Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]=[C:2]([CH2:40][CH2:41][O:42][CH2:43][CH2:44][O:45][CH2:46][CH2:47][O:48][CH2:49][CH2:50][O:51][CH2:52][CH2:53][NH:54][C:55](=[O:69])[CH2:56][CH2:57][CH2:58][CH2:59][CH:60]1[CH:67]2[CH:63]([NH:64][C:65](=[O:68])[NH:66]2)[CH2:62][S:61]1)[NH:3][CH2:4][CH2:5][CH2:6][O:7][C:8]1[CH:39]=[CH:38][C:11]([C:12]([C:14]2[CH:19]=[CH:18][C:17]([NH:20][CH2:21][CH2:22][O:23][CH2:24][CH2:25][O:26][CH2:27][CH2:28][O:29][CH2:30][CH2:31][O:32][CH2:33][CH2:34][C:35]([OH:37])=[O:36])=[CH:16][CH:15]=2)=[O:13])=[CH:10][CH:9]=1.O[N:71]1[C:75](=[O:76])[CH2:74][CH2:73][C:72]1=[O:77].C(Cl)CCl>C(Cl)Cl>[O:1]=[C:2]([CH2:40][CH2:41][O:42][CH2:43][CH2:44][O:45][CH2:46][CH2:47][O:48][CH2:49][CH2:50][O:51][CH2:52][CH2:53][NH:54][C:55](=[O:69])[CH2:56][CH2:57][CH2:58][CH2:59][CH:60]1[CH:67]2[CH:63]([NH:64][C:65](=[O:68])[NH:66]2)[CH2:62][S:61]1)[NH:3][CH2:4][CH2:5][CH2:6][O:7][C:8]1[CH:39]=[CH:38][C:11]([C:12]([C:14]2[CH:19]=[CH:18][C:17]([NH:20][CH2:21][CH2:22][O:23][CH2:24][CH2:25][O:26][CH2:27][CH2:28][O:29][CH2:30][CH2:31][O:32][CH2:33][CH2:34][C:35]([O:37][N:71]3[C:75](=[O:76])[CH2:74][CH2:73][C:72]3=[O:77])=[O:36])=[CH:16][CH:15]=2)=[O:13])=[CH:10][CH:9]=1
Reactant: O=C(O)CCOCCOCCOCCOCCNc1ccc(C(=O)c2ccc(OCCCNC(=O)CCOCCOCCOCCOCCNC(=O)CCCCC3SCC4NC(=O)NC43)cc2)cc1
Reactant: O=C1CCC(=O)N1O
Solvent: ClCCCl
Solvent: ClCCl
Product: O=C(CCCCC1SCC2NC(=O)NC21)NCCOCCOCCOCCOCCC(=O)NCCCOc1ccc(C(=O)c2ccc(NCCOCCOCCOCCOCCC(=O)ON3C(=O)CCC3=O)cc2)cc1
Temperature: 25 °C

Procedure:
To a solution of crude 1-((4-(4-((5,21-dioxo-25-(2-oxohexahydro-1H-thieno[3,4-d]imidazol-4-yl)-8,11,14,17-tetraoxa-4,20-diazapentacosyl)oxy)benzoyl)phenyl)amino)-3,6,9,12-tetraoxapentadecan-15-oic acid (1.85 g, 1.89 mmol) in anhydrous DCM (43.0 ml) was added N-hydroxysuccinimide (239 mg, 2.08 mmol) followed by EDC (471 mg, 2.46 mmol). The reaction was stirred at r.t. for 4 hs. Upon completion, reaction was concentrated under reduced pressure and purified by silica gel chromatography (DCM to DCM:iPrOH, gradient) to provide 2,5-dioxopyrrolidin-1-yl 1-((4-(4-((5,21-dioxo-25-(2-oxohexahydro-1H-thieno[3,4-d]imidazol-4-yl)-8,11,14,17-tetraoxa-4,20-diazapentacosyl)oxy)benzoyl)phenyl)amino)-3,6,9,12-tetraoxapentadecan-15-oate as slightly yellow oil.
Reaction SMILES: [S:1]1[C:9]2[C:4](=[N:5][CH:6]=[CH:7][C:8]=2[CH2:10][C:11]([OH:13])=O)[CH:3]=[CH:2]1.[Cl-].[NH4+:15].N>C(O)C>[S:1]1[C:9]2[C:4](=[N:5][CH:6]=[CH:7][C:8]=2[CH2:10][C:11]([NH2:15])=[O:13])[CH:3]=[CH:2]1
Reactant: O=C(O)Cc1ccnc2ccsc12
Reactant: [NH4+]
Agent: N
Agent: [Cl-]
Solvent: CCO
Product: NC(=O)Cc1ccnc2ccsc12
Temperature: -78 °C
Yield: 55.6 %

