Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O[C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[I:11])[C:5]([OH:7])=[O:6].[C:12](=O)([O-])[O-].[K+].[K+].S([O:23][CH3:24])(OC)(=O)=O>CC(C)=O>[I:11][C:10]1[CH:9]=[CH:8][C:4]([C:5]([O:7][CH3:12])=[O:6])=[CH:3][C:2]=1[O:23][CH3:24]
Reactant: O=C(O)c1ccc(I)c(O)c1
Reactant: O=C([O-])[O-]
Reactant: COS(=O)(=O)OC
Agent: [K+]
Solvent: CC(C)=O
Product: COC(=O)c1ccc(I)c(OC)c1

Procedure:
To a solution of 3-hydroxy-4-iodobenzoic acid (3.0 g, 0.011 mol) in acetone (50 mL) was added in one portion potassium carbonate (3.9 g, 0.028 mol). Dimethyl sulfate (3.5 g, 0.028 mol) was added dropwise and the mixture was heated at reflux overnight. The mixture was concentrated in vacuo and the residue was partitioned between ethyl acetate and aqueous saturated sodium bicarbonate solution. The organic phase was washed with brine, dried over sodium sulfated and concentrated in vacuo to give methyl 4-iodo-3-(methyloxy)benzoate as a yellow oil. 1H NMR (DMSO-d6) δ ppm 3.83 (s, 3H, Me), 3.87 (s, 3H, Me), 7.30 (dd, J=8.0, 1.8 Hz, 1H, Ar), 7.40 (d, J=1.7 Hz, 1H, Ar), 7.92 (d, J=8.0 Hz, 1H, Ar).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][C:9]1([CH:15]([CH2:17][CH3:18])C)[CH2:13][OH:14])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:19](Cl)Cl>>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][C:9]1([CH2:15][CH2:17][CH2:18][CH3:19])[CH:13]=[O:14])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CCC(C)C1(CO)CCCN1C(=O)OC(C)(C)C
Reactant: ClCCl
Product: CCCCC1(C=O)CCCN1C(=O)OC(C)(C)C
Temperature: 25 °C
Yield: 48 %

Procedure:
To a stirred solution of 2-2-butyl-2-hydroxymethyl-pyrrolidine-1-carboxylic acid tert-butyl ester (0.763 g, ca. 2.95 mmol) in DCM (30 mL) at 0° C. under nitrogen was added DMP (2.50 g, 5.90 mmol) in a single portion then the reaction mixture was warmed to ambient temperature. After 14 h the reaction mixture was diluted with DCM (70 mL), washed with 1 N NaOH (2×30 mL) and brine (30 mL) then dried (MgSO4), filtered and concentrated in vacuo. Purification by chromatography (silica, 10-20% EtOAc in hexanes) gave 2-butyl-2-formyl-pyrrolidine-1-carboxylic acid tert-butyl ester (0.359 g, 1.41 mmol, 48%) as a pale yellow oil.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][NH2:5].C(N(CC)CC)C.[Cl:13][C:14]1[N:19]=[C:18]([N:20]2[CH2:29][CH2:28][C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[CH2:21]2)[C:17]([CH3:30])=[C:16]([CH3:31])[N:15]=1>CN(C)C=O>[ClH:13].[CH3:30][C:17]1[C:18]([N:20]2[CH2:29][CH2:28][C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[CH2:21]2)=[N:19][C:14]([NH:5][CH2:4][CH2:3][O:2][CH3:1])=[N:15][C:16]=1[CH3:31]
Reactant: COCCN
Reactant: Cc1nc(Cl)nc(N2CCc3ccccc3C2)c1C
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COCCNc1nc(C)c(C)c(N2CCc3ccccc3C2)n1
Product: Cl
Yield: 74.8 %

Procedure:
After methoxyethylamine(0.23 ml, 2.7 mmol) and triethylamine(0.38 ml, 2.7 mmol) were added to a solution of 2-chloro-5,6-dimethyl-4-(1,2,3,4-tetrahydroisoquinolin-2-yl)pyrimidine (0.5 g, 1.8 mmol) in dimethylformamide, 470 mg of the titled compound was obtained in accordance with the same procedure as in Example 1.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]([CH2:12][CH2:13][CH3:14])CO)=[O:7])([CH3:4])([CH3:3])[CH3:2].Br[C:16]([Br:19])(Br)Br.[C:20]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C(Cl)Cl>[C:1]([O:5][C:6]([NH:8][CH:9]([CH2:12][CH:13]([CH3:14])[CH3:20])[CH2:16][Br:19])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Reactant: CCCC(CO)NC(=O)OC(C)(C)C
Reactant: BrC(Br)(Br)Br
Solvent: ClCCl
Product: CC(C)CC(CBr)NC(=O)OC(C)(C)C
Yield: 68.3 %

