Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: BrC1C2[C:10](=CC=CC=2)[C:9]([C:16]2[CH:17]=[C:18]([C:22]3[N:26]([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)[C:25]4[CH:33]=[CH:34][CH:35]=[CH:36][C:24]=4N=3)C=CC=2)=C2C=1C=CC=C2.[Br:37][C:38]1[C:39]2[C:44]([C:45](Br)=[C:46]3[C:51]=1[CH:50]=[CH:49][CH:48]=[CH:47]3)=[CH:43][CH:42]=[CH:41][CH:40]=2.C([O-])([O-])=O.[Na+].[Na+].O>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.C1COCC1>[Br:37][C:38]1[C:39]2[C:44](=[CH:43][CH:42]=[CH:41][CH:40]=2)[C:45]([C:29]2[CH:28]=[C:27]([N:26]3[C:25]4[CH:24]=[CH:36][CH:35]=[CH:34][C:33]=4[C:10]4[C:22]3=[CH:18][CH:17]=[CH:16][CH:9]=4)[CH:32]=[CH:31][CH:30]=2)=[C:46]2[C:51]=1[CH:50]=[CH:49][CH:48]=[CH:47]2
Reactant: Brc1c2ccccc2c(Br)c2ccccc12
Reactant: Brc1c2ccccc2c(-c2cccc(-c3nc4ccccc4n3-c3ccccc3)c2)c2ccccc12
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+]
Solvent: C1CCOC1
Solvent: O
Product: Brc1c2ccccc2c(-c2cccc(-n3c4ccccc4c4ccccc43)c2)c2ccccc12
Yield: 68 %

Procedure:
Following the procedure as outlined above for synthesizing Compound 5, Compound (2.686 g, 7.274 mmol), 9,10-dibromoanthracene (7.333 g, 21.82 mmol), tetrakis(triphenylphosphine)palladium(0) (0.420 g, 0.364 mmol), Na2CO3 (9.539 g, 90.00 mmol), H2O (90 mL) and THF (150 mL) yielded Compound 8 (2.45 g, 68%) as a light yellow solid after flash chromatography (SiO2, 19:1 to 9:1 hexanes-dichloromethane).
Reaction SMILES: [Br-].[CH3:2]C(C)([O-])C.[K+].[O:8]([C:15]1[CH:22]=[CH:21][C:18]([CH:19]=O)=[CH:17][CH:16]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>C1COCC1.CCCCCC>[O:8]([C:15]1[CH:22]=[CH:21][C:18]([CH:19]=[CH2:2])=[CH:17][CH:16]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: O=Cc1ccc(Oc2ccccc2)cc1
Reactant: CC(C)(C)[O-]
Agent: [Br-]
Agent: [K+]
Solvent: CCCCCC
Solvent: C1CCOC1
Product: C=Cc1ccc(Oc2ccccc2)cc1
Reaction time: 0.5 h

Procedure:
To a suspension of methyltriphenylphosphium bromide (7.85 g, 22 mmol) in THF (10 mL) was added potassium tert-butoxide (1.0M solution in THF, 22 mL). After 30 minutes, 4-phenoxybenzaldehyde (3.96 g, 20 mmol) was added to the above mixture. The reaction was diluted with equal volume of hexane after 20 minutes and filtered through silica gel. The residue was rinsed and washed with 20% ether in hexane. Concentration of the filtrate gave the crude product as an off white solid which was used without further purification.
Reaction SMILES: C[O:2][C:3](=[O:25])[CH2:4][C:5]1[CH:9]=[C:8]([C:10](=[O:18])[C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=2)[S:7][C:6]=1[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.[OH-].[Na+]>C1COCC1.O>[Cl:17][C:14]1[CH:15]=[CH:16][C:11]([C:10]([C:8]2[S:7][C:6]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[C:5]([CH2:4][C:3]([OH:25])=[O:2])[CH:9]=2)=[O:18])=[CH:12][CH:13]=1
Reactant: COC(=O)Cc1cc(C(=O)c2ccc(Cl)cc2)sc1-c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)Cc1cc(C(=O)c2ccc(Cl)cc2)sc1-c1ccccc1
Yield: 98.1 %

