Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: I[C:2]1[C:10]2[C:5](=[N:6][CH:7]=[C:8]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[C:9]=2[N:11]2[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][CH2:12]2)[N:4](CC2C=CC(OC)=CC=2)[N:3]=1.N1C2C(=CC=C3C=2N=CC=C3)C=CC=1.[CH3:53][C:54]1([CH3:61])[O:58][C@H:57]([CH2:59][OH:60])[CH2:56][O:55]1.[F-].[K+]>C1(C)C=CC=CC=1.C(OCC)(=O)C>[CH3:53][C:54]1([CH3:61])[O:58][C@H:57]([CH2:59][O:60][C:2]2[C:10]3[C:5](=[N:6][CH:7]=[C:8]([C:24]4[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=4)[C:9]=3[N:11]3[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][CH2:12]3)[NH:4][N:3]=2)[CH2:56][O:55]1
Reactant: COc1ccc(Cn2nc(I)c3c(N4CCN(C(=O)OC(C)(C)C)CC4)c(-c4ccccc4)cnc32)cc1
Reactant: CC1(C)OC[C@@H](CO)O1
Agent: [F-]
Agent: [K+]
Agent: c1cnc2c(c1)ccc1cccnc12
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N1CCN(c2c(-c3ccccc3)cnc3[nH]nc(OC[C@@H]4COC(C)(C)O4)c23)CC1
Yield: 114.5 %

Procedure:
tert-Butyl 4-(3-iodo-1-(4-methoxybenzyl)-5-phenyl-1H-pyrazolo[3,4-b]pyridin-4-yl)piperazine-1-carboxylate (0.15 g, 0.24 mmol, see Example 9), Cu(I)I (0.046 g, 0.24 mmol), 1,10-phenanthroline (0.043 g, 0.24 mmol), (R)-(2,2-dimethyl-1,3-dioxolan-4-yl)methanol (0.95 g, 7.2 mmol) and KF on Al2O3 (40%; 0.24 g, 1.68 mmol) in toluene (4 mL) was stirred at 110° C. for 60 hours. Ethyl acetate (10 mL) was then added, and the reaction mixture was filtered through a pad of celite. The reaction was then concentrated to dryness, and the residue was purified by column chromatography (hexane:ethyl acetate=1:1) to give (R)-tert-butyl 4-(3-((2,2-dimethyl-1,3-dioxolan-4-yl)methoxy)-5-phenyl-1H-pyrazolo[3,4-b]pyridin-4-yl)piperazine-1-carboxylate (0.14 g, 93%) as a solid. MS APCI (+) m/z 630.2 detected.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][CH:3]=1.[OH:22][C:23]1[CH:24]=[C:25]2[C:30](=[CH:31][CH:32]=1)[C:29]([C:33]([OH:35])=[O:34])=[CH:28][CH:27]=[CH:26]2.[OH-].[K+].O>CS(C)=O>[CH2:15]([O:14][C:8]1[CH:7]=[C:6]2[C:11]([C:2]([O:22][C:23]3[CH:24]=[C:25]4[C:30](=[CH:31][CH:32]=3)[C:29]([C:33]([OH:35])=[O:34])=[CH:28][CH:27]=[CH:26]4)=[CH:3][CH:4]=[N:5]2)=[CH:10][C:9]=1[O:12][CH3:13])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: COc1cc2c(Cl)ccnc2cc1OCc1ccccc1
Reactant: O=C(O)c1cccc2cc(O)ccc12
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CS(C)=O
Product: COc1cc2c(Oc3ccc4c(C(=O)O)cccc4c3)ccnc2cc1OCc1ccccc1
Temperature: 25 °C
Yield: 62 %

