Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][CH:2]1[CH2:8][N:7]([C:9]2[N:13]([CH3:14])[N:12]=[CH:11][C:10]=2[N+:15]([O-])=O)[CH2:6][CH2:5][CH:4]([NH:18]C(=O)OC(C)(C)C)[CH2:3]1.C(OC([NH:33][C:34]1[S:38][C:37]([C:39]2[C:44]([F:45])=[CH:43][CH:42]=[CH:41][C:40]=2[F:46])=[N:36][C:35]=1[C:47](O)=[O:48])=O)(C)(C)C.CO.C(Cl)Cl.N>CO>[NH2:33][C:34]1[S:38][C:37]([C:39]2[C:44]([F:45])=[CH:43][CH:42]=[CH:41][C:40]=2[F:46])=[N:36][C:35]=1[C:47]([NH:15][C:10]1[CH:11]=[N:12][N:13]([CH3:14])[C:9]=1[N:7]1[CH2:6][CH2:5][CH:4]([NH2:18])[CH2:3][CH:2]([F:1])[CH2:8]1)=[O:48]
Reactant: Cn1ncc([N+](=O)[O-])c1N1CCC(NC(=O)OC(C)(C)C)CC(F)C1
Reactant: CC(C)(C)OC(=O)Nc1sc(-c2c(F)cccc2F)nc1C(=O)O
Agent: N
Solvent: CO
Solvent: ClCCl
Product: Cn1ncc(NC(=O)c2nc(-c3c(F)cccc3F)sc2N)c1N1CCC(N)CC(F)C1

Procedure:
Following the procedure for Example 101, Intermediate 20, tert-butyl 6-fluoro-1-(1-methyl-4-nitro-1H-pyrazol-5-yl)azepan-4-ylcarbamate and 5-(tert-butoxycarbonylamino)-2-(2,6-difluorophenyl)thiazole-4-carboxylic acid from Example 25 gave, after silica gel column chromatography (0-10% MeOH/DCM, 1% 7 N ammonia in MeOH), a white solid (273 mg, 19% over three steps). Compound 154 was obtained as a single enantiomer from SFC chiral separation of the racemic mixture. 1H NMR (400 MHz, DMSO) δ 8.77 (s, 1H), 7.61-7.41 (m, 4H), 7.27 (dd, J=14.5, 5.8 Hz, 2H), 4.84-4.56 (m, 1H), 3.67 (d, J=7.4 Hz, 3H), 3.44-3.34 (m, 2H), 3.21-2.86 (m, 3H), 2.22-2.07 (m, 1H), 1.87 (ddt, J=34.3, 21.1, 7.4 Hz, 3H), 1.70-1.53 (m, 1H). MS (ESI) m/z: 466.1 [M+H+].
Reaction SMILES: I[C:2]1[N:3]=[CH:4][N:5]2[C:11]3[S:12](=[O:15])[CH:13]=[CH:14][C:10]=3[CH2:9][N:8]([CH3:16])[CH2:7][C:6]=12.[CH3:17][C:18]([OH:22])([C:20]#[CH:21])[CH3:19]>C(NCC)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[OH:22][C:18]([CH3:19])([CH3:17])[C:20]#[C:21][C:2]1[N:3]=[CH:4][N:5]2[C:11]3[S:12](=[O:15])[CH:13]=[CH:14][C:10]=3[CH2:9][N:8]([CH3:16])[CH2:7][C:6]=12
Reactant: CN1CC2=C(n3cnc(I)c3C1)S(=O)C=C2
Reactant: C#CC(C)(C)O
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCNCC
Product: CN1CC2=C(n3cnc(C#CC(C)(C)O)c3C1)S(=O)C=C2

Procedure:
5.52 g of 5,6-dihydro-7-iodo-5-methyl-4H-imidazo[1,5-a]thieno[3,2-f][1,4]diazepine-one in 30 ml of diethylamine was treated with 1.92 ml of 2-methyl-3-butyn-2-ol, 75 mg of bis-(triphenylphosphine)-palladium(II) chloride and 13 mg of copper(I) iodide. The mixture was stirred at reflux temperature for 2 hours. The reaction mixture was then evaporated in a vacuum. The residue was dissolved in dichloromethane and this solution was washed twice with water. After drying over sodium sulphate this solution was chromatographed through 300 g of silica gel. Unreacted starting material was first recovered with dichloromethane/ethanol mixtures 99:1, 98:2 and 97:3. There was then eluted with dichloromethane/ethanol mixtures 96:4 and 95:5 an oily substance which crystallized from ethyl acelate/diethyl ether. There was obtained 5,6-dihydro-7-(3-hydroxy-3-methyl-1-butynyl)-5-methyl-4H-imidazo[1,5-a]-thieno[3,2-f][1,4]diazepine-one of melting point 180°-181°.
