Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([N:8]([C@H:16]([C@@H:24]([OH:42])[CH2:25][C@@H:26]([NH:34][C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)CC1C=CC=CC=1)C1C=CC=CC=1.C([O-])=O.[NH4+].C(O)(=O)C>CO.[Pd]>[NH2:8][C@H:16]([C@@H:24]([OH:42])[CH2:25][C@@H:26]([NH:34][C:35]([O:37][C:38]([CH3:40])([CH3:39])[CH3:41])=[O:36])[CH2:27][C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1)[CH2:17][C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)C[C@H](O)[C@H](Cc1ccccc1)N(Cc1ccccc1)Cc1ccccc1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CC(=O)O
Solvent: CO
Product: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)C[C@H](O)[C@@H](N)Cc1ccccc1
Temperature: 60 °C
Reaction time: 3 h

Procedure:
To a stirred solution of (2S,3S,5S)-2-(N,N-dibenzylamino)-3-hydroxy-5-(t-butyloxycarbonylamino)-1,6-diphenylhexane (12 g, 21.3 mmol) in methanol (350 mL) was charged ammonium formate (8.05 g, 128 mmol, 6.0 eq) and 10% palladium on carbon (2.4 g). The solution was stirred under nitrogen at 60° C. for three hours and then at 75° C. for 12 hours. An additional amount of ammonium formate (6 g) and 10% palladium on carbon (1.5 g) was added as well as 1 mL of glacial acetic acid. The reaction was driven to completion within 2 hours at a reflux temperature. The reaction mixture was then cooled to room temperature and then filtered through a bed of celite. The filter cake was washed with methanol (75 mL) and the combined filtrates were concentrated under reduced pressure. The residue was taken up in 1 N NaOH (300 mL) and extracted into methylene chloride (2×200 mL). The combined organic layers were washed with brine (250 mL) and dried over sodium sulfate. Concentration of the solution under reduced pressure provided the desired product as a light colored oil which slowly crystallized upon standing (5 g). Further purification of the product could be accomplished by flash chromatography (silica gel, 5% methanol in methylene chloride). 300 MHz 1H NMR (CDCl3) δ 1.42 (s, 9H), 1.58 (m, 1H), 1.70 (m, 1H), 2.20 (s, broad, 2H), 2.52 (m, 1H), 2.76-2.95 (m, 4H), 3.50 (m, 1 H), 3.95 (m, 1H), 4.80 (d, broad, 1H), 7.15-7.30 (m,10H).
Reaction SMILES: C1(C)C=CC(S(O)(=O)=O)=CC=1.[Cl:12][C:13]1[C:31]([F:32])=[C:30]([CH3:33])[C:29]([F:34])=[CH:28][C:14]=1[C:15]([CH:17](C(OCC)=O)[C:18]([O:20][CH2:21][CH3:22])=[O:19])=[O:16]>O>[Cl:12][C:13]1[C:31]([F:32])=[C:30]([CH3:33])[C:29]([F:34])=[CH:28][C:14]=1[C:15]([CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])=[O:16]
Reactant: CCOC(=O)C(C(=O)OCC)C(=O)c1cc(F)c(C)c(F)c1Cl
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Product: CCOC(=O)CC(=O)c1cc(F)c(C)c(F)c1Cl
Yield: 63.9 %

Procedure:
0.1 g of p-toluenesulphonic acid is added to an emulsion of 65.1 g of crude diethyl 2-chloro-3,5-difluoro-4-methyl-benzoyl-malonate in 70 ml of water. The mixture is heated to the boiling point for 4.5 hours, with thorough stirring, the cooled emulsion is extracted several times with methylene chloride, the combined CH2Cl2 solutions are washed once with saturated NaCl solution and dried with Na2SO4 and the solvent is distilled off in vacuo. Fractionation of the residue under a fine vacuum gives 33 g of ethyl 2-chloro-3,5-difluoro-4-methylbenzoyl-acetate of boiling point 108°-118° C./0.09 mbar.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([OH:10])=O)=[N:6][CH:7]=1.C1N=C[N:13](C(N2C=NC=C2)=O)[CH:12]=1.CN.C1COCC1>ClCCCl.C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([NH:13][CH3:12])=[O:10])=[N:6][CH:7]=1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: O=C(O)c1ccc(Cl)cn1
Agent: CN
Solvent: C1CCOC1
Solvent: ClCCl
Solvent: ClCCCl
Product: CNC(=O)c1ccc(Cl)cn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 41 %

