Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([C@@H:33]3[CH2:38][CH2:37][C@H:36]([NH:39][CH2:40][CH2:41][C:42]([O:44]CC)=[O:43])[CH2:35][CH2:34]3)[N:9]=[C:10]([C:11]3[CH:16]=[CH:15][C:14]([NH:17][C:18](=[O:30])[C:19]4[CH:24]=[CH:23][C:22]([C:25]([F:28])([F:27])[F:26])=[CH:21][C:20]=4[F:29])=[C:13]([O:31][CH3:32])[CH:12]=3)[C:3]=12.O1CCOCC1.[OH-].[K+]>O>[NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([C@@H:33]3[CH2:38][CH2:37][C@H:36]([NH:39][CH2:40][CH2:41][C:42]([OH:44])=[O:43])[CH2:35][CH2:34]3)[N:9]=[C:10]([C:11]3[CH:16]=[CH:15][C:14]([NH:17][C:18](=[O:30])[C:19]4[CH:24]=[CH:23][C:22]([C:25]([F:27])([F:28])[F:26])=[CH:21][C:20]=4[F:29])=[C:13]([O:31][CH3:32])[CH:12]=3)[C:3]=12
Reactant: CCOC(=O)CCN[C@H]1CC[C@@H](n2nc(-c3ccc(NC(=O)c4ccc(C(F)(F)F)cc4F)c(OC)c3)c3c(N)ncnc32)CC1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: COc1cc(-c2nn([C@H]3CC[C@@H](NCCC(=O)O)CC3)c3ncnc(N)c23)ccc1NC(=O)c1ccc(C(F)(F)F)cc1F
Temperature: 80 °C

Procedure:
A mixture of cis-ethyl 3-({4-[4-amino-3-(4-{[2-fluoro-4trifluoromethylbenzoyl]amino}-3-methoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl]cyclohexyl}amino)propanoate (0.23 g, 0.36 mmol), p-dioxane (15 mL), potassium hydroxide (0.10 g, 1.81 mmol) and water (1.5 mL) were heated at 80° C. for 3 hours. The solvents were evaporated and the residue was purified by preparative HPLC to yield cis-3-({4-[4-amino-3-(4-{[2-fluoro-4-trifluoromethylbenzoyl]amino}-3-methoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl]cyclohexyl}amino)propanoic acid (0.11 g, 0.18 mmol) as a white solid: 1H NMR (DMSO-d6, 400 MHz) δ 9.91 (dd, 1H), 8.31 (d, 1H), 8.25 (s, 1H), 8.00 (t, 1H), 7.89 (d, 1H), 7.75 (d, 1H), 7.35 (s, 1H), 7.32 (s, 1H), 6.89 (br, 2H), 4.79 (m, 1H), 3.95 (s, 3H), 2.46-3.00 (m, 7H), 2.29 (m, 2H), 1.91 (m, 2H), 1.80 (m, 2H); RP-HPLC (Hitachi HPLC, Hypersil C18, 5 μm, 100 A, 250×4.6 mm; 25%-100% acetonitrile-0.05M ammonium acetate over 10 min, 1 mL/min) Rt 6.06 min. MS: MH+ 616.
Reaction SMILES: Cl[C:2]1[C:10]([S:11](=[O:14])(=[O:13])[NH2:12])=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[N+:15]([O-:17])=[O:16].[F:18][C:19]([F:23])([F:22])[CH2:20][OH:21]>>[N+:15]([C:3]1[CH:4]=[C:5]([CH:9]=[C:10]([S:11](=[O:14])(=[O:13])[NH2:12])[C:2]=1[O:21][CH2:20][C:19]([F:23])([F:22])[F:18])[C:6]([OH:8])=[O:7])([O-:17])=[O:16]
Reactant: OCC(F)(F)F
Reactant: NS(=O)(=O)c1cc(C(=O)O)cc([N+](=O)[O-])c1Cl
Product: NS(=O)(=O)c1cc(C(=O)O)cc([N+](=O)[O-])c1OCC(F)(F)F

