Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:15]=[CH:14][C:13]2[S:12][C:11]3[C:6]4=[C:7]([C:17](=[O:27])[C:18]([CH2:20][C:21]5[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=5)=[CH:19][N:5]4[C:4]=2[CH:3]=1)[CH:8]=[C:9]([OH:16])[CH:10]=3.Cl.Cl[CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][N:32]=1>>[Br:1][C:2]1[CH:15]=[CH:14][C:13]2[S:12][C:11]3[C:6]4=[C:7]([C:17](=[O:27])[C:18]([CH2:20][C:21]5[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=5)=[CH:19][N:5]4[C:4]=2[CH:3]=1)[CH:8]=[C:9]([O:16][CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][N:32]=1)[CH:10]=3
Reactant: ClCc1ccccn1
Reactant: O=c1c(Cc2cccnc2)cn2c3c(cc(O)cc13)Sc1ccc(Br)cc1-2
Agent: Cl
Product: O=c1c(Cc2cccnc2)cn2c3c(cc(OCc4ccccn4)cc13)Sc1ccc(Br)cc1-2
Yield: 6.6 %

Procedure:
According to Example 34, the compound (150 mg) produced in Example 37 was reacted with 2-chloromethylpyridine hydrochloride (84 mg) to obtain the title compound (12 mg; 67%).
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[C:3]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:4]=1[CH:5]=[C:6]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[NH:7]2.[H-].[Na+].ICCCN[C:26](=[O:32])[O:27][C:28]([CH3:31])([CH3:30])[CH3:29]>CN(C)C=O>[C:28]([O:27][C:26]([CH:6]([NH2:7])[CH2:5][CH2:4][N:7]1[C:8]2[C:4](=[C:3]([C:2]([F:1])([F:17])[F:18])[CH:11]=[CH:10][CH:9]=2)[CH:5]=[C:6]1[C:12]([O:14][CH2:15][CH3:16])=[O:13])=[O:32])([CH3:29])([CH3:30])[CH3:31]
Reactant: CC(C)(C)OC(=O)NCCCI
Reactant: CCOC(=O)c1cc2c(C(F)(F)F)cccc2[nH]1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1cc2c(C(F)(F)F)cccc2n1CCC(N)C(=O)OC(C)(C)C

Procedure:
The reaction was carried out in a manner similar to Reference Example 5 (25) except for using 2.60 g (10.11 mmol) of ethyl 4-trifluoromethyl-2-indolecarboxylate, 0.445 g (11.12 mmol) of 60% sodium hydride, 4.32 g (15.17 mmol) of tert-butyl N-(3-iodopropyl)-carbamate and 100 ml of dimethylformamide. Ethyl 1-(3-tert-butoxycarbonyl-aminopropyl)-4-trifluoromethyl-2-indolecarboxylate was thus obtained in an amount of 2.81 g (67.1%).
Reaction SMILES: [CH3:1][CH:2]([S:5][C:6]1[CH:25]=[CH:24][C:9]([O:10][CH2:11][CH2:12][N:13]2C(=O)C3=CC=CC=C3C2=O)=[CH:8][CH:7]=1)[CH2:3][CH3:4].O.NN.[OH-].[Na+]>C(O)C>[CH3:1][CH:2]([S:5][C:6]1[CH:25]=[CH:24][C:9]([O:10][CH2:11][CH2:12][NH2:13])=[CH:8][CH:7]=1)[CH2:3][CH3:4]
Reactant: CCC(C)Sc1ccc(OCCN2C(=O)c3ccccc3C2=O)cc1
Agent: NN
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CCC(C)Sc1ccc(OCCN)cc1

