Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:4]=[C:5]([CH2:27][C:28]([O:30][CH3:31])=[O:29])[CH:6]=[CH:7][C:8]=1[O:9][C:10]1[CH:15]=[CH:14][C:13]([NH:16][C:17](=[O:26])[C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[C:20]([Cl:25])[CH:19]=2)=[CH:12][CH:11]=1.[F:32][C:33]1[CH:38]=[CH:37][C:36]([S:39](Cl)(=[O:41])=[O:40])=[CH:35][CH:34]=1.CCN(C(C)C)C(C)C>C(Cl)Cl>[Cl:25][C:20]1[CH:19]=[C:18]([CH:23]=[CH:22][C:21]=1[Cl:24])[C:17]([NH:16][C:13]1[CH:12]=[CH:11][C:10]([O:9][C:8]2[CH:7]=[CH:6][C:5]([CH2:27][C:28]([O:30][CH3:31])=[O:29])=[CH:4][C:3]=2[CH2:2][NH:1][S:39]([C:36]2[CH:37]=[CH:38][C:33]([F:32])=[CH:34][CH:35]=2)(=[O:41])=[O:40])=[CH:15][CH:14]=1)=[O:26]
Reactant: COC(=O)Cc1ccc(Oc2ccc(NC(=O)c3ccc(Cl)c(Cl)c3)cc2)c(CN)c1
Reactant: O=S(=O)(Cl)c1ccc(F)cc1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)Cc1ccc(Oc2ccc(NC(=O)c3ccc(Cl)c(Cl)c3)cc2)c(CNS(=O)(=O)c2ccc(F)cc2)c1
Yield: 74.7 %

Procedure:
The product of step H (30 mg, 0.065 mmol) was diluted with methylene chloride (1 mL) followed by the addition of 4-fluorobenzene-1-sulfonyl chloride (15 mg, 0.078 mmol) and DIEA (0.024 mL, 0.14 mmol). After stirring the reaction for 4 hours, the reaction mixture was placed directly onto a preparative tlc plate 0.5 mm and eluted with hexanes:ethyl acetate (3:1) to yield 30 mg of methyl 2-(4-(4-(3,4-dichlorobenzamido)phenoxy)-3-((4-fluorophenyl-sulfonamido)methyl)phenyl)acetate.
Reaction SMILES: ClCCl.[CH2:4]([C@@H:6]1[O:8][CH2:7]1)[Cl:5].[C:9]1([OH:15])[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>C(OC)(C)(C)C.C12(CS(O)(=O)=O)C(C)(C)C(CC1)CC2=O>[Cl:5][CH2:4][C@H:6]([OH:8])[CH2:7][O:15][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: Oc1ccccc1
Reactant: ClC[C@H]1CO1
Agent: CC1(C)C2CCC1(CS(=O)(=O)O)C(=O)C2
Solvent: COC(C)(C)C
Solvent: ClCCl
Product: O[C@@H](CCl)COc1ccccc1
Reaction time: 1 h
Yield: 109.6 %

