Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]1[O:17][CH:2]1[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].[NH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][NH2:25]>>[CH2:24]([NH:25][CH2:1][CH:2]([OH:17])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][NH:18][CH2:1][CH:2]([OH:17])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: CCCCCCCCCCCCCCC1CO1
Reactant: NCCCCCCN
Product: CCCCCCCCCCCCCCC(O)CNCCCCCCNCC(O)CCCCCCCCCCCCCC

Procedure:
Condensation of 1-hexadecene oxide and hexamethylenediamine affords N,N'-(1,6-hexylene)-bis[2-hydroxyhexadecylamine] (I: R = CH3 (CH2)13, R' = H, X = (CH2)6, Z = H).
Reaction SMILES: [CH2:1]([C:3]1[C:4]([NH:11][C@@H:12]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[CH2:14][C@@H:13]2[OH:21])=[N:5][C:6]([CH2:9][CH3:10])=[CH:7][N:8]=1)[CH3:2].N[C@@H:23]1C2C(=CC=CC=2)CC[C@H]1O>>[CH2:1]([C:3]1[C:4]([NH:11][C@@H:12]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[CH2:23][CH2:14][C@H:13]2[OH:21])=[N:5][C:6]([CH2:9][CH3:10])=[CH:7][N:8]=1)[CH3:2]
Reactant: CCc1cnc(CC)c(N[C@@H]2c3ccccc3C[C@@H]2O)n1
Reactant: N[C@@H]1c2ccccc2CC[C@H]1O
Product: CCc1cnc(CC)c(N[C@@H]2c3ccccc3CC[C@H]2O)n1

Procedure:
Following the procedure for the preparation of (1R,2S)-1-[(3,6-diethylpyrazin-2-yl)amino]-2,3-dihydro-1H-inden-2-ol but substituting (trans)-1-amino-1,2,3,4-tetrahydronaphthalen-2-ol and making non-critical variations provided the title compound as a oil: 1H NMR (CDCl3) δ 1.27-1.34, 2.01, 2.24, 2.64, 2.84, 2.93, 4.03, 4.76, 5.06, 5.17, 7.19-7.21, 7.25-7.27, 7.34-7.37, 7.66;
Reaction SMILES: [N:1]1([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:6][CH2:5][CH:4]([CH:7]2[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]2)[CH2:3][CH2:2]1.F[C:21]1[CH:28]=[CH:27][C:24]([C:25]#[N:26])=[CH:23][CH:22]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C>[C:16]([O:15][C:13]([N:1]1[CH2:6][CH2:5][CH:4]([CH:7]2[CH2:12][CH2:11][N:10]([C:21]3[CH:28]=[CH:27][C:24]([C:25]#[N:26])=[CH:23][CH:22]=3)[CH2:9][CH2:8]2)[CH2:3][CH2:2]1)=[O:14])([CH3:19])([CH3:18])[CH3:17]
Reactant: CC(C)(C)OC(=O)N1CCC(C2CCNCC2)CC1
Reactant: N#Cc1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(C2CCN(c3ccc(C#N)cc3)CC2)CC1
Temperature: 70 °C
Reaction time: 18 h

Procedure:
A solution of tert-butyl 4,4′-bipiperidine-1-carboxylate (181 mg; 0.674 mmol) in DMF (3 mL) was treated with 4-fluorobenzonitrile (98 mg; 0.809 mmol) and cesium carbonate (264 mg; 0.809 mmol). The mixture was stirred at 70° C. for 18 hr. The mixture was partitioned between isopropyl acetate (25 mL) and pH7 phosphate buffer (10 mL). The organic was washed twice more with pH7 phosphate buffer (2×10 mL). The organic was dried over magnesium sulfate, filtered and evaporated to a solid. The crude product was chromatographed over silica gel (PTLC; 2:1 hex/MTBE). The major band was recovered affording the title compound. LRMS calc: 369.2. obs: 370.1 (M+H), 270.1 (M-BOC+H).
Reaction SMILES: [CH3:1][CH:2]([CH3:31])[C@@H:3]([NH:23]C(=O)OC(C)(C)C)[C:4]([NH:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][C:14]2[CH:19]=[CH:18][C:17]([CH3:20])=[C:16]([O:21][CH3:22])[CH:15]=2)=[CH:9][CH:8]=1)=[O:5].C(O)(C(F)(F)F)=O>ClCCl>[CH3:20][C:17]1[CH:18]=[CH:19][C:14]([O:13][C:10]2[CH:11]=[CH:12][C:7]([NH:6][C:4](=[O:5])[C@@H:3]([CH:2]([CH3:31])[CH3:1])[NH2:23])=[CH:8][CH:9]=2)=[CH:15][C:16]=1[O:21][CH3:22]
Reactant: COc1cc(Oc2ccc(NC(=O)[C@H](NC(=O)OC(C)(C)C)C(C)C)cc2)ccc1C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1cc(Oc2ccc(NC(=O)[C@H](N)C(C)C)cc2)ccc1C
Temperature: 25 °C
Reaction time: 1 h
Yield: 80.7 %

