Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([B-:3]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)#N.[Na+]>CO>[B:3]([C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1)([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: N#C[B-](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Na+]
Solvent: CO
Product: c1ccc(B(c2ccccc2)c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 17 h

Procedure:
0.25 g of the product from c) was dissolved almost completely in 5 ml of methanol. 0.45 g of sodium cyanotriphenylborate was added. The mixture was stirred at room temperature for 17 h, during which the product gradually became crystalline. This product was filtered off with suction and washed with 25 ml of methanol, 25 ml of water and again with 25 ml of methanol. Drying gave 0.15 g (59% of theory) of a pale grey powder of the formula (LXXIV) with X−=NC—B(C6H5)3−.
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7](=[O:16])[C:8]2[C:13]([F:14])=[CH:12][CH:11]=[CH:10][C:9]=2[F:15])[N:5]=[C:4]([NH:17][C:18]2[CH:23]=[CH:22][C:21]([S:24]([NH2:27])(=[O:26])=[O:25])=[CH:20][CH:19]=2)[N:3]=1.CC(C)([O-])C.[K+].Cl[C:35](=[O:43])[CH2:36][CH2:37][C:38]([O:40][CH2:41][CH3:42])=[O:39]>C1COCC1>[CH2:41]([O:40][C:38](=[O:39])[CH2:37][CH2:36][C:35]([NH:27][S:24]([C:21]1[CH:22]=[CH:23][C:18]([NH:17][C:4]2[N:3]=[C:2]([NH2:1])[N:6]([C:7](=[O:16])[C:8]3[C:13]([F:14])=[CH:12][CH:11]=[CH:10][C:9]=3[F:15])[N:5]=2)=[CH:19][CH:20]=1)(=[O:25])=[O:26])=[O:43])[CH3:42]
Reactant: CCOC(=O)CCC(=O)Cl
Reactant: Nc1nc(Nc2ccc(S(N)(=O)=O)cc2)nn1C(=O)c1c(F)cccc1F
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CCOC(=O)CCC(=O)NS(=O)(=O)c1ccc(Nc2nc(N)n(C(=O)c3c(F)cccc3F)n2)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 15 %

Procedure:
To a nitrogen purged flask was added 4-[5-amino-1-(2,6-difluorobenzoyl)-1H-[1,2,4]triazol-3-ylamino]-benzenesulfonamide Compound 1a (1.0 g, 2.5 mmol) and THF (100 mL). The mixture was cooled to 0° C. and potassium tert-butoxide (2.8 mL, 1.0 M solu in THF) was added dropwise. After addition the mixture was stirred at 0° C. for 1 hr, then ethyl 4-chloro-4-oxobutyrate (0.46 g in 10 mL THF, 2.8 mmol) was added dropwise. The stirring was continued for 30 min, then the mixture was warmed to rt and stirred overnight. After being concentrated, the residue was purified by flash chromatography (silica gel, CH2Cl2:MeOH/9:1) to afford the desired product (200 mg, 15%) as a white solid. 1H NMR (300 MHz, CD3OD) δ 7.72 (d, 2H), 7.70 (m, 1H), 7.50 (d, 2H), 7.15 (t, 2H), 4.20 (q, 2H), 3.32 (s, 2H), 2.71 (s, 2H), 1.25 (t, 2H); MS (ESI) m/z: 523 (M+H)+.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([N:7]2[CH:11]=[C:10]([C:12]3[CH:17]=[CH:16][C:15]([O:18]CC4C=CC=CC=4)=[CH:14][CH:13]=3)[N:9]=[C:8]2[C:26]2[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=2)=[CH:3][CH:2]=1>[Pd].CCOC(C)=O>[N:1]1[CH:2]=[CH:3][C:4]([N:7]2[CH:11]=[C:10]([C:12]3[CH:13]=[CH:14][C:15]([OH:18])=[CH:16][CH:17]=3)[N:9]=[C:8]2[C:26]2[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=2)=[CH:5][CH:6]=1
Reactant: Fc1ccc(-c2nc(-c3ccc(OCc4ccccc4)cc3)cn2-c2ccncc2)cc1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: Oc1ccc(-c2cn(-c3ccncc3)c(-c3ccc(F)cc3)n2)cc1
Reaction time: 10 h

