Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]([CH3:25])([CH3:24])[C:3]([N:5]1[C:13]2[C:8](=[CH:9][C:10]([C:14]([O:16]CC3C=CC=CC=3)=[O:15])=[CH:11][CH:12]=2)[CH:7]=[CH:6]1)=[O:4].[H][H]>C(O)C.[Pd]>[CH3:1][C:2]([CH3:25])([CH3:24])[C:3]([N:5]1[C:13]2[C:8](=[CH:9][C:10]([C:14]([OH:16])=[O:15])=[CH:11][CH:12]=2)[CH:7]=[CH:6]1)=[O:4]
Reactant: CC(C)(C)C(=O)n1ccc2cc(C(=O)OCc3ccccc3)ccc21
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: CC(C)(C)C(=O)n1ccc2cc(C(=O)O)ccc21
Yield: 87 %

Procedure:
The benzyl 1-(2,2-dimethylpropionyl)-1H-indole-5-carboxylate (220 mg) obtained above was dissolved in ethanol, and 5% palladium on carbon (44 mg) was added thereto and stirred overnight at room temperature in a hydrogen atmosphere. Insoluble matter was removed by filtration, and the filtrate was concentrated under reduced pressure to give the title compound (140 mg, Y.:86%).
Reaction SMILES: Br[C:2]1[C:10]2[N:9]3[CH2:11][CH2:12][NH:13][C:14](=[O:15])[C:8]3=[C:7]([CH3:16])[C:6]=2[CH:5]=[C:4]([F:17])[CH:3]=1.[OH:18][CH2:19][C:20]1[CH:25]=[CH:24][C:23](B(O)O)=[CH:22][CH:21]=1>>[F:17][C:4]1[CH:3]=[C:2]([C:23]2[CH:24]=[CH:25][C:20]([CH2:19][OH:18])=[CH:21][CH:22]=2)[C:10]2[N:9]3[CH2:11][CH2:12][NH:13][C:14](=[O:15])[C:8]3=[C:7]([CH3:16])[C:6]=2[CH:5]=1
Reactant: Cc1c2n(c3c(Br)cc(F)cc13)CCNC2=O
Reactant: OCc1ccc(B(O)O)cc1
Product: Cc1c2n(c3c(-c4ccc(CO)cc4)cc(F)cc13)CCNC2=O

Procedure:
The title compound, white solid (59 mg, 73%), MS (ISP) m/z=325.5 [(M+H)+], mp 220° C., was prepared in accordance with the general method of example 1 from 6-bromo-8-fluoro-10-methyl-3,4-dihydro-2H-pyrazino[1,2-a]indol-1-one (intermediate 14) (74.3 mg, 0.25 mmol) and commercially available 4-hydroxymethyl-phenylboronic acid (49.4 mg, 0.325 mmol).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([Si:8]([C:11]([CH3:14])([CH3:13])[CH3:12])([CH3:10])[CH3:9])=[CH:4][N:3]=1.[Br-].[N:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[Zn+].N>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.O1CCCC1>[Si:8]([C:5]1[CH:6]=[CH:7][C:2]([C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][N:16]=2)=[N:3][CH:4]=1)([C:11]([CH3:14])([CH3:13])[CH3:12])([CH3:10])[CH3:9]
Reactant: CC(C)(C)[Si](C)(C)c1ccc(Br)nc1
Reactant: [Zn+]c1ccccn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: N
Agent: [Br-]
Solvent: C1CCOC1
Product: CC(C)(C)[Si](C)(C)c1ccc(-c2ccccn2)nc1
Temperature: 25 °C

