Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([C:4]1[CH:26]=[CH:25][C:7]([CH2:8][C:9]2[C:22]([CH3:23])=[CH:21][C:20]([CH3:24])=[CH:19][C:10]=2[O:11][CH2:12][C:13](N2CC2C)=[O:14])=[CH:6][CH:5]=1)([CH3:3])[CH3:2].[CH2:27]([Mg]Br)[CH2:28][CH3:29].O>C1COCC1>[CH:1]([C:4]1[CH:5]=[CH:6][C:7]([CH2:8][C:9]2[C:22]([CH3:23])=[CH:21][C:20]([CH3:24])=[CH:19][C:10]=2[O:11][CH2:12][C:13](=[O:14])[CH2:27][CH2:28][CH3:29])=[CH:25][CH:26]=1)([CH3:2])[CH3:3]
Reactant: CCC[Mg]Br
Reactant: Cc1cc(C)c(Cc2ccc(C(C)C)cc2)c(OCC(=O)N2CC2C)c1
Solvent: O
Solvent: C1CCOC1
Product: CCCC(=O)COc1cc(C)cc(C)c1Cc1ccc(C(C)C)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 95 %

Procedure:
To a solution of 1-((2-(4-isopropylbenzyl)-3,5-dimethylphenoxy)acetyl)-2-methylaziridine obtained in Reference Example 166 (1.0 g, 2.85 mmol) in THF (20 mL) was added dropwise n-propylmagnesium bromide (a 2.0 M THF solution, 1.43 mL, 2.85 mmol) under argon atmosphere with ice-cooling, and the mixture was stirred for 30 minutes. The reaction solution was warmed to room temperature, water was added thereto, which was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, and then was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate:hexane=1:4) to obtain 920 mg (yield 95%) of the title compound. Oily matter.
Reaction SMILES: [N:1]1([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:6][CH2:5][CH:4]([C:7](OCC)=[O:8])[CH2:3][CH2:2]1.O.[NH2:20][NH2:21]>C(O)C>[NH:20]([C:7]([CH:4]1[CH2:5][CH2:6][N:1]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:2][CH2:3]1)=[O:8])[NH2:21]
Reactant: CCOC(=O)C1CCN(C(=O)OC(C)(C)C)CC1
Reactant: NN
Solvent: CCO
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC(C(=O)NN)CC1
Temperature: 25 °C

Procedure:
10.0 g (38.9 mmol) of 1-tert-butyl 4-ethyl piperidine-1,4-dicarboxylate were initially charged in 35 ml of ethanol, and 3.8 ml (3.90 g, 78 mmol) of hydrazine hydrate were added with stirring. The mixture was stirred at reflux for 9 h. The reaction mixture was cooled to RT, 1.9 ml (39 mmol) of hydrazine hydrate were added and the reaction solution was stirred at reflux for another 24 h. The solvent was concentrated, ethanol (50 ml) was added and the mixture was concentrated again. Diethyl ether (150 ml) was added, and the mixture was stirred in an ultrasonic bath for 5 min. The product was filtered off and dried. This gave 9.20 g (97% of theory) of the product.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]2[NH:7][C:6]3[CH2:11][CH2:12][N:13]([CH3:15])[CH2:14][C:5]=3[C:4]=2[CH:3]=1.[CH3:16][C:17]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[C:20]([CH:27]=[CH2:28])=[CH:19][N:18]=1.[OH-].[K+]>CN1C(=O)CCC1>[Cl:1][C:2]1[CH:10]=[CH:9][C:8]2[N:7]([CH2:28][CH2:27][C:20]3[C:21]4[C:26](=[CH:25][CH:24]=[CH:23][CH:22]=4)[C:17]([CH3:16])=[N:18][CH:19]=3)[C:6]3[CH2:11][CH2:12][N:13]([CH3:15])[CH2:14][C:5]=3[C:4]=2[CH:3]=1
Reactant: CN1CCc2[nH]c3ccc(Cl)cc3c2C1
Reactant: C=Cc1cnc(C)c2ccccc12
Agent: [K+]
Agent: [OH-]
Solvent: CN1CCCC1=O
Product: Cc1ncc(CCn2c3c(c4cc(Cl)ccc42)CN(C)CC3)c2ccccc12