Procedure:
To a solution of sodium β, β, β -trifluoroethoxide in β, β, β-trifluoroethanol (prepared by dissolving 2.1 g of sodium in 45 ml of β ,β ,β-trifluoroethanol), 4-chloro-3-nitro-5-sulphamyl-benzoic acid (4.2 g) was added, and the resulting solution was refluxed for 5 days. After evaporation of the reaction mixture in vacuo, water (50 ml) was added, and the aqueous solution was acidified with 4N hydrochloric acid. After standing in a refrigerator, the precipitate was collected by suction. After several recrystallizations from aqueous ethanol, the 3-nitro-5-sulphamyl-4-(β ,β ,β-trifluoroethoxy)-benzoic acid was obtained with a melting point of 195°-197°C.
Reaction SMILES: C[O:2][C:3](=[O:13])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]#[N:12])=[CH:7][CH:6]=1.[OH-].[Na+]>C(O)C>[C:11]([C:8]1[CH:7]=[CH:6][C:5]([CH2:4][C:3]([OH:13])=[O:2])=[CH:10][CH:9]=1)#[N:12]
Reactant: COC(=O)Cc1ccc(C#N)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: N#Cc1ccc(CC(=O)O)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
14.2 g (0.081 mol) of methyl(4-cyano-phenyl)-acetate are dissolved in 100 ml ethanol and after the addition of 20 ml 2N sodium hydroxide solution stirred for 1 hour at ambient temperature. The solvent is distilled off, the residue is mixed with ice water and glacial acetic acid. The substance precipitated is suction filtered and dried.
Reaction SMILES: Br[C:2]1[C:3]([F:9])=[N:4][CH:5]=[C:6]([F:8])[CH:7]=1.C([O-])([O-])=O.[Na+].[Na+].CC1(C)C(C)(C)OB([C:24]2[CH2:25][CH2:26][O:27][CH2:28][CH:29]=2)O1>O1CCOCC1.O.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.Cl[Pd]Cl.[Fe+2]>[O:27]1[CH2:26][CH:25]=[C:24]([C:2]2[C:3]([F:9])=[N:4][CH:5]=[C:6]([F:8])[CH:7]=2)[CH2:29][CH2:28]1
Reactant: CC1(C)OB(C2=CCOCC2)OC1(C)C
Reactant: Fc1cnc(F)c(Br)c1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Solvent: O
Product: Fc1cnc(F)c(C2=CCOCC2)c1
Yield: 90.2 %

Procedure:
To a solution of 3-bromo-2,5-difluoro-pyridine (4.1 g, 20.8 mmol) in dioxane (60 mL) was treated with Na2CO3 (4.4 g, 41.6 mmol) in 20 mL of H2O as a solution, followed by additional of 4-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)-3,6-dihydro-2H-pyran (4.8 g 22.9 mmol) and Pd(dppf)Cl2 (761 mg). The resulting mixture was heated at refluxing overnight under N2 atmosphere. TLC showed that most of the staring materials were consumed. The solution was filtered and the filtrate was concentrated to get a residue, which was purified by silica gel chromatography to give the product (3.7 g).
Reaction SMILES: [N+:1]([C:4]1[N:5]=[CH:6][N:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[CH2:15][OH:16])[CH:8]=1)([O-])=O.[F:17][C:18]1[CH:19]=[C:20]([CH2:25][C:26]([NH:28][C@@H:29]([CH2:33][CH2:34][CH3:35])[C:30](O)=[O:31])=[O:27])[CH:21]=[C:22]([F:24])[CH:23]=1>>[OH:16][CH2:15][C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=1[N:7]1[CH:8]=[C:4]([NH:1][C:30](=[O:31])[C@@H:29]([NH:28][C:26](=[O:27])[CH2:25][C:20]2[CH:21]=[C:22]([F:24])[CH:23]=[C:18]([F:17])[CH:19]=2)[CH2:33][CH2:34][CH3:35])[N:5]=[CH:6]1
Reactant: CCC[C@H](NC(=O)Cc1cc(F)cc(F)c1)C(=O)O
Reactant: O=[N+]([O-])c1cn(-c2ccccc2CO)cn1
Product: CCC[C@H](NC(=O)Cc1cc(F)cc(F)c1)C(=O)Nc1cn(-c2ccccc2CO)cn1

Procedure:
(2-(4-nitro-1H-imidazol-1-yl)phenyl)methanol was reduced and coupled with (S)-2-[2-(3,5-Difluoro-phenyl)-acetylamino]-pentanoic acid (U.S. Ser. No. 11/078,898 filed Mar. 11, 2005) to afford the title compound: MS 443 m/z (M+1).
Reaction SMILES: [NH2:1][C:2]1[C:9]([F:10])=[CH:8][C:5]([C:6]#[N:7])=[C:4]([C:11]([F:14])([F:13])[F:12])[CH:3]=1.[C:15](Cl)(Cl)=[S:16]>C1COCC1.O>[F:10][C:9]1[C:2]([N:1]=[C:15]=[S:16])=[CH:3][C:4]([C:11]([F:14])([F:12])[F:13])=[C:5]([CH:8]=1)[C:6]#[N:7]
Reactant: S=C(Cl)Cl
Reactant: N#Cc1cc(F)c(N)cc1C(F)(F)F
Solvent: O
Solvent: C1CCOC1
Product: N#Cc1cc(F)c(N=C=S)cc1C(F)(F)F
Reaction time: 1 h
Yield: 87.5 %

