Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1([C:7]2[CH:12]=[CH:11][C:10]([C:13]([N:15]3[C:21]4[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=4[CH2:19][N:18]4[C:26]([C:29](=[O:34])C(Cl)(Cl)Cl)=[CH:27][CH:28]=[C:17]4[CH2:16]3)=[O:14])=[CH:9][C:8]=2[S:35]([NH2:38])(=[O:37])=[O:36])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[NH2:39][CH2:40][C:41]1[CH:42]=[N:43][CH:44]=[CH:45][CH:46]=1.O>O1CCOCC1>[OH2:4].[NH2:38][S:35]([C:8]1[CH:9]=[C:10]([CH:11]=[CH:12][C:7]=1[N:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1)[C:13]([N:15]1[C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=2[CH2:19][N:18]2[C:26]([C:29]([NH:39][CH2:40][C:41]3[CH:42]=[N:43][CH:44]=[CH:45][CH:46]=3)=[O:34])=[CH:27][CH:28]=[C:17]2[CH2:16]1)=[O:14])(=[O:37])=[O:36].[NH2:38][S:35]([C:8]1[CH:9]=[C:10]([CH:11]=[CH:12][C:7]=1[N:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1)[C:13]([N:15]1[C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=2[CH2:19][N:18]2[C:26]([C:29]([NH:39][CH2:40][C:41]3[CH:42]=[N:43][CH:44]=[CH:45][CH:46]=3)=[O:34])=[CH:27][CH:28]=[C:17]2[CH2:16]1)=[O:14])(=[O:37])=[O:36]
Reactant: NS(=O)(=O)c1cc(C(=O)N2Cc3ccc(C(=O)C(Cl)(Cl)Cl)n3Cc3ccccc32)ccc1N1CCOCC1
Reactant: NCc1cccnc1
Solvent: C1COCCO1
Solvent: O
Product: NS(=O)(=O)c1cc(C(=O)N2Cc3ccc(C(=O)NCc4cccnc4)n3Cc3ccccc32)ccc1N1CCOCC1
Temperature: 25 °C
Yield: 63 %

Procedure:
A solution containing 0.83 g (0.0014 mol) of 2-morpholin-4-yl-5-{[3-(trichloroacetyl)-5H-pyrrolo[2,1-c][1,4]benzodiazepin-10(11H)-yl]carbonyl}benzenesulfonamide of Step C and 0.30 g (0.0028 mol) of 3-aminomethylpyridine in 25 mL of 1,4-dioxane was stirred under reflux overnight. The reaction mixture was allowed to cool to room temperature and poured into 200 mL of water. The beige solid that precipitated was collected and washed with water to provide the title compound (0.35 g), m.p. 159-161° C.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH:7]=[CH:8][C:9]([OH:11])=O)[CH:2]=1.C(Cl)(=O)C(Cl)=O.[CH:18]([N:31]([CH3:41])[CH2:32][CH2:33][N:34]([CH3:40])[CH2:35][CH2:36][CH2:37][CH2:38][NH2:39])([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>>[CH:18]([N:31]([CH3:41])[CH2:32][CH2:33][N:34]([CH3:40])[CH2:35][CH2:36][CH2:37][CH2:38][NH:39][C:9](=[O:11])[CH:8]=[CH:7][C:3]1[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=1)([C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: O=C(O)C=Cc1cccnc1
Reactant: CN(CCCCN)CCN(C)C(c1ccccc1)c1ccccc1
Agent: O=C(Cl)C(=O)Cl
Product: CN(CCCCNC(=O)C=Cc1cccnc1)CCN(C)C(c1ccccc1)c1ccccc1

Procedure:
Batch size: 5.5 g (36.8 mmol) 3-(3-pyridyl)-acrylic acid, 12.7 g (100.0 mmol) oxalyl chloride and 10.9 g (33.5 mmol) 4-([2-(benzhydryl-methyl-amino)-ethyl]-methyl-amino)-butylamine.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:27]=[CH:26][C:6]([CH2:7][N:8]2[C:16]3[CH:15]=[CH:14][NH:13][C:12](=[O:17])[C:11]=3[C:10]([C:18]3[CH:19]=[C:20]([C:23]([OH:25])=[O:24])[S:21][CH:22]=3)=[N:9]2)=[CH:5][CH:4]=1.[CH3:28]CN=C=NCCCN(C)C.Cl>CC(N(C)C)=O.O>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:7][N:8]2[C:16]3[CH:15]=[CH:14][NH:13][C:12](=[O:17])[C:11]=3[C:10]([C:18]3[CH:19]=[C:20]([C:23]([O:25][CH3:28])=[O:24])[S:21][CH:22]=3)=[N:9]2)=[CH:26][CH:27]=1
Reactant: CCN=C=NCCCN(C)C
Reactant: COc1ccc(Cn2nc(-c3csc(C(=O)O)c3)c3c(=O)[nH]ccc32)cc1
Agent: Cl
Solvent: O
Solvent: CC(=O)N(C)C
Product: COC(=O)c1cc(-c2nn(Cc3ccc(OC)cc3)c3cc[nH]c(=O)c23)cs1
Temperature: 25 °C
Reaction time: 8 h
Yield: 78.1 %

