Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CN(C)C=O.[CH2:6]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9]2([CH2:19][C:18]3[CH:20]=[CH:21][CH:22]=[CH:23][C:17]=3[O:16]2)[CH2:8][NH:7]1.C(=O)(O)[O-].[Na+].Cl[CH2:30][C:31]#[N:32]>O>[C:31]([CH2:30][N:7]1[CH2:8][C:9]2([CH2:19][C:18]3[CH:20]=[CH:21][CH:22]=[CH:23][C:17]=3[O:16]2)[C:10]2[C:15](=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH2:6]1)#[N:32]
Reactant: c1ccc2c(c1)CC1(CNCc3ccccc31)O2
Reactant: N#CCCl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: N#CCN1Cc2ccccc2C2(Cc3ccccc3O2)C1

Procedure:
To dry dimethylformamide is added spiro[benzofuran-2(3H),4'(2'H)-isoquinoline] (11.0 g), sodium bicarbonate (8.4 g) and chloroacetonitrile (6.8 g) and the mixture is heated to 70° for four hours. The dimethylformamide is evaporated to give an oil, which is stirred with water (300 ml) for 15 minutes and then extracted with ether/dichloromethane. The organic extract is washed with water (2x), saturated sodium chloride solution and then dried over anhydrous magnesium sulfate. After filtering, the solvents are evaporated to an oil which solidifies to the product (10.6 g), 83%), as an off-white solid upon trituration with petroleum ether/ether. For analysis, a sample is recrystallized twice from hexane/acetone to yield platelets.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([C:9]([F:12])([F:11])[F:10])[C:4]=1[CH2:13]O.S(Cl)([Cl:17])=O>C(Cl)(Cl)Cl>[Cl:17][CH2:13][C:4]1[C:5]([C:9]([F:12])([F:11])[F:10])=[CH:6][CH:7]=[CH:8][C:3]=1[O:2][CH3:1]
Reactant: O=S(Cl)Cl
Reactant: COc1cccc(C(F)(F)F)c1CO
Solvent: ClC(Cl)Cl
Product: COc1cccc(C(F)(F)F)c1CCl
Temperature: 0 °C

Procedure:
Into a 50-mL round-bottom flask, was placed [2-methoxy-6-(trifluoromethyl)phenyl]methanol (1.0 g, 4.85 mmol, 1.00 equiv), chloroform (10.0 g). This was followed by the addition of thionyl chloride (1.73 g, 14.54 mmol, 3.00 equiv) dropwise with stirring at 0° C. The resulting solution was stirred for 1 h at 30° C. The reaction progress was monitored by GCMS. The reaction was then quenched by the addition of 10 mL of water. The resulting solution was extracted with 3×15 mL of dichloromethane and the organic layers combined and dried over anhydrous sodium sulfate and concentrated under vacuum. This resulted in 1.2 g (crude) of 2-(chloromethyl)-1-methoxy-3-(trifluoromethyl)benzene as yellow oil. This residue could be used for the next step directly.
Reaction SMILES: [O:1]=[C:2]1[CH:11]=[N:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:12]([OH:14])=O)[CH:8]=2)[NH:3]1.[NH:15]1[CH2:20][CH2:19][CH2:18][C@@H:17]2[C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][C:26]=3[CH2:27][C@H:16]12.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1>>[N:15]1([C:12]([C:7]2[CH:8]=[C:9]3[C:4](=[CH:5][CH:6]=2)[NH:3][C:2](=[O:1])[CH:11]=[N:10]3)=[O:14])[CH2:20][CH2:19][CH2:18][C@@H:17]2[C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][C:26]=3[CH2:27][C@H:16]12
Reactant: c1ccc2c(c1)C[C@@H]1NCCC[C@H]21
Reactant: O=C(O)c1ccc2[nH]c(=O)cnc2c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Product: O=C(c1ccc2[nH]c(=O)cnc2c1)N1CCC[C@@H]2c3ccccc3C[C@@H]21
Yield: 45 %

