Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][CH2:3][C@H:4]1[CH2:8][CH2:7][CH2:6][N:5]1[C:9]([C:11]1[S:19][C:18]2[C:13](=[N:14][CH:15]=[CH:16][C:17]=2[O:20][C:21]2[CH:22]=[C:23]3[C:27](=[CH:28][CH:29]=2)[NH:26][C:25]([CH3:30])=[CH:24]3)[CH:12]=1)=[O:10].[C:31](Cl)(=[O:33])[CH3:32]>CN(C1C=CN=CC=1)C.CN(C=O)C>[CH3:1][O:2][CH2:3][CH:4]1[CH2:8][CH2:7][CH2:6][N:5]1[C:9]([C:11]1[S:19][C:18]2[C:13](=[N:14][CH:15]=[CH:16][C:17]=2[O:20][C:21]2[CH:22]=[C:23]3[C:27](=[CH:28][CH:29]=2)[N:26]([C:31](=[O:33])[CH3:32])[C:25]([CH3:30])=[CH:24]3)[CH:12]=1)=[O:10]
Reactant: COC[C@H]1CCCN1C(=O)c1cc2nccc(Oc3ccc4[nH]c(C)cc4c3)c2s1
Reactant: CC(=O)Cl
Agent: CN(C)c1ccncc1
Solvent: CN(C)C=O
Product: COCC1CCCN1C(=O)c1cc2nccc(Oc3ccc4c(c3)cc(C)n4C(C)=O)c2s1
Yield: 69 %

Procedure:
To a solution of (2R)-(2-methoxymethyl-pyrrolidin-1-yl)-[7-(2-methyl-1H-indol-5-yloxy)-thieno[3,2-b]pyridin-2-yl]-methanone and DMAP (120 mg, 0.28 mmol) in DMF (5 mL) was added acetyl chloride (44 mg, 0.56 mmol). After 3 h the reaction was quenched with water (5 mL). The aqueous layer was extracted with CH2Cl2 (2×15 mL). The combined organic extracts were dried (Na2SO4), and concentrated onto silica gel (5 mL). Purification by flash chromatography on silica gel (CH2Cl2/MeOH 97:3) afforded the title compound as a white solid (0.36 g, 69%). MS: 464 (MH+); HPLC Rf: 6.12 min; HPLC purity: 96%.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][CH2:5][OH:6].[H-].[Na+].Cl[C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([NH2:16])[N:11]=1>CN(C=O)C>[CH3:1][O:2][CH2:3][CH2:4][CH2:5][O:6][C:10]1[N:11]=[C:12]([NH2:16])[CH:13]=[CH:14][CH:15]=1
Reactant: Nc1cccc(Cl)n1
Reactant: COCCCO
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COCCCOc1cccc(N)n1
Temperature: 90 °C
Reaction time: 5 h

Procedure:
Into a 250 mL round bottom flask was added 3-methoxy-propanol (5.26 g, 58.4 mmol) and DMF (156 mL). Sodium hydride (60%, 4.67 g, 3 eq) was added slowly to the solution. After addition the mixture was heated to 90° C. for one hour. 2-chloro-6-amino-pyridine was added and the mixture was heated to reflux for four hours. LCMS showed conversion to product. The reaction was cooled to room temperature and solvent was removed under vacuum. The residue was partitioned between water and ethyl acetate. Organic layer was separated and the aqueous was extracted three times with ethyl acetate (3×50 mL). Organic layer dried over sodium sulfate and filtered; the solvent was removed under vacuum. The residue was dissolved with 2N HCl in MeOH and stirred for five hours at room temperature; the solvent was removed and the residue was purified by column chromatography with 20% ethyl acetate in hexanes yielding 3.12 g (45%) of the title compound as a yellow oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:12](=[O:13])[NH:11][N:10]=[C:9]1[C:14]1[S:30][C:17]2[C:18]3[CH:26]=[CH:25][C:24]([C:27](O)=[O:28])=[CH:23][C:19]=3[O:20][CH2:21][CH2:22][C:16]=2[CH:15]=1.[NH2:31][CH2:32][CH2:33][NH:34][C:35](=[O:37])[CH3:36].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>C1COCC1>[C:35]([NH:34][CH2:33][CH2:32][NH:31][C:27]([C:24]1[CH:25]=[CH:26][C:18]2[C:17]3[S:30][C:14]([C:9]4[N:8]([C:3]5[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=5[Cl:1])[C:12](=[O:13])[NH:11][N:10]=4)=[CH:15][C:16]=3[CH2:22][CH2:21][O:20][C:19]=2[CH:23]=1)=[O:28])(=[O:37])[CH3:36]
Reactant: O=C(O)c1ccc2c(c1)OCCc1cc(-c3n[nH]c(=O)n3-c3ccccc3Cl)sc1-2
Reactant: CC(=O)NCCN
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)NCCNC(=O)c1ccc2c(c1)OCCc1cc(-c3n[nH]c(=O)n3-c3ccccc3Cl)sc1-2