Procedure:
In a high pressure flask, dissolve (thieno[3,2-b]pyridin-7-yl)acetic acid (3.02 g, 13.65 mmol) in absolute ethanol (100 mL). Add ammonium chloride (1.09 g, 20.38 mmol) to the solution. Cool the solution to −78° C. Condense ammonia gas into the solution by bubbling (15 minutes at 10 psi). Seal the flask and slowly bring to ambient temperature. Stir the reaction at room temperature for 4 days. Cool the reaction vessel to −78° C. Open the flask and allow it to slowly return to ambient pressure. Filter the contents and wash with water (10 mL) to obtain the title compound as a white solid (1.46 g). Concentrate the filtrate and triturate the residue with diethyl ether. Filter and wash with water (5 mL) to obtain additional pure product (0.46 g).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH2:11])[C:5](=[CH:9][CH:10]=1)[C:6]([OH:8])=[O:7].[F:12][C:13]([F:24])([F:23])[C:14]1[CH:22]=[CH:21][C:17]([C:18](F)=O)=[CH:16][CH:15]=1>>[F:1][C:2]1[CH:10]=[CH:9][C:5]2[C:6](=[O:8])[O:7][C:18]([C:17]3[CH:16]=[CH:15][C:14]([C:13]([F:12])([F:23])[F:24])=[CH:22][CH:21]=3)=[N:11][C:4]=2[CH:3]=1
Reactant: Nc1cc(F)ccc1C(=O)O
Reactant: O=C(F)c1ccc(C(F)(F)F)cc1
Product: O=c1oc(-c2ccc(C(F)(F)F)cc2)nc2cc(F)ccc12
Yield: 91.3 %

Procedure:
When the reaction conditions of Example 1 are employed but 11.6 g of 4-fluoroanthranilic acid and 14.4 g of p-trifluoromethylbenzoyl fluoride are used, 21.1 g (91%) of 7-fluoro-2-(p-trifluoromethylphenyl)-4H-3,1-benzoxazin-4-one of melting point 137°-139° C. are obtained.
Reaction SMILES: C(N(S(F)(F)[F:7])CC)C.[C:10]([O:13][CH2:14][CH2:15][CH2:16][CH:17](O)[CH2:18][CH2:19][CH2:20][O:21][C:22](=[O:24])[CH3:23])(=[O:12])[CH3:11]>C(Cl)Cl.C(OCC)(=O)C>[C:10]([O:13][CH2:14][CH2:15][CH2:16][CH:17]([F:7])[CH2:18][CH2:19][CH2:20][O:21][C:22](=[O:24])[CH3:23])(=[O:12])[CH3:11]
Reactant: CC(=O)OCCCC(O)CCCOC(C)=O
Reactant: CCN(CC)S(F)(F)F
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CC(=O)OCCCC(F)CCCOC(C)=O
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 94.7 %

