Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:18]=[CH:17][C:5]([O:6][C:7]2[CH:8]=[N:9][CH:10]=[C:11]([CH:16]=2)[C:12]([NH:14][CH3:15])=[O:13])=[CH:4][C:3]=1F.COC(=O)C1C=C(OC2C=CC(N)=C([F:37])C=2)C=NC=1>>[NH2:1][C:2]1[CH:18]=[CH:17][C:5]([O:6][C:7]2[CH:8]=[N:9][CH:10]=[C:11]([CH:16]=2)[C:12]([NH:14][CH3:15])=[O:13])=[C:4]([F:37])[CH:3]=1
Reactant: COC(=O)c1cncc(Oc2ccc(N)c(F)c2)c1
Reactant: CNC(=O)c1cncc(Oc2ccc(N)c(F)c2)c1
Product: CNC(=O)c1cncc(Oc2ccc(N)cc2F)c1

Procedure:
The title compound was prepared in the same manner described for 5-(4-amino-3-fluorophenoxy)-N-methylnicotinamide, substituting 5-(4-amino-2-fluorophenoxy)-nicotinic acid methyl ester for 5-(4-amino-3-fluorophenoxy)nicotinic acid methyl ester. 1H NMR (DMSO-d6) 67.80 (d, J=1.8 Hz, 1H), 7.53 (d, J=2.7 Hz, 1H), 6.83 to 6.81 (m, 1H), 6.15 (t, J=8.7 Hz, 1H), 5.78 to 5.67 (m, 2H), 4.07 (s, 3H), 2.07 (s, 3H).
Reaction SMILES: [CH2:1]([C:8]1[CH:9]=[N:10][C:11]2[C:16]([C:17]=1[C:18]1[CH:19]=[C:20]([NH2:24])[CH:21]=[CH:22][CH:23]=1)=[CH:15][CH:14]=[CH:13][C:12]=2[C:25]([F:28])([F:27])[F:26])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:29][C:30]1[CH:31]=[C:32]([CH:35]=[CH:36][C:37]=1[Cl:38])[CH:33]=O>>[CH2:1]([C:8]1[CH:9]=[N:10][C:11]2[C:16]([C:17]=1[C:18]1[CH:19]=[C:20]([NH:24][CH2:33][C:32]3[CH:35]=[CH:36][C:37]([Cl:38])=[C:30]([Cl:29])[CH:31]=3)[CH:21]=[CH:22][CH:23]=1)=[CH:15][CH:14]=[CH:13][C:12]=2[C:25]([F:28])([F:26])[F:27])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=Cc1ccc(Cl)c(Cl)c1
Reactant: Nc1cccc(-c2c(Cc3ccccc3)cnc3c(C(F)(F)F)cccc23)c1
Product: FC(F)(F)c1cccc2c(-c3cccc(NCc4ccc(Cl)c(Cl)c4)c3)c(Cc3ccccc3)cnc12

Procedure:
The title compound was prepared from {3-[3-benzyl-8-(trifluoromethyl)quinolin-4-yl]phenyl}amine and 3,4-dichlorobenzaldehyde according to the procedure of step 1, Example 66. MS (ESI) m/z 537.
Reaction SMILES: CO.[C:3]([NH:11][C:12]1[CH:20]=[C:19](/[CH:21]=[CH:22]/[C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH:18]=[CH:17][C:13]=1[C:14]([OH:16])=[O:15])(=[O:10])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1>[C].[Pd].C(OCC)(=O)C>[C:3]([NH:11][C:12]1[CH:20]=[C:19]([CH2:21][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH:18]=[CH:17][C:13]=1[C:14]([OH:16])=[O:15])(=[O:10])[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: O=C(Nc1cc(/C=C/c2ccccc2)ccc1C(=O)O)c1ccccc1
Agent: [Pd]
Solvent: CO
Solvent: CCOC(C)=O
Product: O=C(Nc1cc(CCc2ccccc2)ccc1C(=O)O)c1ccccc1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
20 mg of 5% palladium-carbon was added to a mixed solution of 1 mL of methanol and 2 mL of ethyl acetate containing 0.10 g of 2-(benzamido)-4-((E)-2-phenylvinyl)benzoic acid and stirred under hydrogen atmosphere at room temperature for 5 hours. Insoluble were removed by filtration and the solvent was evaporated under reduced pressure. Hexane and diisopropyl ether were added to the obtained residue and a solid substance was separated by filtration to obtain 69 mg of 2-(benzamido)-4-phenethylbenzoic acid as white solid.
Reaction SMILES: [CH2:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14](=[O:36])[C@@H:15]([NH:25]C(OCC2C=CC=CC=2)=O)[CH2:16][CH2:17][C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:10][CH2:9]1)=[O:7])[CH2:2][CH2:3][CH3:4]>C(O)C.[Pd]>[CH2:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14](=[O:36])[C@@H:15]([NH2:25])[CH2:16][CH2:17][C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:10][CH2:9]1)=[O:7])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOC(=O)N1CCN(C(=O)[C@H](CCC(=O)OC(C)(C)C)NC(=O)OCc2ccccc2)CC1
Agent: [Pd]
Solvent: CCO
Product: CCCCOC(=O)N1CCN(C(=O)[C@@H](N)CCC(=O)OC(C)(C)C)CC1
Reaction time: 12 h

