Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O[C:2]1[C:11]2[CH2:10][CH2:9][CH2:8][CH2:7][C:6]=2[NH:5][C:4](=[O:12])[C:3]=1[C:13]([O:15][CH2:16][CH3:17])=[O:14].P(Cl)(Cl)([Cl:20])=O>>[Cl:20][C:2]1[C:11]2[CH2:10][CH2:9][CH2:8][CH2:7][C:6]=2[NH:5][C:4](=[O:12])[C:3]=1[C:13]([O:15][CH2:16][CH3:17])=[O:14]
Reactant: O=P(Cl)(Cl)Cl
Reactant: CCOC(=O)c1c(O)c2c([nH]c1=O)CCCC2
Product: CCOC(=O)c1c(Cl)c2c([nH]c1=O)CCCC2
Temperature: 130 °C
Reaction time: 1.5 h
Yield: 17 %

Procedure:
A mixture of ethyl 4-hydroxy-2-oxo-1,2,5,6,7,8-hexahydroquinoline-3-carboxylate (26.0 g, 110 mmol) and phosphorus oxychloride (51.3 mL) was stirred at 130° C. for 1.5 hr. After cooling, the reaction mixture was concentrated under reduced pressure, and ice was added to the residue. The mixture was neutralized with saturated sodium hydrogen carbonate solution, and extracted with ethyl acetate. The extract was washed successively with saturated sodium hydrogen carbonate solution, water and brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was collected by filtration, and washed with ethyl acetate-hexane to give the title compound (4.65 g, 17%) as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[C:11]3[C:16]4=[C:17]([C@@H:19]5[CH2:24][NH:23][CH2:22][CH2:21][C@@H:20]5[N:15]4[CH2:14][CH2:13][CH2:12]3)[CH:18]=2)=[C:5]([C:25]([F:28])([F:27])[F:26])[CH:4]=1.Br[CH2:30][CH:31]([F:33])[F:32].N>>[F:32][CH:31]([F:33])[CH2:30][N:23]1[CH2:22][CH2:21][C@@H:20]2[N:15]3[C:16]4[C:11](=[CH:10][C:9]([C:6]5[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][C:5]=5[C:25]([F:28])([F:26])[F:27])=[CH:18][C:17]=4[C@@H:19]2[CH2:24]1)[CH2:12][CH2:13][CH2:14]3
Reactant: COc1ccc(-c2cc3c4c(c2)[C@@H]2CNCC[C@@H]2N4CCC3)c(C(F)(F)F)c1
Reactant: FC(F)CBr
Agent: N
Product: COc1ccc(-c2cc3c4c(c2)[C@@H]2CN(CC(F)F)CC[C@@H]2N4CCC3)c(C(F)(F)F)c1

Procedure:
The title compound was prepared by the method of Example 382 as a yellow oil (27 mg, 77%) from (7aS,11aR)-2-[4-methoxy-2-(trifluoromethyl)phenyl]-5,6,7a,8,9,10,11,11a-octahydro-4H-pyrido[3′,4′:4,5]pyrrolo[3,2,1-ij]quinoline (30 mg, 0.077 mmol) and 2-bromo-1,1-difluoroethane (35 mg, 0.23 mmol). MS (CI, NH3): 453.1 (base, M+H).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[N+:4]([O-:15])[C:5]2[CH2:6][CH2:7][CH2:8][CH2:9][C:10]=2[C:11]=1[N+]([O-])=O.[OH-].[Na+].O.[CH2:19]([OH:22])[CH:20]=[CH2:21]>>[CH2:19]([O:22][C:11]1[C:10]2[CH2:9][CH2:8][CH2:7][CH2:6][C:5]=2[N+:4]([O-:15])=[CH:3][C:2]=1[CH3:1])[CH:20]=[CH2:21]
Reactant: C=CCO
Reactant: Cc1c[n+]([O-])c2c(c1[N+](=O)[O-])CCCC2
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: C=CCOc1c(C)c[n+]([O-])c2c1CCCC2
Reaction time: 3 h

