Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:7]=[CH:6][S:5][C:4]=1[C:8]([CH:10]1[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]1)=[O:9].O=[CH:17][CH2:18][C@H:19]1[CH2:24][CH2:23][C@H:22]([NH:25][C:26](=[O:28])[CH3:27])[CH2:21][CH2:20]1>>[Cl:2][C:3]1[CH:7]=[CH:6][S:5][C:4]=1[C:8]([CH:10]1[CH2:15][CH2:14][N:13]([CH2:17][CH2:18][C@H:19]2[CH2:24][CH2:23][C@H:22]([NH:25][C:26](=[O:28])[CH3:27])[CH2:21][CH2:20]2)[CH2:12][CH2:11]1)=[O:9]
Reactant: O=C(c1sccc1Cl)C1CCNCC1
Reactant: CC(=O)N[C@H]1CC[C@H](CC=O)CC1
Agent: Cl
Product: CC(=O)N[C@H]1CC[C@H](CCN2CCC(C(=O)c3sccc3Cl)CC2)CC1

Procedure:
From (3-chloro-thiophen-2-yl)-piperidin-4-yl-methanone hydrochloride (78 mg) and N-[trans-4-(2-oxo-ethyl)-cyclohexyl]-acetamide (54 mg, intermediate AG) by procedure A.1. Yield: 52 mg (45%). White solid. MS (m/z): 397.1 ([M+H]+).
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]([C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])[C:13]3[C:18]([CH:19]=2)=[CH:17][C:16]([CH2:20][N:21]2[CH2:26][CH2:25][N:24]([CH2:27][CH2:28][O:29][Si:30]([C:33]([CH3:36])([CH3:35])[CH3:34])([CH3:32])[CH3:31])[CH2:23][CH2:22]2)=[CH:15][CH:14]=3)=[C:7]2[C:3]=1[CH2:4][NH:5][C:6]2=[O:44].C(N(CC)CC)C.[F:52][C:53]([F:59])([F:58])[S:54](Cl)(=[O:56])=[O:55]>ClCCl>[F:52][C:53]([F:59])([F:58])[S:54]([O:1][C:2]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]([C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])[C:13]3[C:18]([CH:19]=2)=[CH:17][C:16]([CH2:20][N:21]2[CH2:22][CH2:23][N:24]([CH2:27][CH2:28][O:29][Si:30]([C:33]([CH3:36])([CH3:34])[CH3:35])([CH3:32])[CH3:31])[CH2:25][CH2:26]2)=[CH:15][CH:14]=3)=[C:7]2[C:3]=1[CH2:4][NH:5][C:6]2=[O:44])(=[O:56])=[O:55]
Reactant: CC(C)(C)OC(=O)n1c(-c2ccc(O)c3c2C(=O)NC3)cc2cc(CN3CCN(CCO[Si](C)(C)C(C)(C)C)CC3)ccc21
Reactant: O=S(=O)(Cl)C(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)n1c(-c2ccc(OS(=O)(=O)C(F)(F)F)c3c2C(=O)NC3)cc2cc(CN3CCN(CCO[Si](C)(C)C(C)(C)C)CC3)ccc21
Yield: 76.9 %

Procedure:
In a similar manner to Step 1 of Example 299, 4-hydroxy-7-(1-(tert-butoxycarbonyl)-5-[4-(2-tert-butyldimethylsilyloxyethyl)pyperazin-1-ylmethyl]indol-2-yl)isoindolinone (150 mg, 0.240-mmol) was suspended in dichloromethane (6.0 mL), and the suspension was treated with triethylamine (0.167 mL, 1.20 mmol) and trifluoromethanesulfonyl chloride (0.046 mL, 0.43 mmol) under ice-cooling, followed by purification by preparative thin-layer chromatography (chloroform/methanol=13/1) to obtain 4-trifluoromethanesulfonyloxy-7-{1-(tert-butoxycarbonyl)-5-[4-(2-tert-butyldimethylsilyloxyethyl)pyperazin-1-ylmethyl]indol-2-yl}isoindolinone (139 mg, yield 77%).
Reaction SMILES: [CH3:1][CH:2]([CH3:14])[CH2:3][CH2:4][NH:5][N:6]1[CH:10]=[CH:9][CH:8]=[C:7]1[C:11]([OH:13])=[O:12].[C:15](=O)([O-])[O-:16].[K+].[K+].C(Cl)(Cl)=O.C(OCC)(=O)C>O>[CH3:1][CH:2]([CH3:14])[CH2:3][CH2:4][N:5]1[C:15](=[O:16])[O:12][C:11](=[O:13])[C:7]2[N:6]1[CH:10]=[CH:9][CH:8]=2
Reactant: CC(C)CCNn1cccc1C(=O)O
Reactant: O=C([O-])[O-]
Agent: O=C(Cl)Cl
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Product: CC(C)CCn1c(=O)oc(=O)c2cccn21
Temperature: 0 °C
Reaction time: 16 h
Yield: 56.7 %

