Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1C=CC(P(C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.I[C:48]1[C:49]2[C:50](=[CH:54][N:55]([CH2:57][C:58]3[CH:63]=[CH:62][C:61]([O:64][CH3:65])=[CH:60][CH:59]=3)[N:56]=2)[N:51]=[CH:52][CH:53]=1.[Cl:66][C:67]1[CH:68]=[CH:69][C:70]([F:80])=[C:71]([C:73]2[CH:78]=[C:77]([NH2:79])[CH:76]=[CH:75][N:74]=2)[CH:72]=1.CC([O-])(C)C.[Na+]>C1(C)C=CC=CC=1.C(O[Pd]OC(=O)C)(=O)C>[Cl:66][C:67]1[CH:68]=[CH:69][C:70]([F:80])=[C:71]([C:73]2[CH:78]=[C:77]([NH:79][C:48]3[C:49]4[C:50](=[CH:54][N:55]([CH2:57][C:58]5[CH:63]=[CH:62][C:61]([O:64][CH3:65])=[CH:60][CH:59]=5)[N:56]=4)[N:51]=[CH:52][CH:53]=3)[CH:76]=[CH:75][N:74]=2)[CH:72]=1
Reactant: COc1ccc(Cn2cc3nccc(I)c3n2)cc1
Reactant: Nc1ccnc(-c2cc(Cl)ccc2F)c1
Agent: CC(=O)O[Pd]OC(C)=O
Agent: CC(C)(C)[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: COc1ccc(Cn2cc3nccc(Nc4ccnc(-c5cc(Cl)ccc5F)c4)c3n2)cc1
Temperature: 40 °C
Reaction time: 0.17 h
Yield: 36.7 %

Procedure:
Into a 5 mL oven-dried microwave vial was added (R)-BINAP (159 mg, 0.255 mmol) and diacetoxypalladium (13.28 mg, 0.059 mmol). Toluene (2 mL) was added and the solution was stirred at 40° C. for 10 min. Then 7-iodo-2-(4-methoxybenzyl)-2H-pyrazolo[4,3-b]pyridine (216 mg, 0.592 mmol) in 2 mL of toluene was added, followed by 2-(5-chloro-2-fluorophenyl)pyridin-4-amine (132 mg, 0.592 mmol) and sodium 2-methylpropan-2-olate (85 mg, 0.887 mmol). Nitrogen was sparged into the solution for about 2 minutes, and the reaction was heated in a 100° C. oil bath over night. The reaction mixture was cooled and purified using silica column chromatography (0-5 methanol/dichloromethane) to give a residue. The residue was further purified by silica column chromatography (1:1 Ethyl acetate/hexanes) gave 100 mg of N-(2-(5-chloro-2-fluorophenyl)pyridin-4-yl)-2-(4-methoxybenzyl)-2H-pyrazolo[4,3-b]pyridin-7-amine. MS [M+H] found 460.3.
Reaction SMILES: [Br:1][C:2]1[C:10]2[N:9]=[C:8]([C:11]3[CH:16]=[CH:15][C:14]([CH:17]([CH3:19])[CH3:18])=[CH:13][CH:12]=3)[N:7]([CH2:20][CH2:21][O:22][CH3:23])[C:6]=2[C:5]([O:24][CH3:25])=[CH:4][C:3]=1[CH:26]=[O:27].[CH3:28][O:29][C:30]1[CH:31]=[C:32]([Mg]Br)[CH:33]=[CH:34][CH:35]=1>>[Br:1][C:2]1[C:10]2[N:9]=[C:8]([C:11]3[CH:12]=[CH:13][C:14]([CH:17]([CH3:19])[CH3:18])=[CH:15][CH:16]=3)[N:7]([CH2:20][CH2:21][O:22][CH3:23])[C:6]=2[C:5]([O:24][CH3:25])=[CH:4][C:3]=1[CH:26]([C:34]1[CH:33]=[CH:32][CH:31]=[C:30]([O:29][CH3:28])[CH:35]=1)[OH:27]
Reactant: COCCn1c(-c2ccc(C(C)C)cc2)nc2c(Br)c(C=O)cc(OC)c21
Reactant: COc1cccc([Mg]Br)c1
Product: COCCn1c(-c2ccc(C(C)C)cc2)nc2c(Br)c(C(O)c3cccc(OC)c3)cc(OC)c21

