Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:3][C:4](=[O:29])[CH:5]=[CH:6][CH:7]1[CH2:13][CH2:12][CH2:11][CH2:10][N:9]([S:14]([C:17]2[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=2)(=[O:16])=[O:15])[CH:8]1[C:25](=[O:28])[NH:26][OH:27])C.[OH-].[Li+]>C1COCC1.O>[OH:27][NH:26][C:25]([CH:8]1[CH:7]([CH:6]=[CH:5][C:4]([OH:29])=[O:3])[CH2:13][CH2:12][CH2:11][CH2:10][N:9]1[S:14]([C:17]1[CH:18]=[CH:19][C:20]([O:23][CH3:24])=[CH:21][CH:22]=1)(=[O:16])=[O:15])=[O:28]
Reactant: CCOC(=O)C=CC1CCCCN(S(=O)(=O)c2ccc(OC)cc2)C1C(=O)NO
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: COc1ccc(S(=O)(=O)N2CCCCC(C=CC(=O)O)C2C(=O)NO)cc1

Procedure:
To a solution of 3-(2-Hydroxycarbamoyl-1-(4-methoxy-benzenesulfonyl)-azepan-3-yl)-acrylic acid ethyl ester (41 mg, 0.096 mmoL) in 0.96 mL THF and 1.1 mL water was added lithium hydroxide (12 mg, 0.288 mmoL) at ambient temperature. After 3.5 hours the reaction solvent was evaporated under reduced pressure, and the residue was diluted with water and washed twice with diethyl ether. The water layer was acidified to pH=1 and extracted twice with ethyl acetate. The organic layer was washed with brine and dried over anhydrous magnesium sulfate, filtered, and the solvent evaporated under reduced pressure. The residue was freeze dried to yield 3-(2-Hydroxycarbamoyl-1-(4-methoxy-benzenesulfonyl)-azepan-3-yl)-acrylic acid; MS: (M+H)+ =399, (M+NH4)+ =416, (M-H)- =397.
Reaction SMILES: [CH3:1][C:2]1[N:3]2[C:9]([CH2:10][OH:11])=[CH:8][N:7]=[C:4]2[S:5][CH:6]=1>CN(C=O)C.C1(C)C=CC=CC=1.O=[Mn]=O>[CH3:1][C:2]1[N:3]2[C:9]([CH:10]=[O:11])=[CH:8][N:7]=[C:4]2[S:5][CH:6]=1
Reactant: Cc1csc2ncc(CO)n12
Agent: O=[Mn]=O
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: Cc1csc2ncc(C=O)n12
Yield: 22.7 %

Procedure:
A solution of 3-Methylimidazo[2,1-b]thiazole-5-methanol (FIG. C-5) (0.9 g) in DMF (10 mL) was diluted with toluene (200 mL), treated with MnO2 (3.0), and azeotropically distilled for 1.5 hours. The suspension was filtered and the filtrate was concentrated to 10 mL. The concentrate was diluted with ice water and the precipitated 3-Methylimidazo[2,1-b]thiazole-5-carboxaldehyde (FIG. C-6) (0.665 g) was filtered. An aliquot (225 mg) was recrystallized from ethyl acetate-hexane to yield pure 3-Methylimidazo[2,1-b]thiazole-5-carboxaldehyde (FIG. C-6) (202 mg), m.p. 163-165°.
Reaction SMILES: [CH:1]1([C:6]2[C:19]3[CH:18]=[CH:17][C:16]4[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=4)[C:10]=3[CH:9]=[CH:8][CH:7]=2)[CH:5]=[CH:4][CH:3]=[CH:2]1.[N:20]1[CH:25]=[CH:24][C:23]([CH2:26]Cl)=[CH:22][CH:21]=1.Cl.[OH-].[Na+]>[Cl-].C([N+](CC)(CC)CC)C1C=CC=CC=1.C1(C)C=CC=CC=1>[N:20]1[CH:25]=[CH:24][C:23]([CH2:26][C:17]2([CH2:26][C:23]3[CH:24]=[CH:25][N:20]=[CH:21][CH:22]=3)[CH2:18][C:19]3[C:6]([CH:1]4[CH:5]=[CH:4][CH:3]=[CH:2]4)=[CH:7][CH:8]=[CH:9][C:10]=3[C:11]3[C:16]2=[CH:15][CH:14]=[CH:13][CH:12]=3)=[CH:22][CH:21]=1
Reactant: C1=CC(c2cccc3c2ccc2ccccc23)C=C1
Reactant: ClCc1ccncc1
Agent: CC[N+](CC)(CC)Cc1ccccc1
Agent: Cl
Agent: [Cl-]
Solvent: Cc1ccccc1
Product: C1=CC(c2cccc3c2CC(Cc2ccncc2)(Cc2ccncc2)c2ccccc2-3)C=C1

