Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:3]1[CH2:8][CH:7]=[C:6]([C:9]2[C:17]3[C:12](=[CH:13][CH:14]=[C:15]([NH2:18])[CH:16]=3)[NH:11][CH:10]=2)[CH2:5][CH2:4]1)[CH3:2].I.[S:20]1[CH:24]=[CH:23][CH:22]=[C:21]1[C:25](SC)=[NH:26].C([O-])(O)=O.[Na+]>C(O)C>[CH2:1]([N:3]1[CH2:4][CH:5]=[C:6]([C:9]2[C:17]3[C:12](=[CH:13][CH:14]=[C:15]([NH:18][C:25]([C:21]4[S:20][CH:24]=[CH:23][CH:22]=4)=[NH:26])[CH:16]=3)[NH:11][CH:10]=2)[CH2:7][CH2:8]1)[CH3:2]
Reactant: CCN1CC=C(c2c[nH]c3ccc(N)cc23)CC1
Reactant: CSC(=N)c1cccs1
Agent: I
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: CCN1CC=C(c2c[nH]c3ccc(NC(=N)c4cccs4)cc23)CC1
Reaction time: 18 h
Yield: 79.6 %

Procedure:
A solution of 3-(1-ethyl-1,2,3,6-tetrahydropyridin-4-yl)-1H-indol-5-amine (0.32 g, 1.326 mmol) in dry ethanol (10 mL) was treated with methyl thiophene-2-carbimidothioate hydroiodide (0.756 g, 2.65 mmol) at room temperature and stirred overnight (18 h). The reaction was basified with sat. NaHCO3 solution (30 mL) and product was extracted into CH2Cl2 (2×25 mL). The combined CH2Cl2 layer was washed with brine (20 mL) and dried (Na2SO4). Solvent was evaporated and crude was purified by column chromatography (2 M NH3 in MeOH:CH2Cl2, 1:9) to obtain N-(3-(1-ethyl-1,2,3,6-tetrahydropyridin-4-yl)-1H-indol-5-yl)thiophene-2-carboximidamide (0.37 g, 80%) as a solid. 1H NMR (DMSO-d6) δ 10.94 (s, 1H), 7.71 (d, 1H, J=3.3 Hz), 7.59 (s, 1H, J=5.1 Hz), 7.31 (dd, 1H, J=2.7, 5.4 Hz), 7.22 (s, 1H), 7.10 (t, 1H, J=4.8 Hz), 6.67 (d, 1H, J=8.4 Hz), 6.26 (brs, 2H), 6.05 (s, 1H), 3.10 (brs, 2H), 2.63 (t, 2H, J=5.1 Hz), 2.54-2.40 (m, 4H, merged with DMSO-peak), 1.06 (t, 3H, J=7.2 Hz); ESI-MS (m/z, %): 351 (MH+, 37), 294 (100); ESI-HRMS calculated for C20H23N4S (MH+), calculated: 351.1637; observed: 351.1636.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH2:12][C:13]3([OH:26])[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15][CH2:14]3)[N:9]=[C:10](I)[C:3]=12.[CH3:27][O:28][C:29]1[CH:34]=[C:33](B2OC(C)(C)C(C)(C)O2)[CH:32]=[CH:31][C:30]=1[NH:44][C:45](=[O:54])[O:46][CH2:47][C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=1.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.O.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>[NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH2:12][C:13]3([OH:26])[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15][CH2:14]3)[N:9]=[C:10]([C:33]3[CH:32]=[CH:31][C:30]([NH:44][C:45]([O:46][CH2:47][C:48]4[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=4)=[O:54])=[C:29]([O:28][CH3:27])[CH:34]=3)[C:3]=12
Reactant: COc1cc(B2OC(C)(C)C(C)(C)O2)ccc1NC(=O)OCc1ccccc1
Reactant: CC(C)(C)OC(=O)N1CCC(O)(Cn2nc(I)c3c(N)ncnc32)CC1
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: COCCOC
Solvent: O
Product: COc1cc(-c2nn(CC3(O)CCN(C(=O)OC(C)(C)C)CC3)c3ncnc(N)c23)ccc1NC(=O)OCc1ccccc1
Temperature: 85 °C
Yield: 29.8 %

