Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[CH:22]=[CH:21][C:6]([O:7][C:8]2[C:9]([CH2:19][CH3:20])=[N:10][N:11]([CH2:15][C:16]([OH:18])=O)[C:12]=2[CH2:13][CH3:14])=[CH:5][CH:4]=1)#[N:2].[C:23]([NH:26][NH2:27])(=[O:25])[CH3:24].Cl.CN(C)CCCN=C=NCC.O.ON1C2C=CC=CC=2N=N1.CN1CCOCC1>CN(C)C=O>[C:23]([NH:26][NH:27][C:16](=[O:18])[CH2:15][N:11]1[C:12]([CH2:13][CH3:14])=[C:8]([O:7][C:6]2[CH:5]=[CH:4][C:3]([C:1]#[N:2])=[CH:22][CH:21]=2)[C:9]([CH2:19][CH3:20])=[N:10]1)(=[O:25])[CH3:24]
Reactant: CC(=O)NN
Reactant: CCc1nn(CC(=O)O)c(CC)c1Oc1ccc(C#N)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Solvent: CN1CCOCC1
Product: CCc1nn(CC(=O)NNC(C)=O)c(CC)c1Oc1ccc(C#N)cc1
Yield: 72 %

Procedure:
The acid of step (a) above (400 mg, 1.34 mmol), acetic hydrazide (109 mg, 1.47 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (372 mg, 1.47 mmol), 1-hydroxybenzotriazole hydrate (192 mg, 1.47 mmol) and N-methylmorpholine (525 mg, 5.36 mmol) were stirred in N,N-dimethylformamide (6 ml) at room temperature for 18 hours. The reaction mixture was then evaporated under reduced pressure and the residue was partitioned between dichloromethane (40 ml) and water (30 ml). The organic layer was dried over magnesium sulphate, filtered, and then concentrated under reduced pressure. The crude product was purified by flash chromatography on silica gel eluting with dichloromethane:methanol:ammonia (93:7:0.5, by volume) to provide the title compound (345 mg, 72%).
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH2:4][CH2:5][NH:6]2.[C:11](OC(=O)C)(=[O:13])[CH3:12]>>[F:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH2:4][CH2:5][N:6]2[C:11](=[O:13])[CH3:12]
Reactant: CC(=O)OC(C)=O
Reactant: Fc1cccc2c1CCN2
Product: CC(=O)N1CCc2c(F)cccc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 77 %

Procedure:
A mixture of 4-fluoro-indoline (1 g, 7.30 mmol) and acetic anhydride (10 mL) was stirred at ambient temperature for 1 h. The resulting mixture was partitioned between ethyl acetate (100 mL) and water (100 mL). The organic layer was separated and the aqueous layer was extracted with ethyl acetate (5×30 mL). The combined organic layers were washed with water (3×20 mL), sodium bicarbonate solution (3×20 mL), brine (3×20 mL), dried over anhydrous sodium sulphate and concentrated in vacuo to afford 1-(4-fluoro-indolin-1-yl)ethanone (1 g, 77%) as a white solid.
Reaction SMILES: [C:1]([O:4][C:5]1[CH:10]=[CH:9][C:8]([S:11](Cl)(=[O:13])=[O:12])=[CH:7][CH:6]=1)(=[O:3])[CH3:2].[CH3:15][O:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[CH2:23][NH2:24].C(N(CC)CC)C>ClCCl>[C:1]([O:4][C:5]1[CH:10]=[CH:9][C:8]([S:11](=[O:13])(=[O:12])[NH:24][CH2:23][C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=2[O:16][CH3:15])=[CH:7][CH:6]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)Oc1ccc(S(=O)(=O)Cl)cc1
Reactant: COc1ccccc1CN
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1ccccc1CNS(=O)(=O)c1ccc(OC(C)=O)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 97.8 %

