Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH:2]([C:4]1[CH:13]=[CH:12][C:11]2[CH2:10][CH2:9][CH2:8][C:7]([CH3:15])([CH3:14])[C:6]=2[CH:5]=1)[CH3:3].[Cr](O[Cr]([O-])(=O)=O)([O-])(=O)=O.[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1.FC(F)(F)C([O-])=O.[NH+]1C=CC=CC=1>C(Cl)Cl>[C:2]([C:4]1[CH:13]=[CH:12][C:11]2[CH2:10][CH2:9][CH2:8][C:7]([CH3:15])([CH3:14])[C:6]=2[CH:5]=1)(=[O:1])[CH3:3]
Reactant: CC(O)c1ccc2c(c1)C(C)(C)CCC2
Agent: O=[Cr](=O)([O-])O[Cr](=O)(=O)[O-]
Agent: O=C([O-])C(F)(F)F
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: CC(=O)c1ccc2c(c1)C(C)(C)CCC2
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a stirred solution of 2.44 g (11.96 mmol) of 2-(1-hydroxyethyl)-8,8-dimethyl-5,6,7,8-tetrahydronaphthalene in 35 ml of methylene chloride was added 6.75 g (17.9 mmol) of pyridinium dichromate and 330 mg (1.68 mmol) of pyridinium trifluoroacetate. The mixture was stirred at room temperature for 24 h and then diluted with 35 ml of low-boiling petroleum ether. The mixture was filtered through a short column of anhydrous MgSO4 and silica and the filtrate then concentrated in-vacuo to give the title compound as a colorless oil.
Reaction SMILES: Br[C:2]1[S:3][CH:4]=[CH:5][N:6]=1.C(N(CC)CC)C.[CH:14]#[C:15][CH2:16][CH2:17][CH3:18]>COCCOC.[Cu]I.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>[C:14]([C:2]1[S:3][CH:4]=[CH:5][N:6]=1)#[C:15][CH2:16][CH2:17][CH3:18]
Reactant: Brc1nccs1
Reactant: C#CCCC
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: COCCOC
Solvent: CCN(CC)CC
Product: CCCC#Cc1nccs1
Temperature: 25 °C
Reaction time: 6 h
Yield: 45.2 %

Procedure:
2-Bromo-1,3-thiazole (2.0 g, 12 mmol) and CuI (183 mg, 0.96 mmol) were combined in DME (30 mL) and argon gas was bubbled through the suspension for several minutes to deoxygenate the mixture. Triethylamine (8 mL, 60 mmol) and PdCl2(PPh3)2 (337 mg, 0.48 mmol) were added and 1-pentyne (979 mg, 14.4 mmol) was added dropwise. The reaction mixture was stirred at ambient temperature for 6 h at which time GC/MS analysis indicated that the reaction was not complete. Additional 1-pentyne (3.0 mL, 29 mmol) was added and the reaction was heated to 35° C. under a condenser. After heating for 16 h, GC/MS analysis indicated that the reaction was complete. The mixture was filtered through Celite.™., and the filter pad was washed thoroughly with ethyl acetate. The combined filtrates were concentrated in vacuo and the residue was dissolved in ethyl acetate (300 mL), washed with water (300 mL), brine (300 mL), dried over Na2SO4 filtered, and concentrated in vacuo. The residue was purified by column chromatography eluting with hexane, 99:1, then 97:3 hexane:ethyl acetate to 2-(1-pentynyl)-1,3-thiazole (820 mg, 44% yield) as a yellow oil. 1H NMR (CDCl3, 300 MHz) Δ7.76 (d, J=3.0 Hz, 1H), 7.28 (d, J=3.0 Hz, 1H), 2.47-2.42 (m, 2H), 1.68-1.60 (m, 2H), 1.08-0.99 (m, 3H). MS (ESI) 151.6 (M+).
Reaction SMILES: CO[C:3]([C:5]1([CH3:31])[CH2:9][CH2:8][N:7]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([C:16]3[N:17]=[C:18]4[C:24]([C:25](=[O:30])[C:26]([CH3:29])([CH3:28])[CH3:27])=[CH:23][NH:22][C:19]4=[N:20][CH:21]=3)[CH:11]=2)[CH2:6]1)=[O:4].[OH-].[K+].C(C1NC=CN=1)([C:36]1[NH:37]C=CN=1)=O.CN>CN(C)C=O.CO>[CH3:36][NH:37][C:3]([C:5]1([CH3:31])[CH2:9][CH2:8][N:7]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([C:16]3[N:17]=[C:18]4[C:24]([C:25](=[O:30])[C:26]([CH3:27])([CH3:29])[CH3:28])=[CH:23][NH:22][C:19]4=[N:20][CH:21]=3)[CH:11]=2)[CH2:6]1)=[O:4]
Reactant: O=C(c1ncc[nH]1)c1ncc[nH]1
Reactant: COC(=O)C1(C)CCN(c2cccc(-c3cnc4[nH]cc(C(=O)C(C)(C)C)c4n3)c2)C1
Agent: CN
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: CN(C)C=O
Product: CNC(=O)C1(C)CCN(c2cccc(-c3cnc4[nH]cc(C(=O)C(C)(C)C)c4n3)c2)C1
Temperature: 65 °C