Procedure:
A mixture of tert-butyl 4-[(4-amino-3-iodo-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl]-4-hydroxy-1-piperidinecarboxylate (0.27 g, 0.00057 mol), benzyl N-[2-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]carbamate (0.26 g, 0.00068 mol), tetrakis(triphenylphosphine)palladium (0.039 g, 0.000034 mol) and sodium carbonate (0.15 g, 0.0014 mol) in ethylene glycol dimethyl ether (7 mL) and water (3 mL) was heated at 85° C. for 16 hours under an atmosphere of nitrogen. The mixture was allowed to cool to ambient temperature and ethylene glycol dimethyl ether was removed under the reduced pressure. The aqueous layer was extracted with dichloromethane (2×100 mL). The combined organic extracts were washed with water and brine, and dried over magnesium sulfate. The organic layer was filtered through silica gel twice to remove the catalyst, and the solvent was removed under reduced pressure. The residue was purified by RP-HPLC (Hypersilprep HS C18, 8μm, 250×21.1 mm; 5%-100% over 35 min with 0.1 M ammonium acetate, 21 mL/min) to yield tert-butyl 4-{[4-amino-3-(4-{[(benzyloxy)carbonyl]amino}-3-methoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl]methyl}-4-hydroxy-1-piperidinecarboxylate (0.1 g, 0.00017 mol). RP-HPLC (Delta Pak C18, 5 μm, 300 A, 15 cm; 5%-85% acetonitrile-0.1M ammonium acetate over 10 min, 1 mL/min) Rt 10.9 min. MS: MH+ 604.
Reaction SMILES: C[O:2][C:3](=O)[CH:4]([C:15]1[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=1)[C:5]([C:7]1[CH:12]=[CH:11][N:10]=[C:9]([S:13][CH3:14])[N:8]=1)=O.Cl.[NH2:24][NH:25]C(N)=O.N1C=CC=CC=1>CO>[F:21][C:18]1[CH:19]=[CH:20][C:15]([C:4]2[C:3](=[O:2])[NH:24][NH:25][C:5]=2[C:7]2[CH:12]=[CH:11][N:10]=[C:9]([S:13][CH3:14])[N:8]=2)=[CH:16][CH:17]=1
Reactant: COC(=O)C(C(=O)c1ccnc(SC)n1)c1ccc(F)cc1
Reactant: NNC(N)=O
Agent: Cl
Solvent: CO
Solvent: c1ccncc1
Product: CSc1nccc(-c2[nH][nH]c(=O)c2-c2ccc(F)cc2)n1

Procedure:
A solution of 2-(4-fluorophenyl)-3-(2-methylsulfanyl-pyrimidin-4-yl)-3-oxo-propionic acid methyl ester, 3, (1 g, 3.7 mmol), semicarbazide HCl (0.653 g, 5.8 mmol) and pyridine (10 mL) is heated at 90° C. for 12 hours. The solution is then concentrated in vacuo to afford a semi-solid residue which is taken up in methanol and the resulting solid removed by filtration. The filtrate is concentrated in vacuo to afford the desired compound as a white solid, which is used without further purification.
Reaction SMILES: COC1C=CC(C[N:8]2[C:12]3=[N:13][CH:14]=[C:15]([NH:17][C:18]4[CH:23]=[CH:22][C:21]([CH2:24][N:25]5[CH2:30][CH2:29][N:28]([CH3:31])[CH2:27][CH2:26]5)=[CH:20][CH:19]=4)[CH:16]=[C:11]3[C:10]([CH3:32])=[N:9]2)=CC=1.FC(F)(F)C(O)=O>C(Cl)(Cl)Cl>[CH3:32][C:10]1[C:11]2[C:12](=[N:13][CH:14]=[C:15]([NH:17][C:18]3[CH:23]=[CH:22][C:21]([CH2:24][N:25]4[CH2:26][CH2:27][N:28]([CH3:31])[CH2:29][CH2:30]4)=[CH:20][CH:19]=3)[CH:16]=2)[NH:8][N:9]=1
Reactant: COc1ccc(Cn2nc(C)c3cc(Nc4ccc(CN5CCN(C)CC5)cc4)cnc32)cc1
Solvent: ClC(Cl)Cl
Solvent: O=C(O)C(F)(F)F
Product: Cc1n[nH]c2ncc(Nc3ccc(CN4CCN(C)CC4)cc3)cc12
Temperature: 60 °C

