Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([Li])CCC.Br[C:7]1[CH:11]=[CH:10][S:9][CH:8]=1.[S:12]1[CH:16]=[CH:15][C:14]([CH:17]=[O:18])=[CH:13]1.[Cl-].[NH4+]>C1COCC1>[S:9]1[CH:10]=[CH:11][C:7]([CH:17]([C:14]2[CH:15]=[CH:16][S:12][CH:13]=2)[OH:18])=[CH:8]1
Reactant: O=Cc1ccsc1
Reactant: Brc1ccsc1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Product: OC(c1ccsc1)c1ccsc1
Reaction time: 0.5 h
Yield: 98.8 %

Procedure:
To cooled (-78° C.) THF (100 ml) was added under nitrogen, n-butyllithium (2.5M, 40 ml) to the above mixture was added N-methyl-N-methoxy-urethane (6.28 g, 0.047 mol) in 5 ml of THF over a 0.5 h period and the mixture was allowed to warm to room temperature. The mixture was quenched with saturated ammonium chloride solution and the aqueous layer was extracted with ether. The combined organic layer was dried over magnesium sulfate, concentrated in vacuo, and the oil residue was crystallized from methanol to afford 1.465 g (16%) of 1,1-di-(3-thienyl)-ketone, m.p. 78°-80° C. Alternatively, 1,1-di-(3-thienyl) ketene was prepared as follows: To 100 ml of THF cooled -78° C. under nitrogen was added 2.5M n-butyllithium (36 ml ), and 14.67 g (0.09 mol) of 3-bromthiophene was added and the resulting mixture was stirred for 30 min. To the above mixture was added 3-thiophenecarboxaldehyde (10 g, 0.089 mol) in 10 ml of THF and the mixture was stirred allowing it to reach room temperature. Saturated ammonium chloride solution was added to the reaction mixture, the aqueous layer was extracted with ether, and the combined organic layer was concentrated in vacuo to yield 17.26 g (98.9%) of 1,1-di(3-thienyl)-methanol, as an oil.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[N:6][CH:7]=[CH:8][CH:9]=1)(=[O:3])[CH3:2].C(O[CH:14](OCCC)[N:15]([CH3:17])[CH3:16])CC>>[CH3:14][N:15]([CH3:17])[CH:16]=[CH:2][C:1]([C:4]1[CH:5]=[N:6][CH:7]=[CH:8][CH:9]=1)=[O:3]
Reactant: CC(=O)c1cccnc1
Reactant: CCCOC(OCCC)N(C)C
Product: CN(C)C=CC(=O)c1cccnc1
Temperature: 100 °C

Procedure:
A mixture of 25 g of 3-acetylpyridine and 35 ml of N,N-dimethylformamide dipropylacetal was heated at 100° C. for 6 hours. The mixture was concentrated in vacuo and the residue crystallized, giving 3-dimethylamino-1-(3-pyridinyl)-2-propen-1-one.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1/[CH:13]=[CH:14]/[CH:15]([CH2:28][C:29]1[CH:34]=[CH:33][C:32]([C:35]#[N:36])=[CH:31][CH:30]=1)[CH2:16][CH2:17][C:18]1[CH:27]=[CH:26][C:21]([C:22]([O:24][CH3:25])=[O:23])=[CH:20][CH:19]=1.[F:37][C:38]1[CH:43]=[CH:42][C:41]([OH:44])=[CH:40][CH:39]=1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[C:35]([C:32]1[CH:33]=[CH:34][C:29]([CH2:28][CH:15](/[CH:14]=[CH:13]/[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[O:6][CH2:5][CH2:4][CH2:3][CH2:2][O:44][C:41]2[CH:42]=[CH:43][C:38]([F:37])=[CH:39][CH:40]=2)[CH2:16][CH2:17][C:18]2[CH:27]=[CH:26][C:21]([C:22]([O:24][CH3:25])=[O:23])=[CH:20][CH:19]=2)=[CH:30][CH:31]=1)#[N:36]
Reactant: COC(=O)c1ccc(CCC(/C=C/c2ccccc2OCCCCBr)Cc2ccc(C#N)cc2)cc1
Reactant: Oc1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COC(=O)c1ccc(CCC(/C=C/c2ccccc2OCCCCOc2ccc(F)cc2)Cc2ccc(C#N)cc2)cc1

