Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[NH2:2][C@H:3]([C:8]1[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=1)[C:4]([O:6][CH3:7])=[O:5].C(OCC)(=O)C.S([O-])([O-])(=O)=O.[Mg+2].[S:27]1[CH:31]=[CH:30][C:29]([CH:32]=O)=[CH:28]1>C(N(CC)CC)C>[OH:14][C:11]1[CH:10]=[CH:9][C:8]([CH:3]([NH:2][CH2:32][C:29]2[CH:30]=[CH:31][S:27][CH:28]=2)[C:4]([O:6][CH3:7])=[O:5])=[CH:13][CH:12]=1
Reactant: O=Cc1ccsc1
Reactant: COC(=O)[C@H](N)c1ccc(O)cc1
Agent: Cl
Agent: O=S(=O)([O-])[O-]
Agent: [Mg+2]
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: COC(=O)C(NCc1ccsc1)c1ccc(O)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
5 g of methyl(R)-amino-(4-hydroxyphenyl)acetate hydrochloride and 100 mL of anhydrous ethyl acetate (thick suspension) are introduced at ambient temperature into a 500 mL Woulff bottle equipped with a nitrogen intake, a magnetic stirrer and a condenser. 3.1 mL of triethylamine, some magnesium sulphate and 3 g of thiophene-3-carbaldehyde are added. After 4 hours under reflux, the white solid is filtered, washed with ethyl acetate and dried under vacuum. The product is taken up in 100 mL of anhydrous dichloromethane. 14 g of sodium triacetoxy borohydride are added and the mixture is stirred at ambient temperature for 2 hours. 100 mL of methanol are added then the reaction mixture is concentrated. The product is extracted with ethyl acetate. It is washed with water then the organic phases are dried over magnesium sulphate. The mixture is concentrated, and the residue is purified over a silica column with 50/50 heptane/ethyl acetate. After concentration and crystallisation in isopropanol, a white solid is obtained (2.35 g; Yd=37%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:8]2[CH:13]([CH2:14][N:15]([C@@H:23]([C:25]3[C:34]4[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=4)[CH:28]=[CH:27][CH:26]=3)[CH3:24])[C:16](=[O:22])[O:17][C:18]([CH3:21])([CH3:20])[CH3:19])[CH2:12][CH2:11][NH:10][CH2:9]2)[CH:5]=[CH:6][CH:7]=1.Cl[C:36](=[O:44])[CH2:37][CH2:38][C:39]([O:41][CH2:42][CH3:43])=[O:40].C1COCC1.[Cl-].[NH4+]>C(N(CC)CC)C>[C:18]([O:17][C:16]([N:15]([CH2:14][CH:13]1[CH2:12][CH2:11][N:10]([C:36](=[O:44])[CH2:37][CH2:38][C:39]([O:41][CH2:42][CH3:43])=[O:40])[CH2:9][CH:8]1[C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[CH:3]=1)[C@@H:23]([C:25]1[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH:28]=[CH:27][CH:26]=1)[CH3:24])=[O:22])([CH3:19])([CH3:21])[CH3:20]
Reactant: CCOC(=O)CCC(=O)Cl
Reactant: C[C@H](c1cccc2ccccc12)N(CC1CCNCC1c1cccc(F)c1)C(=O)OC(C)(C)C
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCOC(=O)CCC(=O)N1CCC(CN(C(=O)OC(C)(C)C)[C@H](C)c2cccc3ccccc23)C(c2cccc(F)c2)C1
Reaction time: 72 h
Yield: 99.7 %

Procedure:
To a mixture of 139 mg of tert-butyl {[3-(3-fluorophenyl)piperidin-4-yl]methyl}[(1R)-1-(1-naphthyl)ethyl]carbamate, 54 mg of ethyl 4-chloro-4-oxobutanoate, and 4.0 mL of THF was added 0.084 mL of triethylamine at room temperature, followed by stirring for 3 days. To the reaction mixture was added a saturated aqueous ammonium chloride solution, followed by extraction with ethyl acetate. Then, the organic layer was washed with water and saturated brine, and then dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure to obtain 177 mg of ethyl 4-[4-({(tert-butoxycarbonyl)[(1R)-1-(1-naphthyl)ethyl]amino}methyl)-3-(3-fluorophenyl)piperidin-1-yl]-4-oxobutanoate as a colorless oily compound. ESI+: 591
