Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[C:3]2[C:4]3[CH2:15][CH2:14][N:13]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:12][CH2:11][C:5]=3[NH:6][C:7]=2[CH:8]=[CH:9][CH:10]=1.CCN(CC)CC.[CH3:30][C:31]1([CH3:38])[C:35]([CH3:37])([CH3:36])[O:34][BH:33][O:32]1>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.O1CCOCC1>[CH3:30][C:31]1([CH3:38])[C:35]([CH3:37])([CH3:36])[O:34][B:33]([C:2]2[C:3]3[C:4]4[CH2:15][CH2:14][N:13]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:12][CH2:11][C:5]=4[NH:6][C:7]=3[CH:8]=[CH:9][CH:10]=2)[O:32]1
Reactant: CC(C)(C)OC(=O)N1CCc2[nH]c3cccc(Br)c3c2CC1
Reactant: CC1(C)OBOC1(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)N1CCc2[nH]c3cccc(B4OC(C)(C)C(C)(C)O4)c3c2CC1
Yield: 92.4 %

Procedure:
tert-Butyl 10-bromo-1,4,5,6-tetrahydroazepino[4,5-b]indole-3(2H)-carboxylate (1.51 g, 4.12 mmol) and dioxane (26 mL) were combined at rt under N2. Et3N (3.43 mL, 2.49 g, 24.6 mmol) and 4,4,5,5-tetramethyl-1,3,2-dioxaborolane (1.28 mL, 1.05 g, 8.21 mmol) were added to the mixture by syringe. trans-Dichlorobis(triphenylphosphine)palladium(II) (0.147 g, 0.209 mmol) was added and Ar was bubbled through the reaction mixture for 15 min. The reaction mixture was refluxed under N2 for 16 h. The cooled reaction mixture was concentrated and the residue was combined with toluene (50 mL), brine (20 mL) and H2O (100 mL). The layers were separated and the aqueous layer was extracted with toluene (2 ×50 mL). The combined organic extracts were washed with brine (40 mL), dried over MgSO4, filtered and concentrated. The crude product (1.90 g) was chromatographed (SiO2 60 g, eluted with 2:2:1 heptane:CH2Cl2:Et2O) to give tert-butyl 10-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,4,5,6-tetrahydroazepino[4,5-b]indole-3(2H)-carboxylate (1.57 g) in 93% yield. MS (ESI+) for C23H33BN2O4 m/z 413.2 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:11])[C@@H:4]([NH2:10])[C@H:5]([OH:9])[CH:6]([CH3:8])[CH3:7].C(N(CC)CC)C.[CH3:19][C:20]1[CH:25]=[CH:24][C:23]([S:26](Cl)(=[O:28])=[O:27])=[CH:22][CH:21]=1>ClCCl>[CH3:1][O:2][C:3](=[O:11])[C@@H:4]([NH:10][S:26]([C:23]1[CH:24]=[CH:25][C:20]([CH3:19])=[CH:21][CH:22]=1)(=[O:28])=[O:27])[C@H:5]([OH:9])[CH:6]([CH3:8])[CH3:7]
Reactant: COC(=O)[C@@H](N)[C@H](O)C(C)C
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)[C@@H](NS(=O)(=O)c1ccc(C)cc1)[C@H](O)C(C)C
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of (2S,3R)-2-amino-3-hydroxy-4-methyl-pentanoic acid methyl ester (0.50 g, 3.4 mmol) and triethylamine (0.69 g, 6.8 mmol) in dichloromethane (10 mL) was added 4-methyl-benzenesulfonyl chloride (0.71 g, 3.7 mmol) at 0° C. After stirring for 2 hours at room temperature, the mixture was washed with water and the organic layer was separated and then dried over sodium sulfate. After removal of solvent, the residue was used in next step without purification. MS: calc'd (MH+) 316, measured (MH+) 316.
Reaction SMILES: [CH3:1][C:2]([CH3:7])([CH2:5][OH:6])[CH:3]=O.O.[CH3:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([CH3:16])[C:11]=1[OH:17].CNC>CO>[CH3:9][C:10]1[CH:15]=[C:14]([CH2:3][C:2]([CH3:1])([CH3:7])[CH:5]=[O:6])[CH:13]=[C:12]([CH3:16])[C:11]=1[OH:17]
Reactant: CC(C)(C=O)CO
Reactant: Cc1cccc(C)c1O
Agent: CNC
Solvent: O
Solvent: CO
Product: Cc1cc(CC(C)(C)C=O)cc(C)c1O
Yield: 91 %