Procedure:
To a mixture of N′,N′-disalicylidene ethylenediaminatocobalt(II) (173 mg, 0.532 mmol) and dichloromethane (13 ml) was added (±) camphorsulfonic acid (148 mg, 0.638 mmol) and the reaction system was stirred for 1 hour while being filled with air. The reaction solution was evaporated to dryness under reduced pressure to give a crude blackish (dark) brown cobalt (III) complex. Thereto was added tert-butylmethyl ether (5 ml) to disperse the crude cobalt (III) complex and then thereto were added (R)-epichlorohydrin (2.50 ml, 31.9 mmol, optical purity 99% e.e.) and phenol (2.50 g, 26.6 mmol) in order. The mixture was stirred for 24 hours under nitrogen atmosphere at room temperature. After the reaction, the reaction mixture was diluted with tert-butylmethyl ether (20 ml), the solution was washed with a 6% aqueous sodium hydroxide solution (10 ml) and a saturated sodium chloride solution (10 ml) in order, and the organic layer was condensed under reduced pressure to give crude (R)-1-chloro-3-phenoxy-2-propanol (5.44 g). This crude compound (5.44 g) was dissolved in isopropanol (10 ml) and thereto was added a 24% aqueous sodium hydroxide solution (6.64 g, 39.8 mmol) under ice-cooling. The mixture was stirred for 1 hour at room temperature. After the reaction, the reaction mixture was diluted with tert-butylmethyl ether (50 ml) and the solution was washed with water (2.0 ml), a saturated aqueous ammonium solution (20 ml) and a saturated aqueous sodium chloride solution (20 ml) in order. The organic layer was condensed under reduced pressure to give crude (S)-glycidylphenyl ether (3.80 g). Quantitative analysis by gas chromatography and optical purity measurement by HLPC were conducted on the compound. As a result the subject compound, (S)-glycidylphenyl ether (3.71 g, 93.0%) was produced with optical purity at 99% e.e.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]([C:11]([F:14])([F:13])[F:12])=[CH2:10])[CH:5]=[C:6]([Cl:8])[CH:7]=1.[Br:15][C:16]1[CH:24]=[CH:23][C:19]([CH:20]=[N:21][OH:22])=[C:18](Cl)[C:17]=1[CH3:26].C(=O)([O-])O.[K+]>O1CCCC1>[Br:15][C:16]1[CH:24]=[CH:23][C:19]([C:20]2[CH2:10][C:9]([C:4]3[CH:3]=[C:2]([Cl:1])[CH:7]=[C:6]([Cl:8])[CH:5]=3)([C:11]([F:14])([F:12])[F:13])[O:22][N:21]=2)=[CH:18][C:17]=1[CH3:26]
Reactant: Cc1c(Br)ccc(C=NO)c1Cl
Reactant: C=C(c1cc(Cl)cc(Cl)c1)C(F)(F)F
Agent: O=C([O-])O
Agent: [K+]
Solvent: C1CCOC1
Product: Cc1cc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)ccc1Br
Temperature: 25 °C
Yield: 90.5 %

Procedure:
In a solution of 22.7 g of 3,5-dichloro-1-(1-trifluoromethylethenyl)benzene produced in Step 1 of Synthetic Example 3 and 26.0 g of 4-bromo-chloro-3-methylbenzaldoxime in 120 ml of tetrahydrofuran, 15.7 g of potassium hydrogen carbonate was added, and stirred under reflux with heat for 5 hours. After the completion of the reaction, the reaction mixture was left and cooled to room temperature, insoluble material was filtered off, then the solvent was distilled off under reduced pressure. 150 ml of water was added in the residue, stirred at room temperature for 18 hours, and precipitated crystal was filtered off and dried to obtain 38.6 g of the aimed product as white crystal. Melting point 105.0 to 108.0° C.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[C:4]([CH3:9])[C:3]=1[S:10](Cl)(=[O:12])=[O:11].[NH2:14][C:15]1[CH:20]=[CH:19][C:18]([S:21]([CH:24]=[CH:25][C:26]#[N:27])(=[O:23])=[O:22])=[CH:17][CH:16]=1.C(N(CC)CC)C>C(Cl)(Cl)Cl>[CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[C:4]([CH3:9])[C:3]=1[S:10]([NH:14][C:15]1[CH:16]=[CH:17][C:18]([S:21]([CH:24]=[CH:25][C:26]#[N:27])(=[O:23])=[O:22])=[CH:19][CH:20]=1)(=[O:12])=[O:11]
Reactant: N#CC=CS(=O)(=O)c1ccc(N)cc1
Reactant: Cc1cc(C)c(S(=O)(=O)Cl)c(C)c1
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: Cc1cc(C)c(S(=O)(=O)Nc2ccc(S(=O)(=O)C=CC#N)cc2)c(C)c1
Reaction time: 0.08 h

