Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:8][NH:9][C:10](=[O:31])[CH2:11][C:12]1([CH2:27][CH:28]([CH3:30])[CH3:29])[C:16](=[O:17])[N:15]([CH2:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:14](=[O:26])[NH:13]1)C1C=CC=CC=1.N#N>CO.CCOC(C)=O.[OH-].[OH-].[Pd+2]>[OH:8][NH:9][C:10](=[O:31])[CH2:11][C:12]1([CH2:27][CH:28]([CH3:29])[CH3:30])[C:16](=[O:17])[N:15]([CH2:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:14](=[O:26])[NH:13]1
Reactant: CC(C)CC1(CC(=O)NOCc2ccccc2)NC(=O)N(CCc2ccccc2)C1=O
Agent: [Pd+2]
Agent: N#N
Agent: [OH-]
Solvent: CO
Solvent: CCOC(C)=O
Product: CC(C)CC1(CC(=O)NO)NC(=O)N(CCc2ccccc2)C1=O
Reaction time: 2.5 h
Yield: 104.5 %

Procedure:
A solution of N-benzyloxy-4-(2-methylpropyl)-2,5-dioxo-1-(2-phenylethyl)-4-imidazolidineacetamide (85.0 mg, 0.201 mmol) in 25% MeOH/EtOAc is purged with N2, treated with palladium hydroxide on carbon (17 mg, 20% by weight), and placed under a H2 atmosphere (balloon). After 2.5 hours, the reaction mixture is filtered through celite and concentrated under reduced pressure to yield 70 mg of an off-white foam. The material is recrystallized from hot EtOAc/hexane to give 36 mg (54%) of the title compound as a white, powdery solid (mp 145°-147° C.).
Reaction SMILES: O[CH:2]=[C:3]1[C:11]2[C:6](=[CH:7][C:8]([C:12]([C:14]3[CH:15]=[C:16]([NH:20][C:21]([C:23]4[S:24][C:25]([C:28](=[O:30])[CH3:29])=[CH:26][CH:27]=4)=[O:22])[CH:17]=[CH:18][CH:19]=3)=[O:13])=[CH:9][CH:10]=2)[NH:5][C:4]1=[O:31].[NH2:32][C:33]1[CH:34]=[C:35]([OH:39])[CH:36]=[CH:37][CH:38]=1>C1COCC1>[OH:39][C:35]1[CH:34]=[C:33]([NH:32][CH:2]=[C:3]2[C:11]3[C:6](=[CH:7][C:8]([C:12]([C:14]4[CH:15]=[C:16]([NH:20][C:21]([C:23]5[S:24][C:25]([C:28](=[O:30])[CH3:29])=[CH:26][CH:27]=5)=[O:22])[CH:17]=[CH:18][CH:19]=4)=[O:13])=[CH:9][CH:10]=3)[NH:5][C:4]2=[O:31])[CH:38]=[CH:37][CH:36]=1
Reactant: CC(=O)c1ccc(C(=O)Nc2cccc(C(=O)c3ccc4c(c3)NC(=O)C4=CO)c2)s1
Reactant: Nc1cccc(O)c1
Solvent: C1CCOC1
Product: CC(=O)c1ccc(C(=O)Nc2cccc(C(=O)c3ccc4c(c3)NC(=O)C4=CNc3cccc(O)c3)c2)s1
Temperature: 65 °C
Reaction time: 24 h
Yield: 81.8 %

Procedure:
A small screw cap test tube was charged with 5-Acetyl-thiophene-2-carboxylic acid [3-(3-hydroxymethylene-2-oxo-2,3-dihydro-1H-indole-6-carbonyl)-phenyl]-amide (as prepared in Example 54, 100 mg, 0.231 mmol) and THF (2 mL). To the resulting solution was added 3-aminophenol (27.76 mg, 0.254 mmol), and the mixture was stirred for 24 h at 65° C. Subsequently, the reaction mixture was cooled to room temperature. Hexanes were added to the reaction mixture. The solid precipitate that formed was washed with ˜1 mL of i-prOH yielding 82% (99 mg, 0.189 mmol) of the title compound.
Reaction SMILES: [CH3:1][N:2]1[C:6]([S:7][CH2:8][CH2:9][CH2:10][C:11](Cl)=[O:12])=[N:5][N:4]=[N:3]1.N1C=CC=CC=1.[SH2:20]>C(Cl)Cl.C(Cl)(Cl)Cl>[CH3:1][N:2]1[C:6]([S:7][CH2:8][CH2:9][CH2:10][C:11]([OH:12])=[S:20])=[N:5][N:4]=[N:3]1
Reactant: Cn1nnnc1SCCCC(=O)Cl
Reactant: S
Solvent: c1ccncc1
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Product: Cn1nnnc1SCCCC(O)=S
Reaction time: 1 h

