Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: ClCCl.[Cl:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[CH2:11][NH:12][C:13](=[O:15])[CH3:14].[C:16](Cl)(=[O:18])[CH3:17].[Cl-].[Al+3].[Cl-].[Cl-]>O>[C:16]([C:8]1[CH:9]=[CH:10][C:5]([Cl:4])=[C:6]([CH2:11][NH:12][C:13](=[O:15])[CH3:14])[CH:7]=1)(=[O:18])[CH3:17]
Reactant: CC(=O)NCc1ccccc1Cl
Reactant: CC(=O)Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: O
Solvent: ClCCl
Product: CC(=O)NCc1cc(C(C)=O)ccc1Cl
Reaction time: 2 h

Procedure:
To 169.9 kg of the dichloromethane solution of N-[(2-chlorophenyl)methyl]acetamide obtained in Example 3-(A), 47.1 kg (0.6 moles) of acetyl chloride was added and 108.0 kg (0.81 kmoles) of aluminum chloride was added at 15 to 30° C. over 1.5 hours. After dichloromethane was distilled off was distilled off under normal pressure until the temperature reaches 50° C. over 2 hours, the mixture was aged for 6 hours (objective product: other position isomers=76.75%:1.65%; GC area %). After the completion of the reaction, the resulting solution was added dropwise to 450 kg of water at 15 to 35° C. over 2 hours. The solution was extracted twice with 90 kg of dichloromethane and 40 kg of dichloromethane to obtain 199.8 kg of a dichloromethane solution of N-[(5-acetyl-2-chlorophenyl)methyl]acetamide.
Reaction SMILES: [Br:1]Br.Cl.[F:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:20]=[C:19]3[C:14]([CH:15]=[CH:16][CH:17]=[N:18]3)=[CH:13][CH:12]=2)=[CH:7][CH:6]=1>[N+](C1C=CC=CC=1)([O-])=O.C1(C)C=CC=CC=1>[Br:1][C:16]1[CH:17]=[N:18][C:19]2[C:14]([CH:15]=1)=[CH:13][CH:12]=[C:11]([C:8]1[CH:9]=[CH:10][C:5]([F:4])=[CH:6][CH:7]=1)[CH:20]=2
Reactant: Fc1ccc(-c2ccc3cccnc3c2)cc1
Reactant: BrBr
Agent: Cl
Solvent: O=[N+]([O-])c1ccccc1
Solvent: Cc1ccccc1
Product: Fc1ccc(-c2ccc3cc(Br)cnc3c2)cc1
Temperature: 140 °C
Reaction time: 6 h
Yield: 57.8 %

Procedure:
A solution of bromine (0.9 mL, 17.6 mmol) in nitrobenzene (2.5 mL) was added dropwise over 15 minutes to a thick slurry of 7-(4-fluorophenyl)quinoline hydrochloride (3.80 g, 14.6 mmol) in nitrobenzene (7.5 mL) at 140° C. (oil bath temperature). The resulting mixture was stirred at 140° C. for 6 hours, allowed to cool to ca. 80° C., diluted with toluene (30 mL) and then cooled to room temperature. The orange solid was collected under suction and washed with toluene followed by diethyl ether. The solid was suspended in water (100 mL), the mixture basified with aqueous sodium carbonate and extracted with dichloromethane (2×50 mL). The combined extracts were dried (MgSO4) and evaporated to give a yellow solid. This was purified by flash chromatography, eluting with 2:1 dichloromethane/isohexane, dichloromethane then 5% ethyl acetate/dichloromethane, to afford 3-bromo-7-(4-fluorophenyl)quinoline as an off-white solid (2.55 g, 58%). 1H NMR (500 MHz, CDCl3) δ 8.93 (1H, d, J 2.2 Hz), 8.33 (1H, d, J 2.1 Hz), 8.24 (1H, s), 7.82-7.78 (2H, m), 7.71-7.69 (2H, m), 7.20 (2H, t, J 8.6 Hz).
Reaction SMILES: Br[CH2:2][C:3]1[CH:10]=[CH:9][CH:8]=[CH:7][C:4]=1[C:5]#[N:6].[N-:11]=[N+:12]=[N-:13].[Na+].C(OCC)(=O)C>CN(C)C=O>[N:11]([CH2:2][C:3]1[CH:10]=[CH:9][CH:8]=[CH:7][C:4]=1[C:5]#[N:6])=[N+:12]=[N-:13]
Reactant: N#Cc1ccccc1CBr
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: N#Cc1ccccc1CN=[N+]=[N-]

