Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1(C[O:8][C:9](=[O:44])[C:10]2[CH:15]=[C:14]([O:16][CH2:17][CH2:18][CH2:19][CH2:20][C:21]([O:23][CH3:24])=[O:22])[CH:13]=[C:12]([O:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH3:43])[CH:11]=2)C=CC=CC=1.[H][H]>[Pd].C1COCC1>[CH2:26]([O:25][C:12]1[CH:11]=[C:10]([CH:15]=[C:14]([O:16][CH2:17][CH2:18][CH2:19][CH2:20][C:21]([O:23][CH3:24])=[O:22])[CH:13]=1)[C:9]([OH:44])=[O:8])[CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH3:43]
Reactant: CCCCCCCCCCCCCCCCCCOc1cc(OCCCCC(=O)OC)cc(C(=O)OCc2ccccc2)c1
Reactant: [H][H]
Agent: [Pd]
Solvent: C1CCOC1
Product: CCCCCCCCCCCCCCCCCCOc1cc(OCCCCC(=O)OC)cc(C(=O)O)c1
Yield: 97.3 %

Procedure:
A mixture of 11.3 g of 3-(octadecyloxy)-5-[(5-methoxy-5-oxopentyl)oxy]benzoic acid phenylmethyl ester and 1.5 g of 10% palladium on carbon in 250 ml of THF was stirred in a hydrogen atmosphere at room temperature for 4 hours. The catalyst was removed by filtration and the filtrate was concentrated at reduced pressure to a solid which was triturated with hexane and filtered to give 9.37 g (98% yield, mp 68°-70°) of 3-(octadecyloxy)-5-[(5-methoxy-5-oxopentyl)oxy]benzoic acid.
Reaction SMILES: [CH3:1][O:2][CH:3]([O:23][CH3:24])[CH2:4][NH:5][C:6]([NH:8][N:9]1[CH2:14][CH2:13][N:12]([C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=2)[CH2:11][CH2:10]1)=[S:7].[I:25][CH2:26][CH3:27].C(OCC)(=O)C.O(C(C)C)C(C)C>C(O)(=O)C>[IH:25].[CH3:24][O:23][CH:3]([O:2][CH3:1])[CH2:4][NH:5][C:6]([S:7][CH2:26][CH3:27])=[N:8][N:9]1[CH2:14][CH2:13][N:12]([C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=2)[CH2:11][CH2:10]1
Reactant: CCI
Reactant: COc1ccc(N2CCN(NC(=S)NCC(OC)OC)CC2)cc1
Solvent: CC(=O)O
Solvent: CC(C)OC(C)C
Solvent: CCOC(C)=O
Product: CCSC(=NN1CCN(c2ccc(OC)cc2)CC1)NCC(OC)OC
Product: I
Reaction time: 3 h

Procedure:
A mixture of 17.3 parts of N-(2,2-dimethoxyethyl)-N'-[4-(4-methoxyphenyl)-1-piperazinyl]thiourea, 17 parts of iodoethane, 180 parts of ethyl acetate and 20 parts of acetic acid is stirred for 3 hours. Upon the addition of 2,2'-oxybispropane, the product is precipitated. It is filtered off and triturated in 4-methyl-2-pentanone. The product is filtered off and crystallized from 2-propanol, yielding 9 parts of ethyl N-(2,2-dimethoxyethyl)-N'-[4-(4-methoxyphenyl)-1-piperazinyl]carbamimidothioate monohydroiodide.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][C:10]2[CH:15]=[CH:14][C:13]([Li])=[CH:12][CH:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CO[P:19]([Cl:21])Cl>>[C:1]1([CH2:7][CH2:8][CH2:9][C:10]2[CH:15]=[CH:14][C:13]([P:19]([C:13]3[CH:14]=[CH:15][C:10]([CH2:9][CH2:8][CH2:7][C:1]4[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=4)=[CH:11][CH:12]=3)[Cl:21])=[CH:12][CH:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: COP(Cl)Cl
Reactant: [Li]c1ccc(CCCc2ccccc2)cc1
Product: ClP(c1ccc(CCCc2ccccc2)cc1)c1ccc(CCCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 90 %

