Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH3:1].[C:2]([OH:6])(=[O:5])[CH:3]=O.[Cl:7][C:8]1[CH:9]=[C:10]([OH:15])[C:11](=[CH:13][CH:14]=1)[OH:12].C>>[Cl:7][C:8]1[CH:9]=[C:10]([OH:15])[C:11]([OH:12])=[CH:13][C:14]=1[NH:1][CH2:3][C:2]([OH:6])=[O:5]
Reactant: N
Reactant: O=CC(=O)O
Reactant: Oc1ccc(Cl)cc1O
Product: O=C(O)CNc1cc(O)c(O)cc1Cl
Reaction time: 8 h

Procedure:
Aqueous ammonia (Sp.Gr 0.88, 37.5 ml) was added dropwise to an ice bath cooled 50% w/v aqueous glyoxylic acid solution (11.25 ml) at <10°. When the addition was complete the solution was heated at 50° for 15 minutes, 4-chlorocatechol (21.7 g) and more aqueous ammonia (12.5 ml) added, then heated at 60° for 4 hours. The solution was allowed to cool, reduced to ca. half volume in vacuo, washed with ethyl acetate (3×40 ml), adjusted to pH 5.5(conc, HCl) and set aside at 0° overnight. The solid was collected, washed with water and methanol, then dried, 2.76 g. The crude product was suspended in water (30 ml), conc. hydrochloric acid added to give a clear solution, treated with decolourising charcoal, filtered, adjusted to pH 5.5(40% sodium hydroxide solution) and left to crystallise at 0°. The product was collected, washed with water and acetone then dried, 2.53 g, 16% δ(CF 3 CO2H), 5.5-5.8(1H, m, CH), 7.10(2H, s, Ar), 7.70 (3H, broad, NH3) Found: C, 40.48; H, 4.27 Cl, 15.03; N, 5.91%. C8H8ClNO4. H2O requires: C, 40.78; H, 4.28; Cl, 15.05; N, 5.95%.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][CH2:12][CH2:13][OH:14].[OH-].[Na+].[Br:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23]Br>O.CCOCC>[Br:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][O:14][CH2:13][CH2:12][CH2:11][C:2]1[CH:3]=[CH:4][C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[N:1]=1
Reactant: BrCCCCCCBr
Reactant: OCCCc1ccc2ccccc2n1
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Solvent: O
Product: BrCCCCCCOCCCc1ccc2ccccc2n1

Procedure:
2-Quinolinepropanol (0.92 g), 50% aqueous sodium hydroxide (5 ml), 1,6-dibromohexane (5 ml) and TAB (57 mg) were vigorously stirred at 21° for 6 h. The mixture was diluted with water (25 ml) and ether (100 ml) and the organic phase dried and evaporated in vacuo. The residue was purified by FCC with hexane eluant to remove 1,6-dibromohexane. Elution with ether afforded the title compound as a yellow oil (0.88 g), t.l.c. ether Rf 0.51.
Reaction SMILES: [CH3:1][S:2][CH3:3].ClN1C(=O)CCC1=O.[CH3:12][O:13][C:14]([C:16]1[CH:24]=[C:23]2[C:19](C=[CH:21][NH:22]2)=[CH:18][CH:17]=1)=[O:15]>ClCCl>[CH3:1][S:2][C:3]1[C:19]2[C:23](=[CH:24][C:16]([C:14]([O:13][CH3:12])=[O:15])=[CH:17][CH:18]=2)[NH:22][CH:21]=1
Reactant: CSC
Reactant: COC(=O)c1ccc2cc[nH]c2c1
Agent: O=C1CCC(=O)N1Cl
Solvent: ClCCl
Product: COC(=O)c1ccc2c(SC)c[nH]c2c1
Temperature: -20 °C
Reaction time: 1 h

