Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][N:8]([CH2:11][CH2:12][CH2:13][NH2:14])[CH2:7][CH2:6]1.[N:15]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH:18]=[CH:17][C:16]=1[CH:25]=O.[BH4-].[Na+].O>C(O)C>[N:15]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH:18]=[CH:17][C:16]=1[CH2:25][NH:14][CH2:13][CH2:12][CH2:11][N:8]1[CH2:7][CH2:6][N:5]([CH2:4][CH2:3][CH2:2][NH:1][CH2:25][C:16]2[CH:17]=[CH:18][C:19]3[C:24](=[CH:23][CH:22]=[CH:21][CH:20]=3)[N:15]=2)[CH2:10][CH2:9]1
Reactant: NCCCN1CCN(CCCN)CC1
Reactant: O=Cc1ccc2ccccc2n1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: c1ccc2nc(CNCCCN3CCN(CCCNCc4ccc5ccccc5n4)CC3)ccc2c1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a solution of 1,4-bis(3-aminopropyl)piperazine (0.513 mL, 2.49 mmol) and 2-quinolinecarbaldehyde (823 mg, 5.24 mmol) in absolute ethanol (20 mL) was added 3 Å molecular sieves (5 g). After stirring the mixture for 12 h at room temperature, sodium borohydride (1.9 g, 49.9 mmol) was added and the mixture was stirred for 12 h at room temperature. Then the reaction mixture was quentched by dropwise addition of water (20 mL) and ethanol was removed under reduced pressure. The aqueous residue was extracted with CH2Cl2 (3×30 mL) and the combined organic layers were extracted with HCl 1N (2×50 mL). The combined aqueous layers were neutralized with NaOH 1N (50 mL) and extracted with CH2Cl2 (3×30 mL). The combined organic layers were dried over MgSO4, evaporated to dryness and the oily residue purified by flash chromatography (neutral aluminium oxide, CH2Cl2/MeOH: 90/10).
Reaction SMILES: [CH3:1][C:2]([O:5][C:6]([N:8]1[C@@H:12]2[CH2:13][C:14]([CH2:16][C@H:9]1[CH2:10][CH2:11]2)=[O:15])=[O:7])([CH3:4])[CH3:3].[Li+].[CH3:18]C([N-]C(C)C)C.C([C:27]([O-:29])=[O:28])#N>C1COCC1>[O:15]=[C:14]1[CH2:13][C@@H:12]2[N:8]([C:6]([O:5][C:2]([CH3:1])([CH3:3])[CH3:4])=[O:7])[C@@H:9]([CH2:10][CH2:11]2)[CH:16]1[C:27]([O:29][CH3:18])=[O:28]
Reactant: CC(C)[N-]C(C)C
Reactant: N#CC(=O)[O-]
Reactant: CC(C)(C)OC(=O)N1[C@@H]2CC[C@H]1CC(=O)C2
Agent: [Li+]
Solvent: C1CCOC1
Product: COC(=O)C1C(=O)C[C@H]2CC[C@@H]1N2C(=O)OC(C)(C)C
Temperature: -78 °C
Reaction time: 1 h
Yield: 79.5 %

Procedure:
N-Boc-nortropinone (10 g, 44.4 mmol) was dissolved in THF (55 mL) and cooled to −78° C., LDA (2M in THF, 24.4 mL, 48.8 mmol) was added dropwise. After 1 h at −78° C., cyanoformate (4.22 mL, 53.2 mmol) was added, and the reaction mixture was warmed up to room temperature and stirred for 5 hours. After quench with saturated NH4Cl, the reaction mixture was extracted with EtOAc. The combined EtOAc layer was washed with water and brine. Dried and concentrated. The crude product was column purified with mixture of Hexane and EtOAc to give 10 g of (1S,5R)-8-tert-butyl 2-methyl 3-oxo-8-azabicyclo[3.2.1]octane-2,8-dicarboxylate.
