Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[OH:10])([O-:3])=[O:2].C(=O)([O-])[O-].[K+].[K+].[CH:17](Br)([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>CC(C)=O>[CH:17]([O:10][C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=1[N+:1]([O-:3])=[O:2])([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: O=[N+]([O-])c1ccccc1O
Reactant: BrC(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: O=[N+]([O-])c1ccccc1OC(c1ccccc1)c1ccccc1

Procedure:
2-Nitrophenol (11.0 g, 79 mmole), anhydrous potassium carbonate (17.6 g, 127.4 mmole) and benzhydryl bromide (19.6 g, 79 mmol) in acetone (220 ml) were refluxed under nitrogen for 5 hours. The mixture was cooled, filtered and evaporated in vacuo. The residue was triturated with diethyl ether, filtered and evaporated. Trituration with 60°-80° C. petroleum ether yielded a brown solid.
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[C:3]1[CH:8]=[C:7]([C:9]([CH3:12])([CH3:11])[CH3:10])[CH:6]=[CH:5][C:4]=1[OH:13].C1N2CN3CN(C2)CN1C3.FC(F)(F)[C:28](O)=[O:29]>O>[OH:13][C:4]1[C:3]([C:2]([F:14])([F:15])[F:1])=[CH:8][C:7]([C:9]([CH3:11])([CH3:12])[CH3:10])=[CH:6][C:5]=1[CH:28]=[O:29]
Reactant: CC(C)(C)c1ccc(O)c(C(F)(F)F)c1
Reactant: O=C(O)C(F)(F)F
Agent: C1N2CN3CN1CN(C2)C3
Solvent: O
Product: CC(C)(C)c1cc(C=O)c(O)c(C(F)(F)F)c1
Temperature: 25 °C
Yield: 40 %

Procedure:
A mixture of 3.41 g (15.5 mmol) of 2-trifluoromethyl-4-(1,1-dimethylethyl)phenol (see E. Stokker, et al, J. Med. Chem., 23:1414 (1980) as an example of how to obtain this material) and 2.24 g (16.0 mmol) of hexamethylenetetramine was refluxed in 30 ml of trifluroacetic acid for 5 hours. The solution was cooled to ambient temperature and diluted with 200 ml of water. The aqueous residue was extracted with hexane. The organic phase was washed with saturated sodium bicarbonate solution, dried and evaporated. The residue was chromatographed on 100 g of silica gel using hexane as eluent. There was obtained 1.54 g (6.25 mmol, 40%) of 2-hydroxy-3-trifluromethyl-5-(1,1-dimethylethyl)benzaldehyde as a white solid; mp 56°-57.5° C.
Reaction SMILES: [OH:1][NH:2][C:3]([C:5]1[CH:31]=[CH:30][C:8]([CH2:9][N:10]([CH2:22][C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[C:11](=[O:21])[C:12]2[CH:17]=[CH:16][C:15]([N+:18]([O-:20])=[O:19])=[CH:14][CH:13]=2)=[CH:7][CH:6]=1)=[NH:4].CCN(C(C)C)C(C)C.[CH3:41][C:42]1[CH:47]=[CH:46][C:45]([C:48]2[CH:53]=[CH:52][C:51]([C:54](Cl)=O)=[CH:50][CH:49]=2)=[CH:44][CH:43]=1>CC(=O)OCC>[CH3:41][C:42]1[CH:47]=[CH:46][C:45]([C:48]2[CH:53]=[CH:52][C:51]([C:54]3[O:1][N:2]=[C:3]([C:5]4[CH:6]=[CH:7][C:8]([CH2:9][N:10]([CH2:22][C:23]([O:25][C:26]([CH3:27])([CH3:28])[CH3:29])=[O:24])[C:11](=[O:21])[C:12]5[CH:13]=[CH:14][C:15]([N+:18]([O-:20])=[O:19])=[CH:16][CH:17]=5)=[CH:30][CH:31]=4)[N:4]=3)=[CH:50][CH:49]=2)=[CH:44][CH:43]=1
Reactant: Cc1ccc(-c2ccc(C(=O)Cl)cc2)cc1
Reactant: CC(C)(C)OC(=O)CN(Cc1ccc(C(=N)NO)cc1)C(=O)c1ccc([N+](=O)[O-])cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: Cc1ccc(-c2ccc(-c3nc(-c4ccc(CN(CC(=O)OC(C)(C)C)C(=O)c5ccc([N+](=O)[O-])cc5)cc4)no3)cc2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 73.2 %

