Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[NH2:2][OH:3].N1C=CC=CC=1.[Cl:10][C:11]1[CH:27]=[CH:26][C:14]2[CH2:15][CH2:16][N:17]([C:20](=[O:25])[C:21]([F:24])([F:23])[F:22])[CH2:18][CH2:19][C:13]=2[C:12]=1[NH:28][CH2:29][C:30]1[CH:35]=[CH:34][C:33]([C:36](=O)[CH2:37][CH:38]([CH3:40])[CH3:39])=[CH:32][CH:31]=1>C(O)C>[Cl:10][C:11]1[CH:27]=[CH:26][C:14]2[CH2:15][CH2:16][N:17]([C:20](=[O:25])[C:21]([F:23])([F:24])[F:22])[CH2:18][CH2:19][C:13]=2[C:12]=1[NH:28][CH2:29][C:30]1[CH:35]=[CH:34][C:33]([C:36](=[N:2][OH:3])[CH2:37][CH:38]([CH3:40])[CH3:39])=[CH:32][CH:31]=1
Reactant: CC(C)CC(=O)c1ccc(CNc2c(Cl)ccc3c2CCN(C(=O)C(F)(F)F)CC3)cc1
Reactant: NO
Agent: Cl
Solvent: c1ccncc1
Solvent: CCO
Product: CC(C)CC(=NO)c1ccc(CNc2c(Cl)ccc3c2CCN(C(=O)C(F)(F)F)CC3)cc1
Yield: 43.6 %

Procedure:
Add hydroxylamine hydrochloride (6.3 mg, 0.091 mmol) and pyridine (15 uL, 0.182 mmol) to a solution of 7-chloro-6-[4-(3-methyl-butyryl)-benzylamino]-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine (42 mg, 0.091 mmol) in ethanol (1 mL). Heat the mixture to reflux for 18 h. Remove the solvent in vacuo and partition the residue between DCM and 0.1N aqueous HCl. Dry the organic phase over Na2SO4, filter and concentrate in vacuo. Purify by chromatography on silica gel eluting with hexane/EtOAc (95:5 to 1:1 gradient over 30 min). Concentrate in vacuo to obtain 7-chloro-6-[4-(1-hydroxyimino-3-methyl-butyl)-benzylamino]-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine as an off-white solid (19.1 mg, 44%). MS (ES+) m/z: 482 (M+H)+.
Reaction SMILES: CO[C:3](=[O:30])/[CH:4]=[CH:5]/[C:6]1[C:7]([NH:21][C:22]2[C:27]([F:28])=[CH:26][CH:25]=[CH:24][C:23]=2[F:29])=[N:8][C:9](SC)=[N:10][C:11]=1[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[F:18].[CH3:31][O-:32].[Na+]>>[F:28][C:27]1[CH:26]=[CH:25][CH:24]=[C:23]([F:29])[C:22]=1[N:21]1[C:7]2[N:8]=[C:9]([O:32][CH3:31])[N:10]=[C:11]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[F:18])[C:6]=2[CH:5]=[CH:4][C:3]1=[O:30]
Reactant: C[O-]
Reactant: COC(=O)/C=C/c1c(Nc2c(F)cccc2F)nc(SC)nc1-c1ccccc1F
Agent: [Na+]
Product: COc1nc(-c2ccccc2F)c2ccc(=O)n(-c3c(F)cccc3F)c2n1

