Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][C:7]([C:11]([NH:13][NH2:14])=[O:12])=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[C:15](=S)=[S:16].C(N(CC)CC)C.[Cl-].[NH4+].[Cl-].[Na+]>C(O)C.O>[N:1]1[C:10]2[C:5](=[CH:6][C:7]([C:11]3[O:12][C:15]([SH:16])=[N:14][N:13]=3)=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: NNC(=O)c1ccc2ncccc2c1
Reactant: S=C=S
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CCO
Solvent: CCN(CC)CC
Solvent: O
Product: Sc1nnc(-c2ccc3ncccc3c2)o1
Yield: 50.5 %

Procedure:
A solution of quinoline-6-carbohydrazide (2.00 g, 10.7 mmol), carbon disulfide (1.61 mL, 26.8 mmol) and triethylamine (1.78 mL, 12.8 mmol) in ethanol (40 mL) was heated under reflux for 4 hr. After cooling, the reaction mixture was poured into water, a saturated aqueous ammonium chloride solution (100 mL) was added, and the mixture was saturated with sodium chloride. The precipitate was collected by filtration and recrystallized from methanol to give the title compound (1.24 g, yield 51%) as pale-yellow crystals.
Reaction SMILES: [CH2:1]([CH:9]1[CH2:17][C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[O:10]1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].C([O-])(O)=O.[Na+].O.[Br:24]Br>ClCCl>[Br:24][C:14]1[CH:15]=[C:16]2[C:11](=[CH:12][CH:13]=1)[O:10][CH:9]([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8])[CH2:17]2
Reactant: CCCCCCCCC1Cc2ccccc2O1
Reactant: BrBr
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: CCCCCCCCC1Cc2cc(Br)ccc2O1
Temperature: 0 °C
Yield: 96.3 %

Procedure:
In a 50 ml-three-necked flask, 2.00 g (8.61 mM) of 2-octylcoumaran and 3.2 ml of dichloremethane were placed and mixed to obtain a solution. To the solution, 0.73 (8.69 mM) of NaHCO3 and 3.2 ml of water were added. To the mixture, a solution of 0.44 ml (0.54 mM) of bromine in 1 ml of dichloromethane were added dropwise in 17 minutes under stirring on an ice bath, followed by stirring for 3 hours and 25 minutes at room temperature. After the reaction, the reaction mixture was poured into ice water and subjected to extraction with dichloromethane, followed by two times washing with a common salt aqueous solution and drying with mirabilite. The resultant mixture was concentrated under reduced pressure to obtain 2.58 g of 5-bromo-2-octylcoumaran (Yield: 96.3%).
Reaction SMILES: P(Cl)(Cl)([Cl:3])=O.[Cl:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[CH:13]1[CH2:22][C:21]2[NH:20][CH:19]=[CH:18][C:17](=O)[C:16]=2[C:15](=[O:24])[CH2:14]1>>[Cl:3][C:17]1[C:16]2[C:15](=[O:24])[CH2:14][CH:13]([C:8]3[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=3[Cl:6])[CH2:22][C:21]=2[N:20]=[CH:19][CH:18]=1
Reactant: O=C1CC(c2ccccc2Cl)Cc2[nH]ccc(=O)c21
Reactant: O=P(Cl)(Cl)Cl
Product: O=C1CC(c2ccccc2Cl)Cc2nccc(Cl)c21
Temperature: 100 °C
Reaction time: 2 h
Yield: 85.9 %

Procedure:
Under ice-cooling, to phosphorus oxychloride (5.4 g) was added 7-(2-chlorophenyl)-1,4,5,6,7,8-hexahydroquinoline-4,5-dione (0.60 g), and the mixture was stirred at 100° C. for 2 hours and cooled. Under reduced pressure, phosphorus oxychloride was evaporated, and to the residue was added 1N sodium hydroxide solution. The mixture was extracted with ethyl acetate, and the organic layer was washed with water and saturated brine, dried with magnesium sulfate and concentrated under reduced pressure to give colorless crystals of 4-chloro-7-(2-chlorophenyl)-5,6,7,8-tetrahydroquinolin-5-one (0.55 g).
Reaction SMILES: [CH:1]1([C:4]2[C:14]3[O:13][CH2:12][CH2:11][N:10](C(OC(C)(C)C)=O)[CH2:9][C:8]=3[CH:7]=[CH:6][CH:5]=2)[CH2:3][CH2:2]1.C(OCC)(=O)C.[ClH:28]>C(OCC)(=O)C>[ClH:28].[CH:1]1([C:4]2[C:14]3[O:13][CH2:12][CH2:11][NH:10][CH2:9][C:8]=3[CH:7]=[CH:6][CH:5]=2)[CH2:3][CH2:2]1
Reactant: CC(C)(C)OC(=O)N1CCOc2c(cccc2C2CC2)C1
Agent: Cl
Solvent: CCOC(C)=O
Product: c1cc2c(c(C3CC3)c1)OCCNC2
Temperature: 25 °C
Reaction time: 1 h
Yield: 54 %

