Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[C:5]([O:9][CH3:10])=[CH:4][N:3]=1.[CH:11]1([CH:16]([N:20]2[CH:24]=[C:23](B3OC(C)(C)C(C)(C)O3)[CH:22]=[N:21]2)[CH2:17][C:18]#[N:19])[CH2:15][CH2:14][CH2:13][CH2:12]1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1.O.CCOC(C)=O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:1][C:2]1[N:7]=[C:6]([C:23]2[CH:22]=[N:21][N:20]([CH:16]([CH:11]3[CH2:15][CH2:14][CH2:13][CH2:12]3)[CH2:17][C:18]#[N:19])[CH:24]=2)[C:5]([O:9][CH3:10])=[CH:4][N:3]=1
Reactant: COc1cnc(Cl)nc1Cl
Reactant: CC1(C)OB(c2cnn(C(CC#N)C3CCCC3)c2)OC1(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: COc1cnc(Cl)nc1-c1cnn(C(CC#N)C2CCCC2)c1
Temperature: 100 °C
Yield: 81.8 %

Procedure:
A mixture of 2,4-dichloro-5-methoxypyrimidine (0.68 g, 3.8 mmol), 3-cyclopentyl-3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)propanenitrile (1.0 g, 3.17 mmol), tetrakis(triphenylphosphine)palladium (200 mg, 0.2 mmol), and potassium phosphate (2.0 g, 9.6 mmol) in 1,4-dioxane (9 mL) and water (0.9 mL) was heated at 100° C. overnight. After cooling to room temperature, the mixture was diluted with EtOAc, washed with water, brine, dried over MgSO4, concentrated. The residue was purified on silica gel, eluting with 0 to 60% EtOAc-hexanes, to give the desired product (860 mg, 82%). LCMS (M+H) 331.9.
Reaction SMILES: [CH2:1]([S:3]([N:6]1[CH2:11][CH2:10][CH:9]([C:12]2[C:20]3[C:15](=[C:16]([C:33]([NH2:35])=[O:34])[CH:17]=[C:18]([C:21]4[CH:22]=[C:23]5[C:27](=[CH:28][CH:29]=4)[CH2:26][N:25]([CH:30]([CH3:32])[CH3:31])[CH2:24]5)[CH:19]=3)[NH:14][CH:13]=2)[CH2:8][CH2:7]1)(=[O:5])=[O:4])[CH3:2].[CH3:36]C(=O)C>>[CH2:1]([S:3]([N:6]1[CH2:7][CH2:8][CH:9]([C:12]2[C:20]3[C:15](=[C:16]([C:33]([NH2:35])=[O:34])[CH:17]=[C:18]([C:21]4[CH:22]=[C:23]5[C:27](=[CH:28][CH:29]=4)[CH2:26][N:25]([CH:30]([CH3:31])[CH2:32][CH3:36])[CH2:24]5)[CH:19]=3)[NH:14][CH:13]=2)[CH2:10][CH2:11]1)(=[O:4])=[O:5])[CH3:2]
Reactant: CC(C)=O
Reactant: CCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(-c4ccc5c(c4)CN(C(C)C)C5)cc23)CC1
Product: CCC(C)N1Cc2ccc(-c3cc(C(N)=O)c4[nH]cc(C5CCN(S(=O)(=O)CC)CC5)c4c3)cc2C1

Procedure:
The title compound was prepared according to the general procedure of 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-[2-(1-methylethyl)-2,3-dihydro-1H-isoindol-5-yl]-1H-indole-7-carboxamide, substituting 2-butanone (14 mg, 0.198 mmol) for 2-propanone to afford 14.6 mg of the title compound.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH:26]=[C:27]([O:29][CH2:30][C:31]2[N:32]=[C:33]([C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=3)[S:34][CH:35]=2)[CH:28]=1)[CH2:7][N:8]1[CH:12]=[C:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:10]([CH2:19][CH2:20][C:21]([O:23]CC)=[O:22])=[CH:9]1)[CH3:2].[OH-].[Na+].O1CCCC1.Cl>C(O)C>[CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH:26]=[C:27]([O:29][CH2:30][C:31]2[N:32]=[C:33]([C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=3)[S:34][CH:35]=2)[CH:28]=1)[CH2:7][N:8]1[CH:12]=[C:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:10]([CH2:19][CH2:20][C:21]([OH:23])=[O:22])=[CH:9]1)[CH3:2]
Reactant: CCOC(=O)CCc1cn(Cc2cc(OCC)cc(OCc3csc(-c4ccccc4)n3)c2)cc1-c1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: CCOc1cc(Cn2cc(CCC(=O)O)c(-c3ccccc3)c2)cc(OCc2csc(-c3ccccc3)n2)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 95.1 %