Procedure:
The title compound is prepared from 4-bromo-2-(4-isopropyl-phenyl)-7-methoxy-1-(2-methoxy-ethyl)-1H-benzoimidazole-5-carbaldehyde and 3-methoxyphenyl-magnesium bromide as described in examples 35 and 51.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][NH:10][C:11]([NH:13][CH:14]([C:26]2[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=2)[C:15](OC)(OC)[C:16]2[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=2)=[O:12])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.[OH-].[Na+]>>[C:1]1([CH2:7][CH2:8][CH2:9][N:10]2[C:15]([C:16]3[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=3)=[C:14]([C:26]3[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=3)[NH:13][C:11]2=[O:12])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: COC(OC)(c1ccncc1)C(NC(=O)NCCCc1ccccc1)c1ccc(F)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: O=c1[nH]c(-c2ccc(F)cc2)c(-c2ccncc2)n1CCCc1ccccc1
Temperature: 25 °C

Procedure:
N-(3-phenylpropyl)-N′-[(2,2-dimethoxy-2-(4-pyridyl)-1-(4-fluorophenyl)ethyl)] urea (224 g, 0.45 mol) was mixed with 4N HCl (800 g) and heated under reflux for 4-5 h (95–100° C.). Upon completion, the reaction was cooled to room temperature and adjusted to pH 13 with 8N NaOH solution (480 g), resulting in precipitation of a solid product. The pH of the suspension was controlled to pH≧13 for 30 min, with addition of sodium hydroxide as needed. The suspension was centrifuged and the aqueous phase removed and discarded. The solid was resuspended in 2N NaOH solution (1000 g), centrifuged a second time and then re-suspended in water (2×1000 g, water phase pH 7). The solid product was dried at 45–50° C., under vacuum (for about 4–5 days), to a final water content of <2%, to yield the product as a tan solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:21]=[CH:20][C:19]([NH:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[N+:30]([O-])=O)=[CH:18][CH:17]=1.[Cl-].[NH4+]>C(O)C.O.O1CCCC1.[Fe]>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:17]=[CH:18][C:19]([NH:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[NH2:30])=[CH:20][CH:21]=1
Reactant: COc1cc2nccc(Oc3ccc(NCc4ccccc4[N+](=O)[O-])cc3)c2cc1OC
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: O
Solvent: CCO
Product: COc1cc2nccc(Oc3ccc(NCc4ccccc4N)cc3)c2cc1OC
Temperature: 25 °C
Yield: 56.9 %

Procedure:
6,7-Dimethoxy-4-(4-(2-nitrophenylmethylamino)phenyloxy)quinoline (150 mg, 0.35 mmol) was dissolved in ethanol (2.8 ml) and water (0.7 ml), and then iron powder (78 mg, 1.4 mmol) and ammonium chloride (150 mg, 2.8 mmol) were added and the mixture was heated to reflux for 1 hour. After cooling to room temperature, the reaction solution was diluted with tetrahydrofuran and water, and the insoluble portion was filtered off. The filtrate was distilled off under reduced pressure, and then the residue was purified with a silica gel column (ethyl acetate system), the obtained amorphous substance was solidified with hexane and ethyl acetate, and the obtained crystals were washed with hexane-ethyl acetate, filtered out, washed with hexane and dried by aspiration at room temperature to obtain the title compound (80 mg, 0.1993 mmol, 56.93%) as milky white crystals.
Reaction SMILES: N1CCCCC1.[N+:7]([C:10]1[CH:23]=[CH:22][CH:21]=[C:20]2[C:11]=1[C:12](=[O:25])[C:13]1[CH2:14][CH2:15][CH2:16][CH2:17][C:18]=1[C:19]2=[O:24])([O-])=O.[H][H]>[Pd].COCCO>[NH2:7][C:10]1[C:11]2[C:12](=[O:25])[C:13]3[C:18](=[CH:17][CH:16]=[CH:15][CH:14]=3)[C:19](=[O:24])[C:20]=2[CH:21]=[CH:22][CH:23]=1
Reactant: O=C1C2=C(CCCC2)C(=O)c2c1cccc2[N+](=O)[O-]
Reactant: [H][H]
Agent: [Pd]
Solvent: COCCO
Solvent: C1CCNCC1
Product: Nc1cccc2c1C(=O)c1ccccc1C2=O
Reaction time: 1 h
Yield: 85.3 %

