Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(O[C:4]1[C:5](=[O:16])[C:6](=[O:15])[C:7]=1[NH:8][C:9]1[CH:14]=[CH:13][N:12]=[CH:11][CH:10]=1)C.[C:17]1([CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][NH2:30])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>>[C:17]1([CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][NH:30][C:4]2[C:5](=[O:16])[C:6](=[O:15])[C:7]=2[NH:8][C:9]2[CH:10]=[CH:11][N:12]=[CH:13][CH:14]=2)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: CCOc1c(Nc2ccncc2)c(=O)c1=O
Reactant: NCCCCCCCc1ccccc1
Product: O=c1c(NCCCCCCCc2ccccc2)c(Nc2ccncc2)c1=O
Yield: 59 %

Procedure:
The title compound was prepared according to the procedure described in example 1B starting from 3-ethoxy-4-(pyridin-4-yl-amino)-3-cyclobutene-1,2-dione prepared according to example 7A and 7-phenylheptylamine.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[CH:3]=1.[Cl-].[Al+3].[Cl-].[Cl-].[Br:13][CH:14]([CH3:18])[C:15](Cl)=[O:16]>C(Cl)Cl>[Br:13][CH:14]([CH3:18])[C:15]([C:5]1[CH:6]=[CH:7][C:2]([F:1])=[CH:3][C:4]=1[F:8])=[O:16]
Reactant: CC(Br)C(=O)Cl
Reactant: Fc1cccc(F)c1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: CC(Br)C(=O)c1ccc(F)cc1F
Temperature: 0 °C

Procedure:
To a mixture of m-difluorobenzene (75 ml) and anhydrous aluminium chloride (115 g) was added dropwise, while stirring, 2-bromopropionyl chloride (100 g) during 50 minutes. The mixture was stirred for 2 hours on an oil bath at 50°-55° C. The reaction mixture was cooled, to which was added methylene chloride (500 ml). The resultant solution was added, in limited amounts, to ice-water (1.5 l) while stirring. The methylene chloride layer was separated, and the aqueous layer was subjected to extraction twice with methylene chloride (100 ml). The methylene chloride layers were combined and washed with water (500 ml), which was dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to leave 2-bromo-2',4'-difluoropropiophenone (142.5 g) as a pale yellow oily product. 1H-NMR (CDCl3) δ: 1.90(3H), 5.25(1H), 6.85~7.06(2H), 7.93~8.05(1H)
Reaction SMILES: [C:1]([O:5][C:6](=[O:19])[NH:7][CH:8]([CH:16]1[CH2:18][O:17]1)[CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:20][O:21][C:22]1[CH:23]=[C:24]([CH:27]=[CH:28][CH:29]=1)[CH2:25][NH2:26]>CC(O)C>[CH3:20][O:21][C:22]1[CH:23]=[C:24]([CH:27]=[CH:28][CH:29]=1)[CH2:25][NH:26][CH2:18][CH:16]([OH:17])[CH:8]([NH:7][C:6](=[O:19])[O:5][C:1]([CH3:4])([CH3:3])[CH3:2])[CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: COc1cccc(CN)c1
Reactant: CC(C)(C)OC(=O)NC(Cc1ccccc1)C1CO1
Solvent: CC(C)O
Product: COc1cccc(CNCC(O)C(Cc2ccccc2)NC(=O)OC(C)(C)C)c1
Yield: 77 %

