Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[C:33]([F:34])=[C:32]([F:35])[C:31]([F:36])=[C:30]([F:37])[C:3]=1[O:4][S:5]([C:8]1[CH:9]=[C:10]2[C:15](=[CH:16][CH:17]=1)[C:14]([CH:18]1[CH2:22][CH2:21][CH2:20][N:19]1C(OC(C)(C)C)=O)=[CH:13][CH:12]=[CH:11]2)(=[O:7])=[O:6].[F:38][C:39]([F:44])([F:43])[C:40]([OH:42])=[O:41]>C(Cl)Cl>[F:38][C:39]([F:44])([F:43])[C:40]([OH:42])=[O:41].[NH:19]1[CH2:20][CH2:21][CH2:22][CH:18]1[C:14]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:15]=1[CH:16]=[CH:17][C:8]([S:5]([O:4][C:3]1[C:30]([F:37])=[C:31]([F:36])[C:32]([F:35])=[C:33]([F:34])[C:2]=1[F:1])(=[O:7])=[O:6])=[CH:9]2
Reactant: CC(C)(C)OC(=O)N1CCCC1c1cccc2cc(S(=O)(=O)Oc3c(F)c(F)c(F)c(F)c3F)ccc12
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=S(=O)(Oc1c(F)c(F)c(F)c(F)c1F)c1ccc2c(C3CCCN3)cccc2c1
Yield: 93.6 %

Procedure:
A 25-mL round-bottom flask was charged with tert-butyl 2-(6-((perfluorophenoxy)sulfonyl)naphthalen-1-yl)pyrrolidine-1-carboxylate (674 mg, 1.240 mmol), DCM (4960 μl), and trifluoroacetic acid (2389 μl, 31.0 mmol) to give a clear, very lightly-colored solution After 1 h, the mixture was concentrated, and the residue was taken up in diethyl ether and sonicated, resulting in the formation of a white solid. The mixture was filtered, and the collected solid was washed with diethyl ether, dried over a stream of N2 (g) for 20 min, then dried under vacuum for 30 min to give perfluorophenyl 5-(pyrrolidin-2-yl)naphthalene-2-sulfonate 2,2,2-trifluoroacetate (647 mg, 1.161 mmol, 94% yield) as a white solid: m/z (ESI) 444.2 (M+H)+.
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:19])=[C:11](F)[C:12]=3[C:14]([F:17])([F:16])[F:15])[C:7](=[O:20])[C:6]([C:21]([OH:23])=[O:22])=[CH:5]2)[CH2:3][CH2:2]1.[NH:24]1[CH2:28][CH2:27][CH:26]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][N:30]=2)[CH2:25]1>>[CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:19])=[C:11]([N:24]4[CH2:28][CH2:27][CH:26]([C:29]5[CH:34]=[CH:33][CH:32]=[CH:31][N:30]=5)[CH2:25]4)[C:12]=3[C:14]([F:15])([F:17])[F:16])[C:7](=[O:20])[C:6]([C:21]([OH:23])=[O:22])=[CH:5]2)[CH2:3][CH2:2]1
Reactant: c1ccc(C2CCNC2)nc1
Reactant: O=C(O)c1cn(C2CC2)c2c(C(F)(F)F)c(F)c(F)cc2c1=O
Product: O=C(O)c1cn(C2CC2)c2c(C(F)(F)F)c(N3CCC(c4ccccn4)C3)c(F)cc2c1=O
Yield: 74 %

