Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl-].O[NH3+:3].[C:4](=[O:7])([O-])[OH:5].[Na+].[CH2:9]([N:11]1[CH2:16][CH2:15][CH:14]([N:17]2[C:22](=[O:23])[C:21]([CH2:24][C:25]3[CH:30]=[CH:29][C:28]([C:31]4[C:32]([C:37]#[N:38])=[CH:33][CH:34]=[CH:35][CH:36]=4)=[CH:27][CH:26]=3)=[C:20]([CH2:39][CH2:40][CH3:41])[N:19]3[N:42]=[CH:43][N:44]=[C:18]23)[CH2:13][CH2:12]1)[CH3:10]>CS(C)=O.C(OCC)(=O)C>[CH2:9]([N:11]1[CH2:12][CH2:13][CH:14]([N:17]2[C:22](=[O:23])[C:21]([CH2:24][C:25]3[CH:30]=[CH:29][C:28]([C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=4[C:37]4[NH:3][C:4](=[O:7])[O:5][N:38]=4)=[CH:27][CH:26]=3)=[C:20]([CH2:39][CH2:40][CH3:41])[N:19]3[N:42]=[CH:43][N:44]=[C:18]23)[CH2:15][CH2:16]1)[CH3:10]
Reactant: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n(C2CCN(CC)CC2)c2ncnn12
Reactant: [NH3+]O
Reactant: O=C([O-])O
Agent: [Cl-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: CCCc1c(Cc2ccc(-c3ccccc3-c3noc(=O)[nH]3)cc2)c(=O)n(C2CCN(CC)CC2)c2ncnn12
Temperature: 60 °C
Reaction time: 0.5 h
Yield: 35 %

Procedure:
A mixture of hydroxylammonium chloride (313 mg), sodium hydrogen carbonate (504 mg) and dimethyl sulfoxide (3 mL) was stirred at 60° C. for 30 min, a solution of 4′-{[4-(1-ethylpiperidin-4-yl)-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl]methyl}biphenyl-2-carbonitrile (145 mg) in dimethyl sulfoxide (2 mL) was added, and the mixture was stirred at 90° C. for 17 hr. The reaction mixture was diluted with ethyl acetate, washed with water and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was dissolved in tetrahydrofuran (10 mL). N,N′-Carbonyldiimidazole (58 mg) and then 1,8-diazabicyclo[5.4.0]undec-7-ene (55 mg) were added, and the mixture was stirred at room temperature for 15 hr. The reaction mixture was diluted with ethyl acetate, washed with saturated aqueous potassium hydrogensulfate solution and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel chromatography [eluent: methanol/ethyl acetate=10/90→30/70 (volume ratio)] and crystallized from acetonitrile to give the title compound as colorless crystals (57 mg, 35%).
Reaction SMILES: [CH:1]1[C:6](N=C=S)=[CH:5][C:4]2[C:10]([O:12][C:13]3([C:23]4[CH:24]=[CH:25][C:26]([OH:28])=[CH:27][C:22]=4[O:21][C:15]4[CH:16]=[C:17]([OH:20])[CH:18]=[CH:19][C:14]3=4)[C:3]=2[CH:2]=1)=[O:11].NC1C=C([B:36]([OH:38])[OH:37])C=CC=1.C(N(CC)CC)C>CO>[CH:1]1[CH:6]=[CH:5][C:4]([C:10]([OH:12])=[O:11])=[C:3]([C:13]2[C:14]3[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][C:15]=3[O:21][C:22]3[C:23]=2[CH:24]=[CH:25][C:26]([CH:27]=3)=[O:28])[CH:2]=1.[BH:36]([OH:38])[OH:37]
Reactant: O=C1OC2(c3ccc(O)cc3Oc3cc(O)ccc32)c2ccc(N=C=S)cc21
Reactant: Nc1cccc(B(O)O)c1
Solvent: CCN(CC)CC
Solvent: CO
Product: O=C(O)c1ccccc1-c1c2ccc(=O)cc-2oc2cc(O)ccc12
Product: OBO
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A fluorescein-boronic acid compound of formula I above was prepared by the following method. Fluorescein isothiocyanate (10 mg), m-aminophenylboronic acid (4 mg) and triethylamine (3 mg) were mixed in 0.9 ml methanol, and 0.1 ml distilled water. The mixture was stirred for one hour at room temperature and then a further 4 mg of m-aminophenyl-boronic acid was added. Stirring was continued for a further hour, and the solution was then purified by thin layer chromatography (eluent dichloromethane:methanol, 9:1).
Reaction SMILES: [F:1][CH:2]([F:12])[C:3]1[C:7]([C:8](Cl)=[O:9])=[CH:6][N:5]([CH3:11])[N:4]=1.[Cl:13][C:14]1[CH:25]=[CH:24][CH:23]=[C:22]([Cl:26])[C:15]=1[CH2:16][CH:17]1[CH2:21][CH2:20][CH2:19][NH:18]1.C(N(CC)CC)C>ClCCl>[Cl:13][C:14]1[CH:25]=[CH:24][CH:23]=[C:22]([Cl:26])[C:15]=1[CH2:16][CH:17]1[CH2:21][CH2:20][CH2:19][N:18]1[C:8]([C:7]1[C:3]([CH:2]([F:12])[F:1])=[N:4][N:5]([CH3:11])[CH:6]=1)=[O:9]
Reactant: Cn1cc(C(=O)Cl)c(C(F)F)n1
Reactant: Clc1cccc(Cl)c1CC1CCCN1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cn1cc(C(=O)N2CCCC2Cc2c(Cl)cccc2Cl)c(C(F)F)n1
Reaction time: 15 h
Yield: 78.8 %