Procedure:
A stirred solution of N-tert-butoxycarbonyl-2-aminopentan-1-ol (2.0 g, 9.2 mmol) in dry DCM (30 ml) at 0° C. was treated with tetrabromomethane (6.1 g, 18.4 mmol) followed by triphenylphosphine (4.84 g, 18.4 mmol). The clear reaction mixture immediately changed to yellow. After 30 min. the solvent was removed under reduced pressure and the residue was purified by column chromatography (flash silica gel; 0-40% ethyl acetate in hexane) to give N-tert-butoxycarbonyl-1-bromo-2-amino-4-methylpentane (1.76 g, 68%) as a colourless oil.
Reaction SMILES: Cl.[CH3:2][N:3]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:5]([CH2:6][C@@H:7]([C:9]([O:11][CH3:12])=[O:10])[NH2:8])=[CH:4]1.C(N(CC)CC)C.[F:26][C:27]1[CH:37]=[CH:36][CH:35]=[CH:34][C:28]=1[CH:29]=[CH:30][C:31](O)=[O:32].CCN=C=NCCCN(C)C.Cl>C(Cl)Cl>[F:26][C:27]1[CH:37]=[CH:36][CH:35]=[CH:34][C:28]=1[CH:29]=[CH:30][C:31]([NH:8][C@H:7]([C:9]([O:11][CH3:12])=[O:10])[CH2:6][C:5]1[C:13]2[C:18](=[CH:17][CH:16]=[CH:15][CH:14]=2)[N:3]([CH3:2])[CH:4]=1)=[O:32]
Reactant: COC(=O)[C@@H](N)Cc1cn(C)c2ccccc12
Reactant: O=C(O)C=Cc1ccccc1F
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)[C@H](Cc1cn(C)c2ccccc12)NC(=O)C=Cc1ccccc1F
Yield: 54.7 %

Procedure:
The same procedures as in Example 2 were carried out from the compound obtained in Example 20 (4.0 g), triethylamine (2.3 mL), 2-fluorocinnamic acid (2.7 g), WSC.HCl (3.1 g), and methylene chloride (100 mL), to give the captioned compound (3.1 g, 54%) as an oily product.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCOC(/N=N/C(OCC)=O)=O.[OH:32][C:33]1[CH:34]=[C:35]2[C:40](=[CH:41][CH:42]=1)[NH:39][C:38](=[O:43])[CH:37]=[CH:36]2.[Cl:44][C:45]1[CH:50]=[CH:49][C:48]([NH:51][C:52]2[N:57]=[C:56]([CH2:58]O)[CH:55]=[CH:54][N:53]=2)=[CH:47][CH:46]=1>C1COCC1.O>[Cl:44][C:45]1[CH:46]=[CH:47][C:48]([NH:51][C:52]2[N:57]=[C:56]([CH2:58][O:32][C:33]3[CH:34]=[C:35]4[C:40](=[CH:41][CH:42]=3)[NH:39][C:38](=[O:43])[CH:37]=[CH:36]4)[CH:55]=[CH:54][N:53]=2)=[CH:49][CH:50]=1
Reactant: OCc1ccnc(Nc2ccc(Cl)cc2)n1
Reactant: O=c1ccc2cc(O)ccc2[nH]1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: O
Product: O=c1ccc2cc(OCc3ccnc(Nc4ccc(Cl)cc4)n3)ccc2[nH]1
Reaction time: 0.17 h
Yield: 18.7 %

