Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([N+:10]([O-:12])=[O:11])=[C:7]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[C:6]=2[CH:19]=1.[Cl:20][CH2:21][C:22](Cl)=[O:23]>C(O)(=O)C>[Cl:20][CH2:21][C:22]([NH:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([N+:10]([O-:12])=[O:11])=[C:7]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[C:6]=2[CH:19]=1)=[O:23]
Reactant: O=C(Cl)CCl
Reactant: Nc1ccc2oc([N+](=O)[O-])c(-c3ccccc3)c2c1
Solvent: CC(=O)O
Product: O=C(CCl)Nc1ccc2oc([N+](=O)[O-])c(-c3ccccc3)c2c1

Procedure:
Using the method of Example 10, 5-amino-2-nitro-3-phenylbenzofuran is reacted with α-chloroacetyl chloride in acetic acid to provide 5-(α-chloroacetamido)-2-nitro-3-phenylbenzofuran.
Reaction SMILES: [CH3:1][CH2:2][C@H:3]1[O:19][C:17](=[O:18])[C@H:16]([CH3:20])[C@@H:15]([O:21][C@@H:22]2[O:27][C@@H:26]([CH3:28])[C@H:25]([OH:29])[C@@:24]([O:31][CH3:32])([CH3:30])[CH2:23]2)[C@H:14]([CH3:33])[C@@H:13]([O:34][C@@H:35]2[O:40][C@H:39]([CH3:41])[CH2:38][C@H:37]([N:42]([CH3:44])[CH3:43])[C@H:36]2[OH:45])[C@@:12]([O:47][CH3:48])([CH3:46])[CH2:11][C@@H:10]([CH3:49])/[C:7](=N\O)/[C@H:6]([CH3:50])[C@@H:5]([OH:51])[C@@:4]1([OH:53])[CH3:52].C(O)C.[OH-:57].[Na+]>O>[CH3:1][CH2:2][C@H:3]1[O:19][C:17](=[O:18])[C@H:16]([CH3:20])[C@@H:15]([O:21][C@@H:22]2[O:27][C@@H:26]([CH3:28])[C@H:25]([OH:29])[C@@:24]([O:31][CH3:32])([CH3:30])[CH2:23]2)[C@H:14]([CH3:33])[C@@H:13]([O:34][C@@H:35]2[O:40][C@H:39]([CH3:41])[CH2:38][C@H:37]([N:42]([CH3:43])[CH3:44])[C@H:36]2[OH:45])[C@@:12]([O:47][CH3:48])([CH3:46])[CH2:11][C@@H:10]([CH3:49])[C:7](=[O:57])[C@H:6]([CH3:50])[C@@H:5]([OH:51])[C@@:4]1([OH:53])[CH3:52]
Reactant: [OH-]
Reactant: CC[C@H]1OC(=O)[C@H](C)[C@@H](O[C@H]2C[C@@](C)(OC)[C@@H](O)[C@H](C)O2)[C@H](C)[C@@H](O[C@@H]2O[C@H](C)C[C@H](N(C)C)[C@H]2O)[C@](C)(OC)C[C@@H](C)/C(=N\O)[C@H](C)[C@@H](O)[C@]1(C)O
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CC[C@H]1OC(=O)[C@H](C)[C@@H](O[C@H]2C[C@@](C)(OC)[C@@H](O)[C@H](C)O2)[C@H](C)[C@@H](O[C@@H]2O[C@H](C)C[C@H](N(C)C)[C@H]2O)[C@](C)(OC)C[C@@H](C)C(=O)[C@H](C)[C@@H](O)[C@]1(C)O
Temperature: 80 °C