Procedure:
Dimethyl sulfide (0.54 mL, 7.42 mmol) was added dropwise at 0° C. to a suspension of N-chlorosuccinimide (0.99 g, 7.42 mmol) in dichloromethane (10 mL). The reaction mixture was cooled to −20° C. and a solution of 1H-indole-6-carboxylic acid methyl ester (1.0 g, 5.71 mmol) in dichloromethane (10 mL) was added. The reaction mixture was warmed to room temperature and stirred for 1 h. The solvent was evaporated and the residue and xylene (50 mL) were refluxed at 140-150° C. for 1 h. The xylene was removed under vacuum and the remnant purified by column chromatography [100-200 mesh silica; dichloromethane/hexane=1:1]. Light brown solid. Yield: 0.9 g (71% of theory). HPLC-MS (method 5): Rt=3.26 min; m/z [M+H]+=222
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:37])[CH:10]([O:20][C:21]2[CH:26]=[CH:25][C:24]([S:27]([C:30]3[CH:35]=[CH:34][C:33]([OH:36])=[CH:32][CH:31]=3)(=[O:29])=[O:28])=[CH:23][CH:22]=2)[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])=[CH:4][C:3]=1[N+:38]([O-:40])=[O:39].O.[NH2:42][NH2:43]>CS(C)=O>[NH:42]([C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:37])[CH:10]([O:20][C:21]2[CH:26]=[CH:25][C:24]([S:27]([C:30]3[CH:35]=[CH:34][C:33]([OH:36])=[CH:32][CH:31]=3)(=[O:29])=[O:28])=[CH:23][CH:22]=2)[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])=[CH:4][C:3]=1[N+:38]([O-:40])=[O:39])[NH2:43]
Reactant: NN
Reactant: CCCCCCCCCC(Oc1ccc(S(=O)(=O)c2ccc(O)cc2)cc1)C(=O)Nc1ccc(F)c([N+](=O)[O-])c1
Solvent: O
Solvent: CS(C)=O
Product: CCCCCCCCCC(Oc1ccc(S(=O)(=O)c2ccc(O)cc2)cc1)C(=O)Nc1ccc(NN)c([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
N-(4-Fluoro-3-nitrophenyl)-2-[4-(4-hydroxyphenylsulphonyl)-phenoxy]undecylamide (86.0 g, 147.0 mmole) was dissolved in dimethyl sulphoxide (500 ml), and hydrazine monohydrate (17.8 g, 355 mmole) was added in a dropwise fashion whilst keeping the temperature below 40° C. The reaction mixture was stirred for 1.5 hr at room temperature, and was then drowned in an ice/brine mixture (61). The red solid obtained was filtered off and dried at room temperature. The product was used in this crude form without any further purification.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:10]=[C:9]([C:11]([C:13]2[C:14](Cl)=[N:15][CH:16]=[CH:17][CH:18]=2)=O)[NH:8][CH:7]=1)=[O:5])[CH3:2].O.[NH2:21][NH2:22]>C(O)C>[CH2:1]([O:3][C:4]([C:6]1[CH:10]=[C:9]([C:11]2[C:13]3[C:14](=[N:15][CH:16]=[CH:17][CH:18]=3)[NH:22][N:21]=2)[NH:8][CH:7]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1c[nH]c(C(=O)c2cccnc2Cl)c1
Reactant: NN
Solvent: CCO
Solvent: O
Product: CCOC(=O)c1c[nH]c(-c2n[nH]c3ncccc23)c1
Temperature: 80 °C

Procedure:
A mixture of 5-(2-chloro-pyridine-3-carbonyl)-1H-pyrrole-3-carboxylic acid ethyl ester (1.2 g, 4.32 mmol) and hydrazine hydrate (6.27 mL) in ethanol (50 mL) was heated at 80° C. for 24 hours. The reaction was concentrated and the residue was neutralized to pH 7 with 1N HCl, extracted with ethyl acetate. The combined ethyl acetate was dried, concentrated and purified on a silica gel column to give the titled compound as a white solid.
Reaction SMILES: O[CH:2]([CH:5]1[CH2:10][CH2:9][CH:8]2[CH:6]1[CH2:7]2)[C:3]#[N:4].N1C=CC=CC=1.S(Cl)(Cl)=O>O>[C:3]([CH:2]=[C:5]1[CH2:10][CH2:9][CH:8]2[CH:6]1[CH2:7]2)#[N:4]
Reactant: N#CC(O)C1CCC2CC21
Solvent: O=S(Cl)Cl
Solvent: c1ccncc1
Solvent: O
Product: N#CC=C1CCC2CC12
Temperature: 25 °C

