Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7](=[O:12])[N+:6]([O-:13])=[C:5]2[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.[C:20](=O)([O-])[O-].[K+].[K+].[K].CI>CN(C)C=O>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH3:20])[C:7](=[O:12])[N+:6]([O-:13])=[C:5]2[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: O=C([O-])[O-]
Reactant: O=c1[nH]c2ccc(Cl)cc2c(-c2ccccc2)[n+]1[O-]
Agent: [K+]
Agent: [K]
Solvent: CI
Solvent: CN(C)C=O
Product: Cn1c(=O)[n+]([O-])c(-c2ccccc2)c2cc(Cl)ccc21
Reaction time: 1 h
Yield: 80 %

Procedure:
A mixture of 125 g (0.458 mole) of 6-chloro-4-phenyl-2(1H)quinazolinone 3-oxide, 3,250 ml of N,N-dimethylformamide and 75 g of powdered anhydrous potassium carbonate was heated to 50°. After heating for approximately 30 minutes at this temperature, an increased solubility of the suspended solid due to formation of the potassium salt of I was observed. At this point, 150 g (65.8 ml) of methyl iodide was added dropwise at a fast rate. The reaction with the methyl iodide was somewhat exothermic and caused the pot temperature to rise to 58°. Stirring at 50°-55° was continued for 1 hour. The contents of the flask were cooled and filtered and the solid obtained was thoroughly washed with water. The product, 6-chloro-1-methyl-4-phenyl-2(1H)quinazolinone 3-oxide was obtained in 80% yield (103.2 g), mp 253.5°-254°.
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[N:11]=[C:10]([C:12]([OH:14])=O)[CH:9]=[CH:8][C:7]=2[N:15]2[CH2:18][C:17]([F:20])([F:19])[CH2:16]2)[CH2:3][CH2:2]1.FC(F)(F)C(O)=O.[CH3:28][NH:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>>[CH3:28][N:29]([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[C:12]([C:10]1[CH:9]=[CH:8][C:7]([N:15]2[CH2:18][C:17]([F:20])([F:19])[CH2:16]2)=[C:6]([O:5][CH2:4][CH:1]2[CH2:2][CH2:3]2)[N:11]=1)=[O:14]
Reactant: O=C(O)c1ccc(N2CC(F)(F)C2)c(OCC2CC2)n1
Reactant: CNc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: CN(C(=O)c1ccc(N2CC(F)(F)C2)c(OCC2CC2)n1)c1ccccc1

Procedure:
The title compound was synthesized in analogy to Example 47b), using 6-(cyclopropylmethoxy)-5-(3,3-difluoroazetidin-1-yl)picolinic acid (Example 1 b) and N-methylaniline 2,2,2-trifluoroacetate (CAS 29885-95-8) as starting materials and isolated as colorless oil. MS (EI): m/e=374.5 [MH+].
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[NH:9][N:8]=[C:7]2[C:11]1[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=1.[H-].[Na+].I[CH2:22][CH2:23][CH3:24]>>[Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[N:9]([CH2:22][CH2:23][CH3:24])[N:8]=[C:7]2[C:11]1[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=1
Reactant: COc1ccc(-c2n[nH]c3c(Cl)cccc23)cc1
Reactant: CCCI
Agent: [H-]
Agent: [Na+]
Product: CCCn1nc(-c2ccc(OC)cc2)c2cccc(Cl)c21
Yield: 53.9 %

Procedure:
Prepared according to Method D step B from 7-chloro-3-(4-methoxyphenyl)-1H-indazole (0.129 g, 0.5 mmol), sodium hydride (60% in oil, 0.024 g, 0.6 mmol) and 1-iodopropane (0.098 mL, 1.0 mmol) to give the title compound (0.081 g) as a white solid.
Reaction SMILES: [CH:1]1([S:4]([CH2:7][C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([N+:14]([O-])=O)[CH:9]=2)(=[O:6])=[O:5])[CH2:3][CH2:2]1>Cl.[Cl-].[Ti+3].[Cl-].[Cl-]>[CH:1]1([S:4]([CH2:7][C:8]2[CH:9]=[C:10]([CH:11]=[CH:12][CH:13]=2)[NH2:14])(=[O:6])=[O:5])[CH2:3][CH2:2]1
Reactant: O=[N+]([O-])c1cccc(CS(=O)(=O)C2CC2)c1
Agent: [Ti+3]
Agent: Cl
Agent: [Cl-]
Product: Nc1cccc(CS(=O)(=O)C2CC2)c1