Procedure:
4-Chloro-7-benzyloxy-6-methoxy-quinoline (3 g) was mixed with 6-Hydroxy-1-naphthoic acid (2 g) and KOH (2.5 g) in DMSO (11 ml). The mixture was heated at 130oC for 5 hours and cooled to RT. The reaction was then poured into a stirred water (60 ml) solution slowly to give a precipitate that was filtered to give 6-(7-(benzyloxy)-6-methoxyquinolin-4-yloxy)-1-naphthoic acid (2.8 g). This product was mixed with MeNH2—HCl (2 g), EDC (3.3 g), HOBt (2 g) and DIPEA (4 ml) in DCM (80 ml). The reaction was stirred at RT overnight and washed with NaHCO3 solution, dried. The solution was evaporated and purified with silica gel column to give 6-(7-(benzyloxy)-6-methoxyquinolin-4-yloxy)-N-methyl-1-naphthamide. The title compound then was prepared according to the same procedures described in Method A.
Reaction SMILES: [C:1](Cl)(=[O:5])[O:2][CH2:3][CH3:4].[F:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[S:18][C:17]([S:19]([N:22]3[CH2:27][CH2:26][NH:25][CH2:24][C@@H:23]3[C:28]([NH:30][O:31][CH:32]3[CH2:37][CH2:36][CH2:35][CH2:34][O:33]3)=[O:29])(=[O:21])=[O:20])=[CH:16][CH:15]=2)=[CH:10][CH:9]=1.C(N(CC)CC)C>C(Cl)(Cl)Cl>[CH2:3]([O:2][C:1]([N:25]1[CH2:26][CH2:27][N:22]([S:19]([C:17]2[S:18][C:14]([C:11]3[CH:12]=[CH:13][C:8]([F:7])=[CH:9][CH:10]=3)=[CH:15][CH:16]=2)(=[O:21])=[O:20])[C@@H:23]([C:28]([NH:30][O:31][CH:32]2[CH2:37][CH2:36][CH2:35][CH2:34][O:33]2)=[O:29])[CH2:24]1)=[O:5])[CH3:4]
Reactant: O=C(NOC1CCCCO1)[C@H]1CNCCN1S(=O)(=O)c1ccc(-c2ccc(F)cc2)s1
Reactant: CCOC(=O)Cl
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CCOC(=O)N1CCN(S(=O)(=O)c2ccc(-c3ccc(F)cc3)s2)[C@@H](C(=O)NOC2CCCCO2)C1
Yield: 82.1 %

Procedure:
A solution of ethyl chlorocarbonate (42 mg) in CHCl3 (1 ml) was added dropwise to a solution of (2R)-1-[5-(4-fluorophenyl)thiophene-2-sulfonyl]-N-(2-tetrahydropyranyloxy)-2-piperazinecarboxamide (150 mg) and triethylamine (39 mg) in CHCl3 (2 ml) with cooling on an ice bath. The reaction mixture was stirred at said temperature for 30 minutes and the reaction was quenched by adding 3-(N,N-dimethylamino)propylamine (0.5 ml). The mixture was concentrated in vacuo, and the residue was partitioned between AcOEt and 5% aqueous citric acid. The organic layer was washed with saturated aqueous NaHCO3 solution and saturated aqueous NaCl solution, dried over MgSO4, and concentrated in vacuo. The residue was purified by SiO2 column chromatography eluted with AcOEt in hexane gradually from 40% to 60%, to give 142 mg of (2R)-4-ethoxycarbonyl-1-[5-(4-fluorophenyl)thiophene-2-sulfonyl]-N-(2-tetrahydropyranyloxy)-2-piperazinecarboxamide.
Reaction SMILES: [C:1]([O:5][C:6](=[O:24])[N:7]([CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[CH2:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=1)([CH3:4])([CH3:3])[CH3:2].C([O-])([O-])=O.[K+].[K+].[Cl:31][C:32]1[CH:39]=[C:38](F)[CH:37]=[CH:36][C:33]=1[C:34]#[N:35].O>CN(C=O)C>[C:1]([O:5][C:6](=[O:24])[N:7]([CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[CH2:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][C:38]2[CH:37]=[CH:36][C:33]([C:34]#[N:35])=[C:32]([Cl:31])[CH:39]=2)=[CH:12][CH:11]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N(CCc1ccc(O)cc1)Cc1ccccc1
Reactant: N#Cc1ccc(F)cc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)N(CCc1ccc(Oc2ccc(C#N)c(Cl)c2)cc1)Cc1ccccc1
Temperature: 25 °C
Yield: 95.8 %

