Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]([CH3:28])[S:3]([C:6]1[CH:7]=[C:8]([C:12]2[C:21]([CH3:23])([CH3:22])[CH2:20][C:19]3[C:14](=[CH:15][CH:16]=[C:17]([C:24]([O:26][CH3:27])=[O:25])[CH:18]=3)[N:13]=2)[CH:9]=[CH:10][CH:11]=1)(=[O:5])=[O:4]>CO.O1CCCC1.[Pd]>[CH3:28][N:2]([CH3:1])[S:3]([C:6]1[CH:7]=[C:8]([CH:12]2[C:21]([CH3:23])([CH3:22])[CH2:20][C:19]3[C:14](=[CH:15][CH:16]=[C:17]([C:24]([O:26][CH3:27])=[O:25])[CH:18]=3)[NH:13]2)[CH:9]=[CH:10][CH:11]=1)(=[O:5])=[O:4]
Reactant: COC(=O)c1ccc2c(c1)CC(C)(C)C(c1cccc(S(=O)(=O)N(C)C)c1)=N2
Agent: [Pd]
Solvent: CO
Solvent: C1CCOC1
Product: COC(=O)c1ccc2c(c1)CC(C)(C)C(c1cccc(S(=O)(=O)N(C)C)c1)N2
Yield: 79.5 %

Procedure:
A mixture of methyl 2-(3-(N,N-dimethylsulfamoyl)phenyl)-3,3-dimethyl-3,4-dihydroquinoline-6-carboxylate (100 mg, 0.25 mmol) and 10% Pd/C (100 mg) in methanol (3 mL) and tetrahydrofuran (3 mL) was hydrogenated by a H2 balloon at 30° C. After filtration, the filtrated was concentrated and purified on preparative thin layer chromatography to afford 80 mg of methyl 2-(3-(N,N-dimethylsulfamoyl)phenyl)-3,3-dimethyl-1,2,3,4-tetrahydroquinoline-6-carboxylate as a crude product.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]3[C:13]([CH3:20])=[C:14]([NH2:19])[C:15]([CH3:18])=[C:16]([CH3:17])[C:11]=3[O:10][C:9]=2[CH3:21])=[CH:4][CH:3]=1.[CH3:22][O:23][C:24]1[CH:32]=[CH:31][C:27]([C:28](Cl)=[O:29])=[CH:26][CH:25]=1>C(OCC)(=O)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]3[C:13]([CH3:20])=[C:14]([NH:19][C:28](=[O:29])[C:27]4[CH:31]=[CH:32][C:24]([O:23][CH3:22])=[CH:25][CH:26]=4)[C:15]([CH3:18])=[C:16]([CH3:17])[C:11]=3[O:10][C:9]=2[CH3:21])=[CH:4][CH:3]=1
Reactant: COc1ccc(C(=O)Cl)cc1
Reactant: Cc1oc2c(C)c(C)c(N)c(C)c2c1-c1ccc(F)cc1
Solvent: CCOC(C)=O
Product: COc1ccc(C(=O)Nc2c(C)c(C)c3oc(C)c(-c4ccc(F)cc4)c3c2C)cc1
Yield: 75 %

Procedure:
By using 3-(4-fluorophenyl)-2,4,6,7-tetramethyl-1-benzofuran-5-amine and 4-methoxybenzoyl chloride, the title compound was synthesized according to Example 1b. Yield: 75%. Melting point: 225-227° C. (Ethyl acetate).
Reaction SMILES: Cl[CH2:2][C:3]([C:5]1[CH:6]=[C:7]([OH:12])[C:8](=[CH:10][CH:11]=1)[OH:9])=[O:4].[N-:13]=[N+:14]=[N-:15].[Na+]>CN(C=O)C.C(OCC)(=O)C>[N:13]([CH2:2][C:3]([C:5]1[CH:6]=[C:7]([OH:12])[C:8](=[CH:10][CH:11]=1)[OH:9])=[O:4])=[N+:14]=[N-:15]
Reactant: O=C(CCl)c1ccc(O)c(O)c1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: [N-]=[N+]=NCC(=O)c1ccc(O)c(O)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 89.6 %

