Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[CH2:2][C:3](Cl)=[O:4].[CH3:6][O:7][C:8]1[CH:19]=[CH:18][C:11]([CH2:12][NH:13][C@H:14]([CH3:17])[CH2:15][OH:16])=[CH:10][CH:9]=1.C(N(CC)CC)C.[H-].[Na+].Cl>O1CCCC1.O>[CH3:6][O:7][C:8]1[CH:19]=[CH:18][C:11]([CH2:12][N:13]2[C@H:14]([CH3:17])[CH2:15][O:16][CH2:2][C:3]2=[O:4])=[CH:10][CH:9]=1
Reactant: O=C(Cl)CCl
Reactant: COc1ccc(CN[C@H](C)CO)cc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: O
Product: COc1ccc(CN2C(=O)COC[C@H]2C)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 62.6 %

Procedure:
Chloroacetyl chloride (15 g, 133 mmol) was added to a solution of (2R)-2-(4-methoxybenzylamino)-propan-1-ol (26 g, 133 mmol) and triethylamine (15 g, 148 mmol) in tetrahydrofuran (200 ml) and the solution was stirred for one hour. The solution was cooled at 0° C. and sodium hydride (60% dispersion in mineral oil, 5.8 g, 145 mol) was added. When the reaction was complete (checked by thin layer chromatography), excess reagent was decomposed by the addition of water and pH was adjusted to 5-6 with 3N aqueous hydrochloric acid. The solution was partitioned between water and chloroform. The organic layer was washed with brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent; 5-10% methanol in chloroform) to afford (5R)-4-(4-methoxybenzyl)-5-methylmorpholin-3-one (19.6 g, 83.3 mmol, 63%) as colorless oil.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[Cl:11].[OH-].[Na+].[Cl:14][C:15]1[CH:20]=[CH:19][C:18]([CH2:21][C:22]#[N:23])=[CH:17][CH:16]=1.Cl>[Cl-].C([N+](CC)(CC)CC1C=CC=CC=1)C.O1CCCC1.O>[Cl:11][C:3]1[CH:4]=[C:5]([N+:8]([O-:10])=[O:9])[CH:6]=[CH:7][C:2]=1[CH:21]([C:18]1[CH:19]=[CH:20][C:15]([Cl:14])=[CH:16][CH:17]=1)[C:22]#[N:23]
Reactant: N#CCc1ccc(Cl)cc1
Reactant: O=[N+]([O-])c1ccc(Cl)c(Cl)c1
Agent: CC[N+](CC)(CC)Cc1ccccc1
Agent: Cl
Agent: [Cl-]
Solvent: C1CCOC1
Solvent: O
Product: N#CC(c1ccc(Cl)cc1)c1ccc([N+](=O)[O-])cc1Cl
Reaction time: 5 h
Yield: 0.1 %

Procedure:
) To a stirred and warm (40° C.) mixture of 1,2-dichloro-4-nitrobenzene (0,250 mol), 450 ml of NaOH solution 50%, 0,002 mol of N,N,N-triethylbenzenemethanaminium chloride and 225 ml of tetrahydrofuran is added dropwise a solution of 0,272 mol of 4-chlorobenzeneacetonitrile in 70 ml of tetrahydrofuran. Upon completion, stirring is continued for 5 hours at ±60° C. The reaction mixture is cooled and diluted with water. The whole is acidified with a hydrochloric acid solution and the product is extracted with Et2O. The extract is washed with water, dried, filtered and evaporated, yielding 80 g of 2-chloro-α-(4-chlorophenyl)-4-nitrobenzeneacetonitrile as an oily solution. (interm. 4)
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[CH:16]=[C:15]2[C:7]([C:8]3[C:9](=[O:17])[CH2:10][CH2:11][CH2:12][C:13]=3[NH:14]2)=[CH:6][CH:5]=1.[CH3:18]I>CN(C=O)C>[Br:3][C:4]1[CH:16]=[C:15]2[C:7]([C:8]3[C:9](=[O:17])[CH2:10][CH2:11][CH2:12][C:13]=3[N:14]2[CH3:18])=[CH:6][CH:5]=1
Reactant: CI
Reactant: O=C1CCCc2[nH]c3cc(Br)ccc3c21
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cn1c2c(c3ccc(Br)cc31)C(=O)CCC2
Reaction time: 0.25 h
Yield: 93.4 %

