Azzindani/Open_Reaction_Data huggingface dataset:
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.[Cl:18][C:19]1[CH:26]=[CH:25][C:22]([CH:23]=[O:24])=[CH:21][CH:20]=1>>[Cl:18][C:19]1[CH:26]=[CH:25][C:22]([CH:23]([C:5]2[N:4]([CH2:3][CH:2]([CH3:17])[CH3:1])[C:16]3[C:15]4[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=4[N:9]=[CH:8][C:7]=3[N:6]=2)[OH:24])=[CH:21][CH:20]=1
Reactant: O=Cc1ccc(Cl)cc1
Reactant: CC(C)Cn1cnc2cnc3ccccc3c21
Product: CC(C)Cn1c(C(O)c2ccc(Cl)cc2)nc2cnc3ccccc3c21

Procedure:
Using the method of Example 45, 1-(2-methylpropyl)-1H-imidazo[4,5-c]quinoline (2.5 g) was reacted with 4-chlorobenzaldehyde to provide 3.1 g of a yellow solid. The structure was confirmed by nuclear magnetic resonance spectroscopy.
Reaction SMILES: [CH:1]([C:3]1[CH:22]=[CH:21][C:6]([N:7]([CH2:19][CH3:20])[CH2:8][CH2:9][O:10]C(=O)C2C=CC=CC=2)=[CH:5][CH:4]=1)=[O:2].C(=O)([O-])[O-].[K+].[K+].Cl.C(OCC)C>CO.O>[CH2:19]([N:7]([CH2:8][CH2:9][OH:10])[C:6]1[CH:21]=[CH:22][C:3]([CH:1]=[O:2])=[CH:4][CH:5]=1)[CH3:20]
Reactant: CCN(CCOC(=O)c1ccccc1)c1ccc(C=O)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOCC
Solvent: O
Solvent: CO
Product: CCN(CCO)c1ccc(C=O)cc1
Reaction time: 4 h
Yield: 50.7 %

Procedure:
4-Formyl-N-ethyl-N-(2-benzoyloxyethyl)aniline (16 g, 51 mmol) was added to a stirring suspension of potassium carbonate (9 g, 65 mmol) in methanol (150 mL) and water (50 mL). Stirring was continued at room temperature for 4 hours followed by addition of 1 molar hydrochloric acid (250 mL) and extraction into diethyl ether (3×100 mL). The combined ether layers were washed with saturated sodium bicarbonate (200 mL), water (200 mL), saturated sodium chloride (200 mL), dried over magnesium sulfate and the solvent was removed under reduced pressure. The crude product was purified using a silica gel chromatography column eluting with 50% ethyl acetate in hexane which gave the compound as a clear yellow oil (5 g, 51% yield).
Reaction SMILES: [CH:1](=O)/[CH:2]=[CH:3]/[CH3:4].[C:6]1([S:12]([C:15]#[N:16])(=[O:14])=[O:13])[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.B(OCCCC)(OCCCC)OCCCC>C1(C)C=CC=CC=1>[C:6]1([S:12]([C:15]2[CH:4]=[CH:3][CH:2]=[CH:1][N:16]=2)(=[O:13])=[O:14])[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1
Reactant: N#CS(=O)(=O)c1ccccc1
Reactant: C/C=C/C=O
Agent: CCCCOB(OCCCC)OCCCC
Solvent: Cc1ccccc1
Product: O=S(=O)(c1ccccc1)c1ccccn1
Temperature: 110 °C
Yield: 86.9 %

