Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:8]1[S:12][C:11]([C:13]2[CH:18]=[C:17]([F:19])[CH:16]=[CH:15][C:14]=2[F:20])=[N:10][C:9]=1[C@H:21]([NH:26][CH2:27][C@H:28]1[C@@H:32]([F:33])[CH2:31][N:30]([C:34]([O:36][CH2:37][C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)=[O:35])[CH2:29]1)[C:22]([CH3:25])([CH3:24])[CH3:23])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)C(C)C)(C)C.[C:53]([O:56][C@@H:57]([CH3:61])[C:58](Cl)=[O:59])(=[O:55])[CH3:54]>ClCCl>[C:53]([O:56][C@@H:57]([CH3:61])[C:58]([N:26]([CH2:27][C@H:28]1[C@@H:32]([F:33])[CH2:31][N:30]([C:34]([O:36][CH2:37][C:38]2[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=2)=[O:35])[CH2:29]1)[C@@H:21]([C:9]1[N:10]=[C:11]([C:13]2[CH:18]=[C:17]([F:19])[CH:16]=[CH:15][C:14]=2[F:20])[S:12][C:8]=1[CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[C:22]([CH3:25])([CH3:24])[CH3:23])=[O:59])(=[O:55])[CH3:54]
Reactant: CC(C)(C)[C@@H](NC[C@@H]1CN(C(=O)OCc2ccccc2)C[C@@H]1F)c1nc(-c2cc(F)ccc2F)sc1Cc1ccccc1
Reactant: CC(=O)O[C@@H](C)C(=O)Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)O[C@@H](C)C(=O)N(C[C@@H]1CN(C(=O)OCc2ccccc2)C[C@@H]1F)[C@@H](c1nc(-c2cc(F)ccc2F)sc1Cc1ccccc1)C(C)(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 74.4 %

Procedure:
to a solution of (3R,4R)-benzyl 3-(((R)-1-(5-benzyl-2-(2,5-difluorophenyl)thiazol-4-yl)-2,2-dimethylpropylamino)methyl)-4-fluoropyrrolidine-1-carboxylate (130 mg, 0.214 mmol) in dichloromethane (2.1 mL, 0.1 M solution) at room temperature was added N,N-diisopropylethylamine (112 μL, 0.64 mmol). (S)-1-Chloro-1-oxopropan-2-yl acetate (54.2 μL, 0.428 mmol) was then added dropwise over 2 min. The resulting solution was stirred at room temperature for 2 h. The reaction mixture was quenched with saturated NaHCO3 solution and extracted with EtOAc. The organic layer was washed with water and brine, dried over anhydrous sodium sulfate and filtered. After the volatile organic materials were removed in vacuo, the crude product was purified on flash column chromatography to yield (3R,4R)-benzyl 3-(((S)-2-acetoxy-N-((R)-1-(5-benzyl-2-(2,5-difluorophenyl)thiazol-4-yl)-2,2-dimethylpropyl)propanamido)methyl)-4-fluoropyrrolidine-1-carboxylate (115 mg, 75%). NMR (CDCl3, 400 MHz): δ 7.85 (1H, m), 7.37-7.24 (7H, m), 7.21 (1H, m), 7.09 (2H, m), 7.05 (1H, m), 6.96 (1H, m), 6.1 (1H, m), 5.4 (2H, m), 5.28 (1H, m), 4.82 (2H, m), 4.19-3.97 (3H, m), 3.70-3.49 (2H, m), 3.13 (1H, m), 2.76 (1H, m), 2.52 (1H, m), 2.18 (3H, s), 1.61 (3H, m), 0.99 (9H, s). LC/MS (uplc): MH+ 722.3, 1.40 min.
Reaction SMILES: [C:1]([C:3]1[CH:15]=[CH:14][C:6]([O:7][CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:5][CH:4]=1)#[CH:2].I[C:17]1[CH:22]=[CH:21][C:20]([OH:23])=[CH:19][CH:18]=1.CCN(C(C)C)C(C)C.[NH4+].[Cl-]>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.[Cu]I.O.CN(C=O)C>[OH:23][C:20]1[CH:21]=[CH:22][C:17]([C:2]#[C:1][C:3]2[CH:15]=[CH:14][C:6]([O:7][CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:5][CH:4]=2)=[CH:18][CH:19]=1
Reactant: C#Cc1ccc(OCC(=O)OCC)cc1
Reactant: Oc1ccc(I)cc1
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cl-]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)COc1ccc(C#Cc2ccc(O)cc2)cc1
Reaction time: 72 h

Procedure:
To a dried Schlenk flask filled with nitrogen was added Pd(PPh3)4 (56.5 mg, 0.049 mmol), CuI (14.2 mg, 0.075 mmol), ethyl 2-(4-ethynylphenoxy)acetate (150.0 mg, 0.734 mmol), and 4-iodophenol (195.3 mg, 0.888 mmol) was added. The flask was evacuated, equipped with a septum, and filled with nitrogen. DMF (10 mL) and DIPEA (0.26 mL, 1.5 mmol) were added through the septum. The reaction was stirred for 3 days and was neutralized with saturated aqueous NH4Cl (5 mL). Water (5 mL) was added and the mixture was extracted with EtOAc (3×10 mL). The combined EtOAc phases was washed with brine, dried over MgSO4, and concentrated under reduced pressure. The product was purified with dry column vacuum chromatography (EtOAc:hexanes 1:90→90:1 v/v). The final product was white and solid (129.6 mg, 60%) Rf=0.48 (EtOAc:hexanes 1:1 v/v). 1H-NMR (DMSO-d6): □ 1.21 (t, 3H, J=7.2 Hz, CH2CH3); 4.17 (q, 2H, J=7.1 Hz, CH2CH3); 4.82 (s, 2H, OCH2); 6.78 (d, 2H, J=8.7 Hz, Ph); 6.95 (d, 2H, J=9.0 Hz, Ph); 7.34 (d, 2H, J=8.7 Hz, Ph); 7.43 (d, 2H, J=8.7 Hz, Ph); 9.67 (s, 1H, OH). 13C-NMR (DMSO-d6): □ 14.0 (CH2CH3); 60.7 (CH2CH3); 64.7 (OCH2); 87.1 (CC); 88.6 (CC); 112.8, 114.9, 115.6, 115.7, 132.6, 132.8, 157.5, 157.8 (Ph); 168.5 (COO). MALDI-MS: m/z calculated for C18H16O3 [M]+ 296.1043. found 296.1046.
Reaction SMILES: [N:1]1([C:6]2[CH:7]=[CH:8][C:9]([N+:18]([O-])=O)=[C:10]([N:12]3[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]3)[CH:11]=2)[CH:5]=[CH:4][N:3]=[CH:2]1>C1COCC1.O>[N:1]1([C:6]2[CH:7]=[CH:8][C:9]([NH2:18])=[C:10]([N:12]3[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]3)[CH:11]=2)[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: O=[N+]([O-])c1ccc(-n2ccnc2)cc1N1CCCCC1
Solvent: O
Solvent: C1CCOC1
Product: Nc1ccc(-n2ccnc2)cc1N1CCCCC1
Reaction time: 0.17 h
Yield: 66 %

Procedure:
To 1-(5-imidazol-1-yl-2-nitro-phenyl)-piperidine (117 mg, 0.430 mmol, as prepared in the previous step) in 3 mL of THF was added 6.5 mL of 10% TiCl3 in H2O dropwise over 3 min. After 10 min, the reaction was extracted with 20 mL of EtOAc, and the organic layer was discarded. The aqueous layer was basified with 10M NaOH to pH>9, then extracted with EtOAc (3×20 mL). The combined organic layers were washed with brine (20 mL), dried (Na2SO4), and concentrated in vacuo to afford 74 mg (66%) of the title compound as a light brown solid. Mass spectrum (ESI, m/z): Calcd. for C14H18N4, 243.1 (M+H), found 243.2;
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:14])[CH2:5][C:6]1[CH:11]=[C:10]([OH:12])[CH:9]=[C:8]([F:13])[CH:7]=1)[CH3:2].[Br:15][C:16]1[CH:17]=[CH:18][C:19](F)=[C:20]([CH:23]=1)[CH:21]=[O:22]>>[CH2:1]([O:3][C:4](=[O:14])[CH2:5][C:6]1[CH:7]=[C:8]([F:13])[CH:9]=[C:10]([O:12][C:19]2[CH:18]=[CH:17][C:16]([Br:15])=[CH:23][C:20]=2[CH:21]=[O:22])[CH:11]=1)[CH3:2]
Reactant: O=Cc1cc(Br)ccc1F
Reactant: CCOC(=O)Cc1cc(O)cc(F)c1
Product: CCOC(=O)Cc1cc(F)cc(Oc2ccc(Br)cc2C=O)c1

Procedure:
Prepared according to the procedure described in Example 24, Step 4, using the following starting materials: (3-fluoro-5-hydroxy-phenyl)-acetic acid ethyl ester and 5-bromo-2-fluorobenzaldehyde.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:26]=[C:11]3[N:12]=[C:13]([CH3:25])[C:14]([C:19](=[O:24])[C:20]([O:22][CH3:23])=[O:21])=[C:15]([CH:16]([CH3:18])[CH3:17])[N:10]3[N:9]=2)[CH:5]=[CH:6][CH:7]=1.CB1N2CCC[C@@H]2C(C2C=CC=CC=2)(C2C=CC=CC=2)O1.C1(C)C=CC=CC=1.C1COCC1>C1(C)C=CC=CC=1.CCOC(C)=O.C([O-])([O-])=O.[Na+].[Na+]>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:26]=[C:11]3[N:12]=[C:13]([CH3:25])[C:14]([C@H:19]([OH:24])[C:20]([O:22][CH3:23])=[O:21])=[C:15]([CH:16]([CH3:18])[CH3:17])[N:10]3[N:9]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)C(=O)c1c(C)nc2cc(-c3cccc(Cl)c3)nn2c1C(C)C
Agent: CB1OC(c2ccccc2)(c2ccccc2)[C@H]2CCCN12
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COC(=O)[C@@H](O)c1c(C)nc2cc(-c3cccc(Cl)c3)nn2c1C(C)C
Temperature: -35 °C
Reaction time: 0.5 h
Yield: 66.8 %

Procedure:
To a stirred yellow solution of methyl 2-(2-(3-chlorophenyl)-7-isopropyl-5-methylpyrazolo[1,5-a]pyrimidin-6-yl)-2-oxoacetate (0.103 g, 0.277 mmol) in anhydrous toluene (5 mL) was added 1.1M (R)-1-methyl-3,3-diphenylhexahydropyrrolo[1,2-c][1,3,2]oxazaborole/toluene (0.101 ml, 0.111 mmol). The mixture was cooled to −35° C. and a solution of 1M catechoborane/THF (0.388 ml, 0.388 mmol) was added over 10 min. After 30 min, the reaction mixture was slowly warmed to −15 C and diluted with EtOAc (5 mL) and sat. Na2CO3 (2 mL). The mixture was stirred vigorously for 30 min, and the organic phase washed with sat Na2CO3 (2×5 mL), dried (Na2SO4), filtered, concentrated and the residue was purified by prep-HPLC to give (S)-methyl 2-(2-(3-chlorophenyl)-7-isopropyl-5-methylpyrazolo[1,5-a]pyrimidin-6-yl)-2-hydroxyacetate (0.0693 g, 0.185 mmol, 66.9% yield) as white solid. 1H NMR (500 MHz, CDCl3) δ: 7.99 (t, J=1.5 Hz, 1H), 7.86 (dt, J=7.4, 1.5 Hz, 1H), 7.41-7.33 (m, 2H), 6.80 (s, 1H), 5.63 (s, 1H), 3.81 (s, 3H), 3.40 (br. s., 1H), 2.62 (s, 3H), 1.68 (d, J=7.0 Hz, 3H), 1.59 (d, J=7.0 Hz, 3H). LCMS (M+H) calcd for C19H21ClN3O3: 374.13. found: 374.2.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[CH:10]=[N:9][C:8]([NH:12][C:13]1[N:14]=[CH:15][C:16]([C:19]#[N:20])=[N:17][CH:18]=1)=[CH:7]2.[NH2:21][CH2:22][CH2:23][N:24]1[CH2:29][CH2:28][O:27][CH2:26][CH2:25]1>>[O:27]1[CH2:28][CH2:29][N:24]([CH2:23][CH2:22][NH:21][C:2]2[CH:3]=[CH:4][CH:5]=[C:6]3[C:11]=2[CH:10]=[N:9][C:8]([NH:12][C:13]2[N:14]=[CH:15][C:16]([C:19]#[N:20])=[N:17][CH:18]=2)=[CH:7]3)[CH2:25][CH2:26]1
Reactant: NCCN1CCOCC1
Reactant: N#Cc1cnc(Nc2cc3cccc(Br)c3cn2)cn1
Product: N#Cc1cnc(Nc2cc3cccc(NCCN4CCOCC4)c3cn2)cn1

Procedure:
The title compound was prepared using methods analogous to those described in Synthesis 5-1, replacing 3,8-dichloroisoquinoline with 5-(8-bromoisoquinolin-3-ylamino)pyrazine-2-carbonitrile and replacing (R)-5-amino-3-(pyrrolidin-3-yloxy)pyrazine-2-carbonitrile with N-(2-aminoethyl)morpholine, and conducting the reaction at 140° C.
Reaction SMILES: [CH2:1]=[C:2]1[CH2:5][CH:4]([C:6]#[N:7])[CH2:3]1.Cl[C:9]1[C:14]([F:15])=[CH:13][CH:12]=[CH:11][N:10]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Na+]>C1(C)C=CC=CC=1>[F:15][C:14]1[C:9]([C:4]2([C:6]#[N:7])[CH2:5][C:2](=[CH2:1])[CH2:3]2)=[N:10][CH:11]=[CH:12][CH:13]=1
Reactant: C=C1CC(C#N)C1
Reactant: Fc1cccnc1Cl
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: Cc1ccccc1
Product: C=C1CC(C#N)(c2ncccc2F)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 89767.9 %

Procedure:
To a solution of 3-methylenecyclobutanecarbonitrile (150 g, 1.61 mol, 1 equiv) and 2-chloro-3-fluoropyridine (212 g, 1.61 mmol, 1 equiv) in toluene (1 L) was added NaHMDS (2 M in THF, 885 mL, 1.1 equiv) dropwise at 0-10° C. Upon completion of addition, the reaction mixture was warmed to rt, stirred overnight, and quenched with NH4C(sat.) solution. The organic layer was washed with water (500 mL×2) and brine (500 mL), dried over Na2SO4, filtered, and concentrated to give a crude title compound (272 g, 90%), which was used in the next step without further purification, LRMS (M+H+) m/z 189.1.
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][C:5]([N+:11]([O-:13])=[O:12])=[CH:4][N:3]=1.[NH:14]1[CH2:19][CH2:18][CH:17]([C:20]([NH2:22])=[O:21])[CH2:16][CH2:15]1>C1COCC1>[N+:8]([C:7]1[C:2]([N:14]2[CH2:19][CH2:18][CH:17]([C:20]([NH2:22])=[O:21])[CH2:16][CH2:15]2)=[N:3][CH:4]=[C:5]([N+:11]([O-:13])=[O:12])[CH:6]=1)([O-:10])=[O:9]
Reactant: NC(=O)C1CCNCC1
Reactant: O=[N+]([O-])c1cnc(Cl)c([N+](=O)[O-])c1
Solvent: C1CCOC1
Product: NC(=O)C1CCN(c2ncc([N+](=O)[O-])cc2[N+](=O)[O-])CC1
Temperature: 60 °C
Yield: 12 %

Procedure:
3 g (14.7 mmol) of 2-chloro-3,5-dinitropyridine, 10 ml of THF and 30 mmol of 4-piperidine carboxamide were placed in a round-bottomed flask. The mixture was maintained at 60° C. for 15 hours with stirring and was then poured into an ice-water mixture with stirring. The precipitate formed was filtered off by suction and dried under vacuum to constant weight. 0.522 g of yellow powder was obtained.
Reaction SMILES: [C:1](=[O:21])(OC1C=CC([N+]([O-])=O)=CC=1)[O:2][CH2:3][CH:4]1[CH2:9][CH2:8][N:7]([CH3:10])[CH2:6][CH2:5]1.CCN(C(C)C)C(C)C.Cl.Cl.[CH3:33][C:34]1[CH:35]=[C:36]([N:40]2[CH2:45][CH2:44][NH:43][CH2:42][CH2:41]2)[CH:37]=[CH:38][CH:39]=1>CN(C=O)C>[CH3:33][C:34]1[CH:35]=[C:36]([N:40]2[CH2:45][CH2:44][N:43]([C:1]([O:2][CH2:3][CH:4]3[CH2:5][CH2:6][N:7]([CH3:10])[CH2:8][CH2:9]3)=[O:21])[CH2:42][CH2:41]2)[CH:37]=[CH:38][CH:39]=1
Reactant: Cc1cccc(N2CCNCC2)c1
Reactant: CN1CCC(COC(=O)Oc2ccc([N+](=O)[O-])cc2)CC1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1cccc(N2CCN(C(=O)OCC3CCN(C)CC3)CC2)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 13.4 %

Procedure:
(1-Methylpiperidin-4-yl)methyl 4-nitrophenyl carbonate (Intermediate 1; 4.30 g, 14.6 mmol) was dissolved in DMF (50 mL). DIPEA (8.91 mL, 51.1 mmol) and 4-(3-methylphenyl)piperazine dihydrochloride (3.64 g, 14.6 mmol) were added. The reaction mixture was stirred at room temperature for 4 hours and then concentrated in vacuo. The residue was dissolved in EtOAc (500 mL) and then washed sequentially with 1 M aq NaOH solution (6×200 mL), brine (50 mL), dried (MgSO4) and concentrated in vacuo. The residue was dissolved in DCM (150 mL) and methyl isocyanate resin (1.0 g) was added and the reaction mixture shaken for 14 h, filtered and then concentrated in vacuo. The residue was purified by reverse phase chromatography (gradient eluting with MeOH in water, with 1% formic acid in each solvent, 0-30%). The resulting residue was dissolved in DCM (70 mL) and stirred with solid K2CO3 for 20 minutes, filtered and concentrated in vacuo to give (1-methylpiperidin-4-yl)methyl 4-(3-methylphenyl)piperazine-1-carboxylate (0.65 g, 13.3%) as a pale yellow oil.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)(=[O:3])[CH3:2].[CH3:10][CH:11]([CH2:18][CH3:19])[CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14]>>[CH3:10][CH:11]([CH:12]([C:1]([OH:3])([CH3:2])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)[C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH2:18][CH3:19]
Reactant: CC(=O)c1ccccc1
Reactant: CCOC(=O)CC(C)CC
Product: CCOC(=O)C(C(C)CC)C(C)(O)c1ccccc1
Yield: 35.9 %

Procedure:
The reaction of acetophenone (12 grams, 0.1 mole) with the enolate of ethyl 3-methylvalerate (14.4 grams, 0.1 mole) is carried out in the manner described in Example I. Distillation yields 9.5 grams (36%) of the pure product, b.p. 75°-80° C. (air bath temperature) at 0.05 mm Hg. I.R., N.M.R. and M.S. data confirm the above structure.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]([CH2:23][O:24][C:25]3[CH:30]=[CH:29][CH:28]=[C:27]([C:31]4([O:37][CH3:38])[CH2:36][CH2:35][O:34][CH2:33][CH2:32]4)[CH:26]=3)[O:11][C:12]=2[C:13]2[CH:18]=[CH:17][C:16]([S:19]([CH3:22])(=[O:21])=[O:20])=[CH:15][CH:14]=2)=[CH:4][CH:3]=1.[F:39]C1C=C(C2(OC)CCOCC2)C=C(O)C=1>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:9]=[C:10]([CH2:23][O:24][C:25]3[CH:26]=[C:27]([C:31]4([O:37][CH3:38])[CH2:36][CH2:35][O:34][CH2:33][CH2:32]4)[CH:28]=[C:29]([F:39])[CH:30]=3)[O:11][C:12]=2[C:13]2[CH:14]=[CH:15][C:16]([S:19]([CH3:22])(=[O:20])=[O:21])=[CH:17][CH:18]=2)=[CH:6][CH:7]=1
Reactant: COC1(c2cccc(OCc3nc(-c4ccc(F)cc4)c(-c4ccc(S(C)(=O)=O)cc4)o3)c2)CCOCC1
Reactant: COC1(c2cc(O)cc(F)c2)CCOCC1
Product: COC1(c2cc(F)cc(OCc3nc(-c4ccc(F)cc4)c(-c4ccc(S(C)(=O)=O)cc4)o3)c2)CCOCC1

Procedure:
4-(4-Fluorophenyl)-2-[[3-fluoro-5-(3,4,5,6-tetrahydro-4-methoxy-2H-pyran-4-yl)phenoxy)methyl]-5-(4-(methylsulfonyl)phenyl)oxazole was prepared in a similar fashion from the reaction of the mesylate (Example 2, Step 4) and 4-(3-fluoro-5-hydroxyphenyl)-4-methoxy-3,4,5,6-tetrahydro-2H-pyran: 1H-NMR (CDCl3, 300 MHz) δ 1.84-2.02 (m, 4H), 2.98 (s, 3H), 3.08 (s, 3H), 3.81 (m, 4H), 5.23 (s, 2H), 6.76 (m, 2H), 6.92 (s, 1H), 7.13 (m, 2H), 7.60 (m, 2H), 7.79 (d, 2H, J=8.5 Hz) and 7.93 (d, 2H, J=8.5 Hz). 19F-NMR (CDCl3, 280 MHz ) δ -110.8 and -111.7. Anal. Calc'd. for C29H27NO6F2 : C, 62.69; H, 4.90; N, 2.52. Found: C, 62.53; H, 4.96; N, 2.51.
Reaction SMILES: [S-:1][C:2]#[N:3].[NH4+].[C:5](Cl)(=[O:12])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1>CC(C)=O>[C:5]([N:3]=[C:2]=[S:1])(=[O:12])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: N#C[S-]
Reactant: O=C(Cl)c1ccccc1
Agent: [NH4+]
Solvent: CC(C)=O
Product: O=C(N=C=S)c1ccccc1
Reaction time: 0.03 h

Procedure:
Ammonium thiocyanate (12.35 g) was dissolved in acetone (AR grade, 120 ml) and benzoylchloride (17.3 ml) was added dropwise with stirring over 2 mins. The temperature rose from 22° C. to 38° C. over the addition and a white precipitate formed. The reaction was stirred at room temperature for a further 75 mins and then filtered, and washed with acetone (20 ml) to give a solution of benzoylisothiocyanate. This was added dropwise with stirring to the amine solution, over 40 mins. The temperature rose from 23° C. to 36° C. during the addition. A thick cream precipitate formed. The reaction was allowed to stir at room temperature for 16 hours and then the product was collected by filtration, washed with water (30 ml), sucked dry and then dried in vacuo at 60° C.
Reaction SMILES: [CH:1]1([NH:7][C:8](=[N:15][CH:16]2[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]2)[O:9][N:10]=[C:11]([CH2:13][CH3:14])[CH3:12])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[C:22]1([N:28]=[C:29]=[O:30])[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>ClCCl>[C:22]1([NH:28][C:29]([N:15]([CH:16]2[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21]2)[C:8](=[N:7][CH:1]2[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]2)[O:9][N:10]=[C:11]([CH2:13][CH3:14])[CH3:12])=[O:30])[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: CCC(C)=NOC(=NC1CCCCC1)NC1CCCCC1
Reactant: O=C=Nc1ccccc1
Solvent: ClCCl
Product: CCC(C)=NOC(=NC1CCCCC1)N(C(=O)Nc1ccccc1)C1CCCCC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 99.9 %

Procedure:
To a solution of 1,3-dicyclohexyl-O—(N-2-butylideneamino)-isourea (Cmpd. 2) (2.93 g, 10 mmol) in dichloromethane (15 ml) is phenylisocyanate (1.19 g, 10 mmol). The mixture is stirred 1 h at room temperature and evaporated to afford 4.12 g of the title compound as a light yellow oil.
Reaction SMILES: [C:1]1([S:7]([N:10]2[C:18]3[CH:17]=[C:16]([Sn](C)(C)C)[CH:15]=[C:14]([NH2:23])[C:13]=3[CH:12]=[N:11]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CN(C=O)C.Br[C:30]1[CH:31]=[C:32]([NH:37][S:38]([CH3:41])(=[O:40])=[O:39])[C:33]([Cl:36])=[N:34][CH:35]=1>C(Cl)Cl.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>[NH2:23][C:14]1[CH:15]=[C:16]([C:30]2[CH:31]=[C:32]([NH:37][S:38]([CH3:41])(=[O:40])=[O:39])[C:33]([Cl:36])=[N:34][CH:35]=2)[CH:17]=[C:18]2[C:13]=1[CH:12]=[N:11][N:10]2[S:7]([C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)(=[O:9])=[O:8]
Reactant: C[Sn](C)(C)c1cc(N)c2cnn(S(=O)(=O)c3ccccc3)c2c1
Reactant: CS(=O)(=O)Nc1cc(Br)cnc1Cl
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CS(=O)(=O)Nc1cc(-c2cc(N)c3cnn(S(=O)(=O)c4ccccc4)c3c2)cnc1Cl
Temperature: 120 °C
Yield: 19.8 %

Procedure:
Four identical reactions were carried out in a 20 ml microwave vial, each using one quarter of the quantities stated. They were then combined for work-up and purification. A solution of a quarter of 1-(phenylsulfonyl)-6-(trimethylstannanyl)-1H-indazol-4-amine (4.329 g, 9.93 mmol) in a quarter of DMF (24 ml) was treated with a quarter of N-(5-bromo-2-chloro-3-pyridinyl)methanesulfonamide (3.26 g, 11.42 mmol) followed by a quarter of Pd(PPh3)4 (1.032 g, 0.893 mmol). Each vial was heated at 120° C. for 50 mins in a Biotage Initiator. The orange solutions were combined and loaded onto a 20 g silica cartridge, and the vials washed with methanol (10 ml) which was also loaded onto the cartridge which was then eluted with methanol. Then eluants were evaporated to leave an orange oil. This was diluted with DCM (10 ml) and loaded directly and evenly onto 2×100 g silica cartridges. These were eluted with 0-100% ethyl acetate/cyclohexane over 80 mins using the Flashmaster II. Appropriate pure fractions were combined and evaporated to give the title compound as a yellow solid (0.939 g).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([N+:11]([O-])=O)[CH:10]=1)[NH:7][C:6]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=1)=[CH:5]2.[NH4+].[Cl-]>O1CCCC1.CO.O.[Fe]>[NH2:11][C:9]1[CH:10]=[C:2]([CH3:1])[CH:3]=[C:4]2[C:8]=1[NH:7][C:6]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=1)=[CH:5]2
Reactant: Cc1cc([N+](=O)[O-])c2[nH]c(-c3ccccn3)cc2c1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: Cc1cc(N)c2[nH]c(-c3ccccn3)cc2c1
Temperature: 60 °C
Reaction time: 0.5 h
Yield: 82 %

Procedure:
5-Methyl-7-nitro-2-(pyridin-2-yl)-1H-indole (6.9 g, 27.3 mmol) prepared in Preparation 8 was dissolved in a solvent mixture of tetrahydrofuran (130 mL), methanol (1 mL) and water (130 mL), and NH4Cl (14.6 g, 27.3 mmol) was added thereto. The reaction mixture was warmed to 60° C., iron powder (15.2 g, 273 mmol) was added thereto, and the mixture was stirred for 30 min. After completion of the reaction, the reaction mixture was filtered through a cellite to remove the solid. Certain amount of the solvent was removed under reduced pressure from the resulting solution, which was then extracted with EtOAc. The extracted organic material was dried over MgSO4, and the solvent was removed under reduced pressure to give the title compound (5.0 g, Yield 40%).
Reaction SMILES: C([O:8][C:9]([C@H:11]1[CH2:16][CH2:15][C@@H:14]([NH:17][C:18]([C:20]2[C:21]([O:26][C:27]3[CH:32]=[CH:31][C:30]([S:33][CH3:34])=[CH:29][CH:28]=3)=[N:22][CH:23]=[CH:24][CH:25]=2)=[O:19])[CH2:13][CH2:12]1)=[O:10])C1C=CC=CC=1>C(O)=O.CO.CN(C)C=O.[Pd]>[CH3:34][S:33][C:30]1[CH:29]=[CH:28][C:27]([O:26][C:21]2[C:20]([C:18]([NH:17][C@@H:14]3[CH2:13][CH2:12][C@H:11]([C:9]([OH:10])=[O:8])[CH2:16][CH2:15]3)=[O:19])=[CH:25][CH:24]=[CH:23][N:22]=2)=[CH:32][CH:31]=1
Reactant: CSc1ccc(Oc2ncccc2C(=O)N[C@H]2CC[C@@H](C(=O)OCc3ccccc3)CC2)cc1
Agent: [Pd]
Solvent: O=CO
Solvent: CN(C)C=O
Solvent: CO
Product: CSc1ccc(Oc2ncccc2C(=O)N[C@H]2CC[C@@H](C(=O)O)CC2)cc1
Reaction time: 2.5 h
Yield: 76.5 %

Procedure:
cis-4-{[2-(4-methylsulfanyl-phenoxy)-pyridine-3-carbonyl]-amino}-cyclohexanecarboxylic acid benzyl ester (4.35 g, 9.13 mmol) was dissolved in a solution of 4.4% formic acid in methanol (100 ml) and dimethylformamide (25 ml) and this was added to a suspension of palladium black (5 g) in 4.4% formic acid in methanol (300 ml) at room temperature under nitrogen. The mixture was stirred for 2.5 h, then filtered through arbocel washing with methanol (4×200 ml). The filtrates were concentrated under reduced pressure and the residue was azeotroped with toluene (2×50 ml). The residue was then diluted with water (50 ml) and basified to pH10 with 1M sodium hydroxide pellets. The aqueous phase was extracted with diethylether (2×50 ml) then acidified to pH1 with concentrated hydrochloric acid. After extraction with diethylether (5×50 ml) the combined organic extracts were washed with water (20 ml), dried over MgSO4 and the solvent removed under reduced pressure to give cis-4-{[2-(4-methylsulfanyl-phenoxy)-pyridine-3-carbonyl]-amino}-cyclohexanecarboxylic acid (2.7 g) as a white solid.
Reaction SMILES: O[CH2:2][C:3]1[C:7]([S:8]([NH:11][CH3:12])(=[O:10])=[O:9])=[CH:6][S:5][CH:4]=1.S(Cl)([Cl:15])=O>>[Cl:15][CH2:2][C:3]1[C:7]([S:8]([NH:11][CH3:12])(=[O:10])=[O:9])=[CH:6][S:5][CH:4]=1
Reactant: O=S(Cl)Cl
Reactant: CNS(=O)(=O)c1cscc1CO
Product: CNS(=O)(=O)c1cscc1CCl

Procedure:
23.8 g (0.115 mol) of 3-hydroxymethyl-N-methyl-4-thiophenesulfonamide are treated within 10 minutes with 120 ml of thionyl chloride and the mixture is boiled under reflux for 20 minutes. Thereafter, the mixture is evaporated to dryness in a water-jet vacuum. The residue is taken up in 500 ml of methylene chloride and stirred with saturated sodium bicarbonate solution until the aqueous phase has an alkaline reaction. The phases are separated and the aqueous phase is extracted with two 100 ml portions of methylene chloride. The combined organic phases are dried over sodium sulfate and evaporated. The residual oil crystallizes out upon cooling. There is obtained 3-chloromethyl-N-methyl-4-thiophenesulfonamide of melting point 75°-76° C.