Procedure:
was prepared under similar conditions as described in the preparation of Intermediate 1.3. using 1-[(cyclopropylsulfonyl)methyl]-3-nitrobenzene and titanium(III)chloride solution (about 15%) in about 10% hydrochloric acid (Merck Schuchardt OHG). The batch was purified by chromatography (DCM/EtOH 95:5).
Reaction SMILES: C([NH:3][CH2:4][C:5]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[CH2:6][CH2:7][CH2:8][N:9]1[CH2:14][CH2:13][CH:12]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:11][CH2:10]1)=O.[OH-].[Na+]>CO>[NH2:3][CH2:4][C:5]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[CH2:6][CH2:7][CH2:8][N:9]1[CH2:14][CH2:13][CH:12]([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH2:11][CH2:10]1
Reactant: O=CNCC(CCCN1CCC(c2ccccc2)CC1)(c1ccccc1)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: NCC(CCCN1CCC(c2ccccc2)CC1)(c1ccccc1)c1ccccc1
Yield: 100.3 %

Procedure:
To a solution of 1-(5-formylamino-4,4-diphenylpentyl)-4-phenylpiperidine (2.07 g) in methanol (50 ml) was added 1N-sodium hydroxide (30 ml) and the mixture was refluxed overnight. This reaction mixture was concentrated to dryness and the group was extracted using methylene chloride and water. The organic layer was washed with water, dried over anhydrous sodium sulfate, and concentrated to dryness to provide the title compound (1.94 g) as yellow powder.
Reaction SMILES: [Cl:1][C:2]1[NH:3][CH:4]=[C:5]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[C:6]=1[Cl:7].[I:13][C:14](=[C:27]([I:29])[I:28])[CH2:15]OS(C1C=CC(C)=CC=1)(=O)=O.C(N(CC)CC)C.O>CN(C)C=O>[I:13][C:14](=[C:27]([I:29])[I:28])[CH2:15][N:3]1[CH:4]=[C:5]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[C:6]([Cl:7])=[C:2]1[Cl:1]
Reactant: Cc1ccc(S(=O)(=O)OCC(I)=C(I)I)cc1
Reactant: CCOC(=O)c1c[nH]c(Cl)c1Cl
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCOC(=O)c1cn(CC(I)=C(I)I)c(Cl)c1Cl
Temperature: 60 °C

Procedure:
To a solution of 104 mg (0.5 mmoles) of 2,3-dichloro-4-ethoxycarbonylpyrrole in 5 ml of dry N,N-dimethylformamide were added 303 mg (0.5 mmoles) of 2,3,3-triiodoallyl-p-toluenesulfonate and 0.07 ml (0.5 mmoles) of triethylamine and the resulting mixture was heated at 60° C. for 2 hours. The reaction mixture was cooled, 10 ml of cold water were added with stirring thereto and the so separated crystalline substance, 1-(2',3',3'-triiodoallyl)-2,3-dichloro-4-ethyoxycarbonylpyrrole, was recovered by filtration, washed with water and then dried. Yield 281 mg (90%), mp 117°-119° C.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH:9]([F:11])[F:10])=[C:4]([CH3:12])[CH:3]=1.[CH3:13][C@H:14]1[CH2:19][NH:18][CH2:17][C@@H:16]([CH3:20])[NH:15]1.C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1.CC([O-])(C)C.[K+]>C1(C)C=CC=CC=1.CC([O-])=O.CC([O-])=O.[Pd+2]>[F:10][CH:9]([F:11])[O:8][C:5]1[CH:6]=[CH:7][C:2]([N:18]2[CH2:17][CH:16]([CH3:20])[NH:15][CH:14]([CH3:13])[CH2:19]2)=[CH:3][C:4]=1[CH3:12]
Reactant: C[C@@H]1CNC[C@H](C)N1
Reactant: Cc1cc(Br)ccc1OC(F)F
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)[O-]
Solvent: Cc1ccccc1
Product: Cc1cc(N2CC(C)NC(C)C2)ccc1OC(F)F
Temperature: 80 °C
Reaction time: 4 h
Yield: 40.7 %