Procedure:
A solution of triphenylphosphine (0.145 g, 0.552 mmol) in THF (2.0 mL) was cooled to 0° C. under N2 and DEAD (0.087 mL, 0.552 mmol) was added dropwise. The mixture was stirred for 10 min, then 6-hydroxyquinolin-2(1H)-one (0.068 g, 0.424 mmol) was added. After stirring for 5 min, a solution of (2-((4-chlorophenyl)amino)pyrimidin-4-yl)methanol (0.1 g, 0.424 mmol) in THF (2.0 mL) was added. The reaction was stirred for 18 h at room temperature. The mixture was diluted with water and filtered. The beige filter cake was stirred in methanol and filtered to give 6-((2-(4-chlorophenylamino)pyrimidin-4-yl)methoxy)quinolin-2(1H)-one as a beige solid (0.03 g, 18%). 1H NMR (400 MHz, DMSO-d6) δ ppm 11.70 (s, 1H), 9.91 (s, 1H), 8.53 (d, J=4.8 Hz, 1H), 7.95-7.72 (m, 3H), 7.44-7.16 (m, 5H), 6.98 (d, J=5.0 Hz, 1H), 6.51 (d, J=9.5 Hz, 1H), 5.16 (s, 2H). LCMS: R.T.=3.74; [M+H]+=379.09.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([N:12]3[C:20]4[C:15](=[CH:16][C:17]([O:21][CH3:22])=[CH:18][CH:19]=4)[C:14]([CH2:23][C:24]([OH:26])=[O:25])=[C:13]3[CH3:27])=[N:7][CH:8]=[N:9]2)=[CH:4][CH:3]=1.B(F)(F)F.[CH3:32]COCC.C([O-])(=O)C.[Na+]>CO>[Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([N:12]3[C:20]4[C:15](=[CH:16][C:17]([O:21][CH3:22])=[CH:18][CH:19]=4)[C:14]([CH2:23][C:24]([O:26][CH3:32])=[O:25])=[C:13]3[CH3:27])=[N:7][CH:8]=[N:9]2)=[CH:4][CH:3]=1
Reactant: COc1ccc2c(c1)c(CC(=O)O)c(C)n2-c1ncnc2cc(Cl)ccc12
Reactant: CCOCC
Agent: CC(=O)[O-]
Agent: FB(F)F
Agent: [Na+]
Solvent: CO
Product: COC(=O)Cc1c(C)n(-c2ncnc3cc(Cl)ccc23)c2ccc(OC)cc12

Procedure:
To a solution of 1-(7-chloroquinazolin-4-yl)-5-methoxy-2-methylindol-3-ylacetic acid (1.0g.) in dry methanol (50ml.) was added freshly distilled boron trifluoride etherate (0.5ml.), and the dark red solution was heated under reflux for 30 mins. To the solution was added saturated sodium acetate solution (5ml.), and the mixture was concentrated in vacuo. The residual mixture was shaken with a mixture of water (50ml.) and chloroform (30ml.). The aqueous layer was separated and extracted with further chloroform (2 × 20 ml.), and the combined extracts were washed successively with saturated sodium hydrogen carbonate solution (2 × 20ml.), water (10ml.) and saturated sodium chloride solution (15ml.). After drying, the extracts were evaporated to give methyl 1(7-chloroquinazolin-4-yl)-5-methoxy-2-methylindol-3-ylacetate, m.p. 111°-113° C.
Reaction SMILES: C(OC([N:11]1[CH2:16][CH2:15][CH:14](N2CCOC2=O)[CH2:13][CH2:12]1)=O)C1C=CC=CC=1.NO.[C:25](N1C=CN=C1)([N:27]1[CH:31]=[CH:30]N=C1)=[O:26]>C(Cl)(Cl)Cl.ClCCl>[O:26]1[CH2:30][CH2:31][N:27]([N:11]2[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16]2)[CH2:25]1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: O=C(OCc1ccccc1)N1CCC(N2CCOC2=O)CC1
Agent: NO
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Product: C1CCN(N2CCOC2)CC1

