Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[F:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)=[CH:5][CH:4]=1.CCN(CC)CC.[Cl:22][S:23](O)(=[O:25])=[O:24].P(Cl)(Cl)(Cl)(Cl)Cl>C(Cl)Cl>[F:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[CH2:10][CH2:11][N:12]([S:23]([Cl:22])(=[O:25])=[O:24])[CH2:13][CH2:14]2)=[CH:5][CH:4]=1
Reactant: Fc1ccc(C2CCNCC2)cc1
Reactant: O=S(=O)(O)Cl
Agent: Cl
Agent: ClP(Cl)(Cl)(Cl)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=S(=O)(Cl)N1CCC(c2ccc(F)cc2)CC1
Temperature: 0 °C
Reaction time: 0.58 h

Procedure:
4-(4Fluoro-phenyl)-piperidine hydrochloride (1.0 g; 4.64 mmol) and Et3N (1.9 ml; 13.9 mmol) was dissolved in DCM (20 ml) and cooled to 0° C. using an ice/water bath. ClSO3H (309 ul; 4.6 mmol) was slowly added droppwise due to highly exothermic reaction. After addition was compleat the mixture was allowed to reach room temperature and stirred over night. The clear yellow solution of the intermediate sulfonicacid derivative was evaporated and dry Toluene (20 ml) was added to form a slurry. To this slurry was added PCl5 (1.06 g; 5.1 mmol) in portions, the mixture was heated on an oil bath to 75° C. for 2 h, and then left over night in room temperature before filtration. The filtercake was washed with Toluene and the filtrate was evaporated. EtOAc was added and precipitating salts was removed by filtration. The crude product was purified on 70 g Si-60 gel using flash chromatography with a gradient 100% Heptane to 100% DCM. Gradient time was 35 min and flow of solvent was 20 ml/min. Fractions containing product was evaporated to give the title compound as a slightly yellow oil that crystallises upon standing. Obtained 0.94 (70% yield) of the title compound.
Reaction SMILES: [CH:1]12[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[C:2]1=[O:11])[CH2:8]2.Br[C:13]1[CH:25]=[CH:24][C:16]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])=[CH:15][C:14]=1[Cl:26].[Cl-].[Li+].C([Mg]Cl)(C)C>O1CCCC1>[Cl:26][C:14]1[CH:15]=[C:16]([CH:24]=[CH:25][C:13]=1[C:2]1([OH:11])[CH:3]2[CH2:9][CH:7]3[CH2:6][CH:5]([CH2:10][CH:1]1[CH2:8]3)[CH2:4]2)[C:17]([O:19][C:20]([CH3:22])([CH3:23])[CH3:21])=[O:18]
Reactant: O=C1C2CC3CC(C2)CC1C3
Reactant: CC(C)(C)OC(=O)c1ccc(Br)c(Cl)c1
Agent: CC(C)[Mg]Cl
Agent: [Cl-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)c1ccc(C2(O)C3CC4CC(C3)CC2C4)c(Cl)c1
Temperature: 25 °C

Procedure:
To a cold (−40° C.) solution of 2-adamantanone (1.50 g, 10.00 mmol) and tert-butyl 4-bromo-3-chlorobenzoate (2.45 g, 10.00 mmol) in anhydrous tetrahydrofuran (120 mL) was added isopropylmagnesium chloride lithium chloride complex (1.3 M solution in tetrahydrofuran, 10 mL, 13 mmol). The reaction mixture was warm to ambient temperature over 2 hours and heated to reflux for 1 hour. After cooling to ambient temperature, the mixture was quenched with saturated aqueous ammonium chloride (10 mL), diluted with ethyl acetate (200 mL), washed with saturated aqueous ammonium chloride
Reaction SMILES: C(O[C:6](=O)[N:7](C)[C@@H:8]([C:16](=[O:27])[N:17]([CH3:26])[CH2:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=1)[CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[CH3:26][N:17]([CH2:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=1)[C:16](=[O:27])[C@H:8]([NH:7][CH3:6])[CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: CN(CCc1ccccn1)C(=O)[C@@H](Cc1ccccc1)N(C)C(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CN[C@H](Cc1ccccc1)C(=O)N(C)CCc1ccccn1
Reaction time: 0.67 h