Procedure:
To a reaction container equipped with a cooling apparatus, 0.64 g of tetrakis(triphenylphosphine)palladium, 1 g of 2-bromo-5-tert-butyldimethylsilylpyridine obtained in the above-mentioned Example 3-1 and 25 mL of tetrahydrofuran were added. To the obtained mixture, 7.35 mL of 2-pyridyl zinc bromide (0.5 M/tetrahydrofuran solution) was added with stirring at room temperature. The obtained mixture was stirred at 50° C. for 7 hours and 40 minutes to effect reaction. The reaction mixture was cooled until room temperature and then, 33 mL of 28% aqueous ammonia solution was added thereto. The obtained mixture was extracted three times with 50 mL of chloroform. The obtained organic layers were mixed and dried with magnesium sulfate. After removing magnesium sulfate by filtration, the filtrate was concentrated to obtain a crude product. The crude product was purified with silica gel column chromatography followed by further recrystallization with hexane to obtain 0.35 g of 5-tert-butyldimethylsilyl-2,2′-bipyridine.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:11])[CH2:9][CH3:10])=[C:4]([NH:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[F:19])[CH:3]=1.[C:20](Cl)(=O)C(Cl)=O>CN(C=O)C>[F:1][C:2]1[CH:3]=[C:4]2[C:5]([C:8](=[O:11])[C:9]([CH3:20])=[CH:10][N:12]2[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[F:19])=[CH:6][CH:7]=1
Reactant: O=C(Cl)C(=O)Cl
Reactant: CCC(=O)c1ccc(F)cc1Nc1ccccc1F
Solvent: CN(C)C=O
Product: Cc1cn(-c2ccccc2F)c2cc(F)ccc2c1=O
Temperature: 0 °C
Yield: 37.8 %

Procedure:
In a 250 mL round bottom flask, 1-[4-fluoro-2-(2-fluoro-phenylamino)-phenyl]-propan-1-one (3.05 g, 11.7 mmol) was added to DMF (4.3 mL) at 0° C. Oxalyl chloride (8.18 mL, 96.7 mmol) was added slowly and the reaction mixture stirred at 0° C. The mixture was then warmed up to room temperature and stirred for 1.5 hr. The mixture was concentrated to dryness and the crude redissolved in toluene (80 mL). The reaction mixture was heated at 115° C. for 24 hr. The mixture was concentrated to dryness and triturated from methanol to afford 7-fluoro-1-(2-fluoro-phenyl)-3-methyl-1H-quinolin-4-one (1.20 g, 37.8%) as a white solid.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([N:8]2[CH2:12][CH:11]([C:13]3[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[C:15]([O:21][CH:22]4[CH2:26][CH2:25][CH2:24][CH2:23]4)[CH:14]=3)[CH2:10][C:9]2=[O:27])[CH:5]=[CH:6][CH:7]=1.[O:28]1[CH2:32][CH2:31][CH:30]([CH2:33]C=O)[CH2:29]1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].CC(O)=O>CN(C=O)C>[CH:22]1([O:21][C:15]2[CH:14]=[C:13]([CH:11]3[CH2:12][N:8]([C:4]4[CH:5]=[CH:6][CH:7]=[C:2]([NH:1][CH2:33][CH:30]5[CH2:31][CH2:32][O:28][CH2:29]5)[CH:3]=4)[C:9](=[O:27])[CH2:10]3)[CH:18]=[CH:17][C:16]=2[O:19][CH3:20])[CH2:26][CH2:25][CH2:24][CH2:23]1
Reactant: O=CCC1CCOC1
Reactant: COc1ccc(C2CC(=O)N(c3cccc(N)c3)C2)cc1OC1CCCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CC(=O)O
Product: COc1ccc(C2CC(=O)N(c3cccc(NCC4CCOC4)c3)C2)cc1OC1CCCC1
Reaction time: 20 h
Yield: 57.7 %

