Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([OH:8])[C:3]=1[NH:9][C:10](=[O:13])[O:11][CH3:12].CC#N.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.[Cl:29]N1C(=O)CCC1=O>C(Cl)(Cl)Cl>[Cl:29][C:7]1[C:2]([F:1])=[C:3]([NH:9][C:10](=[O:13])[O:11][CH3:12])[C:4]([OH:8])=[CH:5][CH:6]=1
Reactant: COC(=O)Nc1c(O)cccc1F
Reactant: O=C1CCC(=O)N1Cl
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: ClC(Cl)Cl
Solvent: O
Solvent: CC#N
Product: COC(=O)Nc1c(O)ccc(Cl)c1F
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 42.2 %

Procedure:
To a mixture of methyl (2-fluoro-6-hydroxyphenyl)carbamate (346 mg) and MeCN (30 mL) was added p-toluenesulfonic acid monohydrate (711 mg), followed by stirring at room temperature for 5 minutes. To the reaction mixture was added N-chlorosuccinimide (250 mg), followed by stirring at room temperature overnight. The reaction mixture was diluted with chloroform, and washed with a 10% aqueous sodium thiosulfate solution and brine in this order. The organic layer was dried over Na2SO4, and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: Hex/EtOAc=80/20-70/30) to obtain methyl (3-chloro-2-fluoro-6-hydroxyphenyl)carbamate (173 mg).
Reaction SMILES: [CH:1]([NH:3][CH:4]1[CH2:12][C:11]2[C:6](=[CH:7][CH:8]=[C:9]([CH2:13][C:14]([OH:16])=O)[CH:10]=2)[CH2:5]1)=[O:2].[NH2:17][CH2:18][CH2:19][CH2:20][C:21]([O:23][CH3:24])=[O:22]>>[CH:1]([NH:3][CH:4]1[CH2:12][C:11]2[C:6](=[CH:7][CH:8]=[C:9]([CH2:13][C:14]([NH:17][CH2:18][CH2:19][CH2:20][C:21]([O:23][CH3:24])=[O:22])=[O:16])[CH:10]=2)[CH2:5]1)=[O:2]
Reactant: O=CNC1Cc2ccc(CC(=O)O)cc2C1
Reactant: COC(=O)CCCN
Product: COC(=O)CCCNC(=O)Cc1ccc2c(c1)CC(NC=O)C2

Procedure:
In the same manner as described in Example 1-(1), (2-formylaminoindan-5-yl)acetic acid (2.20 g) and methyl γ-aminobutyrate are reacted to give methyl 4-[(2-formylaminoindan-5-yl)acetylamino]-n-butyrate (2.57 g).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:10])[CH2:4][CH2:5][C:6]([CH2:8][Cl:9])=[O:7].[CH2:11](O)[CH2:12]C>S(=O)(=O)(O)O>[CH2:1]([O:2][C:3](=[O:10])[CH2:4][CH2:5][C:6]([CH2:8][Cl:9])=[O:7])[CH2:11][CH3:12]
Reactant: COC(=O)CCC(=O)CCl
Reactant: CCCO
Agent: O=S(=O)(O)O
Product: CCCOC(=O)CCC(=O)CCl

Procedure:
To a solution of 5-chlorolevulinic acid methyl ester (10 g) in 1-propanol (50 ml) and concentrated sulfuric acid was added (0.5 ml) and the reaction mixture was refluxed for 3 h. Thereafter, the methanol and the excess 1-propanol were distilled in vacuo. Dichloromethane was added to the residue and the organic layer was washed with saturated aqueous sodium hydrogen carbonate and water. Drying of the organic layer with Na2SO4 followed by distillation of the solvent in vacuo yielded 5.4 g (quant.) 5-chlorolevulinic acid propyl ester. The NMR data agreed with the data for the product obtained according to Example 4.
Reaction SMILES: [F:1][C:2]1[CH:15]=[CH:14][C:5]([CH2:6][N:7]2[CH2:12][CH2:11][NH:10][CH2:9][C:8]2=[O:13])=[CH:4][CH:3]=1.[N:16]#[C:17]Br>C(Cl)Cl>[F:1][C:2]1[CH:15]=[CH:14][C:5]([CH2:6][N:7]2[CH2:12][CH2:11][N:10]([C:17]#[N:16])[CH2:9][C:8]2=[O:13])=[CH:4][CH:3]=1
Reactant: O=C1CNCCN1Cc1ccc(F)cc1
Reactant: N#CBr
Solvent: ClCCl
Product: N#CN1CCN(Cc2ccc(F)cc2)C(=O)C1