Procedure:
A solution of 392 mg (0.72 mmol) of methyl 4-[(4E)-5-[2-(4-bromobutoxy)phenyl]-3-(4-cyanobenzyl)pent-4-en-1-yl]benzoate in 10 ml of dry acetonitrile is mixed with 120 mg (1.08 mmol) of 4-fluorophenol and 148 mg (1.08 mmol) of anhydrous potassium carbonate and then heated under reflux for 12 h. The mixture is subsequently filtered, and the filtrate is evaporated to dryness. 445 mg (0.71 mmol, purity 93%, 99% of theory) of a yellowish oil are isolated.
Reaction SMILES: C([O:8][C@H:9]1[C@H:15]([O:16]CC2C=CC=CC=2)[C@@H:14]([O:24]CC2C=CC=CC=2)[C@:13]2([C:33]3[CH:38]=[CH:37][C:36]([Cl:39])=[C:35]([CH2:40][C:41]4[CH:46]=[CH:45][C:44]([O:47][C:48]([F:51])([F:50])[F:49])=[CH:43][CH:42]=4)[CH:34]=3)[O:32][C@@:10]1([CH2:52][OH:53])[CH2:11][O:12]2)C1C=CC=CC=1.ClC1C=CC=CC=1Cl>[Pd]>[Cl:39][C:36]1[CH:37]=[CH:38][C:33]([C@@:13]23[O:32][C@@:10]([CH2:52][OH:53])([CH2:11][O:12]2)[C@@H:9]([OH:8])[C@H:15]([OH:16])[C@H:14]3[OH:24])=[CH:34][C:35]=1[CH2:40][C:41]1[CH:46]=[CH:45][C:44]([O:47][C:48]([F:50])([F:49])[F:51])=[CH:43][CH:42]=1
Reactant: OC[C@@]12CO[C@@](c3ccc(Cl)c(Cc4ccc(OC(F)(F)F)cc4)c3)(O1)[C@H](OCc1ccccc1)[C@@H](OCc1ccccc1)[C@@H]2OCc1ccccc1
Agent: [Pd]
Solvent: Clc1ccccc1Cl
Product: OC[C@@]12CO[C@@](c3ccc(Cl)c(Cc4ccc(OC(F)(F)F)cc4)c3)(O1)[C@H](O)[C@@H](O)[C@@H]2O
Reaction time: 1 h
Yield: 86 %

Procedure:
[(1S,2S,3S,4R,5S)-2,3,4-tribenzyloxy-5-[4-chloro-3-[[4-(trifluoromethoxy)phenyl]methyl]phenyl]-6,8-dioxabicyclo[3.2.1]octan-1-yl]methanol 6r (150 mg, 0.20 mmol) was dissolved in 10 mL of mixed solution (THF and MeOH, v:v=1:1), followed by addition of o-dichlorobenzene (0.23 mL, 2 mmol) and Palladium/carbon (60 mg, 10%). The mixture was exchanged with H2 three times and stirred for 1 hour. Thereafter, the reaction mixture was filtered. The filtrate was concentrated under reduced pressure and the resulting residue was purified by silica gel chromatography with elution system E to obtain the title compound (1S,2S,3S,4R,5S)-5-[4-chloro-3-[[4-(trifluoromethoxy)phenyl]methyl]phenyl]-1-(hydroxymethyl)-6,8-dioxabicyclo-[3.2.1]octane-2,3,4-triol 6 (82 mg, white solid), yield: 86.0%. MS m/z (ESI): 477.1 [M+1]; 1H NMR (400 MHz, CD3OD): δ 7.54 (d, 1H), 7.46-7.39 (m, 2H), 7.30 (d, 2H), 7.17 (d, 2H), 4.17 (d, 3H), 3.86 (d, 1H), 3.80 (d, 1H), 3.72-3.68 (m, 2H), 3.62 (dd, 1H), 3.58 (d, 1H).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:32]=[CH:33][CH:34]=1)[CH:7]=[C:8]([C:29]([CH3:31])=O)[C:9]([O:11][CH:12]1[CH2:15][N:14]([CH:16]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH2:13]1)=[O:10])([O-:3])=[O:2].Cl.[C:36]([CH2:39][C:40]([O:42][CH:43]([CH3:45])[CH3:44])=[O:41])(=[NH:38])[NH2:37].C[O-].[Na+]>C(O)(C)C>[NH2:38][C:36]1[NH:37][C:29]([CH3:31])=[C:8]([C:9]([O:11][CH:12]2[CH2:15][N:14]([CH:16]([C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)[C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=3)[CH2:13]2)=[O:10])[CH:7]([C:6]2[CH:32]=[CH:33][CH:34]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=2)[C:39]=1[C:40]([O:42][CH:43]([CH3:45])[CH3:44])=[O:41]
Reactant: CC(=O)C(=Cc1cccc([N+](=O)[O-])c1)C(=O)OC1CN(C(c2ccccc2)c2ccccc2)C1
Reactant: CC(C)OC(=O)CC(=N)N
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CC(C)O
Product: CC1=C(C(=O)OC2CN(C(c3ccccc3)c3ccccc3)C2)C(c2cccc([N+](=O)[O-])c2)C(C(=O)OC(C)C)=C(N)N1
Yield: 56.4 %

