Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O.[OH-].[Na+].[C:4]([C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[N:11](S(C1C=CC(C)=CC=1)(=O)=O)[CH:10]=[C:9]2[C@H:25]1[CH2:27][C@H:26]1[CH2:28][N:29]([CH3:31])[CH3:30])#[N:5]>C(O)C>[C:4]([C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[NH:11][CH:10]=[C:9]2[C@H:25]1[CH2:27][C@H:26]1[CH2:28][N:29]([CH3:31])[CH3:30])#[N:5]
Reactant: Cc1ccc(S(=O)(=O)n2cc([C@H]3C[C@H]3CN(C)C)c3cc(C#N)ccc32)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CN(C)C[C@@H]1C[C@@H]1c1c[nH]c2ccc(C#N)cc12
Temperature: 70 °C
Yield: 75 %

Procedure:
Water (4 ml) and an aqueous solution of sodium hydroxide (2 ml, 10 N) were sequentially added to a flask charged with a solution of crude cis-2-[5-cyano-1-(p-toluenesulfonyl)indol-3-yl]-1-(N,N-dimethylaminomethyl)cyclo-propane dissolved in anhydrous ethanol (15 ml). The resulting mixture was heated at 70° C. for 1 h. The solvent was evaporated and the residue was taken up in brine (10 ml). The aqueous layer was extracted with 10% methanol/ethyl acetate (3×5 ml). The combined organic layers were dried over anhydrous magnesium sulfate and concentrated in vacuo. The crude material was purified by silica gel column chromatography and eluted using a step gradient of a solvent mixture [chloroform/(2 M ammonia/methanol), 90/10, 80/20]. The cis-2-[5-cyanoindol-3-yl]-1-(N,N-dimethylaminomethyl)cyclopropane was obtained as a white solid (63 mg, 75% yield over 3 steps): 1H NMR (400 MHz, CDCl3): δ8.47 (1H, br s), 8.07 (1H, s), 7.41 (2H, apparent q, J=8.0 Hz), 7.03 (1H, s), 2.37 (1H, dd, J=12.6, 4.7 Hz), 2.18 (6H, s), 1.97 (1H, m), 1.69 (1H, dd, J=12.6, 8.6 Hz), 1.34 (1H, m), 1.22 (1H, m), 0.71 (1H, q, J=5.0 Hz); MS m/e 240 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:17]2[N:16]=[C:15]([CH2:18][CH3:19])[NH:14][C:13]=2[C:12](=[O:20])[N:11]([CH3:21])[CH2:10]1.C([O-])([O-])=O.[K+].[K+].CS([CH:32]([CH2:36][CH:37]=[CH2:38])[CH2:33][CH:34]=[CH2:35])(=O)=O.CCOCC>CN(C=O)C>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:17]2[N:16]=[C:15]([CH2:18][CH3:19])[N:14]([CH:32]([CH2:36][CH:37]=[CH2:38])[CH2:33][CH:34]=[CH2:35])[C:13]=2[C:12](=[O:20])[N:11]([CH3:21])[CH2:10]1
Reactant: CCc1nc2c([nH]1)C(=O)N(C)CN2c1ccc(Cl)cc1Cl
Reactant: C=CCC(CC=C)S(C)(=O)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOCC
Product: C=CCC(CC=C)n1c(CC)nc2c1C(=O)N(C)CN2c1ccc(Cl)cc1Cl
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 17.9 %

Procedure:
Prepared by the method described in example 8 using the appropriate starting materials except for part “B” to give the desired product. Part “B” was replaced with the following procedure. A solution of 3-(2,4-dichlorophenyl)-8-ethyl-1-methyl-1,2,3,7-tetrahydro-6H-purin-6-one (65 mg, 0.20 mmol) in anhydrous DMF (1.2 mL) was treated with finely ground K2CO3 (83 mg, 0.60 mmol). After stirring 5 min at rt, 4-methanesulfonyl-1,6-heptadiene (203 μL, 1.11 mmol) was added via syringe and the reaction mixture was heated at 90° C. for 4 h. The mixture was cooled to rt and transferred to a separatory funnel containing ether (50 mL). The organic layer was washed with water (4×15 mL), brine (15 mL), dried over MgSO4, filtered, and concentrated. Purification of the residue by prep plate (1000 μM silica gel plate, 25% ethyl acetate in hexanes) followed by further purification by reverse phase HPLC afforded the title compound (15 mg, 18% yield) as a colorless oil; HRMS (ESI) m/e 419.1435 [(M+H)+, calcd for C21H25N4OCl2 419.1405].
