Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]=[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]1[CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10].C(O[CH:17](OCC)[N:18]([CH3:20])[CH3:19])C>CN(C=O)C>[CH3:17][N:18]([CH3:20])[CH:19]=[C:8]([N:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]1=[O:1])[C:9]([O:11][CH2:12][CH3:13])=[O:10]
Reactant: CCOC(=O)Cn1ccccc1=O
Reactant: CCOC(OCC)N(C)C
Solvent: CN(C)C=O
Product: CCOC(=O)C(=CN(C)C)n1ccccc1=O
Yield: 84.5 %

Procedure:
Combined ethyl 2-(2-oxopyridin-1(2H)-yl)acetate (500 mg, 2.76 mmol), 1,1-diethoxy-N,N-dimethylmethanamine (2031 mg, 13.80 mmol) and DMF (2 mL) and heated at 100° C. for 15 h. The reaction mixture was diluted with xylenes and concentrated onto Celite® then purified on a 30 g NH silica column (Moritex) eluted with 0 to 100% EtOAc in hexanes to give the title compound (551 mg, 85% yield) as a light yellow solid. MS m/z 237 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.13 (br. s., 3H) 2.77 (br. s., 6H) 3.94-4.08 (m, 2H) 6.17 (td, J=6.7, 1.3 Hz, 1H) 6.36 (dt, J=9.0, 1.1 Hz, 1H) 7.35-7.45 (m, 2H) 7.47 (s, 1H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[N:9]([CH2:10][C:11]3[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=3)[S:8](=[O:20])(=[O:19])[CH2:7][C:6]=2[C:21]=1[N+:22]([O-])=O.Cl[Sn]Cl.O.C([O-])([O-])=O.[Na+].[Na+]>C(OCC)(=O)C>[F:1][C:2]1[C:21]([NH2:22])=[C:6]2[CH2:7][S:8](=[O:20])(=[O:19])[N:9]([CH2:10][C:11]3[CH:12]=[CH:13][C:14]([O:17][CH3:18])=[CH:15][CH:16]=3)[C:5]2=[CH:4][CH:3]=1
Reactant: COc1ccc(CN2c3ccc(F)c([N+](=O)[O-])c3CS2(=O)=O)cc1
Agent: Cl[Sn]Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Product: COc1ccc(CN2c3ccc(F)c(N)c3CS2(=O)=O)cc1
Reaction time: 12 h
Yield: 95.8 %

