Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[CH3:2][C:3]1[C:7]([CH2:8][C:9]([OH:11])=O)=[C:6]([CH3:12])[NH:5][N:4]=1.[NH2:13][C@@H:14]([CH2:32][O:33][CH2:34][C:35]1[CH:40]=[CH:39][C:38]([F:41])=[CH:37][CH:36]=1)[C:15]([NH:17][C:18]1[CH:23]=[CH:22][C:21]([O:24][C:25]2[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=2)=[CH:20][CH:19]=1)=[O:16]>>[CH3:12][C:6]1[C:7]([CH2:8][C:9]([NH:13][C@@H:14]([CH2:32][O:33][CH2:34][C:35]2[CH:36]=[CH:37][C:38]([F:41])=[CH:39][CH:40]=2)[C:15]([NH:17][C:18]2[CH:19]=[CH:20][C:21]([O:24][C:25]3[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=3)=[CH:22][CH:23]=2)=[O:16])=[O:11])=[C:3]([CH3:2])[NH:4][N:5]=1
Reactant: Cc1n[nH]c(C)c1CC(=O)O
Reactant: N[C@@H](COCc1ccc(F)cc1)C(=O)Nc1ccc(Oc2ccc(F)cc2)cc1
Agent: Cl
Product: Cc1n[nH]c(C)c1CC(=O)N[C@@H](COCc1ccc(F)cc1)C(=O)Nc1ccc(Oc2ccc(F)cc2)cc1
Yield: 50 %

Procedure:
Proceeding as in Example 1, but substituting 2-(3,5-dimethyl-1H-pyrazol-4-yl)acetic acid hydrochloride and (S)-2-amino-3-(4-fluorobenzyloxy)-N-(4-(4-fluorophenoxy)phenyl)propanamide, gave Compound 258, (S)-2-(2-(3,5-dimethyl-1H-pyrazol-4-yl)acetamido)-3-(4-fluorobenzyloxy)-N-(4-(4-fluorophenoxy)phenyl)propanamide (70 mg, 50%). 1H-NMR (400 MHz, CDCl3): δ 8.55 (s, 1H), 7.40-7.25 (m, 6H), 7.15-6.90 (m, 7H), 6.50 (m, 1H), 4.79-4.73 (m, 1H), 4.63 (m, 2H), 3.80-3.50 (m, 4H), 2.20 (s, 6H). MS (EI) for C29H28F2N4O4 found 535 (MH+).
Reaction SMILES: [F:1][C@H:2]1[CH2:19][C@@:17]2([CH3:18])[C@@H:13]([CH2:14][CH2:15][C:16]2=[O:20])[C@H:12]2[C@H:3]1[C@@H:4]1[C:9]([CH2:10][C@H:11]2[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][OH:26])=[CH:8][C:7](=[O:27])[CH2:6][CH2:5]1.[C:28](OC(=O)C)(=[O:30])[CH3:29].O>N1C=CC=CC=1>[C:28]([O:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][C@@H:11]1[CH2:10][C:9]2[C@H:4]([CH2:5][CH2:6][C:7](=[O:27])[CH:8]=2)[C@@H:3]2[C@@H:12]1[C@H:13]1[C@@:17]([CH2:19][C@@H:2]2[F:1])([CH3:18])[C:16](=[O:20])[CH2:15][CH2:14]1)(=[O:30])[CH3:29]
Reactant: CC(=O)OC(C)=O
Reactant: C[C@]12C[C@H](F)[C@H]3[C@@H]([C@H](CCCCCO)CC4=CC(=O)CC[C@@H]43)[C@@H]1CCC2=O
Solvent: c1ccncc1
Solvent: O
Product: CC(=O)OCCCCC[C@@H]1CC2=CC(=O)CC[C@@H]2[C@@H]2[C@@H]1[C@@H]1CCC(=O)[C@@]1(C)C[C@@H]2F
Reaction time: 0.75 h