Procedure:
Following the procedures in Examples 47 and 235, 2-(4-(2-chlorophenyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-3-yl)-4,5-dihydrobenzo[b]thieno[2,3-d]oxepine-8-carboxylic acid was reacted with N-(2-aminoethyl)acetamide, HATU and DIPEA in THF to give 331 as a colorless solid after reverse phase HPLC. MS: (ESI+) 524.0
Reaction SMILES: [CH3:1][C:2]1[C:3]([CH2:9][N:10]([CH2:16][C:17]2[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[CH:20]=[CH:19][N:18]=2)[CH2:11][CH2:12][CH2:13][CH2:14][NH2:15])=[N:4][CH:5]=[C:6]([CH3:8])[CH:7]=1.CCN(CC)CC.[NH:34]1[C:38]2[CH:39]=[CH:40][CH:41]=[C:42]([C:43](Cl)=[O:44])[C:37]=2[N:36]=[CH:35]1>C(Cl)Cl>[CH3:1][C:2]1[C:3]([CH2:9][N:10]([CH2:16][C:17]2[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[CH:20]=[CH:19][N:18]=2)[CH2:11][CH2:12][CH2:13][CH2:14][NH:15][C:43]([C:42]2[C:37]3[N:36]=[CH:35][NH:34][C:38]=3[CH:39]=[CH:40][CH:41]=2)=[O:44])=[N:4][CH:5]=[C:6]([CH3:8])[CH:7]=1
Reactant: O=C(Cl)c1cccc2[nH]cnc12
Reactant: Cc1cnc(CN(CCCCN)Cc2nccc3ccccc23)c(C)c1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1cnc(CN(CCCCNC(=O)c2cccc3[nH]cnc23)Cc2nccc3ccccc23)c(C)c1
Reaction time: 48 h
Yield: 28.8 %

