Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: IC.[CH3:3][C:4]1([CH3:18])[C:8]([CH3:10])([CH3:9])[O:7][B:6]([C:11]2[CH:12]=[CH:13][C:14]([OH:17])=[N:15][CH:16]=2)[O:5]1.[C:19](=O)([O-])[O-].[K+].[K+]>C(#N)C>[CH3:19][N:15]1[CH:16]=[C:11]([B:6]2[O:5][C:4]([CH3:18])([CH3:3])[C:8]([CH3:9])([CH3:10])[O:7]2)[CH:12]=[CH:13][C:14]1=[O:17]
Reactant: CC1(C)OB(c2ccc(O)nc2)OC1(C)C
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CC#N
Product: Cn1cc(B2OC(C)(C)C(C)(C)O2)ccc1=O
Temperature: 50 °C
Reaction time: 16 h
Yield: 75.1 %

Procedure:
Iodomethane (0.283 mL, 4.52 mmol) was added to a mixture of 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-ol (0.500 g, 2.262 mmol) and potassium carbonate (1.563 g, 11.31 mmol) in acetonitrile (10 mL). The reaction vial was sealed and stirred at 50° C. for 16 h. The resulting mixture was filtered to remove the inorganic salt and the filter cake rinsed with ethyl acetate. The filtrate was concentrated, treated with ethyl acetate (20 mL) and dichloromethane (20 mL), and filtered to remove the residual inorganic salt. The filtrate was concentrated and dried under vacuum to give crude 1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2(1H)-one as white solid (399.4 mg). This material was used in subsequent Suzuki coupling reactions without further purification. 1H NMR (400 MHz, chloroform-d) δ ppm 7.76 (d, J=2.0 Hz, 1H), 7.60 (dd, J=9.2, 2.0 Hz, 1H), 6.52 (d, J=9.0 Hz, 1H), 3.55 (s, 3H), 1.31 (s, 12H).
Reaction SMILES: FC(F)(F)[C:3]1[CH:4]=[C:5]([C:9]2[C:10]3[N:11]([N:15]=[C:16]([NH2:18])[N:17]=3)[CH:12]=[CH:13][CH:14]=2)[CH:6]=[CH:7][CH:8]=1.[CH3:21][O:22]C1C=C(B(O)O)C=CC=1>>[CH3:21][O:22][C:3]1[CH:4]=[C:5]([C:9]2[C:10]3[N:11]([N:15]=[C:16]([NH2:18])[N:17]=3)[CH:12]=[CH:13][CH:14]=2)[CH:6]=[CH:7][CH:8]=1
Reactant: Nc1nc2c(-c3cccc(C(F)(F)F)c3)cccn2n1
Reactant: COc1cccc(B(O)O)c1
Product: COc1cccc(-c2cccn3nc(N)nc23)c1

Procedure:
Made by following the procedure described for the preparation of 8-(3-(trifluoromethyl)phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-amine but substituting 3-methoxyphenyl boronic acid and making non-critical variations.
Reaction SMILES: [CH3:1][CH2:2][O:3][C:4]1[CH:5]=[CH:6][C:7]([NH2:10])=[CH:8][CH:9]=1.C(N(CC)CC)C.Cl.Br[C:20]1[C:21]2[N:22]([CH:27]=[CH:28][N:29]=2)[N:23]=[C:24]([Cl:26])[CH:25]=1>CCO>[Cl:26][C:24]1[CH:25]=[C:20]([NH:10][C:7]2[CH:8]=[CH:9][C:4]([O:3][CH2:2][CH3:1])=[CH:5][CH:6]=2)[C:21]2[N:22]([CH:27]=[CH:28][N:29]=2)[N:23]=1
Reactant: Clc1cc(Br)c2nccn2n1
Reactant: CCOc1ccc(N)cc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCO
Product: CCOc1ccc(Nc2cc(Cl)nn3ccnc23)cc1
Temperature: 90 °C
Reaction time: 36 h