Procedure:
Sodium hydride (60% dispersion in oil, 0.342 g, 8.55 mmol) was added to a solution of 7-bromo-2,3-dihydro-1H-carbazol-4(9H)-one (2.46 g, 9.35 mmol) in DMF (33 mL) at room temperature under N2 and stirred for 15 min. Methyl iodide (1.99 mL, 14.0 mmol) was added to the solution, and the resulting solution was stirred for 2 h at ambient temperature. The mixture was quenched with H2O (80 mL), upon which a solid precipitated out of solution. The solids were collected by filtration and were washed thoroughly with water followed by hexanes to provide the title compound (2.43 g, 94%) as a tan solid: 1H NMR (500 MHz, DMSO-d6) δ 7.90 (d, J=8.5 Hz, 1H), 7.81 (d, J=1.5 Hz, 1H), 7.32 (dd, J=8.5, 1.5 Hz, 1H), 3.71 (s, 3H), 2.97 (t, J=6.0 Hz, 2H), 2.42 (t, J=6.0 Hz, 2H), 2.15-2.10 (m, 2H).
Reaction SMILES: [C-:1]#[N:2].[K+].CS(O[CH2:9][CH2:10][CH:11]([C:24]1[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][C:25]=1[CH3:31])[C:12]1[C:20]2[C:15](=[C:16]([CH2:21][S:22][CH3:23])[CH:17]=[CH:18][CH:19]=2)[NH:14][CH:13]=1)(=O)=O>CN(C=O)C>[Cl:30][C:27]1[CH:28]=[CH:29][C:24]([CH:11]([C:12]2[C:20]3[C:15](=[C:16]([CH2:21][S:22][CH3:23])[CH:17]=[CH:18][CH:19]=3)[NH:14][CH:13]=2)[CH2:10][CH2:9][C:1]#[N:2])=[C:25]([CH3:31])[CH:26]=1
Reactant: CSCc1cccc2c(C(CCOS(C)(=O)=O)c3ccc(Cl)cc3C)c[nH]c12
Reactant: [C-]#N
Agent: [K+]
Solvent: CN(C)C=O
Product: CSCc1cccc2c(C(CCC#N)c3ccc(Cl)cc3C)c[nH]c12
Temperature: 80 °C
Reaction time: 2 h

Procedure:
419 mg (6.44 mmol) of potassium cyanide were added to 1.41 g (3.22 mmol) of the compound from Example 61A in 20 ml of DMF. The mixture was stirred at 80° C. for 2 h and then concentrated, and the crude product was purified by preparative HPLC (RP18 column; mobile phase: acetonitrile/water gradient with addition of 0.1% formic acid) to result in 987 mg (83% of theory) of the title compound.
Reaction SMILES: C1(C(C2C=CC=CC=2)(C2C=CC=CC=2)[N:8]2[CH:12]=[C:11]([CH2:13][CH2:14][CH2:15][O-:16])[N:10]=[CH:9]2)C=CC=CC=1.[Na+].[Br-].[CH3:31][CH:32]([CH3:35])[CH2:33][CH3:34].O1CCOCCOCCOCCOCC1>C1(C)C=CC=CC=1>[CH3:31][CH:32]([CH3:35])[CH2:33][CH2:34][O:16][CH2:15][CH2:14][CH2:13][C:11]1[N:10]=[CH:9][NH:8][CH:12]=1
Reactant: [O-]CCCc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Reactant: CCC(C)C
Agent: C1COCCOCCOCCOCCO1
Agent: [Br-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CC(C)CCOCCCc1c[nH]cn1
Temperature: 70 °C

