Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[C:2]([O:6][C:7](=[O:11])[CH2:8][CH2:9][NH2:10])([CH3:5])([CH3:4])[CH3:3].C(N(CC)CC)C.Br[CH2:20][C:21]1[CH:22]=[C:23]([CH:26]=[CH:27][CH:28]=1)[C:24]#[N:25]>C(#N)C.O>[C:24]([C:23]1[CH:22]=[C:21]([CH:28]=[CH:27][CH:26]=1)[CH2:20][NH:10][CH2:9][CH2:8][C:7]([O:6][C:2]([CH3:5])([CH3:4])[CH3:3])=[O:11])#[N:25]
Reactant: N#Cc1cccc(CBr)c1
Reactant: CC(C)(C)OC(=O)CCN
Agent: Cl
Solvent: CCN(CC)CC
Solvent: O
Solvent: CC#N
Product: CC(C)(C)OC(=O)CCNCc1cccc(C#N)c1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To a stirred solution of β-alanine tert-butyl ester hydrochloride (7.1 g, 39.2 mmol) and triethylamine (14.2 mL, 107 mmol) in dry acetonitrile (100 mL) was added 3-(bromomethyl)benzonitrile (7.0 g, 35.7 mmol) in portions over 10 minutes at 0° C. After being stirred at RT for 5 hours, the reaction mixture was diluted with water (100 mL) and extracted with dichloromethane (2×100 mL) The organic layers were combined, dried using sodium sulphate and concentrated under reduced pressure. The residue was purified by flash chromatography affording the title compound as a pale yellow liquid. 1H NMR (DMSO-d6, 400 MHz) δ 7.75 (s, 1H), 7.66 (m, 2H), 7.50 (m, 1H), 3.71 (s, 2H), 2.64 (t, 2H), 2.32 (m, 2H), 1.37 (s, 9H).
Reaction SMILES: [O:1]1[C:5]2([CH2:10][CH2:9][N:8]([C@H:11]3[CH2:28][C@@:27]4([CH3:29])[C@@H:14]([CH2:15][CH2:16][C@@H:17]5[C@@H:26]4[CH2:25][CH2:24][C@@:22]4([CH3:23])[C@H:18]5[CH2:19][C@H:20]([N:31]5[CH2:35][CH2:34][CH2:33][CH2:32]5)[C@@H:21]4[OH:30])[CH2:13][C@@H:12]3[OH:36])[CH2:7][CH2:6]2)[O:4][CH2:3][CH2:2]1.[C:37](Cl)(=[O:39])[CH3:38].O>C(Cl)Cl.C(N(CC)CC)C>[O:4]1[C:5]2([CH2:6][CH2:7][N:8]([C@H:11]3[CH2:28][C@@:27]4([CH3:29])[C@@H:14]([CH2:15][CH2:16][C@@H:17]5[C@@H:26]4[CH2:25][CH2:24][C@@:22]4([CH3:23])[C@H:18]5[CH2:19][C@H:20]([N:31]5[CH2:32][CH2:33][CH2:34][CH2:35]5)[C@@H:21]4[OH:30])[CH2:13][C@@H:12]3[OH:36])[CH2:9][CH2:10]2)[O:1][CH2:2][CH2:3]1.[CH3:38][C:37]([CH2:6][C:5]([OH:4])=[O:1])=[O:39]
Reactant: CC(=O)Cl
Agent: C[C@]12C[C@H](N3CCC4(CC3)OCCO4)[C@@H](O)C[C@@H]1CC[C@@H]1[C@@H]2CC[C@]2(C)[C@@H](O)[C@@H](N3CCCC3)C[C@@H]12
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O
Product: CC(=O)CC(=O)O
Temperature: 0 °C
Reaction time: 16 h

Procedure:
To a solution containing 10 g of 2β-(1,4-dioxa-8-azaspiro[4.5]dec-8-yl)-16β-(1-pyrrolidinyl)-5α-androstane-3α,17β-diol in 50 ml of methylene chloride, 7 ml of triethylamine are added and the solution is cooled to 0° C. To this solution 4.4 ml of acetyl chloride are dropwise added while cooling and stirring at such a rate that the temperature remains below 10° C. After termination of the addition the cooling is stopped and the mixture is allowed to warm to room temperature. The complete reaction requires about 16 hours. Thereafter, the excess of acetyl chloride is decomposed by adding water and the methylene chloride solution is washed with aqueous sodium hydroxide solution and then with water until neutral. The methylene chloride phase is dried, evaporated and the residue is purified on a silica gel column to yield 9 g (77.1%) of the title product as a foam.
