Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([CH2:9][C:10]2[S:14][C:13]([NH2:15])=[N:12][CH:11]=2)=[CH:7][CH:6]=[CH:5][N:4]=1.[O:16]1[C:20]2[CH:21]=[CH:22][C:23]([C:25]3([C:28](O)=[O:29])[CH2:27][CH2:26]3)=[CH:24][C:19]=2[O:18][CH2:17]1.C(N(CC)CC)C.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1>C(#N)C>[CH3:1][O:2][C:3]1[C:8]([CH2:9][C:10]2[S:14][C:13]([NH:15][C:28]([C:25]3([C:23]4[CH:22]=[CH:21][C:20]5[O:16][CH2:17][O:18][C:19]=5[CH:24]=4)[CH2:27][CH2:26]3)=[O:29])=[N:12][CH:11]=2)=[CH:7][CH:6]=[CH:5][N:4]=1
Reactant: O=C(O)C1(c2ccc3c(c2)OCO3)CC1
Reactant: COc1ncccc1Cc1cnc(N)s1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CC#N
Product: COc1ncccc1Cc1cnc(NC(=O)C2(c3ccc4c(c3)OCO4)CC2)s1
Temperature: 78 °C
Reaction time: 12 h

Procedure:
5-(2-Methoxy-pyridin-3-ylmethyl)-thiazol-2-ylamine (221 mg, 1.00 mmol) and 1-benzo[1,3]dioxol-5-yl-cyclopropanecarboxylic acid (206 g, 1.00 mmol) were dissolved in acetonitrile (5 mL) containing triethylamine (0.421 mL, 3.00 mmol). O-(7-Azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (HATU, 760 mg, 2.0 mmol) was added and the solution was allowed to stir at 78° C. for 12 hours. An aliquot of the crude product was purified by reverse-phase preparative liquid chromatography. ESI-MS m/z calc. 409.1. found; 410.3 (M+1)+ Retention time 3.23 minutes.
Reaction SMILES: [F:1][C:2]1[CH:12]=[CH:11][CH:10]=[C:9]([F:13])[C:3]=1[C:4]([N:6]=[C:7]=[O:8])=[O:5].[NH2:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]#[CH:22])=[CH:17][CH:16]=1>CCOCC>[C:21]([C:18]1[CH:19]=[CH:20][C:15]([NH:14][C:7]([NH:6][C:4](=[O:5])[C:3]2[C:2]([F:1])=[CH:12][CH:11]=[CH:10][C:9]=2[F:13])=[O:8])=[CH:16][CH:17]=1)#[CH:22]
Reactant: O=C=NC(=O)c1c(F)cccc1F
Reactant: C#Cc1ccc(N)cc1
Solvent: CCOCC
Product: C#Cc1ccc(NC(=O)NC(=O)c2c(F)cccc2F)cc1

Procedure:
With stirring, 3.2 g of 2,6-difluorobenzoylisocyanate are added dropwise to a ready prepared mixture of 2 g of 4-aminophenylacetylene in 20 ml of absolute ether. The precipitate is filtered with suction after 2 hours and recrystallised from ethanol, yielding N-(4-ethynylphenyl)-N'-(2,6-difluorobenzoyl)urea with a melting point of 213°-217° C. (Compound 1).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([F:8])=[N:6][CH:7]=1.C([Sn](CCCC)(CCCC)[C:14]1[S:15][CH:16]=[CH:17][N:18]=1)CCC>CN(C=O)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[F:8][C:5]1[N:6]=[CH:7][C:2]([C:14]2[S:15][CH:16]=[CH:17][N:18]=2)=[CH:3][CH:4]=1
Reactant: CCCC[Sn](CCCC)(CCCC)c1nccs1
Reactant: Fc1ccc(Br)cn1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CN(C)C=O
Product: Fc1ccc(-c2nccs2)cn1
Temperature: 100 °C
Yield: 77.7 %

