Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([S:7][CH:8]=[C:9]([CH3:11])[CH3:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[N+](=[CH:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])=[N-]>C1CCCCC1>[C:1]1([S:7][CH:8]2[CH:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[C:9]2([CH3:11])[CH3:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CCOC(=O)C=[N+]=[N-]
Reactant: CC(C)=CSc1ccccc1
Solvent: C1CCCCC1
Product: CCOC(=O)C1C(Sc2ccccc2)C1(C)C
Reaction time: 7 h

Procedure:
To a mixture of 1.94 g (11.8 mmol) of 2-methyl-1-propenyl phenyl sulfide, 200 mg anhydrous cupric sulfate and 10 ml cyclohexane heated under reflux is added, dropwise and with stirring over a 7 hr period, a solution of 6.58 g (58 mmol) of ethyl diazoacetate in 40 ml cyclohexane. After addition is complete, refluxing and stirring is continued for an additional 2 hr, and then the reaction mixture is filtered, dried and solvent is removed in vacuo to give ethyl 3-phenylthio-2,2-dimethylcyclopropanecarboxylate.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([N:8]2[CH2:30][CH2:29][C:10]3([CH2:13][CH:12]([NH:14][C:15]([O:17][CH2:18][C:19]4[O:23][N:22]=[C:21]([C:24]([O:26][CH2:27][CH3:28])=[O:25])[CH:20]=4)=[O:16])[CH2:11]3)[CH2:9]2)=[N:6][CH:7]=1.[F:31][C:32]1[CH:37]=[CH:36][C:35](B(O)O)=[CH:34][CH:33]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>C(Cl)Cl>[F:31][C:32]1[CH:37]=[CH:36][C:35]([C:2]2[CH:3]=[CH:4][C:5]([N:8]3[CH2:30][CH2:29][C:10]4([CH2:11][CH:12]([NH:14][C:15]([O:17][CH2:18][C:19]5[O:23][N:22]=[C:21]([C:24]([O:26][CH2:27][CH3:28])=[O:25])[CH:20]=5)=[O:16])[CH2:13]4)[CH2:9]3)=[N:6][CH:7]=2)=[CH:34][CH:33]=1
Reactant: OB(O)c1ccc(F)cc1
Reactant: CCOC(=O)c1cc(COC(=O)NC2CC3(CCN(c4ccc(Br)cn4)C3)C2)on1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: ClCCl
Product: CCOC(=O)c1cc(COC(=O)NC2CC3(CCN(c4ccc(-c5ccc(F)cc5)cn4)C3)C2)on1
Yield: 45.6 %

Procedure:
The process is performed according to the procedure described in Example 2 (step 2.7.). Starting with 0.68 g (1.42 mmol) of ethyl 5-[6-(5-bromopyridin-2-yl)-6-azaspiro[3.4]oct-2-ylcarbamoyloxymethyl]isoxazole-3-carboxylate (isomer 6′) and 0.23 g (1.70 mmol) of 4-fluorophenylboronic acid, 1.38 g (4.26 mmol) of caesium carbonate and 0.11 g (0.14 mmol) of PdCl2dppf.CH2Cl2, 0.32 g of a white solid is obtained.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4]([C:20]1[CH:25]=[C:24]([F:26])[C:23]([F:27])=[CH:22][C:21]=1O)([CH2:18][OH:19])[C:5](=[O:17])[N:6]2[CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13].C1(CCN2C3C(=CC=CC=3)C(C3C(O)=CC4OCOC=4C=3)(CO)C2=O)CC1>>[Br:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4]1([C:20]3[CH:25]=[C:24]([F:26])[C:23]([F:27])=[CH:22][C:21]=3[O:19][CH2:18]1)[C:5](=[O:17])[N:6]2[CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13]
Reactant: CCOC(=O)CN1C(=O)C(CO)(c2cc(F)c(F)cc2O)c2c(Br)cccc21
Agent: O=C1N(CCC2CC2)c2ccccc2C1(CO)c1cc2c(cc1O)OCO2
Product: CCOC(=O)CN1C(=O)C2(COc3cc(F)c(F)cc32)c2c(Br)cccc21
Yield: 81 %

