Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O=[C:2]1[CH:6]2[CH2:7][N:8]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:9][CH2:10][N:5]2C(=O)[O:3]1.[NH2:19][C:20]1[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=1>C1COCC1.O>[N:22]1[CH:23]=[CH:24][CH:25]=[C:20]([NH:19][C:2]([CH:6]2[NH:5][CH2:10][CH2:9][N:8]([C:11]([O:13][C:14]([CH3:15])([CH3:16])[CH3:17])=[O:12])[CH2:7]2)=[O:3])[CH:21]=1
Reactant: Nc1cccnc1
Reactant: CC(C)(C)OC(=O)N1CCN2C(=O)OC(=O)C2C1
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCNC(C(=O)Nc2cccnc2)C1
Temperature: 25 °C
Reaction time: 4 h
Yield: 41.3 %

Procedure:
tert-Butyl 1,3-dioxotetrahydro-1H-oxazolo[3,4-a]pyrazine-7(3H)-carboxylate (1.50 g, 5.85 mmol) and 3-aminopyridine (1.10 g, 11.7 mmol) were heated to reflux in THF (20 mL). After 4 h, the reaction mixture was cooled to rt, diluted with H2O (50 mL), and was extracted with EtOAc (3×75 mL). The combined extracts were dried over Na2SO4, filtered, and concentrated under reduced pressure. The material was purified by column chromatography (0 to 8% MeOH in CH2Cl2 with 0.5% NH4OH gradient), yielding 0.740 g (44%) of the title compound. LC-MS: RT=4.14 min, [M+H]+=307.1.
Reaction SMILES: [OH:1][CH:2]([O:8][CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[O:17][CH3:18])[C:3]([O:5][CH2:6][CH3:7])=[O:4].N1C=CC=CC=1.[C:25](Cl)(=[O:27])[CH3:26]>CN(C)C1C=CN=CC=1.CCCCCCC>[C:25]([O:1][CH:2]([O:8][CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[O:17][CH3:18])[C:3]([O:5][CH2:6][CH3:7])=[O:4])(=[O:27])[CH3:26]
Reactant: CCOC(=O)C(O)OCCc1ccccc1OC
Reactant: CC(=O)Cl
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Solvent: CCCCCCC
Product: CCOC(=O)C(OCCc1ccccc1OC)OC(C)=O
Temperature: 0 °C
Reaction time: 1 h

Procedure:
The solution of ethyl glyoxate (50% toluene sol, 11.66 ml) and 2-methoxybenzeneethano (12.73 ml) were stirred for 1 hr to yield ethyl 2-hydroxy-2-(2-methoxyphenethoxy)acetate. The formation of ethyl 2-hydroxy-2-(2-methoxyphenethoxy)acetate was detected by 1H NMR and the reaction mixture was cooled with ice-bath and treated with pyridine (48.4 ml), 4-dimethylaminopyridine (0.44 g), and acetyl chloride (12.85 ml). After stirring under +7° C. for 1 hr, heptane (50 ml) was added, and the ice-bath cooling was removed to let the reaction mixture reach ambient temperature followed by filtration. The filtare was washed with MTBE (3×50 ml), and the combined solvents were washed with NaHCO3 (sat aq sol), water and NaCl (sat aq sol), dried over Na2SO4, and filtered. Organics were evaporated, toluene added and evaporated. By-products and residual solvents were distilled of (0 mbar-1 mbar/72°-105° C.), and the residual was dissolved in ethyl acetate. Silica gel and active carbon were added, the solution stirred for 10 min, and filtered. Organics were evaporated to yield ethyl 2-acetoxy-2-(2-methoxyphenethoxy)acetate (12.3 g) which was used in the next step.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[N:6][C:5]([NH2:8])=[C:4]([CH3:9])[C:3]=1[CH3:10].Br[CH2:12][C:13]([C:15]1[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=1)=O>C(O)C>[Cl:1][C:2]1[C:3]([CH3:10])=[C:4]([CH3:9])[C:5]2[N:6]([CH:12]=[C:13]([C:15]3[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=3)[N:8]=2)[N:7]=1
Reactant: Cc1c(N)nnc(Cl)c1C
Reactant: O=C(CBr)c1ccc(F)cc1
Solvent: CCO
Product: Cc1c(Cl)nn2cc(-c3ccc(F)cc3)nc2c1C
Yield: 84.4 %

