Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[C:29](=[O:30])[N:28]([CH3:31])[C:12]2[N:13]([CH3:27])[C:14]3[C:19]([C:11]=2[CH:10]=1)=[CH:18][C:17]([C:20]1[N:21]=[C:22]([CH2:25][OH:26])[S:23][CH:24]=1)=[CH:16][CH:15]=3.Br[CH2:33][CH:34]1[CH2:36][CH2:35]1>>[CH:34]1([CH2:33][O:26][CH2:25][C:22]2[S:23][CH:24]=[C:20]([C:17]3[CH:18]=[C:19]4[C:14](=[CH:15][CH:16]=3)[N:13]([CH3:27])[C:12]3[N:28]([CH3:31])[C:29](=[O:30])[C:9]([C:3]5[CH:4]=[CH:5][C:6]([Cl:8])=[CH:7][C:2]=5[Cl:1])=[CH:10][C:11]4=3)[N:21]=2)[CH2:36][CH2:35]1
Reactant: Cn1c(=O)c(-c2ccc(Cl)cc2Cl)cc2c3cc(-c4csc(CO)n4)ccc3n(C)c21
Reactant: BrCC1CC1
Product: Cn1c(=O)c(-c2ccc(Cl)cc2Cl)cc2c3cc(-c4csc(COCC5CC5)n4)ccc3n(C)c21

Procedure:
The process is carried out as indicated in Example 10 above, with the compound from Example 9, 3-(2,4-dichlorophenyl)-6-(2-hydroxymethylthiazol-4-yl)-1,9-dimethyl-1,9-dihydropyrido[2,3-b]indol-2-one, and bromomethylcyclopropane.
Reaction SMILES: [H-].[Na+].[C:3]1([OH:9])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.Cl[C:11]1[C:16]([N+:17]([O-:19])=[O:18])=[C:15]([NH:20][CH2:21][CH2:22][O:23][CH2:24][CH2:25][CH2:26][C:27]2[CH:28]=[N:29][CH:30]=[CH:31][CH:32]=2)[C:14]([CH3:33])=[C:13]([CH3:34])[N:12]=1>COCCOCCOC>[CH3:34][C:13]1[C:14]([CH3:33])=[C:15]([NH:20][CH2:21][CH2:22][O:23][CH2:24][CH2:25][CH2:26][C:27]2[CH:28]=[N:29][CH:30]=[CH:31][CH:32]=2)[C:16]([N+:17]([O-:19])=[O:18])=[C:11]([O:9][C:3]2[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=2)[N:12]=1
Reactant: Oc1ccccc1
Reactant: Cc1nc(Cl)c([N+](=O)[O-])c(NCCOCCCc2cccnc2)c1C
Agent: [H-]
Agent: [Na+]
Solvent: COCCOCCOC
Product: Cc1nc(Oc2ccccc2)c([N+](=O)[O-])c(NCCOCCCc2cccnc2)c1C
Temperature: 90 °C
Reaction time: 1.25 h

