Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=O)=[CH:5][C:4]=1[CH3:12].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(CC)CC.C(OC(=O)[NH:50][CH2:51][CH2:52][O:53][C:54]1[CH:59]=[CH:58][C:57]([NH2:60])=[CH:56][C:55]=1[C:61]1[N:62]([CH3:67])[N:63]=[CH:64][C:65]=1[Cl:66])(C)(C)C.[C:69]([OH:75])([C:71]([F:74])([F:73])[F:72])=[O:70]>C(Cl)Cl>[F:72][C:71]([F:74])([F:73])[C:69]([OH:75])=[O:70].[NH2:50][CH2:51][CH2:52][O:53][C:54]1[CH:59]=[CH:58][C:57]([NH:60][C:7](=[O:9])[C:6]2[CH:10]=[CH:11][C:3]([O:2][CH3:1])=[C:4]([CH3:12])[CH:5]=2)=[CH:56][C:55]=1[C:61]1[N:62]([CH3:67])[N:63]=[CH:64][C:65]=1[Cl:66]
Reactant: COc1ccc(C(=O)O)cc1C
Reactant: Cn1ncc(Cl)c1-c1cc(N)ccc1OCCNC(=O)OC(C)(C)C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc(C(=O)Nc2ccc(OCCN)c(-c3c(Cl)cnn3C)c2)cc1C
Temperature: 90 °C
Reaction time: 8 h
Yield: 69 %

Procedure:
A solution of 4-methoxy-3-methylbenzoic acid (10 mg, 59 μmol), HATU (23 mg, 1.1 eq), and Et3N (11 mg, 1.5 eq.) in DCM (1 mL) was stirred 20 min at 40° C. {2-[4-Amino-2-(4-chloro-2-methyl-2H-pyrazol-3-yl)-phenoxy]-ethyl}-carbamic acid tert-butyl ester (18 mg, 50 μmol) was added into the acid-HATU solution, and the reaction was stirred overnight at 40 C. The reaction was treated with TFA (˜0.2 mL) and heated to ˜90° C. for 1 h. The reaction was filtered through a strong cation exchange resin to remove impurity, TFA, and tetramethyl urea, and purified by prep-HPLC: Waters YMC ODS-A™ C18 column (5μ, 4.6×50 mm), 5% v/v CH3CN (containing 0.05% v/v TFA) in H2O (containing 0.05% v/v TFA) gradient to 60% V/V CH3CN in H2O, 20 mL/min. N-[4-(2-Amino-ethoxy)-3-(4-chloro-2-methyl-2H-pyrazol-3-yl)-phenyl]-4-methoxy-3-methyl-benzamide trifluoroacetate (14 mg, 69%) was obtained as a white powder. LCMS m/z (%)=415.3 (M+H 35Cl, 100), 417.3 (M+H 37Cl, 31). 1H NMR (400 MHz, DMSO-d6) δ: 10.1 (s, 1H), 7.93 (dd, J=2.5 and 8.8 Hz, 1H), 7.91-7.82 (m, 4H), 7.79 (bs, 1H), 7.70 (d, J=2.5 Hz, 1H), 7.65 (s, 1H), 7.27 (d, J=9.0 Hz, 1H), 7.06 (d, J=8.8 Hz, 1H), 4.19 (m, 2H), 3.86 (s, 3H), 3.67 (s, 3H), 3.16 (m, 2H), 2.21 (s, 3H).
Reaction SMILES: [C:1]([N:5]1[C:9]([NH:10][C:11]2[N:16]=[C:15]([CH2:17][C:18]3([C:31]([O:33][CH2:34][CH3:35])=[O:32])[CH2:23][CH2:22][N:21](C(OC(C)(C)C)=O)[CH2:20][CH2:19]3)[CH:14]=[CH:13][CH:12]=2)=[CH:8][CH:7]=[N:6]1)([CH3:4])([CH3:3])[CH3:2].Cl>O1CCOCC1.C(O)C>[C:1]([N:5]1[C:9]([NH:10][C:11]2[N:16]=[C:15]([CH2:17][C:18]3([C:31]([O:33][CH2:34][CH3:35])=[O:32])[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]3)[CH:14]=[CH:13][CH:12]=2)=[CH:8][CH:7]=[N:6]1)([CH3:3])([CH3:4])[CH3:2]
Reactant: CCOC(=O)C1(Cc2cccc(Nc3ccnn3C(C)(C)C)n2)CCN(C(=O)OC(C)(C)C)CC1
Agent: Cl
Solvent: C1COCCO1
Solvent: CCO
Product: CCOC(=O)C1(Cc2cccc(Nc3ccnn3C(C)(C)C)n2)CCNCC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To 1.21 g of 1-tert-butyl 4-ethyl 4-((6-((1-tert-butyl-1H-pyrazol-5-yl)amino)pyridin-2-yl)methyl)piperidine-1,4-dicarboxylate were added 12 ml of 4 M hydrogen chloride in 1,4-dioxane and 3 ml of ethanol at room temperature. The reaction mixture was stirred at room temperature for 30 minutes, and concentrated in vacuo. The resulting residue was basified with saturated aqueous sodium bicarbonate solution, and extracted with ethyl acetate. The resulting ethyl acetate solution was dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated in vacuo to give the title compound as a pale brown oil.
Reaction SMILES: [NH2:1][C:2]1[CH:21]=[CH:20][C:5]2[N:6]([CH3:19])[C:7]([CH2:9][CH2:10][C:11]3[CH:16]=[CH:15][C:14]([C:17]#[N:18])=[CH:13][CH:12]=3)=[N:8][C:4]=2[CH:3]=1.[CH:22]1[CH:27]=[C:26]2[CH:28]=[CH:29][CH:30]=[C:31]([CH:32]=O)[C:25]2=[CH:24][CH:23]=1.Cl.[OH-].[Na+]>ClCCl.O.C(O)(=O)C>[C:17]([C:14]1[CH:15]=[CH:16][C:11]([CH2:10][CH2:9][C:7]2[N:6]([CH3:19])[C:5]3[CH:20]=[CH:21][C:2]([NH:1][CH2:32][C:31]4[C:25]5[C:26](=[CH:27][CH:22]=[CH:23][CH:24]=5)[CH:28]=[CH:29][CH:30]=4)=[CH:3][C:4]=3[N:8]=2)=[CH:12][CH:13]=1)#[N:18]
Reactant: O=Cc1cccc2ccccc12
Reactant: Cn1c(CCc2ccc(C#N)cc2)nc2cc(N)ccc21
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O
Solvent: CC(=O)O
Product: Cn1c(CCc2ccc(C#N)cc2)nc2cc(NCc3cccc4ccccc34)ccc21

