Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[C:8]([N+:10]([O-])=O)[CH:7]=[CH:6][C:5]=1[CH2:13][C:14]([OH:16])=[O:15])([O-])=O.[H][H].C(=O)([O-])O.[Na+:23]>O.[Pd]>[Na+:23].[NH2:1][C:4]1[CH:9]=[C:8]([NH2:10])[CH:7]=[CH:6][C:5]=1[CH2:13][C:14]([O-:16])=[O:15]
Reactant: O=C(O)Cc1ccc([N+](=O)[O-])cc1[N+](=O)[O-]
Reactant: [H][H]
Agent: [Pd]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Product: Nc1ccc(CC(=O)[O-])c(N)c1
Yield: 84.1 %

Procedure:
Five grams of 2,4-dinitrophenylacetic acid were dissolved in a solution of 1.9 gm of sodium hydrogen carbonate in 200 ml water and reduced with hydrogen in the presence of 0.3 gm of palladium on charcoal at room temperature. After completion of the uptake of hydrogen, the catalyst was filtered off, and the filtrate was evaporated in a rotary evaporator at a bath temperature of 30° C. maximum. An amount of 3.5 gm of 2,4-diaminophenylacetic acid sodium salt was obtained.
Reaction SMILES: [Mg].C(Br)C.C([Mg]Br)C.[NH2:9][C:10]1[S:11][CH:12]=[CH:13][CH:14]=1.[C:15]([NH:18][C:19]1[S:23][C:22]2[CH:24]=[CH:25][CH:26]=[CH:27][C:21]=2[C:20]=1[C:28]([O-])=[O:29])(=[O:17])[CH3:16]>O1CCCC1>[S:11]1[CH:12]=[CH:13][CH:14]=[C:10]1[NH:9][C:28]([C:20]1[C:21]2[CH:27]=[CH:26][CH:25]=[CH:24][C:22]=2[S:23][C:19]=1[NH:18][C:15]([CH3:16])=[O:17])=[O:29]
Reactant: CC(=O)Nc1sc2ccccc2c1C(=O)[O-]
Reactant: Nc1cccs1
Agent: CC[Mg]Br
Agent: [Mg]
Solvent: CCBr
Solvent: C1CCOC1
Product: CC(=O)Nc1sc2ccccc2c1C(=O)Nc1cccs1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
3 g of magnesium curlings and 30 ml of anhydrous tetrahydrofuran are initially introduced into a sulfonation flask and 13.5 g of ethyl bromide are added in order to prepare ethyl-magnesium bromide. After the magnesium has dissolved, 6.1 g of 2-aminothiophen, dissolved in 60 ml of absolute tetrahydrofuran, are added dropwise and the mixture is stirred for one hour at room temperature and then refluxed for a further 15 minutes. 8 g of . . . 2-acetamido-benzo[b]thiophen-3-carboxylate, dissolved in 100 ml of absolute tetrahydrofuran, are then added dropwise at room temperature. The mixture is then refluxed for 15 minutes and stirred for a further 15 minutes at room temperature, the reaction solution is evaporated in vacuo, dilute hydrochloric acid is added to the evaporation residue and the mixture is extracted twice with chloroform. The chloroform extracts are combined, dried over sodium sulfate and evaporated to dryness in vacuo. Crude N-(2-thienyl)-2-acetamino-benzo[b]thiophen-3-carboxamide is obtained and this can be used without further purification.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[N:12]=[C:11]([CH2:19][OH:20])[C:10]=1[CH3:21])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:22]([N:27]=[C:28]=[O:29])[CH2:23][CH2:24][CH2:25][CH3:26].CO>C1COCC1>[CH2:1]([O:8][C:9]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[N:12]=[C:11]([CH2:19][O:20][C:28](=[O:29])[NH:27][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])[C:10]=1[CH3:21])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCCCCN=C=O
Reactant: Cc1c(CO)nc2ccccc2c1OCc1ccccc1
Solvent: CO
Solvent: C1CCOC1
Product: CCCCCNC(=O)OCc1nc2ccccc2c(OCc2ccccc2)c1C
Temperature: 25 °C
Reaction time: 1 h
Yield: 101.7 %

Procedure:
To a solution of [4-(benzyloxy)-3-methylquinolin-2-yl]methanol (105 mg) in THF (3 mL) was added pentylisocyanate (45 mg), followed by stirring at room temperature for 1 hour. Pentylisocyanate (20 mg) was further added to the reaction mixture, followed by stirring at room temperature for 16 hours. Methanol (2 mL) was added to the reaction mixture, and then the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: chloroform) to obtain [4-(benzyloxy)-3-methylquinolin-2-yl]methylpentylcarbamate (150 mg).