Procedure:
To a stirred solution of tert-butyl-(1-oxiranyl-2-phenylethyl)-carbamate (131.6 mg, 0.5 mmol), 3-methoxy-benzylamine (0.25 mL, 2 mmol) in 3 mL of 2-propanol was heated to reflux for 12 h to afford tert-butyl 4-(3-methoxybenzylamino)-3-hydroxy-1-phenylbutan-2-ylcarba-mate. The solvent was evaporated and the crude product was purified by silica gel flash column chromatography (5-10% MeOH in CHCl3) to give 4 in 77% yield (154 mg) as a colorless solid.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([N:7]2[C:15]3[C:10](=[CH:11][CH:12]=[C:13]([Cl:16])[N:14]=3)[CH2:9][CH2:8]2)[CH2:3][CH2:2]1.[CH3:17][O:18][C:19]1[CH:27]=[CH:26][C:22]([CH2:23][CH2:24]Br)=[CH:21][CH:20]=1>>[CH3:17][O:18][C:19]1[CH:27]=[CH:26][C:22]([CH2:23][CH2:24][N:1]2[CH2:2][CH2:3][CH:4]([N:7]3[C:15]4[C:10](=[CH:11][CH:12]=[C:13]([Cl:16])[N:14]=4)[CH2:9][CH2:8]3)[CH2:5][CH2:6]2)=[CH:21][CH:20]=1
Reactant: COc1ccc(CCBr)cc1
Reactant: Clc1ccc2c(n1)N(C1CCNCC1)CC2
Product: COc1ccc(CCN2CCC(N3CCc4ccc(Cl)nc43)CC2)cc1
Yield: 16 %

Procedure:
1-(Piperidin-4-yl)-6-chloro-7-azaindoline (0.8 g) and 4-methoxyphenethyl bromide (0.72 g) were treated as in Example 2 to give the hydrochloride (220 mg) of the title compound as a pale yellow powder (yield: 16%).
Reaction SMILES: C[N:2](/[CH:4]=[C:5](/[C:10](=O)[CH2:11][CH3:12])\[C:6]([O:8][CH3:9])=[O:7])C.[C:14]1([NH:20]N)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>C(O)C>[CH2:11]([C:10]1[N:20]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[N:2]=[CH:4][C:5]=1[C:6]([O:8][CH3:9])=[O:7])[CH3:12]
Reactant: CCC(=O)/C(=C/N(C)C)C(=O)OC
Reactant: NNc1ccccc1
Solvent: CCO
Product: CCc1c(C(=O)OC)cnn1-c1ccccc1
Temperature: 150 °C
Reaction time: 0.5 h

Procedure:
Methyl (2Z)-2-[(dimethylamino)methylene]-3-oxopentanoate (383 mg, 2.07 mmol) and phenylhydrazine (0.308 ml, 3.10 mmol) were added to ethanol (4 ml). The reaction mixture was heated to 150° C. in the Biotage Initiator Series microwave. After 30 minutes, the reaction mixture was cooled and concentrated. The residue was purified by column chromatography on silica gel (ethyl acetate/hexanes gradient) to afford methyl 5-ethyl-1-phenyl-1H-pyrazole-4-carboxylate.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:11]([N+:12]([O-])=O)=[C:10]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH:9]=[CH:8][N:7]=1)=[O:5])[CH3:2]>[Pd]>[CH2:1]([O:3][C:4]([C:6]1[C:11]([NH2:12])=[C:10]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH:9]=[CH:8][N:7]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1ccnc(C(=O)OCC)c1[N+](=O)[O-]
Agent: [Pd]
Product: CCOC(=O)c1ccnc(C(=O)OCC)c1N
Temperature: 25 °C
Reaction time: 4 h
Yield: 69.7 %

Procedure:
To a solution of 3-Nitro-pyridine-2,4-dicarboxylic acid diethyl ester (55.00 g; 0.19 mol) was added Palladium on carbon (10% w/w) (6.00 g; 0.01 mol). The mixture was stirred at room temperature for 4 hours under 5 Kg of hydrogen pressure. After completion of the reaction, the reaction mixture was filtered through celite and the filtrate concentrated under vacuum. The residue was purified by column chromatography (60-120 mesh) using 15-20% EtOAc: petroleum ether to afford the title compound as a yellow solid (yield 69.7%). LC-MS [239 (M+H)], 1H NMR (400 MHz, DMSO-d6), 7.94-7.93 (d, 1H), 7.84-7.83 (d, 1H), 4.34-4.27 (m, 4H), 1.33-1.29 (m, 6H)
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:19])[CH:5]=[C:6]([O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([C:15]([F:18])([F:17])[F:16])[CH:10]=1)[CH3:7])[CH3:2].[Br:20]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[CH2:1]([O:3][C:4](=[O:19])[CH:5]=[C:6]([O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([C:15]([F:16])([F:18])[F:17])[CH:10]=1)[CH2:7][Br:20])[CH3:2]
Reactant: O=C1CCC(=O)N1Br
Reactant: CCOC(=O)C=C(C)Oc1cccc(C(F)(F)F)c1
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: CCOC(=O)C=C(CBr)Oc1cccc(C(F)(F)F)c1
Temperature: 25 °C
Yield: 83.1 %

