Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([N:3]=[C:4](OC1C=CC=CC=1)[NH:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([NH:12][C:13]([C:15]2[S:16][CH:17]=[CH:18][C:19]=2[NH:20][CH2:21][C:22]2[C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[N:25]=[CH:24][CH:23]=2)=[O:14])[CH:7]=1)#[N:2].C(N=C(OCC(F)(F)F)NC1C=CC=C(NC(C2SC=CC=2NCC2C3C(=CC=CC=3)N=CC=2)=O)C=1)#[N:40]>>[NH2:40][C:4]([NH:5][C:6]1[CH:7]=[C:8]([NH:12][C:13]([C:15]2[S:16][CH:17]=[CH:18][C:19]=2[NH:20][CH2:21][C:22]2[C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[N:25]=[CH:24][CH:23]=2)=[O:14])[CH:9]=[CH:10][CH:11]=1)=[N:3][C:1]#[N:2]
Reactant: N#CN=C(Nc1cccc(NC(=O)c2sccc2NCc2ccnc3ccccc23)c1)OCC(F)(F)F
Reactant: N#CN=C(Nc1cccc(NC(=O)c2sccc2NCc2ccnc3ccccc23)c1)Oc1ccccc1
Product: N#CN=C(N)Nc1cccc(NC(=O)c2sccc2NCc2ccnc3ccccc23)c1

Procedure:
The following analogues were prepared using phenyl N′-cyano-N-{3-[({3-[(quinolin-4-ylmethyl)amino]thien-2-yl}carbonyl)amino]phenyl}imidocarbamate (EXAMPLE 1) or 2,2,2-Trifluoroethyl N′-Cyano-N-{3-[({3-[(quinolin-4-ylmethyl)amino]thien-2-yl}carbonyl)amino]phenyl}imidocarbamate (EXAMPLE 2) and the appropriate amine, according to the procedure described above for EXAMPLE 3.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:25])[C:4]([N:22]=[N+]=[N-])=[CH:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[C:8]([O:20][CH3:21])[CH:7]=1>C1(C)C(C)=CC=CC=1>[CH3:1][O:2][C:3]([C:4]1[NH:22][C:11]2[C:6]([CH:5]=1)=[CH:7][C:8]([O:20][CH3:21])=[C:9]([O:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[CH:10]=2)=[O:25]
Reactant: COC(=O)C(=Cc1ccc(OCc2ccccc2)c(OC)c1)N=[N+]=[N-]
Solvent: Cc1ccccc1C
Product: COC(=O)c1cc2cc(OC)c(OCc3ccccc3)cc2[nH]1
Temperature: 25 °C

Procedure:
A solution of the azidocinnamate (55) (12.2 g, 36.0 mmol) prepared as described in example 247 in xylene (300 mL) was added dropwise to refluxing xylene (100 mL) over 1.5 h, the reaction mixture was heated at reflux for a further 15 min and then most of the xylene was removed by distillation. The residue, on cooling to room temperature, formed a fine cream precipitate of methyl-6-(benzyloxy)-5-methoxyindole-2-carboxylate which was collected by filtration. The remaining xylene was removed from the mother liquor azeotropically with ethanol, the residue was recrystallized from ethanol to give further methyl-6-(benzyloxy)-5-methoxyindole-2-carboxylate. The mother liquor was again concentrated and the residue recrystallized. The methyl-6-(benzyloxy)-5-methoxyindole-2-carboxylate (56) (9.9 g total, 88%) was used in the next step without purification. Found: C, 69.38; H, 5.54; N, 4.55. C18H17NO4 requires: C, 69.44; H, 5.50; N, 4.50.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:11]=[C:10](Br)[C:9]2[CH:13]=[C:14]([C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([C:22]([F:25])([F:24])[F:23])[CH:17]=3)[S:15][C:8]=2[C:7]=1[OH:26])=[O:5])[CH3:2].[Cu][C:28]#[N:29]>CN(C=O)C>[CH2:1]([O:3][C:4]([C:6]1[N:11]=[C:10]([C:28]#[N:29])[C:9]2[CH:13]=[C:14]([C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([C:22]([F:25])([F:24])[F:23])[CH:17]=3)[S:15][C:8]=2[C:7]=1[OH:26])=[O:5])[CH3:2]
Reactant: N#C[Cu]
Reactant: CCOC(=O)c1nc(Br)c2cc(-c3cccc(C(F)(F)F)c3)sc2c1O
Solvent: CN(C)C=O
Product: CCOC(=O)c1nc(C#N)c2cc(-c3cccc(C(F)(F)F)c3)sc2c1O
Temperature: 135 °C
Yield: 51 %