Procedure:
To a solution of (diethylamino)-sulfur trifluoride (571 mg, 3.54 mmol) in CH2Cl2 was added the solution of acetic acid, 7-acetoxy-4-hydroxy-heptyl ester (403 mg, 1.74 mmol) in CH2Cl2 (10 ml) at −78° C. The resulting mixture was allowed to stir for 15 minutes at −78° C., 30 minutes at room temperature and then diluted with ethyl acetate (300 ml). The organic solution was washed with sat. NaHCO3, brine and dried over Na2SO4. Evaporation of the solvent and purification of the residue by column chromatography on silica gel, using 15% ethyl acetate in hexanes, gave the title compound (386 mg, 94%) as a colorless oil. 1H NMR (CDCl3) δ 1.55–1.83 (m, 8H), 2.05 (s, 6H), 4.05–4.15 (m, 4H), 4.39–4.63 (m, 1H); 13C NMR (CDCl3) δ 20.97, 24.42, 24.48, 31.51, 31.79, 64.03, 92.22, 94.45, 171.12; 19F NMR (CDCl3) δ −106.44–105.27(m); ES-MS m/z 257.3 (M+Na).
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH:14]=[CH:13][C:12]([C@@H:15]3[CH2:17][C@H:16]3[NH:18][S:19]([CH:22]([CH3:24])[CH3:23])(=[O:21])=[O:20])=[CH:11][CH:10]=2)O1.C([O-])([O-])=O.[Na+].[Na+].O1[CH2:37][CH2:36]OCC1>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>[CH3:17][C:16]1[N:18]=[CH:37][C:36]([C:9]2[CH:10]=[CH:11][C:12]([C@@H:15]3[CH2:17][C@H:16]3[NH:18][S:19]([CH:22]([CH3:23])[CH3:24])(=[O:20])=[O:21])=[CH:13][CH:14]=2)=[CH:12][CH:15]=1
Reactant: CC(C)S(=O)(=O)N[C@@H]1C[C@H]1c1ccc(B2OC(C)(C)C(C)(C)O2)cc1
Reactant: C1COCCO1
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+]
Product: Cc1ccc(-c2ccc([C@@H]3C[C@H]3NS(=O)(=O)C(C)C)cc2)cn1
Temperature: 90 °C
Reaction time: 3.5 h

Procedure:
In an 8 ml vial (PLS apparatus) the bromoaryl reagent (3-bromo-6-methylpyridine for Example 2) (0.328 mmol) was placed together with a solution of trans-N-{2-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]cyclopropyl}-2-propanesulfonamide (Intermediate 8) (60 mg, 0.164 mmol) in dry 1,4-dioxane (1.0 ml). Polymer supported Tetrakis catalyst (Pol-Pd(PPh3)4) (15 mg, 0.00164 mmol), and Na2CO3 2M (0.205 ml, 0.41 mmol) were added. The reaction mixture was shaken at 90° C. for 3-4 h (if reaction not complete by LC/MS analysis then heated for an additional 3 h) then left at room temperature overnight. The resin was filtered off (by Alltech filter tube) and washed with dichloromethane, water, methanol and dichloromethane. The liquid phase was evaporated until dryness under reduced pressure and the residue was taken up in dichloromethane (2 ml) and washed with HCl 1M (1 ml) then the acidic solution was basified with K2CO3 2M and extracted with dichloromethane (2×1 ml). The combined organic extracts were concentrated under reduced pressure to give a crude oil which was purified by reverse phase HPLC to give the title compound. The HPLC conditions were as given in “Preparative Chromatography” above.
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])[CH3:2].[Cl:8][C:9]1[CH:10]=[C:11]([NH:16][C:17]2[C:26]3[C:21](=[CH:22][C:23]([O:44][CH2:45][CH:46]4[CH2:48][CH2:47]4)=[C:24]([NH:27][C:28](=[O:43])[CH:29]=[CH:30][CH2:31][N:32]4[CH2:37][CH2:36][NH:35][CH2:34][CH:33]4[C:38]([O:40][CH2:41][CH3:42])=[O:39])[CH:25]=3)[N:20]=[CH:19][N:18]=2)[CH:12]=[CH:13][C:14]=1[F:15].C(N(CC)CC)C>C(Cl)Cl>[Cl:8][C:9]1[CH:10]=[C:11]([NH:16][C:17]2[C:26]3[C:21](=[CH:22][C:23]([O:44][CH2:45][CH:46]4[CH2:47][CH2:48]4)=[C:24]([NH:27][C:28](=[O:43])[CH:29]=[CH:30][CH2:31][N:32]4[CH2:37][CH2:36][N:35]([C:1]([CH3:2])=[O:3])[CH2:34][CH:33]4[C:38]([O:40][CH2:41][CH3:42])=[O:39])[CH:25]=3)[N:20]=[CH:19][N:18]=2)[CH:12]=[CH:13][C:14]=1[F:15]
Reactant: CC(=O)OC(C)=O
Reactant: CCOC(=O)C1CNCCN1CC=CC(=O)Nc1cc2c(Nc3ccc(F)c(Cl)c3)ncnc2cc1OCC1CC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)C1CN(C(C)=O)CCN1CC=CC(=O)Nc1cc2c(Nc3ccc(F)c(Cl)c3)ncnc2cc1OCC1CC1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
0.12 ml of acetic acid anhydride are added dropwise to a mixture of 500 mg of 4-[(3-chloro-4-fluoro-phenyl)amino]-6-({4-[2-(ethoxycarbonyl)-piperazin-1-yl]-1-oxo-2-buten-1-yl}amino)-7-cyclopropylmethoxy-quinazoline and 0.18 ml of triethylamine in 5 ml of methylene chloride at 0° C. The reaction mixture is stirred for one hour at 0° C. followed by one hour at room temperature, washed with water, concentrated sodium chloride solution, dried over magnesium sulfate, and concentrated in vacuo. The crude product is purified by column chromatography on silica gel with ethyl acetate/methanol (98:2 to 95:5). Yield: 291 mg (54% of theory), Melting point: 152-156° C. Mass spectrum (ESI+): m/z=625, 627 [M+H]+
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([C:8]2[CH:12]=[CH:11][S:10][CH:9]=2)[N:3]=1.C([Sn](CCCC)(CCCC)[C:18]1[N:22]2[CH:23]=[CH:24][C:25]([C:27]([F:30])([F:29])[F:28])=[N:26][C:21]2=[N:20][CH:19]=1)CCC>>[S:10]1[CH:11]=[CH:12][C:8]([C:4]2[N:3]=[C:2]([C:18]3[N:22]4[CH:23]=[CH:24][C:25]([C:27]([F:28])([F:29])[F:30])=[N:26][C:21]4=[N:20][CH:19]=3)[CH:7]=[CH:6][CH:5]=2)=[CH:9]1
Reactant: CCCC[Sn](CCCC)(CCCC)c1cnc2nc(C(F)(F)F)ccn12
Reactant: Brc1cccc(-c2ccsc2)n1
Product: FC(F)(F)c1ccn2c(-c3cccc(-c4ccsc4)n3)cnc2n1
Yield: 11.2 %