Procedure:
To a stirred solution of 5-chloropyridine-2-carboxylic acid (315 mg, 2.0 mmol) in DCE (2.5 ml) at 20 to 25° C. was added CDI (324 mg, 2.0 mmol) and the mixture was stirred at RT overnight. The reaction mixture was heated to ca. 50° C. and a solution of methylamine in THF (2 M, 5.0 mmol) was added. The resulting mixture was stirred at 50° C. overnight and then cooled to RT and diluted with DCM (20 mL). the reaction mixture was washed with sat. NaHCO3 (10 ml) and the organic layer dried (Na2SO4), filtered and concentrated in vacuo. Purification by silica flash column chromatography (eluting with DCM/MeOH 95:5) provided the title compound as off-white solid (140 mg, 41%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:17]=[C:16]([CH2:18][OH:19])[CH:15]=[C:14]2[C:9]=1[CH2:10][NH:11][C:12](=[O:28])[N:13]2[C:20]1[C:25]([Cl:26])=[CH:24][CH:23]=[CH:22][C:21]=1[Cl:27].C[N+]1([O-])CCOCC1>C(Cl)Cl.[Ru]([O-])(=O)(=O)=O.C([N+](CCC)(CCC)CCC)CC>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:17]=[C:16]([CH:18]=[O:19])[CH:15]=[C:14]2[C:9]=1[CH2:10][NH:11][C:12](=[O:28])[N:13]2[C:20]1[C:21]([Cl:27])=[CH:22][CH:23]=[CH:24][C:25]=1[Cl:26]
Reactant: O=C1NCc2c(-c3ccccc3Cl)cc(CO)cc2N1c1c(Cl)cccc1Cl
Agent: O=[Ru](=O)(=O)[O-]
Agent: CCC[N+](CCC)(CCC)CCC
Agent: C[N+]1([O-])CCOCC1
Solvent: ClCCl
Product: O=Cc1cc(-c2ccccc2Cl)c2c(c1)N(c1c(Cl)cccc1Cl)C(=O)NC2
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a suspension of 5-(2-chlorophenyl)-1-(2,6-dichlorophenyl)-7-(hydroxymethyl)-3,4-dihydroquinazolin-2(1H)-one (780 mg, 1.8 mmol) in methylene chloride (15 mL) was added 4-methylmorpholine N-oxide (316 mg, 2.7 mmol). To the resulting clear solution was added molecular sieves (900 mg) followed by tetrapropylammonium perruthenate (32 mg, 0.09 mmol). The resulting mixture was stirred at rt for 2 h. The mixture was then filtered through silica gel eluting with ethyl acetate. Removal of the solvent and subsequent purification by flash chromatography using 25% acetone/hexane provided 5-(2-chlorophenyl)-1-(2,6-dichlorophenyl)-2-oxo-1,2,3,4-tetrahydroquinazoline-7-carbaldehyde as a white solid. 1H NMR (CDCl3, 500 MHz): δ 4.43 (abq, 2H, J=15.5 Hz), 5.37 (s, 1H), 6.66 (s, 1H), 7.30-7.60 (m, 8H), 9.85 (s, 1).
Reaction SMILES: C([O:5][C:6]([C:8]1[CH:13]=[C:12](OC2C=CC(NC)=C(N)C=2)[CH:11]=[CH:10][N:9]=1)=[O:7])(C)(C)C.NC(N)=S.IC.C(OC(C1C=C([O:43][C:44]2[CH:65]=[CH:64][C:47]3[N:48]([CH3:63])[C:49]([NH:51][C:52]4[CH:57]=[C:56]([C:58]([F:61])([F:60])[F:59])[CH:55]=[CH:54][C:53]=4[F:62])=[N:50][C:46]=3[CH:45]=2)C=CN=1)=O)(C)(C)C.FC(F)(F)C(O)=O>CO.C(Cl)Cl>[F:62][C:53]1[CH:54]=[CH:55][C:56]([C:58]([F:61])([F:60])[F:59])=[CH:57][C:52]=1[NH:51][C:49]1[N:48]([CH3:63])[C:47]2[CH:64]=[CH:65][C:44]([O:43][C:8]3([C:6]([OH:7])=[O:5])[CH:13]=[CH:12][CH:11]=[CH:10][NH:9]3)=[CH:45][C:46]=2[N:50]=1
Reactant: CNc1ccc(Oc2ccnc(C(=O)OC(C)(C)C)c2)cc1N
Reactant: Cn1c(Nc2cc(C(F)(F)F)ccc2F)nc2cc(Oc3ccnc(C(=O)OC(C)(C)C)c3)ccc21
Agent: NC(N)=S
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: CO
Product: Cn1c(Nc2cc(C(F)(F)F)ccc2F)nc2cc(OC3(C(=O)O)C=CC=CN3)ccc21
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To tert-butyl4-[3-amino-4-(methylamino)phenoxy]pyridine-2-carboxylate (1 eq) in methanol was added 2-fluoro-5-(trifluoromethyl)benzeneisothiocyanate (1 eq) and stir at ambient temperature for 16 h. Formation of the corresponding thiourea was followed by LC/MS. To it was then added iodomethane (1 eq) and heated to 60° C. for 2 h. Formation of tert-butyl4-(2-{[2-fluoro-5-(trifluoromethyl)phenyl]amino)-1-methylbenzimidazol-5-yloxy)pyridine-2-carboxylate was followed by LC/MS. To it in methylene chloride was added trifluoroacetic acid and stirred at ambient temperature overnight. Resulting 4-(2-{[2-fluoro-5-(trifluoromethyl)phenylamino)-1-methylbenzimidazol-5-yloxy)pyridine-2-carboxylic acid was purified by preparative chromatography. MS: MH+=446.
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[C:12]([Cl:13])=[CH:11][C:10]([C:14]([F:17])([F:16])[F:15])=[CH:9][C:8]=2[Cl:18])[N:5]=[C:4]([C:19]#[N:20])[C:3]=1I.C(=O)([O-])O.[Na+].[F:27][C:28]1[CH:33]=[CH:32][C:31](B(O)O)=[CH:30][CH:29]=1.CCOCC>C1(C)C=CC=CC=1.C(O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O>[NH2:1][C:2]1[N:6]([C:7]2[C:12]([Cl:13])=[CH:11][C:10]([C:14]([F:17])([F:16])[F:15])=[CH:9][C:8]=2[Cl:18])[N:5]=[C:4]([C:19]#[N:20])[C:3]=1[C:31]1[CH:32]=[CH:33][C:28]([F:27])=[CH:29][CH:30]=1
Reactant: N#Cc1nn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)c(N)c1I
Reactant: OB(O)c1ccc(F)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Solvent: CCOCC
Product: N#Cc1nn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)c(N)c1-c1ccc(F)cc1
Reaction time: 8 h

