Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:10]2[C:5](=[CH:6][C:7]([N+:11]([O-:13])=[O:12])=[CH:8][CH:9]=2)[N-:4][N:3]=1.[Na+].[CH3:15][O:16][C:17]1[CH:18]=[C:19]([CH:24]=[CH:25][C:26]=1[CH2:27]Br)[C:20]([O:22][CH3:23])=[O:21]>CO>[Cl:1][C:2]1[C:10]2[C:5](=[CH:6][C:7]([N+:11]([O-:13])=[O:12])=[CH:8][CH:9]=2)[N:4]([CH2:27][C:26]2[CH:25]=[CH:24][C:19]([C:20]([O:22][CH3:23])=[O:21])=[CH:18][C:17]=2[O:16][CH3:15])[N:3]=1
Reactant: O=[N+]([O-])c1ccc2c(Cl)n[n-]c2c1
Reactant: COC(=O)c1ccc(CBr)c(OC)c1
Agent: [Na+]
Solvent: CO
Product: COC(=O)c1ccc(Cn2nc(Cl)c3ccc([N+](=O)[O-])cc32)c(OC)c1
Yield: 70 %

Procedure:
A mixture of 2.19 g. of sodium 3-chloro-6-nitroindazolide in 50 ml. methanol was stirred with 2.85 g methyl 3-methoxy-4-bromomethylbenzoate for 2 hours. After addition of 150 ml. water, the resultant precipitate was collected and recrystallised from ethyl acetate to give methyl 4-[3-chloro-6-nitroindazol-1-ylmethyl]-3-methoxybenzoate in 70% yield as a solid, m.p. 167°-168.5° C. A mixture of 1.25 g. of this solid was hydrogenated in the presence of 385 mg. 5% w/w palladium on calcium carbonate in 20 ml. ethyl acetate and 20 ml. methanol for 3 hours at a pressure of 1.1 bar. The catalyst was removed by filtration through diatomaceous earth. The filtrate was concentrated to low volume in vacuo and the residue (ca 3 ml.) was diluted with ether and petroleum ether (b.p. 40°-60° C.) and cooled to -20° C. The precipitated solid was collected and dried at 80° C. to give the ester L in 90% yield, m.p. 131°-131.5° C.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:8]2[N:7]([Si](CCC)(CCC)CCC)[CH:6]=[CH:5][C:4]=2[C:3]=1[C:21]([OH:23])=O.F[P-](F)(F)(F)(F)F.[N:31]1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.O.N.O>CN(C=O)C>[F:1][C:2]1[CH:10]=[CH:9][C:8]2[NH:7][CH:6]=[CH:5][C:4]=2[C:3]=1[C:21]([NH2:31])=[O:23]
Reactant: CCC[Si](CCC)(CCC)n1ccc2c(C(=O)O)c(F)ccc21
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: N
Solvent: O
Solvent: CN(C)C=O
Product: NC(=O)c1c(F)ccc2[nH]ccc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 97.9 %

Procedure:
A mixture of 5-fluoro-1-(tripropylsilyl)-1H-indole-4-carboxylic acid (500 mg, 1.49 mmol), O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (851 mg, 2.24 mmol), and TEA (452 mg, 4.48 mmol) in DMF (5 mL) was stirred at RT for 1 hour. To the mixture was added ammonia water (1 mL), followed by stirring at RT overnight. The reaction mixture was poured into water (100 mL) and extracted with EtOAc (50 mL×3). The combined organic layers were washed with water and brine, dried (Na2SO4), filtered, and concentrated in vacuo. The residue was purified by SiO2 chromatography using petroleum ether/EtOAc (2:1) as eluting solvents to afford 5-fluoro-1H-indole-4-carboxamide as a white solid (260 mg, 52.2%). MS (ESI): m/z=179.2 [M+1]+.
Reaction SMILES: F[C:2]1[CH:3]=[C:4]2[O:8][C:7](C3C=CC=CC=3)=[N:6][C:5]2=[C:15]([C:17]([OH:19])=O)[CH:16]=1.Cl.Cl.[NH2:22]C1CC2N(C)C(CCC2)C1.Cl.C(N=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1.C(N(CC)CC)C>CN(C=O)C>[O:8]1[C:4]2=[CH:3][CH:2]=[CH:16][C:15]([C:17]([NH2:22])=[O:19])=[C:5]2[N:6]=[CH:7]1
Reactant: CN1C2CCCC1CC(N)C2
Reactant: O=C(O)c1cc(F)cc2oc(-c3ccccc3)nc12
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: NC(=O)c1cccc2ocnc12
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 215.9 %