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[CH:14]=[CH:13][C:9]3[O:10][CH2:11][O:12][C:8]=3[C:7]=2[C:15]2[C:16]3[NH:23][CH:22]=[C:21]([C:24](O)=[O:25])[C:17]=3[N:18]=[CH:19][N:20]=2)[CH2:3][CH2:2]1.[C:27]([O:31][C:32]([N:34]1[CH2:38][CH2:37][C@@H:36]([NH2:39])[CH2:35]1)=[O:33])([CH3:30])([CH3:29])[CH3:28]>>[C:27]([O:31][C:32]([N:34]1[CH2:38][CH2:37][C@@H:36]([NH:39][C:24]([C:21]2[C:17]3[N:18]=[CH:19][N:20]=[C:15]([C:7]4[C:8]5[O:12][CH2:11][O:10][C:9]=5[CH:13]=[CH:14][C:6]=4[O:5][CH2:4][CH:1]4[CH2:3][CH2:2]4)[C:16]=3[NH:23][CH:22]=2)=[O:25])[CH2:35]1)=[O:33])([CH3:30])([CH3:28])[CH3:29]
Reactant: O=C(O)c1c[nH]c2c(-c3c(OCC4CC4)ccc4c3OCO4)ncnc12
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](N)C1
Product: CC(C)(C)OC(=O)N1CC[C@@H](NC(=O)c2c[nH]c3c(-c4c(OCC5CC5)ccc5c4OCO5)ncnc23)C1

Procedure:
Starting from 4-(5-cyclopropylmethoxy-1,3-benzodioxol-4-yl)-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylic acid (example A67) and (R)-3-amino-pyrrolidine-1-carboxylic acid tert-butyl ester the title compound is obtained as colorless solid.
Reaction SMILES: [N:1]1([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:6][CH2:5][C:4]2([C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[CH2:9][NH:8][CH2:7]2)[CH2:3][CH2:2]1.[C:23](Cl)(=[O:25])[CH3:24].C(N(CC)CC)C>ClCCl>[C:23]([N:8]1[CH2:7][C:4]2([CH2:3][CH2:2][N:1]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:6][CH2:5]2)[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH2:9]1)(=[O:25])[CH3:24]
Reactant: CC(C)(C)OC(=O)N1CCC2(CC1)CNCc1ccccc12
Reactant: CC(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)N1Cc2ccccc2C2(CCN(C(=O)OC(C)(C)C)CC2)C1
Yield: 126.3 %

Procedure:
tert-Butyl 2,3-dihydro-1H-spiro[isoquinoline-4,4′-piperidine]-1′-carboxylate 6a (2.128 g, 6.28 mmol) was dissolved in anhydrous dichloromethane (30 mL), cooled in an ice-H2O bath and treated dropwise with a solution of acetyl chloride (518 mg, 6.59 mmol) in anhydrous dichloromethane (5 mL). The reaction was then treated dropwise with a solution of triethylamine (1.335 g, 13.2 mmol) in anhydrous dichloromethane (5 mL). The reaction was stirred in the ice-H2O bath for 15 minutes, then diluted with dichloromethane (100 mL), washed with H2O, saturated NaHCO3 (3×), saturated brine, dried (Na2SO4) and filtered. The filtrate was concentrated under reduced pressure to afford crude tert-butyl 2-acetyl-2,3-dihydro-1H-spiro[isoquinoline-4,4′-piperidine]-1′-carboxylate 6b as a colorless oil (2.732 g, quantitative yield). LC/MS m/z [M+H]+ 345.2 retention time 2.98 min (10-99% CH3CN—H2O gradient, with 0.05% TFA, 5 min).