Procedure:
A mixture of 1-(3-aminophenyl)-4-(3-cyclopentyloxy-4-methoxyphenyl)-pyrrolidin-2-one (8 mg, 0.02 mmol), (tetrahydrofuran-3-yl)-acetaldehyde (0.024 mmol), NaB(OAc)3H (0.2 mmol), and AcOH (0.06 mmol) in DMF (0.5 mL) was stirred for 20 h. After concentration under reduced pressure, the residue was dissolved in EtOAc (3 mL), washed with brine (2×3 mL), and dried over Na2SO4. Concentration and chromatography on silica gel (EtOAc:Hexane=1:1) gave 5.2 mg of the desired product. Yield: 57%.
Reaction SMILES: [CH3:1][O:2][C:3]([O:5][CH3:6])=[CH2:4].[C:7]([O:12][CH2:13][CH3:14])(=[O:11])[CH:8]=[C:9]=[CH2:10]>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1([O:5][CH3:6])[CH2:10][C:9](=[CH:8][C:7]([O:12][CH2:13][CH3:14])=[O:11])[CH2:4]1
Reactant: C=C=CC(=O)OCC
Reactant: C=C(OC)OC
Solvent: Cc1ccccc1
Product: CCOC(=O)C=C1CC(OC)(OC)C1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A solution of 3.93 g (44.59 mmol) of 1,1-dimethoxyethene and 5 g (44.59 mmol) of ethyl buta-2,3-dienoate in 50 ml of toluene was heated at reflux and stirred for 24 h. After cooling to room temperature, the reaction mixture was freed from the solvent, and the crude product obtained was purified chromatographically on silica gel (mobile phase cyclohexane/ethyl acetate 20:1). This gave 1.9 g (21% of theory) of the title compound as a colourless liquid which was used without further characterization for subsequent reactions.
Reaction SMILES: [CH3:1][N:2]([CH3:16])[C@@H:3]1[CH2:8][CH2:7][CH2:6][N:5](C(OC(C)(C)C)=O)[CH2:4]1.C(Cl)[Cl:18]>Cl.O1CCOCC1>[ClH:18].[ClH:18].[CH3:1][N:2]([CH3:16])[C@@H:3]1[CH2:8][CH2:7][CH2:6][NH:5][CH2:4]1
Reactant: ClCCl
Reactant: CN(C)[C@@H]1CCCN(C(=O)OC(C)(C)C)C1
Agent: Cl
Solvent: C1COCCO1
Product: CN(C)[C@@H]1CCCNC1
Reaction time: 4 h

Procedure:
1,1-Dimethylethyl (3R)-3-(dimethylamino)-1-piperidinecarboxylate (5.0 g crude, 21.12 assumed mmol) was dissolved and stirred in a mixture of CH2Cl2 (10 mL) and 4M HCl in dioxane (21 mL, 4 eqv.) A white precipitate formed. The reaction appeared to stall at approximately 70% completion, and therefore another 21 mL of 4M HCl in dioxane was added to the reaction mixture. After 4 h at room temperature, the solvent was evaporated, providing (3R)—N,N-dimethyl-3-piperidinamine, dihydrochloride as a white solid (3.5 g, 89% for two steps).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([O:15][CH2:16][O:17][CH3:18])[C:10]=1[I:19])=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[CH2:22](Br)[CH:23]=[CH2:24]>CN(C=O)C>[C:1]([O:5][C:6]([N:8]([C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([O:15][CH2:16][O:17][CH3:18])[C:10]=1[I:19])[CH2:24][CH:23]=[CH2:22])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: C=CCBr
Reactant: COCOc1cccc(NC(=O)OC(C)(C)C)c1I
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C=CCN(C(=O)OC(C)(C)C)c1cccc(OCOC)c1I
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
A solution of 14 (141 mg, 0.37 mmol) in 12 mL anhydrous DMF was cooled to −10° C., and treated with NaH (22.3 mg, 0.55 mmol) in small portions. The resulting suspension was stirred for 15 min and treated with neat allyl bromide (0.16 mL, 1.56 mmol) in a slow dropwise manner. The reaction mixture was warmed to 25° C. and stirred for 1 h. The reaction mixture was quenched with the addition of 5% aqueous NaHCO3 (20mL), and the aqueous layer was extracted with EtOAc (3×10 mL). The combined organic extracts were washed with H2O (5×10 mL), dried (Na2SO4), and condensed under reduced pressure to yield 15 as a 2:1 mixture of amide rotamers as a yellow oil. Flash chromatography (SiO2, 2.5×10 cm, 10% EtOAc/hexane) yielded 15 (149 mg, 96%) as a colorless oil:1H NMR (CDCl3, 250 MHz) δ7.17 (m, 1H), 6.95-6.78 (m, 2H), 5.98-5.84 (m, 1H), 5.21 (s, 2H), 5.09-5.03 (m, 2H), 4.46 (m, 1H), 3.50 (s, 3H), 1.50 and 1.31 (s, 9H);13C NMR (CDCl3, 100 MHz) δ157.5 and 157.0, 153.7, 146.1 and 145.7, 133.8 and 133.6, 129.5 and 129.0, 123.6 and 123.5, 117.6 and 117.1, 113.5 and 113.2, 95.0 and 94.1, 80.5 and 80.1, 56.4, 53.1, 51.9, 28.3 and 28.1; IR (film) νmax 2975, 1688, 1582, 1463, 1381, 1253, 1154, 1065, 990 cm−1; FABHRMS (NBA/NaI) m/z 420.0663 (C16H22INO4+H+ requires 420.0672).
Reaction SMILES: [F:1][C:2]1[C:13]([F:14])=[CH:12][CH:11]=[CH:10][C:3]=1[C:4](N(OC)C)=[O:5].[CH3:15][O:16][C:17]1[CH:22]=[CH:21][C:20]([Mg]Br)=[C:19]([CH3:25])[CH:18]=1>>[F:1][C:2]1[C:13]([F:14])=[CH:12][CH:11]=[CH:10][C:3]=1[C:4]([C:20]1[CH:21]=[CH:22][C:17]([O:16][CH3:15])=[CH:18][C:19]=1[CH3:25])=[O:5]
Reactant: COc1ccc([Mg]Br)c(C)c1
Reactant: CON(C)C(=O)c1cccc(F)c1F
Product: COc1ccc(C(=O)c2cccc(F)c2F)c(C)c1

