Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl-].[Cl-].[CH2:3]([Al+2])[CH3:4].[CH2:6](Cl)Cl.[CH2:9]([C:13]([OH:25])([CH2:21][CH2:22][CH2:23][CH3:24])[C@@H](OS(C)(=O)=O)C)[CH2:10][CH2:11]C>P(=O)(O)(O)O.C(OCC)(=O)C>[CH3:6][C@@H:9]([CH2:10][CH2:11][CH2:3][CH3:4])[C:13](=[O:25])[CH2:21][CH2:22][CH2:23][CH3:24]
Reactant: CC[Al+2]
Reactant: ClCCl
Reactant: CCCCC(O)(CCCC)[C@H](C)OS(C)(=O)=O
Agent: O=P(O)(O)O
Agent: [Cl-]
Solvent: CCOC(C)=O
Product: CCCCC(=O)[C@@H](C)CCCC
Temperature: 0 °C
Yield: 87 %

Procedure:
After 0.95 ml (0.95 mmol) of ethylaluminum dichloride (hexane 1M solution) were added to a dried methylene chloride (3 ml) solution of 101.5 mg (0.38 mmol) of (S)-3-butyl-2-methanesulfonyloxy-3-heptanol (unrefined) at -78° C. under stirring, and stirred for two and a half hours at -78° C., the temperature was raised to 0° C. over an hour and a half. The reaction was stopped with three drops of phosphoric acid buffer solution (pH 7). The resultant suspension was diluted with ethyl acetate, dried with anhydrous sodium sulfate, filtered and concentrated. The oily residue was separated and refined by the use of silica gel column chromatography (hexane/ethyl acetate=35/1) to obtain (S)-6-methyl-5-decanone as a pale yellow oily substance (56.3 mg, yield 87%).
Reaction SMILES: [NH2:1][CH2:2][C@H:3]1[C@H:9]([C:10]2[CH:15]=[CH:14][C:13]([Cl:16])=[C:12]([F:17])[CH:11]=2)[O:8][CH2:7][CH2:6][N:5](C(OC(C)(C)C)=O)[CH2:4]1.[N:25]1[CH:30]=[CH:29][CH:28]=[N:27][C:26]=1[O:31][CH2:32][C:33](O)=[O:34]>>[ClH:16].[Cl:16][C:13]1[CH:14]=[CH:15][C:10]([C@@H:9]2[O:8][CH2:7][CH2:6][NH:5][CH2:4][C@H:3]2[CH2:2][NH:1][C:33](=[O:34])[CH2:32][O:31][C:26]2[N:27]=[CH:28][CH:29]=[CH:30][N:25]=2)=[CH:11][C:12]=1[F:17]
Reactant: CC(C)(C)OC(=O)N1CCO[C@@H](c2ccc(Cl)c(F)c2)[C@H](CN)C1
Reactant: O=C(O)COc1ncccn1
Product: Cl
Product: O=C(COc1ncccn1)NC[C@@H]1CNCCO[C@H]1c1ccc(Cl)c(F)c1

Procedure:
Using tert-butyl (6R,7R)-6-(aminomethyl)-7-(4-chloro-3-fluorophenyl)-1,4-oxazepane-4-carboxylate and (pyrimidin-2-yloxy)acetic acid, and by a method similar to that of Example 39, the title compound was obtained.
Reaction SMILES: [C:1]1([CH2:7][C:8]([OH:10])=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C[NH3+].F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C.[CH2:51]([O:53][C:54]([C:56]1[CH:57]=[C:58]2[C:63](=[CH:64][CH:65]=1)[NH:62][CH:61]([C:66]1[CH:71]=[CH:70][CH:69]=[C:68]([NH2:72])[CH:67]=1)[C:60]([CH3:74])([CH3:73])[CH2:59]2)=[O:55])[CH3:52]>ClCCl>[CH2:51]([O:53][C:54]([C:56]1[CH:57]=[C:58]2[C:63](=[CH:64][CH:65]=1)[NH:62][CH:61]([C:66]1[CH:71]=[CH:70][CH:69]=[C:68]([NH:72][C:8](=[O:10])[CH2:7][C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[CH:67]=1)[C:60]([CH3:73])([CH3:74])[CH2:59]2)=[O:55])[CH3:52]
Reactant: O=C(O)Cc1ccccc1
Reactant: CCOC(=O)c1ccc2c(c1)CC(C)(C)C(c1cccc(N)c1)N2
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: C[NH3+]
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)c1ccc2c(c1)CC(C)(C)C(c1cccc(NC(=O)Cc3ccccc3)c1)N2
Temperature: 25 °C
Reaction time: 8 h
Yield: 98.4 %