Procedure:
Starting from 1-cyclopropyl-6,7-difluoro-1,4-dihydro-4-oxo-8-trifluoromethyl-3-quinolinecarboxylic acid (1.33 g, 4.0 retool) and 2-(3-pyrrolidinyl)pyridine, a procedure analogous to that given in Example 1 provided the title compound(1.36 g, 74%) as a yellow solid, mp 210°-212° C.
Reaction SMILES: N#N.[F:3][C:4]1[CH:5]=[C:6]([C:10]2[S:14][CH:13]=[N:12][C:11]=2[C:15]([OH:17])=O)[CH:7]=[CH:8][CH:9]=1.CN(C=O)C.C(Cl)(=O)C([Cl:26])=O>C1(C)C=CC=CC=1>[F:3][C:4]1[CH:5]=[C:6]([C:10]2[S:14][CH:13]=[N:12][C:11]=2[C:15]([Cl:26])=[O:17])[CH:7]=[CH:8][CH:9]=1
Reactant: O=C(O)c1ncsc1-c1cccc(F)c1
Reactant: O=C(Cl)C(=O)Cl
Agent: N#N
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: O=C(Cl)c1ncsc1-c1cccc(F)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), a suspension of 5-(3-fluoro-phenyl)-thiazole-4-carboxylic acid (55 mg, 0.25 mmol) in toluene (1.0 mL) was treated with a drop of DMF followed by oxalyl chloride (0.08 mL, 0.86 mmol) and the resulting yellow solution was stirred at rt for 30 min. The solvent was then removed under reduced pressure (coevaporation with toluene) to give 5-(3-fluoro-phenyl)-thiazole-4-carbonyl chloride.
Reaction SMILES: N1C=CC=CC=1.[CH2:7]([OH:11])[CH:8]([OH:10])[CH3:9].[C:12]([O:16][O:17][C:18]([CH2:20][CH2:21][C:22](Cl)=[O:23])=[O:19])([CH3:15])([CH3:14])[CH3:13]>C(Cl)Cl>[C:18]([O:17][O:16][C:12]([CH3:15])([CH3:14])[CH3:13])(=[O:19])[CH2:20][CH2:21][C:22]([O:11][CH2:7][CH:8]([OH:10])[CH3:9])=[O:23]
Reactant: CC(C)(C)OOC(=O)CCC(=O)Cl
Reactant: CC(O)CO
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(O)COC(=O)CCC(=O)OOC(C)(C)C
Temperature: 10 °C
Reaction time: 3.5 h
Yield: 97.5 %

Procedure:
A 250 mL 3-neck round-bottom flask, equipped with a magnetic stirrer, a thermometer, a cold water condenser and an addition funnel, was charged with 50 mL of methylene chloride, 4.2 g (0.052 mole) of pyridine and 19.0 g (0.25 mole) of 1,2-propanediol. The resulting vigorously stirred solution was cooled to 10° C. and to it was slowly added a solution of 11.5 g (0.050 mole) of 94% 3-(t-butylperoxycarbonyl)propionyl chloride in 10 mL of methylene chloride over a period of 20 minutes. The reaction mass was warmed to 20° C. and stirred at 20° C. for 210 minutes. The reaction mixture was washed at 10°-15° C. with 50 mL of aqueous 5% HCl solution and then twice with 100 mL portions of 5% aqueous NaHCO3 solution. The methylene chloride solution was then dried over 10% by weight of anhydrous MgSO4 and, after separation of the spent desiccant by filtration, the solvent was removed in vacuo leaving 12.4 g (100% of theory, uncorrected) of a straw-color liquid. An infrared spectrum of the product showed a strong OH band, a strong and broad carbonyl band at ca. 1720-1780 cm-1 and a strong --OO-- band at ca. 850 cm-1. The product had a peroxyester Act[O] content of 6.29%. Based on a theoretical Act[O] of 6.45% for the desired title product, the assay was 97.5% and the corrected yield was 97.5%.
Reaction SMILES: [CH:1]1([N:7]([CH2:17][CH:18]2[CH2:20][CH2:19]2)[C:8]2[N:13]=[CH:12][N:11]=[C:10]([C:14]([OH:16])=O)[CH:9]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[NH:21]1[C:29]2[CH:28]=[CH:27][CH:26]=[C:25]([NH2:30])[C:24]=2[CH:23]=[N:22]1>C(Cl)Cl>[CH:1]1([N:7]([CH2:17][CH:18]2[CH2:20][CH2:19]2)[C:8]2[N:13]=[CH:12][N:11]=[C:10]([C:14]([NH:30][C:25]3[CH:26]=[CH:27][CH:28]=[C:29]4[C:24]=3[CH:23]=[N:22][NH:21]4)=[O:16])[CH:9]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: O=C(O)c1cc(N(CC2CC2)C2CCCCC2)ncn1
Reactant: Nc1cccc2[nH]ncc12
Solvent: ClCCl
Product: O=C(Nc1cccc2[nH]ncc12)c1cc(N(CC2CC2)C2CCCCC2)ncn1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
A solution of 6-(cyclohexyl(cyclopropylmethyl)amino)pyrimidine-4-carboxylic acid (Intermediate 13, 110 mg; 0.40 mmol) in DCM was treated with polymer-supported Mukaiyama reagent (1.1 g) followed by 1H-indazol-4-amine (Key Organics, 58.6 mg; 0.44 mmol). After stirring at RT for 72 hours the mixture was filtered and washed with saturated sodium bicarbonate solution. The organic phase was passed through a hydrophobic frit and the solvent removed in vacuo. The residue was purified by column chromatography (silica) eluting with petroleum ether containing increasing amounts of EtOAc to give the title compound as a white solid.
Reaction SMILES: [CH3:1][C:2]1([CH3:10])[O:7][C:6](=[O:8])[CH2:5][C:4](=[O:9])[O:3]1.N1C=CC=CC=1.[CH:17]1([C:20](Cl)=[O:21])[CH2:19][CH2:18]1>ClCCl>[CH:17]1([C:20]([CH:5]2[C:6](=[O:8])[O:7][C:2]([CH3:10])([CH3:1])[O:3][C:4]2=[O:9])=[O:21])[CH2:19][CH2:18]1
Reactant: O=C(Cl)C1CC1
Reactant: CC1(C)OC(=O)CC(=O)O1
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC1(C)OC(=O)C(C(=O)C2CC2)C(=O)O1
Temperature: 0 °C
Yield: 82.2 %