Procedure:
Prepared according to Method A step B from 2,3-difluoro-N-methoxy-N-methyl-benzamide (3.77 g, 18.7 mmol) and 4-methoxy-2-methyl-phenylmagnesium bromide (49 mL, 0.5 M in THF) to give 1.45 g of the title compound as a white solid.
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1.[Cl:6][C:7]1[CH:12]=[C:11]([Cl:13])[CH:10]=[CH:9][C:8]=1[CH2:14][C:15]([CH3:21])([CH:18]=[CH:19][CH3:20])[CH:16]=O>C(O)=O>[Cl:6][C:7]1[CH:12]=[C:11]([Cl:13])[CH:10]=[CH:9][C:8]=1[CH2:14][C:15]([CH3:21])([CH2:18][CH:19]=[CH2:20])[CH2:16][N:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: C1CCNC1
Reactant: CC=CC(C)(C=O)Cc1ccc(Cl)cc1Cl
Solvent: O=CO
Product: C=CCC(C)(Cc1ccc(Cl)cc1Cl)CN1CCCC1
Temperature: 100 °C
Yield: 47.2 %

Procedure:
149 g of formic acid were added dropwise to 45.8 g of pyrrolidine, while cooling with ice. 181 g of 3-(2,4-dichlorophenyl)-2-methyl-2-propen-1-ylpropionaldehyde were then added, after which the mixture was heated at 100° C. for 12 hours and then evaporated down under reduced pressure. The residue was made alkaline with 25% strength NaOH and extracted with ether, and the organic phase was dried over KOH and evaporated down. Distillation of the residue gave 95 g of (X) of boiling point 130°-138° C./0.1 mbar.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:7]([NH:9][C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([Cl:16])[N:11]=2)=O)=[N:4][O:5][N:6]=1.P(Cl)(Cl)(Cl)(Cl)[Cl:18]>C1C=CC=CC=1>[NH2:1][C:2]1[C:3]([C:7]([Cl:18])=[N:9][C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([Cl:16])[N:11]=2)=[N:4][O:5][N:6]=1
Reactant: ClP(Cl)(Cl)(Cl)Cl
Reactant: Nc1nonc1C(=O)Nc1cccc(Cl)n1
Solvent: c1ccccc1
Product: Nc1nonc1C(Cl)=Nc1cccc(Cl)n1

Procedure:
A solution of 4-amino-N-(6-chloropyridin-2-yl)-1,2,5-oxadiazole-3-carboxamide (62 mg, 0.26 mmol) in benzene (5 mL) was treated with phosphorus pentachloride (0.12 g, 0.57 mmol) and stirred at reflux for 3 h. The reaction mixture was concentrated and rediluted with benzene and concentrated (3×) to give the desired product which was used immediately in the next step.
Reaction SMILES: CC1C=CC(S(O[CH2:12][C@@H:13]2[O:18][C:17]3[CH:19]=[C:20]([S:24]([CH3:27])(=[O:26])=[O:25])[CH:21]=[C:22]([Cl:23])[C:16]=3[O:15][CH2:14]2)(=O)=O)=CC=1.[CH2:28]([NH:30][CH2:31][CH2:32][CH3:33])[CH3:29]>C(#N)C>[CH2:28]([N:30]([CH2:12][C@@H:13]1[O:18][C:17]2[CH:19]=[C:20]([S:24]([CH3:27])(=[O:25])=[O:26])[CH:21]=[C:22]([Cl:23])[C:16]=2[O:15][CH2:14]1)[CH2:31][CH2:32][CH3:33])[CH3:29]
Reactant: Cc1ccc(S(=O)(=O)OC[C@H]2COc3c(Cl)cc(S(C)(=O)=O)cc3O2)cc1
Reactant: CCCNCC
Solvent: CC#N
Product: CCCN(CC)C[C@H]1COc2c(Cl)cc(S(C)(=O)=O)cc2O1