Reaction SMILES: [F:1][C:2]1[CH:16]=[CH:15][C:5]([CH2:6][O:7][C:8]2[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:24][C:25]([O:27][CH2:28][CH3:29])=[O:26].O>CC(=O)CC>[CH2:28]([O:27][C:25](=[O:26])[CH2:24][O:14][C:11]1[CH:12]=[CH:13][C:8]([O:7][CH2:6][C:5]2[CH:15]=[CH:16][C:2]([F:1])=[CH:3][CH:4]=2)=[CH:9][CH:10]=1)[CH3:29]
Reactant: CCOC(=O)CBr
Reactant: Oc1ccc(OCc2ccc(F)cc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Solvent: O
Product: CCOC(=O)COc1ccc(OCc2ccc(F)cc2)cc1
Temperature: 80 °C
Reaction time: 3 h
Yield: 71 %

Procedure:
A solution of 3 g of 4-(4-fluoro-benzyloxy)-phenol in 40 ml of 2-butanone was treated with 2.5 g potassium carbonate and 1.6 ml of ethyl bromoacetate. The mixture was stirred at 80° C. during 3 h, then, in order to complete the reaction, 1.7 g of potassium carbonate and 1.9 ml of ethyl bromoacetate were added successively in four portions during a period of 24 h. For the working-up, the reaction mixture was cooled to room temperature, then treated with water and extracted with ethyl acetate. The organic layer was separated, dried over magnesium sulphate and evaporated under reduced pressure. There were obtained 2.95 g (71% of theory) of [4-(4-fluoro-benzyloxy)-phenoxy]-acetic acid ethyl ester as brownish crystals which were pure enough to be used in the next step without further purification; MS: m/e=304 (M)+.
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH2:16]Br)=[CH:11][C:10]=1[F:18])C1C=CC=CC=1.[NH:19]1[CH2:24][CH2:23][O:22][CH2:21][CH2:20]1.C([O-])([O-])=O.[K+].[K+].O>CN(C=O)C>[F:18][C:10]1[CH:11]=[C:12]([CH2:15][CH2:16][N:19]2[CH2:24][CH2:23][O:22][CH2:21][CH2:20]2)[CH:13]=[CH:14][C:9]=1[OH:8]
Reactant: C1COCCN1
Reactant: Fc1cc(CCBr)ccc1OCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Oc1ccc(CCN2CCOCC2)cc1F
Temperature: 60 °C
Reaction time: 3 h
Yield: 109.6 %

Procedure:
To a solution of 1-benzyloxy-4-(2-bromo-ethyl)-2-fluoro-benzene (1.0 g, 3.2 mmol) and morpholine (278 mg, 3.2 mmol) in DMF (5 mL), was K2CO3 (432 mg, 3.2 mmol) added. The reaction mixture was heated to 60° C. and maintained for 6 hours. The reaction was cooled to room temperature and poured into H2O (50 mL). The organic compound was extracted with ethyl acetate (50 mL) and dried over MgSO4. The ethyl acetate layer was concentrated under vacuum and dissolved in methanol (50 mL). The solution was treated with Pd/C (20 mg) and stirred under H2 (1 atm) for 3 hours. The solid material was filtrated off and the filtrate was concentrated under vacuum to afford the desired compound (790 mg, 93%) as a white oil. The crude compound was used for the next step without further purification. 1H NMR (400 Mz, DMSO-d6) δ 7.33-7.45 (m, 5H), 7.09-7.15 (m, 2H), 6.97-7.01 (m, 1H), 5.13 (s, 2H), 3.56 (m, 4H), 2.64-2.68 (m, 2H), 2.44-2.50 (m, 2H), 2.39 (b, 2H). LCMS 310.5 [MH+].
