Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:3]([N+:12]([O-])=O)=[CH:4][C:5]([N+:9]([O-:11])=[O:10])=[C:6]([CH3:8])[CH:7]=1.CN(C)[CH:17]=[S:18]>>[CH3:8][C:6]1[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][C:3]2[N:12]=[CH:17][S:18][C:2]=2[CH:7]=1
Reactant: Cc1cc(Cl)c([N+](=O)[O-])cc1[N+](=O)[O-]
Reactant: CN(C)C=S
Product: Cc1cc2scnc2cc1[N+](=O)[O-]
Temperature: 120 °C

Procedure:
A mixture of 1.6 g of 5-chloro-2,4-dinitrotoluene and 20 mL of N,N-dimethyl-thioformamide is heated to 120° C. for 16 hours. After cooling to room temperature, the mixture is purified by flash column chromatography on silica gel, eluting with 3% to 10% ethyl acetate/hexanes to provide 0.78 g of 6-methyl-5-nitrobenzothiazole as a yellow solid.
Reaction SMILES: Cl.[Br:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][NH2:10])=[CH:5][CH:4]=1.NC(N)=O.O.N.[CH3:17][N:18]1CCC[C:19]1=[O:23]>>[Br:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH:17]=[N:18][C:19](=[O:23])[NH:10]2)=[CH:5][CH:4]=1
Reactant: NNc1ccc(Br)cc1
Reactant: CN1CCCC1=O
Agent: Cl
Agent: N
Agent: NC(N)=O
Solvent: O
Product: O=c1ncn(-c2ccc(Br)cc2)[nH]1
Temperature: 25 °C

Procedure:
A mixture of 4-bromophenylhydrazine hydrochloride (5.g, 22.4 mmol) and urea (8.1 g, 134 mmol) was heated to 80° C. overnight in 1-methyl-2-pyrrolidinone (25 mL). The reaction was poured into water (250 mL) and concentrated ammonia was added until basic pH. The solution was cooled on an ice bath and the semicarbazone filtered off. The semicarbazone (1.0 g, 4,4 mmol) was stirred in triethyl orthoformiate (B mL) at 90° C. for three days. The reaction mixture was cooled to room temperature and the crude material filtered off. Re-crystallisation from methanol afforded the desired product.
Reaction SMILES: [CH3:1][C:2]1[C:3](B(O)O)=[CH:4][S:5][CH:6]=1.[CH2:10]([CH:12]([C:15]1[C:16]2[N:17]([C:22](I)=[C:23]([CH3:25])[N:24]=2)[N:18]=[C:19]([CH3:21])[CH:20]=1)[CH2:13][CH3:14])[CH3:11].C([O-])([O-])=O.[Na+].[Na+]>O.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>[CH2:10]([CH:12]([C:15]1[C:16]2[N:17]([C:22]([C:3]3[C:2]([CH3:1])=[CH:6][S:5][CH:4]=3)=[C:23]([CH3:25])[N:24]=2)[N:18]=[C:19]([CH3:21])[CH:20]=1)[CH2:13][CH3:14])[CH3:11]
Reactant: Cc1cscc1B(O)O
Reactant: CCC(CC)c1cc(C)nn2c(I)c(C)nc12
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: O
Product: CCC(CC)c1cc(C)nn2c(-c3cscc3C)c(C)nc12
Yield: 86.9 %

