Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:4][CH2:5][C@H:6]([CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[F:22])[NH:7]C(OC(C)(C)C)=O)(=[O:3])[NH2:2].[ClH:23].C(=O)([O-])[O-].[K+].[K+].CCOCC>C1COCC1>[ClH:23].[C:1]([O:4][CH2:5][C@H:6]([CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[F:22])[NH2:7])(=[O:3])[NH2:2]
Reactant: CC(C)(C)OC(=O)N[C@H](COC(N)=O)Cc1ccccc1F
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CCOCC
Product: NC(=O)OC[C@@H](N)Cc1ccccc1F
Temperature: 25 °C
Reaction time: 8 h
Yield: 73 %

Procedure:
In a 100 mL flask equipped with magnetic stirrer, O-carbamoyl-N-(t-butyloxycarbonyl)-o-fluorophenylalaninol obtained in Example 1 was dissolved in 40 ml of THF and was added with 20 ml of 6N aqueous hydrochloric acid solution. The reaction mixture was stirred at room temperature for 8 hours, followed by the neutralization with saturated aqueous potassium carbonate solution. Thereafter, the organic layer was extracted 3 times with dichloromethane, dried over magnesium sulfate and distilled in vacuo, to give a yellowish liquid. This was dissolved in 30 ml of THF and added with anhydrous hydrochloric acid at 0° C., to obtain desirable white precipitates. To this was added 30 ml of anhydrous ether, with the aim of maximizing the precipitation. As a result, 1.22 g of the title compound was obtained: Yield 73%.
Reaction SMILES: [NH2:1][CH2:2][CH:3]1[CH2:12][CH2:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4]1.[CH:13](=O)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.[BH3-]C#N.[Na+].Cl>CO>[CH2:13]([NH:1][CH2:2][CH:3]1[CH2:12][CH2:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4]1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: NCC1CCc2ccccc2C1
Reactant: O=Cc1ccccc1
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Product: c1ccc(CNCC2CCc3ccccc3C2)cc1
Reaction time: 16 h

Procedure:
A solution of 2-aminomethyl-1,2,3,4-tetrahydronaphthalene (XXXI) (14.5 g), benzaldehyde (9.7 g) and NaBH3CN (5.8 g) in methanol (150 ml) was cooled to 0°. Concentrated HCl was added dropwise until the apparent pH (litmus) was 3-4. The mixture was then stirred 16 hours at 0°. The solvent was evaporated, and the residue was dissolved in EtOAc, which was washed with saturated NaHCO3 solution, dried (MgSO4), and evaporated. The residual oil was dissolved in MeOH, and a slight excess of concentrated HCl was added. Adding EtOAc and boiling caused precipitation of Compound XXXIV.HCl, which was collected by filtration. Its NMR was consistent with the structure indicated, and it was used without further purification.
Reaction SMILES: [Cl-].[Cd+2:2].[Cl-].Br[C:5]1[CH:10]=[CH:9][C:8]([CH2:11][CH:12]([CH3:14])[CH3:13])=[CH:7][CH:6]=1.[Mg]>C1COCC1>[CH2:11]([C:8]1[CH:9]=[CH:10][C:5]([Cd:2][C:5]2[CH:10]=[CH:9][C:8]([CH2:11][CH:12]([CH3:14])[CH3:13])=[CH:7][CH:6]=2)=[CH:6][CH:7]=1)[CH:12]([CH3:14])[CH3:13]
Reactant: CC(C)Cc1ccc(Br)cc1
Reactant: [Cd+2]
Agent: [Cl-]
Agent: [Mg]
Solvent: C1CCOC1
Product: CC(C)Cc1ccc([Cd]c2ccc(CC(C)C)cc2)cc1