Procedure:
Prepared using General Procedure 20. To a stirred solution of tert-butyl 2-(N-(4-(N-hydroxycarbamimidoyl)benzyl)-4-nitrobenzamido)acetate (7.25 g, 16.6 mmol) INT-57 in dioxanes (25 mL) was added DIEA (3.19 mL, 18.24 mmol) then 4′-methyl-[1,1′-biphenyl]-4-carbonyl chloride (3.83 g, 16.6 mmol). The reaction mixture was stirred at room temperature for 30 mins then at 120° C. for 3 h. The reaction mixture was allowed to cool to room temperature, diluted with EA (400 mL) and washed with brine (500 mL). The organics were pre-absorbed onto silica gel and purified by chromatography (MeCN/DCM) to provide 7.35 g (73%) of tert-butyl 2-(N-(4-(5-(4′-methyl-[1,1′-biphenyl]-4-yl)-1,2,4-oxadiazol-3-yl)benzyl)-4-nitrobenzamido)acetate INT-58 as a white powder. LCMS-ESI (m/z) calculated for C35H32N4O6: 604; found 549 [M-t-Bu+H]+, tR=3.24 min (Method 10).
Reaction SMILES: [F:1][C:2]([F:47])([F:46])[C@H:3]1[CH2:8][CH2:7][C@H:6]([NH:9][C:10]([C:12]2[C:38]([N:39]([CH3:45])[CH:40]3[CH2:44][CH2:43][S:42][CH2:41]3)=[CH:37][C:15]3[N:16]([CH3:36])[C:17]([NH:19][C:20]4[C:25]([Cl:26])=[CH:24][CH:23]=[C:22]([CH2:27][NH:28][C:29](=[O:34])[C:30]([CH3:33])([CH3:32])[CH3:31])[C:21]=4[Cl:35])=[N:18][C:14]=3[CH:13]=2)=[O:11])[CH2:5][CH2:4]1.C1C=C(Cl)C=C(C(OO)=[O:56])C=1.C(Cl)Cl.C(O)(=O)C>C([O-])(O)=O.[Na+]>[F:47][C:2]([F:1])([F:46])[C@H:3]1[CH2:8][CH2:7][C@H:6]([NH:9][C:10]([C:12]2[C:38]([N:39]([CH3:45])[CH:40]3[CH2:44][CH2:43][S:42](=[O:56])[CH2:41]3)=[CH:37][C:15]3[N:16]([CH3:36])[C:17]([NH:19][C:20]4[C:25]([Cl:26])=[CH:24][CH:23]=[C:22]([CH2:27][NH:28][C:29](=[O:34])[C:30]([CH3:33])([CH3:31])[CH3:32])[C:21]=4[Cl:35])=[N:18][C:14]=3[CH:13]=2)=[O:11])[CH2:5][CH2:4]1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CN(c1cc2c(cc1C(=O)N[C@H]1CC[C@H](C(F)(F)F)CC1)nc(Nc1c(Cl)ccc(CNC(=O)C(C)(C)C)c1Cl)n2C)C1CCSC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Product: CN(c1cc2c(cc1C(=O)N[C@H]1CC[C@H](C(F)(F)F)CC1)nc(Nc1c(Cl)ccc(CNC(=O)C(C)(C)C)c1Cl)n2C)C1CCS(=O)C1
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
A mixture of N-(trans-4-trifluoromethyl-cyclohexyl)-2-{2,6-dichloro-3-[(2,2-dimethyl-propionylamino)-methyl]-phenylamino}-6-[N-methyl-N-(tetrahydro-thiophen-3-yl)-amino]-1-methyl-1H-benzimidazole-5-carboxylic acid amide (compound 117, 70 mg, 0.098 mmol), mCPBA (23 mg, ˜0.10 mmol), DCM (5 mL) and glacial acetic acid (0.5 mL) is stirred for 2.5 h at rt. The mixture is diluted with sat aq NaHCO3, extracted with EtOAc, the combined organic phases are dried with Na2SO4, filtered and concentrated.
Reaction SMILES: [H][H].C([O:10][C:11]1[C:12]([O:30]CC2C=CC=CC=2)=[CH:13][C:14]2[C:15](=[N:22][O:23][CH2:24][CH2:25][CH2:26][N:27]([CH3:29])[CH3:28])[CH:16]3[CH2:21][CH:17]3[O:18][C:19]=2[CH:20]=1)C1C=CC=CC=1>C(OCC)(=O)C.[Pd]>[OH:10][C:11]1[C:12]([OH:30])=[CH:13][C:14]2[C:15](=[N:22][O:23][CH2:24][CH2:25][CH2:26][N:27]([CH3:29])[CH3:28])[CH:16]3[CH2:21][CH:17]3[O:18][C:19]=2[CH:20]=1
Reactant: CN(C)CCCON=C1c2cc(OCc3ccccc3)c(OCc3ccccc3)cc2OC2CC12
Reactant: [H][H]
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CN(C)CCCON=C1c2cc(O)c(O)cc2OC2CC12
Yield: 45.1 %