Procedure:
Prepared as described above in Example 98 starting from (E)-3-[4-(2,6-difluoro-phenyl amino)-6-(2-fluoro-phenyl)-2-methylsulfanyl-pyrimidin-5-yl]-acrylic acid methyl ester and sodium methoxide to afford the title compound 8-(2,6-difluoro-phenyl)-4-(2-fluoro-phenyl)-2-methoxy-8H-pyrido[2,3-d]pyrimidin-7-one. 1H-NMR (CDCl3) δ 3.82 (s, 3H), 6.56 (d, 1H, J=9.6 Hz), 7.08 (m, 2H), 7.26-7.59 (m, 6H). LC MS (m/e)=384 (MH+). Rt=2.22 min.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:23])[CH:4]([NH:8][S:9]([C:12]1[CH:17]=[CH:16][C:15]([O:18][CH2:19][C:20]#[C:21][CH3:22])=[CH:14][CH:13]=1)(=[O:11])=[O:10])[CH:5]([CH3:7])[CH3:6].Cl.Cl[CH2:26][CH2:27][N:28]1[CH2:33][CH2:32][O:31][CH2:30][CH2:29]1>>[CH3:1][O:2][C:3](=[O:23])[CH:4]([N:8]([S:9]([C:12]1[CH:13]=[CH:14][C:15]([O:18][CH2:19][C:20]#[C:21][CH3:22])=[CH:16][CH:17]=1)(=[O:11])=[O:10])[CH2:26][CH2:27][N:28]1[CH2:33][CH2:32][O:31][CH2:30][CH2:29]1)[CH:5]([CH3:7])[CH3:6]
Reactant: CC#CCOc1ccc(S(=O)(=O)NC(C(=O)OC)C(C)C)cc1
Reactant: ClCCN1CCOCC1
Agent: Cl
Product: CC#CCOc1ccc(S(=O)(=O)N(CCN2CCOCC2)C(C(=O)OC)C(C)C)cc1
Yield: 90.5 %

Procedure:
According to the procedure of Example 21, 0.419 g (1.236 mmol) of 2-(4-but-2-ynyloxy-benzenesulfonylamino)-3-methyl-butyric acid methyl ester and 0.408 g (2.20 mmol) of 4-(2-chloroethyl)morpholine hydrochloride provided 0.506 g of 2-[(4-but-2-ynyloxy-benzenesulfonyl)-(2-morpholin-4-yl-ethyl)-amino]-3-methyl-butyric acid methyl ester as a colorless oil. Electrospray Mass Spec 453.0 (M+H)+.
Reaction SMILES: [CH:1]([O:4][CH2:5][CH2:6][OH:7])([CH3:3])[CH3:2].C(N(CC)CC)C.[CH3:15][S:16](Cl)(=[O:18])=[O:17]>CN(C1C=CN=CC=1)C.ClCCl>[CH3:15][S:16]([O:7][CH2:6][CH2:5][O:4][CH:1]([CH3:3])[CH3:2])(=[O:18])=[O:17]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)OCCO
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)OCCOS(C)(=O)=O
Temperature: 0 °C
Yield: 126.4 %

Procedure:
A round bottom flask was charged with 2-isopropoxyethanol (0.5 mL, 4.34 mmol) and dichloromethane (21.68 mL) and was cooled to 0° C. Triethylamine (1.208 mL, 8.67 mmol) was added along with a tip of DMAP. Methanesulfonyl chloride (0.338 mL, 4.34 mmol) was added dropwise. The reaction mixture was slowly warmed to rt over 2 h. The reaction mixture was quenched with saturated aqueous ammonium chloride and transferred to a separatory funnel The aqueous layer was extracted with dichloromethane (2×). The combined organics were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. 2-Isopropoxyethyl methanesulfonate (1 g) was isolated as a clear oil and was immediately used in the next reaction.
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[NH:10][CH:11]1[CH2:16][CH2:15][N:14]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH2:13][CH2:12]1.Cl[CH2:23][C:24]1[O:28][C:27]([C:29]([O:31][CH2:32][CH3:33])=[O:30])=[CH:26][CH:25]=1.C(=O)([O-])[O-].[Na+].[Na+].CN(C)C=O>O>[CH2:32]([O:31][C:29]([C:27]1[O:28][C:24]([CH2:23][N:1]2[C:5]3[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=3[N:3]=[C:2]2[NH:10][CH:11]2[CH2:16][CH2:15][N:14]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH2:13][CH2:12]2)=[CH:25][CH:26]=1)=[O:30])[CH3:33]
Reactant: CCOC(=O)N1CCC(Nc2nc3ccccc3[nH]2)CC1
Reactant: CCOC(=O)c1ccc(CCl)o1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)c1ccc(Cn2c(NC3CCN(C(=O)OCC)CC3)nc3ccccc32)o1
Yield: 70.8 %