Procedure:
The mixture of 13.0 g (82.5 mmol) of 6-chloro-4,5-dimethylpyridazin-3-ylamine and 23.2 g (107 mmol) of 2-bromo-1-(4-fluorophenyl)ethanone in 130 ml of ethanol is refluxed for 16 hours. The solvent is evaporated off under reduced pressure, and the residue is taken up with chloroform and washed with a dilute solution of aqueous ammonia. The organic phase is dried over sodium sulfate and then concentrated under reduced pressure. The brown solid obtained is triturated in acetone, to give 19.2 g of a beige powder after filtration and drying.
Reaction SMILES: [CH2:1]([N:3]1[C:18](=[O:19])[C:7]2[CH:8]=[N:9][C:10]3[C:11]([O:16][CH3:17])=[CH:12][CH:13]=[CH:14][C:15]=3[C:6]=2[N:5](CC2C=CC(OC)=CC=2)[C:4]1=[O:29])[CH3:2].FC(F)(F)C(O)=O>C(Cl)Cl>[CH2:1]([N:3]1[C:18](=[O:19])[C:7]2[CH:8]=[N:9][C:10]3[C:11]([O:16][CH3:17])=[CH:12][CH:13]=[CH:14][C:15]=3[C:6]=2[NH:5][C:4]1=[O:29])[CH3:2]
Reactant: CCn1c(=O)c2cnc3c(OC)cccc3c2n(Cc2ccc(OC)cc2)c1=O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCn1c(=O)[nH]c2c(cnc3c(OC)cccc32)c1=O
Yield: 83.8 %

Procedure:
3-Ethyl-7-methoxy-1H-pyrimido[5,4-c]quinoline-2,4-dione (25 mg) was prepared from 3-ethyl-7-methoxy-1-(4-methoxy-benzyl)-1H-pyrimido[5,4-c]quinoline-2,4-dione (50 mg, 0.11 mmol) via treatment of trifluoroacetic acid in DCM (1 mL). LCMS: m/z 272 [M+1]+.
Reaction SMILES: C[Al](C)C.CCCCCC.[CH3:11][C:12]1[CH:13]=[CH:14][C:15]([NH2:18])=[N:16][CH:17]=1.[CH:19]([O:22][CH2:23][C@H:24]([O:29][C:30]1[N:35]=[CH:34][N:33]=[C:32]2[N:36]([C:39]3[C:44]([CH3:45])=[CH:43][CH:42]=[CH:41][N:40]=3)[N:37]=[CH:38][C:31]=12)[C:25](OC)=[O:26])([CH3:21])[CH3:20]>C1(C)C=CC=CC=1>[CH:19]([O:22][CH2:23][C@H:24]([O:29][C:30]1[N:35]=[CH:34][N:33]=[C:32]2[N:36]([C:39]3[C:44]([CH3:45])=[CH:43][CH:42]=[CH:41][N:40]=3)[N:37]=[CH:38][C:31]=12)[C:25]([NH:18][C:15]1[CH:14]=[CH:13][C:12]([CH3:11])=[CH:17][N:16]=1)=[O:26])([CH3:21])[CH3:20]
Reactant: Cc1ccc(N)nc1
Reactant: COC(=O)[C@H](COC(C)C)Oc1ncnc2c1cnn2-c1ncccc1C
Agent: C[Al](C)C
Solvent: CCCCCC
Solvent: Cc1ccccc1
Product: Cc1ccc(NC(=O)[C@H](COC(C)C)Oc2ncnc3c2cnn3-c2ncccc2C)nc1
Temperature: 5 °C
Reaction time: 0.33 h
Yield: 51.1 %