Reaction SMILES: [CH2:1](Br)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C@@H]1([N:18]2[C:28]3[N:27]=[C:25]([NH2:26])[NH:24][C:22](=[O:23])[C:21]=3[N:20]=[CH:19]2)O[C@H](CO)[C@@H](O)[C@H]1O.[ClH:29].CO>CS(C)=O>[ClH:29].[NH2:26][C:25]1[NH:24][C:22](=[O:23])[C:21]2[N:20]([CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[CH:19]=[N:18][C:28]=2[N:27]=1
Reactant: Nc1nc2c(ncn2[C@@H]2O[C@H](CO)[C@@H](O)[C@H]2O)c(=O)[nH]1
Reactant: BrCc1ccccc1
Agent: Cl
Solvent: CS(C)=O
Solvent: CO
Product: Nc1nc2ncn(Cc3ccccc3)c2c(=O)[nH]1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
Benzyl bromide (100 ml) was added dropwise to a suspension of guanosine (100 g) in dimethyl sulfoxide (500 ml) at room temperature, and the resulting reaction mixture was stirred at room temperature for 4 hours. Then, concentrated hydrochloric acid (250 ml) was added thereto. The reaction mixture was stirred at room temperature for 30 minutes, poured into methanol (3 L), and stirred overnight. Deposited crystals were collected by filtration, washed with methanol, and then dried by ventilation at 60° C. for 24 hours to give 82.5 g of the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[C:18]([CH3:23])[C:17]=1[CH3:24].[F:25][C:26]1[CH:31]=[C:30]([F:32])[CH:29]=[CH:28][C:27]=1[N:33]=[C:34]=[O:35].CCOCC>C(Cl)(Cl)Cl>[F:25][C:26]1[CH:31]=[C:30]([F:32])[CH:29]=[CH:28][C:27]=1[NH:33][C:34]([NH:20][C:19]1[CH:21]=[CH:22][C:16]([O:15][C:6]2[C:5]3[C:10](=[CH:11][C:12]([O:13][CH3:14])=[C:3]([O:2][CH3:1])[CH:4]=3)[N:9]=[CH:8][CH:7]=2)=[C:17]([CH3:24])[C:18]=1[CH3:23])=[O:35]
Reactant: COc1cc2nccc(Oc3ccc(N)c(C)c3C)c2cc1OC
Reactant: O=C=Nc1ccc(F)cc1F
Solvent: ClC(Cl)Cl
Solvent: CCOCC
Product: COc1cc2nccc(Oc3ccc(NC(=O)Nc4ccc(F)cc4F)c(C)c3C)c2cc1OC
Yield: 70 %

Procedure:
4-[(6,7-Dimethoxy-4-quinolyl)oxy]-2,3-dimethyl-aniline (710 mg) was dissolved in chloroform (7 ml), and 2,4-difluorophenyl isocyanate (310 μl) was then added to the solution. The mixture was heated under reflux for one hr, and a large amount of ether was added to the reaction solution. The resultant precipitate was collected by suction filtration to give 735 mg (yield 70%) of the title compound.
Reaction SMILES: [S:1]1[C:5]2[CH2:6][CH2:7][CH2:8][CH2:9][C:4]=2[C:3]([C:10](O)=[O:11])=[CH:2]1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>C(OCC)C>[S:1]1[C:5]2[CH2:6][CH2:7][CH2:8][CH2:9][C:4]=2[C:3]([CH2:10][OH:11])=[CH:2]1
Reactant: O=C(O)c1csc2c1CCCC2
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Product: OCc1csc2c1CCCC2
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 86.4 %

Procedure:
A solution of 4,5,6,7-tetrahydro-1-benzothiophene-3-carboxylic acid (400 mg, 2.2 mmol) in diethyl ether (10 mL) was added under nitrogen to lithium aluminium hydride (1M solution in tetrahydrofuran, 3 mL, 3 mmol) in diethyl ether (10 mL) dropwise over 5 minutes. The reaction was stirred at room temperature for 1.5 hours then quenched with saturated ammonium chloride solution. The products were extracted into diethyl ether (x3). The combined organic layers were washed with water and brine, dried over MgSO4 and evaporated in vacuo to give 4,5,6,7-tetrahydro-1-benzothien-3-ylmethanol (320 mg, 86%). 1H NMR (500 MHz, CDCl3) δ 6.99 (1H, s), 4.56 (2H, s), 2.76 (2H, t, J=5.5 Hz), 2.58 (2H, t, J=5.6 Hz), 1.86–1.79 (4H, m), 1.43 (1H, s).
