Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([CH2:8][NH:9][C:10]2[C:15]([N+:16]([O-:18])=[O:17])=[CH:14][N:13]=[C:12]([NH:19][CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[O:27][C:28]([F:31])([F:30])[F:29])[N:11]=2)[CH2:4][CH2:3]1.Cl.[N:33]1[CH:38]=[CH:37][C:36]([CH2:39][C:40](O)=[O:41])=[CH:35][CH:34]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CCN(C(C)C)C(C)C>C(Cl)Cl.CN(C=O)C>[N+:16]([C:15]1[C:10]([NH:9][CH2:8][C@H:5]2[CH2:4][CH2:3][C@H:2]([NH:1][C:40](=[O:41])[CH2:39][C:36]3[CH:37]=[CH:38][N:33]=[CH:34][CH:35]=3)[CH2:7][CH2:6]2)=[N:11][C:12]([NH:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=2[O:27][C:28]([F:30])([F:31])[F:29])=[N:13][CH:14]=1)([O-:18])=[O:17]
Reactant: N[C@H]1CC[C@H](CNc2nc(NCc3ccccc3OC(F)(F)F)ncc2[N+](=O)[O-])CC1
Reactant: O=C(O)Cc1ccncc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(Cc1ccncc1)N[C@H]1CC[C@H](CNc2nc(NCc3ccccc3OC(F)(F)F)ncc2[N+](=O)[O-])CC1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A mixture of N4-[(trans-4-aminocyclohexyl)methyl]-5-nitro-N2-[2-(trifluoromethoxy)benzyl]-pyrimidine-2,4-diamine (50 mg, 0.11 mmol), 4-pyridylacetic acid hydrochloride (30 mg, 0.17 mmol), TBTU (56 mg, 0.17 mmol), and DIPEA (69 μL, 0.40 mmol) in a mixture of CH2Cl2 (1 mL) and DMF (0.1 mL) was stirred at room temperature for 16 h. The reaction mixture was then diluted with CH2Cl2 and washed with 1M Na2CO3 and water. The organic phase was dried over Na2SO4 and concentrated. The resulting residue was purified by silica gel preparative TLC using 95:5 CH2Cl2:MeOH as an eluent to afford 35 mg (55%) of the title compound as a white solid after washing the obtained product with diethyl ether, m/z 558.4 [M−1]+
Reaction SMILES: [NH2:1][CH:2]([C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([Br:11])[CH:6]=1)[CH2:3][OH:4].[C:12]([N:16]=[C:17]=[S:18])([CH3:15])([CH3:14])[CH3:13]>C(O)C>[C:12]([NH:16][C:17]([NH:1][CH:2]([C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([Br:11])[CH:6]=1)[CH2:3][OH:4])=[S:18])([CH3:15])([CH3:14])[CH3:13]
Reactant: NC(CO)c1cccc(Br)c1
Reactant: CC(C)(C)N=C=S
Solvent: CCO
Product: CC(C)(C)NC(=S)NC(CO)c1cccc(Br)c1

Procedure:
A solution of 3.54 g of 2-amino-2-(3-bromophenyl)-1-ethanol, in 20 cm3 of ethanol containing 0.18 cm3 of tert-butyl isothiocyanate is stirred at a temperature in the region of 20° C. for 5 hours. After concentration of the reaction mass under reduced pressure (5 kPa) at a temperature in the region of 40° C., the residue obtained is taken up in 25 cm3 of petroleum ether. The resulting crystals are spin-filtered, washed with twice 25 cm3 of petroleum ether and then dried under reduced pressure (5 kPa) at a temperature in the region of 20° C. 4 g of N-(tert-butyl)-N′-[2-hydroxy-1-(3-bromophenyl)ethyl]thiourea are obtained in the form of a white solid (Rf=0.68 in a 40/5/0.5 by volume dichloromethane/methanol/aqueous ammonia mixture, on a Merck 60F254R silica plate)
Reaction SMILES: [NH:1](C(OCC1C=CC=CC=1)=O)[C@H:2]([C:10]([O:12][CH3:13])=[O:11])[C@@H:3]([CH3:9])[O:4][C:5]([CH3:8])([CH3:7])[CH3:6].[H][H]>C(O)(=O)C.[Pd].C>[NH2:1][C@H:2]([C:10]([O:12][CH3:13])=[O:11])[C@@H:3]([CH3:9])[O:4][C:5]([CH3:8])([CH3:7])[CH3:6]
Reactant: COC(=O)[C@@H](NC(=O)OCc1ccccc1)[C@@H](C)OC(C)(C)C
Reactant: [H][H]
Agent: [Pd]
Solvent: CC(=O)O
Product: COC(=O)[C@@H](N)[C@@H](C)OC(C)(C)C