Procedure:
1-Benzyloxycarbonyl-4-(2-oxo-1,3-oxazolidin-3-yl)piperidine. A solution of the amino alcohol (1.7 g) and 1,1′-carbonyldiimidazole (2.4 g) in chloroform (30 mL) was heated at reflux for 6 hours. The reaction mixture was diluted with dichloromethane and washed with 1 N sodium hydroxide and water. The separated organic phase was dried and evaporated to give the oxazolidin-3-yl piperidine as a viscous oil (1.9 g); NMR: 7.35 (m,5), 5.13 (s,2), 4.34 (m,4), 3.89 (m,1), 3.49 (m,2), 2.86 (m,2), 1.78 (m,2), 1.58 (m,2); MS: m/z=305(M+1).
Reaction SMILES: [CH:1]1([CH2:4][CH2:5][N:6]2[CH:11]=[CH:10][C:9](O)=[C:8]([C:13]#[N:14])[C:7]2=[O:15])[CH2:3][CH2:2]1.O(Br)[Br:17].[P+3]>CN(C=O)C>[Br:17][C:9]1[CH:10]=[CH:11][N:6]([CH2:5][CH2:4][CH:1]2[CH2:3][CH2:2]2)[C:7](=[O:15])[C:8]=1[C:13]#[N:14]
Reactant: N#Cc1c(O)ccn(CCC2CC2)c1=O
Reactant: BrOBr
Agent: [P+3]
Solvent: CN(C)C=O
Product: N#Cc1c(Br)ccn(CCC2CC2)c1=O
Temperature: 110 °C
Yield: 89.2 %

Procedure:
To a solution of intermediate 6 (6.0 g, 29.37 mmol) in DMF (150 ml) was added phosphorus(III) oxybromide (16.84 g, 58.75 mmol) and the mixture was heated at 110° C. for 3 hours. After cooling in an ice bath the solution was partitioned between water and EtOAc. After three extractions with EtOAc the combined organic fractions were washed with brine, dried over Na2SO4 and the solvent evaporated in vacuo. The crude product was purified by column chromatography (silica gel; DCM as eluent). The desired fractions were collected and evaporated in vacuo to yield intermediate 9 (7.0 g, 89%).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([N:8]2[CH2:12][CH2:11][CH2:10][C:9]2=[O:13])[CH:5]=[CH:6][CH:7]=1.[CH3:14][C:15]([CH3:31])([O:17][C:18](=[O:30])[NH:19][C:20](=S)[NH:21][C:22](=[O:28])[O:23][C:24]([CH3:27])([CH3:26])[CH3:25])[CH3:16]>C(Cl)Cl>[C:24]([O:23][C:22]([NH:21]/[C:20](=[N:19]/[C:18](=[O:30])[O:17][C:15]([CH3:31])([CH3:16])[CH3:14])/[NH:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([N:8]2[CH2:12][CH2:11][CH2:10][C:9]2=[O:13])[CH:3]=1)=[O:28])([CH3:27])([CH3:26])[CH3:25]
Reactant: Nc1cccc(N2CCCC2=O)c1
Reactant: CC(C)(C)OC(=O)NC(=S)NC(=O)OC(C)(C)C
Solvent: ClCCl
Product: CC(C)(C)OC(=O)/N=C(/NC(=O)OC(C)(C)C)Nc1cccc(N2CCCC2=O)c1
Temperature: 25 °C
Reaction time: 14 h

Procedure:
In a 500 mL round bottom flask was charged 1-(3-aminophenyl)pyrrolidin-2-one (5 g, 28.4 mmol), 2,2,10,10-tetramethyl-6-thioxo-3,9-dioxa-5,7-diazaundecane-4,8-dione (9.80 g, 35.5 mmol), polystyrene-carbodiimide (Argonaut P/N 800371, 1.42 mmole/g, 30.0 g, 42.6 mmol) and CH2Cl2 (300 mL). The resulting suspension was stirred at room temperature for 14 hours. The reaction was filtered and the collected solid was washed with 2×30 mL CH2Cl2. The filtrate was concentrated. The concentrate was purified by flash chromatography on a 140 g silica gel plug eluting with CH2Cl2 then 1:1 ethyl acetate/hexanes to provide the title compound. MS (ESI+) m/e 419.1 (M+H)+.
Reaction SMILES: C[O:2][C:3](=O)[CH2:4][C:5]([CH3:7])=[O:6].[H-].[Na+].[Li]CCCC.[CH3:16][O:17][C:18]1[CH:23]=[C:22]([O:24][CH3:25])[CH:21]=[CH:20][C:19]=1[CH2:26][CH2:27][C:28]([CH:30]1[CH2:34][CH2:33][CH2:32][CH2:31]1)=[O:29]>C1COCC1>[CH3:16][O:17][C:18]1[CH:23]=[C:22]([O:24][CH3:25])[CH:21]=[CH:20][C:19]=1[CH2:26][CH2:27][C:28]1([CH:30]2[CH2:31][CH2:32][CH2:33][CH2:34]2)[O:29][C:3](=[O:2])[CH2:4][C:5](=[O:6])[CH2:7]1
Reactant: COC(=O)CC(C)=O
Reactant: COc1ccc(CCC(=O)C2CCCC2)c(OC)c1
Agent: [H-]
Agent: [Li]CCCC
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1ccc(CCC2(C3CCCC3)CC(=O)CC(=O)O2)c(OC)c1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 58.9 %