Procedure:
To a solution of 1,1-dimethylethyl ((1R)-2-methyl-1-{[(4-{[4-methyl-3-(methyloxy)phenyl]oxy}phenyl)amino]carbonyl}propyl)carbamate (Intermediate 82, 110 mg) in dry dichloromethane (3 mL), TFA (1 mL, 12.98 mmol) was added and the reaction mixture was stirred for 1 hour at room temperature. The solvent and the excess of TFA were evaporated and the residue was purified by SCX cartridge (5 g) to afford the title compound as a yellow pale solid (68 mg).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[Br:10])[CH2:5]Br.[C-:11]#[N:12].[Na+]>C(O)C>[F:1][C:2]1[CH:3]=[C:4]([CH2:5][C:11]#[N:12])[CH:7]=[CH:8][C:9]=1[Br:10]
Reactant: [C-]#N
Reactant: Fc1cc(CBr)ccc1Br
Agent: [Na+]
Solvent: CCO
Product: N#CCc1ccc(Br)c(F)c1
Temperature: 80 °C

Procedure:
This crude benzyl bromide (27 mmol) and sodium cyanide (2.38 g, 54 mmol, 2.0 eq.) were combined in ethanol (100 mL) and heated at 80° C. for 2 h. The reaction mixture was concentrated to dryness in vacuo, suspended in water, and extracted with ethyl acetate. Washing with brine and drying over Na2SO4 gave, after removal of the solvent, a red oil which was purified using silica gel chromatography (gradient of 2→12% ethyl acetate/hexanes) to provide 3-fluoro-4-bromophenylacetonitrile as white needles (1.96 g, 35% over 2 steps).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([OH:14])[CH:7]=[C:8]([C:10]([F:13])([F:12])[F:11])[CH:9]=1)([O-:3])=[O:2].C([O-])([O-])=O.[K+].[K+].[CH2:21]([O:28][C:29]([N:31]1[CH2:34][CH:33]([CH2:35]O)[CH2:32]1)=[O:30])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>CN(C=O)C>[CH2:21]([O:28][C:29]([N:31]1[CH2:34][CH:33]([CH2:35][O:14][C:6]2[CH:7]=[C:8]([C:10]([F:11])([F:12])[F:13])[CH:9]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=2)[CH2:32]1)=[O:30])[C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1
Reactant: O=C(OCc1ccccc1)N1CC(CO)C1
Reactant: O=[N+]([O-])c1cc(O)cc(C(F)(F)F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=C(OCc1ccccc1)N1CC(COc2cc([N+](=O)[O-])cc(C(F)(F)F)c2)C1
Temperature: 25 °C

