Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: FC(S(O[C:9]1[CH:14]=[CH:13][C:12]([O:15][C:16]([F:19])([F:18])[F:17])=[CH:11][C:10]=1[Cl:20])(=O)=O)(F)F.[CH3:21][N:22](C=O)C>C(OCC)(=O)C.[C-]#N.[Zn+2].[C-]#N.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>[Cl:20][C:10]1[CH:11]=[C:12]([O:15][C:16]([F:19])([F:18])[F:17])[CH:13]=[CH:14][C:9]=1[C:21]#[N:22]
Reactant: O=S(=O)(Oc1ccc(OC(F)(F)F)cc1Cl)C(F)(F)F
Reactant: CN(C)C=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Agent: [Zn+2]
Solvent: CCOC(C)=O
Product: N#Cc1ccc(OC(F)(F)F)cc1Cl
Temperature: 120 °C

Procedure:
3.00 g of the compound of Example 2A are dissolved in 12 ml of degassed DMF with 2.04 g of zinc cyanide and 1.00 g of tetrakis(triphenylphosphine)palladium and the solution is heated under argon at 120° C. for 2 h. After cooling, the reaction mixture is diluted with ethyl acetate and extracted by shaking twice with a saturated sodium hydrogen carbonate solution and then with a saturated sodium chloride solution. The organic phase is dried over sodium sulfate and concentrated. The residue is purified by silica gel chromatography (cyclohexane/ethyl acetate 10:1). 880 mg (44% of theory) of the title compound are obtained.
Reaction SMILES: [CH3:1][O:2][NH:3][CH:4]([C@@H:6]1[CH2:8][C@H:7]1[C:9]1[C:13]([Cl:14])=[C:12]([Cl:15])[S:11][C:10]=1[Cl:16])[CH3:5].C(N(CC)CC)C.[CH3:24][N:25]1[CH:29]=[C:28]([C:30](Cl)=[O:31])[C:27]([C:33]([F:36])([F:35])[F:34])=[N:26]1>ClCCl.O>[CH3:1][O:2][N:3]([CH:4]([C@@H:6]1[CH2:8][C@H:7]1[C:9]1[C:13]([Cl:14])=[C:12]([Cl:15])[S:11][C:10]=1[Cl:16])[CH3:5])[C:30]([C:28]1[C:27]([C:33]([F:36])([F:35])[F:34])=[N:26][N:25]([CH3:24])[CH:29]=1)=[O:31]
Reactant: Cn1cc(C(=O)Cl)c(C(F)(F)F)n1
Reactant: CONC(C)[C@@H]1C[C@H]1c1c(Cl)sc(Cl)c1Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O
Product: CON(C(=O)c1cn(C)nc1C(F)(F)F)C(C)[C@@H]1C[C@H]1c1c(Cl)sc(Cl)c1Cl
Temperature: 25 °C
Reaction time: 16 h
Yield: 85.9 %

Procedure:
To a stirred solution of trans O-methyl-N-{1-[2-(2,4,5-trichloro-thiophen-3-yl)-cyclopropyl]ethyl}-hydroxylamine (0.25 g; 0.83 mmol) prepared as described in example P17 and triethylamine (0.16 ml; 1.08 mmol) in dichloromethane (5.0 ml) at ambient temperature was added dropwise 1-methyl-3-trifluoromethyl-1H-pyrazole-4-carbonyl chloride (0.18 g; 0.83 mmol). The reaction mixture was stirred for 16 hours at ambient temperature then poured in water (3 ml) and extracted with dichloromethane (3×1 ml). Combined organic layers were washed with water (1 ml), brine and dried over anhydrous sodium sulphate. The solvent was removed in vacuo and the residue was purified by flash chromatography over silica gel (elution gradient: cyclohexane/ethyl acetate 99:1 to 30:70) to afford 0.34 g (85% of theory) of trans 1-methyl-3-trifluoromethyl-1H-pyrazole-4-carboxylic acid methoxy-{1-[2-(2,4,5-trichloro-thiophen-3-yl)-cyclopropyl]-ethyl}-amide as a resin.