Procedure:
125 g (1 mol) of 80% strength aqueous 2,2-dimethyl-3-hydroxypropanal (crude mixture from the synthesis, reduced to a water content of 20% by distillation), 109 g (0.9 mol) of 2,6-dimethylphenol, 12 g (0.11 mol) of 40% strength aqueous dimethylamine and 700 g of methanol are reacted in a stirred autoclave at 180° C. and under the autogenous pressure of 20-30 bar for 10 h. Workup of the reaction mixture by distillation yields 168 g (91%) of 3-(3,5-dimethyl-4-hydroxyphenyl)-2,2-dimethylpropanal (boiling point 140°-142° C.; melting point 72°-73° C.).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[CH:18][CH:17]=1.C(O)C.[CH3:26][C:27]1[CH:28]=[C:29]([C:33]([N:35]=[C:36]=[S:37])=[O:34])[CH:30]=[CH:31][CH:32]=1>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH:20][C:36]([NH:35][C:33](=[O:34])[C:29]2[CH:30]=[CH:31][CH:32]=[C:27]([CH3:26])[CH:28]=2)=[S:37])=[CH:18][CH:17]=1
Reactant: Cc1cccc(C(=O)N=C=S)c1
Reactant: COc1cc2nccc(Oc3ccc(N)cc3)c2cc1OC
Solvent: Cc1ccccc1
Solvent: CCO
Product: COc1cc2nccc(Oc3ccc(NC(=S)NC(=O)c4cccc(C)c4)cc3)c2cc1OC
Temperature: 25 °C
Reaction time: 2 h
Yield: 96 %

Procedure:
4-[(6,7-Dimethoxy-4-quinolyl)oxy]aniline (50 mg) was dissolved in toluene (5 ml) and ethanol (1 ml) to prepare a solution. Commercially available 3-methyl-1-benzenecarbonyl isothiocyanate (50 μl) was then added to the solution, and the mixture was stirred at room temperature for 2 hr. The reaction solution was concentrated, and the residue was purified by chromatography on silica gel using chloroform/acetone for development to give the title compound (77 mg, yield 96%).
Reaction SMILES: [CH3:1][C:2]1([CH3:33])[O:6][C:5]2[C:7]([O:11][CH2:12][CH2:13][CH2:14][CH2:15][O:16][C:17]3[C:22]([Cl:23])=[CH:21][C:20]([O:24]CC4C=CC=CC=4)=[CH:19][C:18]=3[Cl:32])=[CH:8][CH:9]=[CH:10][C:4]=2[CH2:3]1.[H][H]>[Pd]>[CH3:1][C:2]1([CH3:33])[O:6][C:5]2[C:7]([O:11][CH2:12][CH2:13][CH2:14][CH2:15][O:16][C:17]3[C:22]([Cl:23])=[CH:21][C:20]([OH:24])=[CH:19][C:18]=3[Cl:32])=[CH:8][CH:9]=[CH:10][C:4]=2[CH2:3]1
Reactant: [H][H]
Reactant: CC1(C)Cc2cccc(OCCCCOc3c(Cl)cc(OCc4ccccc4)cc3Cl)c2O1
Agent: [Pd]
Product: CC1(C)Cc2cccc(OCCCCOc3c(Cl)cc(O)cc3Cl)c2O1