Procedure:
To a stirred solution of 1-(4-methoxybenzyl)-3-methyl-N-(4-((4-methylpiperazin-1-yl)methyl)phenyl)-1H-pyrazolo[3,4-b]pyridin-5-amine (166) (40 mg, 0.657 mmol) in CHCl3 (10 mL) was added trifluoroacetic acid (6 mL) and the reaction mass heated at 60° C. overnight. After completion of the reaction the solvents were completely distilled off and diluted with water and the pH was adjusted to 9 and extracted with chloroform twice. The combined organic layer was washed with brine solution and dried over sodium sulphate and the solvents were removed and the crude material was passed through 100-200 mesh silica gel, eluting with 8% MeOH/CH2Cl2 obtained pure 3-methyl-N-(4-((4-methylpiperazin-1-yl)methyl)phenyl)-1H-pyrazolo[3,4-b]pyridin-5-amine 167 as a pale yellow colored solid (10 mg). 1H NMR (400 MHz, CDCl3) δ: 8.38 (s, 1H), 7.76 (s, 1H), 7.52 (s, 1H), 7.21 (d, 1H), 7.19 (d, J=8.41, 1H), 7.19 (s, 1H), 6.89 (d, J=7.92, 1H), 3.46 (s, 2H), 2.54 (m, 8H), 2.31 (s, 3H), 2.05 (s, 3H); MS m/z 336.9 (M+H)+.
Reaction SMILES: [CH3:1][Si:2]([CH3:14])([CH3:13])[N:3]1[CH:8]=[CH:7][CH:6]([Si:9]([CH3:12])([CH3:11])[CH3:10])[CH:5]=[CH:4]1.[C:15](#[N:18])[CH:16]=[CH2:17]>>[CH3:1][Si:2]([CH3:14])([CH3:13])[N:3]1[CH:4]=[CH:5][C:6]([Si:9]([CH3:12])([CH3:11])[CH3:10])=[CH:7][CH:8]1[CH:16]([C:15]#[N:18])[CH3:17]
Reactant: C=CC#N
Reactant: C[Si](C)(C)C1C=CN([Si](C)(C)C)C=C1
Product: CC(C#N)C1C=C([Si](C)(C)C)C=CN1[Si](C)(C)C
Temperature: 25 °C
Yield: 71.4 %

Procedure:
To 22.6 g (0.1 mol) of 1,4-bis-(trimethylsilyl)-1,4-dihydropyridine are added by drops 5.31 g (0.1 mol) of acrylonitrile within 30 minutes in an inert atmosphere. The mixture is subsequently stirred for several hours at room temperature. Fractional distillation yields 19.9 g (72%) of 1,4-bis-(trimethylsilyl)-2-(1-cyanoethyl)-1,2-dihydropyridine; b.p. 78°C/0.003 mm; yellow oil.
Reaction SMILES: [CH2:1]([C:3]1[CH:12]=[C:11](C)[C:10]([I:14])=[CH:9][C:4]=1[C:5]([O:7][CH3:8])=[O:6])[CH3:2].[Cl:15]C1C=CC(C(OC)=O)=C(CC)C=1.C(C1C=C(C)C=CC=1C(OC)=O)C>>[Cl:15][C:11]1[C:10]([I:14])=[CH:9][C:4]([C:5]([O:7][CH3:8])=[O:6])=[C:3]([CH2:1][CH3:2])[CH:12]=1
Reactant: CCc1cc(C)c(I)cc1C(=O)OC
Reactant: CCc1cc(Cl)ccc1C(=O)OC
Agent: CCc1cc(C)ccc1C(=O)OC
Product: CCc1cc(Cl)c(I)cc1C(=O)OC

Procedure:
The title compound was prepared using standard chemical manipulations and procedures similar to those used for the preparation of compound 211.2, except methyl 4-chloro-2-ethylbenzoate (compound 178.2) was used in place of methyl 2-ethyl-4-methylbenzoate (compound 48.1).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:14]2([OH:21])[CH2:17][CH:16]([C:18](O)=[O:19])[CH2:15]2)[CH:5]=[CH:6][C:7]=1[CH2:8][N:9]1[CH2:13][CH2:12][CH2:11][CH2:10]1.[CH3:22][NH2:23].C(P1(=O)OP(CCC)(=O)OP(CCC)(=O)O1)CC.[OH-].[Na+]>CCOC(C)=O>[CH3:22][NH:23][C:18]([CH:16]1[CH2:17][C:14]([C:4]2[CH:5]=[CH:6][C:7]([CH2:8][N:9]3[CH2:13][CH2:12][CH2:11][CH2:10]3)=[C:2]([Cl:1])[CH:3]=2)([OH:21])[CH2:15]1)=[O:19]
Reactant: O=C(O)C1CC(O)(c2ccc(CN3CCCC3)c(Cl)c2)C1
Reactant: CN
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Product: CNC(=O)C1CC(O)(c2ccc(CN3CCCC3)c(Cl)c2)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 48.2 %

