Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([C:19]2[S:23][C:22](/[CH:24]=[CH:25]/[C:26]3[CH:35]=[CH:34][C:29]([C:30]([O:32][CH3:33])=[O:31])=[CH:28][CH:27]=3)=[N:21][CH:20]=2)[CH:5]=[C:6]([NH:8][C:9]2[N:14]=[C:13]([C:15]([F:18])([F:17])[F:16])[CH:12]=[CH:11][N:10]=2)[CH:7]=1>CCOC(C)=O.[Pd]>[CH3:1][C:2]1[CH:3]=[C:4]([C:19]2[S:23][C:22]([CH2:24][CH2:25][C:26]3[CH:27]=[CH:28][C:29]([C:30]([O:32][CH3:33])=[O:31])=[CH:34][CH:35]=3)=[N:21][CH:20]=2)[CH:5]=[C:6]([NH:8][C:9]2[N:14]=[C:13]([C:15]([F:18])([F:17])[F:16])[CH:12]=[CH:11][N:10]=2)[CH:7]=1
Reactant: COC(=O)c1ccc(/C=C/c2ncc(-c3cc(C)cc(Nc4nccc(C(F)(F)F)n4)c3)s2)cc1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc(CCc2ncc(-c3cc(C)cc(Nc4nccc(C(F)(F)F)n4)c3)s2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 81.6 %

Procedure:
Methyl 4-{(E)-2-[5-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)-1,3-thiazol-2-yl]ethenyl}benzoate (100 mg, 0.201 mmol) was taken up in EtOAc (5 ml). Palladium on carbon (53.6 mg, 0.050 mmol) was added, and the reaction was purged with hydrogen (3×). The reaction was stirred under a hydrogen balloon at room temperature overnight. Upon complete conversion, the reaction was diluted with EtOAc and filtered through Celite. The filtrate was evaporated to dryness and purified by chromatography on silica gel (Biotage 25 g SNAP, 10-100% EtOAc/hexanes) to give methyl 4-{2-[5-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)-1,3-thiazol-2-yl]ethyl}benzoate (82 mg, 0.164 mmol, 82% yield) as a colorless solid.
Reaction SMILES: CS(O)(=O)=O.[Cl:6][C:7]1[CH:20]=[CH:19][C:10]2[N:11]([CH2:15][CH2:16][CH2:17]O)[C:12](=[O:14])[NH:13][C:9]=2[CH:8]=1.[Cl:21][C:22]1[CH:37]=[CH:36][C:25]2[N:26]([CH:30]3[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]3)[C:27](=[O:29])[NH:28][C:24]=2[CH:23]=1.C(=O)([O-])[O-].[Na+].[Na+]>CN(C)C=O>[Cl:6][C:7]1[CH:20]=[CH:19][C:10]2[N:11]([CH2:15][CH2:16][CH2:17][N:33]3[CH2:32][CH2:31][CH:30]([N:26]4[C:25]5[CH:36]=[CH:37][C:22]([Cl:21])=[CH:23][C:24]=5[NH:28][C:27]4=[O:29])[CH2:35][CH2:34]3)[C:12](=[O:14])[NH:13][C:9]=2[CH:8]=1
Reactant: O=c1[nH]c2cc(Cl)ccc2n1CCCO
Reactant: O=c1[nH]c2cc(Cl)ccc2n1C1CCNCC1
Agent: CS(=O)(=O)O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=c1[nH]c2cc(Cl)ccc2n1CCCN1CCC(n2c(=O)[nH]c3cc(Cl)ccc32)CC1

