Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[NH:4][C:3]=1[C:11]1[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=1.[H-].[Na+].Br[CH2:20][CH2:21][CH2:22][CH2:23][C:24]#[N:25].O>CN(C=O)C>[C:24]([CH2:23][CH2:22][CH2:21][CH2:20][N:4]1[C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[C:2]([CH3:1])=[C:3]1[C:11]1[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=1)#[N:25]
Reactant: Cc1c(-c2cccnc2)[nH]c2ccccc12
Reactant: N#CCCCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1c(-c2cccnc2)n(CCCCC#N)c2ccccc12
Reaction time: 0.5 h

Procedure:
A solution of 3-methyl-2-(3-pyridyl)indole (2.09 g) in 12 ml of DMF is added to a suspension of 0.528 g of 50% sodium hydride (dispersion in mineral oil) in 6 ml of DMF at 0°. The mixture is stirred at 0° for 0.5 hour and is treated with a solution of 1.78 g of 5-bromovaleronitrile in 4 ml of DMF. This mixture is stirred at room temperature overnight and is poured into 125 ml of water. This is extracted with 2×50 ml of ether, the extract is washed with 3×20 ml of water and dried over MgSO4 to give 1-(4-cyanobutyl)-3-methyl-2-(3-pyridyl)-indole as an oil.
Reaction SMILES: [Br:1][C:2]1[C:3]([CH2:10]O)=[N:4][C:5]([Cl:9])=[CH:6][C:7]=1[CH3:8].C(Br)(Br)(Br)[Br:13].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>C(Cl)Cl>[Br:1][C:2]1[C:3]([CH2:10][Br:13])=[N:4][C:5]([Cl:9])=[CH:6][C:7]=1[CH3:8]
Reactant: Cc1cc(Cl)nc(CO)c1Br
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: Cc1cc(Cl)nc(CBr)c1Br
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
A solution of (3-bromo-6-chloro-4-methylpyridin-2-yl)methanol (22.9 g, 97 mmol) in CH2Cl2 (1.5 L) was cooled to 0° C. CBr4 (48.2 g, 145 mmol) was added, followed by Ph3P (38.1 g, 145 mmol). The reaction was stirred at 0° C. for 20 minutes and then warmed to r.t. for 16 hours. The reaction was then concentrated and the residue was purified by flash chromatography on silica gel with 0 to 10% EtOAc/heptanes to afford of 3-bromo-2-(bromomethyl)-6-chloro-4-methylpyridine. 1H NMR (CDCl3, 500 MHz) δ 7.16 (s, 1H), 4.67 (s, 2H), 2.43 (s, 3H).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:14])[C@H:5]([CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[NH2:6])[CH3:2].[CH2:15]([O:17][CH:18]([O:21][CH2:22][CH3:23])[CH2:19]Br)[CH3:16].CCN(C(C)C)C(C)C>CN(C=O)C.C(Cl)(Cl)Cl>[CH2:1]([O:3][C:4](=[O:14])[C@@H:5]([NH:6][CH2:19][CH:18]([O:21][CH2:22][CH3:23])[O:17][CH2:15][CH3:16])[CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[CH3:2]
Reactant: CCOC(CBr)OCC
Reactant: CCOC(=O)[C@@H](N)Cc1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: ClC(Cl)Cl
Product: CCOC(=O)[C@H](Cc1ccccc1)NCC(OCC)OCC
Temperature: 23 °C

Procedure:
A solution of L-phenylalanine ethyl ester (8.37 g, 46.8 mmol, 1 equiv), bromoacetaldehyde diethyl acetal (10.6 mL, 70.1 mmol, 1.5 equiv), and DIEA (16.2 mL, 93.4 mmol, 2.0 equiv) in DMF (100 mL) was heated at 80° C. for 2 d. The resulting solution was cooled to 23° C., taken up in chloroform (200 mL), washed with 10% aqueous potassium carbonate (3×50 mL), dried over potassium carbonate, and concentrated. Purification of the residue by silica gel chromatography yield 7.4 g (54%) of product. 1H NMR (CDCl3) δ 1.13-1.23 (m, 9H), 2.61 (dd, 1H, J=11.8, 5.9), 2.78 (dd, 1H, J=11.8, 5.9), 2.96-3.03 (m, 2H), 3.46-3.53 (m, 1H), 3.55-3.70 (m, 4H), 4.18 (q, 2H, J=7.1), 4.57 (t, 1H, J=5.5), 7.19-7.33 (m, 5H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:20]=[CH:21][CH:22]=1)[CH2:5][N:6]1[C:14](=[O:15])[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([C:16]([OH:18])=O)[CH:12]=2)[C:7]1=[O:19].[N:23]1([CH2:28][CH2:29][CH2:30][NH2:31])[CH2:27][CH2:26][CH2:25][CH2:24]1>>[Cl-:1].[Cl:1][C:2]1[CH:3]=[C:4]([CH:20]=[CH:21][CH:22]=1)[CH2:5][N:6]1[C:14](=[O:15])[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([C:16]([NH:31][CH2:30][CH2:29][CH2:28][NH+:23]3[CH2:27][CH2:26][CH2:25][CH2:24]3)=[O:18])[CH:12]=2)[C:7]1=[O:19]
Reactant: NCCCN1CCCC1
Reactant: O=C(O)c1ccc2c(c1)C(=O)N(Cc1cccc(Cl)c1)C2=O
Product: O=C(NCCC[NH+]1CCCC1)c1ccc2c(c1)C(=O)N(Cc1cccc(Cl)c1)C2=O
Product: [Cl-]

Procedure:
2-(3-chloro-benzyl)-1,3-dioxo-2,3-dihydro-1H-isoindol-5-carboxylic acid (100 mg, 0.316 mmol) and 3-pyrrolidin-1-yl-propylamine (100 μL, 0.792 mmol) were reacted with each other. Target compound in the amount of 46 mg (31%) was obtained by following the procedure described in Example 1.
Reaction SMILES: [NH2:1][C@@H:2]([CH2:15][C@H:16]1[CH2:21][CH2:20][CH2:19][O:18][CH2:17]1)[CH2:3][N:4]([CH3:14])[C:5](=[O:13])[O:6][CH2:7][CH2:8][Si:9]([CH3:12])([CH3:11])[CH3:10].Cl[C:23]([O:25][C:26]1[CH:31]=[CH:30][C:29]([N+:32]([O-:34])=[O:33])=[CH:28][CH:27]=1)=[O:24].C([O-])(O)=O.[Na+]>CC#N>[CH3:14][N:4]([CH2:3][C@@H:2]([NH:1][C:23](=[O:24])[O:25][C:26]1[CH:27]=[CH:28][C:29]([N+:32]([O-:34])=[O:33])=[CH:30][CH:31]=1)[CH2:15][C@H:16]1[CH2:21][CH2:20][CH2:19][O:18][CH2:17]1)[C:5]([O:6][CH2:7][CH2:8][Si:9]([CH3:12])([CH3:11])[CH3:10])=[O:13]
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Reactant: CN(C[C@@H](N)C[C@H]1CCCOC1)C(=O)OCC[Si](C)(C)C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Product: CN(C[C@H](C[C@H]1CCCOC1)NC(=O)Oc1ccc([N+](=O)[O-])cc1)C(=O)OCC[Si](C)(C)C
Temperature: 25 °C
Reaction time: 3 h
Yield: 104.2 %

Procedure:
A solution of 2-(trimethylsilyl)ethyl (S)-2-amino-3-((R)-tetrahydro-2H-pyran-3-yl)propyl(methyl)carbamate (0.7350 g, 2.32 mmol, 1.0 equiv, ˜7% diastereomeric impurities) in CH3CN (50 mL) was treated with 4-nitrophenyl chloroformate (0.4950 g, 2.45 mmol, 1.05 equiv) and 0.600 g (7.14 mmol, 3 equiv) of NaHCO3. The reaction was stirred at rt for 3 hr. The mixture was filtered using Celite® 545. The filtrate was evaporated under reduced pressure to afford 1.1647 g (100%) of (4-nitrophenyl) (S)-1-(N-methyl-N-(trimethylsilylethoxycarbonyl)amino)-3-((R)-tetrahydro-2H-pyran-3-yl)propan-2-ylcarbamate, which was used in the next step without further purification. MS ESI +ve m/z 504 (M+Na).