Procedure:
Ten grams of cadmium chloride was added to a Grignard reagent prepared from 21.7 g of p-bromoisobutylbenzene, 2.5 g of magnesium and 400 ml of THF. The mixture was refluxed for 10 minutes to give a solution of di-(p-isobutylphenyl)cadmium. A solution of 18 g of ethyl α-bromopropionate in 20 ml of THF was added to the reaction mixture which had been cooled. After standing at 20° C. for 24 hours, dilute hydrochloric acid was added to the mixture. The mixture was extracted with diethyl ether. The extract was washed with water, dried, concentrated, and purified by silica gel column chromatography to give 4.05 g (17.4%) of ethyl α-(p-isobutylphenyl)propionate.
Reaction SMILES: [F:1][C:2]1[CH:8]=[CH:7][CH:6]=[C:5]([F:9])[C:3]=1[NH2:4].[Br:10]Br>C(Cl)(Cl)Cl>[Br:10][C:7]1[CH:8]=[C:2]([F:1])[C:3]([NH2:4])=[C:5]([F:9])[CH:6]=1
Reactant: BrBr
Reactant: Nc1c(F)cccc1F
Solvent: ClC(Cl)Cl
Product: Nc1c(F)cc(Br)cc1F

Procedure:
In the method of preparation, Compound [A], 2,6-difluoroaniline, is reacted with bromine in chloroform to yield compound [B], 4-bromo-2,6-difluoroaniline. Compound [B] is mixed with copper (I) cyanide in N-methylpyrrolidone to yield compound [C], 4-cyano-2,6-difluoroaniline. Compound [C] is mixed with sodium nitrite and sulfuric acid in acetic acid to yield a diazonium salt. The diazonium salt is mixed with copper (I) bromide in hydrobromic acid to yield compound [D], 5-cyano-1,3-difluorobenzene.
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:10]=[C:9]([Br:11])[C:8](=[O:12])[N:7]([CH2:13][C:14]2[CH:19]=[CH:18][C:17]([C:20]#[N:21])=[CH:16][CH:15]=2)[C:6]=1[CH2:22][N:23]([CH2:34][C:35]([O:37][CH3:38])=[O:36])S(C1C=CC(C)=CC=1)(=O)=O)=O.C[O-].[Na+].Cl>CO>[CH3:38][O:37][C:35]([C:34]1[C:3]([OH:2])=[C:5]2[C:6](=[CH:22][N:23]=1)[N:7]([CH2:13][C:14]1[CH:15]=[CH:16][C:17]([C:20]#[N:21])=[CH:18][CH:19]=1)[C:8](=[O:12])[C:9]([Br:11])=[CH:10]2)=[O:36]
Reactant: COC(=O)CN(Cc1c(C(=O)OC)cc(Br)c(=O)n1Cc1ccc(C#N)cc1)S(=O)(=O)c1ccc(C)cc1
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: COC(=O)c1ncc2c(cc(Br)c(=O)n2Cc2ccc(C#N)cc2)c1O
Temperature: 25 °C
Reaction time: 16 h
Yield: 72.7 %

Procedure:
5-Bromo-1-(4-cyano-benzyl)-2-{[methoxycarbonylmethyl-(toluene-4-sulfonyl)-amino]-methyl}-6-oxo-1,6-dihydro-pyridine-3-carboxylic acid methyl ester (2 g, 3.32 mmol) was dissolved in 60 mL of MeOH and placed in ice bath. NaOMe solution (2.3 mL, 9.97 mmol, 4.375 M in MeOH) was added and the mixture was stirred for 16 h at r.t. 1 M HCl was added to acidify the mixture, and the resulting suspension was extracted with CH2Cl2. The organic layer was dried over MgSO4 and concentrated. The crude product was purified by silica gel chromatography (0-20% EtOAc/CH2Cl2) to give 1 g of the title compound. MS: (−) m/z 412.07, 414.02 (M-1, 79/81Br).
Reaction SMILES: [OH:1]O.[CH:3]([C:6]1[C:7]([CH3:12])=[N:8][CH:9]=[CH:10][CH:11]=1)([CH3:5])[CH3:4]>CC(O)=O>[CH:3]([C:6]1[C:7]([CH3:12])=[N+:8]([O-:1])[CH:9]=[CH:10][CH:11]=1)([CH3:5])[CH3:4]
Reactant: Cc1ncccc1C(C)C
Reactant: OO
Solvent: CC(=O)O
Product: Cc1c(C(C)C)ccc[n+]1[O-]
Temperature: 70 °C
Reaction time: 18 h
Yield: 94 %