Procedure:
12.92 g (40mmols) of Z-Thr(tBu)-OMe are hydrogenated in 200 ml of glacial acetic acid and 3 g of Pd-charcoal (10%) at room temperature. The hydrogen uptake is finished after 1 hour. The solution is freed of the catalyst by filtration and is evaporated in a waterpump vacuum at 35°C. After drying in a high vacuum at 35°C 7.3 g of an oil result, which according to a thin layer chromatogram is a single substance and is directly further used.
Reaction SMILES: CC(C[C@H](CN)CC(O)=O)C.C(OC(=O)/C=C/CC(C)C)C.C([O:25][C:26](=[O:37])[CH2:27][CH:28]([CH2:33][N+:34]([O-:36])=[O:35])[CH2:29][CH:30]([CH3:32])[CH3:31])C>[N+](C)([O-])=O>[CH3:31][CH:30]([CH3:32])[CH2:29][C@H:28]([CH2:33][N+:34]([O-:36])=[O:35])[CH2:27][C:26]([OH:37])=[O:25]
Reactant: CCOC(=O)CC(CC(C)C)C[N+](=O)[O-]
Agent: CC(C)C[C@H](CN)CC(=O)O
Agent: CCOC(=O)/C=C/CC(C)C
Solvent: C[N+](=O)[O-]
Product: CC(C)C[C@@H](CC(=O)O)C[N+](=O)[O-]

Procedure:
In Synthesis 1989, 953 a synthesis of rac.-Pregabalin, starting from (E)-5-methyl-hex-2-enoic acid ethyl ester, which was converted with nitromethane into 5-methyl-3-nitromethyl-hexanoic acid ethyl ester, has been reported. Subsequent catalytic hydrogenation followed by saponification leads to rac.-Pregabalin. Recently an enzymatic hydrolysis of this racemic nitro ester was carried out (Tetrahedron Asymmetry 2008, 19, 945). With enzyme Novozyme 435 enantiomerically enriched (S)-5-methyl-3-nitromethyl-hexanoic acid could be obtained in a good selectivity if the conversion was stopped at 30%.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6](B2OC(C)(C)C(C)(C)O2)[CH:5]=[CH:4][C:3]=1[C:17]1[CH:18]=[C:19]2[C:23](=[C:24]([NH2:26])[CH:25]=1)[NH:22][CH:21]=[CH:20]2.Br[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1[S:34]([NH:37][C:38]1([CH2:43][OH:44])[CH2:42][CH2:41][CH2:40][CH2:39]1)(=[O:36])=[O:35]>>[NH2:26][C:24]1[CH:25]=[C:17]([C:3]2[CH:4]=[CH:5][C:6]([C:28]3[C:29]([S:34]([NH:37][C:38]4([CH2:43][OH:44])[CH2:42][CH2:41][CH2:40][CH2:39]4)(=[O:36])=[O:35])=[CH:30][CH:31]=[CH:32][CH:33]=3)=[CH:7][C:2]=2[F:1])[CH:18]=[C:19]2[C:23]=1[NH:22][CH:21]=[CH:20]2
Reactant: O=S(=O)(NC1(CO)CCCC1)c1ccccc1Br
Reactant: CC1(C)OB(c2ccc(-c3cc(N)c4[nH]ccc4c3)c(F)c2)OC1(C)C
Product: Nc1cc(-c2ccc(-c3ccccc3S(=O)(=O)NC3(CO)CCCC3)cc2F)cc2cc[nH]c12