Procedure:
2-Bromo-6-(thien-3-yl)pyridine (2.20 g, 9.1 mmol) was coupled to 3-tributylstannyl-7-trifluoromethylimidazo[1,2-α]pyrimidine (9.0 mmol) by the method of Example 1. Purification by chromatography on silica gel eluting with isohexane on a gradient of ethyl acetate (10-80%) and trituration with isohexane followed by crystallisation from ethyl acetate-isohexane gave 3-[6-(thien-3-yl)pyridin-2-yl]-7-trifluoromethyl-imidazo[1,2-α]pyrimidine (350 mg) as a pale yellow solid: δH (400 MHz, CDCl3) 7.40 (1H, d, J 7), 7.48-7.50 (1H, m), 7.60 (1H, d, J 8), 7.69-7.73 (2H, m), 7.86 (1H, dd, J 8 and 8), 7.92-7.94 (1H, m), 8.54 (1H, s), 10.56 (1H, d, J 7); m/z (ES+) 347 (M++H).
Reaction SMILES: [NH2:1][C:2]1[C:7]([O:8][C:9]2[CH:14]=[CH:13][C:12]([Cl:15])=[C:11]([Cl:16])[CH:10]=2)=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:17][C:18]([O:20]CC)=[O:19].[OH-].[Na+].O>C1C=CC=CC=1>[NH2:1][C:2]1[C:7]([O:8][C:9]2[CH:14]=[CH:13][C:12]([Cl:15])=[C:11]([Cl:16])[CH:10]=2)=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:17][C:18]([OH:20])=[O:19]
Reactant: CCOC(=O)Cc1cccc(Oc2ccc(Cl)c(Cl)c2)c1N
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: c1ccccc1
Product: Nc1c(CC(=O)O)cccc1Oc1ccc(Cl)c(Cl)c1
Yield: 63.6 %

Procedure:
A mixture of ethyl 2-[2-amino-3-(3,4-dichlorphenoxy)phenyl]acetate (7.2 g.), sodium hydroxide (1.7 g.) and water (50 ml.) was treated in a similar manner to that of Example 5-(2). The resultant residue was pulverized with benzene, and the precipitates were collected by filtration and dried to give 2-[2-amino-3-(3,4-dichlorophenoxy)phenyl]acetic acid (4.2 g.). mp 125° to 127° C.
Reaction SMILES: Br.[NH2:2][C:3]1[S:4][C:5](Br)=[CH:6][N:7]=1.[SH:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[N:11]1[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=1[S:9][C:5]1[S:4][C:3]([NH2:2])=[N:7][CH:6]=1
Reactant: Nc1ncc(Br)s1
Reactant: Sc1ccccn1
Agent: Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Nc1ncc(Sc2ccccn2)s1
Temperature: 80 °C
Reaction time: 16 h
Yield: 73.1 %