Procedure:
A 50% solution of hydrogen peroxide (24.89 mL) was slowly added to a solution of 3-isopropyl-2-methyl-pyridine (24.5 g, 183 mmol) (Ishiguro, et al., Yakugaku Zasshi (1958) 78:220) in HOAc (280 mL). The mixture was warmed to 70° C. and stirred for 18 h, then cooled to room temperature and concentrated in vacuo to remove the majority of HOAc. The mixture was basified with a saturated solution of NaHCO3 to pH 12 and extracted with CH2Cl2 (3×150 mL). The combined organic layers were dried over Na2SO4 and concentrated in vacuo to afford 3-isopropyl-2-methyl-pyridine 1-oxide (26.05 g, 94%) as a yellow oil. 1H NMR (CDCl3) δ 1.24 (d, 6H, J=7.0 Hz), 2.56 (s, 3H), 3.13 (sep, 1H, J=7.0 Hz), 7.06-7.17 (m, 2H), 8.17 (d, 1H, J=6.6 Hz).
Reaction SMILES: [C:1]([O:5][C:6](=[O:35])[CH2:7][O:8][C:9]1[C:18]2[CH2:17][CH2:16][CH2:15][C@@H:14]([N:19]([S:21]([C:24]3[CH:29]=[C:28]([C:30]([F:33])([F:32])[F:31])[CH:27]=[C:26](F)[CH:25]=3)(=[O:23])=[O:22])[CH3:20])[C:13]=2[CH:12]=[CH:11][CH:10]=1)([CH3:4])([CH3:3])[CH3:2].[Cl:36][C:37]1[CH:42]=[CH:41][C:40]([SH:43])=[CH:39][CH:38]=1.C(=O)([O-])[O-].[K+].[K+].Cl>CN(C)C=O>[C:1]([O:5][C:6](=[O:35])[CH2:7][O:8][C:9]1[C:18]2[CH2:17][CH2:16][CH2:15][C@@H:14]([N:19]([S:21]([C:24]3[CH:29]=[C:28]([C:30]([F:32])([F:31])[F:33])[CH:27]=[C:26]([S:43][C:40]4[CH:41]=[CH:42][C:37]([Cl:36])=[CH:38][CH:39]=4)[CH:25]=3)(=[O:23])=[O:22])[CH3:20])[C:13]=2[CH:12]=[CH:11][CH:10]=1)([CH3:2])([CH3:4])[CH3:3]
Reactant: CN([C@@H]1CCCc2c(OCC(=O)OC(C)(C)C)cccc21)S(=O)(=O)c1cc(F)cc(C(F)(F)F)c1
Reactant: Sc1ccc(Cl)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CN([C@@H]1CCCc2c(OCC(=O)OC(C)(C)C)cccc21)S(=O)(=O)c1cc(Sc2ccc(Cl)cc2)cc(C(F)(F)F)c1
Temperature: 150 °C
Yield: 70.2 %

Procedure:
A mixture of {(R)-5-[(3-fluoro-5-trifluoromethyl-benzenesulfonyl)-methyl-amino]-5,6,7,8-tetrahydro-naphthalen-1-yloxy}-acetic acid tert-butyl ester (80.0 mg, 0.15 mmol), 4-chloro-benzenethiol (50 μL), and potassium carbonate (55.0 mg, 0.40 mmol) in N,N-dimethylformamide (1.0 mL) was heated in a microwave oven at 150° C. for 30 minutes. The resulting mixture was neutralized with 1N hydrochloric acid and then extracted with ethyl acetate (20 mL×3). The combined organic layers were washed with brine (20 mL×3), dried over anhydrous sodium sulfate, and concentrated in vacuo to afford ((R)-5-{[3-(4-chloro-phenylsulfanyl)-5-trifluoromethyl-benzenesulfonyl]-methyl-amino}-5,6,7,8-tetrahydro-naphthalen-1-yloxy)-acetic acid tert-butyl ester (67.5 mg, 70.2%) as a viscous oil, which was used for the next step without any further purification. MS cald. for C30H31ClF3NO5S2 641, obsd. 642 (ESI+) [(M+H)+].
Reaction SMILES: [OH-].[K+].[O:3]1[CH:7]=[CH:6][CH:5]=[C:4]1[C:8]1[CH:28]=[CH:27][C:11]([O:12][C@@H:13]([CH2:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:14]([O:16]CC)=[O:15])=[CH:10][CH:9]=1.O>C(O)C>[O:3]1[CH:7]=[CH:6][CH:5]=[C:4]1[C:8]1[CH:9]=[CH:10][C:11]([O:12][C@@H:13]([CH2:19][CH2:20][C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)[C:14]([OH:16])=[O:15])=[CH:27][CH:28]=1
Reactant: CCOC(=O)[C@H](CCc1ccccc1)Oc1ccc(-c2ccco2)cc1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: O=C(O)[C@H](CCc1ccccc1)Oc1ccc(-c2ccco2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 72.1 %