Procedure:
In the present method, acid is added to the mixture of protected silylated clarithromycin oxime, ethanol, water and deoximating agent and the mixture is heated at reflux (about 80° C.) Heating is then continued and the suspension is stirred for an amount of time sufficient to finish the reaction. The mixture is then cooled to about 20° C. and sodium hydroxide solution having a concentration of from about 20% to about 47%, preferably 47%, is added at this temperature until the pH of the reaction mixture reaches about 10 to about 11, preferably about 10.2 to about 10.5. Crystalline clarithromycin is then isolated, preferably by filtration, with no further water addition. The obtained clarithromycin may subsequently be further purified and/or isolated and the crystalline form of clarithromycin may be altered to the desired form (such as crystal form 0, I, II, or IV) for use.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[O:11][CH2:10][CH2:9][C:8]([C:12]([O:14][CH3:15])=[O:13])=[CH:7][C:6]=2[CH:16]=1.B([O-])([O-])O[C:19]1[CH:24]=[CH:23][C:22]2[O:25][CH2:26][O:27][C:21]=2[CH:20]=1.C(=O)([O-])[O-].[Na+].[Na+].O>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.COCCOC>[CH2:26]1[O:27][C:21]2[CH:20]=[CH:19][C:24]([C:2]3[CH:3]=[CH:4][C:5]4[O:11][CH2:10][CH2:9][C:8]([C:12]([O:14][CH3:15])=[O:13])=[CH:7][C:6]=4[CH:16]=3)=[CH:23][C:22]=2[O:25]1
Reactant: COC(=O)C1=Cc2cc(Br)ccc2OCC1
Reactant: [O-]B([O-])Oc1ccc2c(c1)OCO2
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: O
Solvent: COCCOC
Product: COC(=O)C1=Cc2cc(-c3ccc4c(c3)OCO4)ccc2OCC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 65.9 %

Procedure:
To a mixture of methyl 7-bromo-2,3-dihydro-1-benzoxepine-4-carboxylate (0.57 g), 3,4-methlenedioxy-phenyl borate (0.47 g) and sodium carbonate (0.42 g) were added water (2 ml) and 1,2-dimethoxyethane (12 ml). Under argon atmosphere, the mixture was stirred at room temperature for 30 minutes, and to the mixture was added tetrakistriphenylphosphinepalladium (0.16 g). The mixture was stirred at 80° C. for 14 hours and extracted with ethyl acetate. The organic layer was washed with water and saturated sodium chloride solution and dried with anhydrous magnesium sulfate. Under reduced pressure, the solvent was evaporated, and the residue was purified with silica gel column (ethyl acetate/hexane) to give methyl 7-(3,4-methlenedioxyphenyl)-2,3-dihydro-1-benzoxepine-4-carboxylate (0.43 g).
Reaction SMILES: [Br:1][C:2]1[C:3]([F:10])=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=[O:6].[CH:11]1([Mg]Br)[CH2:13][CH2:12]1>C1COCC1>[Br:1][C:2]1[C:3]([F:10])=[C:4]([CH:5]([CH:11]2[CH2:13][CH2:12]2)[OH:6])[CH:7]=[CH:8][CH:9]=1
Reactant: Br[Mg]C1CC1
Reactant: O=Cc1cccc(Br)c1F
Solvent: C1CCOC1
Product: OC(c1cccc(Br)c1F)C1CC1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 100 %

