Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([O:7][C:8]([N:10]2[CH:23]([C:24]#[C:25]/[CH:26]=[CH:27]\[C:28]#[C:29][Si:30]([CH3:33])([CH3:32])[CH3:31])[C:22]3[CH2:21][CH2:20][CH2:19][CH:18]([O:34][Si:35]([C:38]([CH3:41])([CH3:40])[CH3:39])([CH3:37])[CH3:36])[C:17]=3[C:16]3[CH:15]=[CH:14][C:13]([O:42][C:43](=[O:48])[C:44]([CH3:47])([CH3:46])[CH3:45])=[CH:12][C:11]2=3)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1C=C(Cl)C=C(C(OO)=[O:57])C=1>C(Cl)Cl>[C:1]1([O:7][C:8]([N:10]2[CH:23]([C:24]#[C:25]/[CH:26]=[CH:27]\[C:28]#[C:29][Si:30]([CH3:31])([CH3:33])[CH3:32])[C:22]34[O:57][C:17]3([CH:18]([O:34][Si:35]([C:38]([CH3:41])([CH3:39])[CH3:40])([CH3:36])[CH3:37])[CH2:19][CH2:20][CH2:21]4)[C:16]3[CH:15]=[CH:14][C:13]([O:42][C:43](=[O:48])[C:44]([CH3:47])([CH3:46])[CH3:45])=[CH:12][C:11]2=3)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CC(C)(C)C(=O)Oc1ccc2c(c1)N(C(=O)Oc1ccccc1)C(C#C/C=C\C#C[Si](C)(C)C)C1=C2C(O[Si](C)(C)C(C)(C)C)CCC1
Solvent: ClCCl
Product: CC(C)(C)C(=O)Oc1ccc2c(c1)N(C(=O)Oc1ccccc1)C(C#C/C=C\C#C[Si](C)(C)C)C13CCCC(O[Si](C)(C)C(C)(C)C)C21O3
Temperature: 25 °C
Reaction time: 1 h
Yield: 71.4 %

Procedure:
To a solution of Compound 209 (mixture of diastereomers, 13.0 g, 19.06 mmol) in CH2Cl2 (100 mL) cooled at zero degrees C. was added mCPBA (50 percent, 7.9 g, 22.98 mmol) followed by stirring at 25° C. for one hour. The reaction mixture was diluted with CH2Cl2 (500 mL), washed with saturated aqueous NaHCO3, dried over anhydrous Na2SO4, and concentrated in vacuo. The residue was purified by flash column chromatography (silica gel, 10 percent ethyl ether in petroleum ether) to afford Compound 210 (9.5 g, 71 percent) as a mixture of diastereomers. Major isomer: Rf =0.38 (silica, 10 percent ethyl ether in petroleum ether); IR (CHCl3) νmax 2958, 2933, 1730 (shoulder), 1721, 1382, 1307, 1118, 846 cm 1H NMR (300 MHz, CDCl3) δ 7.28 (d, J=8.6 Hz, 1 H, H1), 7.40-7.10 (m, 6 H, H4 and aromatic), 6.95 (dd, J=8.6, 1.9 Hz, 1 H, H2), 5.84-5.62 (m, 3 H, H6 and olefinic), 4.76 (dd, J=9.6, 5.7 Hz, 1 H, H10), 2.45 (dd, J=14.5, 4.6 Hz, 1 H, H7), 1.97-1.57 (m, 5 H, H7, H8 and H9), 1.31 (br s, 9 H, COC(CH3)3) 10.87 (s, 9 H, SiC(CH3)3), 0.19 (s, 12 H, Si(CH3)3 and SiCH3), 0.06 (s, 3 H, SiCH3); MS (FAB+) m/e (rel intensity) 830 (M+Cs, 100), 681 (6), 624 (9), 534 (11); HRMS for C40H51NO6Si2Cs (M+Cs), calcd 830.2309, found 830.2361. Minor isomer: Rf =0.22 (silica, 10 percent ethyl ether in petroleum ether); IR (CHCl3) νmax 2958, 2933, 1747 (shoulder), 1721, 1494, 1381, 1306, 1256, 1181, 1118, 909, 844 cm-1 ; 1H NMR (300 MHz, CDCl3) δ 7.58 (d, J=8.7 Hz, 1 H, H1), 7.40-7.10(m, 6 H, H4 and aromatic), 6.95 (dd, J=8.7, 2.5 Hz, 1 H, H2), 5.80-5.60 (m, 3 H, H6 and olefinic), 4.89 (d, J=2.4 Hz, 1 H, H10), 2.66-2.50 (m, 1 H, H7), 2.18-1.63 (m, 5 H, H7, H8 and H9), 1.31 (br s, 9 H, COC(CH3)3), 0.94 and 0.79 (s, 9 H, SiC(CH3)3) 10.23, 0.21 and 0.19 (s, 9 H, Si(CH3)3), 0.14 (s, 3 H, SiCH3), 0.06 (s, 3 H, SiCH3); MS (FAB+) m/e (rel intensity) 830 (M+Cs, 100), 708 (8), 640 (13), 534 (7); HRMS for C40H51NO6Si2Cs (M+Cs), calcd 830.2309, found 830.2296.
Reaction SMILES: N[C:2]1[N:6]([C:7]2[C:12]([F:13])=[CH:11][C:10]([C:14]([F:17])([F:16])[F:15])=[CH:9][C:8]=2[Cl:18])[N:5]=[C:4]([C:19]#[N:20])[C:3]=1[S:21]([C:23]([F:26])([F:25])[F:24])=[O:22].N(OCCC(C)C)=O.C(Br)(Br)[Br:36]>>[Br:36][C:2]1[N:6]([C:7]2[C:12]([F:13])=[CH:11][C:10]([C:14]([F:17])([F:16])[F:15])=[CH:9][C:8]=2[Cl:18])[N:5]=[C:4]([C:19]#[N:20])[C:3]=1[S:21]([C:23]([F:26])([F:25])[F:24])=[O:22]
Reactant: BrC(Br)Br
Reactant: N#Cc1nn(-c2c(F)cc(C(F)(F)F)cc2Cl)c(N)c1S(=O)C(F)(F)F
Agent: CC(C)CCON=O
Product: N#Cc1nn(-c2c(F)cc(C(F)(F)F)cc2Cl)c(Br)c1S(=O)C(F)(F)F
Temperature: 60 °C
Reaction time: 0.5 h
Yield: 73 %