Procedure:
To a crude solution of intermediate 17, 3-(3-chloro-4-((pyrrolidin-1-yl)methyl)phenyl)-3-hydroxycyclobutanecarboxylic acid (˜666 mL, ˜121.5 mmol) was added 2.0 M methylamine (95 mL, 190 mmol, in THF) and T3P (50 wt % solution in EtOAc, 96.6 mL, 152 mmol). The resulting reaction mixture was stirred at RT for 1 hr and then 300 ml of 1N NaOH and 400 mL of EtOAc were added and the layers were separated. The aqueous layer was subjected to EtOAc extraction (2×500 ml) again and the combined organic layers were dried over MgSO4 and evaporated. The residue was purified by flash column chromatography using a 75 L Biotage™ column, eluting with gradients of 5%, 8%, 10%, 15% MeOH/CH2Cl2 with 0.25% NH4OH. The product containing fractions were collected and concentrated under reduced pressure to give the title compound (18.9 g, 48% yield). Rf=0.35 (20% MeOH/CH2Cl2+0.2% NH4OH); LRMS m/z Calcd for C17H23ClN2 O2, 322.2, found, 323.1 (M+1) APCI; 400 MHz 1H NMR (CDCl3) δ 7.47-7.45 (m, 2H), 7.33 (dd, J=7.9, 1.7 Hz, 1H), 5.94 (brs, 1H), 5.67 (brs, 1H), 3.75 (s, 3H), 2.85 (d, J=4.9 Hz, 3H), 2.86-2.73 (m, 3H), 2.62-2.56 (m, 4H), 2.54-2.47 (m, 2H), 1.84-1.76 (m 4H); 100 MHz 13C NMR (CDCl3) δ 177.6, 146.0, 135.5, 134.0, 130.8, 126.3, 123.6, 74.3, 56.8, 54.3, 41.1, 33.3, 26.9, 23.7.
Reaction SMILES: [CH2:1]([N:3]([CH2:29][CH3:30])[CH2:4][CH2:5][N:6]1[C:14]2[C:9](=[C:10]([C:16]([F:19])([F:18])[F:17])[CH:11]=[C:12](I)[CH:13]=2)[C:8]([OH:27])([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[Cl:26])[C:7]1=[O:28])[CH3:2].[CH3:31][S:32]([NH:35][CH2:36][C:37]#[CH:38])(=[O:34])=[O:33]>>[CH2:1]([N:3]([CH2:29][CH3:30])[CH2:4][CH2:5][N:6]1[C:14]2[C:9](=[C:10]([C:16]([F:19])([F:18])[F:17])[CH:11]=[C:12]([C:38]#[C:37][CH2:36][NH:35][S:32]([CH3:31])(=[O:34])=[O:33])[CH:13]=2)[C:8]([OH:27])([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[Cl:26])[C:7]1=[O:28])[CH3:2]
Reactant: CCN(CC)CCN1C(=O)C(O)(c2ccccc2Cl)c2c1cc(I)cc2C(F)(F)F
Reactant: C#CCNS(C)(=O)=O
Product: CCN(CC)CCN1C(=O)C(O)(c2ccccc2Cl)c2c1cc(C#CCNS(C)(=O)=O)cc2C(F)(F)F

Procedure:
The title compound (270 mg) was prepared from (+)-1-(2-diethylaminoethyl)-4-trifluoromethyl-6-iodo-3-hydroxy-3-(2-chlorophenyl)oxindole of Example 72(1) (347 mg, 0.628 mmol) and 1-methanesulfonylamino-2-propyne by the procedure similar to that described in Reference Example 21. The hydrochloride of the title compound was obtained by treating with 4 N HCl in dioxane followed by concentration to dryness.
Reaction SMILES: Cl[C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([N+:10]([O-:12])=[O:11])=[CH:4][N:3]=1.[OH-].[NH4+:14].C(O)C>C(OCC)(=O)C>[NH2:14][C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([N+:10]([O-:12])=[O:11])=[CH:4][N:3]=1
Reactant: [NH4+]
Reactant: COc1cc([N+](=O)[O-])cnc1Cl
Agent: [OH-]
Solvent: CCO
Solvent: CCOC(C)=O
Product: COc1cc([N+](=O)[O-])cnc1N
Temperature: 80 °C
Reaction time: 8 h
Yield: 69.6 %

