Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6](O)=[CH:5][CH:4]=1.N12CCCNC1CCCC=C2.[CH3:21][C:22]([OH:26])([C:24]#[CH:25])[CH3:23].FC(F)(F)C(OC(=O)C(F)(F)F)=O.CC1(C)OC2=CC3C(C)=CC(C#N)=NC=3C=C2C=C1.[Cl-].[NH4+]>C(#N)C.[Cu]Cl>[CH3:21][C:22]([CH3:23])([O:26][C:6]1[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=1)[C:24]#[CH:25]
Reactant: C#CC(C)(C)O
Reactant: COc1ccc(O)cc1
Agent: Cl[Cu]
Agent: C1=CN2CCCNC2CCC1
Agent: Cc1cc(C#N)nc2cc3c(cc12)OC(C)(C)C=C3
Solvent: CC#N
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Product: C#CC(C)(C)Oc1ccc(OC)cc1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a solution of 4-methoxyphenol (15.0 g, 121 mmol) in acetonitrile (75 mL), 1,8-diazabicyclo[5.4.0]undecene (23.9 g, 157 mmol) was added under ice cooling and the resulting mixture was stirred at 0° C. for 30 minutes (Solution 1). To a solution of 2-methyl-3-butyn-2-ol (11.7 g, 139 mmol) in acetonitrile (75 mL), 1,8-diazabicyclo[5.4.0]undecene (23.9 g, 157 mmol) was added under ice cooling, the resulting mixture was stirred at 0° C. for 30 minutes, then trifluoroacetic anhydride (25.4 g, 121 mmol) was added and the resulting mixture was stirred at 0° C. for 30 minutes (Solution 2). Copper (I) chloride (36 mg, 0.36 mmol) was added to Solution 1, and then Solution 2 was added dropwise thereto over 15 minutes. Upon the completion of dropwise addition, the temperature was raised to room temperature, and the mixture was stirred overnight. Upon the completion of the reaction, an aqueous solution of ammonium chloride solution was added to the reaction solution, and the solvent was distilled off under a reduced pressure. An aqeuous solution of 1 mol/L hydrochloric acid was added to the residue, the resulting mixture was extracted with ethyl acetate, the organic phase was washed once with an aqeuous solution of 1 mol/L hydrochloric acid, twice with an aqueous solution of saturated sodium hydrogen carbonate and once with saturated sodium chloride solution. Then, the organic phase was dried over anhydrous magnesium sulfate. After distilling off the solvent, the residue was directly used for the subsequent reaction.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][C:8]=2[C:10]([OH:12])=O)[CH:3]=[CH:2]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(CC)C(C)C)(C)C.[C:44]([C:48]1[CH:64]=[CH:63][C:51]([CH2:52][NH:53][CH2:54][CH2:55][C:56]2[CH:61]=[CH:60][C:59]([F:62])=[CH:58][CH:57]=2)=[CH:50][CH:49]=1)([CH3:47])([CH3:46])[CH3:45]>CN(C=O)C.O>[C:44]([C:48]1[CH:64]=[CH:63][C:51]([CH2:52][N:53]([CH2:54][CH2:55][C:56]2[CH:61]=[CH:60][C:59]([F:62])=[CH:58][CH:57]=2)[C:10]([C:8]2[CH:7]=[CH:6][CH:5]=[C:4]3[C:9]=2[NH:1][CH:2]=[CH:3]3)=[O:12])=[CH:50][CH:49]=1)([CH3:47])([CH3:45])[CH3:46]
Reactant: CC(C)(C)c1ccc(CNCCc2ccc(F)cc2)cc1
Reactant: O=C(O)c1cccc2cc[nH]c12
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)c1ccc(CN(CCc2ccc(F)cc2)C(=O)c2cccc3cc[nH]c23)cc1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 83.2 %

Procedure:
To a solution of 48 mg (0.3 mmol) of 1H-indole-7-carboxylic acid and 96 mg of TBTU (0.3 mmol) in 4 ml DMF, were added 0.26 ml (1.5 mmol) of N,N-diisopropylethyl amine. After stirring for 5 min at rt, 86 mg (0.3 mmol) of (4-tert-butyl-benzyl)-[2-(4-fluoro-phenyl)-ethyl]-amine in 1 ml DMF were added. After stirring for 4 h at rt, the reaction mixture was diluted with 50 ml water and extracted with 2×50 ml EtOAc. The combined organic phases were washed with water and brine, dried with magnesium sulfate, filtered and concentrated in vacuo. The orange residue was purified by column chromatography (8 g silica gel; heptane/EtOAc 6:1) to give 107 mg (82%) of a white solid. MS (ISP) 429.6 (M+H)+.
