Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1([CH2:5][CH2:6][OH:7])[CH2:4][CH2:3]1.N1C=CC=CC=1.[Si:14](OS(C(F)(F)F)(=O)=O)([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:16])[CH3:15]>C(Cl)Cl>[Br:1][C:2]1([CH2:5][CH2:6][O:7][Si:14]([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:16])[CH3:15])[CH2:4][CH2:3]1
Reactant: CC(C)(C)[Si](C)(C)OS(=O)(=O)C(F)(F)F
Reactant: OCCC1(Br)CC1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(C)(C)[Si](C)(C)OCCC1(Br)CC1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of the cyclopropyl alcohol (Step A) (1.303 g, 7.95 mmoles) in 30 ml anhydrous DCM was added anhydrous pyridine (1.2 ml, 1,1736 g, 14.8 mmoles), TBSOTf (2.7 ml, 3.1077 g, 11.76 mol) and the solution was stirred at room temperature for 16 h. It was extracted with CHCl3/brine and the organic fraction was dried with MgSO4. The solvent was reduced and the crude product purified using flash-column chromatography (CHCl3/hexanes 1:10, Rf=0.4). Yield: 0.796 g, 36%. 1H-NMR (500 MHz, CDCl3): δ=3.95-3.75 (t, 2H), 1.95-1.85 (t, 2H), 1.15-1.05 (m, 2H), 0.95-0.80 (m, 11H), 0.15-0.05 (s, 6H).
Reaction SMILES: [F:1][C:2]([C:14]([F:17])([F:16])[F:15])([CH2:6][CH:7]=[CH:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13])[C:3]([NH2:5])=[O:4].[H][H]>CO.[C].[Pd]>[F:1][C:2]([C:14]([F:15])([F:17])[F:16])([CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13])[C:3]([NH2:5])=[O:4]
Reactant: CCCCCC=CCC(F)(C(N)=O)C(F)(F)F
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: CCCCCCCCC(F)(C(N)=O)C(F)(F)F
Reaction time: 24 h
Yield: 120.8 %

Procedure:
Into a solution of 3.0 g (9.65 mmol) of 2-fluoro-2-trifluoromethyl-4-decenamide in 30 ml of methanol, palladium-carbon (75 mg) was added under nitrogen. After the atmosphere was replaced with hydrogen, the mixture was stirred for 24 hours. To remove the catalyst, the resulting mixture was filtered with celite and the filtrate was concentrated. The raw product was purified using silica gel column chromatography to obtain 3.0 g of the desired compound. The yield was 99.3%.
Reaction SMILES: [OH-].[CH3:2][N:3]([CH3:16])[C@@H:4]1[CH2:10][CH2:9][C:8]2[CH:11]=[CH:12][CH:13]=[CH:14][C:7]=2[C@H:6]([OH:15])[CH2:5]1.Cl[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[N+:24]([O-:26])=[O:25]>CS(C)=O>[CH3:2][N:3]([CH3:16])[C@@H:4]1[CH2:10][CH2:9][C:8]2[CH:11]=[CH:12][CH:13]=[CH:14][C:7]=2[C@H:6]([O:15][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[N+:24]([O-:26])=[O:25])[CH2:5]1
Reactant: CN(C)[C@@H]1CCc2ccccc2[C@H](O)C1
Reactant: O=[N+]([O-])c1ccccc1Cl
Agent: [OH-]
Solvent: CS(C)=O
Product: CN(C)[C@@H]1CCc2ccccc2[C@H](Oc2ccccc2[N+](=O)[O-])C1
Temperature: 70 °C
Reaction time: 0.17 h
Yield: 196.4 %