Procedure:
To a rapidly stirred solution of 5-amino-3-cyano-1-(2,6-dichloro-4-trifluoromethylphenyl)-4-iodopyrazole (0.25 g) in toluene (2 ml) containing tetrakis(triphenylphosphine)palladium(0) (0.02 g) was added saturated aqueous sodium hydrogen carbonate solution (1 ml) and a solution of 4-fluorophenylboronic acid (0.17 g) in ethanol (1 ml). The mixture was heated under reflux for 1 hour, then left at room temperature overnight and then poured into ether (25 ml) and water (25 ml). The organic layer was separated, dried (MgSO4) and evaporated. The residue was taken up the minimum amount of ethyl acetate and purified by column chromatography on silica gel (20 g) eluted with dichloromethane:hexane (1:1). Combination and evaporation of suitable fractions followed by recrystallisation from ether/hexane gave the title compound as a white solid, m.p. 222-3° C.
Reaction SMILES: [P:1]([O:11][CH2:12][C:13]1[C:18]([O:19][CH3:20])=[CH:17][CH:16]=[CH:15][C:14]=1[CH2:21][O:22][Si](C(C)(C)C)(C)C)([O:7][CH2:8][CH:9]=[CH2:10])([O:3][CH2:4][CH:5]=[CH2:6])=[O:2].[F-].C([N+](CCCC)(CCCC)CCCC)CCC.O.C(OCC)(=O)C>O1CCCC1.CCCCCC>[P:1]([O:11][CH2:12][C:13]1[C:18]([O:19][CH3:20])=[CH:17][CH:16]=[CH:15][C:14]=1[CH2:21][OH:22])([O:7][CH2:8][CH:9]=[CH2:10])([O:3][CH2:4][CH:5]=[CH2:6])=[O:2]
Reactant: C=CCOP(=O)(OCC=C)OCc1c(CO[Si](C)(C)C(C)(C)C)cccc1OC
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CCCCCC
Solvent: O
Solvent: C1CCOC1
Product: C=CCOP(=O)(OCC=C)OCc1c(CO)cccc1OC
Temperature: 25 °C
Reaction time: 1 h
Yield: 93.5 %