Procedure:
To a solution of the compound 25 (660 mg, 3.25 mmol) in THF (6 mL) was added a solution of thiophosgene (1 mL, 13 mmol) in water (1 mL) slowly at room temperature. The reaction mixture was stirred for 1 h, then concentrated in vacuo. The residue was diluted with H2O. The aqueous solution was extracted with ethyl acetate. The organic layers were combined and washed with aq.NaHCO3 and brine, dried over Na2SO4, filtered and concentrated to provide the title compound 3d (700 mg, 88%) as a light yellow solid, which was used directly in next step without further purification. 1H NMR (400 MHz, CDCl3) δ7.63 (d, 1H, J=8.5 Hz), 7.57 (d, 1H, J=6.9 Hz).
Reaction SMILES: C[O:2][C:3]([C:5]1[N:10]=[C:9]([NH:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:8]2[NH:19][C:20](=[O:29])[N:21]([CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[C:7]=2[CH:6]=1)=O.[CH:30]1([CH2:33][NH2:34])[CH2:32][CH2:31]1>>[CH:30]1([CH2:33][NH:34][C:3]([C:5]2[N:10]=[C:9]([NH:11][CH2:12][C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=3)[C:8]3[NH:19][C:20](=[O:29])[N:21]([CH2:22][C:23]4[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=4)[C:7]=3[CH:6]=2)=[O:2])[CH2:32][CH2:31]1
Reactant: COC(=O)c1cc2c([nH]c(=O)n2Cc2ccccc2)c(NCc2ccccc2)n1
Reactant: NCC1CC1
Product: O=C(NCC1CC1)c1cc2c([nH]c(=O)n2Cc2ccccc2)c(NCc2ccccc2)n1
Temperature: 80 °C

Procedure:
1-Benzyl-4-benzylamino-2-oxo-2,3-dihydro-1H-imidazo[4,5-c]pyridine-6-carboxylic acid methyl ester (0.05 g) Was taken up in cyclopropylmethylamine (1 mL) and heated in a ReactiVial at 80° C. for 3 h. The solvent was removed in vacuo and diethyl ether was added which caused a solid to precipitate out. This solid was filtered off and dried in vacuo to give 40 mg of a white solid. This solid was purified by preparative HPLC using mixtures of acetonitrile, water and diethylamine as the eluant to give the title compound as a white solid (18 mg).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][CH:11]([CH:21](OS(C)(=O)=O)[CH3:22])[CH:12]([O:14][CH:15]1[CH2:20][CH2:19][CH2:18][CH2:17][O:16]1)[CH3:13])=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].C(OCC)(=O)C.O>CN(C)C=O>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][CH:11]([CH:12]([O:14][CH:15]2[CH2:20][CH2:19][CH2:18][CH2:17][O:16]2)[CH3:13])[CH:21]1[CH3:22])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(OC1CCCCO1)C(CCNC(=O)OC(C)(C)C)C(C)OS(C)(=O)=O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: CC(OC1CCCCO1)C1CCN(C(=O)OC(C)(C)C)C1C
Temperature: 38 °C
Reaction time: 4 h
Yield: 80.7 %