Reaction SMILES: [Cl:1][C:2]1[CH:15]=[C:14]([F:16])[C:13]([C:17]2[C:21]([Cl:22])=[C:20]([C:23]([F:26])([F:25])[F:24])[N:19]([CH3:27])[N:18]=2)=[CH:12][C:3]=1[O:4][CH:5]([CH3:11])[C:6]([O:8]CC)=[O:7].[OH-].[Na+].Cl>O.O1CCOCC1>[Cl:1][C:2]1[CH:15]=[C:14]([F:16])[C:13]([C:17]2[C:21]([Cl:22])=[C:20]([C:23]([F:25])([F:26])[F:24])[N:19]([CH3:27])[N:18]=2)=[CH:12][C:3]=1[O:4][CH:5]([CH3:11])[C:6]([OH:8])=[O:7]
Reactant: CCOC(=O)C(C)Oc1cc(-c2nn(C)c(C(F)(F)F)c2Cl)c(F)cc1Cl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: CC(Oc1cc(-c2nn(C)c(C(F)(F)F)c2Cl)c(F)cc1Cl)C(=O)O
Reaction time: 0.5 h
Yield: 98.2 %

Procedure:
To a slurry of 1.4 g (3.3 mmole) 2-(2-chloro-5-(4-chloro-1-methyl-5-(trifluoromethyl)-1H-pyrazol-3-yl)-4-fluorophenoxy)-propanoic acid, ethyl ester in 50 mL water and 30 mL 1,4-dioxane was added 1.3 mL (3.3 mmole) of a 10% NaOH solution. After 30 minutes, the solution was cooled and the pH adjusted to 3 with concentrated HCl. The reaction mixture was extracted with diethyl ether. The ether solution was washed with water, dried over anhydrous MgSO4, and concentrated in vacuo. The residue was recrystallized from methylcyclohexane to give 1.3 g (100%) of 2-(2-chloro-5-(4-chloro-1-methyl-5-(tri-fluoromethyl)-1H-pyrazol-3-yl)-4-fluorophenoxy)propanoic acid as a white solid, mp 150°-151° C.
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:10]=[CH:9][N:8]=[C:7]([C:11]2[N:12]=[CH:13][N:14]([CH3:17])[C:15]=2Br)[CH:6]=1)=[O:4].[CH:18]1([CH2:21][O:22][C:23]2[CH:28]=[C:27]([F:29])[CH:26]=[CH:25][C:24]=2B(O)O)[CH2:20][CH2:19]1>>[CH:18]1([CH2:21][O:22][C:23]2[CH:28]=[C:27]([F:29])[CH:26]=[CH:25][C:24]=2[C:15]2[N:14]([CH3:17])[CH:13]=[N:12][C:11]=2[C:7]2[CH:6]=[C:5]([C:3]([OH:2])=[O:4])[CH:10]=[CH:9][N:8]=2)[CH2:19][CH2:20]1
Reactant: OB(O)c1ccc(F)cc1OCC1CC1
Reactant: COC(=O)c1ccnc(-c2ncn(C)c2Br)c1
Product: Cn1cnc(-c2cc(C(=O)O)ccn2)c1-c1ccc(F)cc1OCC1CC1
Yield: 10 %

Procedure:
The title compound was prepared in 10% yield from 2-(5-bromo-1-methyl-1H-imidazol-4-yl)pyridine-4-carboxylic acid methyl ester and 2-(cyclopropylmethoxy)-4-fluorophenylboronic acid according to the procedure for the preparation of Example 3, part A followed by hydrolysis. 1H NMR (400 MHz, DMSO-d6): δ 0.10 (2H, m), 0.32-0.39 (2H, m), 0.88-0.93 (1H, m), 3.44 (3H, s), 3.69 (1H, m), 3.81 (1H, m), 6.80 (1H, td, J=2.4 and 8.4 Hz), 6.96 (1H, dd, J=2.4 and 11.6 Hz), 7.27 (1H, t, J=7.7 Hz), 7.45 (1H, dd, J=1.5 and 5.1 Hz), 7.84 (1H, s), 8.28 (1H, s), 8.31 (1H, d, J=5.0 Hz). [M+H] Calc'd for C20H18FN3O3, 368. Found, 368.