Procedure:
After a mixture of ethyl 3-[1-[3-ethoxy-5-(2-phenyl-4-thiazolylmethoxy)benzyl]-4-phenyl-3-pyrrolyl]propionate (595 mg), 1N aqueous sodium hydroxide solution (2.5 ml), tetrahydrofuran (5 ml) and ethanol (5 ml) was stirred at room temperature for 2 hours, 1 N hydrochloric acid (2.5 ml) was added to the mixture, and then the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated aqueous sodium chloride solution, dried (MgSO4) and concentrated. The resulting colorless crystals were collected by filtration to obtain 3-[1-[3-ethoxy-5-(2-phenyl-4-thiazolylmethoxy)benzyl]-4-phenyl-3-pyrrolyl]propionic acid (538 mg, yield: 95%). This was recrystallized from ethanol-hexane. Melting point: 109–110° C.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:6]=[CH:7][C:8]2[CH2:13][O:12][CH:11]([CH2:14][NH:15][CH2:16][CH2:17][CH3:18])[O:10][C:9]=2[CH:19]=1)(=[O:4])=[O:3].[CH2:20](Br)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.C(=O)([O-])[O-].[K+].[K+].C(#N)C>CCOC(C)=O>[CH2:20]([N:15]([CH2:14][CH:11]1[O:10][C:9]2[CH:19]=[C:5]([S:2]([CH3:1])(=[O:4])=[O:3])[CH:6]=[CH:7][C:8]=2[CH2:13][O:12]1)[CH2:16][CH2:17][CH3:18])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: BrCc1ccccc1
Reactant: CCCNCC1OCc2ccc(S(C)(=O)=O)cc2O1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CC#N
Product: CCCN(Cc1ccccc1)CC1OCc2ccc(S(C)(=O)=O)cc2O1
Yield: 76.1 %

Procedure:
N-{[7-(methylsulfonyl)-4H-1,3-benzodioxin-2-yl]methyl}propan-1-amine (1.2 g, 4.2 mmol), benzylbromide (0.53 ml, 4.4 mmol), potassium carbonate (0.70 g, 5.0 mmol) and ACN (50 ml) were heated at 60° C. for 2.5 h. EtOAc (100 ml) was added and the mixture was filtered and evaporated to dryness. Purification by flash chromatography (isooctane/EtOAc 1:1) and evaporation of pure fractions afforded the title compound (1.2 g). 1H-NMR (400 MHz, MeOH): δ 7.48 (1H, dd, J1 8.0 Hz, J2 2.0 Hz), δ 7.38-7.21 (7H, m), δ 5.18 (1H, t, J 5.6 Hz), δ 4.97 (2H, dd, J1 41.6 Hz, J2 15.6 Hz), δ 3.77 (2H, q, J 13.6 Hz), δ 3.10 (3H, s), δ 2.94-2.84 (2H, m), δ 2.58 (2H, dt, J1 7.2 Hz, J2 1.6 Hz), δ 1.56 (2H, m), δ 0.90 (2H, t, J 7.2 Hz).
Reaction SMILES: C([O:8][C:9]1[C:10]([S:15]([NH2:18])(=[O:17])=[O:16])=[N:11][CH:12]=[CH:13][CH:14]=1)C1C=CC=CC=1>[Pd].CO>[OH:8][C:9]1[C:10]([S:15]([NH2:18])(=[O:17])=[O:16])=[N:11][CH:12]=[CH:13][CH:14]=1
Reactant: NS(=O)(=O)c1ncccc1OCc1ccccc1
Agent: [Pd]
Solvent: CO
Product: NS(=O)(=O)c1ncccc1O