Procedure:
2-Methoxyethyl ether (diglyme) (50 ml) and sodium hydride (60% in oil) (5.77 g) were combined. Under a nitrogen atmosphere, a solution of phenol (13.58 g) and diglyme (250 ml) was added slowly over 10 minutes to allow for controlled gas evolution. 2-chloro-5,6-dimethyl-3-nitro-N-[2-(3-pyridin-3-ylpropoxy)ethyl]pyridin-4-amine (35.1 g) from Part A was then added and the reaction mixture was heated to 90° C. After 1.25 hours, the reaction mixture clouded and the temperature was increased to 110° C. After an additional 3.75 hours, HPLC and TLC analysis indicated the reaction was complete. The reaction mixture was cooled and the solvent was removed under reduced pressure. The resulting oil was dissolved in ethyl acetate and washed once with 20% potassium hydroxide, once with 1N potassium hydroxide, 3 times with water, and 3 times with brine. The combined organic layers were dried with magnesium sulfate and concentrated under reduced pressure. The residue was purified by flash chromatography over silica, eluting with 90/10 ethyl acetate/hexane. The fractions containing purified product were concentrated under reduced pressure and dried under vacuum at 70° C. overnight. NMR analysis of the resulting yellow oil indicated sufficient purity for use of the product in the next step.
Reaction SMILES: Br[C:2]1[C:10]2[C:9]([NH:11][C@H:12]([C:14]3[N:19]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)[C:18](=[O:26])[C:17]4=[C:27]([CH3:30])[CH:28]=[CH:29][N:16]4[N:15]=3)[CH3:13])=[N:8][CH:7]=[N:6][C:5]=2[N:4]([CH2:31][O:32][CH2:33][CH2:34][Si:35]([CH3:38])([CH3:37])[CH3:36])[CH:3]=1.[F:39][C:40]1[CH:41]=[C:42]([CH:53]=[C:54]([O:56][CH3:57])[CH:55]=1)[CH2:43]B1OC(C)(C)C(C)(C)O1.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.O>[F:39][C:40]1[CH:41]=[C:42]([CH:53]=[C:54]([O:56][CH3:57])[CH:55]=1)[CH2:43][C:2]1[C:10]2[C:9]([NH:11][C@H:12]([C:14]3[N:19]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)[C:18](=[O:26])[C:17]4=[C:27]([CH3:30])[CH:28]=[CH:29][N:16]4[N:15]=3)[CH3:13])=[N:8][CH:7]=[N:6][C:5]=2[N:4]([CH2:31][O:32][CH2:33][CH2:34][Si:35]([CH3:38])([CH3:37])[CH3:36])[CH:3]=1
Reactant: Cc1ccn2nc([C@H](C)Nc3ncnc4c3c(Br)cn4COCC[Si](C)(C)C)n(-c3ccccc3)c(=O)c12
Reactant: COc1cc(F)cc(CB2OC(C)(C)C(C)(C)O2)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: COc1cc(F)cc(Cc2cn(COCC[Si](C)(C)C)c3ncnc(N[C@@H](C)c4nn5ccc(C)c5c(=O)n4-c4ccccc4)c23)c1
Yield: 9 %

Procedure:
(S)-2-(1-((5-Bromo-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)ethyl)-5-methyl-3-phenylpyrrolo[2,1-f][1,2,4]triazin-4(3H)-one (93 mg, 0.16 mmol) was treated with 2-(3-fluoro-5-methoxybenzyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (130 mg, 0.38 mmol), sodium carbonate (40 mg, 0.38 mmols) and 1,1′-bis(diphenylphosphino)ferrocene-palladium(II)dichloride dichloromethane complex (11 mg, 0.02 mmol) in a mixture of 1,2-dimethoxyethane (1.1 ml) and water (0.3 ml) according to the method described in Preparation 62. The residue was purified using SP1® Purification System (0% to 40%, hexane-ethyl acetate) to give 14 mg (9% yield, 68% purity) of the title compound.
Reaction SMILES: [C:1]12([C:11]3[CH:16]=[CH:15][C:14]([SH:17])=[CH:13][CH:12]=3)[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.O1CCCC1.[Na].[CH2:24]([O:26][C:27](=[O:32])[CH2:28][CH2:29][CH2:30]Br)[CH3:25]>C(O)C>[CH2:24]([O:26][C:27](=[O:32])[CH2:28][CH2:29][CH2:30][S:17][C:14]1[CH:13]=[CH:12][C:11]([C:1]23[CH2:8][CH:7]4[CH2:9][CH:3]([CH2:4][CH:5]([CH2:6]4)[CH2:10]2)[CH2:2]3)=[CH:16][CH:15]=1)[CH3:25]
Reactant: Sc1ccc(C23CC4CC(CC(C4)C2)C3)cc1
Reactant: CCOC(=O)CCCBr
Agent: [Na]
Solvent: CCO
Solvent: C1CCOC1
Product: CCOC(=O)CCCSc1ccc(C23CC4CC(CC(C4)C2)C3)cc1
Temperature: 50 °C