Procedure:
Preparation according to Example 57 using [(2R)-5-chloro-7-(methylsulfonyl)-2,3-dihydro-1,4-benzodioxin-2-yl]methyl 4-methylbenzenesulfonate (0.027 g, 0.062 mmol), N-ethylpropan-1-amine (0.5 ml), ACN (3 ml). MS m/z (rel. intensity, 70 eV) 347 (M+, 0.2), 101 (7), 100 (bp), 98 (5), 72 (8), 58 (9).
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7](O)=[O:8])=[C:5]([NH:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[N+:17]([O-:19])=[O:18])[C:4]([CH3:20])=[N:3]1.S(Cl)([Cl:23])=O>>[CH3:1][N:2]1[C:6]([C:7]([Cl:23])=[O:8])=[C:5]([NH:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[N+:17]([O-:19])=[O:18])[C:4]([CH3:20])=[N:3]1
Reactant: Cc1nn(C)c(C(=O)O)c1Nc1ccccc1[N+](=O)[O-]
Reactant: O=S(Cl)Cl
Product: Cc1nn(C)c(C(=O)Cl)c1Nc1ccccc1[N+](=O)[O-]

Procedure:
2.6 g of 1,3-dimethyl-4-[(2-nitrophenyl)amino]pyrazole-5-carboxylic acid and 10 ml of thionyl chloride are stirred at 80° C. for 3 hours; the solution is concentrated; 10 ml of toluene are added, and the mixture is re-concentrated, this procedure being carried out 3 times. 2.9 g of 1,3-dimethyl-4-[(2-nitrophenyl)amino]pyrazole-5-carboxylic acid chloride are thus obtained as an orange-colored oil.
Reaction SMILES: [C:1]1([S:7]([N:10]2[C:14]3=[N:15][CH:16]=[C:17]([F:19])[CH:18]=[C:13]3[CH:12]=[C:11]2[CH:20]([OH:27])[CH2:21][CH:22]2[CH2:26][CH2:25][CH2:24][CH2:23]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>ClCCl>[C:1]1([S:7]([N:10]2[C:14]3=[N:15][CH:16]=[C:17]([F:19])[CH:18]=[C:13]3[CH:12]=[C:11]2[C:20](=[O:27])[CH2:21][CH:22]2[CH2:23][CH2:24][CH2:25][CH2:26]2)(=[O:9])=[O:8])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=S(=O)(c1ccccc1)n1c(C(O)CC2CCCC2)cc2cc(F)cnc21
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: ClCCl
Product: O=C(CC1CCCC1)c1cc2cc(F)cnc2n1S(=O)(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 64.9 %

Procedure:
To a solution of 1-(1-benzenesulfonyl-5-fluoro-1H-pyrrolo[2,3-b]pyridin-2-yl)-2-cyclopentyl-ethanol (1.55 g, 3.99 mmol) in dichloromethane (100 ml) was added Dess-Martin periodinane (5.08 g, 11.97 mmol) at 25° C. The reaction mixture was stirred at 25° C. for 1 h and then quenched with a saturated aqueous sodium bicarbonate solution (60 mL). The mixture was extracted with ethyl acetate (150 mL), washed with a saturated aqueous sodium bicarbonate solution (3×30 mL), brine, dried over anhydrous sodium sulfate and then concentrated in vacuo. The residue was purified by flash column chromatography (silica gel from QingDao, 200-300 mesh, 50% dichloromethane/hexanes) to afford 1-(1-benzenesulfonyl-5-fluoro-1H-pyrrolo[2,3-b]pyridin-2-yl)-2-cyclopentyl-ethanone (1.0 g, 65%) as a light yellow solid: LC/MS m/e calcd for C20H19FN2O3S [M+H]+ 387.45, observed 387.1.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[CH2:6]([OH:10])[C:7]#[C:8][CH3:9].C(N(CC)CC)C>C(Cl)Cl>[CH3:1][S:2]([O:10][CH2:6][C:7]#[C:8][CH3:9])(=[O:4])=[O:3]
Reactant: CC#CCO
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC#CCOS(C)(=O)=O
Temperature: 0 °C
Reaction time: 0.67 h
Yield: 96 %