Procedure:
1-{3-[7-(2,2-Dimethyl-propionyl)-5H-pyrrolo[2,3-b]pyrazin-2-yl]-phenyl}-3-methyl-pyrrolidine-3-carboxylic acid methylamide was prepared by treating 1-{3-[7-(2,2-dimethyl-propionyl)-5H-pyrrolo[2,3-b]pyrazin-2-yl]-phenyl}-3-methyl-pyrrolidine-3-carboxylic acid methyl ester (190 mg, 0.3 mmol) with methanol (3 mL) and potassium hydroxide (2 mL, 0.5 M aqueous). Upon partitioning the mixture between 10% aqueous acetic acid and ethyl acetate, the desired acid (110 mg, 0.27 mmol) was dissolved in N,N-dimethylformamide (3 mL) and treated with carbonyl diimidazole (46 mg, 0.28 mmol) and heated to 65° C. for 2 hours. Methylamine (2 mL) was condensed at −20° C. in heavy-walled vessel. The mixture above was added and the vessel was immediately sealed and heated to 50° C. for 5 days. Upon cooling, the volatiles were removed in vacuo and the residue partitioned between 2% aqueous acetic acid and ethyl acetate. The combined organic layers were aged over anhydrous sodium sulfate. The title compound was obtained as a powder (26 mg) following silica gel chromatography (eluant: 40 to 100% ethyl acetate-hexanes): m.p. 252-254° C.; MS m/z 419 (M+H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:34])[CH:4]([NH:26]C(OC(C)(C)C)=O)[CH2:5][C:6]1[CH:15]=[C:14]2[C:9]([CH2:10][CH2:11][N:12]([C:16](=[O:25])[C:17]3[C:22]([Cl:23])=[CH:21][CH:20]=[CH:19][C:18]=3[Cl:24])[CH2:13]2)=[CH:8][CH:7]=1>FC(F)(F)C(O)=O.ClCCl>[CH3:1][O:2][C:3](=[O:34])[CH:4]([NH2:26])[CH2:5][C:6]1[CH:15]=[C:14]2[C:9]([CH2:10][CH2:11][N:12]([C:16](=[O:25])[C:17]3[C:18]([Cl:24])=[CH:19][CH:20]=[CH:21][C:22]=3[Cl:23])[CH2:13]2)=[CH:8][CH:7]=1
Reactant: COC(=O)C(Cc1ccc2c(c1)CN(C(=O)c1c(Cl)cccc1Cl)CC2)NC(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)C(N)Cc1ccc2c(c1)CN(C(=O)c1c(Cl)cccc1Cl)CC2
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 86.5 %

Procedure:
A solution of 2-tert-butyloxycarbonylamino-3-[2-(2,6-dichloro-benzoyl]-1,2,3,4-tetrahydro-isoquinolin-7-yl]-propionic acid methyl ester {1.7 g, Reference Example 9(b)} in a mixture of trifluoroacetic acid (10 mL) and dichloromethane (30 mL), under nitrogen, was stirred at room temperature for 1.5 hours then evaporated. The residue was dissolved in dichloromethane and this solution was washed with aqueous sodium bicarbonate solution, then with water, then dried over magnesium sulfate and then evaporated to give the title compound (1.18 g) which was used without further purification.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH:8][CH2:9][CH3:10])[CH:5]=[CH:6][CH:7]=1.[S:11]1[CH2:17][C:15](=[O:16])[NH:14][C:12]1=S.CCN(C(C)C)C(C)C>C(#N)C>[F:1][C:2]1[CH:3]=[C:4]([N:8]([CH2:9][CH3:10])[C:12]2[S:11][CH2:17][C:15](=[O:16])[N:14]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: O=C1CSC(=S)N1
Reactant: CCNc1cccc(F)c1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: CCN(C1=NC(=O)CS1)c1cccc(F)c1
Temperature: 0 °C
Reaction time: 72 h
Yield: 76.6 %