Procedure:
A solution of 2-bromomethyl-benzonitrile (1.0 g, 5.1 mmol) and sodium azide (0.40 g, 6.1 mmol) in dimethylformamide (10 ml) was stirred at room temperature for 2 h. Ethyl acetate was added and the reaction mixture was washed with water and brine. Drying and solvent evaporation gave 2-azidomethyl-benzonitrile; 1H NMR (CDCl3, 400 MHz) δ7.71 (d, 1H, J=7.7 Hz), 7.64 (m, 1H), 7.53 (d, 1H, J=7.8 Hz), 7.47 (t, 1H, J=7.6 Hz), 4.62 (s, 2H).
Reaction SMILES: [N:1]1[S:5][N:4]=[C:3]2[C:6]([S:10]([NH:13][C:14]3[CH:22]=[C:21]([Cl:23])[CH:20]=[CH:19][C:15]=3[C:16](O)=[O:17])(=[O:12])=[O:11])=[CH:7][CH:8]=[CH:9][C:2]=12.Cl.C[O:26][C:27](=[O:39])[C@H:28]([NH2:38])[CH2:29][C:30]1[CH:35]=[CH:34][C:33]([Cl:36])=[C:32]([Cl:37])[CH:31]=1>>[N:1]1[S:5][N:4]=[C:3]2[C:6]([S:10]([NH:13][C:14]3[CH:22]=[C:21]([Cl:23])[CH:20]=[CH:19][C:15]=3[C:16]([NH:38][C@H:28]([CH2:29][C:30]3[CH:35]=[CH:34][C:33]([Cl:36])=[C:32]([Cl:37])[CH:31]=3)[C:27]([OH:26])=[O:39])=[O:17])(=[O:12])=[O:11])=[CH:7][CH:8]=[CH:9][C:2]=12
Reactant: O=C(O)c1ccc(Cl)cc1NS(=O)(=O)c1cccc2nsnc12
Reactant: COC(=O)[C@H](N)Cc1ccc(Cl)c(Cl)c1
Agent: Cl
Product: O=C(N[C@H](Cc1ccc(Cl)c(Cl)c1)C(=O)O)c1ccc(Cl)cc1NS(=O)(=O)c1cccc2nsnc12

Procedure:
2-(Benzo[1,2,5]thiadiazole-4-sulfonylamino)-4-chloro-benzoic acid was coupled to (R)-2-amino-3-(3,4-dichloro-phenyl)-propionic acid methyl ester hydrochloride as in EXAMPLE 1, Part C. The resulting methyl ester was hydrolyzed as in EXAMPLE 2, Part E, to afford the title compound. HPLC: RT=10.97 min. MS (ESI−): mass calcd. for C22H15Cl3N4O5S2, 585.87; m/z found, 583/585 [M−H]−. 1H NMR (500 MHz, CDCl3): 11.36 (s, 1H), 8.36 (dd, J=7.0, 0.8, 1H), 8.21 (dd, J=8.8, 0.6, 1H), 7.74-7.70 (m, 2H), 7.34 (d, J=8.2, 1H), 7.21 (d, J=1.9, 1H), 7.15 (d, J=8.4, 1H), 6.97 (dd, J=8.2, 2.0, 1H), 6.93 (dd, J=8.4, 2.0, 1H), 6.44 (d, J=7.0, 1H), 4.98 (q, J=5.7, 1H), 3.32-3.15 (m, 2H).
Reaction SMILES: CN(C)/[N:3]=[CH:4]/[C:5]([CH3:7])=[CH2:6].C(OC(=O)C)(=O)C.Br[C:17]1[C:18](=[O:25])[CH:19]=[C:20]([CH3:24])[C:21](=[O:23])[CH:22]=1>CC#N>[CH3:7][C:5]1[CH:4]=[N:3][C:22]2[C:21](=[O:23])[C:20]([CH3:24])=[CH:19][C:18](=[O:25])[C:17]=2[CH:6]=1
Reactant: CC1=CC(=O)C(Br)=CC1=O
Reactant: C=C(C)/C=N/N(C)C
Solvent: CC(=O)OC(C)=O
Solvent: CC#N
Product: CC1=CC(=O)c2cc(C)cnc2C1=O
Temperature: 25 °C

