Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH:7]=[CH:8][C:9]([S:13]([OH:16])(=O)=[O:14])=[CH:10]2)=[CH:5][CH:4]=1.[Na].P(Cl)(Cl)(Cl)(Cl)[Cl:19]>P(Cl)(Cl)(Cl)=O.O>[CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH:7]=[CH:8][C:9]([S:13]([Cl:19])(=[O:16])=[O:14])=[CH:10]2)=[CH:5][CH:4]=1
Reactant: ClP(Cl)(Cl)(Cl)Cl
Reactant: COc1ccc2ccc(S(=O)(=O)O)cc2c1
Agent: [Na]
Solvent: O=P(Cl)(Cl)Cl
Solvent: O
Product: COc1ccc2ccc(S(=O)(=O)Cl)cc2c1
Temperature: 60 °C

Procedure:
To a suspension of 7-hydroxynaphthalene-2-sulfonic acid, sodium salt (15 g, 60.9 mmol) in H2O/ethanol (150 mL, 2:1) is added solid NaOH (2.68 g, 67 mmol) at room temperature. The mixture is stirred until a homogenous solution forms and dimethyl sulfate (6.34 mL, 67 mmol) is then added. A precipitate slowly forms and the mixture is stirred over a period of 16 hours. The crude mixture is concentrated in vacuo and the residue is stirred in absolute EtOH (100 mL) as a slurry for 2 hours. The precipitate is filtered and dried. The solid is heated at reflux in 95% EtOH (100 mL) for 2 h, allowed to cool to room temperature, filtered and dried to give 12.6 g of crude 7-methoxynaphthalene-2-sulfonic acid, sodium salt. A mixture of the sulfonic acid, sodium salt (12.6 g, 48.6 mmol) in phosphorous oxychloride (20 mL) and phosphorous pentachloride (13.2 g, 63.2 mmol) is heated slowly to 60° C. until a homogenous solution forms and then is heated at 120° C. for 4 hours. The resulting mixture is cooled in an ice bath and a mixture of ice/ice water is added slowly with stirring. The mixture is diluted with water and extracted with CHCl3 (2×100 mL). The combined organic layers are washed successively with water, saturated NaHCO3 solution and saturated NaCl. The organic phase is dried over anhydrous MgSO4, filtered and concentrated to give 10 g of a crude oil. The crude product is purified by column chromatography in a gradient of 5% EtOAc/hexanes to 30% EtOAc/hexanes to afford the title compound (3.8 g, 14.8 mmol) as a white crystalline solid.
Reaction SMILES: [CH2:1](Br)[C:2]#[CH:3].[NH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1>C(O)C>[CH2:1]([NH:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[C:2]#[CH:3]
Reactant: C#CCBr
Reactant: Nc1ccccc1
Solvent: CCO
Product: C#CCNc1ccccc1

Procedure:
A solution of propargyl bromide (0.11 mL, 1 mmol) and aniline (0.46 mL, 5 mmol) in ethanol (2 mL) was stirred at room temperature for about 5 days. The solvent was concentrated under vacuum and the residue was purified by flash chromatography on silica gel using hexane/ethyl acetate (20:1) as eluent to provide Example 640. MS (ESI): m/z 132 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][C:5](N)=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].Cl.N([O-])=O.[Na+].O.O.O.[C:20]([O-])(=O)[CH3:21].[Na+]>O.C1C=CC=CC=1>[Cl:1][C:2]1[CH:8]=[CH:7][C:5]([C:21]2[CH:20]=[CH:4][CH:3]=[CH:2][CH:8]=2)=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10]
Reactant: Nc1ccc(Cl)c([N+](=O)[O-])c1
Reactant: CC(=O)[O-]
Agent: Cl
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Solvent: c1ccccc1
Product: O=[N+]([O-])c1cc(-c2ccccc2)ccc1Cl
Temperature: 0 °C
Reaction time: 3 h
Yield: 56 %