Procedure:
A solution of 4-(chlorosulfonyl)phenyl acetate (example 5-42b) (531 mg, 2.265 mmol) in 5.0 mL of dichloromethane, was cooled to 0° C. in an ice bath. (2-methoxyphenyl)methanamine (325 μL, 2.492 mmol) and triethylamine (347 μL, 2.492 mmol) were added. The ice bath was then removed and the mixture warmed to ambient temperature and stirred for 2 hours. The reaction mixture was concentrated and the crude product was purified by column chromatography (hexanes/ethyl acetate=90/10 to 30/70) to afford pure 4-(N-(2-methoxybenzyl)sulfamoyl)phenyl acetate (743 mg, 89%) as a white solid. MS (M+H, 336.1) 1H NMR (400 MHz, CDCl3): δ, ppm: 2.32 (s, 3H), 3.71 (s, 3H), 4.18 (d, 2H, J=5.8 Hz), 5.15 (t, 1H, J=5.8 Hz), 6.71 (d, 1H, J=8.2 Hz), 6.82 (br t, 1H, J=7.4 Hz), 7.07 (br d, 1H, J=7.4 Hz), 7.10 (d, 2H, J=8.7 Hz), 7.19 (br t, 1H, J=7.8 Hz), 7.74 (d, 2H, J=8.7 Hz).
Reaction SMILES: [OH:1][C:2]([PH:5](=[O:8])[O:6][CH3:7])([CH3:4])[CH3:3].O[C:10](P(O)O)([CH3:12])[CH3:11]>O>[OH:1][C:2]([PH:5](=[O:8])[O:6][CH2:7][CH:10]([CH3:12])[CH3:11])([CH3:4])[CH3:3]
Reactant: CO[PH](=O)C(C)(C)O
Reactant: CC(C)(O)P(O)O
Solvent: O
Product: CC(C)CO[PH](=O)C(C)(C)O
Temperature: 5 °C

Procedure:
The methyl (1-hydroxy-1-methylethyl)phosphinate prepared as described immediately above is heated with water (11) on a steam bath for 8 hours until conversion to 1-hydroxy-1-methylethylphosphonous acid is complete (monitored by 31P nmr). The water is removed on a rotary evaporator and the residue is completely dried by co-evaporation with toluene. A sample of this phosphonous acid (4.6 g, 0.037M), isobutyl alcohol (3.02 g, 0.041M) and dimethylaminopyridine (0.5 g, 0.0041M) is stirred at 5° C. in tetrahydrofuran. Dicyclohexylcarbodiimide (8.4 g, 0.041M) is added portionwise over 30 minutes. On completion of the reaction (31P nmr), ether (50 ml) is added and the precipitated dicyclohexyl urea is filtered off.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([C:9]#[N:10])=[CH:7][C:6]2[C:11]3([CH2:30][O:31][C:5]=2[CH:4]=1)[C:19]1[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=1)[N:13](CC1C=CC(OC)=CC=1)[C:12]3=[O:29].FC(F)(F)S(O)(=O)=O>ClCCl.FC(F)(F)C(O)=O>[CH3:1][O:2][C:3]1[C:8]([C:9]#[N:10])=[CH:7][C:6]2[C:11]3([CH2:30][O:31][C:5]=2[CH:4]=1)[C:19]1[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=1)[NH:13][C:12]3=[O:29]
Reactant: COc1ccc(CN2C(=O)C3(COc4cc(OC)c(C#N)cc43)c3ccccc32)cc1
Agent: O=S(=O)(O)C(F)(F)F
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1cc2c(cc1C#N)C1(CO2)C(=O)Nc2ccccc21
Temperature: 25 °C
Reaction time: 18 h
Yield: 96.9 %

Procedure:
To a stirred solution of 6-methoxy-1′-(4-methoxybenzyl)-2′-oxo-1′,2′-dihydrospiro[1-benzofuran-3,3′-indole]-5-carbonitrile (0.50 g, 1.2 mmol) in dichloromethane (5 mL) and trifluoroacetic acid (5 mL) was added trifluoromethanesulfonic acid (1.0 mL, 11 mmol). The reaction mixture was stirred at ambient temperature for 18 h and concentrated in vacuo. The residue was basified with saturated aqueous sodium bicarbonate and extracted with ethyl acetate. The organic phase was washed with water and brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated in vacuo. The residue was purified by column chromatography to afford 6-methoxy-2′-oxo-1′,2′-dihydrospiro[1-benzofuran-3,3′-indole]-5-carbonitrile (0.34 g, 96%): mp 185-186° C.; 1H NMR (300 MHz, CDCl3) δ 8.46 (s, 1H), 7.30-7.25 (m, 1H), 7.11-7.03 (m, 2H), 6.97-6.94 (m, 2H), 6.56 (s, 1H), 4.91 (ABq, 2H), 3.90 (s, 3H); MS (ES+) m/z 292.9 (M+1).
Reaction SMILES: [CH:1]1([Li:6])[CH:5]=[CH:4][CH:3]=[CH:2]1.[N:7](OS(C)(=O)=O)([CH3:9])[CH3:8].C([Li])CCC>C1COCC1.CCCCCC>[CH3:8][N:7]([C:1]1([Li:6])[CH:5]=[CH:4][CH:3]=[CH:2]1)[CH3:9]
Reactant: CN(C)OS(C)(=O)=O
Reactant: [Li]C1C=CC=C1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: [Li]C1(N(C)C)C=CC=C1
Temperature: -20 °C
Reaction time: 0.5 h

