Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([N:8]1[C@H:22]2[C@H:11]([CH2:12][S:13][C@H:14]2[CH2:15][CH2:16][CH2:17][CH2:18][C:19](=[O:21])[OH:20])[N:10](CC2C=CC=CC=2)[C:9]1=[O:30])C1C=CC=CC=1.O.S(=O)(=O)(O)O.[OH-].[Na+]>C1(C)C(C)=CC=CC=1>[OH:21][C:19]([CH2:18][CH2:17][CH2:16][CH2:15][C@H:14]1[C@@H:22]2[C@@H:11]([NH:10][C:9]([NH:8]2)=[O:30])[CH2:12][S:13]1)=[O:20]
Reactant: O=C(O)CCCC[C@@H]1SC[C@H]2[C@@H]1N(Cc1ccccc1)C(=O)N2Cc1ccccc1
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1C
Solvent: O
Product: O=C(O)CCCC[C@@H]1SC[C@@H]2NC(=O)N[C@@H]21
Reaction time: 3 h
Yield: 86.7 %

Procedure:
320 g of crude dibenzylbiotin (containing about 80% of pure dibenzylbiotin, 0.60 mol) are mixed with 125 g of water, and 500 g of sulfuric acid are carefully added with stirring at such a rate that the temperature of the batch does not exceed 115° C. Stirring is then continued at 115° C. for 3 hours. 2.5 l of xylene are added, and the mixture is then firstly neutralized using 5 l of 9% sodium hydroxide solution and then rendered alkaline. The aqueous phase is separated off. The xylene phase is extracted twice more with 0.5 1 of 9% sodium hydroxide solution in each case. The aqueous phase and the sodium hydroxide phases from the post-reactions are combined and adjusted to a pH of 6 at 80° C. using sulfuric acid. 12 g of activated carbon are added, the mixture is subjected to a polishing filtration, and the pH is slowly reduced to 1.5 using sulfuric acid. After the mixture has been cooled overnight, the precipitated biotin is filtered off with suction and dried, giving 128 g of biotin (content: about 99%, corresponding to 126 g of pure biotin=0.52 mol, 86% of theory).
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([NH:8][C:9]([C:11]2[C:15]3[N:16]=[CH:17][N:18]=[C:19]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=4[O:26][CH2:27][CH:28]4[CH2:30][CH2:29]4)[C:14]=3[NH:13][CH:12]=2)=[O:10])[CH2:4][CH2:3]1.[C:31](Cl)(=[O:33])[CH3:32]>>[C:31]([NH:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([NH:8][C:9]([C:11]2[C:15]3[N:16]=[CH:17][N:18]=[C:19]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=4[O:26][CH2:27][CH:28]4[CH2:29][CH2:30]4)[C:14]=3[NH:13][CH:12]=2)=[O:10])[CH2:4][CH2:3]1)(=[O:33])[CH3:32]
Reactant: CC(=O)Cl
Reactant: N[C@H]1CC[C@H](NC(=O)c2c[nH]c3c(-c4ccccc4OCC4CC4)ncnc23)CC1
Product: CC(=O)N[C@H]1CC[C@H](NC(=O)c2c[nH]c3c(-c4ccccc4OCC4CC4)ncnc23)CC1

Procedure:
Starting from trans-4-(2-cyclopropylmethoxy-phenyl)-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylic acid (4-amino-cyclohexyl)-amide (example A161) and acetyl chloride the title compound is obtained as colorless solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[C:11](=[O:17])[CH2:12][CH2:13][C:14]([OH:16])=[O:15].[H-].[Na+].[CH3:20][N:21]([CH3:32])[C:22]1[N:27]=[C:26]([N:28]([CH3:30])[CH3:29])[N:25]=[C:24](Cl)[N:23]=1.Cl>CN(C)C=O.O>[CH3:29][N:28]([CH3:30])[C:26]1[N:27]=[C:22]([N:21]([CH3:32])[CH3:20])[N:23]=[C:24]([N:7]2[C:8]3[C:4](=[CH:3][C:2]([Br:1])=[CH:10][CH:9]=3)[C:5]([C:11](=[O:17])[CH2:12][CH2:13][C:14]([OH:16])=[O:15])=[CH:6]2)[N:25]=1
Reactant: O=C(O)CCC(=O)c1c[nH]c2ccc(Br)cc12
Reactant: CN(C)c1nc(Cl)nc(N(C)C)n1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CN(C)c1nc(N(C)C)nc(-n2cc(C(=O)CCC(=O)O)c3cc(Br)ccc32)n1
Temperature: 70 °C
Reaction time: 0.5 h
Yield: 48.1 %