Procedure:
A mixture of tert-butyl 9-cyclopropyl-2,3-dihydro-1,4-benzoxazepine-4(5H)-carboxylate (70.0 mg, 0.242 mmol), ethyl acetate (1 ml) and 4N hydrogen chloride-ethyl acetate solution (2 ml) was stirred at room temperature for 1 hr, and the solvent was evaporated under reduced pressure. The residue was recrystallized from a mixed solvent of methanol and ether to give the desired product (29.5 mg, 54.0%) as a solid.
Reaction SMILES: [P:1]([O:13][CH2:14][CH2:15][N:16]([CH2:18][CH2:19][C@@H:20]([NH:29][C:30]1[CH:35]=[CH:34][C:33]([S:36](=[O:68])(=[O:67])[NH:37][C:38](=[O:66])[C:39]2[CH:44]=[CH:43][C:42]([N:45]3[CH2:50][CH2:49][CH:48]([C@H:51]([C:53]4[CH:58]=[CH:57][CH:56]=[CH:55][C:54]=4[C:59]4[CH:64]=[CH:63][C:62]([Cl:65])=[CH:61][CH:60]=4)[OH:52])[CH2:47][CH2:46]3)=[CH:41][CH:40]=2)=[CH:32][C:31]=1[S:69]([C:72]([F:75])([F:74])[F:73])(=[O:71])=[O:70])[CH2:21][S:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[CH3:17])([O:8]C(C)(C)C)([O:3]C(C)(C)C)=[O:2].Cl>C(Cl)Cl.CO>[ClH:65].[P:1]([OH:8])([OH:3])([O:13][CH2:14][CH2:15][N:16]([CH2:18][CH2:19][C@@H:20]([NH:29][C:30]1[CH:35]=[CH:34][C:33]([S:36](=[O:68])(=[O:67])[NH:37][C:38](=[O:66])[C:39]2[CH:40]=[CH:41][C:42]([N:45]3[CH2:50][CH2:49][CH:48]([C@H:51]([C:53]4[CH:58]=[CH:57][CH:56]=[CH:55][C:54]=4[C:59]4[CH:60]=[CH:61][C:62]([Cl:65])=[CH:63][CH:64]=4)[OH:52])[CH2:47][CH2:46]3)=[CH:43][CH:44]=2)=[CH:32][C:31]=1[S:69]([C:72]([F:73])([F:75])[F:74])(=[O:70])=[O:71])[CH2:21][S:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[CH3:17])=[O:2]
Reactant: CN(CCOP(=O)(OC(C)(C)C)OC(C)(C)C)CC[C@H](CSc1ccccc1)Nc1ccc(S(=O)(=O)NC(=O)c2ccc(N3CCC([C@@H](O)c4ccccc4-c4ccc(Cl)cc4)CC3)cc2)cc1S(=O)(=O)C(F)(F)F
Agent: Cl
Solvent: CO
Solvent: ClCCl
Product: CN(CCOP(=O)(O)O)CC[C@H](CSc1ccccc1)Nc1ccc(S(=O)(=O)NC(=O)c2ccc(N3CCC([C@@H](O)c4ccccc4-c4ccc(Cl)cc4)CC3)cc2)cc1S(=O)(=O)C(F)(F)F
Yield: 173.8 %