Procedure:
A mixture of 2,2-dimethyl-1,3-dioxan-4,6-dione (20.0 g) and pyridine (22,0 g) in dichloromethane (200 ml) was stirred and cooled to 0° C. in an ice bath. A solution of cyclopropylcarbonyl chloride (16.0 g) in dichloromethane (50 ml) was added dropwise with stirring in an atmosphere of nitrogen whilst maintaining the temperature below 3° C. by external cooling. The mixture was stirred at 0° C. for 1 hour and at ambient temperature for 2 hours. The resultant orange suspension was washed with hydrochloric acid (2M, 2×50 ml), water (2×50 ml), dried (anhydrous sodium sulphate) and filtered. The filtrate was evaporated to dryness. The residue was dissolved in ether (150 ml) and the solution was treated with decolourizing charcoal and filtered. The filtrate was evaporated to dryness to give 5-cyclopropylcarbonyl-2,2-dimethyl-1,3-dioxan-4,6-dione (24.2 g) as a yellow solid mp 44°-46° C.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCOC(/N=N/C(OCC)=O)=O.C1(C)C=CC=CC=1.[OH:39][C:40]1[CH:45]=[CH:44][C:43]([CH2:46][C:47](=[O:49])[CH3:48])=[CH:42][CH:41]=1.[C:50]([O:54][C:55]([N:57]1[CH2:62][CH2:61][CH:60](O)[CH2:59][CH2:58]1)=[O:56])([CH3:53])([CH3:52])[CH3:51]>O1CCCC1>[C:50]([O:54][C:55]([N:57]1[CH2:62][CH2:61][CH:60]([O:39][C:40]2[CH:41]=[CH:42][C:43]([CH2:46][C:47](=[O:49])[CH3:48])=[CH:44][CH:45]=2)[CH2:59][CH2:58]1)=[O:56])([CH3:53])([CH3:51])[CH3:52]
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Reactant: CC(=O)Cc1ccc(O)cc1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: CC(=O)Cc1ccc(OC2CCN(C(=O)OC(C)(C)C)CC2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 58.6 %