Procedure:
A mixture of 6-fluoro-2-phenylbenzo[d]oxazole-4-carboxylic acid (30 mg, 0.12 mmol), 3-amino-9-methyl-9-azabicyclo[3.3.1]nonane dihydrochloride (32 mg, 0.14 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (46 mg, 0.24 mmol) and 1-hydroxybenzotriazole (32 mg, 0.24 mmol) in DMF (5 mL) was stirred under nitrogen at room temperature for 10 min, and then triethylamine (0.10 mL, 0.72 mmol) was added. The resulting reaction mixture was stirred at room temperature overnight, and then was quenched with a saturated solution of sodium bicarbonate, extracted with methylene chloride. The combined organic layers were washed with brine, dried (Na2SO4), filtered and concentrated. The crude material was purified by column chromatography (silica gel, 90:9:1 ethyl acetate/methanol/concentrated ammonium hydroxide) to afford N-(9-methyl-9-azabicyclo[3.3.1]non-3-yl)-6-fluoro-2-phenyl)benzoxazole-4-carboxamide (42 mg, 91%) as a light yellow solid: 1H NMR (500 MHz, CDCl3) δ 8.96 (d, J=7.5 Hz, 1H), 8.23-8.22 (m, 2H), 7.96 (d, J=10.5 Hz, 1H), 7.63-7.55 (m, 3H), 7.42 (d, J=7.0 Hz, 1H), 4.62-4.53 (m, 1H), 3.13-3.11 (m, 2H), 2.67-2.60 (m, 2H), 2.54 (s, 3H), 2.15-1.98 (m, 3H), 1.62-1.46 (m, 3H), 1.18-1.13 (m, 2H); 19F NMR (282 MHz, CDCl3) δ −113.93; MS (ESI+) m/z 394 (M+H); HPLC>99% (AUC), tR=12.78 min.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([OH:24])=[C:6]([C@H:8]2[CH2:12][CH2:11][CH2:10][N:9]2[C:13]2[CH:18]=[CH:17][N:16]3[N:19]=[CH:20][C:21]([CH:22]=[O:23])=[C:15]3[N:14]=2)[CH:7]=1.Br[CH2:26][CH2:27][NH:28][C:29](=[O:35])[O:30][C:31]([CH3:34])([CH3:33])[CH3:32].C(=O)([O-])[O-].[K+].[K+].CN(C=O)C>C(Cl)Cl>[F:1][C:2]1[CH:3]=[CH:4][C:5]([O:24][CH2:26][CH2:27][NH:28][C:29](=[O:35])[O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[C:6]([C@H:8]2[CH2:12][CH2:11][CH2:10][N:9]2[C:13]2[CH:18]=[CH:17][N:16]3[N:19]=[CH:20][C:21]([CH:22]=[O:23])=[C:15]3[N:14]=2)[CH:7]=1
Reactant: CC(C)(C)OC(=O)NCCBr
Reactant: O=Cc1cnn2ccc(N3CCC[C@@H]3c3cc(F)ccc3O)nc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NCCOc1ccc(F)cc1[C@H]1CCCN1c1ccn2ncc(C=O)c2n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 86.6 %