Procedure:
In 20 ml of ethyl acetate was suspended 48 mg of 10% palladium-on-carbon. After displacing the atmosphere with hydrogen by suction, 240 mg of the compound obtained in Example 11 was added to the suspension, and the mixture was stirred at room temperature for 5 hours in a hydrogen stream (atmospheric pressure). The reaction mixture was worked-up in the same manner as in Example 2 to obtain 67.0 mg (41.5%) of the titled compound.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:8]([C:11]#[N:12])[CH2:9][N:10]=2)[CH:7]=1.ClC1C(=O)C(C#N)=C(C#N)C(=O)C=1Cl>O1CCOCC1.C(OCC)(=O)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([C:11]#[N:12])=[CH:9][N:10]=2)[CH:7]=1
Reactant: N#CC1CN=C2C=CC(Br)=CN21
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: N#Cc1cnc2ccc(Br)cn12
Yield: 85.4 %

Procedure:
Method 1) 3.83 g of 6-bromo-2,3-dihydroimidazo[1,2-a]pyridine-3-carbonitrile synthesized in Production Example 242 was dissolved in 34 mL 1,4-dioxane, and the solution together with 4.3 g of 2,3-dichloro-5,6-dicyano-1,4-benzoquinone was heated at 90° C. for 2 hours. The reaction solution was diluted with ethyl acetate, insolubles were filtered off with Celite, and the filtrate was washed with an aqueous saturated sodium bicarbonate solution and brine. The organic layer was dried over anhydrous sodium sulfate and filtered through NH silica gel. The solvent was removed, whereby 3.24 g of the title compound (brown solid) was obtained.
Reaction SMILES: [CH3:1][C:2]1([CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH2:11][CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:12]3[CH:17]=[CH:16][C:15]([N+:18]([O-])=O)=[CH:14][N:13]=3)[CH:8]=2)[C:3]1=[O:21].[NH4+].[Cl-]>C(O)C.O.[Fe]>[NH2:18][C:15]1[CH:16]=[CH:17][C:12]([C:7]2[CH:8]=[C:9]3[C:4](=[CH:5][CH:6]=2)[C:3](=[O:21])[C:2]([CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])([CH3:1])[CH2:11][CH2:10]3)=[N:13][CH:14]=1
Reactant: CCOC(=O)CC1(C)CCc2cc(-c3ccc([N+](=O)[O-])cn3)ccc2C1=O
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CCO
Product: CCOC(=O)CC1(C)CCc2cc(-c3ccc(N)cn3)ccc2C1=O
Yield: 83.4 %