Procedure:
To a solution of 5-bromo-2-fluoropyridine (0.5 g, 2.857 mmol) in DMF (6 mL), 2-(tributylstannyl)thiazole (1.3 mL, 4.285 mmol) and Pd(PPh3)2Cl2(0.2 mg, 0.2857 mmol) were added under argon. The mixture was degassed with argon for 10 min and heated to 100° C. for 30 min. The reaction mixture was filtered through Celite® reagent and the filtrate was diluted with EtOAc (2×100 mL) and water (100 mL). The organic layer was separated, dried over Na2SO4, filtered and concentrated under reduced pressure to obtain crude product. The crude product was purified by Biotage IsoleraOne® column (5% ethyl acetate in hexane) to obtain 2-(6-fluoropyridin-3-yl) thiazole as off-white solid (0.4 g, 80% yield). 1H NMR (400 MHz, DMSO-d6): δ 8.80 (s, 1H), 8.52-8.47 (m, 1H), 7.98 (d, 1H), 7.87 (d, 1H), 7.33 (dd, 1H); LC-MS m/z calculated for [M+11]+181.02. found 180.8.
Reaction SMILES: [OH-].[Na+].[CH:3]1([C:9]2[C:10]3[CH:11]=[CH:12][C:13]([C:32]([O:34][CH3:35])=[O:33])=[CH:14][C:15]=3[N:16]3[CH2:22][C:21]([C:24]([O:26]C)=[O:25])([F:23])[CH2:20][C:19]4[CH:28]=[CH:29][CH:30]=[CH:31][C:18]=4[C:17]=23)[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1.Cl>CO.O1CCCC1>[CH:3]1([C:9]2[C:10]3[CH:11]=[CH:12][C:13]([C:32]([O:34][CH3:35])=[O:33])=[CH:14][C:15]=3[N:16]3[CH2:22][C:21]([C:24]([OH:26])=[O:25])([F:23])[CH2:20][C:19]4[CH:28]=[CH:29][CH:30]=[CH:31][C:18]=4[C:17]=23)[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]1
Reactant: COC(=O)c1ccc2c(C3CCCCC3)c3n(c2c1)CC(F)(C(=O)OC)Cc1ccccc1-3
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: COC(=O)c1ccc2c(C3CCCCC3)c3n(c2c1)CC(F)(C(=O)O)Cc1ccccc1-3
Temperature: 65 °C
Yield: 85 %

Procedure:
Sodium hydroxide (50 μL of 1N, 0.05 mmol) was added to a solution of methyl (±)-13-cyclohexyl-6,7-dihydro-6-carbomethoxy-6-fluoro-5H-indolo[2,1-a][2]benzazepine-10-carboxylate (12.0 mg, 0.027 mmol) in methanol (0.5 mL) and tetrahydrofuran (0.5 mL) in a microwave vial. The vial was sealed and the contents heated at 65° C. for 20 min in a microwave apparatus. The solution was acidified with dilute hydrochloric acid to precipitate the crude acid. The solid was collected and was purified on the Shimadzu preparative liquid chromatograph. The product containing fraction was concentrated on a Speed Vac® to leave the titled compound as a white solid (10 mg, 85%). ESI-MS m/z 436 (MH+).
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][C:11]([N:15]2[C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=3[N:17]([CH3:24])[C:16]2=[O:25])([CH3:14])[CH2:10][CH2:9]1)C1C=CC=CC=1>CO.[Pd]>[CH3:24][N:17]1[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[N:15]([C:11]2([CH3:14])[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]2)[C:16]1=[O:25]
Reactant: Cn1c(=O)n(C2(C)CCN(Cc3ccccc3)CC2)c2ccccc21
Agent: [Pd]
Solvent: CO
Product: Cn1c(=O)n(C2(C)CCNCC2)c2ccccc21
Temperature: 50 °C
Reaction time: 3 h
Yield: 89.2 %