Procedure:
A solution of 5 g of the crude 4-(1-adamantyl)-thiophenol obtained above, in 25 ml of absolute ethanol and 25 ml of absolute tetrahydrofurane is added dropwise to a solution of 500 mg of sodium in 20 ml of absolute ethanol whilst stirring in a dry nitrogen atmosphere, and 2.9 ml of 4-bromobutyric acid ethyl ester are then added under the same conditions. After completion of the addition, the mixture is heated to 50° C for 14 hours. It is then evaporated to dryness in vacuo and the evaporation residue is partitioned between 3 times 100 ml of methylene chloride and 100 ml of 2 N hydrochloric acid. The organic phases are washed until neutral, dried over sodium sulphate and evaporated in vacuo. Chromatography of the evaporation residue on 240 g of silica gel, with benzene as the eluant, yields chromatographically pure 4-[4-(1-adamantyl)-phenylthio]-butyric acid ethyl ester in the form of a yellow-brown oil (IR spectrum: C=O band at 1,740 cm-1 (in CH2Cl2)).
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:8]([NH:10][OH:11])=[O:9])=[N:4][CH:5]=[CH:6][CH:7]=1.[CH:12](O)=O.[K+].[Br-]>O>[OH:11][N:10]1[C:8](=[O:9])[C:3]2[N:4]=[CH:5][CH:6]=[CH:7][C:2]=2[N:1]=[CH:12]1
Reactant: O=CO
Reactant: Nc1cccnc1C(=O)NO
Agent: [Br-]
Agent: [K+]
Solvent: O
Product: O=c1c2ncccc2ncn1O
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
A mixture of 1.224 g (8 mmol) of the product produced in Step D of Example 3 and 3 ml of 98% formic acid were heated under reflux for 15 minutes after which 8 ml of water was added, and the whole was boiled for 15 minutes and cooled to room temperature. The precipitate that separated was collected by filtration and washed with water (2×5 ml). After being boiled with ethanol twice, there was obtained 0.71 g (55%) of HODhad, which was obtained in an analytically pure form as a yellow solid: mp 318.5-320° C. (dec.); 1H NMR (DMSO-d6): δ12.15 (br, 1H, OH), 8.85 (dd, 1H), 8.69 (s, 1H, CH), 8.17 (dd, 1H), 7.84 (dd, 1H); IR (KBr): 2625 (broad, OH), 1683 (sh, vs, CON), 1600 (w), 1446 (m), 1410 (s), 1359 (s), 1223 (s), 990 (s), 902 (m), 791 (s) cm−1.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=O)[CH2:10][C:11]2[NH:12][C:13](=[O:23])[CH:14]=[C:15]([N:17]3[CH2:22][CH2:21][O:20][CH2:19][CH2:18]3)[N:16]=2)=[C:4]([OH:25])[CH:3]=1.O.CC1C=CC(S(O)(=O)=O)=CC=1>C1(C)C(C)=CC=CC=1>[F:1][C:2]1[CH:7]=[CH:6][C:5]2[N:8]=[C:9]([CH2:10][C:11]3[NH:12][C:13](=[O:23])[CH:14]=[C:15]([N:17]4[CH2:18][CH2:19][O:20][CH2:21][CH2:22]4)[N:16]=3)[O:25][C:4]=2[CH:3]=1
Reactant: O=C(Cc1nc(N2CCOCC2)cc(=O)[nH]1)Nc1ccc(F)cc1O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1C
Product: O=c1cc(N2CCOCC2)nc(Cc2nc3ccc(F)cc3o2)[nH]1
Yield: 13.2 %

Procedure:
The product is prepared according to the procedure described in Stage 2 of Example 2, using 120 mg of N-(4-fluoro-2-hydroxyphenyl)-2-[4-(morpholin-4-yl)-6-oxo-1,6-dihydropyrimidin-2-yl]acetamide, and 11 mg of 4-methylbenzenesulphonic acid hydrate, and replacing the toluene with xylene. After purification by silica gel column chromatography, eluent: CH2Cl2/MeOH: 98/02, 15 mg of 2-[(6-fluoro-1,3-benzoxazol-2-yl)methyl]-6-(morpholin-4-yl)pyrimidin-4(3H)-one are obtained in the form of a white solid, the characteristics of which are the following:
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][C:3]=1[OH:12].Br[CH2:14][C:15](Cl)=[O:16]>>[NH:1]1[C:15](=[O:16])[CH2:14][O:12][C:3]2[CH:4]=[CH:5][C:6]3[C:11]([C:2]1=2)=[CH:10][CH:9]=[CH:8][CH:7]=3
Reactant: O=C(Cl)CBr
Reactant: Nc1c(O)ccc2ccccc12
Product: O=C1COc2ccc3ccccc3c2N1

