Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([CH:11]=O)=[CH:9][N:10]=2)[CH:7]=1.[NH:13]1[CH2:18][CH2:17][O:16][CH2:15][CH2:14]1.C(O)(=O)C.[BH4-].[Na+]>C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([CH2:11][N:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)=[CH:9][N:10]=2)[CH:7]=1
Reactant: C1COCCN1
Reactant: O=Cc1cnc2ccc(Br)cn12
Agent: [BH4-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: Cc1ccccc1
Product: Brc1ccc2ncc(CN3CCOCC3)n2c1
Yield: 42.4 %

Procedure:
Reflux a solution of 6-bromo-imidazo[1,2-a]pyridine-3-carbaldehyde (J. Med. Chem. 1970, 13(6), 1048-51; 0.45 g, 1.99 mmol), morpholine (1.7 g, 19.9 mmol), and acetic acid (0.12 mL, 1.99 mmol) in toluene (200 mL) for 3 h. Concentrate to dryness and re-dissolve in methanol (100 mL). Add sodium borohydride (0.226 g, 5.99 mmol) in portions and stir for 30 min. Concentrate to ˜25 mL, dilute with saturated aqueous sodium bicarbonate, extract into ethyl acetate, combine and concentrate. Flash chromatography gives the titled compound (0.25 g, 42%). MS ES+ m/e 295.8, 297.8 (M+1). 1H NMR (400 MHz, DMSO-d6) δ 8.69 (s, 1H), 7.54 (d, J=10 Hz, 1H), 7.51 (s, 1H), 7.35 (d, J=10 Hz, 1H), 3.81 (s, 2H), 3.52 (t, J=4 Hz, 1H), 2.35 (t,J=4 Hz, 4H).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14](=[O:18])[CH2:15][CH2:16][OH:17])[CH2:10][CH2:9]1)=O)(C)(C)C.[ClH:19].O1CCOCC1>CO>[ClH:19].[O:18]=[C:14]([N:11]1[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]1)[CH2:15][CH2:16][OH:17]
Reactant: CC(C)(C)OC(=O)N1CCN(C(=O)CCO)CC1
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: O=C(CCO)N1CCNCC1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A mixture of 1-tert-butoxycarbonylpiperazine, 3-hydroxypropionic acid, 1-hydroxybenzotriazole (HOBt), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDCI) and DMF was stirred for 24 hours at room temperature to give 3-(4-tert-utoxycarbonylpiperazine-1-yl)-3-oxopropane-1-ol. A mixture of the obtained 3-(4-tert-butoxycarbonylpiperazine-1-yl)-3-oxopropane-1-ol, 4M HCl-dioxane solution and MeOH was stirred for 16 hours at room temperature to give 3-oxo-3-piperazine-1-ylpropane-1-ol hydrochloride.
Reaction SMILES: [H-].[Na+].[F:3][C:4]1[CH:5]=[C:6]([CH:18]=[CH:19][C:20]=1[F:21])[O:7][C:8]1[CH:15]=[CH:14][C:13]([CH2:16][OH:17])=[CH:12][C:9]=1[C:10]#[N:11].Cl[C:23]1[CH:24]=[C:25]2[N:32]([CH:33]([CH3:35])[CH3:34])[CH2:31][CH2:30][N:26]2[C:27](=[O:29])[N:28]=1>C1COCC1.CN(C=O)C>[F:3][C:4]1[CH:5]=[C:6]([CH:18]=[CH:19][C:20]=1[F:21])[O:7][C:8]1[CH:15]=[CH:14][C:13]([CH2:16][O:17][C:23]2[CH:24]=[C:25]3[N:32]([CH:33]([CH3:35])[CH3:34])[CH2:31][CH2:30][N:26]3[C:27](=[O:29])[N:28]=2)=[CH:12][C:9]=1[C:10]#[N:11]
Reactant: N#Cc1cc(CO)ccc1Oc1ccc(F)c(F)c1
Reactant: CC(C)N1CCn2c1cc(Cl)nc2=O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: CC(C)N1CCn2c1cc(OCc1ccc(Oc3ccc(F)c(F)c3)c(C#N)c1)nc2=O