Procedure:
A solution of di-tert-butyl 2-(((R)-3-(4-(N-(4-(4-((R)-(4′-chlorobiphenyl-2-yl)(hydroxy)methyl)piperidin-1-yl)benzoyl)sulfamoyl)-2-(trifluoromethylsulfonyl)phenylamino)-4-(phenylthio)butyl)(methyl)amino)ethyl phosphate (INTERMEDIATE 56, 140 mg, 0.13 mmol) in DCM (3 ml) was treated with a solution of HCl (4M in dioxane, 0.6 ml). When the addition was completed, a white precipitate was observed. The mixture was diluted with MeOH after an hour and the volatiles were evaporated under reduced pressure to give a gummy residue. The material was dissolved in MeOH, and diluted with ˜20 ml DCM, resulting in a white precipitate. The mixture was concentrated under reduced pressure to provide a white solid. The material was triturated in 10-15 ml CH2Cl2, and dried under high vacuum to provide the title compound (120 mg, yield: 95%).
Reaction SMILES: [CH3:1][C:2]1[C:10]2[N:9]=[C:8]([CH2:11][CH2:12][CH3:13])[N:7]([CH2:14][C:15]3[CH:32]=[CH:31][C:18]4/[C:19](=[CH:28]/[C:29]#[N:30])/[C:20]5[CH:27]=[CH:26][CH:25]=[CH:24][C:21]=5[CH2:22][CH2:23][C:17]=4[CH:16]=3)[C:6]=2[CH:5]=[C:4]([C:33]([NH:35][NH2:36])=[O:34])[CH:3]=1.[CH:37](OCC)(OCC)OCC.O.N>C(O)(=O)C>[CH3:1][C:2]1[C:10]2[N:9]=[C:8]([CH2:11][CH2:12][CH3:13])[N:7]([CH2:14][C:15]3[CH:32]=[CH:31][C:18]4/[C:19](=[CH:28]/[C:29]#[N:30])/[C:20]5[CH:27]=[CH:26][CH:25]=[CH:24][C:21]=5[CH2:22][CH2:23][C:17]=4[CH:16]=3)[C:6]=2[CH:5]=[C:4]([C:33]2[O:34][CH:37]=[N:36][N:35]=2)[CH:3]=1
Reactant: CCCc1nc2c(C)cc(C(=O)NN)cc2n1Cc1ccc2c(c1)CCc1ccccc1/C2=C\C#N
Reactant: CCOC(OCC)OCC
Agent: N
Solvent: O
Solvent: CC(=O)O
Product: CCCc1nc2c(C)cc(-c3nnco3)cc2n1Cc1ccc2c(c1)CCc1ccccc1/C2=C\C#N
Temperature: 50 °C
Reaction time: 6 h
Yield: 58 %

Procedure:
[step 2] (E)-{2-[4-Methyl-6-(hydrazinocarbonyl)-2-propylbenzimidazol-1-yl]methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5-ylidene}acetonitrile (40 mg, 0.08 mmol) obtained in step 1 was suspended in acetic acid (3 mL), triethyl orthoformate (3 mL) was added, and the mixture was stirred at 50° C. for 6 hr. Water (10 mL) was added to the mixture, and the mixture was neutralized to pH 9 with 30% aqueous ammonia solution, and extracted twice with chloroform. The organic layer was washed with brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform:methanol=9:1) to give (E)-{2-[4-methyl-6-(1,3,4-oxadiazol-2-yl)-2-propylbenzimidazol-1-yl]methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5-ylidene}acetonitrile (24 mg, 58%).
Reaction SMILES: C1(C)C=CC(S(O)(=O)=O)=CC=1.C1CO[C:14]2([CH:19]=[CH:18][C@H:17]3[C@H:20]4[C@H:30]([C@@H:31]([OH:33])[CH2:32][C@:15]23[CH3:16])[C@:28]2([CH3:29])[C:23]([CH2:24][C@@H:25]([OH:34])[CH2:26][CH2:27]2)=[CH:22][CH2:21]4)[O:13]1>O.CC(C)=O>[OH:34][C@H:25]1[CH2:26][CH2:27][C@@:28]2([CH3:29])[C:23](=[CH:22][CH2:21][C@@H:20]3[C@@H:30]2[C@@H:31]([OH:33])[CH2:32][C@@:15]2([CH3:16])[C@H:17]3[CH:18]=[CH:19][C:14]2=[O:13])[CH2:24]1
Reactant: C[C@]12CC[C@H](O)CC1=CC[C@@H]1[C@@H]2[C@@H](O)C[C@@]2(C)[C@H]1C=CC21OCCO1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CC(C)=O
Product: C[C@]12CC[C@H](O)CC1=CC[C@@H]1[C@@H]2[C@@H](O)C[C@]2(C)C(=O)C=C[C@@H]12
Temperature: 25 °C
Reaction time: 6 h

