Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1](Cl)(=[O:19])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].[C:21]([NH2:25])(=[O:24])[CH:22]=[CH2:23].Cl>[Cl-].[Zn+2].[Cl-].CC(C)=O>[C:1]([NH:25][C:21](=[O:24])[CH:22]=[CH2:23])(=[O:19])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: CCCCCCCCCCCCCCCCCC(=O)Cl
Reactant: C=CC(N)=O
Agent: Cl
Agent: [Cl-]
Agent: [Zn+2]
Solvent: CC(C)=O
Product: C=CC(=O)NC(=O)CCCCCCCCCCCCCCCCC
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
Into a 250 -mL-capacity conical flask equipped with an anhydrous calcium chloride (CaCl2) guard tube, 15.1 g 1-octadecanoyl chloride [CH3—(CH2)16—COCl] (0.005 M). 3.5 g acrylamide (CH2═CH—CO—NH2) (0.05 M), and 50 ml acetone were placed to obtained a clear solution. The solution was stirred with a magnetic needle at room temperature. Anhydrous zinc chloride (ZnCl2), 6.5 g (0.05 M), was added and the reaction mixture was stirred at room temperature. After 5-10 min of stirring, vigorous evolution of hydrogen chloride took place which ceased after about 5 min. The temperature of reaction mixture was increased to 40-50° C. It was then cooled to room temperature and poured into 500 ml cold distilled water. A white product precipitated. The product was isolated and purified by reprecipitation from acetone into cold water. The purified product was dried in a vacuum desiccator.
Reaction SMILES: Cl.[F:2][C:3]([F:26])([F:25])[C:4]1[CH:13]=[C:12]2[C:7]([C:8]([NH:14][C:15]3[CH:20]=[CH:19][C:18]([S:21](Cl)(=[O:23])=[O:22])=[CH:17][CH:16]=3)=[CH:9][CH:10]=[N:11]2)=[CH:6][CH:5]=1.Cl.[F:28][C:29]1[CH:42]=[CH:41][C:32]([C:33]([N:35]2[CH2:40][CH2:39][NH:38][CH2:37][CH2:36]2)=[O:34])=[CH:31][CH:30]=1.C(=O)([O-])[O-].[Na+].[Na+]>C(Cl)(Cl)Cl.O>[F:28][C:29]1[CH:42]=[CH:41][C:32]([C:33]([N:35]2[CH2:40][CH2:39][N:38]([S:21]([C:18]3[CH:19]=[CH:20][C:15]([NH:14][C:8]4[C:7]5[C:12](=[CH:13][C:4]([C:3]([F:26])([F:25])[F:2])=[CH:5][CH:6]=5)[N:11]=[CH:10][CH:9]=4)=[CH:16][CH:17]=3)(=[O:23])=[O:22])[CH2:37][CH2:36]2)=[O:34])=[CH:31][CH:30]=1
Reactant: O=C(c1ccc(F)cc1)N1CCNCC1
Reactant: O=S(=O)(Cl)c1ccc(Nc2ccnc3cc(C(F)(F)F)ccc23)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: ClC(Cl)Cl
Product: O=C(c1ccc(F)cc1)N1CCN(S(=O)(=O)c2ccc(Nc3ccnc4cc(C(F)(F)F)ccc34)cc2)CC1
Temperature: 25 °C
Yield: 20.1 %

