Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([CH2:6][CH:7]([C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[C:13]([Cl:18])[CH:12]=2)[C:8](O)=[O:9])[CH2:5][CH2:4][CH2:3][CH2:2]1.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C.[NH2:52][C:53]1[S:54][CH:55]=[N:56][N:57]=1>CN(C)C=O>[CH:1]1([CH2:6][CH:7]([C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[C:13]([Cl:18])[CH:12]=2)[C:8]([NH:52][C:53]2[S:54][CH:55]=[N:56][N:57]=2)=[O:9])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C(O)C(CC1CCCC1)c1ccc(Cl)c(Cl)c1
Reactant: Nc1nncs1
Agent: CN(C)C(On1nnc2ccccc21)=[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(Nc1nncs1)C(CC1CCCC1)c1ccc(Cl)c(Cl)c1
Yield: 76.1 %

Procedure:
A solution of 3-cyclopentyl-2-(3,4-dichlorophenyl)-propionic acid (prepared from Example 38, 200.0 mg, 0.70 mmol), O-benzotriazol-1-yl-N,N,N′,N′-tetramethyluronium hexafluorophosphate (316.9 mg, 0.84 mmol), N,N-diisopropylethylamine (365 mL, 2.09 mmol), and 2-amino-1,3,4-thiadiazole (140.8 mg, 1.39 mmol) in dry N,N-dimethylformamide (2 mL) was stirred at 25° C. under nitrogen for 20 h. The reaction mixture was concentrated in vacuo to remove N,N-dimethylformamide. The resulting residue was diluted with ethyl acetate (100 mL). The organic layer was washed with a saturated aqueous sodium bicarbonate solution (1×50 mL), a 10% aqueous hydrochloric acid solution (1×100 mL), and a saturated aqueous sodium chloride solution (1×100 mL). The organic layer was dried over sodium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230-400 mesh, 2/1 hexanes/ethyl acetate) afforded 3-cyclopentyl-2-(3,4-dichlorophenyl)-N-[1,3,4]thiadiazol-2-yl-propionamide (197.3 mg, 77%) as a white foam: mp 90-91° C.; EI-HRMS m/e calcd for C16H17Cl2N3OS (M+) 369.0469, found 369.0476.
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[CH:13]1([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:15][CH2:14]1.[Br:23][C:24]1[CH:25]=[C:26]([CH:29]=[CH:30][CH:31]=1)[CH2:27]Br.[Cl-].[NH4+]>C1COCC1>[Br:23][C:24]1[CH:25]=[C:26]([CH:29]=[CH:30][CH:31]=1)[CH2:27][C:13]1([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:15][CH2:14]1
Reactant: BrCc1cccc(Br)c1
Reactant: CC(C)(C)OC(=O)C1CC1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: CC(C)(C)OC(=O)C1(Cc2cccc(Br)c2)CC1
Temperature: -40 °C
Reaction time: 0.5 h

Procedure:
Under argon, 14.8 ml (105.48 mmol) of diisopropylamine were initially charged in 66 ml of dry THF, and the mixture was cooled to −40° C. 42.2 ml (105.48 mmol) of n-butyllithium solution (2.5 M in hexane) were slowly added dropwise and the mixture was stirred for 30 min. The reaction solution was then cooled to −78° C., and a solution of 10.0 g (70.32 mmol) of tert-butyl cyclopropanecarboxylate in 17 ml of THF was added. After 4 h of stirring at −78° C., a solution of 19.34 g (77.36 mmol) of 3-bromobenzyl bromide in 17 ml THF was added. The reaction mixture was slowly warmed to RT overnight, and aqueous ammonium chloride solution was then added carefully and the mixture was extracted three times with ethyl acetate. The combined organic phases were washed with saturated sodium chloride solution, dried over magnesium sulphate and concentrated under reduced pressure. The crude product was purified by chromatography on 750 g of silica gel (mobile phase cyclohexane/dichloromethane 50:1, then 5:1). This gave 13.3 g (60.7% of theory) of the title compound.
Reaction SMILES: [O:1]=[S:2]1(=[O:17])[CH2:6][CH2:5][CH2:4][N:3]1[C:7]1[CH:15]=[CH:14][C:10]([C:11]([OH:13])=O)=[CH:9][C:8]=1[F:16].[CH3:18][C:19]1[C:20]([N:26]2[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]2)=[N:21][CH:22]=[C:23]([CH3:25])[CH:24]=1>>[CH3:18][C:19]1[C:20]([N:26]2[CH2:27][CH2:28][N:29]([C:11]([C:10]3[CH:14]=[CH:15][C:7]([N:3]4[CH2:4][CH2:5][CH2:6][S:2]4(=[O:1])=[O:17])=[C:8]([F:16])[CH:9]=3)=[O:13])[CH2:30][CH2:31]2)=[N:21][CH:22]=[C:23]([CH3:25])[CH:24]=1
Reactant: O=C(O)c1ccc(N2CCCS2(=O)=O)c(F)c1
Reactant: Cc1cnc(N2CCNCC2)c(C)c1
Product: Cc1cnc(N2CCN(C(=O)c3ccc(N4CCCS4(=O)=O)c(F)c3)CC2)c(C)c1
Yield: 61.8 %