Reaction SMILES: [CH:1]([C:3]1[CH2:4][S:5][C@@H:6]2[CH:26]([NH:27][C:28](=[O:35])[CH2:29][C:30]3[S:31][CH:32]=[CH:33][CH:34]=3)[C:25](=[O:36])[N:7]2[C:8]=1[C:9]([O:11][CH:12]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:10])=O.[S:37]1([CH2:43][CH2:42][CH:41]([NH:44][NH2:45])[CH2:40]1)(=[O:39])=[O:38].Cl>O1CCCC1.O>[S:37]1([CH2:43][CH2:42][CH:41]([NH:44][N:45]=[CH:1][C:3]2[CH2:4][S:5][C@@H:6]3[CH:26]([NH:27][C:28](=[O:35])[CH2:29][C:30]4[S:31][CH:32]=[CH:33][CH:34]=4)[C:25](=[O:36])[N:7]3[C:8]=2[C:9]([O:11][CH:12]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)=[O:10])[CH2:40]1)(=[O:39])=[O:38]
Reactant: NNC1CCS(=O)(=O)C1
Reactant: O=CC1=C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)C(NC(=O)Cc3cccs3)[C@H]2SC1
Agent: Cl
Solvent: O
Solvent: C1CCOC1
Product: O=C(Cc1cccs1)NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(C=NNC3CCS(=O)(=O)C3)CS[C@H]12
Reaction time: 5 h
Yield: 73 %

Procedure:
To a solution of diphenylmethyl 3-formyl-7-(2-thienylacetamido)-3-cephem-4-carboxylate (155 mg) in tetrahydrofuran (15 ml) is added a solution of (sulfolane-3-yl) hydrazine (70 mg) and 1.5 equivalents of hydrochloric acid in water (3 ml), and the mixture is kept at room temperature 5 hours. The crystals obtained by concentration of the reaction mixture are collected by filtration, washed with ether and water, and dried to give diphenylmethyl 3-(sulfolan-3-ylhydrazono)methyl-7-(2-thienylacetamido)-3-cephem-4-carboxylate (142 mg). m.p. 117°-125° C. Yield: 76%. IR: νmaxNujol 3275, 1785, 1715, 1675, 1530cm-1.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]=[CH:7][NH:8][C:9](=O)[C:10]=2[N:11]=1.C(N(CC)C(C)C)(C)C.O=P(Cl)(Cl)[Cl:24]>C1(C)C=CC=CC=1>[Cl:24][C:9]1[C:10]2[N:11]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]=2[N:6]=[CH:7][N:8]=1
Reactant: O=c1[nH]cnc2ccc(Cl)nc12
Reactant: O=P(Cl)(Cl)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: Cc1ccccc1
Product: Clc1ccc2ncnc(Cl)c2n1
Temperature: 25 °C

Procedure:
To a mixture of 6-chloro-pyrido[3,2-d]pyrimidin-4(3H)one (3.0 g, 16.5 mmole) and N,N-diisopropylethylamine (9 ml, 50 mmole) in toluene (150 ml), was added POCl3 (4.7 ml, 50 mmol). The resulting reaction mixture was refluxed for 1.5 hour. After cooling to room temperature, the solvent was removed under reduced pressure. The residue was dissolved in dichloromethane (200 ml) and washed with cold water till pH=6-7. The organic phase was dried over MgSO4, filtrated and concentrated under reduced pressure to yield crude 4,6-dichloro-pyrido[3,2-d]pyrimidine which was not purified but used as such for further reactions.