Procedure:
To the solution of 4-chloroacetylcatechol (25 g) in DMF (200 ml) was added sodium azide (10.5 g), and the mixture was stirred at room temperature for 1 hour. The reaction mixture was diluted with ethyl acetate, washed with water and dried over anhydrous magnesium sulfate. After the solvent was evaporated, the solids thus obtained was washed with a solution of n-hexane:ether=5:1 to give 23.2 g of 4-azidoacetylcatechol (yield, 90%).
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:13]=[CH:12][CH:11]=[CH:10][C:6]=1[C:7](Cl)=[O:8])([CH3:3])[CH3:2].[NH2:14][C:15]1[CH:16]=[CH:17][C:18]([N+:25]([O-:27])=[O:26])=[C:19]([C:21]([F:24])([F:23])[F:22])[CH:20]=1.C(N(CC)CC)C>ClCCl>[CH:1]([O:4][C:5]1[CH:13]=[CH:12][CH:11]=[CH:10][C:6]=1[C:7]([NH:14][C:15]1[CH:16]=[CH:17][C:18]([N+:25]([O-:27])=[O:26])=[C:19]([C:21]([F:22])([F:23])[F:24])[CH:20]=1)=[O:8])([CH3:3])[CH3:2]
Reactant: CC(C)Oc1ccccc1C(=O)Cl
Reactant: Nc1ccc([N+](=O)[O-])c(C(F)(F)F)c1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)Oc1ccccc1C(=O)Nc1ccc([N+](=O)[O-])c(C(F)(F)F)c1

Procedure:
2-Isopropoxy-benzoyl chloride was condensed with 5-Amino-2-nitrobenzotrifluoride in dichloromethane in presence of triethylamine as acid scavenger to yield 2-Isopropoxy-N-(4-nitro-3-trifluoromethyl-phenyl)-benzamide. The reaction mixture was then concentrated in vacuo and the residue was extracted into ethyl acetate. The ethyl acetate layer was washed with water and with cold aqueous hydrochloric acid, then dried over sodium sulphate and finally concentrated in vacuo. The residue obtained was chromatographed over silica gel to afford the desired product.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:8]23[CH2:15][CH2:14][C:11]([CH2:16][C:17]([O:19][CH3:20])=[O:18])([CH2:12][CH2:13]2)[CH2:10][O:9]3)[CH:5]=[CH:6][CH:7]=1.[O:21]1[CH:26]=[CH:25][CH2:24][CH2:23][CH2:22]1.CC1C=CC(S([O-])(=O)=O)=CC=1.C1C=C[NH+]=CC=1>C(Cl)Cl>[O:21]1[CH2:26][CH2:25][CH2:24][CH2:23][CH:22]1[O:1][C:2]1[CH:3]=[C:4]([C:8]23[CH2:13][CH2:12][C:11]([CH2:16][C:17]([O:19][CH3:20])=[O:18])([CH2:14][CH2:15]2)[CH2:10][O:9]3)[CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)CC12CCC(c3cccc(O)c3)(CC1)OC2
Reactant: C1=COCCC1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: COC(=O)CC12CCC(c3cccc(OC4CCCCO4)c3)(CC1)OC2
Temperature: 25 °C
Reaction time: 96 h
Yield: 76.7 %

Procedure:
A mixture of methyl 2-(1-(3-hydroxyphenyl)-2-oxabicyclo[2.2.2]octan-4-yl)acetate (887 mg, 3.21 mmol), 3,4-dihydro-2H-pyran (0.5 ml, 5.47 mmol), and PPTS (81 mg, 0.321 mmol) in DCM (10 ml) was stirred at rt for 4 days. The reaction was concentrated in vacuo. The crude oil was purified by flash chromatography on SiO2 (0 to 30% EtOAc:hexanes) to afford the title compound (887 mg, 77% yield) as a white solid. LCMS, [M+NH4]+=378.4. 1H NMR (500 MHz, CDCl3) δ 7.21 (t, J=8.0 Hz, 1H), 7.13-7.08 (m, 1H), 6.99 (ddd, J=7.8, 1.5, 1.0 Hz, 1H), 6.93 (ddd, J=8.2, 2.5, 0.9 Hz, 1H), 5.43 (t, J=3.2 Hz, 1H), 3.97-3.86 (m, 3H), 3.67 (s, 3H), 3.64-3.54 (m, 1H), 2.17 (s, 2H), 2.11-1.96 (m, 5H), 1.90-1.74 (m, 6H), 1.72-1.49 (m, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[C:13]3[N:14]=[CH:15][CH:16]=[CH:17][C:12]=3[C:11](=[O:18])[NH:10][N:9]=2)[CH:5]=[CH:6][CH:7]=1.[S:19]1[CH:23]=[CH:22][C:21]([CH2:24]O)=[CH:20]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>O1CCCC1>[S:19]1[CH:23]=[CH:22][C:21]([CH2:24][N:10]2[C:11](=[O:18])[C:12]3[CH:17]=[CH:16][CH:15]=[N:14][C:13]=3[C:8]([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=3)=[N:9]2)=[CH:20]1
Reactant: O=c1[nH]nc(-c2cccc(Cl)c2)c2ncccc12
Reactant: OCc1ccsc1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: O=c1c2cccnc2c(-c2cccc(Cl)c2)nn1Cc1ccsc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 51.7 %

