Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[C:9]1[N:10]=[C:11]([N:29]2[C@H:34]([CH3:35])[CH2:33][N:32](C(OC(C)(C)C)=O)[C@@H:31]([CH3:43])[CH2:30]2)[C:12]2[CH2:18][N:17]([C:19]3[CH:24]=[C:23]([CH:25]([CH3:27])[CH3:26])[CH:22]=[CH:21][C:20]=3[CH3:28])[CH2:16][CH2:15][C:13]=2[N:14]=1.[C:44]([OH:50])([C:46]([F:49])([F:48])[F:47])=[O:45]>C(Cl)Cl>[CH3:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([CH3:1])[C:3]=1[C:9]1[N:10]=[C:11]([N:29]2[CH2:30][C@@H:31]([CH3:43])[NH:32][CH2:33][C@@H:34]2[CH3:35])[C:12]2[CH2:18][N:17]([C:19]3[CH:24]=[C:23]([CH:25]([CH3:27])[CH3:26])[CH:22]=[CH:21][C:20]=3[CH3:28])[CH2:16][CH2:15][C:13]=2[N:14]=1.[C:44]([OH:50])([C:46]([F:49])([F:48])[F:47])=[O:45]
Reactant: Cc1ccc(C(C)C)cc1N1CCc2nc(-c3c(C)cccc3C)nc(N3C[C@H](C)N(C(=O)OC(C)(C)C)C[C@H]3C)c2C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1ccc(C(C)C)cc1N1CCc2nc(-c3c(C)cccc3C)nc(N3C[C@@H](C)NC[C@@H]3C)c2C1

Procedure:
To a solution of racemic tert-butyl 4-(2-(2,6-dimethylphenyl)-6-(5-isopropyl-2-methylphenyl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4-yl)-(trans)-2,5-dimethylpiperazine-1-carboxylate (0.227 g, 0.389 mmol) and DCM (3 mL) at rt was added TFA (1 mL). After 25 min an additional 0.5 mL aliquot of TFA was added. After 1 h more the reaction was concentrated under reduced pressure to give 2-(2,6-dimethylphenyl)-4-((trans)-2,5-dimethylpiperazin-1-yl)-6-(5-isopropyl-2-methylphenyl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine as a TFA salt. MS (ESI+) m/z 484.4 (M+H)+
Reaction SMILES: [OH:1][CH2:2][CH2:3][N:4]1[CH2:9][CH2:8][O:7][CH2:6][CH2:5]1.[C:10](=[O:15])([O:13]C)[O:11][CH3:12]>C(=O)([O-])[O-].[K+].[K+].CO>[CH3:12][O:11][C:10](=[O:13])[OH:15].[OH:1][CH2:2][CH2:3][N:4]1[CH2:9][CH2:8][O:7][CH2:6][CH2:5]1
Reactant: COC(=O)OC
Agent: O=C([O-])[O-]
Agent: OCCN1CCOCC1
Agent: [K+]
Solvent: CO
Product: COC(=O)O
Reaction time: 0.25 h