Procedure:
Following the procedure as described in EXAMPLE 1, and making non-critical variations using ethyl [4-bromo-3-(4,5-difluoro-2-hydroxyphenyl)-3-(hydroxymethyl)-2-oxo-2,3-dihydro-1H-indol-1-yl]acetate to replace 1-(2-cyclopropylethyl)-3-(6-hydroxy-1,3-benzodioxol-5-yl)-3-(hydroxymethyl)-1,3-dihydro-2H-indol-2-one, the title compound was obtained in 81% yield: MS (ES+) m/z 438.4 (M+1), 440.4 (M+1).
Reaction SMILES: [C:1]([CH:5]1[CH2:10][CH2:9][CH:8]([C:11]2[CH:12]=[C:13]([NH:17][C:18](=[O:29])[CH2:19][C:20]3[CH:25]=[CH:24][C:23]([OH:26])=[C:22]([O:27][CH3:28])[CH:21]=3)[CH:14]=[CH:15][CH:16]=2)[CH2:7][CH2:6]1)([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[C:37](Cl)(=[O:39])[CH3:38]>CN(C)C1C=CN=CC=1.C(Cl)Cl>[C:37]([O:26][C:23]1[CH:24]=[CH:25][C:20]([CH2:19][C:18]([NH:17][C:13]2[CH:14]=[CH:15][CH:16]=[C:11]([CH:8]3[CH2:9][CH2:10][CH:5]([C:1]([CH3:4])([CH3:2])[CH3:3])[CH2:6][CH2:7]3)[CH:12]=2)=[O:29])=[CH:21][C:22]=1[O:27][CH3:28])(=[O:39])[CH3:38]
Reactant: CC(=O)Cl
Reactant: COc1cc(CC(=O)Nc2cccc(C3CCC(C(C)(C)C)CC3)c2)ccc1O
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1cc(CC(=O)Nc2cccc(C3CCC(C(C)(C)C)CC3)c2)ccc1OC(C)=O
Temperature: 25 °C
Reaction time: 18 h
Yield: 81.4 %

Procedure:
N-[3-(4-tert-Butylcyclohexan-1-yl)phenyl]-4-hydroxy-3-methoxyphenylacetamide (100 mg) obtained in Example 20, triethylamine (94 mg) and 4-dimethylaminopyridine (5 mg) are dissolved in methylene chloride (5 ml), and thereto is added dropwise acetyl chloride (40 mg) under ice-cooling. The mixture is stirred at 25° C. for 18 hours, and the reaction solution is washed with water. The organic layer is dried over sodium sulfate, and the solvent is evaporated under reduced pressure. The residue is purified by silica gel column chromatography (eluent: gradient from 0% to 100% hexane/ethyl acetate) to give the desired compound (90 mg).
Reaction SMILES: [Br:1][C:2]1[CH:30]=[CH:29][C:5]([CH2:6][N:7]2[C:12](=[O:13])[C:11]([C:14]([NH:16][CH2:17][C:18]([O:20]C(C)(C)C)=[O:19])=[O:15])=[C:10]([OH:25])[C:9]3[CH2:26][S:27][CH2:28][C:8]2=3)=[CH:4][CH:3]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][N:7]2[C:12](=[O:13])[C:11]([C:14]([NH:16][CH2:17][C:18]([OH:20])=[O:19])=[O:15])=[C:10]([OH:25])[C:9]3[CH2:26][S:27][CH2:28][C:8]2=3)=[CH:29][CH:30]=1
Reactant: CC(C)(C)OC(=O)CNC(=O)c1c(O)c2c(n(Cc3ccc(Br)cc3)c1=O)CSC2
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(O)CNC(=O)c1c(O)c2c(n(Cc3ccc(Br)cc3)c1=O)CSC2
Temperature: 40 °C