Procedure:
4-(7-Trifluoromethyl-4-quinolinylamino)benzenesulphonyl chloride hydrochloride (3.5 g, 0.008 mol) was added portionwise to a cold (10°), well stirred mixture of 1-(4-fluorobenzoyl)piperazine hydrochloride (2.0 g, 0.008 mol) in chloroform (50 ml) and sodium carbonate (10.0 g) in water (50 ml). The cooling bath was removed and the mixture was allowed to warm to room temperature. After half an hour, the mixture was filtered and the filtrate separated. The chloroform layer was dried (MgSO4). The solvent was removed by evaporation to give a yellow gum. The gum was crystallised from ethanol-water, then purified by column chromatography (basic Al2O3-chloroform) followed by recrystallisation from ethanol, to give the pure title compound (0.9 g), m.p. 172°-174.5° C.
Reaction SMILES: F[C:2]1[CH:21]=[C:20]([C:22]([F:28])([F:27])[C:23]([F:26])([F:25])[F:24])[CH:19]=[CH:18][C:3]=1[C:4]([NH:6][C:7]1[CH:8]=[CH:9][C:10]([C:13]([O:15]CC)=[O:14])=[N:11][CH:12]=1)=[O:5].[F:29][C:30]1[CH:35]=[CH:34][C:33]([OH:36])=[C:32]([O:37][CH3:38])[CH:31]=1.C([O-])([O-])=O.[Cs+].[Cs+].[OH-].[Na+]>CN1C(=O)CCC1.CO>[F:29][C:30]1[CH:35]=[CH:34][C:33]([O:36][C:2]2[CH:21]=[C:20]([C:22]([F:28])([F:27])[C:23]([F:24])([F:26])[F:25])[CH:19]=[CH:18][C:3]=2[C:4]([NH:6][C:7]2[CH:8]=[CH:9][C:10]([C:13]([OH:15])=[O:14])=[N:11][CH:12]=2)=[O:5])=[C:32]([O:37][CH3:38])[CH:31]=1
Reactant: CCOC(=O)c1ccc(NC(=O)c2ccc(C(F)(F)C(F)(F)F)cc2F)cn1
Reactant: COc1cc(F)ccc1O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Agent: [Na+]
Solvent: CO
Solvent: CN1CCCC1=O
Product: COc1cc(F)ccc1Oc1cc(C(F)(F)C(F)(F)F)ccc1C(=O)Nc1ccc(C(=O)O)nc1
Temperature: 40 °C
Reaction time: 1 h
Yield: 40.8 %

Procedure:
Ethyl 5-[[2-fluoro-4-(1,1,2,2,2-pentafluoroethyl)benzoyl]amino]pyridine-2-carboxylate (40.63 mg, 0.10 mmol), 4-fluoro-2-methoxyphenol (42.64 mg, 0.30 mmol) and Cs2CO3 (97.75 mg, 0.30 mmol) in NMP (0.4 mL) was stirred at 90° C. for 1 hour. Aqueous 3M NaOH (100 μL) and MeOH (0.2 mL) were added and the mixture was stirred at 40° C. for 1 h. The mixture was diluted with methanol, filtered and purified by reverse phase HPLC using a gradient of ACN in Water (1-99%) and HCl as a modifier to give 5-(2-(4-fluoro-2-methoxyphenoxy)-4-(perfluoroethyl)benzamido)picolinic acid (72) (20.42 mg, 36%). ESI-MS m/z calc. 500.08, found 501.3 (M+1)+; Retention time: 1.69 minutes (3 minutes run). 1H NMR (400 MHz, DMSO) δ 11.08 (s, 1H), 8.95 (d, J=2.4 Hz, 1H), 8.33 (dd, J=8.6, 2.5 Hz, 1H), 8.08 (d, J=8.6 Hz, 1H), 7.90 (d, J=8.0 Hz, 1H), 7.54 (d, J=8.0 Hz, 1H), 7.31 (dd, J=8.8, 5.9 Hz, 1H), 7.16 (dd, J=10.7, 2.9 Hz, 1H), 6.98-6.85 (m, 1H), 6.80 (s, 1H), 3.72 (s, 3H) ppm.
Reaction SMILES: [F:1][C:2]1[CH:22]=[C:21]([F:23])[CH:20]=[CH:19][C:3]=1[CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]([F:15])([F:14])[F:13])=[CH:8][C:7]=1B(O)O.[CH2:24]([O:26][C:27](=[O:41])[C:28]1[C:33]([NH2:34])=[CH:32][CH:31]=[C:30]([C:35]2[CH2:39][CH2:38][CH2:37][C:36]=2Br)[CH:29]=1)[CH3:25]>>[CH2:24]([O:26][C:27](=[O:41])[C:28]1[C:33]([NH2:34])=[CH:32][CH:31]=[C:30]([C:35]2[CH2:39][CH2:38][CH2:37][C:36]=2[C:7]2[CH:8]=[C:9]([C:12]([F:15])([F:14])[F:13])[CH:10]=[CH:11][C:6]=2[O:5][CH2:4][C:3]2[CH:19]=[CH:20][C:21]([F:23])=[CH:22][C:2]=2[F:1])[CH:29]=1)[CH3:25]
Reactant: OB(O)c1cc(C(F)(F)F)ccc1OCc1ccc(F)cc1F
Reactant: CCOC(=O)c1cc(C2=C(Br)CCC2)ccc1N
Product: CCOC(=O)c1cc(C2=C(c3cc(C(F)(F)F)ccc3OCc3ccc(F)cc3F)CCC2)ccc1N