Reaction SMILES: CI.[CH3:3][C:4]1([CH3:42])[NH:9][CH2:8][CH2:7][N:6]([CH2:10][C:11]2[N:16]=[CH:15][C:14]([NH:17][C:18]([C:20]3[C:21]4[N:22]=[CH:23][CH:24]=[N:25][C:26]=4[C:27]([C:30]4[C:35]([Cl:36])=[C:34]([O:37][CH3:38])[CH:33]=[C:32]([O:39][CH3:40])[C:31]=4[Cl:41])=[CH:28][CH:29]=3)=[O:19])=[CH:13][CH:12]=2)[CH2:5]1.[C:43](=O)([O-])[O-].[K+].[K+]>CC#N>[CH3:3][C:4]1([CH3:42])[N:9]([CH3:43])[CH2:8][CH2:7][N:6]([CH2:10][C:11]2[N:16]=[CH:15][C:14]([NH:17][C:18]([C:20]3[C:21]4[N:22]=[CH:23][CH:24]=[N:25][C:26]=4[C:27]([C:30]4[C:31]([Cl:41])=[C:32]([O:39][CH3:40])[CH:33]=[C:34]([O:37][CH3:38])[C:35]=4[Cl:36])=[CH:28][CH:29]=3)=[O:19])=[CH:13][CH:12]=2)[CH2:5]1
Reactant: O=C([O-])[O-]
Reactant: COc1cc(OC)c(Cl)c(-c2ccc(C(=O)Nc3ccc(CN4CCNC(C)(C)C4)nc3)c3nccnc23)c1Cl
Agent: [K+]
Solvent: CC#N
Solvent: CI
Product: COc1cc(OC)c(Cl)c(-c2ccc(C(=O)Nc3ccc(CN4CCN(C)C(C)(C)C4)nc3)c3nccnc23)c1Cl
Temperature: 25 °C
Reaction time: 72 h
Yield: 22.7 %

Procedure:
Methyl iodide (15 μL, 0.24 mmol, 1.2 equiv) was added to a mixture of 8-(2,6-dichloro-3,5-dimethoxy-phenyl)-quinoxaline-5-carboxylic acid [6-(3,3-dimethyl-piperazin-1-ylmethyl)pyridin-3-yl]-amide (Example 112) (115 mg, 0.2 mmol) and potassium carbonate (33 mg, 0.24 mmol, 1.2 equiv) in CH3CN (4 mL). The reaction mixture was stirred for 72 h at rt, quenched by addition of a saturated aqueous solution of NaHCO3 and extracted with EtOAc. The organic layer was washed with a saturated aqueous solution of NaHCO3, dried (Na2SO4), filtered and concentrated. The residue was purified by silica gel column chromatography (DCM/NH3aq, 99:1→DCM/MeOH/NH3aq, 96:3:1) followed by trituration id Et2O to afford 27 mg of the title compound as a yellow solid. Title compound: ESI-MS: 595.1/596.6 [M+H]+; tR=3.54 min (System 1); TLC: Rf=0.17 (DCM/MeOH, 9:1).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([OH:9])[CH:5]=[C:6]([CH3:8])[CH:7]=1.Br[CH2:11][C:12]([O:14][CH3:15])=[O:13].C(=O)([O-])[O-].[Cs+].[Cs+]>C(#N)C>[Br:1][C:2]1[CH:3]=[C:4]([CH:5]=[C:6]([CH3:8])[CH:7]=1)[O:9][CH2:11][C:12]([O:14][CH3:15])=[O:13]
Reactant: COC(=O)CBr
Reactant: Cc1cc(O)cc(Br)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: COC(=O)COc1cc(C)cc(Br)c1
Yield: 100 %

Procedure:
A solution of 7.0 g of 3-bromo-5-methylphenol and 5.97 g of methyl bromoacetate and also 13 g of caesium carbonate in 100 ml of acetonitrile is stirred overnight at room temperature. After customary working up, 9.70 g of methyl 3-bromo-5-methylphenoxyacetate (“AB”) are obtained. A suspension of 2.0 g of “AB”, 100 mg of tetrakis(triphenylphosphine)palladium and 0.85 g of sodium carbonate in 50 ml of toluene is heated to boiling. A