Procedure:
A solution of 263.7 g of 3-benzyloxy-pyrid-2-ylsulfonamide in 2.5 of methanol is hydrogenated with the addition of 26 g of 5% Pd/C catalyst. After 23.8 of hydrogen have been absorbed, the catalyst is filtered off. After evaporation of the methanol, 3-hydroxypyrid-2-ylsulfonamide remains in the form of a crystalline mass. Melting point 162°-164° C.
Reaction SMILES: [N:1]1[C:6]([CH2:7][OH:8])=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:9][OH:10].[H-].[Na+].[CH2:13](Br)[CH:14]=[CH2:15].O>CN(C=O)C>[CH2:15]([O:8][CH2:7][C:6]1[N:1]=[C:2]([CH2:9][OH:10])[CH:3]=[CH:4][CH:5]=1)[CH:14]=[CH2:13]
Reactant: C=CCBr
Reactant: OCc1cccc(CO)n1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: C=CCOCc1cccc(CO)n1
Reaction time: 0.5 h
Yield: 24.2 %

Procedure:
A solution of 2,6-pyridinedimethanol (5.0 g, 35.9 mmol) in DMF (30 mL) at 0° C. was treated with sodium hydride (1.44 g, 35.9 mmol), stirred for 30 min, treated with allyl bromide (3.42 ml, 39.5 mmol), stirred for 16 h at room temperature, poured into water (150 mL), extracted with EtOAc (3×30 mL) and the combined organic phase was dried (MgSO4), concentrated in vacuo and purified by chromatography [SiO2; isohexane:EtOAc (3:1 to 1:1)] to give the title compound (1.56 g, 24%) as a colourless oil: NMR δH (400 MHz, CDCl3) 7.69 (1H, t, J 7.5 Hz), 7.37 (1H, d, J 7.5 Hz), 7.13 (1H, d, J 7.5 Hz) 6.04-5.93 (1H, m), 5.38-5.21 (2H, m), 4.74 (2H, d, J 5.0 Hz), 4.65 (2H, s), 4.15-4.09 (2H, m) and 3.76 (1H, t, J 5.0 Hz).
Reaction SMILES: [CH3:1][O:2]/[N:3]=[C:4](/[C:35]1[N:36]=[C:37]([NH:40]C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[S:38][CH:39]=1)\[C:5]([NH:7][CH:8]1[C:33](=[O:34])[N:10]2[C:11]([C:17]([O:19]C(C3C=CC=CC=3)C3C=CC=CC=3)=[O:18])=[C:12]([CH2:15]I)[CH2:13][S:14][C@H:9]12)=[O:6].C(OC([NH:67][CH2:68][C:69]([NH:71][C:72]1[S:73][C:74]2[CH:79]=[CH:78][N:77]=[CH:76][C:75]=2[N:80]=1)=[O:70])=O)(C)(C)C.C(O)(C(F)(F)F)=O>CS(C)=O.CCOCC.C1(OC)C=CC=CC=1>[NH2:40][C:37]1[S:38][CH:39]=[C:35](/[C:4](=[N:3]/[O:2][CH3:1])/[C:5]([NH:7][CH:8]2[C:33](=[O:34])[N:10]3[C:11]([C:17]([O-:19])=[O:18])=[C:12]([CH2:15][N+:77]4[CH:78]=[CH:79][C:74]5[S:73][C:72]([NH:71][C:69](=[O:70])[CH2:68][NH2:67])=[N:80][C:75]=5[CH:76]=4)[CH2:13][S:14][C@H:9]23)=[O:6])[N:36]=1
Reactant: CO/N=C(\C(=O)NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(CI)CS[C@H]12)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Reactant: CC(C)(C)OC(=O)NCC(=O)Nc1nc2cnccc2s1
Solvent: COc1ccccc1
Solvent: O=C(O)C(F)(F)F
Solvent: CCOCC
Product: CO/N=C(\C(=O)NC1C(=O)N2C(C(=O)[O-])=C(C[n+]3ccc4sc(NC(=O)CN)nc4c3)CS[C@H]12)c1csc(N)n1
Reaction time: 2 h
Yield: 96 %