Procedure:
1.6 g (0.0035 mole) of 1-benzhydryl-3-azetidinyl 2-(3-nitrobenzylidene)acetoacetate (prepared as described in Preparation 15) and 0.63 g (0.0035 mole) of isopropyl amidinoacetate hydrochloride were dissolved in 40 ml of isopropanol. 0.19 g (0.0035 mole) of sodium methoxide was then added to the mixture, and the mixture was heated under reflux for 4 hours. At the end of this time, the mixture was cooled, and the insoluble material was filtered off. The solvent was then distilled off under reduced pressure, and the residue was dissolved in ethyl acetate. The resulting solution was washed with water and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography, using a 4:1 by volume mixture of toluene and ethyl acetate as eluent, to give 1.15 g (yield 56%) of the title compound as pale yellow crystals, melting at 104°-107° C.
Reaction SMILES: C([O:3][C:4](=[O:20])[C@@H:5]([O:18][CH3:19])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][CH2:15][CH2:16]Br)=[CH:9][CH:8]=1)C.[F:21][C:22]([F:38])([F:37])[O:23][C:24]1[CH:25]=[C:26]([C:30]2[CH:35]=[CH:34][C:33]([OH:36])=[CH:32][CH:31]=2)[CH:27]=[CH:28][CH:29]=1.[OH-].[Na+]>>[CH3:19][O:18][C@@H:5]([CH2:6][C:7]1[CH:8]=[CH:9][C:10]([O:13][CH2:14][CH2:15][CH2:16][O:36][C:33]2[CH:34]=[CH:35][C:30]([C:26]3[CH:27]=[CH:28][CH:29]=[C:24]([O:23][C:22]([F:21])([F:37])[F:38])[CH:25]=3)=[CH:31][CH:32]=2)=[CH:11][CH:12]=1)[C:4]([OH:3])=[O:20]
Reactant: Oc1ccc(-c2cccc(OC(F)(F)F)c2)cc1
Reactant: CCOC(=O)[C@H](Cc1ccc(OCCCBr)cc1)OC
Agent: [Na+]
Agent: [OH-]
Product: CO[C@@H](Cc1ccc(OCCCOc2ccc(-c3cccc(OC(F)(F)F)c3)cc2)cc1)C(=O)O

Procedure:
(2S)-3-[4-(3-Bromo-propoxy)-phenyl]-2-methoxy-propionic acid ethyl ester from Example 173, Step A was treated with 3′-Trifluoromethoxy-biphenyl-4-ol from Step A under the Standard Procedure J. The compound thus obtained was allowed to react under Standard hydrolysis procedure C (NaOH) to give the title compound. MS(ES) for C26H25F3O6 [M+Na]+: 513, [M+H]+: 491.
Reaction SMILES: [NH:1]1[CH:6]([CH2:7][OH:8])[CH2:5][CH2:4][CH2:3][CH:2]1[CH2:9][OH:10].I[CH2:12][C:13]#[N:14].CCN(CC)CC>CN(C=O)C>[OH:10][CH2:9][CH:2]1[CH2:3][CH2:4][CH2:5][CH:6]([CH2:7][OH:8])[N:1]1[CH2:12][C:13]#[N:14]
Reactant: N#CCI
Reactant: OCC1CCCC(CO)N1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: N#CCN1C(CO)CCCC1CO
Yield: 51.8 %