Procedure:
A mixture of 100 g (0.55 mole) of 97% purity 4-chloro-3-nitroaniline, 200 ml of concentrated hydrochloric acid and 130 ml of water was heated to reflux and then cooled to 0° C. To the resulting slurry was added dropwise a solution of 49 g (0.71 mole)of sodium nitrite in 70 ml of water over a 45 min period while maintaining the temperature at 0°-5° C. To this cold solution was added 1.3 liters of benzene (cooled to 5° C. and the mixture was stirred vigorously while a solution of 190 g sodium acetate trihydrate in 400 ml of water was added over a period of 1 hr. Vigorous stirring was continued first for 3 hr at 5° C. and then for 40 hr at ambient temperature. The organic layer was separated, washed with dilute sodium hydroxide and concentrated under reduced pressure. The residue was purified by chromatography on silica gel, eluting with 30% benzene in ligroin. Recrystallization of the isolated solid from cyclohexane-ligroin gave 71.3 g (56%) of the title product as pale yellow crystals, m.p. 43°-44° C.
Reaction SMILES: [CH3:1][C@H:2]([OH:5])[CH2:3][CH3:4].CCN(CC)CC.[CH3:13][S:14](Cl)(=[O:16])=[O:15]>C(Cl)Cl>[CH3:13][S:14]([O:5][C@@H:2]([CH3:1])[CH2:3][CH3:4])(=[O:16])=[O:15]
Reactant: CS(=O)(=O)Cl
Reactant: CC[C@H](C)O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC[C@H](C)OS(C)(=O)=O
Temperature: 0 °C

Procedure:
An ice cold solution of (S)-2-butanol (888 mg) in DCM (15 ml) was treated with Et3N (1.26 ml) and followed by dropwise addition of methanesulfonyl chloride (0.52 ml). After 1 h the solution was washed with saturated sodium hydrogen carbonate solution (5 ml), water (2×5 ml), brine (5 ml), dried (MgSO4) and evaporated to give the title compound (D32)(1.01 g). 1H NMR δ (CDCl3): 4.74 (1H, m), 3.00 (3H, s), 1.67 (2H, m), 1.41 (1H, d, J=6.5 Hz), 0.99 (3H, t, J=7.5 Hz).
Reaction SMILES: C1(C)C(S(O[CH2:11][CH2:12][CH2:13][CH2:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]#[N:22])=[CH:17][CH:16]=2)(=O)=O)=CC=CC=1.Cl.[CH:25]12[O:33][CH:29]([CH2:30][NH:31][CH2:32]1)[CH2:28][N:27]([C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[CH2:26]2.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[C:21]([C:18]1[CH:17]=[CH:16][C:15]([CH2:14][CH2:13][CH2:12][CH2:11][N:31]2[CH2:32][CH:25]3[O:33][CH:29]([CH2:28][N:27]([C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[CH2:26]3)[CH2:30]2)=[CH:20][CH:19]=1)#[N:22]
Reactant: Cc1ccccc1S(=O)(=O)OCCCCc1ccc(C#N)cc1
Reactant: CC(C)(C)OC(=O)N1CC2CNCC(C1)O2
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CC2CN(CCCCc3ccc(C#N)cc3)CC(C1)O2
Temperature: 85 °C
Reaction time: 22 h

Procedure:
A 2 L three-necked flask was equipped with a magnetic stirrer, a thermometer and a reflux condenser. The flask was charged with a solution of 4-(4-cyanophenyl)butyl toluenesulphonate (72 g, 0.218 mol, see step (iii) above) in dimethylformamide (0.55 L). tert-Butyl 9-oxa-3,7-diazabicyclo[3.3.1]nonane-3-carboxylate hydrochloride (48.2, 0.182 mol, see Preparation B(I)(iv) above) was added, followed by potassium carbonate (62.9 g, 0.455 mol). The heterogeneous mixture was stirred for 22 hours at 85° C. TLC analysis indicated complete consumption of starting material. The reaction mixture was cooled to room temperature and diluted with water (0.5 L). The mixture was extracted with ethyl acetate (3×0.4 L) and the organic fractions were combined. After washing with Water (2×200 mL) and brine (200 mL), the organic layer was dried with magnesium sulfate, filtered and concentrated under vacuum. The crude brown oil was purified by chromatography on silica gel, eluting with 3:2 hexanes/ethyl acetate affording 34 g (48% yield) of sub-title compound as an off-white solid.
Reaction SMILES: [CH2:1]([NH:5][C@H:6]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[CH:7]=[CH2:8])[CH:2]([CH3:4])[CH3:3].C(NC(C)C)(C)C.[C:22](Cl)(=[O:29])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>C(Cl)Cl>[CH2:1]([N:5]([C@H:6]([C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1)[CH:7]=[CH2:8])[C:22](=[O:29])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[CH:2]([CH3:3])[CH3:4]
Reactant: C=C[C@H](NCC(C)C)c1ccccc1
Reactant: O=C(Cl)c1ccccc1
Solvent: ClCCl
Solvent: CC(C)NC(C)C
Product: C=C[C@@H](c1ccccc1)N(CC(C)C)C(=O)c1ccccc1
Reaction time: 1 h
Yield: 38.7 %