Procedure:
First, 8.20 g (115 mmol) of crotonaldehyde and 9.55 g (57.2 mmol) of benzenesulfonyl cyanide were introduced to the same reaction vessel as in Example 1. Toluene (15 ml) was added as the solvent, and 1.33 g (5.78 mmol) of tributyl borate was added. Then the mixture was heated under reflux for 3 hours while agitating at an internal temperature of 110° C. in a nitrogen atmosphere, separating and removing water that was produced. After this solution was cooled to room temperature, the low-boiling components, such as solvent, etc., were removed under reduced pressure and the resulting concentrate was cooled in an ice bath to precipitate crystals. The crystals were filtered with a glass filter and washed with 10 ml of toluene that had been cooled to 5° C. or lower. Then the crystals were dried for 2 hours in vacuo to give 10.9 g of 2-benzenesulfonylpyridine as colorless crystals (purity of 98%, yield of 85% based on benzenesulfonyl cyanide).
Reaction SMILES: I[C:2]1[C:3](=[O:20])[NH:4][C:5](=[O:19])[N:6]([CH:18]=1)[C@@H:7]1[O:14][C@H:11]([CH2:12][OH:13])[C@@H:9]([OH:10])[C@H:8]1N=[N+]=[N-].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O1CCOCC1>[C@@H:7]1([N:6]2[CH:18]=[CH:2][C:3](=[O:20])[NH:4][C:5]2=[O:19])[O:14][C@H:11]([CH2:12][OH:13])[C@@H:9]([OH:10])[CH2:8]1
Reactant: [N-]=[N+]=N[C@@H]1[C@H](O)[C@@H](CO)O[C@H]1n1cc(I)c(=O)[nH]c1=O
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1COCCO1
Product: O=c1ccn([C@H]2C[C@H](O)[C@@H](CO)O2)c(=O)[nH]1
Temperature: 25 °C
Reaction time: 1 h
Yield: 78 %

Procedure:
To a solution of 5-iodo,2'-azido,2'-deoxyuridine (2.48 g, 6.3 mmoles) in dioxane (33 ml) is added triphenylphosphine (5.8 g, 22 mmoles, 3.5 eq.) and the mixture is stirred at room temperature for 1 h, during which time a white precipitate forms. The precipitate is collected and washed three times with diethyl ether (3×50 ml). The filtrate is evaporated to dryness, taken up in a minimum amount of dioxane, and stored at -20° C. for 48 h. The precipitate is collected and washed with diethyl ether. The combined precipitates gave 1.81 g of 5-iodo,2'-amino, 2'-deoxyuridine (78% yield). The spectral properties agreed with those reported in the literature (Verheyden et al. (1971) supra).
Reaction SMILES: [C:1]1([CH:7]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[N:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.Br[CH2:28][C:29]([C:31]1[CH:36]=[CH:35][C:34]([O:37][CH3:38])=[C:33]([O:39][CH3:40])[C:32]=1[O:41][CH3:42])=[O:30].O>C(O)(C)C>[C:14]1([CH:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[N:8]2[CH2:9][CH2:10][N:11]([CH2:28][C:29]([C:31]3[CH:36]=[CH:35][C:34]([O:37][CH3:38])=[C:33]([O:39][CH3:40])[C:32]=3[O:41][CH3:42])=[O:30])[CH2:12][CH2:13]2)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: c1ccc(C(c2ccccc2)N2CCNCC2)cc1
Reactant: COc1ccc(C(=O)CBr)c(OC)c1OC
Solvent: CC(C)O
Solvent: CCN(CC)CC
Solvent: O
Product: COc1ccc(C(=O)CN2CCN(C(c3ccccc3)c3ccccc3)CC2)c(OC)c1OC
Temperature: 25 °C
Reaction time: 3 h
Yield: 68.4 %

Procedure:
In 60 ml of isopropanol were taken up 11.9 g (47 mmol) of 1-diphenylmethylpiperazine and 5.23 g (52 mmol) of triethylamine, and the resultant mixture was added with a solution which had been prepared by dissolving 13.6 g (47 mmol) of 2-bromo-1-(2,3,4-trimethoxyphenyl)ethanone in 50 ml of isopropanol. After being stirred for 3 hours at room temperature, the reaction mixture was poured into 200 ml of water. The mixture was extracted with 150 ml of ethyl acetate. The thus obtained organic layer was washed successively with water and saturated saline and thereafter dried over anhydrous sodium sulfate. After removal of the solvent, the residue was recrystallized from ethanol to give 14.8 g of 2-(4-diphenylmethylpiperazinyl)-1-(2,3,4-trimethoxyphenyl)ethanone (yield: 68%).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:11]=[CH:10][C:9]2[N:12]=[C:13]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[S:14][C:8]=2[C:7]=1[OH:21])=[O:5])[CH3:2].[Br:22]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>[CH2:1]([O:3][C:4]([C:6]1[N:11]=[C:10]([Br:22])[C:9]2[N:12]=[C:13]([C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=3)[S:14][C:8]=2[C:7]=1[OH:21])=[O:5])[CH3:2]
Reactant: CCOC(=O)c1ncc2nc(-c3ccccc3)sc2c1O
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: CCOC(=O)c1nc(Br)c2nc(-c3ccccc3)sc2c1O
Temperature: 25 °C
Yield: 71.3 %