Procedure:
A mixture of 28.8 parts of ethyl 4-(1H-benzimidazol-2-ylamino)-1-piperidinecarboxylate (as prepared in Example XIV of U.S. Pat. No. 4,219,559), 33.9 parts of ethyl 5-chloromethyl-2-furancarboxylate, 15.9 parts of sodium carbonate and 282 parts of N,N-dimethylformamide was stirred for 2 nights at 70° C. The reaction mixture was poured into water and the product was extracted with methylbenzene. The extract was washed with water, dried, filtered and evaporated. The residue was purified by column chromatography (silica gel; CHCl3 /CH3OH 97:3). The eluent of the desired fraction was evaporated and the residue was stirred in 1,1'-oxybisethane. The precipitate was filtered off and dried, yielding 31.2 parts (70.8%) of ethyl 4-[[1-[[5-(ethoxycarbonyl)-2-furanyl]-methyl]-1H-benzimidazol-2-yl]amino]-1-piperidinecarboxylate; mp. 136.0° C. (interm. 1).
Reaction SMILES: [CH3:1][N:2]([C:4]([O:12][Si](C)(C)C)=[CH:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[CH3:3].[F:17]OC(F)(F)F>ClC(F)(F)F>[F:17][CH:5]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[C:4]([N:2]([CH3:3])[CH3:1])=[O:12]
Reactant: FOC(F)(F)F
Reactant: CN(C)C(=Cc1ccccc1)O[Si](C)(C)C
Agent: FC(F)(F)Cl
Product: CN(C)C(=O)C(F)c1ccccc1
Temperature: 25 °C
Yield: 64.7 %

Procedure:
A solution of 3.0 g (0.0127 mol) of β-(N,N-dimethylamino)-β-(trimethylsiloxy)styrene (from above) in 100 ml of chlorotrifluoromethane was cooled to -70° C. and 1.6 g (0.013 mol) of trifluoromethyl hypofluorite were passed into the solution over a period of 3 hours. The reaction mixture was warmed to room temperature and then distilled to give 1.49 g (65% yield) of α-fluoro-N,N-dimethylbenzeneacetamide as a colorless oil: bp 98°-100° C. (0.45 mm); 19F NMR (CCl3F) δ-175.9 ppm (d,J=50 Hz); 1H NMR (CCl3F) δ 2.86 ppm (s, 6H), 5.54 ppm (d,J=50 Hz, 1H) and 7.10-7.8 ppm (m, 5H). Anal. Calcd for C10H12FNO: C, 66.27; H, 6.68; F, 10.49; N, 7.73; Found: C, 66.41; H, 6.75; F, 10.30; N, 7.70.
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([NH2:7])=O.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:20])=CC=1>C1(C)C=CC=CC=1>[I:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([NH2:7])=[S:20]
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: NC(=O)c1cccc(I)c1
Solvent: Cc1ccccc1
Product: NC(=S)c1cccc(I)c1
Yield: 98.8 %

Procedure:
A mixture of 3-iodobenzamide (500 mg, 2.0 mmol) in toluene (5 mL) was treated with Lawesson's reagent (404 mg, 1 mmol) and the mixture heated at reflux for 16 hours. After cooling, silica gel chromatography afforded 260 mg (99% yield) of 3-iodothiobenzamide, as a yellow solid.
Reaction SMILES: [CH:1]([C:3]1[C:11]2[C:10]([C:12]([O:14][CH3:15])=[O:13])=[CH:9][CH:8]=[N:7][C:6]=2[NH:5][CH:4]=1)=O.[NH2:16][CH:17]1[CH2:22][CH2:21][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:19][CH2:18]1.C1COCC1.[BH4-].[Na+]>CO>[C:26]([O:25][C:23]([N:20]1[CH2:21][CH2:22][CH:17]([NH:16][CH2:1][C:3]2[C:11]3[C:10]([C:12]([O:14][CH3:15])=[O:13])=[CH:9][CH:8]=[N:7][C:6]=3[NH:5][CH:4]=2)[CH2:18][CH2:19]1)=[O:24])([CH3:29])([CH3:27])[CH3:28]
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Reactant: COC(=O)c1ccnc2[nH]cc(C=O)c12
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: COC(=O)c1ccnc2[nH]cc(CNC3CCN(C(=O)OC(C)(C)C)CC3)c12
Reaction time: 0.17 h
Yield: 19.7 %