Procedure:
To a solution of 1-(3-methyl-butylamino)-1H-pyrrole-2-carboxylic acid (Example 1d, 0.25 g, 1.27 mmol) in water (2 mL) was added potassium carbonate (0.175 g, 1.27 mmol). The reaction mixture was cooled to 0° C. and phosgene (20% solution in toluene) (0.95 mL, 1.91 mmol) was slowly added dropwise. The resulting yellow solution was stirred for 16 h. Ethyl acetate (4 mL) was added and the layers were separated. The aqueous layer was extracted with ethyl acetate (3×5 mL). The combined organic layers were dried over magnesium sulfate, filtered and concentrated in vacuo. The crude product was purified by column chromatography (Merck silica gel 60, 40-63 μm, ethyl acetate/hexane, 20-50%) to afford the desired product, 4-(3-methyl-butyl)-6-oxa-3a,4-diaza-indene-5,7-dione (0.16 g, 0.72 mmol, 57% yield) as a tan solid. 1H NMR (400 MHz, DMSO-d6) δ 0.93 (6H, d, J=6.8 Hz), 1.56 (2H, m), 1.65 (1H, m), 4.16 (2H, t, J=7.2 Hz), 6.50 (1H, m), 7.08 (1H, m), 7.70 (1H, m).
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Br:20][C:21]1[CH:22]=[C:23]([CH:26]=[CH:27][C:28]=1[OH:29])[CH:24]=[O:25].O[CH2:31][CH2:32][N:33]1[CH2:38][CH2:37][O:36][CH2:35][CH2:34]1.CCOC(/N=N/C(OCC)=O)=O>O1CCCC1>[O:36]1[CH2:37][CH2:38][N:33]([CH2:32][CH2:31][O:29][C:28]2[CH:27]=[CH:26][C:23]([CH:24]=[O:25])=[CH:22][C:21]=2[Br:20])[CH2:34][CH2:35]1
Reactant: O=Cc1ccc(O)c(Br)c1
Reactant: OCCN1CCOCC1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: O=Cc1ccc(OCCN2CCOCC2)c(Br)c1
Reaction time: 12 h
Yield: 56 %

Procedure:
Triphenylphosphine (6.85 g) was added to a solution of 3-bromo-4-hydroxybenzaldehye (5 g) in tetrahydrofuran (40 ml), followed by addition of 2-hydroxyethylmorpholine (3.01 ml) and then the dropwise addition of diethylazodicarboxylate (4.11 ml). After 12 hours, the reaction was concentrated under reduced pressure, poured into 2N hydrochloric acid (200 ml) and extracted with ethyl acetate (2×150 ml). The aqueous layer was basified to pH 9 with solid sodium bicarbonate and extracted with ethyl acetate (2×150 ml). The organic layers were dried over magnesium sulfate and concentrated to afford 4.4 g (56%) of 4-morpholinoethoxy-3-bromobenzaldehyde as a reddish oil.
Reaction SMILES: [CH3:1][C:2]1([CH3:16])[C:11]2[C:6](=[CH:7][C:8]([CH3:15])=[C:9]([C:12]([OH:14])=[O:13])[CH:10]=2)[S:5][CH2:4][CH2:3]1.[CH2:17]([O:19][C:20](=[O:28])[C:21]1[CH:26]=[CH:25][C:24](O)=[CH:23][CH:22]=1)[CH3:18].C1(N=C=NC2CCCCC2)CCCCC1>C(Cl)Cl.CN(C)C1C=CN=CC=1>[CH3:1][C:2]1([CH3:16])[C:11]2[C:6](=[CH:7][C:8]([CH3:15])=[C:9]([C:12]([O:14][C:24]3[CH:25]=[CH:26][C:21]([C:20]([O:19][CH2:17][CH3:18])=[O:28])=[CH:22][CH:23]=3)=[O:13])[CH:10]=2)[S:5][CH2:4][CH2:3]1
Reactant: CCOC(=O)c1ccc(O)cc1
Reactant: Cc1cc2c(cc1C(=O)O)C(C)(C)CCS2
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CCOC(=O)c1ccc(OC(=O)c2cc3c(cc2C)SCCC3(C)C)cc1
Reaction time: 24 h