Procedure:
1-Amino-2-naphthol and bromoacetyl chloride are reacted in the same manner as described in Example 32 to give 1H-naphtho[2,1-b][1,4]oxazin-2(3H)-one.
Reaction SMILES: [Cl:1][C:2]1[C:3]2[N:4]([C:8]([CH:13]([OH:17])[CH2:14][CH2:15][CH3:16])=[C:9]([CH2:11][CH3:12])[N:10]=2)[CH:5]=[CH:6][N:7]=1.I[CH2:19][CH3:20].[H-].[Na+].O>CN(C)C=O>[CH2:19]([O:17][CH:13]([C:8]1[N:4]2[CH:5]=[CH:6][N:7]=[C:2]([Cl:1])[C:3]2=[N:10][C:9]=1[CH2:11][CH3:12])[CH2:14][CH2:15][CH3:16])[CH3:20]
Reactant: CCI
Reactant: CCCC(O)c1c(CC)nc2c(Cl)nccn12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCC(OCC)c1c(CC)nc2c(Cl)nccn12
Reaction time: 3 h

Procedure:
The resulting 1-(8-chloro-2-ethylimidazo[1,2-a]pyrazin-3-yl)-1-butanol was dissolved in N,N-dimethylformamide (2.2 mL), then iodoethane (0.079 mL, 0.99 mmol) and sodium hydride (65% in oil; 49 mg, 1.32 mmol) were added thereto under ice-cooling, and the mixture was stirred for 3 hours. Water was added to the reaction mixture, which was extracted with ethyl acetate and evaporated. The resulting residue was purified by silica gel column chromatography (ethyl acetate:n-hexane=1:3) to give the title compound (55 mg) as a colorless oil.
Reaction SMILES: [C:1]1([C:7]2[CH:8]=[C:9]([NH2:12])[NH:10][N:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C[O:14][C:15](=O)[CH2:16][C:17](=O)[CH3:18]>C(O)(=O)C>[CH3:18][C:17]1[CH:16]=[C:15]([OH:14])[N:10]2[N:11]=[C:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[CH:8]=[C:9]2[N:12]=1
Reactant: COC(=O)CC(C)=O
Reactant: Nc1cc(-c2ccccc2)n[nH]1
Solvent: CC(=O)O
Product: Cc1cc(O)n2nc(-c3ccccc3)cc2n1

Procedure:
To a solution of 5-phenyl-2H-pyrazol-3-ylamine (9.18 g, 57.6 mmol) and 3-oxo-butyric acid methyl ester (9.33 mL, 86.5 mmol) in acetic acid (70 ml) was refluxed for 28 hrs. The reaction mixture was then allowed to cool, filtered, and the precipitated solid washed with acetic acid and dried in vacuo to afford 5-methyl-2-phenyl-pyrazolo[1,5-a]pyrimidin-7-ol as a white solid (11.86 g; 85%) MS m/z @ 242 (m+1).
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[CH:17][C:5]([O:6][C:7]2[CH:12]=[CH:11][C:10]([CH2:13][CH2:14][OH:15])=[CH:9][C:8]=2[F:16])=[CH:4][C:3]=1[F:19].Cl[C:21]1[CH:31]=[C:25]2[N:26]([CH3:30])[CH2:27][CH2:28][CH2:29][N:24]2[C:23](=[O:32])[N:22]=1>>[Cl:1][C:2]1[CH:18]=[CH:17][C:5]([O:6][C:7]2[CH:12]=[CH:11][C:10]([CH2:13][CH2:14][O:15][C:21]3[CH:31]=[C:25]4[N:26]([CH3:30])[CH2:27][CH2:28][CH2:29][N:24]4[C:23](=[O:32])[N:22]=3)=[CH:9][C:8]=2[F:16])=[CH:4][C:3]=1[F:19]
Reactant: CN1CCCn2c1cc(Cl)nc2=O
Reactant: OCCc1ccc(Oc2ccc(Cl)c(F)c2)c(F)c1
Product: CN1CCCn2c1cc(OCCc1ccc(Oc3ccc(Cl)c(F)c3)c(F)c1)nc2=O