Procedure:
Prepared in a manner similar to that described for E1 using sodium hydride (16.85 mg, 0.702 mmol) in THF (4 mL), 2-(3,4-difluorophenoxy)-5-(hydroxymethyl)benzonitrile (100 mg, 0.468 mmol) in DMF (2.00 mL) and 7-chloro-1-isopropyl-2,3-dihydroimidazo[1,2-c]pyrimidin-5(1H)-one.
Reaction SMILES: [Cl:1][C:2]1[CH:16]=[CH:15][C:5]2[C:6]([CH:9]3[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]3)=[N:7][O:8][C:4]=2[CH:3]=1.Br[CH2:18][CH2:19][CH2:20][CH2:21][O:22][C:23]1[CH:28]=[CH:27][C:26]([C:29](=[O:31])[CH3:30])=[CH:25][C:24]=1[O:32][CH3:33].C([O-])([O-])=O.[K+].[K+].[C:40]([OH:47])(=[O:46])/[CH:41]=[CH:42]/[C:43]([OH:45])=[O:44]>C(O)C.C(#N)C>[C:40]([OH:47])(=[O:46])/[CH:41]=[CH:42]/[C:43]([OH:45])=[O:44].[Cl:1][C:2]1[CH:16]=[CH:15][C:5]2[C:6]([CH:9]3[CH2:10][CH2:11][N:12]([CH2:18][CH2:19][CH2:20][CH2:21][O:22][C:23]4[CH:28]=[CH:27][C:26]([C:29](=[O:31])[CH3:30])=[CH:25][C:24]=4[O:32][CH3:33])[CH2:13][CH2:14]3)=[N:7][O:8][C:4]=2[CH:3]=1
Reactant: COc1cc(C(C)=O)ccc1OCCCCBr
Reactant: Clc1ccc2c(C3CCNCC3)noc2c1
Agent: O=C(O)/C=C/C(=O)O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: CCO
Product: COc1cc(C(C)=O)ccc1OCCCCN1CCC(c2noc3cc(Cl)ccc23)CC1
Yield: 71.9 %

Procedure:
A stirred mixture of 6-chloro-3-(4-piperidinyl)-1,2-benzisoxazole (4.7 g, 20 mmol), 1-[4-(4-bromobutoxy)-3-methoxyphenyl]ethanone (6.0 g, 20 mmol), K2CO3 (2.8 g) and acetonitrile (120 ml) was refluxed for 16 hours. The reaction was allowed to cool, filtered, and the filtrate was concentrated to 9.9 g of a brown oil. The oil was chromatographed on a Waters Prep 500 utilizing silica gel columns and eluting with methylene chloride/methanol (5%). Concentration of the appropriate fractions afforded 2:3 g of an off-white solid. The solid was dissolved in ethanol and fumaric acid (0.62 g, 1.1 eq.) was added. Upon concentration of the ethanol, a crude, brown solid was collected, which was taken up in refluxing acetone. Upon cooling, a white solid crystallized from solution yielding 2.2 g (19%) of 1-[4-[4-[4-(6-chloro-1,2-benzisoxazol-3-yl)-1-piperidinyl]-butoxy]-3-methoxyphenyl]ethanone fumarate as a white solid, m.p.=139°-141° C.
Reaction SMILES: S(Cl)(Cl)=O.[NH2:5][C@H:6]1[CH2:10][CH2:9][C@@H:8]([C:11]([OH:13])=[O:12])[CH2:7]1.[CH3:14]O>>[NH2:5][C@H:6]1[CH2:10][CH2:9][C@@H:8]([C:11]([O:13][CH3:14])=[O:12])[CH2:7]1
Reactant: CO
Reactant: N[C@H]1CC[C@@H](C(=O)O)C1
Solvent: O=S(Cl)Cl
Product: COC(=O)[C@@H]1CC[C@H](N)C1
Yield: 87 %

