Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:20]=[CH:19][CH:18]=[CH:17][C:3]=1[C:4]([NH:6][C:7]1[CH:12]=[CH:11][C:10]([CH:13]([CH2:15][CH3:16])[CH3:14])=[CH:9][CH:8]=1)=[O:5].[N:21]1([C:27]2[CH:34]=[CH:33][C:30]([CH:31]=O)=[CH:29][N:28]=2)[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1>CCO>[CH:13]([C:10]1[CH:11]=[CH:12][C:7]([N:6]2[C:4](=[O:5])[C:3]3[C:2](=[CH:20][CH:19]=[CH:18][CH:17]=3)[N:1]=[C:31]2[C:30]2[CH:29]=[N:28][C:27]([N:21]3[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]3)=[CH:34][CH:33]=2)=[CH:8][CH:9]=1)([CH2:15][CH3:16])[CH3:14]
Reactant: CCC(C)c1ccc(NC(=O)c2ccccc2N)cc1
Reactant: O=Cc1ccc(N2CCCCC2)nc1
Solvent: CCO
Product: CCC(C)c1ccc(-n2c(-c3ccc(N4CCCCC4)nc3)nc3ccccc3c2=O)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 35 %

Procedure:
2-amino-N-(4-sec-butylphenyl)benzamide (0.350 g, 1.3 mmol) and 6-(piperidin-1-yl)nicotinaldehyde (1.3 mmol) were mixed in anyhydrous EtOH (40 mL) and anyhydrous CuCl2 (0.524 g, 3.9 mmol) was added. The reaction mixture was heated at reflux for 3 hours, cooled to room temperature, and stirred overnight. The reaction mixture was concentrated, diluted with ethyl acetate (150 mL), washed with water (2×100 mL), dried (MgSO4), filtered, and concentrated. Flash chromatograph on silica gel, eluting with 30% ethyl acetate/heptane to 80% ethyl acetate/heptane, afforded the title compound as a white solid (35%) as a white solid. 1H-NMR (300 MHz, DMSO-d6): δ 8.14-8.17 (m, 1H), 8.05 (d, J=2.4 Hz, 1H), 7.85-7.90 (m, 1H), 7.74 (d, J=7.8 Hz, 1H), 7.53-7.58 (m, 1H), 7.35 (d, J=6.5 Hz, 1H), 7.17-7.24 (m, 4H), 6.55 (d, J=9.1 Hz, 1H), 3.40-3.49 (m, 4H), 2.57-2.66 (m, 1H), 1.44-1.64 (m, 8H), 1.19 (d, J=6.9 Hz, 3H), 0.68 (t, J=7.3 Hz, 3H). MS (APCI) m/z: 439 (M+H)+.
Reaction SMILES: [CH2:1]1[O:9][C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=2[O:2]1.[CH3:10][C:11]([CH:13](OC(=O)C)[O:14][C:15](=[O:17])[CH3:16])=[CH2:12]>>[C:15]([O:14][CH:13]=[C:11]([CH3:12])[CH2:10][C:6]1[CH:7]=[CH:8][C:3]2[O:2][CH2:1][O:9][C:4]=2[CH:5]=1)(=[O:17])[CH3:16]
Reactant: c1ccc2c(c1)OCO2
Reactant: C=C(C)C(OC(C)=O)OC(C)=O
Product: CC(=O)OC=C(C)Cc1ccc2c(c1)OCO2

Procedure:
The production process (A) comprises the steps of (1) reacting 1,2-methylenedioxybenzene and 2-methyl-3,3-diacetoxypropene with each other to produce 1-acetoxy-2-methyl-3-(3,4-methylenedioxyphenyl)-1-propene; and (2) subjecting the obtained 1-acetoxy-2-methyl-3-(3,4-methylenedioxyphenyl)-1-propene to hydrolysis reaction or to transesterification reaction with an alcohol, followed by subjecting the resulting reaction mixture to distillative purification, to thereby adjust a content of 1-acetyl-3,4-methylenedioxybenzene as a by-product in the 2-methyl-3-(3,4-methylenedioxyphenyl)propanal to from 50 to 3000 ppm. (2) Production Process (B):
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][N:5]2[C:10]=1[C:9](=[O:11])[N:8]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:7]([C@@H:18]([NH:20]C(=O)OC(C)(C)C)[CH3:19])=[N:6]2.FC(F)(F)C(O)=O>ClCCl>[NH2:20][C@H:18]([C:7]1[N:8]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:9](=[O:11])[C:10]2=[C:2]([CH3:1])[CH:3]=[CH:4][N:5]2[N:6]=1)[CH3:19]
Reactant: Cc1ccn2nc([C@H](C)NC(=O)OC(C)(C)C)n(-c3ccccc3)c(=O)c12
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1ccn2nc([C@H](C)N)n(-c3ccccc3)c(=O)c12
Temperature: 25 °C
Reaction time: 8 h
Yield: 79.5 %