Procedure:
A mixture of (R)-5-(2-(5-fluoro-2-hydroxyphenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidine-3-carbaldehyde (159 mg, 0.487 mmol), tert-butyl 2-bromoethylcarbamate (131 mg, 0.585 mmol), potassium carbonate (202 mg, 1.46 mmol) and DMF (1 mL) was combined in a sealed vessel and stirred at ambient temperature overnight and then at 60° C. for 3 hours. After diluting with DCM (20 mL), the reaction was filtered through Celite®, concentrated and purified by reverse-phase column chromatography, eluting with 0-70% acetonitrile/H2O to provide (R)-tert-butyl 2-(4-fluoro-2-(1-(3-formylpyrazolo[1,5-a]pyrimidin-5-yl)pyrrolidin-2-yl)phenoxy)ethylcarbamate (198 mg, 86.6% yield) as yellowish solid. MS (apci) m/z=370.4 (M+H-Boc).
Reaction SMILES: [CH2:1]([C:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[NH:12][C:13]([C:15]2[N:19]3[CH:20]=[CH:21][C:22]([CH2:24][CH:25]=O)=[CH:23][C:18]3=[N:17][CH:16]=2)=[O:14])[N:5]([CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[C:30]([CH3:34])[N:29]=2)[N:4]=1)[CH3:2].Cl.[F:36][C@@H:37]1[CH2:41][CH2:40][NH:39][CH2:38]1>>[CH2:1]([C:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[NH:12][C:13]([C:15]2[N:19]3[CH:20]=[CH:21][C:22]([CH2:24][CH2:25][N:39]4[CH2:40][CH2:41][C@@H:37]([F:36])[CH2:38]4)=[CH:23][C:18]3=[N:17][CH:16]=2)=[O:14])[N:5]([CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[C:30]([CH3:34])[N:29]=2)[N:4]=1)[CH3:2]
Reactant: F[C@@H]1CCNC1
Reactant: CCc1nn(Cc2cccc(C)n2)c2cccc(NC(=O)c3cnc4cc(CC=O)ccn34)c12
Agent: Cl
Product: CCc1nn(Cc2cccc(C)n2)c2cccc(NC(=O)c3cnc4cc(CCN5CC[C@@H](F)C5)ccn34)c12

Procedure:
Prepared according to procedure for Example 128 from N-(3-ethyl-1-((6-methylpyridin-2-yl)methyl)-1H-indazol-4-yl)-7-(2-oxoethyl)imidazo[1,2-a]pyridine-3-carboxamide (Example 127, Steps A-B) and (R)-3-fluoropyrrolidin hydrochloride. MS (ES+APCI) m/z=526 (M+H) detected.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][N:8]([CH2:11][CH2:12][CH2:13][NH2:14])[CH2:7][CH2:6]1.[CH:15]1[C:28]2[C:19](=[CH:20][C:21]3[C:26]([C:27]=2[CH:29]=O)=[CH:25][CH:24]=[CH:23][CH:22]=3)[CH:18]=[CH:17][CH:16]=1.[BH4-].[Na+].O>C(O)C>[CH:15]1[C:28]2[C:19](=[CH:20][C:21]3[C:26]([C:27]=2[CH2:29][NH:14][CH2:13][CH2:12][CH2:11][N:8]2[CH2:7][CH2:6][N:5]([CH2:4][CH2:3][CH2:2][NH:1][CH2:29][C:27]4[C:28]5[C:19]([CH:20]=[C:21]6[C:26]=4[CH:25]=[CH:24][CH:23]=[CH:22]6)=[CH:18][CH:17]=[CH:16][CH:15]=5)[CH2:10][CH2:9]2)=[CH:25][CH:24]=[CH:23][CH:22]=3)[CH:18]=[CH:17][CH:16]=1
Reactant: O=Cc1c2ccccc2cc2ccccc12
Reactant: NCCCN1CCN(CCCN)CC1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: c1ccc2c(CNCCCN3CCN(CCCNCc4c5ccccc5cc5ccccc45)CC3)c3ccccc3cc2c1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a solution of 1,4-bis(3-aminopropyl)piperazine (0.513 mL, 2.49 mmol) and 9-anthracenaldehyde (1.080 g, 5.24 mmol) in absolute ethanol (20 mL) was added 3 Å molecular sieves (5 g). After stirring the mixture for 12 h at room temperature, sodium borohydride (1.9 g, 49.9 mmol) was added and the mixture was stirred for 12 h at room temperature. Then the reaction mixture was quentched by dropwise addition of water (20 mL) and ethanol was removed under reduced pressure. The aqueous residue was extracted with CH2Cl2 (3×30 mL) and the combined organic layers were extracted with HCl 1N (2×50 mL). The combined aqueous layers were neutralized with NaOH 1N (50 mL) and extracted with CH2Cl2 (3×30 mL). The combined organic layers were dried over MgSO4, evaporated to dryness and the oily residue purified by flash chromatography (neutral aluminium oxide, CH2Cl2/MeOH: 90/10).
Reaction SMILES: [C:1]([C:3]1[CH:24]=[CH:23][C:6]([C:7]([NH:9][CH:10]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:11]([CH3:16])([CH3:15])[C:12](O)=[O:13])=[O:8])=[CH:5][CH:4]=1)#[N:2].CN([P+](ON1N=NC2C=CC=CC1=2)(N(C)C)N(C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C.[CH2:61]([O:68][C:69](=[O:77])[CH2:70][CH:71]1[CH2:76][CH2:75][NH:74][CH2:73][CH2:72]1)[C:62]1[CH:67]=[CH:66][CH:65]=[CH:64][CH:63]=1>C(Cl)Cl>[CH2:61]([O:68][C:69](=[O:77])[CH2:70][CH:71]1[CH2:72][CH2:73][N:74]([C:12](=[O:13])[C:11]([CH3:15])([CH3:16])[CH:10]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[NH:9][C:7](=[O:8])[C:6]2[CH:23]=[CH:24][C:3]([C:1]#[N:2])=[CH:4][CH:5]=2)[CH2:75][CH2:76]1)[C:62]1[CH:63]=[CH:64][CH:65]=[CH:66][CH:67]=1
Reactant: CC(C)(C(=O)O)C(NC(=O)c1ccc(C#N)cc1)c1ccccc1
Reactant: O=C(CC1CCNCC1)OCc1ccccc1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C(=O)N1CCC(CC(=O)OCc2ccccc2)CC1)C(NC(=O)c1ccc(C#N)cc1)c1ccccc1
Reaction time: 0.5 h
Yield: 69.6 %