Reaction SMILES: [CH2:1]([O:8][C:9]([C:11]1[NH:12][C:13]([CH:16]=[O:17])=[CH:14][CH:15]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.P([O-])(O)(O)=[O:19].[Na+].Cl([O-])=O.[Na+].C=C(C)C>C(O)CCC.O>[CH2:1]([O:8][C:9]([C:11]1[NH:12][C:13]([C:16]([OH:19])=[O:17])=[CH:14][CH:15]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=P([O-])(O)O
Reactant: O=Cc1ccc(C(=O)OCc2ccccc2)[nH]1
Agent: C=C(C)C
Agent: [Na+]
Agent: [O-][Cl+][O-]
Solvent: O
Solvent: CCCCO
Product: O=C(O)c1ccc(C(=O)OCc2ccccc2)[nH]1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
To a solution of 5-formyl-1H-pyrrole-2-carboxylic acid benzyl ester (8.0 g) in n-butanol (300 mL) and water (112 mL) was added sodium dihydrogen phosphate (6.28 g), sodium chlorite (9.47 g) and isobutene (58g). The mixture was stirred for 20 h at RT after which it was concentrated. After purification of the residue by flash column chromatography on silica (DCM/MeOH 15:1 to 1:1) 10.0 g of 1H-pyrrole-2,5-dicarboxylic acid monobenzyl ester were obtained.
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([O:10][CH2:11][CH:12]([OH:16])[CH2:13][CH2:14][NH2:15])[CH:3]=1.[C:17]([OH:23])([C:19]([F:22])([F:21])[F:20])=[O:18].[Cl:24][C:25]1[N:26]=[C:27](Cl)[C:28]2[CH2:33][CH2:32][CH:31]([C:34]3[CH:39]=[CH:38][C:37]([F:40])=[CH:36][CH:35]=3)[C:29]=2[N:30]=1.C(N(C(C)C)C(C)C)C>C(#N)C>[NH2:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([O:10][CH2:11][CH:12]([OH:16])[CH2:13][CH2:14][NH:15][C:27]2[C:28]3[CH2:33][CH2:32][CH:31]([C:34]4[CH:35]=[CH:36][C:37]([F:40])=[CH:38][CH:39]=4)[C:29]=3[N:30]=[C:25]([Cl:24])[N:26]=2)[CH:3]=1.[C:17]([OH:23])([C:19]([F:22])([F:21])[F:20])=[O:18]
Reactant: N#Cc1ccc(N)cc1OCC(O)CCN
Reactant: Fc1ccc(C2CCc3c(Cl)nc(Cl)nc32)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Solvent: O=C(O)C(F)(F)F
Product: N#Cc1ccc(N)cc1OCC(O)CCNc1nc(Cl)nc2c1CCC2c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
The mixture of 4-amino-2-(4-amino-2-hydroxybutoxy)benzonitrile, 2 TFA salt (Preparation Z, 50 mg, 0.111 mmol), 2,4-dichloro-7-(4-fluorophenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine (Preparation R, 31.5 mg, 0.111 mmol) and N-ethyl-N-isopropylpropan-2-amine (97 μL, 0.556 mmol) in acetonitrile (556 μL) was stirred at rt for 24 h. The reaction mixture was concentrated and purified by Prep-HPLC to obtain 4-amino-2-(4-(2-chloro-7-(4-fluorophenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-ylamino)-2-hydroxybutoxy)benzonitrile, TFA (14.73 mg, 22.75% yield). LC-MS (M+H)+=468.2. 1H NMR (500 MHz, methanol-d4) δ 7.27-7.15 (m, 3H), 7.14-7.01 (m, 2H), 6.40-6.24 (m, 2H), 4.44-4.33 (m, 1H), 4.17-4.04 (m, 2H), 4.03-3.95 (m, 1H), 3.89-3.66 (m, 2H), 2.94-2.81 (m, 1H), 2.81-2.67 (m, 2H), 2.14 (td, J=7.5, 4.0 Hz, 1H), 2.10-2.00 (m, 1H), 1.95 (dd, J=14.0, 6.4 Hz, 1H).