Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[C:9]([F:10])=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=O.[CH3:11][C:12]([S@:15]([NH2:17])=[O:16])([CH3:14])[CH3:13]>S([O-])([O-])(=O)=O.[Cu+2].ClCCCl>[F:1][C:2]1[C:9]([F:10])=[CH:8][CH:7]=[CH:6][C:3]=1/[CH:4]=[N:17]/[S@@:15]([C:12]([CH3:14])([CH3:13])[CH3:11])=[O:16]
Reactant: CC(C)(C)[S@](N)=O
Reactant: O=Cc1cccc(F)c1F
Agent: [Cu+2]
Agent: O=S(=O)([O-])[O-]
Solvent: ClCCCl
Product: CC(C)(C)[S@@](=O)/N=C/c1cccc(F)c1F
Temperature: 55 °C
Yield: 92.6 %

Procedure:
To a oven dried round bottom flask with stir bar was added 2,3-difluorobenzaldehyde (0.5 g, 3.52 mmol), (R)-2-methylpropane-2-sulfinamide (0.469 g, 3.87 mmol) and DCE (7.04 mL). To this mixture was then added Copper (II) Sulfate (0.842 g, 5.28 mmol). Reaction mixture heated in a preheated oil bath to 55° C. for 24 hr. The reaction mixture was filtered through a celite pad washing solids with DCE. Combined filtrate was concentrated to afford a viscous yellow oil of (R,E)-N-(2,3-difluorobenzylidene)-2-methylpropane-2-sulfinamide (0.8007 g, 3.26 mmol, 93% yield). MS m/z 246.1 (M+H)+; Rt-0.91 min.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:11][CH2:12][C:13]([C:15]2[S:22][C:21]([CH3:23])=[C:20]3[C:16]=2[CH2:17][C@H:18]2[C:24]([CH3:26])([CH3:25])[C@H:19]23)=[O:14])[CH:5]=[C:6]([O:9][CH3:10])[C:7]=1[OH:8].Br[CH2:28][CH2:29][CH2:30][OH:31]>C(O)(C)C.[OH-].[Na+]>[Cl:1][C:2]1[CH:3]=[C:4]([CH2:11][CH2:12][C:13]([C:15]2[S:22][C:21]([CH3:23])=[C:20]3[C:16]=2[CH2:17][C@H:18]2[C:24]([CH3:26])([CH3:25])[C@H:19]23)=[O:14])[CH:5]=[C:6]([O:9][CH3:10])[C:7]=1[O:8][CH2:28][CH2:29][CH2:30][OH:31]
Reactant: OCCCBr
Reactant: COc1cc(CCC(=O)c2sc(C)c3c2C[C@@H]2[C@H]3C2(C)C)cc(Cl)c1O
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)O
Product: COc1cc(CCC(=O)c2sc(C)c3c2C[C@@H]2[C@H]3C2(C)C)cc(Cl)c1OCCCO
Temperature: 70 °C
Reaction time: 2 h
Yield: 50 %

Procedure:
A solution of 3-(3-chloro-4-hydroxy-5-methoxy-phenyl)-1-((1aS,5aR)-1,1,2-trimethyl-1,1a,5,5a-tetrahydro-3-thia-cyclopropa[a]pentalen-4-yl)-propan-1-one (800 mg, 2.05 mmol, Intermediate 14) in isopropanol (30 mL) and 2 N aq. NaOH (10 mL) is treated with 3-bromopropanol (569 mg, 4.09 mmol). The dark red reaction mixture is stirred at 70° C. After 4.5 and 22 h another portion of 3-bromopropanol (569 mg, 4.09 mmol) is added. Stirring is continued for further 2 h after the last addition. The solvent is removed under reduced pressure and the residue is dissolved in EA and washed twice with water. The organic layer is dried over MgSO4 and evaporated. The crude product is purified by CC on silica gel eluting with heptane:EA 1:1 to give 3-[3-chloro-4-(3-hydroxy-propoxy)-5-methoxy-phenyl]-1-((1aS,5aR)-1,1,2-trimethyl-1,1a,5,5a-tetrahydro-3-thia-cyclopropa[a]pentalen-4-yl)-propan-1-one (460 mg) as a yellow oil; LC-MS: tR=1.10 min, [M+1]+=449.22; 1H NMR (CDCl3): δ 676-674 (m, 1H), 6.64-6.61 (m, 1H), 4.05 (t, J=5.5 Hz, 2H), 3.90-3.85 (m, 2H), 3.77 (s, 3H), 3.01-2.85 (m, 5H), 2.72 (d, J=18.8 Hz, 1H), 2.31 (s, 3H), 1.98-1.90 (m, 2H), 1.85-1.80 (m, 2H), 1.05 (s, 3H), 0.63 (s, 3H).
Reaction SMILES: [F:1][C:2]1[CH:15]=[C:14]([N+:16]([O-:18])=[O:17])[CH:13]=[CH:12][C:3]=1[O:4][C:5]1[N:10]=[CH:9][N:8]=[C:7]([NH2:11])[CH:6]=1.[O:19](C(OC(C)(C)C)=O)[C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=O>CN(C1C=CN=CC=1)C.C1COCC1>[F:1][C:2]1[CH:15]=[C:14]([N+:16]([O-:18])=[O:17])[CH:13]=[CH:12][C:3]=1[O:4][C:5]1[N:10]=[CH:9][N:8]=[C:7]([NH:11][C:20](=[O:19])[O:22][C:23]([CH3:26])([CH3:25])[CH3:24])[CH:6]=1
Reactant: Nc1cc(Oc2ccc([N+](=O)[O-])cc2F)ncn1
Reactant: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Agent: CN(C)c1ccncc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)Nc1cc(Oc2ccc([N+](=O)[O-])cc2F)ncn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 26.2 %