Procedure:
p-(3-phenylpropyl)phenyllithium (8.1 g, 40 mmol) in 150 ml solvent (Et2O/THF 1/1) was added dropwise to CH3OPCl2 (2.66 g, 20 mmol) in 70 ml solvent (Et2O/THF 1/1) at -70° C. The addition was completed in 2 h. The reaction mixture was stirred overnight at room temperature and then brought to reflux for 2 h. The precipitate was filtered and the solvent of the solution was removed by applying vacuum. PCl3 (15 ml) was added to the resulting viscous oil and stirred for 24 h. Then the mixture was kept at 70° C. and 1 mm Hg for 2 h to remove excess PCl3 and byproduct. The product, di[p-(3-phenylpropyl)phenyl]chlorophosphine, was obtained as a pale yellow viscous oil with 90% yield. The product was characterized by 31P NMR. 83.6
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[CH3:12])[C:5]([O:7][CH3:8])=[O:6].[CH:13]([N:16](CC)C(C)C)(C)[CH3:14].BrCC#N.O>O1CCCC1>[C:13]([CH2:14][NH:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[CH3:12])[C:5]([O:7][CH3:8])=[O:6])#[N:16]
Reactant: COC(=O)c1ccc(C)c(N)c1
Reactant: CCN(C(C)C)C(C)C
Agent: N#CCBr
Solvent: O
Solvent: C1CCOC1
Product: COC(=O)c1ccc(C)c(NCC#N)c1
Reaction time: 12 h

Procedure:
To a stirred solution of 3-amino-4-methyl-benzoic acid, methyl ester (10.0 g) in dry tetrahydrofuran was added N,N-diisopropylethylamine (12.6 mL) followed by the addition of bromoacetonitrile (5.1 mL). The reaction was heated at reflux under an atmosphere of nitrogen with stirring for 12 h. Water was added and the mixture extracted with ethyl acetate. The pooled organics were washed with brine, dried (MgSO4), filtered and the solvent removed under reduced pressure to afford the subtitle compound as a solid (12.4 g).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([OH:11])=[C:6]([C:8](=[O:10])[CH3:9])[CH:7]=1.[CH3:12][CH:13]([CH3:17])[CH2:14][CH:15]=O.N1CCCC1.Cl>CCOC(C)=O.CO>[Br:1][C:2]1[CH:7]=[C:6]2[C:5](=[CH:4][CH:3]=1)[O:11][CH:15]([CH2:14][CH:13]([CH3:17])[CH3:12])[CH2:9][C:8]2=[O:10]
Reactant: CC(=O)c1cc(Br)ccc1O
Reactant: CC(C)CC=O
Agent: Cl
Solvent: CO
Solvent: C1CCNC1
Solvent: CCOC(C)=O
Product: CC(C)CC1CC(=O)c2cc(Br)ccc2O1
Reaction time: 72 h
Yield: 68.5 %

Procedure:
To a mixture of 1-(5-bromo-2-hydroxyphenyl)ethanone (10.0 g, 46.5 mmol) and MeOH (0.20 L) were added 3-methylbutanal (7.54 mL, 69.8 mmol) and pyrrolidine (5.77 mL, 69.8 mmol) at ambient temperature, and the mixture was stirred for 3 days at the same temperature. After concentration of the reaction mixture at reduced pressure, the residue was diluted with EtOAc, acidified to pH 3-4 with 1M aqueous HCl, and extracted with EtOAc. The organic layer was washed with water and brine, dried over MgSO4, and filtered. After concentration of the filtrate at reduced pressure, purification of the residue with column chromatography on silica gel (EtOAc-hexane, a linear gradient of EtOAc from 0 to 10%) afforded 6-bromo-2-isobutyl-2,3-dihydro-4H-chromen-4-one (9.02 g).
Reaction SMILES: [NH2:1][C:2]1[CH:23]=[CH:22][C:5]([O:6][C:7]2[CH:8]=[CH:9][C:10]3[N:11]([CH:13]=[C:14]([NH:16][C:17]([CH:19]4[CH2:21][CH2:20]4)=[O:18])[N:15]=3)[CH:12]=2)=[C:4]([F:24])[CH:3]=1.[F:25][C:26]1[CH:27]=[C:28]([N:33]2[C:38]([CH3:39])=[CH:37][CH:36]=[C:35]([C:40](O)=[O:41])[C:34]2=[O:43])[CH:29]=[CH:30][C:31]=1[F:32].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C>CN(C)C(=O)C>[CH:19]1([C:17]([NH:16][C:14]2[N:15]=[C:10]3[CH:9]=[CH:8][C:7]([O:6][C:5]4[CH:22]=[CH:23][C:2]([NH:1][C:40]([C:35]5[C:34](=[O:43])[N:33]([C:28]6[CH:29]=[CH:30][C:31]([F:32])=[C:26]([F:25])[CH:27]=6)[C:38]([CH3:39])=[CH:37][CH:36]=5)=[O:41])=[CH:3][C:4]=4[F:24])=[CH:12][N:11]3[CH:13]=2)=[O:18])[CH2:21][CH2:20]1
Reactant: Cc1ccc(C(=O)O)c(=O)n1-c1ccc(F)c(F)c1
Reactant: Nc1ccc(Oc2ccc3nc(NC(=O)C4CC4)cn3c2)c(F)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CC(=O)N(C)C
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(C(=O)Nc2ccc(Oc3ccc4nc(NC(=O)C5CC5)cn4c3)c(F)c2)c(=O)n1-c1ccc(F)c(F)c1
Yield: 85.6 %