Procedure:
To a solution of (1S)-N-isobutyl-1-phenylprop-2-en-1-amine (9a) (25 mg) and diisopropylamine (19 mg) in DCM (2.5 ml) at RT under N2 was added benzoyl chloride (21 mg). This mixture was stirred for 1 h. The reaction was evaporated and purified by flash chromatography (2% EtOAc/hexane) to afford the title compound (15 mg, 44%) as a pale oil. 1H NMR (300 MHz, CDCl3) δ 0.70 (d, 6H, J=6.6 Hz), 0.81 (bs, 3H), 1.75 (bs, 1H), 2.99-3.06 (m, 1H), 3.25-3.32 (m, 1H), 5.20-5.28 (m, 1H), 5.41 (d, 1H, J=9 Hz), 6.16 (bs, 1H), 7.25-7.46 (m, 5H). MS APCI, m/z=294 (M+1), LC/MS, 2.78 min. Chiral SFC was used to determine ee % by comparing this sample to a known sample of the racemic compound N-isobutyl-N-[(1-phenylprop-2-en-1-yl]benzamide 2.128 min (2.92%) and 2.639 min (97.07%) or 94% ee. Chiral SFC method: 5 μm Chiralpak AS-H column 4.6 mm×250 mm. Isocratic method 10% MeOH in carbon dioxide @ 2.20 ml/mn over 4 minutes.
Reaction SMILES: [O:1]=[C:2]1[CH2:7][CH2:6][CH:5]([CH2:8][NH:9][C:10](=[O:16])[O:11][C:12]([CH3:15])([CH3:14])[CH3:13])[CH2:4][CH2:3]1.[CH3:17][Mg]Br>O1CCCC1>[OH:1][C:2]1([CH3:17])[CH2:3][CH2:4][CH:5]([CH2:8][NH:9][C:10](=[O:16])[O:11][C:12]([CH3:13])([CH3:15])[CH3:14])[CH2:6][CH2:7]1
Reactant: CC(C)(C)OC(=O)NCC1CCC(=O)CC1
Reactant: C[Mg]Br
Solvent: C1CCOC1
Product: CC1(O)CCC(CNC(=O)OC(C)(C)C)CC1
Temperature: -78 °C
Reaction time: 2 h

Procedure:
A solution of tert-butyl (4-oxocyclohexyl)methylcarbamate (1.00 g) was dissolved in tetrahydrofuran (20 mL) and cooled to −78° C. Methylmagnesium bromide (4.40 mL) was added dropwise. The reaction was stirred for 2 hours at −78° C. then allowed to warm to 0° C. and stirred for 30 minutes. The resulting suspension was quenched with water (10 mL), diluted with ether (50 mL) and washed with ammonium chloride (25 mL) and brine (25 mL), dried over magnesium sulfate, filtered, and concentrated. Silica gel chromatography (Reveleris 80 g) eluting using a gradient of 5% to 50% ethyl acetate/dichloromethane over 30 minutes (flow=60 ml/min) gave the title compound as a ˜2:1 mixture of cis and trans isomers.
Reaction SMILES: [OH:1][C@H:2]1[CH2:6][CH2:5][NH:4][C:3]1=[O:7].[C:8](OC(=O)C)(=[O:10])[CH3:9]>N1C=CC=CC=1>[C:8]([O:1][C@H:2]1[CH2:6][CH2:5][NH:4][C:3]1=[O:7])(=[O:10])[CH3:9]
Reactant: O=C1NCC[C@@H]1O
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: CC(=O)O[C@H]1CCNC1=O
Reaction time: 4 h
Yield: 86.3 %