Procedure:
N-4-Cyanobenzoyl-β-phenyl-α,α-dimethyl-β-alanine (0.5 g, 1.55 mmol) was dissolved in methylene chloride (30 ml). To the resulting solution, BOP reagent (0.89 g, 4.03 mmol) and diisopropylethyl-amine (DIEA) (1.67 ml, 9.3 mmol) were added under cooling with ice and the mixture was stirred for 30 minutes. To the reaction mixture was added 4-piperidineacetic acid benzyl ester (1.08 g, 4.65 mmol) and the resulting mixture was stirred overnight. After the solvent was distilled off, the residue was dissolved in ethyl acetate, washed sequentially with a 5% aqueous solution of citric acid, a 5% aqueous solution of sodium bicarbonate and a saturated aqueous solution of NaCl 3 times each and dried over anhydrous sodium sulfate. The solvent was distilled off and the residue was applied to a silica gel column (2.2×20 cm) and eluted with a mixed solution (hexane:ethyl acetate=3:1). The desired fractions were collected and the solvents were distilled off to yield an oil of N-4-cyanobenzoyl-β-phenyl-α,α-dimethyl-β-alanyl-4-piperidineacetic acid benzyl ester (0.58 g, 69.6%).
Reaction SMILES: [CH2:1]1[N:11]2[C:12]3[C:8]([C@@H:9]4[CH2:16][NH:15][CH2:14][CH2:13][C@@H:10]42)=[CH:7][CH:6]=[CH:5][C:4]=3[O:3][CH2:2]1.[NH2:17][C:18]1[CH:23]=[C:22]([F:24])[CH:21]=[CH:20][C:19]=1[C:25](=[O:30])[CH2:26][CH2:27][CH2:28]Cl>>[NH2:17][C:18]1[CH:23]=[C:22]([F:24])[CH:21]=[CH:20][C:19]=1[C:25](=[O:30])[CH2:26][CH2:27][CH2:28][N:15]1[CH2:14][CH2:13][C@@H:10]2[N:11]3[CH2:1][CH2:2][O:3][C:4]4[CH:5]=[CH:6][CH:7]=[C:8]([C:12]3=4)[C@@H:9]2[CH2:16]1
Reactant: c1cc2c3c(c1)[C@@H]1CNCC[C@@H]1N3CCO2
Reactant: Nc1cc(F)ccc1C(=O)CCCCl
Product: Nc1cc(F)ccc1C(=O)CCCN1CC[C@H]2[C@@H](C1)c1cccc3c1N2CCO3