Procedure:
(1c variation 2) p-Phenetidine (1.0 eq, 0.149 mmol) and triethyamine (33 mg, 0.327 mmol) were added to a mixture of 8-bromo-6-chloroimidazo[1,2-b]pyridazine hydrochloride (40 mg, 0.149 mmol) from 1b in EtOH (1.5 mL). The mixture was heated to 90° C. and stirred for 24-48 hours. The solution was then concentrated in vacuo to give crude 6-chloro-N-(4-ethoxyphenyl)imidazo[1,2-b]pyridazin-8-amine.
Reaction SMILES: CS([C:5]1[N:10]=[C:9]2[N:11]=[C:12]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[O:22][CH2:23][CH2:24][CH3:25])[NH:13][C:14](=[O:15])[C:8]2=[CH:7][N:6]=1)(=O)=O.[CH3:26][O-:27].[Na+]>>[CH3:26][O:27][C:5]1[N:10]=[C:9]2[N:11]=[C:12]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[O:22][CH2:23][CH2:24][CH3:25])[NH:13][C:14](=[O:15])[C:8]2=[CH:7][N:6]=1
Reactant: CCCOc1ccccc1-c1nc2nc(S(C)(=O)=O)ncc2c(=O)[nH]1
Reactant: C[O-]
Agent: [Na+]
Product: CCCOc1ccccc1-c1nc2nc(OC)ncc2c(=O)[nH]1

Procedure:
In a similar manner to Example 36 reaction of 7-methylsulphonyl-4-oxo-2-(2-propoxyphenyl)-3,4-dihydropyrimido[4,5-d]pyrimidine (0.50 g) and sodium methoxide solution (from sodium, 0.16 g, and methanol, 20 ml) yielded the title compound, 0.29 g, m.p. 231°-2°° C. (recrystallised from methanol).
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=O)=[CH:5][CH:4]=1.[NH2:14][C:15]1[CH:24]=[CH:23][C:22]2[C:17](=[N:18][C:19]([Cl:25])=[CH:20][CH:21]=2)[N:16]=1.C(#N)C>O>[Cl:25][C:19]1[N:18]=[C:17]2[C:22]([CH:23]=[CH:24][C:15]([NH:14][C:7](=[O:9])[C:6]3[CH:5]=[CH:4][C:3]([C:2]([F:1])([F:13])[F:12])=[CH:11][CH:10]=3)=[N:16]2)=[CH:21][CH:20]=1
Reactant: O=C(O)c1ccc(C(F)(F)F)cc1
Reactant: Nc1ccc2ccc(Cl)nc2n1
Solvent: CC#N
Solvent: O
Product: O=C(Nc1ccc2ccc(Cl)nc2n1)c1ccc(C(F)(F)F)cc1
Temperature: 4 °C
Yield: 77.9 %

Procedure:
The procedure is analogous to that described in Example 1, but starting with 4-trifluoromethylbenzoic acid (10 g), N,N'-carbonyldiimidazole (8.4 g) and 2-amino-7-chloro-1,8-naphthyridine (5.9 g). The product obtained by precipitation in water (11.5 g; m.p. 236° C.) is dissolved in boiling acetonitrile (250 cc). After cooling for 4 hours at 4° C., the crystallized solid is separated by filtration, washed with acetonitrile (2×20 cc) and dried at 45° C. under reduced pressure (0.07 kPa). N-(7-Chloro-1,8-naphthyridin-2-yl)-4-trifluoromethylbenzamide (9 g), m.p. 236° C., is obtained.
Reaction SMILES: [Br:1][CH2:2][C:3]([OH:5])=O.[NH2:6][C:7]1[CH:12]=[C:11]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:10]=[CH:9][C:8]=1[OH:21]>C1COCC1>[Br:1][CH2:2][C:3]([NH:6][C:7]1[CH:12]=[C:11]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:10]=[CH:9][C:8]=1[OH:21])=[O:5]
Reactant: O=C(O)CBr
Reactant: Nc1cc(OCc2ccccc2)ccc1O
Solvent: C1CCOC1
Product: O=C(CBr)Nc1cc(OCc2ccccc2)ccc1O
Yield: 50 %

