Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:5]1[CH:44]=[CH:43][C:8]([C:9]([NH:11][C@@H:12]([CH2:16][C:17]2[CH:22]=[CH:21][C:20]([C:23]3[N:28]=[CH:27][C:26]([C:29]4[CH:34]=[CH:33][C:32]([O:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH3:42])=[CH:31][CH:30]=4)=[CH:25][N:24]=3)=[CH:19][CH:18]=2)[C:13](O)=[O:14])=[O:10])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[NH4+].[Cl-].CC[N:49](C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C.CC(=O)OCC>[NH2:49][C:13](=[O:14])[C@@H:12]([NH:11][C:9](=[O:10])[C:8]1[CH:43]=[CH:44][C:5]([C:1]([CH3:2])([CH3:3])[CH3:4])=[CH:6][CH:7]=1)[CH2:16][C:17]1[CH:18]=[CH:19][C:20]([C:23]2[N:24]=[CH:25][C:26]([C:29]3[CH:30]=[CH:31][C:32]([O:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH3:42])=[CH:33][CH:34]=3)=[CH:27][N:28]=2)=[CH:21][CH:22]=1
Reactant: CCCCCCCOc1ccc(-c2cnc(-c3ccc(C[C@H](NC(=O)c4ccc(C(C)(C)C)cc4)C(=O)O)cc3)nc2)cc1
Reactant: CCN(C(C)C)C(C)C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: [Cl-]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCCCCCCOc1ccc(-c2cnc(-c3ccc(C[C@H](NC(=O)c4ccc(C(C)(C)C)cc4)C(N)=O)cc3)nc2)cc1
Reaction time: 8 h
Yield: 83.3 %

Procedure:
A solution of Compound 85 (245 mg, 0.413 mmol) in DMF (5 mL) was treated with NH4Cl (180 mg, 3.3 mmol), DIEA (760 μl, 4.1 mmol) and HATU (170 mg, 0.4 mmol). After stirring overnight, the reaction mixture was diluted with EA (50 mL), washed with aq. 0.5 M HCl (100 mL) and brine (20 mL), then dried over MgSO4 and concentrated. The residue was re-slurried from ACN (4 mL) to afford 204 mg (77%) of (S)—N-(1-amino-3-(4-(5-(4-(heptyloxy)phenyl)pyrimidin-2-yl)phenyl)-1-oxopropan-2-yl)-4-(tert-butyl)benzamide as a fine white solid. LCMS-ESI (m/z) calculated for C37H44N4O3: 592.3. found 593.0 [M+H]+, tR=3.43 min (Method 6).
Reaction SMILES: [S:1]1[C:5]([NH:6][S:7]([C:10]2[CH:11]=[CH:12][C:13]3[N:18]([C:19]4[CH:24]=[CH:23][C:22]([C:25]([F:28])([F:27])[F:26])=[CH:21][C:20]=4[C:29]4[CH2:34][CH2:33][N:32](C(OC(C)(C)C)=O)[CH2:31][CH:30]=4)[CH2:17][CH2:16][O:15][C:14]=3[CH:42]=2)(=[O:9])=[O:8])=[N:4][CH:3]=[N:2]1>C(Cl)Cl.C(O)(C(F)(F)F)=O>[NH:32]1[CH2:31][CH:30]=[C:29]([C:20]2[CH:21]=[C:22]([C:25]([F:28])([F:27])[F:26])[CH:23]=[CH:24][C:19]=2[N:18]2[CH2:17][CH2:16][O:15][C:14]3[CH:42]=[C:10]([S:7]([NH:6][C:5]4[S:1][N:2]=[CH:3][N:4]=4)(=[O:9])=[O:8])[CH:11]=[CH:12][C:13]2=3)[CH2:34][CH2:33]1
Reactant: CC(C)(C)OC(=O)N1CC=C(c2cc(C(F)(F)F)ccc2N2CCOc3cc(S(=O)(=O)Nc4ncns4)ccc32)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=S(=O)(Nc1ncns1)c1ccc2c(c1)OCCN2c1ccc(C(F)(F)F)cc1C1=CCNCC1
Reaction time: 0.08 h

Procedure:
Tert-butyl 4-(2-(7-(N-(1,2,4-thiadiazol-5-yl)sulfamoyl)-2H-benzo[b][1,4]oxazin-4(3H)-yl)-5-(trifluoromethyl)phenyl)-5,6-dihydropyridine-1(2H)-carboxylate (EXAMPLE 5, 30 mg) was diluted with 0.5 mL of DCM and TFA (0.5 mL) was added. After 5 minutes, complete conversion to the desired deprotected product was observed. The material was concentrated under a vacuum and purified via reverse-phase HPLC (Column: Phenomenex 150×30 mm, 5 micron, C18 column; 0.1% TFA in CH3CN/H2O, gradient 25% to 90% over 20 min) to yield 4-(2-(1,2,3,6-tetrahydropyridin-4-yl)-4-(trifluoromethyl)phenyl)-N-(1,2,4-thiadiazol-5-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-sulfonamide as a light yellow solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 2.39 (m, J=17.50 Hz, 2 H) 3.19 (m, J=12.90 Hz, 2 H) 3.59 (m, J=3.80 Hz, 2 H) 3.65-3.71 (m, 2 H) 4.30 (m, J=4.90 Hz, 2 H) 5.88 (s, 1 H) 6.48 (d, J=8.41 Hz, 1 H) 7.11-7.19 (m, 2 H) 7.59 (d, J=8.12 Hz, 1 H) 7.63 (d, J=2.05 Hz, 1 H) 7.76 (dd, J=8.41, 1.66 Hz, 1 H) 8.39 (s, 1 H) 8.77 (br. s., 2 H). m/z (ESI) 524.0 (M+H)+.
Reaction SMILES: [CH:1]1([C:10]([OH:12])=[O:11])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1.[N+:13]([O-])([OH:15])=[O:14]>ClCCl.OS(O)(=O)=O>[N+:13]([C:7]1[CH:8]=[C:9]2[C:4]([CH2:3][CH2:2][CH:1]2[C:10]([OH:12])=[O:11])=[CH:5][CH:6]=1)([O-:15])=[O:14]
Reactant: O=[N+]([O-])O
Reactant: O=C(O)C1CCc2ccccc21
Agent: O=S(=O)(O)O
Solvent: ClCCl
Product: O=C(O)C1CCc2ccc([N+](=O)[O-])cc21
Yield: 112.1 %

Procedure:
A solution of 1-indancarboxylic acid (30 g), prepared according to the method of Hansen et al. Helv. Chim. Acta 1982, 33, 325-343, in dichloromethane (50 ml) was mixed with concentrated sulphuric acid (300 ml) at −10° C. A mixture of 100% HNO3 (11.4 g) in concentrated H2SO4 (96 ml) was added dropwise under vigorous stirring below −10° C. After stirring for one hour at 10° C., the mixture was poured onto ice. Extraction with ethyl acetate (2×300 ml), drying (anh. MgSO4) and finally evaporation of the organic solvent afforded 42 g of the title compound. Mp 126-130° C.
Reaction SMILES: Br[C:2]1[C:10]2[C:5](=[CH:6][N:7]=[C:8]([O:11][CH3:12])[CH:9]=2)[S:4][CH:3]=1.[Li]CCCC.CCCCCC.C(O[B:28]1[O:32][C:31]([CH3:34])([CH3:33])[C:30]([CH3:36])([CH3:35])[O:29]1)(C)C>C1COCC1>[CH3:12][O:11][C:8]1[CH:9]=[C:10]2[C:2]([B:28]3[O:32][C:31]([CH3:34])([CH3:33])[C:30]([CH3:36])([CH3:35])[O:29]3)=[CH:3][S:4][C:5]2=[CH:6][N:7]=1
Reactant: CC(C)OB1OC(C)(C)C(C)(C)O1
Reactant: COc1cc2c(Br)csc2cn1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: COc1cc2c(B3OC(C)(C)C(C)(C)O3)csc2cn1
Temperature: -78 °C
Reaction time: 1 h
Yield: 37.7 %

Procedure:
To a cooled (−78° C.) solution of 3-bromo-5-methoxythieno[2,3-c]pyridine (14.7 mg, 0.0602 mmol) in THF (2.5 mL) was added dropwise 1.60 M n-BuLi in hexane (56.4 μL, 0.0903 mmol) in 5 min under an atmosphere of nitrogen. After stirring at −78° C. for 1 h, 2-isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (18.8 μL, 0.0903 mmol) was added dropwise. The combined mixture was stirred at −78° C. for another 1 h. The temperature was then gradually raised to RT in 40 min. The reaction was then quenched by addition of MeOH (5 mL) and purified by ISCO chromatography (0 to 20% EtOAc:hexane) to afford 6.6 mg (38%) of the title compound as a light yellow solid. 1H NMR (400 MHz, dioxane-d8): δ 8.72 (d, J=1.2 Hz, 1 H), 8.29 (s, 1 H), 7.48 (d, J=0.8 Hz, 1 H), 3.93 (s, 3 H), 1.35 (s, 12 H); MS (ESI): 292.11 [M+H]+; HPLC tR=1.71 min (TOF: polar—3 min).