Procedure:
A mixture of 4-bromo-7-hydroxy-2-(3-trifluoromethyl-phenyl)-thieno[3,2-c]pyridine-6-carboxylic acid ethyl ester (example 25.a, 108 mg, 0.24 mmol) and copper(I) cyanide (45 mg, 0.5 mmol) suspended in 1 mL DMF was heated at 135° C. for 15 minutes in a CEM microwave reactor. The resultant mixture was partitioned between ethyl acetate and water, and the organic fraction was washed with brine, dried over anhydrous sodium sulfate, and concentrated to a crude residue. The desired product was purified by column chromatography eluting from silica gel with a gradient of 10-60% ethyl acetate in hexanes to give 48 mg of a white solid; MS: (+) m/z 392.9 (M+1)
Reaction SMILES: [C:1]([O:5][C:6](=[O:41])[NH:7][C:8]1([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[C:19]([C:35]4[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=4)=[CH:20][C:21]4[NH:26]/[C:25](=[N:27]/[NH:28][C:29](=O)[CH:30]([F:32])[F:31])/[CH2:24][O:23][C:22]=4[N:34]=3)=[CH:14][CH:13]=2)[CH2:11][CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2]>CC1C=CC(C)=CC=1>[F:31][CH:30]([F:32])[C:29]1[N:26]2[C:21]3[CH:20]=[C:19]([C:35]4[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=4)[C:18]([C:15]4[CH:16]=[CH:17][C:12]([C:8]5([NH:7][C:6](=[O:41])[O:5][C:1]([CH3:4])([CH3:2])[CH3:3])[CH2:11][CH2:10][CH2:9]5)=[CH:13][CH:14]=4)=[N:34][C:22]=3[O:23][CH2:24][C:25]2=[N:27][N:28]=1
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(-c3nc4c(cc3-c3ccccc3)N/C(=N/NC(=O)C(F)F)CO4)cc2)CCC1
Solvent: Cc1ccc(C)cc1
Product: CC(C)(C)OC(=O)NC1(c2ccc(-c3nc4c(cc3-c3ccccc3)-n3c(nnc3C(F)F)CO4)cc2)CCC1
Yield: 19.4 %

Procedure:
A solution of (E)-tert-butyl(1-(4-(2-(2-(2,2-difluoroacetyl)hydrazono)-7-phenyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-6-yl)phenyl)cyclobutyl)carbamate (80 mg, 0.142 mmol) in p-xylene (1 ml) was heated to 150° C. for 15 minutes under microwave irradiation. The resulting reaction mixture was concentrated to dryness under reduced pressure and purified by Biotage silica gel chromatography (gradient 0% to 2% methanol in dichloromethane) to give the title compound (15 mg, 20%). LCMS (Method D): RT=1.529 min, M+1=546.
Reaction SMILES: Br[C:2]1[N:3]=[C:4]2[C:10]([C:11]([NH:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])=[CH:9][N:8]([CH2:18][O:19][CH2:20][CH2:21][Si:22]([CH3:25])([CH3:24])[CH3:23])[C:5]2=[N:6][CH:7]=1.[NH2:26][C:27]1[CH:32]=[CH:31][C:30]([CH2:33][OH:34])=[CH:29][CH:28]=1>C1(C)C=CC=CC=1.CC([O-])=O.CC([O-])=O.[Pd+2].C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1>[C:14]([NH:13][C:11]([C:10]1[C:4]2[C:5](=[N:6][CH:7]=[C:2]([NH:26][C:27]3[CH:32]=[CH:31][C:30]([CH2:33][OH:34])=[CH:29][CH:28]=3)[N:3]=2)[N:8]([CH2:18][O:19][CH2:20][CH2:21][Si:22]([CH3:25])([CH3:24])[CH3:23])[CH:9]=1)=[O:12])([CH3:17])([CH3:16])[CH3:15]
Reactant: CC(C)(C)NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(Br)nc12
Reactant: Nc1ccc(CO)cc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: c1ccc(P(c2ccccc2)c2ccc3ccccc3c2-c2c(P(c3ccccc3)c3ccccc3)ccc3ccccc23)cc1
Solvent: Cc1ccccc1
Product: CC(C)(C)NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(Nc3ccc(CO)cc3)nc12
Temperature: 110 °C
Yield: 91 %