Procedure:
To a solution of 15.8 g 4-((S)-2-Benzyloxycarbonylamino-4-tert-butoxycarbonyl-butyryl)-piperazine-1-carboxylic acid butyl ester in 60 ml ethanol were added 1.8 g Pd/C (10%) and the suspension stirred under an atmosphere of hydrogen (3 bar) for 12 h. The reaction mixture was filtrated over a plug of Celite, washed with ethanol and concentrated to give the crude product which was purified by flash chromatography on silica using dichloro-methane/methanol 90:10 as eluent. Yield: 9.6 g colorless oil.
Reaction SMILES: Br[C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.[CH3:10][Si:11]([C:14]#[CH:15])([CH3:13])[CH3:12]>>[CH3:10][Si:11]([CH3:13])([CH3:12])[C:14]#[C:15][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1
Reactant: O=Cc1ccc(Br)cc1
Reactant: C#C[Si](C)(C)C
Product: C[Si](C)(C)C#Cc1ccc(C=O)cc1

Procedure:
By the method of example 53(A), 4-bromobenzaldehyde is coupled with (trimethylsilyl)acetylene to provide 4-(2-(trimethylsilyl)ethynyl)benzaldehyde as a pale yellow solid after sublimation in vacuo. This material (5.8 g) is desilylated by stirring with potassium carbonate (0.4 g) in methanol (20 ml) for two hours. The solution is evaporated, and the product dissolved in methylene chloride, washed with water, dried, and concentrated to provide 4-ethynylbenzaldehyde as a yellow solid (3.45 g, 90%). By the Wittig reaction of example 1(A), this is chain-extended to provide 1-ethynyl-4-(2-methoxyethenyl)benzene, obtained as a colorless oil after distillation in vacuo (3.10 g, 77%).
Reaction SMILES: [CH:1]([C:4]1[C:9]([C:10]([O:12][CH2:13][CH3:14])=[O:11])=[C:8]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2I)[C:7]([C:22]([O:24][CH2:25][CH3:26])=[O:23])=[C:6]([CH:27]([CH3:29])[CH3:28])[N:5]=1)([CH3:3])[CH3:2].[CH3:30][Si:31]([C:34]#[CH:35])([CH3:33])[CH3:32].C(N(CC)CC)C.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1(C)C=CC=CC=1.[Pd](Cl)Cl.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Cu](I)I>[CH:1]([C:4]1[C:9]([C:10]([O:12][CH2:13][CH3:14])=[O:11])=[C:8]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[C:35]#[C:34][Si:31]([CH3:33])([CH3:32])[CH3:30])[C:7]([C:22]([O:24][CH2:25][CH3:26])=[O:23])=[C:6]([CH:27]([CH3:29])[CH3:28])[N:5]=1)([CH3:3])[CH3:2]
Reactant: CCOC(=O)c1c(C(C)C)nc(C(C)C)c(C(=O)OCC)c1-c1ccccc1I
Reactant: C#C[Si](C)(C)C
Agent: Cl[Pd]Cl
Agent: I[Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CCOC(=O)c1c(C(C)C)nc(C(C)C)c(C(=O)OCC)c1-c1ccccc1C#C[Si](C)(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 83.3 %