Procedure:
At a temperature of 0° C., a solution of 3-difluoromethyl-1-methyl-1H-pyrazole-4-carbonyl chloride (0.97 g; 5.0 mmol) in dichloromethane (5 ml) was added dropwise to a stirred suspension of 2-(2,6-dichloro-benzyl)-pyrrolidine (1.20 g; 5.0 mmol), which was prepared as described in example P17, and triethylamine (1.5 g; 15.0 mmol) in dichloromethane (15 ml). The ice bath was removed and reaction mixture was allowed stirring for 15 hours. The reaction mixture was washed with 2M NaOH (20 ml), 2M HCl (20 ml) and saturated NaCl (20 ml) and then dried over Na2SO4. After removal of the solvent, the residue (1.9 g oil) was purified by flash chromatography over silica gel (eluent:cyclohexane/ethyl acetate 3:7). 1.53 g (78.8% of theory) of [2-(2,6-dichloro-benzyl)-pyrrolidin-1-yl]-(3-difluoromethyl-1-methyl-1H-pyrazol-4-yl)-methanone was obtained in form of an oil.
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:9]([C:12]2[S:13][CH:14]=[C:15]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[C:19]([Cl:24])[CH:18]=3)[N:16]=2)=[CH:8][C:3]=1[C:4]([O:6]C)=[O:5].O1CCOCC1.C([O-])([O-])=O.[K+].[K+].[C:37]1(B(O)O)[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1>C(Cl)Cl.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>[Cl:24][C:19]1[CH:18]=[C:17]([C:15]2[N:16]=[C:12]([C:9]3[CH:8]=[C:3]([C:4]([OH:6])=[O:5])[C:2]([C:37]4[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=4)=[CH:11][CH:10]=3)[S:13][CH:14]=2)[CH:22]=[CH:21][C:20]=1[Cl:23]
Reactant: OB(O)c1ccccc1
Reactant: COC(=O)c1cc(-c2nc(-c3ccc(Cl)c(Cl)c3)cs2)ccc1Br
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: [K+]
Solvent: C1COCCO1
Solvent: ClCCl
Product: O=C(O)c1cc(-c2nc(-c3ccc(Cl)c(Cl)c3)cs2)ccc1-c1ccccc1
Temperature: 100 °C
Yield: 19.4 %