Procedure:
To 1-(4-Fluorobenzyl)piperazin-2-one (0.50 g, 2.40 mmol, Example 1, Step 4) dissolved in methylene chloride (75 mL) was added diisopropylethylaime (0.84 mL, 4.80 mmol) and cyanogen bromide (0.28 g, 2.64 mmol) and the resultant solution was stirred overnight at room temperature. The solvent was removed in vacuo and the residue was purified by flash chromatography on silica gel using a 0-5% MeOH/CHCl3 gradient. The pure fractions were concentrated to yield the title compound as a white solid. 1H NMR (400 MHz, d6 DMSO) δ 7.31 (m, 2H), 7.18 (m, 2H), 4.54 (s, 2H), 3.98 (s, 2H), 3.49 (m, 2H), and 3.33 (m, 2H); ES MS (M+1)=234.3.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([C:8]([O:10][CH3:11])=[O:9])[CH:5]=[C:4]([Br:12])[C:3]=1/[CH:13]=[CH:14]\[C:15]([OH:17])=O.C(Br)(=O)C(Br)=O.C(N(C(C)C)CC)(C)C.[Cl:33][C:34]1[CH:40]=[CH:39][CH:38]=[C:37]([Cl:41])[C:35]=1[NH2:36]>ClCCl.[Cl-].[Na+].O.CN(C)C=O>[Br:12][C:4]1[CH:5]=[C:6]([CH:7]=[C:2]([Br:1])[C:3]=1/[CH:13]=[CH:14]\[C:15]([NH:36][C:35]1[C:34]([Cl:33])=[CH:40][CH:39]=[CH:38][C:37]=1[Cl:41])=[O:17])[C:8]([O:10][CH3:11])=[O:9]
Reactant: Nc1c(Cl)cccc1Cl
Reactant: COC(=O)c1cc(Br)c(/C=C\C(=O)O)c(Br)c1
Agent: O=C(Br)C(=O)Br
Agent: [Cl-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)c1cc(Br)c(/C=C\C(=O)Nc2c(Cl)cccc2Cl)c(Br)c1
Temperature: 25 °C

Procedure:
To a solution of (2Z)-3-[2,6-dibromo-4-(methoxycarbonyl)phenyl]prop-2-enoic acid (1.24 g) (contaminated with 20% of the E isomer) in dichloromethane (34 mL) at 0° C. under nitrogen atmosphere was added oxalyl bromide (2 mL of a 2M solution in dichloromethane) followed by dimethylformamide (170 μL). The mixture was then warmed to rt and stirred until all gas evolution had ceased. The reaction was cooled again to 0° C. where diisopropylethylamine (83 μL) and 2,6-dichloroaniline (607 mg) were added and the reaction warmed to rt and stirred for 16 h. The reaction mixture was then poured into brine and extracted into ethyl acetate. A small amount of unreacted starting acid was removed by washing the organic layer with saturated sodium bicarbonate solution, before drying over MgSO4 and concentrating. The residue was purified by column chromatography on silica gel to give the title compound still contaminated with 20% of the E isomer. 1H NMR (500 MHz, CDCl3): δ 8.99 (br.s, 1H, Z isomer); 8.26 (br.s, 1H, E isomer); 8.20 (s, 1H, Z isomer); 7.80-6.40 (m, 6H); 3.96 (s, 3H, E isomer); 3.92 (s, 3H, Z isomer). Mass spectrum: m/z 507 (M+H).
Reaction SMILES: [CH:1]1([N:7]([CH:12]2[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]2)[C:8](=[O:11])[CH:9]=[CH2:10])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:18][C:19]([C:22]1[CH:27]=[C:26]([SH:28])[CH:25]=[C:24]([C:29]([CH3:32])([CH3:31])[CH3:30])[C:23]=1[OH:33])([CH3:21])[CH3:20].C(N(CC)CC)C>CO>[CH3:32][C:29]([C:24]1[CH:25]=[C:26]([S:28][CH2:10][CH2:9][C:8]([N:7]([CH:12]2[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]2)[CH:1]2[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]2)=[O:11])[CH:27]=[C:22]([C:19]([CH3:21])([CH3:20])[CH3:18])[C:23]=1[OH:33])([CH3:30])[CH3:31]
Reactant: C=CC(=O)N(C1CCCCC1)C1CCCCC1
Reactant: CC(C)(C)c1cc(S)cc(C(C)(C)C)c1O
Solvent: CO
Solvent: CCN(CC)CC
Product: CC(C)(C)c1cc(SCCC(=O)N(C2CCCCC2)C2CCCCC2)cc(C(C)(C)C)c1O