Procedure:
21.5 mmol of potassium hydroxide are added to a solution of 4.3 mmol of ethyl (2S)-2-(4-furan-2-ylphenoxy)-4-phenylbutanoate, obtained in the preceding example, in 30 ml of ethanol. The mixture is refluxed for 30 minutes, 15 ml of water are added and refluxing is continued for 3 hours 30 minutes. After cooling to room temperature, the ethanol is evaporated off under vacuum. The product is taken up in water and washed with ether. The aqueous phase is acidified with 10% hydrochloric acid. A white precipitate forms, which is extracted with ethyl acetate. The organic phase is dried over sodium sulfate and evaporated under vacuum. 1.2 g of a beige-coloured solid, that recrystallizes from a hexane/ethyl acetate mixture to give 1 g of a solid melting at 140-142° C., are obtained.
Reaction SMILES: ClC(Cl)(Cl)[C:3]1[O:7][N:6]=[C:5]([C:8]2[CH:13]=[CH:12][N:11]=[C:10]([N:14]3[CH2:19][CH2:18][N:17]([C:20]([O:22][CH2:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:21])[CH2:16][CH2:15]3)[CH:9]=2)[N:4]=1.[BH4-].[Na+]>CO.C(OCC)(=O)C>[O:7]1[CH:3]=[N:4][C:5]([C:8]2[CH:13]=[CH:12][N:11]=[C:10]([N:14]3[CH2:19][CH2:18][N:17]([C:20]([O:22][CH2:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:21])[CH2:16][CH2:15]3)[CH:9]=2)=[N:6]1
Reactant: CC(C)(C)COC(=O)N1CCN(c2cc(-c3noc(C(Cl)(Cl)Cl)n3)ccn2)CC1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CO
Product: CC(C)(C)COC(=O)N1CCN(c2cc(-c3ncon3)ccn2)CC1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 52.8 %

Procedure:
2,2-Dimethylpropyl 4-[4-(5-trichloromethyl-1,2,4-oxadiazol-3-yl)pyridin-2-yl]-1-piperazinecarboxylate (23.1 mg) obtained in Example 32 was dissolved in methanol (2 mL), and sodium borohydride (10 mg) was added thereto and stirred at room temperature for 10 minutes. Then, the reaction liquid was diluted with ethyl acetate, washed with water and saturated saline water, and dried with anhydrous sodium sulfate. The solvent was evaporated away, and the resulting residue was isolated and purified through thin-layer silica gel chromatography (hexane/ethyl acetate=7/3) to obtain 9.1 mg of the entitled compound as a colorless oil.
Reaction SMILES: [O:1]=[C:2]1[N:7]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([F:17])([F:16])[F:15])[CH:9]=2)[C:6]2[CH2:18][CH2:19][C:20](=[O:21])[C:5]=2[CH:4]([C:22]2[CH:29]=[CH:28][C:25]([C:26]#[N:27])=[CH:24][CH:23]=2)[NH:3]1.[H-].[Na+].Cl[S:33]([CH2:36][CH2:37][CH2:38][C:39]([O:41][CH3:42])=[O:40])(=[O:35])=[O:34]>O1CCCC1.CN(C)C=O.O>[C:26]([C:25]1[CH:24]=[CH:23][C:22]([CH:4]2[N:3]([S:33]([CH2:36][CH2:37][CH2:38][C:39]([O:41][CH3:42])=[O:40])(=[O:35])=[O:34])[C:2](=[O:1])[N:7]([C:8]3[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([F:15])([F:16])[F:17])[CH:9]=3)[C:6]3[CH2:18][CH2:19][C:20](=[O:21])[C:5]2=3)=[CH:29][CH:28]=1)#[N:27]
Reactant: COC(=O)CCCS(=O)(=O)Cl
Reactant: N#Cc1ccc(C2NC(=O)N(c3cccc(C(F)(F)F)c3)C3=C2C(=O)CC3)cc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)CCCS(=O)(=O)N1C(=O)N(c2cccc(C(F)(F)F)c2)C2=C(C(=O)CC2)C1c1ccc(C#N)cc1
Temperature: 50 °C

