Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1[N:2]([C:6]2[CH:11]=[CH:10][C:9](Br)=[CH:8][N:7]=2)[N:3]=[CH:4][CH:5]=1.C[Sn](C)(C)[C:15]1[CH:20]=[CH:19][C:18]([N:21]2[CH2:25][C@H:24]([CH2:26][C:27](=[O:31])[C:28]([NH2:30])=[O:29])[O:23][CH2:22]2)=[CH:17][C:16]=1[F:32]>>[N:1]1[N:2]([C:6]2[CH:11]=[CH:10][C:9]([C:15]3[CH:20]=[CH:19][C:18]([N:21]4[CH2:25][C@H:24]([CH2:26][C:27](=[O:31])[C:28]([NH2:30])=[O:29])[O:23][CH2:22]4)=[CH:17][C:16]=3[F:32])=[CH:8][N:7]=2)[N:3]=[CH:4][CH:5]=1
Reactant: C[Sn](C)(C)c1ccc(N2CO[C@@H](CC(=O)C(N)=O)C2)cc1F
Reactant: Brc1ccc(-n2nccn2)nc1
Product: NC(=O)C(=O)C[C@H]1CN(c2ccc(-c3ccc(-n4nccn4)nc3)c(F)c2)CO1

Procedure:
The same procedure as in Example 1 was conducted, except for adding 2-([1,2,3]triazol-2-yl)-5-bromopyridine and using (S)-3-(4-trimethylstannyl-3-fluorophenyl)-2-oxo-5-oxazolidinylmethyl acetamide as a starting material, to obtain the title compound.
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][C:7](Br)=[C:6]([Cl:11])[C:3]=1[C:4]#[N:5].[Cl:12][C:13]1[CH:14]=[C:15](B(O)O)[CH:16]=[C:17]([Cl:19])[CH:18]=1.C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[NH2:1][C:2]1[CH:9]=[CH:8][C:7]([C:15]2[CH:14]=[C:13]([Cl:12])[CH:18]=[C:17]([Cl:19])[CH:16]=2)=[C:6]([Cl:11])[C:3]=1[C:4]#[N:5]
Reactant: OB(O)c1cc(Cl)cc(Cl)c1
Reactant: N#Cc1c(N)ccc(Br)c1Cl
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: N#Cc1c(N)ccc(-c2cc(Cl)cc(Cl)c2)c1Cl
Yield: 63.9 %

Procedure:
This compound was prepared in a manner analogous to that of Step D of Example 1, using 2.3 grams (0.010 mole) of 2-amino-5-bromo-6-chlorobenzonitrile (prepared as in Step A of Example 2), 2.9 grams (0.015 mole) of 3,5-dichlorophenylboronic acid, 0.1 gram (catalyst) of tetrakis(triphenylphosphine)palladium(0), and 30 mL of aqueous 2M sodium carbonate in 75 mL of toluene. The solid product was recrystallized from toluene, yielding 1.9 grams of 2-amino-6-chloro-5-(3,5-dichlorophenyl)benzonitrile. The NMR spectrum was consistent with the proposed structure.
Reaction SMILES: CO[C:3]([CH:5]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([C:14]3([CH3:19])[O:18]CCO3)[CH:12]=2)[N:7]([CH2:20][CH3:21])[C:6]1=[O:22])=[O:4].[NH2:23][C:24]1[CH:25]=[C:26]([CH:38]=[CH:39][CH:40]=1)[C:27]([NH:29][C:30]1[CH:35]=[CH:34][C:33]([CH2:36][CH3:37])=[CH:32][CH:31]=1)=[O:28]>>[CH2:36]([C:33]1[CH:32]=[CH:31][C:30]([NH:29][C:27]([C:26]2[CH:25]=[C:24]([NH:23][C:3]([CH:5]3[C:13]4[C:8](=[CH:9][CH:10]=[C:11]([C:14](=[O:18])[CH3:19])[CH:12]=4)[N:7]([CH2:20][CH3:21])[C:6]3=[O:22])=[O:4])[CH:40]=[CH:39][CH:38]=2)=[O:28])=[CH:35][CH:34]=1)[CH3:37]
Reactant: CCN1C(=O)C(C(=O)OC)c2cc(C3(C)OCCO3)ccc21
Reactant: CCc1ccc(NC(=O)c2cccc(N)c2)cc1
Product: CCc1ccc(NC(=O)c2cccc(NC(=O)C3C(=O)N(CC)c4ccc(C(C)=O)cc43)c2)cc1