Procedure:
To a solution of 4-(1-(4-methoxybenzyl)-4-oxo-4,5-dihydro-1H-pyrazolo[4,3-c]pyridin-3-yl)thiophene-2-carboxylic acid (38.8 mg) in DMA (3 mL) were added EDCI hydrochloride (23.4 mg) and HOBt ammonium salt (18.6 mg) at room temperature, and the mixture was stirred overnight at room temperature. The reaction mixture was diluted with water, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (basic silica gel, ethyl acetate/methanol) to give the title compound (31.4 mg).
Reaction SMILES: [CH:1]1([CH2:4][N:5]([CH2:15][CH2:16][CH3:17])[C:6]2[N:11]=[CH:10][N:9]=[C:8]([C:12]([OH:14])=O)[CH:7]=2)[CH2:3][CH2:2]1.C(N(C(C)C)CC)(C)C.ClC(OC)=O.[N:32]1([C:37]2[CH:38]=[C:39]([CH:41]=[CH:42][CH:43]=2)[NH2:40])[CH:36]=[N:35][CH:34]=[N:33]1>C(Cl)Cl>[CH:1]1([CH2:4][N:5]([CH2:15][CH2:16][CH3:17])[C:6]2[N:11]=[CH:10][N:9]=[C:8]([C:12]([NH:40][C:39]3[CH:41]=[CH:42][CH:43]=[C:37]([N:32]4[CH:36]=[N:35][CH:34]=[N:33]4)[CH:38]=3)=[O:14])[CH:7]=2)[CH2:2][CH2:3]1
Reactant: Nc1cccc(-n2cncn2)c1
Reactant: CCCN(CC1CC1)c1cc(C(=O)O)ncn1
Agent: COC(=O)Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCCN(CC1CC1)c1cc(C(=O)Nc2cccc(-n3cncn3)c2)ncn1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
A cooled (0° C.) solution of 6-(cyclopropylmethyl(propyl)amino)pyrimidine-4-carboxylic acid (Intermediate 21, 112 mg; 0.45 mmol) in DCM was treated with diisopropylethylamine (78.4 mL; 0.52 mmol) and methyl chloroformate (36.2 mL; 0.47 mmol). After stirring at 0° C. for 15 minutes, 3-(1H-1,2,4-triazol-1-yl)aniline (Maybridge, 108 mg; 0.67 mmol) was added and the mixture stirred for 72 hours. The solvent was evaporated and the compound purified by preparative HPLC to give the title compound as a white solid. 1H NMR (400 MHz, CDCl3) δ 10.16 (1H, s), 8.60 (2H, d, J=18.1 Hz), 8.37 (1H, s), 8.11 (1H, s), 7.68-7.64 (1H, m), 7.53-7.48 (2H, m), 7.36 (1H, s), 3.54 (4H, s), 1.75-1.65 (2H, m), 1.10 (1H, s), 0.97 (3H, t, J=7.3 Hz), 0.58 (2H, d, J=7.7 Hz), 0.36-0.30 (2H, m). MS (ESI+) 387. HPLC (Condition C) Rt 3.77 min (HPLC purity 99.9%).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4](B(O)O)=[CH:3][C:2]=1[CH3:10].[C:11]([C:13]1([NH:16][C:17]([C@H:19]2[CH2:23][C@H:22]([S:24]([C:27]3[CH:32]=[CH:31][C:30](Br)=[CH:29][C:28]=3[C:34]([F:37])([F:36])[F:35])(=[O:26])=[O:25])[CH2:21][C@@H:20]2[O:38][CH:39]([CH3:41])[CH3:40])=[O:18])[CH2:15][CH2:14]1)#[N:12].C(C1(NC([C@H]2C[C@H](S(C3C=CC(Br)=CC=3C(F)(F)F)(=O)=O)C[C@@H]2OC)=O)CC1)#N>>[C:11]([C:13]1([NH:16][C:17]([C@H:19]2[CH2:23][C@H:22]([S:24]([C:27]3[CH:32]=[CH:31][C:30]([C:4]4[CH:5]=[CH:6][N:1]=[C:2]([CH3:10])[CH:3]=4)=[CH:29][C:28]=3[C:34]([F:37])([F:35])[F:36])(=[O:26])=[O:25])[CH2:21][C@@H:20]2[O:38][CH:39]([CH3:41])[CH3:40])=[O:18])[CH2:15][CH2:14]1)#[N:12]
Reactant: Cc1cc(B(O)O)ccn1
Reactant: CC(C)O[C@H]1C[C@@H](S(=O)(=O)c2ccc(Br)cc2C(F)(F)F)C[C@@H]1C(=O)NC1(C#N)CC1
Agent: CO[C@H]1C[C@@H](S(=O)(=O)c2ccc(Br)cc2C(F)(F)F)C[C@@H]1C(=O)NC1(C#N)CC1
Product: Cc1cc(-c2ccc(S(=O)(=O)[C@@H]3C[C@H](OC(C)C)[C@@H](C(=O)NC4(C#N)CC4)C3)c(C(F)(F)F)c2)ccn1

