Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl-].COC1C=C(OC)NN([N+]2(C)CCOCC2)N=1.[Cl:19][CH2:20][CH2:21][CH2:22][O:23][C:24]1[CH:33]=[C:32]2[C:27]([C:28]([NH:34][C:35]3[CH:36]=[N:37][N:38]([CH2:40][C:41](O)=[O:42])[CH:39]=3)=[N:29][CH:30]=[N:31]2)=[CH:26][CH:25]=1.[F:44][C:45]1[CH:51]=[CH:50][CH:49]=[C:48]([F:52])[C:46]=1[NH2:47].O>CN(C)C=O>[Cl:19][CH2:20][CH2:21][CH2:22][O:23][C:24]1[CH:33]=[C:32]2[C:27]([C:28]([NH:34][C:35]3[CH:36]=[N:37][N:38]([CH2:40][C:41]([NH:47][C:46]4[C:45]([F:44])=[CH:51][CH:50]=[CH:49][C:48]=4[F:52])=[O:42])[CH:39]=3)=[N:29][CH:30]=[N:31]2)=[CH:26][CH:25]=1
Reactant: O=C(O)Cn1cc(Nc2ncnc3cc(OCCCCl)ccc23)cn1
Reactant: Nc1c(F)cccc1F
Agent: COC1=CC(OC)=NN([N+]2(C)CCOCC2)N1
Agent: [Cl-]
Solvent: O
Solvent: CN(C)C=O
Product: O=C(Cn1cc(Nc2ncnc3cc(OCCCCl)ccc23)cn1)Nc1c(F)cccc1F
Reaction time: 2 h
Yield: 76.8 %

Procedure:
4-(4,6-dimethoxytriazin-2-yl)-4-methylmorpholinium chloride (0.391 g, 1.32 mmol) was added in one go, at room temperature, to a stirred suspension of (4-{[7-(3-chloropropoxy)quinazolin-4-yl]amino}-1H-pyrazol-1-yl)acetic acid (0.400 g, 1.11 mmol) and 2,6-difluoroaniline (0.171 g, 1.32 mmol) in dimethylformamide (7 ml). The mixture was stirred for 2 hours and then poured into water (30 ml) the resultant solid was filtered to give 2-(4-{[7-(3-chloropropoxy)quinazolin-4-yl]amino}-1H-pyrazol-1-yl)-N-(2,6-difluorophenyl)acetamide (0.403 g, 77% yield) as a pale brown solid:
Reaction SMILES: [CH3:1][S:2][CH:3]([CH2:13][CH2:14][CH2:15][CH:16]([OH:22])[CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][C:10]([OH:12])=[O:11].[OH-].[Na+].I([O-])(=O)(=O)=[O:26].[Na+]>O>[CH3:1][S:2]([CH:3]([CH2:13][CH2:14][CH2:15][CH:16]([OH:22])[CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][C:10]([OH:12])=[O:11])=[O:26]
Reactant: [O-][I+3]([O-])([O-])[O-]
Reactant: CCCCCC(O)CCCC(CCCCCCC(=O)O)SC
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CCCCCC(O)CCCC(CCCCCCC(=O)O)S(C)=O
Temperature: 25 °C
Reaction time: 17 h