solution of 2.94 g of 3-cyanophenylboronic acid in 30 ml of methanol is then added dropwise and the mixture is heated under reflux for 14 hours. It is worked up in the customary manner and 2.17 g of methyl 3′-cyano-5-methylbiphenyl-3-yloxyacetate (“AC”) are obtained. A solution of 1.2 g of “AC” and 0.765 g of NBS in 50 ml of carbon tetrachloride is irradiated with UV light at room temperature. After customary working up, 1.54 g of methyl 3′-cyano-5-bromomethylbiphenyl-3-yloxyacetate (“AD”) are obtained. A solution of 185 mg of “AD”, 63.1 mg of 4-hydroxybenzonitrile and 172.7 mg of caesium carbonate in 10 ml of acetonitrile is stirred at room temperature for 4 days. After customary working up, methyl 3′-cyano-5-(4-cyanophenoxymethyl)biphenyl-3-yloxyacetate (“AE”) is obtained. A solution of 60 mg of “AE”, 69.5 mg of hydroxylammonium chloride and 101 mg of triethylamine in 10 ml of methanol is heated under reflux for 14 hours. After removal of the solvent, the residue is taken up in water. The solid is separated off and 70 mg of methyl 3′-N-hydroxyamidino-5-(4-N-hydroxyamidinophenoxymethyl)biphenyl-3-yloxyacetate (“AF”) are obtained. By reduction with H2/Raney nickel, methyl 3′-amidino-5-(4-amidinophenoxymethyl)biphenyl-3-yloxyacetate, FAB 433
Reaction SMILES: [N:1]1([C:7]2[CH:12]=[CH:11][C:10]([N+:13]([O-])=O)=[CH:9][C:8]=2[C:16]([N:18]2[CH2:23][CH2:22][N:21]([C:24]3[CH:29]=[CH:28][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:26][CH:25]=3)[CH2:20][CH2:19]2)=[O:17])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[H][H]>CO.[Pd]>[NH2:13][C:10]1[CH:11]=[CH:12][C:7]([N:1]2[CH2:2][CH2:3][O:4][CH2:5][CH2:6]2)=[C:8]([C:16]([N:18]2[CH2:19][CH2:20][N:21]([C:24]3[CH:25]=[CH:26][C:27]([C:30]([F:32])([F:33])[F:31])=[CH:28][CH:29]=3)[CH2:22][CH2:23]2)=[O:17])[CH:9]=1
Reactant: [H][H]
Reactant: O=C(c1cc([N+](=O)[O-])ccc1N1CCOCC1)N1CCN(c2ccc(C(F)(F)F)cc2)CC1
Agent: [Pd]
Solvent: CO
Product: Nc1ccc(N2CCOCC2)c(C(=O)N2CCN(c3ccc(C(F)(F)F)cc3)CC2)c1
Yield: 79.1 %

Procedure:
To a solution of (2-Morpholin-4-yl-5-nitro-phenyl)-[4-(4-trifluoromethyl-phenyl)-piperazin-1-yl]-methanone (preparation described in example 57, 150 mg, 0.323 mmol) in methanol (3 ml) was added Pd/C 10% (6.9 mg). The mixture was stirred under an atmospheric pressure of hydrogen at room temperature for 1 hour. Catalyst was filtered and the filtrate was concentrated in vacuo. The residue was chromatographed over silicagel (Eluent: Heptane/Ethylacetate (0-100% in 20 minutes)) to provide the title compound (111 mg, 79% yield) as a yellow solid, MS (m/e): 435.2 (M+H+, 100%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([O:10][C:11]2[C:19]3[N:18]=[N:17][NH:16][C:15]=3[CH:14]=[CH:13][C:12]=2[Cl:20])[CH:9]=1)[C:5]#[N:6].CC(C)([O-])C.