Procedure:
A mixture of 3-nitro-5-trifluoromethyl-phenol (750 mg, Step C), K2CO3 (3 eq., 1.5 g) and 3-hydroxymethyl-azetidine-1-carboxylic acid benzyl ester (1.1 eq., 1.2 g) in DMF was heated to 80 C for 1 h. The solution was cooled to RT then filtered and concentraced under vacuum. The residue was dissolved in CH2Cl2 and washed with H2O twice, followed by brine. The organic layer was dried over Na2SO4 and evaporated under reduced pressure. The residue was purified by column chromatography using 5% MeOH/CH2Cl2 to provide the desired compound as a colorless solid.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][C@H:5]1[CH2:10][CH2:9][CH2:8][C:7](=[O:11])[CH:6]1[CH3:12].N1C=CN=C1.[C:18]([Si:22](Cl)([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)([CH3:21])([CH3:20])[CH3:19]>CN(C=O)C>[CH3:21][C:18]([Si:22]([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)([C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1)[O:1][CH2:2][CH2:3][CH2:4][C@H:5]1[CH2:10][CH2:9][CH2:8][C:7](=[O:11])[CH:6]1[CH3:12])([CH3:19])[CH3:20]
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Reactant: CC1C(=O)CCC[C@@H]1CCCO
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CC1C(=O)CCC[C@@H]1CCCO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C
Temperature: 25 °C
Reaction time: 3 h
Yield: 111.9 %

Procedure:
To a solution of 13.5 g (79.6 mmole) of the (3R)-3-(3-hydroxypropyl)-2-methylcyclohexanone in 240 ml of DMF was added 10.82 g (159.2 mmole) of imidazole followed by a dropwise addition of a solution of 26.2 g (95.3 mmole) of t-butylchlorodiphenyl silane in 25 ml of DMF. After addition, the solution was stirred at room temperature for 3 hours, quenched with 260 ml of iced water and extracted with 2×750 ml of ether. The combined etheral extracts were washed with 3×200 ml of water which was back extracted with 2×200 ml of ether. The combined etheral extracts were washed with brine, dried over MgSO4, filtered and concentrated to give 36.4 g of the crude (3R)-3-[3-[[(1,1-dimethylethyl)diphenylsilyl]oxy]propyl]-2-methylcyclohexanone which was used as such. An analytical sample was obtained by further purification of the above crude on a silica gel column (20:1, hexane/EtOAc). IR (CHCl3 ): 1130, 1700, 2850 cm-1. 1H NMR: δ0.98-1.05 (m, 12H), 1.15-1.70 (m, 7HO, 1.89 (m, 2H), 2.05 (m, 1H), 2.15 (m, 1H), 2.25 (m, 1H), 2.40 (m, 1H), 2.55 (m, 1H), 3.65 (m, 2H), 7.38 (m, 6H), 7.66 (m, 4H). Mass spectrum: M+ -CH3 (393). Anal. for C26H36O2Si: Calc. for C, 76.42; H, 8.88; Si, 6.87. Found: C, 76.16; H, 9.11; Si, 6.98.
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[F:13][C:14]1[N:19]=[CH:18][C:17]([CH2:20][N:21]2[CH2:26][CH2:25][S:24][CH2:23][CH2:22]2)=[CH:16][CH:15]=1.[B:27](OC(C)C)([O:32]C(C)C)[O:28]C(C)C>C1COCC1>[F:13][C:14]1[C:15]([B:27]([OH:32])[OH:28])=[CH:16][C:17]([CH2:20][N:21]2[CH2:26][CH2:25][S:24][CH2:23][CH2:22]2)=[CH:18][N:19]=1
Reactant: Fc1ccc(CN2CCSCC2)cn1
Reactant: CC(C)OB(OC(C)C)OC(C)C
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: OB(O)c1cc(CN2CCSCC2)cnc1F
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 71 %