Procedure:
A solution of 4-(2,5-dioxo-1-(3-(trifluoromethyl)phenyl)-2,3,4,5,6,7-hexahydro-1H-cyclopenta[d]pyrimidin-4-yl)benzonitrile (example 1, 70 mg, 0.18 mmol) in a mixture of tetrahydrofuran (1.5 mL) and N,N-dimethylformamide (150 μL) is treated with sodium hydride (60% in mineral oil, 28 mg, 0.7 mmol) and stirred at room temperature for 5 min Methyl 4-(chlorosulfonyl)butanoate (106 mg, 0.53 mmol) is added, and the mixture is stirred at 50° C. over night. The mixture is diluted with water and N,N-dimethylformamide and purified by reversed phase HPLC (Wate7rs SunFire™-C18, gradient of acetonitrile in water, 0.1% TFA). Yield: 48 mg; ESI mass spectrum [M+H]+=562; Retention time HPLC: 0.95 min (Z018_S04).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[NH:12][CH:11]([C:16]1[CH:21]=[C:20]([F:22])[CH:19]=[C:18](Br)[CH:17]=1)[C:10]([CH3:25])([CH3:24])[CH2:9]2)=[O:5])[CH3:2].[NH:26]1[CH2:30][CH2:29][CH2:28][CH2:27]1.[OH-].[K+].C(OCC)(=O)C>CS(C)=O.[Cu]I>[CH2:1]([O:3][C:4]([C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[NH:12][CH:11]([C:16]1[CH:17]=[C:18]([N:26]3[CH2:30][CH2:29][CH2:28][CH2:27]3)[CH:19]=[C:20]([F:22])[CH:21]=1)[C:10]([CH3:25])([CH3:24])[CH2:9]2)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1ccc2c(c1)CC(C)(C)C(c1cc(F)cc(Br)c1)N2
Reactant: C1CCNC1
Agent: [Cu]I
Agent: [K+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: CCOC(=O)c1ccc2c(c1)CC(C)(C)C(c1cc(F)cc(N3CCCC3)c1)N2
Temperature: 120 °C
Yield: 45.4 %

Procedure:
A mixture of 2-(3-bromo-5-fluoro-phenyl)-3,3-dimethyl-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid ethyl ester (0.41 g, 1.0 mmol), pyrrolidine (0.21 g, 3.0 mmol), copper (I) iodide (0.11 g, 0.6 mmol) and potassium hydroxide (33.6 mg, 0.6 mmol) in DMSO (2 mL) was heated for 3 hours at 120° C. After cooling to room temperature, the mixture was treated with ethyl acetate (50 mL) and washed with water (20 mL). The organic layer was dried over anhydrous sodium sulfate and concentrated in vacuo. Purification on flash silica gel chromatography (silica gel from QingDao, 200-300 mesh, glass column from Shanghai SD company) (20% ethyl acetate/hexanes) to afford 2-(3-fluoro-5-pyrrolidin-1-yl-phenyl)-3,3-dimethyl-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid ethyl ester (0.18 g, 45%) as a white solid: LC/MS m/e calcd for C24H29FN2O2 (M+H)+: 397.5, observed: 397.3.
Reaction SMILES: O[CH2:2][CH2:3][CH2:4][C:5](=[O:26])[CH2:6][PH:7]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[F:27][B-:28]([F:31])([F:30])[F:29].[CH2:32]([O+](CC)CC)C>C(Cl)Cl.C(=O)=O.CC(C)=O>[F:27][B-:28]([F:31])([F:30])[F:29].[C:8]1([P+:7]([C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)([C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:6]=[C:5]2[CH2:4][CH2:3][CH:2]([CH3:32])[O:26]2)[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: O=C(CCCO)C[PH](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CC[O+](CC)CC
Agent: F[B-](F)(F)F
Agent: O=C=O
Solvent: ClCCl
Solvent: CC(C)=O
Product: CC1CCC(=C[P+](c2ccccc2)(c2ccccc2)c2ccccc2)O1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
1.5 g of (5-hydroxy-2-oxopentyl)triphenylphosphorane was dissolved in 20 ml of methylene chloride under a nitrogen atmosphere, cooled in dry ice/acetone bath and 15 ml of triethyloxonium tetrafluoroborate as a 1 M solution in methylene chloride was added. The reaction mixture was stirred at about -78° C. for 0.5 hour and allowed to warm to room temperature over about 2 hours, decanted into ice water and stirred vigorously with the addition of an additional 30 ml of methylene chloride. The extraction was repeated twice, the extracts combined, dried over sodium sulfate, the solvent removed under nitrogen gas followed by warming to 40° C. for 2 hours at 0.5 mm. Crystallization from ethyl acetate gave 700 mg of the desired product, m.p. 118.5°-122.5° C.
Reaction SMILES: [Br:1][C:2]1[CH:6]=[N:5][N:4]([CH2:7][CH3:8])[C:3]=1[CH:9]=[O:10].[C:11]1([CH2:17][CH2:18][CH2:19][Mg]Br)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>>[Br:1][C:2]1[CH:6]=[N:5][N:4]([CH2:7][CH3:8])[C:3]=1[CH:9]([OH:10])[CH2:19][CH2:18][CH2:17][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: CCn1ncc(Br)c1C=O
Reactant: Br[Mg]CCCc1ccccc1
Product: CCn1ncc(Br)c1C(O)CCCc1ccccc1