Reaction SMILES: C(N(CC)CC)C.[CH3:8][S:9](Cl)(=[O:11])=[O:10].[NH2:13][CH:14]([C:29]1[N:30]([C:40]([O:42][C:43]([CH3:46])([CH3:45])[CH3:44])=[O:41])[CH:31]=[C:32]([CH2:34][C:35]([CH3:39])([CH3:38])[CH2:36][CH3:37])[N:33]=1)[CH2:15][C:16]1[CH:21]=[CH:20][C:19]([C:22]2[CH:27]=[CH:26][C:25]([F:28])=[CH:24][N:23]=2)=[CH:18][CH:17]=1>>[CH3:38][C:35]([CH3:39])([CH2:36][CH3:37])[CH2:34][C:32]1[N:33]=[C:29]([CH:14]([NH:13][S:9]([CH3:8])(=[O:11])=[O:10])[CH2:15][C:16]2[CH:21]=[CH:20][C:19]([C:22]3[CH:27]=[CH:26][C:25]([F:28])=[CH:24][N:23]=3)=[CH:18][CH:17]=2)[N:30]([C:40]([O:42][C:43]([CH3:44])([CH3:45])[CH3:46])=[O:41])[CH:31]=1
Reactant: CS(=O)(=O)Cl
Reactant: CCC(C)(C)Cc1cn(C(=O)OC(C)(C)C)c(C(N)Cc2ccc(-c3ccc(F)cn3)cc2)n1
Solvent: CCN(CC)CC
Product: CCC(C)(C)Cc1cn(C(=O)OC(C)(C)C)c(C(Cc2ccc(-c3ccc(F)cn3)cc2)NS(C)(=O)=O)n1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Triethylamine (22 μL, 0.16 mmol) followed by methanesulfonyl chloride (10 μL, 0.1 mmol) were added to an ambient temperature solution of tert-butyl 2-{1-amino-2-[4-(5-fluoropyridin-2-yl)phenyl]ethyl}-4-(2,2-dimethylbutyl)-1H-imidazole-1-carboxylate (for synthesis see Example 39) (24 mg, 0.05 mmol). After stirring at ambient temperature for 1 h, the reaction mixture was quenched with water and extracted with methylene chloride. The combined organic extracts were dried (magnesium sulfate) and concentrated in vacuo. Preparatory plate chromatography eluting with 20% ethyl acetate/hexane afforded tert-butyl 4-(2,2-dimethylbutyl)-2-{2-[4-(5-fluoropyridin-2-yl)phenyl]-1-[(methylsulfonyl)amino]ethyl}-1H-imidazole-1-carboxylate.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[S:11](=[O:13])(=[O:12])[CH2:10][CH2:9][C:8]([C:14]([NH:16][C:17]3[CH:22]=[CH:21][C:20]([CH2:23][N:24]([CH3:31])[CH:25]4[CH2:30][CH2:29][O:28][CH2:27][CH2:26]4)=[CH:19][CH:18]=3)=[O:15])=[CH:7][C:6]=2[CH:32]=1.B([O-])([O-])O[C:35]1[CH:40]=[CH:39][C:38]([O:41][CH2:42][CH2:43][CH3:44])=[C:37]([O:45][CH2:46][CH2:47][CH3:48])[CH:36]=1.C(=O)([O-])[O-].[K+].[K+].C(O)C>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.C1(C)C=CC=CC=1>[CH2:46]([O:45][C:37]1[CH:36]=[C:35]([C:2]2[CH:3]=[CH:4][C:5]3[S:11](=[O:13])(=[O:12])[CH2:10][CH2:9][C:8]([C:14]([NH:16][C:17]4[CH:18]=[CH:19][C:20]([CH2:23][N:24]([CH3:31])[CH:25]5[CH2:30][CH2:29][O:28][CH2:27][CH2:26]5)=[CH:21][CH:22]=4)=[O:15])=[CH:7][C:6]=3[CH:32]=2)[CH:40]=[CH:39][C:38]=1[O:41][CH2:42][CH2:43][CH3:44])[CH2:47][CH3:48]
Reactant: CN(Cc1ccc(NC(=O)C2=Cc3cc(Br)ccc3S(=O)(=O)CC2)cc1)C1CCOCC1
Reactant: CCCOc1ccc(OB([O-])[O-])cc1OCCC
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: CCO