Procedure:
Using 4-(1,1-dioxo-1λ6-isothiazolidin-2-yl)-3-fluorobenzoic acid (223 mg) described in Preparation Example 26 and 1-(3,5-dimethylpyridin-2-yl)piperazine (164 mg) described in Preparation Example 79 and by the reaction and treatment in the same manner as in Example 87, the title compound (229 mg) was obtained.
Reaction SMILES: [C:1]([Si:5]([CH3:23])([CH3:22])[O:6][CH2:7][CH2:8][N:9]1[C:17]2[C:12](=[CH:13][C:14]([CH3:21])=[C:15]([N+:18]([O-])=O)[CH:16]=2)[CH:11]=[N:10]1)([CH3:4])([CH3:3])[CH3:2].[Cl-].[NH4+]>C(O)C.O.[Fe]>[C:1]([Si:5]([CH3:23])([CH3:22])[O:6][CH2:7][CH2:8][N:9]1[C:17]2[C:12](=[CH:13][C:14]([CH3:21])=[C:15]([NH2:18])[CH:16]=2)[CH:11]=[N:10]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1cc2cnn(CCO[Si](C)(C)C(C)(C)C)c2cc1[N+](=O)[O-]
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CCO
Product: Cc1cc2cnn(CCO[Si](C)(C)C(C)(C)C)c2cc1N
Yield: 78.6 %

Procedure:
1-[2-(tert-Butyl-dimethyl-silanyloxy)-ethyl]-5-methyl-6-nitro-1H-indazole (335 mg, 1.00 mmol) was dissolved in 30 ml of a 1:1 mixture of ethanol and water. To this mixture was added ammonium chloride (108 mg) and iron powder (108 mg). The mixture was then stirred at reflux for two hours, then was cooled and filtered. The filtrate was extracted with EtOAc. The organic layer was washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by flash chromatography (95:5 dichloromethane/methanol) to give 240 mg (78.7%) of 1-[2-(tert-butyl-dimethyl-silanyloxy)-ethyl]-5-methyl-1H-indazol-6-ylamine as a tan solid.
Reaction SMILES: [C:1]1([S:7](Cl)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:11][C:12]1[C:13]([Cl:38])=[CH:14][C:15]2[N:21]3[CH2:22][CH2:23][CH2:24][C@@H:25]([NH:26][C:27](=[O:32])[C:28]([F:31])([F:30])[F:29])[C@H:20]3[C:19]3[CH:33]=[CH:34][CH:35]=[CH:36][C:18]=3[O:17][C:16]=2[CH:37]=1>C(Cl)Cl.C(N(CC)CC)C>[Cl:38][C:13]1[C:12]([N:11]([S:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)(=[O:9])=[O:8])[S:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)(=[O:9])=[O:8])=[CH:37][C:16]2[O:17][C:18]3[CH:36]=[CH:35][CH:34]=[CH:33][C:19]=3[C@@H:20]3[C@H:25]([NH:26][C:27](=[O:32])[C:28]([F:31])([F:30])[F:29])[CH2:24][CH2:23][CH2:22][N:21]3[C:15]=2[CH:14]=1
Reactant: Nc1cc2c(cc1Cl)N1CCC[C@@H](NC(=O)C(F)(F)F)[C@H]1c1ccccc1O2
Reactant: O=S(=O)(Cl)c1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(N[C@@H]1CCCN2c3cc(Cl)c(N(S(=O)(=O)c4ccccc4)S(=O)(=O)c4ccccc4)cc3Oc3ccccc3[C@H]12)C(F)(F)F
Temperature: 40 °C
Reaction time: 4 h
Yield: 105.5 %