Procedure:
To tert-butyl N-{[1-(4-bromobenzyl)-4-hydroxy-2-oxo-1,2,5,7-tetrahydrothieno[3,4-b]pyridin-3-yl]carbonyl}glycinate (prepared in similar fashion to Reference Example 3 and the preceding Reference Examples, 1.007 g, 2.033 mmol) was added CH2Cl2 (10.0 mL) and TFA (2.0 mL) at rt. After 1 hr the reaction was heated to 40° C. for an additional 4 h. The reaction was concentrated and then diluted with Et2O and MeOH to crystallize the sample. The liquid was decanted away and the solid was washed twice with hexane to afford the title compound. HPLC/MS: 438.9.0 (M+1); Rt=3.38 min.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:15])/[CH:10]=[CH:11]\[C:12]([OH:14])=[O:13])=[CH:4][CH:3]=1.[OH-].[Na+:17]>O>[NH2:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9](=[O:15])/[CH:10]=[CH:11]\[C:12]([O-:14])=[O:13])=[CH:6][CH:7]=1.[Na+:17]
Reactant: Nc1ccc(NC(=O)/C=C\C(=O)O)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Nc1ccc(NC(=O)/C=C\C(=O)[O-])cc1
Temperature: 5 °C
Reaction time: 8 h

Procedure:
Under a nitrogen atmosphere, into a reaction vessel were charged 195.5 g (1.81 mol) of 1,4-phenylenediamine and 3000 ml of tetrahydrofuran. A solution prepared by dissolving 118.1 g (1.20 mol) of maleic anhydride in 1200 ml of tetrahydrofuran was dropped into this under cooling with ice over a period of about 3 hours, then, the mixture was stirred at room temperature overnight. After completion of the reaction, the deposited crystal was isolated by filtration, washed twice with 250 ml of tetrahydrofuran, and dried at 40° C. to obtain 241.8 g of coarse (2Z)-4-[(4-aminophenyl)amino]-4-oxo-2-butenoic acid as a yellow-orange powder. To 241.8 g of coarse (2Z)-4-[(4-aminophenyl)amino]-4-oxo-2-butenoic acid was added 484 ml of water, and the mixture was cooled to 0 to 10° C., and 216 ml of a 5N sodium hydroxide aqueous solution was dropped, then, 21 ml of a 1N sodium hydroxide aqueous solution was dropped. Thereafter, the solvent was distilled off under reduced pressure to obtain a residue to which 200 ml of 2-propanol was added, and the solvent was distilled off under reduced pressure again. To the resultant yellow-brown solid was added 800 ml of tetrahydrofuran, the mixture was stirred at room temperature overnight, and the solid was isolated by filtration, washed three times with 100 ml of tetrahydrofuran and dried, to obtain 279 g of coarse sodium (2Z)-4-[(4-aminophenyl)amino]-4-oxo-2-butenoate. Coarse sodium (2Z)-4-[(4-aminophenyl)amino]-4-oxo-2-butenoate (279 g) was bisected, 2800 ml of methanol was added to each portion, refluxed with heating for 1 hour, then, hot-filtrated to remove insoluble materials. The filtrates were condensed under reduced pressure, and the resultant solids were combined, 750 ml of tetrahydrofuran was added and the mixture was stirred at room temperature overnight, thermally insulated at 50° C. for 30 minutes, then, hot-filtrated. The resultant solid was washed three times with 150 ml of tetrahydrofuran, dried under reduced pressure at 45° C. for 5 hours, to obtain 264.6 g of sodium (2Z)-4-[(4-aminophenyl)amino]-4-oxo-2-butenoate methanol solvate as a pale brown-white powder. Yield: 84.5%.
Reaction SMILES: [O:1]=[C:2]1[N:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[C:5]([C:14]([O:16]C)=[O:15])[CH:4]=[CH:3]1.[OH-].[Li+]>CO.O>[O:1]=[C:2]1[N:7]([C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:6]=[C:5]([C:14]([OH:16])=[O:15])[CH:4]=[CH:3]1
Reactant: COC(=O)c1ccc(=O)n(-c2ccccc2)c1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C(O)c1ccc(=O)n(-c2ccccc2)c1
Temperature: 50 °C
Reaction time: 5 h
Yield: 67 %

