Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[C:3]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][C:4]=2[S:5][C:6]=1[C:7]1[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[CH:9][CH:8]=1.[NH2:21][C:22]1[CH:34]=[CH:33][C:25]([CH:26]=[CH:27][C:28]([O:30][CH2:31][CH3:32])=[O:29])=[CH:24][CH:23]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+].O1CCOCC1>CCOC(C)=O>[CH3:20][O:19][C:16]1[CH:17]=[CH:18][C:3]2[C:2]([NH:21][C:22]3[CH:23]=[CH:24][C:25](/[CH:26]=[CH:27]/[C:28]([O:30][CH2:31][CH3:32])=[O:29])=[CH:33][CH:34]=3)=[C:6]([C:7]3[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[CH:9][CH:8]=3)[S:5][C:4]=2[CH:15]=1
Reactant: COc1ccc(-c2sc3cc(OC)ccc3c2Br)cc1
Reactant: CCOC(=O)C=Cc1ccc(N)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: CCOC(=O)/C=C/c1ccc(Nc2c(-c3ccc(OC)cc3)sc3cc(OC)ccc23)cc1
Yield: 15 %

Procedure:
To a large microwave vial (10-20 mL) was added 3-bromo-6-methoxy-2-(4-methoxyphenyl)benzo[b]thiophene (350 mg, 1.00 mmol), ethyl 4-aminocinnamate (383 mg, 2.00 mmol) and K3PO4 (425 mg, 2.00 mmol). 1,4-dioxane (6.0 mL) was then added followed by chloro-(2-dicyclohexylphosphino-2′,6′-diisopropoxy-1,1′-biphenyl)[2-(2-aminoethyl)phenyl]palladium(II) methyl-t-butyl ether adduct (RuPhos palladacycle, 73.0 mg, 0.10 mmol) and the reaction was subjected to microwave irradiation at 120° C. for 3 h. Upon completion the reaction mixture was transferred to round bottom flask with EtOAc and concentrated in vacuo. The resulting material was partitioned between water and EtOAc and separated, the aqueous layer was then further extracted with EtOAc (3×) and the combined organic layers were passed through a phase separator to remove water and concentrated in vacuo. The crude material was purified by column chromatography (SiO2, 0-30% EtOAc/heptane) to afford (E)-ethyl 3-(4-((6-methoxy-2-(4-methoxyphenyl)benzo[b]thiophen-3-yl)amino)phenyl)acrylate (69.0 mg, 0.15 mmol, 15% yield) as a white solid. LC/MS (m/z, MH+): 460.3.
Reaction SMILES: Br[C:2]1[C:6]2[C:7]([NH2:20])=[N:8][CH:9]=[C:10](/[CH:11]=[CH:12]/[CH:13]([O:17][CH2:18][CH3:19])[O:14][CH2:15][CH3:16])[C:5]=2[S:4][CH:3]=1.[O:21]([C:28]1[CH:33]=[CH:32][C:31](B(O)O)=[CH:30][CH:29]=1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.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>[CH2:15]([O:14][CH:13]([O:17][CH2:18][CH3:19])/[CH:12]=[CH:11]/[C:10]1[C:5]2[S:4][CH:3]=[C:2]([C:31]3[CH:32]=[CH:33][C:28]([O:21][C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)=[CH:29][CH:30]=3)[C:6]=2[C:7]([NH2:20])=[N:8][CH:9]=1)[CH3:16]
Reactant: OB(O)c1ccc(Oc2ccccc2)cc1
Reactant: CCOC(/C=C/c1cnc(N)c2c(Br)csc12)OCC
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: CCOC(/C=C/c1cnc(N)c2c(-c3ccc(Oc4ccccc4)cc3)csc12)OCC
Temperature: 25 °C
Yield: 54.4 %