Procedure:
N-acylation of an amine of Structure 25 to an amide of Structure 26 Benzenesulfonyl chloride (5 μL, 0.04 mmol) was added under N2 to trans-N-(8-amino-7-chloro-2,3,4,14b-tetrahydro-1H-dibenzo[b,f]pyrido[1,2-d][1,4]oxazepin-1-yl)-2,2,2,-trifluoroacetamide (5.0 mg, 0.01 mmol) in a mixture of 1 mL of CH2Cl2 and 25 μL of triethylamine. The resulting mixture was stirred at 40° C. for 4 h. After cooling the mixture was evaporated and the crude compound was purified by chromatography on silica. Elution with toluene/ethyl acetate 1:0→0:1 (gradient) gave trans-N-(7-chloro-2,3,4,14b-tetrahydro-8-[bis(phenylsulfonyl)amino]-1H-dibenzo[b,f]pyrido[1,2-d][1,4]oxazepin-1-yl)-2,2,2-trifluoroacetamide (7.3 mg, 83%). Data: (m/z)=692 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:12]([OH:14])=[O:13])=[CH:4][C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2.C(O)(C)C.[OH-].[Na+]>[Ni].O>[NH2:1][C:2]1[C:3]([C:12]([OH:14])=[O:13])=[CH:4][C:5]2[CH2:6][CH2:7][CH2:8][CH2:9][C:10]=2[CH:11]=1
Reactant: Nc1cc2ccccc2cc1C(=O)O
Agent: [Ni]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(C)O
Product: Nc1cc2c(cc1C(=O)O)CCCC2
Temperature: 90 °C
Reaction time: 16 h

Procedure:
To a mixture of activated Raney Nickel (200 g of 50% slurry in water on aluminum; 700 mmol, 13 equiv) and 3-amino-2-naphthoic acid (1-1) (10 g, 53 mmol, 1 equiv) in 1:1 isopropanol:water (400 mL) at 90° C. was added 1% aqueous NaOH solution (200 mL) over 1 h. The reaction mixture was stirred for 16 h at 90° C. and additional Raney Nickel (50 g, 180 mmol, 3.4 equiv) was added and the resulting mixture was heated at 90° C. for 24 h. The mixture was filtered and the filtrate was concentrated to 200 mL of water and brought to pH=3 with the addition of 1N aqueous hydrochloric acid solution to precipitate the product. The off-white precipitate was filtered, and purified by reverse phase liquid chromatography (H2O/CH3CN gradient w/0.1% TFA present) to yield 3-amino-5,6,7,8-tetrahydronaphthalene-2-carboxylic acid (1-2) as a white solid. LRMS m/z (M+H) 192.2 found, 192.1 required.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([NH:8][CH3:9])[N:5]=[C:4]([NH:10][CH:11]2[CH2:16][CH2:15][CH2:14][CH:13]([C:17]([OH:19])=O)[CH2:12]2)[N:3]=1.[Cl:20][C:21]1[CH:26]=[C:25]([Cl:27])[CH:24]=[CH:23][C:22]=1[CH2:28][NH2:29].CCN=C=NCCCN(C)C>CN(C1C=CN=CC=1)C>[Cl:20][C:21]1[CH:26]=[C:25]([Cl:27])[CH:24]=[CH:23][C:22]=1[CH2:28][NH:29][C:17]([C@H:13]1[CH2:14][CH2:15][CH2:16][C@@H:11]([NH:10][C:4]2[N:3]=[C:2]([CH3:1])[N:7]=[C:6]([NH:8][CH3:9])[N:5]=2)[CH2:12]1)=[O:19]
Reactant: NCc1ccc(Cl)cc1Cl
Reactant: CNc1nc(C)nc(NC2CCCC(C(=O)O)C2)n1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Product: CNc1nc(C)nc(N[C@@H]2CCC[C@H](C(=O)NCc3ccc(Cl)cc3Cl)C2)n1
Temperature: 25 °C
Reaction time: 4 h
Yield: 34.5 %