Procedure:
After 750 mg (3.27 mmol) of methyl 6-oxo-1-phenyl-1,6-dihydro-3-pyridinecarboxylate was dissolved in 9 mL of methanol and 3 mL of water, 235 mg (9.81 mmol) of lithium hydroxide was added to the solution. Afterward, the resulting reaction solution was stirred at about 50° C. for about 5 hours. After termination of the reaction was determined by liquid chromatography, the solvent was removed in vacuo, followed by addition of aqueous HCl to titrate a pH of the reaction product to pH 2. After filtration of the resulting solid compound (Actual yield: 470 mg, Percent yield: 67%), the resulting compound was used without purification.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([C:27]2[CH2:32][CH2:31][CH2:30][CH2:29][CH:28]=2)=[CH:8][C:9]=1[N:10]([C@H:20]1[CH2:25][CH2:24][C@H:23](O)[CH2:22][CH2:21]1)[C:11]([C@H:13]1[CH2:18][CH2:17][C@H:16]([CH3:19])[CH2:15][CH2:14]1)=[O:12])=[O:4].C(I)(F)F.[H-].[Na+]>CN(C=O)C.C1C=CC=CC=1>[CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([C:27]2[CH2:32][CH2:31][CH2:30][CH2:29][CH:28]=2)=[CH:8][C:9]=1[N:10]([CH:20]1[CH2:25][CH2:24][CH:23]=[CH:22][CH2:21]1)[C:11]([C@H:13]1[CH2:18][CH2:17][C@H:16]([CH3:19])[CH2:15][CH2:14]1)=[O:12])=[O:4]
Reactant: COC(=O)c1sc(C2=CCCCC2)cc1N(C(=O)[C@H]1CC[C@H](C)CC1)[C@H]1CC[C@H](O)CC1
Agent: FC(F)I
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: c1ccccc1
Product: COC(=O)c1sc(C2=CCCCC2)cc1N(C(=O)[C@H]1CC[C@H](C)CC1)C1CC=CCC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 5-cyclohex-1-enyl-3-[(trans-4-hydroxy-cyclohexyl)-(trans-4-methyl-cyclohexanecarbonyl)-amino]-thiophene-2-carboxylic acid methyl ester 390 mg, 0.85 mmol) in dry DMF (3 mL) at 0° C. was added 0.34 mL of 10M solution of CHF2I in benzene, followed by NaH (60% suspension in oil, 68 mg, 1.70 mmol), and the mixture was stirred for 2 h allowing to warm up to room temperature. Then it has been transferred into a sealed tube and heated in a microwave oven for 20 min at 120° C. The mixture was treated as described in example 4, and purified by column chromatography on silica gel eluting with 0→50% ethyl acetate in hexane to give 5-cyclohex-1-enyl-3-[cyclohex-3-enyl-(trans-4-methyl-cyclohexanecarbonyl)-amino]-thiophene-2-carboxylic acid methyl ester (132 mg, 35%).
Reaction SMILES: [CH2:1]([N:8]([CH2:13][C:14]([OH:16])=O)[CH2:9][C:10]([OH:12])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1N=CN(C(N2C=NC=C2)=O)C=1.[NH2:29][C:30]1[CH:31]=[C:32]2[C:36](=[CH:37][CH:38]=1)[NH:35][CH:34]=[CH:33]2>C1COCC1>[CH2:1]([N:8]1[CH2:9][C:10](=[O:12])[N:29]([C:30]2[CH:31]=[C:32]3[C:36](=[CH:37][CH:38]=2)[NH:35][CH:34]=[CH:33]3)[C:14](=[O:16])[CH2:13]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Nc1ccc2[nH]ccc2c1
Reactant: O=C(O)CN(CC(=O)O)Cc1ccccc1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: O=C1CN(Cc2ccccc2)CC(=O)N1c1ccc2[nH]ccc2c1

Procedure:
N-Benzyliminodiacetic acid was reacted with CDI and 5-aminoindole in THF to obtain 4-benzyl-1-(1H-indol-5-yl)piperazine-2,6-dione, which was then reacted with lithium aluminum hydride in THF. Conc. hydrochloric acid and palladium hydroxide were added to an ethanol solution of thus obtained compound and the whole was reacted under a hydrogen atmosphere of 3 atm for 65 hours to obtain an objective compound.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9](=[O:15])[CH2:10][CH2:11][C:12]([OH:14])=[O:13].Cl.[CH3:17]O>C(OCC)C>[CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9](=[O:15])[CH2:10][CH2:11][C:12]([O:14][CH3:17])=[O:13]
Reactant: Cc1ccccc1CC(=O)CCC(=O)O
Reactant: CO
Agent: Cl
Solvent: CCOCC
Product: COC(=O)CCC(=O)Cc1ccccc1C