Procedure:
Prepared by general procedure C(iii) but using 2-(2,4-difluorobenzyloxy)-5-trifluoromethylphenylboronic acid instead of 2-(benzyloxy)-5-chlorophenylboronic acid and 3-(2-bromocyclopent-1-enyl)-6-aminobenzoic acid ethyl ester instead of 3-(2-bromo-cyclopent-1-enyl)-methylbenzoic acid ethyl ester.
Reaction SMILES: C1C2C(COC([NH:18][CH:19]([CH3:36])[CH2:20][C:21]3[C:29]4[C:24](=[CH:25][CH:26]=[C:27]([O:30][C:31](=[O:35])[CH:32]([CH3:34])[CH3:33])[CH:28]=4)[NH:23][N:22]=3)=O)C3C(=CC=CC=3)C=2C=CC=1.N1CCCCC1.C(=O)(O)[O-].[Na+]>CN(C)C=O>[NH2:18][CH:19]([CH3:36])[CH2:20][C:21]1[C:29]2[C:24](=[CH:25][CH:26]=[C:27]([O:30][C:31](=[O:35])[CH:32]([CH3:33])[CH3:34])[CH:28]=2)[NH:23][N:22]=1
Reactant: CC(Cc1n[nH]c2ccc(OC(=O)C(C)C)cc12)NC(=O)OCC1c2ccccc2-c2ccccc21
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: C1CCNCC1
Product: CC(N)Cc1n[nH]c2ccc(OC(=O)C(C)C)cc12
Temperature: 25 °C

Procedure:
A solution of 2-methyl-propionic acid 3-(2-(9fluorenylmethoxycarbonylamino)propyl)-1H-indazol-5-yl ester (0.16 g, 0.33 mmol) in a 1:4 mixture of piperidine and dimethylformamide (2.5 mL) is stirred at ambient temperature. The reaction mixture is poured into dilute aqueous sodium bicarbonate and the resulting mixture is extracted first with ethyl acetate and then with methylene chloride. The combined organic extracts are dried (MgSO4) and concentrated. The residue is purified by chromatography.
Reaction SMILES: [C:1]([O:7][C:8]1([CH3:17])[CH2:13][CH2:12][CH:11]([CH:14]([CH3:16])[CH3:15])[CH2:10][CH2:9]1)(=[O:6])[CH2:2][C:3]([CH3:5])=[O:4]>CO>[OH:4][C@@H:3]([CH3:5])[CH2:2][C:1]([O:7][C:8]1([CH3:17])[CH2:9][CH2:10][CH:11]([CH:14]([CH3:15])[CH3:16])[CH2:12][CH2:13]1)=[O:6]
Reactant: CC(=O)CC(=O)OC1(C)CCC(C(C)C)CC1
Solvent: CO
Product: CC(C)C1CCC(C)(OC(=O)C[C@H](C)O)CC1
Yield: 98.4 %

Procedure:
144.2 g (0.60 mol) of 1-menthyl acetoacetate, 98.8 mg (12.0 mmol) of a catalyst [{RuCl((S)—SEGPHOS)}2(μ-Cl)3][NH2Me2] and 75 ml of methanol were put into a 500 ml capacity autoclave and allowed to undergo the reaction at 70° C. for 5.5 hours under a hydrogen pressure of 4 MPa. The thus obtained reaction solution was subjected to evaporation of the solvent and then distilled under a reduced pressure (121° C./170 Pa) to obtain 143.1 g (yield 98.4%) of the (3S)-1-menthyl 3-hydroxybutyrate of interest as a colorless oily substance.
Reaction SMILES: [OH-].[Na+].[NH:3]1[CH:7]=[CH:6][N:5]=[CH:4]1.[CH2:8](Cl)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>O>[CH2:8]([N:3]1[CH:7]=[CH:6][N:5]=[CH:4]1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: ClCc1ccccc1
Reactant: c1c[nH]cn1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: c1ccc(Cn2ccnc2)cc1
Temperature: 50 °C
Reaction time: 0.5 h