Procedure:
To a solution of N-t-butyloxycarbonyl-N-{3-(1-methanesulfonyloxyethyl)-4-(tetrahydropyran-2-yloxy)pentyl}amine (17 g) in dimethylformamide (200 ml) was added sodium hydride (6.6 g in 60% oil) at 0° C. After stirring for 4 hours at 38° C., the solution was poured into a mixture of ethyl acetate (400 ml) and water (400 ml). The organic layer was washed with water, 1N-hydrochloride solution, saturated sodium bicarbonate, and brine successively. The dried solution was evaporated and then the residue was chromatographed on silica gel eluting with a mixture of hexane and ethyl acetate (3:1, V/V) to give 1-t-butyloxycarbonyl-2-methyl-3-(1-tetrahydropyranyloxyethyl)pyrrolidine (10.5 g).
Reaction SMILES: BrC1C=NN(CC2C=C(C=CC=2)C(OC)=O)C=1.BrC1C=NNC=1.[NH:24]1[CH:28]=[C:27]([C:29]2[CH:38]=[CH:37][CH:36]=[C:35]3[C:30]=2[CH2:31][CH2:32][CH2:33][N:34]3[C:39](=[O:52])[CH2:40][CH2:41][CH2:42][O:43][C:44]2[CH:49]=[CH:48][CH:47]=[C:46]([CH3:50])[C:45]=2[CH3:51])[CH:26]=[N:25]1.BrCC1C=C(C=CC=1)C(OC)=O.[Br:65][C:66]1[CH:71]=[CH:70][CH:69]=[C:68]([CH2:72]Br)[CH:67]=1>>[Br:65][C:66]1[CH:67]=[C:68]([CH:69]=[CH:70][CH:71]=1)[CH2:72][N:24]1[CH:28]=[C:27]([C:29]2[CH:38]=[CH:37][CH:36]=[C:35]3[C:30]=2[CH2:31][CH2:32][CH2:33][N:34]3[C:39](=[O:52])[CH2:40][CH2:41][CH2:42][O:43][C:44]2[CH:49]=[CH:48][CH:47]=[C:46]([CH3:50])[C:45]=2[CH3:51])[CH:26]=[N:25]1
Reactant: BrCc1cccc(Br)c1
Reactant: Cc1cccc(OCCCC(=O)N2CCCc3c(-c4cn[nH]c4)cccc32)c1C
Agent: Brc1cn[nH]c1
Agent: COC(=O)c1cccc(CBr)c1
Agent: COC(=O)c1cccc(Cn2cc(Br)cn2)c1
Product: Cc1cccc(OCCCC(=O)N2CCCc3c(-c4cnn(Cc5cccc(Br)c5)c4)cccc32)c1C

Procedure:
The title compound was prepared using a procedure analogous to methyl 3-((4-bromo-1H-pyrazol-1-yl)methyl)benzoate except that 4-bromo-1H-pyrazole was replaced with 1-(5-(1H-pyrazol-4-yl)-3,4-dihydroquinolin-1(2H)-yl)-4-(2,3-dimethylphenoxy)butan-1-one and methyl 3-(bromomethyl)benzoate was replaced with 1-bromo-3-(bromomethyl)benzene. LCMS, [M+H]+=560.2.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([O:8][CH3:9])[CH:3]=1.C(N(CC)CC)C.[Cl-].ClC1N(C)CC[NH+]1C.[CH3:26][O:27][C:28]1[C:29](=[O:52])[C:30]([CH3:51])=[C:31]([CH2:37][C:38]2[CH:39]=[CH:40][C:41]([O:47][C:48](=[O:50])[CH3:49])=[C:42]([CH:46]=2)[C:43](O)=[O:44])[C:32](=[O:36])[C:33]=1[O:34][CH3:35]>C(Cl)Cl>[CH3:9][O:8][C:4]1[CH:3]=[C:2]([NH:1][C:43](=[O:44])[C:42]2[CH:46]=[C:38]([CH2:37][C:31]3[C:32](=[O:36])[C:33]([O:34][CH3:35])=[C:28]([O:27][CH3:26])[C:29](=[O:52])[C:30]=3[CH3:51])[CH:39]=[CH:40][C:41]=2[O:47][C:48](=[O:50])[CH3:49])[CH:7]=[CH:6][N:5]=1
Reactant: COc1cc(N)ccn1
Reactant: COC1=C(OC)C(=O)C(Cc2ccc(OC(C)=O)c(C(=O)O)c2)=C(C)C1=O
Agent: CN1CC[NH+](C)C1Cl
Agent: [Cl-]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC1=C(OC)C(=O)C(Cc2ccc(OC(C)=O)c(C(=O)Nc3ccnc(OC)c3)c2)=C(C)C1=O
Temperature: 25 °C
Reaction time: 10 h
Yield: 62.3 %

