Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH2:2][CH2:3][N:4]1[C:8]([CH2:9]Br)=[CH:7][C:6]([N+:11]([O-:13])=[O:12])=[N:5]1.[NH3:14]>C1COCC1>[N+:11]([C:6]1[CH:7]=[C:8]2[CH2:9][NH:14][CH2:2][CH2:3][N:4]2[N:5]=1)([O-:13])=[O:12]
Reactant: O=[N+]([O-])c1cc(CBr)n(CCBr)n1
Reactant: N
Solvent: C1CCOC1
Product: O=[N+]([O-])c1cc2n(n1)CCNC2
Temperature: 25 °C
Reaction time: 72 h
Yield: 76 %

Procedure:
A 250-mL single-neck round-bottomed flask equipped with a magnetic stirrer was charged with 1-(2-bromoethyl)-5-(bromomethyl)-3-nitro-1H-pyrazole 125c (3.0 g, 9.64 mmol) in THF (35 mL) and aqueous ammonia (135 mL, 25-28%). The mixture was stirred at room temperature for 72 h under nitrogen. The reaction mixture was then concentrated under reduced pressure and the resulting residue was partitioned between ethyl acetate (100 mL) and water (100 mL). The aqueous layer was extracted with ethyl acetate (2×50 mL). The combined organic layer was washed with 10% potassium carbonate (2×100 mL), brine (200 mL), and dried over sodium sulfate. The drying agent was removed by filtration, and the filtrate was concentrated under reduced pressure to afford 205a as a yellow solid (1.23 g, 76%). MS: [M+H]+ 169
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:17])[C:5]([O:8][C:9]1[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][C:10]=1[CH3:16])([CH3:7])[CH3:6])[CH3:2].Cl[CH2:19][C:20]1[C:21]([CH2:36][CH2:37][O:38][CH3:39])=[N:22][C:23]([C:26]2[CH:31]=[CH:30][C:29]([C:32]([F:35])([F:34])[F:33])=[CH:28][CH:27]=2)=[N:24][CH:25]=1.[I-].[Na+]>>[CH2:1]([O:3][C:4](=[O:17])[C:5]([O:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:19][C:20]2[C:21]([CH2:36][CH2:37][O:38][CH3:39])=[N:22][C:23]([C:26]3[CH:27]=[CH:28][C:29]([C:32]([F:35])([F:34])[F:33])=[CH:30][CH:31]=3)=[N:24][CH:25]=2)=[CH:11][C:10]=1[CH3:16])([CH3:6])[CH3:7])[CH3:2]
Reactant: COCCc1nc(-c2ccc(C(F)(F)F)cc2)ncc1CCl
Reactant: CCOC(=O)C(C)(C)Oc1ccc(O)cc1C
Agent: [I-]
Agent: [Na+]
Product: CCOC(=O)C(C)(C)Oc1ccc(OCc2cnc(-c3ccc(C(F)(F)F)cc3)nc2CCOC)cc1C