Procedure:
5 mmol of sodium 3-(1-triphenylmethyl-1H-imidazol-4-yl)propanolate, 5 mmol of 3-methylbutane bromide and 0.5 mmol of 15-crown-15 (1, 4, 7, 10, 13-pentaoxacyclopentadecane) dissolved in 10 ml of anhydrous toluene are refluxed for 24 hours. The solvent is then evaporated off, and the residue dissolved in 10 ml THF and 30 ml 2N HCl and then heated at 70° C. for 2 hours. The THF is evaporated off under reduced pressure and triphenylmethanol is extracted with diethyl ether. The aqueous phase is neutralized with potassium carbonate and the product is extracted with diethyl ether. The organic extract is dried and evaporated, giving rise to an oil, which is crystallized as hydrogen maleate from diethyl ether and ethanol.
Reaction SMILES: C[O:2][C:3](=[O:30])[C:4]([NH:7][C:8]([C:10]1[CH:19]=[CH:18][C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]=1[O:20][CH2:21][C:22]1[CH:23]=[N:24][C:25]([O:28][CH3:29])=[CH:26][CH:27]=1)=[O:9])([CH3:6])[CH3:5].[OH-].[Na+].O.Cl>C1COCC1.CO>[CH3:29][O:28][C:25]1[N:24]=[CH:23][C:22]([CH2:21][O:20][C:11]2[C:12]3[C:17](=[CH:16][CH:15]=[CH:14][CH:13]=3)[CH:18]=[CH:19][C:10]=2[C:8]([NH:7][C:4]([CH3:6])([CH3:5])[C:3]([OH:30])=[O:2])=[O:9])=[CH:27][CH:26]=1
Reactant: COC(=O)C(C)(C)NC(=O)c1ccc2ccccc2c1OCc1ccc(OC)nc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: COc1ccc(COc2c(C(=O)NC(C)(C)C(=O)O)ccc3ccccc23)cn1
Temperature: 25 °C
Reaction time: 4 h
Yield: 23.9 %

Procedure:
To 191 mg 2-{[1-(6-Methoxy-pyridin-3-ylmethoxy)-naphthalene-2-carbonyl]-amino}-2-methyl-propionic acid methyl ester in 6 mL THF and 1 mL methanol was added 2.3 mL of 1 M aqueous sodium hydroxide solution. After stirring at room temperature for 4 h the mixture was poured into cold water, acidified to pH 4 with 2M HCl and extracted with ethyl acetate three times. The combined organic layers were dried over magnesium sulphate, filtrated and concentrated to provide a yellow oil, which could be crystallized from diethylether and methanol to yield 44 mg of 2-{[1-(6-methoxy-pyridin-3-ylmethoxy)-naphthalene-2-carbonyl]-amino}-2-methyl-propionic acid.
Reaction SMILES: [C:1]([C:6]([C:20]([O:22]CC)=[O:21])([CH2:18][CH3:19])[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]1[C:13](=[O:17])[CH2:14][CH2:15][CH:16]=1)([O:3]CC)=[O:2].[CH:25]1[C:26](/[CH:41]=[N:42]/[OH:43])=[CH:27][CH:28]=[N+:29]([CH2:31][N+:32]2[CH:37]=[CH:36][C:35](/[CH:38]=[N:39]/[OH:40])=[CH:34][CH:33]=2)[CH:30]=1.[Br-:44].[Br-].[OH-].[K+]>CO>[C:1]([C:6]([C:20]([OH:22])=[O:21])([CH2:18][CH3:19])[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]1[C:13](=[O:17])[CH2:14][CH2:15][CH:16]=1)([OH:3])=[O:2].[CH:27]1[C:26](/[CH:41]=[N:42]/[OH:43])=[CH:25][CH:30]=[N+:29]([CH2:31][N+:32]2[CH:33]=[CH:34][C:35](/[CH:38]=[N:39]/[OH:40])=[CH:36][CH:37]=2)[CH:28]=1.[Br-:44].[Br-:44]
Reactant: CCOC(=O)C(CC)(CCCCCC1=CCCC1=O)C(=O)OCC
Agent: O/N=C/c1cc[n+](C[n+]2ccc(/C=N/O)cc2)cc1
Agent: [Br-]
Agent: [K+]
Solvent: CO
Product: CCC(CCCCCC1=CCCC1=O)(C(=O)O)C(=O)O