Reaction SMILES: C(S([N:6]1[CH2:11][CH2:10][N:9]([C:12]2[CH:17]=[CH:16][C:15]([NH:18][C:19]([C:21]3[O:22][C:23]4[C:28]([C:29](=[O:31])[CH:30]=3)=[CH:27][C:26]([F:32])=[CH:25][C:24]=4[N:33]3[CH2:38][CH2:37][N:36]([CH3:39])[CH2:35][CH2:34]3)=[O:20])=[CH:14][CH:13]=2)[CH2:8][CH2:7]1)(=O)=O)C.C(N(CC)CC)C.[CH2:47]([N:49]=[C:50]=[O:51])[CH3:48]>C(Cl)Cl>[CH2:47]([NH:49][C:50]([N:6]1[CH2:11][CH2:10][N:9]([C:12]2[CH:17]=[CH:16][C:15]([NH:18][C:19]([C:21]3[O:22][C:23]4[C:28]([C:29](=[O:31])[CH:30]=3)=[CH:27][C:26]([F:32])=[CH:25][C:24]=4[N:33]3[CH2:34][CH2:35][N:36]([CH3:39])[CH2:37][CH2:38]3)=[O:20])=[CH:14][CH:13]=2)[CH2:8][CH2:7]1)=[O:51])[CH3:48]
Reactant: CCN=C=O
Reactant: CCS(=O)(=O)N1CCN(c2ccc(NC(=O)c3cc(=O)c4cc(F)cc(N5CCN(C)CC5)c4o3)cc2)CC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCNC(=O)N1CCN(c2ccc(NC(=O)c3cc(=O)c4cc(F)cc(N5CCN(C)CC5)c4o3)cc2)CC1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
6-Fluoro-8-(4-methyl-piperazin-1-yl)-4-oxo-4H-chromene-2-carboxylic acid (4-piperazin-1-phenyl)-amide (Example 71) (150 mg, 0.216 mmol) was placed in a 50 mL flask with 10 mL of CH2Cl2. This suspension was treated with triethylamine (0.1 mL, 0.67 mmol) and ethylisocyanate (0.21 mL, 18.7 mg, 0.26 mmol) and the reaction stirred at room temperature for 18 hours. The reaction was concentrated (1 mm Hg pressure) and the concentrate purified by chromatography on silica eluting with 1% methanol in chloroform, then concentrated (1 mm Hg pressure). Then triturated with either to yield a yellow powder with was dried under high vacuum for 48 h at 50° C. (79 mg) LCMS−AP+537.4, mp=236–238° C.
Reaction SMILES: BrBr.Cl[CH2:4][CH2:5][CH2:6][C:7](=[O:9])[CH3:8].[C:10]1([SH:16])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.[OH-].[K+]>C(Cl)Cl.CO>[C:10]1([S:16][C:6]2([C:7]([CH3:8])=[O:9])[CH2:4][CH2:5]2)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: CC(=O)CCCCl
Reactant: Sc1ccccc1
Agent: BrBr
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: ClCCl
Product: CC(=O)C1(Sc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 48.1 %

Procedure:
A solution of 134 g (0.83 mol) of bromine in 130 ml of methylene chloride is added dropwise with stirring at 10° C. to a solution of 100 g (0.83 mol) of 5-chloropentan-2-one in 400 ml of methylene chloride. The reaction mixture is stirred for 1 hour at room temperature, then washed with water and dilute, aqueous sodium carbonate solution and dried over sodium sulphate. The mixture is concentrated by removing the solvent under reduced pressure, and the residue is taken up in 200 ml of methanol and 91.5 g (0.83 mol) of thiophenol are added at 5° C. with stirring. A mixture of 93 g of potassium hydroxide powder in 500 ml of methanol is then added dropwise. The reaction mixture is first stirred at room temperature for 2 hours and then at 40° C. for 4 hours. The mixture is subsequently concentrated by removing the solvent under reduced pressure and the residue which remains is taken up in methylene chloride. The organic solution is washed successively with water, dilute aqueous sodium carbonate solution and again with water, then concentrated under reduced pressure and then subjected to a vacuum distillation. In this manner, 76.8 g (48% of theory) of methyl 1-phenylmercaptocyclopropyl ketone of boiling point 155° C./20 mbar are obtained.