Reaction SMILES: [C:1]([CH:3]([OH:17])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([O:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:5]=1)#[N:2].[CH3:18][S:19](Cl)(=[O:21])=[O:20].C(N(CC)CC)C.O>CCOCC>[S:19]([O:17][CH:3]([C:1]#[N:2])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([O:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:5]=1)(=[O:21])(=[O:20])[CH3:18]
Reactant: N#CC(O)c1cccc(Oc2ccccc2)c1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: CCOCC
Solvent: O
Product: CS(=O)(=O)OC(C#N)c1cccc(Oc2ccccc2)c1
Reaction time: 0.33 h

Procedure:
α-Cyano-m-phenoxybenzyl alcohol (8.5 g, 38 mmol) is dissolved in 150 ml ether and cooled in an ice-bath. To the solution is slowly added methanesulfonyl chloride (5.4 g, 47 mmol) in 20 ml ether. After the mixture is stirred about 20 minutes, triethylamine (4.76 g, 47 mmol) in 20 ml ether is added slowly and the mixture kept at 0° for 24 hours. Water is then added and the organic layer is separated, washed with 30% aqueous sodium bisulfite and water, dried and solvent removed under vacuum to yield α-cyano-m-phenoxybenzyl mesylate.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@:9]12[CH2:17][O:16][C@H:15]([CH2:18]O)[C@H:14]1[CH2:13][S:12][C:11]([NH:20][C:21](=[O:28])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[N:10]2.C(N(CC)CC)C.[F:36]C(F)(C(F)(F)F)C(F)(F)C(F)(F)S(F)(=O)=O>C1COCC1>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@:9]12[CH2:17][O:16][C@H:15]([CH2:18][F:36])[C@H:14]1[CH2:13][S:12][C:11]([NH:20][C:21](=[O:28])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[N:10]2
Reactant: O=S(=O)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Reactant: O=C(NC1=N[C@@]2(c3ccc(F)cc3F)CO[C@H](CO)[C@H]2CS1)c1ccccc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=C(NC1=N[C@@]2(c3ccc(F)cc3F)CO[C@H](CF)[C@H]2CS1)c1ccccc1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 65.6 %

Procedure:
A solution of N-((4aS,5S,7aS)-7a-(2,4-difluorophenyl)-5-(hydroxymethyl)-4a,5,7,7a-tetrahydro-4H-furo[3,4-d][1,3]thiazin-2-yl)benzamide (2.2 g, 5.44 mmol) in dry THF (40 mL) under nitrogen was cooled to 0° C. Triethylamine (4.55 mL, 32.6 mmol), triethylamine tri-hydrogen fluoride (1.77 mL, 10.9 mmol) and nonafluorobutanesulfonyl fluoride (1.95 mL, 10.9 mmol) were then added. The colourless solution was stirred at 0° C. for 10 minutes and then removed from the ice bath. After 120 minutes at RT, the reaction was quenched with saturated aqueous NaHCO3 (25 mL). The THF was removed in vacuo and then the mixture was partitioned between EtOAc and water. The layers were separated and the aqueous layer was further extracted with EtOAc (×2). The combined extracts were washed with brine (×1), then dried (Na2SO4), filtered and evaporated. The residue was treated with DCM (˜20 mL) to give a gelatinous precipitate. This mixture was filtered (washing with DCM). The filtrate was concentrated to ˜3 mL and loaded directly on to the column and purified by chromatography (normal phase, 50 g, Biotage SNAP cartridge KP-Sil, 50 mL per mm, gradient 5% to 35% n-hexane in EtOAc) to give the title compound (1.45 g). 1H NMR (400 MHz, MeOH-d4) δ ppm: 2.97 (br. d, J=13.00 Hz, 1 H) 3.10-3.28 (m, 2 H) 4.02 (br. s., 1 H) 4.45-4.61 (m, 3 H) 4.62-4.71 (m, 1 H) 6.98-7.12 (m, 2 H) 7.40-7.51 (m, 2 H) 7.51-7.62 (m, 2 H) 8.03 (br. s., 2 H).
