Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:7]([S:8]([N:11]2[CH2:16][CH2:15][S:14](=[O:18])(=[O:17])[CH2:13][CH2:12]2)(=[O:10])=[O:9])=[C:6]([OH:19])[C:5]([N+:20]([O-])=O)=[CH:4][CH:3]=1.[H][H]>[Pd]>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH2:20])=[C:6]([OH:19])[C:7]=1[S:8]([N:11]1[CH2:16][CH2:15][S:14](=[O:18])(=[O:17])[CH2:13][CH2:12]1)(=[O:10])=[O:9]
Reactant: [H][H]
Reactant: O=[N+]([O-])c1ccc(Cl)c(S(=O)(=O)N2CCS(=O)(=O)CC2)c1O
Agent: [Pd]
Product: Nc1ccc(Cl)c(S(=O)(=O)N2CCS(=O)(=O)CC2)c1O

Procedure:
Following the general hydrogenation procedure outlined in example 15, 6-chloro-1-(1,1 -dioxidothiomorpholinosulfonyl)-2-hydroxy-3-nitrobenzene (220 mg, 0.60 mmol) was reduced with hydrogen and 10% Pd/C (100 mg) to give the desired (186 mg, 92%). 1H NMR (MeOD-d4): δ 6.88 (m, 2H), 3.85 (t, 4H), 3.22 (t, 4H).
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[C:4]([C:10]([F:13])([F:12])[F:11])[CH:3]=1.[NH:14]1[CH2:19][CH2:18][O:17][CH2:16][CH2:15]1.C(=O)([O-])[O-].[K+].[K+].CS(C)=O>O>[N:14]1([C:2]2[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[C:4]([C:10]([F:13])([F:12])[F:11])[CH:3]=2)[CH2:19][CH2:18][O:17][CH2:16][CH2:15]1
Reactant: C1COCCN1
Reactant: O=Cc1ccc(F)cc1C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: O=Cc1ccc(N2CCOCC2)cc1C(F)(F)F
Temperature: 100 °C
Reaction time: 8 h
Yield: 74 %

Procedure:
A 100 mL round-bottom flask was charged with 4-fluoro-2-(trifluoromethyl)benzaldehyde (1.00 g, 5.21 mmol, 1.00 equiv), morpholine (0.500 g, 5.74 mmol, 1.10 equiv), potassium carbonate (1.40 g, 10.1 mmol, 2.00 equiv), DMSO (15 mL). The resulting solution was stirred overnight at 100° C., diluted with H2O (10 mL), extracted with ethyl acetate (3×10 mL). The organic layers were combined and washed with brine (1×50 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was chromatographed on a silica gel column with ethyl acetate/petroleum ether (25/75) to provide 1.00 g (74% yield) of 4-(morpholin-4-yl)-2-(trifluoromethyl)benzaldehyde as a yellow solid. LCMS (ESI, m/z): 260 [M+H]+.
Reaction SMILES: CC(C)([O-])C.[K+].ClC1C=CC(O[CH2:13][C:14]#[N:15])=CC=1.[CH3:18][N:19]([CH3:29])[C:20]1[CH:25]=[CH:24][C:23]([N+:26]([O-:28])=[O:27])=[CH:22][N:21]=1>CN(C)C=O>[CH3:18][N:19]([CH3:29])[C:20]1[N:21]=[C:22]([CH2:13][C:14]#[N:15])[C:23]([N+:26]([O-:28])=[O:27])=[CH:24][CH:25]=1
Reactant: CN(C)c1ccc([N+](=O)[O-])cn1
Reactant: N#CCOc1ccc(Cl)cc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CN(C)c1ccc([N+](=O)[O-])c(CC#N)n1
Temperature: -10 °C
Reaction time: 1 h
Yield: 83.4 %