Procedure:
Into a 250 mL sealed tube were combined 2-chloro-3-methoxy-5-nitropyridine (0.50 g, 0.00265 mol), concentrated ammonium hydroxide (5 mL, 0.1 mol) and ethanol (20 mL). The mixture was heated to 80° C. and stirred overnight. After allowing to cool to room temperature, the mixture was reduced in vacuo and the residue was taken up in ethyl acetate (50 mL), then washed with equal amounts of brine and water (1×50 mL each). The organic layer was dried (Na2SO4), filtered and concentrated under vacuum to leave a solid (0.312 g, 69%) which was used directly in the next step without further purification. LC-MS 1.94 min. M/Z=171.0 (M+1).
Reaction SMILES: [CH2:1]([OH:3])[CH3:2].[O-]CC.[Na+].C1(O)C=CC=CC=1.[Cl:15][C:16]1[N:25]=[C:24](Cl)[C:23]2[C:18](=[C:19]([O:30][CH3:31])[C:20]([O:28][CH3:29])=[C:21]([Cl:27])[CH:22]=2)[N:17]=1>>[Cl:15][C:16]1[N:25]=[C:24]([O:3][CH2:1][CH3:2])[C:23]2[C:18](=[C:19]([O:30][CH3:31])[C:20]([O:28][CH3:29])=[C:21]([Cl:27])[CH:22]=2)[N:17]=1
Reactant: CCO
Reactant: COc1c(Cl)cc2c(Cl)nc(Cl)nc2c1OC
Agent: CC[O-]
Agent: [Na+]
Solvent: Oc1ccccc1
Product: CCOc1nc(Cl)nc2c(OC)c(OC)c(Cl)cc12
Temperature: 0 °C
Reaction time: 8 h

Procedure:
To 5 liters of ethanol containing 0.2 mole of sodium ethoxide is added slowly with stirring 0.1 mole each of phenol and 2,4,6-trichloro-7,8-dimethoxyquinazoline. The mixture is heated to boiling then allowed to stand at room temperature overnight, poured into ice-water, stirred 15 minutes and the precipitate collected by filtration. The cake is washed with water, then cold ethanol, dried and recrystallized from ethanol/hexane to obtain 2,6-dichloro-7,8-dimethoxy-4-ethoxyquinazoline.
Reaction SMILES: C(O[C:4]([C:6]1[N:7]=[C:8]([C:15]2[C:20]([F:21])=[CH:19][CH:18]=[CH:17][C:16]=2[F:22])[N:9]([CH3:14])[C:10](=[O:13])[C:11]=1[OH:12])=[O:5])C.[CH3:23][C:24]1[CH:31]=[CH:30][C:27]([CH2:28][NH2:29])=[CH:26][CH:25]=1>>[CH3:23][C:24]1[CH:31]=[CH:30][C:27]([CH2:28][NH:29][C:4]([C:6]2[N:7]=[C:8]([C:15]3[C:16]([F:22])=[CH:17][CH:18]=[CH:19][C:20]=3[F:21])[N:9]([CH3:14])[C:10](=[O:13])[C:11]=2[OH:12])=[O:5])=[CH:26][CH:25]=1
Reactant: CCOC(=O)c1nc(-c2c(F)cccc2F)n(C)c(=O)c1O
Reactant: Cc1ccc(CN)cc1
Product: Cc1ccc(CNC(=O)c2nc(-c3c(F)cccc3F)n(C)c(=O)c2O)cc1