Procedure:
To a solution of 1.439 g of (S)-(-)-3-hydroxy-2-pyrrolidinone [P. W. K. Woo, Tetrahedron Letters, 2617 (1971); mp. 103.5°-104.5° C., [α]D26 =-118.8°±2.3° (c=0.688, CHCl3)] in 14 ml of pyridine is added 2.8 ml of acetic anhydride, and the mixture is allowed to stand at room temperature for 4 hours and concentrated under reduced pressure at a temperature below 40° C. The residue is crystallized from ether and recrystallized from methylene chloride-n-hexane to give 1.735 g of (S)-(-)-3-acetoxy-2-pyrrolidinone in 86.3% yield.
Reaction SMILES: [F:1][CH:2]([F:20])[O:3][C:4]1[CH:19]=[CH:18][C:7]([O:8][C:9]2[CH:14]=[CH:13][C:12]([C:15](=O)[CH3:16])=[CH:11][CH:10]=2)=[CH:6][CH:5]=1.[NH2:21][OH:22]>C(O)C>[F:1][CH:2]([F:20])[O:3][C:4]1[CH:19]=[CH:18][C:7]([O:8][C:9]2[CH:14]=[CH:13][C:12]([C:15](=[N:21][OH:22])[CH3:16])=[CH:11][CH:10]=2)=[CH:6][CH:5]=1
Reactant: CC(=O)c1ccc(Oc2ccc(OC(F)F)cc2)cc1
Reactant: NO
Solvent: CCO
Product: CC(=NO)c1ccc(Oc2ccc(OC(F)F)cc2)cc1

Procedure:
A mixture of 1.37 g (4.92 mmol) of 1-[4-(4-difluoromethoxy-phenoxy)-phenyl]-ethanone and 1.16 mL hydroxylamine solution (50% in water) in 5 mL ethanol was refluxed for 3 hours. Then the mixture was concentrated and evaporated down several times with ethanol, and the residue was purified by chromatography (silica gel column, petroleum ether/ethyl acetate).
Reaction SMILES: [CH:1]1([N:7]([C:32]2[S:33][CH:34]=[CH:35][N:36]=2)[C:8](=[O:31])[CH2:9][C:10]2[C:18]3[C:13](=[CH:14][CH:15]=[C:16]([O:19]C)[CH:17]=3)[N:12]([C:21](=[O:29])[C:22]3[CH:27]=[CH:26][C:25](Cl)=[CH:24][CH:23]=3)[C:11]=2[CH3:30])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.B(Br)(Br)Br.[Cl:41]CCl>>[CH:1]1([N:7]([C:32]2[S:33][CH:34]=[CH:35][N:36]=2)[C:8](=[O:31])[CH2:9][C:10]2[C:18]3[C:13](=[CH:14][CH:15]=[C:16]([OH:19])[CH:17]=3)[N:12]([C:21](=[O:29])[C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[Cl:41])[C:11]=2[CH3:30])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: COc1ccc2c(c1)c(CC(=O)N(c1nccs1)C1CCCCC1)c(C)n2C(=O)c1ccc(Cl)cc1
Reactant: ClCCl
Agent: BrB(Br)Br
Product: Cc1c(CC(=O)N(c2nccs2)C2CCCCC2)c2cc(O)ccc2n1C(=O)c1ccccc1Cl
Temperature: 25 °C
Reaction time: 20 h