Procedure:
A mixture of 7.6 parts of 5-chloro-1,3-dihydro-1-(3-hydroxypropyl)-2H-benzimidazol-2-one methanesulfonate, 5.5 parts of 5-chloro-1,3-dihydro-1-(4-piperidinyl)-2H-benzimidazol-2-one, 5parts of sodium carbonate and 63 parts of N,N-dimethylformamide is stirred and heated in an oil bath at 50°-60° C for 2 hours. The reaction mixture is poured onto water. The precipitated product is filtered off, dried and purified by column-chromatography over silica gel using a mixture of trichloromethane and 10% of methanol as eluent. The pure fractions are collected and the eluent is evaporated. The solid residue is crystallized from 4-methyl-2-pentanone. The product is filtered off and recrystallized from a mixture of N,N-dimethylformamide and water. It is filtered off again and dissolved in a mixture of 4-methyl-2-pentanone and a small amount of N,N-dimethylformamide. The solution is filtered till clear and the filtrate is concentrated to a volume of about 10 parts. The concentrate is triturated in methanol. The precipitated product is filtered off and dried, yielding 1.27 parts of 5-chloro-1-{3-[4-(5-chloro-1,3-dihydro-2-oxo-2H-benzimidazol-1-yl)-1-piperidinyl]propyl}-1,3-dihydro-2-H-benzimidazol-2-one; mp. 229°-236° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH3:12])[CH:7]=[C:6]2[CH:13]=O.[NH:15]([CH2:22][CH2:23][C:24]#[N:25])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>>[NH:15]([CH:22]=[C:23]([CH2:13][C:6]1[C:5]2[C:9](=[CH:10][CH:11]=[C:3]([O:2][CH3:1])[CH:4]=2)[N:8]([CH3:12])[CH:7]=1)[C:24]#[N:25])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: COc1ccc2c(c1)c(C=O)cn2C
Reactant: N#CCCNc1ccccc1
Product: COc1ccc2c(c1)c(CC(C#N)=CNc1ccccc1)cn2C

Procedure:
The title compound was prepared from 5-methoxy-1-methylindole-3-carboxaldehyde (S. Misztal, Dessert. Pharm. Pharmacol., 1972, 24, 509) and 3-anilinopropionitrile by the procedure of Example 4A (71%); the structure was confirmed by 1H-NMR.
Reaction SMILES: [NH2:1][C@H:2]1[CH2:11][C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:12]#[N:13])[CH:9]=2)[NH:4][CH2:3]1.[CH:14]1([N:20]=[C:21]=[O:22])[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1>>[C:12]([C:8]1[CH:9]=[C:10]2[C:5](=[CH:6][CH:7]=1)[NH:4][CH2:3][C@@H:2]([NH:1][C:21]([NH:20][CH:14]1[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1)=[O:22])[CH2:11]2)#[N:13]
Reactant: N#Cc1ccc2c(c1)C[C@H](N)CN2
Reactant: O=C=NC1CCCCC1
Product: N#Cc1ccc2c(c1)C[C@H](NC(=O)NC1CCCCC1)CN2

Procedure:
The title compound was prepared from (S)-3-amino-1,2,3,4-tetrahydroquinoline-6-carbonitrile (52 mg, 0.3 mmol), prepared as described in Example 1F, and cyclohexyl isocyanate by procedures analogous to those described in Example 41A.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=1.O[CH2:9][C:10]#[N:11]>O>[NH2:11][CH2:10][CH2:9][NH:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: Nc1cccnc1
Reactant: N#CCO
Solvent: O
Product: NCCNc1cccnc1
Reaction time: 1.5 h
Yield: 81.7 %

Procedure:
3-aminopyridine(1.88 g) and hydroxyacetonitrile(2.49 g) were refluxed in water(20 ml) with stirring for 1.5 hours and then the reaction mixture was extracted with ethyl acetate. The extract was dried over sodium sulfate anhydride and then concentrated under a vacuum. The solution of the residue in tetrahydrofuran(30ml) was dropped into the suspension of lithium aluminium hydride(1.13 g) in tetrahydrofuran (40ml) while being cooled with ice and the mixture was stirred at room temperature for 30 minutes. A small amount of water was added to the reaction mixture and then the resulting deposit was filtrated out. The filtrate was concentrated under a vacuum, thereby yielding 2.24 g of the aimed compound.
Reaction SMILES: [C:1]([O:9][CH2:10][CH2:11][N:12]1[C:24]2[C:23]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[N:17]=[CH:16][C:15]=2[N:14]=[CH:13]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH:25]O>C(O)(=O)C>[C:1]([O:9][CH2:10][CH2:11][N:12]1[C:24]2[C:23]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[N+:17]([O-:25])=[CH:16][C:15]=2[N:14]=[CH:13]1)(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(OCCn1cnc2cnc3ccccc3c21)c1ccccc1
Reactant: OO
Solvent: CC(=O)O
Product: O=C(OCCn1cnc2c[n+]([O-])c3ccccc3c21)c1ccccc1
Temperature: 65 °C