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[C:3]([N:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)=[N:2]1.[Cl:16][CH2:17][CH2:18][C:19]1[CH:20]=[C:21]2[C:25](=[CH:26][CH:27]=1)[NH:24][C:23](=[O:28])[CH2:22]2.C(=O)([O-])[O-].[Na+].[Na+].[I-].[Na+]>CC(CC(C)C)=O>[ClH:16].[S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[C:3]([N:10]2[CH2:11][CH2:12][N:13]([CH2:17][CH2:18][C:19]3[CH:20]=[C:21]4[C:25](=[CH:26][CH:27]=3)[NH:24][C:23](=[O:28])[CH2:22]4)[CH2:14][CH2:15]2)=[N:2]1
Reactant: c1ccc2c(N3CCNCC3)nsc2c1
Reactant: O=C1Cc2cc(CCCl)ccc2N1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [Na+]
Solvent: CC(=O)CC(C)C
Product: Cl
Product: O=C1Cc2cc(CCN3CCN(c4nsc5ccccc45)CC3)ccc2N1

Procedure:
To a 125 ml round-bottom flask equipped with nitrogen inlet and condenser were added 0.70 grams (3.20mmol) N-(3-benzisothiazolyl)-piperazine, 0.62 grams (3.20 mmol) 5-(2-chloroethyl)-oxindole, 0.68 grams (6.40 mmol) sodium carbonate, 2 mg sodium iodide, and 30 ml methylisobutyl ketone. The reaction was refluxed 40 hours, cooled, filtered, and evaporated. The residue was chromatographed on silica gel, eluting the byproducts with ethyl acetate (1:1) and the product with 4% methanol in ethyl acetate (1.5:1). The product fractions (Rf=0.2 in 5% methanol in ethyl acetate) were evaporated, taken up in methylene chloride, and precipitated by addition of ether saturated with HCl; the solid was filtered and washed with ether, dried, and washed with acetone. The latter was done by slurrying the solid acetone and filtering. The title compound was obtained as a high melting, non-hygroscopic solid product, m.p. 288°-288.5° C., 0.78 (59%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:6])[CH2:4]Cl.[C:7]1([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[CH:12]=[CH:11][C:10]([CH2:13][C@@H:14]([NH:23]C(OC(C)(C)C)=O)[CH2:15][C@:16]([CH2:21][OH:22])([CH3:20])[C:17]([OH:19])=[O:18])=[CH:9][CH:8]=1.CCN(CC)CC>CC(C)=O>[CH3:1][O:2][C:3]([CH2:4][O:19][C:17](=[O:18])[C@@:16]([CH2:21][OH:22])([CH3:20])[CH2:15][C@H:14]([NH2:23])[CH2:13][C:10]1[CH:11]=[CH:12][C:7]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)=[CH:8][CH:9]=1)=[O:6]
Reactant: COC(=O)CCl
Reactant: CC(C)(C)OC(=O)N[C@H](Cc1ccc(-c2ccccc2)cc1)C[C@@](C)(CO)C(=O)O
Solvent: CCN(CC)CC
Solvent: CC(C)=O
Product: COC(=O)COC(=O)[C@](C)(CO)C[C@H](N)Cc1ccc(-c2ccccc2)cc1

Procedure:
Chloroacetic acid methyl ester (34 μL, 387 μmol) was added to a mixture of (2S,4R)-5-biphenyl-4-yl-4-t-butoxycarbonylamino-2-hydroxymethyl-2-methyl-pentanoic acid (100 mg, 242 μmol) and Et3N (35 μL, 254 μmol) in acetone (10 mL). The mixture was refluxed for 24 hours and the reaction monitored for completion. When the reaction was complete, the product was purified ((Interchim reverse phase chromatography column) the solvent was removed under vacuum to yield (2S,4R)-4-amino-5-biphenyl-4-yl-2-hydroxymethyl-2-methyl-pentanoic acid methoxycarbonylmethyl ester.
