Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([Li])([CH3:4])([CH3:3])[CH3:2].C(O[C:10]1[C:11](=[O:19])[C:12](=[O:18])[C:13]=1[O:14][CH:15]([CH3:17])[CH3:16])(C)C.FC(F)(F)C(OC(=O)C(F)(F)F)=O.[NH4+].[Cl-]>CCCCC.C1COCC1.CCOC(C)=O>[C:1]([C:10]1[C:11](=[O:19])[C:12](=[O:18])[C:13]=1[O:14][CH:15]([CH3:16])[CH3:17])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)Oc1c(OC(C)C)c(=O)c1=O
Reactant: [Li]C(C)(C)C
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCCCC
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: CCOC(C)=O
Product: CC(C)Oc1c(C(C)(C)C)c(=O)c1=O
Reaction time: 0.5 h
Yield: 69 %

Procedure:
tert-Butyl lithium (2.29 ml of a 1.7M solution in pentane, 3.9 mmol) was added to a solution of 3,4-diisopropoxy-3-cyclobutene-1,2-dione (594 mg, 3 mmol) in THF (30 ml) at −78° C. After 5 h trifluoroactic anhydride (636 μl, 4.5 mmol) was added and stirring continued at −78° C. for 30 min. The cold mixture was poured into NH4Cl(aq), extraced with EtOAc, dried (Na2SO4) and evaporated in vacuo. Column chromatography (SiO2; EtOAc/hexane, 15:85) gave the title compound as a mobile yellow oil (408 mg, 69%). δH (CDCl3) 5.43 (1H, sept, J 6.2 Hz), 1.45 (6H, d, J 6.2 Hz) and 1.33 (9H, s); m/z (ES+, 70V) 197 (M++H).
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][O:11][CH:10]([C:14]2[CH:19]=[CH:18][C:17](Br)=[CH:16][CH:15]=2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:21][C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([CH3:28])[C:23]=1[SH:29].N1C2C(=CC=CC=2O)CCC1.C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C.O>[CH2:1]([N:8]1[CH2:13][CH2:12][O:11][CH:10]([C:14]2[CH:19]=[CH:18][C:17]([S:29][C:23]3[C:24]([CH3:28])=[CH:25][CH:26]=[CH:27][C:22]=3[CH3:21])=[CH:16][CH:15]=2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Brc1ccc(C2CN(Cc3ccccc3)CCO2)cc1
Reactant: Cc1cccc(C)c1S
Agent: O=C([O-])[O-]
Agent: Oc1cccc2c1NCCC2
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1cccc(C)c1Sc1ccc(C2CN(Cc3ccccc3)CCO2)cc1
Temperature: 130 °C
Yield: 68.2 %