Procedure:
To a 100 mL round bottom flask containing 4-methyl 3-thiophene boronic acid (0.27 g, 1.91 mmol), and 8-(1-ethyl-propyl)-3-iodo-2,6-dimethyl-imidazo[1,2-b]pyridazine (0.65 g, 1.91 mmol) in 20 mL of a stock solution (DME:H2O:EtOH=7:3:2) is added 2 M Na2CO3 (1.9 mL). The resulting mixture is degassed by bubbling N2 for 5 min. Then Pd(PPh3)4 (0.11 g, 0.096 mmol) is added. The reaction mixture is refluxed overnight. The reaction is diluted with H2O (20 mL); extracted with EtOAc (3×30 mL); dried (Na2SO4), filtered and purification of the crude material by chromatography gives the title compound (0.52 g, 1.66 mmol, 87%). 1H NMR (CDCl3): δ 0.89 (t, J=7.5 Hz, 6H), 1.75-1.90 (m, 4H), 2.13 (d, J=0.8 Hz, 3H), 2.44 (s, 3H), 2.49 (s, 3H), 3.30-3.39 (m, 1H), 6.64 (s, 1H), 7.08-7.11 (m, 1H), 7.34 (d, J=3.1 Hz, 1H). ES-MS (m/z): calcd for C18H23N3S (M+H)+: 314.5; found: 314.2.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:10]=[C:11]([C:13]([F:16])([F:15])[F:14])[CH:12]=1)[C:7](O)=[O:8])([O-:3])=[O:2].S(Cl)([Cl:19])=O>>[N+:1]([C:4]1[CH:5]=[C:6]([CH:10]=[C:11]([C:13]([F:16])([F:15])[F:14])[CH:12]=1)[C:7]([Cl:19])=[O:8])([O-:3])=[O:2]
Reactant: O=C(O)c1cc([N+](=O)[O-])cc(C(F)(F)F)c1
Reactant: O=S(Cl)Cl
Product: O=C(Cl)c1cc([N+](=O)[O-])cc(C(F)(F)F)c1

Procedure:
A solution of thionyl chloride (30 ml) and 3-nitro-5-(trifluoromethyl)benzoic acid (10 g) was heated to reflux for 2 h. The reaction mixture was concentrated under reduced pressure and azeotroped with toluene (10 ml—removed under reduced pressure) to afford 3-nitro-5-(trifluoromethyl)benzoyl chloride. Step 2: To a solution of 3-nitro-5-(trifluoromethyl)benzoyl chloride (2.35 g, 9.3 mmol) in CH2Cl2 (40 ml) at room temperature was added N-methylpiperazine (1.26 ml, 9.3 mmol) and the mixture was allowed to stir for 30 min. The reaction was concentrated under reduced pressure, taken up in 1 M HCl (50 ml) and the aqueous layer was washed with Et2O (2×20 ml). The aqueous layer was basified to a pH of about 9 with 6N NaOH and extracted with Et2O (3×50 ml). The organic extracts were combined and washed with water (1×20 ml) followed by brine (1×20 ml), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to afford (4-methylpiperazin-1-yl)(3-nitro-5-trifluoromethyl)phenyl)-methanone as a tan oil. MS m/z=318 [M+H]+; Calc'd for C13H14F3N3O3: 317.3.
Reaction SMILES: Br[CH:2]([CH3:12])[CH2:3][CH2:4][O:5][C:6]1[CH:7]=[N:8][CH:9]=[CH:10][CH:11]=1.[CH3:13][NH2:14]>CO>[CH3:13][NH:14][CH:2]([CH3:12])[CH2:3][CH2:4][O:5][C:6]1[CH:7]=[N:8][CH:9]=[CH:10][CH:11]=1
Reactant: CC(Br)CCOc1cccnc1
Reactant: CN
Solvent: CO
Product: CNC(C)CCOc1cccnc1
Temperature: 100 °C

Procedure:
Crude 3-bromo-1-(3-pyridyloxy)butane (2.00 g, 8.69 mmol) from the previous step was dissolved in methanol (10 mL) and added to a 40 wt % aqueous solution of methylamine (30 mL) in a heavy-walled glass pressure-tube apparatus. The mixture was stirred and heated at 100° C. (oil bath temperature) for 16 h. After cooling, the mixture was concentrated by rotary evaporation, and the product was extracted with chloroform (4×50 mL). The combined chloroform extracts were dried (Na2SO4), filtered and concentrated by rotary evaporation to give 1.25 g of a pale-yellow oil. Purification by vacuum distillation yielded 0.94 g (60.3%) of a colorless oil, bp 65-67° C. at 0.5 mm Hg.
Reaction SMILES: [OH-].[K+].C([O:5][C:6]([C:8]1[CH:9]=[CH:10][CH:11]=[C:12]2[O:16][C:15]([CH3:17])=[N:14][C:13]=12)=[O:7])C.Cl>CO>[CH3:17][C:15]1[O:16][C:12]2[C:13](=[C:8]([C:6]([OH:7])=[O:5])[CH:9]=[CH:10][CH:11]=2)[N:14]=1
Reactant: CCOC(=O)c1cccc2oc(C)nc12
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: Cc1nc2c(C(=O)O)cccc2o1
Reaction time: 0.5 h

