Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]1([CH3:11])[O:8][CH:7]([CH2:9][OH:10])[CH2:6][O:5]1.CN(C=O)C.CS([C:21]1[N:22]=[C:23]([NH:42][C:43]2[CH:48]=[CH:47][C:46]([C:49]([F:52])([F:51])[F:50])=[CH:45][CH:44]=2)[C:24]2[CH2:30][CH2:29][N:28]([C:31]3[C:36]([C:37]([F:40])([F:39])[F:38])=[CH:35][CH:34]=[CH:33][N:32]=3)[CH2:27][CH2:26][C:25]=2[N:41]=1)(=O)=O>CO>[CH3:3][C:4]1([CH3:11])[O:8][C@@H:7]([CH2:9][O:10][C:21]2[N:22]=[C:23]([NH:42][C:43]3[CH:48]=[CH:47][C:46]([C:49]([F:52])([F:50])[F:51])=[CH:45][CH:44]=3)[C:24]3[CH2:30][CH2:29][N:28]([C:31]4[C:36]([C:37]([F:40])([F:39])[F:38])=[CH:35][CH:34]=[CH:33][N:32]=4)[CH2:27][CH2:26][C:25]=3[N:41]=2)[CH2:6][O:5]1
Reactant: CC1(C)OCC(CO)O1
Reactant: CS(=O)(=O)c1nc2c(c(Nc3ccc(C(F)(F)F)cc3)n1)CCN(c1ncccc1C(F)(F)F)CC2
Agent: [H-]
Agent: [Na+]
Solvent: CO
Solvent: CN(C)C=O
Product: CC1(C)OC[C@H](COc2nc3c(c(Nc4ccc(C(F)(F)F)cc4)n2)CCN(c2ncccc2C(F)(F)F)CC3)O1
Temperature: 70 °C
Reaction time: 0.5 h
Yield: 71.1 %

Procedure:
A dispersion of NaH in mineral oil (12.0 mg, 0.28 mmol) was added to a flask containing (2,2-dimethyl-[1,3]dioxolan-4-yl)-methanol (116 μL, 0.94 mmol) and DMF (1.0 mL). After 30 min, the mixture was transferred to a flask containing [2-methanesulfonyl-7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-yl]-(4-trifluoromethyl-phenyl)-amine (Example 53; 50 mg, 0.094 mmol). The resulting mixture was then heated at 70° C. for 24 h. The mixture was cooled, diluted with MeOH (1.0 mL) and purified by reverse phase HPLC, yielding 39 mg (70%) of the title compound. MS (ESI): mass calcd. for C27H27F6N5O3, 583.20; m/z found, 584.2 [M+H]+. 1H NMR (CDCl3): 8.39-8.37 (m, 1H), 7.89-7.86 (m, 1H), 7.69 (d, J=11.0 Hz, 2H), 7.59 (d, J=11.0 Hz, 2H), 6.98-6.94 (m, 1H), 6.68 (s, 1H), 4.52-4.56 (m, 1H), 4.42-4.38 (m, 1H), 4.28-4.24 (m, 1H), 4.16-4.12 (m, 1H), 3.94-3.90 (m, 1H), 3.63-3.56 (m, 4H), 3.18-3.15 (m, 2H), 2.96-2.93 (m, 2H), 1.46 (s, 3H), 1.38 (s, 3H).
Reaction SMILES: I[C:2]1[N:3]=[C:4]([NH2:20])[C:5]2[N:6]=[CH:7][N:8]([C:18]=2[N:19]=1)[C@@H:9]1[O:17][C@H:14]([CH2:15][OH:16])[C@@H:12]([OH:13])[C@H:10]1[OH:11].C1(C#C)CCCCC1.[C:29]([C:31]1([OH:37])[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]1)#[CH:30]>>[OH:37][C:31]1([C:29]#[C:30][C:2]2[N:3]=[C:4]([NH2:20])[C:5]3[N:6]=[CH:7][N:8]([C:18]=3[N:19]=2)[C@@H:9]2[O:17][C@H:14]([CH2:15][OH:16])[C@@H:12]([OH:13])[C@H:10]2[OH:11])[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]1
Reactant: Nc1nc(I)nc2c1ncn2[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O
Reactant: C#CC1(O)CCCCC1
Agent: C#CC1CCCCC1
Product: Nc1nc(C#CC2(O)CCCCC2)nc2c1ncn2[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O
Reaction time: 1 h
Yield: 79 %