Procedure:
To a solution of 2 g (3.83 mmol) of N-Cyclohexyl-N-thiazol-2-yl-1-(4-chlorobenzoyl)-5-methoxy-2-methylindole-3-acetamide in 20 mL of anhydrous dichloromethane under nitrogen at −78° C. was added dropwise 1.1 mL (11.5 mmol) of boron tribromide over 15 minutes. The reaction was allowed to warm to room temperature and stirred for 20 hr before quenching with water (5 mL). The layers were separated and the organic layer dried (Na2SO4), filtered and evaporated. The residue was chromatographed on silica to give the title compound. 1H NMR (DMSO) δ 9.24 (1H, s), 7.79 (2H, bs), 7.70 (4H, m), 6.87 (1H, d), 6.81 (1H, d), 6.59 (1H, dd), 4.43 (1H, bs), 3.40 2.08 (1H, m), 1.77 (4H, m), 1.61 (1H, m), 1.32 (4H, m). 5H concealed by DMSO and water signals.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:8]([OH:18])[CH2:9][CH2:10][NH:11][C:12](=[O:17])[C:13]([F:16])([F:15])[F:14])[CH:5]=[CH:6][CH:7]=1.[C:19]([CH:21]1[CH2:26][CH2:25][CH2:24][CH2:23][CH:22]1[OH:27])#[CH:20]>>[F:14][C:13]([F:16])([F:15])[C:12]([NH:11][CH2:10][CH2:9][CH:8]([OH:18])[C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([C:20]#[C:19][CH:21]2[CH2:26][CH2:25][CH2:24][CH2:23][CH:22]2[OH:27])[CH:3]=1)=[O:17]
Reactant: C#CC1CCCCC1O
Reactant: O=C(NCCC(O)c1cccc(Br)c1)C(F)(F)F
Product: O=C(NCCC(O)c1cccc(C#CC2CCCCC2O)c1)C(F)(F)F

Procedure:
Sonogashira coupling of bromide 25 with 2-ethynylcyclohexanol followed by flash chromatography (5-50% EtOAc/hexanes gradient), gave 2,2,2-trifluoro-N-(3-hydroxy-3-(3-((2-hydroxycyclohexyl)ethynyl)phenyl)propyl)acetamide as a yellow oil. Yield (1.9 g, 63%): 1H NMR (400 MHz, CDCl3) δ 7.39-7.41 (m, 1H), 7.23-7.36 (m, 4H), 4.84 (q, J=4.0 Hz, 1H), 3.62-3.72 (m, 1H), 3.50-3.57 (m, 1H), 3.34-3.44 (m, 1H), 2.38-2.46 (m 1H), 2.18 (brs, 2H), 1.90-2.10 (m, 4H), 1.66-1.84 (m, 2H), 1.40-1.53 (m, 1H), 1.16-1.40 (m, 3H).
Reaction SMILES: [F:1][C:2]1[C:10]([F:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4](Cl)=[O:5].[C:12]1([CH:18]([NH:21][C:22]([C:24]2[CH:25]=[C:26]3[C:30](=[CH:31][CH:32]=2)[NH:29][CH:28]=[CH:27]3)=[O:23])[CH2:19][CH3:20])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>>[F:1][C:2]1[C:10]([F:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([N:29]1[C:30]2[C:26](=[CH:25][C:24]([C:22]([NH:21][CH:18]([C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH2:19][CH3:20])=[O:23])=[CH:32][CH:31]=2)[CH:27]=[CH:28]1)=[O:5]
Reactant: O=C(Cl)c1cccc(F)c1F
Reactant: CCC(NC(=O)c1ccc2[nH]ccc2c1)c1ccccc1
Product: CCC(NC(=O)c1ccc2c(ccn2C(=O)c2cccc(F)c2F)c1)c1ccccc1

Procedure:
The title compound was prepared following the same general protocol as described in Example 25, using 2,3-difluorobenzoylchloride and N-(1-phenylpropyl)-1H-indole-5-carboxamide. LC-MS 419 (M+H).
Reaction SMILES: [C:1]1([C:7]2[N:11]([CH2:12][CH2:13][CH3:14])[C:10]3[CH:15]=[CH:16][C:17]([CH2:19]O)=[CH:18][C:9]=3[N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[ClH:21].S(Cl)([Cl:24])=O>ClC(Cl)Cl>[ClH:24].[Cl:21][CH2:19][C:17]1[CH:16]=[CH:15][C:10]2[N:11]([CH2:12][CH2:13][CH3:14])[C:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)=[N:8][C:9]=2[CH:18]=1
Reactant: O=S(Cl)Cl
Reactant: CCCn1c(-c2ccccc2)nc2cc(CO)ccc21
Agent: Cl
Solvent: ClC(Cl)Cl
Product: CCCn1c(-c2ccccc2)nc2cc(CCl)ccc21
Reaction time: 0.5 h
Yield: 96 %