Reaction SMILES: [O:1]=[C:2]1[C:11]2[CH:10]=[CH:9][CH:8]=[C:7]([C:12]([OH:14])=O)[C:6]=2[CH:5]=[CH:4][N:3]1[CH:15]([CH2:19][CH2:20][CH3:21])[CH2:16][CH2:17][CH3:18].Cl.[NH2:23][C@@H:24]([CH2:40][C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1)[C@H:25]([OH:39])[CH2:26][NH:27][CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([C:35]([F:38])([F:37])[F:36])[CH:30]=1.OC1C2N=NNC=2C=CC=1.Cl.CN(C)CCCN=C=NCC.C(N(CC)C(C)C)(C)C>ClCCl.O>[CH2:40]([C@H:24]([NH:23][C:12]([C:7]1[C:6]2[CH:5]=[CH:4][N:3]([CH:15]([CH2:19][CH2:20][CH3:21])[CH2:16][CH2:17][CH3:18])[C:2](=[O:1])[C:11]=2[CH:10]=[CH:9][CH:8]=1)=[O:14])[C@H:25]([OH:39])[CH2:26][NH:27][CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([C:35]([F:36])([F:37])[F:38])[CH:30]=1)[C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1
Reactant: N[C@@H](Cc1ccccc1)[C@H](O)CNCc1cccc(C(F)(F)F)c1
Reactant: CCCC(CCC)n1ccc2c(C(=O)O)cccc2c1=O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: Oc1cccc2[nH]nnc12
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: CCCC(CCC)n1ccc2c(C(=O)N[C@@H](Cc3ccccc3)[C@H](O)CNCc3cccc(C(F)(F)F)c3)cccc2c1=O
Temperature: 25 °C
Reaction time: 20 h

Procedure:
77 mg of 1-oxo-2-(1-propylbutyl)-1,2-dihydroisoquinoline-5-carboxylic acid are dissolved in 4.5 cm3 of dichloromethane under an inert atmosphere at a temperature close to 20° C. 110 mg of (2R,3S)-3-amino-4-phenyl-1-{[3-(trifluoromethyl)benzyl]amino}butan-2-ol hydrochloride (1:1), 5 mg of hydroxybenzotriazole, 61 mg of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride are added to the solution. 0.22 cm3 of N,N-diisopropylethylamine is poured into the reaction medium. The latter is kept stirring for 20 h at ambient temperature. 10 cm3 of water are added to the reaction medium. The organic phase is washed with 5 cm3 of a saturated aqueous solution of sodium chloride, dried over magnesium sulfate and concentrated using a rotary evaporator under reduced pressure (5 kPa). The crude product obtained is purified by flash chromatography over silica (column: 15 g; particle size: 20-40 μm, spherical; flow rate: 20 cm3/min; eluent: 100% ethyl acetate). After concentrating the fractions under reduced pressure, 84 mg of N-[(1S,2R)-1-benzyl-2-hydroxy-3-{[3-(trifluoromethyl)benzyl]amino}propyl]-1-oxo-2-(1-propylbutyl)-1,2-dihydroisoquinoline-5-carboxamide are obtained in the form of a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:23]=[CH:24][CH:25]=1)[CH2:5][O:6][C:7]1[CH:16]=[C:15]2[C:10]([CH:11]=[C:12]([CH2:17][C:18]([O:20][CH2:21]C)=[O:19])[CH:13]=[N:14]2)=[CH:9][CH:8]=1.C([O-])([O-])=O.[K+].[K+]>CO>[Cl:1][C:2]1[CH:3]=[C:4]([CH:23]=[CH:24][CH:25]=1)[CH2:5][O:6][C:7]1[CH:16]=[C:15]2[C:10]([CH:11]=[C:12]([CH2:17][C:18]([O:20][CH3:21])=[O:19])[CH:13]=[N:14]2)=[CH:9][CH:8]=1