Procedure:
A solution of 3-(3-trifluoromethyl-phenoxy)-but-2-enoic acid ethyl ester (1.31 g, 4.77 mmol) in carbon tetrachloride (25 mL) was treated with N-bromosuccinimide (0.94 g, 5.28 mmol) and benzoyl peroxide (0.12 g). The reaction was then warmed to reflux for 5 h. At this time, the reaction was cooled to 25° C. and then placed in the freezer over the weekend. At this time, the reaction was removed from the freezer and allowed to thaw. The resulting precipitate was removed by filtration. The filtrate was concentrated in vacuo. Purification by Analogix flash chromatography (40 g, 1-10% ethyl acetate/hexanes) afforded impure 4-bromo-3-(3-trifluoromethyl-phenoxy)-but-2-enoic acid ethyl ester (1.40 g, 83%) as a pale, yellow oil. The material was used without further purification.
Reaction SMILES: C1(C)C(C)=CC=CC=1.[CH:9]1[CH:14]=[C:13]([OH:15])[C:12]([S:16]([O-:19])(=[O:18])=[O:17])=[CH:11][CH:10]=1.[Na+:20].[C:21]1(=[O:35])[N:25]([CH2:26][C:27](Cl)=[O:28])[C:24](=[O:30])[C:23]2=[CH:31][CH:32]=[CH:33][CH:34]=[C:22]12>CC(C)=O>[C:24]1(=[O:30])[N:25]([CH2:26][C:27]([O:15][C:13]2[CH:14]=[CH:9][CH:10]=[CH:11][C:12]=2[S:16]([O-:19])(=[O:17])=[O:18])=[O:28])[C:21](=[O:35])[C:22]2=[CH:34][CH:33]=[CH:32][CH:31]=[C:23]12.[Na+:20]
Reactant: O=C(Cl)CN1C(=O)c2ccccc2C1=O
Reactant: O=S(=O)([O-])c1ccccc1O
Agent: [Na+]
Solvent: CC(C)=O
Solvent: Cc1ccccc1C
Product: O=C(CN1C(=O)c2ccccc2C1=O)Oc1ccccc1S(=O)(=O)[O-]
Reaction time: 15 h

Procedure:
500 g of xylene are added to 98.0 g (0.5 mol) of anhydrous sodium phenolsulfonate and 112.0 g (0.5 mol) of α-phthalimidoacetyl chloride and the mixture is kept at 140° C. for 15 hours. After cooling, the reaction mixture is taken up in acetone, the solvent is filtered off with suction over a Buchner funnel and the crystal sludge is washed twice more with 80 ml of acetone each time. After recrystallization from 90% strength ethanol, the resulting product is dried at 40° C. under a water pump vacuum.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[OH:9].[P:10]([Cl:14])(Cl)(Cl)=[O:11]>>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[O:9][P:10]([Cl:14])(=[O:11])[O:9][C:3]1[CH:4]=[CH:5][C:6]([Cl:8])=[CH:7][C:2]=1[Cl:1]
Reactant: O=P(Cl)(Cl)Cl
Reactant: Oc1ccc(Cl)cc1Cl
Product: O=P(Cl)(Oc1ccc(Cl)cc1Cl)Oc1ccc(Cl)cc1Cl

