °C
Yield: 60.3 %

Procedure:
To a solution of (R)-3,3-dimethyl-6-(propan-2-ylidene)tetrahydropyrrolo[1,2-c]oxazol-5(3H)-one (4.63 g, 23.73 mmol) in MeOH (50 mL) at room temperature was added p-toluenesulfonic acid monohydrate (0.451 g, 2.373 mmol) and then heated at 60° C. for 45 min. The solvent was evaporated and the crude material was absorbed onto a plug of silica gel and was purified by chromatography through a REDISEP™ pre-packed silica gel column (80 g), eluting with a gradient of 0% to 10% MeOH in DCM to give (R)-5-(hydroxymethyl)-3-(propan-2-ylidene)pyrrolidin-2-one (2.223 g, 14.32 mmol, 60.4% yield) as an yellow solid. 1H NMR (400 MHz, CDCl3) δ 6.60 (br. s., 1H), 3.74 (td, J=8.0, 3.9 Hz, 1H), 3.67 (dd, J=11.1, 3.6 Hz, 1H), 3.44 (dd, J=11.1, 7.3 Hz, 1H), 2.75-2.86 (m, 1H), 2.81 (dd, J=16.5, 8.7 Hz, 1H), 2.33-2.43 (m, 1H), 2.23 (s, 3H), 1.77 (s, 3H). m/z (ESI, +ve) 156 (M+H).
Reaction SMILES: [CH2:1]([O:3][CH2:4][CH2:5][N:6]([CH3:14])[C:7](=O)[O:8]C(C)(C)C)[CH3:2].FC(F)(F)C(O)=O.[Cl:22][CH2:23]Cl>>[Cl:22][CH2:23][C:7]([N:6]([CH2:5][CH2:4][O:3][CH2:1][CH3:2])[CH3:14])=[O:8]
Reactant: CCOCCN(C)C(=O)OC(C)(C)C
Reactant: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCOCCN(C)C(=O)CCl
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of tert-butyl (2-ethoxyethyl)methylcarbamate (1.2 g) in dichloromethane (6 ml) was added trifluoroacetic acid (6 ml) on an ice bath. The solution was stirred for 30 minutes while warming to room temperature, then the solvent was evaporated in vacuo. Synthesized from the resulting (2-ethoxyethyl)methylamine trifluoroacetate (crude product) (2.3 g) according to an analogous synthetic method to Preparation Example 119, the title compound (799 mg) was obtained.
Reaction SMILES: [C:1]([O:5][C:6](=[O:35])[NH:7][C:8]1([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[C:19]([C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)=[CH:20][C:21]4[NH:26][C:25](=S)[CH2:24][O:23][C:22]=4[N:28]=3)=[CH:14][CH:13]=2)[CH2:11][CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].[C:36]([NH:41][NH2:42])(=O)[CH:37]([CH3:39])[CH3:38]>CC1C=CC(C)=CC=1>[CH:37]([C:36]1[N:26]2[C:21]3[CH:20]=[C:19]([C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)[C:18]([C:15]4[CH:16]=[CH:17][C:12]([C:8]5([NH:7][C:6](=[O:35])[O:5][C:1]([CH3:4])([CH3:3])[CH3:2])[CH2:11][CH2:10][CH2:9]5)=[CH:13][CH:14]=4)=[N:28][C:22]=3[O:23][CH2:24][C:25]2=[N:42][N:41]=1)([CH3:39])[CH3:38]
Reactant: CC(C)C(=O)NN
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(-c3nc4c(cc3-c3ccccc3)NC(=S)CO4)cc2)CCC1
Solvent: Cc1ccc(C)cc1
Product: CC(C)c1nnc2n1-c1cc(-c3ccccc3)c(-c3ccc(C4(NC(=O)OC(C)(C)C)CCC4)cc3)nc1OC2
Temperature: 150 °C
Yield: 16.9 %

