Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][CH2:2][C:3]1([S:6]([NH:9]C(=O)OC(C)(C)C)(=[O:8])=[O:7])[CH2:5][CH2:4]1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[F:1][CH2:2][C:3]1([S:6]([NH2:9])(=[O:8])=[O:7])[CH2:5][CH2:4]1
Reactant: CC(C)(C)OC(=O)NS(=O)(=O)C1(CF)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: NS(=O)(=O)C1(CF)CC1
Reaction time: 2 h
Yield: 101.2 %

Procedure:
To a solution of tert-butyl (1-(fluoromethyl)cyclopropyl)sulfonylcarbamate (19.8 g, 38.7 mmol) in DCM (100 ml) was added TFA (30 ml, 387 mmol) drop wise at room temperature. The reaction mass was stirred for 2 hr. The reaction mass was evaporated under reduced pressure to get desired compound (6 g, 100%) as off white solid. 1H NMR (400 MHz, CDCl3): δ ppm 4.78-4.66 (d, J=48 Hz, 2H), 2.61 (br, s, 1H), 1.59-1.56 (m, 2H), 1.13-1.10 (m, 2H).
Reaction SMILES: [ClH:1].Cl.OC1([C:10]2(O)[CH:15]=[CH:14][CH:13]=[CH:12][C:11]2([CH2:21][CH2:22][N:23]2[CH2:28][CH2:27][N:26]([CH3:29])[CH2:25][CH2:24]2)[O:16]C(F)(F)F)CCCCC1.Cl.Cl.OC1(C([C:48]2[CH:53]=[CH:52][C:51]([OH:54])=[C:50]([O:55][C:56]([F:59])([F:58])[F:57])[CH:49]=2)CN2CCNCC2)CCCCC1>>[ClH:1].[ClH:1].[OH:16][C:11]1([CH:21]([C:48]2[CH:53]=[CH:52][C:51]([OH:54])=[C:50]([O:55][C:56]([F:57])([F:59])[F:58])[CH:49]=2)[CH2:22][N:23]2[CH2:24][CH2:25][N:26]([CH3:29])[CH2:27][CH2:28]2)[CH2:10][CH2:15][CH2:14][CH2:13][CH2:12]1
Reactant: CN1CCN(CCC2(OC(F)(F)F)C=CC=CC2(O)C2(O)CCCCC2)CC1
Reactant: Oc1ccc(C(CN2CCNCC2)C2(O)CCCCC2)cc1OC(F)(F)F
Agent: Cl
Product: CN1CCN(CC(c2ccc(O)c(OC(F)(F)F)c2)C2(O)CCCCC2)CC1

Procedure:
In an analogous manner to Example 24, 4-[1-(1-hydroxycyclohexyl)-2-(4-methylpiperazin-1-ylethyl]-2-(trifluoromethoxy)phenol dihydrochloride was prepared from 4-[1-(1-hydroxycyclohexyl)-2-piperazin-1-ylethyl]-2-(trifluoromethoxy)phenol dihydrochloride (see Example 400). MS (ESI) m/z 403; HRMS: calcd for C20H29F3N2O3+H+, 403.22030. found (ESI, [M+H]+), 403.2201.
Reaction SMILES: [C:1]([C:4]1[CH:14]=[CH:13][C:7]([O:8][CH2:9][CH2:10][CH2:11][Br:12])=[C:6]([CH2:15][CH2:16][CH3:17])[C:5]=1[OH:18])(=[O:3])[CH3:2].[C:19]1([P:25]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.CCOCC>C1(C)C=CC=CC=1>[Br-:12].[C:1]([C:4]1[CH:14]=[CH:13][C:7]([O:8][CH2:9][CH2:10][CH2:11][P+:25]([C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)=[C:6]([CH2:15][CH2:16][CH3:17])[C:5]=1[OH:18])(=[O:3])[CH3:2]
Reactant: CCCc1c(OCCCBr)ccc(C(C)=O)c1O
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOCC
Solvent: Cc1ccccc1
Product: CCCc1c(OCCC[P+](c2ccccc2)(c2ccccc2)c2ccccc2)ccc(C(C)=O)c1O
Product: [Br-]
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 27 g of 3-(4-acetyl-3-hydroxy-2-propylphenoxy)-propyl bromide in 50 ml of toluene is heated at reflux with 21.85 g of triphenylphosphine for 20 hours. The resulting suspension is cooled to room temperature; 200 ml of ether are added and the mixture is stirred for 1 hour. The colourless precipitate is filtered off with suction, washed with ether and dried. The title compound has a melting point of 211°-212°.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([O:10][C:11]3[N:19]=[CH:18][CH:17]=[CH:16][C:12]=3[C:13]([OH:15])=O)=[CH:9][C:4]=2[O:3][CH2:2]1.[NH2:20][CH2:21][C@H:22]1[CH2:27][CH2:26][C@H:25]([CH:28]([OH:30])[CH3:29])[CH2:24][CH2:23]1>>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([O:10][C:11]3[N:19]=[CH:18][CH:17]=[CH:16][C:12]=3[C:13]([NH:20][CH2:21][CH:22]3[CH2:27][CH2:26][CH:25]([CH:28]([OH:30])[CH3:29])[CH2:24][CH2:23]3)=[O:15])=[CH:9][C:4]=2[O:3][CH2:2]1
Reactant: CC(O)[C@H]1CC[C@H](CN)CC1
Reactant: O=C(O)c1cccnc1Oc1ccc2c(c1)OCO2
Product: CC(O)C1CCC(CNC(=O)c2cccnc2Oc2ccc3c(c2)OCO3)CC1