Procedure:
To a solution of the above phthalimide (6.84 g, 19.7 mmol) in 100 ml of ethanol, heated to 60°, is added hydrazine hydrate (2.0 ml, 41.0 mmol) with stirring. Additional ethanol (100 ml) is added and the mixture is stirred overnight at 60°. After cooling, 5% sodium hydroxide is added and the basic mixture is extracted with ether. The combined organic layers are washed with water and brine, dried and rotoevaporated to give 2-[4-(1-methylpropylthio)phenoxy]ethylamine.
Reaction SMILES: [C@@H:1]([O:5][C:6]1[CH:14]=[CH:13][C:12]([S:15]([CH3:18])(=[O:17])=[O:16])=[CH:11][C:7]=1[C:8]([OH:10])=O)([CH2:3][CH3:4])[CH3:2].Cl.[F:20][C:21]([F:34])([F:33])[C:22]1[S:26][C:25]([N:27]2[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]2)=[N:24][CH:23]=1>>[C@@H:1]([O:5][C:6]1[CH:14]=[CH:13][C:12]([S:15]([CH3:18])(=[O:17])=[O:16])=[CH:11][C:7]=1[C:8]([N:30]1[CH2:31][CH2:32][N:27]([C:25]2[S:26][C:22]([C:21]([F:34])([F:20])[F:33])=[CH:23][N:24]=2)[CH2:28][CH2:29]1)=[O:10])([CH2:3][CH3:4])[CH3:2]
Reactant: FC(F)(F)c1cnc(N2CCNCC2)s1
Reactant: CC[C@H](C)Oc1ccc(S(C)(=O)=O)cc1C(=O)O
Agent: Cl
Product: CC[C@H](C)Oc1ccc(S(C)(=O)=O)cc1C(=O)N1CCN(c2ncc(C(F)(F)F)s2)CC1
Yield: 13 %

Procedure:
Prepared in analogy to example 1 (b) from 2-((S)-sec-butoxy)-5-methanesulfonyl-benzoic acid (Example A21) and 1-(5-trifluoromethyl-thiazol-2-yl)-piperazine hydrochloride (Example 58(c)). The crude material was purified by reversed phase HPLC (acetonitrile/water) followed by trituration in ether to yield the title compound as an off-white crystalline solid (yield 13%). MS (m/e): 492.4 (M+H+, 100%).
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].[CH2:7]([O:19][C:20]1[CH:29]=[CH:28][C:23]([C:24](OC)=[O:25])=[CH:22][CH:21]=1)[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].C(Cl)Cl>C1COCC1>[CH2:7]([O:19][C:20]1[CH:21]=[CH:22][C:23]([CH2:24][OH:25])=[CH:28][CH:29]=1)[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: CCCCCCCCCCCCOc1ccc(C(=O)OC)cc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: ClCCl
Solvent: C1CCOC1
Product: CCCCCCCCCCCCOc1ccc(CO)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 87.7 %

Procedure:
To a 0° C. slurry of LAH (13.0 g, 343 mmol) in dry THF (400 mL) was added slowly methyl 4-dodecyloxybenzoate (100 g, 312 mmol) in dry THF (350 mL) over 1.5 hours. Upon addition, the mixture was stirred at room temperature for one hour, after which TLC (CH2Cl2) showed completion. Reaction was cooled to 0° C. and quenched by successive addition of H2O (13 mL), 15% NaOH (13 mL), and H2O (39 mL), and stirring continued until H2 evolution ceased. Reaction mixture was then filtered and the lithium salts rinsed generously with CH2Cl2. The filtrate was dried over MgSO4 and concentrated to give the title benzyl alcohol (80 g, 88%), which was taken to the next step without further purification.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:4]=[C:5]([C:9]2[C:14]3[N:15]([C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)[CH:16]=[N:17][C:13]=3[CH:12]=[C:11]([C:24]([F:27])([F:26])[F:25])[CH:10]=2)[CH:6]=[CH:7][CH:8]=1.[CH3:28][NH:29][CH3:30]>CN1C(=O)CCC1>[CH3:28][N:29]([CH2:2][C:3]1[CH:4]=[C:5]([C:9]2[C:14]3[N:15]([C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)[CH:16]=[N:17][C:13]=3[CH:12]=[C:11]([C:24]([F:27])([F:26])[F:25])[CH:10]=2)[CH:6]=[CH:7][CH:8]=1)[CH3:30]
Reactant: CNC
Reactant: FC(F)(F)c1cc(-c2cccc(CCl)c2)c2c(c1)ncn2-c1ccccc1
Solvent: CN1CCCC1=O
Product: CN(C)Cc1cccc(-c2cc(C(F)(F)F)cc3ncn(-c4ccccc4)c23)c1