Procedure:
305 ml methanesulfonyl chloride was added dropwise to a solution of 138 g 2-butyn-1-ol and 683 ml triethylamine in 2.7 L methylene chloride under ice-cooling, and the mixture was stirred at 0° C. for 1 hour and 40 minutes. Ice was added to the reaction solution under ice-cooling, and this mixture was extracted with methylene chloride. The organic layer was successively washed with 1M aqueous hydrochloric acid, a saturated aqueous sodium bicarbonate solution and brine, and the organic layer was dried over magnesium sulfate. This organic layer was filtered and then the solvent was evaporated, to give a dark brown oil (280 g, 96%).
Reaction SMILES: C([O:4][CH2:5][CH2:6][C@:7]([OH:50])([C@@H:11]([C:29](=[O:49])[NH:30][C@H:31]([CH2:44][O:45]C(=O)C)[CH2:32][C:33]1[CH:38]=[CH:37][C:36]([O:39][CH2:40][C:41]#[C:42][CH3:43])=[CH:35][CH:34]=1)/[CH:12]=[CH:13]/[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][C:20](=[O:28])[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])[C:8]([OH:10])=[O:9])(=O)C.CO.[Li+].[OH-]>O>[CH2:40]([O:39][C:36]1[CH:35]=[CH:34][C:33]([CH2:32][C@H:31]([NH:30][C:29]([C@@H:11](/[CH:12]=[CH:13]/[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][C:20](=[O:28])[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])[C@@:7]([OH:50])([CH2:6][CH2:5][OH:4])[C:8]([OH:10])=[O:9])=[O:49])[CH2:44][OH:45])=[CH:38][CH:37]=1)[C:41]#[C:42][CH3:43]
Reactant: CC#CCOc1ccc(C[C@@H](COC(C)=O)NC(=O)[C@@H](/C=C/CCCCCCC(=O)CCCCCCC)[C@@](O)(CCOC(C)=O)C(=O)O)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CC#CCOc1ccc(C[C@@H](CO)NC(=O)[C@@H](/C=C/CCCCCCC(=O)CCCCCCC)[C@@](O)(CCO)C(=O)O)cc1
Temperature: 25 °C
Yield: 59.9 %

Procedure:
To a mixture of No. 5257015 , (E)-(2S,3S)-2-(2-acetoxy-ethyl)-3-[(S)-1-acetoxymethyl-2-(4-but-2-ynyloxy-phenyl)-ethylcarbamoyl]-2-hydroxy-12-oxo-nonadec-4-enoic acid (17 mg, 0.0244 mmol) and methanol (1.7 mL) were added water (49 μL) and LiOH (2.4 mg, 0.0983 mmol), and the mixture was stirred at room temperature. After confirming the consumption of the starting materials by LCMS, the reaction solution was purified directly by preparative HPLC, and freeze-dried to obtain the title compound (9 mg, 60% yield, yellow oil).
Reaction SMILES: [F:1][C:2]([F:32])([F:31])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:10]([C:15]([NH:17][C:18]3[CH:27]=[C:26]4[C:21]([CH:22]=[C:23]([C:28](O)=[O:29])[CH:24]=[N:25]4)=[CH:20][CH:19]=3)=[O:16])=[CH:11][CH:12]=[CH:13][CH:14]=2)=[CH:5][CH:4]=1.[CH:33]([NH2:36])([CH3:35])[CH3:34].Cl.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1.C(N(CC)CC)C>ClCCl>[CH:33]([NH:36][C:28]([C:23]1[CH:24]=[N:25][C:26]2[C:21]([CH:22]=1)=[CH:20][CH:19]=[C:18]([NH:17][C:15]([C:10]1[C:9]([C:6]3[CH:5]=[CH:4][C:3]([C:2]([F:32])([F:1])[F:31])=[CH:8][CH:7]=3)=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:16])[CH:27]=2)=[O:29])([CH3:35])[CH3:34]
Reactant: O=C(O)c1cnc2cc(NC(=O)c3ccccc3-c3ccc(C(F)(F)F)cc3)ccc2c1
Reactant: CC(C)N
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)NC(=O)c1cnc2cc(NC(=O)c3ccccc3-c3ccc(C(F)(F)F)cc3)ccc2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 87.4 %