Procedure:
To a stirred solution of 0.15 g (0.40 mmol) of the above ester in a mixture of 2 mL of THF and 1 mL of H2O was added 0.60 mL (0.60 mmol) of 1 N NaOH at room temperature. The resulting mixture was refluxed for 3 h. The solvent was evaporated in vacuo. The residue was dissolved in 5 mL of H2O and acidified with 0.11 mL of 1N HCl to give 0.14 g (100%) of 1 as a pale yellow solid: mp 142-143° C.; 1H NMR (400 MHz, CDCl3) δ 9.75 (brs, 1H), 7.84 (d, J=8.6 Hz, 2H), 7.62 (s, 1H), 7.462 (d, J=8.6 Hz, 2H), 7.46 (m, 5H), 3.71 (s, 2H); 13C NMR (100 MHz, CDCl3) δ 186.6, 176.5, 150.6, 140.9, 138.8, 137.2, 136.1, 132.4, 130.6, 129.7, 129.3, 129.2, 129.1, 128.9, 34.0; IR (KBr) cm−1 3058, 2921, 1715, 1628; LREIMS C19H13ClO3S requires 356.03. Found: 355 ([M+], 100%), 310 (25%), 244 (25%), 139 (42%).
Reaction SMILES: [CH2:1]([NH:3][CH2:4][CH3:5])[CH3:2].Cl[CH2:7][C:8]([OH:10])=[O:9]>CC(OC)(C)C>[CH2:1]([N:3]([CH2:7][C:8]([OH:10])=[O:9])[CH2:4][CH3:5])[CH3:2]
Reactant: CCNCC
Reactant: O=C(O)CCl
Solvent: COC(C)(C)C
Product: CCN(CC)CC(=O)O
Temperature: 3 °C

Procedure:
Diethylamine (9.5 L) was charged into a 20 L glass-lined reactor and cooled to 3° C. Chloroacetic acid (1.21 kg) in MTBE (1.8 L) was added over 1 hour with cooling—the temperature rose to 16° C. during the addition. The mixture was warmed to 20° C., stirred over night and concentrated on rotary evaporator giving yellow oil. This oil was re-concentrated with iPrOAc, mixed with iPrOAc (4.5 L) and stirred over night. The off-white hygroscopic precipitate was filtered, washed with iPrOAc (1.5 L) and immediately placed into a drying cabinet to avoid deliquescence. After drying, titled product was obtained (820 g, Y=49%).
Reaction SMILES: [CH3:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([O:12][CH2:13][CH2:14][CH2:15][CH2:16][S:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=3)[CH:10]=2)[NH:5][C:4](=[O:24])[CH:3]=1.[OH:25]O>>[CH3:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([O:12][CH2:13][CH2:14][CH2:15][CH2:16][S:17]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=3)=[O:25])[CH:10]=2)[NH:5][C:4](=[O:24])[CH:3]=1
Reactant: Cc1cc(=O)[nH]c2ccc(OCCCCSc3ccccn3)cc12
Reactant: OO
Product: Cc1cc(=O)[nH]c2ccc(OCCCCS(=O)c3ccccn3)cc12

Procedure:
Prepared analogous to Example 123 from 4-methyl-6-[4-(2-pyridyl-mercapto)-butoxy]-carbostyril and hydrogen peroxide.
Reaction SMILES: C(OC([NH:8][C:9]1[C:10]([Cl:30])=[C:11]([N:17]2[CH2:22][CH2:21][N:20](C(OC(C)(C)C)=O)[CH2:19][CH2:18]2)[CH:12]=[C:13]([C:15]#[N:16])[CH:14]=1)=O)(C)(C)C.FC(F)(F)C(O)=O.N>ClCCl>[NH2:8][C:9]1[CH:14]=[C:13]([CH:12]=[C:11]([N:17]2[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]2)[C:10]=1[Cl:30])[C:15]#[N:16]
Reactant: CC(C)(C)OC(=O)Nc1cc(C#N)cc(N2CCN(C(=O)OC(C)(C)C)CC2)c1Cl
Agent: N
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: N#Cc1cc(N)c(Cl)c(N2CCNCC2)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 92.2 %