Procedure:
Bromoacetic acid (13.9 g, 0.01 mole) and dicyclohexyldicarbodiimide (DCCD, 20.6 g, 0.01 mole) were added at room temperature under stirring to the amine (b), 21.5 g, 0.01 mole) in THF (200 ml). After 1 hour the reaction mixture was filtered and the liquid evaporated to dryness under vacuum. The residue was crystallized from acetic acid (50 ml) to give the bromoamide ((c), 17 g, 50%) as white prisms. The product strusture was confirmed by NMR analysis.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[C:11](=[O:12])[N:10]([C:13]3[CH:18]=[CH:17][C:16]([O:19][CH2:20][C:21]([F:24])([F:23])[F:22])=[CH:15][CH:14]=3)[C:9](=[S:25])[NH:8][C:7]=2[N:26]=1.C(=O)([O-])O.[Na+].I[CH2:33][CH2:34][CH3:35].CN(C)C=O>O>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[C:11](=[O:12])[N:10]([C:13]3[CH:14]=[CH:15][C:16]([O:19][CH2:20][C:21]([F:24])([F:23])[F:22])=[CH:17][CH:18]=3)[C:9]([S:25][CH2:33][CH2:34][CH3:35])=[N:8][C:7]=2[N:26]=1
Reactant: CCCI
Reactant: COc1ccc2c(=O)n(-c3ccc(OCC(F)(F)F)cc3)c(=S)[nH]c2n1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCSc1nc2nc(OC)ccc2c(=O)n1-c1ccc(OCC(F)(F)F)cc1
Temperature: 80 °C
Reaction time: 0.17 h

Procedure:
A mixture of 7-methoxy-2-thioxo-3-[4-(2,2,2-trifluoroethoxy)phenyl]-2,3-dihydropyrido[2,3-d]pyrimidin-4(1H)-one (153 mg), 1M aqueous sodium hydrogen carbonate solution (439 μl), 1-iodopropane (117 μl) and N,N-dimethylformamide (3 ml) was stirred at 80° C. for 10 min. The reaction mixture was allowed to be cooled, and water (20 ml) was added thereto. The white precipitate was collected by filtration, washed with water, and dissolved in tetrahydrofuran (10 ml). The solution was diluted with ethyl acetate (20 ml), washed with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the obtained residue was recrystallized from a mixed solvent of ethyl acetate/heptane to give the title compound (114 mg) as cotton-like needle crystals.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[N:9]1[CH2:14][CH2:13][N:12]([C:15]([CH:17]2[N:21]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[C:20](=[O:28])[NH:19][CH2:18]2)=[O:16])[CH2:11][CH2:10]1.[H-].[Na+].[F:31][C:32]1[CH:33]=[C:34]([S:38](Cl)(=[O:40])=[O:39])[CH:35]=[CH:36][CH:37]=1>>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[N:9]1[CH2:14][CH2:13][N:12]([C:15]([CH:17]2[CH2:18][N:19]([S:38]([C:34]3[CH:35]=[CH:36][CH:37]=[C:32]([F:31])[CH:33]=3)(=[O:40])=[O:39])[C:20](=[O:28])[N:21]2[C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)=[O:16])[CH2:11][CH2:10]1
Reactant: Cc1ccc(C)c(N2CCN(C(=O)C3CNC(=O)N3c3ccccc3)CC2)c1
Reactant: O=S(=O)(Cl)c1cccc(F)c1
Agent: [H-]
Agent: [Na+]
Product: Cc1ccc(C)c(N2CCN(C(=O)C3CN(S(=O)(=O)c4cccc(F)c4)C(=O)N3c3ccccc3)CC2)c1

Procedure:
In analogy to example 33, (RS)-5-[4-(2,5-dimethyl-phenyl)-piperazine-1-carbonyl]-1-phenyl-imidazolidin-2-one (example 33, step 1) was reacted with sodium hydride and 3-fluorobenzenesulfonyl chloride to give the title compound as a colorless solid. MS: 537.0 ([M+H]+)
Reaction SMILES: [I-].[Na+].[CH3:3][C:4](=[CH2:18])[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:8]([C:15]([OH:17])=O)=[N:7]1.[NH2:19][C:20]1[S:21][CH:22]=[CH:23][N:24]=1>>[S:21]1[CH:22]=[CH:23][N:24]=[C:20]1[NH:19][C:15]([C:8]1[C:9]2[C:14](=[CH:13][CH:12]=[CH:11][CH:10]=2)[N:6]([CH2:5][C:4]([CH3:3])=[CH2:18])[N:7]=1)=[O:17]
Reactant: Nc1nccs1
Reactant: C=C(C)Cn1nc(C(=O)O)c2ccccc21
Agent: [I-]
Agent: [Na+]
Product: C=C(C)Cn1nc(C(=O)Nc2nccs2)c2ccccc21
Yield: 23.2 %