Procedure:
At 0° C. an aq. KOH solution (1.0 M, 2.40 mL) is added to a solution of 2-methyl-benzoxazole-4-carboxylic acid ethyl ester (0.98 mmol) in MeOH (5.0 mL) and stirred for 30 min. The mixture is allowed to reach RT, stirred for additional 60 min and made acidic by addition of aq. HCl (2.0 M). After removal of MeOH under reduced pressure the obtained precipitate is filtered off to give the desired product which is dried in vacuo. 1H-NMR (DMSO-d6): δ=2.64 (s, 3H); 7.41 (t, J=8.0 Hz, 1H); 7.83 (d, J=7.8 Hz, 1H); 7.88 (d, J=8.0 Hz, 1H); 12.8 (bs, 1H).
Reaction SMILES: CC(C)=O.[CH2:5]([N:12]1[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.O[C:19]([CH3:23])([CH3:22])[C:20]#[N:21]>CN(C)C(=O)C>[CH2:5]([N:12]1[CH2:17][CH2:16][N:15]([C:19]([CH3:23])([CH3:22])[C:20]#[N:21])[CH2:14][CH2:13]1)[C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1
Reactant: CC(C)(O)C#N
Reactant: c1ccc(CN2CCNCC2)cc1
Solvent: CC(C)=O
Solvent: CC(=O)N(C)C
Product: CC(C)(C#N)N1CCN(Cc2ccccc2)CC1
Temperature: 45 °C
Reaction time: 0.5 h

Procedure:
4.5 ml of acetone, 20 g of dry MGSO4, 10 g of N,N-dimethylacetamide, 10 g of 1-benzylpiperazine and 9.5 ml of 2-hydroxyisobutyronitrile are mixed together and heated at 45° C. for 48 hours with vigorous stirring. The reaction mixture is poured onto ice and left stirring for 30 minutes. The mixture is extracted with ether, the organic phase is washed several times with water and dried over Na2SO4, and the solvent is evaporated off under vacuum. 13 g of the expected product are obtained.
Reaction SMILES: [N:1]1([S:7]([C:10]2[CH:15]=[CH:14][C:13]([S:16][C:17](=S)OCC)=[CH:12][CH:11]=2)(=[O:9])=[O:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[OH-:22].[K+].[Cl-].[NH4+]>C(O)C.O>[N:1]1([S:7]([C:10]2[CH:11]=[CH:12][C:13]([S:16][CH2:17][C:2](=[O:22])[CH2:3][CH2:4][CH2:5][CH3:6])=[CH:14][CH:15]=2)(=[O:8])=[O:9])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: CCOC(=S)Sc1ccc(S(=O)(=O)N2CCCCC2)cc1
Reactant: [OH-]
Agent: [Cl-]
Agent: [K+]
Agent: [NH4+]
Solvent: O
Solvent: CCO
Product: CCCCC(=O)CSc1ccc(S(=O)(=O)N2CCCCC2)cc1
Temperature: 111 °C