Procedure:
4 ml of a solution of 100 mg of p-toluenesulphonic acid in 10 ml of water are added to a solution of 800 mg of 17,17-ethylenedioxyandrosta-5,15-diene-3β,11β-diol in 40 ml of acetone and the whole is stirred for 6 hours at room temperature. After dilution with 40 ml of water, the acetone is distilled off under a water-jet vacuum and the oily residue is taken up in chloroform and washed with ice-cold saturated sodium bicarbonate solution. Evaporation of the organic solvent yields amorphous 3β,11β-dihydroxyandrosta-5,15-dien-17-one which can be used for the next step without further purification.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH2:10][CH:11]2[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]2)=[CH:2]1.Cl[CH2:18][CH2:19][N:20]1[C:24]2[CH:25]=[CH:26][CH:27]=[C:28]3[CH:29]=[CH:30][CH:31]=[C:22]([C:23]=23)[S:21]1(=[O:33])=[O:32].C(=O)([O-])O.[Na+]>CN(C)C=O>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH2:10][CH:11]2[CH2:16][CH2:15][N:14]([CH2:18][CH2:19][N:20]3[C:24]4[CH:25]=[CH:26][CH:27]=[C:28]5[CH:29]=[CH:30][CH:31]=[C:22]([C:23]=45)[S:21]3(=[O:33])=[O:32])[CH2:13][CH2:12]2)=[CH:2]1
Reactant: c1ccc2c(CC3CCNCC3)c[nH]c2c1
Reactant: O=S1(=O)c2cccc3cccc(c23)N1CCCl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=S1(=O)c2cccc3cccc(c23)N1CCN1CCC(Cc2c[nH]c3ccccc23)CC1
Yield: 48.1 %

Procedure:
A mixture of 4-(3-indolylmethyl)piperidine (0.4 g), 2-(2-chloroethyl)naphtho[1,8-cd]isothiazole 1,1-dioxide (0.53 g), sodium hydrogen carbonate (0.17 g) and dimethylformamide (10 cc) is brought to reflux for 12 hours. After evaporation to dryness at 80° C. under reduced pressure (20 mm Hg; 2.7 kPa), the residue is taken up with water (30 cc) and extracted with ethyl acetate (2×50 cc). The combined organic phases are dried over magnesium sulphate and taken to dryness at 80° C. under reduced pressure (20 mm Hg; 2.7 kPa). The residue is purified by flash chromatography on a silica column under a stream of nitrogen at moderate pressure (0.5-1.5 bar) with a dichloromethane/methanol mixture (99:1 by volume) as eluent. 2-{2-[4-(3-Indolylmethyl)piperidino]ethyl}naphtho[1,8-cd]isothiazole 1,1-dioxide (0.4 g), m.p. 184° C., is obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:28]=[CH:29][CH:30]=1)[CH2:5][NH:6][C:7]([C:9]1[N:10]([CH2:25][CH2:26]O)[CH:11]=[C:12]([Br:24])[C:13](=[O:23])[C:14]=1[O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:8].C(N(CC)C(C)C)(C)C.CS(Cl)(=O)=O.Cl>O1CCCC1>[CH2:16]([O:15][C:14]1[C:13](=[O:23])[C:12]([Br:24])=[CH:11][N:10]2[CH2:25][CH2:26][N:6]([CH2:5][C:4]3[CH:28]=[CH:29][CH:30]=[C:2]([Cl:1])[CH:3]=3)[C:7](=[O:8])[C:9]=12)[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: O=C(NCc1cccc(Cl)c1)c1c(OCc2ccccc2)c(=O)c(Br)cn1CCO
Agent: CS(=O)(=O)Cl
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: O=C1c2c(OCc3ccccc3)c(=O)c(Br)cn2CCN1Cc1cccc(Cl)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 93.7 %