Procedure:
N-Methyl-N{(1R)-1-[N-methyl-N-(2-(2-pyridyl)ethyl)carbamoyl]-2-phenylethyl}carbamic acid tert-butyl ester was dissolved in dichloromethane (75 mL). Trifluoroacetic acid (75 mL, 0.978 mol) was added to the stirred solution. The reaction mixture was stirred for 40 min. The solvent was removed in vacuo. The product was dissolved in dichloromethane (30 mL) and sat. aqueous sodium hydrogen carbonate solution (20 mL). The reaction mixture was neutralised with solid sodium hydrogen carbonate. Dichloromethane (100 mL) was added and the aqueous phase was extracted with dichloromethane (2×150 mL). The combined organic layers were dried over magnesium sulfate. The solvent was removed in vacuo, to give 7.9 g of (2R)-N-Methyl-2-(methylamino)-3-phenyl-N-(2-(2-pyridyl)ethyl)propionamide.
Reaction SMILES: [F:1][C:2]1[C:3]([O:11][CH3:12])=[C:4]([C@@H:8]([NH2:10])[CH3:9])[CH:5]=[CH:6][CH:7]=1.C([O:17][C:18]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[C:26]1[CH:31]=[CH:30][C:29]([CH2:32][N:33]2[C:41]3[C:36](=[CH:37][C:38]([C:42](O)=[O:43])=[CH:39][CH:40]=3)[C:35]([CH3:45])=[C:34]2[CH3:46])=[CH:28][CH:27]=1)=[O:19])(C)(C)C>>[F:1][C:2]1[C:3]([O:11][CH3:12])=[C:4]([C@@H:8]([NH:10][C:42]([C:38]2[CH:37]=[C:36]3[C:41](=[CH:40][CH:39]=2)[N:33]([CH2:32][C:29]2[CH:28]=[CH:27][C:26]([C:21]4[C:20]([C:18]([OH:19])=[O:17])=[CH:25][CH:24]=[CH:23][CH:22]=4)=[CH:31][CH:30]=2)[C:34]([CH3:46])=[C:35]3[CH3:45])=[O:43])[CH3:9])[CH:5]=[CH:6][CH:7]=1
Reactant: COc1c(F)cccc1[C@H](C)N
Reactant: Cc1c(C)n(Cc2ccc(-c3ccccc3C(=O)OC(C)(C)C)cc2)c2ccc(C(=O)O)cc12
Product: COc1c(F)cccc1[C@H](C)NC(=O)c1ccc2c(c1)c(C)c(C)n2Cc1ccc(-c2ccccc2C(=O)O)cc1

Procedure:
The title compound was prepared following the same general protocol as described in Step 1-2, Example 2, using the (S)-1-(3-fluoro-2-methoxyphenyl)ethanamine and the 1-((2′-(tert-butoxycarbonyl)-[1,1′-biphenyl]-4-yl)methyl)-2,3-dimethyl-1H-indole-5-carboxylic acid. ESI-MS (m/z): 551 [M+H]+.
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([B:6]2[O:14][C:11]([CH3:13])([CH3:12])[C:8]([CH3:10])([CH3:9])[O:7]2)[CH:3]=[N:2]1.[CH2:15]([N:17]([CH2:20]C)[CH2:18]C)[CH3:16]>>[CH3:18][N:17]([CH3:20])[CH2:15][CH2:16][N:2]1[CH:3]=[C:4]([B:6]2[O:7][C:8]([CH3:9])([CH3:10])[C:11]([CH3:13])([CH3:12])[O:14]2)[CH:5]=[N:1]1
Reactant: CCN(CC)CC
Reactant: CC1(C)OB(c2cn[nH]c2)OC1(C)C
Product: CN(C)CCn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Temperature: 90 °C