Procedure:
The title compound of Example 3 (1.9 g, 0.008 mole), 2,6-bis(1,1-dimethylethyl)-4-mercaptophenol(2 g, 0.008 mole) and triethylamine (0.5 ml) were stirred in methanol (25 ml) for about 12 hours. The solvent was removed in vacuo on a rotary evaporator, the crude material purified by chromatography on silica and recrystallized from hexane, m.p. ca. 168.5°-172° C. Analysis calc. for C29H47O2NS(473.76): Calc.: C, 73.52; H, 10.00; N, 2.96; S, 6.77. Found: C, 73.43; H, 10.24; N, 2.91; S, 6.91.
Reaction SMILES: [NH2:1][C:2]1[N:7]2[N:8]=[CH:9][C:10]([C:11]3[CH:12]=[N:13][C:14]4C([CH:20]=3)=CC=CC=4)=[C:6]2[N:5]=[C:4]([CH:21]2[CH2:26][CH2:25][N:24]([CH2:27][C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:23][CH2:22]2)[CH:3]=1.C[N:36]1C=C(C2C=NN3C(N)=CC(C4CCNCC4)=NC=23)C=N1.N1CCC(C2C=C(N)N3N=CC(C4C=NC5C(C=4)=CC=CC=5)=C3N=2)CC1>>[NH2:1][C:2]1[N:7]2[N:8]=[CH:9][C:10]([C:11]3[CH:20]=[N:36][N:13]([CH3:14])[CH:12]=3)=[C:6]2[N:5]=[C:4]([CH:21]2[CH2:26][CH2:25][N:24]([CH2:27][C:28]([O:30][C:31]([CH3:32])([CH3:34])[CH3:33])=[O:29])[CH2:23][CH2:22]2)[CH:3]=1
Reactant: CC(C)(C)OC(=O)CN1CCC(c2cc(N)n3ncc(-c4cnc5ccccc5c4)c3n2)CC1
Reactant: Cn1cc(-c2cnn3c(N)cc(C4CCNCC4)nc23)cn1
Agent: Nc1cc(C2CCNCC2)nc2c(-c3cnc4ccccc4c3)cnn12
Product: Cn1cc(-c2cnn3c(N)cc(C4CCN(CC(=O)OC(C)(C)C)CC4)nc23)cn1

Procedure:
tert-Butyl 2-(4-(7-amino-3-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidin-5-yl)piperidin-1-yl)acetate was synthesized in a manner similar to the synthesis of tert-butyl 2-(4-(7-amino-3-(quinolin-3-yl)pyrazolo[1,5-a]pyrimidin-5-yl)piperidin-1-yl)acetate, but with 3-(1-methyl-1H-pyrazol-4-yl)-5-(piperidin-4-yl)pyrazolo[1,5-a]pyrimidin-7-amine substituted for 5-(piperidin-4-yl)-3-(quinolin-3-yl)pyrazolo[1,5-a]pyrimidin-7-amine.
Reaction SMILES: O([C:8]([C:10]1[CH:19]=[C:18]([OH:20])[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]=1[OH:21])=[O:9])C1C=CC=CC=1.[CH2:22]([NH2:34])[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33]>C(#N)C>[CH2:22]([NH:34][C:8]([C:10]1[CH:19]=[C:18]([OH:20])[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]=1[OH:21])=[O:9])[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33]
Reactant: CCCCCCCCCCCCN
Reactant: O=C(Oc1ccccc1)c1cc(O)c2ccccc2c1O
Solvent: CC#N
Product: CCCCCCCCCCCCNC(=O)c1cc(O)c2ccccc2c1O