Procedure:
A solution of triphenylphosphine (18.5 g, 70.6 mmol) and 40% DEAD in toluene (12.3 g, 70.6 mmol) in 125.0 mL of tetrahydrofuran was cooled to 0° C. under N2 as a solution of 1-(4-hydroxy-phenyl)-propan-2-one (6.54 g, 43.6 mmol) and 4-hydroxy-piperidine-1-carboxylic acid tert-butyl ester (10.7 g, 53.2 mmol) in 125.0 mL of tetrahydrofuran was added dropwise via addition funnel. After stirred at rt overnight, the solvent was evaporated. The residue was stirred in hexane/EtOAc, the solid formed was filtered. The hexane/EtOAC solution was concentrated and purified by ISCO graduate chromatography (hexane-20% EtOAc in hexane) to give 4-[4-[2-oxo-propyl)-phenoxy]-piperidine-1-carboxylic acid tert-butyl ester (8.52 g, 59%).
Reaction SMILES: [CH2:1]([O:8][CH2:9][C:10]([NH:12][NH:13][C:14]([C:16]1[CH:21]=[CH:20][C:19]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[CH:18][CH:17]=1)=O)=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.P(Cl)(Cl)(Cl)=O.[F:33][C:34]1[CH:40]=[CH:39][CH:38]=[CH:37][C:35]=1[NH2:36]>C(OCC)(=O)C>[CH2:1]([O:8][CH2:9][C:10]1[N:36]([C:35]2[CH:37]=[CH:38][CH:39]=[CH:40][C:34]=2[F:33])[C:14]([C:16]2[CH:21]=[CH:20][C:19]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[CH:18][CH:17]=2)=[N:13][N:12]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(COCc1ccccc1)NNC(=O)c1ccc(-c2ccccc2)cc1
Reactant: Nc1ccccc1F
Solvent: O=P(Cl)(Cl)Cl
Solvent: CCOC(C)=O
Product: Fc1ccccc1-n1c(COCc2ccccc2)nnc1-c1ccc(-c2ccccc2)cc1
Temperature: 100 °C
Reaction time: 1 h
Yield: 58 %

Procedure:
To biphenyl-4-carboxylic acid N′-(2-benzyloxyacetyl)hydrazide (9.38 g) was added phosphorus oxychloride (30 ml), and stirred at 100° C. for one hour. After the reaction solution was cooled to ambient temperature, the reaction solution was concentrated under reduced pressure. To the resulting residue was added ethyl acetate, and the separated organic layer was washed with aqueous 1 mol/liter sodium hydroxide solution and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure to afford an oily product. Subsequently, 2-fluoroaniline (5 ml) and p-toluenesulfonic acid·monohydrate (200 mg) were added to the resulting oily product, and stirred at 140° C. for 4 hours. After the reaction solution was cooled to ambient temperature, ethyl acetate was added to the reaction solution. The separated organic layer was washed with aqueous 1 mol/liter sodium hydroxide solution and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The resulting residue was purified by silica gel chromatography (eluent: n-hexane/ethyl acetate=3/1–1/1), to afford the entitled compound 3-benzyloxymethyl-5-biphenyl-4-yl-4-(2-fluorophenyl)-4H-1,2,4-triazole as pale yellow solid (6.60 g, 58%). The physico-chemical values are as follows.
Reaction SMILES: C(OC(=O)[NH:5][C:6]1[CH:10]=[C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[N:8]([C:17]2[CH:22]=[CH:21][C:20]([S:23](=[O:26])(=[O:25])[NH2:24])=[CH:19][CH:18]=2)[N:7]=1)C.[OH-].[Na+].O>CCO>[NH2:5][C:6]1[CH:10]=[C:9]([C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)[N:8]([C:17]2[CH:22]=[CH:21][C:20]([S:23]([NH2:24])(=[O:25])=[O:26])=[CH:19][CH:18]=2)[N:7]=1
Reactant: CCOC(=O)Nc1cc(-c2ccccc2)n(-c2ccc(S(N)(=O)=O)cc2)n1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: Nc1cc(-c2ccccc2)n(-c2ccc(S(N)(=O)=O)cc2)n1
Temperature: 25 °C
Yield: 70 %