Procedure:
20 g of 11β-fluoro-7α-(5-hydroxypentyl)-estr-4-ene-3,17-dione in 100 ml of pyridine can be reacted over a period of 2 hours with 50 ml of acetic anhydride at 25° C. Then, 5 ml of water is added at 0° C., and it is stirred for 45 minutes. It is extracted with diethyl ether, washed with 2N sulfuric acid, pyridine-free, and the solution is neutralized in succession with saturated sodium bicarbonate solution and water. After drying and concentration by evaporation in a vacuum, the crude product is chromatographed on silica gel with a hexane-ethyl acetate-gradient. 17 g of 7α-(5-acetoxypentyl)-11β-fluoro-estr-4-ene-3,17-dione with a melting point of 78.4° C. is obtained.
Reaction SMILES: [Cl:1][C:2]1[C:3]([NH:12][C:13]2[N:23]=[C:22]3[C:16]([N:17]([CH3:30])[C:18](=[O:29])[CH2:19][CH2:20][N:21]3[CH:24]3[CH2:28][CH2:27][CH2:26][CH2:25]3)=[CH:15][N:14]=2)=[CH:4][C:5]([F:11])=[C:6]([CH:10]=1)[C:7](O)=[O:8].[NH2:31][CH:32]1[CH2:37][CH2:36][N:35]([CH3:38])[CH2:34][CH2:33]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C>CN(C=O)C>[Cl:1][C:2]1[C:3]([NH:12][C:13]2[N:23]=[C:22]3[C:16]([N:17]([CH3:30])[C:18](=[O:29])[CH2:19][CH2:20][N:21]3[CH:24]3[CH2:28][CH2:27][CH2:26][CH2:25]3)=[CH:15][N:14]=2)=[CH:4][C:5]([F:11])=[C:6]([CH:10]=1)[C:7]([NH:31][CH:32]1[CH2:37][CH2:36][N:35]([CH3:38])[CH2:34][CH2:33]1)=[O:8]
Reactant: CN1CCC(N)CC1
Reactant: CN1C(=O)CCN(C2CCCC2)c2nc(Nc3cc(F)c(C(=O)O)cc3Cl)ncc21
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CN1CCC(NC(=O)c2cc(Cl)c(Nc3ncc4c(n3)N(C3CCCC3)CCC(=O)N4C)cc2F)CC1
Temperature: 50 °C
Yield: 47.6 %

Procedure:
5-chloro-4-[(2-cyclopentyl-6-methyl-5-oxo-2,6,9,11-tetrazabicyclo[5.4.0]undeca-7,9,11-trien-10-yl)amino]-2-fluoro-benzoic acid (Intermediate 219; 100 mg, 0.23 mmol), 4-amino-1-methylpiperidine (Fluorochem; 40 mg, 0.35 mmol) and HATU (132 mg, 0.35 mmol) were stirred in DMF (3 mL). N,N-diisopropylethylamine (121 μl, 0.69 mmol) was added and the mixture heated at 50° C. for 2 hours. The mixture was cooled and absorbed on to an SCX column, which was subsequently washed with methanol and eluted with ammonia in methanol. Product containing fractions were concentrated and the residue purified by base modified reverse phase preparative chromatography to yield the title compound as a white solid (58 mg, 48%)
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:11]2[CH:16]=[CH:15][C:14]([CH:17]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=3[CH3:35])[CH2:18][C:19](=[N:27][OH:28])[C:20]3[CH:25]=[CH:24][N:23]=[C:22]([CH3:26])[CH:21]=3)=[CH:13][CH:12]=2)[CH:5]=[CH:6][C:7]=1[C:8]([OH:10])=[O:9].Cl>COCCOC.O1CCOCC1>[F:1][C:2]1[CH:3]=[C:4]([C:11]2[CH:16]=[CH:15][C:14]([CH:17]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=3[CH3:35])[CH2:18]/[C:19](=[N:27]\[OH:28])/[C:20]3[CH:25]=[CH:24][N:23]=[C:22]([CH3:26])[CH:21]=3)=[CH:13][CH:12]=2)[CH:5]=[CH:6][C:7]=1[C:8]([OH:10])=[O:9]
Reactant: Cc1cc(C(CC(c2ccc(-c3ccc(C(=O)O)c(F)c3)cc2)c2ccccc2C)=NO)ccn1
Agent: Cl
Solvent: C1COCCO1
Solvent: COCCOC
Product: Cc1cc(/C(CC(c2ccc(-c3ccc(C(=O)O)c(F)c3)cc2)c2ccccc2C)=N/O)ccn1
Temperature: 50 °C
Reaction time: 4 h