Procedure:
To 4-bromo-1-(difluoromethoxy)-2-methylbenzene (2.36 g, 10.00 mmol) in toluene (50 mL) was added cis-2,6-dimethylpiperazine (5 g, 58.14 mmol), Pd(OAc)2 (120 mg, 0.53 mmol), BINAP (380 mg, 0.61 mmol), and t-BuOK (2.2 g, 19.64 mmol). The resulting solution was stirred for 4 hours at 80° C. The solution was cooled to room temperature and washed with H2O (2×50 mL), dried over Na2SO4, concentrated, and purified by silica gel column chromatography (10:1 CH2Cl2/MeOH) to give 1.1 g (41%) of 1-(4-(difluoromethoxy)-3-methylphenyl)-3,5-dimethylpiperazine.
Reaction SMILES: C1(C)C=CC=CC=1.Cl[C:9]1[N:14]=[CH:13][CH:12]=[CH:11][N:10]=1.[CH:15]([C:17]1[CH:18]=[C:19](B(O)O)[CH:20]=[CH:21][CH:22]=1)=[O:16].C([O-])([O-])=O.[K+].[K+]>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.O.CN(C=O)C>[N:10]1[CH:11]=[CH:12][CH:13]=[N:14][C:9]=1[C:21]1[CH:22]=[C:17]([CH:18]=[CH:19][CH:20]=1)[CH:15]=[O:16]
Reactant: O=Cc1cccc(B(O)O)c1
Reactant: Clc1ncccn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: O
Solvent: CN(C)C=O
Product: O=Cc1cccc(-c2ncccn2)c1
Yield: 39.3 %

Procedure:
EX-603A) To a toluene (15 mL) solution of 2-chloropyrirnidine (1.00 g, 8.7 mmol) was added 3-formylphenylboronic acid (1.42 g, 9.5 mmol) and DMF (8 mL). To the resulting solution was added K2CO3 (2.63 g, 19.0 mmol) and Pd(PPh3)4 (0.52 g, 0.45 mmol). The slurry was heated to reflux under argon for 18 h. The cooled mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with brine, dried (MgSO4) and evaporated to an oil. Purification by flash chromatography on silica gel eluting with 20% ethyl acetate in hexane gave 0.63 g (39%) of the desired 3-(2-pyrimidinyl)benzaldehyde product as a brown oil which solidified upon standing. MS: m/z=185.1 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:16]=[CH:15][C:5]([CH2:6][N:7]2[CH:12]=[C:11](Br)[CH:10]=[CH:9][C:8]2=[O:14])=[C:4]([F:17])[CH:3]=1.[CH3:18][O:19][C:20]1[CH:25]=[CH:24][C:23](B(O)O)=[CH:22][CH:21]=1>>[F:17][C:4]1[CH:3]=[C:2]([Cl:1])[CH:16]=[CH:15][C:5]=1[CH2:6][N:7]1[CH:12]=[C:11]([C:23]2[CH:24]=[CH:25][C:20]([O:19][CH3:18])=[CH:21][CH:22]=2)[CH:10]=[CH:9][C:8]1=[O:14]
Reactant: O=c1ccc(Br)cn1Cc1ccc(Cl)cc1F
Reactant: COc1ccc(B(O)O)cc1
Product: COc1ccc(-c2ccc(=O)n(Cc3ccc(Cl)cc3F)c2)cc1
Yield: 100 %