Procedure:
(E)-1,1-dimethyl-2-(2-methylallylidene)hydrazine (2.18 g, 19.50 mmol, 1.3 equiv.) and acetic anhydride (19.15 mL) were added in 250 mL of MeCN and stirred at room temperature. 2-bromo-5-methylcyclohexa-2,5-diene-1,4-dione (3 g, 14.9 mmol, 1 equiv.) in 125 mL of MeCN was then added dropwise (slowly during 60 min). The reaction mixture was stirred at room temperature during 120 minutes.
Reaction SMILES: [Br:1][CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([CH2:11][OH:12])=[CH:7][C:6]=1[CH3:13])=[O:4].O[CH:15](C1C=CC(C(=O)C)=C(C)C=1)C>>[Br:1][CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([CH:11]([OH:12])[CH3:15])=[CH:7][C:6]=1[CH3:13])=[O:4]
Reactant: CC(=O)c1ccc(C(C)O)cc1C
Reactant: Cc1cc(CO)ccc1C(=O)CBr
Product: Cc1cc(C(C)O)ccc1C(=O)CBr
Yield: 82 %

Procedure:
2-Bromo-1-[4-(1-hydroxy-ethyl)-2-methyl-phenyl]ethanone is prepared following preparation 1b employing 1-[4-(1-hydroxy-ethyl)-2-methyl-phenyl]-ethanone instead of 1-(4-hydroxymethyl-2-methyl-phenyl)-ethanone.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([CH3:12])[CH:8]=[C:7]2Cl.[Cl:14][C:15]1[CH:16]=[C:17]([CH:20]=[CH:21][C:22]=1[Cl:23])[CH2:18][NH2:19].O>CS(C)=O>[Br:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([CH3:12])[CH:8]=[C:7]2[NH:19][CH2:18][C:17]1[CH:20]=[CH:21][C:22]([Cl:23])=[C:15]([Cl:14])[CH:16]=1
Reactant: Cc1cc(Cl)c2cccc(Br)c2n1
Reactant: NCc1ccc(Cl)c(Cl)c1
Solvent: CS(C)=O
Solvent: O
Product: Cc1cc(NCc2ccc(Cl)c(Cl)c2)c2cccc(Br)c2n1
Yield: 20.2 %

Procedure:
8-Bromo-4-chloro-2-methylquinoline (4.50 g, 17.5 mmole) and 3,4-dichlorobenzylamine (6.30 g, 35.8 mmole) in dimethylsulfoxide (6 mL) were stirred at 140° C. for 2 h in a microwave oven. Water was added and the mixture was decanted to obtain an oily residue. The residue was washed with ethyl acetate to give a white solid (1.40 g, 20%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:13](=[O:14])[CH:12]=[CH:11][C:10]([C:15](O)=[O:16])=[CH:9]2)=[CH:4][CH:3]=1.CCN(CC)CC.ClC(OCC)=O.[BH4-].[Na+]>C1COCC1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:9]=[C:10]([CH2:15][OH:16])[CH:11]=[CH:12][C:13]2=[O:14])=[CH:4][CH:3]=1
Reactant: O=C(O)c1ccc(=O)n(-c2ccc(F)cc2)c1
Agent: CCOC(=O)Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=c1ccc(CO)cn1-c1ccc(F)cc1
Temperature: -10 °C
Reaction time: 0.75 h