Procedure:
To a solution of an ethyl carbamate 5 (0.39 g, 1 mmol) in EtOH (10 mL) was added 10% NaOH solution (3.2 mL) at room temperature. The reaction mixture was refluxed for 5 hours. The reaction mixture was cooled to room temperature and water was added. The resulting white precipitate was filtered and washed with water thoroughly to give the titled compound (0.22 g, 70%) as a white solid. mp 286.3-290.2° C. 1H NMR (DMSO-d6): δ 7.70 (d, J=9 Hz, 2H), 7.43-7.20 (m, 9H), 5.89 (s, 1H), 5.17 (br s, 2H).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]1[N:12]=[C:11]2[C:7]([N:8]=[CH:9][N:10]2[C@H:13]2[C@H:17]([O:18][Si:19]([C:22]([CH3:25])([CH3:24])[CH3:23])([CH3:21])[CH3:20])[C@H:16]([O:26][Si:27]([C:30]([CH3:33])([CH3:32])[CH3:31])([CH3:29])[CH3:28])[C@@H:15]([CH2:34][O:35][CH3:36])[O:14]2)=[C:6]([NH:37][CH2:38][CH:39]([C:46]2[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=2)[C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)[N:5]=1.[CH:52]1([CH:55]=O)[CH2:54][CH2:53]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>O1CCCC1>[Si:19]([O:18][C@@H:17]1[C@H:16]([O:26][Si:27]([C:30]([CH3:31])([CH3:32])[CH3:33])([CH3:29])[CH3:28])[C@@H:15]([CH2:34][O:35][CH3:36])[O:14][C@H:13]1[N:10]1[CH:9]=[N:8][C:7]2[C:11]1=[N:12][C:4]([CH2:3][CH2:2][NH:1][CH2:55][CH:52]1[CH2:54][CH2:53]1)=[N:5][C:6]=2[NH:37][CH2:38][CH:39]([C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1)[C:46]1[CH:47]=[CH:48][CH:49]=[CH:50][CH:51]=1)([C:22]([CH3:23])([CH3:24])[CH3:25])([CH3:21])[CH3:20]
Reactant: COC[C@H]1O[C@@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(CCN)nc32)[C@H](O[Si](C)(C)C(C)(C)C)[C@@H]1O[Si](C)(C)C(C)(C)C
Reactant: O=CC1CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: C1CCOC1
Product: COC[C@H]1O[C@@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(CCNCC4CC4)nc32)[C@H](O[Si](C)(C)C(C)(C)C)[C@@H]1O[Si](C)(C)C(C)(C)C
Yield: 78.8 %

Procedure:
The title compound was prepared by a similar method to example 5 from N-{2-(2-aminoethyl)-9-[(2R,3R,4R,5R)-3,4-bis{[tert-butyl(dimethyl)silyl]oxy}-5-(methoxymethyl)tetrahydro-2-furanyl]-9H-purin-6-yl)-N-(2,2-diphenylethyl)amine (430 mg, 0.58 mmol) (preparation 18), cyclopropanecarbaldehyde (45 mg, 0.64 mmol) and sodium triacetoxyborohydride (270 mg, 1.27 mmol) in tetrahydrofuran (10 ml). The product was purified by column chromatography on silica gel eluting with a solvent gradient of dichloromethane rising in polarity to dichloromethane:methanol:ammonia (95:5:0.5) to give the title compound (360 mg) as a gum. MS: 788 (MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[C:13]3[C:18]([CH:19]=2)=[CH:17][C:16]([CH:20]=O)=[CH:15][CH:14]=3)=[C:7]2[C:3]=1[CH2:4][NH:5][C:6]2=[O:29].[CH3:30][N:31]([CH3:36])[CH2:32][CH2:33][NH:34][CH3:35].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl>[Cl:1][C:2]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]([C:22]([O:24][C:25]([CH3:27])([CH3:28])[CH3:26])=[O:23])[C:13]3[C:18]([CH:19]=2)=[CH:17][C:16]([CH2:20][N:34]([CH2:33][CH2:32][N:31]([CH3:36])[CH3:30])[CH3:35])=[CH:15][CH:14]=3)=[C:7]2[C:3]=1[CH2:4][NH:5][C:6]2=[O:29]
Reactant: CC(C)(C)OC(=O)n1c(-c2ccc(Cl)c3c2C(=O)NC3)cc2cc(C=O)ccc21
Reactant: CNCCN(C)C
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: CN(C)CCN(C)Cc1ccc2c(c1)cc(-c1ccc(Cl)c3c1C(=O)NC3)n2C(=O)OC(C)(C)C