Procedure:
Methyl 3-formyl-1H-pyrrolo[2,3-b]pyridine-4-carboxylate (160 mg, 0.784 mmol) and tert-butyl 4-aminopiperidine-1-carboxylate (188 mg, 0.940 mmol) were combined in MeOH (3 mL) and THF (3 mL) at 50° C. for 3 H. Then sodium borohydride (59 mg, 1.567 mmol) was added at room temperature and allowed to stir for 10 min. The mixture was quenched with water and extracted with ethyl acetate. The organics were dried over MgSO4 and concentrated in vacuo to give methyl 3-((1-(tert-butoxycarbonyl)piperidin-4-ylamino)methyl)-1H-pyrrolo[2,3-b]pyridine-4-carboxylate (60 mg) which was carried on to the next step. 1H NMR (400 MHz, CD3OD) δ 8.32 (d, 1H, J=5.1 Hz), 7.61-7.62 (m, 2H), 4.07-4.13 (m, 4H), 4.01 (s, 3H), 2.81-2.84 (m, 3H), 1.96-1.98 (m, 2H), 1.45-1.47 (m, 2H), 1.45 (s, 9H). [M+H] found 389.
Reaction SMILES: [O:1]1[CH2:3][C@H:2]1[CH2:4][N:5]1[CH2:14][CH2:13][C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH2:6]1.[NH3:15]>CCO>[NH2:15][CH2:3][C@H:2]([OH:1])[CH2:4][N:5]1[CH2:14][CH2:13][C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH2:6]1
Reactant: N
Reactant: c1ccc2c(c1)CCN(C[C@@H]1CO1)C2
Solvent: CCO
Product: NC[C@H](O)CN1CCc2ccccc2C1
Temperature: 80 °C
Yield: 92 %

Procedure:
To a solution of (R)-2-(oxiran-2-ylmethyl)-1,2,3,4-tetrahydroisoquinoline (15 g, 0.08 mol) in EtOH (100 mL) at −78° C. was slowly bubbled NH3 (g). The reaction mixture was then sealed and heated at 80° C. for 3 h. The reaction mixture was concentrated and the crude product was used in next step without further purification (15 g, Yield 92%). LCMS (m/z): 207.1 (M+1).
Reaction SMILES: [CH2:1]([O:3][C:4]([CH2:6][N:7]1[CH:11]=[CH:10][N:9]=[C:8]1/[CH:12]=[C:13]1\[CH2:14][N:15]([C:20]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH2:16][CH2:17][CH:18]\1O)=[O:5])[CH3:2].C(OC(OCC(C)(C)C)N(C)C)C(C)(C)C.[C:55]([OH:58])(=[S:57])[CH3:56]>C1(C)C=CC=CC=1>[C:55]([S:57][CH:12]([C:8]1[N:7]([CH2:6][C:4]([O:3][CH2:1][CH3:2])=[O:5])[CH:11]=[CH:10][N:9]=1)[C:13]1[CH2:14][N:15]([C:20]([C:33]2[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=2)([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH2:16][CH2:17][CH:18]=1)(=[O:58])[CH3:56]
Reactant: CC(O)=S
Reactant: CCOC(=O)Cn1ccnc1/C=C1\CN(C(c2ccccc2)(c2ccccc2)c2ccccc2)CCC1O
Agent: CN(C)C(OCC(C)(C)C)OCC(C)(C)C
Solvent: Cc1ccccc1
Product: CCOC(=O)Cn1ccnc1C(SC(C)=O)C1=CCCN(C(c2ccccc2)(c2ccccc2)c2ccccc2)C1
Temperature: 25 °C
Yield: 78 %