Procedure:
The title compound is prepared from a mixture of 8-chloro-2,3,4,5-tetrahydro-2-methyl-1H-pyrido[4,3-b]indole, 1-methyl-4-vinylisoquinoline and KOH (5-7 equiv) in NMP at a temperature ranging between 25 deg C. to 10 deg C. The product obtained is isolated by preparative HPLC.
Reaction SMILES: Br[CH:2]1[CH2:7][N:6]([CH2:8][CH2:9][N:10]([CH2:13][CH3:14])[CH2:11][CH3:12])[C:5](=[O:15])[C:4]2[C:16]([CH3:31])=[C:17]([CH:19]=[C:20]3[C:28]4[C:23](=[CH:24][CH:25]=[C:26]([F:29])[CH:27]=4)[NH:22][C:21]3=[O:30])[NH:18][C:3]1=2.BrCC1C2C(=[O:50])N(CCN(CC)CC)CCC=2NC=1C=C1C2C(=CC=C(F)C=2)NC1=O.C(=O)([O-])[O-].[K+].[K+].O>CO>[CH2:13]([N:10]([CH2:11][CH3:12])[CH2:9][CH2:8][N:6]1[CH2:7][CH2:2][C:3]2[NH:18][C:17]([CH:19]=[C:20]3[C:28]4[C:23](=[CH:24][CH:25]=[C:26]([F:29])[CH:27]=4)[NH:22][C:21]3=[O:30])=[C:16]([CH2:31][OH:50])[C:4]=2[C:5]1=[O:15])[CH3:14]
Reactant: CCN(CC)CCN1CC(Br)c2[nH]c(C=C3C(=O)Nc4ccc(F)cc43)c(C)c2C1=O
Reactant: CCN(CC)CCN1CCc2[nH]c(C=C3C(=O)Nc4ccc(F)cc43)c(CBr)c2C1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CO
Product: CCN(CC)CCN1CCc2[nH]c(C=C3C(=O)Nc4ccc(F)cc43)c(CO)c2C1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 72 %

Procedure:
A solution of 7-bromo-5-(2-diethylamino-ethyl)-2-(5-fluoro-2-oxo-1,2-dihydro-indol-3-ylidenemethyl)-3-methyl-1,5,6,7-tetrahydro-pyrrolo[3,2-c]pyridin-4-one and 3-bromomethyl-5-(2-diethylamino-ethyl)-2-(5-fluoro-2-oxo-1,2-dihydro-indol-3-ylidenemethyl)-1,5,6,7-tetrahydro-pyrrolo[3,2-c]pyridin-4-one in 10 ml of methanol was added with saturated potassium carbonate (2 ml). The mixture was stirred at room temperature overnight, added with water (20 ml) and extracted with the 6 to 1 mixture of dichloromethane and methanol (10 ml×4). The combined extracts were concentrated to give 5-(2-diethylamino-ethyl)-2-(5-fluoro-2-oxo-1,2-dihydro-indol-3-ylidenemethyl)-3-hydroxymethyl-1,5,6,7-tetrahydro-pyrrolo[3,2-c]pyridin-4-one (13 mg, 72%) as a yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([O:11][CH3:12])[C:8]([O:13][CH3:14])=[CH:7][C:3]=1[C:4](O)=[O:5].P(Cl)(Cl)(Cl)(Cl)[Cl:16]>>[Cl:1][C:2]1[CH:10]=[C:9]([O:11][CH3:12])[C:8]([O:13][CH3:14])=[CH:7][C:3]=1[C:4]([Cl:16])=[O:5]
Reactant: COc1cc(Cl)c(C(=O)O)cc1OC
Reactant: ClP(Cl)(Cl)(Cl)Cl
Product: COc1cc(Cl)c(C(=O)Cl)cc1OC
Temperature: 120 °C
Yield: 96.2 %