Procedure:
A mixture of 7-hydroxy-2-phenyl-thiazolo[4,5-c]pyridine-6-carboxylic acid ethyl ester (81 mg, 0.27 mmol), N-bromosuccinimide (50 mg, 0.30 mmol) and benzoyl peroxide (3.2 mg, 0.01 mmol) in carbon tetrachloride (2 mL) was refluxed for 4 h before it was cooled to room temperature and partitioned between dichloromethane and water. The organic layer was washed with saturated aqueous sodium bicarbonate solution, brine, dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel with a gradient of ethyl acetate and dichloromethane to give the title compound as a white solid (73 mg): MS: (+) m/z 376.9, 378.9 (M+1, 79Br/81Br), MS: (−) m/z 377.1, 379.1 (M−1, 79Br/81Br)
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][CH:5]([C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([OH:17])[CH:15]=3)[NH:10][CH:9]=2)[CH2:4][CH2:3]1.C(N(CC)CC)C.[F:25][C:26]1[CH:31]=[CH:30][C:29]([S:32](Cl)(=[O:34])=[O:33])=[CH:28][CH:27]=1>C1COCC1.CN(C=O)C.C(OCC)(=O)C>[CH3:1][N:2]1[CH2:7][CH2:6][CH:5]([C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([O:17][S:32]([C:29]4[CH:30]=[CH:31][C:26]([F:25])=[CH:27][CH:28]=4)(=[O:34])=[O:33])[CH:15]=3)[NH:10][CH:9]=2)[CH2:4][CH2:3]1
Reactant: O=S(=O)(Cl)c1ccc(F)cc1
Reactant: CN1CCC(c2c[nH]c3ccc(O)cc23)CC1
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CN1CCC(c2c[nH]c3ccc(OS(=O)(=O)c4ccc(F)cc4)cc23)CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 42.1 %

Procedure:
To a solution-of 3-(1-methylpiperidin-4-yl)-5-hydroxy-1H-indole (500 mg, 2.2 mmol) and triethylamine (333 μL, 2.4 mmol) in THF (5 mL) and DMF (5 mL) was added 4-fluorobenzenesulfonyl chloride (465 mg, 2.4 mmol). The reaction mixture was stirred at ambient temperature for 18 h. The reaction mixture was cooled on an ice bath and diluted with ethyl acetate. The diluted reaction mixture was washed with cold 0.2 N NaOH, cold water, brine, dried (Na2SO4), filtered and concentrated under reduced pressure to give a white foam. The foam was crystallized from ethyl acetate to give 360 mg of a white powder. The mother liquors were purified by radial chromatography (silica gel, 2000 micron rotor, 5% methanol and 0.5% ammonium hydroxide in methylene chloride then 10% methanol and 0.5% ammonium hydroxide in methylene chloride) to give 297 mg (78%) total yield of a clear oil. The oil was crystallized from ethyl acetate/hexanes to give a white powder: mp 170-172° C.; MS(m/e): 388 (M+); Calculated for C20H21FN2O3S: C, 61.84; H, 5.45; N, 7.21. Found: C, 62.13; H, 5.58; N, 7.25.
Reaction SMILES: [F:1][C:2]1[C:8]([C:9]([F:12])([F:11])[F:10])=[CH:7][CH:6]=[CH:5][C:3]=1[NH2:4].C1C(=O)N([Br:20])C(=O)C1>CN(C=O)C>[Br:20][C:7]1[CH:6]=[CH:5][C:3]([NH2:4])=[C:2]([F:1])[C:8]=1[C:9]([F:10])([F:11])[F:12]
Reactant: Nc1cccc(C(F)(F)F)c1F
Reactant: O=C1CCC(=O)N1Br
Solvent: CN(C)C=O
Product: Nc1ccc(Br)c(C(F)(F)F)c1F
Reaction time: 2.5 h