Procedure:
The title compound was prepared following the procedure of Example 1 from 5.0 g (0.0263 m) of cyclopentadienylphenanthrene, 9.51 g (58 mmole) 4-picolylchloride .HCl, 11.1 ml 50% sodium hydroxide, 1.2 g benzyltriethylammonium chloride, and 100 ml toluene by reaction at 50° for 6 hrs. The material was chromatographed (silica, EtOAc/MeOH,95:5) to yield 1.9 g of product, m.p. 201°-202°.
Reaction SMILES: [OH:1][N:2]1[C:6](=[O:7])[C:5]2=[CH:8][CH:9]=[CH:10][CH:11]=[C:4]2[C:3]1=[O:12].[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([S:20](Cl)(=[O:22])=[O:21])=[CH:16][CH:15]=1.C(N(CC)CC)C.O>ClCCl>[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([S:20]([O:1][N:2]2[C:3](=[O:12])[C:4]3=[CH:11][CH:10]=[CH:9][CH:8]=[C:5]3[C:6]2=[O:7])(=[O:22])=[O:21])=[CH:16][CH:15]=1
Reactant: O=S(=O)(Cl)c1ccc(Cl)cc1
Reactant: O=C1c2ccccc2C(=O)N1O
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O
Product: O=C1c2ccccc2C(=O)N1OS(=O)(=O)c1ccc(Cl)cc1
Reaction time: 72 h
Yield: 30.2 %

Procedure:
In a 3-neck, 500 ml round bottom flask, dichloromethane (100 ml) was added to 16.3 g (0.10 mole) of N-hydroxyphthalimide. To this was added 21.1 g (0.10 mole) of 4-chlorobenzenesulfonyl chloride. To this suspension at ice-bath temperature, with slow stirring, was added dropwise 10.1 g (0.10 mole) of triethylamine in 50 ml of dichloromethane. This stirred reaction mixture was held at ambient temperature for 72 hours. Then, more dichloromethane and 100 ml of water were added to the suspension. The dichloromethane extract was dried with magnesium sulfate. Solvent was removed under reduced pressure and the residue was recrystallized from 500 ml of ethyl acetate to give 10.2 g of a white solid, mp 178°-180° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:13]=[CH:12][N:11]=[CH:10][C:9]=1[N:14]([CH2:31][C:32]([O:34][CH3:35])=[O:33])[C:15](=[O:30])[C:16]1[CH:21]=[C:20]([C:22](F)(F)F)N=[C:18]([C:26]([F:29])([F:28])[F:27])[CH:17]=1.[CH3:36][S:37](C1C=C(C=C(C(F)(F)F)C=1)C(O)=O)(=[O:39])=[O:38]>>[CH3:35][O:34][C:32](=[O:33])[CH2:31][N:14]([C:9]1[CH:10]=[N:11][CH:12]=[CH:13][C:8]=1[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[F:1])[C:15](=[O:30])[C:16]1[CH:17]=[C:18]([C:26]([F:27])([F:29])[F:28])[CH:22]=[C:20]([S:37]([CH3:36])(=[O:39])=[O:38])[CH:21]=1
Reactant: COC(=O)CN(C(=O)c1cc(C(F)(F)F)nc(C(F)(F)F)c1)c1cnccc1-c1ccccc1F
Reactant: CS(=O)(=O)c1cc(C(=O)O)cc(C(F)(F)F)c1
Product: COC(=O)CN(C(=O)c1cc(C(F)(F)F)cc(S(C)(=O)=O)c1)c1cnccc1-c1ccccc1F

