Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1[C:14]2[C:5](=[N:6][CH:7]=[C:8]3[C:13]=2[CH:12]=[CH:11][CH:10]=[CH:9]3)[CH:4]=[CH:3][CH:2]=1.II.C(N(CC)CC)C.[F:24]F>S(S([O-])=O)([O-])(=O)=O.[Na+].[Na+]>[F:24][C:7]1[N:6]=[C:5]2[C:14](=[C:13]3[C:8]=1[CH:9]=[CH:10][CH:11]=[CH:12]3)[CH:1]=[CH:2][CH:3]=[CH:4]2
Reactant: FF
Reactant: c1ccc2c(c1)cnc1ccccc12
Agent: II
Agent: O=S([O-])S(=O)(=O)[O-]
Agent: [Na+]
Solvent: CCN(CC)CC
Product: Fc1nc2ccccc2c2ccccc12
Yield: 35.3 %

Procedure:
A solution containing phenanthridine (1.0 g, 5.6 mmol), iodine (1.4 g, 5.6 mmol) and triethylamine (0.56 g, 5.6 mmol) in CF2ClCFCl2 (30 ml) was placed in a fluorination apparatus fitted with a drying tube filled with soda lime. Elemental fluorine (7 mmol) as a 10% mixture in dry nitrogen was then passed through the stirred solution using narrow bore PTFE tubing at ca. 15 ml/min. After the fluorine had been added the solution was poured into 10% aqueous sodium metabisulfite solution (30 ml) and extracted with dichloromethane. The organic extracts were dried and evaporated to a brown oil (0.92 g). GC/MS analysis showed a 53% conversion of starting material. Column chromatography on silica gel with dichloromethane as eluant gave 6-fluoro-phenanthridine (0.39 g, 67%), RF 0.78 (CH2Cl2); δH (400 MHz, CDCl3, Me4Si) 7.61 ppm (1H, d d d, JH1,H2 =JH2,H3 =7.8, JH2,H4 1.2, H-2), 7.69 (2H, m, H-3 and H-9), 7.88 (1H, d d d, JH7,H8 8.4, JH8,H9 7.2, JH8,H10 1.4, H-8), 7.97 (1H, d d, JH3,H4 8.0, JH2,H4 1.2, H-4), 8.21 (1H, d d, JH9,H10 8.0, JH8,H10 1.4, H-10) 8.45 (1H, d d, JH1,H2 8.0, JH1,H3 0.8, H-1), 8.52 (1H, d d, JH7,H8 8.4 JH7,H9 1.2, H-7); δF (376 MHz, CDCl3, CFCl3), 68.2 ppm (s); δC (100 MHz, CDCl3, Me4Si) 117.3 ppm (d, 2J 35.1, C-6a), 122.2 (d, 3J 3.8, C-7), 122.2 (s, C-1), 123.9 (d, 4J 1.9, C-10b), 124.2 (s, C-10), 126.5, (d, 6J 2.3, C-2), 127.9 (s, C-9), 128.7 (d, 4J 1.6, C-4), 129.4 (s, C-3), 132.1 (s, C8), 136.5 (d, 3J 7.2, C-10a), 141.5 (d, 3J 17.9, C-4a), 158.1 (d, 1J 248.7, C-6); m/z (E1+) 197 (M+, 100%).
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[NH:10][N:11]=[CH:12][C:13]1[O:14][C:15]([N+:18]([O-:20])=[O:19])=[CH:16][CH:17]=1.[N+](C1OC(C=O)=CC=1)([O-])=O.N(C1SC2C=C([O:42][C:43]([F:46])([F:45])[F:44])C=CC=2N=1)N>>[F:44][C:43]([F:46])([F:45])[O:42][C:7]1[CH:8]=[CH:9][C:4]2[N:3]=[C:2]([NH:10][N:11]=[CH:12][C:13]3[O:14][C:15]([N+:18]([O-:20])=[O:19])=[CH:16][CH:17]=3)[S:1][C:5]=2[CH:6]=1
Reactant: O=[N+]([O-])c1ccc(C=NNc2nc3ccccc3s2)o1
Reactant: NNc1nc2ccc(OC(F)(F)F)cc2s1
Agent: O=Cc1ccc([N+](=O)[O-])o1
Product: O=[N+]([O-])c1ccc(C=NNc2nc3ccc(OC(F)(F)F)cc3s2)o1