Reactant: CCOC(=O)Cc1cnc2cc(OCc3cccc(Cl)c3)ccc2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: COC(=O)Cc1cnc2cc(OCc3cccc(Cl)c3)ccc2c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 69 %

Procedure:
To a solution of ethyl 2-(7-((3-chlorobenzyl)oxy)quinolin-3-yl)acetate (Example 51, 50 mg, 0.14 mmol) in MeOH (3.0 mL) was added K2CO3 (50 mg, 0.36 mmol). The reaction was stirred at ambient temperature for 30 minutes. The reaction was loaded directly onto the column and purification (FCC, SiO2, 0-50%, EtOAc/hexanes) afforded the title compound as a white solid (33 mg, 69%). 1H NMR (400 MHz, CDCl3) δ 8.75 (d, J=2.0 Hz, 1H), 8.01 (s, 1H), 7.71 (d, J=9.0 Hz, 1H), 7.49 (s, 1H), 7.45 (d, J=2.7 Hz, 1H), 7.38-7.27 (m, 4H), 5.19 (s, 2H), 3.79 (s, 2H), 3.73 (s, 3H). [M+H]=342.2.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][C@@H:3]([NH:7][C:8](=[O:14])[O:9][C:10]([CH3:13])([CH3:12])[CH3:11])[CH2:2]1.[CH3:15][NH:16][C:17]1[CH:25]=[CH:24][C:20]([C:21](O)=[O:22])=[CH:19][C:18]=1[N+:26]([O-:28])=[O:27].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C)C=O.CCOCC.O>[C:10]([O:9][C:8](=[O:14])[NH:7][C@@H:3]1[CH2:4][CH2:5][CH2:6][N:1]([C:21](=[O:22])[C:20]2[CH:24]=[CH:25][C:17]([NH:16][CH3:15])=[C:18]([N+:26]([O-:28])=[O:27])[CH:19]=2)[CH2:2]1)([CH3:11])([CH3:13])[CH3:12]
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCCNC1
Reactant: CNc1ccc(C(=O)O)cc1[N+](=O)[O-]
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOCC
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: CNc1ccc(C(=O)N2CCC[C@@H](NC(=O)OC(C)(C)C)C2)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of (R)-tert-butyl piperidin-3-ylcarbamate (1.460 g, 7.29 mmol) (available from, for example, Apollo Scientific Ltd), 4-(methylamino)-3-nitrobenzoic acid (1.43 g, 7.29 mmol) and HATU (2.77 g, 7.29 mmol) in N,N-dimethylformamide (DMF) (50 mL) was added DIPEA (2.55 mL, 14.58 mmol) and the reaction stirred at r.t. for 16 h. Water (200 mL) and Et2O (200 mL) were added and the layers separated. The aqueous layer was extracted with further Et2O (2×200 mL) and the combined organics washed with water (2×50 mL), dried (Na2SO4) and concentrated in vacuo to afford a bright yellow oil. The crude product was purified on silica (100 g) using a gradient of 40% EtOAc/cyclohexane→100% ethyl acetate/cyclohexane. The appropriate fractions were combined and evaporated under vacuum to give the title product as an orange-gold solid (2.76 g, 7.29 mmol, 100% yield).