Procedure:
Thionyl chloride (1.30 ml, 18.2 mmol) was added to a stirred solution of (1R,3S)-3-amino cyclo pentyl carboxylic acid (2.00 g, 12.1 mmol) in MeOH (20 ml) and refluxed for 3 h. The reaction mixture was concentrated under reduced pressure and co-distilled with toluene to afford 1.9 g (87%) of (1R,3S)-methyl 3-aminocyclopentanecarboxylate as off-white solid.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:13][CH2:12][N:11]([C:14]([O:16][CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[O:15])[CH2:10][CH:9]2[O:24][CH2:25][C:26]2[CH:27]=[CH:28][C:29]3[O:34][CH2:33][CH2:32][N:31]([CH2:35][CH2:36][CH2:37][O:38][CH3:39])[C:30]=3[CH:40]=2)=[CH:4][CH:3]=1.I[CH:42]([CH3:44])[CH3:43]>>[CH:42]([O:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:13][CH2:12][N:11]([C:14]([O:16][CH2:17][C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=3)=[O:15])[CH2:10][CH:9]2[O:24][CH2:25][C:26]2[CH:27]=[CH:28][C:29]3[O:34][CH2:33][CH2:32][N:31]([CH2:35][CH2:36][CH2:37][O:38][CH3:39])[C:30]=3[CH:40]=2)=[CH:4][CH:3]=1)([CH3:44])[CH3:43]
Reactant: CC(C)I
Reactant: COCCCN1CCOc2ccc(COC3CN(C(=O)OCc4ccccc4)CCC3c3ccc(O)cc3)cc21
Product: COCCCN1CCOc2ccc(COC3CN(C(=O)OCc4ccccc4)CCC3c3ccc(OC(C)C)cc3)cc21

Procedure:
Analogously to Method F, 0.05 g of benzyl 4-(4-hydroxyphenyl)-3-[4-(3-methoxypropyl)-3,4-dihydro-2H-benzo[1,4]oxazin-6-ylmethoxy]piperidine-1 carboxylate and 0.0316 g of 2-iodopropane are reacted at 50° C. The title compound is obtained as an orange oil. Rf=0.34 (1:1 EtOAc-heptane). Rt=5.78.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[CH2:11][CH2:10][C:9]([CH2:15][N:16]1[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1)=[CH:8]2)([CH3:4])([CH3:3])[CH3:2].Cl.N1CCCCC1.C(C1C=C2C(CCCC2=[O:43])=CC=1)(C)(C)C.C=O>C(O)C.Cl>[C:1]([C:5]1[CH:6]=[C:7]2[C:12]([CH2:11][CH2:10][CH:9]([CH2:15][N:16]3[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]3)[C:8]2=[O:43])=[CH:13][CH:14]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1ccc2c(c1)C(=O)CCC2
Reactant: CC(C)(C)c1ccc2c(c1)C=C(CN1CCCCC1)CC2
Agent: C=O
Agent: Cl
Solvent: C1CCNCC1
Solvent: CCO
Product: CC(C)(C)c1ccc2c(c1)C(=O)C(CN1CCCCC1)CC2
Yield: 43 %

Procedure:
This Example illustrates the preparation of 6-tert-butyl-3-piperidinomethyl-1,2-dihydronaphthalene (Compound number 4 of Table I). Piperidine hydrochloride (8.9 g, 0.073 mol), 7-tert-butyl-1,2,3,4-tetrahydronaphthalen-1-one (7.0 g, 0.035 mol) and paraformaldehyde (2.2 g, 0.073 mol) were refluxed together in ethanol (150 ml) along with concentrated hydrochloric acid (1 ml) as a catalyst for 16 hours. The reaction mixture was concentrated under reduced pressure and the residue dissolved in water then extracted with diethyl ether. The resulting aqueous solution was neutralized with sodium bicarbonate and extracted with diethyl ether (2×200 ml); the ethereal extracts were dried over magnesium sulphate and concentrated under reduced pressure to give 7-tert-butyl-2-piperidinomethyl-1,2,3,4-tetrahydronaphthalen-1-one (4.5 g, 43% yield) as a buff coloured solid melting at 62°-3°. The 7-tert-butyl-2-piperidinomethyl-1,2,3,4-tetrahydronaphthalen-1-one (4.5 g, 0.015 mol) was dissolved in methanol (100 ml) and sodium borohydride (0.6 g, 0.016 mol) was added portionwise over 30 minutes at room temperature. It was stirred for 3 hours at room temperature then the methanol was evaporated under reduced pressure and the residue treated with water (100 ml) and extracted with ether (2×100 ml) which was washed with brine, dried over magnesium sulphate and evaporated under reduced pressure to give a viscous oil (4.0 g) which crystallised on standing. Separation by column chromatography on silica gel (Merck 60) using a gradient elution of petrol 60°-80° to ethyl acetate gave the alcohol as two isomers:
Reaction SMILES: [F:1][C:2]1[CH:35]=[CH:34][C:5]([CH2:6][N:7]2[C:19]3[C:18]([O:20][CH3:21])=[CH:17][CH:16]=[C:15]([C:22]([O:24]C4C=CC([N+]([O-])=O)=CC=4)=O)[C:14]=3[C:13]3[C:8]2=[CH:9][CH:10]=[CH:11][CH:12]=3)=[CH:4][CH:3]=1.[Cl:36][C:37]1[CH:38]=[N:39][CH:40]=[C:41]([Cl:44])[C:42]=1[NH2:43].[H-].[Na+].Cl>CN(C=O)C.O>[Cl:36][C:37]1[CH:38]=[N:39][CH:40]=[C:41]([Cl:44])[C:42]=1[NH:43][C:22]([C:15]1[C:14]2[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[N:7]([CH2:6][C:5]3[CH:34]=[CH:35][C:2]([F:1])=[CH:3][CH:4]=3)[C:19]=2[C:18]([O:20][CH3:21])=[CH:17][CH:16]=1)=[O:24]
Reactant: COc1ccc(C(=O)Oc2ccc([N+](=O)[O-])cc2)c2c3ccccc3n(Cc3ccc(F)cc3)c12
Reactant: Nc1c(Cl)cncc1Cl
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc(C(=O)Nc2c(Cl)cncc2Cl)c2c3ccccc3n(Cc3ccc(F)cc3)c12
Temperature: 25 °C
Reaction time: 2 h
Yield: 28.6 %