Procedure:
A mixture of Example 176A (250 mg, 0.70 mmol), 4-phenoxyphenylboronic acid (180 mg, 0.84 mmol), Pd(PPh3)4 (50 mg, 0.04 mmol), and sodium carbonate (150 mg, 1.4 mmol) in 1,2-dimethoxyethane (8 mL) and water (4 mL) was heated to reflux for 15 hours. The mixture was cooled to room temperature and concentrated under reduced pressure. The mixture was extracted with dichloromethane and the extract was dried (MgSO4), filtered, and concentrated. The residue was purified by flash column chromatography on silica gel to provide the desired product (170 mg, 55%). 1H NMR (DMSO-d6, 400 MHz) δ 8.00 (s, 1H), 7.56 (s, 1H), 7.47 (m, 4H), 7.20 (t, 1H), 7.13 (m, 4H), 6.81 (d, 1H), 6.17 (dd, 1H), 5.67 (br s, 2H), 5.13 (d, 1H), 3.57 (m, 4H), 1.18 (t, 6H); MS m/e 447.3 (M+H)+.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C@H:11]([S:13][C:14]([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)[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:10][C@H:9]1[CH2:33][N:34]=[N+]=[N-])=[O:7])([CH3:4])([CH3:3])[CH3:2].C(OC(N1C[C@H](SC(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)C[C@H]1CN)=O)(C)(C)C.[F:71][C:72]1[CH:79]=[CH:78][C:77]([F:80])=[CH:76][C:73]=1[CH:74]=O>>[C:1]([O:5][C:6]([N:8]1[CH2:12][C@H:11]([S:13][C:14]([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)[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:10][C@H:9]1[CH2:33][NH:34][CH2:74][C:73]1[CH:76]=[C:77]([F:80])[CH:78]=[CH:79][C:72]=1[F:71])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: O=Cc1cc(F)ccc1F
Reactant: CC(C)(C)OC(=O)N1C[C@H](SC(c2ccccc2)(c2ccccc2)c2ccccc2)C[C@H]1CN=[N+]=[N-]
Agent: CC(C)(C)OC(=O)N1C[C@H](SC(c2ccccc2)(c2ccccc2)c2ccccc2)C[C@H]1CN
Product: CC(C)(C)OC(=O)N1C[C@H](SC(c2ccccc2)(c2ccccc2)c2ccccc2)C[C@H]1CNCc1cc(F)ccc1F

Procedure:
From (2S,4R)-2-azidomethyl-4-tritylsulfanyl-pyrrolidine-1-carboxylic acid tert-butyl ester was prepared via (2S,4R)-2-aminomethyl-4-tritylsulfanyl-pyrrolidine-1-carboxylic acid tert-butyl ester [as light brown foam, MS: 475 (MH+)] and further reaction with 2,5-difluoro benzaldehyde analogously to reductive amination gave (2S,4R)-2-[(2,5-difluoro-benzylamino)-methyl]-4-tritylsulfanyl-pyrrolidine-1-carboxylic acid tert-butyl ester as colorless oil MS: 601 (MH+) which was treated according to trityl cleavage (method 5) to give (2S,4R)-2-[(2,5-difluoro-benzylamino)-methyl]-4-mercapto-pyrrolidine-1-carboxylic acid tert-butyl ester as colorless liquid MS: 359 (MH+).
Reaction SMILES: [F:1][C:2]([C:5]1[CH:10]=[C:9]([N+:11]([O-])=O)[CH:8]=[CH:7][C:6]=1[F:14])([F:4])[CH3:3]>CO>[F:4][C:2]([C:5]1[CH:10]=[C:9]([NH2:11])[CH:8]=[CH:7][C:6]=1[F:14])([F:1])[CH3:3]
Reactant: CC(F)(F)c1cc([N+](=O)[O-])ccc1F
Solvent: CO
Product: CC(F)(F)c1cc(N)ccc1F
Reaction time: 2 h

Procedure:
To a solution of 2-(1,1-difluoro-ethyl)-1-fluoro-4-nitro-benzene (10.4 g, 50.6 mmol) in methanol (200 ml) palladium on carbon (10%, 4 g) was added and the resulting mixture was hydrogenated for 2 h at 20° C. After filtration of the catalyst the solvent was evaporated to yield the title compound as a yellow semi solid mass. (8.5 g, 96%). MS: m/e=175 (M+).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[C:9]([CH:10]=1)=[N:8][N:7]([CH2:11][C:12]([NH:16][C:17](=[O:29])[C:18]1[CH:23]=[CH:22][C:21]([O:24][C:25]([F:28])([F:27])[F:26])=[CH:20][CH:19]=1)([C:14]#[N:15])[CH3:13])[CH:6]=2.[Cl:30]N1C(=O)CCC1=O>C(#N)C.O>[C:14]([C:12]([NH:16][C:17](=[O:29])[C:18]1[CH:23]=[CH:22][C:21]([O:24][C:25]([F:26])([F:27])[F:28])=[CH:20][CH:19]=1)([CH3:13])[CH2:11][N:7]1[C:6]([Cl:30])=[C:5]2[C:9]([CH:10]=[C:2]([Cl:1])[CH:3]=[CH:4]2)=[N:8]1)#[N:15]
Reactant: O=C1CCC(=O)N1Cl
Reactant: CC(C#N)(Cn1cc2ccc(Cl)cc2n1)NC(=O)c1ccc(OC(F)(F)F)cc1
Solvent: O
Solvent: CC#N
Product: CC(C#N)(Cn1nc2cc(Cl)ccc2c1Cl)NC(=O)c1ccc(OC(F)(F)F)cc1
Temperature: 60 °C
Yield: 85.1 %