Procedure:
Using a solution of N-[6-(4-amino-2-fluorophenoxy)imidazo[1,2-a]pyridin-2-yl]cyclopropanecarboxamide (200 mg, 0.613 mmol) and 1-(3,4-difluorophenyl)-6-methyl-2-oxo-1,2-dihydropyridine-3-carboxylic acid (244 mg, 0.919 mmol) in N,N-dimethylacetamide (2.0 mL), HATU (350 mg, 0.919 mmol) and N,N-diisopropylethylamine (160 μL, 0.919 mmol) and in the same manner as in Example 44, the title compound (301 mg, 86%) was obtained as a white solid.
Reaction SMILES: [C:1](N1C=CN=C1)(N1C=CN=C1)=[S:2].[CH2:13]([NH:20][C:21]1[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[N:24]=[CH:23][C:22]=1[NH2:31])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>N1C=CC=CC=1.C1COCC1>[CH2:13]([N:20]1[C:21]2[C:30]3[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=3[N:24]=[CH:23][C:22]=2[N:31]=[C:1]1[SH:2])[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: S=C(n1ccnc1)n1ccnc1
Reactant: Nc1cnc2ccccc2c1NCc1ccccc1
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: Sc1nc2cnc3ccccc3c2n1Cc1ccccc1
Temperature: 25 °C