Procedure:
The title compound is prepared from 2-oxo-1,2-dihydro-quinoxaline-6-carboxylic acid and cis-2,3,4,4a,9,9a-hexahydro-1H-indeno[2,1-b]pyridine following a procedure analogous to that described in Example 1 [2-(7-aza-1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate is used]. Yield: 45% of theory; LC (method 4): tR=1.89 min; Mass spectrum (ESI+): m/z=346 [M+H]+.
Reaction SMILES: [CH:1]([C:4]1[CH:24]=[CH:23][CH:22]=[CH:21][C:5]=1[O:6][C:7]1C(C(C)C)=C(S([O-])(=O)=O)C=[CH:9][C:8]=1C)([CH3:3])[CH3:2].[N-:25]=[N+:26]=[N-:27].[Na+]>CN(C)C=O>[CH:1]([C:4]1[CH:24]=[CH:23][CH:22]=[CH:21][C:5]=1[O:6][CH2:7][CH:8]([N:25]=[N+:26]=[N-:27])[CH3:9])([CH3:3])[CH3:2]
Reactant: Cc1ccc(S(=O)(=O)[O-])c(C(C)C)c1Oc1ccccc1C(C)C
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(COc1ccccc1C(C)C)N=[N+]=[N-]
Yield: 164.2 %

Procedure:
A mixture consisting of 21.0 g of 2-(2-isopropylphenoxy)-1-methylethyl-p-toluenesulfonate, 3.9 g of sodium azide and N,N-dimethylformamide was heated at 70° to 75° C. for 5 hr. with stirring. Upon completion of the reaction, the mixture was extracted with ethyl acetate; the extract was washed consecutively with water and saturated saline; and subsequently dried with anhydrous sodium sulfate. The solvent was thereafter distilled off under reduced pressure and yielded 21.6 g of 2-(2-isopropylphenoxy)-1-methylethylazide.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][CH:12]1[CH:25]2[CH:16]([C:17](=[O:27])[C:18]3[C:23]([C:24]2=[O:26])=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH2:15][CH:14]=[CH:13]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>[Cu]Cl.N1C=CC=CC=1>[CH2:1]([O:8][C:9]([NH:11][C:12]1[C:25]2[C:24](=[O:26])[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[C:17](=[O:27])[C:16]=2[CH:15]=[CH:14][CH:13]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(NC1C=CCC2C(=O)c3ccccc3C(=O)C12)OCc1ccccc1
Agent: Cl[Cu]
Solvent: c1ccncc1
Product: O=C(Nc1cccc2c1C(=O)c1ccccc1C2=O)OCc1ccccc1
Yield: 88.2 %

Procedure:
0.47 g of 1-benzyloxycarbonylamino-1,4,4a,9a-tetrahydroanthraquinone, 6 mg of copper(I) chloride and 10 ml of pyridine were stirred at 25° C. for 30 hours under a gentle stream of air and the solution was then concentrated in vacuo. The residue was taken up in chloroform, the solution was extracted with 2N hydrochloric acid and the organic phase was concentrated in vacuo. 0.41 g of 1-benzyloxycarbonylaminoanthraquinone (86% pure; 76% of theory) was obtained.
Reaction SMILES: [CH3:1][NH:2][C:3]([CH:5]1[CH2:10][NH:9][CH2:8][CH2:7][NH:6]1)=[O:4].[Cl:11][C:12]1[CH:13]=[C:14]([CH2:19][OH:20])[CH:15]=[N:16][C:17]=1Cl>>[CH3:1][NH:2][C:3]([CH:5]1[CH2:10][N:9]([C:17]2[C:12]([Cl:11])=[CH:13][C:14]([CH2:19][OH:20])=[CH:15][N:16]=2)[CH2:8][CH2:7][NH:6]1)=[O:4]
Reactant: CNC(=O)C1CNCCN1
Reactant: OCc1cnc(Cl)c(Cl)c1
Product: CNC(=O)C1CN(c2ncc(CO)cc2Cl)CCN1