Procedure:
To a solution of 4-Nitrophenyl 9-(4-fluoro benzyl)-1-methoxy-9H-4-carbazole carboxylate (50 mg, 0.106 mmoles) in dry DMF (4 ml) under nitrogen atmosphere, 3,5dichloro-4-amino pyridine (17.34 mg, 0.106 mmoles) was added followed by sodium hydride (60% suspension, 8.5 mg, 0.212 mmoles) and the reaction mixture was stirred at room temperature for two hours. Ice pieces were added to the reaction mixture, diluted with water (15 ml) and neutralized with 1N HCl. The precipitated product was filtered, washed with water and dried under vacuum to give 15 mg of the title compound as an off white solid, m.p: 222-225° C.
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[C:4]([N:9]=[C:10]=S)[N:3]=1.C(N(CC)CC)C.Cl.Cl.[NH2:21][CH2:22][C:23]1([OH:31])[CH:28]2[CH2:29][CH2:30][N:25]([CH2:26][CH2:27]2)[CH2:24]1.C(N=C=NC(C)C)(C)C>CN(C)C=O>[Cl:8][C:7]1[CH:6]=[CH:5][C:4]([NH:9][C:10]2[O:31][C@:23]3([CH2:22][N:21]=2)[CH:28]2[CH2:29][CH2:30][N:25]([CH2:26][CH2:27]2)[CH2:24]3)=[N:3][C:2]=1[Cl:1]
Reactant: NCC1(O)CN2CCC1CC2
Reactant: S=C=Nc1ccc(Cl)c(Cl)n1
Agent: CC(C)N=C=NC(C)C
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Clc1ccc(NC2=NC[C@@]3(CN4CCC3CC4)O2)nc1Cl
Temperature: 70 °C
Reaction time: 2 h
Yield: 47.2 %