Reaction SMILES: C([NH:4][C:5]1[N:6]=[C:7](C2N=CNN=2)[C:8]2[N:14]=[C:13]([C:15]3[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=3)[CH:12]=[CH:11][C:9]=2[N:10]=1)(=O)C.[H-].[Na+].[CH:29]1([CH2:32][OH:33])[CH2:31][CH2:30]1>O1CCOCC1>[NH2:4][C:5]1[N:6]=[C:7]([O:33][CH2:32][CH:29]2[CH2:31][CH2:30]2)[C:8]2[N:14]=[C:13]([C:15]3[CH:16]=[CH:17][C:18]([F:21])=[CH:19][CH:20]=3)[CH:12]=[CH:11][C:9]=2[N:10]=1
Reactant: OCC1CC1
Reactant: CC(=O)Nc1nc(-c2nc[nH]n2)c2nc(-c3ccc(F)cc3)ccc2n1
Agent: [H-]
Agent: [Na+]
Solvent: C1COCCO1
Product: Nc1nc(OCC2CC2)c2nc(-c3ccc(F)cc3)ccc2n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 47 %

Procedure:
To a solution of 2-acetamido-4-(1,2,4-triazolyl)-6-(4-fluorophenyl)-pyrido[3,2-d]pyrimidine (52 mg, 0.15 mmol) in cyclopropylmethanol (1 ml) and dioxane (3 ml) was added NaH (60% dispersion in mineral oil, 0.25 mmol, 15 mg). The reaction mixture was stirred overnight at room temperature. The solvents were evaporated in vacuo, and the residue was purified by preparative TLC, the mobile phase being a methanol/dichloromethane mixture in a ratio of 10:90, yielding the pure title compound (22 mg, yield: 47%) which was characterised as follows: MS (m/z): 311 ([M+H]+, 100).
Reaction SMILES: [CH2:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]#[C:12][C:13]2[CH:42]=[CH:41][C:16]([CH2:17][N:18]([C:28]3[CH:29]=[CH:30][C:31]4[C:36](=[O:37])[O:35]C(C)(C)[O:33][C:32]=4[CH:40]=3)[C:19](=[O:27])[CH2:20][CH2:21][CH:22]3[CH2:26][CH2:25][CH2:24][CH2:23]3)=[CH:15][CH:14]=2)=[CH:7][CH:6]=1)[CH2:2][CH2:3][CH3:4].[OH-].[Na+]>>[CH2:1]([C:5]1[CH:6]=[CH:7][C:8]([C:11]#[C:12][C:13]2[CH:42]=[CH:41][C:16]([CH2:17][N:18]([C:19](=[O:27])[CH2:20][CH2:21][CH:22]3[CH2:23][CH2:24][CH2:25][CH2:26]3)[C:28]3[CH:29]=[CH:30][C:31]([C:36]([OH:37])=[O:35])=[C:32]([OH:33])[CH:40]=3)=[CH:15][CH:14]=2)=[CH:9][CH:10]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1ccc(C#Cc2ccc(CN(C(=O)CCC3CCCC3)c3ccc4c(c3)OC(C)(C)OC4=O)cc2)cc1
Agent: [Na+]
Agent: [OH-]
Product: CCCCc1ccc(C#Cc2ccc(CN(C(=O)CCC3CCCC3)c3ccc(C(=O)O)c(O)c3)cc2)cc1

Procedure:
The titled compound was prepared following the procedure C using N-{4-[(4-butylphenyl)ethynyl]benzyl}-3-cyclopentyl-N-(2,2-dimethyl-4-oxo-4H-1,3-benzodioxin-7-yl)propanamide and NaOH as a yellow powder (74%). 1H NMR (DMSO-d6, 300 MHz) δ 7.76 (d, J=8.3 Hz, 1H), 7.45 (m, 4H), 7.23 (m, 4H) 6.84 (m, 1H), 6.77 (m, 1H), 4.92 (s, 2H), 2.60 (t, J=7.6 Hz, 2H), 2.20 (t, J=7.3 Hz, 2H), 1.70-1.21 (m, 13H), 1.00-0.84 (m, 5H). HPLC, Rt: 5.84 min (Purity: 100%).
