Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[CH:8][C:9]=1[NH2:10])=[O:4].[CH2:17]1[O:27][C:20]2([CH2:25][CH2:24][C:23](=O)[CH2:22][CH2:21]2)[O:19][CH2:18]1.C([Sn](Cl)(Cl)CCCC)CCC.C1([SiH3])C=CC=CC=1>C1COCC1>[CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[CH:8][C:9]=1[NH:10][CH:23]1[CH2:24][CH2:25][C:20]2([O:27][CH2:17][CH2:18][O:19]2)[CH2:21][CH2:22]1)=[O:4]
Reactant: COC(=O)c1sc(-c2ccccc2)cc1N
Reactant: O=C1CCC2(CC1)OCCO2
Agent: CCCC[Sn](Cl)(Cl)CCCC
Agent: [SiH3]c1ccccc1
Solvent: C1CCOC1
Product: COC(=O)c1sc(-c2ccccc2)cc1NC1CCC2(CC1)OCCO2
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 77.2 %

Procedure:
To a suspension of 3-amino-5-phenyl-thiophene-2-carboxylic acid methyl ester (987 mg, 4.23 mmol) in dry THF (1.0 ml), at room temperature, was added 1,4-cyclohexanedione monoethylene ketal (661 mg, 4.23 mmol), followed by dibutyltin dichloride (129 mg, 0.42 mmol). After 5 min, phenyl silane (575 μL, 4.65 mmol) was added and the reaction mixture was stirred at room temperature for 4 days when a clear solution resulted. It was then concentrated and the residue purified by flash chromatography (0% to 30% EtOAc/Hexane) to obtain 1.22 g (77%) of 3-(1,4-Dioxa-spiro[4.5]dec-8-ylamino)-5-phenyl-thiophene-2-carboxylic acid methyl ester.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[C:9]1[CH:14]=[C:13]([CH3:15])[C:12]([N+:16]([O-:18])=[O:17])=[CH:11][N:10]=1.CC(O[CH:24](N(C)C)[N:25]([CH3:27])[CH3:26])(C)C>CN(C=O)C>[CH3:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([CH3:1])[C:3]=1[C:9]1[CH:14]=[C:13](/[CH:15]=[CH:24]/[N:25]([CH3:27])[CH3:26])[C:12]([N+:16]([O-:18])=[O:17])=[CH:11][N:10]=1
Reactant: Cc1cc(-c2c(C)cccc2C)ncc1[N+](=O)[O-]
Reactant: CN(C)C(OC(C)(C)C)N(C)C
Solvent: CN(C)C=O
Product: Cc1cccc(C)c1-c1cc(/C=C/N(C)C)c([N+](=O)[O-])cn1
Temperature: 90 °C

Procedure:
To a solution of the 2-(2,6-dimethyl-phenyl)4-methyl-5-nitro-pyridine (8 g, 33.0 mmol) in anhydrous DMF (30 mL), Bredereck's reagent (20 mL, 99.0 mmol) is added, and the mixture is heated for 1 h at 90° C. The mixture is concentrated under reduced pressure, and the residue is dissolved a mixture of EtOAc-hexane-DCM (1:1:1, 200 mL) and filtered over small pad of silica gel. Removal of the solvent under reduced pressure gives the crude {(E)-2-[2-(2,6-dimethyl-phenyl)-5-nitro-pyridin-4-yl]-vinyl}-dimethyl-amine which is used in the following step.