Procedure:
3-Benzyloxy-5-bromo-1-(2-hydroxyethyl)-4-oxo-1,4-dihydropyridine-2-carboxylic acid 3-chlorobenzylamide (1.75 g) was suspended in tetrahydrofuran (50 ml), and N,N-diisopropylethylamine (3.72 ml) and methanesulfonyl chloride (1.38 ml) were added. After stirring at room temperature for 1 hr, 0.5N aqueous hydrochloric acid (40 ml) was added, and the mixture was extracted twice with ethyl acetate (100 ml each). The ethyl acetate layer was washed with aqueous sodium hydrogen carbonate, dried and concentrated. The obtained residue was dissolved in dimethylformamide (50 ml) and 60% sodium hydride was added by small portions with stirring at room temperature. After confirming the completion of the reaction by thin layer chromatography (TLC), the reaction mixture was ice-cooled, 0.33N aqueous hydrochloric acid (300 ml) was added, and the mixture was extracted twice with ethyl acetate (250 ml each). The ethyl acetate layer was washed with water, dried, concentrated, and crystallized from ethyl acetate-hexane to give 9-benzyloxy-7-bromo-2-(3-chlorobenzyl)-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,8-dione (1.58 g).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:9]([OH:11])=[O:10])=[N:6][C:7]=1Cl.[CH3:12][C:13]1([CH2:17][OH:18])[CH2:16][O:15][CH2:14]1.[H-].[Na+].Cl>CN(C=O)C.C(OCC)(=O)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:9]([OH:11])=[O:10])=[N:6][C:7]=1[O:18][CH2:17][C:13]1([CH3:12])[CH2:16][O:15][CH2:14]1
Reactant: O=C(O)c1ccc(Br)c(Cl)n1
Reactant: CC1(CO)COC1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC1(COc2nc(C(=O)O)ccc2Br)COC1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 27.1 %

Procedure:
To a solution of 5-bromo-6-chloropicolinic acid (Example 280a) (0.75 g, 3.17 mmol) in dry DMF (18 ml) under argon was added (3-methyloxetan-3-yl)-methanol (389 mg, 3.81 mmol) and NaH (279 mg, 6.98 mmol) was added by portions. The reaction mixture was stirred at room temperature for 20 min until gas release ceased. The reaction mixture was then stirred at 110° C. for 16 h. The reaction mixture was diluted with ethyl acetate, and the solution was poured into a separatory funnel with 10 ml aq. solution 1.0M HCl. After extraction, the organic phase was collected and the aqueous phase was back extracted with ethylacetate. The organic phases were combined, dried over Na2SO4 and evaporated down in vacuo. The residue was purified by preparative HPLC to give the title compound (260 mg, 27%), MS (EI): m/e=302.0 [M+H]+.
Reaction SMILES: [O:1]=[C:2]1[CH2:5][CH:4]([C:6]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[O:7])[CH2:3]1.[CH3:16][Mg]Br.[NH4+].[Cl-]>C1COCC1>[OH:1][C:2]1([CH3:16])[CH2:5][CH:4]([C:6]([O:8][CH2:9][C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)=[O:7])[CH2:3]1
Reactant: C[Mg]Br
Reactant: O=C1CC(C(=O)OCc2ccccc2)C1
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CC1(O)CC(C(=O)OCc2ccccc2)C1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 46.9 %