Procedure:
To a solution of diallyl 2-[(tert-butyldimethylsilyl)oxymethyl]-6-methoxybenzyl phosphate (1.03 g, 2.33 mmol) obtained from Example 21(3) in tetrahydrofuran (10 ml) was added tetrabutylammonium fluoride (1N tetrahydrofuran solution; 2.5 ml, 2.5 mmol), and the mixture was stirred at room temperature for 1 hour. Water was added to the reaction mixture, then the product was extracted with ethyl acetate, and the solvent was evaporated under reduced pressure to give an oily residue. The residue was subjected to chromatography on a silica gel (50 g) column (eluent; ethyl acetate:hexane=3:1˜1:0) to afford the title compound (715.0 mg, 93% yield) as a colorless oil.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[C:10]([CH3:13])[C:9]=2[CH:14]([OH:24])[CH2:15][CH2:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[CH:4][CH:3]=1.[CH2:25]([O:27][C:28](=[O:48])[CH2:29][C:30]1([C:33]2[CH:38]=[CH:37][C:36](B3OC(C)(C)C(C)(C)O3)=[CH:35][CH:34]=2)[CH2:32][CH2:31]1)[CH3:26]>>[CH2:25]([O:27][C:28](=[O:48])[CH2:29][C:30]1([C:33]2[CH:38]=[CH:37][C:36]([C:2]3[CH:7]=[CH:6][C:5]([C:8]4[O:12][N:11]=[C:10]([CH3:13])[C:9]=4[CH:14]([OH:24])[CH2:15][CH2:16][CH2:17][C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)=[CH:4][CH:3]=3)=[CH:35][CH:34]=2)[CH2:32][CH2:31]1)[CH3:26]
Reactant: Cc1noc(-c2ccc(Br)cc2)c1C(O)CCCc1ccccc1
Reactant: CCOC(=O)CC1(c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)CC1
Product: CCOC(=O)CC1(c2ccc(-c3ccc(-c4onc(C)c4C(O)CCCc4ccccc4)cc3)cc2)CC1