Procedure:
Methylacetoacetate (1.63 mL, 15.1 mmol) was dissolved in dry THF (42 mL) and cooled to 0° C. NaH (60% in mineral oil, 0.604 g, 15.1 mmol) were carefully added and the reaction mixture was stirred for 20 min. A solution of BuLi in hexanes (1.6 M, 9.44 mL, 15.1 mmol) was added dropwise and the resulting mixture was stirred an additional 20 min. A solution of 3-(2,4-dimethoxyphenyl)-1-cyclopentylpropan-1-one (2.33 g, 7.55 mmol) from Step 1 above in THF (37 mL) was added dropwise. After stirring 1 h, the reaction mixture was quenched with saturated aq NH4Cl (100 mL) and extracted with Et2O (600 mL). The organic phase was dried over MgSO4 and evaporated. The residue was then stirred overnight in a mixture of 0.1 M NaOH (370 mL) and THF (37 mL). After the addition of an aq solution of 10% aq KHSO4 (50 mL) the resulting mixture was stirred 30 min and then extracted with Et2O (600 mL). The organic phase was washed with brine, dried over MgSO4 and evaporated. The residue was purified by flash column chromatography (50% EtOAc in hexanes) to give the product (1.54 g, 52%) as a white foam. 1H NMR (CDCl3) δ 1.43 (m, 2H), 1.78 (m, 8H), 2.33 (m, 1H), 2.58 (m, 2H), 2.78 (s, 2H), 3.43 (s, 2H), 3.78 (s, 6H), 6.37 (s, 1H), 6.47 (s, 1H), 6.93 (d, 1H, J=7.93 Hz).
Reaction SMILES: [Cl:1][CH2:2][C:3]1[N:7]([CH3:8])[N:6]=[C:5]([C:9]2[CH:10]=[C:11]3[C:15](=[CH:16][CH:17]=2)[N:14]([CH3:18])[C:13]2[N:19]([CH3:32])[C:20](=[O:31])[C:21]([C:23]4[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][C:24]=4[Cl:30])=[CH:22][C:12]3=2)[CH:4]=1.C([O-])([O-])=O.[K+].[K+].[NH:39]1[CH2:44][CH2:43][O:42][CH2:41][CH2:40]1.Cl>CN(C=O)C.CCOC(C)=O.O>[ClH:1].[Cl:30][C:24]1[CH:25]=[C:26]([Cl:29])[CH:27]=[CH:28][C:23]=1[C:21]1[C:20](=[O:31])[N:19]([CH3:32])[C:13]2[N:14]([CH3:18])[C:15]3[C:11]([C:12]=2[CH:22]=1)=[CH:10][C:9]([C:5]1[CH:4]=[C:3]([CH2:2][N:39]2[CH2:44][CH2:43][O:42][CH2:41][CH2:40]2)[N:7]([CH3:8])[N:6]=1)=[CH:17][CH:16]=3
Reactant: C1COCCN1
Reactant: Cn1nc(-c2ccc3c(c2)c2cc(-c4ccc(Cl)cc4Cl)c(=O)n(C)c2n3C)cc1CCl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: Cn1nc(-c2ccc3c(c2)c2cc(-c4ccc(Cl)cc4Cl)c(=O)n(C)c2n3C)cc1CN1CCOCC1
Temperature: 80 °C