Procedure:
4-Amino-2-methoxypyridine (0.167 g, 1.340 mmol), triethylamine (0.176 g, 1.740 mmol) and 2-chloro-1,3-dimethylimidazolinium chloride (0.147 g, 0.869 mmol) were added to a methylene chloride solution (100 ml) of 5-(5,6-dimethoxy-3-methyl-1,4-benzoquinon-2-yl)methyl-2-acetoxybenzoic acid (0.250 g, 0.668 mmol) and the resulting solution was stirred at room temperature for 10 hours. The reaction solution was poured into ice water and then extracted with methylene chloride. The extract was washed with water and then dried, and the solvent was removed by distillation. The obtained residue was purified by preparative thin-layer chromatography (chloroform:methanol=10:1) and then recrystallized from ether to obtain the titled compound (0.200 g, 0.416 mmol, 62%).
Reaction SMILES: [C:1]([OH:12])(=[O:11])[C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=1>C(O)CO>[C:1]([O:12][CH2:2][CH2:1][OH:11])(=[O:11])[C:2]1[CH:10]=[CH:9][C:5]([C:6]([O:8][CH2:5][CH2:6][OH:7])=[O:7])=[CH:4][CH:3]=1
Reactant: O=C(O)c1ccc(C(=O)O)cc1
Solvent: OCCO
Product: O=C(OCCO)c1ccc(C(=O)OCCO)cc1

Procedure:
Terephthalic acid was reacted with ethylene glycol to form bis-(2-hydroxyethyl) terephthalate and low oligomers thereof, in a standard direct esterification reaction. At the end of the direct esterification reaction 400 ppm of phosphoric acid stabiliser was added, followed by 500 ppm of antimony trioxide polycondensation catalyst and 500 ppm of "Irganox 1010" antioxidant. 0.3% of silica of particle size 4 μm, and 0.3% of titanium dioxide of particle size 0.2 μm were also added at this stage. A standard batch polycondensation reaction was performed until the intrinsic viscosity of the resultant polyethylene terephthalate was approximately 0.52. The polyethylene terephthalate was further polymerised by means of a batch solid phase polymerisation process, until the intrinsic viscosity (IV) of the polyethylene terephthalate was approximately 0.7 to 0.75. The solid phase polymerisation process utilised a fluidised bed, fluidised with nitrogen.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)[C:5]2[N:11]=[C:10]([CH2:12][CH:13]3[CH2:18][CH2:17][N:16]([C:19](=[O:21])[CH3:20])[CH2:15][CH2:14]3)[CH:9]=[CH:8][C:6]=2[N:7]=1.[CH3:28][N:29]([CH3:39])[C:30]1[NH:34][C:33]2[CH:35]=[CH:36][CH:37]=[CH:38][C:32]=2[N:31]=1>>[CH3:28][N:29]([CH3:39])[C:30]1[N:31]([C:2]2[N:3]=[C:4]([N:22]3[CH2:23][CH2:24][O:25][CH2:26][CH2:27]3)[C:5]3[N:11]=[C:10]([CH2:12][CH:13]4[CH2:14][CH2:15][N:16]([C:19](=[O:21])[CH3:20])[CH2:17][CH2:18]4)[CH:9]=[CH:8][C:6]=3[N:7]=2)[C:32]2[CH:38]=[CH:37][CH:36]=[CH:35][C:33]=2[N:34]=1
Reactant: CC(=O)N1CCC(Cc2ccc3nc(Cl)nc(N4CCOCC4)c3n2)CC1
Reactant: CN(C)c1nc2ccccc2[nH]1
Product: CC(=O)N1CCC(Cc2ccc3nc(-n4c(N(C)C)nc5ccccc54)nc(N4CCOCC4)c3n2)CC1

Procedure:
1-(4-((2-Chloro-4-morpholinopyrido[3,2-d]pyrimidin-6-yl)methyl)piperidin-1-yl)ethanone from Example 148 (0.125 g) was reacted with N,N-dimethyl-1H-benzo[d]imidazol-2-amine via General Procedure D to produce 47.5 mg of 165 following reverse phase HPLC purification. MS (Q1) 515.2 (M)+
Reaction SMILES: [C:1]([C:5]1[C:6]([O:37][CH3:38])=[C:7](/[CH:21]=[CH:22]/[C:23]2[CH:28]=[CH:27][C:26]([NH:29][S:30]([CH3:33])(=[O:32])=[O:31])=[CH:25][C:24]=2[CH2:34]OC)[CH:8]=[C:9]([C:11]2[C:12]([O:19]C)=[N:13][C:14]([O:17][CH3:18])=[CH:15][CH:16]=2)[CH:10]=1)([CH3:4])([CH3:3])[CH3:2].[BrH:39].C([O-])(O)=O.[Na+]>CC(O)=O>[Br:39][CH2:34][C:24]1[CH:25]=[C:26]([NH:29][S:30]([CH3:33])(=[O:31])=[O:32])[CH:27]=[CH:28][C:23]=1/[CH:22]=[CH:21]/[C:7]1[CH:8]=[C:9]([C:11]2[C:12](=[O:19])[NH:13][C:14]([O:17][CH3:18])=[CH:15][CH:16]=2)[CH:10]=[C:5]([C:1]([CH3:4])([CH3:2])[CH3:3])[C:6]=1[O:37][CH3:38]
Reactant: COCc1cc(NS(C)(=O)=O)ccc1/C=C/c1cc(-c2ccc(OC)nc2OC)cc(C(C)(C)C)c1OC
Reactant: Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Product: COc1ccc(-c2cc(/C=C/c3ccc(NS(C)(=O)=O)cc3CBr)c(OC)c(C(C)(C)C)c2)c(=O)[nH]1
Yield: 83.7 %