Procedure:
920 mg of 4-(1-methyltetrazol-5-ylthio)-butyric acid chloride are dissoved in 1.4 ml of absolute methylene chloride and added dropwise at 0° to 5.54 ml of a pyridine/H2S solution in methylene chloride (30 ml of absolute pyridine and 6 g of H2S in 100 ml of methylene chloride). The whole is then stirred for one hour at 0° under a nitrogen atmosphere. The reaction mixture is taken up in chloroform, the aqueous phase is acidified to a pH of 2 using 2N H2SO4 and extraction is carried out twice with chloroform. The combined organic phases are washed twice with 5 ml of 10% NaHCO3 solution. The pH is then adjusted to 3 using 2N H2SO4 and the title compound is extracted several times with chloroform. The title compound is obtained after drying over sodium sulphate and concentrating.
Reaction SMILES: S(Cl)(Cl)=O.[Cl:5][C:6]1[N:14]=[CH:13][CH:12]=[C:11]([I:15])[C:7]=1[C:8]([OH:10])=O.CN(C)C=O.[F:21][C:22]([F:40])([F:39])[C:23]1[CH:24]=[C:25]([CH:32]=[C:33]([C:35]([F:38])([F:37])[F:36])[CH:34]=1)[CH2:26][NH:27][CH2:28][CH2:29][CH2:30][OH:31]>O1CCCC1.O.C(N(CC)CC)C>[F:21][C:22]([F:39])([F:40])[C:23]1[CH:24]=[C:25]([CH:32]=[C:33]([C:35]([F:36])([F:38])[F:37])[CH:34]=1)[CH2:26][N:27]([CH2:28][CH2:29][CH2:30][OH:31])[C:8](=[O:10])[C:7]1[C:11]([I:15])=[CH:12][CH:13]=[N:14][C:6]=1[Cl:5]
Reactant: O=C(O)c1c(I)ccnc1Cl
Reactant: OCCCNCc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Solvent: O
Solvent: C1CCOC1
Solvent: O=S(Cl)Cl
Product: O=C(c1c(I)ccnc1Cl)N(CCCO)Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Temperature: 100 °C
Reaction time: 3 h
Yield: 91.7 %

Procedure:
To thionyl chloride (20 mL), 2-chloro-4-iodonicotinic acid (8.40 g) were added along with N,N-dimethylformamide (3 droplets) and the mixture was stirred at 100° C. for 3 hours. The reaction mixture was then distilled under reduced pressure to obtain a yellow residue. 3-(3,5-bis(trifluoromethyl)benzylamino)propanol (10.7 g) and triethylamine (20.6 mL) were dissolved in tetrahydrofuran (150 mL). While the mixture was chilled on an ice bath, a tetrahydrofuran solution of the yellow residue (50 mL) was added. After stirred for 1 hour, the mixture was further stirred for additional two hours at room temperature. Subsequently, water was added to the reaction mixture and the mixture was extracted with ethyl acetate. The extract was then dried on anhydrous sodium sulfate. Following the removal of the solvent, the remaining residue was purified on a silica gel column chromatography (ethyl acetate:n-hexane=3:1) to obtain N-[3,5-bis(trifluoromethyl)benzyl]-2-chloro-N-(3-hydroxypropyl)-4-iodonicotinamide (15.4 g, 92%).
Reaction SMILES: [CH2:1]=O.Cl.[N+:4]([C:7]1[CH:8]=[N:9][N:10]([CH:12]2[CH2:16][CH2:15][NH:14][CH2:13]2)[CH:11]=1)([O-:6])=[O:5]>C(O)=O>[CH3:1][N:14]1[CH2:15][CH2:16][CH:12]([N:10]2[CH:11]=[C:7]([N+:4]([O-:6])=[O:5])[CH:8]=[N:9]2)[CH2:13]1
Reactant: O=[N+]([O-])c1cnn(C2CCNC2)c1
Reactant: C=O
Agent: Cl
Solvent: O=CO
Product: CN1CCC(n2cc([N+](=O)[O-])cn2)C1
Temperature: 100 °C