Procedure:
In analogy to the procedure described in example 101A], 2-(4-hydroxy-2-methyl-phenoxy)-2-methyl-propionic acid ethyl ester (described in WO 02/092590) was reacted with 5-chloromethyl-4-(2-methoxy-ethyl)-2-(4-trifluoromethyl-phenyl)-pyrimidine (example 110B]) in the presence of catalytic amount of sodium iodide to give 2-{4-[4-(2-methoxy-ethyl)-2-(4-trifluoromethyl-phenyl)-pyrimidin-5-ylmethoxy]-2-methyl-phenoxy}-2-methyl-propionic acid ethyl ester, which was subsequently saponified in analogy to the procedure described in example 102] to yield the title compound as white crystals of mp. 119.5–120.0° C.
Reaction SMILES: [CH3:1][N:2]1[C:6]([CH2:7][O:8][CH2:9][C:10]2[CH:11]=[C:12]([NH:16][C:17]3[C:18]([NH2:27])=[CH:19][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:21][CH:22]=3)[CH:13]=[CH:14][CH:15]=2)=[N:5][CH:4]=[N:3]1.[CH:28](OCC)(OCC)OCC.C1(C)C=CC(S(O)(=O)=O)=CC=1.CC1C=CC2N(C3C=CC=C(COCC4N(C)N=CN=4)C=3)C=NC=2C=1.CC1C=C(N)C(NC2C=CC=C(COCC3N(C)N=CN=3)C=2)=CC=1.CN1C(COCC2C=C(N3C4C=CC(C(=O)C)=CC=4N=C3)C=CC=2)=NC=N1.NC1C=C(C(=O)C)C=CC=1NC1C=CC=C(COCC2N(C)N=CN=2)C=1>C1COCC1>[CH3:1][N:2]1[C:6]([CH2:7][O:8][CH2:9][C:10]2[CH:11]=[C:12]([N:16]3[C:17]4[CH:22]=[CH:21][C:20]([C:23]([F:24])([F:26])[F:25])=[CH:19][C:18]=4[N:27]=[CH:28]3)[CH:13]=[CH:14][CH:15]=2)=[N:5][CH:4]=[N:3]1
Reactant: Cn1ncnc1COCc1cccc(Nc2ccc(C(F)(F)F)cc2N)c1
Reactant: CCOC(OCC)OCC
Agent: CC(=O)c1ccc(Nc2cccc(COCc3ncnn3C)c2)c(N)c1
Agent: CC(=O)c1ccc2c(c1)ncn2-c1cccc(COCc2ncnn2C)c1
Agent: Cc1ccc(Nc2cccc(COCc3ncnn3C)c2)c(N)c1
Solvent: C1CCOC1
Product: Cn1ncnc1COCc1cccc(-n2cnc3cc(C(F)(F)F)ccc32)c1
Yield: 67 %

Procedure:
To a solution of compound 20a in anhydrous THF (15 ml) was added triethyl orthoformate (0.75 ml, 4.4 mmol) and a catalytic amount of p-toluenesulphonic acid. The resultant mixture was stirred at reflux for 1 hour. The solvent was removed in vacuo and the residue was purified by column chromatography on silica gel, eluting with a mixture of ethyl acetate and methanol (9:1 v/v). Compound 21a (0.87 g) was precipitated as the hydro chloride by addition of etheral hydrogen chloride to the pure fractions. LC-ESI-HRMS of [M+H]+ shows 388.14 Da. Calc. 388.138519 Da, dev. 3.8 ppm The following compounds were prepared in analogy herewith: 1-[3-(2-Ethyl-2H-[1,2,4]triazol-3-ylmethoxymethyl)-phenyl]-5-trifluoromethyl-1H-benzoimidazole (21b) from compound 20b. Yield: 67%. LC-ESI-HRMS of [M+H]+ shows 402.1548 Da. Calc. 402.154169 Da, dev. 1.6 ppm 5-Methyl-1-[3-(2-methyl-2H-[1,2,4]triazol-3-ylmethoxymethyl)-phenyl]-1H-benzoimidazole (21c) from compound 20c. Yield: 7% (3 steps). LC-ESI-HRMS of [M+H]+ shows 334.1679 Da. Calc. 334.166785 Da, dev. 3.3 ppm 1-{1-[3-(2-Methyl-2H-[1,2,4]triazol-3-ylmethoxymethyl)-phenyl]-1H-benzoimidazol-5-yl}-ethanone (21d) from compound 20d. Yield: 53% isolated as the free base. Mp 121.4-123.6° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[C:24]([C:25]([O:27]C)=[O:26])=[CH:23][C:22]([N+:29]([O-:31])=[O:30])=[CH:21][C:16]=2[C:17]([O:19]C)=[O:18])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]>Cl>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][CH:11]([O:14][C:15]2[C:24]([C:25]([OH:27])=[O:26])=[CH:23][C:22]([N+:29]([O-:31])=[O:30])=[CH:21][C:16]=2[C:17]([OH:19])=[O:18])[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)c1cc([N+](=O)[O-])cc(C(=O)OC)c1OC1CCN(C(=O)OC(C)(C)C)CC1
Agent: Cl
Product: CC(C)(C)OC(=O)N1CCC(Oc2c(C(=O)O)cc([N+](=O)[O-])cc2C(=O)O)CC1
Temperature: 40 °C
Reaction time: 1 h
Yield: 40.9 %