Procedure:
Methyl 2-bromo-5-(4-(3,4-dichlorophenyl)thiazol-2-yl)benzoate (177 mg, 0.4 mmol) was taken up in CH2Cl2 and washed with aqueous Na2CO3. The organic layer was dried (MgSO4), filtered, and evaporated. Dioxane (2 mL) was added, along with tetrakis(triphenylphosphine)palladium(0) (37 mg, 0.032 mmol), 3 M aqueous K2CO3 (267 μL, 0.8 mmol) and phenylboronic acid (available from ASDI Incorporated; 97.5 mg, 0.8 mmol). The vial was evacuated and filled with nitrogen, and then the mixture was heated at 100° C. for 20 h. The mixture was purified on an ISCO Combiflash system, using 0-15% ethyl acetate/hexanes as eluent. Fractions homogeneous for the product were evaporated, and the resulting material was dissolved in THF (2 mL). 1 M aqueous NaOH (2 mL) was added and the mixture was heated at 60° C. overnight. 1 M aqueous HCl was added to bring the pH to approximately 2, and the mixture was extracted 4 times with EtOAc. The combined organic layers were washed with brine, dried (Na2SO4), filtered, evaporated, and purified by preparative HPLC, using the conditions outlined in General Procedure A for Suzuki Coupling and Hydrolysis in Parallel Mode, to give 4-[4-(3,4-dichloro-phenyl)-thiazol-2-yl]-biphenyl-2-carboxylic acid (33 mg, 20%) as a yellow solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.45 (s, 1H), 8.32 (d, J=1.6 Hz, 2H), 8.20 (dd, J=8.2, 2.0 Hz, 1H), 8.07 (dd, J=8.2, 2.0 Hz, 1H), 7.74 (d, J=8.6 Hz, 1H), 7.55 (d, J=8.2 Hz, 1H), 7.35-7.48 (m, 5H).
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][C:9]([O:12][Si](C(C)(C)C)(C)C)=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([C:20]([F:23])([F:22])[F:21])=[N:7]2.Cl.O>CO>[Br:1][C:2]1[CH:11]=[CH:10][C:9]([OH:12])=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([C:20]([F:21])([F:22])[F:23])=[N:7]2
Reactant: CC(C)(C)[Si](C)(C)Oc1ccc(Br)c2ccc(C(F)(F)F)nc12
Agent: Cl
Solvent: O
Solvent: CO
Product: Oc1ccc(Br)c2ccc(C(F)(F)F)nc12
Yield: 79.5 %

Procedure:
A solution of 5-bromo-8-(tert-butyldimethylsilanyloxy)-2-trifluoromethylquinoline (21 g) in methanol (150 ml) was treated with 37% hydrochloric acid solution (5 ml) and water (5 ml). The mixture was stirred for 12h at room temperature and at 45° C. for 2 h. The methanol was removed in vacuo and the residue partitioned between 10% sodium hydroxide solution (100 ml) and dichloromethane (50 ml). The aqueous layer was neutralised with 37% hydrochloric acid solution to pH 7.2 and extracted with dichloromethane (4×50 ml). The combined organic extracts were dried over magnesium sulfate, filtered and the solvent removed in vacuo to give the product (12 g) as a cream solid.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[CH2:4][CH2:5][OH:6].[C:11]1([CH3:21])[CH:16]=[CH:15][C:14]([S:17](Cl)(=[O:19])=[O:18])=[CH:13][CH:12]=1>N1C=CC=CC=1>[CH3:21][C:11]1[CH:16]=[CH:15][C:14]([S:17]([O:6][CH2:5][CH2:4][C:3]2[CH:7]=[CH:8][CH:9]=[CH:10][C:2]=2[Br:1])(=[O:19])=[O:18])=[CH:13][CH:12]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: OCCc1ccccc1Br
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)OCCc2ccccc2Br)cc1