Reaction SMILES: C(OC([N:8]1[CH2:24][CH2:23][C@@H:11]2[N:12]([CH3:22])[C:13]3[C:14]([C:20]#[N:21])=[CH:15][C:16](Br)=[CH:17][C:18]=3[C@@H:10]2[CH2:9]1)=O)(C)(C)C.[Br-].[CH2:26]([Zn+])[CH2:27][CH2:28][CH3:29]>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>[CH2:26]([C:16]1[CH:17]=[C:18]2[C:13](=[C:14]([C:20]#[N:21])[CH:15]=1)[N:12]([CH3:22])[C@H:11]1[CH2:23][CH2:24][NH:8][CH2:9][C@@H:10]21)[CH2:27][CH2:28][CH3:29]
Reactant: CN1c2c(C#N)cc(Br)cc2[C@@H]2CN(C(=O)OC(C)(C)C)CC[C@@H]21
Reactant: CCCC[Zn+]
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Br-]
Product: CCCCc1cc(C#N)c2c(c1)[C@@H]1CNCC[C@@H]1N2C

Procedure:
Following the general procedure for Example 127–146, the title compound was prepared (8 mg, 30%) as a light yellow oil using (4aS,9bR)-8-bromo-6-cyano-5-methyl-1,3,4,4a,5,9b-hexahydro-pyrido[4,3-b]indole-2-carboxylic acid tert-butyl ester (Example 158, 40 mg, 0.10 mmol), n-butylzinc bromide (0.5 M in THF, 2.5 mole equivalent) and Pd(PPh3)4 (0.06 mole equivalent).: MS (ESI): 270 (base, M+H).
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][C:5]([C:6](=[O:9])[CH2:7]Br)=[CH:4][CH:3]=1.[CH2:12]([N:14]1[CH2:19][NH:18][C:17](=[S:20])[NH:16][CH2:15]1)[CH3:13]>CC(C)=O>[Br:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]2([OH:9])[N:18]3[CH2:19][N:14]([CH2:12][CH3:13])[CH2:15][N:16]=[C:17]3[S:20][CH2:7]2)=[CH:4][CH:3]=1
Reactant: O=C(CBr)c1ccc(Br)cc1
Reactant: CCN1CNC(=S)NC1
Solvent: CC(C)=O
Product: CCN1CN=C2SCC(O)(c3ccc(Br)cc3)N2C1

Procedure:
A solution of 6.95 grams (0.025 moles) of p-bromophenacylbromide in 60 milliliters of acetone was mixed with a solution of 3.62 grams (0.025 moles) of 5-ethyl 3,4,5,6-tetrahydro-s-triazin 2(1H) thione in 500 milliliters of acetone. After 10 minutes 6-p-bromophenyl-3-ethyl-6-hydroxy-3,4,6,7-tetrahydro-2H-thiazolo(3,2-a)-s-triazine hydrobromide crystallized out as a colourless solid, m.p. 132°-134° C. The yield was 9.27 grams (88%).
Reaction SMILES: F[P-](F)(F)(F)(F)F.C[N+](C)=C(N(C)C)ON1C2N=CC=CC=2N=N1.[CH3:25][O:26][C:27]1[CH:41]=[CH:40][C:30]([O:31][C:32]2[CH:33]=[C:34]([CH2:38][NH2:39])[CH:35]=[CH:36][CH:37]=2)=[CH:29][CH:28]=1.[NH2:42][C:43]1[N:52]=[C:51]([N:53]2[CH2:58][CH2:57][N:56]([CH3:59])[CH2:55][CH2:54]2)[C:50]2[C:45](=[CH:46][C:47]([C:60](O)=[O:61])=[CH:48][CH:49]=2)[N:44]=1.C(N(CC)C(C)C)(C)C>CN(C)C=O>[NH2:42][C:43]1[N:52]=[C:51]([N:53]2[CH2:54][CH2:55][N:56]([CH3:59])[CH2:57][CH2:58]2)[C:50]2[C:45](=[CH:46][C:47]([C:60]([NH:39][CH2:38][C:34]3[CH:35]=[CH:36][CH:37]=[C:32]([O:31][C:30]4[CH:40]=[CH:41][C:27]([O:26][CH3:25])=[CH:28][CH:29]=4)[CH:33]=3)=[O:61])=[CH:48][CH:49]=2)[N:44]=1
Reactant: COc1ccc(Oc2cccc(CN)c2)cc1
Reactant: CN1CCN(c2nc(N)nc3cc(C(=O)O)ccc23)CC1
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: COc1ccc(Oc2cccc(CNC(=O)c3ccc4c(N5CCN(C)CC5)nc(N)nc4c3)c2)cc1
Reaction time: 1 h
Yield: 54 %

Procedure:
N,N,N′,N′-Tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate (0.030 g, 0.078 mmol) was added to a solution of crude 1-[3-(4-methoxyphenoxy)phenyl]methanamine (0.045 g) and 2-amino-4-(4-methylpiperazin-1-yl)quinazoline-7-carboxylic acid (0.015 g, 0.052 mmol) in N,N-dimethylformamide (2.0 mL) with N,N-diisopropylethylamine (0.027 mL, 0.16 mmol) at r.t. The reaction was stirred for 1 h. The product was purified without workup by RP-HPLC (pH=10) to give the desired product (0.014 g, 44%) as a white amorphous solid. Analytical LCMS (M+H)+: m/z=499.0.