Procedure:
Prepared from 2-(Benzo[1,3]dioxol-5-yloxy)-nicotinic acid and (+)-trans-1-(4-Aminomethyl-cyclohexyl)-ethanol. 1HNMR (CDCl3) δ0.97 (1,m), 1.10 (3, m), 1.17 (4, m), 1.19 (4,m), 3.23 (1,t), 3.44(2,q), 6.00(2,s), 6.58 (1, dd), 6.64 (1,s), 6.8 (1, d), 7.10 (1,m), 7.9 (1,m), 8.18 (1,m), 8.53 (1, d); MS: m/e 399 (M++1).
Reaction SMILES: [C:1]([C:3]1[CH:26]=[CH:25][C:6]([O:7][C@H:8]2[CH2:13][CH2:12][C@H:11]([C:14]([N:16]3[CH2:21][CH2:20][N:19]([CH:22]([CH3:24])[CH3:23])[CH2:18][CH2:17]3)=[O:15])[CH2:10][CH2:9]2)=[CH:5][CH:4]=1)#[N:2].Cl.[NH2:28][OH:29].C(N(CC)CC)C>C(O)C>[OH:29][NH:28][C:1](=[NH:2])[C:3]1[CH:4]=[CH:5][C:6]([O:7][C@H:8]2[CH2:13][CH2:12][C@H:11]([C:14]([N:16]3[CH2:17][CH2:18][N:19]([CH:22]([CH3:23])[CH3:24])[CH2:20][CH2:21]3)=[O:15])[CH2:10][CH2:9]2)=[CH:25][CH:26]=1
Reactant: NO
Reactant: CC(C)N1CCN(C(=O)[C@H]2CC[C@H](Oc3ccc(C#N)cc3)CC2)CC1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCO
Product: CC(C)N1CCN(C(=O)[C@H]2CC[C@H](Oc3ccc(C(=N)NO)cc3)CC2)CC1

Procedure:
A mixture of 0.15 g (0.42 mmol) of trans-[4-(4-cyano-phenoxy)-cyclohexyl]-(4-isopropyl-piperazin-1-yl)-methanone, 0.118 g (1.69 mmol) of hydroxylamine hydrochloride, 0.24 ml (1.73 mmol) of triethylamine in 3 ml ethanol was refluxed for 1 hr. The mixture was evaporated to dryness to yield 0.34 g (84% yields, about 40% purity) of the titled compound. MS (m/e): 389.3 (MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:10][N:9]2[S:11]([C:14]2[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][CH:15]=2)(=[O:13])=[O:12])=[CH:4][CH:3]=1.[CH3:23][OH:24]>ClCCl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([O:24][CH3:23])[CH2:10][NH:9][S:11]([C:14]2[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][CH:15]=2)(=[O:13])=[O:12])=[CH:4][CH:3]=1
Reactant: CO
Reactant: O=[N+]([O-])c1ccc(S(=O)(=O)N2CC2c2ccc(Cl)cc2)cc1
Solvent: ClCCl
Product: COC(CNS(=O)(=O)c1ccc([N+](=O)[O-])cc1)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 120 h
Yield: 76.5 %

