Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1(B(O)O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(=O)([O-])[O-].[Cs+].[Cs+].Br[C:17]1[C:25]([CH3:26])=[CH:24][CH:23]=[C:22]2[C:18]=1[CH:19]=[CH:20][CH2:21]2.O>COCCOC.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>[C:1]1([C:17]2[C:25]([CH3:26])=[CH:24][CH:23]=[C:22]3[C:18]=2[CH:19]=[CH:20][CH2:21]3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Cc1ccc2c(c1Br)C=CC2
Reactant: OB(O)c1ccccc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: COCCOC
Product: Cc1ccc2c(c1-c1ccccc1)C=CC2
Yield: 85.8 %

Procedure:
phenylboronic acid (8.3 g, 68 mmol) was dissolved in ethylene glycol dimethylether (DME, 100 mL), and aqueous solution (100 mL) of cesium carbonate (30 g), 4-bromo-5-methylindene (10 g, 48 mmol), tetrakis(triphenylphosphine)palladium (3.0 g, 2.6 mmol) were sequentially added. Solution was reacted for 55 hours while heating under reflux, then, reaction solution was added into water (200 mL), and extracted with diisopropylether. Organic layer was washed with 1N hydrochloric acid and saturated aqueous solution of sodium chloride, then was dried over sodium sulfate, and solvent was distilled off under reduced pressure to obtain the crude product. This was purified by silica-gel column chromatography (Silica-gel 60: produced by Kanto Chemical Co., Inc, hexane) to obtain 4-phenyl-5-methylindene (8.5 g, yield: 86%) as colorless liquid.
Reaction SMILES: [Si:1]([O:8][CH2:9][C:10]([O:12]CC)=O)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].Cl.[CH3:16][NH:17][O:18][CH3:19].C([Mg]Cl)(C)C>C1COCC1>[Si:1]([O:8][CH2:9][C:10]([N:17]([O:18][CH3:19])[CH3:16])=[O:12])([C:4]([CH3:5])([CH3:6])[CH3:7])([CH3:2])[CH3:3]
Reactant: CNOC
Reactant: CCOC(=O)CO[Si](C)(C)C(C)(C)C
Agent: CC(C)[Mg]Cl
Agent: Cl
Solvent: C1CCOC1
Product: CON(C)C(=O)CO[Si](C)(C)C(C)(C)C
Reaction time: 3 h
Yield: 70.7 %

Procedure:
To a solution of ethyl 2-(tert-butyldimethylsilyloxy)acetate (59, 20.0 g, 91.59 mmol), N,O-dimethylhydroxylamine hydrochloride (18.76 g, 192.3 mmol) and THF (800 mL) cooled to 0° C. was added dropwise via addition funnel isopropylmagnesium chloride (183.2 mL, 366.4 mmol) and the reaction was stirred for 3 h. The reaction was quenched with saturated NH4Cl and extracted with EtOAc. The organic layer was dried, filtered and concentrated. The crude product was purified by passage through a SiO2 plug eluting with 20% EtOAc/hexane to afford 15.12 g (70.7%) of 2-(tert-butyldimethylsilyloxy)-N-methoxy-N-methylacetamide (60).
Reaction SMILES: I[C:2]1[CH:3]=[CH:4][C:5]([O:9][CH2:10][CH2:11][N:12]2[CH2:16][CH2:15][CH2:14][CH2:13]2)=[C:6]([OH:8])[CH:7]=1.[Cl:17][C:18]1[CH:23]=[CH:22][C:21]([C:24]2[CH:25]=[CH:26][C:27]([C:30]#[CH:31])=[N:28][CH:29]=2)=[CH:20][CH:19]=1>>[Cl:17][C:18]1[CH:19]=[CH:20][C:21]([C:24]2[CH:25]=[CH:26][C:27]([C:30]#[C:31][C:2]3[CH:3]=[CH:4][C:5]([O:9][CH2:10][CH2:11][N:12]4[CH2:16][CH2:15][CH2:14][CH2:13]4)=[C:6]([OH:8])[CH:7]=3)=[N:28][CH:29]=2)=[CH:22][CH:23]=1
Reactant: C#Cc1ccc(-c2ccc(Cl)cc2)cn1
Reactant: Oc1cc(I)ccc1OCCN1CCCC1
Product: Oc1cc(C#Cc2ccc(-c3ccc(Cl)cc3)cn2)ccc1OCCN1CCCC1