Procedure:
A mixture of 11 ml of dimethylsulfoxide and 1.1 g of hydroxide as a 50% oil dispersion was heated in a bath at 70° C. for 30 minutes and after cooling the mixture to 20° C., 4.1 g of cis 7-dimethylamino-6,7,8,9-tetrahydro-5H-benzocyclohepten-5-ol were added thereto. The mixture was stirred for 10 minutes at room temperature and then 6.32 g of o-chloronitrobenzene were added thereto while cooling in an ice bath. The mixture was stirred for 30 minutes at 20° C. and was extracted with methylene chloride. The organic phase was washed with water, dried over magnesium sulfate and was filtered. The filtrate was evaporated to dryness under reduced pressure to obtain 12.8 g of cis N,N-dimethyl-5-[2-nitrophenoxy]-6,7,8,9-tetrahydro-5H-benzocyclohepten-7-amine in the form of a brown oil.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([N+:13]([O-])=O)[CH:5]=[C:6]2[C:11]=1[NH:10][C:9](=[O:12])[CH2:8][CH2:7]2.C.O.NN>C(O)C>[NH2:13][C:4]1[CH:5]=[C:6]2[C:11](=[C:2]([CH3:1])[CH:3]=1)[NH:10][C:9](=[O:12])[CH2:8][CH2:7]2
Reactant: Cc1cc([N+](=O)[O-])cc2c1NC(=O)CC2
Agent: NN
Solvent: CCO
Solvent: O
Product: Cc1cc(N)cc2c1NC(=O)CC2
Reaction time: 1 h
Yield: 91.3 %

Procedure:
To a suspension of 8-methyl-6-nitro-3,4-dihydro-2(1H)-quinolinone (25 g), activated charcoal (8 g) and ferric chloride (2.5 g) in ethanol (700 ml) was dropwise added hydrazine monohydrate (30 g) over the period of 20 minutes at 77° C., and the mixture was stirred for 1 hour. Then, to the reaction mixture were added activated charcoal (3 g) and ferric chloride (1.5 g) and was dropwise added hydrazine monohydrate (10 g). After refluxed for 1.5 hours, the reaction mixture was filtered and the insoluble material was washed with ethanol and a mixture of ethanol and chloroform successively. The solvent was evaporated under reduced pressure and the residue was dissolved in chloroform. The organic layer was washed with water, dried over magnesium sulfate and concentrated under reduced pressure to give 6-amino-8-methyl-3,4-dihydro-2(1H)-quinolinone (19.5 g).
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][N:8]([C:17](=[O:35])[C:18]([N:20]([C:31]([CH3:34])([CH3:33])[CH3:32])[CH2:21][CH2:22][CH2:23][C:24]#[C:25][C:26]3[S:27][CH:28]=[CH:29][CH:30]=3)=[O:19])[CH:9]2[C:12]([O:14]CC)=[O:13])=[CH:4][C:3]=1[O:36][CH3:37].[OH-].[K+].Cl>O1CCOCC1.O>[Br:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][N:8]([C:17](=[O:35])[C:18]([N:20]([C:31]([CH3:34])([CH3:32])[CH3:33])[CH2:21][CH2:22][CH2:23][C:24]#[C:25][C:26]3[S:27][CH:28]=[CH:29][CH:30]=3)=[O:19])[CH:9]2[C:12]([OH:14])=[O:13])=[CH:4][C:3]=1[O:36][CH3:37]
Reactant: CCOC(=O)C1c2cc(Br)c(OC)cc2CCN1C(=O)C(=O)N(CCCC#Cc1cccs1)C(C)(C)C
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: COc1cc2c(cc1Br)C(C(=O)O)N(C(=O)C(=O)N(CCCC#Cc1cccs1)C(C)(C)C)CC2
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A solution of 3.1 g of 3b in 30 ml of dioxane and a solution of 1.5 g of KOH in 10 ml of water were mixed and stirred for 3 hr at RT. 75 ml of water was added and the mixture was acidified with 0.5N HCl to pH3. The product was extracted with ethyl acetate. The material 3c which remained after washing, drying and concentration was used, as such, in the cyclization step.
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]=1[C:13]([NH:15][NH2:16])=[O:14].[CH3:17][O:18][C:19]1[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][C:20]=1[C:21](O)=O>>[CH3:17][O:18][C:19]1[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][C:20]=1[C:21]1[O:14][C:13]([C:3]2[C:4]([C:7]3[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=3)=[N:5][O:6][C:2]=2[CH3:1])=[N:15][N:16]=1
Reactant: COc1ccc(OC)c(C(=O)O)c1
Reactant: Cc1onc(-c2ccccc2)c1C(=O)NN
Product: COc1ccc(OC)c(-c2nnc(-c3c(-c4ccccc4)noc3C)o2)c1
Yield: 53 %

