Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][NH2:7])=[C:4]([F:10])[CH:3]=1.C(N(CC)CC)C.[Br:18][C:19]1[CH:27]=[CH:26][C:22]([C:23](Cl)=[O:24])=[C:21]([N+:28]([O-:30])=[O:29])[CH:20]=1>C(Cl)(Cl)Cl>[Br:18][C:19]1[CH:27]=[CH:26][C:22]([C:23]([NH:7][CH2:6][C:5]2[CH:8]=[CH:9][C:2]([Br:1])=[CH:3][C:4]=2[F:10])=[O:24])=[C:21]([N+:28]([O-:30])=[O:29])[CH:20]=1
Reactant: O=C(Cl)c1ccc(Br)cc1[N+](=O)[O-]
Reactant: NCc1ccc(Br)cc1F
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: O=C(NCc1ccc(Br)cc1F)c1ccc(Br)cc1[N+](=O)[O-]
Yield: 81.9 %

Procedure:
To a solution of 4-bromo-2-fluorobenzylamine (2.3 g) and triethylamine (1.55 ml) in chloroform (40 ml) was added dropwise a solution of 4-bromo-2-nitrobenzoyl chloride (2.69 g) in chloroform (10 ml) at 0° C. with stirring and the mixture was stirred at the same temperature for 1 hour. The reaction mixture was washed in turn with diluted aqueous hydrochloric acid and water, and then dried. Evaporation of the solvent followed by recrystallization from diethyl ether gave 4-bromo-N-(4-bromo-2-fluorobenzyl)-2-nitrobenzamide (3.60 g).
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[Cl:5][CH2:6][C:7](Cl)=[O:8].[NH:10]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH2:12][C:11]1=[O:19]>C(=S)=S>[Cl:5][CH2:6][C:7]([C:15]1[CH:14]=[C:13]2[C:18](=[CH:17][CH:16]=1)[NH:10][C:11](=[O:19])[CH2:12]2)=[O:8]
Reactant: O=C(Cl)CCl
Reactant: O=C1Cc2ccccc2N1
Agent: [Al+3]
Agent: [Cl-]
Solvent: S=C=S
Product: O=C1Cc2cc(C(=O)CCl)ccc2N1
Reaction time: 0.17 h
Yield: 98.9 %

Procedure:
To a 250 ml round-bottomed flask equipped with condenser and nitrogen inlet were added 30.7 grams (230 mmol) aluminum chloride, 150 ml carbon disulfide, and 3.8 ml (48 mmol) chloroacetyl chloride. To the stirring mixture was added 5.0 grams (37 mmol) of oxindole portionwise over 15 minutes. The reaction was stirred a further 10 minutes, then refluxed 2 hours. The reaction was cooled, added to ice, stirred thoroughly, and the beige precipitate filtered, washed with water, and dried to afford 7.67 grams (97%) of 5-chloroacetyl-oxindole. NMR (d, DMSO-d6): 3.40 (s, 2H), 5.05 (s, 2H), 6.8-7.9 (m, 3H).
Reaction SMILES: CN(C=O)C.[OH:6][C:7]1[CH:16]=[C:15]([OH:17])[CH:14]=[CH:13][C:8]=1[C:9]([O:11][CH3:12])=[O:10].C(=O)([O-])[O-].[K+].[K+].[CH2:24](Br)/[CH:25]=[C:26](/[CH2:28][CH2:29][CH:30]=[C:31]([CH3:33])[CH3:32])\[CH3:27]>O>[CH3:27]/[C:26](/[CH2:28][CH2:29][CH:30]=[C:31]([CH3:33])[CH3:32])=[CH:25]\[CH2:24][O:17][C:15]1[CH:14]=[CH:13][C:8]([C:9]([O:11][CH3:12])=[O:10])=[C:7]([OH:6])[CH:16]=1
Reactant: COC(=O)c1ccc(O)cc1O
Reactant: CC(C)=CCC/C(C)=C/CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1ccc(OC/C=C(\C)CCC=C(C)C)cc1O
Temperature: 25 °C
Reaction time: 1 h
Yield: 76.2 %