Solvent: Cc1ccccc1
Product: CCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(CN(C)C4CCOCC4)cc2)CCS3(=O)=O)cc1OCCC
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 73.9 %

Procedure:
A mixture of 7-bromo-N-(4-((N-methyl-N-(tetrahydro-2H-pyran-4-yl)amino)methyl)phenyl)-1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxamide (0.3 g), 3,4-dipropoxyphenyl borate (0.17 g), 1M potassium carbonate solution (1.3 ml), ethanol (1.3 ml) and toluene (25 ml) was stirred under argon atmosphere at room temperature for 30 minutes. To the mixture was added tetrakis(triphenylphosphine)palladium (0.03 g), and the mixture was refluxed under argon atmosphere for 6 hours and extracted with ethyl acetate. The organic layer washed with water and saturated brine and dried with anhydrous magnesium sulfate, and the solvent was evaporated. The residue was purified with silica gel column chromatography (ethyl acetate/methanol/triethylamine) to give crude crystals, which were recrystallized from ethanol to give 7-(3,4-dipropoxyphenyl)-N-(4-((N-methyl-N-(tetrahydro-2H-pyran-4-yl)amino)methyl)phenyl)-1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxamide (Compound 155) (0.27 g) as colorless crystals.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[C:13]([C:15]([CH3:23])([CH3:22])[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])[CH:12]=[CH:11][C:10]=1[CH:24]1[CH2:29][C:28](=[O:30])[CH:27]=[C:26]([CH3:31])[CH2:25]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H][H]>[Pd]>[CH2:1]([O:8][C:9]1[CH:14]=[C:13]([C:15]([CH3:22])([CH3:23])[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])[CH:12]=[CH:11][C:10]=1[C@H:24]1[CH2:25][C@@H:26]([CH3:31])[CH2:27][C:28](=[O:30])[CH2:29]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCCCCCC(C)(C)c1ccc(C2CC(=O)C=C(C)C2)c(OCc2ccccc2)c1
Reactant: [H][H]
Agent: [Pd]
Product: CCCCCCC(C)(C)c1ccc([C@@H]2CC(=O)C[C@H](C)C2)c(OCc2ccccc2)c1
Reaction time: 0.5 h
Yield: 32.1 %

Procedure:
A mixture of 5-[2-benzyloxy-4-(1,1-dimethylheptyl)-phenyl]-3-methyl-2-cyclohexen-1-one (1.00 g, 2.39 mmole) and 500 mg of 5% palladium on carbon-50% water was stirred under one atmosphere of hydrogen for one hour. A second 500 mg portion of catalyst was added and stirring continued for 30 minutes. A third 500 mg portion of catalyst was added and stirring continued for 13 minutes. The reaction mixture was then filtered through sodium bicarbonate and magnesium sulfate and the filtrate evaporated. The residue was purified via column chromatography on 140 g of silica gel eluted with 10% ether-petroleum ether to yield 323 mg (32%) of the title compound as an oil.