Procedure:
A mixture of 6-(2-fluoro-4-nitrophenoxy)pyrimidin-4-amine (439 mg, 1.2 mmol), BOC2O (261 mg, 1.2 mmol), DMAP (10 mg), and THF (10 mL) was stirred at RT for 1 h then concentrated in vacuo to give the crude product. The product was purified by flash chromatography using 1-2% MeOH in CH2Cl2 as the eluent to give tert-butyl 6-(2-fluoro-4-nitrophenoxy)pyrimidin-4-ylcarbamate as a white solid (110 mg, 26%). 1H NMR (DMSO-d6) δ 10.59 (s, 1H), 8.39 (dd, 1H, J=8.8, 1.1 Hz), 8.32 (dd, 1H, J=10.3, 2.4 Hz), 8.15 (ddd, 1H, J=9.1, 2.5, 1.0 Hz), 7.67 (dd, 1H, J=8.8, 8.8 Hz), 7.45 (s, 1H), 1.44 (s, 9H); MS (ESI−) m/z 349.08 (M−H).
Reaction SMILES: O.[Cl-].COC1N=C(OC)N=C([N+]2(C)CCOCC2)N=1.[C:20]([O:24][C:25]([N:27]1[CH2:32][CH2:31][N:30]([CH2:33][CH3:34])[CH2:29][C@@H:28]1[C:35]([OH:37])=O)=[O:26])([CH3:23])([CH3:22])[CH3:21].[NH:38]1[CH2:43][CH2:42][NH:41][CH2:40][CH2:39]1>ClCCl>[CH2:33]([N:30]1[CH2:31][CH2:32][N:27]([C:25]([O:24][C:20]([CH3:21])([CH3:22])[CH3:23])=[O:26])[C@@H:28]([C:35]([N:38]2[CH2:43][CH2:42][NH:41][CH2:40][CH2:39]2)=[O:37])[CH2:29]1)[CH3:34]
Reactant: CCN1CCN(C(=O)OC(C)(C)C)[C@@H](C(=O)O)C1
Reactant: C1CNCCN1
Agent: COc1nc(OC)nc([N+]2(C)CCOCC2)n1
Agent: [Cl-]
Solvent: ClCCl
Solvent: O
Product: CCN1CCN(C(=O)OC(C)(C)C)[C@@H](C(=O)N2CCNCC2)C1
Reaction time: 18 h
Yield: 50.4 %