Procedure:
1-(2-Methylallyl)-indazole-3-carboxylic acid (440 mg) was obtained from methyl indazole-3-carboxylate (0.5 g, 2.84 mmol) and 1-chloro-2-methylpropene (0.28 mL, 2.84 mmol, with a catalytic amount of sodium iodide) following the general procedures G and E. 1-(2-Methylallyl)-indazole-3-carboxylic acid thiazol-2-ylamide (45 mg) was prepared from 1-(2-methylallyl)-indazole-3-carboxylic acid (140 mg, 0.65 mmol) and 2-aminothiazole (65 mg, 0.65 mmol) following the general procedure H.
Reaction SMILES: [CH2:1]([O:3][CH:4]([N:8]1[CH2:16][C:15]2[C:10](=[CH:11][C:12]([CH3:17])=[CH:13][CH:14]=2)[C:9]1=[O:18])[C:5]([OH:7])=O)[CH3:2].[CH2:19]([O:26][C:27](=[O:39])/[N:28]=[C:29](\[NH2:38])/[C:30]1[CH:35]=[CH:34][C:33]([CH2:36][NH2:37])=[CH:32][CH:31]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>>[CH2:19]([O:26][C:27](=[O:39])/[N:28]=[C:29](\[NH2:38])/[C:30]1[CH:31]=[CH:32][C:33]([CH2:36][NH:37][C:5](=[O:7])[CH:4]([O:3][CH2:1][CH3:2])[N:8]2[CH2:16][C:15]3[C:10](=[CH:11][C:12]([CH3:17])=[CH:13][CH:14]=3)[C:9]2=[O:18])=[CH:34][CH:35]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: CCOC(C(=O)O)N1Cc2ccc(C)cc2C1=O
Reactant: NCc1ccc(/C(N)=N/C(=O)OCc2ccccc2)cc1
Product: CCOC(C(=O)NCc1ccc(/C(N)=N/C(=O)OCc2ccccc2)cc1)N1Cc2ccc(C)cc2C1=O

Procedure:
According to general procedure C, (RS)-ethoxy-(6-methyl-1-oxo-1,3-dihydro-isoindol-2-yl)-acetic acid was reacted with [1-amino-1-(4-aminomethyl-phenyl)-meth-(Z)-ylidene]-carbamic acid benzyl ester to give (RS)-[1-amino-1-(4-{[2-ethoxy-2-(6-methyl-1-oxo-1,3-dihydro-isoindol-2-yl)-acetylamino]-methyl}-phenyl)-meth-(Z)-ylidene]-carbamic acid benzyl ester as light yellow foam, MS 515.5 ([M+H]+).
Reaction SMILES: [H-].[Na+].[SH:3][C:4]1[N:9]2[CH:10]=[CH:11][N:12]=[C:8]2[CH:7]=[CH:6][CH:5]=1.Cl[CH2:14][CH2:15][CH2:16][CH2:17][N:18]1[C:23](=[O:24])[C:22]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[C:21]2[S:31](=[O:35])(=[O:34])[CH2:32][CH2:33][N:20]2[C:19]1=[O:36].[I-].[Na+]>CN(C)C=O.O>[N:12]1[CH:11]=[CH:10][N:9]2[C:4]([S:3][CH2:14][CH2:15][CH2:16][CH2:17][N:18]3[C:23](=[O:24])[C:22]([C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)=[C:21]4[S:31](=[O:35])(=[O:34])[CH2:32][CH2:33][N:20]4[C:19]3=[O:36])=[CH:5][CH:6]=[CH:7][C:8]=12
Reactant: O=c1c(-c2ccccc2)c2n(c(=O)n1CCCCCl)CCS2(=O)=O
Reactant: Sc1cccc2nccn12
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: O=c1c(-c2ccccc2)c2n(c(=O)n1CCCCSc1cccc3nccn13)CCS2(=O)=O
Reaction time: 0.17 h