Procedure:
100 mg (0.2 mmol) of compound A, 6-(5-chloromethyl-1-methyl-1H-pyrazol-3-yl)-3-(2,4-dichlorophenyl)-1,9-dimethyl-1,9-dihydropyrido[2,3-b]indol-2-one are dissolved in 5 ml of anhydrous DMF. 55 mg (0.4 mmol) of K2CO3 and 22 μl (0.25 mmol) of morpholine are added. The mixture is heated at 80° C. overnight. It is allowed to return to ambient temperature and poured into water. The mixture is extracted with EtOAc. The organic phase is washed with a saturated NaCl solution. It is dried over Na2SO4, filtered and evaporated to dryness. Purification is carried out on a silica column, elution being carried out with a 95/05 EtOAc/MeOH mixture. The product obtained is dissolved in EtOAc and 0.5 ml of a saturated solution of HCl in Et2O/petroleum ether is added. The precipitate formed is filtered off and washed with ether. The product is taken up in MeOH and evaporated to dryness.
Reaction SMILES: [O:1]=[C:2]1[CH2:8][O:7][CH:6]([C:9]2C=[CH:13][CH:12]=[CH:11][C:10]=2C(F)(F)F)[C:5]2[CH:19]=[C:20]([Cl:23])[CH:21]=[CH:22][C:4]=2[NH:3]1.[BH4-].[Na+].Cl.C[N:28](C)C=O>>[O:1]=[C:2]1[CH2:8][O:7][CH:6]([C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][N:28]=2)[C:5]2[CH:19]=[C:20]([Cl:23])[CH:21]=[CH:22][C:4]=2[NH:3]1
Reactant: O=C1COC(c2ccccc2C(F)(F)F)c2cc(Cl)ccc2N1
Reactant: CN(C)C=O
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Product: O=C1COC(c2ccccn2)c2cc(Cl)ccc2N1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To a solution of Compound 2 (9.8 g) in dimethylformamide (80 ml) is gradually added sodium borohydride (1.1 g) at 0° C., and the mixture is stirred at the same temperature for 2 hours, mixed with ice water, acidified with hydrochloric acid, and extracted with ethyl acetate. The organic layer is washed with water, dried over anhydrous sodium sulfate, and concentrated. The residue is purified on column chromatography [silica gel/methylene chloride-ethyl acetate (20:3 v/v)] to give crystalline 2-(2-chloroacetyl)amino-2'-trifluoromethylbenzohydrol (4.8 g), which is recrystallized from ether-n-hexane to give pure crystals of Compound 3, mp. 116°-117° C.
Reaction SMILES: [CH3:1][CH2:2][C:3]1[C@H:8]2[N:9]3[CH2:11][CH2:12][C:13]4[C:21]5[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=5)[NH:15][C:14]=4[C@@:7]2([C:22]([O:24][CH3:25])=[O:23])[CH2:6][C@@H:5]([CH2:10]3)[CH:4]=1.ClC1C=CC=C(C(OO)=[O:34])C=1>C(Cl)Cl>[CH3:1][CH2:2][C:3]1[C@H:8]2[N@+:9]3([O-:34])[CH2:11][CH2:12][C:13]4[C:21]5[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=5)[NH:15][C:14]=4[C@@:7]2([C:22]([O:24][CH3:25])=[O:23])[CH2:6][C@@H:5]([CH2:10]3)[CH:4]=1
Reactant: CCC1=C[C@@H]2CN3CCc4c([nH]c5ccccc45)[C@@](C(=O)OC)(C2)[C@@H]13
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: CCC1=C[C@H]2C[C@]3(C(=O)OC)c4[nH]c5ccccc5c4CC[N@+]([O-])(C2)[C@H]13
Reaction time: 0.08 h

Procedure:
To a solution of catharanthine (Formula III, 20 mg, 0.6 mmol) in dry methylene chloride (2 ml) at -20° C. under a positive atmosphere of argon was added m-chloroperbenzoic acid (132 mg, 0.8 mmol), and the mixture was stirred for 5 minutes. To the catharanthine N-oxide (IIIa; R=COOCH3 ; R1, R2, R3, and R4 =H), thus formed was added a solution of vindoline (IV, 270 mg, 0.6 mmol) in methylene chloride (1 ml) and the mixture was cooled to -60° C. Trifluoroacetic anhydride (0.2 ml, 1.5 mmol) was added to the stirred reaction mixture maintained at -60° C. for 2 hours. After this time, the solvent and excess reagents were removed in vacuo at -20° C. to leave a reddish-brown residue containing the iminium intermediate. The intermediate was characterized by reverse phase high performance liquid chromatography (HPLC) (Waters Radial-Pak C18 or CN cartridge, methanol-H2O-Et3N as solvent system). It was shown that the yield of the iminium intermediate of Formula VI in this reaction exceeded 80%.
Reaction SMILES: [O:1]1[CH:6]([C:7]([OH:9])=[O:8])[CH:2]1[C:3]([OH:5])=O.[CH2:10]([K])[CH3:11].C(Cl)(=O)C(Cl)=O.[C:19]([NH:29][CH2:30][CH2:31][CH2:32][CH2:33][NH2:34])([O:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)=[O:20].C(N(CC)CC)C>C(OCC)C>[C:19]([NH:29][CH2:30][CH2:31][CH2:32][CH2:33][NH:34][C:3](=[O:5])[CH:2]1[O:1][CH:6]1[C:7]([O:9][CH2:10][CH3:11])=[O:8])([O:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)=[O:20]
Reactant: O=C(O)C1OC1C(=O)O
Reactant: CC[K]
Reactant: NCCCCNC(=O)OCc1ccccc1
Agent: O=C(Cl)C(=O)Cl
Solvent: CCOCC
Solvent: CCN(CC)CC
Product: CCOC(=O)C1OC1C(=O)NCCCCNC(=O)OCc1ccccc1
Yield: 69.2 %