Procedure:
A −78° C. solution of benzyl 3-oxocyclobutanecarboxylate (11.05 g, 54.1 mmol) in THF (155 mL) was treated drop-wise with methyl magnesium bromide (3M in Et2O, 27.1 mL, 81 mmol) and the mixture stirred at −78° C. for 30 min. Saturated NH4Cl was added, the mixture extracted with EtOAc (2×) and the combined organic extracts were dried, evaporated and purified via silica gel chromatography (acetone/Hex) to afford benzyl 3-hydroxy-3-methylcyclobutanecarboxylate (5.589 g, 47%) as a colorless oil. 1H NMR (400 MHz, DMSO-d6): δ 7.36-7.29 (m, 5H); 5.08 (m, 3H); 2.75-2.66 (m, 1H); 2.13-2.12 (m, 4H); 1.21 (s, 3H); MS (ESI) m/z: 243.1 (M+Na+).
Reaction SMILES: [CH3:1][CH2:2][C:3]1[CH2:22][N:20]2[CH2:21][C@@H:5]([CH2:6][C@:7]([C:56]([O:58][CH3:59])=[O:57])([C:23]3[CH:24]=[C:25]4[C@:33]56[C@@H:37]7[C@:38]([CH2:53][CH3:54])([C@@H:42]([O:49][C:50]([CH3:52])=[O:51])[C@:43]([OH:48])([C:44]([O:46][CH3:47])=[O:45])[C@@H:32]5[N:31]([CH3:55])[C:26]4=[CH:27][C:28]=3[O:29][CH3:30])[CH:39]=[CH:40][CH2:41][N:36]7[CH2:35][CH2:34]6)[C:8]3[NH:16][C:15]4[CH:14]=[CH:13][C:12]([Br:17])=[CH:11][C:10]=4[C:9]=3[CH2:18][CH2:19]2)[CH:4]=1.Cl.C(C[OH:66])(F)(F)F.[BH4-].[Na+]>O.O.O.O.O.O.O.C([O-])(=O)C([O-])=O.[Fe+3].C([O-])(=O)C([O-])=O.C([O-])(=O)C([O-])=O.[Fe+3].CCOC(C)=O.CO.CCN(CC)CC>[CH3:1][CH2:2][C@@:3]1([OH:66])[CH2:22][N:20]2[CH2:21][C@@H:5]([CH2:6][C@:7]([C:56]([O:58][CH3:59])=[O:57])([C:23]3[CH:24]=[C:25]4[C@:33]56[C@@H:37]7[C@:38]([CH2:53][CH3:54])([C@@H:42]([O:49][C:50]([CH3:52])=[O:51])[C@:43]([OH:48])([C:44]([O:46][CH3:47])=[O:45])[C@@H:32]5[N:31]([CH3:55])[C:26]4=[CH:27][C:28]=3[O:29][CH3:30])[CH:39]=[CH:40][CH2:41][N:36]7[CH2:35][CH2:34]6)[C:8]3[NH:16][C:15]4[CH:14]=[CH:13][C:12]([Br:17])=[CH:11][C:10]=4[C:9]=3[CH2:18][CH2:19]2)[CH2:4]1
Reactant: CCC1=C[C@H]2CN(CCc3c([nH]c4ccc(Br)cc34)[C@@](C(=O)OC)(c3cc4c(cc3OC)N(C)[C@H]3[C@@](O)(C(=O)OC)[C@H](OC(C)=O)[C@]5(CC)C=CCN6CC[C@]43[C@@H]65)C2)C1
Reactant: OCC(F)(F)F
Agent: [Fe+3]
Agent: Cl
Agent: O=C([O-])C(=O)[O-]
Solvent: O
Solvent: CO
Solvent: CCN(CC)CC
Product: CC[C@]1(O)C[C@H]2CN(CCc3c([nH]c4ccc(Br)cc34)[C@@](C(=O)OC)(c3cc4c(cc3OC)N(C)[C@H]3[C@@](O)(C(=O)OC)[C@H](OC(C)=O)[C@]5(CC)C=CCN6CC[C@]43[C@@H]65)C2)C1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 22 %