Procedure:
2-(4-Chlorophenyl)-1-(4-nitrophenylsulfonyl)aziridine (0.276 g, 0.815 mmol) was dissolved in 8 ml of methanol and 4 ml of dichloromethane. The reaction was stirred at ambient temperature for 5 days, and then concentrated. The crude material was on a Biotage SP1 system eluting with a 5-50% linear gradient of EtOAc in hexanes to yield 231 mg of the title compound (76.5% yield).
Reaction SMILES: [CH:1]([C:5]1[N:6]([CH2:13][C:14]2[CH:19]=[CH:18][C:17]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[C:26]([O:28][CH3:29])=[O:27])=[CH:16][CH:15]=2)[C:7]([CH2:11][OH:12])=[C:8]([Cl:10])[N:9]=1)=[CH:2][CH2:3][CH3:4].[Si:30](Cl)([C:33]([CH3:36])([CH3:35])[CH3:34])([CH3:32])[CH3:31].N1C=CN=C1>CN(C=O)C>[CH:1]([C:5]1[N:6]([CH2:13][C:14]2[CH:19]=[CH:18][C:17]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[C:26]([O:28][CH3:29])=[O:27])=[CH:16][CH:15]=2)[C:7]([CH2:11][O:12][Si:30]([C:33]([CH3:36])([CH3:35])[CH3:34])([CH3:32])[CH3:31])=[C:8]([Cl:10])[N:9]=1)=[CH:2][CH2:3][CH3:4]
Reactant: CCC=Cc1nc(Cl)c(CO)n1Cc1ccc(-c2ccccc2C(=O)OC)cc1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CCC=Cc1nc(Cl)c(CO[Si](C)(C)C(C)(C)C)n1Cc1ccc(-c2ccccc2C(=O)OC)cc1
Yield: 83.8 %

Procedure:
2-(But-1-en-1-yl)-1-[(2'-carbomethoxybiphenyl-4-yl)methyl]-4-chloro-5-(hydroxymethyl)-imidazole (1.4 g), t-butyldimethylsilyl chloride (0.55 g), and imidazole (0.5 g) were mixed and stirred in DMF (5 mL) for 18 hours at room temperature. Dilution with ethyl acetate and washing the organic phase with water followed by drying (MgSO4), evaporation of the solvent in vacuo, and flash chromatography in 3:1 hexane/ethyl acetate yielded 1.5 g of a clear oil. NMR (200 MHz, CDCl3) δ 7.83 (d, 1H); 7.52 (t, 1H); 7.40 (t, 1H); 7.33-7.24 (m, 3H); 7.08 (d, 2H); 6.83 (d of t, 1H); 6.13 (d, 1H); 5.30 (s, 2H); 4.57 (s, 2H); 3.64 (s, 3H); 2.21 (quint. 2H); 1.04 (t, 3H); 0.86 (s, 9H); 0.05 (s, 6H).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][CH:11]=1)[CH:7]=O)([O-:3])=[O:2].[C:12]([O:18][CH2:19][CH2:20][N:21]1[CH2:26][CH2:25][N:24]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=2[O:33][CH3:34])[CH2:23][CH2:22]1)(=[O:17])[CH2:13][C:14]([CH3:16])=O.[NH2:35]/[C:36](/[CH3:42])=[CH:37]\[C:38]([O:40][CH3:41])=[O:39]>C(O)(C)C>[CH3:16][C:14]1[NH:35][C:36]([CH3:42])=[C:37]([C:38]([O:40][CH3:41])=[O:39])[CH:7]([C:6]2[CH:9]=[CH:10][CH:11]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=2)[C:13]=1[C:12]([O:18][CH2:19][CH2:20][N:21]1[CH2:26][CH2:25][N:24]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=2[O:33][CH3:34])[CH2:23][CH2:22]1)=[O:17]
Reactant: COC(=O)/C=C(/C)N
Reactant: COc1ccccc1N1CCN(CCOC(=O)CC(C)=O)CC1
Reactant: O=Cc1cccc([N+](=O)[O-])c1
Solvent: CC(C)O
Product: COC(=O)C1=C(C)NC(C)=C(C(=O)OCCN2CCN(c3ccccc3OC)CC2)C1c1cccc([N+](=O)[O-])c1
Yield: 55.6 %