Procedure:
To a solution of 2-fluoro-3-trifluoromethylaniline (5.0 g, 28 mmol) in DMF (25 mL) is added a solution of NBS (5.0 g, 28 mmol) in DMF (25 mL). After 2.5 h, the reaction is partitioned between ether and saturated aqueous NaCl. The separated organic phase is washed twice with fresh saturated aqueous NaCl, dried over Na2SO4, and concentrated under reduced pressure to give 4-bromo-2-fluoro-3-trifluoromethylaniline as an oil.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.O[CH:10]([C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)[CH2:11][CH2:12][CH2:13][CH2:14][N:15]1[CH2:20][CH2:19][CH:18]([C:21]2[CH:22]=[C:23]([NH:27][C:28](=[O:32])[CH:29]([CH3:31])[CH3:30])[CH:24]=[CH:25][CH:26]=2)[CH2:17][CH2:16]1.Cl>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH:10]([C:33]2[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=2)[CH2:11][CH2:12][CH2:13][CH2:14][N:15]2[CH2:20][CH2:19][CH:18]([C:21]3[CH:22]=[C:23]([NH:27][C:28](=[O:32])[CH:29]([CH3:31])[CH3:30])[CH:24]=[CH:25][CH:26]=3)[CH2:17][CH2:16]2)=[CH:4][CH:3]=1
Reactant: Oc1ccc(Br)cc1
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CCCCC(O)c3ccccc3)CC2)c1
Agent: Cl
Product: CC(C)C(=O)Nc1cccc(C2CCN(CCCCC(Oc3ccc(Br)cc3)c3ccccc3)CC2)c1

Procedure:
Prepared by Procedure A and Scheme AN using 4-bromophenol and N-{3-[1-(5-hydroxy-5-phenylpentyl]-4-piperidinyl]phenyl}-2-methylpropanamide: 1H NMR (400 MHz, CDCl3), HCl salt δ 7.74–6.66 (m, 13H), 5.13–5.02 (m, 1H), 3.73–3.51 (m, br, 2H), 3.05–2.83 (br, 2H), 2.83–2.62 (br, 4H), 2.62–2.42 (m, br, 2H), 2.10–1.80 (m, br, 6H), 1.65–1.37 (m, br, 2H), 1.25 (d, 6H, J=6.8 Hz); ESMS m/e: 562.9 (M+H)+.
Reaction SMILES: [OH-].[Na+].C[O:4][C:5]([C:7]1[C:15]2[S:14][CH:13]=[N:12][C:11]=2[CH:10]=[CH:9][CH:8]=1)=[O:6].C1COCC1.O>CO>[S:14]1[C:15]2[C:7]([C:5]([OH:6])=[O:4])=[CH:8][CH:9]=[CH:10][C:11]=2[N:12]=[CH:13]1
Reactant: COC(=O)c1cccc2ncsc12
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: O=C(O)c1cccc2ncsc12
Reaction time: 4 h