Procedure:
8-Methylthio-12-hydroxyheptadecanoic acid (Ex. 1) (6.7 g., 0.0202 mole) is dissolved in a solution of sodium hydroxide (1.0 g., 0.025 mole) in water (80 ml.). Sodium metaperiodate (4.7 g., 0.022 mole) is added and the resulting mixture is stirred at room temperature overnight (17 hours). The solids present are then filtered off and the filtrate is acidified with dilute hydrochloric acid to liberate the oily acid product. The oil is taken up in ether, washed with water and dried over sodium sulfate. The ether is evaporated in vacuo to leave the crude 8-methylsulfinyl-12-hydroxy-heptadecanoic acid as a viscous yellowish oil weighing 5.8 g. Purification is effected by chromatography on a column containing 125 g. of silica gel using 4% methanol is chloroform as eluant. There is obtained 2.2 g. of pure 8-methylsulfinyl-12-hydroxyheptadecanoic acid, a colorless viscous oil with Rf 0.14 on silica gel thin layer chromatograms with chloroform-methanol-acetic acid 96:3:1 as eluant; pmr (CDCl3) δ 0.90 (3H, t); 2.50 (3H, s CH3SO); 3.64 (1H, m HCO).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C:12]2[C:13]([C:19]3[N:23]([CH:24]([CH3:26])[CH3:25])[CH:22]=[N:21][N:20]=3)=[N:14][CH:15]=[C:16]([Cl:18])[CH:17]=2)(=[O:10])=[O:9])=[CH:4][C:3]=1[C:27]([F:30])([F:29])[F:28].[CH3:31][N+:32]([CH3:34])=[CH2:33].[I-]>CN(C=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C:12]2[C:13]([C:19]3[N:23]([CH:24]([CH3:25])[CH3:26])[C:22]([CH2:31][N:32]([CH3:34])[CH3:33])=[N:21][N:20]=3)=[N:14][CH:15]=[C:16]([Cl:18])[CH:17]=2)(=[O:9])=[O:10])=[CH:4][C:3]=1[C:27]([F:30])([F:29])[F:28]
Reactant: C=[N+](C)C
Reactant: CC(C)n1cnnc1-c1ncc(Cl)cc1NS(=O)(=O)c1ccc(Cl)c(C(F)(F)F)c1
Agent: [I-]
Solvent: CN(C)C=O
Product: CC(C)n1c(CN(C)C)nnc1-c1ncc(Cl)cc1NS(=O)(=O)c1ccc(Cl)c(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A 25 mL scintillation vial was charged with 4-Chloro-N-[5-chloro-2-(4-isopropyl-4H-1,2,4-triazol-3-yl)pyridin-3-yl]-3-(trifluoromethyl)benzenesulfonamide (60 mg, 0.14 mmol), Eschenmoser salt (25 mg, 0.2 mmol) and anhydrous DMF (2 mL). The resultant mixture was heated to 130° C. and stirred for 3 h. After cooling to room temperature, the residue was purified through preparative HPLC (10% to 90% gradient of MeCN-water) and dried (Lyophilizer) to afford the title compound. 1H NMR (400 MHz, CDCl3) 8.35 (d, 1H), 8.16 (d, 1H), 8.02 (d, 1H), 7.88 (dd, 1H), 7.50 (d. 1H), 5.40 (m, 1H), 3.65 (s, 2H), 2.23 (s, 6H), 1.42 (d, 6H). MS (ES) [M+H]+ expected 537.0, found 537.0.
Reaction SMILES: [CH3:1][C:2]1([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[C:10]([O:16][CH2:17][CH3:18])[CH:9]=2)[O:6][C:5](=[O:7])[NH:4][CH2:3]1.[H-].[Na+].Br[CH2:22][CH:23]1[CH2:25][CH2:24]1.O>CN(C)C=O>[CH3:1][C:2]1([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[C:10]([O:16][CH2:17][CH3:18])[CH:9]=2)[O:6][C:5](=[O:7])[N:4]([CH2:22][CH:23]2[CH2:25][CH2:24]2)[CH2:3]1
Reactant: CCOc1cc(C2(C)CNC(=O)O2)ccc1OC
Reactant: BrCC1CC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOc1cc(C2(C)CN(CC3CC3)C(=O)O2)ccc1OC
Yield: 71.7 %