Procedure:
To a solution of 3-bromo-2-fluorobenzaldehyde (0.500 g, 2.463 mmol) in THF (10.71 mL) cooled to −78° C. was added cyclopropylmagnesium bromide (5.91 mL, 2.96 mmol). The reaction mixture was maintained at −78° C. for at least 2 hr, then allowed to warm to room temperature. During this time, additional cyclopropylmagnesium bromide (5.91 mL, 2.96 mmol) was added. After 30 min, the reaction was quenched with a saturated aqueous solution of NH4Cl. The reaction mixture was diluted with CH2Cl2. The layers were separated and the aqueous phase extracted with CH2Cl2 (2×). The organics were combined, dried over Na2SO4, filtered, and concentrated to afford the title compound (0.604 g, 2.464 mmol, 100% yield) as a yellow residue.
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]1[CH:5]=[CH:6][C:7]([F:29])=[C:8]([N:10]2[C:15]([CH3:16])=[CH:14][C:13]([O:17][CH2:18][C:19]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][C:20]=3[F:26])=[C:12]([Cl:27])[C:11]2=[O:28])[CH:9]=1.[C:30](Cl)(=[O:33])[CH2:31][CH3:32].C(N(CC)CC)C.[NH4+].[Cl-]>O1CCCC1>[Cl:27][C:12]1[C:11](=[O:28])[N:10]([C:8]2[CH:9]=[C:4]([CH:5]=[CH:6][C:7]=2[F:29])[CH2:3][NH:2][C:30](=[O:33])[CH2:31][CH3:32])[C:15]([CH3:16])=[CH:14][C:13]=1[O:17][CH2:18][C:19]1[CH:24]=[CH:23][C:22]([F:25])=[CH:21][C:20]=1[F:26]
Reactant: CCC(=O)Cl
Reactant: Cc1cc(OCc2ccc(F)cc2F)c(Cl)c(=O)n1-c1cc(CN)ccc1F
Agent: Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCC(=O)NCc1ccc(F)c(-n2c(C)cc(OCc3ccc(F)cc3F)c(Cl)c2=O)c1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
A 10 mL round bottomed flask equipped with stirbar and nitrogen inlet was charged with 1-[5-(aminomethyl)-2-fluorophenyl]-3-chloro-4-[(2,4 difluorobenzyl)oxy]-6-methylpyridin-2(1H)-one hydrochloride (250 mg, 0.56 mmol), propionyl chloride (49 μL, 0.56 mmol), triethylamine (195 μL, 1.4 mmol) and tetrahydrofuran (4.0 mL). After stirring at 25° C. for 5 min the reaction was completed by LC-MS. The reaction mixture was poured into a saturated aqueous NH4Cl solution. The aqueous mixture was extracted with ethyl acetate. The organic phase was dried with Na2SO4 and concentrated in vacuo to obtain (240 mg, 91%) as a yellow solid. 1H NMR (400 MHz, (CD3)2SO) δ 8.3 (t, J=5.8 Hz, 1H), 7.6 (q, J=8.7 and 6.58 Hz, 1H), 7.38 (d, J=7.78 Hz, 1H), 7.3 (dd, J=2.6 and 7.6 Hz, 1H), 7.22 (d, J=7.51 Hz, 1H), 7.12 (td, J=2.0 and 6.5 Hz, 1H), 6.65 (s, 1H), 5.3 (s, 2H), 4.23 (d, J=3.6 Hz, 2H), 2.1 (q, J=7.7 Hz 2H), 1.98 (s, 3H), 0.98 (t, J=7.5 Hz, 3H) ppm. ES-HRMS m/z 465.1203 (M+H calcd for C23H21ClF3N2O3 requires 465.1187).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]([C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=2[CH3:12])=[CH:2]1.[Br:13]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[S:1]1[CH:5]=[CH:4][C:3]([C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=2[CH2:12][Br:13])=[CH:2]1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1ccccc1-c1ccsc1
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: BrCc1ccccc1-c1ccsc1

Procedure:
To a solution of Compound 2a (7.23 mmol) in carbon tetrachloride (150 mL) was added N-bromosuccinimide (7.5 mmol) and benzoyl peroxide (0.1 g). The solution was heated at reflux and irradiated with 250 watt sunlamp for 2 hours. The cooled reaction mixture was filtered through a pad of silica gel and the silica gel washed with diethyl ether (3×75 mL). The solvent was removed in vacuo and the residue fractionated to afford Compound 2b as a clear oil (b.p. 100°-103° C./0.1 mm).
Reaction SMILES: C([O:3][C:4](=[O:24])[CH:5]([CH2:15][C:16]([N:18]1[CH2:23][CH2:22][O:21][CH2:20][CH2:19]1)=[O:17])[CH2:6][CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)C.CO.O>>[N:18]1([C:16](=[O:17])[CH2:15][CH:5]([CH2:6][CH2:7][CH2:8][C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:4]([OH:24])=[O:3])[CH2:19][CH2:20][O:21][CH2:22][CH2:23]1
Reactant: CCOC(=O)C(CCCc1ccccc1)CC(=O)N1CCOCC1
Solvent: O
Solvent: CO
Product: O=C(O)C(CCCc1ccccc1)CC(=O)N1CCOCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 89 %

Procedure:
To a solution of 2-(2-morpholin-4-yl-2-oxo-ethyl)-5-phenyl-pentanoic acid ethyl ester (604 mg, 1.81 mmol) in a 2:1 mixture of MeOH—H2O (12 ml) LiOH.H2O (228 mg, 5.43 mmol) was added and stirred overnight at room temperature. Ethanol was removed under reduced pressure, residue diluted with water (40 ml) and washed with ether. The aqueous layer was acidified to pH1 with 1N HCl and extracted with diethyl ether (3×25 ml). The combined organic extracts were dried with MgSO4 and concentrated under reduced pressure to give 2-(2-morpholin-4-yl-2-oxo-ethyl)-5-phenyl-pentanoic acid as a white solid (492 mg); 1H NMR (CDCl3) 8.0–7.5 (1H), 7.4–7.1 (m, 5H), 3.8–3.4 (m, 8H), 3.0 (m, 1H), 2.8 (dd, J=16.4, 9.6 Hz, 1H), 2.65 (t, J=7.2 Hz, 2H), 2.40 (dd, J=16.4, 4.3 Hz, 1H), 1.9–1.5 (m, 4H). MS: 306 (MH+).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([CH2:6][C:7]#[N:8])=[CH:4][CH:3]=1.[CH3:11]OC(=O)OC.C([O-])([O-])=O.[K+].[K+]>CCOC(C)=O>[Br:1][C:2]1[CH:10]=[CH:9][C:5]([CH:6]([CH3:11])[C:7]#[N:8])=[CH:4][CH:3]=1
Reactant: N#CCc1ccc(Br)cc1
Reactant: COC(=O)OC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Product: CC(C#N)c1ccc(Br)cc1
Temperature: 180 °C
Reaction time: 16 h

