Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH:3]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:9]3([CH2:19][O:18][C:17]4[CH:20]=[C:21]5[C:25](=[CH:26][C:16]3=4)[CH2:24][CH2:23][O:22]5)[C:8]2=[O:27])[CH2:2]1.C(N(CC)CC)C.[CH:35]([N:38]=[C:39]=[O:40])([CH3:37])[CH3:36]>ClCCl.C(=O)(O)[O-].[Na+]>[CH3:36][CH:35]([NH:38][C:39]([N:1]1[CH2:5][CH2:4][CH:3]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:9]3([CH2:19][O:18][C:17]4[CH:20]=[C:21]5[C:25](=[CH:26][C:16]3=4)[CH2:24][CH2:23][O:22]5)[C:8]2=[O:27])[CH2:2]1)=[O:40])[CH3:37]
Reactant: CC(C)N=C=O
Reactant: O=C1N(CC2CCNC2)c2ccccc2C12COc1cc3c(cc12)CCO3
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)NC(=O)N1CCC(CN2C(=O)C3(COc4cc5c(cc43)CCO5)c3ccccc32)C1
Temperature: 25 °C
Reaction time: 0.58 h
Yield: 82.5 %

Procedure:
To a solution of 1′-(pyrrolidin-3-ylmethyl)-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one (0.24 g, 0.65 mmol) and triethylamine (0.15 mL, 1.1 mmol) in dichloromethane (5 mL) was added isopropyl isocyanate (0.10 mL, 1.0 mmol) and the solution was stirred at ambient temperature for 35 min. The reaction was diluted with saturated sodium bicarbonate (40 mL) and was extracted with dichloromethane (3×20 mL). The combined organic solution was dried over sodium sulfate, filtered and concentrated under reduced pressure. Purification by flash column chromatography with dichloromethane/diethyl ether (2/1) afforded N-(1-methylethyl)-3-[(2′-oxo-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-1′(2′H)-yl)methyl]pyrrolidine-1-carboxamide (0.24 g, 81%) as a colorless solid: mp 107-115° C. (hexanes); 1H NMR (300 MHz, CDCl3) (diastereomers) δ7.31 (dd, J=7.6, 7.6 Hz, 0.5H), 7.30 (dd, J=7.7, 7.7 Hz, 0.5H), 7.18 (d, J=6.8 Hz, 1H), 7.07 (dd, J=7.5, 7.5 Hz, 1H), 6.90 (d, J=7.8 Hz, 1H), 6.45 (s, 1H), 6.42 (s, 1H), 4.912 (d, J=9.0 Hz, 0.5H), 4.906 (d, J=8.9 Hz, 0.5H), 4.67 (d, J=8.9 Hz, 0.5H), 4.66 (d, J=9.0 Hz, 0.5H), 4.53 (t, J=8.6 Hz, 2H), 4.03-3.44 (m, 6H), 3.35-3.17 (m, 2H), 3.00 (t, J=8.5 Hz, 2H), 2.77 (septet, J=6.9 Hz, 1H), 2.09-1.98 (m, 1H), 1.87-1.73 (m, 1H), 1.15 (d, J=5.7 Hz, 3H), 1.14 (d, J=6.0 Hz, 3H); 13C NMR (75 MHz, CDCl3) (diastereomers) δ178.33, 178.26, 162.0, 161.4, 156.3, 142.41, 142.36, 132.80, 132.75, 129.0, 124.25, 124.23, 123.6, 120.16, 120.10, 120.07, 118.9, 118.8, 108.4, 93.39, 93.36, 80.8, 72.5, 57.8, 49.2, 44.7, 44.6, 42.6, 42.5, 42.43, 42.40, 37.7, 37.5, 29.35, 29.32, 29.1, 23.7; MS (ES+) m/z 448.2 (M+1).
Reaction SMILES: FC(F)(F)C(O)=O.[CH3:8][N:9]1[CH:13]=[CH:12][N:11]=[C:10]1[CH:14]([C:21]1[CH:26]=[CH:25][C:24]([O:27]C2CCCCO2)=[CH:23][CH:22]=1)[CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17]>C(Cl)Cl>[OH:27][C:24]1[CH:25]=[CH:26][C:21]([CH:14]([C:10]2[N:9]([CH3:8])[CH:13]=[CH:12][N:11]=2)[CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:22][CH:23]=1
Reactant: CCOC(=O)CC(c1ccc(OC2CCCCO2)cc1)c1nccn1C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCOC(=O)CC(c1ccc(O)cc1)c1nccn1C
Reaction time: 4 h