Procedure:
To a solution of N1-(3,5-dimethyl-pyridin-2-ylmethyl)-N1isoquinolin-1-ylmethyl-butane-1,4-diamine (83 mg, 0.24 mmol) in CH2Cl2 (5 mL) was added Et3N (0.13 mL, 0.96 mmol) and 1H-benzoimidazole-4-carbonyl chloride (86 mg, 0.48 mmol) and the mixture was stirred for 2 d. Then it was diluted with CH2Cl2 (20 mL) and washed with saturated NaHCO3 (3×15 mL). The organic layer was dried (MgSO4), filtered, and concentrated to afford a yellow oil. Purification by radial chromatography on silica gel (1 mm plate; using CH2Cl2/MeOH/NH4OH; 50:1:1) afforded the product as a yellow oil (34 mg, 29%). 1H NMR (CDCl3) δ 1.48-1.53 (m, 2H), 1.66 (s, 6H), 1.72 (br m, 2H), 2.03 and 2.07 (s, total 3H), 2.25 and 2.27 (s, total 3H), 2.64 (t, 2H, J=7.5 Hz), 3.30 (br m, 1H), 3.40 (br m, 1H), 3.81 and 3.87 (s, total 2H), 4.21 and 4.25 (s, total 2H), 7.37-7.42 (m, 2H), 7.55-7.57 (m, 2H), 8.04-8.07 (m, 2H), 8.13-8.17 (m, 2H), 8.38 and 8.40 (s, total 1H), 9.79 (br s, 1H). 13C NMR (CDCl3) δ 18.32, 18.43, 24.42, 26.61, 27.88, 30.10, 39.57, 53.83, 54.90, 58.23, 59.54, 115.20, 121.06, 123.26, 123.88, 126.80, 127.01, 127.27, 128.13, 130.33, 132.48, 133.33, 136.67, 139.37, 141.47, 146.47, 146.58, 154.16, 159.19. ES-MS m/z 493 [M+H]+. Anal. Calcd. for C30H32N6O.1.4CH2Cl2: C, 61.67; H, 5.74; N, 13.74. Found: C, 62.01; H, 5.79; N, 13.67.
Reaction SMILES: F[C:2](F)(F)C(O)=O.[CH3:8][N:9]1[CH2:14][CH2:13][N:12]([C:15]2[N:20]=[C:19]3[NH:21][N:22]=[C:23]([C:24]([OH:26])=[O:25])[C:18]3=[CH:17][CH:16]=2)[CH2:11][CH2:10]1.OS(O)(=O)=O>CO>[CH3:8][N:9]1[CH2:10][CH2:11][N:12]([C:15]2[N:20]=[C:19]3[NH:21][N:22]=[C:23]([C:24]([O:26][CH3:2])=[O:25])[C:18]3=[CH:17][CH:16]=2)[CH2:13][CH2:14]1
Reactant: O=C(O)C(F)(F)F
Reactant: CN1CCN(c2ccc3c(C(=O)O)n[nH]c3n2)CC1
Agent: O=S(=O)(O)O
Solvent: CO
Product: COC(=O)c1n[nH]c2nc(N3CCN(C)CC3)ccc12

Procedure:
6-(4-Methyl-1-piperazinyl)-1H-pyrazolo[3,4-b]pyridine-3-carboxylate trifluoroacetate (1.82 g, 4.8 mmole) was refluxed overnight in 300 mL of MeOH containing 2 mL of concentrated H2SO4. The reaction mixture was concentrated to ca. 100 mL and then distributed between EtOAc and an aqueous NaHCO3 solution. The aqueous phase was extracted additional two times with EtOAc and then the combined organic phase was dried and concentrated. Recrystallization from MeOH gave 1.21 g (91%) of analytically pure product, mp 230° -231° C.
Reaction SMILES: [NH2:1][C:2]([C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([Br:20])[N:15]=1)([CH3:13])[CH2:3][O:4][C@@:5]([CH3:12])([C:8]([F:11])([F:10])[F:9])[C:6]#[N:7].C(N[C@H](C(O)=O)CS)(=O)C.C([O-])([O-])=O.[K+].[K+]>CCO>[Br:20][C:16]1[N:15]=[C:14]([C:2]2([CH3:13])[CH2:3][O:4][C@@:5]([CH3:12])([C:8]([F:10])([F:9])[F:11])[C:6]([NH2:7])=[N:1]2)[CH:19]=[CH:18][CH:17]=1
Reactant: CC(N)(CO[C@](C)(C#N)C(F)(F)F)c1cccc(Br)n1
Agent: CC(=O)N[C@@H](CS)C(=O)O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: CC1(c2cccc(Br)n2)CO[C@@](C)(C(F)(F)F)C(N)=N1