Procedure:
To a solution of (E)-3-{[1-(ethoxycarbonylmethyl)-1H-imidazol-2-yl]methylidene}-1-(triphenylmethyl)piperidin-4-ol (4.52 g) in toluene (80 ml) were added N,N-dimethylformamide dineopentyl acetal (5.0 ml) and thioacetic acid (1.3 ml) at 0° C. After the mixture was stirred at room temperature, the reaction was quenched by addition of water. The product was extracted with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution and dried over anhydrous sodium sulfate. Removal of the solvent under reduced pressure followed by purification of the residue by silica gel chromatography using ethyl acetate and hexane (25:75 to 70:30) gave 5-{(acetylsulfanyl)[1-(ethoxycarbonylmethyl)-1H-imidazol-2-yl]methyl}-1-(triphenylmethyl)-1,2,3,6-tetrahydropyridine (3.92 g, yield: 78%) as a pale yellow amorphous solid.
Reaction SMILES: [CH3:1][N:2]([CH2:4][CH:5]1[CH2:14][CH2:13][C:12]2[C:7](=[CH:8][CH:9]=[C:10]([OH:15])[CH:11]=2)[CH2:6]1)[CH3:3].Cl[CH2:17][C:18]1[O:19][C:20]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[N:21][N:22]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.O>[CH3:3][N:2]([CH2:4][CH:5]1[CH2:14][CH2:13][C:12]2[C:7](=[CH:8][CH:9]=[C:10]([O:15][CH2:17][C:18]3[O:19][C:20]([C:23]4[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=4)=[N:21][N:22]=3)[CH:11]=2)[CH2:6]1)[CH3:1]
Reactant: ClCc1nnc(-c2ccccc2)o1
Reactant: CN(C)CC1CCc2cc(O)ccc2C1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CN(C)CC1CCc2cc(OCc3nnc(-c4ccccc4)o3)ccc2C1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
To a solution of 2-(N,N-dimethylamino)methyl-6-hydroxytetralin (206 mg, a free form of Reference Example 16) and 2-chloromethyl-5-phenyl-1,3,4-oxadiazole (231 mg) in DMF (5 ml) was added potassium carbonate (215 mg) and the reaction mixture was stirred at room temperature for 15 hr. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was washed with water and saturated aqueous sodium chloride, dried, and concentrated. The residue was purified by alumina column chromatography (eluent: ethyl acetate: hexane=1:2) to obtain the titled compound (307 mg).
Reaction SMILES: [CH2:1]([N:8]1[C:12]([C:13]([F:16])([F:15])[F:14])=[CH:11][C:10]([C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=2)=[C:9]1[C:24]([N:26]([CH2:28][C:29]([C:32](=[O:34])[NH2:33])([CH3:31])[CH3:30])[CH3:27])=[O:25])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CCN(CC)CC.C1C=CC(P([N:56]=[N+:57]=[N-])(C2C=CC=CC=2)=O)=CC=1>C1(C)C=CC=CC=1>[CH2:1]([N:8]1[C:12]([C:13]([F:14])([F:15])[F:16])=[CH:11][C:10]([C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=2)=[C:9]1[C:24]([N:26]([CH2:28][C:29]([CH3:31])([CH3:30])[C:32]([N:33]=[N+:56]=[N-:57])=[O:34])[CH3:27])=[O:25])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CN(CC(C)(C)C(N)=O)C(=O)c1c(-c2ccc(Cl)cc2)cc(C(F)(F)F)n1Cc1ccccc1
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CN(CC(C)(C)C(=O)N=[N+]=[N-])C(=O)c1c(-c2ccc(Cl)cc2)cc(C(F)(F)F)n1Cc1ccccc1
Reaction time: 8 h