Procedure:
Trifluoroacetic acid (21 mL) was added to a solution of protected ester 9.4 (21 g) in dry DCM (210 mL) with caution at 0° C. The mixture was brought to room temperature over 4 hours. The reaction mixture was concentrated under reduced pressure to provide a yellow oily residue, which was re-dissolved in DCM (200 mL) and washed with water, saturated NaHCO3, water and brine, and dried over Na2SO4. After filtration, the solvent was removed under reduced pressure, and the product was crystallized in EtOAc-hexane. The mother liquid was concentrated and flash chromatographed (silica gel, 50% EtOAc in hexane as eluant). The product, (±)-ethyl 3-(4-hydroxyphenyl)-3-(1-methyl-1H-imidazol-2-yl)propanoate (9.5) was obtained as a colorless crystal (combined yield 11 g). LC-MS ESI (pos.) m/e: 275 (M+H). 1H NMR (500 MHz) (CDCl3) δ 9.28 (s, 1H); 6.98-7.00 (m, 3H); 6.65-6.77(m, 3H); 4.41 (dd, J=9.0, 3.0 Hz, 1H); 3.96 (q, J=7.0, 2H); 3.39 (s, 3H); 3.19 (dd, J=16.0, 7.0 Hz, 1H); 2.78 (dd, J=16.0, 6.5 Hz, 1H); 1.80 (t, J=7.0 Hz, 3H).
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]([C:10]2[CH:15]=[C:14]([F:16])[CH:13]=[CH:12][C:11]=2[O:17][CH3:18])=[O:9])=[CH:6][N:5]=[C:4]([NH:19][CH:20]2[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]2)[N:3]=1.[C:26]([C:30]1[S:31][CH:32]=[CH:33][C:34]=1[S:35](Cl)(=[O:37])=[O:36])([O:28][CH3:29])=[O:27]>>[CH3:29][O:28][C:26]([C:30]1[S:31][CH:32]=[CH:33][C:34]=1[S:35]([N:23]1[CH2:22][CH2:21][CH:20]([NH:19][C:4]2[N:3]=[C:2]([NH2:1])[C:7]([C:8](=[O:9])[C:10]3[CH:15]=[C:14]([F:16])[CH:13]=[CH:12][C:11]=3[O:17][CH3:18])=[CH:6][N:5]=2)[CH2:25][CH2:24]1)(=[O:37])=[O:36])=[O:27]
Reactant: COc1ccc(F)cc1C(=O)c1cnc(NC2CCNCC2)nc1N
Reactant: COC(=O)c1sccc1S(=O)(=O)Cl
Product: COC(=O)c1sccc1S(=O)(=O)N1CCC(Nc2ncc(C(=O)c3cc(F)ccc3OC)c(N)n2)CC1

Procedure:
This compound was prepared from [4-amino-2-(piperidin-4-ylamino)-pyrimidin-5-yl]-(5-fluoro-2-methoxy-phenyl)-methanone, Example 59, and 2-carbomethoxy-3-thiophenesulfonyl chloride (Maybridge) by the procedure described in Example 152. HR-MS (ES, m/z) calculated for C23H25FN5O6S2 [(M+H)+]550.1225, observed 550.1232.
Reaction SMILES: C[O:2][C:3](=[O:22])[C:4]1[CH:9]=[CH:8][C:7]([C:10]2[NH:14][C:13]3[C:15]([CH:20]=[O:21])=[C:16]([OH:19])[CH:17]=[CH:18][C:12]=3[N:11]=2)=[CH:6][CH:5]=1>O1CCOCC1.[OH-].[Na+]>[CH:20]([C:15]1[C:13]2[NH:14][C:10]([C:7]3[CH:8]=[CH:9][C:4]([C:3]([OH:22])=[O:2])=[CH:5][CH:6]=3)=[N:11][C:12]=2[CH:18]=[CH:17][C:16]=1[OH:19])=[O:21]
Reactant: COC(=O)c1ccc(-c2nc3ccc(O)c(C=O)c3[nH]2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: O=Cc1c(O)ccc2nc(-c3ccc(C(=O)O)cc3)[nH]c12
Temperature: 50 °C
Reaction time: 1 h
Yield: 88.5 %