Procedure:
To a solution of 4-benzyl-2-(4-bromo-phenyl)-morpholine (2.00 g; 6.02 mmol) and 2,6-dimethylthiophenol (0.88 mL; 6.62 mmol) in DMF (15 mL) was added CuBr (0.43 g; 3.01 mmol), 1,2,3,4-tetrahydro-quinolin-8-ol (0.45 g; 3.01 mmol) and Cs2CO3 (2.45 g; 7.52 mmol; 1.25 eq.). The resulting mixture was heated, in a closed vessel, at 130° C., for 2 days. After cooling to RT, water was added and the mixture extracted with Et2O. The combined organic layers were washed with water, dried (Na2SO4), filtered and concentrated in vacuo. The residue was purified by column chromatography (Et2O/hexanes 1:1) to afford 4-benzyl-2-[4-(2,6-dimethyl-phenylsulfanyl)-phenyl]-morpholine (1.60 g).
Reaction SMILES: [CH3:1][C:2]1[N:3]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:4]2[CH:9]=[CH:8][N:7]=[CH:6][C:5]=2[N:10]=1.C(Br)C1C=CC=CC=1>C(Cl)Cl>[CH3:1][C:2]1[N:3]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:4]2[CH2:9][CH2:8][NH:7][CH2:6][C:5]=2[N:10]=1
Reactant: Cc1nc2cnccc2n1-c1ccccc1
Agent: BrCc1ccccc1
Solvent: ClCCl
Product: Cc1nc2c(n1-c1ccccc1)CCNC2
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of 2-methyl-1-phenyl-1H-imidazo[4,5-c]pyridine (1.05 g, 5 mmol) in CH2Cl2 (5 mL) was added benzyl bromide (3.0 mL, 25 mmol). The solution stirred at rt for 4 h after which time it was concentrated to dryness. The residue was dissolved in MeOH (10 mL) and to it 20% Pd(OH)2C (0.24 g) was added. The reaction was stirred under an atmosphere of hydrogen for 3 h at rt. The mixture was filtered and the filtrate was concentrated under reduced pressure to a white solid (0.60 g, 56% over 2 steps).
Reaction SMILES: Cl[CH2:2][C:3]([NH:5][C@@H:6]1[CH2:11][O:10][C:9]2=[N:12][C:13]([N+:15]([O-:17])=[O:16])=[CH:14][N:8]2[CH2:7]1)=[O:4].[F:18][CH:19]([F:34])[O:20][C:21]1[CH:33]=[CH:32][C:24]([O:25][CH:26]2[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]2)=[CH:23][CH:22]=1>>[F:34][CH:19]([F:18])[O:20][C:21]1[CH:33]=[CH:32][C:24]([O:25][CH:26]2[CH2:27][CH2:28][N:29]([CH2:2][C:3]([NH:5][C@@H:6]3[CH2:11][O:10][C:9]4=[N:12][C:13]([N+:15]([O-:17])=[O:16])=[CH:14][N:8]4[CH2:7]3)=[O:4])[CH2:30][CH2:31]2)=[CH:23][CH:22]=1
Reactant: O=C(CCl)N[C@@H]1COc2nc([N+](=O)[O-])cn2C1
Reactant: FC(F)Oc1ccc(OC2CCNCC2)cc1
Product: O=C(CN1CCC(Oc2ccc(OC(F)F)cc2)CC1)N[C@@H]1COc2nc([N+](=O)[O-])cn2C1
Yield: 35.1 %

Procedure:
Similar to the manipulation of example 1, with (S)-2-chloro-N-(2-nitro-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazin-6-yl)acetamide (130 mg, 0.50 mmol) and 4-(4-(difluoromethoxy)phenoxy)piperidine (243 mg, 1.0 mmol) as crude materials, 82 mg title compound was generated and yield was 43%.
Reaction SMILES: [C:1]1(=[O:7])[O:6][C:4](=[O:5])[CH2:3][CH2:2]1.[C:8]([O:12][C:13](=[O:25])[NH:14][C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([C:21](=[NH:24])[NH:22]O)[CH:16]=1)([CH3:11])([CH3:10])[CH3:9]>CN(C=O)C>[C:8]([O:12][C:13]([NH:14][C:15]1[CH:16]=[C:17]([C:21]2[N:24]=[C:4]([CH2:3][CH2:2][C:1]([OH:6])=[O:7])[O:5][N:22]=2)[CH:18]=[CH:19][CH:20]=1)=[O:25])([CH3:11])([CH3:9])[CH3:10]
Reactant: CC(C)(C)OC(=O)Nc1cccc(C(=N)NO)c1
Reactant: O=C1CCC(=O)O1
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)Nc1cccc(-c2noc(CCC(=O)O)n2)c1
Temperature: 120 °C

Procedure:
Succinic anhydride (14 mg, 0.14 mmol) and [3-(N-hydroxycarbamimidoyl)-phenyl]-carbamic acid tert-butyl ester (35 mg, 0.14 mmol) were dissolved in 0.25 mL DMF and heated at 120° C. for 2 h. The cooled solution was evaporated and dried to yield 3-[3-(3-tert-butoxycarbonylamino-phenyl)-[1,2,4]oxadiazol-5-yl]-propionic acid which was used without further purification.
Reaction SMILES: C(N(CC)CC)C.[CH2:8]([O:15][C:16]([NH:18][CH2:19][C:20]([OH:22])=O)=[O:17])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.[NH2:44][CH2:45][CH:46]1[CH2:51][CH2:50][N:49]([C:52]([O:54][C:55]([CH3:58])([CH3:57])[CH3:56])=[O:53])[CH2:48][CH2:47]1.[OH-].[Na+]>C(Cl)(Cl)Cl>[CH2:8]([O:15][C:16]([NH:18][CH2:19][C:20]([NH:44][CH2:45][CH:46]1[CH2:51][CH2:50][N:49]([C:52]([O:54][C:55]([CH3:58])([CH3:57])[CH3:56])=[O:53])[CH2:48][CH2:47]1)=[O:22])=[O:17])[C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1
Reactant: CC(C)(C)OC(=O)N1CCC(CN)CC1
Reactant: O=C(O)CNC(=O)OCc1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCC(CNC(=O)CNC(=O)OCc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 15 h
Yield: 93.7 %