Procedure:
The title compound was prepared by the general method of Example 1 with the following modifications. (1) The molar ratio of 2,4-dichlorophenol to phosphorus oxychloride was increased from 1.33 to 1.85 by using 189.99 g (1.165 mole) of 2,4-dichlorophenol and 96.60 g (0.63 mole) of phosphorus oxychloride. (2) The reaction time at 120° was increased to about 24 hours. (3) The product was crystallized using a larger quantity of hexane (570 ml, or 3 ml per gram of starting 2,4-dichlorophenol) at -15°. Analysis by GLPC indicated 82% purity (by weight) of bis(2,4-dichlorophenyl)phosphorochloridate, with contamination by a trace of 2,4-dichlorophenyl phosphorodichloridate and 18% (by weight) of tris(2,4-dichlorophenyl)phosphate. The yield of the bis(2,4-dichlorophenyl)phosphorochloridate when corrected for purity was 125 g (53%). Subsequent reactions were unaffected by the presence of the tris(2,4-dichlorophenyl)phosphate, as illustrated by Examples 3 and 4.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:26])[C:4]([CH3:25])([O:6][C:7]1[CH:8]=[C:9]([CH:22]=[CH:23][CH:24]=1)/[CH:10]=[N:11]/[C:12]1[CH:21]=[CH:20][C:15]([C:16]([O:18][CH3:19])=[O:17])=[CH:14][CH:13]=1)[CH3:5]>O1CCCC1.FC(F)(F)S([O-])(=O)=O.[Y+3].FC(F)(F)S([O-])(=O)=O.FC(F)(F)S([O-])(=O)=O>[OH:2][CH:3]1[C:21]2[C:12](=[CH:13][CH:14]=[C:15]([C:16]([O:18][CH3:19])=[O:17])[CH:20]=2)[NH:11][CH:10]([C:9]2[CH:22]=[CH:23][CH:24]=[C:7]([O:6][C:4]([CH3:5])([CH3:25])[C:3]([O:2][CH3:1])=[O:26])[CH:8]=2)[C:4]1([CH3:25])[CH3:5]
Reactant: COC(=O)c1ccc(/N=C/c2cccc(OC(C)(C)C(=O)OC)c2)cc1
Agent: O=S(=O)([O-])C(F)(F)F
Agent: [Y+3]
Solvent: C1CCOC1
Product: COC(=O)c1ccc2c(c1)C(O)C(C)(C)C(c1cccc(OC(C)(C)C(=O)OC)c1)N2
Temperature: 25 °C
Reaction time: 17 h
Yield: 95.4 %

Procedure:
To a solution of (E)-methyl 4-(3-(1-methoxy-2-methyl-1-oxopropan-2-yloxy)benzylideneamino)benzoate (888 mg, 2.5 mmol) and yttrium(III) trifluoromethanesulfonate (5 mL) in tetrahydrofuran (6 mL) was added a solution of isobutyl aldehyde (216 mg, 3.0 mmol) in tetrahydrofuran (1 mL) under nitrogen. The mixture was stirred at room temperature for 17 h. The mixture was purified by column chromatography to afford 510 mg of methyl 4-hydroxy-2-(3-(1-methoxy-2-methyl-1-oxopropan-2-yloxy)phenyl)-3,3-dimethyl-1,2,3,4-tetrahydroquinoline-6-carboxylate as a white solid. (Yield: 48%, 2 steps).
Reaction SMILES: Cl.C([NH:5][CH2:6][C:7]1[CH:12]=[CH:11][C:10]([CH3:13])=[C:9]([Cl:14])[CH:8]=1)(=O)C>C(O)C>[ClH:14].[NH2:5][CH2:6][C:7]1[CH:12]=[CH:11][C:10]([CH3:13])=[C:9]([Cl:14])[CH:8]=1
Reactant: CC(=O)NCc1ccc(C)c(Cl)c1
Agent: Cl
Solvent: CCO
Product: Cc1ccc(CN)cc1Cl
Yield: 198.1 %