Procedure:
A solution of 83.7 mg (0.35 mmol) of 4,4,7-trimethyl-6-carboxythiochroman and 59.1 mg (0.35 mmol) of ethyl-4-hydroxybenzoate in 2 ml of methylene chloride was treated sequentially with 74.5 mg (0.36 mmol) of 1,3-dicyclohexylcarbodiimide and 11.1 mg (0.09 mmol) of 4-dimethylaminopyridine. The mixture was stirred under nitrogen for 24 h and then filtered. The fillrate was concentrated in-vacuo and the residue purified by flash chromatography (silica; 15% ethyl acetate in henane) to give the title compound as a pale yellow oil. PMR (CDCl3): δ1.37 (6H, s), 1.41 (3H, t, J~7.1 Hz), 1.92-2.00 (2H, m), 2.56 (3H, s), 3.02-3.10 (2H, m), 4.40 (2H, q, J~7.1 Hz), 7.03 (1H, s), 7.29 (2H, d, J~8.7 Hz), 8.13 (2H, d, J~8.7 Hz), 8.18 (1H, s).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:35])[CH2:5][CH:6]([C:29]1[CH:30]=[N:31][CH:32]=[N:33][CH:34]=1)[CH:7]=[CH:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([NH:19][CH2:20][C:21]2[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][CH:22]=2)[N:14]=1)[CH3:2].C=O.[C:38](O)(=O)C.[BH3-]C#N.[Na+]>CO>[CH2:1]([O:3][C:4](=[O:35])[CH2:5][CH:6]([C:29]1[CH:30]=[N:31][CH:32]=[N:33][CH:34]=1)[CH:7]=[CH:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([N:19]([CH2:20][C:21]2[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][CH:22]=2)[CH3:38])[N:14]=1)[CH3:2]
Reactant: CCOC(=O)CC(C=CCCCCc1cccc(NCc2ccc(OC)cc2)n1)c1cncnc1
Reactant: CC(=O)O
Agent: C=O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Product: CCOC(=O)CC(C=CCCCCc1cccc(N(C)Cc2ccc(OC)cc2)n1)c1cncnc1
Temperature: 50 °C
Reaction time: 0.25 h
Yield: 75 %

Procedure:
To a solution of 6-10 (1.6 g, 3.37 mmol) in methanol (30 mL) was added paraformaldehyde (0.80 g) and acetic acid (0.96 mL, 16.8 mmol). After stirring at 50° C. for 15 minutes, NaCNBH3 (0.275 g, 4.38 mmol) was added and the mixture stirred for an additional 30 minutes at 50° C. Evaporation of the solvents and purification on silica gel (5% MeOH/CHCl3) afforded 6-10 in 75% yield.
Reaction SMILES: [C:1]1([C:7]2[O:11][CH:10]=[N:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Li]CCCC.[Cl:17]C(Cl)(Cl)C(Cl)(Cl)Cl>C1COCC1>[Cl:17][C:10]1[O:11][C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)=[CH:8][N:9]=1
Reactant: ClC(Cl)(Cl)C(Cl)(Cl)Cl
Reactant: c1ccc(-c2cnco2)cc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: Clc1ncc(-c2ccccc2)o1
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 48.5 %