Procedure:
Dithiocarbonic acid O-ethyl ester S-[4-(piperidine-1-sulfonyl)-phenyl]ester (1.24 g, 3.6 mmol) in ethanol (5 mL) and water (0.5 mL) was heated to 60° C. to form a solution. The flask was removed from the oil bath and KOH (561 mg, 10 mmol) added portionwise (exothermic reaction). The mixture was heated to 111° C. for one hour and 33 was added (553 mg, 4.13 mmol)The reaction mixture was then heated to 110° C. for 3 hours. The mixture was allowed to cool to r.t. and a saturated aqueous solution of ammonium chloride added (20 mL). The aqueous phase was extracted with EtOAc, the combined organics dried, and the solvent evaporated in vacuo. The resultant crude product 35 was taken on without purification. Mass Spectrum m/e=356.0 (M+1)
Reaction SMILES: [NH2:1][C:2]1[O:3][C:4]2[CH:10]=[C:9]([CH2:11][CH2:12][C:13]3[N:14]=[C:15]4[CH:20]=[C:19]([CH2:21]Cl)[CH:18]=[CH:17][N:16]4[C:23]=3[CH3:24])[CH:8]=[CH:7][C:5]=2[N:6]=1.[N-:25]=[N+:26]=[N-:27].[Na+].[N-]=[N+]=[N-].[K+].O>CN(C)C=O>[NH2:1][C:2]1[O:3][C:4]2[CH:10]=[C:9]([CH2:11][CH2:12][C:13]3[N:14]=[C:15]4[CH:20]=[C:19]([CH2:21][N:25]=[N+:26]=[N-:27])[CH:18]=[CH:17][N:16]4[C:23]=3[CH3:24])[CH:8]=[CH:7][C:5]=2[N:6]=1
Reactant: [N-]=[N+]=[N-]
Reactant: Cc1c(CCc2ccc3nc(N)oc3c2)nc2cc(CCl)ccn12
Agent: [K+]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1c(CCc2ccc3nc(N)oc3c2)nc2cc(CN=[N+]=[N-])ccn12
Temperature: 25 °C
Reaction time: 17 h
Yield: 91.3 %

Procedure:
A mixture of 2-amino-6-[2-(7-chloromethyl-3-methylimidazo[1,2-a]pyridin-2-yl)ethyl]benzoxazole (1.3 g), sodium azide (0.5 g) and potassium azide (1.3 g) in N,N-dimethylformamide (26 ml) was stirred for 17 hours at ambient temperature and the mixture was poured into water. The mixture was extracted with a mixture of ethyl acetate and tetrahydrofuran. The extract was washed with brine and dried over magnesium sulfate. The solvent was evaporated and the residue was triturated with diethyl ether to give 2-amino-6-[2-(7-azidomethyl-3-methylimidazo[1,2-a]pyridin-2-yl)ethyl]benzoxazole (1.21 g).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[F:12])[N:8]=[C:7]([CH2:13][O:14][C:15]1[CH:16]=[CH:17][C:18]3[CH2:24][N:23]([CH3:25])[C:22]4[N:26]=[CH:27][CH:28]=[CH:29][C:21]=4[CH:20](O)[C:19]=3[CH:31]=1)[CH:6]=[CH:5]2.Cl.[CH2:33]([O:35][C:36](=[O:41])[C@H:37]([CH2:39][SH:40])[NH2:38])[CH3:34].FC(F)(F)C(O)=O>ClCCl>[CH2:33]([O:35][C:36](=[O:41])[CH:37]([NH2:38])[CH2:39][S:40][CH:20]1[C:19]2[CH:31]=[C:15]([O:14][CH2:13][C:7]3[CH:6]=[CH:5][C:4]4[C:9](=[CH:10][C:11]([F:12])=[C:2]([F:1])[CH:3]=4)[N:8]=3)[CH:16]=[CH:17][C:18]=2[CH2:24][N:23]([CH3:25])[C:22]2[N:26]=[CH:27][CH:28]=[CH:29][C:21]1=2)[CH3:34]
Reactant: CN1Cc2ccc(OCc3ccc4cc(F)c(F)cc4n3)cc2C(O)c2cccnc21
Reactant: CCOC(=O)[C@@H](N)CS
Agent: Cl
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCOC(=O)C(N)CSC1c2cc(OCc3ccc4cc(F)c(F)cc4n3)ccc2CN(C)c2ncccc21
Temperature: 45 °C
Reaction time: 16 h