Procedure:
4-(7-Formyl-6-hydroxy-1H-benzoimidazol-2-yl)-benzoic acid methyl ester (360 mg, 1.22 mmol) was dissolved in a mixture of dioxane (6 mL) and 1N NaOH (6 mL) and was stirred at 50° C. for 1 h. The mixture was evaporated to half volume and acidified with glacial acetic acid. The precipitate was collected, washed with acetone and dried. The title compound (305 mg, 1.08 mmol, 89%) was isolated as a brown solid.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH2:4][N:5]([CH3:12])[C:6]2=[O:11].[N+:13]([O-])([OH:15])=[O:14]>S(=O)(=O)(O)O>[Br:1][C:2]1[CH:10]=[CH:9][C:8]([N+:13]([O-:15])=[O:14])=[C:7]2[C:3]=1[CH2:4][N:5]([CH3:12])[C:6]2=[O:11]
Reactant: CN1Cc2c(Br)cccc2C1=O
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Product: CN1Cc2c(Br)ccc([N+](=O)[O-])c2C1=O
Temperature: 0 °C
Reaction time: 2 h
Yield: 73.8 %

Procedure:
To a cold suspension of 4-bromo-2-methyl-2,3-dihydroisoindol-1-one (60 g, 265 mmol) in concentrated sulfuric acid (60 mL) was added pre-cooled mixture of conc. nitric acid (12.5 mL, 265 mmol) and conc. sulfuric acid (60 mL) over 20 min. The reaction mixture was stirred for 30 min at 0° C. and 2 h at room temperature. The reaction mixture was poured over ice-water mixture (300 mL). The precipitate was filtered, washed with water (3×100 mL) and suspended in isopropanol (200 mL). The slurry was heated on steam bath and cooled. The solid was filtered and dried in air to give 53 g (74%) of the title compound. 1H NMR (CDCl3, 300 MHz) δ 3.22 (s, 3H), 4.36 (s, 2H), 7.67 (d, J=8.4 Hz, 1H), 7.78 (d, J=8.4 Hz, 1H).
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7]([OH:9])=O)=[CH:5][CH:4]=[N:3]1.O1CCCC1.S(Cl)(Cl)=O.[NH2:19][C:20]1[CH:21]=[C:22]([CH:39]=[CH:40][C:41]=1[F:42])[O:23][C:24]1[CH:25]=[CH:26][C:27]2[N:28]([N:30]=[C:31]([NH:33][C:34]([CH:36]3[CH2:38][CH2:37]3)=[O:35])[N:32]=2)[CH:29]=1>CN(C)C=O.CN(C)C(=O)C>[CH:36]1([C:34]([NH:33][C:31]2[N:32]=[C:27]3[CH:26]=[CH:25][C:24]([O:23][C:22]4[CH:39]=[CH:40][C:41]([F:42])=[C:20]([NH:19][C:7]([C:6]5[N:2]([CH3:1])[N:3]=[CH:4][CH:5]=5)=[O:9])[CH:21]=4)=[CH:29][N:28]3[N:30]=2)=[O:35])[CH2:37][CH2:38]1
Reactant: Nc1cc(Oc2ccc3nc(NC(=O)C4CC4)nn3c2)ccc1F
Reactant: Cn1nccc1C(=O)O
Solvent: CN(C)C=O
Solvent: O=S(Cl)Cl
Solvent: C1CCOC1
Product: Cn1nccc1C(=O)Nc1cc(Oc2ccc3nc(NC(=O)C4CC4)nn3c2)ccc1F
Yield: 67 %

Procedure:
In the same manner as in Example 55 and using 1-methyl-1H-pyrazole-5-carboxylic acid (50.9 mg, 0.404 mmol), tetrahydrofuran (5 mL), thionyl chloride (70.0 μL, 0.807 mmol), N,N-dimethylformamide (2 drops), N-[6-(3-amino-4-fluorophenoxy)[1,2,4]triazolo[1,5-a]pyridin-2-yl]cyclopropanecarboxamide (120 mg, 0.367 mmol) and N,N-dimethylacetamide (5 mL) as starting materials, the title compound (107 mg, 67%) was obtained as a white solid.
Reaction SMILES: [CH3:1][CH:2]([CH3:17])[CH2:3][N:4]1[C:16]2[C:15]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[N:9]=[CH:8][C:7]=2[N:6]=[CH:5]1.[CH:18](=[O:20])[CH3:19]>>[CH3:19][CH:18]([C:5]1[N:4]([CH2:3][CH:2]([CH3:17])[CH3:1])[C:16]2[C:15]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[N:9]=[CH:8][C:7]=2[N:6]=1)[OH:20]
Reactant: CC=O
Reactant: CC(C)Cn1cnc2cnc3ccccc3c21
Product: CC(C)Cn1c(C(C)O)nc2cnc3ccccc3c21