Procedure:
A mixture containing 1-(4-pyridyl)-2-(4-fluorophenyl)-4-(4-benzyloxyphenyl)imidazole (0.13 g, 0.3 mmol) and 10% palladium on activated carbon (100 mg) in EtOAc was stirred under an atmosphere of H2 for 10 h, at which time the reaction mixture was filtered through a pad of Celite. The filtrate was concentrated under reduced pressure, and the residue was purified by flash chromatography, eluting with 1:1 EtOAc/hexanes.
Reaction SMILES: [CH:1]1[C:11]2[CH2:10][CH2:9][C:8]3[CH:12]=[CH:13][CH:14]=[CH:15][C:7]=3[CH:6]([CH2:16][CH2:17][OH:18])[C:5]=2[CH:4]=[CH:3][CH:2]=1.C(O)C.[Cl-].[NH4+]>O1CCCC1>[CH2:12]1[C:8]2[CH2:9][CH2:10][C:11]3[CH:1]=[CH:2][CH:3]=[CH:4][C:5]=3[CH:6]([CH2:16][CH2:17][OH:18])[C:7]=2[CH2:15][CH:14]=[CH:13]1
Reactant: OCCC1c2ccccc2CCc2ccccc21
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Solvent: C1CCOC1
Product: OCCC1C2=C(CC=CC2)CCc2ccccc21

Procedure:
A mixture of 80.0 g of 10,11-dihydro-5H-dibenzo[a,d]cycloheptene-5-ethanol, 195.7 ml of dry ethanol, 2.0 l of dry tetrahydrofuran and 3.2 l of dry distilled ammonia, stirred under argon, is treated at -30° to -31° with 25.09 g of sodium (3 to 4 pieces). After the exothermic reaction has faded, the mixture is stirred for about an additional 10 minutes and subsequently treated portionwise with a total of 60 g of ammonium chloride. After removal of the ammonia, the suspension remaining is washed three times with 800 ml of saturated ammonium chloride solution each time. The aqueous extracts are extracted twice with 1.5 l of ether each time. The organic phases are washed with 800 ml of water, combined, dried and evaporated in vacuo. There is obtained crude 4,5,10,11-tetrahydro-1H-dibenzo[a,d]cycloheptene-5-ethanol in the form of an oil which is used in the next step without further purification.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][C:11]([C:25]2[CH:30]=[CH:29][C:28](Br)=[CH:27][CH:26]=2)([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH2:21][CH2:22][O:23][CH3:24])=[CH:16][CH:15]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.CC1(C)C(C)(C)OB([C:40]2[CH:41]=[N:42][NH:43][CH:44]=2)O1>[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH3:24][O:23][CH2:22][CH2:21][O:20][C:17]1[CH:16]=[CH:15][C:14]([C:11]2([C:25]3[CH:26]=[CH:27][C:28]([C:40]4[CH:41]=[N:42][NH:43][CH:44]=4)=[CH:29][CH:30]=3)[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]2)=[CH:19][CH:18]=1
Reactant: CC1(C)OB(c2cn[nH]c2)OC1(C)C
Reactant: COCCOc1ccc(C2(c3ccc(Br)cc3)CCN(C(=O)OC(C)(C)C)CC2)cc1
Agent: [Pd]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: COCCOc1ccc(C2(c3ccc(-c4cn[nH]c4)cc3)CCNCC2)cc1