Procedure:
The product was obtained analogously to Example 7.1e starting from 5-iodo-2-(2-pyrrolidin-1-ylethoxy)phenol and 5-(4-chlorophenyl)-2-ethynylpyridine. Yield: 0.75 g (48% of theoretical); C25H23ClN2O2 (M=418.915); calc.: molpeak (M+H)+: 419/421 (Cl); found: molpeak (M+H)+: 419/421 (Cl); HPLC-MS: 7.33 minutes (method A).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][S:15]([C:18]2[C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[C:21](F)=[CH:20][CH:19]=2)(=[O:17])=[O:16])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C-:29]#[N:30].[Na+].CO>CN(C=O)C.[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.ClCCl>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][S:15]([C:18]2[C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[C:21]([C:29]#[N:30])=[CH:20][CH:19]=2)(=[O:17])=[O:16])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCC(NS(=O)(=O)c2ccc(F)c3ccccc23)CC1
Reactant: [C-]#N
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCC(NS(=O)(=O)c2ccc(C#N)c3ccccc23)CC1
Temperature: 100 °C

Procedure:
4-(4-Fluoro-naphthalene-1-sulfonylamino)-piperidine-1-carboxylic acid tert-butyl ester 28 (2.00 g, 4.9 mmol) was dissolved in DMF (20 mL). Sodium cyanide (1.2 g, 24.5 mmol) and tetra-n-butylammonium bromide (7.9 g, 24.5 mmol) were added and the reaction was heated to 100° C. overnight. The reaction was diluted with dichloromethane (100 mL) and charged to a separatory funnel. The organic layer was washed three times with water, brine and dried over MgSO4. Filtration and concentration in vacuo afforded a dark colored oil. Flash column chromatography (98:2 dichloromethane:methanol) afforded an oil that was rechromatographed (99:1 dichloromethane:methanol) to afford 29 as an orange solid. Wt.: 640 mg (31%). 1H NMR (300 MHz, CDCl3) δ 8.71 (m, 1H), 8.40 (m, 1H), 8.34 (d, 1H), 8.00 (d, 1H), 7.83 (m, 2H), 4.80 (d, 1H), 3.87 (m, 2H), 3.32 (m, 1H), 2.61 (m, 2H), 1.63 (m, 2H), 1.38 (s, 9H), 1.27 (m, 2H); LC/MS m/z 414 (M−H)−
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:28])[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][CH2:14][CH2:15][CH2:16][NH:17]C(OCC2C=CC=CC=2)=O)=[CH:9][CH:8]=1)[CH3:2].[H][H]>[Pd].CO>[CH2:1]([O:3][C:4](=[O:28])[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][CH2:14][CH2:15][CH2:16][NH2:17])=[CH:9][CH:8]=1)[CH3:2]
Reactant: CCOC(=O)COc1ccc(CCCCNC(=O)OCc2ccccc2)cc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: CCOC(=O)COc1ccc(CCCCN)cc1
Yield: 88.4 %

Procedure:
A suspension of 47 (1.11 g, 2.88 mmol) and 10% palladium on carbon (0.40 g, wet) in methanol (50 mL) was stirred at room temperature for 2 h under atmospheric pressure of hydrogen. The mixture was then filtered through a silica gel pad. The solvent was evaporated to provide 48 (0.64 g, 88%) as a white solid. 1H NMR (300 MHz, DMSO-d6) δ 1.21 (m, 3H), 1.30-1.63 (m, 6H), 3.13 (m, 2H), 4.17 (m, 2H), 4.72 (br s, 2H), 6.84 (m, 2H), 7.10 (m, 2H).
Reaction SMILES: [O:1]1[CH:5]=[CH:4][C:3]([CH2:6][C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2Br)=[CH:2]1.C([Li])CCC.CCCCCC.[CH:25](N1CCCCC1)=[O:26]>O1CCCC1>[O:1]1[CH:5]=[CH:4][C:3]([CH2:6][C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[CH:25]=[O:26])=[CH:2]1
Reactant: Brc1ccccc1Cc1ccoc1
Reactant: O=CN1CCCCC1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: O=Cc1ccccc1Cc1ccoc1
Temperature: -10 °C
Reaction time: 0.5 h