Procedure:
(I11B): To the stirred solution of tert-butyl 4-(3-((tert-butoxycarbonyl)amino)-2-chloro-5-cyanophenyl)piperazine-1-carboxylate (2.0 g, 4.58 mmol) in dichloromethane (40 mL) was added trifluoroacetic acid (8.89 mL, 115 mmol) slowly drop wise at room temperature, stirred it for 3 hours at room temperature. On completion of the reaction, the reaction mixture was diluted with methylene chloride (300 mL), cooled it to 0° C., basified with ammonia solution and extracted twice, the organic layer was washed with brine, dried over anhydrous sodium sulfate and concentrated. The crude material was washed with diethyl ether several times and dried under vacuum to get 3-amino-4-chloro-5-(piperazin-1-yl)benzonitrile (1.0 g) as a brown color solid. MS (ESI) m/z 237.5
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[CH2:9][CH2:10][OH:11].C(N(CC)CC)C.[CH3:19][S:20](Cl)(=[O:22])=[O:21]>C(Cl)Cl>[CH3:19][S:20]([O:11][CH2:10][CH2:9][C:3]1[CH:4]=[C:5]([Cl:8])[CH:6]=[CH:7][C:2]=1[Br:1])(=[O:22])=[O:21]
Reactant: OCCc1cc(Cl)ccc1Br
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)OCCc1cc(Cl)ccc1Br
Reaction time: 2 h
Yield: 96.1 %

Procedure:
A solution of 2-(2-bromo-5-chloro-phenyl)ethanol (1.65 g, 7.00 mmol) [as prepared in preparation 6] and triethylamine (922 mg, 1.27 mL, 9.11 mmol) in DCM (20 mL) was cooled to 0° C. and methanesulfonyl chloride (883 mg, 597 μL, 7.71 mmol) was added. The mixture was stirred for 2 h and then diluted with DCM and washed sequentially with water and brine, the organic layer dried (MgSO4) and concentrated to afford 2-bromo-5-chlorophenethyl methanesulfonate as a yellow solid (2.11 g, 96%). 1H NMR (500 MHz, d6-DMSO) δ 7.67 (1H, d), 7.55 (1H, s), 7.32 (1H, d), 4.44 (2H, t), 3.13-3.36 (5H, m).
Reaction SMILES: [N:1]1[C:11]2[S:10][C:9]3[CH:12]=[CH:13][C:14]([CH2:16][C:17]([OH:19])=[O:18])=[CH:15][C:8]=3[CH2:7][CH2:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.S(=O)(=O)(O)O.C(=O)([O-])O.[Na+].[CH2:30](O)[CH3:31]>>[N:1]1[C:11]2[S:10][C:9]3[CH:12]=[CH:13][C:14]([CH2:16][C:17]([O:19][CH2:30][CH3:31])=[O:18])=[CH:15][C:8]=3[CH2:7][CH2:6][C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: CCO
Reactant: O=C(O)Cc1ccc2c(c1)CCc1cccnc1S2
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Product: CCOC(=O)Cc1ccc2c(c1)CCc1cccnc1S2
Temperature: 0 °C
Yield: 85 %

Procedure:
A mixture of 30 mg of (5,6-dihydro benzo[b]pyrido[3,2-f]-thiepin-8-yl)-acetic acid, 3 ml of ethanol and 100 mg of sulfuric acid was refluxed for 1 hour. After the completion of the reaction, the solvent was distilled off to obtain a residue, to which was added ice water, and the mixture was basified with a 5% sodium hydrogen carbonate solution and extracted with ethyl acetate. The extract was washed with water and dried over anhydrous sodium sulfate. The solvent was removed by distillation to obtain an oil, which was chromatographed over silica gel and eluted with benzene/chloroform (2/1), thereby yielding 28 mg (yield: 85%) of ethyl (5,6-dihydro benzo[b]pyrido[3,2-f]thiepin-8-yl)-acetate as an oil.
Reaction SMILES: [I:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([CH3:11])[C:3]=1[C:4]([OH:6])=[O:5].[CH3:12][Si](C=[N+]=[N-])(C)C>C(Cl)Cl.CO>[I:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([CH3:11])[C:3]=1[C:4]([O:6][CH3:12])=[O:5]
Reactant: Cc1cccc(I)c1C(=O)O
Reactant: C[Si](C)(C)C=[N+]=[N-]
Solvent: CO
Solvent: ClCCl
Product: COC(=O)c1c(C)cccc1I
Temperature: 0 °C
Reaction time: 0.75 h
Yield: 76 %