Reaction SMILES: BrC1C=CC=C(C)C=1.[Li]CCCC.CCCCCC.COC(NCC[O:27][C@@H:28]([C:42]1[CH:43]=[C:44]([CH3:48])[CH:45]=[CH:46][CH:47]=1)[C@@H:29]1[CH2:34][CH2:33][CH2:32][N:31]([C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[CH2:30]1)=O>C1COCC1>[CH3:48][C:44]1[CH:43]=[C:42]([CH:47]=[CH:46][CH:45]=1)[C:28]([C@@H:29]1[CH2:34][CH2:33][CH2:32][N:31]([C:35]([O:37][C:38]([CH3:41])([CH3:39])[CH3:40])=[O:36])[CH2:30]1)=[O:27]
Reactant: COC(=O)NCCO[C@@H](c1cccc(C)c1)[C@@H]1CCCN(C(=O)OC(C)(C)C)C1
Agent: Cc1cccc(Br)c1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: Cc1cccc(C(=O)[C@@H]2CCCN(C(=O)OC(C)(C)C)C2)c1
Temperature: -78 °C
Reaction time: 1 h
Yield: 125.8 %

Procedure:
To a solution of 1-bromo-3-methylbenzene (88.4 g, 0.52 mol) in anhydrous THF (550 mL) at −78° C. under nitrogen was added dropwise a solution of 2.5 M n-BuLi in hexane (210 mL, 0.52 mol). After stirring for 1 hr at −78° C., a solution of (R)-tert-butyl 3-((R)-(2-(methoxycarbonylamino)ethoxy)(m-tolyl)methyl)piperidine-1-carboxylate (120 g, 0.44 mol) in anhydrous THF (500 mL) was added dropwise. After addition, the reaction mixture was allowed to warm to rt and stirred for 2 hr. The mixture was quenched with saturated NH4Cl solution (500 mL) and extracted with ethyl acetate (3×400 mL). The combined organic layers were washed with brine, dried over Na2SO4 and concentrated in vacuo to give crude (R)-tert-butyl 3-(3-methylbenzoyl)piperidine-1-carboxylate (168 g), which was used immediately for next step without purification.
Reaction SMILES: [Cl:1][C:2]1[N:3]([C@@H:15]2[O:21][C@H:20]([CH2:22][OH:23])[C@@H:18]([OH:19])[C@H:16]2[OH:17])[C:4]2[C:9]([C:10]=1[CH:11]=O)=[CH:8][C:7]([Cl:13])=[C:6]([Cl:14])[CH:5]=2.[CH3:24][C:25]([NH:27][NH2:28])=[O:26].O>CO>[Cl:1][CH:2]1[C:10](=[C:11]=[N:28][NH:27][C:25](=[O:26])[CH3:24])[C:9]2[C:4](=[CH:5][C:6]([Cl:14])=[C:7]([Cl:13])[CH:8]=2)[N:3]1[C@@H:15]1[O:21][C@H:20]([CH2:22][OH:23])[C@@H:18]([OH:19])[C@H:16]1[OH:17]
Reactant: CC(=O)NN
Reactant: O=Cc1c(Cl)n([C@@H]2O[C@H](CO)[C@@H](O)[C@H]2O)c2cc(Cl)c(Cl)cc12
Solvent: CO
Solvent: O
Product: CC(=O)NN=C=C1c2cc(Cl)c(Cl)cc2N([C@@H]2O[C@H](CO)[C@@H](O)[C@H]2O)C1Cl
Temperature: 25 °C
Yield: 55.3 %

Procedure:
2,5,6-Trichloro-3-formyl-1-(β-D-ribofuranosyl)indole (4.3, 109 mg, 0.29 mmol) was dissolved in MeOH (5 mL) to which was added acethydrazine (85 mg, 1.1 mmol). The resulting solution was heated on a 45 C oil bath for 16 h, then cooled to room temperature and poured into 15 mL of water. The resulting suspension was cooled to 4C, then filtered and the solids rinsed with cold water (25 mL). The solids were