Procedure:
2-phenoxycarbonyl-1,4-dihydroxynaphthalene (28 g) was suspended in acetonitrile (150 ml) and laurylamine (22.2 g) was dropwise added. The resulting mixture was refluxed for 4 hours. After completion of the reaction, the reaction mixture was cooled and the produced crystals were filtered off. (Yield: 26.8 g)
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[C:17]([I:19])[CH:16]=[C:15]([Cl:20])[C:3]=1[C:4]([NH:6][C:7]1[C:12]([F:13])=[CH:11][N:10]=[CH:9][C:8]=1[F:14])=O.S(Cl)([Cl:23])=O>>[Cl:1][C:2]1[CH:18]=[C:17]([I:19])[CH:16]=[C:15]([Cl:20])[C:3]=1[C:4]([Cl:23])=[N:6][C:7]1[C:12]([F:13])=[CH:11][N:10]=[CH:9][C:8]=1[F:14]
Reactant: O=S(Cl)Cl
Reactant: O=C(Nc1c(F)cncc1F)c1c(Cl)cc(I)cc1Cl
Product: Fc1cncc(F)c1N=C(Cl)c1c(Cl)cc(I)cc1Cl
Temperature: 25 °C

Procedure:
A mixture of 2,6-dichloro-N-(3,5-difluoropyridin-4-yl)-4-iodobenzamide (21.3 g, 49.7 mmol) in thionyl chloride (118 mL) was heated under reflux for 20 hours under a nitrogen atmosphere. After cooling to room temperature, the volatiles were removed under reduced pressure and the resultant residue was azeotroped with toluene (×3) and dried under vacuum to afford the title compound as a brown solid (22.4 g, quantitative). LCMS (Method E): RT=4.69 min, m/z: 448 [M+H+].
Reaction SMILES: Cl[C:2]1[C:7]([NH:8][C:9]([NH:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[O:10])=[CH:6][CH:5]=[CH:4][N:3]=1.C(=O)([O-])[O-].[K+].[K+]>[Cu].CN(C)C=O>[C:12]1([N:11]2[C:2]3=[N:3][CH:4]=[CH:5][CH:6]=[C:7]3[NH:8][C:9]2=[O:10])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: O=C(Nc1ccccc1)Nc1cccnc1Cl
Agent: [Cu]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=c1[nH]c2cccnc2n1-c1ccccc1

Procedure:
A mixture of 5.7 g. (0.023 mole) of the product from Step A, 3.45 g. (0.025 mole) of potassium carbonate, 20 mg. of copper powder and 50 ml. of dimethyl formamide was refluxed for 21/2 hours. The cooled mixture was filtered and the solvent was evaporated in vacuo. The oily residue was extracted with 100 ml. of 1 N. sodium hydroxide solution and the extract was treated with decolorizing charcoal and filtered. The filtrate was neutralized with acetic acid. The crystalline precipitate of 600 mg. of 3-phenyl-1,3-dihydroimidazo[4,5-b]pyridin-2-one, m.p. 233°-235° C. was collected.
Reaction SMILES: [Mg].Br[CH2:3][CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[C:8]([O:14][CH3:15])[CH:7]=1.[Cl:16][C:17]1[CH:21]([O:22][Si:23]([C:26]([CH3:29])([CH3:28])[CH3:27])([CH3:25])[CH3:24])[CH2:20][C:19](=[O:30])[CH:18]=1.[Cl-].[NH4+]>O1CCCC1>[Si:23]([O:22][CH:21]1[CH2:20][C:19]([CH2:3][CH2:4][CH2:5][C:6]2[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[C:8]([O:14][CH3:15])[CH:7]=2)([OH:30])[CH:18]=[C:17]1[Cl:16])([C:26]([CH3:29])([CH3:28])[CH3:27])([CH3:25])[CH3:24]
Reactant: CC(C)(C)[Si](C)(C)OC1CC(=O)C=C1Cl
Reactant: COc1ccc(CCCBr)cc1OC
Agent: [Cl-]
Agent: [Mg]
Agent: [NH4+]
Solvent: C1CCOC1
Product: COc1ccc(CCCC2(O)C=C(Cl)C(O[Si](C)(C)C(C)(C)C)C2)cc1OC
Temperature: -78 °C
Reaction time: 1.5 h
Yield: 26.6 %