Procedure:
The reaction and work up was conducted as described in the preparation of compound 163 using 2-bromophenethyl alcohol (5 g, 25 mmol) in pyridine (12 mL) and p-toluenesulfonyl chloride (5.2 g, 27.5 mmol). The crude product was purified by flash chromatography eluting with EtOAc/petroleum ether 1:4. This afforded the title compound as a colourless crystalline compound.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([OH:9])=[CH:5][C:4]=1[C:10]1[CH:34]=[C:33]([CH3:35])[C:13]2[N:14]=[C:15]([NH:18][C:19]3[CH:24]=[CH:23][C:22]([O:25][CH2:26][CH2:27][N:28]4[CH2:32][CH2:31][CH2:30][CH2:29]4)=[CH:21][CH:20]=3)[N:16]=[N:17][C:12]=2[CH:11]=1.CCN(CC)CC.[C:43](Cl)(=[O:45])[CH3:44]>C(Cl)Cl>[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([O:9][C:43](=[O:45])[CH3:44])=[CH:5][C:4]=1[C:10]1[CH:34]=[C:33]([CH3:35])[C:13]2[N:14]=[C:15]([NH:18][C:19]3[CH:24]=[CH:23][C:22]([O:25][CH2:26][CH2:27][N:28]4[CH2:32][CH2:31][CH2:30][CH2:29]4)=[CH:21][CH:20]=3)[N:16]=[N:17][C:12]=2[CH:11]=1
Reactant: CC(=O)Cl
Reactant: Cc1cc(-c2cc(O)ccc2Cl)cc2nnc(Nc3ccc(OCCN4CCCC4)cc3)nc12
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)Oc1ccc(Cl)c(-c2cc(C)c3nc(Nc4ccc(OCCN5CCCC5)cc4)nnc3c2)c1
Reaction time: 0.17 h
Yield: 80.8 %

Procedure:
To a solution of 4-chloro-3-{5-methyl-3-[4-(2-pyrrolidin-1-yl-ethoxy)-phenylamino]-benzo[1,2,4]triazin-7-yl}-phenol hydrochloride (1.0 equiv., 0.978 mmol) in DCM (30 mL) was added neat Et3N (10 equiv., 4.89 mmol) under an argon rich atmosphere and stirred for 10 minutes. Neat Acetyl chloride (1.2 equiv., 1.17 mmol) was added dropwise via syringe to the reaction mixture and allowed to stir at room temperature for 24 h. The reaction was quenched using saturated NaHCO3; the organics were dried over Na2SO4 and then concentrated down under reduced pressure. The resulting crude solid was then brought up in DCM and purified by flash chromatography using a solvent system of 85:10:5 (v/v/v) DCM/MeOH/Et3N. The fractions were concentrated under reduced pressure and precipitated out using 1:5 (v/v) DCM/hexanes to afford an orange solid (409.1 mg, 75% yield). 1H NMR (DMSO-d6): δ 1.68 (m, 4H), 2.29 (s, 3H), 2.51 (m, 4H), 2.63 (s, 3H), 2.78 (t, J=5.94 Hz, 2H), 4.07 (t, J=5.99 Hz, 2H), 6.99 (dd, J=7.05 Hz, 12.55 Hz, 2H), 7.27 (dd, J=5.90 Hz, 8.75 Hz, 1H), 7.41 (d, J=2.80 Hz, 1H), 7.67 (d, J=8.75 Hz, 1H), 7.85 (m, 1H), 7.93 (d, J=9.05 Hz, 2H), 8.17 (m, 1H), 10.83 (s, 1H). Rf=0.29 MS (ES+) m/z 520, LC retention time 2.57 minutes.
Reaction SMILES: [CH3:1][N:2]([CH2:4][C:5]1[O:9][C:8]([CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][NH2:15])=[CH:7][CH:6]=1)[CH3:3].[CH3:16][N:17]=[C:18]=[S:19]>C(#N)C>[CH3:7][CH2:8][O:9][CH2:5][CH3:4].[CH3:1][N:2]([CH2:4][C:5]1[O:9][C:8]([CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][NH:15][C:18]([NH:17][CH3:16])=[S:19])=[CH:7][CH:6]=1)[CH3:3]
Reactant: CN=C=S
Reactant: CN(C)Cc1ccc(CCCCCN)o1
Solvent: CC#N
Product: CCOCC
Product: CNC(=S)NCCCCCc1ccc(CN(C)C)o1