Procedure:
A suspension of tert-butyl(1-(4-(7-phenyl-2-thioxo-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-6-yl)phenyl)cyclobutyl)carbamate (150 mg, 0.308 mmol) and isobutyrohydrazide (28 mg, 0.308 mmol) in p-xylene (1.5 ml) was heated to 150° C. for 15 minutes under microwave irradiation. The resulting reaction mixture was concentrated to dryness under reduced pressure. The crude residue was purified by Biotage silica gel chromatography (gradient 0% to 20% ethyl acetate in n-hexanes) to give the title compound (28 mg, 17%). LCMS (Method D): RT=1.497 min, M+1=538. 1H NMR (500 MHz, CDCl3) δ 7.85 (1H, s), 7.36-7.31 (5H, m), 7.28 (2H, m), 7.24-7.19 (2H, m), 5.56 (2H, s), 3.46-3.36 (1H, m), 2.57-2.39 (4H, m), 2.13-2.02 (1H, m), 1.88-1.76 (1H, m), 1.57-1.53 (6H, d), 1.44-1.29 (9H, bs).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][CH2:6][CH2:7][O:8][CH2:9][C:10]#[CH:11].[Cl:12][C:13]1[CH:14]=[N:15][CH:16]=[C:17]([Cl:40])[C:18]=1[CH2:19][C:20]1[C:29]2[C:24](=[C:25](OS(C(F)(F)F)(=O)=O)[C:26]([O:30][CH3:31])=[CH:27][CH:28]=2)[CH:23]=[N:22][N:21]=1.C(NCC)C>C(OCC)C.[Cu]I>[Cl:12][C:13]1[CH:14]=[N:15][CH:16]=[C:17]([Cl:40])[C:18]=1[CH2:19][C:20]1[C:29]2[C:24](=[C:25]([C:11]#[C:10][CH2:9][O:8][CH2:7][CH2:6][O:5][CH2:4][CH2:3][O:2][CH3:1])[C:26]([O:30][CH3:31])=[CH:27][CH:28]=2)[CH:23]=[N:22][N:21]=1
Reactant: COc1ccc2c(Cc3c(Cl)cncc3Cl)nncc2c1OS(=O)(=O)C(F)(F)F
Reactant: C#CCOCCOCCOC
Agent: [Cu]I
Solvent: CCOCC
Solvent: CCNCC
Product: COCCOCCOCC#Cc1c(OC)ccc2c(Cc3c(Cl)cncc3Cl)nncc12
Yield: 46.2 %

Procedure:
A suspension under N2 of 3-[2-(2-methoxy-ethoxy)-ethoxy]-propyne (810 mg, 5.12 mmoles), prepared as described in example 133, trifluoro-methanesulfonic acid 1-(3,5-dichloro-pyridin-4-ylmethyl)-6-methoxy-phthalazin-5-yl ester (2 g, 4.27 mmoles), prepared as described in example 73, and diethylamine (40 ml) was added under stirring with bis(triphenylphosphine)PdCl2 (60 mg, 0.085 mmole) and CuI (16.18 mg, 0.085 mmole). The mixture was refluxed for 6 hours, then dried. The residue was flash chromatographed (eluent: ethyl acetate) to give a solid which was taken up in ethyl ether, filtered and dried under vacuum, at 40° C. to give 940 mg of the title compound (yield: 46%).
Reaction SMILES: CS(O[CH2:6][C:7]1[N:11]([C:12]2[CH:17]=[CH:16][C:15]([C:18]([NH:20][CH2:21][CH3:22])=[O:19])=[CH:14][CH:13]=2)[N:10]=[N:9][C:8]=1[C:23]([NH:25][CH:26]1[CH2:28][CH2:27]1)=[O:24])(=O)=O.C(=O)([O-])[O-].[K+].[K+].[CH3:35][S-:36].[Na+]>C(O)C.C(OCC)(=O)C>[CH:26]1([NH:25][C:23]([C:8]2[N:9]=[N:10][N:11]([C:12]3[CH:13]=[CH:14][C:15]([C:18]([NH:20][CH2:21][CH3:22])=[O:19])=[CH:16][CH:17]=3)[C:7]=2[CH2:6][S:36][CH3:35])=[O:24])[CH2:27][CH2:28]1
Reactant: C[S-]
Reactant: CCNC(=O)c1ccc(-n2nnc(C(=O)NC3CC3)c2COS(C)(=O)=O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CCO
Product: CCNC(=O)c1ccc(-n2nnc(C(=O)NC3CC3)c2CSC)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 92.5 %