Reaction SMILES: C([N:8]1[C:12]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:11][C:10]([C:19]([CH3:23])([CH3:22])[CH2:20][NH2:21])=[N:9]1)C1C=CC=CC=1>CO.[Pd]>[CH3:23][C:19]([C:10]1[CH:11]=[C:12]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[NH:8][N:9]=1)([CH3:22])[CH2:20][NH2:21]
Reactant: CC(C)(CN)c1cc(-c2ccccc2)n(Cc2ccccc2)n1
Agent: [Pd]
Solvent: CO
Product: CC(C)(CN)c1cc(-c2ccccc2)[nH]n1
Reaction time: 72 h

Procedure:
2-(1-Benzyl-5-phenyl-1H-pyrazol-3-yl)-2-methylpropan-1-amine (50 mg, 0.2 mmol) was stirred under an atmosphere of hydrogen in methanol/concentrated sulfuric acid (5:1, 5 mL) with 5% palladium on carbon (350 mg). After several h, more palladium on carbon was added (350 mg). The reaction was stopped after 3 days with starting material remaining. The solution was degassed and filtered through Celite. Methanol was removed under vacuum and 1 M potassium carbonate was added until the reaction was basic. The slurry was extracted multiple times with 30% isopropanol/chloroform. The combined organic layers were dried over sodium sulfate and concentrated under reduced pressure to yield 2-methyl-2-(5-phenyl-1H-pyrazol-3-yl)propan-1-amine, which was carried through without further purification.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C@@H:11]([OH:13])[CH2:10][C@H:9]1[C:14]([OH:16])=[O:15])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:17](Br)[CH3:18]>C(OCC)(=O)C>[CH3:17][CH2:18][O:15][C:14]([C@@H:9]1[CH2:10][C@H:11]([OH:13])[CH2:12][N:8]1[C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])=[O:16]
Reactant: CC(C)(C)OC(=O)N1C[C@@H](O)C[C@H]1C(=O)O
Reactant: CCBr
Solvent: CCOC(C)=O
Product: CCOC(=O)[C@@H]1C[C@H](O)CN1C(=O)OC(C)(C)C
Reaction time: 0.08 h

Procedure:
To a stirred solution of (2S,4S)-4-hydroxy-pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester (1.0 eq, 5.0 g) in ethyl acetate (250 mL) was added dicyclohexamine (2.0 eq, 8.62 mL) and the reaction stirred for 5 mins during which time a white precipitate formed. Part of the ethyl acetate was evaporated and the slurry left to stand for 30 mins, then filtered and washed with diethyl ether (30 mL). The filtrate was dried briefly under high vacuum and then resuspended in anhydrous DMF (50 mL). The reaction mixture was then treated with ethyl bromide (4.0 eq, 6.46 mL) and stirred in a sealed flask for 18 hours. TLC and MS revealed that the reaction was complete. The reaction mixture was filtered and washed with ethyl acetate (2×20 mL). The filtrate was then evaporated to dryness, the residue taken up in ethyl acetate (50 mL) and the organic layer washed once with water and once with brine, dried over sodium sulfate, filtered and evaporated to yield a colourless oil (4.87 g; 87%). The crude product was used without further purification. MS (ESI): m/z=204.1 [M+H-Boc]+.