Reaction SMILES: C([Li])CCC.C([Mg]Cl)CCC.Br[C:13]1[CH:14]=[C:15]([OH:20])[CH:16]=[C:17]([Br:19])[CH:18]=1.CN([CH:24]=[O:25])C>C1(C)C=CC=CC=1>[Br:19][C:17]1[CH:18]=[C:13]([CH:14]=[C:15]([OH:20])[CH:16]=1)[CH:24]=[O:25]
Reactant: CN(C)C=O
Reactant: Oc1cc(Br)cc(Br)c1
Agent: CCCC[Mg]Cl
Agent: [Li]CCCC
Solvent: Cc1ccccc1
Product: O=Cc1cc(O)cc(Br)c1
Temperature: -10 °C
Reaction time: 0.5 h

Procedure:
To a toluene solution (1.6 M) of n-butyl lithium (2.5 M hexane solution, 2.1 eq.) was added at −10° C. n-butyl magnesium chloride (2.0 M THF solution, 0.6 eq.). The reaction mixture was stirred at −10° C. for 30 min before a toluene solution (0.7 M) of 3,5-dibromophenol (1 eq.) was added dropwise at −10° C. over a period of 35 min. After stirring at −10° C. for a further 30 min, the reaction mixture was cooled to −40° C. before DMF (20 eq.) was added dropwise over 20 min. The reaction mixture was then slowly warmed to rt and allowed to stir at rt for 1 h. The reaction was carefully quenched at 0° C. with 10% aqueous HCl and extracted with ether. The combined organic extracts were washed with water and brine and dried over MgSO4. Concentration of the filtrate in vacuo afforded a yellow solid. Recrystallization of the crude product in ether/hexane afforded the title compound as a beige powder.
Reaction SMILES: [CH2:1]([N:3]([CH2:33][CH3:34])[CH2:4]/[CH:5]=[CH:6]\[C:7]1[CH:12]=[C:11]([F:13])[CH:10]=[CH:9][C:8]=1[S:14]([NH:17][C:18]1[C:27]([C:28]([O:30][CH3:31])=[O:29])=[C:26]2[C:21]([CH:22]3[CH2:32][CH:23]3[CH2:24][O:25]2)=[CH:20][CH:19]=1)(=[O:16])=[O:15])[CH3:2].Br[C:36]1C=C(F)C=CC=1S(NC1C(C(OC)=O)=C2C(C3(C)CC3CO2)=CC=1)(=O)=O.C(N(CC)C/C=C\[Sn](CCCC)(CCCC)CCCC)C>>[CH2:33]([N:3]([CH2:1][CH3:2])[CH2:4]/[CH:5]=[CH:6]\[C:7]1[CH:12]=[C:11]([F:13])[CH:10]=[CH:9][C:8]=1[S:14]([NH:17][C:18]1[C:27]([C:28]([O:30][CH3:31])=[O:29])=[C:26]2[C:21]([C:22]3([CH3:36])[CH2:32][CH:23]3[CH2:24][O:25]2)=[CH:20][CH:19]=1)(=[O:15])=[O:16])[CH3:34]
Reactant: COC(=O)c1c(NS(=O)(=O)c2ccc(F)cc2Br)ccc2c1OCC1CC21C
Reactant: CCN(CC)C/C=C\c1cc(F)ccc1S(=O)(=O)Nc1ccc2c(c1C(=O)OC)OCC1CC21
Agent: CCCC[Sn](/C=C\CN(CC)CC)(CCCC)CCCC
Product: CCN(CC)C/C=C\c1cc(F)ccc1S(=O)(=O)Nc1ccc2c(c1C(=O)OC)OCC1CC21C

Procedure:
Prepared by proceeding in a similar manner to Intermediate 40, starting from methyl (1aRS,7bSR)-5-(2-bromo-4-fluorobenzenesulfonylamino)-7b-methyl-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-4-carboxylate (Intermediate 49) and N,N-diethyl-N—((Z)-1-tributylstannanylprop-1-en-3-yl)amine (Intermediate 11).