Procedure:
1.0 g (3.6 mmol) of 5-amino-2-[2-(4-cyanophenyl)-ethyl]-1-methyl-benzimidazole and 1-naphthylaldehyde (0.33 mL, 3.6 mmol) are combined with 0.22 mL acetic acid in 25 mL of dichloromethane at ambient temperature and Na[HB(Oac)3] is added thereto with stirring. The mixture is stirred for 1 h at ambient temperature, covered with water, carefully acidified with concentrated aqueous hydrochloric acid and then made alkaline with 4N NaOH solution. The organic phase is separated off, dried and evaporated down. The product is chromatographed over silica gel and optionally crystallised from diethyl ether.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][C@H:3]([NH:7][C:8]([C:10]2[C:18]3[C:13](=[N:14][CH:15]=[C:16]([C:19]4[C:27]5[C:22](=[CH:23][C:24]([Cl:28])=[CH:25][CH:26]=5)[N:21]([CH3:29])[N:20]=4)[N:17]=3)[N:12](COCC[Si](C)(C)C)[CH:11]=2)=[O:9])[CH2:2]1.FC(F)(F)C(O)=O.C(N)CN.O>ClCCl.C(OCC)(=O)C>[O:1]1[CH2:6][CH2:5][CH2:4][C@H:3]([NH:7][C:8]([C:10]2[C:18]3[C:13](=[N:14][CH:15]=[C:16]([C:19]4[C:27]5[C:22](=[CH:23][C:24]([Cl:28])=[CH:25][CH:26]=5)[N:21]([CH3:29])[N:20]=4)[N:17]=3)[NH:12][CH:11]=2)=[O:9])[CH2:2]1
Reactant: Cn1nc(-c2cnc3c(n2)c(C(=O)N[C@H]2CCCOC2)cn3COCC[Si](C)(C)C)c2ccc(Cl)cc21
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: NCCN
Product: Cn1nc(-c2cnc3[nH]cc(C(=O)N[C@H]4CCCOC4)c3n2)c2ccc(Cl)cc21
Temperature: 25 °C
Reaction time: 3 h
Yield: 73 %