Procedure:
To 2,3-dichloro-6-isothiocyanatopyridine (0.47 g, 2.29 mmol) in N,N-dimethylformamide (20 mL) was added triethylamine (0.8 mL, 5.7 mmol) and 3-(aminomethyl)quinuclidin-3-ol dihydrochloride (0.54 g, 2.34 mmol) at room temperature. The reaction was stirred at 70° C. for 2 hours, cooled to room temperature and concentrated in vacuo. The crude urea was purified by chromatography (Biotage: 85% CHCl3, 14% MeOH, 1% NH4OH). The product was then treated with N,N-dimethylformamide (20 mL) and N,N′-diisopropylcarbodiimide (1.07 mL, 6.88 mmol). The reaction was heated to 70° C. for 2 hours. The reaction was cooled to room temperature and concentrated in vacuo. The crude product was purified by chromatography (Biotage: 85% CHCl3, 14% MeOH, 1% NH4OH) to yield (R)—N-(5,6-dichloropyridin-2-yl)-4H-1′-azaspiro[oxazole-5,3′-bicyclo[2.2.2]octan]-2-amine (0.36 g, 1.08 mmol, 47% yield) as a white powder. 1H NMR (500 MHz, DMSO-D6) δ ppm 8.31 (d, J=1.22 Hz, 1H), 7.84 (s, 1H), 6.80 (s, 1H), 3.85 (d, J=10.07 Hz, 1H), 3.57 (d, J=10.38 Hz, 2H), 2.98 (s, 3H), 2.69-2.78 (m, 3H), 2.65 (t, J=7.78 Hz, 3H), 2.00 (s, 2H), 1.86 (s, 2H), 1.58 (dd, J=7.48, 2.90 Hz, 2H), 1.56 (s, 1H), 1.41-1.49 (m, 2H). MS (LC/MS) R.T.=0.81; [M+H]+=327.1.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([CH2:8][O:9][CH2:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3[C:18]([C:23]#[N:24])=[CH:19][CH:20]=[CH:21][CH:22]=3)=[CH:13][CH:12]=2)=[CH:4][CH:3]=1.O.[NH2:26][NH2:27]>C(O)C>[NH:26]([C:2]1[N:7]=[CH:6][C:5]([CH2:8][O:9][CH2:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3[C:18]([C:23]#[N:24])=[CH:19][CH:20]=[CH:21][CH:22]=3)=[CH:13][CH:12]=2)=[CH:4][CH:3]=1)[NH2:27]
Reactant: N#Cc1ccccc1-c1ccc(COCc2ccc(Cl)nc2)cc1
Reactant: NN
Solvent: CCO
Solvent: O
Product: N#Cc1ccccc1-c1ccc(COCc2ccc(NN)nc2)cc1
Yield: 56 %

Procedure:
4′-{[(6-Chloropyridin-3-yl)methoxy]methyl}biphenyl-2-carbonitrile (1.7 g) and hydrazine monohydrate (3 mL) were suspended in ethanol (8 mL), and the suspension was reacted at 150° C. for 2 hours using a microwave reaction apparatus (Biotage Ltd.). The reaction solution was concentrated under reduced pressure, and the obtained residue was then purified by NH-silica gel column chromatography (Moritex Corporation, elution solvent: ethyl acetate) to obtain the title compound (0.90 g) as a yellow oil (yield: 56%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]2[C:13]([C:14]([O-:16])=[O:15])=[C:12]([CH3:17])[NH:11][C:10]([CH3:18])=[C:9]2[C:19]([O:21][CH2:22][CH2:23][C:24]#[N:25])=[O:20])[CH:5]=[CH:6][CH:7]=1.[C:26]1([O:32][CH2:33][CH2:34][CH2:35]O)[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.Cl.CN(C)CCCN=C=NCC.O>CN(C)C1C=CN=CC=1.ClCCl>[Cl:1][C:2]1[CH:3]=[C:4]([CH:8]2[C:13]([C:14]([O:16][CH2:35][CH2:34][CH2:33][O:32][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)=[O:15])=[C:12]([CH3:17])[NH:11][C:10]([CH3:18])=[C:9]2[C:19]([O:21][CH2:22][CH2:23][C:24]#[N:25])=[O:20])[CH:5]=[CH:6][CH:7]=1
Reactant: OCCCOc1ccccc1
Reactant: CC1=C(C(=O)[O-])C(c2cccc(Cl)c2)C(C(=O)OCCC#N)=C(C)N1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: O
Solvent: ClCCl
Product: CC1=C(C(=O)OCCC#N)C(c2cccc(Cl)c2)C(C(=O)OCCCOc2ccccc2)=C(C)N1