Procedure:
2.0 Grams of 3-methyl-4-nitro-5,6,7,8tetrahydroquinoline-N-oxide was dissolved in allyl alcohol. Then 0.6 g of sodium hydroxide was added thereto, and the mixture was stirred at 70°-80° C. for 3 hours. After the reaction was completed, the reaction mixture was concentrated under reduced pressure, to the residue thus obtained was added water, and was extracted with chloroform. The chloroform layer was washed with an aqueous solution saturated with sodium chloride, then dried with anhydrous magnsium sulfate. Chloroform was removed by evaporation under reduced pressure to obtain 1.4 g of 4-allyloxy-3-methyl-5,6,7,8-tetrahydroquinoline-N-oxide in the form of brown oily substance.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][C:11]([OH:13])=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.OC1C2N=NNC=2C=CC=1.Cl.C(N=C=NCCCN(C)C)C.[NH2:36][C@H:37]([C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1)[CH2:38][OH:39]>CN(C=O)C.O>[C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][C:11]([NH:36][C@H:37]([C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)[CH2:38][OH:39])=[O:13])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C(O)CCCCc1ccccc1
Reactant: N[C@@H](CO)c1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: Oc1cccc2[nH]nnc12
Solvent: CN(C)C=O
Solvent: O
Product: O=C(CCCCc1ccccc1)N[C@@H](CO)c1ccccc1
Reaction time: 1 h
Yield: 52.4 %

Procedure:
To a solution of 5-phenylpentanoic acid (1.25 g) and hydroxybenzotriazole (1.18 g) in N,N′-dimethylformamide (25 ml) was added 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (1.74 g) at 0° C. and the mixture was stirred for 1 hour. To the mixture was added (2R)-2-amino-2-phenylethanol (960 mg) and the mixture was stirred for 2 hours at room temperature. The reaction mixture was poured into water (150 ml) and then extracted with ethyl acetate. The organic layer was washed with 2N hydrochloric acid, 2N aqueous solution of sodium hydroxide and a saturated aqueous solution of sodium chloride, successively, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The obtained crystal was washed with diethy ether to give the title compound (1.09 g) having the following physical data.
Reaction SMILES: [NH2:1][C@@:2]([C:14]1([CH2:17][OH:18])[CH2:16][CH2:15]1)([C:4]1[CH:9]=[C:8]([N+:10]([O-:12])=[O:11])[CH:7]=[CH:6][C:5]=1[F:13])[CH3:3].[C:19](Br)#[N:20].C([O-])(=O)C.[Na+]>C1COCC1.Cl.O1CCOCC1>[F:13][C:5]1[CH:6]=[CH:7][C:8]([N+:10]([O-:12])=[O:11])=[CH:9][C:4]=1[C@:2]1([CH3:3])[C:14]2([CH2:15][CH2:16]2)[CH2:17][O:18][C:19]([NH2:20])=[N:1]1
Reactant: C[C@@](N)(c1cc([N+](=O)[O-])ccc1F)C1(CO)CC1
Reactant: N#CBr
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: C1COCCO1
Solvent: C1CCOC1
Product: C[C@]1(c2cc([N+](=O)[O-])ccc2F)N=C(N)OCC12CC2
Temperature: 80 °C
Reaction time: 8 h
Yield: 54.6 %

Procedure:
Intermediate Ea3 (R1,2=cyclopropyl, R3=Me): To a solution of {1-[(S)-1-amino-1-(2-fluoro-5-nitro-phenyl)-ethyl]-cyclopropyl}-methanol (0.50 g) in dry THF (20 ml) was added bromocyanogen (0.24 g) and sodium acetate (0.19 g) and the mixture was stirred at 80° C. overnight. The mixture was cooled to 22° C., diluted with HCl in dioxane (4M, 2.4 ml) and stirring was continued for 1 h. The mixture was partitioned between aqueous saturated Na2CO3 and ethyl acetate, the organic layer was dried, evaporated and the residue purified by chromatography over silca-NH2 using ethyl acetate to give (S)-8-(2-fluoro-5-nitro-phenyl)-8-methyl-5-oxa-7-aza-spiro[2.5]oct-6-en-6-ylamine (0.30 g) as a pale yellow solid. MS (ESI): m/z=280.1 [M+H]+.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH:9]1[CH2:14][C:15]([O:17]C)=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].O.[NH2:20][NH2:21]>C(O)C>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH:9]1[CH2:14][C:15]([NH:20][NH2:21])=[O:17])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: NN
Reactant: COC(=O)CC1CCCCN1C(=O)OC(C)(C)C
Solvent: CCO
Solvent: O
Product: CC(C)(C)OC(=O)N1CCCCC1CC(=O)NN
Reaction time: 16 h