Procedure:
The title compound was prepared in analogy to example 90, from [4-(2-fluoro-phenyl)-pyridin-3-ylamino]-acetic acid methyl ester (example 196, intermediate) and 3-methanesulfonyl-5-trifluoromethyl-benzoic acid (280 mg, 1.05 mmol, example 114, intermediate a) after a reaction time of 22 hours. The compound was purified by silica gel chromatography on a 20 g column using an MPLC (Flashmaster) system eluting with a gradient of n-heptane:EtOAc (100:0 to 0:100). Light brown foam (323 mg, 61%). MS (ESI): m/z=511.094 [M+H]+.
Reaction SMILES: [CH2:1]1[C:9]2[C:4](=[CH:5][C:6]([C:10]3[S:11][C:12]4[C:17]([N:18]=3)=[CH:16][CH:15]=[C:14]([C:19]3([C:22]5[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=5)[CH2:21][CH2:20]3)[N:13]=4)=[CH:7][CH:8]=2)[CH2:3][NH:2]1.C(Cl)Cl.[C:31]([O:35][CH2:36]C)(=[O:34])[CH:32]=[CH2:33].CN1CCCN2CCCN=C12>CO>[C:22]1([C:19]2([C:14]3[N:13]=[C:12]4[S:11][C:10]([C:6]5[CH:5]=[C:4]6[C:9](=[CH:8][CH:7]=5)[CH2:1][N:2]([CH2:33][CH2:32][C:31]([O:35][CH3:36])=[O:34])[CH2:3]6)=[N:18][C:17]4=[CH:16][CH:15]=3)[CH2:20][CH2:21]2)[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1
Reactant: c1ccc(C2(c3ccc4nc(-c5ccc6c(c5)CNC6)sc4n3)CC2)cc1
Reactant: C=CC(=O)OCC
Agent: CN1CCCN2CCCN=C12
Solvent: ClCCl
Solvent: CO
Product: COC(=O)CCN1Cc2ccc(-c3nc4ccc(C5(c6ccccc6)CC5)nc4s3)cc2C1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
2-(Isoindolin-5-yl)-5-(1-phenylcyclopropyl)thiazolo[5,4-b]pyridine (75 mg, 0.203 mmol) was dissolved in methanol (2.0 mL) and DCM (1 mL) before ethyl acrylate (27.1 μL, 0.244 mmol) and 1-methyl-2,3,4,6,7,8-hexahydro-1H-pyrimido[1,2-a]pyrimidine (1.457 μL, 10.15 μmol) were added and stirred at ambient temperature for 16 h. Methyl 3-(5-(5-(1-phenylcyclopropyl)-thiazolo[5,4-b]pyridin-2-yl)isoindolin-2-yl)propanoate was obtained after purification via flash chromatography. MS (ESI) m/z: Calculated: 455.2; Observed: 456.4 (M++H).
Reaction SMILES: [Cl:1][C:2]1[CH:20]=[CH:19][C:5]2[NH:6][C:7]3[N:8]=[CH:9][CH:10]=[CH:11][C:12]=3[C:13]([C:17]#N)([CH:14]([F:16])[F:15])[C:4]=2[CH:3]=1.CC(C[AlH]CC(C)C)C.CC[O:32]C(C)=O.CCCCCC>C(Cl)Cl>[Cl:1][C:2]1[CH:20]=[CH:19][C:5]2[NH:6][C:7]3[N:8]=[CH:9][CH:10]=[CH:11][C:12]=3[C:13]([CH:14]([F:16])[F:15])([CH:17]=[O:32])[C:4]=2[CH:3]=1
Reactant: N#CC1(C(F)F)c2cc(Cl)ccc2Nc2ncccc21
Reactant: CCOC(C)=O
Agent: CC(C)C[AlH]CC(C)C
Solvent: ClCCl
Solvent: CCCCCC
Product: O=CC1(C(F)F)c2cc(Cl)ccc2Nc2ncccc21
Reaction time: 3 h
Yield: 39 %

Procedure:
Method LLL To a stirred solution of 7-chloro-5-cyano-5-(difluoromethyl)-5,10-dihydrobenzo[b][1,8]naphthyridine (92) (747 mg, 2.55 mmol) in anhydrous methylene chloride (40 mL) at −78° C. was added DIBAL (1.0 M in CH2Cl2, 7.67 mL) dropwise. After 3 h at −50° C., the reaction was quenched with 1.0 N HCl (40 mL), and extracted with EtOAc (3×). The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated in vacuo. Flash chromatography (SiO2, 30% EtOAc-hexane) furnished 93 (299 mg, 39% yield) as a yellow solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:12]([CH2:13][O:14][C:15]3[N:16]=[CH:17][C:18]([C:21]([OH:23])=O)=[N:19][CH:20]=3)=[C:11]([CH3:24])[O:10][N:9]=2)=[N:6][CH:7]=1.CC1O[N:29]=[C:28](C2C=CC=CC=2)[C:27]=1[CH2:37][O:38][C:39]1N=CC(C(O)=O)=N[CH:44]=1.NC1CCOCC1.C(OCC)(=O)C>CO.C(Cl)Cl>[O:38]1[CH2:37][CH2:27][CH:28]([NH:29][C:21]([C:18]2[CH:17]=[N:16][C:15]([O:14][CH2:13][C:12]3[C:8]([C:5]4[CH:4]=[CH:3][C:2]([F:1])=[CH:7][N:6]=4)=[N:9][O:10][C:11]=3[CH3:24])=[CH:20][N:19]=2)=[O:23])[CH2:44][CH2:39]1
Reactant: Cc1onc(-c2ccccc2)c1COc1cnc(C(=O)O)cn1
Reactant: Cc1onc(-c2ccc(F)cn2)c1COc1cnc(C(=O)O)cn1
Agent: NC1CCOCC1
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: CO
Product: Cc1onc(-c2ccc(F)cn2)c1COc1cnc(C(=O)NC2CCOCC2)cn1