Procedure:
1.4 Grams of 5% palladium on carbon catalyst and 52 grams of piperidine were added to a mixture of 154 grams of 5-nitrotetrahydroanthraquinone and 3,000 grams of methyl cellosolve, into which was fed hydrogen at room temperature and under normal pressure for having hydrogen absorbed in the starting 5-nitro compound in an amount of 2 mols per mol of the 5-nitro compound. After completion of the hydrogenation, the catalyst was separated by filtration and air was fed into the resultant filtrate at normal temperature for 1 hour. Then, the resultant solution was concentrated by distilling off the methyl cellosolve until crystals began to precipitate. The thus concentrated solution was allowed to cool and the resultant crystals were separated by filtration, washed with water and dried to obtain 114 grams of 1-aminoanthraquinone having a purity of 98.0%.
Reaction SMILES: [C:1]([NH:5][C:6]([C:8]1[C:16]2[C:11](=[N:12][C:13]([CH3:18])=[C:14](Br)[N:15]=2)[N:10]([CH2:19][O:20][CH2:21][CH2:22][Si:23]([CH3:26])([CH3:25])[CH3:24])[CH:9]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:27][N:28]1[CH:32]=[C:31]([NH2:33])[CH:30]=[N:29]1.C1(P(C2C=CC=CC=2)C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(C)([O-])C.[Na+]>C1(C)C=CC=CC=1.C(OCC)(=O)C.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[C:1]([NH:5][C:6]([C:8]1[C:16]2[C:11](=[N:12][C:13]([CH3:18])=[C:14]([NH:33][C:31]3[CH:30]=[N:29][N:28]([CH3:27])[CH:32]=3)[N:15]=2)[N:10]([CH2:19][O:20][CH2:21][CH2:22][Si:23]([CH3:26])([CH3:25])[CH3:24])[CH:9]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: Cn1cc(N)cn1
Reactant: Cc1nc2c(nc1Br)c(C(=O)NC(C)(C)C)cn2COCC[Si](C)(C)C
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: Cc1nc2c(nc1Nc1cnn(C)c1)c(C(=O)NC(C)(C)C)cn2COCC[Si](C)(C)C
Temperature: 110 °C
Reaction time: 18.5 h

Procedure:
A mixture of 2-bromo-3-methyl-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid tert-butylamide (0.110 g, 0.25 mmol), 1-methyl-1H-pyrazol-4-ylamine 1.35-HCl salt (0.073 g, 0.5 mmol), tris(dibenzylideneacetone)dipalladium (0.011 g, 0.0125 mmol), racemic BINAP [rac-2,2′-bis(diphenylphosphino)-1,1′-binaphthyl](0.023 g, 0.038 mmol) and sodium tert-butoxide (0.094 g, 0.98 mmol) in toluene (2½ mL), under an argon atmosphere, was heated and stirred in a sealed vessel at 110° C. for 18.5 h. The cooled reaction mixture was diluted with ethyl acetate, washed once with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. Purification by chromatography (silica, 70% ethyl acetate in hexanes) gave 0.104 g of slightly impure 3-methyl-2-(1-methyl-1H-pyrazol-4-ylamino)-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid tert-butylamide as a yellow-brown solid. This material was combined with 0.022 g of partially purified product obtained from a separate, lower yielding, coupling reaction (palladium acetate was used in place of tris(dibenzylideneacetone)dipalladium), and purified by chromatography (silica, ethyl acetate) to give 3-methyl-2-(1-methyl-1H-pyrazol-4-ylamino)-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid tert-butylamide (0.112 g) as a light yellow solid. 1H NMR (400 MHz, DMSO-d6) δ ppm −0.08 (s, 9H), 0.83 (t, J=8.2 Hz, 2H), 1.38 (s, 9H), 2.54 (s, 3H), 3.51 (t, J=8.2 Hz, 2H), 3.80 (s, 3H), 5.55 (s, 2H), 7.61 (s, 1H), 7.68 (s, 1H), 7.85 (s, 1H), 8.01 (s, 1H), 8.19 (s, 1H); MS (EI/CI) m/z: 458 [M+H].
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([S:9][CH2:10][CH2:11][NH:12][C:13]([N:15]2[CH2:20][CH2:19][O:18][CH2:17][CH2:16]2)=[O:14])=[CH:5][CH:4]=1.C=O.[C:23]1(C)C=CC(S(O)(=O)=O)=CC=1>C1C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[S:9][CH2:10][CH2:11][N:12]([C:13]([N:15]3[CH2:20][CH2:19][O:18][CH2:17][CH2:16]3)=[O:14])[CH2:23][C:7]=2[CH:8]=1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: COc1ccc(SCCNC(=O)N2CCOCC2)cc1
Agent: C=O
Solvent: c1ccccc1
Product: COc1ccc2c(c1)CN(C(=O)N1CCOCC1)CCS2
Temperature: 72.5 °C
Reaction time: 14 h
Yield: 50 %