Procedure:
The title compound was prepared from pyrazole-4-boronic acid pinacol ester and 2-chloro-N,N-(dimethyl)ethylamine hydrochloride according to Method AC (heating to 90° C. for 6 days before addition of further 2-chloro-N,N-(dimethyl)ethylamine hydrochloride and triethylamine, then heating to 90° C. for a further 3 days) and was isolated as a brown oil (43%). LCMS (ES+) 266 (M+H)+, RT 1.73 minutes (Method 1).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8]([CH2:12][O:13][C:14]3[CH:29]=[CH:28][C:17]4[O:18][CH2:19][C:20]5[CH:27]=[CH:26][CH:25]=[CH:24][C:21]=5[CH:22](O)[C:16]=4[CH:15]=3)=[N:9]2)=[CH:4][C:3]=1[S:30][CH2:31][CH3:32].[SH:33][CH2:34][CH2:35][C:36]([OH:38])=[O:37]>>[C:36]([CH2:35][CH2:34][S:33][CH:22]1[C:21]2[CH:24]=[CH:25][CH:26]=[CH:27][C:20]=2[CH2:19][O:18][C:17]2[CH:28]=[CH:29][C:14]([O:13][CH2:12][C:8]3[CH:7]=[CH:6][C:5]4[C:10](=[CH:11][C:2]([Cl:1])=[C:3]([S:30][CH2:31][CH3:32])[CH:4]=4)[N:9]=3)=[CH:15][C:16]1=2)([OH:38])=[O:37]
Reactant: CCSc1cc2ccc(COc3ccc4c(c3)C(O)c3ccccc3CO4)nc2cc1Cl
Reactant: O=C(O)CCS
Product: CCSc1cc2ccc(COc3ccc4c(c3)C(SCCC(=O)O)c3ccccc3CO4)nc2cc1Cl

Procedure:
2-(7-Chloro-6-ethylthioquinolin-2-yl)methoxy-11-hydroxy-6,11-dihydrodibenz[b,e]oxepine and 3-mercaptopropionic acid were used and reacted in the same manner as in Example 1 to obtain the title compound.
Reaction SMILES: [C:1]([C:4]1[CH:8]=[C:7]([C:9]([O:11][CH3:12])=[O:10])[NH:6][N:5]=1)(=[O:3])[CH3:2].[Cl:13][O-].[Na+].O>C(O)(=O)C>[C:1]([C:4]1[C:8]([Cl:13])=[C:7]([C:9]([O:11][CH3:12])=[O:10])[NH:6][N:5]=1)(=[O:3])[CH3:2]
Reactant: COC(=O)c1cc(C(C)=O)n[nH]1
Reactant: [O-]Cl
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: COC(=O)c1[nH]nc(C(C)=O)c1Cl
Temperature: 25 °C
Yield: 23 %

Procedure:
Into a flask containing methyl 3-acetyl-1H-pyrazole-5-carboxylate (4.0 g, 0.0238 mol) in acetic acid (60 ml), 5% sodium hypochlorite (284 ml, 0.190 mol) was added dropwise at 10-12° C. The mixture was stirred at RT over three nights adding more 5% sodium hypochlorite (177 ml, 0.119 mol in total) during the second and third day. Water was added to the reaction mixture and the product was extracted with ethyl acetate. Organic layer was dried with anhydrous Na2SO4 and concentrated. The crude product was recrystallized twice from n-hexane. Yield 23%. LC-MS: [M+1]=203.5.
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH:8]=[O:9])=[CH:6][CH:5]=[C:4]([C:10]2[CH:15]=[CH:14][C:13]([C:16]([F:19])([F:18])[F:17])=[CH:12][CH:11]=2)[N:3]=1.[CH3:20][Mg]Cl>C1COCC1>[CH3:1][C:2]1[C:7]([CH:8]([OH:9])[CH3:20])=[CH:6][CH:5]=[C:4]([C:10]2[CH:15]=[CH:14][C:13]([C:16]([F:17])([F:19])[F:18])=[CH:12][CH:11]=2)[N:3]=1
Reactant: Cc1nc(-c2ccc(C(F)(F)F)cc2)ccc1C=O
Reactant: C[Mg]Cl
Solvent: C1CCOC1
Product: Cc1nc(-c2ccc(C(F)(F)F)cc2)ccc1C(C)O