Procedure:
A mixture of 67.5 g (0.213 mole) of 1-(2-benzoyloxyethyl)-1H-imidazo[4,5-c]quinoline (from Example 115), 36.3 g (0.32 mole) of 30% hydrogen peroxide and 450 ml of glacial acetic acid was heated at 65° C. for 2 days with stirring. The solution was evaporated in vacuo, and the residue was then added to water. The mixture was neutralized with aqueous sodium hydroxide solution and sodium bicarbonate. The solid was separated by filtration, washed with water and recrystallized form methanol to provide tan solid 1-(2-benzoyloxyethyl)-1H-imidazo[4,5-c]-quinolin-5-oxide.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:24]=[CH:23][C:12]([O:13][C:14]2[C:15]3[CH:22]=[CH:21][CH:20]=[CH:19][C:16]=3[S:17][CH:18]=2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([Li])CCC.[I:30]I>O1CCCC1>[I:30][C:18]1[S:17][C:16]2[CH:19]=[CH:20][CH:21]=[CH:22][C:15]=2[C:14]=1[O:13][C:12]1[CH:23]=[CH:24][C:9]([O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[CH:10][CH:11]=1
Reactant: c1ccc(COc2ccc(Oc3csc4ccccc34)cc2)cc1
Reactant: II
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: Ic1sc2ccccc2c1Oc1ccc(OCc2ccccc2)cc1
Temperature: -78 °C
Reaction time: 0.33 h
Yield: 85.6 %

Procedure:
To a solution of 3-(4-benzyloxyphenoxy) benzo[b]thiophene (6.00 g, 18.1 mmol) in anhydrous tetrahydrofuran (100 mL) under N2 at -78° C. was added n-butyllithium (12.4 mL, 19.9 mmol, 1.6 M in hexanes) dropwise via syringe. The solution turned from colorless to deep orange. After stirring for 20 minutes at -78° C., the lithio species was treated with I2 (5.03, 19.9 mmol), added dropwise via canula as a solution in 50 mL of anhydrous tetrahydrofuran. Upon completion of the addition, the reaction turned light yellow in color, and was allowed to slowly warm to room temperature. The reaction was quenched by the addition of 0.1 N sodium sulfite solution (200 mL). The layers were separated and the aqueous extracted with ethyl acetate (2×150 mL). The organic layers were combined, dried (sodium sulfate), and concentrated in vacuo to give an oil that crystallized on standing. Recrystallization from hexanes/ethyl ether yielded 7.10 g (86%) of 2-iodo-3-(4-benzyloxyphenoxy)benzo[b]thiophene as a white crystalline powder. mp 87-92° C. 1H NMR (CDCl3) d 7.72 (d, J=8.1 Hz, 1H), 7.47-7.20 (m, 8H), 6.89 (s, 4H), 5.01 (s, 2H). Anal. Calcd. for C21H15O2SI: C, 55.03; H, 3.30. Found: C, 55.29; H, 3.31.
Reaction SMILES: [CH3:1][N:2]1[CH2:6][C:5](=[O:7])[NH:4][C:3]1=[N:8][C:9](=[O:11])O.[NH2:12][C:13]1[CH:21]=[CH:20][C:16]([C:17]([NH2:19])=[O:18])=[CH:15][N:14]=1.O>CN(C=O)C>[NH2:19][C:17]([C:16]1[CH:20]=[CH:21][C:13]([NH:12][C:9]([N:8]=[C:3]2[NH:4][C:5](=[O:7])[CH2:6][N:2]2[CH3:1])=[O:11])=[N:14][CH:15]=1)=[O:18]
Reactant: CN1CC(=O)NC1=NC(=O)O
Reactant: NC(=O)c1ccc(N)nc1
Solvent: O
Solvent: CN(C)C=O
Product: CN1CC(=O)NC1=NC(=O)Nc1ccc(C(N)=O)cn1
Temperature: 65 °C
Reaction time: 1.5 h
Yield: 71.5 %