Procedure:
Combine the compound from Example 218 step 2 (692 mg, 2.12 mmol) and K2CO3 (323 mg, 2.33 mmol) in DMF (9 mL), stir the mixture at room temperature for 30 min and then add 2-chloro-4-fluoro-benzonitrile (330 mg, 2.12 mmol), and heat at 100° C. overnight. Cool to ambient temperature and pour into water. Extract the aqueous layer with EtOAc. Dry the organic layer over Na2SO4 and eliminate the solvent. Purify by flash chromatography on silica gel (eluent: EtOAc/hexane 15/85) to obtain the title compound (940 mg, 95%). Electrospray MS M−1 ion=461, 1H-NMR (CDCl3, 400 MHz): 7.57 (d, 1H, J=7.8 Hz), 7.36-7.13 (m, 7H), 7.00-6.85 (m, 4H), 4.44-4.36 (m, 2H), 3.49-3.32 (m, 2H), 2.83-2.73 (m, 2H), 1.51-1.43 (m, 9H).
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([CH3:13])[CH:5]=[C:6]2[CH2:11][CH2:10][O:9][C:8](=[O:12])[C:7]=12.C([Sn](CCCC)(CCCC)[C:19]1[O:20][CH:21]=[CH:22][CH:23]=1)CCC.[F-].[K+].O>C1(C)C=CC=CC=1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:13][C:4]1[CH:5]=[C:6]2[CH2:11][CH2:10][O:9][C:8](=[O:12])[C:7]2=[C:2]([C:19]2[O:20][CH:21]=[CH:22][CH:23]=2)[N:3]=1
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccco1
Reactant: Cc1cc2c(c(Cl)n1)C(=O)OCC2
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [F-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: O
Product: Cc1cc2c(c(-c3ccco3)n1)C(=O)OCC2
Temperature: 0 °C
Yield: 77.6 %

Procedure:
8-chloro-6-methyl-3,4-dihydro-pyrano[3,4-c]pyridine-1-on (250 mg, 1.265 mmol) and Pd(PPh3)4 (146 mg, 0.127 mmol) were dissolved in 12 mL of anhydrous toluene, dropwisely added with 2-(tributylstannyl)furan (0.80 mL, 2.530 mmol) and then heated to reflux for about 15 hours under the nitrogen atmosphere. The mixture was added with 15 mL of 2% KF solution and 20 mL of distilled water while stirring at 0° C. and then extracted twice with 50 mL of methylene chloride. The resulting organic layer was dried using anhydrous sodium sulfate, filtered and concentrated. A silica gel column chromatography (5% EtOAc/MC) was performed on the resulting residue and 225 mg (78%) of 6-methyl-8-furan-2-yl-3,4-dihydro-pyrano[3,4-c]pyridine-1-on was obtained in white solid.
Reaction SMILES: [NH2:1][CH2:2][CH:3]1[CH2:12][CH2:11][CH2:10][C:9]2[C:8]([O:13][C:14]3[CH:22]=[CH:21][C:17]([C:18]([NH2:20])=[O:19])=[CH:16][N:15]=3)=[CH:7][CH:6]=[CH:5][C:4]1=2.[C:23]1(=O)[CH2:27][CH2:26][CH2:25][CH2:24]1.[BH3-]C#N.[Na+]>>[CH:23]1([NH:1][CH2:2][CH:3]2[CH2:12][CH2:11][CH2:10][C:9]3[C:8]([O:13][C:14]4[CH:22]=[CH:21][C:17]([C:18]([NH2:20])=[O:19])=[CH:16][N:15]=4)=[CH:7][CH:6]=[CH:5][C:4]2=3)[CH2:27][CH2:26][CH2:25][CH2:24]1
Reactant: O=C1CCCC1
Reactant: NCC1CCCc2c(Oc3ccc(C(N)=O)cn3)cccc21
Agent: [BH3-]C#N
Agent: [Na+]
Product: NC(=O)c1ccc(Oc2cccc3c2CCCC3CNC2CCCC2)nc1
Yield: 37.5 %