Reaction SMILES: C(=O)([O-])O.[Na+].[CH2:6]([O:8][C:9]([C@:11]1([F:31])[C@@H:16]2[C@H:12]1[CH2:13][C@@H:14]([O:21][CH2:22][C:23]1[CH:28]=[CH:27][C:26]([Cl:29])=[C:25]([Cl:30])[CH:24]=1)[C@@:15]2([NH2:20])[C:17]([OH:19])=[O:18])=[O:10])[CH3:7].Cl[C:33]([O:35][CH2:36][CH:37]=[CH2:38])=[O:34].Cl>O1CCOCC1.O>[CH2:6]([O:8][C:9]([C@:11]1([F:31])[C@@H:16]2[C@H:12]1[CH2:13][C@@H:14]([O:21][CH2:22][C:23]1[CH:28]=[CH:27][C:26]([Cl:29])=[C:25]([Cl:30])[CH:24]=1)[C@@:15]2([NH:20][C:33]([O:35][CH2:36][CH:37]=[CH2:38])=[O:34])[C:17]([O:19][CH:11]([CH2:12][CH3:13])[CH3:9])=[O:18])=[O:10])[CH3:7]
Reactant: CCOC(=O)[C@@]1(F)[C@@H]2C[C@@H](OCc3ccc(Cl)c(Cl)c3)[C@@](N)(C(=O)O)[C@@H]21
Reactant: C=CCOC(=O)Cl
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: C=CCOC(=O)N[C@@]1(C(=O)OC(C)CC)[C@H](OCc2ccc(Cl)c(Cl)c2)C[C@@H]2[C@H]1[C@@]2(F)C(=O)OCC
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
2 mL of saturated sodium hydrogen carbonate was added to 200 mg of (1R,2R,3R,5R,6R)-2-amino-3-(3,4-dichlorobenzyloxy)-6-fluorobicyclo[3.1.0]hexane-2,6-dicarboxylic acid 6-ethyl ester suspended in 1 mL of dioxane, and the mixture was stirred for 10 minutes at room temperature. 0.18 mL of allyl chloroformate was added thereto, and the solution was stirred for 8 hours at room temperature. After the reaction solution was acidified with 1 mL of 1N hydrochloric acid, 10 mL of water was added thereto, and the mixture was extracted twice with ethyl acetate. The ethyl acetate layers were combined, dried over anhydrous sodium sulfate and concentrated under reduced pressure, and the obtained residue was dissolved in 20 mL of N,N-dimethylformamide. 141 mg of 1-iodobutane and 106 mg of potassium carbonate were added to the solution, and the mixture was stirred for 16 hours at room temperature. Water was added thereto, and the reaction solution was extracted twice with ethyl acetate. After the ethyl acetate layers were combined and dried over anhydrous sodium sulfate, the solvent was distilled under reduced pressure and purified by column chromatography (silica gel: Kanto Chemical silica gel 60 (spherical), eluent: hexane-ethyl acetate=5:1), thereby yielding 159 mg of (1R,2R,3R,5R,6R)-2-allyloxycarbonylamino-3-(3,4-dichlorobenzyloxy)-6-fluorobicyclo[3.1.0]hexane-2,6-dicarboxylic acid 2-butyl ester 6-ethyl ester.