Procedure:
Prepared as in Example 1 from 1-ethyl-5-(2-methyl-[1,3]dioxolan-2-yl)-2-oxo-2,3-dihydro-1H-indole-3-carboxylic acid methyl ester and 3-amino-N-(4-ethyl-phenyl)-benzamide. Purified by chromatography (chloroform/methanol, 10:1). 1H NMR (DMSO-d6) δ 1.15 (m, 6 H), 2.5 (q, 2 H), 3.85 (q, 2 H), 6.85-8.3 (m, 11 H), 10.0 (s, 1 H), 11.1 (s, 1 H).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]([NH:13][C:14](=[O:18])OCC)=[N:11][C:10]2[C:5](=[CH:6][CH:7]=[C:8]([O:19][CH3:20])[CH:9]=2)[N:4]=1.[Cl:21][C:22]1[CH:27]=[CH:26][C:25]([N:28]2[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]2)=[CH:24][CH:23]=1>>[CH3:1][O:2][C:3]1[C:12]([NH:13][C:14]([N:31]2[CH2:30][CH2:29][N:28]([C:25]3[CH:24]=[CH:23][C:22]([Cl:21])=[CH:27][CH:26]=3)[CH2:33][CH2:32]2)=[O:18])=[N:11][C:10]2[C:5](=[CH:6][CH:7]=[C:8]([O:19][CH3:20])[CH:9]=2)[N:4]=1
Reactant: CCOC(=O)Nc1nc2cc(OC)ccc2nc1OC
Reactant: Clc1ccc(N2CCNCC2)cc1
Product: COc1ccc2nc(OC)c(NC(=O)N3CCN(c4ccc(Cl)cc4)CC3)nc2c1
Yield: 86 %

Procedure:
Ethyl N-(2,6-dimethoxyquinoxalin-3-yl)carbamate and 1-(4-chlorophenyl)piperazine were reacted by the same way with the example 64 to obtain the titled compound (yield, 86%). 1H NMR (300 MHz, CDCl3): δ 3.25 (s, 4H), 3.77 (s, 3H), 3.87 (s, 3H), 4.09-4.12 (m, 4H), 6.86-7.00 (m, 3H), 7.12-7.24 (m, 3H), 7.55-7.65 (m, 2H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:17]=[CH:18][CH:19]=1)[CH2:5][O:6][C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][CH:16]=1)[CH2:13][NH:12][CH2:11][CH2:10]2.C(=O)([O-])[O-].[K+].[K+].Br[CH:27]([CH3:31])[C:28]([NH2:30])=[O:29]>CC(C)=O>[F:1][C:2]1[CH:3]=[C:4]([CH:17]=[CH:18][CH:19]=1)[CH2:5][O:6][C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][CH:16]=1)[CH2:13][N:12]([CH:27]([CH3:31])[C:28]([NH2:30])=[O:29])[CH2:11][CH2:10]2
Reactant: Fc1cccc(COc2ccc3c(c2)CCNC3)c1
Reactant: CC(Br)C(N)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CC(C(N)=O)N1CCc2cc(OCc3cccc(F)c3)ccc2C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 73.8 %

Procedure:
To a mixture of 6-(3-fluoro-benzyloxy)-1,2,3,4-tetrahydro-isoquinoline (0.200 g, 0.78 mmol) and potassium carbonate (0.215 mg, 1.56 mmol) in acetone, 2-bromo-propionamide (0.142 mg, 0.936 mmol) was added and the resulting mixture was stirred overnight at room temperature. The mixture, after filtration and evaporation, was purified by chromatography (SiO2, hexane/Et2O 3:2 v:v) to give the title compound as a white solid (0.189 g, 74%). MS: m/e=329.3 (M+H+).
Reaction SMILES: C12CCC(CC1)CN(C(C[N:13]1[C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=3[C:17]([CH2:24][CH:25]3[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]3)=[N:16][CH:15](NC(OCC3C=CC=CC=3)=O)[C:14]1=[O:42])=O)C2>CO.[OH-].[OH-].[Pd+2]>[CH:25]1([CH2:24][C:17]2[C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[NH:13][C:14](=[O:42])[CH2:15][N:16]=2)[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30]1
Reactant: O=C(NC1N=C(CC2CCCCC2)c2ccccc2N(CC(=O)N2CC3CCC(CC3)C2)C1=O)OCc1ccccc1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Product: O=C1CN=C(CC2CCCCC2)c2ccccc2N1
Yield: 167.5 %