Procedure:
To a solution of 5-amino-1-(2-chloro-6-fluoro-4-(trifluoromethyl)phenyl)-4-(trifluoromethylsulfinyl)-1H-pyrazole-3-carbonitrile (130 g, 310.3 mmol, 1.00 eq.) in CHBr3 (520 mL) was added dropwise isoamyl nitrite (109 g, 930.8 mmol, 3.00 eq.) at 55˜60° C. After all the isoamyl nitrite was added, the solution was stirred at 60° C. for 30 min. Then the mixture was concentrated under vacuum to give red solid. The solid was recrystallized with isopropyl alcohol to give 5-bromo-1-(2-chloro-6-fluoro-4-(trifluoromethyl)phenyl)-4-(trifluoromethylsulfinyl)-1H-pyrazole-3-carbonitrile (110 g, 73%) as yellow solid.
Reaction SMILES: Cl.[CH3:2][C:3]1[C:7]([B:8]2[O:12][C:11]([CH3:14])([CH3:13])[C:10]([CH3:16])([CH3:15])[O:9]2)=[CH:6][N:5]([C:17]2([CH2:21][C:22]#[N:23])[CH2:20][NH:19][CH2:18]2)[N:4]=1.Cl[C:25]1[N:26]=[CH:27][C:28]([C:31]([NH:33][CH:34]([CH3:36])[CH3:35])=[O:32])=[N:29][CH:30]=1.C(N(CC)C(C)C)(C)C.C(O)(C)(C)C>>[C:22]([CH2:21][C:17]1([N:5]2[CH:6]=[C:7]([B:8]3[O:9][C:10]([CH3:16])([CH3:15])[C:11]([CH3:13])([CH3:14])[O:12]3)[C:3]([CH3:2])=[N:4]2)[CH2:18][N:19]([C:25]2[N:26]=[CH:27][C:28]([C:31]([NH:33][CH:34]([CH3:36])[CH3:35])=[O:32])=[N:29][CH:30]=2)[CH2:20]1)#[N:23]
Reactant: CC(C)NC(=O)c1cnc(Cl)cn1
Reactant: Cc1nn(C2(CC#N)CNC2)cc1B1OC(C)(C)C(C)(C)O1
Agent: Cl
Solvent: CC(C)(C)O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1nn(C2(CC#N)CN(c3cnc(C(=O)NC(C)C)cn3)C2)cc1B1OC(C)(C)C(C)(C)O1
Temperature: 100 °C