dissolved in DMF (0.5 mL) and subjected to column chromatography (40×350 mm) on C18-reverse phase silica gel with 75% MeOH/H2O. Fractions containing product were pooled and evaporated to yield a white crystalline solid, which was recrystallized from acetone/MeOH to yield 70 mg (56%) of 4.32 as a white microcrystalline solid which is an inseparable mixture of isomers in a ratio of 60:40: mp 270-271 C; Rf 0.2 (10% MeOH/CHCI3); 1H-NMR (500 MHz, DMSO-d6): (major isomer) δ 11.25 (s, 1H, D2O exch.), 8.56 (s, 1H), 8.27 (s, 1H), 8.18 (s, 1H), 5.94 (d, 1H), 5.40-5.36 (m, 2H, D2O exch.), 5.25 (d, 1H, D2O exch.), 4.42 (q, 1H), 4.13 (s, 1H), 3.98 (s, 1H), 3.70(s, 2H), 2.24 (s, 3H); (minor isomer) δ 11.41 (s, 1H, D2O exch.), 8.56 (s, 1H), 8.44 (s, 1H), 8.32 (s, 1H), 5.94 (d, 1H), 5.40-5.36 (m, 2H, D2O exch.), 5.25 (d, 1H, D2O exch.), 4.42 (q, 1H), 4.13 (s, 1H), 3.98 (s, 1H), 3.70(s, 2H), 1.95 (s, 3H). 13C-NMR (125 MHz, DMSO-d6): (major isomer) δ 171.39, 135.98, 133.15, 129.73, 126.01, 124.96, 123.86, 121.69, 115.41, 108.31, 88.78, 86.09, 71.41, 69.66, 61.10, 20.36; (minor isomer) δ 165.24, 138.70, 133.12, 129.82, 126.06, 124.96, 123.99, 122.17, 115.33, 108.51, 88.78, 86.09, 71.41, 69.66, 61.10, 21.67. HRMS (ES) m/z calcd. for C16H16Cl3N3O5·Na 458.0053, found 458.0043. Anal calcd for C16H16Cl3N3O5: C, 44.01; H, 3.69; N, 9.62. Found: C, 43.76; H, 3.75; N, 9.67.
Reaction SMILES: [C:1]([CH:5]1[CH2:15][CH2:14][CH2:13][CH2:12][C:6]21[O:10][CH:9]([CH3:11])[CH2:8][O:7]2)([CH3:4])([CH3:3])[CH3:2].C(C1CCCCC1=O)(C)(C)C.C(O)C(O)C>[Pd].[Ru].C(O)(C)C>[C:1]([CH:5]1[CH2:15][CH2:14][CH2:13][CH2:12][CH:6]1[O:7][CH2:8][CH:9]([OH:10])[CH3:11])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC1COC2(CCCCC2C(C)(C)C)O1
Agent: [Pd]
Agent: [Ru]
Agent: CC(C)(C)C1CCCCC1=O
Solvent: CC(C)O
Solvent: CC(O)CO
Product: CC(O)COC1CCCCC1C(C)(C)C
Yield: 81.6 %

Procedure:
A 500 ml capacity autoclave was charged with 30 g (0.14 mol) of 6-t-butyl-2-methyl-1,4-dioxaspiro[4.5]decane which has been prepared from 2-t-butylcyclohexanone and 1,2-propanediol, 150 ml of isopropyl alcohol, 0.29 g of a catalyst of 5% palladium supported on active carbon and 0.01 gof a catalyst of 5% ruthenium supported on active carbon. The reaction was carried out under a hydrogen pressure of 70 kg/cm2 and at a temperature of 190° C. for 10 hours until completion of the absorption of hydrogen. After the reaction, the catalysts were removed by filtration and the resulting filtrate was subjected to distillation to obtain 24.5 g of 1-(2-t-butylcyclohexyloxy)-2-propanol (b.p.=112° to 113° C./5 mmHg; yield=81%; cis:trans=66:34).