Procedure:
The procedure of Example 1 was repeated except that 1.14 g (2.9 mmol) of 2-iodoadenosine was used as the starting compound, that the cyclohexylacetylene was replaced by 1-ethynyl-1-cyclohexanol, and that the reaction was carried out at a temperature of 100° C. for one hour, respectively, whereby 0.91 g (2.3 mmol) of crystalline 2-[(1-hydroxycyclohexane-1-yl)ethynyl]adenosine was obtained (yield: 79%).
Reaction SMILES: [F:1][C:2]1[C:3]([CH2:14][N:15]([CH3:23])[C:16](=[O:22])[O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[CH:4][NH:5][C:6]=1[C:7]1[C:8]([F:13])=[N:9][CH:10]=[CH:11][CH:12]=1.[H-].[Na+].C1OCCOCCOCCOCCOC1.[F:41][C:42]1[CH:47]=[CH:46][CH:45]=[C:44]([F:48])[C:43]=1[S:49](Cl)(=[O:51])=[O:50]>O1CCCC1.O>[F:41][C:42]1[CH:47]=[CH:46][CH:45]=[C:44]([F:48])[C:43]=1[S:49]([N:5]1[C:6]([C:7]2[C:8]([F:13])=[N:9][CH:10]=[CH:11][CH:12]=2)=[C:2]([F:1])[C:3]([CH2:14][N:15]([CH3:23])[C:16](=[O:22])[O:17][C:18]([CH3:19])([CH3:20])[CH3:21])=[CH:4]1)(=[O:51])=[O:50]
Reactant: CN(Cc1c[nH]c(-c2cccnc2F)c1F)C(=O)OC(C)(C)C
Reactant: O=S(=O)(Cl)c1c(F)cccc1F
Agent: C1COCCOCCOCCOCCO1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CN(Cc1cn(S(=O)(=O)c2c(F)cccc2F)c(-c2cccnc2F)c1F)C(=O)OC(C)(C)C
Reaction time: 0.25 h
Yield: 85.9 %

Procedure:
To a solution of tert-butyl {[4-fluoro-5-(2-fluoropyridin-3-yl)-1H-pyrrol-3-yl]methyl}methylcarbamate (324 mg) in tetrahydrofuran (20 mL) was added sodium hydride (60% in oil, 121 mg) at room temperature and the mixture was stirred for 15 min. 15-Crown-5 (664 mg) was added dropwise, and the mixture was stirred for 5 min. 2,6-Difluorobenzenesulfonyl chloride (320 mg) was added, and the mixture was further stirred for 30 min. The reaction mixture was diluted with water, and extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate=1:4→2:3) to give the title compound as a colorless oil (yield 430 mg, 86%).
Reaction SMILES: [CH3:1][C@@H:2]1[CH2:7][CH2:6][CH2:5][N:4](C(=O)C2C=C(C)C=CC=2C2C=NN(C)C=2)[C@@H:3]1[CH2:23][N:24]1[C:32](=[O:33])[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[C:25]1=[O:34].[Br:35][C:36]1[CH:44]=[CH:43][C:42]([F:45])=[CH:41][C:37]=1[C:38]([OH:40])=O>>[Br:35][C:36]1[CH:44]=[CH:43][C:42]([F:45])=[CH:41][C:37]=1[C:38]([N:4]1[CH2:5][CH2:6][CH2:7][C@@H:2]([CH3:1])[C@H:3]1[CH2:23][N:24]1[C:32](=[O:33])[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[C:25]1=[O:34])=[O:40]
Reactant: O=C(O)c1cc(F)ccc1Br
Reactant: Cc1ccc(-c2cnn(C)c2)c(C(=O)N2CCC[C@@H](C)[C@H]2CN2C(=O)c3ccccc3C2=O)c1
Product: C[C@@H]1CCCN(C(=O)c2cc(F)ccc2Br)[C@@H]1CN1C(=O)c2ccccc2C1=O