Procedure:
Iron powder (0.2 g, 3.58 mmol) was added to a solution of 3F (1.32 g, 3.58 mmol) in 10 mL of ethanol-water mixture (2:1) followed by NH4Cl (0.192 g, 3.58 mmol), and the mixture was refluxed for 3 h. The solvent was removed under reduced pressure, and residue was partitioned between ethyl acetate and water. The separated organic layer was dried over sodium sulfate and filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by flash chromatography using 25% ethyl acetate in hexane to afford the title compound (1.01 g, 82%) as a solid. 1H NMR (300 MHz, DMSO-d6): δ 8.05 (d, J=2.7 Hz, 1H), 7.94-7.86 (m, 3H), 7.74 (d, J=8.5 Hz, 1H), 7.00 (dd, J1=2.8 Hz, J2=8.6 Hz, 1H), 5.67 (s, 2H), 4.00 (q, J=7.2 Hz, 2H), 3.18-2.88 (m, 2H), 2.82 (d, J=15.8 Hz, 1H), 2.48-2.26 (m, 2H), 1.90 (dt, J1=13.2 Hz, J2=4.5 Hz, 1H), 1.17 (s, 3H), 1.13 (t, J=6.9 Hz, 3H). ESI-MS m/z: 339 (M+H)+.
Reaction SMILES: C[O:2][C:3](=[O:19])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH2:10][O:11][C:12]2[CH:17]=[CH:16][C:15](I)=[CH:14][CH:13]=2)[CH:5]=1.[N:20]1[CH:25]=[CH:24][CH:23]=[C:22](B(O)O)[CH:21]=1>>[N:20]1[CH:25]=[CH:24][CH:23]=[C:22]([C:15]2[CH:16]=[CH:17][C:12]([O:11][CH2:10][C:6]3[CH:5]=[C:4]([CH:9]=[CH:8][CH:7]=3)[C:3]([OH:2])=[O:19])=[CH:13][CH:14]=2)[CH:21]=1
Reactant: COC(=O)c1cccc(COc2ccc(I)cc2)c1
Reactant: OB(O)c1cccnc1
Product: O=C(O)c1cccc(COc2ccc(-c3cccnc3)cc2)c1

Procedure:
3-(4-Pyridin-3-yl-phenoxymethyl)-benzoic acid was prepared using the procedure described above for the synthesis of Example 3 from 3-(4-iodo -phenoxymethyl)-benzoic acid methyl ester (of Intermediate 1) and pyridine-3-boronic acid (available from Aldrich Chemical Company, Inc., Milwaukee, Wis.). Mass spectrum MH+=306.
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[C:5]([CH3:7])[NH:4][C:3]=1[CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[S:15]([N:18]1[CH2:22][CH2:21][CH2:20][CH2:19]1)(=[O:17])=[O:16].[CH3:23][N:24](C=O)C>C(#N)C>[CH3:7][C:5]1[NH:4][C:3]([CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[S:15]([N:18]2[CH2:22][CH2:21][CH2:20][CH2:19]2)(=[O:17])=[O:16])=[C:2]([CH3:1])[C:6]=1[C:23]#[N:24]
Reactant: Cc1cc(C)c(Cc2ccccc2S(=O)(=O)N2CCCC2)[nH]1
Reactant: CN(C)C=O
Solvent: CC#N
Product: Cc1[nH]c(Cc2ccccc2S(=O)(=O)N2CCCC2)c(C)c1C#N
Temperature: 25 °C
Reaction time: 1 h
Yield: 82.6 %

Procedure:
A mixture of 3,5-dimethyl-2-(2-(pyrrolidin-1-ylsulfonyl)benzyl)-1H-pyrrole (576.0 mg, 1.809 mmol) and N-chlorosulfonylisocyanide (197 μl, 2.261 mmol) in acetonitrile (9.0 ml) was stirred at 25° C. for 1 hour. DMF (140 μl, 1.809 mmol) was then added and the resulting mixture was stirred for an additional 16 hours. It was quenched with water (100 ml) and extracted with dichloromethane (100 ml×2). The organic layers were combined, filtered, and evaporated to give an oil. The oil was purified by column chromatography (0 to 70% ethyl acetate in hexanes) to give 2,4-dimethyl-5-(2-(pyrrolidin-1-ylsulfonyl)benzyl)-1H-pyrrole-3-carbonitrile (513.6 mg, 1.495 mmol, 83% yield) as brown oil. 1H NMR (CDCl3/400 MHz) δ (ppm) 9.10 (bs, 1H), 7.82-7.77 (m, 1H), 7.46-7.40 (m, 1H), 7.30-7.23 (m, 2H), 4.10 (s, 2H), 3.33-3.27 (m, 4H), 2.20 (s, 3H), 2.18 (s, 3H), 1.92-1.88 (m, 4H). MS m/z: 344.3 (M+1).
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[C:18]3[C:13](=[CH:14][C:15]([O:19][CH2:20][CH2:21][NH:22][CH2:23]CC4C=CC=CC=4)=[CH:16][CH:17]=3)[C:12](=[O:31])[C:11]([CH3:33])([CH3:32])[CH2:10]2)=[CH:5][CH:4]=1.[H][H]>C(O)C.[Pd]>[ClH:2].[Cl:2][C:3]1[CH:4]=[CH:5][C:6]([CH:9]2[C:18]3[C:13](=[CH:14][C:15]([O:19][CH2:20][CH2:21][NH:22][CH3:23])=[CH:16][CH:17]=3)[C:12](=[O:31])[C:11]([CH3:33])([CH3:32])[CH2:10]2)=[CH:7][CH:8]=1
Reactant: [H][H]
Reactant: CC1(C)CC(c2ccc(Cl)cc2)c2ccc(OCCNCCc3ccccc3)cc2C1=O
Agent: [Pd]
Agent: Cl
Solvent: CCO
Product: CNCCOc1ccc2c(c1)C(=O)C(C)(C)CC2c1ccc(Cl)cc1