Reaction SMILES: [F:1][C:2]([F:8])([F:7])[CH2:3][C:4](O)=[O:5].C1N=CN(C(N2C=NC=C2)=O)C=1.C[C:22]1([CH3:30])[O:27][C:26](=O)[CH2:25][C:24](=O)[O:23]1.S([O-])(O)(=O)=O.[K+].[CH2:37](O)[C:38]1C=CC=[CH:40][CH:39]=1>C1COCC1.C1(C)C=CC=CC=1.C(N(CC)CC)C>[F:1][C:2]([F:8])([F:7])[CH2:3][C:4](=[O:5])[CH2:30][C:22]([O:23][CH2:24][C:25]1[CH:26]=[CH:40][CH:39]=[CH:38][CH:37]=1)=[O:27]
Reactant: OCc1ccccc1
Reactant: CC1(C)OC(=O)CC(=O)O1
Reactant: O=C(O)CC(F)(F)F
Agent: O=C(n1ccnc1)n1ccnc1
Agent: O=S(=O)([O-])O
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=C(CC(=O)OCc1ccccc1)CC(F)(F)F
Temperature: 25 °C
Reaction time: 6 h

Procedure:
3,3,3-Trifluoropropanoic acid (5 g) in dry THF (50 mL) was treated with N,N-carbonyldiimidazole (7.6 g) and the mixture was stirred at room temperature for 6 h. 2,2-Dimethyl-1,3-dioxane-4,6-dione (5.63 g) and triethylamine (5.4 mL) were added and the mixture was stirred at room temperature for 18 h. Aqueous potassium hydrogen sulphate solution (10% w/v) was added and the mixture was extracted with diethyl ether. The organic layer was separated and washed with water, then brine and dried over sodium sulphate and filtered. The solvent was concentrated in vacuo to yield a pale yellow solid. Toluene was added, followed by benzyl alcohol. The mixture was heated at 80° C. for 6 h and was then concentrated in vacuo. Purification by flash chromatography (eluent 5:95 ethyl acetate/isohexane) yielded the title compound as a beige solid (3.1 g).
Reaction SMILES: [N:1]1[NH:2][C:3](=[O:10])[N:4]2[CH:9]=[CH:8][CH:7]=[N:6][C:5]=12.[Br:11][CH2:12][CH2:13][CH2:14]Br.[H-].[Na+].CN(C)C=O>C(OCC)(=O)C.O>[Br:11][CH2:12][CH2:13][CH2:14][N:2]1[C:3](=[O:10])[N:4]2[CH:9]=[CH:8][CH:7]=[N:6][C:5]2=[N:1]1
Reactant: O=c1[nH]nc2ncccn12
Reactant: BrCCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: O=c1n(CCCBr)nc2ncccn12
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A mixture of 2H-[1,2,4]triazolo[4,3-a]pyrimidin-3-one (CAS 63206-77-9) (1.0 g), 1,3-dibromopropane (1.55 ml), sodium hydride (60% in oil) (353 mg) and N,N-dimethylformamide (20 ml) was stirred at room temperature for one day. After further addition of 1,3-dibromopropane (3.88 ml) and sodium hydride (60% in oil) (353 mg), stirring was continued at 80° C. for 2 hours. Water was added to the reaction mixture, and extraction was performed with ethyl acetate. The organic layer was washed with brine and dried over anhydrous magnesium sulfate. After filtration, the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography to obtain the title compound (190 mg).