Procedure:
To a solution of (3RS)-1-[(3-azabicyclo[3.2.2]non-3-yl)carbonylmethyl]-3-benzyloxycarbonylamino-5-cyclohexylmethyl-2,3-dihydro-1H-1,4-benzodiazepin-2-one (0.396 g) in methanol (15 ml) was added Pearlman's catalyst (0.111 g). The mixture was stirred under H2 atmosphere over night. The catalyst was filtered off by suction filtration on Celite®. The filtrate was concentrated in vacuo to give (3RS)-3-amino-1-[(3-azalicyclo[3.2.2]non-3-yl)carbonylmethyl]-5-cyclohexylmethyl-2,3-dihydro-1H-1,4-benzodiazepin-2-one (0.298 g), which was used in a following reaction step without further purification.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][CH2:10][C:11]([CH3:14])([CH3:13])[N:12]=2)=[CH:4][CH:3]=1.[C:15]([N:19]1[C:23]([CH:24]([CH3:26])[CH3:25])=[CH:22][C:21]([CH:27]=[O:28])=[N:20]1)([CH3:18])([CH3:17])[CH3:16].[Cl-].[NH4+].C(OCC)(=O)C.CCCCCC>O1CCCC1.[Li]CCCC>[C:15]([N:19]1[C:23]([CH:24]([CH3:25])[CH3:26])=[CH:22][C:21]([CH:27]([OH:28])[C:2]2[CH:7]=[CH:6][C:5]([C:8]3[O:9][CH2:10][C:11]([CH3:14])([CH3:13])[N:12]=3)=[CH:4][CH:3]=2)=[N:20]1)([CH3:17])([CH3:18])[CH3:16]
Reactant: CC(C)c1cc(C=O)nn1C(C)(C)C
Reactant: CC1(C)COC(c2ccc(Br)cc2)=N1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CC(C)c1cc(C(O)c2ccc(C3=NC(C)(C)CO3)cc2)nn1C(C)(C)C
Yield: 53.9 %

Procedure:
To 20 ml of a solution of 1.15 g of 4-bromo-1-(4,4-dimethyl-1,3-oxazolin-2-yl)benzene in tetrahydrofuran, 3.23 ml of n-BuLi (1.53M hexane solution) were added dropwise at −78° C. under stirring, followed by stirring at the same temperature for 15 minutes. To the reaction mixture was added dropwise a solution of 0.8 g of 1-tert-butyl-5-isopropylpyrazole-3-carbaldehyde in 5 ml of tetrahydrofuran. The resulting mixture was stirred for 30 minutes. After the reaction, 10 ml of a saturated aqueous solution of ammonium chloride were added to the reaction mixture and the resulting mixture was extracted with ethyl acetate. The organic layer was washed with saturated saline, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue so obtained was subjected to chromatography on a silica gel column (developing solvent: 50% ethyl acetate/n-hexane), whereby 0.82 g of the title compound was obtained in the form of a colorless oil.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[N:12]3[CH:13]=[CH:14][CH:15]=[CH:16][C:11]3=[N:10][C:9]=2[C:17]2[CH:18]=[C:19]([CH:31]=[CH:32][CH:33]=2)[C:20]([NH:22][C:23]2[C:28]([F:29])=[CH:27][CH:26]=[CH:25][C:24]=2[F:30])=[O:21])[CH:5]=[CH:4][N:3]=1.[CH2:34]([O:36][C:37]1[CH:42]=[C:41]([N:43]2[CH2:48][CH2:47][N:46]([CH:49]3[CH2:54][CH2:53][N:52]([CH2:55][CH2:56][F:57])[CH2:51][CH2:50]3)[CH2:45][CH2:44]2)[CH:40]=[CH:39][C:38]=1[NH2:58])[CH3:35].O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C[O-].[Na+]>FC(F)(F)CO.CO.C(Cl)Cl.CCCCCC>[F:30][C:24]1[CH:25]=[CH:26][CH:27]=[C:28]([F:29])[C:23]=1[NH:22][C:20](=[O:21])[C:19]1[CH:31]=[CH:32][CH:33]=[C:17]([C:9]2[N:10]=[C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][N:12]3[C:8]=2[C:6]2[CH:5]=[CH:4][N:3]=[C:2]([NH:58][C:38]3[CH:39]=[CH:40][C:41]([N:43]4[CH2:48][CH2:47][N:46]([CH:49]5[CH2:54][CH2:53][N:52]([CH2:55][CH2:56][F:57])[CH2:51][CH2:50]5)[CH2:45][CH2:44]4)=[CH:42][C:37]=3[O:36][CH2:34][CH3:35])[N:7]=2)[CH:18]=1
Reactant: CCOc1cc(N2CCN(C3CCN(CCF)CC3)CC2)ccc1N
Reactant: O=C(Nc1c(F)cccc1F)c1cccc(-c2nc3ccccn3c2-c2ccnc(Cl)n2)c1
Agent: C[O-]
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Solvent: CO
Product: CCOc1cc(N2CCN(C3CCN(CCF)CC3)CC2)ccc1Nc1nccc(-c2c(-c3cccc(C(=O)Nc4c(F)cccc4F)c3)nc3ccccn23)n1
Temperature: 150 °C
Yield: 55 %