Procedure:
4-(4-Bromo-phenyl)-4-[4-(2-methoxy-ethoxy)-phenyl]-piperidine-1-carboxylic acid tert-butyl ester was reacted with 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)1H-pyrazole following the procedure set out in Example 1, substituting tetrads triphenylphosphine palladium (0) as catalyst, the title compound was obtained. LC/MS: (PS-A2)Rt 3.27 [M+H]+ 478.
Reaction SMILES: [C:1]([O:12][CH3:13])(=[O:11])[C:2]1[CH:10]=[CH:9][CH:8]=[C:4]([C:5]([OH:7])=O)[CH:3]=1.C(N(C(C)C)CC)(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.Cl.[CH3:48][O:49][C:50](=[O:57])[CH2:51][CH2:52][C:53]([CH2:55][NH2:56])=[O:54]>C(Cl)Cl.CN(C=O)C>[CH3:48][O:49][C:50](=[O:57])[CH2:51][CH2:52][C:53](=[O:54])[CH2:55][NH:56][C:5]([C:4]1[CH:3]=[C:2]([CH:10]=[CH:9][CH:8]=1)[C:1]([O:12][CH3:13])=[O:11])=[O:7]
Reactant: COC(=O)CCC(=O)CN
Reactant: COC(=O)c1cccc(C(=O)O)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COC(=O)CCC(=O)CNC(=O)c1cccc(C(=O)OC)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Methyl hydrogen isophthalate (1.8 g, 10.2 mmol) is dissolved in methylene chloride (10 mL) and DMF (10 mL), and diisopropylethylamine (4.4 mL, 25.5 mmol), HATU (4.6 g, 12.2 mmol), and 5-aminolevulinic acid methyl ester hydrochloride (2 g, 11.2 mmol) are added. The reaction stirred at room temperature 1 h. The reaction is partitioned between ethyl acetate and water. The organic layer is washed with 1 N hydrochloric acid, saturated sodium bicarbonate, and brine, dried (magnesium sulfate), filtered, and concentrated under reduced pressure. Purification by flash column chromatography (silica, 4% methanol/chloroform) provides the title compound. ESI MS m/z 306.1 [M−H]−.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][N:3]=1.[N+:9]([O-])([OH:11])=[O:10].[OH-].[Na+]>S(=O)(=O)(O)O>[NH2:1][C:2]1[C:7]([N+:9]([O-:11])=[O:10])=[CH:6][C:5]([Br:8])=[CH:4][N:3]=1
Reactant: Nc1ccc(Br)cn1
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Product: Nc1ncc(Br)cc1[N+](=O)[O-]
Temperature: 60 °C
Reaction time: 0.5 h

Procedure:
100 ml of concentrated sulfuric acid were added to 25.0 g of 2-amino-5-bromopyridine, and 8.9 ml of concentrated nitric acid were then added dropwise to the mixture at a temperature of 50 to 60° C. over a period of 1 hour. The mixture was then stirred at 60° C. for 30 minutes. At the end of this time, the reaction mixture was poured into ice-water and neutralized by the addition of an aqueous solution of sodium hydroxide. The crystals which precipitated were collected by filtration and washed with ethanol, to give 19.1 g of the title compound, melting at 180-182° C.
Reaction SMILES: C[O:2][C:3](=[O:19])[CH2:4][CH2:5][CH:6]1[CH2:11][CH2:10][N:9]([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=2)[CH2:8][CH2:7]1.[OH-].[Li+:21].O1CCCC1>O.C(#N)C>[Li+:21].[Cl:18][C:15]1[CH:16]=[CH:17][C:12]([N:9]2[CH2:8][CH2:7][CH:6]([CH2:5][CH2:4][C:3]([O-:19])=[O:2])[CH2:11][CH2:10]2)=[CH:13][CH:14]=1
Reactant: COC(=O)CCC1CCN(c2ccc(Cl)cc2)CC1
Agent: [Li+]
Agent: [OH-]
Solvent: CC#N
Solvent: C1CCOC1
Solvent: O
Product: O=C([O-])CCC1CCN(c2ccc(Cl)cc2)CC1
Yield: 90.2 %