Reaction SMILES: C([N:4]1[C:8]([C:9]([OH:11])=[O:10])=[C:7]([N:12]2[C:16](=[O:17])[NH:15][C:14]([CH:18]([NH:30][C:31]3[CH:36]=[CH:35][C:34]([C:37]#[N:38])=[C:33]([CH2:39][NH:40]C(OC(C)(C)C)=O)[CH:32]=3)[C:19]3[CH:24]=[C:23]([O:25][CH3:26])[C:22]([O:27][CH3:28])=[CH:21][C:20]=3[F:29])=[N:13]2)[N:6]=[CH:5]1)C=C.CN1C(=O)CC(=O)N(C)C1=O.FC(F)(F)C(O)=O.C1(C)C=CC=CC=1>ClCCl.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>[F:29][C:20]1[CH:21]=[C:22]([O:27][CH3:28])[C:23]([O:25][CH3:26])=[CH:24][C:19]=1[CH:18]([NH:30][C:31]1[CH:32]=[C:33]2[C:34](=[CH:35][CH:36]=1)[C:37](=[NH:38])[NH:40][CH2:39]2)[C:14]1[NH:15][C:16](=[O:17])[N:12]([C:7]2[N:6]=[CH:5][NH:4][C:8]=2[C:9]([OH:11])=[O:10])[N:13]=1
Reactant: C=CCn1cnc(-n2nc(C(Nc3ccc(C#N)c(CNC(=O)OC(C)(C)C)c3)c3cc(OC)c(OC)cc3F)[nH]c2=O)c1C(=O)O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CN1C(=O)CC(=O)N(C)C1=O
Solvent: Cc1ccccc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1cc(F)c(C(Nc2ccc3c(c2)CNC3=N)c2nn(-c3nc[nH]c3C(=O)O)c(=O)[nH]2)cc1OC
Temperature: 25 °C
Reaction time: 8 h
Yield: 12.8 %

Procedure:
To a mixture of 3-allyl-5-(3-{[3-(t-butoxycarbonylaminomethyl)-4-cyanophenylamino]-(2-fluoro-4,5-dimethoxyphenyl)methyl}-5-oxo-4,5-dihydro-[1,2,4]triazol-1-yl)-3H-imidazole-4-carboxylic acid (2.5 mg) in dichloromethane (2 mL) there were added tetrakis(triphenylphosphine)palladium(0)(0.5 mg) and 1,3-dimethylbarbituric acid (1.5 mg) under a nitrogen atmosphere, and the mixture was stirred overnight at room temperature. Trifluoroacetic acid (0.4 mL) was added, the mixture was stirred at room temperature for 30 minutes, and then toluene (10 mL) was added to the mixture and the solvent in the mixture was distilled off. The residue was purified by reverse-phase high performance liquid chromatography (acetonitrile/water mixed solvent, 0.1% acetic acid) to obtain the target compound (0.25 mg).