Procedure:
A solution of 1.50 g (3 mmole) of the intermediate obtained in Step A in toluene was treated with 1.48 g (15 mmole) of trimethylsilyl acetylene, 87.1 g (0.86 mol) of triethylamine, 0.1 g (0.15 mmol) of bis(triphenylphosphine) palladium(II) chloride, 0.2 g (0.8 mmole) of triphenyl phosphine and 0.2 g (1.17 mmole) of copper iodide. This reaction mixture was stirred at rt for 1 hr and heated at 90° C., in a sealed reaction vessel, for 16 hrs. The reaction mixture was to cooled to temperature, filtered through Celite, and stripped to give a dark oil which upon purification by flash silica gel chromatography to yield 1.22 g (2.5 mmole) of the product. 1H NMR (300 MHz, CDCl3): δ 0.0 (s, 9 H), 0.93 (t, J=7.0, 61), 1.32 (d, J=6.6 Hz, 6 H), 1.33 (d, J=6.6 Hz, 6 H), 3.18 (septet, J=6.6, 2 H), 3.90 (q, J=7.0 Hz, 4 H), 7.20-7.50 (m, 4 H).
Reaction SMILES: C([O:3][C:4]([C:6]1[S:10][C:9]([NH2:11])=[N:8][C:7]=1[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=O)C.O.[NH2:19][NH2:20].O>CO>[NH2:11][C:9]1[S:10][C:6]([C:4]([NH:19][NH2:20])=[O:3])=[C:7]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[N:8]=1
Reactant: CCOC(=O)c1sc(N)nc1-c1ccccc1
Reactant: NN
Solvent: O
Solvent: CO
Product: NNC(=O)c1sc(N)nc1-c1ccccc1
Yield: 70 %

Procedure:
2-Amino-4-phenyl-thiazole-5-carboxylic acid ethyl ester (5.0 g, 20 mmol) was suspended in methanol. Hydrazine monohydrate (5 mL, 100 mmol) was added and heated to reflux for 2 h. Hydrazine monohydrate (10 mL) was added and heated to reflux for 48 h. Water (100 mL) was added to the reaction mixture and the methanol was removed by evaporation in vacuo. The product precipitates and the solid product is collected by filtration. Yield: 70%.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:10]=[C:11]([CH2:20]OS(C)(=O)=O)[C:12](=[O:19])[N:13]([CH2:15][CH:16]([CH3:18])[CH3:17])[N:14]=2)[CH:5]=[CH:6][C:7]=1[F:8].[CH3:26][N:27]1[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1>>[F:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:10]=[C:11]([CH2:20][N:30]3[CH2:31][CH2:32][N:27]([CH3:26])[CH2:28][CH2:29]3)[C:12](=[O:19])[N:13]([CH2:15][CH:16]([CH3:18])[CH3:17])[N:14]=2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: CN1CCNCC1
Reactant: CC(C)Cn1nc(-c2ccc(F)c(F)c2)cc(COS(C)(=O)=O)c1=O
Product: CC(C)Cn1nc(-c2ccc(F)c(F)c2)cc(CN2CCN(C)CC2)c1=O
Yield: 79.1 %

Procedure:
Following the procedure of Example 1(10), 6-(3,4-difluorophenyl)-2-isobutyl-4-methanesulfonyloxymethyl-2H-pyridazin-3-one and 1-methylpiperazine were reacted to yield the title compound as a yellow oil (yield: 79.1%).
Reaction SMILES: [CH3:1][C:2]1[N:6]([CH2:7][C:8]([N:10]2[CH2:15][CH2:14][CH:13]([C:16]3[S:17][CH:18]=[C:19]([C:21](Cl)=[O:22])[N:20]=3)[CH2:12][CH2:11]2)=[O:9])[N:5]=[C:4]([C:24]([F:27])([F:26])[F:25])[CH:3]=1.[CH3:28][NH:29][C@H:30]1[C:38]2[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=2)[CH2:32][CH:31]1C.C(N(CC)CC)C.Cl>ClCCl>[C@H:30]1([N:29]([CH3:28])[C:21]([C:19]2[N:20]=[C:16]([CH:13]3[CH2:14][CH2:15][N:10]([C:8](=[O:9])[CH2:7][N:6]4[C:2]([CH3:1])=[CH:3][C:4]([C:24]([F:27])([F:26])[F:25])=[N:5]4)[CH2:11][CH2:12]3)[S:17][CH:18]=2)=[O:22])[C:38]2[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=2)[CH2:32][CH2:31]1
Reactant: Cc1cc(C(F)(F)F)nn1CC(=O)N1CCC(c2nc(C(=O)Cl)cs2)CC1
Reactant: CN[C@H]1c2ccccc2CC1C
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1cc(C(F)(F)F)nn1CC(=O)N1CCC(c2nc(C(=O)N(C)[C@@H]3CCc4ccccc43)cs2)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 80.5 %