Procedure:
(S)-tert-Butyl (1-(5-methyl-4-oxo-3-phenyl-3,4-dihydropyrrolo[2,1-f][1,2,4]triazin-2-yl)ethyl)carbamate (950 mg, 2.58 mmol) was dissolved in 5 mL dichloromethane and trifluoroacetic acid (993 μl, 12.89 mmol) was added. The mixture was stirred at room temperature overnight. The reaction mixture was evaporated to dryness and was partitioned between ethyl acetate and potassium bicarbonate. The organic layer was washed with water, brine and dried over sodium sulphate, filtered and concentrated under reduced pressure to give 0.55 g (78% yield) of the title compound that was used in the next step without any further purification. Purity 97%.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([SH:9])[CH:5]=[CH:6][C:7]=1[Cl:8].Br[CH2:11][CH2:12][CH2:13][N:14]1[C:22](=[O:23])[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[C:15]1=[O:24].C([O-])([O-])=O.[Cs+].[Cs+].O>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([S:9][CH2:11][CH2:12][CH2:13][N:14]2[C:22](=[O:23])[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[C:15]2=[O:24])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: Sc1ccc(Cl)c(Cl)c1
Reactant: O=C1c2ccccc2C(=O)N1CCCBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: O=C1c2ccccc2C(=O)N1CCCSc1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Reaction time: 14 h
Yield: 74.4 %

Procedure:
3,4-Dichlorobenzenethiol (500 mg, 2.79 mmol) and 2-(3-bromopropyl)isoindoline-1,3-dione (823 mg, 3.07 mmol) were stirred in DMF (2 mL) at rt. Cs2CO3 (1.64 g, 5.03 mmol) was added. The reaction mixture was stirred at rt for 14 h. H2O was added and the aqueous phase was extracted with EtOAc. The organic layer was dried over MgSO4, filtered and concentrated to give crude product. It was then triturated with ether to yield a white precipitate which was filtered and dried to give Intermediate 7A (760 mg, 2.075 mmol, 74.3% yield). LC-MS (ESI) 365.8 (M+H). RT=4.00 min (Method A).
Reaction SMILES: CO[C:3]([C:5]1[C:6]([CH:24]([CH3:26])[CH3:25])=[N:7][C:8]([CH:21]([CH3:23])[CH3:22])=[C:9]([CH2:18][CH:19]=O)[C:10]=1[C:11]1[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=1)=[O:4].[Br-].[CH3:28][C:29]1[CH:54]=[CH:53][C:32]([CH2:33][P+](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=[CH:31][CH:30]=1>C(OCC)(=O)C.CCCCCC>[CH:24]([C:6]1[C:5]([CH2:3][OH:4])=[C:10]([C:11]2[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=2)[C:9]([CH2:18][CH2:19][CH2:28][C:29]2[CH:54]=[CH:53][C:32]([CH3:33])=[CH:31][CH:30]=2)=[C:8]([CH:21]([CH3:22])[CH3:23])[N:7]=1)([CH3:26])[CH3:25]
Reactant: COC(=O)c1c(C(C)C)nc(C(C)C)c(CC=O)c1-c1ccc(F)cc1
Reactant: Cc1ccc(C[P+](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Br-]
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: Cc1ccc(CCCc2c(C(C)C)nc(C(C)C)c(CO)c2-c2ccc(F)cc2)cc1