Reaction SMILES: [OH-:1].[K+].[C:3]([C:5]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[CH2:6][CH2:7][N:8]([CH3:18])[CH2:9][CH2:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)#[N:4]>O.C(O)C>[C:19]1([C:5]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)([CH2:6][CH2:7][N:8]([CH3:18])[CH2:9][CH2:10][CH2:11][C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:3]([NH2:4])=[O:1])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: [OH-]
Reactant: CN(CCCc1ccccc1)CCC(C#N)(c1ccccc1)c1ccccc1
Agent: [K+]
Solvent: CCO
Solvent: O
Product: CN(CCCc1ccccc1)CCC(C(N)=O)(c1ccccc1)c1ccccc1
Temperature: 150 °C

Procedure:
A solution of potassium hydroxide (0.2 g) in water (10 ml) was added to a solution of 1-cyano-1,1-diphenyl-3-[N-methyl-N-(3-phenylprop-I-yl)amino]propane (0.22 g--see Preparation 23) in ethanol (10 ml) and the mixture was heated at 150° C. for 20 hours in a stainless steel pressure vessel then concentrated in vacuo. Water (30 ml) was added to the residue and the mixture was extracted with dichloromethane (3×30 ml). The combined dichloromethane extracts were dried (Na2SO4) and concentrated in vacuo to give a gum which was purified by column chromatography on silica eluting with dichloromethane containing methanol (0% up to 10%). The product-containing fractions were combined and concentrated in vacuo to give the title compound as a viscous gum, yield, 0.11 g.
Reaction SMILES: C[O:2][C:3](=[O:23])[CH:4]([NH:15]C(OC(C)(C)C)=O)[CH2:5][C:6]1[CH:11]=[C:10]([Br:12])[C:9]([OH:13])=[C:8]([Br:14])[CH:7]=1.Br[CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([I:32])[CH:27]=1>>[NH2:15][CH:4]([CH2:5][C:6]1[CH:7]=[C:8]([Br:14])[C:9]([O:13][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[C:28]([I:32])[CH:27]=2)=[C:10]([Br:12])[CH:11]=1)[C:3]([OH:2])=[O:23]
Reactant: BrCc1cccc(I)c1
Reactant: COC(=O)C(Cc1cc(Br)c(O)c(Br)c1)NC(=O)OC(C)(C)C
Product: NC(Cc1cc(Br)c(OCc2cccc(I)c2)c(Br)c1)C(=O)O
Yield: 38 %

Procedure:
Methyl-2-tert-butoxycarbonylamino-3-(3,5-dibromo-4-hydroxyphenyl)propionate (0.035 mmol) was coupled with 1-bromomethyl-3-iodobenzene and hydrolyzed using the method described in “General procedure for the preparation of Examples 8-22”. This gave 38% yield of 2-amino-3-[3,5-dibromo-4-(3-iodobenzyloxy)phenyl]propionic acid. LC/MS (electrospray): m/z 554 (M−1).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:17])[NH:5][C:6]1[CH:15]=[CH:14][C:13]2[C:8](=[CH:9][CH:10]=[C:11]([OH:16])[CH:12]=2)[CH:7]=1)[CH3:2].C(N(CC)CC)C.[C:25](Cl)(=[O:27])[CH3:26]>ClCCl>[CH2:1]([O:3][C:4](=[O:17])[NH:5][C:6]1[CH:15]=[CH:14][C:13]2[C:8](=[CH:9][CH:10]=[C:11]([O:16][C:25](=[O:27])[CH3:26])[CH:12]=2)[CH:7]=1)[CH3:2]
Reactant: CC(=O)Cl
Reactant: CCOC(=O)Nc1ccc2cc(O)ccc2c1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)Nc1ccc2cc(OC(C)=O)ccc2c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of N-(6-hydroxy-2-naphthyl)carbamic acid ethyl ester (1 g, 4.32 mmol) and triethylamine (1.80 mL, 13 mmol) in dichloromethane (20 mL) at room temperature, is added acetyl chloride (0.369 mL, 5.19 mmol) dropwise. After stirring at room temperature for 3 hours, the reaction mixture is concentrated and purified by flash chromatography on silica gel (2:1 hexane/EtOAc) to give N-(6-acetyloxy-2-naphthyl)carbamic acid ethyl ester as a white solid.