Procedure:
As described for example 2b, 5-[3-(5-fluoro-pyridin-2-yl)-5-methyl-isoxazol-4-ylmethoxy]-pyrazine-2-carboxylic acid (44 mg, 13.3 mmol), instead of 5-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-pyrazine-2-carboxylic acid, was converted, using 4-aminotetrahydropyran instead of aminomethylcyclopropane, to the title compound (SiO2, ethyl acetate then DCM:MeOH=90:10, 31 mg, 56%) which was obtained as a white solid. MS: m/e=414.2 [M+H]+.
Reaction SMILES: [C:1]([C:3]1[N:7]([C:8]2[CH:13]=[C:12]([S:14][CH2:15][C:16]([F:19])([F:18])[F:17])[C:11]([CH3:20])=[CH:10][C:9]=2[F:21])[N:6]=[C:5]([O:22][CH2:23][C:24]([F:30])([F:29])[C:25]([F:28])([F:27])[F:26])[CH:4]=1)#[N:2].ClC1C=CC=C(C(OO)=[O:39])C=1>C(Cl)(Cl)Cl>[C:1]([C:3]1[N:7]([C:8]2[CH:13]=[C:12]([S:14]([CH2:15][C:16]([F:17])([F:18])[F:19])=[O:39])[C:11]([CH3:20])=[CH:10][C:9]=2[F:21])[N:6]=[C:5]([O:22][CH2:23][C:24]([F:30])([F:29])[C:25]([F:28])([F:27])[F:26])[CH:4]=1)#[N:2]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: Cc1cc(F)c(-n2nc(OCC(F)(F)C(F)(F)F)cc2C#N)cc1SCC(F)(F)F
Solvent: ClC(Cl)Cl
Product: Cc1cc(F)c(-n2nc(OCC(F)(F)C(F)(F)F)cc2C#N)cc1S(=O)CC(F)(F)F
Reaction time: 1 h
Yield: 96.7 %

Procedure:
0.40 g of 5-cyano-1-{2-fluoro-4-methyl-5-(2,2,2-trifluoroethylthio)phenyl}-3-(2,2,3,3,3-pentafluoropropoxy)pyrazole was dissolved in 10 mL of chloroform, and 200mg of m-chloroperbenzoic acid (purity: 75%) was added under cooling with ice. After stirring for one hour under cooling with ice, the solution was washed with an aqueous sodium thiosulfate solution and then washed with an aqueous sodium hydrogen carbonate solution, and then dried over anhydrous magnesium sulfate. Then, the solvent was distilled off under reduced pressure, and the obtained residue was purified by column chromatography (developing solvent ethyl acetate:hexane=1:2) to obtain 0.40 g of 5-cyano-1-{2-fluoro-4-methyl-5-(2,2,2-trifluoroethylsulfinyl)phenyl}-3-(2,2,3,3,3-pentafluoropropoxy)pyrazole.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:27]=[C:28](Br)[CH:29]=1)[CH2:5][O:6][CH2:7][C:8]1([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH2:9]1.[C:31]([C:33]1[CH:38]=[CH:37][C:36](B(O)O)=[CH:35][CH:34]=1)#[N:32].[OH-].[K+]>O1CCCC1.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[NH2:1][C:2]1[CH:3]=[C:4]([CH2:5][O:6][CH2:7][C:8]2([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH2:9]2)[CH:27]=[C:28]([C:36]2[CH:37]=[CH:38][C:33]([C:31]#[N:32])=[CH:34][CH:35]=2)[CH:29]=1
Reactant: N#Cc1ccc(B(O)O)cc1
Reactant: CC(C)(C)OC(=O)N1CCC(COCc2cc(N)cc(Br)c2)(c2ccccc2)CC1
Agent: [Pd]
Agent: [K+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(COCc2cc(N)cc(-c3ccc(C#N)cc3)c2)(c2ccccc2)CC1
Temperature: 120 °C