[Li+].Cl[CH2:28][C:29]([N:31]([CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=1[Cl:40])[CH3:32])=[O:30]>CN(C=O)C>[Cl:40][C:35]1[CH:36]=[CH:37][CH:38]=[CH:39][C:34]=1[CH2:33][N:31]([CH3:32])[C:29](=[O:30])[CH2:28][N:16]1[C:15]2[CH:14]=[CH:13][C:12]([Cl:20])=[C:11]([O:10][C:8]3[CH:7]=[C:4]([C:5]#[N:6])[CH:3]=[C:2]([Cl:1])[CH:9]=3)[C:19]=2[N:18]=[N:17]1
Reactant: CN(Cc1ccccc1Cl)C(=O)CCl
Reactant: N#Cc1cc(Cl)cc(Oc2c(Cl)ccc3[nH]nnc23)c1
Agent: CC(C)(C)[O-]
Agent: [Li+]
Solvent: CN(C)C=O
Product: CN(Cc1ccccc1Cl)C(=O)Cn1nnc2c(Oc3cc(Cl)cc(C#N)c3)c(Cl)ccc21
Temperature: 0 °C
Reaction time: 0.08 h

Procedure:
3-chloro-5-[(5-chloro-1H-1,2,3-benzotriazol-4-yl)oxy]benzonitrile (25 mg, 0.082 mmol) and lithium tert-butoxide (6.9 mg, 0.089 mmol) were dissolved in DMF (0.5 mL) and allowed to stir for 5 minutes. After this time, the reaction was cooled to 0° C. and 2-chloro-N-(2-chlorobenzyl)-N-methylacetamide as a solution in DMF (0.5 mL) was added dropwise. This was allowed to warm to room temperature and after 16 hours, the reaction was quenched with TFA, diluted with MeCN and purified by reverse phase chromatography eluting with 30-95% MeCN/H2O+0.1% TFA. Product fractions were lyophilized to yield the title compound. 1H NMR (DMSO-d6) δ 7.84 (m, 1H), 7.83 (d, J=9.0 Hz, 1H), 7.79 (d, J=9.0 Hz, 1H), 7.58 (m, 1H), 7.51 (m, 1H), 7.47 (m, 1H), 7.35 (m, 3H), 6.05 (s, 2H), 4.62 (s, 2H), 3.20 (s, 3H).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[N:10]=[CH:9][N:8]=[C:7]2[NH:14][CH:15]=[C:16]([C:22]([O:24][CH2:25][CH3:26])=[O:23])[C:17]([O:19][CH2:20][CH3:21])=[O:18])([O-])=O.C1C=CC=CC=1>CN(C)C=O.[Pd].[H][H]>[NH2:1][C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[N:10]=[CH:9][N:8]=[C:7]2[NH:14][CH:15]=[C:16]([C:22]([O:24][CH2:25][CH3:26])=[O:23])[C:17]([O:19][CH2:20][CH3:21])=[O:18]
Reactant: [H][H]
Reactant: CCOC(=O)C(=CNc1ncnc2ccc([N+](=O)[O-])cc12)C(=O)OCC
Agent: [Pd]
Solvent: c1ccccc1
Solvent: CN(C)C=O
Product: CCOC(=O)C(=CNc1ncnc2ccc(N)cc12)C(=O)OCC

Procedure:
A solution of diethyl [(6-nitro-4-quinazolinylamino)methylene]propanedioate (10.8 g) in N,N-dimethylformamide (325 ml) was shaken with 10% palladium on carbon (3.6 g) in hydrogen atmosphere at ambient temperature. After the absorption of hydrogen was finished, the catalyst was removed by filtration. The filtrate was concentrated under reduced pressure to give a residue, to which was added benzene. The mixture was concentrated under reduced pressure to give crude crystals of diethyl [(6-amino-4-quinazolinylamino)methylene]propanedioate.