Procedure:
To 3-[3-(2-chloro-4-pyrimidinyl)imidazo[1,2-a]pyridin-2-yl]-N-(2,6-difluorophenyl)-benzamide (Intermediate Example 1) (100 mg, 0.22 mmol) and (2-(ethyloxy)-4-{4-[1-(2-fluoroethyl)-4-piperidinyl]-1-piperazinyl}phenyl)amine (68 mg, 0.20 mmol) in 2,2,2-trifluoroethanol (2 mL) was added p-toluenesulfonic acid monohydrate (140 mg, 0.74 mmol). The mixture was stirred and heated on a Biotage microwave at 150° C. for 45 min, then cooled to rt. The mixture was neutralized with 0.5M sodium methoxide in MeOH. The mixture was concentrated under vacuum and the residue purified by silica gel chromatography to give a yellow solid. The solid was dissolved in minimal DCM, then hexane was added until a precipitate was formed. The slurry was cooled at −10° C. for 30 min, then poured through a Teflon filter, washing the solids with cold hexanes. The solids were dried under vacuum to give the title compound (90 mg, 0.11 mmol, 54%) as a light yellow solid. 1H NMR (400 MHz, DMSO-d6) δ 10.24 (s, 1H), 9.37 (s, 1H), 8.36 (m, 2H), 8.22 (d, 1H, J=5.13 Hz), 8.05 (d, 1H, J=7.88 Hz), 7.81 (d, 1H, J=7.88 Hz), 7.73 (d, 1H, J=8.98 Hz), 7.61 (t, 1H, J=7.70 Hz), 7.35-7.50 (m, 3H), 7.21 (t, 2H, J=8.06 Hz), 6.97 (t, 1H, J=8.96 Hz), 6.65 (d, 1H, J=2.38 Hz), 6.44-6.50 (m, 2H), 4.56 (t, 1H, J=4.95 Hz), 4.44 (t, 1H, J=4.95 Hz), 4.06 (q, 2H, J=6.96 Hz), 3.11 (m, 4H), 2.92 (m, 2H), 2.60-2.64 (m, 4H), 2.49 (m, 1H), 2.18 (m, 1H), 1.94-2.03 (m, 2H), 1.72-1.79 (m, 2H), 1.37-1.48 (m, 2H), 1.24 (t, 3H, J=6.87 Hz), 0.82-0.87 (m, 1H). MS (ESI): 776 [M+H]+.
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][CH2:9][NH:10][C:11]1[N:20]=[C:19]([N:21]([C:23]2[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=2)[CH3:22])[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[N:12]=1)(C)(C)C.ClC1N=C(N(C2C=CC(OC)=CC=2)C)C2C(=CC=CC=2)N=1.C(OC(=O)NCCN)(C)(C)C.CCN(CC)CC>C(O)(C)C.C(Cl)Cl.CO.C(Cl)Cl>[NH2:7][CH2:8][CH2:9][NH:10][C:11]1[N:20]=[C:19]([N:21]([C:23]2[CH:24]=[CH:25][C:26]([O:29][CH3:30])=[CH:27][CH:28]=2)[CH3:22])[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[N:12]=1
Reactant: COc1ccc(N(C)c2nc(NCCNC(=O)OC(C)(C)C)nc3ccccc23)cc1
Agent: CC(C)(C)OC(=O)NCCN
Agent: COc1ccc(N(C)c2nc(Cl)nc3ccccc23)cc1
Solvent: CCN(CC)CC
Solvent: CC(C)O
Solvent: ClCCl
Product: COc1ccc(N(C)c2nc(NCCN)nc3ccccc23)cc1
Temperature: 85 °C
Reaction time: 48 h