Procedure:
The title compound was prepared by the method of Example 355 Step B as a yellow oil (172 mg, 57%) from (6bR,10aS)-1,2,6b,7,8,9,10,10a-octahydro[1,4]oxazino[2,3,4-hi]pyrido[4,3-b]indole (165 mg, 0.76 mmol) and 1-(2-amino-4-fluorophenyl)-4-chloro-1-butanone (329 mg, 1.5 mmol). The title compound was spectroscopically identical to Example 529.
Reaction SMILES: C(O[C:4](=[O:20])[CH2:5][C:6](=O)[C:7]1[CH:12]=[CH:11][N:10]=[C:9]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[N:8]=1)C.[CH3:21][NH:22][C:23]([NH2:25])=[S:24].N12CCCN=C1CCCCC2.Cl>C(O)C>[SH:24][C:23]1[N:22]([CH3:21])[C:4](=[O:20])[CH:5]=[C:6]([C:7]2[CH:12]=[CH:11][N:10]=[C:9]([C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=3)[N:8]=2)[N:25]=1
Reactant: CCOC(=O)CC(=O)c1ccnc(-c2ccccc2)n1
Reactant: CNC(N)=S
Agent: Cl
Solvent: C1CCC2=NCCCN2CC1
Solvent: CCO
Product: Cn1c(S)nc(-c2ccnc(-c3ccccc3)n2)cc1=O
Yield: 92.9 %

Procedure:
A solution of 3-oxo-3-(2-phenyl-pyrimidin-4-yl)-propionic acid ethyl ester (2.74 g, 10.1 mmol), N-methylthiourea (1.39 g, 15.5 mmol) and 1,8-diazabicyclo[5,4,0]undec-7-en (1.57 g, 10.3 mmol) in ethanol (30 ml) was heated under reflux for 18 hours. After the solution was acidified by addition of hydrochloric acid, ethanol was removed under reduced pressure, and the resulting solid was filtered, washed with water and dried to afford 2-mercapto-1-methyl-2′-phenyl-1H-[4,4′]bipyrimidinyl-6-one (2.78 g, 93%).
Reaction SMILES: [C:1]1([S:7]([C:10]2[CH:11]=[C:12]3[C:17](=[CH:18][CH:19]=2)[CH:16]([CH2:20][CH2:21]OS(C)(=O)=O)[CH2:15][CH2:14][CH2:13]3)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH:27]1[CH:31]=[CH:30][N:29]=[CH:28]1.C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>O.C(#N)C>[C:1]1([S:7]([C:10]2[CH:11]=[C:12]3[C:17](=[CH:18][CH:19]=2)[CH:16]([CH2:20][CH2:21][N:27]2[CH:31]=[CH:30][N:29]=[CH:28]2)[CH2:15][CH2:14][CH2:13]3)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CS(=O)(=O)OCCC1CCCc2cc(S(=O)(=O)c3ccccc3)ccc21
Reactant: c1c[nH]cn1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: O=S(=O)(c1ccccc1)c1ccc2c(c1)CCCC2CCn1ccnc1
Yield: 77.4 %