Procedure:
To a solution of 2-amino-5-bromothiazole hydrobromide (1.00 g, 3.85 mmol) in DMF (8 mL) was added 2-mercaptopyridine (428 mg, 3.85 mmol) followed by addition of powdered K2CO3 (1.81 g, 15.09 mmol). The mixture was stirred at 80° C. for 1 h and at rt for 16 h. The solvent was removed in vacuo at 80° C. and the compound was partitioned between H2O and EtOAc. The aqueous layer was extracted with EtOAc and the organic phase was extracted with HCl 1N. The acidic extract was neutralized with saturated NaHCO3 and the precipitate was extracted with EtOAc, washed with brine, dried over MgSO4 and concentrated in vacuo to afford the title compound 169 (589 mg, 73% yield). 1H NMR: (Acetone-d6) δ (ppm): 8.36 (s, 1H), 7.66 (s, 1H), 7.20 (s, 1H), 7.12-7.05 (m, 2H), 6.84 (s, 2H). m/z: 210.1 (MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=O)[NH:7][C:8]([N:12]3[CH:16]=[C:15]([C:17]([O:19]CC)=[O:18])[CH:14]=[N:13]3)=[N:9]2)=[CH:4][C:3]=1[N:23]1[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1.[CH2:29]([NH:31][CH2:32][CH3:33])[CH3:30]>>[CH2:29]([N:31]([CH2:32][CH3:33])[C:6]1[C:5]2[C:10](=[CH:11][C:2]([Cl:1])=[C:3]([N:23]3[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]3)[CH:4]=2)[N:9]=[C:8]([N:12]2[CH:16]=[C:15]([C:17]([OH:19])=[O:18])[CH:14]=[N:13]2)[N:7]=1)[CH3:30]
Reactant: CCOC(=O)c1cnn(-c2nc3cc(Cl)c(N4CCCCC4)cc3c(=O)[nH]2)c1
Reactant: CCNCC
Product: CCN(CC)c1nc(-n2cc(C(=O)O)cn2)nc2cc(Cl)c(N3CCCCC3)cc12

Procedure:
The above compound may be made analogous to Example 1 using ethyl 1-(7-chloro-4-oxo-6-(piperidin-1-yl)-3,4-dihydroquinazolin-2-yl)-1H-pyrazole-4-carboxylate in step D and diethylamine in step E. MS (ESI): predicted mass calcd. for C21H25ClN6O2, 428.9
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C@@H:12](O)[CH2:13][CH2:14][NH:15][C:16](=[O:22])[O:17][C:18]([CH3:21])([CH3:20])[CH3:19])[CH:5]=[CH:6][C:7]=1[C:8]([F:11])([F:10])[F:9].[C:24]1(=[O:34])[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[C:26](=[O:33])[NH:25]1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CCOC(/N=N/C(OCC)=O)=O>C1COCC1>[O:34]=[C:24]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[C:26](=[O:33])[N:25]1[C@@H:12]([C:4]1[CH:5]=[CH:6][C:7]([C:8]([F:11])([F:10])[F:9])=[C:2]([F:1])[CH:3]=1)[CH2:13][CH2:14][NH:15][C:16](=[O:22])[O:17][C:18]([CH3:21])([CH3:20])[CH3:19]
Reactant: O=C1NC(=O)c2ccccc21
Reactant: CC(C)(C)OC(=O)NCC[C@H](O)c1ccc(C(F)(F)F)c(F)c1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NCC[C@H](c1ccc(C(F)(F)F)c(F)c1)N1C(=O)c2ccccc2C1=O
Temperature: 25 °C
Reaction time: 20 h
Yield: 42.2 %