Procedure:
The title compound was prepared following the same general protocol as described for 2-(((2S,3R)-3-methyl-1-(5-methyl-2-(1-methyl-1H-pyrazol-4-yl)benzoyl)piperidin-2-yl)methyl)isoindoline-1,3-dione in Example A1, using 2-bromo-5-fluorobenzoic acid. ESI-MS (m/z): 459, 461 [M]+[M+2]+.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:8]([OH:10])=O)=[N:4][CH:5]=[CH:6][CH:7]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[NH:44]1[C:52]2[C:47](=[C:48]([C:53]3[CH:54]=[C:55]([NH2:62])[C:56]4[CH:57]=[N:58][NH:59][C:60]=4[CH:61]=3)[CH:49]=[CH:50][CH:51]=2)[CH:46]=[CH:45]1>CN(C=O)C.CO>[Cl:1][C:2]1[C:3]([C:8]([NH:62][C:55]2[CH:54]=[C:53]([C:48]3[CH:49]=[CH:50][CH:51]=[C:52]4[C:47]=3[CH:46]=[CH:45][NH:44]4)[CH:61]=[C:60]3[C:56]=2[CH:57]=[N:58][NH:59]3)=[O:10])=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: Nc1cc(-c2cccc3[nH]ccc23)cc2[nH]ncc12
Reactant: O=C(O)c1ncccc1Cl
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: CO
Product: O=C(Nc1cc(-c2cccc3[nH]ccc23)cc2[nH]ncc12)c1ncccc1Cl
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 27.7 %

Procedure:
To a solution of 3-chloropicolinic acid (380 mg, 2.42 mmol, available from Fluorochem Ltd.) in DMF (5 ml) was added HATU (920 mg, 2.42 mmol) and DIPEA (1.266 ml, 7.25 mmol). The mixture was stirred at room temperature for 20 mins then 6-(1H-indol-4-yl)-1H-indazol-4-amine (300 mg, 1.21 mmol) was added and the mixture stirred at room temperature overnight. The reaction mixture was concentrated in vacuo to give a volume of approx. 1 ml which was added to the top of a 20 g aminopropyl cartridge that had been preconditioned with MeOH. The reaction mixture remained on the cartridges for 2 h before being eluted with MeOH. The solvent was removed in vacuo to give a brown oil that was purified by chromatography using silica gel (70 g cartridge, FlashMaster II) eluting with 0-25% MeOH in DCM over 30 mins to afford the title compound (130 mg) as a brown solid.
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][N:5]([CH2:8][CH2:9][CH:10]([C:22]2[CH:27]=[CH:26][C:25]([Cl:28])=[C:24]([Cl:29])[CH:23]=2)[CH2:11][N:12]([CH3:21])[C:13](=[O:20])[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:4][CH2:3]1.C(N(CC)CC)C.[C:37](OC(=O)C)(=[O:39])[CH3:38]>ClCCl>[C:37]([NH:1][CH:2]1[CH2:3][CH2:4][N:5]([CH2:8][CH2:9][CH:10]([C:22]2[CH:27]=[CH:26][C:25]([Cl:28])=[C:24]([Cl:29])[CH:23]=2)[CH2:11][N:12]([CH3:21])[C:13](=[O:20])[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:6][CH2:7]1)(=[O:39])[CH3:38]
Reactant: CC(=O)OC(C)=O
Reactant: CN(CC(CCN1CCC(N)CC1)c1ccc(Cl)c(Cl)c1)C(=O)c1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)NC1CCN(CCC(CN(C)C(=O)c2ccccc2)c2ccc(Cl)c(Cl)c2)CC1
Reaction time: 0.5 h