Procedure:
A solution of dimethyl 2-(1-t-butoxycarbonylpiperidin-4-yloxy)-5-nitroisophthalate (10.7 g) in concentrated hydrochloric acid (100 ml) was stirred at 80° C. for 10 hours. The reaction mixture was concentrated in vacuo. To the residue was added hexane to afford a white solid which was collected by filtration. To a solution of the solid in a mixture of water (50 ml) and acetone (50 ml) were added sodium hydrogencarbonate (4.6 g) and di-t-butyl dicarbonate (5.9 g) at room temperature. The resulting mixture was stirred at 40° C. for 1 hour. The reaction mixture was extracted with ethyl acetate. The extract was washed with brine. The organic layer was dried over anhydrous magnesium sulfate, filtered and the filtrate was concentrated in vacuo. To the residue was added hexane and the mixture was filtered to give the desired compound (4.1 g, yield 40%) as a pale yellow solid.
Reaction SMILES: [C:1]1([N:7]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[CH:9]=[C:8]2[S:16][CH2:17][CH:18]=[CH:19][CH2:20]O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CO.Cl.[OH:25][NH2:26]>N1C=CC=CC=1>[OH:25][N:26]=[CH:20][CH:19]1[C:9]2[C:10]3[C:15](=[CH:14][CH:13]=[CH:12][CH:11]=3)[N:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[C:8]=2[S:16][CH2:17][CH2:18]1
Reactant: NO
Reactant: OCC=CCSc1cc2ccccc2n1-c1ccccc1
Agent: Cl
Solvent: c1ccncc1
Solvent: CO
Product: ON=CC1CCSc2c1c1ccccc1n2-c1ccccc1
Temperature: 25 °C
Reaction time: 0.83 h
Yield: 84.7 %

Procedure:
A solution of the product of the above (2) (3.71 g) in pyridine (75 ml) is heated at 110° C. for 70 minutes. After cooling, methanol (25 ml) and hydroxyamine hydrochloride (2.2 g) are added thereto. The mixture is stirred at room temperature for 50 minutes and evaporated. The residue is acidified with ice-cooled 3 N-hydrochloric acid and extracted with chloroform. The extract is evaporated to give oily residue. The residue is chromatographed on a column of silica gel and eluted with benzene. The eluate is evaporated to give 4-hydroxyiminomethyl-9-phenyl-2,3,4,9-tetrahydrothiopyrano[2,3-b]indole (3.28 g). The product is dissolved into tetrahydrofuran (55 ml) and lithium aluminium hydride (1.4 g) is added thereto at room temperature. The mixture is refluxed for 1 hour. Ethyl acetate, an 10% aqueous solution of sodium hydroxide and water are successively added thereto. The precipitate is collected by filtration, washed with ethyl acetate and chloroform, and added to the filtrate. The organic layer is separated, washed with water, dried and evaporated to give the free base of the title compound as an oil.
Reaction SMILES: [CH:1]12[O:8][CH:5]([CH2:6][CH2:7]1)[CH2:4][N:3]([C:9]1[N:14]=[C:13]([N:15]3[CH2:20][CH2:19][C:18](=O)[CH2:17][CH2:16]3)[N:12]=[C:11]([C:22]3[CH:27]=[CH:26][C:25]([NH:28][C:29]([NH:31][C:32]4[CH:37]=[CH:36][N:35]=[CH:34][CH:33]=4)=[O:30])=[CH:24][CH:23]=3)[N:10]=1)[CH2:2]2.C(O)(C(F)(F)F)=O.[CH3:45][N:46]1[CH2:51][CH2:50][NH:49][CH2:48][CH2:47]1>>[CH:5]12[O:8][CH:1]([CH2:7][CH2:6]1)[CH2:2][N:3]([C:9]1[N:14]=[C:13]([N:15]3[CH2:20][CH2:19][CH:18]([N:49]4[CH2:50][CH2:51][N:46]([CH3:45])[CH2:47][CH2:48]4)[CH2:17][CH2:16]3)[N:12]=[C:11]([C:22]3[CH:23]=[CH:24][C:25]([NH:28][C:29]([NH:31][C:32]4[CH:37]=[CH:36][N:35]=[CH:34][CH:33]=4)=[O:30])=[CH:26][CH:27]=3)[N:10]=1)[CH2:4]2
Reactant: O=C1CCN(c2nc(-c3ccc(NC(=O)Nc4ccncc4)cc3)nc(N3CC4CCC(C3)O4)n2)CC1
Reactant: CN1CCNCC1
Solvent: O=C(O)C(F)(F)F
Product: CN1CCN(C2CCN(c3nc(-c4ccc(NC(=O)Nc5ccncc5)cc4)nc(N4CC5CCC(C4)O5)n3)CC2)CC1