Procedure:
To a mixture of 80 ml of concentrated hydrochloric acid and 8 ml of ethanol, was added 8.0 g of 4-acetamidomethyl-2-chlorotoluene. The stirred mixture was heated overnight under reflux. The solvent was removed by distillation and the residue was washed out with acetone to yield 7.7 g of 4-aminomethyl-2-chlorotoluene hydrochloride; m.p. ≤242° C.
Reaction SMILES: [NH:1]([C:14]([O:16]C(C)(C)C)=O)[C@H:2]([C:7]([NH:9][CH2:10][C:11]([OH:13])=[O:12])=[O:8])[CH2:3][CH:4]([CH3:6])[CH3:5].[NH:21]([C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[CH2:22]C(ON1C(=O)CCC1=O)=O>>[NH:21]([C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[CH2:22][C:14]([NH:1][C@H:2]([C:7]([NH:9][CH2:10][C:11]([OH:13])=[O:12])=[O:8])[CH2:3][CH:4]([CH3:5])[CH3:6])=[O:16]
Reactant: CC(C)(C)OC(=O)NCC(=O)ON1C(=O)CCC1=O
Reactant: CC(C)C[C@H](NC(=O)OC(C)(C)C)C(=O)NCC(=O)O
Product: CC(C)C[C@H](NC(=O)CNC(=O)OC(C)(C)C)C(=O)NCC(=O)O
Yield: 60.9 %

Procedure:
By using 6.41 g of Boc-Leu-Gly-OH and 6.04 g of Boc-Gly-OSu, and the same procedure as in Reference Example 31 was repaeted to obtain 4.67 g (yield: 61.4%) of the above-mentioned objective product.
Reaction SMILES: Cl[CH2:2][C:3]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[O:5][N:4]=1.[OH:14][C:15]1[CH:38]=[CH:37][C:18]([CH2:19][N:20]2[CH:24]=[C:23]([CH2:25][CH2:26][C:27]([O:29][CH3:30])=[O:28])[C:22]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)=[N:21]2)=[CH:17][CH:16]=1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[C:31]1([C:22]2[C:23]([CH2:25][CH2:26][C:27]([O:29][CH3:30])=[O:28])=[CH:24][N:20]([CH2:19][C:18]3[CH:17]=[CH:16][C:15]([O:14][CH2:2][C:3]4[N:7]=[C:6]([C:8]5[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=5)[O:5][N:4]=4)=[CH:38][CH:37]=3)[N:21]=2)[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1
Reactant: ClCc1noc(-c2ccccc2)n1
Reactant: COC(=O)CCc1cn(Cc2ccc(O)cc2)nc1-c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)CCc1cn(Cc2ccc(OCc3noc(-c4ccccc4)n3)cc2)nc1-c1ccccc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 88.6 %

Procedure:
A mixture of 3-chloromethyl-5-phenyl-1,2,4-oxadiazole (307 mg), methyl 3-[1-(4-hydroxybenzyl)-3-phenyl-1H-pyrazol-4-yl]propionate (500 mg), potassium carbonate (397 mg) and N,N-dimethylformamide (7 ml) was stirred at room temperature for 18 hours. The reaction mixture was poured into water, which was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated aqueous sodium chloride solution, dried (MgSO4), then concentrated. The residue was subjected to silica gel column chromatography, and methyl 3-[3-phenyl-1-[4-(5-phenyl-1,2,4-oxadiazole-3-ylmethoxy)benzyl]-1H-pyrazol-4-yl]propionate (651 mg, yield: 89%) was obtained as a colorless oily substance from the fraction eluted with ethyl acetate-hexane (1:2, volume ratio).
Reaction SMILES: [C:1]([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15](=[O:26])[CH2:16][C:17]2[CH:22]=[CH:21][C:20]([C:23]#[N:24])=[CH:19][C:18]=2Br)[CH2:10][CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C.C(=O)([O-])[O-].[K+].[K+].C1(B(O)O)C=CC=CC=1>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C(O)(C)(C)C>[C:1]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[C:22]3[C:17](=[CH:18][CH:19]=[C:20]([C:23]#[N:24])[CH:21]=3)[CH2:16][C:15]2=[O:26])[CH2:10][CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2]
Reactant: CC(C)(C)OC(=O)N1CCC(NC(=O)Cc2ccc(C#N)cc2Br)CC1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Solvent: CC(C)(C)O
Product: CC(C)(C)OC(=O)N1CCC(N2C(=O)Cc3ccc(C#N)cc32)CC1
Temperature: 85 °C
Yield: 61.9 %