Reaction SMILES: [F:1][C:2]1[C:7]2[NH:8]C(=O)[O:10][C:11](=O)[C:6]=2[CH:5]=[CH:4][CH:3]=1.[Br:14][C:15]1[C:16]([CH3:22])=[C:17]([CH:19]=[CH:20][CH:21]=1)[NH2:18]>>[NH2:8][C:7]1[C:2]([F:1])=[CH:3][CH:4]=[CH:5][C:6]=1[C:11]([NH:18][C:17]1[CH:19]=[CH:20][CH:21]=[C:15]([Br:14])[C:16]=1[CH3:22])=[O:10]
Reactant: O=c1[nH]c2c(F)cccc2c(=O)o1
Reactant: Cc1c(N)cccc1Br
Product: Cc1c(Br)cccc1NC(=O)c1cccc(F)c1N
Temperature: 25 °C
Reaction time: 6 h
Yield: 83.9 %

Procedure:
A suspension of 8-fluoro-1H-benzo[d][1,3]oxazine-2,4-dione (3.00 g, 16.6 mmol) in xylenes (50 mL) was treated with 3-bromo-2-methylaniline (3.08 g, 16.6 mmol) and heated to reflux. After 6 h the mixture was allowed to cool to room temperature overnight. The resulting suspension was diluted with hexanes and the precipitate was collected by filtration, rinsed with hexanes and air-dried to provide 2-amino-N-(3-bromo-2-methylphenyl)-3-fluorobenzamide as a white solid (4.50 g, 84% yield). 1H NMR (400 MHz, chloroform-d) δ 7.69 (d, J=7.9 Hz, 1H), 7.65 (br. s., 1H), 7.50-7.46 (m, 1H), 7.32 (d, J=8.1 Hz, 1H), 7.19-7.11 (m, 2H), 6.73-6.64 (m, 1H), 5.69 (br. s., 2H), 2.44 (s, 3H).
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)(=[O:4])=[O:3].C([Li])CCC.CN(C)CCN(C)C.Cl[CH2:25][C:26]1([CH2:30]Cl)[CH2:29][O:28][CH2:27]1>C1COCC1.O>[C:5]1([S:2]([CH:1]2[CH2:30][C:26]3([CH2:29][O:28][CH2:27]3)[CH2:25]2)(=[O:4])=[O:3])[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: ClCC1(CCl)COC1
Reactant: CS(=O)(=O)c1ccccc1
Agent: CN(C)CCN(C)C
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Product: O=S(=O)(c1ccccc1)C1CC2(COC2)C1
Temperature: -20 °C
Reaction time: 1 h

Procedure:
To a solution of methylsulfonylbenzene (2.00 g; 12.8 mmol) in dry THF (40 mL) under nitrogen at 0° C. was added butyl lithium (25.6 mmol; 2.5M solution on hexane). The mixture was stirred for 1 hour and then cooled to −20° C. Tetramethylethylenediamine (1.93 mL; 12.8 mmol) was added followed by a solution of 3,3-bis(chloromethyl)oxetane (1.98 g; 12.8 mmol) in dry THF (10 mL). The mixture was allowed to warm to 0° C. and then slowly allowed to reach 15° C. over 12 hours. Water (100 mL) was added and the mixture was extracted into ethyl acetate (4×50 mL). The combined extracts were dried over sodium sulfate, filtered and concentrated under reduced pressure. The material was purified on silica gel (Biotage system, utilizing two 120 g columns in series) eluting with hexane/ethyl acetate (2:1 to 1:2 gradient). The desired product was obtained as an off white solid (700 mg).