Reaction SMILES: [N+:1]([C:4]1[C:9]([CH:10]=[CH2:11])=[CH:8][CH:7]=[CH:6][N:5]=1)([O-:3])=[O:2].[NH2:12][CH:13]1[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15][CH2:14]1.C(N(CC)CC)C>C(O)C>[N+:1]([C:4]1[C:9]([CH2:10][CH2:11][NH:12][CH:13]2[CH2:14][CH2:15][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:17][CH2:18]2)=[CH:8][CH:7]=[CH:6][N:5]=1)([O-:3])=[O:2]
Reactant: C=Cc1cccnc1[N+](=O)[O-]
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Solvent: CCO
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCC(NCCc2cccnc2[N+](=O)[O-])CC1
Temperature: 90 °C
Yield: 48 %

Procedure:
2-Nitro-3-vinylpyridine (0.300 g, 2 mmol), tert-butyl 4-aminopiperidine-1-carboxylate (0.601 g, 3.00 mmol), and ethanol (5 ml) were combined. Triethylamine (0.836 ml, 6.00 mmol) was added. The vial was capped and heated at 90° C. for 62 hours. More tert-butyl 4-aminopiperidine-1-carboxylate (0.601 g, 3.00 mmol), and triethylamine (0.836 ml, 6.00 mmol) were added and the mixture was heated at 90° C. for 20 hours. Mixture was concentrated by roto-vap. Silica gel chromatography eluting ethyl acetate-hexanes afforded the title compound as tan solid in 48% yield. 1H NMR (500 MHz, CHLOROFORM-D) δ ppm 8.38 (dd, J=4.58, 1.53 Hz, 1 H) 7.84 (dd, J=7.63, 1.53 Hz, 1 H) 7.49 (dd, J=7.63, 4.58 Hz, 1 H) 3.92 (s, 2 H) 2.85-2.98 (m, 3 H) 2.75 (t, J=11.75 Hz, 2 H) 2.50-2.62 (m, 1 H) 1.75 (d, J=12.51 Hz, 2 H) 1.40 (s, 9 H) 1.00-1.27 (m, 4 H).
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)(=[O:3])[CH3:2].[OH-].[Na+].[CH:12]([C:14]1[CH:22]=[CH:21][C:17]([C:18]([OH:20])=[O:19])=[CH:16][CH:15]=1)=O.Cl>C(O)C.O>[C:18]([C:17]1[CH:21]=[CH:22][C:14]([CH:12]=[CH:2][C:1]([C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=2)=[O:3])=[CH:15][CH:16]=1)([OH:20])=[O:19]
Reactant: O=Cc1ccc(C(=O)O)cc1
Reactant: CC(=O)c1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: O=C(O)c1ccc(C=CC(=O)c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 59.9 %

Procedure:
Acetophenone (44b, 0.50 ml, 4.3 mmol) and sodium hydroxide (0.50 g, 12.5 mmol) were combined in ethanol (2 ml) and water (2 ml) and stirred for 30 min at room temperature. 4-Formylbenzoic acid (1ad, 0.71 g, 4.7 mmol) was added and the mixture stirred for 48 hr at room temperature. Water (25 ml) was added, the mixture acidified with hydrochloric acid (1 N) and the resulting precipitate was filtered and recrystallized from ethyl acetate to give 0.65 g (60%) of a white solid: mp 222-224° C. [expected mp 227-229° C.]; NMR: (DMSO) δ 7.67 (m, 4H), 7.99 (m, 4H), 8.18 (m, 3H), 13.14 (s, 1H); 13C NMR: (DMSO) δ 124.2, 128.5, 128.7, 128.8, 129.6, 132.1, 133.2, 137.3, 138.7, 142.4, 166.7, 189.0.