Procedure:
To a solution of (3-fluorophenyl)-ethylamine (3.06 g, 22 mmol) and rhodanine (2.66 g, 20 mmol) in acetonitrile (70 mL) was added DIEA (7.66 mL, 44 mmol) at room temperature. Then, this solution was cooled to 0° C. and mercuric chloride (5.97 g, 22 mmol) was added in two portions. After addition, the suspension was allowed to warm to room temperature and stirred for 3 days. The resulting black solids were filtered through a plug of celite and washed with dichloromethane (500 mL) and methanol (250 mL). The combined solvents were removed under the vacuum and the crude residue was dissolved in ethyl acetate (25 mL) at hot condition and stored in the refrigerator overnight. Then, the solids were collected by filtration and washed with ethyl acetate. After drying in air, 3.65 g (76.6% yield) of 2-[(3-fluorophenyl)-ethylamino]-thiazol-4-one was isolated as a white amorphous solid: HRES(+) m/e calcd for C11H11FN2OS (M+H)+239.0649, found 239.0647.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[O:13][C:12]([CH2:14][CH2:15][NH:16][C:17]([C:19]3[NH:23][N:22]=[C:21]([C:24](O)=[O:25])[CH:20]=3)=[O:18])=[CH:11][CH:10]=2)[CH:5]=[CH:6][C:7]=1[Cl:8].[O:27]1[CH2:32][CH2:31][N:30]([CH:33]2[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]2)[CH2:29][CH2:28]1>>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[O:13][C:12]([CH2:14][CH2:15][NH:16][C:17]([C:19]3[NH:23][N:22]=[C:21]([C:24]([N:36]4[CH2:37][CH2:38][CH:33]([N:30]5[CH2:31][CH2:32][O:27][CH2:28][CH2:29]5)[CH2:34][CH2:35]4)=[O:25])[CH:20]=3)=[O:18])=[CH:11][CH:10]=2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: O=C(O)c1cc(C(=O)NCCc2ccc(-c3ccc(Cl)c(Cl)c3)o2)[nH]n1
Reactant: C1CC(N2CCOCC2)CCN1
Product: O=C(NCCc1ccc(-c2ccc(Cl)c(Cl)c2)o1)c1cc(C(=O)N2CCC(N3CCOCC3)CC2)n[nH]1

Procedure:
The title compound was prepared as in Example 1 starting from 5-{2-[5-(3,4-dichlorophenyl)furan-2-yl]ethylcarbamoyl}-1H-pyrazole-3-carboxylic acid and 4-morpholinopiperidine. The crude product was purified by flash chromatography using CH2Cl2-MeOH as a gradient eluent (100:0-96:4). 1H NMR (400 MHz, DMSO-d6): about 1.32 (2H, m), about 1.82 (2H, m), 2.45-2.47 (5H, m), about 2.78 (1H, m), 2.95 (2H, t), about 3.11 (1H, m), 3.55-3.57 (6H, m), about 4.45 (1H, m), 6.34 (1H, d), 7.02 (1H, d), about 7.03 (1H, broad s), 7.59 (1H, distorted dd), 7.63 (1H, distorted d), 7.84 (1H, d), 8.6 (1H, broad s), 13.9 (1H, broad s).
Reaction SMILES: [CH3:1][S:2][CH:3]([S:6][CH3:7])[S:4][CH3:5].C([Li])CCC.[F:13][C:14]([F:41])([F:40])[C:15]1[CH:39]=[CH:38][C:18]([O:19][CH2:20][C:21]2[NH:25][C:24]3[CH:26]=[CH:27][C:28]([C:30]4[CH:37]=[CH:36][CH:35]=[CH:34][C:31]=4[CH:32]=[O:33])=[CH:29][C:23]=3[N:22]=2)=[CH:17][CH:16]=1>C1COCC1>[CH3:1][S:2][C:3]([S:6][CH3:7])([S:4][CH3:5])[CH:32]([C:31]1[CH:34]=[CH:35][CH:36]=[CH:37][C:30]=1[C:28]1[CH:27]=[CH:26][C:24]2[NH:25][C:21]([CH2:20][O:19][C:18]3[CH:38]=[CH:39][C:15]([C:14]([F:41])([F:40])[F:13])=[CH:16][CH:17]=3)=[N:22][C:23]=2[CH:29]=1)[OH:33]
Reactant: O=Cc1ccccc1-c1ccc2[nH]c(COc3ccc(C(F)(F)F)cc3)nc2c1
Reactant: CSC(SC)SC
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CSC(SC)(SC)C(O)c1ccccc1-c1ccc2[nH]c(COc3ccc(C(F)(F)F)cc3)nc2c1
Reaction time: 0.5 h
Yield: 219.7 %