Procedure:
Using a method similar to Example 204, using 6-(5-aminomethyl-5,6,7,8-tetrahydro-naphthalen-1-yloxy)-nicotinamide (intermediate 20, 297 mg, 1.00 mmol), cyclopentanone (168 mg, 2.00 mmol), and NaBH3CN (125 mg, 2.00 mmol) gives the title compound (137 mg) as a white foam. Mass spectrum (ion spray): m/z=366 (M+1); 1HNMR (CDCl3): 8.56 (s, 1H), 8.15 (d, 1H), 7.22-7.15 (m 2H), 6.93-4.89 (m, 2H), 5.82 (br. s, 2H), 3.11 (m, 1H), 3.02 (m, 1H), 2.92-2.78 (m, 2H), 2.63-2.42 (m, 2H), 1.91-1.50 (m, 10H), 1.35 (m, 2H).
Reaction SMILES: [C:1]([N:8]([CH2:20][C:21]([CH3:25])([CH3:24])[CH2:22][OH:23])[C:9](=[O:19])[C@H:10]([CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[NH2:11])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].C1([CH:32]([S:39]([O:42][C:43]2[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=2)(=[O:41])=[O:40])[CH2:33][CH2:34][S:35](Cl)(=[O:37])=[O:36])C=CC=CC=1>N1C=CC=CC=1.ClCCl.ClCCl>[C:1]([N:8]([CH2:20][C:21]([CH3:25])([CH3:24])[CH2:22][O:23][S:35]([CH2:34][CH2:33][CH2:32][S:39]([O:42][C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1)(=[O:41])=[O:40])(=[O:36])=[O:37])[C:9](=[O:19])[C@H:10]([CH2:12][C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1)[NH2:11])([O:3][C:4]([CH3:5])([CH3:7])[CH3:6])=[O:2]
Reactant: O=S(=O)(Cl)CCC(c1ccccc1)S(=O)(=O)Oc1ccccc1
Reactant: CC(C)(CO)CN(C(=O)OC(C)(C)C)C(=O)[C@@H](N)Cc1ccccc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(C)(COS(=O)(=O)CCCS(=O)(=O)Oc1ccccc1)CN(C(=O)OC(C)(C)C)C(=O)[C@@H](N)Cc1ccccc1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
To a stirred solution of 3-(N-Boc-L-phenylalaninamido)-2,2-dimethylpropanol from Step 1 (2 mmol) in a mixture of pyridine/dichloromethane (5 mL:10 mL) was added a solution of phenyl 3-phenoxysulfonyl-1-propanesulfonyl chloride (Example 1 (b)) (2.2 mmol) in dichloromethane (5 mL). The reaction mixture was stirred at room temperature for 15 h, then concentrated and rediluted with ethyl acetate and aqueous hydrochloric acid (1 N). The organic phase was isolated, washed with aqueous hydrochloric acid (1 N) and concentrated. The residual material was purified by silica gel chromatography using hexanes/ethyl acetate (70:30 to 50:50) as eluent to afford 3-phenoxysulfonyl-1-propanesulfonic acid 3-(N-Boc-L-phenylalaninamido)-2,2-dimethylpropyl ester.
Reaction SMILES: [CH3:1][C@H:2]1[N:7]([C:8]2[N:9]([CH3:21])[C:10](=[O:20])[CH:11]=[C:12]([C:14]3[CH:19]=[CH:18][N:17]=[CH:16][N:15]=3)[N:13]=2)[CH2:6][CH2:5][N:4]([C:22]2[CH:29]=[CH:28][C:25]([C:26]#[N:27])=[CH:24][CH:23]=2)[CH2:3]1.[Cl-].[OH:31][NH3+:32].C(=O)([O-])[O-].[Na+].[Na+]>C(O)C.O>[OH:31][NH:32][C:26](=[NH:27])[C:25]1[CH:28]=[CH:29][C:22]([N:4]2[CH2:5][CH2:6][N:7]([C:8]3[N:9]([CH3:21])[C:10](=[O:20])[CH:11]=[C:12]([C:14]4[CH:19]=[CH:18][N:17]=[CH:16][N:15]=4)[N:13]=3)[C@H:2]([CH3:1])[CH2:3]2)=[CH:23][CH:24]=1
Reactant: [NH3+]O
Reactant: C[C@@H]1CN(c2ccc(C#N)cc2)CCN1c1nc(-c2ccncn2)cc(=O)n1C
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: C[C@@H]1CN(c2ccc(C(=N)NO)cc2)CCN1c1nc(-c2ccncn2)cc(=O)n1C
Reaction time: 2 h