Reaction SMILES: [N:1]1[C:10]2[CH2:9][CH2:8][CH2:7][CH2:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.C([Li])(C)(C)C.C[OH:17].OS(O)(=O)=O.C1[CH2:27][O:26][CH2:25]C1>>[C:25]([CH:9]1[C:10]2[N:1]=[CH:2][CH:3]=[CH:4][C:5]=2[CH2:6][CH2:7][CH2:8]1)([O:26][CH3:27])=[O:17]
Reactant: CO
Reactant: C1CCOC1
Reactant: c1cnc2c(c1)CCCC2
Agent: O=S(=O)(O)O
Agent: [Li]C(C)(C)C
Product: COC(=O)C1CCCc2cccnc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 72 %

Procedure:
To a cold (−78° C.), stirred solution of 5,6,7,8-tetrahydroquinoline (0.713 g, 5.35 mmol) in dry THF (50 mL) was added tert-butyllithium (1.7 M in pentane, 4.5 mL, 7.65 mmol). The initially colorless solution turned deep red. After one hour, CO2 gas was bubbled through the reaction mixture for 15 minutes. The red color faded and the solution became cloudy and colorless. The reaction mixture was warmed to room temperature, treated with water (30 mL), and diluted with diethyl ether (30 mL). The phases were separated and the aqueous phase was extracted with ether (3×30 mL). The aqueous phase was concentrated under reduced pressure to provide a white solid. Methanol (50 mL) was added to the solid followed by the dropwise addition of concentrated H2SO4 (˜1 mL) until the mixture became homogenous. The resultant solution was heated to reflux overnight and then was cooled to room temperature. The solution was concentrated and the residue was dissolved in saturated aqueous Na2CO3 (30 mL) and CH2Cl2 (30 mL). The phases were separated and the aqueous phase was extracted with CH2Cl2 (3×30 mL). The combined organic extracts were dried (Na2SO4) and concentrated. Purification of the crude material by radial chromatography on silica gel (4 mm plate, 20:1 CH2Cl2-CH3OH) provided 8-carbomethoxy-5,6,7,8-tetrahydroquinoline (0.724 g; 72%) as a pale yellow oil. 1H NMR (CDCl3) δ 1.72-1.82 (m, 1H), 1.92-2.03 (m, 1H), 2.12-2.24 (m, 2H), 2.71-2.91 (m, 2H), 3.74 (s, 3H), 3.98 (dd, 1H, J=6.6, 6.6 Hz), 7.09 (dd, 1H, J=7.8, 4.8 Hz), 7.40 (dd, 1H, J=7.5, 0.9 Hz), 8.40 (d, 1H, J=4.8. Hz); 13C NMR (CDCl3) δ 20.68, 27.31, 28.70, 48.55, 52.40, 122.39, 132.83, 137.48, 147.60, 154.13, 175.13. ES-MS m/z 192 (M+H).
Reaction SMILES: [N:1]12[CH2:8][CH2:7][C:4]([C:9]([C:21]3[CH:30]=[CH:29][C:28]4[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=4)[CH:22]=3)([C:11]3[CH:20]=[CH:19][C:18]4[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=4)[CH:12]=3)[OH:10])([CH2:5][CH2:6]1)[CH2:3][CH2:2]2.[C:31]1([CH2:37][O:38][CH2:39][CH2:40][Br:41])[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>CC#N>[Br-:41].[OH:10][C:9]([C:21]1[CH:30]=[CH:29][C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH:22]=1)([C:11]1[CH:20]=[CH:19][C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:12]=1)[C:4]12[CH2:3][CH2:2][N+:1]([CH2:40][CH2:39][O:38][CH2:37][C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)([CH2:6][CH2:5]1)[CH2:8][CH2:7]2
Reactant: BrCCOCc1ccccc1
Reactant: OC(c1ccc2ccccc2c1)(c1ccc2ccccc2c1)C12CCN(CC1)CC2
Solvent: CC#N
Product: OC(c1ccc2ccccc2c1)(c1ccc2ccccc2c1)C12CC[N+](CCOCc3ccccc3)(CC1)CC2
Product: [Br-]
Yield: 25 %

Procedure:
Following the general procedure outlined in Example 3, 1-azabicyclo[2.2.2]oct-4-yl(di-2-naphthalenyl)methanol (0.063.7 g, 0.162 mmol) and 2-bromoethyl phenylmethyl ether (0.0384 mL, 0.243 mmol) in 2 CH3CN/3 CHCl3 (4.0 mL) were reacted to give the desired product (0.0246 g, 25.0%). EI-MS m/z 528 (M+) Rt (2.36 min).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][C:11]=1[O:12][CH:13]([CH3:15])[CH3:14])[C:6]([OH:8])=O)#[N:2].CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.O[NH:38][C:39](=[NH:56])[C:40]1[CH:41]=[C:42]2[C:46](=[CH:47][CH:48]=1)[N:45]([CH2:49][CH2:50][C:51]([O:53][CH2:54][CH3:55])=[O:52])[N:44]=[CH:43]2>CN(C=O)C>[C:1]([C:3]1[CH:4]=[C:5]([C:6]2[O:8][N:38]=[C:39]([C:40]3[CH:41]=[C:42]4[C:46](=[CH:47][CH:48]=3)[N:45]([CH2:49][CH2:50][C:51]([O:53][CH2:54][CH3:55])=[O:52])[N:44]=[CH:43]4)[N:56]=2)[CH:9]=[CH:10][C:11]=1[O:12][CH:13]([CH3:15])[CH3:14])#[N:2]
Reactant: CC(C)Oc1ccc(C(=O)O)cc1C#N
Reactant: CCOC(=O)CCn1ncc2cc(C(=N)NO)ccc21
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: CCOC(=O)CCn1ncc2cc(-c3noc(-c4ccc(OC(C)C)c(C#N)c4)n3)ccc21
Temperature: 80 °C
Reaction time: 0.17 h
Yield: 64.9 %

Procedure:
A mixture of 3-cyano-4-[(1-methylethyl)oxy]benzoic acid (can be prepared as described in WO2005/58848) (371 mg, 1.81 mmol), EDAC (547 mg, 2.85 mmol) and HOBt (437 mg, 2.85 mmol) in DMF (5 ml) was left standing at RT for 10 minutes. Added ethyl 3-{5-[(hydroxyamino)(imino)methyl]-1H-indazol-1-yl}propanoate (D52) (500 mg, 1.81 mmol) and left standing overnight at RT. Added EDAC (200 mg, 1.04 mmol) and left standing for 24 hours. The mixture was heated at 80° C. for 2 days, standing at RT each night. The mixture was heated at 80° C. for a further 4 hours. Added EtOAc (50 ml) and washed with water (60 ml), sat. NaHCO3 (60 ml) and water (60 ml). The EtOAc layer was dried (MgSO4) and the solvent evaporated. Triturating with ethanol gave the title compound (523 mg) as a beige solid. MS (ES): C24H23N5O4 requires 445; found (MH+) 446.
Reaction SMILES: C[O:2][C:3](=[O:23])[C@@H:4]([NH:12][C:13]([O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:14])[CH:5]([CH2:9][O:10][CH3:11])[CH2:6][O:7][CH3:8].[Li+].[OH-]>C1COCC1.CO.O>[CH2:16]([O:15][C:13]([NH:12][C@@H:4]([CH:5]([CH2:9][O:10][CH3:11])[CH2:6][O:7][CH3:8])[C:3]([OH:23])=[O:2])=[O:14])[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: COCC(COC)[C@H](NC(=O)OCc1ccccc1)C(=O)OC
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: COCC(COC)[C@H](NC(=O)OCc1ccccc1)C(=O)O
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a solution of (S)-2-Benzyloxycarbonylamino-4-methoxy-3-methoxymethyl-butyric acid methyl ester (100 mg, 0.30 mmol, 1.0 equiv) in THF/MeOH/water (0.5 mL/0.5 mL/0.5 mL) was added LiOH*H2O (38.7 mg, 0.92 mmol, 3.0 equiv). After stirring at 0° C. for 1 hour, the reaction was quenched by addition of 1.0 N aq. HCl solution until the pH of the solution was approximately 4. The mixture was extracted with EtOAc. The organic layer was washed with brine, dried over MgSO4 and concentrated. MS m/z (M+1) 312.2
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH3:14])([CH3:13])[C:7](=[O:12])[N:8]2[CH3:11])=[CH:4][C:3]=1[F:15].[F:16][C:17]1[CH:25]=[N:24][CH:23]=[CH:22][C:18]=1[C:19](O)=[O:20]>>[F:16][C:17]1[CH:25]=[N:24][CH:23]=[CH:22][C:18]=1[C:19]([NH:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH3:13])([CH3:14])[C:7](=[O:12])[N:8]2[CH3:11])=[CH:4][C:3]=1[F:15])=[O:20]
Reactant: CN1C(=O)C(C)(C)c2cc(F)c(N)cc21
Reactant: O=C(O)c1ccncc1F
Product: CN1C(=O)C(C)(C)c2cc(F)c(NC(=O)c3ccncc3F)cc21

Procedure:
Prepared in analogy to example 26 from 6-amino-5-fluoro-1,3,3-trimethylindolin-2-one (example 20 f) and 3-fluoroisonicotinic acid. The title compound was obtained as light yellow crystals.