Procedure:
To a solution of Compound 3b (0.5 mmol) in tetrahydrofuran (2 mL) at -78° C. under nitrogen was added n-butyllithium in hexane (0.5 mmol). After 30 minutes, a solution of N- formylpiperidine (0.55 mmol) in tetrahydrofuran (0.5 mL) was added dropwise at -78° C. The reaction mixture was stirred for 5 hours while allowing it to warm to -10° C. The reaction was quenched with saturated aqueous ammonium chloride (1 mL) and diluted with diethyl ether (10 mL). The aqueous phase was extracted with diethyl ether (2×10 mL) and the combined organic phases were washed with saturated aqueous ammonium chloride (3×5 mL) and brine and then dried over anhydrous sodium sulfate. The solvent was removed in vacuo and the residue purified by flash chromatography on silica gel eluted with ethyl acetate:hexane (2:98) to afford Compound 3c as an oil (Rf =0.2).
Reaction SMILES: [N:1]([CH2:4][CH2:5][OH:6])=[N+:2]=[N-:3].[C:7]([Si:11](Cl)([CH3:13])[CH3:12])([CH3:10])([CH3:9])[CH3:8].N1C=CN=C1.O>CN(C)C=O>[N:1]([CH2:4][CH2:5][O:6][Si:11]([C:7]([CH3:10])([CH3:9])[CH3:8])([CH3:13])[CH3:12])=[N+:2]=[N-:3]
Reactant: [N-]=[N+]=NCCO
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)[Si](C)(C)OCCN=[N+]=[N-]
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 94.7 %

Procedure:
2. 2-Azidoethanol, 1, (105 g, 1.21 mol), crude from above preparation, and tert-butylchlorodimethylsilane (200 g. 1.33 mol) were dissolved in 200 mL of dry N,N-dimethylformamide (DMF) and stirred under nitrogen. Over a period of 20 min, imidazole (204 g, 3.00 mol) was added portionwise with stirring and the temperature of the reaction rose to about 40° C. The solution was stirred at 40° C. under nitrogen for 24 h. The reaction mixture was cooled to room temperature, poured into 1 L of water, and extracted with pentane (4×300 mL). The pentane layers were dried over anhydrous sodium sulfate, concentrated on a rotary evaporator at 25° C., and distilled at reduced pressure through a 4 in. Vigreux column to give 230 g (1.14 mol, 94.7%) of 1-azido-2-(tert-butyldimethylsiloxy)ethane, 2: bp 37°-39° C. (0.02 mm); IR (CH2Cl2) 2940, 2860, 2120, 1115, 940, 840 cm10-1,1H NMR (CDl3, Me4Si) δ 0.09 6H,s), 0.92 (9H,s), 3.27 (2H,t,J=5 Hz), 3.80 (2H,t,J=5 Hz); proton decoupled 13C NMR (CDCl3, Me4Si)) δ-5.54, 18.18, 25.77, 53.16, 62.59.
Reaction SMILES: [OH-].[Na+].[NH:3]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:6](=O)[C:4]1=[O:5].[CH3:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]([CH3:23])=O)=[CH:17][CH:16]=1.S(=O)(=O)(O)[OH:25]>C(O)C>[CH3:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]2[CH:23]=[C:6]([C:4]([OH:25])=[O:5])[C:8]3[C:13](=[CH:12][CH:11]=[CH:10][CH:9]=3)[N:3]=2)=[CH:17][CH:16]=1
Reactant: O=C1Nc2ccccc2C1=O
Reactant: O=S(=O)(O)O
Reactant: CC(=O)c1ccc(C)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cc1ccc(-c2cc(C(=O)O)c3ccccc3n2)cc1