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9](=[O:32])[NH:10][C:11]1[CH:16]=[CH:15][C:14]([CH2:17][C:18]([O:20]C2C(F)=C(F)C(F)=C(F)C=2F)=O)=[CH:13][CH:12]=1.[NH2:33][C@@H:34]([CH3:47])[CH2:35][O:36][C:37]1[CH:46]=[CH:45][C:40]([C:41]([O:43]C)=[O:42])=[CH:39][CH:38]=1.CN([CH:51]=[O:52])C>CCOC(C)=O>[CH3:51][O:52][C:16]1[CH:15]=[C:14]([CH2:17][C:18]([NH:33][C@@H:34]([CH3:47])[CH2:35][O:36][C:37]2[CH:46]=[CH:45][C:40]([C:41]([OH:43])=[O:42])=[CH:39][CH:38]=2)=[O:20])[CH:13]=[CH:12][C:11]=1[NH:10][C:9]([NH:8][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[CH3:1])=[O:32]
Reactant: CN(C)C=O
Reactant: Cc1ccccc1NC(=O)Nc1ccc(CC(=O)Oc2c(F)c(F)c(F)c(F)c2F)cc1
Reactant: COC(=O)c1ccc(OC[C@H](C)N)cc1
Solvent: CCOC(C)=O
Product: COc1cc(CC(=O)N[C@@H](C)COc2ccc(C(=O)O)cc2)ccc1NC(=O)Nc1ccccc1C
Temperature: 25 °C
Reaction time: 3 h
Yield: 36 %

Procedure:
A mixture of pentafluorophenyl 4-[N′-(2-methylphenyl)ureido]phenylacetate (560 mg, 1.24 mmol), methyl (S)-4-(2-amino-1-propoxy)benzoate (260 mg, 1.24 mmol), Et3 N (0.260 mL, 1.87 mmol) in DMF (8 mL) was stirred at room temp for 3 hr. The mixture was diluted with EtOAc and the solution was washed with 0.5 N HCl, brine, and dried over Na2SO4. After removal of the solvent, the residue was purified by recrystallization from MeOH—CHCl3-n-hexane to give 210 mg (36%) (S)-4-[2-[3-methoxy-4-[N′-(2-methylphenyl)ureido]phenylacetylamino]-1-propoxy]benzoic acid as a white crystalline powder. 1H-NMR (DMSO-d6) δ 1.17 (d, 3 H, J=6.8 Hz), 2.24 (s, 3 H), 3.32 (s, 2 H), 3.81 (s, 3 H), 3.92–4.03 (m, 2 H), 4.08–4.15 (m, 1 H), 6.92–6.95 (m, 1 H), 7.04–7.06 (m, 2 H), 7.12–7.18 (m, 4 H), 7.35–7.39 (m, 2 H), 7.83–7.85 (m, 1 H), 7.89–7.92 (m, 3 H), 8.12–8.14 (m, 1 H), 8.97 (s, 1 H).
Reaction SMILES: [NH2:1][CH2:2][C:3]1[C:12](=[O:13])[C:11]2[C:6](=[CH:7][C:8]([Cl:14])=[CH:9][CH:10]=2)[N:5]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:4]=1.[F:21][C:22]1[C:30]([F:31])=[CH:29][CH:28]=[CH:27][C:23]=1[C:24](Cl)=[O:25]>>[Cl:14][C:8]1[CH:7]=[C:6]2[C:11]([C:12](=[O:13])[C:3]([CH2:2][NH:1][C:24](=[O:25])[C:23]3[CH:27]=[CH:28][CH:29]=[C:30]([F:31])[C:22]=3[F:21])=[CH:4][N:5]2[C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)=[CH:10][CH:9]=1
Reactant: NCc1cn(-c2ccccc2)c2cc(Cl)ccc2c1=O
Reactant: O=C(Cl)c1cccc(F)c1F
Product: O=C(NCc1cn(-c2ccccc2)c2cc(Cl)ccc2c1=O)c1cccc(F)c1F

Procedure:
N-(7-Chloro-4-oxo-1-phenyl-1,4-dihydro-quinolin-3-ylmethyl)-2,3-difluoro-benzamide was prepared starting from intermediate D and 2,3-difluoro-benzoyl chloride. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.75 (s, 1H) 8.28 (d, J=8.66 Hz, 1H) 8.00 (s, 1H) 7.15-7.80 (m, 9H) 6.92 (d, J=1.81 Hz, 1H) 0.39 (d, J=5.64 Hz, 2H).