Reaction SMILES: ClC1C=CC=C(C(OO)=[O:9])C=1.[CH3:12][CH:13]([C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([CH:21]([CH3:23])[CH3:22])[C:16]=1[NH:24][C:25]([NH:27][C:28]1[NH:32][C:31]([S:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH3:46])=[N:30][N:29]=1)=[O:26])[CH3:14]>ClCCl>[CH3:14][CH:13]([C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([CH:21]([CH3:22])[CH3:23])[C:16]=1[NH:24][C:25]([NH:27][C:28]1[N:32]=[C:31]([S:33]([CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH3:46])=[O:9])[NH:30][N:29]=1)=[O:26])[CH3:12]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CCCCCCCCCCCCCSc1nnc(NC(=O)Nc2c(C(C)C)cccc2C(C)C)[nH]1
Solvent: ClCCl
Product: CCCCCCCCCCCCCS(=O)c1nc(NC(=O)Nc2c(C(C)C)cccc2C(C)C)n[nH]1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
m-Chloroperbenzoic acid (0.26 g, 1.49 mmol) was added to a cooled (0° C.) solution of the compound of Example 15 in dichloromethane (25 mL). The solution was allowed to warm to room temperature and stirred for 4 hours. The mixture was diluted with CH2Cl2 (100 mL) and washed sequentially with NaHSO3, water, NaHCO3, and brine, dried over Na2SO4, concentrated, and triturated with hexane to give a white solid which was filtered and dried in vacuo to yield 0.42 g; m.p. 178°-181° C.
Reaction SMILES: C([Li])CCC.Br[C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([Br:13])[CH:8]=1.[F:14][C:15]1[CH:20]=[CH:19][C:18]([C:21](=O)[CH3:22])=[CH:17][CH:16]=1>O1CCCC1>[Br:13][C:9]1[CH:10]=[CH:11][CH:12]=[C:7]([C:21]([C:18]2[CH:19]=[CH:20][C:15]([F:14])=[CH:16][CH:17]=2)=[CH2:22])[CH:8]=1
Reactant: CC(=O)c1ccc(F)cc1
Reactant: Brc1cccc(Br)c1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: C=C(c1ccc(F)cc1)c1cccc(Br)c1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
A solution of n-butyllithium (1.6 M in hexane, 21 mL, 33.5 mmol, 1.16 eq.) was added dropwise over 20 min to a solution of 1,3-dibromobenzene (3.8 mL, 31.8 mmol, 1.1 eq) in 30 mL of dry tetrahydrofuran at −78° C. and under an inert atmosphere. The white suspension formed was stirred at −78° C. for 30 min. A solution of 4′-fluoro-acetophenone (3.5 mL, 28.9 mmol, 1.0 eq.) in 20 mL of tetrahydrofuran was then added dropwise and the reaction stirred for 1 h. The reaction mixture was examined by LC-MS which showed the complete formation of tertiary alcohol. The solution was quenched with a saturated solution of ammonium chloride and water. 2 N HCl was then added to reach pH=5. The two phases were separated; the organic layer was dried over anhydrous magnesium sulfate, filtered and evaporated under reduced pressure. The residual material (tertiary alcohol) was dissolved in a mixture of acetic acid/sulfuric acid (10 mL of acetic acid, 0.3 mL of sulfuric acid) and the reaction mixture was stirred for 1 h at room temperature; then it was examined by LC-MS which showed the complete formation of desired product. The solution was quenched with ice and dichloromethane (20 mL) was added. The two phases formed and were separated. The organic layer was washed with a saturated solution of sodium bicarbonate and brine. It was then dried over anhydrous magnesium sulfate, filtered and evaporated under reduced pressure. The crude was purified by flash chromatography eluting with cyclohexane. The desired product was obtained as a liquid (5.89 g, Yield: 73%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:14])[C:4]1[CH:9]=[C:8](I)[C:7]([CH2:11][F:12])=[CH:6][C:5]=1[NH2:13].[CH:15]([N:18]1[C:22]([Sn](CCCC)(CCCC)CCCC)=[CH:21][CH:20]=[N:19]1)([CH3:17])[CH3:16]>O1CCOCC1.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:14])[C:4]1[CH:9]=[C:8]([C:22]2[N:18]([CH:15]([CH3:17])[CH3:16])[N:19]=[CH:20][CH:21]=2)[C:7]([CH2:11][F:12])=[CH:6][C:5]=1[NH2:13]
Reactant: COC(=O)c1cc(I)c(CF)cc1N