Procedure:
Triethylamine (2.8 mL, 20 mmol), N-(benzyloxycarbonyl)glycine (3.77 g, 18 mmol), EDCI (3.45 g, 18 mmol) and HOBt (2.43 g, 18 mmol) were added to a chloroform (80 mL) solution of 4-(aminomethyl)-1-(tert-butoxycarbonyl)piperidine (3.54 g, 16.5 mmol). The resulting mixture was stirred at room temperature for 15 hours, and a 2 M aqueous solution of NaOH (100 mL) was then added to the mixture. The organic layer was separated, and the aqueous layer was extracted with dichloromethane (100 mLX 3). The organic layers were combined, dried over anhydrous sodium sulfate, filtered and concentrated. The obtained crude product was purified by column chromatography (SiO2, ethyl acetate) to provide 4-[[(N-(benzyloxycarbonyl) glycyl)amino]methyl]-1-(tert-butoxycarbonyl)piperidine as an amorphous solid (6.27 g, 94%).
Reaction SMILES: [O:1]=[C:2]1[NH:7][C:6]([C:8]([F:14])([F:13])[C:9]([F:12])([F:11])[F:10])=[C:5]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH2:4][CH2:3]1.BrN1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl>[O:1]=[C:2]1[NH:7][C:6]([C:8]([F:13])([F:14])[C:9]([F:10])([F:11])[F:12])=[C:5]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH:4]=[CH:3]1
Reactant: CCOC(=O)C1=C(C(F)(F)C(F)(F)F)NC(=O)CC1
Agent: O=C1CCC(=O)N1Br
Solvent: ClC(Cl)(Cl)Cl
Product: CCOC(=O)c1ccc(=O)[nH]c1C(F)(F)C(F)(F)F
Temperature: 80 °C
Yield: 43.8 %

Procedure:
A suspension of ethyl 6-oxo-2-(pentafluoroethyl)-1,4,5,6-tetrahydropyridine-3-carboxylate (0.690 g) and N-bromosuccinimide (0.427 g) in carbon tetrachloride (5 mL) was heated at 80° C. for 20 h. The reaction mixture was concentrated in vacuo and subjected to flash column chromatography (eluent 1:3 ethyl acetate/isohexane) to yield a colourless solid (0.30 g).
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5]([I:8])=[CH:4][CH:3]=1.[CH3:9][C:10]1[NH:11][CH:12]=[C:13]([CH:15]=[O:16])[N:14]=1.C([O-])([O-])=O.[K+].[K+].OC1C=CC=C2C=1N=CC=C2>CS(C)=O.O1CCOCC1.[Cu]I.O>[I:8][C:5]1[CH:6]=[CH:7][C:2]([N:11]2[CH:12]=[C:13]([CH:15]=[O:16])[N:14]=[C:10]2[CH3:9])=[CH:3][CH:4]=1
Reactant: Cc1nc(C=O)c[nH]1
Reactant: Ic1ccc(I)cc1
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: Oc1cccc2cccnc12
Solvent: CS(C)=O
Solvent: O
Solvent: C1COCCO1
Product: Cc1nc(C=O)cn1-c1ccc(I)cc1
Temperature: 120 °C
Reaction time: 48 h