Procedure:
A mixture of m-nitrobenzaldehyde, 2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl acetoacetate and methyl 3-aminocrotonate was worked up in isopropyl alcohol in the same manner as Example 1 to give 2-[4-(2-methoxyphenyl)-1-piperazinyl]-ethyl methyl 2,6-dimethyl-4-(3-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylate as a light yellow powder, m.p. 58° C. (sintering). Yield 55.6%. NMR(CDCl3) δ: 2.34(6H,s, ##STR32## 3.63(3H,s,OCH3), 3.83(3H,s,OCH3), 4.21(2H,t,J=6, --COOCH2CH2 --), 5.14(1H,s,C(4) --H), 6.60(1H,s,NH).
Reaction SMILES: Br[C:2]1[S:3][CH:4]=[CH:5][CH:6]=1.[F:7][C:8]1[CH:13]=[CH:12][C:11](B(O)O)=[CH:10][CH:9]=1.C([O-])([O-])=O.[Na+].[Na+].C(Cl)Cl>COCCOC.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[F:7][C:8]1[CH:13]=[CH:12][C:11]([C:2]2[S:3][CH:4]=[CH:5][CH:6]=2)=[CH:10][CH:9]=1
Reactant: OB(O)c1ccc(F)cc1
Reactant: Brc1cccs1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: COCCOC
Product: Fc1ccc(-c2cccs2)cc1
Temperature: 80 °C
Yield: 95 %

Procedure:
To a solution of 2-bromothiophene (1.0 g, 6.14 mmol) in 1,2-dimethoxyethane (11 mL) was added 4-fluorophenylboronic acid (1.12 g, 7.99 mmol), followed by Pd(PPh3)4 (360 mg, 0.31 mmol) and a 2M Na2CO3 aq. solution (8 mL). The reaction mixture was heated at 80° C. for 4 h, then was poured onto a mixture of ice and CH2Cl2. The aqueous layer was extracted with CH2Cl2 (3×20 mL). The organic layers were dried (MgSO4) and concentrated under reduced pressure to yield a yellow oil. The crude product was filtered through a plug of silica with the aid of hexanes to give 4-fluorophenylthiphene (1.04 g, 95%). TLC (hex) Rf=0.40.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([CH2:7][C:8]2[CH:16]=[CH:15][C:11]([C:12]([OH:14])=[O:13])=[CH:10][CH:9]=2)[CH2:3][CH2:2]1.O[C:18]1[CH:23]=[CH:22][C:21]([C:24](=[O:40])[CH:25]([N:27]2[CH2:32][CH2:31][C:30]([OH:39])([C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)[CH2:29][CH2:28]2)[CH3:26])=[CH:20][CH:19]=1.Cl.C(N=C=NCCCN(C)C)C>C(Cl)Cl.CN(C)C1C=CN=CC=1>[OH:39][C:30]1([C:33]2[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=2)[CH2:31][CH2:32][N:27]([CH:25]([CH3:26])[C:24]([C:21]2[CH:20]=[CH:19][C:18]([O:13][C:12](=[O:14])[C:11]3[CH:15]=[CH:16][C:8]([CH2:7][N:4]4[CH2:3][CH2:2][O:1][CH2:6][CH2:5]4)=[CH:9][CH:10]=3)=[CH:23][CH:22]=2)=[O:40])[CH2:28][CH2:29]1
Reactant: CC(C(=O)c1ccc(O)cc1)N1CCC(O)(c2ccccc2)CC1
Reactant: O=C(O)c1ccc(CN2CCOCC2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: CC(C(=O)c1ccc(OC(=O)c2ccc(CN3CCOCC3)cc2)cc1)N1CCC(O)(c2ccccc2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 79.6 %