Procedure:
To a solution of 3-{[4-methyl-6-(methylamino)-1,3,5-triazin-2-yl]amino}cyclohexanecarboxylic acid (100 mg, 0.377 mmol) was added [(2,4-dichlorophenyl)methyl]amine (82 mg, 0.47 mmol), DMAP (10 mg, 0.08 mmol) and EDCI (108 mg, 0.56 mmol). The mixture was stirred at room temperature for 4 h. The mixture was filtered and the filtrate concentrated. The crude product was purified by HPLC to provide 55 mg (0.13 mmol, 35% yield) of the desired material as a single major racemic diastereomer. MS (ES+): m/e 423.0 [M+H]+.
Reaction SMILES: Cl.[C:2]([CH2:4][NH:5][C:6]([C@@H:8]1[CH2:12][C@@H:11]([S:13]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[C:22]([F:25])([F:24])[F:23])(=[O:15])=[O:14])[CH2:10][NH:9]1)=[O:7])#[N:3].C(N(C(C)C)CC)(C)C.Cl[C:36]([O:38][CH:39]1[CH2:43][CH2:42][CH2:41][CH2:40]1)=[O:37]>C(#N)C>[CH:39]1([O:38][C:36]([N:9]2[CH2:10][C@H:11]([S:13]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[C:22]([F:25])([F:23])[F:24])(=[O:15])=[O:14])[CH2:12][C@H:8]2[C:6](=[O:7])[NH:5][CH2:4][C:2]#[N:3])=[O:37])[CH2:43][CH2:42][CH2:41][CH2:40]1
Reactant: O=C(Cl)OC1CCCC1
Reactant: N#CCNC(=O)[C@@H]1C[C@@H](S(=O)(=O)c2ccccc2C(F)(F)F)CN1
Agent: Cl
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: N#CCNC(=O)[C@@H]1C[C@@H](S(=O)(=O)c2ccccc2C(F)(F)F)CN1C(=O)OC1CCCC1
Reaction time: 2 h

Procedure:
L21. To a suspension of (2S,4R)-4-(2-trifluoromethyl-benzenesulfonyl)-pyrrolidine-2-carboxylic acid cyanomethyl-amide hydrochloride (0.13 mmole) from experiment K2 in acetonitrile (1 ml) was added at 22° C. diisopropyl ethyl amine (0.40 mmole) and cyclopentyl chloroformate (0.15 mmole) and stirring was continued for 2 h. The mixture was quenched with methanol, acidified with acetic acid and subjected to prep. HPLC (RP-18) using a mixture of acetonitrile and water to give (2S,4R)-2-(cyanomethyl-carbamoyl)-4-(2-trifluoromethyl-benzenesulfonyl)-pyrrolidine-1-carboxylic acid cyclopentyl ester as a colorless oil. MS: 474.1 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9](=O)[NH:8][C:7]([C:14]#[N:15])=[C:6]2[C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([F:22])[CH:17]=1.O=P(Cl)(Cl)[Cl:25]>>[Cl:25][C:9]1[C:10]2[C:5](=[CH:4][C:3]([O:2][CH3:1])=[CH:12][CH:11]=2)[C:6]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([F:22])[CH:17]=2)=[C:7]([C:14]#[N:15])[N:8]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: COc1ccc2c(=O)[nH]c(C#N)c(-c3cccc(F)c3)c2c1
Product: COc1ccc2c(Cl)nc(C#N)c(-c3cccc(F)c3)c2c1
Reaction time: 2 h