Procedure:
2-(6-Chloro-1-methyl-1H-indazol-3-yl)-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid (S)—N-(tetrahydro-pyran-3-yl)-amide (55 mg, 0.10 mmol) was dissolved in dichloromethane (1.2 ml) and cooled in ice bath. Trifluoroacetic acid (0.6 ml) was slowly added and the reaction was stirred at room temperature for 3 h. The reaction was evaporated and the residue was dissolved in dichloromethane (1 ml). Ethylenediamine (0.41 ml, 6.1 mmol) was added and the mixture was stirred for 18 h. Water and then ethyl acetate were added to the mixture. The layers were separated and the aqueous layer was extracted twice with ethyl acetate. The combined organic layers were washed with sodium chloride solution, dried over sodium sulfate and evaporated. The residue was purified by silica gel chromatography (methanol/dichloromethane) to give 30 mg (71%) of 2-(6-chloro-1-methyl-1H-indazol-3-yl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid (S)—N-(tetrahydro-pyran-3-yl)-amide. MS: (M+H)+=411; mp=320-323° C. 1H NMR (300 MHz, DMSO-d6) δ: 9.10 (s, 1H), 8.50 (d, J=8.7 Hz, 1H), 8.44 (s, 1H), 8.16 (d, J=7.6 Hz, 1H), 7.96 (d, J=1.9 Hz, 1H), 7.24 (dd, J=8.5, 1.7 Hz, 1H), 4.16 (s, 3H), 4.04-4.14 (m, 1H), 3.86-3.94 (m, 1H), 3.62-3.73 (m, 2H), 3.46-3.55 (m, 1H), 1.93-2.08 (m, 1H), 1.69-1.89 (m, 2H), 1.50-1.68 (m, 1H).
Reaction SMILES: [CH:1]12[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH:2]1[N:11]1[CH:15]=[C:14]([CH:16]3[CH2:18][CH2:17]3)[NH:13][C:12]1=[O:19])[CH2:8]2.Br[CH2:21][CH:22]1[CH2:24][CH2:23]1>>[CH:1]12[CH2:8][CH:7]3[CH2:6][CH:5]([CH2:4][CH:3]([CH2:9]3)[CH:2]1[N:11]1[CH:15]=[C:14]([CH:16]3[CH2:17][CH2:18]3)[N:13]([CH2:21][CH:22]3[CH2:24][CH2:23]3)[C:12]1=[O:19])[CH2:10]2
Reactant: BrCC1CC1
Reactant: O=c1[nH]c(C2CC2)cn1C1C2CC3CC(C2)CC1C3
Product: O=c1n(C2C3CC4CC(C3)CC2C4)cc(C2CC2)n1CC1CC1

Procedure:
This material was obtained in analogy to the procedure outlined in example 23 from 1-adamantan-2-yl-4-cyclopropyl-1,3-dihydro-imidazol-2-one (obtained in example 15, 100 mg) by alkylation with bromomethylcyclopropane (57 mg). 1-Adamantan-2-yl-4-cyclopropyl-3-cyclopropylmethyl-1,3-dihydro-imidazol-2-one was obtained as a light yellow oil (11 mg). MS (EI): 312.3 (M+).
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([CH3:10])[N:5]=[C:4](Cl)[CH:3]=1.[C:12]1([C@H:18]([NH:20][C:21]([NH2:23])=[O:22])[CH3:19])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.O1CCCC1>[Cl:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([CH3:10])[N:5]=[C:4]([NH:23][C:21]([NH:20][C@@H:18]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH3:19])=[O:22])[CH:3]=1
Reactant: Cc1nc(Cl)cc(Cl)c1C#N
Reactant: C[C@@H](NC(N)=O)c1ccccc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Solvent: C1CCOC1
Product: Cc1nc(NC(=O)N[C@H](C)c2ccccc2)cc(Cl)c1C#N
Temperature: 50 °C
Yield: 86.7 %