Procedure:
(a-5) A solution of 70.5 parts of 2-phenyl-1-propyl-1H-benzimidazole-5-methanol in 300 parts of trichloromethane was saturated with gaseous hydrogen chloride. Then there are added dropwise 55.9 parts of thionyl chloride (exothermic reaction). Upon completion, stirring was continued for 30 minutes at reflux temperature. The reaction mixture was evaporated, the residue was taken up in 90 parts of methylbenzene and the latter was evaporated again. The residue was crystallized from 320 parts of 4-methyl-2-pentanone, yielding 80 parts (96%) of 5-(chloromethyl)-2-phenyl-1-propyl-1H-benzimidazole monohydrochloride; mp. 138.5° C. (int. 61).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9](=[O:14])[C:10]([CH3:13])([CH3:12])[CH3:11])=[CH:4][CH:3]=1.CO[CH:17](OC)[N:18]([CH3:20])[CH3:19]>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([C:9](=[O:14])[C:10]([CH3:11])([CH3:13])[CH3:12])=[CH:17][N:18]([CH3:20])[CH3:19])=[CH:6][CH:7]=1
Reactant: CC(C)(C)C(=O)Cc1ccc(Cl)cc1
Reactant: COC(OC)N(C)C
Solvent: Cc1ccccc1
Product: CN(C)C=C(C(=O)C(C)(C)C)c1ccc(Cl)cc1
Temperature: 103 °C
Reaction time: 5 h

Procedure:
(b′) A 3 L, 4-necked, round-bottomed flask, equipped with a mechanical stirrer, digital thermometer, reflux condenser, and nitrogen inlet-outlet, is charged with 953 g (1.05 L) of a toluene solution containing 1-(4-chlorophenyl)-3,3-dimethyl-2-butanone and 173 g (200 mL) of toluene; then add by pump 232 g (259 mL) of N,N-dimethylformamide dimethyl acetal. The solution is heated to an internal temperature at 97-109° C. (reflux) and stirred at this temperature for 5 hours. One hundred (100) mL of solvent is distilled off over a period of 0.5 hours. After distillation is stopped, the mixture is heated to an internal temperature at 107-114° C. (reflux). The mixture is stirred at this temperature for an additional 1 hour. Three more distillations follow in a similar procedure. Then the reaction mixture is cooled to an internal temperature at 20-25° C. over 1 hour, and stirred at this temperature for 1 hour, filtered over a pad of 70 g of Celite and the pad was washed with 300 mL of toluene. Filtrates are combined and concentrated under vacuum (30-80 torr) at an internal temperature at 25-40° C. (maximum jacket temperature 50° C.) to collect about 800 g or 925 mL of solvent to afford 275 g of crude 2-(4-chlorophenyl)-1-(dimethylamino)-4,4-dimethyl-1-pentene-3-one (Theoretical yield: 173.6 g). This crude product is dissolved in 440 mL (380 g) of toluene and the removal of excess N,N-dimethylformamide dimethyl acetal is confirmed by 1H NMR. The solution can be held at 21-23° C. under nitrogen and then used in the next step.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([Br:23])[C:10]=1[O:11][C:12]1[CH:17]=[CH:16][C:15]([O:18]C)=[C:14]([CH:20]([CH3:22])[CH3:21])[CH:13]=1)[C:5](O)=[O:6].[Cl:24][C:25]1[CH:30]=[CH:29][C:28]([S:31]([NH2:34])(=[O:33])=[O:32])=[CH:27][CH:26]=1>>[Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([Br:23])[C:10]=1[O:11][C:12]1[CH:17]=[CH:16][C:15]([OH:18])=[C:14]([CH:20]([CH3:21])[CH3:22])[CH:13]=1)[C:5]([C:29]1[CH:30]=[C:25]([Cl:24])[CH:26]=[CH:27][C:28]=1[S:31]([NH2:34])(=[O:32])=[O:33])=[O:6]
Reactant: COc1ccc(Oc2c(Br)cc(C(=O)O)cc2Br)cc1C(C)C
Reactant: NS(=O)(=O)c1ccc(Cl)cc1
Product: CC(C)c1cc(Oc2c(Br)cc(C(=O)c3cc(Cl)ccc3S(N)(=O)=O)cc2Br)ccc1O
Yield: 61.5 %