Procedure:
A solution of 3 g of cyclopentadienyllithium (0.042 moles) in 30 ml of THF was added slowly at −30° C. to a solution of 5.9 g of compound 6 (0.042 moles) in 20 ml of THF. The mixture was then heated to −20° C. and stirred for 30 min. Hexane was then added and the solution was filtered. 1.8 ml of a 2.3 molar solution of butyllithium (0.042 moles) in hexane were then added at −20° C. to produce a precipitate. The precipitate was filtered off and washed with twice 20 ml of hexane. After drying under vacuum, 2.0 g (40% of the theoretical yield) of compound 7 were obtained in the form of a white powder; cf. Angew. Chem., Int. Ed. Engl. 19, (1980), 1010. 1H NMR (400 MHz, THF): δ=5.34 (bd, J=2.2 Hz, 2H); 5.15 (bd, J 2.2 Hz, 2H); 2.56 (s, 6H).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.[CH2:8]([C:12]1[S:13][C:14]2[CH:20]=[CH:19][CH:18]=[C:17]([F:21])[C:15]=2[N:16]=1)[CH2:9][C:10]#[CH:11]>>[F:21][C:17]1[C:15]2[N:16]=[C:12]([CH2:8][CH2:9][C:10]#[C:11][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=3)[S:13][C:14]=2[CH:20]=[CH:19][CH:18]=1
Reactant: C#CCCc1nc2c(F)cccc2s1
Reactant: Brc1ccccn1
Product: Fc1cccc2sc(CCC#Cc3ccccn3)nc12
Yield: 2 %

Procedure:
The title compound was prepared in accordance with the general method of Example 1, from 2-bromopyridine (291 mg, 1.84 mmol) and 2-but-3-ynyl-4-fluoro-benzo[d]thiazole (378 mg, 1.84 mmol). The crude residue was purified by flash chromatography (DCM/MeOH 99:1) to yield 10 mg (37 μmol, 2%) of 4-fluoro-2-(4-(pyridin-2-yl)but-3-ynyl)benzo[d]thiazole as a yellow solid.
Reaction SMILES: [ClH:1].Cl.[CH:3]1([NH:6][C:7]([C:9]2[C:17]3[CH:16]=[C:15]([C:18]4[C:23](F)=[CH:22][N:21]=[C:20]([NH:25][CH2:26][CH2:27][CH2:28][CH:29]5[CH2:34][CH2:33][N:32]([CH3:35])[CH2:31][CH2:30]5)[N:19]=4)[S:14][C:13]=3[CH:12]=[CH:11][CH:10]=2)=[O:8])CC1.[CH3:36]NC(C1C2C=C(C3C(C)=CN=C(NCCCC4CCNCC4)N=3)SC=2C=CC=1)=O>>[ClH:1].[ClH:1].[CH3:3][NH:6][C:7]([C:9]1[C:17]2[CH:16]=[C:15]([C:18]3[C:23]([CH3:36])=[CH:22][N:21]=[C:20]([NH:25][CH2:26][CH2:27][CH2:28][CH:29]4[CH2:34][CH2:33][N:32]([CH3:35])[CH2:31][CH2:30]4)[N:19]=3)[S:14][C:13]=2[CH:12]=[CH:11][CH:10]=1)=[O:8]
Reactant: CN1CCC(CCCNc2ncc(F)c(-c3cc4c(C(=O)NC5CC5)cccc4s3)n2)CC1
Reactant: CNC(=O)c1cccc2sc(-c3nc(NCCCC4CCNCC4)ncc3C)cc12
Agent: Cl
Product: CNC(=O)c1cccc2sc(-c3nc(NCCCC4CCN(C)CC4)ncc3C)cc12