Procedure:
The compound 3i was prepared according procedure described for 3a by employing 5-nitrofuran aldehyde (141 mg, 1 mmol) and 2-hydrazino-6-trifluoromethoxy-benzothiazole (249 mg, 1 mmol) at 70° C. for 2 h (yield 298 mg, 80%).
Reaction SMILES: [C:1]([OH:4])(=[S:3])[CH3:2].C[O-].[Na+].[CH2:8](Br)[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21].Cl>CO.O>[CH2:21]([CH2:2][C:1]([OH:4])=[S:3])[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH3:8]
Reactant: CC(O)=S
Reactant: CCCCCCCCCCCCCCBr
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CCCCCCCCCCCCCCCC(O)=S
Temperature: 25 °C
Reaction time: 48 h
Yield: 87.7 %

Procedure:
Thioacetic acid (3.32 g, 36.0 mmol) in MeOH (150 ml) was treated successively with NaOMe (25% in MeOH, 12 g, 0.08 mol) and tetradecyl bromide (10.0 g, 0.036 mol) and stirred vigorously at room temperature for 48 h. The mixture was poured into H2O, acidified to pH 2 (conc. HCl) and extracted with diethyl ether. Drying (MgSO4) and concentration in vacuo afforded a crude solid which was purified by flash column chromatography (FCC) (25% EtOAc in hexanes to 35% EtOAc in hexanes) to yield 3 as a colourless solid (8.6 g, 82%); m.p. 64-66° C. (lit. 65-67° C.); δH(300 M, CDCl3) 0.89 (t, 3H, J=6.7 Hz), 1.27 (m, 22H), 1.32 (m, 2H), 1.61 (m, 2H), 2.67 (t, 2H, J 7.4) and 3.28 (s, 2H); MS (FAB+) 289 (M+H)+, 288 M+; HRMS: Found M+0288.211823. Calc. for C16H32O2S: M+0288.212302.
Reaction SMILES: [CH:1]1([C:4]2[N:5]=[C:6](O)[C:7]3[N:12]([CH3:13])[N:11]=[C:10]([CH3:14])[C:8]=3[N:9]=2)[CH2:3][CH2:2]1.P(Cl)(Cl)(Cl)(Cl)[Cl:17]>P(Cl)(Cl)(Cl)=O>[Cl:17][C:6]1[C:7]2[N:12]([CH3:13])[N:11]=[C:10]([CH3:14])[C:8]=2[N:9]=[C:4]([CH:1]2[CH2:3][CH2:2]2)[N:5]=1
Reactant: ClP(Cl)(Cl)(Cl)Cl
Reactant: Cc1nn(C)c2c(O)nc(C3CC3)nc12
Solvent: O=P(Cl)(Cl)Cl
Product: Cc1nn(C)c2c(Cl)nc(C3CC3)nc12
Yield: 89.2 %

Procedure:
A mixture of 5-cyclopropyl-1,3-dimethyl-1H-pyrazolo[4,3-d]pyrimidin-7-ol (14.3 g, 0.07 mol) and 18 g (0.088 mol) phosphorus pentachloride in 150 ml of phosphorus oxychloride is stirred under reflux for seven hours and evaporated in vacuo. The residue is dissolved in methylene dichloride and stirred with a saturated aqueous solution of NaHCO3. The organic layer is separated, dried (MgSO4), and evaporated in vacuo to give 13.9 g (84%) of 7-chloro-5-cyclopropyl-1,3-dimethyl-pyrazolo[4,3-d]pyrimidine, mp 87°-90° C. from heptane.
Reaction SMILES: O[CH2:2][C:3]([C:5]1[CH:6]=[C:7]([OH:12])[C:8](=[CH:10][CH:11]=1)[OH:9])=O.[Na].[Cl-].[H][H].[CH3:17][OH:18]>[Pd].O>[CH:11]1[C:5]([CH2:3][CH2:2][CH2:17][OH:18])=[CH:6][C:7]([OH:12])=[C:8]([OH:9])[CH:10]=1
Reactant: CO
Reactant: [H][H]
Reactant: O=C(CO)c1ccc(O)c(O)c1
Agent: [Pd]
Agent: [Cl-]
Agent: [Na]
Solvent: O
Product: OCCCc1ccc(O)c(O)c1