Procedure:
Using the general method of Example 45, 1-(2-methylpropyl)-1H-imidazo[4,5-c]quinoline (20 g; 89 mmol) was reacted with acetaldehyde to provide the desired product. The structure was confirmed by nuclear magnetic resonance spectroscopy.
Reaction SMILES: [C:1]1([S:7]([C:10]2[C:11]([S:28][CH3:29])=[N:12][N:13]3[C:18](O)=[CH:17][C:16]([CH2:20][N:21]4[CH2:26][CH2:25][N:24]([CH3:27])[CH2:23][CH2:22]4)=[N:15][C:14]=23)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.O=P(Cl)(Cl)[Cl:32]>>[C:1]1([S:7]([C:10]2[C:11]([S:28][CH3:29])=[N:12][N:13]3[C:18]([Cl:32])=[CH:17][C:16]([CH2:20][N:21]4[CH2:26][CH2:25][N:24]([CH3:27])[CH2:23][CH2:22]4)=[N:15][C:14]=23)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CSc1nn2c(O)cc(CN3CCN(C)CC3)nc2c1S(=O)(=O)c1ccccc1
Reactant: O=P(Cl)(Cl)Cl
Product: CSc1nn2c(Cl)cc(CN3CCN(C)CC3)nc2c1S(=O)(=O)c1ccccc1
Temperature: 25 °C
Yield: 98 %

Procedure:
A suspension of 4.0 g (9 mmol) of 3-benzenesulphonyl-5-(4-methyl-piperazin-1-ylmethyl)-2-methylsulphanyl-pyrazolo[1,5-a]pyrimidin-7-ol in 100 ml of POCl3 was heated at reflux for 3 hrs. The reaction solution was cooled to RT and evaporated. The residue was treated with 100 ml of ice-water and the pH value of the solution was adjusted to 8 with sat. NaHCO3 solution. The aqueous phase was extracted three times with 150 ml of CH2Cl2 and the organic phases were dried (MgSO4), filtered and evaporated. Chroma-tography (SiO2CH2Cl2/MeOH 10:1) of the residue yielded 4.0 g (98%) of 3-benzenesulphonyl-7-chloro-5-(4-methyl-piperazin-1-ylmethyl)-2-methylsulphanyl-pyrazolo[1,5-a]pyrimidine as a pale brown powder, m.p. 113-116°.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[C:18]2[CH:17]=[C:16]([CH2:19][OH:20])[CH:15]=[CH:14][C:13]=2[C:12]2[N:21](COCC[Si](C)(C)C)[N:22]=[C:23]([NH:24][CH:25]3[CH2:30][CH2:29][N:28]([S:31]([CH3:34])(=[O:33])=[O:32])[CH2:27][CH2:26]3)[C:11]=2[N:10]=1.C(O)(C(F)(F)F)=O.N>C(Cl)Cl.O>[F:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[C:3]=1[C:9]1[C:18]2[CH:17]=[C:16]([CH2:19][OH:20])[CH:15]=[CH:14][C:13]=2[C:12]2[NH:21][N:22]=[C:23]([NH:24][CH:25]3[CH2:30][CH2:29][N:28]([S:31]([CH3:34])(=[O:32])=[O:33])[CH2:27][CH2:26]3)[C:11]=2[N:10]=1
Reactant: C[Si](C)(C)CCOCn1nc(NC2CCN(S(C)(=O)=O)CC2)c2nc(-c3c(F)cccc3F)c3cc(CO)ccc3c21
Agent: N
Solvent: O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CS(=O)(=O)N1CCC(Nc2n[nH]c3c2nc(-c2c(F)cccc2F)c2cc(CO)ccc23)CC1
Temperature: 0 °C
Reaction time: 2 h
Yield: 35.8 %