Procedure:
The title compound was prepared in analogy to example 62 using 2-picoline-4-boronic acid instead of 2.4-difluorophenylboronic acid and (1R,2R,4R) and (1S,2S,4S)-4-(4-bromo-2-trifluoromethyl-benzenesulfonyl)-2-isopropoxy-cyclopentanecarboxylic acid (1-cyano-cyclopropyl)-amide instead of (1R,2R,4R) and (1S,2S,4S)-4-(4-bromo-2-trifluoromethyl-benzenesulfonyl)-2-methoxy-cyclopentanecarboxylic acid (1-cyano-cyclopropyl)-amide. White solid. MS (EI): 536.2 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[N:6][CH:5]=[C:4]2[S:8][C:9]([C:11]3[S:15][C:14]([NH:16][CH2:17][C@@H:18]([NH:30]C(=O)OC(C)(C)C)[CH2:19][C:20]4[CH:25]=[CH:24][CH:23]=[C:22]([C:26]([F:29])([F:28])[F:27])[CH:21]=4)=[N:13][N:12]=3)=[CH:10][C:3]=12.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:30][C@@H:18]([CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([C:26]([F:27])([F:29])[F:28])[CH:21]=1)[CH2:17][NH:16][C:14]1[S:15][C:11]([C:9]2[S:8][C:4]3=[CH:5][N:6]=[CH:7][C:2]([Cl:1])=[C:3]3[CH:10]=2)=[N:12][N:13]=1
Reactant: CC(C)(C)OC(=O)N[C@H](CNc1nnc(-c2cc3c(Cl)cncc3s2)s1)Cc1cccc(C(F)(F)F)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: N[C@H](CNc1nnc(-c2cc3c(Cl)cncc3s2)s1)Cc1cccc(C(F)(F)F)c1