Procedure:
The title compound was prepared from methyl-2,6-diisopropyl-4-(4-fluorophenyl)-5-(2-oxoethyl)-3-pyridinecarboxylate (Example 82, Step A) and 4-methylbenzyl triphenylphosphonium bromide according to the procedures described in Example 1, Steps F-H. 1H NMR (300 MHz, CDCl3): δ 7.08 (m, 4 H), 7.01 (d, J=8 Hz, 2 H), 6.85 (d, J=8 Hz, 2 H), 4.30 (s, 2 H), 3.39 (sept, J=6.6 Hz, 1 H), 3.13 (sept, J=6.6 Hz, 1 H), 2.41 (t, J=7 Hz, 2 H), 2.31 (s, 3 H), 2.27 (m, 2 H), 1.58 (m, 2 H), 1.31 (d, J=6.6 Hz, 6 H), 1.26 (d, J=6.6 Hz, 6 H), 1.15 (m, 1 H). FAB-MS: calcd for (C28H34FNO) 419, found 420 (M+H). Anal. Calcd for C28H34FNO: C, 80.15; H, 8.17; N, 3.34. Found: C, 80.33; H, 8.28; N, 3.22. mp 79-80° C. Rf=0.4 (20% ethyl acetate/hexane).
Reaction SMILES: Cl[C:2]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[C:14]1([CH2:20][CH2:21][CH2:22][NH2:23])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.O.Cl>CC(N(C)C)=O>[N+:11]([C:8]1[CH:9]=[CH:10][C:2]([NH:23][CH2:22][CH2:21][CH2:20][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[C:3]([CH:7]=1)[C:4]([OH:6])=[O:5])([O-:13])=[O:12]
Reactant: O=C(O)c1cc([N+](=O)[O-])ccc1Cl
Reactant: NCCCc1ccccc1
Agent: Cl
Solvent: O
Solvent: CC(=O)N(C)C
Product: O=C(O)c1cc([N+](=O)[O-])ccc1NCCCc1ccccc1

Procedure:
A solution of 15.3 g of 2-chloro-5-nitrobenzoic acid and 49 g of 3-phenylpropylamine in 60 ml of dimethylacetamide is heated at 145° C. for 2 hours. After cooling, 300 ml of water are added, and the mixture is acidified (pH 2 to 1) with 2 N HCl.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:4]=[C:5]([CH:16]=[CH:17][CH:18]=1)[CH2:6][CH:7]([C:12]([O:14][CH3:15])=[O:13])[C:8]([O:10][CH3:11])=[O:9].[C:19]1([N:25]=[C:26]=[O:27])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>>[NH:25]([C:26]([O:1][CH2:2][C:3]1[CH:4]=[C:5]([CH:16]=[CH:17][CH:18]=1)[CH2:6][CH:7]([C:8]([O:10][CH3:11])=[O:9])[C:12]([O:14][CH3:15])=[O:13])=[O:27])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: O=C=Nc1ccccc1
Reactant: COC(=O)C(Cc1cccc(CO)c1)C(=O)OC
Product: COC(=O)C(Cc1cccc(COC(=O)Nc2ccccc2)c1)C(=O)OC

Procedure:
Using dimethyl 2-[3-(hydroxymethyl)benzyl]malonate and phenylisocyanate, the title compound was obtained in the same manner as described in Example 192b).
Reaction SMILES: [F:1][C:2]1[C:8]([F:9])=[CH:7][CH:6]=[CH:5][C:3]=1[NH2:4].C(=O)([O-])[O-].[K+].[K+].[Br:16][CH2:17][C:18](Br)=[O:19].O>ClCCl>[Br:16][CH2:17][C:18]([NH:4][C:3]1[CH:5]=[CH:6][CH:7]=[C:8]([F:9])[C:2]=1[F:1])=[O:19]
Reactant: Nc1cccc(F)c1F
Reactant: O=C(Br)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: ClCCl
Product: O=C(CBr)Nc1cccc(F)c1F
Reaction time: 5 h

Procedure:
To a mixture of 2,3-difluoroaniline (630 mg) and potassium carbonate (1.01 g) in dichloromethane (30 mL) was added bromoacetyl bromide (0.86 mL). The reaction mixture was stirred for 5 h then water was added and the phases separated. The organic layer was concentrated to give a 2:1 mixture of the sub-titled compound and bromoacetyl bromide. The residue was dissolved up in dichloromethane and washed with water. The volatiles were evaporated to give the sub-titled compound (1.15 g) as an off-white solid that was used without further purification.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[C:12]([F:14])[CH:11]=[CH:10][C:9]=2[N+:15]([O-])=[O:16])[C:5]([C:18]([O:20]C)=O)=[CH:4][CH:3]=1.[H][H]>[Pd].CO>[F:14][C:12]1[CH:11]=[CH:10][C:9]2[N:15]([OH:16])[C:18](=[O:20])[C:5]3[C:6](=[CH:7][C:2]([F:1])=[CH:3][CH:4]=3)[C:8]=2[CH:13]=1
Reactant: COC(=O)c1ccc(F)cc1-c1cc(F)ccc1[N+](=O)[O-]
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: O=c1c2ccc(F)cc2c2cc(F)ccc2n1O
Reaction time: 16 h
Yield: 18.3 %