Procedure:
To a suspension of 60 mg (1.5 mmol) of 60% oily sodium hydride in 10 ml of N,N-dimethylformamide, 225 mg (1.5 mmol) of 5-mercaptoimidazo[1,2-a]pyridine was added at room temperature, followed by stirring for 10 minutes. To this mixture, 480 mg (1.3 mmol) of 6-(4-chlorobutyl)-1,1-dioxo-8-phenyl-2,3-dihydro-5H-thiazolo[3,2-c]pyrimidine-5,7(6H)-dione and 225 mg (1.5 mmol) of sodium iodide were added, followed by stirring at 80° C. for 3 hours. After cooling, the reaction mixture was poured into water and extracted with ethyl acetate 3 times. The organic layer was washed with water and dried, after which the solvent was distilled off. The residue was purified by column chromatography (eluent, ethyl acetate/ethanol=10/1) to yield 400 mg (65.7%, white foamy substance) of the desired product.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[CH:4][C:3]=1[F:11].[CH2:12]1[C@H:21]2[C@H:16]([CH2:17][CH2:18][C:19]3[CH:25]=[CH:24][CH:23]=[CH:22][C:20]=32)[NH:15][CH2:14][CH2:13]1.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1>>[NH2:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([N:15]2[C@@H:16]3[C@@H:21]([C:20]4[CH:22]=[CH:23][CH:24]=[CH:25][C:19]=4[CH2:18][CH2:17]3)[CH2:12][CH2:13][CH2:14]2)=[O:8])=[CH:4][C:3]=1[F:11]
Reactant: Nc1ccc(C(=O)O)cc1F
Reactant: c1ccc2c(c1)CC[C@@H]1NCCC[C@H]21
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Product: Nc1ccc(C(=O)N2CCC[C@@H]3c4ccccc4CC[C@@H]32)cc1F
Yield: 64 %

Procedure:
The title compound is prepared from 4-amino-3-fluoro-benzoic acid and cis-1,2,3,4,4a,5,6,10b-octahydro-benzo[f]quinoline following a procedure analogous to that described in Example 1 [2-(7-aza-1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexa-fluorophosphate is used]. Yield: 64% of theory; LC (method 4): tR=1.94 min; Mass spectrum (ESI+): m/z=325 [M+H]+.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]=[C:4]([C:8]#[N:9])[CH:3]=1.[CH3:10][NH2:11]>C1COCC1>[CH3:10][NH:11][C:2]1[N:7]=[CH:6][N:5]=[C:4]([C:8]#[N:9])[CH:3]=1
Reactant: N#Cc1cc(Cl)ncn1
Reactant: CN
Solvent: C1CCOC1
Product: CNc1cc(C#N)ncn1

Procedure:
To 6-chloro-pyrimidine-4-carbonitrile (1.37 g, 9.84 mmol) stirring in 10 ml THF under N2 was added a methylamine solution (2.0 M in THF, Aldrich) in aliquots, causing immediate precipitation. Reaction progress was monitored after addition of 5 ml methylamine solution, then 3 ml, then 2 ml. The mixture was concentrated and filtered through a pad of silica, eluting with 2%->5% MeOH in CH2Cl2 to obtain 6-methylamino-pyrimidine-4-carbonitrile as a pale yellow solid. MS: 135.0 (M+1); Calc'd. for C6H6N4—134.14.
Reaction SMILES: [C:1]([S@:5]([NH:7][C@@:8]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[F:26])([CH:17]([F:19])[F:18])[C:9]([F:16])([F:15])[C:10](OCC)=[O:11])=[O:6])([CH3:4])([CH3:3])[CH3:2].[H-].C([Al+]CC(C)C)C(C)C.C1(C)C=CC=CC=1>C1COCC1>[CH3:4][C:1]([S@:5]([NH:7][C@:8]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[F:26])([C:9]([F:15])([F:16])[CH:10]=[O:11])[CH:17]([F:19])[F:18])=[O:6])([CH3:2])[CH3:3]
Reactant: CCOC(=O)C(F)(F)[C@](N[S@](=O)C(C)(C)C)(c1ccccc1F)C(F)F
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: CC(C)(C)[S@@](=O)N[C@@](c1ccccc1F)(C(F)F)C(F)(F)C=O
Temperature: -78 °C
Reaction time: 2 h