Procedure:
A mixture of compound 16 (100 mg), paraformaldehyde (110 mg), p-toluenesulfonic acid (60 mg) in benzene (5 mL) was stirred at 70-75° C. for 14 h. The reaction solution was filtrated, washed with sat. NaHCO3 and concentrated to give crude title product 17 in an estimated yield of ˜50% by TLC and NMR. Chromatography on SiO2 (CH2Cl2/EtOAc 10:1) provided pure sample for confirmation of the structure.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]1[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]1.[Br:15]Br>ClCCl>[Br:15][C:7]1[CH:6]=[CH:5][C:4]([N:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)=[C:3]([O:2][CH3:1])[CH:8]=1
Reactant: COc1ccccc1N1CCNCC1
Reactant: BrBr
Solvent: ClCCl
Product: COc1cc(Br)ccc1N1CCNCC1
Temperature: 0 °C
Yield: 99.3 %

Procedure:
Dissolve 1-(2-methoxy-phenyl)-piperazine (5.0 g, 26.0 mmol) in dichloromethane 450 mL) and cool to 0° C. Add bromine (4.16 g, 26.0 mmol) slowly dropwise. After 2 h wash the reaction mixture with 1 N sodium hydroxide (250 mL). Separate the organic portion, dry (Na2SO4), filter and concentrate in vacuo to afford 7.0 g (99%) of the title compound. MS/ES m/z (81Br) 273.0 [M+H]+.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:26])[CH:5]([CH2:11][C:12]1[CH:13]=[N:14][C:15]([NH:18][C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])=[CH:16][CH:17]=1)[CH2:6][S:7]C(=O)C)[CH3:2]>C(O)C.N>[CH2:1]([O:3][C:4](=[O:26])[CH:5]([CH2:11][C:12]1[CH:13]=[N:14][C:15]([NH:18][C:19]([O:21][C:22]([CH3:23])([CH3:24])[CH3:25])=[O:20])=[CH:16][CH:17]=1)[CH2:6][S:7][S:7][CH2:6][CH:5]([C:4]([O:3][CH2:1][CH3:2])=[O:26])[CH2:11][C:12]1[CH:13]=[N:14][C:15]([NH:18][C:19]([O:21][C:22]([CH3:23])([CH3:24])[CH3:25])=[O:20])=[CH:16][CH:17]=1)[CH3:2]
Reactant: CCOC(=O)C(CSC(C)=O)Cc1ccc(NC(=O)OC(C)(C)C)nc1
Agent: N
Solvent: CCO
Product: CCOC(=O)C(CSSCC(Cc1ccc(NC(=O)OC(C)(C)C)nc1)C(=O)OCC)Cc1ccc(NC(=O)OC(C)(C)C)nc1
Reaction time: 2.67 h
Yield: 97.7 %