Procedure:
500 mg (2.0 mmol) of 5-methyl-5-(3-ethoxy-4-methoxyphenyl)-2-oxazolidinone was first stirred with 60 mg (2.5 mmol) of sodium hydride in 14 ml of dimethylformamide for 30 minutes and, after addition of 0.26 ml (3.0 mmol) of (bromomethyl)cyclopropane for 17 hours at room temperature. The reaction mixture was combined with 50 ml of water and then extracted with ethyl acetate. The ethyl acetate phase was washed with water, dried over sodium sulfate, filtered, and concentrated (766 mg of a yellow oil). Chromatography on silica gel with methylene chloride/ether (1:1) yielded 438 mg of 5-methyl-5-(3-ethoxy-4-methoxyphenyl)-3-cyclopropylmethyl-2-oxazolidinone as an oil.
Reaction SMILES: [CH3:1][N:2]([CH3:31])[C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]=[C:8]1[CH2:13][CH2:14][C:15](=[O:16])[C:7]1=[C:6]2[C:17]1[CH:30]=[CH:29][C:20]([CH2:21][N:22]2[C:26](=[O:27])[CH:25]=[CH:24][C:23]2=[O:28])=[CH:19][CH:18]=1.[CH2:32]([O:34][C:35](=[O:47])[C@H:36]([CH2:45][SH:46])[NH:37][C:38]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:39])[CH3:33]>C(Cl)Cl.CO>[C:41]([O:40][C:38]([NH:37][CH:36]([CH2:45][S:46][CH:25]1[CH2:24][C:23](=[O:28])[N:22]([CH2:21][C:20]2[CH:29]=[CH:30][C:17]([C:6]3[C:5]4[C:10](=[CH:11][CH:12]=[C:3]([N:2]([CH3:31])[CH3:1])[CH:4]=4)[CH:9]=[C:8]4[CH2:13][CH2:14][C:15](=[O:16])[C:7]=34)=[CH:18][CH:19]=2)[C:26]1=[O:27])[C:35]([O:34][CH2:32][CH3:33])=[O:47])=[O:39])([CH3:43])([CH3:44])[CH3:42]
Reactant: CCOC(=O)[C@H](CS)NC(=O)OC(C)(C)C
Reactant: CN(C)c1ccc2cc3c(c(-c4ccc(CN5C(=O)C=CC5=O)cc4)c2c1)C(=O)CC3
Solvent: ClCCl
Solvent: CO
Product: CCOC(=O)C(CSC1CC(=O)N(Cc2ccc(-c3c4c(cc5ccc(N(C)C)cc35)CCC4=O)cc2)C1=O)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 60.6 %

Procedure:
An oven-dried 25 mL one-necked round-bottomed flask equipped with a septum and a stir bar was charged with compound 17 (0.006 g, 0.015 mmol) in CH2Cl2/MeOH 1:1 (5 mL). N-Boc-L-cysteine ethyl ester (0.0036 g, 0.015 mmol) was added in one portion and the mixture mas stirred at rt for 10 min. The consumption of the starting material was monitored by TLC (AcOEt/n-hexane 1:1). The solution was then concentrated under reduced pressure and the reaction residue was purified by silica gel flash column chromatography, eluting with AcOEt/n-hexane 1:1, to provide 0.006 g of the title compound as a 1:1 mixture of two inseparable diastereomers (d1 and d2) in a 60% yield.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]2[CH:6]=[C:7]([OH:10])[CH:8]=[CH:9][C:2]1=2.C([Mg]Cl)(C)C.[C:16]1([CH:22]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[N:23]2[C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[C:25](=[O:32])[C:24]2=[O:33])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.[Cl-].[NH4+]>O1CCCC1.ClCCCl>[C:34]1([CH:22]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[N:23]2[C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[C:25]([OH:32])([C:8]3[C:7]([OH:10])=[CH:6][C:3]4[CH:4]=[CH:5][S:1][C:2]=4[CH:9]=3)[C:24]2=[O:33])[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=1
Reactant: Oc1ccc2sccc2c1
Reactant: O=C1C(=O)N(C(c2ccccc2)c2ccccc2)c2ccccc21
Agent: CC(C)[Mg]Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: ClCCCl
Product: O=C1N(C(c2ccccc2)c2ccccc2)c2ccccc2C1(O)c1cc2sccc2cc1O
Temperature: 5 °C
Reaction time: 0.25 h
Yield: 59.3 %