Procedure:
tert-Butyl 4-((3-amino-5-bromobenzyloxy)methyl)-4-phenylpiperidine-1-carboxylate (220.0 mg, 0.46 mmol), 4-cyanophenylboronic acid (273.0 mg, 1.86 mmol), and tetrakis(triphenylphosphine) palladium(0) (71.7 mg, 0.046 mmol) were combined in dry tetrahydrofuran (5 mL) in a microwave tube and sealed. The mixture was flushed with nitrogen. To this was added potassium hydroxide (1 N in water, 1.4 mL, 1.4 mmol). The mixture was heated at 120° C. for 1 h via microwave. After cooling to room temperature, the reaction mixture was concentrated and purified by flash chromatography on silica gel (25% ethyl acetate/hexanes) to afford 140.0 mg (61%). LC/MS (HPLC method 3): tR=2.85 min, 498.24 (MH)+.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[CH:4][CH:3]=1.[NH:10]1[CH2:15][CH:14]=[CH:13][CH2:12][CH2:11]1.Cl.C([BH3-])#N.[Na+]>CO>[OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][N:10]2[CH2:11][CH:12]=[CH:13][CH2:14][CH2:15]2)=[CH:4][CH:3]=1
Reactant: O=Cc1ccc(O)cc1
Reactant: C1=CCNCC1
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Product: Oc1ccc(CN2CC=CCC2)cc1
Reaction time: 96 h

Procedure:
A mixture of 4-hydroxybenzaldehyde (6.1 g.) and 1,2,3,6-tetrahydropyridine (8.3 g.) in methanol (70 ml.) was adjusted to pH7 by addition of ethereal hydrogen chloride. Sodium cyanoborohydride (3.15 g.) was then added in portions to the stirred solution at 25° C. The mixture was stirred at 20°-25° C. for four days, evaporated, and water (100 ml.) added to the resultant residue. The mixture obtained was adjusted to pH2 with dilute hydrochloric acid and extracted with ether (2×50 ml.). The extracts were discarded. The aqueous phase was separated and adjusted to pH9 with 10% w/v sodium carbonate solution, to give crude 1-(4-hydroxybenzyl)-1,2,3,6-tetrahydropyridine as a solid. This solid was dissolved in acetone (100 ml.) and the solution acidified to pH2 with ethereal hydrogen chloride to give 1-(4-hydroxybenzyl)-1,2,3,6-tetrahydropyridine hydrochloride (6.7 g.), m.p. 234°-236° C. (after recrystallisation from methanol/ethyl acetate.)
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][S:5]([O:8][CH2:9][C:10]([CH3:26])([CH3:25])[C@@H:11]([O:15][CH2:16][C:17]1[CH:22]=[CH:21][C:20](OC)=[CH:19][CH:18]=1)[C:12]([OH:14])=[O:13])(=[O:7])=[O:6].[CH3:27][CH:28]([O:30][C:31]([O:33][CH:34](Cl)[CH3:35])=[O:32])[CH3:29]>C1(C)C=CC=CC=1.C(=O)([O-])[O-].[Ag+2]>[Cl:1][CH2:2][CH2:3][CH2:4][S:5]([O:8][CH2:9][C:10]([CH3:25])([CH3:26])[C@@H:11]([O:15][CH2:16][C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1)[C:12]([O:14][CH2:35][CH2:34][O:33][C:31]([O:30][CH:28]([CH3:29])[CH3:27])=[O:32])=[O:13])(=[O:6])=[O:7]
Reactant: COc1ccc(CO[C@@H](C(=O)O)C(C)(C)COS(=O)(=O)CCCCl)cc1
Reactant: CC(C)OC(=O)OC(C)Cl
Agent: [Ag+2]
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Product: CC(C)OC(=O)OCCOC(=O)[C@H](OCc1ccccc1)C(C)(C)COS(=O)(=O)CCCCl
Yield: 50 %