Procedure:
0.470 g (1.77 mmol) of the above prepared 2-methyl-6-(4-trifluoromethyl-phenyl)-pyridine-3-carbaldehyde was dissolved in 9 ml of abs. THF and treated at −10° C. with 0.89 ml of 3M methyl magnesium chloride solution (in THF). After 15 Min., the reaction mixture was carefully poured onto crashed ice/NH4Cl, extracted twice with AcOEt, washed with water and brine, dried over sodium sulfate, and evaporated to dryness to leave 0.508 g of the title product, pure according to NMR.
Reaction SMILES: Cl.[OH:2][C@@H:3]([CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])[CH:4]=[CH:5][CH:6]1[CH:10]=[CH:9][C:8](=[O:11])[CH:7]1[CH2:12][CH:13]=[CH:14][CH2:15][CH2:16][CH2:17][C:18]([OH:20])=[O:19]>C(O)C>[OH:2][C@@H:3]([CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])[CH:4]=[CH:5][CH:6]1[CH2:10][CH2:9][C:8](=[O:11])[CH:7]1[CH2:12][CH:13]=[CH:14][CH2:15][CH2:16][CH2:17][C:18]([OH:20])=[O:19]
Reactant: CCCCC[C@H](O)C=CC1C=CC(=O)C1CC=CCCCC(=O)O
Agent: Cl
Solvent: CCO
Product: CCCCC[C@H](O)C=CC1CCC(=O)C1CC=CCCCC(=O)O
Reaction time: 25 h

Procedure:
After 25 hours of growth, the pH of the flasks is adjusted to 6.7 with 5 N HCl. Forty mg. of 7-(2-[(3S)-3-hydroxy-1-octenyl]-5-oxo-3-cyclopenten-1-yl)-5-heptenoic acid diluted in 2 ml. of ethanol is added to each one liter flask, and 20 mg. in one ml. of ethanol is added to the single 500 ml. flask. The flasks are put under N2 and incubated as above. Following 22.5 hours of shaking, the flasks are harvested. The mixture is filtered and the filtrate acidified with acetic acid and extracted with ether. After washing and drying, the filtrate is evaporated and the resulting residue chromatographed on silica. Elution with 40% ethyl acetate in hexane affords 0.42 g. of the title product. I.R. Analysis: λmaxfilm 3.0 (shoulder), 3.4, 5.7, 7.05, 8.1, 8.6, 10.3μ .
Reaction SMILES: C(OC1C=CC(C[O:11][NH:12][C:13]([CH:15]2[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[C:18](=[O:25])[N:17]([CH:26]3[CH2:31][CH2:30][CH2:29][CH2:28][CH:27]3[NH:32][S:33]([CH3:36])(=[O:35])=[O:34])[CH:16]2[C:37]2[CH:42]=[CH:41][C:40]([Cl:43])=[CH:39][C:38]=2[Cl:44])=[O:14])=CC=1)(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[Cl:44][C:38]1[CH:39]=[C:40]([Cl:43])[CH:41]=[CH:42][C:37]=1[CH:16]1[CH:15]([C:13]([NH:12][OH:11])=[O:14])[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[C:18](=[O:25])[N:17]1[CH:26]1[CH2:31][CH2:30][CH2:29][CH2:28][CH:27]1[NH:32][S:33]([CH3:36])(=[O:34])=[O:35]
Reactant: CC(C)(C)Oc1ccc(CONC(=O)C2c3ccccc3C(=O)N(C3CCCCC3NS(C)(=O)=O)C2c2ccc(Cl)cc2Cl)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CS(=O)(=O)NC1CCCCC1N1C(=O)c2ccccc2C(C(=O)NO)C1c1ccc(Cl)cc1Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 73.7 %

Procedure:
To a solution of 644 mg of (3RS,4RS)—N-[(4-tert-butoxybenzyl)oxy]-3-(2,4-dichlorophenyl)-2-{(1SR,2SR)-2-[(mesyl)amino]cyclohexyl}-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxamide in 8.4 ml of dichloromethane was added 0.94 ml of trifluoroacetic acid under ice-cooling, followed by stirring at room temperature for 1 hour. The solution was concentrated under reduced pressure and then recrystallized from ethyl acetate to obtain 363 mg of (3RS,4RS)-3-(2,4-dichlorophenyl)-N-hydroxy-2-{(1SR,2SR)-2-[(mesyl)amino]cyclohexyl}-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxamide as a colorless crystal.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH:3]=1.[F:13][C:14]1[CH:15]=[C:16]([OH:23])[CH:17]=[CH:18][C:19]=1[N+:20]([O-:22])=[O:21].ClC1C=CC=CC=1.C(=O)([O-])O.[Na+]>C(OCC)(=O)C>[F:13][C:14]1[CH:15]=[C:16]([CH:17]=[CH:18][C:19]=1[N+:20]([O-:22])=[O:21])[O:23][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH:3]=1
Reactant: O=[N+]([O-])c1ccc(O)cc1F
Reactant: CCOC(=O)c1cc(Cl)ccn1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Clc1ccccc1
Solvent: CCOC(C)=O
Product: CCOC(=O)c1cc(Oc2ccc([N+](=O)[O-])c(F)c2)ccn1
Temperature: 120 °C
Reaction time: 4 h
Yield: 40.3 %