Procedure:
0.078 Mole of 2-hydroxy-2-(bicyclo[3.1.0]hex-2-yl)acetonitrile is dissolved in 200 ml. of anhydrous pyridine under nitrogen, and cooled to -50° C. 0.0942 Mole of thionyl chloride is added dropwise and the mixture allowed to warm to room temperature and then recooled to 0° C. Excess thionyl chloride is then decomposed by the addition of 2 ml. of water. The pyridine is removed by evaporation under vacuum and the resulting residue dissolved in 300 ml. of ethyl acetate. The ethyl acetate solution is then washed twice with water, dried over anhydrous magnesium sulfate, and filtered. The filtrate is evaporated to dryness, under vacuum, and the resulting residue is chromatographed with silica gel eluting with 10% ethyl acetate-90%, vol., hexane, affording 2-(cyanomethylene)bicyclo[3.1.0]hexane.
Reaction SMILES: [CH2:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][N:2]1[C:10]([O:12][CH:13]1[CH2:31][CH:30]2[N:15]([C:16](=[O:36])[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH:23]=[CH:24][CH:25]3[C:27]([C:33](O)=[O:34])([NH:28][C:29]2=[O:32])[CH2:26]3)[CH2:14]1)=[O:11].C1N=CN(C(N2C=NC=C2)=O)C=1.[CH:49]1([S:52]([NH2:55])(=[O:54])=[O:53])[CH2:51][CH2:50]1.C1CCN2C(=NCCC2)CC1>C1COCC1>[CH2:3]1[C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[CH2:1][N:2]1[C:10]([O:12][CH:13]1[CH2:31][CH:30]2[N:15]([C:16](=[O:36])[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH:23]=[CH:24][CH:25]3[C:27]([C:33]([NH:55][S:52]([CH:49]4[CH2:51][CH2:50]4)(=[O:54])=[O:53])=[O:34])([NH:28][C:29]2=[O:32])[CH2:26]3)[CH2:14]1)=[O:11]
Reactant: O=C1NC2(C(=O)O)CC2C=CCCCCCCC(=O)N2CC(OC(=O)N3Cc4ccccc4C3)CC12
Reactant: NS(=O)(=O)C1CC1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Solvent: C1CCC2=NCCCN2CC1
Product: O=C1NC2(C(=O)NS(=O)(=O)C3CC3)CC2C=CCCCCCCC(=O)N2CC(OC(=O)N3Cc4ccccc4C3)CC12
Temperature: 25 °C