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccnn1C(C)C
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Solvent: C1COCCO1
Product: COC(=O)c1cc(-c2ccnn2C(C)C)c(CF)cc1N
Temperature: 90 °C
Reaction time: 18 h
Yield: 39.7 %

Procedure:
To a solution of 2-amino-4-fluoromethyl-5-iodo-benzoic acid methyl ester (650 mg, 2.10 mmol) in dioxane (30 mL) were added 1-isopropyl-5-tributylstannanyl-1H-pyrazole (1.01 g, 1.2 equiv) and Pd(dppf)2Cl2 (172 mg, 0.1 equiv) and the resulting mixture was stirred at 90° C. for 18 h. 0.1 equiv of catalyst was added and the mixture was stirred at 90° C. for 24 h. The solvent was removed in vacuo to afford a dark oil. The crude product was purified by flash chromatography (silica gel, EtOAc/hexanes (0:100 to 35:75)) to provide a light yellow solid (243 mg, 40%) (ES-MS: m/z 292.3 [M+H]+, rt 5.31 min).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4](/[CH:9]=[CH:10]/[C:11]([N:13]2[CH2:19][CH2:18][C:17](=[O:20])[NH:16][CH2:15][CH2:14]2)=[O:12])[CH:5]=[CH:6][C:7]=1[Cl:8].I[CH2:22][C:23]([CH3:32])([CH3:31])[CH2:24][N:25]1[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]1>>[Cl:1][C:2]1[CH:3]=[C:4](/[CH:9]=[CH:10]/[C:11]([N:13]2[CH2:19][CH2:18][C:17](=[O:20])[N:16]([CH2:22][C:23]([CH3:32])([CH3:31])[CH2:24][N:25]3[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]3)[CH2:15][CH2:14]2)=[O:12])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: CC(C)(CI)CN1CCCCC1
Reactant: O=C1CCN(C(=O)/C=C/c2ccc(Cl)c(Cl)c2)CCN1
Product: CC(C)(CN1CCCCC1)CN1CCN(C(=O)/C=C/c2ccc(Cl)c(Cl)c2)CCC1=O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
In analogy to the procedure described for intermediate 4A, 1-[(E)-3-(3,4-dichloro-phenyl)-acryloyl]-[1,4]diazepan-5-one (intermediate 1A]) and 1-(3-iodo-2,2-dimethyl-propyl)-piperidine stirred 2 h at RT, gave the title compound as white solid. MS: 466.3 (MH+, 2Cl).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5](/[CH:8]=[CH:9]/[C:10]([O:12][CH3:13])=[O:11])=[CH:4][CH:3]=1.[N+](=[CH2:16])=[N-]>C(Cl)Cl.CC([O-])=O.CC([O-])=O.[Pd+2]>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C@H:8]2[CH2:16][C@@H:9]2[C:10]([O:12][CH3:13])=[O:11])=[CH:6][CH:7]=1
Reactant: COC(=O)/C=C/c1ccc(Br)cc1
Reactant: C=[N+]=[N-]
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: ClCCl
Product: COC(=O)[C@H]1C[C@@H]1c1ccc(Br)cc1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
To a mixture of compound 66c (1.50 g, 6.22 mmol) and Pd(OAc)2 (90 mg, 0.40 mmol) in DCM (20 mL) was added an ethereal solution of compound 66b (200 mL). After stirring for 10 min at 0° C., the reaction mixture was concentrated under reduced pressure to yield a residue, which was subjected to flash column chromatography on silica gel (10% EtOAc/petroleum ether) to afford compound 66d as colorless oil. Mass Spectrum (GCMS, ESI pos.): Calcd. for C11H11BrO2: 254.0 (M). found: 254.0.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[C:4]1[CH:13]=[C:12]([OH:14])[CH:11]=[C:6]([C:7]([O:9][CH3:10])=[O:8])[CH:5]=1.Cl[C:17]([F:23])([F:22])C(OC)=O.C(=O)([O-])[O-].[Cs+].[Cs+]>C(C(C)=O)C>[CH3:10][O:9][C:7](=[O:8])[C:6]1[CH:11]=[C:12]([O:14][CH:17]([F:23])[F:22])[CH:13]=[C:4]([C:3]([O:2][CH3:1])=[O:15])[CH:5]=1
Reactant: COC(=O)C(F)(F)Cl
Reactant: COC(=O)c1cc(O)cc(C(=O)OC)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCC(C)=O
Product: COC(=O)c1cc(OC(F)F)cc(C(=O)OC)c1
Temperature: 25 °C
Yield: 37.1 %

Procedure:
React 5-hydroxy-isophthalic acid dimethyl ester (5.88 g, 28 mmol), methyl 2-chloro-2,2-difluoroacetate (5.9 mL, 56 mmol), cesium carbonate (18.2 g, 56 mmol) in methyl ethyl ketone at reflux for 2 days. Cool to room temperature, filter though a filtering agent, wash with ethyl acetate, concentrate and purify (silica gel chromatography, eluting with 10:90 to 30:70 ethyl acetate:hexanes) to give the title compound (2.7 g, 37%).