Procedure:
Using the method of 2-{5-fluoro-2-[3-(1-methylpiperidin-4-yl)-propylamino]-pyrimidin-4-yl}-benzo[b]thiophene-4-carboxylic acid cyclopropylamide di-hydrochloride, the title compound is synthesized from 2-[5-methyl-2-(3-piperidin-4-yl-propylamino)-pyrimidin-4-yl]-benzo[b]thiophene-4-carboxylic acid methylamide and isolated as a yellow solid. ES+(m/z) 438 [M(free base)+H].
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[NH2:7][CH:8]1[CH2:13][CH2:12][O:11][CH2:10][CH2:9]1.[C:14]([C:16]1[N:21]=[CH:20][C:19]([C:22]2[C:34]3[C:33]4[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=4)[N:27]([C:35]4[CH:47]=[CH:46][C:38]([C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40])=[C:37](F)[CH:36]=4)[C:26]=3[CH:25]=[CH:24][CH:23]=2)=[CH:18][CH:17]=1)#[N:15]>CS(C)=O.O>[C:14]([C:16]1[N:21]=[CH:20][C:19]([C:22]2[C:34]3[C:33]4[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=4)[N:27]([C:35]4[CH:36]=[CH:37][C:38]([C:39]([O:41][C:42]([CH3:43])([CH3:44])[CH3:45])=[O:40])=[C:46]([NH:7][CH:8]5[CH2:13][CH2:12][O:11][CH2:10][CH2:9]5)[CH:47]=4)[C:26]=3[CH:25]=[CH:24][CH:23]=2)=[CH:18][CH:17]=1)#[N:15]
Reactant: CC(C)(C)OC(=O)c1ccc(-n2c3ccccc3c3c(-c4ccc(C#N)nc4)cccc32)cc1F
Reactant: NC1CCOCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: CC(C)(C)OC(=O)c1ccc(-n2c3ccccc3c3c(-c4ccc(C#N)nc4)cccc32)cc1NC1CCOCC1
Temperature: 90 °C
Yield: 40.1 %

Procedure:
0.95 g of potassium carbonate and 4.62 g of 4-aminotetrahydropyran are successively added to a solution of 1.06 g of 2-methylpropan-2-yl 4-[4-(6-cyanopyridin-3-yl)-9H-carbazol-9-yl]-2-fluorobenzoate, obtained in stage 1 of Example 49, in 8 ml of dimethyl sulphoxide. The reaction mixture is heated at 90° C. for 3 hours in a microwave, and then diluted with distilled water. The aqueous phase is washed twice with ethyl acetate and the combined organic phases are washed with water and a saturated solution of sodium chloride, dried over magnesium sulphate and filtered. The residue is purified by silica gel chromatography, elution being carried out with a mixture of cyclohexane and ethyl acetate (85/15 by volume), so as to give 0.5 g of 2-methylpropan-2-yl 4-[4-(6-cyanopyridin-3-yl)-9H-carbazol-9-yl]-2-(tetrahydro-2H-pyran-4-ylamino)benzoate in the form of a white foam, the characteristics of which are the following:
Reaction SMILES: [CH3:1][Si:2]([CH3:9])([CH3:8])[CH2:3][C:4]#[C:5][CH2:6]O.P(Br)(Br)[Br:11]>C(OCC)C>[Br:11][CH2:6][C:5]#[C:4][CH2:3][Si:2]([CH3:9])([CH3:8])[CH3:1].[Br-:11]
Reactant: BrP(Br)Br
Reactant: C[Si](C)(C)CC#CCO
Solvent: CCOCC
Product: C[Si](C)(C)CC#CCBr
Product: [Br-]
Reaction time: 2.5 h
Yield: 42.2 %