Procedure:
To a stirred solution of potassium tert-butoxide (12.34 g, 110 mmol, 2.2 eq) in anhydrous dimethylformamide (100 mL) at -10° C. was added dropwise a solution of (4-chlorophenoxy)acetonitrile (9.22 g, 55 mmol, 1.1eq) and 2-dimethylamino-5-nitropyridine (Pfaltz and Bauer, Inc., 8.36 g, 50.0 mmol) in anhydrous dimethylformamide (50 mL). The resultant deep purple-colored solution was stirred at -10° C. under nitrogen for 1hour. Then an aqueous 5% HCL solution (85 mL) added dropwise to the reaction solution at 0° C., and the precipitated solid was filteredand dried to yield Compound 5c (8.60 g, 41.7 mmol, 83%) as a yellow solid: mp, 156.0-158.0° C.; IR (KBr) 2240, 1600, 1580, 1530, 1485, 1420, 1385, 1335 cm-1 ; 1H NMR (CDCl3) δ 8.25 (d, J=9.0 Hz, 1H), 6.45 (d, J=9.6 Hz, 1H), 4.38 (s, 2H), 3.25 (br s, 6H); LRMS (m/z,relative intensity) 207 (13), 206 (M+, 100), 191 (54), 189 (26), 177 (88), 160 (35), 159 (22), 145 (94), 134 (30), 131 (24), 119 (29), 118 (59), 93 (27). Anal. calcd. for C9H10N4O2 : C, 52,42; H, 4.89; N, 27.17; found: C, 52.19; H, 4.93; N, 26.93.
Reaction SMILES: [CH3:1][O:2][NH:3][C:4](=[O:7])[CH2:5][Cl:6].[N+:8]([C:11]1[CH:16]=[CH:15][C:14]([N:17]=[C:18]=[O:19])=[CH:13][CH:12]=1)([O-:10])=[O:9]>C([O-])(=O)CCCCCCCCCCC.C([O-])(=O)CCCCCCCCCCC.C([Sn+2]CCCC)CCC.C1C=CC=CC=1>[Cl:6][CH2:5][C:4]([O:7][C:18](=[O:19])[NH:17][C:14]1[CH:13]=[CH:12][C:11]([N+:8]([O-:10])=[O:9])=[CH:16][CH:15]=1)=[N:3][O:2][CH3:1]
Reactant: O=C=Nc1ccc([N+](=O)[O-])cc1
Reactant: CONC(=O)CCl
Agent: CCCCCCCCCCCC(=O)[O-]
Agent: CCCC[Sn+2]CCCC
Solvent: c1ccccc1
Product: CON=C(CCl)OC(=O)Nc1ccc([N+](=O)[O-])cc1
Temperature: 25 °C

Procedure:
N-Methoxychloroacetamide (12.3 grams; 0.1 mole), benzene (80 ml) and dibutyltin dilaurate (1 drop) are charged into a glass reaction flask equipped with a mechanical stirrer, thermometer and reflux condenser. 4-Nitrophenylisocyanate (16.4 grams; 0.1 mole) dissolved in benzene (30 ml) is incrementally added to the reaction mixture, with stirring, at room temperature. After the addition is completed the reaction mixture is heated at reflux for a period of about 4 hours. After this time the reaction mixture is distilled to remove benzene and unreacted starting material thereby yielding the desired product 1-chloro-2-(N-4-nitrophenylcarbamoyloxy)-2-methoxyiminoethane.
Reaction SMILES: C[O:2][C:3]([C@H:5]1[NH:18][C:17](=[S:19])[CH2:16][CH2:15][CH2:14][CH2:13][O:12][C:11](=[O:20])[C:10]2[C:21]([CH3:28])=[C:22]([O:26][CH3:27])[CH:23]=[C:24]([OH:25])[C:9]=2[CH2:8][S:7][CH2:6]1)=O>CO.C(N)C#C>[CH2:17]([NH:18][C:3]([C@H:5]1[NH:18][C:17](=[S:19])[CH2:16][CH2:15][CH2:14][CH2:13][O:12][C:11](=[O:20])[C:10]2[C:21]([CH3:28])=[C:22]([O:26][CH3:27])[CH:23]=[C:24]([OH:25])[C:9]=2[CH2:8][S:7][CH2:6]1)=[O:2])[C:16]#[CH:15]
Reactant: COC(=O)[C@@H]1CSCc2c(O)cc(OC)c(C)c2C(=O)OCCCCC(=S)N1
Agent: C#CCN
Solvent: CO
Product: C#CCNC(=O)[C@@H]1CSCc2c(O)cc(OC)c(C)c2C(=O)OCCCCC(=S)N1
Temperature: 50 °C
Yield: 97.1 %

Procedure:
A solution of 43 mg of the product of Example 23 in a mixture of 0.5 ml of methanol and 0.5 ml of prop-2-ynylamine was heated to 50° C. for 8 h. The solution was evaporated in vacuo, the residue was dissolved in ethyl acetate, and the solution was washed with 1N hydrochloric acid and water. The organic layer was dried over sodium sulfate and evaporated in vacuo and the residue was chromatographed on silica gel using ethyl acetate/hexane (1:2, v/v) as eluent. The purified product was crystallized from ethyl acetate/hexane to afford 22 mg (R)-16-hydroxy-14-methoxy-13-methyl-12-oxo-6-thioxo-1,3,4,5,6,7,8,9,10,12-decahydro-11,2,5benzoxathiaazacyclotetradecine-4-carboxylic acid prop-2-ynylamide as a white solid.
Reaction SMILES: [C:1]([NH:4][C@:5]1([C@@H:60]([CH2:62][CH3:63])[CH3:61])[CH2:9][CH2:8][N:7]([C@@H:10]([CH2:51][CH2:52][C:53]2[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=2)[C:11]([NH:13][C@@H:14]([CH2:42][C:43]2[CH:48]=[C:47]([F:49])[CH:46]=[C:45]([F:50])[CH:44]=2)[C@@H:15]([C@H:17]2[CH2:21][C@H:20]([O:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25]C=3)[CH2:19][N:18]2C(C2C=CC=CC=2)C2C=CC=CC=2)[OH:16])=[O:12])[C:6]1=[O:59])(=[O:3])[CH3:2].C([NH:67][C@]1([C@@H](CC)C)CCN([C@@H](CCC2C=CC=CC=2)C(N[C@@H](CC2C=C(F)C=C(F)C=2)[C@@H]([C@H]2C[C@H](OC3C=CC=CN=3)CN2C(C2C=CC=CC=2)C2C=CC=CC=2)O)=O)C1=O)(=O)C.C(N[C@]1([C@@H](CC)C)CCN([C@@H](CCC2C=CC=CC=2)C(O)=O)C1=O)(=O)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.N[C@@H](CC1C=C(F)C=C(F)C=1)[C@@H]([C@H]1C[C@H](OC2C=CC=CN=2)CN1C(C1C=CC=CC=1)C1C=CC=CC=1)O.CN1CCOCC1>CN(C=O)C>[C:1]([NH:4][C@:5]1([C@@H:60]([CH2:62][CH3:63])[CH3:61])[CH2:9][CH2:8][N:7]([C@@H:10]([CH2:51][CH2:52][C:53]2[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=2)[C:11]([NH:13][C@@H:14]([CH2:42][C:43]2[CH:48]=[C:47]([F:49])[CH:46]=[C:45]([F:50])[CH:44]=2)[C@H:15]([OH:16])[C@H:17]2[CH2:21][C@H:20]([O:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][N:67]=3)[CH2:19][NH:18]2)=[O:12])[C:6]1=[O:59])(=[O:3])[CH3:2]
Reactant: CC[C@@H](C)[C@@]1(NC(C)=O)CCN([C@@H](CCc2ccccc2)C(=O)N[C@@H](Cc2cc(F)cc(F)c2)[C@H](O)[C@H]2C[C@H](Oc3ccccn3)CN2C(c2ccccc2)c2ccccc2)C1=O
Reactant: CC[C@@H](C)[C@@]1(NC(C)=O)CCN([C@@H](CCc2ccccc2)C(=O)N[C@@H](Cc2cc(F)cc(F)c2)[C@H](O)[C@H]2C[C@H](Oc3ccccc3)CN2C(c2ccccc2)c2ccccc2)C1=O
Agent: CC[C@@H](C)[C@@]1(NC(C)=O)CCN([C@@H](CCc2ccccc2)C(=O)O)C1=O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: CC[C@@H](C)[C@@]1(NC(C)=O)CCN([C@@H](CCc2ccccc2)C(=O)N[C@@H](Cc2cc(F)cc(F)c2)[C@H](O)[C@H]2C[C@H](Oc3ccccn3)CN2)C1=O
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Step 10 (C): (S)-2-((S)-3-acetamido-3-((R)-sec-butyl)-2-oxopyrrolidin-1-yl)-N-((1S,2S)-1-((2R,4S)-1-benzhydryl-4-(pyridin-2-yloxy)pyrrolidin-2-yl)-3-(3,5-difluorophenyl)-1-hydroxypropan-2-yl)-4-phenylbutanamide. To a solution of (S)-2-((S)-3-acetamido-3-((R)-sec-butyl)-2-oxopyrrolidin-1-yl)-4-phenylbutanoic acid (Preparation A, 20.2 mg, 0.056 mmol) in DMF (2 mL) was added HATU (25.6 mg, 0.067 mmol). A solution of (1S,2S)-2-amino-1-((2R,4S)-1-benzhydryl-4-(pyridin-2-yloxy)pyrrolidin-2-yl)-3-(3,5-difluorophenyl)propan-1-ol (Step 10 (B), 29.0 mg, 0.056 mmol) in DMF (2 mL) was then added, followed by N-methylmorpholine (22 μl, 0.196 mmol). The reaction mixture was stirred at rt for 3 h. pH 4 buffer was then added to quench. The mixture was extracted with ethyl acetate. The organic phase was washed with sat. aqueous NaCl, dried (MgSO4), and concentrated in vacuo. The crude mixture was purified by reverse phase Prep HPLC to give the title compound (19 mg):
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([F:10])[C:5]=1[C:11]1[C:12]([Cl:19])=[N:13][C:14](Cl)=[CH:15][C:16]=1[Cl:17].[NH:20]1[CH:24]=[N:23][CH:22]=[N:21]1.P([O-])(O)(O)=O.[Na+]>CN(C)C=O>[Cl:3][C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([F:10])[C:5]=1[C:11]1[C:12]([Cl:19])=[N:13][C:14]([N:20]2[CH:24]=[N:23][CH:22]=[N:21]2)=[CH:15][C:16]=1[Cl:17]
Reactant: Fc1cccc(Cl)c1-c1c(Cl)cc(Cl)nc1Cl
Reactant: c1nc[nH]n1
Agent: O=P([O-])(O)O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Fc1cccc(Cl)c1-c1c(Cl)cc(-n2cncn2)nc1Cl
Temperature: 25 °C
Reaction time: 72 h

Procedure:
0.42 g (11.0 mmol) of 60% sodium hydride in paraffin was added a little at a time to 3.00 g (9.6 mmol) of 3-(2-chloro-6-fluorophenyl)-2,4,6-trichloropyridine and 0.70 g (9.6 mmol) of [1,2,4]triazole dissolved in 30 ml of dimethylformamide. The mixture was stirred at room temperature for 3 d, added to 50 ml of sodium dihydrogenphosphate solution, extracted three times with in each case 50 ml of methyl tert-butyl ether, dried over sodium sulfate and concentrated under reduced pressure. The crude product was chromatographed on silica gel using cyclohexane/ethyl acetate. Yield 1.5 g of a colorless solid of m.p. 210° C.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([N:10]2[CH:14]=[C:13]([CH3:15])[N:12]=[CH:11]2)=[C:6]([CH:9]=1)[C:7]#[N:8].[Cl:16][C:17]1[CH:18]=[C:19]([CH:27]=[CH:28][CH:29]=1)[CH2:20][N:21]1[CH:25]=[CH:24][C:23]([NH2:26])=[N:22]1>>[Cl:16][C:17]1[CH:18]=[C:19]([CH:27]=[CH:28][CH:29]=1)[CH2:20][N:21]1[CH:25]=[CH:24][C:23]([NH:26][C:2]2[CH:3]=[CH:4][C:5]([N:10]3[CH:14]=[C:13]([CH3:15])[N:12]=[CH:11]3)=[C:6]([CH:9]=2)[C:7]#[N:8])=[N:22]1
Reactant: Cc1cn(-c2ccc(Br)cc2C#N)cn1
Reactant: Nc1ccn(Cc2cccc(Cl)c2)n1
Product: Cc1cn(-c2ccc(Nc3ccn(Cc4cccc(Cl)c4)n3)cc2C#N)cn1

Procedure:
Prepared in analogy to example 1b) starting with 5-bromo-2-(4-methyl-imidazol-1-yl)-benzonitrile and 1-(3-chloro-benzyl)-1H-pyrazol-3-ylamine. The title compound was obtained as a light yellow solid (Yield=56%). MS ISP (m/e): 389.2 (100) [(M+H)+].
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([C:14]2[CH2:19][C:18]([CH3:21])([CH3:20])[CH2:17][C:16]([CH3:23])([CH3:22])[CH:15]=2)=[C:6]([CH:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)[CH:7]=1.[CH:24](=O)[CH2:25][CH2:26][CH3:27].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(=O)C.C(=O)([O-])O.[Na+]>O1CCCC1.C(OCC)(=O)C>[CH2:24]([N:11]1[CH2:10][CH2:9][CH:8]([C:6]2[CH:7]=[C:2]([F:1])[CH:3]=[CH:4][C:5]=2[C:14]2[CH2:19][C:18]([CH3:21])([CH3:20])[CH2:17][C:16]([CH3:23])([CH3:22])[CH:15]=2)[CH2:13][CH2:12]1)[CH2:25][CH2:26][CH3:27]
Reactant: CC1(C)C=C(c2ccc(F)cc2C2CCNCC2)CC(C)(C)C1
Reactant: CCCC=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: CCCCN1CCC(c2cc(F)ccc2C2=CC(C)(C)CC(C)(C)C2)CC1
Temperature: 25 °C
Reaction time: 15 h
Yield: 67.3 %

Procedure:
To a solution of 4-[5-fluoro-2-(3,3,5,5-tetramethylcyclohex-1-enyl)phenyl]piperidine (70 mg, 0.22 mmol) produced in Example (106g) in tetrahydrofuran (2 mL) were added butyraldehyde (19.2 mg, 0.27 mmol), sodium triacetoxyborohydride (71 mg, 0.33 mmol) and acetic acid (27 mg, 0.44 mmol), followed by stirring for 15 hours at room temperature. Saturated aqueous solution of sodium hydrogencarbonate was added to the reaction mixture and extraction was performed with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate and the filtrate was concentrated under reduced pressure to give a residue, which was purified by NH silica gel column chromatography (ethyl acetate/heptane) to give 55 mg of 1-butyl-4-[5-fluoro-2-(3,3,5,5-tetramethylcyclohex-1-enyl)phenyl]piperidine as a light yellow oil.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:12]([C:13]3[CH:18]=[CH:17][C:16]([F:19])=[CH:15][C:14]=3[F:20])[CH2:11][C:10]([C:21]([F:27])([F:26])[C:22]([F:25])([F:24])[F:23])=[N:9]2)=[CH:4][CH:3]=1.[CH3:28][S:29][C:30]1[CH:31]=[C:32](B(O)O)[CH:33]=[CH:34][CH:35]=1.C(=O)([O-])[O-].[Na+].[Na+].C(O)C>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.COCCOC>[F:20][C:14]1[CH:15]=[C:16]([F:19])[CH:17]=[CH:18][C:13]=1[CH:12]1[N:8]([C:5]2[CH:4]=[CH:3][C:2]([C:34]3[CH:33]=[CH:32][CH:31]=[C:30]([S:29][CH3:28])[CH:35]=3)=[CH:7][CH:6]=2)[N:9]=[C:10]([C:21]([F:26])([F:27])[C:22]([F:23])([F:25])[F:24])[CH2:11]1
Reactant: CSc1cccc(B(O)O)c1
Reactant: Fc1ccc(C2CC(C(F)(F)C(F)(F)F)=NN2c2ccc(Br)cc2)c(F)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: CCO
Product: CSc1cccc(-c2ccc(N3N=C(C(F)(F)C(F)(F)F)CC3c3ccc(F)cc3F)cc2)c1
Temperature: 90 °C
Reaction time: 3 h
Yield: 36.5 %

Procedure:
1-(4-Bromo-phenyl)-5-(2,4-difluoro-phenyl)-3-pentafluoroethyl-4,5-dihydro-1H-pyrazole (50.0 mg, 0.11 mmol) prepared in Preparation 15, 3-(methylthio)phenylboronic acid (28.0 mg, 0.17 mmol), Pd(PPh3)4 (13.0 mg, cat.) and a 2N sodium carbonate solution (550.0 uL) were added to a mixed solvent of ethanol (550.0 uL) and 1,2-dimethoxyethane (2.0 mL). The reaction mixture was stirred at 90° C. for 3 hours and then filtered through celite pad. A saturated solution of ammonium chloride was added to the filtrate, which was then extracted with ethyl acetate three times. The combined extract was washed with brine, dried on anhydrous magnesium sulfate, and then concentrated under reduced pressure to give a yellow liquid residue. The resulting residue was purified by silica gel column chromatography (eluent: ethyl acetate/n-hexane=1/6) to give 20.0 mg of the titled compound as a white liquid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]=[C:9]=[O:10])=[CH:4][CH:3]=1.[NH2:11][CH2:12][CH2:13][N:14]1[C:18]([CH3:19])=[CH:17][CH:16]=[C:15]1[CH3:20].C(OCC)C>O1CCCC1>[CH3:20][C:15]1[N:14]([CH2:13][CH2:12][NH:11][C:9]([NH:8][C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)=[O:10])[C:18]([CH3:19])=[CH:17][CH:16]=1
Reactant: Cc1ccc(C)n1CCN
Reactant: O=C=Nc1ccc(Cl)cc1
Solvent: CCOCC
Solvent: C1CCOC1
Product: Cc1ccc(C)n1CCNC(=O)Nc1ccc(Cl)cc1
Temperature: 20 °C
Reaction time: 1 h

Procedure:
7.7 g (0.05 mol) of 4-chlorophenyl isocyanate, dissolved in 10 ml of tetrahydrofura, are added dropwise, over the coruse of 30 minutes, to 6.9 g (0.05 mol) of 1-(2-aminoethyl)-2,5-dimethylpyrrole, dissolved in 10 ml of tetrahydrofuran, a 20° C. The mixture is then left to stir at 20° C. for 60 minutes. After addition of diethyl ether to the reaction mixture the product crystallizes out, and is filtered off with suction and recrystallized from isopropanol. Yield: 8.4 g (58% of theory), Melting point: 175°-177° C. Elemental analysis: C15H18ClN3 0 (291.83) calculated: C 61.7 H 6.2 CL 12.2 N 14.4 0 5.5 found: C 61.0 H 6.5 Cl 12.5 N 14.6 0 5.8
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([CH3:11])=[CH:5]2.C([BH3-])#N.[Na+]>C(O)(=O)C.C(OCC)(=O)C>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]([CH3:11])[CH2:5]2
Reactant: Cc1cc2cc(Cl)ccc2[nH]1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: CC1Cc2cc(Cl)ccc2N1
Temperature: 25 °C
Reaction time: 16 h
Yield: 98.8 %

Procedure:
To a solution of 5-chloro-2-methylindole (1.00 g, 6.04 mmol) in acetic acid (7 ml) was added portionwise sodium cyanoborohydride (0.76 g, 12.1 mmol) and the reaction mixture was stirred at room temperature for 16 hours. The resulting solution was diluted with ethyl acetate and washed sequentially with water and with 5 N aq. sodium hydroxide solution. The organic phase was dried over sodium sulphate and concentrated in vacuo. The residue was purified by chromatography on silica gel (eluant: heptane/ethyl acetate gradient) to yield the title compound as a colourless oil (1.00 g, 100%); MS (ISP): 170.2 ([{37Cl}M+H]+), 168.3 ([{35Cl}M+H]+).
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][CH:10]([S:29][CH2:30][CH2:31][C:32](O)=[O:33])[C:11]2[CH:16]=[CH:15][C:14]([O:17][CH2:18][C:19]3[CH:28]=[CH:27][C:26]4[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=4)[N:20]=3)=[CH:13][CH:12]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CC[N:37](CC)CC>C(Cl)Cl.CC#N>[C:1]1([CH2:7][CH2:8][CH2:9][CH:10]([S:29][CH2:30][CH2:31][C:32]([NH2:37])=[O:33])[C:11]2[CH:16]=[CH:15][C:14]([O:17][CH2:18][C:19]3[CH:28]=[CH:27][C:26]4[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=4)[N:20]=3)=[CH:13][CH:12]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CCN(CC)CC
Reactant: O=C(O)CCSC(CCCc1ccccc1)c1ccc(OCc2ccc3ccccc3n2)cc1
Solvent: CC#N
Solvent: ClCCl
Product: NC(=O)CCSC(CCCc1ccccc1)c1ccc(OCc2ccc3ccccc3n2)cc1
Reaction time: 1.25 h

Procedure:
To a solution of the title acid of Example 2 (200 mg) in CH2Cl2 (3 mL) and CH3CN (1 mL) at 0° C. was added Et3N (120 μL) followed by 2-chlorol-methylpyridinium iodide (220 mg). After stirring for 75 mins. at 0° C., an excess of NH3 was slowly bubbled into the mixture and the reaction was allowed to stir at RT for 12 h. It was then diluted with ethyl acetate and washed successively with aq. NH4OAc (x2) and brine. After drying, the organic solution was concentrated and the residue was purified on a column of silica to afford the title compound.
Reaction SMILES: [CH3:1][N:2]([CH3:16])[S:3]([C:6]1[CH:7]=[CH:8][C:9](F)=[C:10]([CH:14]=1)[C:11]([OH:13])=[O:12])(=[O:5])=[O:4].[CH3:17][NH2:18]>>[CH3:17][NH:18][C:9]1[CH:8]=[CH:7][C:6]([S:3](=[O:5])(=[O:4])[N:2]([CH3:16])[CH3:1])=[CH:14][C:10]=1[C:11]([OH:13])=[O:12]
Reactant: CN
Reactant: CN(C)S(=O)(=O)c1ccc(F)c(C(=O)O)c1
Product: CNc1ccc(S(=O)(=O)N(C)C)cc1C(=O)O

Procedure:
A mixture of 5-dimethylsulfamoyl-2-fluorobenzoic acid (10 g) and 40% aqueous methylamine solution (85 ml) is refluxed for 24 hours and then evaporated under reduced pressure. The residue is adjusted to the pH of about 4 with acetic acid. The precipitate is collected, washed with water, and dried to give the title compound (6.0 g).
Reaction SMILES: Cl[C:2]1[O:3][C:4]([C:13]2[CH:18]=[CH:17][C:16]([S:19]([NH2:22])(=[O:21])=[O:20])=[CH:15][CH:14]=2)=[C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[N:6]=1.CN(C=O)C.C(=O)([O-])[O-].[K+].[K+].[F:34][C:35]1[CH:36]=[C:37]([C:42]2([O:48][CH3:49])[CH2:47][CH2:46][O:45][CH2:44][CH2:43]2)[CH:38]=[C:39]([OH:41])[CH:40]=1>C(OCC)(=O)C>[F:34][C:35]1[CH:40]=[C:39]([CH:38]=[C:37]([C:42]2([O:48][CH3:49])[CH2:43][CH2:44][O:45][CH2:46][CH2:47]2)[CH:36]=1)[O:41][C:2]1[O:3][C:4]([C:13]2[CH:18]=[CH:17][C:16]([S:19]([NH2:22])(=[O:21])=[O:20])=[CH:15][CH:14]=2)=[C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[N:6]=1
Reactant: NS(=O)(=O)c1ccc(-c2oc(Cl)nc2-c2ccccc2)cc1
Reactant: COC1(c2cc(O)cc(F)c2)CCOCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC1(c2cc(F)cc(Oc3nc(-c4ccccc4)c(-c4ccc(S(N)(=O)=O)cc4)o3)c2)CCOCC1
Yield: 34.7 %