Reaction SMILES: Cl[C:2]1[C:7]([NH:8][C:9](=[O:22])[C:10]2[CH:15]=[CH:14][C:13]([O:16][CH2:17][CH:18]3[CH2:20][CH2:19]3)=[C:12]([F:21])[CH:11]=2)=[CH:6][N:5]=[C:4]([O:23][CH2:24][C@@H:25]([NH:27][C:28](=[O:34])[O:29][C:30]([CH3:33])([CH3:32])[CH3:31])[CH3:26])[CH:3]=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C.[Cu]I>[CH:18]1([CH2:17][O:16][C:13]2[CH:14]=[CH:15][C:10]([C:9]3[O:22][C:2]4[CH:3]=[C:4]([O:23][CH2:24][C@@H:25]([NH:27][C:28](=[O:34])[O:29][C:30]([CH3:33])([CH3:32])[CH3:31])[CH3:26])[N:5]=[CH:6][C:7]=4[N:8]=3)=[CH:11][C:12]=2[F:21])[CH2:20][CH2:19]1
Reactant: C[C@@H](COc1cc(Cl)c(NC(=O)c2ccc(OCC3CC3)c(F)c2)cn1)NC(=O)OC(C)(C)C
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: C[C@@H](COc1cc2oc(-c3ccc(OCC4CC4)c(F)c3)nc2cn1)NC(=O)OC(C)(C)C
Temperature: 160 °C
Reaction time: 5 h
Yield: 42.9 %

Procedure:
A suspension of tert-butyl ((2S)-1-((4-chloro-5-((4-(cyclopropylmethoxy)-3-fluorobenzoyl)amino)pyridin-2-yl)oxy)propan-2-yl)carbamate (990 mg), potassium carbonate (554 mg) and copper(I) iodide (38.2 mg) in DMF (10 mL) was stirred at 160° C. for 5 hr under microwave irradiation. To the reaction mixture was added water, and the obtained mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and subjected to silica gel column chromatography (NH, ethyl acetate). The solvent was evaporated, and the obtained solid was washed with ethyl acetate/hexane to give the title compound (393 mg).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([C:9]2[NH:10][C:11]3[C:16]([CH:17]=2)=[CH:15][CH:14]=[CH:13][CH:12]=3)[CH:3]=1.[F-].[Cs+].[N+](C1C=C(S(O[CH2:33][CH:34]2[CH2:36][O:35]2)(=O)=O)C=CC=1)([O-])=O>CN(C=O)C.C(OCC)(=O)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:33][CH:34]2[CH2:36][O:35]2)=[C:4]([C:9]2[NH:10][C:11]3[C:16]([CH:17]=2)=[CH:15][CH:14]=[CH:13][CH:12]=3)[CH:3]=1
Reactant: O=[N+]([O-])c1cccc(S(=O)(=O)OCC2CO2)c1
Reactant: Oc1ccc(Br)cc1-c1cc2ccccc2[nH]1
Agent: [Cs+]
Agent: [F-]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Brc1ccc(OCC2CO2)c(-c2cc3ccccc3[nH]2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 83.5 %

Procedure:
To a solution of compound 4-bromo-2-(1H-indol-2-yl)phenol (1 g, 3.48 mmol) in DMF (35 mL) was added CsF (1.59 g, 10.45 mmol) and oxiran-2-ylmethyl 3-nitrobenzenesulfonate (1.81 g, 6.97 mmol). The resulting mixture was stirred at room temperature overnight and then diluted with ethyl acetate and washed with water and brine. The crude product was purified using chromatography (petroleum ether:EA=14:1) to provide compound 2-(5-bromo-2-(oxiran-2-ylmethoxy)phenyl)-1H-indole (1 g, yield: 84.0%). 1H-NMR (DMSO-d6, 400 MHz) δ 11.33 (s, 1H), 7.96 (d, J=2.4 Hz, 1H), 7.51 (d, J=7.6 Hz, 1H), 7.38˜7.44 (m, 2H), 7.07˜7.12 (m, 3H), 6.97 (t, J=7.2 Hz, 1H), 4.49˜4.53 (m, 1H), 3.97˜4.01 (m, 1H), 3.46˜3.49 (m, 1H), 2.88 (t, J=4.4 Hz, 1H), 2.74˜2.76 (m, 1H). MS (M+H)+: 344/346.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]#[C:9][Si](C)(C)C)[CH:5]=[CH:4][C:3]=1[NH:14][C:15]1[C:27]([F:28])=[C:26]([F:29])[CH:25]=[CH:24][C:16]=1[C:17]([NH:19][O:20][CH2:21][CH2:22][OH:23])=[O:18].C(O)(=O)C.[F-].[Cs+]>CO>[Cl:1][C:2]1[CH:7]=[C:6]([C:8]#[CH:9])[CH:5]=[CH:4][C:3]=1[NH:14][C:15]1[C:27]([F:28])=[C:26]([F:29])[CH:25]=[CH:24][C:16]=1[C:17]([NH:19][O:20][CH2:21][CH2:22][OH:23])=[O:18]