Procedure:
As described for example 2, 5-methyl-3-phenyl-isoxazole-4-carboxylic acid hydrazide (200 mg, 0.92 mmol) was converted using 2,5-dimethoxybenzoic acid instead of o-toluic acid to the title compound (SiO2, heptane:ethyl acetate:dichloromethane=75:5:20 to 60:20:20, 176 mg, 53%) which was obtained as a white solid. MS: m/e=364.2 [M+H]+.
Reaction SMILES: [N+:1]([C:4]1[C:9]2[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][C:8]=2[CH:7]=[CH:6][CH:5]=1)([O-])=O.[C:15](OC(=O)C)(=[O:17])[CH3:16]>[Ni].C(O)(=O)C>[C:15]([NH:1][C:4]1[C:9]2[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][C:8]=2[CH:7]=[CH:6][CH:5]=1)(=[O:17])[CH3:16]
Reactant: O=[N+]([O-])c1cccc2c1CCCCC2
Reactant: CC(=O)OC(C)=O
Agent: [Ni]
Solvent: CC(=O)O
Product: CC(=O)Nc1cccc2c1CCCCC2

Procedure:
8.7 gm of 1-nitro-6,7,8,9-tetrahydro-5H-benzocycloheptene [J. Am. Chem. Soc., 5820 (9169)] was dissolved into a mixed solvent of 150 ml of acetic anhydride and 50 ml of acetic acid. The mixture was catalytically hydrogenated with the addition of 10 ml of raney nickel. After removing the catalyst by filtration, the reaction mixture was concentrated, the residue was washed with saturated aqueous solution of sodium bicarbonate and saturated brine, and dried over anhydrous sodium sulfate. The product was concentrated to produce 6.17 gm of the title compound.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([C:13]2[CH:18]=[CH:17][N:16]=[C:15](S(C)=O)[N:14]=2)=[C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[N:6]=1.[NH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>B(F)(F)F.CCOCC>[NH2:1][C:2]1[S:3][C:4]([C:13]2[CH:18]=[CH:17][N:16]=[C:15]([NH:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[N:14]=2)=[C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[N:6]=1
Reactant: Nc1ccccc1
Reactant: CS(=O)c1nccc(-c2sc(N)nc2-c2ccccc2)n1
Agent: FB(F)F
Solvent: CCOCC
Product: Nc1nc(-c2ccccc2)c(-c2ccnc(Nc3ccccc3)n2)s1

Procedure:
A mixture of 4-(2-amino-4-phenyl-thiazol-5-yl)-2-methylsulfinyl-pyrimidine (0.5 g, 1.58 mmol) and aniline (1.5 g, 15.8 mmol) is heated at +100° C. After the addition of boron trifluoride diethyl etherate (3 drops) the solution is heated at +150° C. for half an hour. On cooling the product starts to crystallize. The crystals are filtered and washed thoroughly with diethyl ether to give the N-[4-(2-amino-4-phenyl-thiazol-5-yl)-pyrimidin-2-yl]-N-phenyl-amine in pure form, having a m.p. of 244–245° C.
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][C@@H:6]([C:8]([F:11])([F:10])[F:9])[CH2:5][N:4]([C:12]2[C:17]([NH:18][C:19]([C:21]3[CH:26]=[CH:25][C:24]([F:27])=[C:23]([C:28]4[C:33]([F:34])=[CH:32][C:31]([C:35]([OH:38])([CH3:37])[CH3:36])=[CH:30][C:29]=4[F:39])[N:22]=3)=[O:20])=[CH:16][N:15]=[C:14]3[C@H:40]([OH:43])[CH2:41][CH2:42][C:13]=23)[CH2:3]1.N[C@H]1C[C@@H](C(F)(F)F)CN(C2C(NC(C3C=CC(F)=C(C4C(F)=CC(C(O)(C)C)=CC=4F)N=3)=O)=CN=C3[C@@H](O)CCC=23)C1>>[NH2:1][C@H:2]1[CH2:7][C@@H:6]([C:8]([F:9])([F:10])[F:11])[CH2:5][N:4]([C:12]2[C:17]([NH:18][C:19]([C:21]3[CH:26]=[CH:25][C:24]([F:27])=[C:23]([C:28]4[C:29]([F:39])=[CH:30][C:31]([C:35]([OH:38])([CH3:37])[CH3:36])=[CH:32][C:33]=4[F:34])[N:22]=3)=[O:20])=[CH:16][N:15]=[C:14]3[CH:40]([OH:43])[CH2:41][CH2:42][C:13]=23)[CH2:3]1
Reactant: CC(C)(O)c1cc(F)c(-c2nc(C(=O)Nc3cnc4c(c3N3C[C@@H](N)C[C@@H](C(F)(F)F)C3)CC[C@H]4O)ccc2F)c(F)c1
Agent: CC(C)(O)c1cc(F)c(-c2nc(C(=O)Nc3cnc4c(c3N3C[C@@H](N)C[C@@H](C(F)(F)F)C3)CC[C@@H]4O)ccc2F)c(F)c1
Product: CC(C)(O)c1cc(F)c(-c2nc(C(=O)Nc3cnc4c(c3N3C[C@@H](N)C[C@@H](C(F)(F)F)C3)CCC4O)ccc2F)c(F)c1