Procedure:
A mixture of 5-fluoro-1,3-dihydro-1-[(4-methoxyphenyl)methyl]-4-nitro-2,1-benzisothiazole 2,2-dioxide (1.54 g, 4.37 mmol) and SnCl2.H2O (4.93 g, 21.9 mmol) in ethyl acetate (200 mL) was heated at reflux for 3 h. Then the reaction mixture was cooled, diluted with ethyl acetate (200 mL) and solid Na2CO3 (15 g) was added. The resulting mixture was vigorously stirred for 12 h and filtered through a pad of diatomaceous earth (Celite®). The filtrate was concentrated and the residue was subjected to flash chromatography to give 1.35 g of the title compound of Step C as brown solid melting at 154°-157° C. 1H NMR (CDCl3, 400 MHz): δ7.33 (d,2H), 6.87 (d,2H), 6.82 (dd,1H, J=11.3 and 8.75 Hz), 5.91 (dd,1H, J=8.5 and 3.5 Hz), 4.65 (s,2H), 4.22 (s,2H), 3.79 (s,3H), 3.75 (br s,2H).
Reaction SMILES: Cl.[CH2:2]([O:4][C:5](=[O:16])[C@H:6]([CH2:8][C:9]1[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=1)[NH2:7])[CH3:3].[C:17]([NH:24][C:25]1([C:30](O)=[O:31])[CH2:29][CH2:28][CH2:27][CH2:26]1)([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18].C1C=CC2N(O)N=NC=2C=1.C1CCC(N=C=NC2CCCCC2)CC1.CCN(CC)CC>C(Cl)Cl>[CH2:2]([O:4][C:5](=[O:16])[CH:6]([NH:7][C:30]([C:25]1([NH:24][C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:29][CH2:28][CH2:27][CH2:26]1)=[O:31])[CH2:8][C:9]1[CH:10]=[CH:11][C:12]([OH:15])=[CH:13][CH:14]=1)[CH3:3]
Reactant: CC(C)(C)OC(=O)NC1(C(=O)O)CCCC1
Reactant: CCOC(=O)[C@@H](N)Cc1ccc(O)cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)C(Cc1ccc(O)cc1)NC(=O)C1(NC(=O)OC(C)(C)C)CCCC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
3.0 g (12.2 mmol) of tyrosine ethyl ester hydrochloride and 2.8 g (12.2 mmol) of N-Boc-cycloleucine are suspended in 10 mL of CH2Cl2. 1.65 g (12.2 mmol) of HOBT, 3.02 g (14.6 mmol) of DCC, and 1.7 mL (12.2 mmol) of Et3N are added, and the solution is stirred at room temperature overnight. The reaction mixture is filtered, and CH2Cl2 is removed in vacuo. The residue is taken up in EtOAc, filtered, and washed successively with 1 N HCl, water, saturated aqueous NaHCO3 solution, and brine, then dried over MgSO4, filtered, and concentrated. The residue is purified by chromatography on silica gel (50% EtOAc/hexane) to yield 2-[(1-tert-butoxycarbonylamino-cyclopentanecarbonyl)-amino]-3-(4-hydroxy-phenyl)-propionic acid ethyl ester; 1H NMR (250 MHz, CDCl3) δ 7.97 (d, 2H), 6.7 (d, 2H), 7.51 (d, 1H), 5.58 (s, 1H), 4.70-4.80 (m, 2H), 4.12 (q, 2H), 3.02 (d, 2H), 2.07-2.35 (m, 2H), 1.60-2.00 (m, 6H), 1.40 (s, 9H), 1.20 (t, 3H).
Reaction SMILES: CS(C)=O.[CH2:5]1[O:13][C:12]2[C:7](=[C:8]([CH2:14][C:15]#[N:16])[CH:9]=[CH:10][CH:11]=2)[O:6]1.[CH2:17](Br)[CH2:18][CH2:19][CH2:20][CH3:21].[OH-].[Na+]>O>[CH2:5]1[O:13][C:12]2[C:7](=[C:8]([CH:14]([C:15]#[N:16])[CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])[CH:9]=[CH:10][CH:11]=2)[O:6]1
Reactant: CCCCCBr
Reactant: N#CCc1cccc2c1OCO2
Agent: [Na+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: O
Product: CCCCCC(C#N)c1cccc2c1OCO2
Temperature: 25 °C
Yield: 81.1 %

Procedure:
Into 5 ml of dimethylsulfoxide, was added 0.26 g (1.6 mmol) of 2,3-methylenedioxyphenylacetonitrile, then, 0.24 g (1.6 mmol) of n-pentyl bromide and a 50% aqueous solution of sodium hydroxide were added dropwise thereinto simultaneously under cooling with ice. After 30-minute stirring at room temperature, the mixutre was added with water and extracted with ether. The ether extract was dried over magnesium chloride and then the solvent was evaporated off to obtain 0.30 g of oily 1-(2,3-methylenedioxyphenyl)hexane carbonitrile.
Reaction SMILES: [C:1]([NH:4][C@@H:5]([CH3:30])[CH2:6][O:7][C:8]1[N:13]=[CH:12][C:11]([NH:14][C:15](=[O:28])[C:16]2[CH:21]=[C:20]([Cl:22])[C:19]([O:23][CH2:24][CH:25]3[CH2:27][CH2:26]3)=[N:18][CH:17]=2)=[C:10](Cl)[CH:9]=1)(=[O:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C.[Cu]I>[Cl:22][C:20]1[CH:21]=[C:16]([C:15]2[O:28][C:10]3[CH:9]=[C:8]([O:7][CH2:6][C@@H:5]([NH:4][C:1](=[O:3])[CH3:2])[CH3:30])[N:13]=[CH:12][C:11]=3[N:14]=2)[CH:17]=[N:18][C:19]=1[O:23][CH2:24][CH:25]1[CH2:27][CH2:26]1
Reactant: CC(=O)N[C@@H](C)COc1cc(Cl)c(NC(=O)c2cnc(OCC3CC3)c(Cl)c2)cn1
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(=O)N[C@@H](C)COc1cc2oc(-c3cnc(OCC4CC4)c(Cl)c3)nc2cn1
Temperature: 160 °C
Reaction time: 3 h
Yield: 18.3 %