Procedure:
To a suspension of 8-(3-chlorophenyl) pyrido[2,3-d]pyridazin-5-one (0.21 g, 0.82 mmoles) in tetrahydrofuran (25 ml) was added 3-thiophenemethanol (0.085 ml, 0.9 moles) and triphenyl phosphine (0.32 g, 1.22 moles). To this mixture was added a solution of diisopropyl azodicarboxylate (0.24 ml, 1.22 moles) in tetrahydrofuran (5 ml) in a dropwise manner. The solution was stirred for 3 hours at room temperature. The solvent was removed and the residue chromatographed from hot methanol, yielding 0.15 g of 6-(3-thienylmethyl)-8-(3-chlorophenyl) pyrido[2,3-d]pyridazin-5-one, mp 165°-166° C.
Reaction SMILES: C([NH:4][C:5]1[C:23]([N+:24]([O-:26])=[O:25])=[CH:22][C:8]2[N:9]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][N+:16]=3[O-:21])[CH2:10][C:11]([CH3:14])([CH3:13])[O:12][C:7]=2[CH:6]=1)(=O)C.Cl.C(=O)(O)[O-].[Na+]>C(O)C>[NH2:4][C:5]1[C:23]([N+:24]([O-:26])=[O:25])=[CH:22][C:8]2[N:9]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][N+:16]=3[O-:21])[CH2:10][C:11]([CH3:13])([CH3:14])[O:12][C:7]=2[CH:6]=1
Reactant: CC(=O)Nc1cc2c(cc1[N+](=O)[O-])N(c1cccc[n+]1[O-])CC(C)(C)O2
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: CC1(C)CN(c2cccc[n+]2[O-])c2cc([N+](=O)[O-])c(N)cc2O1
Temperature: 100 °C
Reaction time: 2 h
Yield: 81.3 %

Procedure:
To a suspension of 0.50 g 2-(7-acetamido-3,4-dihydro-2,2-dimethyl-6-nitro-2H-1,4-benzoxazin-4-yl)pyridine N-oxide in 6 ml ethanol, was added 6 ml of 5N HCl, the mixture was stirred at 100° C. for two hours, the reaction mixture was poured to ice water, and the resulting mixture was neutralized with sodium bicarbonate and extracted with chloroform. The extract was dried over anhydrous magnesium sulfate, the solvents were distilled off from the dried solution, and the residue thus obtained was recrystallized from ethanol, thus giving 359 mg of 2-(7-amino-3,4-dihydro-2,2-dimethyl-6-nitro-2H-1,4-benzoxazin-4-yl)pyridine N-oxide.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C@H:9]([CH3:12])[CH2:10][OH:11])[C:5]([C:13]2[S:14][CH:15]=[CH:16][CH:17]=2)=[CH:4][N:3]=1.[NH2:18][C:19]1[CH:24]=[CH:23][C:22]([S:25]([CH3:38])(=[N:27][C:28](=[O:37])[NH:29][C:30]2[CH:35]=[CH:34][C:33]([CH3:36])=[CH:32][CH:31]=2)=[O:26])=[CH:21][CH:20]=1>>[C:33]1([CH3:36])[CH:32]=[CH:31][C:30]([NH:29][C:28]([N:27]=[S:25]([C:22]2[CH:21]=[CH:20][C:19]([NH:18][C:2]3[N:7]=[C:6]([NH:8][C@H:9]([CH3:12])[CH2:10][OH:11])[C:5]([C:13]4[S:14][CH:15]=[CH:16][CH:17]=4)=[CH:4][N:3]=3)=[CH:24][CH:23]=2)([CH3:38])=[O:26])=[O:37])=[CH:35][CH:34]=1
Reactant: C[C@H](CO)Nc1nc(Cl)ncc1-c1cccs1
Reactant: Cc1ccc(NC(=O)N=S(C)(=O)c2ccc(N)cc2)cc1
Product: Cc1ccc(NC(=O)N=S(C)(=O)c2ccc(Nc3ncc(-c4cccs4)c(N[C@H](C)CO)n3)cc2)cc1
Yield: 21 %