Procedure:
Ten milliliters (2.2N) of a sodium hydroxide aqueous solution was added dropwise to an ethanol (20 ml) suspension containing 1.47 g of isatin and 2.67 ml of 4-methylacetophenone at room temperature, and the reaction mixture was then heat-refluxed for 5.5 hours. The resulting reaction mixture was allowed to cool, and then acidified with 2N sulfuric acid to obtain an orange-colored precipitate. This precipitate was collected by filtration, and dried to form 2.34 g of the above-mentioned compound.
Reaction SMILES: C1[CH:5]2[C@@H:6]3[CH:10]=[CH:9][C@H:8]([CH:4]2C=C1)[CH2:7]3.[CH2:11]([O:15][C:16](=[O:19])C=C)[CH2:12][CH2:13][CH3:14].C1(C=CC(O)=CC=1)O>>[CH2:11]([O:15][C:16]([C:6]12[CH2:7][CH:8]([CH2:4][CH2:5]1)[CH:9]=[CH:10]2)=[O:19])[CH2:12][CH2:13][CH3:14]
Reactant: C=CC(=O)OCCCC
Reactant: C1=CC2C(C1)[C@@H]1C=C[C@H]2C1
Agent: Oc1ccc(O)cc1
Product: CCCCOC(=O)C12C=CC(CC1)C2
Temperature: 190 °C
Reaction time: 5 h
Yield: 78 %

Procedure:
DCPD (dicyclopentadiene, Aldrich, 180 mL, 1.34 mol), butylacrylate (Junsei, 500 mL, 3.49 mol), and hydroquinone (2.7 g, 0.025 mol) were put in a 2 L autoclave. After heating to 190° C., reaction was carried out for 5 hours while stirring at 300 rpm. After the reaction was completed, the reaction mixture was cooled down and transferred to a distillation unit. The reaction mixture was distilled at 1 torr using a vacuum pump at 80° C. to obtain the product (yield: 78%). The mole ratio (mol %) of the exo-isomers to endo-isomers of the product was 56.2:43.8.
Reaction SMILES: Cl.CO[C:4]([CH2:6][CH2:7][NH:8][C:9](=[O:29])[C:10]1[CH:15]=[CH:14][C:13]([NH:16][CH2:17]CCN2CCSCC2)=[C:12]([N+:26]([O-:28])=[O:27])[CH:11]=1)=O.[C:30]([O:33][CH2:34]C)(=[O:32])[CH3:31].C(O)C>>[CH3:34][O:33][C:30]([CH:31]1[CH2:4][CH2:6][CH2:7][N:8]1[C:9](=[O:29])[C:10]1[CH:15]=[CH:14][C:13]([NH:16][CH3:17])=[C:12]([N+:26]([O-:28])=[O:27])[CH:11]=1)=[O:32]
Reactant: CCOC(C)=O
Reactant: COC(=O)CCNC(=O)c1ccc(NCCCN2CCSCC2)c([N+](=O)[O-])c1
Agent: Cl
Solvent: CCO
Product: CNc1ccc(C(=O)N2CCCC2C(=O)OC)cc1[N+](=O)[O-]

Procedure:
The same procedure is used as in (1). Rf value: 0.57 (silica gel; ethyl acetate/ethanol=9:1)
Reaction SMILES: [NH2:1][CH:2]1[CH:14]2[CH:6]([CH2:7][C:8]3[C:13]2=[CH:12][CH:11]=[CH:10][CH:9]=3)[CH2:5][CH2:4][CH2:3]1.C([O-])([O-])=O.[K+].[K+].[CH2:21](Br)[CH3:22].[CH2:24](C(C)=O)[CH3:25]>>[CH2:24]([N:1]([CH2:21][CH3:22])[CH:2]1[CH:14]2[CH:6]([CH2:7][C:8]3[C:13]2=[CH:12][CH:11]=[CH:10][CH:9]=3)[CH2:5][CH2:4][CH2:3]1)[CH3:25]
Reactant: CCBr
Reactant: CCC(C)=O
Reactant: NC1CCCC2Cc3ccccc3C12
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CCN(CC)C1CCCC2Cc3ccccc3C21