Procedure:
3-Acetylsulfanyl-2-(6-tert-butoxycarbonylamino-pyridin-3-ylmethyl)-propionic acid ethyl ester (150 mg, 0.392 mmol) was dissolved in ethanol (15 mL) saturated with NH3 (g). After stirring for 160 min., the mixture was concentrated under reduced pressure. The residue was dissolved in EtOH (10 mL) whereafter a solution of 12 in EtOH (0.5 M, 0.784 mL) was added. The reaction was stirred for 30 min. at room temperature, then diluted with CH2Cl2, washed with saturated aqueous Na2S2O5 and saturated aqueous NaHCO3, dried, filtered and concentrated under reduced pressure to give 3-[3-(6-tert-butoxycarbonylamino-pyridin-3-yl)-2-ethoxycarbonyl-propyldisulfanyl]-2-(6-tert-butoxycarbonylamino-pyridin-3-ylmethyl)-propionic acid ethyl ester (130 mg, 98%).
Reaction SMILES: [CH3:1][CH:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH2:5][CH2:4][NH:3]1.[Cl:12][C:13]1[NH:18][C:17]2=[CH:19][CH:20]=[CH:21][C:16]2=[C:15](Cl)[N:14]=1>>[CH3:1][CH:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH2:5][CH2:4][N:3]1[C:15]1[N:14]=[C:13]([Cl:12])[NH:18][C:17]2=[CH:19][CH:20]=[CH:21][C:16]=12
Reactant: Clc1nc(Cl)c2cccc-2[nH]1
Reactant: CC1NCCc2ccccc21
Product: CC1c2ccccc2CCN1c1nc(Cl)[nH]c2cccc1-2
Yield: 62.4 %

Procedure:
In accordance with the same procedure as in Step 1 of Example 1, except that 1-methyl-1,2,3,4-tetrahydroisoquinoline(1.7 g, 11.55 mmol) and 2,4-dichlorocyclopenta[d]pyrimidine(2.0 g, 10.5 mmol) prepared in the above Step 3 were used as starting materials, 1.95 g of the title compound was prepared. (Yield: 62%)
Reaction SMILES: [N:1]1[CH:2]=[N:3][N:4]2[CH:9]=[CH:8][N:7]=[CH:6][C:5]=12>C(O)C.[Pd]>[N:1]1[CH:2]=[N:3][N:4]2[CH2:9][CH2:8][NH:7][CH2:6][C:5]=12
Reactant: c1cn2ncnc2cn1
Agent: [Pd]
Solvent: CCO
Product: c1nc2n(n1)CCNC2
Reaction time: 8 h

Procedure:
A mixture of [1,2,4]triazolo[1,5-a]pyrazine (10 g) in ethanol (150 mL) and 10% Pd-C (3 g) was stirred under a hydrogen atmosphere overnight and filtered over Celite®. The filtrate was evaporated and the residue purified by column chromatography (silica, 10% methanol/dichloromethane) to yield 5,6,7,8-tetrahydro[1,2,4]triazolo[1,5-a]pyrazine. LC-MS 125.1 (M+1).
Reaction SMILES: ClC1C(C(OCC)=O)=[N:4]N2C=1CCOC1C=CC(I)=CC2=1.C([C@]1(O)CCN(C)C1=O)#C.[Cl:32][C:33]1[C:34]([C:57]([O:59]CC)=O)=[N:35][N:36]2[C:42]=1[CH2:41][CH2:40][O:39][C:38]1[CH:43]=[CH:44][C:45]([C:47]#[C:48][C@:49]3([OH:56])[CH2:53][CH2:52][N:51]([CH3:54])[C:50]3=[O:55])=[CH:46][C:37]2=1>>[Cl:32][C:33]1[C:34]([C:57]([NH2:4])=[O:59])=[N:35][N:36]2[C:42]=1[CH2:41][CH2:40][O:39][C:38]1[CH:43]=[CH:44][C:45]([C:47]#[C:48][C@:49]3([OH:56])[CH2:53][CH2:52][N:51]([CH3:54])[C:50]3=[O:55])=[CH:46][C:37]2=1
Reactant: CCOC(=O)c1nn2c(c1Cl)CCOc1ccc(C#C[C@]3(O)CCN(C)C3=O)cc1-2
Reactant: CCOC(=O)c1nn2c(c1Cl)CCOc1ccc(I)cc1-2
Agent: C#C[C@]1(O)CCN(C)C1=O
Product: CN1CC[C@@](O)(C#Cc2ccc3c(c2)-n2nc(C(N)=O)c(Cl)c2CCO3)C1=O