Procedure:
2-[1-[[5-Methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl]acetyl]-4-piperidinyl]-4-thiazolecarbonyl chloride (210 mg, 0.5 mmol) (i.e. the product of Example 19, Step D) was treated with a solution of (1R)-2,3-dihydro-N,2-dimethyl-1H-inden-1-amine (147 μL, 1.0 mmol) and triethylamine (139 μL, 1.0 mmol) in 5 mL of dichloromethane. The reaction mixture was stirred at room temperature for 2 h, passed through a Varian 1005 Chem Elut™ column pretreated with 3 mL of 1 N aqueous hydrochloric acid. The column was flushed with three column volumes of dichloromethane. The collected dichloromethane solution was evaporated in vacuo and purified by medium-pressure liquid chromatography on silica gel using 50-100% of ethyl acetate in 1-chlorobutane as eluant to give 214 mg of the title compound, the product of present invention as a white foam.
Reaction SMILES: [CH:1]([N:14]1[CH2:19][CH2:18][CH:17]([CH2:20][OH:21])[CH2:16][CH2:15]1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:22][C:23]1[C:24](F)=[CH:25][C:26]([F:36])=[C:27]([CH:35]=1)[C:28]([O:30]C(C)(C)C)=[O:29].C([O-])(C)(C)C.[K+]>CS(C)=O>[CH:1]([N:14]1[CH2:19][CH2:18][CH:17]([CH2:20][O:21][C:24]2[C:23]([Cl:22])=[CH:35][C:27]([C:28]([OH:30])=[O:29])=[C:26]([F:36])[CH:25]=2)[CH2:16][CH2:15]1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)c1cc(Cl)c(F)cc1F
Reactant: OCC1CCN(C(c2ccccc2)c2ccccc2)CC1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: O=C(O)c1cc(Cl)c(OCC2CCN(C(c3ccccc3)c3ccccc3)CC2)cc1F
Temperature: 25 °C
Reaction time: 16 h
Yield: 81.3 %

Procedure:
A mixture of (1-benzhydrylpiperidin-4-yl)methanol (370 mg, 1.3 mmol), tert-butyl 5-chloro-2,4-difluorobenzoate (328 mg, 1.3 mmol) and potassium tert-butanolate (295 mg, 2.6 mmol) in DMSO (4 mL) was stirred at room temperature for 16 h. The reaction mixture was quenched by water (50 mL) and extracted with ethyl acetate (10 mL×4). The combined organic layers were washed with brine (20 mL), dried over anhydrous sodium sulfate, filtered and concentrated. The residue was washed with ethyl acetate (5 mL) and filtered to afford 4-((1-benzhydrylpiperidin-4-yl)methoxy)-5-chloro-2-fluorobenzoic acid (480 mg, 82%) as a white solid. LCMS (ESI) m/z: 454.2 [M+H]+.
Reaction SMILES: [S:1]1[C:5]([C:6]2[CH:7]=[CH:8][C:9]3[O:15][CH2:14][CH2:13][N:12](C(OC(C)(C)C)=O)[CH2:11][C:10]=3[CH:23]=2)=[CH:4][N:3]=[CH:2]1.Cl>CO.O1CCOCC1>[S:1]1[C:5]([C:6]2[CH:7]=[CH:8][C:9]3[O:15][CH2:14][CH2:13][NH:12][CH2:11][C:10]=3[CH:23]=2)=[CH:4][N:3]=[CH:2]1
Reactant: CC(C)(C)OC(=O)N1CCOc2ccc(-c3cncs3)cc2C1
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: c1ncc(-c2ccc3c(c2)CNCCO3)s1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
To tert-butyl 7-(thiazol-5-yl)-2,3-dihydrobenzo[f][1,4]oxazepine-4(5H)-carboxylate (41 mg, 0.12 mmol) in methanol (5.0 mL) added 4.0 M hydrogen chloride in dioxane (3.0 mL) and the mixture stirred at 25° C. for 20 minutes then concentrated to give 7-(thiazol-5-yl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine as the hydrochloride salt.
Reaction SMILES: [CH3:1][S:2]([OH:5])(=[O:4])=[O:3].O.[C:7]1([CH3:17])[CH:12]=[CH:11][C:10]([S:13]([OH:16])(=[O:15])=[O:14])=[CH:9][CH:8]=1.O>C(O)(C)C>[S:13]([C:10]1[CH:11]=[CH:12][C:7]([CH3:17])=[CH:8][CH:9]=1)([O-:16])(=[O:15])=[O:14].[CH3:1][S:2]([OH:5])(=[O:4])=[O:3]
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Agent: CS(=O)(=O)O
Solvent: O
Solvent: CC(C)O
Product: Cc1ccc(S(=O)(=O)[O-])cc1
Temperature: 22.5 °C
Reaction time: 18 h