Procedure:
piperazine-2-carboxylic acid methylamide from step (c) above (570 mg, 4.0 mmol) and (5,6-dichloro-pyridin-3-yl)-methanol (710 mg, 4.0 mmol, TCI-US) reacted under the conditions of Example 3a to give the title compound as a light-yellow gum. MS ESI, pos. ion) m/e: 285 (M+1).
Reaction SMILES: [CH2:1](Br)[CH:2]=[CH2:3].[F:5][C:6]1[C:7](=[O:19])[O:8][C:9]2[C:14]([C:15]=1[CH3:16])=[CH:13][CH:12]=[C:11]([OH:17])[C:10]=2[CH3:18].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[F:5][C:6]1[C:7](=[O:19])[O:8][C:9]2[C:14]([C:15]=1[CH3:16])=[CH:13][CH:12]=[C:11]([O:17][CH2:3][CH:2]=[CH2:1])[C:10]=2[CH3:18]
Reactant: Cc1c(F)c(=O)oc2c(C)c(O)ccc12
Reactant: C=CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: C=CCOc1ccc2c(C)c(F)c(=O)oc2c1C
Temperature: 25 °C
Reaction time: 28 h
Yield: 77.6 %

Procedure:
Allyl bromide (1.08 mL, 12.48 mmoles) was added to a mixture of 3-fluoro-4,8-dimethyl-7-hydroxycoumarin (1.73 g, 8.31 mmoles), ca. 5 g of potassium carbonate and 45 mL of dry acetone. The reaction mixture was stirred under an inert atmosphere at room temperature for 28 hours. During this time, excess allyl bromide (1.44 mL, 16.64 mmoles) was added in two portions. The carbonate salt was removed by suction filtration washed with acetone and the solvent evaporated under reduced pressure yielding a solid, which was purified by recrystallisation from a mixture of methanol:water. Thus, 1.60 g (78% yield) of 3-fluoro-4,8-dimethyl-7-allyloxycoumarin was obtained as a white solid: mp 117° C.
Reaction SMILES: [Br:1][C:2]1[C:3]([OH:17])=[C:4]([C:10]2[CH:11]=[CH:12][C:13](=[O:16])[NH:14][N:15]=2)[CH:5]=[C:6]([Br:9])[C:7]=1[CH3:8].[C:18](OC(=O)C)(=[O:20])[CH3:19]>C1C=CC=CC=1>[C:18]([O:17][C:3]1[C:2]([Br:1])=[C:7]([CH3:8])[C:6]([Br:9])=[CH:5][C:4]=1[C:10]1[CH:11]=[CH:12][C:13](=[O:16])[NH:14][N:15]=1)(=[O:20])[CH3:19]
Reactant: Cc1c(Br)cc(-c2ccc(=O)[nH]n2)c(O)c1Br
Reactant: CC(=O)OC(C)=O
Solvent: c1ccccc1
Product: CC(=O)Oc1c(-c2ccc(=O)[nH]n2)cc(Br)c(C)c1Br
Yield: 71.5 %

Procedure:
A mixture of 1.0 g. of 6-(3,5-dibromo-2-hydroxy-4-methylphenyl)-3-(2H)pyridazinone and 2 ml. of acetic anhydride in 10 ml. of benzene was heated under reflux for 3 hours. After cooling, the so separated crystalline substance was recovered by filtration and dried to give 0.8 g. of the desired product as yellow needles of m.p. 220° C. (Yield 71.5%).
Reaction SMILES: [Cl:1][C:2]1[C:3]([OH:11])=[C:4]([C:8](=O)[CH3:9])[CH:5]=[CH:6][CH:7]=1.[C:12]([NH:20][NH2:21])(=[O:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(O)(=O)C>C(O)C>[Cl:1][C:2]1[C:3]([OH:11])=[C:4]([C:8](=[N:21][NH:20][C:12](=[O:19])[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH3:9])[CH:5]=[CH:6][CH:7]=1
Reactant: NNC(=O)c1ccccc1
Reactant: CC(=O)c1cccc(Cl)c1O
Solvent: CCO
Solvent: CC(=O)O
Product: CC(=NNC(=O)c1ccccc1)c1cccc(Cl)c1O
Temperature: 60 °C
Yield: 59.1 %