Procedure:
2.5 g palladium charcoal was added to 4.6 g 1-(1-benzyl-4-methyl-piperidin-4-yl)-3-methyl-1,3-dihydro-benzoimidazol-2-one in 100 mL methanol. The reaction was stirred 3 h at 50° C. and 30 bar under hydrogen. The reaction was filtered and evaporated to yields 3 g of the desired product. (M+H)+: 246
Reaction SMILES: [F:1][C:2]1([F:36])[CH2:8][N:7]([CH2:9][CH2:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:6]2[N:18]=[C:19]([NH:22][C:23]3[CH:31]=[CH:30][C:26]([C:27]([OH:29])=O)=[CH:25][C:24]=3[O:32][CH3:33])[N:20]=[CH:21][C:5]=2[N:4]([CH3:34])[C:3]1=[O:35].[CH2:37]([N:39](C(C)C)C(C)C)C.Cl.CN>CN(C)C=O>[F:1][C:2]1([F:36])[CH2:8][N:7]([CH2:9][CH2:10][CH2:11][C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:6]2[N:18]=[C:19]([NH:22][C:23]3[CH:31]=[CH:30][C:26]([C:27]([NH:39][CH3:37])=[O:29])=[CH:25][C:24]=3[O:32][CH3:33])[N:20]=[CH:21][C:5]=2[N:4]([CH3:34])[C:3]1=[O:35]
Reactant: COc1cc(C(=O)O)ccc1Nc1ncc2c(n1)N(CCCc1ccccc1)CC(F)(F)C(=O)N2C
Reactant: CCN(C(C)C)C(C)C
Agent: CN
Agent: Cl
Solvent: CN(C)C=O
Product: CNC(=O)c1ccc(Nc2ncc3c(n2)N(CCCc2ccccc2)CC(F)(F)C(=O)N3C)c(OC)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 49 %

Procedure:
To a mixture of 0.05 g (0.10 mmole) of 4-[7,7-difluoro-5-methyl-6-oxo-9-(3-phenyl-propyl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino]-3-methoxy-benzoic acid (I-281), 0.07 mL (0.40 mmole) of ethyldiisopropyl amine and 0.0074 g (0.11 mmole) of methylamine hydrochloride in 2.0 mL of dimethylformamide was added 0.048 g (0.11 mmole) of 1-(di-1-pyrrolidinylmethylene)-1H-benzotriazolium 3-oxide hexafluorophosphate. The mixture was stirred at room temperature for 1 hour, then diluted with 10 mL of ice water. The mixture was extracted with dichloromethane 3 times. The combined organic layers were washed three times with sodium carbonate, three times with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. Purification by silica gel chromatography, eluting with dichloromethane-methanol (gradient, 100:0-90:10) gave 0.025 g of 4-[7,7-difluoro-5-methyl-6-oxo-9-(3-phenyl-propyl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino]-3-methoxy-N-methyl-benzamide (I-284) as a white solid.
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[Na+].[CH3:11][N:12]([CH3:48])[CH2:13][CH2:14][O:15][C:16]1[CH:17]=[C:18]([NH:22][C:23]2[N:28]=[C:27]([C:29]3[N:33]4[CH:34]=[CH:35][CH:36]=[CH:37][C:32]4=[N:31][C:30]=3[C:38]3[CH:39]=[C:40]([CH:45]=[CH:46][CH:47]=3)[C:41](OC)=[O:42])[CH:26]=[CH:25][N:24]=2)[CH:19]=[CH:20][CH:21]=1.[Cl:49][C:50]1[CH:51]=[CH:52][C:53]([F:57])=[C:54]([CH:56]=1)[NH2:55]>C1COCC1>[Cl:49][C:50]1[CH:51]=[CH:52][C:53]([F:57])=[C:54]([NH:55][C:41](=[O:42])[C:40]2[CH:45]=[CH:46][CH:47]=[C:38]([C:30]3[N:31]=[C:32]4[CH:37]=[CH:36][CH:35]=[CH:34][N:33]4[C:29]=3[C:27]3[CH:26]=[CH:25][N:24]=[C:23]([NH:22][C:18]4[CH:19]=[CH:20][CH:21]=[C:16]([O:15][CH2:14][CH2:13][N:12]([CH3:11])[CH3:48])[CH:17]=4)[N:28]=3)[CH:39]=2)[CH:56]=1
Reactant: COC(=O)c1cccc(-c2nc3ccccn3c2-c2ccnc(Nc3cccc(OCCN(C)C)c3)n2)c1
Reactant: Nc1cc(Cl)ccc1F
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: C1CCOC1
Product: CN(C)CCOc1cccc(Nc2nccc(-c3c(-c4cccc(C(=O)Nc5cc(Cl)ccc5F)c4)nc4ccccn34)n2)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 92.4 %

