Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[C:18]3[C:13](=[CH:14][C:15]([OH:21])=[C:16]([O:19][CH3:20])[CH:17]=3)[N:12]=[CH:11][N:10]=2)[CH:5]=[CH:4][C:3]=1[NH:22][C:23]([NH:25][CH2:26][CH2:27][CH3:28])=[O:24].C(=O)([O-])[O-].[K+].[K+].C(Br)[CH2:36][CH2:37][CH2:38][CH2:39][Br:40]>CN(C)C=O>[Br:40][CH2:39][CH2:38][CH2:37][CH2:36][O:21][C:15]1[CH:14]=[C:13]2[C:18]([C:9]([O:8][C:6]3[CH:5]=[CH:4][C:3]([NH:22][C:23]([NH:25][CH2:26][CH2:27][CH3:28])=[O:24])=[C:2]([Cl:1])[CH:7]=3)=[N:10][CH:11]=[N:12]2)=[CH:17][C:16]=1[O:19][CH3:20]
Reactant: BrCCCCCBr
Reactant: CCCNC(=O)Nc1ccc(Oc2ncnc3cc(O)c(OC)cc23)cc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCNC(=O)Nc1ccc(Oc2ncnc3cc(OCCCCBr)c(OC)cc23)cc1Cl
Temperature: 25 °C
Reaction time: 3 h
Yield: 46 %

Procedure:
N-{2-Chloro-4-[(7-hydroxy-6-methoxy-4-quinazolinyl)oxy]phenyl}-N′-propylurea (70 mg), potassium carbonate (30 mg), and pentamethylene bromide (80 μl) were dissolved in N,N-dimethylformamide (5 ml), and the solution was stirred at room temperature for 3 hr. The solvent was removed by distillation under the reduced pressure. Water was added to the residue, and the mixture was extracted with chloroform. The organic layer was dried over anhydrous sodium sulfate. The solvent was removed by distillation under the reduced pressure. The residue was washed with ether to give 43 mg (yield 46%) of N-(4-{[7-(4-bromobutoxy)-6-methoxy-4-quinazolinyl]-oxy}-2-chlorophenyl)-N′-propylurea as an intermediate. The intermediate (43 mg), potassium carbonate (30 mg), and morpholine (40 μl) were dissolved in N,N-dimethylformamide (4 ml), and the solution was stirred at room temperature overnight. The solvent was removed by distillation under the reduced pressure. A saturated aqueous sodium hydrogencarbonate solution was added to the residue, and the mixture was extracted with chloroform. The organic layer was dried over anhydrous sodium sulfate. The solvent was removed by distillation under the reduced pressure. The residue was purified by chromatography on silica gel by development with chloroform/methanol to give 23 mg (yield 53%) of the title compound.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([C:13]1[CH:14]=[C:15]([C:21]2[CH:22]=[C:23]3[C:29](I)=[C:28]([CH:31]4[CH2:33][CH2:32]4)[N:27]([C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[C:24]3=[N:25][CH:26]=2)[CH:16]=[CH:17][C:18]=1[O:19][CH3:20])[S:9]([CH3:12])(=[O:11])=[O:10])=[O:7])([CH3:4])([CH3:3])[CH3:2].[F:41][C:42]1[CH:43]=[C:44]([CH:62]=[CH:63][CH:64]=1)[CH2:45][N:46]1[C:50]([CH3:51])=[C:49](B2OC(C)(C)C(C)(C)O2)[C:48]([CH3:61])=[N:47]1.C(=O)([O-])[O-].[Na+].[Na+]>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.COCCOC.O>[C:1]([O:5][C:6]([N:8]([C:13]1[CH:14]=[C:15]([C:21]2[CH:22]=[C:23]3[C:29]([C:49]4[C:48]([CH3:61])=[N:47][N:46]([CH2:45][C:44]5[CH:62]=[CH:63][CH:64]=[C:42]([F:41])[CH:43]=5)[C:50]=4[CH3:51])=[C:28]([CH:31]4[CH2:33][CH2:32]4)[N:27]([C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[C:24]3=[N:25][CH:26]=2)[CH:16]=[CH:17][C:18]=1[O:19][CH3:20])[S:9]([CH3:12])(=[O:11])=[O:10])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1nn(Cc2cccc(F)c2)c(C)c1B1OC(C)(C)C(C)(C)O1
Reactant: COc1ccc(-c2cnc3c(c2)c(I)c(C2CC2)n3C(=O)OC(C)(C)C)cc1N(C(=O)OC(C)(C)C)S(C)(=O)=O
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: [Na+]
Solvent: COCCOC
Solvent: O
Product: COc1ccc(-c2cnc3c(c2)c(-c2c(C)nn(Cc4cccc(F)c4)c2C)c(C2CC2)n3C(=O)OC(C)(C)C)cc1N(C(=O)OC(C)(C)C)S(C)(=O)=O
Yield: 122.6 %