Procedure:
5-(2-Methylphenyl)-4-oxopentanoic acid (prepared as described above; 535 g.) was heated under reflux for 1 hour in methanol (5.5 liters) through which was passed gaseous hydrogen chloride. The flow of hydrogen chloride was then stopped and the solution was heated for a further 2 hours. The solution was then evaporated to give a dark coloured oil which was dissolved in diethyl ether (1500 ml.), washed with water and aqueous sodium bicarbonate solution, dried over sodium sulphate and distilled to give methyl 5-(2-methylphenyl)-4-oxopentanoate (248 g.), in the form of a clear yellow oil, b.p. 170°-200° C./0.7-1.0 mm.Hg.
Reaction SMILES: [CH2:1]([N:3]1[C:12]2[C:7](=[C:8]([F:33])[C:9]([O:23][CH2:24][C:25]3[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][CH:26]=3)=[C:10]([O:13][CH2:14][C:15]3[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=3)[CH:11]=2)[C:6](=[O:34])[C:5]([CH2:35][OH:36])=[CH:4]1)[CH3:2]>ClCCl.[O-2].[O-2].[Mn+4]>[CH2:1]([N:3]1[C:12]2[C:7](=[C:8]([F:33])[C:9]([O:23][CH2:24][C:25]3[CH:26]=[CH:27][C:28]([O:31][CH3:32])=[CH:29][CH:30]=3)=[C:10]([O:13][CH2:14][C:15]3[CH:16]=[CH:17][C:18]([O:21][CH3:22])=[CH:19][CH:20]=3)[CH:11]=2)[C:6](=[O:34])[C:5]([CH:35]=[O:36])=[CH:4]1)[CH3:2]
Reactant: CCn1cc(CO)c(=O)c2c(F)c(OCc3ccc(OC)cc3)c(OCc3ccc(OC)cc3)cc21
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClCCl
Product: CCn1cc(C=O)c(=O)c2c(F)c(OCc3ccc(OC)cc3)c(OCc3ccc(OC)cc3)cc21
Temperature: 25 °C
Reaction time: 6.5 h
Yield: 89.5 %

Procedure:
To a yellow solution of 1-ethyl-5-fluoro-3-(hydroxymethyl)-6,7-bis((4-methoxybenzyl)oxy) quinolin-4(1H)-one (11 g, 22.29 mmol) in Dichloromethane (DCM) (100 mL) was added manganese dioxide (19.38 g, 223 mmol). The mixture was stirred at rt for 6.5 h. The mixture was then filtered through Celite and washed with DCM, the filtrate was concentrated to afford 1-ethyl-5-fluoro-6,7-bis((4-methoxybenzyl)oxy)-4-oxo-1,4-dihydroquinoline-3-carbaldehyde (9.8 g, 19.94 mmol, 89% yield) as a yellow solid, which was used in the next step without further purification. LCMS: (M+H)+: 492.2.
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[C:11]2[C:7]([CH:8]=[CH:9][NH:10]2)=[CH:6][CH:5]=1)([O-:3])=[O:2].ClS([N:17]=[C:18]=O)(=O)=O>CN(C=O)C>[C:18]([C:8]1[C:7]2[C:11](=[CH:12][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=2)[NH:10][CH:9]=1)#[N:17]
Reactant: O=[N+]([O-])c1ccc2cc[nH]c2c1
Reactant: O=C=NS(=O)(=O)Cl
Solvent: CN(C)C=O
Product: N#Cc1c[nH]c2cc([N+](=O)[O-])ccc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 94.2 %

Procedure:
To a solution of 6-nitroindole (16.2 g, 100 mmol) in DMF (60 mL) at 0° C. was added chlorosulfonylisocyanate (10.9 mL, 125.0 mmol). The mixture was then stirred at room temperature overnight, poured into ice-water (1.0 L) and stirred for 3 h. The precipitate was filtered, washed with water and dried in air to provide 3-cyano-6-nitroindole (17.63 g, 94%).
Reaction SMILES: [CH3:1][CH:2]1[C:6](=[O:7])[CH:5]([OH:8])[CH:4]([CH3:9])[O:3]1.[Bi]=O>C(O)(=O)C>[CH3:9][CH:4]1[C:5](=[O:8])[C:6]([OH:7])=[C:2]([CH3:1])[O:3]1
Reactant: CC1OC(C)C(O)C1=O
Agent: O=[Bi]
Solvent: CC(=O)O
Product: CC1=C(O)C(=O)C(C)O1