Procedure:
The title compound was prepared in a manner similar to that described in Example 571 using 5-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-1H-indol-7-amine and 2-bromo-N-(1-(hydroxymethyl)-cyclopentyl)benzene-sulfonamide in Step B. MS (ESI): mass calcd. for C26H26FN3O3S, 479.17; m/z found, 480.3 [M+H]+. 1H NMR (500 MHz, CDCl3) δ 8.18 (dd, J=8.1, 1.4, 1H), 8.13 (s, 1H), 7.65-7.50 (m, 3H), 7.42 (s, 1H), 7.41-7.31 (m, 3H), 6.87 (m, 1H), 6.61 (dd, J=3.1, 2.0, 1H), 4.05 (s, 1H), 3.48 (s, 2H), 1.50-1.34 (m, 4H), 1.37-1.22 (m, 2H), 0.93-0.73 (m, 2H).
Reaction SMILES: CC(OC(/N=N/C(OC(C)C)=O)=O)C.[NH2:15][C:16]1[N:20]([C:21]2[CH:22]=[C:23]([OH:27])[CH:24]=[CH:25][CH:26]=2)[N:19]=[C:18]([C:28]([CH3:31])([CH3:30])[CH3:29])[CH:17]=1.[O:32]1[CH2:37][CH2:36][CH2:35][CH2:34][CH:33]1[O:38][CH2:39][CH2:40]O.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>C1COCC1>[C:28]([C:18]1[CH:17]=[C:16]([NH2:15])[N:20]([C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([O:27][CH2:40][CH2:39][O:38][CH:33]3[CH2:34][CH2:35][CH2:36][CH2:37][O:32]3)[CH:22]=2)[N:19]=1)([CH3:31])([CH3:30])[CH3:29]
Reactant: CC(C)(C)c1cc(N)n(-c2cccc(O)c2)n1
Reactant: OCCOC1CCCCO1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)(C)c1cc(N)n(-c2cccc(OCCOC3CCCCO3)c2)n1

Procedure:
DIAD (847 μl, 4.32 mmol) was added slowly to a solution of 3-(5-amino-3-tert-butyl-1H-pyrazol-1-yl)phenol (US 2006/35922, which is incorporated herein by reference in its entirety; 500 mg, 2.16 mmol), 2-(tetrahydro-pyran-2-yloxy)-ethanol (439 4, 3.25 mmol) and Ph3P (1.13 g, 4.32 mmol) in THF (10.0 mL) and the mixture stirred for 72 h. The reaction mixture was partitioned between EtOAc (75 mL) and H2O (75 mL) and the aqueous layer extracted with EtOAc (3×). The combined organic layers were dried (MgSO4), filtered and evaporated in vacuo. Purification by FCC, using 5-60% EtOAc in cyclohexane, gave the title compound (1.26 g). LCMS (Method 4): Rt 2.77, m/z 360 [MH+].
Reaction SMILES: [F:1][C:2]([F:28])([F:27])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:13]3[CH:14]=[CH:15][C:16]([CH2:18][CH2:19][CH2:20][CH2:21]OS(C)(=O)=O)=[CH:17][C:12]=3[S:11][N:10]=2)=[CH:5][CH:4]=1.[CH3:29][NH:30][CH3:31]>>[CH3:29][N:30]([CH3:31])[CH2:21][CH2:20][CH2:19][CH2:18][C:16]1[CH:15]=[CH:14][C:13]2[C:9]([C:6]3[CH:7]=[CH:8][C:3]([C:2]([F:28])([F:27])[F:1])=[CH:4][CH:5]=3)=[N:10][S:11][C:12]=2[CH:17]=1
Reactant: CS(=O)(=O)OCCCCc1ccc2c(-c3ccc(C(F)(F)F)cc3)nsc2c1
Reactant: CNC
Product: CN(C)CCCCc1ccc2c(-c3ccc(C(F)(F)F)cc3)nsc2c1

Procedure:
In analogy to example 17.1; Methanesulfonic acid 4-[3-(4-trifluoromethyl-phenyl)-benzo[d]isothiazol-6-yl]-butyl ester and Dimethylamine were converted to yield Dimethyl-{4-[3-(4-trifluoromethyl-phenyl)-benzo[d]isothiazol-6-yl]-butyl}-amine as yellow oil, MS: 379 (MH+).
Reaction SMILES: [Br:1][C:2]1[N:7]=[CH:6][C:5]([CH:8]=[O:9])=[CH:4][CH:3]=1.[CH2:10](O)[CH2:11][OH:12]>C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]2[O:12][CH2:11][CH2:10][O:9]2)=[CH:6][N:7]=1
Reactant: OCCO
Reactant: O=Cc1ccc(Br)nc1
Solvent: Cc1ccccc1
Product: Brc1ccc(C2OCCO2)cn1
Temperature: 25 °C