Procedure:
A total of 13.1 grams (0.1 moles) of 4-(2-hydroxyethyl)morpholine, 27.0 grams (0.3 moles) of dimethyl carbonate and 0.4 grams of anhydrous potassium carbonate were combined in a 50 milliliter 3-neck round bottom flask equipped with a 4 inch vacuum-jacketed vigreaux column and a distillation head. The contents were heated to reflux under nitrogen, and after a period of 15 minutes (kettle temperature of 93° C. and a head temperature of 63° C.) methanol (with some dimethyl carbonate) was slowly removed overhead. After a period of about 2.5 hours, an additional 4.5 grams of dimethyl carbonate was added and the contents heated to reflux for another 1.5 hours. Capillary gas chromatographic analysis showed complete reaction of 4-(2-hydroxyethyl)morpholine. The flask was then cooled, filtered to remove potassium carbonate and charged to a clean 50 milliliter round bottom flask. The contents were distilled under vacuum (5 mm Hg) to give 9.14 grams (boiling point 117°-119° C. at 5 mm Hg) of 4-(2-hydroxyethyl)morpholine methyl carbonate (99 percent). The kettle residue (4.3 grams) analyzed (area percent) by capillary gas chromatography as follows: 4-(2-hydroxyethyl)morpholine methyl carbonate (32.8 percent) and bis(2-N-morpholinoethyl)carbonate (65.5 percent).
Reaction SMILES: [CH2:1]([N:3]1[C:8]2[CH:9]=[C:10]([C:14]3[CH:15]=[C:16]([CH:19]=[CH:20][C:21]=3[O:22][CH2:23][C:24]([F:27])([F:26])[F:25])C=O)[C:11]([CH3:13])=[CH:12][C:7]=2[O:6][C:5]([CH3:29])([CH3:28])[C:4]1=[O:30])[CH3:2].[C:31]([O:35][C:36](=[O:66])[CH:37]=[CH:38]C1C=CC(OC(F)(F)F)=C(C2C(C)=CC3OC(C)(C)C(=O)N(CC)C=3C=2)C=1)([CH3:34])([CH3:33])[CH3:32]>>[C:31]([O:35][C:36](=[O:66])[CH:37]=[CH:38][C:16]1[CH:19]=[CH:20][C:21]([O:22][CH2:23][C:24]([F:25])([F:27])[F:26])=[C:14]([C:10]2[C:11]([CH3:13])=[CH:12][C:7]3[O:6][C:5]([CH3:28])([CH3:29])[C:4](=[O:30])[N:3]([CH2:1][CH3:2])[C:8]=3[CH:9]=2)[CH:15]=1)([CH3:34])([CH3:33])[CH3:32]
Reactant: CCN1C(=O)C(C)(C)Oc2cc(C)c(-c3cc(C=O)ccc3OCC(F)(F)F)cc21
Reactant: CCN1C(=O)C(C)(C)Oc2cc(C)c(-c3cc(C=CC(=O)OC(C)(C)C)ccc3OC(F)(F)F)cc21
Product: CCN1C(=O)C(C)(C)Oc2cc(C)c(-c3cc(C=CC(=O)OC(C)(C)C)ccc3OCC(F)(F)F)cc21

Procedure:
This was made from Compound 2C using a procedure similar to that described for Compound 1E. MS (electrospray): mass calculated for C28H32F3NO5, 519.2; m/z found 520.2, [M+H]+.
Reaction SMILES: [C:1]1([N:11]=[C:12]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([C:20](=O)[CH3:21])[N:15]=2)[CH3:13])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[C:23]([C:27]1[CH:33]=[CH:32][C:30]([NH2:31])=[CH:29][CH:28]=1)([CH3:26])([CH3:25])[CH3:24]>C1(C)C=CC=CC=1>[C:1]1([N:11]=[C:12]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([C:20](=[N:31][C:30]3[CH:32]=[CH:33][C:27]([C:23]([CH3:26])([CH3:25])[CH3:24])=[CH:28][CH:29]=3)[CH3:21])[N:15]=2)[CH3:13])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: CC(=O)c1cccc(C(C)=Nc2cccc3ccccc23)n1
Reactant: CC(C)(C)c1ccc(N)cc1
Solvent: Cc1ccccc1
Product: CC(=Nc1ccc(C(C)(C)C)cc1)c1cccc(C(C)=Nc2cccc3ccccc23)n1
Reaction time: 16 h

Procedure:
Monoimine (6, 1.25 g, 4.34 mmol) and 4-tert-butylaniline (0.65 g, 4.34 mmol) were dissolved in 50 ml of toluene. To this solution, molecular sieves (4 Å) were added. After standing for 16 hours the mixture was filtered. The solvent was removed in vacuo. The residue was recrystallised from ethanol. Yield 0.44 g (24%) of mixed diimine (7, 96% purity by NMR). H-NMR (CDCl3) δ 8.51 (d, 1H, Py-Hm), 8.38 (d, 1H, Py-Hm), 7.91 (t, 1H, Py-Hp), 7.86 (d, 1H, ArH), 7.78 (d, 1H, ArH), 7.63 (d, 1H, ArH), 7.4-7.6 (m, 5H, ArH), 6.8-6.9 (m, 3H, ArH), 2.43 (s, 3H, Me), 2.37 (s, 3H, Me), 1.34 (s, 9H, But).
Reaction SMILES: B(O)(O)O.[CH3:5][C:6]1[CH:7]=[C:8]([CH:11]=[CH:12][CH:13]=1)[CH:9]=O.[CH3:14][C:15]([C:17]1[CH:22]=[CH:21][C:20]([N+:23]([O-:25])=[O:24])=[CH:19][CH:18]=1)=[O:16].O>C1(C)C(C)=CC=CC=1>[N+:23]([C:20]1[CH:19]=[CH:18][C:17]([C:15](/[CH:14]=[CH:5]/[C:6]2[CH:13]=[CH:12][CH:11]=[C:8]([CH3:9])[CH:7]=2)=[O:16])=[CH:22][CH:21]=1)([O-:25])=[O:24]
Reactant: Cc1cccc(C=O)c1
Reactant: CC(=O)c1ccc([N+](=O)[O-])cc1
Agent: OB(O)O
Solvent: Cc1ccccc1C
Solvent: O
Product: Cc1cccc(/C=C/C(=O)c2ccc([N+](=O)[O-])cc2)c1
Reaction time: 8 h