Procedure:
A mixture of N-[2-(6-chloro-2H-indazol-2-yl)-1-cyano-1-methylethyl]-4-trifluoromethoxybenzamide (50 mg, described in Example 132), and N-chlorosuccinimide (16 mg) in acetonitrile (1 mL) was heated to 60° C. for 3.5 hours. The mixture was cooled to room temperature, diluted with water and extracted with ethyl acetate. The organic layer was collected, dried over sodium sulfate, filtered and concentrated under reduced pressure to give a residue that was purified by chromatography (SiO2, heptane/EA) to afford the title compound (46 mg, 85%). MS (ES): M/Z [M+H]=457. 1H NMR: (400 MHz, CHLOROFORM-d): 1.92 (s, 3H), 4.80 (d, J=14.3 Hz, 1H), 5.03 (d, J=14.3 Hz, 1H), 7.15 (dd, J=9.0, 1.4 Hz, 1H), 7.35 (d, J=8.5 Hz, 2H), 7.57 (d, J=9.0 Hz, 1H), 7.63 (s, 1H), 7.93 (d, J=8.7 Hz, 2H) and 8.65 (s, 1H). 19F NMR (376 MHz, CHLOROFORM-d): −58.1 (s, 3F).
Reaction SMILES: N1(C(C2CCCCC2C(O)=O)=O)CCOCC1.[Cl:18][C:19]1[CH:34]=[CH:33][C:22]2[NH:23][C:24]([C:26]3[CH:31]=[CH:30][C:29]([NH2:32])=[CH:28][CH:27]=3)=[N:25][C:21]=2[CH:20]=1.C[O:36][C:37](=[O:50])[C@H:38]([CH2:43][CH:44]1[CH2:49][CH2:48][CH2:47][CH2:46][CH2:45]1)[CH2:39][C:40](O)=[O:41]>>[Cl:18][C:19]1[CH:34]=[CH:33][C:22]2[NH:23][C:24]([C:26]3[CH:27]=[CH:28][C:29]([NH:32][C:40](=[O:41])[CH2:39][CH:38]([CH2:43][CH:44]4[CH2:49][CH2:48][CH2:47][CH2:46][CH2:45]4)[C:37]([OH:50])=[O:36])=[CH:30][CH:31]=3)=[N:25][C:21]=2[CH:20]=1
Reactant: Nc1ccc(-c2nc3cc(Cl)ccc3[nH]2)cc1
Reactant: COC(=O)[C@@H](CC(=O)O)CC1CCCCC1
Agent: O=C(O)C1CCCCC1C(=O)N1CCOCC1
Product: O=C(CC(CC1CCCCC1)C(=O)O)Nc1ccc(-c2nc3cc(Cl)ccc3[nH]2)cc1
Yield: 51 %

Procedure:
This compound was prepared by the procedure described in Example 1 part (a) from 4-(5-Chloro-1H-benzoimidazol-2-yl) phenylamine and (R)-2-(Cyclohexylmethyl) succinic acid 1-methyl ester to give the crude product (2.0 g, 51%), which was used in the next step without further purification.
Reaction SMILES: COC[N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][C:11]=2[N:13]([CH2:22][CH:23]2[CH2:25][CH2:24]2)[S:14]([C:17]2[S:18][CH:19]=[CH:20][CH:21]=2)(=[O:16])=[O:15])[CH:6]=[C:5]1[C:26]([NH2:28])=[O:27].O.O.C(O)(=O)C(O)=O.CO>O>[CH:23]1([CH2:22][N:13]([S:14]([C:17]2[S:18][CH:19]=[CH:20][CH:21]=2)(=[O:15])=[O:16])[C:11]2[CH:10]=[CH:9][CH:8]=[C:7]3[C:12]=2[NH:4][C:5]([C:26]([NH2:28])=[O:27])=[CH:6]3)[CH2:25][CH2:24]1
Reactant: COCn1c(C(N)=O)cc2cccc(N(CC3CC3)S(=O)(=O)c3cccs3)c21
Agent: O=C(O)C(=O)O
Solvent: O
Solvent: CO
Product: NC(=O)c1cc2cccc(N(CC3CC3)S(=O)(=O)c3cccs3)c2[nH]1
Temperature: 70 °C
Reaction time: 1 h
Yield: 81.9 %