Procedure:
In 80 m of DMF were poured 13.1 g (78.0 mmol) of methyl 2,4-dihydroxybenzoate and 18.9 g (86.9 mmol) of potassium carbonate, and 12.0 g (86.9 mmol) of geranyl bromide was added thereto dropwise at 5° C. After the addition, the mixture was stirred at room temperature for 1 hour, poured into 300 ml of water, and extracted with 250 ml of ethyl acetate. The extract was washed with water and a saturated sodium chloride aqueous solution, dried over sodium sulfate, and concentrated. The resulting crude product was purified by column chromatography to obtain 18.1 g (yield: 75%) of methyl 4-{(2E)-3,7-dimethylocta-2,6-dienyloxy}-2-hydroxybenzoate represented by the following chemical formula (hereinafter referred to as compound 31) as a colorless, clear and oily substance. The analytical results are shown below. ##STR52##
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[CH2:9][S:10]([C:13]1[CH:14]=[C:15]2[C:19](=[CH:20][CH:21]=1)[NH:18][C:17](=[O:22])/[C:16]/2=[CH:23]\[C:24]1[NH:28][C:27]([CH3:29])=[C:26]([C:30](O)=[O:31])[C:25]=1[CH3:33])(=[O:12])=[O:11].[N:34]1([CH:39]2[CH2:44][CH2:43][NH:42][CH2:41][CH2:40]2)[CH2:38][CH2:37][CH2:36][CH2:35]1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl>CN(C=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[CH2:9][S:10]([C:13]1[CH:14]=[C:15]2[C:19](=[CH:20][CH:21]=1)[NH:18][C:17](=[O:22])/[C:16]/2=[CH:23]\[C:24]1[NH:28][C:27]([CH3:29])=[C:26]([C:30]([N:42]2[CH2:43][CH2:44][CH:39]([N:34]3[CH2:38][CH2:37][CH2:36][CH2:35]3)[CH2:40][CH2:41]2)=[O:31])[C:25]=1[CH3:33])(=[O:12])=[O:11]
Reactant: C1CCN(C2CCNCC2)C1
Reactant: Cc1[nH]c(/C=C2\C(=O)Nc3ccc(S(=O)(=O)Cc4cc(Cl)ccc4Cl)cc32)c(C)c1C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: Cc1[nH]c(/C=C2\C(=O)Nc3ccc(S(=O)(=O)Cc4cc(Cl)ccc4Cl)cc32)c(C)c1C(=O)N1CCC(N2CCCC2)CC1

Procedure:
5-[5-(2,5-Dichloro-phenylmethanesulfonyl)-2-oxo-1,2-dihydro-indol-(3Z)-ylidenemethyl]-2,4-dimethyl-1H-pyrrole-3-carboxylic acid was coupled with 4-pyrrolidin-1-yl-piperidine using HOBt, EDAC.HCl and TEA in DMF to give the titled compound.
Reaction SMILES: [CH:1]1([OH:11])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH2:2]1.[H-].[Na+].[Cl:14][C:15]1[CH:20]=[C:19]([N+]([O-])=O)[CH:18]=[CH:17][N:16]=1>>[Cl:14][C:15]1[CH:20]=[C:19]([O:11][CH:1]2[C:10]3[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=3)[CH2:4][CH2:3][CH2:2]2)[CH:18]=[CH:17][N:16]=1
Reactant: O=[N+]([O-])c1ccnc(Cl)c1
Reactant: OC1CCCc2ccccc21
Agent: [H-]
Agent: [Na+]
Product: Clc1cc(OC2CCCc3ccccc32)ccn1
Yield: 98.8 %