Reactant: C[Si](C)(C)C#Cc1ccc(Nc2c(C(=O)NOCCO)ccc(F)c2F)c(Cl)c1
Agent: [Cs+]
Agent: [F-]
Solvent: CO
Solvent: CC(=O)O
Product: C#Cc1ccc(Nc2c(C(=O)NOCCO)ccc(F)c2F)c(Cl)c1
Reaction time: 26 h

Procedure:
To a solution of the product of Example 8, Step A, 2-(2-Chloro-4-trimethylsilanylethynyl-phenylamino)-3,4-difluoro-N-(2-hydroxy-ethoxy)-benzamide (0.704 g, 1.60 mmol) in methanol (21 mL) was added acetic acid (0.1 mL) and cesium fluoride (0.600 g, 3.95 mmol). The resultant solution was stirred at ambient temperature. After 26 hours, the reaction mixture was partitioned between ethyl acetate (100 mL) and water (25 mL) and the organic layer was further washed with water (25 mL) and saturated brine (25 mL). The combined aqueous was extracted with ethyl acetate (50 mL). The combined organics were dried over magnesium sulfate and concentrated to a dark brown oil. Ether (15 mL) was added and crystallization ensued. The cream-colored solid was collected and dried under vacuum at 70° C. to afford 2-(2-chloro-4-ethynyl-phenylamino)-3,4-difluoro-N-(2-hydroxy-ethoxy)-benzamide (0.290 g): m.p. 155–157° C.; 1H NMR (400 MHz, DMSO-d6) δ 11.94 (br s, 1 H), 8.95 (br s, 1 H), 7.55 (d, J=2.0 Hz, 1 H), 7,48 (m, 1H), 7.34–7.27 (m, 2 H), 6.74 (dd, J=8.4, 6.5 Hz, 1 H), 4.71 (br s, 1 H), 4.13 (s, 1 H), 3.88 (t, J=4.6 Hz, 2 H), 3.58 (t, J=4.7 Hz, 2 H); MS (APCI+)=367.0; MS (APCI−)=365.0; Anal. Calcd/found for C17H13ClF2N2O3: C, 55.67/55.54; H, 3.57/3.23; N, 7.64/7.31. Concentration of the mother liquor afforded an additional crop of product (0.209 g, 85% total yield).
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[K+].C([O:18][C:19](=[O:52])[N:20]([CH2:43][CH:44](O)[C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][N:46]=1)[CH2:21][C:22]1[CH:27]=[C:26]([C:28]([F:31])([F:30])[F:29])[CH:25]=[CH:24][C:23]=1[C:32]1[CH:37]=[C:36]([CH:38]([CH3:40])[CH3:39])[CH:35]=[CH:34][C:33]=1[O:41][CH3:42])C1C=CC=CC=1>C1(C)C=CC=CC=1.C1COCC1>[CH:38]([C:36]1[CH:35]=[CH:34][C:33]([O:41][CH3:42])=[C:32]([C:23]2[CH:24]=[CH:25][C:26]([C:28]([F:30])([F:29])[F:31])=[CH:27][C:22]=2[CH2:21][N:20]2[CH2:43][CH:44]([C:45]3[CH:50]=[CH:49][CH:48]=[CH:47][N:46]=3)[O:18][C:19]2=[O:52])[CH:37]=1)([CH3:40])[CH3:39]
Reactant: COc1ccc(C(C)C)cc1-c1ccc(C(F)(F)F)cc1CN(CC(O)c1ccccn1)C(=O)OCc1ccccc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: COc1ccc(C(C)C)cc1-c1ccc(C(F)(F)F)cc1CN1CC(c2ccccn2)OC1=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of potassium bis(trimethylsilyl)amide (464 μL of a 0.5M solution in toluene, 0.232 mmol) was added dropwise to a stirred solution of benzyl(2-hydroxy-2-pyridin-2-ylethyl){[5′-isopropyl-2′-methoxy-4-(trifluoromethyl)biphenyl-2-yl]methyl}carbamate (134.3 mg, 0.232 mmol) in dry THF (10 mL) at room temperature under N2. After stirring at room temperature for 1 h, the reaction was quenched with saturated NH4Cl (10 mL) and extracted with EtOAc (3×20 mL). The combined extracts were dried (Na2SO4) and concentrated in vacuo to give the crude product. This was purified by flash chromatography (Si, 25×160 mm, 0-70% EtOAc in hexanes gradient) to afford 3-{[5′-isopropyl-2′-methoxy-4-(trifluoromethyl)biphenyl-2-yl]methyl}-5-pyridin-2-yl-1,3-oxazolidin-2-one. Rf=0.58 (50% EtOAc/hexanes). LCMS calc.