Procedure:
4-(trimethylsilyl)-2-butynol [J. Pernet, B. Randrianoelina, and L. Miginiac, Tetrahedron Letters, 25, 651, (1984)] (10 g, 70 mmol) is dissolved in dry diethyl ether (150 ml) and phosphorous tribromide (2.2 ml, 23.3 mmol) is added dropwise. Then the mixture is refluxed, protected from the light during 2.5 hours. The reaction is washed twice with water, once with aqueous sodium bicarbonate and then once with water. The organic layer is dried over sodium sulfate. The solvent is evaporated under reduced pressure to afford the expected bromide (4-bromo-2-butynyl)trimethylsilane (1.4 g, 97%) which is used without purification.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]([CH3:11])[CH2:9]O)=[CH:4][CH:3]=1.[C:12]1(=[O:22])[NH:16][C:15](=[O:17])[C:14]2=[CH:18][CH:19]=[CH:20][CH:21]=[C:13]12.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCOC(/N=N/C(OCC)=O)=O>C1COCC1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]([CH3:11])[CH2:9][N:16]2[C:12](=[O:22])[C:13]3[C:14](=[CH:18][CH:19]=[CH:20][CH:21]=3)[C:15]2=[O:17])=[CH:4][CH:3]=1
Reactant: C[C@H](CO)c1ccc(F)cc1
Reactant: O=C1NC(=O)c2ccccc21
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: C[C@H](CN1C(=O)c2ccccc2C1=O)c1ccc(F)cc1
Reaction time: 72 h
Yield: 59.4 %

Procedure:
To a solution of (S)-2-(4-fluorophenyl)propan-1-ol (0.82 g, 5.35 mmol, 1.0 equiv), phthalimide (0.82 g, 5.6 mmol, 1.05 equiv), and triphenyl phosphine (2.1 g, 8.03 mmol, 1.5 equiv) in dry THF (18 mL) was added dropwise diethylazodicarboxylate (3.6 mL, 15% in toluene, 8.0 mmol, 1.5 equiv). The reaction mixture was stirred over 72 h and then concentrated in vacuo. Purification by silica gel chromatography (15-25% EtOAc/hexanes) provided the title compound (0.9 g, 59%).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]3[N:12]=[C:13]4[C:19]([C:20]([NH:22][CH:23]([CH3:25])[CH3:24])=[O:21])=[CH:18][N:17]([CH2:26][O:27][CH2:28][CH2:29][Si:30]([CH3:33])([CH3:32])[CH3:31])[C:14]4=[N:15][CH:16]=3)=[N:7][NH:8]2)=[CH:4][CH:3]=1.[H-].[Na+].[CH:36]1([CH2:39]Br)[CH2:38][CH2:37]1>CN(C=O)C.O>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]3[N:12]=[C:13]4[C:19]([C:20]([NH:22][CH:23]([CH3:25])[CH3:24])=[O:21])=[CH:18][N:17]([CH2:26][O:27][CH2:28][CH2:29][Si:30]([CH3:31])([CH3:33])[CH3:32])[C:14]4=[N:15][CH:16]=3)=[N:7][N:8]2[CH2:39][CH:36]2[CH2:38][CH2:37]2)=[CH:4][CH:3]=1
Reactant: CC(C)NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(-c3n[nH]c4cc(Cl)ccc34)nc12
Reactant: BrCC1CC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(-c3nn(CC4CC4)c4cc(Cl)ccc34)nc12
Temperature: 0 °C
Reaction time: 15 h
Yield: 74.5 %

Procedure:
2-(6-Chloro-1H-indazol-3-yl)-N-isopropyl-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide (120 mg, 247 μmol) was dissolved in DMF (1 mL) and cooled to 0° C. Sodium hydride (12.9 mg, 322 μmol) was added. After 30 min cyclopropylmethyl bromide (50.1 mg, 0.0360 mL, 371 μmol) was added and the mixture warmed to room temperature. After 15 h, the mixture was diluted with water and extracted with ethyl acetate. The organic extracts were washed with brine, dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by chromatography (silica, 40 g Analogix column, 20-50% ethyl acetate in hexanes, 15 min gradient) to give 2-(6-chloro-1-(cyclopropylmethyl)-1H-indazol-3-yl)-N-isopropyl-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide (99 mg, 184 μmol, 74.2%) as a yellow powder. 1H NMR (CDCl3) δ: 9.27 (s, 1H), 8.43-8.50 (m, 2H), 8.31 (d, J=8.3 Hz, 1H), 7.54 (s, 1H), 7.23 (s, 1H), 5.73 (s, 2H), 4.40-4.56 (m, 1H), 4.35 (d, J=6.8 Hz, 2H), 3.54-3.64 (m, 2H), 1.42 (d, J=6.4 Hz, 7H), 0.89-1.00 (m, 2H), 0.62-0.71 (m, 2H), 0.51 (q, J=4.9 Hz, 2H), −0.07-−0.01 (m, 9H)
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[C:10]([C:18](O)=[O:19])=[CH:11][N:12]([CH3:17])[C:13](=[O:16])[C:14]=2[F:15])=[C:4]([F:21])[CH:3]=1.CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)[N:41]=[N:40]C=2C=1.NN.CCN(CC)CC>CN(C=O)C.CCOC(C)=O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[C:10]([C:18]([NH:40][NH2:41])=[O:19])=[CH:11][N:12]([CH3:17])[C:13](=[O:16])[C:14]=2[F:15])=[C:4]([F:21])[CH:3]=1
Reactant: Cn1cc(C(=O)O)c(Nc2ccc(Br)cc2F)c(F)c1=O
Reactant: On1nnc2ccccc21
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: NN
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Cn1cc(C(=O)NN)c(Nc2ccc(Br)cc2F)c(F)c1=O
Reaction time: 0.5 h
Yield: 88 %