Procedure:
250 mg (0.69 mmol) of mono(2-cyanoethyl) 4-(3-chlorophenyl)-2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylate, 130 mg (0.85 mmol) of 3-phenyloxypropanol, 162 mg (0.84 mmol) of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride and 21 mg (0.17 mmol) of 4-dimethylaminopyridine were stirred together in 10 ml of dichloromethane at room temperature overnight. Water was added to the reaction liquid. After the extraction with dichloromethane, the organic layer was dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by the silica gel chromatography (hexane/ethyl acetate=2/1) to obtain the title compound.
Reaction SMILES: Cl.[NH2:2][C:3]1[CH:4]=[CH:5][C:6]([OH:12])=[C:7]([CH:11]=1)[C:8]([OH:10])=[O:9].[CH3:13]O>>[NH2:2][C:3]1[CH:4]=[CH:5][C:6]([OH:12])=[C:7]([CH:11]=1)[C:8]([O:10][CH3:13])=[O:9]
Reactant: CO
Reactant: Nc1ccc(O)c(C(=O)O)c1
Agent: Cl
Product: COC(=O)c1cc(N)ccc1O
Temperature: 25 °C
Reaction time: 16 h
Yield: 78.5 %

Procedure:
To a solution of saturated HCl in CH3OH (20 mL) at RT was slowly added 5-amino-2-hydroxybenzoic acid (2 g, 13.06 mmol). The resulting mixture was stirred at (RT, 16 h) and then heated (reflux, 24 h). The mixture was cooled and the solvent was removed under reduced pressure. The residue was diluted with EtOAc (50 mL) and washed with saturated aqueous NaHCO3. The organic solution was dried over MgSO4, filtered, concentrated under reduced pressure to afford methyl 5-amino-2-hydroxybenzoate as a pale yellow solid (1.72 g, 78.5%). Mass calculated for C8H9NO3=167.16. found: [M+H]+=168.2.
Reaction SMILES: [CH2:1]([CH:3]([O:6][C:7]1[N:12]=[C:11]([CH3:13])[N:10]=[C:9]([NH:14][C:15]2[C:20]([CH3:21])=[CH:19][C:18]([CH3:22])=[CH:17][C:16]=2[CH3:23])[C:8]=1[NH2:24])[CH2:4][CH3:5])[CH3:2].C(N(CC)CC)C.Cl[C:33](Cl)([O:35]C(=O)OC(Cl)(Cl)Cl)Cl>C1COCC1>[CH2:1]([CH:3]([O:6][C:7]1[N:12]=[C:11]([CH3:13])[N:10]=[C:9]2[C:8]=1[NH:24][C:33](=[O:35])[N:14]2[C:15]1[C:20]([CH3:21])=[CH:19][C:18]([CH3:22])=[CH:17][C:16]=1[CH3:23])[CH2:4][CH3:5])[CH3:2]
Reactant: CCC(CC)Oc1nc(C)nc(Nc2c(C)cc(C)cc2C)c1N
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCC(CC)Oc1nc(C)nc2c1[nH]c(=O)n2-c1c(C)cc(C)cc1C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 254.8 %

Procedure:
A mixture of 6-(1-ethyl-propoxy)-2-methyl-N4-(2,4,6-trimethyl-phenyl)-pyrimidine-4,5-diamine (182 mg, 0.554 mmol), triethylamine (39 mg, 0.388 mmol) and triphosgene (58 mg, 0.196 mmol) in 6 ml of dry THF was stirred at room temperature for 30 min. The mixture was quenched with water and extracted with chloroform. The organic layer was dried and concentrated to give 177 mg (90%) of the title compound as a white solid, mp 159–160° C. 1H NMR(CDCl3) δ 8.50(s,1H), 6.99(s,2H), 5.30(m,1H), 2.47(s,3H), 2.32(s,3H), 2.08(s,6H), 1.73(m,4H), 0.94(t,6H) ppm.
Reaction SMILES: [CH2:1]([N:5]1[C:9](=[O:10])[N:8]([CH2:11][CH:12]2[O:14][CH2:13]2)[N:7]([CH2:15][CH:16]2[O:18][CH2:17]2)[C:6]1=[O:19])[CH:2]1[O:4][CH2:3]1.[OH2:20]>>[OH:20][CH:17]([OH:18])[CH2:16][CH2:15][N:7]1[C:6](=[O:19])[N:5]([CH2:1][CH:2]2[O:4][CH2:3]2)[C:9](=[O:10])[N:8]1[CH2:11][CH:12]1[O:14][CH2:13]1
Reactant: O=c1n(CC2CO2)c(=O)n(CC2CO2)n1CC1CO1
Reactant: O
Product: O=c1n(CC2CO2)c(=O)n(CC2CO2)n1CCC(O)O