Procedure:
The mixture of carboxylic acid 18 (30 mg, 0.06 mmole) and CDI (20 mg, 2 eq) in dry THF (3 mL) was stirred at reflux for 2 h30 under nitrogen. Optionally, the azalactone derivative, if desired, can be isolated. Then, the reaction mixture was cooled at room temperature and cyclopropylsulfonamide (15 mg, 2 eq) and DBU (18 mg, 2 eq) were added. The reaction mixture was stirred at 50° C. until completion as indicated by LC-MS. The RM was then concentrated, redissolved in DCM and extracted with HCl 1M then brine, dried and concentrated. Purification by flash chromatography on silica gel afforded the desired product 19. m/z=599 (M+H+).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]3[CH:20]=[CH:19][C:18]([C:21]4[CH:22]=[C:23]([CH:27]=[CH:28][CH:29]=4)[C:24]([OH:26])=O)=[CH:17][C:11]=3[C:12]=2[C:13](=[O:16])[NH:14][CH3:15])=[CH:4][CH:3]=1.CCN=C=NCCCN(C)C.Cl.[CH3:42][NH:43][S:44]([C:47]1[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1)(=[O:46])=[O:45].ClCCCl>CN(C1C=CN=CC=1)C.CN(C=O)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]3[CH:20]=[CH:19][C:18]([C:21]4[CH:29]=[CH:28][CH:27]=[C:23]([C:24](=[O:26])[N:43]([CH3:42])[S:44]([C:47]5[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=5)(=[O:46])=[O:45])[CH:22]=4)=[CH:17][C:11]=3[C:12]=2[C:13]([NH:14][CH3:15])=[O:16])=[CH:4][CH:3]=1
Reactant: CNC(=O)c1c(-c2ccc(F)cc2)oc2ccc(-c3cccc(C(=O)O)c3)cc12
Reactant: CNS(=O)(=O)c1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: CNC(=O)c1c(-c2ccc(F)cc2)oc2ccc(-c3cccc(C(=O)N(C)S(=O)(=O)c4ccccc4)c3)cc12
Yield: 55.3 %

Procedure:
In a 1 dram vial with stir bar were combined 3-(2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-5-yl)benzoic acid (35 mg, 0.090 mmol), DMAP (33 mg, 0.27 mmol), EDC hydrochloride (26 mg, 0.14 mmol), and N-methylbenzenesulfonamide (50 μL, 0.26 mmol). 1,2-Dichloroethane (0.5 mL) and DMF (0.5 mL) were added, the vial was capped, and the reaction was stirred at r.t. overnight. The reaction was filtered, purified by prep HPLC, and concentrated on a speedvac to give 27 mg (55% yield) of the title compound as a white powder. 1H NMR (500 MHz, CDCl3) δ ppm 7.91-8.02 (m, 5H) 7.75-7.82 (m, 2H) 7.65 (t, J=7.48 Hz, 1H) 7.47-7.60 (m, 6H) 7.15-7.24 (m, 2H) 5.91 (d, J=4.27 Hz, 1H) 3.36 (s, 3H) 3.04 (d, J=4.88 Hz, 3H). LC/MS was performed by using Shimadzu-VP instrument with UV detection at 220 nm and Waters Micromass. LC/MS method: solvent A=10% CH3CN/90% H2O/0.1% TFA, Solvent B=90% CH3CN/10% H2O/0.1% TFA, start % B=0, final % B=100, gradient time=2 min, stop time=3 min, flow rate=4 ml/min, column: Sunfire C18 5 μm 4.6×50 mm; HPLC Rt=1.89 min, (ES+) m/z (MH+)=543. Analytical HPLC were performed using a Shimadzu-VP instrument with UV detection at 220 nm and 254 nm. Analytical HPLC method: solvent A=5% CH3OH/95% H2O/10 mM NH4HCO3, solvent B=95% CH3OH/5% H2O/10 mM NH4HCO3, start % B=10, final % B=100, gradient time=15 min, stop time=18 min, flow rate=1 ml/min. Column: Phenomenex Gemini C18, 4.6 mm, 3 μam, Rt=17.42 min, purity=92%; column: Waters Xbridge Phenyl 4.6×150 mm, 3.5 μm, Rt=17.86 min, purity >90%.
Reaction SMILES: Cl.Cl.Cl.[CH2:4]([O:6][CH2:7][C:8]1[N:9]([CH2:28][CH:29]2[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]2)[C:10]2[C:19]3[CH:18]=[CH:17][C:16]([C:20]4[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=4)=[CH:15][C:14]=3[N:13]=[C:12]([NH2:26])[C:11]=2[N:27]=1)[CH3:5].C(N(CC)CC)C.[O:42]1[CH2:46][CH2:45][CH2:44][CH:43]1[C:47](O)=[O:48].Cl.CON(OC)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1>C(Cl)(Cl)Cl>[CH2:4]([O:6][CH2:7][C:8]1[N:9]([CH2:28][CH:29]2[CH2:30][CH2:31][N:32]([C:47]([CH:43]3[CH2:44][CH2:45][CH2:46][O:42]3)=[O:48])[CH2:33][CH2:34]2)[C:10]2[C:19]3[CH:18]=[CH:17][C:16]([C:20]4[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=4)=[CH:15][C:14]=3[N:13]=[C:12]([NH2:26])[C:11]=2[N:27]=1)[CH3:5]
Reactant: CCOCc1nc2c(N)nc3cc(-c4cccnc4)ccc3c2n1CC1CCNCC1
Reactant: O=C(O)C1CCCO1
Agent: CCN=C=NCCCN(OC)OC
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CCOCc1nc2c(N)nc3cc(-c4cccnc4)ccc3c2n1CC1CCN(C(=O)C2CCCO2)CC1
Temperature: 4 °C
Reaction time: 2 h
Yield: 69.5 %