Procedure:
A mixture of diphenylmethyl 7-[(Z)-2-methoxyimino-2-(2-tritylaminothiazol-4-yl)acetamido]-3-iodomethyl-3-cephem-4-carboxylate [VIIa] (237 mg, 0.29 mmole) and 2-(N-t-butoxycarbonylglycylamino)thiazolo[4,5-c]pyridine (95 mg, 0.31 mmole) in 2 ml of dry DMSO was allowed to stand at room temperature for 2 hours and then diluted with ether to give the crude quaternary salt, which was treated with 90% TFA and 2 drops of anisole at room temperature for 30 minutes. The mixture was evaporated and triturated with ether to afford 168 mg of pale yellow precipitate, which was purified by a column of HP-20 resin (40 ml) using 30% aqueous CH3OH as an eluant to give 88 mg of the title product Iq. Mp. 178°-187° C. (dec.). Estimated purity by HPLC: 60%.
Reaction SMILES: OC1C=CC=CN=1.[C:8]([O:12][C:13](=[O:42])[NH:14][C@H:15]([C@@H:33]1[CH2:37][C@@H:36]([CH2:38][CH2:39][CH3:40])[C:35](=[O:41])[O:34]1)[CH2:16][N:17]1[CH2:22][C:21](=[O:23])[N:20]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[Cl:30])[CH2:19][C:18]1([CH3:32])[CH3:31])([CH3:11])([CH3:10])[CH3:9].O.[CH3:44][C:45]([CH3:49])([CH3:48])[CH2:46][NH2:47]>>[C:8]([O:12][C:13](=[O:42])[NH:14][C@@H:15]([CH2:16][N:17]1[CH2:22][C:21](=[O:23])[N:20]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[Cl:30])[CH2:19][C:18]1([CH3:32])[CH3:31])[C@@H:33]([OH:34])[CH2:37][C@H:36]([C:35](=[O:41])[NH:47][CH2:46][C:45]([CH3:49])([CH3:48])[CH3:44])[CH2:38][CH2:39][CH3:40])([CH3:11])([CH3:9])[CH3:10]
Reactant: CC(C)(C)CN
Reactant: CCC[C@@H]1C[C@@H]([C@H](CN2CC(=O)N(c3ccccc3Cl)CC2(C)C)NC(=O)OC(C)(C)C)OC1=O
Agent: Oc1ccccn1
Solvent: O
Product: CCC[C@H](C[C@H](O)[C@H](CN1CC(=O)N(c2ccccc2Cl)CC1(C)C)NC(=O)OC(C)(C)C)C(=O)NCC(C)(C)C
Temperature: 80 °C
Reaction time: 5 h
Yield: 94 %

Procedure:
3.8 mg of 2-hydroxypyridine (0.04 mmol) was added to a solution of 101 mg of {(S)-2-[4-(2-chlorophenyl)-2,2-dimethyl-5-oxopiperazin-1-yl]-1-[(2S,4R)-5-oxo-4-propyltetrahydrofuran-2-yl]ethyl}carbamic acid t-butyl ester obtained in Example (116i) (0.2 mmol) in (2,2-dimethylpropyl)amine (1 ml), and the mixture was stirred at 80° C. for five hours. The reaction mixture was cooled and then water was added, followed by extraction with ethyl acetate. Then, the organic layer was dried over anhydrous magnesium sulfate. After filtration, the solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (elution solvent:methylene chloride/methanol=30/1-20/1) to obtain 111 mg of the title compound (yield: 94%).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C@H:9]([C:11]2[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=2)[CH3:10])[N:5]=[C:4]([C:18]2[CH:19]=[N:20][CH:21]=[N:22][CH:23]=2)[CH:3]=1.[NH2:24][C:25]1[CH:30]=[N:29][CH:28]=[CH:27][N:26]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1>[F:17][C:14]1[CH:15]=[CH:16][C:11]([C@@H:9]([NH:8][C:6]2[N:5]=[C:4]([C:18]3[CH:19]=[N:20][CH:21]=[N:22][CH:23]=3)[CH:3]=[C:2]([NH:24][C:25]3[CH:30]=[N:29][CH:28]=[CH:27][N:26]=3)[N:7]=2)[CH3:10])=[CH:12][CH:13]=1
Reactant: C[C@H](Nc1nc(Cl)cc(-c2cncnc2)n1)c1ccc(F)cc1
Reactant: Nc1cnccn1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: C[C@H](Nc1nc(Nc2cnccn2)cc(-c2cncnc2)n1)c1ccc(F)cc1
Temperature: 100 °C
Reaction time: 3 h
Yield: 28.3 %