Procedure:
In a similar manner to Step 1 of Example 56, 4-chloro-7-[1-(tert-butoxycarbonyl)-5-formylindol-2-yl]isoindolinone (20.0 mg, 0.0487 mmol) was dissolved in dichloromethane (0.5 mL). The solution was treated with N,N,N′-trimethylethylenediamine (32 mg, 0.20 mmol) and sodium triacetoxyborohydride (32 mg, 0.15 mmol) to obtain 4-chloro-7-(1-(tert-butoxycarbonyl)-5-[N-(2-(dimethylamino)ethyl)-N-methylaminomethyl]indol-2-yl)isoindolinone.
Reaction SMILES: [CH3:1][C:2]1[C:10]2[CH2:9][O:8][C:7](=[O:11])[C:6]=2[CH:5]=[CH:4][C:3]=1[CH2:12][CH2:13][N:14]1[CH2:19][CH2:18][NH:17][CH2:16][C:15]1=[O:20].[CH3:21][C:22]1[C:30]2[CH2:29][O:28][C:27](=[O:31])[C:26]=2[CH:25]=[CH:24][C:23]=1[C@H:32]1[CH2:34][O:33]1>CCO>[OH:33][C@@H:32]([C:23]1[CH:24]=[CH:25][C:26]2[C:27](=[O:31])[O:28][CH2:29][C:30]=2[C:22]=1[CH3:21])[CH2:34][N:17]1[CH2:18][CH2:19][N:14]([CH2:13][CH2:12][C:3]2[CH:4]=[CH:5][C:6]3[C:7](=[O:11])[O:8][CH2:9][C:10]=3[C:2]=2[CH3:1])[C:15](=[O:20])[CH2:16]1
Reactant: Cc1c([C@H]2CO2)ccc2c1COC2=O
Reactant: Cc1c(CCN2CCNCC2=O)ccc2c1COC2=O
Solvent: CCO
Product: Cc1c(CCN2CCN(C[C@@H](O)c3ccc4c(c3C)COC4=O)CC2=O)ccc2c1COC2=O
Temperature: 100 °C

Procedure:
A sealed tube containing 1-[2-(4-Methyl-1-oxo-1,3-dihydro-2-benzofuran-5-yl)ethyl]piperazin-2-one (60 mg, 0.19 mmol) and 4-methyl-5-[(2S)-oxiran-2-yl]-2-benzofuran-1(3H)-one dissolved in 1 mL of EtOH was heated to 100° C. overnight. After 16 hrs the solvent was removed and the material purified via flash chromatography to give desired product. LC-MS (IE, m/z): 465 [M+1]+.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([N:8]([CH:18]([CH3:20])[CH3:19])[CH2:9][C:10]([F:17])([F:16])[C:11](OCC)=[O:12])[C:5]([N+:21]([O-])=O)=[CH:4][N:3]=1>CC(O)=O.Cl.O.[Fe]>[Cl:1][C:2]1[N:3]=[CH:4][C:5]2[NH:21][C:11](=[O:12])[C:10]([F:17])([F:16])[CH2:9][N:8]([CH:18]([CH3:20])[CH3:19])[C:6]=2[N:7]=1
Reactant: CCOC(=O)C(F)(F)CN(c1nc(Cl)ncc1[N+](=O)[O-])C(C)C
Agent: [Fe]
Agent: Cl
Solvent: CC(=O)O
Solvent: O
Product: CC(C)N1CC(F)(F)C(=O)Nc2cnc(Cl)nc21
Temperature: 60 °C
Reaction time: 8 h
Yield: 54.2 %