Procedure:
A solution of 2-ethoxymethyl-1-(piperidin-4-ylmethyl)-7-(pyridin-3-yl)-1H-imidazo[4,5-c]quinolin-4-amine trihydrochloride (1.0 g, 1.90 mmol) and triethylamine (1.35 mL, 9.50 mmol) in chloroform (80 mL) was cooled to 4° C. 2-Tetrahydrofuroic acid (0.243 g, 2.09 mmol) and 1-(3-dimethoxyaminopropyl)-3-ethylcarbodiimide hydrochloride (0.401 g, 2.09 mmol) were sequentially added, and the reaction was stirred for two hours. The reaction was incomplete as determined by thin layer chromatography (TLC) analysis. The reaction was cooled to 4° C., and 1-hydroxybenzotriazole (0.283 g, 2.09 mmol) was added. The reaction was allowed to warm to ambient temperature, stirred for 16 hours, and then diluted with chloroform (100 mL). The resulting solution was washed sequentially with water (100 mL), 4% aqueous sodium carbonate (2×100 mL), water (200 mL), and brine (150 mL); dried over sodium sulfate; filtered; and concentrated under reduced pressure. The residue was purified by HPFC followed by recrystallization from ethyl acetate to provide 0.68 g of 2-ethoxymethyl-7-(pyridin-3-yl)-1-{[1-(tetrahydrofuran-2-ylcarbonyl)piperidin-4-yl]methyl}-1H-imidazo[4,5-c]quinolin-4-amine as a white, crystalline solid, mp 191–192° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[NH:11][NH2:12].C(N(C(C)C)C(C)C)C.[C:22](Cl)(=[O:27])[C:23]([CH3:26])([CH3:25])[CH3:24]>O1CCCC1>[Cl:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[NH:11][NH:12][C:22](=[O:27])[C:23]([CH3:26])([CH3:25])[CH3:24]
Reactant: NNc1ccc([N+](=O)[O-])cc1Cl
Reactant: CC(C)(C)C(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)C(=O)NNc1ccc([N+](=O)[O-])cc1Cl
Temperature: 0 °C
Yield: 89.9 %