Procedure:
A suspension of (R)-2-[(RS)-2-amino-2-(6-bromo-pyridin-2-yl)-propoxy]-3,3,3-trifluoro-2-methyl-propionitrile (0.688 g, 1.172 mmol), N-acetyl-L-cysteine (0.383 g, 2.344 mmol) and K2CO3 (0.356 g, 2.560 mmol) in abs. EtOH (4 ml) was stirred at 80° C. for 18 h. The reaction mixture was quenched with 10% aq. K2CO3 soln. and 3× extracted with TBME. The combined org. phases were washed with brine, dried over Na2SO4, filtered and concentrated to leave the title compound as a colourless solid. HPLC RtH4=0.68-0.70 min; ESIMS: 352, 354 [(M+H)+].
Reaction SMILES: [C:1]([O:5][C:6](=[O:31])[NH:7][CH2:8][CH2:9][CH2:10][CH2:11][C@H:12]([NH2:30])[C:13](=[O:29])[NH:14][CH2:15][CH2:16][N:17]([C:19]([O:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)=[O:20])[CH3:18])([CH3:4])([CH3:3])C.CCN(C(C)C)C(C)C.[CH3:41][C:42](OC(C)=O)=[O:43]>C(Cl)(Cl)Cl>[CH:1]([O:5][C:6](=[O:31])[NH:7][CH2:8][CH2:9][CH2:10][CH2:11][C@H:12]([NH:30][C:42](=[O:43])[CH3:41])[C:13](=[O:29])[NH:14][CH2:15][CH2:16][N:17]([C:19]([O:21][CH2:22][C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1)=[O:20])[CH3:18])([CH3:3])[CH3:4]
Reactant: CN(CCNC(=O)[C@@H](N)CCCCNC(=O)OC(C)(C)C)C(=O)OCc1ccccc1
Reactant: CC(=O)OC(C)=O
Solvent: ClC(Cl)Cl
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)N[C@@H](CCCCNC(=O)OC(C)C)C(=O)NCCN(C)C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 97.2 %

Procedure:
To a solution of compound H (1.4 g, 3.21 mmol) in CHCl3 (10 mL) at room temperature was added DIEA (2.6 mL, 15 mmol) followed by Ac2O (0.85 mL, 9.0 mmol). The reaction mixture was stirred at room temperature for 2 h. Solvents were removed in vacuo and then the residue was dissolved in dichloromethane (100 mL). The organic layer was washed with 10% citric acid (75 mL), saturated NaHCO3 (75 mL) and brine (75 mL). The organic layer was separated, dried over Na2SO4 and solvent removed in vacuo to afford compound I (1.45 g, 99%). LC-MS [M+H] 479.5 (C24H38N4O6+H, calc: 479.5).
Reaction SMILES: [O:1]=[C:2](C=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[CH2:3][C:4]([O-])=O.C1(C2C(C=O)=C(C3C=CC(F)=CC=3)C3C(=CC=CC=3)N=2)CC1.CCCCCC.[CH2:55]([O:57][C:58](=[O:60])[CH3:59])[CH3:56]>C(#N)C>[CH2:55]([O:57][C:58](=[O:60])[CH2:59][C:2](=[O:1])[CH:3]=[CH2:4])[CH3:56]
Reactant: CCOC(C)=O
Reactant: O=C([O-])CC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=Cc1c(C2CC2)nc2ccccc2c1-c1ccc(F)cc1
Solvent: CC#N
Solvent: CCCCCC
Product: C=CC(=O)CC(=O)OCC
Temperature: 25 °C

Procedure:
The ylide 3-oxo-4-(triphenylphosphoranylidene)butanoate (4.82 g, 12.36 mmol) is solved under argon atmosphere in 100 ml acetonitrile. Under vigorous stirring 2-cyclopropyl-4-(4-fluoro-phenyl)-quinoline-3-carbaldehyde (3 g, 10.3 mmol) is added in 5 portions and then heated to reflux. After 50 h the reaction is cooled to room temperature. The slight brown solvent is evaporated and the residue is dried under vacuum to obtain a brown waxy oil. Chromatography over silica gel with hexane:ethylacetate (4:1/v:v) give a yellow oil of 5-(2-cyclopropyl-4-fluoro-phenyl)-quinolin-3-yl)-3-oxo-pent-4-enoic acid ethyl ester. MS: 403.45
Reaction SMILES: [CH:1]([O:3][C@H:4]([CH2:21][CH2:22][C:23]1[CH:28]=[CH:27][C:26]([C:29]2[CH:34]=[C:33]([F:35])[CH:32]=[C:31]([F:36])[CH:30]=2)=[CH:25][CH:24]=1)[C@@H:5]([CH:19]=[O:20])[CH2:6][CH2:7][N:8]1[C:16](=[O:17])[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9]1=[O:18])=[O:2].P([O-])(O)(O)=[O:38].[Na+].OO.Cl([O-])=O.[Na+]>C(#N)C.O>[F:35][C:33]1[CH:34]=[C:29]([C:26]2[CH:25]=[CH:24][C:23]([CH2:22][CH2:21][C@@H:4]([O:3][CH:1]=[O:2])[C@H:5]([CH2:6][CH2:7][N:8]3[C:9](=[O:18])[C:10]4[C:15](=[CH:14][CH:13]=[CH:12][CH:11]=4)[C:16]3=[O:17])[C:19]([OH:38])=[O:20])=[CH:28][CH:27]=2)[CH:30]=[C:31]([F:36])[CH:32]=1
Reactant: O=P([O-])(O)O
Reactant: O=CO[C@H](CCc1ccc(-c2cc(F)cc(F)c2)cc1)[C@@H](C=O)CCN1C(=O)c2ccccc2C1=O
Agent: OO
Agent: [Na+]
Agent: [O-][Cl+][O-]
Solvent: CC#N
Solvent: O
Product: O=CO[C@H](CCc1ccc(-c2cc(F)cc(F)c2)cc1)[C@H](CCN1C(=O)c2ccccc2C1=O)C(=O)O
Temperature: 0 °C
Reaction time: 1 h
Yield: 96.8 %