Procedure:
A mixture of 1-(methoxymethyl)-7-[(cyclopropylmethyl)(2-thienylsulfonyl)amino]-1H-indole-2-carboxamide (390 mg), oxalic acid dihydrate (351 mg), methanol (15 ml) and water (15 ml) was stirred at 70° C. for 1 hr, and then at 90° C. for 14 hr. The reaction mixture was allowed to cool to room temperature, and the resulting crystals were collected by filtration, washed successively with water and diethyl ether-hexane mixture, and dried to give the title compound (286 mg, yield 81%) as crystals. melting point 229-231° C.
Reaction SMILES: [CH3:1][N:2]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[O:5][CH:4]([C:12]([OH:14])=O)[CH2:3]1.[CH2:15]([NH2:18])[CH:16]=[CH2:17]>C(O)C>[CH3:1][N:2]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[O:5][CH:4]([C:12]([NH:18][CH2:15][CH:16]=[CH2:17])=[O:14])[CH2:3]1
Reactant: C=CCN
Reactant: CN1CC(C(=O)O)Oc2ccccc21
Solvent: CCO
Product: C=CCNC(=O)C1CN(C)c2ccccc2O1

Procedure:
A solution of 1.1 g of 2A, and 5 ml of 2-propenamine in 25 ml of ethanol was refluxed for 16 hours. The solvent and excess amine were stripped off and the residue was passed through a silica gel column using Solvent No. 3 as eluent. The solvent was stripped off to give 2, as light yellow liquid, boiling point not determined.
Reaction SMILES: B(Br)(Br)Br.C[O:6][C:7](=[O:31])[C:8]1[CH:13]=[CH:12][C:11]([O:14][CH2:15][C:16]([N:18]2[CH2:23][CH2:22][N:21]([CH2:24][CH2:25][C:26]([CH3:29])([CH3:28])[CH3:27])[CH2:20][CH2:19]2)=[O:17])=[C:10]([CH3:30])[CH:9]=1>ClCCl>[CH3:27][C:26]([CH3:29])([CH3:28])[CH2:25][CH2:24][N:21]1[CH2:20][CH2:19][N:18]([C:16](=[O:17])[CH2:15][O:14][C:11]2[CH:12]=[CH:13][C:8]([C:7]([OH:31])=[O:6])=[CH:9][C:10]=2[CH3:30])[CH2:23][CH2:22]1
Reactant: COC(=O)c1ccc(OCC(=O)N2CCN(CCC(C)(C)C)CC2)c(C)c1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: Cc1cc(C(=O)O)ccc1OCC(=O)N1CCN(CCC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 20 h
Yield: 72 %

Procedure:
1M Boron tribromide solution (2.66 ml, 2.66 mmol) was added dropwise to a solution of 4-{2-[4-(3,3-dimethyl-butyl)-piperazin-1-yl]-2-oxo-ethoxy}-3-methyl-benzoic acid methyl ester from Example E41.3 (500 mg, 1.33 mmol) in dichloromethane (20 ml) at 0° C. under an inert atmosphere. The mixture was stirred for 20 h at room temperature then cooled down to 0° C. 1M Boron tribromide solution (1.33 ml, 1.33 mmol) was added and the mixture was stirred for 2 h at room temperature. Solvents were re-moved in vacuo and azeotroped with toluene. The residue was purified by flash chromatography on silica gel (eluant; 1% acetic acid:5% methanol:94% chloroform) to yield the title compound (350 mg, 72%).
Reaction SMILES: CS(O)(=O)=O.[Cl:6][C:7]1[CH:12]=[C:11]([Cl:13])[CH:10]=[CH:9][C:8]=1[C:14]1([CH2:17][N:18]2[CH:22]=[N:21][CH:20]=[N:19]2)[CH2:16][O:15]1.[Cl:23][C:24]1[CH:31]=[CH:30][C:27]([CH2:28][SH:29])=[CH:26][CH:25]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.O>[Cl:23][C:24]1[CH:31]=[CH:30][C:27]([CH2:28][S:29][CH2:16][C:14]([C:8]2[CH:9]=[CH:10][C:11]([Cl:13])=[CH:12][C:7]=2[Cl:6])([OH:15])[CH2:17][N:18]2[CH:22]=[N:21][CH:20]=[N:19]2)=[CH:26][CH:25]=1
Reactant: SCc1ccc(Cl)cc1
Reactant: Clc1ccc(C2(Cn3cncn3)CO2)c(Cl)c1
Agent: CS(=O)(=O)O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: OC(CSCc1ccc(Cl)cc1)(Cn1cncn1)c1ccc(Cl)cc1Cl
Yield: 53.6 %