Procedure:
To a stirred solution of 1-02 [see step 4 SC-174] (110 mg, 0.223 mmol) in dry toluene (4 mL) was added Et3N (62 μL, 0.446 mmol) and DPPA (63 μL, 0.290 mmol). The reaction mixture was stirred overnight and concentrated in vacuo to give the desired product as a yellow oil.
Reaction SMILES: [O:1]=[C:2]1[N:6]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[C@@H:5]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH2:4][CH2:3]1.[C:19]1([CH2:25][O:26][C:27]2[CH:32]=[CH:31][C:30](I)=[CH:29][CH:28]=2)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>>[CH3:11][C:10]([O:9][C:7]([NH:6][C@H:5]([CH2:4][CH2:3][C:2](=[O:1])[C:30]1[CH:31]=[CH:32][C:27]([O:26][CH2:25][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[CH:28][CH:29]=1)[C:14]([O:16][CH2:17][CH3:18])=[O:15])=[O:8])([CH3:13])[CH3:12]
Reactant: Ic1ccc(OCc2ccccc2)cc1
Reactant: CCOC(=O)[C@H]1CCC(=O)N1C(=O)OC(C)(C)C
Product: CCOC(=O)[C@@H](CCC(=O)c1ccc(OCc2ccccc2)cc1)NC(=O)OC(C)(C)C

Procedure:
The title compound was prepared (2.9 g, 16%) using a similar procedure as set out earlier in Description 2 starting from 1-(1,1-dimethylethyl) 2-ethyl (2R)-5-oxo-1,2-pyrrolidinedicarboxylate (D14, 10.5 g 40.8 mmol) and 4-iodophenyl phenylmethyl ether (13.34 g, 43 mmol); Rt (HPLC): 6.37 min; MS: (ES/+) 464 m/z: [M+Na+]; C25H31NO6 requires 441; 1H NMR (400 MHz, CDCl3) δ (ppm): 7.92 (d, 2H); 7.29-7.45 (m, 5H); 6.99 (d, 2H); 5.18 (bs, 1H); 5.12 (s, 2H); 4.29-4.4 (bm, 1H); 4.20 (q, 2H); 2.94-3.16 (m, 2H); 2.22-2.33 (m, 1H); 2.00-2.15 (m, 1H); 1.39 (s, 9H); 1.28 (t, 3H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH2:11])[C:6]([NH:9][CH3:10])=[CH:7][CH:8]=1.[Br:12][C:13]1[CH:14]=[C:15]([CH:19]=O)[CH:16]=[N:17][CH:18]=1.OOS([O-])=O.[K+].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.O>[Br:12][C:13]1[CH:14]=[C:15]([C:19]2[N:9]([CH3:10])[C:6]3[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][C:5]=3[N:11]=2)[CH:16]=[N:17][CH:18]=1
Reactant: CNc1ccc(OC)cc1N
Reactant: O=Cc1cncc(Br)c1
Agent: O=C([O-])[O-]
Agent: O=S([O-])OO
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc2c(c1)nc(-c1cncc(Br)c1)n2C
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 4-methoxy-N1-methyl-benzene-1,2-diamine (34; 0.5 g, 0.00328 mol) and 5-bromo-pyridine-3-carbaldehyde (0.61 g, 0.00328 mol) in DMF (10 ml) and H2O (4 ml) was added OXONE® monopersulphate (2.42 g, 0.00394 mol). Reaction mass was stirred at room temperature for 3 h. The reaction mixture was basified with 10% K2CO3 solution to pH˜8-10 and extracted with EtOAc (3×20 ml). The combined organic layers were washed with brine dried over Na2SO4 and concentrated under vacuum to afford the crude compound which was purified by column chromatography to obtain title compound 2-(5-bromo-pyridin-3-yl)-5-methoxy-1-methyl-1H-benzoimidazole (35).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH:4]([CH2:7][NH:8][C:9]([C:11]2[C:12]3[CH:20]=[CH:19][NH:18][C:13]=3[C:14](Cl)=[N:15][CH:16]=2)=[O:10])[CH2:3][CH2:2]1.[Cl:21][C:22]1[CH:23]=[C:24]([CH:26]=[CH:27][CH:28]=1)[NH2:25].CS(O)(=O)=O>O1CCOCC1.CO>[O:1]1[CH2:6][CH2:5][CH:4]([CH2:7][NH:8][C:9]([C:11]2[C:12]3[CH:20]=[CH:19][NH:18][C:13]=3[C:14]([NH:25][C:24]3[CH:26]=[CH:27][CH:28]=[C:22]([Cl:21])[CH:23]=3)=[N:15][CH:16]=2)=[O:10])[CH2:3][CH2:2]1
Reactant: Nc1cccc(Cl)c1
Reactant: O=C(NCC1CCOCC1)c1cnc(Cl)c2[nH]ccc12
Agent: CS(=O)(=O)O
Solvent: CO
Solvent: C1COCCO1
Product: O=C(NCC1CCOCC1)c1cnc(Nc2cccc(Cl)c2)c2[nH]ccc12
Temperature: 180 °C