Reaction SMILES: N#N.[Br:3][C:4]1[S:5][C:6]([CH:9]=[O:10])=[CH:7][N:8]=1.[CH3:11][Al](C)C.[NH4+].[Cl-].Cl>C(Cl)Cl.C1(C)C=CC=CC=1>[Br:3][C:4]1[S:5][C:6]([CH:9]([OH:10])[CH3:11])=[CH:7][N:8]=1
Reactant: O=Cc1cnc(Br)s1
Reactant: C[Al](C)C
Agent: Cl
Agent: N#N
Agent: [Cl-]
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: CC(O)c1cnc(Br)s1
Temperature: 0 °C
Reaction time: 0.75 h

Procedure:
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), a solution of commercially available 2-bromo-thiazole-5-carbaldehyde (1.96 g, 10.00 mmol) in CH2Cl2 (20 mL) was treated at 0° C. with trimethylaluminum (15 mL of a 2M solution in toluene, 30.00 mmol). The reaction mixture was then stirred at 0° C. for 45 min. CH2Cl2 (100 mL) was then added followed by sat. aq. NH4Cl (100 mL). The mixture was then treated with 1N HCl (50 mL) and the aq. layer was extracted with CH2Cl2 (150 mL). The combined org. extracts were dried over MgSO4, filtered, and the solvents were removed under reduced pressure to give the title compound as an orange oil. TLC:rf (1:1 hept-EA)=0.38. LC-MS-conditions 02: tR=0.70 min; [M+H]+=208.38.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[C:4]([C:11]#[N:12])=[C:5]1[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]1.[N+]([CH3:17])([O-])=O.C1CCN2C(=NCCC2)CC1>C(#N)C.CCOCC>[CH3:1][O:2][C:3]([C:4]1([C:11]#[N:12])[C:5]2([CH2:6][CH2:7][CH2:8][CH2:9][CH2:10]2)[CH2:17]1)=[O:13]
Reactant: COC(=O)C(C#N)=C1CCCCC1
Reactant: C[N+](=O)[O-]
Solvent: CCOCC
Solvent: CC#N
Solvent: C1CCC2=NCCCN2CC1
Product: COC(=O)C1(C#N)CC12CCCCC2
Temperature: 25 °C
Reaction time: 5.5 h
Yield: 85.9 %

Procedure:
To a solution of cyano-cyclohexylidene-acetic acid methyl ester (20.0 g, 112 mmol) in acetonitrile (400 mL) was added nitromethane (30 mL, 558 mmol) followed by dropwise addition of DBU (16.9 mL, 113 mmol) over five minutes. The solution went from clear to orange and was stirred at room temperature for 5.5 hours. The solution was diluted with ether (1 L), washed with 1N HCl (2×250 mL) and then brine (2×250 mL). The organic layer was dried over sodium sulfate, filtered and evaporated. The residue was chromatographed on a wet-packed silica gel column (6.5×40 cm) eluting with 95:5 hexanes/ethyl acetate. The appropriate fractions were combined and evaporated to give 18.6 g (86%) of 1-cyano-spiro[2.5]octane-1-carboxylic acid methyl ester as a clear oil: 1H NMR (300 MHz, CDCl3) δ 1.35 (m, 1H), 1.49 (d, J=5.0 Hz, 1H), 1.5–1.75 (m, 9H), 1.82 (d, J=5.0 Hz, 1H), 3.83 (s, 3H).
Reaction SMILES: C1(C2CC(O)C3C(=CC=C(O)C=3)O2)C=CC=CC=1.[Cl:19][C:20]1[CH:25]=[C:24]([Cl:26])[CH:23]=[CH:22][C:21]=1[CH:27]1[CH2:36][C:35](=[O:37])[C:34]2[C:29](=[CH:30][CH:31]=[C:32]([OH:38])[CH:33]=2)[O:28]1>>[Cl:19][C:20]1[CH:25]=[C:24]([Cl:26])[CH:23]=[CH:22][C:21]=1[CH:27]1[CH2:36][CH:35]([OH:37])[C:34]2[C:29](=[CH:30][CH:31]=[C:32]([OH:38])[CH:33]=2)[O:28]1
Reactant: O=C1CC(c2ccc(Cl)cc2Cl)Oc2ccc(O)cc21
Agent: Oc1ccc2c(c1)C(O)CC(c1ccccc1)O2
Product: Oc1ccc2c(c1)C(O)CC(c1ccc(Cl)cc1Cl)O2

Procedure:
2-(2,4-Dichlorophenyl)chroman-4,6-diol was prepared as described for 2-phenylchroman-4,6-diol in Example 8(a) starting from 1.2 g of 2-(2,4-dichlorophenyl)-6-hydroxychroman-4-one. The product was purified by column chromatography using heptane-ethyl acetate (2:1) as an eluant. 1H NMR (400 MHz, d6-DMSO) δ: 8.89 (s, 1H), 7.66 (d, 1H, J 2.1 Hz), 7.64 (d, 1H, J 8.5 Hz), 7.51 (dd, 1H, J 2.1, 8.5 Hz), 6.89 (d, 1H, J 2.7 Hz), 6.63 (d, 1H, J 8.7 Hz), 6.56 (dd, 1H, J 2.7, 8.7 Hz), 5.50 (d, 1H, J 6.8 Hz), 5.37 (d, 1H, J 10.4 Hz), 4.90 (m, 1H), 2.32 (m, 1H), 1.80 (m, 1H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[N:9]=[CH:8][N:7]([C:10]3[N:15]=[C:14]([NH:16][C@H:17]4[C:26]5[C:21](=[C:22]([F:27])[CH:23]=[CH:24][CH:25]=5)[O:20][CH2:19][CH2:18]4)[C:13]([N+:28]([O-])=O)=[CH:12][N:11]=3)[C:6]=2[CH:31]=1>CCOC(C)=O.[Pt]>[F:1][C:2]1[CH:3]=[CH:4][C:5]2[N:9]=[CH:8][N:7]([C:10]3[N:15]=[C:14]([NH:16][C@H:17]4[C:26]5[C:21](=[C:22]([F:27])[CH:23]=[CH:24][CH:25]=5)[O:20][CH2:19][CH2:18]4)[C:13]([NH2:28])=[CH:12][N:11]=3)[C:6]=2[CH:31]=1
Reactant: O=[N+]([O-])c1cnc(-n2cnc3ccc(F)cc32)nc1N[C@@H]1CCOc2c(F)cccc21
Agent: [Pt]
Solvent: CCOC(C)=O
Product: Nc1cnc(-n2cnc3ccc(F)cc32)nc1N[C@@H]1CCOc2c(F)cccc21
Reaction time: 18 h

Procedure:
To a solution of the 2-(6-fluoro-1H-benzo[d]imidazol-1-yl)-N—((R)-8-fluorochroman-4-yl)-5-nitropyrimidin-4-amine in EtOAc (20 mL) was added 5 mol % of Platinum, 5% on activated carbon power, sulfide, 0.5% S (as sulfide) (45.6 mg). The mixture was sparged with argon, transferred to the Parr hydrogenation apparatus, then subjected to a purge/fill sequence with hydrogen (repeated 5×). The mixture was hydrogenated for 18 hr at 40 psi. Filtration through a pad of Celite and concentration of the filtrate gave crude 2-(6-fluoro-1H-benzo[d]imidazol-1-yl)N4—((R)-8-fluorochroman-4-yl)pyrimidine-4,5-diamine that was carried on without further purification. MH+=425.
Reaction SMILES: [CH:1]1[CH2:6][CH2:5][CH:4]=[CH:3][CH:2]=1.[NH:7]1[CH2:12][CH2:11][O:10][CH2:9][CH2:8]1>C1(C)C=CC=CC=1.C1CC=CCCC=C1.C1CC=CCCC=C1.[Ni].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.[Fe+2].FC(F)(F)C(O)=O>[CH:2]1([N:7]2[CH2:12][CH2:11][O:10][CH2:9][CH2:8]2)[CH2:1][CH2:6][CH2:5][CH:4]=[CH:3]1
Reactant: C1=CCCC=C1
Reactant: C1COCCN1
Agent: [Fe+2]
Agent: [Ni]
Agent: C1=C\CC/C=C\CC/1
Solvent: Cc1ccccc1
Solvent: C1=CCCC=CCC1
Solvent: O=C(O)C(F)(F)F
Product: C1=CC(N2CCOCC2)CCC1
Temperature: 25 °C
Reaction time: 14 h
Yield: 81.9 %

Procedure:
Ni(cod)2 (11.0 mg, 0.040 mmol) and DPPF (44.0 mg, 0.080 mmol) were suspended in 0.3 mL of toluene in a screw-capped vial. The vial was sealed with a cap containing a PTFE septum and removed from the dry box. 1,3-Cyclohexadiene (160 mg, 2.00 mmol), morpholine (183 mg, 2.10 mmol) and trifluoroacetic acid (9.0 mg, 0.080 mmol) were added to the reaction mixture by syringe. The reaction mixture was stirred at room temperature for 14 h. The volatile compounds were evaporated under reduced pressure, and the residue was adsorbed onto silica gel. The product was eluted with 90% ethyl acetate/hexenes to give 274 mg (82%) of 4-(2-cyclohexenyl)morpholine: 1H NMR (500 MHz, [D]chloroform, 25° C.): δ=5.84-5.83 (m, 1H; H-C3), 5.68-5.66 (m, 1H; H-C2), 3.74-3.72 (m, 4H; CH2), 3.17 (brs, 1H; H-C1), 2.64-2.56 (m, 4H; CH2), 2.00-1.98 (m, 2H; CH2), 1.82-1.80 (m, 2H; CH2), 1.57-1.54 (m, 2H; CH2); 13C{1H} NMR (125 MHz, [D]chloroform, 25° C.): δ=130.08, 128.77, 67.34, 60.22, 49.12, 25.15, 23.07, 21.29.