Procedure:
An autoclave is charged with 25.0 g (128 mmol) 4-bromobenzylcyanide, 190 mL dimethylcarbonate and 0.900 g (6.51 mmol) K2CO3 and stirred for 16 h at 180° C. Then the reaction mixture is allowed to cool to r.t., the mixture is diluted with EtOAc and washed with water (1×), aq. 10% Na2S2O3 solution (1×) and brine (1×). The organic layer is dried with MgSO4 and the solvent is removed in vacuo. The residue is purified by destillation (bath temperature 204° C., head temperature 153° C.).
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[C:3]1[CH:11]=[C:10]2[C:6]([CH2:7][CH2:8][CH:9]2O)=[CH:5][CH:4]=1.S(Cl)([Cl:17])=O>>[Cl:17][CH:9]1[C:10]2[C:6](=[CH:5][CH:4]=[C:3]([C:2]([F:14])([F:13])[F:1])[CH:11]=2)[CH2:7][CH2:8]1
Reactant: O=S(Cl)Cl
Reactant: OC1CCc2ccc(C(F)(F)F)cc21
Product: FC(F)(F)c1ccc2c(c1)C(Cl)CC2
Temperature: 25 °C
Reaction time: 2 h
Yield: 90 %

Procedure:
6-(Trifluoromethyl)indan-1-ol (1.52 g, 7.5 mmol) was dissolved in thionyl chloride (15 mL). After being stirred at room temperature for 2 hrs, the solution was concentrated in vacuo to provide the title compound (1.5 g, 90%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[O:13][N:12]=[CH:11][C:10]=2[C:14]([OH:16])=O)=[CH:5][CH:4]=1.[CH2:17]([NH:19][CH2:20][CH3:21])[CH3:18]>>[CH2:17]([N:19]([CH2:20][CH3:21])[C:14]([C:10]1[CH:11]=[N:12][O:13][C:9]=1[C:6]1[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=1)=[O:16])[CH3:18]
Reactant: COc1ccc(-c2oncc2C(=O)O)cc1
Reactant: CCNCC
Product: CCN(CC)C(=O)c1cnoc1-c1ccc(OC)cc1

Procedure:
The title compound was prepared from 5-(4-methoxyphenyl)isoxazole-4-carboxylic acid (11.0 mg, 0.050 mmol) and diethylamine (4.4 mg, 0.060 mmol) as described in synthetic method A and thereafter purified by preparative HPLC method A to give a solid (7.8 mg). MS (pos) m/z 275.2 (M+1).
Reaction SMILES: [CH2:1]([O:3][CH:4](OCC)[CH:5]1[C:14]2([CH2:19][CH2:18][N:17](C(OC(C)(C)C)=O)[CH2:16][CH2:15]2)[O:13][C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]1=[O:27])[CH3:2].[ClH:31]>C1(C)C=CC=CC=1>[ClH:31].[CH2:1]([O:3]/[CH:4]=[C:5]1\[C:6](=[O:27])[C:7]2[C:12]([O:13][C:14]3\1[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]3)=[CH:11][CH:10]=[CH:9][CH:8]=2)[CH3:2]
Reactant: CCOC(OCC)C1C(=O)c2ccccc2OC12CCN(C(=O)OC(C)(C)C)CC2
Agent: Cl
Solvent: Cc1ccccc1
Product: CCO/C=C1\C(=O)c2ccccc2OC12CCNCC2
Temperature: 60 °C
Yield: 63.2 %