Procedure:
4-(4,6-Dimethoxy[1.3.5]triazin-2-yl)-4-methylmorpholinium chloride hydrate (253 mg, Acros chemicals) was added to a solution of (2R)-1-(tert-butoxycarbonyl)-4-ethylpiperazine-2-carboxylic acid (212 mg) in dry dichloromethane (6 ml) followed by addition on N-methyl morpholine (0.28 ml) and stirring under argon for 1 h. piperazine (234 mg) was then added and stirring was continued for 18 h. Dichloromethane (30 ml) was added and extracted with 1M NaOH (2×10 mL). The organic layer was dried (MgSO4), filtered and evaporated. Purification by chromatography (5-50% MeOH:DCM) afforded the title compound (135 mg) as a foam.
Reaction SMILES: [CH2:1]([N:5]1[CH:9]=[C:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[N:7]=[C:6]1[I:16])[CH2:2][CH2:3][CH3:4].[C:17](O)(=[O:19])C.C([O-])(=O)C.[Na+]>C=O.O>[CH2:1]([N:5]1[C:9]([CH2:17][OH:19])=[C:8]([C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)[NH:7][CH:6]1[I:16])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCn1cc(-c2ccccc2)nc1I
Reactant: CC(=O)O
Agent: C=O
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: O
Product: CCCCN1C(CO)=C(c2ccccc2)NC1I

Procedure:
1-Butyl-2-iodo-4-phenyl-1H-imidazole (3.26 g) is dissolved in formaldehyde (16.1 mL). Acetyl alcohol (5.5 mL) and sodium acetate (20 g) are added to the solution and the mixture is refluxed under N2 for 4 hours. The reaction mixture is diluted with H2O, adjusted to pH 9, extracted with ethyl acetate, and dried over Na2SO4. Concentration and purification of the extract via flash chromatography yields (1-butyl-2-iodo-4-phenyl-3H-imidazol-5-yl)-methanol.
Reaction SMILES: [H][H].[CH3:3][O:4][C:5]1[C:10]([O:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[CH3:18])=[CH:9][CH:8]=[CH:7][C:6]=1[CH:19]=[CH:20][C:21]([OH:23])=[O:22].C(O)(=O)C>[Pd].O1CCOCC1>[CH3:3][O:4][C:5]1[C:10]([O:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[CH3:18])=[CH:9][CH:8]=[CH:7][C:6]=1[CH2:19][CH2:20][C:21]([OH:23])=[O:22]
Reactant: [H][H]
Reactant: COc1c(C=CC(=O)O)cccc1Oc1ccccc1C
Agent: [Pd]
Solvent: C1COCCO1
Solvent: CC(=O)O
Product: COc1c(CCC(=O)O)cccc1Oc1ccccc1C
Yield: 90 %

Procedure:
Hydrogen gas was introduced to a mixture of 3-[2-methoxy-3-(o-tolyloxy)phenyl]acrylic acid (17 g), palladium on carbon (5%, 3.4 g) and a small amount of glacial acetic acid in dioxane (200 ml) with stirring. The reaction mixture was filtered, and the filtrate was evaporated. The residue was pulverized with n-hexane to give 3-[2-methoxy-3-(o-tolyloxy)phenyl]propionic acid (15.4 g). mp 71°-75° C.
Reaction SMILES: [CH3:1][C:2]1([CH3:26])[CH2:11][CH2:10][C:9]([CH3:13])([CH3:12])[C:8]2[CH:7]=[C:6]([C:14]3[N:15]=[C:16]([N:19]4[CH2:24][CH2:23][CH2:22][CH:21]([NH2:25])[CH2:20]4)[S:17][CH:18]=3)[CH:5]=[CH:4][C:3]1=2.C([O:30][CH2:31][CH2:32][CH2:33][CH2:34]Br)(=O)C.[OH-].[Na+].Cl>CO>[CH3:1][C:2]1([CH3:26])[CH2:11][CH2:10][C:9]([CH3:12])([CH3:13])[C:8]2[CH:7]=[C:6]([C:14]3[N:15]=[C:16]([N:19]4[CH2:24][CH2:23][CH2:22][CH:21]([NH:25][CH2:34][CH2:33][CH2:32][CH2:31][OH:30])[CH2:20]4)[S:17][CH:18]=3)[CH:5]=[CH:4][C:3]1=2
Reactant: CC(=O)OCCCCBr
Reactant: CC1(C)CCC(C)(C)c2cc(-c3csc(N4CCCC(N)C4)n3)ccc21
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC1(C)CCC(C)(C)c2cc(-c3csc(N4CCCC(NCCCCO)C4)n3)ccc21