Procedure:
5 g of triglycidyl urazole (0.019 mole) are stirred for 3 hours at 70° C. in 50 ml of water. The solution is concentrated in a rotary evaporator and dried in a high vacuum. The colourless, oily crude product (5.8 g) is purified by column chromatography.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([OH:8])[CH:5]=[CH:6][CH:7]=1.CS(C)=O.[OH-].[Na+].Cl[CH2:16][CH2:17][CH2:18][Si:19]([O:24][CH3:25])([O:22][CH3:23])[O:20][CH3:21]>C1(C)C=CC=CC=1>[NH2:1][C:2]1[CH:3]=[C:4]([CH:5]=[CH:6][CH:7]=1)[O:8][CH2:16][CH2:17][CH2:18][Si:19]([O:24][CH3:25])([O:22][CH3:23])[O:20][CH3:21]
Reactant: CO[Si](CCCCl)(OC)OC
Reactant: Nc1cccc(O)c1
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Solvent: CS(C)=O
Product: CO[Si](CCCOc1cccc(N)c1)(OC)OC
Yield: 85 %

Procedure:
Using the general procedure described in the preceding Example 1, a reactor was charged with 300 g (2.75 mole) m-aminophenol, 560 cc dimethylsulfoxide, 600 cc toluene and 216 cc of a 50% aqueous solution of sodium hydroxide (2.70 moles NaOH). The water present in the reactor was removed by azeotropic distillation under a nitrogen atmosphere at a temperature of 120° C. The temperature of the reaction mixture was then lowered to 90° C. and maintained at about this value during the gradual addition of 545 g (2.75 mole) of 3-chloropropyl trimethoxysilane. Following completion of the addition, which required 2 hours, the reaction mixture was heated at the boiling point for 16 hours. The product was recovered and fractionally distilled as described in the preceding example. The fraction boiling from 178° to 180° C. at a pressure of 3 mm of mercury was collected and weighed 630 g (85% yield). The infrared and nuclear magnetic resonance spectra of the distillate confirm the proposed structure ##STR16## A vapor phase chromatogram of the product indicated a purity of greater than 98%.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[CH:4][C:3]=1[O:11][C:12]([F:15])([F:14])[F:13].[NH2:16][CH:17]1[CH2:22][CH2:21][N:20]([CH3:23])[CH2:19][CH2:18]1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[NH2:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH:16][CH:17]2[CH2:22][CH2:21][N:20]([CH3:23])[CH2:19][CH2:18]2)=[O:8])=[CH:4][C:3]=1[O:11][C:12]([F:15])([F:14])[F:13]
Reactant: Nc1ccc(C(=O)O)cc1OC(F)(F)F
Reactant: CN1CCC(N)CC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CN1CCC(NC(=O)c2ccc(N)c(OC(F)(F)F)c2)CC1
Temperature: 25 °C
Yield: 77.6 %

Procedure:
To a solution of 4-amino-3-(trifluoromethoxy)benzoic acid (Maybridge; 1.05 g, 4.75 mmol) in DMF (20 ml) was added 4-amino-1-methylpiperidine (Fluorochem; 604 mg, 5.29 mmol) followed by DIPEA (1.6 ml, 9.19 mmol) and HATU (2.06 g, 5.42 mmol). The reaction mixture was stirred at ambient temperature O/N. The reaction mixture was evaporated to dryness and the residue partitioned between DCM (75 mL) and saturated aqueous sodium bicarbonate solution (75 mL). The aqueous phase was re-extraced with DCM (50 ml) and the combined organic phases washed with brine, dried over magnesium sulphate, filtered and evaporated to give the title compound as an amber gum (1.17 g, 78%)
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:10]([CH2:23][CH:24]2[CH2:29][CH2:28][O:27][CH2:26][CH2:25]2)[C:11](=O)[CH2:12][CH2:13][C:14]([C:16]2[CH:21]=[N:20][CH:19]=[CH:18][N:17]=2)=O)[CH:5]=[CH:6][C:7]=1[S:8][CH3:9].C([O-])(=O)C.[NH4+:34].C(=O)([O-])O.[Na+]>C(O)(=O)C.C(OCC)(=O)C>[F:1][C:2]1[CH:3]=[C:4]([CH:10]([C:11]2[NH:34][C:14]([C:16]3[CH:21]=[N:20][CH:19]=[CH:18][N:17]=3)=[CH:13][CH:12]=2)[CH2:23][CH:24]2[CH2:29][CH2:28][O:27][CH2:26][CH2:25]2)[CH:5]=[CH:6][C:7]=1[S:8][CH3:9]
Reactant: CSc1ccc(C(CC2CCOCC2)C(=O)CCC(=O)c2cnccn2)cc1F
Reactant: [NH4+]
Agent: CC(=O)[O-]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: CSc1ccc(C(CC2CCOCC2)c2ccc(-c3cnccn3)[nH]2)cc1F
Temperature: 110 °C
Reaction time: 2.5 h
Yield: 87.8 %