Procedure:
2-(2,4-Dichlorophenyl)-2-(1H-1,2,4-triazol-1-ylmethyl)oxirane methanesulphonate salt (0.336 g, 1 mmole), 4-chlorobenzyl mercaptan, (0.159 g, 1 mmole) and anhydrous potassium carbonate (0.414 g, 3 mmole) were stirred in dry N,N-dimethylformamide (15 ml) at 70° C. for 72 hours. The reaction mixture was diluted with water (70 ml) and extracted with ethyl acetate (2×70 ml). The extracts were combined and evaporated to give an oil which crystallized on standing. Recrystallization from a mixture of ethyl acetate and n-hexane gave the title compound (0.23 g, 53%) m.p. 106°-107° C.
Reaction SMILES: C(OC([N:8]([CH2:21][CH:22]1[CH2:27][CH2:26][N:25]([C:28]2[S:29][C:30]([C:33]([OH:35])=[O:34])=[CH:31][N:32]=2)[CH2:24][CH:23]1[C:36]1[CH:41]=[CH:40][CH:39]=[C:38]([F:42])[CH:37]=1)[C@@H:9]([C:11]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:14]=[CH:13][CH:12]=1)[CH3:10])=O)(C)(C)C.[ClH:43].C(OCC)(=O)C>C1COCC1>[ClH:43].[F:42][C:38]1[CH:37]=[C:36]([CH:23]2[CH:22]([CH2:21][NH:8][C@@H:9]([C:11]3[C:20]4[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=4)[CH:14]=[CH:13][CH:12]=3)[CH3:10])[CH2:27][CH2:26][N:25]([C:28]3[S:29][C:30]([C:33]([OH:35])=[O:34])=[CH:31][N:32]=3)[CH2:24]2)[CH:41]=[CH:40][CH:39]=1
Reactant: C[C@H](c1cccc2ccccc12)N(CC1CCN(c2ncc(C(=O)O)s2)CC1c1cccc(F)c1)C(=O)OC(C)(C)C
Agent: Cl
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: C[C@@H](NCC1CCN(c2ncc(C(=O)O)s2)CC1c1cccc(F)c1)c1cccc2ccccc12
Reaction time: 1 h

Procedure:
To a solution of 172 mg of the crude 2-[4-({(tert-butoxycarbonyl)[(1R)-1-(1-naphthyl)ethyl]amino}methyl)-3-(3-fluorophenyl)piperidin-1-yl]-1,3-thiazole-5-carboxylic acid in 2.0 mL of THF was added 1.00 mL of a 4 M hydrogen chloride/ethyl acetate solution at room temperature, followed by stirring for 1 hour. The solvent was removed by distillation under reduced pressure. The residue was purified by reverse phase silica gel column chromatography (acetonitrile-0.001 M hydrochloric acid) to obtain 19 mg of 2-[3-(3-fluorophenyl)-4-({[(1R)-1-(1-naphthyl)ethyl]amino}methyl)piperidin-1-yl]-1,3-thiazole-5-carboxylic acid hydrochloride as a white solid.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[N:6][C:5]([C:8]2[CH:13]=[CH:12][C:11](OC)=[CH:10][C:9]=2[OH:16])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:23]([CH:25]1[O:27][CH2:26]1)Br>CC(=O)CC>[Cl:1][C:2]1[N:7]=[N:6][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[O:16][CH2:23][CH:25]2[O:27][CH2:26]2)=[CH:4][CH:3]=1
Reactant: BrCC1CO1
Reactant: COc1ccc(-c2ccc(Cl)nn2)c(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: Clc1ccc(-c2ccccc2OCC2CO2)nn1