Procedure:
Similar to as described in General Procedure G, racemic ethyl 3-chloro-9-iodo-4,5-dihydrobenzo[b]pyrazolo[1,5-d][1,4]oxazepine-2-carboxylate was reacted with (R)-3-ethynyl-3-hydroxy-1-methylpyrrolidin-2-one to give a diasteromeric mixture of (R)-ethyl 3-chloro-9-((3-hydroxy-1-methyl-2-oxopyrrolidin-3-yl)ethynyl)-4,5-dihydrobenzo[b]pyrazolo[1,5-d][1,4]oxazepine-2-carboxylate. Following aminolysis of the ethyl ester (similar to as described in General Procedure M) the titled compound was obtained after purification by prep HPLC.
Reaction SMILES: C([NH:4][C:5]1[NH:6][C:7](=[O:45])[C:8]([CH2:18][CH2:19][CH2:20][NH:21][C:22]2[CH:43]=[CH:42][C:25]([C:26]([NH:28][C@H:29]([C:37]([O:39]CC)=[O:38])[CH2:30][CH2:31][C:32]([O:34]CC)=[O:33])=[O:27])=[CH:24][C:23]=2[CH3:44])=[C:9]([N:11](C(=O)C)C(=O)C)[N:10]=1)(=O)C.Cl>[OH-].[Na+]>[NH2:4][C:5]1[NH:6][C:7](=[O:45])[C:8]([CH2:18][CH2:19][CH2:20][NH:21][C:22]2[CH:43]=[CH:42][C:25]([C:26]([NH:28][C@H:29]([C:37]([OH:39])=[O:38])[CH2:30][CH2:31][C:32]([OH:34])=[O:33])=[O:27])=[CH:24][C:23]=2[CH3:44])=[C:9]([NH2:11])[N:10]=1
Reactant: CCOC(=O)CC[C@H](NC(=O)c1ccc(NCCCc2c(N(C(C)=O)C(C)=O)nc(NC(C)=O)[nH]c2=O)c(C)c1)C(=O)OCC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: Cc1cc(C(=O)N[C@@H](CCC(=O)O)C(=O)O)ccc1NCCCc1c(N)nc(N)[nH]c1=O
Reaction time: 2 h

Procedure:
A solution of diethyl N-[4-(3-(2-acetylamino-4-diacetylamino-1,6-dihydro-6-oxo-5-pyrimidinyl)propylamino)-3-methylbenzoyl]-(L)-glutamate (0.70 g, 1.1 mmoles) in 1.0N sodium hydroxide (20 mL) was stirred at 55° C. under nitrogen for 18 hours. The reaction mixture was chilled (ice bath) and adjusted to pH 2.5 by the gradual dropwise addition of 6.0N hydrochloric acid. After stirring cold 2 hours, the resulting precipitate was filtered. An attempted recrystallization of the wet cake from dimethylformamide/water failed, so the solution was spin evaporated to a clear oil. The oil was mixed with pH 2.1 aqueous HCl (20 mL) and sonicated 5 minutes to obtain a cream solid which was filtered and dried to give the product; yield, 0.12 g (24%); mp 181° C. (eff.); 1H-NMR (DMSO-d6) δ 1.58 (m, 2H), 1.8-2.1 (m, 2H), 2.12 (s, 3H), 2.2-2.4 (m, 4H), 3.08 (m, 2H), 4.34 (m, 1H), 5.78 (br s, 2H), 5.94 (br s, 2H), 6.52 (d, Jo=9 Hz, 1H), 7.53 (s overlapped, 1H), 7.57 (d overlapped, Jo=10 Hz, 1H), 8.06 (d, 1H), 10.0 (v br s, 1H), 12.2 (v br s, 2H); uv (0.1N NaOH) 296 nm max (18000), 286 min (17500), 274 max (19900), 247 min (5890), 215 max (21000).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([O:23]C)=[C:9]2[CH2:15][CH:14]3[N:16]([C:17]4[N:22]=[CH:21][CH:20]=[CH:19][N:18]=4)[CH:11]([CH2:12][CH2:13]3)[CH2:10]2)=[CH:4][CH:3]=1.Cl.C([O-])(O)=O.[Na+]>C1COCC1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([CH:9]2[CH2:15][CH:14]3[N:16]([C:17]4[N:18]=[CH:19][CH:20]=[CH:21][N:22]=4)[CH:11]([CH2:12][CH2:13]3)[CH2:10]2)=[O:23])=[CH:4][CH:3]=1
Reactant: COC(=C1CC2CCC(C1)N2c1ncccn1)c1ccc(Br)cc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: O=C(c1ccc(Br)cc1)C1CC2CCC(C1)N2c1ncccn1