Procedure:
A suspension of 1-(3-chloro-2-hydroxyphenyl)-ethanone (0.100 g, 0.586 mmol), benzoic acid hydrazide (0.080 g, 0.586 mmol), and glacial acetic acid (0.180 mL) in ethanol (1.8 mL) was heated to 60° C. for 18 hours. The reaction mixture was cooled to room temperature to precipitate the product. The solid was collected via suction filtration and rinsed with ethanol to furnish benzoic acid [1-(3-chloro-2-hydroxy-phenyl)-ethylidene]-hydrazide as a yellow solid (0.100 g, 59%): mp 202-203° C.; 1H NMR (400 MHz, DMSO) δ 14.36 (s, 1H), 11.50 (s, 1H), 7.96 (d, J=7.3 Hz, 2H), 7.68-7.61 (m, 2H), 7.56 (t, J=6.7 Hz, 2H), 7.49 (d, J=7.8 Hz, 1H), 6.92 (t, J=8.0 Hz, 1H), 2.52 (s, 3H); ESIMS m/z 289 ([M+H]+), 287 ([M−H]−).
Reaction SMILES: [OH-:1].[Na+].OO.[Cl:5][C:6]1[CH:7]=[C:8]([S:12]([N:15]2[CH2:20][CH2:19][C:18]([NH:23][C:24]([CH:26]3[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]3)=O)([C:21]#[N:22])[CH2:17][CH2:16]2)(=[O:14])=[O:13])[CH:9]=[CH:10][CH:11]=1.O>C(O)C>[Cl:5][C:6]1[CH:7]=[C:8]([S:12]([N:15]2[CH2:20][CH2:19][C:18]3([N:23]=[C:24]([CH:26]4[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]4)[NH:22][C:21]3=[O:1])[CH2:17][CH2:16]2)(=[O:14])=[O:13])[CH:9]=[CH:10][CH:11]=1
Reactant: N#CC1(NC(=O)C2CCCCC2)CCN(S(=O)(=O)c2cccc(Cl)c2)CC1
Reactant: [OH-]
Agent: OO
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: O=C1NC(C2CCCCC2)=NC12CCN(S(=O)(=O)c1cccc(Cl)c1)CC2
Temperature: 25 °C
Yield: 52 %

Procedure:
A 6 M aqueous sodium hydroxide solution (0.74 mL) and a 30% aqueous hydrogen peroxide solution (0.25 mL) were added to a solution of cyclohexanecarboxylic[1-(3-chloro-benzenesulfonyl)-4-cyano-piperidin-4-yl]-amide (100 mg, 0.244 mmol) in ethanol (1.60 mL), and the mixture was heated under reflux for 4.5 hours. The reaction mixture was cooled to room temperature and water was then added, followed by concentration under reduced pressure. The residue was neutralized with a saturated aqueous ammonium chloride solution, followed by extraction with dichloromethane. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane:methanol=90:10) to give 8-(3-chloro-benzenesulfonyl)-2-cyclohexyl-1,3,8-triaza-spiro[4.5]dec-1-en-4-one as a white solid (52 mg, 52%).
Reaction SMILES: C1(C([O:9]C(C2C=CC=CC=2)=[Se])=[Se])C=CC=CC=1.[Cl:18][C:19]1[CH:20]=[C:21]2[C:26](=[CH:27][CH:28]=1)[C:25]([OH:29])=[CH:24][CH:23]=[CH:22]2>O1CCCC1>[Cl:18][C:19]1[CH:20]=[C:21]2[C:26](=[CH:27][CH:28]=1)[C:25](=[O:29])[C:24](=[O:9])[CH:23]=[CH:22]2
Reactant: Oc1cccc2cc(Cl)ccc12
Reactant: [Se]=C(OC(=[Se])c1ccccc1)c1ccccc1
Solvent: C1CCOC1
Product: O=C1C=Cc2cc(Cl)ccc2C1=O
Temperature: 70 °C
Yield: 82.2 %