Procedure:
A 100 mL round-bottomed flask was charged with 1-(4-fluorophenyl)-6-oxo-1,6-dihydropyridine-3-carboxylic acid (1.8 g, 7.7 mmol) and 20 mL of THF. After cooling to −10° C., NEt3 (1.2 mL, 8.9 mmol) and ethyl chloroformate (0.84 mL, 8.5 mmol) were added. This mixture was stirred at that temp for 45 min, then an aq soln of NaBH4 (0.58 g, 15 mmol, in 10 mL of water) was added. After stirring for 3 h at −10° C., an additional 2 equiv of NaBH4 (solid) were added. The reaction was quenched with aq 1N HCl (50 mL) and extracted with CH2Cl2 (3×75 mL). The residue was purified by MPLC to give 1-(4-fluorophenyl)-5-(hydroxymethyl)pyridin-2(1H)-one.
Reaction SMILES: [C:1]([C:5]1[CH:15]=[C:8]2[N:9]=[CH:10][C:11]([C:13]#[CH:14])=[CH:12][N:7]2[N:6]=1)([CH3:4])([CH3:3])[CH3:2].[Cl:16][C:17]1[CH:22]=[CH:21][C:20](I)=[CH:19][N:18]=1>>[C:1]([C:5]1[CH:15]=[C:8]2[N:9]=[CH:10][C:11]([C:13]#[C:14][C:20]3[CH:19]=[N:18][C:17]([Cl:16])=[CH:22][CH:21]=3)=[CH:12][N:7]2[N:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: C#Cc1cnc2cc(C(C)(C)C)nn2c1
Reactant: Clc1ccc(I)cn1
Product: CC(C)(C)c1cc2ncc(C#Cc3ccc(Cl)nc3)cn2n1

Procedure:
The title compound, light yellow solid, MS: m/e=311.3 (M+H+), can be prepared in accordance with the general method of example 1 from 2-tert-butyl-6-ethynyl-pyrazolo[1,5-a]pyrimidine (example 21, step 2) and 2-chloro-5-iodopyridine.
Reaction SMILES: [CH:1]1[C:14]2[C:5](=[CH:6][C:7]3[C:12]([C:13]=2[CH:15]=[O:16])=[CH:11][CH:10]=[CH:9][CH:8]=3)[CH:4]=[CH:3][CH:2]=1.[C:17]([C:20]1[C:21]2[C:26]([CH:27]=[C:28]3[C:33]=1[CH:32]=[CH:31][CH:30]=[CH:29]3)=[CH:25][CH:24]=[CH:23][CH:22]=2)(=O)[CH3:18].CO[Na].CO>CN(C=O)C>[CH:11]1[C:12]2[C:7](=[CH:6][C:5]3[C:14]([C:13]=2[C:15](=[O:16])[CH:18]=[CH:17][C:20]2[C:33]4[C:28]([CH:27]=[C:26]5[C:21]=2[CH:22]=[CH:23][CH:24]=[CH:25]5)=[CH:29][CH:30]=[CH:31][CH:32]=4)=[CH:1][CH:2]=[CH:3][CH:4]=3)[CH:8]=[CH:9][CH:10]=1
Reactant: CC(=O)c1c2ccccc2cc2ccccc12
Reactant: O=Cc1c2ccccc2cc2ccccc12
Agent: CO[Na]
Solvent: CN(C)C=O
Solvent: CO
Product: O=C(C=Cc1c2ccccc2cc2ccccc12)c1c2ccccc2cc2ccccc12
Reaction time: 8 h
Yield: 91.3 %

Procedure:
9-anthraldehyde (10 mmol, 2.06 g) and 9-acetylanthracene (10 mmol, 2.2 g) were combined in dry DMF under N2 and MeONa (28 mmol, 1.5 g) was added. The reaction mixture is stirred overnight. Then MeOH was added (60 mL) and the precipitate was filtered off and vacuum dried to afford 3.73 g of pure 1,3-di(anthracene-9-yl)-2-propene-1-one. Portion of it (2.5 mmol, 1 g) was suspended in a mixture of dioxane and MeOH (60 mL and 20 mL respectively) and heated to 75° C. at which point sodium borohydride (5.3 mmol, 200 mg) was added. The mixture was stirred for 5 min and 50 mL of water was added. After the mixture had cooled to ambient, the solids were filtered off, washed with water and vacuum dried affording 620 mg of the title product.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[CH:9][CH:8]=[CH:7][C:4]=1[CH2:5][OH:6].[H-].[Na+].[F:13][C:14]1[CH:21]=[CH:20][CH:19]=[C:18](F)[C:15]=1[C:16]#[N:17]>CN(C)C=O>[F:13][C:14]1[CH:21]=[CH:20][C:19]([O:6][CH2:5][C:4]2[CH:7]=[CH:8][CH:9]=[CH:10][C:3]=2[O:2][CH3:1])=[CH:18][C:15]=1[C:16]#[N:17]
Reactant: COc1ccccc1CO
Reactant: N#Cc1c(F)cccc1F
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccccc1COc1ccc(F)c(C#N)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 83.7 %