Procedure:
A solution of 2-iodo-6-methylbenzoic acid (I57) (2.50 g, 9.54 mmol) in DCM (30 mL) and methanol (8 mL) under an atmosphere of nitrogen was cooled to 0° C. and trimethylsilyldiazomethane (2.0 M in diethyl ether, 9.54 mL, 19.1 mmol) was added dropwise. The reaction was stirred at 0° C. for 45 minutes and then quenched with 2 M aq. HCl (50 mL). DCM (150 mL) was added to the quenched reaction and the layers were separated. The aqueous layer was extracted with DCM (100 mL), the organics were combined and washed with sat. aq. NaHCO3 (100 mL), water (100 mL), brine (100 mL), dried (MgSO4), filtered and concentrated in vacuo to give a yellow oil. The crude product was purified by silica gel chromatography (Biotage Isolera, 40 g Si Cartridge, 0-20% EtOAc in petroleum benzine 40-60° C.) to give the title compound (I58) (2.00 g, 76% yield) as a colourless oil; 1H NMR (400 MHz, CDCl3) δ 7.65 (ddd, J=7.9, 1.0, 0.5 Hz, 1H), 7.19-7.15 (m, 1H), 6.99 (t, J=7.8 Hz, 1H), 3.95 (s, 3H), 2.33 (s, 3H). LCMS Method C: rt 6.08 min; m/z 277.0 [M+H]+.
Reaction SMILES: [CH2:1]([C:5]1([CH2:32][CH2:33][CH2:34][CH3:35])[C:17]2[CH:16]=[C:15]([N:18]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH:14]=[CH:13][C:12]=2[C:11]2[C:6]1=[CH:7][C:8](Br)=[CH:9][CH:10]=2)[CH2:2][CH2:3][CH3:4].C([Li])CCC.[B:41](OC)([O:44]C)[O:42]C.Cl>O.C1COCC1>[CH2:1]([C:5]1([CH2:32][CH2:33][CH2:34][CH3:35])[C:17]2[CH:16]=[C:15]([N:18]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH:14]=[CH:13][C:12]=2[C:11]2[C:6]1=[CH:7][C:8]([B:41]([OH:44])[OH:42])=[CH:9][CH:10]=2)[CH2:2][CH2:3][CH3:4]
Reactant: COB(OC)OC
Reactant: CCCCC1(CCCC)c2cc(Br)ccc2-c2ccc(N(c3ccccc3)c3ccccc3)cc21
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Product: CCCCC1(CCCC)c2cc(B(O)O)ccc2-c2ccc(N(c3ccccc3)c3ccccc3)cc21
Temperature: -30 °C
Reaction time: 1 h
Yield: 79.4 %