Procedure:
At 0° C. an aq. NaOH solution (50%, 6.0 mL) is added to a solution of benzothiazole-7-carboxylic acid methyl ester in a mixture of MeOH (39 mL), THF (11.7 mL) and water (3.0 mL). The mixture is stirred for 4 h and concentrated in vacuo. At 0° C. water (60 mL) is added and the mixture is made acidic (pH 5) by addition of conc. hydrochloric acid. After 30 min the precipitate is filtered off, washed with water and dried in vacuo to give the desired product. LC-MS: tR=0.77 min; [M+CH3CN+H]+=221.1.
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([S:9]([NH:12][C:13]2[CH:14]=[CH:15][CH:16]=[C:17]3[C:22]=2[N:21]=[CH:20][CH:19]=[CH:18]3)(=[O:11])=[O:10])=[C:4]([N+:23]([O-])=O)[CH:3]=1.O.O.[Sn](Cl)Cl>>[NH2:23][C:4]1[CH:3]=[C:2]([CH3:1])[C:7]([CH3:8])=[CH:6][C:5]=1[S:9]([NH:12][C:13]1[CH:14]=[CH:15][CH:16]=[C:17]2[C:22]=1[N:21]=[CH:20][CH:19]=[CH:18]2)(=[O:11])=[O:10]
Reactant: Cc1cc([N+](=O)[O-])c(S(=O)(=O)Nc2cccc3cccnc23)cc1C
Agent: Cl[Sn]Cl
Solvent: O
Product: Cc1cc(N)c(S(=O)(=O)Nc2cccc3cccnc23)cc1C
Yield: 65.3 %

Procedure:
In a similar fashion using route 15 general procedure 29, 4,5-dimethyl-2-nitro-N-quinolin-8-yl-benzenesulfonamide (Intermediate 147) (0.52 g, 1.45 mmol) and tin (II) chloride dihydrate (1.37 g, 7.26 mmol) gave the title compound (0.31 g, 66%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:13][N:12]([CH2:14][C:15]([OH:17])=O)[C:11](=[O:18])[C:10]3[S:19][C:20]([N:22]4[CH2:27][CH2:26][O:25][CH2:24][CH2:23]4)=[CH:21][C:9]2=3)=[CH:4][CH:3]=1.O.O[N:30]1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.[NH4+].[OH-]>CN(C=O)C.C(OCC)(=O)C.O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:13][N:12]([CH2:14][C:15]([NH2:30])=[O:17])[C:11](=[O:18])[C:10]3[S:19][C:20]([N:22]4[CH2:27][CH2:26][O:25][CH2:24][CH2:23]4)=[CH:21][C:9]2=3)=[CH:4][CH:3]=1
Reactant: On1nnc2ccccc21
Reactant: O=C(O)CN1CC(c2ccc(Cl)cc2)c2cc(N3CCOCC3)sc2C1=O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: [NH4+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: NC(=O)CN1CC(c2ccc(Cl)cc2)c2cc(N3CCOCC3)sc2C1=O
Reaction time: 0.5 h
Yield: 52.6 %

Procedure:
To a solution of 2-(4-(4-chlorophenyl)-2-morpholino-7-oxo-4,5-dihydrothieno[2,3-c]pyridin-6(7H)-yl)acetic acid (95.2 mg, 0.234 mmol) in DMF (3.0 mL) was added 1-hydroxybenzotriazole hydrate (39.4 mg, 0.297 mmol) and N-(3-Dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (80.7 mg, 0.421 mmol) and the resulting solution was stirred for 30 minutes. 33% NH4OH (202 uL, 2.34 mmol) was added and the resulting solution was stirred at room temperature overnight. The reaction was diluted with ethyl acetate (40 mL) and water (15 mL). The layers were separated and the organic layer was washed with water (3×10 mL). The organic layer was dried over MgSO4, filtered and concentrated in vacuo to give 77 mg crude. The residue was purified by analytical chromatography to give 50 mg (53% yield) of the title compound as a white solid. LC/MS (FA) ES+ 406. 1H NMR (400 MHz, DMSO-d6) δ: 7.42-7.39 (m, 2H), 7.28-7.26 (m and bs, 3H total), 7.01 (bs, 1H), 5.78 (s, 1H), 4.30-4.27 (m, 1H), 4.04 (d, 1H, J=17.2 Hz), 3.84-3.79 (m, 1H), 3.77 (d, 1H, J=17.2 Hz), 3.70-3.67 (m, 4H), 3.64-3.59 (m, 1H), 3.13-3.10 (m, 4H).
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[C:9]([Cl:10])=[C:8]([O:11][CH3:12])[CH:7]=[CH:6][C:5]=1[SH:13].Br[CH:15]([CH:19]([CH3:21])[CH3:20])[C:16]([OH:18])=[O:17]>CN(C)C=O.O>[Cl:3][C:4]1[C:9]([Cl:10])=[C:8]([O:11][CH3:12])[CH:7]=[CH:6][C:5]=1[S:13][CH:15]([CH:19]([CH3:21])[CH3:20])[C:16]([OH:18])=[O:17]
Reactant: COc1ccc(S)c(Cl)c1Cl
Reactant: CC(C)C(Br)C(=O)O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc(SC(C(=O)O)C(C)C)c(Cl)c1Cl
Reaction time: 0.2 h
Yield: 80.5 %