Procedure:
260 ml of 50% strength sodium hydroxide solution, 102 g (1.5 mol) of imidazole and 18 g (0.11 mol) of 1-benzimidazole were introduced into a 1 1 four-neck flask with stirrer, thermometer, dropping funnel and reflux condenser, and 209 g (1.65 mol) of benzyl chloride were added dropwise at 50° C., cooling with a water bath. After the addition was complete, the mixture was stirred at 50° C. for 30 min. and then diluted with 350 g of water in order to dissolve the salts completely. The organic phase was then separated off, the aqueous phase was extracted with toluene, and the combined organic phases were dried over sodium sulfate. Removal of the toluene was followed by distillation under reduced pressure. 243 g of 99% pure 1-benzylimidazole (yield 222 g (94%) after subtraction of the product employed as catalyst) of boiling point 132°-135° C. under 0.5 mbar were obtained.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N+:8]([O-:10])=[O:9].[F:11][CH:12]([F:15])[CH2:13][NH2:14].O>C(#N)C>[F:11][CH:12]([F:15])[CH2:13][NH:14][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N+:8]([O-:10])=[O:9]
Reactant: NCC(F)F
Reactant: O=[N+]([O-])c1ccccc1Cl
Solvent: O
Solvent: CC#N
Product: O=[N+]([O-])c1ccccc1NCC(F)F
Reaction time: 24 h
Yield: 95 %

Procedure:
2 ml (19 mM) of 2-Chloronitrobenzene and 2,7 ml (36 mM) of 2,2-difluoroethyl amine in 2 ml of acetonitrile were refluxed under stirring for 24 h. Water was added and the aqueous layer was extracted with ethyl acetate. The organic layer was washed with water and dried over anhydrous sodium sulfate. The solvent was removed under vacuum to give 3,65 g of N-(2,2-difluoroethyl)-2-nitroaniline as an orange solid. Yield: 95%.
Reaction SMILES: [C:1]([NH:4][C:5](=[CH:10][C:11]1[CH:16]=[C:15]([CH3:17])[C:14]([O:18]CC2C=CC=CC=2)=[C:13]([Cl:26])[CH:12]=1)[C:6]([O:8][CH3:9])=[O:7])(=[O:3])[CH3:2].[H][H]>[Ni].CO>[C:1]([NH:4][CH:5]([CH2:10][C:11]1[CH:16]=[C:15]([CH3:17])[C:14]([OH:18])=[C:13]([Cl:26])[CH:12]=1)[C:6]([O:8][CH3:9])=[O:7])(=[O:3])[CH3:2]
Reactant: COC(=O)C(=Cc1cc(C)c(OCc2ccccc2)c(Cl)c1)NC(C)=O
Reactant: [H][H]
Agent: [Ni]
Solvent: CO
Product: COC(=O)C(Cc1cc(C)c(O)c(Cl)c1)NC(C)=O
Temperature: 25 °C

Procedure:
A mixture of 7.40 g (19.8 mmol) methyl 2-acetylamino-3-(4-benzyloxy-3-chloro-5-methyl-phenyl)-acrylate, 300 mL MeOH and 800 mg Raney nickel was shaken at RT and 3000 hPa hydrogen pressure for 7 h. After the reaction had ended the catalyst was filtered off and the remainder was evaporated down i.vac.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[C:10]1[S:11][C:12]2[C:17]([N:18]=1)=[CH:16][CH:15]=[C:14]([C:19]1([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1)[N:13]=2)[CH:5]=O.Cl.[NH:32]1[CH2:35][CH:34]([C:36]([O:38][CH3:39])=[O:37])[CH2:33]1>>[F:1][C:2]1[CH:3]=[C:4]([CH2:5][N:32]2[CH2:35][CH:34]([C:36]([O:38][CH3:39])=[O:37])[CH2:33]2)[CH:7]=[CH:8][C:9]=1[C:10]1[S:11][C:12]2[C:17]([N:18]=1)=[CH:16][CH:15]=[C:14]([C:19]1([C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=3)[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24]1)[N:13]=2
Reactant: COC(=O)C1CNC1
Reactant: O=Cc1ccc(-c2nc3ccc(C4(c5ccccc5)CCCCC4)nc3s2)c(F)c1
Agent: Cl
Product: COC(=O)C1CN(Cc2ccc(-c3nc4ccc(C5(c6ccccc6)CCCCC5)nc4s3)c(F)c2)C1