Procedure:
In the reaction of (R)-2-(2-chloro-5-(2-thienyl)pyrimidine-4-ylamino)propan-1-ol (39.1 mg, 0.15 mmol) with (RS)—S-(4-aminophenyl)-N-(p-tolylcarbamoyl)-S-methylsulphoximide (40 mg, 0.13 mmol) according to procedure 5c, the desired product is obtained in 21% yield (15 mg) after chromatographic purification (silica gel, dichloromethane/ethanol (0%-20% ethanol)).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]([CH3:13])=[N:11][N:12]=2)=[CH:4][C:3]=1[C:14]1[CH:19]=[CH:18][C:17]([C:20]([OH:22])=O)=[CH:16][CH:15]=1.C1C=CC2N(O)N=NC=2C=1.Cl.CN(C)CCCN=C=NCC.[CH3:45][CH:46]([NH2:55])[CH2:47][CH2:48][C:49]1[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=1>CN(C=O)C>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]([CH3:13])=[N:11][N:12]=2)=[CH:4][C:3]=1[C:14]1[CH:19]=[CH:18][C:17]([C:20]([NH:55][CH:46]([CH3:45])[CH2:47][CH2:48][C:49]2[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=2)=[O:22])=[CH:16][CH:15]=1
Reactant: Cc1nnc(-c2ccc(C)c(-c3ccc(C(=O)O)cc3)c2)o1
Reactant: CC(N)CCc1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: Cc1nnc(-c2ccc(C)c(-c3ccc(C(=O)NC(C)CCc4ccccc4)cc3)c2)o1
Reaction time: 18 h

Procedure:
2′-Methyl-5′-(5-methyl-1,3,4-oxadiazol-2-yl)-1,1′-biphenyl-4-carboxylic acid (11.3 mg, 0.034 mmol), HOBT (6.0 mg, 0.044 mmol), 1-(3-dimethylaminopropyl)3-ethyl carbodiimide hydrochloride (8.0 mg, 0.042 mmol) and 1-methyl-3-phenylpropylamine (0.34 mmol) were mixed in DMF (0.7 ml) and the reaction left at room temperature for 18 h. The DMF was evaporated under vacuum and the residue partitioned between DCM (0.4 ml) and water (0.4 ml). The organic phase was washed with aqueous sodium hydroxide (0.5M, 0.2 ml) and the DCM evaporated under vacuum. The residue was purified by mass directed HPLC to give 2′-methyl-5′-(5-methyl-1,3,4-oxadiazol-2-yl)-N-(1-methyl-3-phenylpropyl)-1,1′-biphenyl-4-carboxamide. LCMS; retention time 3.56 min, MH+ 426.
Reaction SMILES: [C:1]1([CH2:7][C:8](Cl)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:11][O:12][C:13]1[CH:14]=[C:15]([C:19]2([OH:25])[CH2:24][CH2:23][CH2:22][NH:21][CH2:20]2)[CH:16]=[CH:17][CH:18]=1>>[OH:25][C:19]1([C:15]2[CH:16]=[CH:17][CH:18]=[C:13]([O:12][CH3:11])[CH:14]=2)[CH2:24][CH2:23][CH2:22][N:21]([C:8](=[O:9])[CH2:7][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH2:20]1
Reactant: O=C(Cl)Cc1ccccc1
Reactant: COc1cccc(C2(O)CCCNC2)c1
Product: COc1cccc(C2(O)CCCN(C(=O)Cc3ccccc3)C2)c1