Procedure:
A solution of diisopropylamine (0.767 mL, 5.43 mmol) in 2 mL of THF at −40° C. was treated with n-butyllithium (3.4 ml of 1.6 M solution in hexanes, 5.43 mmol) and stirred at this temperature for 30 min. The solution was cooled to −78° C. and treated dropwise via cannula with a solution of 4-((6-fluoropyridin-3-yl)methyl)thiomorpholine (922 mg, 4.34 mmol) in THF (2+2 mL) over 10 min. The brown mixture was stirred at −78° C. for 90 min and then treated dropwise via syringe with a solution of triisopropyl borate (1.49 mL, 6.51 mmol) in THF (1 mL). The mixture was stirred at −78° C. for 30 min. The cooling bath was removed, and the reaction mixture was allowed to warm up to RT. The mixture was quenched with 1.0N NaOH (5 mL) and stirred for an additional 30 min. The mixture was transferred to a separatory funnel and extracted with 5 mL of ether. The ether layer was discarded, and the aqueous layer was carefully acidified with 2.5N aqueous HCl until acidic (pH 4 about 5) and the resulting cloudy mixture was diluted with EtOAc (50 mL). The separated aqueous layer was extracted with EtOAc (2×15 mL) and the combined organic extracts were washed with brine, dried (Na2SO4), filtered, and concentrated to give 2-fluoro-5-(thiomorpholinomethyl)pyridin-3-ylboronic acid (790 mg, 3.08 mmol, 71.0% yield) as an off-white crystalline solid. 1H NMR (400 MHz, d4-MeOH) δ 8.11 (1H, d, J=2.5 Hz); 8.00 (1H, dd, J=8.0, 2.5 Hz); 3.75 (2H, s.); 2.91 (4H, m); 2.73 (4H, br. s.). m/z (ESI, +ve ion) 257 (M+H)+.
Reaction SMILES: [CH:1]([C:4]1[C:12]([CH:13](O)[CH:14]([CH3:16])[CH3:15])=[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][N:6]2[N:5]=1)([CH3:3])[CH3:2].P(Cl)(Cl)(Cl)(Cl)Cl.N1C=CC=CC=1>C1C=CC=CC=1>[CH:1]([C:4]1[C:12]([CH:13]=[C:14]([CH3:16])[CH3:15])=[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][N:6]2[N:5]=1)([CH3:3])[CH3:2]
Reactant: CC(C)c1nn2ccccc2c1C(O)C(C)C
Agent: ClP(Cl)(Cl)(Cl)Cl
Solvent: c1ccncc1
Solvent: c1ccccc1
Product: CC(C)=Cc1c(C(C)C)nn2ccccc12
Temperature: 25 °C
Reaction time: 3 h
Yield: 26.3 %

Procedure:
To a solution of 9.2 g of 1-(2-isopropylpyrazolo[1,5-a]pyridin-3-yl)-2-methylpropan-1-one in 25 ml of MeOH was added 1.5 g of NaBH4. The solution was stirred at RT overnight. 10.25 g of oily 1-(2-isopropylpyrazolo[1,5-a]pyridin-3-yl)-2-methylpropan-1-ol was obtained after workup. 1.05 g of 1-(2-isopropylpyrazolo[1,5-a]pyridin-3-yl)-2-methylpropan-1-ol in 10 ml of benzene was treated with 0.92 g of PCl5 and 1 ml of pyridine with stirring for 3 hours at RT. The crude 2-isopropyl-3-(2-methylprop-1-enyl)pyrazolo[1,5-a]pyridine obtained was purified on an Al2O3 column to furnish 255 mg of pure compound. Compound 1049.
Reaction SMILES: C(N(CC)C(C)C)(C)C.[Br:10][C:11]1[CH:12]=[C:13]2[C:18](=[CH:19][CH:20]=1)[N:17]([C:21](=[O:26])[C:22]([F:25])([F:24])[F:23])[C@@H:16]([CH3:27])[CH2:15][NH:14]2.Cl[C:29]([O:31][CH:32]1[CH2:36][CH2:35][CH2:34][CH2:33]1)=[O:30]>ClCCCl>[Br:10][C:11]1[CH:12]=[C:13]2[C:18]([N:17]([C:21](=[O:26])[C:22]([F:23])([F:25])[F:24])[C@@H:16]([CH3:27])[CH2:15][N:14]2[C:29]([O:31][CH:32]2[CH2:36][CH2:35][CH2:34][CH2:33]2)=[O:30])=[CH:19][CH:20]=1
Reactant: C[C@H]1CNc2cc(Br)ccc2N1C(=O)C(F)(F)F
Reactant: O=C(Cl)OC1CCCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCCl
Product: C[C@H]1CN(C(=O)OC2CCCC2)c2cc(Br)ccc2N1C(=O)C(F)(F)F
Temperature: 50 °C
Reaction time: 72 h
Yield: 96.6 %