Procedure:
A solution of 4-(4-chlorophenyl)-7-(2-benzylmethylaminoethoxy)-2,2-dimethyl-1-tetralone hydrochloride (4.3 g) in ethanol (100 ml) was hydrogenated in the presence of 10% palladium on charcoal (0.43 g) until hydrogen uptake was complete. After filtration the solvent was removed in vacuo to give 4-(4-chlorophenyl)-2,2-dimethyl-7-(2-methylaminoethoxy)-1-tetralone hydrochloride. Recrystallisation from ether-ethyl acetate gave white crystals m.p. 150°-3° (2.6 g, 74%).
Reaction SMILES: [CH2:1]([NH2:4])[C:2]#[CH:3].CCN(CC)CC.[C:12]1([CH3:22])[CH:17]=[CH:16][C:15]([S:18](Cl)(=[O:20])=[O:19])=[CH:14][CH:13]=1>C(Cl)Cl>[CH3:22][C:12]1[CH:17]=[CH:16][C:15]([S:18]([NH:4][CH2:1][C:2]#[CH:3])(=[O:20])=[O:19])=[CH:14][CH:13]=1
Reactant: C#CCN
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C#CCNS(=O)(=O)c1ccc(C)cc1

Procedure:
To solution of propargylamine (2.00 g, 36.29 mmol) and Et3N (7.30 g, 72.59 mmol) in CH2Cl2 was added in small portions p-toluenesulfonyl chloride (6.90 g, 36.29 mmol) (J. T. Baker) at 0° C. After 5 min the mixture was filtered and the filtrate was concentrated to a residue that upon direct application on a silica gel column with a 0-40% EtOAc in hexanes gradient yielded 4-Methyl-N-(prop-2-ynyl)-benzenesulfonamide. (Yield 7.30 g, 96%).
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:28])=[C:4]([CH:8]2[C:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[F:22])([C:13]#[N:14])[CH:11]([CH2:23][C:24]([CH3:27])([CH3:26])[CH3:25])[CH2:10][NH:9]2)[CH:5]=[CH:6][CH:7]=1.[CH2:29]([O:31][C:32](=[O:38])[CH2:33][CH2:34][N:35]=[C:36]=[O:37])[CH3:30]>>[CH2:29]([O:31][C:32](=[O:38])[CH2:33][CH2:34][NH:35][C:36]([N:9]1[CH2:10][C@@H:11]([CH2:23][C:24]([CH3:25])([CH3:27])[CH3:26])[C@@:12]([C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=2[F:22])([C:13]#[N:14])[C@H:8]1[C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[C:3]=1[F:28])=[O:37])[CH3:30]
Reactant: CC(C)(C)CC1CNC(c2cccc(Cl)c2F)C1(C#N)c1ccc(Cl)cc1F
Reactant: CCOC(=O)CCN=C=O
Product: CCOC(=O)CCNC(=O)N1C[C@@H](CC(C)(C)C)[C@](C#N)(c2ccc(Cl)cc2F)[C@H]1c1cccc(Cl)c1F
Yield: 84.7 %