Procedure:
Using the method of Example 3, Step A, 1,2,3,4-tetrahydronaphthalen-1-ol (935 mg, 6.31 mmol), 60% sodium hydride in mineral oil (252 mg, 6.31 mmol), and 2-chloro-4-nitropyridine (1.00 g, 6.31 mmol) were reacted to provide 2-chloro-4-(1,2,3,4-tetrahydronaphthalen-1-yloxy)pyridine (1.62 g, 99% yield) as an oil. 1H NMR (CDCl3) δ 8.21 (d, 1H), 7.17-7.30 (m, 4H), 6.95 (s, 1H), 6.83 (d, 1H), 5.46 (t, 1H), 2.89 (ddd, 1H), 2.80 (ddd, 1H), 2.17 (m, 1H), 2.06 (m, 1H), 1.97 (m, 1H), 1.84 (m, 1H).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1([CH2:11][CH2:12][OH:13])[CH2:10][CH2:9][NH:8][CH2:7]1.[CH3:14][O:15][C:16]1[CH:17]=[C:18]([CH:22]=[C:23]([O:27][CH3:28])[C:24]=1[O:25][CH3:26])[C:19](Cl)=[O:20]>>[S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1([CH2:11][CH2:12][OH:13])[CH2:10][CH2:9][N:8]([C:19](=[O:20])[C:18]2[CH:17]=[C:16]([O:15][CH3:14])[C:24]([O:25][CH3:26])=[C:23]([O:27][CH3:28])[CH:22]=2)[CH2:7]1
Reactant: COc1cc(C(=O)Cl)cc(OC)c1OC
Reactant: OCCC1(c2cccs2)CCNC1
Product: COc1cc(C(=O)N2CCC(CCO)(c3cccs3)C2)cc(OC)c1OC

Procedure:
Prepare by the method of example 3.1 using 2-[3-(thiophen-2-yl)-pyrrolidin-3-yl]-ethanol (23 mmol) and 3,4,5-trimethoxy-benzoyl chloride (23 mmol). Chromatograph on silica gel to give the title compound.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[O:7][C:6]([C:8]2[CH:9]=[C:10]([CH2:16][CH3:17])[C:11](=[O:15])[NH:12][C:13]=2[CH3:14])=[CH:5][CH:4]=1.[N:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[C:24](Cl)=[O:25]>>[CH2:16]([C:10]1[C:11](=[O:15])[NH:12][C:13]([CH3:14])=[C:8]([C:6]2[O:7][C:3]([CH2:2][NH:1][C:24]([C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][N:18]=3)=[O:25])=[CH:4][CH:5]=2)[CH:9]=1)[CH3:17]
Reactant: CCc1cc(-c2ccc(CN)o2)c(C)[nH]c1=O
Reactant: O=C(Cl)c1ccccn1
Product: CCc1cc(-c2ccc(CNC(=O)c3ccccn3)o2)c(C)[nH]c1=O

Procedure:
Example 269 is substantially repeated except for utilizing 5-(5-aminomethylfuran-2-yl)-3-ethyl-6-methyl-1H-pyridin-2-one and pyridine-2-carboxylic acid chloride to afford the title compound. MS: m/e=338 (M+H).
Reaction SMILES: [OH:1][CH:2]1[CH2:23][NH:22][CH2:21][CH2:20][C:3]21[C:7](=[O:8])[N:6]([C:9]1[CH:14]=[CH:13][C:12]([CH2:15][C:16]([F:19])([F:18])[F:17])=[CH:11][CH:10]=1)[CH2:5][CH2:4]2.[CH3:24][N:25]1[C:29]([S:30](Cl)(=[O:32])=[O:31])=[CH:28][CH:27]=[N:26]1>>[OH:1][CH:2]1[CH2:23][N:22]([S:30]([C:29]2[N:25]([CH3:24])[N:26]=[CH:27][CH:28]=2)(=[O:32])=[O:31])[CH2:21][CH2:20][C:3]21[C:7](=[O:8])[N:6]([C:9]1[CH:14]=[CH:13][C:12]([CH2:15][C:16]([F:19])([F:17])[F:18])=[CH:11][CH:10]=1)[CH2:5][CH2:4]2
Reactant: Cn1nccc1S(=O)(=O)Cl
Reactant: O=C1N(c2ccc(CC(F)(F)F)cc2)CCC12CCNCC2O
Product: Cn1nccc1S(=O)(=O)N1CCC2(CCN(c3ccc(CC(F)(F)F)cc3)C2=O)C(O)C1