Procedure:
Using similar reaction conditions as described in step-ii of example-1, tert-butyl 5-(3-(N-(tert-butoxycarbonyl)methylsulfonamido)-4-methoxyphenyl)-2-cyclopropyl-3-iodo-1H-pyrrolo[2,3-b]pyridine-1-carboxylate (intermediate 36) (110 mg, 0.1610 mmol) was coupled with 1-(3-fluorobenzyl)-3,5-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (intermediate 16) (61 mg, 0.1771 mmol) in sodium carbonate (51 mg, 0.4831 mmol), Pd(PPh3)4 (10 mg, 0.0080 mmol) and DME/water (3/1 ml) to afford 150 mg of the crude product which was taken as such for next reaction.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5]([C:8]2[CH:16]=[CH:15][C:11]([C:12]([OH:14])=O)=[CH:10][CH:9]=2)=[CH:4][C:3]=1[C:17](=[O:25])[NH:18][C:19]1[CH:24]=[CH:23][N:22]=[CH:21][CH:20]=1.[OH:26][CH2:27][CH2:28][NH:29][CH2:30][CH2:31][OH:32]>>[NH2:1][C:2]1[N:7]=[CH:6][C:5]([C:8]2[CH:9]=[CH:10][C:11]([C:12](=[O:14])[N:29]([CH2:30][CH2:31][OH:32])[CH2:28][CH2:27][OH:26])=[CH:15][CH:16]=2)=[CH:4][C:3]=1[C:17]([NH:18][C:19]1[CH:20]=[CH:21][N:22]=[CH:23][CH:24]=1)=[O:25]
Reactant: OCCNCCO
Reactant: Nc1ncc(-c2ccc(C(=O)O)cc2)cc1C(=O)Nc1ccncc1
Product: Nc1ncc(-c2ccc(C(=O)N(CCO)CCO)cc2)cc1C(=O)Nc1ccncc1

Procedure:
Reaction of 4-[6-amino-5-(pyridin-4-ylcarbamoyl)-pyridin-3-yl]-benzoic acid with 2-(2-hydroxy-ethylamino)-ethanol gives “A93”; method 2: HPLC/MS: 1.62 min, [M+H]=422;
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([CH2:7][CH2:8][N:9]2[CH:14]=[CH:13][N:12]3[CH:15]=[CH:16][CH:17]=[C:11]3[CH2:10]2)=[CH:3][CH:2]=1.Cl>O=[Pt]=O.C(O)C>[NH:1]1[CH2:6][CH2:5][CH:4]([CH2:7][CH2:8][N:9]2[CH:14]=[CH:13][N:12]3[CH:15]=[CH:16][CH:17]=[C:11]3[CH2:10]2)[CH2:3][CH2:2]1
Reactant: C1=Cn2cccc2CN1CCc1ccncc1
Agent: O=[Pt]=O
Agent: Cl
Solvent: CCO
Product: C1=Cn2cccc2CN1CCC1CCNCC1
Yield: 121.9 %