Reaction SMILES: Br[C:2]1[S:3][C:4]2[C:10]([C:11]3[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=3)=[C:9]([C@H:18]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])[C:19]([O:21][CH3:22])=[O:20])[C:8]([CH3:28])=[CH:7][C:5]=2[N:6]=1.[Cl:29][C:30]1[CH:35]=[C:34](B(O)O)[CH:33]=[CH:32][N:31]=1.C([O-])([O-])=O.[K+].[K+].CCOC(C)=O>O1CCOCC1.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>[C:24]([O:23][C@@H:18]([C:9]1[C:8]([CH3:28])=[CH:7][C:5]2[N:6]=[C:2]([C:34]3[CH:33]=[CH:32][N:31]=[C:30]([Cl:29])[CH:35]=3)[S:3][C:4]=2[C:10]=1[C:11]1[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=1)[C:19]([O:21][CH3:22])=[O:20])([CH3:27])([CH3:26])[CH3:25]
Reactant: COC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2nc(Br)sc2c1-c1ccc(Cl)cc1
Reactant: OB(O)c1ccnc(Cl)c1
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: [K+]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: COC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2nc(-c3ccnc(Cl)c3)sc2c1-c1ccc(Cl)cc1
Temperature: 95 °C

Procedure:
The reaction mixture of (S)-methyl 2-(2-bromo-7-(4-chlorophenyl)-5-methylbenzo[d]thiazol-6-yl)-2-tert-butoxyacetate (370 mg, 0.769 mol), 2-chloropyridine-4-boronic acid (157 mg, 0.99 mmol), 2N K2CO3 (1.9 mL), Pd(PPh3)4 (80 mg, 0.077 mmol) in dioxane (10 mL) was heated at 95° C. for 2 h. The reaction mixture was diluted by EtOAc, washed by sat. NaHCO3, extracted by EtOAc, the organic phase was dried over MgSO4, filtered, concentrated down and purified by silica gel column, eluting by 0-100% EtOAc in hexanes to give the product. LCMS-ESI+: calc'd for C26H24Cl2N2O3S: 515.1 (M+H+). Found: 515.1 (M+H+).
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[CH:6]2)[CH3:2].Cl.[CH3:13][NH:14][CH3:15].[CH2:16]=O>C(O)(C)C>[CH2:1]([C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[C:6]2[CH2:13][N:14]([CH3:16])[CH3:15])[CH3:2]
Reactant: CCc1ccc2[nH]ccc2c1
Reactant: CNC
Reactant: C=O
Agent: Cl
Solvent: CC(C)O
Product: CCc1ccc2[nH]cc(CN(C)C)c2c1
Temperature: 25 °C
Yield: 97 %

Procedure:
5-Ethylindole 10 (1.0 g, 6.89 mmol) was combined with isopropyl alcohol (200 mL), N,N-dimethylamine hydro chloride (718 mg, 6.95 mmol) and aqueous formaldehyde (37%, 589 mg, 6.95 mmol) and heated at reflux for 2 hours. The reaction mixture was allowed to cool to room temperature, the solvent was evaporated and the resulting residue was dissolved in EtOAc and washed with saturated NaHCO3. The organic layer was dried over MgSO4, filtered and evaporated to give compound 11 as a solid in (1.35 g for a 97% yield; M+1=203.2)
Reaction SMILES: [CH3:1][N:2]([CH3:7])[CH2:3][CH2:4][NH:5][CH3:6].[Cl:8][C:9]1[C:10]([C:28]2[C:36]3[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=3)[N:30]([CH3:37])[CH:29]=2)=[N:11][C:12]([NH:15][C:16]2[CH:21]=[C:20]([N+:22]([O-:24])=[O:23])[C:19](F)=[CH:18][C:17]=2[O:26][CH3:27])=[N:13][CH:14]=1.CCN(C(C)C)C(C)C>CC(N(C)C)=O.CO>[Cl:8][C:9]1[C:10]([C:28]2[C:36]3[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=3)[N:30]([CH3:37])[CH:29]=2)=[N:11][C:12]([NH:15][C:16]2[CH:21]=[C:20]([N+:22]([O-:24])=[O:23])[C:19]([N:5]([CH2:4][CH2:3][N:2]([CH3:7])[CH3:1])[CH3:6])=[CH:18][C:17]=2[O:26][CH3:27])=[N:13][CH:14]=1