Procedure:
To a stirred solution of 4-[(3R)-3-methyl-4-(1-methyl-6-oxo-1,6-dihydro-[4,4′]bipyrimidinyl-2-yl)-piperazin-1-yl]-benzonitrile (1.50 mg, 3.87 mmol) in ethanol (8.0 ml) and water (4.0 ml) was added hydroxylammonium chloride (807 mg, 11.6 mmol) and sodium carbonate (2.05 g, 19.4 mmol), and the reaction mixture was stirred for 2 hours under reflux. The solution was partitioned between water and chloroform, and the organic layer was washed with water and brine, dried over magnesium sulfate, and concentrated in vacuo. The resulting solid was used for next reaction without further purification.
Reaction SMILES: O[CH2:2][C:3]1[CH:8]=[CH:7][N:6]=[C:5]([NH:9][C:10]2[S:11][C:12]([C:15]#[N:16])=[CH:13][N:14]=2)[CH:4]=1.CN(C)C=O.P(Cl)(Cl)([Cl:24])=O>C(Cl)Cl>[Cl:24][CH2:2][C:3]1[CH:8]=[CH:7][N:6]=[C:5]([NH:9][C:10]2[S:11][C:12]([C:15]#[N:16])=[CH:13][N:14]=2)[CH:4]=1
Reactant: N#Cc1cnc(Nc2cc(CO)ccn2)s1
Reactant: O=P(Cl)(Cl)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: N#Cc1cnc(Nc2cc(CCl)ccn2)s1

Procedure:
2-(4-Hydroxymethyl-pyridin-2-ylamino)-thiazole-5-carbonitrile (0.883 g, 3.80 mmol) was stirred in anh CH2Cl2 (12 mL) under N2. Dimethylformamide (0.354 mL, 3.80 mmol, 1 equiv) was added followed by the addition of phosphorous oxychloride (0.294 mL, 3.80 mmol). After 4 h the reaction was concentrated and quenched by the addition of saturated NaHCO3 (aq). A precipitate formed which was filtered and washed with water to provide the titled compound. 1H NMR (DMSO-d6) δ12.35 (bs, 1H), 8.40 (d, 1H, J=5.3 Hz), 8.28 (s, 1H), 7.20 (s, 1H), 7.12 (d, 1H, J=5.3 Hz), 4.82 (s, 2H).
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][S:5][C:6]1[N:11]2[CH:12]=[CH:13][N:14]=[C:10]2[CH:9]=[CH:8][CH:7]=1.C(N(CC)CC)C.[CH3:22][S:23](Cl)(=[O:25])=[O:24]>C(Cl)Cl>[CH3:22][S:23]([O:1][CH2:2][CH2:3][CH2:4][S:5][C:6]1[N:11]2[CH:12]=[CH:13][N:14]=[C:10]2[CH:9]=[CH:8][CH:7]=1)(=[O:25])=[O:24]
Reactant: OCCCSc1cccc2nccn12
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)OCCCSc1cccc2nccn12

Procedure:
To a solution of 5-[3-(hydroxy)propylthio]imidazo[1,2-a]pyridine (1.030 g, 4.95 moles) and triethylamine (1.03 ml, 7.4 mmoles) in methylene chloride (30 ml) was added methanesulfonyl chloride (0.46 ml, 5.9 mmoles) with stirring under ice-cooling and the mixture was further stirred under ice-cooling for 10 minutes. The reaction mixture was washed with water and the aqueous layer was extracted with methylene chloride (30 ml×3). The methylene chloride layers were combined and dried over anhydrous magnesium sulfate. Then, the solvent was distilled off to obtain crude 5-[3-(methanesulfonyloxy)propylthio]imidazo[1,2-a]pyridine as a yellow oily product.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:26]=[CH:25][C:6]([CH2:7][N:8]2[C:16]3([CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]3)[C:15]3[C:14](=[O:22])[CH:13]=[CH:12][N:11]([CH3:23])[C:10]=3[C:9]2=[O:24])=[CH:5][CH:4]=1.[Br:27]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl.O>[Br:27][C:13]1[C:14](=[O:22])[C:15]2[C:16]3([CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]3)[N:8]([CH2:7][C:6]3[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:26][CH:25]=3)[C:9](=[O:24])[C:10]=2[N:11]([CH3:23])[CH:12]=1
Reactant: COc1ccc(CN2C(=O)c3c(c(=O)ccn3C)C23CCCCC3)cc1
Reactant: O=C1CCC(=O)N1Br
Solvent: O
Solvent: ClC(Cl)(Cl)Cl
Product: COc1ccc(CN2C(=O)c3c(c(=O)c(Br)cn3C)C23CCCCC3)cc1
Temperature: 90 °C