Procedure:
tert-Butyl (S)-1-(5-(4-chlorothieno[2,3-c]pyridin-2-yl)-1,3,4-thiadiazol-2-ylamino)-3-(3-(trifluoromethyl)phenyl)propan-2-ylcarbamate (0.070 g, 0.12 mmol) was treated with 1 mL TFA in 1 mL DCM for 30 minutes. After removing the solvent, the residue was mixed with 10 mL 2M ammonia in MeOH. The solvent was removed again and the remaining residue was subjected to a silica gel flash chromatography separation using 3.5% 2M ammonia MeOH solution in DCM as the eluant. An-off white solid was obtained as the pure product (0.03 g, y=52%). LCMS (API-ES) m/z (%): 470.1 (100%, M++H); 1H NMR (300 MHz, CDCL3) δ ppm 1.48-1.82 (b, 3H) 2.72 (dd, J=13.56, 8.48 Hz, 1H) 3.00 (dd, J=13.66, 4.99 Hz, 1H) 3.26-3.35 (m, 1H) 3.40-3.50 (m, 1H) 3.61 (dd, J=12.72, 3.67 Hz, 1H) 7.41-7.56 (m, 6H) 8.46 (s, 1H) 8.95 (s, 1H).
Reaction SMILES: [CH:1]1([NH:4][C:5](=[O:48])[NH:6][C:7]2[CH:46]=[CH:45][C:10]([O:11][C:12]3[CH:17]=[CH:16][N:15]=[C:14]4[CH:18]=[C:19]([C:21]5[N:26]=[CH:25][C:24]([CH2:27][N:28]([CH:32]6[CH2:37][CH2:36][N:35](C(OCCCC)=O)[CH2:34][CH2:33]6)[C:29](=[O:31])[CH3:30])=[CH:23][CH:22]=5)[S:20][C:13]=34)=[C:9]([F:47])[CH:8]=2)[CH2:3][CH2:2]1.Cl.CCOC(C)=O>CCOC(C)=O>[CH:1]1([NH:4][C:5](=[O:48])[NH:6][C:7]2[CH:46]=[CH:45][C:10]([O:11][C:12]3[CH:17]=[CH:16][N:15]=[C:14]4[CH:18]=[C:19]([C:21]5[N:26]=[CH:25][C:24]([CH2:27][N:28]([CH:32]6[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]6)[C:29](=[O:31])[CH3:30])=[CH:23][CH:22]=5)[S:20][C:13]=34)=[C:9]([F:47])[CH:8]=2)[CH2:2][CH2:3]1
Reactant: CCCCOC(=O)N1CCC(N(Cc2ccc(-c3cc4nccc(Oc5ccc(NC(=O)NC6CC6)cc5F)c4s3)nc2)C(C)=O)CC1
Agent: Cl
Solvent: CCOC(C)=O
Product: CC(=O)N(Cc1ccc(-c2cc3nccc(Oc4ccc(NC(=O)NC5CC5)cc4F)c3s2)nc1)C1CCNCC1
Reaction time: 8 h
Yield: 72.2 %

Procedure:
To a suspension of 608 (0.314 g, 0.465 mmol) in EtOAc (6 mL) was added 1N HCl-EtOAc (2.0 ml, 2.0 mmol) at RT. The reaction mixture was stirred overnight then concentrated and co-evaporated with EtOAc. The residue was purified by flash chromatography using Hi-Flash column (Yamazen Corporation) packed with amino silica gel (DCM/MeOH:96/4 to 80/20) to afford title compound 609 (0.193 g, 72% yield) as a white amorphous solid. 1H NMR (300 MHz, DMSO-d6) δ (ppm): 8.71 (s, 1H), 8.54-8.46 (m, 2H), 8.34 (s, 0.3H), 8.30 (s, 0.7H), 8.26 (d, J=8.1 Hz, 0.3H), 8.18 (d, J=8.1 Hz, 0.7H), 7.82-7.69 (m, 2H), 7.38 (t, J=9.0 Hz, 1H), 7.25-7.15 (m, 1H), 6.68-6.62 (m, 1H), 6.57 (d, J=3.0 Hz, 1H), 4.66 (s, 0.7H), 4.54 (s, 1.3H), 3.90-3.75 (m, 1H), 3.00-2.90 (m, 2H), 2.61-2.40 (m, 3H), 2.20 (s, 2H), 1.99 (s, 1H), 1.65-1.40 (m, 4H), 0.71-0.62 (m, 2H), 0.48-0.40 (m, 2H).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([OH:11])[CH:7]=[CH:8][C:9]=1Cl)([O-:3])=[O:2].[C:12]([NH:15][C:16]1[CH:21]=[CH:20][C:19]([SH:22])=[CH:18][CH:17]=1)(=[O:14])[CH3:13].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C>[OH:11][C:6]1[CH:7]=[CH:8][C:9]([S:22][C:19]2[CH:18]=[CH:17][C:16]([NH:15][C:12](=[O:14])[CH3:13])=[CH:21][CH:20]=2)=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=1
Reactant: CC(=O)Nc1ccc(S)cc1
Reactant: O=[N+]([O-])c1cc(O)ccc1Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CC(=O)Nc1ccc(Sc2ccc(O)cc2[N+](=O)[O-])cc1
Temperature: 100 °C
Yield: 98.9 %