Procedure:
The preparation is carried out as described starting from 75 mg (0.20 mmol) of 1-[4(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)thiazol-2-yl]piperidin-3-ylamine and 45 μl (0.31 mmol) of 4-bromobutyl acetate. The protecting group is cleaved off by means of a 1N NaOH solution in methanol. The product is in the form of the hydrochloride.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:28][CH:29]([F:31])[F:30])=[C:6]([C:8]2[C:13]([O:14][CH3:15])=[CH:12][N:11]([CH:16]([CH2:20][C@H:21]3[CH2:26][CH2:25][CH2:24][CH2:23][O:22]3)[C:17]([OH:19])=O)[C:10](=[O:27])[CH:9]=2)[CH:7]=1.[NH2:32][C:33]1[CH:45]=[CH:44][C:36]([C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])=[CH:35][CH:34]=1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:28][CH:29]([F:30])[F:31])=[C:6]([C:8]2[C:13]([O:14][CH3:15])=[CH:12][N:11]([CH:16]([CH2:20][C@H:21]3[CH2:26][CH2:25][CH2:24][CH2:23][O:22]3)[C:17]([NH:32][C:33]3[CH:45]=[CH:44][C:36]([C:37]([O:39][C:40]([CH3:41])([CH3:42])[CH3:43])=[O:38])=[CH:35][CH:34]=3)=[O:19])[C:10](=[O:27])[CH:9]=2)[CH:7]=1
Reactant: CC(C)(C)OC(=O)c1ccc(N)cc1
Reactant: COc1cn(C(C[C@H]2CCCCO2)C(=O)O)c(=O)cc1-c1cc(Cl)ccc1OC(F)F
Product: COc1cn(C(C[C@H]2CCCCO2)C(=O)Nc2ccc(C(=O)OC(C)(C)C)cc2)c(=O)cc1-c1cc(Cl)ccc1OC(F)F

Procedure:
82 mg (purity 85%, 0.15 mmol) of 2-{4-[5-chloro-2-(difluoromethoxy)phenyl]-5-methoxy-2-oxopyridin-1(2H)-yl}-3-[(2R)-tetrahydro-2H-pyran-2-yl]propanoic acid (mixture of enantiomerically pure diastereomers 1 and 2) and 32 mg (0.17 mmol, 1.1 eq.) of tert-butyl 4-aminobenzoate were reacted according to General Method 5A. Yield: 67 mg (70% of theory)
Reaction SMILES: [CH2:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][N:2]1[CH2:11][C:12]([O:14]CC)=O.[NH2:17][NH2:18]>C(O)C>[CH2:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][N:2]1[CH2:11][C:12]([NH:17][NH2:18])=[O:14]
Reactant: CCOC(=O)CN1CCc2ccccc2C1
Reactant: NN
Solvent: CCO
Product: NNC(=O)CN1CCc2ccccc2C1
Yield: 99.9 %

Procedure:
A solution of 90 (2.0 g, 9.12 mmol) and hydrazine (5.1 g, 91 mmol) in ethanol (30 mL) was heated at reflux overnight. The mixture was concentrated under reduced pressure to give 91 (1.87 g ˜100%) which was used without further purification.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[CH:4][C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2.[N+:12]([O-])([O-:14])=[O:13].[K+].C(=O)([O-])[O-].[K+].[K+]>S(=O)(=O)(O)O>[CH3:1][C:2]1[N:3]=[CH:4][C:5]2[C:10]([CH:11]=1)=[C:9]([N+:12]([O-:14])=[O:13])[CH:8]=[CH:7][CH:6]=2
Reactant: Cc1cc2ccccc2cn1
Reactant: O=[N+]([O-])[O-]
Agent: O=C([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [K+]
Product: Cc1cc2c([N+](=O)[O-])cccc2cn1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
A solution of 3-methylisoquinoline (5.4 g, 0.04 mol) in concentrated sulfuric acid (30 ml) was cautiously added to a solution of potassium nitrate (4.25 g, 1.1 eq) in concentrated sulfuric acid (23 ml) whilst maintaining the temperature below 4° C. (ice bath). Stirring was continued for 2 h and then temperature raised to ambient. Reaction was further stirred for 3 h and then poured into ice-water slurry (500 mL. Neutralisation using solid potassium carbonate affored a yellow solid which was filtered and washed with water. This material was dissolved in ethanol (200 mL, filtered and concentrated under reduced pressure to afford the title compound as a yellow solid.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:19]=[CH:18][C:12]2[CH2:13][CH2:14][NH:15][CH2:16][CH2:17][C:11]=2[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:20]1(=O)[CH2:23][CH2:22][CH2:21]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)([O-])[O-].[Na+].[Na+]>C(O)(=O)C.ClCCl>[CH2:1]([O:8][C:9]1[CH:19]=[CH:18][C:12]2[CH2:13][CH2:14][N:15]([CH:20]3[CH2:23][CH2:22][CH2:21]3)[CH2:16][CH2:17][C:11]=2[CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: c1ccc(COc2ccc3c(c2)CCNCC3)cc1
Reactant: O=C1CCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Product: c1ccc(COc2ccc3c(c2)CCN(C2CCC2)CC3)cc1
Reaction time: 0.5 h