Procedure:
the resulting 2,5-dimethyl-4-hydroxy-tetrahydrofuran-3-one is oxidized with bismuth oxide, in concentrated acetic acid solution, to give 2,5-dimethyl-4-hydroxy-2,3-dihydrofuran-3-one.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]([CH3:13])[CH3:12])(=[O:10])=[O:9])=[CH:4][CH:3]=1.S(=O)(=O)(O)O.[Br:19]N1C(=O)CCC1=O>>[Br:19][C:7]1[CH:6]=[C:5]([S:8]([N:11]([CH3:13])[CH3:12])(=[O:10])=[O:9])[CH:4]=[CH:3][C:2]=1[F:1]
Reactant: O=C1CCC(=O)N1Br
Reactant: CN(C)S(=O)(=O)c1ccc(F)cc1
Agent: O=S(=O)(O)O
Product: CN(C)S(=O)(=O)c1ccc(F)c(Br)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 81.6 %

Procedure:
A solution of 4-fluoro-N,N-dimethylbenzenesulfonamide (1.80 g; 8.86 mmol) in conc. sulfuric acid (7 ml; 130 mmol) was treated with N-bromosuccinimide (1 730 mg; 9.74 mmol) and stirred at RT for 3 h. The reaction mixture was carefully poured on crushed ice, extracted with AcOEt and the organic phase was washed with a 0.1 N solution of NaOH in water twice, then with brine twice. The organic phase was dried on MgSO4, filtered and concentrated under reduced pressure to give the title compound as a white solid (2.04 g, 82%).
Reaction SMILES: [Br:1][C:2]1[CH:13]=[C:12]([O:14][C@@H:15]([C@H:17]2[CH2:21][N:20]([C@@H](C3C=CC(OC)=CC=3)C)[C:19](=[O:32])[CH2:18]2)[CH3:16])[C:5]2[N:6]([CH:9]3[CH2:11][CH2:10]3)[CH:7]=[N:8][C:4]=2[CH:3]=1.C(O)(C(F)(F)F)=O>>[Br:1][C:2]1[CH:13]=[C:12]([O:14][C@@H:15]([C@H:17]2[CH2:21][NH:20][C:19](=[O:32])[CH2:18]2)[CH3:16])[C:5]2[N:6]([CH:9]3[CH2:10][CH2:11]3)[CH:7]=[N:8][C:4]=2[CH:3]=1
Reactant: COc1ccc([C@@H](C)N2C[C@H]([C@@H](C)Oc3cc(Br)cc4ncn(C5CC5)c34)CC2=O)cc1
Solvent: O=C(O)C(F)(F)F
Product: C[C@@H](Oc1cc(Br)cc2ncn(C3CC3)c12)[C@H]1CNC(=O)C1
Temperature: 70 °C
Reaction time: 19 h