Procedure:
The compound of Example 27 was prepared according to the general preparation protocol A from phenylacetyl chloride and 3-(3-methoxy-phenyl)-piperidine-3-ol.
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]([N:8]2[N:12]=[N:11][C:10]([CH2:13][OH:14])=[N:9]2)[CH:5]=[CH:6][CH:7]=1.[H-].[Na+].CS([C:21]1[N:22]([CH3:32])[C:23]([C:26]2[CH:31]=[CH:30][N:29]=[CH:28][CH:27]=2)=[N:24][N:25]=1)(=O)=O>>[I:1][C:2]1[CH:3]=[C:4]([N:8]2[N:12]=[N:11][C:10]([CH2:13][O:14][C:21]3[N:22]([CH3:32])[C:23]([C:26]4[CH:31]=[CH:30][N:29]=[CH:28][CH:27]=4)=[N:24][N:25]=3)=[N:9]2)[CH:5]=[CH:6][CH:7]=1
Reactant: OCc1nnn(-c2cccc(I)c2)n1
Reactant: Cn1c(-c2ccncc2)nnc1S(C)(=O)=O
Agent: [H-]
Agent: [Na+]
Product: Cn1c(OCc2nnn(-c3cccc(I)c3)n2)nnc1-c1ccncc1

Procedure:
The title compound is prepared from [2-(3-iodo-phenyl)-2H-tetrazol-5-yl]-methanol (1 mmol), sodium hydride (1.5 mmol) and 4-(5-methanesulfonyl-4-methyl-4H-[1,2,4]triazol-3-yl)-pyridine (1.25 mmol).
Reaction SMILES: [F:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:4]([OH:12])[CH:3]=1.[H-].[Na+].Br[CH2:16][C:17]1[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=1.Cl>CN(C)C=O>[CH3:9][O:8][C:6](=[O:7])[C:5]1[CH:10]=[CH:11][C:2]([F:1])=[CH:3][C:4]=1[O:12][CH2:16][C:17]1[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=1
Reactant: COc1ccc(CBr)cc1
Reactant: COC(=O)c1ccc(F)cc1O
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(F)cc1OCc1ccc(OC)cc1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
Methyl 4-fluoro-2-hydroxybenzoate (1661 mg) was added to N,N-dimethylformamide (50 mL). Sodium hydride (60% in mineral oil, 430 mg) was added, the solution stirred for 15 minutes at room temperature, and 1-(bromomethyl)-4-methoxybenzene (2061 mg) was added. The solution was stirred at room temperature for three days, added to 0.01M aqueous HCl, and extracted with ethyl acetate. The organic phase was washed with water twice, washed with brine, and dried over anhydrous sodium sulfate. After filtration, the solvent was removed under vacuum.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH2:8][C:9]([O:11][CH3:12])=[O:10])[CH:5]=[N:6][CH:7]=1.[H-].[Na+].Br[CH2:16][CH2:17]Br.O>CN(C=O)C>[Br:1][C:2]1[CH:3]=[C:4]([C:8]2([C:9]([O:11][CH3:12])=[O:10])[CH2:17][CH2:16]2)[CH:5]=[N:6][CH:7]=1
Reactant: BrCCBr
Reactant: COC(=O)Cc1cncc(Br)c1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)C1(c2cncc(Br)c2)CC1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 106.9 %