Procedure:
4-[2-Chloro-4-phenyl-5-oxazolyl]benzenesulfonamide from Step 3 (0.74 g, 2.2 mmol), N,N'-dimethylformamide (DMF) (20 mL), potassium carbonate (0.61 g, 4.4 mmol), and 4-(3-fluoro-5-hydroxyphenyl)-4-methoxy-3,4,5,6-tetrahydro-2H-pyran [prepared as described by G. C. Crawley, et al, J. Med. Chem., 35, 2600-2609 (1992)] (0.75 g, 7.5 mmol) were stirred at room temperature for 16.0 hours. The solution was diluted with ethyl acetate (100 mL), washed with 1N HCl, brine and water, dried over MgSO4 and concentrated. The residue was dissolved in ethyl acetate/hexanes (1:1) and filtered through silica. The eluant was concentrated and the residue was recrystallized from ethyl acetate/hexanes to afford 4-[2-[3-fluoro-5-(4-methoxy-3,4,5,6-tetrahydro-2H - pyran-4-yl)phenoxy]-4 -phenyl-5-oxazolyl]benzenesulfonamide as a white solid (0.4 g, 35%): mp 159°-161° C. 1H NMR (CDCl3) 300 MHz δ 7.9 (d, J=8.7 Hz, 2H) 7.72 (d, J=8.7 Hz, 2H) 7.6 (m, 2H) 7.4 (m, 3H) 7.24-7.30 (m, 2H) 7.0-7.1 (dt, J=9.5 Hz and J=1.8 Hz, 1H) 4.85 (bs, 2H) 3.85 (dd, J=9.9 Hz and J=1.8 Hz, 4H) 3.05 (s, 3H) 2.0 (m, 4H). Anal. Calc'd. for C27H25N2O6SF: C, 61.82; H, 4.80; N, 5.34. Found: C, 61.77; H, 4.82; N, 4.31.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([O:12][CH3:13])[C:5]([O:10][CH3:11])=[C:6]([O:8][CH3:9])[CH:7]=1.[CH3:14][Si:15]([C:18]#[CH:19])([CH3:17])[CH3:16].C(N(C(C)C)CC)(C)C.[Cl-]>ClCCl>[CH3:14][Si:15]([CH3:17])([CH3:16])[C:18]#[C:19][C:2]1[CH:3]=[C:4]([O:12][CH3:13])[C:5]([O:10][CH3:11])=[C:6]([O:8][CH3:9])[CH:7]=1
Reactant: COc1cc(Br)cc(OC)c1OC
Reactant: C#C[Si](C)(C)C
Agent: [Cl-]
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc(C#C[Si](C)(C)C)cc(OC)c1OC
Temperature: 80 °C
Reaction time: 1 h

Procedure:
1 g 5-bromo-1,2,3-trimethoxybenzene, 1.14 mL of trimethylsilylacetylene, 1.4 mL of diisopropylethylamine (DIPEA) and 290 mg of triphenylphosphinpalladium(II) chloride and 39 mg Cu(I)iodide were placed in a dried flask under argon. The mixture was stirred for 1 h at 80° C., after cooling diluted with dichloromethane (DCM) and filtered through a plug of silica. The filtrate was extracted with aqueous ammonia, saturated brine and concentrated. The residue was purified via flash chromatography (SiO2: cyclohexane→cyclohexane/ethylacetate 9:1) to give trimethyl((3,4,5-trimethoxyphenyl)ethynyl)silane.
Reaction SMILES: N[C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[C:11]([F:14])([F:13])[F:12])[C:5]([OH:7])=[O:6].C(O)(=O)C.[BrH:19].N([O-])=O.[Na+]>O>[Br:19][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[C:11]([F:14])([F:13])[F:12])[C:5]([OH:7])=[O:6]
Reactant: Br
Reactant: Nc1cc(C(=O)O)ccc1C(F)(F)F
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: O=C(O)c1ccc(C(F)(F)F)c(Br)c1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
5.0 g of 3-amino-4-trifluoromethyl-benzoic acid were dissolved using 50 ml of acetic acid. Then, 50 g of ice and 50 ml of a saturated aqueous HBr-solution were added and a solution of 2.0 g NaNO2 in 10 ml of water was added dropwise at 0° C. The reaction mixture was then stirred at room temperature for 10 minutes. Then, the reaction mixture was added dropwise to a suspension of 7.0 g CuBr and 10.9 g CuBr2 in 100 ml of a half-concentrated aqueous solution of HBr. The resulting mixture was then stirred for 2 h at room temperature, then diluted using 21 of water, stirred for 1 h and finally the precipitate was isolated by filtration. The precipitate was dried in vacuo to yield 5.2 g of the title compound that was used without further purification.