Procedure:
By reacting 1-(4-(4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-6-(4-oxopiperidin-1-yl)-1,3,5-triazin-2-yl)phenyl)-3-(pyridin-4-yl)urea.TFA (40 mg) and 1-methylpiperazine (0.050 mL) and following the procedure as outlined in example 118, the titled compound was isolated after HPLC purification as its tri-TFA salt; MS (ES+) 585.9 (M+H)+
Reaction SMILES: [CH3:1][NH:2][NH2:3].[F:4][C:5]([F:15])([F:14])[C:6](=O)[CH2:7][C:8](OCC)=[O:9]>C1(C)C=CC=CC=1>[OH:9][C:8]1[N:2]([CH3:1])[N:3]=[C:6]([C:5]([F:15])([F:14])[F:4])[CH:7]=1
Reactant: CCOC(=O)CC(=O)C(F)(F)F
Reactant: CNN
Solvent: Cc1ccccc1
Product: Cn1nc(C(F)(F)F)cc1O
Temperature: 25 °C
Reaction time: 1 h
Yield: 73930.8 %

Procedure:
Methyl hydrazine (13.3 ml, 11.5 g, 0.25 mol) was added dropwise to a chilled (ice-bath) solution of ethyl 4,4,4-trifluoroacetoacetate (46.0 g, 0.25 mmol) in toluene (250 ml) at such a rate that the temperature of the reaction could be maintained below 10° C. (ice-bath cooling). Once the addition was complete the ice-bath was removed and stirring continued at room temperature for 1 hour and then at reflux (Dean-Stark) for 3 h. The mixture was allowed to cool to room temperature and allowed to stand over 3 days. The precipitate was collected by filtration and washed with hexane to give 5-hydroxy-1-methyl-3-trifluoromethylpyrazole (30.7 g) as a colorless solid, m.p. 170°-173° C.
Reaction SMILES: [NH2:1][N:2]1[C:7](=[O:8])[C:6]([C:9]2[NH:14][C:13]3[CH:15]=[CH:16][CH:17]=[CH:18][C:12]=3[S:11](=[O:20])(=[O:19])[N:10]=2)=[C:5]([OH:21])[C:4]2[S:22][CH:23]=[CH:24][C:3]1=2.[C:25]1([C:31](=O)[CH3:32])[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>CN(C)C(=O)C>[O:19]=[S:11]1(=[O:20])[C:12]2[CH:18]=[CH:17][CH:16]=[CH:15][C:13]=2[NH:14][C:9]([C:6]2[C:7](=[O:8])[N:2]([N:1]=[C:31]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[CH3:32])[C:3]3[CH:24]=[CH:23][S:22][C:4]=3[C:5]=2[OH:21])=[N:10]1
Reactant: Nn1c(=O)c(C2=NS(=O)(=O)c3ccccc3N2)c(O)c2sccc21
Reactant: CC(=O)c1ccccc1
Solvent: CC(=O)N(C)C
Product: CC(=Nn1c(=O)c(C2=NS(=O)(=O)c3ccccc3N2)c(O)c2sccc21)c1ccccc1
Temperature: 25 °C