Procedure:
A mixture of 4-(4-bromo-2-fluorophenylamino)-5-fluoro-1-methyl-6-oxo-1,6-dihydropyridine-3-carboxylic acid (70 mg, 0.195 mmol), EDCl (112 mg, 0.585 mmol), and HOBt (79 mg, 0.585 mmol) in DMF (3 mL) was stirred for 30 minutes. Hydrazine (19 mg, 0.585 mmol) was added followed by Et3N (0.082 mL, 0.585 mmol). After 3 hours, the reaction mixture was diluted with EtOAc and washed with saturated NH4Cl solution, saturated NaHCO3 solution and brine. The organic layer was dried (MgSO4) and concentrated to yield 64 mg (89%) desired product.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([Cl:8])[N:5]=[C:4]([Cl:9])[N:3]=1.O1CCCC1.[NH2:15][C:16]1[CH:23]=[CH:22][C:19]([C:20]#[N:21])=[CH:18][CH:17]=1.C(N(CC)CC)C>O1CCOCC1>[Cl:9][C:4]1[N:5]=[C:6]([Cl:8])[N:7]=[C:2]([NH:15][C:16]2[CH:23]=[CH:22][C:19]([C:20]#[N:21])=[CH:18][CH:17]=2)[N:3]=1
Reactant: Clc1nc(Cl)nc(Cl)n1
Reactant: N#Cc1ccc(N)cc1
Solvent: C1COCCO1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: N#Cc1ccc(Nc2nc(Cl)nc(Cl)n2)cc1
Temperature: -75 °C
Reaction time: 4 h
Yield: 64.4 %

Procedure:
2,4,6-trichloro-1,3,5-triazine (0.07440 mol) and tetrahydrofuran (100 ml) were combined and cooled to −75° C, under Ar atmosphere. 4-aminobenzonitrile (0.07440 mol) was added and the solution was stirred for 4 hours at −75° C. Triethylamine (0.07440 mol) was added dropwise and the reaction mixture was allowed to warm up slowly to room temperature and stirred for 3 days. After adding 1,4-dioxane (100 ml), the resulting precipitate was collected by filtration, washed with tetrahydrofuran, and dried, yielding 12.74 g 4-[(4,6-dichloro-1,3,5-triazin-2-yl)amino]benzonitrile (interm. 1).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([NH2:8])=[N:6][CH:7]=1.[CH3:9][O:10][C:11]1[CH:18]=[C:17]([O:19][CH3:20])[CH:16]=[CH:15][C:12]=1[CH:13]=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[OH-].[Na+]>ClCCl>[CH3:9][O:10][C:11]1[CH:18]=[C:17]([O:19][CH3:20])[CH:16]=[CH:15][C:12]=1[CH2:13][NH:8][C:5]1[CH:4]=[CH:3][C:2]([F:1])=[CH:7][N:6]=1
Reactant: Nc1ccc(F)cn1
Reactant: COc1ccc(C=O)c(OC)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: COc1ccc(CNc2ccc(F)cn2)c(OC)c1
Yield: 112.7 %