Procedure:
To a 10 ml seal tube, 2-bromo-N-tert-butyl-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide (0.05 g, 0.000117 mol) and (4-aminophenyl)methanol (0.017 g, 0.00014 mol) was taken in toluene (2.0 ml). The reaction mixture was purged with argon for 15 min at RT after which CS2CO3 (0.189 g, 0.000586 mol) was added and the reaction mixture was further purged for 30 min with argon. BINAP (0.0015 g, 0.0000023 mol) and Pd(OAc)2 (0.0005 g, 0.0000023 mol) were added to reaction mixture and heated to 110° C. for 4 hr. After completion of the reaction, the reaction mixture was filtered through celite bed and washed with ethyl acetate. Filtrate was collected and concentrated to afford crude product which was purified using column purification by eluting the compound with 20-25% ethyl acetate in hexanes to yield 0.05 g of N-tert-butyl-2-(4-(hydroxymethyl)phenyl-amino)-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide.
Reaction SMILES: [NH2:1][C:2]1[CH:20]=[CH:19][C:18]([C:21]([O:23][CH2:24][CH3:25])=[O:22])=[CH:17][C:3]=1[CH2:4][N:5](CC1C=CC=CC=1)[C:6]([CH3:9])([CH3:8])[CH3:7].Cl.C.[H][H]>C(O)C>[NH2:1][C:2]1[CH:20]=[CH:19][C:18]([C:21]([O:23][CH2:24][CH3:25])=[O:22])=[CH:17][C:3]=1[CH2:4][NH:5][C:6]([CH3:9])([CH3:8])[CH3:7]
Reactant: CCOC(=O)c1ccc(N)c(CN(Cc2ccccc2)C(C)(C)C)c1
Reactant: [H][H]
Agent: Cl
Solvent: CCO
Product: CCOC(=O)c1ccc(N)c(CNC(C)(C)C)c1

Procedure:
3.4 gm of 2-amino-N-benzyl-N-tert.butyl-5-carbethoxy-benzylamine were dissolved in 50 ml of ethanol. Ethanolic hydrochloric acid was added to the solution until a pH of about 2 was reached. The solution was then hydrogenated in the presence of palladized (10%) charcoal. After absorption of 1 mol of hydrogen, the hydrogenation was terminated, the catalyst was filtered off, the filtrate was evaporated to dryness in vacuo, and the residue was distributed between a mixture of dilute ammonia and chloroform. The chloroform phase was dried and evaporated to dryness, and the residue was recrystallized from ethanol, yielding 2-amino-N-tert.butyl-5-carbethoxy-benzylamine, m.p. 77°-79° C.
Reaction SMILES: [CH3:1][C:2]1[O:3][C:4]2[C:11]([C@H:12]([OH:15])[CH2:13]O)=[CH:10][CH:9]=[CH:8][C:5]=2[C:6]=1[CH3:7].N1C=CC=CC=1.[S:22](Cl)([C:25]1[CH:31]=[CH:30][C:28]([CH3:29])=[CH:27][CH:26]=1)(=[O:24])=[O:23].Cl>CN(C1C=CC=CN=1)C.S(Cl)(C1C=CC(C)=CC=1)(=O)=O.C(OCC)(=O)C>[CH3:1][C:2]1[O:3][C:4]2[C:11]([C@H:12]([OH:15])[CH2:13][S:22]([C:25]3[CH:31]=[CH:30][C:28]([CH3:29])=[CH:27][CH:26]=3)(=[O:24])=[O:23])=[CH:10][CH:9]=[CH:8][C:5]=2[C:6]=1[CH3:7]
Reactant: Cc1oc2c([C@H](O)CO)cccc2c1C
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: CN(C)c1ccccn1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)C[C@@H](O)c2cccc3c(C)c(C)oc23)cc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 71.2 %