Procedure:
To a stirred solution of phenylacetic acid (850 mg, 6.2 mmol), 2-(1H-7-Azabenzotriazol-1-yl)-1,1,3,3-tetramethyl uronium hexafluorophosphate Methanaminium (HATU) (3.5 g, 9.3 mmol) and triethyl amine (2.6 mL, 18.6 mmol) in dichloromethane (20 mL) was added 2-(3-amino-phenyl)-3,3-dimethyl-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid ethyl ester (2.0 g, 6.2 mmol) at room temperature and stirred at room temperature for overnight. Then the reaction mixture was concentrated in vacuo and the residue was extracted with ethyl acetate (2×200 mL), washed with brine, dried over anhydrous sodium sulfate and concentrated in vacuo to afford 3,3-dimethyl-2-(3-phenylacetylamino-phenyl)-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid ethyl ester (2.7 g, quant.) as a light yellow solid which was used for next step without further purification: LC/MS m/e calcd for C28H30N2O3 (M+H)+: 443.56, observed: 443.1.
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:14]=[C:13]2[C:9]([C:10]([C:24](=[O:35])[NH:25][CH2:26][C:27]3[CH:32]=[CH:31][C:30]([F:33])=[C:29]([F:34])[CH:28]=3)=[C:11]([CH:21]([CH3:23])[CH3:22])[N:12]2[CH2:15][C:16]2[O:17][CH:18]=[CH:19][N:20]=2)=[CH:8][CH:7]=1)=[O:5])C.[OH-].[Na+].O>CCO>[F:34][C:29]1[CH:28]=[C:27]([CH:32]=[CH:31][C:30]=1[F:33])[CH2:26][NH:25][C:24]([C:10]1[C:9]2[C:13](=[CH:14][C:6]([C:4]([OH:5])=[O:3])=[CH:7][CH:8]=2)[N:12]([CH2:15][C:16]2[O:17][CH:18]=[CH:19][N:20]=2)[C:11]=1[CH:21]([CH3:23])[CH3:22])=[O:35]
Reactant: CCOC(=O)c1ccc2c(C(=O)NCc3ccc(F)c(F)c3)c(C(C)C)n(Cc3ncco3)c2c1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CC(C)c1c(C(=O)NCc2ccc(F)c(F)c2)c2ccc(C(=O)O)cc2n1Cc1ncco1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
Following General Procedure F, ethyl3-(3,4-difluorobenzylcarbamoyl)-2-isopropyl-1-(oxazol-2-ylmethyl)-1H-indole-6-carboxylate (Compound 47, 197 mg, 0.414 mmol) in EtOH (12 ml) was added NaOH (82 mg, 2.07 mmol) and H2O (1 ml). The reaction was stirred at 25° C. for 12 h, concentrated in vacuo to an oil then acidified to PH=5 with 10% HCl, diluted with EtOAc, washed organic with H2O, brine, dried over Na2SO4 and concentrated in vacuo to yield the title compound as a white solid.
Reaction SMILES: Cl.Cl.[NH2:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:15]=[CH:14][C:13]([NH:16][C:17]([C@@H:19]3[CH:24]4[CH2:25][CH2:26][N:21]([CH2:22][CH2:23]4)[CH2:20]3)=[O:18])=[CH:12][CH:11]=2)=[CH:6][CH:5]=1.[C:27]1([CH2:33][S:34]([Cl:37])(=[O:36])=[O:35])[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>N1C=CC=CC=1>[ClH:37].[CH2:33]([S:34]([NH:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:11]=[CH:12][C:13]([NH:16][C:17]([C@@H:19]3[CH:24]4[CH2:23][CH2:22][N:21]([CH2:26][CH2:25]4)[CH2:20]3)=[O:18])=[CH:14][CH:15]=2)=[CH:6][CH:5]=1)(=[O:36])=[O:35])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: O=S(=O)(Cl)Cc1ccccc1
Reactant: Nc1ccc(-c2ccc(NC(=O)[C@H]3CN4CCC3CC4)cc2)cc1
Agent: Cl
Solvent: c1ccncc1
Product: O=C(Nc1ccc(-c2ccc(NS(=O)(=O)Cc3ccccc3)cc2)cc1)[C@H]1CN2CCC1CC2