Procedure:
To a solution of N-[4-(4-aminopiperidino)-2-(3,4-dichlorophenyl)butyl]-N-methylbenzamide (1.5 g) in dichloromethane (35 mL) was added triethylamine (0.60 mL) and acetic anhydride (0.41 mL), and the resulting solution was allowed to stir for 30 minutes. The mixture was diluted with dichloromethane and was washed (0.3N sodium hydroxide, water), dried, and evaporated. The material was dissolved in toluene and the resulting solution was evaporated to give the title compound (1.63 g) as a white solid; MS: m/z=476(M+1). Analysis for C25H31Cl2N3O2 ·0.2 C6H5CH3 : Calculated: C, 64.07; H, 6.63; N, 8.49; Found: C, 64.04; H, 6.59; N, 8.32.
Reaction SMILES: C(OC([N:8]1[CH2:11][CH:10]([C:12]2[CH:44]=[CH:43][C:15]3[C:16]4[N:17]=[C:18]([C:24]5[N:25]([CH:40]([CH3:42])[CH3:41])[N:26]=[C:27]([NH:29][C:30]([O:32][CH2:33][C:34]6[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=6)=[O:31])[N:28]=5)[S:19][C:20]=4[CH2:21][CH2:22][O:23][C:14]=3[CH:13]=2)[CH2:9]1)=O)(C)(C)C.[ClH:45].CO>C(Cl)Cl.O1CCOCC1>[ClH:45].[CH2:33]([O:32][C:30](=[O:31])[NH:29][C:27]1[N:28]=[C:24]([C:18]2[S:19][C:20]3[CH2:21][CH2:22][O:23][C:14]4[CH:13]=[C:12]([CH:10]5[CH2:9][NH:8][CH2:11]5)[CH:44]=[CH:43][C:15]=4[C:16]=3[N:17]=2)[N:25]([CH:40]([CH3:41])[CH3:42])[N:26]=1)[C:34]1[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=1
Reactant: CC(C)n1nc(NC(=O)OCc2ccccc2)nc1-c1nc2c(s1)CCOc1cc(C3CN(C(=O)OC(C)(C)C)C3)ccc1-2
Agent: Cl
Solvent: ClCCl
Solvent: CO
Solvent: C1COCCO1
Product: CC(C)n1nc(NC(=O)OCc2ccccc2)nc1-c1nc2c(s1)CCOc1cc(C3CNC3)ccc1-2
Reaction time: 1 h
Yield: 84 %

Procedure:
To a solution of 3-[2-(5-benzyloxycarbonylamino-2-isopropyl-2H-[1,2,4]-triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulen-8-yl]-azetidine-1-carboxylic acid tert-butyl ester (504 mg, 0.82 mmol) in DCM (10 mL) was added 4N HCl in dioxan (2 mL) at RT. After stirring for 2 hours MeOH (2 mL) and 4N HCl in dioxan (3 mL) were added to the mixture. After stirring for 60 minutes the reaction mixture was concentrated in vacuo. The resulting solid was treated with ether, collected by filtration and dried under vacuum to afford [5-(8-azetidin-3-yl-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulen-2-yl)-1-isopropyl-1H-[1,2,4]triazol-3-yl]-carbamic acid benzyl ester hydrochloride salt (379 mg, 84%). LCMS: RT=3.04 min, [M+H]+=517
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][O:17][CH3:18])=[CH:11][C:10]=1[CH2:19]O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Br)(Br)(Br)[Br:41].CN(C)C=O>O>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][O:17][CH3:18])=[CH:11][C:10]=1[CH2:19][Br:41])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: BrC(Br)(Br)Br
Reactant: COCOc1ccc(OCc2ccccc2)c(CO)c1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: CN(C)C=O
Product: COCOc1ccc(OCc2ccccc2)c(CBr)c1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 45.7 %

Procedure:
A mixture of (2-benzyloxy-5-methoxymethoxyphenyl)methanol (8.0 g), triphenylphosphine (7.66 g), carbon tetrabromide (9.68 g) and N,N-dimethylformamide (100 mL) was stirred at room temperature for 1.5 hrs. To the reaction mixture was added water and the mixture was extracted with ethyl acetate. The organic layer was washed successively with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated. The obtained residue was subjected to silica gel column chromatography to give crystals (4.49 g, 46%) of 1-benzyloxy-2-bromomethyl-4-methoxymethoxybenzene from a fraction eluted with ethyl acetate-hexane (1:4, v/v). Recrystallization from ethyl acetate-hexane gave colorless prism crystals. melting point: 55-57° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]=[C:8]([C@H:13]([CH3:23])[C:14]([O:16][CH2:17][CH:18](OC)OC)=[O:15])[CH:7]=[CH:6]2.C12(CS(O)(=O)=O)C(C)(C)C(CC1)CC2=O.S([O-])([O-])(=O)=O.[Mg+2].[SH:45][CH2:46][C:47]([OH:49])=[O:48]>ClC(Cl)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]=[C:8]([C@H:13]([CH3:23])[C:14]([O:16][CH2:17][C@@H:18]1[S:45][CH2:46][C:47](=[O:49])[O:48]1)=[O:15])[CH:7]=[CH:6]2
Reactant: COc1ccc2cc([C@H](C)C(=O)OCC(OC)OC)ccc2c1
Reactant: O=C(O)CS
Agent: CC1(C)C2CCC1(CS(=O)(=O)O)C(=O)C2
Agent: O=S(=O)([O-])[O-]
Agent: [Mg+2]
Solvent: CC(Cl)Cl
Product: COc1ccc2cc([C@H](C)C(=O)OC[C@H]3OC(=O)CS3)ccc2c1
Temperature: 25 °C
Yield: 53.3 %