Procedure:
42 mg of 6-methoxy-1-oxo-4-(3-fluorophenyl)-1,2-dihydroisoquinoline-3-carbonitrile in 3 mL POCl3 was heated from room temp to 80 C. After 2 h, the temperature was raised to 90 C, and heating was continued for 20 h. The reaction was concentrated, redissolved in EtOAc, cooled to 0 C, and saturated aqueous sodium bicarbonate was added dropwise to quench the remaining reagent. The mixture was separated, and the aqueous solution was extracted with EtOAc (3×). The combined organic solutions were dried over MgSO4 and concentrated. Flash chromatography (3% to 30% EtOAc in hexanes) gave a white solid.
Reaction SMILES: [CH2:1]([C:4]1[C:9]([C:10]([O:12][CH2:13][CH:14]=[CH2:15])=[O:11])=[C:8]([OH:16])[CH:7]=[CH:6][CH:5]=1)[CH:2]=[CH2:3].[C:17]([O-])([O-])=O.[K+].[K+].CI>CC(C)=O>[CH2:1]([C:4]1[C:9]([C:10]([O:12][CH2:13][CH:14]=[CH2:15])=[O:11])=[C:8]([O:16][CH3:17])[CH:7]=[CH:6][CH:5]=1)[CH:2]=[CH2:3]
Reactant: O=C([O-])[O-]
Reactant: C=CCOC(=O)c1c(O)cccc1CC=C
Agent: [K+]
Solvent: CI
Solvent: CC(C)=O
Product: C=CCOC(=O)c1c(CC=C)cccc1OC
Temperature: 25 °C
Reaction time: 40 h
Yield: 98 %

Procedure:
To a solution of allyl 6-allyl-2-hydroxybenzoate (v) (1.2 g, 5.5 mmol) in acetone (12 mL) was added K2CO3 (0.84 g, 6.05 mmol) and MeI (1.04 mL, 16.5 mmol) and the mixture was stirred for 40 h at rt. After filtration of the mixture through a short plug of silicagel, the filtrate was concentrated in vacuo and the residue purified by 1FC (3% Et2O/pentane) to give 1.25 of allyl 6-allyl-2-methoxybenzoate (via) (98%) as a colorless oil. via: IR 2918, 2850, 1733, 1715, 1585, 1363, 1244, 1223, 914, 733 cm−1; 1H NMR (400 MHz, CDCl3) δ 7.29 (1H, app.t, J=8.0 Hz), 6.83 (1H, d, J=7.6 Hz), 6.79 (1H, d, J=8.4 Hz), 5.97-6.06 (1H, m), 5.86-5.96 (1H, m), 5.42 (1H, br d, J=17.2 Hz), 5.28 (1H, br d, J=10.4 Hz), 5.0 (1H, br d, J=16.8 Hz), 5.04 (1H, br d, J=10.0 Hz), 4.82 (2H, br d, J=6.0 Hz), 3.82 (3H, s), 3.36 (2H, d, J=6.8 Hz); 13C NMR (75 MHz, CDCl3) δ 167.8, 156.6, 138.7, 136.4, 132.1, 130.6, 123.6, 121.8, 118.8, 116.5, 109.2, 66.0, 56.1, 37.9; MS (EI) 232 (M+, 18), 191 (28), 175 (34), (147 (50), 132 (100), 115 (58). Anal. Calcd for C14H16O3: C, 72.39; H, 6.94. Found: C, 72.10; (MOM): IR 2956, 2928, 2853, 1732, 1636, 1589, 1466, 1256, 1153, 1031, 919 cm−1; 1H NMR (400 MHz, CDCl3) δ 7.26 (1H, dd, J=7.6, 8.4 Hz), 7.01 (1H, d, J=7.6 Hz), 6.88 (1H, d, J=Hz), 6.01 (1H, ddt, J=5.6, 10.0, 17.2 Hz), 5.90 (1H, ddt, J=6.8, 10.4, 16.8 Hz), 5.42 (1H, br d, J=17.2 Hz), 5.28 (1H, br d, J=10.0 Hz), 5.17 (2H, s), 5.06 (1H, br d, J=16.8 Hz), 5.05 (1H, br d, J=10.4 Hz), 4.81 (2H, d, J=5.6 Hz), 3.46 (3H, s), 3.37 (2H, d, J=6.8 Hz), 13C NMR (75 MHz, CDCl3) 8167.8, 154.2, 138.8, 136.5, 132.2, 130.7, 124.7, 123.0, 118.9, 116.6, 112.9, 94.9, 66.0, 56.4, 37.8. HRMS Calcd for C15H804Li (MLi+): 269.1365. Found: 269.1371.
Reaction SMILES: C([O:3][C:4]([C:6]1([N:9]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH3:10])[CH2:8][CH2:7]1)=[O:5])C.O>CO.[OH-].[Na+]>[C:14]([O:13][C:11]([N:9]([CH3:10])[C:6]1([C:4]([OH:5])=[O:3])[CH2:8][CH2:7]1)=[O:12])([CH3:17])([CH3:16])[CH3:15]
Reactant: CCOC(=O)C1(N(C)C(=O)OC(C)(C)C)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CN(C(=O)OC(C)(C)C)C1(C(=O)O)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 84.8 %