Procedure:
A solution of 80 mg (0.20 mmol) of ((3R)—N-(4′-aminobiphenyl-4-yl)quinuclidine-3-carboxamide dihydrochloride (Example 7A) and 77.4 mg (0.41 mmol) of phenylmethanesulfonyl chloride in 1.0 ml of pyridine is stirred at room temperature for 18 h. The reaction mixture is concentrated in vacuo and the residue is purified by preparative HPLC. The product fractions are concentrated, mixed with 3 ml of 1 N hydrochloric acid, again concentrated and dried under high vacuum. 34 mg (32.7% of theory) of the title compound are obtained.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C@H:9]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[CH3:26])[CH2:10][C:11]([C:13]2[CH:18]=[CH:17][N:16]=[C:15]([CH3:19])[CH:14]=2)=[O:12])=[CH:5][CH:4]=1)#[CH:2].I[CH3:28].[N-:29]=[N+:30]=[N-:31].[Na+]>C(OCC)(=O)C.O.[Cu]>[CH3:19][C:15]1[CH:14]=[C:13]([C:11](=[O:12])[CH2:10][CH:9]([C:6]2[CH:5]=[CH:4][C:3]([C:1]3[N:29]=[N:30][N:31]([CH3:28])[CH:2]=3)=[CH:8][CH:7]=2)[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[CH3:26])[CH:18]=[CH:17][N:16]=1
Reactant: [N-]=[N+]=[N-]
Reactant: CI
Reactant: C#Cc1ccc([C@@H](CC(=O)c2ccnc(C)c2)c2ccccc2C)cc1
Agent: [Cu]
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Product: Cc1cc(C(=O)CC(c2ccc(-c3cn(C)nn3)cc2)c2ccccc2C)ccn1

Procedure:
Synthesis conducted in flow using a FlowSyn (Uniqsis) flow system equipped with a home-made copper coil reactor, a standard T-piece mixer and 250 psi back-pressure regulator: A stream of a solution containing (−)-3-(4-ethynyl-phenyl)-1-(2-methyl-pyridin-4-yl)-3-o-tolyl-propan-1-one (150 mg in 5 mL, c=0.088 mol/L; example 287, step 2) and iodomethane (125 mg in 5 mL, c=0.177 mol/L) in ethyl acetate was combined with a second stream of sodium azide (58 mg in 5 mL, c=0.177 mol/L) in water and directed through a copper coil (volume=21 mL) at 150° C. Both channels were running at a flow rate of 0.4 mL/min, which equals to a residence time of 26 min. The product stream was collected in a 25% solution of ammonium hydroxide and extracted with ethyl acetate (3×50 mL). The combined organic phases were dried over sodium sulfate and the crude reaction product purified by silica gel chromatography using a MPLC system (CombiFlash Companion, Isco Inc.) eluting with a gradient of n-heptane/ethyl acetate (1:1 to 2:1) to provide the title compound as a colorless solid. MS (ESI+): m/z=397.3 ([M+H]+).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]([C:11]2[CH:12]=[C:13]([NH:17][S:18]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)(=[O:20])=[O:19])[CH:14]=[N:15][CH:16]=2)[CH:8]=[C:7]2[C:3]=1[CH:4]=[N:5][N:6]2S(C1C=CC=CC=1)(=O)=O.N1C=CC=CC=1.[CH3:42][C:43]1[S:44][CH:45]=[C:46]([C:48](Cl)=[O:49])[N:47]=1>C(Cl)Cl>[CH3:42][C:43]1[S:44][CH:45]=[C:46]([C:48]([NH:1][C:2]2[CH:10]=[C:9]([C:11]3[CH:16]=[N:15][CH:14]=[C:13]([NH:17][S:18]([C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)(=[O:20])=[O:19])[CH:12]=3)[CH:8]=[C:7]3[C:3]=2[CH:4]=[N:5][NH:6]3)=[O:49])[N:47]=1
Reactant: Cc1nc(C(=O)Cl)cs1
Reactant: Nc1cc(-c2cncc(NS(=O)(=O)c3ccccc3)c2)cc2c1cnn2S(=O)(=O)c1ccccc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: Cc1nc(C(=O)Nc2cc(-c3cncc(NS(=O)(=O)c4ccccc4)c3)cc3[nH]ncc23)cs1
Temperature: 25 °C
Reaction time: 18 h
Yield: 22.7 %