Procedure:
Prepared according to the procedure described in Example 5, Step 1, using the following starting materials: 4-bromo-2-ethyl-2H-pyrazole-3-carbaldehyde and 3-phenyl-propyl magnesium bromide.
Reaction SMILES: [Br-].[CH2:2]([P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[CH2:3][CH2:4][CH2:5][CH3:6].[Li]N([Si](C)(C)C)[Si](C)(C)C.[OH:36][C:37]1[CH:44]=[CH:43][C:40]([CH:41]=O)=[CH:39][CH:38]=1>C1COCC1>[CH:41]([C:40]1[CH:43]=[CH:44][C:37]([OH:36])=[CH:38][CH:39]=1)=[CH:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: CCCCC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: O=Cc1ccc(O)cc1
Agent: [Br-]
Agent: [Li]N([Si](C)(C)C)[Si](C)(C)C
Solvent: C1CCOC1
Product: CCCCC=Cc1ccc(O)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 85.1 %

Procedure:
To a suspension of pentyl triphenylphosphonium bromide (4.76 g, 11.5 mMol) in freshly distilled THF (40 ml) was added LiN(SiMe3)2 (1N in THF, 23 ml). The red solution was stirred at ambient temperature for 30 minutes then a solution of p-hydroxybenzaldehyde (1.06 g, 10 mMol) in THF (10 ml) added. The reaction was stirred at ambient temperature for 4 days, then partitioned between ethyl ether and dilute aqueous HCl (1N). The combined etherial extracts were washed with brine, dried (MgSO4) and evaporated. The crude oil was purified by chromatography (eluant: ethyl ether/hexane) to give 4-(1-hexenyl)phenol as a pale yellow solid (1.5 g, 85%).
Reaction SMILES: [F:1][CH:2]([F:28])[O:3][C:4]1[CH:5]=[C:6]([NH:10][C:11]2[C:20]3[C:15](=[CH:16][CH:17]=[C:18]([NH2:21])[CH:19]=3)[N:14]=[C:13]([C:22]3[CH:27]=[N:26][CH:25]=[CH:24][N:23]=3)[N:12]=2)[CH:7]=[CH:8][CH:9]=1.CCN(CC)CC.[CH3:36][O:37][C:38]1[CH:46]=[CH:45][C:41]([C:42](Cl)=[O:43])=[CH:40][N:39]=1>C1COCC1>[F:28][CH:2]([F:1])[O:3][C:4]1[CH:5]=[C:6]([NH:10][C:11]2[C:20]3[C:15](=[CH:16][CH:17]=[C:18]([NH:21][C:42](=[O:43])[C:41]4[CH:45]=[CH:46][C:38]([O:37][CH3:36])=[N:39][CH:40]=4)[CH:19]=3)[N:14]=[C:13]([C:22]3[CH:27]=[N:26][CH:25]=[CH:24][N:23]=3)[N:12]=2)[CH:7]=[CH:8][CH:9]=1
Reactant: Nc1ccc2nc(-c3cnccn3)nc(Nc3cccc(OC(F)F)c3)c2c1
Reactant: COc1ccc(C(=O)Cl)cn1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COc1ccc(C(=O)Nc2ccc3nc(-c4cnccn4)nc(Nc4cccc(OC(F)F)c4)c3c2)cn1
Temperature: 25 °C
Reaction time: 18 h
Yield: 18.8 %