Procedure:
In a first step as depicted in Scheme 1, an appropriately substituted phenol, for example, the known compound 2,6-dichloro-4-phenylmethoxyphenol, was reacted under basic conditions with a haloalkane derivative of a desired carbon chain length, for example 1-bromo-4-chlorobutane, to attach the bridging group B, thereby affording the corresponding 1,3-dichloro-2-(4-chlorobutoxy)-5-(phenylmethoxy)benzene (A). Intermediate (A) was then reacted under basic conditions with, for example, the known compound 2,2-dimethyl-2,3-dihydrobenzo[b]furan-7-ol, to attach moiety D, as well as the benzo-fused ring, affording the corresponding 2-[4-(2,2-dimethyl-(2,3-dihydrobenzo[2,3-b]furan-7-yloxy))butoxy]-1,3-dichloro-5-(phenylmethoxy)benzene (B). Intermediate (B), for example 2-[4-(2,2-dimethyl-(2,3-dihydrobenzo[2,3-b]furan-7-yloxy))butoxy]-1,3-dichloro-5-(phenylmethoxy)benzene, as set forth above, was then reduced with hydrogen gas in the presence of a catalyst, for example 10% palladium on carbon, providing the corresponding 4-[4-(2,2-dimethyl(2,3-dihydrobenzo[2,3-b]furan-7-yloxy))butoxy]-3,5-dichlorophenol (C). Intermediate (C) was then reacted under basic conditions with, for example, 1,1,1,3-tetrachloropropane, which simultaneously dehydrohalogenates, thereby introducing the moiety —E—G—C(R4)═C(R5)(R5) into the molecule to provide Compound 12, a novel compound of formula I. Example 1 set forth below, provides a detailed method to how Compound 12 shown in Scheme 1 was prepared.
Reaction SMILES: [C:1]([Si:5]([O:8][C:9]1[CH:14]=[C:13]([N+:15]([O-])=O)[CH:12]=[CH:11][C:10]=1[O:18][CH3:19])([CH3:7])[CH3:6])([CH3:4])([CH3:3])[CH3:2].[H][H]>C(OCC)(=O)C.[Pd]>[Si:5]([O:8][C:9]1[CH:14]=[C:13]([NH2:15])[CH:12]=[CH:11][C:10]=1[O:18][CH3:19])([C:1]([CH3:4])([CH3:3])[CH3:2])([CH3:7])[CH3:6]
Reactant: COc1ccc([N+](=O)[O-])cc1O[Si](C)(C)C(C)(C)C
Reactant: [H][H]
Agent: [Pd]
Solvent: CCOC(C)=O
Product: COc1ccc(N)cc1O[Si](C)(C)C(C)(C)C
Yield: 74 %

Procedure:
A mixture of tert-butyl-(2-methoxy-5-nitrophenoxy)dimethylsilane (3.0 g, 10.6 mmol) and 5% Pd—C (0.3 g) in 30 mL of ethyl acetate was hydrogenated under 50 psi of hydrogen gas for 14 hours. The mixture was filtered through Celite and the filtrate was evaporated. The residue was chromatographed using a hexanes-ethyl acetate gradient, eluting 2.0 g of the product at 85:15 hexanes-ethyl acetate, in 74% yield: 1H NMR (CDCl3) δ 0.15 (s, 6H), 0.99 (s, 9H), 3.37 (br, 2H), 3.72 (s, 3H), 6.23-6.29 (m, 2H), 6.68 (d, J=8.1 Hz, 1H).
Reaction SMILES: [CH:1]1([C:4]2[CH:5]=[CH:6][C:7]([C:15]([OH:17])=O)=[N:8][C:9]=2[O:10][CH2:11][CH:12]2[CH2:14][CH2:13]2)[CH2:3][CH2:2]1.[CH3:18][C:19]1[O:23][N:22]=[C:21]([CH:24]([CH2:26][CH:27]([CH3:29])[CH3:28])[NH2:25])[N:20]=1.CO>CCCCCCC>[CH3:28][CH:27]([CH3:29])[CH2:26][CH:24]([NH:25][C:15]([C:7]1[CH:6]=[CH:5][C:4]([CH:1]2[CH2:2][CH2:3]2)=[C:9]([O:10][CH2:11][CH:12]2[CH2:13][CH2:14]2)[N:8]=1)=[O:17])[C:21]1[N:20]=[C:19]([CH3:18])[O:23][N:22]=1
Reactant: Cc1nc(C(N)CC(C)C)no1
Reactant: O=C(O)c1ccc(C2CC2)c(OCC2CC2)n1
Solvent: CO
Solvent: CCCCCCC
Product: Cc1nc(C(CC(C)C)NC(=O)c2ccc(C3CC3)c(OCC3CC3)n2)no1