Procedure:
A mixture of 3-nitro-4-chloro phenol (1.59 g, 8.97 mmol), 4-acetamidothiophenol (2 g, 10.76 mmol) and cesium carbonate (7.0 g, 21.53 mmol) in DMF (20 mL) was heated 2.5 h at 100° C. The mixture was cooled, poured onto ice and the resulting solid is collected by filtration and dried under vacuum the title compound leaving a yellow solid (2.7 g, 100%).
Reaction SMILES: [CH2:1]([NH2:4])[CH:2]=[CH2:3].C(O)(=O)C.[C:9]([O:13][C:14]([N:16]1[CH2:21][CH2:20][C:19](=O)[CH2:18][CH2:17]1)=[O:15])([CH3:12])([CH3:11])[CH3:10].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[CH2:1]([NH:4][CH:19]1[CH2:20][CH2:21][N:16]([C:14]([O:13][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:15])[CH2:17][CH2:18]1)[CH:2]=[CH2:3]
Reactant: C=CCN
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCCl
Product: C=CCNC1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 99.7 %

Procedure:
Allylamine (0.45 mL, 0.34 g, 6.0 mmol), acetic acid (0.300 mL, 315 mg, 5.24 mmol), and 3 A molecular sieves (2.00 g) were added to a solution of 1-(tert-butyoxycarbonyl)-4-piperidone (1.00 g, 5.01 mmol) in 14 mL of 1,2-dichloroethane. After stirring 0.5 h at RT, sodium triacetoxyborohydride (1.62 g, 7.6 mmol) was added in two portions 5 min apart. After an additional 3 h, the mixture was partitioned between 30 mL of ethyl acetate and 20 mL of saturated aqueous sodium bicarbonate. The aqueous layer was extracted with 30 mL of ethyl acetate and the organic layers were washed in succession with 20 mL of brine, combined, dried over sodium sulfate, and evaporated to give 1.20 g of crude 4-(allylamino)-1-(tert-butoxycarbonyl)piperidine as a yellow syrup.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([O:11][Si:12]([CH2:17][CH3:18])([CH2:15][CH3:16])[CH2:13][CH3:14])[CH2:9]I)=[CH:4][C:3]=1[NH:19][S:20]([CH3:23])(=[O:22])=[O:21].[CH2:24]([NH:31][CH2:32][CH2:33][OH:34])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>>[CH2:24]([N:31]([CH2:32][CH2:33][OH:34])[CH2:9][C@@H:8]([C:5]1[CH:6]=[CH:7][C:2]([F:1])=[C:3]([NH:19][S:20]([CH3:23])(=[O:22])=[O:21])[CH:4]=1)[O:11][Si:12]([CH2:17][CH3:18])([CH2:15][CH3:16])[CH2:13][CH3:14])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: OCCNCc1ccccc1
Reactant: CC[Si](CC)(CC)O[C@@H](CI)c1ccc(F)c(NS(C)(=O)=O)c1
Product: CC[Si](CC)(CC)O[C@@H](CN(CCO)Cc1ccccc1)c1ccc(F)c(NS(C)(=O)=O)c1
Temperature: 100 °C
Reaction time: 8 h
Yield: 91 %

Procedure:
(R)—N-(2-Fluoro-5-(2-iodo-1-(triethylsilyloxy)ethyl)phenyl)methanesulfonamide (500 mg) and 2-(benzylamino)ethanol (1.6 g) were admixed with each other and stirred overnight at 100° C. After cooling to room temperature, the reaction solution was purified by column chromatography (“COLUMN-H”; n-hexane:ethyl acetate=2:1) to obtain (R)—N-(5-(2-(benzyl(2-hydroxyethyl)amino)-1-(triethylsilyloxy)ethyl)-2-fluorophenyl)methanesulfonamide (477.5 mg), which was then added with 4-N,N-dimethylaminopyridine (12 mg), triethylamine (163 μL), and THF (15 mL), and then Boc2O-THF solution [10 mL; solution prepared by dissolving Boc2O (230 mg) in THF (10 mL)] was added dropwise thereto. The mixture was stirred at room temperature for 3 hours. After concentrating the reaction solution under reduced pressure, the residue was purified by column chromatography (“COLUMN-H”; n-hexane:ethyl acetate=3:1) to obtain the title compound (500.3 mg).
Reaction SMILES: NC1CCN(CC2C=CC=CC=2)C1.C(OC(N[C@H](C(O)=O)CCC)=O)(C)(C)C.ON1C(=O)CCC1=O.Cl[C:38]1[CH:39]=[CH:40][N:41]2[C:46]([CH:47]=1)=[CH:45][CH:44]=[C:43]([C:48]([O:50]CC)=[O:49])[C:42]2=[O:53].C([NH:61][C@H:62]([C:66]([NH:68][CH:69]1[CH2:73][CH2:72][NH:71][CH2:70]1)=[O:67])[CH2:63][CH2:64][CH3:65])(OC(C)(C)C)=O>>[NH2:61][C@H:62]([C:66]([NH:68][CH:69]1[CH2:73][CH2:72][N:71]([C:38]2[CH:39]=[CH:40][N:41]3[C:46]([CH:47]=2)=[CH:45][CH:44]=[C:43]([C:48]([OH:50])=[O:49])[C:42]3=[O:53])[CH2:70]1)=[O:67])[CH2:63][CH2:64][CH3:65]
Reactant: CCOC(=O)c1ccc2cc(Cl)ccn2c1=O
Reactant: CCC[C@H](NC(=O)OC(C)(C)C)C(=O)NC1CCNC1
Agent: CCC[C@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: NC1CCN(Cc2ccccc2)C1
Agent: O=C1CCC(=O)N1O
Product: CCC[C@H](N)C(=O)NC1CCN(c2ccn3c(=O)c(C(=O)O)ccc3c2)C1