Procedure:
To 90 mg of (S)-6-chloro-N-[1-(4-fluorophenyl)ethyl]-4,5′-bipyrimidine-2-amine, 31 mg of 2-aminopyrazine, 31 mg of 4,5-bis(diphenylphosphino)-9,9′-dimethylxanthene, 116 mg of tripotassium phosphate and 28 mg of tris(dibenzylideneacetone)(chloroform)dipalladium, was added 2 ml of 1,4-dioxane, and the mixture was subjected to degassing, and substituted by argon gas, and then was stirred at 100° C. for 3 hours. The reaction solution was diluted with ethyl acetate. The solution was washed in turn with water and brine and then dried over magnesium sulfate. The solvent was distilled off under reduced pressure, and then the obtained residue was purified by silica gel column chromatography to obtain 30 mg of the objective compound as pale yellow powder.
Reaction SMILES: C(Cl)Cl.[OH:4][C:5]1[C:14]2[C:9](=[C:10]([F:17])[C:11]([F:16])=[C:12]([F:15])[CH:13]=2)[N:8]=[C:7]([SH:18])[C:6]=1[C:19]([O:21][CH2:22][CH3:23])=[O:20].C(N(CC)CC)C.[C:31]([O:34][CH2:35][C:36]([CH2:38]Cl)=[O:37])(=[O:33])[CH3:32]>C(Cl)(Cl)Cl>[C:31]([O:34][CH2:35][C:36](=[O:37])[CH2:38][S:18][C:7]1[C:6]([C:19]([O:21][CH2:22][CH3:23])=[O:20])=[C:5]([OH:4])[C:14]2[C:9](=[C:10]([F:17])[C:11]([F:16])=[C:12]([F:15])[CH:13]=2)[N:8]=1)(=[O:33])[CH3:32]
Reactant: CCOC(=O)c1c(S)nc2c(F)c(F)c(F)cc2c1O
Reactant: CC(=O)OCC(=O)CCl
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CCOC(=O)c1c(SCC(=O)COC(C)=O)nc2c(F)c(F)c(F)cc2c1O
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 81.9 %

Procedure:
To methylene chloride (500 ml) were added ethyl 4-hydroxy-2-mercapto-6,7,8-trifluoroquinoline-3-carboxylate (33 g), triethylamine (22 g) and 1-acetoxy-3-chloroacetone (16.4 g) and the mixture was stirred at room temperature for 15 minutes. Chloroform (700 ml) was added to the reaction solution and washed with 0.1N hydrochloric acid, water and a NaCl solution in this order, dried over anhydrous magnesium sulfate and evaporated to dryness under reduced pressure. The residue was recrystallized from ethyl acetate to give the title compound (37.2 g) as colorless crystals, m.p. 175°-180° C.
Reaction SMILES: C(C1C=CC=CC=1S(O)(=O)=O)CCCCCCCCCCC.CO[CH2:25][CH:26]1[O:31][CH2:30][C:29]2([CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]2)[CH2:28][O:27]1>>[CH2:28]1[C:29]2([CH2:32][CH2:33][CH2:34][CH2:35][CH2:36]2)[CH2:30][O:31][CH:26]=[CH:25][O:27]1
Reactant: COCC1OCC2(CCCCC2)CO1
Agent: CCCCCCCCCCCCc1ccccc1S(=O)(=O)O
Product: C1=COCC2(CCCCC2)CO1

Procedure:
250 g of vacuum gas oil were initially taken with 2.5 g of dodecylbenzenesulfonic acid at 250° C. in a stirred flask and nitrogen was passed in. 3-Methoxymethyl2,4-dioxaspiro[5.5]undecane was pumped in at a rate of 20 ml/h and the reaction products were distilled off simultaneously. The crude distillate was then worked up by distillation and gave, in addition to methanol, 83 g of 2,5-dioxaspiro[6.5]dodec-3-ene of boiling point 117° C./30 mbar and 268 g of unconsumed starting material; this corresponded to a conversion with respect to 3-methoxymethyl-2,4-dioxaspiro[5.5]undecane of 31% and a selectivity of 82%.
Reaction SMILES: C(OC([N:8]1[C@H:12]([C:13](O)=O)[C@@H:11]([CH3:16])[O:10]C1(C)C)=O)(C)(C)C.[NH2:19][C:20]1[C:21]([Cl:36])=[C:22]([C:27]2[CH:32]=[CH:31][C:30]([C:33]#[N:34])=[C:29]([F:35])[CH:28]=2)[CH:23]=[CH:24][C:25]=1[NH2:26]>>[NH2:8][C@H:12]([C:13]1[NH:26][C:25]2[CH:24]=[CH:23][C:22]([C:27]3[CH:32]=[CH:31][C:30]([C:33]#[N:34])=[C:29]([F:35])[CH:28]=3)=[C:21]([Cl:36])[C:20]=2[N:19]=1)[C@H:11]([OH:10])[CH3:16]
Reactant: N#Cc1ccc(-c2ccc(N)c(N)c2Cl)cc1F
Reactant: C[C@H]1OC(C)(C)N(C(=O)OC(C)(C)C)[C@@H]1C(=O)O
Product: C[C@@H](O)[C@H](N)c1nc2c(Cl)c(-c3ccc(C#N)c(F)c3)ccc2[nH]1