Procedure:
To a 5-L 3-neck flask under an inert nitrogen atmosphere, 2.0 L of isopropanol (IPA) was charged. A slurry was prepared by adding 289 g of the amorphous free base of Compound 1 to the flask. A solution of p-toluenesulfonic acid hydrate (97.0 g) in IPA (400 mL) was then added to the slurry. The water content of the slurry supernatant was adjusted to 0.6 g/L with the addition of water (9 mL), and the slurry was stirred at 20-25° C. for 18 hours to produce a thick crystalline slurry. The slurry was filtered and washed with IPA (2×500 mL). Excess IPA was removed from the crystalline cake by blowing dry nitrogen through the cake for 24 hours. With the solids containing 3 weight-percent (wt %) of IPA, the cake was further dried by blowing humidified nitrogen through the cake at a relative humidity of 70-75% for 24 hours. The cake retained 0.9 wt % of IPA that was not further reduced by this method. Excess water was then removed from the cake by blowing dry nitrogen through the cake for 24 hours. The tosylate salt of Compound 1 was isolated as an orange powder (337 g). The isolated tosylate salt of Compound 1 was crystalline with only one observed form: a non-stoichiometric hemihydrate, as determined by x-ray powder diffraction (XPRD) and thermogravimetric (TG) analysis.
Reaction SMILES: [OH:1][CH:2]1[CH2:16][CH:5]2[CH2:6][N:7]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:8][CH:4]2[CH2:3]1.[CH3:17][S:18](Cl)(=[O:20])=[O:19]>CN(C1C=CN=CC=1)C.C(Cl)Cl>[CH3:17][S:18]([O:1][CH:2]1[CH2:16][CH:5]2[CH2:6][N:7]([C:9]([O:11][C:12]([CH3:13])([CH3:15])[CH3:14])=[O:10])[CH2:8][CH:4]2[CH2:3]1)(=[O:20])=[O:19]
Reactant: CC(C)(C)OC(=O)N1CC2CC(O)CC2C1
Reactant: CS(=O)(=O)Cl
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CC2CC(OS(C)(=O)=O)CC2C1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 75 %

Procedure:
To a solution of the title compound from Step A above (550 mg, 2.4 mmol) and DMAP (296 mg) in DCM (15 mL) was added MsCl (189 μL) at 0° C. The mixture was stirred for 10 min at the same temperature and for an additional hour at RT. The mixture was quenched with ice water and extracted with ethyl acetate (2×50 mL). The organic layer was washed with water and brine, dried over sodium sulfate, filtered, and concentrated under vacuum. The residue oil was purified via prep-plate purification eluting with 50% ethyl acetate in hexane to afford the title compound (i-39) (555 mg, 75%). ESI-MS calculated for C13H23NO5S: Exact Mass: 305.13. Found 328.14 (MNa)+.
Reaction SMILES: [CH3:1][C:2]1([C:7]2[O:11][C:10]([CH2:12][N:13]3[CH:17]=[CH:16][C:15]([NH2:18])=[N:14]3)=[CH:9][CH:8]=2)[O:6]CCO1.[CH3:19][O:20][CH2:21][CH2:22][C:23]1[CH:24]=[C:25]([C:29]2[O:33][CH:32]=[N:31][C:30]=2[C:34](O)=[O:35])[CH:26]=[CH:27][CH:28]=1>>[C:2]([C:7]1[O:11][C:10]([CH2:12][N:13]2[CH:17]=[CH:16][C:15]([NH:18][C:34]([C:30]3[N:31]=[CH:32][O:33][C:29]=3[C:25]3[CH:26]=[CH:27][CH:28]=[C:23]([CH2:22][CH2:21][O:20][CH3:19])[CH:24]=3)=[O:35])=[N:14]2)=[CH:9][CH:8]=1)(=[O:6])[CH3:1]
Reactant: COCCc1cccc(-c2ocnc2C(=O)O)c1
Reactant: CC1(c2ccc(Cn3ccc(N)n3)o2)OCCO1
Product: COCCc1cccc(-c2ocnc2C(=O)Nc2ccn(Cc3ccc(C(C)=O)o3)n2)c1