Procedure:
step 2—A solution of 322 (104 mg, 0.193 mmol), HBr 48% (0.100 mL, 0.871 mmol) in HOAc (4 mL) was heated at 75° C. for 4 h in a sealed tube. The reaction mixture was carefully poured into a mixture of saturated NaHCO3 and ice, extracted with EtOAc, dried (Na2SO4), filtered and concentrated to afford 93 mg (84%) of N-(3-bromomethyl-4-{(E)-2-[3-tert-butyl-2-methoxy-5-(6-methoxy-2-oxo-1,2-dihydro-pyridin-3-yl)-phenyl]-vinyl}-phenyl)-methanesulfonamide (324) as a purple oil.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:14]2[CH:19]=[CH:18][C:17]([S:20]([CH3:23])(=[O:22])=[O:21])=[CH:16][CH:15]=2)[N:5]2[C:10]=1[CH:9]=[N:8][C:7](S(C)=O)=[N:6]2.[CH3:24][N:25]1[CH2:30][CH2:29][N:28]([C:31]2[CH:36]=[CH:35][C:34]([NH2:37])=[CH:33][CH:32]=2)[CH2:27][CH2:26]1.CN1CCCC1=O>>[Br:1][C:2]1[CH:3]=[C:4]([C:14]2[CH:19]=[CH:18][C:17]([S:20]([CH3:23])(=[O:22])=[O:21])=[CH:16][CH:15]=2)[N:5]2[C:10]=1[CH:9]=[N:8][C:7]([NH:37][C:34]1[CH:33]=[CH:32][C:31]([N:28]3[CH2:27][CH2:26][N:25]([CH3:24])[CH2:30][CH2:29]3)=[CH:36][CH:35]=1)=[N:6]2
Reactant: CS(=O)c1ncc2c(Br)cc(-c3ccc(S(C)(=O)=O)cc3)n2n1
Reactant: CN1CCN(c2ccc(N)cc2)CC1
Solvent: CN1CCCC1=O
Product: CN1CCN(c2ccc(Nc3ncc4c(Br)cc(-c5ccc(S(C)(=O)=O)cc5)n4n3)cc2)CC1
Temperature: 150 °C
Yield: 43.5 %

Procedure:
Into a 30 mL vial, 5-Bromo-2-methanesulfinyl-7-(4-methanesulfonyl-phenyl)-pyrrolo[2,1-f][1,2,4]triazine (0.14 g, 0.00034 mol), 4-(4-Methyl-piperazin-1-yl)-phenylamine (0.194 g, 0.00101 mol), and N-Methylpyrrolidinone (0.22 mL, 0.0023 mol) were added. The mixture was heated at 150° C. for 3 hours. The mixture was purified via ISCO column chromatography with DCM and MeOH as eluant (0 to 15% methanol). The collected fractions afforded [5-Bromo-7-(4-methanesulfonyl-phenyl)-pyrrolo[2,1-f][1,2,4]triazin-2-yl]-[4-(4-methyl-piperazin-1-yl)-phenyl]-amine as a yellow solid (80 mg, 44%). MP 265-266° C. LCMS (E/I+) 543.11 (M+H). NMR 1H (DSMO-d6)-9.49 (s, 1H), 8.93 (s, 1H), 8.45 (d, 2H, J=8.56 Hz), 8.03 (d, 2H, J=8.60 Hz), 7.55 (d, 2H, J=9.01 Hz), 7.35 (s, 1H), 6.96 (d, 2H, J=9.08 Hz), 3.39 (s, 3H), 3.10 (t, 4H, J=5.00 Hz), 2.47 (t, 4H, J=5.13 Hz), 2.23 (s, 3H).
Reaction SMILES: N(CCCCN=C=O)=C=O.N(CC(C)(C)CCCN=C=O)=C=O.N(CCCCCCCCCCN=C=O)=C=O.[CH2:40]1[CH:45]([CH2:46][CH:47]2[CH2:52][CH2:51][CH:50]([N:53]=[C:54]=[O:55])[CH2:49][CH2:48]2)[CH2:44][CH2:43][CH:42]([N:56]=[C:57]=[O:58])[CH2:41]1.C(CCN=C=O)CCCN=C=O.N(C1CC(C)(CN=C=O)CC(C)(C)C1)=C=O.[C:87]1([N:96]=[C:97]=[O:98])[CH:92]=[CH:91][C:90]([N:93]=[C:94]=[O:95])=[CH:89][CH:88]=1>>[CH:44]1[C:45]([CH2:46][C:47]2[CH:52]=[CH:51][C:50]([N:53]=[C:54]=[O:55])=[CH:49][CH:48]=2)=[CH:40][CH:41]=[C:42]([N:56]=[C:57]=[O:58])[CH:43]=1.[C:87]1([N:96]=[C:97]=[O:98])[CH:88]=[CH:89][C:90]([N:93]=[C:94]=[O:95])=[CH:91][CH:92]=1
Reactant: O=C=NC1CCC(CC2CCC(N=C=O)CC2)CC1
Agent: CC(C)(CCCN=C=O)CN=C=O
Agent: CC1(C)CC(N=C=O)CC(C)(CN=C=O)C1
Agent: O=C=NCCCCCCCCCCN=C=O
Product: O=C=Nc1ccc(Cc2ccc(N=C=O)cc2)cc1