Reactant: CNCCN(C)C
Reactant: COc1cc(F)c([N+](=O)[O-])cc1Nc1ncc(Cl)c(-c2cn(C)c3ccccc23)n1
Solvent: CC(=O)N(C)C
Solvent: CO
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc(N(C)CCN(C)C)c([N+](=O)[O-])cc1Nc1ncc(Cl)c(-c2cn(C)c3ccccc23)n1
Temperature: 140 °C
Yield: 88.7 %

Procedure:
N1,N1,N2-trimethylethane-1,2-diamine (0.189 mL, 1.49 mmol) was added to a suspension 5-chloro-N-(4-fluoro-2-methoxy-5-nitrophenyl)-4-(1-methylindol-3-yl)pyrimidin-2-amine (Intermediate 87, 700 mg, 1.24 mmol) and DIPEA (0.431 mL, 2.48 mmol) in DMA (5 mL). The mixture was then heated in a microwave at 140° C. for 0.5 h. The mixture was diluted with CH3OH and absorbed onto an SCX column. The column was washed with CH3OH and eluted with ˜1M methanolic ammonia. Appropriate fractions were concentrated and further purification by FCC, eluting with 0-5% methanolic ammonia in CH2Cl2 gave the title compound (561 mg, 89%) as an orange oil; 1H NMR: (CDCl3) 2.26 (6H, s), 2.53-2.58 (2H, m), 2.88 (3H, s), 3.24-3.28 (2H, m), 3.91 (3H, s), 3.98 (3H, s), 6.68 (1H, s), 7.26-7.3 (1H, m), 7.31-7.4 (2H, m), 7.50 (1H, s), 8.23 (1H, s), 8.39 (1H, s), 8.47 (1H, d), 9.07 (1H, s); m/z: ES+ MH+ 510.27.
Reaction SMILES: [N:1]1([C:7]2[CH:12]=[CH:11][N:10]=[CH:9][N:8]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.C(N(CC)CC)C.Br[CH2:21][C:22]([C:24]1[CH:35]=[CH:34][C:27]([O:28][CH2:29][C:30]([O:32][CH3:33])=[O:31])=[CH:26][CH:25]=1)=[O:23]>C(#N)C>[N:10]1[CH:11]=[CH:12][C:7]([N:1]2[CH2:6][CH2:5][N:4]([CH2:21][C:22]([C:24]3[CH:35]=[CH:34][C:27]([O:28][CH2:29][C:30]([O:32][CH3:33])=[O:31])=[CH:26][CH:25]=3)=[O:23])[CH2:3][CH2:2]2)=[N:8][CH:9]=1
Reactant: COC(=O)COc1ccc(C(=O)CBr)cc1
Reactant: c1cc(N2CCNCC2)ncn1
Solvent: CCN(CC)CC
Solvent: CC#N
Product: COC(=O)COc1ccc(C(=O)CN2CCN(c3ccncn3)CC2)cc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 26.1 %

Procedure:
To a mixture of 4-(1-piperazinyl)pyrimidine (preparation described in DE 2316920) (1.57 g) and triethylamine (3.87 g) in acetonitrile (40 ml) at room temperature was added dropwise over about 0.5 hour a solution of methyl 4-bromoacetylphenoxyacetate (2.73 g) in acetonitrile (25 ml). On completion of the addition the reaction mixture was stirred at room temperature for 2 days. The precipitated solid was filtered off, washed with acetonitrile and the combined filtrate and washings evaporated to dryness. The resultant red oil was purified by flash chromatography, first on silica by elution with 1-5% v/v methanol/dichloromethane, then on neutral alumina by elution with 3% v/v methanol/dichloromethane, to yield the title compound (0.92 g) as an off-white solid: NMR (CDCl3) δ 2.69 (4H, m), 3.72 (4H, m), 3.80 (2H, s), 3.82 (3H, s), 4.71 (2H, s), 6.49 (1H, m), 6.94 (2H, d), 8.01 (2H, d), 8.20 (1H, d), 8.60 (1H, s); m/Z 371 (M+H)+ ; calculated for C19H22N4O4. 0.4 H2O: C 60.4%; H, 6.09%; N, 14.8%; found: C, 60.7%; H, 6.2%; N, 14.7%.