Procedure:
To a mixture of 4-(morpholinomethyl)benzoic acid (3.17 g, 12.3 mmol), 1-(4-hydroxyphenyl)-2-(4-hydroxy-4-phenylpiperidino)-1-propanone (4.0 g, 12.29 mmol), and 1-ethyl-3-(3-dimethylaminopropyl)-carbodiimide hydrochloride (2.36 g, 12.31 mmol) in methylene chloride (75 mL) was added 4-dimethylaminopyridine (1.88 g, 15.39 mmol). The heterogeneous mixture was allowed to stir overnight under a nitrogen atmosphere at ambient temperature. The mixture was washed with saturated aqueous bicarbonate (2×50 mL), dried by filtration through phase separating filter paper, and concentrated to a glassy yellow solid. Trituration with ether and hexane yielded 5.17 g, 80% of a light yellow solid product which was suitable for further reaction without additional purification. A sample recrystallized from ethyl acetate/hexane had: m.p. 126°-126.5° C.; NMR (CDCl3) 8.22 (d, J=8.6 Hz, 2H), 8.13 (d, J=7.8 Hz, 2H), 7.47 (t, J=7.3 Hz, 4H), 7.34-7.19 (m, 5H), 4.13 (q, J=6.6 Hz, 1H), 3.70 (t, J=4.4 Hz, 4H), 3.57 (s, 2H), 2.97-2.79 (m, 2H), 2.67-2.60 (m, 2H), 2.44 (t, J=4.5 Hz, 4H), 2.18-1.98 (m, 2H), 1.78-1.67 (m, 3H), 1.31 (d, J=6.6 Hz, 3H). IR (KBr) 3270, 2960, 2942, 2912, 2830, 2821, 1743, 1682, 1596, 1390, 1273, 1199.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([NH:10][C:11]([CH:13]2[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15][CH2:14]2)=O)=S)=[CH:4][CH:3]=1.[NH:26]([C:28]1[N:33]=[CH:32][CH:31]=[CH:30][N:29]=1)[NH2:27].C([O-])(=O)C.[Na+]>O1CCOCC1.C(O)(=O)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:10]=[C:11]([CH:13]3[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15][CH2:14]3)[N:26]([C:28]3[N:33]=[CH:32][CH:31]=[CH:30][N:29]=3)[N:27]=2)=[CH:4][CH:3]=1
Reactant: NNc1ncccn1
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)NC(=S)c2ccc(F)cc2)CC1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)N1CCC(c2nc(-c3ccc(F)cc3)nn2-c2ncccn2)CC1
Temperature: 80 °C

Procedure:
tert-Butyl 4-{[(4-fluorophenyl)carbonothioyl]-carbamoyl}piperidine-1-carboxylate (0.37 g, 1.01 mmol) was mixed with 2-hydrazinylprimidine (0.13 g, 1.21 mmol) and sodium acetate (0.099 g, 1.21 mmol) in 3 ml of 1,4-dioxane and acetic acid (1:1). After heating at 80° C. for 45 min, the solvents were removed under vacuum. The resulting residue was re-dissolved in dichloromethane and washed with saturated sodium bicarbonate solution and water. The organic layers were concentrated, and the residue was purified by column chromatography using a gradient of 0˜50% ethyl acetate in hexanes. LC-MS (m/z): 369.10 [M−56+H]+, 447.14 [M+Na+H]+. 1HNMR (CDCl3, 500 MHz): δ 8.92 (d, J=4.8 Hz, 2H), 8.25-8.28 (m, 2H), 7.38 (t, J=4.8 Hz, 1H), 7.15 (t, J=8.7 Hz, 2H), 4.24-4.27 (br, 2H), 3.94-4.00 (m, 2H), 2.91-2.96 (br, 2H), 2.00-2.10 (br, 4H), 1.52 (s, 9H).
Reaction SMILES: [K].[C:2]1([C:8]2[CH:16]=[C:12]3[CH:13]=[CH:14][CH:15]=[C:11]3[O:10][C:9]=2[CH2:17][C:18]([OH:20])=[O:19])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:21]([O:24][CH2:25]Cl)(=[O:23])[CH3:22]>CN(C)C=O>[C:2]1([C:8]2[CH:16]=[C:12]3[CH:13]=[CH:14][CH:15]=[C:11]3[O:10][C:9]=2[CH2:17][C:18]([O:20][CH2:25][O:24][C:21](=[O:23])[CH3:22])=[O:19])[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)Cc1oc2cccc-2cc1-c1ccccc1
Reactant: CC(=O)OCCl
Agent: [K]
Solvent: CN(C)C=O
Product: CC(=O)OCOC(=O)Cc1oc2cccc-2cc1-c1ccccc1

Procedure:
The potassium salt of 3-phenyl-7-benzofuranacetic acid is reacted with chloromethyl acetate in dimethylformamide to provide acetoxymethyl 3-phenyl-7-benzofuranacetate.
Reaction SMILES: Cl([O-])=O.[Na+].[OH:5][C:6]1[CH:7]=[C:8]([CH:11]=[C:12]([N+:15]([O-:17])=[O:16])[C:13]=1[OH:14])[CH:9]=[O:10].P([O-])(O)(O)=[O:19].[Na+].C([O-])(O)=O.[Na+]>O.CS(C)=O.O>[OH:5][C:6]1[CH:7]=[C:8]([CH:11]=[C:12]([N+:15]([O-:17])=[O:16])[C:13]=1[OH:14])[C:9]([OH:19])=[O:10]
Reactant: O=Cc1cc(O)c(O)c([N+](=O)[O-])c1
Reactant: O=P([O-])(O)O
Agent: O=C([O-])O
Agent: [Na+]
Agent: [O-][Cl+][O-]
Solvent: CS(C)=O
Solvent: O
Product: O=C(O)c1cc(O)c(O)c([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 93.9 %