Procedure:
The compound (0.12 g) obtained from step d was taken in acetonitrile (6 mL) and water (1 mL), to this solution sodiumdihydrogen phosphate (0.05 g) was added. Reaction mixture was cooled to 0° C. and hydrogen peroxide (0.5 mL) and sodium chlorite (0.15 g) were added. After stirring the reaction mixture for additional 1 hour, solvents were evaporated on rotaevaporator, the residue was taken into water and extracted with ethyl acetate. Organic layer was washed with water and brine solution and dried over anhydrous sodium sulphate. Solvent was evaporated under the reduced pressure, to get the title compound (0.12 g)
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH2:8][C@H:9]([OH:14])[C:10]([O:12][CH3:13])=[O:11])[CH:5]=[CH:6][CH:7]=1.C(N(CC)CC)C.[C:22](Cl)(=[O:27])[C:23]([CH3:26])([CH3:25])[CH3:24].Cl>C(OC)(C)(C)C>[C:22]([O:1][C:2]1[CH:3]=[C:4]([CH2:8][C@H:9]([OH:14])[C:10]([O:12][CH3:13])=[O:11])[CH:5]=[CH:6][CH:7]=1)(=[O:27])[C:23]([CH3:26])([CH3:25])[CH3:24]
Reactant: CC(C)(C)C(=O)Cl
Reactant: COC(=O)[C@@H](O)Cc1cccc(O)c1
Agent: Cl
Solvent: COC(C)(C)C
Solvent: CCN(CC)CC
Product: COC(=O)[C@@H](O)Cc1cccc(OC(=O)C(C)(C)C)c1
Temperature: 10 °C
Reaction time: 17 h
Yield: 87 %

Procedure:
Methyl (2S)-3-(3-hydroxyphenyl)-2-hydroxypropionate (8.93 kg, 45.1 mol) was dissolved in tert-butylmethyl ether (133 L), and triethylamine (12.7 L, 91 mol) was added to the reaction mixture at room temperature, followed by cooling. Pivaloyl chloride (5.89 L, 48 mol) was added dropwise to the reaction mixture at an internal temperature of 2° C. After the end of the dropwise addition, the reaction mixture was stirred at 10° C. for 17 hours. To the reaction mixture was added 43 L of a 1N hydrochloric acid aqueous solution before stirring, followed by allowing to stand and then separating the mixture. The organic layer was washed twice each with a 0.25N sodium hydroxide aqueous solution (45 L) and water (45 L), and further washed with 42 L of a 5% sodium chloride solution, and then the organic layer was subjected to vacuum concentration at 50° C. After that, 1,2-dimethoxyethane (45 L) was added to the residue and then again subjected to vacuum concentration to obtain 11.0 kg of the title compound (yield: 86%).
Reaction SMILES: [OH:1][N:2]=[C:3]([C:11]#[N:12])[C:4]1[CH:9]=[CH:8][C:7]([CH3:10])=[CH:6][CH:5]=1.C(N(CC)CC)C.[CH3:20][S:21](Cl)(=[O:23])=[O:22]>O1CCCC1>[CH3:20][S:21]([O:1][N:2]=[C:3]([C:11]#[N:12])[C:4]1[CH:9]=[CH:8][C:7]([CH3:10])=[CH:6][CH:5]=1)(=[O:23])=[O:22]
Reactant: CS(=O)(=O)Cl
Reactant: Cc1ccc(C(C#N)=NO)cc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: Cc1ccc(C(C#N)=NOS(C)(=O)=O)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 74.5 %