Procedure:
To a solution of methyl 2-(5-bromopyridin-3-yl)acetate (4 g, 17.4 mmol) in DMF (80 mL), cooled at 0° C. with an ice bath, was added 60% NaH in mineral oil (0.918 g, 38.3 mmol) and the reaction mixture was stirred at 0° C. for 15 min. Then, a solution of 1,2-dibromoethane (3.27 g, 17.4 mmol) in DMF (16 mL) was added at 0° C. After the addition, the mixture was stirred at room temperature for 1 h. Two other portions of 60% NaH in mineral oil (2×0.2 g) were added sequentially, until conversion was complete. Then, the reaction mixture was poured into H2O (50 mL) and extracted with EtOAc (3×125 mL). The organic layers were combined, dried over Na2SO4, filtered and evaporated to dryness to give the title compound (4.764 g, 99%) as a brown oil, which was used with no further purification. MS: 256.0 and 258.0 (M+H+).
Reaction SMILES: [Br:1][C:2]1[CH:38]=[CH:37][C:36]([F:39])=[CH:35][C:3]=1[O:4][CH:5]1[CH2:10][CH2:9][N:8]([C:11]2[S:15][C:14]([C:16]3[N:20]=[C:19]([CH2:21][C@@H:22]([C:30]([O:32]CC)=[O:31])[NH:23]C(=O)C(F)(F)F)[O:18][N:17]=3)=[N:13][N:12]=2)[CH2:7][CH2:6]1.[OH-].[Na+].Cl>CCO.O>[Br:1][C:2]1[CH:38]=[CH:37][C:36]([F:39])=[CH:35][C:3]=1[O:4][CH:5]1[CH2:10][CH2:9][N:8]([C:11]2[S:15][C:14]([C:16]3[N:20]=[C:19]([CH2:21][C@@H:22]([C:30]([OH:32])=[O:31])[NH2:23])[O:18][N:17]=3)=[N:13][N:12]=2)[CH2:7][CH2:6]1
Reactant: CCOC(=O)[C@H](Cc1nc(-c2nnc(N3CCC(Oc4cc(F)ccc4Br)CC3)s2)no1)NC(=O)C(F)(F)F
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: N[C@@H](Cc1nc(-c2nnc(N3CCC(Oc4cc(F)ccc4Br)CC3)s2)no1)C(=O)O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a suspension of ethyl 3-(3-{5-[4-(2-bromo-5-fluorophenoxy)piperidin-1-yl]-1,3,4-thiadiazol-2-yl}-1,2,4-oxadiazol-5-yl)-N-(trifluoroacetyl)-L-alaninate (550 mg, 0.86 mmol) in EtOH (5 mL) and water (5 mL) was added NaOH (104 mg, 2.6 mmol) and the resulting solution was stirred at rt overnight. The solution was adjusted to pH 7 with HCl solution (1 mol/L), then extracted with EtOAc. The combined organic layers were dried over anhydrous Na2SO4, filtered and evaporated in vacuo. The crude product was washed with petroleum ether/EtOAc to afford the title compound.
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[C:9]([NH2:17])[C:10]([F:16])=[C:11](F)[C:12]=3[F:14])[C:7](=[O:18])[C:6]([C:19]([OH:21])=[O:20])=[CH:5]2)[CH2:3][CH2:2]1.[OH:22][CH2:23][C:24]1[CH:25]=[C:26]2[C:30](=[CH:31][CH:32]=1)[CH2:29][NH:28][CH2:27]2.C1CCN2C(=NCCC2)CC1>CN(C=O)C>[OH:22][CH2:23][C:24]1[CH:25]=[C:26]2[C:30](=[CH:31][CH:32]=1)[CH2:29][N:28]([C:11]1[C:12]([F:14])=[C:13]3[C:8]([C:7](=[O:18])[C:6]([C:19]([OH:21])=[O:20])=[CH:5][N:4]3[CH:1]3[CH2:3][CH2:2]3)=[C:9]([NH2:17])[C:10]=1[F:16])[CH2:27]2
Reactant: Nc1c(F)c(F)c(F)c2c1c(=O)c(C(=O)O)cn2C1CC1
Reactant: OCc1ccc2c(c1)CNC2
Solvent: C1CCC2=NCCCN2CC1
Solvent: CN(C)C=O
Product: Nc1c(F)c(N2Cc3ccc(CO)cc3C2)c(F)c2c1c(=O)c(C(=O)O)cn2C1CC1
Yield: 24.8 %

Procedure:
298 mg of 1-cyclopropyl-5-amino-6,7,8-trifluoro-1,4- dihydro-4-oxoquinoline-3-carboxylic acid, 179 mg of 5-hydroxymethylisoindoline, 304 mg of DBU, and 2 ml of anhydrous DMF were processed in the same manner as in Example 20 to produce 106 mg of the target compound.
Reaction SMILES: C([O:8][C@@H:9]1[C@@H:14]([O:15]CC2C=CC=CC=2)[C@H:13]([O:23]CC2C=CC=CC=2)[C@@H:12]([CH2:31][O:32]CC2C=CC=CC=2)[CH2:11][C@@:10]1([C:41]1[CH:46]=[C:45]([CH2:47][C:48]2[CH:53]=[CH:52][C:51]([CH2:54][CH3:55])=[CH:50][CH:49]=2)[CH:44]=[CH:43][C:42]=1[O:56][CH2:57][CH3:58])O)C1C=CC=CC=1>C1COCC1.CO.[OH-].[Pd+2].[OH-]>[CH2:57]([O:56][C:42]1[CH:43]=[CH:44][C:45]([CH2:47][C:48]2[CH:49]=[CH:50][C:51]([CH2:54][CH3:55])=[CH:52][CH:53]=2)=[CH:46][C:41]=1[C@@H:10]1[CH2:11][C@H:12]([CH2:31][OH:32])[C@@H:13]([OH:23])[C@H:14]([OH:15])[C@H:9]1[OH:8])[CH3:58]
Reactant: CCOc1ccc(Cc2ccc(CC)cc2)cc1[C@@]1(O)C[C@H](COCc2ccccc2)[C@@H](OCc2ccccc2)[C@H](OCc2ccccc2)[C@H]1OCc1ccccc1
Agent: [Pd+2]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CCOc1ccc(Cc2ccc(CC)cc2)cc1[C@@H]1C[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O
Reaction time: 19 h
Yield: 20.3 %