Procedure:
A solution of 3-[(4-bromo-phenyl)-methoxy-methylene]-8-pyrimidin-2-yl-8-aza-bicyclo[3.2.1]octane (2.44 g, 6.32 mmol), aqueous HCl (10.5 ml, 6N) and THF (50 ml) was stirred at room temperature overnight. The mixture was added by saturated aq. NaHCO3 until bubbling was gone. The mixture was diluted with ethyl acetate and the organic phase was dried over MgSO4 and concentrated. ISCO was used to do purification and (4-bromo-phenyl)-(8-pyrimidin-2-yl-8-aza-bicyclo[3.2.1]oct-3-yl)-methanone was obtained as white solid (2.16 g, 92%). MS (M+1)=374. 1H NMR (CDCl3) 8.33 (d, J=12 Hz 2H), 7.84 (d, J=13 Hz 2H), 7.62 (d, J=13 Hz 2H), 6.51 (t, J=12 Hz 1H), 4.87 (m, 2H), 3.90 (m, 1H), 2.23 (m, 2H), 2.08 (m, 2H), 1.97 (m, 2H), 1.72 (m, 2H).
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([Br:11])=[C:7]([CH3:12])[CH:6]=1)=[O:4].[C:13]1([P:19]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(=O)(O)[O-].[Na+]>ClCCl.C1(C)C=CC=CC=1.O>[Br:11][C:8]1[CH:9]=[CH:10][C:5]([C:3](=[O:4])[CH:2]=[P:19]([C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)=[CH:6][C:7]=1[CH3:12]
Reactant: Cc1cc(C(=O)CBr)ccc1Br
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: Cc1cc(C(=O)C=P(c2ccccc2)(c2ccccc2)c2ccccc2)ccc1Br
Reaction time: 8 h

Procedure:
1300 mg of 2-Bromo-1-(4-bromo-3-methyl-phenyl)-ethanone (VIIa) (Journal of Organic Chemistry (1947), 12, 617-703) was stirred with 1300 mg of triphenylphosphine in 20 ml of dichloromethane at ambient temperature for 18 hours. The mixture was diluted with toluene and the separated phosphonium salt was filtered off. It was then suspended in 20 ml of dichloromethane and 20 ml of water. 800 mg (7.55 mmol) of sodium bicarbonate was then added in 20 ml of water and the mixture was stirred overnight. The organic layer was separated, dried and evaporated under reduced pressure. The residue was triturated with hexane giving 1.6 g (86%) of 1-(4-Bromo-3-methyl-phenyl)-2-(triphenylphosphanylidene)-ethanone (Va) as a solid. 1H-NMR (CDCl3, δ in ppm): 7.40-7.90 (m, 18H), 4.40 (m, 1H).
Reaction SMILES: C([O:3][C:4]([C:6]1[O:7][C:8]([CH2:11][O:12][C:13]2[CH:18]=[CH:17][C:16]([C:19]3[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][CH:20]=3)=[CH:15][CH:14]=2)=[CH:9][CH:10]=1)=[O:5])C.O.[OH-].[Li+]>O1CCCC1.CO.O>[CH3:25][C:22]1[CH:23]=[CH:24][C:19]([C:16]2[CH:17]=[CH:18][C:13]([O:12][CH2:11][C:8]3[O:7][C:6]([C:4]([OH:5])=[O:3])=[CH:10][CH:9]=3)=[CH:14][CH:15]=2)=[CH:20][CH:21]=1
Reactant: CCOC(=O)c1ccc(COc2ccc(-c3ccc(C)cc3)cc2)o1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: Cc1ccc(-c2ccc(OCc3ccc(C(=O)O)o3)cc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 88 %