Reaction SMILES: C([Li])(C)(C)C.[C:6]([C:8]1[CH:13]=[CH:12][C:11]([N:14]2[C@H:19]([CH3:20])[CH2:18][N:17]([C:21]([NH:23][C:24]3[CH:25]=[N:26][C:27]([S:30](C)(=[O:32])=[O:31])=[CH:28][CH:29]=3)=[O:22])[C@@H:16]([CH3:34])[CH2:15]2)=[CH:10][C:9]=1[C:35]([F:38])([F:37])[F:36])#[N:7].C(B(CCCC)CCCC)CCC.C([O-])(=O)C.[Na+].[NH2:57]OS(O)(=O)=O>O.O1CCCC1.CCCCC>[NH2:57][S:30]([C:27]1[N:26]=[CH:25][C:24]([NH:23][C:21]([N:17]2[CH2:18][C@@H:19]([CH3:20])[N:14]([C:11]3[CH:12]=[CH:13][C:8]([C:6]#[N:7])=[C:9]([C:35]([F:38])([F:37])[F:36])[CH:10]=3)[CH2:15][C@@H:16]2[CH3:34])=[O:22])=[CH:29][CH:28]=1)(=[O:32])=[O:31]
Reactant: NOS(=O)(=O)O
Reactant: C[C@@H]1CN(C(=O)Nc2ccc(S(C)(=O)=O)nc2)[C@@H](C)CN1c1ccc(C#N)c(C(F)(F)F)c1
Agent: CC(=O)[O-]
Agent: CCCCB(CCCC)CCCC
Agent: [Li]C(C)(C)C
Solvent: CCCCC
Solvent: C1CCOC1
Solvent: O
Product: C[C@@H]1CN(C(=O)Nc2ccc(S(N)(=O)=O)nc2)[C@@H](C)CN1c1ccc(C#N)c(C(F)(F)F)c1
Temperature: -30 °C
Reaction time: 0.25 h
Yield: 19.8 %

Procedure:
A 7.3 ml portion of 1.54 M pentane solution of tert-butyl lithium was added dropwise to 100 ml of THF solution containing 2.48 g of trans-4-(4-cyano-3-trifluoromethylphenyl)-N-(6-methanesulfonyl-3-pyridyl)-2,5-dimethylpiperazine-1-carboxamide at −78° C., and then the mixture was stirred at −30° C. for 15 minutes. After cooling again to −78° C., this was mixed with 15.5 ml of 1.0 M tetrahydrofuran solution of tri-n-butyl borane, warmed up to room temperature spending 1 hour and then heated under refulx for 18 hours. Under ice-cooling, this was mixed with 5.91 g of sodium acetate, 50 ml of water and 491 mg of hydroxylamine-O-sulfonic acid and stirred overnight at room temperature. The reaction mixture was extracted with ethyl acetate, the organic layer was washed with saturated sodium bicarbonate solution and saturated brine in that order and dried over magnesium sulfate, and then the solvent was evaporated. The thus obtained mixture was subjected to a silica gel column chromatography and eluted with chloroform-methanol (9:1, v/v) to obtain 414 mg of the title compound. Thereafter, this was crystallized twice from ethanol to obtain 271 mg of the title compound as crystals.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:26])[C:5]1[CH:10]=[C:9]([C:11](=[O:24])[NH:12][C:13]2[CH:18]=[CH:17][C:16]([O:19][C:20]([F:23])([F:22])[F:21])=[CH:15][CH:14]=2)[CH:8]=[N:7][C:6]=1Cl)[CH3:2].[NH:27]1[CH2:31][CH2:30][C@@H:29]([OH:32])[CH2:28]1.CCN(C(C)C)C(C)C>CC(O)C>[CH2:1]([O:3][C:4](=[O:26])[C:5]1[CH:10]=[C:9]([C:11](=[O:24])[NH:12][C:13]2[CH:18]=[CH:17][C:16]([O:19][C:20]([F:23])([F:22])[F:21])=[CH:15][CH:14]=2)[CH:8]=[N:7][C:6]=1[N:27]1[CH2:31][CH2:30][C@@H:29]([OH:32])[CH2:28]1)[CH3:2]