Procedure:
A mixture of 1.00 g (4.29 mM) of the phenyl carbamate 8 and 0.59 g (4.29 mM) of 6-aminonicotinamide in 4 ml of anhydrous DMF was stirred at 65° C. for 1.5 hr., cooled and poured into water. The resulting precipitate was collected, washed with acetone and air dried to give 0.85 g of the above urea as a pale yellow solid, m.p. 240°-243° C. (dec.).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:29]C)=[C:6]2[C:11]=1[CH:10]([NH:12][C:13]1[CH:21]=[CH:20][CH:19]=[C:18]3[C:14]=1[CH:15]=[N:16][NH:17]3)[C:9]([C:23]([F:26])([F:25])[F:24])([OH:22])[CH2:8][C:7]2([CH3:28])[CH3:27].B(Br)(Br)Br.C(=O)(O)[O-].[Na+]>C(OCC)(=O)C>[Br:1][C:2]1[C:11]2[CH:10]([NH:12][C:13]3[CH:21]=[CH:20][CH:19]=[C:18]4[C:14]=3[CH:15]=[N:16][NH:17]4)[C:9]([C:23]([F:24])([F:25])[F:26])([OH:22])[CH2:8][C:7]([CH3:27])([CH3:28])[C:6]=2[C:5]([OH:29])=[CH:4][CH:3]=1
Reactant: COc1ccc(Br)c2c1C(C)(C)CC(O)(C(F)(F)F)C2Nc1cccc2[nH]ncc12
Agent: BrB(Br)Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Product: CC1(C)CC(O)(C(F)(F)F)C(Nc2cccc3[nH]ncc23)c2c(Br)ccc(O)c21
Temperature: 25 °C
Reaction time: 19 h
Yield: 84.6 %

Procedure:
21 mg (0.043 mmol) of 8-bromo-5-methoxy-1-[(1H-indazol-4-yl)amino]-4,4-dimethyl-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalen-2-ol is mixed at room temperature with 0.4 ml of a 1 M BBr3 solution and stirred for 19 hours at room temperature. After the reaction mixture is mixed with ice, saturated sodium bicarbonate solution is added drop by drop, and it is diluted with ethyl acetate. The organic phases are washed neutral as usual, and the residue that remains after the solvent is spun in is chromatographed on silica gel (mobile solvent methanol/dichloromethane); 17.1 mg (83.8%) of the desired compound (together with the Desbrom compound) is isolated.
Reaction SMILES: [C:1]([O:10]C)(=O)[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[SH:4].[C:12]([C:14]1[CH:23]=[CH:22][C:21]2[CH2:20][CH2:19][CH2:18][CH2:17][C:16]=2[N:15]=1)#[N:13].C(N(CC)CC)C>C1(C)C=CC=CC=1>[N:15]1[C:16]2[CH2:17][CH2:18][CH2:19][CH2:20][C:21]=2[CH:22]=[CH:23][C:14]=1[C:12]1[S:4][C:3]2[CH:5]=[CH:6][CH:7]=[CH:8][C:2]=2[C:1](=[O:10])[N:13]=1
Reactant: N#Cc1ccc2c(n1)CCCC2
Reactant: COC(=O)c1ccccc1S
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: O=c1nc(-c2ccc3c(n2)CCCC3)sc2ccccc12
Yield: 29.9 %

Procedure:
A mixture of methyl thiosalicylate (0.43 g, 2.5 mmol), 2-cyano-5,6,7,8-tetrahydroquinoline (0.40 g, 2.5 mmol), triethylamine (0.50 ml, 3.8 mmol) and toluene (2.0 ml) was refluxed for 17 hrs. After cooling, the precipitated crystals were collected by filtration and recrystallized from ethanol to give the titled compound (0.22 g, 30%).
Reaction SMILES: [F:1][CH:2]([F:16])[O:3][N:4]=[C:5]([C:13](=[O:15])[CH3:14])[C:6]([O:8]C(C)(C)C)=[O:7].S(Cl)([Cl:20])(=O)=O>C(O)(=O)C>[Cl:20][CH2:14][C:13](=[O:15])[C:5](=[N:4][O:3][CH:2]([F:16])[F:1])[C:6]([OH:8])=[O:7]
Reactant: CC(=O)C(=NOC(F)F)C(=O)OC(C)(C)C
Reactant: O=S(=O)(Cl)Cl
Solvent: CC(=O)O
Product: O=C(O)C(=NOC(F)F)C(=O)CCl
Reaction time: 7 h