Procedure:
The title compound or its salt was prepared by a procedure similar to that described for E2 starting from 2-(4-(4-chloro-3-fluorophenoxy)-3-fluorophenyl)ethanol and 8-chloro-1-methyl-3,4-dihydro-1H-pyrimido[1,6-a]pyrimidin-6(2H)-one.
Reaction SMILES: [CH3:1][O:2][C:3]([O:19][CH3:20])([C:13]1[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=1)[CH:4]([C:6]1[CH:11]=[CH:10][C:9]([F:12])=[CH:8][CH:7]=1)[NH2:5].[N:21]([CH2:24][CH2:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)=[C:22]=[O:23]>C1COCC1>[C:27]1([CH2:26][CH2:25][CH2:24][NH:21][C:22]([NH:5][CH:4]([C:6]2[CH:7]=[CH:8][C:9]([F:12])=[CH:10][CH:11]=2)[C:3]([O:2][CH3:1])([O:19][CH3:20])[C:13]2[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=2)=[O:23])[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: O=C=NCCCc1ccccc1
Reactant: COC(OC)(c1ccncc1)C(N)c1ccc(F)cc1
Solvent: C1CCOC1
Product: COC(OC)(c1ccncc1)C(NC(=O)NCCCc1ccccc1)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 2,2-dimethoxy-2-(4-pyridyl)-1-(4-fluorophenyl)ethanamine (1.22 g, 4.4 mmol) in THF (10 mL) was added a solution of (3-isocyanatopropyl)-benzene (1.61 g, 10 mmol) in THF (10 mL). The resulting mixture was stirred at room temperature for 30 minutes. The reaction was quenched by addition of water (50 mL) and extracted with ethyl acetate (2×50 mL). The combined ethyl acetate extract was washed with water (50 mL), brine (50 mL) and dried with Na2SO4. After removal of solvent, the crude product was purified by column chromatography to yield the product as a light brown solid.
Reaction SMILES: C(OC([N:8]1[CH2:12][CH2:11][C@H:10]([C@@H:13]([OH:17])[CH2:14][O:15][CH3:16])[CH2:9]1)=O)(C)(C)C.[H-].[Na+].[Cl:20][C:21]1[CH:26]=[C:25]([Cl:27])[CH:24]=[CH:23][C:22]=1F.CCO>CN(C=O)C.Cl>[Cl:20][C:21]1[CH:26]=[C:25]([Cl:27])[CH:24]=[CH:23][C:22]=1[O:17][C@H:13]([C@H:10]1[CH2:11][CH2:12][NH:8][CH2:9]1)[CH2:14][O:15][CH3:16]
Reactant: COC[C@H](O)[C@H]1CCN(C(=O)OC(C)(C)C)C1
Reactant: Fc1ccc(Cl)cc1Cl
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCO
Product: COC[C@H](Oc1ccc(Cl)cc1Cl)[C@H]1CCNC1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
(S)-3-((R)-1-Hydroxy-2-methoxyethyl)pyrrolidine-1-carboxylic acid t-butyl ester (10.0 mg, 40.8 μmol) was dissolved in DMF (0.1 mL). NaH (1.5 mg, 61.1 μmol) was slowly added and the mixture was stirred at room temperature for 15 minutes. Then, 2,4-dichloro-1-fluorobenzene (20.2 mg, 122 μmol) was added. The mixture was stirred at 100° C. for 1 hour, then cooled to room temperature. The mixture was concentrated then dissolved in 1.2M HCl in EtOH (1.0 mL, 1.2 mmol) and stirred overnight at room temperature. The product was concentrated and purified by preparative HPLC to yield the title compound as a mono-TFA salt (12.8 mg, 99% purity). MS m/z: [M+H] calcd for C13H17Cl2NO2, 290.06. found 290.0.
Reaction SMILES: [F:1][C:2]([F:33])([F:32])[C:3]1[CH:27]=[C:26]([C:28]([F:31])([F:30])[F:29])[CH:25]=[CH:24][C:4]=1[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][C:11]([CH:15]=[C:16]3[S:20][C:19](SC)=[N:18][C:17]3=[O:23])=[CH:12][CH:13]=2)[CH:8]=[N:7]1.[NH:34]1[CH2:39][CH2:38][CH2:37][C@@H:36]([C:40]([OH:42])=[O:41])[CH2:35]1>>[F:33][C:2]([F:1])([F:32])[C:3]1[CH:27]=[C:26]([C:28]([F:29])([F:31])[F:30])[CH:25]=[CH:24][C:4]=1[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][C:11]([CH:15]=[C:16]3[S:20][C:19]([N:34]4[CH2:39][CH2:38][CH2:37][C@@H:36]([C:40]([OH:42])=[O:41])[CH2:35]4)=[N:18][C:17]3=[O:23])=[CH:12][CH:13]=2)[CH:8]=[N:7]1
Reactant: O=C(O)[C@@H]1CCCNC1
Reactant: CSC1=NC(=O)C(=Cc2ccc3c(cnn3Cc3ccc(C(F)(F)F)cc3C(F)(F)F)c2)S1
Product: O=C1N=C(N2CCC[C@@H](C(=O)O)C2)SC1=Cc1ccc2c(cnn2Cc2ccc(C(F)(F)F)cc2C(F)(F)F)c1