Reaction SMILES: [C:1]([SiH2:5][O:6][C:7]([CH3:25])([CH3:24])[C:8]1[CH:13]=[CH:12][N:11]=[CH:10][C:9]=1[C:14]1[N:15]([CH3:23])[C:16]2[C:21]([CH:22]=1)=[CH:20][CH:19]=[CH:18][CH:17]=2)([CH3:4])([CH3:3])[CH3:2].ClS([N:30]=[C:31]=O)(=O)=O.CN(C=O)C>C(Cl)Cl>[C:1]([SiH2:5][O:6][C:7]([CH3:25])([CH3:24])[C:8]1[CH:13]=[CH:12][N:11]=[CH:10][C:9]=1[C:14]1[N:15]([CH3:23])[C:16]2[C:21]([C:22]=1[C:31]#[N:30])=[CH:20][CH:19]=[CH:18][CH:17]=2)([CH3:4])([CH3:3])[CH3:2]
Reactant: Cn1c(-c2cnccc2C(C)(C)O[SiH2]C(C)(C)C)cc2ccccc21
Reactant: O=C=NS(=O)(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: Cn1c(-c2cnccc2C(C)(C)O[SiH2]C(C)(C)C)c(C#N)c2ccccc21
Reaction time: 0.08 h

Procedure:
To a solution of 2-[4-(tert-butyl-dimethyl-silanyloxymethyl)-pyridin-3-yl]-1-methyl-1H-indole (0.263 g, 0.747 mmol) in DCM (5 mL) is added chlorosulfonyl isocyanate (0.162 mL, 1.867 mmol). After 5 min, DMF (1 mL) is added. After another 30 min, the reaction is concentrated under vacuo to afford 2-[4-(tert-butyl-dimethyl-silanyloxymethyl)-pyridin-3-yl]-1-methyl-1H-indole-3-carbonitrile as a light yellow solid, which is redissolved in DCM (3 mL). 4 M HCl in 1,4-dioxane (1 mL) is added, and the mixture is stirred at room temperature for 30 min. Purification by reverse phase HPLC with Xbridge Shield RP18 column and a 0.1% aqueous NH4OH in acetonitrile gradient affords 2-(4-hydroxymethyl-pyridin-3-yl)-1-methyl-1H-indole-3-carbonitrile as a solid. 1H NMR (400 MHz, MeOD) δ ppm 3.67 (s, 3H), 4.44-4.67 (m, 2H), 7.39 (t, J=7.6 Hz, 1H), 7.47 (t, J=8.3 Hz, 1H), 7.66 (d, J=8.3 Hz, 1H), 7.74 (d, J=7.8 Hz, 1H), 7.87 (d, J=5.3 Hz, 1H), 8.60 (s, 1H), 8.80 (d, J=5.3 Hz, 1H). HRMS (ESI) m/z 264.1142 [(M+H)+ Calcd for C16H14N3O: 264.11379].
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([C:8](=[O:19])[C:9]2[CH:14]=[CH:13][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:11][CH:10]=2)[N:3]=1.BrC1C=CC=C(Br)N=1.FC(F)(F)C1C=CC(C#N)=CC=1.C([Li])CCC.[C:45]([O:49][CH2:50][CH3:51])(=[O:48])[CH:46]=[CH2:47].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>CCOCC.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C(N(CC)CC)C>[CH2:50]([O:49][C:45](=[O:48])/[CH:46]=[CH:47]/[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([C:8](=[O:19])[C:9]2[CH:14]=[CH:13][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:11][CH:10]=2)[N:3]=1)[CH3:51]
Reactant: C=CC(=O)OCC
Reactant: O=C(c1ccc(C(F)(F)F)cc1)c1cccc(Br)n1
Agent: [Pd+2]
Agent: Brc1cccc(Br)n1
Agent: CC(=O)[O-]
Solvent: CCN(CC)CC
Solvent: CCOCC
Product: CCOC(=O)/C=C/c1cccc(C(=O)c2ccc(C(F)(F)F)cc2)n1
Temperature: 150 °C
Reaction time: 6 h

Procedure:
2-Bromo-6-(4-trifluoromethylbenzoyl)pyridine, m.p. 66°-68° C. (prepared by reacting 2,6-dibromopyridine and 4-trifluoromethylbenzonitrile in dry ether in the presence of butyllithium) ethyl acrylate, triethylamine, palladium(II) acetate, triphenylphosphine and acetronitrile were heated at 150° C. in an autoclave with stirring for six hours to yield (E)-ethyl-3-[6-(4-trifluoromethylbenzoyl)-2-pyridyl]acrylate, m.p. 129°-132° C. Butyllithium was added under nitrogen to a stirred suspension of triphenyl-2-pyrrolidinoethylphosphonium bromide in dry toluene to form a Wittig reagent. After 0.5 hours, the acrylate compound prepared above, in toluene was added and the resulting suspension was heated at 75° C. with stirring for 2 hours. The cooled solution was diluted with ether and treated with hydrochloric acid (2M). The aqueous phase was separated, washed with ether, and basified with potassium carbonate (ice) and extracted with ether. The mixture of isomeric esters obtained by evaporation was dissolved in ethanol containing sodium hydroxide solution (1M) and partially evaporated on the steam bath under reduced pressure for 5 minutes. The residual aqueous solution was neutralized with sulfuric acid and evaporated to dryness. The solid residue was extracted with hot isopropanol and the extracts were concentrated until crystallization commenced. The (E)-3-{6-[3-pyrrolidino-1-(4-Trifluoromethylphenyl)prop-1E-enyl]-2-pyridyl}acrylic acid after recrystallization from isopropanol, melted at m.p. 223°-225° C. (decomp).