Procedure:
To a solution of 2-methoxybenzyl alcohol (1.0 g, 7.2 mmol) in dimethylformamide was added to a cooled (0° C.) slurry of sodium hydride (0.32 g, 7.91 mmol) in dimethylformamide under nitrogen atmosphere. The reaction mixture was slowly warmed to room temperature, stirred for 1 hour. Again, cooled (0° C.), then a solution of 2,6-difluorobenzonitrile (1.0 g, 7.2 mmol) in dimethylfomamide was added, stirred overnight at room temperature. The reaction mixture was poured on crushed ice-water, stirred, filtered and dried to afford 1.55 g of 2-fluoro-5-(2-methoxybenzyloxy)benzonitrile.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([OH:35])[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][CH:16]=[C:17]3[C:23]4[CH:24]=[CH:25][CH:26]=[N:27][C:22]=4[CH2:21][O:20][C:19]4[CH:28]=[CH:29][C:30]([OH:32])=[CH:31][C:18]3=4)[CH2:10][C:9]2([CH3:34])[CH3:33])=[CH:4][CH:3]=1.[H-].[Na+].Cl.Cl[CH2:40][CH2:41][N:42]1[CH2:47][CH2:46][O:45][CH2:44][CH2:43]1>CN(C=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([OH:35])[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][CH:16]=[C:17]3[C:23]4[CH:24]=[CH:25][CH:26]=[N:27][C:22]=4[CH2:21][O:20][C:19]4[CH:28]=[CH:29][C:30]([O:32][CH2:40][CH2:41][N:42]5[CH2:47][CH2:46][O:45][CH2:44][CH2:43]5)=[CH:31][C:18]3=4)[CH2:10][C:9]2([CH3:33])[CH3:34])=[CH:4][CH:3]=1
Reactant: ClCCN1CCOCC1
Reactant: CC1(C)CN(CCC=C2c3cc(O)ccc3OCc3ncccc32)CCC1(O)c1ccc(Cl)cc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC1(C)CN(CCC=C2c3cc(OCCN4CCOCC4)ccc3OCc3ncccc32)CCC1(O)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 29.6 %

Procedure:
To a solution of 5-{3-[4-(4-chloro-phenyl)-4-hydroxy-3,3-dimethyl-piperidin-1-yl]-propylidene}-5,11-dihydro-10-oxa-1-aza-dibenzo[a,d]cyclohepten-7-ol (0.15 g, 0.28 mmol) in DMF (1.5 mL) was added NaH (0.034 g, 0.84 mmol) and stirred for 20 min. at room temperature. 4-(2-Chloro-ethyl)-morpholine HCl (0.063 g, 0.34 mmol) was added and the solution was heated to 50° C. for 16 h. The reaction was quenched with water and extracted with ethyl acetate (3×). The organics were combined, dried over Mg2SO4, filtered and concentrated, then purified by Biotage flash chromatography (5-10% methanol/dichloromethane) to yield the title compound (0.050 g). 1H-NMR (MeOD) δ: 0.73 (3H, s), 0.85 (3H, s), 2.39-2.90 (11H, m), 3.29-3.31 (3H, m), 3.69-3.72 (4H, m), 4.1 (2H, t), 5.20 (2H, br s), 6.18 (1H, t), 6.74-6.79 (2H, m), 6.89 (1H, d), 7.27-7.30 (2H, m), 7.43-7.47 (3H, m), 7.79 (1H, dd), 8.46 (1H, dd). ESI-MS m/z: 604 (M), UV retention time: 1.20 min.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH2:20][C:21](O)=[O:22])[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:19]=[CH:18][C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[N:11]=1.[CH3:24][S:25]([NH2:28])(=[O:27])=[O:26].Cl.C(N=C=NCCCN(C)C)C.CN(C1C=CC=CN=1)C>>[Br:1][C:2]1[CH:3]=[C:4]([CH2:20][C:21]([CH2:24][S:25]([NH2:28])(=[O:27])=[O:26])=[O:22])[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:19]=[CH:18][C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[N:11]=1
Reactant: CS(N)(=O)=O
Reactant: O=C(O)Cc1ccc(OCc2ccc3ccccc3n2)c(Br)c1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccccn1
Agent: Cl
Product: NS(=O)(=O)CC(=O)Cc1ccc(OCc2ccc3ccccc3n2)c(Br)c1