Procedure:
Examples of suitable polyisocyanates as such or employed to make other polyisocyanates adducts or prepolymers include, but are not limited to, 1,4-diisocyanatobutane, 1,5-diisocyanato-2,2-dimethylpentane, 2,2,4- and 2,4,4-trimethyl-1,6-diisocyanatohexane, 1,10-diisocyanatodecane, 4,4′-diisocyanatodicyclohexylmethane, 1,6-hexamethylene diisocyanate, 1,12-dodecane diisocyanate, cyclobutane-1,3-diisocyanate, cyclohexane-1,3- and/or 1,4-diisocyanate, 1-isocyanato-3,3,5-trimethyl-5-isocyanatomethyl cyclohexane (isophorone or IPDI), 2,4- and/or 2,6-hexahydrotoluylene diisocyanate, hexahydro-1,3- and/or 1,4-phenylene diisocyanate, perhydro-2,4′- and/or -4,4′diphenylmethane diisocyanate, 1,3- and/or 1,4-phenylene diisocyanate, 2,4- and/or 2,6-toluylene diisocyanate, diphenyl methane-2,4′- and/or -4,4′-diisocyanate, naphthalene-1,5-diisocyanate, triphenyl methane-4,4′4″-triisocyanate and polyphenyl polymethylene polyisocyanates obtained by phosgenating-aniline/formaldehyde condensation products.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([CH2:15][C:16](N(OC)C)=[O:17])=[CH:11][CH:10]=2)[C:3]=1[C:22]1[CH:27]=[CH:26][C:25]([O:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)=[CH:24][CH:23]=1.[CH2:35]1[CH2:39]OC[CH2:36]1.C([Mg]Br)#CC>>[NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([CH2:15][C:16](=[O:17])[C:36]#[C:35][CH3:39])=[CH:11][CH:10]=2)[C:3]=1[C:22]1[CH:27]=[CH:26][C:25]([O:28][C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=2)=[CH:24][CH:23]=1
Reactant: C1CCOC1
Reactant: CON(C)C(=O)Cc1ccc(Nc2ncnc(N)c2-c2ccc(Oc3ccccc3)cc2)cc1
Agent: CC#C[Mg]Br
Product: CC#CC(=O)Cc1ccc(Nc2ncnc(N)c2-c2ccc(Oc3ccccc3)cc2)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 25.9 %