Procedure:
To a solution of benzo[b]thiophen-5-ol (1.39 g, 9.25 mmol) in tetrahydrofuran (50 mL) at 5° C. was added a 2 M solution of isopropylmagnesium chloride in tetrahydrofuran (5.0 mL, 10 mmol). The reaction mixture was stirred at 5° C. for 15 min and concentrated in vacuo. To the residue were added 1,2-dichloroethane (100 mL) and 1-(diphenylmethyl)-1H-indole-2,3-dione (2.5 g, 8.0 mmol). The reaction mixture was heated at reflux for 3 h, allowed to cool to ambient temperature and stirred for 48 h. Saturated aqueous ammonium chloride (10 mL) was added and the phases were separated. The organic phase was dried over magnesium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography and eluted with a 0% to 20% gradient of ethyl acetate in dichloromethane to afford 1-(diphenylmethyl)-3-hydroxy-3-(5-hydroxy-1-benzothiophen-6-yl)-1,3-dihydro-2H-indol-2-one (2.2 g, 59%) as an off-white solid: MS (ES+) m/z 486.0 (M+23).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:10]2([C:27]([F:30])([F:29])[F:28])[CH2:14][C:13]([C:15]3[CH:22]=[CH:21]C(C#N)=[C:17]([C:23]([F:26])([F:25])[F:24])[CH:16]=3)=[N:12][CH2:11]2)[CH:5]=[C:6]([Cl:9])[C:7]=1[Cl:8].O.[CH3:32][C:33]([OH:35])=[O:34]>OS(O)(=O)=O.O>[Cl:1][C:2]1[CH:3]=[C:4]([C:10]2([C:27]([F:28])([F:30])[F:29])[CH2:14][C:13]([C:15]3[CH:22]=[CH:21][C:32]([C:33]([OH:35])=[O:34])=[C:17]([C:23]([F:24])([F:25])[F:26])[CH:16]=3)=[N:12][CH2:11]2)[CH:5]=[C:6]([Cl:9])[C:7]=1[Cl:8]
Reactant: CC(=O)O
Reactant: N#Cc1ccc(C2=NCC(c3cc(Cl)c(Cl)c(Cl)c3)(C(F)(F)F)C2)cc1C(F)(F)F
Agent: O=S(=O)(O)O
Solvent: O
Product: O=C(O)c1ccc(C2=NCC(c3cc(Cl)c(Cl)c(Cl)c3)(C(F)(F)F)C2)cc1C(F)(F)F
Yield: 82 %

Procedure:
4-[3-(3,4,5-Trichlorophenyl)-3-(trifluoromethyl)-3,4-dihydro-2H-pyrrol-5-yl]-2-(trifluoromethyl)benzonitrile (0.82 g, 1.68 mmol) was dissolved in AcOH and suspended in conc. H2SO4—H2O mixture. The reaction mixture was stirred vigorously and refluxed for 26 hours. The reaction mixture was then poured to a mixture of ice and water. The resulting mixture was then extracted with EtOAc and the organic layer was washed with brine and dried over Na2SO4. The solvent was evaporated to obtain the product (0.70 g, 82%).
Reaction SMILES: [C:1]([O:7][CH2:8][CH3:9])(=[O:6])[CH2:2][C:3]([CH3:5])=[O:4].[O-]CC.[Na+].Br[CH2:15][CH2:16][CH:17]=[CH2:18]>C(O)C>[C:3]([CH:2]([CH2:18][CH2:17][CH:16]=[CH2:15])[C:1]([O:7][CH2:8][CH3:9])=[O:6])(=[O:4])[CH3:5]
Reactant: CCOC(=O)CC(C)=O
Reactant: C=CCCBr
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: C=CCCC(C(C)=O)C(=O)OCC
Temperature: 25 °C
Yield: 91 %