Procedure:
(4-[(Cyclopropylamino)carbonyl]-1-{4-[(ethylamino)carbonyl]phenyl}-1H-1,2,3-triazol-5-yl)methyl methanesulfonate (196 mg, 0.481 mmol) obtained in Example 126a), potassium carbonate (33.2 mg, 0.241 mmol, 0.5 eq.) and 15% aqueous sodium thiomethoxide solution (0.449 ml, 0.962 mmol, 2.0 eq.) were dissolved in ethanol (3.5 ml), and the mixture was stirred at room temperature for 2 hr. The reaction mixture was diluted with ethyl acetate (30 ml), washed twice with 2% aqueous sodium carbonate solution and with saturated brine, dried over anhydrous sodium sulfate and concentrated. Diethyl ether was added and the precipitate was collected by filtration, washed with diethyl ether and dried to give the title compound as a white powder (160 mg, 0.445 mmol, 92.5%).
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15]Br.C([CH:19]1[CH2:23][CH2:22][CH2:21][N:20]1[C:24](=[O:32])[C:25]1[CH:30]=[CH:29][C:28]([NH2:31])=[CH:27][CH:26]=1)C>CN(C)P(N(C)C)(N(C)C)=O>[OH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][NH:31][C:28]1[CH:27]=[CH:26][C:25]([C:24]([N:20]2[CH2:19][CH2:23][CH2:22][CH2:21]2)=[O:32])=[CH:30][CH:29]=1
Reactant: CCC1CCCN1C(=O)c1ccc(N)cc1
Reactant: OCCCCCCCCCCCCCCBr
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: O=C(c1ccc(NCCCCCCCCCCCCCCO)cc1)N1CCCC1

Procedure:
A solution of 10 g. of 14-hydroxytetradecyl bromide and 10.8 g. of ethyl 1-(4-aminobenzoyl)pyrrolidine in 75 ml. hexamethylphosphoramide is heated at 110° C. for 17 hours. The cooled solution is diluted with 100 ml. water, filtered, and the residue is washed in portions with 100 ml. 50% ethanol-water. After drying the product is crystallized from ethanol to yield 1-[4-(14-hydroxytetradecylamino)benzoyl]pyrrolidine as a white solid.
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5]([CH2:7]P(OC)(OC)=O)=[O:6].[F:14][C:15]1[CH:16]=[C:17]([NH:24][C:25](=[O:30])[O:26][CH:27]([CH3:29])[CH3:28])[CH:18]=[C:19]([F:23])[C:20]=1[CH:21]=O.Cl>CN(C=O)C>[F:14][C:15]1[CH:16]=[C:17]([NH:24][C:25]([O:26][CH:27]([CH3:28])[CH3:29])=[O:30])[CH:18]=[C:19]([F:23])[C:20]=1/[CH:21]=[CH:7]/[C:5]([O:4][CH3:3])=[O:6]
Reactant: CC(C)OC(=O)Nc1cc(F)c(C=O)c(F)c1
Reactant: COC(=O)CP(=O)(OC)OC
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)/C=C/c1c(F)cc(NC(=O)OC(C)C)cc1F
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
Sodium hydride (1.4 g of 60% dispersion, 35 mmol) was placed in a flask and washed three times with hexane. The resulting solid was suspended in DMF (29 mL) and cooled to 0° C. Trimethyl phosphonoacetate (5.95 mL, 36.75 mmol) was added dropwise to this suspension to give a clear homogeneous solution. After stirring for another 15 minutes at 0° C., a solution of isopropyl 3,5-difluoro-4-formylphenylcarbamate (8.51 g, 35 mmol) in DMF (25 mL) was added dropwise. The resulting orange suspension was allowed to warm slowly to room temperature and stirred for 16 hours. The reaction mixture was then poured into 0.5 N HCl and extracted with three portions of dichloromethane. Combined organic phases were washed with saturated NaHCO3, H2O, brine, and dried (MgSO4) filtered and concentrated. The resulting orange solid was washed with hexane, 30% ethyl acetate-hexane, and then purified by column chromatography (15-30% ethyl acetate-hexane) to provide title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]([CH2:11][NH:12]C(=O)C(F)(F)F)=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].Cl>CO>[ClH:1].[NH2:12][CH2:11][C:8]1[CH:9]=[CH:10][C:2]([Cl:1])=[C:3]([CH:7]=1)[C:4]([OH:6])=[O:5]
Reactant: O=C(O)c1cc(CNC(=O)C(F)(F)F)ccc1Cl
Agent: Cl
Solvent: CO
Product: NCc1ccc(Cl)c(C(=O)O)c1