Procedure:
In a manner similar to the method described in Example 49, rac-(2S,3S,4S)-2-(3-chloro-2-fluoro-phenyl)-3-(4-chloro-2-fluoro-phenyl)-4-(2,2-dimethyl-propyl)-pyrrolidine-3-carbonitrile (100 mg, 0.236 mmol) was reacted with 3-isocyanato-propionic acid ethyl ester (168 mg, 1.174 mmol) to give rac-3-{[(2S,3S,4S)-2-(3-chloro-2-fluoro-phenyl)-3-(4-chloro-2-fluoro-phenyl)-3-cyano-4-(2,2-dimethyl-propyl)-pyrrolidine-1-carbonyl]-amino}-propionic acid ethyl ester (113.2 mg, 85%). HRMS (ES+) m/z Calcd for C28H31Cl2F2N3O3+H [(M+H)+]: 566.1784; Found: 566.1785.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([C:10](=O)[C:11](OC(C)C)=[O:12])=[CH:2]1.[BH4-].[Li+].Cl>C(O)(C)C.O>[OH:12][CH2:11][CH2:10][C:3]1[C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[NH:1][CH:2]=1
Reactant: CC(C)OC(=O)C(=O)c1c[nH]c2ccccc12
Agent: Cl
Agent: [BH4-]
Agent: [Li+]
Solvent: O
Solvent: CC(C)O
Product: OCCc1c[nH]c2ccccc12
Reaction time: 5 h

Procedure:
To a stirred suspension of isopropyl 3-indolylglyoxylate (46.4 g.) in isopropanol (500 ml.), lithium borohydride (13.1 g.) was added in small portions. The resulting solution was heated to reflux and stirred for 5 hours then cooled and diluted with water (2 l.). The mixture was acidified with hydrochloric acid and the product extracted into dichloromethane. The extract was washed with sodium carbonate solution then with water and the solvent was evaporated under reduced pressure to give an oil which was crystallised from toluene (50 ml.). The crude product was a red-brown powder, yield 25.0 g. (78%). This was distilled at 0.5 - 1mm. pressure and the distillate crystallised from toluene (100 ml.), giving 3-(2-hydroxyethyl)indole as white crystals, mp. 57°-59°. Yield 20.7g(64.5%)
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C:7](=[O:11])[CH2:6][CH2:5]2.[CH3:12][CH:13](O)[CH:14]=[CH2:15].C1(C)C=CC(S(O)(=O)=O)=CC=1.O>COC(OC)(C)C>[CH2:12]([CH:6]1[CH2:5][C:4]2[C:8](=[CH:9][CH:10]=[C:2]([F:1])[CH:3]=2)[C:7]1=[O:11])[CH:13]=[CH:14][CH3:15]
Reactant: C=CC(C)O
Reactant: O=C1CCc2cc(F)ccc21
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: COC(C)(C)OC
Product: CC=CCC1Cc2cc(F)ccc2C1=O
Yield: 68 %

Procedure:
A solution of 20.0 g of 5-fluoro-1-indanone, 27.5 ml of 3-buten-2-ol and 200 mg of p-toluenesulfonic acid in 200 ml of 2,2-dimethoxy-propane was boiled under reflux for 63 hours on a water separator filled with molecular sieve (0.4 nm, 2 mm pearl shaped). The reaction mixture was subsequently concentrated in a vacuum and purified by column chromatography on silica gel (hexane/diethyl ether 4:1). 18.6 g (68%) of (RS)-2-(2-buten-1-yl)-5-fluoro-1-indanone were obtained as a yellow oil.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]=[CH:3][C:2]=1[C:11](Cl)=[O:12].[C:14]1([C@H:20]([CH3:23])[CH2:21][NH2:22])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.N1C=CC=CC=1>O>[C:14]1([C@H:20]([CH3:23])[CH2:21][NH:22][C:11]([C:2]2[CH:3]=[N:4][C:5]3[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=3)[N:1]=2)=[O:12])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: C[C@H](CN)c1ccccc1
Reactant: O=C(Cl)c1cnc2ccccc2n1
Solvent: O
Solvent: c1ccncc1
Product: C[C@H](CNC(=O)c1cnc2ccccc2n1)c1ccccc1
Yield: 74.9 %