Procedure:
To a suspension of 3-fluoro-4′-[3-[hydroxyimino]-3-(2-methyl-pyridin-4-yl)-1-o-tolyl-propyl]-biphenyl-4-carboxylic acid (example 112; 151 mg) in DME (2.5 mL) was added HCl in dioxane (4M, 0.8 mL) at rt. The reaction mixture was stirred at 50° C. for 4 hours, was concentrated and dissolved in ethyl acetate (5 mL) and a saturated aqueous solution of NaHCO3 (0.1 mL). A saturated aqueous solution of NH4Cl was added, the phases were separated and the inorganic one was extracted with EtOAc (2×). The combined organic phases were washed with brine, dried over Na2SO4, filtered and concentrated in vacuo to give 3-fluoro-4′-[3-[(E)-hydroxyimino]-3-(2-methyl-pyridin-4-yl)-1-o-tolyl-propyl]-biphenyl-4-carboxylic acid as a yellow solid, MS (ESI+): m/z=469.3 ([M+H]+).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([C:10]([OH:12])=O)=[CH:7][C:6]=2[CH:13]=1.[ClH:14].Cl.[NH2:16][C@@H:17]1[CH:22]2[CH2:23][CH2:24][N:19]([CH2:20][CH2:21]2)[CH2:18]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C>CN(C=O)C>[ClH:14].[N:19]12[CH2:24][CH2:23][CH:22]([CH2:21][CH2:20]1)[C@@H:17]([NH:16][C:10]([C:8]1[O:9][C:5]3[CH:4]=[CH:3][C:2]([Br:1])=[CH:13][C:6]=3[CH:7]=1)=[O:12])[CH2:18]2
Reactant: N[C@H]1CN2CCC1CC2
Reactant: O=C(O)c1cc2cc(Br)ccc2o1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(N[C@H]1CN2CCC1CC2)c1cc2cc(Br)ccc2o1

Procedure:
240 mg (0.98 mmol) of 5-bromobenzofuran-2-carboxylic acid, 200 mg (0.98 mmol) of (R)-3-aminoquinuclidine dihydrochloride, 450 mg (1.18 mmol) of HATU, 460 mg (3.54 mmol) of N,N-diisopropylethylamine and 2.0 ml of DMF are reacted by general method C. The reaction mixture is purified by preparative HPLC. Finally, an excess of 1N hydrochloric acid is added to the product. The solvent is removed under reduced pressure. 202 mg (53% of theory) of the title compound are isolated.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:21])[CH:4]([OH:20])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:8][CH:7]=1.[C:22]1(O)[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>>[CH3:1][O:2][C:3](=[O:21])[CH:4]([O:20][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:8][CH:7]=1
Reactant: COC(=O)C(O)Cc1ccc(OCc2ccccc2)cc1
Reactant: Oc1ccccc1
Product: COC(=O)C(Cc1ccc(OCc2ccccc2)cc1)Oc1ccccc1

Procedure:
3-(4-Benzyloxyphenyl)-2-hydroxypropanoic acid methyl ester was reacted with phenol using the same method as in Example 38(c) to give 3-(4-benzyloxyphenyl)-2-phenoxypropanoic acid methyl ester.
Reaction SMILES: [Na].[C:2]([O:10]CC)(=[O:9])[CH2:3][C:4]([O:6]CC)=[O:5].C1(C)C=CC(S(O[CH2:23][CH2:24][CH2:25][CH:26]2[CH2:31][CH2:30][N:29]([C:32]([O:34][CH2:35][C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=3)=[O:33])[CH2:28][CH2:27]2)(=O)=O)=CC=1.[OH-].[Na+]>C(O)C.O>[CH2:35]([O:34][C:32]([N:29]1[CH2:30][CH2:31][CH:26]([CH2:25][CH2:24][CH2:23][CH:3]([C:4]([OH:6])=[O:5])[C:2]([OH:10])=[O:9])[CH2:27][CH2:28]1)=[O:33])[C:36]1[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=1
Reactant: Cc1ccc(S(=O)(=O)OCCCC2CCN(C(=O)OCc3ccccc3)CC2)cc1
Reactant: CCOC(=O)CC(=O)OCC
Agent: [Na+]
Agent: [Na]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: O=C(O)C(CCCC1CCN(C(=O)OCc2ccccc2)CC1)C(=O)O