Procedure:
The product of Example 268D (0.073 g, 0.2 mmol) was reacted with 1-phenylethanone (1.2 g, 10.0 mmol) in N,N-dimethylacetamide (2 mL) in a sealed tube at 135° C. for 75 minutes in a microwave reactor. The reaction was cooled to 25° C. and concentrated under vacuum. The resulting residue was triturated with diethyl ether (3 mL) and filtered to give the title compound.
Reaction SMILES: [C:1]([Si:5]([CH3:16])([CH3:15])[O:6][CH2:7][CH2:8][N:9]1[CH:13]=[CH:12][C:11]([NH2:14])=[N:10]1)([CH3:4])([CH3:3])[CH3:2].N1C(C)=CC=CC=1C.[Cl:25][C:26]1[CH:27]=[C:28]([C@@H:36]([CH2:40][C@H:41]2[CH2:45][CH2:44][C:43](=[O:46])[CH2:42]2)[C:37](Cl)=[O:38])[CH:29]=[CH:30][C:31]=1[S:32]([CH3:35])(=[O:34])=[O:33]>C(Cl)Cl>[C:1]([Si:5]([CH3:16])([CH3:15])[O:6][CH2:7][CH2:8][N:9]1[CH:13]=[CH:12][C:11]([NH:14][C:37](=[O:38])[C@@H:36]([C:28]2[CH:29]=[CH:30][C:31]([S:32]([CH3:35])(=[O:33])=[O:34])=[C:26]([Cl:25])[CH:27]=2)[CH2:40][C@H:41]2[CH2:45][CH2:44][C:43](=[O:46])[CH2:42]2)=[N:10]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CS(=O)(=O)c1ccc([C@@H](C[C@H]2CCC(=O)C2)C(=O)Cl)cc1Cl
Reactant: CC(C)(C)[Si](C)(C)OCCn1ccc(N)n1
Solvent: Cc1cccc(C)n1
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)OCCn1ccc(NC(=O)[C@H](C[C@H]2CCC(=O)C2)c2ccc(S(C)(=O)=O)c(Cl)c2)n1
Temperature: 25 °C
Reaction time: 16 h
Yield: 77 %

Procedure:
In a round bottom flask was placed 1-[2-(tert-butyl-dimethyl-silanyloxy)-ethyl]-1H-pyrazol-3-ylamine (prepared in Example 67, 54 mg, 0.22 mmol), 2,6-lutidine (35 μL, 0.30 mmol) and methylene chloride (5 mL) which was then cooled to 0° C. in an ice bath. To this solution was then added dropwise a solution of (R)-2-(3-chloro-4-methanesulfonyl-phenyl)-3-((R)-3-oxo-cyclopentyl)-propionyl chloride in methylene chloride (prepared as in Example 96, ˜0.10 M solution, 2 mL, 0.20 mmol). The reaction was then allowed to warm up to 25° C. and stirred for 16 h. After this time the reaction mixture was diluted with methylene chloride (5 mL) transferred to a separatory funnel and washed with a saturated aqueous sodium bicarbonate solution (10 mL) and then a 1 N aqueous hydrochloric acid solution (10 mL) and then dried over magnesium sulfate, filtered and concentrated in vacuo. Purification on an AnaLogix Intelliflash system (4 g column, 50% ethyl acetate/hexanes to 70% ethyl acetate/hexanes) afforded (R)—N-{1-[2-(tert-butyl-dimethyl-silanyloxy)-ethyl]-1H-pyrazol-3-yl}-2-(3-chloro-4-methanesulfonyl-phenyl)-3-((R)-3-oxo-cyclopentyl)-propionamide (88 mg, 77%) as a yellow foam: [α]30589=−74.3° (c=0.14, methylene chloride); ES-HRMS m/e calcd for C26H38N3O5SSiCl (M+H)+ 568.2063, observed 568.2063; 1H NMR (300 MHz, DMSO-d6) δ −0.09 (s, 6H, 2×SiCH3), 0.77 (s, 9H, 3×CH3), 1.51 (m, 1H, CH), 1.79-2.29 (m, 8 H, 4×CH2), 3.34 (s, 3H, SO2CH3), 3.84 (m, 2H, OCH2), 3.96 (m, 1H, ArCHCO), 3.96 (m, 2H, NCH2), 6.41 (d, J=2.2 Hz, 1H, Ar), 7.53 (d, J=2.2 Hz, 1H, Ar), 7.61 (dd, Jo=8.2 Hz, Jm=1.4 Hz, 1H, Ar), 7.73 (d, Jm=1.4 Hz, 1H, Ar), 8.01 (d, Jo=8.2 Hz, 1H, Ar), 10.83 (s, 1H, NH).
Reaction SMILES: [OH:1][CH2:2][C:3]([CH2:8][OH:9])([CH2:6][CH3:7])[CH2:4][SH:5].CO[C:12](OC)(OC)[C:13]1[CH:18]=[CH:17][C:16]([Br:19])=[CH:15][CH:14]=1>C(N(CC)CC)C>[Br:19][C:16]1[CH:17]=[CH:18][C:13]([C:12]23[S:5][CH2:4][C:3]([CH2:6][CH3:7])([CH2:8][O:9]2)[CH2:2][O:1]3)=[CH:14][CH:15]=1
Reactant: CCC(CO)(CO)CS
Reactant: COC(OC)(OC)c1ccc(Br)cc1
Solvent: CCN(CC)CC
Product: CCC12COC(c3ccc(Br)cc3)(OC1)SC2
Reaction time: 0.75 h