Procedure:
The mixture of 1,4-diiodobenzene 1-1 (600 mg, 1.8 mmol), 2-methyl-1H-imidazole-4-carbaldehyde (200 mg, 1.8 mmol), K2CO3 (503 mg, 3.6 mmol), CuI (105 mg, 0.55 mmol) and 8-hydroxyquinoline (80 mg, 0.55 mol) in 5 mL DMSO and 5 mL dioxane in a sealed tube was stirred for 2 days at 120° C. It was cooled to rt, and to it was added 60 mL water. The mixture was stirred for 30 min and filtered through a celite layer. The filtrate was concentrated in vacuo and subjected to reverse phase preparative HPLC to isolate 1-(4-iodophenyl)-2-methyl-1H-imidazole-4-carbaldehyde 5-1. MS found for C11H9IN2O (M+H)+313.0.
Reaction SMILES: C(O[CH2:5][CH2:6][CH2:7][CH2:8][CH:9]=[CH:10][CH2:11][CH2:12][CH2:13][CH3:14])(=O)C.C(O)CCCC=CCCCC.C([O-])(=O)C.[Cl:30]CCCCC=C.C=CCCCC>>[Cl:30][CH2:5][CH2:6][CH2:7][CH2:8][CH:9]=[CH:10][CH2:11][CH2:12][CH2:13][CH3:14]
Reactant: C=CCCCCCl
Reactant: CCCCC=CCCCCOC(C)=O
Agent: CC(=O)[O-]
Agent: CCCCC=CCCCCO
Solvent: C=CCCCC
Product: CCCCC=CCCCCCl

Procedure:
Peach Twig Borer (PTB) pheromone is a mixture of 5-decenyl acetate and 5-decenol of approximately 85:15 molar ratio of the acetate to the alcohol. The synthesis of PTB pheromoneqcouples 1-chloro-5-hexene and 1-hexene to yield 1-chloro-5-decene. 1-chloro-5-decene is converted to 5-decenyl acetate, isomerized and a portion of the acetate is hydrolyzed to the corresponding alcohol to yield PTB pheromone. The overall scheme using the catalyst of Example 1 is shown below, followed by details of the synthesis. ##STR1##
Reaction SMILES: [C:1]([O:4][C@@H:5]1[C@@H:19]([O:20][C:21](=[O:23])[CH3:22])[C@H:18]([O:24][C:25](=[O:27])[CH3:26])[CH2:17][S:16][C@H:6]1[O:7][C:8]1[C:9](I)=[N:10][C:11]([CH3:14])=[CH:12][CH:13]=1)(=[O:3])[CH3:2].[N:28]1[CH:33]=[CH:32][CH:31]=[C:30](B(O)O)[CH:29]=1>>[C:1]([O:4][C@@H:5]1[C@@H:19]([O:20][C:21](=[O:23])[CH3:22])[C@H:18]([O:24][C:25](=[O:27])[CH3:26])[CH2:17][S:16][C@H:6]1[O:7][C:8]1[C:9]([C:30]2[CH:29]=[N:28][CH:33]=[CH:32][CH:31]=2)=[N:10][C:11]([CH3:14])=[CH:12][CH:13]=1)(=[O:3])[CH3:2]
Reactant: OB(O)c1cccnc1
Reactant: CC(=O)O[C@@H]1[C@@H](OC(C)=O)[C@H](OC(C)=O)CS[C@H]1Oc1ccc(C)nc1I
Product: CC(=O)O[C@@H]1[C@@H](OC(C)=O)[C@H](OC(C)=O)CS[C@H]1Oc1ccc(C)nc1-c1cccnc1

Procedure:
By carrying out the operation analogously to example 177, starting from 2-iodo-6-methyl-3-pyridinyl 2,3,4-tri-O-acetyl-5-thio-β-D-xylopyranoside, obtained according to preparation V, and 3-pyridineboronic acid, the desired product is obtained in the form of an ocher powder (yield=42%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[N:9]=[C:10]1[NH:14][CH2:13][CH2:12][N:11]1[OH:15].[Cl:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][N+:19]=1[O-:24].CC(C)=O.[ClH:29]>O1CCOCC1>[ClH:16].[ClH:29].[F:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[C:3]=1[N:9]=[C:10]1[NH:14][CH2:13][CH2:12][N:11]1[O:15][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][N+:19]=1[O-:24]
Reactant: ON1CCNC1=Nc1c(F)cccc1F
Reactant: [O-][n+]1ccccc1CCl
Agent: Cl
Solvent: C1COCCO1
Solvent: CC(C)=O
Product: [O-][n+]1ccccc1CON1CCNC1=Nc1c(F)cccc1F