Procedure:
1,1′-Thiocarbonyldiimidazole (5.74 g, 32.2 mmol) was added to a solution of N4-benzylquinoline-3,4-diamine, see U.S. Pat. No. 4,689,338 (Gerster), Example 124, Parts A and B, (6.69 g, 26.8 mmol) in pyridine (50 mL) and THF (50 mL), and the reaction was heated at 80° C. for two hours and cooled to room temperature. A precipitate was present and was isolated by filtration and washed with diethyl ether to provide 4.17 g of 1-benzyl-1H-imidazo[4,5-c]quinoline-2-thiol as a white solid. The filtrate was treated with diethyl ether, and additional precipitate formed. The precipitate was isolated by filtration and washed with diethyl ether to provide an additional 1.90 g of product as a pale yellow solid.
Reaction SMILES: [CH3:1][C@H:2]1[CH2:33][C:32]([CH3:34])=[CH:31][C@@H:30]([CH2:35][CH:36]=[CH2:37])[C:28](=[O:29])[CH2:27][C@H:26](O)[C@@H:25]([CH3:39])[C@@H:24](/[C:40](/[CH3:51])=[CH:41]/[C@H:42]2[CH2:47][C@@H:46]([O:48][CH3:49])[C@H:45](O)[CH2:44][CH2:43]2)[O:23][C:21](=[O:22])[C@H:20]2[N:15]([CH2:16][CH2:17][CH2:18][CH2:19]2)[C:13](=[O:14])[C:11](=[O:12])[C@:9]2([OH:52])[O:10][C@@H:5]([C@@H:6]([O:54][CH3:55])[CH2:7][C@H:8]2[CH3:53])[C@@H:4]([O:56][CH3:57])[CH2:3]1.[I:58][C:59]1[CH:64]=[CH:63][C:62]([S:65](Cl)(=[O:67])=[O:66])=[CH:61][CH:60]=1.C(OCC)(=[O:71])C>N1C=CC=CC=1>[CH2:35]([CH:30]1[CH:31]=[C:32]([CH3:34])[CH2:33][CH:2]([CH3:1])[CH2:3][CH:4]([O:56][CH3:57])[CH:5]2[O:10][C:9]([OH:52])([CH:8]([CH3:53])[CH2:7][CH:6]2[O:54][CH3:55])[C:11](=[O:12])[C:13](=[O:14])[N:15]2[CH:20]([CH2:19][CH2:18][CH2:17][CH2:16]2)[C:21](=[O:22])[O:23][CH:24]([C:40]([CH3:51])=[CH:41][CH:42]2[CH2:43][CH2:44][CH:45]([O:66][S:65]([C:62]3[CH:63]=[CH:64][C:59]([I:58])=[CH:60][CH:61]=3)(=[O:67])=[O:71])[CH:46]([O:48][CH3:49])[CH2:47]2)[CH:25]([CH3:39])[CH:26]=[CH:27][C:28]1=[O:29])[CH:36]=[CH2:37]
Reactant: C=CC[C@@H]1C=C(C)C[C@H](C)C[C@H](OC)[C@H]2O[C@@](O)(C(=O)C(=O)N3CCCC[C@H]3C(=O)O[C@H](/C(C)=C/[C@@H]3CC[C@@H](O)[C@H](OC)C3)[C@H](C)[C@@H](O)CC1=O)[C@H](C)C[C@@H]2OC
Reactant: O=S(=O)(Cl)c1ccc(I)cc1
Reactant: CCOC(C)=O
Agent: C=CC[C@@H]1/C=C(\C)C[C@H](C)C[C@H](OC)[C@H]2O[C@@](O)(C(=O)C(=O)N3CCCC[C@H]3C(=O)O[C@H](/C(C)=C/[C@@H]3CC[C@@H](O)[C@H](OC)C3)[C@H](C)[C@@H](O)CC1=O)[C@H](C)C[C@@H]2OC
Solvent: c1ccncc1
Product: C=CCC1C=C(C)CC(C)CC(OC)C2OC(O)(C(=O)C(=O)N3CCCCC3C(=O)OC(C(C)=CC3CCC(OS(=O)(=O)c4ccc(I)cc4)C(OC)C3)C(C)C=CC1=O)C(C)CC2OC
Temperature: 25 °C
Reaction time: 36 h

Procedure:
To a solution of the FR-900506 substance (100.7 mg) in pyridine (3 ml) was added p-iodobenzenesulfonyl chloride (500 mg), and the mixture was stirred at room temperature for 36 hours. The solution was diluted with ethyl acetate and washed with a saturated aqueous sodium hydrogen carbonate, water and an aqueous sodium chloride. The organic layer was dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was chromatographed on silica gel (developing solvent: diethyl ether and hexane, 3:1 v/v) to give 17-allyl-11,14-dihydroxy-12-[2-[4-(p-iodobenzenesulfonyloxy)-3-methoxycyclohexyl]-1-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.04,9]octacos-18-ene-2,3,10,16tetraone (61 m) and 17-allyl-1-hydroxy-12-[2-[4-(p-iodobenzenesulfonyloxy)-3-methoxycyclohexyl]-1-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.04,9]octacosa-14,18-diene-2,3,10,16-tetraone (12 mg), respectively.
Reaction SMILES: [CH3:1][C:2]1[S:22][C:5]2[N:6]=[C:7]([N:16]3[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]3)[N:8]=[C:9]([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)[C:4]=2[CH:3]=1.[F:23][C:24]1[CH:33]=[CH:32][C:27]([C:28](=[O:31])[CH2:29]Cl)=[CH:26][CH:25]=1.C(N(CC)CC)C.C(Cl)(Cl)Cl>CC(CC)=O>[F:23][C:24]1[CH:33]=[CH:32][C:27]([C:28](=[O:31])[CH2:29][N:19]2[CH2:20][CH2:21][N:16]([C:7]3[N:8]=[C:9]([C:10]4[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=4)[C:4]4[CH:3]=[C:2]([CH3:1])[S:22][C:5]=4[N:6]=3)[CH2:17][CH2:18]2)=[CH:26][CH:25]=1
Reactant: Cc1cc2c(-c3ccccc3)nc(N3CCNCC3)nc2s1
Reactant: O=C(CCl)c1ccc(F)cc1
Solvent: CCN(CC)CC
Solvent: CCC(C)=O
Solvent: ClC(Cl)Cl
Product: Cc1cc2c(-c3ccccc3)nc(N3CCN(CC(=O)c4ccc(F)cc4)CC3)nc2s1
Yield: 91.8 %