Procedure:
To a round bottom flask is added 2,2-dimethoxyethyl (S)-6-methoxy-α-methyl-2-naphthaleneacetate (13.8 g), dichloroethane (60 mL), camphorsulfonic acid (0.7 g) and magnesium sulfate (1.0 g). The reaction mixture is heated to reflux and a solution of mercaptoacetic acid (13.5 g) in dichloroethane (15 mL) is added dropwise. The mixture is removed from the oil bath and a sample is taken for TLC and NMR analysis. Additional camphorsulfonic acid (0.6 g) is added and the mixture is heated in an oil bath to reflux for 2 hours. The mixture is cooled to room temperature and then shaken with water (50 mL) and saturated sodium bicarbonate (50 mL). The separated lower phase is shaken with saturated sodium bicarbonate (25 mL) and water (50 mL), the phases are separated and the lower cloudy organic phase is vacuum concentrated to give 17.4 g of crude product. The obtained syrup is applied to a silica column and eluted with EtOAc/heptanes (15:85) to provide 8.0 g of product.
Reaction SMILES: Cl.[NH:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[N:4]=[C:3]1[C@@H:11]1[CH2:15][C:14](=[N:16][O:17][CH3:18])[CH2:13][N:12]1C(OC(C)(C)C)=O>C(Cl)Cl>[CH3:18][O:17][N:16]=[C:14]1[CH2:15][C@@H:11]([C:3]2[NH:2][C:6]3[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=3[N:4]=2)[NH:12][CH2:13]1
Reactant: CON=C1C[C@@H](c2nc3ccccc3[nH]2)N(C(=O)OC(C)(C)C)C1
Agent: Cl
Solvent: ClCCl
Product: CON=C1CN[C@H](c2nc3ccccc3[nH]2)C1
Yield: 114.5 %

Procedure:
Hydrogen chloride gas was bubbled into a solution of the fused heterocyclic product from the previous step, e.g. tert-butyl (2S,4EZ)-2-(1H-benzimidazol-2-yl)-4-(methoxyimino)-1-pyrrolidinecarboxylate (740 mg, 2.2 mmol) in dry DCM (20 ml) for 30 min. The solvent was removed in vacuo to give the desired product, e.g. (3EZ,5S)-5-(1H-benzimidazol-2-yl)-3-pyrrolidinone O-methyloxime (0.58 g, 99%), as a brown amorphous powder which was used without further purification.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Br[CH2:8][CH2:9][O:10][N:11]1[C:15](=[O:16])[C:14]2=[CH:17][CH:18]=[CH:19][CH:20]=[C:13]2[C:12]1=[O:21].C(=O)([O-])[O-].[Na+].[Na+].[I-].[Na+]>C(C(C)=O)C>[N:1]1([CH2:8][CH2:9][O:10][N:11]2[C:15](=[O:16])[C:14]3=[CH:17][CH:18]=[CH:19][CH:20]=[C:13]3[C:12]2=[O:21])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C1c2ccccc2C(=O)N1OCCBr
Reactant: C1CCNCC1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [Na+]
Solvent: CCC(C)=O
Product: O=C1c2ccccc2C(=O)N1OCCN1CCCCC1