Procedure:
3,5-Dibromo-4-(4-methoxy-3-isopropylphenoxy)benzoic acid (0.035 mmol) was coupled with 4-chlorobenzenesulphonamide (0.175 mmol) using the method described in Example 58. Purification on HPLC of the residue gave 13 mg (62%) of the title compound.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][C:6]([OH:12])=[CH:7][CH:8]=2)[C:3]=1[N:13]1[N:17]=[C:16]2[CH:18]=[CH:19][CH:20]=[CH:21][C:15]2=[N:14]1.[OH-].[Na+].[C:24](Cl)(=[O:28])[C:25]([CH3:27])=[CH2:26]>O.C(Cl)(Cl)Cl>[OH:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][C:6]([O:12][C:24](=[O:28])[C:25]([CH3:27])=[CH2:26])=[CH:7][CH:8]=2)[C:3]=1[N:13]1[N:17]=[C:16]2[CH:18]=[CH:19][CH:20]=[CH:21][C:15]2=[N:14]1
Reactant: Oc1ccc2ccc(O)c(-n3nc4ccccc4n3)c2c1
Reactant: C=C(C)C(=O)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: ClC(Cl)Cl
Product: C=C(C)C(=O)Oc1ccc2ccc(O)c(-n3nc4ccccc4n3)c2c1
Yield: 40 %

Procedure:
To a solution of BDHN or 2(2,7-dihydroxynaphthyl) 2H-benzotriazole (5.0 g 18 m mol) and NaOH (0.8 g, 20 m mol) in water (100 ml) a solution of methacryloyl chloride (20 m mol, 4 ml) in chloroform (50 ml) was added dropwise with vigorous stirring. The mixture was stirred for 1 additional hour. The organic layer was separated and washed thoroughly with water before evaporation to yield a crude product that was recrystallized from carbon tetrachloride to give a yellow solid (2.5 g, 40% yield) of 2(2-hydroxy-7-methacryloxynaphthyl) 2H-benzotriazole--m.p. 167°-168° C.
Reaction SMILES: [CH:1](NC(C)C)(C)C.C([Li])CCC.[Cl:13][C:14]1[CH:15]=[N:16][CH:17]=[C:18]([Cl:20])[CH:19]=1.[I-]>C1COCC1.O>[Cl:13][C:14]1[C:15]([CH3:1])=[N:16][CH:17]=[C:18]([Cl:20])[CH:19]=1
Reactant: CC(C)NC(C)C
Reactant: Clc1cncc(Cl)c1
Agent: [I-]
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Product: Cc1ncc(Cl)cc1Cl
Reaction time: 0.08 h
Yield: 91 %

Procedure:
N,N-diisopropylamine (65.6 ml) was dissolved in anhydrous THF (150 ml), to which was dropwise added n-butyl lithium (1.54 mols/liter hexane solution, 300 ml) in an argon atmosphere at −78° C., and directly stirred for 5 minutes. An anhydrous THF (600 ml) solution of 3,5-dichloropyridine (63 g) was dropwise added to this, and stirred for 1 hour, and thenmethyl iodide (29.2 ml) was dropwise added thereto, and stirred for further 1.5 hours. Water was added to this to stop the reaction, which was then extracted with ethyl acetate. The organic layer was washed with a saturated saline solution, then dried over magnesium sulfate, and the solvent was distilled under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=10:1), then suspended in hexane, and taken out through filtration to obtain 3,5-dichloropicoline (62.8 g, 91%) as colorless crystals.
Reaction SMILES: [CH2:1]([N:8]1[CH2:15][CH2:14][C:11]2([O:13][CH2:12]2)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[CH3:17][C:18](=[CH2:21])[CH2:19][NH2:20].CCN(C(C)C)C(C)C>C(O)C>[CH2:1]([N:8]1[CH2:15][CH2:14][C:11]([CH2:12][NH:20][CH2:19][C:18]([CH3:21])=[CH2:17])([OH:13])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C=C(C)CN
Reactant: c1ccc(CN2CCC3(CC2)CO3)cc1
Agent: Cl
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Product: C=C(C)CNCC1(O)CCN(Cc2ccccc2)CC1
Temperature: 70 °C