Procedure:
To a solution of tris(methylthio)methane (0.640 g, 4.15 mmol) in THF (12 mL) at −78° C. was added n-butyllithium (1.6 mL, 4.15 mmol). After stirring for 30 min, 2-[2-(4-trifluoromethyl-phenoxymethyl)-1H-benzoimidazol-5-yl]-benzaldehyde (0.274 g, 0.691 mmol, Example 9, Step A) in THF (2 mL) was carefully added to the reaction mixture at −78° C. After 20 min, the reaction was quenched by addition of methanol. The reaction mixture was purified by chromatography (silica, hexanes: EtOAc, 2:1) to afford the title compound as a yellow oil (0.836 g, 94%).
Reaction SMILES: [C:1]12([C:11]3[CH:35]=[CH:34][C:14]([C:15]([O:17][C:18]4[CH:33]=[CH:32][C:21]([C:22]([O:24]CC5C=CC=CC=5)=[O:23])=[CH:20][CH:19]=4)=[O:16])=[CH:13][C:12]=3[O:36][CH3:37])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2>O1CCOCC1>[C:1]12([C:11]3[CH:35]=[CH:34][C:14]([C:15]([O:17][C:18]4[CH:19]=[CH:20][C:21]([C:22]([OH:24])=[O:23])=[CH:32][CH:33]=4)=[O:16])=[CH:13][C:12]=3[O:36][CH3:37])[CH2:2][CH:3]3[CH2:9][CH:7]([CH2:6][CH:5]([CH2:4]3)[CH2:10]1)[CH2:8]2
Reactant: COc1cc(C(=O)Oc2ccc(C(=O)OCc3ccccc3)cc2)ccc1C12CC3CC(CC(C3)C1)C2
Solvent: C1COCCO1
Product: COc1cc(C(=O)Oc2ccc(C(=O)O)cc2)ccc1C12CC3CC(CC(C3)C1)C2
Temperature: 25 °C
Reaction time: 3 h

Procedure:
1.8 g (3.6 mmol) of benzyl 4-[4-(1-adamantyl)-3-methoxybenzoyloxy]benzoate and 50 ml of dioxane were introduced into a reactor. After flushing the reactor with nitrogen, 1 g of Pd-on-charcoal (10%) was introduced, followed by hydrogen at a pressure of 7.5 bar. The mixture was stirred at room temperature for 3 hours, the catalyst was filtered off and the filtrate was evaporated. The residue obtained was triturated from 40 ml of ethyl ether and filtered. 1.1 g (71%) of the expected acid, having a melting point of 273°-4° C., was recovered.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[C:12]([NH:14][CH:15]1[CH2:20][CH2:19][CH2:18][CH:17]([C:21]([O:23][CH3:24])=[O:22])[CH2:16]1)=[O:13].[C:25]1([O:31][CH2:32][CH2:33][CH2:34]/[CH:35]=[CH:36]/[C:37]2[CH:42]=[CH:41][C:40]([CH2:43][CH2:44][CH2:45]Br)=[CH:39][CH:38]=2)[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>>[CH3:24][O:23][C:21]([CH:17]1[CH2:18][CH2:19][CH2:20][CH:15]([NH:14][C:12]([C:3]2[CH:4]=[C:5]([CH:10]=[CH:11][C:2]=2[O:1][CH2:45][CH2:44][CH2:43][C:40]2[CH:41]=[CH:42][C:37](/[CH:36]=[CH:35]/[CH2:34][CH2:33][CH2:32][O:31][C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=3)=[CH:38][CH:39]=2)[C:6]([O:8][CH3:9])=[O:7])=[O:13])[CH2:16]1)=[O:22]
Reactant: BrCCCc1ccc(/C=C/CCCOc2ccccc2)cc1
Reactant: COC(=O)c1ccc(O)c(C(=O)NC2CCCC(C(=O)OC)C2)c1
Product: COC(=O)c1ccc(OCCCc2ccc(/C=C/CCCOc3ccccc3)cc2)c(C(=O)NC2CCCC(C(=O)OC)C2)c1