Procedure:
A solution of 4-(5-bromo-1H-indol-3-yl)-4-oxobutyric acid (148 mg, 0.5 mmol) in anhydrous dimethylformamide (5 mL) was added dropwise to a stirred suspension of sodium hydride (95%, 50 mg, 2.0 mmol) in dimethylformamide (5 mL). After 30 mins, a solution of N2,N2,N4,N4-tetramethyl-6-chloro-[1,3,5]-triazine-2,4-diamine (100 mg, 0.5 mmol) in dimethylformamide (5 mL) was added dropwise. The reaction mixture was stirred at 70° C. for 16 hours, cooled to room temperature and then poured carefully into water (20 mL), acidified to pH 4 with 0.5N hydrochloric acid and extracted with ethyl acetate (3×25 mL). The combined extract was washed with water, brine, dried over anhydrous MgSO4, filtered and concentrated in vacuo. Purification by flash column chromatography (5% methanol in dichloromethane) afforded the title compound as a white solid (111 mg, 48%), Rf: 0.40 (10% methanol in dichloromethane); 1H NMR (DMSO-d6, 300 MHz) δ 8.96 (1H, s, ArH), 8.55 (1H, d, J=9 Hz, ArH), 8.33 (1H, d, J=2 Hz, ArH), 7.47 (1H, dd, J=9, 2 Hz, ArH), 3.22 (2H, t, J=7 Hz, CH2), 3.18 (6H, s, 2×Me), 3.12 (6H, s, 2×Me), 2.59 (2H, t, J=7 Hz, CH2); ESI-LCMS e/z calculated for C19H21BrN6O3 461.318, found 461 [M+H (79Br)]+, 463 [M+H (81Br)]+, 483 [M+Na (79Br)]+, 485 [M+Na (81Br)]+.
Reaction SMILES: [C:1]([NH:4][CH:5]([CH3:15])[CH2:6][C:7]1[CH:14]=[CH:13][C:10]([CH:11]=O)=[CH:9][CH:8]=1)(=[O:3])[CH3:2].C(O)(=O)[CH2:17][C:18]([OH:20])=[O:19]>>[C:1]([NH:4][CH:5]([CH3:15])[CH2:6][C:7]1[CH:14]=[CH:13][C:10]([CH:11]=[CH:17][C:18]([OH:20])=[O:19])=[CH:9][CH:8]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)NC(C)Cc1ccc(C=O)cc1
Reactant: O=C(O)CC(=O)O
Product: CC(=O)NC(C)Cc1ccc(C=CC(=O)O)cc1

Procedure:
The ester hydrochloride used as starting material is prepared in the following manner: N-acetyl-4-acetylamphetamino (m.p. 99°-100° C.) is oxidized to 4-(2-acetamidopropyl)-benzoic acid (m.p. 207°-208° C.), this is reduced to give 4-(2-acetamidopropyl)-benzyl alcohol (oil) which is then oxidized to 4-(2-acetamidopropyl)-benzaldehyde (m.p. 84°-86° C.) and this is condensed with malonic acid to give 4-(2-acetamidopropyl)-cinnamic acid (m.p. 207°-208° C.) which is hydrogenated to give β-[4-(2-acetamidopropyl)-phenyl]-propionic acid (m.p. 93°-96° C.). Subsequent acid hydrolysis gives the hydrochloride of β-[4-(2-aminopropyl)-phenyl]-propionic acid which is esterified to give the above-mentioned ethyl ester hydrochloride.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][CH:8]([N:11]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH:13]=[CH:12]2)[CH2:7][CH2:6]1.C(=O)([O-])[O-].[K+].[K+].Cl.[CH3:27][NH2+:28][CH3:29]>C(O)C>[N:11]1([CH:8]2[CH2:9][CH2:10][N:5]([CH2:4][CH2:3][CH2:2][N:28]([CH3:29])[CH3:27])[CH2:6][CH2:7]2)[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH:13]=[CH:12]1
Reactant: C[NH2+]C
Reactant: ClCCCN1CCC(n2ccc3ccccc32)CC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: CN(C)CCCN1CCC(n2ccc3ccccc32)CC1
Yield: 107.8 %