Procedure:
Ethyl acetoacetate (6.57 g, 0.05 mol) was dissolved in ethanol (25 ml) and sodium ethoxide (3.9 g, 0.55 mol) was added. The solution was cooled to room temperature and 4-bromo-1-butene (6.96 g, 0.05 mole) was added. The mixture was refluxed for 5 hours. The resulting solution was filtered, ethyl acetate was added (75 ml), and washed with a solution of hydrochloric acid (2×200 ml, 5N) and brine (100 ml). The organic layer was dried (MgSO4), filtered, and solvent removed under reduced pressure to give ethyl 2-acetyl-5-hexenoate in the form of a light yellow liquid (9.29 g) in 91% yield.
Reaction SMILES: C([Sn](CCCC)(CCCC)[C:6]1[N:7]=[CH:8][N:9]([C:11]2[CH:16]=[C:15]([C:17]3[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:19][CH:18]=3)[CH:14]=[C:13]([C:27]([F:30])([F:29])[F:28])[N:12]=2)[CH:10]=1)CCC.[C:39]([NH:43][S:44]([C:47]1[S:48][C:49](Br)=[CH:50][CH:51]=1)(=[O:46])=[O:45])([CH3:42])([CH3:41])[CH3:40].CCCCCCC>C1(C)C=CC=CC=1>[C:39]([NH:43][S:44]([C:47]1[S:48][C:49]([C:6]2[N:7]=[CH:8][N:9]([C:11]3[CH:16]=[C:15]([C:17]4[CH:18]=[CH:19][C:20]([C:23]([F:25])([F:26])[F:24])=[CH:21][CH:22]=4)[CH:14]=[C:13]([C:27]([F:28])([F:29])[F:30])[N:12]=3)[CH:10]=2)=[CH:50][CH:51]=1)(=[O:45])=[O:46])([CH3:42])([CH3:40])[CH3:41]
Reactant: CC(C)(C)NS(=O)(=O)c1ccc(Br)s1
Reactant: CCCC[Sn](CCCC)(CCCC)c1cn(-c2cc(-c3ccc(C(F)(F)F)cc3)cc(C(F)(F)F)n2)cn1
Solvent: CCCCCCC
Solvent: Cc1ccccc1
Product: CC(C)(C)NS(=O)(=O)c1ccc(-c2cn(-c3cc(-c4ccc(C(F)(F)F)cc4)cc(C(F)(F)F)n3)cn2)s1
Temperature: 25 °C
Yield: 57.4 %

Procedure:
A stirred mixture of 2-(4-tributylstannanyl-imidazol-1-yl)-6-trifluoromethyl-4-(4-trifluoromethyl-phenyl)-pyridine (Example G.12) (0.570 g, 0.88 mmol), commercially available 5-bromo-thiophene-2-sulfonic acid tert-butylamide (0.295 g, 0.99 mmol), tetrakis(triphenyl-phosphine)palladium (0.061 g, 0.046 mmol) in toluene (6 mL) was heated under reflux conditions for 16 h. Cooled to rt, some precipitate occurred, diluted with toluene (˜5 mL), added heptane, filtered the precipitate off, washed with toluene/heptane, dried in HV to give the title compound as a white solid (290 mg, 57%). MS (ISP) 575.2 [(M+H)+]; mp>250° C.
Reaction SMILES: [C:1]([N:9]1[CH2:14][CH2:13][N:12]([C:15]2[C:20]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[N:19][NH:18][C:17](=O)[CH:16]=2)[CH2:11][CH2:10]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.P(Cl)(Cl)([Cl:30])=O>>[Cl:30][C:17]1[N:18]=[N:19][C:20]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[C:15]([N:12]2[CH2:13][CH2:14][N:9]([C:1]([C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)=[O:8])[CH2:10][CH2:11]2)[CH:16]=1
Reactant: O=C(c1ccccc1)N1CCN(c2cc(=O)[nH]nc2-c2ccccc2)CC1
Reactant: O=P(Cl)(Cl)Cl
Product: O=C(c1ccccc1)N1CCN(c2cc(Cl)nnc2-c2ccccc2)CC1
Temperature: 80 °C