Procedure:
Reaction of 3-fluoro-4-(5-(1-phenylcyclohexyl)thiazolo[5,4-b]pyridine-2-yl)-benzaldehyde (0.36 g, 0.85 mmol), methyl azetidine-3-carboxylate hydrochloride (0.388 g, 2.56 mmol) according to Reference R and the general procedure for reductive amination to give methyl 1-((3-fluoro-4-(5-(1-phenylcyclohexyl)thiazolo[5,4-b]pyridine-2-yl)phenyl)-methyl)azetidine-3-carboxylate as an oil which solidified to a white solid. MS (ESI) m/z: Calculated: 515.2; Observed: 516.1 (M++1).
Reaction SMILES: C([N:8]1[C:12]([CH:13]=[C:14]2[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[CH2:16][CH:15]2[C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[CH:11][N:10]=[CH:9]1)C1C=CC=CC=1.C(N1C(C=C2C3C(=CC=C(OC)C=3)CC2C2C=CC=CC=2)=CN=C1)C1C=CC=CC=1>C(O)(=O)C.[Pd]>[C:23]1([CH:15]2[CH2:16][C:17]3[C:22](=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH:14]2[CH2:13][C:12]2[N:8]=[CH:9][NH:10][CH:11]=2)[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: C(=C1c2ccccc2CC1c1ccccc1)c1cncn1Cc1ccccc1
Agent: [Pd]
Agent: COc1ccc2c(c1)C(=Cc1cncn1Cc1ccccc1)C(c1ccccc1)C2
Solvent: CC(=O)O
Product: c1ccc(C2Cc3ccccc3C2Cc2c[nH]cn2)cc1

Procedure:
The crude 1-benzyl-5-(2-phenylindan-1-ylidenemethyl)-1H-imidazole in acetic acid was shaken with palladium on charcoal as 1-benzyl-5-(6-methoxy-2-phenylindan-1-ylidenemethyl)-1H-imidazole above except in this case for 2 days at 60-70° C. under normal pressure. The hydrochloride salt of the purified product was the mixture of the cis and trans diastereomers (cis:trans 96:4).
Reaction SMILES: C(=O)([O-])[O-].[Na+].[Na+].Cl[C:8]1[C:17]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:16][C:15]2[C:10](=[CH:11][C:12]([F:24])=[C:13]([F:23])[CH:14]=2)[N:9]=1.[CH2:25]([NH:27][CH2:28][CH2:29][C:30]([O:32][CH2:33][CH3:34])=[O:31])[CH3:26]>C1(C)C=CC=CC=1>[CH2:21]([O:20][C:18]([C:17]1[C:8]([N:27]([CH2:25][CH3:26])[CH2:28][CH2:29][C:30]([O:32][CH2:33][CH3:34])=[O:31])=[N:9][C:10]2[C:15]([CH:16]=1)=[CH:14][C:13]([F:23])=[C:12]([F:24])[CH:11]=2)=[O:19])[CH3:22]
Reactant: CCOC(=O)c1cc2cc(F)c(F)cc2nc1Cl
Reactant: CCNCCC(=O)OCC
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CCOC(=O)CCN(CC)c1nc2cc(F)c(F)cc2cc1C(=O)OCC
Temperature: 90 °C
Reaction time: 4 h
Yield: 92.8 %

Procedure:
7.8 g of sodium carbonate are added to a solution of 10 g of 2-chloro-3-ethoxycarbonyl-6,7-difluoroquinoline, prepared as described in Application Example 1, and 9.7 g of N-ethyl-N-(b-ethoxycarbonylethyl)amine in 120 cm3 of toluene. The suspension obtained is heated to approximately 90° C. and then stirred for 4 hours at this temperature. The reaction mixture is then cooled to approximately 20° C. and thereafter washed with 3 times 100 cm3 of water. The organic phase is concentrated to dryness under reduced pressure (20 kPa) at approximately 50° C. 13 g of 3-ethoxycarbonyl-6,7-difluoro-2-[N-ethyl-N-(b-ethoxycarbonylethyl)amino]quinoline are obtained in the form of an oil, which is used without further purification for the subsequent steps.
Reaction SMILES: Cl[C:2]1[C:3]2[CH:11]=[C:10]([Cl:12])[N:9]=[CH:8][C:4]=2[N:5]=[CH:6][N:7]=1.[F:13][C:14]1[CH:15]=[C:16]([CH:26]=[CH:27][CH:28]=1)[CH2:17][O:18][C:19]1[CH:25]=[CH:24][C:22]([NH2:23])=[CH:21][CH:20]=1>C(#N)C>[Cl:12][C:10]1[N:9]=[CH:8][C:4]2[N:5]=[CH:6][N:7]=[C:2]([NH:23][C:22]3[CH:21]=[CH:20][C:19]([O:18][CH2:17][C:16]4[CH:26]=[CH:27][CH:28]=[C:14]([F:13])[CH:15]=4)=[CH:25][CH:24]=3)[C:3]=2[CH:11]=1
Reactant: Nc1ccc(OCc2cccc(F)c2)cc1
Reactant: Clc1cc2c(Cl)ncnc2cn1
Solvent: CC#N
Product: Fc1cccc(COc2ccc(Nc3ncnc4cnc(Cl)cc34)cc2)c1