Procedure:
The method follows that of S5. 2,6-piperidinedimethanol (3.80 g, 26.21 mmol), iodoacetonitrile (5.24 g, 31.45 mmol), Et3N (4.38 mL, 31.45 mmol) and dry DMF (20 mL). Purification by flash chromatography using CH2Cl2/CH3OH (9:1) as eluent afforded the title compound as a straw-coloured oil (2.5 g, 53%). FAB MS, m/z(M+H)+ 185.
Reaction SMILES: [C:1]([C:9]1[C:10]([CH2:33]Br)=[N:11][C:12]2[C:17]([C:18]=1[C:19]1[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[C:21]([O:27][CH3:28])[CH:20]=1)=[CH:16][C:15]([O:29][CH3:30])=[C:14]([O:31][CH3:32])[CH:13]=2)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:35]([NH:37][CH2:38][CH3:39])[CH3:36]>ClCCl>[C:1]([C:9]1[C:10]([CH2:33][N:37]([CH2:38][CH3:39])[CH2:35][CH3:36])=[N:11][C:12]2[C:17]([C:18]=1[C:19]1[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[C:21]([O:27][CH3:28])[CH:20]=1)=[CH:16][C:15]([O:29][CH3:30])=[C:14]([O:31][CH3:32])[CH:13]=2)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCNCC
Reactant: COc1ccc(-c2c(C(=O)c3ccccc3)c(CBr)nc3cc(OC)c(OC)cc23)cc1OC
Solvent: ClCCl
Product: CCN(CC)Cc1nc2cc(OC)c(OC)cc2c(-c2ccc(OC)c(OC)c2)c1C(=O)c1ccccc1
Yield: 65.6 %

Procedure:
A mixture of 3-benzoyl-2-bromomethyl-4-(3,4-dimethoxyphenyl)-6,7-dimethoxyquinoline (1.5 g), diethylamine (1.05 g) and dichloromethane (40 ml) was stirred under reflux for 14 hours. The reaction mixture was washed with water, dried over magnesium sulfate, and the solvent was evaporated. The residue was subjected to column chromatography on silica gel. The fractions eluted with chloroform gave 3-benzoyl-2-(N,N-diethylaminomethyl)-4-(3,4-dimethoxyphenyl)-6,7-dimethoxyquinoline (0.97 g, 66%). This compound was recrystallized from ethyl acetate-hexane to give colorless prisms, mp. 150°-151° C.
Reaction SMILES: [O:1]=[C:2]1[CH2:7][CH2:6][C:5]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)([C:8]#[N:9])[CH2:4][CH2:3]1.[CH2:16](O)[CH2:17][OH:18].O>C1(C)C=CC=CC=1>[C:10]1([C:5]2([C:8]#[N:9])[CH2:4][CH2:3][C:2]3([O:18][CH2:17][CH2:16][O:1]3)[CH2:7][CH2:6]2)[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: N#CC1(c2ccccc2)CCC(=O)CC1
Reactant: OCCO
Solvent: O
Solvent: Cc1ccccc1
Product: N#CC1(c2ccccc2)CCC2(CC1)OCCO2
Reaction time: 3 h