Procedure:
To a solution of tert-butyl 2-difluoromethoxyimino-3-oxobutyrate (5.0 g) in acetic acid (5 ml) was added sulfuryl chloride (8.5 ml). The mixture was stirred at 60°-63° C. for 7 hours. The solvent was evaporated in vacuo to give 4-chloro-2-difluoromethoxyimino-3-oxobutyric acid (4.5 g) as a glassy mass.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH:11]([F:13])[CH2:10][CH:9]1[C:14](O)=[O:15])=[O:7])([CH3:4])([CH3:3])[CH3:2].B.C1COCC1>C1COCC1>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH:11]([F:13])[CH2:10][CH:9]1[CH2:14][OH:15])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CC(F)CC1C(=O)O
Agent: B
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CC(F)CC1CO
Temperature: 25 °C
Reaction time: 1 h
Yield: 97 %

Procedure:
To a stirred solution of 1-tert-butoxycarbonyl-4-fluoropyrrolidine-2-carboxylic acid (1.1 g, 4.7 mmol) in THF (10.0 ml) was added BH3.THF (1.0 M solution in THF, 10.0 ml, 10.0 mmol) at 0° C. After stirred at room temperature for 1.0 h. After cooled, the mixture was concentrated in vacuo. Water was added thereto at 0° C., and extracted with EtOAc. The extract was washed with water, then dried over Na2SO4, and concentrated in vacuo to give 1-tert-butoxycarbonyl-4-fluoro-2-pyrrolidinylmethanol (1.0 g, quant) as a a colorless oil. 1H-NMR (CDCl3) δ1.48 (s, 9H), 2.29-2.39 (m, 1H), 3.38-3.59 (m, 2H), 3.74-3.88 (m, 2H), 4.09-4.14 (m, 2H), 4.85 (m, 1H), 5.03 (br s, 1H), 5.16 (br s, 1H).
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][CH2:12][CH2:13][NH:14][C:15](=[O:26])[C@H:16]([CH3:25])[NH:17]C(OC(C)(C)C)=O)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.FC(F)(F)C(O)=O>ClCCl>[CH2:1]([O:8][C:9]([NH:11][CH2:12][CH2:13][NH:14][C:15](=[O:26])[C@H:16]([CH3:25])[NH2:17])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C[C@H](NC(=O)OC(C)(C)C)C(=O)NCCNC(=O)OCc1ccccc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: C[C@H](N)C(=O)NCCNC(=O)OCc1ccccc1
Reaction time: 0.33 h
Yield: 89.8 %

Procedure:
A solution of 12.0 g (0.033 mol) of (1g) in 25 ml of dichloromethane was cooled with an ice bath and 25 ml of trifluoroacetic acid was added. The solution was stirred at ca 5° C. for 20 minutes, then allowed to stir to room temperature. After 90 minutes, the dichloromethane and trifluoroacetic acid were removed in vacuo. The resulting residue was dissolved in 200 ml of ethyl acetate and washed with 2M sodium hydroxide (200 ml) and brine (100 ml). After drying over anhydrous magnesium sulfate, the solution was filtered and concentrated in vacuo to produce 7.86 g (90% yield) of L-alanine, 2-(benzyloxycarbonylamino)ethyl amide (1h) as a white solid. 1H NMR(CDCl3) δ 1.28(d, 3H), 2.09(m, 2H), 3.33(m, 4H), 3.47(q, 1H), 5.07(s, 2H), 5.59(bt, 1H), 7.33(bs, 5H), 7.69(bt, 1H);13C NMR (CDCl3) δ 21.3, 39.5, 40.9, 50.4, 66.6, 128.0, 128.1, 128.4, 136.4, 156.9, 176.7.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:6]([C:7]([O:9][CH3:10])=[O:8])[C:5]([OH:12])=[CH:4][CH:3]=1.Br[CH:14]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[CH3:15].C([O-])([O-])=O.[K+].[K+]>CC(C)=O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:12][CH:14]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH3:15])=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8]
Reactant: CC(Br)c1ccccc1
Reactant: COC(=O)c1cc(Br)ccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COC(=O)c1cc(Br)ccc1OC(C)c1ccccc1