Procedure:
This was prepared analogeously to the above product from 7-(3-(chloromethyl)phenyl)-1-phenyl-5-trifluoromethylbenzimidazole (0.97 g, 2.5 mmol) and dimethyl amine (2 ml) in NMP (5 ml) to yield 0.54 g (55%), m/z, 396.2 (M+H)+.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[C:8]([N+:10]([O-:12])=[O:11])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:20][CH2:21][CH2:22][CH2:23][NH:24][C:25](=[O:31])[O:26][C:27]([CH3:30])([CH3:29])[CH3:28]>CN(C=O)C>[C:4]([C:3]1[CH:6]=[CH:7][C:8]([N+:10]([O-:12])=[O:11])=[CH:9][C:2]=1[O:1][CH2:20][CH2:21][CH2:22][CH2:23][NH:24][C:25](=[O:31])[O:26][C:27]([CH3:30])([CH3:29])[CH3:28])#[N:5]
Reactant: N#Cc1ccc([N+](=O)[O-])cc1O
Reactant: CC(C)(C)OC(=O)NCCCCBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NCCCCOc1cc([N+](=O)[O-])ccc1C#N
Temperature: 25 °C
Reaction time: 18 h
Yield: 51.4 %

Procedure:
To a stirred mixture of 2-hydroxy-4-nitrobenzonitrile (2 g, 12.19 mmol), cesium carbonate (6 g, 18.29 mmol) and DMF (20 mL) was added tert-butyl 4-bromobutylcarbamate (4.59 g, 18.29 mmol). The reaction mixture was stirred at room temperature for 18 h. The solvent was removed under reduced pressure and the residue was dissolved in ethyl acetate (100 mL), and washed with brine (2×50 mL). The organic layer was dried with anhydrous sodium sulphate and concentrated in vacuo to give tert-butyl 4-(2-cyano-5-nitrophenoxy)butylcarbamate (2.1 g, 52%) as a light yellow solid. LC-MS (M+H)+=335.0. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.07 (1H, d, J=8.4 Hz), 7.96 (1H, s), 7.90 (2H, d, J=8.8 Hz), 6.84 (1H, br s), 4.30 (2H, t, J=6.4 Hz), 3.53 (2H, t, J=6.4 Hz), 2.98-2.89 (2H, m), 1.81-1.76 (2H, m), 1.48 (9H, s).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]2[N:8]=[CH:9][C:10]([C:11](Cl)=[O:12])=[C:4]2[N:3]=1.CCN(C(C)C)C(C)C.Cl.[Cl:24][CH2:25][CH2:26][NH2:27]>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][N:5]2[N:8]=[CH:9][C:10]([C:11]([NH:27][CH2:26][CH2:25][Cl:24])=[O:12])=[C:4]2[N:3]=1
Reactant: O=C(Cl)c1cnn2ccc(Cl)nc12
Reactant: NCCCl
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NCCCl)c1cnn2ccc(Cl)nc12
Temperature: 0 °C
Reaction time: 1 h
Yield: 85.4 %

Procedure:
To a suspension of 5-chloropyrazolo[1,5-a]pyrimidine-3-carbonyl chloride (284 mg, 1.31 mmol) in DCM (10 mL) was added DIEA (1.14 mL, 6.57 mmol). The solution was cooled to 0° C., then treated with 2-chloroethylamine hydrochloride (183 mg, 1.58 mmol) and stirred for 1 hour. The mixture was partitioned between water (30 mL) and DCM (30 mL) and the layers were separated. The aqueous layer was extracted with DCM (2×20 mL) and the combined organic phases were washed with brine (20 mL), dried over Na2SO4, filtered and concentrated to afford 5-chloro-N-(2-chloroethyl)pyrazolo[1,5-a]pyrimidine-3-carboxamide (290 mg, 85% yield) as a beige solid. MS (apci) m/z=258.9 (M+H).
Reaction SMILES: [CH3:1][Si:2]([C:5]1[C:6]([Si](C)(C)C)=[C:7]([Si:11]([CH3:14])([CH3:13])[CH3:12])[CH:8]=[CH:9][CH:10]=1)([CH3:4])[CH3:3].[N+:19]([O-])([OH:21])=[O:20].[OH-].[Na+]>C(OC(=O)C)(=O)C>[N+:19]([C:9]1[CH:10]=[C:5]([Si:2]([CH3:4])([CH3:3])[CH3:1])[CH:6]=[C:7]([Si:11]([CH3:14])([CH3:13])[CH3:12])[CH:8]=1)([O-:21])=[O:20]
Reactant: O=[N+]([O-])O
Reactant: C[Si](C)(C)c1cccc([Si](C)(C)C)c1[Si](C)(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)OC(C)=O
Product: C[Si](C)(C)c1cc([N+](=O)[O-])cc([Si](C)(C)C)c1
Reaction time: 2 h
Yield: 59 %