Reaction SMILES: [CH3:1][C:2]1[C:7]([B:8]2[O:12][C:11]([CH3:14])([CH3:13])[C:10]([CH3:16])([CH3:15])[O:9]2)=[CH:6][CH:5]=[CH:4][C:3]=1[NH2:17].C(N(CC)CC)C.[CH:25]([O:28][C:29]1[CH:37]=[CH:36][C:32]([C:33](O)=[O:34])=[CH:31][CH:30]=1)([CH3:27])[CH3:26].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[CH:25]([O:28][C:29]1[CH:37]=[CH:36][C:32]([C:33]([NH:17][C:3]2[CH:4]=[CH:5][CH:6]=[C:7]([B:8]3[O:12][C:11]([CH3:13])([CH3:14])[C:10]([CH3:16])([CH3:15])[O:9]3)[C:2]=2[CH3:1])=[O:34])=[CH:31][CH:30]=1)([CH3:27])[CH3:26]
Reactant: CC(C)Oc1ccc(C(=O)O)cc1
Reactant: Cc1c(N)cccc1B1OC(C)(C)C(C)(C)O1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Cc1c(NC(=O)c2ccc(OC(C)C)cc2)cccc1B1OC(C)(C)C(C)(C)O1
Temperature: 25 °C
Reaction time: 19 h
Yield: 88 %

Procedure:
To a solution of 117 mg (0.500 mmol) of 2-Methyl-3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenylamine, 0.26 mL (1.5 mmol) of triethylamine, and 4-isopropoxybenzoic acid in 2.5 mL of DMF was added HATU at RT. The reaction mixture was stirred at RT for 19 hours then partitioned between 50 mL of EtOAc and 50 mL of water. The organic layer was washed with 50 mL of saturated NaHCO3 solution, dried (MgSO4) and concentrated. Column chromatography (0->30% ethyl acetate/hexanes in 10 minutes) gave 175 mg (0.443 mmol, 88%) of the title compound.