Procedure:
The title compound was prepared in analogy to example 2 step B from a mixture of (5SR,6RS)-6-hydroxy-2-[4-(2,2,2-trifluoro-ethyl)-phenyl]-2,8-diaza-spiro[4.5]decan-1-one (described in example 7 step B) and 2-methyl-2H-pyrazole-3-sulfonyl chloride. Light yellow solid. MS (ESI): 473.2 (MH+)
Reaction SMILES: C[O:2][C:3](=[O:35])[CH2:4][CH:5]([C:27]1[CH:32]=[C:31]([F:33])[CH:30]=[C:29]([F:34])[CH:28]=1)[C:6]1[CH:11]=[CH:10][N:9]=[C:8]([O:12][C:13]2[CH:18]=[CH:17][C:16]([CH2:19][NH:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][N:22]=3)=[CH:15][CH:14]=2)[N:7]=1.O.[OH-].[Li+:38]>C1COCC1.O>[Li+:38].[F:33][C:31]1[CH:32]=[C:27]([CH:5]([C:6]2[CH:11]=[CH:10][N:9]=[C:8]([O:12][C:13]3[CH:14]=[CH:15][C:16]([CH2:19][NH:20][C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][N:22]=4)=[CH:17][CH:18]=3)[N:7]=2)[CH2:4][C:3]([O-:35])=[O:2])[CH:28]=[C:29]([F:34])[CH:30]=1
Reactant: COC(=O)CC(c1cc(F)cc(F)c1)c1ccnc(Oc2ccc(CNc3ccccn3)cc2)n1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C([O-])CC(c1cc(F)cc(F)c1)c1ccnc(Oc2ccc(CNc3ccccn3)cc2)n1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
The compound of Example 4 (40 mg, 0.088 mmol) in THF (10 ml) and water (5 ml) was stirred at room temperature and lithium hydroxide monohydrate (37 mg, 0.88 mmol) added. The solution was stirred at room temperature for 72 h, then the solvents were removed in vacuo, and the crude white solid partitioned between ethyl acetate (10 ml) and water (10 ml). The water layer was freeze dried and the title compound was obtained as a white solid. 1H NMR (d6 DMSO) δ 8.29 (1H, d, J 5.1 Hz), 7.81 (1H, d, J 5.1 Hz), 7.21 (4H, m), 7.09 (1H, d, J 5.1 Hz), 6.80 (4H, m), .6.52 (1H, t, J 10.0 Hz), 6.42 (1H, t, J 5.8 Hz), 6.39 (1H, d, J 8.6 Hz), 4.42 (1H, t, J 7.9 Hz), 4.34 (2H, s), 2.98 (1H, dd, J 15.6, 8.4 Hz) and 2.77 (1H, dd, J 15.2, 7.5 Hz). MS (ES) m/e 463 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH2:4][C:5](=[O:11])[NH:6]2.[Cl:12]N1C(=O)CCC1=O.FC(F)(F)C(O)=O>C(#N)C>[Cl:12][C:10]1[C:2]([CH3:1])=[C:3]2[C:7](=[CH:8][CH:9]=1)[NH:6][C:5](=[O:11])[CH2:4]2
Reactant: Cc1cccc2c1CC(=O)N2
Reactant: O=C1CCC(=O)N1Cl
Solvent: O=C(O)C(F)(F)F
Solvent: CC#N
Product: Cc1c(Cl)ccc2c1CC(=O)N2
Temperature: 25 °C
Reaction time: 72 h
Yield: 67.5 %

Procedure:
A suspension of 3.0 g of 4-methyl-2-oxindole was stirred in 50 ml of acetonitrile at room temperature while 3.3 g of N-chlorosuccinimide was added in portions. Trifluoroacetic acid (1 ml) was then added. The suspension was stirred at room temperature for 3 days during which time solids were always present. The solids were collected by vacuum filtration, washed with a small amount of cold acetone and dried overnight in a vacuum oven at 40° C. to give 2.5 g (68%) of 5-chloro-4-methyl-2-oxindole.
Reaction SMILES: O1CCO[CH:2]1[C:6]1[CH:11]=[C:10]([CH3:12])[C:9]([NH:13][OH:14])=[CH:8][N:7]=1.[NH2:15][NH:16][C:17]([NH2:19])=[S:18].Cl.C(=O)(O)[O-].[Na+]>>[OH:14][NH:13][C:9]1[C:10]([CH3:12])=[CH:11][C:6]([CH:2]=[N:15][NH:16][C:17]([NH2:19])=[S:18])=[N:7][CH:8]=1
Reactant: Cc1cc(C2OCCO2)ncc1NO
Reactant: NNC(N)=S
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: Cc1cc(C=NNC(N)=S)ncc1NO