Reaction SMILES: C([O:5][C:6](=[O:23])[CH2:7][N:8]([C:16]([C:18]1[NH:19][CH:20]=[CH:21][CH:22]=1)=[O:17])[CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)(C)(C)C.C(O)(C(F)(F)F)=O>ClCCl>[NH:19]1[CH:20]=[CH:21][CH:22]=[C:18]1[C:16]([N:8]([CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[CH2:7][C:6]([OH:23])=[O:5])=[O:17]
Reactant: CC(C)(C)OC(=O)CN(Cc1ccccc1)C(=O)c1ccc[nH]1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)CN(Cc1ccccc1)C(=O)c1ccc[nH]1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a solution containing 2.85 (9.01 mmol) of (Pyrrole-2-carbonyl)-N-(benzyl)glycine-t-butyl ester in 50 mL of anhydrous dichloromethane cooled to 0° C. was added 25 mL of TFA dropwise. After 90 minutes an additional 25 mL of TFA was added and allowed to stir for 30 minutes. The mixture was evaporated in vacuo to afford 2.19 g of (Pyrole-2-carbonyl)-N-(benzyl)glycine as a tan solid. FAB MS [M+H] m/z; Calcd. 259, Found 259.
Reaction SMILES: CCCCCC.[H-].[Na+].[CH2:9]([C:11]1[CH:20]=[C:19]([CH3:21])[C:18]2[C:17](=[O:22])[NH:16][C@@H:15]3[CH2:23][N:24]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:25][C@H:14]3[C:13]=2[CH:12]=1)[CH3:10].[CH2:33](Br)[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1>C1COCC1>[CH2:33]([N:16]1[C@@H:15]2[CH2:23][N:24]([C:26]([O:28][C:29]([CH3:31])([CH3:30])[CH3:32])=[O:27])[CH2:25][C@H:14]2[C:13]2[CH:12]=[C:11]([CH2:9][CH3:10])[CH:20]=[C:19]([CH3:21])[C:18]=2[C:17]1=[O:22])[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1
Reactant: CCc1cc(C)c2c(c1)[C@@H]1CN(C(=O)OC(C)(C)C)C[C@H]1NC2=O
Reactant: BrCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CCc1cc(C)c2c(c1)[C@@H]1CN(C(=O)OC(C)(C)C)C[C@H]1N(Cc1ccccc1)C2=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 88 %

Procedure:
To a suspension of hexane-washed sodium hydride (6 mg of 60% dispersion in mineral oil, 0.15 mmol) in 1 mL THF was added (±)-trans-tert-butyl 8-ethyl-6-methyl-5-oxo-3,3a,4,5-tetrahydro-1H-pyrrolo[3,4-c]isoquinoline-2(9bH)-carboxylate from Example 74, Part A (25 mg, 0.076 mmol) in 2 mL of THF. The mixture was stirred at ambient temperature for 30 min, at which time gas evolution had ceased. Then there was added benzyl bromide (0.027 mL, 0.23 mmol) and the resulting mixture was allowed to stir at ambient temperature for 18 h. The reaction was quenched with 1N HCl and diluted with ethyl acetate. The organics were washed sequentially with sat'd aq. NaHCO3, and brine, dried (MgSO4), and concentrated. The residue was purified by flash chromatography (elution with 4:1 hexane/EtOAc) to afford 28 mg (88%) of the title compound as an oil. LRMS (ESI): 421.1 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH2:8][OH:9])[CH:5]=[N:6][CH:7]=1.[Cl:10][C:11]1[C:16]([Cl:17])=[CH:15][CH:14]=[CH:13][C:12]=1[S:18]([NH:21][C:22]1[C:27](Cl)=[N:26][C:25]([Cl:29])=[CH:24][N:23]=1)(=[O:20])=[O:19]>>[Br:1][C:2]1[CH:3]=[C:4]([CH2:8][O:9][C:27]2[C:22]([NH:21][S:18]([C:12]3[CH:13]=[CH:14][CH:15]=[C:16]([Cl:17])[C:11]=3[Cl:10])(=[O:20])=[O:19])=[N:23][CH:24]=[C:25]([Cl:29])[N:26]=2)[CH:5]=[N:6][CH:7]=1
Reactant: O=S(=O)(Nc1ncc(Cl)nc1Cl)c1cccc(Cl)c1Cl
Reactant: OCc1cncc(Br)c1
Product: O=S(=O)(Nc1ncc(Cl)nc1OCc1cncc(Br)c1)c1cccc(Cl)c1Cl

Procedure:
Prepared by the method of Example 31 using (5-bromo-3-pyridinyl)methanol (0.2 g) and 2,3-dichloro-N-(3,5-dichloro-2-pyrazinyl)benzenesulphonamide (Example 74) (0.25 g).