Procedure:
21.3 g (0.25 mol) of piperidine are added to a solution of 54 g (0.2 mol) of N-(2-bromoethoxy)phthalimide in 800 ml of methyl ethyl ketone, in the presence of 31.5 g (0.3 mol) of sodium carbonate and 1 g of sodium iodide.
Reaction SMILES: [C:1]([OH:5])(=[O:4])[CH2:2][OH:3].C(N(CC)CC)C.Cl[C:14]([O:16][CH2:17][C:18]1[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[CH:20][CH:19]=1)=[O:15]>O1CCCC1.C(OCC)(=O)C>[N+:24]([C:21]1[CH:20]=[CH:19][C:18]([CH2:17][O:16][C:14]([O:3][CH2:2][C:1]([OH:5])=[O:4])=[O:15])=[CH:23][CH:22]=1)([O-:26])=[O:25]
Reactant: O=C(O)CO
Reactant: O=C(Cl)OCc1ccc([N+](=O)[O-])cc1
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: O=C(O)COC(=O)OCc1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a mixture of glycolic acid (760 mg) and triethylamine (1.1 g) in tetrahydrofuran (20 ml) was added p-nitrobenzyl chloroformate (2.26 g) with ice-cooling and the resulting mixture was stirred for 1 hour at room temperature. The reaction mixture was diluted with ethyl acetate, washed successively with diluted hydrochloric acid and water, dried over anhydrous sodium sulfate and evaporated to give p-nitrobenzyloxycarbonyloxyacetic acid.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]2[N:10]([CH2:11][C:12]3[C:17]([CH3:18])=[C:16]([O:19][CH2:20][C:21]([F:24])([F:23])[F:22])[CH:15]=[CH:14][N:13]=3)[CH:9]=[C:8]([C:25](O)=[O:26])[C:5]2=[N:6][CH:7]=1.CN1C(=O)CCC1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH2:59]([CH2:61][NH2:62])[OH:60].C(N(CC)CC)C>>[OH:60][CH2:59][CH2:61][NH:62][C:25]([C:8]1[C:5]2=[N:6][CH:7]=[C:2]([CH3:1])[CH:3]=[C:4]2[N:10]([CH2:11][C:12]2[C:17]([CH3:18])=[C:16]([O:19][CH2:20][C:21]([F:22])([F:24])[F:23])[CH:15]=[CH:14][N:13]=2)[CH:9]=1)=[O:26]
Reactant: Cc1cnc2c(C(=O)O)cn(Cc3nccc(OCC(F)(F)F)c3C)c2c1
Reactant: NCCO
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN1CCCC1=O
Solvent: CCN(CC)CC
Product: Cc1cnc2c(C(=O)NCCO)cn(Cc3nccc(OCC(F)(F)F)c3C)c2c1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 25.4 %

Procedure:
See FIG. 23(b). 6-methyl-1-((3-methyl-4-(2,2,2-trifluoroethoxy)pyridin-2-yl)methyl)-1H-pyrrolo[3,2-b]pyridine-3-carboxylic acid (55 mg, 0.14 mmol) and NMP (13.95 μl, 0.14 mmol) was taken in a 50 ml single necked flask equipped with an air condenser connected to nitrogen source. HATU (66.2 mg, 0.17 mmol) was added to get a suspension. Added ethanol amine (17.50 μl, 0.29 mmol) followed by the addition of triethyl amine (60.6 μl, 0.43 mmol). The reaction mass was stirred at RT for 5 minutes. LCMS showed completion of the reaction. The crude compound was purified by Gilson Prep HPLC to get pure N-(2-hydroxyethyl)-6-methyl-1-((3-methyl-4-(2,2,2-trifluoroethoxy)pyridin-2-yl)methyl)-1H-pyrrolo[3,2-b]pyridine-3-carboxamide (15.00 mg, 24.49%). ES+MS m/z: 423 (M+I). 1H NMR (300 MHz, DMSO-d6) δ ppm 2.23 (s, 3 H ) 2.39 (s, 3 H ) 3.45 (br. s., 2 H ) 3.53 (br. s., 2 H ) 4.83 (s, 1 H ) 4.90 (d, J=9.04 Hz, 2 H ) 5.62 (s, 2 H ) 7.06 (d, J=5.65 Hz, 1 H ) 7.75 (s, 1 H ) 8.07 (s, 1 H ) 8.17 (d, J=5.09 Hz, 1 H ) 8.32 (s, 1H ) 8.79 (s, 1 H ).
Reaction SMILES: ClC1C=CC=C([C:8](OO)=[O:9])C=1.[CH3:12][C:13]1[NH:14][C:15](=[O:19])[CH2:16][S:17][CH:18]=1>CO>[CH3:8][O:9][CH:16]1[C:15](=[O:19])[NH:14][C:13]([CH3:12])=[CH:18][S:17]1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CC1=CSCC(=O)N1
Solvent: CO
Product: COC1SC=C(C)NC1=O
Temperature: 25 °C
Reaction time: 24 h
Yield: 61.1 %