Procedure:
A solution of N-Boc 4-{[(2-bromo-4-cyanophenyl)acetyl]amino}piperidine (D135, 100 mg, 0.189 mmol) in anhydrous degassed tert-butanol (2 mL) was treated with X-PHOS (10 mg, 0.021 mmol), potassium carbonate (70 mg, 0.506 mmol), palladium (II) acetate (2 mg, 8.91 μmol), and phenylboronic acid (2 mg, 0.016 mmol), then heated at 85° C. for 1 h then cooled and evaporated. Chromatography on silica (20 g), eluting with 10-50% ethyl acetate-isohexane, gave N-Boc-4-(6-cyano-2-oxo-2,3-dihydro-1H-indol-1-yl)-piperidine (40 mg, 0.117 mmol, 61.8% yield) as a colourless oil.
Reaction SMILES: [C:1]([O:5][C:6](=[O:39])[NH:7][C:8]1([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[C:23]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)=[CH:22][N:21]4[N:30]=[C:31]([C:33]5[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=5)[CH:32]=[C:20]4[N:19]=3)=[CH:14][CH:13]=2)[CH2:11][CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].C1C(=O)N([Br:47])C(=O)C1>C(Cl)(Cl)Cl.C(Cl)Cl>[C:1]([O:5][C:6](=[O:39])[NH:7][C:8]1([C:12]2[CH:13]=[CH:14][C:15]([C:18]3[C:23]([C:24]4[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=4)=[CH:22][N:21]4[N:30]=[C:31]([C:33]5[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=5)[C:32]([Br:47])=[C:20]4[N:19]=3)=[CH:16][CH:17]=2)[CH2:11][CH2:10][CH2:9]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(-c3nc4cc(-c5ccccc5)nn4cc3-c3ccccc3)cc2)CCC1
Reactant: O=C1CCC(=O)N1Br
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NC1(c2ccc(-c3nc4c(Br)c(-c5ccccc5)nn4cc3-c3ccccc3)cc2)CCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 69.7 %

Procedure:
To a solution of compound 9-1 (104 mg, 0.2 mmol) in CHCl3 (5 mL) was added NBS (40 mg 0.22 mmol.) and the mixture was stirred at room temperature overnight. The mixture was diluted with 15 mL of DCM, the combined organic phase was washed with 0.1N HClaq and brine, dried over anhydrous Na2SO4 and concentrated. The residue was purified by prep.TLC to give 83 mg of 9-3.
Reaction SMILES: [OH-].[K+].[CH2:3]([O:10][C:11]1[CH:20]=[C:19]([O:21][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:18]([C:29]([CH3:31])=[CH2:30])=[CH:17][C:12]=1[C:13]([O:15]C)=[O:14])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1>CO.O>[CH2:3]([O:10][C:11]1[CH:20]=[C:19]([O:21][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:18]([C:29]([CH3:31])=[CH2:30])=[CH:17][C:12]=1[C:13]([OH:15])=[O:14])[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: C=C(C)c1cc(C(=O)OC)c(OCc2ccccc2)cc1OCc1ccccc1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: C=C(C)c1cc(C(=O)O)c(OCc2ccccc2)cc1OCc1ccccc1
Temperature: 40 °C
Yield: 95.2 %