Procedure:
In a reactor as described in Example 5 well dried samples of 1.5 g of 4-hydroxyacetyl-catechol with very low sodium and chloride content (<0.15%) were hydrogenated in the presence or absence of added water. All reactions were run with 0.15 g Pd/C (10%) in 30 ml of solvent at 5 bar and 40° C. at least to the end of hydrogen uptake. The catalyst was filtered off and washed with ethyl acetate. The solutions were concentrated and the residues analyzed quantitatively. The results are summarized in Table 3 snowing the influence of the added water. The starting material was totally consumed in every experiment at the end. The data shows that the result is clearly improved at a relation of 1 mol water added per 3 moles of 4-hydroxyacetyl-catechol and is even better at a relation of 1/1 mole. The lower suitability of methanol as solvent is also demonstrated.
Reaction SMILES: [F:1][C:2]1[CH:20]=[CH:19][C:5]2[C:6]([CH:9]3[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][CH2:17][OH:18])[CH2:11][CH2:10]3)=[N:7][O:8][C:4]=2[CH:3]=1.[CH3:21][N:22]([C:26]1[CH:31]=[CH:30][C:29]2[O:32][CH2:33][O:34][C:28]=2[CH:27]=1)[C:23]([Cl:25])=[O:24]>>[ClH:25].[F:1][C:2]1[CH:20]=[CH:19][C:5]2[C:6]([CH:9]3[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][CH2:17][O:18][C:23](=[O:24])[N:22]([CH3:21])[C:26]4[CH:31]=[CH:30][C:29]5[O:32][CH2:33][O:34][C:28]=5[CH:27]=4)[CH2:11][CH2:10]3)=[N:7][O:8][C:4]=2[CH:3]=1
Reactant: CN(C(=O)Cl)c1ccc2c(c1)OCO2
Reactant: OCCCN1CCC(c2noc3cc(F)ccc23)CC1
Product: CN(C(=O)OCCCN1CCC(c2noc3cc(F)ccc23)CC1)c1ccc2c(c1)OCO2
Product: Cl
Yield: 34.6 %

Procedure:
By following the procedure described in example 2B 3-(4-(6-fluoro -1,2-benzisoxazol-3-yl)piperidino)propanol (278 mg, 1 mmol) was reacted with N-methyl-N-(3,4-methylenedioxyphenyl)carbamoylchloride (240 mg, 1.12 mmol) to give 170 mg of the title compound. M.p. 126°-129° C.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:18]=[CH:17][CH:16]=[CH:15][C:10]=1[CH:11]=[CH:12][CH2:13]Cl)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:19][C:20]1[S:21][C:22]2[CH2:23][CH2:24][NH:25][CH2:26][CH2:27][C:28]=2[N:29]=1.CCOCC>C(Cl)(Cl)Cl>[NH2:19][C:20]1[S:21][C:22]2[CH2:23][CH2:24][N:25]([CH2:13][CH:12]=[CH:11][C:10]3[CH:15]=[CH:16][CH:17]=[CH:18][C:9]=3[O:8][CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[CH2:26][CH2:27][C:28]=2[N:29]=1
Reactant: Nc1nc2c(s1)CCNCC2
Reactant: ClCC=Cc1ccccc1OCc1ccccc1
Solvent: CCOCC
Solvent: ClC(Cl)Cl
Product: Nc1nc2c(s1)CCN(CC=Cc1ccccc1OCc1ccccc1)CC2
Yield: 36 %