Procedure:
In 6 ml of methylethylketone, 2.03 g of 6-methyl-4-phenyl-2-piperazinyl-thieno[2,3-d]pyrimidine, 1.25 g of 4-fluorophenacyl chloride and 0.73 g of triethylamine are reacted under reflux for 5 hours. After cooling, 70 ml of chloroform is added to the reaction mixture. The solution is washed twice with 100 ml of water and then saturated aqueous solution of sodium chloride, and dried over anhydrous sodium sulfate. After distilling off chloroform, crystallization from diethylether/methanol gives 2.68 g of the product which has a melting point of 141°-142° C.
Reaction SMILES: [C:1]1([C@H:7]([CH3:16])[CH2:8][CH2:9][CH:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.[CH:18]([C@@H:20]1[C@@H:24]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH2:23][N:22]([C@H:31]([CH:42]2[CH2:47][CH2:46][CH2:45][CH2:44][CH2:43]2)[C:32]([O:34]CC2C=CC=CC=2)=[O:33])[CH2:21]1)=O>>[C:1]1([C@H:7]([CH3:16])[CH2:8][CH2:9][CH:10]2[CH2:11][CH2:12][N:13]([CH2:18][C@@H:20]3[C@@H:24]([C:25]4[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=4)[CH2:23][N:22]([C@H:31]([CH:42]4[CH2:47][CH2:46][CH2:45][CH2:44][CH2:43]4)[C:32]([OH:34])=[O:33])[CH2:21]3)[CH2:14][CH2:15]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: C[C@H](CCC1CCNCC1)c1ccccc1
Reactant: O=C[C@H]1CN([C@@H](C(=O)OCc2ccccc2)C2CCCCC2)C[C@@H]1c1ccccc1
Agent: Cl
Product: C[C@H](CCC1CCN(C[C@H]2CN([C@@H](C(=O)O)C3CCCCC3)C[C@@H]2c2ccccc2)CC1)c1ccccc1
Yield: 53.6 %

Procedure:
The title compound was prepared from 30 mg (0.13 mmol) of 4-(3-(R)-phenylbutyl)piperidine.HCl and 50 mg (0.13 mmol) of 2-(R)-(3-(R)-formyl-4-(S)-phenylpyrrolidin-1-yl)-2-(cyclohexyl)acetic acid, benzyl ester (from EXAMPLE 1, Step I) using procedures analogous to those described in EXAMPLE 1, Steps J and H. 36 mg (54%) of the title compound was obtained: 1H NMR (500 MHz, CD3OD) δ 0.94-1.84 (23H). 2.06-2.14 (m, 1H). 2.36-2.42 (m, 1H). 2.57-2.60 (2H). 2.74-3.02 (3H). 3.10-3.12 (m, 1H). 3.30-3.60 (7H). 7.10-7.13 (3H). 7.21-7.29 (3H), 7.34-7.39 (4H); ESI-MS 517 (M+H).
Reaction SMILES: Cl.[C:2](Cl)(=[O:9])[C:3]1[CH:8]=[CH:7][CH:6]=[N:5][CH:4]=1.[CH3:11][C:12]([CH3:24])([CH2:15][CH2:16][CH2:17][CH2:18][C:19]([CH3:23])([CH3:22])[CH2:20][OH:21])[CH2:13][OH:14]>N1C=CC=CC=1>[C:2]([O:21][CH2:20][C:19]([CH3:23])([CH3:22])[CH2:18][CH2:17][CH2:16][CH2:15][C:12]([CH3:24])([CH3:11])[CH2:13][O:14][C:2](=[O:9])[C:3]1[CH:8]=[CH:7][CH:6]=[N:5][CH:4]=1)(=[O:9])[C:3]1[CH:8]=[CH:7][CH:6]=[N:5][CH:4]=1
Reactant: CC(C)(CO)CCCCC(C)(C)CO
Reactant: O=C(Cl)c1cccnc1
Agent: Cl
Solvent: c1ccncc1
Product: CC(C)(CCCCC(C)(C)COC(=O)c1cccnc1)COC(=O)c1cccnc1
Reaction time: 36 h
Yield: 53.3 %