Procedure:
The diastereoisomers correspond to the (7R) and (7S) diastereoisomers of the title compound, N-{4-[(3S,5R)-3-amino-5-(trifluoromethyl)piperidin-1-yl]-(7R)-7-hydroxy-6,7-dihydro-5H-cyclopenta[b]pyridin-3-yl}-6-[2,6-difluoro-4-(1-hydroxy-1-methylethyl)phenyl]-5-fluoropyridine-2-carboxamide and N-{4-[(3S,5R)-3-amino-5-(trifluoromethyl)piperidin-1-yl]-(7S)-7-hydroxy-6,7-dihydro-5H-cyclopenta[b]pyridin-3-yl}-6-[2,6-difluoro-4-(1-hydroxy-1-methylethyl)phenyl]-5-fluoropyridine-2-carboxamide. The alternative enantiomers, N-{4-[(3R,5S)-3-amino-5-(trifluoromethyl)piperidin-1-yl]-(7R)-7-hydroxy-6,7-dihydro-5H-cyclopenta[b]pyridin-3-yl}-6-[2,6-difluoro-4-(1-hydroxy-1-methylethyl)phenyl]-5-fluoropyridine-2-carboxamide and N-{4-[(3R,5S)-3-amino-5-(trifluoromethyl)piperidin-1-yl]-(7S)-7-hydroxy-6,7-dihydro-5H-cyclopenta[b]pyridin-3-yl}-6-[2,6-difluoro-4-(1-hydroxy-1-methylethyl)phenyl]-5-fluoropyridine-2-carboxamide, are prepared by an analogous route starting from using tert-butyl [(3R,5S)-1-(3-nitro-6,7-dihydro-5H-cyclopenta[b]pyridin-4-yl)-5-(trifluoromethyl)piperidin-3-yl]carbamate (Enantiomer 1) from step 1.
Reaction SMILES: [F-].[Cs+].[F:3][C:4]([F:41])([F:40])[C:5]1[CH:6]=[C:7]([CH:33]=[C:34]([C:36]([F:39])([F:38])[F:37])[CH:35]=1)[CH2:8][N:9]([C@H:16]1[CH2:22][CH2:21][CH2:20][NH:19][C:18]2[C:23](Br)=[C:24]([C:28]([F:31])([F:30])[F:29])[C:25]([CH3:27])=[CH:26][C:17]1=2)[C:10]1[N:11]=[N:12][N:13]([CH3:15])[N:14]=1.[CH3:42]B(O)O.ClCCl>O1CCOCC1>[F:3][C:4]([F:41])([F:40])[C:5]1[CH:6]=[C:7]([CH:33]=[C:34]([C:36]([F:39])([F:38])[F:37])[CH:35]=1)[CH2:8][N:9]([C@H:16]1[CH2:22][CH2:21][CH2:20][NH:19][C:18]2[C:23]([CH3:42])=[C:24]([C:28]([F:31])([F:30])[F:29])[C:25]([CH3:27])=[CH:26][C:17]1=2)[C:10]1[N:11]=[N:12][N:13]([CH3:15])[N:14]=1
Reactant: CB(O)O
Reactant: Cc1cc2c(c(Br)c1C(F)(F)F)NCCC[C@@H]2N(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1nnn(C)n1
Agent: [Cs+]
Agent: [F-]
Solvent: ClCCl
Solvent: C1COCCO1
Product: Cc1cc2c(c(C)c1C(F)(F)F)NCCC[C@@H]2N(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1nnn(C)n1
Temperature: 25 °C
Yield: 83 %