Reaction SMILES: [C:1]([C:5]1[O:9][N:8]=[C:7]([NH:10][C:11](=[O:38])[NH:12][C:13]2[CH:18]=[CH:17][C:16]([C:19]3[N:23]4[CH:24]=[CH:25][C:26]([C:28]5[CH:36]=[CH:35][C:31]([C:32](O)=[O:33])=[CH:30][CH:29]=5)=[CH:27][C:22]4=[N:21][CH:20]=3)=[CH:15][C:14]=2[F:37])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[C:39]([O:43][C:44]([N:46]1[CH2:51][CH2:50][NH:49][CH2:48][CH2:47]1)=[O:45])([CH3:42])([CH3:41])[CH3:40].Cl.CN(C)CCCN=C=NCC.C(N(CC)CC)C.ON1C2C=CC=CC=2N=N1>CN(C=O)C>[C:39]([O:43][C:44]([N:46]1[CH2:51][CH2:50][N:49]([C:32](=[O:33])[C:31]2[CH:35]=[CH:36][C:28]([C:26]3[CH:25]=[CH:24][N:23]4[C:19]([C:16]5[CH:17]=[CH:18][C:13]([NH:12][C:11]([NH:10][C:7]6[CH:6]=[C:5]([C:1]([CH3:2])([CH3:3])[CH3:4])[O:9][N:8]=6)=[O:38])=[C:14]([F:37])[CH:15]=5)=[CH:20][N:21]=[C:22]4[CH:27]=3)=[CH:29][CH:30]=2)[CH2:48][CH2:47]1)=[O:45])([CH3:42])([CH3:40])[CH3:41]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: CC(C)(C)c1cc(NC(=O)Nc2ccc(-c3cnc4cc(-c5ccc(C(=O)O)cc5)ccn34)cc2F)no1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCN(C(=O)c2ccc(-c3ccn4c(-c5ccc(NC(=O)Nc6cc(C(C)(C)C)on6)c(F)c5)cnc4c3)cc2)CC1
Temperature: 25 °C
Reaction time: 14 h

Procedure:
Combine 4-(3-{4-[3-(5-tert-Butyl-isoxazol-3-yl)-ureido]-3-fluoro-phenyl}-imidazo[1,2-a]pyridin-7-yl)-benzoic acid (2.00 g, 3.89 mmol), piperazine-1-carboxylic acid tert-butyl ester (1.09 g, 5.84 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.821 g, 4.28 mmol), triethylamine (1.63 mL, 11.68 mmol), and 1-hydroxybenzotriazole (0.579 g, 4.28 mmol) in DMF (50 mL). Stir at room temperature for 14 hours. Partition between ethyl acetate and 1 N NaOH, wash with aqueous saturated sodium chloride, dry over magnesium sulfate, filter, and concentrate. Triturate the resulting solid from CH2Cl2/hexanes, filter, and dry to give off-white solid as product (1.53 g, 58%). MS (ES), m/z 683 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:20])[NH:4][CH:5]1[CH2:17][C:16]2[C:15]3[C:10](=[CH:11][CH:12]=[C:13]([C:18]#[N:19])[CH:14]=3)[NH:9][C:8]=2[CH2:7][CH2:6]1.C[Si]([N-][Si](C)(C)C)(C)C.[K+].[F:31][C:32]1[CH:33]=[C:34]([CH:37]=[CH:38][CH:39]=1)[CH2:35]Br>CN(C)C=O>[CH3:1][O:2][C:3](=[O:20])[NH:4][CH:5]1[CH2:17][C:16]2[C:15]3[C:10](=[CH:11][CH:12]=[C:13]([C:18]#[N:19])[CH:14]=3)[N:9]([CH2:35][C:34]3[CH:37]=[CH:38][CH:39]=[C:32]([F:31])[CH:33]=3)[C:8]=2[CH2:7][CH2:6]1
Reactant: Fc1cccc(CBr)c1
Reactant: COC(=O)NC1CCc2[nH]c3ccc(C#N)cc3c2C1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)NC1CCc2c(c3cc(C#N)ccc3n2Cc2cccc(F)c2)C1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 74 %

Procedure:
Combine (6-cyano-2,3,4,9-tetrahydro-1H-carbazol-3-yl)-carbamic acid methyl ester (460 mg, 1.7 mmol) and anhydrous dimethylformamide (15 mL) under nitrogen. Chill the mixture to 0° C. and add potassium bis(trimethylsilyl)amide (0.5M toluene solution, 3.4 mL, 1.7 mmol). Stir the resulting mixture for 30 minutes, then add 3-fluorobenzyl bromide (210 μL, 1.7 mmol) and stir the reaction mixture for 4 h allowing slow warming to room temperature. Quench the reaction with water (50 mL) and extract the product with ethyl acetate (2×50 mL). Dry the combined extracts