Procedure:
The above amine is added to a suspension of 40 g of K2CO3 in 200 ml of methyl ethyl ketone and stirred while 22 g of ethyl bromide is added slowly over 2 hrs. The mixture is then heated under reflux for 5 hrs., cooled and filtered. Solvent is removed from the filtrate and the residue mixed with water and CHCl3. The organic layer is dried and freed of solvent to leave about 15 g of N,N-diethyl-4-amino-1,2,3,4,4a,9a-hexahydrofluorene which is subjected to a Birch reduction as per Example 1E to give N,N-diethyl-4-amino-1,2,3,4,5,8,4a,9a-octahydrofluorene which is reacted with hydrogen peroxide in the presence of formic acid as per Example 1 F to form the title compound.
Reaction SMILES: [S:1]1[C:5]([C:6]2[C:14]3[C:9](=[CH:10][CH:11]=[C:12]([C:15](N)=[O:16])[CH:13]=3)[N:8](C3CCCCO3)[N:7]=2)=[CH:4][C:3]2[CH:24]=[CH:25][CH:26]=[CH:27][C:2]1=2.Cl.[OH-:29].[Na+].[CH3:31]O>>[S:1]1[C:5]([C:6]2[C:14]3[C:9](=[CH:10][CH:11]=[C:12]([C:15]([O:29][CH3:31])=[O:16])[CH:13]=3)[NH:8][N:7]=2)=[CH:4][C:3]2[CH:24]=[CH:25][CH:26]=[CH:27][C:2]1=2
Reactant: NC(=O)c1ccc2c(c1)c(-c1cc3ccccc3s1)nn2C1CCCCO1
Reactant: CO
Reactant: [OH-]
Agent: Cl
Agent: [Na+]
Product: COC(=O)c1ccc2[nH]nc(-c3cc4ccccc4s3)c2c1
Temperature: 65 °C
Yield: 26 %

Procedure:
A mixture of 3-benzo[b]thiophen-2-yl-1-perhydro-2H-pyran-2-yl-1H-indazole-5-carboxamide (126 mg, 0.334 mmol), 10.0 mL of MeOH, and 10.0 mL of 6.0 N aq. HCl were heated at 65° C. for 24 h. The reaction mixture was added dropwise to 50 mL of 6.0 N aq. NaOH with stirring. This mixture was extracted with 3×EtOAc and the combined organics were dried (Na2SO4). Purification by silica gel chromatography using 30–40% EtOAc in hexanes afforded the title compound (27.0 mg, 26% yield): 1H NMR (DMSO-d6) δ 13.75 (br s, 1H), 8.84 (s, 1H), 8.19 (s, 1H), 8.15–7.95 (m, 3H), 7.74 (d, 1H), 7.45–7.35 (m, 2H), 3.94 (s, 3H); ES-MS (m/z) 378 [M+1]+.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[C:4]([N+:9]([O-])=O)[CH:3]=1.[C:12](OC(=O)C)(=[O:14])[CH3:13]>C(O)(=O)C.[Fe]>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[C:4]([NH:9][C:12](=[O:14])[CH3:13])[CH:3]=1
Reactant: CC(=O)OC(C)=O
Reactant: O=[N+]([O-])c1cc(Br)ccc1F
Agent: [Fe]
Solvent: CC(=O)O
Product: CC(=O)Nc1cc(Br)ccc1F

Procedure:
4-Bromo-1-fluoro-2-nitrobenzene (5.81 g), iron powder (6.20 g) and acetic anhydride (5 ml) were stirred in acetic acid (50 ml) at 60° C. for 16 h. Acetic acid was evaporated under reduced pressure and water and ethyl acetate were added. The organic layer was washed with aqueous sodium hydrogen carbonate and brine, dried over magnesium sulfate and concentrated under reduced pressure. The residue was recrystallized from hexane-ethyl acetate to give the title compound (3.56 g) as colorless prism crystals.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][CH:5]([CH2:8][N:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)[CH2:4][CH2:3]1.[C:15]1([CH:21]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH2:22][C:23](O)=[O:24])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C(Cl)CCl>C(Cl)Cl.CN(C1C=CN=CC=1)C>[CH3:1][N:2]1[CH2:7][CH2:6][CH:5]([CH2:8][N:9]2[CH2:14][CH2:13][N:12]([C:23](=[O:24])[CH2:22][CH:21]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[CH2:11][CH2:10]2)[CH2:4][CH2:3]1
Reactant: O=C(O)CC(c1ccccc1)c1ccccc1
Reactant: CN1CCC(CN2CCNCC2)CC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: ClCCCl
Product: CN1CCC(CN2CCN(C(=O)CC(c3ccccc3)c3ccccc3)CC2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 69 %