Procedure:
N,N-Diisopropylethylamine (0.486 mL, 2.79 mmol) was added to a solution of (S)-1-(6-bromo-2-methyl-3,4-dihydroquinoxaline-1(2H)-yl)-2,2,2-trifluoroethanone (0.300 g, 0.928 mmol) and cyclopentyl chloroformate (0.144 mL, 1.114 mmol) in 1,2-dichloroethane (6.0 mL), and the mixture stirred at 50° C. for 3 days. Additional N,N-diisopropylethylamine (0.486 mL, 2.79 mmol) and cyclopentyl chloroformate (0.28 mL, 2.22 mmol) were added, and the mixture stirred at 50° C. for 16 h. The reaction mixture was concentrated to afford an off-white solid. This material was purified via column chromatography on silica gel (Biotage 25 g column, gradient elution with 0-25% ethyl acetate-hexane) to afford (S)-cyclopentyl 7-bromo-3-methyl-4-(2,2,2-trifluoroacetyl)-3,4-dihydroquinoxaline-1(2H)-carboxylate (0.390 g, 97%) as a yellow oil. MS (ESI, pos. ion) m/z 435, 437 [M+1]+.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]([CH3:15])[CH2:10][C:11](=[O:14])[NH:12][N:13]=2)=[CH:4][C:3]=1[N+:16]([O-:18])=[O:17].[CH2:19]([O:21][C:22]([CH:24]1[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]1)=[O:23])[CH3:20].N1C=CC=CC=1>O1CCOCC1>[CH2:19]([O:21][C:22]([CH:24]1[CH2:29][CH2:28][N:27]([C:2]2[CH:7]=[CH:6][C:5]([C:8]3[CH:9]([CH3:15])[CH2:10][C:11](=[O:14])[NH:12][N:13]=3)=[CH:4][C:3]=2[N+:16]([O-:18])=[O:17])[CH2:26][CH2:25]1)=[O:23])[CH3:20]
Reactant: CCOC(=O)C1CCNCC1
Reactant: CC1CC(=O)NN=C1c1ccc(Cl)c([N+](=O)[O-])c1
Solvent: c1ccncc1
Solvent: C1COCCO1
Product: CCOC(=O)C1CCN(c2ccc(C3=NNC(=O)CC3C)cc2[N+](=O)[O-])CC1
Temperature: 0 °C

Procedure:
2.68 g (10 mmol) of 6-(4-chloro-3-nitro-phenyl)-5-methyl-4,5-dihydro-3(2H)-pyridazinone are boiled under reflux with 3.14 g (20 mmol) of piperidine-4-carboxylic acid ethyl ester and 0.81 ml (10 mmol) of pyridine in 50 ml of dioxane for 5 hours. The reaction mixture is then poured out on 200 ml of ice water and suction filtered to separate the solid, and the filter cake is then washed with water.
Reaction SMILES: O=[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[N:10][N:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=23)=[N:4][NH:3]1.P(Cl)(Cl)([Cl:25])=O>>[Cl:25][C:2]1[N:3]=[N:4][C:5]([C:8]2[C:9]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[N:10][N:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=23)=[CH:6][CH:7]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: O=c1ccc(-c2c(-c3ccccc3)nn3ccccc23)n[nH]1
Product: Clc1ccc(-c2c(-c3ccccc3)nn3ccccc23)nn1

Procedure:
A mixture of 3-(3-oxo-2,3-dihydropyridazin-6-yl)-2-phenylpyrazolo[1,5-a]pyridine (2.91 g) and phosphorus oxychloride (10 ml) was heated under reflux for 1 hour. Phosphorus oxychloride was evaporated in vacuo. The residue was neutralized by saturated aqueous solution of sodium hydrogen carbonate and extracted with chloroform (30 ml×3). The combined extract was washed with a saturated aqueous solution of sodium chloride (20 ml) and dried over magnesium sulfate. The solvent was evaporated in vacuo and the residue was triturated with ethanol, collected by filtration, washed with ethanol and dried to give crystals of 3-(3-chloropyridazin-6-yl)-2-phenylpyrazolo[1,5-a]pyridine (2.42 g).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH2:8][C:9]([OH:11])=O)[CH:5]=[CH:6][CH:7]=1.O.ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.[Cl:35][C:36]1[CH:37]=[C:38]([CH:40]=[CH:41][C:42]=1[Cl:43])[NH2:39]>CN(C=O)C>[Cl:35][C:36]1[CH:37]=[C:38]([NH:39][C:9](=[O:11])[CH2:8][C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([OH:1])[CH:3]=2)[CH:40]=[CH:41][C:42]=1[Cl:43]
Reactant: Nc1ccc(Cl)c(Cl)c1
Reactant: O=C(O)Cc1cccc(O)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Product: O=C(Cc1cccc(O)c1)Nc1ccc(Cl)c(Cl)c1
Reaction time: 8 h
Yield: 61.9 %