Procedure:
A mixture of 7-chloro-1H-pyrrolo[2,3-c]pyridine-4-carboxylic acid (tetrahydro-pyran-4-ylmethyl)-amide (20 mg), 3-chloroaniline (15 ul), and methanesulfonic acid (9 ul) in 1,4-dioxane (0.5 ml) was heated under microwave conditions at 180° C. for 30 minutes. The solid mass obtained was dissolved in methanol, transferred to a round bottom flask and evaporated. The residue was partitioned between ethyl acetate and 5% sodium hydrogen carbonate solution whereby the title compound remained as a solid at the interface. The solid was filtered off, and washed with 5% sodium hydrogen carbonate solution, water and diethyl ether, then sucked dry and dried at 60° C. under vacuum to afford the title compound (17 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([CH3:14])[C:11]=1[O:12][CH3:13])[O:8][CH:7]([C:15]([F:18])([F:17])[F:16])[C:6]([C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:5]2.C1C(=O)N([Br:31])C(=O)C1>C(Cl)(Cl)(Cl)Cl>[Br:31][CH2:14][C:10]1[C:11]([O:12][CH3:13])=[C:2]([Cl:1])[CH:3]=[C:4]2[C:9]=1[O:8][CH:7]([C:15]([F:18])([F:16])[F:17])[C:6]([C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:5]2
Reactant: CCOC(=O)C1=Cc2cc(Cl)c(OC)c(C)c2OC1C(F)(F)F
Reactant: O=C1CCC(=O)N1Br
Solvent: ClC(Cl)(Cl)Cl
Product: CCOC(=O)C1=Cc2cc(Cl)c(OC)c(CBr)c2OC1C(F)(F)F
Temperature: 60 °C

Procedure:
The ethyl 6-chloro-7-methoxy-8-methyl-2-(trifluoromethyl)-2H-chromene-3-carboxylate from Example 3a, Step 3 (3.3 g, 9.4 mmole) was dissolved in CCl4 (30 mL) and the solution was heated to 60° C. NBS (1.84 g, 10.3 mmole) and Bzo2O (100 mg) were added to the above warm solution and the reaction was heated to reflux overnight. Additional NBS (1.84 g, 10.3 mmole) and Bzo2O (100 mg) were added to the above warm solution and the reaction was heated for 2 hrs. LCMS indicated that >95% product was formed. The reaction was cooled down and solid was filtered off. The filtrate was washed with NaHCO3 and brine. The organic layer was dried over anhydrous MgSO4 and evaporated to dry. The crude compound was used as crude (1H NMR indicated that the ratio of starting material/product is 40/60).
Reaction SMILES: [CH3:1][CH:2]([O:5][C:6]1[CH:11]=[CH:10][C:9]([S:12][CH2:13][CH2:14][NH2:15])=[CH:8][CH:7]=1)[CH2:3][CH3:4].Cl[C:17]([O:19][CH2:20][CH3:21])=[O:18].[OH-].[Na+].O>CCOCC>[CH3:1][CH:2]([O:5][C:6]1[CH:7]=[CH:8][C:9]([S:12][CH2:13][CH2:14][NH:15][C:17](=[O:18])[O:19][CH2:20][CH3:21])=[CH:10][CH:11]=1)[CH2:3][CH3:4]
Reactant: CCC(C)Oc1ccc(SCCN)cc1
Reactant: CCOC(=O)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCOCC
Product: CCOC(=O)NCCSc1ccc(OC(C)CC)cc1
Reaction time: 0.25 h