Procedure:
A 1.0M solution of NaHMDS in THF (0.59 mL, 0.59 mmol) was added dropwise to a stirring solution of methyl 3-(3-{2-[(3-{[2-(dimethylamino)ethyl]oxy}phenyl)amino]-4-pyrimidinyl}imidazo[1,2-a]pyridin-2-yl)benzoate (0.100 g, 0.20 mmol) and 5-chloro-2-fluoroaniline (0.09 g, 0.59 mmol) in THF (2 mL) at rt. The reaction mixture was stirred for 0.5 h at room temperature then quenched with methanol and concentrated onto silica gel. Flash chromatography afforded the title compound (0.115 g, 94%) as a yellow solid. 1H NMR (400 MHz, DMSO-d6) δ 10.31 (s, 1H), 9.75 (s, 1H), 9.52-9.50 (m, 1H), 8.35 (d, J=5.2 Hz, 1H), 8.31 (s, 1H), 8.01 (d, J=7.7 Hz, 1H), 7.83 (d, J=7.7 Hz, 1H), 7.77-7.72 (m, 2H), 7.61-7.57 (m, 1H), 7.51-7.47 (m, 2H), 7.36-7.24 (m, 3H), 7.17-7.06 (m, 2H), 6.60 (d, J=5.3 Hz, 1H), 6.53 (dd, J=8.2, 2.4 Hz, 1H), 3.95 (t, J=5.9 Hz, 2H), 2.55 (t, J=5.7 Hz, 2H), 2.14 (s, 6H). MS (ES+, m/z) 622 (M+1).
Reaction SMILES: [CH3:1][S:2]([NH:5][C:6]1[C:18]([O:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[CH:17][C:9]2[C:10](=[O:16])[CH:11]([S:14][CH3:15])[CH2:12][O:13][C:8]=2[CH:7]=1)(=[O:4])=[O:3].ClC1C(=O)C(C#N)=C(C#N)C(=O)C=1Cl>O1CCOCC1>[CH3:1][S:2]([NH:5][C:6]1[C:18]([O:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[CH:17][C:9]2[C:10](=[O:16])[C:11]([S:14][CH3:15])=[CH:12][O:13][C:8]=2[CH:7]=1)(=[O:3])=[O:4]
Reactant: CSC1COc2cc(NS(C)(=O)=O)c(Oc3ccccc3)cc2C1=O
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Solvent: C1COCCO1
Product: CSc1coc2cc(NS(C)(=O)=O)c(Oc3ccccc3)cc2c1=O
Yield: 46 %

Procedure:
350 mg of 2,3-dihydro-7-methylsulfonylamino-3-methylthio-6-phenoxy-4H-1-benzopyran-4-one and 1.08 g of 2,3-dichloro-5,6-dicyano-1,4-benzoquinone were refluxed in 14 ml of dioxane for 9 hours. The solvent was removed by distillation under reduced pressure. The residue was purified by a column chromatography (eluant: a 10 : 1 mixture of toluene and ethyl acetate) to obtain 160 mg (yield: 45.7%) of 7-methylsulfonylamino-3-methylthio-6-phenoxy-4H-1-benzopyran-4-one [Compound No. 4].
Reaction SMILES: Cl[C:2]1[N:3]([CH2:10][C:11]([OH:30])([CH3:29])[CH2:12][N:13]2[CH2:18][CH2:17][N:16]([C:19]([O:21][CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)=[O:20])[CH2:15][CH2:14]2)[CH:4]=[C:5]([N+:7]([O-:9])=[O:8])[N:6]=1.[H-].[Na+]>O1CCOCC1>[CH3:29][C:11]1([CH2:12][N:13]2[CH2:18][CH2:17][N:16]([C:19]([O:21][CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)=[O:20])[CH2:15][CH2:14]2)[O:30][C:2]2=[N:6][C:5]([N+:7]([O-:9])=[O:8])=[CH:4][N:3]2[CH2:10]1
Reactant: CC(O)(CN1CCN(C(=O)OCc2ccccc2)CC1)Cn1cc([N+](=O)[O-])nc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1COCCO1
Product: CC1(CN2CCN(C(=O)OCc3ccccc3)CC2)Cn2cc([N+](=O)[O-])nc2O1
Yield: 52.4 %