Procedure:
To a solution of 1-(1-methyl-piperidin-4ylmethyl)-piperazine (0.25 g, 1.26 mmol) in dry CH2Cl2 (25 ml) was added 3,3-diphenylpropanoic acid (0.26 g, 1.15 mmol) under nitrogen. To the reaction was added EDC (0.48 g, 2.53 mmol) and DMAP (cat) and the reaction mixture stirred under nitrogen at room temperature overnight. The reaction was then concentrated under reduced pressure. The residue dissolved in ethyl acetate:water (10:1) (100 ml). The organic was washed with water (25 ml, 2×) and 10% NaOH (25 ml) and dried over MgSO4 and evaporated to dryness. The resulting residue was purified by column chromatography using CH2Cl2:MeOH (5:1) to give desired product in 69% yield.
Reaction SMILES: [Li+].[OH-].[Cl:3][C:4]1[CH:8]=[C:7]([CH:9]=[O:10])[NH:6][C:5]=1[C:11]([O:13]C)=[O:12]>C1COCC1.CO>[Cl:3][C:4]1[CH:8]=[C:7]([CH:9]=[O:10])[NH:6][C:5]=1[C:11]([OH:13])=[O:12]
Reactant: COC(=O)c1[nH]c(C=O)cc1Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: O=Cc1cc(Cl)c(C(=O)O)[nH]1
Temperature: 25 °C
Reaction time: 8 h
Yield: 114.6 %

Procedure:
LiOH (2 mL, 2 mmol) was added to a solution of methyl 3-chloro-5-formyl-1H-pyrrole-2-carboxylate (0.050 g, 0.26 mmol) in THF (2 mL) and methanol (2 mL). The solution was stirred at room temperature overnight. The solvents were evaporated and the residue was partitioned between EtOAc and 1 N HCl. The organic layer was separated, dried over MgSO4, filtered and evaporated to a solid to afford the title compound (0.0517 g) as a crude product which was used with no further purification. 1H NMR (400 MHz, Acetone-d6) δ ppm 11.87 (br. s., 1H), 9.72 (s, 1H), 7.02 (s, 1H). LCMS: m/z 174.2 (M+1).
Reaction SMILES: [CH3:1][C@:2]1([NH:35]C(=O)OC(C)(C)C)[CH2:6][CH2:5][N:4]([C@@H:7]([C:12]2[CH:13]=[CH:14][C:15]3[N:16]([C:18]([C:21]4[CH:30]=[CH:29][C:28]5[C:23](=[C:24]([O:31][CH:32]([CH3:34])[CH3:33])[CH:25]=[CH:26][CH:27]=5)[N:22]=4)=[N:19][N:20]=3)[CH:17]=2)[C:8]([F:11])([F:10])[F:9])[CH2:3]1.[ClH:43].O1CCOCC1.C(OCC)C>C(Cl)Cl>[ClH:43].[ClH:43].[CH3:1][C@:2]1([NH2:35])[CH2:6][CH2:5][N:4]([C@@H:7]([C:12]2[CH:13]=[CH:14][C:15]3[N:16]([C:18]([C:21]4[CH:30]=[CH:29][C:28]5[C:23](=[C:24]([O:31][CH:32]([CH3:33])[CH3:34])[CH:25]=[CH:26][CH:27]=5)[N:22]=4)=[N:19][N:20]=3)[CH:17]=2)[C:8]([F:10])([F:11])[F:9])[CH2:3]1
Reactant: CC(C)Oc1cccc2ccc(-c3nnc4ccc([C@H](N5CC[C@](C)(NC(=O)OC(C)(C)C)C5)C(F)(F)F)cn34)nc12
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Solvent: CCOCC
Product: CC(C)Oc1cccc2ccc(-c3nnc4ccc([C@H](N5CC[C@](C)(N)C5)C(F)(F)F)cn34)nc12
Temperature: 25 °C
Reaction time: 3 h
Yield: 97 %