Procedure:
To a solution of 6-methoxynicotinic acid (100 mg, 0.65 mmol) in SOCK, (2 mL) was added DMF (1 drop). The mixture was stirred at 60° C. for 20 min. The volatiles were removed in vacuo to give 6-methoxynicotinoyl chloride, which was used for the next step directly. To a suspension of N4-(3-(difluoromethoxy)phenyl)-2-(pyrazin-2-yl)quinazoline-4,6-diamine (130 mg, 0.34 mmol, 0.5 eq.) in THF (5 mL) and Et3N (101 mg, 1 mmol, 3.0 eq) was added 6-methoxynicotinoyl chloride in anhydrous THF (5 mL) dropwise. The resulting mixture was stirred at room temperature for 18 h. The volatiles were removed in vacuo. The residue was washed with MeOH and re-crystallized from THF/MeOH twice, and purified by reverse phase chromatography PREP-HPLC (A=NH4HCO3—H2O, 10 mmol/L, B=MeOH) to afford 33 mg of N-(4-(3-(difluoromethoxy)phenylamino)-2-(pyrazin-2-yl)quinazolin-6-yl)-6-methoxynicotinamide as a pale yellow solid (18.8%). LCMS m/z=516.1 (M+1), 258.6 (M/2+1) (Method A) (retention time=1.57 min), 1H-NMR (400 MHz, DMSO-(d6): δ 10.71 (s, 1H), 10.18 (s, 1H), 9.57 (d, J=1.6 Hz, 1H), 9.01 (d, J=1.6 Hz, 1H), 8.91 (d, J=2.4 Hz, 1H), 8.81 (t, J=2.0 Hz, 1H), 8.76 (d, J=2.4 Hz, 1H), 8.34 (dd, J=8.8, 2.8 Hz, 1H), 8.23 (s, 1H), 8.08 (dd, J=8.8, 2.0 Hz, 1H), 8.00 (d, J=9.2 Hz, 1H), 7.90 (d, J=9.2 Hz, 1H), 7.46-7.50 (m, 1H), 7.32 (t, J=74.4 Hz 1H), 7.02 (d, J=8.8 Hz, 1H), 6.95 (dd, J=8.0, 2.0 Hz, 1H), 3.97 (s, 3H).
Reaction SMILES: [NH:1]([CH2:5][C:6]#[N:7])[CH2:2][C:3]#[N:4].[N:8]1[C:15]([Cl:16])=[N:14][C:12](Cl)=[N:11][C:9]=1[Cl:10]>O1CCOCC1>[Cl:10][C:9]1[N:8]=[C:15]([Cl:16])[N:14]=[C:12]([N:1]([CH2:5][C:6]#[N:7])[CH2:2][C:3]#[N:4])[N:11]=1
Reactant: Clc1nc(Cl)nc(Cl)n1
Reactant: N#CCNCC#N
Solvent: C1COCCO1
Product: N#CCN(CC#N)c1nc(Cl)nc(Cl)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 80 %

Procedure:
A solution of 9.5 g. (0.1 mole) of iminodiacetonitrile in 100 ml. dioxane was added to a stirred solution of 9.2 g. (0.05 mole) of cyanuric chloride in 100 ml. dioxane. The suspension was stirred at ambient temperature for 1 hour. An additional 100 ml. dioxane was added and mixture heated to 50°C. for 1 hour and filtered. The filtrate was diluted with 500 ml. ice/water and the solid filtered and dried to give 9.6 g. (80% yield), m.p. 154°-158°C.
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].[N:7]([CH2:10][C@:11]([C:14]1[CH:19]=[C:18]([Br:20])[CH:17]=[CH:16][C:15]=1[F:21])([OH:13])[CH3:12])=[N+]=[N-]>C1COCC1>[NH2:7][CH2:10][C@:11]([C:14]1[CH:19]=[C:18]([Br:20])[CH:17]=[CH:16][C:15]=1[F:21])([OH:13])[CH3:12]
Reactant: C[C@@](O)(CN=[N+]=[N-])c1cc(Br)ccc1F
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: C[C@@](O)(CN)c1cc(Br)ccc1F
Temperature: 2.5 °C
Reaction time: 1 h