Procedure:
To a solution of benzeneselenic anhydride (3.18 g, 8.8 mmol) in tetrahydrofuran (30 ml), which had been heated to 70° C. was added a solution of 6-chloro-1-naphthol (1.5 g, 8.4 mmol) in tetrahydrofuran (5 ml). The reaction was maintained at 70° C. for 15 minutes. The mixture was then concentrated under reduced pressure. The residue was suspended in hexanes (100 ml) and filtered. This was repeated 5 times. The residue was dissolved in dichloromethane (100 ml), filtered and concentrated under reduced pressure to afford the product as an orange solid (1.33 g, 82%); 400 MHz 1H NMR (CDCl3) δ: 8.06 (d, J=8.4 Hz, 1H), 7.49 (dd, J=2 and 8.4 Hz, 1H), 7.41-7.38 (m, 2H), 6.50 (d, J=10 Hz, 1H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:29]=[C:30]([N:32]2[CH2:37][CH2:36][O:35][CH2:34][CH2:33]2)[CH:31]=1)[C:5]([NH:7][C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]([O:18][C:19]2[CH:24]=[CH:23][N:22]=[C:21](S(C)(=O)=O)[N:20]=2)=[CH:10][CH:9]=1)=[O:6].[C:38]([O:42][C:43]([N:45]1[CH2:50][CH2:49][NH:48][CH2:47][CH2:46]1)=[O:44])([CH3:41])([CH3:40])[CH3:39]>>[C:38]([O:42][C:43]([N:45]1[CH2:50][CH2:49][N:48]([C:21]2[N:20]=[C:19]([O:18][C:11]3[C:12]4[C:17](=[CH:16][CH:15]=[CH:14][CH:13]=4)[C:8]([NH:7][C:5](=[O:6])[C:4]4[CH:29]=[C:30]([N:32]5[CH2:37][CH2:36][O:35][CH2:34][CH2:33]5)[CH:31]=[C:2]([F:1])[CH:3]=4)=[CH:9][CH:10]=3)[CH:24]=[CH:23][N:22]=2)[CH2:47][CH2:46]1)=[O:44])([CH3:41])([CH3:39])[CH3:40]
Reactant: CS(=O)(=O)c1nccc(Oc2ccc(NC(=O)c3cc(F)cc(N4CCOCC4)c3)c3ccccc23)n1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Product: CC(C)(C)OC(=O)N1CCN(c2nccc(Oc3ccc(NC(=O)c4cc(F)cc(N5CCOCC5)c4)c4ccccc34)n2)CC1

Procedure:
Compound is prepared from 3-fluoro-N-(4-{[2-(methylsulfonyl)pyrimidin-4-yl]oxy}-1-naphthyl)-5-morpholin-4-ylbenzamide and piperazine-1-carboxylic acid t-butyl ester according to conditions described in general procedure C. Mp: 131-133° C.; 1HNMR (400 MHz, DMSO-d6) δ 1.38 (s, 9 H), 3.27-3.34 (m, 8H), 3.50 (bs, 4 H), 3.77 (t, J=4.38 Hz, 4 H), 6.24-25 (m, 1 H), 7.04 (d, J=11.3 Hz, 1 H), 7.26 (d, J=8.4 Hz, 1H), 7.44 (d, J=8.0 Hz, 1H), 7.50 (s, 1H), 7.56-7.63 (m, 3 H), 7.85 (d, J=8.4 Hz, 1H), 8.01 (d, J=8.8 Hz, 1 H), 8.29-8.30 (m, 1 H), 10.48 (s, 1 H).
Reaction SMILES: [N:1]1([C:7]2[N:12]=[CH:11][NH:10][C:9](=[O:13])[CH:8]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[OH:14][C:15]1[CH:22]=[CH:21][C:20]([O:23][C:24]([F:27])([F:26])[F:25])=[CH:19][C:16]=1[CH:17]=O>>[OH:14][C:15]1[CH:22]=[CH:21][C:20]([O:23][C:24]([F:25])([F:26])[F:27])=[CH:19][C:16]=1[CH2:17][N:4]1[CH2:5][CH2:6][N:1]([C:7]2[N:12]=[CH:11][NH:10][C:9](=[O:13])[CH:8]=2)[CH2:2][CH2:3]1
Reactant: O=c1cc(N2CCNCC2)nc[nH]1
Reactant: O=Cc1cc(OC(F)(F)F)ccc1O
Product: O=c1cc(N2CCN(Cc3cc(OC(F)(F)F)ccc3O)CC2)nc[nH]1