Procedure:
A suspension of N-(6-(((2S)-2-acetamidopropyl)oxy)-4-chloropyridin-3-yl)-5-chloro-6-(cyclopropylmethoxy)nicotinamide (910 mg), potassium carbonate (555 mg) and copper(I) iodide (38.2 mg) in DMF (10 mL) was stirred at 160° C. for 3 hr under microwave irradiation. To the reaction mixture was added water, and the obtained mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and subjected to silica gel column chromatography (NH, ethyl acetate). The solvent was evaporated, and the obtained solid was washed with ethyl acetate/hexane to give the title compound (153 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[Cl:10])[CH2:5]Br.[C:11]([O:14][C:15]1[C:23]([O:24][CH3:25])=[CH:22][CH:21]=[C:20]2[C:16]=1[CH:17]=[C:18]([C:26]([O:28][CH3:29])=[O:27])[NH:19]2)(=[O:13])[CH3:12].C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[C:11]([O:14][C:15]1[C:23]([O:24][CH3:25])=[CH:22][CH:21]=[C:20]2[C:16]=1[CH:17]=[C:18]([C:26]([O:28][CH3:29])=[O:27])[N:19]2[CH2:5][C:4]1[CH:7]=[CH:8][C:9]([Cl:10])=[C:2]([Cl:1])[CH:3]=1)(=[O:13])[CH3:12]
Reactant: COC(=O)c1cc2c(OC(C)=O)c(OC)ccc2[nH]1
Reactant: Clc1ccc(CBr)cc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COC(=O)c1cc2c(OC(C)=O)c(OC)ccc2n1Cc1ccc(Cl)c(Cl)c1
Temperature: 80 °C

Procedure:
3,4-Dichlorobenzyl bromide (1.02 g) was added to a stirred solution of methyl 4-acetoxy-5-methoxyindole-2-carboxylate (0.8 g) and potassium carbonate (0.97 g) in acetonitrile (30 ml) under an atmosphere of argon. The reaction was heated at 80° C. for 16 hours, then concentrated in vacuo and the residue partitioned between ethyl acetate and water.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([C:27]2[CH2:32][CH2:31][CH2:30][CH2:29][CH:28]=2)=[CH:8][C:9]=1[N:10]([C@H:20]1[CH2:25][CH2:24][C@H:23]([OH:26])[CH2:22][CH2:21]1)[C:11]([C@H:13]1[CH2:18][CH2:17][C@H:16]([CH3:19])[CH2:15][CH2:14]1)=[O:12])=[O:4].C(N(C(C)C)CC)(C)C.[CH3:42][O:43][CH2:44]Cl>ClCCl.CN(C1C=CN=CC=1)C>[CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([C:27]2[CH2:32][CH2:31][CH2:30][CH2:29][CH:28]=2)=[CH:8][C:9]=1[N:10]([C@H:20]1[CH2:25][CH2:24][C@H:23]([O:26][CH2:42][O:43][CH3:44])[CH2:22][CH2:21]1)[C:11]([C@H:13]1[CH2:14][CH2:15][C@H:16]([CH3:19])[CH2:17][CH2:18]1)=[O:12])=[O:4]
Reactant: COC(=O)c1sc(C2=CCCCC2)cc1N(C(=O)[C@H]1CC[C@H](C)CC1)[C@H]1CC[C@H](O)CC1
Reactant: COCCl
Agent: CN(C)c1ccncc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COCO[C@H]1CC[C@H](N(c2cc(C3=CCCCC3)sc2C(=O)OC)C(=O)[C@H]2CC[C@H](C)CC2)CC1