Procedure:
i. A stirred mixture of 6-chloro-3-(2-hydroxy-4-methoxyphenyl)pyridazine (0.1 mole), potassium carbonate (0.3 mole) and epibromohydrin (0.4 mole) in butan-2-one was heated under reflux overnight. The filtered solution was evaporated to give an oil which was purified by elution with mixtures of chloroform-methanol on a silica column to give 6-chloro-3-[2-(2,3-epoxypropoxy)phenyl]pyridazine.
Reaction SMILES: [OH:1][C@@H:2]([C@H:4]1[C:25](=[O:26])[N:6]2[C@@H:7]([C:12]([O:14][CH2:15][C:16]3[CH:21]=[CH:20][C:19]([N+:22]([O-:24])=[O:23])=[CH:18][CH:17]=3)=[O:13])[C:8](=O)[C@H:9]([CH3:10])[C@H:5]12)[CH3:3].[CH2:27]([S:34][C:35]1[N:36]=[CH:37][N:38]2[CH:42]=[C:41]([Sn](CCCC)(CCCC)CCCC)[S:40][C:39]=12)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>>[CH2:27]([S:34][C:35]1[N:36]=[CH:37][N:38]2[CH:42]=[C:41]([C:8]3[C@H:9]([CH3:10])[C@@H:5]4[C@@H:4]([C@H:2]([OH:1])[CH3:3])[C:25](=[O:26])[N:6]4[C:7]=3[C:12]([O:14][CH2:15][C:16]3[CH:21]=[CH:20][C:19]([N+:22]([O-:24])=[O:23])=[CH:18][CH:17]=3)=[O:13])[S:40][C:39]=12)[C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1
Reactant: CCCC[Sn](CCCC)(CCCC)c1cn2cnc(SCc3ccccc3)c2s1
Reactant: C[C@@H](O)[C@H]1C(=O)N2[C@@H](C(=O)OCc3ccc([N+](=O)[O-])cc3)C(=O)[C@H](C)[C@H]12
Product: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(c3cn4cnc(SCc5ccccc5)c4s3)[C@H](C)[C@H]12
Yield: 66.4 %

Procedure:
The procedure of Example 1a) was repeated, except that 424 mg of 4-nitrobenzyl (1R,3R,5R,6S)-6-((1R)-1-hydroxyethyl)-1-methyl-2-oxo-1-carbapenam-3-carboxylate and 658 mg of 7-benzylthio-2-(tri-n-butylstannyl) imidazo[5,1-b]thiazole were used as the starting compounds. Thus, 459 mg of 4-nitrobenzyl (1S,5R,6S)-2-(7-benzylthioimidazo[5,1-b]thiazol-2-yl)-6-((1R)-1-hydroxyethyl)-1-methyl-1-carbapen-2-em-3-carboxylate was prepared.
Reaction SMILES: [OH:1][C:2]1[CH:14]=[C:13]2[C:5]([C:6]3[CH2:7][CH2:8][CH:9]([NH:15][C:16](=[O:18])[CH3:17])[CH2:10][C:11]=3[NH:12]2)=[CH:4][CH:3]=1.[CH2:19](I)[CH3:20].C([O-])([O-])=O.[K+].[K+].C(Cl)(Cl)Cl>O>[CH2:19]([O:1][C:2]1[CH:14]=[C:13]2[C:5]([C:6]3[CH2:7][CH2:8][CH:9]([NH:15][C:16](=[O:18])[CH3:17])[CH2:10][C:11]=3[NH:12]2)=[CH:4][CH:3]=1)[CH3:20]
Reactant: CCI
Reactant: CC(=O)NC1CCc2c([nH]c3cc(O)ccc23)C1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: ClC(Cl)Cl
Product: CCOc1ccc2c3c([nH]c2c1)CC(NC(C)=O)CC3