Procedure:
5-Fluoropyridin-2-amine (500 mg, 4.46 mmol) and 2,4-dimethoxybenzaldehyde (674 mg, 4.06 mmol) were stirred in dichloromethane (10 mL) at room temperature for 30 minutes. Sodium triacetoxyborohydride (1.3 g, 6.08 mmol) was added portion wise. The mixture was then stirred at room temperature for 18 hours before treatment with 1M aqueous sodium hydroxide solution (10 mL). The aqueous layer was separated and extracted with dichloromethane (10 mL). The combined organic layers were dried through a phase separating cartridge and evaporated to afford the title compound (1.2 g) as a brown solid.
Reaction SMILES: [CH3:1][CH2:2][CH2:3][CH2:4][CH2:5]C.C([Li])CCC.[C:12]1([CH2:18][C@H:19]2[CH2:23][O:22][C:21](=[O:24])[NH:20]2)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.Cl.C1C[O:29]CC1>O>[O:29]=[C:5]([N:20]1[C@@H:19]([CH2:18][C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH2:23][O:22][C:21]1=[O:24])[CH2:4][CH2:3][CH:2]=[CH2:1]
Reactant: C1CCOC1
Reactant: CCCCCC
Reactant: O=C1N[C@@H](Cc2ccccc2)CO1
Agent: Cl
Agent: [Li]CCCC
Solvent: O
Product: C=CCCC(=O)N1C(=O)OC[C@@H]1Cc1ccccc1
Reaction time: 0.5 h
Yield: 74 %

Procedure:
Another solution was prepared by adding dropwise a 1.6M hexane solution of butyllithium (38.8 mL, 62.1 mmol) to a cooled (-78°) solution of (S)-4-(phenylmethyl)-2-oxazolidinone [10.0 g, 56.4 mmol, described by L. N. Predgen et al., J. Org. Chem., 54, 3231 (1989)] in THF (250 mL). The freshly prepared second solution was kept at -78° for 30 min and then quickly added via a cannula to the solution of mixed anhydride at -78°. The reaction mixture was stirred at -78° for 3 h. Thereafter, H2O (100 mL) and 10% aqueous HCl (50 mL) were added. The resulting mixture was extracted with EtOAc (2×250 mL). The combined extract was washed with a saturated aqueous solution of NaHCO3 and with brine, dried (Na2SO4) and concentrated under reduced pressure. Purification of the residue by flash chromatography (SiO2, eluent: hexane-EtOAc, 15:1) gave (4S)-3-(1-oxo-4-pentenyl)-4-(phenylmethyl)-2-oxazolidinone (10.85 g, 74%) as a colorless oil, 1H NMR (CDCl3) δ 7.34-7.2 (m,5H), 6.0-5.8 (m,1H), 5.16-5.0 (m,2H), 4.7 (m,1H), 4.2 (m,2H), 3.3 (dd,J=3.1 Hz,13.2 Hz,1H), 3.1-3.0 (m,2H), 2.75 (dd,J=9.6 Hz,13.3 Hz,1H), 2.5 (m,2H), mass spectrum: 260 (M+H)+.
Reaction SMILES: [CH3:1][C@H:2]1[NH:7][C@@H:6]([CH3:8])[CH2:5][N:4]([C:9]2[CH:16]=[CH:15][C:12]([C:13]#[N:14])=[C:11]([N+:17]([O-])=O)[CH:10]=2)[CH2:3]1>C(O)C.CO.[Pd]>[NH2:17][C:11]1[CH:10]=[C:9]([N:4]2[CH2:5][C@H:6]([CH3:8])[NH:7][C@H:2]([CH3:1])[CH2:3]2)[CH:16]=[CH:15][C:12]=1[C:13]#[N:14]
Reactant: C[C@@H]1CN(c2ccc(C#N)c([N+](=O)[O-])c2)C[C@H](C)N1
Agent: [Pd]
Solvent: CO
Solvent: CCO
Product: C[C@@H]1CN(c2ccc(C#N)c(N)c2)C[C@H](C)N1
Reaction time: 16 h