Procedure:
To a dry 100 mL two-neck flask containing 1.3 g (2.47 mmol) of compound 2 and 30 mL of dry THF was dropwise added 2.3 mL (3.71 mmol) of 1.6 M of n-butyl lithium under N2 at −78° C. while maintaining a good stirring. After stirring for 1 h, trimethyl borate (0.4 mL, 3.71 mmol) was added in one portion. The reaction mixture was then stirred for 1 h at −78° C. When the mixture was naturally warmed to −30° C., water and HCl (3 M) were added. Then the solution mixture was poured into water wad extracted with ethyl acetate (3×50 mL). The combined organic phase was dried over anhydrous sodium sulfate, filtered and evaporated to dryness under 35° C. The crude product was purified by silica gel column chromatography using dichloromethane and petroleum ether/ethyl acetate as eluent affording a light-yellow solid (0.96 g, 79%). 1H NMR (400 MHz, DMSO-d6, δ) 8.02 (s, 2H), 7.80 (s, 1H), 7.77 (d, J=7.6 Hz, 1H), 7.71 (d, J=8.4 Hz, 1H), 7.27 (t, J=7.6 Hz, 1H), 7.08 (d, J=1.6 Hz, 1H), 6.93-7.01 (m, 6H), 6.91 (d, J=2.0 Hz, 1H), 1.79-1.88 (m, 4H), 0.95-1.04 (m, 4H), 0.65 (t, J=7.4 Hz, 6H), 0.50-0.58 (m, 4H). 13C NMR (100 MHz, DMSO-d6, δ) 152.1, 148.9, 147.4, 146.8, 142.1, 136.1, 133.1, 129.4, 129.3, 128.2, 123.3, 122.7, 121.1, 119.1, 118.3, 54.3, 39.2, 25.8, 22.4, 13.8. MS (FAB) m/z 489.7 (M+).
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].[NH2:5][C:6]1[CH:7]=[CH:8][C:9]([N+:18]([O-:20])=[O:19])=[C:10]([CH:17]=1)[C:11]([O:13][CH2:14][CH:15]=[CH2:16])=[O:12].C(N(CC)CC)C>ClCCl>[C:1]([NH:5][C:6]1[CH:7]=[CH:8][C:9]([N+:18]([O-:20])=[O:19])=[C:10]([CH:17]=1)[C:11]([O:13][CH2:14][CH:15]=[CH2:16])=[O:12])(=[O:3])[CH3:2]
Reactant: C=CCOC(=O)c1cc(N)ccc1[N+](=O)[O-]
Reactant: CC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C=CCOC(=O)c1cc(NC(C)=O)ccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 8 h
Yield: 94.2 %

Procedure:
A solution of acetyl chloride (3.18 g, 40.5 mM) in dichloromethane (10 ml) under an argon atmosphere was added at 0° to a solution of allyl 5-amino-2-nitrobenzoate (3.0 g, 13.5 mM) in dichloromethane (30 ml). After addition of a solution of triethylamine (1.88 ml, 13.5 mM) in dichloromethane (10 ml) the mixture was stirred at ambient temperature overnight. The solvent was evaporated and the residue purified by chromatography on silica. Elution with ethyl acetate/petroleum ether (50/50) gave allyl 5-acetamido-2-nitrobenzoate (3.36 g, 94%).
Reaction SMILES: [Br:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([C:10]2[O:11][CH:12]=[CH:13][CH:14]=2)=[CH:4][C:3]=1[O:15][CH3:16].CON(C)[C:20](=[O:36])[CH:21]([O:34][CH3:35])[C:22]1[CH:27]=[CH:26][C:25]([C:28]2[CH:33]=[N:32][CH:31]=[CH:30][N:29]=2)=[CH:24][CH:23]=1>>[Br:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([C:10]2[O:11][C:12]([C:20](=[O:36])[CH:21]([O:34][CH3:35])[C:22]3[CH:23]=[CH:24][C:25]([C:28]4[CH:33]=[N:32][CH:31]=[CH:30][N:29]=4)=[CH:26][CH:27]=3)=[CH:13][CH:14]=2)=[CH:4][C:3]=1[O:15][CH3:16]
Reactant: COc1cc(-c2ccco2)cc(OC)c1Br
Reactant: COC(C(=O)N(C)OC)c1ccc(-c2cnccn2)cc1
Product: COc1cc(-c2ccc(C(=O)C(OC)c3ccc(-c4cnccn4)cc3)o2)cc(OC)c1Br

Procedure:
1-(5-(4-Bromo-3,5-dimethoxyphenyl)furan-2-yl)-2-methoxy-2-(4-(pyrazin-2-yl)phenyl)ethanone was prepared from 2-(4-bromo-3,5-dimethoxyphenyl)furan and N,2-dimethoxy-N-methyl-2-(4-(pyrazin-2-yl)phenyl)acetamide according to the procedure used in Example 30. Purification by chromatography (60% EtOAc/hexanes) gave the product as a pale yellow solid (0.060 g, 17% yield). MS: m/z 509.3 [M+H]+.
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][CH2:5][C:6]([OH:8])=[O:7].[CH2:9](O)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>C1(C)C=CC=CC=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>[Br:1][CH2:2][CH2:3][CH2:4][CH2:5][C:6]([O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:7]
Reactant: OCc1ccccc1
Reactant: O=C(O)CCCCBr
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: O=C(CCCCBr)OCc1ccccc1
Yield: 95.9 %