Procedure:
In anology to the procedure of Example XVI, the title compound is prepared from 2.8 g (7.5 mmol) of the compound from Example XXI, 0.71 g (7.5 mmol) of dried methanesulphonamide, 1.44 g (7.5 mmol) of N-ethyl-N'-dimethylaminopropylcarbodiimide hydrochloride and 0.92 g (7.5 mmol) of dimethylaminopyridine.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][CH2:6][O:7][C:8]1[CH:9]=[C:10](I)[CH:11]=[CH:12][CH:13]=1.N1CCCCC1.[CH3:21][Si:22]([C:25]#[CH:26])([CH3:24])[CH3:23]>C1COCC1.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>[CH3:1][O:2][CH2:3][CH2:4][O:5][CH2:6][O:7][C:8]1[CH:9]=[C:10]([C:26]#[C:25][Si:22]([CH3:24])([CH3:23])[CH3:21])[CH:11]=[CH:12][CH:13]=1
Reactant: C#C[Si](C)(C)C
Reactant: COCCOCOc1cccc(I)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: C1CCNCC1
Product: COCCOCOc1cccc(C#C[Si](C)(C)C)c1
Reaction time: 2 h

Procedure:
3-(2-Methoxy-ethoxymethoxy)-phenyliodide (12.1 g, 39 mmol, 96) and tetrakis(triphenylphosphine)palladium (1.2 g, 1.0 mmol) and cuprous iodide (0.096 g, 0.5 mmol) are dissolved in THF (120 mL) and to this is added piperidine (12 mL) and (trimethylsilyl)acetylene (8 mL, 57 mmol). This mixture is degassed and is then stirred for 2 hours. The reaction is then diluted with ether and washed twice with water and brine and the organic layer dried over magnesium sulfate. The solvent is removed in vacuo to give the title compound. MS (EI) 206 (M)+.
Reaction SMILES: [CH3:1][S:2][CH2:3][S:4](=[O:6])[CH3:5].O1[CH2:11][CH2:10][CH2:9][CH2:8]1.C([Li])CCC.BrCCC(Br)C>C(Cl)Cl.CCCCCC>[CH3:1][S:2][C:3]1([S:4](=[O:6])[CH3:5])[CH2:11][CH2:10][CH:9]1[CH3:8]
Reactant: C1CCOC1
Reactant: CSCS(C)=O
Agent: CC(Br)CCBr
Agent: [Li]CCCC
Solvent: ClCCl
Solvent: CCCCCC
Product: CSC1(S(C)=O)CCC1C
Reaction time: 1.33 h

Procedure:
Formaldehyde dimethyl mercaptal S-oxide (1.571 g) was dissolved in 15 ml. of tetrahydrofuran, and 8.9 ml. of an n-hexane solution of n-butyl lithium (1.4 millimols/milliliter) was added at -10° C. The mixture was stirred for 80 minutes, and then at -70° C., 1.125 g of 1,3-dibromobutane was added, and the mixture was stirred for 46.5 hours at room temperature. Methylene chloride (100 ml) was added. The mixture was washed with water and dried with anhydrous magnesium sulfate. It was concentrated at reduced pressure, and the residue was separated by column chromatography (Florisil, eluted with methylene chloride) to afford 746 mg of 2-methylcyclobutanone dimethyl mercaptal S-oxide. The product was oxidized with hydrogen peroxide and Na2WO4 to form its disulfone derivative.
Reaction SMILES: [H-].[Na+].C([O:5][C:6](=[O:33])[C:7]([CH3:32])([O:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[CH2:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][CH2:17][CH:18]2[CH2:22][NH:21][C:20](=[O:23])[N:19]2[CH3:24])=[CH:11][CH:10]=1)C.[F:34][C:35]([F:46])([F:45])[O:36][C:37]1[CH:44]=[CH:43][C:40]([CH2:41]Br)=[CH:39][CH:38]=1>CN(C=O)C>[CH3:32][C:7]([O:25][C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1)([CH2:8][C:9]1[CH:10]=[CH:11][C:12]([O:15][CH2:16][CH2:17][CH:18]2[CH2:22][N:21]([CH2:41][C:40]3[CH:43]=[CH:44][C:37]([O:36][C:35]([F:34])([F:45])[F:46])=[CH:38][CH:39]=3)[C:20](=[O:23])[N:19]2[CH3:24])=[CH:13][CH:14]=1)[C:6]([OH:5])=[O:33]
Reactant: CCOC(=O)C(C)(Cc1ccc(OCCC2CNC(=O)N2C)cc1)Oc1ccccc1
Reactant: FC(F)(F)Oc1ccc(CBr)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN1C(=O)N(Cc2ccc(OC(F)(F)F)cc2)CC1CCOc1ccc(CC(C)(Oc2ccccc2)C(=O)O)cc1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 32 %