Procedure:
To ethyl 4-chloropyridine-2-carboxylate (19.4 g) were added 3-fluoro-4-nitrophenol (24.7 g) and chlorobenzene (7.0 ml), followed by heating and stirring under a nitrogen atmosphere at 120° C. for 4 hr. The reaction mixture was allowed to cool down to room temperature. Ethyl acetate (400 ml) and a saturated aqueous solution of sodium hydrogencarbonate (400 ml) were added thereto, followed by stirring at room temperature for 27 hr. Stirring was stopped and the aqueous layer was separated. To the organic layer was added again a saturated aqueous solution of sodium hydrogencarbonate, followed by stirring at room temperature for 2 days. Stirring was stopped and the aqueous layer was separated. The aqueous layer was extracted with ethyl acetate (300 ml). The organic layers were combined and washed with brine. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent; heptane:ethyl acetate=2:1, 1:1, then ethyl acetate). Fractions containing the target compound were concentrated to provide the titled compound as a brown oil (12.9 g, 40.2%).
Reaction SMILES: ClC1C(OCC2(C(F)(F)F)CCCCC2)=C[C:5](F)=[C:6]([CH:14]=1)C(OC(C)(C)C)=O.[CH:28]12[CH2:37][CH:32]3[CH2:33][CH:34]([CH2:36][CH:30]([CH2:31]3)[CH:29]1[CH2:38][O:39][C:40]1[C:52](Cl)=[CH:51][C:43]([C:44]([O:46][C:47]([CH3:50])([CH3:49])[CH3:48])=[O:45])=[C:42]([F:54])[CH:41]=1)[CH2:35]2>>[CH:28]12[CH2:37][CH:32]3[CH2:33][CH:34]([CH2:36][CH:30]([CH2:31]3)[CH:29]1[CH2:38][O:39][C:40]1[C:52]([CH:14]3[CH2:6][CH2:5]3)=[CH:51][C:43]([C:44]([O:46][C:47]([CH3:50])([CH3:49])[CH3:48])=[O:45])=[C:42]([F:54])[CH:41]=1)[CH2:35]2
Reactant: CC(C)(C)OC(=O)c1cc(Cl)c(OCC2(C(F)(F)F)CCCCC2)cc1F
Reactant: CC(C)(C)OC(=O)c1cc(Cl)c(OCC2C3CC4CC(C3)CC2C4)cc1F
Product: CC(C)(C)OC(=O)c1cc(C2CC2)c(OCC2C3CC4CC(C3)CC2C4)cc1F

Procedure:
Following the procedure as described in Example 158 step 3, and making variations as required to replace tert-butyl 5-chloro-2-fluoro-4-((1-(trifluoromethyl)-cyclohexyl)methoxy)benzoate with tert-butyl 4-(adamantan-2-ylmethoxy)-5-chloro-2-fluorobenzoate, the title compound was obtained as colorless oil (1.99 g, 92%): MS (E+) m/z 401.3 (M+1).
Reaction SMILES: [CH2:1]([NH:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([Br:11])[CH:6]=1)[CH3:2].[Cl:12][CH:13]=[CH:14][CH2:15]Cl.C(=O)([O-])[O-].[K+].[K+].C(OCC)(=O)C>CN(C)C=O>[Cl:12]/[CH:13]=[CH:14]/[CH2:15][N:3]([CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([Br:11])[CH:6]=1)[CH2:1][CH3:2]
Reactant: ClC=CCCl
Reactant: CCNCc1cccc(Br)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCN(C/C=C/Cl)Cc1cccc(Br)c1
Temperature: 60 °C
Reaction time: 8 h
Yield: 64 %