Procedure:
A pressure bottle was charged with 1 g PtO2, 4.5 g of 2-(4-pyridylethyl)pyrrolo[1,2-a]pyrazine (0.0195 mole), 180 ml aqueous ethanol (2/1), and 13 ml of concentrated hydrochloric acid and shaken under 60 psi on a Parr hydrogenation apparatus. When hydrogenation was completed the reaction mixture was filtered free of catalyst, the catalyst washed with ethanol and the combined filtrate concentrated under reduced pressure. The residue was crystallized from methanol. There was obtained 5.5 g (80%) of 2-(4-piperidylethyl)-pyrrolo[1,2-a]pyrazine as the hydrochloride; m.p. 295°-298° C.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][N:11](C(OC(C)(C)C)=O)[CH2:10][CH2:9]2)=[CH:4][C:3]=1[NH:21][S:22]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)(=[O:24])=[O:23].[C:31]1([CH3:41])[CH:36]=[CH:35][C:34]([S:37](Cl)(=[O:39])=[O:38])=[CH:33][CH:32]=1>>[CH3:41][C:31]1[CH:36]=[CH:35][C:34]([S:37]([NH:1][C:2]2[CH:7]=[CH:6][C:5]([N:8]3[CH2:9][CH2:10][NH:11][CH2:12][CH2:13]3)=[CH:4][C:3]=2[NH:21][S:22]([C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)(=[O:23])=[O:24])(=[O:39])=[O:38])=[CH:33][CH:32]=1
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(N)c(NS(=O)(=O)c3ccccc3)c2)CC1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Product: Cc1ccc(S(=O)(=O)Nc2ccc(N3CCNCC3)cc2NS(=O)(=O)c2ccccc2)cc1

Procedure:
4-Methyl-N-[2-[(phenylsulfonyl)amino]-4-(1-piperazinyl)phenyl]benzenesulfonamide was synthesized from N-{2-amino-5-(4-t-butyloxycarbonyl-piperazinyl)-phenyl}benzenesulfonamide and p-toluenesulfonylchloride (46 mg, 0.239 mmol) according to general method 3 to give 70 mg of a purple solid. MS (posES-FIA) m/z=Found: 487.2; Calcd: 487.14; 1H-NMR δ 7.73-7.45 (m, 7H), 7.26 (d, 2H), 6.74 (s, 1H), 6.62-6.60 (m, 2H), 3.69 (app t, 2H), 3.39 (app t, 2H), 3.29-3.74 (m, 4H), 2.38 (s, 3H).
Reaction SMILES: [C:1]([CH2:3][C:4]([NH2:6])=[O:5])#[N:2].[O-]CC.[Na+].[NH2:11][C:12]1[CH:19]=[CH:18][CH:17]=[CH:16][C:13]=1[CH:14]=O>C(O)C>[NH2:2][C:1]1[C:3]([C:4]([NH2:6])=[O:5])=[CH:14][C:13]2[C:12](=[CH:19][CH:18]=[CH:17][CH:16]=2)[N:11]=1
Reactant: N#CCC(N)=O
Reactant: Nc1ccccc1C=O
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: NC(=O)c1cc2ccccc2nc1N
Temperature: 50 °C
Yield: 84 %

Procedure:
Cyanoacetamide (19.4 g., 0.23 mole) is added to a solution of sodium ethoxide (6.65 g., 0.29 mole) in absolute ethanol (460 ml.) maintained at 50° C. The mixture is stirred and o-aminobenzaldehyde (28.0 g., 0.23 mole) in absolute ethanol (100 ml.) added. After fifteen minutes stirring at 50° C., the reaction mixture is cooled in an ice bath, filtered and dried to give 34.5 g. (84% yield) of product; m.p. 240°-242° C.
Reaction SMILES: [OH-].[Na+].[C:3]([NH:7][NH:8][C:9]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=1)=[O:10])([CH3:6])([CH3:5])[CH3:4].[Br:17][C:18]1[CH:26]=[CH:25][CH:24]=[CH:23][C:19]=1[C:20](Cl)=[O:21]>C1(C)C=CC=CC=1>[C:3]([N:7]([C:20](=[O:21])[C:19]1[CH:23]=[CH:24][CH:25]=[CH:26][C:18]=1[Br:17])[NH:8][C:9]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=1)=[O:10])([CH3:6])([CH3:4])[CH3:5]
Reactant: CC(C)(C)NNC(=O)c1ccccn1
Reactant: O=C(Cl)c1ccccc1Br
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Product: CC(C)(C)N(NC(=O)c1ccccn1)C(=O)c1ccccc1Br
Temperature: 23 °C
Reaction time: 8 h
Yield: 49.3 %