Procedure:
According to Scheme 3 Method A: The title compound was prepared from 1-(4-chloro-2-fluorobenzyl)-5-bromopyridin-2(1H)-one (1 eq, 16.4 mmol, 5.20 g, Example 1 Step 2) and 4-methoxyphenylboronic acid (1.5 eq, 25.0 mmol, 3.80 g) according to the procedure described for Example 1 Step 3. The crude product was purified by flash chromatography over silica gel using CH2Cl2/AcOEt 95/5 to 80/20 as eluent to afford 1-(2-fluoro-4-chlorobenzyl)-5-(4-methoxyphenyl)pyridin-2(1H)-one (16.4 mmol, 5.64 g, 100%) as a white solid.
Reaction SMILES: [CH3:1][NH:2][C:3]1[CH:11]=[CH:10][C:6]([C:7](Cl)=[O:8])=[CH:5][C:4]=1[N+:12]([O-:14])=[O:13].[C:15]([O:19][C:20](=[O:23])[CH2:21][NH2:22])([CH3:18])([CH3:17])[CH3:16].C(N(CC)CC)C.C(=O)(O)[O-].[Na+]>C(Cl)Cl>[C:15]([O:19][C:20](=[O:23])[CH2:21][NH:22][C:7](=[O:8])[C:6]1[CH:10]=[CH:11][C:3]([NH:2][CH3:1])=[C:4]([N+:12]([O-:14])=[O:13])[CH:5]=1)([CH3:18])([CH3:17])[CH3:16]
Reactant: CC(C)(C)OC(=O)CN
Reactant: CNc1ccc(C(=O)Cl)cc1[N+](=O)[O-]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CNc1ccc(C(=O)NCC(=O)OC(C)(C)C)cc1[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 1 h
Yield: 83.3 %

Procedure:
(4-Methylamino-3-nitro-benzoylamino)-acetic acid tert-butyl ester (1.2 g) was prepared starting from 4-methylamino-3-nitro-benzoyl chloride (1 g), amino-acetic acid tert-butyl ester (721 mg), triethylamine (1.4 mL) in DCM (10 mL). The reaction was stirred at 0° C. for 1 h. The reaction was added to DCM (50 mL) and saturated sodium bicarbonate solution (50 mL). The phases were separated, and the aqueous phase was extracted twice with DCM. The combined organics were dried over sodium sulfate and then filtered. The solvent was evaporated and crude compound was purified by flash chromatography using DCM:methanol gradient.
Reaction SMILES: [N:1]1([CH2:6][CH2:7][O:8][C:9]2[CH:14]=[CH:13][C:12]([N:15]([CH2:24][C:25]3[CH:30]=[CH:29][CH:28]=[C:27]([O:31]C4CCCCO4)[CH:26]=3)[C:16]([CH:18]3[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]3)=[O:17])=[CH:11][CH:10]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.Cl.C(=O)(O)[O-].[Na+]>C(O)C>[OH:31][C:27]1[CH:26]=[C:25]([CH:30]=[CH:29][CH:28]=1)[CH2:24][N:15]([C:12]1[CH:13]=[CH:14][C:9]([O:8][CH2:7][CH2:6][N:1]2[CH2:5][CH2:4][CH2:3][CH2:2]2)=[CH:10][CH:11]=1)[C:16]([CH:18]1[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1)=[O:17]
Reactant: O=C(C1CCCCC1)N(Cc1cccc(OC2CCCCO2)c1)c1ccc(OCCN2CCCC2)cc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: O=C(C1CCCCC1)N(Cc1cccc(O)c1)c1ccc(OCCN2CCCC2)cc1

Procedure:
Cyclohexanecarboxylic acid [4-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-[3-(tetrahydro-pyran-2-yloxy)-benzyl]-amide was deprotected by stirring in a 3:1 solution of ethanol:1N HCl at room temperature for 24 hr. Saturated sodium bicarbonate solution was added until basic, and the aqueous solution was washed with methylene chloride. The organic layer was poured onto a silica gel plug and the product was eluted using a solvent gradient (methylene chloride to 10% methanol/methylene chloride) to obtain the title compound. MS 423.2 (M+1)+
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[C:4]1[C:9]([F:10])=[CH:8][CH:7]=[CH:6][C:5]=1[NH2:11].[F:13][C:14]1[CH:19]=[CH:18][C:17]([CH2:20][C:21](Cl)=[O:22])=[CH:16][CH:15]=1.C(=O)(O)[O-].[Na+]>C(Cl)Cl.CN(C1C=CN=CC=1)C>[CH3:1][O:2][C:3](=[O:12])[C:4]1[C:5]([NH:11][C:21](=[O:22])[CH2:20][C:17]2[CH:18]=[CH:19][C:14]([F:13])=[CH:15][CH:16]=2)=[CH:6][CH:7]=[CH:8][C:9]=1[F:10]
Reactant: COC(=O)c1c(N)cccc1F
Reactant: O=C(Cl)Cc1ccc(F)cc1
Agent: CN(C)c1ccncc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: COC(=O)c1c(F)cccc1NC(=O)Cc1ccc(F)cc1
Yield: 66.5 %