Procedure:
A solution of sodium chlorite (47.6 g, 526 mmol) in water (350 mL) was added dropwise to a solution of 3,4-dihydroxy-5-nitrobenzaldehyde (68.8 g, 376 mmol) and sodium dihydrogen phosphate (45.1 g, 376 mmol) in DMSO/H2O mixture (375 mL/150 mL) at room temperature for 1.5 hours. The reaction mixture was stirred at room temperature for 1 hour and poured into a separatory funnel containing a 5% solution NaHCO3 (500 mL). The product was extracted with dichloromethane (3×100 mL). The water layer was acidified with concentrated HCl to pH˜1 and extracted with ether (3×250 mL). The combined organic layers were washed with brine (200 mL), dried over Na2SO4, and evaporated to afford 3,4-dihydroxy-5-nitrobenzoic acid (70.3 g, 353 mmol, 94% yield).
Reaction SMILES: C[O:2][C:3](=[O:29])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([O:10][C:11]2[CH:16]=[CH:15][CH:14]=[C:13](/[CH:17]=[CH:18]/[CH:19]([OH:28])[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])[N:12]=2)[CH:5]=1.[OH-].[Na+]>CO>[OH:28][CH:19]([CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])/[CH:18]=[CH:17]/[C:13]1[N:12]=[C:11]([O:10][C:6]2[CH:5]=[C:4]([CH:9]=[CH:8][CH:7]=2)[C:3]([OH:29])=[O:2])[CH:16]=[CH:15][CH:14]=1
Reactant: CCCCCCCCC(O)/C=C/c1cccc(Oc2cccc(C(=O)OC)c2)n1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCCCCCCCC(O)/C=C/c1cccc(Oc2cccc(C(=O)O)c2)n1
Yield: 75.2 %

Procedure:
Under the conditions of example 2, 40 mg of 3-{6-[(1E)-(3RS)-3-hydroxy-1-undecenyl]-2-pyridyloxy}-benzoic acid methyl ester in 1 ml of methanol is saponified with 1 ml of 1 n sodium hydroxide solution and worked up. 29 mg of the title compound of melting point 85°-87° C. is obtained.
Reaction SMILES: [H-].[Na+].[CH2:3]([O:5][C:6](=[O:22])[CH:7]([CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])[N:8]1[CH:12]=[C:11]([C:13]([OH:15])=O)[N:10]=[CH:9]1)[CH3:4].C(Cl)(=O)C(Cl)=O.N[C:30]1[C:42]2[CH2:41][C:40]3[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=3)[C:34]=2[CH:33]=[CH:32][CH:31]=1.[N:43]1C=CC=CC=1>O1CCCC1.C(OCC)(=O)C>[CH2:3]([O:5][C:6](=[O:22])[CH:7]([CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])[N:8]1[CH:12]=[C:11]([C:13]([NH:43][CH:41]2[C:40]3[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=3[C:34]3[C:42]2=[CH:30][CH:31]=[CH:32][CH:33]=3)=[O:15])[N:10]=[CH:9]1)[CH3:4]
Reactant: c1ccncc1
Reactant: CCCCCCC(C(=O)OCC)n1cnc(C(=O)O)c1
Reactant: Nc1cccc2c1Cc1ccccc1-2
Agent: O=C(Cl)C(=O)Cl
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCCCCCC(C(=O)OCC)n1cnc(C(=O)NC2c3ccccc3-c3ccccc32)c1
Reaction time: 0.17 h