Procedure:
The title compound was prepared according to Method 4 using (4S,5R)-3-(tert-butoxycarbonyl)-2,2,5-trimethyl-1,3-oxazolidine-4-carboxylic acid (Preparation 57) and 3′,4′-diamino-2′-chloro-3-fluorobiphenyl-4-carbonitrile (Preparation 80). The final residue was purified using silica gel column chromatography eluting with DCM:MeOH (7N NH3), 97:3 to 93:7 and freeze dried for 18 hours.
Reaction SMILES: [Cr](Cl)([O-])(=O)=O.[NH+]1C=CC=C[CH:7]=1.[OH:12][CH2:13][C:14]1[CH:19]=[C:18]([CH2:20][O:21][CH3:22])[C:17]([CH:23]([CH3:25])[CH3:24])=[CH:16][C:15]=1[CH:26]([CH3:28])[CH3:27]>C(Cl)Cl>[CH:26]([C:15]1[CH:16]=[C:17]([CH:23]([CH3:24])[CH3:25])[C:18]([CH2:20][O:21][CH2:22][CH3:7])=[CH:19][C:14]=1[CH:13]=[O:12])([CH3:28])[CH3:27]
Reactant: COCc1cc(CO)c(C(C)C)cc1C(C)C
Reactant: c1cc[nH+]cc1
Agent: O=[Cr](=O)([O-])Cl
Solvent: ClCCl
Product: CCOCc1cc(C=O)c(C(C)C)cc1C(C)C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
17.2 g (80 mmol) of pyridinium chlorochromate are added to a solution of 15.7 g (66.5 mmol) of the compound from Example 4 in 300 ml of methylene chloride, the mixture is stirred overnight at room temperature, filtered with suction through kieselgur, washed with 200 ml of methylene chloride, and dried using sodium sulphate.
Reaction SMILES: Br[C:2]1[CH:6]=[CH:5][S:4][C:3]=1[C:7]([N:9]([C:17]1[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[C:19]([F:25])[C:18]=1[F:26])C(=O)OC(C)(C)C)=[O:8]>CC(C)([P](C(C)(C)C)([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)C(C)(C)C)C>[F:26][C:18]1[C:17]2[NH:9][C:7](=[O:8])[C:3]3[S:4][CH:5]=[CH:6][C:2]=3[C:22]=2[CH:21]=[C:20]([O:23][CH3:24])[C:19]=1[F:25]
Reactant: COc1ccc(N(C(=O)OC(C)(C)C)C(=O)c2sccc2Br)c(F)c1F
Agent: CC(C)(C)[P]([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)(C(C)(C)C)C(C)(C)C
Product: COc1cc2c([nH]c(=O)c3sccc32)c(F)c1F
Yield: 7 %

Procedure:
Following Step 3 from General Procedure A, tert-butyl 3-bromothiophene-2-carbonyl(2,3-difluoro-4-methoxyphenyl)carbamate (1.4 g, 3.1 mmol) was reacted with bis(tri-tert-butylphosphine)palladium (80 mg, 0.15 mmol) to afford the desired product (58 mg, 65%) as a brown solid: ESI MS m/z 268 [C12H7F2NO2S+H]+.
Reaction SMILES: [C:1]1([S:7][C:8]([CH3:18])([CH3:17])[C:9]([CH2:11][C:12]([O:14]CC)=O)=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl:19][C:20]1[CH:26]=[CH:25][C:24]([NH:27][C:28](=[O:49])[CH:29]([O:32][C:33]2[CH:38]=[CH:37][C:36]([C:39]([CH2:42][CH3:43])([CH3:41])[CH3:40])=[CH:35][C:34]=2[C:44]([CH2:47][CH3:48])([CH3:46])[CH3:45])[CH2:30][CH3:31])=[CH:23][C:21]=1[NH2:22]>>[Cl:19][C:20]1[CH:26]=[CH:25][C:24]([NH:27][C:28](=[O:49])[CH:29]([O:32][C:33]2[CH:38]=[CH:37][C:36]([C:39]([CH2:42][CH3:43])([CH3:41])[CH3:40])=[CH:35][C:34]=2[C:44]([CH2:47][CH3:48])([CH3:46])[CH3:45])[CH2:30][CH3:31])=[CH:23][C:21]=1[NH:22][C:12](=[O:14])[CH2:11][C:9](=[O:10])[C:8]([S:7][C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)([CH3:17])[CH3:18]
Reactant: CCC(Oc1ccc(C(C)(C)CC)cc1C(C)(C)CC)C(=O)Nc1ccc(Cl)c(N)c1
Reactant: CCOC(=O)CC(=O)C(C)(C)Sc1ccccc1
Product: CCC(Oc1ccc(C(C)(C)CC)cc1C(C)(C)CC)C(=O)Nc1ccc(Cl)c(NC(=O)CC(=O)C(C)(C)Sc2ccccc2)c1
Temperature: 150 °C
Reaction time: 3 h
Yield: 75 %