Procedure:
First, 2-amino-6-fluoro-benzoic acid methyl ester (1.00 g, 5.91 mmol) was dissolved in purified CH2Cl2, and after adding DMAP (0.04 g, 0.30 mmol) and (4-fluoro-phenyl)-acetyl chloride (1.22 g, 6.50 mmol) at 0° C., reacted together at normal temperature for 10 hours. After adding cold sodium bicarbonate solution containing ice, the reaction mixture was extracted with CH2Cl2, washed with distilled water, dried with MgSO4, and then concentrated under reduced pressure to obtain crude 2-fluoro-6-[2-(4-fluoro-phenyl)-acetylamino]-benzoic acid methyl ester (1.20 g, 61%) as the solid.
Reaction SMILES: Cl.[CH2:2]([N:6]([CH2:11][CH2:12][CH2:13]Cl)[CH2:7][CH2:8][CH2:9][CH3:10])[CH2:3][CH2:4][CH3:5].[OH:15][C:16]1[CH:23]=[CH:22][C:19]([CH:20]=[O:21])=[CH:18][CH:17]=1.C(=O)([O-])[O-].[K+].[K+].CCC(C)=O>O>[CH2:2]([N:6]([CH2:7][CH2:8][CH2:9][CH3:10])[CH2:11][CH2:12][CH2:13][O:15][C:16]1[CH:23]=[CH:22][C:19]([CH:20]=[O:21])=[CH:18][CH:17]=1)[CH2:3][CH2:4][CH3:5]
Reactant: CCCCN(CCCC)CCCCl
Reactant: O=Cc1ccc(O)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCC(C)=O
Product: CCCCN(CCCC)CCCOc1ccc(C=O)cc1
Temperature: 80 °C
Reaction time: 10 h
Yield: 90.9 %

Procedure:
9.69 g of dibutylamino propylchloride HCl salt (IV) (0.04 mol, 1 eq), 5 g of 4-hydroxybenzaldehyde (III) (0.04 mol, 1 eq), 17 g of potassium carbonate (0.12 mol, 3 eq) and 30 mL of MEK are added to the reaction flask. The suspension is heated to 80° C. and it is stirred for 10 hours at this temperature. Then the mixture is cooled to room temperature, 40 mL of water is added and the brown solution is stirred for 30 min. After phase separation the organic phase is washed with 15 mL of water and the solvent is evaporated to obtain 10.6 g of compound (V) as a yellowish-brown solid (89%).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:8]([Br:11])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].N1C=CC=CC=1.Cl[C:19](Cl)([O:21]C(=O)OC(Cl)(Cl)Cl)Cl>C(#N)C.ClCCl>[Br:11][C:8]1[CH:9]=[CH:10][C:2]2[NH:1][C:19](=[O:21])[O:5][C:4](=[O:6])[C:3]=2[CH:7]=1
Reactant: Nc1ccc(Br)cc1C(=O)O
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: ClCCl
Solvent: CC#N
Solvent: c1ccncc1
Product: O=c1[nH]c2ccc(Br)cc2c(=O)o1
Reaction time: 2 h
Yield: 292.1 %