Procedure:
5-[5-(Dimethylamino)methyl-2-furanyl]pentanamine (0.5 g) and methylisothiocyanate (0.25 g) were stirred in acetonitrile at room temperature for 24 hr. Solvent was removed and the product purified by column chromatography (silica/methanol) to give after trituration with ether N-[5-[5-(dimethylamino)methyl-2-furanyl]pentyl]-N'-methylthiourea as off-white crystals m.p. 66°-69°.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:24])[C:7]=1[S:8][C:9]1[S:13][C:12]([C:14]([NH:16][CH2:17][C:18]([OH:20])=O)=[O:15])=[CH:11][C:10]=1[N+:21]([O-:23])=[O:22].[CH3:25][O:26][CH2:27][CH2:28][NH2:29]>>[Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:24])[C:7]=1[S:8][C:9]1[S:13][C:12]([C:14]([NH:16][CH2:17][C:18]([NH:29][CH2:28][CH2:27][O:26][CH3:25])=[O:20])=[O:15])=[CH:11][C:10]=1[N+:21]([O-:23])=[O:22]
Reactant: COCCN
Reactant: O=C(O)CNC(=O)c1cc([N+](=O)[O-])c(Sc2c(Cl)cncc2Cl)s1
Product: COCCNC(=O)CNC(=O)c1cc([N+](=O)[O-])c(Sc2c(Cl)cncc2Cl)s1

Procedure:
Prepared according to the procedure described for example 70 from 2-(5-((3,5-dichloropyridin-4-yl)thio)-4-nitrothiophene-2-carboxamido)acetic acid (120.0 mg, 0.29 mmol) from example 210 and 2-methoxyethylamine (26.4 mg, 0.35 mmol). The title compound was obtained as a solid (70.0 mg, 52% yield). 1H NMR (400 MHz, d6-DMSO) δ: 9.17 (1H, m), 8.99 (2H, m), 8.47 (1H, s), 8.04 (1H, m), 3.79 (2H, m), 3.33 (2H, m), 3.22 (3H, s), 3.20 (2H, m). MS m/z: 463.09, 465.12 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]=[C:6]2[O:15][C:16]1[CH:17]=[C:18]([CH:20]=[CH:21][CH:22]=1)[NH2:19].[C:23](=O)([O-])[NH2:24].COC1C=C2C(=CC=1OC)N=CN=C2OC1C=C(N[C:49]([NH:51][C:52]2[O:56][N:55]=[C:54]([CH:57]([CH3:59])[CH3:58])[CH:53]=2)=[O:50])C=CC=1>>[C:23]([C:57]([C:54]1[CH:53]=[C:52]([NH:51][C:49]([NH:19][C:18]2[CH:20]=[CH:21][CH:22]=[C:16]([O:15][C:6]3[C:5]4[C:10](=[CH:11][C:12]([O:13][CH3:14])=[C:3]([O:2][CH3:1])[CH:4]=4)[N:9]=[CH:8][N:7]=3)[CH:17]=2)=[O:50])[O:56][N:55]=1)([CH3:58])[CH3:59])#[N:24]
Reactant: COc1cc2ncnc(Oc3cccc(N)c3)c2cc1OC
Reactant: COc1cc2ncnc(Oc3cccc(NC(=O)Nc4cc(C(C)C)no4)c3)c2cc1OC
Reactant: NC(=O)[O-]
Product: COc1cc2ncnc(Oc3cccc(NC(=O)Nc4cc(C(C)(C)C#N)no4)c3)c2cc1OC
Temperature: 25 °C
Reaction time: 3 h
Yield: 39 %