Procedure:
(iv)a) 2,2-Di-(hydroxymethyl)-butanethiol (0.5 g.), trimethyl 4-bromo-orthobenzoate 2 (1.0 g.) and triethylamine (0.1 ml.) were heated at 130°, under a current of nitrogen, for 45 minutes. The volatile components were removed in vacuo (2.00 mm.), at 140°. The residue was purified by chromatography on alumina (alumina Woelm TSC) eluting with 1:6 dichloromethane: hexane, saturated with ammonia. 1-(4-Bromophenyl)-4-ethyl-2,6-dioxa-7-thiabicyclo[2,2,2]octane was obtained as colourless crystals (80 mg.).
Reaction SMILES: [C:1]([C:5]1[N:6]=[C:7]([N:16]2[CH2:20][CH2:19][C:18]([F:22])([F:21])[CH2:17]2)[C:8]2[N:13]=[N:12][N:11]([CH2:14][CH3:15])[C:9]=2[N:10]=1)([CH3:4])([CH3:3])[CH3:2].C(C1N=C(N2CCC(F)(F)C2)C2N=NNC=2N=1)(C)(C)C.BrC1C[O:46][CH2:45]1>>[C:1]([C:5]1[N:6]=[C:7]([N:16]2[CH2:20][CH2:19][C:18]([F:21])([F:22])[CH2:17]2)[C:8]2[N:13]=[N:12][N:11]([CH:14]3[CH2:45][O:46][CH2:15]3)[C:9]=2[N:10]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CCn1nnc2c(N3CCC(F)(F)C3)nc(C(C)(C)C)nc21
Reactant: BrC1COC1
Agent: CC(C)(C)c1nc(N2CCC(F)(F)C2)c2nn[nH]c2n1
Product: CC(C)(C)c1nc(N2CCC(F)(F)C2)c2nnn(C3COC3)c2n1

Procedure:
In analogy to the procedure described for the synthesis of 5-tert-butyl-7-(3,3-difluoropyrrolidin-1-yl)-3-ethyl-3H-[1,2,3]triazolo[4,5-d]pyrimidine (example 61), the title compound was prepared from 5-tert-butyl-7-(3,3-difluoropyrrolidin-1-yl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine and 3-bromooxetane and isolated as light-yellow gum. MS(m/e): 339.3 (MH+).
Reaction SMILES: [CH3:1][N:2]([CH2:12][CH2:13][OH:14])[C:3]1[CH:8]=[CH:7][C:6]([N+:9]([O-])=O)=[CH:5][CH:4]=1>C(O)C.[Pd]>[NH2:9][C:6]1[CH:5]=[CH:4][C:3]([N:2]([CH3:1])[CH2:12][CH2:13][OH:14])=[CH:8][CH:7]=1
Reactant: CN(CCO)c1ccc([N+](=O)[O-])cc1
Agent: [Pd]
Solvent: CCO
Product: CN(CCO)c1ccc(N)cc1

Procedure:
A solution of 2-(methyl-4-nitroanilino)ethanol (0.20 g, 1.0 mmol) in ethanol (25 mL) is hydrogenated for two hours at atmospheric pressure over 10% Pd/C. The mixture is filtered through a pad of diatomaceous earth and concentrated under reduced pressure to give 2-[(4-amino-phenyl)-methyl-amino]-ethanol as a dark oil, which solidified upon standing.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:6]=[N:7][N:8]2[C:13](Cl)=[C:12]([C:15]3[C:20]([F:21])=[CH:19][CH:18]=[CH:17][C:16]=3[F:22])[C:11]([Cl:23])=[N:10][C:9]=12)=[O:4]>C(O)C.O.C1COCC1.[Zn]>[CH3:1][O:2][C:3]([C:5]1[CH:6]=[N:7][N:8]2[CH:13]=[C:12]([C:15]3[C:20]([F:21])=[CH:19][CH:18]=[CH:17][C:16]=3[F:22])[C:11]([Cl:23])=[N:10][C:9]=12)=[O:4]
Reactant: COC(=O)c1cnn2c(Cl)c(-c3c(F)cccc3F)c(Cl)nc12
Agent: [Zn]
Solvent: C1CCOC1
Solvent: O
Solvent: CCO
Product: COC(=O)c1cnn2cc(-c3c(F)cccc3F)c(Cl)nc12
Temperature: 25 °C
Reaction time: 3 h

