Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][C:10]#N)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].C([Al+]CC(C)C)C(C)C.CC[O:24]CC>C1(C)C=CC=CC=1>[C:1]1([CH2:7][CH2:8][CH2:9][CH:10]=[O:24])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CCOCC
Reactant: N#CCCCc1ccccc1
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: Cc1ccccc1
Product: O=CCCCc1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a stirred suspension of 4-phenylbutyronitrile (21.7 g, 0.12 mole) in ether (400 ml) at 78° C. is added 85 ml. of 25.3% diisobutylaluminum hydride in toluene over a period of 1 hour. After an additional 1 hour, the dry ice-acetone bath is removed and the reaction mixture is stirred at ambient temperature for 3 hours. The reaction mixture is added slowly to 5% aqueous sulfuric acid and then is extracted with several portions of ether. The ether extracts are combined, washed with water and saturated aqueous sodium chloride solution and dried over magnesium sulfate. After removal of the ether, the residual yellow oil is distilled in vacuo to give an oil.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][N:24]=[C:23]([CH3:26])[C:22]=4[NH2:27])=[CH:17][CH:16]=3)=[CH:11][CH:10]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2].Br[C:29]1[CH:30]=[N:31][CH:32]=[C:33]([C:35]2[CH:40]=[CH:39][CH:38]=[C:37]([F:41])[C:36]=2[Cl:42])[CH:34]=1>>[CH2:1]([O:3][C:4]([C:6]1([C:9]2[CH:10]=[CH:11][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][N:24]=[C:23]([CH3:26])[C:22]=4[NH:27][C:29]4[CH:30]=[N:31][CH:32]=[C:33]([C:35]5[CH:40]=[CH:39][CH:38]=[C:37]([F:41])[C:36]=5[Cl:42])[CH:34]=4)=[CH:17][CH:16]=3)=[CH:13][CH:14]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4N)cc3)cc2)CC1
Reactant: Fc1cccc(-c2cncc(Br)c2)c1Cl
Product: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4Nc4cncc(-c5cccc(F)c5Cl)c4)cc3)cc2)CC1

Procedure:
Prepared according to the procedure described in Example 41, Step 2, using 1-[4′-(4-amino-3-methyl-isoxazol-5-yl)-biphenyl-4-yl]-cyclopropanecarboxylic acid ethyl ester and 3-bromo-5-(2-chloro-3-fluoro-phenyl)-pyridine.
Reaction SMILES: [N:1]1[C:9]2[C:4](=[N:5][CH:6]=[CH:7][CH:8]=2)[N:3]([C:10]2[CH:15]=[CH:14][C:13]([CH2:16][C:17]([OH:19])=O)=[CH:12][CH:11]=2)[CH:2]=1.[CH3:20][N:21]1[CH2:26][CH2:25][N:24]([CH2:27][C:28]2[CH:33]=[CH:32][C:31]([NH2:34])=[CH:30][C:29]=2[C:35]([F:38])([F:37])[F:36])[CH2:23][CH2:22]1>C(Cl)Cl.CO>[N:1]1[C:9]2[C:4](=[N:5][CH:6]=[CH:7][CH:8]=2)[N:3]([C:10]2[CH:11]=[CH:12][C:13]([CH2:16][C:17]([NH:34][C:31]3[CH:32]=[CH:33][C:28]([CH2:27][N:24]4[CH2:23][CH2:22][N:21]([CH3:20])[CH2:26][CH2:25]4)=[C:29]([C:35]([F:38])([F:37])[F:36])[CH:30]=3)=[O:19])=[CH:14][CH:15]=2)[CH:2]=1
Reactant: CN1CCN(Cc2ccc(N)cc2C(F)(F)F)CC1
Reactant: O=C(O)Cc1ccc(-n2cnc3cccnc32)cc1
Solvent: CO
Solvent: ClCCl
Product: CN1CCN(Cc2ccc(NC(=O)Cc3ccc(-n4cnc5cccnc54)cc3)cc2C(F)(F)F)CC1