Procedure:
To a solution of 2-chloro-5-((2,2,2-trifluoroacetamido)methyl)benzoic acid (step-1 of Intermediate-26, 10.0 g, 35.50 mmol) in methanol (100 mL) was added conc. HCl (10 mL). The reaction mixture was refluxed for 18 h. The reaction mixture was concentrated and crude reaction mixture was used for next step.
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]1[NH:8][C:7]2[CH:9]=[CH:10][CH:11]=[CH:12][C:6]=2[N:5]=1.[Cl:13][CH2:14][CH2:15][O:16][CH2:17][CH2:18]Cl.[I-].[Na+]>C(OCC)(=O)C>[Cl:13][CH2:14][CH2:15][O:16][CH2:17][CH2:18][N:5]1[C:6]2[CH:12]=[CH:11][CH:10]=[CH:9][C:7]=2[N:8]=[C:4]1[CH3:3]
Reactant: Cc1nc2ccccc2[nH]1
Reactant: ClCCOCCCl
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: CCOC(C)=O
Product: Cc1nc2ccccc2n1CCOCCCl
Temperature: 0 °C

Procedure:
Part A. A mineral oil suspension of sodium hydride (0.91 g, 50%, 37.8 mmol) was washed with hexane and dried under vacuum, then suspended in dimethylsulfoxide (20 mL). The mixture was cooled to 0° C., and a solution of 2-methyl-1H-benzimidazole (5.00 g, 37.8 mmol) was added dropwise with stirring. The mixture was stirred for 5 hours with warming to ambient temperature, then was treated dropwise with a solution of chloroethyl ether (8.90 mL, 75.6 mmol). Sodium iodide (2.83 g, 18.9 mmol) was added, and the mixture was heated to 90° C. for 18 hours. After being cooled to ambient temperature, the reaction mixture was poured into 400 mL ethyl acetate, and washed with water (3×400 mL). The aqueous phases were back-extracted in sequence with ethyl acetate (400 mL). The organic phases were combined, dried over anhydrous magnesium sulfate, filtered and evaporated. The residual oil was separated by flash chromatography to afford the product, 1-[ 2-(2-chloroethoxy)ethyl]-2-methyl-1H-benzimidazole, as a white solid, m.p. 96°-98° C. 1H NMR (CDCl3): 7.74-7.64 (1H, m); 7.31-7.20 (3H, m); 4.31 (2H, t, J=5.4 Hz); 3.81 (2H, t, J=5.4 Hz); 3.59 (2H, t, J=5.1 Hz); 3.51 (2H, t, J=5.1 Hz); 2.64 (3H, s).
Reaction SMILES: [C:1]1([CH:8]=[CH:7][CH:6]=[C:4]([OH:5])[CH:3]=1)[OH:2].[C:9](O)(=[O:16])[C:10]([CH2:12][C:13]([OH:15])=[O:14])=[CH2:11]>C1(C)C=CC=CC=1.O1CCOCC1>[OH:2][C:1]1[CH:3]=[C:4]2[C:6]([CH2:11][CH:10]([CH2:12][C:13]([OH:15])=[O:14])[C:9](=[O:16])[O:5]2)=[CH:7][CH:8]=1
Reactant: C=C(CC(=O)O)C(=O)O
Reactant: Oc1cccc(O)c1
Solvent: C1COCCO1
Solvent: Cc1ccccc1
Product: O=C(O)CC1Cc2ccc(O)cc2OC1=O
Temperature: 100 °C
Yield: 50 %