Procedure:
A 2M solution of trimethylaluminium in hexane (0.404 mL, 0.81 mmol) was added to 5-methylpyridin-2-amine (84 mg, 0.77 mmol) in toluene (22 mL) at 5° C. under nitrogen. The resulting solution was stirred at 5° C. for 20 minutes. (2S)-Methyl 3-isopropoxy-2-(1-(3-methylpyridin-2-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-yloxy)propanoate (300 mg, 0.70 mmol) (Intermediate J5) in toluene (6 mL) was added dropwise at 5° C. After the addition was complete, the solution was allowed to warm to ambient temperature and was then heated to reflux for 16 hours. The solution was allowed to cool to ambient temperature. The reaction mixture was concentrated, diluted with EtOAc (100 mL) and washed sequentially with 1M citric acid (50 mL), then saturated brine (50 mL). The organic layer was separated, dried (MgSO4) and evaporated. The residue was purified by flash silica chromatography, eluting with EtOAc to afford (2S)-3-isopropoxy-N-(5-methylpyridin-2-yl)-2-(1-(3-methylpyridin-2-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-yloxy)propanamide (160 mg, 51%). 1H NMR (400 MHz, CDCl3) δ 1.09-1.12 (6H, m), 2.23 (3H, s), 2.26 (3H, s), 3.62-3.68 (1H, m), 4.00-4.09 (2H, m), 5.97 (1H, t), 7.30-7.33 (1H, m), 7.56-7.59 (1H, d), 7.70-7.73 (1H, d), 8.01-8.01 (1H, s), 8.21 (1H, d), 8.44 (1H, s), 8.46 (1H, m) 8.53 (1H, s), 9.5 (1H, broad s); m/z (ESI+) (M+H)+=448; HPLC tR=1.98 min.
Reaction SMILES: C(O[C:4]([C:6]1[O:7][CH:8]=[CH:9][CH:10]=1)=[O:5])C.[H-].[Na+].[C:13](#[N:15])[CH3:14].CO>C1(C)C=CC=CC=1>[O:7]1[CH:8]=[CH:9][CH:10]=[C:6]1[C:4]([CH2:14][C:13]#[N:15])=[O:5]
Reactant: CC#N
Reactant: CCOC(=O)c1ccco1
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CO
Product: N#CCC(=O)c1ccco1
Yield: 75.9 %

Procedure:
63.05 grams (0.5 mole) of furan-2-carboxylic acid ethyl ester and 30.0 grams (1 mole) of sodium hydride (80 weight % suspension in white oil) were reacted with 41 grams (1 mole) of acetonitrile in 500 ml of toluene with the addition of 1 ml of methanol at 90° C. After 3 hours reaction time the toluene was distilled off, the residue stirred with 500 ml of water, acidified with hydrochloric acid to pH 1.5 and the precipitated product filtered off with suction and recrystallized from methanol. There were obtained 51.3 grams (76% of theory) of 2-furanoylacetonitrile having a melting point of 74°-75° C.
Reaction SMILES: [CH3:1][S:2]([NH:5][C:6]1[CH:7]=[CH:8][C:9]2[N:10]([CH:12]=[C:13]([C:15]([OH:17])=O)[N:14]=2)[CH:11]=1)(=[O:4])=[O:3].[NH2:18][C@@H:19]([CH3:36])[CH2:20][N:21]1[CH:25]=[CH:24][C:23]([C:26]2[CH:33]=[C:32]([F:34])[C:29]([C:30]#[N:31])=[C:28]([Cl:35])[CH:27]=2)=[N:22]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C(Cl)Cl>[Cl:35][C:28]1[CH:27]=[C:26]([C:23]2[CH:24]=[CH:25][N:21]([CH2:20][C@@H:19]([NH:18][C:15]([C:13]3[N:14]=[C:9]4[CH:8]=[CH:7][C:6]([NH:5][S:2]([CH3:1])(=[O:3])=[O:4])=[CH:11][N:10]4[CH:12]=3)=[O:17])[CH3:36])[N:22]=2)[CH:33]=[C:32]([F:34])[C:29]=1[C:30]#[N:31]
Reactant: C[C@H](N)Cn1ccc(-c2cc(F)c(C#N)c(Cl)c2)n1
Reactant: CS(=O)(=O)Nc1ccc2nc(C(=O)O)cn2c1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Product: C[C@@H](Cn1ccc(-c2cc(F)c(C#N)c(Cl)c2)n1)NC(=O)c1cn2cc(NS(C)(=O)=O)ccc2n1
Yield: 18.8 %