Procedure:
NaH (8.8 mg, 0.22 mmol, 60% w/w in mineral oil) is added to a cooled (0° C.) solution of 2-Methyl-3-{4-[2-(3-methyl-2-oxo-imidazolidin-4-yl)-ethoxy]-phenyl}-2-phenoxy-propionic acid ethyl ester (78.5 mg, 0.18 mmol) in DMF (1 ml). After 5 minutes, the reaction mixture is removed from the cooling bath and stirred while warming to ambient temperature over one hour. After the solution is cooled again to 0° C., 4-(trifluoromethoxy)benzyl bromide (59 ul, 0.37 mmol) is added in a single portion, the cooling bath removed, and the mixture stirred for one hour. The reaction mixture is quenched with 1N HCl and extracted with ethyl acetate (2×). The organic extracts were washed with water, brine, dried (Na2SO4), and concentrated to an oil. The crude product is dissolved in methanol (5 ml), treated with 5N NaOH (0.5 ml), and stirred for 14 hours at ambient temperature. After concentration to remove methanol, the residue is partitioned between diethyl ether and water. The aqueous layer is adjusted to pH 2 with conc. HCl, then extracted with ethyl acetate (2×15 ml). The combined ethyl acetate extracts were washed with water, brine, dried (Na2SO4), and concentrated to an oil which is purified by MS/LC to yield an oil (33 mg, 31%).
Reaction SMILES: [H-].[Na+].[CH2:3]([OH:10])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[Br:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16]Br.O>CN(C)C=O>[CH2:3]([O:10][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][Br:11])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: OCc1ccccc1
Reactant: BrCCCCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: BrCCCCCOCc1ccccc1
Yield: 100.9 %

Procedure:
60% Sodium hydride (1.33 g) was suspended in dimethylformamide (40 ml), and benzyl alcohol (3 g) was added under ice-cooilng with stirring. The mixture was stirred at room temperature for 1 hr. The mixture was again ice-cooled, and 1,5-dibromopentane (6.4 g) was added, which was followed by stirring at room temperature for 3 hr. Water was added to the reaction mixture and the mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried and the solvent was evaporated under reduced pressure to give 7.2 g of 5-benzyloxypentyl bromide.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[CH:7][CH:6]=1)=[O:4].[N-:13]=[N+:14]=[N-:15].[Na+]>C1COCC1.O>[N:13]([CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[CH:7][CH:6]=1)=[O:4])=[N+:14]=[N-:15]
Reactant: COc1ccc(C(=O)CBr)cc1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: COc1ccc(C(=O)CN=[N+]=[N-])cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 102.7 %

Procedure:
A mixture of 2-bromo-1-[4-(methyloxy)phenyl]ethanone (3.5 g, 15.28 mmol) and sodium azide (1.490 g, 22.92 mmol) in THF (40 mL) and water (13.33 mL) was stirred at 25° C. for 2 hours. The mixture was diluted with water (150 mL), and extracted with Et2O (3×100 mL), dried (Na2SO4), filtered, concentrated to afford the title compound (3.0 g) as a pink solid. 1H NMR (400 MHz, DMSO-d6): δ 3.87 (s, 3H), 4.83 (s, 2H), 7.07 (d, 2H), 7.93 (d, 2H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH2:8][N:9]2[CH2:14][CH2:13][NH:12][C@@H:11]([CH3:15])[CH2:10]2)[CH:5]=[CH:6][CH:7]=1.Cl[C:17]([O:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:18].C(OCC)(=O)C.C([O-])(O)=O.[Na+]>CN(C1C=CN=CC=1)C.CS(C)=O>[Br:1][C:2]1[CH:3]=[C:4]([CH2:8][N:9]2[CH2:14][CH2:13][N:12]([C:17]([O:19][CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[O:18])[C@@H:11]([CH3:15])[CH2:10]2)[CH:5]=[CH:6][CH:7]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: C[C@H]1CN(Cc2cccc(Br)c2)CCN1
Agent: CN(C)c1ccncc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: C[C@H]1CN(Cc2cccc(Br)c2)CCN1C(=O)OCc1ccccc1
Temperature: 25 °C
Yield: 89.3 %