Procedure:
Treatment of 2-(6,6-dicarbethoxyoctyl)-2-cyclopentenone methoxime (Example 27) with potassium hydroxide, and 1:1 aqueous methanol in the manner described in Example 20 gives a light yellow oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4](=[O:26])[C:5]([CH3:25])=[C:6]([CH2:12][C:13]2[CH:14]=[C:15]([CH2:19][CH2:20][CH2:21][C:22](O)=[O:23])[CH:16]=[CH:17][CH:18]=2)[C:7](=[O:11])[C:8]=1[O:9][CH3:10].[CH:27]([NH2:30])([CH3:29])[CH3:28]>>[CH3:1][O:2][C:3]1[C:4](=[O:26])[C:5]([CH3:25])=[C:6]([CH2:12][C:13]2[CH:14]=[C:15]([CH2:19][CH2:20][CH2:21][C:22]([NH:30][CH:27]([CH3:29])[CH3:28])=[O:23])[CH:16]=[CH:17][CH:18]=2)[C:7](=[O:11])[C:8]=1[O:9][CH3:10]
Reactant: COC1=C(OC)C(=O)C(Cc2cccc(CCCC(=O)O)c2)=C(C)C1=O
Reactant: CC(C)N
Product: COC1=C(OC)C(=O)C(Cc2cccc(CCCC(=O)NC(C)C)c2)=C(C)C1=O
Yield: 21.5 %

Procedure:
4-[3-(5,6-dimethoxy-3-methyl-1,4-benzoquinon-2-ylmethyl)phenyl]-n-butyric acid (73 mg, 0.20 mmol) obtained in Example 62 and isopropylamine (0.019 ml, 0.30 mmol) were used, and a method similar to that described in Example 46 was employed to obtain the title compound (17 mg, 0.043 mmol, yield 21%).
Reaction SMILES: [CH2:1]([O:4][N:5]1[C:14](=[O:15])[C:13]2[C:8](=[CH:9][C:10]([F:17])=[C:11]([F:16])[CH:12]=2)[NH:7][C:6]1=[O:18])[CH:2]=[CH2:3].[H-].[Na+].[CH2:21](Br)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>CN(C=O)C>[CH2:1]([O:4][N:5]1[C:14](=[O:15])[C:13]2[C:8](=[CH:9][C:10]([F:17])=[C:11]([F:16])[CH:12]=2)[N:7]([CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:6]1=[O:18])[CH:2]=[CH2:3]
Reactant: BrCc1ccccc1
Reactant: C=CCOn1c(=O)[nH]c2cc(F)c(F)cc2c1=O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C=CCOn1c(=O)c2cc(F)c(F)cc2n(Cc2ccccc2)c1=O
Reaction time: 0.5 h
Yield: 107.9 %

Procedure:
A solution of 3-allyloxy-6,7-difluoro-1H-quinazoline-2,4-dione (Example Z-3, 0.7 g, 2.8 mmol) in 20 mL of DMF was added to a suspension of sodium hydride (0.12 g, 3.0 mmol) in 15 mL of DMF and stirred for 30 minutes. Benzyl bromide (0.65 mL, 5.5 mmol) was added, and the mixture was stirred at 25° C. for 18 hours. The reaction was quenched with 1 mL of water and concentrated to an oil. The residue was dissolved in chloroform washed with water and brine and dried over magnesium sulfate. The solution was concentrated to give 1.04 g of the title compound as a solid, mp 130-132° C.
Reaction SMILES: [OH:1][CH2:2][CH:3]([O:6][CH2:7][C@@H:8]([NH:11][C:12](=[O:18])[O:13][C:14]([CH3:17])([CH3:16])[CH3:15])[CH:9]=[CH2:10])[CH:4]=[CH2:5].C(N(CC)CC)C.[C:26](Cl)(=[O:28])[CH3:27]>C(Cl)Cl>[C:26]([O:1][CH2:2][CH:3]([O:6][CH2:7][C@@H:8]([NH:11][C:12]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:18])[CH:9]=[CH2:10])[CH:4]=[CH2:5])(=[O:28])[CH3:27]
Reactant: CC(=O)Cl
Reactant: C=CC(CO)OC[C@H](C=C)NC(=O)OC(C)(C)C
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C=CC(COC(C)=O)OC[C@H](C=C)NC(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 2 h
Yield: 83.5 %