Procedure:
7-Benzyloxy-1,2,4,5-tetrahydro-benzo[d]azepine (D2) (25.3 g, 100 mmol) was dissolved in 2.5% acetic acid in dichloromethane (400 ml) at 0° C. and treated dropwise with cyclobutanone (11.2 ml, 150 mmol). The mixture was stirred for 30 minutes and then sodium triacetoxyborohydride (31.8 g, 150 mmol) was added portion wise. The reaction mixture was stirred at room temperature for 4 hours, basified with saturated sodium carbonate solution and extracted with dichloromethane. The combined extracts were washed with water, brine, dried over anhydrous sodium sulfate and concentrated in vacuo. The crude residue was triturated with hexane and filtered to afford the title product (E1). MS (ES+) m/e 308 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[O:9][CH3:10].[C:11](Cl)(=[O:15])[CH:12]([CH3:14])[CH3:13].[Cl-].[Al+3].[Cl-].[Cl-].Cl>C(Cl)Cl>[Cl:8][C:7]1[C:2]([Cl:1])=[C:3]([O:9][CH3:10])[CH:4]=[CH:5][C:6]=1[C:11](=[O:15])[CH:12]([CH3:14])[CH3:13]
Reactant: COc1cccc(Cl)c1Cl
Reactant: CC(C)C(=O)Cl
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: COc1ccc(C(=O)C(C)C)c(Cl)c1Cl
Temperature: 5 °C

Procedure:
A stirred mixture of 2,3-dichloroanisole (I) (100 g., 0.565 mole) and isobutyryl chloride (II) (66 g., 0.62 mole) in methylene chloride (400 ml.) is cooled to 5°C. and treated with aluminum chloride (83 g., 0.62 mole) during a 1 hour period. The reaction mixture is allowed to warm to 25°C. and after 24 hours is poured into ice water (400 ml.) and hydrochloric acid (30 ml.). The organic phase is washed with 5% sodium hydroxide, water, dried over magnesium sulfate and distilled at reduced pressure affording 68 g. of 2',3'-dichloro-4'-methoxyisobutyrophenone (III) which distills at 120°-130°C./0.5 mm.
Reaction SMILES: CCOC(/N=N/C(OCC)=O)=O.[F:13][C:14]1[CH:15]=[CH:16][C:17]([N+:21]([O-:23])=[O:22])=[C:18]([OH:20])[CH:19]=1.[CH:24]1(O)[CH2:29][CH2:28][CH2:27][CH:26]=[CH:25]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C(Cl)Cl>[CH:29]1([O:20][C:18]2[CH:19]=[C:14]([F:13])[CH:15]=[CH:16][C:17]=2[N+:21]([O-:23])=[O:22])[CH2:28][CH2:27][CH2:26][CH:25]=[CH:24]1
Reactant: O=[N+]([O-])c1ccc(F)cc1O
Reactant: OC1C=CCCC1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: O=[N+]([O-])c1ccc(F)cc1OC1C=CCCC1
Temperature: 25 °C

Procedure:
1.89 ml DEAD were added to an ice-cooled solution of the 1.57 g 5-Fluoro-2-nitrophenol, 1.18 ml 2-cyclohexenol and 3.15 g triphenylphosphin in methylene chloride. The reaction mixture was stirred and allowed to warm to rt overnight. The solvent was removed in vacuo. Purification is achieved by silica gel column chromatography with iso-hexane/EtOAc (gradient: 100% i-hexane→10:1 i-hexane/EtOAc).
Reaction SMILES: Cl.[N:2]1([CH:7]2[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]2)[CH:6]=[CH:5][N:4]=[N:3]1.C1CCN2C(=NCCC2)CC1.[NH2:24][C:25]1[C:34]([F:35])=[C:33](F)[C:32]([F:37])=[C:31]2[C:26]=1[C:27](=[O:44])[C:28]([C:41]([OH:43])=[O:42])=[CH:29][N:30]2[CH:38]1[CH2:40][CH2:39]1>C(#N)C>[NH2:24][C:25]1[C:34]([F:35])=[C:33]([N:10]2[CH2:11][CH2:12][CH:7]([N:2]3[CH:6]=[CH:5][N:4]=[N:3]3)[CH2:8][CH2:9]2)[C:32]([F:37])=[C:31]2[C:26]=1[C:27](=[O:44])[C:28]([C:41]([OH:43])=[O:42])=[CH:29][N:30]2[CH:38]1[CH2:40][CH2:39]1
Reactant: Nc1c(F)c(F)c(F)c2c1c(=O)c(C(=O)O)cn2C1CC1
Reactant: c1cn(C2CCNCC2)nn1
Agent: Cl
Solvent: CC#N
Solvent: C1CCC2=NCCCN2CC1
Product: Nc1c(F)c(N2CCC(n3ccnn3)CC2)c(F)c2c1c(=O)c(C(=O)O)cn2C1CC1
Yield: 44.4 %