Reaction SMILES: [CH:1]#[C:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7].[C:8]1(C)[CH:13]=CC(S(OCC#C)(=O)=O)=C[CH:9]=1>Cl[Cu].O>[CH:1]#[C:2][CH2:3][C:4]#[C:5][CH2:6][CH2:7][CH2:9][CH2:8][CH3:13]
Reactant: C#CCOS(=O)(=O)c1ccc(C)cc1
Reactant: C#CCCCCC
Agent: Cl[Cu]
Solvent: O
Product: C#CCC#CCCCCC
Reaction time: 0.25 h

Procedure:
Into a 1 l vessel, there were charged 19.2 g of magnesium chips (0.8 mole) into 550 ml of tetrahydrofuran (THF) under nitrogen. To this mixture, there were added dropwise 84 g (0.77 mole) of ethyl bromide so as to maintain the THF in reflux. Once the ethyl magnesium bromide had been formed, 62.4 g (0.65 mole) of 1-heptyne were added dropwise at 10°, over 10 min, and the mixture was heated to 60° for 45 min. After cooling to 10°, 1.93 g (19.5 mmole) of CuCl were added thereto and the mixture was left at rest for 15 min. 138 G (0.65 mole) of propargyl p-toluenesulfonate were then added over 20 min to the reaction mixture maintained at 0°. The latter was left at rest for 30 min while surveying that the temperature did not rise above 5°. It was then heated to 15° to complete the reaction. The reaction mixture was hydrolyzed with 100 ml of water and the aqueous phase was separated and extracted with two fractions of 80 ml THF each. The combined organic extracts were then washed with an aqueous solution saturated with NaCl, two fractions of 50 ml each of a 5% aqueous solution of KCN and was then dried over Na2SO4. After filtration and evaporation, a concentrated solution of deca-1,4-diyne in THF was obtained, which was used in the following reaction step.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH3:9])[C:6]([S:10]([N:13]2[CH2:18][CH2:17][CH2:16][CH2:15][C@H:14]2[CH2:19][O:20][CH2:21][C:22]([O:24]C(C)(C)C)=[O:23])(=[O:12])=[O:11])=[C:5]([CH3:29])[CH:4]=1.FC(F)(F)C(O)=O>ClCCl>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH3:9])[C:6]([S:10]([N:13]2[CH2:18][CH2:17][CH2:16][CH2:15][C@H:14]2[CH2:19][O:20][CH2:21][C:22]([OH:24])=[O:23])(=[O:12])=[O:11])=[C:5]([CH3:29])[CH:4]=1
Reactant: COc1cc(C)c(S(=O)(=O)N2CCCC[C@H]2COCC(=O)OC(C)(C)C)c(C)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1cc(C)c(S(=O)(=O)N2CCCC[C@H]2COCC(=O)O)c(C)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
(S)-tert-butyl 2-((1-(4-methoxy-2,6-dimethylphenylsulfonyl)piperidin-2-yl)-methoxy)acetate (1 eq.) was dissolved in dichloromethane (10 ml/mmol) and cooled, and trifluoroacetic acid (13 eq.) was added slowly at 0° C. After stirring for 2 h at room temperature, the reaction mixture was concentrated in vacuo and dried. The crude product was used in the next stage without being purified further. Yield: quantitative
Reaction SMILES: CON(C)[C:4](=[O:18])[C:5]1[CH:10]=[C:9]([CH:11]2[O:15][CH2:14][CH2:13][O:12]2)[CH:8]=[CH:7][C:6]=1[O:16][CH3:17].[CH3:20][Mg]I.CCOCC.[Cl-].[NH4+]>O1CCCC1>[O:15]1[CH2:14][CH2:13][O:12][CH:11]1[C:9]1[CH:8]=[CH:7][C:6]([O:16][CH3:17])=[C:5]([C:4](=[O:18])[CH3:20])[CH:10]=1
Reactant: COc1ccc(C2OCCO2)cc1C(=O)N(C)OC
Reactant: C[Mg]I
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCOCC
Product: COc1ccc(C2OCCO2)cc1C(C)=O
Yield: 79 %

Procedure:
N-Methoxy-N-methyl-5-(1,3-dioxolan-2-yl)-2-methoxybenzamide (6.60 g, 24.7 mmol) and dehydrated tetrahydrofuran (200 mL) were mixed, and under an atmosphere of argon, the mixture was cooled using dry ice-acetone bath, and 3.0 mol/L solution of methyl magnesium iodide in ether (24.7 mL, 74.1 mmol) was added dropwise slowly under stirring. After completion of the dropwise addition, the mixture was stirred for 1.5 hours under cooling with ice. A saturated aqueous solution of ammonium chloride (200 mL) was added dropwise thereto under cooling with ice and stirring. After separated the organic layer, the aqueous layerwas extracted with ethyl acetate. Respective organic layers were combined, washed with water and saturated brine in sequence, then dried over anhydrous sodium sulfate and concentrated. The residue was purified by silica gel chromatography (eluate n-hexane:ethyl acetate=4:1 v/v) to obtain 4.31 g (79%) of the title compound as colorless crystals.