Procedure:
2-Methoxycarbonylmethyl-piperidine-1-carboxylic acid tert butyl ester (8.14 g) in ethanol (150 ml) was treated with hydrazine hydrate (19 ml) and the mixture boiled for 16 h. Solvent was removed at reduced pressure and the residue azeotroped with toluene to give the title compound (8.34 g)
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([F:11])[C:3]=1[C:4]([OH:6])=O.[NH2:12][C:13]1[CH:22]=[CH:21][C:20]2[C:15](=[N:16][C:17]([O:23][CH3:24])=[CH:18][CH:19]=2)[N:14]=1.C(O)C>O>[CH3:24][O:23][C:17]1[N:16]=[C:15]2[C:20]([CH:21]=[CH:22][C:13]([NH:12][C:4](=[O:6])[C:3]3[C:7]([F:11])=[CH:8][CH:9]=[CH:10][C:2]=3[F:1])=[N:14]2)=[CH:19][CH:18]=1
Reactant: O=C(O)c1c(F)cccc1F
Reactant: COc1ccc2ccc(N)nc2n1
Solvent: O
Solvent: CCO
Product: COc1ccc2ccc(NC(=O)c3c(F)cccc3F)nc2n1
Temperature: 4 °C
Yield: 40.4 %

Procedure:
The procedure is similar to that described in Example 1, but starting with 2,6-difluorobenzoic acid (5.1 g), N,N'-carbonyldiimidazole (5.2 g) and 2-amino-7-methoxy-1,8-naphthyridine (4.4 g). The product produced by precipitation in water (4.5 g; m.p. 215°-217° C.) is dissolved in boiling ethanol (70 cc). After 1 hour's cooling at 4° C., the crystallised solid is separated by filtration, washed with ethanol (10 cc) and dried at 45° C. under reduced pressure (0.067 kPa). N-(7-methoxy-1,8-naphthyridin-2-yl)-2,6-difluorobenzamide (3.2 g) is produced, m.p. 219°-220° C.
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[CH:3]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:15]=[CH:14][O:13][CH:12]=2)=[CH:7][CH:6]=1)[OH:4].[NH2:18][C:19]1[N:24]=[C:23](Cl)[CH:22]=[C:21]([Cl:26])[N:20]=1.C(=O)([O-])[O-].[Cs+].[Cs+].O1CCOCC1>C(OCC)(=O)C>[Cl:26][C:21]1[CH:22]=[C:23]([O:4][CH:3]([C:5]2[CH:6]=[CH:7][C:8]([C:11]3[CH:15]=[CH:14][O:13][CH:12]=3)=[CH:9][CH:10]=2)[C:2]([F:1])([F:16])[F:17])[N:24]=[C:19]([NH2:18])[N:20]=1
Reactant: Nc1nc(Cl)cc(Cl)n1
Reactant: OC(c1ccc(-c2ccoc2)cc1)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: Nc1nc(Cl)cc(OC(c2ccc(-c3ccoc3)cc2)C(F)(F)F)n1
Temperature: 110 °C
Yield: 82.6 %

Procedure:
The mixture of 2,2,2-trifluoro-1-(4-furan-3-yl-phenyl)-ethanol (100 mg, 0.4 mmol), 2-amino-4,6-dichloro-pyrimidine (60 mg, 0.36 mmol), cesium carbonate (468 mg, 1.44 mmol) and 1,4-dioxane (1 ml) was heated at 110° C. overnight. The reaction mixture was cooled to room temperature; 10 ml of ethyl acetate was added. The mixture was then filtered through Celite, the filtrate was concentrated to give 110 mg of 4-chloro-6-[2,2,2-trifluoro-1-(4-furan-3-yl-phenyl)-ethoxy]-pyrimidin-2-ylamine, yield: 72%.
Reaction SMILES: [C:1]1([CH:7]([C:9]2[CH:18]=[C:17]3[C:12]([CH:13]=[CH:14][CH:15]=[N:16]3)=[CH:11][CH:10]=2)O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.S(Cl)([Cl:21])=O>ClCCl>[Cl:21][CH:7]([C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[C:9]1[CH:18]=[C:17]2[C:12]([CH:13]=[CH:14][CH:15]=[N:16]2)=[CH:11][CH:10]=1
Reactant: O=S(Cl)Cl
Reactant: OC(c1ccccc1)c1ccc2cccnc2c1
Solvent: ClCCl
Product: ClC(c1ccccc1)c1ccc2cccnc2c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 98.5 %