Procedure:
N-{5-[4-Amino-1-(phenylsulfonyl)-1H-indazol-6-yl]-3-pyridinyl}benzenesulfonamide (100 mg) was dissolved in DCM (5 ml) and pyridine (0.024 ml) was added. The reaction was stirred at RT for 2 min before 2-methyl-1,3-thiazole-4-carbonyl chloride (35 mg) was added. The reaction was stirred at RT for 18 h. Further 2-methyl-1,3-thiazole-4-carbonyl chloride (10 mg) was added and stirring continued for 2 h at RT. Further 2-methyl-1,3-thiazole-4-carbonyl chloride (35 mg) was added and the reaction stirred at RT for 18 h before being quenched with water. DCM was added and the reaction was passed through a hydrophobic frit and evaporated to dryness. The residue was dissolved in DMSO:MeOH (1:1, v/v, 1 ml) and purified by MDAP (method E). The desired dried intermediate was dissolved in MeOH and 2M NaOH (1 ml) was added. The reaction was stirred at RT for 30 min. The reaction was neutralised with 2M HCl (aq) then evaporated to dryness. The residue was dissolved in MeOH and loaded onto a SCX-2 SPE cartridge pre-conditioned with MeOH. After eluting with MeOH then 10% NH3 in MeOH, the basic fraction was evaporated to dryness to give the title compound (22 mg).
Reaction SMILES: [O:1]=[C:2]1[N:6]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH:5]2[CH:14]=[CH:15][CH2:16][CH:4]2[CH2:3]1.C(O[CH:22](N(C)C)[N:23]([CH3:25])[CH3:24])(C)(C)C.O>C1(C)C=CC=CC=1.C(OCC)(=O)C>[C:10]([O:9][C:7]([N:6]1[C:2](=[O:1])[C:3](=[CH:22][N:23]([CH3:25])[CH3:24])[CH:4]2[CH2:16][CH:15]=[CH:14][CH:5]12)=[O:8])([CH3:12])([CH3:13])[CH3:11]
Reactant: CC(C)(C)OC(=O)N1C(=O)CC2CC=CC21
Reactant: CN(C)C(OC(C)(C)C)N(C)C
Solvent: CCOC(C)=O
Solvent: O
Solvent: Cc1ccccc1
Product: CN(C)C=C1C(=O)N(C(=O)OC(C)(C)C)C2C=CCC12
Temperature: 110 °C
Yield: 58 %

Procedure:
To a solution of tert-butyl 2-oxo-3,3a,4,6a-tetrahydrocyclopenta[b]pyrrole-1-carboxylate IV-1 (500 mg, 2.23 mmol) in toluene (11 mL) was added tert-butoxybis(dimethylamino)methane (1.39 mL, 6.71 mmol) The solution was heated for 2 h at 110° C. It was then cooled to room temperature, poured into water (20 mL), diluted with ethyl acetate (20 mL), and extracted 3 times. The combined organic layers were washed with brine, dried, concentrated and purified by flash chromatography (5% MeOH in CH2Cl2) giving the desired compound as a brown solid (367 mg, 58%); 1H NMR (400 MHz, CDCl3) 7.12 (1H, s), 5.99 (1H, m), 5.85 (1H, m), 4.91 (1H, d), 3.70 (1H, m), 3.03 (6H, s), 2.79 (1H, m), 2.40 (1H, dd), 1.54 (9H, s); LCMS (Method A): 0.83 min; ES+279 (M+H+).
Reaction SMILES: [CH3:1][C:2]1[C:3]2[N:4]([C:8]([CH:11]3[CH2:16][CH2:15][N:14]([CH:17]4[CH2:22][CH2:21][O:20][CH2:19][CH2:18]4)[CH2:13][CH2:12]3)=[N:9][CH:10]=2)[CH:5]=[CH:6][N:7]=1.C(O)(=O)C.[Br:27]Br.O>ClCCl>[Br:27][C:10]1[N:9]=[C:8]([CH:11]2[CH2:12][CH2:13][N:14]([CH:17]3[CH2:22][CH2:21][O:20][CH2:19][CH2:18]3)[CH2:15][CH2:16]2)[N:4]2[CH:5]=[CH:6][N:7]=[C:2]([CH3:1])[C:3]=12
Reactant: BrBr
Reactant: Cc1nccn2c(C3CCN(C4CCOCC4)CC3)ncc12
Solvent: CC(=O)O
Solvent: ClCCl
Solvent: O
Product: Cc1nccn2c(C3CCN(C4CCOCC4)CC3)nc(Br)c12
Yield: 76.6 %