Procedure:
To a mixture of benzyl 4-[3-(2-chloro-4-nitroimidazol-1-yl)-2-hydroxy-2-methylpropyl]-piperazine-1-carboxylate prepared in Example 315 (55.22 g, 126.11 mmol) and 1,4-dioxane (550 ml), sodium hydride (6.05 g, 151.25 mmol) was added followed by stirring under reflux for 14 hours. The reaction mixture was allowed to return to room temperature and concentrated under reduced pressure. To the residue, water was added, and the solution was extracted with methylene chloride twice. The organic phases were washed with a saturated saline solution, dried over magnesium sulfate and then filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate) to afford benzyl 4-(2-methyl-6-nitro-2,3-dihydroimidazo[2,1-b]oxazol-2-ylmethyl)piperazine-1-carboxylate (26.54 g, yield 52%) as a white powder.
Reaction SMILES: C([O:5][C:6]([C@H:8]1[CH2:12][CH2:11][CH2:10][N:9]1[C:13](=[O:42])[CH2:14][O:15][C:16]1[C:21]([Cl:22])=[C:20]([Cl:23])[C:19]([Cl:24])=[C:18]([Cl:25])[C:17]=1[O:26][CH2:27][C:28]([N:30]1[CH2:34][CH2:33][CH2:32][C@@H:31]1[C:35]([O:37]C(C)(C)C)=[O:36])=[O:29])=[O:7])(C)(C)C>FC(F)(F)C(O)=O>[C:6]([C@H:8]1[CH2:12][CH2:11][CH2:10][N:9]1[C:13](=[O:42])[CH2:14][O:15][C:16]1[C:21]([Cl:22])=[C:20]([Cl:23])[C:19]([Cl:24])=[C:18]([Cl:25])[C:17]=1[O:26][CH2:27][C:28]([N:30]1[CH2:34][CH2:33][CH2:32][C@@H:31]1[C:35]([OH:37])=[O:36])=[O:29])([OH:7])=[O:5]
Reactant: CC(C)(C)OC(=O)[C@H]1CCCN1C(=O)COc1c(Cl)c(Cl)c(Cl)c(Cl)c1OCC(=O)N1CCC[C@@H]1C(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)[C@H]1CCCN1C(=O)COc1c(Cl)c(Cl)c(Cl)c(Cl)c1OCC(=O)N1CCC[C@@H]1C(=O)O
Reaction time: 8 h
Yield: 90.6 %

Procedure:
A solution of 220 mg (0.34 mmol) (R)-1-[[2-[2-[(R)-2-tert-butoxycarbonyl-pyrrolidin-1-yl]-2-oxo-ethoxy]-3,4,5,6-tetrachloro-phenoxy]-acetyl]-pyrrolidine-2-carboxylic acid tert-butyl ester in 1.5 ml trifluoroacetic acid was stirred for 4 h at room temperature. The solvent was removed in vacuo and the residue suspended in 10 ml ether. The resulting suspension was stirred overnight. Filtration and drying gave 172 mg (94%) of the title compound as a white powder.
Reaction SMILES: [C:1]1(C)[CH:6]=[CH:5]C=[CH:3][CH:2]=1.O=O.[C:10]([OH:13])(=[O:12])[CH3:11]>[Cr].[Co].O.O.O.O.C([O-])(=O)C.[Co+2].C([O-])(=O)C.[Br-].[Na+]>[C:10]([OH:13])(=[O:12])[C:11]1[CH:5]=[CH:6][CH:1]=[CH:2][CH:3]=1
Reactant: Cc1ccccc1
Reactant: CC(=O)O
Agent: [Co+2]
Agent: [Co]
Agent: [Cr]
Solvent: O
Product: O=C(O)c1ccccc1
Temperature: 23 °C
Yield: 81.9 %