Procedure:
Following the general procedure for the preparation of acyloxyalkyl/alkoxycarbonyloxyalkyl carboxylic esters from carboxylic acids of Description 22, (2R)-4-[(3-chloropropyl)sulfonyloxy]-3,3-dimethyl-2-(phenylmethoxy)butanoic acid (11) (34.0 g, 89.7 mmol) dissolved in 300 mL of anhydrous toluene was reacted with 30 g (179.5 mmol) of commercially available 1-chloroethyl methylethoxyformate in the presence of 47 g (179.5 mmol) of silver carbonate (Ag2CO3). After work-up, the crude material was purified by silica gel column chromatography using a mixture of ethyl acetate (EtOAc) and hexane (Hxn) (EtOAc/Hxn=1:2) as eluent to provide 23.0 g (50% yield) of the title compound (40a). Rf=0.32 (EtOAc/Hxn=1:4). 1H NMR (400 MHz, CDCl3, both diastereomers): δ=1.06-1.08 (m, 6H), 1.24-1.35 (m, 6H), 1.57 (d, J=5.2 Hz, 3H), 2.24-2.31 (m, 2H), 3.20-3.26 (m, 2H), 3.63-3.66 (m, 2H), 3.85-3.86 (2s, 1H), 3.94-3.97 (2d, J=9.6, 9.6 Hz, 1H), 4.19-4.23 (2d, J=9.2, 9.6 Hz, 1H), 4.33-4.38 (2d, J=11.2, 11.6 Hz, 1H), 4.64 (t, J=11.2 Hz, 1H), 4.81-4.97 (m, 1H), 6.81-6.87 (m, 1H), 7.30-7.37 (m, 5H) ppm. MS (ESI) m/z 531.02 (M+Na)+. The analytical data was consistent with the proposed structure.
Reaction SMILES: [CH3:1][C@H:2]1[CH2:19][CH2:18][C@@:17]2([CH3:20])[C:4](=[CH:5][CH2:6][C@@H:7]3[C@@H:16]2[CH2:15][CH2:14][C@@:12]2([CH3:13])[C@H:8]3[CH2:9][C@H:10](OS(C(F)(F)F)(=O)=O)[C:11]2=[O:21])[CH2:3]1.C[C@H]1CC[C@@]2(C)C(=CC[C@@H]3[C@@H]2CC[C@@]2(C)[C@H]3C[C@H](O)C2=O)C1.FC(F)(F)S(O)(=O)=O.[Cl-:60].[Li+]>CN(C=O)C.O>[CH3:1][C@H:2]1[CH2:19][CH2:18][C@@:17]2([CH3:20])[C:4](=[CH:5][CH2:6][C@@H:7]3[C@@H:16]2[CH2:15][CH2:14][C@@:12]2([CH3:13])[C@H:8]3[CH2:9][C@@H:10]([Cl:60])[C:11]2=[O:21])[CH2:3]1
Reactant: C[C@H]1CC[C@@]2(C)C(=CC[C@@H]3[C@@H]2CC[C@]2(C)C(=O)[C@@H](OS(=O)(=O)C(F)(F)F)C[C@@H]32)C1
Reactant: [Cl-]
Agent: C[C@H]1CC[C@@]2(C)C(=CC[C@@H]3[C@@H]2CC[C@]2(C)C(=O)[C@@H](O)C[C@@H]32)C1
Agent: O=S(=O)(O)C(F)(F)F
Agent: [Li+]
Solvent: CN(C)C=O
Solvent: O
Product: C[C@H]1CC[C@@]2(C)C(=CC[C@@H]3[C@@H]2CC[C@]2(C)C(=O)[C@H](Cl)C[C@@H]32)C1
Reaction time: 21 h
Yield: 96.5 %

Procedure:
800 mg of 3β-methyl-16β-trifluoromethylsulfonyloxy-5-androsten-17-one, prepared from 3β-methyl-16β-hydroxy-5-androsten-17-one and trifluoromethane sulfonic acid was placed in 16 ml DMF and was treated with 100 mg Lithium chloride at room temperature. The reaction mixture was stirred magnetically for 21 hours. Water is then added and the resulting crystalline ppt was collected. The crystals were washed with additional water and were then dissolved in CH2Cl2, filtered through anhydrous sodium sulfate and the solvent was evaporated off. The resulting crystals were recrystallized from CH3OH, yielding 570 mg of final product. m.p. 159°-165° C.
Reaction SMILES: CCCCCC.C([Li])CCC.Br[C:13]1[CH:18]=[CH:17][C:16]([C:19]2[N:24]=[C:23]([C:25]3[CH:30]=[CH:29][C:28]([C:31]([CH3:34])([CH3:33])[CH3:32])=[CH:27][CH:26]=3)[N:22]=[C:21]([C:35]3[CH:40]=[CH:39][C:38]([C:41]([CH3:44])([CH3:43])[CH3:42])=[CH:37][CH:36]=3)[N:20]=2)=[CH:15][CH:14]=1.Br[C:46]1[CH:47]=[CH:48][C:49]([C:52]2[CH:57]=[CH:56][CH:55]=[CH:54][N:53]=2)=[N:50][CH:51]=1>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O1CCCC1>[C:31]([C:28]1[CH:27]=[CH:26][C:25]([C:23]2[N:22]=[C:21]([C:35]3[CH:40]=[CH:39][C:38]([C:41]([CH3:43])([CH3:44])[CH3:42])=[CH:37][CH:36]=3)[N:20]=[C:19]([C:16]3[CH:15]=[CH:14][C:13]([C:46]4[CH:47]=[CH:48][C:49]([C:52]5[CH:57]=[CH:56][CH:55]=[CH:54][N:53]=5)=[N:50][CH:51]=4)=[CH:18][CH:17]=3)[N:24]=2)=[CH:30][CH:29]=1)([CH3:32])([CH3:33])[CH3:34]
Reactant: CC(C)(C)c1ccc(-c2nc(-c3ccc(Br)cc3)nc(-c3ccc(C(C)(C)C)cc3)n2)cc1
Reactant: Brc1ccc(-c2ccccn2)nc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CC(C)(C)c1ccc(-c2nc(-c3ccc(-c4ccc(-c5ccccn5)nc4)cc3)nc(-c3ccc(C(C)(C)C)cc3)n2)cc1
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 55.6 %