Procedure:
In 300 ml of ethanol is dissolved 5.8 g of sodium, and 40 g of diethyl malonate is added to the solution, followed by stirring. 3-(1-Benzyloxycarbonyl-4-piperidyl)propyl p-toluenesulfonate (90.5 g) is added to this mixture followed by refluxing with stirring for 2 hours. After cooling, 1 l of water is added to the reaction solution, which is then extracted with 500 ml of ethyl acetate. The extract is dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give ethyl 5-(1-benzyloxycarbonyl-4-piperidy)-2-ethoxycarbonylvalearate as an oily material. This product is dissolved in 200 ml of ethanol, and a solution of 34 g of sodium hydroxide in 200 ml of water is added dropwise to the solution with stirring. After the addition is completed, 300 ml of water is added to the reaction solution, which is then extracted with a mixture of ether and petroleum ether (1:1, 300 ml). The aqeuous layer is made acidic with conc. hydrochloric acid, followed by extraction with 500 ml of ethyl acetate. The extract is washed with water, dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give 5-(1-benzyloxycarbonyl-4-piperidyl)-2-carboxyvaleric acid as an oily material. This product is heated at 160° to 170° C. with stirring for 45 minutes to give 50 g of 5-(1-benzyloxycarbonyl-4-piperidyl)valeric acid as an oily material.
Reaction SMILES: [CH3:1][CH:2]([C:4]1[N:8]=[C:7](C(Cl)(Cl)Cl)[O:6][N:5]=1)[CH3:3].[NH:13]1[CH2:18][CH2:17][CH:16]([CH2:19][OH:20])[CH2:15][CH2:14]1>CO>[CH3:1][CH:2]([C:4]1[N:8]=[C:7]([N:13]2[CH2:18][CH2:17][CH:16]([CH2:19][OH:20])[CH2:15][CH2:14]2)[O:6][N:5]=1)[CH3:3]
Reactant: CC(C)c1noc(C(Cl)(Cl)Cl)n1
Reactant: OCC1CCNCC1
Solvent: CO
Product: CC(C)c1noc(N2CCC(CO)CC2)n1
Temperature: 50 °C
Yield: 34.1 %

Procedure:
A solution of 3-(1-methylethyl)-5-(trichloromethyl)-1,2,4-oxadiazole (prepared as in Example 158, Alternative synthesis, Step 3, 179 g, 0.78 mol) in MeOH (300 mL) was treated with 4-piperidinemethanol (108 g, 0.94 mol) and stirred and heated at 50° C. overnight. The solvent was removed and the residue was purified by flash chromatography on a silica gel column to give {1-[3-(1-methylethyl)-1,2,4-oxadiazol-5-yl]-4-piperidinyl}methanol (60 g, 34%) as a pale yellow oil.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([OH:8])[CH:5]=[CH:6][CH:7]=1.[C:9]([N:13]1[CH2:16][CH:15]([OH:17])[CH2:14]1)([CH3:12])([CH3:11])[CH3:10].[OH-].[K+]>>[NH2:1][C:2]1[CH:3]=[C:4]([CH:5]=[CH:6][CH:7]=1)[O:8][CH2:16][CH:15]([OH:17])[CH2:14][NH:13][C:9]([CH3:12])([CH3:11])[CH3:10]
Reactant: Nc1cccc(O)c1
Reactant: CC(C)(C)N1CC(O)C1
Agent: [K+]
Agent: [OH-]
Product: CC(C)(C)NCC(O)COc1cccc(N)c1
Temperature: 140 °C
Yield: 42.3 %