Procedure:
To 3-[1-(4-chloro-phenyl)-piperidin-4-yl]-propionic acid methyl ester (345 mg; 1.22 mmol, prepared in accordance with Example 142) is added lithium hydroxide (72 mg; 3.00 mmol) dissolved in water (6.5 mL). After dilution with tetrahydrofuran (10 mL) the reaction mixture is stirred for 2-4 hours. The mixture is then diluted with acetonitrile until a precipitate is formed. The solid is collected by filtration and dried under high vacuum to deliver the desired product (300 mg; 1.10 mmol).
Reaction SMILES: [CH:1]([CH2:3][C:4]1[CH:18]=[CH:17][C:7]([O:8][CH2:9][C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])=[CH:6][CH:5]=1)=O.Cl.[NH2:20][CH:21]([CH:23]([OH:31])[C:24]1[CH:29]=[CH:28][C:27]([OH:30])=[CH:26][CH:25]=1)[CH3:22]>>[OH:31][CH:23]([C:24]1[CH:25]=[CH:26][C:27]([OH:30])=[CH:28][CH:29]=1)[CH:21]([NH:20][CH2:1][CH2:3][C:4]1[CH:18]=[CH:17][C:7]([O:8][CH2:9][C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])=[CH:6][CH:5]=1)[CH3:22]
Reactant: CC(N)C(O)c1ccc(O)cc1
Reactant: CC(C)(C)OC(=O)COc1ccc(CC=O)cc1
Agent: Cl
Product: CC(NCCc1ccc(OCC(=O)OC(C)(C)C)cc1)C(O)c1ccc(O)cc1
Yield: 50.9 %

Procedure:
The ester 20 was prepared by condensation of tert-butyl 4-[formylmethyl]phenoxyacetate (10.0 g, 0.04 mole) with α-(1-aminoethyl)-4-hydroxybenzyl alcohol 13 (8.2 g, 0.04 mole) using the same method as described for the preparation of 5, 8, and 16. The ester 20 (8.18 g, 51%) was obtained as a yellow oil.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([SH:8])=[CH:4][CH:3]=1.[F:9][C:10]1[CH:11]=[C:12](I)[CH:13]=[C:14]([F:16])[CH:15]=1.CC(CCC)C(=O)C(=O)C(C)(C)C.C(=O)([O-])[O-].[Cs+].[Cs+]>C(OCC)(=O)C.Cl[Cu].CN1CCCC1=O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][C:12]2[CH:11]=[C:10]([F:9])[CH:15]=[C:14]([F:16])[CH:13]=2)=[CH:4][CH:3]=1
Reactant: Sc1ccc(Br)cc1
Reactant: Fc1cc(F)cc(I)c1
Agent: Cl[Cu]
Agent: CCCC(C)C(=O)C(=O)C(C)(C)C
Agent: O=C([O-])[O-]
Solvent: CN1CCCC1=O
Solvent: CCOC(C)=O
Product: Fc1cc(F)cc(Sc2ccc(Br)cc2)c1
Temperature: 130 °C
Reaction time: 2 h
Yield: 78.2 %

Procedure:
N-Methyl-2-pyrrolidone (10 mL) was added to 4-bromothiophenol (0.500 g, 2.64 mmol) in a sealed tube and the mixture was purged with argon for 5 minutes. After this time, 3,5-difluoroiodobenzene (0.63 g, 2.64 mmol), CuCl (0.131 g, 1.32 mmol), tetramethyl heptanedione (0.14 mL, 0.66 mmol) and cesium carbonate (1.70 g, 5.28 mmol) were added to the reaction mixture. The reaction mixture was stirred at 130° C. under argon for 2 hours. The reaction mixture was cooled to room temperature, diluted with ethyl acetate, and filtered through a celite bed. The filtrate was washed with water and brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure to yield the crude product. Silica gel chromatography (neat hexanes) provided impure 1-(4-bromo-phenylsulfanyl)-3,5-difluorobenzene (0.622 g). MS calcd. for C12H8BrF2S [(M+H)+] 302, obsd. 302.
Reaction SMILES: [O:1]=[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:11])[N:3]1[CH2:12][CH2:13][CH2:14][C:15]1[CH:16]=[C:17]([CH:20]=[CH:21][CH:22]=1)[CH:18]=O.[Br-].[C:24]1([C:50]2[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=2)[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[CH2:30][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>>[C:24]1([C:50]2[CH:51]=[CH:52][CH:53]=[CH:54][CH:55]=2)[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1/[CH:30]=[CH:18]/[C:17]1[CH:16]=[C:15]([CH2:14][CH2:13][CH2:12][N:3]2[C:4](=[O:11])[C:5]3[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=3)[C:2]2=[O:1])[CH:22]=[CH:21][CH:20]=1
Reactant: O=Cc1cccc(CCCN2C(=O)c3ccccc3C2=O)c1
Reactant: c1ccc(-c2ccccc2C[P+](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Br-]
Product: O=C1c2ccccc2C(=O)N1CCCc1cccc(/C=C/c2ccccc2-c2ccccc2)c1
Yield: 13 %