Procedure:
A suspension of 106.2 grams (0.6 mole) of nicotinoyl chloride hydrochloride in 300 ml of anhydrous pyridine was added in 2 hours under stirring with a solution of 20.2 grams (0.1 mole) of 2,2,7,7-tetramethyl-1,8-octanediol in 60 ml of anhydrous pyridine while keeping the temperature at about 70° C. The reaction was refluxed and stirred for 36 hours, then, after cooling, the formed precipitate was removed by filtration. The filtrate was evaporated under vacuum and the obtained residue was treated with a mixture of 200 ml of diethyl ether and 100 ml of an 8% aqueous solution of sodium bicarbonate. The organic layer was separated, washed first with 100 ml of a 3% aqueous solution of sodium bicarbonate, then with 100 ml of water and finally concentrated under vacuum to about half of the initial volume. After standing overnight, the product which separated was recovered by filtration and recrystallized from ethanol thus obtaining 22 grams of the title product, having m.p. 89° -90° C. Yield 53.4% of theoretical.
Reaction SMILES: [CH:1]([NH:4][CH2:5][CH:6]1[CH2:10][O:9][C:8]2([CH:18]([Br:19])[CH2:17][CH2:16][C:15]3[N:14]([S:20]([C:23]4[CH:28]=[CH:27][C:26]([CH3:29])=[CH:25][CH:24]=4)(=[O:22])=[O:21])[CH:13]=[CH:12][C:11]2=3)[O:7]1)([CH3:3])[CH3:2].[C:30](Cl)(=[O:37])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>N1C=CC=CC=1>[CH:1]([N:4]([CH2:5][CH:6]1[CH2:10][O:9][C:8]2([CH:18]([Br:19])[CH2:17][CH2:16][C:15]3[N:14]([S:20]([C:23]4[CH:28]=[CH:27][C:26]([CH3:29])=[CH:25][CH:24]=4)(=[O:22])=[O:21])[CH:13]=[CH:12][C:11]2=3)[O:7]1)[C:30](=[O:37])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)([CH3:3])[CH3:2]
Reactant: O=C(Cl)c1ccccc1
Reactant: Cc1ccc(S(=O)(=O)n2ccc3c2CCC(Br)C32OCC(CNC(C)C)O2)cc1
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)n2ccc3c2CCC(Br)C32OCC(CN(C(=O)c3ccccc3)C(C)C)O2)cc1
Reaction time: 14 h
Yield: 91.5 %

Procedure:
A solution of 4'-isopropylaminomethyl-1-p-toluenesulfonyl-5-bromo-4,5,6,7-tetrahydroindole-4-spiro-2'-[1,3]dioxolane (100 parts) dissolved in pyridine (343 parts) is prepared and placed in a three necked flask equipped with a stirrer and a thermometer. Benzoyl chloride (35 parts) is added dropwise at 0° C. to 5° C. After standing at room temperature for 14 hours, the reaction mixture is evaporated to remove pyridine at below 70° C. Obtained residue is dissolved in a dichloromethane (300 parts) and washed three times with water (50 parts). Aqueous washings are combined and washed with dichloromethane (50 parts). Dichloromethane solution and dichloromethane washing are combined, washed with water (30 parts), are dried over anhydrous sodium sulfate. After 1 hour, the drying agent is removed by filtration, and obtained filtrate is concentrated to dryness under reduced pressure. Obtained residue (132 parts) is dissolved in dichloromethane (270 parts), allowed to stand for half an hour with active charcoal (30 parts), and filtered through Florisil filter-bed. The resulting filtrate is concentrated under reduced pressure to dryness at below 30° C. and the obtained residue is triturated in a small amount of a mixture of benzene and dichloromethane to give amorphous powder. The product is collected by filtration and dried to give 4'-(N-isopropyl-N-benzoylaminomethyl)-1-p-toluenesulfonyl-5-bromo-4,5,6,7-tetrahydroindole-4-spiro-2'-[1,3]dioxolane (111 parts) in 91.5% yield.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][C:6]1[N:11]2[CH:12]=[N:13][CH:14]=[C:10]2[CH:9]=[CH:8][CH:7]=1.[C-:15]#[N:16].[K+].C1OCCOC2C(=CC=CC=2)OCCOCCOC2C(=CC=CC=2)OC1>C(#N)C>[C:15]([CH2:2][CH2:3][CH2:4][CH2:5][C:6]1[N:11]2[CH:12]=[N:13][CH:14]=[C:10]2[CH:9]=[CH:8][CH:7]=1)#[N:16]
Reactant: ClCCCCc1cccc2cncn12
Reactant: [C-]#N
Agent: [K+]
Agent: c1ccc2c(c1)OCCOCCOc1ccccc1OCCOCCO2
Solvent: CC#N
Product: N#CCCCCc1cccc2cncn12