Procedure:
To a solution of 5-cyclohex-1-enyl-3-[(trans-4-hydroxy-cyclohexyl)-(trans-4-methyl-cyclohexanecarbonyl)-amino]-thiophene-2-carboxylic acid methyl ester (1 g, 2.18 mmol) in dichloromethane (10 mL) was added diisopropyl ethylamine (0.6 mL, 3.3 mmol), chloromethyl methyl ether (250 μL, 3.3 mmol) and DMAP (40 mg, 0.33 mmol). The reaction mixture was refluxed for 12 h. Solvents were removed and the residue as purified by silica gel column chromatography using ethyl acetate and hexane (1:3) as eluent to obtain 5-cyclohex-1-enyl-3-[(trans-4-methoxymethoxy-cyclohexyl)-(trans-4-methyl-cyclohexanecarbonyl)-amino]-thiophene-2-carboxylic acid methyl ester (780 mg, 71%) as a syrup.
Reaction SMILES: [NH2:1][C:2]1[NH:6][N:5]=[C:4]([CH2:7][C:8]#[N:9])[C:3]=1[C:10]#[N:11].CN(C)[CH:14]=[CH:15][C:16]([C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([C:24]([F:27])([F:26])[F:25])[CH:19]=1)=O>C(O)(=O)C>[C:10]([C:3]1[C:4]([CH2:7][C:8]#[N:9])=[N:5][N:6]2[C:16]([C:18]3[CH:19]=[C:20]([C:24]([F:25])([F:26])[F:27])[CH:21]=[CH:22][CH:23]=3)=[CH:15][CH:14]=[N:1][C:2]=12)#[N:11]
Reactant: CN(C)C=CC(=O)c1cccc(C(F)(F)F)c1
Reactant: N#CCc1n[nH]c(N)c1C#N
Solvent: CC(=O)O
Product: N#CCc1nn2c(-c3cccc(C(F)(F)F)c3)ccnc2c1C#N

Procedure:
A mixture of 2.94 g. of 5-amino-4-cyano-3-cyanomethyl pyrazole and 4.86 g. of 3-dimethylamino-3'-trifluoromethylacrylophenone in 25 ml. of glacial acetic acid is refluxed for 16 hours. The reaction mixture is evaporated to dryness and then extracted with methylene chloride. This solution is washed with a saturated sodium bicarbonate solution and dried with sodium sulfate. After passage of this solution through a short column of hydrous magnesium silicate, the effluent from this column is refluxed with gradual addition of hexane until the product crystallizes. Filtration gives crystals, m.p. 180°-181° C.
Reaction SMILES: [CH3:1][NH:2][S:3]([C:6]1[CH:7]=[N:8][CH:9]=[CH:10][C:11]=1[NH2:12])(=[O:5])=[O:4].[C:13](N1C=CN=C1)(N1C=CN=C1)=[S:14]>O1CCOCC1.CN(C=O)C>[CH3:1][N:2]1[C:13](=[S:14])[NH:12][C:11]2[CH:10]=[CH:9][N:8]=[CH:7][C:6]=2[S:3]1(=[O:5])=[O:4]
Reactant: S=C(n1ccnc1)n1ccnc1
Reactant: CNS(=O)(=O)c1cnccc1N
Solvent: CN(C)C=O
Solvent: C1COCCO1
Product: CN1C(=S)Nc2ccncc2S1(=O)=O
Reaction time: 0.5 h

Procedure:
A solution of N-methyl-4-aminopyridine-3-sulfonamide (de Tullio et al., Tetrahedron 1995, 3221-3234) (5.0 g) and thiocarbonyidiimidazole (7.5 g) in dioxane (30 mL) and DMF (15 mL) was heated at 90° C. for 2 h. The solvents were removed by distillation under reduced pressure. The residue was dispersed in 0.6N NaOH (20 mL) and stirred for 30 min. The alkaline solution was treated with charcoal, filtered, and the filtrate was adjusted to pH 4-5. The precipitate was collected by filtration, washed with water and dried (yield: 4 g); m.p. 195°-198° C. (Compound IV).
Reaction SMILES: [O-]CC.[K+].C(O)C.[C:8]([C:11]1[C:15]([NH:16][C:17](=O)[C:18]2[CH:23]=[C:22]([S:24]([N:27]3[CH2:32][CH2:31][N:30]([CH2:33][CH3:34])[CH2:29][CH2:28]3)(=[O:26])=[O:25])[CH:21]=[N:20][C:19]=2[O:35][CH2:36][CH3:37])=[C:14]([CH2:39][CH3:40])[N:13]([CH2:41][C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][N:43]=2)[N:12]=1)(=[O:10])[NH2:9]>C(OCC)(=O)C>[CH2:36]([O:35][C:19]1[N:20]=[CH:21][C:22]([S:24]([N:27]2[CH2:28][CH2:29][N:30]([CH2:33][CH3:34])[CH2:31][CH2:32]2)(=[O:25])=[O:26])=[CH:23][C:18]=1[C:17]1[NH:9][C:8](=[O:10])[C:11]2[C:15](=[C:14]([CH2:39][CH3:40])[N:13]([CH2:41][C:42]3[CH:47]=[CH:46][CH:45]=[CH:44][N:43]=3)[N:12]=2)[N:16]=1)[CH3:37]
Reactant: CCOc1ncc(S(=O)(=O)N2CCN(CC)CC2)cc1C(=O)Nc1c(C(N)=O)nn(Cc2ccccn2)c1CC
Agent: CC[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CCO
Product: CCOc1ncc(S(=O)(=O)N2CCN(CC)CC2)cc1-c1nc2c(CC)n(Cc3ccccn3)nc2c(=O)[nH]1
Temperature: 120 °C
Yield: 83 %

Procedure:
Potassium ethoxide solution (86 g, 0.25 mol, 24% w/w in ethanol) was charge to the vessel. To this was added ethanol (235 mL). Ethyl acetate (10.8 g) was added to reaction mixture at ambient. N-[3-carbamoyl-5-ethyl-1-(2-pyridylmethyl)-1H-pyrazol4-yl]-2-ethoxy-5-(4-ethyl-1-piperazinylsulfonyl) nicotinamide (70 g, 0.122 mol) was added in one portion to the solvent mixture and the reaction was stirred at ambient. The reaction mixture was warmed in a pressurised vessel to a temperature of 120° C., producing an internal pressure of approximately 50-60 p.s.i., the pressure was then made up to 80 p.s.i. by applying a nitrogen pressure and the reaction was stirred for 8 hours. The reaction was cooled after 8 hours and ethanol is then reduced under atmospheric distillation to a volume of about 720 ml (3 ml/g). Ethyl Acetate (840 ml) was added to the ethanol solution and then reduced under atmospheric distillation to a volume of 1920 ml (8 ml/g). Dilute aqueous hydrochloric acid was added to adjust the pH of the reaction mixture from about pH=13 to pH=8. This was a slow addition over 30 min showing no exotherm. The mixture was stirred for 5 minutes, warmed to 50° C. and the phases were separated. The aqueous was run off to the effluent. Water (140 mL) was added to ethyl acetate layer (remaining in the vessel), stirred, warmed to 50° C. and the phases were separated. The aqueous was run off to the effluent. The ethyl acetate phase was slowly cooled from 50° C. to 0-5° C. over two hours, and stirred for a further hour, filtered of the solid, wash with ethyl acetate (3) 0-5° C. and dried under vacuum at 60° C. to afford the title compound (83%) as a white solid. Mpt 178-180° C. (CDCl3): 1.02 (3H, t), 1.30, 3H, t), 1.58 (3H, t), 2.21 (2H, q), 2.55 (4H, m), 3.04 (2H, q), 3.10 (4m), 4.75 (2H, q), 5.69 (2H, s), 7.10 (1H, d), 7.22 (1H, m), 7.63 (1H, m), 8.57 (1H, d), 8.63 (1H, d), 9.02 (1H, d). m/z (Found:553 [M+H]+, 100%. C26H32N8O4S requires 553.66).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:26])[CH:4]([C:18]1[CH:23]=[CH:22][C:21]([Cl:24])=[C:20]([Cl:25])[CH:19]=1)[CH2:5][CH:6]1[CH2:10][CH2:9][CH2:8][CH:7]1[O:11]C1CCCCO1.C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1>C(O)C>[CH3:1][O:2][C:3](=[O:26])[CH:4]([C:18]1[CH:23]=[CH:22][C:21]([Cl:24])=[C:20]([Cl:25])[CH:19]=1)[CH2:5][CH:6]1[CH2:10][CH2:9][CH2:8][CH:7]1[OH:11]
Reactant: COC(=O)C(CC1CCCC1OC1CCCCO1)c1ccc(Cl)c(Cl)c1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: CCO
Product: COC(=O)C(CC1CCCC1O)c1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Yield: 101.2 %

Procedure:
A solution of 2-(3,4-dichloro-phenyl)-3-[2-(tetrahydro-pyran-2-yloxy)-cyclopentyl]-propionic acid methyl ester (prepared as in Example 24, 2.3 g, 5.73 mmol) in ethanol (57.3 mL) at 25° C. was treated with pyridinium p-toluenesulfonate (144 mg, 0.57 mmol). The resulting solution was heated under reflux for 18 h. At this time, the reaction was cooled to 25° C. and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230-400 mesh, 50/50 hexanes/ethyl acetate) afforded 2-(3,4-dichloro-phenyl)-3-(2-hydroxy-cyclopentyl)-propionic acid methyl ester (1.84 g, 100%) as a clear oil: EI-HRMS m/e calcd for C15H18Cl2O3 (M+Na)+ 339.0527. found 339.0528.
Reaction SMILES: C(OC([N:8]([CH2:27][CH2:28][O:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=1[O:36][CH2:37][CH3:38])[CH:9]([CH3:26])[CH2:10][C:11]1[CH:12]=[C:13]2[C:17](=[C:18]([C:20]([NH2:22])=[O:21])[CH:19]=1)[N:16]([CH2:23][CH2:24][OH:25])[CH2:15][CH2:14]2)=O)(C)(C)C.C(N(CC)CC)C.[C:46](OC(=O)C)(=[O:48])[CH3:47]>C(Cl)Cl>[C:46]([O:25][CH2:24][CH2:23][N:16]1[C:17]2[C:13](=[CH:12][C:11]([CH2:10][CH:9]([NH:8][CH2:27][CH2:28][O:29][C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=3[O:36][CH2:37][CH3:38])[CH3:26])=[CH:19][C:18]=2[C:20]([NH2:22])=[O:21])[CH2:14][CH2:15]1)(=[O:48])[CH3:47]
Reactant: CCOc1ccccc1OCCN(C(=O)OC(C)(C)C)C(C)Cc1cc2c(c(C(N)=O)c1)N(CCO)CC2
Reactant: CC(=O)OC(C)=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOc1ccccc1OCCNC(C)Cc1cc2c(c(C(N)=O)c1)N(CCOC(C)=O)CC2

Procedure:
To a solution of 5-[2-[N-tert-butoxycarbonyl-2-(2-ethoxyphenoxy)ethylamino]propyl]-1-(2-hydroxyethyl)indoline-7-carboxamide (60 mg) in methylene chloride (3 ml) were added triethylamine (24 μl) and acetic anhydride (13 μl) with stirring under ice cooling, and the mixture was stirred at room temperature for 16 hours. The reaction mixture was concentrated under reduced pressure and to the concentrate was added water. The mixture was extracted with ethyl acetate. The extract was washed with a saturated aqueous sodium bicarbonate solution and water, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was dissolved in methylene chloride (2 ml). To the solution was added trifluoroacetic acid (0.5 ml), the mixture was stirred at room temperature for 30 minutes, and the reaction mixture was concentrated under reduced pressure. To the concentrate was added a saturated aqueous sodium bicarbonate solution, and the mixture was extracted with ethyl acetate. The extract was washed with water, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by medium pressure liquid column chromatography on silica gel using a mixture of chloroform and methanol (7/1) as eluent to give 41 mg of 1-(2-acetoxyethyl)-5-[2-[2-(2-ethoxyphenoxy)ethylamino]propyl]indoline-7-carboxamide as an oil.
Reaction SMILES: [F:1][C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][CH:5]=[CH:4][C:3]=1[C:12]([C:15]1[N:16]=[CH:17][N:18](C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[CH:19]=1)([OH:14])[CH3:13].[OH-].[Na+]>C(O)(=O)C.O>[F:1][C:2]1[C:7]([C:8]([F:9])([F:10])[F:11])=[CH:6][CH:5]=[CH:4][C:3]=1[C:12]([C:15]1[N:16]=[CH:17][NH:18][CH:19]=1)([OH:14])[CH3:13]
Reactant: CC(O)(c1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1)c1cccc(C(F)(F)F)c1F
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: O
Product: CC(O)(c1c[nH]cn1)c1cccc(C(F)(F)F)c1F
Yield: 85.4 %