Reaction SMILES: [Cl:1][C:2]1[CH:20]=[CH:19][C:5]([C:6]([C:8]2[N:12]([CH3:13])[C:11]([C:14]([O:16][CH3:17])=[O:15])=[CH:10][C:9]=2[CH3:18])=[O:7])=[C:4]([O:21][CH3:22])[CH:3]=1.[Br:23]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl>[Br:23][CH2:18][C:9]1[CH:10]=[C:11]([C:14]([O:16][CH3:17])=[O:15])[N:12]([CH3:13])[C:8]=1[C:6](=[O:7])[C:5]1[CH:19]=[CH:20][C:2]([Cl:1])=[CH:3][C:4]=1[O:21][CH3:22]
Reactant: O=C1CCC(=O)N1Br
Reactant: COC(=O)c1cc(C)c(C(=O)c2ccc(Cl)cc2OC)n1C
Solvent: ClC(Cl)(Cl)Cl
Product: COC(=O)c1cc(CBr)c(C(=O)c2ccc(Cl)cc2OC)n1C

Procedure:
Methyl 5-(4-chloro-2-methoxybenzoyl)-1,4-dimethylpyrrole-2-carboxylate (0.5 g, 0.0015 m) was brominated with N-bromosuccinimide (0.32 g, 0.0018 m) in carbon tetrachloride according to the procedure of Example 4, Step A, to afford methyl 4-(bromomethyl)-5-(4-chloro-2-methoxybenzoyl)-1-methyl-pyrrole-2-carboxylate.
Reaction SMILES: [C:1]([O:5][C:6](=[O:20])[NH:7][C@@H:8]1[C:14](=[O:15])[NH:13][C:12]2[CH:16]=[CH:17][CH:18]=[CH:19][C:11]=2[NH:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].O([CH2:29][C:30]([F:33])([F:32])[F:31])S(C(F)(F)F)(=O)=O.ClCCl>CO>[C:1]([O:5][C:6](=[O:20])[NH:7][C@@H:8]1[C:14](=[O:15])[N:13]([CH2:29][C:30]([F:33])([F:32])[F:31])[C:12]2[CH:16]=[CH:17][CH:18]=[CH:19][C:11]=2[NH:10][CH2:9]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: O=S(=O)(OCC(F)(F)F)C(F)(F)F
Reactant: CC(C)(C)OC(=O)N[C@H]1CNc2ccccc2NC1=O
Solvent: ClCCl
Solvent: CO
Product: CC(C)(C)OC(=O)N[C@H]1CNc2ccccc2N(CC(F)(F)F)C1=O

Procedure:
In an analogous manner to that described in Example 53 a), the alkylation of the (S)-(2-oxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-3-yl)-carbamic acid tert-butyl ester with 2,2,2-trifluoroethyl triflate, yielded, after chromatography on silica gel using a 99:1-mixture of dichloromethane and methanol as the eluent, the title compound as a white foam; MS: m/e=360 (M+H)+.