Procedure:
To a round bottom flask was added 5-phenyloxazole (1.0 gm, 6.89 mmol) and THF (10 mL). The reaction was cooled to −78° C. Then 2.5 M nBuLi (3.03 mL, 7.58 mmol) was added to the reaction at −78° C. The reaction turned to deep red color. After 15 min, hexachloroethane (1.170 mL, 10.33 mmol) was added at −78° C. The reaction was slowly warmed to rt over 2 hrs and then was poured onto ice. The resulting solution was extracted with EtOAc (2×30 ml). The combined EtOAc layers were washed with saturated aqueous NaCl, dried over MgSO4, filtered and concentrated. The resulting residue was purified using silica gel chromatography (ISCO system) eluting with a gradient of 0-100% EtOAc/Hex to give the product, 2-chloro-5-phenyloxazole, (600 mg, 3.34 mmol, 49% yield) as a light pale liquid. Anal. Calcd. for C9H6ClNO m/z 179.1, found: 180.1 (M+H)+; 1H NMR (500 MHz, CDCl3) δ ppm 7.60 (d, J=7.15 Hz, 2H), 7.43 (t, J=7.42 Hz, 2H), 7.38-7.33 (m, 1H), 7.29 (s, 1H); 13C NMR (126 MHz, CDCl3) δ ppm 153.78, 146.16, 129.01, 126.93, 124.03, 123.31.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH:21]([C:22](O)=[O:23])[CH2:20][C:19]2[CH:18]=[C:17]3[C:12]([O:13][C@@H:14]([C:27]4[CH:32]=[CH:31][C:30]([O:33][CH2:34][C:35]5[CH:40]=[CH:39][C:38]([Cl:41])=[C:37]([Cl:42])[CH:36]=5)=[CH:29][CH:28]=4)[C:15](=[O:26])[N:16]3[CH3:25])=[CH:11][C:10]=2[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.[CH3:44][O:45][C:46](=[O:64])[C@@H:47]([NH2:63])[CH2:48][C:49]1[CH:54]=[CH:53][C:52]([C:55]2[CH:60]=[CH:59][C:58]([C:61]#[N:62])=[CH:57][CH:56]=2)=[CH:51][CH:50]=1>>[C:1]([O:5][C:6]([N:8]1[CH:21]([C:22](=[O:23])[NH:63][C@H:47]([C:46]([O:45][CH3:44])=[O:64])[CH2:48][C:49]2[CH:50]=[CH:51][C:52]([C:55]3[CH:60]=[CH:59][C:58]([C:61]#[N:62])=[CH:57][CH:56]=3)=[CH:53][CH:54]=2)[CH2:20][C:19]2[CH:18]=[C:17]3[C:12]([O:13][C@@H:14]([C:27]4[CH:32]=[CH:31][C:30]([O:33][CH2:34][C:35]5[CH:40]=[CH:39][C:38]([Cl:41])=[C:37]([Cl:42])[CH:36]=5)=[CH:29][CH:28]=4)[C:15](=[O:26])[N:16]3[CH3:25])=[CH:11][C:10]=2[CH2:9]1)=[O:7])([CH3:3])([CH3:2])[CH3:4]
Reactant: CN1C(=O)[C@H](c2ccc(OCc3ccc(Cl)c(Cl)c3)cc2)Oc2cc3c(cc21)CC(C(=O)O)N(C(=O)OC(C)(C)C)C3
Reactant: COC(=O)[C@@H](N)Cc1ccc(-c2ccc(C#N)cc2)cc1
Agent: Cl
Product: COC(=O)[C@H](Cc1ccc(-c2ccc(C#N)cc2)cc1)NC(=O)C1Cc2cc3c(cc2CN1C(=O)OC(C)(C)C)O[C@@H](c1ccc(OCc2ccc(Cl)c(Cl)c2)cc1)C(=O)N3C
Yield: 72.5 %

Procedure:
(S)-3-[4-(3,4-Dichloro-benzyloxy)-phenyl]-1-methyl-2-oxo-1,2,3,5,7,8-hexahydro-4-oxa-1,6-diaza-anthracene-6,7-dicarboxylic acid 6-tert-butyl ester (2.9 g) was coupled to (S)-2-amino-3-(4′-cyano-biphenyl-4-yl)-propionic acid methyl ester hydrochloride (1.5 g) following general procedure A to provide (S)-7-[(S)-2-(4′-Cyano-biphenyl-4-yl)-1-methoxycarbonyl-ethylcarbamoyl]-3-[4-(3,4-dichloro-benzyloxy)-phenyl]-1-methyl-2-oxo-1,2,3,5,7,8-hexahydro-4-oxa-1,6-diaza-anthracene-6-carboxylic acid tert-butyl ester (3.0 g). LC-MS (m/z) 878.
Reaction SMILES: [CH2:1]([O:3]C(=O)OCC)C.[H-].[Na+].[Br:11][C:12]1[C:13]([OH:22])=[C:14]([C:19](=[O:21])[CH3:20])[CH:15]=[C:16]([Br:18])[CH:17]=1.[OH-].[Na+]>C1(C)C=CC=CC=1>[Br:18][C:16]1[CH:17]=[C:12]([Br:11])[C:13]2[O:22][C:1](=[O:3])[CH:20]=[C:19]([OH:21])[C:14]=2[CH:15]=1
Reactant: CCOC(=O)OCC
Reactant: CC(=O)c1cc(Br)cc(Br)c1O
Agent: [H-]
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Product: O=c1cc(O)c2cc(Br)cc(Br)c2o1
Temperature: 105 °C
Reaction time: 5 h
Yield: 18.4 %