Procedure:
Condensation of 2-(1,3-dioxolanyl)-4-methyl-5-hydroxyaminopyridine with thiosemicarbazide in the presence of concentrated hydrochloric acid, followed by treatment with sodium bicarbonate afforded the desired 5-hydroxyamino-4-methyl-2-formylpyridine thiosemicarbazone.
Reaction SMILES: Cl[C:2]1[N:9]=[CH:8][CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[CH3:10][NH2:11]>>[CH3:10][NH:11][C:2]1[N:9]=[CH:8][CH:7]=[CH:6][C:3]=1[C:4]#[N:5]
Reactant: N#Cc1cccnc1Cl
Reactant: CN
Product: CNc1ncccc1C#N
Temperature: 25 °C

Procedure:
A solution of 2-chloronicotinonitrile (97.82 g, 706 mmol) in 40% aqueous methylamine (706 ml) was heated to reflux for 1.5 hour. The excess methylamine was evaporated off and the resulting solids filtered and washed with water (250 mL). The crude product was dissolved in boiling water (1.4 l) and treated with charcoal and filtered through Celite. The aqueous filtrate was cooled to room temperature. After 10 hours the crystalline solid was collected, washed with water and dried to leave 71.10 g of 2-(methylamino)-nicotinonitrile (mp. 86-88 degrees C.). A sample was further purified by sublimation (100 degrees C. at 0.025 mm) mp. (87-88 degrees C.).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:14](=[O:15])[CH2:13][C:12](=[O:16])[NH:11][C:10]3[C:17]4[CH2:18][CH2:19][CH2:20][CH2:21][C:22]=4[CH:23]=[CH:24][C:9]2=3)=[CH:4][CH:3]=1.[C:25](Cl)(=[O:29])[CH:26]([CH3:28])[CH3:27].Cl>N1C=CC=CC=1>[CH:26]([C:25]([NH:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:14](=[O:15])[CH2:13][C:12](=[O:16])[NH:11][C:10]3[C:17]4[CH2:18][CH2:19][CH2:20][CH2:21][C:22]=4[CH:23]=[CH:24][C:9]2=3)=[CH:6][CH:7]=1)=[O:29])([CH3:28])[CH3:27]
Reactant: CC(C)C(=O)Cl
Reactant: Nc1ccc(N2C(=O)CC(=O)Nc3c2ccc2c3CCCC2)cc1
Agent: Cl
Solvent: c1ccncc1
Product: CC(C)C(=O)Nc1ccc(N2C(=O)CC(=O)Nc3c2ccc2c3CCCC2)cc1
Temperature: 80 °C
Reaction time: 1 h
Yield: 94.8 %

Procedure:
To a pyridine solution (0.5 mL) of 5-(4-aminophenyl)-1,5,8,9,10,11-hexahydronaphtho[1,2-b][1,4]diazepine-2,4-dione (20 mg, 0.062 mmol) obtained in Example 10 was added isobutyryl chloride (10 μL, 0.093 mmol). The mixture was stirred at 80° C. for 1 hour. To the reaction mixture was added aqueous solution of hydrochloric acid under cooling in ice-bath. The mixture was stirred for 20 minutes. Insoluble was collected by filtration, and washed with water. The residue was purified by silica gel column chromatography (chloroform/methanol=99/1) to give the titled compound as white powder (23 mg, yield 95%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10](=O)[C:11](=O)[CH2:12][CH2:13][CH2:14][C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=2)=[CH:5][CH:4]=1.O.Cl>C1(C)C=CC=CC=1.[Zn]>[CH3:22][O:21][C:18]1[CH:17]=[CH:16][C:15]([CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=2)=[CH:20][CH:19]=1
Reactant: COc1ccc(CCCC(=O)C(=O)Cc2ccc(OC)cc2)cc1
Agent: Cl
Agent: [Zn]
Solvent: Cc1ccccc1
Solvent: O
Product: COc1ccc(CCCCCCc2ccc(OC)cc2)cc1
Reaction time: 8 h