Procedure:
To 3.13 g of 99% sodium hydride under nitrogen at room temperature is added a solution of 12.26 g of 2,3-dichloro-4-methoxythiophenol in 100 ml of sieve-dried dimethylformamide over 2 minutes. The reaction is stirred for 12 minutes. A solution of 9.56 g of α-bromoisovaleric acid in 85 ml of dimethylformamide is added over 4 minutes. The reaction is stirred at room temperature for 3 hours, cooled in ice, diluted with 500 ml of water and filtered. The solution is cooled and acidified with 3N hydrochloric acid to give the product. The precipitate is filtered, washed with a small amount of water, dried and recrystallized from acetone-pentane to give 13.14 g of α-(2,3-dichloro-4-methoxyphenylthio)isovaleric acid as a white crystalline powder mp 176.5°-178.5°.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([OH:12])[CH:8]=2)[CH:3]=1.C(N(CC)CC)C.[C:20](Cl)(=[O:29])[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28].CN(C1C=CC=CN=1)C>ClCCl.CCCCCC.C(OCC)(=O)C>[OH:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([O:12][C:20](=[O:29])[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])[CH:8]=2)[CH:3]=1
Reactant: Oc1ccc2cc(O)ccc2c1
Reactant: CCCCCCCCC(=O)Cl
Agent: CN(C)c1ccccn1
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCCCCCCC(=O)Oc1ccc2cc(O)ccc2c1
Temperature: 25 °C
Reaction time: 20 h
Yield: 32.2 %

Procedure:
2,6-dihydroxynaphthalene (0.48 g) and triethylamine (0.31 g) were dissolved in 20 ml of dichloromethane. Nonanoyl chloride (0.55 g) and dimethylaminopyridine (0.13 g) were added to the solution, and the mixture was stirred at room temperature for about 20 hours. The reaction mixture was poured into ice-water, extracted with dichloromethane and dried over anhydrous magnesium sulfate, and the solvent was removed by evaporation to give a crude product, which was treated with a silica gel column chromatograph (eluent: hexane/ethyl acetate=10/2) to give 0.29 g of the desired product.
Reaction SMILES: [CH2:1]([N:3]1[C:8]2[CH:9]=[C:10]([CH3:13])[CH:11]=[N:12][C:7]=2[S:6](=[O:15])(=[O:14])[N:5]=[CH:4]1)[CH3:2].[BH4-].[Na+]>C(O)(C)C.C(Cl)(Cl)Cl>[CH2:1]([N:3]1[C:8]2[CH:9]=[C:10]([CH3:13])[CH:11]=[N:12][C:7]=2[S:6](=[O:14])(=[O:15])[NH:5][CH2:4]1)[CH3:2]
Reactant: CCN1C=NS(=O)(=O)c2ncc(C)cc21
Agent: [BH4-]
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: CC(C)O
Product: CCN1CNS(=O)(=O)c2ncc(C)cc21
Reaction time: 0.5 h