Procedure:
128 mg (5.3 mmoles) of magnesium was taken, and 4 ml of dry tetrahydrofuran was added. Then, a small amount of a solution of 1.37 g of 1-bromo-3-(3,4-dimethoxyphenyl)propane in 10 ml of dry tetrahydrofuran was added. The mixture was heated. After the initiation of the reaction, a solution of 1-bromo-3-(3,4-dimethoxyphenyl)propane in tetrahydrofuran was added little by little, and the solution was refluxed for 1.5 hours. The resulting reagent was cooled to -78° C., and a cooled solution of 1.305 g of 3-chloro-4-t-butyldimethylsilyloxy-2-cyclopentenone in dry tetrahydrofuran was added. The mixture was stirred at -78° C. for 1.5 hours. A saturated aqueous solution of ammonium chloride was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with a saturated aqueous solution of sodium chloride, and dried over anhydrous sodium sulfate. After filtration and concentration, the residue was chromatographed on a silica gel column to give 600 mg (yield 27%) of 4-t-butyldimethylsilyloxy-3-chloro-1-(3,4-dimethoxyphenylpropyl)-1-hydroxy-2-cyclopentene.
Reaction SMILES: [C:1]([OH:10])(=[O:9])[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[SH:4].N1C=CC=CC=1.[CH3:17][O:18][C:19]1[CH:27]=[CH:26][CH:25]=[CH:24][C:20]=1[C:21](Cl)=[O:22]>O1CCCC1.O.Cl>[CH3:17][O:18][C:19]1[CH:27]=[CH:26][CH:25]=[CH:24][C:20]=1[C:21]([S:4][C:3]1[CH:5]=[CH:6][CH:7]=[CH:8][C:2]=1[C:1]([OH:10])=[O:9])=[O:22]
Reactant: O=C(O)c1ccccc1S
Reactant: COc1ccccc1C(=O)Cl
Agent: Cl
Solvent: C1CCOC1
Solvent: c1ccncc1
Solvent: O
Product: COc1ccccc1C(=O)Sc1ccccc1C(=O)O
Yield: 80.2 %

Procedure:
Thiosalicylic acid (1.38 g, 9.0 mmol) was suspended in tetrahydrofuran (10 ml). While stirring under ice cooling, pyridine (1.77 g, 22 mmol) and then a tetrahydrofuran solution (5 ml) of 2-methoxybenzoyl chloride (1.68 g, 9.9 mmol) were dropwise added to the suspension. After the reaction mixture was stirred for 15 hours, the mixture was diluted with water and 6N hydrochloric acid was added thereto to make its liquid property acidic. The mixture was extracted (50 ml×2) with ethyl acetate. The extract was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was removed by distillation. The residue was recrystallized from tetrahydrofuran-isopropyl ether to give the title compound (2.08 g, 73%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]=[CH:9][CH2:10][OH:11])=[N:6][CH:7]=1.[CH2:12](N(CC)CC)[CH3:13].CS(Cl)(=O)=O>O1CCCC1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]=[CH:9][CH2:10][O:11][CH2:12][CH3:13])=[N:6][CH:7]=1
Reactant: OCC=Cc1ccc(Br)cn1
Reactant: CCN(CC)CC
Agent: CS(=O)(=O)Cl
Solvent: C1CCOC1
Product: CCOCC=Cc1ccc(Br)cn1
Reaction time: 0.42 h
Yield: 65 %