Procedure:
To a solution of (3S)-1-[(3-Bromophenyl)methyl]-3-methylpiperazine (250 mg, 0.5 mmol), TEA (0.5 ml, 3.5 mmol), and DMAP (12 mg, 0.1 mmol) in 1 mL of dry DMSO was added dropwise benzyl chloroformate (0.34 mL, 2.25 mmol) at 10° C. while stirring. The mixture was then heated and stirred at 50° C. for 1.5 h. After cooling to room temperature, 15 mL of ethyl acetate and 5 mL of saturated NaHCO3 were added. The organic layer was separated, concentrated under vacuum and purified by Gilson reverse phase HPLC, eluting with acetonitrile/water/0.1% TFA (10/90 to 70/30, v/v, over 12 min), to give the title compound (180 mg, 70%). LC/MS: m/z, 403 (M+H), 1.74 min.
Reaction SMILES: [C:1]([C:3]1[CH:37]=[CH:36][C:6]2[N:7]([CH2:22][C:23]3[C:32]4[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=4)[N:26]=[CH:25][C:24]=3[CH:33]3[CH2:35][CH2:34]3)[C:8](=[O:21])[C@@H:9]([NH:13][C:14](=[O:20])[O:15][C:16]([CH3:19])([CH3:18])[CH3:17])[C@H:10]([CH3:12])[NH:11][C:5]=2[CH:4]=1)#[N:2].[O:38]1[CH2:43][CH2:42][CH:41]([C:44](Cl)=[O:45])[CH2:40][CH2:39]1>N1C=CC=CC=1.CCOC(C)=O>[C:1]([C:3]1[CH:37]=[CH:36][C:6]2[N:7]([CH2:22][C:23]3[C:32]4[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=4)[N:26]=[CH:25][C:24]=3[CH:33]3[CH2:34][CH2:35]3)[C:8](=[O:21])[C@@H:9]([NH:13][C:14](=[O:20])[O:15][C:16]([CH3:19])([CH3:18])[CH3:17])[C@H:10]([CH3:12])[N:11]([C:44]([CH:41]3[CH2:42][CH2:43][O:38][CH2:39][CH2:40]3)=[O:45])[C:5]=2[CH:4]=1)#[N:2]
Reactant: O=C(Cl)C1CCOCC1
Reactant: C[C@@H]1Nc2cc(C#N)ccc2N(Cc2c(C3CC3)cnc3ccccc23)C(=O)[C@H]1NC(=O)OC(C)(C)C
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: C[C@H]1[C@H](NC(=O)OC(C)(C)C)C(=O)N(Cc2c(C3CC3)cnc3ccccc23)c2ccc(C#N)cc2N1C(=O)C1CCOCC1
Temperature: 80 °C
Reaction time: 2 h
Yield: 60.5 %

Procedure:
To a rt solution of tert-butyl(3S,4S)-7-cyano-1-((3-cyclopropylquinolin-4-yl)methyl)-4-methyl-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-3-ylcarbamate (93 mg, 187 μmol) in pyridine (374 μl) was added tetrahydro-2H-pyran-4-carbonyl chloride (139 mg, 935 μmol) dropwise. The reaction was stirred at 80° C. for 2 h, then cooled to rt, diluted with EtOAc, washed with H2O, sat. aq. NaHCO3, and sat. aq. NaCl, dried over Na2SO4, filtered, and concentrated. The crude material was purified by flash chromatography to provide tert-butyl(3S,4S)-7-cyano-1-((3-cyclopropylquinolin-4-yl)methyl)-4-methyl-2-oxo-5-(tetrahydro-2H-pyran-4-carbonyl)-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-3-ylcarbamate (69 mg, 61%) as an off-white solid. MS m/z 610 (MH)+.