Procedure:
Prepared according to the procedure described in Example 110, Step 3, using 1-[5-(4-bromo-phenyl)-3-methyl-isoxazol-4-yl]-4-phenyl-butan-1-ol (Enantiomer B) and {1-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-cyclopropyl}-acetic acid ethyl ester.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([S:10][CH2:11][CH2:12][CH2:13][Cl:14])=[C:6]([NH:8]N)[CH:7]=1.O.[NH:16]1[CH2:21][CH2:20][C:19](=O)[CH2:18][CH2:17]1.Cl>CCO>[Br:1][C:2]1[C:7]2[C:18]3[CH2:17][NH:16][CH2:21][CH2:20][C:19]=3[NH:8][C:6]=2[C:5]([S:10][CH2:11][CH2:12][CH2:13][Cl:14])=[CH:4][CH:3]=1
Reactant: O=C1CCNCC1
Reactant: NNc1cc(Br)ccc1SCCCCl
Agent: Cl
Solvent: O
Solvent: CCO
Product: ClCCCSc1ccc(Br)c2c3c([nH]c12)CCNC3
Temperature: 25 °C
Yield: 58 %

Procedure:
1-{5-Bromo-2-[(3-chloropropyl)sulfanyl]phenyl}hydrazine hydrochloroide (784 mg, 2.4 mmol) and 4-piperidone monohydrate.HCl (398 mg, 2.6) were dissolved in EtOH (5mL). Conc. Hcl (0.2 mL, 2.4 mmol) were added. The reaction was refluxed for 18 hrs and then cooled to rt. The ppt was collected by filtration and the residue was washed with EtOH (3mL). 9-bromo-6-[(3-chloropropyl)sulfanyl]-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole hydrochloroide (500.4 mg, 58%) was isolated as a white powder. 1H NMR (CD3OD, 300 Mhz) δ7.18 (d, 1H, 8.0 Hz), 7.12 (d, 1H, 8.0 Hz), 4.73 (s, 2H), 3.64 (t, 2H, 6.6 Hz), 3.58 (t, 2H, 6.3 Hz), 3.16 (t, 2H, 6.3 Hz), 3.02 (t, 2H, 6.6 Hz), 1.87-1.96 (m, 2H) ppm.
Reaction SMILES: Cl.[CH2:2]([O:9][C:10]([NH:12][C:13]1([CH2:26][N:27]2[CH2:32][CH2:31][N:30]([S:33]([C:36]3[CH:45]=[CH:44][C:43]4[C:38](=[CH:39][CH:40]=[C:41]([Cl:46])[CH:42]=4)[CH:37]=3)(=[O:35])=[O:34])[CH2:29][C:28]2=[O:47])[CH2:18][CH2:17][N:16](C(OC(C)(C)C)=O)[CH2:15][CH2:14]1)=[O:11])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1>C(OCC)(=O)C.C(O)C>[CH2:2]([O:9][C:10]([NH:12][C:13]1([CH2:26][N:27]2[CH2:32][CH2:31][N:30]([S:33]([C:36]3[CH:45]=[CH:44][C:43]4[C:38](=[CH:39][CH:40]=[C:41]([Cl:46])[CH:42]=4)[CH:37]=3)(=[O:34])=[O:35])[CH2:29][C:28]2=[O:47])[CH2:18][CH2:17][N:16]([C:13]2[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=2)[CH2:15][CH2:14]1)=[O:11])[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: CC(C)(C)OC(=O)N1CCC(CN2CCN(S(=O)(=O)c3ccc4cc(Cl)ccc4c3)CC2=O)(NC(=O)OCc2ccccc2)CC1
Agent: Cl
Solvent: CCO
Solvent: CCOC(C)=O
Product: O=C(NC1(CN2CCN(S(=O)(=O)c3ccc4cc(Cl)ccc4c3)CC2=O)CCN(c2ccncc2)CC1)OCc1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 99.9 %