Procedure:
A solution is prepared of diethylcarbonate (62.5 mmol, 7.6 mL) in 150 mL of toluene to which is added NaH (37.5 mmol, 1.5 g of 60% dispersion in mineral oil) in portions. To this solution is added, dropwise, 3′,5′-dibromo-2′-hydroxyacetophenone (12.5 mmol, 3.67 g) in 50 mL of toluene. The reaction is heated to 105° C. overnight, cooled to ambient temperature, 100 mL of 1N NaOH, is added and the reaction is stirred vigorously for 5 hrs at ambient temperature. The layers are separated and the aqueous layer is washed with EtOAc 2×. The combined organic layers are washed with H2O 1×. The combined aqueous layers are acidified to pH 2 with conc HCl to form a precipitate that is filtered and is washed with H2O. The solid material is dissolved in ACN/H2O and speed vacced to dryness to afford the title compound as a light tan solid (0.737 g, 18%). 1H NMR (DMSO-d6, 300 MHz) δ 12.98 (1H, br s), 8.18 (1H, d, J=2.25 Hz), 7.90 (1H, d, J=2.25 Hz), 5.64 (1H, s); MS (ESI, Pos.) calcd for C9H4Br2O3 m/z [M+H]=318.9, found 318.9.
Reaction SMILES: C[N:2](C)[CH:3]=[CH:4][C:5]([C:7]1[S:8][CH:9]=[CH:10][CH:11]=1)=O.O.[NH2:14]N>C(O)C>[S:8]1[CH:9]=[CH:10][CH:11]=[C:7]1[C:5]1[CH:4]=[CH:3][NH:2][N:14]=1
Reactant: CN(C)C=CC(=O)c1cccs1
Reactant: NN
Solvent: O
Solvent: CCO
Product: c1csc(-c2cc[nH]n2)c1
Temperature: 25 °C
Yield: 89.7 %

Procedure:
A mixture of 3-(dimethylamino)-1-(2-thienyl)prop-2-en-1-one (193 mmol) and hydrazine hydrate (396 mmol) in 50 mL ethanol was refluxed for 18 h and then allowed to cool to room temperature. The solvent was evaporated under reduced pressure and the residue was partitioned between ethyl acetate and water. The organic phase was successively washed with saturated aqueous ammonium chloride solution, saturated aqueous sodium bicarbonate solution and brine, dried over MgSO4, filtered and concentrated. The residue was recrystallized (dichloromethane/cyclohexane) to afford 26.0 g 3-(2-thienyl)-1H-pyrazole (90% yield).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][C@H:9]([C:11]2[N:16]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:15](=[O:23])[C:14]3=[C:24]([CH3:27])[CH:25]=[CH:26][N:13]3[N:12]=2)[CH3:10])[C:3]=1Br.[F:29][C:30]1[CH:31]=[C:32]([NH:45][S:46]([C:49]2[CH:54]=[CH:53][C:52]([OH:55])=[CH:51][CH:50]=2)(=[O:48])=[O:47])[CH:33]=[C:34](B2OC(C)(C)C(C)(C)O2)[CH:35]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>>[NH2:1][C:2]1[C:3]([C:34]2[CH:33]=[C:32]([NH:45][S:46]([C:49]3[CH:54]=[CH:53][C:52]([OH:55])=[CH:51][CH:50]=3)(=[O:48])=[O:47])[CH:31]=[C:30]([F:29])[CH:35]=2)=[C:4]([NH:8][C@H:9]([C:11]2[N:16]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:15](=[O:23])[C:14]3=[C:24]([CH3:27])[CH:25]=[CH:26][N:13]3[N:12]=2)[CH3:10])[N:5]=[CH:6][N:7]=1
Reactant: Cc1ccn2nc([C@H](C)Nc3ncnc(N)c3Br)n(-c3ccccc3)c(=O)c12
Reactant: CC1(C)OB(c2cc(F)cc(NS(=O)(=O)c3ccc(O)cc3)c2)OC1(C)C
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: Cc1ccn2nc([C@H](C)Nc3ncnc(N)c3-c3cc(F)cc(NS(=O)(=O)c4ccc(O)cc4)c3)n(-c3ccccc3)c(=O)c12
Yield: 50.2 %