Procedure:
5 g (13.96 mmol) 5,7-Dichloro-6-(2,6-difluorophenyl)pyrazolo[1,5-a]pyrimidine-3-carboxylic acid methyl ester are dissolved in a mixture of 355 mL ethanol, 253 mL water and 136 mL THF. After addition of 5.8 g (89 mmol) zinc in portions, the mixture is vigorously stirred at rt for three hours. Stirring is continued over night. The reaction mixture is filtered via a glass microfibre filter and washed with plenty of ethanol. The solvent has been removed and the residue redissolved in ethyl acetate. After washing twice with brine and drying over Na2SO4, the solvent is evaporated and the residue is used in the next step as the crude contaminated product (2.3 g=51%).
Reaction SMILES: [NH2:1][C:2]1[C:3]([CH2:8][OH:9])=[N:4][CH:5]=[CH:6][N:7]=1>C(Cl)(Cl)Cl.[O-2].[O-2].[Mn+4]>[NH2:1][C:2]1[C:3]([CH:8]=[O:9])=[N:4][CH:5]=[CH:6][N:7]=1
Reactant: Nc1nccnc1CO
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClC(Cl)Cl
Product: Nc1nccnc1C=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 82 %

Procedure:
A suspension of 3-aminopyrazine methanol, 6.3 g (0.05 mol) and manganese dioxide (38.0 g) in 400 mL of chloroform is stirred at room temperature for two hours and the resulting solid is filtered off. The filtrate is evaporated to dryness which gives the desired product as a yellow crystalline solid, (5.00 g, 82% yield) having a melting point 110°-114° C.
Reaction SMILES: [OH:1][C:2]1[C:11]([CH3:12])=[CH:10][CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].[N+:13]([O-])([O-:15])=[O:14].[Na+]>FC(F)(F)C(O)=O>[OH:1][C:2]1[C:11]([CH3:12])=[CH:10][C:9]([N+:13]([O-:15])=[O:14])=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5]
Reactant: COC(=O)c1cccc(C)c1O
Reactant: O=[N+]([O-])[O-]
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)c1cc([N+](=O)[O-])cc(C)c1O
Temperature: 0 °C
Reaction time: 1 h
Yield: 64 %