Procedure:
To a solution of 1.18 g (4.00 mmol) of sym-tris(trimethylsilyl)benzene in 1.7 ml of acetic anhydride was added a solution of 0.4 ml (9.1 mmol) of 94% nitric acid in 1.7 ml of acetic anhydride at -10° C. The mixture was stirred at 10° to -5° C. for 2 hours and then at room temperature for 22 hours. The reaction mixture was poured into sodium hydroxide solution and the aqueous solution was extracted with methylene chloride. The extract was evaporated. The residue was purified by column chromatography on silica gel [eluent: petroleum ether] to give 636 mg of pale yellow crystals, m.p. 86°-87° C. (yield 59%). 1H-NMR spectrum δ(CDCl3)ppm: 0.33 (18H,s), 7.90 (1H,t,J=1.1 Hz), 8.29 (2H,d,J=1.1 Hz).
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:18][CH:17]2[CH:13]([CH2:14][CH2:15][C:16]2=O)[CH:12]1[C:20]([O:22][CH2:23][CH3:24])=[O:21])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N+](C1C=CC=CC=1[Se]C#N)([O-])=[O:26].C(P(CCCC)CCCC)CCC.OO.Cl>O1CCCC1.N1C=CC=CC=1>[CH2:1]([O:8][C:9]([N:11]1[CH2:18][CH:17]2[CH:13]([CH:14]([OH:26])[CH:15]=[CH:16]2)[CH:12]1[C:20]([O:22][CH2:23][CH3:24])=[O:21])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: N#C[Se]c1ccccc1[N+](=O)[O-]
Reactant: CCOC(=O)C1C2CCC(=O)C2CN1C(=O)OCc1ccccc1
Agent: CCCCP(CCCC)CCCC
Agent: Cl
Agent: OO
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: CCOC(=O)C1C2C(O)C=CC2CN1C(=O)OCc1ccccc1
Temperature: -20 °C
Reaction time: 1 h
Yield: 72.2 %

Procedure:
A solution of the compound prepared as described in Example 3 (6.89 g) and 2-nitrophenyl selenocyanate (4.72 g) in tetrahydrofuran (100 ml) was cooled to about -20° C. under a nitrogen atmosphere. The cooled solution was treated with tributylphosphine (5.2 ml) in one portion. After one hour, the reaction solution was treated with pyridine (100 ml) and the resulting mixture allowed to warm to room temperature. The reaction was then treated with 30% hydrogen peroxide (35 ml). After an additional two hours, the reaction mixture was added to 1N hydrochloric acid (200 ml), and the title compound was extracted with diethyl ember. The diethyl ether extracts were dried over magnesium sulfate and concentrated in vacuo. The residue was purified by preparative HPLC, eluting with a linear gradient of hexane to hexane/ethyl acetate (1:1), to give 4.97 g of compound 7.
Reaction SMILES: Cl[CH2:2][C:3]1[N:4]=[C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([F:17])([F:16])[F:15])[CH:9]=2)[S:6][CH:7]=1.[I-:18].[Na+].O>CC(C)=O>[I:18][CH2:2][C:3]1[N:4]=[C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([F:17])([F:16])[F:15])[CH:9]=2)[S:6][CH:7]=1
Reactant: [I-]
Reactant: FC(F)(F)c1cccc(-c2nc(CCl)cs2)c1
Agent: [Na+]
Solvent: O
Solvent: CC(C)=O
Product: FC(F)(F)c1cccc(-c2nc(CI)cs2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 27.8 %