Procedure:
A slurry of 0.062 g of 55% sodium hydride in oil in tetrahydrofuran was added to 0.4 g of 4-carboxy-α-hexyl-1H-imidazole-1-acetic acid ethyl ester. After 10 minutes of stirring, 0.125 ml of oxalyl chloride were added. After stirring for 2 hours at room temperature, 0.31 g of 1-aminofluorene were added followed by 0.16 ml of pyridine. The mixture was stirred at room temperature for 3 hours, taken up in ethyl acetate,, and washed twice with a saturated citric acid solution followed by a water wash. The organic layer was dried over sodium sulfate, filtered, and concentrated in vacuo. Flash chromatography using 1:1 ethyl acetate/hexane and silica gel was performed on the residue and the resulting fractions combined and concentrated in vacuo to provide the desired titled intermediate.
Reaction SMILES: ClC(Cl)(Cl)C([O:6][C:7]([N:9]1[CH:14]2[C:15]([C:36](O)=[O:37])=[C:16]([C:18]3[CH:23]=[CH:22][C:21]([O:24][CH2:25][CH2:26][O:27][C:28]4[CH:33]=[C:32]([F:34])[CH:31]=[CH:30][C:29]=4[Cl:35])=[CH:20][CH:19]=3)[CH2:17][CH:10]1[CH2:11][N:12]([C:39](=[O:41])[CH3:40])[CH2:13]2)=[O:8])(C)C.[CH:44]1([NH:47][CH2:48][C:49]2[CH:54]=[C:53]([O:55][CH3:56])[CH:52]=[CH:51][C:50]=2[F:57])[CH2:46][CH2:45]1>>[CH:7]([OH:8])=[O:6].[CH:44]1([N:47]([CH2:48][C:49]2[CH:54]=[C:53]([O:55][CH3:56])[CH:52]=[CH:51][C:50]=2[F:57])[C:36]([C:15]2[C@@H:14]3[NH:9][C@H:10]([CH2:17][C:16]=2[C:18]2[CH:23]=[CH:22][C:21]([O:24][CH2:25][CH2:26][O:27][C:28]4[CH:33]=[C:32]([F:34])[CH:31]=[CH:30][C:29]=4[Cl:35])=[CH:20][CH:19]=2)[CH2:11][N:12]([C:39](=[O:41])[CH3:40])[CH2:13]3)=[O:37])[CH2:45][CH2:46]1
Reactant: CC(=O)N1CC2CC(c3ccc(OCCOc4cc(F)ccc4Cl)cc3)=C(C(=O)O)C(C1)N2C(=O)OC(C)(C)C(Cl)(Cl)Cl
Reactant: COc1ccc(F)c(CNC2CC2)c1
Product: COc1ccc(F)c(CN(C(=O)C2=C(c3ccc(OCCOc4cc(F)ccc4Cl)cc3)C[C@@H]3CN(C(C)=O)C[C@H]2N3)C2CC2)c1
Product: O=CO

Procedure:
Synthesized according to typical procedures H and E from bicyclononene BN10 and cyclopropyl-(2-fluoro-5-methoxybenzyl)amine. LC-MS: Rt=0.88; ES+: 652.26.
Reaction SMILES: [NH2:1][C:2]([NH2:4])=[NH:3].[Na].Cl.NC(N)=N.[CH3:11][C:12]1[C:13]([C:24]([O:26]C)=O)=[CH:14][C:15]2[S:19](=[O:21])(=[O:20])[CH2:18][C:17](=[CH2:22])[C:16]=2[CH:23]=1.[CH3:28][OH:29]>>[NH2:3][C:2]([NH2:4])=[N:1][C:24]([C:13]1[C:12]([CH3:11])=[CH:23][C:16]2[C:17]([O:29][CH3:28])([CH3:22])[CH2:18][S:19](=[O:20])(=[O:21])[C:15]=2[CH:14]=1)=[O:26]
Reactant: C=C1CS(=O)(=O)c2cc(C(=O)OC)c(C)cc21
Reactant: N=C(N)N
Reactant: CO
Agent: Cl
Agent: [Na]
Product: COC1(C)CS(=O)(=O)c2cc(C(=O)N=C(N)N)c(C)cc21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A guanidine solution prepared--as described in Example 3--from 547 mg of sodium, 12 ml of methanol and 2.5 g of guanidine hydrochloride is treated with 1.2 g of methyl 2,3-dihydro-5-methyl-3-methylene-1-benzothiophene-6-carboxylate-1,1-dioxide [prepared by cyclization of methyl 4-acetyl-2-methyl-5-methylsulfonylbenzoate and subsequent dehydration] and the mixture is boiled for 1 hour, then stirred at room temperature for a further hour and worked up in the customary manner. N-Diaminomethylene-2,3-dihydro-3-methoxy-3,5-dimethyl-1-benzothiophene-6-carboxamide-1,1-dioxide is obtained. Treatment with methanesulfonic acid in methanol gives the corresponding methanesulfonate, m.p. 214-215°.
Reaction SMILES: Cl[C:2]1[CH:17]=[C:6]2[C:7]3[C:12]([CH2:13][CH2:14][N:5]2[C:4](=[O:18])[N:3]=1)=[CH:11][C:10]([O:15][CH3:16])=[CH:9][CH:8]=3.[F:19][C:20]([F:29])([F:28])[C:21]1[CH:27]=[CH:26][CH:25]=[CH:24][C:22]=1[NH2:23]>>[CH3:16][O:15][C:10]1[CH:11]=[C:12]2[C:7](=[CH:8][CH:9]=1)[C:6]1=[CH:17][C:2]([NH:23][C:22]3[CH:24]=[CH:25][CH:26]=[CH:27][C:21]=3[C:20]([F:19])([F:28])[F:29])=[N:3][C:4](=[O:18])[N:5]1[CH2:14][CH2:13]2
Reactant: Nc1ccccc1C(F)(F)F
Reactant: COc1ccc2c(c1)CCn1c-2cc(Cl)nc1=O
Product: COc1ccc2c(c1)CCn1c-2cc(Nc2ccccc2C(F)(F)F)nc1=O