Procedure:
The title compound was prepared using the procedure described in Example 3(h) starting from 6-(methylsulfonamido)imidazo[1,2-a]pyridine-2-carboxylic acid (0.215 mmol, 0.055 g) and (S)-4-(1-(2-aminopropyl)-1H-pyrazol-3-yl)-2-chloro-6-fluorobenzo-nitrile (0.179 mmol, 0.050 g) using DCM (10 ml) as the solvent. HBTU (0.018 mmol, 6.80 mg) was used instead of HOBt. The mixture was diluted with DCM and washed with Na2CO3 solution and water. The organic phase was evaporated. The water phase and Na2CO3 phase were washed with EtOAc. The evaporated organic phases were combined and purified by preparative HPLC. 0.0174 g of the title compound was obtained. 1H-NMR (400 MHz, DMSO-d6): δ 1.14 (d, 3H), 3.04 (s, 3H), 4.27-4.58 (m, 3H), 7.00 (d, 1H), 7.27 (dd, 1H), 7.57-7.62 (m, 1H), 7.87 (d, 1H), 7.91 (dd, 1H), 7.95-7.97 (m, 1H), 8.36 (d, 1H), 8.49-8.51 (m, 1H), 8.55 (d, 1H), 9.77 (s, 1H).
Reaction SMILES: [CH:1]([O:4][C:5]1[N:10]=[CH:9][C:8]([OH:11])=[CH:7][CH:6]=1)([CH3:3])[CH3:2].[Br:12][C:13]1[CH:14]=[CH:15][C:16](F)=[N:17][CH:18]=1.C([O-])([O-])=O.[K+].[K+].O>CS(C)=O>[Br:12][C:13]1[CH:18]=[N:17][C:16]([O:11][C:8]2[CH:9]=[N:10][C:5]([O:4][CH:1]([CH3:3])[CH3:2])=[CH:6][CH:7]=2)=[CH:15][CH:14]=1
Reactant: Fc1ccc(Br)cn1
Reactant: CC(C)Oc1ccc(O)cn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: CC(C)Oc1ccc(Oc2ccc(Br)cn2)cn1
Yield: 0 %

Procedure:
The mixture of Example 68B (1.0821 g, 7.064 mmol), 5-bromo-2-fluoropyridine (1.245 g, 7.074 mmol, 1.0 eq.), and K2CO3 (1.17 g, 8.47 mmol, 1.2 eq.) in dimethylsulfoxide (8 mL) was heated to 160° C. under microwave for 30 min. The reaction mixture was poured into water. The aqueous layer was extracted with ether (1×). The ether layer was washed with 10% NaOH (1×), brine (1×), dried over MgSO4, filtered and concentrated. The product was purified on silica gel eluting with ethyl acetate: hexane gradient to give the desired product as a solid (0.845 mg, 39%).
Reaction SMILES: [CH:1]([C:3]1[CH:12]=[CH:11][CH:10]=[C:9]([O:13][CH3:14])[C:4]=1[C:5]([O:7][CH3:8])=[O:6])=O.[C:15]([NH:23][CH2:24][C:25]([OH:27])=[O:26])(=O)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.CC([O-])=O.[Na+]>C(OC(=O)C)(=O)C>[CH3:14][O:13][C:9]1[CH:10]=[CH:11][CH:12]=[C:3](/[CH:1]=[C:24]2\[N:23]=[C:15]([C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=3)[O:27][C:25]\2=[O:26])[C:4]=1[C:5]([O:7][CH3:8])=[O:6]
Reactant: COC(=O)c1c(C=O)cccc1OC
Reactant: O=C(O)CNC(=O)c1ccccc1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)OC(C)=O
Product: COC(=O)c1c(/C=C2\N=C(c3ccccc3)OC2=O)cccc1OC
Temperature: 100 °C
Yield: 251.8 %