Procedure:
Add cesium fluoride (2.44 g, 16.1 mmol) to a mixture of (S)-(3,5-Bis-trifluoromethyl-benzyl)-(9-bromo-7-methyl-8-trifluoromethyl-2,3,4,5-tetrahydro-1H-benzo[b]azepin-5-yl)-(2-methyl-2H-tetrazol-5-yl)-amine and methyl boronic acid (0.820 g, 13.8 mmol) in dioxane (50.0 mL). Purge the mixture with nitrogen for 15 min. Add 1,1′-bis(diphenylphosphino)ferrocene palladium (II) chloride, complex with dichloromethane (0.290 g, 0.355 mmol) under nitrogen. Heat the reaction mixture for 3 h. Cool down to room temperature and then evaporate the solvent under reduced pressure. Partition the residue between ethyl acetate (100 mL) and water (100 mL). Separate the layers and extract the aqueous with more ethyl acetate (2×50 mL). Combine the organic layers, dry over Na2SO4, filter and concentrate. Purify the residue by column chromatography on silica gel, eluting with ethyl acetate/hexanes (0-35%), to provide the title compound as an off-white solid (2.16 g, 83%). MS (ES+): 567 (M+H).
Reaction SMILES: O[CH2:2][C:3]1[N:4]=[C:5]([C:9]2[CH:14]=[CH:13][C:12]([CH3:15])=[CH:11][CH:10]=2)[O:6][C:7]=1[CH3:8].S(Cl)([Cl:18])=O>ClCCl>[Cl:18][CH2:2][C:3]1[N:4]=[C:5]([C:9]2[CH:14]=[CH:13][C:12]([CH3:15])=[CH:11][CH:10]=2)[O:6][C:7]=1[CH3:8]
Reactant: Cc1ccc(-c2nc(CO)c(C)o2)cc1
Reactant: O=S(Cl)Cl
Solvent: ClCCl
Product: Cc1ccc(-c2nc(CCl)c(C)o2)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 4-hydroxymethyl-2-(4-methylphenyl)-5-methyl-1,3-oxazole (3 g) in 30 ml of dichloromethane was cooled to 0° C., and thionyl chloride (1.75 g) added dropwise. The reaction was stirred for 1 hour at room temperature, then washed twice with dilute sodium bicarbonate solution, the organic layer separated, dried over sodium sulfate, and the solvent evaporated under reduced pressure, to yield 4-chloromethyl-2-(4-methylphenyl)-5-methyl-l,3-oxazole, which was used in the next reaction without further purification.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N+:8]([C:11]1[CH:19]=[CH:18][CH:17]=[CH:16][C:12]=1[C:13](Cl)=[O:14])([O-:10])=[O:9]>>[N+:8]([C:11]1[CH:19]=[CH:18][CH:17]=[CH:16][C:12]=1[C:13]([NH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)=[O:14])([O-:10])=[O:9]
Reactant: O=C(Cl)c1ccccc1[N+](=O)[O-]
Reactant: Nc1ccccc1
Product: O=C(Nc1ccccc1)c1ccccc1[N+](=O)[O-]
Yield: 80.3 %