Procedure:
A mixture of {3-[3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile HCl salt (0.43 g, 1.3 mmol), 5-chloro-N-isopropylpyrazine-2-carboxamide (0.24 g, 1.2 mmol) and N,N-diisopropylethylamine (0.63 mL, 3.6 mmol) in tert-butyl alcohol (12 mL, 120 mmol) was heated at 100° C. for 4 h. After cooling, the solvent was removed under reduced pressure. The residue was purified by flash chromatography on a silica gel column eluting with ethyl acetate in hexanes (0-60%) to afford the desired product. LCMS cacld. for C23H33BN7O3 (M+1)+: m/z=466.3. Found: 466.2.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]([N:13]3[CH2:18][CH2:17][CH:16]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=4[O:25][C:26]([F:29])([F:28])[F:27])[CH2:15][CH2:14]3)=[O:12])=[CH:7][NH:8]2)=[CH:4][CH:3]=1.Cl[CH2:31][C:32]([N:34]([CH3:36])[CH3:35])=[O:33]>>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]([N:13]3[CH2:18][CH2:17][CH:16]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=4[O:25][C:26]([F:27])([F:28])[F:29])[CH2:15][CH2:14]3)=[O:12])=[CH:7][N:8]2[CH2:31][C:32]([N:34]([CH3:36])[CH3:35])=[O:33])=[CH:4][CH:3]=1
Reactant: O=C(c1c[nH]c2cc(Cl)ccc12)N1CCC(c2ccccc2OC(F)(F)F)CC1
Reactant: CN(C)C(=O)CCl
Product: CN(C)C(=O)Cn1cc(C(=O)N2CCC(c3ccccc3OC(F)(F)F)CC2)c2ccc(Cl)cc21

Procedure:
Analogous to general procedure II, the alkylation of (6-chloro-1H-indol-3-yl)-[4-(2-trifluoromethoxy-phenyl)-piperidin-1-yl]-methanone (prepared herein) with (commercially available) 2-chloro-N,N-dimethyl-acetamide gave the title compound.
Reaction SMILES: [NH:1]([C:5]1[CH:6]=[CH:7][C:8]2[N:12]=[C:11]([CH2:13][CH2:14][CH2:15][CH3:16])[N:10]([CH2:17][C:18]3[CH:23]=[CH:22][C:21]([C:24]4[C:25]([C:30]([O:32]C(C)(C)C)=[O:31])=[CH:26][CH:27]=[CH:28][CH:29]=4)=[CH:20][CH:19]=3)[C:9]=2[CH:37]=1)[C:2]([CH3:4])=[O:3].FC(F)(F)C(O)=O>>[NH:1]([C:5]1[CH:6]=[CH:7][C:8]2[N:12]=[C:11]([CH2:13][CH2:14][CH2:15][CH3:16])[N:10]([CH2:17][C:18]3[CH:23]=[CH:22][C:21]([C:24]4[C:25]([C:30]([OH:32])=[O:31])=[CH:26][CH:27]=[CH:28][CH:29]=4)=[CH:20][CH:19]=3)[C:9]=2[CH:37]=1)[C:2]([CH3:4])=[O:3]
Reactant: CCCCc1nc2ccc(NC(C)=O)cc2n1Cc1ccc(-c2ccccc2C(=O)OC(C)(C)C)cc1
Solvent: O=C(O)C(F)(F)F
Product: CCCCc1nc2ccc(NC(C)=O)cc2n1Cc1ccc(-c2ccccc2C(=O)O)cc1

Procedure:
Prepared in analogous manner to Example 9 from tert.butyl 4'-[(6-acetamino-2-n-butyl-benzimidazol-1-yl)-methyl]biphenyl-2-carboxylate and trifluoroacetic acid.
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]([CH3:23])=[C:5](CC(O)=O)[CH:6]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([Cl:17])[C:12]=2[Cl:18])[C:7]=1[C:8]([OH:10])=[O:9].[H-].[Na+].[C:26]([O:30][CH2:31]Cl)(=[O:29])[CH2:27][CH3:28]>CN(C=O)C>[Cl:18][C:12]1[C:13]([Cl:17])=[CH:14][CH:15]=[CH:16][C:11]=1[CH:6]1[C:5]([C:26]([O:30][CH3:31])=[O:29])=[C:4]([CH3:23])[NH:3][C:2]([CH3:1])=[C:7]1[C:8]([O:10][CH2:31][O:30][C:26](=[O:29])[CH2:27][CH3:28])=[O:9]
Reactant: CC1=C(CC(=O)O)C(c2cccc(Cl)c2Cl)C(C(=O)O)=C(C)N1
Reactant: CCC(=O)OCCl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCC(=O)OCOC(=O)C1=C(C)NC(C)=C(C(=O)OC)C1c1cccc(Cl)c1Cl
Temperature: 80 °C
Yield: 71.4 %