with magnesium sulfate and concentrate in vacuo. Purify the product via flash chromatography (25% ethyl acetate/hexanes isocratic) to afford 475 mg (74%) of a white solid. LCMS (Method E): 100% (m/z) 378 (M+1, APCI-pos); 1H NMR (DMSO, 400 MHz): δ 11.33 (s, 1H), 7.85 (s, 1H), 7.46 (d, 1H, J=7.9 Hz), 7.39-7.27 (m, 7H), 5.03 (q, 2H, J=8.8 Hz), 3.87-3.75 (m, 1H), 3.87-3.75 (m, 1H), 2.96 (dd, 1H, J=15.2, 5.1 Hz), 2.85-2.77 (m, 2H), 2.55-2.49 (m, 1H), 2.07-1.97 (m, 1H), 1.85-1.71 (m, 1H).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][C@H:10]1[CH2:15][CH2:14][C@H:13]([C:16]([OH:18])=O)[CH2:12][CH2:11]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.[CH3:20][NH:21][O:22][CH3:23].CN1CCOCC1.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1>C(Cl)Cl>[C:1]([O:5][C:6](=[O:7])[NH:8][CH2:9][C@H:10]1[CH2:11][CH2:12][C@H:13]([C:16](=[O:18])[N:21]([O:22][CH3:23])[CH3:20])[CH2:14][CH2:15]1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)NC[C@H]1CC[C@H](C(=O)O)CC1
Reactant: CNOC
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: CON(C)C(=O)[C@H]1CC[C@H](CNC(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A solution of 81 g (314.77 mmol) trans-4-[(tert-Butoxyformamido)methyl]cyclohexanecarboxylic acid in 4 l CH2Cl2 was treated with 50.13 g (503.63 mmol) N,O-dimethyl-hydroxylamine hydrochloride, 55.37 ml (503.63 mmol) N-methylmorpholine and at 0° C. with 78.45 g (409.2 mmol) EDCI and 9.67 g (62.95 mmol) HOBT. The reaction mixture was stirred 16 h at room temperature, evaporated and extracted with aqueous 10% KHSO4/Et2O (3×). The organic phases were washed with aqueous saturated NaHCO3, 10% NaCl and dried over Na2SO4 to yield 100.03 g (quantitative) of trans-[4-(Methoxy-methyl-carbamoyl)-cyclohexylmethyl]-carbamic acid tert-butyl ester, MS: 301 (MH+).
Reaction SMILES: Cl[C:2]1[C:3](=[O:18])[N:4]([CH2:14][CH2:15][O:16][CH3:17])[C:5](=[O:13])[C:6]=1[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[F:19][CH:20]([F:29])[O:21][C:22]1[CH:28]=[CH:27][C:25]([NH2:26])=[CH:24][CH:23]=1>CN(C=O)C>[F:19][CH:20]([F:29])[O:21][C:22]1[CH:23]=[CH:24][C:25]([NH:26][C:2]2[C:3](=[O:18])[N:4]([CH2:14][CH2:15][O:16][CH3:17])[C:5](=[O:13])[C:6]=2[C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[CH:27][CH:28]=1
Reactant: Nc1ccc(OC(F)F)cc1
Reactant: COCCN1C(=O)C(Cl)=C(c2ccccc2)C1=O
Solvent: CN(C)C=O
Product: COCCN1C(=O)C(Nc2ccc(OC(F)F)cc2)=C(c2ccccc2)C1=O
Temperature: 150 °C
Yield: 25.7 %

Procedure:
3-Chloro-1-(2-methoxyethyl)-4-phenyl-1H-pyrrole-2,5-dione (0.13 mmol, 36 mg) and 4-difluoromethoxyaniline (0.28 mmol, 45 mg) were dissolved in DMF (1 mL). The mixture was heated in a microwave reactor at 150° C. for 20 min. After cooling, the reaction mixture was purified by HPLC (95% 0.1M ammonium acetate buffer: 5% CH3CN→100% CH3CN) to give 13 mg (24%) of the title compound. 1H NMR (400 MHz, CDCl3): δ 7.25 (bs, 1H), 7.19-7.08 (m, 3H), 7.02-6.97 (m, 2H), 6.81-6.75 (m, 2H), 6.66-6.60 (m, 2H), 6.36 (t, J=74.0 Hz, 1H), 3.83 (t, J=5.7 Hz, 2H), 3.63 (t, J=5.7 Hz, 2H), 3.38 (s, 3H)