Procedure:
To a solution of 5-[3-fluoro-4-(methylsulfanyl)phenyl]-1-(pyrazin-2-yl)-6-(tetrahydro-2H-pyran-4-yl)hexane-1,4-dione (438 mg) in acetic acid (5 mL) was added ammonium acetate (1.29 g), and the mixture was stirred at 110° C. for 2.5 hr. After cooling to room temperature, the mixture was neutralized with saturated aqueous sodium hydrogen carbonate solution. The reaction mixture was diluted with ethyl acetate and washed with water. The ethyl acetate layer was dried (MgSO4) and concentrated. The residue was subjected to silica gel column chromatography, and the title compound (367 mg, yield 88%) was obtained as a colorless amorphous solid from a fraction eluted with ethyl acetate-hexane (1:1, volume ratio). MS: 398 (MH+).
Reaction SMILES: ClC1C=CC=C(C(OO)=[O:9])C=1.[CH3:12][C:13]1([CH3:32])[CH:18]=[C:17]([C:19]2[CH:24]=[C:23]([CH3:25])[CH:22]=[CH:21][N:20]=2)[C:16]2[CH:26]=[C:27]([C:30]#[N:31])[CH:28]=[CH:29][C:15]=2[O:14]1>ClCCl>[C:30]([C:27]1[CH:28]=[CH:29][C:15]2[O:14][C:13]([CH3:32])([CH3:12])[CH:18]=[C:17]([C:19]3[CH:24]=[C:23]([CH3:25])[CH:22]=[CH:21][N+:20]=3[O-:9])[C:16]=2[CH:26]=1)#[N:31]
Reactant: Cc1ccnc(C2=CC(C)(C)Oc3ccc(C#N)cc32)c1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: Cc1cc[n+]([O-])c(C2=CC(C)(C)Oc3ccc(C#N)cc32)c1
Reaction time: 1 h
Yield: 24 %

Procedure:
406 mg of m-chloroperbenzoic acid were added to a solution of 552 mg of 2,2-dimethyl-4-(4-methyl-2-pyridyl)-2H-1-benzopyran-6-carbonitrile in 20 ml of dichloromethane and the mixture was stirred for 1 hour. Subsequently, the mixture was washed with sodium bicarbonate solution, dried over sodium sulphate and evaporated. The residue was chromatographed on silica gel using methanol/ethyl acetate (1:4) for the elution. After recrystallization from ethyl acetate there were obtained 140 mg of 2-(6-cyano-2,2-dimethyl-2H-1-benzopyran-4-yl)-4-methylpyridine N-oxide of melting point 199°-201° C.
Reaction SMILES: [C:1]1([NH:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl:13][S:14](O)(=[O:16])=[O:15]>>[CH2:11]([O:10][C:8](=[O:9])[NH:7][C:1]1[CH:6]=[CH:5][C:4]([S:14]([Cl:13])(=[O:16])=[O:15])=[CH:3][CH:2]=1)[CH3:12]
Reactant: CCOC(=O)Nc1ccccc1
Reactant: O=S(=O)(O)Cl
Product: CCOC(=O)Nc1ccc(S(=O)(=O)Cl)cc1
Temperature: 60 °C

Procedure:
To a stirred solution of chlorosulfonic acid (20 ml) at 0° C., was added N-phenylurethane (9.90 g) at such a rate that the temperature did not exceed 20° C. The reaction was then heated at 60° C. for 3 hours, cooled to ambient temperature and poured carefully onto ice. The resultant precipitate was collected by filtration and dried in vacuo to give (4-chlorosulfonyl-phenyl)-carbamic acid ethyl ester (140.50 g) as an off-white solid. LC-MS (METHOD B): RT=3.11 minutes, 284.23 (M+H)+.