Procedure:
A mixture of 21.8 parts of m-aminophenol, 22 parts of 1-(tert.-butyl)-3-azetidinol and 0.7 part of potassium hydroxide was heated under nitrogen gas at 140° C. for 8 hours with agitation. The reaction mixture was cooled and treated in the same manner as in Example 39. Recrystallization from benzene gave 17.2 parts of 1-(3'-aminophenoxy)-3-(tert.-butylamino)-2-propanol in the form of colorless needles melting at 105°-106° C. The yield was 42.3%. The results of infra-red spectrum analysis are as follows:
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH2:7](Br)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[CH3:15][C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([CH2:22][C:23]([F:26])([F:25])[F:24])[C:17]=1[OH:27]>CN(C=O)C>[CH2:7]([O:27][C:17]1[C:18]([CH2:22][C:23]([F:24])([F:25])[F:26])=[CH:19][CH:20]=[CH:21][C:16]=1[CH3:15])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: BrCc1ccccc1
Reactant: Cc1cccc(CC(F)(F)F)c1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1cccc(CC(F)(F)F)c1OCc1ccccc1
Temperature: 25 °C
Reaction time: 15 h
Yield: 108.7 %

Procedure:
Potassium carbonate (953 mg, 6.89 mmol) followed by benzyl bromide (0.8 mL, 6.89 mmol) were added to a solution of 2-methyl-6-(2,2,2-trifluoro-ethyl)-phenol (1.78 g, 6.89 mmol) in DMF (20 mL). The mixture was stirred at room temperature for 15 hours and then partitioned between H2O and EtOAc. The organic layer was washed with 1N HCl, brine, dried over Na2SO4 and concentrated to a brown oil. Purification by flash column chromatography (0% to 20% EtOAc in hexanes) gave the product as a clear oil (2.1 g). LCMS: APCI−VE=279
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][N:5]([CH:22]2[CH2:24][CH2:23]2)[C:6]=1[N:7]1[CH2:13][CH2:12][CH:11]([F:14])[CH:10]([NH:15]C(=O)C(F)(F)F)[CH2:9][CH2:8]1.C(OC([NH:32][C:33]1[S:37][C:36]([C:38]2[C:43]([F:44])=[CH:42][CH:41]=[CH:40][C:39]=2[F:45])=[N:35][C:34]=1[C:46](O)=[O:47])=O)(C)(C)C>>[NH2:32][C:33]1[S:37][C:36]([C:38]2[C:43]([F:44])=[CH:42][CH:41]=[CH:40][C:39]=2[F:45])=[N:35][C:34]=1[C:46]([NH:1][C:2]1[CH:3]=[N:4][N:5]([CH:22]2[CH2:23][CH2:24]2)[C:6]=1[N:7]1[CH2:13][CH2:12][C@H:11]([F:14])[C@@H:10]([NH2:15])[CH2:9][CH2:8]1)=[O:47]
Reactant: CC(C)(C)OC(=O)Nc1sc(-c2c(F)cccc2F)nc1C(=O)O
Reactant: Nc1cnn(C2CC2)c1N1CCC(F)C(NC(=O)C(F)(F)F)CC1
Product: Nc1sc(-c2c(F)cccc2F)nc1C(=O)Nc1cnn(C2CC2)c1N1CC[C@H](N)[C@@H](F)CC1