Reaction SMILES: C(O)(=O)/C=C/C(O)=O.[NH2:9][C:10]1[CH:18]=[C:17]([C:19]([NH:21][CH2:22][CH:23]2[CH2:27][CH2:26][CH2:25][N:24]2[CH2:28][CH3:29])=[O:20])[C:13]2[O:14][CH2:15][CH2:16][C:12]=2[CH:11]=1.[CH3:30][S:31](Cl)(=[O:33])=[O:32]>C(Cl)Cl>[CH2:28]([N:24]1[CH2:25][CH2:26][CH2:27][CH:23]1[CH2:22][NH:21][C:19]([C:17]1[C:13]2[O:14][CH2:15][CH2:16][C:12]=2[CH:11]=[C:10]([NH:9][S:31]([CH3:30])(=[O:33])=[O:32])[CH:18]=1)=[O:20])[CH3:29]
Reactant: CS(=O)(=O)Cl
Reactant: CCN1CCCC1CNC(=O)c1cc(N)cc2c1OCC2
Agent: O=C(O)/C=C/C(=O)O
Solvent: ClCCl
Product: CCN1CCCC1CNC(=O)c1cc(NS(C)(=O)=O)cc2c1OCC2
Yield: 98.8 %

Procedure:
A solution of 5-amino-N-(1-ethyl-2-pyrrolidinylmethyl)-2,3-dihydrobenzo[b]furan-7-carboxamide (161) (1.80 g, 6.2 mmol) and methanesulfonyl chloride (12.78 g, 0.11 mol) in 30 ml of methylene chloride was heated to reflux overnight. The solution was diluted with CH2Cl2 (30 ml), and then extracted with water (2×30 ml). The combined aqueous layers were made basic with NaHCO3 powder, and extracted with CH2Cl2 (4×50 ml). The organic extracts were combined, dried over anhydrous Na2SO4, and evaporated to give crude 16n (2.25 g, 98.8%). This was recrystallized from EtOH/charcoal to afford 1.70 g of amide as a white solid, mp 180°-182° C.
Reaction SMILES: [OH-].[K+].[Cl:3][C:4]1[CH:11]=[C:10]([Cl:12])[CH:9]=[CH:8][C:5]=1[CH:6]=O.[CH3:13][CH:14]1[CH2:19][CH2:18][CH2:17][CH2:16][C:15]1=[O:20]>O>[CH3:13][CH:14]1[CH2:19][CH2:18][CH2:17][C:16](=[CH:6][C:5]2[CH:8]=[CH:9][C:10]([Cl:12])=[CH:11][C:4]=2[Cl:3])[C:15]1=[O:20]
Reactant: O=Cc1ccc(Cl)cc1Cl
Reactant: CC1CCCCC1=O
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: CC1CCCC(=Cc2ccc(Cl)cc2Cl)C1=O
Temperature: 150 °C
Reaction time: 10 h
Yield: 86 %

Procedure:
A solution of 1.5 g of 85% strength aqueous potassium hydroxide solution in 135 ml of water was charged to a 0.31 stainless-steel autoclave, and then 47.5 g of 2,4-dichlorobenzaldehyde and 30.5 g of 2-methylcyclohexanone were added, and the mixture was subsequently heated to 150° C. under the intrinsic pressure (to 3.8 bar). Stirring was subsequently carried out at this temperature for 10 hours. After cooling to room temperature, the suspension was filtered with suction and the solid product was washed to neutrality with water and dried in a vacuum oven at 55° C. In this way 62.8 g of 2-methyl-6-(2,4-dichlorobenzylidene)-cyclohexanone (99.5% pure) were obtained. This corresponds to a yield of 86% of theory.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][CH:8]([CH3:10])[C:7](=O)[C:6]=2[CH:12]=1.[CH2:13]([O:15][C:16](=[O:37])[CH:17]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[CH3:14]>C1(C)C=CC=CC=1.Cl.C(O)C>[CH2:13]([O:15][C:16](=[O:37])[CH2:17][C:7]1[C:6]2[CH:12]=[C:2]([Br:1])[CH:3]=[CH:4][C:5]=2[O:9][C:8]=1[CH3:10])[CH3:14]