Procedure:
To 5-(4-benzoylpiperazin-1-yl)-6-phenylpyridazin-3(2H)-one (1.3 g) taken in single necked round bottom flask, phosphorusoxychloride (10 ml) was added and the mixture was heated to 80° C. for 4 hrs. Reaction mixture was cooled to room temperature and concentrated to remove excess phosphorus oxychloride. Residue was slowly poured into ice and neutralized with solid sodium bicarbonate. The mixture was extracted with Ethyl acetate (3×100 ml). The combined organic layer was dried over anhydrous sodium sulphate and concentrated to afford (4-(6-chloro-3-phenylpyridazin-4-yl)piperazin-1-yl)(phenyl)methanone as white solid.
Reaction SMILES: CS(O[C@H:6]1[C@@H:10]([O:11][C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[C:14]([F:19])[CH:13]=2)[CH2:9][N:8]([CH3:20])[CH2:7]1)(=O)=O.CN(C=O)C.[N-:26]=[N+:27]=[N-:28].[Na+]>O>[N:26]([C@H:6]1[C@H:10]([O:11][C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[C:14]([F:19])[CH:13]=2)[CH2:9][N:8]([CH3:20])[CH2:7]1)=[N+:27]=[N-:28]
Reactant: CN1C[C@H](Oc2ccc(Cl)c(F)c2)[C@H](OS(C)(=O)=O)C1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CN1C[C@@H](N=[N+]=[N-])[C@H](Oc2ccc(Cl)c(F)c2)C1
Temperature: 90 °C
Yield: 89.4 %

Procedure:
To a solution of 424 (400 mg, 1.24 mmol) and DMF (2.0 mL) was added sodium azide (0.806 g, 12.4 mmol). The mixture was heated at 90° C. overnight. The mixture was cooled, diluted with H2O (30 mL) and extracted with EtOAc (3×50 mL). The combined extracts were washed with water (3×30 mL), dried (Na2SO4), filtered and concentrated in vacuo to afford 300 mg of trans-(±)-3-azido-4-(4-chloro-3-fluorophenoxy)-1-methylpyrrolidine (426) which was used for next step without further purification: LC-MS (ESI) m/z 271 (M+H).
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]([CH2:12]Br)[CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].[NH3:14]>CO>[NH2:14][CH2:12][C:10]1[CH:9]=[CH:8][C:3]([C:4]([O:6][CH3:7])=[O:5])=[C:2]([Br:1])[CH:11]=1
Reactant: COC(=O)c1ccc(CBr)cc1Br
Reactant: N
Solvent: CO
Product: COC(=O)c1ccc(CN)cc1Br
Reaction time: 3 h

Procedure:
A solution of methyl 2-bromo-4-(bromomethyl)benzoate (4.57 g; 14.84 mmol) in 50 mL of methanol is added dropwise to a well-stirred solution of ammonia in methanol (7M; 315 mL) at ambient temperature, and the solution is then stirred for 3 hours. All the solvents are evaporated off and the residue is purified by chromatography over silica gel using dichloromethane-methanol as eluants to yield the title compound.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:10]2[N:11]=[CH:12][N:13]=[C:14](Cl)[C:9]=2[NH:8][CH:7]=1)=[O:5])[CH3:2].[CH2:16]([O:18][C:19]1[CH:27]=[CH:26][C:22]2[O:23][CH2:24][O:25][C:21]=2[C:20]=1B1OC(C)(C)C(C)(C)O1)[CH3:17]>>[CH2:1]([O:3][C:4]([C:6]1[C:10]2[N:11]=[CH:12][N:13]=[C:14]([C:20]3[C:21]4[O:25][CH2:24][O:23][C:22]=4[CH:26]=[CH:27][C:19]=3[O:18][CH2:16][CH3:17])[C:9]=2[NH:8][CH:7]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1c[nH]c2c(Cl)ncnc12
Reactant: CCOc1ccc2c(c1B1OC(C)(C)C(C)(C)O1)OCO2
Product: CCOC(=O)c1c[nH]c2c(-c3c(OCC)ccc4c3OCO4)ncnc12