Procedure:
(2-{4-[(4-Methoxy-phenyl)-methyl-amino]-quinazolin-2-ylamino}-ethyl)-carbamic acid tert-butyl ester: A mixture of (2-chloro-quinazolin-4-yl)-(4-methoxy-phenyl)-methyl-amine 1.50 g (4.47 mmol) and (2-amino-ethyl)-carbamic acid tert-butyl ester 0.94 g (5.60 mmol) with Et3N 2 mL in isopropanol was stirred at 85° C. for 48 h. The reaction mixture was diluted with CH2Cl2 and directly charged to gradient column chromatography (MeOH/CH2Cl2, 0% to 10%) to obtain the title compound. 1H NMR (CDCl3, 400 MHz) δ 7.44 (d, 1H, J=8.2 Hz), 7.40-7.36 (m, 1H), 7.11 (d, 2H, J=9.0 Hz), 6.91 (d, 2H, J=9.0 Hz), 6.85 (d, 1H, J=8.6 Hz), 6.72-6.67 (m, 1H), 3.84 (s, 3H), 3.68 (q, 2H, J=5.4 Hz), 3.52 (s, 3H), 3.43 (q, 2H, J=5.4 Hz), 1.43 (s, 9H); LC-MS (ESI+; 424 ([M+H]+)).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][OH:5].[Cl:6][C:7]1[CH:12]=[C:11]([O:13][CH2:14][CH:15]=[C:16]([Cl:18])[Cl:17])[CH:10]=[C:9]([Cl:19])[C:8]=1[OH:20].[OH-].[Na+].S(=O)(=O)(O)O>[Cl-].C([N+](CCCC)(CCCC)CCCC)CCC.O.C1(C)C=CC=CC=1>[Cl:6][C:7]1[CH:12]=[C:11]([O:13][CH2:14][CH:15]=[C:16]([Cl:18])[Cl:17])[CH:10]=[C:9]([Cl:19])[C:8]=1[O:20][CH2:2][CH2:3][CH2:4][OH:5]
Reactant: Oc1c(Cl)cc(OCC=C(Cl)Cl)cc1Cl
Reactant: OCCCBr
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=S(=O)(O)O
Agent: [Cl-]
Solvent: Cc1ccccc1
Solvent: O
Product: OCCCOc1c(Cl)cc(OCC=C(Cl)Cl)cc1Cl
Temperature: 60 °C
Reaction time: 14 h
Yield: 91.5 %

Procedure:
To a mixture of 0.72 g of 3-bromopropanol, 1.0 g of 2,6-dichloro-4-(3,3-dichloro-2-propenyloxy)phenol, 5.0 g of toluene, 0.04 g of tetra-n-butylammonium chloride and 5.0 g of water was added 0.77 g of a 27% aqueous sodium hydroxide solution. The mixture was heated to 60° C. and stirred for 14 hours. The reaction mixture was then cooled to 20° C. After 2.0 g of a 20% aqueous sulfuric acid solution was added thereto, the mixture was stirred and then separated. The obtained organic layer was washed with 5.0 g of water and concentrated under reduced pressure to give 1.1 g of 3-(2,6-dichloro-4-(3,3-dichloro-2-propenyloxy)phenoxy)-1-propyl alcohol (purity: 93%, yield: 82%).
Reaction SMILES: N#N.[H-].[Al+3].[Li+].[H-].[H-].[H-].[CH3:9][O:10][C:11]1[CH:12]=[C:13]([CH2:19][CH2:20][C:21](OC)=[O:22])[CH:14]=[CH:15][C:16]=1[O:17][CH3:18].[NH4+].[Cl-]>C1COCC1>[CH3:9][O:10][C:11]1[CH:12]=[C:13]([CH2:19][CH2:20][CH2:21][OH:22])[CH:14]=[CH:15][C:16]=1[O:17][CH3:18]
Reactant: COC(=O)CCc1ccc(OC)c(OC)c1
Agent: N#N
Agent: [Al+3]
Agent: [Cl-]
Solvent: C1CCOC1
Product: COc1ccc(CCCO)cc1OC
Temperature: 25 °C
Reaction time: 8 h
Yield: 13.9 %