Reaction SMILES: I[Si](C)(C)C.O1CCCC1.C1(C[O:18][C:19]2[CH:24]=[CH:23][C:22]([C:25]3[CH:33]=[C:32]4[C:28]([C:29]([NH:34][C:35](=[O:39])[CH2:36][CH2:37][CH3:38])=[N:30][NH:31]4)=[CH:27][CH:26]=3)=[CH:21][CH:20]=2)C=CC=CC=1>C(#N)C>[OH:18][C:19]1[CH:20]=[CH:21][C:22]([C:25]2[CH:33]=[C:32]3[C:28]([C:29]([NH:34][C:35](=[O:39])[CH2:36][CH2:37][CH3:38])=[N:30][NH:31]3)=[CH:27][CH:26]=2)=[CH:23][CH:24]=1
Reactant: CCCC(=O)Nc1n[nH]c2cc(-c3ccc(OCc4ccccc4)cc3)ccc12
Agent: C[Si](C)(C)I
Solvent: CC#N
Solvent: C1CCOC1
Product: CCCC(=O)Nc1n[nH]c2cc(-c3ccc(O)cc3)ccc12
Temperature: 82 °C
Reaction time: 17 h

Procedure:
0.15 cm3 of iodotrimethylsilane and then 5 cm3 of tetrahydrofuran are added to 200 mg of N-[6-[4-(phenylmethoxy)phenyl]-1H-indazol-3-yl]butanamide, described previously, in 7.5 cm3 of acetonitrile, and the medium is heated at about 82° C. for 2 hours. 0.15 cm3 of iodotrimethylsilane is added and heating is continued for 17 hours. The reaction medium is then evaporated to dryness under reduced pressure (2 kPa; 40° C.). The residue is taken up in 75 cm3 of ethyl acetate, and this mixture is then washed with 2×50 cm3 of saturated aqueous sodium sulphate solution and with 50 cm3 of saturated sodium chloride solution. The organic phase is dried over magnesium sulphate, filtered and then evaporated under reduced pressure (2 kPa; 45° C.). The residue is purified by chromatography under an argon pressure of 50 kPa, on a column of silica gel (particle size 40-60 μm; diameter 1.5 cm), eluting with ethyl acetate and collecting 30 cm3 fractions. The fractions containing the expected product are combined and evaporated under reduced pressure (2 kPa; 50° C.). The residue is washed with 3×5 cm3 of diisopropyl ether. It is filtered off on a sinter funnel and, after drying (90 Pa; 40° C.), 100 mg of N-[6-(4-hydroxyphenyl)]-1H-indazol-3-yl]butanamide are thus obtained in the form of a white solid melting at about 235° C.
Reaction SMILES: C(OCC[CH:6]([C:31]([OH:33])=[O:32])[N:7]([CH2:18][P:19]([S:26][CH2:27][CH2:28][CH2:29][CH3:30])([S:21][CH2:22][CH2:23][CH2:24][CH3:25])=[S:20])[C:8](OCC1C=CC=CC=1)=O)C.Br.[CH2:35]([O:37][CH2:38]C)[CH3:36]>C(O)(=O)C>[CH2:35]([O:37][CH2:38][CH2:8][N:7]([CH2:18][P:19]([S:21][CH2:22][CH2:23][CH2:24][CH3:25])([S:26][CH2:27][CH2:28][CH2:29][CH3:30])=[S:20])[CH2:6][C:31]([OH:33])=[O:32])[CH3:36]
Reactant: CCCCSP(=S)(CN(C(=O)OCc1ccccc1)C(CCOCC)C(=O)O)SCCCC
Reactant: CCOCC
Agent: Br
Solvent: CC(=O)O
Product: CCCCSP(=S)(CN(CCOCC)CC(=O)O)SCCCC
Reaction time: 6 h

Procedure:
2-Ethoxyethyl-N-[bis(butylthio)phosphinothioylmethyl]-N-(benzyloxycarbonyl)glycine (9.2 g., 0.017 mole) was dissolved in 30 ml. of 35% hydrobromic acid in acetic acid. The reaction was stirred for approximately 6 hours. Diethyl ether was added which precipitated a viscous oil. The oil was washed three additional times with diethyl ether and then dissolved in benzene. The benzene solution was treated with excess propylene oxide. The propylene oxide treated solution was concentrated in vacuo and the residue chromatographed on silica gel employing diethyl ether as an eluant to yield 2-ethoxyethyl-N-[bis(butylthio)phosphinothioylmethyl]glycine as an oil, ND25 =1.5490, which gave the following analysis.