Procedure:
A mixture of iron(III) oxalate hexahydrate (148.2 mg, 0.31 mmol, 30 equiv) in H2O (41 mL) was cooled to 0° C. and air was bubbled through the mixture for 10 minutes. A solution of 10′-bromoanhydro-vinblastine (17a, 8.9 mg, 0.010 mmol, 1 equiv) in H2O (0.5 mL), aqueous 0.1 N HCl (0.5 mL), and CF3CH2OH (0.1 mL) was transferred by pipette to the mixture and NaBH4 (7.7 mg, 0.20 mmol, 20 equiv) in H2O (1 mL) was added to the mixture at 0° C. The resulting mixture was stirred for 30 minutes before being quenched by addition of 28-30% aqueous NH4OH (10 mL). The mixture was extracted with 10% MeOH in CH2Cl2 and the organic layer was dried over Na2SO4 and concentrated under reduced pressure. PTLC (SiO2, Et3N:MeOH:EtOAc=3:3:97) provided 10′-bromo-vinblastine (17b, 2.0 mg, 0.0022 mmol, 22%) and 10′-bromoleurosidine (1.3 mg, 0.0015 mmol, 14%).
Reaction SMILES: [C:1](Cl)(=[O:40])[O:2][C@@:3]([CH3:39])([C:6](=[O:38])[C@@H:7]([NH:15][C:16](=[O:37])[C@@H:17]([NH:21][C:22](=[O:36])[C@@H:23]([NH:27][C:28]([C:30]1[S:34][C:33]([CH3:35])=[N:32][CH:31]=1)=[O:29])[CH2:24][O:25][CH3:26])[CH2:18][O:19][CH3:20])[CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[CH2:4][I:5].[CH2:42]([OH:44])[CH3:43]>>[C:1](=[O:40])([O:2][C@@:3]([CH3:39])([C:6](=[O:38])[C@@H:7]([NH:15][C:16](=[O:37])[C@@H:17]([NH:21][C:22](=[O:36])[C@@H:23]([NH:27][C:28]([C:30]1[S:34][C:33]([CH3:35])=[N:32][CH:31]=1)=[O:29])[CH2:24][O:25][CH3:26])[CH2:18][O:19][CH3:20])[CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[CH2:4][I:5])[O:44][CH2:42][CH3:43]
Reactant: COC[C@H](NC(=O)c1cnc(C)s1)C(=O)N[C@@H](COC)C(=O)N[C@@H](Cc1ccccc1)C(=O)[C@@](C)(CI)OC(=O)Cl
Reactant: CCO
Product: CCOC(=O)O[C@](C)(CI)C(=O)[C@H](Cc1ccccc1)NC(=O)[C@H](COC)NC(=O)[C@H](COC)NC(=O)c1cnc(C)s1

Procedure:
Prepared according to procedures described above, by reacting ethanol with the intermediate (2S,4S)-1-iodo-4-((S)-3-methoxy-2-((S)-3-methoxy-2-(2-methylthiazole-5-carboxamido)propanamido)propanamido)-2-methyl-3-oxo-5-phenylpentan-2-yl carbonochloridate. 1H NMR (CDCl3): δ 8.05 (s, 1H), 7.28-7.16 (m, 5H), 7.08 (d, J=9.2 Hz, 1H), 6.96 (d, J=7.2 Hz, 1H), 6.84 (d, J=6 Hz, 1H), 5.44-5.40 (m, 1H). 4.71-4.66 (m, 1H), 4.48-4.44 (m, 1H), 4.21 (q, J=7.2 Hz, 2H), 3.84-3.79 (m, 2H). 3.75-3.72 (m, 1H), 3.62 (d, J=11.2 Hz, 1H), 3.55 (t, J=4.8 Hz, 1H), 3.45 (s, 3H), 3.41-3.38 (m, 1H), 3.28 (s, 3H), 3.19-3.14 (m, 1H), 2.89-2.83 (m, 1H), 2.74 (s, 3H), 1.51 (s, 3H), 1.35 (t, J=7.2 Hz, 3H); MS for C28H37IN4O9S m/z: 733 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[CH3:10])[CH:5]=[O:6].[CH3:11][Mg]Br.Cl>C1COCC1>[OH:6][CH:5]([C:4]1[CH:7]=[CH:8][C:9]([CH3:10])=[C:2]([F:1])[CH:3]=1)[CH3:11]
Reactant: Cc1ccc(C=O)cc1F
Reactant: C[Mg]Br
Agent: Cl
Solvent: C1CCOC1
Product: Cc1ccc(C(C)O)cc1F
Temperature: 0 °C
Reaction time: 1 h
Yield: 100.5 %