Procedure:
7-[(4′-Trifluoromethyl-biphenyl-2-carbonyl)-amino]-quinoline-3-carboxylic acid (100 mg, 0.23 mmol) was combined with isopropylamine (16 mg, 0.27 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (53 mg, 0.27 mmol), 1-hydroxybenzotriazole (34 mg, 0.25 mmol), and triethylamine (0.13 ml, 0.92 mmol) in 1.5 ml of dichloromethane. After stirring overnight at ambient temperature the reaction mixture was diluted with 50 ml of dichloromethane, and the organic phase washed sequentially with water, and brine, and then dried over anhydrous magnesium sulfate, filtered and concentrated under vacuum to afford 96 mg of the title compound as a yellow solid.
Reaction SMILES: [CH2:1]([S:3]([C:6]1[CH:7]=[C:8]([C:12]2[CH:20]=[CH:19][C:18]([OH:21])=[C:17]3[C:13]=2[C:14]2[CH:25]=[C:24]([CH3:26])[CH:23]=[N:22][C:15]=2[NH:16]3)[CH:9]=[CH:10][CH:11]=1)(=[O:5])=[O:4])[CH3:2].C(S(C1C=C(C2C=C[C:44]([O:47][CH2:48]CCN(C)C)=[C:43]3C=2C2C=C(C)C=NC=2N3)C=CC=1)(=O)=O)C>>[CH2:1]([S:3]([C:6]1[CH:7]=[C:8]([C:12]2[CH:20]=[CH:19][C:18]([O:21][CH2:43][CH2:44][O:47][CH3:48])=[C:17]3[C:13]=2[C:14]2[CH:25]=[C:24]([CH3:26])[CH:23]=[N:22][C:15]=2[NH:16]3)[CH:9]=[CH:10][CH:11]=1)(=[O:5])=[O:4])[CH3:2]
Reactant: CCS(=O)(=O)c1cccc(-c2ccc(OCCCN(C)C)c3[nH]c4ncc(C)cc4c23)c1
Reactant: CCS(=O)(=O)c1cccc(-c2ccc(O)c3[nH]c4ncc(C)cc4c23)c1
Product: CCS(=O)(=O)c1cccc(-c2ccc(OCCOC)c3[nH]c4ncc(C)cc4c23)c1

Procedure:
The title compound was synthesized from Compound 157 using an analogous procedure to that outlined in the preparation of Compound 205. 1H NMR (400 MHz, CDCl3) δ 8.22 (s, 1 H) 8.19 (s, 1 H) 8.14 (m, 1 H) 8.06 (m, 1 H) 7.91 (m, 1 H) 7.81 (m, 1 H) 7.28 (d, J=8.32 Hz, 1 H) 7.22 (d, J=8.32 Hz, 1 H) 4.44 (m, 2 H) 3.95 (m, 2 H) 3.58 (s, 3 H) 3.23 (q, J=7.32 Hz, 2 H) 2.49 (s, 3 H) 1.37 (t, J=7.32 Hz, 3 H). [M+H] calc'd for C23H25N2O4S, 425; found, 425.
Reaction SMILES: [CH3:1][C:2]([CH3:9])([CH2:7][OH:8])[C@@H:3]([OH:6])[CH2:4][OH:5].[CH3:10][C:11]1C=CC(S(O)(=O)=O)=C[CH:12]=1>CC(C)=O>[CH3:10][C:11]1([CH3:12])[O:6][C@H:3]([C:2]([CH3:9])([CH3:1])[CH2:7][OH:8])[CH2:4][O:5]1
Reactant: CC(C)(CO)[C@@H](O)CO
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CC(C)=O
Product: CC1(C)OC[C@@H](C(C)(C)CO)O1
Temperature: 25 °C
Reaction time: 8 h
Yield: 9756.8 %