Procedure:
A solution of 0.6 g of 4-ethyl-6-methyl-4H- pyrido[3,2-e][1,2,4]thiadiazine 1,1-dioxide (Example 78}in 30 cm3 of a 1/1 isopropanol/chloroform mixture is treated, in small portions, with 0.45 g of sodium borohydride with good stirring and under an inert atmosphere. After 30 minutes at ambient temperature, the excess borohydride is destroyed by addition of a few drops of acetic acid and the solvent is removed under reduced pressure. The residue is taken up in 10 cm3 of water and the pH of the mixture is brought to neutrality. The precipitate obtained is collected on a filter, washed with water and dried.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][CH2:5][NH:6][C:7](=[O:26])[NH:8][C:9]1[S:13][N:12]=[C:11]([C:14]2[CH:19]=[CH:18][C:17]([N+:20]([O-])=O)=[CH:16][CH:15]=2)[C:10]=1[C:23]([NH2:25])=[O:24].[H][H]>CO.[Pt]=O>[NH2:20][C:17]1[CH:18]=[CH:19][C:14]([C:11]2[C:10]([C:23]([NH2:25])=[O:24])=[C:9]([NH:8][C:7]([NH:6][CH2:5][CH2:4][CH2:3][O:2][CH3:1])=[O:26])[S:13][N:12]=2)=[CH:15][CH:16]=1
Reactant: COCCCNC(=O)Nc1snc(-c2ccc([N+](=O)[O-])cc2)c1C(N)=O
Reactant: [H][H]
Agent: O=[Pt]
Solvent: CO
Product: COCCCNC(=O)Nc1snc(-c2ccc(N)cc2)c1C(N)=O
Reaction time: 17 h

Procedure:
A mixture of 5-(3-(3-methoxypropyl)ureido)-3-(4-nitrophenyl)isothiazole-4-carboxamide (4 mg, 0.009 mmol) and catalytic platinum oxide in 4 mL MeOH was hydrogenated under 60 PSI hydrogen. After 17 hours, the mixture was filtered and rotary evaporated to a white solid. The solid was partitioned between EtOAc and aqueous NaHCO3 solution, the EtOAc layer dried with anhydrous Na2SO4 and evaporated to the title compound as a white solid (2 mg, 66%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C@H:8]([O:10][C:11](=[O:26])[NH:12][C:13]1[C:14]([CH3:25])=[N:15][O:16][C:17]=1[C:18]1[CH:23]=[CH:22][C:21](Br)=[CH:20][CH:19]=1)[CH3:9].[CH2:27]([O:29][C:30](=[O:49])[C:31]([CH3:48])([C:33]1[CH:38]=[CH:37][C:36](B2OC(C)(C)C(C)(C)O2)=[CH:35][CH:34]=1)[CH3:32])[CH3:28]>>[CH2:27]([O:29][C:30](=[O:49])[C:31]([C:33]1[CH:38]=[CH:37][C:36]([C:21]2[CH:22]=[CH:23][C:18]([C:17]3[O:16][N:15]=[C:14]([CH3:25])[C:13]=3[NH:12][C:11]([O:10][C@@H:8]([C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=3[Cl:1])[CH3:9])=[O:26])=[CH:19][CH:20]=2)=[CH:35][CH:34]=1)([CH3:48])[CH3:32])[CH3:28]
Reactant: Cc1noc(-c2ccc(Br)cc2)c1NC(=O)O[C@H](C)c1ccccc1Cl
Reactant: CCOC(=O)C(C)(C)c1ccc(B2OC(C)(C)C(C)(C)O2)cc1
Product: CCOC(=O)C(C)(C)c1ccc(-c2ccc(-c3onc(C)c3NC(=O)O[C@H](C)c3ccccc3Cl)cc2)cc1

Procedure:
Prepared as described in Example 36, Step 6 using [5-(4-bromo-phenyl)-3-methyl-isoxazol-4-yl]-carbamic acid (R)-1-(2-chloro-phenyl)-ethyl ester and 2-methyl-2-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-propionic acid ethyl ester.
Reaction SMILES: Cl[C:2]1[C:7]([NH2:8])=[C:6]([Cl:9])[N:5]=[C:4]([CH3:10])[N:3]=1.[CH3:11][O:12][CH2:13][CH2:14][NH2:15].C(N(C(C)C)CC)(C)C>C(O)(C)C.ClCCl>[Cl:9][C:6]1[N:5]=[C:4]([CH3:10])[N:3]=[C:2]([NH:15][CH2:14][CH2:13][O:12][CH3:11])[C:7]=1[NH2:8]
Reactant: COCCN
Reactant: Cc1nc(Cl)c(N)c(Cl)n1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)O
Solvent: ClCCl
Product: COCCNc1nc(C)nc(Cl)c1N
Temperature: 25 °C
Yield: 115.4 %