Procedure:
A solution of 2-amino-5-bromo-benzoic acid (280 g, 1.3 mol) in acetonitrile (1.3 l) was warmed up to 50–55° C. Pyridine (206 g, 2.61 mol) and a solution of triphosgene (128.8 g, 0.43 mol) in dichloromethane (720 ml) were simultaneously added dropwise. After completion of the addition, the mixture was stirred at 50–55° C. for an additional 2 h. The solvent was removed under reduced pressure and water was added. The precipitate was collected by filtration, successively washed with water and chilled dichloromethane, and then dried under vacuum to afford the desired product 6-bromo-1H-benzo[d][1,3]oxazine-2,4-dione (304 g, 98%). This material was used in the next step without further purification.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5](/[C:11](=[CH:14]/[C:15]2[CH:20]=[CH:19][C:18]([N+:21]([O-])=O)=[CH:17][CH:16]=2)/[C:12]#[N:13])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]>C(O)(=O)C.[Zn]>[NH2:21][C:18]1[CH:19]=[CH:20][C:15](/[CH:14]=[C:11](/[C:5]2[CH:6]=[CH:7][C:8]([O:9][CH3:10])=[C:3]([O:2][CH3:1])[CH:4]=2)\[C:12]#[N:13])=[CH:16][CH:17]=1
Reactant: COc1ccc(/C(C#N)=C/c2ccc([N+](=O)[O-])cc2)cc1OC
Agent: [Zn]
Solvent: CC(=O)O
Product: COc1ccc(/C(C#N)=C/c2ccc(N)cc2)cc1OC
Yield: 95.6 %

Procedure:
Compound 19 (880 mg) was dissolved in acetic acid. Zinc powder was added to the resultant solution, and the resultant mixture was stirred for four hours. The mixture was concentrated to dryness under reduced pressure, followed by purification by use of a silica gel column, to thereby produce the target product (760 mg, yield: 95%).
Reaction SMILES: [CH3:1][C@H:2]([NH2:9])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH2:10]([O:17][C:18]1[CH:19]=[C:20]([CH:23]=[CH:24][CH:25]=1)[CH:21]=O)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>COC(C)(C)C>[CH2:10]([O:17][C:18]1[CH:19]=[C:20]([CH:23]=[CH:24][CH:25]=1)[CH:21]=[N:9][C@@H:2]([CH3:1])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1)[C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: O=Cc1cccc(OCc2ccccc2)c1
Reactant: C[C@H](N)c1ccccc1
Solvent: COC(C)(C)C
Product: C[C@H](N=Cc1cccc(OCc2ccccc2)c1)c1ccccc1
Temperature: 25 °C
Reaction time: 72 h
Yield: 115.5 %