Procedure:
To a solution (10 mL) of the compound (1.0 g, 3.6 mmol) obtained in Example 21a in acetone was added sodium iodide (1.6 g, 11 mmol), and the mixture was stirred at room temperature overnight. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The obtained organic layer was washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The resulting crude title compound was purified by column chromatography (hexane-hexane/ethyl acetate=70/30) to give the title compound (370 mg, 28%) as a colorless solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:13]=[CH:12][CH:11]=[CH:10][C:4]=1[O:5][CH2:6][C:7]([OH:9])=O.[N+]([O-])(O)=O.[O:18]([CH2:22][CH2:23][NH2:24])[N+:19]([O-:21])=[O:20].C(OC(C)C)(C)C>>[O:18]([CH2:22][CH2:23][NH:24][C:7](=[O:9])[CH2:6][O:5][C:4]1[CH:10]=[CH:11][CH:12]=[CH:13][C:3]=1[O:2][CH3:1])[N+:19]([O-:21])=[O:20]
Reactant: NCCO[N+](=O)[O-]
Reactant: COc1ccccc1OCC(=O)O
Solvent: O=[N+]([O-])O
Solvent: CC(C)OC(C)C
Product: COc1ccccc1OCC(=O)NCCO[N+](=O)[O-]
Yield: 28.2 %

Procedure:
Following a similar treatment to that in Example 2 and using 0.77 g of 2-methoxyphenoxyacetic acid and 0.60 g of nitroxyethylamine nitrate, 0.27 g of the title compound was obtained as colorless needles (solvent for recrystallization; diisopropyl ether).
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[N:12]([C:13]3[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=3)[C:11](=[O:20])[CH:10]2[CH2:21][CH2:22][CH:23]([C:25]2[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=2)[OH:24])=[CH:5][CH:4]=1.C(N(C(C)C)CC)(C)C.[S:41]([CH2:45][C:46](O)=[O:47])([OH:44])(=[O:43])=[O:42].C(N=C=NC(C)C)(C)C.OC1C2N=NNC=2C=CC=1>CN(C)C=O>[F:19][C:16]1[CH:15]=[CH:14][C:13]([N:12]2[C:11](=[O:20])[CH:10]([CH2:21][CH2:22][CH:23]([C:25]3[CH:26]=[CH:27][C:28]([F:31])=[CH:29][CH:30]=3)[OH:24])[CH:9]2[C:6]2[CH:7]=[CH:8][C:3]([CH2:2][NH:1][C:46]([CH2:45][S:41]([OH:44])(=[O:43])=[O:42])=[O:47])=[CH:4][CH:5]=2)=[CH:18][CH:17]=1
Reactant: O=C(O)CS(=O)(=O)O
Reactant: NCc1ccc(C2C(CCC(O)c3ccc(F)cc3)C(=O)N2c2ccc(F)cc2)cc1
Agent: CC(C)N=C=NC(C)C
Agent: Oc1cccc2[nH]nnc12
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(CS(=O)(=O)O)NCc1ccc(C2C(CCC(O)c3ccc(F)cc3)C(=O)N2c2ccc(F)cc2)cc1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
A solution of 120 mg of 4-(4-aminomethylphenyl)-1-(4-fluorophenyl)-3-[3-(4-fluorophenyl)-3-hydroxypropyl]azetidin-2-one (17), and 48 μl of diisopropylethylamine in 1 ml of dimethylformamide was added to a solution of 40 mg of sulfoacetic acid, 110 μl of diisopropylcarbodiimide, and 76 mg of hydroxybenzotriazole in 2 ml of dimethylformamide, and the mixture was stirred at room temperature for 12 h. The reaction solution was concentrated and separated by HPLC (Knauer Eurospher-100-10-C18, water (0.1% trifluoroacetic acid)/acetonitrile (0.1% trifluoroacetic acid)=80/20->10/90). This gave the product of molecular weight 544.58 (C27H26F2N2O6S1); MS (ESI) 527.10 (M+H+—H2O)
Reaction SMILES: [CH3:1][N:2]1[C:6]2[S:7][CH:8]=[CH:9][C:5]=2[C:4]([CH3:10])=[N:3]1.C([Li])CCC.[CH2:16]([Sn:20]([CH2:26][CH2:27][CH2:28][CH3:29])([CH2:22][CH2:23][CH2:24][CH3:25])Cl)[CH2:17][CH2:18][CH3:19]>C1COCC1>[CH3:1][N:2]1[C:6]2[S:7][C:8]([Sn:20]([CH2:22][CH2:23][CH2:24][CH3:25])([CH2:26][CH2:27][CH2:28][CH3:29])[CH2:16][CH2:17][CH2:18][CH3:19])=[CH:9][C:5]=2[C:4]([CH3:10])=[N:3]1
Reactant: CCCC[Sn](Cl)(CCCC)CCCC
Reactant: Cc1nn(C)c2sccc12
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCCC[Sn](CCCC)(CCCC)c1cc2c(C)nn(C)c2s1
Temperature: -78 °C
Reaction time: 1 h
Yield: 55.2 %