Procedure:
An aqueous solution of sodium hydroxide (1.24 g of 50% NaOH diluted with 5 ml of water) was added to a solution of N'-t-butyl-N-(2-pyridinecarbonyl)hydrazine (1.0 g, 0.00518 mol) in 20 ml of toluene at 23° C. The mixture was cooled and treated with 2-bromobenzoyl chloride (1.137 g, 0.00518 mol). The mixture was then stirred at 23° C. overnight. The solids were removed by filtration, washed with water and dried to afford 0.96 g of N'-t-butyl-N-(2-pyridinecarbonyl)-N'-(2-bromobenzoyl)hydrazine as a white solid. m.p. 179°-180° C.
Reaction SMILES: C([N:8](CC1C=CC=CC=1)[C:9]1[CH:14]=[CH:13][C:12]([F:15])=[C:11]([C:16]2[C:20]([C:21]3[CH:26]=[CH:25][N:24]=[CH:23][CH:22]=3)=[CH:19][NH:18][N:17]=2)[C:10]=1[F:27])C1C=CC=CC=1>CO.[OH-].[OH-].[Pd+2]>[F:27][C:10]1[C:11]([C:16]2[C:20]([C:21]3[CH:26]=[CH:25][N:24]=[CH:23][CH:22]=3)=[CH:19][NH:18][N:17]=2)=[C:12]([F:15])[CH:13]=[CH:14][C:9]=1[NH2:8]
Reactant: Fc1ccc(N(Cc2ccccc2)Cc2ccccc2)c(F)c1-c1n[nH]cc1-c1ccncc1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Product: Nc1ccc(F)c(-c2n[nH]cc2-c2ccncc2)c1F
Reaction time: 12 h
Yield: 56 %

Procedure:
To dibenzyl-[2,4-difluoro-3-(4-pyridin-4-yl-1H-pyrazol-3-yl)-phenyl]-amine (1.795 g, 3.97 mmol) in methanol (100 mL) was added 20% palladium hydroxide on carbon (646 mg). The reaction was stirred under hydrogen atmosphere for 12 hours (45 psi). The reaction was filtered to remove the catalyst, and then concentrated under reduced pressure. The crude was purified by silica gel column chromatography eluting with methanol 7% in methylene chloride to give 2,4-difluoro-3-(4-pyridin-4-yl-1H-pyrazol-3-yl)-phenylamine (yield 56% over three steps).
Reaction SMILES: [C:1]([C:3]1[CH:22]=[CH:21][C:6]([C:7]([N:9]2[CH2:14][CH2:13][N:12]([CH2:15][C:16](OCC)=[O:17])[CH2:11][CH2:10]2)=[O:8])=[CH:5][CH:4]=1)#[N:2].[NH2:23][NH2:24]>CCO>[C:1]([C:3]1[CH:22]=[CH:21][C:6]([C:7]([N:9]2[CH2:14][CH2:13][N:12]([CH2:15][C:16]([NH:23][NH2:24])=[O:17])[CH2:11][CH2:10]2)=[O:8])=[CH:5][CH:4]=1)#[N:2]
Reactant: CCOC(=O)CN1CCN(C(=O)c2ccc(C#N)cc2)CC1
Reactant: NN
Solvent: CCO
Product: N#Cc1ccc(C(=O)N2CCN(CC(=O)NN)CC2)cc1
Yield: 55.8 %