Procedure:
The title compound is prepared as described in Example 1 but using (4-imidazo[4,5-b]pyridin-3-yl-phenyl)-acetic acid (Step 7.1) and 4-(4-methyl-piperazin-1-ylmethyl)-3-trifluoromethyl-phenylamine (see WO 03/099771). Title compound: ES-MS: 509.0 [M+H]+; tR=3.07 min (System 1); Rf=0.10 (CH2Cl2/MeOH, 9:1).
Reaction SMILES: [CH:1]1([S:4]([C:7]2[CH:12]=[CH:11][C:10]([CH:13]([C:21]3[NH:25][C:24]([C:26]4[N:31]=[CH:30][C:29]([OH:32])=[CH:28][CH:27]=4)=[CH:23][CH:22]=3)[CH2:14][CH:15]3[CH2:20][CH2:19][O:18][CH2:17][CH2:16]3)=[CH:9][CH:8]=2)(=[O:6])=[O:5])[CH2:3][CH2:2]1.[CH2:33](O)[CH3:34].C(P(CCCC)CCCC)CCC.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O>O1CCCC1>[CH:1]1([S:4]([C:7]2[CH:12]=[CH:11][C:10]([CH:13]([C:21]3[NH:25][C:24]([C:26]4[CH:27]=[CH:28][C:29]([O:32][CH2:33][CH3:34])=[CH:30][N:31]=4)=[CH:23][CH:22]=3)[CH2:14][CH:15]3[CH2:20][CH2:19][O:18][CH2:17][CH2:16]3)=[CH:9][CH:8]=2)(=[O:6])=[O:5])[CH2:3][CH2:2]1
Reactant: O=S(=O)(c1ccc(C(CC2CCOCC2)c2ccc(-c3ccc(O)cn3)[nH]2)cc1)C1CC1
Reactant: CCO
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: C1CCOC1
Product: CCOc1ccc(-c2ccc(C(CC3CCOCC3)c3ccc(S(=O)(=O)C4CC4)cc3)[nH]2)nc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 80 %

Procedure:
To a solution of 6-(5-{1-[4-(cyclopropylsulfonyl)phenyl]-2-(tetrahydro-2H-pyran-4-yl)ethyl}-1H-pyrrol-2-yl)pyridin-3-ol (0.260 g) in tetrahydrofuran (10 mL) were added ethanol (0.067 tributylphosphine (0.29 mL) and 1,1′-(azodicarbonyl)dipiperidine (290 mg), and the mixture was stirred at room temperature for 16 hr. The reaction mixture was concentrated under reduced pressure, the residue was dissolved in toluene (10 mL), and hexane (10 mL) was added. The obtained suspension was filtered to remove the precipitate, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:hexane=20:80-70:30, volume ratio) to give the title compound (0.220 g, yield 80%) as a colorless amorphous solid. MS: 481 (MH+).
Reaction SMILES: [C:1]([N:4]([C:8]1[C:12]2[CH:13]=[C:14]([N+:17]([O-])=O)[CH:15]=[CH:16][C:11]=2[S:10][N:9]=1)[C:5](=[O:7])[CH3:6])(=[O:3])[CH3:2].C(O)(=O)C.C(=O)(O)[O-].[Na+]>[Fe].C(OCC)(=O)C>[C:1]([N:4]([C:8]1[C:12]2[CH:13]=[C:14]([NH2:17])[CH:15]=[CH:16][C:11]=2[S:10][N:9]=1)[C:5](=[O:7])[CH3:6])(=[O:3])[CH3:2]
Reactant: CC(=O)N(C(C)=O)c1nsc2ccc([N+](=O)[O-])cc12
Agent: [Fe]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: CC(=O)N(C(C)=O)c1nsc2ccc(N)cc12
Temperature: 50 °C
Reaction time: 5 h
Yield: 37.8 %