Procedure:
m-Chloroperbenzoic acid (28.8 g) was added dropwise to a stirred solution of 5-methyl-2H-1,4-thiazin-3(4H)-one (15 g) in methanol (300 ml) under ice-cooling and the mixture was stirred at room temperature for 1 day. After the mixture was evaporated to dryness, the residue was extracted with ethyl acetate, washed with saturated sodium bicarbonate aqueous solution and dried over anhydrous magnesium sulfate. The solvent was evaporated to dryness to give 2-methoxy-5-methyl-2H-1,4-thiazin-3(4H)-one (11.3 g, yield 61%) as pale yellow powder.
Reaction SMILES: [CH2:1]1[C:22]2[C:4](=[CH:5][C:6]3[S:12][C:11]4[CH:13]=[C:14]([C:17]([O:19][CH3:20])=[O:18])[CH:15]=[CH:16][C:10]=4[CH2:9][CH2:8][C:7]=3[CH:21]=2)[CH2:3][CH2:2]1.ClC1C=CC=C(C(OO)=[O:31])C=1.[OH-].[Ca+2].[OH-]>C(Cl)Cl>[CH2:1]1[C:22]2[C:4](=[CH:5][C:6]3[S:12](=[O:31])[C:11]4[CH:13]=[C:14]([C:17]([O:19][CH3:20])=[O:18])[CH:15]=[CH:16][C:10]=4[CH2:9][CH2:8][C:7]=3[CH:21]=2)[CH2:3][CH2:2]1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: COC(=O)c1ccc2c(c1)Sc1cc3c(cc1CC2)CCC3
Agent: [Ca+2]
Agent: [OH-]
Solvent: ClCCl
Product: COC(=O)c1ccc2c(c1)S(=O)c1cc3c(cc1CC2)CCC3
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 66 %

Procedure:
To a solution of methyl 2,3,10,11-tetrahydro1H-benzo[b]indeno[5,6-f]thiepin-7-carboxylate (3.05 g; 9.84 mmole) in methylene chloride (200 ml) stirred in a cooling bath at 0°-5° C. was added 85% m-chloroperbenzoic acid (2.00 g; 9.85 mmole) in small portions during 1 hour. After stirring the reaction mixture for 30 minutes at room temperature, more methylene chloride was added to get a clear solution and then calcium hydroxide (4 g) was added. The suspension was stirred for 25 minutes, filtered and evaporated. The crude product was purified by column chromatography (Merck silica gel eluted with 1:4 ethyl acetate/toluene) to yield 2.121 g (66%) of the title compound, m.p. 150°-154° C. (from MeCN).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH2:9][NH:10][CH2:11][CH2:12][CH2:13][NH:14][CH2:15][CH2:16][CH2:17][CH2:18][NH:19][CH2:20][CH2:21][CH2:22][NH2:23])[CH:6]=[CH:5][C:4]=1[OH:24].[Cl:25][C:26]1[N:31]=[C:30]([NH:32][CH:33]([CH2:44][CH3:45])[CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][O:40][C:41](Cl)=[O:42])[CH:29]=[C:28]([CH2:46][CH3:47])[N:27]=1.C(N(CC)CC)C.[NH:55]1[CH:59]=[CH:58][N:57]=[CH:56]1>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH2:9][NH:10][CH2:11][CH2:12][CH2:13][NH:14][CH2:15][CH2:16][CH2:17][CH2:18][NH:19][CH2:20][CH2:21][CH2:22][NH2:23])[CH:6]=[CH:5][C:4]=1[OH:24].[Cl:25][C:26]1[N:31]=[C:30]([NH:32][CH:33]([CH2:44][CH3:45])[CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][O:40][C:41]([N:55]2[CH:59]=[CH:58][N:57]=[CH:56]2)=[O:42])[CH:29]=[C:28]([CH2:46][CH3:47])[N:27]=1
Reactant: CCc1cc(NC(CC)CCCCCCOC(=O)Cl)nc(Cl)n1
Reactant: c1c[nH]cn1
Agent: COc1cc(CNCCCNCCCCNCCCN)ccc1O
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CCc1cc(NC(CC)CCCCCCOC(=O)n2ccnc2)nc(Cl)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 76.5 %