Procedure:
To a solution of Formic acid (50 ml) and Formaldehyde solution (50 mL) was added 4-Nitro-1-pyrrolidin-3-yl-1H-pyrazole hydrochloride (10 g). The reaction mixture was heated at 100° C. for 16 h. The reaction mixture was concentrated under reduced pressure. The residue was tarturated with acetonitrile (150 mL), filtered off solid and filtrate was concentrated. The crude material was basified with ammonia solution, extracted with ethyl acetate, dried over sodium sulphate and evaporated to afford (7 g, 78%) as pale yellow liquid. 1H NMR (400 Mz, DMSO-d6) δ 8.85 (s, 1H), 8.24 (s, 1H), 5.24 (m, 1H), 2.75-2.81 (m, 3H), 2.33-2.49 (m, 2H), 2.27 (s, 3H), 2.12 (m, 1H).
Reaction SMILES: [CH:1]1[C:11]2[C:10]3[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=3[CH2:8][N:7]([C:16]#[N:17])[CH2:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.[Cl:18][C:19]1[CH:26]=[CH:25][C:22]([CH2:23][OH:24])=[CH:21][CH:20]=1>>[CH:1]1[C:11]2[C:10]3[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=3[CH2:8][N:7]([C:16](=[NH:17])[O:24][CH2:23][C:22]3[CH:25]=[CH:26][C:19]([Cl:18])=[CH:20][CH:21]=3)[CH2:6][C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: OCc1ccc(Cl)cc1
Reactant: N#CN1Cc2ccccc2-c2ccccc2C1
Product: N=C(OCc1ccc(Cl)cc1)N1Cc2ccccc2-c2ccccc2C1

Procedure:
starting from 5,7-dihydro-6H-dibenz[c,e]azepine-6-carbonitrile and p-chlorobenzyl alcohol, there is obtained p-chlorobenzyl 5,7-dihydro-6H-dibenz[c,e]azepine-6-carboximidate, m.p. 103°-105° C.;
Reaction SMILES: [C:1]1([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH:7][C:8]([O:10][CH:11]1[CH2:16][CH2:15][N:14]([CH2:17][CH2:18][C:19](O)=[O:20])[CH2:13][CH2:12]1)=[O:9].C(N(CC)C(C)C)(C)C.[I-].ClC1C=CC=C[N+]=1C.Cl.[CH:47]1[C:59]2[CH:58]([CH2:60][O:61][C:62](=[O:69])[NH:63][CH2:64][CH2:65][CH2:66][NH:67][CH3:68])[C:57]3[C:52](=[CH:53][CH:54]=[CH:55][CH:56]=3)[C:51]=2[CH:50]=[CH:49][CH:48]=1>CN(C=O)C>[CH:56]1[C:57]2[CH:58]([CH2:60][O:61][C:62]([NH:63][CH2:64][CH2:65][CH2:66][N:67]([CH3:68])[C:19]([CH2:18][CH2:17][N:14]3[CH2:13][CH2:12][CH:11]([O:10][C:8](=[O:9])[NH:7][C:2]4[CH:3]=[CH:4][CH:5]=[CH:6][C:1]=4[C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[CH2:16][CH2:15]3)=[O:20])=[O:69])[C:59]3[C:51](=[CH:50][CH:49]=[CH:48][CH:47]=3)[C:52]=2[CH:53]=[CH:54][CH:55]=1
Reactant: O=C(O)CCN1CCC(OC(=O)Nc2ccccc2-c2ccccc2)CC1
Reactant: CNCCCNC(=O)OCC1c2ccccc2-c2ccccc21
Agent: C[n+]1ccccc1Cl
Agent: Cl
Agent: [I-]
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CN(CCCNC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)CCN1CCC(OC(=O)Nc2ccccc2-c2ccccc2)CC1
Temperature: 25 °C
Yield: 99.8 %