Procedure:
Using the procedure described in Example 93, Part A, aniline (11 mmol) and 2-nitrobenzoyl chloride (12.1 mmol) yielded 2.14 g (80%) of the title compound.
Reaction SMILES: [CH:1]([Mg]Cl)([CH3:3])[CH3:2].[Br:6][C:7]1[CH:16]=[C:15]2[C:10]([C:11]([C:17]3[C:21]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=4)=[N:20][N:19]4[CH2:28][CH2:29][CH2:30][C:18]=34)=[CH:12][CH:13]=[N:14]2)=[CH:9][CH:8]=1.C(N(CC)CC)C.CS(Cl)(=O)=O>O1CCCC1.O>[Br:6][C:7]1[CH:16]=[C:15]2[C:10]([C:11]([C:17]3[C:21]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=4)=[N:20][N:19]4[CH2:28][CH2:29][CH2:30][C:18]=34)=[CH:12][C:13]([CH:1]([CH3:3])[CH3:2])=[N:14]2)=[CH:9][CH:8]=1
Reactant: CC(C)[Mg]Cl
Reactant: Brc1ccc2c(-c3c(-c4ccccn4)nn4c3CCC4)ccnc2c1
Agent: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: O
Product: CC(C)c1cc(-c2c(-c3ccccn3)nn3c2CCC3)c2ccc(Br)cc2n1
Temperature: -78 °C
Reaction time: 2 h

Procedure:
A 2 M solution of isopropyl magnesium chloride in tetrahydrofuran (65 μL, 0.13 mmol) is added to solution of 7-bromo-4-(2-pyridin-2-yl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)-quinoline (50.0 mg, 0.13 mmol) in tetrahydrofuran (1 mL) at room, temperature with stirring for 2 h. The mixture is cooled to −78° C. and triethylamine (21.4 μL, 0.154 mmol) and methanesulfonyl chloride (11 μL, 0.14 mmol) added. The mixture is warmed to room temperature and allowed to stand 18 h. The mixture is treated with water, extracted with ethyl acetate, dried (sodium sulfate), filtered, and concentrated in vacuo. The residue is chromatographed on SiO2 (dichloromethane to 75% ethyl acetate/dichloromethane) to yield the title compound as a solid, 4.5 mg (9%).
Reaction SMILES: [C:1]([O:18][CH:19]([CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH3:38])[CH2:20][C:21]([OH:23])=O)(=[O:17])[CH2:2][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].ON1C(=O)CCC1=O.[NH2:47][CH2:48][CH2:49][C:50]([NH:52][C@H:53]([C:56]([OH:58])=[O:57])[CH2:54][OH:55])=[O:51].Cl>O1CCOCC1.CN(C)C=O.O.C(N(CC)CC)C>[C:1]([O:18][CH:19]([CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH3:38])[CH2:20][C:21]([NH:47][CH2:48][CH2:49][C:50]([NH:52][C@H:53]([C:56]([OH:58])=[O:57])[CH2:54][OH:55])=[O:51])=[O:23])(=[O:17])[CH2:2][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: NCCC(=O)N[C@@H](CO)C(=O)O
Reactant: CCCCCCCCCCCCCCCC(=O)OC(CCCCCCCCCCCCCCC)CC(=O)O
Agent: Cl
Agent: O=C1CCC(=O)N1O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: C1COCCO1
Product: CCCCCCCCCCCCCCCC(=O)OC(CCCCCCCCCCCCCCC)CC(=O)NCCC(=O)N[C@@H](CO)C(=O)O
Reaction time: 8 h
Yield: 40.2 %