Reaction SMILES: [F:1][C:2]([N+:20]([O-:22])=[O:21])([N+:17]([O-:19])=[O:18])[CH2:3][N:4]([CH2:8][C:9]([N+:14]([O-:16])=[O:15])([N+:11]([O-:13])=[O:12])[F:10])[C:5](Cl)=[O:6].[F:23][C:24]([N+:30]([O-:32])=[O:31])([N+:27]([O-:29])=[O:28])[CH2:25][NH2:26]>>[F:1][C:2]([N+:20]([O-:22])=[O:21])([N+:17]([O-:19])=[O:18])[CH2:3][N:4]([CH2:8][C:9]([N+:14]([O-:16])=[O:15])([N+:11]([O-:13])=[O:12])[F:10])[C:5]([NH:26][CH2:25][C:24]([N+:30]([O-:32])=[O:31])([N+:27]([O-:29])=[O:28])[F:23])=[O:6]
Reactant: NCC(F)([N+](=O)[O-])[N+](=O)[O-]
Reactant: O=C(Cl)N(CC(F)([N+](=O)[O-])[N+](=O)[O-])CC(F)([N+](=O)[O-])[N+](=O)[O-]
Product: O=C(NCC(F)([N+](=O)[O-])[N+](=O)[O-])N(CC(F)([N+](=O)[O-])[N+](=O)[O-])CC(F)([N+](=O)[O-])[N+](=O)[O-]

Procedure:
A previous method for the preparation of N,N-bis(2-fluoro-2,2-dinitroethyl)carbamyl chloride (I) has been reported by W. H. Gilligan and M. J. Kamlet in U.S. Pat. No. 3,850,978, which issued on Nov. 26, 1974. However, that method suffers from the serious disadvantage that the carbamyl chloride (I) can not be separated from the reaction mixture and must be used in crude form for subsequent reactions. This drawback greatly hinders the preparation of derivatives of the carbamyl chloride (I) and heretofore certain derivatives of it could be prepared only in very low yield or not at all. For example, reaction of crude N,N-bis(2-fluoro-2,2-dinitroethyl)carbamyl chloride (prepared by the procedure of Gilligan and Kamlet, supra) with 2-fluoro-2,2-dinitroethyl amine gave none of the desired N,N,N'-tris(2-fluoro-2,2-dinitroethyl)urea. Less than a 5% yield of N,N-bis(2-fluoro-2,2-dinitroethyl)-O-(2,2,2-trinitroethyl)carbamate was obtain when the crude N,N-bis(2-fluoro-2,2-dinitroethyl)carbamyl chloride was reacted with 2,2,2-trinitroethanol.
Reaction SMILES: [OH:1][C@@H:2]1[CH2:7][N:6]([CH3:8])[C@H:5]([C:9]([N:11]2[CH2:16][CH:15]=[C:14]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH2:13][CH2:12]2)=[O:10])[C@@H:4]([C:23]([O:25][CH3:26])=[O:24])[CH2:3]1.C(Cl)Cl.C1N=CN([C:35]([N:37]2[CH:41]=N[CH:39]=[CH:38]2)=[O:36])C=1.N1CCC[CH2:44][CH2:43]1>>[N:37]1([C:35]([O:1][C@H:2]2[CH2:3][C@H:4]([C:23]([O:25][CH3:26])=[O:24])[C@@H:5]([C:9]([N:11]3[CH2:12][CH:13]=[C:14]([C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=4)[CH2:15][CH2:16]3)=[O:10])[N:6]([CH3:8])[CH2:7]2)=[O:36])[CH2:38][CH2:39][CH2:44][CH2:43][CH2:41]1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: COC(=O)[C@H]1C[C@H](O)CN(C)[C@@H]1C(=O)N1CC=C(c2ccccc2)CC1
Reactant: C1CCNCC1
Solvent: ClCCl
Product: COC(=O)[C@H]1C[C@H](OC(=O)N2CCCCC2)CN(C)[C@@H]1C(=O)N1CC=C(c2ccccc2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of methyl(2S,3S,5S)-5-hydroxy-1-methyl-2-[(4-phenyl-3,6-dihydropyridin-1(2H)-yl)carbonyl]piperidine-3-carboxylate (72 mg, 0.00020 mol) in methylene chloride (2.0 mL, 0.031 mol) was treated with N,N-carbonyldiimidazole (50 mg, 0.0003 mol) at rt for 2 h. To the mixture was added piperidine (0.060 mL, 0.00060 mol). After stirred at rt overnight, the mixture was concentrated to dry and used directly in next step.