Procedure:
To a cold (−78° C.) mixture of 1,3-dimethyl-1H-thieno[2,3-c]pyrazole (1.0 g, 6.57 mmol) and THF (50 mL) was added n-butyllithium (4.52 mL, 7.23 mmol) dropwise and allowed under a nitrogen atmosphere. The reaction mixture was stirred at −78° C. for 1 hour. To this solution was added tributylchlorostannane (2.13 mL, 7.88 mmol) and the mixture was stirred at −78° C. for 1 hour and then warmed to room temperature over a period of 2 hours. The reaction was quenched with brine (100 mL) and extracted with ethyl acetate (2×100 mL). The organic layers were combined, dried over sodium sulfate, concentrated, and purified via silica gel flash chromatography, eluting with 20% EtOAc and hexane to give the title compound as a clear oil (1.60 g, 55%). 1H NMR (400 MHz, DMSO-d6) δ ppm 0.86 (t, J=7.33 Hz, 9H), 1.02-1.06 (m, 6H), 1.30 (dq, J=7.29, 14.75 Hz, 6H), 1.44-1.64 (m, 6H), 2.31 (s, 3H), 3.80 (s, 3H), 6.94 (s, 1H).
Reaction SMILES: [CH2:1]([OH:7])[CH2:2]/[CH:3]=[CH:4]\[CH2:5][CH3:6].[H-].[Na+].Cl[C:11]1[C:12]([C:16]2[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=2)=[N:13][S:14][N:15]=1.O>O1CCCC1>[CH2:1]([O:7][C:11]1[C:12]([C:16]2[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=2)=[N:13][S:14][N:15]=1)[CH2:2]/[CH:3]=[CH:4]\[CH2:5][CH3:6]
Reactant: Clc1nsnc1-c1cccnc1
Reactant: CC/C=C\CCO
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CC/C=C\CCOc1nsnc1-c1cccnc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of cis-3-hexen-1-ol (900 mg, 9 mmol) and sodium hydride (310 mg, 9 mmol) in dry tetrahydrofuran was added a solution of 3-(4-chloro-1,2,5-thiadiazol-3-yl) pyridine (590 mg, 3 mmol) in dry tetrahydrofuran. The reaction mixture was stirred at room temperature for 1 h. Water was added and the mixture was extracted with ether. The ether phase was dried and evaporated to give the title compound.
Reaction SMILES: [Br:1][C:2]1[C:7]([NH:8][C:9](=[O:14])[C:10]([F:13])([F:12])[F:11])=[CH:6][CH:5]=[C:4]([F:15])[N:3]=1.[CH2:16](Br)[CH:17]=[CH2:18].C(=O)([O-])[O-].[Na+].[Na+]>CC#N>[CH2:18]([N:8]([C:7]1[C:2]([Br:1])=[N:3][C:4]([F:15])=[CH:5][CH:6]=1)[C:9](=[O:14])[C:10]([F:12])([F:13])[F:11])[CH:17]=[CH2:16]
Reactant: O=C(Nc1ccc(F)nc1Br)C(F)(F)F
Reactant: C=CCBr
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Product: C=CCN(C(=O)C(F)(F)F)c1ccc(F)nc1Br
Yield: 86.7 %