Procedure:
8-Methyl-3-(1-(tetrahydro-2H-pyran-4-yl)piperidin-4-yl)imidazo[1,5-a]pyrazine (0.303 mmol, 91 mg) was dissolved in dichloromethane (2 ml) and acetic acid (30.3 mmol, 1.734 ml). With stirring, bromine (0.303 mmol, 0.016 ml) in dichloromethane (0.2 mL) was added. After stirring at room temperature for one hour water was added and the mixture concentrated in vacuo. To the residue was added saturated aqueous sodium hydrogencarbonate and the mixture extracted twice with dichloromethane/methanol. The combined organic layers were concentrated in vacuo to yield 1-bromo-8-methyl-3-(1-(tetrahydro-2H-pyran-4-yl)piperidin-4-yl)imidazo[1,5-a]pyrazine (88 mg).
Reaction SMILES: C(O[C:6]1[C:7](=[O:17])[C:8](=[O:16])[C:9]=1[NH:10][C:11]([CH3:15])([CH3:14])[CH2:12][CH3:13])CCC.[NH2:18][CH2:19][C:20]1[CH:25]=[CH:24][N:23]=[CH:22][CH:21]=1>O1CCCC1>[CH3:15][C:11]([NH:10][C:9]1[C:8](=[O:16])[C:7](=[O:17])[C:6]=1[NH:18][CH2:19][C:20]1[CH:25]=[CH:24][N:23]=[CH:22][CH:21]=1)([CH3:14])[CH2:12][CH3:13]
Reactant: CCCCOc1c(NC(C)(C)CC)c(=O)c1=O
Reactant: NCc1ccncc1
Solvent: C1CCOC1
Product: CCC(C)(C)Nc1c(NCc2ccncc2)c(=O)c1=O
Yield: 60.9 %

Procedure:
A solution of the above 3-butoxy-4-(1,1-dimethylpropylamino)-cyclobut-3-ene-1,2-dione (1.197 g, 5.0 mmol) and 4-aminomethylpyridine (0.541 g) in tetrahydrofuran (10 mL) was stirred at room temperature for 23 hours. The mixture was freed of solvent and the residue was triturated with diethyl ether and dried to provide 1.154 g of a buff solid. Recrystallization (twice) of the crude product from methanol gave 0.832 g (61%) of 3-(1,1-dimethylpropylamino)-4-[(pyridin-4-ylmethyl)-amino]cyclobut-3-ene-1,2-dione as a white compound: mp 258.0°-259.5° C. dec (softens 257.5° C.); 1H NMR (DMSO-d6): δ 8.56 (m, 2H), 7.86 (m, br, 1H), 7.46 (s, br, 1H), 7.32 (m, 2H), 4.77 (d, 2H), 1.67 (q, 2H), 1.32 (s, 6H), 0.83 (t, 3H). IR (KBr): 3270, 1790, 1650 cm-1 ; MS (m/z) 273 (M+).
Reaction SMILES: [Cl:1][C:2]1[CH:24]=[C:23]([C:25]([NH:27][CH2:28][C:29]2[CH:34]=[C:33]([OH:35])[CH:32]=[C:31]([OH:36])[CH:30]=2)=[O:26])[CH:22]=[CH:21][C:3]=1[C:4]([NH:6][C@H:7]([C:17]([O:19]C)=[O:18])[CH2:8][NH:9][C:10]([C:12]1[S:13][CH:14]=[CH:15][CH:16]=1)=[O:11])=[O:5].O.[OH-].[Li+].O>O1CCCC1.CO>[Cl:1][C:2]1[CH:24]=[C:23]([C:25]([NH:27][CH2:28][C:29]2[CH:34]=[C:33]([OH:35])[CH:32]=[C:31]([OH:36])[CH:30]=2)=[O:26])[CH:22]=[CH:21][C:3]=1[C:4]([NH:6][C@H:7]([C:17]([OH:19])=[O:18])[CH2:8][NH:9][C:10]([C:12]1[S:13][CH:14]=[CH:15][CH:16]=1)=[O:11])=[O:5]
Reactant: COC(=O)[C@H](CNC(=O)c1cccs1)NC(=O)c1ccc(C(=O)NCc2cc(O)cc(O)c2)cc1Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: O=C(NCc1cc(O)cc(O)c1)c1ccc(C(=O)N[C@@H](CNC(=O)c2cccs2)C(=O)O)c(Cl)c1
Yield: 8.7 %