Procedure:
To a suspension of LiAlH4 (4.65 g, 122 mmol) in THF (250 ml) was added under argon at 0-5° C. a solution of (S)-1-azido-2-(5-bromo-2-fluoro-phenyl)-propan-2-ol (33.4 g, 122 mmol) dissolved in THF (150 ml) over a period of 30 min. After stirring for 1 h at 0-5° C., the reaction was quenched by careful addition of water (4.7 ml), 4 N NaOH (4.7 ml) and water (14.1 ml) and stirred again for 3 h at 25° C. The white suspension was dried with MgSO4, filtered and concentrated. The solidified product was re-crystallized from TBME-hexane to provide the title compound as beige crystals: 98% ee (Chiralpak AD-H hexane-EtOH 75-25+0.05% NEt3); TLC(CH2Cl2-MeOH 10:1) Rf=0.10; UPLC RtH5=0.558 min; ESIMS: 248, 250 [(M+H)+]; 1H NMR (360 MHz, CDCl3): δ 7.76 (dd, 1H), 7.25 (m, 1H), 6.82 (dd, 1H), 4.16 (br s, 1H), 3.19 (d, 1H), 2.72 (d, 1H), 1.44 (s, 3H), 0.95 (br s, 2H).
Reaction SMILES: [CH:1]1([O:8][C:9]2[CH:16]=[CH:15][C:12]([CH2:13][NH2:14])=[CH:11][CH:10]=2)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[Cl:17][C:18]1[CH:34]=[CH:33][C:21]2[CH2:22][CH2:23][N:24]([C:27](=[O:32])[C:28]([F:31])([F:30])[F:29])[CH2:25][CH2:26][C:20]=2[C:19]=1OS(C(F)(F)F)(=O)=O.C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CCOC(C)=O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C1(C)C=CC=CC=1>[Cl:17][C:18]1[CH:34]=[CH:33][C:21]2[CH2:22][CH2:23][N:24]([C:27](=[O:32])[C:28]([F:29])([F:31])[F:30])[CH2:25][CH2:26][C:20]=2[C:19]=1[NH:14][CH2:13][C:12]1[CH:11]=[CH:10][C:9]([O:8][CH:1]2[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)=[CH:16][CH:15]=1
Reactant: O=C(N1CCc2ccc(Cl)c(OS(=O)(=O)C(F)(F)F)c2CC1)C(F)(F)F
Reactant: NCc1ccc(OC2CCCCCC2)cc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: O=C(N1CCc2ccc(Cl)c(NCc3ccc(OC4CCCCCC4)cc3)c2CC1)C(F)(F)F
Temperature: 90 °C
Yield: 66.3 %

Procedure:
Under a nitrogen atmosphere, add 4-cycloheptyloxy-benzylamine (451 mg, 2.06 mmol), 7-chloro-3-(2,2,2-trifluoroacetyl)-6-trifluoromethanesulfonyloxy-2,3,4,5-tetrahydro-1H-benzo[d]azepine (500 mg, 1.17 mmol), palladium(II) acetate (26 mg, 0.117 mmol), BINAP (110 mg, 0.176 mmol), and cesium carbonate (1.15 g, 3.52 mmol) to toluene (20 mL). Heat the mixture at 90° C. for 12 h. Cool the mixture to room temperature and dilute with EtOAc (25 mL). Filter the solids through cellulose (20 g) and concentrate in vacuo. Purify the crude mixture by chromatography on silica gel (45 g RediSep column) eluting with hexane/EtOAc (1:0 to 4:1 gradient over 1 h; 80 mL/min) to provide 7-chloro-6-(4-cycloheptyloxy-benzylamino)-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine as a colorless oil (384 mg, 61%). MS (APCI) m/z: 495 (M+H)+.