Procedure:
Starting from 4-chloro-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylic acid ethyl ester and 5-ethoxy-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzo[1,3]dioxole (example A31) the title compound is obtained as colorless solid.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([O:8][C:9]2[CH:14]=[CH:13][C:12]([S:15]([NH:18][C:19]3[N:20]=[CH:21][S:22][CH:23]=3)(=[O:17])=[O:16])=[CH:11][C:10]=2[C:24]#[N:25])=[C:4]([C:26]2[CH:27]=[N:28][NH:29][CH:30]=2)[CH:3]=1.[F:31][C:32]1[CH:33]=[C:34](B(O)O)[CH:35]=[CH:36][CH:37]=1.C([O-])([O-])=O.[K+].[K+].O>O1CCOCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:24]([C:10]1[CH:11]=[C:12]([S:15]([NH:18][C:19]2[N:20]=[CH:21][S:22][CH:23]=2)(=[O:17])=[O:16])[CH:13]=[CH:14][C:9]=1[O:8][C:5]1[CH:6]=[N:7][C:2]([C:36]2[CH:35]=[CH:34][CH:33]=[C:32]([F:31])[CH:37]=2)=[CH:3][C:4]=1[C:26]1[CH:27]=[N:28][NH:29][CH:30]=1)#[N:25]
Reactant: N#Cc1cc(S(=O)(=O)Nc2cscn2)ccc1Oc1cnc(Cl)cc1-c1cn[nH]c1
Reactant: OB(O)c1cccc(F)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: N#Cc1cc(S(=O)(=O)Nc2cscn2)ccc1Oc1cnc(-c2cccc(F)c2)cc1-c1cn[nH]c1
Reaction time: 0.33 h
Yield: 34.7 %

Procedure:
25.0 mg (0.05 mmol) of 4-((6-chloro-4-(1H-pyrazol-4-yl)pyridin-3-yl)oxy)-3-cyano-N-(thiazol-4-yl)benzenesulfonamide was dissolved in 1.5 mL of 1,4-dioxane, and 10.5 mg (0.08 mmol) of (3-fluorophenyl)boronic acid was added thereto, and then 5.8 mg (10 mol %) of Pd(PPh3)4, 20.7 mg (0.15 mmol) of K2CO3, and 0.3 mL of H2O were added thereto. After reacting with microwave reactor at 120° C. for 20 minutes, the solvent was removed, and the remaining material was diluted with ethyl acetate and the organic layer was separated, and washed with saturated sodium chloride. The organic layer was collected, dried with magnesium sulfate to remove water, and concentrated under reduced pressure, and the residue was purified by column chromatography (developing solvent, hexane:ethyl acetate=1:1) to obtain 9.0 mg (31.9% yield) of the title compound.
Reaction SMILES: [CH2:1]([NH2:4])[CH2:2][NH2:3].[N+:5]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[S:14](Cl)(=[O:16])=[O:15])([O-:7])=[O:6]>C(Cl)Cl>[NH2:3][CH2:2][CH2:1][NH:4][S:14]([C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=1[N+:5]([O-:7])=[O:6])(=[O:15])=[O:16]
Reactant: O=[N+]([O-])c1ccccc1S(=O)(=O)Cl
Reactant: NCCN
Solvent: ClCCl
Product: NCCNS(=O)(=O)c1ccccc1[N+](=O)[O-]
Temperature: 0 °C
Yield: 76 %

Procedure:
A solution of ethylene diamine (268 mL, 20 equiv) in DCM (400 mL) was added to an ice-cooled solution of o-nitrobenzene sulfonyl chloride (44.4 gm, 0.2 mole) in DCM (200 mL) over 1 hr. Concentration on the rotary evaporator left an oil which was partitioned between DCM and sat. aq. Na2CO3 solution. The aqueous phase was backextracted with DCM and the combined organic phases were dried (Na2SO4). Removal of the solvents followed by silica gel chromatography (step gradient elution with DCM containing 0, 5, 10, 20, 30% MeOH) afforded the title compound as an oil (37.2 gm, 76%). 1H NMR (CDCl3+D2O) δ 2.82 (t, 2H, J=5.1 Hz), 3.10 (t, 2H, J=5.1 Hz), 7.73 (m, 2H), 7.83 (m, 1H), 8.11 (m, 1H); MS: 246 (M+H)+; HPLC Ret Time: 0.39 min (YMC Xterra 3.0×50 mm S7 C18 column, 3 min gradient, 4 mL/min).
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1.[NH:10]1[CH2:15][CH2:14][O:13][CH2:12][CH2:11]1.[F-].[K+]>CS(C)=O.CCOC(C)=O>[N:10]1([C:2]2[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=2)[CH2:15][CH2:14][O:13][CH2:12][CH2:11]1
Reactant: N#Cc1ccc(F)cc1
Reactant: C1COCCN1
Agent: [F-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: N#Cc1ccc(N2CCOCC2)cc1
Temperature: 150 °C
Yield: 59.8 %