Procedure:
A solution of N-[2-chloro-4-[[[(3,5-dihydroxyphenyl)methyl]amino]carbonyl]benzoyl]-3-[thiophene-2-carbonyl]amino-L-alanine, methyl ester (250 mg, 0.47 mmol), and lithium hydroxide monohydrate (200 mg, 4.8 mmol) in tetrahydrofuran (30 mL), methanol (10 mL), and water (10 mL) was stirred at room temperature overnight. The solution was concentrated to remove methanol and tetrahydrofuran, and then water (50 mL) and 1 M HCl (20 mL) were added. The mixture was extracted with ethyl acetate (2×30 mL), and the solvent was evaporated from the extracts. The residue was dissolved in methanol (30 mL) and 10 mL of this solution was purified by HPLC to give N-[2-chloro-4-[[[(3,5-dihydroxyphenyl)methyl]amino]carbonyl]benzoyl]-3-[thiophene-2-carbonyl]amino-L-alanine (21.2 mg, 26%) as an off-white solid.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]([I:11])[CH:8]=[CH:7][C:3]=1[C:4](O)=[O:5].CC[N:14]=C=NCCCN(C)C.ON1C2C=CC=CC=2N=N1.CCN(C(C)C)C(C)C.N>CN(C=O)C.O>[NH2:1][C:2]1[CH:10]=[C:9]([I:11])[CH:8]=[CH:7][C:3]=1[C:4]([NH2:14])=[O:5]
Reactant: CCN=C=NCCCN(C)C
Reactant: Nc1cc(I)ccc1C(=O)O
Agent: N
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: NC(=O)c1ccc(I)cc1N
Temperature: 25 °C
Reaction time: 8 h
Yield: 52.2 %

Procedure:
To a solution of 2-amino-4-iodobenzoic acid (2.5 g, 9.50 mmol) in DMF (10 mL) at rt under argon were added EDCI (2.18 g, 11.40 mmol), 1-hydroxybenzotriazole (1.54 g, 11.40 mmol), DIEA (1.98 mL, 11.40 mmol), and ammonia (7.0 N solution in MeOH; 1.90 mL, 13.30 mmol). The dark solution was stirred at rt overnight and diluted with H2O until precipitate formed. The precipitate was separated by filtration, washed with H2O, and dried under high vacuum for several hours to afford 2-amino-4-iodobenzamide as a tan solid (1.3 g, 52%). LC-MS (ESI) m/z 263 (M+H)+.
Reaction SMILES: [N:1]1([CH:10]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)C(C2C=CC=CC=2)=O)[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2N=N1.[CH:25]([NH2:27])=O>>[C:19]1([C:10]2[N:27]=[C:25]([C:4]3[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=3)[C:4]3[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=3)[N:1]=2)[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: NC=O
Reactant: O=C(c1ccccc1)C(c1ccccc1)n1nnc2ccccc21
Product: c1ccc(-c2nc(-c3ccccc3)c3ccccc3n2)cc1
Yield: 50 %