Procedure:
The title compound was synthesized in analogy to Example 1, using 5-cyclopropyl-6-cyclopropylmethyloxy-pyridine-2-carboxylic acid (Example 42a) and 5-methyl-α-(2-methylpropyl)-1,2,4-oxadiazole-3-methanamine (CAN 1155538-06-9) as starting materials. The product was isolated by chiral chromatography on Chiralpak AD using heptane/8% ethanol as eluent. The (−)-enantiomer was isolated. LC-MS (UV peak area/ESI) 100%, 385.2234 (M+H)+, αD20 (MeOH)=−24.8°.
Reaction SMILES: [O:1]([C:8]1[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[CH2:16][CH2:17][N:18]([CH3:24])[C:19](=[O:23])[O:20][CH2:21][CH3:22].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[O:1]([C:8]1[CH:9]=[CH:10][C:11]([O:14][CH2:16][CH2:17][N:18]([CH3:24])[C:19](=[O:23])[O:20][CH2:21][CH3:22])=[CH:12][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)N(C)CCCl
Reactant: Oc1ccc(Oc2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)N(C)CCOc1ccc(Oc2ccccc2)cc1
Temperature: 80 °C
Reaction time: 15 h

Procedure:
18.6 g of p-phenoxyphenol are dissolved in 100 ml of dimethylformamide. 18.2 g of ethyl (2-chloroethyl)-methylcarbamate and 27.6 g of potassium carbonate are added thereto and the reaction mixture is heated at 80° C. while stirring for 15 hours. The reaction mixture is poured into 300 ml of water and extracted with diethyl ether. The ether extract is washed with semi-saturated and saturated sodium chloride solution, dried over sodium sulfate and evaporated. Chromatography on silica gel using n-hexane/ethyl acetate (9:1) as the eluent yields ethyl [2-(p-phenoxyphenoxy)ethyl]methylcarbamate; nD20 =1.5503.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[CH3:6][C:7]1[N:11]([C:12]2[CH:13]=[C:14]([CH2:22][OH:23])[CH:15]=[C:16]([C:18]([F:21])([F:20])[F:19])[CH:17]=2)[N:10]=[N:9][N:8]=1.C(N(CC)CC)C>ClCCl>[CH3:1][S:2]([O:23][CH2:22][C:14]1[CH:15]=[C:16]([C:18]([F:19])([F:21])[F:20])[CH:17]=[C:12]([N:11]2[C:7]([CH3:6])=[N:8][N:9]=[N:10]2)[CH:13]=1)(=[O:4])=[O:3]
Reactant: Cc1nnnn1-c1cc(CO)cc(C(F)(F)F)c1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1nnnn1-c1cc(COS(C)(=O)=O)cc(C(F)(F)F)c1
Temperature: -30 °C
Reaction time: 0.75 h
Yield: 93.1 %