Procedure:
A solution of methyl 5-bromosalicylate (12.70 g, 55 mmol), (1-bromoethyl)benzene (7.05 mL, 50 mmol), and K2CO3 (20.73 g, 150 mmol) in acetone (250 mL) is refluxed 18 hours. The mixture is then filtered and the filtrate is concentrated in vacuo. The residue is dissolved in EtOAc (250 mL) and then washed with 1 N NaOH (2×150 mL) and brine (1×100 mL), and dried over MgSO4. Concentration in vacuo yields methyl 5-bromo-2-(1-phenylethoxy)-benzoate.
Reaction SMILES: O.[NH2:2][NH2:3].Cl[C:5]1[CH:14]=[CH:13][C:8]([C:9]([O:11][CH3:12])=[O:10])=[CH:7][C:6]=1[N+:15]([O-:17])=[O:16]>C(O)C>[CH3:12][O:11][C:9]([C:8]1[CH:13]=[CH:14][C:5]([NH:2][NH2:3])=[C:6]([N+:15]([O-:17])=[O:16])[CH:7]=1)=[O:10]
Reactant: NN
Reactant: COC(=O)c1ccc(Cl)c([N+](=O)[O-])c1
Solvent: O
Solvent: CCO
Product: COC(=O)c1ccc(NN)c([N+](=O)[O-])c1
Reaction time: 0.75 h
Yield: 85 %

Procedure:
80 ml of hydrazine hydrate were poured into the suspension of 172.5 g of methyl 4-chloro-3-nitrobenzoate in 1600 ml of abs. ethanol under stirring, then the reaction mixture was refluxed while stirring for 45 minutes. The starting material dissolved and the product started to precipitate. After cooling down, the product was filtered by suction, washed with abs. ethanol and water successively until it became free from chloride ion. Thus, 4-methoxycarbonyl-2-nitrophenylhydrazine (143.6 g, 85%) was obtained as yellow crystals m.p.: 169°-171° C.
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[C:3]1[C:8]([C:9]([O:11][CH2:12][CH3:13])=[O:10])=[C:7](Cl)[CH:6]=[C:5]([C:15]([F:18])([F:17])[F:16])[N:4]=1.[N-:21]=[N+:22]=[N-:23].[Na+].CN(C=O)C>O>[N:21]([C:7]1[CH:6]=[C:5]([C:15]([F:18])([F:17])[F:16])[N:4]=[C:3]([C:2]([F:20])([F:19])[F:1])[C:8]=1[C:9]([O:11][CH2:12][CH3:13])=[O:10])=[N+:22]=[N-:23]
Reactant: CCOC(=O)c1c(Cl)cc(C(F)(F)F)nc1C(F)(F)F
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)c1c(N=[N+]=[N-])cc(C(F)(F)F)nc1C(F)(F)F
Reaction time: 1 h
Yield: 83.1 %

Procedure:
A mixture of 5.0 g (0.0155 mol) of product of Example 19, 1.0 g (0.0154 mol) of sodium azide and 20 ml of DMF was stirred for 1 hour and poured into 100 ml of water. The organic was extracted into 100 ml of CH2Cl2 which was washed with 50 ml of water and concentrated. The residue (6.0 g) was dissolved in 50 ml of petroleum ether then washed with 50 ml of water twice, dried (MgSO4) and concentrated to give a solid which was recrystallized from petroluem ether at low temperature to give 4.2 g (82%) of product as a light yellow solid; mp 63°-64.5° C.
Reaction SMILES: ClC1N=C(N2CCOCC2)C2SC([C:11]3[CH:12]=[C:13]([C:17]([OH:19])=O)[CH:14]=[N:15][CH:16]=3)=CC=2N=1.C[N:27](C)CCN>>[N:15]1[CH:16]=[CH:11][CH:12]=[C:13]([C:17]([NH2:27])=[O:19])[CH:14]=1
Reactant: CN(C)CCN
Reactant: O=C(O)c1cncc(-c2cc3nc(Cl)nc(N4CCOCC4)c3s2)c1
Product: NC(=O)c1cccnc1