Procedure:
To a suspension of monoethyl potassium epoxysuccinate (0.77 g) in ethyl ether (30 ml), oxalyl chloride (0.75 g) in ethyl ether was added dropwise with stirring under ice-cooling and the mixture was stirred for an hour at room temperature. To the resulting mixture, a solution of N-carbobenzoxy 1,4-diaminobutane (1.1 g) and triethylamine (0.48 g) in ethyl ether was added dropwise with stirring under ice-cooling, and the mixture was stirred for an additional hour at room temperature. The resulting precipitate was filtered off and the filtrate was washed with a saturated aqueous sodium chloride solution, dried over magnesium sulfate and concentrated to dryness. The residue was purified by silica gel column chromatography using benzene as a developer. The crude crystals thus obtained were recrystallized from acetone-n-hexane to give 0.97 g of ethyl N-carbobenzoxyaminobutyl-2,3-epoxysuccinamate (Compound No. 68) as colorless plates melting at 94°-95° C.
Reaction SMILES: [C:1]1([C@@H:7]2[NH:11][C@H:10]([CH2:12][O:13][C:14]3[CH:23]=[CH:22][C:17]([C:18]([O:20][CH3:21])=[O:19])=[CH:16][CH:15]=3)[CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[NH:31][C:32](=[O:46])[NH:33][C:34]1[CH:39]=[CH:38][C:37]([CH2:40][C:41](O)=[O:42])=[CH:36][C:35]=1[O:44][CH3:45].CCN=C=NCCCN(C)C.Cl.O>CN(C=O)C>[CH3:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[NH:31][C:32](=[O:46])[NH:33][C:34]1[CH:39]=[CH:38][C:37]([CH2:40][C:41]([N:11]2[C@@H:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[CH2:8][CH2:9][C@H:10]2[CH2:12][O:13][C:14]2[CH:15]=[CH:16][C:17]([C:18]([O:20][CH3:21])=[O:19])=[CH:22][CH:23]=2)=[O:42])=[CH:36][C:35]=1[O:44][CH3:45]
Reactant: COC(=O)c1ccc(OC[C@@H]2CC[C@H](c3ccccc3)N2)cc1
Reactant: COc1cc(CC(=O)O)ccc1NC(=O)Nc1ccccc1C
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(OC[C@@H]2CC[C@H](c3ccccc3)N2C(=O)Cc2ccc(NC(=O)Nc3ccccc3C)c(OC)c2)cc1
Reaction time: 8 h
Yield: 103.7 %