Procedure:
This compound was prepared from 5-bromopentanoic acid (1.81 g; 10.0 mmol), benzyl alcohol (1.62 g; 15.0 mmol), and p-toluenesulphonic acid (50 mg) in toluene (100 mL) using Procedure B. 2.60 g (96%) product was obtained (clear oil). The product was used in 8c without further purification.
Reaction SMILES: [CH2:1]([C:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[NH:12][C:13]([C:15]2[N:19]3[CH:20]=[CH:21][C:22]([CH2:24]O)=[CH:23][C:18]3=[N:17][CH:16]=2)=[O:14])[N:5]([CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[C:29]([CH3:33])[N:28]=2)[N:4]=1)[CH3:2].CS(Cl)(=O)=O.C([O-])([O-])=O.[K+].[K+].[N:45]1([C:51]([O:53][C:54]([CH3:57])([CH3:56])[CH3:55])=[O:52])[CH2:50][CH2:49][NH:48][CH2:47][CH2:46]1>C(Cl)Cl.CN(C=O)C>[CH2:1]([C:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[NH:12][C:13]([C:15]2[N:19]3[CH:20]=[CH:21][C:22]([CH2:24][N:48]4[CH2:49][CH2:50][N:45]([C:51]([O:53][C:54]([CH3:57])([CH3:56])[CH3:55])=[O:52])[CH2:46][CH2:47]4)=[CH:23][C:18]3=[N:17][CH:16]=2)=[O:14])[N:5]([CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[C:29]([CH3:33])[N:28]=2)[N:4]=1)[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: CCc1nn(Cc2cccc(C)n2)c2cccc(NC(=O)c3cnc4cc(CO)ccn34)c12
Agent: CS(=O)(=O)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CCc1nn(Cc2cccc(C)n2)c2cccc(NC(=O)c3cnc4cc(CN5CCN(C(=O)OC(C)(C)C)CC5)ccn34)c12
Temperature: 50 °C
Reaction time: 0.5 h
Yield: 39.7 %

Procedure:
To N-(3-ethyl-1-((6-methylpyridin-2-yl)methyl)-1H-indazol-4-yl)-7-(hydroxymethyl)imidazo[1,2-a]pyridine-3-carboxamide (40 mg, 0.091 mmol) in DCM (3 mL) was added methanesulfonyl chloride (21 mg, 0.18 mmol). The reaction mixture was stirred for 30 minutes, diluted with DCM (10 mL), washed with saturated NaHCO3 aqueous solution (3 mL) and brine (3 mL). The organic phase was concentrated under reduced pressure to a residue, to which was added DMF (2 mL), K2CO3 (38 mg, 0.27 mmol) and tert-butyl piperazine-1-carboxylate (51 mg, 0.27 mmol). The reaction mixture was heated to 50° C. for 2 hours. The mixture was concentrated under reduced pressure to remove DMF. Silica gel chromatography (DCM/MeOH) gave the product (22 mg).
Reaction SMILES: Br[CH2:2][CH2:3][CH:4]([CH3:6])[CH3:5].C([N:10]1[C:18]2[CH:17]=[CH:16][N:15]=[CH:14][C:13]=2[NH:12][C:11]1=[O:19])(C)=C>>[CH3:5][CH:4]([CH3:6])[CH2:3][CH2:2][N:12]1[C:13]2[CH:14]=[N:15][CH:16]=[CH:17][C:18]=2[NH:10][C:11]1=[O:19]
Reactant: C=C(C)n1c(=O)[nH]c2cnccc21
Reactant: CC(C)CCBr
Product: CC(C)CCn1c(=O)[nH]c2ccncc21