Procedure:
To a solution of 48 mg of 1-(tert-butoxycarbonyl-methyl-amino)-cyclopropane carboxylic acid ethyl ester in 0.4 mL of methanol, 0.1 mL of 5N sodium hydroxide aqueous solution was added and stirred at room temperature overnight. After adding water, the reaction solution was washed with diethyl ether. The aqueous layer was added with 0.7 mL of 1N hydrochloric acid, and extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated, to afford 36 mg of the title compound as white crystals.
Reaction SMILES: [C:1]([C:9]1[N:10](C(OCC)=O)[C:11]2[C:16]([C:17]=1[N:18]([CH3:20])[CH3:19])=[CH:15][CH:14]=[C:13]([Cl:21])[CH:12]=2)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>C(OCC)C.CCCCCC>[C:1]([C:9]1[NH:10][C:11]2[C:16]([C:17]=1[N:18]([CH3:19])[CH3:20])=[CH:15][CH:14]=[C:13]([Cl:21])[CH:12]=2)(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)n1c(C(=O)c2ccccc2)c(N(C)C)c2ccc(Cl)cc21
Solvent: CCOCC
Solvent: CCCCCC
Product: CN(C)c1c(C(=O)c2ccccc2)[nH]c2cc(Cl)ccc12

Procedure:
The title compound was prepared according to the procedure described in step 2 of Example 2 from 2-benzoyl-6-chloro-1-ethoxycarbonyl-3-(N,N-dimethylamino)indole (step 1). m.p.: 178-180° C. (diethyl ether/hexane)
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[CH:11][C:10]([O:13][C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][C:15]=2[Cl:24])=[CH:9][C:5]=1[C:6](O)=[O:7])([O-:3])=[O:2].S(Cl)([Cl:27])=O>>[N+:1]([C:4]1[CH:12]=[CH:11][C:10]([O:13][C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][C:15]=2[Cl:24])=[CH:9][C:5]=1[C:6]([Cl:27])=[O:7])([O-:3])=[O:2]
Reactant: O=C(O)c1cc(Oc2ccc(C(F)(F)F)cc2Cl)ccc1[N+](=O)[O-]
Reactant: O=S(Cl)Cl
Product: O=C(Cl)c1cc(Oc2ccc(C(F)(F)F)cc2Cl)ccc1[N+](=O)[O-]

Procedure:
0.3 Part of 2-nitro-5-(2-chloro-4-trifluoromethylphenoxy)benzoic acid and 0.83 part of thionyl chloride for 2 hours. After the reaction, the excess of thionyl chloride was removed under reduced pressure to give 0.31 part of 2-nitro-5-(2-chloro-4-trifluoromethylphenoxy)benzoyl chloride. The resulting benzoyl chloride was added dropwise to a mixture of 0.14 part of diethylaminomethyl phosphonate, 0.095 part of triethylamine and 6 parts by volume of benzene with ice cooling. After the addition, the mixture was stirred at room temperature for 4 hours, and water was added. The mixture was then extracted with benzene, and the extract was washed with a saturated aqueous solution of sodium hydrogen carbonate and water, and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure to give 0.3 part of the desired compound (100). The IR and NMR spectral data of the compound are shown in Table 1.
Reaction SMILES: O1CCO[CH:2]1[CH2:6][CH:7]([CH3:16])[C:8]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=O.[C:17]([NH:20][CH2:21][CH2:22][NH2:23])(=[O:19])[CH3:18]>C(O)(=O)C>[CH3:16][C:7]1[CH:6]=[CH:2][N:23]([CH2:22][CH2:21][NH:20][C:17](=[O:19])[CH3:18])[C:8]=1[C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: CC(=O)NCCN
Reactant: CC(CC1OCCO1)C(=O)c1ccccc1
Solvent: CC(=O)O
Product: CC(=O)NCCn1ccc(C)c1-c1ccccc1
Reaction time: 18 h
Yield: 58.9 %