Procedure:
2-Chloro-4,5-dimethoxybenzoic acid (0.5 g, 2.3 mmol) and PCl5 (0.54 g, 2.6 mmol) were placed in a round bottomed flask fitted with a reflux condenser. The mixture was heated in an oil bath at 120° C. for 70 min. The mixture was allowed to cool and the formed phosphorus oxychloride was removed under vacuum to give 0.52 g (96%) of 2-chloro-4,5-dimethoxybenzoyl chloride as a solid. 2-Chloro-4,5-dimethoxybenzoyl chloride (0.52 g, 2.2 mmol) was treated in a manner similar to that for Example 32 step (a) to give 2-bromo-1-(2-chloro-4,5-dimethoxyphenyl)ethan-1-one. The dry solid (0.65 g, 2.2 mmol) was dissolved in acetone (25 ml). To this solution 5-(methoxycarbonyl)-2-(methylthio)-thiophene-3-thiocarboxamide (0.55 g, 2.2 mmol) was added and heated at reflux for 5 h. At this point the solid that precipitated was filtered off and washed with acetone and dried under vacuum to give 0.53 g (54%) of methyl 4-[4-(2-chloro-4,5-dimethoxyphenyl)(1,3-thiazol-2-yl)]-5-methylthiothiophene-2-carboxylate. 1H-NMR (DMSO-d6; 300 MHz) δ2.73 (s, 3H), 3.83 (s, 3H), 3.84 (s, 3H), 3.85 (s, 3H), 7.13 (s, 1H), 7.69 (s, 1H), 8.13 (s, 1H), 8.17 (s, 1H).
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[C:14]([CH:19]=O)[CH:13]=2)=[N:4][CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.C(=O)(O)[O-].[Na+].Cl.[NH2:27][OH:28]>O1CCCC1>[Cl:1][C:2]1[C:3]([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[C:14]([CH:19]=[N:27][OH:28])[CH:13]=2)=[N:4][CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1
Reactant: NO
Reactant: O=Cc1cc(-c2ncc(C(F)(F)F)cc2Cl)ccc1Cl
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: ON=Cc1cc(-c2ncc(C(F)(F)F)cc2Cl)ccc1Cl

Procedure:
22.6 g of 3-chloro-2-(4-chloro-3-formylphenyl)-5-trifluoromethylpyridine, 6.5 g of sodium bicarbonate and 5.4 g of hydroxylamine hydrochloride in 100 ml of tetrahydrofuran were stirred at 23° C. for 24 hours. The tetrahydrofuran was then removed, after which the residue was taken up in 100 ml of methylene chloride. The solution was washed twice with 100 ml of water. The solid formed during this was removed, washed with water and dried. Concentration of the organic phase resulted in a residue which was purified by chromatography on silica gel with cyclohexane/ethyl acetate (7:3). Yield: 26.1 g (82%) of colorless crystals; melting point: 173°-174° C.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[C:3]=1N.[F:15][B-](F)(F)F.[H+].N(OCCC(C)C)=O>O1CCCC1.O>[F:15][C:3]1[C:2]([CH3:1])=[CH:7][CH:6]=[CH:5][C:4]=1[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: Cc1cccc(-c2ccccc2)c1N
Reactant: F[B-](F)(F)F
Agent: CC(C)CCON=O
Agent: [H+]
Solvent: O
Solvent: C1CCOC1
Product: Cc1cccc(-c2ccccc2)c1F
Reaction time: 0.25 h