Procedure:
To a mixture of tert-butyl [(1S)-1-({[1-(hydroxymethyl)prop-2-en-1-yl]oxy}methyl)prop-2-en-1-yl]carbamate (268 mg, 1.04 mmol) in methylene chloride (10 mL) was added with triethylamine (435 μL, 3.12 mmol). The mixture was cooled to 0° C., and acetyl chloride (150 μL, 2.1 mmol) was added drop wise. The reaction was stirred at room temperature for 2 h, then quenched with water. The organic layer was concentrated and the resultant residue purified on silica gel (eluting with 20% ethyl acetate/hexanes) to give the desired product (0.26 g, 85%). LCMS calculated for C10H18NO3 (M−100+H)+: m/z=200.1. Found: 200.1.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:26])=[C:6]([C:8]([C:10]2[CH:15]=[CH:14][C:13]([NH:16][C:17]3[CH:22]=[CH:21][C:20]([F:23])=[CH:19][C:18]=3[F:24])=[CH:12][C:11]=2[Cl:25])=[O:9])[CH:7]=1.[CH2:27]([S:29](Cl)(=[O:31])=[O:30])[CH3:28]>N1C=CC=CC=1>[Cl:25][C:11]1[CH:12]=[C:13]([NH:16][C:17]2[CH:22]=[CH:21][C:20]([F:23])=[CH:19][C:18]=2[F:24])[CH:14]=[CH:15][C:10]=1[C:8]([C:6]1[CH:7]=[C:2]([NH:1][S:29]([CH2:27][CH3:28])(=[O:31])=[O:30])[CH:3]=[CH:4][C:5]=1[CH3:26])=[O:9]
Reactant: CCS(=O)(=O)Cl
Reactant: Cc1ccc(N)cc1C(=O)c1ccc(Nc2ccc(F)cc2F)cc1Cl
Solvent: c1ccncc1
Product: CCS(=O)(=O)Nc1ccc(C)c(C(=O)c2ccc(Nc3ccc(F)cc3F)cc2Cl)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Compound 494 (0.045 g, 0.12 mmol) was dissolved in pyridine (0.3 mL). Ethanesulphonyl chloride (0.017 mL, 0.18 mmol) was added and the solution was stirred at room temperature for 1 h. The reaction mixture was concentrated in vacuo and the oil was dissolved in EtOAc and washed with H2O. The water phase was extracted with EtOAc and the combined organic phases were dried (MgSO4), filtered and concentrated in vacuo. The crude product was purified by flash chromatography using a gradient of EtOAc/petroleum ether (40-60) 15:85→40:60 as the eluent. This afforded the title compound as yellow solid. 13C NMR (CDCl3) δ 195.5, 159.3 (dd), 155.7 (dd), 148.3, 140.4, 135.3, 134.5, 134.5, 133.8, 132.5, 128.5, 124.6 (dd), 124.2 (dd), 123.2, 121.6, 116.1, 112.8, 111.6 (dd), 105.0 (dd), 45.9, 19.7, 8.1
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]1[CH:5]=[CH:6][C:7]([Cl:28])=[C:8]([C:10]2[NH:14][C:13](=[O:15])[N:12]([C:16]3[CH:25]=[CH:24][C:19]([C:20]([O:22][CH3:23])=[O:21])=[C:18]([O:26][CH3:27])[CH:17]=3)[N:11]=2)[CH:9]=1.CCN(C(C)C)C(C)C.[CH:38]1([C:41](Cl)=[O:42])[CH2:40][CH2:39]1>C1COCC1>[Cl:28][C:7]1[CH:6]=[CH:5][C:4]([CH2:3][NH:2][C:41]([CH:38]2[CH2:40][CH2:39]2)=[O:42])=[CH:9][C:8]=1[C:10]1[NH:14][C:13](=[O:15])[N:12]([C:16]2[CH:25]=[CH:24][C:19]([C:20]([O:22][CH3:23])=[O:21])=[C:18]([O:26][CH3:27])[CH:17]=2)[N:11]=1
Reactant: COC(=O)c1ccc(-n2nc(-c3cc(CN)ccc3Cl)[nH]c2=O)cc1OC
Reactant: O=C(Cl)C1CC1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: COC(=O)c1ccc(-n2nc(-c3cc(CNC(=O)C4CC4)ccc3Cl)[nH]c2=O)cc1OC
Temperature: 25 °C
Reaction time: 3 h
Yield: 67.9 %