Procedure:
Prepared from 2-benzyloxy-cinnamyl chloride and 2 equivalents of 2-amino-4,5,7,8-tetrahydro-6 H-thiazolo[5,4-d]azepine in chloroform for 5 hours at 50° C. Yield: 36% of theory, Melting point: 103°-107° C. (ether).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:31]=[CH:30][C:6]([CH2:7][S:8][C@@H:9]2[CH2:13][N:12]([C:14]([O:16][CH2:17][C:18]3[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[CH:20][CH:19]=3)=[O:15])[C@H:11]([C:27]([OH:29])=O)[CH2:10]2)=[CH:5][CH:4]=1.FC(F)(F)C(O)=O.FC(F)(F)C(O)=O.[N+:46]([C:49]1[CH:66]=[CH:65][C:52]([CH2:53][O:54][C:55]([CH2:57][N:58]2[CH2:64][CH2:63][CH2:62][NH:61][CH2:60][CH2:59]2)=[O:56])=[CH:51][CH:50]=1)([O-:48])=[O:47]>C(#N)C.C(N(C(C)C)CC)(C)C>[CH3:1][O:2][C:3]1[CH:31]=[CH:30][C:6]([CH2:7][S:8][C@@H:9]2[CH2:13][N:12]([C:14]([O:16][CH2:17][C:18]3[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[CH:20][CH:19]=3)=[O:15])[C@H:11]([C:27]([N:61]3[CH2:62][CH2:63][CH2:64][N:58]([CH2:57][C:55]([O:54][CH2:53][C:52]4[CH:65]=[CH:66][C:49]([N+:46]([O-:48])=[O:47])=[CH:50][CH:51]=4)=[O:56])[CH2:59][CH2:60]3)=[O:29])[CH2:10]2)=[CH:5][CH:4]=1
Reactant: O=C(CN1CCCNCC1)OCc1ccc([N+](=O)[O-])cc1
Reactant: COc1ccc(CS[C@H]2C[C@@H](C(=O)O)N(C(=O)OCc3ccc([N+](=O)[O-])cc3)C2)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: COc1ccc(CS[C@H]2C[C@@H](C(=O)N3CCCN(CC(=O)OCc4ccc([N+](=O)[O-])cc4)CC3)N(C(=O)OCc3ccc([N+](=O)[O-])cc3)C2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 58.8 %

Procedure:
3.5 g of N,N'-carbonyldiimidazole were added to a solution of 8.0 g of (2S,4S)-4-(4-methoxybenzylthio)-1-(4-nitrobenzyloxycarbonyl)-2-pyrrolidinecarboxylic acid in 80 ml of dry acetonitrile, and the resulting mixture was stirred at room temperature for 30 minutes. A solution of 14.0 g of 1-(4-nitrobenzyloxycarbonylmethyl)homopiperazine bis(trifluoroacetate) in 80 ml of dry acetonitrile and 14.1 ml of diisopropylethylamine were added, whilst ice-cooling, to the mixture, and the resulting mixture was stirred at room temperature for 1.5 hours and then at 30° C. for a further 1.5 hours, after which it was allowed to stand overnight at room temperature. At the end of this time, the reaction mixture was concentrated by evaporation under reduced pressure, and the resulting residue was diluted with ethyl acetate. The dilute solution was washed with water and with an aqueous solution of sodium chloride, in that order, and it was then dried over anhydrous magnesium sulfate. The solvent was then removed by distillation under reduced pressure, and the resulting residue was purified by column chromatography through silica gel (Merck Art 9385), using ethyl acetate as the eluent, to give 7.6 g of the title compound as an amorphous solid.
Reaction SMILES: N[N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3]1.[C:11]1([CH2:17][C:18](=O)[CH3:19])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C([O-])(=O)C.[Na+]>C(O)(=O)C>[CH3:19][C:18]1[N:2]2[C:10]3[C:5]([CH2:4][CH2:3]2)=[CH:6][CH:7]=[CH:8][C:9]=3[C:17]=1[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: CC(=O)Cc1ccccc1
Reactant: Nn1ccc2ccccc21
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: Cc1c(-c2ccccc2)c2cccc3c2n1CC3

Procedure:
A mixture of 50 g. (0.372 mole) of 1-aminoindole, 50 g. (0.372 mole) of phenylacetone, 600 ml. of acetic acid and 50 g. of sodium acetate was heated for one hour on a steam bath. The precipitate which separated from the cooled mixture was collected and washed with isopropyl ether. The product melted at 145°C. The literature m.p. is 145°C., Chemical Abstracts 54, 19641 (1960).
Reaction SMILES: [CH2:1]([OH:23])[C@H:2]1[O:7][C@H:6]([O:8][C@]2(CO)O[C@H](CO)[C@@H](O)[C@@H]2O)[C@H:5]([OH:20])[C@@H:4]([OH:21])[C@@H:3]1[OH:22].O=C[C@@H]([C@H]([C@@H]([C@@H](CO)O)O)O)O>>[OH:23][CH2:1][C:2]([C@H:3]([C@@H:4]([C@@H:5]([CH2:6][OH:8])[OH:20])[OH:21])[OH:22])=[O:7]
Reactant: OC[C@H]1O[C@@](CO)(O[C@H]2O[C@H](CO)[C@@H](O)[C@H](O)[C@H]2O)[C@@H](O)[C@@H]1O
Agent: O=C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Product: O=C(CO)[C@@H](O)[C@H](O)[C@H](O)CO