Procedure:
A 30 ml round-bottomed flask equipped with a magnetic stirrer and with a septum having a top-mounted argon intake is charged with 46 mg of [5-(2,6-difluorophenyl)-3-{[1-(methylsulphonyl)piperidin-4-yl]amino}-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrazolo[4,3-c]isoquinolin-7-yl]methanol in 4 ml of DCM. After cooling to 0° C. using an ice bath, 0.45 ml of TFA are added and the mixture is stirred at RT for 2 h. It is concentrated under RP and the solid obtained is taken up in 25 ml of water and 0.75 ml of a 0.75M aqueous ammonia solution. It is extracted with AcOEt, washed with saturated NaCl solution, dried over MgSO4, filtered and concentrated under RP. Chromatography on silica gel (20-45 μm), eluting with a mixture of DCM and methanol (92.5/7.5 by vol.), gives 13 mg of [5-(2,6-difluorophenyl)-3-{[1-(methylsulphonyl)piperidin-4-yl]amino}-1H-pyrazolo[4,3-c]isoquinolin-7-yl]methanol (yellow solid). MS (E/I): m/z=487 (M+); 1H NMR: 1.67 (m, 2H); 2.11 (m, 2H); 2.87 (s, 3H); 2.90 (m, 2H); 3.56 (m, 2H); 3.79 (m, 1H); 4.63 (d,. J=57 Hz, 2H); 5.34 (t, J=5.7 Hz, 1H); 5.98 (d, J=7.8 Hz, 1H); 7.31 (m, 2H); 7.59 (broad s, 1H); 7.66 (m, 1H); 7.83 (broad d, J=8.3 Hz, 1H); 8.35 (d, J=8.3, 1H); 12.68 (s, 1H).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][NH:5][C:4](=[O:8])[C:3]=1[C:9]1[NH:20][C:19]2[C:11](=[CH:12][C:13]3[CH2:14][N:15]([CH:22]4[CH2:27][CH2:26][N:25]([CH3:28])[CH2:24][CH2:23]4)[C:16](=[O:21])[C:17]=3[CH:18]=2)[N:10]=1.[NH2:29][CH2:30][CH2:31][NH:32][S:33]([C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][C:37]=1[Br:42])(=[O:35])=[O:34].CCN(CC)CC>CCO>[Br:42][C:37]1[CH:38]=[CH:39][CH:40]=[CH:41][C:36]=1[S:33]([NH:32][CH2:31][CH2:30][NH:29][C:2]1[CH:7]=[CH:6][NH:5][C:4](=[O:8])[C:3]=1[C:9]1[NH:20][C:19]2[C:11]([N:10]=1)=[CH:12][C:13]1[CH2:14][N:15]([CH:22]3[CH2:27][CH2:26][N:25]([CH3:28])[CH2:24][CH2:23]3)[C:16](=[O:21])[C:17]=1[CH:18]=2)(=[O:35])=[O:34]
Reactant: CN1CCC(N2Cc3cc4nc(-c5c(Cl)cc[nH]c5=O)[nH]c4cc3C2=O)CC1
Reactant: NCCNS(=O)(=O)c1ccccc1Br
Solvent: CCO
Solvent: CCN(CC)CC
Product: CN1CCC(N2Cc3cc4nc(-c5c(NCCNS(=O)(=O)c6ccccc6Br)cc[nH]c5=O)[nH]c4cc3C2=O)CC1
Temperature: 95 °C
Yield: 11.4 %