Procedure:
To a solution of 6′-(4-methoxybenzyl)-1′-methylspiro[cyclohexane-1,5′-pyrrolo[3,4-b]pyridine]-4′,7′(1′H,6′H)-dione (1.0 mmol, 1 eq) in carbon tetrachloride (25 mL), add N-bromosuccinimide and heat the mixture at 90° C. for 16 h. After completion the mixture was diluted with water and extracted with ethyl acetate. Remove the solvent under reduced pressure to get the crude. Purify the crude by column chromatography to afford 3′-bromo-6′-(4-methoxybenzyl)-1′-methylspiro[cyclohexane-1,5′-pyrrolo[3,4-b]pyridine]-4′,7′(1′H,6′H)-dione (7).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[C:7](OC)(=[O:14])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>C(Cl)Cl>[C:7]([N:1]1[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1)(=[O:14])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: C1CNCCN1
Reactant: COC(=O)c1ccccc1
Solvent: ClCCl
Product: O=C(c1ccccc1)N1CCNCC1

Procedure:
Mono-benzoylation of unsymmetric substituted piperazines could be achieved by using one of the following procedures (Scheme 57), in which all the methods were exemplified by mono-alkyl substituted piperazines. (a) Unsymmetric piperazines were treated with 2 equivalents of n-butyllithium, followed by the addition of benzoyl chloride at room temperature to afford a mixture of two regioisomers, which could be separated by chromatography (Wang et al, Ref. 89 and 90(b), Scheme 58 eq. 06); (b) Benzoic acid was converted to its pentafluorophenyl ester, and then further reaction with 2-alkylpiperazine to provide the mono-benzoylpiperazines with the benzoyl group at the less hindered nitrogen (Adamczyk et al, Ref. 90(a), Scheme 58, eq. 07); (c) A mixture of piperazine and methyl benzoate was treated with dialkylaluminum chloride in methylene chloride for 2-4 days to yield the mono-benzoylpiperazine with the benzoyl group at the less hindered nitrogen (Scheme 58 eq. 08); (d) Unsymmetric piperazines were treated with 2 equivalents of n-butyllithium, followed by subsequent addition of triethylsilyl chloride and benzoyl chloride in THF at room temperature to afford mono-benzoylpiperazines with the benzoyl group at the more hindered nitrogen (Wang et al, Ref. 90(b), Scheme 58, eq. 09). When the substituent at position 2 was a ester or amide, the mono-benzoylation with benzoyl chloride occurred at the less hindered nitrogen of the piperazine with triethylamine as base in THF (Scheme 58, eq. 10).
Reaction SMILES: [CH3:1][C:2]1[C:3]([Se:16][C:17]#[C:18][C:19]2[CH:27]=[CH:26][C:22]([C:23]([OH:25])=O)=[CH:21][N:20]=2)=[CH:4][C:5]2[C:6]([CH3:15])([CH3:14])[CH2:7][CH2:8][C:9]([CH3:13])([CH3:12])[C:10]=2[CH:11]=1.O[N:29]1[C:33]2C=C[CH:36]=[CH:37][C:32]=2N=N1.C1(N=C=NC2CCCCC2)CCCCC1.C(N)CCC>C1COCC1>[CH2:33]([NH:29][C:23](=[O:25])[C:22]1[CH:26]=[CH:27][C:19]([C:18]#[C:17][Se:16][C:3]2[C:2]([CH3:1])=[CH:11][C:10]3[C:9]([CH3:12])([CH3:13])[CH2:8][CH2:7][C:6]([CH3:14])([CH3:15])[C:5]=3[CH:4]=2)=[N:20][CH:21]=1)[CH2:32][CH2:37][CH3:36]
Reactant: Cc1cc2c(cc1[Se]C#Cc1ccc(C(=O)O)cn1)C(C)(C)CCC2(C)C
Reactant: On1nnc2ccccc21
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: CCCCN
Solvent: C1CCOC1
Product: CCCCNC(=O)c1ccc(C#C[Se]c2cc3c(cc2C)C(C)(C)CCC3(C)C)nc1