Reactant: CC1Oc2ccc(Br)cc2C1=O
Reactant: CCOC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: Cl
Solvent: CCO
Solvent: Cc1ccccc1
Product: CCOC(=O)Cc1c(C)oc2ccc(Br)cc12
Temperature: 120 °C
Yield: 77.6 %

Procedure:
A mixture of 5-bromo-2-methyl-benzofuran-3-one (6.8 g, 29.9 mmol) and (triphenyl-phosphanylidene)-acetic acid ethyl ester (17.4 g, 44.9 mmol) in anhydrous toluene is heated for 40 h at 120° C. under an argon atmosphere. After cooling to room temperature the volatiles are removed by rotary evaporation. The residue is purified by flash column chromatography (silica gel, gradient of cyclohexane/EtOAc 100:0 to 90:10) to afford a mixture of two regioisomeric products. The product mixture (7.1 g, 31.3 mmol) is dissolved in a 1.25 M solution of HCl in ethanol and heated at reflux for 1 h. After cooling to room temperature the solvent is removed by rotary evaporation to yield the title compound as a pale yellow oil (6.9 g, 23.2 mmol, 78%). 1H NMR (400 MHz, CDCl3, 298 K): δ=7.59 (d, J=2.0 Hz, 1H), 7.31-7.22 (m, 2H), 4.15 (q, J=7.1 Hz, 2H), 3.54 (s, 2H), 2.42 (s, 3H), 1.25 (t, J=7.1 Hz, 3H). MS (ES+): 297 (M(C13H1379BrO3)+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:10]2[CH:14]=[CH:13][N:12]([CH2:15][C@@H:16]([NH:18][C:19]([C:21]3[N:22]=[C:23]([C:26]4[N:30](C5CCCCO5)[N:29]=[CH:28][CH:27]=4)[O:24][CH:25]=3)=[O:20])[CH3:17])[N:11]=2)[CH:5]=[CH:6][C:7]=1[C:8]#[N:9].Cl.CCO>C(OCC)(=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([C:10]2[CH:14]=[CH:13][N:12]([CH2:15][C@@H:16]([NH:18][C:19]([C:21]3[N:22]=[C:23]([C:26]4[CH:27]=[CH:28][NH:29][N:30]=4)[O:24][CH:25]=3)=[O:20])[CH3:17])[N:11]=2)[CH:5]=[CH:6][C:7]=1[C:8]#[N:9]
Reactant: C[C@@H](Cn1ccc(-c2ccc(C#N)c(Cl)c2)n1)NC(=O)c1coc(-c2ccnn2C2CCCCO2)n1
Agent: Cl
Solvent: CCO
Solvent: CCOC(C)=O
Product: C[C@@H](Cn1ccc(-c2ccc(C#N)c(Cl)c2)n1)NC(=O)c1coc(-c2cc[nH]n2)n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 29.6 %

Procedure:
N—((S)-1-(3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1-yl)propan-2-yl)-2-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl)oxazole-4-carboxamide (56 mg, 0.111 mmol) was added into a flask under nitrogen atmosphere. 10% HCl/EtOH (0.126 ml, 0.277 mmol) was added and the reaction mixture was stirred in RT for 2 h. The reaction mixture was diluted with ethyl acetate and washed with 1M Na2CO3. The organic phase was dried, filtered and evaporated. The product was triturated using acetonitrile and THF, respectively. Yield 29.6%. 1H-NMR (400 MHz; CDCl3): δ 1.27 (d, 3H), 4.31 (dd, 1H), 4.43 (dd, 1H), 4.61 (m, 1H), 6.61 (d, 1H), 6.86 (d, 1H), 7.49 (d, 1H), 7.60 (d, 1H), 7.66 (d, 1H), 7.72 (d, 1H), 7.87 (dd, 1H), 7.92 (d, 1H), 8.23 (s, 1H), 10.78 (s, 1H).