Procedure:
A solution of the product of Step 1 (186 mg, 0.71 mmol) in ethanol (14 ml) and methanol (3-4 ml) was treated with palladium on charcoal (37 mg, 10% paste) and stirred under an atmosphere of hydrogen for 16 hours. The mixture was then filtered through celite, washing with ethanol and the then evaporated in vacuo. Purification of the residue by mass directed autoprep HPLC gave the title compound (D20) as the formic acid salt. MS (ES+) m/e 231 [M+H]+.
Reaction SMILES: [C:1]1([C:7]2[CH:12]=[CH:11][N:10]3[N:13]=[N:14][C:15]([CH2:16][OH:17])=[C:9]3[CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[AlH4-].[Li+].C1([C:26]2[CH:31]=[CH:30][N:29]3N=N[C:34]([C:35]([O:37][CH3:38])=O)=[C:28]3[CH:27]=2)C=CC=CC=1.[CH2:39]1COC[CH2:40]1>CCOC(C)=O>[CH3:38][O:37][C:35]1[CH:34]=[C:28]2[C:27]([C:26]([O:17][CH2:16][C:15]3[N:14]=[N:13][N:10]4[CH:11]=[CH:12][C:7]([C:1]5[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=5)=[CH:8][C:9]=34)=[CH:31][CH:30]=[N:29]2)=[CH:40][CH:39]=1
Reactant: OCc1nnn2ccc(-c3ccccc3)cc12
Reactant: COC(=O)c1nnn2ccc(-c3ccccc3)cc12
Reactant: C1CCOC1
Agent: [AlH4-]
Agent: [Li+]
Solvent: CCOC(C)=O
Product: COc1ccc2c(OCc3nnn4ccc(-c5ccccc5)cc34)ccnc2c1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
(5-Phenyl-[1,2,3]triazolo[1,5-a]pyridin-3-yl)methanol. To a cooled (ice bath) suspension of lithium tetrahydroaluminate (0.0929 g, 2.45 mmol) in 2 mL THF (anhy) was added slowly a solution of methyl 5-phenyl-[1,2,3]triazolo[1,5-a]pyridine-3-carboxylate (0.310 g, 1.22 mmol) in 20 mL THF (internal temp remained <20 C). The mixture was allowed to stir in the ice bath 10 minutes. The mixture was diluted with EtOAc, washed with water, sat. NaHCO3, the organic layer dried over Na2SO4, and filtered. The aqueous layer still had uv activity so a solution of Rochelle's salt and EA were added and the mixture stirred 30 min. The organic layer was washed with sat NaHCO3, dried over Na2SO4, filtered, combined with main portion and evaporated. The title compound was isolated as a yellow solid.
Reaction SMILES: CC1C2C(=CC=CC=2)CCN1.C(O)C(O)C.[Cl:17]C1C(C)=C(C)N=C(NC2C=CC(F)=CC=2)N=1.[CH3:34][C:35]1[C:36]([N:50]2[CH2:59][CH2:58][C:57]3[C:52](=[CH:53][CH:54]=[CH:55][CH:56]=3)[CH:51]2[CH3:60])=[N:37][C:38]([NH:42][C:43]2[CH:48]=[CH:47][C:46]([F:49])=[CH:45][CH:44]=2)=[N:39][C:40]=1[CH3:41]>C(N(CC)CC)C>[ClH:17].[CH3:34][C:35]1[C:36]([N:50]2[CH2:59][CH2:58][C:57]3[C:52](=[CH:53][CH:54]=[CH:55][CH:56]=3)[CH:51]2[CH3:60])=[N:37][C:38]([NH:42][C:43]2[CH:48]=[CH:47][C:46]([F:49])=[CH:45][CH:44]=2)=[N:39][C:40]=1[CH3:41]
Reactant: Cc1nc(Nc2ccc(F)cc2)nc(Cl)c1C
Agent: CC1NCCc2ccccc21
Agent: Cc1nc(Nc2ccc(F)cc2)nc(N2CCc3ccccc3C2C)c1C
Solvent: CC(O)CO
Solvent: CCN(CC)CC
Product: Cl

Procedure:
75 ml of triethylamine and 65 g(442 mmole) of 1-methyl-1,2,3,4-tetrahydroisoquinoline as prepared in Example 7 were added to 100 ml of 1,2-propylene glycol. 100.9 g(0.40 mmole) of 4-chloro-2-(4-fluorophenylamino)-5,6-dimethylpyrimidine was added thereto and then reacted at 120° C. for 64 hours to prepare 5,6-dimethyl-2-(4-fluorophenylamino)-4-(1-methyl-1,2,3,4-tetrahydroisoquinolin-2-yl)pyrimidine. This product was treated according to the procedure detailed in Example 21 to obtain 95.1 g of purified 5,6-dimethyl-2-(4-fluorophenylamino)-4-(1-methyl-1,2,3,4-tetrahydroisoquinolin-2-yl)pyrimidine hydrochloride.