Procedure:
A stirred solution of 3-methyl-[1,1'-biphenyl]-2-amine (7.5 g, 0.041 mole, as prepared in method K) in 20 ml of tetrahydrofuran was cooled to 5°. A solution of 40 ml tetrafluoroboric acid (48-50% solution) in 20 ml of water was added to the cooled reaction mixture, followed by dropwise addition of isoamyl nitrite (6.2 g, 0.053 mole). After complete addition, the reaction mixture was stirred for 15 minutes and filtered. The filter cake was rinsed successively with 50 ml each of 5% aqueous tetrafluoroboric acid, cold methanol, and cold diethyl ether. The filter cake was added to 100 ml of toluene and the mixture stirred and heated at 60° until the solid dissolved and bubbling subsided. The mixture was heated at reflux for 30 minutes, then held at room temperature for two days, causing separation of an oil. The toluene was decanted from the oil and evaporated under reduced pressure to give a second oil, which was purified by column chromatography on silica gel, elution by toluene:n-heptane (6:94), to give 2-fluoro-3-methyl-[1,1'biphenyl].
Reaction SMILES: [O:1]=[C:2]1[C:10]2[C:5](=[CH:6][C:7]([O:12][CH2:13][C:14]([OH:16])=[O:15])=[CH:8][C:9]=2[Br:11])[CH2:4][CH:3]1[CH2:17][CH3:18].[Br:19]Br.O.S(=O)(O)[O-].[Na+]>C(O)(=O)C>[O:1]=[C:2]1[C:10]2[C:5](=[CH:6][C:7]([O:12][CH2:13][C:14]([OH:16])=[O:15])=[CH:8][C:9]=2[Br:11])[CH2:4][C:3]1([CH2:17][CH3:18])[Br:19]
Reactant: BrBr
Reactant: CCC1Cc2cc(OCC(=O)O)cc(Br)c2C1=O
Agent: O=S([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: CCC1(Br)Cc2cc(OCC(=O)O)cc(Br)c2C1=O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A stirred suspension of (1-oxo-2-ethyl-7-bromo-5-indanyloxy)acetic acid in acetic acid is treated over a 10-minute period with a solution of bromine in acetic acid. The reaction mixture is stirred at ambient temperature for 0.5 hour and poured into water containing sodium bisulfite (1 g.). The (1oxo-2-ethyl-2,7-dibromo-5-indanyloxy)-acetic acid is extracted from the reaction mixture with ether, and the ether solution washed with water and dried over anhydrous magnesium sulfate. Removal of the solvent yields the products as an oil.
Reaction SMILES: [Br-:1].[CH3:2][N+:3]([CH3:23])([CH2:20][CH2:21]O)[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19].P(Br)(Br)[Br:25]>C1C=CC=CC=1>[Br-:25].[CH3:2][N+:3]([CH3:23])([CH2:20][CH2:21][Br:1])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19]
Reactant: BrP(Br)Br
Reactant: CCCCCCCCCCCCCCCC[N+](C)(C)CCO
Agent: [Br-]
Solvent: c1ccccc1
Product: CCCCCCCCCCCCCCCC[N+](C)(C)CCBr
Reaction time: 24 h
Yield: 213.3 %

Procedure:
A total of 3.95 g (0.010 mole) of dimethyl-(2-hydroxy)ethylhexadecyl ammonium bromide and 0.9910 g (0.00366 mole) of phosphorous tribromide was slurried in 20 ml of benzene and allowed to react at room temperature (about 25° C.) with stirring for 24 hours under nitrogen. The solvent was removed in vacuo and the residue washed several times with anhydrous ether. The resulting amorphous solid was recrystallized from ethyl acetate, filtered and dried to yield 3.57 g (77%) of the desired product. Calc. % C 52.51, % H 9.49, % N 3.06, % Br 34.93; Found % C 51.80, % H 10.06, % N 3.06, % Br 34.18; m.p. 185°-190° C. The 1H NMR and IR agree with the proposed structure.
Reaction SMILES: Cl[CH2:2][C:3]([O:5][CH3:6])=[O:4].[S:7]([O-:10])([O-:9])=[O:8].[Na+:11].[Na+]>O>[CH3:6][O:5][C:3]([CH2:2][S:7]([O-:10])(=[O:9])=[O:8])=[O:4].[Na+:11]
Reactant: COC(=O)CCl
Reactant: O=S([O-])[O-]
Agent: [Na+]
Solvent: O
Product: COC(=O)CS(=O)(=O)[O-]
Reaction time: 56 h