Procedure:
A heated autoclave of Hastelloy C, equipped with stirrer, gas introduction tube, temperature sensor, pressure gauge and a pressurized reflux condenser was charged with 300 g of toluene, 100 g of acetic acid, 3 g of cobalt acetate tetrahydrate (Co(OAc)2.4H2O) and 1.5 g of sodium bromide. Through this mixture air was passed at 125°-130° C. and a pressure of 25 bar, with stirring, with a constant exhaust of 3 1/min. The reaction was observed by continuous measurement of the oxygen content in the exhaust gas. The end of the reaction 220 minutes later was manifested by the fact that the oxygen in the exhaust gas returned to the initial level of 21%. Then the passage of air was stopped, and, after the addition of 450 g of 50% acetic acid, the mixture was cooled to 23° C. with stirring. The crystalline target product was separated from the reaction mixture using a pressure filter, washed with 450 g of 50% acetic acid, and dried. 325.5 g of pure white benzoic acid was obtained.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([F:21])=[C:6]([C@:8]2([CH2:19][F:20])[CH2:13][C@@H:12]([C:14]([F:17])([F:16])[F:15])[O:11][C:10]([NH2:18])=[N:9]2)[CH:7]=1.C(N(CC)CC)C.[CH2:29]([Si:31]([CH2:36][CH3:37])([CH2:34][CH3:35])[C:32]#[CH:33])[CH3:30]>[Cu]I.C1COCC1>[F:21][C:5]1[CH:4]=[CH:3][C:2]([C:30]#[C:29][Si:31]([CH2:36][CH3:37])([CH2:34][CH3:35])[CH2:32][CH3:33])=[CH:7][C:6]=1[C@:8]1([CH2:19][F:20])[CH2:13][C@@H:12]([C:14]([F:17])([F:16])[F:15])[O:11][C:10]([NH2:18])=[N:9]1
Reactant: NC1=N[C@](CF)(c2cc(Br)ccc2F)C[C@@H](C(F)(F)F)O1
Reactant: C#C[Si](CC)(CC)CC
Agent: [Cu]I
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC[Si](C#Cc1ccc(F)c([C@]2(CF)C[C@@H](C(F)(F)F)OC(N)=N2)c1)(CC)CC
Temperature: 110 °C
Reaction time: 0.42 h
Yield: 76 %