Procedure:
Prepared from 3-(6,7-dimethoxyquinazolin-4-yloxy)aniline from Example 113A (89 mg, 0.30 mmol) and the carbamate from the previous step (90 mg, 0.332 mmol) according to the method described for 1-(3-(6,7-dimethoxyquinazolin-4-yloxy)phenyl)-3-(3-isopropylisoxazol-5-yl)urea in Example 122B, except the reaction mixture was stirred at room temperature for 3 h. Purification via silica gel chromatography eluting with 100% dichloromethane to 10% methanol in dichloromethane afforded 1-(3-(2-cyanopropan-2-yl)isoxazol-5-yl)-3-(3-(6,7-dimethoxyquinazolin-4-yloxy)phenyl)urea as a colorless solid (55 mg, 39%). 1H NMR (300 MHz, DMSO-d6) δ 10.51 (brs, 1H), 9.12 (brs, 1H), 8.57 (s, 1H), 7.56-7.57 (m, 2H), 7.31-7.45 (m, 3H), 7.01 (m, 1H), 6.27 (s, 1H), 4.00 (s, 6H), 1.68 (s, 6H); LC-MS (ESI) m/z 475 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[C:17]([CH3:19])([CH3:18])[CH2:16][C:15]3[C:10](=[CH:11][CH:12]=[C:13]([C:20]([O:22][CH3:23])=[O:21])[CH:14]=3)[NH:9]2)=[CH:4][CH:3]=1.[CH:24]1([C:28](O)=[O:29])[CH2:27][CH2:26][CH2:25]1.C(N(CC)C(C)C)(C)C.P(Cl)(Cl)(Cl)=O>ClCCl>[CH:24]1([C:28]([NH:1][C:2]2[CH:3]=[CH:4][C:5]([CH:8]3[C:17]([CH3:18])([CH3:19])[CH2:16][C:15]4[C:10](=[CH:11][CH:12]=[C:13]([C:20]([O:22][CH3:23])=[O:21])[CH:14]=4)[NH:9]3)=[CH:6][CH:7]=2)=[O:29])[CH2:27][CH2:26][CH2:25]1
Reactant: O=C(O)C1CCC1
Reactant: COC(=O)c1ccc2c(c1)CC(C)(C)C(c1ccc(N)cc1)N2
Solvent: O=P(Cl)(Cl)Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)c1ccc2c(c1)CC(C)(C)C(c1ccc(NC(=O)C3CCC3)cc1)N2
Temperature: 25 °C
Reaction time: 16 h
Yield: 67 %

Procedure:
To a solution of methyl 2-(4-aminophenyl)-3,3-dimethyl-1,2,3,4-tetrahydroquinoline-6-carboxylate (50 mg, 0.16 mmol), cyclobutanecarboxylic acid (0.025 mL, 0.24 mmol) and N,N-diisopropylethylamine (0.05 mL, 0.32 mmol) in dichloromethane (5 mL) was added phosphorus oxychloride (0.02 mL, 0.24 mmol) via syringe below 0° C. The mixture was stirred at room temperature for 16 hrs under nitrogen. The solvent was removed and the residue was washed with dichloromethane/petroleum ether, the precipitate was collected to afford methyl 2-(4-(cyclobutane carboxamido)phenyl)-3,3-dimethyl-1,2,3,4-tetrahydroquinoline-6-carboxylate as a yellow solid, 42 mg, yield: 67%.
Reaction SMILES: C(Cl)(=O)C.[NH:5]1[CH2:10][CH:9]=[C:8]([C:11]2[CH:16]=[CH:15][C:14]([NH:17][C:18]([N:20]3[CH2:28][C:27]4[CH:26]=[CH:25][N:24]=[CH:23][C:22]=4[CH2:21]3)=[O:19])=[CH:13][CH:12]=2)[CH2:7][CH2:6]1.NC1C=C2C(=CC=1)CN(C(NC1C=[CH:46][C:45]([C:48](=[O:53])NCCC)=[CH:44]C=1)=O)C2>>[C:48]([N:5]1[CH2:6][CH:7]=[C:8]([C:11]2[CH:16]=[CH:15][C:14]([NH:17][C:18]([N:20]3[CH2:28][C:27]4[CH:26]=[CH:25][N:24]=[CH:23][C:22]=4[CH2:21]3)=[O:19])=[CH:13][CH:12]=2)[CH2:9][CH2:10]1)(=[O:53])[CH:45]([CH3:46])[CH3:44]
Reactant: O=C(Nc1ccc(C2=CCNCC2)cc1)N1Cc2ccncc2C1
Reactant: CCCNC(=O)c1ccc(NC(=O)N2Cc3ccc(N)cc3C2)cc1
Solvent: CC(=O)Cl
Product: CC(C)C(=O)N1CC=C(c2ccc(NC(=O)N3Cc4ccncc4C3)cc2)CC1