Procedure:
A solution of 6.6 g (0.03 mol) of 2,4,6-trimethylbenzenesulfonyl chloride in 50 ml chloroform is added at room temperature to a stirred slurry of 6.3 g (0.03 mol) of 3-(4-aminobenzenesulfonyl)acrylonitrile in 100 ml chloroform, the slurry additionally containing 4 ml (0.03 mol) triethylamine, portionwise over a five minute period. After 3 hours stirring the reaction mixture is filtered. The chloroform solution is thereafter washed with water, dilute hydrochloric acid, and water, in that order, separated from the water layer, dried over anhydrous magnesium sulfate and evaporated. The recovered 3-[4-(2,4,6-trimethylbenzenesulfonamido)benzenesulfonyl]acrylonitrile has the formula: ##SPC18##
Reaction SMILES: Br[CH2:2][C:3]1[C:13]([Cl:14])=[N:12][CH:11]=[CH:10][C:4]=1[C:5]([O:7]CC)=O.Cl.[CH3:16][C:17]1[CH:18]=[C:19]([CH:30]([NH2:32])[CH3:31])[CH:20]=[N:21][C:22]=1[O:23][CH2:24][CH2:25][C:26]([F:29])([F:28])[F:27]>>[Cl:14][C:13]1[C:3]2[CH2:2][N:32]([CH:30]([C:19]3[CH:20]=[N:21][C:22]([O:23][CH2:24][CH2:25][C:26]([F:29])([F:27])[F:28])=[C:17]([CH3:16])[CH:18]=3)[CH3:31])[C:5](=[O:7])[C:4]=2[CH:10]=[CH:11][N:12]=1
Reactant: CCOC(=O)c1ccnc(Cl)c1CBr
Reactant: Cc1cc(C(C)N)cnc1OCCC(F)(F)F
Agent: Cl
Product: Cc1cc(C(C)N2Cc3c(ccnc3Cl)C2=O)cnc1OCCC(F)(F)F
Yield: 61 %

Procedure:
The title compound is prepared in 61% yield (260 mg, colorless amorphous solid) from ethyl 3-(bromomethyl)-2-chloroisonicotinate (300 mg, 1.08 mmol) and 1-(5-methyl-6-(3,3,3-trifluoropropoxy)pyridin-3-yl)ethanamine hydrochloride (337 mg, 1.19 mmol, Amine-36, single enantiomer) in a similar manner to Intermediate-2.
Reaction SMILES: [CH2:1]([N:3]1[N:7]=[N:6][C:5]([CH2:8][N:9]2[C:14]3[CH:15]=[C:16]([C:18]4[CH:23]=[C:22]([F:24])[CH:21]=[CH:20][C:19]=4[O:25][CH3:26])[S:17][C:13]=3[C:12](=[O:27])[N:11]([CH:28]3[CH2:33][CH2:32][N:31](C(OC(C)(C)C)=O)[CH2:30][CH2:29]3)[C:10]2=[O:41])=[N:4]1)[CH3:2].[ClH:42]>O1CCOCC1>[ClH:42].[CH2:1]([N:3]1[N:7]=[N:6][C:5]([CH2:8][N:9]2[C:14]3[CH:15]=[C:16]([C:18]4[CH:23]=[C:22]([F:24])[CH:21]=[CH:20][C:19]=4[O:25][CH3:26])[S:17][C:13]=3[C:12](=[O:27])[N:11]([CH:28]3[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]3)[C:10]2=[O:41])=[N:4]1)[CH3:2]
Reactant: CCn1nnc(Cn2c(=O)n(C3CCN(C(=O)OC(C)(C)C)CC3)c(=O)c3sc(-c4cc(F)ccc4OC)cc32)n1
Agent: Cl
Solvent: C1COCCO1
Product: CCn1nnc(Cn2c(=O)n(C3CCNCC3)c(=O)c3sc(-c4cc(F)ccc4OC)cc32)n1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
To a solution of tert-butyl 4-{1-[(2-ethyl-2H-tetrazol-5-yl)methyl]-6-(5-fluoro-2-methoxyphenyl)-2,4-dioxo-1,4-dihydrothieno[3,2-d]pyrimidin-3(2H)-yl}piperidine-1-carboxylate (435 mg; compound B57) in 1,4 dioxane (10 ml) is added a solution of hydrogen chloride in 1,4-dioxane (1.858 ml, 4.0 M). The reaction mixture is stirred for 3 d at RT. To complete the reaction an additional amount of a solution of hydrogen chloride in 1,4-dioxane (0.9 ml, 4.0 M) is added and the mixture is stirred for 1 h at 60° C. Subsequently all volatiles are evaporated and the residue is treated with DCM and after removal of the solvent under reduced pressure the title compound is obtained as a solid.
Reaction SMILES: OS(O)(=O)=O.[CH3:6][C:7]([O:9][CH2:10][C:11]1[CH2:20][S:19][C@@H:14]2[C@H:15]([NH2:18])[C:16](=[O:17])[N:13]2[C:12]=1[C:21]([OH:23])=[O:22])=[O:8].[CH3:24][C:25](=[CH2:27])[CH3:26]>O1CCOCC1>[NH2:18][C@@H:15]1[C:16](=[O:17])[N:13]2[C:12]([C:21]([O:23][C:25]([CH3:27])([CH3:26])[CH3:24])=[O:22])=[C:11]([CH2:10][O:9][C:7](=[O:8])[CH3:6])[CH2:20][S:19][C@H:14]12
Reactant: C=C(C)C
Reactant: CC(=O)OCC1=C(C(=O)O)N2C(=O)[C@@H](N)[C@H]2SC1
Agent: O=S(=O)(O)O
Solvent: C1COCCO1
Product: CC(=O)OCC1=C(C(=O)OC(C)(C)C)N2C(=O)[C@@H](N)[C@H]2SC1
Temperature: 30 °C
Reaction time: 2 h
Yield: 63 %