Procedure:
To a solution of 2-(4-chloro-2-oxo-1,2-dihydro-pyridin-3-yl)-6-(1-methyl-piperidin-4-yl)-6,7-dihydro-3H-1,3,6-triaza-s-indacen-5-one (40 mg, 0.1 mmol) and N-(2-amino-ethyl)-2-bromo-benzenesulfonamide (56 mg, 0.20 mmol) in EtOH (4 mL) was added Et3N (500 μL, 3.6 mmol) and the reaction was heated at 95° C. for 16 h. The solvent was evaporated in vacuo and the residue was purified by flash chromatography with CH2Cl2/MeOH/28% aqueous NH4OH (100:10:1) afforded the title compound (7.3 mg, 11%). 1H NMR (DMSO-d6) δ 1.70 (m, 2H), 1.85 (m, 2H), 2.15 (m, 2H), 2.29 (s, 3H, CH3), 2.96 (m, 2H), 3.19 (m, 1H), 3.50 (m, 2H), 4.05 (m, 1H), 4.48 (s, 1H), 6.05 (d, J=7 Hz, 1H), 7.32 (br s, 1H), 7.38-7.50 (1.5H), 7.62-7.70 (1.5H), 7.82 (s, 0.5H), 7.87 (s, 0.5H), 7.96-7.99 (2H), 8.20) br S, 1H, NH), 11.02 (br s, 1H, NH), 11.26 (br s, 1H, NH); ESI-MS m/z 640.5 (MH+).
Reaction SMILES: [C:1]([O:5][C:6]([C:8]1[CH:9]=[CH:10][C:11]2[S:15][N:14]=[CH:13][C:12]=2[C:16]=1[NH:17][C:18]1[CH:23]=[CH:22][C:21]([Si](C)(C)C)=[CH:20][C:19]=1[F:28])=[O:7])([CH3:4])([CH3:3])[CH3:2].[I:29]Cl>C(Cl)Cl.S([O-])([O-])(=O)=S.[Na+].[Na+]>[C:1]([O:5][C:6]([C:8]1[CH:9]=[CH:10][C:11]2[S:15][N:14]=[CH:13][C:12]=2[C:16]=1[NH:17][C:18]1[CH:23]=[CH:22][C:21]([I:29])=[CH:20][C:19]=1[F:28])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: ClI
Reactant: CC(C)(C)OC(=O)c1ccc2sncc2c1Nc1ccc([Si](C)(C)C)cc1F
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClCCl
Product: CC(C)(C)OC(=O)c1ccc2sncc2c1Nc1ccc(I)cc1F
Temperature: -78 °C
Reaction time: 1 h
Yield: 98 %

Procedure:
To a solution 4-(2-fluoro-4-trimethylsilanyl-phenylamino)-benzo[d]isothiazole-5-carboxylic acid tert-butyl ester (416 mg, 1.0 mmol) in DCM (10 mL) at −78° C. was added iodine monochloride as a solution in DCM (2.0 mL, 1M, 2.0 mmol). The reaction mixture was stirred at −78° C. for 1 hour then diluted with saturated aqueous sodium thiosulfate solution and extracted with DCM. The combined organic extracts were washed with brine, dried (Na2SO4) and concentrated in vacuo to yield the title compound as a yellow foam (459 mg, 98%). LCMS (Method B): RT=5.32 min, [M+H]+=471.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3](/[C:7](/[CH3:14])=[CH:8]\[C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH:2]=1>C(O)C.[Pd]>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH:7]([CH3:14])[CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH:2]=1
Reactant: CCOC(=O)/C=C(/C)c1cccnc1
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)CC(C)c1cccnc1

Procedure:
Ethyl 3-(3-pyridyl)crotonate (prepared from treating 3-acetylpyridine with ethoxycarbonylmethyltriphenylphosphonium bromide and sodium ethoxide) was hydrogenated in ethanol at 40 p.s.i. with 10% palladium on charcoal catalyst to give ethyl 3-(3-pyridyl)-butyrate, b.p. 74°/0.15 mmHg.
Reaction SMILES: [CH3:1][O:2][C@H:3]([CH3:7])[C:4]([OH:6])=O.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[OH:41][C:42]([C:44]([F:47])([F:46])[F:45])=[O:43].[F:48][CH:49]([F:77])[CH2:50][NH:51][C:52]1[N:57]=[C:56]2[CH2:58][NH:59][CH2:60][CH2:61][C:55]2=[N:54][C:53]=1[N:62]1[CH2:67][CH2:66][CH:65]([O:68][C:69]2[CH:74]=[CH:73][C:72]([F:75])=[CH:71][C:70]=2[F:76])[CH2:64][CH2:63]1>CN(C=O)C>[F:77][CH:49]([F:48])[CH2:50][NH:51][C:52]1[N:57]=[C:56]2[CH2:58][N:59]([C:4](=[O:6])[C@H:3]([O:2][CH3:1])[CH3:7])[CH2:60][CH2:61][C:55]2=[N:54][C:53]=1[N:62]1[CH2:63][CH2:64][CH:65]([O:68][C:69]2[CH:74]=[CH:73][C:72]([F:75])=[CH:71][C:70]=2[F:76])[CH2:66][CH2:67]1.[C:42]([OH:43])([C:44]([F:47])([F:46])[F:45])=[O:41]
Reactant: Fc1ccc(OC2CCN(c3nc4c(nc3NCC(F)F)CNCC4)CC2)c(F)c1
Reactant: CO[C@H](C)C(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CO[C@H](C)C(=O)N1CCc2nc(N3CCC(Oc4ccc(F)cc4F)CC3)c(NCC(F)F)nc2C1
Reaction time: 8 h