Procedure:
(S)-2-(1-((6-Amino-5-bromopyrimidin-4-yl)amino)ethyl)-5-methyl-3-phenylpyrrolo[2,1-f][1,2,4]triazin-4(3H)-one (30 mg, 0.07 mmol) was treated with N-(3-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-4-hydroxybenzenesulfonamide (42 mg, 0.11 mmol), cesium carbonate (2M, 120 μl, 0.24 mmol) and 1,1′-bis(diphenylphosphino)ferrocene-palladium(II)dichloride dichloromethane complex (8 mg, 0.01 mmol) according to the method described in Example 3 to give 22 mg (52% yield) of the title compound. Purity 100%.
Reaction SMILES: [F:1][CH2:2][C:3]([CH:7]([F:9])[F:8])=[C:4]([F:6])[F:5].S(=O)(=O)(O)[OH:11]>O>[F:1][CH2:2][C:3]([OH:11])([CH:7]([F:9])[F:8])[CH:4]([F:6])[F:5]
Reactant: FCC(=C(F)F)C(F)F
Reactant: O=S(=O)(O)O
Solvent: O
Product: OC(CF)(C(F)F)C(F)F

Procedure:
As another example, 2-fluoromethyl-1,1,3,3-tetrafluoro-2-propanol may be prepared by fluorinating commercially available 1,1,3-trichloro-2-propanone to form 1,1,3-trifluoro-2-propanone which may then be reacted with CF2 carbene to form 2-fluoromethyl-1,1,3,3-tetrafluoro-1-propene. The 2-fluoromethyl-1,1,3,3-tetrafluoro-1-propene may then be reacted with sulfuric acid and then water to form 2-fluoromethyl-1,1,3,3-tetrafluoro-2-propanol.
Reaction SMILES: [CH2:1]([N:8]=[C:9]=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:11]1([C:17]2([CH2:27][CH2:28][CH2:29][CH3:30])[C:21]3[CH2:22][NH:23][CH2:24][CH2:25][C:20]=3[C:19](=[O:26])[O:18]2)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>ClCCl>[CH2:1]([NH:8][C:9]([N:23]1[CH2:24][CH2:25][C:20]2[C:19](=[O:26])[O:18][C:17]([CH2:27][CH2:28][CH2:29][CH3:30])([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[C:21]=2[CH2:22]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCCCC1(c2ccccc2)OC(=O)C2=C1CNCC2
Reactant: O=C=NCc1ccccc1
Solvent: ClCCl
Product: CCCCC1(c2ccccc2)OC(=O)C2=C1CN(C(=O)NCc1ccccc1)CC2
Temperature: 25 °C
Reaction time: 1 h
Yield: 50 %

Procedure:
Benzyl isocyanate (0.02 g, 0.14 mmol) was added to a solution of 3-phenyl-3-butyl-4,5,6,7-tetrahydrofuro[3,4-c]pyridin-1(3H)-one (0.025 g, 0.09 mmol prepared in a manner analogous to compound 2) in dichloromethane (5 mL) and was stirred at room temperature for 1 h. The solvent was removed and the resulting residue was purified on silica to give the desired product (0.018 g, 50%). 1H NMR (300 MHz, CHLOROFORM-d) δ ppm 0.79 (t, J=7.16 Hz, 3H), 1.06-1.33 (m, 4H), 1.83-1.97 (m, 1H), 2.14-2.43 (m, 3H), 3.18-3.31 (m, 1H), 3.36-3.51 (m, 1H), 3.85 (dt, J=18.84, 2.64 Hz, 1H), 4.26-4.39 (m, 3H), 4.90 (t, J=5.27 Hz, 1H), 7.11-7.36 (m, 10H).
Reaction SMILES: [Na].[Cl:2][C:3]1[C:4](=[O:11])[N:5]([CH3:10])[N:6]=[CH:7][C:8]=1Cl.[Cl-].[NH4+].[CH3:14][OH:15]>>[Cl:2][C:3]1[C:4](=[O:11])[N:5]([CH3:10])[N:6]=[CH:7][C:8]=1[O:15][CH3:14]
Reactant: Cn1ncc(Cl)c(Cl)c1=O
Reactant: CO
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na]
Product: COc1cnn(C)c(=O)c1Cl
Temperature: 25 °C
Reaction time: 4 h
Yield: 97 %