Procedure:
Dry dioxane was freed from peroxide by passage through a column of neutral activated alumina. To 100 ml of this solvent was added, in turn, with ice-cooling 10 ml of concentrated H2SO4, 10.9 g of 7-ACA and 50 ml of liquid isobutylene. The mixture was sealed in a pressure bottle, stirred at 30° C. for 2 hours, poured into excess of ice-cold aqueous sodium bicarbonate solution. The solution was extracted with ethyl acetate. The combined ethyl acetate extract was washed with brine and dried over sodium sulfate. Evaporation of the filtrate under reduced pressure gave a light brown foam, 8.3 g (63%) of t-butyl 7β-amino-3-acetoxymethyl-3-cephem-4-carboxylate.
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[CH2:7])=[CH:4][CH:3]=1.[CH2:10]([N:14]=[C:15]=[O:16])[CH2:11][CH2:12][CH3:13]>C(Cl)(Cl)Cl>[CH2:7]=[CH:6][C:5]1[CH:8]=[CH:9][CH:2]=[CH:3][CH:4]=1.[CH2:10]([NH:14][C:15]([NH2:1])=[O:16])[CH2:11][CH2:12][CH3:13]
Reactant: CCCCN=C=O
Reactant: C=Cc1ccc(N)cc1
Solvent: ClC(Cl)Cl
Product: C=Cc1ccccc1
Product: CCCCNC(N)=O

Procedure:
1.00 g (8.40 mmol) of p-aminostyrene (99% Tokyo Kasei) was added to a 250 ml round bottom flask containing 10 ml of chloroform. After ten minutes of mixing, 0.84 g (8.47 mmol) of n-butyl isocyanate (99% Aldrich) was added dropwise. Within seconds, a yellow precipitate formed. Chloroform (20 ml) was added to aid stirring. The precipitate was filtered to remove the reaction liquid, then washed with 20 ml of chloroform resulting in a pale yellow powder (1.78 g, 96% crude yield, mp=116° C.).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][N:8]([CH2:11][C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=2)[CH2:7][CH2:6]1.[CH:19]1([N:25]=[C:26]=[S:27])[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1>C(Cl)Cl>[Cl:18][C:15]1[CH:14]=[CH:13][C:12]([CH2:11][N:8]2[CH2:9][CH2:10][N:5]([CH2:4][CH2:3][CH2:2][NH:1][C:26]([NH:25][CH:19]3[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]3)=[S:27])[CH2:6][CH2:7]2)=[CH:17][CH:16]=1
Reactant: NCCCN1CCN(Cc2ccc(Cl)cc2)CC1
Reactant: S=C=NC1CCCCC1
Solvent: ClCCl
Product: S=C(NCCCN1CCN(Cc2ccc(Cl)cc2)CC1)NC1CCCCC1
Yield: 36.4 %