Procedure:
A mixture of 5.2 g of ethyl (2-phenylthio-2-methylpropionyl)acetate obtained in Step 1 of Synthesis Example 8 and 8.8 g of 2-chloro-5-[2-(2,4-di-tert-amylphenoxy)butyramido]aniline was stirred in an oil bath at 150° C for three hours under a reduced pressure of 15 to 20 mmHg. The reaction mixture was recrystallized from n-hexane to obtain 9.8 g (yield 75%) of Coupler (17) having a melting point of 73° to 75° C.
Reaction SMILES: [CH3:1][C:2]1[NH:6][CH:5]=[N:4][C:3]=1[C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([N+:13]([O-])=O)[CH:8]=1.[H][H]>CO.[Pd]>[CH3:1][C:2]1[NH:6][CH:5]=[N:4][C:3]=1[C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([NH2:13])[CH:8]=1
Reactant: [H][H]
Reactant: Cc1[nH]cnc1-c1cccc([N+](=O)[O-])c1
Agent: [Pd]
Solvent: CO
Product: Cc1[nH]cnc1-c1cccc(N)c1
Yield: 87.3 %

Procedure:
Eighty-four grams of 5-methyl-4-(3-nitrophenyl)-1-H-imidazole [R. Morgenstern et al., Pharmazie 30, 103 (1975)] dissolved in methanol were hydrogenated in the presence of 0.8 gm of 5% Pd catalyst at atmospheric pressure and at room temperature. When the calculated amount of hydrogen was taken up, the catalyst was filtered off, and the remaining solution was evaporated to dryness to produce 62.5 gm of the desired compound.
Reaction SMILES: CO.[BH4-].[Na+].[CH:5]1([N:10]=[CH:11][C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=2)[CH2:9][CH2:8][CH2:7][CH2:6]1.O>C(Cl)Cl>[F:18][C:15]1[CH:14]=[CH:13][C:12]([CH2:11][NH:10][CH:5]2[CH2:9][CH2:8][CH2:7][CH2:6]2)=[CH:17][CH:16]=1
Reactant: Fc1ccc(C=NC2CCCC2)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Solvent: ClCCl
Product: Fc1ccc(CNC2CCCC2)cc1
Yield: 93.7 %

Procedure:
160 ml of methanol are added to 18.2 g of sodium borohydride. 90.7 g of 4-fluorobenzaldehyde-cyclopentylimide are added dropwise at 10°-15° C., while cooling with ice and stirring, and the mixture was then stirred for 1.5 hours at room temperature. 120 ml of H2O and 150 ml of methylene chloride were then added, the methylene chloride phase was separated off, and the aqueous phase was further extracted twice with CH2Cl2. The combined methylene chloride phases were washed with water and dried with Na2SO4, and the solvent was stripped off in vacuo. Distillation of the residue under a medium vacuum gave 85.9 g of N-4-fluorobenzyl-N-cyclopentylamine of boiling point 106° C. 0.25 bar.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].C([O-])([O-])=O.[K+].[K+].Br[CH2:19][C:20]1[CH:25]=[CH:24][C:23]([B:26]2[O:34][C:31]([CH3:33])([CH3:32])[C:28]([CH3:30])([CH3:29])[O:27]2)=[CH:22][CH:21]=1>C(#N)C>[CH3:32][C:31]1([CH3:33])[C:28]([CH3:29])([CH3:30])[O:27][B:26]([C:23]2[CH:22]=[CH:21][C:20]([CH2:19][O:1][C:2]3[CH:11]=[CH:10][CH:9]=[CH:8][C:3]=3[C:4]([O:6][CH3:7])=[O:5])=[CH:25][CH:24]=2)[O:34]1
Reactant: COC(=O)c1ccccc1O
Reactant: CC1(C)OB(c2ccc(CBr)cc2)OC1(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COC(=O)c1ccccc1OCc1ccc(B2OC(C)(C)C(C)(C)O2)cc1
Temperature: 70 °C
Yield: 77 %