Procedure:
14 g (67.96 mmol) of (+)-2,3-dimethyl-7-(2-hydroxy-1(S)-hydroxyethyl)benzofuran and 250 ml of pyridine are introduced into a 500 ml three-necked flask. The mixture is cooled to 0° C. and 11.62 g (61.16 mmol) of tosyl chloride and then 0.5 g of dimethylaminopyridine are added. The reaction mixture is stirred for 2 h at room temperature, 0.645 g of tosyl chloride is added and stirring is continued for 16 h. The mixture is cooled to 0° C. and 300 ml of ethyl acetate and then 250 ml of a hydrochloric acid solution (4M) are added. Extraction is carried out with ethyl acetate (2×400 ml). The organic phases are combined, washed with 2×250 ml of a hydrochloric acid solution (4M), dried over magnesium sulphate and concentrated. The residue is purified by silica column chromatography (elution solvent: 25% ethyl acetate in cyclohexane). 15 g of (+)-2,3-dimethyl-7-(2-para-methylphenylsulphonyl-1(S)-hydroxyethyl)benzofuran are obtained in the form of a white solid--M.p.: 90° C.
Reaction SMILES: CS([C:4]1[N:16]=[CH:15][C:7]2=[CH:8][C:9]3[C:14]([N:6]2[N:5]=1)=[CH:13][CH:12]=[CH:11][CH:10]=3)=O.[CH2:17]1[N:22]([C:23]2[CH:28]=[CH:27][C:26]([NH2:29])=[CH:25][CH:24]=2)[CH2:21][CH2:20][O:19][CH2:18]1.CN1CCCC1=O>CO.ClCCl>[N:22]1([C:23]2[CH:24]=[CH:25][C:26]([NH:29][C:4]3[N:16]=[CH:15][C:7]4=[CH:8][C:9]5[C:14]([N:6]4[N:5]=3)=[CH:13][CH:12]=[CH:11][CH:10]=5)=[CH:27][CH:28]=2)[CH2:21][CH2:20][O:19][CH2:18][CH2:17]1
Reactant: Nc1ccc(N2CCOCC2)cc1
Reactant: CS(=O)c1ncc2cc3ccccc3n2n1
Solvent: CN1CCCC1=O
Solvent: CO
Solvent: ClCCl
Product: c1ccc2c(c1)cc1cnc(Nc3ccc(N4CCOCC4)cc3)nn12
Temperature: 145 °C
Yield: 0 %

Procedure:
Into a 30 ml, vial 2-methanesulfinyl-[1,2,4]triazino[1,6-a]indole (50.00 mg, 0.216 mol), 4-(4-morpholino)aniline (84.8 mg, 0.476 mol), and N-methylpyrrolidinone (0.10 mL) were combined and heated at 145° C. for 2 hours. The reaction was cooled to room temperature and the product was isolated by flash chromatography (ISCO, Silicagel, methanol/dichloromethane 0-10%) to provide (4-morpholin-4-yl-phenyl)-[1,2,4]triazino[1,6-a]indol-2-yl-amine as a brown solid (14 mg, 19%). MP: 205-210° C.; 1H-NMR (CDCl3) δ 9.00 (s, 1H), 8.10 (d, J=8.5 Hz, 1H), 7.81 (d, J=8.4 Hz, 1H), 7.68 (d, J=8.8 Hz, 2H), 7.42 (m, 1H), 7.31 (m, 1H), 6.99 (d, J=8.8 Hz, 2H), 6.94 (s, 1H), 6.80 (s, 1H), 3.89 (m, 4H), 3.16 (m, 4H); LC/MS (ESI+): 346.7 (M+H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([CH:8]2[CH2:13][CH2:12][N:11]([CH3:14])[CH2:10][CH2:9]2)[C:5]([F:15])=[CH:4][C:3]=1[C:16](=[O:23])[CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19]>C(OC(=O)C)(=O)C.C(OCC)(OCC)OCC>[CH2:18]([O:20][CH:21]=[C:17]([C:16](=[O:23])[C:3]1[CH:4]=[C:5]([F:15])[C:6]([CH:8]2[CH2:9][CH2:10][N:11]([CH3:14])[CH2:12][CH2:13]2)=[CH:7][C:2]=1[F:1])[C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH3:17]
Reactant: CCOC(=O)CC(=O)c1cc(F)c(C2CCN(C)CC2)cc1F
Solvent: CCOC(OCC)OCC
Solvent: CC(=O)OC(C)=O
Product: CCOC=C(C(=O)OCC)C(=O)c1cc(F)c(C2CCN(C)CC2)cc1F