Procedure:
To a 5 1, 3-neck flask, fitted with a condenser, mechanical stirrer and septum inlet, was added by needle/N2 pressure a solution of lithium aluminum hydride in THF (1M, 912 cc). Methyl 3-(3,4-dimethoxyphenyl)propionate (213 g, 0.95 mole) was dissolved in dry THF (total volume 900 cc and the resulting solution was added dropwise over a period of 5 hours using needle/N2 pressure to the stirred LAH solution at a rate to maintain gentle reflux under a continuous N2 atmosphere. The reaction mixture was stirred overnight at room temperature, cooled in an ice/acetone bath and treated dropwise over about 2 hours with saturated NH4Cl solution (104 cc), the nitrogen pressure being continued to this point. After stirring for several hours, the mixture was filtered and the salts were washed with dry THF. The filtrate was evaporated in vacuo to a light yellow oil; yield: 160 g. The salts from the above filtration were air-dried for several days, combined with CH2Cl2 (700 cc), stirred overnight and filtered. The filtrate was evaporated in vacuo to give an additional 26 g of product. The overall yield of a light yellow oil was: 186 g (100%).
Reaction SMILES: [CH3:1][N:2]1[C:6]([O:7][CH3:8])=[C:5]([C:9](O)=[O:10])[C:4]([CH3:12])=[N:3]1.C(N1C=CN=C1)(N1C=CN=C1)=O.[NH2:25][CH2:26][CH:27]1[CH2:31][CH2:30][CH2:29][N:28]1[CH2:32][CH3:33]>CN(C)C=O.O1CCCC1>[CH2:32]([N:28]1[CH2:29][CH2:30][CH2:31][CH:27]1[CH2:26][NH:25][C:9]([C:5]1[C:4]([CH3:12])=[N:3][N:2]([CH3:1])[C:6]=1[O:7][CH3:8])=[O:10])[CH3:33]
Reactant: CCN1CCCC1CN
Reactant: COc1c(C(=O)O)c(C)nn1C
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: CCN1CCCC1CNC(=O)c1c(C)nn(C)c1OC
Reaction time: 1 h
Yield: 90 %

Procedure:
3.1 g (0.0178 mole) of 1,3-dimethyl-5-methoxy-4-pyrazole carboxylic acid was dissolved in 15 ml of dry N,N-dimethylformamide. Then 3.18 g (0.0196 mole) of 1,1'-carbonyl-diimidazole was added. The reaction mixture was stirred for one hour. A solution of 2.28 g (0.0178 mole) of 2-(aminomethyl)-1-ethylpyrrolidine in 10 ml of dry tetrahydrofuran was added dropwise with stirring over 1/2 hour. The reaction was then stirred overnight at room temperature and the solvent evaporated under vacuum (1 mm) and a water bath (60° C.). The resultant oil was then taken up in chloroform, washed with a saturated solution of sodium chloride, dried over sodium sulfate and evaporated. 4.5 g of amber colored oil (90% yield) was obtained.
Reaction SMILES: [N:1]([CH:4]([C:8]1[CH:9]=[N:10][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:12][CH:13]=1)[CH2:5][CH2:6][OH:7])=[N+]=[N-]>[Pd].C(OCC)(=O)C>[NH2:1][CH:4]([C:8]1[CH:9]=[N:10][C:11]([C:14]([F:17])([F:15])[F:16])=[CH:12][CH:13]=1)[CH2:5][CH2:6][OH:7]
Reactant: [N-]=[N+]=NC(CCO)c1ccc(C(F)(F)F)nc1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: NC(CCO)c1ccc(C(F)(F)F)nc1
Reaction time: 8 h