Procedure:
A mixture of 6-benzyl-1-oxa-6-azaspiro[2.5]octane (2 g) and 2-methylprop-2-en-1-amine HCl (2 g) and Hunig's Base (3.44 mL) in ethanol (30 mL) was heated at 70° C. for 18 hours. The mixture was cooled to room temperature and the solvent evaporated under reduced pressure. The residue was partitioned between DCM and brine, the aqueous layer was re-extracted with fresh DCM and the combined organics dried over sodium sulphate, filtered and the solvent evaporated under reduced pressure to afford the subtitled compound. Yield 2.70 g.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([CH:12]=[N:13]O)[CH:8]=[CH:7]2>[Pd].[C].CO>[NH2:13][CH2:12][C:9]1[CH:8]=[CH:7][C:6]2[C:11](=[C:2]([OH:1])[CH:3]=[CH:4][CH:5]=2)[N:10]=1
Reactant: ON=Cc1ccc2cccc(O)c2n1
Agent: [Pd]
Solvent: CO
Product: NCc1ccc2cccc(O)c2n1
Reaction time: 4 h
Yield: 82 %

Procedure:
8-Hydroxy-quinoline-2-carboxaldehyde oxime DI (167 mg, 0.888 mmol) and MeOH (50 mL) was treated under hydrogenolysis conditions (atmospheric H2, catalytic 10% Pd/carbon) at RT. After 4 h, the catalyst was filtered off and the volatiles removed which afforded 2-aminomethyl-quinolin-8-ol E1 as a light brown solid (126 mg, 82%); spectral data of this compound are given in Table 2.
Reaction SMILES: [CH2:1]([N:3]1[C:12]2[C:7](=[CH:8][C:9]([F:18])=[C:10](S(CC)(=O)=O)[N:11]=2)[C:6](=[O:19])[C:5]([C:20]([OH:22])=[O:21])=[CH:4]1)[CH3:2].Cl.Cl.[N:25]12[CH2:32][CH:29]([CH2:30][CH2:31]1)[NH:28][CH2:27][CH2:26]2.N12CCCN=C1CCCCC2>C(#N)C>[CH2:1]([N:3]1[C:12]2[C:7](=[CH:8][C:9]([F:18])=[C:10]([N:28]3[CH:29]4[CH2:32][N:25]([CH2:31][CH2:30]4)[CH2:26][CH2:27]3)[N:11]=2)[C:6](=[O:19])[C:5]([C:20]([OH:22])=[O:21])=[CH:4]1)[CH3:2]
Reactant: C1CN2CCC(C2)N1
Reactant: CCn1cc(C(=O)O)c(=O)c2cc(F)c(S(=O)(=O)CC)nc21
Agent: Cl
Solvent: CC#N
Solvent: C1CCC2=NCCCN2CC1
Product: CCn1cc(C(=O)O)c(=O)c2cc(F)c(N3CCN4CCC3C4)nc21
Reaction time: 8 h
Yield: 18.4 %

Procedure:
A suspension of 2.06 g (6.28 mmol) 1-ethyl-7-ethanesulfonyl-6-fluoro-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxylic acid and 1.29 g (6.97 mmol) 1,4-diazabicyclo[3.2.1]octane dihydrochloride in 30 ml acetonitrile was treated with 3.10 g (20.4 mmol) 1,8-diazabicyclo[5.4.0]undec-7-ene. The resulting solution was stirred overnight and the precipitate which formed was filtered to afford 0.40 g of the title compound, mp 228°-229° C.