Procedure:
To a stirred mixture of 1,4-dihydro-2,6-dimethyl-4-(2',3'-dichorophenyl)-5-carboxymethyl-3-pyridinecarboxylic acid (5 g,14 mmol) and sodium hydride (0.6 g, 14 mmol) in DMF (25 ml) under nitrogen atmosphere was added chloromethyl propionate (1.71 g, 14 mmol). The reaction mixture was heated at 80° C. for 16 h. Workup by evaporation of solvent and addition of water. Extraction with dichloromethane, the extract was dried over sodium sulfate and concentrated. The resulting yellow crystals was subjected to flash chromatography [silica gel, dichloromethane - dichloromethane/methanol (9/1) gradient] to give pale yellow crystals (2.21 g, 36%), mp.123.8°-125.5° C. 1H-NMR (CDCl3): 7.30-7.03 (Ar, 3H); 5.97 (s, 1H); 5.75 (d, J=5.5 Hz, 1H); 5.72 (d, J=5.5 Hz, 1H); 5.46 (s, 1H); 3.60 (s, 3H); 2.34-2.25 (m, 8H); 1.09 (t, J=7.5 Hz, 3H). 13C-NMR (CDCl3): 173.11; 167.65; 165.83; 147.47; 146.70; 143.87; 132.86; 131.14; 129.83; 128.30; 126.96; 103.95; 101.94; 78.70; 50.92; 38.45; 27.25; 19.86; 19.25; 8.61.
Reaction SMILES: [F:1][CH:2]([F:48])[C:3]1[N:7]([C:8]2[N:13]=[C:12]([N:14]3[CH2:19][CH2:18][N:17]([S:20]([CH2:23][CH2:24][N:25]([CH3:27])[CH3:26])(=[O:22])=[O:21])[CH2:16][CH2:15]3)[N:11]=[C:10]([N:28]3[CH2:33][CH2:32][O:31][CH2:30][CH2:29]3)[N:9]=2)[C:6]2[CH:34]=[C:35]([NH:40]C(=O)OC(C)(C)C)[CH:36]=[C:37]([O:38][CH3:39])[C:5]=2[N:4]=1.N>C(Cl)Cl.C(O)(C(F)(F)F)=O>[NH2:40][C:35]1[CH:36]=[C:37]([O:38][CH3:39])[C:5]2[N:4]=[C:3]([CH:2]([F:48])[F:1])[N:7]([C:8]3[N:9]=[C:10]([N:28]4[CH2:33][CH2:32][O:31][CH2:30][CH2:29]4)[N:11]=[C:12]([N:14]4[CH2:19][CH2:18][N:17]([S:20]([CH2:23][CH2:24][N:25]([CH3:27])[CH3:26])(=[O:22])=[O:21])[CH2:16][CH2:15]4)[N:13]=3)[C:6]=2[CH:34]=1
Reactant: COc1cc(NC(=O)OC(C)(C)C)cc2c1nc(C(F)F)n2-c1nc(N2CCOCC2)nc(N2CCN(S(=O)(=O)CCN(C)C)CC2)n1
Agent: N
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1cc(N)cc2c1nc(C(F)F)n2-c1nc(N2CCOCC2)nc(N2CCN(S(=O)(=O)CCN(C)C)CC2)n1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of the above carbamate (0.244 g, 0.035 mmol) in a mixture of 10 mL CH2Cl2 and 5 mL TFA was stirred at room temperature for 2 hrs. The mixture was diluted with CH2Cl2 and then made basic with dil. aq. NH3. The organic layer was dried and concentrated to give a quantitative yield of N-[2-({4-[4-[6-amino-2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-6-(4-morpholinyl)-1,3,5-triazin-2-yl]-1-piperazinyl}sulfonyl)ethyl]-N,N-dimethylamine: 1H NMR (CDCl3) δ 7.35 (t, JHF=53.8 Hz, 1H), 7.15 (d, J=1.9 Hz, 1H), 6.22 (d, J=1.9 Hz, 1H), 3.98 (m, 7H), 3.90-3.75 (m, 10H), 3.38 (m, 4H), 3.11 (dd, J=8.1, 6.5 Hz, 2H), 2.78 (dd, J=8.1, 6.4 Hz, 2H), 2.26 (s, 6H).
Reaction SMILES: [CH3:1][C:2]1[N:7]=[CH:6][C:5]([NH:8][C:9](=[O:20])[C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([C:16]([F:19])([F:18])[F:17])[CH:11]=2)=[CH:4][C:3]=1[C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([N+:27]([O-])=O)[CH:22]=1.C(O)(=O)C.C([O-])([O-])=O.[Na+].[Na+]>C(O)C.[Fe]>[NH2:27][C:23]1[CH:22]=[C:21]([C:3]2[CH:4]=[C:5]([NH:8][C:9](=[O:20])[C:10]3[CH:15]=[CH:14][CH:13]=[C:12]([C:16]([F:19])([F:17])[F:18])[CH:11]=3)[CH:6]=[N:7][C:2]=2[CH3:1])[CH:26]=[CH:25][CH:24]=1
Reactant: Cc1ncc(NC(=O)c2cccc(C(F)(F)F)c2)cc1-c1cccc([N+](=O)[O-])c1
Agent: [Fe]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CCO
Product: Cc1ncc(NC(=O)c2cccc(C(F)(F)F)c2)cc1-c1cccc(N)c1
Temperature: 87 °C

Procedure:
To a solution of N-[6-methyl-5-(3-nitrophenyl)pyridin-3-yl]-3-(trifluoromethyl)benzamide (0.150 g, 0.000374 mol) in ethanol (3 mL) was added acetic acid (0.5 mL, 0.009 mol) and iron powder (0.11 g, 0.0020 mol). The reaction was heated at 87° C. for 2 hours. It was then neutralized with Na2CO3 and extracted with EtOAc and the organic extracts were washed with water, saturated NaCl, dried (MgSO4) and stripped in vacuo. The residue was used in the next reaction without purification. MS (ES) (M+H)=372.
Reaction SMILES: [O:1]=[CH:2][C:3]1[CH:11]=[CH:10][C:8]([OH:9])=[C:5]([O:6][CH3:7])[CH:4]=1.[CH2:12](Br)[CH:13]=[CH2:14].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH3:7][O:6][C:5]1[CH:4]=[C:3]([CH:11]=[CH:10][C:8]=1[O:9][CH2:14][CH:13]=[CH2:12])[CH:2]=[O:1]
Reactant: COc1cc(C=O)ccc1O
Reactant: C=CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: C=CCOc1ccc(C=O)cc1OC

Procedure:
Vanillin (20.0 g, 0.130 mol) and allyl bromide (19.9 g, 0.160 mol) were heated under reflux together with potassium carbonate (27.3 g, 0.200 mol) in 150 ml acetone (abs.) for 8 hours. After cooling, the solid was filtered off and washed with acetone. A yellow oil was obtained after a thorough concentration of the organic phases.
Reaction SMILES: [Br:1][C:2]1[N:3]=[C:4]([CH:12]2[CH2:15][N:14](C(OCC3C=CC=CC=3)=O)[CH2:13]2)[N:5]2[CH:10]=[CH:9][N:8]=[C:7]([CH3:11])[C:6]=12>Cl>[NH:14]1[CH2:15][CH:12]([C:4]2[N:5]3[CH:10]=[CH:9][N:8]=[C:7]([CH3:11])[C:6]3=[C:2]([Br:1])[N:3]=2)[CH2:13]1
Reactant: Cc1nccn2c(C3CN(C(=O)OCc4ccccc4)C3)nc(Br)c12
Agent: Cl
Product: Cc1nccn2c(C3CNC3)nc(Br)c12
Temperature: 25 °C
Yield: 104.6 %

Procedure:
Benzyl 3-(1-bromo-8-methylimidazo[1,5-a]pyrazin-3-yl)azetidine-1-carboxylate (1.58 g) was dissolved in 37% hydrochloric acid (14.84 ml) and stirred at room temperature. After one hour the reaction mixture was concentrated in vacuo and coevaporated with toluene. Then the residue was dissolved in dichloromethane/methanol, 15 gram of Silica-carbonate (0.77 mmol/gram) was added and the suspension was stirred for 15 minutes. The suspension was filtered, the solids rinsed with methanol and the filtrate was concentrated in vacuo to give crude 3-(azetidin-3-yl)-1-bromo-8-methylimidazo[1,5-a]pyrazine (1.1 g).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:18]=[C:19]([CH3:21])[CH:20]=1)[O:5][CH2:6][C:7]([NH:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][C:15]([OH:17])=[O:16])=[O:8].[N+:22]([C:25]1[CH:26]=[C:27]([S:31]([CH2:34][CH2:35]O)(=[O:33])=[O:32])[CH:28]=[CH:29][CH:30]=1)([O-:24])=[O:23].O.C1(C)C=CC(S(O)(=O)=O)=CC=1.O>C1(C)C=CC=CC=1>[N+:22]([C:25]1[CH:26]=[C:27]([S:31]([CH2:34][CH2:35][O:16][C:15](=[O:17])[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][NH:9][C:7](=[O:8])[CH2:6][O:5][C:4]2[CH:18]=[C:19]([CH3:21])[CH:20]=[C:2]([CH3:1])[CH:3]=2)(=[O:33])=[O:32])[CH:28]=[CH:29][CH:30]=1)([O-:24])=[O:23]
Reactant: O=[N+]([O-])c1cccc(S(=O)(=O)CCO)c1
Reactant: Cc1cc(C)cc(OCC(=O)NCCCCCC(=O)O)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: Cc1cc(C)cc(OCC(=O)NCCCCCC(=O)OCCS(=O)(=O)c2cccc([N+](=O)[O-])c2)c1
Yield: 94.8 %

Procedure:
A mixture of 6-[2-(3,5-dimethyl-phenoxy)acetylamino]hexanoic acid (Intermediate 15, 3.0 g, 10.2 mmol), 2-(m-nitrobenzenesulfonyl)ethanol (available from Aldrich 2.3 g, 10.0 mmol), and p-toluenesulfonic acid hydrate (0.5 g) in 100 mL of toluene was refluxed overnight with Dean-Stark trap. Then water was added and the mixture was extracted with CH2Cl2. The combined organic layers were washed with saturated NaHCO3 solution two times, dried over anhydrous MgSO4, and concentrated under reduced pressure. The resulting residual oil was purified by column chromatography (1% MeOH in CH2Cl2) to give Intermediate 16 (4.8 g, 89%) as a yellowish thick oil.
Reaction SMILES: I.[CH3:2][NH:3][C:4](=[NH:7])[S:5][CH3:6].[CH:8]1([N:14]([C:18](Cl)=[O:19])[C:15](Cl)=[O:16])[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1>>[CH:8]1([N:14]2[C:18](=[O:19])[NH:7][CH:4]([S:5][CH3:6])[N:3]([CH3:2])[C:15]2=[O:16])[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1
Reactant: CNC(=N)SC
Reactant: O=C(Cl)N(C(=O)Cl)C1CCCCC1
Agent: I
Product: CSC1NC(=O)N(C2CCCCC2)C(=O)N1C

Procedure:
Analogously to Example 24, N,S-dimethyl-isothiourea hydroiodide and N-cyclohexyl-bis-(chlorocarbonyl)-amine (prepared analogously to Synthesis 1970, pages 542-543; boiling point 80°-82° C/0.3 mm Hg) yielded 1-cyclohexyl-3-methyl-4-methylmercapto-tetrahydro-1,3,5-triazine-2,6-dione as a colorless powder of melting point 135°-137° C.
Reaction SMILES: [Al+3].[Cl-].[Cl-].[Cl-].[N+](C)([O-])=O.[CH3:9][O:10][C:11]1[CH:16]=[N:15][C:14]([N:17]2[CH:21]=[N:20][C:19]([NH:22][C:23](=[O:28])[C:24]([CH3:27])([CH3:26])[CH3:25])=[N:18]2)=[C:13]2[NH:29][CH:30]=[CH:31][C:12]=12.Cl[C:33](=[O:38])[C:34]([O:36][CH3:37])=[O:35]>C(Cl)Cl>[CH3:9][O:10][C:11]1[CH:16]=[N:15][C:14]([N:17]2[CH:21]=[N:20][C:19]([NH:22][C:23](=[O:28])[C:24]([CH3:27])([CH3:26])[CH3:25])=[N:18]2)=[C:13]2[NH:29][CH:30]=[C:31]([C:33](=[O:38])[C:34]([O:36][CH3:37])=[O:35])[C:12]=12
Reactant: COC(=O)C(=O)Cl
Reactant: COc1cnc(-n2cnc(NC(=O)C(C)(C)C)n2)c2[nH]ccc12
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Solvent: C[N+](=O)[O-]
Product: COC(=O)C(=O)c1c[nH]c2c(-n3cnc(NC(=O)C(C)(C)C)n3)ncc(OC)c12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 34.9 %

Procedure:
To an oven-dried flask in ice bath was added AlCl3 (382 mg, 2.86 mmol), then CH2Cl2 (4 mL) was introduced at 0° C. Nitromethane (10.84 μL, 0.201 mmol) was added at that temperature. Ice bath was removed and the mixture was stirred at room temperature for 30 min. N-(1-(4-methoxy-1H-pyrrolo[2,3-c]pyridin-7-yl)-1H-1,2,4-triazol-3-yl)pivalamide (90 mg, 0.286 mmol) and methyl 2-chloro-2-oxoacetate (0.079 mL, 0.859 mmol) were added at 0° C. The reaction mixture was stirred for three hours at room temperature. The reaction mixture was quenched with ammonium acetate (8 mL) and extracted with ethyl acetate (3×10 mL). The organic layer was washed with brine, dried over MgSO4, filtered and concentrated under reduced pressure to afford methyl 2-(4-methoxy-7-(3-pivalamido-1H-1,2,4-triazol-1-yl)-1H-pyrrolo[2,3-c]pyridin-3-yl)-2-oxoacetate (40 mg, 45%) as white solid.
Reaction SMILES: [CH:1]1([N:4]([CH2:18][C:19](O)=[O:20])[S:5]([C:8]2[C:13]([CH3:14])=[CH:12][C:11]([O:15][CH3:16])=[CH:10][C:9]=2[CH3:17])(=[O:7])=[O:6])[CH2:3][CH2:2]1.[NH2:22][C:23]1[C:32]([NH2:33])=[CH:31][CH:30]=[CH:29][C:24]=1[C:25]([O:27][CH3:28])=[O:26].CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C>>[NH2:22][C:23]1[C:32]([NH:33][C:19](=[O:20])[CH2:18][N:4]([CH:1]2[CH2:2][CH2:3]2)[S:5]([C:8]2[C:13]([CH3:14])=[CH:12][C:11]([O:15][CH3:16])=[CH:10][C:9]=2[CH3:17])(=[O:6])=[O:7])=[CH:31][CH:30]=[CH:29][C:24]=1[C:25]([O:27][CH3:28])=[O:26]
Reactant: COC(=O)c1cccc(N)c1N
Reactant: COc1cc(C)c(S(=O)(=O)N(CC(=O)O)C2CC2)c(C)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)c1cccc(NC(=O)CN(C2CC2)S(=O)(=O)c2c(C)cc(OC)cc2C)c1N
Yield: 75 %

Procedure:
2-(N-Cyclopropyl-4-methoxy-2,6-dimethylphenylsulfonamido)acetic acid was reacted with methyl 2,3-diaminobenzoate (1.3 eq.) in the presence of EDCl (1 eq.), HOBT (1 eq.) and DIPEA (10 eq.) and the desired product thereby formed was employed directly in the next stage without further working up. Yield: 75%
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][CH2:10]O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(Br)(Br)(Br)[Br:13].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>ClCCl>[Br:13][CH2:10][CH2:9][CH2:8][CH2:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: BrC(Br)(Br)Br
Reactant: OCCCCc1ccccc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: BrCCCCc1ccccc1
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 99.9 %

Procedure:
15.0 g (0.1 mol) 4-phenylbutanol and 39.8 g (0.12 mol) carbontetrabromide were dissolved in 500 ml dry dichloromethane and cooled to 0° C., 36.7 g (0.14 mol) triphenylphosphine was then added and the mixture stirred 1.5 hours under argon at 0° C. then evaporated in vacuo. The resulting mixture was stirred in ether-hexane (1:1) and filtered to remove insoluble material. The filtrate was then passed through a pad of silica gel and concentrated to give a pale yellow liquid 21.3 g.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[CH2:7]1[CH2:11][O:10][CH2:9][CH2:8]1>>[CH:11]12[O:10][CH:9]([CH:8]([CH2:9][OH:10])[CH2:7]1)[CH:8]=[CH:7]2
Reactant: C1CCOC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Product: OCC1CC2C=CC1O2
Temperature: 25 °C
Reaction time: 12 h