Procedure:
A mixture of 6.6 g (15.7 mmol) of the product from Example 21, step 5, 6.0 g (32.3 mmol) of L-cystein ethyl ester hydrochloride and 136 ml of trifluoroacetic acid in 198 ml of dichloromethane is stirred at 45° C. for 16 hr. The solvent is evaporated and the residue partitioned between sat. NaHCO3 and chloroform. The organic layer is washed with water, dried and concentrated, giving an oil, which solidifies with the aid of diisopropyl ether/petroleum ether. Yield 7.9 g (91%).
Reaction SMILES: [NH:1]1[C:5]2[N:6]=[CH:7][CH:8]=[C:9]([C:10]#[N:11])[C:4]=2[CH:3]=[CH:2]1.[F:12][C:13]1[C:18]([CH:19]=[O:20])=[C:17]([F:21])[CH:16]=[CH:15][C:14]=1[NH:22][S:23]([C:26]1[CH:31]=[CH:30][C:29]([C:32]([F:35])([F:34])[F:33])=[CH:28][CH:27]=1)(=[O:25])=[O:24].[OH-].[K+].Cl>CO>[C:10]([C:9]1[CH:8]=[CH:7][N:6]=[C:5]2[NH:1][CH:2]=[C:3]([CH:19]([OH:20])[C:18]3[C:13]([F:12])=[C:14]([NH:22][S:23]([C:26]4[CH:27]=[CH:28][C:29]([C:32]([F:35])([F:34])[F:33])=[CH:30][CH:31]=4)(=[O:25])=[O:24])[CH:15]=[CH:16][C:17]=3[F:21])[C:4]=12)#[N:11]
Reactant: N#Cc1ccnc2[nH]ccc12
Reactant: O=Cc1c(F)ccc(NS(=O)(=O)c2ccc(C(F)(F)F)cc2)c1F
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: N#Cc1ccnc2[nH]cc(C(O)c3c(F)ccc(NS(=O)(=O)c4ccc(C(F)(F)F)cc4)c3F)c12
Temperature: 25 °C
Reaction time: 46 h
Yield: 9.3 %

Procedure:
Into a round bottom flask 1H-pyrrolo[2,3-b]pyridine-4-carbonitrile (5, 0.054 g, 0.38 mmol), N-(2,4-difluoro-3-formyl-phenyl)-4-trifluoromethyl-benzenesulfonamide (4, 0.179 g, 0.49 mmol), 0.75 mL of methanol and potassium hydroxide (0.103 g, 1.89 mmol) were combined. The reaction was stirred at room temperature for 46 hours, then neutralized with 0.1 N aqueous hydrochloric acid and extracted 3× with ethyl acetate. The organic layers were combined and washed with brine, then dried over sodium sulfate, filtered and the filtrate concentrated under vacuum. The material was purified by silica gel column chromatography eluting with ethyl acetate and hexane. The appropriate fractions were combined and the solvent removed under vacuum to provide the desired compound (6, 0.018 g). MS (ESI) [M+H+]+=509.1.
Reaction SMILES: [C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([NH2:14])=[CH:11][CH:12]=2)[C:7]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)([CH3:15])[CH2:6][C:5]1([CH3:23])[CH3:22])(=[O:3])[CH3:2].[C:24]12([CH2:34][CH2:35][C:36](O)=[O:37])[CH2:33][CH:28]3[CH2:29][CH:30]([CH2:32][CH:26]([CH2:27]3)[CH2:25]1)[CH2:31]2.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C>ClCCl>[C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([NH:14][C:36](=[O:37])[CH2:35][CH2:34][C:24]34[CH2:33][CH:28]5[CH2:29][CH:30]([CH2:32][CH:26]([CH2:27]5)[CH2:25]3)[CH2:31]4)=[CH:11][CH:12]=2)[C:7]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)([CH3:15])[CH2:6][C:5]1([CH3:23])[CH3:22])(=[O:3])[CH3:2]
Reactant: CC(=O)N1c2ccc(N)cc2C(C)(c2ccccc2)CC1(C)C
Reactant: O=C(O)CCC12CC3CC(CC(C3)C1)C2
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(=O)N1c2ccc(NC(=O)CCC34CC5CC(CC(C5)C3)C4)cc2C(C)(c2ccccc2)CC1(C)C