Procedure:
A mixture of 3-azido-3-(6-(trifluoromethyl)pyridin-3-yl)propan-1-ol (7.29 g, 29.6 mmol), ethyl acetate (320 mL), and 10% Pd—C (3.2 g) was stirred under H2 (1 atm) overnight. The catalyst was filtered off and the filtrate was concentrated to give the title product.
Reaction SMILES: [Cl:1][C:2]1[C:7]([N:8]([C:10](=[O:28])[CH2:11][NH:12][C:13](=[O:27])/[CH:14]=[CH:15]/[C:16]2[CH:17]=[N:18][C:19]([C:22]([O:24][CH2:25][CH3:26])=[O:23])=[CH:20][CH:21]=2)[CH3:9])=[CH:6][CH:5]=[C:4]([Cl:29])[C:3]=1[CH2:30][OH:31].S(Cl)(C)(=O)=O.O[C:38]1[CH:39]=[CH:40][CH:41]=[C:42]2[C:47]=1[N:46]=[C:45]([CH3:48])[CH:44]=[C:43]2[N:49]1[CH:53]=[CH:52][N:51]=[CH:50]1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.C(OCC)(=O)C.O.C(N(CC)CC)C>[Cl:1][C:2]1[C:7]([N:8]([C:10](=[O:28])[CH2:11][NH:12][C:13](=[O:27])/[CH:14]=[CH:15]/[C:16]2[CH:17]=[N:18][C:19]([C:22]([O:24][CH2:25][CH3:26])=[O:23])=[CH:20][CH:21]=2)[CH3:9])=[CH:6][CH:5]=[C:4]([Cl:29])[C:3]=1[CH2:30][O:31][C:38]1[CH:39]=[CH:40][CH:41]=[C:42]2[C:47]=1[N:46]=[C:45]([CH3:48])[CH:44]=[C:43]2[N:49]1[CH:53]=[CH:52][N:51]=[CH:50]1
Reactant: Cc1cc(-n2ccnc2)c2cccc(O)c2n1
Reactant: CCOC(=O)c1ccc(/C=C/C(=O)NCC(=O)N(C)c2ccc(Cl)c(CO)c2Cl)cn1
Agent: CS(=O)(=O)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCOC(=O)c1ccc(/C=C/C(=O)NCC(=O)N(C)c2ccc(Cl)c(COc3cccc4c(-n5ccnc5)cc(C)nc34)c2Cl)cn1
Reaction time: 0.5 h
Yield: 79 %

Procedure:
To a stirred solution of 2,6-dichloro-3-[N-[(E)-3-(6-ethoxycarbonylpyridin-3-yl)acryloylglycyl]-N-methylamino]-1-(hydroxymethyl)benzene (150 mg) and triethylamine (60 mg) in N,N-dimethylformamide (1.5 ml) was dropwise added mesyl chloride (35.7 mg) under ice-cooling, and the mixture was stirred for 30 minutes at the same temperature. To the mixture was added 8-hydroxy-4-(imidazol-1-yl)-2-methylquinoline (66.9 mg) and potassium carbonate (205 mg) at ambient temperature, and the mixture was stirred overnight at the same temperature. Water and ethyl acetate were added thereto, and the separated organic layer was washed with 1N sodium hydroxide solution and water, dried over magnesium sulfate and evaporated in vacuo. The residue was purified by flash chromatography on silica gel (chloroform-methanol) to give 8-[2,6-dichloro-3-[N-[(E)-3-(6-ethoxycarbonylpyridin-3-yl)acryloylglycyl]-N-methylamino]benzyloxy]-4-(imidazol-1-yl)-2-methylquinoline (158 mg) as pale yellow amorphous.
Reaction SMILES: [C:1]1([C@@H:7]2[CH2:9][C@H:8]2[N:10]=[C:11]=[O:12])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:13][CH2:14][CH2:15][N:16]1[C:24]2[C:23]([CH3:25])=[C:22]([CH3:26])[N:21]=[C:20]([NH2:27])[C:19]=2[N:18]=[C:17]1[CH3:28]>>[NH2:27][C:20]1[C:19]2[N:18]=[C:17]([CH3:28])[N:16]([CH2:15][CH2:14][NH:13][C:11]([NH:10][C@@H:8]3[CH2:9][C@H:7]3[C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)=[O:12])[C:24]=2[C:23]([CH3:25])=[C:22]([CH3:26])[N:21]=1
Reactant: Cc1nc(N)c2nc(C)n(CCN)c2c1C
Reactant: O=C=N[C@@H]1C[C@H]1c1ccccc1
Product: Cc1nc(N)c2nc(C)n(CCNC(=O)N[C@@H]3C[C@H]3c3ccccc3)c2c1C

Procedure:
Using the method of Examples 118-133, trans-2-phenylcyclopropyl isocyanate was reacted with 1-(2-aminoethyl)-2,6,7-trimethyl-1H-imidazo[4,5-c]pyridin-4-amine to provide the desired compound. The observed accurate mass was 379.2235.
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].[CH3:5][O:6][C:7]1[CH:8]=[C:9]([C@H:15]2[C@@H:20]([OH:21])[CH2:19][CH2:18][CH2:17][NH:16]2)[CH:10]=[CH:11][C:12]=1[O:13][CH3:14]>C(Cl)Cl.[OH-].[Na+]>[C:1]([N:16]1[CH2:17][CH2:18][CH2:19][C@H:20]([OH:21])[C@@H:15]1[C:9]1[CH:10]=[CH:11][C:12]([O:13][CH3:14])=[C:7]([O:6][CH3:5])[CH:8]=1)(=[O:3])[CH3:2]
Reactant: COc1ccc([C@@H]2NCCC[C@@H]2O)cc1OC
Reactant: CC(=O)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: COc1ccc([C@H]2[C@@H](O)CCCN2C(C)=O)cc1OC
Reaction time: 0.5 h