Procedure:
The title compound was prepared as described in Example 278, substituting isobutyryl chloride for acetyl chloride and N-(4-(1,2,3,6-tetrahydropyridin-4-yl)phenyl)-1H-pyrrolo[3,4-c]pyridine-2(3H)-carboxamide for 5-amino-N-(4-(propylcarbamoyl)phenyl)isoindoline-2-carboxamide. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.61 (s, 1H), 8.50 (d, J=5.0 Hz, 1H), 8.46 (s, 1H), 7.54-7.57 (m, 2H), 7.43 (d, J=5.1 Hz, 1H), 7.34-7.38 (m, 2H), 6.10-6.13 (bs, 1H), 4.79-4.82 (m, 4H), 4.07-4.21 (m, 2H), 3.67-3.70 (m, 2H), 2.85-3.01 (m, 1H), 2.39-2.55 (m, 2H), 0.97-1.08 (m, 6H); MS (ESI(+)) m/e 391 (M+H)+.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][OH:10].[C:11]1([CH3:21])[CH:16]=[CH:15][C:14]([S:17](Cl)(=[O:19])=[O:18])=[CH:13][CH:12]=1.C(N(CC)CC)C>ClCCl>[CH3:21][C:11]1[CH:16]=[CH:15][C:14]([S:17]([O:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][O:2][CH3:1])(=[O:19])=[O:18])=[CH:13][CH:12]=1
Reactant: COCCCCCCCO
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COCCCCCCCOS(=O)(=O)c1ccc(C)cc1
Temperature: 25 °C
Reaction time: 27.5 h
Yield: 76.6 %

Procedure:
To a mixture of 7-methoxy-1-heptanol (18.1 g) and p-toluenesulfonyl chloride (28.4 g) in dichloromethane (180 ml) was added triethylamine. After stirring for 27.5 hours at room temperature, the solvent was evaporated in vacuo. Then the residue was poured into a mixture of ethyl acetate and water. The organic layer was successively washed with water and brine and dried over magnesium sulfate. The solvent was evaporated in vacuo and the residue was purified by column chromatography on silica gel eluting with a mixture of hexane and ethyl acetate (8:1→5:1). The eluted fractions containing the desired product were collected and evaporated in vacuo to give 7-methoxyheptyl 4-methylbenzenesulfonate (28.5 g).
Reaction SMILES: [CH3:1][CH:2]([N:4]1[C:12](/[CH:13]=[CH:14]/[C@H:15]([OH:24])[CH2:16][C@H:17]([OH:23])[CH2:18][C:19]([O:21]C)=[O:20])=[C:11]([C:25]2[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=2)[C:10]2[C:5]1=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH3:3].[OH-].[Na+:33]>C1COCC1>[CH3:3][CH:2]([N:4]1[C:12](/[CH:13]=[CH:14]/[CH:15]([OH:24])[CH2:16][CH:17]([OH:23])[CH2:18][C:19]([O-:21])=[O:20])=[C:11]([C:25]2[CH:26]=[CH:27][C:28]([F:31])=[CH:29][CH:30]=2)[C:10]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]1=2)[CH3:1].[Na+:33]
Reactant: COC(=O)C[C@@H](O)C[C@@H](O)/C=C/c1c(-c2ccc(F)cc2)c2ccccc2n1C(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CC(C)n1c(/C=C/C(O)CC(O)CC(=O)[O-])c(-c2ccc(F)cc2)c2ccccc21
Temperature: 25 °C
Yield: 39 %