Procedure:
From pure crystalline saccharose and after enzymatic hydrolysis with invertase, specific biological oxidation of the glucose and glucose--fructose mixture obtained was carried out; to do this, a strain of Acetobacter suboxydans was cultured on 350 g/l of glucids, in a culture medium supplemented with 7 g/l of Fould-Springer yeast extract and 50 g/l of CaCO3.
Reaction SMILES: [CH3:1][N:2]([S:9]([C:12]1[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=1)(=[O:11])=[O:10])[C:3]1([C:6]([OH:8])=O)[CH2:5][CH2:4]1.CCOC(OC(OCC)=O)=O.[F:30][C:31]([F:48])([F:47])[O:32][C:33]1[CH:38]=[CH:37][C:36]([C:39]2[CH:40]=[C:41]([CH2:45][NH2:46])[CH:42]=[CH:43][CH:44]=2)=[CH:35][CH:34]=1>C1COCC1>[F:18][C:15]1[CH:16]=[CH:17][C:12]([S:9]([N:2]([CH3:1])[C:3]2([C:6]([NH:46][CH2:45][C:41]3[CH:42]=[CH:43][CH:44]=[C:39]([C:36]4[CH:37]=[CH:38][C:33]([O:32][C:31]([F:30])([F:47])[F:48])=[CH:34][CH:35]=4)[CH:40]=3)=[O:8])[CH2:4][CH2:5]2)(=[O:11])=[O:10])=[CH:13][CH:14]=1
Reactant: CN(C1(C(=O)O)CC1)S(=O)(=O)c1ccc(F)cc1
Reactant: NCc1cccc(-c2ccc(OC(F)(F)F)cc2)c1
Agent: CCOC(=O)OC(=O)OCC
Solvent: C1CCOC1
Product: CN(C1(C(=O)NCc2cccc(-c3ccc(OC(F)(F)F)cc3)c2)CC1)S(=O)(=O)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 15 %

Procedure:
Acid 15A (350 mg, 1.28 mmol) was dissolved in 5 ml of THF and at rt DEPC (0.25 mL, 1.3 mol eq) and [3-[4-(trifluoromethoxy)phenyl]phenyl]methanamine 23B (0.376 g, 1.1 mol eq) were added to the solution. The mixture was stirred at rt overnight then evaporated. he residue was dissolved in AcOEt (30 ml) and washed with water (1×20 ml) and brine. The organic phase was dried over sodium sulfate and concentrated under vacuum. The purification of the crude by chromatographic column (3:7 EtOAc:Petroleum ether) afforded 100 mg of a white solid. Yield=15% 1HNMR (DMSO, 200 MHz) δ 1.09 (2H, bs), 1.34 (2H, bs), 3.00 (3H, s), 4.35 (2H, d, J=5.8 Hz), 7.43 (8H, m), 7.81 (4H, m), 8.17 (1H, bt); [M+1] 523.9 (C25H22F4N2O4S requires 522.51).
Reaction SMILES: [Si:1]([O:18][CH2:19][C:20]1[C:21]([N:35]2[CH2:40][C@H:39]([CH3:41])[O:38][C@H:37]([CH3:42])[CH2:36]2)=[C:22]([F:34])[C:23]2[O:27][N:26]=[C:25]([C:28]([O:30]CC)=O)[C:24]=2[CH:33]=1)([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:43][NH2:44]>>[Si:1]([O:18][CH2:19][C:20]1[C:21]([N:35]2[CH2:40][C@H:39]([CH3:41])[O:38][C@H:37]([CH3:42])[CH2:36]2)=[C:22]([F:34])[C:23]2[O:27][N:26]=[C:25]([C:28]([NH:44][CH3:43])=[O:30])[C:24]=2[CH:33]=1)([C:14]([CH3:16])([CH3:15])[CH3:17])([C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: CCOC(=O)c1noc2c(F)c(N3C[C@@H](C)O[C@@H](C)C3)c(CO[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)cc12
Reactant: CN
Product: CNC(=O)c1noc2c(F)c(N3C[C@@H](C)O[C@@H](C)C3)c(CO[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)cc12