Procedure:
To a solution of 286 (0.600 g, 1.78 mmol) and THF (15 mL) cooled to 0° C. was added isoindoline-1,3-dione (0.288 g, 1.96 mmol) and PPh3 (0.700 g, 2.67 mmol) followed by the dropwise addition of a THF (6 mL) solution of DEAD (0.420 mL, 2.67 mmol). The reaction was warmed to RT and stirred for 20 h. The reaction was concentrated, triturated with ether and filtered. The resulting filtrate was poured into water and extracted with DCM. The combined organic extracts were dried (MgSO4), filtered, and concentrated in vacuo. The crude product was purified by SiO2 chromatography eluting with hexane/EtOAc (4:1) to afford 0.350 g (42.4%) of (R)-tert-butyl 3-(1,3-dioxoisoindolin-2-yl)-3-(3-fluoro-4-(trifluoromethyl)phenyl)propylcarbamate (288).
Reaction SMILES: C(OC([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:10]=[C:9]1[C:17]1[C:18](=[O:46])[N:19](COCC[Si](C)(C)C)[CH:20]=[C:21]([C:23](=[O:37])[NH:24][C:25]2[CH:26]=[N:27][N:28]([CH2:30][C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[CH:29]=2)[CH:22]=1)=O)(C)(C)C.NCCN.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1>[CH2:30]([N:28]1[CH:29]=[C:25]([NH:24][C:23]([C:21]2[CH:22]=[C:17]([C:9]3[NH:8][C:16]4[C:11]([CH:10]=3)=[CH:12][CH:13]=[CH:14][CH:15]=4)[C:18](=[O:46])[NH:19][CH:20]=2)=[O:37])[CH:26]=[N:27]1)[C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1
Reactant: CC(C)(C)OC(=O)n1c(-c2cc(C(=O)Nc3cnn(Cc4ccccc4)c3)cn(COCC[Si](C)(C)C)c2=O)cc2ccccc21
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: NCCN
Product: O=C(Nc1cnn(Cc2ccccc2)c1)c1c[nH]c(=O)c(-c2cc3ccccc3[nH]2)c1
Temperature: 25 °C

Procedure:
Intermediate (1d), 2-[5-(1-benzyl-1H-pyrazol-4-ylcarbamoyl)-2-oxo-1-(2-trimethylsilanyl-ethoxymethyl)-1,2-dihydro-pyridin-3-yl]indole-1-carboxylic acid tert-butyl ester (315 mg, 0.492 mmol) was stirred in tetrahydrofuran (15 mL) and 1,2-diaminoethane (89 mg, 98 ul, 1.48 mmol) was added followed by tetrabutylammonium fluoride solution 1.0M in tetrahydrofuran (2.46 mL, 2.46 mmol). The reaction mixture was heated at reflux for 18 hours, and cooled to ambient temperature. The reaction mixture was concentrated in vacuo. The residue was partitioned between water and dichloromethane, and the organic layer was separated. The aqueous was extracted with a further portion of dichloromethane and the combined dichloromethane layers were washed with water (×3) dried (Na2SO4) and concentrated in vacuo. The resultant crude product was purified by flash chromatography on SiO2 eluting with dichloromethane—8% methanol/dichloromethane (gradient) to afford a solid. This solid was triturated with diethyl ether to afford the desired title compound as a yellow solid, 41 mg, 20%.
Reaction SMILES: [ClH:1].[N:2]1([CH2:8][CH2:9][O:10][C:11]2[CH:19]=[CH:18][C:14]([C:15](O)=[O:16])=[CH:13][CH:12]=2)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1.S(Cl)([Cl:22])=O>>[ClH:22].[N:2]1([CH2:8][CH2:9][O:10][C:11]2[CH:19]=[CH:18][C:14]([C:15]([Cl:1])=[O:16])=[CH:13][CH:12]=2)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1
Reactant: O=C(O)c1ccc(OCCN2CCCCC2)cc1
Reactant: O=S(Cl)Cl
Agent: Cl
Product: O=C(Cl)c1ccc(OCCN2CCCCC2)cc1
Temperature: 25 °C