Procedure:
Phthalimide 29 was coupled with biphenyl-2-ylmethyl triphenylphosphonium bromide. Purification by flash chromatography (5% EtOAc-hexanes) gave (E)-2-(3-(3-(2-(biphenyl-2-yl)vinyl)phenyl)propyl)isoindoline-1,3-dione (0.100 g, 13%) and (E/Z)-2-(3-(3-(2-(biphenyl-2-yl)vinyl)phenyl)propyl)isoindoline-1,3-dione (0.230 g, 30%) as colorless oils. Trans-isomer: 1H NMR (400 MHz, CDCl3) δ 781-7.83 (m, 2H), 7.72-7.74 (m, 1H), 7.68-7.70 (m, 2H), 7.63-7.65 (m, 2H), 7.42-7.52 (m, 6H), 7.35-7.40 (m, 2H), 7.22-7.24 (m, 1H), 7.09-7.14 (m, 3H), 3.79 (t, J=7.2 Hz, 2H), 2.73 (t, J=7.6 Hz, 2H), 2.05-2.13 (m, 2H).
Reaction SMILES: Cl[CH2:2][C:3]([NH:5][C:6]1[CH:11]=[C:10]([F:12])[CH:9]=[CH:8][C:7]=1[CH3:13])=[O:4].[CH3:14][C:15]1([CH3:24])[N:19]2[CH2:20][CH2:21][NH:22][CH2:23][CH:18]2[CH2:17][O:16]1.C(N(CC)CC)C>CN(C)C=O>[F:12][C:10]1[CH:9]=[CH:8][C:7]([CH3:13])=[C:6]([NH:5][C:3](=[O:4])[CH2:2][N:22]2[CH2:21][CH2:20][N:19]3[C:15]([CH3:24])([CH3:14])[O:16][CH2:17][CH:18]3[CH2:23]2)[CH:11]=1
Reactant: Cc1ccc(F)cc1NC(=O)CCl
Reactant: CC1(C)OCC2CNCCN21
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Cc1ccc(F)cc1NC(=O)CN1CCN2C(COC2(C)C)C1
Temperature: 70 °C

Procedure:
A mixture of 6.6 parts of 2-chloro-N-(5-fluoro-2-methylphenyl)acetamide, 5 parts of hexahydro-3,3-dimethyl-3H-oxazolo[3,4-a]pyrazine, 6.1 parts of N,N-diethylethanamine and 67.5 parts of N,N-dimethylformamide was stirred and heated for 8 hours at about 70° C. After cooling overnight to room temperature, the reaction mixture was evaporated. The residue was dissolved in trichloromethane. The solution was washed with water, dried, filtered and evaporated, yielding 8.5 parts of N-(5-fluoro-2-methylphenyl)-tetrahydro-3,3-dimethyl-3H-oxazolo[3,4-a]pyrazine-7(8H)-acetamide as an oily residue (intermediate 121).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:9])=[C:6]([NH2:8])[CH:7]=1.C(N(CC)CC)C.[C:17](OC(=O)C)(=[O:19])[CH3:18]>C1COCC1.O.C(OCC)(=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:9])=[C:6]([NH:8][C:17](=[O:19])[CH3:18])[CH:7]=1
Reactant: Cc1ccc(Cl)cc1N
Reactant: CC(=O)OC(C)=O
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(=O)Nc1cc(Cl)ccc1C
Temperature: 60 °C
Reaction time: 8 h