Procedure:
To a suspension of N-acetyl-N-(5-nitro-benzo[d]isothiazol-3-yl)-acetamide (1.133 g, 4.06 mmol) in a 1:1 acetic acid:ethyl acetate solution (70 mL) at 50° C. was added iron powder (680 mg, 12.2 mmol). The resulting mixture was stirred at 50° C. for 5 h, then cooled, poured into saturated sodium bicarbonate and extracted into ethyl acetate. The organic layers were combined, washed with water and then brine, dried (MgSO4), filtered, and evaporated. The residue was purified using flash chromatography on silica to afford the desired amine as an orange solid (383 mg, 38%), single spot at Rf 0.30 (1:1 dichloromethane:ethyl acetate). mp 213.0-214.2° C. 1H NMR (CDCl3): δ 8.56 (1H, d, J=9.2 Hz), 7.48 (d, J=2.7 Hz), 7.14 (1H, dd, J=9.2, 2.7 Hz), 2.62 (3H, s), 2.56 (3H, s).
Reaction SMILES: C(P(C(C)(C)C)C1C=CC=CC=1C1C=CC=CC=1)(C)(C)C.CC(C)([O-])C.[Na+].Cl[CH:29]([O:42][CH:43]1[CH:48]([C:49]2[CH:54]=[CH:53][C:52]([O:55][CH2:56][CH2:57][CH2:58][O:59][CH2:60][C:61]3[CH:66]=[CH:65][CH:64]=[CH:63][C:62]=3[O:67][CH3:68])=[CH:51][CH:50]=2)[CH2:47][CH2:46][N:45]([C:69]([O:71][C:72]([CH3:75])([CH3:74])[CH3:73])=[O:70])[CH2:44]1)[C:30]1[CH:35]=[CH:34][CH:33]=[C:32]([O:36][CH2:37][CH2:38][CH2:39][O:40][CH3:41])[CH:31]=1.[NH:76]1[CH2:81][CH2:80][O:79][CH2:78][CH2:77]1>C1(C)C=CC=CC=1>[CH3:68][O:67][C:62]1[CH:63]=[CH:64][CH:65]=[CH:66][C:61]=1[CH2:60][O:59][CH2:58][CH2:57][CH2:56][O:55][C:52]1[CH:53]=[CH:54][C:49]([CH:48]2[CH2:47][CH2:46][N:45]([C:69]([O:71][C:72]([CH3:75])([CH3:74])[CH3:73])=[O:70])[CH2:44][CH:43]2[O:42][CH2:29][C:30]2[CH:35]=[CH:34][C:33]([N:76]3[CH2:81][CH2:80][O:79][CH2:78][CH2:77]3)=[C:32]([O:36][CH2:37][CH2:38][CH2:39][O:40][CH3:41])[CH:31]=2)=[CH:50][CH:51]=1
Reactant: C1COCCN1
Reactant: COCCCOc1cccc(C(Cl)OC2CN(C(=O)OC(C)(C)C)CCC2c2ccc(OCCCOCc3ccccc3OC)cc2)c1
Agent: CC(C)(C)P(c1ccccc1-c1ccccc1)C(C)(C)C
Agent: CC(C)(C)[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: COCCCOc1cc(COC2CN(C(=O)OC(C)(C)C)CCC2c2ccc(OCCCOCc3ccccc3OC)cc2)ccc1N1CCOCC1
Temperature: 110 °C
Reaction time: 16 h

Procedure:
The mixture of 0.0074 g of 2-(di-t-butylphosphino)biphenyl, 0.017 g of dipalladiumtris (dibenzylidenacetone)-chloroform complex and 0.055 g of sodium tert-butoxide is admixed under argon with the solution of 0.280 g of tert-butyl 3-[chloro-3-(3-methoxypropoxy)benzyloxy]-4-{4-[3-(2-methoxybenzyloxy)propoxy]phenyl}piperidine-1-carboxylate (Example 31a) and 0.043 ml of morpholine in 2.0 ml of toluene. The reaction mixture is stirred at 110° C. over 16 hours, subsequently cooled, poured onto water (20 ml) and extracted with ethyl acetate (2×20 ml). The organic phases are washed with brine (20 ml), dried over sodium sulphate, filtered and concentrated by evaporation. The title compound is obtained as a white foam from the residue by means of flash chromatography (SiO2 60F). Rf=0.23 (2:1 EtOAc-heptane); Rt=5.46.
Reaction SMILES: [OH:1][C:2]1([C:14](O)=[O:15])[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[CH:4][CH2:3]1.C(OCC)(=O)C.Cl>O>[OH:1][C:2]1([CH2:14][OH:15])[CH:3]=[CH:4][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[CH:6][CH2:7]1
Reactant: O=C(O)C1(O)C=CC(c2ccccc2)=CC1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: O
Product: OCC1(O)C=CC(c2ccccc2)=CC1
Reaction time: 0.5 h
Yield: 29 %