=471.19; found=471.2 (M+1)+.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]=[CH:9][C:10]2[CH:19]=[CH:18][C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[N:11]=2)=[CH:4][C:3]=1[O:20][CH3:21].[C:22]([O:27][CH2:28][CH:29]1[O:31][CH2:30]1)(=[O:26])[C:23]([CH3:25])=[CH2:24].O>CN(C)C(=O)C.[Cl-].C([N+](CCCC)(CCCC)CCCC)CCC>[CH3:21][O:20][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][C:10]2[CH:19]=[CH:18][C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[N:11]=2)[CH:6]=[CH:7][C:2]=1[O:1][CH2:30][CH:29]([OH:31])[CH2:28][O:27][C:22](=[O:26])[C:23]([CH3:25])=[CH2:24]
Reactant: C=C(C)C(=O)OCC1CO1
Reactant: COc1cc(C=Cc2ccc3ccccc3n2)ccc1O
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Cl-]
Solvent: CC(=O)N(C)C
Solvent: O
Product: C=C(C)C(=O)OCC(O)COc1ccc(C=Cc2ccc3ccccc3n2)cc1OC
Yield: 50 %

Procedure:
In 5 cm3 of N,N-dimethylacetamide, 2.77 g of the produced quinoline derivative was dissolved and 1.42 g of glycidyl methacrylate and 0.10 g of tetrabutylammonium chloride were added thereto. The resultant mixture was reacted by maintaining it at 90° to 100° C. for 5 hours. The reaction product was mixed with water. The oily substance separated consequently was extracted via ethyl acetate, washed thoroughly with water, and dried. The dry product was distilled to expel the solvent and then separated and purified by silica gel chromatography, to afford 2-{2-[3-methoxy-4-(2-hydroxy-3-methacryloyloxypropyloxy)-phenyl]-ethenyl}-quinoline in a yield of 50%. When this product was recrystallized via ethyl acetatehexane, there was obtained a pure product having a melting point of 119° C. It was identified by elementary analysis and infrared absorption spectrometry.
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[N:11]=[C:10]([C:12]([OH:14])=O)[CH:9]=[CH:8][C:7]=2[C:15]([F:18])([F:17])[F:16])[CH2:3][CH2:2]1.[CH3:19][C:20]([NH2:27])([C:22]1[N:26]=[CH:25][O:24][N:23]=1)[CH3:21]>>[CH3:19][C:20]([NH:27][C:12]([C:10]1[CH:9]=[CH:8][C:7]([C:15]([F:18])([F:17])[F:16])=[C:6]([O:5][CH2:4][CH:1]2[CH2:2][CH2:3]2)[N:11]=1)=[O:14])([C:22]1[N:26]=[CH:25][O:24][N:23]=1)[CH3:21]
Reactant: O=C(O)c1ccc(C(F)(F)F)c(OCC2CC2)n1
Reactant: CC(C)(N)c1ncon1
Product: CC(C)(NC(=O)c1ccc(C(F)(F)F)c(OCC2CC2)n1)c1ncon1

Procedure:
The title compound was synthesized in analogy to Example 1, using 6-cyclopropylmethoxy-5-trifluoromethyl-pyridine-2-carboxylic acid (Example 113 d) and 1-methyl-1-[1,2,4]oxadiazol-3-yl ethylamine (CAN 1153757-41-5) as starting materials, MS (EI): m/e=371.2 [M+H]+.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[CH:9][N:10]=2)[CH:7]=1.[C:11]1([C:17]#[CH:18])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>>[C:11]1([C:17]#[C:18][C:2]2[CH:3]=[N:4][C:5]3[N:6]([N:8]=[CH:9][N:10]=3)[CH:7]=2)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: Brc1cnc2ncnn2c1
Reactant: C#Cc1ccccc1
Product: C(#Cc1cnc2ncnn2c1)c1ccccc1

Procedure:
The title compound, light brown solid, MS: m/e=221.2 (M+H+), can be prepared in accordance with the general method of example 1 from 6-bromo-[1,2,4]triazolo[1,5-a]pyrimidine (example 32, step 1) and phenylacetylene.