Procedure:
A solution of 3 25 g (10 mmoles) of ethyl 2,5-difluoro-4-(1-methyl-4-piperidinyl)-β-oxobenzenepropionate in 20 ml of acetic anhydride and 2.5 ml of triethyl orthoformate was refluxed 11/4 hours and evaporated under vacuum to give the title compound.
Reaction SMILES: [C:1]1(=O)[O:5][CH2:4][CH2:3][O:2]1.CC(=O)CCCCCCCC.[Cl-].[Cs+].[CH2:20]1[O:34][CH2:33][CH2:32][O:31][CH2:30][CH2:29][O:28][CH2:27]CO[CH2:24][CH2:23][O:22][CH2:21]1>>[CH2:3]1[O:2][CH2:24][CH2:23][O:22][CH2:21][CH2:20][O:34][CH2:33][CH2:32][O:31][CH2:30][CH2:29][O:28][CH2:27][CH2:1][O:5][CH2:4]1
Reactant: C1COCCOCCOCCOCCO1
Reactant: O=C1OCCO1
Agent: CCCCCCCCC(C)=O
Agent: [Cl-]
Agent: [Cs+]
Product: C1COCCOCCOCCOCCOCCO1
Reaction time: 8 h

Procedure:
According to this invention, 22 grams of ethylene carbonate, 11 grams of 2-decanone and 0.565 grams of CsCl were placed in a 100 ml round-bottomed flask which was fitted with a thermometer, distillation head and a cold trap. The flask was heated in an oil bath (with magnetic stirring) at about 150° C. to about 175° C. for about 8 hours. Analysis of the reaction mixture by gas chromatography showed that 15-Crown-5 and 18-Crown-6 were formed.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH:6]1[CH2:12][NH:11][C:10](=[O:13])[CH:9]([N:14]2[C:18](=[O:19])[C:17]3=[CH:20][CH:21]=[CH:22][CH:23]=[C:16]3[C:15]2=[O:24])[CH2:8][S:7]1.Br[CH2:26][C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28]>>[O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH:6]1[CH2:12][N:11]([CH2:26][C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[C:10](=[O:13])[CH:9]([N:14]2[C:18](=[O:19])[C:17]3=[CH:20][CH:21]=[CH:22][CH:23]=[C:16]3[C:15]2=[O:24])[CH2:8][S:7]1
Reactant: CC(C)(C)OC(=O)CBr
Reactant: O=C1NCC(c2ccco2)SCC1N1C(=O)c2ccccc2C1=O
Product: CC(C)(C)OC(=O)CN1CC(c2ccco2)SCC(N2C(=O)c3ccccc3C2=O)C1=O

Procedure:
Following the procedure described in Example 42(f), 1.15 g of 2-(2-furyl)-5-oxo-6-phthalimidoperhydro-1,4-thiazepine [prepared as described in step (d) above] was treated with t-butyl bromoacetate, to give 0.86 g of the title compound as crystals, melting at 158°-161° C.
Reaction SMILES: [F:1][C:2]1[CH:21]=[CH:20][C:5]([C:6]([NH:8][CH2:9][C:10]([O:12]CC2C=CC=CC=2)=[O:11])=[O:7])=[CH:4][C:3]=1[N+:22]([O-])=O>CCOC(C)=O.[Pd]>[NH2:22][C:3]1[CH:4]=[C:5]([CH:20]=[CH:21][C:2]=1[F:1])[C:6]([NH:8][CH2:9][C:10]([OH:12])=[O:11])=[O:7]
Reactant: O=C(CNC(=O)c1ccc(F)c([N+](=O)[O-])c1)OCc1ccccc1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: Nc1cc(C(=O)NCC(=O)O)ccc1F
Reaction time: 0.42 h
Yield: 70 %