Reaction SMILES: [OH:1][CH:2]([CH2:16][CH2:17][S:18][CH3:19])[C:3]([O:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15])=[O:4].C1C=C(Cl)C=C(C(OO)=[O:28])C=1>ClCCl>[OH:1][CH:2]([CH2:16][CH2:17][S:18]([CH3:19])=[O:28])[C:3]([O:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15])=[O:4]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CCCCCCCCCCOC(=O)C(O)CCSC
Solvent: ClCCl
Product: CCCCCCCCCCOC(=O)C(O)CCS(C)=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 102.5 %

Procedure:
To a solution of decyl 2-hydroxy-4-(methylthio)butanoate (20.05 g, 69.03 mmol) in dichloromethane (300 mL) at 0° C. was added mCPBA (77%, 14.7 g, 65.6 mmol) portionwise over 30 min. The resulting mixture was allowed to warm to room temperature with stirring overnight. Another portion of mCPBA (77%, 1.4 g, 6.25 mmol) was added to the solution at 0° C. and the resulting mixture was allowed to warm to room temperature with stirring over the weekend. The reaction was washed with 10% sodium bisulfite (2×100 mL), saturated sodium bicarbonate (3×150 mL), 1N HCl (1×150 mL), and brine (1×200 mL). The organic layer was dried over magnesium sulfate, filtered and evaporated to give a crude oil. The oil was purified by silica gel chromatography with 0-6% methanol/dichloromethane to give a light yellow oil (20.61 g, 97%). 1H NMR (500 MHz, DMSO-d6) δ ppm 0.85 (t, J=6.83 Hz, 3 H) 1.10-1.37 (m, 14 H) 1.50-1.65 (m, 2 H) 1.80-1.93 (m, 1 H) 1.97-2.08 (m, 1 H) 2.52 (d, J=3.81 Hz, 3 H) 2.60-2.75 (m, 1 H) 2.75-2.91 (m, 1 H) 3.98-4.12 (m, 2 H) 4.12-4.20 (m, 1 H) 5.62 (dd, J=5.72, 2.54 Hz, 1 H). m/z 307 (MH+).