Reactant: CCOC(=O)c1cc(C(=O)Nc2ccc(OC(F)(F)F)cc2)cnc1Cl
Reactant: O[C@@H]1CCNC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)O
Product: CCOC(=O)c1cc(C(=O)Nc2ccc(OC(F)(F)F)cc2)cnc1N1CC[C@@H](O)C1
Temperature: 22 °C
Reaction time: 1 h

Procedure:
A mixture of 2-chloro-5-((4-(trifluoromethoxy)phenyl)carbamoyl)nicotinic acid ethyl ester (Stage 72.5, 3.00 g, 7.7 mmol), (R)-3-pyrrolidinol (0.807 g, 9.26 mmol) and DIPEA (2.19 g, 17.0 mmol) in iPrOH (50 mL) was stirred at 22° C. for 60 min. The solvent was evaporated off under reduced pressure and the residue was dissolved in EtOAc, washed with sat. aq. NaHCO3 and brine, dried over anhydrous Na2SO4 and the solvent was evaporated off under reduced pressure to give the title compound as a foam. HPLC (Condition 4) tR=5.63 min, UPLC-MS (Condition 8) tR=1.06 min, m/z=440.1 [M+H]+; 1H-NMR (400 MHz, DMSO-d6) δ ppm 1.32 (t, J=7.04 Hz, 3H), 1.79-2.01 (m, 2H), 3.09 (d, J=11.73 Hz, 1H), 3.41 (d, J=8.21 Hz, 1H), 3.54 (dd, J=11.73, 4.30 Hz, 1H), 3.65 (dd, J=10.17, 3.52 Hz, 1H), 4.25-4.39 (m, 3H), 4.96 (d, J=3.13 Hz, 1H), 7.34 (d, J=8.21 Hz, 2H), 7.78-7.90 (m, 2H), 8.36 (d, J=2.35 Hz, 1H), 8.81 (d, J=2.35 Hz, 1H), 10.28 (s, 1H).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]([N+:10]([O-:12])=[O:11])=[C:6]([CH:9]=1)[CH:7]=[O:8].C(=O)([O-])[O-].[K+].[K+].[CH2:19](Br)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>[I-].C([N+](CCCC)(CCCC)CCCC)CCC.CN(C)C=O>[CH2:19]([O:1][C:2]1[CH:3]=[CH:4][C:5]([N+:10]([O-:12])=[O:11])=[C:6]([CH:9]=1)[CH:7]=[O:8])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: O=Cc1cc(O)ccc1[N+](=O)[O-]
Reactant: BrCc1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])[O-]
Agent: [I-]
Solvent: CN(C)C=O
Product: O=Cc1cc(OCc2ccccc2)ccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 5 h
Yield: 87.5 %

Procedure:
To a suspension of 5-hydroxy-2-nitrobenzaldehyde (300 mg, 1.80 mmol), potassium carbonate (498 mg, 3.60 mmol), and tetrabutylammonium iodide (66 mg, 0.18 mmol) in 1.8 mL of dry N,N-dimethylformamide was added benzyl bromide (0.32 mL, 2.7 mmol) at 0° C. After being stirred at room temperature for 5 h, the reaction mixture was filtrated to remove inorganic salts. The filtrate was diluted with diethyl ether, and the solution was washed with water, saturated NaHCO3 aqueous solution, brine, and dried over MgSO4. After filtration, the filtrate was concentrated in vacuo, and the residue was purified by silica gel column chromatography (hexane/ethyl acetate=90/10 to 75/25) to obtain the title compound as a pale yellow solid (405 mg, 87%).