Procedure:
The title compound of step 2 (43.3 g, 217 mmol) and ethylene glycol (27.4 g, 435 mmol) were boiled in toluol (430 mL) with the addition of p-toluol sulphonic acid (1.87 g, 10.9 mmol) at a water separator for 3 h with reflux. After the reaction had ended, the mixture was cooled, washed with NaHCO3 solution and saturated NaCl solution, dried with Na2SO4 and concentrated to low volume in a vacuum.
Reaction SMILES: [C:1]([O-])([O-])=O.[K+].[K+].[I:7][C:8]1[CH:9]=[C:10]2[C:14](=[CH:15][CH:16]=1)[N:13]([C:17]1[CH:25]=[CH:24][C:20]([C:21]([OH:23])=[O:22])=[CH:19][CH:18]=1)[N:12]=[CH:11]2.CI>CN(C=O)C>[CH3:1][O:22][C:21](=[O:23])[C:20]1[CH:19]=[CH:18][C:17]([N:13]2[C:14]3[C:10](=[CH:9][C:8]([I:7])=[CH:16][CH:15]=3)[CH:11]=[N:12]2)=[CH:25][CH:24]=1
Reactant: O=C([O-])[O-]
Reactant: O=C(O)c1ccc(-n2ncc3cc(I)ccc32)cc1
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Product: COC(=O)c1ccc(-n2ncc3cc(I)ccc32)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 76.8 %

Procedure:
K2CO3 (7.35 g, 53.2 mmol) is suspended in 110 mL DMF. 4-(5-iodoindazole-1-yl)-benzoic acid (17.6 g, 48.33 mmol), dissolved in 25 mL DMF, is added dropwise. The reaction mixture is stirred for 30 min at r.t. Subsequently CH3I (3.31 mL, 53.2 mmol) is added dropwise (temperature rises to 30° C.). The reaction mixture is stirred overnight at r.t. and then poured on ice water. It is three times extracted with ethyl acetate. The combined organic extracts are washed twice with water and brine. After drying over Na2SO4 and filtration the solvent is evaporated. The residue is purified by chromatography (silicagel, eluents: ethyl acetate/hexane) yielding 14.03 g (76.8%) of the title compound.
Reaction SMILES: [CH3:1][N:2]([CH3:32])[CH2:3][CH2:4][CH2:5][N:6]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:8]([C:15]2[C:16]([N:18]([CH3:31])C(=O)[C:20]=2C2C3C(=CC=CC=3)NC=2)=[O:17])=[CH:7]1.[CH3:33][OH:34]>[C].[Pd]>[CH3:32][N:2]([CH3:1])[CH2:3][CH2:4][CH2:5][N:6]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:8]([C:15]2([C:8]3[C:9]4[C:14](=[CH:13][CH:12]=[CH:11][CH:10]=4)[NH:6][CH:7]=3)[CH2:20][C:33](=[O:34])[N:18]([CH3:31])[C:16]2=[O:17])=[CH:7]1
Reactant: CO
Reactant: CN(C)CCCn1cc(C2=C(c3c[nH]c4ccccc34)C(=O)N(C)C2=O)c2ccccc21
Agent: [Pd]
Product: CN(C)CCCn1cc(C2(c3c[nH]c4ccccc34)CC(=O)N(C)C2=O)c2ccccc21
Temperature: 25 °C
Reaction time: 24 h
Yield: 81.5 %

Procedure:
To a solution of 2-[1-(3-dimethylaminopropyl)-1H-indol-3-yl]-3-(1H-indol-3-yl)-N-methylmaleimide (60 mg, 0.14 mmol) in MeOH (3 mL) was added a small amount of 10% palladium-carbon, and the whole was stirred at room temperature for 1 day under hydrogen atmosphere. The palladium-carbon was removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography over silica gel (dichloromethan:methanol=8:1) to obtain 3-[1-(3-dimethylaminopropyl)-1H-indol-3-yl]-3-(1H-indol-3-yl)-1-methyl-2,5-dioxopyrrolidine (49 mg, 81.5%) as pale red solids.
Reaction SMILES: [N:1]1([C:5]([C@@H:7]2[CH2:12][C@H:11]([N:13]([C:18]([C:20]3[N:24]([CH2:25][CH2:26][CH2:27][CH2:28][O:29][CH3:30])[C:23]4[CH:31]=[CH:32][CH:33]=[CH:34][C:22]=4[N:21]=3)=[O:19])[CH2:14][CH:15]([CH3:17])[CH3:16])[CH2:10][N:9](C(OC(C)(C)C)=O)[CH2:8]2)=[O:6])[CH2:4][CH2:3][CH2:2]1.C(O)(C(F)(F)F)=O>ClCCCl>[N:1]1([C:5]([C@H:7]2[CH2:8][NH:9][CH2:10][C@@H:11]([N:13]([CH2:14][CH:15]([CH3:17])[CH3:16])[C:18]([C:20]3[N:24]([CH2:25][CH2:26][CH2:27][CH2:28][O:29][CH3:30])[C:23]4[CH:31]=[CH:32][CH:33]=[CH:34][C:22]=4[N:21]=3)=[O:19])[CH2:12]2)=[O:6])[CH2:2][CH2:3][CH2:4]1
Reactant: COCCCCn1c(C(=O)N(CC(C)C)[C@H]2C[C@@H](C(=O)N3CCC3)CN(C(=O)OC(C)(C)C)C2)nc2ccccc21
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCCl
Product: COCCCCn1c(C(=O)N(CC(C)C)[C@@H]2CNC[C@H](C(=O)N3CCC3)C2)nc2ccccc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 52.7 %