Procedure:
Synthesized according to General Procedure C with modification as noted: 51e (5.59 g, 18.6 mmol, 1.0 equiv.), anhydrous hydrazine (2.4 mL, 74.4 mmol, 4.0 equiv.), EtOH (35 mL, 0.5 M). After extraction with CH2Cl2, the aqueous layer was extracted with EtOAc (3×). 46e (2.98 g, 55.8%) was obtained as an off-white solid after extraction without further purification. 1H-NMR (500 MHz, CDCl3) δ 8.02 (br s, 1H), 7.70 (d, 2H, J=8.5 Hz), 7.48 (d, 2H, J=8.5 Hz), 3.86 (br d, 2H, J=3.5 Hz), 3.78 (br s, 2H), 3.37 (br s, 2H), 3.11 (s, 2H), 2.60 (br s, 2H), 2.46 (br s, 2H). 13C-NMR (125 MHz, CDCl3) δ 169.8, 168.4, 139.8, 132.6, 127.9, 118.1, 113.8, 60.6, 53.8 (br), 53.3 (br), 47.6 (br), 42.2 (br). HRMS (ESI): 288.1464 (M+1); calcd. for C14H18N5O2: 288.1461.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[CH:9]([OH:12])[CH:10]=[CH2:11].[Cr](O[Cr]([O-])(=O)=O)([O-])(=O)=O.[K+].[K+].S(=O)(=O)(O)O>C(OCC)(=O)C>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9](=[O:12])[CH:10]=[CH2:11]
Reactant: C=CC(O)c1ccc(Cl)cc1Cl
Agent: O=[Cr](=O)([O-])O[Cr](=O)(=O)[O-]
Agent: O=S(=O)(O)O
Agent: [K+]
Solvent: CCOC(C)=O
Product: C=CC(=O)c1ccc(Cl)cc1Cl
Temperature: 17.5 °C
Reaction time: 1.5 h
Yield: 55 %

Procedure:
73.5 g (362 mmol) of the compound from Example 185A in 2.21 of dichloromethane were mixed with 105 g (1.21 mol) of activated manganese dioxide and heated under reflux for 20 h. A further 105 g (1.21 mol) of activated manganese dioxide was added in each case after 2 and 4 h. Filtration with suction through kieselguhr, washing with dichloromethane and concentration resulted in 57.0 g of a mixture of the title compound and the compound from Example 185A. 47.7 g (162 mmol) of potassium dichromate were added to 47.0 g of this mixture in 329 ml of 10% strength sulfuric acid, occasionally cooling at 15-20° C., and the mixture was stirred for 1.5 h. This was followed by addition of 400 ml of ethyl acetate, neutralization by adding sodium bicarbonate, filtration through kieselguhr, washing with ethyl acetate, separation of the phases, drying of the organic phase and concentration. The crude product was purified by column chromatography on silica gel (mobile phase: cyclohexane/ethyl acetate 6/1) to result in 17.8 g (55%) of the title compound.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([O:8]C)[C:5]([C:10]([NH:12][CH2:13][CH:14]2[CH2:19][CH2:18][N:17]([CH2:20][CH2:21][CH2:22][O:23][CH3:24])[CH2:16][CH2:15]2)=[O:11])=[CH:4][C:3]=1[Cl:25]>Cl>[NH2:1][C:2]1[NH:7][C:6](=[O:8])[C:5]([C:10]([NH:12][CH2:13][CH:14]2[CH2:19][CH2:18][N:17]([CH2:20][CH2:21][CH2:22][O:23][CH3:24])[CH2:16][CH2:15]2)=[O:11])=[CH:4][C:3]=1[Cl:25]
Reactant: COCCCN1CCC(CNC(=O)c2cc(Cl)c(N)nc2OC)CC1
Agent: Cl
Product: COCCCN1CCC(CNC(=O)c2cc(Cl)c(N)[nH]c2=O)CC1
Temperature: 25 °C
Yield: 55.4 %