Procedure:
Following general procedure B followed by C, 1-[5-(2-methyl-[1,3]dioxolan-2-yl)-furan-2-ylmethyl]-1H-pyrazol-3-ylamine and 5-[3-(2-methoxy-ethyl)-phenyl]-oxazole-4-carboxylic acid. LC-MS-conditions 02: tR=0.98 min; [M+H]+=435.45.
Reaction SMILES: [CH2:1]([N:8]1[C:16]([C:17]2[CH:18]=[C:19]([OH:23])[CH:20]=[CH:21][CH:22]=2)=[C:15]2[C:10]([C:11]([C:24]([F:27])([F:26])[F:25])=[CH:12][CH:13]=[CH:14]2)=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:28][O:29][C:30](=[O:49])[C:31]([CH3:48])([C:33]1[CH:38]=[CH:37][CH:36]=[C:35](B2OC(C)(C)C(C)(C)O2)[CH:34]=1)[CH3:32].N1C=CC=CC=1>C(Cl)Cl.Cl.CC([O-])=O.CC([O-])=O.[Cu+2]>[CH3:28][O:29][C:30](=[O:49])[C:31]([C:33]1[CH:34]=[CH:35][CH:36]=[C:37]([O:23][C:19]2[CH:20]=[CH:21][CH:22]=[C:17]([C:16]3[N:8]([CH2:1][C:2]4[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=4)[N:9]=[C:10]4[C:15]=3[CH:14]=[CH:13][CH:12]=[C:11]4[C:24]([F:27])([F:25])[F:26])[CH:18]=2)[CH:38]=1)([CH3:48])[CH3:32]
Reactant: COC(=O)C(C)(C)c1cccc(B2OC(C)(C)C(C)(C)O2)c1
Reactant: Oc1cccc(-c2c3cccc(C(F)(F)F)c3nn2Cc2ccccc2)c1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Agent: Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: COC(=O)C(C)(C)c1cccc(Oc2cccc(-c3c4cccc(C(F)(F)F)c4nn3Cc3ccccc3)c2)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
3-(2-Benzyl-7-trifluoromethyl-2H-indazol-3-yl)-phenol (96 mg, 0.26 mmol), 2-methyl-2-[3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-propionic acid methyl ester (80 mg, 0.26 mmol), Cu(OAc)2 (47 mg, 0.26 mmol) and pyridine (42 μL, 0.52 mmol) were dissolved in 3 ml anhydrous CH2Cl2 and stirred at room temperature with crushed molsieves (4 Å) overnight. The reaction mixture was diluted with 1 M HCl (aq.) and the product was extracted three times with CH2Cl2. The combined organic phases were dried, evaporated and the crude material was purified by preparative HPLC using a gradient with an acidic mobile phase on an ACE-C8 column to afford 8.4 mg of analytically pure product.
Reaction SMILES: [CH2:1]([C:5]1[N:9]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3[C:18]([C:23]([O:25]C)=[O:24])=[CH:19][CH:20]=[CH:21][CH:22]=3)=[CH:13][CH:12]=2)[C:8]2[CH:27]=[C:28]([C:31](=[O:37])[CH:32]([C:34]([OH:36])=[O:35])[CH3:33])[CH:29]=[CH:30][C:7]=2[N:6]=1)[CH2:2][CH2:3][CH3:4].[OH-].[Na+]>CO>[CH2:1]([C:5]1[N:9]([CH2:10][C:11]2[CH:12]=[CH:13][C:14]([C:17]3[C:18]([C:23]([OH:25])=[O:24])=[CH:19][CH:20]=[CH:21][CH:22]=3)=[CH:15][CH:16]=2)[C:8]2[CH:27]=[C:28]([C:31](=[O:37])[CH:32]([C:34]([OH:36])=[O:35])[CH3:33])[CH:29]=[CH:30][C:7]=2[N:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nc2ccc(C(=O)C(C)C(=O)O)cc2n1Cc1ccc(-c2ccccc2C(=O)OC)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCCCc1nc2ccc(C(=O)C(C)C(=O)O)cc2n1Cc1ccc(-c2ccccc2C(=O)O)cc1