Procedure:
Starting materials: Ethyl 5-((tert-butyldiphenylsilyloxy)methyl)-6-((2R,6S)-2,6-dimethylmorpholino)-7-fluorobenzo[d]isoxazole-3-carboxylate (Intermediate 204) and methylamine (2M in THF)
Reaction SMILES: [H-].[Na+].[CH3:3][N:4]1[C:8]2[NH:9][C:10](=[O:13])[CH:11]=[CH:12][C:7]=2[C:6]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[N:5]1.Br[CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23]>CN(C=O)C>[CH3:3][N:4]1[C:8]2=[N:9][C:10]([O:13][CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23])=[CH:11][CH:12]=[C:7]2[C:6]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[N:5]1
Reactant: Cn1nc(-c2ccccc2)c2ccc(=O)[nH]c21
Reactant: CCOC(=O)CBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)COc1ccc2c(-c3ccccc3)nn(C)c2n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 78.6 %

Procedure:
NaH (0.115 g, 2.886 mmol) was added to an ice cold solution of 1-methyl-3-phenyl-1H-pyrazolo[3,4-b]pyridin-6(7H)-one (0.325 g, 1.443 mmol) in DMF (5.0 mL) and stirred at ambient temperature for 30 min. Ethyl bromoacetate (0.482 g, 2.886 mmol) was added to the reaction mixture dropwise and stirring was continued for 2 h. After completion of the reaction, the excess of NaH was quenched by the addition of ice cold water. Diethyl ether was added and the mixture was extracted with water and brine. The organic layer was dried over Na2SO4 and filtered. Concentration of the organic layer furnished the title compound as a white solid (0.353 g, 79%). [1H-NMR (CDCl3, 300 MHz) δ 8.2 (d, 1H), 7.94-7.87 (m, 2H), 7.54-7.36 (m, 3H), 6.79 (d, 1H), 5.0 (s, 2H), 4.29 (q, 2H), 4.05 (s, 3H), 1.30 (t, 3H); HPLC RtA=5.555 min (95%); LCMS RtC=1.967 min; [M+H]+=312.1]
Reaction SMILES: [OH:1][CH:2]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[CH2:3][CH2:4][CH2:5][N:6]1[CH2:11][CH2:10][CH:9]([C:12]2[CH:13]=[C:14]([NH:18][C:19](=[O:23])[CH:20]([CH3:22])[CH3:21])[CH:15]=[CH:16][CH:17]=2)[CH2:8][CH2:7]1.[Cl:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=1[C:37]1[C:41]([C:42](Cl)=[O:43])=[C:40]([CH3:45])[O:39][N:38]=1>>[Cl:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=1[C:37]1[C:41]([C:42]([O:1][CH:2]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH2:3][CH2:4][CH2:5][N:6]2[CH2:7][CH2:8][CH:9]([C:12]3[CH:17]=[CH:16][CH:15]=[C:14]([NH:18][C:19](=[O:23])[CH:20]([CH3:22])[CH3:21])[CH:13]=3)[CH2:10][CH2:11]2)=[O:43])=[C:40]([CH3:45])[O:39][N:38]=1
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CCCC(O)c3ccccc3)CC2)c1
Reactant: Cc1onc(-c2ccccc2Cl)c1C(=O)Cl
Product: Cc1onc(-c2ccccc2Cl)c1C(=O)OC(CCCN1CCC(c2cccc(NC(=O)C(C)C)c2)CC1)c1ccccc1

Procedure:
Prepared by Procedure Q1 and Scheme C2 (TEA) using N-{3-[1-(4-hydroxy-4-phenylbutyl)-4-piperidinyl]phenyl}-2-methylpropanamide and 3-(2-chlorophenyl)-5-methyl-4-isoxazolecarbonyl chloride: ESMS m/e: 614.2 (M+H)+.
Reaction SMILES: Cl[CH2:2][C:3]([N:5]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[C:9](=[O:16])[NH:8][C:7]2[CH:17]=[CH:18][CH:19]=[CH:20][C:6]1=2)=[O:4].[CH2:21]([N:23]([CH2:26][C@@H:27]1[CH2:31][CH2:30][CH2:29][NH:28]1)[CH2:24][CH3:25])[CH3:22]>C(O)C>[CH2:21]([N:23]([CH2:26][C@@H:27]1[CH2:31][CH2:30][CH2:29][N:28]1[CH2:2][C:3]([N:5]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[C:9](=[O:16])[NH:8][C:7]2[CH:17]=[CH:18][CH:19]=[CH:20][C:6]1=2)=[O:4])[CH2:24][CH3:25])[CH3:22]
Reactant: O=C1Nc2ccccc2N(C(=O)CCl)c2ccccc21
Reactant: CCN(CC)C[C@@H]1CCCN1
Solvent: CCO
Product: CCN(CC)C[C@@H]1CCCN1CC(=O)N1c2ccccc2NC(=O)c2ccccc21