Procedure:
Preparation takes place in analogy to Example 22 from the (+)-B-enantiomer of methyl 4-hydroxy-3-({[3-(methoxycarbonyl)cyclohexyl]amino}carbonyl)benzoate (see Example IX, method 2) and (4E)-5-[4-(3-bromopropyl)phenyl]pent-4-en-1-yl phenyl ether.
Reaction SMILES: [OH:1][C:2]([C:5]1[N:9]=[C:8]([C:10]([O:12]CC)=O)[O:7][N:6]=1)([CH3:4])[CH3:3].[NH2:15][C@@H:16]([CH3:33])[CH2:17][N:18]1[CH:22]=[CH:21][C:20]([C:23]2[CH:30]=[C:29]([F:31])[C:26]([C:27]#[N:28])=[C:25]([Cl:32])[CH:24]=2)=[N:19]1>>[Cl:32][C:25]1[CH:24]=[C:23]([C:20]2[CH:21]=[CH:22][N:18]([CH2:17][C@@H:16]([NH:15][C:10]([C:8]3[O:7][N:6]=[C:5]([C:2]([OH:1])([CH3:3])[CH3:4])[N:9]=3)=[O:12])[CH3:33])[N:19]=2)[CH:30]=[C:29]([F:31])[C:26]=1[C:27]#[N:28]
Reactant: C[C@H](N)Cn1ccc(-c2cc(F)c(C#N)c(Cl)c2)n1
Reactant: CCOC(=O)c1nc(C(C)(C)O)no1
Product: C[C@@H](Cn1ccc(-c2cc(F)c(C#N)c(Cl)c2)n1)NC(=O)c1nc(C(C)(C)O)no1

Procedure:
The title compound was prepared using the procedure described in Example 52(g) starting from ethyl 3-(2-hydroxypropan-2-yl)-1,2,4-oxadiazole-5-carboxylate (2 mmol, 400 mg) and (S)-4-(1-(2-aminopropyl)-1H-pyrazol-3-yl)-2-chloro-6-fluoro-benzonitrile (2 mmol, 556 mg). Yield 202 mg. 1H-NMR (400 MHz; DMSO-d6): δ 1.12 (d, 3H), 1.51 (bs, 6H), 4.34-4.37 (m, 2H), 4.43-4.51 (m, 1H), 5.70 (s, 1H), 7.02 (d, 1H), 7.83-7.88 (m, 2H), 7.96 (s, 1H), 9.41 (d, 1H). LC-MS: [M+1]=433.20.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4](=[O:12])[C:5](=[O:11])[NH:6]2.[NH2:13]C1C=CC=C(Br)C=1C(N)=O.[N-]=C=O.[Na+]>>[Br:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4](=[O:12])[NH:13][C:5](=[O:11])[NH:6]2
Reactant: O=C1Nc2cccc(Br)c2C1=O
Reactant: NC(=O)c1c(N)cccc1Br
Agent: [N-]=C=O
Agent: [Na+]
Product: O=c1[nH]c(=O)c2c(Br)cccc2[nH]1