Procedure:
Prepared from 2-quinoxaloyl chloride (0.47 g, 2.4 mmol), (S)-2-phenyl-1-propylamine (0.30 g, 2.2 mmol), pyridine (5 mL), and water (50 mL) yielding 0.48 g (74%) of (173):
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[CH:9][CH:8]=[CH:7]2.[F:12][C:13]([F:25])([F:24])[C:14]1[CH:15]=[C:16]([S:20](Cl)(=[O:22])=[O:21])[CH:17]=[N:18][CH:19]=1.N1C=CC=CC=1>CN(C1C=CN=CC=1)C.C(Cl)Cl>[N:10]1[C:11]2[C:6](=[CH:5][CH:4]=[CH:3][C:2]=2[NH:1][S:20]([C:16]2[CH:17]=[N:18][CH:19]=[C:14]([C:13]([F:25])([F:12])[F:24])[CH:15]=2)(=[O:22])=[O:21])[CH:7]=[CH:8][CH:9]=1
Reactant: O=S(=O)(Cl)c1cncc(C(F)(F)F)c1
Reactant: Nc1cccc2cccnc12
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: O=S(=O)(Nc1cccc2cccnc12)c1cncc(C(F)(F)F)c1
Yield: 17.7 %

Procedure:
In a similar fashion using route 14 general procedure 27, 8-aminoquinoline (70 mg, 0.48 mmol), 5-trifluoromethyl-pyridine-3-sulfonyl chloride (Intermediate 442) (153 mg, 0.63 mmol), DMAP (cat.), pyridine (1.5 ml) and DCM (2 ml) gave the title compound (30 mg, 11%) after purification by column chromatography with n-hexane/EtOAc (85:15) as the eluent.
Reaction SMILES: [Cl:1][C:2]1[N:10](CC=C)[C:9]2[C:8](=[O:14])[N:7]([CH2:15][CH2:16][CH2:17][C:18]([F:21])([F:20])[F:19])[C:6](=[O:22])[N:5]([CH2:23][CH2:24][CH2:25][C:26]([F:29])([F:28])[F:27])[C:4]=2[N:3]=1.N1CCOCC1>O1CCCC1.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>[Cl:1][C:2]1[NH:10][C:9]2[C:8](=[O:14])[N:7]([CH2:15][CH2:16][CH2:17][C:18]([F:20])([F:21])[F:19])[C:6](=[O:22])[N:5]([CH2:23][CH2:24][CH2:25][C:26]([F:29])([F:27])[F:28])[C:4]=2[N:3]=1
Reactant: C=CCn1c(Cl)nc2c1c(=O)n(CCCC(F)(F)F)c(=O)n2CCCC(F)(F)F
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: C1COCCN1
Product: O=c1c2[nH]c(Cl)nc2n(CCCC(F)(F)F)c(=O)n1CCCC(F)(F)F
Temperature: 25 °C
Reaction time: 8 h
Yield: 16.9 %

Procedure:
8-chloro-7-(2-propen-1-yl)-1,3-bis(4,4,4-trifluorobutyl)-3,7-dihydro-1H-purine-2,6-dione (478 mg, 1.1 mmol) and morpholine (937 ul, 11 mmol) were degassed with nitrogen in tetrahydrofuran (10 ml) and then tetrakis(triphenylphosphine)palladium(0) (123 mg, 0.11 mmol) was added and the reaction stirred at room temperature overnight. The reaction mixture was partitioned between dichloromethane and hydrochloric acid 2N. The organic phase was separated and reduced to give the crude product. This was purified by aminopropyl SPE (5 g) followed by re-crystallisation from acetonitrile to afford the title compound (75.5 mg, 16.9%). NMR. δH (400 MHz, CDCl3) 1.96-2.13 (m, 4H), 2.15-2.29 (m, 4H), 4.15-4.23 (m, 4H), 12.94 (br. s, 1H); m/z 407 [MH+].
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[C:10]([CH3:13])[CH:9]=2)=[CH:4][CH:3]=1.[CH2:14]([O:16][C:17]([C:19]1([C:22]2[CH:27]=[CH:26][C:25](B3OC(C)(C)C(C)(C)O3)=[CH:24][CH:23]=2)[CH2:21][CH2:20]1)=[O:18])[CH3:15]>>[CH2:14]([O:16][C:17]([C:19]1([C:22]2[CH:27]=[CH:26][C:25]([C:2]3[CH:7]=[CH:6][C:5]([C:8]4[O:12][N:11]=[C:10]([CH3:13])[CH:9]=4)=[CH:4][CH:3]=3)=[CH:24][CH:23]=2)[CH2:20][CH2:21]1)=[O:18])[CH3:15]
Reactant: Cc1cc(-c2ccc(Br)cc2)on1
Reactant: CCOC(=O)C1(c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)CC1
Product: CCOC(=O)C1(c2ccc(-c3ccc(-c4cc(C)no4)cc3)cc2)CC1