Procedure:
A solution of (R)-2-methoxypropanoic acid (2.9 mg, 0.028 mmol), DIPEA (10.8 mg, 0.083 mmol), and HATU (10.6 mg, 0.028 mmol) in DMF (278 μL) was stirred at room temperature for 10 min followed by the addition of N-(2,2-difluoroethyl)-2-(4-(2,4-difluorophenoxyl)piperidin-1-yl)-5,6,7,8-tetrahydropyrido[3,4-b]pyrazin-3-amine TFA salt (15 mg, 0.028 mmol) and stirring overnight. The crude reaction mixture was diluted in DMF, filtered through a hydrophilic PTFE 0.45 μm filter (Millipore® Millex-LCR), and purified via HPLC Method A to give the title compound as a TFA salt (3 mg) as a clear oil. 1H NMR (400 MHz, methanol-d4, mixture of rotamers) δ ppm 1.32 (d, J=6.8 Hz, 1.3H), 1.38 (d, J=6.6 Hz, 1.6H), 1.90-2.04 (m, 2H), 2.09-2.18 (m, 2H), 2.76 (t, J=6.6 Hz, 0.9H), 2.84 (t, J=6.1 Hz, 1.1H), 3.00 (ddd, J=12.3, 8.6, 3.3 Hz, 2H), 3.33 (s, 3H), 3.34-3.43 (m, 2H), 3.72-3.84 (m, 2H), 3.84-3.98 (m, 2H), 4.32-4.41 (m, 1H), 4.42-4.50 (m, 1H), 4.51-4.55 (m, 0.6H), 4.62-4.69 (m, 1.4H), 5.89-6.22 (m, 1H), 6.84-6.91 (m, 1H), 6.98 (ddd, J=11.2, 8.5, 3.0 Hz, 1H), 7.17 (td, J=9.2, 5.6 Hz, 1H); ESI-MS m/z [M+H]+ 512.4.
Reaction SMILES: [CH2:1]([O:8][CH2:9][C@:10]1(C[O:31][C@@H:30]([CH2:33][O:34][CH2:35][C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[C@H:21]([O:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C@H:12]1[O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[OH:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1(C=C(O)C=C(O)C=1)O>O1CCOCC1.Cl>[CH2:1]([O:8][CH2:9][C@@H:10]([C@@H:12]([C@H:21]([C@H:30]([CH2:33][O:34][CH2:35][C:36]1[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=1)[OH:31])[O:22][CH2:23][C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1)[O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[OH:11])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O[C@]1(COCc2ccccc2)CO[C@@H](COCc2ccccc2)[C@H](OCc2ccccc2)[C@H]1OCc1ccccc1
Agent: Cl
Agent: Oc1cc(O)cc(O)c1
Solvent: C1COCCO1
Product: O[C@@H](COCc1ccccc1)[C@H](OCc1ccccc1)[C@@H](OCc1ccccc1)[C@@H](O)COCc1ccccc1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
1,3,4,6-Tetra-O-benzyl-2,5-O-methylene-L-mannitol (7.5 g.) and phloroglucinol (14.3 g.) were dissolved in 1,4-dioxane (400 ml.) and the solution was diluted with 0.6 M hydrochloric acid (290 ml.). The reaction mixture was boiled gently under reflux for 24 hours, at which time t.l.c. (Solvent C) showed the hydrolysis to be complete. To this solution was then added concentrated hydrochloric acid (30 ml.) and heating was continued for a further 12 hours. The mixture was then cooled and concentrated under reduced pressure to a dry crystalline mass which was shaken with dichloromethane (75 ml.) at room temperature. Unchanged phloroglucinol was removed by filtration and washed with more dichloromethane (40 ml.). The combined filtrate and washings were washed with aqueous sodium hydrogen carbonate (saturated solution) and then with water. The solution was dried over magnesium sulfate, filtered through a pad of Celite and decolorizing charcoal and then concentrated to a syrup which was dissolved in a 5:6 mixture of ether and pentane. Crystallization was allowed to progress at 5° to give 5.5 g. (75%) of product in two crops. The product was recrystallized from isopropyl ether to give pure 1,3,4,6-tetra-O-benzyl-L-mannitol, m.p. 52.5°-53°, [α]D -31.5° (c 2.6, chloroform). These values compared favourably with the data obtained for the D-isomer m.p. 55°-56°, and [α]D +31.2° (c 0.87, chloroform).
Reaction SMILES: C[O:2][C:3]([C:5]1[S:6][C:7]([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH2:17][C:18]3[C:19]([C:26]4[C:31]([Cl:32])=[CH:30][CH:29]=[CH:28][C:27]=4[Cl:33])=[N:20][O:21][C:22]=3[CH:23]3[CH2:25][CH2:24]3)=[CH:12][C:11]=2[CH3:34])=[CH:8][CH:9]=1)=[O:4].[OH-].[Li+]>CO.C1COCC1.O.Cl>[CH:23]1([C:22]2[O:21][N:20]=[C:19]([C:26]3[C:27]([Cl:33])=[CH:28][CH:29]=[CH:30][C:31]=3[Cl:32])[C:18]=2[CH2:17][O:16][C:13]2[CH:14]=[CH:15][C:10]([C:7]3[S:6][C:5]([C:3]([OH:4])=[O:2])=[CH:9][CH:8]=3)=[C:11]([CH3:34])[CH:12]=2)[CH2:24][CH2:25]1
Reactant: COC(=O)c1ccc(-c2ccc(OCc3c(-c4c(Cl)cccc4Cl)noc3C3CC3)cc2C)s1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: Cc1cc(OCc2c(-c3c(Cl)cccc3Cl)noc2C2CC2)ccc1-c1ccc(C(=O)O)s1
Temperature: 55 °C