Procedure:
To a solution of benzyl 2-(4-fluoro-3-nitrobenzamido)acetate (85 mg) in EtOAc (10 mL) was added Pd/C (10%, 100 mg) at rt and stirred under the atmosphere of H2 gas for 25 min. Work-up of the reaction mixture as described in example 1 gave the product as a white color solid (38 mg, 70%), mp 150-152° C. 1H NMR (400 MHz, CDCl3+DMSO-d6): δ 7.74 (1H, br s), 7.37 (1H, dd, J=8.6, 1.8 Hz), 7.12-7.16 (1H, m), 6.97 (1H, dd, J=10.6, 8.6 Hz), 4.07 (2H, d, J=5.6 Hz); 13C NMR (100 MHz, CDCl3+DMSO-d6): δ 170.6, 165.9, 151. 9 (d, J=242 Hz), 134.5 (d, J=13 Hz), 129.6 (d, J=3 Hz), 115.4 (d, J=8 Hz), 115.1 (d, J=6 Hz), 113.6 (d, J=19 Hz), 40.5; LC-MS (negative ion mode): m/z 211 (M−H)−.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[CH:4][CH:3]=1.[CH:11]([NH:14][CH:15]1[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1)([CH3:13])[CH3:12]>O1CCCC1>[Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([N:14]([CH:15]2[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]2)[CH:11]([CH3:13])[CH3:12])=[O:7])=[CH:4][CH:3]=1
Reactant: O=C(Cl)c1ccc(Br)cc1
Reactant: CC(C)NC1CCCCC1
Solvent: C1CCOC1
Product: CC(C)N(C(=O)c1ccc(Br)cc1)C1CCCCC1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a stirred, cold (0° C.) solution of 4-bromobenzoyl chloride (5.305 g, 24.2 mmol) in tetrahydrofuran (20 ml) was added dropwise a solution of isopropyl cylcohexyl amine (6.841 g, 48.4 mmol) in tetrahydrofuran (THF) (7ml). After stirring for 1 hr at 0° C., the reaction was stirred at room temperature for 3 hr. and reflexed for 3 hr. The reaction was concentrated in vacuo and the residual mass was dissolved in ethyl ether and water. The layers were separated and the organic layer washed once with water, twice with 0.5N HCl, once more with water, twice with 5% aqueous NaHCO3 solution, and once with water. After drying over sodium sulfate, the organic layer was filtered, and the filtrate concentrated in vacuo to give the crude product. This material was purified by chromatography on silica el suing mixtures of EtOAc, and hexane as eluents to give the title compound.
Reaction SMILES: C([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([C:13]([O:15][CH3:16])=[O:14])[CH:11]=2)[C:6](=[C:17](OCC)[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:5]1=[O:27])(=O)C.[N:28]1([CH2:34][C:35]([N:37]([CH3:45])[C:38]2[CH:43]=[CH:42][C:41]([NH2:44])=[CH:40][CH:39]=2)=[O:36])[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]1>>[N:28]1([CH2:34][C:35]([N:37]([C:38]2[CH:39]=[CH:40][C:41]([NH:44]/[C:17](=[C:6]3\[C:5](=[O:27])[NH:4][C:12]4[C:7]\3=[CH:8][CH:9]=[C:10]([C:13]([O:15][CH3:16])=[O:14])[CH:11]=4)/[C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[CH:42][CH:43]=2)[CH3:45])=[O:36])[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]1
Reactant: CN(C(=O)CN1CCCCC1)c1ccc(N)cc1
Reactant: CCOC(=C1C(=O)N(C(C)=O)c2cc(C(=O)OC)ccc21)c1ccccc1
Product: COC(=O)c1ccc2c(c1)NC(=O)/C2=C(\Nc1ccc(N(C)C(=O)CN2CCCCC2)cc1)c1ccccc1

Procedure:
Prepared from 1-acetyl-3-(1-ethoxy-1-phenylmethylene)-6-methoxycarbonyl-2-indolinone and N-(piperidin-1-yl-methylcarbonyl)-N-methyl-p-phenylenediamine Rf value: 0.5 (silica gel, methylene chloride/methanol=9:1) C31H32N4O4
Reaction SMILES: [CH3:1][NH:2][NH2:3].Br[CH2:5][C:6]([O:8][CH2:9][CH3:10])=[O:7]>>[CH3:1][N:2]([CH2:5][C:6]([O:8][CH2:9][CH3:10])=[O:7])[NH2:3]
Reactant: CNN
Reactant: CCOC(=O)CBr
Product: CCOC(=O)CN(C)N
Reaction time: 8 h
Yield: 77.2 %