Procedure:
A flask was charged with 4,6-dichloro-2-methylnicotinonitrile (1500 mg), (R)-1-(1-phenylethyl)urea (1449 mg), xantphos (371 mg), palladium(II)acetate (90 mg) and cesium carbonate (5.23 g). Tetrahydrofuran (53 mL) was injected and the reaction was heated to 50° C. for 3 hours. LC/MS showed that the reaction cleanly proceeded to completion. The reaction mixture was filtered through celite and the filtrate was concentrated and purified by silica gel chromatography (0-30% DCM/EtOAc). (R) -1-(4-chloro-5-cyano-6-methylpyridin-2-yl)-3-(1-phenylethyl)urea (2.19 g, 87%) was isolated as an off-white solid. MS ESI calc'd for C16H15ClN4O [M+H]+ 315. found 315.
Reaction SMILES: [CH2:1]([CH:8]1[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][CH2:16][N:17]([C:26]2[CH:31]=[CH:30][C:29]([Cl:32])=[C:28]([Cl:33])[CH:27]=2)[C:18]([CH:20]2[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]2)=[O:19])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[S:34](N)([NH2:37])(=[O:36])=[O:35]>CC(O)C>[CH2:1]([CH:8]1[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][CH2:16][N:17]([C:26]2[CH:31]=[CH:30][C:29]([Cl:32])=[C:28]([Cl:33])[CH:27]=2)[C:18]([CH:20]2[CH2:21][CH2:22][N:23]([S:34](=[O:36])(=[O:35])[NH2:37])[CH2:24][CH2:25]2)=[O:19])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NS(N)(=O)=O
Reactant: O=C(C1CCNCC1)N(CCCN1CCC(Cc2ccccc2)CC1)c1ccc(Cl)c(Cl)c1
Solvent: CC(C)O
Product: NS(=O)(=O)N1CCC(C(=O)N(CCCN2CCC(Cc3ccccc3)CC2)c2ccc(Cl)c(Cl)c2)CC1
Yield: 51.2 %

Procedure:
A mixture of the compound obtained in Example 66 (391 mg, 0.80 mmol), sulfamide (1.54 g, 16.0 mmol), 2-propanol (20 mL) and distilled water (10 mL) was stirred under reflux for 4 days. The reaction mixture was concentrated under reduced pressure, and to the concentrate was added a saturated aqueous solution of sodium hydrogen carbonate. The mixture was extracted with dichloromethane. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The concentrate was subjected to column chromatography (silica gel 10 g, ethyl acetate/methanol=1/0 to 9/1), and the desired fraction was concentrated under reduced pressure. To the concentrate were added diethyl ether and ethyl acetate, and the resulting precipitates were collected by filtration. The precipitates were washed with diethyl ether, and dried under reduced pressure to give the titled compound (230 mg, 0.41 mmol, Yield 51%) as white crystals.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:11][CH:10]([O:12][C:13]2[CH:18]=[C:17]([Cl:19])[CH:16]=[CH:15][C:14]=2[OH:20])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C([O-])([O-])=O.[Cs+].[Cs+].[C:27]([O:30][CH2:31][CH2:32]Br)(=[O:29])[CH3:28].O>CN(C=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH:10]([O:12][C:13]2[CH:18]=[C:17]([Cl:19])[CH:16]=[CH:15][C:14]=2[O:20][CH2:28][C:27]([O:30][CH2:31][CH3:32])=[O:29])[CH2:11]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(=O)OCCBr
Reactant: CC(C)(C)OC(=O)N1CC(Oc2cc(Cl)ccc2O)C1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)COc1ccc(Cl)cc1OC1CN(C(=O)OC(C)(C)C)C1
Reaction time: 18 h
Yield: 101.1 %

Procedure:
To 3-(5-Chloro-2-hydroxy-phenoxy)-azetidine-1-carboxylic acid tert-butyl ester (1.5 g, 5.0 mmol) in DMF (20 mL) was added Cs2CO3 (2.1 g, 6.4 mmol), KI (0.84 g, 5.0 mmol) and bromoethyl acetate (0.84 g, 0.55 mL, 5.0 mmol). After 18 h, H2O was added and the mixture extracted with EtOAc (2×). The combined organics were washed with brine and dried. Silica gel chromatography (5-30% EtOAc in hexanes) gave 1.95 g (99%) of the title compound as a clear oil. 1H NMR (CDCl3): 6.91 (dd, J=8.7, 2.4 Hz, 1H), 6.79 (d, J=8.7 Hz, 1H), 6.58 (d, J=2.4 Hz, 1H), 4.91-4.87 (m, 1H), 4.65 (s, 2H), 4.32-4.25 (m, 4H), 4.01 (dd, J=10.5, 4.2 Hz, 2H), 1.44 (s, 9H), 1.30 (t, J=7.1 Hz, 3H).
Reaction SMILES: [BH4-].[Na+].[NH2:3][C:4]1[C:5](/[C:14](=[N:22]/[CH2:23][CH2:24][N:25]([CH3:27])[CH3:26])/[C:15]2[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=2)=[CH:6][CH:7]=[C:8]2[C:13]=1[N:12]=[CH:11][CH:10]=[CH:9]2>CCO>[NH2:3][C:4]1[C:5]([CH:14]([C:15]2[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=2)[NH:22][CH2:23][CH2:24][N:25]([CH3:27])[CH3:26])=[CH:6][CH:7]=[C:8]2[C:13]=1[N:12]=[CH:11][CH:10]=[CH:9]2
Reactant: CN(C)CC/N=C(\c1ccc(F)cc1)c1ccc2cccnc2c1N
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: CN(C)CCNC(c1ccc(F)cc1)c1ccc2cccnc2c1N
Temperature: 80 °C
Yield: 76.1 %