Procedure:
A slurry of 217 g (2 mols) methyl chloroactate and 252 g (2 mols) sodium sulfite in 500 ml water was stirred and heated under reflux for about 2 hours. The resulting solution was allowed to stand at about 25° C. for 56 hours and then evaporated under reduced pressure to give solid residue. The residue was washed with acetone and dried under vacuum at 80°-90° C. to give crude sodium methoxycarbonylmethylsulfonate salt.
Reaction SMILES: [CH3:1][C:2]1[N:11]=[C:10]2[C:5]([C:6](O)=[CH:7][CH:8]=[N:9]2)=[CH:4][CH:3]=1.O=P(Cl)(Cl)[Cl:15]>>[Cl:15][C:6]1[CH:7]=[CH:8][N:9]=[C:10]2[C:5]=1[CH:4]=[CH:3][C:2]([CH3:1])=[N:11]2
Reactant: O=P(Cl)(Cl)Cl
Reactant: Cc1ccc2c(O)ccnc2n1
Product: Cc1ccc2c(Cl)ccnc2n1
Temperature: 50 °C
Reaction time: 6 h
Yield: 90 %

Procedure:
A mixture of the product from Example 1c (320 mg, 2.0 mmol) in 6 mL of POCl3 was heated at 50° C. with stirring for 6 h. Cooled to room temperature and quenched by pouring into ice. Adjusted to pH 10 with NH4OH and extracted with CH2Cl2. Dried over Na2SO4, filtered and concentrated under vacuum giving the title compound as a tan solid (322 mg, 90%).
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[C:3]1[CH:4]=[C:5]2[C:9](=[C:10]([CH:12]=[O:13])[CH:11]=1)[NH:8][N:7]=[CH:6]2.[Br:16]Br>C(O)(=O)C.C(Cl)Cl>[Br:16][C:6]1[C:5]2[C:9](=[C:10]([CH:12]=[O:13])[CH:11]=[C:3]([C:2]([F:1])([F:14])[F:15])[CH:4]=2)[NH:8][N:7]=1
Reactant: O=Cc1cc(C(F)(F)F)cc2cn[nH]c12
Reactant: BrBr
Solvent: CC(=O)O
Solvent: ClCCl
Product: O=Cc1cc(C(F)(F)F)cc2c(Br)n[nH]c12
Reaction time: 1 h

Procedure:
To a mixture of 5-(trifluoromethyl)-1H-indazole-7-carbaldehyde (270 mg, 1.26 mmol) in acetic acid (5 mL) was added bromine (97 μL, 1.89 mmol) slowly over 5 min. After 1 h, the reaction mixture was diluted with methylene chloride, washed with water (2×), saturated sodium thiosulfate (2×), saturated sodium bicarbonate (2×), brine (2×), dried over sodium sulfate, and concentrated to afford 340 mg (92%) as a yellow powder. 1H-NMR (CDCl3, 300 MHz) δ 10.18 (s, 1H), 8.22 (s, 1H), 8.15 (s, 1H). Mass spec.: 294.81 (MH)+.
Reaction SMILES: [C:1]([N:4]1[C@@H:10]([CH3:11])[C@H:9]([NH:12]C(=O)OC(C)(C)C)[C:8](=[O:20])[N:7]([CH2:21][C:22]2[C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[CH:25]=[CH:24][C:23]=2[CH3:32])[C:6]2[CH:33]=[CH:34][C:35]([C:37]#[N:38])=[CH:36][C:5]1=2)(=[O:3])[CH3:2].[ClH:39]>O1CCOCC1.CCOCC>[ClH:39].[C:1]([N:4]1[C@@H:10]([CH3:11])[C@H:9]([NH2:12])[C:8](=[O:20])[N:7]([CH2:21][C:22]2[C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[CH:25]=[CH:24][C:23]=2[CH3:32])[C:6]2[CH:33]=[CH:34][C:35]([C:37]#[N:38])=[CH:36][C:5]1=2)(=[O:3])[CH3:2]
Reactant: CC(=O)N1c2cc(C#N)ccc2N(Cc2c(C)ccc3ccccc23)C(=O)[C@@H](NC(=O)OC(C)(C)C)[C@@H]1C
Agent: Cl
Solvent: C1COCCO1
Solvent: CCOCC
Product: CC(=O)N1c2cc(C#N)ccc2N(Cc2c(C)ccc3ccccc23)C(=O)[C@@H](N)[C@@H]1C
Yield: 79 %