Procedure:
4,6-Dichloro-pyrido[3,4-d]pyrimidine (1 g) and 4-(3-fluorobenzyloxy)aniline (1.08 g) in acetonitrile (70 ml) were reacted together as in Procedure A. The product was collected by fiftration as a yellow solid (1.86 g); m/z 381 (M+1)+.
Reaction SMILES: [O:1]1[C@H:7]2[C@@H:2]1[C:3]([CH3:18])([CH3:17])[O:4][C:5]1[CH:11]=[C:10]([N+:12]([O-:14])=[O:13])[C:9]([O:15][CH3:16])=[CH:8][C:6]=12.O.[NH3:20]>C(O)C>[NH2:20][C@H:7]1[C:6]2[CH:8]=[C:9]([O:15][CH3:16])[C:10]([N+:12]([O-:14])=[O:13])=[CH:11][C:5]=2[O:4][C:3]([CH3:18])([CH3:17])[C@@H:2]1[OH:1]
Reactant: N
Reactant: COc1cc2c(cc1[N+](=O)[O-])OC(C)(C)[C@@H]1O[C@H]21
Solvent: CCO
Solvent: O
Product: COc1cc2c(cc1[N+](=O)[O-])OC(C)(C)[C@H](O)[C@H]2N
Temperature: 100 °C
Reaction time: 2 h
Yield: 84 %

Procedure:
To a solution of (3R*,4R*)-3,4-epoxy-6-methoxy-2,2-dimethyl-7-nitro-3,4-dihydro-2H-1-benzopyran (2.64 g, 10.5 mmol) in ethanol (26 mL), an ammonia water (26 mL) was added, and the resulting mixture was stirred in a sealed tube at 100° C. for 2 hours. Upon the completion of the reaction, the solvent was distilled off. An aqueous solution of saturated sodium carbonate was added to the residue, and the resulting mixture was extracted with ethyl acetate. The organic phase was washed with saturated sodium chloride solution, dried over anhydrous magnesium sulfate and thereby the aimed product was obtained as red amorphous substance (yield: 84%).
Reaction SMILES: [CH2:1]([CH:3]1[CH:29]=[C:28]([CH3:30])[CH2:27][CH:26]([CH3:31])[CH2:25][CH:24]([O:32][CH3:33])[CH:23]2[O:34][C:19]([OH:38])([CH:20]([CH3:37])[CH2:21][CH:22]2[O:35][CH3:36])[C:18](=[O:39])[C:17](=[O:40])[N:16]2[CH:11]([CH2:12][CH2:13][CH2:14][CH2:15]2)[C:10](=[O:41])[O:9][CH:8]([C:42]([CH3:72])=[CH:43][CH:44]2[CH2:49][CH2:48][CH:47]([O:50][C:51]3[CH:52]=[C:53]4[C:57](=[CH:58][CH:59]=3)[NH:56][C:55]([CH:60]([O:62][Si](C(C)(C)C)(C)C)[CH3:61])=[CH:54]4)[CH:46]([O:70][CH3:71])[CH2:45]2)[CH:7]([CH3:73])[CH:6]([OH:74])[CH2:5][C:4]1=[O:75])[CH3:2].C1(C)C=CC(S(O)(=O)=O)=CC=1.C(OCC)(=O)C.C([O-])(O)=O.[Na+]>C(Cl)Cl.CO>[CH2:1]([CH:3]1[CH:29]=[C:28]([CH3:30])[CH2:27][CH:26]([CH3:31])[CH2:25][CH:24]([O:32][CH3:33])[CH:23]2[O:34][C:19]([OH:38])([CH:20]([CH3:37])[CH2:21][CH:22]2[O:35][CH3:36])[C:18](=[O:39])[C:17](=[O:40])[N:16]2[CH:11]([CH2:12][CH2:13][CH2:14][CH2:15]2)[C:10](=[O:41])[O:9][CH:8]([C:42]([CH3:72])=[CH:43][CH:44]2[CH2:49][CH2:48][CH:47]([O:50][C:51]3[CH:52]=[C:53]4[C:57](=[CH:58][CH:59]=3)[NH:56][C:55]([CH:60]([OH:62])[CH3:61])=[CH:54]4)[CH:46]([O:70][CH3:71])[CH2:45]2)[CH:7]([CH3:73])[CH:6]([OH:74])[CH2:5][C:4]1=[O:75])[CH3:2]
Reactant: CCC1C=C(C)CC(C)CC(OC)C2OC(O)(C(=O)C(=O)N3CCCCC3C(=O)OC(C(C)=CC3CCC(Oc4ccc5[nH]c(C(C)O[Si](C)(C)C(C)(C)C)cc5c4)C(OC)C3)C(C)C(O)CC1=O)C(C)CC2OC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: CO
Product: CCC1C=C(C)CC(C)CC(OC)C2OC(O)(C(=O)C(=O)N3CCCCC3C(=O)OC(C(C)=CC3CCC(Oc4ccc5[nH]c(C(C)O)cc5c4)C(OC)C3)C(C)C(O)CC1=O)C(C)CC2OC
Yield: 72.2 %