Procedure:
A solution of 5-(4′-methyl-biphenyl-4-yloxymethyl)-furan-2-carboxylic acid ethyl ester (2.00 g, 5.9 mmol) in tetrahydrofuran (30 mL) and methanol (10 mL) was added to a solution of lithium hydroxide monohydrate (0.476 g, 11.3 mmol) in water (15 mL). Methanol (5 mL) and tetrahydrofuran (10 mL) were added, and the reaction mixture was stirred at room temperature overnight. The solvents were evaporated, and the residue was suspended in water and acidifed to pH 2.5 with 1 M HCl. The resulting white solid was filtered off, and twice suspended in ethyl acetate and evaporated to give 5-(4′-methyl-biphenyl-4-yloxymethyl)-furan-2-carboxylic acid (1.6 g, 88%) as a white solid.
Reaction SMILES: [O:1]=[O+][O-].[Br:4][C:5]1[C:13]2[O:12]C(C)=[CH:10][C:9]=2[C:8]([F:15])=[CH:7][CH:6]=1.CSC>>[Br:4][C:5]1[C:13]([OH:12])=[C:9]([C:8]([F:15])=[CH:7][CH:6]=1)[CH:10]=[O:1]
Reactant: Cc1cc2c(F)ccc(Br)c2o1
Reactant: O=[O+][O-]
Solvent: CSC
Product: O=Cc1c(F)ccc(Br)c1O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 98 %

Procedure:
Ozone was conducted into a solution of 8.0 g (35 mmol) of 7-bromo-4-fluoro-2-methylbenzofuran at -78° C. until the colour became blue. Subsequently, argon was conducted through the solution which was then treated at -78° C. with 13 ml of dimethyl sulfide. After warming to room temperature the solution was concentrated in a vacuum and the residue was dissolved in 50 ml of ethanol. After the addition of 50 ml of 3% sodium hydrogen carbonate solution the mixture was stirred at 70° for 30 minutes. Subsequently, the mixture was poured on to 200 ml of ice-water, made acid with 10% HCl and extracted three times with 150 ml of diethyl ether. After drying over sodium sulfate concentration was carried out in a vacuum. The crude product obtained was purified by column chromatography on silica gel (dichloromethane/hexane 4:1). There were obtained 7.5 g (98%) of 3-bromo-6-fluoro-2-hydroxy-benzaldehyde as a pale yellow oil, which was used immediately in the next reaction.
Reaction SMILES: [CH3:1][N:2]([CH3:12])[CH2:3][CH2:4][C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][CH:6]=1.[H-].[Na+].Br[CH2:16][CH2:17][CH2:18][N:19]1[C:23](=[O:24])[C:22]2=[CH:25][CH:26]=[CH:27][CH:28]=[C:21]2[C:20]1=[O:29].O>CN(C)C=O>[CH3:12][N:2]([CH3:1])[CH2:3][CH2:4][C:5]1[CH:10]=[CH:9][C:8]([O:11][CH2:16][CH2:17][CH2:18][N:19]2[C:23](=[O:24])[C:22]3[C:21](=[CH:28][CH:27]=[CH:26][CH:25]=3)[C:20]2=[O:29])=[CH:7][CH:6]=1
Reactant: O=C1c2ccccc2C(=O)N1CCCBr
Reactant: CN(C)CCc1ccc(O)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CN(C)CCc1ccc(OCCCN2C(=O)c3ccccc3C2=O)cc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A mixture of 4-[2-(dimethylamino)ethyl]phenol (4.13 g) and sodium hydride (0.67 g) in dimethylformamide was stirred at room temperature for 24 h. N-(3-Bromopropyl) phthalimide (6.7 g) was added at 0° and stirring was continued for 24 h. The solution was treated with water and extracted with ether. Evaporation of the solvent gave the title compound as a white solid which was recrystallised from light petroleum (b.p. 60°-80°) 2.3 g) m.p. 81°-82°. TLC silica; ethyl acetate:water:isopropanol:0.88 ammonia 25:8:15:2; Rf 0.45.