Procedure:
To a solution of methyl 2-formyl-6-methoxybenzoate (1.6 g, 8.24 mmol) in acetic anhydride (10 mL) was added 2-benzamidoacetic acid (1.77 g, 9.88 mmol) and NaOAc (810 mg, 9.88 mmol). The mixture was heated at 100° C. in a microwave reactor. The reactant mixture was partitioned between EtOAc (30 mL) and H2O (50 mL). The organic layer was washed with saturated aqueous Na2CO3 (5×30 mL), dried over Na2SO4, and concentrated to give the title compound (7 g). ESI-MS m/z [M+H]+ 338.1.
Reaction SMILES: B.CSC.[C:5]([O:9][C:10]([NH:12][C@@:13]1([C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])[C@H:18]([CH2:19][S:20][C:21]2[CH:26]=[CH:25][C:24]([F:27])=[C:23]([F:28])[CH:22]=2)[C:17](=[O:29])[C@@H:16]2[C@H:14]1[C@H:15]2[C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])=[O:11])([CH3:8])([CH3:7])[CH3:6]>C(OCC)C>[C:5]([O:9][C:10]([NH:12][C@@:13]1([C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])[C@H:18]([CH2:19][S:20][C:21]2[CH:26]=[CH:25][C:24]([F:27])=[C:23]([F:28])[CH:22]=2)[C@@H:17]([OH:29])[C@@H:16]2[C@H:14]1[C@H:15]2[C:30]([O:32][C:33]([CH3:35])([CH3:34])[CH3:36])=[O:31])=[O:11])([CH3:8])([CH3:6])[CH3:7]
Reactant: CC(C)(C)OC(=O)N[C@]1(C(=O)OC(C)(C)C)[C@@H]2[C@@H](C(=O)OC(C)(C)C)[C@@H]2C(=O)[C@H]1CSc1ccc(F)c(F)c1
Agent: B
Solvent: CCOCC
Solvent: CSC
Product: CC(C)(C)OC(=O)N[C@]1(C(=O)OC(C)(C)C)[C@@H]2[C@@H](C(=O)OC(C)(C)C)[C@@H]2[C@H](O)[C@H]1CSc1ccc(F)c(F)c1
Temperature: 25 °C
Yield: 60.7 %

Procedure:
Di-tert-butyl (1S,2R,5R,6R)-2-[(tert-butoxycarbonyl)amino]-3-methylidene-4-oxobicyclo[3.1.0]hexane-2,6-dicarboxylate (1.03 g, 2.43 mmol) in diethyl ether (100 mL) is bubbled with nitrogen gas for 10 minutes. Add 3,4-difluorobenzenethiol (0.36 g, 2.43 mmol) and triethylamine (0.01 mL, 0.05 μmol). The mixture is warmed to 40° C. and stirred for 15 minutes. The mixture is then allowed to cool to ambient temperature, transferred to a separatory funnel, diluted with hexane (40 mL), washed with of 2N aqueous KOH (1×30 mL), dried over magnesium sulfate, filtered, and concentrated under reduced pressure giving di-tert-butyl (1S,2R,3S,5R,6R)-2-[(tert-butoxycarbonyl)amino]-3-{[(3,4-difluorophenyl)sulfanyl]methyl}-4-oxobicyclo[3.1.0]hexane-2,6-dicarboxylate (1.35 g, 2.37 mmol): MS (m/z): 567.8 (M−H). This material is taken up in 120 mL of diethyl ether and added slowly over 2 hours to a 200 mL ether solution at −10° C. which contains R-(+)-2-methyl-CBS-oxazaborolidine (981.72 mg, 3.54 mmol) and borane-methyl sulfide complex (2M in tetrahydrofuran, 5.02 mL, 10.04 mmol). The mixture is stirred for an additional hour after final addition of di-tert-butyl (1S,2R,3S,5R,6R)-2-[(tert-butoxycarbonyl)amino]-3-{[(3,4-difluorophenyl)sulfanyl]methyl}-4-oxobicyclo[3.1.0]hexane-2,6-dicarboxylate. Silica gel (30 g) is added over 30 minutes and the reaction mixture is gradually warmed to ambient temperature. The suspension is filtered, and washed with 300 mL of diethyl ether. The solvent is concentrated under reduced pressure giving a residue. The residue is purified by flash chromatography, eluting with (0 to 15% ethyl acetate/hexanes) to give the title compound (0.844 g, 1.48 mmol, 60.7% yield): MS (m/z): 569.8 (M−H).
Reaction SMILES: [NH2:1][C:2]1[C:3]([F:27])=[CH:4][C:5]([F:26])=[C:6]([N:8]2[C:17]3[C:12](=[CH:13][C:14]([N+:19]([O-:21])=[O:20])=[C:15](F)[CH:16]=3)[C:11](=[O:22])[C:10]([C:23]([OH:25])=[O:24])=[CH:9]2)[CH:7]=1.[NH3:28].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>N1C=CC=CC=1>[NH2:28][C:15]1[CH:16]=[C:17]2[C:12]([C:11](=[O:22])[C:10]([C:23]([OH:25])=[O:24])=[CH:9][N:8]2[C:6]2[CH:7]=[C:2]([NH2:1])[C:3]([F:27])=[CH:4][C:5]=2[F:26])=[CH:13][C:14]=1[N+:19]([O-:21])=[O:20]
Reactant: N
Reactant: Nc1cc(-n2cc(C(=O)O)c(=O)c3cc([N+](=O)[O-])c(F)cc32)c(F)cc1F
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: c1ccncc1
Product: Nc1cc(-n2cc(C(=O)O)c(=O)c3cc([N+](=O)[O-])c(N)cc32)c(F)cc1F
Temperature: 50 °C
Reaction time: 15 h
Yield: 72 %