Procedure:
A mixture of 0.02 mol of N-(1,3,4,9-tetrahydro-7-hydroxy-2H-carbazol-2-yl)acetamide, 0.022 mol of ethyl iodide, 0.022 mol of anhydrous K2CO3, and 50 ml of Me2CO was stirred and refluxed for 48 hr. Sufficient CHCl3 and H2O were added to the cooled reaction mixture to give two clear layers. The CHCl3 layer was washed with 1 N NaOH, H2O, dried, evaporated, and the resulting solid residue was recrystallized from i-PrOH to give the title compound, mp 184°-186°.
Reaction SMILES: I([O-])(=O)(=O)=[O:2].[Na+].[Cl:7][C:8]1[CH:13]=[CH:12][C:11]([S:14]([NH:17][CH:18]2[CH2:27][CH2:26][C:25]3[C:24]([CH2:28][CH2:29][C:30]([O:32][CH3:33])=[O:31])=[CH:23][C:22]([CH:34]=C)=[CH:21][C:20]=3[CH2:19]2)(=[O:16])=[O:15])=[CH:10][CH:9]=1>CC(O)(C)C.O1CCOCC1.O.ClCCl.[Os](=O)(=O)(=O)=O>[Cl:7][C:8]1[CH:9]=[CH:10][C:11]([S:14]([NH:17][CH:18]2[CH2:27][CH2:26][C:25]3[C:24]([CH2:28][CH2:29][C:30]([O:32][CH3:33])=[O:31])=[CH:23][C:22]([CH:34]=[O:2])=[CH:21][C:20]=3[CH2:19]2)(=[O:15])=[O:16])=[CH:12][CH:13]=1
Reactant: C=Cc1cc(CCC(=O)OC)c2c(c1)CC(NS(=O)(=O)c1ccc(Cl)cc1)CC2
Reactant: [O-][I+3]([O-])([O-])[O-]
Agent: O=[Os](=O)(=O)=O
Agent: [Na+]
Solvent: C1COCCO1
Solvent: ClCCl
Solvent: O
Product: COC(=O)CCc1cc(C=O)cc2c1CCC(NS(=O)(=O)c1ccc(Cl)cc1)C2
Temperature: 25 °C

Procedure:
2.5 g of a solution of osmium tetroxide (2.5% by weight) in 2-methyl-2-propanol, and then 20 g of sodium periodate, are added at ambient temperature to a solution of 10 g (23 mmol) of methyl 3-(6-{[(4-chlorophenyl)sulphonyl]amino}-3-vinyl-5,6,7,8-tetrahydro-1-naphth-yl)propanoate, described in Application EP 864 561, in a mixture of 100 ml of dioxan and 50 ml of water. After stirring for one night at ambient temperature, the solution is filtered and the filtrate is concentrated. The residue obtained is taken up in dichloromethane and washed with water, and the organic phase is dried and concentrated and then purified by chromatography on silica gel, using as eluant a cyclohexane/ethyl acetate mixture (60/40), to yield the expected compound.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][CH:11]([O:14][C:15]3[CH:20]=[CH:19][C:18]([O:21][C:22]([F:25])([F:24])[F:23])=[CH:17][CH:16]=3)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[Cl:26][C:27]1[N:28]([CH2:35][C@@:36]2([CH3:39])[O:38][CH2:37]2)[CH:29]=[C:30]([N+:32]([O-:34])=[O:33])[N:31]=1>>[Cl:26][C:27]1[N:28]([CH2:35][C@:36]([OH:38])([CH3:37])[CH2:39][O:1][C:2]2[CH:3]=[CH:4][C:5]([N:8]3[CH2:9][CH2:10][CH:11]([O:14][C:15]4[CH:20]=[CH:19][C:18]([O:21][C:22]([F:25])([F:23])[F:24])=[CH:17][CH:16]=4)[CH2:12][CH2:13]3)=[CH:6][CH:7]=2)[CH:29]=[C:30]([N+:32]([O-:34])=[O:33])[N:31]=1
Reactant: C[C@@]1(Cn2cc([N+](=O)[O-])nc2Cl)CO1
Reactant: Oc1ccc(N2CCC(Oc3ccc(OC(F)(F)F)cc3)CC2)cc1
Product: C[C@](O)(COc1ccc(N2CCC(Oc3ccc(OC(F)(F)F)cc3)CC2)cc1)Cn1cc([N+](=O)[O-])nc1Cl
Temperature: 100 °C
Reaction time: 8 h