Procedure:
Prepared according to the procedure described in Example 1, Step 7, using 5-(4-bromo-phenyl)-3-methyl-isoxazole and 1-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-cyclopropanecarboxylic acid ethyl ester.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([O:10]C)[C:5]([O:8]C)=[CH:6][CH:7]=1.B(Br)(Br)Br>ClCCl>[Br:1][C:2]1[CH:3]=[C:4]([OH:10])[C:5](=[CH:6][CH:7]=1)[OH:8]
Reactant: COc1ccc(Br)cc1OC
Agent: BrB(Br)Br
Solvent: ClCCl
Product: Oc1ccc(Br)cc1O
Temperature: 25 °C
Reaction time: 3 h
Yield: 96.1 %

Procedure:
6.51 g (0.0300 mol) of 4-bromoveratrole is dissolved in 50 ml of dichloromethane. To this suspension is added 37.6 g (0.150 mol) of boron tribromide at 0° C. The mixture was stirred for 3 hours at room temperature. Solvents were removed under reduced pressure. The resulting brown oil was dissolved in ethyl acetate and filtered through a pad of silica gel. The filtrate was concentrated to afford 5.45 g of 4-bromo catechol as a fight, brown oil.
Reaction SMILES: [NH:1]1[CH:5]=[N:4][CH:3]=[N:2]1.[H-].[Na+].Br[C:9]1[O:13][C:12]2[C:14]([O:20]C(=O)C)=[C:15]([O:18][CH3:19])[CH:16]=[CH:17][C:11]=2[C:10]=1[C:24](=[O:37])[C:25]1[CH:30]=[C:29]([O:31][CH3:32])[C:28]([O:33][CH3:34])=[C:27]([O:35][CH3:36])[CH:26]=1>O1CCCC1.C1(C)C=CC=CC=1>[N:1]1([C:9]2[O:13][C:12]3[C:14]([OH:20])=[C:15]([O:18][CH3:19])[CH:16]=[CH:17][C:11]=3[C:10]=2[C:24](=[O:37])[C:25]2[CH:26]=[C:27]([O:35][CH3:36])[C:28]([O:33][CH3:34])=[C:29]([O:31][CH3:32])[CH:30]=2)[CH:5]=[N:4][CH:3]=[N:2]1
Reactant: COc1cc(C(=O)c2c(Br)oc3c(OC(C)=O)c(OC)ccc23)cc(OC)c1OC
Reactant: c1nc[nH]n1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: COc1cc(C(=O)c2c(-n3cncn3)oc3c(O)c(OC)ccc23)cc(OC)c1OC

Procedure:
To a solution of 1,2,4-triazole (22 mg, 0.32 mmol) in dry tetrahydrofuran (2 mL) was added sodium hydride (60%, 24 mg, 0.60 mmol) and resulting suspension was treated with a solution of 2-bromo-7-acetoxy-3-(3,4,5-trimethoxybenzoyl)-6-methoxy-benzo[b]furan (50 mg, 0.10 mmol) in dry toluene (2 mL). The mixture was stirred at reflux for 6 hours (tlc), quenched with saturated ammonium chloride solution, extracted with dichloromethane (10 mL), dried over magnesium sulphate and the solvent distilled under vacuum. The crude residue was purified by PTLC (eluent=ethyl acetate: 1% triethylamine) to give the title compound as a yellow solid; (22 mg, 50%); 1H NMR (300 MHz, CDCl3) δ 8.64 (bs, 1H), 8.06 (bs, 1H), 7.10 (d, 1H, J=8.60 Hz), 7.05 (s, 2H, benzoyl Hs), 6.98 (d, 1H, J=8.65 Hz), 3.98 (s, 3H, OMe), 3.89 (s, 3H, OMe), 3.77 (s, 6H, 2×OMe).