Procedure:
The title compound is prepared analogously to Example 31 from 5-(chloroacetyl)-5,10-dihydro-11H-dibenzo[b,e][1,4]diazepin-11-one and (S)-(+)-2-[(diethylamino)methyl]pyrrolidine to give a colorless highly viscous oil, [α]D20 =-10.5° (ethanol).
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[CH:13]1([C:18]([O:20][CH3:21])=[O:19])[CH2:17][CH2:16][CH2:15][CH2:14]1.[Br:22][CH2:23][CH2:24][CH2:25][CH2:26]Br.[Cl-].[NH4+]>C1COCC1>[CH3:21][O:20][C:18]([C:13]1([CH2:26][CH2:25][CH2:24][CH2:23][Br:22])[CH2:17][CH2:16][CH2:15][CH2:14]1)=[O:19]
Reactant: COC(=O)C1CCCC1
Reactant: BrCCCCBr
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: COC(=O)C1(CCCCBr)CCCC1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 48.6 %

Procedure:
To a solution of diisopropylamine (150 mmol, 21 mL) in THF (100 mL) was added dropwise a solution of n-butyl lithium (145 mmol, 58 mL, 2.5M) in hexanes at −10° C. while maintaining the temperature below 0° C. After addition, the solution was stirred for 30 min at 0° C. To this a solution of methyl cyclopentane carboxylate (100 mmol, 13.1 g) in THF (20 mL) was added dropwise at −70° C. maintaining the internal temperature between −60 to −70° C. After addition, the reaction mixture was stirred for 1 h at −50 to −60° C. Then, a solution of 1,4-dibromobutane (100 mmol, 21.59 g) in THF (20 mL) was added dropwise and the light brown suspension was stirred for 1 h at −60 to −70° C. Then, it was allowed to warm to room temperature and stirred overnight. The reaction mixture was poured into a saturated solution of ammonium chloride (200 mL) and the organic compound was extracted into ether (2×100 mL). The combined extracts were washed with a saturated brine solution (150 mL) and dried over anhydrous magnesium sulfate. After filtration of the drying agent, the solution was concentrated under vacuum and the resulting residue was distilled at 120-133° C./2.5 mm Hg to obtain 1-(4-bromobutyl)cyclopentane carboxylic acid methyl ester as a colorless oil (12.8 g, 48%). HR MS (C11H19BrO2): Obs mass, a 262.0565. Calcd mass, 262.0568 (M+).
Reaction SMILES: [NH2:1][C:2]1[C:3]([O:5][C@H:6]([CH3:13])[C:7]=1[C:8]([O:10][CH2:11][CH3:12])=[O:9])=[O:4].[OH2:14].[C:15]1([CH3:25])C(S(O)(=O)=O)=CC=CC=1>C(OC(=O)C)(=O)C>[C:15]([NH:1][C:2]1[C:3]([O:5][C@H:6]([CH3:13])[C:7]=1[C:8]([O:10][CH2:11][CH3:12])=[O:9])=[O:4])(=[O:14])[CH3:25]
Reactant: Cc1ccccc1S(=O)(=O)O
Reactant: O
Reactant: CCOC(=O)C1=C(N)C(=O)O[C@@H]1C
Solvent: CC(=O)OC(C)=O
Product: CCOC(=O)C1=C(NC(C)=O)C(=O)O[C@@H]1C
Temperature: 40 °C
Reaction time: 8 h