Procedure:
To tert-butyl (3R,5S)-3-(azetidin-1-ylcarbonyl)-5-[{[1-(4-methoxybutyl)-1H-benzimidazol-2-yl]carbonyl}(2-methylpropyl)amino]piperidine-1-carboxylate (230 mg) in 1,2-dichloroethane (3 ml) was added TFA (3 ml) and the mixture was stirred at room temperature for 1 hr. The solvent was evaporated under reduced pressure, and the residue was dissolved in ethyl acetate-water, and neutralized with saturated aqueous sodium hydrogen carbonate. The organic layer was dried over anhydrous sodium sulfate and the solvent was evaporated under reduced pressure to give the object product (100 mg).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([OH:9])[CH:5]=[CH:6][C:7]=1[F:8].CC(C)([O-])C.[K+].Br[C:17]1[CH:18]=[CH:19][C:20]([C:23]([F:26])([F:25])[F:24])=[N:21][CH:22]=1>CC(N(C)C)=O.O>[F:8][C:7]1[CH:6]=[CH:5][C:4]([O:9][C:17]2[CH:22]=[N:21][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:19][CH:18]=2)=[CH:3][C:2]=1[NH2:1]
Reactant: FC(F)(F)c1ccc(Br)cn1
Reactant: Nc1cc(O)ccc1F
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Solvent: O
Product: Nc1cc(Oc2ccc(C(F)(F)F)nc2)ccc1F
Temperature: 75 °C
Yield: 26.8 %

Procedure:
In DMA (8 mL) was placed 3-amino-4-fluorophenol (281 mg, 2.21 mmol), potassium t-butoxide (248 mg, 2.21 mmol) and 5-bromo-2-(trifluoromethyl)pyridine (500 mg, 2.21 mmol). The mixture was warmed to 75° C. overnight, then cooled to RT and diluted with water (75 mL). The mixture was extracted with ethyl acetate (2×40 mL) and the combined organic phases washed with brine (40 mL), dried (Na2SO4), concentrated in vacuo and purified by column chromatography to yield 2-fluoro-5-(6-(trifluoromethyl)pyridin-3-yloxy)benzenamine (161 mg, 26% yield) as an oil which was used without further purification. MS (ESI) m/z: 273.0 (M+H+).
Reaction SMILES: [CH3:1][NH:2][C@H:3]([C:8]([NH:10][C@@H:11]1[C@H:18]2[C@H:14]([CH2:15][N:16]([CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([C:26]([F:29])([F:28])[F:27])[CH:21]=3)[CH2:17]2)[CH2:13][CH2:12]1)=[O:9])[CH2:4][CH:5]([CH3:7])[CH3:6].C(N(CC)C(C)C)(C)C.[CH3:39][S:40](Cl)(=[O:42])=[O:41]>ClCCl>[CH3:1][N:2]([S:40]([CH3:39])(=[O:42])=[O:41])[C@H:3]([C:8]([NH:10][C@@H:11]1[C@H:18]2[C@H:14]([CH2:15][N:16]([CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([C:26]([F:28])([F:27])[F:29])[CH:21]=3)[CH2:17]2)[CH2:13][CH2:12]1)=[O:9])[CH2:4][CH:5]([CH3:7])[CH3:6]
Reactant: CS(=O)(=O)Cl
Reactant: CN[C@@H](CC(C)C)C(=O)N[C@H]1CC[C@H]2CN(Cc3cccc(C(F)(F)F)c3)C[C@H]21
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)C[C@@H](C(=O)N[C@H]1CC[C@H]2CN(Cc3cccc(C(F)(F)F)c3)C[C@H]21)N(C)S(C)(=O)=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To N2-methyl-N1-{(3aS,4S,6aR)-2-[3-(trifluoromethyl)benzyl]octahydrocyclopenta[c]pyrrol-4-yl}-L-leucinamide from Example 164 (122 mg, 0.296 mmol) in dichloromethane (0.5 mL) was added N,N-diisopropylethylamine (78 μL, 0.445 mmol) followed by methanesulfonyl chloride (25.4 μL, 0.326 mmol), and the reaction mixture was stirred at room temperature overnight. The reaction was reduced in volume and loaded onto a silica gel cartridge (Analogix®, Burlington, Wis., RS-12). The title compound was eluted with a gradient of 0% to 5% methanol (2 N ammonia)/dichloromethane over 20 minutes: 1H NMR (500 MHz, pyridine-d5) δ ppm 8.59 (d, J=6.7, 1H), 7.73 (s, 1H), 7.66 (d, J=7.6, 1H), 7.62 (d, J=7.8, 1H), 7.51 (t, J=7.7, 1H), 4.78 (dd, J=6.2, 9.5, 1H), 4.41-4.33 (m, 1H), 3.67 (d, J=13.3, 1H), 3.16 (s, 3H), 3.15 (s, 3H), 2.90 (qd, J=3.3, 7.9, 1H), 2.75 (dd, J=3.3, 9.6, 1H), 2.53-2.44 (m, 1H), 2.38-2.29 (m, 3H), 1.89-1.70 (m, 4H), 1.70-1.58 (m, 3H), 1.36-1.26 (m, 1H), 0.83 (d, J=6.6, 3H), 0.81 (d, J=6.5, 3H); MS (ESI+) m/z 490 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[O:8][C:7](=[O:12])[CH:6]=[C:5]2[NH:13][CH:14]1[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]1.[CH3:20][C:21](=[CH:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[CH:22]=O>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[O:8][C:7](=[O:12])[CH:6]=[C:5]2[NH:13][CH:14]1[CH2:19][CH2:18][N:17]([CH2:20][C:21]([CH3:22])=[CH:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH2:16][CH2:15]1
Reactant: O=c1cc(NC2CCNCC2)c2cc(Cl)ccc2o1
Reactant: CC(C=O)=Cc1ccccc1
Product: CC(=Cc1ccccc1)CN1CCC(Nc2cc(=O)oc3ccc(Cl)cc23)CC1
Yield: 25.8 %

Procedure:
According to Procedure A above, 6-chloro-4-(piperidin-4-ylamino)-chromen-2-one and 2-methyl-3-phenyl-propenal (0.031 g, 0.216 mmol) were allowed to react to give the title compound (0.008 g, 25.8%, mono-TFA salt) as a off-white solid. 1H NMR (400 MHz, DMSO) δ ppm 8.35 (d, J=3, 1H), 7.66 (dd, J=3, 9, 1H), 7.32-7.47 (m, 6H), 6.76 (br s, 1H), 5.46 (s, 1H), 3.94-3.99 (m, 1H), 3.86 (d, J=3, 9, 1H), 3.53-3.60 (m, 2H), 3.05-3.20 (m, 2H), 2.18-2.28 (m, 2H), 2.05-2.15 (m, 1H), 2.01 (s, 3H), 1.82-1.91 (m, 2H); MS (ESI+Q1MS) m/z 409 [M]+
Reaction SMILES: [C:1]1([C:7]([CH3:12])([OH:11])[C:8]([OH:10])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.S(=O)(=O)(O)O.[CH2:18](O)[CH3:19]>CCOCC>[C:1]1([C:7]([CH3:12])([OH:11])[C:8]([O:10][CH2:18][CH3:19])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CC(O)(C(=O)O)c1ccccc1
Reactant: CCO
Agent: O=S(=O)(O)O
Solvent: CCOCC
Product: CCOC(=O)C(C)(O)c1ccccc1