Procedure:
Prepared according to the procedure described for example 2 from 2-(2,6-difluoro-phenyl)-5-hydroxy-1-methyl-6-oxo-1,6-dihydro-pyrimidine-4-carboxylic acid ethyl ester (31 mg, 0.1 mmol) and 4-methylbenzylamine (61 mg, 0.5 mmol). The title product was obtained as an off-white solid (32 mg, 83% yield). 1HNMR (500 MHz, CDCl3) δ: 12.39 (1H, s), 7.55 (1H, br s), 7.51–7.45 (1H, m), 7.20 (2H, d, J=7.94 Hz), 7.14 (2H, d, J=7.63 Hz), 7.03 (2H, d, J=8.55, 7.33 Hz), 4.54 (2H, d, J=6.10 Hz), 3.40 (3H, s), 2.32 (3H, s). HRMS (ESI) calcd for C20H18F2N3O3 (M+H): 386.1316; found: 386.1313.
Reaction SMILES: [C:1]([C:9]1[CH:10]=[N:11][C:12]2[C:17]([C:18]=1[C:19]1[CH:20]=[C:21]([CH:24]=[CH:25][CH:26]=1)[CH:22]=O)=[CH:16][CH:15]=[CH:14][C:13]=2[C:27]([F:30])([F:29])[F:28])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:31][O:32][C:33]1[CH:40]=[CH:39][CH:38]=[CH:37][C:34]=1[CH2:35][NH2:36]>>[CH3:31][O:32][C:33]1[CH:40]=[CH:39][CH:38]=[CH:37][C:34]=1[CH2:35][NH:36][CH2:22][C:21]1[CH:20]=[C:19]([C:18]2[C:17]3[C:12](=[C:13]([C:27]([F:29])([F:30])[F:28])[CH:14]=[CH:15][CH:16]=3)[N:11]=[CH:10][C:9]=2[C:1]([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[O:8])[CH:26]=[CH:25][CH:24]=1
Reactant: COc1ccccc1CN
Reactant: O=Cc1cccc(-c2c(C(=O)c3ccccc3)cnc3c(C(F)(F)F)cccc23)c1
Product: COc1ccccc1CNCc1cccc(-c2c(C(=O)c3ccccc3)cnc3c(C(F)(F)F)cccc23)c1

Procedure:
The title compound was prepared from 3-[3-benzoyl-8-(trifluoromethyl)quinolin-4-yl]benzaldehyde and 2-methoxy-benzylamine according to the procedure of Example 66. MS (ES) m/z 527.2.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:23])[CH:4]([NH:8][S:9]([C:12]1[CH:17]=[CH:16][C:15]([O:18][CH2:19][C:20]#[C:21][CH3:22])=[CH:14][CH:13]=1)(=[O:11])=[O:10])[CH:5]([CH3:7])[CH3:6].Br[CH2:25][CH2:26][CH2:27][Cl:28]>>[CH3:1][O:2][C:3](=[O:23])[CH:4]([N:8]([S:9]([C:12]1[CH:13]=[CH:14][C:15]([O:18][CH2:19][C:20]#[C:21][CH3:22])=[CH:16][CH:17]=1)(=[O:11])=[O:10])[CH2:25][CH2:26][CH2:27][Cl:28])[CH:5]([CH3:7])[CH3:6]
Reactant: CC#CCOc1ccc(S(=O)(=O)NC(C(=O)OC)C(C)C)cc1
Reactant: ClCCCBr
Product: CC#CCOc1ccc(S(=O)(=O)N(CCCCl)C(C(=O)OC)C(C)C)cc1
Yield: 75 %

Procedure:
According to the procedure of Example 5, 1.00 g (2.95 mmol) 2-(4but-2-ynyloxy-benzenesulfonylamino)-3-methyl-butyric acid methyl ester and 0.88 mL (8.849 mmol) of 1-bromo-3-chloropropane provided 0.92 g of methyl2-[{[4-(2-butynyloxy)penyl]sulfonyl}(3-chloropropyl)amino]-3-methylbutanoate as a white solid. Electrospray Mass Spec 416.2 (M+H)+
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[N:14]=[C:13]([N:15]3[CH2:20][CH2:19][O:18][CH2:17][CH2:16]3)[CH:12]=[CH:11][CH:10]=2)O1.Br[C:23]1[CH:28]=[CH:27][C:26]([C@@H:29]([N:31]2[CH2:36][CH2:35][C@:34]([CH2:43][C:44]([OH:47])([CH3:46])[CH3:45])([C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=3)[O:33][C:32]2=[O:48])[CH3:30])=[CH:25][CH:24]=1>>[OH:47][C:44]([CH3:45])([CH3:46])[CH2:43][C@@:34]1([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[O:33][C:32](=[O:48])[N:31]([C@H:29]([C:26]2[CH:25]=[CH:24][C:23]([C:9]3[CH:10]=[CH:11][CH:12]=[C:13]([N:15]4[CH2:16][CH2:17][O:18][CH2:19][CH2:20]4)[N:14]=3)=[CH:28][CH:27]=2)[CH3:30])[CH2:36][CH2:35]1
Reactant: C[C@@H](c1ccc(Br)cc1)N1CC[C@](CC(C)(C)O)(c2ccccc2)OC1=O
Reactant: CC1(C)OB(c2cccc(N3CCOCC3)n2)OC1(C)C
Product: C[C@@H](c1ccc(-c2cccc(N3CCOCC3)n2)cc1)N1CC[C@](CC(C)(C)O)(c2ccccc2)OC1=O