Procedure:
To a stirred mixture of 3-[4-(biphenyl-2-ylcarbamoyloxy)piperidin-1-yl]-propionic acid (2.8 g, 7.6 mmol) and N,N-diisopropylethylamine (2.6 mL, 15 mmol) in DMF (31 mL) was added 2-chloro-1-methylpyridinium iodide (3.9 g, 15 mmol). Once the solids had dissolved, (3-methylaminopropyl)carbamic acid 9H-fluoren-9-ylmethyl ester hydrochloride salt (2.63 g, 7.58 mmol) was added and the resulting mixture was stirred at room temperature until essentially complete by HPLC and LCMS. The mixture was then concentrated under reduced pressure to remove most of the DMF and the residue was dissolved in DCM (30 mL). This mixture was washed with water (3×20 mL) and brine (3×20 mL), dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography (0-20% MeOH in DCM) to give the title compound (5.0 g, 97% yield) as a white solid.
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][CH2:11][CH:10]=[CH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH:13]S(O)(=O)=O.O.C1C=C(Cl)C=C(C(OO)=O)C=1>CC(C)=O>[CH2:1]([N:8]1[CH2:12][CH:11]2[CH:10]([O:13]2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C1=CN(Cc2ccccc2)CC1
Reactant: O=S(=O)(O)O
Agent: O=C(OO)c1cccc(Cl)c1
Solvent: CC(C)=O
Solvent: O
Product: c1ccc(CN2CC3OC3C2)cc1
Temperature: 0 °C
Yield: 77 %

Procedure:
To an ice-cooled solution of 1-benzyl pyrroline (0.01 mol), 98% H2SO4 (0.012 mol), water (1.5 g), and acetone (10 mL) in a round bottom flask was added 77% m-CPBA (0.013 mol) with stirring, and allowed to react for about 50 h at room temperature. After completion of the reaction (TLC monitor), acetone was evaporated under reduced pressure, and the mixture was neutralized by 1M NaOH, and extracted with toluene (30 mL×3). The precipitates that appeared were filtered, and the filtrate was repeatedly washed with water (30 mL×2). After the solvent was evaporated under reduced pressure, pure product was obtained in 77% yield via column chromatography (silica gel, CH2Cl2:EtOAc:MeOH, 7.5:2.00:0.5).
Reaction SMILES: BrN1C(=O)CCC1=O.Br[C:10]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[P:12](=[O:21])([CH:19]=[CH2:20])[CH:11]=1.C(N(CC)CC)C>C(Cl)(Cl)(Cl)Cl.[Hg]>[CH:19]([P:12]1(=[O:21])[C:13]2[C:18](=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:10]=[CH:11]1)=[CH2:20]
Reactant: C=CP1(=O)C=C(Br)c2ccccc21
Agent: O=C1CCC(=O)N1Br
Agent: [Hg]
Solvent: ClC(Cl)(Cl)Cl
Solvent: CCN(CC)CC
Product: C=CP1(=O)C=Cc2ccccc21

Procedure:
To a solution of 1-vinylphosphindoline 1-oxide (6.4g, 36.0 mmol) in carbon tetrachloride (80 ml) was added N-bromosuccinimide (6.8g, 38.6 mmol) and the two phase mixture stirred under reflux whilst being irradiated with a 500 watt mercury lamp. After 15 mins the solution was washed with water, the washings were extracted with chloroform and the combined organic extract was dried and evaporated to give a light yellow oil. A p.m.r. spectrum of this indicated that it was 3-bromo-1-vinylphosphindole 1-oxide. This material was heated under reflux with triethylamine (10 ml) for 5 mins, cooled, and the precipitated hydrobromide filtered off. The benzene filtrate was washed with water, dried and evaporated. Distillation gave an oil (5.8g, b.p. 170°/0.01 min), g.l.c. of which showed it to be about 90% pure.
Reaction SMILES: [SH:1][C:2]1[NH:3][C:4]2[C:5](=[CH:7][S:8][CH:9]=2)[N:6]=1.Br.[CH2:11]([N:13]([CH2:22][CH3:23])[C:14]1[CH:21]=[CH:20][CH:19]=[CH:18][C:15]=1[CH2:16]Br)[CH3:12]>>[CH2:22]([N:13]([CH2:11][CH3:12])[C:14]1[CH:21]=[CH:20][CH:19]=[CH:18][C:15]=1[CH2:16][S:1][C:2]1[NH:6][C:5]2=[CH:7][S:8][CH:9]=[C:4]2[N:3]=1)[CH3:23]
Reactant: CCN(CC)c1ccccc1CBr
Reactant: Sc1nc2cscc2[nH]1
Agent: Br
Product: CCN(CC)c1ccccc1CSc1nc2cscc2[nH]1

Procedure:
1.47 g of 2-mercaptothieno[3,4-d]imidazole are reacted with 3.05 g of 2-diethylaminobenzyl bromide hydrobromide, and the product is worked up in analogy to the procedure described in Example 1.
Reaction SMILES: [C:1]1([CH:7]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[O:8][CH:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][OH:28].[I-].[Na+].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[C:15]1([CH:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[O:8][CH:9]2[CH2:14][CH2:13][N:12]([CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][OH:28])[CH2:11][CH2:10]2)[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: c1ccc(C(OC2CCNCC2)c2ccccc2)cc1
Reactant: OCCCCCCBr
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Product: OCCCCCCN1CCC(OC(c2ccccc2)c2ccccc2)CC1
Temperature: 100 °C
Reaction time: 1 h

Procedure:
1.00 g of 4-(diphenylmethoxy)piperidine was dissolved in 10 ml of N,N-dimethylformamide; 0.49 ml of 6-bromo-hexanol, 0.56 g of sodium iodide and 0.62 g of potassium carbonate were added, followed by stirring at 100° C. for 1 hour. Ice water was added, followed by extraction with ethyl ether; the extract was washed with saline and dried with magnesium sulfate. After the dry product was concentrated under reduced pressure, the residue was subjected to silica gel column chromatography and eluted with ethyl acetate:methanol:triethylamine (90:10:1). The desired fraction was collected and concentrated to yield 1.24 g of the title compound.
Reaction SMILES: FC(F)(F)C(O)=O.[CH3:8][N:9]1[CH2:14][CH2:13][N:12]([C:15]2[CH:23]=[CH:22][C:18]([C:19]([OH:21])=O)=[C:17]([N:24]([CH:31]3[CH2:36][CH2:35][O:34][CH2:33][CH2:32]3)[C:25](=[O:30])[C:26]([F:29])([F:28])[F:27])[CH:16]=2)[CH2:11][CH2:10]1.C(Cl)(=O)C(Cl)=O.C(N(CC)C(C)C)(C)C.[F:52][C:53]1[CH:54]=[C:55]([S:60]([C:63]2[CH:64]=[C:65]3[C:69](=[CH:70][CH:71]=2)[N:68]([C:72]([C:85]2[CH:90]=[CH:89][CH:88]=[CH:87][CH:86]=2)([C:79]2[CH:84]=[CH:83][CH:82]=[CH:81][CH:80]=2)[C:73]2[CH:78]=[CH:77][CH:76]=[CH:75][CH:74]=2)[N:67]=[C:66]3[NH2:91])(=[O:62])=[O:61])[CH:56]=[C:57]([F:59])[CH:58]=1>ClCCl.CN(C)C=O>[F:52][C:53]1[CH:54]=[C:55]([S:60]([C:63]2[CH:64]=[C:65]3[C:69](=[CH:70][CH:71]=2)[N:68]([C:72]([C:79]2[CH:80]=[CH:81][CH:82]=[CH:83][CH:84]=2)([C:73]2[CH:78]=[CH:77][CH:76]=[CH:75][CH:74]=2)[C:85]2[CH:86]=[CH:87][CH:88]=[CH:89][CH:90]=2)[N:67]=[C:66]3[NH:91][C:19](=[O:21])[C:18]2[CH:22]=[CH:23][C:15]([N:12]3[CH2:13][CH2:14][N:9]([CH3:8])[CH2:10][CH2:11]3)=[CH:16][C:17]=2[N:24]([CH:31]2[CH2:36][CH2:35][O:34][CH2:33][CH2:32]2)[C:25](=[O:30])[C:26]([F:28])([F:27])[F:29])(=[O:62])=[O:61])[CH:56]=[C:57]([F:59])[CH:58]=1
Reactant: Nc1nn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c2ccc(S(=O)(=O)c3cc(F)cc(F)c3)cc12
Reactant: CN1CCN(c2ccc(C(=O)O)c(N(C(=O)C(F)(F)F)C3CCOCC3)c2)CC1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CN1CCN(c2ccc(C(=O)Nc3nn(C(c4ccccc4)(c4ccccc4)c4ccccc4)c4ccc(S(=O)(=O)c5cc(F)cc(F)c5)cc34)c(N(C(=O)C(F)(F)F)C3CCOCC3)c2)CC1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 93 %