Procedure:
1-(3-Aminopropyl)-4-(4-chlorobenzyl)piperazine (5.36 g; 20 mmole) was reacted with cyclohexyl isothiocyanate (2.82 g; 20 mmole) in methylene chloride (35 ml) for two hours in the manner described in Example 17. The crude product was isolated and chromatographed on silica gel in analogous manner. The product, on recrystallization from ethanol, yielded the title compound (2.98 g; 36% yield) as colorless crystals, m.p. 127°-128° C.
Reaction SMILES: [NH2:1][C:2](=O)[CH2:3][C:4]1[C:5]([Cl:33])=[N:6][C:7]([CH2:13][C:14]2[CH:19]=[CH:18][C:17]([NH:20][C:21]([C:23]3[CH:32]=[CH:31][C:30]4[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=4)[CH:24]=3)=[O:22])=[CH:16][CH:15]=2)=[N:8][C:9]=1[N:10]([CH3:12])[CH3:11].FC(F)(F)C(OC(=O)C(F)(F)F)=O>N1C=CC=CC=1>[Cl:33][C:5]1[C:4]([CH2:3][C:2]#[N:1])=[C:9]([N:10]([CH3:12])[CH3:11])[N:8]=[C:7]([CH2:13][C:14]2[CH:19]=[CH:18][C:17]([NH:20][C:21]([C:23]3[CH:32]=[CH:31][C:30]4[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=4)[CH:24]=3)=[O:22])=[CH:16][CH:15]=2)[N:6]=1
Reactant: CN(C)c1nc(Cc2ccc(NC(=O)c3ccc4ccccc4c3)cc2)nc(Cl)c1CC(N)=O
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: c1ccncc1
Product: CN(C)c1nc(Cc2ccc(NC(=O)c3ccc4ccccc4c3)cc2)nc(Cl)c1CC#N
Temperature: 25 °C
Reaction time: 15 h
Yield: 99.6 %

Procedure:
To a solution of N-(4-{[5-(2-amino-2-oxoethyl)-4-chloro-6-(dimethylamino)pyrimidin-2-yl]methyl}phenyl)-2-naphthamide (0.360 g, 0.76 mmol) in pyridine (15 mL) at rt was added trifluoroacetic anhydride (0.161 mL, 1.14 mmol) dropwise and the resulting reaction mixture was stirred at room temperature for 15 hours. The volatiles were removed in vacuo and the remaining residue was partitioned between EtOAc and saturated aqueous ammonium chloride solution. The separated organic layer was washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. Purification of the resulting crude product by silica gel chromatography eluting with 20% EtOH in CHCl3 gave N-(4-{[4-chloro-5-(cyanomethyl)-6-(dimethyl-amino)pyrimidin-2-yl]methyl}phenyl)-2-naphthamide as an amorphous solid (0.345 g, 100%).
Reaction SMILES: [F:1][C:2]1[C:9]([O:10][CH3:11])=[CH:8][C:7]([F:12])=[CH:6][C:3]=1[CH2:4]O.C1(C)C=CC(S(Cl)(=O)=O)=CC=1.[CH2:24]([N:26](CC)CC)C.[C-]#N.[Na+]>ClCCl.O.CS(C)=O>[F:1][C:2]1[C:9]([O:10][CH3:11])=[CH:8][C:7]([F:12])=[CH:6][C:3]=1[CH2:4][C:24]#[N:26]
Reactant: CCN(CC)CC
Reactant: COc1cc(F)cc(CO)c1F
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: [C-]#N
Agent: [Na+]
Solvent: CS(C)=O
Solvent: ClCCl
Solvent: O
Product: COc1cc(F)cc(CC#N)c1F
Reaction time: 3.5 h
Yield: 68.1 %

Procedure:
To a stirred solution of 2,5-difluoro-3-methoxybenzyl alcohol (8.26 g, 47.4 mmol) in dichloromethane (100 ml) was added p-toluenesulfonyl chloride (9.95 g, 52.2 mmol) and triethylamine (7.30 ml, 52.2 mmol) at room temperature. After 3.5 hr, the mixture was poured into water (200 ml) and extracted with ether (200 ml). The extract was washed with brine (200 ml), dried (magnesium sulfate) and evaporated. To the residue was added DMSO (200 ml) and sodium cyanide (3.48 g, 71 mmol). The resulting mixture was stirred for 2 hr and then poured into water (200 ml) and extracted with ether (300 ml). The extract was washed with water (100 ml), brine (100 ml) and dried over magnesium sulfate. Removal of solvent gave 5.91 g (63%) of the titled compound as a red oil.
Reaction SMILES: [OH:1][CH2:2][C:3]1[O:7][C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([I:14])[CH:9]=2)=[N:5][CH:4]=1>ClCCl.[O-2].[O-2].[Mn+4]>[CH:2]([C:3]1[O:7][C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([I:14])[CH:9]=2)=[N:5][CH:4]=1)=[O:1]
Reactant: OCc1cnc(-c2cccc(I)c2)o1
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClCCl
Product: O=Cc1cnc(-c2cccc(I)c2)o1
Temperature: 25 °C
Reaction time: 2 h
Yield: 91.4 %