Procedure:
To a solution of 2-[4-(1-methylpropoxy)phenylthio]-ethylamine (2.21 g, 8.65 mmol) in 25 ml of ether, at 0° and under N2, is added ethyl chloroformate (0.52 g, 4.76 mmol) by syringe, followed by addition of 10% aqueous sodium hydroxide (3.5 ml) and additional ethyl chloroformate (0.51 g, 4.76 mmol). After 15 min., the reaction is worked up by addition of water and extraction with ether. The combined organic phases are washed with 1N sulfuric acid, with water and with brine, dried and filtered, the filtrate is concentrated in vacuo and the product is purified by prep. TLC to give ethyl N-{2-[4-(1-methylpropoxy)-phenylthio]ethyl}carbamate (compound 76, Table A).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][C:3]=1[N+:12]([O-:14])=[O:13].C=C.[Na].C(OCC)(=O)C.[CH2:24]([OH:27])[CH2:25][OH:26]>>[Cl:8][C:6]1[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][C:3]([N+:12]([O-:14])=[O:13])=[C:2]([CH:7]=1)[O:26][CH2:25][CH2:24][OH:27]
Reactant: O=[N+]([O-])c1cc([N+](=O)[O-])c(Cl)cc1Cl
Reactant: OCCO
Agent: C=C
Agent: [Na]
Solvent: CCOC(C)=O
Product: O=[N+]([O-])c1cc([N+](=O)[O-])c(OCCO)cc1Cl
Temperature: 25 °C

Procedure:
94.8 g (0.40 moles) 1,5-dichloro-2,4-dinitrobenzene in 580 ml ethylene glycol is heated to 50° C. To the mixture is then very gradually added, with stirring, 50.4 g (0.60 moles) sodium ethylene glycoxide over approximately 6 hours. One hour after addition is complete, TLC (ethyl acetate) shows the reaction is complete. The heat is turned off and the mixture is allowed to cool to room temperature. The precipitated product is collected by vacuum filtration and is washed with water. The water causes additional product to precipitate in the filtrate. The product is dried in a vacuum oven at 50° C. Yield of the combined crops is 82.7 g (78.8%), m.p. 98°-100° C.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]1[CH2:17][C:16]2[C:11](=[CH:12][CH:13]=[C:14]([OH:18])[CH:15]=2)[CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].N1C=CC=CC=1.[C:25](OC(=O)C)(=[O:27])[CH3:26]>C(Cl)Cl>[C:25]([O:18][C:14]1[CH:15]=[C:16]2[C:11](=[CH:12][CH:13]=1)[CH2:10][CH:9]([NH:8][C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[CH2:17]2)(=[O:27])[CH3:26]
Reactant: CC(=O)OC(C)=O
Reactant: CC(C)(C)OC(=O)NC1Cc2ccc(O)cc2C1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(=O)Oc1ccc2c(c1)CC(NC(=O)OC(C)(C)C)C2
Temperature: 25 °C
Reaction time: 2 h
Yield: 100 %

Procedure:
2-(tert-butoxycarbonylamino)-5-hydroxyindan (100 mg, 0.40 mmol) synthesized in Reference Production Example 1 was dissolved in dry methylene chloride (2 ml), to which pyridine (0.19 ml, 2.3 mmol) and acetic anhydride (0.11 ml, 1.2 mmol) were added, and the mixture was stirred at room temperature for 2 hours. The reaction mixture then was concentrated under reduced pressure, to which diethylether was added. The organic layer was washed with, in the order of, an aqueous solution of saturated potassium hydrogen sulfate, brine, an aqueous solution of saturated sodium hydrogen carbonate, and brine, and then was dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to obtain 5-acetoxy-2-(tert-butoxycarbonylamino)indan (120 mg, 0.40 mmol) having the following physical properties: