Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[C:18]2[CH:17]=[C:16]([C:19]#[N:20])[CH:15]=[CH:14][C:13]=2[C:12]2[NH:21][N:22]=[C:23]([NH:24][CH:25]3[CH2:30][CH2:29][N:28]([S:31]([CH3:34])(=[O:33])=[O:32])[CH2:27][CH2:26]3)[C:11]=2[N:10]=1.CO.[NH2:37][OH:38].Cl>O.C(N(CC)CC)C.C1COCC1>[F:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[C:3]=1[C:9]1[C:18]2[CH:17]=[C:16]([C:19](=[NH:20])[NH:37][OH:38])[CH:15]=[CH:14][C:13]=2[C:12]2[NH:21][N:22]=[C:23]([NH:24][CH:25]3[CH2:30][CH2:29][N:28]([S:31]([CH3:34])(=[O:32])=[O:33])[CH2:27][CH2:26]3)[C:11]=2[N:10]=1
Reactant: CS(=O)(=O)N1CCC(Nc2n[nH]c3c2nc(-c2c(F)cccc2F)c2cc(C#N)ccc23)CC1
Reactant: NO
Agent: Cl
Solvent: O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CS(=O)(=O)N1CCC(Nc2n[nH]c3c2nc(-c2c(F)cccc2F)c2cc(C(=N)NO)ccc23)CC1
Temperature: 65 °C
Yield: 30.3 %

Procedure:
A 10 ml round-bottomed flask is charged with 30 mg of 5-(2,6-difluorophenyl)-3-{[1-(methylsulphonyl)piperidin-4-yl]amino}-1H-pyrazolo[4,3-c]isoquinoline-7-carbonitrile, prepared in example 12, 1.3 ml of methanol, 0.8 ml of THF and 62 mg of triethylamine. 44 mg of hydroxylamine as the hydrochloride are added. The mixture is heated at 65° C. for 3 h and then evaporated under RP. The solid obtained is taken up in 10 ml of water and extracted with AcOEt. The organic phase is dried over MgSO4, filtered and concentrated under RP. It is purified by flash chromatography on silica gel (15-40 μm), eluting with DCM and then with a DCM/methanol mixture (80/20 by vol.), to give 9.7 mg of 5-(2,6-difluorophenyl)-N-hydroxy-3-{[1-(methylsulphonyl)piperidin-4-yl]amino}-1H-pyrazolo[4,3-c]isoquinoline-7-carboximidamide in the form of a yellow solid. 1H NMR (300 MHz, DMSO-d6) δ ppm 1.67 (m, 2 H) 2.11 (m, 2 H) 2.91 (m, 2 H) 2.87 (s, 3 H) 3.56 (m, 2 H) 3.79 (m, 1 H) 5.95 (broad s, 2 H) 6.03 (d, J=7.9 Hz, 1 H) 7.31 (m, 2 H) 7.66 (m, 1 H) 7.95 (broad s, 1 H) 8.18 (dd, J=8.5, 1,6 Hz, 1H) 8.39 (d, J=8.5 Hz, 1 H) 9.82 (s, 1 H) 12.76 (s, 1H). LC-MS-DAD-ELSD: 516 (+)=(M+H)(+).
Reaction SMILES: C(O[C:4]1[C:5](=[O:17])[C:6](=[O:16])[C:7]=1[NH:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[OH:15])C.[CH2:18]([C:20]1[CH:26]=[CH:25][CH:24]=[CH:23][C:21]=1[NH2:22])[CH3:19]>CS(C)=O>[CH2:18]([C:20]1[CH:26]=[CH:25][CH:24]=[CH:23][C:21]=1[NH:22][C:4]1[C:5](=[O:17])[C:6](=[O:16])[C:7]=1[NH:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[OH:15])[CH3:19]
Reactant: CCc1ccccc1N
Reactant: CCOc1c(Nc2ccccc2O)c(=O)c1=O
Solvent: CS(C)=O
Product: CCc1ccccc1Nc1c(Nc2ccccc2O)c(=O)c1=O
Temperature: 110 °C
Reaction time: 8 h

Procedure:
To a solution of 3-ethoxy-4-(2-hydroxyanilino)-cyclobut-3-ene-1,2-dione (50 mg, 0.21 mmol) in DMSO (1.5 mL) was added 2-ethylaniline (0.024 mL, 0.21 mmol) and reaction was stirred at 110° C. overnight. Reaction was purified on HPLC (acetonitrile:water) and product was concentrated down. Solid was dried in vacuo. LC-MS (m/z) 309 (M+).
Reaction SMILES: [CH2:1](Br)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH:9][C:10]1[CH:11]=[C:12]([CH:15]=[CH:16][C:17]=1[O:18][CH2:19][C:20]1[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=1)[CH:13]=[O:14].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C=O>[CH3:27][O:26][C:23]1[CH:24]=[CH:25][C:20]([CH2:19][O:18][C:17]2[CH:16]=[CH:15][C:12]([CH:13]=[O:14])=[CH:11][C:10]=2[O:9][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[CH:21][CH:22]=1
Reactant: COc1ccc(COc2ccc(C=O)cc2O)cc1
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: COc1ccc(COc2ccc(C=O)cc2OCc2ccccc2)cc1
Reaction time: 8 h
Yield: 71.4 %

Procedure:
Benzyl bromide (13.56 mL, 0.11 mol, 1.1 eq) was added to a solution of 3-hydroxy-4-[(4-methoxyphenyl)methoxy]benzaldehyde (26.91 g, 0.10 mL, 1 eq) and cesium carbonate (20.37 g, 0.06 mol, 0.6 eq) in N,N-dimethylformamide (150 mL). The reaction mixture was stirred overnight and then concentrated in vacuo. The residual solution was diluted with ethyl acetate (200 mL) and washed with water (200 mL), saturated sodium chloride solution (3×200 mL), and 0.5M aqueous sodium hydroxide (3×200 mL), then dried over sodium sulfate and evaporated in vacuo. This gave a gummy solid which was recrystallized from ethyl acetate and petroleum ether to give the product as a pale brown powder (25.93 g, 71%). 1H NMR (CDCl3) δ 9.81 (s, 1H, O═C—H), 5.21 (s, 2H, CH2Ar), 5.20 (s, 2H, CH2Ar), 3.84 (s, 3H, OCH3).
Reaction SMILES: FC(F)(F)OC1C=CC(CN)=CC=1.FC1C=C(C=CC=1[N+]([O-])=O)OCC1C=CN(C)N=1.[CH3:32][N:33]1[CH:37]=[CH:36][C:35]([CH2:38][O:39][C:40]2[CH:45]=[C:44]([NH:46][CH2:47][C:48]3[CH:53]=[CH:52][C:51]([O:54][C:55]([F:58])([F:57])[F:56])=[CH:50][CH:49]=3)[C:43]([NH2:59])=[CH:42][CH:41]=2)=[N:34]1.[CH3:60][C:61]1([CH3:69])[C@@H:66]2[C@H:62]1[C:63](=[O:68])[O:64][C:65]2=O>>[CH3:60][C:61]1([CH3:69])[C@H:66]([C:65]2[N:46]([CH2:47][C:48]3[CH:53]=[CH:52][C:51]([O:54][C:55]([F:56])([F:57])[F:58])=[CH:50][CH:49]=3)[C:44]3[CH:45]=[C:40]([O:39][CH2:38][C:35]4[CH:36]=[CH:37][N:33]([CH3:32])[N:34]=4)[CH:41]=[CH:42][C:43]=3[N:59]=2)[C@@H:62]1[C:63]([OH:68])=[O:64]
Reactant: Cn1ccc(COc2ccc(N)c(NCc3ccc(OC(F)(F)F)cc3)c2)n1
Reactant: CC1(C)[C@@H]2C(=O)OC(=O)[C@@H]21
Agent: Cn1ccc(COc2ccc([N+](=O)[O-])c(F)c2)n1
Agent: NCc1ccc(OC(F)(F)F)cc1
Product: Cn1ccc(COc2ccc3nc([C@@H]4[C@H](C(=O)O)C4(C)C)n(Cc4ccc(OC(F)(F)F)cc4)c3c2)n1

Procedure:
The title compound was prepared using analogous conditions described for Example 1 using (4-(trifluoromethoxy)phenyl)methanamine and 3-((3-fluoro-4-nitrophenoxy)methyl)-1-methyl-1H-pyrazole in Step A then for Intermediate I using 5-((1-methyl-1H-pyrazol-3-yl)methoxy)-N1-(4-(trifluoromethoxy)benzyl)benzene-1,2-diamine and cis-6,6-dimethyl-3-oxabicyclo[3.1.0]hexane-2,4-dione followed by the hydrolysis according to Example Example 111. MS (ESI): mass calcd. for C26H25F3N4O4, 514.18; m/z found, 515.1 [M+H]+. 1H NMR (400 MHz, CDCl3) δ 7.60 (d, J=8.9, 1H), 7.33 (d, J=2.2, 1H), 7.21 (d, J=8.1, 2H), 7.09 (d, J=8.8, 2H), 7.06 (dd, J=8.9, 2.3, 1H), 6.94 (d, J=2.2, 1H), 6.31 (d, J=2.2, 1H), 5.39 (d, J=16.9, 1H), 5.31 (d, J=16.9, 1H), 5.09 (s, 2H), 3.86 (s, 3H), 2.31 (d, J=8.2, 1H), 2.04 (d, J=8.3, 1H), 1.20 (s, 3H), 0.97 (s, 3H).
Reaction SMILES: [CH2:1](Br)[C:2]1C=CC=C[CH:3]=1.[Cl:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[NH:21][C:20](=[O:22])[C:19]([C:23]([O:25][CH3:26])=[O:24])=[CH:18][C:17]=2[C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[CH:12][CH:11]=1>>[CH2:3]([O:22][C:20]1[C:19]([C:23]([O:25][CH3:26])=[O:24])=[CH:18][C:17]([C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)=[C:16]([C:13]2[CH:12]=[CH:11][C:10]([Cl:9])=[CH:15][CH:14]=2)[N:21]=1)[CH:2]=[CH2:1]
Reactant: COC(=O)c1cc(-c2ccccc2)c(-c2ccc(Cl)cc2)[nH]c1=O
Reactant: BrCc1ccccc1
Product: C=CCOc1nc(-c2ccc(Cl)cc2)c(-c2ccccc2)cc1C(=O)OC

Procedure:
Using essentially the same procedure as in Example 1, Step E, but substituting allyl bromide for benzyl bromide, methyl 6-(4-chlorophenyl)-5-(phenyl)-2-oxo-1,2-dihydropyridine-3-carboxylate (500 mg, 1.47 mmol) from Example 1, Step D afforded the desired higher Rf O-alkylation title compound after purification by flash column chromatography on silica gel (eluted with a gradient of 5 to 10% ethyl acetate in hexanes). HPLC/MS: 380 (M+1); Rt=4.7 min. 1HNMR (CDCl3): δ 3.954 (s, 3H), 5.09 (br d, J=5 Hz, 2H), 5.32 (dd, J=1.5 and 10.5 Hz, 1H), 5.45 (br dd, J=1.6 and 18 Hz, 1H), 6.13-6.23 (m, 1H), 7.16-7.21 (m, 2H), 7.22 (d, J=8.6 Hz, 2H), 7.30-7.36 (m, 3H), 7.37 (d, J=8.6 Hz, 2H), 8.246 (s, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[O:10][C:11]3[CH:27]=[CH:26][C:25]([NH:28]C(=O)C)=[CH:24][C:12]=3[C:13](=[O:23])[C:14]=2[O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[CH:5][CH:4]=1.[ClH:32].[K+].[Br-]>C(Cl)(Cl)Cl.CO>[ClH:32].[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:9]2[O:10][C:11]3[CH:27]=[CH:26][C:25]([NH2:28])=[CH:24][C:12]=3[C:13](=[O:23])[C:14]=2[O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[CH:7][CH:8]=1
Reactant: COc1ccc(-c2oc3ccc(NC(C)=O)cc3c(=O)c2OCc2ccccc2)cc1
Agent: Cl
Agent: [Br-]
Agent: [K+]
Solvent: ClC(Cl)Cl
Solvent: CO
Product: COc1ccc(-c2oc3ccc(N)cc3c(=O)c2OCc2ccccc2)cc1
Yield: 54 %

Procedure:
Prepared analogously to Example 5c) starting from 2-(4-methoxyphenyl)-3-benzyloxy-6-acetamido-4H-1-benzopyran-4-one. Yield: 54%; TLC (9/1 Chloroform/Methanol) Rf: 0.60; Elem. anal. C23H19NO4*HCl; theory C, 67.40; H, 4.92; N, 3.42. found C, 64.24; H, 4.73; N, 3.20. IR (KBr): 3433, 2833, 2592, 1629, 1498, 1167 cm−1, 1H-NMR (d6-DMSO): 8.0 (m, 2H), 7.73 (m, 2H), 7.52 (dd, 1H), 7.37-7.22 (m, 5H), 7.10 (m, 2H).
Reaction SMILES: [O:1]=[C:2]1[C:10]2[C:5](=[N:6][C:7]([CH2:11][CH2:12][CH:13]=O)=[CH:8][CH:9]=2)[CH2:4][O:3]1.[CH2:15]([N:17](CC)[CH2:18][CH2:19]NC)[CH3:16]>>[CH2:15]([N:17]([CH2:18][CH3:19])[CH2:13][CH2:12][CH2:11][C:7]1[N:6]=[C:5]2[CH2:4][O:3][C:2](=[O:1])[C:10]2=[CH:9][CH:8]=1)[CH3:16]
Reactant: CCN(CC)CCNC
Reactant: O=CCCc1ccc2c(n1)COC2=O
Product: CCN(CC)CCCc1ccc2c(n1)COC2=O
Yield: 75.5 %

Procedure:
In a process similar to that described in Preparation 8, 3-(5-Oxo-5,7-dihydro-furo[3,4-b]pyridin-2-yl)-propionaldehyde (61 mg, 0.32 mmol) and N,N-diethyl-N′-methylethylenediamine (33 μL, 0.32 mmol) are reacted to provide the title compound as white solid (60 mg, 76%).
Reaction SMILES: Cl[C:2]1[C:6]2[C:7]([O:11][CH:12]([F:14])[F:13])=[CH:8][CH:9]=[CH:10][C:5]=2[S:4](=[O:16])(=[O:15])[N:3]=1.[CH:17]([NH2:20])([CH3:19])[CH3:18]>C1COCC1>[F:13][CH:12]([F:14])[O:11][C:7]1[C:6]2[C:2]([NH:20][CH:17]([CH3:19])[CH3:18])=[N:3][S:4](=[O:16])(=[O:15])[C:5]=2[CH:10]=[CH:9][CH:8]=1
Reactant: O=S1(=O)N=C(Cl)c2c(OC(F)F)cccc21
Reactant: CC(C)N
Solvent: C1CCOC1
Product: CC(C)NC1=NS(=O)(=O)c2cccc(OC(F)F)c21
Temperature: 0 °C
Reaction time: 14 h

Procedure:
400 mg (1.5 mmol) 3-Chloro-4-difluoromethoxy-benzo[d]isothiazole 1,1-dioxide were dissolved in 5 ml dry THF and cooled to 0° C. 883 mg (15.0 mmol) isopropylamine was dissolved in 5 ml dry THF and added slowly. Stirring was continued for 1 h at this temperature and for 14 h at room temperature. The mixture was concentrated in vacuum. The residue was purified on silica (eluent: cyclohexane/ethyl acetate 4:1) to afford 140 mg (0.48 mmol; 32% of theory) of the title compound (C.26).
Reaction SMILES: [C:1]([C:3]1[C:4]([C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][C:18]=2[Cl:24])=[C:5]([C:14]([NH2:16])=[O:15])[S:6][C:7]=1[N:8]1[CH2:13][CH2:12][O:11][CH2:10][CH2:9]1)#[N:2].CO[CH:27](OC)[N:28]([CH3:30])[CH3:29]>>[C:1]([C:3]1[C:4]([C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][C:18]=2[Cl:24])=[C:5]([C:14]([N:16]=[CH:27][N:28]([CH3:30])[CH3:29])=[O:15])[S:6][C:7]=1[N:8]1[CH2:9][CH2:10][O:11][CH2:12][CH2:13]1)#[N:2]
Reactant: COC(OC)N(C)C
Reactant: N#Cc1c(N2CCOCC2)sc(C(N)=O)c1-c1ccc(Cl)cc1Cl
Product: CN(C)C=NC(=O)c1sc(N2CCOCC2)c(C#N)c1-c1ccc(Cl)cc1Cl

Procedure:
A mixture of 4-cyano-3-(2,4-dichlorophenyl)-5-morpholin-4-ylthiophene-2-carboxamide (31.6 mg, 0.0000827 mol) in 1,1-dimethoxy-N,N-dimethylmethanamine (1.0 mL, 0.0075 mol) was flushed with argon and then irradiated in microwave at 160° C. for 60 min. The reaction mixture was concentrated to give 4-cyano-3-(2,4-dichlorophenyl)-N-((dimethylamino)methylene)-5-morpholinothiophene-2-carboxamide as intermediate (31 mg, 86%). LCMS: (FA) ES+ 437.13. 1H NMR (400 MHz, d6-DMSO) δ: 8.34 (s, 1H), 7.69 (d, 1H), 7.47 (d, 1H), 7.33 (d, 1H), 3.79-3.74 (m, 4H), 3.59-3.54 (m, 4H), 3.07 (s, 3H), 2.72 (s, 3H). To the above intermediate in AcOH (1.8 mL, 0.032 mol) was added hydrazine hydrate (50 mg, 0.001 mol). The mixture was flushed with argon and then irradiated in microwave at 120° C. for 20 min. The mixture was concentrated to remove most of the solvent. Water was added to the residue and the precipitate was collected, washed with water, dried to afford 4-(2,4-dichlorophenyl)-2-morpholino-5-(4H-1,2,4-triazol-3-yl)thiophene-3-carbonitrile (12.8 mg, 55%). LCMS: (FA) ES+ 406.11, ES− 404.21, 1H NMR (400 MHz, d6-DMSO) δ: 14.00 (s, 1H), 8.43 (s, 1H), 7.74 (d, 1H), 7.49 (d, 1H), 7.41 (d, 1H), 3.82-3.76 (m, 4H), 3.56-3.51 (m, 4H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[N:9]([CH3:11])[CH:8]=[C:7]2[CH:12]=[O:13].P([O-])([O-])(O)=[O:15].[Na+].[Na+].[Mn]([O-])(=O)(=O)=O.[K+].Cl>C(O)(C)(C)C>[F:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[N:9]([CH3:11])[CH:8]=[C:7]2[C:12]([OH:15])=[O:13]
Reactant: O=P([O-])([O-])O
Reactant: Cn1cc(C=O)c2cccc(F)c21
Agent: O=[Mn](=O)(=O)[O-]
Agent: Cl
Agent: [K+]
Solvent: CC(C)(C)O
Product: Cn1cc(C(=O)O)c2cccc(F)c21
Reaction time: 16 h

Procedure:
7-Fluoro-1-methylindole-3-carboxaldehyde (1.0 g) was dissolved in t-butanol (50 ml). 1.25M Sodium hydrogen phosphate (20 ml) was added followed by 1.0M potassium permanganate (30 ml), and the mixture was stirred at 20 for 16h. 2M Hydrochloric acid (200 ml) was then added and the mixture was extracted with ethyl acetate (2×200 ml). The combined, dried organic extracts were evaporated in vacuo to leave a solid which was purified by FCC eluting with hexane:ether (1:1) followed by hexane:ether:acetic acid (50:50:1) to give the title compound (192 mg), m.p. 225°-227°.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:30])[C:4]1[CH:9]=[CH:8][C:7]([C:10]([N:12]2[CH2:17][CH2:16][C:15]([NH:19]C(OCC3C=CC=CC=3)=O)([CH3:18])[CH2:14][CH2:13]2)=[O:11])=[CH:6][CH:5]=1.I[Si](C)(C)C>C(#N)C>[CH3:1][O:2][C:3](=[O:30])[C:4]1[CH:5]=[CH:6][C:7]([C:10]([N:12]2[CH2:13][CH2:14][C:15]([NH2:19])([CH3:18])[CH2:16][CH2:17]2)=[O:11])=[CH:8][CH:9]=1
Reactant: COC(=O)c1ccc(C(=O)N2CCC(C)(NC(=O)OCc3ccccc3)CC2)cc1
Agent: C[Si](C)(C)I
Solvent: CC#N
Product: COC(=O)c1ccc(C(=O)N2CCC(C)(N)CC2)cc1
Temperature: 50 °C
Reaction time: 0.5 h

Procedure:
To a stirred solution of Example 32A (0.2 g, 0.49 mmol) in acetonitrile (4.0 mL) at room temperature was added iodotrimethysilane (0.11 mL, 0.75 mmol). The reaction mixture was stirred at 50° C. for 30 minutes and then concentrated under reduced pressure. The solid residue was washed with acetone and ether and filtered to provide titled compound. MS (CI) m/z 277 (M+1)+; 1H NMR (300 MHz, DMSO-d6) δ ppm 8.04 (d, 2H), 7.90 (bs, 2H NH2-DMSO solvent), 7.50 (d, 2H), 3.88 (s, 3H), 3.35-3.20 (m, 4H), 1.79-1.58 (m, 4H), 1.35 (s, 3H).
Reaction SMILES: [CH2:1]([N:3]([CH2:6][C:7]1[S:11][C:10]([C:12]2[O:16][N:15]=[C:14]([C:17]3[CH:22]=[CH:21][C:20]([CH2:23][CH:24]([OH:27])[CH2:25][OH:26])=[CH:19][CH:18]=3)[N:13]=2)=[CH:9][C:8]=1[CH3:28])[CH2:4][CH3:5])[CH3:2].CCN(C(C)C)C(C)C.[CH3:38][S:39](Cl)(=[O:41])=[O:40]>C1COCC1.C(Cl)Cl>[CH2:1]([N:3]([CH2:6][C:7]1[S:11][C:10]([C:12]2[O:16][N:15]=[C:14]([C:17]3[CH:18]=[CH:19][C:20]([CH2:23][CH:24]([OH:27])[CH2:25][O:26][S:39]([CH3:38])(=[O:41])=[O:40])=[CH:21][CH:22]=3)[N:13]=2)=[CH:9][C:8]=1[CH3:28])[CH2:4][CH3:5])[CH3:2]
Reactant: CCN(CC)Cc1sc(-c2nc(-c3ccc(CC(O)CO)cc3)no2)cc1C
Reactant: CS(=O)(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: C1CCOC1
Product: CCN(CC)Cc1sc(-c2nc(-c3ccc(CC(O)COS(C)(=O)=O)cc3)no2)cc1C
Temperature: 0 °C
Reaction time: 1 h
Yield: 129.3 %

Procedure:
To a cooled (0° C.) solution of rac-3-{4-[5-(5-diethylaminomethyl-4-methyl-thiophen-2-yl)-[1,2,4]oxadiazol-3-yl]-phenyl}-propane-1,2-diol (619 mg, 1.54 mmol) in THF (15 mL), DIPEA (399 mg, 3.08 mmol) followed by methansulfonyl chloride (247 mg, 2.16 mmol) is added. The mixture is stirred at 0° C. for 1 h, then at rt for 1 h. The mixture is diluted with DCM, washed with brine (3×50 mL), dried over MgSO4, filtered, concentrated and dried to give crude rac-methanesulfonic acid 3-{4-[5-(5-diethylaminomethyl-4-methyl-thiophen-2-yl)-[1,2,4]oxadiazol-3-yl]-phenyl}-2-hydroxy-propyl ester (955 mg) as a light brown oil; LC-MS: tR=0.54 min; [M+1]+=480.10. b) A solution of the above rac-methanesulfonic acid 3-{4-[5-(5-diethylaminomethyl-4-methyl-thiophen-2-yl)-[1,2,4]oxadiazol-3-yl]-phenyl}-2-hydroxy-propyl ester (600 mg, 1.33 mmol) in 7 M NH3 in methanol (10 mL) is stirred in a sealed vessel at 80° C. for 16 h. The mixture is diluted with EA and washed with water and brine. The organic extract is dried over MgSO4, filtered and concentrated. The crude product is purified on prep. TLC plates using DCM containing 10% of methanol to give the title compound (242 mg) as a pale yellow resin; LC-MS: tR=0.63 min; [M+1]+=400.93.
Reaction SMILES: [CH2:1]([NH:5][CH2:6][C:7]1[S:8][C:9]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([S:18]([CH3:21])(=[O:20])=[O:19])[CH:13]=2)=[CH:10][CH:11]=1)[CH:2]([CH3:4])[CH3:3].[CH3:22][S:23](Cl)(=[O:25])=[O:24].C(N(CC)C(C)C)(C)C>ClCCl>[CH2:1]([N:5]([CH2:6][C:7]1[S:8][C:9]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([S:18]([CH3:21])(=[O:20])=[O:19])[CH:13]=2)=[CH:10][CH:11]=1)[S:23]([CH3:22])(=[O:25])=[O:24])[CH:2]([CH3:4])[CH3:3]
Reactant: CC(C)CNCc1ccc(-c2cccc(S(C)(=O)=O)c2)s1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)CN(Cc1ccc(-c2cccc(S(C)(=O)=O)c2)s1)S(C)(=O)=O

Procedure:
In analogy to example 13, step 2, isobutyl-[5-(3-methanesulfonyl-phenyl)-thiophen-2-ylmethyl]-amine was reacted with methanesulfonyl chloride in presence of N,N-diisopropyl ethyl amine in dichloromethane to give N-isobutyl-N-[5-(3-methanesulfonyl-phenyl)-thiophen-2-ylmethyl]-methanesulfonamide as a colorless solid. MS: 419.3 ([M+NH4]+)
Reaction SMILES: [Na].[C:2]([O:10][CH2:11][CH3:12])(=[O:9])[CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5].O.[C:14]1([CH3:21])[C:15](C)=CC=[CH:18][CH:19]=1>>[CH2:19]([CH:14]1[CH2:21][C:3]([C:4]([O:6][CH2:7][CH3:8])=[O:5])([C:2]([O:10][CH2:11][CH3:12])=[O:9])[CH2:15]1)[CH3:18]
Reactant: Cc1ccccc1C
Reactant: CCOC(=O)CC(=O)OCC
Agent: [Na]
Solvent: O
Product: CCOC(=O)C1(C(=O)OCC)CC(CC)C1
Temperature: 130 °C
Reaction time: 18 h

Procedure:
Sodium metal (7.6 g, 0.33 g/atom) was dispersed in 50 ml of dry xylene (distilled from sodium hydride) by heating to 130° C. with rapid stirring. Dry xylene (168 ml) and 47.8 g (45.2 ml, 0.298 mole) of diethyl malonate were then added thereto and the mixture was allowed to react at 120° C. To the resultant mixture there was then added 48.1 g (0.116 mole) of 2-ethyl-propyl-1,3-ditosylate (prepared in 1B) dissolved in 120 ml of dry xylene. This reaction mixture was heated to about 150° C. and stirred for 18 hr. The mixture was cooled and poured into 500 ml of water and extracted with 600 ml (3×300 ml) of ether. The aqueous material was made acidic with 10% aqueous HCl and then extracted with 600 ml (2×300 ml) of ether. The combined ether extract was washed with 200 ml of saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, filtered and the solvent was removed in vacuo. Distillation of the product at reduced pressure yielded 7.0 g of the title compound having the following physical characteristics:
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]#[N:10])=[CH:4][C:3]=1[O:11][CH3:12].[CH2:13](Br)[CH2:14][CH2:15][CH3:16].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O.C(OCC)C>[CH2:13]([O:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]#[N:10])=[CH:4][C:3]=1[O:11][CH3:12])[CH2:14][CH2:15][CH3:16]
Reactant: COc1cc(CC#N)ccc1O
Reactant: CCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOCC
Solvent: CC(C)=O
Product: CCCCOc1ccc(CC#N)cc1OC
Temperature: 25 °C
Yield: 104.7 %

Procedure:
A mixture of 15 grams 4-hydroxy-3-methoxyphenylacetonitrile (91.91 mmol), 26.40 ml (33.59 grams) n-butyl bromide (245 mmol) and 21.17 grams potassium carbonate (153.2 mmol) in 150 ml acetone was heated to reflux under nitrogen for 18 hours. After cooling to room temperature, the mixture was diluted with diethyl ether and the inorganic salts were removed by filtration and were washed with diethyl ether. The filtrate and wash solutions were evaporated in vacuo to provide 21.11 grams of Compound 10c as a straw-colored viscous oil (99.9% yield) which was dried in vacuo at 50° C.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH2:8][O:9][CH2:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:3]=1.[C:18]([O:22][C:23]([N:25]1[CH2:28][CH2:27][C@H:26]1[CH2:29][O:30][C:31]1[CH:32]=[N:33][CH:34]=[C:35]([Sn](C)(C)C)[CH:36]=1)=[O:24])([CH3:21])([CH3:20])[CH3:19].[F-].[Cs+]>CN(C=O)C.[Cu]I.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:18]([O:22][C:23]([N:25]1[CH2:28][CH2:27][C@H:26]1[CH2:29][O:30][C:31]1[CH:32]=[N:33][CH:34]=[C:35]([C:2]2[CH:7]=[CH:6][CH:5]=[C:4]([CH2:8][O:9][CH2:10][CH2:11][C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[CH:3]=2)[CH:36]=1)=[O:24])([CH3:21])([CH3:19])[CH3:20]
Reactant: Ic1cccc(COCCc2ccccc2)c1
Reactant: CC(C)(C)OC(=O)N1CC[C@H]1COc1cncc([Sn](C)(C)C)c1
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CC[C@H]1COc1cncc(-c2cccc(COCCc3ccccc3)c2)c1
Temperature: 50 °C
Reaction time: 5 h
Yield: 54.5 %

Procedure:
A solution/suspension of 1-iodo-3-(phenethoxymethyl)benzene (300 mg, 0.89 mmol, 1.0 equiv.), 3-[[1-(tert-butoxycarbonyl)-2(S)-azetidinyl]methoxy]-5-(trimethylstannyl)pyridine (380 mg, 0.89 mmol), CsF (271 mg, 1.78 mmol, 2.0 equiv.), CuI (17 mg, 0.09 mmol, 0.10 equiv.) and Pd(PPh3)4 (46 mg, 0.04 mmol, 0.05 equiv.) in anhydrous DMF (5 mL) was stirred for 5 h at 50° C. under nitrogen. The reaction progress was monitored by TLC (EtOAc/petroleum ether 1:1). The mixture was concentrated under vacuum, the residue was diluted with water and extracted with EtOAc (2×50 mL), and the combined organic layers were dried over Na2SO4. After concentration in vacuo, the residue was applied onto a silica gel column, which was eluted with EtOAc/petroleum ether/Et3N 3:6:0.5 to give the title compound (230 mg, 55%) as a yellow oil. 1H NMR (CDCl3, 300 MHz) δ 8.48 (s, 1H), 8.36 (d, J=2.1 Hz, 1H), 7.53-7.43 (m, 4H), 7.38 (s, 1H), 7.35-7.23 (m, 5H), 4.62 (s, 3H), 4.43 (s, 1H), 4.25 (dd, J=7.5, 3.0 Hz, 1H), 3.94 (t, J=7.5 Hz, 2H), 3.77 (t, J=7.5 Hz, 2H), 2.99 (t, J=7.2 Hz, 2H), 2.43-2.33 (m, 2H), 1.43 (s, 9H). LC-MS (ESI) m/z 475 (M+H+).
Reaction SMILES: Cl[CH2:2][C:3]1[C:8]([CH2:9]Cl)=[CH:7][C:6]([C:11]([F:14])([F:13])[F:12])=[CH:5][N:4]=1.[C:15]1([C:21]([NH2:34])([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>>[F:12][C:11]([F:14])([F:13])[C:6]1[CH:7]=[C:8]2[CH2:9][N:34]([C:21]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)([C:28]3[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=3)[C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=3)[CH2:2][C:3]2=[N:4][CH:5]=1
Reactant: FC(F)(F)c1cnc(CCl)c(CCl)c1
Reactant: NC(c1ccccc1)(c1ccccc1)c1ccccc1
Product: FC(F)(F)c1cnc2c(c1)CN(C(c1ccccc1)(c1ccccc1)c1ccccc1)C2

Procedure:
Prepared in analogy to Example A2(b) from 2,3-Bis-chloromethyl-5-trifluoromethyl-pyridine and triphenylmethylamine. White solid. MS (m/e): 431.3 ([MH+, 100%).