Procedure:
A solution of methyl 4-(3-(5-(aminomethyl)-2-chlorophenyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-2-methoxybenzoate hydrochloride (0.500 g, 1.29 mmol) in THF (20 mL) was added DIPEA (2 mL) and cyclopropyl carbonyl chloride (0.201 g, 1.9 mmol) under nitrogen atmosphere. The reaction mass was stirred at RT for 2-4 h. The reaction mass was quenched in water, extracted with DCM and concentrated to afford 0.400 g of desired product. 1H NMR (300 MHz, DMSO d6): δ 0.69 (m, 4H), 1.60 (s, 1H), 3.79 (s, 3H), 3.86 (s, 3H), 4.33 (d, J=5.4 Hz, 2H), 7.41-7.54 (m, 3H), 7.61 (d, J=8.4 Hz, 1H), 7.73 (s, 1H), 7.79 (d, 1H), 8.71 (m, H); MS (m/z): 456.97 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([C:7]([CH3:10])([CH3:9])[CH3:8])=[N:5][N:6]=1.[Cl:11][C:12]1[CH:13]=[CH:14][C:15]([O:21][CH3:22])=[C:16]([CH:20]=1)[C:17](O)=[O:18].C(N(CC)CC)C.CCCP1(OP(CCC)(=O)OP(CCC)(=O)O1)=O.C(OCC)(=O)C>O1CCCC1>[C:7]([C:4]1[S:3][C:2]([NH:1][C:17](=[O:18])[C:16]2[CH:20]=[C:12]([Cl:11])[CH:13]=[CH:14][C:15]=2[O:21][CH3:22])=[N:6][N:5]=1)([CH3:10])([CH3:9])[CH3:8]
Reactant: COc1ccc(Cl)cc1C(=O)O
Reactant: CC(C)(C)c1nnc(N)s1
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: COc1ccc(Cl)cc1C(=O)Nc1nnc(C(C)(C)C)s1
Reaction time: 14 h
Yield: 87.6 %

Procedure:
To a solution of 2-amino-5-tert-butyl-1,3,4-thiadiazole (Aldrich) (2.5 g, 16.3 mmol) in tetrahydrofuran (30 mL) were added 5-chloro-2-methoxybenzoic acid (Aldrich) (3.65 g, 19.6 mmol), triethylamine (5.5 mL, 39.5 mmol), and 1-propanephosphonic acid cyclic anhydride 50% solution in ethyl acetate (Aldrich) (11.6 mL, 19.6 mmol). The reaction mixture was stirred at about room temperature for 14 hours, cooled with external ice bath while quenching with saturated aqueous NaHCO3 (20 mL). The aqueous layer was extracted with ethyl acetate (2×40 mL). The combined organic extracts were dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography using an Analogix® Intelliflash280™ (SiO2, 0-100% ethyl acetate in hexanes) to afford 4.65 g of the title compound. 1H NMR (300 MHz, DMSO-d6) δ ppm 1.43 (s, 9H), 3.88 (s, 3H), 7.22 (d, J=8.7 Hz, 1H), 7.55-7.64 (m, 2H), 12.41 (s, 1H); MS (ESI+) m/z 326 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5](I)=[C:4]([F:9])[CH:3]=1.[CH2:10]([C:14]1[CH:19]=[CH:18][C:17](B(O)O)=[CH:16][CH:15]=1)[CH2:11][CH2:12][CH3:13].C1(C)C=CC=CC=1.C(=O)([O-])[O-].[Na+].[Na+]>O1CCCC1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl.B.[Na].COC(C)(C)C.O.C(O)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:17]2[CH:18]=[CH:19][C:14]([CH2:10][CH2:11][CH2:12][CH3:13])=[CH:15][CH:16]=2)=[C:4]([F:9])[CH:3]=1
Reactant: CCCCc1ccc(B(O)O)cc1
Reactant: Fc1cc(Br)ccc1I
Agent: Cl[Pd]Cl
Agent: B
Agent: O=C([O-])[O-]
Solvent: O
Solvent: COC(C)(C)C
Solvent: Cc1ccccc1
Product: CCCCc1ccc(-c2ccc(Br)cc2F)cc1
Temperature: 55 °C
Yield: 89.6 %