Reaction SMILES: [CH:1]1([CH:7]([OH:42])[CH2:8][N:9]2[C:14](=[O:15])[C:13]([CH2:16][C:17]3[CH:22]=[CH:21][C:20]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=4[C:29]4[NH:33][C:32](=[O:34])[O:31][N:30]=4)=[CH:19][CH:18]=3)=[C:12]([CH2:35][CH2:36][CH3:37])[N:11]3[N:38]=[C:39]([CH3:41])[N:40]=[C:10]23)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.C(=O)([O-])O.[Na+].O.O.O.O.O.S([O-])([O-])(=O)=S.[Na+].[Na+]>C(OCC)(=O)C.C(#N)C>[CH:1]1([C:7](=[O:42])[CH2:8][N:9]2[C:14](=[O:15])[C:13]([CH2:16][C:17]3[CH:18]=[CH:19][C:20]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=4[C:29]4[NH:33][C:32](=[O:34])[O:31][N:30]=4)=[CH:21][CH:22]=3)=[C:12]([CH2:35][CH2:36][CH3:37])[N:11]3[N:38]=[C:39]([CH3:41])[N:40]=[C:10]23)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CCCc1c(Cc2ccc(-c3ccccc3-c3noc(=O)[nH]3)cc2)c(=O)n(CC(O)C2CCCCC2)c2nc(C)nn12
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: O=C([O-])O
Agent: O=S([O-])([O-])=S
Solvent: O
Solvent: CCOC(C)=O
Solvent: CC#N
Product: CCCc1c(Cc2ccc(-c3ccccc3-c3noc(=O)[nH]3)cc2)c(=O)n(CC(=O)C2CCCCC2)c2nc(C)nn12
Temperature: 25 °C
Reaction time: 3 h
Yield: 87 %

Procedure:
A mixture of 4-(2-cyclohexyl-2-hydroxyethyl)-2-methyl-6-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-7-propyl[1,2,4]triazolo[1,5-a]pyrimidin-5(4H)-one (0.6 g), Dess-Martin reagent (0.89 g) and acetonitrile (10 mL) was stirred at room temperature for 3 hr. Saturated aqueous sodium hydrogen carbonate and sodium thiosulfate-pentahydrate were added to the reaction mixture, and the mixture was stirred at room temperature for 2 hr. The reaction mixture was diluted with ethyl acetate, washed with water and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography to give the title compound as colorless crystals (0.52 g, 87%).
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[C:10]([NH:12][CH2:13][CH2:14][NH2:15])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.C(N(CC)CC)C.[CH3:23][CH:24]([CH3:31])/[CH:25]=[CH:26]/[S:27](Cl)(=[O:29])=[O:28]>C(#N)C.ClCCl>[CH3:23][CH:24]([CH3:31])/[CH:25]=[CH:26]/[S:27]([NH:15][CH2:14][CH2:13][NH:12][C:10]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=[C:2]([CH3:1])[CH:11]=1)(=[O:29])=[O:28]
Reactant: CC(C)/C=C/S(=O)(=O)Cl
Reactant: Cc1cc(NCCN)c2ccccc2n1
Solvent: ClCCl
Solvent: CC#N
Solvent: CCN(CC)CC
Product: Cc1cc(NCCNS(=O)(=O)/C=C/C(C)C)c2ccccc2n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 41.3 %

Procedure:
To a solution of N1-(2-methylquinolin-4-yl)ethane-1,2-diamine (161 mg, 0.800 mmol) and triethylamine (0.350 ml, 2.51 mmol) in acetonitrile (5 ml) was added a solution of (E)-3-methylbut-1-ene-1-sulfonyl chloride (102 mg of step D) in dichloromethane (1 ml). The mixture was stirred 30 minutes at room temperature, concentrated under reduced pressure and the residue was purified by column chromatography over aluminum oxide using a gradient of methanol (2-10%) in dichloromethane to yield 83 mg of an off-white foam (0.25 mmol; 13% over 4 steps).