Procedure:
Under a stream of argon, 0.35 ml of a hexane solution containing 0.55 mmol of butyl lithium was slowly added to 15 ml of tetrahydrofuran cooled to −78° C. in which 0.25 g of 2-(4-bromophenyl)-4,6-bis(4-tert-butylphenyl)-1,3,5-triazine obtained by Reference Example 1 had been dissolved. After stirring at −78° C. for 15 minutes, 0.15 g of dichloro(tetramethylethylenediamine)zinc(II) was added thereto and stirred at −78° C. for 10 minutes and then at room temperature for 2 hours. A 5 ml portion of tetrahydrofuran prepared by dissolving 0.14 g of 5-bromo-2,2′-bipyridyl and 0.03 g of tetrakis(triphenylphosphine)palladium(0) therein was added to this solution and stirred under heating reflux for 15 hours. The reaction solution was concentrated under a reduced pressure and the thus obtained solid was recrystallized from dichloromethane-methanol. The thus obtained crude product was purified by a silica gel column chromatography (eluting solution hexane:chloroform=1:1 to 0:1) and then again recrystallized from dichloromethane-methanol to obtain a white solid of the intended 5-{4-[4,6-bis(4-tert-butylphenyl)-1,3,5-triazin-2-yl]phenyl}-2,2′-bipyridyl (0.16 g, yield 56%). Its melting point and glass transition temperature are shown in Table 4.
Reaction SMILES: COC(=O)C(CCCC1CCCCC1)=C.C[O:17][P:18]([CH:35]([NH:37]C(OCC1C=CC=CC=1)=O)[CH3:36])([CH2:20][CH:21]([C:31]([O:33]C)=[O:32])[CH2:22][CH2:23][CH2:24][CH:25]1[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]1)=[O:19]>>[NH2:37][CH:35]([P:18]([CH2:20][CH:21]([C:31]([OH:33])=[O:32])[CH2:22][CH2:23][CH2:24][CH:25]1[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]1)(=[O:17])[OH:19])[CH3:36]
Reactant: COC(=O)C(CCCC1CCCCC1)CP(=O)(OC)C(C)NC(=O)OCc1ccccc1
Agent: C=C(CCCC1CCCCC1)C(=O)OC
Product: CC(N)P(=O)(O)CC(CCCC1CCCCC1)C(=O)O

Procedure:
By methods outlined in Example 2 and using methyl-2-[3-cyclohexyl-1-propyl]acrylate was prepared methyl-1-benzyloxycarbonylaminoethyl-[2-carbomethoxy-5-cyclohexyl-1-n-pentyl]phosphinate. NMR (CDCl3) δ 0.8-3.1 (m, 23H); 3.6 (s, 3H); 3.6 (d, 3H); 3.6-4.2 (m, 1H); 5.0 (s, 2H); 5.2 (d, 0.5H); 5.5 (d, 0.5H); 7.2 (s, 5H).
Reaction SMILES: C[CH:2]1[C:11]2[C:10]3[CH:12]=[CH:13][CH2:14][CH2:15][C:9]=3[CH:8]=[CH:7][C:6]=2[NH:5][CH2:4][CH2:3]1.N.[Li].[CH2:18](O)C>CCOCC.O>[CH3:18][N:5]1[CH:6]2[CH:11]([C:10]3[CH2:12][CH:13]=[CH:14][CH2:15][C:9]=3[CH2:8][CH2:7]2)[CH2:2][CH2:3][CH2:4]1
Reactant: CCO
Reactant: CC1CCNc2ccc3c(c21)C=CCC3
Agent: N
Agent: [Li]
Solvent: CCOCC
Solvent: O
Product: CN1CCCC2C3=C(CC=CC3)CCC21