Procedure:
(R)-3,3-dimethylbutane-1,2,4-triol (2.7 g, 20 mmol) and 4-methylbenzenesulfonic acid (0.017 g, 0.10 mmol) were added to 25 mL of acetone and catalytic 4-methylbenzenesulfonic acid (0.017 g, 0.10 mmol) and stirred overnight at ambient temperature. The solution was evaporated, and to the residue was added ethyl acetate. The organic layer was washed with aqueous Na2CO3, dried over MgSO4 and filtered. The filtrate was concentrated to provide 1.7 g of the desired product as a clear oil.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([NH2:8])[N:3]=1.[Br:9]N1C(=O)CCC1=O.C(Cl)Cl>C(Cl)(Cl)Cl>[Br:9][C:7]1[C:2]([CH3:1])=[N:3][C:4]([NH2:8])=[N:5][CH:6]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1ccnc(N)n1
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Product: Cc1nc(N)ncc1Br
Reaction time: 15 h
Yield: 100 %

Procedure:
To a solution of 4-methylpyrimidine-2-ylamine (10.9 g, 100 mmol) in chloroform (400 mL) was added N-bromosuccinimide (17.8 g, 100 mmol). The solution was stirred in the dark for 15 hours, at which time it was added to CH2Cl2 (1400 mL), washed with 1N NaOH (3×200 mL) and NaCl(sat.) (100 mL), dried over Na2SO4, filtered and concentrated, yielding 5-bromo-4-methylpyrimidine-2-ylamine (18.8 g, 99%). LCMS (m/z): 188.0/190.0 (MH+). 1H NMR (CDCl3): δ 8.22 (s, 1H), 5.02 (bs, 2H), 2.44 (s, 3H).
Reaction SMILES: Cl.[NH2:2][C@@H:3]1[C:19](=[O:20])[N:5]2[C:6]([C:11]([O:13][CH2:14][C:15]([Cl:18])([Cl:17])[Cl:16])=[O:12])=[C:7]([CH3:10])[CH2:8][S:9][C@H:4]12.O.C(=O)(O)[O-].[Na+].[OH:27][C:28]1[C:35]([C:36]([CH3:39])([CH3:38])[CH3:37])=[CH:34][C:31]([CH:32]=O)=[CH:30][C:29]=1[C:40]([CH3:43])([CH3:42])[CH3:41]>CO>[OH:27][C:28]1[C:35]([C:36]([CH3:38])([CH3:37])[CH3:39])=[CH:34][C:31]([CH:32]=[N:2][C@@H:3]2[C:19](=[O:20])[N:5]3[C:6]([C:11]([O:13][CH2:14][C:15]([Cl:16])([Cl:18])[Cl:17])=[O:12])=[C:7]([CH3:10])[CH2:8][S:9][C@H:4]23)=[CH:30][C:29]=1[C:40]([CH3:43])([CH3:42])[CH3:41]
Reactant: CC1=C(C(=O)OCC(Cl)(Cl)Cl)N2C(=O)[C@@H](N)[C@H]2SC1
Reactant: CC(C)(C)c1cc(C=O)cc(C(C)(C)C)c1O
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CC1=C(C(=O)OCC(Cl)(Cl)Cl)N2C(=O)[C@@H](N=Cc3cc(C(C)(C)C)c(O)c(C(C)(C)C)c3)[C@H]2SC1
Reaction time: 4 h

Procedure:
To 10 g. of 2,2,2-trichloroethyl 7β-amino-3-methyl-3-cephem-4-carboxylate hydrochloride was added about 70 ml. of water. About 2.5 g. of sodium bicarbonate was added thereto and, after stirring for a while, the resultant was extracted with ethyl acetate. The extract was dried over anhydrous sodium sulfate and concentrated at a temperature below 35° C. The so obtained free base was dissolved in 40 ml. of methanol and 5 g. of 4-hydroxy-3,5-di-tert.-butylbenzaldehyde was added thereto and stirring was continued at room temperature for 4 hours. The insolubles were dissolved by heating briefly and the reaction mixture was concentrated into a half amount thereof, which was then cooled to separate out crystalline substances. The substances were recovered by filtration and washed with cold methanol to give 2,2,2-trichloroethyl 7β-(4-hydroxy-3,5-di-tert.-butylbenzylideneamino)-3-methyl-3-cephem-4-carboxylate. Yield 7 g. The product was recrystallized from a small amount of methanol to give the pure product as slightly yellow colored crystals. m.p. 94° C.