Procedure:
Methanesulfonyl chloride (0.26 ml, 0.39 g, 3.4 mmol) was added dropwise to a stirred, cooled (-30° C.) solution of 3-(5-methyltetrazol-1-yl)-5-(trifluoromethyl)phenylmethanol (725 mg, 2.8 mmol) and triethylamine (0.59 ml, 0.43 g, 4.2 mmol) in dichloromethane (15 ml). The mixture was stirred at -30° C. for 45 minutes, diluted with dichloromethane (20 ml), washed with aqueous citric acid (10%, 20 ml) and saturated aqueous sodium hydrogen carbonate (20 ml), dried (MgSO4) and the solvent was evaporated under reduced pressure to give 1-(methanesulfonyloxymethyl)-3-(5-methyltetrazol-1-yl)-5-(trifluoromethyl)benzene as a yellow oil (877 mg, 93%), 1H (CDCl3) δ 7.86 (1H, s), 7.81 (2H, s), 5.38 (2H, s), 3.14 (3H, s), and 2.69 (3H, s).
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([CH:11]2[NH:16][CH2:15][CH2:14][NH:13][C:12]2=[O:17])=[CH:3]1.C(O[C:21]1[CH:31]=[CH:30][CH:29]=[CH:28][C:22]=1[O:23][CH2:24][CH:25]1OC1)C>C(O)CC(C)C>[CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([CH:11]2[N:16]([CH2:21][CH:22]([OH:23])[CH2:28][C:21]3[CH:31]=[CH:30][CH:29]=[CH:28][C:22]=3[O:23][CH2:24][CH3:25])[CH2:15][CH2:14][NH:13][C:12]2=[O:17])=[CH:3]1
Reactant: CCOc1ccccc1OCC1CO1
Reactant: Cn1cc(C2NCCNC2=O)c2ccccc21
Solvent: CC(C)CCO
Product: CCOc1ccccc1CC(O)CN1CCNC(=O)C1c1cn(C)c2ccccc12
Temperature: 120 °C
Reaction time: 5 h

Procedure:
11.5 g (0.05 mol) of 3-(1-methylindol-3-yl)-piperazin-2-one, prepared in accordance with Example 34, are dissolved in 100 ml of isoamyl alcohol, 9.7 g (0.05 mol) of 3-(2-ethoxyphenoxy)-1,2-epoxypropane are added and the mixture is stirred for 5 hours at 120° C. The reaction mixture is evaporated in vacuo, the residue is dissolved in ethyl acetate, and the hydrochloride is precipitated by adding hydrochloric acid in ether. The product is filtered off with suction and dried.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[CH:14]=[C:13](F)[CH:12]=[CH:11][C:10]=1[N+:16]([O-:18])=[O:17].[NH2:19][C:20]1[C:25]([N+:26]([O-:28])=[O:27])=[CH:24][CH:23]=[C:22]([NH:29][CH2:30][CH2:31][NH2:32])[N:21]=1.C(N(CC)C(C)C)(C)C>CN(C)C=O>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[C:10]([N+:16]([O-:18])=[O:17])=[CH:11][CH:12]=[C:13]([NH:32][CH2:31][CH2:30][NH:29][C:22]2[N:21]=[C:20]([NH2:19])[C:25]([N+:26]([O-:28])=[O:27])=[CH:24][CH:23]=2)[CH:14]=1
Reactant: NCCNc1ccc([N+](=O)[O-])c(N)n1
Reactant: O=[N+]([O-])c1ccc(F)cc1-c1ccc(Cl)cc1Cl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Nc1nc(NCCNc2ccc([N+](=O)[O-])c(-c3ccc(Cl)cc3Cl)c2)ccc1[N+](=O)[O-]
Temperature: 80 °C
Yield: 25.2 %

Procedure:
To 2-(2,4-dichlorophenyl)-4-fluoro-1-nitrobenzene (20 mgs, 0.06 mmol) in N,N-dimethylformamide was added 2-amino-3-nitro-6-(2-aminoethylamino)pyridine (14 mgs, 0.07 mmol) and N,N-diisopropylethyl amine (16 μl, 0.07 mmol) and heated to 80° C. over-night. The mixture was partitioned between ethyl acetate and water and the organic layer was dried (MgSO4) and concentrated. Purification on silica gel with 5% methanol in dichloromethane as eluent yielded 7 mgs of N˜6˜-{2-[(2′,4′-dichloro-6-nitro-1,1′-biphenyl-3-yl)amino] ethyl}-3-nitropyridine-2,6-diamine.
Reaction SMILES: [C:1]([CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]([C:17](=[O:26])[C:18]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[O:19])=[CH:13]N(C)C)=[CH:8][CH:7]=1)([OH:3])=[O:2].Cl.[OH-:28].[K+]>>[OH:19][C:18]1([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:17](=[O:26])[C:12]([C:9]2[CH:10]=[CH:11][C:6]([CH2:5][CH2:4][C:1]([OH:3])=[O:2])=[CH:7][CH:8]=2)=[CH:13][O:28]1
Reactant: CN(C)C=C(C(=O)C(=O)c1ccccc1)c1ccc(CCC(=O)O)cc1
Reactant: [OH-]
Agent: Cl
Agent: [K+]
Product: O=C(O)CCc1ccc(C2=COC(O)(c3ccccc3)C2=O)cc1
Yield: 93 %