Procedure:
10 g of boric acid are added to a solution of 76 g (0.63 mole) of 3-methylbenzaldehyde and 104.5 g (0.63 mole) of 4-nitroacetophenone in 1 l of xylene, and the mixture is refluxed for 8 hours under a water separator. A further 5 g of boric acid are added, after which the mixture is boiled for a further 8 hours. This process is repeated until the theoretical amount of water has been separated off (2-3 times). The cooled reaction mixture is filtered under suction and the residue is washed with toluene and dried under reduced pressure to give 131 g (77% of theory) of a yellowish brown powder of melting point 130°-132° C.
Reaction SMILES: [CH3:1][CH:2]([C:5](=O)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[C:3]#[N:4].[NH2:13][NH2:14].CCO.CO>C(Cl)Cl>[CH3:1][C:2]1[C:5]([C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=2)=[N:14][NH:13][C:3]=1[NH2:4]
Reactant: CC(C#N)C(=O)c1ccccc1
Reactant: NN
Solvent: CCO
Solvent: CO
Solvent: ClCCl
Product: Cc1c(-c2ccccc2)n[nH]c1N

Procedure:
A vial was charged with 2-Methyl-3-oxo-3-phenyl-propionitrile (1.0 g, 6.28 mmol), hydrazine (0.2 mL) and EtOH (1 mL), and subject to microwave irradiation at 100° C. for 50 min. Flach chromatography of the crude product using 3%-5% MeOH in CH2Cl2 gave the pyrazolylamine as a yellow oil (0.21 g). LC/MS (10% MeOH, 90% H20, 0.2% H3PO4 to 90% MeOH, 10% H20, 0.2% H3PO4, 2 minute gradient with an Exterra C18 S-5 column 4.6×30 mm): [M+H]+ m/z=174.10; retention time=1.02 min.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([C:8]2[NH:9][N:10]=[C:11]([CH:13]3[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]3)[N:12]=2)[N:3]=1.[F:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[C:26]1[C:27]([C:35]2[CH:42]=[CH:41][C:38]([CH:39]=O)=[CH:37][CH:36]=2)=[N:28][C:29]2[N:30]([CH:32]=[CH:33][N:34]=2)[CH:31]=1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].C([O-])(O)=O.[Na+]>CN1C(=O)CCC1.C(O)(=O)C.C(N(CC)CC)C>[F:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[C:26]1[C:27]([C:35]2[CH:36]=[CH:37][C:38]([CH2:39][N:16]3[CH2:17][CH2:18][CH:13]([C:11]4[N:12]=[C:8]([C:4]5[CH:5]=[CH:6][CH:7]=[C:2]([CH3:1])[N:3]=5)[NH:9][N:10]=4)[CH2:14][CH2:15]3)=[CH:41][CH:42]=2)=[N:28][C:29]2[N:30]([CH:32]=[CH:33][N:34]=2)[CH:31]=1
Reactant: O=Cc1ccc(-c2nc3nccn3cc2-c2ccccc2F)cc1
Reactant: Cc1cccc(-c2nc(C3CCNCC3)n[nH]2)n1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CCN(CC)CC
Solvent: CN1CCCC1=O
Product: Cc1cccc(-c2nc(C3CCN(Cc4ccc(-c5nc6nccn6cc5-c5ccccc5F)cc4)CC3)n[nH]2)n1
Reaction time: 1 h
Yield: 20.3 %