Procedure:
Methyl 2-hydroxy-3-methylbenzoate (Reference Compound No. 1-4-(1), 22.9 g, 0.138 mol) was dissolved in trifluoroacetic acid (190 mL), then an aqueous solution (90 mL) of sodium nitrate (12.9 g, 152 mmol) was added dropwise thereto over 1 hour at −10° C. After the reaction mixture was stirred at 0° C. for 1.5 hours, it was poured into ice-water (600 mL). The appeared solid was filtered and washed with methanol (100 mL) to give the titled reference compound (18.7 g) as a pale red solid. (Yield 64%)
Reaction SMILES: [F:1][CH:2]1[N:8]=[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[Cl:15])[C:6]2[CH:16]=[C:17]([Cl:20])[CH:18]=[CH:19][C:5]=2[NH:4][C:3]1=[O:21].CI.O.[CH3:25]CCCCC>O1CCCC1.C1C=CC=CC=1>[F:1][CH:2]1[N:8]=[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[Cl:15])[C:6]2[CH:16]=[C:17]([Cl:20])[CH:18]=[CH:19][C:5]=2[N:4]([CH3:25])[C:3]1=[O:21]
Reactant: O=C1Nc2ccc(Cl)cc2C(c2ccccc2Cl)=NC1F
Reactant: CCCCCC
Solvent: c1ccccc1
Solvent: CI
Solvent: C1CCOC1
Product: CN1C(=O)C(F)N=C(c2ccccc2Cl)c2cc(Cl)ccc21
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Sodium hydride (0.25 g of 50% mineral oil emulsion washed twice with tetrahydrofuran, 0.0050 mole) in 10 ml tetrahydrofuran was added portionwise at ambient temperature to a well stirred solution of 1.7 g (0.0053 mole) 3-fluoro-7-chloro-5-(2-chlorophenyl)-1,3-dihydro-2H-1,4-benzodiazepin-2-one and 5.6 g (0.039 mole) methyl iodide in 50 ml tetrahydrofuran under nitrogen. The solution was stirred 2 hr at room temperature, then poured into 100 ml water. The product was extracted with methylene chloride, the extract dried over MgSO4 and the solvent evaporated, yielding a tan solid. The crude product was dissolved in benzene and allowed to crystallize giving a white solid; a second crop was obtained by addition of n-hexane, yielding a total of 1.1 g of 3-fluoro-7-chloro-5-(2-chlorophenyl)-1,3-dihydro-1-methyl-2H-1,4-benzodiazepin-2-one: mp 204°-205°; 1H nmr (DMSO-d6) δ 7.6 ppm (m, 6 H), δ 7.0 ppm (m, 1H), δ 5.94 ppm (d, 56 Hz, 1H), δ 3.45 ppm (s, 3H); 19F nmr (DMSO-d6) δ -161.8 ppm (d, J=56 Hz).
Reaction SMILES: [C:1]([OH:10])(=[O:9])[C@H:2]([C@@H:4]([C:6]([OH:8])=[O:7])[OH:5])[OH:3].[Cl:11][C:12]1[CH:17]=[CH:16][C:15]([N:18]2[CH2:22][CH2:21][CH:20]([CH2:23][N:24]3[CH2:29][CH2:28][N:27]([CH2:30][CH2:31][O:32][CH3:33])[CH2:26][CH2:25]3)[C:19]2=[O:34])=[CH:14][CH:13]=1>C(O)C>[C:6]([C@H:4]([C@@H:2]([C:1]([OH:10])=[O:9])[OH:3])[OH:5])([OH:8])=[O:7].[C:6]([C@H:4]([C@@H:2]([C:1]([OH:10])=[O:9])[OH:3])[OH:5])([OH:8])=[O:7].[Cl:11][C:12]1[CH:17]=[CH:16][C:15]([N:18]2[CH2:22][CH2:21][C@H:20]([CH2:23][N:24]3[CH2:25][CH2:26][N:27]([CH2:30][CH2:31][O:32][CH3:33])[CH2:28][CH2:29]3)[C:19]2=[O:34])=[CH:14][CH:13]=1
Reactant: COCCN1CCN(CC2CCN(c3ccc(Cl)cc3)C2=O)CC1
Agent: O=C(O)[C@@H](O)[C@H](O)C(=O)O
Solvent: CCO
Product: COCCN1CCN(C[C@H]2CCN(c3ccc(Cl)cc3)C2=O)CC1
Yield: 38.1 %

Procedure:
A solution of D-tartaric acid (450 mg) in ethanol (6 ml) was added dropwise at an outer temperature between 50 and 60° C. to a solution of 1-(4-chlorophenyl)-3-(4-(2-methoxyethyl)piperazin-1-yl)methyl-2-pyrrolidinone (1056mg) in ethanol (6ml). The reaction mixture was allowed to stand for cooling and the solid material thus precipitated was collected by filtration. The solid material was further crystallized in 10 ml of ethanol to obtain 372 mg of the title compound. Enantiomer excess: 97% ee
Reaction SMILES: [N+:1]([C:4]1[C:5]([O:10][C@H:11]([CH3:16])[C:12]([O:14]C)=[O:13])=[N:6][CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].[OH-].[Na+].Cl>CO>[N+:1]([C:4]1[C:5]([O:10][C@H:11]([CH3:16])[C:12]([OH:14])=[O:13])=[N:6][CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: COC(=O)[C@@H](C)Oc1ncccc1[N+](=O)[O-]
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: C[C@@H](Oc1ncccc1[N+](=O)[O-])C(=O)O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A mixture of 3.0 g (13.3 mmol) of methyl (2R)-2-[(3-nitro-2-pyridyl)oxy]propanoate and 5.0 ml 4 mol/l aq. NaOH solution in methanol are stirred at RT for 30 min. 5.0 ml 4 mol/l aq. HCl are added and the reaction mixture concentrated. The precipitate is filtered off, dissolved in DCM, dried and evaporated yielding (2R)-2-[(3-nitro-2-pyridyl)oxy]propanoic acid.