Reaction SMILES: [Br:1]Br.[Cl:3][C:4]1[CH:5]=[C:6]([C:11]2([C:15](=[O:17])[CH3:16])[CH2:14][CH2:13][CH2:12]2)[CH:7]=[CH:8][C:9]=1[Cl:10]>ClCCl.CO>[Br:1][CH2:16][C:15]([C:11]1([C:6]2[CH:7]=[CH:8][C:9]([Cl:10])=[C:4]([Cl:3])[CH:5]=2)[CH2:14][CH2:13][CH2:12]1)=[O:17]
Reactant: CC(=O)C1(c2ccc(Cl)c(Cl)c2)CCC1
Reactant: BrBr
Solvent: ClCCl
Solvent: CO
Product: O=C(CBr)C1(c2ccc(Cl)c(Cl)c2)CCC1
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
A solution of bromine (10.2 ml) in dichloromethane (50 ml) was added dropwise over 3.5 hours at 10-15° C. under nitrogen to a stirred solution of 1-[1-(3,4-dichlorophenyl)cyclobutyl]ethanone (47 g) in a mixture of methanol (75 ml) and dichloromethane (15 ml). After the addition was complete, the mixture was stirred at ambient temperature for 2.5 hours, then poured onto ice-water (500 ml). The aqueous layer was separated and washed with dichloromethane (3×100 ml), then the combined organic solutions were washed with saturated aqueous sodium hydrogen carbonate solution (2×100 ml) and water (100 ml), dried (CaCl2), and the solvents removed in vacua. The residue was distilled to give 2-bromo-1-[1-(3,4-dichlorophenyl)cyclobutyl]ethanone as a pale yellow oil (40.2 g), b.p. 156-164° C. at 0.8 mbar.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][S:9]([C:12]([F:15])([F:14])[F:13])(=[O:11])=[O:10])=[C:4]([C:16](=O)[CH:17]([CH3:19])[CH3:18])[CH:3]=1.Cl.[Cl:22][C:23]1[CH:28]=[CH:27][C:26]([O:29][NH2:30])=[CH:25][CH:24]=1.CC([O-])=O.[Na+]>CCO>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][S:9]([C:12]([F:15])([F:14])[F:13])(=[O:11])=[O:10])=[C:4]([C:16](=[N:30][O:29][C:26]2[CH:27]=[CH:28][C:23]([Cl:22])=[CH:24][CH:25]=2)[CH:17]([CH3:19])[CH3:18])[CH:3]=1
Reactant: NOc1ccc(Cl)cc1
Reactant: CC(C)C(=O)c1cc(Cl)ccc1NS(=O)(=O)C(F)(F)F
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: CC(C)C(=NOc1ccc(Cl)cc1)c1cc(Cl)ccc1NS(=O)(=O)C(F)(F)F
Yield: 19.3 %

Procedure:
A solution of N-(4-chloro-2-isobutyrylphenyl)trifluoromethanesulfonamide 31B (244 mg, 1.11 mmol), O-(4-Chlorophenyl)hydroxylamine hydrochloride (200 mg, 0.91 mmol) and anhydrous NaOAc (91 mg, 1.11 mmol) in EtOH (10 mL) was stirred for 48 h at RT. The reaction mixture was concentrated under vacuum, and the residue purified by column chromatography (eluting with CH2Cl2/PE, 3:7) to afford N-{4-chloro-2-[1-(4-chlorophenoxyimino)-2-methylpropyl]phenyl}trifluoromethanesulfonamide 215 (80 mg, 24%), as an orange oil. 1H n.m.r. (200 MHz, CDCl3) δ 7.56, d, J=8.8 Hz, 1H; 7.45, dd, J=2.4 and 8.8 Hz, 1H, 7.27, d, J==90 Hz, 2H, 7.23, d, J=2.4 Hz, 1H, 7.07, d, J=9.0 Hz, 2H, 2.94, m, 1H, 1.37, s, 3H, 1.19, s, 3H.
Reaction SMILES: [O:1]([C:3]1[CH:10]=[CH:9][CH:8]=[C:7]([O:11][CH3:12])[C:4]=1[CH2:5][OH:6])[CH3:2].N(C(OC(C)C)=O)=NC(OC(C)C)=O.O[C:28]1[CH:29]=[C:30]([CH2:34][C:35]([O:37][CH2:38][CH3:39])=[O:36])[CH:31]=[CH:32][CH:33]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1COCC1.CCOCC>[CH3:2][O:1][C:3]1[CH:10]=[CH:9][CH:8]=[C:7]([O:11][CH3:12])[C:4]=1[CH2:5][O:6][C:32]1[CH:31]=[C:30]([CH2:34][C:35]([O:37][CH2:38][CH3:39])=[O:36])[CH:29]=[CH:28][CH:33]=1
Reactant: COc1cccc(OC)c1CO
Reactant: CCOC(=O)Cc1cccc(O)c1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CCOCC
Product: CCOC(=O)Cc1cccc(OCc2c(OC)cccc2OC)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 2,6-Dimethoxylbenzyl alcohol (3.33 g, 19.8 mmol) and diisopropyl azodicarboxylate (DIAD, 4.36 g, 21.6 mmol) in THF (30 ml) was added drop wise to a solution of Ethyl 2-(3-hydroxyphenyl)acetate (4 g, 22.2 mmol) and triphenylphosphine (5.66 g, 21.6 mmol) in THF (80 ml). The reaction mixture was stirred at room temperature for 8 hours, diluted with ether and washed with water and brine. The organic layer was dried over Na2SO4, filtered, concentrated, and purified by flash chromatography on a silica gel column (hex:ethyl acetate 4:1) to give the title compound.