Procedure:
Sodium metal (613 mg, 26.7 at-g) were dissolved in 35 ml of methanol. To this solution were added 4.15 g (23.18 mmol) of 4,5-dichloro-2-methyl-2H-pyridazin-3-one in four portions over 5 min. After stirring the suspension for 4 h at room temperature, the solution was neutralized by addition of 1 ml sat. ammonium chloride solution and concentrated in vaccuo. The residue was taken up in 100 ml of ethyl acetate, washed twice with water, drie over magnesium sulfate and concentrated in vaccuo to yield 3.94 g (22.6 mmol, 97%) of the title compound as a crystalline white solid, MS: 175.2, 177.0 (M+H+).
Reaction SMILES: Cl[C:2]([O:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:3].[NH2:12][C:13]1[C:22]2[N:23]=[C:24]([CH2:31][CH2:32][CH2:33][CH3:34])[N:25]([CH2:26][CH2:27][CH2:28][CH2:29][NH2:30])[C:21]=2[C:20]2[N:19]=[CH:18][CH:17]=[CH:16][C:15]=2[N:14]=1>>[NH2:12][C:13]1[C:22]2[N:23]=[C:24]([CH2:31][CH2:32][CH2:33][CH3:34])[N:25]([CH2:26][CH2:27][CH2:28][CH2:29][NH:30][C:2](=[O:3])[O:4][CH2:5][C:6]3[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=3)[C:21]=2[C:20]2[N:19]=[CH:18][CH:17]=[CH:16][C:15]=2[N:14]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: CCCCc1nc2c(N)nc3cccnc3c2n1CCCCN
Product: CCCCc1nc2c(N)nc3cccnc3c2n1CCCCNC(=O)OCc1ccccc1
Yield: 84 %

Procedure:
Using the general method of Example 55, benzyl chloroformate (83 μL, 0.58 mmol) was reacted with 4-(4-amino-2-butyl-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl)butaneamine (0.15 g, 0.48 mmol) to provide 0.18 g of benzyl N-[4-(4-amino-2-butyl-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl)butyl]carbamate as a white powder.
Reaction SMILES: [CH3:1][C:2]([CH3:44])=[CH:3][CH2:4][C@H:5]1[C:15]([CH3:17])([CH3:16])[C@:12]2([CH2:18][CH:19]=[C:20]([CH3:22])[CH3:21])[C:13](=[O:14])[C@@:7]([CH2:34][C@@H:35]([C:41]([CH3:43])=[CH2:42])[CH2:36][CH:37]=[C:38]([CH3:40])[CH3:39])([C:8]([OH:33])=[C:9]([C:23]([C:25]3[CH:26]=[CH:27][C:28]([OH:32])=[C:29]([OH:31])[CH:30]=3)=[O:24])[C:10]2=[O:11])[CH2:6]1.Cl>C1(C)C=CC=CC=1>[CH3:1][C:2]([CH3:44])=[CH:3][CH2:4][C@H:5]1[C:15]([CH3:16])([CH3:17])[C@:12]2([CH2:18][CH:19]=[C:20]([CH3:21])[CH3:22])[C:13](=[O:14])[C@@:7]3([C:8](=[C:9]([C:23]([C:25]4[CH:26]=[CH:27][C:28]([OH:32])=[C:29]([OH:31])[CH:30]=4)=[O:24])[C:10]2=[O:11])[O:33][C:41]([CH3:43])([CH3:42])[C@@H:35]([CH2:36][CH:37]=[C:38]([CH3:40])[CH3:39])[CH2:34]3)[CH2:6]1
Reactant: C=C(C)[C@@H](CC=C(C)C)C[C@@]12C[C@@H](CC=C(C)C)C(C)(C)[C@@](CC=C(C)C)(C(=O)C(C(=O)c3ccc(O)c(O)c3)=C1O)C2=O
Agent: Cl
Solvent: Cc1ccccc1
Product: CC(C)=CC[C@H]1C[C@@]23C[C@@H](CC=C(C)C)C(C)(C)[C@@](CC=C(C)C)(C(=O)C(C(=O)c4ccc(O)c(O)c4)=C2OC1(C)C)C3=O
Yield: 45.8 %