Procedure:
According to the procedure described in the synthesis method of Compound XV-1 with the modification that the reaction was carried out overnight, methylhydrazine 7.13 ml (150 mmol) was reacted with ethyl 2-bromoacetate 16.7 g (100 mmol) to obtain the title compound 10.2 g (77%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[CH:5]2.[CH2:11]1[O:21][C:14]2([CH2:19][CH2:18][C:17](=O)[CH2:16][CH2:15]2)[O:13][CH2:12]1.[OH-].[K+]>CO>[O:13]1[C:14]2([CH2:19][CH2:18][C:17]([C:5]3[C:4]4[C:8](=[CH:9][CH:10]=[C:2]([F:1])[CH:3]=4)[NH:7][CH:6]=3)=[CH:16][CH2:15]2)[O:21][CH2:11][CH2:12]1
Reactant: O=C1CCC2(CC1)OCCO2
Reactant: Fc1ccc2[nH]ccc2c1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: Fc1ccc2[nH]cc(C3=CCC4(CC3)OCCO4)c2c1
Yield: 87.3 %

Procedure:
5-Fluoroindole (4.96 g, 0.036 mol), 1,4-cyclohexanedione monoethylene ketal (7.17 g, 0.046 mol) and potassium hydroxide (6 g, 91 mmol) were heated to reflux in 70 ml methanol for 6 hours. The reaction was cooled and the product was isolated by filtration and washed with water to give 8.59 g (86%) of product as a white solid: mp 153-155° C.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([C:12]([F:21])([F:20])[C:13]1[CH:18]=[CH:17][C:16]([F:19])=[CH:15][N:14]=1)[N:8]=[C:7]2[S:22][CH3:23].C1(P(C2C=CC=CC=2)C2C3OC4C(=CC=CC=4P(C4C=CC=CC=4)C4C=CC=CC=4)C(C)(C)C=3C=CC=2)C=CC=CC=1.[CH3:66][S:67]([NH2:70])(=[O:69])=[O:68].C([O-])([O-])=O.[Cs+].[Cs+]>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].O1CCOCC1>[F:20][C:12]([F:21])([C:13]1[CH:18]=[CH:17][C:16]([F:19])=[CH:15][N:14]=1)[C:9]1[N:8]=[C:7]([S:22][CH3:23])[C:6]2[C:11](=[C:2]([NH:70][S:67]([CH3:66])(=[O:69])=[O:68])[CH:3]=[CH:4][CH:5]=2)[N:10]=1
Reactant: CS(N)(=O)=O
Reactant: CSc1nc(C(F)(F)c2ccc(F)cn2)nc2c(Br)cccc12
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: CSc1nc(C(F)(F)c2ccc(F)cn2)nc2c(NS(C)(=O)=O)cccc12
Temperature: 100 °C
Yield: 84.9 %