Procedure:
3-Amino-1-benzylpyrrolidine (I. Sumio and T. Matsuo, Japanese Kokai JP 5328161, published Mar. 16, 1978) is coupled to N-t-butoxycarbonyl norvaline (Boc-nVal) using conventional N-hydroxysuccinimide coupling procedures. The 1-benzyl group is removed by hydrogenolysis in methanol using palladium on carbon catalyst. The 3-(N-Boc-norvalyl)aminopyrrolidine is then reacted with ethyl 8-chloro-4H-quinolizin-4-one-3-carboxylate, the product of Step 3 of Example 58, as described in Step 4 of Example 58, replacing 3-(N-t-butoxycarbonylamino)pyrrolidine with 3-(N-Boc-norvalyl)aminopyrrolidine, to give 8-(3-(N-norvalyl)amino-pyrrolidinyl)-4H-quinolizin-4-one-3-carboxylic acid with the nitrogen of the amino acid protected with a Boc group. The Boc protecting group is removed by standard hydrolysis using trifluoroacetic acid and dilute aqueous hydrochloric acid.
Reaction SMILES: [F:1][C:2]([F:23])([F:22])[C:3]1[CH:4]=[C:5]([CH:19]=[CH:20][CH:21]=1)[C:6]([NH:8][C:9]1[CH:10]=[CH:11][C:12]([Cl:18])=[C:13]([CH:17]=1)[C:14]([OH:16])=O)=[O:7].ClC1N=C(OC)N=C(OC)N=1.CN1CCOCC1.[NH2:42][C:43]1[CH:44]=[N:45][C:46]([NH:49][C:50]2[CH:51]=[C:52]([CH:58]=[CH:59][CH:60]=2)[C:53]([O:55][CH2:56][CH3:57])=[O:54])=[N:47][CH:48]=1>C(Cl)Cl.CN(C=O)C>[CH2:56]([O:55][C:53](=[O:54])[C:52]1[CH:58]=[CH:59][CH:60]=[C:50]([NH:49][C:46]2[N:45]=[CH:44][C:43]([NH:42][C:14](=[O:16])[C:13]3[CH:17]=[C:9]([NH:8][C:6](=[O:7])[C:5]4[CH:19]=[CH:20][CH:21]=[C:3]([C:2]([F:1])([F:23])[F:22])[CH:4]=4)[CH:10]=[CH:11][C:12]=3[Cl:18])=[CH:48][N:47]=2)[CH:51]=1)[CH3:57]
Reactant: CCOC(=O)c1cccc(Nc2ncc(N)cn2)c1
Reactant: O=C(Nc1ccc(Cl)c(C(=O)O)c1)c1cccc(C(F)(F)F)c1
Agent: COc1nc(Cl)nc(OC)n1
Solvent: ClCCl
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: CCOC(=O)c1cccc(Nc2ncc(NC(=O)c3cc(NC(=O)c4cccc(C(F)(F)F)c4)ccc3Cl)cn2)c1
Temperature: 25 °C
Reaction time: 1.25 h
Yield: 42.8 %