Procedure:
Potassium hydroxide (0.527 Kg, 9.4 mol) was added to a stirred suspension of methyl 2,4-bis-benzyloxy-5-isopropenyl-benzoate (3.1 Kg, 8 mol, step 4) in methanol (18.6 L) and water (12.4 L) and the mixture was stirred and held at reflux for 3 hours. The methanol was removed under partial vacuum from the vessel, and to the remaining solution was added toluene (62 L). The solution was heated to 40° C. and to the mixture was added conc HCl (1.36 L). The biphasic mixture is heated to 50° C. and the phases separated. The organic phase was washed with water (31 L) at 50° C. and the organic phase was evaporated under reduced pressure to give 2,4-bis-benzyloxy-5-isopropenyl-benzoic acid 2.851 Kg (95% yield) as a colourless solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH3:19])=[C:7]2[C:15]=1[C:14](=[CH:16][O:17]C)[CH:13]1[CH:8]2[CH2:9][CH2:10][CH2:11][CH2:12]1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>O1CCOCC1.O>[CH:16]([CH:14]1[CH:13]2[CH:8]([CH2:9][CH2:10][CH2:11][CH2:12]2)[C:7]2[C:15]1=[C:3]([O:2][CH3:1])[CH:4]=[CH:5][C:6]=2[CH3:19])=[O:17]
Reactant: COC=C1c2c(OC)ccc(C)c2C2CCCCC12
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: C1COCCO1
Solvent: O
Product: COc1ccc(C)c2c1C(C=O)C1CCCCC21

Procedure:
4.54 Grams of 8-methoxy-9-methoxymethylene-5-methyl-1,2,3,4,4a,9a-hexahydrofluorene was dissolved in 200 ml of 1,4-dioxane and 50 ml of water. To the solution was added 0.90 g of p-toluenesulfonic acid monohydrate and this was refluxed for 18 hours. To the reaction mixture was added 200 ml of water and extraction was carried out with diethyl ether. The organic layer was dried with magnesium sulfate, filtered and concentrated and the residue was purified by a silica gel column chromatography (eluent: ethyl acetate:n-hexane=1:10) and recrystallized from ethanol to obtain 3.94 g of 9-formyl-8-methoxy-5-methyl-1,2,3,4,4a,9a-hexahydrofluorene having a melting point of 92°-93° C. and of colorless needle-like crystal.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[C:10]([CH3:11])=[CH:9][C:8]([O:12][CH2:13][CH:14]2[CH2:16][CH2:15]2)=[CH:7][C:6]=1[CH3:17])=O.[NH2:18][C:19]([NH2:21])=[S:20]>CCO>[CH:14]1([CH2:13][O:12][C:8]2[CH:9]=[C:10]([CH3:11])[C:5]([C:3]3[N:18]=[C:19]([NH2:21])[S:20][CH:2]=3)=[C:6]([CH3:17])[CH:7]=2)[CH2:16][CH2:15]1
Reactant: Cc1cc(OCC2CC2)cc(C)c1C(=O)CBr
Reactant: NC(N)=S
Solvent: CCO
Product: Cc1cc(OCC2CC2)cc(C)c1-c1csc(N)n1
Yield: 61.4 %

Procedure:
A mixture of 2-bromo-1-(4-(cyclopropylmethoxy)-2,6-dimethylphenyl)ethanone (4-4, 2.06 g, 7.0 mmol) and thiourea (0.61 g, 8.0 mmol) in 95% EtOH (30.0 mL) was heated at reflux for 60 min. The solution was concentrated and added with water (50.0 mL) and saturated aqueous Na2CO3 (1.0 mL). The resultant precipitate was filtered and washed with hot water. The solids were filtered and dried under vacuum to give 4-(4-(cyclopropylmethoxy)-2,6-dimethylphenyl)thiazol-2-amine (4-5, 1.18 g) as yellow solids in 61% yield: 1H NMR (500 MHz, DMSO-d6) δ 9.00 (s, 2 H), 6.73 (s, 2 H), 3.81 (d, J=7.0 Hz, 1 H), 2.10 (s, 6 H), 1.19 (s, 1 H), 0.55 (m, 2 H), 0.30 (m, 2 H).
Reaction SMILES: CC(C)([S@@]([NH:6][C@@H:7]([C:13]([CH3:17])([CH3:16])[CH2:14][F:15])[C:8]([O:10][CH2:11][CH3:12])=[O:9])=O)C.[ClH:19].O1CCOCC1>CO>[NH2:6][C@@H:7]([C:13]([CH3:16])([CH3:17])[CH2:14][F:15])[C:8]([O:10][CH2:11][CH3:12])=[O:9].[ClH:19]
Reactant: CCOC(=O)[C@@H](N[S@@](=O)C(C)(C)C)C(C)(C)CF
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: CCOC(=O)[C@@H](N)C(C)(C)CF
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 100.5 %