Procedure:
A mixture of 3.2 parts of intermediate 2, namely α-phenyl-7-quinolinemethanol, 8 parts of thionyl chloride and 65 parts of dichloromethane was stirred for 4 hours at room temperature. The reaction mixture was evaporated and the residue was poured into water. The product was extracted with dichloromethane (3×39 parts) and the combined extracts were dried, filtered and evaporated, yielding 3.4 parts (98.5%) of 7-(chlorophenylmethyl)quinoline (interm. 23).
Reaction SMILES: [CH:1]([C:4]1[CH:12]=[CH:11][C:7]([C:8]([OH:10])=O)=[C:6]([CH3:13])[CH:5]=1)([CH3:3])[CH3:2].Cl.CN(C)CCCN=C=NCC.C(N(CC)CC)C.[NH2:33][CH2:34][C:35]1[C:36]([OH:43])=[N:37][C:38]([CH3:42])=[CH:39][C:40]=1[CH3:41]>ClCCl>[OH:43][C:36]1[C:35]([CH2:34][NH:33][C:8](=[O:10])[C:7]2[CH:11]=[CH:12][C:4]([CH:1]([CH3:2])[CH3:3])=[CH:5][C:6]=2[CH3:13])=[C:40]([CH3:41])[CH:39]=[C:38]([CH3:42])[N:37]=1
Reactant: Cc1cc(C)c(CN)c(O)n1
Reactant: Cc1cc(C(C)C)ccc1C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1cc(C)c(CNC(=O)c2ccc(C(C)C)cc2C)c(O)n1
Temperature: 20 °C
Reaction time: 13 h
Yield: 35.6 %

Procedure:
To a solution of 4-isopropyl-2-methylbenzoic acid (80 mg, 0.45 mmol), 1-hydroxybenzotriozole (91 mg, 0.68 mmol), 1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (130 mg, 0.68 mmol), triethylamine (0.3 mL) in dichloromethane (15 mL) was added 3-(aminomethyl)-4,6-dimethylpyridin-2-ol (69 mg, 0.45 mmol). The reaction mixture was stirred at 20° C. for 13 hours. The mixture was washed with water (20 mL×2). The organic phase was dried over sodium sulfate and filtered. The filtrate was concentrated. The residue was purified by column chromatography (silica gel, dichloromethane/methanol=10:1) to give N-((2-hydroxy-4,6-dimethylpyridin-3-yl)methyl)-4-isopropyl-2-methylbenzamide as a white solid (50 mg, 36%). LRMS (M+H+) m/z: calcd 312.18. found 312. HPLC Purity (214 nm): 99%. 1H NMR (300 MHz, d6-DMSO): δ 11.45 (s, 1H), 8.00 (t, J=4.8 Hz, 1H), 7.20-7.06 (m, 3H), 5.85 (s, 1H), 4.25 (d, J=4.8 Hz, 2H), 2.91-2.82 (m, 1H), 2.29 (s, 4H), 2.12 (s, 2H), 2.10 (s, 1H), 1.17 (m, 1H) (d, J=6.9 Hz, 6H).
Reaction SMILES: [O:1]1[CH2:3][CH:2]1[C:4]1[CH:8]=[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[O:6][N:5]=1.[OH:15][CH:16]1[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]1>>[OH:1][CH:2]([C:4]1[CH:8]=[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[O:6][N:5]=1)[CH2:3][N:19]1[CH2:20][CH2:21][CH:16]([OH:15])[CH2:17][CH2:18]1
Reactant: OC1CCNCC1
Reactant: c1ccc(-c2cc(C3CO3)no2)cc1
Product: OC1CCN(CC(O)c2cc(-c3ccccc3)on2)CC1
Temperature: 80 °C
Reaction time: 0.5 h
Yield: 50.4 %