Procedure:
From 2-[(2,6-difluorophenyl)imino]-1-hydroxy-imidazolidine and 2-chloromethyl-pyridine N-oxide there is obtained, in analogy to the details in Example 1,2-([{2-[(2,6-difluorophenyl)imino]-1-imidazolidinyl}oxy]methyl)-pyridine 1-oxide dihydrochloride of melting point 188°-189° (acetone/hydrogen chloride in dioxane).
Reaction SMILES: [NH2:1][C@H:2]1[C@H:8]([C:9]2[CH:14]=[CH:13][C:12]([Cl:15])=[C:11]([Cl:16])[CH:10]=2)[O:7][CH2:6][CH2:5][N:4]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:3]1.[CH3:24][NH:25][S:26](=O)(=[O:35])[O:27]C1C=CC=CC=1O.C(N(CC)CC)C>C(#N)C.CN(C1C=CN=CC=1)C.C(OCC)(=O)C>[Cl:16][C:11]1[CH:10]=[C:9]([C@@H:8]2[O:7][CH2:6][CH2:5][N:4]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:3][C@H:2]2[NH:1][S:26](=[O:35])(=[O:27])[NH:25][CH3:24])[CH:14]=[CH:13][C:12]=1[Cl:15]
Reactant: CC(C)(C)OC(=O)N1CCO[C@@H](c2ccc(Cl)c(Cl)c2)[C@H](N)C1
Reactant: CNS(=O)(=O)Oc1ccccc1O
Agent: CN(C)c1ccncc1
Solvent: CCOC(C)=O
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CNS(=O)(=O)N[C@@H]1CN(C(=O)OC(C)(C)C)CCO[C@H]1c1ccc(Cl)c(Cl)c1
Temperature: 80 °C
Reaction time: 8 h
Yield: 64.4 %

Procedure:
To a solution of tert-butyl (6R,7S)-6-amino-7-(3,4-dichlorophenyl)-1,4-oxazepane-4-carboxylate (100 mg) in acetonitrile (3 mL) were added 2-hydroxyphenyl methylsulfamate (86 mg), triethylamine (56 mg) and N,N-dimethyl-4-aminopyridine (3.3 mg) at room temperature, and the mixture was stirred at 80° C. overnight. The reaction mixture was diluted with ethyl acetate. The diluted solution was washed with distilled water and brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel chromatography (hexane/ethyl acetate) to give the title compound (81 mg).
Reaction SMILES: [F:1][C:2]([F:30])([F:29])/[C:3](/[C:18]1[CH:23]=[CH:22][C:21]([N:24]2[CH:28]=[CH:27][CH:26]=[N:25]2)=[CH:20][CH:19]=1)=[CH:4]\[C:5]1[NH:6][CH:7]=[C:8]([CH2:10][C:11]2([C:14]([F:17])([F:16])[F:15])[CH2:13][CH2:12]2)[N:9]=1.[H][H]>[Pd].C(O)C>[F:30][C:2]([F:1])([F:29])[CH:3]([C:18]1[CH:19]=[CH:20][C:21]([N:24]2[CH:28]=[CH:27][CH:26]=[N:25]2)=[CH:22][CH:23]=1)[CH2:4][C:5]1[NH:6][CH:7]=[C:8]([CH2:10][C:11]2([C:14]([F:15])([F:16])[F:17])[CH2:12][CH2:13]2)[N:9]=1
Reactant: [H][H]
Reactant: FC(F)(F)/C(=C\c1nc(CC2(C(F)(F)F)CC2)c[nH]1)c1ccc(-n2cccn2)cc1
Agent: [Pd]
Solvent: CCO
Product: FC(F)(F)C(Cc1nc(CC2(C(F)(F)F)CC2)c[nH]1)c1ccc(-n2cccn2)cc1
Temperature: -78 °C
Reaction time: 2 h