Procedure:
0.12 g (0.97 mmol) of (S)-α-methylbenzylamine and 0.25 g (1.19 mmol) of 3-benzyloxybenzaldehyde are mixed in 4 ml of t-butyl methyl ether and stirred for three days at room temperature, and then evaporated under reduced pressure to give 0.35 g (1.12 mmol) of (S)-N-(3-benzyloxybenzylidene)-α-methylbenzylamine (Yield: 115%, purity 85%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:35]=[CH:36][C:37]=1[F:38])[CH2:5][N:6]1[CH:11]=[CH:10][CH:9]=[C:8]([C:12]([NH:14][CH2:15][C:16]2[CH:17]=[C:18]([C:22]3[C:30]4[C:25](=[N:26][CH:27]=[C:28]([C:31]([OH:33])=O)[CH:29]=4)[NH:24][CH:23]=3)[CH:19]=[CH:20][CH:21]=2)=[O:13])[C:7]1=[O:34].[Cl-].[NH4+].F[P-](F)(F)(F)(F)F.C[N+:49](C)=C(N(C)C)ON1C2N=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C.FC(F)(F)C(O)=O>CN(C)C=O>[F:1][C:2]1[CH:3]=[C:4]([CH:35]=[CH:36][C:37]=1[F:38])[CH2:5][N:6]1[CH:11]=[CH:10][CH:9]=[C:8]([C:12]([NH:14][CH2:15][C:16]2[CH:17]=[C:18]([C:22]3[C:30]4[C:25](=[N:26][CH:27]=[C:28]([C:31]([NH2:49])=[O:33])[CH:29]=4)[NH:24][CH:23]=3)[CH:19]=[CH:20][CH:21]=2)=[O:13])[C:7]1=[O:34]
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Reactant: O=C(O)c1cnc2[nH]cc(-c3cccc(CNC(=O)c4cccn(Cc5ccc(F)c(F)c5)c4=O)c3)c2c1
Agent: F[P-](F)(F)(F)(F)F
Agent: [Cl-]
Agent: [NH4+]
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O=C(O)C(F)(F)F
Product: NC(=O)c1cnc2[nH]cc(-c3cccc(CNC(=O)c4cccn(Cc5ccc(F)c(F)c5)c4=O)c3)c2c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Into a vial was dissolved 3-[3-({[1-(3,4-difluoro-benzyl)-2-oxo-1,2-dihydro-pyridine-3-carbonyl]-amino}-methyl)-phenyl]-1H-pyrrolo[2,3-b]pyridine-5-carboxylic acid (53 mg, 0.00010 mol) and ammonium chloride (15 mg, 0.00028 mol, Aldrich) and N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate (58 mg, 0.00015 mol, Applied Biosystems) in N,N-dimethylformamide (1.0 mL, Acros). To this was added N,N-diisopropylethylamine (89 uL, 0.00051 mol, Aldrich) and the reaction was stirred at room temperature for 2 hours. The reaction was neutralized with trifluoroacetic acid (100 uL) and purified directly by preparative HPLC to yield the title compound in 30.2 mg (47%) yield. 1H NMR (400 MHz, CDCl3-MeOH-d4) d ppm 9.158 (m, 1H) 8.849 (m, 1H) 8.378 (m, 1H) 7.679 (m, 1H) 7.601-7.477 (m, 2H) 7.435-7.289 (m, 2H) 7.066-6.868 (m, 4H) 6.396 (m, 1H) 5.035 (m, 2H), 4.561 (m, 2H); MS m/z=514.29 M+H.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([C:7]2[CH:12]=[CH:11][C:10]([C:13]3[N:22]=[C:21]([NH:23][CH2:24][CH:25]4S[CH2:29][CH2:28][N:27]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH2:26]4)[C:20]4[C:15](=[N:16][CH:17]=[CH:18][N:19]=4)[CH:14]=3)=[CH:9][CH:8]=2)[CH2:3][CH2:2]1.ClC1C=C(C=CC=1)C(OO)=O.[S:49]([O-:53])([O-])(=[O:51])=S.[Na+].[Na+]>C(Cl)Cl>[O:1]1[CH2:6][CH2:5][N:4]([C:7]2[CH:12]=[CH:11][C:10]([C:13]3[N:22]=[C:21]([NH:23][CH2:24][CH:25]4[S:49](=[O:53])(=[O:51])[CH2:29][CH2:28][N:27]([C:31]([O:33][C:34]([CH3:35])([CH3:37])[CH3:36])=[O:32])[CH2:26]4)[C:20]4[C:15](=[N:16][CH:17]=[CH:18][N:19]=4)[CH:14]=3)=[CH:9][CH:8]=2)[CH2:3][CH2:2]1
Reactant: O=S([O-])([O-])=S
Reactant: CC(C)(C)OC(=O)N1CCSC(CNc2nc(-c3ccc(N4CCOCC4)cc3)cc3nccnc23)C1
Agent: O=C(OO)c1cccc(Cl)c1
Agent: [Na+]
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCS(=O)(=O)C(CNc2nc(-c3ccc(N4CCOCC4)cc3)cc3nccnc23)C1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of tert-butyl 2-((7-(4-morpholinophenyl)pyrido[4,3-b]pyrazin-5-ylamino)methyl)thiomorpholine-4-carboxylate (178 mg, 0.34 mmol) in CH2Cl2 (5 mL) was added 3-chloroperoxybenzoic acid (70%, 251 mg, 1.02 mmol) at 0° C. The resulting mixture was stirred at room temperature for 3 hours, and subsequently, a saturated aqueous sodium thiosulfate solution was added and the mixture was stirred for another 30 minutes. The layers were separated and the aqueous layer was extracted twice with EtOAc. The combined EtOAc layers were washed twice with an aqueous Na2CO3 solution. The combined organic layers were dried (Na2SO4), filtered and concentrated in vacuo to afford title compound 52 mg. MS (m/z): 555 (M+H)+
Reaction SMILES: [CH:1]1([O:6][C:7]2[CH:8]=[C:9]([CH:15]3[CH2:19][CH2:18][CH:17](O)[CH2:16]3)[CH:10]=[CH:11][C:12]=2[O:13][CH3:14])[CH2:5][CH2:4][CH2:3][CH2:2]1.[OH-].[Na+].[CH3:23][O:24]S(OC)(=O)=O.O>C(Cl)Cl.[Br-].C([N+](CCCC)(CCCC)CCCC)CCC>[CH:1]1([O:6][C:7]2[CH:8]=[C:9]([C:15]3([O:24][CH3:23])[CH2:19][CH2:18][CH2:17][CH2:16]3)[CH:10]=[CH:11][C:12]=2[O:13][CH3:14])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COc1ccc(C2CCC(O)C2)cc1OC1CCCC1
Reactant: COS(=O)(=O)OC
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: COc1ccc(C2(OC)CCCC2)cc1OC1CCCC1
Reaction time: 72 h