Procedure:
5-(2-Chloro-4-morpholinothieno[3,2-d]pyrimidin-6-yl)pyridine-3-carboxylic acid (40 mg) was reacted with N,N-dimethylethylenediamine via General Procedure B to yield 5-(2-chloro-4-morpholinothieno[3,2-d]pyrimidin-6-yl)-N-(2-dimethylamino)ethyl)pyridine-3-carboxamide. Crude 5-(2-chloro-4-morpholinothieno[3,2-d]pyrimidin-6-yl)-N-(2-dimethylamino)ethyl)pyridine-3-carboxamide (46 mg) was coupled to 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazole 7 via General Procedure A to yield 22.3 mg of 343. MS (Q1) 529.0 (M)+
Reaction SMILES: [OH:1]O.[CH3:3][C:4]([C:7]1[CH:12]=[C:11]([C:13]2[S:14][C:15]([S:18][CH3:19])=[N:16][N:17]=2)[CH:10]=[C:9]([C:20]([CH3:23])([CH3:22])[CH3:21])[C:8]=1[OH:24])([CH3:6])[CH3:5]>C(O)(=O)C>[CH3:21][C:20]([C:9]1[CH:10]=[C:11]([C:13]2[S:14][C:15]([S:18]([CH3:19])=[O:1])=[N:16][N:17]=2)[CH:12]=[C:7]([C:4]([CH3:3])([CH3:5])[CH3:6])[C:8]=1[OH:24])([CH3:23])[CH3:22]
Reactant: OO
Reactant: CSc1nnc(-c2cc(C(C)(C)C)c(O)c(C(C)(C)C)c2)s1
Solvent: CC(=O)O
Product: CS(=O)c1nnc(-c2cc(C(C)(C)C)c(O)c(C(C)(C)C)c2)s1
Temperature: 90 °C
Yield: 26.5 %

Procedure:
30% aqueous hydrogen peroxide (1.7 g, 0.015 mole) is added to a stirred solution of 2,6-bis(1,1-dimethylethyl)-4-[5-(methylthio)-1,3,4-thiadiazol-2-yl]-phenol (5.0 g, 0.015 mole) in glacial acetic acid (20 ml). The resulting mixture is heated to 90° C. for three hours. The mixture is cooled and concentrated in vacuo. The residue is purified by flash chromatography (SiO2, 25% ethyl acetate/hexane eluent) to provide a solid which is recrystallized from ethyl acetate/hexane to give 1.4 g of 2,6-bis(1,1-dimethylethyl)-4-[5-(methylsulfinyl)-1,3,4-thiadiazol-2-yl]-phenol (5.3 g theor., 26%), mp 141.2° C.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][C:3]=1[CH:4]=O.[CH:11]([CH:13]=[CH2:14])=[O:12].C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1.O>[OH:10][C:7]1[CH:6]=[C:3]2[C:2](=[CH:9][CH:8]=1)[O:1][CH2:14][C:13]([CH:11]=[O:12])=[CH:4]2
Reactant: C=CC=O
Reactant: O=Cc1cc(O)ccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: O=CC1=Cc2cc(O)ccc2OC1