Procedure:
6-Bromo-3-pyridinecarbaldehyde (500 mg, 2.7 mmol) and 1,2-ethanediol (200 mg, 3.2 mmol) are dissolved in toluene (50 ml) together with Amberlyst 15 (100 mg) in a round bottom flask equipped with a reflux condenser and a Dean-Stark trap. The solution is stirred at reflux overnight, then cooled to room temperature, filtered and concentrated in vacuo. The crude product is chromatographed over silica gel with cyclohexane and ethyl acetate as the eluent to afford the title compound as a colorless oil.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([OH:11])=O)=[CH:4][C:3]=1[C:12]([F:15])([F:14])[F:13].[NH2:16][C:17]1[N:22]=[CH:21][C:20]([N:23]2[CH2:28][CH2:27][N:26]([C:29](=[O:31])[CH3:30])[CH2:25][CH2:24]2)=[CH:19][CH:18]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[C:29]([N:26]1[CH2:25][CH2:24][N:23]([C:20]2[CH:19]=[CH:18][C:17]([NH:16][C:9](=[O:11])[CH2:8][C:5]3[CH:6]=[CH:7][C:2]([Br:1])=[C:3]([C:12]([F:15])([F:14])[F:13])[CH:4]=3)=[N:22][CH:21]=2)[CH2:28][CH2:27]1)(=[O:31])[CH3:30]
Reactant: O=C(O)Cc1ccc(Br)c(C(F)(F)F)c1
Reactant: CC(=O)N1CCN(c2ccc(N)nc2)CC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)N1CCN(c2ccc(NC(=O)Cc3ccc(Br)c(C(F)(F)F)c3)nc2)CC1
Temperature: 25 °C
Yield: 94.8 %

Procedure:
To a mixture of 2-(4-bromo-3-(trifluoromethyl)phenyl)acetic acid 46-6 (564 mg, 2.0 mmol), 1-(4-(6-aminopyridin-3-yl)piperazin-1-yl)ethanone 111-4 (440 mg, 2.0 mmol) and HATU (798 mg, 2.1 mmol) in DMF (6 mL) was added DIEA (1.04 mL, 6.0 mmol) and the mixture was stirred at room temperature over night. The reaction mixture was partitioned between ethyl acetate and water. The organic phase was washed with brine and dried over Na2SO4 and the solvent was evaporated. The residue was subject to silica gel flash chromatography to give N-(5-(4-acetylpiperazin-1-yl)pyridin-2-yl)-2-(4-bromo-3-(trifluoromethyl)phenyl)acetamide 192-1 (920 mg, 95%). MS m/z 485.1 (M+1).
Reaction SMILES: [CH3:1][S:2]([O:5][CH2:6][C@H:7]1[CH2:18][CH2:17][C:16]2[S:15][C:14]3[N:13]=[CH:12][N:11]=[C:10]([O:19][CH:20]4[CH2:25][CH2:24][C:23](=O)[CH2:22][CH2:21]4)[C:9]=3[C:8]1=2)(=[O:4])=[O:3].[NH:27]1[CH2:32][CH2:31][NH:30][CH2:29][C:28]1=[O:33].C(O)(=O)C.[Na]BCC(O)=O.C(OOC(=O)C)(=O)C>CO>[CH3:1][S:2]([O:5][CH2:6][C@H:7]1[CH2:18][CH2:17][C:16]2[S:15][C:14]3[N:13]=[CH:12][N:11]=[C:10]([O:19][CH:20]4[CH2:25][CH2:24][CH:23]([N:30]5[CH2:31][CH2:32][NH:27][C:28](=[O:33])[CH2:29]5)[CH2:22][CH2:21]4)[C:9]=3[C:8]1=2)(=[O:4])=[O:3]
Reactant: O=C1CNCCN1
Reactant: CS(=O)(=O)OC[C@H]1CCc2sc3ncnc(OC4CCC(=O)CC4)c3c21
Agent: CC(=O)OOC(C)=O
Agent: O=C(O)CB[Na]
Solvent: CO
Solvent: CC(=O)O
Product: CS(=O)(=O)OC[C@H]1CCc2sc3ncnc(OC4CCC(N5CCNC(=O)C5)CC4)c3c21
Reaction time: 1 h
Yield: 74.3 %