Procedure:
To a solution of intermediate 1 (Example 2) (280 mg, 0.8 mmol) in anhydrous CH2Cl2 (15 mL), 2-chloro-4,6-dimethoxy-1,3,5-triazine (180 mg, 1 mmol) and 4-methylmorpholine (250 mg, 2.5 mmol) were added. After the reaction mixture was stirred at room temperature for 75 minutes, intermediate 6 (Example 11) (110 mg, 0.4 mmol) in anhydrous DMF (2.5 mL) was added into the solution. The solution was stirred under argon for overnight. The residue was dissolved in CH2Cl2 (20 mL) and washed with aqueous saturated NaHCO3 solution (20 mL). The aqueous layer was extracted with CH2Cl2 (50 mL). The combined organic phase was dried (Na2SO4) and the solvent was removed. The crude product was purified by silica gel column with CHCl3 to 10% CH3OH/CHCl3 as eluents to give the final product as a pale yellow solid (100 mg, 21%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:28]([F:31])([F:30])[F:29])=[C:6]([C:8]2[CH:13]=[CH:12][N:11]([CH:14]([CH2:20][C:21]3[CH:26]=[CH:25][N:24]=[CH:23][CH:22]=3)[C:15]([O:17]CC)=[O:16])[C:10](=[O:27])[CH:9]=2)[CH:7]=1.[OH-].[Li+]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:28]([F:30])([F:29])[F:31])=[C:6]([C:8]2[CH:13]=[CH:12][N:11]([CH:14]([CH2:20][C:21]3[CH:26]=[CH:25][N:24]=[CH:23][CH:22]=3)[C:15]([OH:17])=[O:16])[C:10](=[O:27])[CH:9]=2)[CH:7]=1
Reactant: CCOC(=O)C(Cc1ccncc1)n1ccc(-c2cc(Cl)ccc2C(F)(F)F)cc1=O
Agent: [Li+]
Agent: [OH-]
Product: O=C(O)C(Cc1ccncc1)n1ccc(-c2cc(Cl)ccc2C(F)(F)F)cc1=O

Procedure:
452 mg (1.0 mmol) of ethyl 2-{4-[5-chloro-2-(trifluoromethyl)phenyl]-2-oxopyridin-1(2H)-yl}-3-(pyridin-4-yl)propanoate (racemate) were hydrolysed with lithium hydroxide according to General Method 6B. Yield: 289 mg (68% of theory)
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[CH2:12][CH2:11][C:10]2[CH:13]=[C:14]([OH:17])[CH:15]=[CH:16][C:9]=2[CH2:8][CH2:7]1)=[O:5])[CH3:2].C(O)(C(F)(F)F)=O.C1C(=O)N([I:32])C(=O)C1>C(#N)C.O>[CH2:1]([O:3][C:4]([N:6]1[CH2:12][CH2:11][C:10]2[CH:13]=[C:14]([OH:17])[C:15]([I:32])=[CH:16][C:9]=2[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: O=C1CCC(=O)N1I
Reactant: CCOC(=O)N1CCc2ccc(O)cc2CC1
Solvent: O
Solvent: O=C(O)C(F)(F)F
Solvent: CC#N
Product: CCOC(=O)N1CCc2cc(O)c(I)cc2CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 84 %

Procedure:
Into a 100 ml flask, the product of step (c) (503 mg, 2.14 mmol) dissolved in acetonitrile (20 ml) and TFA (2 ml) was added. To this stirred solution, NIS (458 mg, 2.03 mmol) was added. After stirring for 30 minutes at room temperature, the reaction was diluted with water (200 ml) and extracted with EtOAc (3×). The combined EtOAc extracts were washed with brine, dried over Na2SO4, and solvent evaporated in vacuo to give the crude product. Purification by silica-gel chromatography (gradient elution: 0 to 40% EtOAc in hexanes) gave the sub-title compound as a yellow solid (616 mg). 1H NMR (300 MHz, CDCl3) δ 7.39 (s, 1H); 6.77 (s, 1H); 5.42 (bs, 1H); 4.18 (q, J=7.2 Hz, 2H); 3.61-3.52 (m, 4H); 2.81-2.72 (m, 4H); 1.26 (t, J=6.9 Hz, 3H); MS: ESI (positive): 362 (M+H).
Reaction SMILES: [CH3:1]C(C)([O-])C.[K+].[OH:7][CH2:8][C@H:9]([N:11]1[CH:20]=[CH:19][C:18]2[C:13](=[CH:14][CH:15]=[CH:16][C:17]=2[N+:21]([O-:23])=[O:22])[C:12]1=[O:24])[CH3:10].Cl.FC(F)(F)C(O)=O.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.C(OCC)(=O)C.O.C(O)(=O)C>[OH:7][CH2:8][C@H:9]([N:11]1[CH:20]=[CH:19][C:18]2[C:13](=[CH:14][CH:15]=[C:16]([CH3:1])[C:17]=2[N+:21]([O-:23])=[O:22])[C:12]1=[O:24])[CH3:10]
Reactant: CC(C)(C)[O-]
Reactant: C[C@H](CO)n1ccc2c([N+](=O)[O-])cccc2c1=O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Cc1ccc2c(=O)n([C@H](C)CO)ccc2c1[N+](=O)[O-]
Reaction time: 0.75 h