Procedure:
Heat a solution of 4,6-dichloro-2-methyl-pyrimidin-5-ylamine (5.0 g, 0.02 mol), 2-methoxyethylamine (2.32 g, 0.03 mol) and diisopropylethylamine (3.9 g, 0.03 mol) in isopropanol (70 mL) at 150° C. in a sealed tube for 16 h. Cool the reaction mixture to room temperature, and remove the isopropanol under reduced pressure to give a residue. Dissolve the residue in dichloromethane and wash with water and brine. Dry the organic layer over anhydrous sodium sulfate, filter, and concentrate under reduced pressure to give a residue. Purify the residue on a silica gel column eluting with methanol:dichloromethane (4:96) to give the title compound (5.0 g). ES/MS m/z 217 (M+1).
Reaction SMILES: [F:1][C:2]1[C:9]([O:10][CH3:11])=[CH:8][CH:7]=[C:6]([F:12])[C:3]=1[CH:4]=O.[CH2:13]([NH2:17])[CH2:14][CH2:15][CH3:16].C1(C)C=CC(S(O)(=O)=O)=CC=1>>[CH2:13](/[N:17]=[CH:4]/[C:3]1[C:6]([F:12])=[CH:7][CH:8]=[C:9]([O:10][CH3:11])[C:2]=1[F:1])[CH2:14][CH2:15][CH3:16]
Reactant: COc1ccc(F)c(C=O)c1F
Reactant: CCCCN
Agent: Cc1ccc(S(=O)(=O)O)cc1
Product: CCCC/N=C/c1c(F)ccc(OC)c1F

Procedure:
Butyl-[1-(2,6-difluoro-3-methoxy-phenyl)-meth-(E)-ylidene]-amine was prepared from 2,6-difluoro-3-methoxybenzaldehyde, N-butylamine and p-toluenesulphonic acid in analogy to Example 186a): red oil; MS (ISP): 228.4 ([M+H]+, 100%).
Reaction SMILES: [CH:1]1([NH2:6])[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:7][C:8]1[C:12]([C:13]2[CH:14]=[C:15]([S:23](Cl)(=[O:25])=[O:24])[C:16]3[CH:17]=[CH:18][CH:19]=[N:20][C:21]=3[CH:22]=2)=[C:11]([CH3:27])[O:10][N:9]=1>C(OCC)(=O)C>[CH:1]1([NH:6][S:23]([C:15]2[C:16]3[CH:17]=[CH:18][CH:19]=[N:20][C:21]=3[CH:22]=[C:13]([C:12]3[C:8]([CH3:7])=[N:9][O:10][C:11]=3[CH3:27])[CH:14]=2)(=[O:24])=[O:25])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: Cc1noc(C)c1-c1cc(S(=O)(=O)Cl)c2cccnc2c1
Reactant: NC1CCCC1
Solvent: CCOC(C)=O
Product: Cc1noc(C)c1-c1cc(S(=O)(=O)NC2CCCC2)c2cccnc2c1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
Cyclopentyl amine (0.4 mL, 4 mmol) was added to a solution of 7-(3,5-dimethylisoxazol-4-yl)quinoline-5-sulfonyl chloride (500 mg, 1.55 mmol) in ethyl acetate (15 mL). The reaction was stirred at room temperature for 15 minutes before being partitioned between an aqueous solution of citric acid and ethyl acetate. The organic layer was washed with brine and dried over sodium sulfate. Purification on silica gel (rf=0.07 in 2:1 hexanes ethyl acetate) afforded N-cyclopentyl-7-(3,5-dimethylisoxazol-4-yl)quinoline-5-sulfonamide.