Procedure:
3-(3-Cyclopentyloxy-4-methoxyphenyl)-cyclopentan-1-ol (predominantly cis, 130 mg, 0.47 mmol) (E9) in methylene chloride (5 ml) was stirred vigorously with aqueous sodium hydroxide (50%, 0.2 ml), tetrabutylammonium bromide (3 mg) and dimethylsulfate (0.1 ml, 1.05 mmol) under an argon atmosphere. The resulting mixture was stirred at room temperature for 24 hr, whereupon additional aqueous sodium hydroxide (0.2 ml) , tetrabutylammonium bromide (3 mg) and dimethylsulfate (0.1 ml) were added. After an additional 72 hr, the mixture was poured into water and extracted with methylene chloride. The extracts were dried (sodium sulfate) and concentrated under reduced pressure. Purification by flash chromatography, eluting with 1.5:1 ether/hexanes, provided the title compound as an oil.
Reaction SMILES: C(OC([N:8]1[CH:13]2[CH2:14][CH2:15][CH:9]1[CH2:10][C:11]([OH:22])([C:16]1[N:21]=[CH:20][CH:19]=[CH:18][N:17]=1)[CH2:12]2)=O)(C)(C)C.[ClH:23]>O1CCOCC1>[ClH:23].[N:17]1[CH:18]=[CH:19][CH:20]=[N:21][C:16]=1[C:11]1([OH:22])[CH2:12][CH:13]2[NH:8][CH:9]([CH2:15][CH2:14]2)[CH2:10]1
Reactant: CC(C)(C)OC(=O)N1C2CCC1CC(O)(c1ncccn1)C2
Agent: Cl
Solvent: C1COCCO1
Product: OC1(c2ncccn2)CC2CCC(C1)N2
Reaction time: 1 h

Procedure:
3-Hydroxy-3-pyrimidin-2-yl-8-aza-bicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (0.13 g, 0.426 mmol) was dissolved in a solution of hydrogen chloride in dioxane (4 N, 3 mL). The mixture was stirred for 1 hour and the solvent removed by evaporation under vacuum. The solid was triturated from ether to afford the title compound (0.113 g). LCMS m/z 206.1 [M+H]+. R.T.=0.34 min (Analytical Method 3).
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[C:4]([O:11][CH3:12])[N:3]=1.[CH3:13][N:14]([CH3:19])[CH2:15][CH2:16][CH2:17][NH2:18]>C(O)C>[CH3:12][O:11][C:4]1[N:3]=[C:2]([NH:18][CH2:17][CH2:16][CH2:15][N:14]([CH3:19])[CH3:13])[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=1
Reactant: CN(C)CCCN
Reactant: COc1ccc([N+](=O)[O-])c(Cl)n1
Solvent: CCO
Product: COc1ccc([N+](=O)[O-])c(NCCCN(C)C)n1
Temperature: 0 °C
Yield: 78.1 %

Procedure:
4 g (0.0212 mol) of the product 2-chloro-3-nitro-6-methoxypyridine, 40 ml of ethanol and 5.33 ml (0.0424 mol) of 3-dimethylaminopropylamine are placed in a fully equipped round-bottomed flask. The mixture is refluxed for 2 hours with stirring and is then poured onto an ice/water mixture with stirring. The precipitate formed is filtered off by suction and dried under vacuum to constant weight. 4.2 g of yellow powder are obtained, ie a yield of 78.1%.