Procedure:
To a solution of [(3S)-12-[(4-oxocyclohexyl)oxy]-7-thia-9,11-diazatricyclo[6.4.0.0[2,6]]dodeca-1(8),2(6),9,11-tetraen-3-yl]methyl methanesulfonate (500 mg, 1.26 mmol, 1.00 equiv) in methanol (10 mL) was added piperazin-2-one (126 mg, 1.26 mmol, 1.00 equiv) and acetic acid (1 mL). The solution was stirred for 1 h and then acetyl ethaneperoxoate sodioboranyl acetate (534 mg, 2.52 mmol, 2.00 equiv) was added. Stirring was continued for 2 h at 0° C. The mixture was then quenched with saturated aqueous sodium bicarbonate, extracted with DCM (60 mL), dried over anhydrous sodium sulfate and concentrated under vacuum. The desired [(3S)-12-[[4-(3-oxopiperazin-1-yl)cyclohexyl]oxy]-7-thia-9,11-diazatricyclo[6.4.0.0[2,6]]dodeca-1(8),2(6),9,11-tetraen-3-yl]methyl methanesulfonate (450 mg, 74%) was obtained as a yellow solid.
Reaction SMILES: [ClH:1].[NH:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[N:4]=[N:3]1.[N:11]#[C:12][NH2:13]>CCOCC>[ClH:1].[N:2]1([C:12](=[NH:11])[NH2:13])[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[N:4]=[N:3]1
Reactant: c1ccc2[nH]nnc2c1
Reactant: N#CN
Agent: Cl
Solvent: CCOCC
Product: N=C(N)n1nnc2ccccc21
Temperature: 80 °C
Yield: 71.2 %

Procedure:
To a 5 mL CEM microwave reaction vessel, was charged benzotriazole HCl salt (0.5 g, 3.2 mmol) and cyanamide (0.16 g, 3.9 mmol). The vessel was sealed and heated at 80° C. for 1 minute under microwave irradiation (CEM Discovery™). After this time, TLC analysis showed no starting material remaining so the mixture was diluted with ether. The precipitate was collected by filtration and washed with ether and dried under vacuum to afford the titled product as a white solid (0.45 g, 71% yield). 1H NMR (400 MHz, d6-DMSO) δ: 10.14 (4H, s), 8.31 (1H, m), 8.05 (1H, m), 7.90 (1H, m), 7.67 ('H, m). MS m/z: 162.13 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[CH2:10][N:9]([C@H:12]([CH:16]([CH3:18])[CH3:17])[C:13](O)=[O:14])[C:8](=[O:19])[C:7]3=[CH:20][NH:21][C:5]([C:6]=23)=[N:4][CH:3]=1.[NH2:22][CH2:23][C:24]#[N:25].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C1COCC1>[Cl:1][C:2]1[C:11]2[CH2:10][N:9]([C@H:12]([CH:16]([CH3:18])[CH3:17])[C:13]([NH:25][CH2:24][C:23]#[N:22])=[O:14])[C:8](=[O:19])[C:7]3=[CH:20][NH:21][C:5]([C:6]=23)=[N:4][CH:3]=1
Reactant: N#CCN
Reactant: CC(C)[C@H](C(=O)O)N1Cc2c(Cl)cnc3[nH]cc(c23)C1=O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1CCOC1
Product: CC(C)[C@H](C(=O)NCC#N)N1Cc2c(Cl)cnc3[nH]cc(c23)C1=O
Yield: 34.3 %