Procedure:
Compounds of formula I may be synthesized according to Scheme 1. Commercially available 4-bromoindoline-2,3-dione may be hydrolyzed to 2-amino-6-bromobenzamide followed by condensation with sodium isocyanate to form 5-bromoquinazoline-2,4(1H,3H)-dione. The protocols include, but are not limited to, palladium mediated cross coupling between 5-bromoquinazoline-2,4(1H,3H)-dione and the aryl boronic acid or ester to form the intermediate 5-substituted quinazoline-2,4(1H, 3H)-dione. Conversion to the corresponding dichloro quinazoline and sequential displacement at the 4-position followed by transition metal mediated cross coupling or displacement of the C2 chloride forms compounds I as described.
Reaction SMILES: [Cl:1][C:2]1[CH:20]=[C:19]([C:21]([F:24])([F:23])[F:22])[CH:18]=[CH:17][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[C:7]([N+]([O-])=O)[CH:6]=1.[SH:25][CH2:26][P:27](=[O:32])([O:30][CH3:31])[O:28][CH3:29]>>[N+:11]([C:8]1[CH:9]=[CH:10][C:5]([O:4][C:3]2[CH:17]=[CH:18][C:19]([C:21]([F:24])([F:23])[F:22])=[CH:20][C:2]=2[Cl:1])=[CH:6][C:7]=1[S:25][CH2:26][P:27](=[O:32])([O:30][CH3:31])[O:28][CH3:29])([O-:13])=[O:12]
Reactant: COP(=O)(CS)OC
Reactant: O=[N+]([O-])c1ccc(Oc2ccc(C(F)(F)F)cc2Cl)cc1[N+](=O)[O-]
Product: COP(=O)(CSc1cc(Oc2ccc(C(F)(F)F)cc2Cl)ccc1[N+](=O)[O-])OC

Procedure:
In like manner, 4-(2-chloro-4-trifluoromethylphenoxy)-1,2-dinitrobenzene and dimethyl sulfhydrylmethylphosphonate is reacted together to yield dimethyl 2-nitro-5-(2-chloro-4-trifluoromethylphenoxy)phenylthiomethylphosphonate.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[O:9][CH3:10].C1C(=O)N([Br:18])C(=O)C1.CC(N=NC(C#N)(C)C)(C#N)C>C(Cl)(Cl)(Cl)Cl>[Br:18][CH2:8][C:5]1[CH:6]=[CH:7][C:2]([Cl:1])=[C:3]([O:9][CH3:10])[CH:4]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: COc1cc(C)ccc1Cl
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: COc1cc(CBr)ccc1Cl
Yield: 91.6 %

Procedure:
To a solution of 1-chloro-2-methoxy-4-methyl-benzene (50 g, 0.32 mol) in CCl4 (350 mL) was added NBS (57.2 g, 0.32 mol) and AIBN (10 g, 60 mmol). The mixture was heated at reflux for 3 hours. The solvent was evaporated under vacuum and the residue was purified by column chromatography on silica gel (Petroleum Ether/EtOAc=20:1) to give 4-bromomethyl-1-chloro-2-methoxy-benzene (69 g, 92%). 1H NMR (400 MHz, CDCl3) δ 7.33-7.31 (m, 1 H), 6.95-6.91 (m, 2 H), 4.46 (s, 2 H), 3.92 (s, 3 H).
Reaction SMILES: [F-].C([N+](CCCC)(CCCC)CCCC)CCC.[CH3:19][O:20][C:21]1[N:26]=[C:25]([C:27]2[CH:34]=[CH:33][C:30]([CH:31]=[O:32])=[CH:29][CH:28]=2)[CH:24]=[CH:23][CH:22]=1.[F:35][C:36]([Si](C)(C)C)([F:38])[F:37].Cl>C1COCC1>[CH3:19][O:20][C:21]1[N:26]=[C:25]([C:27]2[CH:34]=[CH:33][C:30]([CH:31]([OH:32])[C:36]([F:38])([F:37])[F:35])=[CH:29][CH:28]=2)[CH:24]=[CH:23][CH:22]=1
Reactant: COc1cccc(-c2ccc(C=O)cc2)n1
Reactant: C[Si](C)(C)C(F)(F)F
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: Cl
Agent: [F-]
Solvent: C1CCOC1
Product: COc1cccc(-c2ccc(C(O)C(F)(F)F)cc2)n1
Temperature: 25 °C
Reaction time: 4 h
Yield: 88.3 %