Procedure:
The conversion of benzotriazene derivatives into 4-phenyl quinazolines, such as the transformation of 1,2-diaryl-2-(benzotriazol-1-yl)enamines prepared from lithiated (α-arylbenzotriazol-1-yl)methane and nitriles to afford 2,4-arylquinazolines, and the reaction between 2-(benzotriazol-1-yl)-1,2-diphenylethanone and formamide at 150° C. to afford 50% of 2,4-diphenylquinazoline [41]; and
Reaction SMILES: [Cl:1][C:2]1[CH:20]=[CH:19][C:5]([CH2:6][NH:7][C:8]2[CH:13]=[C:12]([CH3:14])[N:11]=[C:10]([S:15][CH2:16][C:17]#[N:18])[N:9]=2)=[CH:4][CH:3]=1.Cl.[NH2:22][OH:23].C(=O)([O-])[O-].[Na+].[Na+].Cl>CN(C)C=O.C(O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][NH:7][C:8]2[CH:13]=[C:12]([CH3:14])[N:11]=[C:10]([S:15][CH2:16][C:17](=[N:22][OH:23])[NH2:18])[N:9]=2)=[CH:19][CH:20]=1
Reactant: Cc1cc(NCc2ccc(Cl)cc2)nc(SCC#N)n1
Reactant: NO
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCO
Product: Cc1cc(NCc2ccc(Cl)cc2)nc(SCC(N)=NO)n1

Procedure:
A mixture of 10.6g. (0.035 mole) of [4-(p-chlorobenzylamino)-6-methyl-2-pyrimidinylthio]acetonitrile, 4.83 g. (0.07 mole) of hydroxylamine hydrochloride and 14.7 g. (0.14 mole) of sodium carbonate in 100 ml of N,N-dimethylformamide was heated on a steam bath for 3 hours. The mixture was filtered and the filtrate evaporated in a rotary-evaporator. The residue was triturated with petroleum ether containing a little ethyl acetate. The solid which crystallized was collected and recrystallized from ethyl acetate to give pure free base, m.p. 113°-116°. This free base was dissolved in absolute ethanol and acidified with an ethereal hydrochloric acid solution to give 3.5 g. of product, as the dihydrochloric salt, m.p. 230°-232° d.
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([CH2:6][CH2:7][CH2:8]Cl)[N:3]=[CH:2]1.[C:10]1([CH2:16][CH2:17][CH2:18][SH:19])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.[Na]>C(O)C>[NH:1]1[CH:5]=[C:4]([CH2:6][CH2:7][CH2:8][S:19][CH2:18][CH2:17][CH2:16][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[N:3]=[CH:2]1
Reactant: SCCCc1ccccc1
Reactant: ClCCCc1c[nH]cn1
Agent: [Na]
Solvent: CCO
Product: c1ccc(CCCSCCCc2c[nH]cn2)cc1

Procedure:
5mmol of 3-(1H-imidazol-4-yl)propyl chloride are introduced into a solution of 6 mmol of 3-phenylpropanethiol and 10 mmol of sodium in 30 ml of ethanol and the mixture is brought to reflux for 3 h. The suspension is evaporated under vacuum until dryness, potassium carbonate is added and the mixture is stirred in methanol/water. The residual semi-solid oil is brought to boiling in ethanol with active charcoal, filtered and recrystallized in the hydrogenmaleate form from ethanol/diethyl ether.
Reaction SMILES: [CH3:1][C:2]1[C:6]([C:7]([OH:9])=O)=[CH:5][O:4][N:3]=1.S(Cl)(Cl)=O.[NH2:14][C:15]1[CH:16]=[C:17]([CH:30]=[CH:31][CH:32]=1)[C:18]([C:20]1[CH:28]=[C:27]2[C:23]([CH2:24][C:25](=[O:29])[NH:26]2)=[CH:22][CH:21]=1)=[O:19]>C1COCC1>[O:29]=[C:25]1[CH2:24][C:23]2[C:27](=[CH:28][C:20]([C:18]([C:17]3[CH:16]=[C:15]([NH:14][C:7]([C:6]4[C:2]([CH3:1])=[N:3][O:4][CH:5]=4)=[O:9])[CH:32]=[CH:31][CH:30]=3)=[O:19])=[CH:21][CH:22]=2)[NH:26]1
Reactant: Cc1nocc1C(=O)O
Reactant: Nc1cccc(C(=O)c2ccc3c(c2)NC(=O)C3)c1
Solvent: O=S(Cl)Cl
Solvent: C1CCOC1
Product: Cc1nocc1C(=O)Nc1cccc(C(=O)c2ccc3c(c2)NC(=O)C3)c1
Temperature: 79 °C
Reaction time: 3 h
Yield: 66.1 %