Procedure:
Following the procedure for Example 107 starting from N-(1-(4-amino-1-cyclopropyl-1H-pyrazol-5-yl)-5-fluoroazepan-4-yl)-2,2,2-trifluoroacetamide and 5-(tert-butoxycarbonyl-amino)-2-(2,6-difluorophenyl)thiazole-4-carboxylic acid gave, after purification via preparative HPLC, 278 as the monoformate salt as an off-white solid (209 mg, 50% over two steps). 1H NMR (400 MHz, d4-MeOD) δ 8.54 (s, 1H), 7.52 (s, 1H), 7.51-7.44 (m, 1H), 7.19-7.12 (m, 2H), 4.86 (dtd, J=48.0, 9.3, 3.0 Hz, 1H), 3.61-3.47 (m, 2H), 3.48-3.36 (m, 4H), 2.46-2.32 (m, 1H), 2.26-2.05 (m, 2H), 1.99-1.86 (m, 1H), 1.23-1.11 (m, 2H), 1.13-1.05 (m, 2H). LCMS (ES+) m/z 492 (M+1)
Reaction SMILES: CS(O[CH2:6][CH2:7][CH2:8][S:9][C:10]1[N:11]([CH2:26][C:27]2[C:36]3[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=3)[CH:30]=[CH:29][CH:28]=2)[CH:12]=[C:13]2[C:18]=1[C:17](=[O:19])[N:16]([CH3:20])[C:15](=[O:21])[N:14]2[CH2:22][CH:23]([CH3:25])[CH3:24])(=O)=O.[C-:37]#[N:38].[Na+]>CN(C)C=O>[CH3:20][N:16]1[C:17](=[O:19])[C:18]2=[C:10]([S:9][CH2:8][CH2:7][CH2:6][C:37]#[N:38])[N:11]([CH2:26][C:27]3[C:36]4[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=4)[CH:30]=[CH:29][CH:28]=3)[CH:12]=[C:13]2[N:14]([CH2:22][CH:23]([CH3:24])[CH3:25])[C:15]1=[O:21]
Reactant: CC(C)Cn1c(=O)n(C)c(=O)c2c(SCCCOS(C)(=O)=O)n(Cc3cccc4ccccc34)cc21
Reactant: [C-]#N
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)Cn1c(=O)n(C)c(=O)c2c(SCCCC#N)n(Cc3cccc4ccccc34)cc21
Yield: 27.9 %

Procedure:
5-[(3-{Methanesulphonyloxy}propyl)thio]-3-methyl-1-(2-methylpropyl)-6-(1-naphthalenylmethyl)-1H-pyrrolo[3,4-d]pyrimidine-2,4(3H,6H)-dione (391 mg) was dissolved in dimethyformamide (15 ml) and sodium cyanide (254 mg) was added. The mixture was sonicated for 4 hours and then poured onto sodium bicarbonate (aqueous). The mixture was extracted thrice with ethyl acetate, the extracts were combined, washed twice with water and once with brine, then dried, filtered and evaporated. The resultant oil was chromatographed, eluting with ethyl acetate:isohexane (4:5) and then triturated with cyclohexane-ethyl acetate to give the title compound (95 mg).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]2[CH2:13][CH2:12][CH2:11][NH:10]2)[CH:6]=[CH:7][CH:8]=1.Br[CH2:15][CH2:16][N:17]1[C:21](=[O:22])[C:20]2=[CH:23][CH:24]=[CH:25][CH:26]=[C:19]2[C:18]1=[O:27].C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>C(#N)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]2[CH2:13][CH2:12][CH2:11][N:10]2[CH2:15][CH2:16][N:17]2[C:18](=[O:27])[C:19]3[C:20](=[CH:23][CH:24]=[CH:25][CH:26]=3)[C:21]2=[O:22])[CH:6]=[CH:7][CH:8]=1
Reactant: O=C1c2ccccc2C(=O)N1CCBr
Reactant: COc1cccc(C2CCCN2)c1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC#N
Product: COc1cccc(C2CCCN2CCN2C(=O)c3ccccc3C2=O)c1
Temperature: 25 °C
Yield: 55.9 %