Procedure:
Condensation of 1-acetyl-6-amino-4-phenyl-1,2,3,4-tetrahydro-2,2,4-trimethylquinoline (10 mg) with 3-(adamantan-1-yl)propionic acid (10 mg) under the agency of HATU (25 mg) and N,N-diisopropylethylamine (22 μl) in dichloromethane (1 ml) was performed according to the method described in example 11.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:13]=[C:12]2[C:8]([C:9]3[CH:17]=[C:16]([CH3:18])[CH:15]=[N:14][C:10]=3[NH:11]2)=[C:7](N)[CH:6]=1)=[O:4].[I:20]C1C=C(C#N)C=C2C=1C1C=C(C)C=NC=1N2>>[CH3:1][O:2][C:3]([C:5]1[CH:13]=[C:12]2[C:8]([C:9]3[CH:17]=[C:16]([CH3:18])[CH:15]=[N:14][C:10]=3[NH:11]2)=[C:7]([I:20])[CH:6]=1)=[O:4]
Reactant: COC(=O)c1cc(N)c2c(c1)[nH]c1ncc(C)cc12
Reactant: Cc1cnc2[nH]c3cc(C#N)cc(I)c3c2c1
Product: COC(=O)c1cc(I)c2c(c1)[nH]c1ncc(C)cc12
Yield: 69 %

Procedure:
The title compound was prepared in 69% yield from Compound 130 according to the procedure outlined for the preparation of Compound 125. MS (ES) [m+H] calc'd for C14H11IN2O2, 367; found 367.
Reaction SMILES: [NH2:1][C:2]1[C:7](I)=[C:6]([Cl:9])[N:5]=[C:4]([C:10]([O:12][CH3:13])=[O:11])[C:3]=1[Cl:14].[CH3:15][Sn](C)(C)C>ClCCCl.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[NH2:1][C:2]1[C:7]([CH3:15])=[C:6]([Cl:9])[N:5]=[C:4]([C:10]([O:12][CH3:13])=[O:11])[C:3]=1[Cl:14]
Reactant: C[Sn](C)(C)C
Reactant: COC(=O)c1nc(Cl)c(I)c(N)c1Cl
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: ClCCCl
Product: COC(=O)c1nc(Cl)c(C)c(N)c1Cl
Yield: 82.4 %

Procedure:
A mixture of methyl 4-amino-3,6-dichloro-5-iodopicolinate (8.1 g, 23.4 mmol), tetramethylstannane (8.35 g, 46.7 mmol), and bis(triphenylphosphine)palladium(II) chloride (2.5 g, 3.5 mmol) in 1,2-dichloroethane (40 mL) was irradiated in a Biotage Initiator™ microwave at 120° C. for 30 min, with external IR-sensor temperature monitoring from the side. The reaction mixture was loaded directly onto a silica gel cartridge and purified by flash chromatography (silica gel, 0-50% ethyl acetate/hexanes) to provide the title compound as an orange solid (4.53 g, 19.27 mmol, 83%): mp 133-136° C.; 1H NMR (400 MHz, CDCl3) δ 4.92 (s, 2H), 3.96 (s, 3H), 2.29 (s, 3H); 13C NMR (101 MHz, CDCl3) δ 164.34, 150.24, 148.69, 143.94, 117.01, 114.60, 53.02, 14.40; ESIMS m/z 236 ([M+H]+), 234 ([M−H]−).
Reaction SMILES: [CH2:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][N:2]1[C:11]1[C:12]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[N:13][C:14]2[C:19]([N:20]=1)=[CH:18][C:17]([C:21]([O:23]C)=[O:22])=[CH:16][CH:15]=2.[OH-].[Na+]>CO.O>[CH2:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][N:2]1[C:11]1[C:12]([C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)=[N:13][C:14]2[C:19]([N:20]=1)=[CH:18][C:17]([C:21]([OH:23])=[O:22])=[CH:16][CH:15]=2
Reactant: COC(=O)c1ccc2nc(-c3ccccc3)c(N3CCc4ccccc4C3)nc2c1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C(O)c1ccc2nc(-c3ccccc3)c(N3CCc4ccccc4C3)nc2c1
Temperature: 50 °C
Reaction time: 8 h