Procedure:
A solution of 3.95 g of 2-[4-(2-carboxyethyl)phenyl]-1-dimethylamino-4-phenyl-1-butene-3,4-dione in 100 ml of 2% potassium hydroxide solution was stirred at room temperature for 31/2 hrs. The reaction mixture was poured onto 300 ml of icewater, acidified with 100 ml of 1N hydrochloric acid and extracted with methylene chloride. The organic extract was washed with water, dried, filtered and evaporated. Recrystallization of a sample of the residue from methylene chloride-petroleum ether gave 2-hydroxy-2-phenyl-4-[4-(2-carboxyethyl)phenyl]-3(2H)-furanone as colorless crystals, m.p. 89°-95° dec., after drying at 50° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5](N)=[CH:4][C:3]=1[C:9]1[CH:10]=[N:11][CH:12]=[CH:13][CH:14]=1.N([O-])=O.[Na+].[BrH:19]>O1CCOCC1.O.[Cu]Br>[Br:19][C:5]1[CH:6]=[CH:7][C:2]([F:1])=[C:3]([C:9]2[CH:10]=[N:11][CH:12]=[CH:13][CH:14]=2)[CH:4]=1
Reactant: Nc1ccc(F)c(-c2cccnc2)c1
Reactant: Br
Agent: [Cu]Br
Agent: O=N[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: Fc1ccc(Br)cc1-c1cccnc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 64 %

Procedure:
A warm solution of 4-fluoro-3-(pyridin-3-yl)phenylamine (3.64 g, 19.3 mmol) in 1,4-dioxane (10 ml) was treated with a solution of 48% aqueous hydrobromic acid (100 ml). The resulting suspension was cooled to 0° C. before being treated dropwise over 20 min with a solution of sodium nitrite (1.53 g, 22.2 mmol) in water (4 ml). After stirring at 0° C. for 2 h, a cooled (0° C.) solution of copper(I) bromide (8.31 g, 57.9 mmol) in 48% aqueous hydrobromic acid (30 ml) was added to the reaction which was stirred at 0° C. for 10 min then heated at 50° C. for 20 min. The reaction was cooled to ambient temperature, poured onto ice-cold concentrated ammonia (500 ml) and the product was extracted into ethyl acetate (500 ml). The organics were washed with water (300 ml) and brine (300 ml), dried (Na2SO4), filtered and concentrated in vacuo to give a dark oil. Purification by dry flash column chromatography (silica gel, 10-30% EtOAc/isohexane) gave 3-(5-bromo-2-fluorophenyl)pyridine (3.1 g, 64%) as a white solid: 1H NMR (360 MHz, CDCl3) δ7.09 (1H, dd, J 9, 1 Hz), 7.37-7.40 (1H, m), 7.46-7.51 (1H, m), 7.56-7.59 (1H, m), 7.83-7.86 (1H, m), 8.63-8.65 (1H, m), 8.77-8.79 (1H, m).
Reaction SMILES: [CH3:1][C:2]1[N:3]([C:17](=[O:27])[C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([N+:24]([O-])=O)[CH:19]=2)[C:4]2[C:9]([C:10]=1[CH2:11][CH2:12][CH2:13][C:14]([OH:16])=[O:15])=[CH:8][CH:7]=[CH:6][CH:5]=2>CO.O1CCOCC1.[Pd]>[NH2:24][C:20]1[CH:19]=[C:18]([CH:23]=[CH:22][CH:21]=1)[C:17]([N:3]1[C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[C:10]([CH2:11][CH2:12][CH2:13][C:14]([OH:16])=[O:15])=[C:2]1[CH3:1])=[O:27]
Reactant: Cc1c(CCCC(=O)O)c2ccccc2n1C(=O)c1cccc([N+](=O)[O-])c1
Agent: [Pd]
Solvent: C1COCCO1
Solvent: CO
Product: Cc1c(CCCC(=O)O)c2ccccc2n1C(=O)c1cccc(N)c1
Temperature: 20 °C
Reaction time: 0.75 h
Yield: 88.9 %