Procedure:
In a 25-mL round-bottom flask, a mixture of 1-{4-[(Z)-1-(trifluoromethyl)-2-(4-{[1-(trifluoromethyl)cyclopropyl]methyl}-1H-imidazol-2-yl)vinyl]phenyl}-1H-pyrazole (52.8 mg, 0.124 mmol) and palladium on carbon (11.4 mg, 0.107 mmol) was suspended in ethanol (5 mL), and a hydrogen balloon was put on top of the flask. It was cooled to −78° C., degassed and saturated with hydrogen three times. The reaction is mostly complete 2 hours after operation. The reaction mixture was filtered through syringe filter to afford the title compound. LCMS (M+H) found: 429.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[N:6]([CH2:23][C:24]2[CH:29]=[CH:28][C:27]([NH2:30])=[CH:26][CH:25]=2)[C:7](=[O:22])[C:8]2[C:13]([C:14]=1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[CH:12][C:11]([Br:21])=[CH:10][CH:9]=2)=[O:4].C(N(CC)CC)C.[CH3:38][S:39](Cl)(=[O:41])=[O:40]>O1CCCC1>[CH3:1][O:2][C:3]([C:5]1[N:6]([CH2:23][C:24]2[CH:25]=[CH:26][C:27]([NH:30][S:39]([CH3:38])(=[O:41])=[O:40])=[CH:28][CH:29]=2)[C:7](=[O:22])[C:8]2[C:13]([C:14]=1[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1)=[CH:12][C:11]([Br:21])=[CH:10][CH:9]=2)=[O:4]
Reactant: COC(=O)c1c(-c2ccccc2)c2cc(Br)ccc2c(=O)n1Cc1ccc(N)cc1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COC(=O)c1c(-c2ccccc2)c2cc(Br)ccc2c(=O)n1Cc1ccc(NS(C)(=O)=O)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 55 %

Procedure:
To a solution of 2-(4-aminobenzyl)-6-bromo-1-oxo-4-phenyl-1,2-dihydroisoquinoline-3-carboxylic acid methyl ester (139 mg) in tetrahydrofuran (5 ml) was added triethylamine (0.083 ml) and then methanesulfonyl chloride (0.028 ml) was added. The mixture was stirred at room temperature for 3 hrs. The solvent was evaporated under reduced pressure, 1N hydrochloric acid was added, and the mixture was extracted with dichloromethane. The extract was washed with saturated brine and dried by adding sodium sulfate. The solvent was evaporated under reduced pressure and the obtained residue was purified by silica gel column chromatography (n-hexane/ethyl acetate=3/1→2/3) to give the title compound (90 mg, 55%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[O:9][CH3:10].[Li]CCCC.CN(C)[CH:18]=[O:19].Cl>O1CCCC1.CCCCCC>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:18]=[O:19])=[C:4]([F:8])[C:3]=1[O:9][CH3:10]
Reactant: COc1c(F)cccc1Cl
Reactant: CN(C)C=O
Agent: Cl
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: COc1c(Cl)ccc(C=O)c1F
Temperature: -49 °C
Reaction time: 0.25 h
Yield: 74.8 %

Procedure:
To a solution of 2-chloro-6-fluoroanisole (321.2 g) in 2 L of dry tetrahydrofuran (THF), cooled to −70° C., was added 890 mL of 2.5 M n-BuLi in hexane over 30 min with good mechanical stirring. During the addition the reaction warmed to −48 to −50° C. and was held there for 15 min after addition was complete. The solution was cooled to −75° C. before a solution of 177 g of dimethylformamide (DMF) in 100 mL of THF was added keeping the temperature below −50° C. The reaction was warmed to room temperature and 260 g of 37% aqueous HCl was slowly added and stirring was continued for 2 hours. The phases were separated and the organic phase concentrated and taken into 2 L of ether. The solution was washed twice with 500 mL of aqueous 10% HCl. The organic phase was dried over MgSO4, filtered and concentrated to 372 g of a light gold oil (93% pure by GC). This oil was distilled bulb to bulb to give 282 g (75% yield) of a light gold oil that solidified upon standing. A small sample was crystallized from pentane to give fine white needles; MP 44-45° C.; 1H NMR (CDCl3, 300 MHz) δ 10.3 (s, 1H); 7.5 (dd, 1H, J=6.6, 8.5 Hz); 7.3 (m, 1H); 4.0 (s, 3H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7](Cl)[CH:6]=[CH:5]2.[CH3:13][S-:14].[Na+]>CN(C=O)C.[Cl-].[Na+].O>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([S:14][CH3:13])[CH:6]=[CH:5]2
Reactant: Clc1ccc2cc(Br)ccc2n1
Reactant: C[S-]
Agent: [Cl-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CSc1ccc2cc(Br)ccc2n1
Reaction time: 1 h