Procedure:
A solution of 4-fluorobenzonitrile (1.00 g, 8.26 mmol) and morpholine (0.77 mL, 9.08 mmol) in dimethyl sulfoxide (40 mL) was treated with 37% KF on alumina, and the mixture was heated at 150° C. for 5 h. After cooling, the mixture was diluted with EtOAc and filtered through diatomaceous earth. The filtrate was washed with water (3×), brine (1×), and then dried with magnesium sulfate. The extract was concentrated and the residue was purified by chromatography (SiO2, 20 to 30% EtOAc in hexanes) yielding 930 mg (60%) of the title compound.
Reaction SMILES: [Cl:1][C:2]1[C:11]([Cl:12])=[C:10]([CH3:13])[CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].[Br:14]N1C(=O)CCC1=O.C(Cl)(Cl)(Cl)Cl>C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1.CCCCC>[Br:14][CH2:13][C:10]1[CH:9]=[CH:8][C:3]([C:4]([O:6][CH3:7])=[O:5])=[C:2]([Cl:1])[C:11]=1[Cl:12]
Reactant: COC(=O)c1ccc(C)c(Cl)c1Cl
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Solvent: CCCCC
Product: COC(=O)c1ccc(CBr)c(Cl)c1Cl
Temperature: 25 °C
Yield: 99 %

Procedure:
A mixture of 40 g (0.183 mol) of methyl 2,3-dichloro-4-methylbenzoate, 34.17 g (0.192 mol) of N-bromosuccinimide, 0.4 g (0.0017 mol) of benzoylperoxide, and 640 mL of carbon tetrachloride was stirred at room temperature while being irradiated with a 150 watt flood lamp for 2.5 hours. Concentration of the filtered reaction mixture under vacuum gave 54 g of material which on trituration with pentane followed by storage of the slurry at 5° C. for 18 hours gave 34.6 g (63.5%) of product; mp 57°-61° C.
Reaction SMILES: [H-].[Na+].[F:3][CH2:4][CH2:5][O:6][C:7]1[CH:8]=[C:9]([CH:12]=[CH:13][CH:14]=1)[CH2:10][OH:11].[CH2:15](Br)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.O>O1CCCC1>[CH2:15]([O:11][CH2:10][C:9]1[CH:12]=[CH:13][CH:14]=[C:7]([O:6][CH2:5][CH2:4][F:3])[CH:8]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: BrCc1ccccc1
Reactant: OCc1cccc(OCCF)c1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: FCCOc1cccc(COCc2ccccc2)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 78.5 %

Procedure:
Sodium hydride (0.24 g; 60% in oil) was suspended in 30 ml of dry tetrahydrofuran, and then 1.0 g of 3-(2-fluoroethoxy)benzyl alcohol was added. The mixture was stirred at 50° to 60° C. for 30 minutes, and 1.7 g of benzyl bromide was added. The mixture was heated under reflux for 3 hours. The reaction mixture was cooled to room temperature, poured into water, and extracted with toluene. The toluene layer was washed with water and dried over anhydrous sodium sulfate. Toluene was evaporated under reduced pressure. The resulting crude ether was purified by silica gel (50 g) column chromatography (developing solvent: toluene) to give 1.2 g of 3-(2-fluoroethoxy)benzyl benzyl ether.