Reaction SMILES: C([Li])CCC.[OH:6][CH2:7][C:8]1[N:12]=[C:11]([CH3:13])[O:10][N:9]=1.CN(C)CCN(C)C.[C:22](=[O:24])=[O:23]>CCCCCC.O1CCCC1>[OH:6][CH2:7][C:8]1[N:12]=[C:11]([CH2:13][C:22]([OH:24])=[O:23])[O:10][N:9]=1
Reactant: O=C=O
Reactant: Cc1nc(CO)no1
Agent: CN(C)CCN(C)C
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: O=C(O)Cc1nc(CO)no1
Temperature: 35 °C
Yield: 55 %

Procedure:
Under anhydrous conditions, a solution of approximately 1.2 mol of n-butyl lithium in n-hexane was added dropwise over 3 hours to an efficiently cooled solution of 66 g (0.58 mol) of 3-hydroxymethyl-5-methyl-1,2,4-oxadiazol and 87 ml of N,N,N',N'-tetramethyl ethylene diamine in 1200 ml of tetrahydrofuran and during the addition, the reaction temperature was not allowed to rise above -70° C. The reaction mixture was stirred for 1 hour at -70° C. and under efficient cooling, dried gaseous carbon dioxide was passed over the surface of the stirred reaction mixture for ten hours at -70° C. Subsequently, the temperature was allowed to rise gradually to -5° C. and the formed precipitate was collected by vacuum filtration and was washed with dry ethyl acetate and with n-hexane. The precipitate was dissolved slowly by adding it in small portions to a stirred icy-cold mixture of 500 ml of water and 500 ml of diethyl ether and concentrated phosphoric acid was added till the pH was 4.0. The layers were separated and the organic layer discarded. The water-layer was further acidified to a pH of 2.0 and subsequently evaporated in vacuo. Remnants of water in the residue were removed in vacuo with the help of benzene and the residue was dried in vacuo over phosphorous pentoxide for 16 hours. The syrupy product was stirred with 500 ml of acetone at about 35° C. and the acetone was decanted. This was repeated once whereupon the residue became a solid mass which was transferred to a filter and repeatedly stirred with 500 ml portions of acetone until according to thin-layer chromatograms the filtrate no longer contained the desired compound. All filtrates were combined (total of about 4000 ml) and concentrated in vacuo to a volume of about 300 ml. 600 ml of ethyl acetate were added and the resulting solution was again concentrated in vacuo to a final volume of about 250 ml. The resulting crystalline precipitate was vacuum filtered, washed with dry ethyl acetate and with carbon tetrachloride. After drying in vacuo, 41 g of 3-hydroxymethyl-1,2,4-oxadiazol-5-yl-acetic acid were obtained with melting and decomposition taking place between about 96° and 98° C. The filtrate was evaporated in vacuo and the oily residue was repeatedly stirred with small volumes of dichloromethane. The resulting solid was transferred to a filter and washed with ethyl acetate and carbon tetrachloride. After drying, the second crop of said product weighed 14.1 g and melted with extensive decomposition at 92°-96° C. According to thin-layer chromatograms, IR and PMR spectra both crops were virtually identical for a total of 45.1 g (about 55% yield) of about 96% purity.
Reaction SMILES: C([O:8][C:9]1[CH:30]=[CH:29][C:12]([CH2:13][N:14]([C:21]2[CH:28]=[CH:27][C:24]([C:25]#[N:26])=[CH:23][CH:22]=2)[C:15]2[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=2)=[CH:11][CH:10]=1)C1C=CC=CC=1.[H][H]>C(OCC)(=O)C>[OH:8][C:9]1[CH:10]=[CH:11][C:12]([CH2:13][N:14]([C:21]2[CH:28]=[CH:27][C:24]([C:25]#[N:26])=[CH:23][CH:22]=2)[C:15]2[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=2)=[CH:29][CH:30]=1