Procedure:
To a solution of 4-hydroxy-4-biphenylcarboxylic acid (2.14 g) in tetrahydroftiran (25 ml) under an argon atmosphere was added slowly 1M borane-THF complex (50 ml). The resulting mixture was stirred for 18 hours before the addition of ethyl acetate (10 ml) and water (100 ml). The resulting mixture was acidified with 2N hydrochloric acid and stirred for 30 minutes. The aqueous layer was extracted with ethyl acetate (2×100 ml). The organic extracts were combined, dried (MgSO4) and evaporated . Recrystallisation from a small volume of ethyl acetate gave 4-hydroxy-4-biphenylmethanol (580 mg): NMR (d6DMSO) δ 4.5(s,2H), 6.85(d,2H), 7.35(d,2H), 7.45-7.55(dd,4H), 9.45(s,1H); m/e 201(M+H)+.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:16]=[C:15]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:14]=[CH:13][C:10]=1[CH:11]=[O:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[BH4-].[Na+].O>CO>[CH2:1]([O:8][C:9]1[CH:16]=[C:15]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:14]=[CH:13][C:10]=1[CH2:11][OH:12])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=Cc1ccc(OCc2ccccc2)cc1OCc1ccccc1
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: OCc1ccc(OCc2ccccc2)cc1OCc1ccccc1
Yield: 98.4 %

Procedure:
2,4-Dibenzyloxybenzaldehyde [V] (20 g) was dissolved in methanol (700 ml) and then, thereto was added sodium borohydride (3.6 g) and this was left to stand at room temperature (20° C.) for 1.5 hour. To the reaction mixture was added water (1.5 liter) and the resulting precipitate was collected by filtration and recrystallized from ethanol to obtain 2,4-dibenzyloxybenzyl alcohol [VI] (19.8 g, yield 98%). Melting point: 84°-85° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:9](=[O:19])[CH2:10]P(=O)(OCC)OCC)[CH:6]=[CH:7][CH:8]=1.O1CCCC1.[H-].[Na+].O=[C:28]1[CH2:33][CH2:32][N:31]([C:34]([O:36][CH2:37][CH3:38])=[O:35])[CH2:30][CH2:29]1>O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:9](=[O:19])[CH2:10][C:28]2[CH2:33][CH2:32][N:31]([C:34]([O:36][CH2:37][CH3:38])=[O:35])[CH2:30][CH:29]=2)[CH:6]=[CH:7][CH:8]=1
Reactant: CCOC(=O)N1CCC(=O)CC1
Reactant: CCOP(=O)(CC(=O)c1cccc(OC)c1)OCC
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CCOC(=O)N1CC=C(CC(=O)c2cccc(OC)c2)CC1
Temperature: 15 °C
Reaction time: 0.5 h
Yield: 83 %

Procedure:
To a stirred mixture of 41 parts of diethyl [2-(3-methoxyphenyl)-2-oxoethyl]phosphonate and 180 parts of tetrahydrofuran are added portionwise 5 parts of sodium hydride dispersion 61% while cooling at about 15° C. Upon completion, stirring is continued for 30 minutes at room temperature. Then there are added dropwise 21 parts of ethyl 4-oxo-1-piperidinecarboxylate at about 20° C. Stirring is continued for 4 hours at 60° C. The reaction mixture is cooled, water is added and the layers are separated. The organic phase is dried, filtered and evaporated. The residue is distilled, yielding 30 parts (83%) of ethyl 2,3-dihydro-4-[2-(3-methoxyphenyl)-2-oxoethyl]-1(6H)-pyridinecarboxylate; bp. 200°-210° C. at 1 mm. pressure.
Reaction SMILES: [Br:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][C:3]=1[F:9].Cl[C:11]([O:13][CH3:14])=[O:12]>>[CH3:14][O:13][C:11](=[O:12])[NH:6][C:5]1[CH:7]=[CH:8][C:2]([Br:1])=[C:3]([F:9])[CH:4]=1
Reactant: COC(=O)Cl
Reactant: Nc1ccc(Br)c(F)c1
Product: COC(=O)Nc1ccc(Br)c(F)c1