Procedure:
6-[4-(2-Hydroxy-5-trifluoromethoxy-benzyl)-piperazin-1-yl]-3H-pyrimidin-4-one was prepared using Procedure A from 6-piperazin-1-yl-3H-pyrimidin-4-one (Intermediate 4) and 2-hydroxy-5-trifluoromethoxybenzaldehyde. Mass spectrum (ES) MH+=371.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:28]2[CH2:33][CH2:32][O:31][CH2:30][CH2:29]2)[C:5]2[S:10][C:9]([CH2:11][N:12]3[CH2:17][CH2:16][N:15]([S:18]([C:21]4[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=4)(=[O:20])=[O:19])[CH2:14][CH2:13]3)=[CH:8][C:6]=2[N:7]=1.[NH2:34][C:35]1[N:40]=[CH:39][C:38](B(O)O)=[CH:37][N:36]=1>>[O:31]1[CH2:32][CH2:33][N:28]([C:4]2[C:5]3[S:10][C:9]([CH2:11][N:12]4[CH2:13][CH2:14][N:15]([S:18]([C:21]5[CH:22]=[CH:23][C:24]([F:27])=[CH:25][CH:26]=5)(=[O:19])=[O:20])[CH2:16][CH2:17]4)=[CH:8][C:6]=3[N:7]=[C:2]([C:38]3[CH:37]=[N:36][C:35]([NH2:34])=[N:40][CH:39]=3)[N:3]=2)[CH2:29][CH2:30]1
Reactant: Nc1ncc(B(O)O)cn1
Reactant: O=S(=O)(c1ccc(F)cc1)N1CCN(Cc2cc3nc(Cl)nc(N4CCOCC4)c3s2)CC1
Product: Nc1ncc(-c2nc(N3CCOCC3)c3sc(CN4CCN(S(=O)(=O)c5ccc(F)cc5)CC4)cc3n2)cn1

Procedure:
2-Chloro-6-[4-(4-fluoro-benzenesulfonyl)-piperazin-1-ylmethyl]-4-morpholin-4-yl-thieno[3,2-d]pyrimidine was reacted with 2-aminopyrimidine-5-boronic acid in General Procedure A. Purification on silica and recrystallization from hot DCM/hexane gave 286. NMR (DMSO): 2.55-2.58 (4H, m), 2.98-3.03 (4H, m), 3.73-3.77 (4H, m), 3.88 (2H, s), 3.90-3.94 (4H, m), 7.06 (2H, br. s), 7.32 (1H, s), 7.50-7.55 (2H, t), 7.80-7.84 (2H, m), 9.10 (2H, s). MS (ESI+): MH+ 570.23 (100%)
Reaction SMILES: [OH:1][CH2:2][CH2:3][C:4]1[CH:5]=[C:6]([CH2:12][CH:13]([O:19][CH:20]([CH3:22])[CH3:21])[C:14]([O:16]CC)=[O:15])[CH:7]=[CH:8][C:9]=1[O:10][CH3:11].[C:23]1([N:29]=[C:30]=[O:31])[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>>[NH:29]([C:30]([O:1][CH2:2][CH2:3][C:4]1[CH:5]=[C:6]([CH2:12][CH:13]([O:19][CH:20]([CH3:21])[CH3:22])[C:14]([OH:16])=[O:15])[CH:7]=[CH:8][C:9]=1[O:10][CH3:11])=[O:31])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: O=C=Nc1ccccc1
Reactant: CCOC(=O)C(Cc1ccc(OC)c(CCO)c1)OC(C)C
Product: COc1ccc(CC(OC(C)C)C(=O)O)cc1CCOC(=O)Nc1ccccc1

Procedure:
Using ethyl 3-[3-(2-hydroxyethyl)-4-methoxyphenyl]-2-isopropoxypropanoate and phenylisocyanate, the title compound was obtained in the same manner as described in Example 148.
Reaction SMILES: [H-].[Na+].[OH:3][C@H:4]1[CH2:8][CH2:7][NH:6][C:5]1=[O:9].Cl[C:11]1[N:16]=[CH:15][N:14]=[C:13]2[N:17]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[Cl:26])[N:18]=[CH:19][C:12]=12>C1COCC1.CN(C=O)C>[Cl:26][C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=1[N:17]1[C:13]2=[N:14][CH:15]=[N:16][C:11]([O:3][C@H:4]3[CH2:8][CH2:7][NH:6][C:5]3=[O:9])=[C:12]2[CH:19]=[N:18]1
Reactant: O=C1NCC[C@@H]1O
Reactant: Clc1ccccc1-n1ncc2c(Cl)ncnc21
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: O=C1NCC[C@@H]1Oc1ncnc2c1cnn2-c1ccccc1Cl
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 24.8 %