Procedure:
To a solution of 4.28 g (20 mmol) of N-ethyl-3-bromobenzylamine in 30 ml of N,N-dimethylformamide were added 2.44 g (22 mmol) of 1,3-dichloropropene and 1.70 g (12 mmol) of ground potassium carbonate under ice cooling. The mixture was stirred for 8 hours at 60° C., poured into 40 ml of ethyl acetate, washed with 40 ml×2 of water and 40 ml of saturated sodium chloride aqueous solution, dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The residue was subjected to silica gel chromatography (n-hexane→n-hexane/ethyl acetate=9/1). The desired fractions were put together and concentrated under reduced pressure to obtain 3.70 g (yield: 64%) of the above identified compound as an oil.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[N:7]1[C:15]2[C:10](=[CH:11][C:12]([C:16]3[N:20]=[CH:19][N:18]([C:21]([C:34]4[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=4)([C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)[C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[N:17]=3)=[CH:13][CH:14]=2)[C:9]([C:40]2[CH:41]=[C:42]([NH2:46])[CH:43]=[CH:44][CH:45]=2)=[N:8]1.[NH:47]1[C:55]2[C:50](=[CH:51][CH:52]=[CH:53][CH:54]=2)[C:49]([C:56](=[O:60])[C:57](Cl)=[O:58])=[CH:48]1.C(N(CC)CC)C>O1CCCC1>[NH:47]1[C:55]2[C:50](=[CH:51][CH:52]=[CH:53][CH:54]=2)[C:49]([C:56](=[O:60])[C:57]([NH:46][C:42]2[CH:43]=[CH:44][CH:45]=[C:40]([C:9]3[C:10]4[C:15](=[CH:14][CH:13]=[C:12]([C:16]5[N:20]=[CH:19][N:18]([C:21]([C:28]6[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=6)([C:22]6[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=6)[C:34]6[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=6)[N:17]=5)[CH:11]=4)[N:7]([CH:2]4[CH2:3][CH2:4][CH2:5][CH2:6][O:1]4)[N:8]=3)[CH:41]=2)=[O:58])=[CH:48]1
Reactant: O=C(Cl)C(=O)c1c[nH]c2ccccc12
Reactant: Nc1cccc(-c2nn(C3CCCCO3)c3ccc(-c4ncn(C(c5ccccc5)(c5ccccc5)c5ccccc5)n4)cc23)c1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=C(Nc1cccc(-c2nn(C3CCCCO3)c3ccc(-c4ncn(C(c5ccccc5)(c5ccccc5)c5ccccc5)n4)cc23)c1)C(=O)c1c[nH]c2ccccc12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 3-{1-perhydro-2H-pyran-2-yl-5-[1-(triphenylmethyl)(1,2,4-triazol-3-yl)]-1H-indazol-3-yl}phenylamine (0.150 g, 0.248 mmol) in 2.5 mL of tetrahydrofuran was added 2-indol-3-yl-2-oxoacetyl chloride (0.103 g, 0.496 mmol), followed by triethyl amine (0.173 mL, 1.24 mmol). The reaction was stirred at room temperature overnight. The reaction mixture was then partitioned between ethyl acetate and water. The crude material that was obtained from evaporation of the extracts was not purified further. (Yield not calculated) ES-MS (m/z) 774 [M+H]+.
Reaction SMILES: [C:1]([C:6](=[CH:12][NH:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[C:20](=[O:22])[CH3:21])[C:7]([O:9]CC)=O)(=[O:5])[CH2:2][CH2:3][CH3:4].C1(OC2C=CC=CC=2)C=CC=CC=1>CCOCC>[C:1]([C:6]1[C:7](=[O:9])[C:19]2[C:14](=[C:15]([C:20](=[O:22])[CH3:21])[CH:16]=[CH:17][CH:18]=2)[NH:13][CH:12]=1)(=[O:5])[CH2:2][CH2:3][CH3:4]
Reactant: CCCC(=O)C(=CNc1ccccc1C(C)=O)C(=O)OCC
Solvent: c1ccc(Oc2ccccc2)cc1
Solvent: CCOCC
Product: CCCC(=O)c1c[nH]c2c(C(C)=O)cccc2c1=O
Yield: 70.1 %