Procedure:
The title compound, m.p. 121-122° C., was prepared in accordance with the general method of example 81a) from 4-bromo-3-fluoroaniline and methyl chloroformate.
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([C:14]3[O:15][C:16]4[CH:22]=[CH:21][CH:20]=[CH:19][C:17]=4[N:18]=3)=[CH:10][C:9]=2[O:23][CH3:24])[CH:5]=[CH:4][CH:3]=1.[CH3:25]OC1C=C(C2OC3C=CC=CC=3N=2)C=CC=1B1OC(C)(C)C(C)(C)O1.BrC1C=CC=C(C)N=1>>[CH3:24][O:23][C:9]1[CH:10]=[C:11]([C:14]2[O:15][C:16]3[CH:22]=[CH:21][CH:20]=[CH:19][C:17]=3[N:18]=2)[CH:12]=[CH:13][C:8]=1[C:6]1[CH:5]=[CH:4][CH:3]=[C:2]([CH3:25])[N:7]=1
Reactant: COc1cc(-c2nc3ccccc3o2)ccc1-c1cccc(Br)n1
Reactant: COc1cc(-c2nc3ccccc3o2)ccc1B1OC(C)(C)C(C)(C)O1
Agent: Cc1cccc(Br)n1
Product: COc1cc(-c2nc3ccccc3o2)ccc1-c1cccc(C)n1

Procedure:
Utilizing the general procedure outlined in the synthesis of 2-[4-(6-bromopyridin-2-yl)-3-methoxyphenyl]-1,3-benzoxazole, 2-[3-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-1,3-benzoxazole (200 mg, 0.57 mmol) was reacted with 2-bromo-6-methylpyridine (65 μL, 0.57 mmol) to afford the desired 2-[3-methoxy-4-(6-methylpyridin-2-yl)phenyl]-1,3-benzoxazole as a colorless solid: 1H NMR (CDCl3, 300 MHz) δ 7.96–7.95 (m, 2H), 7.89 (s, 1H), 7.82–7.79 (m, 1H), 7.67–7.60 (m, 3H), 7.39–7.36 (m, 2H), 7.14–7.12 (m, 1H), 4.00 (s, 3H), 2.65 (s, 3H). MS (ESI) 317 (M+H)+.
Reaction SMILES: ClCCl.[F:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]#[C:12][CH2:13][CH2:14][OH:15])=[CH:7][CH:6]=1.[CH3:16][S:17](Cl)(=[O:19])=[O:18]>C(N(CC)CC)C>[F:4][C:5]1[CH:6]=[CH:7][C:8]([C:11]#[C:12][CH2:13][CH2:14][O:15][S:17]([CH3:16])(=[O:19])=[O:18])=[CH:9][CH:10]=1
Reactant: OCCC#Cc1ccc(F)cc1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)OCCC#Cc1ccc(F)cc1

Procedure:
To a mixture of 250 ml. of dichloromethane, 25 g. 4-(4-fluorophenyl)-3-butyn-1-ol and 16.7 g. of triethylamine cooled in an ice-salt bath to -10° C. is added dropwise, over 15 minutes, 18.9 g. of methanesulfonyl chloride. The mixture is cooled at -10° C. to -15° C. for 30 minutes and then washed with 300 ml. each of cold water, 10% hydrochloric acid, sodium carbonate solution and with saturated sodium chloride solution. The organic layer is dried with magnesium sulfate and concentrated in vacuo to give a pale yellow oil.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][CH:3]=1.N([O-])=O.[Na+].[N-:13]=[N+:14]=[N-].[Na+]>Cl.O>[N:1]([C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][CH:3]=1)=[N+:13]=[N-:14]
Reactant: Cc1ccc(N)cc1
Reactant: [N-]=[N+]=[N-]
Agent: Cl
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Product: Cc1ccc(N=[N+]=[N-])cc1
Reaction time: 0.33 h