Procedure:
In a round bottom flask with stirbar was added 2-{4-[6-amino-5-(4-phenoxy-phenyl)-pyrimidin-4-ylamino]-phenyl}-N-methoxy-N-methyl-acetamide (275.0 mg; 0.604 mmol; 1.0 eq.), suspended in THF (2.5 ml; 30.857 mmol; 51.1 eq.). The suspension was cooled to 0° C. At this temperature was added 1-propynylmagnesium bromide (12.1 ml; 6.037 mmol; 10.0 eq.) drop by drop at constant temperature to afford a red solution. After complete addition, the reaction mixture was stirred 30 min at room temperature. The reaction suspension was quenched with aqueous solution of ammonium chloride, and extracted with EtOAc (3×). The combined organic phase were dried over sodium sulfate, filtered and concentrated in vacuo. The crude compound was dissolved in DMSO and purified by preparative HPLC to afford 1-(4-(6-amino-5-(4-phenoxyphenyl)-pyrimidin-4-ylamino)-phenyl)-pent-3-yn-2-one (68 mg, 17% yield) as light yellow solid. MS: m/z=435 [M+H]+. 1H-NMR (DMSO-d6) □δ 8.43 (bs, 1H), 8.28 (s, 1H), 7.46 (t, 2H), 7.42 (d, 2h), 7.37 (d, 2H), 7.31-7.13 (m, 7H), 6.99 (bs, 2H), 3.87 (s, 2H), 2.04 (s, 3H).
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([P:15]([CH3:18])([CH3:17])=[O:16])=[CH:11][CH:10]=2)[N:3]=1.C(N(CC)CC)C.[CH3:26][N:27]1[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1>C(O)C>[CH3:17][P:15]([C:12]1[CH:13]=[CH:14][C:9]([NH:8][C:4]2[N:3]=[C:2]([N:30]3[CH2:31][CH2:32][N:27]([CH3:26])[CH2:28][CH2:29]3)[N:7]=[CH:6][N:5]=2)=[CH:10][CH:11]=1)([CH3:18])=[O:16]
Reactant: CP(C)(=O)c1ccc(Nc2ncnc(Cl)n2)cc1
Reactant: CN1CCNCC1
Solvent: CCN(CC)CC
Solvent: CCO
Product: CN1CCN(c2ncnc(Nc3ccc(P(C)(C)=O)cc3)n2)CC1

Procedure:
To a solution of 4-chloro-N-[4-(dimethylphosphoryl)phenyl]-1,3,5-triazin-2-amine (0.072 mmol) in 1.5 mL of ethanol is added 10 L of triethylamine and 1-Methyl piperazine (7.2 mg, 0.072 mmol). The mixture can be microwaved at 120 degrees until formation of the desired compound. The reaction mixture is filtered through a syringe filter and purified by prep-HPLC.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([Cl:22])=[C:6]([CH:21]=1)[C:7]([NH:9][CH2:10][C:11]12[CH2:20][CH:15]3[CH2:16][CH:17]([CH2:19][CH:13]([CH2:14]3)[CH2:12]1)[CH2:18]2)=[O:8].C[Li].C([Li])(C)(C)C.[CH2:30]1[O:32][CH2:31]1>O1CCCC1>[Cl:22][C:5]1[CH:4]=[CH:3][C:2]([CH2:30][CH2:31][OH:32])=[CH:21][C:6]=1[C:7]([NH:9][CH2:10][C:11]12[CH2:20][CH:15]3[CH2:16][CH:17]([CH2:19][CH:13]([CH2:14]3)[CH2:12]1)[CH2:18]2)=[O:8]
Reactant: C1CO1
Reactant: O=C(NCC12CC3CC(CC(C3)C1)C2)c1cc(Br)ccc1Cl
Agent: [Li]C
Agent: [Li]C(C)(C)C
Solvent: C1CCOC1
Product: O=C(NCC12CC3CC(CC(C3)C1)C2)c1cc(CCO)ccc1Cl
Temperature: -78 °C
Reaction time: 0.17 h

Procedure:
A solution of 5-bromo-2-chloro-N-(tricyclo[3.3.1.13,7]dec-1-ylmethyl)-benzamide (3.0 g, Example 23a) in anhydrous tetrahydrofuran (100 ml) was cooled to −78° C. under a nitrogen atmosphere. A solution of methyllithium (1.4M in diethyl ether, 4.9 ml) was added over 2 min. The mixture was stirred at −78° C. for 10 min., then a solution tert-butyllithium (1.7M in pentane, 9.3 ml) was added dropwise. The mixture was stirred at −78° C. for a further 10 min., then ethylene oxide (1.0 ml) was added. The resulting solution was stirred at −78° C. for 30 min. then was warmed to 0° C. and stirred for another 6 h. The reaction mixture was quenched with saturated aqueous ammonium chloride solution (70 ml) and extracted with ethyl acetate (3×100 ml). The combined extracts were dried over anhydrous magnesium sulfate, filtered, and the filtrate concentrated under reduced pressure. The residue was purified by chromatography over silica gel eluting with dichloromethane:ethanol (98:2) to give the subtitle compound as a pale yellow solid (0.89 g).