Procedure:
A mixture of 3-(1,2-epoxyethyl)-5-phenylisoxazole (580 mg) and 4-hydroxypiperidine (625 mg) is stirred for 0.5 hour at 80°C and then the mixture is subjected to a column chromatography using silica gel to give 3-[1-hydroxy-2-(4-hydroxypiperidino ) ethyl]-5-phenylisoxazole (450 mg). Recrystallization from ethyl acetate-hexane gives colorless prisms (259 mg). M. p. 117-119°C.
Reaction SMILES: [CH2:1]([O:8][CH2:9][C:10]1[N:19]=[C:18](Cl)[C:17]2[C:12](=[CH:13][CH:14]=[C:15]([O:21][CH3:22])[CH:16]=2)[N:11]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:23]([NH2:33])[C:24]1[CH:32]=[CH:31][C:30]2[O:29][CH2:28][O:27][C:26]=2[CH:25]=1.C(=O)([O-])[O-].[Na+].[Na+]>C(O)(C)C>[CH2:1]([O:8][CH2:9][C:10]1[N:19]=[C:18]([NH:33][CH2:23][C:24]2[CH:32]=[CH:31][C:30]3[O:29][CH2:28][O:27][C:26]=3[CH:25]=2)[C:17]2[C:12](=[CH:13][CH:14]=[C:15]([O:21][CH3:22])[CH:16]=2)[N:11]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1ccc2nc(COCc3ccccc3)nc(Cl)c2c1
Reactant: NCc1ccc2c(c1)OCO2
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(C)O
Product: COc1ccc2nc(COCc3ccccc3)nc(NCc3ccc4c(c3)OCO4)c2c1
Reaction time: 6 h
Yield: 98 %

Procedure:
0.74 g (2.4 mmol) of the 2-benzyloxymethyl-4-chloro-6-methoxyquinazoline prepared in Example 246, 0.55 g (3.6 mmol) of piperonylamine and 0.50 g of sodium carbonate were mixed with 20 ml of isopropyl alcohol. The obtained mixture was heated under reflux. After 6 hours, the reaction mixture was distilled under a reduced pressure to remove the solvent and the residue was purified by silica gel column chromatography (ethyl acetate/n-hexane) and recrystallized from chloroform/n-hexane to give 1.01 g of the title compound as a yellow crystal.
Reaction SMILES: [NH2:1][CH2:2][C:3]([C@@H:5]1[C@@H:10]([OH:11])[C@H:9]([OH:12])[C@@H:8]([CH2:13][OH:14])[O:7][C@@:6]1([NH2:47])[N:15]([CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][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])[C:16](=[O:28])[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])=[O:4].[C:48]([NH:58][C@H:59]([C:65](O)=[O:66])[CH2:60][CH2:61][C:62](=[O:64])[NH2:63])([O:50][CH2:51][C:52]1[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=1)=[O:49]>>[C:48]([NH:58][C@H:59]([C:65]([NH:1][CH2:2][C:3]([C@@H:5]1[C@@H:10]([OH:11])[C@H:9]([OH:12])[C@@H:8]([CH2:13][OH:14])[O:7][C@@:6]1([NH2:47])[N:15]([CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][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])[C:16](=[O:28])[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])=[O:4])=[O:66])[CH2:60][CH2:61][C:62](=[O:64])[NH2:63])([O:50][CH2:51][C:52]1[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=1)=[O:49]
Reactant: CCCCCCCCCCCCCCCCCCN(C(=O)CCCCCCCCCCC)[C@]1(N)O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1C(=O)CN
Reactant: NC(=O)CC[C@H](NC(=O)OCc1ccccc1)C(=O)O
Product: CCCCCCCCCCCCCCCCCCN(C(=O)CCCCCCCCCCC)[C@]1(N)O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1C(=O)CNC(=O)[C@H](CCC(N)=O)NC(=O)OCc1ccccc1

Procedure:
from N-(2-glycyl-amino-2-deoxy-β-D-glucopyranosyl)-N-octadecyl-dodecanamide and N-carbobenzoxy-L-glutamine.
Reaction SMILES: N1C=CN=C1.[Si:6](Cl)([C:9]([CH3:12])([CH3:11])[CH3:10])([CH3:8])[CH3:7].[CH2:14]([O:21][CH2:22][CH2:23][CH2:24][C@H:25]([CH3:28])[CH2:26][OH:27])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>CN(C)C=O>[CH2:14]([O:21][CH2:22][CH2:23][CH2:24][C@H:25]([CH3:28])[CH2:26][O:27][Si:6]([C:9]([CH3:12])([CH3:11])[CH3:10])([CH3:8])[CH3:7])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: C[C@H](CO)CCCOCc1ccccc1
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: C[C@@H](CCCOCc1ccccc1)CO[Si](C)(C)C(C)(C)C
Temperature: 40 °C
Reaction time: 1 h
Yield: 88.5 %