Procedure:
A mixture of 1-N-[1-N-(3-chloro-propyl)-piperidin-4-yl]-indole (900 mg, 3.25 mmol), anhydrous potassium carbonate (440 mg, 3.25 mmol) and dimethylammonium hydrochloride (260 mg, 3.25 mmol) in absolute ethanol (10 mL) was refluxed for 6 hours, evaporated and suspended in water. The mixture was extracted with methylene chloride, dried over anhydrous potassium carbonate, and evaporated to yield 1 g of the desired compound (100% of theory).
Reaction SMILES: Cl.[NH2:2][OH:3].[CH2:4]([C:7]1[C:14]([OH:15])=[CH:13][C:12]([CH2:16][CH:17]=[CH2:18])=[C:11]([OH:19])[C:8]=1[CH:9]=O)[CH:5]=[CH2:6].C(O)C>O>[CH2:4]([C:7]1[C:14]([OH:15])=[CH:13][C:12]([CH2:16][CH:17]=[CH2:18])=[C:11]([OH:19])[C:8]=1[CH:9]=[N:2][OH:3])[CH:5]=[CH2:6]
Reactant: NO
Reactant: C=CCc1cc(O)c(CC=C)c(C=O)c1O
Agent: Cl
Solvent: O
Solvent: CCO
Product: C=CCc1cc(O)c(CC=C)c(C=NO)c1O

Procedure:
Hydroxylamine hydrochloride (2 g) was dissolved in 20 ml of water and added to 2,5-diallyl-3,6-dihydroxybenzaldehyde (2 g). Enough ethanol was added to completely solubilise the aldehyde. The mixture was heated on a steam bath for ten minutes until TLC showed the reaction to be complete. The water and ethanol were evaporated and the solid recrystallised from ethanol/water, to give a beige solid, m.p. 241°-243° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:15][CH2:14][C:11]2([O:13][CH2:12]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].B(F)(F)[F:17].CCOCC>[OH-].[Na+]>[C:1]([O:5][C:6]([N:8]1[CH2:15][CH2:14][C:11]([F:17])([CH2:12][OH:13])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCC2(CC1)CO2
Reactant: FB(F)F
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Product: CC(C)(C)OC(=O)N1CCC(F)(CO)CC1
Reaction time: 1 h

Procedure:
A mixed solution of 6-aza-1-oxaspiro[2.5]octane-6-carboxylic acid tert-butyl ester (10.0 g, 46.9 mmol) in benzene-ether (2:1) (750 mL) was cooled to 0° C., and after adding BF3.OEt2 (29.6 mL, 234 mmol) to the solution, it was stirred 1 hour. The reaction mixture was poured into ice-cooled 1N NaOH (500 ml) and stirred. After extraction with AcOEt (500 ml×3 times), the extract was washed with water and then with saturated brine, and finally dried over anhydrous MgSO4. The solvent was distilled off, and the crude product was purified by silica gel column chromatography (30% AcOEt/hexane) to obtain 4-fluoro-4-(hydroxymethyl)piperidinecarboxylic acid tert-butyl ester. The compound was identified by 1H-NMR. The yield was 4.26 g (39%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:14]2[N:23]=[C:22]([NH:24][C:25]3[CH:26]=[C:27]4[C:31](=[CH:32][CH:33]=3)[N:30]([C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[N:29]=[CH:28]4)[C:21]3[C:16](=[CH:17][C:18]([O:42][CH3:43])=[C:19]([OH:41])[CH:20]=3)[N:15]=2)[CH:5]=[CH:6][C:7]=1[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.Br[CH2:45][CH2:46][Cl:47].C([O-])([O-])=O.[K+].[K+].O>CN(C=O)C>[Cl:47][CH2:46][CH2:45][O:41][C:19]1[CH:20]=[C:21]2[C:16](=[CH:17][C:18]=1[O:42][CH3:43])[N:15]=[C:14]([C:4]1[CH:5]=[CH:6][C:7]([C:8]3[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=3)=[C:2]([F:1])[CH:3]=1)[N:23]=[C:22]2[NH:24][C:25]1[CH:26]=[C:27]2[C:31](=[CH:32][CH:33]=1)[N:30]([C:34]([O:36][C:37]([CH3:38])([CH3:39])[CH3:40])=[O:35])[N:29]=[CH:28]2
Reactant: COc1cc2nc(-c3ccc(-c4ccccc4)c(F)c3)nc(Nc3ccc4c(cnn4C(=O)OC(C)(C)C)c3)c2cc1O
Reactant: ClCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1cc2nc(-c3ccc(-c4ccccc4)c(F)c3)nc(Nc3ccc4c(cnn4C(=O)OC(C)(C)C)c3)c2cc1OCCCl
Temperature: 85 °C
Yield: 54.5 %