Procedure:
A 4N hydrochloric acid solution in ethyl acetate (50 ml) and ethanol (10 ml) was added to 1-[4-benzyloxycarbonylamino-1-(tert-butoxycarbonyl)-4-piperidylmethyl]-4-(6-chloronaphthalene-2-sulfonyl)-2-piperazinone (7.42 g), and the mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure, 4-chloropyridine hydrochloride (1.80 g), triethylamine(6.97 ml) and ethanol (100 ml) were added to the residue, and the mixture was heated at 150° C. for 5 hours in a sealed tube. After cooling, the reaction mixture was diluted with ethyl acetate, and washed with water. The ethyl acetate layer was dried with magnesium sulfate, and concentrated under reduced pressure. The residue was purified by basic silica gel chromatography (ethyl acetate-ethyl acetate/methanol=8/1) to obtain the title compound (3.58 g, 55%) as powders.
Reaction SMILES: [C:1]([O:5][NH:6][C:7]([C:9]1[C:14]([CH3:15])=[C:13]([N+:16]([O-])=O)[CH:12]=[CH:11][CH:10]=1)=[O:8])([CH3:4])([CH3:3])[CH3:2].C(ONC(C1C=C(C=CC=1)N)=O)(C)(C)C>>[NH2:16][C:13]1[CH:12]=[CH:11][CH:10]=[C:9]([C:7](=[O:8])[NH:6][O:5][C:1]([CH3:2])([CH3:3])[CH3:4])[C:14]=1[CH3:15]
Reactant: Cc1c(C(=O)NOC(C)(C)C)cccc1[N+](=O)[O-]
Agent: CC(C)(C)ONC(=O)c1cccc(N)c1
Product: Cc1c(N)cccc1C(=O)NOC(C)(C)C
Yield: 98.9 %

Procedure:
This compound was prepared from 6-tert-butyloxycarbamoyl-2-nitrotoluene (4.60 g, 18.2 mmol) in a manner similar to that described for 3-tert-butyloxycarbamoylaniline (EXAMPLE 147), affording 4.00 g (99%) of 2-amino-6-tert-butyloxycarbamoyltoluene as a colorless oil. Data for 2-amino-6-tert-butyloxycarbamoyltoluene:
Reaction SMILES: Br[C:2]1[CH:6]=[CH:5][S:4][C:3]=1[C:7]1[CH:12]=[CH:11][N:10]=[C:9]2[N:13](S(C3C=CC(C)=CC=3)(=O)=O)[CH:14]=[CH:15][C:8]=12.[C:26]([NH:33][C:34]1[CH:39]=[CH:38][C:37](B(O)O)=[CH:36][CH:35]=1)([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27].O.[OH-].[Ba+2].[OH-]>COCCOC.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[NH:13]1[C:9]2=[N:10][CH:11]=[CH:12][C:7]([C:3]3[S:4][CH:5]=[CH:6][C:2]=3[C:37]3[CH:36]=[CH:35][C:34]([NH:33][C:26](=[O:27])[O:28][C:29]([CH3:31])([CH3:30])[CH3:32])=[CH:39][CH:38]=3)=[C:8]2[CH:15]=[CH:14]1
Reactant: CC(C)(C)OC(=O)Nc1ccc(B(O)O)cc1
Reactant: Cc1ccc(S(=O)(=O)n2ccc3c(-c4sccc4Br)ccnc32)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Ba+2]
Agent: [OH-]
Solvent: COCCOC
Solvent: O
Product: CC(C)(C)OC(=O)Nc1ccc(-c2ccsc2-c2ccnc3[nH]ccc23)cc1
Temperature: 80 °C
Yield: 40 %