Procedure:
1-(5-Amino-2,4-difluorophenyl)-7-fluoro-6-nitro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (70 mg) was added to a mixed liquid of 28% aqueous ammonia (85 mg) and pyridine (2 ml), and the mixture was stirred at 50° C. for 15 hours. The reaction mixture was acidified with 3% citric acid (20 ml), and solids formed were collected by filtration. The solids were subjected to azeotropic distillation with ethanol and toluene. Hexane was added to the residue to conduct filtration, thereby obtain the title compound (50 mg) as a yellow powder.
Reaction SMILES: Br[C:2]1[C:7]2[S:8][CH:9]=[CH:10][C:6]=2[CH:5]=[CH:4][CH:3]=1.[Mg].[C:12](=O)([O:16]CC)[O:13][CH2:14][CH3:15].[Cl-].[NH4+]>C1COCC1>[CH2:14]([O:13][C:12]([C:2]1[C:7]2[S:8][CH:9]=[CH:10][C:6]=2[CH:5]=[CH:4][CH:3]=1)=[O:16])[CH3:15]
Reactant: Brc1cccc2ccsc12
Reactant: CCOC(=O)OCC
Agent: [Cl-]
Agent: [Mg]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CCOC(=O)c1cccc2ccsc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 71 %

Procedure:
7-bromobenzo[b]thiophene (500 mg, 2.36 mmol) is dissolved in dry THF (5.0 mL) under nitrogen. Magnesium turnings (530 mg, 2.83 mmol, 1.20 equiv.) are added and the resulting mixture is heated at reflux until dissolution of the magnesium has occurred. The resulting cloudy yellow solution is allowed to cool to rt and diethyl carbonate (2 mL, excess) is added and stirring continued for one hour, when ammonium chloride (10% aq) is added. The resulting mixture is partitioned between DCM and water and the aqueous layer is extracted with DCM. The organic fractions are combined, washed with brine, dried over Na2SO4 and adsorbed onto silica. Purification by LC using 8/2 cyclohexane/dichloromethane as the eluent afforded the title compound as a pale orange oil (346.2 mg, 71%).
Reaction SMILES: [Br:1][C:2]1[CH:9]=[C:6]([CH:7]=O)[C:5]([OH:10])=[CH:4][CH:3]=1.[CH3:11][O:12][C:13]1[CH:18]=[CH:17][C:16]([C:19](=[O:21])[CH3:20])=[CH:15][CH:14]=1.[OH-].[K+].Cl>C(O)C.O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([OH:10])=[C:6]([CH:7]=[CH:20][C:19]([C:16]2[CH:17]=[CH:18][C:13]([O:12][CH3:11])=[CH:14][CH:15]=2)=[O:21])[CH:9]=1
Reactant: O=Cc1cc(Br)ccc1O
Reactant: COc1ccc(C(C)=O)cc1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: COc1ccc(C(=O)C=Cc2cc(Br)ccc2O)cc1
Reaction time: 8 h

Procedure:
5-Bromosalicylaldehyde (20.1 g) and p-methoxyacetophenone (15.0 g) were dissolved in ethanol (80 ml) and a solution of potassium hydroxide (26.5 g) in water (40 ml) was added, with cooling. The reaction mixture was allowed to stand overnight, and then was acidified by addition to excess hydrochloric acid. The precipitated 5-bromo-2-hydroxy.4'-methoxychalcone was filtered off, washed with water, and recrystallised from ethanol, 27.5 g, m.p. 177°-179°.
Reaction SMILES: N1C=CC=CC=1.[Cl-].[O:8]([C:15]1[CH:16]=[C:17]([CH:20]=[CH:21][CH:22]=1)[CH2:18][OH:19])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>C(Cl)Cl.[O-2].[O-2].[O-2].[Cr+6]>[O:8]([C:15]1[CH:16]=[C:17]([CH:20]=[CH:21][CH:22]=1)[CH:18]=[O:19])[C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1
Reactant: OCc1cccc(Oc2ccccc2)c1
Agent: [Cr+6]
Agent: [Cl-]
Agent: [O-2]
Solvent: c1ccncc1
Solvent: ClCCl
Product: O=Cc1cccc(Oc2ccccc2)c1
Reaction time: 0.25 h