Procedure:
12.04 g of (R)-2-amino-3-ethoxycarbonyl-2-penten-4-olide are dissolved in 48 ml of acetic anhydride, 125 mg of toluenesulphonic acid monohydrate are added and the whole is stirred overnight at 40° C. The mixture is concentrated by evaporation, dissolved in ethyl acetate and washed with water. The ethyl acetate is distilled off and the residue is recrystallised from ethyl acetate/cyclohexane, [α]D20 =+62.3° (3% in CHCl3), m.p. 119°-122° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([NH:11][S:12]([CH3:15])(=[O:14])=[O:13])[CH:10]=1)[C:5](O)=[O:6].[CH3:16][N:17](C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)[CH3:18].F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.CNC>CN(C=O)C.ClCCl>[Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([NH:11][S:12]([CH3:15])(=[O:14])=[O:13])[CH:10]=1)[C:5]([N:17]([CH3:18])[CH3:16])=[O:6]
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Reactant: CS(=O)(=O)Nc1cc(Br)cc(C(=O)O)c1
Agent: CNC
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CN(C)C(=O)c1cc(Br)cc(NS(C)(=O)=O)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 82.9 %

Procedure:
To a mixture of 3-bromo-5-(methylsulfonamido)benzoic acid (360 mg, 1.22 mmol), HATU (490 mg, 1.29 mmol) and DIEA (260 μl, 1.49 mmol) in DMF (5 ml) was added dimethylamine (3.10 ml, 6.20 mmol, 2N in THF) and the resulting mixture was stirred at room temperature overnight. 30 ml of dichloromethane were added and washed with sodium bicarbonate 4%. The aqueous phase was further extracted with ethyl acetate. The organics were washed with water and brine, dried over magnesium sulphate and the solvent was removed to give a residue which purified by reverse phase chromatography using SP1® Purification System (C-18 silica from Waters®, water/1:1 acetonitrile-methanol as eluents [0.1% v/v formic acid buffered] 0% to 100%) to give 325 mg (83% yield) of the title compound. Purity 99%.
Reaction SMILES: O1CCCCC1[O:7][CH2:8][C:9]1[C:17]2[C:12](=[CH:13][CH:14]=[C:15]([CH:18]=O)[CH:16]=2)[NH:11][N:10]=1.[NH2:20][C:21]1[CH:29]=[C:28]([O:30][CH3:31])[CH:27]=[C:26]([O:32][CH3:33])[C:22]=1[C:23]([NH2:25])=[O:24].OS([O-])=O.[Na+].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>CN(C)C(=O)C>[OH:7][CH2:8][C:9]1[C:17]2[C:12](=[CH:13][CH:14]=[C:15]([C:18]3[NH:25][C:23](=[O:24])[C:22]4[C:21](=[CH:29][C:28]([O:30][CH3:31])=[CH:27][C:26]=4[O:32][CH3:33])[N:20]=3)[CH:16]=2)[NH:11][N:10]=1
Reactant: O=Cc1ccc2[nH]nc(COC3CCCCO3)c2c1
Reactant: COc1cc(N)c(C(N)=O)c(OC)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=S([O-])O
Agent: [Na+]
Solvent: O
Solvent: CC(=O)N(C)C
Product: COc1cc(OC)c2c(=O)[nH]c(-c3ccc4[nH]nc(CO)c4c3)nc2c1
Temperature: 120 °C

Procedure:
To a solution of 3-(tetrahydro-pyran-2-yloxymethyl)-1H-indazole-5-carbaldehyde (0.32 g, 1.23 mmol) and 2-amino-4,6-dimethoxy-benzamide (0.24 g, 1.23 mmol) in N,N-dimethylacetamide (10 mL) were added NaHSO3 (58.5 wt %, 0.27 g, 1.48 mmol) and p-toluenesulfonic acid monohydrate (0.05 g, 0.25 mmol); the reaction mixture was heated at 120° C. for 16 hours, then cooled to room temperature. Solvent was removed under reduced pressure. The residue was diluted with water (100 mL). The separated solid was filtered and washed with water and dried under vacuum. The residue was purified by the Simpliflash system (0-5% methanol in CH2Cl2 as eluent) to give the title compound as an off-white solid. Yield: 30 mg (7%). MP 264-266° C. 1H NMR (400 MHz, CD3OD): δ 8.60 (s, 1H), 8.10 (d, J=8.98 Hz, 1H), 7.65 (d, J=8.98 Hz, 1H), 6.85 (d, J=1.95 Hz, 1H), 6.55 (d, J=1.95 Hz, 1H), 5.05 (s, 2H), 3.96 (s, 6H).