Reaction SMILES: C1([O:7][C:8](=O)[NH:9][CH2:10][C:11]#[C:12][C:13]2[CH:14]=[C:15]3[C:20](=[CH:21][CH:22]=2)[N:19]=[CH:18][N:17]=[C:16]3[NH:23][C:24]2[CH:29]=[CH:28][C:27]([O:30][C:31]3[CH:32]=[N:33][C:34]([CH3:37])=[CH:35][CH:36]=3)=[C:26]([Cl:38])[CH:25]=2)C=CC=CC=1.[CH3:40][NH2:41]>CS(C)=O>[Cl:38][C:26]1[CH:25]=[C:24]([NH:23][C:16]2[C:15]3[C:20](=[CH:21][CH:22]=[C:13]([C:12]#[C:11][CH2:10][NH:9][C:8]([NH:41][CH3:40])=[O:7])[CH:14]=3)[N:19]=[CH:18][N:17]=2)[CH:29]=[CH:28][C:27]=1[O:30][C:31]1[CH:32]=[N:33][C:34]([CH3:37])=[CH:35][CH:36]=1
Reactant: CN
Reactant: Cc1ccc(Oc2ccc(Nc3ncnc4ccc(C#CCNC(=O)Oc5ccccc5)cc34)cc2Cl)cn1
Solvent: CS(C)=O
Product: CNC(=O)NCC#Cc1ccc2ncnc(Nc3ccc(Oc4ccc(C)nc4)c(Cl)c3)c2c1
Temperature: 80 °C
Reaction time: 8 h
Yield: 94 %

Procedure:
A mixture of (3-{4-[3-Chloro-4-(6-methyl-pyridin-3-yloxy)-phenylamino]-quinazolin-6-yl}-prop-2-ynyl)-carbamic acid phenyl ester (0.1 g, 0.18 mmol) prepared by Method B, methyl amine (2.0M methanol solution, 1 mL, 2 mmol) and DMSO (0.5 mL) was stirred at 80° C. overnight. The solvents were removed under vacuum (GeneVac HT-8) and the residue was re-dissolved in MeOH (˜1 mL). HCl gas was bubbled through the solution and EtOAc resulting in precipitation of the desired product. The title compound (80 mg, 90% yield) was obtained by filtration as a yellow solid. 1HNMR (400 MHz, CD3OD) δ 2.72 (3H,s), 2.76 (3H, s), 4.19 (2H, s), 7.49 (1H, d, J=9 Hz), 7.84 (1H, d, J=2 Hz), 7.86 (1H, d, J=2 Hz), 7.92 (1H, d, J=9 Hz), 8.12 (2H, m, J=2 Hz), 8.16 (1H, d, J=2.4 Hz), 8.60 (1H, d, J=3.2 Hz), 8.74 (1H, d, J=1.2 Hz), 8.87 (1H, s ). LRMS (M+): 473.0, 475.0, 476.0.