Procedure:
1-(2-fluoro-3-trifluoromethyl-phenyl)-1-(1-trityl-1H-imidazol-4-yl)-ethanol (Intermediate B2) (4.7 mmol) in acetic acid (13 mL) and water (3 mL) was heated to 100° C. for 1 h. The mixture was cooled to rt and basified with 2M NaOH. The compound was extracted with ethyl acetate and the solution was concentrated onto silica gel. The product was eluted with 3-5% NH3-MeOH: CH2Cl2 to give 1-(2-fluoro-3-trifluoromethyl-phenyl)-1-(1H-imidazol-4-yl)-ethanol (Intermediate B3) 1.1 g (85%).
Reaction SMILES: [Cl:1][C:2]1[CH:12]=[C:11]([F:13])[C:10]([F:14])=[CH:9][C:3]=1[C:4]([N:6]=[C:7]=[O:8])=[O:5].[Cl:15][C:16]1[CH:21]=[C:20]([C:22]2[NH:26][N:25]=[N:24][N:23]=2)[CH:19]=[CH:18][C:17]=1[NH2:27]>C(#N)C>[Cl:1][C:2]1[CH:12]=[C:11]([F:13])[C:10]([F:14])=[CH:9][C:3]=1[C:4]([NH:6][C:7]([NH:27][C:17]1[CH:18]=[CH:19][C:20]([C:22]2[NH:26][N:25]=[N:24][N:23]=2)=[CH:21][C:16]=1[Cl:15])=[O:8])=[O:5]
Reactant: Nc1ccc(-c2nnn[nH]2)cc1Cl
Reactant: O=C=NC(=O)c1cc(F)c(F)cc1Cl
Solvent: CC#N
Product: O=C(NC(=O)c1cc(F)c(F)cc1Cl)Nc1ccc(-c2nnn[nH]2)cc1Cl
Temperature: 40 °C
Reaction time: 1 h

Procedure:
The solution of equivalent amounts of 2-chloro-4,5-difluorobenzoyl isocyanate was added dropwise to the solution of 100 mg of 2-chloro-4-(1H-tetrazol-5-yl)phenylamine in 3 ml of acetonitrile and the mixture was stirred at 40° C. for 60 minutes. The solid formed was filtered off with suction and dried under reduced pressure.
Reaction SMILES: OO.[CH3:3][N:4]([CH3:21])[CH:5]1[CH2:20][C:19]2[C:7](=[CH:8][C:9]3[N+:14]([O-:15])=[N:13][C:12]([CH2:16][CH3:17])=[N:11][C:10]=3[CH:18]=2)[CH2:6]1.C(O)(C(F)(F)F)=[O:23].N>C(Cl)Cl.C(Cl)(Cl)Cl>[CH3:21][N:4]([CH3:3])[CH:5]1[CH2:20][C:19]2[C:7](=[CH:8][C:9]3[N+:14]([O-:15])=[N:13][C:12]([CH2:16][CH3:17])=[N+:11]([O-:23])[C:10]=3[CH:18]=2)[CH2:6]1
Reactant: CCc1nc2cc3c(cc2[n+]([O-])n1)CC(N(C)C)C3
Reactant: O=C(O)C(F)(F)F
Agent: N
Agent: OO
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Product: CCc1n[n+]([O-])c2cc3c(cc2[n+]1[O-])CC(N(C)C)C3
Temperature: 20 °C
Reaction time: 0.17 h
Yield: 20.7 %