Procedure:
The title compound was prepared according to the procedure described in the literature (Meth-Cohn, O.; Smith, D. I. J.C.S. Perkin Trans. 1, 1982, 261-270.; Vernin G. et al. J. Heterocyclic Chem. 1981, 18, 85-89.) from 1-bromo-3-methylbutane and 1-isopropenyl-1,3-dihydro-2H-imidazo[4,5-c]pyridin-2-one (Israel, M.; Jones, L. C. J. Heterocyclic Chem. 1971, 8, 797.
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.[CH3:9][C:10]1([CH3:28])[CH:14]([C:15]2[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=2)[C:13]2[C:22]([CH3:27])=[CH:23][C:24]([CH3:26])=[CH:25][C:12]=2[O:11]1>C(#N)C>[Br:1][C:23]1[C:24]([CH3:26])=[CH:25][C:12]2[O:11][C:10]([CH3:28])([CH3:9])[CH:14]([C:15]3[CH:16]=[CH:17][C:18]([CH3:21])=[CH:19][CH:20]=3)[C:13]=2[C:22]=1[CH3:27]
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1ccc(C2c3c(C)cc(C)cc3OC2(C)C)cc1
Solvent: CC#N
Product: Cc1ccc(C2c3c(cc(C)c(Br)c3C)OC2(C)C)cc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 66.7 %

Procedure:
N-bromosuccinimide (2.1 g, 11.6 mmol) was added to a solution of 2,2,4,6-tetramethyl-3-(4-methylphenyl)-2,3-dihydro-1-benzofuran (3.1 g, 11.6 mmol) in acetonitrile (30 ml) with ice cooling and the mixture was stirred at room temperature for 1.5 hours. The resulting mixture was concentrated under reduced pressure. After the remaining solids were removed with filtration, the filtrate was concentrated under reduced pressure. The residue was purified using silica gel column chromatography (hexane) to obtain 2.67 g (yield 67%) of the title compound via recrystallization (methanol). mp. 116–118° C.
Reaction SMILES: CS(O[CH2:6][CH2:7][N:8]1[C:20]2[C:19]3[CH2:18][CH2:17][CH2:16][CH2:15][C:14]=3[N:13]=[C:12]([N:21]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[C:11]=2[N:10]=[C:9]1[CH2:36][CH2:37][CH2:38][CH3:39])(=O)=O.[C:40]1([SH:46])[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1.C(N(CC)CC)C>CN(C)C=O>[CH2:36]([C:9]1[N:8]([CH2:7][CH2:6][S:46][C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)[C:20]2[C:19]3[CH2:18][CH2:17][CH2:16][CH2:15][C:14]=3[N:13]=[C:12]([N:21]([C:22]([O:24][C:25]([CH3:26])([CH3:28])[CH3:27])=[O:23])[C:29]([O:31][C:32]([CH3:35])([CH3:33])[CH3:34])=[O:30])[C:11]=2[N:10]=1)[CH2:37][CH2:38][CH3:39]
Reactant: Sc1ccccc1
Reactant: CCCCc1nc2c(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)nc3c(c2n1CCOS(C)(=O)=O)CCCC3
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCCCc1nc2c(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)nc3c(c2n1CCSc1ccccc1)CCCC3
Temperature: 80 °C
Yield: 86.1 %