Procedure:
With stirring, 212.2 g (0.65 mole) of 1,6-bis(4-methoxyphenyl)hexanedione in 500 ml of toluene are heated to 80° C. Then 520 g of amalgamated zinc filings as well as 150 ml of water and 500 ml of hydrochloric acid are added, whereupon evolution of H2 gas commences. After the evolution of gas has subsided, the reaction solution is gently refluxed overnight. After filtration, the aqueous phase which has been separated from the organic phase is extracted with 200 ml of toluene. The organic phases are combined and subjected to fractional distillation, affording 412.6 g (69.1% of theory) of almost colourless crystals of 1,6-bis(4-methoxyphenyl)hexane.
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([OH:9])=[C:4]([N+:10]([O-])=O)[CH:3]=1.O1CCCC1>[Pd].C(O)C>[CH3:8][C:7]1[C:2]([CH3:1])=[CH:3][C:4]([NH2:10])=[C:5]([OH:9])[CH:6]=1
Reactant: Cc1cc(O)c([N+](=O)[O-])cc1C
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CCO
Product: Cc1cc(N)c(O)cc1C
Reaction time: 5 h
Yield: 77 %

Procedure:
To 4,5-dimethyl-2-nitrophenol(11.7 g, 0.07 mol), tetrahydrofuran(100 ml) and ethanol(40 ml) were added, and 10% palladium/activated carbon(0.57 g) was added slowly, and then the mixture was hydrogenated for 5 hours. The reaction mixture was concentrated and chromatographed by the same way above to obtain the titled compound.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N+:8]([O-:10])=[O:9].[CH:11]([NH2:14])([CH3:13])[CH3:12]>CCO>[CH:11]([NH:14][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N+:8]([O-:10])=[O:9])([CH3:13])[CH3:12]
Reactant: O=[N+]([O-])c1ccccc1F
Reactant: CC(C)N
Solvent: CCO
Product: CC(C)Nc1ccccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 8 h
Yield: 93.1 %

Procedure:
To a solution of 1-fluoro-2-nitrobenzene (4.406 g, 31.22 mmol) in EtOH (32 mL) was added at 0° C. isopropyl amine (2.97 mL, 32.80 mmol). The mixture turned from light yellow to bright orange instantly. It was stirred overnight at RT. Another 1 eq of isopropyl amine (2.97 mL, 32.80 mmol) was added and after 3 h of stirring 2 eq of isopropyl amine were added (6 mL, 64 mmol) and the resulting solution was kept at room temperature overnight. The reaction mixture was concentrated and another equivalent of isopropyl amine was added (2.97 mL) following by EtOH (2 mL). For completion, the reaction was heated at 50° C. for 2 h. Mixture was evaporated to dryness and dissolved in EtOAc (25 mL) and the organic phase was washed with water (3*10 mL). Aqueous phase was re-extracted with EtOAc (10 mL) and the combined organics were washed with brine and dried over Na2SO4. The solvent was evaporated under reduced pressure to afford 5.24 g of N-isopropyl-2-nitrobenzenamine (Yield: 93%) as an orange liquid
Reaction SMILES: [CH:1]([C:12]1[NH:13][C:14]2[C:19]([CH:20]=1)=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11].[H][H]>C(O)C.[Pd]>[CH2:1]([C:12]1[NH:13][C:14]2[C:19]([CH:20]=1)=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11]
Reactant: [H][H]
Reactant: CCCCCCCCCC=Cc1cc2ccccc2[nH]1
Agent: [Pd]
Solvent: CCO
Product: CCCCCCCCCCCc1cc2ccccc2[nH]1

Procedure:
2-undec-1-enyl-1H-indole was dissolved in ethanol and 10% palladium on carbon was added to the solution. The reaction flask was sealed and exposed to hydrogen gas under pressure and was stirred until hydrogen consumption was completely stopped. The reaction mixture was filtered through celite. The solvent was evaporated to afford the desired product.
Reaction SMILES: [NH2:1][C:2]1[CH:18]=[CH:17][CH:16]=[CH:15][C:3]=1[C:4]([NH:6][C:7]1[CH:12]=[CH:11][C:10]([Cl:13])=[C:9]([Cl:14])[CH:8]=1)=[O:5].[CH2:19](OC(OCC)(OCC)C)[CH3:20]>O>[CH3:19][C:20]1[N:6]([C:7]2[CH:12]=[CH:11][C:10]([Cl:13])=[C:9]([Cl:14])[CH:8]=2)[C:4](=[O:5])[C:3]2[C:2](=[CH:18][CH:17]=[CH:16][CH:15]=2)[N:1]=1
Reactant: CCOC(C)(OCC)OCC
Reactant: Nc1ccccc1C(=O)Nc1ccc(Cl)c(Cl)c1
Solvent: O
Product: Cc1nc2ccccc2c(=O)n1-c1ccc(Cl)c(Cl)c1