Procedure:
To a solution of 17-ethyl-1,14-dihydroxy-12-[2'-(4"-(1-t-butyldimethylsilyloxyethylindol-5-yl)oxy-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo-[22.3.1.04,9 ]octacos-18-ene-2,3,10,16-tetraone (0.38 gm) in CH2Cl2 (10 ml) at room temperature was added a solution of paratoluene sulfonic acid (0.05 gm) in CH3OH (10 ml). The reaction mixture was stirred for 3 hours until TLC (silica, 2:1, hexanes:ethyl acetate) verified that reaction was complete. The reaction mixture was poured into saturated NaHCO3 and extracted twice with CH2Cl2. The combined organic extracts were dried over Na2SO4, filtered and concentrated in vacuo. The crude product was purified by chromatography (silica, 2:1 hexanes:ethyl acetate) to provide the title compound 0.245 gm. MASS (FAB) M+Li 957. Partial 1H NMR (CDCl3, 200 MHz) δ:7.18 (d, J=10 Hz, 1H); 7.16 (bs, 1H); 7.06 (d, J=4 Hz, 1H); 6.86 (dd, J=3 Hz and 10 Hz, 1H); 6.33 (d, J=4 Hz, 1H); 4.13 (t, J=6.7 Hz, 2H); 3.83 (t, J=6.7 Hz, 2H); 3.43 (s, 3H).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[Cl-].[Al+3].[Cl-].[Cl-].[Br:18][CH2:19][C:20](Br)=[O:21].C>CO.CC(C)=O.C(O)(=O)C.C(=S)=S>[Br:18][CH2:19][C:20]([C:11]1[CH:10]=[CH:9][C:8]([C:5]2[CH:6]=[CH:7][C:2]([CH3:1])=[CH:3][CH:4]=2)=[CH:13][CH:12]=1)=[O:21]
Reactant: O=C(Br)CBr
Reactant: Cc1ccc(-c2ccccc2)cc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: CC(C)=O
Solvent: CC(=O)O
Solvent: CO
Product: Cc1ccc(-c2ccc(C(=O)CBr)cc2)cc1
Reaction time: 2 h

Procedure:
An 11.7 g. portion of 4-methylbiphenyl was dissolved in 75 ml. of carbon disulfide and cooled in an ice bath while 11.6 g. of aluminum chloride was added portionwise with vigorous stirring. A 15.9 g. portion of bromoacetylbromide was added dropwise and after completion and the reaction subsided the mixture was heated at reflux for 3 hours, then cooled overnight. The mixture was poured into crushed ice and 150 ml. of acetic acid and stirred for 1.5 hours. The resulting gum was collected and stirred in methanol for 2 hours, giving a solid. This solid was dissolved in methanol:acetone, treated with charcoal and cooled. The solution was decanted, concentrated to about 150 ml., decanted and recooled giving a solid which was collected, giving the desired intermediate as a beige solid, m.p. 120°-122° C.
Reaction SMILES: N[C:2]1[C:11]([Cl:12])=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[Cl:13].N([O-])=O.[Na+].[BrH:18]>>[Br:18][C:2]1[C:11]([Cl:12])=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[Cl:13]
Reactant: Br
Reactant: COC(=O)c1cc(Cl)c(N)c(Cl)c1
Agent: O=N[O-]
Agent: [Na+]
Product: COC(=O)c1cc(Cl)c(Br)c(Cl)c1