Procedure:
NaBH4 (181 mg, 4.9 mmol) was added to a solution of N-[1-(8-amino-quinolin-7-yl)-1-(4-fluoro-phenyl)-meth-(E)-ylidene]-N′,N′-dimethyl-ethane-1,2-diamine 414 (550 mg, 1.63 mmol) in EtOH (12 ml) at 0° C. and the mixture was heated at 80° C. for 4 h. After cooling, the reaction was quenched with water and the aqueous phase was extracted with EtOAc. The organic phase was washed with brine, dried (Na2SO4) and concentrated in vacuo. The crude residue was purified by column chromatography with DCM/MeOH (97:3) to give the title compound (420 mg, 75%).
Reaction SMILES: [C:1]([NH:5][S:6]([C:9]1[S:10][C:11]([C:14]2[N:19]=[C:18]([NH:20][C:21]3[CH:25]=[C:24]([CH:26]4[CH2:28][CH2:27]4)[NH:23][N:22]=3)[C:17]([CH2:29][O:30][Si](C(C)(C)C)(C)C)=[CH:16][N:15]=2)=[CH:12][CH:13]=1)(=[O:8])=[O:7])([CH3:4])([CH3:3])[CH3:2].CCCC[N+](CCCC)(CCCC)CCCC.[F-].O>C1COCC1>[C:1]([NH:5][S:6]([C:9]1[S:10][C:11]([C:14]2[N:19]=[C:18]([NH:20][C:21]3[CH:25]=[C:24]([CH:26]4[CH2:28][CH2:27]4)[NH:23][N:22]=3)[C:17]([CH2:29][OH:30])=[CH:16][N:15]=2)=[CH:12][CH:13]=1)(=[O:7])=[O:8])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)NS(=O)(=O)c1ccc(-c2ncc(CO[Si](C)(C)C(C)(C)C)c(Nc3cc(C4CC4)[nH]n3)n2)s1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)NS(=O)(=O)c1ccc(-c2ncc(CO)c(Nc3cc(C4CC4)[nH]n3)n2)s1
Yield: 82671.5 %

Procedure:
A solution of N-tert-butyl-5-(5-((tert-butyldimethylsilyloxy)methyl)-4-(5-cyclopropyl-1H-pyrazol-3-ylamino)pyrimidin-2-yl)thiophene-2-sulfonamide (120 mg, 0.24 mmol, 1.0 equiv.) and TBAF (0.3 ml, 0.29 mmol, 1.2 equiv.) in THF (5 mL) was stirred for 0.5 h at 23° C. Water was added and the reaction was extracted with EtOAc (3×50 ml). The combined organic phases were washed (brine), dried (Na2SO4), filtered and concentrated to afford N-tert-butyl-5-(4-(5-cyclopropyl-1H-pyrazol-3-ylamino)-5-(hydroxymethyl)pyrimidin-2-yl) thiophene-2-sulfonamide (Compound 163) (89.0 g, 86.34%) as white solid. LC-MS (m/z)=449.1 [M+H]+; 1H NMR (400 MHz, DMSO-d6): δ 0.75 (m, 2H), 0.96-0.98 (m, 2H), 1.20 (s, 9H), 1.93 (m, 1H), 4.56 (d, 4.4 Hz, 2H), 5.62 (s, 1H), 6.52 (s, 1H), 7.59 (d, J=3.6 Hz, 1H), 7.76 (d, J=3.6 Hz, 1H), 7.86 (s, 1H), 8.23 (s, 1H), 8.96 (s, 1H), 12.18 (s, 1H)
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8](F)(=[O:10])=[O:9].C[Si]([C:16]([F:19])([F:18])[F:17])(C)C>>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([C:16]([F:19])([F:18])[F:17])(=[O:10])=[O:9]
Reactant: C[Si](C)(C)C(F)(F)F
Reactant: O=S(=O)(F)c1ccccc1F
Product: O=S(=O)(c1ccccc1F)C(F)(F)F