Procedure:
p-Toluidine (9.3 mM) was dissolved in hydrochloric acid (5M; 10 ml), and the mixture cooled to <0° C. Sodium nitrite (10.28 mM) was dissolved in a minimum amount of water, and this solution was added dropwise to the reaction over 30 minutes. The solution was stirred for 20 minutes, then the presence of the oxidising agent was tested for using starch/iodide paper. Sodium azide (37.38 mM) was then added slowly to the reaction mixture over a period of 1 hour (due to vigorous effervescing). The reaction was quenched, once all the sodium azide had been added, in water (50 ml), and quantitatively transferred to a conical flask with water (50 ml). The mixture was neutralised with sodium carbonate, until pH=6. The organics were extracted into dichloromethane (3×30 ml), washed with water (2×20 ml), dried over magnesium sulphate, and excess solvent removed under vacuum. The p-azidotoluene thus obtained was an oil and was isolated via chromatography (100% petroleum/ether 40-60). 1H NMR: d6DMSO: δ: 2.37 (s; 3H; CH3); 7.0 (d;2H; H3 ;H5); 7.3 (d; 2H; H2 ; H6)
Reaction SMILES: [Cl:1][C:2]1[C:3]2[CH:10]=[C:9]([C:11]([O-:13])=O)[N:8]([CH3:14])[C:4]=2[N:5]=[CH:6][N:7]=1.[Li+].C(Cl)(=O)C(Cl)=O.[CH3:22][N:23](C=O)[CH3:24].N(C)C>C(Cl)Cl.C1COCC1>[Cl:1][C:2]1[C:3]2[CH:10]=[C:9]([C:11]([N:23]([CH3:24])[CH3:22])=[O:13])[N:8]([CH3:14])[C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: Cn1c(C(=O)[O-])cc2c(Cl)ncnc21
Reactant: CN(C)C=O
Agent: CNC
Agent: O=C(Cl)C(=O)Cl
Agent: [Li+]
Solvent: C1CCOC1
Solvent: ClCCl
Product: CN(C)C(=O)c1cc2c(Cl)ncnc2n1C
Temperature: 25 °C
Reaction time: 4 h
Yield: 58 %

Procedure:
A reaction mixture containing carboxylate 275 (78 mg, 0.36 mmo), oxalyl chloride (63 uL, 0.72 mmol), and a drop of DMF in DCM was stirred for 2 h. Solvents were removed under reduced pressure and the residue was re-dissolved in DCM (4 mL). To this solution Me2NH (360 μL, 0.72 mmol, 2M in THF) in THF was added and the mixture was stirred at room temperature for 4 h. The solvent was removed under reduced pressure and the residue was purified by flash column chromatography (eluent EtOAc) to afford the title compound 276 (50 mg, 58% yield) as a yellowish solid. MS (m/z): 239.1(M+H) (found).
Reaction SMILES: [Cl:1][C:2]1[C:7]([N:8]([CH3:23])[C:9](=[O:22])[CH2:10][N:11]2[C:15](=[O:16])[C:14]3=[CH:17][CH:18]=[CH:19][CH:20]=[C:13]3[C:12]2=[O:21])=[CH:6][CH:5]=[C:4]([Cl:24])[C:3]=1[CH2:25][OH:26].C(N(CC)CC)C.[CH3:34][S:35](Cl)(=[O:37])=[O:36]>C(Cl)Cl>[Cl:1][C:2]1[C:7]([N:8]([CH3:23])[C:9](=[O:22])[CH2:10][N:11]2[C:12](=[O:21])[C:13]3=[CH:20][CH:19]=[CH:18][CH:17]=[C:14]3[C:15]2=[O:16])=[CH:6][CH:5]=[C:4]([Cl:24])[C:3]=1[CH2:25][O:26][S:35]([CH3:34])(=[O:37])=[O:36]
Reactant: CS(=O)(=O)Cl
Reactant: CN(C(=O)CN1C(=O)c2ccccc2C1=O)c1ccc(Cl)c(CO)c1Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CN(C(=O)CN1C(=O)c2ccccc2C1=O)c1ccc(Cl)c(COS(C)(=O)=O)c1Cl
Reaction time: 1 h