Procedure:
To an 8 mL scintillation vial equipped for stirring was added (R)-2-(6-chloro-3-oxopyrrolo[4,3,2-de][2,6]naphthyridin-4(1H,3H,5H)-yl)-3-methylbutanoic acid (10 mg, 0.032 mmol). THF (0.5 mL), 2-aminoacetonitrile (3.64 mg, 0.065 mmol) and HATU (14.83 mg, 0.039 mmol) were added and the solution was stirred at 25° C. for 1 h. The reaction mixture was purified via preparative mass trigger LC-MS (AcCN/H2O, 5-50%). The fractions were collected, concentrated, and dried in vacuo to afford the title compound as a yellow oil (3.8 mg, 33.8%). 1H NMR (400 MHz, CD3OD) δ 0.85-0.97 (m, 3 H) 1.02 (d, J=6.57 Hz, 1 H) 1.07 (d, J=6.32 Hz, 2 H) 2.53 (dt, J=11.18, 6.54 Hz, 1 H) 3.52-3.86 (m, 2 H) 4.89-5.04 (m, 1 H) 5.07 (d, J=11.37 Hz, 1 H) 5.51 (d, J=10.86 Hz, 1 H) 7.80-7.89 (m, 1 H) 8.13-8.34 (m, 1 H). [M+H] calc'd for C16H16ClN5O2, 346; found, 346.4.
Reaction SMILES: [N+:1](/[CH:4]=[CH:5]/[C:6]1[CH:14]=[CH:13][C:9]2[O:10][CH2:11][O:12][C:8]=2[CH:7]=1)([O-:3])=[O:2].[C:15]([O:22][CH3:23])(=[O:21])[CH2:16][C:17]([O:19][CH3:20])=[O:18]>C1(C)C=CC=CC=1>[CH3:20][O:19][C:17]([CH:16]([CH:5]([C:6]1[CH:14]=[CH:13][C:9]2[O:10][CH2:11][O:12][C:8]=2[CH:7]=1)[CH2:4][N+:1]([O-:3])=[O:2])[C:15]([O:22][CH3:23])=[O:21])=[O:18]
Reactant: O=[N+]([O-])/C=C/c1ccc2c(c1)OCO2
Reactant: COC(=O)CC(=O)OC
Solvent: Cc1ccccc1
Product: COC(=O)C(C(=O)OC)C(C[N+](=O)[O-])c1ccc2c(c1)OCO2
Temperature: 0 °C
Reaction time: 48 h

Procedure:
[(S,S)-N-(pentamethylbenzenesulfonyl)-1,2-diphenyl-ethylenediamine](hexamethylbenzene)ruthenium (13.7 mg, 0.02 mmol, S/C=50), 5-[(1E)-2-nitroethenyl]-1,3-benzodioxole (193 mg, 1.0 mmol), dimethyl malonate (137 μl, 1.2 mmol) and toluene (4 ml) were added into Schlenk (20 ml) under an argon atmosphere, and stirred at 0° C. for 48 hours. The reaction solution was purified by flash column chromatography (hexane/acetone=90/10, SiO2), showing that the isolation yield of the product was 99%. The optical purity was measured by HPLC (CHIRALPACK AS-H manufactured by Daicel Co., Ltd., hexane:2-propanol=90:10, flow rate 1 m/min, detection by 210 nm), resulting to 95% ee.
Reaction SMILES: [CH2:1]([NH2:4])[C:2]#[CH:3].Cl[C:6]([N:8]1[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=2[C:12](=[O:19])[NH:11][C:10]2[CH:20]=[CH:21][CH:22]=[N:23][C:9]1=2)=[O:7].C(N(CC)CC)C>C(Cl)(Cl)Cl>[CH2:1]([NH:4][C:6]([N:8]1[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=2[C:12](=[O:19])[NH:11][C:10]2[CH:20]=[CH:21][CH:22]=[N:23][C:9]1=2)=[O:7])[C:2]#[CH:3]
Reactant: C#CCN
Reactant: O=C1Nc2cccnc2N(C(=O)Cl)c2ccccc21
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: C#CCNC(=O)N1c2ccccc2C(=O)Nc2cccnc21
Temperature: 40 °C
Reaction time: 0.5 h

Procedure:
5.5 g (0.1 mol) of propargylamine were added dropwise with stirring at ambient temperature to a suspension of 27.3 g (0.1 mol) of 11-chlorocarbonyl-5,11-dihydro-6H-pyrido[2,3-b][1,4]benzodiazepin-6-one and 10.0 g (0.1 mol) of triethylamine in 500 ml of chloroform, whereupon the temperature rises to 35° C. The mixture is stirred for a further 30 minutes at 40° C., then filtered over activated charcoal and the reaction solution is evaporated to dryness in vacuo. After the oily residue has been decocted with ethyl acetate the desired product is obtained in the form of a colourless crystalline mass in a yield of 20.7 g (71% of theory).
Reaction SMILES: [Cl:1][C:2]1[CH:16]=[CH:15][C:5]([CH2:6][O:7][C:8]2[CH:13]=[CH:12][NH:11][C:10](=[O:14])[CH:9]=2)=[CH:4][CH:3]=1.Br[C:18]1[CH:19]=[CH:20][C:21]2[N:25]=[C:24]([CH2:26][CH:27]([CH3:29])[CH3:28])[N:23]([CH3:30])[C:22]=2[CH:31]=1.C(=O)([O-])[O-].[K+].[K+].CNCCNC>[Cu](I)I.O.CS(C)=O>[Cl:1][C:2]1[CH:16]=[CH:15][C:5]([CH2:6][O:7][C:8]2[CH:13]=[CH:12][N:11]([C:18]3[CH:19]=[CH:20][C:21]4[N:25]=[C:24]([CH2:26][CH:27]([CH3:28])[CH3:29])[N:23]([CH3:30])[C:22]=4[CH:31]=3)[C:10](=[O:14])[CH:9]=2)=[CH:4][CH:3]=1
Reactant: O=c1cc(OCc2ccc(Cl)cc2)cc[nH]1
Reactant: CC(C)Cc1nc2ccc(Br)cc2n1C
Agent: I[Cu]I
Agent: CNCCNC
Agent: O=C([O-])[O-]
Solvent: CS(C)=O
Solvent: O
Product: CC(C)Cc1nc2ccc(-n3ccc(OCc4ccc(Cl)cc4)cc3=O)cc2n1C
Temperature: 120 °C
Yield: 11.2 %