Procedure:
Sodium hydride (60% in oil) (0.435 g, 10.88 mmol) was added to (S)-3-hydroxypyrrolidin-2-one (CAS no. 34368-52-0) (1 g, 9.89 mmol) in THF (50 mL) at 0° C. under nitrogen. The resulting suspension was stirred at 0° C. for 10 minutes. A solution of 4-chloro-1-(2-chlorophenyl)-1H-pyrazolo[3,4-d]pyrimidine (Intermediate B15) (4.01 g, 15.13 mmol) in DMF (25 mL) was added and the resulting mixture was stirred at r.t. for 16 hours. The reaction mixture was quenched with water (20 mL) and extracted with ethyl acetate (2×50 mL). The combined organic layers were dried (MgSO4) and evaporated (3.8 g). The crude product was purified by flash silica chromatography, eluting with 0-50% MeOH in ethyl acetate to afford the product (0.810 g, 24.8%). 1H NMR (400 MHz, CDCl3) δ 2.30-2.42 (1H, m), 2.81-2.91 (1H, m), 3.45-3.64 (2H, m), 6.05 (1H, t), 6.44 (1H, s), 7.42-7.51 (2H, m), 7.51-7.56 (1H, m), 7.57-7.66 (1H, m), 8.33 (1H, s), 8.60 (1H, s); m/z (ES+) (M+H)+=330.27; HPLC tR=1.61 min.
Reaction SMILES: [CH2:1]1[O:3][CH2:2]1.[CH3:4][O:5][N:6]=[C:7]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[O:9][C:8]1=[N:16][OH:17].[OH-].[Na+]>O>[CH3:4][O:5][N:6]=[C:7]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[O:9][C:8]1=[N:16][O:17][CH2:1][CH2:2][OH:3]
Reactant: C1CO1
Reactant: CON=C1C(=NO)Oc2ccccc21
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CON=C1C(=NOCCO)Oc2ccccc21
Temperature: 5 °C
Yield: 60.5 %

Procedure:
At 20° C., 264.3 g (6.0 mol) of ethylene oxide are passed into a solution of 192.2 g (1.0 mol) of benzofuran-2,3-dione 3-(O-methyl-oxime) 2-oxime in 2 l of water over a period of 85 minutes. The solution is cooled to 5° C. and 70 g (1.06 mol) of sodium hydroxide pellets are added, on which the temperature increases to 10° C. The mixture is stirred without further cooling for another 165 minutes and the precipitate that has formed is filtered off with suction, washed with 500 ml of ice-water a little at a time and dried at 40° C. in a vacuum drying cabinet. 143.0 g (61% of theory) of benzofuran-2,3-dione 2-[O-(2-hydroxy-ethyl)-oxime] 3-(O-methyl-oxime) are obtained as a mixture of two stereoisomers.
Reaction SMILES: [CH2:1]1[O:9][C:8]2[CH:7]=[CH:6][C:5]([CH:10]3[C:22]4[NH:21][C:20]5[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=5)[C:14]=4[CH2:13][CH2:12][NH:11]3)=[CH:4][C:3]=2[O:2]1.Cl[C:24]1[N:29]=[CH:28][C:27]([C:30]2[CH:35]=[CH:34][C:33]([O:36][CH3:37])=[C:32]([O:38][CH3:39])[CH:31]=2)=[CH:26][N:25]=1>CN(C=O)C>[CH2:1]1[O:9][C:8]2[CH:7]=[CH:6][C:5]([CH:10]3[C:22]4[NH:21][C:20]5[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=5)[C:14]=4[CH2:13][CH2:12][N:11]3[C:24]3[N:25]=[CH:26][C:27]([C:30]4[CH:35]=[CH:34][C:33]([O:36][CH3:37])=[C:32]([O:38][CH3:39])[CH:31]=4)=[CH:28][N:29]=3)=[CH:4][C:3]=2[O:2]1
Reactant: c1ccc2c3c([nH]c2c1)C(c1ccc2c(c1)OCO2)NCC3
Reactant: COc1ccc(-c2cnc(Cl)nc2)cc1OC
Solvent: CN(C)C=O
Product: COc1ccc(-c2cnc(N3CCc4c([nH]c5ccccc45)C3c3ccc4c(c3)OCO4)nc2)cc1OC