Procedure:
A rt solution of tert-butyl(3S,4S)-5-acetyl-7-cyano-4-methyl-1-((2-methylnaphthalen-1-yl)methyl)-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-3-ylcarbamate (235 mg, 458 μmol) in 4 M HCl in dioxane (2.29 ml) was stirred for 2 h. The reaction was diluted with Et2O and the solids were collected by vacuum filtration to provide (3S,4S)-5-acetyl-3-amino-4-methyl-1-((2-methylnaphthalen-1-yl)methyl)-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepine-7-carbonitrile hydrochloride (162 mg, 79%) as a white solid.
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:9]2[N:8]=[CH:7][C:6]3[N:12]([CH3:24])[C:13](=[O:23])[N:14]([C:15]4[C:16]([CH3:22])=[N:17][N:18]([CH2:20][CH3:21])[CH:19]=4)[C:5]=3[C:4]=2[CH:3]=1.[CH3:25][O:26][C:27]1[C:32](B2OC(C)(C)C(C)(C)O2)=[CH:31][N:30]=[C:29]([NH:42][CH3:43])[N:28]=1>>[CH2:20]([N:18]1[CH:19]=[C:15]([N:14]2[C:5]3[C:4]4[CH:3]=[C:2]([C:32]5[C:27]([O:26][CH3:25])=[N:28][C:29]([NH:42][CH3:43])=[N:30][CH:31]=5)[CH:11]=[CH:10][C:9]=4[N:8]=[CH:7][C:6]=3[N:12]([CH3:24])[C:13]2=[O:23])[C:16]([CH3:22])=[N:17]1)[CH3:21]
Reactant: CNc1ncc(B2OC(C)(C)C(C)(C)O2)c(OC)n1
Reactant: CCn1cc(-n2c(=O)n(C)c3cnc4ccc(Br)cc4c32)c(C)n1
Product: CCn1cc(-n2c(=O)n(C)c3cnc4ccc(-c5cnc(NC)nc5OC)cc4c32)c(C)n1

Procedure:
The title compound was synthesized in a similar manner as described for Example 1.1 using 8-bromo-1-(1-ethyl-3-methyl-1H-pyrazol-4-yl)-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one (Intermediate F) and [4-methoxy-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyrimidin-2-yl]-methyl-amine (stage 236.1.1) to give the title compound as a white solid. (HPLC: tR 2.19 min (Method A); M+H=445 MS-ES; 1H-NMR (d6-DMSO, 400 MHz) 8.91 (s, 1H), 8.11 (s, 1H), 8.08-8.02 (m, 1H), 8.01-7.97 (m, 1H), 7.74-7.69 (m, 1H), 7.50-7.48 (m, 1H), 7.27-7.16 (m, 1H), 4.15 (q, 2H), 3.85 (s, br, 3H), 3.56 (s, 3H), 2.82 (d, 3H), 1.95 (s, 3H) 1.36 (t, 3H))
Reaction SMILES: [CH3:1][O:2][C:3](=[O:20])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([C:10](=[O:19])[CH2:11][C:12](OC(C)(C)C)=O)[CH:5]=1.[CH2:21](Br)[CH:22]=C.[H-].[Na+]>CN(C=O)C>[CH3:1][O:2][C:3](=[O:20])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([C:10](=[O:19])[CH2:11][CH2:12][CH:21]=[CH2:22])[CH:5]=1
Reactant: COC(=O)c1cccc(C(=O)CC(=O)OC(C)(C)C)c1
Reactant: C=CCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C=CCCC(=O)c1cccc(C(=O)OC)c1
Temperature: 100 °C
Reaction time: 0.5 h