Procedure:
3-Hexadecanoyloxyoctadecanoic acid (150 mg) prepared by the method described in Preparation 2-(3) and N-hydroxysuccinimide (38 mg) were dissolved in dioxane (2 ml). N,N-Dicyclohexylcarbodiimide (68 mg) was added thereto under ice cooling. The mixture was reached to ambient temperature and stirred at the same temperature overnight. The crystallized urea was filtered off and the filtrate was concentrated to give a residue which was dissolved in N,N-dimethylformamide (7 ml). To this solution was added a solution of N-β-alanyl-L-serine (100 mg) and triethylamine (100 μl) in water (4 ml) at 0° C. The resulting mixture was reached to ambient temperature and stirred at the same temperature overnight. The reaction mixture was acidified with 1 N hydrochloric acid, extracted with ethyl acetate, washed with water and dried over magnesium sulfate. Ethyl acetate was distilled off to give a residue which was subjected to preparative thin layer chromatography (Merck, 0.25 mm×5) and eluted with a mixture of benzene, dioxane and acetic acid (10:5:1). The band containing the object compound was extracted with a mixture of methanol and chloroform (3:7) and the solvent was evaporated off under reduced pressure to afford powder of N-[N-(3-hexadecanoyloxyoctadecanoyl)-β-alanyl]-L-serine (78 mg).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:13][NH:12][CH2:11][CH2:10][NH:9]2)=[CH:4][CH:3]=1.[CH2:14](N(CC)CC)C.CI.[Cl-].[NH4+]>CC(C)=O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]2[NH:9][CH2:10][CH2:11][N:12]([CH3:14])[CH2:13]2)=[CH:6][CH:7]=1
Reactant: Brc1ccc(C2CNCCN2)cc1
Reactant: CCN(CC)CC
Agent: [Cl-]
Agent: [NH4+]
Solvent: CI
Solvent: CC(C)=O
Product: CN1CCNC(c2ccc(Br)cc2)C1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 46.3 %

Procedure:
To a cooled (0° C.) solution of 2-(4-bromophenyl)piperazine (4.07 g, 16.0 mmol) and triethylamine (17 mL, 122 mmol) in acetone (50 mL) was added a solution of methyl iodide (1.4 mL, 22 mmol) in acetone (20 mL) over 50 min and the reaction mixture was stirred at 0° C. for 15 minutes, warmed to room temperature, and stirred for 16 h. The reaction mixture was slowly treated with saturated ammonium chloride (150 mL) and extracted with ethyl acetate (200 mL×3). The organic layers were combined, dried over magnesium sulfate, filtered and concentrated in vacuo. Purification via flash silica gel column chromatography (heptane/ethyl acetate) gave 3-(4-bromo-phenyl)-1-methyl-piperazine (1.89 g, 46% yield). LCMS (m/z): 257.00 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:23]=[CH:22][C:6]2[N:7]=[C:8]([S:10][CH2:11][C:12]3[C:17]([CH3:18])=[C:16]([O:19][CH3:20])[C:15]([CH3:21])=[CH:14][N:13]=3)[NH:9][C:5]=2[C:4]=1[S:24]([C:27]1[C:38]([CH3:39])=[CH:37][C:30]([O:31][CH2:32][C:33]([O:35][CH3:36])=[O:34])=[CH:29][C:28]=1[CH3:40])(=[O:26])=[O:25].ClC1C=C(C=CC=1)C(OO)=[O:46]>O1CCCC1.C(OCC)(=O)C>[CH3:1][O:2][C:3]1[CH:23]=[CH:22][C:6]2[N:7]=[C:8]([S:10]([CH2:11][C:12]3[C:17]([CH3:18])=[C:16]([O:19][CH3:20])[C:15]([CH3:21])=[CH:14][N:13]=3)=[O:46])[NH:9][C:5]=2[C:4]=1[S:24]([C:27]1[C:28]([CH3:40])=[CH:29][C:30]([O:31][CH2:32][C:33]([O:35][CH3:36])=[O:34])=[CH:37][C:38]=1[CH3:39])(=[O:26])=[O:25]
Reactant: COC(=O)COc1cc(C)c(S(=O)(=O)c2c(OC)ccc3nc(SCc4ncc(C)c(OC)c4C)[nH]c23)c(C)c1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COC(=O)COc1cc(C)c(S(=O)(=O)c2c(OC)ccc3nc(S(=O)Cc4ncc(C)c(OC)c4C)[nH]c23)c(C)c1
Reaction time: 16 h