Procedure:
Methyl 4-amino-3,5-dichlorobenzoate (32 g.) dissolved in 48% hydrobromic acid (100 ml.) was cooled to 0° and sodium nitrite (10.5 g.) was added. The solution was added slowly to a mixture of 48% hydrobromic acid (80 ml.) and cuprous bromide (35 g.) and the mixture heated at reflux for 2 hours. After cooling, the mixture was extracted with ethyl acetate and the organic extracts washed with brine, dried (anhydrous magnesium sulphate) and evaporated to give a dark solid. Crystallisation from ethyl acetate gave methyl 4-bromo-3,5-dichlorobenzoate (20 g.). Nuclear Magnetic Resonance Spectrum (NMR) was as follows: 1H: 4.0,3H,s; 7.9,2H,s.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([C:8]2[C:20]3[C:19]([CH3:21])=[C:18]([CH2:22][N:23]([CH2:26][CH3:27])[CH2:24][CH3:25])[S:17][C:16]=3[C:15]([Br:28])=[C:14]3[C:9]=2[CH:10]=[CH:11][CH:12]=[CH:13]3)[CH:5]=[C:4]([Br:29])[C:3]=1[OH:30].O[C@@H:32]([CH2:37][C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)[C:33]([O:35]C)=[O:34]>C(#N)C>[Br:29][C:4]1[CH:5]=[C:6]([C:8]2[C:20]3[C:19]([CH3:21])=[C:18]([CH2:22][N:23]([CH2:24][CH3:25])[CH2:26][CH3:27])[S:17][C:16]=3[C:15]([Br:28])=[C:14]3[C:9]=2[CH:10]=[CH:11][CH:12]=[CH:13]3)[CH:7]=[C:2]([Br:1])[C:3]=1[O:30][C@H:32]([CH2:37][C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)[C:33]([OH:35])=[O:34]
Reactant: CCN(CC)Cc1sc2c(Br)c3ccccc3c(-c3cc(Br)c(O)c(Br)c3)c2c1C
Reactant: COC(=O)[C@@H](O)Cc1ccccc1
Solvent: CC#N
Product: CCN(CC)Cc1sc2c(Br)c3ccccc3c(-c3cc(Br)c(O[C@H](Cc4ccccc4)C(=O)O)c(Br)c3)c2c1C

Procedure:
Prepared from 2,6-dibromo-4-(9-bromo-2-diethylaminomethyl-3-methyl-naphtho[2,3-b]thiophen-4-yl)-phenol (Example 18) and (S)-2-hydroxy-3-phenylpropionic acid, methyl ester (Example 25) according to the procedure of Example 30. White solid: NMR (DMSO-d6); δ 13.3 (broad band, 1H), 8.20 (d, J=8 Hz, 1H), 7.70(s, 2H), 7.66 (ddd, J=8, 7, 1 Hz, 1H), 7.51(ddd, J=8, 7, 1 Hz, 1H), 7.40-7.25(m, 6H), 5.21(t, J=7 Hz, 1H), 3.75(s, 2H), 3.32(dd, J=4, 3 Hz, 2H), 2.55 (q, J=7 Hz, 4H), 1.63(s, 3H), 1.02 (t, J=7 Hz, 6H) MS [(+)FAB]: [M+H]+ @ m/z 758, 3bromine isotope pattern, 758(25%), 760(80%), 762(75%), 764(35%), 689(100%); Anal HPLC, Primesphere 5C-18 column, eluent 62% acetonitrile for 15 minutes indicated 97.8% purity; High Resolution MS (FAB)+ve: Calculated Sample Mass: 759.95556 for formula C33H31NO3Br3 as [M+H], Measured Mass 759.97370 mass deviation: 18.14 mmu.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[NH:8][CH2:9][C:10]#[N:11].[CH3:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1B(O)O>CCCCCCC.CCOC(C)=O>[C:13]1([CH3:12])[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[NH:8][CH2:9][C:10]#[N:11]
Reactant: Cc1ccccc1B(O)O
Reactant: N#CCNc1cnccc1I
Solvent: CCCCCCC
Solvent: CCOC(C)=O
Product: Cc1ccccc1-c1ccncc1NCC#N

Procedure:
The title compound was prepared in analogy to example 72, from (4-iodo-pyridin-3-ylamino)-acetonitrile and 2-methylphenylboronic acid (CAS RN 16419-60-6) and using a gradient of n-heptane:EtOAc (100:0 to 0:100) for the chromatographic purification. Light brown solid (48%). MS (ESI): m/z=224.12 [M+H]+.