Procedure:
To a solution of ethyl (S)-3-(((R)-tert-butylsulfinyl)amino)-2,2,4,4-tetrafluoro-3-(2-fluorophenyl)-butanoate (3.20 g, 7.97 mmol) in dry THF (35 mL) was added dropwise a solution of DIBAL-H (diisobutylaluminium hydride) in toluene (1.0 M, 16 mL, 16 mmol) at −78° C. under N2. The mixture was stirred at −78° C. for 2 hours. The reaction was quenched carefully with methanol (3 mL) at −78° C. Then water (20 mL) and ethyl acetate (200 mL) were added and the mixture was warmed to 25° C. The mixture was aged for 30 minutes. The resulting mixture was filtered through a Celite pad. The organic layer was washed with brine and dried over Na2SO4. The organic layer was concentrated to give crude product (R)-2-methyl-N—((S)-1,1,3,3-tetrafluoro-2-(2-fluorophenyl)-4-oxobutan-2-yl)propane-2-sulfinamide, which was used immediately in the next step without further purification.
Reaction SMILES: [CH2:1](O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH:9][C:10]1[CH:20]=[CH:19][C:13]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:12][CH:11]=1.P(Cl)(Cl)(Cl)(Cl)Cl.O>CCOCC>[CH2:17]([O:16][C:14]([C:13]1[CH:12]=[CH:11][C:10]([O:9][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[CH:20][CH:19]=1)=[O:15])[CH3:18]
Reactant: CCOC(=O)c1ccc(O)cc1
Reactant: OCc1ccccc1
Agent: ClP(Cl)(Cl)(Cl)Cl
Solvent: O
Solvent: CCOCC
Product: CCOC(=O)c1ccc(OCc2ccccc2)cc1

Procedure:
Benzyl alcohol (2.70g.; 0.025 mole) was added to a solution of ethyl 4-hydroxybenzoate (4.15g.; 0.025 mole) in dry ether followed by the careful addition of phosphorus pentachloride (2.5g). The mixture was boiled under reflux for 24 hrs. then poured into water and the ether layer removed. The aqueous solution was extracted with ether and the combined organic extracts dried (anhyd. MgSO4) to yield, on evaporation and purification by chromatography, 4-ethoxycarbonylphenoxy phenyl methane, m.p. 45° C.
Reaction SMILES: [Cl:1][C:2]1[CH:22]=[CH:21][C:5]2[CH2:6][CH:7]([CH3:20])[NH:8][N:9]=[C:10]([C:11]3[CH:16]=[CH:15][C:14]([N+:17]([O-:19])=[O:18])=[CH:13][CH:12]=3)[C:4]=2[CH:3]=1.[CH2:23]([N:26]=[C:27]=[O:28])[CH2:24][CH3:25]>>[Cl:1][C:2]1[CH:22]=[CH:21][C:5]2[CH2:6][CH:7]([CH3:20])[N:8]([C:27](=[O:28])[NH:26][CH2:23][CH2:24][CH3:25])[N:9]=[C:10]([C:11]3[CH:12]=[CH:13][C:14]([N+:17]([O-:19])=[O:18])=[CH:15][CH:16]=3)[C:4]=2[CH:3]=1
Reactant: CCCN=C=O
Reactant: CC1Cc2ccc(Cl)cc2C(c2ccc([N+](=O)[O-])cc2)=NN1
Product: CCCNC(=O)N1N=C(c2ccc([N+](=O)[O-])cc2)c2cc(Cl)ccc2CC1C
Yield: 83 %