Procedure:
Methanesulfonic acid 2-(6-benzenesulfonyl-1,2,3,4-tetrahydro-naphthalen-1-yl)-ethyl ester (0.250 g, 0.634 mmol), imidazole (0.173 g, 2.54 mmol), potassium carbonate (0.175 g, 1.27 mmol) and potassium iodide (0.25 g) were added to 50 mL of acetonitrile, and the reaction mixture was refluxed for 16 hours under argon. The reaction mixture was cooled and poured into 300 mL of water, extracted twice with 250 mL of EtOAc, and the combined organic layers were washed with water, saturated brine, and dried (MgSO4). The solvent was removed under reduced pressure to yield an oil that was purified via silica gel column, eluting with MeOH/CHCl3 (5:95). Solvent was removed under reduced pressure to afford 0.180 g (0.491 mmol, 77.5% of 1-[2-(6-benzenesulfonyl-1,2,3,4-tetrahydro-naphthalen-1-yl)-ethyl]-1H-imidazole as an oil. The oil was recrystallized from EtOH/HCl to give 0.130 g of the corresponding hydrochloride salt (0.323 mol, 50.9%). MS: 367 (M+H)+.
Reaction SMILES: [BrH:1].C(O)(=O)C.[CH3:6][C:7]1[CH:8]=[C:9]([C:13](=O)[CH2:14][S:15][C:16]#[N:17])[CH:10]=[CH:11][CH:12]=1.O>C(O)(=O)C>[Br:1][C:16]1[S:15][CH:14]=[C:13]([C:9]2[CH:10]=[CH:11][CH:12]=[C:7]([CH3:6])[CH:8]=2)[N:17]=1
Reactant: Br
Reactant: Cc1cccc(C(=O)CSC#N)c1
Solvent: CC(=O)O
Solvent: O
Product: Cc1cccc(-c2csc(Br)n2)c1
Temperature: 130 °C
Reaction time: 2 h
Yield: 66.8 %

Procedure:
A 25% hydrogen bromide/acetic acid (20 ml) solution was added to a solution of 2-(3-methylphenyl)-2-oxoethyl thiocyanate (2.29 g, 12.0 mmol) in acetic acid (20 ml), and the mixture was stirred at 130° C. for 2 hours. Water was poured to the reaction mixture, and the mixture was extracted with chloroform. The extract was washed with water, and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=9:1) to give 2.03 g (66.8%) of the desired product as an oil.
Reaction SMILES: [OH:1][CH:2]1[CH2:6][N:5]([C:7]([O:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:8])[CH2:4][CH:3]1[C:17]([OH:19])=O.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH:44]1[C:52]2[C:47](=[C:48]([C:53]3[CH:54]=[C:55]([NH2:62])[C:56]4[CH:57]=[N:58][NH:59][C:60]=4[CH:61]=3)[CH:49]=[CH:50][CH:51]=2)[CH:46]=[CH:45]1.CCN(C(C)C)C(C)C>CN(C=O)C>[OH:1][CH:2]1[CH:3]([C:17]([NH:62][C:55]2[CH:54]=[C:53]([C:48]3[CH:49]=[CH:50][CH:51]=[C:52]4[C:47]=3[CH:46]=[CH:45][NH:44]4)[CH:61]=[C:60]3[C:56]=2[CH:57]=[N:58][NH:59]3)=[O:19])[CH2:4][N:5]([C:7]([O:9][CH2:10][C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)=[O:8])[CH2:6]1
Reactant: O=C(O)C1CN(C(=O)OCc2ccccc2)CC1O
Reactant: Nc1cc(-c2cccc3[nH]ccc23)cc2[nH]ncc12
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Nc1cc(-c2cccc3[nH]ccc23)cc2[nH]ncc12)C1CN(C(=O)OCc2ccccc2)CC1O
Reaction time: 0.17 h
Yield: 6.4 %

Procedure:
To a solution of 4-hydroxy-1-{[(phenylmethyl)oxy]carbonyl}-3-pyrrolidinecarboxylic acid (available from Fluorochem, 59 mg, 0.22 mmol) in DMF (1 ml) was added HATU (85 mg, 0.22 mmol) and the mixture stirred for 10 mins. Then 6-(1H-indol-4-yl)-1H-indazol-4-amine (46 mg, 0.19 mmol) and DIPEA (0.065 ml, 0.37 mmol) were added and the mixture allowed to stand for 18 h at 20° C. The solvent was removed under a stream of nitrogen and the residue purified by Mass Directed Automated Preparative HPLC (Method E), to give the title compound (6 mg) as a brown solid.
Reaction SMILES: C1([C@H](CO)N)C=CC=CC=1.[F:11][C:12]1[CH:13]=[C:14]([CH:32]=[CH:33][CH:34]=1)[CH2:15][O:16][C:17]1[CH:22]=[CH:21][C:20]([N:23]2[C:27](=[O:28])[CH2:26][CH:25]([C:29]([OH:31])=[O:30])[CH2:24]2)=[CH:19][CH:18]=1>C(#N)C.O>[F:11][C:12]1[CH:13]=[C:14]([CH:32]=[CH:33][CH:34]=1)[CH2:15][O:16][C:17]1[CH:18]=[CH:19][C:20]([N:23]2[C:27](=[O:28])[CH2:26][C@H:25]([C:29]([OH:31])=[O:30])[CH2:24]2)=[CH:21][CH:22]=1
Reactant: O=C(O)C1CC(=O)N(c2ccc(OCc3cccc(F)c3)cc2)C1
Agent: N[C@@H](CO)c1ccccc1
Solvent: CC#N
Solvent: O
Product: O=C(O)[C@H]1CC(=O)N(c2ccc(OCc3cccc(F)c3)cc2)C1
Yield: 44.1 %