Procedure:
To a mixture of 2,6-dichloro-1-hydroxymethyl-3-[N-methyl-N-(phthalimidoacetyl)amino]benzene (399 mg) and triethylamine (0.17 ml) in methylene chloride (8 ml) was added methanesulfonyl chloride (0.086 ml) under -20° C., and the mixture was stirred for 1 hour. The mixture was washed with sodium bicarbonate solution and brine, dried over magnesium sulfate and concentrated in vacuo to give 2,6-dichloro-1-methylsulfonyloxymethyl-3-[N-methyl-N-(phthalimidoacetyl)amino]benzene (561 mg)
Reaction SMILES: [NH2:1][CH2:2][CH:3]1[CH2:8][CH2:7][N:6]([C:9]2[C:14]([F:15])=[CH:13][N:12]=[C:11]([NH:16][C:17]3[CH:18]=[C:19]4[C:24](=[CH:25][CH:26]=3)[NH:23][C:22](=[O:27])[CH2:21][CH2:20]4)[N:10]=2)[CH2:5][CH2:4]1.[O-:28][C:29]#[N:30].[K+]>CC#N.O>[F:15][C:14]1[C:9]([N:6]2[CH2:7][CH2:8][CH:3]([CH2:2][NH:1][C:29]([NH2:30])=[O:28])[CH2:4][CH2:5]2)=[N:10][C:11]([NH:16][C:17]2[CH:18]=[C:19]3[C:24](=[CH:25][CH:26]=2)[NH:23][C:22](=[O:27])[CH2:21][CH2:20]3)=[N:12][CH:13]=1
Reactant: N#C[O-]
Reactant: NCC1CCN(c2nc(Nc3ccc4c(c3)CCC(=O)N4)ncc2F)CC1
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: NC(=O)NCC1CCN(c2nc(Nc3ccc4c(c3)CCC(=O)N4)ncc2F)CC1
Temperature: 70 °C
Reaction time: 1 h
Yield: 27.6 %

Procedure:
To a suspension of 6-(4-(4-(aminomethyl)piperidin-1-yl)-5-fluoropyrimidin-2-ylamino)-3,4-dihydroquinolin-2(1H)-one (26 mg, 0.070 mmol) in CH3CN (1 mL), an aqueous solution of potassium cyanate (34 mg, 0.42 mmol) in H2O (1 mL) was added. The mixture was stirred at 70° C. for 1 h. Solvents were removed in vacuo. The residue was purified by HPLC to give the titled compound (8 mg). MS 414.3 (M+H);); UV 205.8, 276.8 nm
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]2[N:9]=[C:10]([NH:12][C:13](=[O:22])[C:14]3[CH:19]=[CH:18][N:17]=[C:16]([CH:20]=[CH2:21])[CH:15]=3)[S:11][C:7]=2[C:6]([CH:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)=[CH:5][CH:4]=1>CO.ClCCl.[Pd]>[CH2:20]([C:16]1[CH:15]=[C:14]([CH:19]=[CH:18][N:17]=1)[C:13]([NH:12][C:10]1[S:11][C:7]2[C:6]([CH:23]3[CH2:24][CH2:25][O:26][CH2:27][CH2:28]3)=[CH:5][CH:4]=[C:3]([O:2][CH3:1])[C:8]=2[N:9]=1)=[O:22])[CH3:21]
Reactant: C=Cc1cc(C(=O)Nc2nc3c(OC)ccc(C4CCOCC4)c3s2)ccn1
Agent: [Pd]
Solvent: ClCCl
Solvent: CO
Product: CCc1cc(C(=O)Nc2nc3c(OC)ccc(C4CCOCC4)c3s2)ccn1
Temperature: 25 °C
Reaction time: 16 h
Yield: 87.5 %