Procedure:
5-Hydroxymethyl-2-(3-iodophenyl)-1,3-oxazole (747 mg, 2.48 mmol) obtained in Step 2 of Example 122 was dissolved in dichloromethane (30 mL), and the mixture was stirred at room temperature for 2 hours after adding manganese dioxide (2.16 g, 24.8 mmol). The solid was separated by filtration through sellite. The filtrate was concentrated, and purified by silica gel column chromatography to give 5-formyl-2-(3-iodophenyl)-1,3-oxazole (678 mg, 91%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:16]=[C:15]([O:17][CH3:18])[CH:14]=[CH:13][C:4]=1[CH2:5][NH:6][CH2:7][CH2:8][CH2:9][N:10]([CH3:12])[CH3:11].Cl[S:20]([C:23]1[CH:31]=[CH:30][CH:29]=[CH:28][C:24]=1[C:25](Cl)=[O:26])(=[O:22])=[O:21].[NH2:32][C:33]1[C:42]([C:43]([O:45][C:46]([CH3:49])([CH3:48])[CH3:47])=[O:44])=[C:41]2[C:36]([CH:37]3[CH2:50][CH:38]3[CH2:39][O:40]2)=[CH:35][CH:34]=1>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:16]=[C:15]([O:17][CH3:18])[CH:14]=[CH:13][C:4]=1[CH2:5][N:6]([CH2:7][CH2:8][CH2:9][N:10]([CH3:11])[CH3:12])[C:25]([C:24]1[CH:28]=[CH:29][CH:30]=[CH:31][C:23]=1[S:20]([NH:32][C:33]1[C:42]([C:43]([O:45][C:46]([CH3:48])([CH3:47])[CH3:49])=[O:44])=[C:41]2[C:36]([CH:37]3[CH2:50][CH:38]3[CH2:39][O:40]2)=[CH:35][CH:34]=1)(=[O:22])=[O:21])=[O:26]
Reactant: COc1ccc(CNCCCN(C)C)c(OC)c1
Reactant: O=C(Cl)c1ccccc1S(=O)(=O)Cl
Reactant: CC(C)(C)OC(=O)c1c(N)ccc2c1OCC1CC21
Solvent: ClCCl
Product: COc1ccc(CN(CCCN(C)C)C(=O)c2ccccc2S(=O)(=O)Nc2ccc3c(c2C(=O)OC(C)(C)C)OCC2CC32)c(OC)c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 6.2 %

Procedure:
A solution of N-(2,4-dimethoxybenzyl)-N-(3-dimethylaminopropyl)amine (Intermediate 120, 0.179 g) in DCM (2 mL) was added dropwise with stirring to a cooled solution of 2-chlorosulfonylbenzoyl chloride (Intermediate 121, 0.17 g) in DCM (20 mL) at 0° C. The mixture was stirred at 0° C. for 1 hour then a solution of tert-butyl (1aRS,7bSR)-5-amino-1,1a,2,7b-tetrahydro-cyclopropa-[c]chromene-4-carboxylate (Intermediate 122, 0.185 g) in DCM (2 mL) was added. The resultant mixture was stirred and heated at 30-35° C. overnight. After cooling, the mixture was concentrated under vacuum and the residue was purified by HPLC (C18) to give tert-butyl (1aRS,7bSR)-5-{2-[N-(2,4-dimethoxybenzyl)-N-(3-dimethylaminopropyl)carbamoyl]-benzenesulfonylamino}-1,1a,2,7b-tetrahydro-cyclopropa-[c]chromene-4-carboxylate (0.03 g) as a yellow oil.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([N:8]([CH3:13])[CH2:9][CH2:10][CH2:11][OH:12])[C:5]([CH3:14])=[CH:4][N:3]=1.O[C:16]1[CH:17]=[C:18]2[C:22](=[CH:23][CH:24]=1)[NH:21][CH:20]=[CH:19]2.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O>ClCCl.CCOC(C)=O>[Cl:1][C:2]1[N:7]=[C:6]([N:8]([CH2:9][CH2:10][CH2:11][O:12][C:16]2[CH:17]=[C:18]3[C:22](=[CH:23][CH:24]=2)[NH:21][CH:20]=[CH:19]3)[CH3:13])[C:5]([CH3:14])=[CH:4][N:3]=1
Reactant: Oc1ccc2[nH]ccc2c1
Reactant: Cc1cnc(Cl)nc1N(C)CCCO
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: Cc1cnc(Cl)nc1N(C)CCCOc1ccc2[nH]ccc2c1
Temperature: 25 °C
Reaction time: 24 h
Yield: 24.1 %