Procedure:
To a solution of 5-(4-(5-cyclopropyl-3-(2,6-dichloro-phenyl)-isoxazol-4-ylmethoxy)-2-methyl-phenyl)-thiophene-2-carboxylic acid methyl ester (0.138 g, 0.27 mmol) in 3 mL of methanol and 3 mL of THF is added a solution of lithium hydroxide (0.06 g, 2.7 mmol) in 3 mL of water. The reaction is heated to 55° C. for 1 hour. The solvent is evaporated to give a white solid. The solid is dissolved in aqueous 1M HCl and is extracted with ethyl acetate. The organic layer is washed with brine and dried over sodium sulfate. The reaction is filtered and concentrated under reduced pressure to yield the title compound. ES/MS m/e 500.0; 498.1 (M+1).
Reaction SMILES: F[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([F:21])([F:20])[F:19])[CH:13]=1)[C:6]([CH3:22])=[C:5]2[C:23]([O:25][CH3:26])=[O:24].[CH3:27][S-:28].[Na+].[H-].[Na+].CI>CN(C)C=O.O>[CH3:22][C:6]1[C:7]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([F:21])([F:20])[F:19])[CH:13]=2)=[N:8][C:9]2[C:4]([C:5]=1[C:23]([O:25][CH3:26])=[O:24])=[CH:3][C:2]([S:28][CH3:27])=[CH:11][CH:10]=2
Reactant: COC(=O)c1c(C)c(-c2cccc(C(F)(F)F)c2)nc2ccc(F)cc12
Reactant: C[S-]
Agent: [H-]
Agent: [Na+]
Solvent: CI
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1c(C)c(-c2cccc(C(F)(F)F)c2)nc2ccc(SC)cc12
Temperature: 100 °C
Reaction time: 8 h
Yield: 98.2 %

Procedure:
A suspension of methyl 6-fluoro-3-methyl-2-[3-(trifluoromethyl)phenyl]-4-quinolinecarboxylate (2.4 g, 6.61 mmol) and sodium thiomethoxide (1.158 g, 16.52 mmol) in N,N-dimethylformamide (40 mL) was stirred at 100° C. overnight. The mixture was cooled to room temperature, treated with NaH (0.264 mg, 6.61 mmol), and stirred for 20 min. Methyl iodide (1.5 g, 9.92 mmol) was added, and the mixture was stirred for 2 h. The mixture was diluted with water and extracted with methylene chloride (three times). The combined organic extracts were washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified via column chromatography (ISCO, 120 g Silica, 0-30% ethyl acetate/hexanes) to afford methyl 3-methyl-6-(methylthio)-2-[3-(trifluoromethyl)phenyl]-4-quinolinecarboxylate (2.54 g, 95% yield). MS (m/z) 392.1 (M+H+).