Procedure:
In 20 ml of toluene was dissolved 1.00 g of dl-5-chloro-6-ethyl-4-[1-ethyl-7-(chlorocarbonyloxy)heptyl]aminopyrimidine, and 0.50 g of triethylamine and 0.22 g of imidazole were added to the solution and the mixture was stirred at room temperature for one hour. After completion of the reaction, the reaction mixture was filtered, and excessive triethylamine and the solvent was removed under reduced pressure. The resulting oily product was isolated through a column chromatography (Wako gel C-200, trade name, eluent; toluene:ethyl acetate=3:1) to give 0.80 g of the title compound as pale yellow oily product. nD21.9 1.5332.
Reaction SMILES: [C:1]([O:5][C:6](=[O:14])[N:7]([CH3:13])[CH:8]1[CH2:12][CH2:11][NH:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].Cl[CH2:16][CH2:17][NH:18][C:19]([NH:21][C:22]1[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[N:25]=[C:24]([CH3:32])[CH:23]=1)=[O:20].C([O-])(O)=O.[Na+].N[C@H](C(O)=O)CC1C=C2C(C=CC=C2)=CC=1>C1COCC1>[C:1]([O:5][C:6](=[O:14])[N:7]([CH3:13])[CH:8]1[CH2:12][CH2:11][N:10]([CH2:16][CH2:17][NH:18][C:19]([NH:21][C:22]2[C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[N:25]=[C:24]([CH3:32])[CH:23]=2)=[O:20])[CH2:9]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CN(C(=O)OC(C)(C)C)C1CCNC1
Reactant: Cc1cc(NC(=O)NCCCl)c2ccccc2n1
Agent: N[C@@H](Cc1ccc2ccccc2c1)C(=O)O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1cc(NC(=O)NCCN2CCC(N(C)C(=O)OC(C)(C)C)C2)c2ccccc2n1
Temperature: 70 °C
Reaction time: 144 h

Procedure:
A mixture of methyl-pyrrolidin-3-yl-carbamic acid tert-butyl ester (10 mmol), 1-(2-chloro-ethyl)-3-(2-methyl-quinolin-4-yl)-urea (10 mmol), NaHCO3 (20 mmol), Nal (0.5 mmol), and THF (70 mL) is stirred in a sealed vessel at 70° C. for 6 d. The reaction mixture is filtered, evaporated to dryness, and the residue is purified by preparative HPLC to provide the title compound.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][N:5]1[C:9](=[O:10])[C:8]2=[CH:11][CH:12]=[CH:13][CH:14]=[C:7]2[C:6]1=[O:15].[CH:16]([N:19]1[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1)([CH3:18])[CH3:17].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH:16]([N:19]1[CH2:24][CH2:23][N:22]([CH2:2][CH2:3][CH2:4][N:5]2[C:9](=[O:10])[C:8]3=[CH:11][CH:12]=[CH:13][CH:14]=[C:7]3[C:6]2=[O:15])[CH2:21][CH2:20]1)([CH3:18])[CH3:17]
Reactant: CC(C)N1CCNCC1
Reactant: O=C1c2ccccc2C(=O)N1CCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CC(C)N1CCN(CCCN2C(=O)c3ccccc3C2=O)CC1
Reaction time: 4 h
Yield: 122.8 %

Procedure:
To the solution of N-(3-bromopropyl)phthalimide (30.1 g) in acetone (200 ml) were added 1-isopropyl piperazine (23.0 g) and potassium carbonate (41.4 g). The resulting mixture was refluxed with stirring for 4 hours. The reaction maxture was cooled and then filtered. The filter cake was washed with acetone. The filtrate and washing were combined and evaporated under reduced pressure to give an oil of N-[3-(4-isopropyl-1-piperazinyl)propyl]phthalimide (43.5 g).