Procedure:
2.106 g of bis(triphenylphosphine) palladium(II)chloride (Merck Schuchart, Art. No. 804 174) were suspended in 20.0 ml tetrahydrofurane (Merck KGaA, Art. No.108 107) in a 50 ml, four necked vessel and heated to 55° C. Now 0.113 g sodiumboric hydride (Merck Schuchart, Art. Nr. 806 372) were added slowly while the suspension was stirred with a magnetic stirrer. The dark mixture was heated under reflux for 30 minutes and then allowed to cool to 40° C. 49.648 g of 1-bromo-3-fluoro-4-iodo-benzene (Wychem, Art. No. 45 570 300/12) 35.60 g of 4-n-butyl-phenylboronic acid, prepared in house), 330 ml toluene (Merck KGaA, Art. No.108 325), 130 ml ethanol (Merck KGaA, Art. No.100 983) and 170 ml of a solution of sodium carbonate (Merck KGaA, Art. No.106 384) were placed in an 1 I, four necked vessel at ambient temperature and heated to 50° C. Now the freshly prepared 40° C. warm solution of the Pd0-catalyst was rapidly added dropwise to the vigorously stirred reaction mixture. The brown mixture was stirred at 50° C. for 16 hours. The completeness of the reaction was confirmed by thin sheet chromatography. The reaction mixture was cooled to ambient temperature. Then distilled water and methyl-t-butyl ether were added and the phases separated. The aquous phase was extracted twice with methyl-t-butyl ether. The combined organic phases were washed twice with distilled water, dried over Na2SO4 filtered and the solvent evaporated. The crude product of 74 g of 4-bromo-4′-n-butyl-2-fluoro-biphenyl was purified over 3 I silica gel with 1-chloro-butane. The resultant 61.4 g of crude product were distilled under reduced pressure. Thus 45.4 g of 4-bromo-4′-n-butyl-2-fluoro-biphenyl with a purity of 90.6% by GC were obtained.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:28])[NH:4][C@H:5]([C:9]([N:11]1[CH2:15][CH2:14][CH2:13][C@H:12]1[C:16]1[NH:17][CH:18]=[C:19]([C:21]2[CH:26]=[CH:25][C:24](Br)=[CH:23][CH:22]=2)[N:20]=1)=[O:10])[CH:6]([CH3:8])[CH3:7].CC1(C)C(C)(C)OB([C:37]2[CH:43]=[CH:42][C:40]([NH2:41])=[CH:39][CH:38]=2)O1.C(=O)([O-])[O-].[Na+].[Na+].C(OCC)(=O)C>O1CCOCC1.O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH3:1][O:2][C:3](=[O:28])[NH:4][C@H:5]([C:9]([N:11]1[CH2:15][CH2:14][CH2:13][C@H:12]1[C:16]1[NH:17][CH:18]=[C:19]([C:21]2[CH:26]=[CH:25][C:24]([C:37]3[CH:43]=[CH:42][C:40]([NH2:41])=[CH:39][CH:38]=3)=[CH:23][CH:22]=2)[N:20]=1)=[O:10])[CH:6]([CH3:8])[CH3:7]
Reactant: COC(=O)N[C@H](C(=O)N1CCC[C@H]1c1nc(-c2ccc(Br)cc2)c[nH]1)C(C)C
Reactant: CC1(C)OB(c2ccc(N)cc2)OC1(C)C
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: O
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: COC(=O)N[C@H](C(=O)N1CCC[C@H]1c1nc(-c2ccc(-c3ccc(N)cc3)cc2)c[nH]1)C(C)C
Temperature: 25 °C
Reaction time: 4 h
Yield: 74.6 %