Procedure:
To a suspension of 4-(4-methyl-piperazin-1-yl)-2-[(tetrahydro-pyran-4-yl)-(2,2,2-trifluoro-acetyl)-amino]-benzoic acid trifluoroacetate (2.16 g, 4.1 mmol) in dry dichloromethane (20 mL) were added oxalyl chloride (0.69 mL, 8.2 mmol) and N,N-dimethylformamide (1-2 drops). The mixture was stirred at room temperature for 1.5 hours then evaporated to dryness. The resulting crude acyl chloride was taken-up with toluene and evaporated again then dissolved in dry tetrahydrofuran (30 mL) and N,N-diisopropylethylamine (2.8 mL, 16.4 mmol) and treated with 5-(3,5-difluoro-benzenesulfonyl)-1-trityl-1H-indazol-3-ylamine (1.5 g, 2.72 mmol). The mixture was stirred at room temperature overnight then evaporated to dryness. The residue was dissolved in dichloromethane, washed with saturated solution of sodium hydrogenocarbonate and with brine, dried over sodium sulfate and evaporated to dryness. The crude was purified by flash chromatography on silica gel using dichloromethane/acetone 1:1 as the eluant, affording the title compound as a pale yellow solid (2.4 g, 93% yield).
Reaction SMILES: CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.[CH3:23][O:24][C:25](=[O:50])[C:26]1[C:31]([NH:32][CH:33]([CH2:37][CH3:38])[CH:34]([OH:36])[CH3:35])=[CH:30][C:29]([CH3:39])=[N:28][C:27]=1[O:40][C:41]1[C:46]([CH3:47])=[CH:45][C:44]([Cl:48])=[CH:43][C:42]=1[CH3:49]>>[CH3:23][O:24][C:25](=[O:50])[C:26]1[C:31]([NH:32][CH:33]([CH2:37][CH3:38])[C:34](=[O:36])[CH3:35])=[CH:30][C:29]([CH3:39])=[N:28][C:27]=1[O:40][C:41]1[C:46]([CH3:47])=[CH:45][C:44]([Cl:48])=[CH:43][C:42]=1[CH3:49]
Reactant: CCC(Nc1cc(C)nc(Oc2c(C)cc(Cl)cc2C)c1C(=O)OC)C(C)O
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Product: CCC(Nc1cc(C)nc(Oc2c(C)cc(Cl)cc2C)c1C(=O)OC)C(C)=O