Procedure:
5-Chloro-2-methyl-phenylamine (50 g, 353.11 mmol) was dissolved in dry THF (500 mL) followed by addition of triethylamine (61.53 mL, 441.39 mmol) and the whole heated to 60° C. To the stirring solution at 60° C. was added dropwise a solution of acetic anhydride (50 ml, 529.66 mmol) in dry THF (100 mL) and the reaction was stirred at 60° C. overnight. Upon cooling, the reaction was diluted with H2O (500 mL), ethyl acetate (250 mL) and the layers separated. The organics were washed with H2O (250 mL), 1N HCl (250 mL), sat Na2CO3 (250 mL), brine (250 mL), dried (MgSO4) and concentrated to a solid (59.67 g, 324.97 mmol).
Reaction SMILES: [C:1]([C:4]1[CH:9]=[C:8]([N:10]2[C:15]([CH3:16])=[CH:14][C:13]([O:17][CH2:18][C:19]3[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=3)=[CH:12][C:11]2=[O:27])[C:7]([CH3:28])=[CH:6][N:5]=1)(=[O:3])[CH3:2].[Cl:29]N1C(=O)CCC1=O>CC(O)C.ClC(Cl)C(O)=O>[C:1]([C:4]1[CH:9]=[C:8]([N:10]2[C:15]([CH3:16])=[CH:14][C:13]([O:17][CH2:18][C:19]3[CH:20]=[CH:21][C:22]([O:25][CH3:26])=[CH:23][CH:24]=3)=[C:12]([Cl:29])[C:11]2=[O:27])[C:7]([CH3:28])=[CH:6][N:5]=1)(=[O:3])[CH3:2]
Reactant: O=C1CCC(=O)N1Cl
Reactant: COc1ccc(COc2cc(C)n(-c3cc(C(C)=O)ncc3C)c(=O)c2)cc1
Agent: O=C(O)C(Cl)Cl
Solvent: CC(C)O
Product: COc1ccc(COc2cc(C)n(-c3cc(C(C)=O)ncc3C)c(=O)c2Cl)cc1
Temperature: 60 °C

Procedure:
To a solution of 2′-acetyl-4-((4-methoxybenzyl)oxy)-5′,6-dimethyl-2H-[1,4′-bipyridin]-2-one of part C (689 mg, 1.82 mmol) in 2-propanol (15 mL) was added N-chlorosuccinimide (266 mg, 2.00 mmol) and 3 drops of dichloroacetic acid. The slurry was heated at 60° C. for 3 hours. The solution was cooled using an ice bath and the resulting white solid was collected by vacuum filtration. The filtrate was partitioned between ethyl acetate and water. The organic layer was washed with water and brine and dried over magnesium sulfate. The solution was concentrated in vacuo and purified using normal phase chromatography (ethyl acetate/heptane) and the desired product was combined with material obtained via filtration (568 mg): MS (M+H) 414.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][N+:9]([O-])=O)[S:5][CH:6]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>>[CH3:1][C:2]1[CH:3]=[C:4]([CH2:7][CH2:8][NH2:9])[S:5][CH:6]=1
Reactant: Cc1csc(C=C[N+](=O)[O-])c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Product: Cc1csc(CCN)c1
Yield: 85 %

Procedure:
In close analogy to the procedure described above, 4-Methyl-2-(2-nitro-vinyl)-thiophene is reacted with lithium aluminium hydride to provide the title compound.
Reaction SMILES: P(Cl)(Cl)([Cl:3])=O.[CH:6]([NH:9][C:10]1[N:15]=[C:14](O)[C:13]([CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:12][N:11]=1)([CH3:8])[CH3:7]>>[CH:6]([NH:9][C:10]1[N:15]=[C:14]([Cl:3])[C:13]([CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:12][N:11]=1)([CH3:8])[CH3:7]
Reactant: CCOC(=O)Cc1cnc(NC(C)C)nc1O
Reactant: O=P(Cl)(Cl)Cl
Product: CCOC(=O)Cc1cnc(NC(C)C)nc1Cl
Yield: 73.9 %