Procedure:
0.6 g (1.9 mmoles) of 8-chloro-4-methyl-1-(4-nitrophenyl)-4,5-dihydro-3H-2,3-benzodiazepine (prepared in Example 5, Step D or in Example 36, starting compound) are reacted with n-propyl isocyanate according to the method described in Example 44. The crude product is recrystallized from ethanol. Thus, 0.63 g (83%) of the title compound are obtained. M.p.: 186°-187° C.
Reaction SMILES: [CH:1](=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:9](#[N:13])[CH2:10][C:11]#[N:12].N1CCCCC1>C(O)CCC>[C:2]1([CH:1]=[C:10]([C:9]#[N:13])[C:11]#[N:12])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=Cc1ccccc1
Reactant: N#CCC#N
Solvent: C1CCNCC1
Solvent: CCCCO
Product: N#CC(C#N)=Cc1ccccc1
Temperature: 20 °C
Reaction time: 16 h

Procedure:
Into a 50-mL round-bottom flask, was placed benzaldehyde (4 g, 37.69 mmol, 1.00 equiv), propanedinitrile (3.3 g, 49.95 mmol, 1.30 equiv), n-butanol (10 mL), piperidine (1 mL). The resulting solution was stirred for 16 h at 20° C. The resulting mixture was concentrated under vacuum. The resulting mixture was washed with 1×33 mL of H2O/EtOH(10/1). The solids were collected by filtration. The solid was dried in an oven. This resulted in 4.2 g (69%) of 2-(phenylmethylidene)propanedinitrile as a yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:30]=[CH:29][C:5]([CH2:6][NH:7][C:8]([C:10]2[CH:11]=[N:12][C:13]3[C:18]([C:19]=2[OH:20])=[CH:17][C:16]([CH2:21][N:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)=[CH:15][C:14]=3I)=[O:9])=[CH:4][CH:3]=1.[CH2:31]([OH:35])[CH2:32][C:33]#[CH:34]>CCN(CC)CC.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[Cl:1][C:2]1[CH:30]=[CH:29][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:19](=[O:20])[C:18]3[C:13]4=[C:14]([CH:34]=[C:33]([CH2:32][CH2:31][OH:35])[N:12]4[CH:11]=2)[CH:15]=[C:16]([CH2:21][N:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)[CH:17]=3)=[O:9])=[CH:4][CH:3]=1
Reactant: C#CCCO
Reactant: O=C(NCc1ccc(Cl)cc1)c1cnc2c(I)cc(CN3CCOCC3)cc2c1O
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Product: O=C(NCc1ccc(Cl)cc1)c1cn2c(CCO)cc3cc(CN4CCOCC4)cc(c1=O)c32
Temperature: 25 °C
Reaction time: 48 h
Yield: 56 %

Procedure:
To a suspension of N-(4-chlorobenzyl)-4-hydroxy-8-iodo-6-(4-morpholinylmethyl)-3-quinolinecarboxamide (581.4 mg) and PdCl2(PPh3)2 (37.9 mg) in Et3N (20 mL) is added CuI (10.3 mg) and 3-butyn-1-ol (0.082 mL). The reaction is stirred at room temperature for 2 days under N2. After 2 days the solvent evaporates. The resulting solid is dissolved in CH2Cl2 and partitioned against H2O. The aqueous layer is extracted with CH2Cl2 (2×). The combined organic layers are washed with brine (1×), dried over Na2SO4, filtered, and condensed. The crude solid is adsorbed onto silica and chromatographed (Biotage flash 40S, gradient from CH2Cl2 to 3% MeOH in CH2Cl2). Product-containing fractions are combined and concentrated to yield a creme solid. The solid is recrystallized from hot acetonitrile to afford 290 mg (56%) of N-(4-chlorobenzyl)-2-(2-hydroxyethyl)-8-(4-morpholinylmethyl)-6-oxo-6H-pyrrolo[3,2,1-ij]quinoline-5-carboxamide as an off-white solid, m.p. 169-172° C.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:10]2[NH:14][CH2:13][CH2:12][O:11]2)[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].C(Cl)Cl.[Cl:18][CH:19]([Cl:23])[C:20](Cl)=[O:21]>C(N(CC)CC)C>[N+:1]([C:4]1[CH:5]=[C:6]([CH:10]2[N:14]([C:20](=[O:21])[CH:19]([Cl:23])[Cl:18])[CH2:13][CH2:12][O:11]2)[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: O=C(Cl)C(Cl)Cl
Reactant: O=[N+]([O-])c1cccc(C2NCCO2)c1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(C(Cl)Cl)N1CCOC1c1cccc([N+](=O)[O-])c1
Temperature: 25 °C