Procedure:
A mixture of tert-butyl 5-(2-(3-fluoro-4-(phenyl)phenyl)-6-hydroxy-7-methoxyquinazolin-4-ylamino)-1H-indazole-1-carboxylate (0.61 g, 1.06 mmol), 1-bromo-2-chloro ethane (0.475 g, 3.31 mmol) and K2CO3 (0.533 g, 3.86 mmol) in DMF (5 mL) was heated at 85° C. for 2.5 h. the mixture was allowed to cool to RT upon which, it was poured into water. A solid separated out which was collected via filtration and dried under vacuum. The residue was purified via preparative TLC (SiO2, CH2Cl2:MeOH 9:1) to give the desired compound tert-butyl 5-(6-(2-chloroethoxy)-2-(3-fluoro-4-(phenyl)phenyl)-7-methoxyquinazolin-4-ylamino)-1H-indazole-1-carboxylate (0.37 g, 0.578 mmol, 55%). MS 640.3 (M+1 Cl isotope pattern).
Reaction SMILES: C(OC([N:8]([C:17]1([C:24]([O:26][CH2:27][CH3:28])=[O:25])[CH2:21][C:20](=[O:22])[NH:19][C:18]1=[O:23])NC(OC(C)(C)C)=O)=O)(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[NH2:8][C:17]1([C:24]([O:26][CH2:27][CH3:28])=[O:25])[CH2:21][C:20](=[O:22])[NH:19][C:18]1=[O:23]
Reactant: CCOC(=O)C1(N(NC(=O)OC(C)(C)C)C(=O)OC(C)(C)C)CC(=O)NC1=O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCOC(=O)C1(N)CC(=O)NC1=O
Temperature: 25 °C
Reaction time: 6 h
Yield: 64.9 %

Procedure:
To a solution of the compound of Example 4 (970 mg) in dichloromethane (8 ml) was added trifluoroacetic acid (4 ml) and the mixture was stirred at room temperature for 6 hours. The reaction mixture was concentrated and to the resulting residue was added toluene to remove azeotropically the residual trifluoroacetic acid and then the mixture was concentrated again. The residue was dissolved in ethanol (25 ml) and thereto was added an appropriate amount of Raney nickel. This mixture was stirred vigorously at 40° C. under hydrogen (atmospheric pressure) for 24 hours. To the reaction mixture was added water (20 ml) and the mixture was filtered through a Celite pad and then the Celite was washed with ethanol. The mixture of the filtrate combined with the washers was adjusted to pH 7-8 with sodium bicarbonate and then thereto was added pH 7.4 phosphate buffer solution. This mixture was extracted with ethyl acetate and the extract was dried over magnesium sulfate and filtered. The filtrate was concentrated to give an oil which was then purified by a flash column chromatography (chloroform:methanol=20:1→10:1) to give the desired product (292 mg, 65%) as crystal.
Reaction SMILES: [CH3:1][S:2][C:3]1[C:4]2[C:5]([CH2:22][C:23]3[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=3)=[CH:6][N:7]([Si](C(C)C)(C(C)C)C(C)C)[C:8]=2[CH:9]=[CH:10][CH:11]=1.CCCC[N+](CCCC)(CCCC)CCCC.[F-].O>C1COCC1>[CH3:1][S:2][C:3]1[C:4]2[C:5]([CH2:22][C:23]3[CH:24]=[CH:25][C:26]([Cl:29])=[CH:27][CH:28]=3)=[CH:6][NH:7][C:8]=2[CH:9]=[CH:10][CH:11]=1
Reactant: CSc1cccc2c1c(Cc1ccc(Cl)cc1)cn2[Si](C(C)C)(C(C)C)C(C)C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: O
Solvent: C1CCOC1
Product: CSc1cccc2[nH]cc(Cc3ccc(Cl)cc3)c12
Temperature: 0 °C
Reaction time: 0.02 h
Yield: 56.6 %