Procedure:
To a stirred and chilled (0° C.) solution containing 25 g (0.133 mol) of 2-chloro-4-nitrophenylhydrazine and 18.06 g (0.14 mol) of ethyldiisopropylamine in 200 ml of tetrahydrofuran was added dropwise 16.75 g (0.139 mol) of pivaloyl chloride. The reaction mixture was briefly heated to reflux and then concentrated under reduced pressure. The residue was treated with water, filtered and dried to give 32.5 g (90% yield) of the desired product as a yellowish solid; m.p. 123° C.
Reaction SMILES: [OH:1][C:2]([CH3:35])([CH3:34])[CH2:3][C@@:4]1([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[O:9][C:8](=[O:10])[N:7]([C@H:11]([C:13]2[CH:18]=[CH:17][C:16](B3OC(C)(C)C(C)(C)O3)=[CH:15][CH:14]=2)[CH3:12])[CH2:6][CH2:5]1.Cl[C:37]1[N:38]=[N:39][C:40]([CH3:43])=[CH:41][CH:42]=1>>[OH:1][C:2]([CH3:34])([CH3:35])[CH2:3][C@@:4]1([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[O:9][C:8](=[O:10])[N:7]([C@H:11]([C:13]2[CH:14]=[CH:15][C:16]([C:37]3[N:38]=[N:39][C:40]([CH3:43])=[CH:41][CH:42]=3)=[CH:17][CH:18]=2)[CH3:12])[CH2:6][CH2:5]1
Reactant: Cc1ccc(Cl)nn1
Reactant: C[C@@H](c1ccc(B2OC(C)(C)C(C)(C)O2)cc1)N1CC[C@](CC(C)(C)O)(c2ccccc2)OC1=O
Product: Cc1ccc(-c2ccc([C@H](C)N3CC[C@](CC(C)(C)O)(c4ccccc4)OC3=O)cc2)nn1

Procedure:
(S)-6-(2-Hydroxy-2-methyl-propyl)-3-{(S)-1-[4-(6-methyl-pyridazin-3-yl)-phenyl]-ethyl}-6-phenyl-[1,3]oxazinan-2-one was prepared from (S)-6-(2-hydroxy-2-methylpropyl)-6-phenyl-3-[(S)-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethyl]-1,3-oxazinan-2-one and 3-chloro-6-methyl-pyridazine following a procedure analogous to that described in Example 138 Method 2. Yield: 3.09 g (62% of theory). Mass spectrum (ESI+): m/z=446 [M+H]+.
Reaction SMILES: CC1C=CC(S(O[CH2:12][C@H:13]2[CH2:17][CH2:16][C:15]([CH3:19])([CH3:18])[O:14]2)(=O)=O)=CC=1.[N-:20]=[N+:21]=[N-:22].[Na+]>CN(C=O)C.O.C(OCC)(=O)C>[N:20]([CH2:12][C@@H:13]1[O:14][C:15]([CH3:19])([CH3:18])[CH2:16][CH2:17]1)=[N+:21]=[N-:22]
Reactant: Cc1ccc(S(=O)(=O)OC[C@H]2CCC(C)(C)O2)cc1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOC(C)=O
Product: CC1(C)CC[C@H](CN=[N+]=[N-])O1
Temperature: 70 °C

Procedure:
(R)-(5,5-Dimethyltetrahydrofuran-2-yl)methyl 4-methylbenzenesulfonate (step 1) (12.8 g, 45.0 mmol) in DMF (50 ml) was treated with sodium azide (3.80 g, 58.5 mmol) at RT overnight then warmed to 70° C. for 3 hrs. Sodium azide (3.80 g, 58.5 mmol) was added and the mixture was warmed to 100° C. for 3 hrs, allowed to cool to RT. The mixture was diluted with water and ethyl acetate. The ethyl acetate layer was washed with 0.5 M lithium chloride in water and the organic layers were dried MgSO4, filtered and evaporated to dryness to afford the title compound;
Reaction SMILES: C(N(CC)CC)C.[Cl:8][CH2:9][C:10](Cl)=[O:11].[NH2:13][C:14]1[CH:23]=[C:22]2[C:17]([CH:18]=[C:19]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[NH:20][C:21]2=[O:24])=[CH:16][CH:15]=1>Cl>[Cl:8][CH2:9][C:10]([NH:13][C:14]1[CH:23]=[C:22]2[C:17]([CH:18]=[C:19]([C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=3)[NH:20][C:21]2=[O:24])=[CH:16][CH:15]=1)=[O:11]
Reactant: Nc1ccc2cc(-c3ccccc3)[nH]c(=O)c2c1
Reactant: O=C(Cl)CCl
Agent: Cl
Solvent: CCN(CC)CC
Product: O=C(CCl)Nc1ccc2cc(-c3ccccc3)[nH]c(=O)c2c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 86.1 %