Procedure:
3-(1,3-Dioxolan-2-yl)-2-methylpropiophenone (7.1 g) was added to a solution of 6.6 g of N-acetylethylenediamine in 100 ml of acetic acid under argon and while stirring. The reaction solution was boiled for 18 hours and the acetic acid was subsequently removed in a vacuum. The residue was taken up in 200 ml of methylene chloride and washed with a mixture of 100 ml of saturated sodium hydrogen carbonate solution and 160 ml of 2N sodium hydroxide solution. The aqueous phase was back-extracted twice with 100 ml of methylene chloride each time. The organic phases were combined, dried with MgSO4 and freed from solvent. The residue, 7.6 g of brown oil was chromatographed on 350 g of silica gel with ethyl acetate/hexane mixtures (1:3 to 2:1) as the eluent. 4.6 g (59%) of N-[2-[3-methyl-2-phenylpyrrol-1-yl]ethyl]acetamide were isolated as a brown, amorphous solid. MS: m/e=242 (M+ ).
Reaction SMILES: [Br:1][C:2]1[CH:25]=[CH:24][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([O:16][CH3:17])=[CH:13][CH:14]=3)[C:9]([C@H:18]([CH3:22])[CH2:19][CH:20]=[O:21])=[C:8]2[CH3:23])=[CH:4][CH:3]=1.[OH-:26].[Na+].O>C(O)C.[N+]([O-])([O-])=O.[Ag+]>[Br:1][C:2]1[CH:25]=[CH:24][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([O:16][CH3:17])=[CH:13][CH:14]=3)[C:9]([C@H:18]([CH3:22])[CH2:19][C:20]([OH:26])=[O:21])=[C:8]2[CH3:23])=[CH:4][CH:3]=1
Reactant: COc1ccc2c(c1)c([C@H](C)CC=O)c(C)n2Cc1ccc(Br)cc1
Reactant: [OH-]
Agent: [Ag+]
Agent: O=[N+]([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: COc1ccc2c(c1)c([C@H](C)CC(=O)O)c(C)n2Cc1ccc(Br)cc1
Yield: 97 %