Procedure:
To a solution of 3-hydroxyphenyl acetic acid (5.0 g, 0.03 mol) in DMF (50 ml) was added 1-hydroxybenzotriazole hydrate (4.86 g, 0.03 mol) and 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (6.9 g, 0.036 mol). To the flask was added 3,4-dichloroaniline (4.86 g, 0.03 mol). The reaction was allowed to stir overnight. Solvent was removed and the reaction was diluted with ethyl acetate. The reaction mixture was washed with 1N HCl, 10% sodium carbonate solution, and brine. The organic layer was dried over MgSO4, filtered and concentrated to provide the title compound (5.5 g, 62% yield): ES-MS (m/z) 296 [M+H]+.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([S:16][CH2:17][CH2:18][CH2:19][CH2:20][O:21][C:22]2[CH:23]=[CH:24][C:25]3[NH:30][C:29](=[O:31])[O:28][C:27]([CH3:33])([CH3:32])[C:26]=3[CH:34]=2)[CH:8]=[C:9]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:10]=1[OH:11])([CH3:4])([CH3:3])[CH3:2].[OH:35]O>>[C:12]([C:9]1[CH:8]=[C:7]([S:16]([CH2:17][CH2:18][CH2:19][CH2:20][O:21][C:22]2[CH:23]=[CH:24][C:25]3[NH:30][C:29](=[O:31])[O:28][C:27]([CH3:33])([CH3:32])[C:26]=3[CH:34]=2)=[O:35])[CH:6]=[C:5]([C:1]([CH3:2])([CH3:3])[CH3:4])[C:10]=1[OH:11])([CH3:15])([CH3:14])[CH3:13]
Reactant: OO
Reactant: CC(C)(C)c1cc(SCCCCOc2ccc3c(c2)C(C)(C)OC(=O)N3)cc(C(C)(C)C)c1O
Product: CC(C)(C)c1cc(S(=O)CCCCOc2ccc3c(c2)C(C)(C)OC(=O)N3)cc(C(C)(C)C)c1O

Procedure:
Prepared analogously to Example 2 from 6-[4-(3,5-ditert.butyl-4-hydroxy-phenylmercapto)-butoxy]-4,4-dimethyl-4H-3,1-benzoxazin-2-one and hydrogen peroxide.
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[C:7]([O:9][CH3:10])[N:6]=[C:5]([CH:11]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[NH:13][C:12]2=[O:20])[N:4]=1.CN1C=CN=C1.[F:27][CH:28]([F:33])[S:29](Cl)(=[O:31])=[O:30].O>ClCCl>[F:27][CH:28]([F:33])[S:29]([N:13]1[C:14]2[C:19](=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:11]([C:5]2[N:4]=[C:3]([O:2][CH3:1])[N:8]=[C:7]([O:9][CH3:10])[N:6]=2)[C:12]1=[O:20])(=[O:31])=[O:30]
Reactant: O=S(=O)(Cl)C(F)F
Reactant: COc1nc(OC)nc(C2C(=O)Nc3ccccc32)n1
Agent: Cn1ccnc1
Solvent: O
Solvent: ClCCl
Product: COc1nc(OC)nc(C2C(=O)N(S(=O)(=O)C(F)F)c3ccccc32)n1
Temperature: -5 °C