Procedure:
0.236 ml (1.69 mmol) of triethylamine and 0.101 ml (1.27 mmol) of chloroacetyl chloride were added in this order to 200 mg (0.85 mmol) of 7-amino-3-phenyl-2H-isoquinolin-1-one obtained in Example 39. The obtained mixture was stirred at a room temperature for 2 hours. Thereafter, 30 ml of 1 N hydrochloric acid was added to the reaction solution, and the mixture was then extracted with methylene chloride (30 ml×2). The extract was dried over anhydrous magnesium sulfate, and the solvent was then distilled away under reduced pressure. The precipitated solid was collected by filtration, and the filtrate was then washed with a suitable amount of ether, so as to obtain 229 mg (86%) of 2-chloro-N-(1-oxo-3-phenyl-1,2-dihydroisoquinolin-7-yl)acetamide in the form of a light brown solid.
Reaction SMILES: [OH:1][N:2]1[C:6](=[O:7])[C:5]2=[CH:8][CH:9]=[CH:10][CH:11]=[C:4]2[C:3]1=[O:12].[CH2:13](Br)[C:14]#[CH:15].C(N(CC)CC)C>CN(C=O)C>[CH2:15]([O:1][N:2]1[C:3](=[O:12])[C:4]2[C:5](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]1=[O:7])[C:14]#[CH:13]
Reactant: C#CCBr
Reactant: O=C1c2ccccc2C(=O)N1O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: C#CCON1C(=O)c2ccccc2C1=O
Temperature: 25 °C
Reaction time: 4 h
Yield: 76.3 %

Procedure:
To a stirred solution of N-hydroxyphthalimide (50.5 g) and propargyl bromide (37.0 g) in DMF (250 ml) at 0° C. was added drop-wise triethylamine (50 ml). The cooling bath was removed and the reaction mixture was stirred at room temperature for 4 hours. The mixture was poured into water containing some ice and the precipitated material was isolated by filtration. The crude product was recrystallised from ethanol and gave 2-prop-2-ynyloxy-isoindole-1,3-dione (47.5 g). Step 2: The above obtained phthalimide intermediate (1 mmol) was mixed with p-tolyl isocyanate (2.8 mmol), triethylamine (0.05 mmol) and 1-nitrobutane (1.44 mmol) in toluene (3 ml). The reaction mixture was stirred at room temperature for 48 hours, filtrated and subjected to column chromatography on silica, affording 2-(3-propyl-isoxazol-5-ylmethoxy)-isoindole-1,3-dione. Step 3: The above cycloaddition product was dissolved in methanol+dichloromethane and hydrazine monohydrate (1 eq.) was added. The reaction mixture was stirred at room temperature for 20 hours and placed at 5° C. for 3 hours. The solid material was removed by filtration and the filtrate was evaporated under reduced pressure and gave the title compound. 13C-NMR (DMSO-d6) δ 169.0, 163.2, 103.0, 67.4, 27.2, 21.0, 13.5.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([F:11])=[CH:7][CH:6]=1)=[O:4].[C:12]1(=[O:22])[NH:16][C:15](=[O:17])[C:14]2=[CH:18][CH:19]=[CH:20][CH:21]=[C:13]12.[K]>CN(C=O)C>[F:11][C:8]1[CH:9]=[CH:10][C:5]([C:3](=[O:4])[CH2:2][N:16]2[C:12](=[O:22])[C:13]3[C:14](=[CH:18][CH:19]=[CH:20][CH:21]=3)[C:15]2=[O:17])=[CH:6][CH:7]=1
Reactant: O=C(CBr)c1ccc(F)cc1
Reactant: O=C1NC(=O)c2ccccc21
Agent: [K]
Solvent: CN(C)C=O
Product: O=C(CN1C(=O)c2ccccc2C1=O)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 91.3 %