Procedure:
A 25 mL microwave vial was charged with (4S,6S)-4-(5-bromo-2-fluorophenyl)-4-(fluoromethyl)-6-(trifluoromethyl)-5,6-dihydro-4H-1,3-oxazin-2-amine (1.465 g, 3.93 mmol), triethylamine (2.74 mL, 19.63 mmol), 10 mL of THF, triethyl(ethynyl)silane (2.176 mL, 11.78 mmol), Pd(0) tetrakis(triphenylphosphine) (0.343 g, 0.297 mmol), and copper(I) iodide (0.112 g, 0.589 mmol). The resulting mixture was then heated at 110° C. for 30 min in a Biotage microwave synthesizer (waited for 25 min to get on the instrument). The solids were filtered off and the solvent was removed under vacuum and the residue was redissolved in 60 mL of EtOAc, washed with 50 mL of saturated NH4Cl solution twice, dried (Na2SO4) and concentrated to give an oil that was purified by Shoko silica gel instrument (pre-packed GRACE column 120 g, with EtOAc in hexane as eluent, 0-10% 17 min; 10% 8 min; 10-30% 5 min; 30% 10 min) to give the titled compound as a light yellow oil, 1.285 g, 76% yield. MS m/z=433.0 [M+H]+. Calculated for C20H25F5N2OSi: 432.2.
Reaction SMILES: C(O)(C(F)(F)F)=O.[N:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[N:14]1[CH2:30][CH2:29][C:17]2([CH2:21][N:20](C(OC(C)(C)C)=O)[CH2:19][CH2:18]2)[CH2:16][CH2:15]1>C(Cl)Cl>[N:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[N:14]1[CH2:30][CH2:29][C:17]2([CH2:21][NH:20][CH2:19][CH2:18]2)[CH2:16][CH2:15]1
Reactant: CC(C)(C)OC(=O)N1CCC2(CCN(c3ccccn3)CC2)C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: c1ccc(N2CCC3(CCNC3)CC2)nc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
TFA (1 ml) was added to a solution of tert-butyl 8-(pyridin-2-yl)-2,8-diazaspiro[4.5]decane-2-carboxylate (0.47 mmol, 1.0 eq.) in methylene chloride (3 ml) at 0° C. and the reaction mixture was stirred at 25° C. for 1 h. When the reaction was complete (TLC), the solvent was removed in vacuo in order to obtain the desired amine (AMN-20).
Reaction SMILES: [NH2:1][C:2]1[N:11]=[C:10]([NH2:12])[C:9]2[C:4](=[N:5][C:6]([NH2:20])=[C:7]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[Cl:19])[N:8]=2)[N:3]=1.CO[CH:23](OC)[N:24]([CH3:26])[CH3:25]>>[CH3:23][N:24]([CH:26]=[N:1][C:2]1[N:11]=[C:10]([N:12]=[CH:23][N:24]([CH3:26])[CH3:25])[C:9]2[C:4](=[N:5][C:6]([N:20]=[CH:23][N:24]([CH3:26])[CH3:25])=[C:7]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[Cl:19])[N:8]=2)[N:3]=1)[CH3:25]
Reactant: COC(OC)N(C)C
Reactant: Nc1nc(N)c2nc(-c3ccccc3Cl)c(N)nc2n1
Product: CN(C)C=Nc1nc(N=CN(C)C)c2nc(-c3ccccc3Cl)c(N=CN(C)C)nc2n1

Procedure:
Under a nitrogen atmosphere, a stirred solution of 0.5 gram (0.002 mole) of 2,4,7-triamino-6-(2-chlorophenyl)pteridine (prepared in Example 2) in 50 mL of N,N-dimethylformamide dimethylacetal was heated at reflux for about 5 hours. After this time the reaction mixture was cooled in an ice-bath, and a solid was collected by filtration. The solid was washed with diethyl ether, yielding, when dried, 0.5 gram of 2,4,7-tri-(dimethylaminomethyleneamino)-6-(2-chlorophenyl)pteridine. The NMR spectrum was consistent with the proposed structure.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[CH:9][CH:8]=[CH:7]2.Cl[CH2:13][CH2:14][N:15]([CH2:23][CH2:24]Cl)[CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.[OH-].[Na+]>C(O)CCC>[CH2:16]([N:15]1[CH2:23][CH2:24][N:1]([C:2]2[CH:3]=[CH:4][CH:5]=[C:6]3[C:11]=2[N:10]=[CH:9][CH:8]=[CH:7]3)[CH2:13][CH2:14]1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: Nc1cccc2cccnc12
Reactant: ClCCN(CCCl)Cc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCCCO
Product: c1ccc(CN2CCN(c3cccc4cccnc34)CC2)cc1
Temperature: 85 °C
Yield: 45.7 %