Procedure:
5-Bromo-2-(3-hydroxy-1-propenyl)pyridine (3.718 g) was dissolved in tetrahydrofuran (60 ml), followed by the sequential addition of triethylamine (7.1 ml) and methanesulfonyl chloride (1.6 ml) under ice-cooling, and the resulting mixture was stirred as it was, for 25 min. After the resulting insoluble matters were filtered off, the mixture was evaporated. The resulting residue was dissolved in ethanol (60 ml), followed by the addition of sodium ethoxide (1.388 g)/ethanol (25 ml) solution under ice-cooling, and the mixture was stirred at room temperature for 3.5 hr. The reaction mixture was evaporated, and the resulting residue was partitioned between ethyl acetate and water. The resulting organic layer was washed with water, dried (over MgSO4) and evaporated. The resulting residue was purified by silica gel column chromatography (ethyl acetate/hexane system), to give the title compound as a yellow oil (2.607 mg, yield; 65%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9]([C:11]2[C:16]([NH:17]C3C=NC=CC=3)=[CH:15][CH:14]=[C:13]([CH3:24])[N:12]=2)=[O:10])=[N:6][CH:7]=1.Br[C:26]1[CH:31]=[C:30]([F:32])[CH:29]=[C:28]([F:33])[CH:27]=1>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9]([C:11]2[C:16]([NH:17][C:26]3[CH:31]=[C:30]([F:32])[CH:29]=[C:28]([F:33])[CH:27]=3)=[CH:15][CH:14]=[C:13]([CH3:24])[N:12]=2)=[O:10])=[N:6][CH:7]=1
Reactant: Cc1ccc(Nc2cccnc2)c(C(=O)Nc2ccc(F)cn2)n1
Reactant: Fc1cc(F)cc(Br)c1
Product: Cc1ccc(Nc2cc(F)cc(F)c2)c(C(=O)Nc2ccc(F)cn2)n1

Procedure:
The title compound, was prepared from 3-Amino-6-methyl-pyridine-2-carboxylic acid (5-fluoro-pyridin-2-yl)-amide (example 8) in accordance with the general method of example 20 using 1-Bromo-3,5-difluorobenzene instead of 3-Bromo-4-methylpyridine to yield the final compound as an off-white crystalline solid, MS (ISP): m/e=358.9 (M+H+).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]([CH3:16])[C:9]1[C:10]([NH2:15])=[CH:11][CH:12]=[CH:13][CH:14]=1.I[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[N+:24]([O-:26])=[O:25].C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1.C([O-])([O-])=O.[Cs+].[Cs+]>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].C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]([CH3:16])[C:9]1[C:10]([NH:15][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[N+:24]([O-:26])=[O:25])=[CH:11][CH:12]=[CH:13][CH:14]=1
Reactant: CN(c1ccccc1N)c1ccccc1Cl
Reactant: O=[N+]([O-])c1ccccc1I
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Product: CN(c1ccccc1Cl)c1ccccc1Nc1ccccc1[N+](=O)[O-]
Reaction time: 30 h
Yield: 61.3 %