Procedure:
To a stirred solution of 3-tert-butoxycarbonylacetyl-benzoic acid methyl ester (11.1 g) and allyl bromide (3.0 mL) in DMF (40 mL) was added portionwise at 0° C. NaH (55% dispersion in mineral oil, 1.44 g). Stirring was continued at 0° C. for 20 min and at 20° C. for 30 min. The mixture was partitioned between AcOEt and brine, the pH being set to 7 by the addition of 3N HCl. The organic layer was dried and evaporated. The residual oil was stirred in a mixture of CH2Cl2 (30 mL) and TFA (30 mL) for 40 min at 20° C. The solvents were evaporated. The solution of the residue in AcOEt was extracted with ice-cold sat. Na2CO3 solution and the aqueous extracts were immediately acidified with 3N HCl and extracted with AcOEt. The solvent of this extract was evaporated and the residue heated in a mixture of toluene (40 mL) and 3N HCl (2 mL) to 100° C. for 1 h. The cooled mixture was diluted with AcOEt, washed with sat. NaHCO3 and brine, dried and evaporated to give 3-pent-4-enoyl-benzoic acid methyl ester (5.11 g) as a pale-yellow oil, MS (ISP) 236.2 [(M+NH4)+].
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[CH:11]=[N:12][C:13]([F:16])=[CH:14][CH:15]=2)[C:5]([NH2:8])=[CH:6][CH:7]=1.[C:17]([O:21][C:22]([NH:24][C@@H:25]([CH3:29])[C:26](O)=[O:27])=[O:23])([CH3:20])([CH3:19])[CH3:18].C1C=NC2N(O)N=NC=2C=1.CN1CCOCC1.Cl.CN(C)CCCN=C=NCC>C(Cl)Cl>[C:17]([O:21][C:22](=[O:23])[NH:24][C@H:25]([C:26](=[O:27])[NH:8][C:5]1[CH:6]=[CH:7][C:2]([F:1])=[CH:3][C:4]=1[NH:9][C:10]1[CH:11]=[N:12][C:13]([F:16])=[CH:14][CH:15]=1)[CH3:29])([CH3:18])([CH3:19])[CH3:20]
Reactant: Nc1ccc(F)cc1Nc1ccc(F)nc1
Reactant: C[C@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: C[C@H](NC(=O)OC(C)(C)C)C(=O)Nc1ccc(F)cc1Nc1ccc(F)nc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 104.6 %

Procedure:
A mixture of 4-fluoro-N2-(6-fluoropyridin-3-yl)benzene-1,2-diamine (524 mg, 2.37 mmol), (S)-2-tertbutoxycarbonylaminopropionic acid (493 mg, 2.61 mmol), HOAt (355 mg, 2.61 mmol), 4-methylmorpholine (575 μL, 5.21 mmol) and N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (500 mg, 2.61 mmol) in DCM (20 mL) was stirred at RT for 3 h. The reaction mixture was partitioned between DCM and a saturated aqueous solution of NaHCO3. The organic layer was washed with brine, dried (Na2SO4) and concentrated in vacuo to afford the title compound as a yellow solid (973 mg, quantitative). LCMS (Method C): RT 3.25 min [M+H]+ 393.3.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5](B2OC(C)(C)C(C)(C)O2)[CH:4]=[N:3]1.Br[C:17]1[CH:18]=[C:19]2[CH:25]=[CH:24][N:23]([S:26]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)(=[O:28])=[O:27])[C:20]2=[N:21][CH:22]=1.C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1.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][N:2]1[CH:6]=[C:5]([C:17]2[CH:18]=[C:19]3[CH:25]=[CH:24][N:23]([S:26]([C:29]4[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=4)(=[O:27])=[O:28])[C:20]3=[N:21][CH:22]=2)[CH:4]=[N:3]1
Reactant: O=S(=O)(c1ccccc1)n1ccc2cc(Br)cnc21
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
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: C1COCCO1
Product: Cn1cc(-c2cnc3c(ccn3S(=O)(=O)c3ccccc3)c2)cn1
Temperature: 100 °C
Reaction time: 2 h