Procedure:
A solution of 6-amino-5-chloro-2-(methyloxy)-N-({1-[3-(methyloxy)propyl]-4-piperidinyl}methyl)-3-pyridinecarboxamide (step 3, 160 g, 0.43 mmol) in concentrated hydrochloric acid (2.5 ml) and 10% methanolic hydrochloric acid (10 ml) was stirred at 80° C. for 7 h. After cooling to room temperature, the solvent was removed in vacuo. The residue was suspended in diisopropyl ether and the precipitate was collected by filtration to give 85 mg (46%) of the title compound as a white amorphous solid.
Reaction SMILES: [Na].[O:2]=[C:3]1[NH:7][C:6](=[O:8])[CH:5](P(OCC)(=O)OCC)[NH:4]1.[N+:17]([C:20]1[CH:27]=[CH:26][C:25]([N:28]2[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]2)=[CH:24][C:21]=1[CH:22]=O)([O-:19])=[O:18]>C(O)C>[N+:17]([C:20]1[CH:27]=[CH:26][C:25]([N:28]2[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]2)=[CH:24][C:21]=1[CH:22]=[C:5]1[NH:4][C:3](=[O:2])[NH:7][C:6]1=[O:8])([O-:19])=[O:18]
Reactant: O=Cc1cc(N2CCCCC2)ccc1[N+](=O)[O-]
Reactant: CCOP(=O)(OCC)C1NC(=O)NC1=O
Agent: [Na]
Solvent: CCO
Product: O=C1NC(=O)C(=Cc2cc(N3CCCCC3)ccc2[N+](=O)[O-])N1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 92.9 %

Procedure:
Sodium (0.6 g, 0.026 g atom) was dissolved in absolute ethanol (200 mL) and diethyl 2,4-dioxoimidazolidine-5-phosphonate (6.0 g, 25 mmol) added. After 10 minutes, 2-nitro-5-(1-piperidinyl)benzaldehyde (5.0 g, 21 mmol) was added in one portion and the mixture stirred at room temperature for 5 hours. The yellow precipitate was filtered off, washed with water and dried in air to give 5-[[2-nitro-5-(1-piperidinyl)phenyl]methylene]-2,4-imidazolidinedione (6.17 g, 92%), m.p. 273°-276° C. A sample dried in vacuo in 110° C. had m.p. 280° C. (dec.).
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:9](=[N:24][OH:25])[CH2:10][NH:11][C:12](=[O:23])[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[C:19]([F:22])([F:21])[F:20])=[N:4][CH:5]=[C:6]([Cl:8])[CH:7]=1.C(=O)([O-])[O-].[K+].[K+].I[CH:33]([CH3:35])[CH3:34].Cl>CN(C)C=O.C(O)C.O1CCOCC1.O>[Cl:1][C:2]1[C:3]([C:9](=[N:24][O:25][CH:33]([CH3:35])[CH3:34])[CH2:10][NH:11][C:12](=[O:23])[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[C:19]([F:20])([F:22])[F:21])=[N:4][CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: O=C(NCC(=NO)c1ncc(Cl)cc1Cl)c1ccccc1C(F)(F)F
Reactant: CC(C)I
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)ON=C(CNC(=O)c1ccccc1C(F)(F)F)c1ncc(Cl)cc1Cl
Temperature: 25 °C
Reaction time: 12 h
Yield: 19.9 %