Procedure:
To a solution of 3-[(2-chloro-5-methyl-4-pyrimidinyl)(methyl)amino]-1-propanol (0.316 g, 1.47 mmol) (prepared in similar fashion as Example 83) and 5-hydroxyindole (0.195 g, 1.47 mmol) in dichloromethane (7 mL) was added triphenylphosphine (1.15 g, 4.40 mmol) and 1,1′-(azodicarbonyl)-dipiperidine (1.11 g, 4.40 mmol) under argon. The golden yellow mixture was stirred at rt for 24 h. The desired product (0.117 g, 24%) was obtained after column chromatography (50% hexanes in EtOAc). LC/MS m/z 331.3 (M+H)+, RT 2.76 min.
Reaction SMILES: [NH2:1][C:2]1[CH:12]=[CH:11][C:10](Br)=[C:4]2[C:5]([NH:7][C:8](=[O:9])[C:3]=12)=[O:6].[C:14]([O:18][C:19]([N:21]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH:23]=[C:22]1B(O)O)=[O:20])([CH3:17])([CH3:16])[CH3:15].C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.C(N(CC)CC)C>C(#N)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.O>[NH2:1][C:2]1[CH:12]=[CH:11][C:10]([C:22]2[N:21]([C:19]([O:18][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:20])[C:29]3[C:24]([CH:23]=2)=[CH:25][CH:26]=[CH:27][CH:28]=3)=[C:4]2[C:5]([NH:7][C:8](=[O:9])[C:3]=12)=[O:6]
Reactant: CC(C)(C)OC(=O)n1c(B(O)O)cc2ccccc21
Reactant: Nc1ccc(Br)c2c1C(=O)NC2=O
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CC#N
Solvent: CCN(CC)CC
Solvent: O
Product: CC(C)(C)OC(=O)n1c(-c2ccc(N)c3c2C(=O)NC3=O)cc2ccccc21
Yield: 67.7 %

Procedure:
3-Amino-6-bromophthalimide (100 mg, 0.415 mmol) was dissolved in acetonitrile (7 mL), and the solution was added with 1-(tert-butoxycarbonyl)indole-2-boronic acid (217 mg, 0.830 mmol), palladium acetate (7.5 mg, 0.033 mmol), tri(o-tolyl)phosphine (20 mg, 0.066 mmol) and triethylamine (0.578 mL, 4.15 mmol), followed by stirring under reflux for 7.5 hours under argon atmosphere. The reaction mixture was added with water and extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by preparative thin-layer chromatography (chloroform/methanol=20/1, chloroform/acetonitrile=15/1) to obtain 3-amino-6-[1-(tert-butoxycarbonyl)indol-2-yl]phthalimide (106 mg, yield 67%).
Reaction SMILES: [CH2:1]([O:8][C:9]([C:11]1C(C2C=CC=C([N+]([O-])=O)C=2)C(C(OC)=O)=C(C)[NH:15][C:16]=1[CH3:17])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O)C>N1C=CC=CC=1>[CH2:1]([O:8][C:9](=[O:10])/[CH:11]=[C:16](\[NH2:15])/[CH3:17])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)C1=C(C)NC(C)=C(C(=O)OCc2ccccc2)C1c1cccc([N+](=O)[O-])c1
Solvent: CCO
Solvent: c1ccncc1
Product: C/C(N)=C/C(=O)OCc1ccccc1
Yield: 75 %