Procedure:
Into a 50-mL round-bottom flask, was placed a solution of methyl 3-(3,4-dihydroisoquinolin-2(1H)-yl)-2-phenylquinoxaline-6-carboxylate (110 mg, 0.26 mmol, 1.00 equiv, 95%) in methanol (15 mL). This was followed by the addition of a solution of sodium hydroxide (55.7 mg, 1.39 mmol, 5.00 equiv) in water (1.5 mL) dropwise with stiffing. The resulting solution was stirred for overnight at 50° C. in an oil bath. The resulting solution was concentrated under vacuum. The residue was diluted with water. The pH value of the aqueous solution was adjusted to 3-4 with 1N hydrogen chloride. The resulting solids were collected by filtration and washed with methanol. This resulted in 68.1 mg (66%) of 3-(3,4-dihydroisoquinolin-2(1H)-yl)-2-phenylquinoxaline-6-carboxylic acid as a yellow solid.
Reaction SMILES: [C:1]1([C:7]2[O:16][C:10]3[N:11]=[CH:12][NH:13][C:14](=O)[C:9]=3[CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.O=P(Cl)(Cl)[Cl:19]>>[Cl:19][C:14]1[C:9]2[CH:8]=[C:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[O:16][C:10]=2[N:11]=[CH:12][N:13]=1
Reactant: O=c1[nH]cnc2oc(-c3ccccc3)cc12
Reactant: O=P(Cl)(Cl)Cl
Product: Clc1ncnc2oc(-c3ccccc3)cc12
Temperature: 60 °C
Reaction time: 3 h
Yield: 74 %

Procedure:
A mixture of 6-phenylfuro[2,3-d]pyrimidin-4(3H)-one (1.0 g) and POCl3 (10 mL) was stirred at 55-65° C. for 3 h. The reaction mixture was poured into ice cold water and stirred for 10 min. The solution was extracted with chloroform (3×100 mL) and the combined chloroform layer was washed with aq. NaHCO3 solution, water, brine and dried over sodium sulfate. The residue was chromatographed over silica gel column using hexane-EtOAc (95:5) as eluents to give the product as a white color solid (800 mg, 74%), mp 136-138° C. 1H NMR (400 MHz, CDCl3): δ 8.74 (1H, s), 7.90-7.93 (2H, m), 7.45-7.54 (3H, m), 7.08 (1H, s).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N+:8]([C:11]1[CH:19]=[CH:18][CH:17]=[CH:16][C:12]=1[C:13](Cl)=[O:14])([O-:10])=[O:9]>>[N+:8]([C:11]1[CH:19]=[CH:18][CH:17]=[CH:16][C:12]=1[C:13]([NH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)=[O:14])([O-:10])=[O:9]
Reactant: Nc1ccccc1
Reactant: O=C(Cl)c1ccccc1[N+](=O)[O-]
Product: O=C(Nc1ccccc1)c1ccccc1[N+](=O)[O-]
Yield: 80.3 %

Procedure:
Using the procedure described in Example 93, Part A, aniline (11 mmol) and 2-nitrobenzoyl chloride (12.1 mmol) yielded 2.14 g (80%) of the title compound.
Reaction SMILES: [CH:1]([C:4]1[CH:5]=[CH:6][C:7]([O:22][CH3:23])=[C:8]([C:10]2[C:11]([CH:20]=O)=[CH:12][C:13]([C:16]([F:19])([F:18])[F:17])=[CH:14][CH:15]=2)[CH:9]=1)([CH3:3])[CH3:2].Cl.NO.[N:27]1C=CC=CC=1.C(OCC)(=O)C>C(O)C>[CH:1]([C:4]1[CH:5]=[CH:6][C:7]([O:22][CH3:23])=[C:8]([C:10]2[CH:15]=[CH:14][C:13]([C:16]([F:19])([F:18])[F:17])=[CH:12][C:11]=2[CH2:20][NH2:27])[CH:9]=1)([CH3:3])[CH3:2]
Reactant: COc1ccc(C(C)C)cc1-c1ccc(C(F)(F)F)cc1C=O
Reactant: c1ccncc1
Agent: Cl
Agent: NO
Solvent: CCO
Solvent: CCOC(C)=O
Product: COc1ccc(C(C)C)cc1-c1ccc(C(F)(F)F)cc1CN
Temperature: 80 °C
Reaction time: 1 h