Procedure:
To the product of Example 38a (279.8 mg) was added methanol (7.5 mL) and 10% palladium on carbon (76 mg, 0.071 mmol). The flask was fitted with a hydrogen balloon and the mixture was de-gased and back-filled with hydrogen three times. The mixture was stirred under hydrogen for 16 h, diluted with dimethylformamide and filtered. The filtrate was concentrated to give a red solid. This material was triturated with dichloromethane/hexane (9/1) and filtered to provide the title compound (Example 38b, 43.15 mg, 0.175 mmol, quantitative yield).
Reaction SMILES: [C:1]1([C:7]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[N:8]2[CH:12]=[C:11]([CH2:13][CH2:14][CH:15]=O)[N:10]=[CH:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:29]([C:31]1[CH:32]=[C:33]([CH:35]=[CH:36][CH:37]=1)[NH2:34])[CH3:30]>C1(C)C=CC=CC=1>[C:1]1([C:7]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[N:8]2[CH:12]=[C:11]([CH2:13][CH2:14][CH2:15][NH:34][C:33]3[CH:35]=[CH:36][CH:37]=[C:31]([CH2:29][CH3:30])[CH:32]=3)[N:10]=[CH:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CCc1cccc(N)c1
Reactant: O=CCCc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Solvent: Cc1ccccc1
Product: CCc1cccc(NCCCc2cn(C(c3ccccc3)(c3ccccc3)c3ccccc3)cn2)c1

Procedure:
0.4 g (1.10 mmol) of 3-(1-triphenylmethyl-4-imidazolyl)propionaldehyde is treated with 0.13 g (1.10 mmol) of 3-ethylaniline in anhydrous toluene, and then reduced as described for Example 154 to yield 1-triphenylmethyl-4-[3-(3-ethylphenylamino)propyl]-imidazole in the form of a colourless oil. The latter is deprotected with HCl in tetrahydrofuran, and the oil obtained is converted to oxalate as described for Example 154, to yield the product, m.p. 189-191° C. after recrystallization in a mixture of 2-propanol and diethyl ether.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([C:13]([OH:15])=[O:14])[C:7](=[CH:11][CH:12]=1)[C:8]([OH:10])=[O:9])([O-:3])=[O:2].S(=O)(=O)(O)O.[CH:21]1(O)[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1>>[N+:1]([C:4]1[CH:5]=[C:6]([C:13]([O:15][CH:4]2[CH2:5][CH2:6][CH2:7][CH2:11][CH2:12]2)=[O:14])[C:7](=[CH:11][CH:12]=1)[C:8]([O:10][CH:21]1[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1)=[O:9])([O-:3])=[O:2]
Reactant: O=C(O)c1ccc([N+](=O)[O-])cc1C(=O)O
Reactant: OC1CCCCC1
Agent: O=S(=O)(O)O
Product: O=C(OC1CCCCC1)c1ccc([N+](=O)[O-])cc1C(=O)OC1CCCCC1
Temperature: 120 °C
Yield: 65.5 %