Procedure:
reacting the 2-fluorobenzenesulfonyl fluoride, Rupert's reagent (CH3SiCF3), and tris(dimethylamino)sulfonium difluorotrimethylsilicate at about room temperature to provide 1-fluoro-2-((trifluoromethyl)sulfonyl)benzene and isolating or not isolating the 1-fluoro-2-((trifluoromethyl)sulfonyl)benzene;
Reaction SMILES: [C:1](=[O:23])([O:3][CH2:4][CH:5]1[C:17]2([OH:19])[O:18][N:12]([CH2:13][CH:14]3[CH:16]2[NH:15]3)[C:11]2[C:6]1=[C:7]([OH:22])[CH:8]=[C:9]([CH:20]=O)[CH:10]=2)[NH2:2].Cl.[CH3:25][O:26][NH2:27].C(=O)(O)[O-].[Na+]>CO>[C:1](=[O:23])([O:3][CH2:4][CH:5]1[C:17]2([OH:19])[O:18][N:12]([CH2:13][CH:14]3[CH:16]2[NH:15]3)[C:11]2[C:6]1=[C:7]([OH:22])[CH:8]=[C:9]([CH:20]=[N:27][O:26][CH3:25])[CH:10]=2)[NH2:2]
Reactant: NC(=O)OCC1c2c(O)cc(C=O)cc2N2CC3NC3C1(O)O2
Reactant: CON
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Product: CON=Cc1cc(O)c2c(c1)N1CC3NC3C(O)(O1)C2COC(N)=O
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 73.4 %

Procedure:
To a solution of 4-formyl-6,9-dihydroxy-14-oxa-1,11-diazatetracyclo[7.4.1.02,7.010,12 ]tetradeca-2,4,6-trien-8-ylmethyl carbamate (100 mg) in methanol (5 ml) were added O-methylhydroxylamine hydrochloride (105 mg) and sodium bicarbonate (106 mg). The mixture was stirred for 1.5 hours at ambient temperature and evaporated in vacuo. The residue was subjected to preparative thin layer chromatography, which was developed with a mixture of chloroform and methanol (4:1, v/v) to afford 6,9-dihydroxy-4-methoxyiminomethyl-14-oxa-1,11-diazatetracyclo[7.4.1.02,7.010,12 ]tetradeca-2,4,6-trien-8-ylmethyl carbamate (80 mg).
Reaction SMILES: [CH:1]1([NH:4][C:5]([C:7]2[C:15]3[CH:14]=[C:13]([C:16]4[C:21]([CH3:22])=[CH:20][N:19]=[C:18](Cl)[N:17]=4)[S:12][C:11]=3[CH:10]=[CH:9][CH:8]=2)=[O:6])[CH2:3][CH2:2]1.C(OC([N:31]1[CH2:36][CH2:35][CH2:34][CH:33]([CH2:37][CH2:38][CH2:39][NH2:40])[CH2:32]1)=O)(C)(C)C.C(N(C(C)C)CC)(C)C.C([SiH](CC)CC)C.C(O)(C(F)(F)F)=O.[Li+].[OH-]>O1CCOCC1.ClCCl>[CH:1]1([NH:4][C:5]([C:7]2[C:15]3[CH:14]=[C:13]([C:16]4[C:21]([CH3:22])=[CH:20][N:19]=[C:18]([NH:40][CH2:39][CH2:38][CH2:37][CH:33]5[CH2:34][CH2:35][CH2:36][NH:31][CH2:32]5)[N:17]=4)[S:12][C:11]=3[CH:10]=[CH:9][CH:8]=2)=[O:6])[CH2:3][CH2:2]1
Reactant: Cc1cnc(Cl)nc1-c1cc2c(C(=O)NC3CC3)cccc2s1
Reactant: CC(C)(C)OC(=O)N1CCCC(CCCN)C1
Agent: CC[SiH](CC)CC
Agent: [Li+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1cnc(NCCCC2CCCNC2)nc1-c1cc2c(C(=O)NC3CC3)cccc2s1
Temperature: 90 °C
Reaction time: 16 h
Yield: 23.7 %