Procedure:
Prepared in analogous manner to Example 72 from methyl 4'-[(2-n-butyl-6-(2-carboxy-propionyl)-benzimidazol-1-yl)-methyl]biphenyl-2-carboxylate and sodium hydroxide solution/methanol.
Reaction SMILES: [Cl:1][C:2]1[CH:27]=[CH:26][C:5]([CH2:6][S:7][C:8]([N:10]2[C@H:22]([C:23]([OH:25])=[O:24])[CH2:21][C:20]3[C:19]4[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=4)[NH:13][C:12]=3[CH2:11]2)=[S:9])=[CH:4][CH:3]=1.S(Cl)(Cl)=O.[CH:32](O)([CH3:34])[CH3:33]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][S:7][C:8]([N:10]2[C@H:22]([C:23]([O:25][CH:32]([CH3:34])[CH3:33])=[O:24])[CH2:21][C:20]3[C:19]4[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=4)[NH:13][C:12]=3[CH2:11]2)=[S:9])=[CH:26][CH:27]=1
Reactant: O=C(O)[C@@H]1Cc2c([nH]c3ccccc23)CN1C(=S)SCc1ccc(Cl)cc1
Reactant: CC(C)O
Solvent: O=S(Cl)Cl
Product: CC(C)OC(=O)[C@@H]1Cc2c([nH]c3ccccc23)CN1C(=S)SCc1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 17 h

Procedure:
(3S)-2-[(4-Chlorobenzylthio)thiocarbonyl]-1,2,3,4-tetrahydro-β-carboline-3-carboxylic acid (2.08 g) is suspended in isopropyl alcohol (30 ml) and thereto is added dropwise thionyl chloride (0.47 ml) at -20° C. The mixture is stirred at room temperature for 17 hours and then refluxed at 90° C. for 4 hours. After distilling off the solvent, the residue is dissolved in ethyl acetate. The solution is washed with water, dried and distilled to remove the solvent. The residue is recrystallized from ethyl acetate-n-hexane to give the title compound (477 mg), m.p. 178°-180° C. (decomp.).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:25]=[CH:26][CH:27]=1)[CH2:5][O:6][C:7]1[CH:16]=[C:15]2[C:10]([CH2:11][CH2:12][C:13](=[O:24])[N:14]2[C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])=[CH:9][CH:8]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].Br[CH2:39][C:40]([O:42][CH2:43][CH3:44])=[O:41]>C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]([CH:25]=[CH:26][CH:27]=1)[CH2:5][O:6][C:7]1[CH:16]=[C:15]2[C:10]([CH2:11][CH:12]([CH2:39][C:40]([O:42][CH2:43][CH3:44])=[O:41])[C:13](=[O:24])[N:14]2[C:17]([O:19][C:20]([CH3:23])([CH3:21])[CH3:22])=[O:18])=[CH:9][CH:8]=1
Reactant: CCOC(=O)CBr
Reactant: CC(C)(C)OC(=O)N1C(=O)CCc2ccc(OCc3cccc(Cl)c3)cc21
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CCOC(=O)CC1Cc2ccc(OCc3cccc(Cl)c3)cc2N(C(=O)OC(C)(C)C)C1=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of tert-butyl 7-((3-chlorobenzyl)oxy)-2-oxo-3,4-dihydroquinoline-1(2H)-carboxylate (34 g, 0.09 mol) in THF (50.09 mL) was added a solution of lithium bis(trimethylsilyl)amide (1.06 M in THF, 99.24 mL, 0.11 mol) at −78° C. The reaction was stirred at that temperature for 30 minutes after which ethyl bromoacetate (9.70 mL, 0.09 mol) was added. The reaction was allowed to warm to ambient temperature, stirred overnight and quenched into water (250 mL). The aqueous layer was extracted with EtOAc (2×50 mL) and the combined organic layers were washed with brine and dried over MgSO4. The organics were concentrated under reduced pressure to afford a yellow-brown oil and carried on crude to the next step. 1H NMR (400 MHz, CDCl3) δ 7.35 (s, 1H), 7.27-7.22 (m, 3H), 7.02 (d, J=8.4 Hz, 1H), 6.59 (dd, J=8.3, 2.5 Hz, 1H), 6.49 (d, J=2.4 Hz, 1H), 4.95 (s, 2H), 4.12 (q, J=7.2 Hz, 2H), 3.06-2.91 (m, 1H), 2.87-2.70 (m, 2H), 2.60 (d, J=7.5 Hz, 1H), 2.37 (d, J=8.9 Hz, 1H), 1.54-1.44 (m, 9H), 1.26-1.19 (m, 3H). [M+H]=374.2.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[C:5]([NH:9][NH2:10])[CH:6]=[CH:7][CH:8]=1.[CH3:11][C:12]([CH3:19])([CH3:18])[C:13](=O)[CH2:14][C:15]#[N:16]>>[C:12]([C:13]1[CH:14]=[C:15]([NH2:16])[N:9]([C:5]2[CH:6]=[CH:7][CH:8]=[C:3]([Cl:2])[CH:4]=2)[N:10]=1)([CH3:19])([CH3:18])[CH3:11]
Reactant: NNc1cccc(Cl)c1
Reactant: CC(C)(C)C(=O)CC#N
Agent: Cl
Product: CC(C)(C)c1cc(N)n(-c2cccc(Cl)c2)n1
Yield: 71.3 %