Procedure:
To a stirred solution of 90 mg (0.23 mmol) N-[4-methoxy-7-(tetrahydro-pyran-4-yl)-benzothiazol-2-yl]-2-vinyl-isonicotinamide in 10 ml methanol and 10 ml dichloromethane was added a spatula end of 10% palladium on charcoal and the mixture was then stirred for 16 h at room temperature under an atmosphere of hydrogen. The mixture was then filtered, washing with dichloromethane, and the filtrate concentrated in vacuo and triturated in ether to afford 80 mg (88%) 2-ethyl-N-[4-methoxy-7-(tetrahydro-pyran-4-yl)-benzothiazol-2-yl]-isonicotinamide as a yellow solid. ES-MS m/e (%): 398 (M+H+, 100).
Reaction SMILES: [BH3-]C#N.[Na+].[NH2:5][CH2:6][CH:7]1[CH2:16][CH2:15][CH2:14][C:13]2[C:12]([O:17][C:18]3[CH:26]=[CH:25][C:21]([C:22]([NH2:24])=[O:23])=[CH:20][N:19]=3)=[CH:11][CH:10]=[CH:9][C:8]1=2.[C:27]1(=O)[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]1>CC(O)=O.CO>[CH:27]1([NH:5][CH2:6][CH:7]2[CH2:16][CH2:15][CH2:14][C:13]3[C:12]([O:17][C:18]4[CH:26]=[CH:25][C:21]([C:22]([NH2:24])=[O:23])=[CH:20][N:19]=4)=[CH:11][CH:10]=[CH:9][C:8]2=3)[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]1
Reactant: NCC1CCCc2c(Oc3ccc(C(N)=O)cn3)cccc21
Reactant: O=C1CCCCC1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: NC(=O)c1ccc(Oc2cccc3c2CCCC3CNC2CCCCC2)nc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 76.4 %

Procedure:
Add NaBH3CN (63 mg, 1.00 mmol) to a solution of 6-(5-aminomethyl-5,6,7,8-tetrahydro-naphthalen-1-yloxy)-nicotinamide (intermediate 20, 148 mg, 0.500 mmol) and cyclohexanone (98 mg, 1.00 mmol) dissolved in 5% AcOH/MeOH (5 ml) and stir at ambient temperature for 16 hours. Concentrate the reaction mixture and redissolved in EtOAc. Wash the EtOAc solution with 5% aq. KOH and brine before drying (MgSO4) and concentrating. Purify on silica gel (5% (1N NH3/MeOH)/DCM) to obtain 145 mg of the title compound as a white foam. Mass spectrum (ion spray): m/z=380 (M+1); 1HNMR (CDCl3): 8.56 (s, 1H), 8.15 (d, 1H), 7.22-7.14 (m, 2H), 6.90 (m, 2H), 5.79 (br. s, 2H), 2.99 (m, 1H), 2.96-2.79 (m, 2H), 2.63-2.41 (m, 3H), 1.91 (m, 2H), 1.85-1.67 (m, 6H), 1.31-1.04 (m, 6H).
Reaction SMILES: [Na].O=[C:3]([CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])[C:4]([O:6][CH2:7][CH3:8])=[O:5].[Br:15][C:16]1[CH:27]=[CH:26][C:19]2[C:20](=O)[O:21]C(=O)[NH:23][C:18]=2[CH:17]=1>CN(C)C=O>[Br:15][C:16]1[CH:17]=[C:18]2[C:19]([C:20]([OH:21])=[C:9]([C:10]([O:12][CH2:13][CH3:14])=[O:11])[C:3]([C:4]([O:6][CH2:7][CH3:8])=[O:5])=[N:23]2)=[CH:26][CH:27]=1
Reactant: O=c1[nH]c2cc(Br)ccc2c(=O)o1
Reactant: CCOC(=O)CC(=O)C(=O)OCC
Agent: [Na]
Solvent: CN(C)C=O
Product: CCOC(=O)c1nc2cc(Br)ccc2c(O)c1C(=O)OCC
Temperature: 130 °C
Yield: 23.7 %

Procedure:
To a stirred mixture of diethyl oxosuccinate sodium salt (1.31 g, 6.23 mM) in dimethylformamide (DMF, 15 mL) under a nitrogen atmosphere was added a solution of 7-bromo-2H-3,1-benzoxazine-2,4(1H)-dione (1.50 g, 6.20 mM) in DMF (15 mL). The resulting reaction mixture was heated to 130° C. over 2.5 hr and then refluxed for 5 hr. After cooling to room temperature, the reaction mixture was concentrated and the residue was chromatographed over silica gel (eluant: ethyl acetate/methylene chloride; 5/95). The fractions containing the desired material were combined and concentrated. The solid residue was recrystallized from ethanol/ether to provide (0.54 g, 24%) the title compound as a tan solid, mp 233.5°-234.5° C.; MS(CI): 368, 369 (M+H).