Procedure:
33.6 g (0.21 mol) of α-hydroxyimino-4-methylbenzylcyanide and 31.9 g (0.31 mol) of triethylamine are dissolved in 425 ml of tetrahydrofuran and to this solution is then added dropwise a solution of 26.44 g (0.23 mol) of methanesulfonyl chloride at 0-5° C. After the addition is complete, the mixture is stirred for 30 minutes at 0° C. and then overnight at room temperature. Subsequently, the reaction mixture is filtered and the filtrate is washed with a saturated sodium chloride solution and dried over magnesium sulfate. The solvent is then distilled off on a rotary evaporator, giving a solid residue which is recrystallised from toluene. 37.3 g (75%) of α-(methylsulfonyloxyimino)-4-methylbenzylcyanide are obtained in the form of a colourless powder having an m.p. of 97.5-102.5° C. The 1H-NMR spectrum shows it to be a pure stereoisomer.
Reaction SMILES: [N:1]1[C:10]2[CH:9]([NH:11][CH2:12][CH2:13][CH2:14][CH2:15][N:16]3[C:24](=[O:25])[C:23]4[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=4)[C:17]3=[O:26])[CH2:8][CH2:7][CH2:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.[BH-](O[C:37]([CH3:39])=O)(OC(C)=O)OC(C)=O.[Na+]>ClCCl>[CH3:2][N:1]1[C:10]2[CH:5]=[CH:6][CH:7]=[CH:8][C:9]=2[N:11]=[C:37]1[CH2:39][N:11]([CH:9]1[C:10]2[N:1]=[CH:2][CH:3]=[CH:4][C:5]=2[CH2:6][CH2:7][CH2:8]1)[CH2:12][CH2:13][CH2:14][CH2:15][N:16]1[C:24](=[O:25])[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[C:17]1=[O:26]
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Reactant: O=C1c2ccccc2C(=O)N1CCCCNC1CCCc2cccnc21
Agent: [Na+]
Solvent: ClCCl
Product: Cn1c(CN(CCCCN2C(=O)c3ccccc3C2=O)C2CCCc3cccnc32)nc2ccccc21
Temperature: 25 °C
Reaction time: 96 h
Yield: 72 %

Procedure:
To a solution of 2-[4-(5,6,7,8-Tetrahydro-quinolin-8-ylamino)-butyl]-isoindole-1,3-dione (0.2011 g, 0.58 mmol) in dichloromethane (5.8 mL) was added 1-Methyl-1H-benoimidazole-2-carbaldehyde (0.1844 g, 1.15 mmol) and NaBH(OAc)3 (0.2462 g, 1.16 mmol), and was stirred at room temperature for four days. The organic phase was washed with NaHCO3 (2×10 mL), dried over Na2SO4, filtered, and concentrated. Purification of the crude material by column chromatography on silica gel (47:2:1 CH2Cl2—MeOH—NH4OH) provided 103 mg (36%) of 2-{4-[(1-Methyl-1H-benzoimidazol-2-ylmethyl)-(5,6,7,8-tetrahydro-quinolin-8-yl)-amino]-butyl}-isoindole-1,3-dione. 1H NMR (CDCl3) δ 1.30-1.44 (m, 2H), 1.48-1.63 (m, 3H), 1.84-1.96 (m, 2H), 2.03-2.07 (m, 1H), 2.54-2.81 (m, 4H), 3.51 (t, 2H, J=7.2 Hz), 3.95 (s, 3H), 3.99-4.06 (m, 2H), 4.19 (d, 1H, J=13.5Hz), 6.94-6.98 (m, 1H), 7.13-7.21 (m, 2H), 7.24-7.29 (m, 2H), 7.63-7.68 (m, 3H), 7.74-7.78 (m, 2H), 8.40 (d, 1H, J=3.6 Hz).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH:16](Cl)[C:17]([O:19][CH3:20])=[O:18])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:22]1([S:28]([O-:30])=[O:29])[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.[Na+].CN(C)C=O>O>[C:22]1([S:28]([CH:16]([CH2:15][C:12]2[CH:13]=[CH:14][C:9]([O:8][CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)=[CH:10][CH:11]=2)[C:17]([O:19][CH3:20])=[O:18])(=[O:30])=[O:29])[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: O=S([O-])c1ccccc1
Reactant: COC(=O)C(Cl)Cc1ccc(OCc2ccccc2)cc1
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)C(Cc1ccc(OCc2ccccc2)cc1)S(=O)(=O)c1ccccc1
Temperature: 80 °C