Procedure:
The title compound was prepared by Dess-Martin oxidation of 2-(4-chloro-2,6-dimethyl-phenoxy)-4-(1-ethyl-2-hydroxy-propylamino)-6-methyl-nicotinic acid methyl ester. A white solid was obtained after silica gel column chromatography. 1H NMR(CDCl3) d 8.6(d, 1H), 7.01(s, 2H), 5.899s, 1H), 3.9-4.0(m, 1H), 3.90(s, 3H), 2.17(s, 3H), 2.07(s, 3H), 2.05(s, 3H), 1.859m, 1H), 1,93(m, 1H), 1.00(t, 3H) ppm.
Reaction SMILES: [CH:1]1([C:7]2[C:8]3[CH:9]=[CH:10][C:11](C(OC)=O)=[CH:12][C:13]=3[N:14]3[C:21]=2[C:20]2C=[CH:23][CH:24]=[CH:25][C:19]=2[O:18][CH2:17][CH:16]([CH2:26][OH:27])[CH2:15]3)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C[CH2:33][O:34][C:35]([CH3:37])=[O:36]>C(Cl)Cl>[CH:1]1([C:7]2[C:8]3[CH:9]=[CH:10][CH:11]=[CH:12][C:13]=3[N:14]3[C:21]=2[C:20]2=[C:37]([C:35]([O:34][CH3:33])=[O:36])[CH:23]=[CH:24][CH:25]=[C:19]2[O:18][CH2:17][CH:16]([CH:26]=[O:27])[CH2:15]3)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: CCOC(C)=O
Reactant: COC(=O)c1ccc2c(C3CCCCC3)c3n(c2c1)CC(CO)COc1ccccc1-3
Solvent: ClCCl
Product: COC(=O)c1cccc2c1-c1c(C3CCCCC3)c3ccccc3n1CC(C=O)CO2
Temperature: 25 °C
Reaction time: 1 h
Yield: 98 %