Procedure:
To a solution of 4-(3-bromo-2-thienyl)-1-[(4-methylphenyl)sulfonyl]-1H-pyrrolo[2,3-b]pyridine (5.3 mmol) in 40 mL of 1,2-dimethoxyethane was added 4-(N-Boc-amino)phenyl boronic acid (13.8 mmol), tetrakis(triphenylphosphine)palladium(0), (0.17 mmol), water (16 mL) and barium hydroxide (21.2 mmol). The reaction was heated at 80° C. for 36 h. The 1,2-dimethoxyethane was evaporated and the residue taken up in ethyl acetate and washed with water (50 mL). The crude product was purified by silica gel chromatography (0-50% ethyl acetate/hexanes) to give the title compound (40%). ESMS [M+H]+: 392.2
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:31])[CH:5]([OH:30])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][CH2:14][N:15]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])=[CH:9][CH:8]=1)[CH3:2].[CH2:32](Br)[CH:33]=[CH2:34]>>[CH2:1]([O:3][C:4](=[O:31])[CH:5]([O:30][CH2:34][CH:33]=[CH2:32])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][CH2:14][N:15]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])=[CH:9][CH:8]=1)[CH3:2]
Reactant: CCCCCCCN(CCc1ccc(CC(O)C(=O)OCC)cc1)C(=O)OC(C)(C)C
Reactant: C=CCBr
Product: C=CCOC(Cc1ccc(CCN(CCCCCCC)C(=O)OC(C)(C)C)cc1)C(=O)OCC
Yield: 41 %

Procedure:
Synthesized from 3-{4-[2-(tert-butoxycarbonyl-heptyl-amino)-ethyl]-phenyl}-2-hydroxy-propionic acid ethyl ester using a procedure analogous to that used for Example 47 and substituting allyl bromide as the electrophile to give 2-allyloxy-3-{4-[2-(tert-butoxycarbonyl-heptyl-amino)-ethyl]-phenyl}-propionic acid ethyl ester as a clear oil (187 mg, 41%)
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([N+:9]([O-])=O)=[C:6]([OH:8])[CH:7]=1>CO.[Pd]>[NH2:9][C:5]1[CH:4]=[CH:3][C:2]([F:1])=[CH:7][C:6]=1[OH:8]
Reactant: O=[N+]([O-])c1ccc(F)cc1O
Agent: [Pd]
Solvent: CO
Product: Nc1ccc(F)cc1O
Temperature: 25 °C
Reaction time: 8 h
Yield: 88.6 %

Procedure:
To a solution of 5-fluoro-2-nitrophenol (9.50 g) in methanol (10 ml), 5% palladium on activated carbon (1.90 g) was added and stirred overnight under a hydrogen atmosphere at room temperature. The catalyst was filtered off and the solvent was distilled off under reduced pressure. The resulting residue was converted into a powder form by addition of chloroform, and then collected by filtration to give 2-amino-5-fluorophenol (6.81 g) as a brown powder. To a solution of 2-amino-5-fluorophenol thus obtained (3.00 g) in N,N-dimethylformamide (20 ml), potassium carbonate (16.31 g) and 1,2-dibromoethane (3.05 ml) were added and stirred at 125° C. for 10 hours. The reaction mixture was allowed to stand overnight at room temperature, to which additional 1,2-dibromoethane (1.52 ml) was then added and stirred at 125° C. for 7 hours. After cooling at room temperature, the reaction mixture was diluted with water under ice cooling and extracted with ethyl acetate. The organic layer was washed sequentially with water and brine, dried over anhydrous sodium sulfate and then filtered to remove the desiccant, followed by distilling off the solvent under reduced pressure. The resulting residue was purified by NH silica gel column chromatography (eluting solvent: n-hexane:ethyl acetate=9:1 to 7:3) to give the titled compound, i.e., 7-fluoro-3,4-dihydro-2H-1,4-benzoxazine (1.15 g) as a red-brown oil.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:10]2[CH:19]=[CH:18][C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[CH:11]=2)[CH:5]=[CH:6][C:7]=1[O:8]C.B(Br)(Br)Br>>[F:1][C:2]1[CH:3]=[C:4]([C:10]2[CH:19]=[CH:18][C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[CH:11]=2)[CH:5]=[CH:6][C:7]=1[OH:8]
Reactant: COc1ccc(-c2ccc3ccccc3c2)cc1F
Agent: BrB(Br)Br
Product: Oc1ccc(-c2ccc3ccccc3c2)cc1F