Procedure:
1-{5-[1-(2,4-Bis-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-4-oxo-4,5-dihydro-thiazol-2-yl}-piperidine-3-(R)-carboxylic acid was prepared from 5-[1-(2,4-bis-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-methylsulfanyl-thiazol-4-one and piperidine-3-(R)-carboxylic acid following General Procedure C.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[Cl:6][C:7]1[CH:8]=[C:9]([C:13]2[O:17][N:16]=[C:15]([CH:18]([OH:20])[CH3:19])[N:14]=2)[CH:10]=[CH:11][CH:12]=1>C(Cl)Cl>[CH3:1][S:2]([O:20][CH:18]([C:15]1[N:14]=[C:13]([C:9]2[CH:10]=[CH:11][CH:12]=[C:7]([Cl:6])[CH:8]=2)[O:17][N:16]=1)[CH3:19])(=[O:4])=[O:3]
Reactant: CC(O)c1noc(-c2cccc(Cl)c2)n1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Product: CC(OS(C)(=O)=O)c1noc(-c2cccc(Cl)c2)n1
Reaction time: 0.25 h

Procedure:
Methane sulfonyl chloride (40 μl, 0.49 mmol) was added to a mixture of TEA (95 μl, 0.67 mmol) and 1-[5-(3-chlorophenyl)-1,2,4-oxadiazol-3-yl]ethanol (100 mg, 0.45 mmol) in DCM (5 ml). After stirring for 15 min the mixture was washed with water and brine, dried and concentrated and the title compound was obtained in 135 mg yield. 1H NMR: 1.9 (d, 3H), 3.1 (s, 3H), 5.9 (q, 1H), 7.5 (t, 1H), 7.6 (m, 1H), 8.0 (m, 1H), 8.1 (t, 1H)
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][CH:7]([CH:10]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[NH:12][CH2:11]2)[CH2:6][CH2:5]1)(=[O:3])[CH3:2].[C:19](OC(=O)C)(=[O:21])[CH3:20]>>[C:1]([N:4]1[CH2:9][CH2:8][CH:7]([CH:10]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[N:12]([C:19](=[O:21])[CH3:20])[CH2:11]2)[CH2:6][CH2:5]1)(=[O:3])[CH3:2]
Reactant: CC(=O)N1CCC(C2CNc3ccccc32)CC1
Reactant: CC(=O)OC(C)=O
Product: CC(=O)N1CCC(C2CN(C(C)=O)c3ccccc32)CC1