Procedure:
A mixture of 4-((4-chlorobenzyl)oxy)pyridin-2(1H)-one (115 mg), 6-bromo-2-isobutyl-1-methyl-1H-benzimidazole (130 mg), potassium carbonate (202 mg), copper iodide (93 mg), N,N′-dimethylethylenediamine (0.052 ml) and DMSO (3 ml) was heated at 120° C. for 3 h under microwave irradiation. The mixture was poured into water and extracted with EtOAc. The organic layer was separated, washed with water and brine, dried over MgSO4 and concentrated in vacuo. The precipitate was collected by filtration, and washed with IPE and EtOAc to give the title compound (23 mg) as an off-white solid.
Reaction SMILES: [Br:1][C:2]1[C:3]([C:7]2[C:8]([F:28])=[C:9]([N:13]([CH2:25][O:26][CH3:27])[S:14]([C:17]3[CH:22]=[C:21]([F:23])[CH:20]=[CH:19][C:18]=3[F:24])(=[O:16])=[O:15])[CH:10]=[CH:11][CH:12]=2)=[N:4][NH:5][CH:6]=1.[H-].[Na+].Br[CH2:32][CH2:33][O:34][CH:35]1[CH2:40][CH2:39][CH2:38][CH2:37][O:36]1>CN(C=O)C.CCOC(C)=O>[Br:1][C:2]1[C:3]([C:7]2[C:8]([F:28])=[C:9]([N:13]([CH2:25][O:26][CH3:27])[S:14]([C:17]3[CH:22]=[C:21]([F:23])[CH:20]=[CH:19][C:18]=3[F:24])(=[O:16])=[O:15])[CH:10]=[CH:11][CH:12]=2)=[N:4][N:5]([CH2:32][CH2:33][O:34][CH:35]2[CH2:40][CH2:39][CH2:38][CH2:37][O:36]2)[CH:6]=1
Reactant: COCN(c1cccc(-c2n[nH]cc2Br)c1F)S(=O)(=O)c1cc(F)ccc1F
Reactant: BrCCOC1CCCCO1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COCN(c1cccc(-c2nn(CCOC3CCCCO3)cc2Br)c1F)S(=O)(=O)c1cc(F)ccc1F
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 55.4 %