Procedure:
In a manner similar to that of Example 10, 300 mg (0.72 mmol) of 6-(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydro-2-naphthylselanylethynyl)nicotinic acid are reacted with 194 mg (1.45 mmol) of 1-hydroxybenzotriazole, 300 mg (1.45 mmol) of 1,3-dicyclohexylcarbodiimide and 63.5 mg (0.87 mmol) of butylamine in 20 ml of THF. After purification on a column of silica (ethyl acetate 20/heptane 80), 60 mg (17%) of a yellow solid are obtained. m.p.=172° C.
Reaction SMILES: C([O:3][C:4](=[O:30])[CH:5]([N:15]1[CH2:19][C:18]([O:20][C:21]2[C:26]([F:27])=[CH:25][CH:24]=[CH:23][C:22]=2[F:28])=[CH:17][C:16]1=[O:29])[CH2:6][C:7]1[C:12]([F:13])=[CH:11][CH:10]=[CH:9][C:8]=1[F:14])C.O.[OH-].[Li+].Cl>O1CCCC1.O>[F:28][C:22]1[CH:23]=[CH:24][CH:25]=[C:26]([F:27])[C:21]=1[O:20][C:18]1[CH2:19][N:15]([CH:5]([CH2:6][C:7]2[C:8]([F:14])=[CH:9][CH:10]=[CH:11][C:12]=2[F:13])[C:4]([OH:30])=[O:3])[C:16](=[O:29])[CH:17]=1
Reactant: CCOC(=O)C(Cc1c(F)cccc1F)N1CC(Oc2c(F)cccc2F)=CC1=O
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)C(Cc1c(F)cccc1F)N1CC(Oc2c(F)cccc2F)=CC1=O
Temperature: 25 °C
Reaction time: 3 h
Yield: 99 %

Procedure:
To a solution containing 2-[4-(2,6-difluoro-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-3-(2,6-difluoro-phenyl)-propionic acid ethyl ester (96 mg, 0.23 mmol) in tetrahydrofuran (1 mL) was treated with an aqueous solution of lithium hydroxide monohydrate (12 mg, 0.27 mmol) in water (2 mL). The mixture was stirred at 25° C. for 3 h, then acidified with 2N aqueous hydrochloric acid. The mixture was extracted with dichloromethane (2×30 mL). The combined organic layers were dried over magnesium sulfate and concentrated to afford 2-[4-(2,6-difluoro-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-3-(2,6-difluoro-phenyl)-propionic acid (90 mg, 100%) as an off-white solid. LR-ES-MS m/z calculated for C19H13F4NO4 [M]+ 395, observed [M+H]+ 396.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]Cl)=[CH:4][CH:3]=1.[CH3:10][C:11]1([CH3:25])[O:19][C:18]2[C:13](=[CH:14][CH:15]=[CH:16][C:17]=2[O:20][C:21]([NH:23][CH3:24])=[O:22])[CH2:12]1>N1C=CC=CC=1>[CH3:24][N:23]([S:8][C:5]1[CH:6]=[CH:7][C:2]([CH3:1])=[CH:3][CH:4]=1)[C:21](=[O:22])[O:20][C:17]1[C:18]2[O:19][C:11]([CH3:10])([CH3:25])[CH2:12][C:13]=2[CH:14]=[CH:15][CH:16]=1
Reactant: CNC(=O)Oc1cccc2c1OC(C)(C)C2
Reactant: Cc1ccc(SCl)cc1
Solvent: c1ccncc1
Product: Cc1ccc(SN(C)C(=O)Oc2cccc3c2OC(C)(C)C3)cc1

Procedure:
A solution of 8.75 g of 4-methylbenzenesulfenyl chloride in 25 ml of pyridine was added to a solution of 10.9 g of carbofuran in 25 ml of pyridine. A precipitate formed immediately. The reaction mixture was processed as described in Example I to give a residue which could not be distilled even at 0.005 mm. Passage through a falling film still at 140° at 0.01 mm, then at 168° at 0.01 mm gave a liquid which crystallized on standing to a solid, m.p. 62°. Recrystallization several times from petroleum ether gave 2,3-dihydro-2,2-dimethyl-7-benzofuranyl (methyl)(4-methylphenylthio)carbamate, m.p. 65°.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:6]([C:7]([OH:9])=O)[C:5]([OH:11])=[CH:4][CH:3]=1.[CH:12]([C:14]1[CH:15]=[C:16]([CH:18]=[CH:19][CH:20]=1)[NH2:17])=[CH2:13]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([OH:11])=[C:6]([CH:10]=1)[C:7]([NH:17][C:16]1[CH:18]=[CH:19][CH:20]=[C:14]([CH:12]=[CH2:13])[CH:15]=1)=[O:9]
Reactant: C=Cc1cccc(N)c1
Reactant: O=C(O)c1cc(Cl)ccc1O
Product: C=Cc1cccc(NC(=O)c2cc(Cl)ccc2O)c1