Procedure:
4-(1,2,3-triazol-1-yl)piperidine hydrochloride (126 mg, 0.66 mmol) and DBU (130 mg, 0.85 mmol) were added to a suspension of 5-amino-1-cyclopropyl-6,7,8-trifluoro -1,4-dihydro-4-oxoquinoline-3-carboxylic acid (100 mg, 0.34 mmol) in acetonitrile (10 ml). The reaction mixture was refluxed for 24 hrs and then concentrated to dryness. The residue was diluted with water and thus separated solid was filtered, washed with water, acetonitrile and dried to give 65 mg of the desired product. m.p. 274°-276° C.; 1H NMR (TFA) δ: 9.38 (s, 1H), 8.64 (s, 1H), 8.52 (s, 1H), 5.25 (m, 1H), 4.60 (m, 1H), 4.15 (m, 2H), 3.80 (m, 2H), 2.65 (m, 4H), 1.34-1.70 (m, 4H).
Reaction SMILES: [CH3:1][O:2][C:3]([C@H:5]1[CH2:9][CH2:8][C@@H:7]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([F:16])[CH:11]=2)[NH:6]1)=[O:4].CCN(CC)CC.[Cl:24][C:25]1[CH:30]=[CH:29][C:28]([S:31](Cl)(=[O:33])=[O:32])=[CH:27][CH:26]=1>ClCCCl>[CH3:1][O:2][C:3]([C@H:5]1[CH2:9][CH2:8][C@@H:7]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([F:16])[CH:11]=2)[N:6]1[S:31]([C:28]1[CH:29]=[CH:30][C:25]([Cl:24])=[CH:26][CH:27]=1)(=[O:33])=[O:32])=[O:4]
Reactant: COC(=O)[C@H]1CC[C@@H](c2cccc(F)c2)N1
Reactant: O=S(=O)(Cl)c1ccc(Cl)cc1
Solvent: CCN(CC)CC
Solvent: ClCCCl
Product: COC(=O)[C@H]1CC[C@@H](c2cccc(F)c2)N1S(=O)(=O)c1ccc(Cl)cc1
Temperature: 100 °C
Yield: 75.4 %

Procedure:
(2R,5S)-5-(3-fluoro-phenyl)-pyrrolidine-2-carboxylic acid methyl ester (0.33 g, 1.5 mmol) was dissolved in 1,2-dichloroethane (2 mL) and Et3N (1.0 mL, 7.4 mmol, 5 eq) was added followed by 4-chlorobenzenesulfonyl chloride (0.78 g, 3.7 mmol, 2.5 eq). The mixture was heated at 100° C. for 16 hr. Solvent was removed under vacuum and the residue was dissolved in EtOAc (10 mL), washed with 10% NaHCO3 and brine, dried (Na2SO4) and concentrated under vacuum. Chromatography on silica gel (5–10% EtOAc/hexanes) yielded 0.45 g (75%) of pure (2R,5S)-1-(4-chloro-benzenesulfonyl)-5-(3-fluoro-phenyl)-pyrrolidine-2-carboxylic acid methyl ester as yellowish solid. 1H NMR (CDCl3, 300 MHz) δ 7.67 (2H, d), 7.42 (2H, d), 7.24 (3H, m), 6.98 (1H, m), 4.95 (1H, t), 4.82 (1H, q), 3.94 (3H, s), 2.45–2.25 (3H, m), 2.05 (1H, m).
Reaction SMILES: Cl[C:2]1[C:11]2[CH:10]=[C:9]3[N:12]=[CH:13][N:14]([CH2:15][CH2:16][N:17]4[CH2:22][CH2:21][O:20][CH2:19][CH2:18]4)[C:8]3=[CH:7][C:6]=2[N:5]=[CH:4][C:3]=1[C:23]#[N:24].[O:25]([C:32]1[CH:38]=[CH:37][C:35]([NH2:36])=[CH:34][CH:33]=1)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.Cl.N1C=CC=CC=1>C(OCCO)C>[N:17]1([CH2:16][CH2:15][N:14]2[C:8]3[C:9](=[CH:10][C:11]4[C:2]([NH:36][C:35]5[CH:34]=[CH:33][C:32]([O:25][C:26]6[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=6)=[CH:38][CH:37]=5)=[C:3]([C:23]#[N:24])[CH:4]=[N:5][C:6]=4[CH:7]=3)[N:12]=[CH:13]2)[CH2:22][CH2:21][O:20][CH2:19][CH2:18]1
Reactant: Nc1ccc(Oc2ccccc2)cc1
Reactant: N#Cc1cnc2cc3c(cc2c1Cl)ncn3CCN1CCOCC1
Agent: Cl
Solvent: c1ccncc1
Solvent: CCOCCO
Product: N#Cc1cnc2cc3c(cc2c1Nc1ccc(Oc2ccccc2)cc1)ncn3CCN1CCOCC1
Yield: 69 %