Procedure:
A mixture of methyl 3-(4-benzyloxyphenyl)-2-chloropropanoate (International Patent Appl., Publication No. WO 9101337) (0.50 g), sodium benzenesulphinate (0.29 g) and dry N,N-dimethylformamide (25 mL) was heated at 80° C. for 24 hrs. The mixture was cooled and diluted with water (500 mL), then extracted with dichloromethane (2×250 mL). The combined organic solutions were washed with water (2×250 mL) and brine (250 mL), dried (MgSO4) and evaporated. The residue was chromatographed on silica gel with dichloromethane as eluent to afford the title compound.
Reaction SMILES: C(N(CC)CC)C.[CH2:8]([N:15]1[CH2:19][C@H:18]([OH:20])[CH2:17][C@H:16]1[C:21]([OH:24])([CH3:23])[CH3:22])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[CH3:25][S:26](Cl)(=[O:28])=[O:27]>ClCCl>[CH2:8]([N:15]1[CH2:19][C@H:18]([O:20][S:26]([CH3:25])(=[O:28])=[O:27])[CH2:17][C@H:16]1[C:21]([OH:24])([CH3:22])[CH3:23])[C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(O)[C@@H]1C[C@@H](O)CN1Cc1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(O)[C@@H]1C[C@@H](OS(C)(=O)=O)CN1Cc1ccccc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of triethylamine (4.32 ml) and (2S,4R)-1-benzyl-2-(1-hydroxy-1-methylethyl)-4-hydroxypyrrolidine (4.87 g) in dichloromethane (50 ml) was added methanesulfonyl chloride (2.4 ml) at 0° C. After stirring at room temperature for 4 hours, the mixture was quenched with water and extracted with ethyl acetate (×2). The combined extracts were washed with brine, dried over magnesium sulfate, evaporated under reduced pressure, and purified with column chromatography (silica gel, 500 ml, methanol:dichloromethane=4:96) to give (2S,4R)-1-benzyl-2-(1-hydroxy-1-methylethyl)-4-(methanesulfonyloxy)pyrrolidine (3.34 g) as a pale yellow solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([OH:11])[C:9]=1[OH:10])[CH:5]=[O:6].C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:19][CH2:20]Br>CN(C=O)C.ClCCl>[F:1][C:2]1[C:9]2[O:10][CH2:19][CH2:20][O:11][C:8]=2[CH:7]=[C:4]([CH:5]=[O:6])[CH:3]=1
Reactant: O=Cc1cc(O)c(O)c(F)c1
Reactant: BrCCBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=Cc1cc(F)c2c(c1)OCCO2
Temperature: 80 °C
Reaction time: 2.5 h
Yield: 86.7 %