Procedure:
The title compound was prepared by reacting 2-(3-fluoro-4-methoxyphenyl)naphthalene (0.22 g, 0.87 mmol) with boron tribromide (1.75 mL of 1N solution, 1.75 mmol) according to method D to yield 0.13 g (63%) of a white solid: mp 110–112° C.; 1H NMR (DMSO-d6): δ 7.05–7.11 (1H, m), 7.47–7.54 (3H, m), 7.65 (1H, dd, J=2.20 Hz, J=12.92 Hz), 7.82 (1H, dd, J=1.80 Hz, J=8.62), 7.90–7.98 (3H, m), 8.17 (1H, bs), 10.07 (1H, bs); MS (ESI) m/z 237 (M−H)−.
Reaction SMILES: [ClH:1].[CH3:2][NH:3][S:4](/[CH:7]=[CH:8]/[C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[NH:14][CH:13]=[C:12]2[C:18]1[CH2:19][CH2:20][N:21]([CH3:24])[CH2:22][CH:23]=1)(=[O:6])=[O:5].C>CN(C=O)C.CO.[Pd]=O>[ClH:1].[CH3:2][NH:3][S:4]([CH2:7][CH2:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[NH:14][CH:13]=[C:12]2[CH:18]1[CH2:19][CH2:20][N:21]([CH3:24])[CH2:22][CH2:23]1)(=[O:5])=[O:6]
Reactant: CNS(=O)(=O)/C=C/c1ccc2[nH]cc(C3=CCN(C)CC3)c2c1
Agent: O=[Pd]
Agent: Cl
Solvent: CN(C)C=O
Solvent: CO
Product: CNS(=O)(=O)CCc1ccc2[nH]cc(C3CCN(C)CC3)c2c1
Reaction time: 24 h

Procedure:
A mixture of (E)-N-methyl-2-[3-(1,2,3,6-tetrahydro-1-methyl-4-pyridinyl)-1H-indol-5-yl]ethenesulphonamide hydrochloride (500 g) and 10% palladium oxide on charcoal (50% wet paste, 700g added as three charges) in DMF (3L), water (3L) and methanol (1.5L) was hydrogenated at atmospheric pressure over 24 hr. The suspension was filtered and the filter cake washed with water (500 mL). The filtrate was concentrated to approximately 2L by distillation in vacuo. Ethyl acetate (5L) was added over 10 mins and the mixture cooled to 5°. The product was filtered off, washed with ethyl acetate (1L) and dried in vacuo at 45° overnight (453 g, 90.1% of theory). Recrystallisation from hot water (1.36L) afforded white crystals (324.0 g, 71.2% of theory).
Reaction SMILES: C[O:2][C:3](=[O:14])[C@@:4]([CH3:13])([CH2:7][O:8][C:9]([F:12])([F:11])[F:10])[CH:5]=[CH2:6].O.[OH-].[Li+].Cl>O1CCCC1.O>[CH3:13][C@:4]([CH2:7][O:8][C:9]([F:10])([F:12])[F:11])([CH:5]=[CH2:6])[C:3]([OH:14])=[O:2]
Reactant: C=C[C@](C)(COC(F)(F)F)C(=O)OC
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: C=C[C@](C)(COC(F)(F)F)C(=O)O
Temperature: 5 °C
Reaction time: 1 h
Yield: 103.8 %

Procedure:
A solution of crude (R)-2-methyl-2-trifluoromethoxymethyl-but-3-enoic acid methyl ester (98 mg) in tetrahydrofuran (4 mL) was stirred at 5° C. under nitrogen. A solution of lithium hydroxide monohydrate (63 mg, 1.5 mmol) in water (1 mL) was added and the reaction mixture was stirred at 5° C. for 1 h and then at room temperature for 3 days. Water was added and the mixture was acidified to pH 2 with hydrochloric acid (2 M) and the mixture was extracted with diethyl ether. The organic extracts were combined and washed with brine. The organic solution was filtered through a hydrophobic frit and the filtrate was evaporated to afford the crude title compound (95 mg) as a clear oil which was used in the next step. LCMS (m/z) 197.1 [M−H], Tr=2.16 min.