Procedure:
(R)-4-((R)-1-((5-bromo-1-cyclopropyl-1H-benzo[d]imidazol-7-yl)oxy)ethyl)-1-((R)-1-(4-methoxyphenyl)ethyl)pyrrolidin-2-one 2.74 (2.09 g, 4.19 mmol) was dissolved in TFA (42 mL, 550 mmol). The resulting solution was heated to 70° C. and was stirred for 19 h. The reaction mixture was concentrated and partitioned between EtOAc (100 mL) and saturated aqueous NaHCO3 (75 mL). The phases were separated, and the aqueous phase was extracted with EtOAc (2×75 mL). The combined organic phase was dried over Na—2SO4, filtered, and concentrated, and the crude concentrate was purified by silica gel chromatography (0-20% MeOH in DCM) to provide (R)-4-((R)-1-((5-bromo-1-cyclopropyl-1H-benzo[d]imidazol-7-yl)oxy)ethyl)pyrrolidin-2-one (2.75). LCMS-ESI+ (m/z): [M+H]+ calcd for C16H19BrN3O2: 364.07; found: 364.05.
Reaction SMILES: [C:1]([OH:9])(=[O:8])[C:2]([CH2:4][C:5]([OH:7])=O)=[CH2:3].[CH3:10][O:11][C:12]1[CH:19]=[C:18]([O:20][CH3:21])[CH:17]=[CH:16][C:13]=1[CH2:14][NH2:15]>C1(C)C=CC=CC=1>[CH3:10][O:11][C:12]1[CH:19]=[C:18]([O:20][CH3:21])[CH:17]=[CH:16][C:13]=1[CH2:14][N:15]1[C:5](=[O:7])[CH2:4][CH:2]([C:1]([OH:9])=[O:8])[CH2:3]1
Reactant: COc1ccc(CN)c(OC)c1
Reactant: C=C(CC(=O)O)C(=O)O
Solvent: Cc1ccccc1
Product: COc1ccc(CN2CC(C(=O)O)CC2=O)c(OC)c1
Temperature: 25 °C
Reaction time: 15 h
Yield: 90.6 %

Procedure:
To a solution of itaconic acid (65.3 g) in toluene (400 ml) was added a solution of 2,4-dimethoxybenzylamine (84.0 g) in toluene (100 ml), and the mixture was stirred for 15 hours at reflux. This reaction solution was cooled to room temperature, and concentrated under reduced pressure. To the resulting residue was added diethyl ether (600 ml), and the mixture was stirred. The precipitated solid was collected by filtration, washed with diethyl ether and a small amount of ethyl acetate, and then dried under reduced pressure to give the titled compound (127 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5](B(O)O)[CH:6]=[CH:7][CH:8]=1.Br[C:13]1[S:17][C:16]([S:18]([N:21]2[CH:25]=[CH:24][CH:23]=[CH:22]2)(=[O:20])=[O:19])=[CH:15][CH:14]=1>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:13]2[S:17][C:16]([S:18]([N:21]3[CH:25]=[CH:24][CH:23]=[CH:22]3)(=[O:19])=[O:20])=[CH:15][CH:14]=2)[CH:6]=[CH:7][CH:8]=1
Reactant: COc1cccc(B(O)O)c1
Reactant: O=S(=O)(c1ccc(Br)s1)n1cccc1
Product: COc1cccc(-c2ccc(S(=O)(=O)n3cccc3)s2)c1
Yield: 93 %

Procedure:
N-[5-(3-methoxyphenyl)thiophene-2-sulfonyl]pyrrole was prepared in the same manner as described in Example 32C from 3-methoxyphenylboronic acid and N-(5-bromothiophene-2-sulfonyl)pyrrole in 93% yield. This was purified by recrystallization using hexane/ethyl acetate as solvent.
Reaction SMILES: CCN(C(C)C)C(C)C.C([Si](C)(C)[O:15][C:16]1[CH:21]=[CH:20][C:19]([O:22][CH2:23][CH:24]2[CH2:26][O:25]2)=[CH:18][CH:17]=1)(C)(C)C.Cl.[N:30]1[C:35]2[CH:36]=[CH:37][S:38][C:34]=2[C:33]([N:39]2[CH2:44][CH2:43][CH:42]([NH2:45])[CH2:41][CH2:40]2)=[N:32][CH:31]=1>CC(O)C.CS(C)=O>[OH:25][CH:24]([CH2:26][NH:45][CH:42]1[CH2:43][CH2:44][N:39]([C:33]2[C:34]3[S:38][CH:37]=[CH:36][C:35]=3[N:30]=[CH:31][N:32]=2)[CH2:40][CH2:41]1)[CH2:23][O:22][C:19]1[CH:18]=[CH:17][C:16]([OH:15])=[CH:21][CH:20]=1
Reactant: CC(C)(C)[Si](C)(C)Oc1ccc(OCC2CO2)cc1
Reactant: NC1CCN(c2ncnc3ccsc23)CC1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Solvent: CC(C)O
Product: Oc1ccc(OCC(O)CNC2CCN(c3ncnc4ccsc34)CC2)cc1
Yield: 13 %