Procedure:
A mixture of 3-(1-acetyl-4-piperidyl)indoline (41.1 g) and acetic anhydride (300 ml) was refluxed for 3 hours. The excess acetic anhydride was distilled off under reduced pressure and the residue was dissolved in ethyl acetate (500 ml). The solution was washed with a saturated aqueous solution of sodium hydrogen carbonate (100 ml), water (100 ml) and a saturated aqueous solution of sodium chloride successively and dried over magnesium sulfate. The solvent was distilled off and the residue was subjected to column chromatography on silica gel, elution being carried out with a mixture of chloroform and methanol (40:1 V/V) to give 3-(1-acetyl-4-piperidyl)-1-acetylindoline (32 g).
Reaction SMILES: [CH:1]1([C:4]2[CH:12]=[CH:11][C:7]([C:8]([OH:10])=[O:9])=[CH:6][C:5]=2[CH:13]([OH:16])[CH2:14][CH3:15])[CH2:3][CH2:2]1.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>ClCCCl>[CH:1]1([C:4]2[CH:12]=[CH:11][C:7]([C:8]([OH:10])=[O:9])=[CH:6][C:5]=2[C:13](=[O:16])[CH2:14][CH3:15])[CH2:2][CH2:3]1
Reactant: CCC(O)c1cc(C(=O)O)ccc1C1CC1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: ClCCCl
Product: CCC(=O)c1cc(C(=O)O)ccc1C1CC1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 68.3 %

Procedure:
Into a 500-mL round-bottom flask, was placed a mixture of 4-cyclopropyl-3-(1-hydroxypropyl)benzoic acid (compound 10.5, 3.4 g, 15.44 mmol) in 1,2-dichloroethane (300 mL) and Dess-Martin periodinane (7.2 g, 16.9 mmol). The mixture was stirred for 1.5 h at room temperature and then the solids were removed with filtration. The filtrate was concentrated under reduced pressure and the residue was purified by silica gel column chromatography with ethyl acetate:PE (1:9) to methanol/ethyl acetate (20:1) as the eluent to yield 2.3 g (68%) of the title compound as a light yellow solid.
Reaction SMILES: [C:1]([Si:5]([CH3:23])([CH3:22])[O:6][C@H:7]1[C@H:12]([O:13]C(=O)C)[C@@H:11]([CH2:17][O:18]C(=O)C)[O:10][CH:9]=[CH:8]1)([CH3:4])([CH3:3])[CH3:2].C[O-].[Na+].O.Cl>CO>[C:1]([Si:5]([CH3:23])([CH3:22])[O:6][C@H:7]1[C@H:12]([OH:13])[C@@H:11]([CH2:17][OH:18])[O:10][CH:9]=[CH:8]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(=O)OC[C@H]1OC=C[C@@H](O[Si](C)(C)C(C)(C)C)[C@@H]1OC(C)=O
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CC(C)(C)[Si](C)(C)O[C@@H]1C=CO[C@H](CO)[C@H]1O
Temperature: 25 °C
Reaction time: 6 h
Yield: 85.7 %

Procedure:
3-O-(tert-butyldimethyl-silyl)-4,6-di-O-acetyl-D-glucal (11.9 g, 34.5 mmol) was dissolved in methanol (120 mL), then 1M solution of sodium methanolate in methanol (1 mL) was added. The reaction mixture was stirred in room temperature for 6 hours and 1M water solution of hydrochloric acid (1 mL) was added. Reaction mixture was evaporated to dryness and crude product was purified by column chromatography (SilicaGel 60 Merck), using hexanes:ethyl acetate as eluents to give 7.7 g of 3-O-(tert-butyldimethyl-silyl)-D-glucal, yield (85%), mp. 55.0-56.0° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][C:5]2[NH:6][C:7]3[CH:8]=[CH:9][CH:10]=[C:11]([CH:23]=3)[CH2:12][NH:13][C:14]3[CH:22]=[C:18]([NH:19][C:20]=1[N:21]=2)[CH:17]=[CH:16][CH:15]=3.C(N(CC)CC)C.[C:31](Cl)(=[O:38])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>CN(C)C=O>[C:31]([N:13]1[CH2:12][C:11]2[CH:23]=[C:7]([CH:8]=[CH:9][CH:10]=2)[NH:6][C:5]2=[N:21][C:20](=[C:2]([Cl:1])[CH:3]=[N:4]2)[NH:19][C:18]2=[CH:22][C:14]1=[CH:15][CH:16]=[CH:17]2)(=[O:38])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1
Reactant: Clc1cnc2nc1Nc1cccc(c1)NCc1cccc(c1)N2
Reactant: O=C(Cl)c1ccccc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=C(c1ccccc1)N1Cc2cccc(c2)Nc2ncc(Cl)c(n2)Nc2cccc1c2
Yield: 41.6 %