Procedure:
A stirred mixture of 2-(2-chloro-5-methylpyrimidin-4-yl)-benzo[b]thiophene-4-carboxylic acid cyclopropylamide (0.50 g, 1.5 mmol), racemic 3-(3-aminopropyl)-piperidine-1-carboxylic acid tert-butyl ester (0.88 g, 3.6 mmol) and diisopropylethylamine (0.47 g, 3.6 mmol) in 1,4-dioxane (7 mL) is heated at 90° C. under a nitrogen atmosphere for 48 hours. After concentration and subsequent chromatography on silica gel, eluting with 2 M NH3/MeOH in dichloromethane 1-10%, the intermediate is obtained as a solid. The solid is suspended in dichloromethane (3 mL), followed by the successive addition of triethylsilane (0.50 mL) and TFA (3 mL), the resultant yellow solution is stirred for 16 hours. After concentration a wet solid is obtained. It is treated with 2 N LiOH, with sonication, until pH reaches 12. The mixture is filtered and the solid is dried before it is subjected to chromatography on silica gel, eluting with 2 M NH3/MeOH in dichloromethane 10-20%, to give the title compound as a yellow solid (160 mg, 25% yield). ES+(m/z) 450 [M+H].
Reaction SMILES: [N:1]1([CH2:7][CH2:8][CH2:9][O:10][C:11]2[CH:12]=[C:13]([CH:17]3[CH2:21][CH2:20][CH2:19][N:18]3[CH2:22][C:23]([C:25]3[CH:30]=[C:29]([O:31][CH3:32])[C:28]([O:33][CH3:34])=[C:27]([O:35][CH3:36])[CH:26]=3)=O)[CH:14]=[CH:15][CH:16]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.N>CO.C(Cl)Cl>[CH3:32][O:31][C:29]1[CH:30]=[C:25]([C@H:23]2[C:14]3[C:13](=[CH:12][C:11]([O:10][CH2:9][CH2:8][CH2:7][N:1]4[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]4)=[CH:16][CH:15]=3)[C@@H:17]3[CH2:21][CH2:20][CH2:19][N:18]3[CH2:22]2)[CH:26]=[C:27]([O:35][CH3:36])[C:28]=1[O:33][CH3:34]
Reactant: COc1cc(C(=O)CN2CCCC2c2cccc(OCCCN3CCCCC3)c2)cc(OC)c1OC
Agent: N
Solvent: CO
Solvent: ClCCl
Product: COc1cc([C@@H]2CN3CCC[C@H]3c3cc(OCCCN4CCCCC4)ccc32)cc(OC)c1OC
Yield: 85 %

Procedure:
2-{2-[3-(3-Piperidin-1-yl-propoxy)-phenyl-pyrrolidin-1-yl}-1-(3,4,5-trimethoxy-phenyl)-ethanone. Prepared as described in Example 8, Step 1, on a 3.47 mmol scale, to give 1.47 g (85%) of the desired product as a pale yellow oil after chromatography (NH3 in MeOH/CH2Cl2). MS: exact mass calcd for C29H40N2O5, 496.3; m/z found, 497.4 [M+H]+. 1H NMR (MeOH-d4): 7.10 (m, 3H), 6.86 (m, 2H), 6.68 (m, 1H), 3.85 (m, 3H), 3.72 (s, 6H), 3.71 (s, 3H), 3.35 (m, 2H), 3.22 (m, 1H), 2.36 (m, 6H), 2.07 (m, 1H), 1.86 (m, 3H), 1.72 (m, 1H), 1.65 (m, 1H), 1.50 (m, 4H), 1.37 (br s, 2H).
Reaction SMILES: [CH2:1]([C:3]1([CH2:26][OH:27])[CH2:8][O:7][C:6]2([CH2:13][CH:12]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[S:11][CH:10]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH2:9]2)[O:5][CH2:4]1)[CH3:2].[C:28](OC)(=[O:35])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>C1(C)C(C)=CC=CC=1>[CH2:1]([C:3]1([CH2:26][O:27][C:28](=[O:35])[C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH2:4][O:5][C:6]2([CH2:9][CH:10]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[S:11][CH:12]([C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=3)[CH2:13]2)[O:7][CH2:8]1)[CH3:2]
Reactant: CCC1(CO)COC2(CC(c3ccccc3)SC(c3ccccc3)C2)OC1
Reactant: COC(=O)c1ccccc1
Solvent: Cc1ccccc1C
Product: CCC1(COC(=O)c2ccccc2)COC2(CC(c3ccccc3)SC(c3ccccc3)C2)OC1
Temperature: 25 °C