Reaction SMILES: Cl[CH2:2][CH2:3][NH:4][CH2:5][CH2:6]Cl.Cl.[NH2:9][C:10]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH:13]=[CH:12][C:11]=1[CH3:20]>ClC1C=CC=CC=1>[CH3:20][C:11]1[CH:12]=[CH:13][C:14]2[C:19](=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:10]=1[N:9]1[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1
Reactant: ClCCNCCCl
Reactant: Cc1ccc2ccccc2c1N
Agent: Cl
Solvent: Clc1ccccc1
Product: Cc1ccc2ccccc2c1N1CCNCC1
Yield: 62 %

Procedure:
14.7 g (82.7 mM [sic]) of bis(2-chloroethyl)amine ×HCl were added to 13.0 g (82.7 mM [sic]) of 1-amino-2-methylnaphthalene in 100 ml of chlorobenzene and refluxed under nitrogen for 90 h. The mixture was then concentrated and partitioned between methylene chloride and water at pH=9, and the organic phase was dried and concentrated. The crude product was purified by column chromatography (silica gel, eluent/THF/methanol/ammonia 85/13/2. 11.6 g (62%) of product were isolated.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]2[C:15](=[O:16])[CH:14]=[C:13]([C:17]([F:20])([F:19])[F:18])[NH:12][C:11]2=[O:21])=[CH:6][CH:5]=1)([O-:3])=[O:2].CI.[C:24](=O)([O-])[O-].[K+].[K+]>O>[CH3:24][N:12]1[C:13]([C:17]([F:20])([F:19])[F:18])=[CH:14][C:15](=[O:16])[N:10]([C:7]2[CH:8]=[CH:9][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=2)[C:11]1=[O:21]
Reactant: O=c1cc(C(F)(F)F)[nH]c(=O)n1-c1ccc([N+](=O)[O-])cc1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: O
Product: Cn1c(C(F)(F)F)cc(=O)n(-c2ccc([N+](=O)[O-])cc2)c1=O
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To the stirred reaction mixture containing the crude 3-(4-nitrophenyl)-6-trifluoromethyluracil (14.5 grams--0.048 mole) from the preceding step was added 13.6 grams (0.096 mole) of methyl iodide and 3.3 grams (0.096 mole) of potassium carbonate. Upon completion of the addition, the reaction mixture was stirred at ambient temperature for about five hours, after which the reaction mixture was poured into water, and the resultant solid was collected by filtration. The solid was washed with petroleum ether and dried, yielding 13.0 grams of 1-methyl-3-(4-nitrophenyl)-6-trifluoromethyluracil. The NMR spectrum was consistent with the proposed structure.