Procedure:
The title compound was prepared from 2-chloro-9-methoxy-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one (4) and 2-trifluoromethyl-aniline as in Example 1 d. 1H-NMR (400 MHz, d6-DMSO) δ 9.10 (br, 1H), 7.90-7.35 (5H), 6.98 (2H), 6.42 (br, 1H), 3.94 (brt, 2H), 3.83 (s, 3H) and 2.95 (t, 2H); MS (ESI) (M+H)+ 388.
Reaction SMILES: [CH3:1][N:2]1[CH2:9][C@@H:8]2[C@@H:4]([N:5]([C:10]3[CH:15]=[CH:14][C:13]([C:16]4[CH:21]=[CH:20][C:19]([N:22]5[C:27](=[O:28])[CH:26]=[CH:25][CH:24]=[N:23]5)=[CH:18][CH:17]=4)=[CH:12][CH:11]=3)[CH2:6][CH2:7]2)[CH2:3]1.[OH:29]O>C(Cl)Cl.CO>[CH3:1][N@+:2]1([O-:29])[CH2:9][C@@H:8]2[C@@H:4]([N:5]([C:10]3[CH:15]=[CH:14][C:13]([C:16]4[CH:21]=[CH:20][C:19]([N:22]5[C:27](=[O:28])[CH:26]=[CH:25][CH:24]=[N:23]5)=[CH:18][CH:17]=4)=[CH:12][CH:11]=3)[CH2:6][CH2:7]2)[CH2:3]1
Reactant: OO
Reactant: CN1C[C@H]2CCN(c3ccc(-c4ccc(-n5ncccc5=O)cc4)cc3)[C@H]2C1
Solvent: ClCCl
Solvent: CO
Product: C[N@+]1([O-])C[C@H]2CCN(c3ccc(-c4ccc(-n5ncccc5=O)cc4)cc3)[C@H]2C1
Temperature: 50 °C

Procedure:
A solution of the product from Example 1G (5 g, 13.44 mmol) in DCM (80 mL) and MeOH (40 mL) was treated with hydrogen peroxide (5.2 mL, 30% in H2O, 53.8 mmol). The mixture was heated to 50° C. for 48 hours. The mixture was concentrated under reduced pressure to a smaller volume while still in a solution. The solution was loaded onto an ANALOGIX SuperFlash silica gel column (ANALOGIX is a registered trademark of Analogix Inc. of Burlington, Wis.) and eluted with NH4OH /MeOH/DCM (1/10/90) to obtain the slower moving component (comparing with Example 1H) as the title product. 1H NMR (300 MHz, DMSO) δ ppm 8.07 (m, 1 H), 7.70 (d, J=9 Hz, 2 H), 7.57 (d, J=9 Hz, 4 H), 7.50 (d, J=6 Hz, 1 H), 7.08 (dd, dd, J=9, 4.0 Hz, 1 H), 6.65 (d, J=9 Hz, 2 H), 4.48-4.54 (m, 1 H), 3.81-3.87 (m, 1 H), 3.66-3.74 (m, 2 H), 3.36-3.42 (m, 2 H), 3.24 (m, 1 H), 3.09 (s, 3 H), 2.11-2.17 (m, 1 H); MS (DCI,) M+=388.