Procedure:
A solution of 6-Bromo-2-chloroquinoline (0.68 g, 2.8 mmol) in DMF was treated with sodium thiomethoxide (0.22 g, 3.1 mmol). After 1 h at RT, the LC-MS indicated conversion. The solution was diluted with brine and extracted with EtOAc. The organic layer was removed, dried, filtered and concentrated. The crude product was used in the next step. LC-MS (IE, m/z): 256 [M+1]+.
Reaction SMILES: O[CH2:2][C:3]1[C:4]([I:13])=[N:5][C:6]2[C:11]([CH:12]=1)=[CH:10][CH:9]=[CH:8][CH:7]=2.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Cl:33]N1C(=O)CCC1=O.C([O-])(O)=O.[Na+]>CN(C=O)C>[Cl:33][CH2:2][C:3]1[C:4]([I:13])=[N:5][C:6]2[C:11]([CH:12]=1)=[CH:10][CH:9]=[CH:8][CH:7]=2
Reactant: O=C1CCC(=O)N1Cl
Reactant: OCc1cc2ccccc2nc1I
Agent: O=C([O-])O
Agent: [Na+]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Product: ClCc1cc2ccccc2nc1I
Temperature: -23 °C
Reaction time: 1 h
Yield: 84 %

Procedure:
To a stirred mixture of 3-hydroxymethyl-2-iodoquinoline prepared in accordance with Example 10 above (350 mg, 1.23 mmol) and triphenylphosphine (483 mg, 1.84 mmol) in 10 mL of dry DMF at -23° C. was added N-chlorosuccinimide (246 mg, 1.84 mmol), and the mixture was stirred for 1 h at -23° C. After the addition of 40 mL of dilute aqueous NaHCO3, the mixture was extracted with ethyl acetate (20 mL) and then ether (2×15 mL). The combined organic extracts were washed successively with 20-mL portions of dilute NaHCO3, water and brine, and were dried over MgSO4. Concentration and purification of the residue by radial PLC (silica gel, 10% ethyl acetate/hexanes) afforded 312 mg (84%) of 3-chloromethyl-2-iodoquinoline as a white crystalline solid: mp 138°-140° C. Recrystallization from hexanes afforded an analytical sample as colorless needles: mp 139°-140° C. H NMR (300 MHz, CDCl3) δ 8.17 (s, 1H), 8.07 (d, 1H, J=9 Hz), 7.84 (d, 1H, J=9 Hz), 7.75 (t, 1H, J=9 Hz), 7.62 (t, 1H, J=9 Hz), 4.80 (s, 1H); IR (nujol) 1585, 1555, 1260, 1010, 780, 755, 710 cm-1.
Reaction SMILES: Cl.[CH3:2][N:3]1[C:7]([C@@H:8]2[CH2:13][CH2:12][CH2:11][N:10](C(OC(C)(C)C)=O)[CH2:9]2)=[N:6][C:5]([C:21]2[CH:22]=[C:23]3[C:27](=[CH:28][CH:29]=2)[NH:26][N:25]=[C:24]3[C:30]2[CH:35]=[CH:34][N:33]=[CH:32][CH:31]=2)=[N:4]1>O1CCOCC1.C(Cl)Cl>[CH3:2][N:3]1[C:7]([C@@H:8]2[CH2:13][CH2:12][CH2:11][NH:10][CH2:9]2)=[N:6][C:5]([C:21]2[CH:22]=[C:23]3[C:27](=[CH:28][CH:29]=2)[NH:26][N:25]=[C:24]3[C:30]2[CH:31]=[CH:32][N:33]=[CH:34][CH:35]=2)=[N:4]1
Reactant: Cn1nc(-c2ccc3[nH]nc(-c4ccncc4)c3c2)nc1[C@@H]1CCCN(C(=O)OC(C)(C)C)C1
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: Cn1nc(-c2ccc3[nH]nc(-c4ccncc4)c3c2)nc1[C@@H]1CCCNC1
Temperature: 25 °C
Reaction time: 4 h
Yield: 77.3 %