Procedure:
A solution of N-(2-bromo-6-fluoropyridin-3-yl)-2,2,2-trifluoro-acetamide (9.16 g, 31.9 mmol), allyl bromide (6.18 g, 47.9 mmol) and sodium carbonate (8.82 g, 63.8 mmol) in CH3CN (80 mL) is stirred at 80° C. for 2 h. The reaction mixture is concentrated in vacuo and the residue is purified by silica gel chromatography eluting with 0-60% DCM in heptane to afford N-allyl-N-(2-bromo-6-fluoro-pyridin-3-yl)-2,2,2-trifluoro-acetamide (9.05 g) as an oil. 1H NMR (300 MHz, CDCl3) δ 3.68 (q, H), 5.01 (q, H), 5.17 (d, H), 5.29 (d, H), 6.85(m, H), 7.00 (dd, H), 7.64(t, H).
Reaction SMILES: [CH3:1][C:2]1[NH:6][N:5]=[C:4]([NH2:7])[CH:3]=1.[I-].[K+].[F:10][C:11]1[CH:48]=[CH:47][C:14]([C:15]([C:17]2[N:26]=[C:25](C3C(C(C)C)=C(S([O-])(=O)=O)C(C(C)C)=CC=3C(C)C)[C:24]3[C:19](=[CH:20][C:21]([CH3:46])=[CH:22][CH:23]=3)[N:18]=2)=[O:16])=[CH:13][CH:12]=1.O>CC(N(C)C)=O>[F:10][C:11]1[CH:12]=[CH:13][C:14]([C:15]([C:17]2[N:26]=[C:25]([NH:7][C:4]3[CH:3]=[C:2]([CH3:1])[NH:6][N:5]=3)[C:24]3[C:19](=[CH:20][C:21]([CH3:46])=[CH:22][CH:23]=3)[N:18]=2)=[O:16])=[CH:47][CH:48]=1
Reactant: Cc1ccc2c(-c3c(C(C)C)cc(C(C)C)c(S(=O)(=O)[O-])c3C(C)C)nc(C(=O)c3ccc(F)cc3)nc2c1
Reactant: Cc1cc(N)n[nH]1
Agent: [I-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Solvent: O
Product: Cc1ccc2c(Nc3cc(C)[nH]n3)nc(C(=O)c3ccc(F)cc3)nc2c1
Yield: 14.4 %

Procedure:
A solution of 5-methyl-1H-pyrazol-3-amine (225 mg, 2.31 mmol), potassium iodide (188 mg, 0.088 mmol), and 2-(4-fluorobenzoyl)-7-methylquinazolin-4-yl-2,4,6-triisopropylbenzenesulfonate (380 mg, 0.69 mmol) in DMA (2 mL) was stirred at 50° C. for 6 h, then water was added and the solution was filtered. The solid was then dried and triturated with acetonitrile to give (4-fluorophenyl)(7-methyl-4-(5-methyl-1H-pyrazol-3-ylamino)quinazolin-2-yl)methanone (36 mg, 14%). 1H NMR (300 MHz, DMSO-d6) δ 2.18 (s, 3H), 2.50 (s, 3H), 6.53 (s, 1H), 7.38 (t, 2H), 7.51 (d, 2H), 7.66 (s, 1H), 8.08 (m, 2H), 8.62 (d, 1H), 10.57 (s, 1H), 12.18 (s, 1H); LC-MS (ESI) m/z 362 (M+H)+.
Reaction SMILES: [CH2:1]([C:3]1[C:8](=[O:9])[NH:7][C:6]([CH3:10])=[C:5]([C:11]2[CH:12]=[N:13][CH:14]=[C:15]([C:17]([OH:19])=O)[CH:16]=2)[CH:4]=1)[CH3:2].[CH3:20][NH:21][CH2:22][C:23]([NH2:25])=[O:24]>>[C:23]([CH2:22][N:21]([CH3:20])[C:17]([C:15]1[CH:16]=[C:11]([C:5]2[CH:4]=[C:3]([CH2:1][CH3:2])[C:8](=[O:9])[NH:7][C:6]=2[CH3:10])[CH:12]=[N:13][CH:14]=1)=[O:19])(=[O:24])[NH2:25]
Reactant: CNCC(N)=O
Reactant: CCc1cc(-c2cncc(C(=O)O)c2)c(C)[nH]c1=O
Product: CCc1cc(-c2cncc(C(=O)N(C)CC(N)=O)c2)c(C)[nH]c1=O