Procedure:
Compound 3 (0.842 g, 3.62 mmol), o-iodonitrobenzene (1.35 g, 5.43 mmol), Pd2(dba)3 (0.104 g, 5% mol), BINAP (0.170 g, 7.5%), Cs2CO3 (2.35 g, 7.42 mmol) and 12 mL of toluene were placed in a pressure tube. The mixture was purged with argon at room temperature for 15 min. The tube was sealed and placed in an oil bath at 80-90° C. for 30 h. When thin-layer chromatography (TLC) showed consumption of compound 3, the reaction mixture was filtered through silica gel with a 90:10 mixture of ethyl acetate:dichloromethane. The solvent was then removed under vacuum. The product was purified by column chromatography on silica gel using a 8:92 mixture of methyl chloride:petroleum ether as the eluent to afford the product as a red crystalline solid (0.785 g, 80% yield). 1H NMR (300 MHz, CDCl3) δ 9.03 (1H, bs), 8.07 (1H, dd, J=8.7, 1.5 Hz), 7.32-7.19 (4H, m), 7.12-6.99 (5H, m), 6.90 (1H, ddd, J=8.0, 6.9, 2.2 Hz), 6.68 (1H, ddd, J=8.4, 6.9, 1.2 Hz), 3.16 (3H, s); 13C (75 MHz, CDCl3) δ 147.2 (q), 145.1 (q), 142.4 (q), 135.2 (t), 131.6 (q), 130.7 (t), 129.5 (q), 127.4 (t), 126.5 (t), 126.5 (t), 126.0 (t), 124.8 (t), 124.0 (t), 123.2 (t), 121.7 (t), 117.0 (t), 115.8 (t), 40.6.
Reaction SMILES: [Si:1]([O:8][CH2:9][CH2:10][O:11][C:12]1[S:13][CH:14]=[CH:15][N:16]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[Li]CCCC.[CH3:22][O:23][C:24]([C:26]1[CH:27]2[N:42]([C:43]([O:45][C:46]([CH3:49])([CH3:48])[CH3:47])=[O:44])[CH:31]([CH2:32][C:33]=1OS(C(F)(F)F)(=O)=O)[CH2:30][N:29]([C:50]([O:52][C:53]([CH3:56])([CH3:55])[CH3:54])=[O:51])[CH2:28]2)=[O:25].CCOC(C)=O>C1COCC1.[NH4+].[Cl-].[Cl-].[Cl-].[Zn+2].C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:22][O:23][C:24]([C:26]1[CH:27]2[N:42]([C:43]([O:45][C:46]([CH3:49])([CH3:47])[CH3:48])=[O:44])[CH:31]([CH2:32][C:33]=1[C:14]1[S:13][C:12]([O:11][CH2:10][CH2:9][O:8][Si:1]([C:4]([CH3:7])([CH3:5])[CH3:6])([CH3:2])[CH3:3])=[N:16][CH:15]=1)[CH2:30][N:29]([C:50]([O:52][C:53]([CH3:56])([CH3:55])[CH3:54])=[O:51])[CH2:28]2)=[O:25]
Reactant: CC(C)(C)[Si](C)(C)OCCOc1nccs1
Reactant: COC(=O)C1=C(OS(=O)(=O)C(F)(F)F)CC2CN(C(=O)OC(C)(C)C)CC1N2C(=O)OC(C)(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cl-]
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COC(=O)C1=C(c2cnc(OCCO[Si](C)(C)C(C)(C)C)s2)CC2CN(C(=O)OC(C)(C)C)CC1N2C(=O)OC(C)(C)C
Temperature: -78 °C
Reaction time: 1 h
Yield: 99.2 %

Procedure:
A sol. of 2-[2-(tert-butyldimethylsilanyloxy)ethoxy]thiazole (3.75 g; 14.46 mmol) in THF (72 mL) was cooled to −78° C. BuLi (1.6M in hexane, 9.5 mL; 15.2 mmol) was added dropwise over 5 min. After completion of the addition, the resulting solution was stirred further at −78° C. for 1 h. ZnCl2 (1.0 M in THF; 16.7 mL, 16.7 mmol) was added dropwise over 5 min, and the reaction mixture was allowed to warm up to rt, and stirred for 1.5 h. A sol. of compound Y (3.84 g; 7.23 mmol) in THF (5 mL) was added, followed by Pd(PPh3)4 (0.25 g; 0.22 mmol). The resulting sol. was stirred at 50° C. for 45 min. The reaction mixture was cooled to rt, and EtOAc (80 mL) was added. The mixture was then poured in sat. aq. NH4Cl (150 mL). The phases were shaken, separated and the aq. phase was extracted with EtOAc (2×150 mL). The combined org. extracts were dried over MgSO4, filtered, and the solvents were removed under reduced pressure. Purification of the residue by FC (EtOAc/heptane 30/70) yielded the title compound (4.59 g, 99%). LC-MS: tR=1.20 min; ES+: 640.31.
Reaction SMILES: [Br:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([CH2:12][OH:13])=[CH:9][CH:10]=2)[C:5](=[O:14])[N:4]([CH:15]([CH3:17])[CH3:16])[N:3]=1.[H-].[Na+].[CH3:20]I>C1COCC1>[Br:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([CH2:12][O:13][CH3:20])=[CH:9][CH:10]=2)[C:5](=[O:14])[N:4]([CH:15]([CH3:17])[CH3:16])[N:3]=1
Reactant: CI
Reactant: CC(C)n1nc(Br)c2ccc(CO)cc2c1=O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COCc1ccc2c(Br)nn(C(C)C)c(=O)c2c1
Reaction time: 20 h
Yield: 69.5 %