Procedure:
To a solution of 2-(3-methoxyphenyl)pyrrolidine (1.9 g) in dry acetonitrile (50 ml) was added N-(2-bromoethyl)phthalimide (3.6 g) followed by milled potassium carbonate (3.8 g) and potassium iodide (catalytic amount) at ambient temperature, under nitrogen. The reaction mixture was warmed under reflux for 18.5 hrs, cooled to ambient temperature and filtered through a pad of celite. The filter cake was washed with ethyl acetate, and the combined filtrates were concentrated. The residue was diluted with ether and methanol, the mixture was filtered, and the filtrate was concentrated. The residue was purified by flash column chromatography (silica gel, dichloromethane). The appropriate fractions were collected and concentrated to afford a total 2.1 g (54%) of product. Recrystallization from ether gave the analytical sample, mp 110°-111° C.
Reaction SMILES: Br[C:2]1[C:10]2[C:9]([NH:11][C@H:12]([C:14]3[N:19]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)[C:18](=[O:26])[C:17]4=[C:27]([CH3:30])[CH:28]=[CH:29][N:16]4[N:15]=3)[CH3:13])=[N:8][CH:7]=[N:6][C:5]=2[N:4]([CH2:31][O:32][CH2:33][CH2:34][Si:35]([CH3:38])([CH3:37])[CH3:36])[CH:3]=1.[NH2:39][C:40]1[CH:41]=[C:42]([OH:55])[CH:43]=[C:44](B2OC(C)(C)C(C)(C)O2)[CH:45]=1.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.O>[NH2:39][C:40]1[CH:45]=[C:44]([C:2]2[C:10]3[C:9]([NH:11][C@H:12]([C:14]4[N:19]([C:20]5[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=5)[C:18](=[O:26])[C:17]5=[C:27]([CH3:30])[CH:28]=[CH:29][N:16]5[N:15]=4)[CH3:13])=[N:8][CH:7]=[N:6][C:5]=3[N:4]([CH2:31][O:32][CH2:33][CH2:34][Si:35]([CH3:38])([CH3:37])[CH3:36])[CH:3]=2)[CH:43]=[C:42]([OH:55])[CH:41]=1
Reactant: Cc1ccn2nc([C@H](C)Nc3ncnc4c3c(Br)cn4COCC[Si](C)(C)C)n(-c3ccccc3)c(=O)c12
Reactant: CC1(C)OB(c2cc(N)cc(O)c2)OC1(C)C
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: Cc1ccn2nc([C@H](C)Nc3ncnc4c3c(-c3cc(N)cc(O)c3)cn4COCC[Si](C)(C)C)n(-c3ccccc3)c(=O)c12
Yield: 64.9 %

Procedure:
(S)-2-(1-((5-Bromo-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)ethyl)-5-methyl-3-phenylpyrrolo[2,1-f][1,2,4]triazin-4(3H)-one (0.53 g, 0.89 mmol) was treated with 3-amino-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (0.52 g, 2.22 mmol), sodium carbonate (0.24 g, 2.22 mmol), 1,1′-bis(diphenylphosphino)ferrocene-palladium(II)dichloride dichloromethane complex (0.22 g, 0.27 mmol) and 22 ml 1,2-dimethoxyethane and 5 ml water as a solvents according to the method described in Preparation 62. The residue was purified using SP1® Purification System (0% to 15% dichloromethane-2-propanol) to obtain 0.36 g (62% yield) of the title compound.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:30])=[C:6]([S:8]([N:11]([CH3:29])[N:12]=[CH:13][C:14]2[N:18]3[CH:19]=[C:20]([C:23]4[CH:24]=[N:25][CH:26]=[CH:27][CH:28]=4)[CH:21]=[CH:22][C:17]3=[N:16][CH:15]=2)(=[O:10])=[O:9])[CH:7]=1.ClC1C=C(C=CC=1)C(OO)=[O:36].O>C(Cl)Cl>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:30])=[C:6]([S:8]([N:11]([CH3:29])[N:12]=[CH:13][C:14]2[N:18]3[CH:19]=[C:20]([C:23]4[CH:24]=[N+:25]([O-:36])[CH:26]=[CH:27][CH:28]=4)[CH:21]=[CH:22][C:17]3=[N:16][CH:15]=2)(=[O:9])=[O:10])[CH:7]=1
Reactant: Cc1ccc(F)cc1S(=O)(=O)N(C)N=Cc1cnc2ccc(-c3cccnc3)cn12
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: O
Solvent: ClCCl
Product: Cc1ccc(F)cc1S(=O)(=O)N(C)N=Cc1cnc2ccc(-c3ccc[n+]([O-])c3)cn12
Temperature: 25 °C
Reaction time: 3 h
Yield: 64 %