Procedure:
3-fluoro-4,5-dihydroxybenzaldehyde (0.9 g; 5.7 mmol) and cesium carbonate (4.6 g; 14.2 mmol) were stirred in DMF (15 ml) at room temperature for 15 min. 1,2 Dibromoethane (638 μl; 7.4 mmol) was added and reaction mixture was stirred at 80° C. for 2.5 h and then diluted with dichloromethane (100 ml). The mixture was washed with water (2×50 ml), 10% aqueous citric acid (50 ml), brine (50 ml), dried over sodium sulfate and evaporated to dryness to yield 8-fluoro-2,3-dihydro-1,4-benzodioxine-6-carbaldehyde (0.9 g; 87% yield). 1H NMR (400 MHz, CD3OD) δ 9.74 (d, 1H), 7.25 (m, 2H), 4.37 (m, 4H).
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[C:3]1[CH:4]=[CH:5][C:6]2[CH2:12][CH2:11][C:10](=O)[CH2:9][CH2:8][C:7]=2[CH:14]=1.[CH2:17]([NH:19][CH:20]=[O:21])[CH3:18]>C(O)=O>[F:1][C:2]([F:16])([F:15])[C:3]1[CH:4]=[CH:5][C:6]2[CH2:12][CH2:11][CH:10]([N:19]([CH2:17][CH3:18])[CH:20]=[O:21])[CH2:9][CH2:8][C:7]=2[CH:14]=1
Reactant: O=C1CCc2ccc(C(F)(F)F)cc2CC1
Reactant: CCNC=O
Solvent: O=CO
Product: CCN(C=O)C1CCc2ccc(C(F)(F)F)cc2CC1
Yield: 99.2 %

Procedure:
A mixture of 228.2 g of 2-trifluoromethyl-6,7,8,9-tetrahydro-[5H]-benzocyclohepten-7-one, 219 g of N-ethylformamide and 151 g of formic acid is heated under reflux for 14 hours. After concentration in vacuo, while heating on a bain-marie, the residue is taken up in 2300 ml of methylene chloride. After washing twice with 800 ml of water each time, the organic layer is dried over magnesium sulphate and, after filtration, the solvent is removed in vacuo. 283 g of 2-trifluoromethyl-7-(N-ethyl-N-formylamino)-6,7,8,9-tetrahydro-[5H]-benzocycloheptene are obtained in the form of an oil.
Reaction SMILES: [C:1]1(=O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[NH:8]1[CH2:13][CH2:12][O:11][CH2:10][CH2:9]1.C1(C)C(S(O)(=O)=O)=CC=CC=1.O>C1C=CC=CC=1>[O:11]1[CH2:12][CH2:13][N:8]([C:1]2[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]=2)[CH2:9][CH2:10]1
Reactant: C1COCCN1
Reactant: O=C1CCCCC1
Agent: Cc1ccccc1S(=O)(=O)O
Solvent: c1ccccc1
Solvent: O
Product: C1=C(N2CCOCC2)CCCC1

Procedure:
295g of cyclohexanone and 261 g of morpholine are dissolved in 800ml of benzene. After the whole has been dissolved, 1.5g of p. toluene sulphonic acid are added and the mixture is heated under reflux. The water formed is extracted continuously by azeotropic distillation. After 20 hours reflux, the remaining solvent is distilled off and the oily residue is recovered. 379 g of the enamine are so obtained, boiling under 2mm at 115° to 117°. The yield amounts to 76%.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[C:10]2[C:6]([CH:7]=[C:8]([C:12]([O:14][CH3:15])=[O:13])[NH:9]2)=[CH:5][CH:4]=1.[Br:16]N1C(=O)CCC1=O>CN(C=O)C>[Br:16][C:7]1[C:6]2[C:10](=[CH:11][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)[NH:9][C:8]=1[C:12]([O:14][CH3:15])=[O:13]
Reactant: COC(=O)c1cc2ccc(OC)cc2[nH]1
Reactant: O=C1CCC(=O)N1Br
Solvent: CN(C)C=O
Product: COC(=O)c1[nH]c2cc(OC)ccc2c1Br
Reaction time: 38 h
Yield: 53.9 %

Procedure:
Methyl 6-(methyloxy)-1H-indole-2-carboxylate (0.10 g, 0.49 mmol) was dissolved in DMF (2 mL) then N-bromosuccinimide (0.095 g, 0.53 mmol) added and the reaction stirred for 38 h. The solvent was evaporated and the reaction mixture was purified by column chromatography (hexanes/EtOAc) to afford the title compound (0.075 g, 54%) as a white solid. 1H NMR (400 MHz, DMSO-d6): δ 12.08 (s, 1H), 7.41 (d, 1H), 6.82-6.89 (m, 2H), 3.88 (s, 3H), 3.80 (s, 3H). MS: m/z 284.0 (M+1).