Procedure:
3-(4,6-Dimethoxy-1,3,5-triazin-2-yl)-1,3-dihydro-2H-indol-2-one (10 g) and 1-methyl-1H-imidazole (5.4 g) are introduced as initial charge in 100 ml of dichloromethane and cooled to −5° C. under nitrogen. With stirring, difluoromethanesulfonyl chloride (7.03 g) is added dropwise at −5° C. to 0° C. over the course of 20 minutes, and the mixture is after-stirred at this temperature for 2.5 hours. The reaction mixture is admixed with 50 ml of water and mixed thoroughly. The organic solvent is largely distilled off in vacuo and the residue is filtered. The solid product is washed with water and acetonitrile and dried in a vacuum drying cabinet. This gives the title compound as a solid in an HPLC purity of 93% (12.5 g, 92% of theory). The UV absorption (maximum at 360 nm) verifies the N-sulfonylation of the product.
Reaction SMILES: [F:1][C:2]([F:36])([F:35])[C:3]1[CH:4]=[C:5]([CH:28]=[C:29]([C:31]([F:34])([F:33])[F:32])[CH:30]=1)[C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14](=[O:17])[CH2:15]Cl)[CH2:10][C@H:9]1[CH2:18][C:19]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[NH:21][CH:20]=1)=[O:7].[C:37]1(=[O:47])[NH:41][C:40](=[O:42])[C:39]2=[CH:43][CH:44]=[CH:45][CH:46]=[C:38]12.[K].[Cl-].[Na+]>CN(C)C=O>[F:1][C:2]([F:36])([F:35])[C:3]1[CH:4]=[C:5]([CH:28]=[C:29]([C:31]([F:34])([F:33])[F:32])[CH:30]=1)[C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]([CH2:15][N:41]2[C:40](=[O:42])[C:39]3=[CH:43][CH:44]=[CH:45][CH:46]=[C:38]3[C:37]2=[O:47])=[O:17])[CH2:10][C@H:9]1[CH2:18][C:19]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[NH:21][CH:20]=1)=[O:7]
Reactant: O=C(CCl)N1CCN(C(=O)c2cc(C(F)(F)F)cc(C(F)(F)F)c2)[C@H](Cc2c[nH]c3ccccc23)C1
Reactant: O=C1NC(=O)c2ccccc21
Agent: [Cl-]
Agent: [K]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C(CN1C(=O)c2ccccc2C1=O)N1CCN(C(=O)c2cc(C(F)(F)F)cc(C(F)(F)F)c2)[C@H](Cc2c[nH]c3ccccc23)C1
Temperature: 25 °C
Reaction time: 7 h
Yield: 56.7 %

Procedure:
A mixture of (2R)-1-[3,5-bis(trifluoromethyl)benzoyl]-4-(2-chloroacetyl)-2-(1H-indol-3-yl-methyl)piperazine (730 mg), potassium phthalimide (260 mg) in dimethylformamide (10 ml) was stirred at room temperature for 7 hours and then poured into aqueous sodium chloride solution (100 ml). The resulting precipitate was collected by filtration, washed with water and dried. The crude product was dissolved in toluene (7 ml) and filtered. To the filtrate was added n-hexane (35 ml) and the whole was stirred for 10 minutes. The resulting powder was collected by filtration, washed with ethyl ether and dried to give (2R)-1-[3,5-bis(trifluoromethyl)benzoyl]-2-(1H-indol-3-yl-methyl)-4-(phthalimidomethylcarbonyl)piperazine (500 mg).
Reaction SMILES: I[C:2]1[C:10]2[C:5](=[CH:6][C:7]([C@H:11]3[C@@:13]4([C:21]5[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=5)[NH:15][C:14]4=[O:22])[CH2:12]3)=[CH:8][CH:9]=2)[NH:4][N:3]=1.CC1(C)C(C)(C)OB(/[CH:31]=[CH:32]/[C:33]2[CH:34]=[CH:35][C:36]3[O:42][CH2:41][CH2:40][N:39](C(OC(C)(C)C)=O)[CH2:38][C:37]=3[CH:50]=2)O1.[C:52]([OH:58])([C:54]([F:57])([F:56])[F:55])=[O:53]>C(Cl)Cl>[F:55][C:54]([F:57])([F:56])[C:52]([OH:58])=[O:53].[O:42]1[C:36]2[CH:35]=[CH:34][C:33](/[CH:32]=[CH:31]/[C:2]3[C:10]4[C:5](=[CH:6][C:7]([C@H:11]5[C@@:13]6([C:21]7[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=7)[NH:15][C:14]6=[O:22])[CH2:12]5)=[CH:8][CH:9]=4)[NH:4][N:3]=3)=[CH:50][C:37]=2[CH2:38][NH:39][CH2:40][CH2:41]1
Reactant: O=C1Nc2ccccc2[C@]12C[C@H]2c1ccc2c(I)n[nH]c2c1
Reactant: CC(C)(C)OC(=O)N1CCOc2ccc(/C=C/B3OC(C)(C)C(C)(C)O3)cc2C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C1Nc2ccccc2[C@]12C[C@H]2c1ccc2c(/C=C/c3ccc4c(c3)CNCCO4)n[nH]c2c1
Reaction time: 1 h
Yield: 30 %