Procedure:
The title compound was prepared from 3-chlorophenylhydrazine hydrochloride (1.43 g, 8.0 mmol) and 4,4-dimethyl-3-oxopentanenitrile (1.0 g, 8.0 mmol) using the procedure in Example 161A Step 3 to give 3-tert-butyl-1-(3-chlorophenyl)-1H-pyrazol-5-amine (1.42 g, 5.70 mmol, 71%). 1H NMR (300 MHz, DMSO-d6) δ 7.67 (s, 1H), 7.61 (d, 1H), 7.46 (t, 1H), 7.30 (d, 1H), 5.42 (s, 1H), 5.34 (s, 2H), 1.09 (s, 9H); LC-MS (ESI) m/z 250 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9](=[O:24])[N:10]([C@H:12]2[C@H:16]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)[CH2:15][NH:14][CH2:13]2)[CH3:11])=[CH:4][CH:3]=1.[CH3:25][C:26]1[CH:31]=[CH:30][N:29]=[C:28]([N:32]2[CH2:37][CH2:36][CH:35]([C:38](O)=[O:39])[CH2:34][CH2:33]2)[N:27]=1>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9](=[O:24])[N:10]([C@H:12]2[C@H:16]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)[CH2:15][N:14]([C:38]([CH:35]3[CH2:34][CH2:33][N:32]([C:28]4[N:27]=[C:26]([CH3:25])[CH:31]=[CH:30][N:29]=4)[CH2:37][CH2:36]3)=[O:39])[CH2:13]2)[CH3:11])=[CH:4][CH:3]=1
Reactant: CN(C(=O)Oc1ccc(F)cc1)[C@@H]1CNC[C@H]1c1ccc(Cl)cc1
Reactant: Cc1ccnc(N2CCC(C(=O)O)CC2)n1
Product: Cc1ccnc(N2CCC(C(=O)N3C[C@@H](N(C)C(=O)Oc4ccc(F)cc4)[C@H](c4ccc(Cl)cc4)C3)CC2)n1

Procedure:
In analogy to the procedure described for the synthesis of example 44 (step c), the title compound {(3S,4R)-4-(4-chloro-phenyl)-1-[1-(4-methyl-pyrimidin-2-yl)-piperidine-4-carbonyl]-pyrrolidin-3-yl}-methyl-carbamic acid 4-fluoro-phenyl ester was prepared from [(3S,4R)-4-(4-chloro-phenyl)-pyrrolidin-3-yl]-methyl-carbamic acid 4-fluoro-phenyl ester instead of [(3S,4R)-4-(3,4-dichloro-phenyl)-pyrrolidin-3-yl]-methyl-carbamic acid 4-fluoro-phenyl ester using 1-(4-methyl-pyrimidin-2-yl)-piperidine-4-carboxylic acid instead of 1-methylcyclopropane-1-carboxylic acid and was obtained as a yellow foam. MS m/e: 552.4 [M]+.