Procedure:
Following the same procedure as outlined in Example 12, 1-(3,4-methylenedioxyphenyl)-2,3,4,9-tetrahydro-1H-β-carboline (3.73 g, 12.8 mmol) (prepared according to the process as disclosed in WO97/43287, Intermediate 7, page 24) and 2-chloro-5-(3,4-dimethoxylphenyl)pyrimidine (1.60 g, 6.4 mmol) in DMF (50 mL, anhydrous) were reacted to yield the product as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9](=[O:31])[N:10]([C@H:12]2[C@H:16]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)[CH2:15][N:14]([C:24]([CH:26]3[CH2:30][CH2:29][NH:28][CH2:27]3)=[O:25])[CH2:13]2)[CH3:11])=[CH:4][CH:3]=1.[C:32](Cl)(=[O:35])[CH2:33][CH3:34]>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9](=[O:31])[N:10]([C@H:12]2[C@H:16]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)[CH2:15][N:14]([C:24]([CH:26]3[CH2:30][CH2:29][N:28]([C:32](=[O:35])[CH2:33][CH3:34])[CH2:27]3)=[O:25])[CH2:13]2)[CH3:11])=[CH:4][CH:3]=1
Reactant: CN(C(=O)Oc1ccc(F)cc1)[C@@H]1CN(C(=O)C2CCNC2)C[C@H]1c1ccc(Cl)cc1
Reactant: CCC(=O)Cl
Product: CCC(=O)N1CCC(C(=O)N2C[C@@H](N(C)C(=O)Oc3ccc(F)cc3)[C@H](c3ccc(Cl)cc3)C2)C1

Procedure:
In analogy to the procedure described for the synthesis of example 73, the title [(3S,4R)-4-(4-chloro-phenyl)-1-(1-propionyl-pyrrolidine-3-carbonyl)-pyrrolidin-3-yl]-methyl-carbamic acid 4-fluoro-phenyl ester was prepared from [(3S,4R)-4-(4-chloro-phenyl)-1-(pyrrolidine-3-carbonyl)-pyrrolidin-3-yl]-methyl-carbamic acid 4-fluoro-phenyl ester instead of rac-[(3R,4S)-4-(3,4-dichloro-phenyl)-1-(piperidine-4-carbonyl)-pyrrolidin-3-yl]-methyl-carbamic acid 4-fluoro-phenyl ester using propionyl chloride and was obtained as a light yellow oil. MS m/e: 502.2 [M+H]+.
Reaction SMILES: [C:1]1(=[O:11])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[N:3][NH:2]1.[H-].[Na+].[CH3:14][O:15][C:16](=[O:25])[CH:17](Br)[CH2:18][CH:19]1[CH2:23][CH2:22][CH2:21][CH2:20]1.O>O1CCCC1>[CH3:14][O:15][C:16](=[O:25])[CH:17]([N:2]1[N:3]=[CH:4][C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[C:1]1=[O:11])[CH2:18][CH:19]1[CH2:20][CH2:21][CH2:22][CH2:23]1
Reactant: COC(=O)C(Br)CC1CCCC1
Reactant: O=c1[nH]ncc2ccccc12
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)C(CC1CCCC1)n1ncc2ccccc2c1=O
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 65.1 %

Procedure:
A solution of 2H-phthalazin-1-one (1.33 g, 9.1 mmol) in tetrahydrofuran (45.5 mL, 0.2M) cooled to 0° C. was treated with a 60% dispersion of sodium hydride in mineral oil (437 mg, 10.9 mmol). The reaction was stirred at 0° C. for 5 min and then at 25° C. for 30 min. After this time, the reaction was treated with 2-bromo-3-cyclopentyl-propionic acid methyl ester (Intermediate 10, 2.35 g, 10 mmol). The reaction was then warmed to 50° C. where it stirred overnight. At this time, the reaction was cooled to 25° C., poured into water (100 mL), and extracted with methylene chloride (3×100 mL). The organics were dried over sodium sulfate, filtered and concentrated in vacuo. Silica gel column chromatography (ISCO, 80 g, 20-50% ethyl acetate/hexanes) afforded 3-cyclopentyl-2-(1-oxo-1H-phthalazin-2-yl)-propionic acid methyl ester (1.78 g, 61%) as a clear oil; ES+-HRMS m/e calcd for C17H20N2O3 [M+H+] 301.1547 found 301.1546.