Reactant: [H][H]
Reactant: N#Cc1ccc(N(Cc2ccc(OCc3ccccc3)cc2)c2cccnc2)cc1
Solvent: CCOC(C)=O
Product: N#Cc1ccc(N(Cc2ccc(O)cc2)c2cccnc2)cc1
Yield: 55.6 %

Procedure:
The procedure of Preparation Example 9 was repeated, except that 222 mg of 4-[N-(4-benzyloxybenzyl)-N-(3-pyridyl)amino]benzonitrile was used in place of 4-[N-(4-benzyloxybenzyl)-N-methylsulfonylamino]-phenyl methanesulfonate, and 3 ml of ethyl acetate was used in place of dioxane. The resulting mixture was stirred for 3 days under an atmospheric pressure of hydrogen. The reaction mixture was filtered to remove any insoluble matter, and the solvent was distilled off from the filtrate. The resulting crude product was purified by TLC (using a 1:1 mixture of ethyl acetate and hexane as the developing solvent) to obtain 95 mg of 4-[N-(4-hydroxybenzyl)-N-(3-pyridyl)amino]benzonitrile.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.[Cl:8][C:9]1[CH:10]=[C:11]([C:16]2[O:20][C:19]([CH2:21][CH2:22][NH:23][C:24]([C:26]3[NH:30][N:29]=[C:28]([C:31](O)=[O:32])[CH:27]=3)=[O:25])=[CH:18][CH:17]=2)[CH:12]=[CH:13][C:14]=1[Cl:15]>>[Cl:8][C:9]1[CH:10]=[C:11]([C:16]2[O:20][C:19]([CH2:21][CH2:22][NH:23][C:24]([C:26]3[NH:30][N:29]=[C:28]([C:31]([N:5]4[CH2:6][CH2:7][N:2]([CH3:1])[CH2:3][CH2:4]4)=[O:32])[CH:27]=3)=[O:25])=[CH:18][CH:17]=2)[CH:12]=[CH:13][C:14]=1[Cl:15]
Reactant: CN1CCNCC1
Reactant: O=C(O)c1cc(C(=O)NCCc2ccc(-c3ccc(Cl)c(Cl)c3)o2)[nH]n1
Product: CN1CCN(C(=O)c2cc(C(=O)NCCc3ccc(-c4ccc(Cl)c(Cl)c4)o3)[nH]n2)CC1
Yield: 35 %

Procedure:
The title compound was synthesized as in Example 1 starting from 1-methylpiperazine and 5-{2-[5-(3,4-dichlorophenyl)furan-2-yl]ethylcarbamoyl}-1H-pyrazole-3-carboxylic acid. Crude product was purified by chromatography (CombiFlash, silica column, eluent 0-10% MeOH/DCM) and crystallized from DCM/heptane to give 1.06 g (35%) of the title compound. 1H-NMR (400 MHz; d6-DMSO): δ 2.19 (s, 3H), 2.33 (br s, 4H), 2.95 (t, 2H), 3.56 (q, 2H), 3.62 (br s, 2H), 3.85 (br s, 2H), 6.34 (d, 1H), 7.02 (d, 1H), 7.07 (br s, 1H), 7.60 (dd, 1H), 7.63 (d, 1H), 7.84 (d, 1H), 8.61 (s, 1H), 13.92 (s, 1H).
Reaction SMILES: [CH3:1][C:2]([CH3:7])=[CH:3][C:4]([OH:6])=[O:5].[CH2:8]([SH:15])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>N1CCCCC1>[CH2:8]([S:15][C:2]([CH3:7])([CH3:1])[CH2:3][C:4]([OH:6])=[O:5])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: SCc1ccccc1
Reactant: CC(C)=CC(=O)O
Solvent: C1CCNCC1
Product: CC(C)(CC(=O)O)SCc1ccccc1
Yield: 99 %

Procedure:
A solution of 3,3-dimethylacrylic acid (7 g, 70 mmol) and benzyl mercaptan (8.9 mL, 7.5 mmol) in piperidine (70 mL) was heated to reflux for 2 days. Piperidine was then evaporated and the product was partitioned between EtOAc and an aqueous solution of 1N HCl. The organic phases were washed with brine and dried over MgSO4. After evaporation of the solvent the product was distilled with a Kugelrohr apparatus under high vacuum (1 mmHg) to give 15.5 g with 99% yield.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([CH2:8][CH3:9])[N:5]=[CH:4][N:3]=1.C(=O)([O-])O.[Na+].[Br:15]Br.C(=O)=O>O>[OH:1][C:2]1[C:7]([Br:15])=[C:6]([CH2:8][CH3:9])[N:5]=[CH:4][N:3]=1
Reactant: BrBr
Reactant: CCc1cc(O)ncn1
Agent: O=C([O-])O
Agent: O=C=O
Agent: [Na+]
Solvent: O
Product: CCc1ncnc(O)c1Br

Procedure:
24.8 g (0.20 mol) of 4-hydroxy-6-ethylpyrimidine are dissolved with 16.8 g (0.20 mol) of sodium hydrogen carbonate in 50 ml of water, and 32 g (0.20 mol) of bromine are slowly added dropwise at 8° to 10° C., with cooling. In the course of the addition, carbon dioxide evolves, and the product precipitates in the form of crystals. The product is separated off by extraction with ethyl acetate and crystallises out when the extract is concentrated using a rotary evaporator. There are obtained 22.7 g (55.9% of the theoretical yield) of a first fraction having a melting point of 177°-179° C. Concentration of the mother liquor yields a further 3.5 g (8.6%); m.p. 175°-177° C.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[CH:5][N:4]=[CH:3]1.[Br-:7].[Br:8][CH2:9][CH2:10][CH2:11][P+:12]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>C(O)C>[Br-:8].[CH3:1][N:2]1[CH:6]=[CH:5][N+:4]([CH2:9][CH2:10][CH2:11][P+:12]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)([C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[CH:3]1.[Br-:7]
Reactant: BrCCC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: Cn1ccnc1
Agent: [Br-]
Solvent: CCO
Product: Cn1cc[n+](CCC[P+](c2ccccc2)(c2ccccc2)c2ccccc2)c1
Yield: 32 %

Procedure:
1-Methyl-3-(3-(triphenylphosphonio)propyl)-1H-imidazol-3-ium bromide was synthesized by refluxing the mixture of 1-methyl-1H-imidazole and (3-bromopropyl)triphenylphosphonium bromide (1:1) in ethanol for 12 h; after cooling down, the solvent was removed and the crude product was washed with ethyl acetate. Then the white product was treated with silver (I) oxide in CH2Cl2 for 12 h, and the crude Ag—NHC product was filtered and washed with CH2Cl2 and then with diethyl ether, and was used for the next step directly. The procedure for the synthesis of 3 is similar to that for 1. Total yield 32%; 1H NMR (400 MHz, CD3CN, 25° C.): δ=8.21 (t, J=8.0 Hz, 1H), 7.82 (m, 3H), 7.69-7.72 (m, 3H), 7.66 (d, J=2.0 Hz, 1H), 7.55-7.63 (m, 12H), 7.17 (d, J=0.9 Hz, 2H), 6.98 (d, J=0.9 Hz, 2H), 4.57 (t, J=7.1 Hz, 2H), 3.94 (s, 3H), 3.27 (m, 2H), 2.11 (m, 2H); FAB-MS: m/z 940 [M−OTf]+; Elemental Analysis calcd (%) for C38H33AuF6N7O6PS2.H2O: C, 41.20; H, 3.18; N, 8.85; found: C, 41.25; H, 3.29; N, 8.72.
Reaction SMILES: C[O:2][C:3](=[O:37])[CH2:4][C:5]1[CH:6]=[C:7]([C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][C:14]=2[CH2:23][N:24]2[C@@H:28]3[C:29]4[CH:30]=[CH:31][CH:32]=[CH:33][C:34]=4[CH2:35][C@@H:27]3[O:26][C:25]2=[O:36])[C:8]([O:11][CH3:12])=[CH:9][CH:10]=1.Cl>C1COCC1.CO.[OH-].[Na+]>[CH3:12][O:11][C:8]1[C:7]([C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:21])([F:20])[F:22])=[CH:15][C:14]=2[CH2:23][N:24]2[C@@H:28]3[C:29]4[CH:30]=[CH:31][CH:32]=[CH:33][C:34]=4[CH2:35][C@@H:27]3[O:26][C:25]2=[O:36])=[CH:6][C:5]([CH2:4][C:3]([OH:37])=[O:2])=[CH:10][CH:9]=1
Reactant: COC(=O)Cc1ccc(OC)c(-c2ccc(C(F)(F)F)cc2CN2C(=O)O[C@H]3Cc4ccccc4[C@H]32)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: COc1ccc(CC(=O)O)cc1-c1ccc(C(F)(F)F)cc1CN1C(=O)O[C@H]2Cc3ccccc3[C@H]21
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To [6-methoxy-2′-((3aR,8aS)-2-oxo-8,8a-dihydro-3aH-indeno[1,2-d]oxazol-3-ylmethyl)-4′-trifluoromethyl-biphenyl-3-yl]-acetic acid methyl ester (0.091 g, 0.18 mmol) in THF (0.9 mL) and MeOH (0.7 mL) was added IN aqueous NaOH (0.45 mL), and the reaction was stirred at room temperature for 2 hours. The mixture was acidified with 1N aqueous HCl and extracted with CH2Cl2. The combined organic layers were washed with H2O, dried over MgSO4, filtered, and concentrated to give the title compound. M+H is 498.