Procedure:
A 50 ml round-bottomed flask equipped with a magnetic stirrer and with a septum having a top-mounted argon intake is charged with 4.2 g of 2-bromo-1-(4-fluorophenyl)ethanone in 10 ml of DMF and 3.6 g of potassium phthalimide. The mixture is stirred at RT for 4 h and the precipitate formed is filtered off on a glass frit and washed with 3 times 50 ml of isopropyl ether. This, after drying under RP, gives 5 g of 2-[2-(4-fluorophenyl)-2-oxoethyl]isoindole-1,3-dione (white solid), which is used as it is in the following step. Melting point (Kofler): 140° C.; MS (E/I): m/z=283 (M+); 1H NMR: 5.25 (s, 2 H) 7.44 (t, J=9.0 Hz, 2 H) 7.85-8.00 (m, 4 H) 8.19 (dd, J=9.8, 5.4 Hz, 2 H).
Reaction SMILES: [ClH:1].F[C:3]1[CH:20]=[CH:19][CH:18]=[CH:17][C:4]=1[CH2:5][C:6]1[N:11]=[CH:10][C:9]2[C:12]([CH3:16])([CH3:15])[CH2:13][NH:14][C:8]=2[CH:7]=1.[Cl-].[Cl:22]C1C=CC=CC=1C[Zn+]>>[ClH:22].[Cl:1][C:17]1[CH:18]=[CH:19][CH:20]=[CH:3][C:4]=1[CH2:5][C:6]1[N:11]=[CH:10][C:9]2[C:12]([CH3:16])([CH3:15])[CH2:13][NH:14][C:8]=2[CH:7]=1
Reactant: CC1(C)CNc2cc(Cc3ccccc3F)ncc21
Reactant: Clc1ccccc1C[Zn+]
Agent: Cl
Agent: [Cl-]
Product: CC1(C)CNc2cc(Cc3ccccc3Cl)ncc21

Procedure:
Prepared in an analogous manner to 6-(2-fluoro-benzyl)-3,3-dimethyl-2,3-dihydro-1H-pyrrolo[3,2-c]pyridine hydrochloride (Preparation 119) using 2-chlorobenzylzinc chloride instead of 2-fluorobenzylzinc chloride. MS: [M+H]+=273.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([F:13])=[CH:9][C:10]=2[F:12])[N:5]=[C:4]([C:14]2[CH:15]=[N:16][CH:17]=[C:18](SC)[CH:19]=2)[C:3]=1[CH3:22].O[O:24][S:25]([O-:27])=O.[K+].[CH2:29]1COCC1>O.CCOC(C)=O>[Cl:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([F:13])=[CH:9][C:10]=2[F:12])[N:5]=[C:4]([C:14]2[CH:15]=[N:16][CH:17]=[C:18]([S:25]([CH3:29])(=[O:27])=[O:24])[CH:19]=2)[C:3]=1[CH3:22]
Reactant: O=S([O-])OO
Reactant: C1CCOC1
Reactant: CSc1cncc(-c2nc3cc(F)cc(F)c3c(Cl)c2C)c1
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Product: Cc1c(-c2cncc(S(C)(=O)=O)c2)nc2cc(F)cc(F)c2c1Cl
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a stirring suspension of 4-chloro-5,7-difluoro-3-methyl-2-(5-(methylthio)pyridin-3-yl)quinoline (200 mg, 0.594 mmol) in THF (4.5 mL) and water (1.5 mL) was added oxone (913 mg, 1.485 mmol). The reaction was stirred at rt for 18 h, then poured into 15 mL water and stirred for 10 min. The resulting precipitate was isolated by filtration, then dissolved in EtOAc, dried over MgSO4, and concentrated under reduced pressure to give 4-chloro-5,7-difluoro-3-methyl-2-(5-(methylsulfonyl)pyridin-3-yl)quinoline. Mass Spectrum (ESI) m/e=369.0 (M+1).