Procedure:
To an ice-cold solution of 3-fluoro-4-methylbenzaldehyde (50 mg, 0.36 mmol) in THF (0.5 mL) was added dropwise a 0.93 M solution (0.47 mL) of methylmagnesium bromide (0.44 mmol) in THF. The temperature of the reaction mixture was allowed to rise back to room temperature, at which the reaction mixture was stirred for 1 hour. Then, 2 mol/L hydrochloric acid was added, and the mixture was extracted with ethyl acetate. The extract was washed with brine and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to yield title compound as a pale yellow oil (55.8 mg, quantitative).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C@@H:10]2[CH2:12][C@H:11]2[C:13]([OH:15])=O)=[CH:6][CH:5]=1)([O-:3])=[O:2].O1CCCC1.ClC(OCC)=O.[CH3:27][CH:28]([NH2:38])[CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37]>C(Cl)(Cl)Cl.C(N(CC)CC)C>[CH3:27][CH:28]([NH:38][C:13]([C@@H:11]1[CH2:12][C@H:10]1[C:7]1[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:9][CH:8]=1)=[O:15])[CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37]
Reactant: CCCCCCCCCC(C)N
Reactant: O=C(O)[C@@H]1C[C@H]1c1ccc([N+](=O)[O-])cc1
Agent: CCOC(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CCCCCCCCCC(C)NC(=O)[C@@H]1C[C@H]1c1ccc([N+](=O)[O-])cc1
Temperature: 5 °C
Reaction time: 0.25 h

Procedure:
To a stirred slurry of 2.1 g. of trans-2-(4-nitrophenyl)cyclopropanecarboxylic acid in 30 ml. of tetrahydrofuran was added 1.1 g. of triethylamine. The clear solution thus obtained was cooled to ca. 5° C., and a solution of 1.2 g. of ethyl chloroformate in 5 ml. of chloroform was added dropwise, with stirring, during 15 minutes. Stirring was continued for 20 minutes, and then a solution of 1.9 g. of 1-methyldecylamine in 5 ml. of chloroform was added dropwise during 15 minutes. The cooling bath was removed, and stirring was continued for 1 hour. At this point the solvent was removed in vacuo and the residue was triturated with ether. The solid which remained out of solution was removed by filtration and discarded. The ether was evaporated in vacuo, and the residue was recrystallized from a 1:1 mixture of isopropanol and petroleum ether. This afforded 2.9 g. of the title compound as a waxy solid.
Reaction SMILES: [C:1]1([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:6]=[CH:5][C:4]([N:7]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:9]([CH:16]=[O:17])=[C:8]2[Cl:18])=[CH:3][CH:2]=1.[NH:25]1[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]1.Cl>>[ClH:18].[C:1]1([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:6]=[CH:5][C:4]([N:7]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:9]([CH:16]=[O:17])=[C:8]2[N:25]2[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]2)=[CH:3][CH:2]=1
Reactant: C1CNCCN1
Reactant: O=Cc1c(Cl)n(-c2ccc(-c3ccccc3)cc2)c2ccccc12
Agent: Cl
Product: O=Cc1c(N2CCNCC2)n(-c2ccc(-c3ccccc3)cc2)c2ccccc12
Yield: 44 %

Procedure:
1-(Biphenyl-4-yl)-2-chloro-1H-indole-3-carboxaldehyde is reacted with piperazine as described in Step 2 of Example 29 and subsequently treated with hydrochloric acid as described in Example 44 to afford 1-(biphenyl-4-yl)-2-(piperazin-1-yl)-1H-indole-3-carboxaldehyde hydrochloride (44% yield) as a cream solid. ESI/MS 382 (M+H), RT=2.87 min.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][CH:10]2[CH2:15][CH2:14][N:13]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:12][CH2:11]2)=[CH:5][CH:4]=1.Cl[CH2:24][C:25]1[CH:30]=[CH:29][N:28]=[C:27]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=2[O:37][CH3:38])[CH:26]=1>>[C:19]([O:18][C:16]([N:13]1[CH2:14][CH2:15][CH:10]([N:9]([C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=2)[CH2:24][C:25]2[CH:30]=[CH:29][N:28]=[C:27]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=3[O:37][CH3:38])[CH:26]=2)[CH2:11][CH2:12]1)=[O:17])([CH3:22])([CH3:21])[CH3:20]
Reactant: COc1ccc(NC2CCN(C(=O)OC(C)(C)C)CC2)cc1
Reactant: COc1ccccc1-c1cc(CCl)ccn1
Product: COc1ccc(N(Cc2ccnc(-c3ccccc3OC)c2)C2CCN(C(=O)OC(C)(C)C)CC2)cc1

Procedure:
4-(p-Anisidino)-1-(tert-butoxycarbonyl)piperidine (306 mg) and 4-chloromethyl-2-(2-methoxyphenyl)pyridine (234 mg) were condensed in the same manner as described in Example 9 to give the title compound.