Procedure:
Imidazole (1.230 g, 18.06 mmol, 2.6 equiv) and tert-butyl-dimethylsilyl chloride (1.230 g, 9.03 mmol, 1.3 equiv) are added to a solution of (S)-5-benzyloxy-2-methyl-pentan-1-ol- 4 (1.447 g, 6.95 mmol) in dimethyl formamide (5.5 ml). The mixture is stirred for 1 h at 40° C. Purification of the reaction mixture by flash column chromatography (pentane/diethyl ether 20:1) affords (s)-1-benzyloxy-5-(tert-butyldimethylsilyloxy)-4-methyl-pentane 5 (1.985 g, 89%) as a colouriess oil (the reaction mixture is poured directly without aqueous workup onto a flash chromatography column which is pre-wetted with the eluent). 13C-NMR (100 MHz, CDCl3): δ=138.7; 128.3; 127.5; 127.4; 72.8; 70.8; 68.2; 35.6; 29.6; 27.2; 25.9; 18.3; 16.6; −5.4.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12](=[O:14])[CH3:13])=[C:5]2[NH:15][C:16]1[CH:17]=[N:18][C:19]([NH:22][CH2:23][CH2:24][N:25]([CH3:27])[CH3:26])=[CH:20][CH:21]=1.[Cl:28][C:29]1[CH:34]=[C:33](B2OC(C)(C)C(C)(C)O2)[CH:32]=[C:31]([F:44])[C:30]=1[OH:45]>>[Cl:28][C:29]1[CH:34]=[C:33]([C:2]2[CH:3]=[C:4]3[C:9](=[CH:10][CH:11]=2)[N:8]=[CH:7][C:6]([C:12](=[O:14])[CH3:13])=[C:5]3[NH:15][C:16]2[CH:17]=[N:18][C:19]([NH:22][CH2:23][CH2:24][N:25]([CH3:27])[CH3:26])=[CH:20][CH:21]=2)[CH:32]=[C:31]([F:44])[C:30]=1[OH:45]
Reactant: CC1(C)OB(c2cc(F)c(O)c(Cl)c2)OC1(C)C
Reactant: CC(=O)c1cnc2ccc(Br)cc2c1Nc1ccc(NCCN(C)C)nc1
Product: CC(=O)c1cnc2ccc(-c3cc(F)c(O)c(Cl)c3)cc2c1Nc1ccc(NCCN(C)C)nc1
Yield: 15.8 %

Procedure:
Following general procedure D, 1-(6-bromo-4-(6-(2-(dimethylamino)ethylamino)pyridine-3-ylamino)quinolin-3-yl)ethanone (100 mg, 0.23 mmol) was reacted with 2-chloro-6-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (82 mg, 0.35 mmol) to afford the desired product (18 mg, 16%) as a green-yellow solid: 1H NMR (500 MHz, CD3OD+TFA-d) δ 9.29 (s, 1H), 8.26-8.20 (m, 2H), 8.05-7.99 (m, 2H), 7.69 (dd, J=9.0, 2.7 Hz, 1H), 7.18-7.07 (m, 2H), 6.96 (d, J=9.0 Hz, 1H), 3.89-3.83 (m, 2H), 3.46-3.37 (m, 2H), 2.96 (s, 6H), 2.80 (s, 3H); ESI MS m/z 494 [C26H25ClFN5O2+H]+; HPLC 97.2% (AUC), tR=10.46 min.
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][C:8]([N+:11]([O-])=O)=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].CCO>CCOC(C)=O.[Pd]>[NH2:11][C:8]1[CH:9]=[CH:10][C:2]([CH3:1])=[C:3]([CH:7]=1)[C:4]([OH:6])=[O:5]
Reactant: Cc1ccc([N+](=O)[O-])cc1C(=O)O
Agent: [Pd]
Solvent: CCO
Solvent: CCOC(C)=O
Product: Cc1ccc(N)cc1C(=O)O
Reaction time: 24 h