Procedure:
Added 4M HCl in dioxane (2 ml) to a solution of (R)-tert-butyl 3-(1-methyl-3-(3-(pyridin-4-yl)-1H-indazol-5-yl)-1H-1,2,4-triazol-5-yl)piperidine-1-carboxylate (25 mg, 0.054 mmol) in DCM (5 ml), then stirred 4 hours at room temperature. The solvent was evaporated to yield (R)-5-(1-methyl-5-(piperidin-3-yl)-1H-1,2,4-triazol-3-yl)-3-(pyridin-4-yl)-1H-indazole as a white solid (15 mg).
Reaction SMILES: Cl.[C@H:2]12[CH2:8][C@H:5]([NH:6][CH2:7]1)[CH2:4][N:3]2[CH2:9][C:10]1[CH:25]=[CH:24][C:13]([O:14][C:15]2[S:16][C:17]3[CH:23]=[CH:22][CH:21]=[CH:20][C:18]=3[N:19]=2)=[CH:12][CH:11]=1.CCN(CC)CC.C[Si]([N:37]=[C:38]=[O:39])(C)C>C(Cl)Cl>[S:16]1[C:17]2[CH:23]=[CH:22][CH:21]=[CH:20][C:18]=2[N:19]=[C:15]1[O:14][C:13]1[CH:12]=[CH:11][C:10]([CH2:9][N:3]2[CH2:4][C@@H:5]3[CH2:8][C@H:2]2[CH2:7][N:6]3[C:38]([NH2:37])=[O:39])=[CH:25][CH:24]=1
Reactant: C[Si](C)(C)N=C=O
Reactant: c1ccc2sc(Oc3ccc(CN4C[C@@H]5C[C@H]4CN5)cc3)nc2c1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: NC(=O)N1C[C@@H]2C[C@H]1CN2Cc1ccc(Oc2nc3ccccc3s2)cc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 85 %

Procedure:
To a stirred suspension of (S,S)-2-[4-(2,5-diaza-bicyclo[2.2.1]hept-2-ylmethyl)-phenoxy]-benzothiazole hydrochloride (2.8 g, 6.8 mmol) and Et3N (9.1 mL, 68.5 mmol) in CH2Cl2 (50 mL) was added trimethylsilylisocyanate (3.8 mL, 27.4 mmol), and the resulting solution was stirred at rt for 1.5 h. The solution was then partitioned between CH2Cl2 (500 mL) and satd. aq. NaHCO3 (80 mL). The organic layer was separated, dried (Na2SO4), filtered and concentrated. Purification by silica gel flash chromatography (5% to 10% CH3OH in CH2Cl2) afforded the title compound as a white solid (2.2 g, 85%).
Reaction SMILES: [C:1]([O:4][C:5]1[C:34]([CH3:35])=[CH:33][C:8]([CH:9]=[CH:10][C:11]([NH:13][C:14]2[CH:15]=[N:16][C:17]3[C:22]([C:23]=2[C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[Cl:30])=[CH:21][C:20]([CH3:31])=[CH:19][C:18]=3[CH3:32])=[O:12])=[CH:7][C:6]=1[CH3:36])(=[O:3])[CH3:2]>O1CCCC1CO.[C].[Pd]>[C:1]([O:4][C:5]1[C:6]([CH3:36])=[CH:7][C:8]([CH2:9][CH2:10][C:11]([NH:13][C:14]2[CH:15]=[N:16][C:17]3[C:22]([C:23]=2[C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[Cl:30])=[CH:21][C:20]([CH3:31])=[CH:19][C:18]=3[CH3:32])=[O:12])=[CH:33][C:34]=1[CH3:35])(=[O:3])[CH3:2]
Reactant: CC(=O)Oc1c(C)cc(C=CC(=O)Nc2cnc3c(C)cc(C)cc3c2-c2ccccc2Cl)cc1C
Agent: [Pd]
Solvent: OCC1CCCO1
Product: CC(=O)Oc1c(C)cc(CCC(=O)Nc2cnc3c(C)cc(C)cc3c2-c2ccccc2Cl)cc1C

Procedure:
5% of palladium-carbon (including 50% water, 40 mg) was added to a solution of 3-(4-acetoxy-3,5-dimethylcinnamoylamino)-4-(2-chlorophenyl)-6,8-dimethylquinoline (200 mg) in tetrahydrofuran-methanol (1:1, 5 ml). The solution was catalytically reduced at room temperature under atmospheric pressure. After the reduction, the catalyst was removed and the filtrate was concentrated to give crystals of 3-[3-(4-acetoxy-3,5-dimethylphenyl) propionylamino]-4-(2-chlorophenyl)-6,8-dimethylquinoline. The crystals were recrystallized from ethanol to afford colorless needles (146 mg, 73.0%)