Procedure:
To a solution of ((S)-1-{(S)-2-[4-(4-bromo-phenyl)-1H-imidazol-2-yl]-pyrrolidine-1-carbonyl}-2-methyl-propyl)-carbamic acid methyl ester (9.10 g, 20.34 mmol) in dioxane:water (3:1) (200 mL), was added 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (4.9 g, 22.37 mmol), sodium carbonate (4.3 g, 40.68 mmol) and Pd(dppf)2Cl2 (0.83 g, 5%). The reaction mixture was warmed to reflux under nitrogen, stirred for 4 h, cooled to RT, filtered, and concentrated. The residue was extracted with ethyl acetate and water, dried with sodium sulfate and concentrated. The crude product was purified by silica gel chromatography eluting with 1:1 hexane:ethyl acetate, to provide the title compound (7 g, 75% yield) as a yellow solid. 1H NMR (CDCl3, 400 MHz) δ (ppm) 7.62-7.55 (m, 1H), 7.50 (d, J=8.0 Hz, 2H), 7.40 (m, 3H), 7.18 (s, 1H), 6.75 (d, J=8.4 Hz, 2H), 5.50 (d, J=9.2 Hz, 1H), 5.25-5.23 (m, 1H), 4.31 (t, J=2.4 Hz, 1H), 3.83-3.80 (m, 1H), 3.67 (s, 3H), 3.59-3.53 (m, 1H), 3.05-2.95 (m, 1H), 2.40-2.30 (m, 1H), 2.19-2.11 (m, 1H), 2.08-2.03 (m, 1H), 1.98-1.93 (m, 1H), 1.07-1.01 (m, 1H), 0.85 (d, J=6.8 Hz, 6H).
Reaction SMILES: Br[C:2]1[C:12]2[O:11][CH2:10][CH2:9][N:8]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:7][C:6]=2[CH:5]=[CH:4][CH:3]=1.[CH3:20][C:21]([CH3:26])=[CH:22]B(O)O.C(=O)([O-])[O-].[Na+].[Na+].O>C(COC)OC.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][C:21]([CH3:26])=[CH:20][C:2]1[C:12]2[O:11][CH2:10][CH2:9][N:8]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:7][C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)N1CCOc2c(Br)cccc2C1
Reactant: CC(C)=CB(O)O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: CC(C)=Cc1cccc2c1OCCN(C(=O)OC(C)(C)C)C2
Temperature: 85 °C
Reaction time: 12 h
Yield: 89 %

Procedure:
A mixture of tert-butyl 9-bromo-2,3-dihydro-1,4-benzoxazepine-4(5H)-carboxylate (328 mg, 1.00 mmol), 2,2-dimethylethenylboronic acid (98.0 mg, 1.00 mmol), saturated aqueous sodium carbonate solution (14 ml) and tetrakis(triphenylphosphine)palladium(0) (32.6 mg, 0.0282 mmol) in dimethoxyethane (10 ml) was stirred at 85° C. for 12 hr under a nitrogen atmosphere. The reaction mixture was poured into water, and the mixture was extracted with ethyl acetate. The extract was washed with water, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane:ethyl acetate=9:1) to give the desired product (270 mg, 89.1%) as an oil.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:16])[CH:4]=[CH:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([S:12](Cl)(=[O:14])=[O:13])[CH:7]=1.[NH2:17][C:18]1[CH:27]=[CH:26][C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH:19]=1.C([O-])(O)=O.[Na+]>O1CCOCC1.O>[CH3:1][O:2][C:3](=[O:16])[CH:4]=[CH:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([S:12](=[O:14])(=[O:13])[NH:17][C:18]2[CH:27]=[CH:26][C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[CH:19]=2)[CH:7]=1
Reactant: Nc1ccc2ccccc2c1
Reactant: COC(=O)C=Cc1cccc(S(=O)(=O)Cl)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: COC(=O)C=Cc1cccc(S(=O)(=O)Nc2ccc3ccccc3c2)c1
Yield: 37 %

Procedure:
A solution of 3-(3-chlorosulfonylphenyl)acrylic acid methyl ester (3) (1.0 g, 3.83 mmol) in dioxane (10 ml) was added to a mixture of 2-aminonaphthalene (0.55 g, 3.83 mmol) and NaHCO3 (0.48 g, 5.71 mmol) in water (6 ml), and the resultant solution was stirred at room temperature until the completion of the reaction (control by TLC). The reaction mixture was evaporated and the residue was partitioned between ethyl acetate and 2N HCl. The organic layer was washed successively with water, saturated NaCl, and dried (Na2SO4). The solvent was removed and the residue was chromatographed on silica gel with petroleum ether-ethyl acetate (3:2, v/v) as eluent. The obtained product was crystallised from petroleum ether-ethyl acetate to give the title compound (0.52 g, 34%) as a white solid. 1H NMR (DMSO-d6, HMDSO), δ: 3.73 (3H, s); 6.67 (1H, d, J=16.0 Hz); 7.21-8.07 (11H, m); 8.16 (1H, s); 10.55 (1H, s).