Reaction SMILES: [C:1](N1C=CN=C1)(N1C=CN=C1)=[O:2].[Br:13][C:14]1[CH:19]=[CH:18][C:17]([OH:20])=[C:16]([CH2:21][NH:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH:15]=1>CN(C1C=CN=CC=1)C.C(Cl)Cl>[Br:13][C:14]1[CH:19]=[CH:18][C:17]2[O:20][C:1](=[O:2])[N:22]([C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=3)[CH2:21][C:16]=2[CH:15]=1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: Oc1ccc(Br)cc1CNc1ccccc1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: O=C1Oc2ccc(Br)cc2CN1c1ccccc1
Temperature: 25 °C
Reaction time: 60 h
Yield: 99.6 %

Procedure:
Step 2 Carbonyldiimidazole (0.874 g, 5.39 mmol) and DMAP (0.088 g, 0.719 mmol) were added to a solution of 4-bromo-2-((phenylamino)methyl)phenol (1.00 g, 3.60 mmol) in DCM (100 mL) and the resulting mixture was stirred at rt for 60 h. The mixture was diluted with hexanes (100 mL), washed with NaHCO3 (aq) (2×25 mL), 1 M hydrochloric acid (25 mL) and brine (25 mL), dried and filtered through a pad of silica gel. The solids were rinsed with 1:1 EtOAc-hexane and the filtrate was concentrated to give 6-bromo-3-phenyl-3,4-dihydro-2H-benzo[e][1,3]oxazin-2-one as a white solid (1.09 g, 100%). 1H NMR (400 MHz, DMSO-d6) δ 7.41-7.56 (3 H, m), 7.30-7.41 (3 H, m), 7.21-7.29 (1 H, m), 7.01 (1 H, d, J=8.80 Hz), 4.80 (2 H, s). Mass spectrum m/z 304, 306 (M+H)+.
Reaction SMILES: [N:1]([C@H:4]1[CH2:9][C:8]([CH3:11])([CH3:10])[O:7][CH2:6][C@H:5]1[NH:12][C:13](=[O:21])[O:14][CH2:15][CH2:16][Si:17]([CH3:20])([CH3:19])[CH3:18])=[N+]=[N-].[H][H]>[Pd].CO>[NH2:1][C@H:4]1[CH2:9][C:8]([CH3:11])([CH3:10])[O:7][CH2:6][C@H:5]1[NH:12][C:13](=[O:21])[O:14][CH2:15][CH2:16][Si:17]([CH3:18])([CH3:20])[CH3:19]
Reactant: CC1(C)C[C@H](N=[N+]=[N-])[C@H](NC(=O)OCC[Si](C)(C)C)CO1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: CC1(C)C[C@H](N)[C@H](NC(=O)OCC[Si](C)(C)C)CO1
Yield: 124.8 %

Procedure:
A mixture of 2-(trimethylsilyl)ethyl (3S,4S)-4-azido-6,6-dimethyl-tetrahydro-2H-pyran-3-ylcarbamate (510 mg, 1.25 mmol), 10% palladium on carbon (50 mg) in methanol (10 mL) was stirred at room temperature under 1 atm hydrogen atmosphere (hydrogen balloon) overnight. After that, the mixture was filtered through a pad of celite. The filtrate was concentrated to get the title compound (450 mg, crude) as a brown oil, which was used directly for the next step without further purification.