Procedure:
(±)-Phenyllactic acid (4.96 g) and 1/2 ml concentrated sulfuric acid in 150 ml absolute ethanol is refluxed for 18 hours. Solvent is stripped, the residue is dissolved in ether, and extracted with saturated sodium bicarbonate solution. The ether is dried, filtered, and stripped to leave (±)-ethyl phenyllactate. NMR (CDCl3): δ1.3 (t, 3H), 3.0(d of d, 1H), 3.1 (d of d, 1H), 4.2 (q, 2H), 4.4 (d of d, 1H), 7.3 (m, 5H).
Reaction SMILES: C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[NH2:15][C:16]1([C:21]([OH:23])=[O:22])[CH2:20][CH2:19][CH2:18][CH2:17]1.[CH:24]([C:26]1[CH:31]=[CH:30][N:29]=[C:28]2[N:32]([C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40])[CH:33]=[C:34]([C:35]([O:37][CH3:38])=[O:36])[C:27]=12)=O>C(Cl)Cl>[C:42]([O:41][C:39]([N:32]1[C:28]2=[N:29][CH:30]=[CH:31][C:26]([CH2:24][NH:15][C:16]3([C:21]([OH:23])=[O:22])[CH2:20][CH2:19][CH2:18][CH2:17]3)=[C:27]2[C:34]([C:35]([O:37][CH3:38])=[O:36])=[CH:33]1)=[O:40])([CH3:45])([CH3:44])[CH3:43]
Reactant: NC1(C(=O)O)CCCC1
Reactant: COC(=O)c1cn(C(=O)OC(C)(C)C)c2nccc(C=O)c12
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: COC(=O)c1cn(C(=O)OC(C)(C)C)c2nccc(CNC3(C(=O)O)CCCC3)c12
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a 10 mL round bottom flask was added sodium triacetoxyborohydride (104 mg, 0.493 mmol) and 1-aminocyclopentanecarboxylic acid (42.4 mg, 0.329 mmol) in DCM (2 mL). The reaction mixture was stirred at room temperature for 30 min after which was added 1-tert-butyl 3-methyl 4-formyl-1H-pyrrolo[2,3-b]pyridine-1,3-dicarboxylate (50 mg, 0.164 mmol) in DCM (2 mL). The reaction was stirred at room temperature for 2 h and then quenched with MeOH (3 drops). The mixture was concentrated to afford the title compound, which was used in the next step without further purification. [M+H] calc'd for C21H27N3O6, 418; found, 418.3.
Reaction SMILES: [C:1]([O:4][C@H:5]1[C@H:10]2[CH2:11][C@H:7]([C@@H:8]([C:20]([O:22][CH3:23])=[O:21])[N:9]2[C@@H](C2C=CC=CC=2)C)[CH2:6]1)(=[O:3])[CH3:2].[H][H]>CO.[OH-].[OH-].[Pd+2]>[C:1]([O:4][C@H:5]1[C@H:10]2[CH2:11][C@H:7]([C@@H:8]([C:20]([O:22][CH3:23])=[O:21])[NH:9]2)[CH2:6]1)(=[O:3])[CH3:2]
Reactant: [H][H]
Reactant: COC(=O)[C@@H]1[C@H]2C[C@H]([C@H](OC(C)=O)C2)N1[C@H](C)c1ccccc1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Product: COC(=O)[C@H]1N[C@@H]2C[C@H]1C[C@H]2OC(C)=O

Procedure:
A solution of methyl (1R,3S,4S,6R)-6-acetyloxy-2-[(1R)-1-phenylethyl]-2-azabicyclo[2.2.1]heptane-3-carboxylate obtained in Example 42-4 (1.25 g) in methanol (20 mL) containing 20% Pd(OH)2 (250 mg) was stirred at room temperature for 17 hrs under 4 atm pressure with hydrogen.