Procedure:
To a solution of (S)-ethyl 2-((S)-1,1-dimethylethylsulfinamido)-4-fluoro-3,3-dimethylbutanoate (0.38 g, 1.350 mmol) in MeOH (10 mL) was added HCl/dioxane (1.350 mL, 5.40 mmol). The reaction mixture was stirred at rt for 30 min and concentrated to afford (S)-ethyl 2-amino-4-fluoro-3,3-dimethylbutanoate/HCl as a white solid (0.29 g).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([N+:8]([O-])=O)[CH:5]=[CH:4][C:3]=1[N:11]1[CH:15]=[CH:14][CH:13]=[CH:12]1.C(O)(=O)C>O.[Fe]>[Cl:1][C:2]1[CH:7]=[C:6]([CH:5]=[CH:4][C:3]=1[N:11]1[CH:15]=[CH:14][CH:13]=[CH:12]1)[NH2:8]
Reactant: O=[N+]([O-])c1ccc(-n2cccc2)c(Cl)c1
Agent: [Fe]
Solvent: CC(=O)O
Solvent: O
Product: Nc1ccc(-n2cccc2)c(Cl)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 63 %

Procedure:
A stirred mixture of 15.0 g (0.07 mole) of 1-(2-chloro-4-nitrophenyl)pyrrole and 30.0 g (0.53 mole) of iron powder in 100 ml of water was heated at reflux. During a three hour period 59.0 g (0.98 mole) of glacial acetic acid was added dropwise to the refluxing reaction mixture. Reflux was continued for one hour after complete addition. The mixture was cooled to room temperature, filtered and the filter cake rinsed with toluene. The filtrate was extracted with toluene (three 150 ml portions) and the extracts combined with the toluene rinse. The toluene solution was dried over anhydrous magnesium sulfate and filtered. The filtrate was evaporated under reduced pressure to leave an oil which solidified. The solid was purified by column chromatography using silica gel and eluting with methylene chloride, to yield 8.5 g of 3-chloro-4-(pyrrol-1-yl)aniline.
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]([F:11])[CH:8]=[C:7]2[C:3]=1[CH2:4][CH2:5]/[C:6]/2=[CH:12]\[C:13]([OH:15])=O.C(Cl)(=O)C([Cl:19])=O>ClCCl.CN(C)C=O>[F:1][C:2]1[CH:10]=[C:9]([F:11])[CH:8]=[C:7]2[C:3]=1[CH2:4][CH2:5]/[C:6]/2=[CH:12]\[C:13]([Cl:19])=[O:15]
Reactant: O=C(Cl)C(=O)Cl
Reactant: O=C(O)/C=C1\CCc2c(F)cc(F)cc21
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=C(Cl)/C=C1\CCc2c(F)cc(F)cc21
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A suspension of (E)-2-(4,6difluoro-1-indanylidene)acetic Acid (5.49 g, 0.026 mol) in a mixture of dichloromethane: dimethylformamide (50 mL: 5 drops) was treated with oxalyl chloride (6.6 g 0.052 mol, Aldrich) and allowed to stir at ambient temperature for 18 h. The resulting solution was concentrated in vacuo and the residue used without further purification.