Procedure:
To a stirred solution of methyl 4-[5-(R)-phenyl-2-(S)-pirrolidinylmethoxy]benzoate (135 mg, 0.43 mmol), 4-[N′-(2-methylphenyl)ureido]-3-methoxyphenylacetic acid (136 mg, 0.43 mmol) and N,N-dimethylaminopyridine (52.9 mg, 0.43 mmol) in DMF (10 ml) was added EDC.HCl (90.8 mg, 0.48 mmol) at rt, and the resulting mixture was stirred overnight. The reaction mixture was poured into water and extracted with EtOAc. The organic layer was washed with brine, drying over anhydrous Na2SO4, then concentrated in vacuo. The residue was chromatographed on silica gel with hexane-EtOAc (1:5) as eluent to give methyl 4-[1-[4-[N′-(2-methylphenyl)ureido]-3-methoxyphenylacetyl]-5-(R)-phenyl-2-(S)-pyrrolidinylmethoxy]benzoate (271 mg, quant.) as a colorless amorphous solid. 1H-NMR (CDCl3) δ2.00-2.18 (m, 3 H), 2.31-2.41 (m, 1 H), 2.27 (s, 3 H), 3.31 (s, 2 H), 3.67 (s, 3 H), 3.89 (s, 3 H), 4.35-4.48 (m, 2 H), 4.60 (brs, 1 H), 4.92 (t, J=6.8 Hz, 1 H), 6.51 (d, J=8.4 Hz, 1 H), 6.62 (s, 1 H), 6.96 (d, J=8.8 Hz, 1 H), 7.11-7.40 (series of m, 8 H), 7.51 (d, J=8.0 Hz, 1 H), 7.97-8.00 (m, 2 H); MS (ESI) m/z, 608 (M++H).
Reaction SMILES: [Cl:1][C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[C:4]([Cl:9])[C:3]=1[NH:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[C:17](=[O:22])[CH2:18]S(C)=O.[Al]>O.O1CCCC1>[Cl:1][C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[C:4]([Cl:9])[C:3]=1[NH:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[C:17](=[O:22])[CH3:18]
Reactant: Cc1ccc(Cl)c(Nc2ccccc2C(=O)CS(C)=O)c1Cl
Agent: [Al]
Solvent: O
Solvent: C1CCOC1
Product: CC(=O)c1ccccc1Nc1c(Cl)ccc(C)c1Cl
Temperature: 0 °C
Reaction time: 0 h
Yield: 60.6 %

Procedure:
1-[2-[(2,6-Dichloro-3-methylphenyl)amino]phenyl]-2-(methylsulfinyl)ethanone (2.0 g, 5.61 mmol) is dissolved in 100 ml of 10% water/tetrahydrofuran and cooled to 0° C. in an ice bath. Aluminum amalgam is prepared by addition of aluminum foil (1.5 g, 56.1 mmol) to 350 ml of 2% aqueous mercuric chloride. After 15 seconds, the liquid is decanted, and the foil is washed twice with absolute ethanol followed by tetrahydrofuran. The freshly prepared aluminum amalgam is added to the reaction mixture which is then stirred for 30 minutes at 0° C. The reaction mixture is filtered through celite, and the solids are washed with tetrahydrofuran. The filtrate is evaporated, and the residue is taken up in ether. The ether solution is washed with 100 ml of water and dried over magnesium sulfate. Evaporation of the solvent gives a yellow solid which is recrystallized from diethyl ether/hexane. Yield (1.0 g, 60%) of 1-[2-[(2,6-dichloro-3 -methylphenyl)amino]phenyl]ethanone; mp 122°-125° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:6]([CH:7]=O)=[CH:5][C:4]=1[N+:11]([O-:13])=[O:12].S(=O)(O)[O-].[Na+].[Cl:19][C:20]1[CH:25]=[C:24]([NH2:26])[C:23]([NH2:27])=[CH:22][C:21]=1[Cl:28]>C(O)C>[Cl:19][C:20]1[C:21]([Cl:28])=[CH:22][C:23]2[NH:27][C:7]([C:6]3[CH:9]=[CH:10][C:3]([O:2][CH3:1])=[C:4]([N+:11]([O-:13])=[O:12])[CH:5]=3)=[N:26][C:24]=2[CH:25]=1
Reactant: Nc1cc(Cl)c(Cl)cc1N
Reactant: COc1ccc(C=O)cc1[N+](=O)[O-]
Agent: O=S([O-])O
Agent: [Na+]
Solvent: CCO
Product: COc1ccc(-c2nc3cc(Cl)c(Cl)cc3[nH]2)cc1[N+](=O)[O-]

Procedure:
4-Methoxy-3-nitrobenzaldehyde (4.65 g, 27.6 mmol) and sodium bisulfite (5.79 g, 55.2 mmol) were added to ethanol (200 mL) and refluxed for 4 hours at which time, 1,2-dichloro-4,5-phenylenediamine (4.56 g, 27.6 mmol) was added and the mixture was refluxed overnight. The reaction mixture was filtered while hot and the pea-green solid washed with ethanol (3.09 g), mp>250° C.