Procedure:
A solution of 5-(4-chlorobutyl)imidazo[1,5-a]pyridine (5.73 g), potassium cyanide (7.18 g) and 1.0 g of dibenzo-18-crown-6 in 190 ml of acetonitrile is heated at reflux for 18 hours, cooled and evaporated to a residual oil which is partitioned between water and methylene chloride. The organic phase is dried over sodium sulfate and evaporated. The resulting solid is dissolved in ethyl acetate and filtered through 60.0 g of silica gel to yield 5-(4-cyanobutyl)-imidazo[1,5-a]pyridine m.p. 72°-75°.
Reaction SMILES: [CH3:1][CH:2]([N:4]1[C:8]2[N:9]=[C:10]([C:16]3[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=3)[CH:11]=[C:12]([C:13]([OH:15])=O)[C:7]=2[CH:6]=[N:5]1)[CH3:3].[NH2:22][CH2:23][C:24]1[C:25](=[O:34])[NH:26][C:27]([CH3:33])=[CH:28][C:29]=1[CH:30]1[CH2:32][CH2:31]1.C(Cl)CCl.C1C=NC2N(O)N=NC=2C=1.CN1CCOCC1>CN(C=O)C>[CH:30]1([C:29]2[CH:28]=[C:27]([CH3:33])[NH:26][C:25](=[O:34])[C:24]=2[CH2:23][NH:22][C:13]([C:12]2[C:7]3[CH:6]=[N:5][N:4]([CH:2]([CH3:1])[CH3:3])[C:8]=3[N:9]=[C:10]([C:16]3[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=3)[CH:11]=2)=[O:15])[CH2:31][CH2:32]1
Reactant: Cc1cc(C2CC2)c(CN)c(=O)[nH]1
Reactant: CC(C)n1ncc2c(C(=O)O)cc(-c3ccncc3)nc21
Agent: On1nnc2cccnc21
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: Cc1cc(C2CC2)c(CNC(=O)c2cc(-c3ccncc3)nc3c2cnn3C(C)C)c(=O)[nH]1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
1-(1-Methylethyl)-6-(4-pyridinyl)-1H-pyrazolo[3,4-b]pyridine-4-carboxylic acid (100 mg, 0.354 mmol), 3-(aminomethyl)-4-cyclopropyl-6-methyl-2(1H)-pyridinone (104 mg, 0.354 mmol), EDC (81 mg, 0.425 mmol), HOAt (48 mg, 0.354 mmol), and N-methylmorpholine (0.156 mL, 1.42 mmol) were suspended in DMF(5 mL) and stirred at room temperature overnight. The contents were filtered, washed with ethanol, and then concentrated in vacuo. The crude solid was purified by reverse phase HPLC (mobile phase: 20-40%, ACN in H2O, 0.1% TFA). The isolated solid was then neutralized with saturated NaHCO3, and washed with EtOAc (3×). The combined organic layers were dried over Na2SO4, filtered, and concentrated in vacuo to afford the title compound as an off-white solid, 0.042 g (26%). LCMS E-S (M+H)=443.3. 1H NMR (400 MHz, DMSO-d6) δ ppm 0.71-0.78 (m, 2 H), 0.94 (dd, J=8.34, 2.27 Hz, 2 H), 1.57 (d, J=6.57 Hz, 6 H), 2.12 (s, 3 H), 2.13-2.18 (m, 1 H), 4.62 (d, J=4.80 Hz, 2 H), 5.38 (s, 1 H), 5.54 (s, 1 H), 8.37 (s, 1 H), 8.44-8.54 (m, 3 H), 8.91 (d, J=6.06 Hz, 2 H), 9.04 (s, 1 H), 11.51 (br. s., 1 H).
Reaction SMILES: C1CCC(N=C=NC2CCCCC2)CC1.[Br:16][CH2:17]/[CH:18]=[CH:19]/[C:20]([OH:22])=O.[F:23][C:24]1[CH:29]=[CH:28][C:27]([NH:30][C:31]2[C:32]3[CH:40]=[C:39]([NH2:41])[N:38]=[CH:37][C:33]=3[N:34]=[CH:35][N:36]=2)=[CH:26][C:25]=1[C:42]([F:45])([F:44])[F:43].C(N(C(C)C)CC)(C)C>C1COCC1.CC(N(C)C)=O>[Br:16][CH2:17]/[CH:18]=[CH:19]/[C:20]([NH:41][C:39]1[N:38]=[CH:37][C:33]2[N:34]=[CH:35][N:36]=[C:31]([NH:30][C:27]3[CH:28]=[CH:29][C:24]([F:23])=[C:25]([C:42]([F:45])([F:44])[F:43])[CH:26]=3)[C:32]=2[CH:40]=1)=[O:22]
Reactant: Nc1cc2c(Nc3ccc(F)c(C(F)(F)F)c3)ncnc2cn1
Reactant: O=C(O)/C=C/CBr
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: CC(=O)N(C)C
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: O=C(/C=C/CBr)Nc1cc2c(Nc3ccc(F)c(C(F)(F)F)c3)ncnc2cn1
Reaction time: 2 h