Procedure:
To a solution of the (1S,2R,3S,4R,5R)-2,3,4-tris-benzyloxy-5-benzyloxymethyl-1-[2-ethoxy-5-(4-ethylbenzyl)-phenyl]cyclohexanol (402 mg, 0.517 mmol) in THF (4 ml) and methanol (2 mL) as obtained in Example 67, a 20% palladium hydroxide catalyst (78 mg) was added and the mixture solution was stirred under a hydrogen atmosphere for 19 hours. After filtering the catalyst, the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography [developing solution=methylene chloride:methanol (10:1)] to obtain the title compound (42 mg, 20%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5](B(O)O)=[C:4]([F:11])[CH:3]=1.Cl[C:13]1[N:18]=[N:17][C:16]([N:19]([CH3:30])[CH:20]2[CH2:25][C:24]([CH3:27])([CH3:26])[NH:23][C:22]([CH3:29])([CH3:28])[CH2:21]2)=[CH:15][CH:14]=1.C([O-])([O-])=O.[Na+].[Na+].N#N>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:13]2[N:18]=[N:17][C:16]([N:19]([CH3:30])[CH:20]3[CH2:25][C:24]([CH3:26])([CH3:27])[NH:23][C:22]([CH3:29])([CH3:28])[CH2:21]3)=[CH:15][CH:14]=2)=[C:4]([F:11])[CH:3]=1
Reactant: OB(O)c1ccc(Cl)cc1F
Reactant: CN(c1ccc(Cl)nn1)C1CC(C)(C)NC(C)(C)C1
Agent: N#N
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: CN(c1ccc(-c2ccc(Cl)cc2F)nn1)C1CC(C)(C)NC(C)(C)C1
Temperature: 90 °C
Yield: 95.2 %

Procedure:
(4-Chloro-2-fluorophenyl)boronic acid (4.29 g, 24.6 mmol), Intermediate 1-1 (6.63 g, 23.4 mmol) and Na2CO3 (7.45 g, 70.3 mmol) were degassed for 10 minutes with N2, then PdCl2(dppf)CH2Cl2 (0.96 g, 1.17 mmol) was added. The reaction mixture was heated at 90° C. for 2 h. The reaction mixture was concentrated in vacuo then CH2Cl2 and 1 M HCl were added. The aqueous phase was washed with CH2Cl2, then basified to pH 14 with a 6 M NaOH solution. The aqueous phase was then extracted with CH2Cl2 (3×). The combined organic phases were dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to afford 6-(4-chloro-2-fluorophenyl)-N-methyl-N-(2,2,6,6-tetramethylpiperidin-4-yl)pyridazin-3-amine as a brown solid (8.40 g, 95%). [M+H]: 377.2; 1H NMR (400 MHz, MeOD) δ 7.87 (t, J=8.5 Hz, 1H), 7.76 (dd, J=9.5, 2.4 Hz, 1H), 7.32-7.40 (m, 2H), 7.17 (d, J=9.5 Hz, 1H), 5.13-5.36 (m, 1H), 1.69 (dd, J=12.5, 3.5 Hz, 2H), 1.57 (t, J=12.5 Hz, 2H), 1.38 (s, 6H), 1.23 (s, 6H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH2:15])[CH:6]=[CH:7][C:8]=1[N:9]1[CH:13]=[C:12]([CH3:14])[N:11]=[CH:10]1.[C:16](N1C=CC=CC1=O)(N1C=CC=CC1=O)=[S:17]>ClCCl>[N:15]([C:5]1[CH:6]=[CH:7][C:8]([N:9]2[CH:13]=[C:12]([CH3:14])[N:11]=[CH:10]2)=[C:3]([O:2][CH3:1])[CH:4]=1)=[C:16]=[S:17]
Reactant: O=c1ccccn1C(=S)n1ccccc1=O
Reactant: COc1cc(N)ccc1-n1cnc(C)c1
Solvent: ClCCl
Product: COc1cc(N=C=S)ccc1-n1cnc(C)c1
Yield: 93.8 %