Procedure:
A dry flask was charged with 3-Methyl-isoxazole-4-carboxylic acid (0.500 g, 3.9339 mmol) and thionyl chloride (10 mL) and allowed to stir at 79° C. for 3 h. The thionyl chloride was then removed by concentration in vacuo. The crude acid chloride was cooled to room temperature, and then dissolved in THF (39 mL). 6-(3-Amino-benzoyl)-1,3-dihydro-indol-2-one (as prepared in Example 40, 0.992 g, 3.932 mmol) was added to the THF solution of the acid chloride, and the mixture was allowed to reflux overnight. The reaction mixture was then allowed to cool to room temperature and filtered. The solid residue was washed with 0° C. THF (5 mL) and collected to afford the 3-Methyl-isoxazole-4-carboxylic acid [3-(2-oxo-2,3-dihydro-1H-indole-6-carbonyl)-phenyl]-amide as a solid (0.938 g, 2.60 mmol, 66%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[CH:14]=[CH:13][C:12]([NH:15][C:16]([C:18]3([C:21]([NH:23][C:24]4[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=4)=[O:22])[CH2:20][CH2:19]3)=[O:17])=[CH:11][C:10]=2[F:31])[CH:5]=[CH:4][N:3]=1.C(N(CC)CC)C.Cl[C:40](OC1C=CC=CC=1)=[O:41].FC(F)(F)C(O)=O.[OH:56][CH2:57][CH:58]1[CH2:61][NH:60][CH2:59]1>O1CCCC1>[F:31][C:10]1[CH:11]=[C:12]([NH:15][C:16]([C:18]2([C:21]([NH:23][C:24]3[CH:25]=[CH:26][C:27]([F:30])=[CH:28][CH:29]=3)=[O:22])[CH2:20][CH2:19]2)=[O:17])[CH:13]=[CH:14][C:9]=1[O:8][C:6]1[CH:5]=[CH:4][N:3]=[C:2]([NH:1][C:40]([N:60]2[CH2:61][CH:58]([CH2:57][OH:56])[CH2:59]2)=[O:41])[CH:7]=1
Reactant: Nc1cc(Oc2ccc(NC(=O)C3(C(=O)Nc4ccc(F)cc4)CC3)cc2F)ccn1
Reactant: O=C(Cl)Oc1ccccc1
Reactant: OCC1CNC1
Solvent: C1CCOC1
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(CC)CC
Product: O=C(Nc1cc(Oc2ccc(NC(=O)C3(C(=O)Nc4ccc(F)cc4)CC3)cc2F)ccn1)N1CC(CO)C1
Reaction time: 1 h
Yield: 38.1 %

Procedure:
N-{4-[(2-Aminopyridin-4-yl)oxy]-3-fluorophenyl}-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide (297 mg) was dissolved in tetrahydrofuran (8.0 ml) under a nitrogen atmosphere, and triethylamine (0.293 ml) and phenyl chloroformate (0.193 ml) were added dropwise at room temperature in this order, followed by stirring for 1 hr. The reaction mixture was partitioned between ethyl acetate and water. The organic layer was washed with a 1N aqueous solution of sodium hydroxide, water and brine in this order, and dried over anhydrous sodium sulfate. The solvent was concentrated under reduced pressure. The residue was dissolved in N,N-dimethylformamide (8.0 ml). This solution was added to a mixture of a crude product of 3-(hydroxymethyl)azetidine trifluoroacetate (corresponds to 2.58 mmol) and triethylamine (2.0 ml), followed by stirring at room temperature for 11 hr. The reaction mixture was partitioned between ethyl acetate and water. The organic layer was washed with a 1N aqueous solution of sodium hydroxide, water and brine in this order, and dried over anhydrous sodium sulfate. The solvent was removed, and the residue was purified by silica gel column chromatography (eluent; heptane:ethyl acetate=1:2, ethyl acetate, ethyl acetate:methanol=50:1, then 20:1). Fractions containing the target compound were concentrated. To the resultant residue (159.4 mg) was added diethyl ether:heptane=1:2 to suspend a solid. The solid was collected by filtration and washed with heptane. This was dried under aeration to provide the titled compound as white powder (143.2 mg, 38.1%).