Procedure:
To a solution of 4-[2-methyl-1-(3-nitrobenzoyl)indol-3-yl]butyric acid (600 mg) in a mixture of methanol (30 ml) and 1,4-dioxane (30 ml) was added 10% palladium on activated carbon (300 mg), and the mixture was stirred under hydrogen atmosphere (3 atm) at 20° C. for 45 minutes. The catalyst was filtered off and the filtrate was evaporated. The residue was chromatographed on a silica gel column (25 ml) eluting with a mixture of chloroform and methanol (10:1) to give 4-[1-(3-aminobenzoyl)-2-methylindol-3-yl]butyric acid (490 mg) as a yellow foam.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[C:13]3[CH2:12][CH2:11][CH2:10][CH2:9][C:8]=3[NH:7][C:6]=2[N:14]=1.ClC1C(=O)C(C#N)=C(C#N)C(=[O:23])C=1Cl>C1COCC1.O.C([O-])(O)=O.[Na+]>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[C:13]3[C:12](=[O:23])[CH2:11][CH2:10][CH2:9][C:8]=3[NH:7][C:6]=2[N:14]=1
Reactant: Brc1ccc2c3c([nH]c2n1)CCCC3
Reactant: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: O=C1CCCc2[nH]c3nc(Br)ccc3c21
Temperature: 25 °C
Reaction time: 5 h
Yield: 39.2 %

Procedure:
A solution of 2-bromo-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]indole (3.84 g, 15.2 mmol) in THF (135 mL) and H2O (15.2 mL) was cooled to 0° C. and treated with a solution of 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (6.92 g, 30.5 mmol) in THF (60.3 mL) at such a rate that the reaction mixture did not exceed 0° C. The resulting solution was warmed to ambient temperature and stirred for 5 h. The solution was diluted with saturated NaHCO3 solution (100 mL), and the aqueous solution was extracted with EtOAc (3×75 mL). The combined organic extracts were dried over Na2SO4, filtered and concentrated to dryness under reduced pressure. Flash chromatography (80 g ISCO dry load 80:18:2 CH2Cl2/MeOH/NH4OH, 1000 mL) followed by trituration with MeOH provided the title compound (1.58 g, 39%) as an off-white solid: 1H NMR (500 MHz, THF-d8) δ 8.23 (d, J=8.0 Hz, 1H), 7.32 (d, J=8.0, 1H), 4.73 (s, 1H), 3.02 (t, J=8.0 Hz, 2H), 2.51-2.47 (m, 2H), 2.27-2.22 (m, 2H); ESI MS m/z 265 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][CH:8]([OH:10])[C:7]([CH3:12])([CH3:11])[C:6]=2[CH:13]=1.[CH2:14](O)[CH3:15]>S(=O)(=O)(O)O.C(N(CC)CC)C.CCOCC>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][CH:8]([O:10][CH2:14][CH3:15])[C:7]([CH3:11])([CH3:12])[C:6]=2[CH:13]=1
Reactant: CCO
Reactant: CC1(C)c2cc(Br)ccc2OC1O
Agent: O=S(=O)(O)O
Solvent: CCN(CC)CC
Solvent: CCOCC
Product: CCOC1Oc2ccc(Br)cc2C1(C)C
Yield: 86 %