Procedure:
H2O2 (70%, 0.47 mL, ca. 9.7 mmol) was added dropwise to a stirred solution of TFM (1.35 mL, 9.7 mmol) in DCM (15 mL) at 0° C. The solution was stirred at 20° C. for 10 min, then cooled to 0° C. and added to a solution of 1-oxide 115 (250 mg, 0.97 mmol) and TFA (0.16 mL, 2.07 mmol) in CHCl3 (15 mL) at 0° C. The solution was stirred at 20° C. for 5 h. The solution was made basic with dilute aqueous NH3 solution and extracted with CHCl3 (3×30 mL). The combined organic fraction was dried and the solvent evaporated. The residue was purified by column chromatography, eluting with a gradient (0-10%) of MeOH/DCM, to give 1,4-dioxide 116 (55 mg, 21%) as an unstable brown solid: 1H NMR δ 8.30 (s, 1H, H-9), 8.25 (s, 1H, H-5), 3.07-3.37 (m, 7H, H-6, H-7, H-8, CH2), 2.36 [s, 6H, N(CH3)2], 1.43 (t, J=7.5 Hz, 3H, CH3); HRMS calcd for C14H18N4O2 (M+) m/z 274.1430, found 274.1428.
Reaction SMILES: [Cl:1][C:2]1[CH:24]=[C:23]([O:25][CH3:26])[CH:22]=[C:21]([Cl:27])[C:3]=1[CH2:4][CH:5]1[CH2:9][CH2:8][N:7]([CH:10]2[CH2:19][CH2:18][C:13]3(OCC[O:14]3)[CH2:12][CH2:11]2)[C:6]1=[O:20].O.C1(C)C=CC(S(O)(=O)=O)=CC=1.Cl>CC(C)=O>[Cl:1][C:2]1[CH:24]=[C:23]([O:25][CH3:26])[CH:22]=[C:21]([Cl:27])[C:3]=1[CH2:4][CH:5]1[CH2:9][CH2:8][N:7]([CH:10]2[CH2:11][CH2:12][C:13](=[O:14])[CH2:18][CH2:19]2)[C:6]1=[O:20]
Reactant: COc1cc(Cl)c(CC2CCN(C3CCC4(CC3)OCCO4)C2=O)c(Cl)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: Cl
Solvent: CC(C)=O
Solvent: O
Product: COc1cc(Cl)c(CC2CCN(C3CCC(=O)CC3)C2=O)c(Cl)c1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
Dissolve 3-(2,6-Dichloro-4-methoxy-benzyl)-1-(1,4-dioxa-spiro[4.5]dec-8-yl)-pyrrolidin-2-one (6.5 g, 15.7 mmol) in acetone (100 mL), add p-toluenesulfonic acid hydrate (3 g, 15.7 mmol) and stir for 24 hr at room temp. Add 5N HCl (10 mL) and heat to 45° C. for 1 hr. Reaction progress can be monitored by TLC. Concentrate the reaction mixture, dilute with saturated aqueous sodium hydrogen carbonate (500 mL) and extract with ethyl acetate (3×150 mL). Wash the combined extracts with water (100 mL) and brine (100 mL), dry over anhydrous sodium sulfate, filtered, and concentrate to about 50 mL volume, dilute with hexanes (50 mL) and filter to give 5.5 g, 95%, as a white solid. 1H NMR (CDCl3) δ 6.78 (s, 2H), 4.44-4.52 (m, 1H), 3.78 (s, 3H), 3.37-3.47 (m, 1H), 3.29-3.36 (m, 1H), 3.15-3.23 (m, 2H), 2.39-2.62 (m, 4H), 1.80-2.11 (m, 6H). LCMS m+1 370.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH2:10][C:11]#[N:12])=[CH:2]1.[CH2:13](Br)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.[OH-].[Na+].O>CO>[CH2:13]([N:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH2:10][C:11]#[N:12])=[CH:2]1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: BrCc1ccccc1
Reactant: N#CCc1c[nH]c2ccccc12
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: N#CCc1cn(Cc2ccccc2)c2ccccc12
Temperature: 20 °C
Reaction time: 2 h

Procedure:
A mixture of 3-indolylacetonitrile (5 g, 32 mmol), triton B (40% in MeOH, 0.5 g), benzyl bromide (7.8 mL, 2 eq.) and aqueous NaOH (50%, 12.6 mL) was stirred for 2 hours at 20° C. Water was added. Solid was collected by filtration and washed with water and hexane and dried under high vacuum to give [1-benzyl-1H-indol-3-yl]acetonitrile (6.97 g). MS (ES): 247 (MH+).