Reaction SMILES: [CH3:1][CH:2]1[CH2:7][CH2:6][N:5]([C:8]([N:10]2[CH2:16][C:15]3[CH:17]=[C:18](B(O)O)[CH:19]=[CH:20][C:14]=3[O:13][CH2:12][CH2:11]2)=[O:9])[CH2:4][CH2:3]1.C(=O)([O-])[O-].[K+].[K+].[C:30](#[N:32])[CH3:31]>CC(N(C)C)=O.O>[CH3:1][CH:2]1[CH2:7][CH2:6][N:5]([C:8]([N:10]2[CH2:16][C:15]3[CH:17]=[C:18]([C:31]4[CH:30]=[N:32][C:8]([NH2:10])=[N:5][CH:4]=4)[CH:19]=[CH:20][C:14]=3[O:13][CH2:12][CH2:11]2)=[O:9])[CH2:4][CH2:3]1
Reactant: CC1CCN(C(=O)N2CCOc3ccc(B(O)O)cc3C2)CC1
Reactant: CC#N
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Solvent: O
Product: CC1CCN(C(=O)N2CCOc3ccc(-c4cnc(N)nc4)cc3C2)CC1
Temperature: 95 °C
Reaction time: 2.5 h

Procedure:
To a mixture of 2-amino-5-bromopryimidine (65 mg, 0.37 mmol), {4-[(4-methylpiperidin-1-yl)carbonyl]-2,3,4,5-tetrahydro-1,4-benzoxazepine-7-yl}boronic acid (100 mg, 0.31 mmol) and potassium carbonate (215 mg, 1.6 mmol) in DMA (5.0 mL) and water (0.5 mL) was added dichloro[1,1-bis(diphenylphosphino]ferrocenepalladium (II) dichloromethane adduct (23 mg, 0.03 mmol). The reaction mixture was stirred at 95° C. for 2.5 hours and then partitioned between dichloromethane (10 mL) and 1M aqueous sodium hydroxide (10 mL). The organic layer was separated and washed with brine (10 mL) then dried over anhydrous magnesium sulfate, filtered and concentrated. The residue was chromatographed on silica gel using 2% methanol in dichloromethane as eluent and the combined product containing fractions were concentrated. The residue thus obtained was taken into a minimum of acetonitrile and purified by preparative reverse phase HPLC to afford 5-{4-[(4-methylpiperidin-1-yl)carbonyl]-2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl}pyrimidin-2-amine (24 mg) as an amorphous solid. 1H NMR (400 mHz, DSMO-d6): 8.51 (s, 2H), 7.47 (d, 1H), 7.42 (dd, 1H), 6.98 (d, 1H), 6.75 (s, 2H), 4.39 (s, 2H), 4.12-4.18 (m, 2H), 3.46-3.59 (m, 4H), 2.70 (t, 2H), 1.42-1.61 (m, 3H), 1.04-1.18 (m, 2H), 0.91 (d, 3H); MS (EI) for C20H25N5O2: 368 (MH+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]=[CH2:10])=[CH:5][C:4]=1[N+:11]([O-])=O>[Pd].C(OCC)(=O)C>[CH2:9]([C:6]1[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[C:4]([NH2:11])[CH:5]=1)[CH3:10]
Reactant: C=Cc1ccc(OC)c([N+](=O)[O-])c1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CCc1ccc(OC)c(N)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 1-methoxy-2-nitro-4-vinyl-benzene (150 mg) and palladium on carbon (10%, 25 mg) in ethyl acetate (10 mL) was stirred under hydrogen atmosphere (balloon pressure) at room temperature overnight. The reaction mixture was filtered on a CELITE™ pad and the filtrate was evaporated to give 5-ethyl-2-methoxy-phenylamine without further purifications.
Reaction SMILES: [F:1][C:2]1[N:7]=[C:6]([C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([C:17]4[S:21][C:20]([NH:22]CC5C=CC(OC)=CC=5)=[N:19][N:18]=4)[CH:15]=3)[N:10]([S:32]([C:35]3[CH:41]=[CH:40][C:38]([CH3:39])=[CH:37][CH:36]=3)(=[O:34])=[O:33])[CH:9]=2)[CH:5]=[CH:4][CH:3]=1>C(O)(C(F)(F)F)=O>[F:1][C:2]1[N:7]=[C:6]([C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([C:17]4[S:21][C:20]([NH2:22])=[N:19][N:18]=4)[CH:15]=3)[N:10]([S:32]([C:35]3[CH:36]=[CH:37][C:38]([CH3:39])=[CH:40][CH:41]=3)(=[O:34])=[O:33])[CH:9]=2)[CH:5]=[CH:4][CH:3]=1
Reactant: COc1ccc(CNc2nnc(-c3ccc4c(c3)c(-c3cccc(F)n3)cn4S(=O)(=O)c3ccc(C)cc3)s2)cc1
Solvent: O=C(O)C(F)(F)F
Product: Cc1ccc(S(=O)(=O)n2cc(-c3cccc(F)n3)c3cc(-c4nnc(N)s4)ccc32)cc1
Temperature: 120 °C
Yield: 78.6 %

Procedure:
A glass microwave reaction vessel was charged with 5-(3-(6-fluoropyridin-2-yl)-1-tosyl-1H-indol-5-yl)-N-(4-methoxybenzyl)-1,3,4-thiadiazol-2-amine (400 mg, 0.683 mmol) in TFA (0.5 mL). The reaction was stirred and heated in a Initiator microwave reactor (Personal Chemistry, Biotage AB, Inc., Uppsala, Sweden) at 120° C. for 30 min. The solvent was removed and the residue was diluted with DCM and washed with sat. NaHCO3. The organic layer was dried, filtered and concentrated. The residue was purified with silica gel chromatography (eluting with 10-25% EtOAc in DCM with 1% MeOH) to give 5-(3-(6-fluoropyridin-2-yl)-1-tosyl-1H-indol-5-yl)-1,3,4-thiadiazol-2-amine (250 mg, 0.537 mmol, 79%) as a white solid. MS (ESI, pos. ion) m/z: 466 (M+1).