Reaction SMILES: [N:1]1([C:6]2[CH:11]=[C:10]([Cl:12])[C:9]([S:13]([NH2:16])(=[O:15])=[O:14])=[C:8]([OH:17])[C:7]=2[N+:18]([O-])=O)[CH2:5][CH2:4][CH2:3][CH2:2]1.[H][H]>[Pd]>[N:1]1([C:6]2[CH:11]=[C:10]([Cl:12])[C:9]([S:13]([NH2:16])(=[O:15])=[O:14])=[C:8]([OH:17])[C:7]=2[NH2:18])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: [H][H]
Reactant: NS(=O)(=O)c1c(Cl)cc(N2CCCC2)c([N+](=O)[O-])c1O
Agent: [Pd]
Product: Nc1c(N2CCCC2)cc(Cl)c(S(N)(=O)=O)c1O
Yield: 98.5 %

Procedure:
Following the general hydrogenation procedure outlined in example 15, (N-pyrrolidinyl)-6-chloro-2-hydroxy-3-nitrobenzenesulfonamide (0.73 g, 2.4 mmol) was reduced with hydrogen and 10% Pd/C (0.73 g) to form the desired product (0.69 g, crude). MS m/z (M+H) 276.9, 278.89, 279.88.
Reaction SMILES: CCN(C(C)C)C(C)C.Cl.[CH2:11]([O:13][C:14](=[O:18])[C@H:15]([CH3:17])[NH2:16])[CH3:12].[Br:19][C:20]1[CH:25]=[CH:24][CH:23]=[C:22](F)[C:21]=1[N+:27]([O-:29])=[O:28].O>CN(C)C(=O)C.[NH4+].[Cl-]>[Br:19][C:20]1[C:21]([N+:27]([O-:29])=[O:28])=[C:22]([NH:16][C@@H:15]([CH3:17])[C:14]([O:13][CH2:11][CH3:12])=[O:18])[CH:23]=[CH:24][CH:25]=1
Reactant: CCOC(=O)[C@H](C)N
Reactant: O=[N+]([O-])c1c(F)cccc1Br
Agent: Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(=O)N(C)C
Solvent: O
Product: CCOC(=O)[C@H](C)Nc1cccc(Br)c1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 102.7 %

Procedure:
DIPEA (45.1 mL, 259 mmol) was added to a stirred solution of L-alanine ethyl ester hydrochloride (Aldrich; 34.1 g, 222 mmol) and 1-bromo-3-fluoro-2-nitrobenzene (126a; Ark Pharm, Inc., Libertyville, Ill.; 16.29 g, 74.0 mmol) in N,N-dimethylacetamide (15 mL) and the resulting yellow solution was stirred at RT for 15 min. A water-cooled reflux condenser was attached to the flask, and the resulting mixture was heated at 80° C. for 18 h. The reaction was cooled to RT, diluted with saturated aq. NH4Cl (100 mL), and extracted with EtOAc (4×75 mL). The combined organic extracts were dried over Na2SO4, filtered, and concentrated in vacuo to provide (S)-ethyl 2-((3-bromo-2-nitrophenyl)amino)propanoate (126b; 24.1 g) as a brown residue (contains 10% starting material by LCMS and 1H NMR), which was used directly in the subsequent step: 1H NMR (400 MHz, CDCl3) δ ppm 7.13 (1H, t, J=8.2 Hz), 7.00 (1H, d, J=8.0 Hz), 6.64 (1H, d, J=8.4 Hz), 5.89 (1H, d, J=6.8 Hz), 4.22 (2H, m, J=7.0, 7.0, 7.0 Hz), 4.14 (1H, quin, J=7.1 Hz), 1.51 (3H, d, J=7.0 Hz), 1.27 (3H, t, J=7.1 Hz). m/z (ESI, +ve) 317.0 (M+H)+.