Procedure:
To a suspension of 450 mg of N-[2-(3,5-dichloropyridin-2-yl)-2-(hydroxyimino)ethyl]-2-(trifluoromethyl)benzamide and 476 mg of potassium carbonate in 5 ml of N,N-dimethylformamide, 313 mg of 2-iodopropane was added, and the mixture was stirred at room temperature for 12 hours. After completion of the reaction, the reaction mixture was mixed with 20 ml of water and extracted with ethyl acetate (25 ml×2), the resulting organic layers were combined, washed with water (20 ml×1) and dried over saturated aqueous sodium chloride and then anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The resulting residue was purified by silica gel column chromatography using ethyl acetate-hexane (with a gradient of from 1:9 to 3:7) as the eluent to obtain 121 mg of a colorless resinous substance. The resinous substance was dissolved in 10 ml of ethanol, the solution was mixed with 1 ml of a 1,4-dioxane solution (4 mol/L) of hydrogen chloride and stirred at 70° C. for 5 hours, and the solvent was evaporated under reduced pressure. The resulting residue was purified by silica gel column chromatography using ethyl acetate-hexane (with a gradient of from 1:9 to 3:7) as the eluent to obtain 99 mg of the desired product as a colorless resinous substance (E/Z=50/50).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[S:16][C:9]2[N:10]=[C:11]([NH2:15])[N:12]=[C:13](Cl)[C:8]=2[CH:7]=1)=[O:5])[CH3:2].[CH3:17][C:18]1[CH:25]=[CH:24][C:21]([CH:22]=[O:23])=[CH:20][C:19]=1B1OC(C)(C)C(C)(C)O1.C(=O)([O-])O.[Na+].CN(C=O)C>[Pd](Cl)Cl.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.O>[CH2:1]([O:3][C:4]([C:6]1[S:16][C:9]2[N:10]=[C:11]([NH2:15])[N:12]=[C:13]([C:25]3[CH:24]=[C:21]([CH:22]=[O:23])[CH:20]=[CH:19][C:18]=3[CH3:17])[C:8]=2[CH:7]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cc2c(Cl)nc(N)nc2s1
Reactant: Cc1ccc(C=O)cc1B1OC(C)(C)C(C)(C)O1
Agent: Cl[Pd]Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)c1cc2c(-c3cc(C=O)ccc3C)nc(N)nc2s1
Temperature: 85 °C
Reaction time: 18 h
Yield: 53.7 %

Procedure:
2-Amino-4-chloro-thieno[2,3-d]pyrimidine-6-carboxylic acid ethyl ester (7.62 g, 29.57 mmol) was added to 4-Methyl-3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzaldehyde (7.28 g, 29.57 mmol) followed by sodium hydrogen carbonate (7.45 g, 88.71 mmol). DMF (110 mL) was added followed by water (22 mL) and the suspension was degassed by evacuation—nitrogen purge (3 cycles), followed by bubbling nitrogen gas through the stirred reaction mixture for 5 minutes. Bis(triphenylphosphine) palladium (II) chloride (500 mg, 0.739 mmol) was added and reaction mixture was heated to 85 degrees C. (oil-bath temperature) for 18 hours. Reaction mixture was allowed to cool to room temperature and DMF removed in vacuo. The residue was partitioned between ethyl acetate (500 mL) and water (400 mL) and the mixture was stirred vigorously for 15 min before being filtered through a pad of celite to remove Pd solids. Filter cake was washed with ethyl acetate (2×50 mL) and combined filtrate phases were separated and the organic phase was washed with water (1×300 mL) then saturated sodium chloride solution (250 mL). Organic phase was dried over Na2SO4 and filtered, and filtrate solvents removed in vacuo to afford a brown oily solid which was triturated with ethyl acetate to afford product as a brown solid (5.42 g, 56%)
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C@@H:12]([CH2:13][OH:14])[CH2:11][CH2:10][C@H:9]1[C:15]([OH:17])=[O:16])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:18]([Li])CCC.S(OC)(OC)(=O)=O>C1COCC1>[C:1]([O:5][C:6]([N:8]1[C@@H:12]([CH2:13][O:14][CH3:18])[CH2:11][CH2:10][C@H:9]1[C:15]([OH:17])=[O:16])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1[C@@H](CO)CC[C@H]1C(=O)O
Reactant: [Li]CCCC
Solvent: COS(=O)(=O)OC
Solvent: C1CCOC1
Product: COC[C@H]1CC[C@@H](C(=O)O)N1C(=O)OC(C)(C)C
Reaction time: 1 h
Yield: 23 %