Procedure:
1-(4-hydroxyphenyl)-4-(4-trifluoromethoxyphenoxy)piperidine (2034 g) and 2-chloro-1-[(2R)-2-methyl-2,3-epoxypropyl]-4-nitroimidazole (1388 g) were heated with stirring for 8 hours at about 100° C. and crude 1-{4-[(2R)-3-(2-chloro-4-nitroimidazole-1-yl)-2-hydroxy-2-methylpropoxy]phenyl}-4-(4-trifluoromethoxyphenoxy)piperidine was obtained. At the point where this was cooled to 88° C., dimethylformamide (2.5 L) was added and dissolved therein. After leaving the mixture at room temperature for 13 hours, dimethylformamide (15.8 L) was further added and the mixture was cooled to −9° C. Sodium tert-butoxide (715 g) was gradually added thereto at not more than 0° C. over 3.5 hours. After stirring for further 15 minutes, the reaction mixture was poured into a mixture of water (41.2 L) and ethyl acetate (2.1 L) at room temperature. After stirring for an hour at 30° C., the precipitate was filtrated. Crystals were washed with water (9.2 L) and then with ethyl acetate (8.2 L) under reflux. Upon cooling to 5° C., the precipitate was filtrated. The precipitate washed with ethyl acetate (2.2 L), and dried by air blasting at 60° C. for 18 hours to obtain (2R)-2-methyl-6-nitro-2-{4-[4-(4-trifluoromethoxyphenoxy)piperidine-1-yl]phenoxymethyl}-2,3-dihydroimidazo[2,1-b]oxazole (1548 g; yield 50%).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6](Cl)[C:5]([C:9]#[N:10])=[C:4]([CH3:11])[N:3]=1.[NH2:12][C@H:13]([C:15]1[N:20]=[C:19]2[CH:21]=[CH:22][N:23]([CH3:24])[C:18]2=[CH:17][C:16]=1[N:25]1[CH2:29][CH2:28][C@H:27]([N:30]([CH3:38])[C:31](=[O:37])[O:32][C:33]([CH3:36])([CH3:35])[CH3:34])[CH2:26]1)[CH3:14].C(N(CC)CC)C>CS(C)=O>[NH2:1][C:2]1[N:7]=[C:6]([NH:12][C@H:13]([C:15]2[N:20]=[C:19]3[CH:21]=[CH:22][N:23]([CH3:24])[C:18]3=[CH:17][C:16]=2[N:25]2[CH2:29][CH2:28][C@H:27]([N:30]([CH3:38])[C:31](=[O:37])[O:32][C:33]([CH3:35])([CH3:34])[CH3:36])[CH2:26]2)[CH3:14])[C:5]([C:9]#[N:10])=[C:4]([CH3:11])[N:3]=1
Reactant: C[C@H](N)c1nc2ccn(C)c2cc1N1CC[C@H](N(C)C(=O)OC(C)(C)C)C1
Reactant: Cc1nc(N)nc(Cl)c1C#N
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: Cc1nc(N)nc(N[C@@H](C)c2nc3ccn(C)c3cc2N2CC[C@H](N(C)C(=O)OC(C)(C)C)C2)c1C#N
Temperature: 90 °C
Yield: 67.8 %

Procedure:
To a 25 mL pear flask were added 2-amino-4-chloro-6-methylpyrimidine-5-carbonitrile (63.4 mg, 0.376 mmol) and tert-butyl ((S)-1-(5-((S)-1-aminoethyl)-1-methyl-1H-pyrrolo[3,2-b]pyridin-6-yl)pyrrolidin-3-yl)(methyl)carbamate (78 mg, 0.21 mmol) in DMSO (1.0 mL). Triethylamine (146 μL, 1.04 mmol) was added to the mixture, which was then heated to 90° C. for 2 hours. The reaction mixture was partitioned between saturated NaHCO3 and ethyl acetate. The aqueous layer was extracted with ethyl acetate. The organic layers were combined, dried over MgSO4, filtered, and concentrated. The residue was purified by liquid chromatography (SiO2, 25-100% EtOAc/heptanes gradient) to give the title compound as a foam (72 mg, 68%). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.36-1.48 (m, 12H), 1.93-2.05 (m, 2H), 2.17-2.30 (m, 4H), 2.92 (s, 3H), 2.97-3.13 (m, 2H), 3.16-3.29 (m, 2H), 3.80 (s, 3H), 4.84 (br s, 1H), 5.71-5.89 (m, 1H), 6.39-6.55 (m, 1H), 6.84 (br s, 1H), 6.96 (d, J=7.58 Hz, 1H), 7.16 (br s, 1H), 7.55 (d, J=3.03 Hz, 1H), 7.85 (s, 1H); ESI-MS m/z [M+H]+ calc'd for C26H35N9O2, 506. found 506.