Procedure:
To a mixture of 8-bromo-2-(difluoro(5-fluoropyridin-2-yl)methyl)-4-(methylthio)quinazoline from Example 35 step B (250 mg, 0.625 mmol), tris(dibenzylideneacetone)dipalladium (57 mg, 0.063 mmol), 4,5-Bis(diphenylphosphino)-9,9-dimethylxanthene (108 mg, 0.187 mmol), methanesulfonamide (83 mg, 0.87 mmol) and Cs2CO3 (284 mg, 0.87 mmol) was added dioxane (5 mL). The reaction vessel was evacuated and flushed with argon (3×), and the mixture was heated at 100° C. overnight. The mixture was allowed to cool and was then diluted with DCM and concentrated under reduced pressure onto Celite. The residue was purified by silica gel flash chromatography eluting with 10-100% EtOAc/hexanes to afford impure N-(2-(difluoro(5-fluoropyridin-2-yl)methyl)-4-(methylthio)quinazolin-8-yl)methanesulfonamide (220 mg, 85%). LC-MS (ESI) m/z 415 (M+H)+.
Reaction SMILES: [N:1]1([C:6]2[CH:11]=[CH:10][C:9]([S:12][C:13]3[CH:18]=[CH:17][N:16]=[C:15](Cl)[N:14]=3)=[CH:8][CH:7]=2)[CH:5]=[N:4][N:3]=[N:2]1.[O:20]1[CH2:25][CH2:24][N:23]([C:26]2[CH:32]=[CH:31][C:29]([NH2:30])=[CH:28][CH:27]=2)[CH2:22][CH2:21]1>>[N:1]1([C:6]2[CH:11]=[CH:10][C:9]([S:12][C:13]3[CH:18]=[CH:17][N:16]=[C:15]([NH:30][C:29]4[CH:28]=[CH:27][C:26]([N:23]5[CH2:24][CH2:25][O:20][CH2:21][CH2:22]5)=[CH:32][CH:31]=4)[N:14]=3)=[CH:8][CH:7]=2)[CH:5]=[N:4][N:3]=[N:2]1
Reactant: Clc1nccc(Sc2ccc(-n3cnnn3)cc2)n1
Reactant: Nc1ccc(N2CCOCC2)cc1
Product: c1cc(Sc2ccc(-n3cnnn3)cc2)nc(Nc2ccc(N3CCOCC3)cc2)n1
Yield: 38.1 %

Procedure:
In a procedure analogous to Example 8, reaction of 4-(4-(1H-tetrazol-1-yl)phenylthio)-2-chloropyrimidine (100 mg, 0.34 mmol) and 4-morpholinoaniline (75 mg, 0.41 mmol) furnished the product (56 mg, 38%).
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[CH2:3][O:4][C:5]1[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][C:6]=1[CH2:7]O.C1(P([N:30]=[N+:31]=[N-:32])(C2C=CC=CC=2)=O)C=CC=CC=1.C1CCN2C(=NCCC2)CC1>C1COCC1>[F:1][C:2]([F:15])([F:14])[CH2:3][O:4][C:5]1[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][C:6]=1[CH2:7][N:30]=[N+:31]=[N-:32]
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Reactant: OCc1cc(Cl)ccc1OCC(F)(F)F
Solvent: C1CCC2=NCCCN2CC1
Solvent: C1CCOC1
Product: [N-]=[N+]=NCc1cc(Cl)ccc1OCC(F)(F)F
Temperature: 25 °C

Procedure:
To a solution of 2-(2,2,2-trifluoroethoxy)-5-chlorobenzyl alcohol (1.9 g, 7.9 mmol) in THF (20 mL) at 0° C. was added diphenyl phosphoryl azide (2.2 mL, 10.2 mmol) followed by DBU (1.5 mL, 10.0 mmol). The reaction mixture was allowed to warm to room temperature overnight following which the solvent was removed under reduced pressure. The residue was partitioned between ether and water and the organic layer dried over sodium sulfate. Filtration, concentration and purification by flash chromatography (19:1 hexane/ether) gave the azide as a white solid: 1H NMR (CDCl3) δ7.31 (m, 2H), 6.82 (d, J=8.8 Hz, 1H), 4.40 (m, 4H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:16])[CH2:4][CH:5]1[CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[NH:7][C:6]1=[O:15].Br[CH2:18][CH2:19][CH:20]([CH3:22])[CH3:21]>>[CH3:1][O:2][C:3](=[O:16])[CH2:4][CH:5]1[CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[N:7]([CH2:18][CH2:19][CH:20]([CH3:22])[CH3:21])[C:6]1=[O:15]
Reactant: CC(C)CCBr
Reactant: COC(=O)CC1Cc2ccccc2NC1=O
Product: COC(=O)CC1Cc2ccccc2N(CCC(C)C)C1=O

Procedure:
Following a similar N-alkylation procedure described in example 9, the (2-oxo-1,2,3,4-tetrahydro-quinolin-3-yl)-acetic acid methyl ester (0.068 mmol) obtained in the previous step is alkylated with 1-bromo-3-methylbutane to give the crude [1-(3-methyl-butyl)-2-oxo-1,2,3,4-tetrahydro-quinolin-3-yl]-acetic acid methyl ester, which is used in the next step without further purification.