Procedure:
The title compound was prepared from 4-[6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl]morpholine (purchased from CombiPhos Catalysts Inc., Princeton, N.J., USA) and (S)-3-[(S)-1-(4-bromophenyl)ethyl]-6-(2-hydroxy-2-methyl-propyl)-6-phenyl-1,3-oxazinan-2-one following a procedure analogous to that described in Example 35. LC (method 5): tR=1.68 min; Mass spectrum (ESI+): m/z=516 [M+H]+; 1H NMR (CD3OD) δ 0.95 (s, 3H), 1.24 (s, 3H), 1.58 (d, 3H), 2.17 (s, 2H), 2.25 (m, 1H), 2.47 (m, 2H), 3.08 (m, 1H), 3.66 (m, 4H), 3.83 (m, 4H), 5.58 (q, 1H), 7.12 (4H), 7.25-7.40 (5H), 7.63 (d, 2H), 7.88 (m, 1H).
Reaction SMILES: [CH3:1][N:2]1[C:6](=[O:7])[NH:5][NH:4][C:3]1=[O:8].C1C=CC=CC=1.CN(C)C=O.CC(C)([O-])C.[K+].[CH:26]([C:28]([CH2:30][CH2:31][CH2:32][CH2:33][CH3:34])=[O:29])=[CH2:27]>CN(C)C=O>[O:29]=[C:28]([CH2:30][CH2:31][CH2:32][CH2:33][CH3:34])[CH2:26][CH2:27][N:4]1[C:3](=[O:8])[N:2]([CH3:1])[C:6](=[O:7])[NH:5]1
Reactant: C=CC(=O)CCCCC
Reactant: Cn1c(=O)[nH][nH]c1=O
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: c1ccccc1
Product: CCCCCC(=O)CCn1[nH]c(=O)n(C)c1=O
Temperature: 25 °C
Reaction time: 48 h
Yield: 47453.9 %

Procedure:
A solution of 4-methyl-1,2,4-triazolidine-3,5-dione (16 g; 0.14 mmole) in dry 1:1 benzene-dimethylformamide (100 ml) was heated under reflux, with stirring under nitrogen, and potassium t-butoxide (17.62 g), was added. The resultant suspension was heated under reflux for 2 hr. and then n-pentyl vinyl ketone (12,568; 0.10 mole) in dry dimethylformamide (10 ml) added dropwise. After 2 days the mixture was allowed to cool to room temperature and partitioned between 5 M HCl (200 ml) and ethyl acetate (100 ml). The aqueous layer was extracted with ethyl acetate (5×70 ml) and the combined organic layers washed with water (2×100 ml) and brine (100 ml) and dried (Na2SO4). Evaporation in vacuo gave an oil. Recrystallisation from ethyl acetate - 60/80 petroleum ether gave 2-(3'-oxo-octyl)-4-methyl-1,2,4-triazolidine-3,5-dione (16.03 g; 66%). m.pt., 75°-76°
Reaction SMILES: C(OO)(=[O:3])C.[Cl:6][C:7]1[C:8]([O:22][CH:23]2[CH2:26][CH2:25][CH2:24]2)=[N:9][CH:10]=[C:11](B2OC(C)(C)C(C)(C)O2)[CH:12]=1.S([O-])([O-])(=O)=S.[Na+].[Na+]>C(O)(=O)C.O>[Cl:6][C:7]1[CH:12]=[C:11]([OH:3])[CH:10]=[N:9][C:8]=1[O:22][CH:23]1[CH2:26][CH2:25][CH2:24]1
Reactant: CC1(C)OB(c2cnc(OC3CCC3)c(Cl)c2)OC1(C)C
Reactant: CC(=O)OO
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: Oc1cnc(OC2CCC2)c(Cl)c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 72.3 %

Procedure:
Acetic acid solution of peracetic acid (35%, 4.2 mL, 21.3 mmol) was added to a solution of 3-chloro-2-cyclobutoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (Preparation 20, 4.4 g, 14.2 mmol) in glacial acetic acid (26 mL) and water (13 mL) at 0° C. The reaction mixture was stirred at 0° C. for 1 hour. Aqueous solution of sodium thiosulfate (0.5 M, 80 mL) was added and the mixture was stirred for 30 minutes at room temperature. The aqueous layer was extracted with EtOAc (3×40 mL). The combined organics were dried over magnesium sulfate, filtered and concentrated in vacuo. The crude residue was purified by silica gel chromatography eluting with 10% EtOAc in heptane to afford the title compound as a clear oil (2.05 g, 72%):
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]([N+:9]([O-:11])=[O:10])=[C:6]([OH:8])[CH:7]=1.C(=O)([O-])[O-].[K+].[K+].C[CH2:19][O:20][CH2:21][CH3:22]>CN(C=O)C.C(C1OC1)Br>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([N+:9]([O-:11])=[O:10])=[C:6]([CH:7]=1)[O:8][CH2:22][CH:21]1[CH2:19][O:20]1
Reactant: Cc1ccc([N+](=O)[O-])c(O)c1
Reactant: CCOCC
Agent: BrCC1CO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1ccc([N+](=O)[O-])c(OCC2CO2)c1
Temperature: 100 °C
Reaction time: 2.5 h
Yield: 83 %