Procedure:
Five and eight tenths grams of 2-m-nitrophenyl oxazolidine was dissolved in 50 ml. methylene chloride containing 3.5 g. of triethylamine. Dichloroacetyl chloride 4.4 g. was added dropwise with stirring to the reaction flask and cooled in a water bath at room temperature. When addition was complete, the mixture was stirred at room temperature for about 30 minutes, washed with water, separated and dried over anhydrous magnesium sulfate. The solvent was stripped off under vacuum. There was obtained a yield of 8.6 g. of the title compound, ND30 = 1.5590.
Reaction SMILES: [H-].[Na+].[F:3][C:4]1[CH:5]=[C:6]([NH:10][C:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=2)=[O:12])[CH:7]=[CH:8][CH:9]=1.I[CH3:20]>CN(C)C=O>[F:3][C:4]1[CH:5]=[C:6]([N:10]([CH3:20])[C:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=2)=[O:12])[CH:7]=[CH:8][CH:9]=1
Reactant: CI
Reactant: O=C(Nc1cccc(F)c1)c1ccccn1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN(C(=O)c1ccccn1)c1cccc(F)c1
Reaction time: 0.5 h
Yield: 51.7 %

Procedure:
To a suspension of 60% sodium hydride (1.76 g, 44 mmol) in dry dimethylformamide (50 mL) under nitrogen was added dropwise a solution of N-(3-fluorophenyl)-2-pyridinecarboxamide (6.87 g, 32 mmol), prepared by the process of Example 4, Step 1, in dimethylformamide (25 mL) over 30 minutes. After 30 minutes more, iodomethane (3.58 mL, 57 mmol) was added. The reaction mixture was quenched with water (500 mL), extracted with ether (3×400 mL) and further extracted with ethyl acetate (300 mL). After washing with brine the ethyl acetate layer was combined with the other organic extracts, which were dried and preadsorbed onto silica gel. Flash chromatography (250 g of silica gel gradient elution with 20-50% ethyl acetate in petroleum ether) was utilized to afford N-(3-fluorophenyl)-N-methyl-2-pyridinecarboxamide (3.81 g, 52%) m.p. 75°-78° C.
Reaction SMILES: [CH2:1]([O:8][C:9]1[N:14]=[C:13]([NH:15][C:16]2[CH:21]=[CH:20][C:19]([Br:22])=[CH:18][CH:17]=2)[C:12]([NH2:23])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N:24]#[C:25]Br.C(O)(C(F)(F)F)=O.C([O-])([O-])=O.[Na+].[Na+]>O>[CH2:1]([O:8][C:9]1[N:14]=[C:13]2[N:15]([C:16]3[CH:21]=[CH:20][C:19]([Br:22])=[CH:18][CH:17]=3)[C:25]([NH2:24])=[N:23][C:12]2=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Nc1ccc(OCc2ccccc2)nc1Nc1ccc(Br)cc1
Reactant: N#CBr
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: Nc1nc2ccc(OCc3ccccc3)nc2n1-c1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
To a suspension of 6-(benzyloxy)-N2-(4-bromophenyl)pyridine-2,3-diamine (3.86 g, 10.4 mmol) in H2O was added cyanogen bromide (1.44 g, 13.5 mmol) and TFA (200 μL). The reaction mixture was stirred at room temperature for 2.5 h, added 2 M aqueous Na2CO3 and extracted with DCM. The organic extract was dried over MgSO4, filtered, and concentrated. The residue was purified by column chromatography to give 5-(benzyloxy)-3-(4-bromophenyl)-3H-imidazo[4,5-b]pyridin-2-amine intermediate. The benzyl group was removed in a similar manner as the one described in Example 1.102 to give the title compound. LCMS m/z=305.1 [M+H]+; 1H NMR (400 MHz, DMSO-d6) δ ppm 6.22 (broad s, 2H), 6.29 (d, J=8.2 Hz, 1H), 7.39-7.46 (m, 3H), 7.77 (m, 2H), 9.96 (s, 1H).