Procedure:
4-nitrophthalic acid (2.0 g, 9.5 mmol) was dissolved in 30 ml of cyclohexanol, and then 0.3 ml of conc. sulfuric acid was added. The mixture was heated at 120° C. for 24 hours and the solvent was evaporated under reduced pressure. The oily residue was dissolved in diethyl ether and washed three times with water and once with 10% Na2CO3 solution. The ether solution was dried over anhydrous sodium sulfate. After evaporation of the solvent, the residue was purified by silica gel column chromatography (n-hexane: acetic acid =10:1) to give 2.3 g (65.5%) of dicyclohexyl 4-nitrophthalate (compound 405).
Reaction SMILES: [Cl:1][C:2]1[CH:29]=[CH:28][C:5]([C:6]([C:8]2[CH:27]=[CH:26][C:11]([CH2:12][N:13]3[C:17]4[N:18]=[C:19]([S:23][CH3:24])[NH:20][C:21](=[O:22])[C:16]=4[C:15]([CH3:25])=[CH:14]3)=[CH:10][CH:9]=2)=[O:7])=[CH:4][CH:3]=1.[H-].[Na+].[CH3:32]I>COCCOC.C(OCC)(=O)C>[Cl:1][C:2]1[CH:29]=[CH:28][C:5]([C:6]([C:8]2[CH:27]=[CH:26][C:11]([CH2:12][N:13]3[C:17]4[N:18]=[C:19]([S:23][CH3:24])[N:20]([CH3:32])[C:21](=[O:22])[C:16]=4[C:15]([CH3:25])=[CH:14]3)=[CH:10][CH:9]=2)=[O:7])=[CH:4][CH:3]=1
Reactant: CI
Reactant: CSc1nc2c(c(C)cn2Cc2ccc(C(=O)c3ccc(Cl)cc3)cc2)c(=O)[nH]1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: COCCOC
Product: CSc1nc2c(c(C)cn2Cc2ccc(C(=O)c3ccc(Cl)cc3)cc2)c(=O)n1C
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 67.1 %

Procedure:
Under argon gas, 7-[4-(4-chlorobenzoyl)benzyl]-5-methyl-2-methylthio-7H-pyrrolo[2, 3-d]pyrimidin-4(3H)-one (254 mg) was dissolved in anhydrous DME (10 ml)-anhydrous DMF (6 ml). Then, 60% sodium hydride-oil (26.4 mg) was added with ice-cooling and, after 30 minutes of agitation, methyl iodide (98 mg) was added. Then, at room temperature, the mixture was stirred for 2.5 hours. This reaction mixture was diluted with ethyl acetate, washed with saturated aqueous NaCl solution, and dried over anhydrous sodium sulfate. The solvent was then distilled off under reduced pressure and the residue was purified by flash column chromatography (chloroform) to provide the title compound (176 mg). 1H-NMR (CDCl3) δ: 2.39(3H,s), 2.56(3H,s), 3.56(3H,s), 5.29(2H,s), 6.47(1H,d,J=l.OHz), 7.29(2H,d,J=8.4Hz), 7.45(2H,d,J=8.4Hz), 7.73(4H,d,J=8.4Hz).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[S:10][CH:11]=[C:12](/[C:14](=[N:42]/[O:43][C@@H:44]([CH2:57][C:58]([O:60][C:61]([CH3:64])([CH3:63])[CH3:62])=[O:59])[C:45]([O:47][CH2:48][C:49]2[CH:54]=[CH:53][C:52]([O:55][CH3:56])=[CH:51][CH:50]=2)=[O:46])/[C:15]([NH:17][C@@H:18]2[C:25](=[O:26])[N:24]3[C@@H:19]2[S@:20](=[O:41])[CH2:21][C:22]([CH2:39]Cl)=[C:23]3[C:27]([O:29][CH2:30][C:31]2[CH:36]=[CH:35][C:34]([O:37][CH3:38])=[CH:33][CH:32]=2)=[O:28])=[O:16])[N:13]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[I-:65].[Na+]>CC(C)=O>[C:1]([O:5][C:6]([NH:8][C:9]1[S:10][CH:11]=[C:12](/[C:14](=[N:42]/[O:43][C@@H:44]([CH2:57][C:58]([O:60][C:61]([CH3:64])([CH3:63])[CH3:62])=[O:59])[C:45]([O:47][CH2:48][C:49]2[CH:54]=[CH:53][C:52]([O:55][CH3:56])=[CH:51][CH:50]=2)=[O:46])/[C:15]([NH:17][C@@H:18]2[C:25](=[O:26])[N:24]3[C@@H:19]2[S@:20](=[O:41])[CH2:21][C:22]([CH2:39][I:65])=[C:23]3[C:27]([O:29][CH2:30][C:31]2[CH:36]=[CH:35][C:34]([O:37][CH3:38])=[CH:33][CH:32]=2)=[O:28])=[O:16])[N:13]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: [I-]
Reactant: COc1ccc(COC(=O)C2=C(CCl)C[S@@](=O)[C@@H]3[C@H](NC(=O)/C(=N\O[C@@H](CC(=O)OC(C)(C)C)C(=O)OCc4ccc(OC)cc4)c4csc(NC(=O)OC(C)(C)C)n4)C(=O)N23)cc1
Agent: [Na+]
Solvent: CC(C)=O
Product: COc1ccc(COC(=O)C2=C(CI)C[S@@](=O)[C@@H]3[C@H](NC(=O)/C(=N\O[C@@H](CC(=O)OC(C)(C)C)C(=O)OCc4ccc(OC)cc4)c4csc(NC(=O)OC(C)(C)C)n4)C(=O)N23)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 84.8 %