Procedure:
3 g (21.7 mmol) of 2,5-dihydroxybenzaldehyde and also 2.2 ml (32.6 mmol) of acrolein are added to a suspension of 6 g (43.5 mmol) of potassium carbonate in 50 ml of 1,4-dioxane; the medium is then heated at reflux for 12 hours. The salts are filtered off over Celite; the solvent is then evaporated in vacuo. The residue obtained is taken up in water; the aqueous phase is then extracted with ether. After drying over magnesium sulphate and evaporation of the solvent in vacuo, the crude product is triturated in dichloromethane to yield the title compound in the form of a yellow solid.
Reaction SMILES: [CH3:1][C:2]1([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:14]2[NH:13][C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[C:6]=2[CH2:5][CH2:4][NH:3]1.[F:21][C:22]1[CH:23]=[C:24]([CH:28]=[CH:29][C:30]=1[F:31])[C:25](Cl)=[O:26].CCN(C(C)C)C(C)C>C(Cl)(Cl)Cl>[F:21][C:22]1[CH:23]=[C:24]([C:25]([N:3]2[CH2:4][CH2:5][C:6]3[C:7]4[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=4)[NH:13][C:14]=3[C:2]2([CH3:1])[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[O:26])[CH:28]=[CH:29][C:30]=1[F:31]
Reactant: CC1(c2ccccc2)NCCc2c1[nH]c1ccccc21
Reactant: O=C(Cl)c1ccc(F)c(F)c1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClC(Cl)Cl
Product: CC1(c2ccccc2)c2[nH]c3ccccc3c2CCN1C(=O)c1ccc(F)c(F)c1
Temperature: 60 °C
Reaction time: 17 h
Yield: 21.7 %

Procedure:
The title compound was prepared by the addition of 1-methyl-1-phenyl-1,3,4,9-tetrahydrobeta-carboline (105 mg, 400 μmol), CHCl3 (9 mL), 3,4-difluorobenzoyl chloride (85 mg, 480 μmol), and DIEA (140 μL, 800 μmol) to a 25 mL flask. The solution was allowed to stir at 60° C. under N2 for 17 hours. The reaction solution was concentrated, and the crude sample was chromatographed (SiO2, 100% hexane to 20% EtOAc) to yield 35 mg of title compound; 1H NMR (CDCl3) δ 7.54 (1H, d), 7.48 (2H, d), 7.12-7.32 (9H, m), 4.05 (1H, m), 3.64-3.70 (1H, m), 3.19 (1H, m), 2.96 (1H, m), 2.29 (3H, s); MS (ESI): 403 (MH+).
Reaction SMILES: N[C:2]1([CH:8]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:6]=[C:5]([C:13]([F:16])([F:15])[F:14])[CH:4]1[NH2:17])[NH2:3].O.O.[C:20](O)(=[O:24])[C:21](O)=[O:22]>Cl>[F:14][C:13]([F:16])([F:15])[C:5]1[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=[C:2]2[C:4]=1[NH:17][C:20](=[O:24])[C:21](=[O:22])[NH:3]2
Reactant: NC1C(C(F)(F)F)=CC(C(F)(F)F)=CC1(N)N
Reactant: O=C(O)C(=O)O
Agent: Cl
Solvent: O
Product: O=c1[nH]c2cc(C(F)(F)F)cc(C(F)(F)F)c2[nH]c1=O
Temperature: 25 °C
Yield: 39.7 %

Procedure:
A mixture of 1,2-diamino-3,5-bis(trifluoromethyl)aniline (94 mg, 0.38 mmol) and oxalic acid dihydrate (53 mg, 0.42 mmol, used as received) in 4N HCl (2 mL) was refluxed at 120°-5° C. for 3 h, then cooled to room temperature. The mixture was centrifuged and the liquid layer was removed. The yellow solid was washed by cold water (2×2 mL), collected by filtration, and dried at 60° C. under reduced pressure for 2 h, affording 45 mg of crude 5,7-bis(trifluoromethyl)-1,4-dihydro-2,3-quinoxalinedione (40% ) as a yellow powder. The crude compound was dissolved in 1N NaOH (6 mL) and filtered. The filtrate was acidified to pH=5, affording 23 mg of pure 5,7-bis(trifluoromethyl)-1,4-dihydro-2,3-quinoxalinedione. Mp: 305°-8° C. (dec. from 295° C.). IR (KBr, cm-1) 3421, 3235, 1749, 1690, 1631. 1H NMR (DMSO-d6): δ 7.654 (s, 1H); 7.687 (s, 1H); 11.584 (s, 1H); 12.311 (s, 1H). HRMS: calcd for C10F6H4N2O2 (M+) m/z: 298.0176; found: 298.0170.