Procedure:
Ethyl 3-((2-chloro-5-nitropyrimidin-4-yl)(isopropyl)amino)-2,2-difluoropropanoate (1.90 g, 5.39 mmol) was dissolved in HOAc (10 mL) and HCl (conc, 3.1 mL). Iron (0.610 g, 10.9 mmol) was added and the rm was stirred at rt for 3 h and at 60° C. overnight. The mixture was diluted with water and extracted with ethyl acetate. The combined organic extracts were dried, filtered and concentrated in vacuo. The residue was purified using flash column chromatography on silica gel (40 g SiO2, hexanes:ethyl acetate 2:1-1:1) to afford the title compounds as a light yellow solid (0.809 g, 54%). 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.27 (d, J=6.82 Hz, 6H) 3.42 (s, 3H) 3.89 (t, J=12.38 Hz, 2H) 4.97-5.10 (m, 1H) 8.06 (s, 1H).
Reaction SMILES: [C:1]1([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:2]([C:7]([NH:9][C:10]2[N:15]=[CH:14][C:13]([C:16]([O:18]C)=[O:17])=[CH:12][CH:11]=2)=[O:8])=[CH:3][CH:4]=[CH:5][CH:6]=1.CO.[OH-].[Na+]>O1CCCC1>[C:1]1([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:2]([C:7]([NH:9][C:10]2[N:15]=[CH:14][C:13]([C:16]([OH:18])=[O:17])=[CH:12][CH:11]=2)=[O:8])=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: COC(=O)c1ccc(NC(=O)c2ccccc2-c2ccccc2)nc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)c1ccc(NC(=O)c2ccccc2-c2ccccc2)nc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 83.5 %

Procedure:
To a stirred solution of 2.5 g of methyl 6-[([1,1'-Biphenyl]-2-carbonyl)amino]-pyridine-3 -carboxylate in 50 ml of 1:1 tetrahydrofuran:methanol is added 10 ml of 5N sodium hydroxide and the mixture stirred at room temperature for 16 hours. The reaction mixture is concentrated in vacuo to a residue which is dissolved in water and neutralized with acetic acid. The separated colorless solid is filtered and air dried to give 2.0 g of the desired product:M+ =318.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5](F)=[C:6]([CH:9]=1)[CH:7]=[O:8].[C:11]([C:13]1[CH:14]=[C:15]([OH:19])[CH:16]=[CH:17][CH:18]=1)#[N:12].C([O-])([O-])=O.[K+].[K+]>CN(C)C(=O)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:19][C:15]2[CH:14]=[C:13]([CH:18]=[CH:17][CH:16]=2)[C:11]#[N:12])=[C:6]([CH:7]=[O:8])[CH:9]=1
Reactant: O=Cc1cc(Br)ccc1F
Reactant: N#Cc1cccc(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Product: N#Cc1cccc(Oc2ccc(Br)cc2C=O)c1
Yield: 90.3 %

Procedure:
In a manner similar to the method described in Example 50a, 5-bromo-2-fluorobenzaldehyde (2.2 g, 11 mmol) (Alfa) was reacted with 3-cyanophenol (1.4 g, 12 mmol)(Aldrich) and K2CO3 in N,N-dimethylacetamide to give 3-(4-bromo-2-formyl-phenoxy)-benzonitrile as a brown solid (Yield 3 g, 100%).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([CH:11]=1)=[CH:9][C:8]([CH2:12][C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])=[CH:7][CH:6]=2.CO.[CH2:22](P(CCCC)CCCC)CCC.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O>C1C=CC=CC=1>[CH3:22][O:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([CH:11]=1)=[CH:9][C:8]([CH2:12][C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])=[CH:7][CH:6]=2
Reactant: CCCCP(CCCC)CCCC
Reactant: CC(C)(C)OC(=O)Cc1ccc2ncc(O)cc2c1
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: c1ccccc1
Solvent: CO
Product: COc1cnc2ccc(CC(=O)OC(C)(C)C)cc2c1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
To a suspension of tert-butyl 2-(3-hydroxyquinolin-6-yl)acetate (0.1 g, 0.4 mmol) in benzene (5 mL) was added methanol (0.05 ml, 1 mmol) and tributylphosphine (0.1 ml, 0.6 mmol). The resulting mixture was cooled to 0° C. followed by adding 1.1′-(azodicarbonyl)dipiperidine (0.1 g, 0.6 mmol). After 10 min, ice bath was removed; the reaction mixture was warmed up to rt. The reaction mixture was continued to stir for 20 h. TLC showed about 80% conversion. More MeOH (1 ml), tibutylphosphine (0.05 mL), and ADDP (50 mg) were added and allowed to stir for 3 h. Hexane was added to the reaction mixture and dihydro-ADDP separated out and was filtered off. The filtrate was concentrated. The crude product was purified using SiO2 chromatography (Teledyne Isco RediSep®, P/N 68-2203-027, 40 g SiO2) to afford the desired product as colorless liquid. MS m/z: 274.3 (M+H). Calc'd. for C16H19NO3—273.2.
Reaction SMILES: [H-].[Na+].[CH2:3]([OH:10])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[Br:11][CH2:12][CH2:13][CH2:14][CH2:15]Br.O>O1CCCC1>[CH2:3]([O:10][CH2:15][CH2:14][CH2:13][CH2:12][Br:11])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: BrCCCCBr
Reactant: OCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: BrCCCCOCc1ccccc1
Yield: 56.3 %