Procedure:
To a degassed (sparging with argon for 5 minutes), stirred solution of 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (0.617 g, 2.97 mmol) and 5-bromo-1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridine (1.00 g, 2.97 mmol) in dioxane (12.0 ml) was added Pd(Ph3P)4 (0.171 g, 0.148 mmol), followed by a degassed aqueous solution of sodium carbonate (4.45 ml, 8.90 mmol). The reaction mixture was stirred under nitrogen at 100° C. for 2 h. The reaction mixture was cooled to room temperature and partitioned between EtOAc (25 mL) and saturated aqueous ammonium chloride (25 mL). The organic layer was dried over magnesium sulfate, filtered and concentrated to a crude residue. The residue was purified by silica gel chromatography (EtOAc/Hexanes gradient) to afford 5-(1-methyl-1H-pyrazol-4-yl)-1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridine as a white solid. LRMS (ESI) calculated for C17H14N4O2S [M+H]+, 339.1; found 339.1.
Reaction SMILES: [Br:1][C:2]1[C:11]([CH3:12])=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([O:13][CH3:14])[CH:8]=2)[C:3]=1[OH:15].C(N(CC)C(C)C)(C)C.Cl[CH2:26][O:27][CH3:28]>C1COCC1>[Br:1][C:2]1[C:11]([CH3:12])=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([O:13][CH3:14])[CH:8]=2)[C:3]=1[O:15][CH2:26][O:27][CH3:28]
Reactant: COCCl
Reactant: COc1ccc2c(O)c(Br)c(C)cc2c1
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: COCOc1c(Br)c(C)cc2cc(OC)ccc12
Temperature: 0 °C
Yield: 79.6 %

Procedure:
To an ice-water cooled solution of 2-bromo-3-methyl-6-(methyloxy)-1-naphthalenol (13) (6.8 g, 25.5 mmol) in THF (70 mL) was slowly added N,N-diisopropylethylamine (7 mL, 5.19 g, 40 mmol, 1.58 eq) followed by the slow addition of chloromethylmethyl ether (3.2 mL, 3.39 g, 42.1 mmol, 1.65 eq) between 0-5° C. with stirring under N2. The ice-water bath was removed and the reaction mixture was allowed to stir at RT overnight. The reaction mixture was diluted with Et2O (400 mL), washed with H2O (2×250 mL) followed by 1 N HCl (2×250 mL), dried over MgSO4, filtered, and the filtrate was concentrated to give the crude product as a dark orange oil. The crude product was partially purified by flash chromatography over SiO2 with hexanes:EtOAc (12:1 to 9:1) to give 6.32 g of the impure title compound. The impure compound was purified by flash chromatography over SiO2 with hexanes:EtOAc (15:1) to give 4.8 g (60%) of compound 14 as a pale yellow oil. 1H NMR (400 MHz; DMSO-d6): δ 3.59 (s, 3H), 3.85 (s, 3H), 5.18 (s, 2H), 7.17 (dd, J=2.5 Hz, 9.3 Hz, 1H), 7.26 (d, J=2.4 Hz, 1H), 7.60 (s, 1H), 7.95 (d, J=9.2 Hz, 1H). 1H NMR (400 MHz; CDCl3): δ 2.54 (s, 3H), 3.72 (s, 3H), 3.90 (s, 3H), 5.24 (s, 2H), 7.02 (d, J=2.4 Hz, 1H), 7.12 (dd, J=2.6 Hz, 9.2 Hz, 1H), 7.42 (s, 1H), 8.03 (d, J=9.1 Hz, 1H). (Note: In DMSO-d6, the 3-methyl group is coincident with the DMSO peak.) HRMS (EI+) calcd for C14H15BrO3: 310.0205 (M•+). Found: 310.0196.