Procedure:
To a stirring solution of 6-chloro-2,4,8,14,22-pentaazatetracyclo[14.3.1.1(3,7).1(9,13)]docosa-1(20),3(22),4,6,9(21),10,12,16,18-nonaene (20.0 mg, 0.0618 mmol) in N,N-dimethylformamide (0.24 mL) was added triethylamine (17.2 μL), followed by the addition of benzoyl chloride (17.4 mg, 0.12 mmol). The resultant solution was stirred at rt for 30 min. The mixture was quenched with H2O and concentrated. The residue was purified by silica gel column chromatography to give the desired product as an off-white powder (11 mg, 42%). LCMS for C24H19ClN5O (M+H)+: m/z=428.1. 1H NMR (300 MHz, DMSO-d6): δ 9.42 (s, 1H), 9.11 (s, 1H), 8.12 (s, 2H), 7.82 (s, 1H), 7.25 (m, 4H), 7.15 (m, 4H), 7.03 (m, 3H), 4.86 (m, 2H).
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][CH:14]([NH:17][C:18]2[C:27]3[C:22](=[CH:23][CH:24]=[C:25]([C:28]4[CH:29]=[N:30][C:31]5[C:36]([CH:37]=4)=[CH:35][CH:34]=[CH:33][CH:32]=5)[N:26]=3)[N:21]=[CH:20][C:19]=2[C:38]([O:40]C)=[O:39])[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Li+].C(O)C>O>[CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][CH:14]([NH:17][C:18]2[C:27]3[C:22](=[CH:23][CH:24]=[C:25]([C:28]4[CH:29]=[N:30][C:31]5[C:36]([CH:37]=4)=[CH:35][CH:34]=[CH:33][CH:32]=5)[N:26]=3)[N:21]=[CH:20][C:19]=2[C:38]([OH:40])=[O:39])[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)c1cnc2ccc(-c3cnc4ccccc4c3)nc2c1NC1CCN(C(=O)OCc2ccccc2)CC1
Agent: [Li+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: O=C(O)c1cnc2ccc(-c3cnc4ccccc4c3)nc2c1NC1CCN(C(=O)OCc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 97.5 %

Procedure:
A mixture of compound 46 (8.2 g, 15 mmol) and lithium hydroxide (480 mg, 20 mmol) in 2:1 ethanol:water (150 mL) was heated to 75° C. resulting in a solution. After 2 hours, the solution was cooled to room temperature and concentrated. The residue was taken up in water (200 mL) and the solution was acidified with 1 N HCl (20 mL). The precipitate was collected by filtration and dried at 60° C. under vacuum to afford 4-({1-[(benzyloxy)carbonyl]piperidin-4-yl}amino)-6-quinolin-3-yl-1,5-naphthyridine-3-carboxylic acid (compound 47) (7.8 g, 98%).
Reaction SMILES: Cl.[NH2:2][N:3]1[CH2:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[F:12])[CH2:4]1.C([N:16]1[CH2:20][CH2:19][NH:18][C:17]1=O)(=O)C>O=P(Cl)(Cl)Cl>[F:12][C:9]1[CH:8]=[CH:7][CH:6]=[C:5]2[C:10]=1[CH2:11][N:3]([NH:2][C:17]1[NH:18][CH2:19][CH2:20][N:16]=1)[CH2:4]2
Reactant: CC(=O)N1CCNC1=O
Reactant: NN1Cc2cccc(F)c2C1
Agent: Cl
Solvent: O=P(Cl)(Cl)Cl
Product: Fc1cccc2c1CN(NC1=NCCN1)C2
Yield: 89.3 %

Procedure:
6.0 g (0.03 mol) of 2-amino-4-fluoro-isoindoline hydrochloride and 4.5 g (0.035 mol) of 1-acetyl-imidazolin-2-one are heated at 100° C. in 70 ml of phosphorus oxytrichloride for 4 hours. After removal of the POCl3 in vacuo, the residue is dissolved in 100 ml of ethanol and the solution is heated at the boiling point for 3 hours. The solvent is distilled off, 5N NaOH is added to the residue and the crude base is extracted with methylene chloride. Recrystallization from toluene gives 5.9 g of 4-fluoro-2-(2-imidazolin-2-ylamino)-isoindoline.