Procedure:
Chromium trioxide (3.00 g.) was added to a stirred solution of pyridine (4.75 g.) in dry methalene chloride (75 ml.), and stirring was continued for a further 15 minutes. 3-Phenoxybenzyl alcohol (1 g.) in methylene chloride (5 ml.) was added, the mixture stirred for a further 15 minutes, decanted and the residue washed with diethyl ether (100 ml.). The filtrate was washed with 55 sodium hydroxide solution (3 × 50 ml), 2.5 NHCl (50 ml.) and 5% sodium carbonate solution (50 ml.) and dried over Na2SO4 to give 3-phenoxy-benzaldehyde. Alternatively the alcohol can be oxidized using Jones' reagent, a similar yield of aldehyde being obtained. Yield (0.80 g.), b.p. 126°/0.8 mm.Hg, nD = 1.5984.
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][C:10]([NH:13][CH2:14][C:15]3[N:19]([CH3:20])[C:18]4[CH:21]=[CH:22][C:23]([C@@:25]([NH2:34])([C:27]([N:29]5[CH2:33][CH2:32][CH2:31][CH2:30]5)=[O:28])[CH3:26])=[CH:24][C:17]=4[N:16]=3)=[CH:9][CH:8]=2)[N:3]=1.Br[CH2:36][C:37]#[N:38].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:8]=[CH:9][C:10]([NH:13][CH2:14][C:15]3[N:19]([CH3:20])[C:18]4[CH:21]=[CH:22][C:23]([C@@:25]([NH:34][CH2:36][C:37]#[N:38])([C:27]([N:29]5[CH2:33][CH2:32][CH2:31][CH2:30]5)=[O:28])[CH3:26])=[CH:24][C:17]=4[N:16]=3)=[CH:11][CH:12]=2)[N:3]=1
Reactant: N#CCBr
Reactant: Cc1nc(-c2ccc(NCc3nc4cc([C@@](C)(N)C(=O)N5CCCC5)ccc4n3C)cc2)no1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: Cc1nc(-c2ccc(NCc3nc4cc([C@@](C)(NCC#N)C(=O)N5CCCC5)ccc4n3C)cc2)no1

Procedure:
Prepared analogously to Example 1k from (R)-2-[4-(5-methyl-1,2,4-oxadiazol-3-yl)-phenylaminomethyl]-1-methyl-5-[1-amino-1-(pyrrolidinocarbonyl)-ethyl]-benzimidazole and bromoacetonitrile/potassium carbonate in acetone.
Reaction SMILES: [Na].[CH:2]([OH:5])([CH3:4])[CH3:3].Br[CH2:7][C:8]1[C:15]([F:16])=[C:14]([F:17])[C:11]([CH2:12][OH:13])=[C:10]([F:18])[C:9]=1[F:19].Cl>O>[F:17][C:14]1[C:15]([F:16])=[C:8]([CH2:7][O:5][CH:2]([CH3:4])[CH3:3])[C:9]([F:19])=[C:10]([F:18])[C:11]=1[CH2:12][OH:13]
Reactant: CC(C)O
Reactant: OCc1c(F)c(F)c(CBr)c(F)c1F
Agent: Cl
Agent: [Na]
Solvent: O
Product: CC(C)OCc1c(F)c(F)c(CO)c(F)c1F
Temperature: 40 °C
Reaction time: 16 h