Reaction SMILES: C(N(C(C)C)CC)(C)C.[C:10]([C:14]1[CH:19]=[CH:18][C:17]([NH:20][C:21]2[C:22]3[CH2:37][CH2:36][NH:35][CH2:34][C:23]=3[N:24]=[C:25]([CH2:27][N:28]3[CH2:33][CH2:32][O:31][CH2:30][CH2:29]3)[N:26]=2)=[CH:16][CH:15]=1)([CH3:13])([CH3:12])[CH3:11].Cl[C:39]1[C:44]([Cl:45])=[CH:43][CH:42]=[CH:41][N:40]=1>O1CCOCC1.C(N(CC)C(=O)C)C>[C:10]([C:14]1[CH:19]=[CH:18][C:17]([NH:20][C:21]2[C:22]3[CH2:37][CH2:36][N:35]([C:39]4[C:44]([Cl:45])=[CH:43][CH:42]=[CH:41][N:40]=4)[CH2:34][C:23]=3[N:24]=[C:25]([CH2:27][N:28]3[CH2:29][CH2:30][O:31][CH2:32][CH2:33]3)[N:26]=2)=[CH:16][CH:15]=1)([CH3:13])([CH3:11])[CH3:12]
Reactant: Clc1cccnc1Cl
Reactant: CC(C)(C)c1ccc(Nc2nc(CN3CCOCC3)nc3c2CCNC3)cc1
Agent: CCN(CC)C(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: CC(C)(C)c1ccc(Nc2nc(CN3CCOCC3)nc3c2CCN(c2ncccc2Cl)C3)cc1
Temperature: 180 °C
Yield: 30.4 %

Procedure:
A mixture of diisopropylethylamine (35 mg, 0.27 mmol), N-(4-tert-butylphenyl)-5,6,7,8-tetrahydro-2-(morpholinomethyl)pyrido[3,4-d]pyrimidin-4-amine (70 mg, 0.18 mmol) and 2,3-dichloropyridine (54 mg, 0.36 mmol) in dioxane (2 mL) and N,N-diethylacetamide (0.2 mL) was heated via microwave in a sealed tube at 180° C. for 10 hr. Solvent was removed in vacuo and residue was purified by column chromatography, product was obtained as a light yellow foam (27 mg).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:17][CH2:16][C:15]2[C:10](=[CH:11][C:12]([CH2:18]Br)=[CH:13][CH:14]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C-:20]#[N:21].[Na+]>CN(C=O)C.[Cl-].[Na+].O>[C:1]([O:5][C:6]([N:8]1[CH2:17][CH2:16][C:15]2[C:10](=[CH:11][C:12]([CH2:18][C:20]#[N:21])=[CH:13][CH:14]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: [C-]#N
Reactant: CC(C)(C)OC(=O)N1CCc2ccc(CBr)cc2C1
Agent: [Cl-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)N1CCc2ccc(CC#N)cc2C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 94.5 %

Procedure:
To a solution of 21.76 mmol of tert-butyl-7-(bromomethyl)-3,4-dihydroisoquinoline-2(1H)-carboxylate in 80 ml DMF were added at 0° C. 65.3 mmol sodium cyanide in small portions. The mixture was stirred at room temperature for 2 h. Brine solution was added to the mixture and the aqueous phase was extracted with EtOAc. The combined organic layers were washed with brine, dried over MgSO4 and filtered. Evaporation of the solvent gave 5.6 g of a brown oil. The material was purified by flash chromatography to yield 1.63 g of a pale yellow solid (27.5%).
Reaction SMILES: F[C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[N+:11]([O-:13])=[O:12].[NH2:14][C:15]1[CH:16]=[C:17]([NH:21][C:22](=[O:24])[CH3:23])[CH:18]=[CH:19][CH:20]=1.CCN(CC)CC>CCO>[C:22]([NH:21][C:17]1[CH:16]=[C:15]([NH:14][C:2]2[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=2[N+:11]([O-:13])=[O:12])[CH:20]=[CH:19][CH:18]=1)(=[O:24])[CH3:23]
Reactant: CC(=O)Nc1cccc(N)c1
Reactant: O=C(O)c1ccc(F)c([N+](=O)[O-])c1
Solvent: CCO
Solvent: CCN(CC)CC
Product: CC(=O)Nc1cccc(Nc2ccc(C(=O)O)cc2[N+](=O)[O-])c1

Procedure:
A mixture of 4-fluoro-3-nitrobenzoic acid (5) (10.2 g, 54.9 mmol), N-(3-aminophenyl)acetamide (9.21 g, 66.6 mmol) and Et3N (1.4 mL, 10.1 mmol) in anhydrous EtOH (160 mL) was heated at reflux under N2 overnight. The reaction mixture was then cooled and filtered, and the orange solid collected by filtration. It was then washed with 2 M HCl(aq), and dried in vacuo to give 4-{[3-(acetylamino)phenyl]amino}-3-nitrobenzoic acid. 1H NMR (400 MHz, DMSO-d6): δ 2.03 (s, 3H), 7.02 (d, J=7.9 Hz, 1H), 7.13 (d, J=9.0 Hz, 1H), 7.37 (t, J=8.0 Hz, 1H), 7.42 (d, J=8.0 Hz, 1H), 7.68 (s, 1H), 7.93 (dd, J=9.0, 1.9 Hz, 1H), 8.62 (s, 1H), 9.76 (s, 1H), 10.08 (s, 1H), 13.02 (br, 1H); MS (ES+): m/z 316 [MH+]
Reaction SMILES: [C:1]([O:5][C:6](=[O:21])[NH:7][C@H:8]([C:10]1[CH:15]=[CH:14][C:13]([C:16](=[O:20])[CH2:17][NH:18][CH3:19])=[CH:12][CH:11]=1)[CH3:9])([CH3:4])([CH3:3])[CH3:2].[CH:22](=O)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)([O-])O.[Na+]>C(Cl)(Cl)Cl>[C:1]([O:5][C:6](=[O:21])[NH:7][C@H:8]([C:10]1[CH:11]=[CH:12][C:13]([C:16](=[O:20])[CH2:17][N:18]([CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH3:19])=[CH:14][CH:15]=1)[CH3:9])([CH3:2])([CH3:4])[CH3:3]
Reactant: CNCC(=O)c1ccc([C@H](C)NC(=O)OC(C)(C)C)cc1
Reactant: O=Cc1ccccc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: C[C@H](NC(=O)OC(C)(C)C)c1ccc(C(=O)CN(C)Cc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
The compound [2-3] was dissolved in 3 mL of chloroform, and 76 μL of benzaldehyde and 158 mg of sodium triacetoxyborohydride were added thereto. After an overnight stirring at room temperature, to the mixture was added a saturated aqueous solution of sodium hydrogen carbonate, and the mixture was extracted with a mixed solvent of chloroform and methanol (mixing ratio: 9/1). The resulting organic layer was washed with saturated brine, and then dried over anhydrous sodium sulfate. The insolubles were filtered, the filtrate was concentrated under reduced pressure, and then the resulting residue was purified by preparative thin-layer chromatography, to obtain 64 mg of tert-butyl{(1S)-1-[4-(N-benzyl-N-methylglycyl)phenyl]ethyl}carbamate [24] (hereinafter, referred to as the compound [2-4]) as a colorless oily product.
Reaction SMILES: C[Zn]C.[CH2:4]([Mg]Br)[CH:5]([CH3:7])[CH3:6].[F:10][C:11]([F:33])([F:32])[C:12]1[CH:17]=[CH:16][C:15]([C:18]2[N:23]=[CH:22][C:21](/[CH:24]=[N:25]/[S@:26]([C:28]([CH3:31])([CH3:30])[CH3:29])=[O:27])=[CH:20][N:19]=2)=[CH:14][CH:13]=1>>[CH3:6][CH:5]([CH3:7])[CH2:4][C@H:24]([NH:25][S@:26]([C:28]([CH3:31])([CH3:30])[CH3:29])=[O:27])[C:21]1[CH:22]=[N:23][C:18]([C:15]2[CH:16]=[CH:17][C:12]([C:11]([F:33])([F:32])[F:10])=[CH:13][CH:14]=2)=[N:19][CH:20]=1
Reactant: CC(C)(C)[S@](=O)/N=C/c1cnc(-c2ccc(C(F)(F)F)cc2)nc1
Reactant: CC(C)C[Mg]Br
Agent: C[Zn]C
Product: CC(C)C[C@H](N[S@@](=O)C(C)(C)C)c1cnc(-c2ccc(C(F)(F)F)cc2)nc1
Temperature: -78 °C
Reaction time: 1.25 h
Yield: 68.3 %

Procedure:
Dimethyl zinc (117 mL, 2.0 M in toluene, 234 mmol) was added to an oven-dried and nitrogen-purged 500 mL round bottom flask with stir bar. Isobutylmagnesium bromide (103 mL, 2.0 M in ether, 206 mmol) was added over 5 min with stirring and the solution was allowed to stir at room temperature for 30 minutes. (S)-2-Methyl-propane-2-sulfinic acid 1-[2-(4-trifluoromethyl-phenyl)-pyrimidin-5-yl]-meth-(E)-ylideneamide (48.83 g, 137.4 mmol) was placed in an oven dried nitrogen-purged 2 L 3-necked flask with addition funnel, overhead stirring, and internal temperature. The solid was dissolved in anhydrous THF (690 mL) and cooled to −78° C. where it was a white suspension. The zincate solution was cannulated into the addition funnel and then added dropwise over 75 min to the sulfinyl imine, maintaining an internal temperature of less than −72° C. The reaction was then allowed to stir at −78° C. as a yellow solution. At 75 min, the reaction was quenched with saturated NH4Cl, adding 100 mL over 45 min, keeping the internal temperature below-70° C. A second 400 mL was then added more quickly (˜20 min), keeping the internal temperature below −47° C. Gas evolution was observed at these higher temperatures indicating perhaps a latency period. Upon adding a final 100 mL, no gas evolution was observed indicating the reaction was quenched. The cold bath was removed, another 300 mL of water was added and the reaction allowed to warm to 5° C. at which point the contents were added to an addition funnel, along with ethyl acetate and some additional water. The layers were separated and the aqueous layer extracted with three additional portions of ethyl acetate. The combined organics were dried over MgSO4. Purification was done on half the material in two batches by silica gel flash chromatography (ethyl acetate/heptane) to give (S)-2-methyl-propane-2-sulfinic acid {(S)-3-methyl-1-[2-(4-trifluoromethyl-phenyl)-pyrimidin-5-yl]-butyl}-amide (38.83 g, 68%) as a yellow solid. 1H NMR (400 MHz, CDCl3, δ): 8.82 (s, 2H) 8.57 (d, J=8.2 Hz, 2H) 7.75 (d, J=8.4 Hz, 2H) 4.49 (q, J=7.2 Hz, 1H) 3.44 (d, J=5.7 Hz, 1H) 1.99 (dt, J=13.9, 7.3 Hz, 1H) 1.51-1.77 (m, 2H) 1.24 (s, 9H) 0.99 (d, J=6.6 Hz, 3H) 0.95 (d, J=6.4 Hz, 3H); MS (M+1): 414.3.
Reaction SMILES: [Cl:1][C:2]1[C:7]([NH:8][S:9]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)(=[O:11])=[O:10])=[CH:6][C:5]([C:18]2[CH:19]=[C:20]3[C:25](=[CH:26][CH:27]=2)[N:24]=[CH:23][C:22]([N:28]2[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]2)=[N:21]3)=[CH:4][N:3]=1.C(N(CC)CC)C.[CH3:41][S:42](Cl)(=[O:44])=[O:43]>ClCCl>[Cl:1][C:2]1[C:7]([NH:8][S:9]([C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)(=[O:10])=[O:11])=[CH:6][C:5]([C:18]2[CH:19]=[C:20]3[C:25](=[CH:26][CH:27]=2)[N:24]=[CH:23][C:22]([N:28]2[CH2:29][CH2:30][N:31]([S:42]([CH3:41])(=[O:44])=[O:43])[CH2:32][CH2:33]2)=[N:21]3)=[CH:4][N:3]=1
Reactant: O=S(=O)(Nc1cc(-c2ccc3ncc(N4CCNCC4)nc3c2)cnc1Cl)c1ccccc1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)N1CCN(c2cnc3ccc(-c4cnc(Cl)c(NS(=O)(=O)c5ccccc5)c4)cc3n2)CC1
Temperature: 50 °C
Reaction time: 18 h
Yield: 6.1 %

Procedure:
To a solution of N-{2-chloro-5-[3-(1-piperazinyl)-6-quinoxalinyl]-3-pyridinyl}benzenesulfonamide (0.23 mmol), triethylamine (0.92 mmol), in dichloromethane (5 ml) was added methanesulfonyl chloride (0.25 mmol), which stirred at 50° C. for 18 hours. The reaction was cooled to ambient temperature, concentrated, redissolved in methanol and purified on reverse phase HPLC (0.1% ammonium hydroxide/water in acetonitrile). The desired fractions were combined and concentrated to give the title compound (7.8 mg, 2%) as a white solid. MS(ES)+ m/e 560.2 [M+H]+.