Procedure:
Following the procedure of Example 7, a mixture of 82.2 mg (0.24 mmol) of 8-chloro-3-[2-(4-morpholinyl)ethyl]-3H-imidazo[4,5-g]quinoline-7-carbonitrile, 53.3 mg (0.29 mmol) of 4-phenoxyaniline and 33.5 mg (0.29 mmol) of pyridine hydrochloride in 3.5 mL of 2-ethoxyethanol is heated at 130–135° C. for 1 hour to yield 81.2 mg (69%) of the product as a yellow solid, mp>260° C.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=[O:6].[CH2:10](I)[CH2:11][CH3:12].C(=O)([O-])[O-].[K+].[K+]>CC(=O)CC>[CH2:10]([O:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=[O:6])[CH2:11][CH3:12]
Reactant: CCCI
Reactant: O=Cc1cccc(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: CCCOc1cccc(C=O)c1
Temperature: 25 °C
Reaction time: 17 h

Procedure:
Combine 3-hydroxybenzaldehyde (7.50 gm; 61.4 mmol), n-propyl iodide (17.3. gm; 102 mmol), and potassium carbonate (16.90 gm; 122 mmol) in 2-butanone (100 mL) and reflux. After 17 h, allow the mixture to cool to room temperature, decant the solution and concentrate by rotary evaporation. Partition the residue between diethyl ether (150 mL) and water (150 mL), separate the layers and extract the aqueous layer with diethyl ether (2×100 mL). Combine organic layers and wash with water, 1 N NaOH, and then water, dry over MgSO4, and concentrate to give a residue. Distill the residue to give the title compound: bp: 122–125° C. (15 mm); TLC (10% Et2O/hexanes; Rf 0.35).
Reaction SMILES: [OH:1][C:2]1[N:6]([C:7]2[CH:12]=[C:11]([C:13]#[N:14])[CH:10]=[CH:9][N:8]=2)[N:5]=[CH:4][CH:3]=1.[CH2:15]([C:17]1[CH:22]=[CH:21][C:20]([CH2:23]O)=[C:19]([F:25])[CH:18]=1)[CH3:16]>>[CH2:15]([C:17]1[CH:22]=[CH:21][C:20]([CH2:23][O:1][C:2]2[N:6]([C:7]3[CH:12]=[C:11]([C:13]#[N:14])[CH:10]=[CH:9][N:8]=3)[N:5]=[CH:4][CH:3]=2)=[C:19]([F:25])[CH:18]=1)[CH3:16]
Reactant: CCc1ccc(CO)c(F)c1
Reactant: N#Cc1ccnc(-n2nccc2O)c1
Product: CCc1ccc(COc2ccnn2-c2cc(C#N)ccn2)c(F)c1