Procedure:
The salt of the (S)-(II) compound with (R)-(−)-2-phenylglycinol was prepared in an analogous manner as described in Example 2 a) from rac-1-[4-(3-fluoro-benzyloxy)-phenyl]-5-oxo-pyrrolidine-3-carboxylic acid (5 g, 15.2 mmol) in acetonitrile/water 95:5 (50 mL) using a solution of only 1.46 g (R)-(−)-2-phenylglycinol (10.6 mmol, 0.7 eq) in acetonitrile/water 95:5 (3.3 mL). From the salt (3.2 g, 45% based on racemic acid) obtained in 99.7:0.3 diastereomeric ratio the (S)-(II) compound was liberated and purified in a similar manner as described in Example 2b) to afford (S)-1-[4-(3-fluoro-benzyloxy)-phenyl]-5-oxo-pyrrolidine-3-carboxylic acid (2.21 g, 44% based on racemic acid) in high purity (HPLC: 99.4% area) and with >99.9:0.1% er.
Reaction SMILES: C1(S(O[CH2:11][CH2:12][C:13]2[C:22]3[C:17](=[CH:18][CH:19]=[C:20]([O:23][CH3:24])[CH:21]=3)[CH:16]=[CH:15][CH:14]=2)(=O)=O)C=CC=CC=1.[C:25]1(=[O:35])[NH:29][C:28](=[O:30])[C:27]2=[CH:31][CH:32]=[CH:33][CH:34]=[C:26]12.[K].C(#N)C>O>[CH3:24][O:23][C:20]1[CH:21]=[C:22]2[C:17]([CH:16]=[CH:15][CH:14]=[C:13]2[CH2:12][CH2:11][N:29]2[C:28](=[O:30])[C:27]3=[CH:31][CH:32]=[CH:33][CH:34]=[C:26]3[C:25]2=[O:35])=[CH:18][CH:19]=1
Reactant: O=C1NC(=O)c2ccccc21
Reactant: COc1ccc2cccc(CCOS(=O)(=O)c3ccccc3)c2c1
Agent: [K]
Solvent: CC#N
Solvent: O
Product: COc1ccc2cccc(CCN3C(=O)c4ccccc4C3=O)c2c1
Temperature: 25 °C
Yield: 84.6 %

Procedure:
The compound IV (14 g, 0.041 mol) produced as described above and potassium phthalimide (9.3 g, 0.050 mol) were added into a reaction vessel, and acetonitrile (150 ml) was added. The mixture was heated and refluxed for 4 hours. After cooling it to room temperature, 200 ml of water was added, and the mixture was stirred and filtered. The filter cake formed was washed with water and dried, to produce 11.5 g of N-[2-(7-methoxy-1-naphthyl)ethyl]phthalimide (II). The yield was 85%. The melting point was 160-161° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[C:9]1[CH:13]=[C:12](I)[S:11][C:10]=1[C:15]([O:17][CH3:18])=[O:16])=[O:7])([CH3:4])([CH3:3])[CH3:2].CC1(C)C(C)(C)OB([C:34]2[CH:39]=[CH:38][C:37]([C:40]3[O:48][C:47]4[C:42](=[N:43][CH:44]=[CH:45][CH:46]=4)[CH:41]=3)=[CH:36][CH:35]=2)O1>>[C:1]([O:5][C:6]([N:8]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[C:9]1[CH:13]=[C:12]([C:34]2[CH:35]=[CH:36][C:37]([C:40]3[O:48][C:47]4[C:42](=[N:43][CH:44]=[CH:45][CH:46]=4)[CH:41]=3)=[CH:38][CH:39]=2)[S:11][C:10]=1[C:15]([O:17][CH3:18])=[O:16])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC1(C)OB(c2ccc(-c3cc4ncccc4o3)cc2)OC1(C)C
Reactant: COC(=O)c1sc(I)cc1N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Product: COC(=O)c1sc(-c2ccc(-c3cc4ncccc4o3)cc2)cc1N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C