Procedure:
Synthesis followed SP6 (iPrOH:DMSO 1:1, 1.2 eq. DIEA, 120° C., 48 h), using 200 μmol tert-butyldimethyl(4-(oxiran-2-ylmethoxy)phenoxy)silane and 1-(thieno[3,2-d]pyrimidin-4-yl)piperidin-4-amine HCl-salt to give O-silylated intermediate upon purification by prep. HPLC (reversed phase) and prep. TLC (1 mm silica gel, PE/CH2Cl2/MeOH 6:4:1) with 13% yield. Product was obtained by deprotection according to SP7 and purification by prep. HPLC (reversed phase) with 37% yield.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:12](=[C:13]([NH2:17])[C:14]=1[O:15][CH3:16])[NH:11][C:10]1[CH:9]=[N:8][CH:7]=[CH:6][C:5]2=1.[CH3:18][N:19]([CH3:31])[CH2:20][CH2:21][N:22]1[C:26](=[O:27])[CH2:25][CH:24]([C:28](O)=[O:29])[CH2:23]1>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:12](=[C:13]([NH:17][C:28]([CH:24]3[CH2:25][C:26](=[O:27])[N:22]([CH2:21][CH2:20][N:19]([CH3:31])[CH3:18])[CH2:23]3)=[O:29])[C:14]=1[O:15][CH3:16])[NH:11][C:10]1[CH:9]=[N:8][CH:7]=[CH:6][C:5]2=1
Reactant: CN(C)CCN1CC(C(=O)O)CC1=O
Reactant: COc1c(Cl)cc2c([nH]c3cnccc32)c1N
Product: COc1c(Cl)cc2c([nH]c3cnccc32)c1NC(=O)C1CC(=O)N(CCN(C)C)C1
Yield: 60 %

Procedure:
Prepared according to Method A from 6-chloro-7-methoxy-9H-β-carboline-8-ylamine and 1-(2-dimethylamino-ethyl)-5-oxo-pyrrolidine-3-carboxylic acid in 60% yield following purification using a semi-preparative Chiralcel OD column with 85/7.5/7.5 hexane/EtOH/MeOH as the eluant. 1H-NMR (300 MHz, DMSO-d6): δ 2.44 (s, 6H), 2.75 (t, 2H), 2.88 (d, 2H), 3.56 (t, 2H), 3.66 (m, 1H), 3.85 (m, 2H), 3.90 (s, 3H), 8.03 (d, 1H), 8.21 (s, 1H), 8.28 (d,1H), 8.79 (s,1H). Retention Time (LC, method: ammonium acetate standard): 1.42 min. MS (M+H+): 430.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]([CH3:25])=[C:11]([CH2:13][N:14]3[CH2:19][CH2:18][CH:17]([C:20]([O:22]CC)=[O:21])[CH2:16][CH2:15]3)[N:12]=2)=[CH:4][CH:3]=1.[Li+].[OH-].CO.Cl>O1CCOCC1.O.C1COCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]([CH3:25])=[C:11]([CH2:13][N:14]3[CH2:19][CH2:18][CH:17]([C:20]([OH:22])=[O:21])[CH2:16][CH2:15]3)[N:12]=2)=[CH:4][CH:3]=1
Reactant: CCOC(=O)C1CCN(Cc2nc(-c3ccc(Cl)cc3)oc2C)CC1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: C1COCCO1
Solvent: CO
Product: Cc1oc(-c2ccc(Cl)cc2)nc1CN1CCC(C(=O)O)CC1
Reaction time: 2 h

Procedure:
Ethyl 1-((2-(4-chlorophenyl)-5-methyloxazol-4-yl)methyl)piperidine-4-carboxylate (1.0 g, 2.7 mmole) and LiOH (240 mg, 10 mmol) were mixed with MeOH (5 mL), THF (5 ml) and Water (2 mL). The mixture was stirred at 50 for 2 h. 4N HCl in dioxane (3 mL) was added the reaction solution was stirred at room temperature for another 1 h. The solvent was removed under vacuum to give 1-((2-(4-chlorophenyl)-5-methyloxazol-4-yl)methyl)piperidine-4-carboxylic acid as white solid, the crude product was used without purification.