Procedure:
4-Bromo-7-hydroxymethyl-2-isopropyl-2H-phthalazin-1-one (0.11 g, 0.37 mmol) was dissolved in THF (2 ml). To this was added NaH (60%, 0.019 g, 0.44 mmol) as a THF suspension (2 ml). To this was added methyl iodide (0.063 g, 0.48 mmol) and the reaction mixture was stirred for 20 hours. The reaction mixture was concentrated under vacuum and the residue was purified by flash column chromatography (elution: 80% heptane, 20% EtOAc) to give the title compound (0.08 g, 69% yield) as a white solid.
Reaction SMILES: [F:1][C:2]1[C:7]2[CH2:8][CH2:9][N:10]([C:13](=[O:18])[C:14]([F:17])([F:16])[F:15])[CH2:11][CH2:12][C:6]=2[C:5]([O:19]C)=[CH:4][CH:3]=1.B(Br)(Br)Br>C(Cl)Cl>[F:1][C:2]1[C:7]2[CH2:8][CH2:9][N:10]([C:13](=[O:18])[C:14]([F:16])([F:17])[F:15])[CH2:11][CH2:12][C:6]=2[C:5]([OH:19])=[CH:4][CH:3]=1
Reactant: COc1ccc(F)c2c1CCN(C(=O)C(F)(F)F)CC2
Agent: BrB(Br)Br
Solvent: ClCCl
Product: O=C(N1CCc2c(O)ccc(F)c2CC1)C(F)(F)F
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 99 %

Procedure:
Dissolve 9-fluoro-6-methoxy-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine (8.1 g, 27.7 mmol) in DCM (250 mL), cool to 0° C. and add boron tribromide (5.24 mL, 55.5 mmol). Stir at ambient temperature for 1.5 h, wash the mixture with brine, dry the organic layer over Na2SO4 and concentrate in vacuo to obtain the desired intermediate (7.6 g, 99%). MS (ES+) m/z: 278 (M+H)+.
Reaction SMILES: [F:1][C:2]1[C:3]([OH:12])=[C:4]([CH:8]=[CH:9][C:10]=1[F:11])[C:5](O)=[O:6].S(C)C.CO>C1COCC1>[F:1][C:2]1[C:10]([F:11])=[CH:9][CH:8]=[C:4]([CH2:5][OH:6])[C:3]=1[OH:12]
Reactant: O=C(O)c1ccc(F)c(F)c1O
Solvent: C1CCOC1
Solvent: CO
Solvent: CSC
Product: OCc1ccc(F)c(F)c1O
Temperature: 25 °C
Reaction time: 3 h
Yield: 91.7 %

Procedure:
To a solution of 3,4-difluoro-2-hydroxy benzoic acid (3.2 g 18.39 mmol) in THF (20 mL) was added BH3.Me2S (7 mL 73.56 mmol) drop wise, over a period of 20 min. at RT. The reaction mixture was stirred at RT for 3 h and monitored by TLC. Methanol (20 mL) was added and the solvent was removed under vacuum. The crude compound was purified by column chromatography over silica gel using a mixture of ethyl acetate and hexane (20:80) as eluent to give the alcohol (2.7 g, 91% yield) MS: m/z 159 (M+1).