Reaction SMILES: [Br:1][C:2]1[C:11]2[C:6](=[C:7]([F:14])[CH:8]=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][C:3]=1[C:15]([O:17]CC)=[O:16].[OH-].[Na+].Cl>O1CCCC1.O>[Br:1][C:2]1[C:11]2[C:6](=[C:7]([F:14])[CH:8]=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][C:3]=1[C:15]([OH:17])=[O:16]
Reactant: CCOC(=O)c1cnc2c(F)cc(OC)cc2c1Br
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: COc1cc(F)c2ncc(C(=O)O)c(Br)c2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 90.2 %

Procedure:
A solution of ethyl 4-bromo-8-fluoro-6-(methoxy)-3-quinolinecarboxylate (12.2 g, 37.3 mmol) in tetrahydrofuran (450 mL) was diluted by addition of a solution of sodium hydroxide 2N (27 mL) in water (75 mL). The reaction mixture was stirred overnight at room temperature then acidified to pH 3 with a solution of hydrogen chloride 5N. The solvents were evaporated to half the volume in vacuo. The reaction mixture was acidified to pH 1 by further addition of hydrogen chloride 5N, cooled to 4° C. for 30 minutes then filtered. The precipitate was dried in vacuo to afford the product as a white solid (10.1 g, 90%); MS (+ve ion electrospray) m/z 301 (MH+).
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[S:9][C:8]([OH:10])=[N:7][C:6]=1[C:11]([O:13][CH2:14][CH3:15])=[O:12])=O.[NH2:16][C:17]1[C:22]([CH3:23])=[CH:21][CH:20]=[CH:19][N:18]=1>COCCOC>[CH2:14]([O:13][C:11]([C:6]1[N:7]=[C:8]([OH:10])[S:9][C:5]=1[C:3]1[N:16]=[C:17]2[C:22]([CH3:23])=[CH:21][CH:20]=[CH:19][N:18]2[CH:2]=1)=[O:12])[CH3:15]
Reactant: CCOC(=O)c1nc(O)sc1C(=O)CBr
Reactant: Cc1cccnc1N
Solvent: COCCOC
Product: CCOC(=O)c1nc(O)sc1-c1cn2cccc(C)c2n1
Yield: 58 %

Procedure:
A solution of ethyl 5-(2-bromoacetyl)-2-hydroxy-4-thiazolecarboxylate (2.94 g) and 2-amino-3-methylpyridine (3.24 g) in 1,2-dimethoxyethane (100 ml) was refluxed for 1.5 hours. The reaction mixture was evaporated in vacuo. To the residue was added a mixture of ethyl acetate and water, and the resulting mixture was acidified to pH 0.8 with 10% hydrochloric acid. The separated aqueous layer was adjusted to pH 7.5 with 20% potassium carbonate and extracted with ethyl acetate. The extract was washed with brine, dried over magnesium sulfate, and evaporated in vacuo. The residue was triturated and diethyl ether and recrystallized from a mixture of ethyl acetate and tetrahydrofuran to give 2-(4-ethoxycarbonyl-2-hydroxy-5-thiazolyl)-8-methylimidazo[1,2-a]pyridine (1.76 g). mp 240°-242° C. (dec.)