Procedure:
Ethyl 2-butyryl-3-(2-acetylphenylamino)acrylate (14.8 g, 48.8 mmol) was added to boiling diphenyl ether (50 ml) and heated at reflux for 3.5 hours. After cooling, the solution was poured into ether, and the solid filtered off and washed with ether to obtain 3-butyryl-8-acetyl-4(1H)-quinolone (8.8 g), contaminated with some diphenyl ether. This material was used without further purification.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([O:17][C@@H:18]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[C@H:19]([NH2:21])[CH3:20])=[CH:14][CH:15]=3)[CH:10]=[N:9]2)=[CH:4][CH:3]=1.Cl[C:29](=[O:34])[C:30]([O:32][CH3:33])=[O:31]>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([O:17][C@H:18]([C:22]4[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=4)[C@@H:19]([NH:21][C:29]([C:30]([O:32][CH3:33])=[O:31])=[O:34])[CH3:20])=[CH:14][CH:15]=3)[CH:10]=[N:9]2)=[CH:6][CH:7]=1
Reactant: COC(=O)C(=O)Cl
Reactant: C[C@@H](N)[C@@H](Oc1ccc2c(cnn2-c2ccc(F)cc2)c1)c1ccccc1
Product: COC(=O)C(=O)N[C@@H](C)[C@H](Oc1ccc2c(cnn2-c2ccc(F)cc2)c1)c1ccccc1

Procedure:
Prepared as described in Example 1 using (1S,2R)-1-{[1-(4-fluorophenyl)-1H-indazol-5-yl]oxy}-1-phenylpropan-2-amine (1a, 18 mg, 50 μmol) and methyl cloro(oxo)acetate (18 mg, 150 μmol). Yield 18 mg (82%).
Reaction SMILES: [O:1]=[C:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[S:4][N:3]1[C:11]1[CH:16]=[CH:15][C:14]([S:17]([NH2:20])(=[O:19])=[O:18])=[CH:13][CH:12]=1.[C:21]([O:30][CH3:31])(=[O:29])[C:22]1[C:23](=[CH:25][CH:26]=[CH:27][CH:28]=1)[SH:24]>CO.O1CCCC1>[S:17]([C:14]1[CH:15]=[CH:16][C:11]([NH:3][C:2]([C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[S:4][S:24][C:23]2[CH:25]=[CH:26][CH:27]=[CH:28][C:22]=2[C:21]([O:30][CH3:31])=[O:29])=[O:1])=[CH:12][CH:13]=1)(=[O:19])(=[O:18])[NH2:20]
Reactant: NS(=O)(=O)c1ccc(-n2sc3ccccc3c2=O)cc1
Reactant: COC(=O)c1ccccc1S
Solvent: CO
Solvent: C1CCOC1
Product: COC(=O)c1ccccc1SSc1ccccc1C(=O)Nc1ccc(S(N)(=O)=O)cc1
Yield: 92.7 %

Procedure:
This compound was prepared according to the method of Example 132 using a suspension of 0.46 g (1.5 mmol) of 4-(3-oxo-3H-benzo[d]isothiazol-2-yl)benzene sulfonamide in a mixture of 15 mL of methanol and 15 mL of tetrahydrofuran, and 0.27 g (1.6 mmol) of methyl thiosalicylate. The product was triturated with ether, filtered, washed with ether and dried in vacuo to give 0.66 g of the title compound, mp 288-290° C.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].O[C:13]1[CH:18]=CC(C(C2C=CC(O)=CC=2)(C)C)=C[CH:14]=1.B(F)(F)F.CCOCC>C1(C)C=CC=CC=1>[OH:11][C:8]1[CH:7]=[C:6]2[C:5](=[CH:10][CH:9]=1)[C:1]([CH3:4])([CH3:2])[CH2:3][C:13]2([CH3:18])[CH3:14]
Reactant: CC(C)(c1ccc(O)cc1)c1ccc(O)cc1
Reactant: CC(C)(C)c1ccc(O)cc1
Agent: FB(F)F
Solvent: Cc1ccccc1
Solvent: CCOCC
Product: CC1(C)CC(C)(C)c2cc(O)ccc21
Yield: 37.2 %