Procedure:
A mixture of 5-Methyl-2-nitrophenol (7.7 g, 50 mmol), potassium carbonate (13.8 g, 0.1 mmol) and epibromohydrine (8.25 mL, 0.1 mmol) was dissolved in DMF (100 mL) and stirred 2-3 h at 100° C. under an atmosphere of nitrogen. The mixture was diluted with ether (0.5 L) and extracted with water until pH=7. The organic phase was evaporated and the residue was purified by flash-chromatography on silica (DCM) to give the sub-title compound as a yellow solid (8.65 g, 83%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:8]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([I:18])=[CH:14][C:13]=2[F:19])=[CH:9][N:10]=1)[C:5]([OH:7])=O.[N:20]1([CH2:26][CH2:27][NH2:28])[CH2:25][CH2:24][O:23][CH2:22][CH2:21]1>>[Br:1][C:2]1[CH:3]=[C:4]([C:8]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([I:18])=[CH:14][C:13]=2[F:19])=[CH:9][N:10]=1)[C:5]([NH:28][CH2:27][CH2:26][N:20]1[CH2:25][CH2:24][O:23][CH2:22][CH2:21]1)=[O:7]
Reactant: O=C(O)c1cc(Br)ncc1Nc1ccc(I)cc1F
Reactant: NCCN1CCOCC1
Product: O=C(NCCN1CCOCC1)c1cc(Br)ncc1Nc1ccc(I)cc1F

Procedure:
2-Bromo-5-(2-fluoro-4-iodo-phenylamino)-N-(2-morpholin-4-yl-ethyl)-isonicotinamide was synthesized according to the General Method 3 starting with 145 mg (0.33 mmol) of 2-bromo-5-[(2-fluoro-4-iodophenyl)amino]isonicotinic acid and 108 mg (0.83 mmol) of 2-morpholin-4-yl-ethylamine. Yield: 95 mg, 52%. LC/MS: [7.08 min, 550, 552 (M+1)]
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([S:8]([C:11]2[CH:20]=[C:19]3[C:14]([CH2:15][CH2:16][C@H:17]([CH2:21]OS(C)(=O)=O)[O:18]3)=[CH:13][CH:12]=2)(=[O:10])=[O:9])[CH:5]=[CH:6][CH:7]=1.O.[CH3:28][NH2:29]>>[F:1][C:2]1[CH:3]=[C:4]([S:8]([C:11]2[CH:20]=[C:19]3[C:14]([CH2:15][CH2:16][C@H:17]([CH2:21][NH:29][CH3:28])[O:18]3)=[CH:13][CH:12]=2)(=[O:10])=[O:9])[CH:5]=[CH:6][CH:7]=1
Reactant: CN
Reactant: CS(=O)(=O)OC[C@H]1CCc2ccc(S(=O)(=O)c3cccc(F)c3)cc2O1
Solvent: O
Product: CNC[C@H]1CCc2ccc(S(=O)(=O)c3cccc(F)c3)cc2O1
Temperature: 100 °C
Yield: 97 %

Procedure:
A mixture of methanesulfonic acid (R)-7-(3-fluoro-benzenesulfonyl)-chroman-2-ylmethyl ester (1.145 g, 2.86 mmol) and methylamine hydrate (10.mL) was heated in a sealed tube at 100° C. for 24 hours. The mixture was cooled and extracted with methylene chloride. The combined organic layers were washed with water and brine, dried (Na2SO4), filtered and concentrated under reduced pressure. The residue was purified by flash chromatography (methylene chloride:MeOH 4:1) to give 0.932 g (97%) of [(R)-7-(3-fluoro-benzenesulfonyl)-chroman-2-ylmethyl]-methyl-amine. MP=259.0-261.0° C.; MS (M+H)=336.