Reaction SMILES: [CH2:1]([S:8][CH2:9][C@@H:10]1[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.ClC1C=C(C=CC=1)C(OO)=[O:27].C([O-])(O)=O.[Na+]>C(OCC)(=O)C>[CH2:1]([S:8]([CH2:9][C@@H:10]1[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11]1)=[O:27])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](CSCc2ccccc2)C1
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CC[C@@H](CS(=O)Cc2ccccc2)C1
Temperature: 0 °C
Yield: 88.7 %

Procedure:
To a stirred solution of (3R)-3-(benzylthio)methyl-1-(tert-butoxycarbonyl)pyrrolidine (0.2553 g, 0.830 mmol) in ethyl acetate (15 ml), under argon, cooled in a bath at ca. -40° C., was added portionwise 57-86% 3-chloroperoxybenzoic acid (0.2094 g). The mixture was then allowed to warm to 0° C. over 1.5 h, before pouring into 5% NaHCO3 solution (15 ml). The organic layer was separated and washed with more 5% NaHCO3 solution (15 ml), then saturated NaCl solution (10 ml), dried (MgSO4) and evaporated in vacuo. The residue was purified by flash chromatography (silica gel, 3% MeOH/CH2Cl2) to give 0.2381 g (89%) of the title compound as a colourless oil. δH (250 MHz, CDCl3) 1.44 (9H, s), 1.61 (1H, m), 2.15 (1H, m), 2.52 (1H, m), 2.66 (2H, m), 3.00 (1H, m), 3.29 (1H, m), 3.43 (1H, m), 3.63 (1H, m), 3.96 (1H, d, J=12.9 Hz), 4.07 (1H, d, J=12.9 Hz), 7.28-7.30 (2H, m), 7.35-7.39 (3H, m). m/e (ES+) 324 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]([C@@H:5]1[C@H:9]([OH:10])[CH2:8][CH2:7][N:6]1[C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])=[O:4].N1C=CN=C1.[Si:23](Cl)([C:26]([CH3:29])([CH3:28])[CH3:27])([CH3:25])[CH3:24]>C(Cl)Cl>[CH3:1][O:2][C:3]([C@@H:5]1[C@H:9]([O:10][Si:23]([C:26]([CH3:29])([CH3:28])[CH3:27])([CH3:25])[CH3:24])[CH2:8][CH2:7][N:6]1[C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])=[O:4]
Reactant: COC(=O)[C@@H]1[C@H](O)CCN1C(=O)OC(C)(C)C
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: ClCCl
Product: COC(=O)[C@@H]1[C@H](O[Si](C)(C)C(C)(C)C)CCN1C(=O)OC(C)(C)C
Reaction time: 3 h
Yield: 98.9 %

Procedure:
To a solution of (2S,3R)—N-tert-butyloxycarbonyl-3-hydroxy-2 pyrrolidinecarboxylic acid methyl ester (1D) (0.63 g, 2.56 mmol) in CH2Cl2 (12 mL) at rt was added imidazole (0.35 g, 5.14 mmol), and then tert-butydimethylsilyl chloride (0.43 g, 2.83 mmol). After stirring for 3 h, the reaction mixture was partitioned between H2O and CH2Cl2. The CH2Cl2 layer was washed with 1 M H3PO4, NaHCO3 and brine, dried (MgSO4), then filtered and concentrated under reduced pressure. The residue was chromatographed (silica gel) eluting with 30% EtOAc/hexane to yield the title compound (0.91 g). LC/MS m/z 360 [M+H]+.
Reaction SMILES: [CH:1]1([O:7][C:8]2[CH:9]=[C:10]3[C:14](=[CH:15][CH:16]=2)[NH:13][CH:12]=[C:11]3[C:17]2[CH2:18][CH2:19][N:20]([CH3:23])[CH2:21][CH:22]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[F:24][C:25]1[CH:33]=[CH:32][C:28]([C:29](Cl)=[O:30])=[CH:27][CH:26]=1>>[CH:1]1([O:7][C:8]2[CH:9]=[C:10]3[C:14](=[CH:15][CH:16]=2)[N:13]([C:29](=[O:30])[C:28]2[CH:32]=[CH:33][C:25]([F:24])=[CH:26][CH:27]=2)[CH:12]=[C:11]3[C:17]2[CH2:18][CH2:19][N:20]([CH3:23])[CH2:21][CH:22]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CN1CC=C(c2c[nH]c3ccc(OC4CCCCC4)cc23)CC1
Reactant: O=C(Cl)c1ccc(F)cc1
Product: CN1CC=C(c2cn(C(=O)c3ccc(F)cc3)c3ccc(OC4CCCCC4)cc23)CC1

Procedure:
(24.0 mg, 68%); from 5-cyclohexyloxy-3-(1-methyl-1,2,3,6-tetrahydro-4-pyridinyl)-1H-indole (Example 4c, 25.6 mg, 0.082 mmol) and 4-fluorobenzoyl chloride (25 uL, 0.21 mmol); HRMS-FAB+ for C27H29N2O2F: calculated MH+ : 433.22913; found: 433.22733.