Procedure:
To the solution of (S)-4-tert-butyl 1-(4-methoxybenzyl) 2-(((Z)-(1-(2-((tert-butoxycarbonyl)amino)thiazol-4-yl)-2-(((5R,6R,7R)-3-(chloromethyl)-2-(((4-methoxybenzyl)oxy)carbonyl)-5-oxido-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-en-7-yl)amino)-2-oxoethylidene)amino)oxy)succinate (1.183 g, 1.25 mmol) in acetone (50 mL) at room temperature was added sodium iodide (0.234 g, 1.563 mmol). The mixture stirred at room temperature for 2 hours. Filtered and evaporated to give (S)-4-tert-butyl 1-(4-methoxybenzyl) 2-(((Z)-(1-(2-((tert-butoxycarbonyl)amino)thiazol-4-yl)-2-(((5R,6R,7R)-3-(iodomethyl)-2-(((4-methoxybenzyl)oxy)carbonyl)-5-oxido-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-en-7-yl)amino)-2-oxoethylidene)amino)oxy)succinate (1.1 g, 1.060 mmol, 85% yield). LCMS (M+H)+: 1038.9
Reaction SMILES: [N:1]12[CH2:8][CH:5]([CH2:6][CH2:7]1)[CH:4]=[C:3]([C:9]([O:11]CC)=O)[CH2:2]2.Cl.[CH3:15][NH:16][O:17][CH3:18].N1C=CC=CC=1>Cl>[N:1]12[CH2:8][CH:5]([CH2:6][CH2:7]1)[CH:4]=[C:3]([C:9]([N:16]([O:17][CH3:18])[CH3:15])=[O:11])[CH2:2]2
Reactant: CCOC(=O)C1=CC2CCN(C1)C2
Reactant: CNOC
Agent: Cl
Solvent: c1ccncc1
Product: CON(C)C(=O)C1=CC2CCN(C1)C2
Temperature: 25 °C
Reaction time: 1 h
Yield: 53.4 %

Procedure:
A solution of (±)ethyl 1-azabicyclo[3.2.1]oct-3-en-3-yl carboxylate (D6) (1.9 g, 10.5 mmole) in 5M hydrochloric acid (25 ml) was heated at 100° C. for 7h. The reaction was concentrated in vacuo and dried by co-distillation with toluene. The resulting brown solid (2.0 g) was suspended in thionyl chloride (20 ml) and heated under reflux until all the acid had dissolved (approx. 10 minutes). After concentrating the reaction in vacuo, residual traces of volatile material were removed by co-distillation with toluene, and the residue was finally dried under high vacuum. A suspension of the acid chloride in absolute chloroform (50 ml) was treated with N,O-dimethylhydroxylamine hydrochloride (1.13 g, 11.5 mmole) and cooled in an ice-salt bath. Pyridine (4.2 ml, 5.3 mmole) was added dropwise with good stirring over a period of 1h. The reaction was allowed to warm to room temperature and stirred overnight. After cooling in an ice bath, the reaction was quenched with a saturated aqueous solution of potassium carbonate (25 ml). The aqueous layer was extracted with chloroform (3×25 ml), and the combined organic extracts were dried (Na2SO4) and concentrated in vacuo to give an oil which was extracted into ether, and then distilled on a kugelrohr (175° C./0.2 mmHg) to afford the title compound (D8) as a pale yellow oil (1.1 g, 54%) which solidified on cooling.
Reaction SMILES: [CH2:1]([C:3]1[S:26][C:6]2[N:7]([CH2:11][C:12]3[CH:17]=[CH:16][C:15]([C:18]4[C:19]([C:24]#[N:25])=[CH:20][CH:21]=[CH:22][CH:23]=4)=[CH:14][CH:13]=3)[C:8](=[O:10])[NH:9][C:5]=2[CH:4]=1)[CH3:2].Br[CH2:28][C:29]1[CH:34]=[CH:33][C:32]([F:35])=[CH:31][CH:30]=1.CN(C)C=O.[H-].[Na+]>C(OCC)(=O)C>[CH2:1]([C:3]1[S:26][C:6]2[N:7]([CH2:11][C:12]3[CH:17]=[CH:16][C:15]([C:18]4[C:19]([C:24]#[N:25])=[CH:20][CH:21]=[CH:22][CH:23]=4)=[CH:14][CH:13]=3)[C:8](=[O:10])[N:9]([CH2:28][C:29]3[CH:34]=[CH:33][C:32]([F:35])=[CH:31][CH:30]=3)[C:5]=2[CH:4]=1)[CH3:2]
Reactant: Fc1ccc(CBr)cc1
Reactant: CCc1cc2[nH]c(=O)n(Cc3ccc(-c4ccccc4C#N)cc3)c2s1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCc1cc2c(s1)n(Cc1ccc(-c3ccccc3C#N)cc1)c(=O)n2Cc1ccc(F)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 80 %