Procedure:
A solution of 3-methoxy-4-(4-methyl-imidazol-1-yl)-phenylamine (203 mg, 1 mmol) and of 1,1′-thiocarbonyldi-2(1H)-pyridone (263 mg, 1.1 mmol) in dichloromethane (10 mL) was stirred at room temperature over night to yield an orange solution. The reaction was concentrated under reduced pressure to ¼ of its volume and directly purified on silica gel using dichloromethane/methanol (95:5 v/v) as eluent to yield the title compound (230 mg, 94%) as a yellow oil, which solidifies on standing. MS ISP (m/e): 246.3 (100) [(M+H)+]. 1H NMR (CDCl3, 300 MHz): δ (ppm)=7.67 (s, 1H), 7.21 (d, 1H), 6.91-6.86 (m, 3H), 3.86 (s, 3H), 2.29 (s, 3H).
Reaction SMILES: [F:1][C@@H:2]1[C@@H:7](OS(C)(=O)=O)[CH2:6][CH2:5][N:4]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:3]1.[CH:20]1([O:24][C:25]2[C:34]([C:35]3[CH:36]=[N:37][NH:38][CH:39]=3)=[CH:33][CH:32]=[C:31]3[C:26]=2[CH2:27][CH2:28][C@H:29]([CH3:44])[N:30]3[C:40]([O:42][CH3:43])=[O:41])[CH2:23][CH2:22][CH2:21]1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C.O>[C:16]([O:15][C:13]([N:4]1[CH2:5][CH2:6][C@@H:7]([N:37]2[CH:36]=[C:35]([C:34]3[C:25]([O:24][CH:20]4[CH2:21][CH2:22][CH2:23]4)=[C:26]4[C:31](=[CH:32][CH:33]=3)[N:30]([C:40]([O:42][CH3:43])=[O:41])[C@@H:29]([CH3:44])[CH2:28][CH2:27]4)[CH:39]=[N:38]2)[C@@H:2]([F:1])[CH2:3]1)=[O:14])([CH3:19])([CH3:18])[CH3:17]
Reactant: CC(C)(C)OC(=O)N1CC[C@H](OS(C)(=O)=O)[C@@H](F)C1
Reactant: COC(=O)N1c2ccc(-c3cn[nH]c3)c(OC3CCC3)c2CC[C@@H]1C
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)N1c2ccc(-c3cnn([C@@H]4CCN(C(=O)OC(C)(C)C)C[C@@H]4F)c3)c(OC3CCC3)c2CC[C@@H]1C
Temperature: 100 °C
Yield: 56 %

Procedure:
(3S,4S)-tert-Butyl 3-fluoro-4-((methylsulfonyl)oxy)piperidine-1-carboxylate (96 mg, 0.322 mmol) was added to a solution of (S)-methyl 5-cyclobutoxy-2-methyl-6-(1H-pyrazol-4-yl)-3,4-dihydroquinoline-1(2H)-carboxylate (100 mg, 0.293 mmol) and cesium carbonate (153 mg, 0.469 mmol) in DMF (1.0 mL), and the reaction mixture was heated at 100° C. for 1 hour. The reaction solution was cooled to room temperature, diluted with water and extracted with ethyl acetate (3×50 mL). The combined organic layers were washed with water (2×25 mL) and brine (25 mL), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The crude product was purified via column chromatography on silica gel (Biotage 25 g column, gradient elution with 20-30% ethyl acetate in hexanes) to afford methyl (S)-6-(1-((3S,4R)-1-(tert-butoxycarbonyl)-3-fluoropiperidin-4-yl)-1H-pyrazol-4-yl)-5-cyclobutoxy-2-methyl-3,4-dihydroquinoline-1(2H)-carboxylate (89 mg, 56%) as a colorless oil. MS (ESI, pos. ion) m/z 543 [M+H]+.