Procedure:
To a stirred solution of tert-butyl (S)-3-methyl-1-((S)-2,2,2-trifluoro-1-(3-(8-isopropoxyquinolin-2-yl)-[1,2,4]triazolo[4,3-a]pyridin-6-yl)ethyl)pyrrolidin-3-ylcarbamate (1.30 g, 2.22 mmol) in DCM (20 mL) was added 4N HCl in dioxane (5.56 mL, 22.2 mmol). The reaction mixture was stirred at ambient temperature for 3 hours. Diethyl ether (100 mL) was added to the reaction mixture. The suspension was stirred for 10 min. The solid was collected by filtration to give (S)-3-methyl-1-((S)-2,2,2-trifluoro-1-(3-(8-isopropoxyquinolin-2-yl)-[1,2,4]triazolo[4,3-a]pyridin-6-yl)ethyl)pyrrolidin-3-amine dihydrochloride (1.20 g, 97%). MS APCI (+) m/z 485 (M+1) detected. Specific rotation: [α]20D=−2.14° (c=0.97, MeOH).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([OH:10])=[C:6]([CH:9]=1)[C:7]#[N:8].[H-].[Na+].Br[CH2:14][CH2:15][O:16][CH:17]1[CH2:22][CH2:21][CH2:20][CH2:19][O:18]1>CN(C=O)C.C(Cl)Cl>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:10][CH2:14][CH2:15][O:16][CH:17]2[CH2:22][CH2:21][CH2:20][CH2:19][O:18]2)=[C:6]([CH:9]=1)[C:7]#[N:8]
Reactant: BrCCOC1CCCCO1
Reactant: N#Cc1cc(Br)ccc1O
Agent: [H-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: N#Cc1cc(Br)ccc1OCCOC1CCCCO1
Temperature: 25 °C
Reaction time: 5 h
Yield: 97.1 %

Procedure:
A solution of 5-bromo-2-hydroxybenzonitrile (1 g, 5.05 mmol) in DMF was treated with 95% NaH (242 mg, 9.6 mmol) for 20 min at room temperature. 2-(2-Bromoethoxy)tetrahydro-2H-pyran (0.839 ml, 5.56 mmol) was then added to the reaction and the mixture was stirred at room temperature for 5 hrs. The reaction was then diluted with DCM and washed with water. The organic phase was dried over Na2SO4, filtered, and concentrated to dryness to provide the crude title compound, 5-bromo-2-(2-(tetrahydro-2H-pyran-2-yloxy)ethoxy)benzonitrile (1.6 g, 9.75% yield) which was used without further purification.
Reaction SMILES: [NH2:1][C@H:2]([C:18]([N:20]([O:22][CH3:23])[CH3:21])=[O:19])[CH2:3][C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11](=[O:17])[O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[CH:6][CH:5]=1.CCN(C(C)C)C(C)C.[CH2:33]([O:40][C:41](Cl)=[O:42])[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1.CCOC(C)=O>C1COCC1>[C:13]([O:12][C:11]([NH:10][C:7]1[CH:8]=[CH:9][C:4]([CH2:3][C@H:2]([NH:1][C:41](=[O:42])[O:40][CH2:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[C:18]([N:20]([O:22][CH3:23])[CH3:21])=[O:19])=[CH:5][CH:6]=1)=[O:17])([CH3:14])([CH3:15])[CH3:16]
Reactant: O=C(Cl)OCc1ccccc1
Reactant: CON(C)C(=O)[C@@H](N)Cc1ccc(NC(=O)OC(C)(C)C)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CON(C)C(=O)[C@H](Cc1ccc(NC(=O)OC(C)(C)C)cc1)NC(=O)OCc1ccccc1
Reaction time: 4 h