Procedure:
To tert-butyl 3-(diethoxymethyl)-4-oxo-spiro[chromane-2,4′-piperidine]-1′-carboxylate (33.0 g, 78.7 mmol) in toluene (73.33 mL) was added hydrochloric acid (68.8 mL of 4.0 M in dioxane, 275 mmol). The reaction mixture was heated at 60° C. for 15 min. Most of the solvent was removed under vacuum, and the tan slurry was filtered using a medium frit. The solids were washed with 500 mL of toluene. The solids were dried to give (Z)-3-(ethoxymethylene)spiro[chroman-2,4′-piperidin]-4-one hydrochloride (15.4 g, 63%). ESI-MS m/z calc. 273.1. found 274.3 (M+1)+; Retention time: 0.85 minutes (3 min run).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:20]=[CH:19][C:6]2[NH:7][C:8](=[O:18])[CH2:9][N:10](C(=O)C(F)(F)F)[CH2:11][C:5]=2[C:4]=1[N+:21]([O-:23])=[O:22].N>CO>[CH3:1][O:2][C:3]1[CH:20]=[CH:19][C:6]2[NH:7][C:8](=[O:18])[CH2:9][NH:10][CH2:11][C:5]=2[C:4]=1[N+:21]([O-:23])=[O:22]
Reactant: COc1ccc2c(c1[N+](=O)[O-])CN(C(=O)C(F)(F)F)CC(=O)N2
Agent: N
Solvent: CO
Product: COc1ccc2c(c1[N+](=O)[O-])CNCC(=O)N2
Temperature: 25 °C
Reaction time: 22 h
Yield: 90.9 %

Procedure:
A mixture of 7-Methoxy-6-nitro-4-(2,2,2-trifluoro-acetyl)-1,3,4,5-tetrahydro-benzo[e][1,4]diazepin-2-one (1.70 g, 0.00510 mol) and 7.0 M of Ammonia in Methanol (30 mL) was stirred at room temperature for 22 hrs. The reaction was evaporated to give 7-Methoxy-6-nitro-1,3,4,5-tetrahydro-benzo[e][1,4]diazepin-2-one as a tan solid (1.10 g, 90%). Mp 220-222° C.; LCMS (m/e) 237 (M); 1H-NMR (DMSO, 400 MHz) 6 1H-NMR (DMSO, 400 MHz) δ 9.92 (s, 1H), 7.257-20 (q, 2H, J=3.79 Hz), 3.83 (s, 3H), 3.69 (d, 2H), 3.43 (d. 2H, J=4.29 Hz), 3.11 (br, 1H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[S:9][C:8](=[O:10])[NH:7][C:6]=2[CH:11]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:19][CH2:20][OH:21].Cl>CN(C=O)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[S:9][C:8](=[O:10])[N:7]([CH2:19][CH2:20][OH:21])[C:6]=2[CH:11]=1
Reactant: OCCBr
Reactant: O=c1[nH]c2cc(Br)ccc2s1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=c1sc2ccc(Br)cc2n1CCO
Reaction time: 48 h

Procedure:
5-Bromobenzo[d]thiazol-2(3H)-one (1 g) and potassium carbonate (1.5 g) were stirred in DMF (7 mL) at room temperature and 2-bromoethanol (0.4 mL) added. The mixture was stirred for 48 h. The mixture was poured onto water and acidified with dilute hydrochloric acid and extracted with ethyl acetate. The extracts were washed with dilute hydrochloric acid, water and brine then dried over sodium sulfate and evaporated. Purification by flash silica chromatography eluting with 25% ethyl acetate in isohexane afforded the subtitle compound as a colourless solid (0.540 g).
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][C:7]([S:11]([NH:14][C:15]3[CH:20]=[C:19]([O:21][CH3:22])[C:18]([O:23][CH3:24])=[C:17]([O:25][CH3:26])[CH:16]=3)(=[O:13])=[O:12])=[CH:8][CH:9]=2)[CH:4]=[CH:3]1.Cl.[CH3:28][N:29]([CH2:31][C:32](Cl)=[O:33])[CH3:30].C(N(C(C)C)CC)(C)C>C1COCC1.CN(C1C=CN=CC=1)C>[CH3:28][N:29]([CH2:31][C:32]([N:14]([C:15]1[CH:16]=[C:17]([O:25][CH3:26])[C:18]([O:23][CH3:24])=[C:19]([O:21][CH3:22])[CH:20]=1)[S:11]([C:7]1[CH:6]=[C:5]2[C:10](=[CH:9][CH:8]=1)[N:2]([CH3:1])[CH:3]=[CH:4]2)(=[O:13])=[O:12])=[O:33])[CH3:30]
Reactant: COc1cc(NS(=O)(=O)c2ccc3c(ccn3C)c2)cc(OC)c1OC
Reactant: CN(C)CC(=O)Cl
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: COc1cc(N(C(=O)CN(C)C)S(=O)(=O)c2ccc3c(ccn3C)c2)cc(OC)c1OC
Temperature: 0 °C
Reaction time: 8 h
Yield: 91.6 %