Procedure:
To a mixture of 4′-[(5-ethyl-2-oxo-1,2-dihydro-3H-thieno[2,3-d]imidazol-3-yl)methyl]biphenyl-2-carbonitrile (0.35 g), 1-(bromomethyl)-4-fluorobenzene (0.18 mL) and N,N-dimethylformamide (15 mL) was added 60% sodium hydride (0.057 g), and the mixture was stirred at room temperature for 2 hr. The reaction mixture was diluted with ethyl acetate, washed successively with 5% aqueous potassium hydrogensulfate solution and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography to give the title compound as colorless crystals (0.36 g, 80%).
Reaction SMILES: [CH:1]1[C:14]2[C:13]3([CH2:16][N:17]4[CH2:22][CH2:21][C:20]([C:24]5[CH:25]=[N:26][CH:27]=[C:28]([CH:30]=[O:31])[CH:29]=5)([OH:23])[CH2:19][CH2:18]4)[CH2:15][CH:6]([C:7]4[C:12]3=[CH:11][CH:10]=[CH:9][CH:8]=4)[C:5]=2[CH:4]=[CH:3][CH:2]=1.[CH3:32][Li]>O1CCCC1>[CH:1]1[C:14]2[C:13]3([CH2:16][N:17]4[CH2:18][CH2:19][C:20]([C:24]5[CH:25]=[N:26][CH:27]=[C:28]([CH:30]([OH:31])[CH3:32])[CH:29]=5)([OH:23])[CH2:21][CH2:22]4)[CH2:15][CH:6]([C:7]4[C:12]3=[CH:11][CH:10]=[CH:9][CH:8]=4)[C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: O=Cc1cncc(C2(O)CCN(CC34CC(c5ccccc53)c3ccccc34)CC2)c1
Reactant: [Li]C
Solvent: C1CCOC1
Product: CC(O)c1cncc(C2(O)CCN(CC34CC(c5ccccc53)c3ccccc34)CC2)c1
Temperature: 0 °C
Reaction time: 2.5 h
Yield: 77 %