Procedure:
A mixture of 62 (2.8 g, 0.009 mol) and 1,1,1-triethoxy-ethane (5.2 mL, 0.028 mol) were heated for 5 hours. The reaction mixture was poured into water, filtered, washed with water yielding compound 63 (55%). After recrystallization from EtOH, the material was used in next step without further purification.
Reaction SMILES: Br[C:2]1[C:3]([F:21])=[C:4]([F:20])[C:5]([NH:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[F:19])=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8].C(N(CC)C(C)C)(C)C.CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.[CH3:73][O:74][C:75]1[CH:80]=[CH:79][C:78]([CH2:81][SH:82])=[CH:77][CH:76]=1>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[F:20][C:4]1[C:5]([NH:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[F:19])=[C:6]([CH:11]=[C:2]([S:82][CH2:81][C:78]2[CH:79]=[CH:80][C:75]([O:74][CH3:73])=[CH:76][CH:77]=2)[C:3]=1[F:21])[C:7]([O:9][CH3:10])=[O:8]
Reactant: COc1ccc(CS)cc1
Reactant: COC(=O)c1cc(Br)c(F)c(F)c1Nc1ccccc1F
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: COC(=O)c1cc(SCc2ccc(OC)cc2)c(F)c(F)c1Nc1ccccc1F
Temperature: 100 °C
Reaction time: 8 h
Yield: 81.9 %

Procedure:
To a solution of methyl 5-bromo-3,4-difluoro-2-((2-fluorophenyl)amino)benzoate (12.85 g, 35.6 mmol) in anhydrous 1,4-dioxane (30 mL) was added N,N-diisopropylethylamine (9.21 g, 71.2 mmol). Then Pd2(dba)3 (1.63 g, 1.78 mmol) followed by Xantphos (2.06 g, 3.56 mmol) and 4-methoxy-α-toluenethiol (5.48 g, 35.6 mmol) was added under nitrogen atmosphere. The mixture was stirred overnight at 100° C. under N2 atmosphere and then allowed to cool to ambient temperature. The reaction was quenched with water (150 mL) and extracted with ethyl acetate (200 mL×3). The combined organic extract was washed with water (200 mL×3) and brine (200 mL) sequentially, dried over Na2SO4, filtered and concentrated. The crude product was purified by column chromatography on silica gel (petroleum ether/ethyl acetate, 50:1, v/v) to give the desired product (pale yellow solid, 12.64 g, 82% yield). 1H NMR (400 MHz, CDCl3): δ 9.12 (s, 1H), 7.78 (d, 1H), 7.06-7.44 (m, 6H), 6.82-6.88 (m, 2H), 4.03 (s, 2H), 3.90 (s, 3H), 3.80 (s, 3H).
Reaction SMILES: Cl[CH2:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][CH:11]=1)[C:6]([OH:8])=[O:7].[H-].[Na+].[CH2:14]([O:18]CC1C=CC(C(O)=O)=CC=1)[CH2:15][CH:16]=C>C(O)CC>[CH2:14]([O:18][CH2:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][CH:11]=1)[C:6]([OH:8])=[O:7])[CH2:15][CH3:16]
Reactant: C=CCCOCc1ccc(C(=O)O)cc1
Reactant: O=C(O)c1cccc(CCl)c1
Agent: [H-]
Agent: [Na+]
Solvent: CCCO
Product: CCCOCc1cccc(C(=O)O)c1