Procedure:
The title compound was prepared from 2-(5-hydroxy-1H-pyrazol-1-yl)pyridine-4-carbonitrile and (4-ethyl-2-fluorophenyl)methanol according to the procedure for the preparation of Example 39, part C. 1H NMR (400 MHz, CDCl3): δ 1.23 (3H, t, J=7.6 Hz), 2.66 (2H, q, J=7.6 Hz), 5.26 (2H, s), 5.81 (1H, d, J=2.0 Hz), 6.95 (1H, d, J=11.2 Hz), 7.00 (1H, d, J=7.6 Hz), 7.35 (1H, d, J=8.0 Hz), 7.38 (1H, dd, J=1.6 Hz, 5.2 Hz), 7.57 (1H, d, J=1.6 Hz), 8.00-8.01 (1H, m), 8.69 (1H, d, J=0.8 Hz, 5.2 Hz). [M+H] Calc'd for C18H15FN4O, 323. Found, 323.
Reaction SMILES: ClCCl.[NH2:4][C:5]1[CH:13]=[C:12]([F:14])[CH:11]=[CH:10][C:6]=1[C:7]([OH:9])=[O:8].C(=O)([O-])O.[Na+].[I:20](Cl)(=O)=O.I(Cl)(=O)=O.C([N+](C)(C)C)C1C=CC=CC=1>CO>[NH2:4][C:5]1[CH:13]=[C:12]([F:14])[C:11]([I:20])=[CH:10][C:6]=1[C:7]([OH:9])=[O:8]
Reactant: O=I(=O)Cl
Reactant: Nc1cc(F)ccc1C(=O)O
Agent: C[N+](C)(C)Cc1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Product: Nc1cc(F)c(I)cc1C(=O)O
Reaction time: 48 h
Yield: 77 %

Procedure:
To a vigorously stirred solution of dichloromethane (700 ml), methanol (320 ml), and 2-amino-4fluoro-benzoic acid (33.35 grams, 215 mmoles) was added solid sodium hydrogencarbonate (110 grams, 1.31 moles) followed by portion addition of benzyltrimethyl ammonium dichloroiodate (82.5 grams, 237 mmoles). The mixture was allowed to stir for 48 hours. The mixture was filtered to remove the insolubles. The remaining solid residue was washed with 200 ml of dichloromethane. The filtrate was concentrated and redissolved in a one to one mixture of ethyl acetate (1 litre) and a 0.2 N solution of sodium hydroxide (1 litre), added to a 2 litre separatory funnel and extracted. The organic layer was washed with an additional 200 ml of water. The aqueous layers were combined and acidified with 2N hydrochloric acid. The resulting precipitate was collected by suction filtration, washed with water and dried under vacuum at 60° C. to yield 46.5 grams (77%) of the title compound. 1H NMR (400 MHz, DMSO-6) δ: 8.04(d, 1H), 7.1(s, broad, 2H), 6.63(d, 1H). ESI-MS m/z 280 (M−1).
Reaction SMILES: [CH3:1][N:2]([S:15]([C:18]1[S:19][CH:20]=[CH:21][CH:22]=1)(=[O:17])=[O:16])[C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:11]=1[NH:10][C:9]([C:12](=[S:14])[NH2:13])=[CH:8]2.Br[CH:24]([CH:31]=O)[CH2:25][C:26]([O:28][CH2:29][CH3:30])=[O:27].CN(C)C(=O)C>O>[CH3:1][N:2]([S:15]([C:18]1[S:19][CH:20]=[CH:21][CH:22]=1)(=[O:17])=[O:16])[C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:11]=1[NH:10][C:9]([C:12]1[S:14][C:24]([CH2:25][C:26]([O:28][CH2:29][CH3:30])=[O:27])=[CH:31][N:13]=1)=[CH:8]2
Reactant: CN(c1cccc2cc(C(N)=S)[nH]c12)S(=O)(=O)c1cccs1
Reactant: CCOC(=O)CC(Br)C=O
Solvent: O
Solvent: CC(=O)N(C)C
Product: CCOC(=O)Cc1cnc(-c2cc3cccc(N(C)S(=O)(=O)c4cccs4)c3[nH]2)s1
Temperature: 90 °C
Reaction time: 2 h
Yield: 53.3 %

Procedure:
A mixture of 7-[methyl(2-thienylsulfonyl)amino]-1H-indole-2-carbothioamide (0.40 g), ethyl 3-bromo-4-oxobutyrate (0.48 g) and N,N-dimethylacetamide (25 mL) was stirred at 90° C. for 2 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried (MgSO4) and concentrated. The obtained residue was subjected to silica gel column chromatography and the title compound (0.28 g, yield 55%) was obtained as pale-yellow crystals from a fraction eluted with ethyl acetate-hexane (2:3, volume ratio). melting point 126-127° C.