Procedure:
To a solution of amine 62 (0.79 g, 2.43 mmol) in THF (20 mL) was added DiPEA (1.2 eq., 2.91 mmol, 482 μL), and benzylchloroformate (1.1 eq., 2.67 mmol, 392 μL) and the mixture was stirred for 4 hours in which a colorless solid precipitated. EtOAc was added and the mixture was extracted with 1 M aq. HCl (2×), sat. aq. NaHCO3 and brine, dried over MgSO4 and concentrated under reduced pressure. The title compound was obtained after column chromatography (10%->75% EtOAc/PE) as a colorless foam (yield: 0.95 g, 2.06 mmol, 85%). 1H NMR (400 MHz, CDCl3): δ=7.33-7.23 (m, 7H), 7.14 (s, 1H), 7.05 (d, J=8.21 Hz, 2H), 5.80 (d, J=8.71 Hz, 1H), 5.04 (dd, J=26.77, 12.39 Hz, 2H), 4.98-4.94 (m, 1H), 3.62 (s, 3H), 3.13 (s, 3H), 3.01 (dd, J=13.65, 5.91 Hz, 1H), 2.85 (dd, J=13.58, 7.35 Hz, 1H), 1.49 (s, 9H) ppm. 13C NMR (100 MHz, CDCl3): δ=171.72, 155.64, 152.64, 137.21, 136.07, 130.35, 129.52, 128.13, 127.69, 127.64, 118.18, 79.88, 66.41, 61.21, 51.95, 37.53, 31.73, 28.05 ppm. [α]D23=+8.1 (c=1, CHCl3). HRMS: calcd. for C24H31N3O6 458.22856 [M+H]+. found 458.22845.
Reaction SMILES: C(O[C:6]([N:8]1[CH2:12][C:11](=[N:13][O:14][CH3:15])[CH2:10][C@H:9]1[C:16]([OH:18])=O)=[O:7])(C)(C)C.[CH3:19][O:20][CH2:21]C(Cl)=O.[CH2:25]([N:27]1[C:39]2[CH:38]=[CH:37][C:36]([NH2:40])=[CH:35][C:34]=2[C:33]2[C:28]1=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH3:26]>>[CH2:25]([N:27]1[C:39]2[CH:38]=[CH:37][C:36]([NH:40][C:16]([C@@H:9]3[CH2:10][C:11](=[N:13][O:14][CH3:15])[CH2:12][N:8]3[C:6](=[O:7])[CH2:21][O:20][CH3:19])=[O:18])=[CH:35][C:34]=2[C:33]2[C:28]1=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH3:26]
Reactant: CON=C1C[C@@H](C(=O)O)N(C(=O)OC(C)(C)C)C1
Reactant: CCn1c2ccccc2c2cc(N)ccc21
Reactant: COCC(=O)Cl
Product: CCn1c2ccccc2c2cc(NC(=O)[C@@H]3CC(=NOC)CN3C(=O)COC)ccc21

Procedure:
Following the general method as outlined in Example 22, starting from (2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarboxylic acid, methoxyacetyl chloride, and 9-ethyl-9H-carbazol-3-amine the title compound was obtained in 73% purity by LC/MS. MS(ESI+): m/z=423.4.
Reaction SMILES: Cl.[CH2:2]([CH2:4][NH2:5])[OH:3].CCN(CC)CC.[C:13](Cl)([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>C(Cl)Cl.CC#N.C(Cl)Cl>[C:13]([NH:5][CH2:4][CH2:2][OH:3])([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1)[C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: NCCO
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CC#N
Solvent: ClCCl
Product: OCCNC(c1ccccc1)(c1ccccc1)c1ccccc1
Reaction time: 0.5 h

Procedure:
Ethanolamine hydrochloride (9.9 g; 100 mmol) is partially dissolved in CH2Cl2 /CH3CN (200 ml/100 ml) and Et3N (23 ml; 170 mmol) is then added. Tritylchloride (18.9 g; 67.6 mmol) is added portionwise over 30 minutes. After the addition is complete the reaction mixture is allowed to stir an additional 30 minutes, diluted with CH2Cl2, washed With H2O 2× and brine, dried (MgSO4), concentrated in vacuo and purified by column chromatography with silica/CH2Cl2 to give N-tritylethanolamine as an oil which is used directly in Step B.