Procedure:
A round bottom flask was charged with a magnetic stir bar, 2-{4[bis(tert-butoxycarbonyl)amino]-2-butyl-6,7,8,9-tetrahydro-1H-imidazo[4,5-c]quinolin-1-yl}ethyl methanesulfonate (0.61 g, 1.08 mmol), benzenethiol (0.21 g, 1.88 mmol), triethylamine (0.25 g, 2.43 mmol) and anhydrous dimethyl formamide (11 mL) under a nitrogen atmosphere. The reaction mixture was heated to 80° C. to give a dark yellow, homogeneous solution that was maintained at 80° C. for 2.5 hours at which time the reaction was judged to be complete. The solution was cooled and then partitioned between ethyl acetate and saturated aqueous sodium bicarbonate. The layers were separated. The organic layer was washed with saturated aqueous sodium bicarbonate and brine, dried over anhydrous sodium sulfate, filtered and then concentrated under reduced pressure to afford a yellow oil. The material was purified by chromatography over silica gel (95/5 dichloromethane/methanol) to provide di(tert-butyl) 2-butyl-1-[2-(phenylthio)ethyl]-6,7,8,9-tetrahydro-1H-imidazo[4,5-c]quinolin-4-ylimidodicarbonate (0.54 g, 0.93 mmol) as a light yellow oil. MS (CI) for C32H44N4O4S m/z 581 (MH+), 481, 381, 245.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([O:8][C:9]2[CH:10]=[C:11]([C:15]3[O:19][C:18]([NH:20][C:21]4[CH:26]=[C:25]([S:27]([CH2:30][CH3:31])(=[O:29])=[O:28])[CH:24]=[CH:23][C:22]=4[O:32][CH3:33])=[N:17][CH:16]=3)[CH:12]=[CH:13][CH:14]=2)[CH:5]=[CH:4][N:3]=1.[CH:34]([NH2:37])([CH3:36])[CH3:35]>>[CH2:30]([S:27]([C:25]1[CH:24]=[CH:23][C:22]([O:32][CH3:33])=[C:21]([NH:20][C:18]2[O:19][C:15]([C:11]3[CH:10]=[C:9]([CH:14]=[CH:13][CH:12]=3)[O:8][C:6]3[CH:5]=[CH:4][N:3]=[C:2]([NH:37][CH:34]([CH3:36])[CH3:35])[N:7]=3)=[CH:16][N:17]=2)[CH:26]=1)(=[O:29])=[O:28])[CH3:31]
Reactant: CCS(=O)(=O)c1ccc(OC)c(Nc2ncc(-c3cccc(Oc4ccnc(Cl)n4)c3)o2)c1
Reactant: CC(C)N
Product: CCS(=O)(=O)c1ccc(OC)c(Nc2ncc(-c3cccc(Oc4ccnc(NC(C)C)n4)c3)o2)c1
Temperature: 100 °C
Reaction time: 8 h
Yield: 67 %

Procedure:
The title compound of Example 168 (40 mg) was treated with isopropylamine (2 mL) and stirred at 100° C. overnight in a sealed tube. The mixture was evaporated to dryness and purified by thin layer chromatography to afford the title compound (28 mg, 67% yield) as a yellow solid, which was isolated as the HCl salt 1H NMR (400 MHz, d6-DMSO): δ 9.77 (bs, 1H), 8.68 (s, 1H), 8.26 (d, J=6.4, 1H), 7.58 7.45 (m, 5H), 7.23 (d, J=8.4, 1H), 7.14 (m, 1H), 6.61–6.64 (m, 2H), 3.92 (s, 3H), 3.32 (m, 1H), 3.15 (q, J=7.3, 2H), 1.05 (m, 9H). MS (ES+, m/z)=510 (m+H)+.
Reaction SMILES: [O:1]=[C:2]1[CH2:5][CH:4]([C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH2:3]1.[BH4-].[Na+].O>C(O)C>[OH:1][C@@H:2]1[CH2:5][C@H:4]([C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH2:3]1
Reactant: CCOC(=O)C1CC(=O)C1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CCOC(=O)[C@H]1C[C@@H](O)C1
Temperature: -30 °C
Reaction time: 0.5 h

Procedure:
To a cooled (-30° C.) solution of ethyl 3-oxocyclobutanecarboxylate (J. Org. Chem. 1988, 53, 3481) (18.1 g, 130 mmol) in ethanol (100 ml) was added NaBH4 (4.92 g, 130 mmol) in small potions over 0.25 h. The reaction mixture was stirred at -30° C. for 0.5 h and then at room temperature for 0.5 h. The reaction mixture was poured into water (200 ml) and extracted with ether (500 ml). The organic phase was washed with brine (200 ml), dried (MgSO4) and concentrated. The residue was distilled to afford 15.1 g (81%) of ethyl cis-3-hydroxycyclobutanecarboxylate as a colorless oil: bp 86°-88° C. (1 mmHg); 1H NMR δ4.24 (m, 3H), 2.66-2.52 (m, 3H), 2.28-2,09 (m, 2H), 2.03 (br s, 1H), 1.26 (t, J=7.3 Hz, 3H).