Procedure:
5′-Isopropyl-2′-methoxy-4-trifluoromethyl-biphenyl-2-carbaldehyde (8.0 g), hydroxylamine hydrochloride (3.45 g) and pyridine (28 ml) are dissolved in ethanol (140 ml), and the mixture is stirred at 80° C. for 1 hour. The reaction solution is cooled to room temperature, and thereto are added ethyl acetate and a 1N-hydrochloric acid, and the mixture is separated, and the organic layer is washed with a saturated sodium carbonate, water and a saturated brine, and the mixture is dried over magnesium sulfate and concentrated under reduced pressure. Thereto are added ethyl acetate and a 1N-hydrochloric acid, and the mixture is separated, and the organic layer is washed with a 1N-hydrochloric acid, a saturated sodium carbonate, water and a saturated brine, and the mixture is dried over magnesium sulfate and concentrated under reduced pressure. The residue is dissolved in methanol (100 ml), and thereto is added Raney nickel, and the mixture is stirred under hydrogen atmosphere at room temperature for 30 minutes and at 50° C. overnight. The reaction solution is cooled to room temperature, and Raney nickel is removed by filtration, and the filtrate is concentrated under reduced pressure. The residue is purified by silica gel column chromatography (chloroform:methanol=1:0→23:2) to give C-(5′-isopropyl-2′-methoxy-4-trifluoromethyl-biphenyl-2-yl)-methylamine (5.50 g). MS (m/z): 324 [M+H]+
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[C:7]([CH3:9])[CH:6]=[C:5]([CH2:10][CH3:11])[C:4]=1[C:12](=[O:18])[C:13]([N:15]([CH3:17])[NH2:16])=[O:14])[CH3:2].[CH3:19]O.C=O>O>[CH2:1]([C:3]1[CH:8]=[C:7]([CH3:9])[CH:6]=[C:5]([CH2:10][CH3:11])[C:4]=1[C:12](=[O:18])[C:13]([N:15]([CH3:17])[N:16]=[CH2:19])=[O:14])[CH3:2]
Reactant: CO
Reactant: CCc1cc(C)cc(CC)c1C(=O)C(=O)N(C)N
Agent: C=O
Solvent: O
Product: C=NN(C)C(=O)C(=O)c1c(CC)cc(C)cc1CC
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 92.5 %

Procedure:
To a test tube (outside diameter 21 mmφ×overall length 160 mm), 100 mg of 1-[2-(2,6-diethyl-4-methylphenyl)-2-oxoacetyl]-1-methylhydrazine ((12-2)-(11)-39), 380 mg of methanol and 130 μl of 37 wt % formalin aqueous solution were added and the mixture was stirred at room temperature for 2.5 hours. Water was added to the reaction mixture and the resultant was extracted with chloroform three times. The organic layers were combined, dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give 97 mg of 1-[2-(2,6-diethyl-4-methylphenyl)-2-oxoacetyl]-1-methyl-2-methylidenehydrazine ((40-b)-(15)-1).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[N:8](S(C3C=CC=CC=3)(=O)=O)[CH:9]=[C:10]([C:11]#[N:12])[C:3]=12.[OH-].[Na+].O>O1CCCC1>[Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[NH:8][CH:9]=[C:10]([C:11]#[N:12])[C:3]=12
Reactant: N#Cc1cn(S(=O)(=O)c2ccccc2)c2nccc(Cl)c12
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: N#Cc1c[nH]c2nccc(Cl)c12

Procedure:
4-Chloro-1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonitrile was treated with 2M NaOH solution (4 ml) in tetrahydrofuran (8 ml) at ambient temperature for 1 hour. The reaction mixture was cooled and was added water. The aqueous layer was extracted with EtOAc. And the organic layer was washed with brine, dried over MgSO4 and concentrated. Resultings were purified by silica gel column chromatography to give 4-chloro-1H-pyrrolo[2,3-b]-pyridine-3-carbonitrile as colorless powder.