Procedure:
150 mg (0.249 mmol) of garcinol in toluene (1.2 mL) was stirred with 60 μL of concentrated hydrochloric acid at room temperature for 10 hours. The resulting mixture was allowed to stand in a refrigerator overnight, and the precipitated solid was collected by filtration and rinsed with 6 mL of water. 0.6 mL of acetonitrile was added to the solid to form a slurry, and the slurry was filtered. The slurry obtained from the filtrate was filtered. The collected solids were combined and dried to give 68.7 mg of isogarcinol (yield 46%).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][O:11][C:12]1[CH:16]=[C:15]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[O:14][N:13]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C([Li])CCC.[CH3:28][C:29]([CH3:31])=[O:30].P([O-])(O)(O)=O.[K+]>O1CCCC1>[C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][O:11][C:12]1[C:16]([C:29]([OH:30])([CH3:31])[CH3:28])=[C:15]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[O:14][N:13]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)=O
Reactant: CC(C)(C)OC(=O)NCCOc1cc(-c2ccccc2)on1
Agent: O=P([O-])(O)O
Agent: [K+]
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NCCOc1noc(-c2ccccc2)c1C(C)(C)O
Temperature: -70 °C
Reaction time: 0.17 h
Yield: 44 %

Procedure:
3-(2-(N-tert-Butoxycarbonylamino)ethoxy)-5-phenylisoxazole (0.8 g) was dissolved in tetrahydrofuran (16 ml), butyllithium (1.6M hexane solution, 3.7 ml) was added dropwise thereto at -70° C. under a nitrogen atmosphere, and the resulting mixture was stirred at the same temperature for 10 minutes. After acetone (0.3 ml) was added dropwise to the reaction mixture and the mixture was stirred for 10 minutes, the temperature of the mixture was raised to 0° C. The reaction mixture was poured into ice-cold water and the pH of the mixture was adjusted to a value of 6 with an aqueous potassium dihydrogenphosphate solution. The mixture was extracted with ethyl acetate and the organic layer was washed with a saturated aqueous NaCl solution, followed by evaporation of the solvent under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane/ethyl acetate=3/1) to obtain the title compound (0.42 g, 44%) as a colorless oil.
Reaction SMILES: [F:1][C:2]1[C:3]([C:22]2[S:26][C:25]([C:27]3([OH:31])[CH2:30][CH2:29][CH2:28]3)=[N:24][CH:23]=2)=[C:4]2[CH:10]=[C:9](I)[N:8]([S:12]([C:15]3[CH:21]=[CH:20][C:18]([CH3:19])=[CH:17][CH:16]=3)(=[O:14])=[O:13])[C:5]2=[N:6][CH:7]=1.[CH3:32][S:33]([C:36]1[CH:37]=[C:38](B(O)O)[CH:39]=[CH:40][CH:41]=1)(=[O:35])=[O:34].C(=O)(O)[O-]>CN(C)C=O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[F:1][C:2]1[C:3]([C:22]2[S:26][C:25]([C:27]3([OH:31])[CH2:30][CH2:29][CH2:28]3)=[N:24][CH:23]=2)=[C:4]2[CH:10]=[C:9]([C:40]3[CH:39]=[CH:38][CH:37]=[C:36]([S:33]([CH3:32])(=[O:35])=[O:34])[CH:41]=3)[N:8]([S:12]([C:15]3[CH:21]=[CH:20][C:18]([CH3:19])=[CH:17][CH:16]=3)(=[O:14])=[O:13])[C:5]2=[N:6][CH:7]=1
Reactant: CS(=O)(=O)c1cccc(B(O)O)c1
Reactant: Cc1ccc(S(=O)(=O)n2c(I)cc3c(-c4cnc(C5(O)CCC5)s4)c(F)cnc32)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])O
Solvent: CN(C)C=O
Product: Cc1ccc(S(=O)(=O)n2c(-c3cccc(S(C)(=O)=O)c3)cc3c(-c4cnc(C5(O)CCC5)s4)c(F)cnc32)cc1
Temperature: 70 °C

Procedure:
To a stirred ambient solution of 1-(5-(5-fluoro-2-iodo-1-tosyl-1H-pyrrolo[2,3-b]pyridin-4-yl)thiazol-2-yl)cyclobutanol (Example 59A) (200 mg, 0.351 mmol) and 3-(methylsulfonyl)phenyl boronic acid (105 mg, 0.527 mmol) in N,N-dimethylformamide (2.63 mL) was added saturated aqueous bicarbonate solution (880 μL) followed by bis(triphenylphosphine)palladium dichloride (17.26 mg, 0.025 mmol). The mixture was heated to 70° C. for 4 hours and was quenched by the addition of water and dichloromethane. The layers were separated, and the aqueous layer was extracted with additional dichloromethane. The combined organics were dried with anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel, eluting with a gradient of 0 to 100% ethyl acetate in hexane, to give the title compound MS ESI(+) m/z 598.1 [M+H]+.