Reaction SMILES: [ClH:1].[N:2]1([CH2:9][CH2:10][NH:11][C:12]([N:14]2[CH2:19][CH2:18][N:17]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22]C=3)[CH2:16][CH2:15]2)=[O:13])[CH2:8][CH2:7]CC[CH2:4][CH2:3]1.[N:26]1C=CC=CC=1N1CCNCC1.O1CCCC1>Cl>[ClH:1].[CH2:8]([N:2]([CH2:3][CH3:4])[CH2:9][CH2:10][NH:11][C:12]([N:14]1[CH2:15][CH2:16][N:17]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][N:26]=2)[CH2:18][CH2:19]1)=[O:13])[CH3:7]
Reactant: c1ccc(N2CCNCC2)nc1
Reactant: O=C(NCCN1CCCCCC1)N1CCN(c2ccccc2)CC1
Agent: Cl
Solvent: C1CCOC1
Product: CCN(CC)CCNC(=O)N1CCN(c2ccccn2)CC1

Procedure:
This compound was prepared according to the procedure used to synthesize the compound of Example 9. A mixture of 5.0 g (0.03 mole) of 1',1'-carbonyldiimidazole, 3.6 g (0.03 mole) of unsym-diethylethylenediamine, and 5.0 g (0.03 mole) of 1-(2-pyridinyl)piperazine in a total of 200 ml of tetrahydrofuran gave an oil as residue. The hydrochloride was formed in ethereal hydrogen chloride and the collected solid was recrystallized from methanol-ethyl ether to yield 7.3 g (63%) of title compound as a white solid, m.p. 183°-185° C.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH3:10])[CH3:9])=[CH:4][CH:3]=1.[CH2:11]([NH:13][C:14](=[O:25])[CH:15]([C:17]1[CH:22]=[CH:21][C:20]([C:23]#[CH:24])=[CH:19][CH:18]=1)[CH3:16])[CH3:12].CC(N)CC.O>C1COCC1.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH2:11]([NH:13][C:14](=[O:25])[CH:15]([C:17]1[CH:18]=[CH:19][C:20]([C:23]#[C:24][C:2]2[CH:7]=[CH:6][C:5]([CH:8]([CH3:10])[CH3:9])=[CH:4][CH:3]=2)=[CH:21][CH:22]=1)[CH3:16])[CH3:12]
Reactant: CC(C)c1ccc(I)cc1
Reactant: C#Cc1ccc(C(C)C(=O)NCC)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CCC(C)N
Solvent: C1CCOC1
Solvent: O
Product: CCNC(=O)C(C)c1ccc(C#Cc2ccc(C(C)C)cc2)cc1
Temperature: 80 °C
Reaction time: 5 h

Procedure:
To 0.025 g (0.10 mmol) 4-iodoisopropylbenzene are added 20 g (0.10 mmol) N-ethyl-2-(4-ethynyl-phenyl)-propionamide (XVII.1) in 1 mL THF, followed by the addition of 0.5 mL 2-butylamine and 0.75 mL water. Subsequently 3 mg (0.05 mmol) bis-(triphenylphosphine)-palladium dichloride are added and the mixture is stirred at 80° C. for 5 h. After that time, the solvent is removed. The residue is taken up in DMF and the desired product was purified using RP-HPLC (water/MeOH+0.1% TFA).