Procedure:
This material was prepared according to the method of Example 1 using 5-chlorosalicylic acid and 3-vinylaniline, with reagents and solvents employed in similar molar ratios. 1HNMR (500 MHz, DMSO-d6): δ 5.32 (m, 1H, C═CH2 cis), 5.83 (m, 1H, C═CH2 trans), 6.75 (m, 1H, ArCH═CH2), 7.02 (m, 1H, H3), 7.28 (m, 1H, H6′), 7.37 (m, 1H, H5′), 7.49 (m, 1H, H4), 7.62 (m, 1H, H4′), 7.80 (m, 1H, H2′), 7.90 (m, 1H, H6).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[CH:9][CH:8]=[CH:7]2.[NH:12]1[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1>>[N:12]1([C:2]2[CH:3]=[CH:4][CH:5]=[C:6]3[C:11]=2[N:10]=[CH:9][CH:8]=[CH:7]3)[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1
Reactant: Brc1cccc2cccnc12
Reactant: C1CNCCN1
Product: c1cnc2c(N3CCNCC3)cccc2c1

Procedure:
8-(Piperazin-1-yl)quinoline is prepared from 8-bromoquinoline and piperazine as described in Step 1 of Preparation 54A to afford about 490 mg (95%). EIS-MS 207.8 (M+1).
Reaction SMILES: [CH2:1]([C@H:8]1[CH2:12][O:11][C:10](=[O:13])[N:9]1[C:14](=[O:19])[CH2:15][O:16][CH2:17][CH3:18])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:20]([O:27][C:28]1[CH:35]=[CH:34][C:31]([CH:32]=[O:33])=[C:30]([CH2:36][CH3:37])[CH:29]=1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.[O-]S(C(F)(F)F)(=O)=O.C([B+]CCCC)CCC>C(N(CC)CC)C>[CH2:1]([C@H:8]1[CH2:12][O:11][C:10](=[O:13])[N:9]1[C:14](=[O:19])[C@@H:15]([O:16][CH2:17][CH3:18])[C@@H:32]([C:31]1[CH:34]=[CH:35][C:28]([O:27][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[CH:29][C:30]=1[CH2:36][CH3:37])[OH:33])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCc1cc(OCc2ccccc2)ccc1C=O
Reactant: CCOCC(=O)N1C(=O)OC[C@@H]1Cc1ccccc1
Agent: CCCC[B+]CCCC
Agent: O=S(=O)([O-])C(F)(F)F
Solvent: CCN(CC)CC
Product: CCO[C@H](C(=O)N1C(=O)OC[C@@H]1Cc1ccccc1)[C@H](O)c1ccc(OCc2ccccc2)cc1CC

Procedure:
In analogy to the procedure described in example 1 a], (S)-4-benzyl-3-ethoxyacetyl-oxazolidin-2-one (for the preparation of (S)-4-benzyl-3-ethoxyacetyl-oxazolidin-2-one see: D. Haigh, H. C. Birrell, B. C. C. Cantello, D. S. Eggleston, R. C. Haltiwanger, R. M. Hindley, A. Ramaswamy, N. C. Stevens, Tetrahedron: Asymmetry 1999, 10, 1353-1367) was reacted with 4-benzyloxy-2-ethyl-benzaldehyde in the presence of triethylamine and di-n-butylboron triflate to give (S)-4-benzyl-3-[(2S,3R)-3-(4-benzyloxy-2-ethyl-phenyl)-2-ethoxy-3-hydroxy-propionyl]-oxazolidin-2-one as yellow foam. According to 1H-NMR spectroscopy, one of the four isomers is strongly predominating. The configuration was tentatively assigned as 2S,3R according to D. Haigh et al., Tetrahedron: Asymmetry 1999, 10, 1353-1367.