Procedure:
A solution of (R)-3-[1-(4-Bromo-benzyl)-5-methoxy-2-methyl-1H-indol-3-yl]-butanal (110 mg, 0.250 mmol) and silver nitrate (59.7 mg, 0.275 mmol) in 1.3 ml absolute ethanol was treated with a solution of 5N NaOH in ethanol (1:5, 0.9 ml, 0.75 mmol NaOH). After 45 min this was treated with 10 ml water, acidified to pH 3 and extracted with CHCl3 (5×20 ml) rinsing each extract with brine. The combined organics were dried over Na2SO4 and concentrated in vacuo to provide, after silica gel chromatography the title compound as a pale yellow solid (101 mg, 97% yield). IR (film) 3425, 2961, 2934, 2833, 1706, 1483, 1451, 1405, 1228, 1156, 1010, 796, 755 cm−1; 1H NMR (300 MHz, CDCl3) δ 7.36 (d, J=9.0 Hz, 2H, ArH), 7.11 (d, J=2.4 Hz, 1H, ArH), 7.04 (d, J=8.7, 1H, ArH), 6.77-6.73 (m, 3H, ArH), 5.18 (s, 2H NCH2), 3.86 (s, 3H, OCH3) 3.56 (dt, J=7.2, 21.9 Hz, 1H ArCH), 2.86 (d, J=3.6 Hz, 1H, CH2CO); 2.83 (d, J=3.3 Hz, 1H, CH2CO); 2.27 (s, 3H, ArCH3) 1.49 (d, J=7.2 Hz, 3H, CHCH3); 13C NMR (75 MHz, CDCl3) δ 178.0, 153.7, 137.3, 133.8, 133.0, 132.0, 127.7, 126.7, 121.2, 118.8, 114.6, 110.1, 109.9, 102.4, 56.3, 46.3, 41.5, 28.6, 21.1, 10.9; HRMS (CI) exact mass calcd for (C21H23BrNO3) (M+1) requires m/z 416.0861, found m/z 416.0867. [α]D=−30.9 (c=1.0, CHCl3).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH2:11][CH:12]([NH:21][C:22](=[O:31])[O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:13]([NH:15][CH2:16][C:17]([CH3:20])([CH3:19])[CH3:18])=O)[CH:5]=[C:6]2[C:10]=1[NH:9][N:8]=[CH:7]2.P(Cl)(Cl)(Cl)(Cl)Cl.N1C2C(=CC=CC=2)C=CC=1.[N-:48]=[N+:49]=[N-:50].[Na+]>C(Cl)(Cl)Cl>[CH3:1][C:2]1[CH:3]=[C:4]([CH2:11][CH:12]([NH:21][C:22](=[O:31])[O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:13]2[N:15]([CH2:16][C:17]([CH3:20])([CH3:19])[CH3:18])[N:50]=[N:49][N:48]=2)[CH:5]=[C:6]2[C:10]=1[NH:9][N:8]=[CH:7]2
Reactant: [N-]=[N+]=[N-]
Reactant: Cc1cc(CC(NC(=O)OCc2ccccc2)C(=O)NCC(C)(C)C)cc2cn[nH]c12
Agent: ClP(Cl)(Cl)(Cl)Cl
Agent: [Na+]
Solvent: c1ccc2ncccc2c1
Solvent: ClC(Cl)Cl
Product: Cc1cc(CC(NC(=O)OCc2ccccc2)c2nnnn2CC(C)(C)C)cc2cn[nH]c12
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of benzyl 3-(7-methyl-1H-indazol-5-yl)-1-(neopentylamino)-1-oxopropan-2-ylcarbamate (0.17 g, 0.402 mmol) in chloroform (0.5 mL) was added to a mixture of phosphorus pentachloride (0.17 g, 0.802 mmol) and quinoline (0.2 mL) in chloroform (1.0 mL). After stirring at room temperature for 2 h, the solvents were removed in vacuo. The crude mixture was dissolved in acetonitrile (2.0 mL) and treated with sodium azide (78 mg, 3.0 equiv). After stirring the mixture at 40° C. overnight, the solvents were removed and the crude mixture dissolved in methylene chloride which was washed with water (2×), brine (2×), dried over sodium sulfate, and concentrated. Column chromatography afforded 73 mg (40%, 2 steps). 1H-NMR (CD3OD, 500 MHz) δ 0.82 (s, 9H), 2.46 (s, 3H), 2.30-3.46 (m, 2H), 3.69 (d, J=14.3, 1H), 3.93 (d, J=14.3, 1H), 4.98-5.13 (m, 2H), 5.30 (m, 1H), 6.02 (d, J=8.9, 1H), 6.86 (s, 1H), 7.25-7.35 (m, 5H), 7.94 (s, 1H). Mass spec.: 448.19 (MH)+.
Reaction SMILES: Cl[CH2:2][C:3]1[O:4][CH:5]=[C:6]([OH:10])[C:7](=[O:9])[CH:8]=1.[N-:11]=[N+:12]=[N-:13].[Na+]>CN(C=O)C.O>[N:11]([CH2:2][C:3]1[O:4][CH:5]=[C:6]([OH:10])[C:7](=[O:9])[CH:8]=1)=[N+:12]=[N-:13]
Reactant: [N-]=[N+]=[N-]
Reactant: O=c1cc(CCl)occ1O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: [N-]=[N+]=NCc1cc(=O)c(O)co1
Temperature: 25 °C
Reaction time: 16 h
Yield: 63.8 %

Procedure:
To a stirred solution of 2-chloromethyl-5-hydroxy-pyran-4-one (2) (105.0 g, 656.2 mmol) in DMF (600 mL) was added NaN3 (55.45 g, 853.12 mmol) and the reaction mixture was stirred at room temperature for 16 h. After completion of the reaction, the reaction mixture was diluted with water and extracted with ethyl acetate. Then, the combined organic layer was washed with water and brine, and dried over Na2SO4 and concentrated under reduced pressure to get 2-azidomethyl-5-hydroxy-pyran-4-one (3) (70.0 g, 63.83%) as a light brown solid.