Procedure:
Phosphorus oxychloride (26.2 g) was added to 2.26 g (9.45 mmoles) of ethyl 2-isopropylamino-4-hydroxypyrimidine-5-acetate, and the mixture was heated under reflux for 3 hours. The reaction mixture was concentrated under reduced pressure, and chloroform and ice water were added. It was then neutralized with sodium hydrogen carbonate. The chloroform layer was separated, and the solvent was evaporated. The residue was purified by silica gel column chromatography to give 1.80 g (yield 74%; melting point 67°-71° C.) of ethyl 2-isopropylamino-4-chloropyrimidine-5-acetate. To the product were added 1.05 g (13.5 mmoles) of a 40% methanol solution of methylamine and 10 ml of ethanol were added, and the mixture was reacted at 120 ° C. for 7 hours in an autoclave. Water was added, and the mixture was extracted with chloroform. The solvent was evaporated. The residue was purified by silica gel column chromatography to give 0.50 g (yield 35%) of the desired compound.
Reaction SMILES: Br[C:2](Br)=[CH:3][C:4]1[C:12]([O:13][CH3:14])=[CH:11][C:10]([CH3:15])=[C:9]2[C:5]=1[CH:6]=[CH:7][N:8]2[C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17].[NH2:24][C:25]1[CH:26]=[C:27]([CH:30]=[CH:31][C:32]=1[NH2:33])[C:28]#[N:29].C1N2CCN(CC2)C1>CN1C(=O)CCC1.CCOC(C)=O>[C:28]([C:27]1[CH:30]=[CH:31][C:32]2[NH:33][C:2]([CH2:3][C:4]3[C:12]([O:13][CH3:14])=[CH:11][C:10]([CH3:15])=[C:9]4[C:5]=3[CH:6]=[CH:7][N:8]4[C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])=[N:24][C:25]=2[CH:26]=1)#[N:29]
Reactant: COc1cc(C)c2c(ccn2C(=O)OC(C)(C)C)c1C=C(Br)Br
Reactant: N#Cc1ccc(N)c(N)c1
Agent: C1CN2CCN1CC2
Solvent: CN1CCCC1=O
Solvent: CCOC(C)=O
Product: COc1cc(C)c2c(ccn2C(=O)OC(C)(C)C)c1Cc1nc2cc(C#N)ccc2[nH]1
Temperature: 110 °C
Reaction time: 8 h

Procedure:
A mixture of tert-butyl 4-(2,2-dibromovinyl)-5-methoxy-7-methyl-1H-indole-1-carboxylate (1.3 g, 2.92 mmol), 3,4-diaminobenzonitrile (700 mg, 5.26 mmol) and DABCO (819 mg, 7.30 mmol) in NMP (12 mL) was stirred at 110° C. for overnight. The reaction mixture was then cooled to room temperature, diluted with EtOAc, and washed with water. The organic layer was dried over magnesium sulfate, filtered and concentrated. The residue was purified using FCC eluting with heptane/EtOAc(60-80%) to provide the title compound. MS (ESI+) m/z 417.2 (M+H).
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].[CH3:10][O:11][C:12](=[O:33])[CH2:13][C@@H:14]1[CH2:18][S:17][C:16]([C:19]2[NH:20][C:21]3[C:26]([CH:27]=2)=[CH:25][C:24]([CH2:28]Cl)=[CH:23][C:22]=3[N+:30]([O-:32])=[O:31])=[N:15]1.[NH4+].[Cl-]>CN(C=O)C>[CH3:10][O:11][C:12](=[O:33])[CH2:13][C@@H:14]1[CH2:18][S:17][C:16]([C:19]2[NH:20][C:21]3[C:26]([CH:27]=2)=[CH:25][C:24]([CH2:28][O:7][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)=[CH:23][C:22]=3[N+:30]([O-:32])=[O:31])=[N:15]1
Reactant: COC(=O)C[C@@H]1CSC(c2cc3cc(CCl)cc([N+](=O)[O-])c3[nH]2)=N1
Reactant: Oc1ccccc1
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: CN(C)C=O
Product: COC(=O)C[C@@H]1CSC(c2cc3cc(COc4ccccc4)cc([N+](=O)[O-])c3[nH]2)=N1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
Phenol (192 mg, 2.04 mmol) was dissolved in DMF. NaH (60% mineral oil, 82 mg, 2.04 mmol) was added, and the reaction solution was cooled to 0° C. (R)-2-(5-chloromethyl-7-nitro-1H-indol-2-yl)-4,5-dihydro-thiazol-4-yl-acetic acid methyl ester (500 mg, 1.36 mmol) prepared in Preparation 42, which was dissolved in DMF, was slowly added thereto. The reaction solution was warmed to room temperature, and stirred for 4 h. After saturated aqueous NH4Cl solution was added to quench the reaction, the reaction mixture was extracted with EtOAc, dried over MgSO4, and filtered. The solvent was removed under reduced pressure, and the residue was purified by column chromatography (eluent: EtOAc/n-Hex=1/2) to give the title compound.
Reaction SMILES: [N+:1]([C:4]1[CH2:8][CH2:7][CH2:6][CH:5]=1)([O-:3])=[O:2].I[CH2:10][CH2:11][CH:12]1[O:17][CH2:16][CH2:15][CH2:14][O:13]1.C([Cu])#N.[Li+].[Cl-].Cl>C1COCC1.[Cu].[Zn].[Zn].CC(O)=O>[N+:1]([CH:4]1[CH2:8][CH2:7][CH2:6][CH:5]1[CH2:10][CH2:11][CH:12]1[O:17][CH2:16][CH2:15][CH2:14][O:13]1)([O-:3])=[O:2]
Reactant: ICCC1OCCCO1
Reactant: O=[N+]([O-])C1=CCCC1
Agent: N#C[Cu]
Agent: [Cu]
Agent: Cl
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: O=[N+]([O-])C1CCCC1CCC1OCCCO1
Temperature: 0 °C
Yield: 85.3 %