Procedure:
A solution of N-[3-(4-Bromo-1H-pyrazol-3-yl)-2-fluoro-phenyl]-2,5-difluoro-N-methoxymethyl-benzenesulfonamide (346 mg, 0.726 mmol)(prepared as described in Preparation 1) in anhydrous DMF (4 mL) was cooled to 0° C. under an argon atmosphere and sodium hydride (60% in mineral oil, 87 mg, 2.179 mmol, 3 eq) was added. The mixture was stirred at 0° C. for 30 minutes, then 2-(2-bromo-ethoxy)-tetrahydro-pyran (0.165 mL, 1.089 mmol, 1.5 eq) was added dropwise and the mixture was stirred at 0° C. for 1 hour. The reaction mixture was then diluted with AcOEt and washed with water and brine. The organic layer was dried over Na2SO4 and evaporated to dryness. The crude product was purified by flash chromatography on silica gel (cyclohexane/AcOEt 55:45) affording 243 mg (55%) of the desired regioisomer N-(3-{4-Bromo-1-[2-(tetrahydro-pyran-2-yloxy)-ethyl]-1H-pyrazol-3-yl}-2-fluoro-phenyl)-2,5-difluoro-N-methoxymethyl-benzenesulfonamide. HPLC (254 nm): Rt: 7.21 min; 1H NMR (DMSO-d6) Shift (selected signals): 8.07 (s, 1H), 7.55-7.69 (m, 2H), 7.47-7.53 (m, 2H), 7.39-7.45 (m, 1H), 7.30-7.35 (m, 1H), 5.09 (s, 2H), 4.51-4.57 (m, 1H), 4.29-4.35 (m, 2H), 3.89-3.97 (m, 1H), 3.70-3.78 (m, 1H), 3.42-3.51 (m, 1H), 3.38 (s, 3H), 1.29-1.69 (3 m, 6H); HRMS (ESI) calcd for C24H26BrF3N3O5S [M+H]+ 604.0723. found 604.0693.
Reaction SMILES: C(N(CC)CC)C.I[C:9]1[CH:21]=[CH:20][C:12]2[S:13][C:14]([C:16]([O:18][CH3:19])=[O:17])=[CH:15][C:11]=2[CH:10]=1.[Cl:22][C:23]1[CH:28]=[CH:27][C:26]([C:29]2[CH:30]=[CH:31][C:32]([C:35]#[CH:36])=[N:33][CH:34]=2)=[CH:25][CH:24]=1.CCOC(C)=O>C1COCC1.[Cu]I>[Cl:22][C:23]1[CH:24]=[CH:25][C:26]([C:29]2[CH:30]=[CH:31][C:32]([C:35]#[C:36][C:9]3[CH:21]=[CH:20][C:12]4[S:13][C:14]([C:16]([O:18][CH3:19])=[O:17])=[CH:15][C:11]=4[CH:10]=3)=[N:33][CH:34]=2)=[CH:27][CH:28]=1
Reactant: C#Cc1ccc(-c2ccc(Cl)cc2)cn1
Reactant: COC(=O)c1cc2cc(I)ccc2s1
Agent: [Cu]I
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: COC(=O)c1cc2cc(C#Cc3ccc(-c4ccc(Cl)cc4)cn3)ccc2s1
Temperature: 25 °C
Reaction time: 70 h

Procedure:
Under an argon atmosphere 3.7 mL (26.72 mmol) of triethylamine was added to a solution of 3.4 g (10.69 mmol) of methyl 5-iodobenzo[b]thiophen-2-carboxylate and 2.48 g (10.69 mmol) of 5-(4-chlorophenyl)-2-ethynylpyridine in 20 mL of THF and the reaction mixture was evacuated three times and in each case gassed with argon. Then 195 mg (0.267 mmol) of PdCl2(dppf)*DCM complex and 51 mg (0.267 mmol) of CuI were added and the reaction mixture was stirred for 70 hours at RT. EtOAc was added, and the precipitated product was filtered off, washed with a little EtOAc, and dried in the air. Yield: 3.0 g (70% of theoretical); C23H14ClNO2S (M=403.881); calc.: molpeak (M+H)+: 404/406 (Cl); found: molpeak (M+H)+: 404/406 (Cl); HPLC-MS: 7.3 minutes (method B).
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[O:10][C:11]3[CH:17]=[CH:16][CH:15]=[CH:14][C:12]=3[N:13]=2)=[C:5]([F:18])[CH:4]=1)[CH3:2].[Br:19]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[Br:19][CH:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[O:10][C:11]3[CH:17]=[CH:16][CH:15]=[CH:14][C:12]=3[N:13]=2)=[C:5]([F:18])[CH:4]=1)[CH3:2]
Reactant: O=C1CCC(=O)N1Br
Reactant: CCc1ccc(-c2nc3ccccc3o2)c(F)c1
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: CC(Br)c1ccc(-c2nc3ccccc3o2)c(F)c1

Procedure:
A mixture of 26 gm. 2-(4-ethyl-2-fluorophenyl) benzoxazole, 19.76 gm. of N-bromosuccinimide and 50 mg. of dibenzoyl peroxide in 150 cc. of carbon tetrachloride is refluxed until the N-bromosuccinimide is consumed. The reaction mixture is filtered and the filtrate concentrated to give a 2-[4-(1-bromoethyl)-2-fluorophenyl]benzoxazole, m.p., 103°-104° C.