Procedure:
The reaction of propanol and 3-Chloromethyl-benzoic acid in the presence of sodium hydride was performed as described for Compound 33 to give 3-propoxymethyl-benzoic acid as white powder. 1H-NMR (400 MHz, d6-DMSO): 7.89 (m, 1 arom.H); 7.84 (m, 1 arom.H); 7.53 (m, 1 arom.H); 7.46 (m, 1 arom.H); 4.50 (s, OCH2C6H4—); 3.38 (t, CH3CH2CH2O); 1.54 (m, CH3CH2CH2O); 0.87 (t, CH3CH2CH2O). 13C-NMR (100 MHz, d6-DMSO): 167.25 (—C═O); 139.31; 131.63; 130.77; 128.51; 128.22; 128.01; 71.40; 71.16; 22.43; 10.56.
Reaction SMILES: [C:1]([OH:10])(=[O:9])[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[SH:4].[S:11]([CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23]Br)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[S:11]([CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][S:4][C:3]1[CH:5]=[CH:6][CH:7]=[CH:8][C:2]=1[C:1]([OH:10])=[O:9])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: BrCCCCCCSc1ccccc1
Reactant: O=C(O)c1ccccc1S
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=C(O)c1ccccc1SCCCCCCSc1ccccc1
Temperature: 100 °C

Procedure:
Thiosalicylic acid (1.2 g, 0.008 mole) and 6-thiophenoxyhexylbromide (2.5 g, 0.009 mole) are dissolved in dimethylformamide (50 ml) and the solution is stirred under argon. Potassium carbonate (1.5 g, 0.011 mole) is added carefully to the reaction. After the addition is complete the mixture is slowly warmed to 100° C. The solvents are evaporated, and the residue is dissolved in water, acidified with dilute hydrochloric acid, extracted with ethyl acetate, dried over anhydrous sodium sulfate, filtered, and evaporated. The residue is flash chromatographed on silica gel to give the desired product.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:17](/[CH:18]=[CH:19]/[C@H:20]3[O:25][C:24](=[O:26])[CH2:23][C@H:22]([OH:27])[CH2:21]3)=[C:16]([CH:28]([CH3:30])[CH3:29])[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:9]2=[O:31])=[CH:4][CH:3]=1>ClCCl.[Pd]>[F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:17]([CH2:18][CH2:19][C@H:20]3[O:25][C:24](=[O:26])[CH2:23][C@H:22]([OH:27])[CH2:21]3)=[C:16]([CH:28]([CH3:29])[CH3:30])[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:9]2=[O:31])=[CH:4][CH:3]=1
Reactant: CC(C)c1c(/C=C/[C@@H]2C[C@@H](O)CC(=O)O2)n(-c2ccc(F)cc2)c(=O)c2ccccc12
Agent: [Pd]
Solvent: ClCCl
Product: CC(C)c1c(CC[C@@H]2C[C@@H](O)CC(=O)O2)n(-c2ccc(F)cc2)c(=O)c2ccccc12

Procedure:
A solution of (4R,6S)-(E)-6-[2-{2-(4-fluorophenyl)-4-isopropyl-1-oxo-1,2-dihydroisoquinolin-3-yl}ethen-1-yl]-4-hydroxy-3,4,5,6-tetrahydro-2H-pyran-2-one (0.6 g) in dichloromethane (20 ml) was hydrogenated at atmospheric pressure over 5% palladium on charcoal catalyst for 36 hours. The mixture was diluted with dichloromethane (100 ml) and filtered through diatomaceous earth to remove the catalyst. The filtrate was evaporated to give a gum. The gum was purified by flash chromatography (silica, ethyl acetate as eluent) to give a white solid which was recrystallised from a mixture of cyclohexane and dichloromethane to give (4R,6R)-6-[2-{2-(4-fluorophenyl)-4-isopropyl-1-oxo-1,2-dihydroisoquinolin-3-yl}ethyl]-4-hydroxy-3,4,5,6-tetrahydro-2H-pyran-2-one as a white solid, m.p.192°-193° C. Found: C,70.7; H,6.15; N,3.24%. Required: C,70.9; H,6.15; N,3.31%. [NMR in CDCl3 /D2O, 1.20-1.88 (10H,m), 2.30-2.89 (4H,m), 3.46 (1H,sept,J=8 Hz), 4.26 (1H,m), 4.40 (1H,m), 7.24 (4H,m), 7.47 (1H,m), 7.69 (1H,m), 8.03 (1H,d,J=8 Hz), 8.44 (1H,m)].