Procedure:
A solution of Example 4 (20.0 g, 53.2 mmol) in THF (250 mL) at room temperature was treated with dimethylaminoacetyl chloride hydrochloride (12.3 g, 77.8 mmol), DMAP (650 mg, 5.3 mmol), and diisopropylethylamine (25.2 g, 195.0 mmol), stirred for 8 hours, and concentrated to ⅓ its original volume. The mixture was diluted with ethyl acetate (400 mL), washed with 5% NaHCO3 (2×200 mL) and water (200 mL), dried (Na2SO4), filtered, concentrated to a volume of 120 mL, diluted with methyl tert-butyl ether (120 mL), stirred for 18 hours, cooled to 0° C., stirred for 2 hours, and filtered. The resulting solid was washed with 1:1 ethyl acetate/methyl tert-butyl ether (100 mL) and dried under vacuum to provide 22.5 g (92%) of the desired product.
Reaction SMILES: [CH2:1]([N:4]([CH2:19][CH2:20][CH3:21])[CH2:5][CH2:6][CH2:7][CH2:8][NH:9][CH2:10][C:11]1[CH:18]=[CH:17][C:14]([C:15]#[N:16])=[CH:13][CH:12]=1)[CH2:2][CH3:3].[CH3:22][C:23]1[O:27][C:26]([CH:28]=O)=[CH:25][CH:24]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)(O)[O-].[Na+]>C(O)C>[CH2:19]([N:4]([CH2:1][CH2:2][CH3:3])[CH2:5][CH2:6][CH2:7][CH2:8][N:9]([CH2:10][C:11]1[CH:12]=[CH:13][C:14]([C:15]#[N:16])=[CH:17][CH:18]=1)[CH2:28][C:26]1[O:27][C:23]([CH3:22])=[CH:24][CH:25]=1)[CH2:20][CH3:21]
Reactant: Cc1ccc(C=O)o1
Reactant: CCCN(CCC)CCCCNCc1ccc(C#N)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: CCCN(CCC)CCCCN(Cc1ccc(C#N)cc1)Cc1ccc(C)o1
Temperature: 0 °C
Reaction time: 19 h
Yield: 99.3 %

Procedure:
0.485 g (1.69 mmol) of 4-[(4-dipropylaminobutyl)amino]methylbenzonitrile (2a), 9.7 ml of ethanol, and 371 mg (3.37 mmol, 2.0 equivalents) of 5-methyl-2-furaldehyde were charged in a 50 ml recovery flask under a nitrogen stream. The mixture was then cooled to 0° C. After the addition of 0.857 g (4.05 mmol, 2.4 equivalents) of sodium triacetoxyborohydride, the mixture was stirred at room temperature for 19 hours. After confirming the disappearance of the raw material by TLC, the reaction solution was added to 50 ml of a saturated sodium bicarbonate aqueous solution, and extracted twice with 50 ml of chloroform. The chloroform layer was washed with 100 ml of a saturated sodium chloride aqueous solution, dried over anhydrous sodium sulfate, concentrated, and purified by silica gel column chromatography (Chromatorex NH, chloroform:n-hexane=11:1), thereby obtaining 0.640 g of 4-{[(4-dipropylaminobutyl)-(5-methylfuran-2-ylmethyl)amino]methyl}benzonitrile (17) as a light yellow oily substance (yield: 99.5%). [HPLC: 98.9% (HPLC measurement conditions B)]
Reaction SMILES: [CH3:1][S:2][C:3]1[N:4]=[CH:5][C:6]2[CH2:12][NH:11][CH2:10][CH2:9][C:7]=2[N:8]=1.Br[C:14]1[CH:15]=[N:16][CH:17]=[C:18]([CH:31]=1)[C:19]([NH:21][C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([CH:28]([CH3:30])[CH3:29])[CH:23]=1)=[O:20]>>[CH:28]([C:24]1[CH:23]=[C:22]([NH:21][C:19](=[O:20])[C:18]2[CH:31]=[C:14]([N:11]3[CH2:10][CH2:9][C:7]4[N:8]=[C:3]([S:2][CH3:1])[N:4]=[CH:5][C:6]=4[CH2:12]3)[CH:15]=[N:16][CH:17]=2)[CH:27]=[CH:26][CH:25]=1)([CH3:30])[CH3:29]
Reactant: CC(C)c1cccc(NC(=O)c2cncc(Br)c2)c1
Reactant: CSc1ncc2c(n1)CCNC2
Product: CSc1ncc2c(n1)CCN(c1cncc(C(=O)Nc3cccc(C(C)C)c3)c1)C2