Procedure:
1-Methyl-1,2,3,4,7,8-hexahydrobenzo[f]-quinoline is dissolved in 200 ml of ether and added to 1.5 l of liquid ammonia. Lithium ribbon (16 g) is added portionwise over a period of 15 minutes. After stirring a few minutes, absolute ethanol is added dropwise until the color is discharged (500 ml added over a period of 2.5 hours). More ether is added and the ammonia is boiled off. While cooling in an ice bath, the mixture is diluted to about 1500 ml with water. The layers are separated and the aqueous layer is reextracted with ether. The combined organic layers are dried over potassium carbonate, filtered and the solvent is removed in vacuo leaving the title compound as a crude product.
Reaction SMILES: [Cl:1][C:2]1[C:7](=[O:8])[N:6]([CH3:9])[CH:5]=[C:4]2[C:10](=[O:26])[N:11]([CH2:14][CH2:15][C:16]3[CH:25]=[CH:24][C:23]4[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=4)[N:17]=3)[C:12](=[O:13])[C:3]=12>C(O)(=O)C.[Cl-].[Na+].O.[Zn]>[Cl:1][C:2]1[C:7](=[O:8])[N:6]([CH3:9])[CH:5]=[C:4]2[C:10](=[O:26])[N:11]([CH2:14][CH2:15][C:16]3[CH:25]=[CH:24][C:23]4[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=4)[N:17]=3)[CH:12]([OH:13])[C:3]=12
Reactant: Cn1cc2c(c(Cl)c1=O)C(=O)N(CCc1ccc3ccccc3n1)C2=O
Agent: [Cl-]
Agent: [Na+]
Agent: [Zn]
Solvent: CC(=O)O
Solvent: O
Product: Cn1cc2c(c(Cl)c1=O)C(O)N(CCc1ccc3ccccc3n1)C2=O
Temperature: 25 °C
Reaction time: 3 h
Yield: 139.2 %

Procedure:
Zinc (0.44 g, 6.8 mmol) was added to a solution of 7-chloro-5-methyl-2-(2-quinolin-2-yl-ethyl)-5H-pyrrolo[3,4-c]pyridine-1,3,6-trione (1 g, 2.72 mmol, see Example c1)) in acetic acid (10 ml) and the reaction was stirred for 3 h under reflux. The reaction was cooled to r.t. and brine (20 ml) was added. The aqueous layer was extracted with THF (3×25 ml) and the combined organic phase was concentrated to dryness. The mixture was diluted with THF (30 ml)/MeOH (5 ml), filtered through a pad of silica gel and concentrated to give crude product (1.4 g 139% yield), which was used in the next steps without further purification.
Reaction SMILES: C[C:2](C)=[O:3].[CH3:5][C:6]1[C:12](=[O:13])[C:11]2[N:14]3[C@@:18]([O:25][CH3:26])([C@H:19]([CH2:20][O:21][C:22]([NH2:24])=[O:23])[C:10]=2[C:8](=[O:9])[C:7]=1N)[C@H:17]1[NH:27][C@H:16]1[CH2:15]3>CO>[CH3:5][C:6]1[C:12](=[O:13])[C:11]2[N:14]3[C@@:18]([O:25][CH3:26])([C@H:19]([CH2:20][O:21][C:22]([NH2:24])=[O:23])[C:10]=2[C:8](=[O:9])[C:7]=1[O:3][CH3:2])[C@H:17]1[NH:27][C@H:16]1[CH2:15]3
Reactant: CO[C@@]12[C@H](COC(N)=O)C3=C(C(=O)C(C)=C(N)C3=O)N1C[C@@H]1N[C@@H]12
Reactant: CC(C)=O
Solvent: CO
Product: COC1=C(C)C(=O)C2=C(C1=O)[C@@H](COC(N)=O)[C@@]1(OC)[C@H]3N[C@H]3CN21

Procedure:
TLC (ETOAC:Acetone) one spot Rf =0.91; UV (MeOH) 216 and 358 mu NMR(CDCl3); appearance of singlet at 4.04 corresponding to the 7-methoxy group which is not present in the parent compound mitomycin C.