Procedure:
Fluvastatin methyl ester (3.0 g) was dissolved in THF (30 ml) and the NaOH (1 eq.) was added. After 2.5 h hexanes (60 ml) was added and the slurry stirred at room temperature over night. The product was isolated by filtration under nitrogen, washed with hexanes (30 ml) and dried at 50EC in a vacuum oven for 24 h to obtain 1.2 g (39%) of fluvastatin sodium Form CIV.
Reaction SMILES: [H-].[Na+].[C:3]([O:7][C:8]([N:10]1[CH2:23][CH2:22][C:21]2[C:20]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[NH:14][C:13]=2[CH2:12][CH2:11]1)=[O:9])([CH3:6])([CH3:5])[CH3:4].CN(C=O)C.Br[CH2:30][CH2:31][CH2:32][Cl:33]>CCOC(C)=O>[C:3]([O:7][C:8]([N:10]1[CH2:23][CH2:22][C:21]2[C:20]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[N:14]([CH2:30][CH2:31][CH2:32][Cl:33])[C:13]=2[CH2:12][CH2:11]1)=[O:9])([CH3:6])([CH3:4])[CH3:5]
Reactant: ClCCCBr
Reactant: CC(C)(C)OC(=O)N1CCc2[nH]c3ccccc3c2CC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCc2c(n(CCCCl)c3ccccc23)CC1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
Sodium hydride (335 mg, 60%) was added to a solution of 3-tert-butyloxycarbonyl-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole (1.99 g) and DMF (21.0 mL) at 0° C. The solution was stirred at 0° C. for 30 min and then 1-bromo-3-chloropropane (0.74 mL) was added. The solution was stirred at 0° C. for 1 h and 16 h at room temperature. The solution was diluted with EtOAc, which was washed with water (3×20 mL). The combined aqueous layers were extracted with EtOAc (2×20 mL). The combined organic layers were dried (MgSO4), filtered, and concentrated. The crude material was purified by chromatography (Biotage, silica gel, 4:1-1:1 hexane:EtOAc) to give 1.38 g of the title compound as an oil: 1H NMR (300 MHz, CDCl3) δ 7.50, 7.10-7.40, 4.28, 3.55-3.82, 3.52, 2.95-3.10, 2.15-2.30, 1.51; MS (ESI) m/z 363 (M+).
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([NH:7][C:8](=[O:10])[CH3:9])[S:5][CH:6]=1.[Br:11]Br.O>C(O)(=O)C>[Br:11][C:6]1[S:5][C:4]([NH:7][C:8](=[O:10])[CH3:9])=[N:3][C:2]=1[CH3:1]
Reactant: BrBr
Reactant: CC(=O)Nc1nc(C)cs1
Solvent: CC(=O)O
Solvent: O
Product: CC(=O)Nc1nc(C)c(Br)s1
Reaction time: 2 h

Procedure:
To N-(4-methylthiazol-2-yl)acetamide (39.48 g) in acetic acid (200 ml) under a water-ice bath was added dropwise bromine (16 ml). After 2 h, water (500 ml) was added. Filtration, washing with water (3×) and drying gave N-(5-bromo-4-methylthiazol-2-yl) acetamide as off-white solid (52.13 g). H1-NMR (300 MHz, d6-DMSO) 12.27 (s, 1 H), 2.22 (s, 3 H), 2.13 (s, 3 H) ppm.
Reaction SMILES: [H-].[Na+].[CH2:3]([OH:8])[CH2:4][S:5][CH2:6][CH3:7].[Br:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15]Br>CCCCCC.C1COCC1>[CH2:10]([Br:9])[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][O:8][CH2:3][CH2:4][S:5][CH2:6][CH3:7]
Reactant: BrCCCCCCBr
Reactant: CCSCCO
Agent: [H-]
Agent: [Na+]
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CCSCCOCCCCCCBr
Temperature: 25 °C
Reaction time: 1 h
Yield: 31 %

Procedure:
NaH (1.85 g, 0.046 mol) was washed with hexane and then suspended in dry THF (60 mL). 3-Thiapentane-1-ol (4.67 g, 0.04 mol) in THF (20 mL) was added and stirred for 1 h at room temperature. 1,6-Dibromohexane (9.76 g, 0.04 mol) in THF (20 mL) was added and the mixture was refluxed for 20 h. After evaporation of the solvent, the residue was dissolved in ethyl acetetate (200 mL). The organic phase was washed with water (2×50 mL), and dried (Na2SO4). The crude product was purified by Kugelrohr distillation to give 7-oxa-10-thiadodecyl bromide (3.34 g, 31%); bp 48° C. -56° C./0.04 torr; NMR: 1.25 (3H, t, J=7 Hz), 1.2-1.9 (8H, m), 2.59 (2H, q, J=7 Hz), 2.68 (2H, t, J=7 Hz), and 3.2-3.7 ppm (6H, m).