Procedure:
In a manner similar to that described for Example 138, 2-(methylsulfanyl)-5,6,7,8-tetrahydropyrido[4,3-d]-pyrimidine and 5-bromo-N-(3-isopropylphenyl)nicotinamide were converted to the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([Cl:19])=[C:6]([C:8]([C:10]2[CH:15]=[C:14]([F:16])[C:13]([OH:17])=[C:12]([F:18])[CH:11]=2)=[O:9])[CH:7]=1.IC.[C:22](=O)([O-])[O-].[K+].[K+]>CC(C)=O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([Cl:19])=[C:6]([C:8]([C:10]2[CH:11]=[C:12]([F:18])[C:13]([O:17][CH3:22])=[C:14]([F:16])[CH:15]=2)=[O:9])[CH:7]=1
Reactant: O=C([O-])[O-]
Reactant: O=C(c1cc(F)c(O)c(F)c1)c1cc(Br)ccc1Cl
Agent: [K+]
Solvent: CI
Solvent: CC(C)=O
Product: COc1c(F)cc(C(=O)c2cc(Br)ccc2Cl)cc1F
Temperature: 25 °C
Reaction time: 8 h
Yield: 102.3 %

Procedure:
To a solution of (5-bromo-2-chlorophenyl)(3,5-difluoro-4-hydroxyphenyl)methanone (600 mg, 1.7 mmol) in acetone (5 mL) was added iodomethane (50 μL, 2.6 mmol) and potassium carbonate (470 mg, 3.4 mmol), and the mixture was stirred overnight at 25° C. After the volatiles were removed under reduced pressure, the residue was dissolved in ethyl acetate (30 mL), washed with brine, and concentrated to give 629 mg of crude product, which was used in the next step without further purification.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:22])[CH:4]([C:13]1[CH:18]=[CH:17][C:16]([C:19]#[N:20])=[CH:15][C:14]=1[Cl:21])[N:5]1[C:9]([CH2:10][CH2:11][OH:12])=[CH:8][N:7]=[CH:6]1.CCN(CC)CC.[CH3:30][S:31](Cl)(=[O:33])=[O:32]>C(Cl)Cl>[CH3:1][O:2][C:3](=[O:22])[CH:4]([C:13]1[CH:18]=[CH:17][C:16]([C:19]#[N:20])=[CH:15][C:14]=1[Cl:21])[N:5]1[C:9]([CH2:10][CH2:11][O:12][S:31]([CH3:30])(=[O:33])=[O:32])=[CH:8][N:7]=[CH:6]1
Reactant: COC(=O)C(c1ccc(C#N)cc1Cl)n1cncc1CCO
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)C(c1ccc(C#N)cc1Cl)n1cncc1CCOS(C)(=O)=O

Procedure:
The crude (2-chloro-4-cyanophenyl)-[5-(2-hydroxyethyl)imidazol-1-yl]acetic acid methyl ester (2.06 g, 6.46 mmol) is dissolved in CH2Cl2 (25 mL) and stirred at 0° C. before Et3N (1.4 mL, 9.69 mmol) and methanesulfonyl chloride (0.6 mL, 7.75 mmol) are added. After completion of the reaction, the solution is partitioned between CH2Cl2 and aqueous saturated NaHCO3. The organic layer is dried (Na2SO4) and evaporated to give the crude (2-chloro-4-cyanophenyl)-[5-(2-methanesulfonyloxyethyl)imidazol-1-yl]-acetic acid methyl ester that is used without further purification. MS (ESI) m/z 398.2, 400.2 (M+H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[NH:10][CH:11]=[C:12]([C:14]([F:17])([F:16])[F:15])[N:13]=2)=[CH:5][CH:4]=1.[ClH:18]>O>[Cl:18][C:8]1[CH:7]=[C:6]([C:9]2[NH:10][CH:11]=[C:12]([C:14]([F:17])([F:15])[F:16])[N:13]=2)[CH:5]=[CH:4][C:3]=1[O:2][CH3:1]
Reactant: COc1ccc(-c2nc(C(F)(F)F)c[nH]2)cc1
Reactant: Cl
Solvent: O
Product: COc1ccc(-c2nc(C(F)(F)F)c[nH]2)cc1Cl
Temperature: 25 °C
Yield: 89 %