Reaction SMILES: CCN(C(C)C)C(C)C.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.[N:31]1([C:36]2[CH:37]=[CH:38][C:39]3[N:40]([CH:42]=[C:43]([C:45]([OH:47])=O)[N:44]=3)[CH:41]=2)[CH:35]=[CH:34][CH:33]=[N:32]1.Cl.[NH2:49][CH2:50][C:51]([N:53]1[CH2:58][CH2:57][CH:56]([O:59][C:60]2[CH:65]=[CH:64][CH:63]=[CH:62][C:61]=2[Cl:66])[CH2:55][CH2:54]1)=[O:52]>CN(C=O)C.O>[Cl:66][C:61]1[CH:62]=[CH:63][CH:64]=[CH:65][C:60]=1[O:59][CH:56]1[CH2:55][CH2:54][N:53]([C:51](=[O:52])[CH2:50][NH:49][C:45]([C:43]2[N:44]=[C:39]3[CH:38]=[CH:37][C:36]([N:31]4[CH:35]=[CH:34][CH:33]=[N:32]4)=[CH:41][N:40]3[CH:42]=2)=[O:47])[CH2:58][CH2:57]1
Reactant: O=C(O)c1cn2cc(-n3cccn3)ccc2n1
Reactant: NCC(=O)N1CCC(Oc2ccccc2Cl)CC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NCC(=O)N1CCC(Oc2ccccc2Cl)CC1)c1cn2cc(-n3cccn3)ccc2n1
Reaction time: 0.03 h
Yield: 36.1 %

Procedure:
DIPEA (169 mg, 1.3 mmol) followed by HOBt (39 mg, 0.29 mmol) and EDCI (75 mg, 0.39 mmol) was added to a stirred solution of 6-pyrazol-1-yl-imidazo[1,2-a]pyridine-2-carboxylic acid (60 mg, 0.26 mmol) in DMF (1 mL). After 2 minutes of stirring, 2-amino-1-[4-(2-chloro-phenoxy)-piperidin-1-yl]-ethanone hydrochloride (80 mg, 0.26 mmol) (prepared according to Step 1 and 5 of the General Scheme) was added and the resulting mixture was stirred at room temperature overnight. Cold water was added and the reaction mixture was partitioned with ethyl acetate, the organic layer was dried over sodium sulfate and concentrated under reduced pressure. Purification by preparative HPLC afforded 45 mg (33% Yield) of 6-pyrazol-1-yl-imidazo[1,2-a]pyridine-2-carboxylic acid {2-[4-(2-chloro-phenoxy)-piperidin-1-yl]-2-oxo-ethyl}-amide. LC/MS [M+H]+: 479, 97.25%. 1H NMR (300 MHz, DMSO-d6): δ 9.2 (s, 1H), 8.5 (m, 2H), 8.4 (t, 1H), 8.0 (dd, 1H), 7.8 (m, 2H), 7.4 (dd, 1H), 7.53 (m, 2H), 7.0 (m, 1H), 6.6 (t, 1H), 4.8 (m, 1H), 4.0 (bs, 1H), 4.2 (d, 2H), 3.7 (m, 2H), 3.4 (m, 2H), 2.0 (m, 2H), 1.7 (m, 2H).
Reaction SMILES: [CH3:1][N:2]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[CH2:3][C:4]([OH:6])=[O:5].C([O-])([O-])=O.[Cs+].[Cs+].[Cl:19][C:20]1[CH:27]=[CH:26][C:23]([CH2:24]Cl)=[CH:22][CH:21]=1>CN(C=O)C.CCOC(C)=O>[CH3:1][N:2]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[CH2:3][C:4]([O:6][CH2:24][C:23]1[CH:26]=[CH:27][C:20]([Cl:19])=[CH:21][CH:22]=1)=[O:5]
Reactant: CN(CC(=O)O)c1ccccc1
Reactant: ClCc1ccc(Cl)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CN(CC(=O)OCc1ccc(Cl)cc1)c1ccccc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 68 %

Procedure:
The product from step 2 (220 mg, 1.3 mmol) was dissolved in DMF (7 mL) and Cs2CO3 (652 mg, 2.0 mmol) added, followed by 4-chlorobenzyl chloride (214 mg, 1.3 mmol). Allow reaction mixture to stir at ambient temperature over 18 hours. The reaction mixture was diluted with EtOAc and washed several times with brine. The organic layer was dried (Na2SO4), filtered and concentrated to afford the title compound as a yellow oil (68%). MS (ES+) m/z 290 (MH+).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[CH2:7]=O.[NH2:9][C:10]1[C:15]2=[C:16]([C:27]3[CH:32]=[CH:31][C:30]([NH:33][C:34]([NH:36][C:37]4[CH:42]=[CH:41][CH:40]=[C:39]([C:43]([F:46])([F:45])[F:44])[N:38]=4)=[O:35])=[CH:29][CH:28]=3)[C:17]([C:19]([NH:21][CH2:22][C:23]([F:26])([F:25])[F:24])=[O:20])=[CH:18][N:14]2[N:13]=[CH:12][N:11]=1>C(O)(=O)C>[NH2:9][C:10]1[C:15]2=[C:16]([C:27]3[CH:32]=[CH:31][C:30]([NH:33][C:34]([NH:36][C:37]4[CH:42]=[CH:41][CH:40]=[C:39]([C:43]([F:46])([F:45])[F:44])[N:38]=4)=[O:35])=[CH:29][CH:28]=3)[C:17]([C:19]([NH:21][CH2:22][C:23]([F:26])([F:25])[F:24])=[O:20])=[C:18]([CH2:7][N:1]3[CH2:6][CH2:5][O:4][CH2:3][CH2:2]3)[N:14]2[N:13]=[CH:12][N:11]=1
Reactant: C1COCCN1
Reactant: C=O
Reactant: Nc1ncnn2cc(C(=O)NCC(F)(F)F)c(-c3ccc(NC(=O)Nc4cccc(C(F)(F)F)n4)cc3)c12
Solvent: CC(=O)O
Product: Nc1ncnn2c(CN3CCOCC3)c(C(=O)NCC(F)(F)F)c(-c3ccc(NC(=O)Nc4cccc(C(F)(F)F)n4)cc3)c12
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 31.5 %

Procedure:
To a solution of morpholine (80.9 mg, 0.93 mmol) in acetic acid (1 mL) was added a 37% aqueous formaldehyde solution (0.07 mL, 0.93 mmol). The mixture was stirred at rt under nitrogen for 20 min and was added to a solution of Intermediate AP (4-amino-N-(2,2,2-trifluoroethyl)-5-{4-[({[6-(trifluoromethyl)pyridin-2-yl]amino}-carbonyl)-amino]phenyl}pyrrolo[2,1-f][1,2,4]triazine-6-carboxamide (50.0 mg, 0.093 mmol)) in acetic acid (2 mL). The resultant solution was heated (60° C.) overnight and concentrated. The crude material was directly purified by HPLC using a gradient of 35-40% MeCN in water containing 0.1% trifluoroacetic acid. The combined fractions were concentrated under reduced pressure. The residue was dissolved in EtOAc (15 mL). The organic layer was washed with a 2.0 M Na2CO3 aqueous solution (15 mL), brine (15 mL), dried (Na2SO4) and concentrated under reduced pressure to yield 18.7 mg (32%) of the title compound. 1H-NMR (DMSO-d6) δ 10.0 (t, J=6.3 Hz, 1H), 9.89 (bs, 1H), 9.71 (bs, 1H), 8.05-8.00 (m, 2H), 7.98 (s, 1H), 7.52-7.49 (m, 3H), 7.31 (d, J=8.6 Hz, 2H), 4.12-3.98 (m, 4H), 3.56 (bs, 4H), 2.44 ((bs, 4H); MS [M+H]+=638.1; LCMS RT=2.92 min.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][OH:7].C(N(CC)CC)C.[CH3:15][S:16](Cl)(=[O:18])=[O:17]>C(Cl)Cl>[S:16]([O:7][CH2:6][C:2]1[S:1][CH:5]=[CH:4][CH:3]=1)(=[O:18])(=[O:17])[CH3:15]
Reactant: OCc1cccs1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)OCc1cccs1
Temperature: 0 °C

Procedure:
2-thienylmethanol mesylate is prepared by treating a solution of 2-thienylmethanol (5.57 g; 50 mmol) in methylene chloride (100 ml) and triethylamine (15.05 g, 150 mmol) at 0° C. with methanesulfonyl chloride (11.45 g, 100 mmol) dropwise and at RT 1 hr after the addition. The reaction mixture is poured into ice-water and the organic layer is separated, dried (MgSO4), and evaporated.