Reaction SMILES: [C:1]([CH:3]1[CH2:6][N:5]([C:7](=[O:31])[C@H:8]([NH:10][C:11]([C:13]2[C:21]3[C:16](=[N:17][CH:18]=[C:19](Br)[N:20]=3)[N:15]([CH2:23][O:24][CH2:25][CH2:26][Si:27]([CH3:30])([CH3:29])[CH3:28])[CH:14]=2)=[O:12])[CH3:9])[CH2:4]1)#[N:2].[Cl:32][C:33]1[CH:41]=[C:40]2[C:36]([C:37]([Sn](CCCC)(CCCC)CCCC)=[N:38][NH:39]2)=[CH:35][CH:34]=1>CN(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.[Cu]I>[C:1]([CH:3]1[CH2:6][N:5]([C:7](=[O:31])[C@H:8]([NH:10][C:11]([C:13]2[C:21]3[C:16](=[N:17][CH:18]=[C:19]([C:37]4[C:36]5[C:40](=[CH:41][C:33]([Cl:32])=[CH:34][CH:35]=5)[NH:39][N:38]=4)[N:20]=3)[N:15]([CH2:23][O:24][CH2:25][CH2:26][Si:27]([CH3:30])([CH3:29])[CH3:28])[CH:14]=2)=[O:12])[CH3:9])[CH2:4]1)#[N:2]
Reactant: C[C@@H](NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(Br)nc12)C(=O)N1CC(C#N)C1
Reactant: CCCC[Sn](CCCC)(CCCC)c1n[nH]c2cc(Cl)ccc12
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Product: C[C@@H](NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(-c3n[nH]c4cc(Cl)ccc34)nc12)C(=O)N1CC(C#N)C1
Temperature: 90 °C
Reaction time: 3 h
Yield: 73 %

Procedure:
In a round-bottomed flask, 2-bromo-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid [(R)-2-(3-cyano-azetidin-1-yl)-1-methyl-2-oxo-ethyl]-amide (190 mg, 0.37 mmol) and 6-chloro-3-tributylstannyl-1H-indazole (crude form step 1, 619 mg, 0.70 mmol) were dissolved in DMF (3.4 ml). The flask was evacuated and backfilled with argon then tetrakis(triphenylphosphine)palladium(0) (22 mg, 0.019 mmol) and copper(I) iodide (15 mg, 0.079 mmol) were added. The reaction mixture was stirred at 90° C. in an oil bath for 3 h then cooled to room temperature, quenched with water and extracted with diethyl ether (2×). The combined organic layers were washed twice with water and once with brine then concentrated. The residue was absorbed on silica gel and chromatographed with MeOH/CH2Cl2/0.5% NH4OH (gradient 0-3% MeOH) then triturated with diethyl ether/ethyl acetate to afford 159 mg (73%) of 2-(6-chloro-1H-indazol-3-yl)-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid [(R)-2-(3-cyano-azetidin-1-yl)-1-methyl-2-oxo-ethyl]-amide as a light brown powder.
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH2:11][CH2:12]O)=[CH:4][N:3]=1.C(Br)(Br)(Br)[Br:15].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O>O1CCOCC1>[NH2:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH2:11][CH2:12][Br:15])=[CH:4][N:3]=1
Reactant: BrC(Br)(Br)Br
Reactant: Nc1ncc2ncn(CCO)c2n1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: C1COCCO1
Product: Nc1ncc2ncn(CCBr)c2n1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
17.92 g (0.1 mole) of 2-amino-9-(2-hydroxyethyl)purine was completely dissolved in 200 ml of 1,4-dioxane. The solution was added with 49.75 g (0.15 mole) of carbon tetrabromide and cooled below 5° C. To the cooled material, 39.34 g (0.15 mole) of triphenylphosphine was added, followed by stirring for 5 hours at room temperature. After completion of the reaction, 300 ml of water was added to the reaction product, which was then extracted four times with 500 ml portions of a mixed solution of chloroform and methanol (4:1). The organic layer was collected, and dried with anhydrous magnesium sulfate, followed by filtration and washing. The resulting filtrate was concentrated under reduced pressure, and crystallized from chloroform, 15.74 g (65%) of white 2-amino-9-(2-bromoethyl)purine.