Procedure:
Tetrabutylammonium fluoride (TBAF) (0.1 ml of 1M in THF) was added to a solution of 4-(6-methoxy-pyridine-2-yl)-benzaldehyde (213 mg, 1 mmol) and trifluoromethyl trimethylsilane (0.2 ml, 1.2 mmol) in 10 ml THF at 0° C. The mixture was warmed up to room temperature and stirred for 4 hours. The reaction mixture was then treated with 12 ml of 1M HCl and stirred overnight. The product was extracted with ethyl acetate (3×20 ml). The organic layer was separated and dried over sodium sulfate. The organic solvent was evaporated to give 0.25 g of 1-[4-(6-methoxy-pyridine-2-yl)-phenyl]-2,2,2-trifluoro-ethanol which was directly used in next step without purification. yield: 90%.
Reaction SMILES: [NH:1]([CH2:3][CH2:4][CH:5]1[CH2:10][CH2:9][N:8]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:7][CH2:6]1)[NH2:2].[Cl:18][C:19]1[N:24]=[C:23](Cl)[C:22]([C:26]([NH:28][C:29]2[C:34]([Cl:35])=[CH:33][CH:32]=[CH:31][C:30]=2[Cl:36])=[O:27])=[CH:21][N:20]=1.C(N(CC)CC)C>C1COCC1>[Cl:18][C:19]1[N:20]=[C:21]([NH:2][NH:1][CH2:3][CH2:4][CH:5]2[CH2:6][CH2:7][N:8]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:9][CH2:10]2)[C:22]([C:26](=[O:27])[NH:28][C:29]2[C:30]([Cl:36])=[CH:31][CH:32]=[CH:33][C:34]=2[Cl:35])=[CH:23][N:24]=1
Reactant: O=C(Nc1c(Cl)cccc1Cl)c1cnc(Cl)nc1Cl
Reactant: CC(C)(C)OC(=O)N1CCC(CCNN)CC1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(CCNNc2nc(Cl)ncc2C(=O)Nc2c(Cl)cccc2Cl)CC1
Temperature: 25 °C
Reaction time: 66 h

Procedure:
A solution of 618 mg (2.5 mmol) of tert-butyl 4-(2-hydrazinylethyl)piperidine-1-carboxylate in 10 mL THF was cooled to 0° C. and treated sequentially with 763 mg (2.3 mmol) of 2,4-dichloro-N-(2,6-dichlorophenyl)pyrimidine-5-carboxamide and 355 μl (2.5 mmol) of triethylamine. The resulting yellow slurry was warmed to room temperature and stirred for 66 h. The reaction mixture was quenched with saturated aqueous ammonium chloride (20 mL) and extracted with CH2Cl2 (3×30 mL). The combined organic layers were dried over Na2SO4, filtered, and the filtrate was purified by chromatography on silica gel (CH2Cl2:MeOH, 99.5:0.5 grading to CH2Cl2:MeOH, 98:2) to give the title compound 92. 1H-NMR (CDCl3) δ 1.08-1.23 (m, 3H), 1.45 (s, 9H), 1.58-1.66 (m, 2H), 1.72-1.79 (m, 2H), 2.61-2.75 (m, 2H), 3.87 (t, J=7.1 Hz, 2H), 3.99-4.14 (m, 4H), 7.24 (t, J=8.4 Hz, 1H), 7.43 (d, J=8.1 Hz, 2H), 7.48 (s, 1H), 8.40 (s, 1H). Mass Spectrum (ESI) m/e=543.1 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]([O:13][CH3:14])=[C:11]([O:15][CH3:16])[CH:10]=[C:9]2[C:4]=1[C:5]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[N:6][C:7](O)=[N:8]2.P(Cl)(Cl)([Cl:26])=O.[OH-].[Na+]>>[Cl:26][C:7]1[N:6]=[C:5]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:4]2[C:9](=[CH:10][C:11]([O:15][CH3:16])=[C:12]([O:13][CH3:14])[C:3]=2[O:2][CH3:1])[N:8]=1
Reactant: COc1cc2nc(O)nc(-c3ccccc3)c2c(OC)c1OC
Reactant: O=P(Cl)(Cl)Cl
Agent: [Na+]
Agent: [OH-]
Product: COc1cc2nc(Cl)nc(-c3ccccc3)c2c(OC)c1OC
Yield: 11.3 %