Procedure:
A round bottom flask was charged with potassium tert-Butoxide (3.62 g, 0.0322 mol) and N,N-dimethylformamide (100 mL, 1 mol) and a solution of acetic acid, chloro-, 1,1-dimethylethyl ester (1.3 mL, 0.0089 mol) and (R)-2-(1-hydroxypropan-2-yl)-5-nitroisoquinolin-1(2H)-one (2.00 g, 0.00806 mol) in N,N-dimethylformamide (20 mL, 0.2 mol) was added at −20° C. dropwise over a period of 8 minutes and the reaction was stirred for an additional 45 minutes at the same temperature. The reaction mixture was poured onto 4 ml of hydrochloric acid and 80 mL of water, and extracted with dichloromethane, washed with brine and dried. the solvent was removed under reduced pressureunder reduced pressure and the residue was used in the next reaction without purification (two isomers in the ratio of 3:1). The residue was treated with trifluoroacetic acid (10 mL, 0.1 mol) for 30 minutes and the trifluoroacetic acid was removed under reduced pressure. The residue was stirred with potassium carbonate (2.2 g, 0.016 mol) in N,N-dimethylformamide (10 mL) at 50° C. for 1 hour. The reaction mixture was cooled and diluted with ethyl acetate (400 mL), washed with 6 N hydrochloric acid (50 mL×4) and the brine (50 mL×2), and dried. The volatiles were removed under reduced pressure and the residue was purified by column chromatography to afford the product as a yellow solid.
Reaction SMILES: [CH2:1]1[C@H:6](N)[C@@H:5](O[C@H]2O[C@H](CN)[C@@H](O)[C@H](O)[C@H]2O)[C@H:4](O)[C@@H:3](O[C@H]2O[C@H](CO)[C@@H](O)[C@H](N)[C@H]2O)[C@@H:2]1N.[NH2:34][C@H:35]([C:40]([OH:42])=[O:41])[CH2:36]C(C)C.N[C@H](C(O)=O)CCCNC(=N)N.OP([O-])(O)=O.[K+].OP([O-])([O-])=O.[K+].[K+].C([O-])(=O)CC(CC([O-])=O)(C([O-])=O)O.[Na+].[Na+].[Na+].O=C[C@@H]([C@H]([C@@H]([C@@H](CO)O)O)O)O>>[NH2:34][C@H:35]([C:40]([OH:42])=[O:41])[CH2:36][C:6]1[CH:5]=[CH:4][CH:3]=[CH:2][CH:1]=1
Reactant: NC[C@H]1O[C@H](O[C@H]2[C@H](O)[C@@H](O[C@H]3O[C@H](CO)[C@@H](O)[C@H](N)[C@H]3O)[C@H](N)C[C@@H]2N)[C@H](O)[C@@H](O)[C@@H]1O
Reactant: CC(C)C[C@H](N)C(=O)O
Agent: N=C(N)NCCC[C@H](N)C(=O)O
Agent: O=C([O-])CC(O)(CC(=O)[O-])C(=O)[O-]
Agent: O=C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Product: N[C@@H](Cc1ccccc1)C(=O)O
Reaction time: 72 h

Procedure:
The cell-suspension was transferred onto a minimum medium prepared by adding 5 μg/dl kanamycin, 10 mg/dl L-leucine, 10 mg/dl L-leucine, 10 mg/dl L-arginine, 100 mg/dl D, L-m-fluorophenylalanine and 2 g/dl agar to a basal minimum medium of pH 7.2 containing 0.6 g/dl KH2PO4, 1.4 g/dl K2HPO4, 0.2 g/dl (NH4)2SO4, 0.1 g/dl sodium citrate, 0.02 g/dl MgSO4.7H2O, and 0.5 g/dl glucose. After 3 days cultivation at 37° C., two colonies appeared on the agar-medium.