Procedure:
A stirred solution of DCC (633 mg, 3.07 mmol) in THF (2 mL) under nitrogen was treated with a solution of acid 9 (506 mg, 3.07 mmol) in anhydrous THF (2 mL) at 0° C. The mixture was stirred for 2 h, then treated with compound 168 (200 mg, 0.62 mmol) in DMA (2 mL) followed by di-iso-propylethylamine (DIPEA) (535 μL, 3.07 mmol), before being stirred for a further 3 h at 0° C. The resulting crude (E)-4-bromo-N-(4-(4-fluoro-3-(trifluoromethyl)phenylamino)pyrido[3,4-d]pyrimidin-6-yl)but-2-enamide thus formed was treated in situ with 40% aqueous dimethylamine (942 μL, 18.60 mmol) at 0° C. with stirring for 1 h. The mixture was then diluted with ethyl acetate (300 mL), then poured into a beaker of ice-water (600 mL), stirred for 10 min and then extracted with EtOAc. The combined organic extracts were washed with 2% cold aqueous Na2CO3, water and brine before being dried (Na2SO4) and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel eluting with EtOAc/MeOH (9:1). Recrystallization from CH2Cl2/diisopropyl ether then gave (2E)-4-(dimethylamino)-N-{4-[4-fluoro-3-(trifluoromethyl)anilino]pyrido[3,4-d]pyrimidin-6-yl}-2-butenamide (170) (175 mg, 65%) as a pale yellow solid, 170-172° C. 1H NMR [(CD)2SO] δ 10.93 (s, 1H), 10.42 (s, 1H), 9.04 (s, 1H), 9.01 (s, 1H), 8.64 (s, 1H), 8.24-8.28 (m, 2H), 7.56 (t, J=9.6 Hz, 1H), 6.88 (dt, J=15.4, 6.0 Hz, 1H), 6.53 (d, J=15.4 Hz, 1H), 3.10 (dd, J=6.0, 1.1 Hz, 2H), 2.19 (s, 6H). Anal. Calcd for C20H18F4N6O.0.4CH2Cl2: C, 52.32; H, 4.05; N, 17.94%. found: C, 51.99; H, 4.28; N, 18.07%.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=2)=[CH:4][N:3]=1.Cl[CH2:16][C:17]([NH:19][C:20](=[O:23])[O:21][CH3:22])=O>>[CH3:22][O:21][C:20]([NH:19][C:17]1[N:1]=[C:2]2[CH:7]=[CH:6][C:5]([O:8][C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=3)=[CH:4][N:3]2[CH:16]=1)=[O:23]
Reactant: Nc1ccc(Oc2ccccn2)cn1
Reactant: COC(=O)NC(=O)CCl
Product: COC(=O)Nc1cn2cc(Oc3ccccn3)ccc2n1

Procedure:
Reaction of 2-amino-5-(2-pyridyloxy) pyridine with methyl chloroacetylcarbamate as in Example 3 yields 2-(methoxycarbonylamino)-6-(2-pyridyloxy) imidazo [1,2-a] pyridine.