Procedure:
Solutions of methyl {4-[(5-methoxy-2{[4-methoxy,3,5-dimethyl(2-pyridyl)methyl]thio}benzimidazolyl)sulfonyl]-3,5-dimethylphenoxy}acetate (Intermediate A5, 7.1 g, 0.12 mol) in 100 mL of tetrahydrofuran and 3-chloroperoxybenzoic acid (2.6 g, 0.15 mol) in 20 mL of the same solvent were cooled in a freezer for 1 hr and then mixed. The solution was left in the freezer for about 16 hr, diluted with ethyl acetate, and washed with several portions each of 5% sodium metabisulfite, 5% sodium bicarbonate, and saturated sodium chloride. The organic phase was concentrated and then purified on flash silica gel (hexanes→ethyl acetate→1% methanol in ethyl acetate). The title compound recovered weighed 3.3 g (46%).
Reaction SMILES: [Cl:1][C:2]1[CH:31]=[CH:30][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([CH:16]=[C:17]4[S:21][C:20]([N:22]5[CH2:28][CH2:27][CH2:26][NH:25][CH2:24][CH2:23]5)=[N:19][C:18]4=[O:29])=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:32]([F:35])([F:34])[F:33])[CH:3]=1.[CH3:36][S:37](Cl)(=[O:39])=[O:38]>>[Cl:1][C:2]1[CH:31]=[CH:30][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([CH:16]=[C:17]4[S:21][C:20]([N:22]5[CH2:28][CH2:27][CH2:26][N:25]([S:37]([CH3:36])(=[O:39])=[O:38])[CH2:24][CH2:23]5)=[N:19][C:18]4=[O:29])=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:32]([F:35])([F:34])[F:33])[CH:3]=1
Reactant: CS(=O)(=O)Cl
Reactant: O=C1N=C(N2CCCNCC2)SC1=Cc1ccc2c(cnn2Cc2ccc(Cl)cc2C(F)(F)F)c1
Product: CS(=O)(=O)N1CCCN(C2=NC(=O)C(=Cc3ccc4c(cnn4Cc4ccc(Cl)cc4C(F)(F)F)c3)S2)CC1

Procedure:
5-[1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-(4-methanesulfonyl-[1,4]diazepan-1-yl)-thiazol-4-one was prepared from 5-[1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-[1,4]diazepan-1-yl-thiazol-4-one and methane sulfonyl chloride according to Example 133.
Reaction SMILES: [CH3:1][N:2]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[CH:5][CH2:4][C:3]1=[O:15].O1CCCC1.[N:21](OCCC(C)C)=[O:22].CC(C)([O-])C.[K+]>Cl.C(OC)(C)(C)C.C1CCCCC1>[CH3:1][N:2]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[CH:5][C:4](=[N:21][OH:22])[C:3]1=[O:15]
Reactant: CN1C=CC(c2ccccc2)=CCC1=O
Reactant: CC(C)CCON=O
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: C1CCCCC1
Solvent: C1CCOC1
Solvent: COC(C)(C)C
Product: Cn1ccc(-c2ccccc2)cc(=NO)c1=O
Temperature: -10 °C
Reaction time: 8 h
Yield: 80.6 %

Procedure:
The 1-methyl-5-phenyl-1,3-dihydro-azepin-2-one (183 g, 918.4 mmol) is combined with tetrahydrofuran (1500 mL) and the solution cooled to −25° C. to −30° C. Isoamyl nitrite (148.1 mL, 1.102 mol) is added followed by potassium tertiary-butoxide (108.2 g, 964.4 mmol) providing an exotherm to about −5° C. The solution is re-cooled to −10° C., then allowed to slowly warm to room temperature. The reaction contents are allowed to stir overnight. The reaction contents are diluted with 3N aqueous HCl (300 mL) providing a pH of about 2. It is then diluted with methyl tertiary-butyl ether (4 L) and washed the contents with 0.5-1.0 N HCl (2×600 mL) and saturated aqueous sodium chloride. The dark organic layer is dried over MgSO4, filtered, and concentrated to provide a residue wet with tetrahydrofuran. The residue is diluted with cyclohexane (300 mL) and concentrated to provide about 275 g of a crude residue that is slurried in methyl tertiary-butyl ether (450 mL) and cyclohexane (1000 mL). Heat the slurry to about 40° C., cool to room temperature, filter, and rinse with cyclohexane. Vacuum dry at 40° C. to provide the title compound (169 g, 81%) as a brown powder.