Procedure:
A suspension of 1-(9,10-dihydro-9,10-methanoanthracen-9-ylmethyl)-4-(5-formyl-3-pyridyl)piperidin-4-ol (0.350 g, 0.852 mmol) in tetrahydrofuran (20 mL) under nitrogen was cooled to 0° C. Methyl lithium (1.0M in diethyl ether, 1.72 mL, 2 eq) was added dropwise with dissolution of the suspension as addition proceeded. The solution became a golden brown color. The reaction was warmed to 10° C. and stirred at this temperature for 2.5 h. At the end of this time period, the reaction was quenched with water (25 mL) and the aqueous phase extracted with ethyl acetate (3×20 mL). Combined organic extracts were dried over anhydrous magnesium sulfate, filtered, and reduced to an oil. The reaction product was purified by flash chromatography over silica gel (30 mL, eluent: 10% methanol in diethyl ether) to yield 0.280 g (77%) of the title compound as a white solid. TLC analysis (Rf 0.17, 10% methanol in diethyl ether). 1H NMR (CDCl3, 300 MHz) 8.65 (d, J=2.2 Hz, 1H), 8.48 (d, J=2.0 Hz, 1H), 7.83 (t, J=2.1Hz, 1H), 7.24 (m, 2H), 7.18 (m, 2H), 6.95 (m, 4H), 4.95 (q, J=6.5 Hz, 1H), 4.28 (br s, 1H), 3.49 (br s, 2H), 2.94 (m, 2H), 2.74 (m, 2H), 2.63 (br s, 2H), 2.13 (m, 2H), 1.76 (m, 2H), 1.59 (m, 3H) MS (CI, CH4) m/z 427 (M+1,100), 455 (M+29,17), 409 (62), 235 (11), 221 (22), 206 (17), 169 (28) The free base was dissolved in methylene chloride containing small amounts of methanol and acidified with ethereal HCl. The hydrochloride salt was precipitated by ether dilution, filtered, rinsed with fresh ether, and dried in vacuo (60° C., 10 pascal, 18 h) to yield a white solid, mp 177°-183° C. The analysis for dihydrochloride was not in agreement with calculated; 1H NMR and MS of salt were completely consistent with the proposed structure.
Reaction SMILES: C([O:3][C:4](=O)[CH2:5][C:6]1[S:7][C:8]2[CH:14]=[CH:13][C:12]([Br:15])=[CH:11][C:9]=2[N:10]=1)C.[BH4-].[Na+]>C1COCC1.CCO>[Br:15][C:12]1[CH:13]=[CH:14][C:8]2[S:7][C:6]([CH2:5][CH2:4][OH:3])=[N:10][C:9]=2[CH:11]=1
Reactant: CCOC(=O)Cc1nc2cc(Br)ccc2s1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: C1CCOC1
Product: OCCc1nc2cc(Br)ccc2s1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
(5-Bromo-benzothiazol-2-yl)-acetic acid ethyl ester (1.25 g, 4.2 mmol) was dissolved in THF (20 mL) and EtOH (5 mL) under N2. Then 0.24 g of NaBH4 was dissolved in EtOH (3 mL) and added to the above solution. The reaction mixture was stirred at room temperature for 2 hours. After the completion the mixture was quenched with water and extracted with CH2Cl2. The aqueous layer was extracted again with more CH2Cl2. The combined methylene chloride layer was dried over anhydrous MgSO4 and filtered. Removal of solvent gave crude product with a yield of 1.11 g. The crude product was used directly in the next step.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([S:8]([CH2:11][CH3:12])(=[O:10])=[O:9])[CH:5]=[CH:4][C:3]=1F.[F:14][C:15]1[CH:20]=[C:19]([F:21])[CH:18]=[CH:17][C:16]=1[OH:22].C([O-])([O-])=O.[Cs+].[Cs+].CC(=O)OCC>CS(C)=O>[Br:1][C:2]1[CH:7]=[C:6]([S:8]([CH2:11][CH3:12])(=[O:10])=[O:9])[CH:5]=[CH:4][C:3]=1[O:22][C:16]1[CH:17]=[CH:18][C:19]([F:21])=[CH:20][C:15]=1[F:14]
Reactant: CCS(=O)(=O)c1ccc(F)c(Br)c1
Reactant: Oc1ccc(F)cc1F
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: CCS(=O)(=O)c1ccc(Oc2ccc(F)cc2F)c(Br)c1
Yield: 81.2 %

Procedure:
2-bromo-1-fluoro-4-ethylsulfonylbenzene (130 mg, 0.49 mmol), 2,4-difluorophenol (78 mg, 0.60 mmol) and Cs2CO3 (478 mg, 1.47 mmol) in DMSO (5 mL) were heated at 100° C. for 12 h. EA extractive work up gave the title compound (150 mg, yield: 80.5%) as a grey solid. 1H NMR (CDCl3, 400 MHz) δ 8.18 (d, J=2.0 Hz, 1H), δ 7.75 (dd, J1=8.4 Hz, J2=1.6 Hz, 1H), 7.22-7.16 (m, 1H), 7.06-6.95 (m, 2H), 6.80 (d, J=8.8 Hz, 1H), 3.16 (q, J=7.2 Hz, 2H), 1.33 (t, J=7.6 Hz, 3H). LCMS: 395.8 (M+NH4)+.