Procedure:
In a round-bottomed flask equipped with a Dean-Stark apparatus, 10 g of resorcinol and 11.8 g of itaconic acid were dissolved in 150 ml of a toluene/dioxane mixture (volume ratio 1/1) in the presence of Amberlyst 15 resin from Aldrich. The reaction mixture was heated at 100° C. for 3 hours. After cooling, the crude reaction product was filtered and the filtrate was concentrated under vacuum. The crude product was recrystallized hot from ethyl acetate. This gave 10 g of a white powder, which corresponds to the expected product (50% yield).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:18]=[CH:19][C:20]=1[O:21]C(C)=C)[C:12]([O:14]C(C)=C)=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N12CCN(CC1)CC2.Cl>C(O)C.O>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:18]=[CH:19][C:20]=1[OH:21])[C:12]([OH:14])=[O:13])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C=C(C)OC(=O)c1ccc(OC(=C)C)c(OCc2ccccc2)c1
Agent: C1CN2CCN1CC2
Agent: Cl
Solvent: O
Solvent: CCO
Product: O=C(O)c1ccc(O)c(OCc2ccccc2)c1
Reaction time: 1 h
Yield: 83.4 %

Procedure:
A mixture of propen-2-yl 3-benzyloxy-4-(propen-2-yloxy)benzoate (1.0356 g, 3.19 mmol), tris(triphenyl-phosphine)rhodium chloride1 (204 mg, 0.22 mmol) and 1,4-diazabicyclo[2.2.2]octane (74 mg, 0.66 mmol) in ethanol (18 cm3) and water (2 cm3) was heated under reflux under an atmosphere of nitrogen for 16 h. The cooled mixture was poured into 1 M hydrochloric acid (100 cm3), stirred for 60 min, then extracted with dichloromethane (3×100 cm3). The combined extracts were dried over MgSO4 and evaporated to an orange solid which was purified by flash column chromatography (eluent: 1:1 EtOAc:light petroleum) to give 3-benzyloxy-4-hydroxybenzoic acid as an orange solid (650 mg, 83%), m.p. 167.2-171.3° C.
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7]([NH2:9])=[O:8])=[C:5]([NH2:10])[C:4]([CH2:11][CH2:12][CH3:13])=[N:3]1.[CH2:14]([O:16][C:17]1[CH:25]=[CH:24][C:23]([S:26]([N:29]2[CH2:34][CH2:33][N:32]([CH3:35])[CH2:31][CH2:30]2)(=[O:28])=[O:27])=[CH:22][C:18]=1[C:19](Cl)=O)[CH3:15]>>[CH3:13][CH2:12][CH2:11][C:4]1[C:5]2[N:10]=[C:19]([C:18]3[CH:22]=[C:23]([S:26]([N:29]4[CH2:30][CH2:31][N:32]([CH3:35])[CH2:33][CH2:34]4)(=[O:27])=[O:28])[CH:24]=[CH:25][C:17]=3[O:16][CH2:14][CH3:15])[NH:9][C:7](=[O:8])[C:6]=2[N:2]([CH3:1])[N:3]=1
Reactant: CCCc1nn(C)c(C(N)=O)c1N
Reactant: CCOc1ccc(S(=O)(=O)N2CCN(C)CC2)cc1C(=O)Cl
Product: CCCc1nn(C)c2c(=O)[nH]c(-c3cc(S(=O)(=O)N4CCN(C)CC4)ccc3OCC)nc12

Procedure:
An reaction between 1-methyl-3-propyl-4-aminopyrazole-5-carboxamide and 2-ethoxy-5-(4-methylpiperazine-1-sulfonyl)-benzoyl chloride is performed, and then Sildenafil is obtained by ring closure.