Reaction SMILES: C[O:2][C:3](=O)[CH2:4][C:5]1[N:14]=[C:13]([C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[C:17]([O:23][CH3:24])[CH:16]=2)[C:12]2[C:7](=[CH:8][C:9]([O:28][CH3:29])=[C:10]([O:26][CH3:27])[C:11]=2C)[N:6]=1.[BH4-].[Na+].O1CCCC1.CO>O>[CH3:27][O:26][C:10]1[CH:11]=[C:12]2[C:7](=[CH:8][C:9]=1[O:28][CH3:29])[N:6]=[C:5]([CH2:4][CH2:3][OH:2])[N:14]=[C:13]2[C:15]1[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[C:17]([O:23][CH3:24])[CH:16]=1
Reactant: COC(=O)Cc1nc(-c2ccc(OC)c(OC)c2)c2c(C)c(OC)c(OC)cc2n1
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: COc1ccc(-c2nc(CCO)nc3cc(OC)c(OC)cc23)cc1OC
Yield: 83.5 %

Procedure:
To a mixture of methyl 6,7-dimethoxy-4-(3,4-dimethoxyphenyl)quinazoline-2-acetic acid methyl ester(4.0 g), sodium borohydride (1.9 g) and tetrahydrofuran (80 ml), methanol (15 ml) was added dropwise under continuous reflux, followed by refluxing for 2 hours. The reaction mixture was poured into water and extracted with ethyl acetate. The ethyl acetate layer was washed with water, dried (MgSO4) and concentrated under reduced pressure to yield 6,7-dimethoxy-4-(3,4-dimethoxyphenyl)-2-(2-hydroxyethyl) quinazoline (3.0 g, 81%). Recrystallization from ethyl acetate gave a colorless needle crystal having a melting point of 165 to 166° C.
Reaction SMILES: Br[C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH:7]([CH3:19])[N:8]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:9]2)=[CH:4][CH:3]=1.[CH3:20][N:21]1[CH:25]=[C:24](B2OC(C)(C)C(C)(C)O2)[CH:23]=[N:22]1.C(=O)([O-])[O-].[K+].[K+].ClCCl>O1CCOCC1.O>[CH3:19][CH:7]1[CH2:6][C:5]2[C:10](=[CH:11][C:2]([C:24]3[CH:23]=[N:22][N:21]([CH3:20])[CH:25]=3)=[CH:3][CH:4]=2)[CH2:9][N:8]1[C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13]
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Reactant: CC1Cc2ccc(Br)cc2CN1C(=O)OC(C)(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: O
Solvent: C1COCCO1
Product: CC1Cc2ccc(-c3cnn(C)c3)cc2CN1C(=O)OC(C)(C)C
Temperature: 120 °C
Yield: 97.7 %

Procedure:
A mixture of tert-butyl 7-bromo-3-methyl-3,4-dihydroisoquinoline-2(1H)-carboxylate (0.326 g, 1.00 mmol), 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (0.31 g, 1.50 mmol, Aldrich, Cat. No. 595314), in 1,4-dioxane (4.0 mL) was stirred at r.t. for 10 min. Potassium carbonate (415 mg, 3.00 mmol) in water (2.0 mL) was added to give a deep red solution. The mixture was degassed and refilled with nitrogen three times. [1,1′-Bis(diphenylphosphino)ferrocene]dichloropalladium(II) complex with dichloromethane (1:1) (35.0 mg, 0.0424 mmol) was added and the mixture was degassed and refilled with nitrogen three times and then heated at 120° C.)(oil bath temperature) for 3 h. After cooling, the mixture was diluted with ethyl acetate, washed with water and brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by flash chromatography on a silica gel column with methanol in DCM (0-10%) to give the desired product (320 mg, 97.7%). LCMS (M+H)+: m/z=328.1.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:6]([C:7]#[N:8])=[CH:5][CH:4]=1.C[O-].[Na+].[Cl-:14].[NH4+:15]>CO>[ClH:14].[CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:6]([C:7]([NH2:15])=[NH:8])=[CH:5][CH:4]=1
Reactant: [NH4+]
Reactant: [Cl-]
Reactant: COc1ccc(C#N)cc1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: COc1ccc(C(=N)N)cc1
Product: Cl
Temperature: 25 °C
Reaction time: 120 h
Yield: 26.9 %

Procedure:
To a solution of 4-methoxybenzonitrile (10.0 g) in methanol (75 ml) was added sodium methoxide (0.41 g) and the reaction was stirred at room temperature for 5 days. Ammonium chloride (4.6 g) was added and the reaction was stirred overnight. The reaction was filtered and the filtrate concentrated to an oil. After the addition of ether the off-white precipitate was collected and dried to yield the title compound (3.77 g). Electrospray MS m/z 151 [M+H]+.