Procedure:
To an ice-cooled solution of 5-fluoro-N, 2-dimethyl-N′-((6-(pyridin-3-yl)imidazo[1,2-a]pyridin-3-yl)methylene) benzenesulfonohydrazide (step 1, 18 mg, 0.043 mmol) in CH2Cl2 was added 3-chloroperoxybenzoic acid (14.46 mg, 0.065 mmol). The reaction mixture was stirred for 3 h at RT. The reaction mixture was then poured on to water. Organic layer was separated, washed with saturated solution of NaHCO3 and dried over Na2SO4. Crude compound was purified by column chromatography (silica gel, 5% EtOAc in petroleum ether) to obtain the title compound. Yield: 64%; 1H NMR (DMSO-d6; 300 MHz,): δ 9.45 (s, 1H), 8.57 (s, 1H), 8.32-8.31 (m, 2H), 8.03 (s, 1H), 7.83-7.79 (m, 2H), 7.67-7.64 (dd, 1H, J=8.4 Hz, 2.4 Hz), 7.56 (m, 1H), 7.43-7.36 (m, 3H), 3.40 (s, 3H), 2.54 (s, 3H); MS: m/z 440 (M+1)+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH2:10][CH2:11][OH:12])[CH:5]=[CH:6][C:7]=1[O:8][CH3:9].[CH2:13]([O:15][CH:16]([O:22]CC)[C:17](OCC)=O)C>C[N+]([O-])=O.Cl[Ti](Cl)(Cl)Cl>[Br:1][C:2]1[CH:3]=[C:4]2[C:5](=[CH:6][C:7]=1[O:8][CH3:9])[CH:17]([C:16]([O:15][CH3:13])=[O:22])[O:12][CH2:11][CH2:10]2
Reactant: COc1ccc(CCO)cc1Br
Reactant: CCOC(=O)C(OCC)OCC
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: C[N+](=O)[O-]
Product: COC(=O)C1OCCc2cc(Br)c(OC)cc21
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
To an ice-cooled mixture of 2-[3-bromo-4-(methyloxy)phenyl]ethanol (9.5 g, 41 mmol) and ethyl bis(ethyloxy)acetate (8.7 g, 48 mmol) in 60 mL of CH3NO2 was added TiCl4 (31.2 g, 169 mmol) over a period of 20 min. After stirring for 10 min, the ice bath was removed and the mixture was allowed to stir at room temperature over night. The mixture was poured onto ice/aqueous 1N HCl. Extracted by DCM and backwashed with 1N HCl and brine, dried over anhydrous sodium sulfate and concentrated. The residue was purified via column chromatography to give methyl 6-bromo-7-(methyloxy)-3,4-dihydro-1H-isochromene-1-carboxylate.
Reaction SMILES: C([O:3][C:4](=[O:40])[CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][O:21][C:22]2[CH:27]=[C:26]([S:28]([CH3:31])(=[O:30])=[O:29])[CH:25]=[C:24]([I:32])[CH:23]=2)[C:10]=1[CH2:33][CH2:34][C:35]([O:37]CC)=[O:36])C.[OH-].[Na+]>C(O)C.CCOC(C)=O>[C:35]([CH2:34][CH2:33][C:10]1[C:11]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][O:21][C:22]2[CH:27]=[C:26]([S:28]([CH3:31])(=[O:30])=[O:29])[CH:25]=[C:24]([I:32])[CH:23]=2)=[CH:12][CH:13]=[CH:14][C:9]=1[O:8][CH2:7][CH2:6][CH2:5][C:4]([OH:40])=[O:3])([OH:37])=[O:36]
Reactant: CCOC(=O)CCCOc1cccc(CCCCCCOc2cc(I)cc(S(C)(=O)=O)c2)c1CCC(=O)OCC
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CCO
Product: CS(=O)(=O)c1cc(I)cc(OCCCCCCc2cccc(OCCCC(=O)O)c2CCC(=O)O)c1
Temperature: 60 °C
Reaction time: 4 h
Yield: 97.2 %

Procedure:
To a solution of 4-{2-(2-ethoxycarbonyl-ethyl)-3-[6-(3-iodo-5-methanesulfonyl-phenoxy)-hexyl]-phenoxy}-butyric acid ethyl ester (0.9 g, 1.31 mmol) in hot ethanol (40 mL) was added aqueous 1.0 N sodium hydroxide (10 mL). The resulting solution was heated to 60° C. and stirred for 4 h. Then, the reaction mixture was cooled down and diluted with EtOAc, washed with 10% HCl and brine. The combined ethyl acetate extracts were dried over anhydrous sodium sulfate, concentrated under reduced pressure to afford 805 mg (97%) of title compound as a light yellow oil. HR-ES(+) m/e calcd for C26H33O8SI (M+H)+ 633.1014, found 633.1008.