Procedure:
Method 1, Example 205 is substantially repeated except for utilizing 5′-ethyl-2′-methyl-6′-oxo-1′,6′-dihydro-[3,3′]bipyridinyl-5-carboxylic acid and 2-methylamino-acetamide to afford the title compound. MS: m/e=329 (M+H).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([C:14]([OH:16])=O)[C:10]([CH3:13])([CH3:12])[CH3:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH2:17][C@H:18]([CH2:26][OH:27])[CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.OC1C2N=NNC=2C=CC=1.Cl.C(N=C=NCCCN(C)C)C>CN(C)C=O>[C:6]([NH:8][C@H:9]([C:14]([NH:17][C@H:18]([CH2:26][OH:27])[CH2:19][C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1)=[O:16])[C:10]([CH3:11])([CH3:12])[CH3:13])([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7]
Reactant: CC(C)(C)OC(=O)N[C@H](C(=O)O)C(C)(C)C
Reactant: N[C@H](CO)Cc1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: Oc1cccc2[nH]nnc12
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N[C@H](C(=O)N[C@H](CO)Cc1ccccc1)C(C)(C)C
Reaction time: 24 h

Procedure:
25 g of tert-butyloxycarbonyl-L-tert-leucine are dissolved in 250 ml of dry dimethylformamide, 16.36 g of phenylalaninol, 14.62 g of hydroxybenzotriazole and 24.9 g of N-ethyl-N'-(3-dimethylaminopropyl)carbodiimide hydrochloride are added. The mixture is stirred for one day. The precipitate is filtered off, washed carefully with ethyl acetate and dried in vacuo (m.p. 198°-201°).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:11])[CH3:10])=[C:4]([F:12])[CH:3]=1.[S:13](=O)(=[O:16])([OH:15])[OH:14]>>[C:9]([NH:8][C:5]1[C:4]([F:12])=[CH:3][C:2]([Br:1])=[C:7]([S:13]([OH:16])(=[O:15])=[O:14])[CH:6]=1)(=[O:11])[CH3:10]
Reactant: CC(=O)Nc1ccc(Br)cc1F
Reactant: O=S(=O)(O)O
Product: CC(=O)Nc1cc(S(=O)(=O)O)c(Br)cc1F
Temperature: 20 °C
Reaction time: 2 h

Procedure:
N-(4-Bromo-2-fluorophenyl)acetamide (173.2 g) was suspended in conc. sulfuric acid (80 ml), and 60% fuming sulfuric acid (340 ml) was dropwise added thereto at 10° to 20° C., followed by stirring at 20° C., for 2 hours. The reaction mixture was dropwise added to ice water (500 g) at 10° to 20° C., and the precipitated crystals were collected by filtration, washed with cold water (400 ml) and dried under reduced pressure to give 175.8 g of 5-(N-acetylamino)-2-bromo-4-fluorobenzenesulfonic acid. M.P., more than 300° C.
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[CH:11][C:7]([C:8](Cl)=[O:9])=[CH:6][CH:5]=1)([O-:3])=[O:2].[NH2:13][C:14](=[N:20][OH:21])[C:15]([O:17][CH2:18][CH3:19])=[O:16]>O1CCCC1>[NH2:13][C:14](=[N:20][O:21][C:8](=[O:9])[C:7]1[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:12][CH:11]=1)[C:15]([O:17][CH2:18][CH3:19])=[O:16]
Reactant: O=C(Cl)c1ccc([N+](=O)[O-])cc1
Reactant: CCOC(=O)C(N)=NO
Solvent: C1CCOC1
Product: CCOC(=O)C(N)=NOC(=O)c1ccc([N+](=O)[O-])cc1
Reaction time: 2 h
Yield: 80.7 %

Procedure:
To a solution of 4-nitrobenzoyl chloride (10 g) in tetrahydrofuran (150 ml) was added a suspension of ethyl 2-amino-2-hydroxyiminoacetate (7.1 g) in tetrahydrofuran (30 ml). After stirring for 2 hours, the precipitates were collected by filtration and washed with diethyl ether to afford ethyl 2-amino-2-(4-nitrobenzoyloxyimino)acetate (12.19 g).