Procedure:
A solution of methyl 7-oxanorborn-2-en-5-ylcarbonate (16.163 g, 105 mmol, see Example 1) in THF (75 ml) was added dropwise with stirring and under nitrogen to a suspension of lithium aluminium hydride (4.376 g, 115 mmol) in anhydrous THF (100 ml), in such a way that the solution boiled gently. The reaction mixture was subsequently stirred at room temperature for another 12 h and then quenched by cautiously adding an ice-water mixture. The organic phase was removed and the aqueous phase extracted with ethyl acetate (3×200 ml). The combined organic phases were washed with water (600 ml) and saturated sodium chloride solution (600 ml), dried over sodium sulphate and concentrated under reduced pressure.
Reaction SMILES: COP([CH2:7][C:8]1[S:16][C:15]2[C:14]([N:17]3[CH2:22][CH2:21][O:20][CH2:19][CH2:18]3)=[N:13][C:12]([Cl:23])=[N:11][C:10]=2[CH:9]=1)(=O)OC.[Li+].C[Si]([N-][Si](C)(C)C)(C)C.[C:34]([O:38][C:39]([N:41]1[CH2:44][C:43](=O)[CH2:42]1)=[O:40])([CH3:37])([CH3:36])[CH3:35]>C1COCC1>[C:34]([O:38][C:39]([N:41]1[CH2:44][C:43](=[CH:7][C:8]2[S:16][C:15]3[C:14]([N:17]4[CH2:18][CH2:19][O:20][CH2:21][CH2:22]4)=[N:13][C:12]([Cl:23])=[N:11][C:10]=3[CH:9]=2)[CH2:42]1)=[O:40])([CH3:37])([CH3:35])[CH3:36]
Reactant: CC(C)(C)OC(=O)N1CC(=O)C1
Reactant: COP(=O)(Cc1cc2nc(Cl)nc(N3CCOCC3)c2s1)OC
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CC(=Cc2cc3nc(Cl)nc(N4CCOCC4)c3s2)C1
Reaction time: 0.5 h
Yield: 63.7 %

Procedure:
To a suspension of (2-chloro-4-morpholin-4-ylthieno[3,2-d]pyrimidin-6-ylmethyl)phosphonic acid dimethyl ester (3.0 g, 7.94 mmol) in THF (150 mL) at −78° C. was added LiHMDS (8.8 mL, 8.80 mmol, 1M solution in THF) and the resulting mixture stirred for 30 min then warmed to r.t. before the addition of a solution of 3-oxo-azetidine-1-carboxylic acid tert-butyl ester (1.51 g, 8.82 mmol) in THF (20 mL) The reaction mixture was stirred at r.t. for 16 h then quenched with H2O and MeOH and concentrated in vacuo. The resulting residue was purified by column chromatography (Si—PCC, EtOAc:DCM, 5-100%) affording the title compound as a yellow solid (2.14 g, 63%). LCMS (method A): RT 3.97 min [M+H]+ 423.3
Reaction SMILES: [OH-].[Na+].[F:3][C:4]1[C:13]([N:14](S(CCC)(=O)=O)[S:15]([CH2:18][CH2:19][CH3:20])(=[O:17])=[O:16])=[CH:12][CH:11]=[C:10]([F:27])[C:5]=1[C:6]([O:8]C)=[O:7]>C1COCC1.CO>[F:3][C:4]1[C:13]([NH:14][S:15]([CH2:18][CH2:19][CH3:20])(=[O:16])=[O:17])=[CH:12][CH:11]=[C:10]([F:27])[C:5]=1[C:6]([OH:8])=[O:7]
Reactant: CCCS(=O)(=O)N(c1ccc(F)c(C(=O)OC)c1F)S(=O)(=O)CCC
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CCCS(=O)(=O)Nc1ccc(F)c(C(=O)O)c1F
Temperature: 25 °C
Reaction time: 8 h
Yield: 76.5 %

Procedure:
A 1N aqueous NaOH solution (150 mL, 150 mmol) was added to a solution of methyl 2,6-difluoro-3-(N-(propylsulfonyl)propylsulfonamido)benzoate (20.0 g, 50.1 mmol) in 4:1 THF/MeOH (250 mL, 0.2M). The reaction mixture was stirred at room temperature overnight. The majority of the organic solvents were then removed in vacuo (water bath temperature 35° C.). 1N HCl (150 mL) was slowly added to the mixture, and the resulting solid was filtered and rinsed with water (4×50 mL). The material was then washed with Et2O (4×15 mL) to give 2,6-difluoro-3-(propylsulfonamido)benzoic acid as a solid (10.7 g, 77% yield). 1H NMR (400 MHz, d6-DMSO) δ 9.74 (s, 1H), 7.57-7.50 (m, 1H), 7.23-7.17 (m, 1H), 3.11-3.06 (m, 2H), 1.79-1.69 (m, 2H), 0.98 (t, J=7.4 Hz, 3H). m/z (APCI-neg) M−1=278.0.