Procedure:
A solution of (2S,5R)-1-(tert-butoxycarbonyl)-5-(hydroxymethyl)pyrrolidine-2-carboxylic acid (820 mg, 3.34 mmol) in 11 mL THF was cooled in a −10° C. bath and treated with n-butyl lithium (1.6M in hexanes, 6.5 mL, 10.36 mmol) and kept cold for 1 hour, then dimethyl sulphate (0.380 mL, 4.01 mmol) was added. The temperature was held at −5° C. to 5° C. and then the reaction mixture was held in the −20° C. freezer overnight. The reaction was quenched cold, with water. Next, the mixture was concentrated under reduced pressure to remove THF. The aqueous mixture was acidified with 2N HCl and extracted with ethyl acetate. The organic layer was dried over sodium sulphate, filtered, and concentrated under reduced pressure to give 788 mg crude product, which was then purified by silica gel chromatography to give 199 mg clean product, 140 mg recovered starting material, and 317 mg of a mixture of starting material and product.
Reaction SMILES: Br[C:2]1[C:3]([N:22]2[CH2:26][CH2:25][C@H:24]([NH:27]C(=O)OC(C)(C)C)[CH2:23]2)=[N:4][CH:5]=[C:6]([C:8](=[O:21])[NH:9][C:10]2[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=2)[CH:7]=1.[CH3:35][C:36]1[N:41]=[CH:40][C:39](B(O)O)=[CH:38][CH:37]=1>>[NH2:27][C@H:24]1[CH2:25][CH2:26][N:22]([C:3]2[C:2]([C:39]3[CH:40]=[N:41][C:36]([CH3:35])=[CH:37][CH:38]=3)=[CH:7][C:6]([C:8]([NH:9][C:10]3[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=3)=[O:21])=[CH:5][N:4]=2)[CH2:23]1
Reactant: Cc1ccc(B(O)O)cn1
Reactant: CC(C)(C)OC(=O)N[C@H]1CCN(c2ncc(C(=O)Nc3ccc(OC(F)(F)F)cc3)cc2Br)C1
Product: Cc1ccc(-c2cc(C(=O)Nc3ccc(OC(F)(F)F)cc3)cnc2N2CC[C@H](N)C2)cn1

Procedure:
The title compound was prepared in an analogous fashion to that described in Example 93 using (S)-tert-butyl (1-(3-bromo-5-((4-(trifluoromethoxy)phenyl)carbamoyl)pyridin-2-yl)pyrrolidin-3-yl)carbamate (Stage 96.1) and (6-methylpyridin-3-yl)boronic acid. LC-MS (Condition 6) tR=0.79 min, m/z=448.0 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[NH2:9].[C:10]1([C:16]([C:18]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=O)=O)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>C(O)(=O)C>[CH3:8][C:5]1[CH:4]=[C:3]2[C:2](=[CH:7][CH:6]=1)[N:1]=[C:18]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C:16]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[N:9]2
Reactant: Cc1ccc(N)c(N)c1
Reactant: O=C(C(=O)c1ccccc1)c1ccccc1
Solvent: CC(=O)O
Product: Cc1ccc2nc(-c3ccccc3)c(-c3ccccc3)nc2c1

Procedure:
1,2-Diamino-4-methylbenzene (25.0 g, 0.20 mol) and benzil (43 g, 0.20 mol) were refluxed in ethanoic acid (250 ml) overnight. The solvent was evaporated in vacua and the black residue recrystallised three times from ethanol to give pale brown crystals of 6-methyl-2,3-diphenylquinoxaline, 39.6 g, 65% (m.pt. 114.5-116° C. (lit.i 115-116° C.)). 1H NMR (CDCl3, 300 MHz) δ 8.08 (d, J 8.4 Hz, 1H, Hs of quinoxaline), 7.97 (bs, 1H, Hs of quinoxaline), 7.60 (d of d, J 8.4 Hz, J 1.8 Hz, 1H, Hs of quinoxaline), 7.50-7.58 (m, 4H, phenyl rings), 7.30-7.38 (m, 6H, phenyl rings), 2.62 (s, 3H, CH3).