Procedure:
A solution of 8-amino-quinoline (12.91 g, 89 mmol) and bis(2-chloroethyl)-benzylamine (25.95 g, 112 mmol) in n-butanol (65 ml) was allowed to heat at 85° C. for 11 hours. The mixture was poured into 50% sodium hydroxide, extracted with methylene chloride and water. The organic layer was dried over anhydrous magnesium sulfate, and filtered. The solvent was removed under vacuum. Chromatography (methanol-methylene chloride) afforded 12.34 g of product as a solid: mp 116.5-118° C.
Reaction SMILES: [F:1][C:2]1[C:3]([C:16]2[S:20][C:19]3[C:21]([C:25]4[CH:32]=[CH:31][CH:30]=[CH:29][C:26]=4[CH:27]=O)=[CH:22][CH:23]=[CH:24][C:18]=3[CH:17]=2)=[N:4][C:5]([NH:8][CH2:9][CH2:10][N:11]2[CH:15]=[CH:14][N:13]=[N:12]2)=[N:6][CH:7]=1.[C:33]([BH3-])#[N:34].CC(C)(C)C(O)=O.CN>O1CCOCC1.C(Cl)(Cl)Cl.CC(O)C>[N:11]1([CH2:10][CH2:9][NH:8][C:5]2[N:4]=[C:3]([C:16]3[S:20][C:19]4[C:21]([C:25]5[CH:32]=[CH:31][CH:30]=[CH:29][C:26]=5[CH2:27][NH:34][CH3:33])=[CH:22][CH:23]=[CH:24][C:18]=4[CH:17]=3)[C:2]([F:1])=[CH:7][N:6]=2)[CH:15]=[CH:14][N:13]=[N:12]1
Reactant: O=Cc1ccccc1-c1cccc2cc(-c3nc(NCCn4ccnn4)ncc3F)sc12
Reactant: [BH3-]C#N
Agent: CC(C)(C)C(=O)O
Agent: CN
Solvent: CC(C)O
Solvent: ClC(Cl)Cl
Solvent: C1COCCO1
Product: CNCc1ccccc1-c1cccc2cc(-c3nc(NCCn4ccnn4)ncc3F)sc12
Temperature: 100 °C
Yield: 51.4 %

Procedure:
Combine 2-{2-[5-fluoro-2-(2-[1,2,3]triazol-1-yl-ethylamino)-pyrimidin-4-yl]-benzo[b]thiophen-7-yl}-benzaldehyde (800 mg, 1.8 mmol), cyanoborohydride (silica supported, 1 mmol/g, 2.7 g, 2.7 mmol), trimethylacetic acid (0.55 g, 4.7 mmol), and mono-methylamine (0.42 g, 5.4 mmol) in 12 mL of dioxane. Heat the reaction mixture at 100° C. for 20 min in microwave reactor. Cool it to RT. Dilute with chloroform/IPA (3:1, v/v), 50 mL. Wash with water, aqueous saturated sodium chloride, and dry over magnesium sulfate. Remove the organic solvent. Purify the residue by column chromatography [chloroform/methanol/ammonium hydroxide (35% in water), 7/3/0.05] to give the title compound (425 mg, 38%). MS (ES) m/z 460 [M+1]+.
Reaction SMILES: Cl.Cl.[O:3]1[C:7]2[CH:8]=[CH:9][CH:10]=[C:11]([CH:12]3[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][C@H:20]4[CH2:25][CH2:24][C@H:23]([NH2:26])[CH2:22][CH2:21]4)[CH2:14][CH2:13]3)[C:6]=2[CH2:5][CH2:4]1.[O:27]1[CH2:31][CH2:30][CH2:29][CH:28]1[CH2:32][C:33](O)=[O:34]>>[O:3]1[C:7]2[CH:8]=[CH:9][CH:10]=[C:11]([CH:12]3[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][C@H:20]4[CH2:21][CH2:22][C@H:23]([NH:26][C:33](=[O:34])[CH2:32][CH:28]5[CH2:29][CH2:30][CH2:31][O:27]5)[CH2:24][CH2:25]4)[CH2:14][CH2:13]3)[C:6]=2[CH2:5][CH2:4]1
Reactant: N[C@H]1CC[C@H](CCN2CCC(c3cccc4c3CCO4)CC2)CC1
Reactant: O=C(O)CC1CCCO1
Agent: Cl
Product: O=C(CC1CCCO1)N[C@H]1CC[C@H](CCN2CCC(c3cccc4c3CCO4)CC2)CC1

Procedure:
The title compound, white solid (72 mg, 65%), MS (ISP) m/z=441.5 [(M+H)+], mp 192° C., was prepared in accordance with the general method of example 1 from trans-4-{2-[4-(2,3-dihydro-benzofuran-4-yl)-piperidin-1-yl]-ethyl}-cyclohexylamine dihydrochloride (intermediate B) (100 mg, 0.25 mmol) and rac-2-(tetrahydro-furan-2-yl)-acetic acid.