Procedure:
A 500 mL round-bottom flask is charged with 4-(2-piperidin-1-yl-ethoxy)-benzoic acid hydrochloride, (25 g, 0.08748 mol) and thionyl chloride (150 mL, 2.0564 mol). The mixture is brought to reflux for 15 minutes whereupon it becomes a clear solution. The reaction is cooled to room temperature and the excess thionyl chloride is removed to give a quantitative yield of the desired product. 1H NMR: ∂ 8.08 (app. d, J=8.8 Hz, 2H), 6.99 (app. d, J=9.2 Hz, 2H), 4.71 (t, J=4.6 Hz, 2H), 3.65 (d, J=12 Hz, 2H), 3.43 (quart., J=4.6 Hz, 2H), 2.76–2.85 (m, 2H), 2.22–2.32 (m, 2H), 1.87–1.94 (m, 3H), 1.37–1.49 (m, 1H).
Reaction SMILES: [Cl-].[Br:2][C:3]1[C:4]([O:16][CH3:17])=[C:5]([C:9]([O:14][CH3:15])=[C:10]([O:12][CH3:13])[CH:11]=1)[C:6]([NH2:8])=[O:7].C([N:37]1[CH2:41][CH2:40][CH2:39][C@H:38]1[CH2:42]N)(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>ClCCl>[Br:2][C:3]1[C:4]([O:16][CH3:17])=[C:5]([C:9]([O:14][CH3:15])=[C:10]([O:12][CH3:13])[CH:11]=1)[C:6]([NH:8][CH2:42][C@@H:38]1[CH2:39][CH2:40][CH2:41][NH:37]1)=[O:7]
Reactant: COc1cc(Br)c(OC)c(C(N)=O)c1OC
Reactant: NC[C@@H]1CCCN1C(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cl-]
Solvent: ClCCl
Product: COc1cc(Br)c(OC)c(C(=O)NC[C@@H]2CCCN2)c1OC
Yield: 79.2 %

Procedure:
3-Bromo-2,5,6-trimethoxybenzamide chloride (1.48 g, 4.8 mmol) was reacted with (S)-(-)-1-trityl-2-aminomethylpyrrolidine (1.51 g, 4.4 mmol) in 10 ml dichloromethane at room temperature for 1 h. The solvent was evaporated and the residue was treated with 10 ml ethanol and 0.1 ml conc. HCl during 1 h. After evaporation the residue was partitioned between 0.5M HCl and Et2O. The aqueous phase was made alkaline, extracted with dichloromethane, dried (Na2SO4) and evaporated to give 1.30 g (79%) (S)-(+)-3-bromo-N-(2-pyrrolidinylmethyl)-2,5,6-trimethoxybenzamide. An analytical sample of the hydrochloride was prepared. M.p. 181°-182° C. (EtOH/acetone/Et2O).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][N:9]2[C:12]([C:15]([NH:17][C:18]3[CH:26]=[CH:25][CH:24]=[C:23]4[C:19]=3[CH:20]=[N:21][N:22]4[CH2:27][CH:28]3[CH2:33][CH2:32][CH2:31][N:30](C(OC(C)(C)C)=O)[CH2:29]3)=[O:16])=[CH:13][N:14]=[C:8]2[CH:7]=1.[ClH:41]>C(Cl)Cl.O1CCOCC1>[ClH:41].[CH3:1][O:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][N:9]2[C:12]([C:15]([NH:17][C:18]3[CH:26]=[CH:25][CH:24]=[C:23]4[C:19]=3[CH:20]=[N:21][N:22]4[CH2:27][CH:28]3[CH2:33][CH2:32][CH2:31][NH:30][CH2:29]3)=[O:16])=[CH:13][N:14]=[C:8]2[CH:7]=1
Reactant: COCCOc1ccn2c(C(=O)Nc3cccc4c3cnn4CC3CCCN(C(=O)OC(C)(C)C)C3)cnc2c1
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: COCCOc1ccn2c(C(=O)Nc3cccc4c3cnn4CC3CCCNC3)cnc2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 93 %