Procedure:
Acetyl chloride (9.75 g, 125 mmoles) is added dropwise to a cooled (0° to 10° C) and stirred solution of cis-2-(3,4-dimethoxyphenyl)-3-piperidinol (25.0 g, 105 mmoles, described in Example 4) in methylene chloride (200 ml) and 8N sodium hydroxide (100 ml). The mixture is stirred for 30 minutes and the organic phase is separated. The aqueous phase is extracted with methylene chloride. The organic extracts are washed with dilute hydrochloric acid, aqueous sodium carbonate, brine, dried (MgSO4) and evaporated. The residue is subjected to chromatography on silica gel using methanol-ether 1:3 and the eluates are evaporated to give cis-1-acetyl-2-(3,4-dimethoxyphenyl)-3-piperidinol; nmr (CDCl3) δ 2.12 (s, 3H), 3.86 (s, 6H) and 7.0 (m, 3H).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7]([CH3:17])=[N:8][C:9](Cl)=[C:10]([N+:13]([O-:15])=[O:14])[C:11]=1[Cl:12])=[O:5])[CH3:2].C(N(CC)CC)C.[CH3:25][N:26]1[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1>>[CH2:1]([O:3][C:4]([C:6]1[C:7]([CH3:17])=[N:8][C:9]([N:29]2[CH2:30][CH2:31][N:26]([CH3:25])[CH2:27][CH2:28]2)=[C:10]([N+:13]([O-:15])=[O:14])[C:11]=1[Cl:12])=[O:5])[CH3:2]
Reactant: CCOC(=O)c1c(C)nc(Cl)c([N+](=O)[O-])c1Cl
Reactant: CN1CCNCC1
Solvent: CCN(CC)CC
Product: CCOC(=O)c1c(C)nc(N2CCN(C)CC2)c([N+](=O)[O-])c1Cl

Procedure:
55.8 g. of 4,6-dichloro-2-methyl-5-nitropyridine-3-carboxylic acid ethyl ester (0.2 mol.) are dissolved in 300 ml. of alcohol. After addition of 25 g. of triethylamine (0.25 mol.), the mixture is heated at reflux temperature and then 20 g. of N-methylpiperazine are dropped in with stirring. When the addition is completed, the temperature is maintained for 30 minutes. The solvent is distilled off, the residue is dissolved in benzene and the precipitated triethylammonium chloride filtered off. After evaporation of the solvent, the residual 4-chloro-2-methyl-6-(4-methyl-1-piperazinyl)-5-nitropyridine-3-carboxylic acid ethyl ester is recrystallized from methanol, yield 40 g. (60%), m.p. 59°-61°.
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6]2[C:7]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[N:8][O:9][C:10]=2[CH3:11])[N:3]=[CH:2]1.[N+:18]([C:21]1[CH:22]=[C:23](B(O)O)[CH:24]=[CH:25][CH:26]=1)([O-:20])=[O:19]>>[CH3:11][C:10]1[O:9][N:8]=[C:7]([C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:6]=1[C:4]1[N:3]=[CH:2][N:1]([C:25]2[CH:24]=[CH:23][CH:22]=[C:21]([N+:18]([O-:20])=[O:19])[CH:26]=2)[CH:5]=1
Reactant: Cc1onc(-c2ccccc2)c1-c1c[nH]cn1
Reactant: O=[N+]([O-])c1cccc(B(O)O)c1
Product: Cc1onc(-c2ccccc2)c1-c1cn(-c2cccc([N+](=O)[O-])c2)cn1
Yield: 74.2 %

Procedure:
As described for Example 3, 4-(1H-imidazol-4-yl)-5-methyl-3-phenyl-isoxazole (100 mg, 0.44 mmol) was converted, using 3-nitrophenylboronic acid (120 mg, 0.88 mmol) instead of 4-fluorophenylboronic acid, to the title compound (113 mg, 73%) which was obtained as a light yellow foam. MS: m/e=347.1 [M+H]+.