Procedure:
A solution (0.03 M) of methyl 14-cyclohexyl-7-(hydroxymethyl)-7,8-dihydro-6H-indolo[1,2-e][1,5]benzoxazocine-11-carboxylate (prepared as described in example 13, steps 1-2) in DCM was added to a solution of DMP (0.04 M; 1.25 eq) in DCM at RT. The reaction was then left to stir at RT for 1 h. The mixture was diluted with EtOAc and washed with a 1:1 mixture of sat. aq. NaHCO3 and sodium thiosulfate (aq) (3×) before washing with brine, drying (Na2SO4), filtering and concentrating in vacuo to afford the product as a tinted glass (98%). The material was taken on without further purification. (ES+) m/z 418 (M+H)+; 436 (M+H2O+H)+.
Reaction SMILES: [Si:1]([O:8][CH2:9][C:10]([NH:13][C:14]([C:16]1[C:20]2=[N:21][C:22]([C:25]3[C:33]4[C:28](=[CH:29][C:30]([F:34])=[CH:31][CH:32]=4)[N:27]([CH2:35][CH2:36][C:37](=[O:39])[CH3:38])[N:26]=3)=[CH:23][N:24]=[C:19]2[N:18]([C:40]([C:53]2[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=2)([C:47]2[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=2)[C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)[CH:17]=1)=[O:15])([CH3:12])[CH3:11])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[BH4-].[Na+].[NH4+].[Cl-]>CO>[Si:1]([O:8][CH2:9][C:10]([NH:13][C:14]([C:16]1[C:20]2=[N:21][C:22]([C:25]3[C:33]4[C:28](=[CH:29][C:30]([F:34])=[CH:31][CH:32]=4)[N:27]([CH2:35][CH2:36][CH:37]([OH:39])[CH3:38])[N:26]=3)=[CH:23][N:24]=[C:19]2[N:18]([C:40]([C:53]2[CH:54]=[CH:55][CH:56]=[CH:57][CH:58]=2)([C:41]2[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=2)[C:47]2[CH:48]=[CH:49][CH:50]=[CH:51][CH:52]=2)[CH:17]=1)=[O:15])([CH3:11])[CH3:12])([C:4]([CH3:7])([CH3:5])[CH3:6])([CH3:3])[CH3:2]
Reactant: CC(=O)CCn1nc(-c2cnc3c(n2)c(C(=O)NC(C)(C)CO[Si](C)(C)C(C)(C)C)cn3C(c2ccccc2)(c2ccccc2)c2ccccc2)c2ccc(F)cc21
Agent: [BH4-]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CO
Product: CC(O)CCn1nc(-c2cnc3c(n2)c(C(=O)NC(C)(C)CO[Si](C)(C)C(C)(C)C)cn3C(c2ccccc2)(c2ccccc2)c2ccccc2)c2ccc(F)cc21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of N-(1-(tert-butyldimethylsilyloxy)-2-methylpropan-2-yl)-2-(6-fluoro-1-(3-oxobutyl)-1H-indazol-3-yl)-5-trityl-5H-pyrrolo[3,2-b]pyrazine-7-carboxamide (40 mg, 0.05 mmol) in MeOH (5 mL) was added NaBH4 (10 mg, 0.25 mmol) at 0° C. The mixture was stirred at room temperature for 1 hour. NH4Cl (aqueous) was added to the mixture to quench the reaction. The mixture was extracted with EtOAc (3×5 mL). The combined organic layers were washed with brine and dried over Na2SO4. After filtration and concentration, the crude was used into the next step without purification. LCMS: (M+H)+=797.
Reaction SMILES: C([Li])CCC.Br[C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([Br:13])[CH:8]=1.[F:14][C:15]1[CH:20]=[CH:19][C:18]([C:21](=O)[CH3:22])=[CH:17][CH:16]=1>O1CCCC1>[Br:13][C:9]1[CH:10]=[CH:11][CH:12]=[C:7]([C:21]([C:18]2[CH:19]=[CH:20][C:15]([F:14])=[CH:16][CH:17]=2)=[CH2:22])[CH:8]=1
Reactant: Brc1cccc(Br)c1
Reactant: CC(=O)c1ccc(F)cc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: C=C(c1ccc(F)cc1)c1cccc(Br)c1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
A solution of n-butyllithium (1.6 M in hexane, 21 mL, 33.5 mmol, 1.16 eq.) was added dropwise over 20 min to a solution of 1,3-dibromobenzene (3.8 mL, 31.8 mmol, 1.1 eq) in 30 mL of dry tetrahydrofuran at −78° C. and under an inert atmosphere. The white suspension formed was stirred at −78° C. for 30 min. A solution of 4′-fluoro-acetophenone (3.5 mL, 28.9 mmol, 1.0 eq.) in 20 mL of tetrahydrofuran was then added dropwise and the reaction stirred for 1 h. The reaction mixture was examined by LC-MS which showed the complete formation of tertiary alcohol. The solution was quenched with a saturated solution of ammonium chloride and water. 2 N HCl was then added to reach pH=5. The two phases were separated; the organic layer was dried over anhydrous magnesium sulfate, filtered and evaporated under reduced pressure. The residual material (tertiary alcohol) was dissolved in a mixture of acetic acid/sulfuric acid (10 mL of acetic acid, 0.3 mL of sulfuric acid) and the reaction mixture was stirred for 1 h at room temperature; then it was examined by LC-MS which showed the complete formation of desired product. The solution was quenched with ice and dichloromethane (20 mL) was added. The two phases formed and were separated. The organic layer was washed with a saturated solution of sodium bicarbonate and brine. It was then dried over anhydrous magnesium sulfate, filtered and evaporated under reduced pressure. The crude was purified by flash chromatography eluting with cyclohexane. The desired product was obtained as a liquid (5.89 g, Yield: 73%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C@@H:12]([C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([OH:19])[CH:14]=3)[CH2:11][O:10][C:9]2=[O:20])=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].F[C:28]1[CH:35]=[CH:34][CH:33]=[CH:32][C:29]=1[C:30]#[N:31]>CS(C)=O>[C:30]([C:29]1[CH:32]=[CH:33][CH:34]=[CH:35][C:28]=1[O:19][C:15]1[CH:14]=[C:13]([C@H:12]2[CH2:11][O:10][C:9](=[O:20])[N:8]2[C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=2)[CH:18]=[CH:17][CH:16]=1)#[N:31]
Reactant: N#Cc1ccccc1F
Reactant: O=C1OC[C@H](c2cccc(O)c2)N1c1ccc(Cl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: N#Cc1ccccc1Oc1cccc([C@H]2COC(=O)N2c2ccc(Cl)cc2)c1
Temperature: 80 °C
Reaction time: 2.5 h

Procedure:
To (S)-3-(4-chlorophenyl)-4-(3-hydroxyphenyl)oxazolidin-2-one (0.07 mmol) is added K2CO3 (0.14 mmol) and 2-fluorobenzonitrile (0.08 mmol) in DMSO (1 mL). The mixture is degassed with N2 (2×) and stirred at 80° C. for 2-3 hours. The mixture is filtered through a Whatman 0.42 μM filter and purified by preparatory LC-MS (C-18, 10-90% ACN/water (0.05% TFA)). HPLC-MS calculated for C22H15ClN2O3 (M+H+): 391.1, found 391.0.