Procedure:
Analogously to Example 1 heating a solution of 75 mmols of 3'-nitrobenzylideneacetoacetic acid methyl ester and 75 mmols of β-aminocrotonic acid benzyl ester in 120 ml of pyridine for 10 hours gave 2,6-dimethyl-3-methoxycarbonyl-4-(3'-nitrophenyl)-1,4-dihydropyridine-5-carboxylic acid benzyl ester of melting point 133° C (from ethanol).
Reaction SMILES: I[C:2]1[C:10]2[C:9]([N:11]3[CH2:16][CH2:15][O:14][CH2:13][CH2:12]3)=[N:8][C:7]([CH3:17])=[N:6][C:5]=2[N:4]([CH2:18][O:19][CH2:20][CH2:21][Si:22]([CH3:25])([CH3:24])[CH3:23])[CH:3]=1.[C:26]([C:28]1[CH:29]=[C:30](B(O)O)[CH:31]=[CH:32][CH:33]=1)#[N:27].C(=O)([O-])[O-].[K+].[K+]>C(O)C.O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:17][C:7]1[N:8]=[C:9]([N:11]2[CH2:16][CH2:15][O:14][CH2:13][CH2:12]2)[C:10]2[C:2]([C:32]3[CH:33]=[C:28]([CH:29]=[CH:30][CH:31]=3)[C:26]#[N:27])=[CH:3][N:4]([CH2:18][O:19][CH2:20][CH2:21][Si:22]([CH3:25])([CH3:24])[CH3:23])[C:5]=2[N:6]=1
Reactant: Cc1nc(N2CCOCC2)c2c(I)cn(COCC[Si](C)(C)C)c2n1
Reactant: N#Cc1cccc(B(O)O)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCO
Product: Cc1nc(N2CCOCC2)c2c(-c3cccc(C#N)c3)cn(COCC[Si](C)(C)C)c2n1
Temperature: 90 °C

Procedure:
To a solution of 5-iodo-2-methyl-4-(morpholin-4-yl)-7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidine (C24) (100 mg, 0.21 mmol), (3-cyanophenyl)boronic acid (62 mg, 0.42 mmol) and potassium carbonate (100 mg, 0.72 mmol) in a mixture of ethanol and water (4:1, 5 mL) was added dichlorobis(triphenylphosphine)palladium (15 mg, 21 μmol). The reaction mixture was degassed and purged with nitrogen; this procedure was carried out a total of three times. After the reaction mixture had heated at 90° C. for 3 hours, it was allowed to cool and concentrated in vacuo. Purification via preparative thin layer chromatography (Eluent: 1:1 petroleum ether/ethyl acetate) provided the product as a yellow oil. Yield: 52 mg, 0.12 mmol, 57%. LCMS m/z 451.3 [M+H+].
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[CH:4][CH:3]=1.[N+:10]([C:13]1[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][C:14]=1[CH2:20][C:21]([OH:23])=[O:22])([O-:12])=[O:11].C(N(CC)CC)C>C(OC(=O)C)(=O)C>[N+:10]([C:13]1[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][C:14]=1[C:20](=[CH:6][C:5]1[CH:8]=[CH:9][C:2]([Br:1])=[CH:3][CH:4]=1)[C:21]([OH:23])=[O:22])([O-:12])=[O:11]
Reactant: Cc1ccc([N+](=O)[O-])c(CC(=O)O)c1
Reactant: O=Cc1ccc(Br)cc1
Solvent: CC(=O)OC(C)=O
Solvent: CCN(CC)CC
Product: Cc1ccc([N+](=O)[O-])c(C(=Cc2ccc(Br)cc2)C(=O)O)c1
Temperature: 40 °C
Yield: 98.6 %

Procedure:
To a mixture of 4-bromobenzaldehyde (19.5 g, 106 mmol) and 2-nitro-5-methyl-phenylacetic acid (20.6 g, 106 mmol; J. G. Atkinson et. al., Tetrahedron Lett., 2857, 1979) in 100 ml of acetic anhydride was added triethylamine (14.7 ml, 106 mmol) and the resulting reddish solution was heated at 40° C. for 70 hours. Most of the acetic anhydride was evaporated under vacuum and the residue was diluted with ethyl acetate and washed with sat. NH4Cl, H2O, and brine. Drying (MgSO4) and evaporation yielded 37.87 g (99%) of product as a yellow solid which was used in the next reaction without purification.