Procedure:
5-Bromo-2,3-dihydro-3,3-dimethyl-2-hydroxybenzofuran (5 g, 0.02 mole) was heated under reflux in ethanol (30 ml) with sulphuric acid (4 drops) for 11/2 hour. The solution was cooled, neutralised with a few drops of triethylamine and run down. The residue was redissolved in ether and the solution washed with water, dried over magnesium sulphate and the solvent removed under vacuum leaving 4.7 g (86%) title product as a buff-coloured oil. The structure was confirmed by NMR.
Reaction SMILES: C[O:2][C:3](=O)[C:4]([C:11]#[N:12])=[CH:5][CH:6]1[CH2:10][CH2:9][CH2:8][CH2:7]1.FC(F)(F)C(O)=O.[NH2:21][C:22]1[CH2:27][C:26]([CH3:29])([CH3:28])[CH2:25][C:24](=[O:30])[CH:23]=1>C(#N)C>[CH:6]1([CH:5]2[C:23]3[C:24](=[O:30])[CH2:25][C:26]([CH3:29])([CH3:28])[CH2:27][C:22]=3[NH:21][C:3](=[O:2])[CH:4]2[C:11]#[N:12])[CH2:10][CH2:9][CH2:8][CH2:7]1
Reactant: CC1(C)CC(=O)C=C(N)C1
Reactant: COC(=O)C(C#N)=CC1CCCC1
Solvent: O=C(O)C(F)(F)F
Solvent: CC#N
Product: CC1(C)CC(=O)C2=C(C1)NC(=O)C(C#N)C2C1CCCC1
Temperature: 0 °C

Procedure:
13.3 g 2-Cyano-3-cyclopentyl-acrylic acid methyl ester and 5.8 ml trifluoroacetic acid are dissolved in 70 ml acetonitrile and heated for 7 days to reflux. During the first 5 days 3-amino-5,5-dimethyl-cyclohex-2-enone is added in daily portions (12 g in total). Afterwards the reaction mixture is cooled to 0° C., the precipitate is isolated by filtration, washed 2 times with cold acetonitrile and dried in vacuo. The product is obtained as a mixture of diastereomers.
Reaction SMILES: [C:1]1([CH3:40])[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH:7][C:8]1[O:9][C:10]2[CH:16]=[C:15]([CH2:17][C:18](NC3C=CC(C4(CC(O)=O)CC5C(=CC=CC=5)C4)=CC=3)=[O:19])[CH:14]=[CH:13][C:11]=2[N:12]=1.C1(C)C(N=C=S)=CC=CC=1.C1(N=C=NC2CCCCC2)CCCCC1.C([OH:68])C>>[C:1]1([CH3:40])[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH:7][C:8]1[O:9][C:10]2[CH:16]=[C:15]([CH2:17][C:18]([OH:19])=[O:68])[CH:14]=[CH:13][C:11]=2[N:12]=1
Reactant: Cc1ccccc1Nc1nc2ccc(CC(=O)Nc3ccc(C4(CC(=O)O)Cc5ccccc5C4)cc3)cc2o1
Reactant: CCO
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cc1ccccc1N=C=S
Product: Cc1ccccc1Nc1nc2ccc(CC(=O)O)cc2o1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of (4-amino-3-hydroxy-phenyl)-acetic acid ethyl ester (3.3 g, Reference Example 3) and o-tolylisothiocyanate (2.5 mL) in ethanol (150 mL) was stirred at room temperature for about 2 hours. After standing at room temperature overnight the mixture was evaporated and the residue was subjected to flash chromatography on silica eluting with a mixture of pentane and ethyl acetate (7:3, v/v) to give a yellow foam. A solution of this material in ethanol (150 mL) was treated with dicyclohexylcarbodiimide (3.0 g) and the mixture was heated at reflux temperature for 2 hours. The mixture was evaporated and the residue subjected to short column chromatography (on silica eluting with a mixture of tert-butyl methyl ether and dichloromethane, 1:19 to 1:9 v/v). The resulting light yellow oil was dissolved in ethanol (100 mL) and the solution was treated with sodium hydroxide solution (15 mL, 1M) then heated at reflux temperature for 2 hours. The reaction mixture was evaporated and the residue was dissolved in water. The solution was washed with ethyl acetate and the aqueous layer was acidified to pH 1 by addition of concentrated hydrochloric acid. The resulting white precipitate was collected by filtration, then washed thoroughly with water, and then dried to give the title compound (1.8 g) as a white solid.