Procedure:
To a solution of the indole of Step 5 (1.9 g, 4.3 mmol) in THF (20 ml at 0° C. was added 1M TBAF (7 mL, 6 mmol). The reaction mixture was stirred for 1 minutes at 0° C. and water was added. The phases were separated and the aqueous layer was extracted with Et2O. The combined organic layers were dried over MgSO and concentrated The residue was purified by silica gel chromatography eluted with 20% EtOAc in Hexanes to provide 700 mg of the title compound as a pale yellow oil.
Reaction SMILES: [N:1]1[N:2]=[C:3]([CH2:13][C@H:14]([NH:25]C(=O)C)[CH2:15][C:16]2[CH:21]=[C:20]([F:22])[C:19]([F:23])=[CH:18][C:17]=2[F:24])[N:4]2[CH:9]=[CH:8][C:7]3=[N:10][CH:11]=[N:12][N:6]3[C:5]=12>Cl>[N:1]1[N:2]=[C:3]([CH2:13][C@H:14]([NH2:25])[CH2:15][C:16]2[CH:21]=[C:20]([F:22])[C:19]([F:23])=[CH:18][C:17]=2[F:24])[N:4]2[CH:9]=[CH:8][C:7]3=[N:10][CH:11]=[N:12][N:6]3[C:5]=12
Reactant: CC(=O)N[C@H](Cc1cc(F)c(F)cc1F)Cc1nnc2n1ccc1ncnn12
Agent: Cl
Product: N[C@H](Cc1cc(F)c(F)cc1F)Cc1nnc2n1ccc1ncnn12

Procedure:
A solution of 26.1 mg (0.067 mmol) of N-[(1R)-2-bis[1,2,4]triazolo[1,5-c:4′,3′-a]pyrimidin-3-yl-1-(2,4,5-trifluorobenzyl)ethyl]acetamide in 3 mL of 6N hydrochloric acid was stirred at reflux under nitrogen for 12 h. The solution was evaporated to dryness, and the residue was purified by preparative thin-layer chromatography on silica gel (90:10:1 dichloromethane:methanol:concentrated ammonium hydroxide) to give the title compound as a white solid. LC-MS 348 (M+1).
Reaction SMILES: [C:1]([C:4]1[C:5]([CH2:28]Br)=[N:6][C:7]2[C:12]([C:13]=1[C:14]1[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[C:16]([O:22][CH3:23])[CH:15]=1)=[CH:11][C:10]([O:24][CH3:25])=[C:9]([O:26][CH3:27])[CH:8]=2)(=[O:3])[CH3:2].[C:30]([NH:34][CH2:35][CH3:36])([CH3:33])([CH3:32])[CH3:31]>>[C:1]([C:4]1[C:5]([CH2:28][N:34]([C:30]([CH3:33])([CH3:32])[CH3:31])[CH2:35][CH3:36])=[N:6][C:7]2[C:12]([C:13]=1[C:14]1[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[C:16]([O:22][CH3:23])[CH:15]=1)=[CH:11][C:10]([O:24][CH3:25])=[C:9]([O:26][CH3:27])[CH:8]=2)(=[O:3])[CH3:2]
Reactant: COc1ccc(-c2c(C(C)=O)c(CBr)nc3cc(OC)c(OC)cc23)cc1OC
Reactant: CCNC(C)(C)C
Product: CCN(Cc1nc2cc(OC)c(OC)cc2c(-c2ccc(OC)c(OC)c2)c1C(C)=O)C(C)(C)C