Procedure:
172 g (1.15 mol) of 4-tert.-butylphenol, 57.5 g (0.25 mol) of 2,2-bis-(4- hydroxyphenyl)-propane and 5 g of boron trifluoride etherate are stirred in an autoclave for 6 hours at around 150° C. The reaction mixture is then diluted with 400 ml of toluene and the catalyst washed out with 900 ml of water used in several portions. The solvent is then distilled off. 17.6 g (0.093 mol) of 5-hydroxy-1,1,3,3-tetramethyl indane were isolated from the 216.7 g reaction product by fractional distillation.
Reaction SMILES: C(O)(C(F)(F)F)=O.[C:8]([C:10]1[CH:15]=[CH:14][C:13]([C:16]2[CH:17]=[N:18][N:19]([C:22]3[CH:30]=[CH:29][C:25]([C:26](O)=[O:27])=[CH:24][N:23]=3)[C:20]=2[OH:21])=[C:12]([CH3:31])[CH:11]=1)#[N:9].[CH3:32][N:33]1[CH2:38][CH2:37][CH:36]([NH2:39])[CH2:35][CH2:34]1>>[C:8]([C:10]1[CH:15]=[CH:14][C:13]([C:16]2[CH:17]=[N:18][N:19]([C:22]3[CH:30]=[CH:29][C:25]([C:26]([NH:39][CH:36]4[CH2:37][CH2:38][N:33]([CH3:32])[CH2:34][CH2:35]4)=[O:27])=[CH:24][N:23]=3)[C:20]=2[OH:21])=[C:12]([CH3:31])[CH:11]=1)#[N:9]
Reactant: CN1CCC(N)CC1
Reactant: Cc1cc(C#N)ccc1-c1cnn(-c2ccc(C(=O)O)cn2)c1O
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc(C#N)ccc1-c1cnn(-c2ccc(C(=O)NC3CCN(C)CC3)cn2)c1O

Procedure:
The title compound, as a TFA salt, was prepared in a manner similar to Example 74 using 6-(4-(4-cyano-2-methylphenyl)-5-hydroxy-1H-pyrazol-1-yl)nicotinic acid and 1-methylpiperidin-4-amine 1H NMR (400 MHz, DMSO-d6) δ ppm 1.71-1.85 (m, 2 H) 1.92-2.14 (m, 2 H) 2.38-2.47 (m, 3 H) 2.70-2.89 (m, 3 H) 3.06-3.18 (m, 2 H) 3.24-3.40 (m, 1H) 3.49 (d, J=11.87 Hz, 1 H) 3.98-4.24 (m, 1 H) 7.67 (d, J=7.58 Hz, 1 H) 7.71-7.87 (m, 2H) 8.21 (d, J=12.13 Hz, 1 H) 8.35-8.59 (m, 2 H) 8.72 (d, J=6.32 Hz, 1 H) 8.88-8.98 (m, 1H) 9.46 (br. s., 1 H) 12.72-13.42 (m, 1 H). MS m/z [M+H]+ 417.2.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]([CH3:27])([CH3:26])[CH2:10][C:11]([NH:13][C@@H:14]1[CH2:20][CH2:19][C:18]2[CH:21]=[CH:22][CH:23]=[CH:24][C:17]=2[NH:16][C:15]1=[O:25])=[O:12])=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl[CH2:29][C:30]1[CH:35]=[CH:34][C:33]([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)=[CH:32][CH:31]=1>>[C:1]([O:5][C:6]([NH:8][C:9]([CH3:27])([CH3:26])[CH2:10][C:11]([NH:13][C@@H:14]1[CH2:20][CH2:19][C:18]2[CH:21]=[CH:22][CH:23]=[CH:24][C:17]=2[N:16]([CH2:29][C:30]2[CH:35]=[CH:34][C:33]([C:36]3[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=3)=[CH:32][CH:31]=2)[C:15]1=[O:25])=[O:12])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(CC(=O)N[C@@H]1CCc2ccccc2NC1=O)NC(=O)OC(C)(C)C
Reactant: ClCc1ccc(-c2ccccc2)cc1
Product: CC(C)(CC(=O)N[C@@H]1CCc2ccccc2N(Cc2ccc(-c3ccccc3)cc2)C1=O)NC(=O)OC(C)(C)C

Procedure:
Prepared from the intermediate obtained in Step A and 4-chloromethylbiphenyl by the procedure described in Example 1, Step K. FAB-MS: calculated for C33H39N3O4 541; found 542 (M+H,31%).