Procedure:
Intermediate VII.5 was prepared starting from methyl 3-(bis[ter-butoxycarbonyl]amino)-5-iodo-2-thiophenecarboxylate and 2-[4(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]furo[3,2-b]pyridine (according to the general procedure in WO 2008/017688) as described for Intermediate VII.1. Intermediate VII.5 was used for the next step without purification.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:16](=[O:17])[C:15]([C:18]([OH:20])=[O:19])=[CH:14][N:6]3[CH2:7][CH2:8][N:9]([CH3:13])[C:10]([C:11]=1F)=[C:5]23.[CH3:21][N:22]1[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1>>[F:1][C:2]1[CH:3]=[C:4]2[C:16](=[O:17])[C:15]([C:18]([OH:20])=[O:19])=[CH:14][N:6]3[CH2:7][CH2:8][N:9]([CH3:13])[C:10]([C:11]=1[N:25]1[CH2:26][CH2:27][N:22]([CH3:21])[CH2:23][CH2:24]1)=[C:5]23
Reactant: CN1CCNCC1
Reactant: CN1CCn2cc(C(=O)O)c(=O)c3cc(F)c(F)c1c32
Product: CN1CCN(c2c(F)cc3c(=O)c(C(=O)O)cn4c3c2N(C)CC4)CC1

Procedure:
Using 9,10-difluoro-1-methyl-7-oxo-2,3-dihydro-1H,7H-pyrido[1,2,3-de]quinoxaline-6-carboxylic acid and 4-methylpiperazine, the same procedure as in Production Example 1 was followed to yield the title compound.
Reaction SMILES: [OH:1][CH:2]([C:11]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[NH:13][CH:12]=1)[CH2:3][N:4]1[CH2:9][CH2:8][N:7]([NH2:10])[CH2:6][CH2:5]1.C(N(CC)CC)C.[C:27](Cl)(=[O:34])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.[OH-].[Na+]>C(Cl)(Cl)Cl>[OH:1][CH:2]([C:11]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[NH:13][CH:12]=1)[CH2:3][N:4]1[CH2:9][CH2:8][N:7]([NH:10][C:27](=[O:34])[C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH2:6][CH2:5]1
Reactant: O=C(Cl)c1ccccc1
Reactant: NN1CCN(CC(O)c2c[nH]c3ccccc23)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: O=C(NN1CCN(CC(O)c2c[nH]c3ccccc23)CC1)c1ccccc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a stirred slurry of 8.60 g (0.0334 mol) of 3-[1-hydroxy-2-(4aminopiperazin-1-yl)ethyl]indole in 50 ml. of chloroform is added 4.55 g (0.045 mol) of triethylamine. The mixture is cooled to 0° C. under a nitrogen atmosphere, and a solution of 5.64 g (0.040 mol) benzoyl chloride in 10 ml. of chloroform is introduced dropwise for 1 hour, while maintaining the reaction temperature of 0°-5° C. The resulting mixture is stirred at 0° C. for one hour, and at ambient temperature for another hour. The mixture is diluted with 150 ml. of chloroform and then 100 ml. of 10% sodium hydroxide. This mixture is stirred for 15 minutes and then filtered; the cake is washed well with water and dried to give a white solid. This product is recrystallized first from an ethanol and water mixture and then twice from DMF and water to give pure white crystals of 3-[1-hydroxy-2-(4-benzamidopiperazin-1-yl)ethyl]indole, m.p. 211°-213° C. dec. Analysis: Calculated for C21H24N4 02 : 69.21% C; 6.64% H; 15.37% N Found: 69.00% C; 6.60% H; 15.28% N.