Procedure:
19.2 g of 3-ethyl-3-hydroxymethyl-8,10-diphenyl-1,5-dioxa-9-thiaspiro[5.5]-undecane and 6.8 g of methyl benzoate are dissolved in 100 ml of xylene. About 20 ml of xylene are distilled off under a weak stream of nitrogen. After cooling to 110°, 0.1 g of LiNH2 are added and the mixture is heated at 135° for 8 hours, with stirring, the methanol formed being continuously distilled off together with a little xylene. After cooling to room temperature, 0.25 ml of glacial acetic acid and 3 g of bleaching earth are added. After stirring for 15 minutes, the mixture is filtered. The filtrate is filtered over 100 g of silica gel and evaporated in vacuo. The oily residue is dried at 70° in vacuo. 3-Ethyl-3-benzoyloxymethyl-8,10-diphenyl-1,5-dioxa-9-thiaspiro[5.5]-undecane is obtained as a pale yellowish resin.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([C:11]#[C:12][C:13]2[CH:23]=[CH:22][C:16]([C:17]([O:19]CC)=[O:18])=[CH:15][N:14]=2)[CH:8]=[CH:9][CH:10]=1)([CH3:4])([CH3:3])[CH3:2]>[OH-].[K+]>[C:1]([C:5]1[CH:6]=[C:7]([C:11]#[C:12][C:13]2[CH:23]=[CH:22][C:16]([C:17]([OH:19])=[O:18])=[CH:15][N:14]=2)[CH:8]=[CH:9][CH:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOC(=O)c1ccc(C#Cc2cccc(C(C)(C)C)c2)nc1
Agent: [K+]
Agent: [OH-]
Product: CC(C)(C)c1cccc(C#Cc2ccc(C(=O)O)cn2)c1

Procedure:
A solution of 60 mg (0.195 mmol) of ethyl 6-(3-tert-butylphenylethynyl)nicotinate (Compound 1) in 4 ml of aqueous ethanolic KOH was stirred at room temperature for 24 hours. The mixture was concentrated in-vacuo and the residue was treated with 5 ml of water and 5 ml of ether. The aqueous layer was separated and washed with a further 5 ml of ether. The aqueous layer was then acidified with 3 ml of 10 percent HCl and extracted with 2×5 ml of ether. The ether extracts were combined and washed with saturated NaCl solution and then dried (MgSO4). The solution was concentrated in-vacuo to give the title compound as a pale yellow solid. PMR (CDCl3): & 1.26 (9H, s), 7.25 (1H, t, J~7.8 Hz), 7.35-7.42 (2H, m), 7.56-7.63 (2H, m), 8.35 (1H, dd, J~8.2H, 2.1 Hz), 9.31 (1H, d, J~2.1 Hz).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[CH2:15][CH2:16][NH:17][CH2:18][CH:19]2[CH2:23][O:22]C(C)(C)[O:20]2)[CH:5]=[CH:4][C:3]=1[C:26]([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1[CH3:34])=[O:27].C([O-])(O)=O.[Na+]>Cl.C1COCC1>[Cl:1][C:2]1[CH:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[CH2:15][CH2:16][NH:17][CH2:18][CH:19]([OH:20])[CH2:23][OH:22])[CH:5]=[CH:4][C:3]=1[C:26]([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1[CH3:34])=[O:27]
Reactant: Cc1ccccc1C(=O)c1ccc(Nc2ccccc2CCNCC2COC(C)(C)O2)cc1Cl
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1ccccc1C(=O)c1ccc(Nc2ccccc2CCNCC(O)CO)cc1Cl
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Compound 144 was dissolved in 1M HCl/THF 1:1 (1.2 mL) and the mixture was stirred for 18 h at RT. The reaction mixture was poured into 10% aqueous NaHCO3 (10 mL) and the aqueous phase was extracted with EtOAc (3×10 mL). The combined organic phases were dried (MgSO4), filtered and evaporated in vacuo. This afforded the title compound as a yellow oil.