Reaction SMILES: [CH2:1]([N:5]1[N:9]=[C:8]([C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=2)[CH:7]=[N:6]1)[CH2:2][C:3]#[CH:4].Br[C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([CH2:24][F:25])[N:19]=1>>[F:25][CH2:24][C:20]1[CH:21]=[CH:22][CH:23]=[C:18]([C:4]#[C:3][CH2:2][CH2:1][N:5]2[N:9]=[C:8]([C:10]3[CH:11]=[CH:12][C:13]([F:16])=[CH:14][CH:15]=3)[CH:7]=[N:6]2)[N:19]=1
Reactant: FCc1cccc(Br)n1
Reactant: C#CCCn1ncc(-c2ccc(F)cc2)n1
Product: FCc1cccc(C#CCCn2ncc(-c3ccc(F)cc3)n2)n1
Yield: 44.3 %

Procedure:
The title compound was prepared in accordance with the general method of Example 1, from 2-(but-3-ynyl)-4-(4-fluorophenyl)-2H-1,2,3-triazole (150 mg, 0.70 mmol; Example 254(B)) and 2-bromo-6-(fluoromethyl)pyridine (146 mg, 0.77 mmol, Example 190(E)). The crude residue was purified by flash chromatography (DCM/MeOH 99.5:0.5 to 99:1) to yield 101 mg (0.31 mmol, 45%) of 2-(fluoromethyl)-6-(4-(4-(4-fluorophenyl)-2H-1,2,3-triazol-2-yl)but-1-ynyl)pyridine as a yellow solid (M.P.=84-86° C.).
Reaction SMILES: [C:1]([C:5]1[CH:18]=[CH:17][C:8]([O:9][C:10]2[CH:15]=[CH:14][C:13]([NH2:16])=[CH:12][CH:11]=2)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].Cl[S:20]([C:23]1[CH:24]=[CH:25][C:26]([CH3:32])=[C:27]([CH:31]=1)[C:28]([OH:30])=[O:29])(=[O:22])=[O:21].N1C=CC=CC=1>O1CCCC1.C(OCC)(=O)C>[C:1]([C:5]1[CH:18]=[CH:17][C:8]([O:9][C:10]2[CH:11]=[CH:12][C:13]([NH:16][S:20]([C:23]3[CH:24]=[CH:25][C:26]([CH3:32])=[C:27]([CH:31]=3)[C:28]([OH:30])=[O:29])(=[O:22])=[O:21])=[CH:14][CH:15]=2)=[CH:7][CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1C(=O)O
Reactant: CC(C)(C)c1ccc(Oc2ccc(N)cc2)cc1
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: Cc1ccc(S(=O)(=O)Nc2ccc(Oc3ccc(C(C)(C)C)cc3)cc2)cc1C(=O)O
Temperature: 25 °C
Yield: 82 %

Procedure:
A solution of 4-(4-tert-butyl-phenoxy)-phenylamine (0.1 g, 0.41 mmol). 5-chlorosulfonyl-2-methylbenzoic acid (0.097 g, 0.41 mmol) and pyridine (0.1 ml, 1.24 mmol) in 2 ml anhydrous tetrahydrofuran was heated at 60° C. for 2 hr. The reaction mixture was cooled to room temperature and diluted with 30 ml ethyl acetate. The ethyl acetate solution was washed sequentially with 25 ml 1N aqueous hydrochloric acid solution and 25 ml brine, dried (anhydrous sodium sulfate) and concentrated to dryness under reduced pressure. The crude product was purified by preparative thick layer chromatography (silica gel), eluting with 9:1 chloroform/methanol to yield the title compound.