Procedure:
Sodium (1.0 g) was added to dry isopropanol (200 cm3), maintained at 40° C. under an atmosphere of dry nitrogen. After dissolution was complete, 4-(bromomethyl)-2,3,5,6-tetrafluorobenzyl alcohol (10.9 g) was added and the reaction was stirred for 16 hours, at the ambient temperature. The reaction mixture was poured into water, acidified with dilute aqueous hydrochloric acid, and extracted into ethyl acetate. The combined organic extracts were washed with water, dried over anhydrous magnesium sulphate, and concentrated by evaporation of the solvent under reduced pressure. The residue was combined with the product of a similar reaction and distilled under reduced pressure to give 2,3,5,6-tetrafluoro-4-[(1-methyl-ethoxy)methyl]-benzyl alcohol (0.8 g).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:25])[CH:5]=[CH:6][C:7]1[CH:15]=[CH:14][CH:13]=[C:12]2[C:8]=1[CH:9]=[CH:10][N:11]2[S:16]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)(=[O:18])=[O:17])[CH3:2]>C(OCC)(=O)C.C(O)C.[Pd]>[CH2:1]([O:3][C:4](=[O:25])[CH2:5][CH2:6][C:7]1[CH:15]=[CH:14][CH:13]=[C:12]2[C:8]=1[CH:9]=[CH:10][N:11]2[S:16]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)(=[O:17])=[O:18])[CH3:2]
Reactant: CCOC(=O)C=Cc1cccc2c1ccn2S(=O)(=O)c1ccccc1
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CCO
Product: CCOC(=O)CCc1cccc2c1ccn2S(=O)(=O)c1ccccc1

Procedure:
3-[1-(Benzenesulphonyl)-1H-indol-4-yl]acrylic acid ethyl ester (2.48 g, 6.98 mmol) was hydrogenated over 10% Pd-C (500 mg) in ethyl acetate-ethanol (4:1; 75 ml), under an atmosphere of hydrogen. The catalyst was removed by filtration after 4 h, and the solvents were removed to obtain the title compound as a colourless oil which crystallised on standing (2.47 g, 100%); δH (CDCl3, 360 MHZ) 1.10 (3H, t, J=6.8 Hz), 2.57 (2H, t, J=7.5 Hz), 3.06 (2H, t, J=7.5 Hz), 4.02 (2H, q, J=7.2 Hz), 6.66 (1H, d, J=0.72 Hz), 6.98 (1H, d, J=7.5 Hz), 7.14-7.18 (1H, m), 7.34-7.38 (2H, m), 7.43-7.48 (1H, m), 7.50 (1H, d, J=3.9 Hz), 7.77-7.82 (3H, m).
Reaction SMILES: [Cl:1][C:2]1[C:7]2[C:8](=[O:21])[N:9]([CH3:20])[CH2:10][C:11]3[N:12]([CH:13]=[N:14][C:15]=3[C:16](=[N:18][OH:19])[NH2:17])[C:6]=2[CH:5]=[CH:4][C:3]=1[F:22].[Cl:23][CH2:24][C:25](OC(=O)CCl)=O.C>CN(C)C=O.C(#N)C>[Cl:1][C:2]1[C:7]2[C:8](=[O:21])[N:9]([CH3:20])[CH2:10][C:11]3[N:12]([CH:13]=[N:14][C:15]=3[C:16]3[N:17]=[C:25]([CH2:24][Cl:23])[O:19][N:18]=3)[C:6]=2[CH:5]=[CH:4][C:3]=1[F:22]
Reactant: CN1Cc2c(C(N)=NO)ncn2-c2ccc(F)c(Cl)c2C1=O
Reactant: O=C(CCl)OC(=O)CCl
Solvent: CC#N
Solvent: CN(C)C=O
Product: CN1Cc2c(-c3noc(CCl)n3)ncn2-c2ccc(F)c(Cl)c2C1=O
Reaction time: 2 h
Yield: 68.4 %

Procedure:
A suspension of 7.0 g (0.0216 mol) of 7-chloro-8-fluoro-5-methyl-6-oxo-5,6-dihydro-4H-imidazo[1,5-a][1,4]benzodiazepine-3-carboxamidoxime in 70 ml of N,N-dimethylformamide was treated with 4.38 g (0.0256 mol) of chloroacetic anhydride. The yellow solution obtained was stirred at 100° for 2 hrs. and then completely freed from the solvents. The oily product was taken up in 300 ml of acetonitrile, whereupon the solution was treated with active charcoal, boiled at reflux and filtered while hot over 100 g of silica gel; the silica gel was rinsed with 200 ml of acetone and the filtrate was evaporated. The crystalline foam was suspended in 100 ml of ether and suction filtered. Additional material could be obtained from the mother liquor. There was obtained a total of 5.65 g (68%) of 7-chloro-3-(5-chloromethyl-1,2,4-oxadiazol-3-yl)-8-fluoro-5-methyl-5,6-dihydro-4H-imidazo[1,5-a ][1,4]benzodiazepin-6-one as white-yellowish crystals; m.p. 215°-218°.