Procedure:
At -78° C., add 1-nitrocyclopentene (1.8 ml, 18.4 mmol) in THF (20 ml) to a THF solution (33 ml) of the zinc-copper reagent prepared from 2-(2-iodoethyl)-1,3-dioxane (5.6 gm, 23 mm), zinc powder (1.58 g), CuCN (1.9 g) and LiCl (1.7 g), according to the general procedure of P. Knochel et. al. (J, Org. Chem. 1989, 54, 5200). After 15 min. warm to 0° C. for one hour, then recool to -78° C. and add AcOH (2.0 ml). Warm to RT, add AcOH:0.1N HCl (15 ml, 1:2) and stir for one hr. Partition between EtOAc and brine. Concentrate the organic layer and purify by silica gel chromatography using EtOAc/Hex 1:3 to elute the title compound (3.6 g 15.7 mmol) as an oil. CI MS: M+1=230.
Reaction SMILES: C(N(CC)CC)C.Cl.[CH3:9][C@@:10]12[C:17]([CH3:19])([CH3:18])[CH:14]([CH2:15][CH2:16]1)[CH2:13][NH:12][CH2:11]2.[CH3:20][CH:21]1[CH2:26][CH2:25][CH:24]([CH2:27][C:28](O)=[O:29])[CH2:23][CH2:22]1.CCN=C=NCCCN(C)C>C(Cl)Cl>[CH3:20][CH:21]1[CH2:26][CH2:25][CH:24]([CH2:27][C:28]([N:12]2[CH2:13][CH:14]3[C:17]([CH3:19])([CH3:18])[C@:10]([CH3:9])([CH2:16][CH2:15]3)[CH2:11]2)=[O:29])[CH2:23][CH2:22]1
Reactant: CC1(C)C2CC[C@]1(C)CNC2
Reactant: CC1CCC(CC(=O)O)CC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC1CCC(CC(=O)N2CC3CC[C@](C)(C2)C3(C)C)CC1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
Triethylamine 0.84 ml was added in a methylene chloride 20 ml solution of (IS)-1,8,8-trimethyl-3-azabicyclo[3.2.1]octane hydrochloride 0.95 g, and stirred at 0° C. for 30 min. 4-methylcyclohexyl acetic acid 0.94 g and WSC 1.35 g were added therein, then temperature of the reaction mixture was gradually changed to room temperature and stirred for 24 hours. The reaction mixture was washed with saturated sodium chloride solution and dried by anhydrous sodium sulfate. After filtering the drying agent, the filtrate was concentrated in vacuo to obtain crude (IS)-3-(4-methylcyclohexylacetyl)-1,8,8-trimethyl-3-azabicyclo[3.2.1]octane. The concentrate was added to THF 30 ml solution of lithium aluminum hydride 0.39 g and refluxed for 1 hour. The reaction mixture was cooled, then added water, and filtered the insoluble material. The filtrate was concentrated in vacuo. The thus obtained residue was purified by means of silica gel column chromatography (Wako gel, C200, chloroform:acetone=10:1) to obtain the product.