Procedure:
A solution of tert-butyl 3-((4-(7-(2-methoxyethoxy)imidazo[1,2-a]pyridine-3-carboxamido)-1H-indazol-1-yl)methyl)piperidine-1-carboxylate (0.056 g, 0.10 mmol) in DCM (1 mL) was treated with 4N hydrochloric acid in dioxane (1 mL) at ambient temperature. The mixture was stirred at ambient temperature overnight, concentrated to afford 7-(2-methoxyethoxy)-N-(1-(piperidin-3-ylmethyl)-1H-indazol-4-yl)imidazo[1,2-a]pyridine-3-carboxamide hydrochloride (0.0046 g, 93% yield) as a brown oil. MS (APCI) m/z=449 (M+H).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([NH2:8])[CH:5]=[N:6][CH:7]=1.F[C:10]1[C:15]([C:16]2[N:21]=[C:20]([CH3:22])[N:19]=[C:18]([N:23]([CH2:33][C:34]3[CH:39]=[CH:38][C:37]([O:40][CH3:41])=[CH:36][CH:35]=3)[CH2:24][C:25]3[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][CH:26]=3)[N:17]=2)=[CH:14][CH:13]=[CH:12][N:11]=1>>[CH3:41][O:40][C:37]1[CH:36]=[CH:35][C:34]([CH2:33][N:23]([CH2:24][C:25]2[CH:26]=[CH:27][C:28]([O:31][CH3:32])=[CH:29][CH:30]=2)[C:18]2[N:19]=[C:20]([CH3:22])[N:21]=[C:16]([C:15]3[C:10]([NH:8][C:4]4[CH:5]=[N:6][CH:7]=[C:2]([CH3:1])[CH:3]=4)=[N:11][CH:12]=[CH:13][CH:14]=3)[N:17]=2)=[CH:39][CH:38]=1
Reactant: Cc1cncc(N)c1
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)c2nc(C)nc(-c3cccnc3F)n2)cc1
Product: COc1ccc(CN(Cc2ccc(OC)cc2)c2nc(C)nc(-c3cccnc3Nc3cncc(C)c3)n2)cc1
Yield: 25.7 %

Procedure:
The title compound was prepared in an analogous manner to that described in Example 164 using 5-methylpyridin-3-amine (0.075 g, 0.690 mmol) (Aldrich) and 4-(2-fluoropyridin-3-yl)-N,N-bis(4-methoxybenzyl)-6-methyl-1,3,5-triazin-2-amine. Purification using an ISCO Combiflash Companion (12 g column, 30-70% EtOAc in hexanes over 30 min; the product eluted with 45% EtOAc) gave the title compound as a yellow amorphous solid (25.7%). 1H NMR (400 MHz, d6-DMSO) δ 11.93 (s, 1H); 8.81 (dd, J=7.8, 1.8 Hz, 1H); 8.61 (d, J=2.3 Hz, 1H); 8.39 (dd, J=4.7, 2.0 Hz, 1H); 8.02 (s, 1H); 7.93 (s, 1H); 7.25 (dd, J=10.2, 8.8 Hz, 4H); 6.85-7.00 (m, 5H); 4.82 (d, J=14.7 Hz, 4H); 3.74 (s, 3H); 3.71 (s, 3H); 2.59 (s, 3H); 2.26 (s, 3H). m/z (ESI, +ve ion) 534.0 (M+H)+.
Reaction SMILES: C[Sn](C)(C)[C:3]1[CH:20]=[CH:19][C:6]2[C:7](=[O:18])[C:8]([CH2:11][C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[CH:9][O:10][C:5]=2[CH:4]=1.[CH3:23][O:24][C:25](=[O:33])[C:26]1[CH:31]=[CH:30][CH:29]=[C:28](I)[CH:27]=1.[Cl-].[NH4+]>CN(C)C=O.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>[C:25]([C:26]1[CH:27]=[C:28]([C:3]2[CH:20]=[CH:19][C:6]3[C:7](=[O:18])[C:8]([CH2:11][C:12]4[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=4)=[CH:9][O:10][C:5]=3[CH:4]=2)[CH:29]=[CH:30][CH:31]=1)([O:24][CH3:23])=[O:33]
Reactant: COC(=O)c1cccc(I)c1
Reactant: C[Sn](C)(C)c1ccc2c(=O)c(Cc3ccccc3)coc2c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: CN(C)C=O
Product: COC(=O)c1cccc(-c2ccc3c(=O)c(Cc4ccccc4)coc3c2)c1
Temperature: 25 °C
Yield: 100.4 %

Procedure:
To a stirred solution of the compound of step F (7.0 g, 17.5 mmole) in dimethylformamide (DMF) (35 mL) was added Pd(PPh3)2Cl2 (490 mg, 0.7 mmole), 3 crystals of BHT and methyl-3-iodobenzoate (5.0 g, 19.1 mmole). The mixture was stirred at reflux for 1.5 hours, cooled to room temperature and poured into 150 mL of saturated aqueous ammonium chloride solution. The mixture was extracted with 3×150 mL of diethyl ether, and the combined extract was washed with 2×100 mL of water, and then brine. The solution was dried over sodium sulfate, filtered and evaporated in vacuo to afford a yellow oil. Chromatography over silica gel (4:1 hexane:ether elution) afforded 6.51 g of the title compound as a viscous oil.