Procedure:
According to the same manner as that described in Example 1, 3-acetyl-2-bromomethyl-4-(3,4-dimethoxyphenyl)-6,7-dimethoxyquinoline was reacted with N-tert-butyl-N-ethylamine to give 3-acetyl-2-(N-tert-butyl-N-ethylaminomethyl)-4-(3,4-dimethoxyphenyl)-6,7-dimethoxyquinoline. This compound was recrystallized from methanol to give colorless prisms. mp. 156°-157° C.
Reaction SMILES: [Br:1][C:2]1[S:12][C:5]2[N:6]=[C:7]([CH3:11])[CH:8]=[C:9]([NH2:10])[C:4]=2[C:3]=1[C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([O:19][CH3:20])[CH:14]=1.CC(C)([O-])C.[Na+].[Cl:27][C:28]1[CH:29]=[C:30]([S:34](Cl)(=[O:36])=[O:35])[CH:31]=[CH:32][CH:33]=1>CN(C=O)C.C(OCC)(=O)C.C([O-])(O)=O.[Na+]>[Br:1][C:2]1[S:12][C:5]2=[N:6][C:7]([CH3:11])=[CH:8][C:9]([NH:10][S:34]([C:30]3[CH:31]=[CH:32][CH:33]=[C:28]([Cl:27])[CH:29]=3)(=[O:36])=[O:35])=[C:4]2[C:3]=1[C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([O:19][CH3:20])[CH:14]=1
Reactant: COc1cccc(-c2c(Br)sc3nc(C)cc(N)c23)c1
Reactant: O=S(=O)(Cl)c1cccc(Cl)c1
Agent: CC(C)(C)[O-]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COc1cccc(-c2c(Br)sc3nc(C)cc(NS(=O)(=O)c4cccc(Cl)c4)c23)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 64.8 %

Procedure:
Alternatively, to a stirred solution of 2-bromo-6-methyl-3-[3-(methyloxy)phenyl]thieno-[2,3-b]pyridin-4-amine (460 mg, 1.317 mmol) (Description 17) in DMF (10 mL) was added sodium tert-butoxide (316 mg, 3.29 mmol) and 3-chlorobenzenesulfonyl chloride (0.371 mL, 2.63 mmol). The reaction mixture was stirred at RT under nitrogen for 1 h. The reaction mixture was then diluted with ethyl acetate (25 mL) and NaHCO3 (50 mL). The organic layer was then separated and the aqueous layer re-extracted with ethyl acetate (2×20 mL). The combined organic layer was dried over Na2SO4 and the solvent concentrated in vacuo. Purification by chromatography on silica gel, eluting with a gradient of 0-50% ethyl acetate in cyclohexane, afforded the title compound (447 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([CH3:36])[C:12]([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=3)([CH3:13])[N:11]([C:21](Cl)=[O:22])[C:10]([C:24]3[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][C:25]=3[O:32][CH:33]([CH3:35])[CH3:34])=[N:9]2)=[CH:4][CH:3]=1.[N:37]1([C:43](=[O:51])[CH2:44][N:45]2[CH2:50][CH2:49][NH:48][CH2:47][CH2:46]2)[CH2:42][CH2:41][O:40][CH2:39][CH2:38]1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@@:8]2([CH3:36])[C@:12]([C:14]3[CH:15]=[CH:16][C:17]([Cl:20])=[CH:18][CH:19]=3)([CH3:13])[N:11]([C:21]([N:48]3[CH2:47][CH2:46][N:45]([CH2:44][C:43]([N:37]4[CH2:38][CH2:39][O:40][CH2:41][CH2:42]4)=[O:51])[CH2:50][CH2:49]3)=[O:22])[C:10]([C:24]3[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][C:25]=3[O:32][CH:33]([CH3:34])[CH3:35])=[N:9]2)=[CH:4][CH:3]=1
Reactant: COc1ccc(C2=NC(C)(c3ccc(Cl)cc3)C(C)(c3ccc(Cl)cc3)N2C(=O)Cl)c(OC(C)C)c1
Reactant: O=C(CN1CCNCC1)N1CCOCC1
Product: COc1ccc(C2=N[C@@](C)(c3ccc(Cl)cc3)[C@@](C)(c3ccc(Cl)cc3)N2C(=O)N2CCN(CC(=O)N3CCOCC3)CC2)c(OC(C)C)c1