Procedure:
To a 250 mL round-bottomed flask was added 2-methyl-5-nitrobenzoic acid (5.0 g, 28 mmol) and palladium 10% on carbon (1.5 g, 14 mmol). The mixture was taken up in EtOAc (30 mL) then EtOH (70 mL) was added. The mixture was purged with H2 then allowed to stir at 1 atm. H2 for 24 h. LCMS indicated about 10% conversion to product. About 0.5 g 10% Pd/C and ˜30 mL MeOH was added to the reaction. The reaction was purged with H2 and let to stir at 1 atm H2 for 20 h. They reaction was monitored for complete conversion by LCMS. The mixture was passed through a pad of celite, washing with MeOH and concentrated to afford 5-amino-2-methylbenzoic acid as an off-white solid MS m/z found 152.1 (ESI, neg. ion).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([F:8])=[N:6][CH:7]=1.[B:9](OC(C)C)([O:14]C(C)C)[O:10]C(C)C.C([Li])CCC.Cl>O1CCCC1.C1(C)C=CC=CC=1>[F:8][C:5]1[N:6]=[CH:7][C:2]([B:9]([OH:14])[OH:10])=[CH:3][CH:4]=1
Reactant: CC(C)OB(OC(C)C)OC(C)C
Reactant: Fc1ccc(Br)cn1
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: OB(O)c1ccc(F)nc1
Temperature: -42.5 °C
Reaction time: 5 h
Yield: 1624.3 %

Procedure:
A 72 L reactor equipped with reflux condenser, and temperature probe. To the reactor 5-bromo-2-fluoropyridine (1.17 L, 0.568 mol), toluene (18.2 L), and triisopropyl borate (3.13 L, 0.68 mol, 1.2 equiv.) were charged and stirred. Tetrahydrofuran (4.4 L) was added to the reactor and the reaction mixture was cooled to between −35 to −50° C. While maintaining a temperature between −35 to −45° C., n-butyl lithium (2.5 M solution of hexanes, 5.44 L, 0.68 mol, 1.2 equiv.) was cautiously added to the reactor. After 5 h, the reaction was deemed complete and the reaction mixture was warmed to between −15 to −20° C. To the reaction was added 2M HCl (11.80 L) to the reactor while maintaining a temperature between −15° C. and 0° C. The reaction mixture was stirred at 18 to 23° C. for (16 h) and the phases were separated. The organics were then extracted with 6 M sodium hydroxide (6.0 L). The acidic anbasic aqueous phases were mixed in the reactor and 6 M HCl (2.5 L) was added until pH 7.5 was achieved. Sodium chloride (6.0 kg) was then added to the aqueous phase. The aqueous phase was then extracted with THF (3×20 L). The combined organics were dried with magnesium sulfate and concentrated to give 1300 g of a tan solid (81% crude yield).
Reaction SMILES: [CH:1]([C@H:3]1[CH2:8][CH2:7][C@H:6]([CH2:9][O:10][C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([F:17])[C:12]=2[F:18])[CH2:5][CH2:4]1)=O.[Cl-].[CH3:20][O:21]C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.CC(C)([O-])C.[K+].O>C1COCC1>[CH:20]([CH2:1][C@H:3]1[CH2:8][CH2:7][C@H:6]([CH2:9][O:10][C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([F:17])[C:12]=2[F:18])[CH2:5][CH2:4]1)=[O:21]
Reactant: O=C[C@H]1CC[C@H](COc2cccc(F)c2F)CC1
Reactant: COC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CC(C)(C)[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: O=CC[C@H]1CC[C@H](COc2cccc(F)c2F)CC1
Reaction time: 0.5 h

Procedure:
11.5 g of 1-((trans-4-formylcyclohexyl)methoxy)-2,3-difluorobenzene was dissolved in 50 mL of THF, and 18.6 g of methoxymethyl triphenylphosphonium chloride was added thereto. To this solution, the THF (20 mL) solution containing 6.1 g of potassium-t-butoxide was added dropwise at an internal temperature of 5 to 20° C., and the solution was stirred for 30 min. 10 mL of water was added thereto, and the solvent was evaporated under reduced pressure. Hexane and 50% methanol aqueous solution were added thereto, and the organic layer was fractioned. This organic layer was washed with 50% methanol aqueous solution and saturated saline, and subjected to column chromatography. After evaporating the solvent under reduced pressure, the residue was dissolved in 70 mL of THF, and 70 mL of 10% hydrochloric acid was added thereto, followed by reflux with heating for 2 hours. To the solution, water and ethyl acetate were added, and the organic layer was fractioned, washed with saturated saline 3 times, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, to thereby obtain 8.2 g of 1-((trans-4-(formylmethyl)cyclohexyl)methoxy)-2,3-difluorobenzene.