Procedure:
The title compound was synthesized according to the method of Example A51B, by using (1R,2S)-2-(3-iodo-1H-indazol-6-yl)spiro[cyclopropane-1,3′-indolin]-2′-one (105 mg, 0.27 mmol) and (E)-tert-butyl 7-(2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)vinyl)-2,3-dihydrobenzo[f][1,4]oxazepine-4(5H)-carboxylate (130 mg, 0.32 mmol). The residue from the reaction was dissolved into CH2Cl2 (5 mL) and TFA (0.2 mL) was added and the mixture was stirred for 1 h and concentrated to dryness. Purification by preparative HPLC gave the title compound as a cream solid (40 mg, 30%). 1H NMR (400 MHz, CD3OD) δ 7.97 (d, J=8.2 Hz, 1H), 7.68-7.64 (m, 2H), 7.50-7.39 (m, 3H), 7.16 (d, J=8.2 Hz, 1H), 7.07-7.01 (m, 2H), 6.94 (d, J=7.8 Hz, 1H), 6.57 (t, J=7.6 Hz, 1H), 5.98 (d, J=7.4 Hz, 1H), 4.45 (s, 2H), 4.39 (br. s, 2H), 3.68 (br. s, 2H), 3.39-3.33 (m, 1H) 2.25-2.16 (m, 2H); MS ESI 449.3 [M+H]+, calcd for [C28H24N4O2+H]+ 449.2.
Reaction SMILES: C1(C(C2C=CC=CC=2)(C2C=CC=CC=2)[N:8]2[CH:12]=[C:11]([CH2:13][CH2:14][CH2:15][OH:16])[N:10]=[CH:9]2)C=CC=CC=1.[CH3:29][O:30][C:31]1[CH:36]=[CH:35][C:34](O)=[CH:33][CH:32]=1>>[CH3:29][O:30][C:31]1[CH:36]=[CH:35][C:34]([O:16][CH2:15][CH2:14][CH2:13][C:11]2[N:10]=[CH:9][NH:8][CH:12]=2)=[CH:33][CH:32]=1
Reactant: COc1ccc(O)cc1
Reactant: OCCCc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Product: COc1ccc(OCCCc2c[nH]cn2)cc1

Procedure:
5 mmol of 3-(1-triphenylmethyl-1H-imidazol-4-yl)propanol and 6 mmol of 4-methoxyphenol are treated as described in Example 76.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.[C:10]([OH:14])(=[O:13])[CH:11]=[CH2:12]>C(O)(=O)C>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH2:12][CH2:11][C:10]([OH:14])=[O:13])=[CH:2]1
Reactant: C=CC(=O)O
Reactant: c1ccc2[nH]ccc2c1
Solvent: CC(=O)O
Product: O=C(O)CCc1c[nH]c2ccccc12

Procedure:
Reaction of indole XXI with acrylic acid in the presence of acetic acid affords the indole-3-propionic acid. Esterification, alkylation of the indole nitrogen, if desired, and trifluoroacetic acid hydrolysis gives rise to indoles of Formula VII in which R is (CH2)mCO2R9, m is 2 and R2 is H or C1 -C3 alkyl. ##STR29##