Procedure:
In a manner analogous to the method described in example 5, rac-(4S*,5R*)-4,5-bis-(4-chloro-phenyl)-2-(2-isopropoxy-4-methoxy-phenyl)-4,5-dimethyl-4,5-dihydro-imidazole-1-carbonyl chloride was reacted with 1-morpholin-4-yl-2-piperazin-1-yl-ethanone (Oakwood Products) to give the title compound. HR-MS (ES, m/z) calculated for C38H46N5O5Cl2 [(M+H)+] 722.2871, observed 722.2874.
Reaction SMILES: Cl.[F:2][C:3]1[CH:4]=[C:5]([CH:17]=[CH:18][CH:19]=1)[CH2:6][CH:7]1[C:15](=[O:16])[N:10]2[CH2:11][CH2:12][NH:13][CH2:14][C@@H:9]2[CH2:8]1.[F:20][C:21]([F:33])([F:32])[C:22]1[CH:27]=[CH:26][C:25]([S:28](Cl)(=[O:30])=[O:29])=[CH:24][CH:23]=1.C(N(CC)CC)C>C(Cl)Cl>[F:2][C:3]1[CH:4]=[C:5]([CH:17]=[CH:18][CH:19]=1)[CH2:6][CH:7]1[C:15](=[O:16])[N:10]2[CH2:11][CH2:12][N:13]([S:28]([C:25]3[CH:24]=[CH:23][C:22]([C:21]([F:20])([F:32])[F:33])=[CH:27][CH:26]=3)(=[O:30])=[O:29])[CH2:14][C@@H:9]2[CH2:8]1
Reactant: O=C1C(Cc2cccc(F)c2)C[C@H]2CNCCN12
Reactant: O=S(=O)(Cl)c1ccc(C(F)(F)F)cc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C1C(Cc2cccc(F)c2)C[C@H]2CN(S(=O)(=O)c3ccc(C(F)(F)F)cc3)CCN12
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 93.9 %

Procedure:
The product from Example 213B (20 mg, 0.070 mmol) was suspended in CH2Cl2 (0.5 mL), 4-(trifluoromethyl)benzene-1-sulfonyl chloride (21 mg, 0.084 mmol) and triethylamine (0.049 mL, 0.35 mmol) were added, and the resulting mixture was stirred at room temperature for 90 minutes. The mixture was partitioned between water and CH2Cl2, and the organic layer was dried over Na2SO4. The drying agent was removed by filtration, and the filtrate was concentrated in vacuo. The crude product was purified by column chromatography on silica gel using a solvent gradient of 0-5% CH3OH in CH2Cl2 to give the title compound (30 mg, 94%). 1H NMR (300 MHz, CDCl3) δ ppm 1.16-1.51 (m, 1H) 1.59-1.72 (m, 1H) 1.88-2.03 (m, 1H) 2.09-2.32 (m, 1H) 2.64-3.12 (m, 4H) 3.27-3.64 (m, 1H) 3.73-3.86 (m, 2H) 4.11 (dd, J=13.22, 2.37 Hz, 1H) 6.68-6.98 (m, 3H) 7.08-7.29 (m, 1H) 7.77-7.89 (m, 4H); MS (ESI) m/z 457 (M+H)+.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([NH:13][C:14]2[C:19]([C:20]([F:23])([F:22])[F:21])=[CH:18][N:17]=[C:16]([NH:24][C:25]3[CH:39]=[CH:38][C:28]([CH2:29][P:30](=[O:37])([O:34][CH2:35][CH3:36])[O:31][CH2:32][CH3:33])=[CH:27][C:26]=3[O:40][CH3:41])[N:15]=2)=[C:6]2[C:10]=1[CH2:9][N:8]([CH3:11])[C:7]2=[O:12].C([O:46][C:47](=[O:55])[CH2:48][N:49]1[CH2:54][CH2:53][NH:52][CH2:51][CH2:50]1)(C)(C)C>>[CH2:35]([O:34][P:30]([CH2:29][C:28]1[CH:38]=[CH:39][C:25]([NH:24][C:16]2[N:15]=[C:14]([NH:13][C:5]3[CH:4]=[CH:3][C:2]([N:52]4[CH2:51][CH2:50][N:49]([CH2:48][C:47]([OH:46])=[O:55])[CH2:54][CH2:53]4)=[C:10]4[C:6]=3[C:7](=[O:12])[N:8]([CH3:11])[CH2:9]4)[C:19]([C:20]([F:21])([F:23])[F:22])=[CH:18][N:17]=2)=[C:26]([O:40][CH3:41])[CH:27]=1)([O:31][CH2:32][CH3:33])=[O:37])[CH3:36]
Reactant: CC(C)(C)OC(=O)CN1CCNCC1
Reactant: CCOP(=O)(Cc1ccc(Nc2ncc(C(F)(F)F)c(Nc3ccc(Br)c4c3C(=O)N(C)C4)n2)c(OC)c1)OCC
Product: CCOP(=O)(Cc1ccc(Nc2ncc(C(F)(F)F)c(Nc3ccc(N4CCN(CC(=O)O)CC4)c4c3C(=O)N(C)C4)n2)c(OC)c1)OCC