Procedure:
60% Sodium hydride (1.2 g) was suspended in tetrahydrofuran (30 ml), and benzyl alcohol (3.0 g) was added under ice-cooling with stirring. The mixture was stirred at room temperature for 30 min, and again ice-cooled. 1,4-Dibromobutane (6.0 g) was added and the mixture was stirred for 3 hr. Water was added to the reaction mixture and the mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried and the solvent was evaporated under reduced pressure to give 3.8 g of 4-benzyloxybutyl bromide.
Reaction SMILES: Br[C:2]1[CH:16]=[CH:15][C:5]([CH2:6][N:7]2[CH2:12][C@H:11]([CH3:13])[O:10][C@H:9]([CH3:14])[CH2:8]2)=[CH:4][CH:3]=1.[CH3:17][C:18]1([CH3:27])[C:22]([CH3:24])([CH3:23])[O:21][B:20]([CH:25]=[CH2:26])[O:19]1.C(N(CC)CC)C>C1(C)C=CC=CC=1.CC(C)([P](C(C)(C)C)([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)C(C)(C)C)C>[CH3:14][C@H:9]1[O:10][C@@H:11]([CH3:13])[CH2:12][N:7]([CH2:6][C:5]2[CH:15]=[CH:16][C:2](/[CH:26]=[CH:25]/[B:20]3[O:21][C:22]([CH3:24])([CH3:23])[C:18]([CH3:27])([CH3:17])[O:19]3)=[CH:3][CH:4]=2)[CH2:8]1
Reactant: C[C@@H]1CN(Cc2ccc(Br)cc2)C[C@H](C)O1
Reactant: C=CB1OC(C)(C)C(C)(C)O1
Agent: CC(C)(C)[P]([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)(C(C)(C)C)C(C)(C)C
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: C[C@@H]1CN(Cc2ccc(/C=C/B3OC(C)(C)C(C)(C)O3)cc2)C[C@H](C)O1
Temperature: 80 °C
Yield: 63.1 %

Procedure:
To a solution of 4-(4-bromobenzyl)-cis-2,6-dimethylmorpholine (20 g, 71 mmol) and 4,4,5,5-tetramethyl-2-vinyl-1,3,2-dioxaborolane (13 mL, 77 mmol, 1.1 eq.) in toluene (250 mL) was added triethylamine (19.7 mL, 142 mmol) and Pd(PtBu3)2 (368 mg, 0.71 mmol) and the solution was heated to 80° C. for 2 h under argon. After cooling to rt, the reaction was quenched with sat. NaHCO3 (50 mL), water (50 mL), extracted with EtOAc (3×100 mL) and dried over MgSO4. After evaporation of the solvents, the residue was purified by Biotage column system (EtOAc/hex gradient: 0-100%) to give the title compound as a white solid (16 g, 64%). 1H NMR (400 MHz, CDCl3) δ 7.46 (d, J=8.0 Hz, 2H), 7.40 (d, J=18.4 Hz, 1H), 7.30 (d, J=7.6 Hz, 2H), 6.16 (d, J=18.4 Hz, 1H), 3.75-3.65 (m, 2H), 3.47 (s, 2H), 2.70 (d, J=10.8 Hz, 2H), 1.75 (t, J=10.2 Hz, 2H), 1.32 (s, 12H), 1.14 (d, J=6.4 Hz, 6H); MS ESI 358.2 [M+H]+, calcd for [C21H32BNO3+H]+ 358.2.