Procedure:
A solution of 5,6,7-trimethoxy-4-phenyl-quinazolin-2-ol (0.21 g, 0.67 mmol, 1.0 equiv) in phosphorus oxychloride (25.0 mL, 41.9 g, 273.1 mmol, 407.6 equiv) was heated to 110° C. for 1.5 h. The reaction mixture was poured on ice, the pH adjusted to 9 by addition of a 1 M solution of NaOH and the solution extracted with ethyl acetate (3×10 mL). The organic phase was dried over Na2SO4 and concentrated by evaporation under reduced pressure yielding 25.0 mg (11%) of the title compound which was used in the consecutive step without further purification. MS (ISP): 331.3 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([CH2:10][CH2:11][C:12]2[C:13]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[N:14][O:15][C:16]=2[CH3:17])[S:5][C:6]=1[C:7](O)=[O:8].C(N1C=CN=C1)([N:26]1C=CN=C1)=O.[OH-].[NH4+]>CN(C=O)C>[CH3:1][C:2]1[N:3]=[C:4]([CH2:10][CH2:11][C:12]2[C:13]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[N:14][O:15][C:16]=2[CH3:17])[S:5][C:6]=1[C:7]([NH2:26])=[O:8]
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: Cc1nc(CCc2c(-c3ccccc3)noc2C)sc1C(=O)O
Agent: [NH4+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: Cc1nc(CCc2c(-c3ccccc3)noc2C)sc1C(N)=O
Temperature: 60 °C
Reaction time: 1 h
Yield: 87 %

Procedure:
To a solution of 4-methyl-2-[2-(5-methyl-3-phenyl-isoxazol-4-yl)-ethyl]-thiazole-5-carboxylic acid (65 mg, 0.2 mmol) in DMF (82 mL) was added 1,1′-carbonyldiimidazole (39 mg, 0.24 mmol). The resulting reaction mixture was stirred for 1 h at 60° C. and then treated with an ammonium hydroxide solution (300 μL, 2.0 mmol) and stirred for 2 h at room temperature. The reaction mixture was then evaporated. Purification by chromatography (silica, dichloromethane:methanol=99:1 to 95:5) afforded the title compound (57 mg, 87%) as a white solid. MS: m/e=328.2 [M+H]+.
Reaction SMILES: F[C:2]1[C:7]([F:8])=[CH:6][C:5]([C:9]([F:12])([F:11])[F:10])=[CH:4][N:3]=1.[C:13]1([SH:19])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>C(Cl)Cl.[Cu]>[F:8][C:7]1[C:2]([S:19][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[N:3][CH:4]=[C:5]([C:9]([F:12])([F:11])[F:10])[CH:6]=1
Reactant: Sc1ccccc1
Reactant: Fc1cc(C(F)(F)F)cnc1F
Agent: [Cu]
Solvent: ClCCl
Product: Fc1cc(C(F)(F)F)cnc1Sc1ccccc1
Temperature: 160 °C
Reaction time: 2.5 h

Procedure:
Over a period of 2.5 h, 59.6 g (0.326 mol) of 2,3-difluoro-5-trifluoromethylpyridine were added at 148-156° C. to 37.7 g (0.338 mol) of 98.7% pure thiophenol and 2.1 mg (0.01 mol %) of copper powder, and the mixture was stirred at 156-164° C. for 2 hours. After cooling, the residue was taken up in methylene chloride, washed with 0.5 N of aqueous sodium hydroxide solution and with water, dried over magnesium sulfate and concentrated under reduced pressure. 88.9 g (100% of theory) of the title compound of n24/D=1.5539 were obtained.
Reaction SMILES: [NH2:1][C:2]1[C:3]([NH:13][CH3:14])=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[CH:9][C:8]([CH3:12])=[CH:7]2.[F:15][C:16]([F:21])([F:20])[C:17](O)=O.[OH-].[Na+]>Cl>[CH3:14][N:13]1[C:3]2[CH:4]=[CH:5][C:6]3[CH:7]=[C:8]([CH3:12])[CH:9]=[N:10][C:11]=3[C:2]=2[N:1]=[C:17]1[C:16]([F:21])([F:20])[F:15]
Reactant: O=C(O)C(F)(F)F
Reactant: CNc1ccc2cc(C)cnc2c1N
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: Cc1cnc2c(ccc3c2nc(C(F)(F)F)n3C)c1
Temperature: 95 °C

Procedure:
A mixture of 5.61 g (30 mmol) of 8-amino-3-methyl-7-methylaminoquinoline and 3.02 ml (40 mmol) of trifluoroacetic acid in 40 ml of 4N hydrochloric acid is heated at 95° C. for 2 h. It is then allowed to cool to room temperature and poured into 250 g of ice, the pH is adjusted to 9 with concentrated sodium hydroxide solution, and the precipitate is filtered off with suction. The crude product is dried and recrystallized from ethyl acetate/petroleum ether.