Procedure:
To 5 ml, of acetonitrile was added methyl 2-hydroxybenzoate (85 μL, 0.66 mmol), K2CO3 (273 mg, 2.0 mmol), and 4-bromomethylphenyl boronic acid pinacol ester (217 mg, 0.73 mmol). The reaction was heated to 70° C. under nitrogen overnight. After removal of the solvent via rotary evaporation, the resulting oil was brought up in EtOAc and washed with a saturated sodium bicarbonate solution to remove starting materials. The organic layer was dried over MgSO4, filtered and concentrated. The product was purified on a silica gel column eluting with 5% EtOAc in hexanes to yield B1 as a white solid in 77% yield (186 mg, 0.5 mmol). 1H NMR (400 MHz, CDCl3) δ=7.85-7.81 (m, 3H), 7.49 (d, J=7.6 Hz, 2H), 7.40 (dt, J1=8.4 Hz, J2=1.8 Hz, 1H), 7.00-6.96 (m, 2H), 5.20 (s, 2H), 3.90 (s, 3H), 1.35 (s, 12H). 13C NMR (100 MHz, CDCl3) δ=140.2, 135.2, 133.6, 132.0, 126.2, 121.0, 120.8, 114.0, 84.0, 70.7, 52.3, 25.1. ESI-MS(+): m/z 368.82 [M+H]+, 385.69 [M+NH4]+.
Reaction SMILES: [CH2:1]([C:3]1([CH2:18][CH:19]([OH:21])[CH3:20])[C:8]2[NH:9][C:10]3[C:15]([C:7]=2[CH2:6][CH2:5][O:4]1)=[CH:14][CH:13]=[CH:12][C:11]=3[CH2:16][CH3:17])[CH3:2].C(Cl)Cl.CS(C)=O.N1C=CC=CC=1.S(=O)(=O)=O>[Cl-].[Na+].O>[CH2:1]([C:3]1([CH2:18][C:19](=[O:21])[CH3:20])[C:8]2[NH:9][C:10]3[C:15]([C:7]=2[CH2:6][CH2:5][O:4]1)=[CH:14][CH:13]=[CH:12][C:11]=3[CH2:16][CH3:17])[CH3:2]
Reactant: CCc1cccc2c3c([nH]c12)C(CC)(CC(C)O)OCC3
Agent: O=S(=O)=O
Agent: [Cl-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Solvent: ClCCl
Product: CCc1cccc2c3c([nH]c12)C(CC)(CC(C)=O)OCC3
Reaction time: 8 h
Yield: 50.6 %

Procedure:
To a solution of compound 12 (77 mg, 0.27 mmol), CH2Cl2 (2 mL), dry DMSO (76 μL, 1.07 mmol, 4.0 eq), and dry TEA (374 μL, 2.68 mmol, 10.0 eq) at room temperature under argon, sulfur trioxide-pyridine complex (Pyr-SO3, 171 mg, 1.07 mmol, 4.0 eq) was added in a portion-wise manner and stirred overnight. The resulting mixture was then diluted with brine and extracted three times with EtOAc. The combined organic phases were dried with Na2SO4, concentrated, and purified by column chromatography using 15:85:EtOAc:Hexane to give an off-white solid (39 mg, 51%): mp 154-155° C. 1HNMR (CDCl3, δ TMS): 0.80 (t, 3H), 1.37 (t, 3H), 2.02 (m, 2H), 2.21 (s, 3H), 2.78 (m, 2H), 2.88 (q, 2H), 3.14 (s, 2H), 3.98 (m, 2H), 7.01-7.37 (m, 3H, Ar—H), 9.01 (br, 1H, NH). MS−: m/z 284 ([M−H]−). Anal. (C18H23NO2): C, H, N.