Procedure:
To a mixture of 7 (7.9 g, 0.033 mol), H2O (60 ml) and concentrated HCl (150 ml) stirred at room temperature was added dropwise a solution of KC103 (1.5 g, 0.012 mol) in H2O (65 ml). After 4 1/2 hours, the suspension was filtered and the solid washed with H2O and dried in vacuo to yield 8.1 g (89%) of 55, m.p. 208-210.
Reaction SMILES: [CH:1]12[CH:6]([CH2:7][N:8]([C:16]3[CH:21]=[CH:20][C:19]([N:22]4[CH2:27][CH2:26][O:25][CH2:24][CH2:23]4)=[C:18]([F:28])[CH:17]=3)[C:9]([C:11]3[S:12][CH:13]=[CH:14][CH:15]=3)=[O:10])[CH:5]1[CH2:4][NH:3][CH2:2]2.CCN(C(C)C)C(C)C.[C:38]([C:42]1[CH:47]=[CH:46][C:45]([S:48](Cl)(=[O:50])=[O:49])=[CH:44][CH:43]=1)([CH3:41])([CH3:40])[CH3:39]>ClCCCl.CN(C1C=CN=CC=1)C>[C:38]([C:42]1[CH:47]=[CH:46][C:45]([S:48]([N:3]2[CH2:4][CH:5]3[CH:1]([CH:6]3[CH2:7][N:8]([C:16]3[CH:21]=[CH:20][C:19]([N:22]4[CH2:27][CH2:26][O:25][CH2:24][CH2:23]4)=[C:18]([F:28])[CH:17]=3)[C:9]([C:11]3[S:12][CH:13]=[CH:14][CH:15]=3)=[O:10])[CH2:2]2)(=[O:50])=[O:49])=[CH:44][CH:43]=1)([CH3:41])([CH3:39])[CH3:40]
Reactant: CC(C)(C)c1ccc(S(=O)(=O)Cl)cc1
Reactant: O=C(c1cccs1)N(CC1C2CNCC21)c1ccc(N2CCOCC2)c(F)c1
Agent: CN(C)c1ccncc1
Solvent: ClCCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)c1ccc(S(=O)(=O)N2CC3C(CN(C(=O)c4cccs4)c4ccc(N5CCOCC5)c(F)c4)C3C2)cc1
Temperature: 80 °C
Yield: 78.1 %

Procedure:
To a stirring solution of thiophene-2-carboxylic acid (3-aza-bicyclo[3.1.0]hex-6-ylmethyl)-(3-fluoro-4-morpholin-4-yl-phenyl)-amide (60 mg, 0.15 mmol) in 3 mL of DCE was added DIEA (0.026 mL, 0.45 mmol), DMAP (cat.) and 4-tert-butylbenzene sulfonyl chloride (0.10 mL, 0.45 mmol). The resulting mixture was heated to 80° C. for 1.5 hours, cooled to room temperature and quenched with saturated NaHCO3. The layers were separated, the aqueous layer was extracted with CH2Cl2, and the combined organic layers were dried and concentrated. The resulting crude material was purified via flash chromatography with 40% EtOAc/hexanes. The product containing fractions were collected and concentrated to yield 70 mg of a white foam. 400 MHz 1H NMR (CDCl3) δ 7.62-7.66 (m, 2H), 7.47-7.50 (m, 2H), 7.29-7.31 (m, 1H), 6.79-6.95 (m, 5H), 3.87-3.89 (m, 4H), 3.68 (d, J=7.47 Hz, 2H), 3.46 (d, J=9.13 Hz, 2H), 3.13-3.15 (m, 4H), 2.94-2.96 (m, 2H), 1.64 (s, 2H), 1.31 (s, 9H), 1.12-1.14 (m, 1H); MS (M+1) 598.2.