Procedure:
The title compound was prepared according to the procedure for Example 251 using diethyl [4-({4-[(7-bromo-2-methyl-3-oxo-2,3-dihydro-1H-isoindol-4-yl)amino]-5-(trifluoromethyl) pyrimidin-2-yl}amino)-3-methoxybenzyl]phosphonate and piperazine-1-acetic acid tert-butyl ester. MS (ES+): m/z 722.28 (100) [MH+]; HPLC: tR=0.80 min (UPLC, purity).
Reaction SMILES: C[C:2]1[C:14]2[CH2:13][C:12]3[C:7](=[CH:8][CH:9]=[C:10](N)[CH:11]=3)[C:6]=2[CH:5]=[CH:4][C:3]=1[CH2:16][C:17]([OH:19])=[O:18].Cl.N([O-])=[O:22].[Na+].S(=O)(=O)(O)O>O>[OH:22][C:9]1[CH:8]=[C:7]2[C:12]([C:13]3[CH:5]=[CH:4][C:3]([CH2:16][C:17]([OH:19])=[O:18])=[CH:2][C:14]=3[CH2:6]2)=[CH:11][CH:10]=1
Reactant: Cc1c(CC(=O)O)ccc2c1Cc1cc(N)ccc1-2
Reactant: O=N[O-]
Agent: Cl
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Product: O=C(O)Cc1ccc2c(c1)Cc1cc(O)ccc1-2
Reaction time: 2 h

Procedure:
A solution of 14.5g. of methyl 7-aminofluorene-2-acetic acid in 380ml. of water containing 14ml. of concentrated hydrochloric acid is cooled to 2° and a solution of 3.63g. of sodium nitrite in 15ml. of water added dropwise while stirring. The diazonium solution is added over a 1 hour period while stirring to a refluxing solution of 1.1 liters of water containing 18ml. of sulfuric acid. The mixture is cooled and the solid collected by filtration. The solid is refluxed with 120ml. of 10% aqueous potassium hydroxide solution for 2 hr., and treated with Darco. The suspension is filtered, acidified with hydrochloric acid and the solid collected by filtration, dried, and crystallized from acetonitrile to give 9.4g. of the title compound, 240°-241° C.
Reaction SMILES: C(O[C:4]1[C:5](=[O:12])[C:6](=[O:11])[C:7]=1[O:8][CH2:9][CH3:10])C.[NH2:13][C@@H:14]([C:16]([CH3:19])([CH3:18])[CH3:17])[CH3:15]>C(O)C>[CH2:9]([O:8][C:7]1[C:6](=[O:11])[C:5](=[O:12])[C:4]=1[NH:13][C@H:14]([CH3:15])[C:16]([CH3:19])([CH3:18])[CH3:17])[CH3:10]
Reactant: CCOc1c(OCC)c(=O)c1=O
Reactant: C[C@@H](N)C(C)(C)C
Solvent: CCO
Product: CCOc1c(N[C@H](C)C(C)(C)C)c(=O)c1=O
Temperature: 25 °C
Reaction time: 24 h
Yield: 74 %

Procedure:
A solution of 3,4-diethoxy-3-cyclobutene-1,2-dione (10 g, 59 mmol) and (R)-2-amino-3,3-dimethylbutane (353 mL of a 0.2M solution in absolute ethanol, 71 mmol) was stirred at room temperature for 24 hours. Another portion of (R)-2-amino-3,3-dimethylbutane (150 mL of a 0.2M solution in absolute ethanol, 30 mmol) was added and the resulting solution was stirred at room temperature for 24 hours. The slurry was filtered, and the filtrate concentrated under reduced pressure. The resulting solid was trituated with hexane:ethyl acetate (150:5 mL), then washed with hexane to give 9.78 g (74%) of (R)-3-ethoxy-4-(1,2,2-trimethyl-propylamino)-cyclobut-3-ene-1,2-dione as a white solid: 1H NMR: (DMSO-d6): δ 8.72 and 8.50 (two d, 1H, rotamers), 4.65 (m, 2H), 3.90 and 3.42 (two m, 1H, rotamers), 1.37 and 1.35 (two overlapping t, 3H, rotamers), 1.10 (two overlapping d, 3H, rotamers), 0.85 and 0.84 (two s, 9H, rotamers) ppm. IR (KBr): 3150, 2950, 1800, 1700 cm-1 ; MS (m/z): 225 (M+).