Procedure:
398.6 mg (1.26 mmol) 2-Methyl-6-(5-piperidine-4-yl-2H-[1,2,4]triazole-3-yl)pyridine×2HCl are dissolved in 10.9 mL NMP. After addition of 0.42 mL triethylamine the reaction mixture is stirred for one hour. 400 mg (1.26 mmol) 4-[6-(2-Fluorophenyl)-imidazo[1,2-a]pyrimidin-7-yl]-benzaldehyde and 0.13 mL acetic acid are added. The reaction mixture is stirred over night at room temperature. 293.9 mg (1.39 mmol) NaBH(OAc)3, are added in portions and the reaction mixture is stirred at room temperature for 22 hours. The reaction mixture is treated with saturated NaHCO3 and stirred for 60 minutes. The precipitate is filtered off, washed with water, dried and purified by HPLC yielding 139.1 mg (19.3%) of the title compound.
Reaction SMILES: [CH3:1][Si:2]([CH3:16])([CH3:15])[O:3][CH:4]1[CH2:9][C:8]([CH3:11])([CH3:10])[NH+:7]([O-:12])[C:6]([CH3:14])([CH3:13])[CH2:5]1.[CH2:17]1[CH2:21]OC[CH2:18]1>>[CH2:18]([O:12][N:7]1[C:6]([CH3:14])([CH3:13])[CH2:5][CH:4]([O:3][Si:2]([CH3:1])([CH3:15])[CH3:16])[CH2:9][C:8]1([CH3:10])[CH3:11])[CH2:17][CH3:21]
Reactant: CC1(C)CC(O[Si](C)(C)C)CC(C)(C)[NH+]1[O-]
Reactant: C1CCOC1
Product: CCCON1C(C)(C)CC(O[Si](C)(C)C)CC1(C)C

Procedure:
In another reaction vessel, 96.2 g (394 mmol) of 4-trimethylsilyloxy-2,2,6,6-tetramethylpiperidine-N-oxide was dissolved in 100 ml of dehydrated THF, and the Grignard reactant prepared was dropped at 0° C. After a reaction for 3 hours, the solution was concentrated by a rotary evaporator. 500 mL of water was added to the residue and an extraction was carried out using 500 mL in total of ethyl acetate, and the organic layer was concentrated by a rotary evaporator. The residue was purified by column chromatography (silica gel, hexane/ethyl acetate=20/1, volume ratio) to obtain 38.5 g of 1-(1-propyl)oxy-2,2,6,6-tetramethyl-4-trimethylsilyloxypiperidine.
Reaction SMILES: FC(F)(F)C(O)=O.C(O[C:13](=O)[N:14]([C@H:16]([CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[C:17]([N:19]1[CH2:24][CH2:23][CH2:22][C@@H:21]([CH2:25][N:26]([CH3:28])[CH3:27])[CH2:20]1)=[O:18])C)(C)(C)C>ClCCl>[CH3:27][N:26]([CH2:25][C@@H:21]1[CH2:22][CH2:23][CH2:24][N:19]([C:17](=[O:18])[C@H:16]([NH:14][CH3:13])[CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[CH2:20]1)[CH3:28]
Reactant: CN(C)C[C@@H]1CCCN(C(=O)[C@@H](Cc2ccccc2)N(C)C(=O)OC(C)(C)C)C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CN[C@H](Cc1ccccc1)C(=O)N1CCC[C@@H](CN(C)C)C1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 90.2 %

Procedure:
At 0° C., trifluoroacetic acid (25 ml) was added to a solution of N-[(1R)-1-benzyl-2-((3S)-3-(dimethylaminomethyl)piperidin-1-yl)-2-oxoethyl]-N-methylcarbamic acid tert-butyl ester (1.69 g, 4.2 mmol) in dichloromethane (25 ml). The reaction mixture was stirred for 30 min at 0° C. The solvent was removed in vacuo. The residue was dissolved in dichloromethane (100 ml) and the solvent was removed in vacuo. The latter procedure was repeated two times. The crude product was purified by flash chromatography on silica (90 g), using dichloromethane/methanol/25% aqueous ammonia (100:10:1) as eluent, to give 1.15 g of (2R)-1-((3S)-3-((dimethylamino)methyl)piperidin-1-yl)-2-methylamino-3-phenylpropan-1-one.
Reaction SMILES: C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[C:15]([O:19][C:20](=[O:27])[NH:21][C:22]([CH3:26])([CH3:25])[CH:23]=O)([CH3:18])([CH3:17])[CH3:16].[CH3:28][C:29]1[CH:35]=[CH:34][CH:33]=[CH:32][C:30]=1[NH2:31].C(O)(=O)C.C(=O)(O)[O-].[Na+]>C(Cl)Cl>[C:15]([O:19][C:20](=[O:27])[NH:21][C:22]([CH3:26])([CH3:25])[CH2:23][NH:31][C:30]1[CH:32]=[CH:33][CH:34]=[CH:35][C:29]=1[CH3:28])([CH3:18])([CH3:17])[CH3:16]
Reactant: Cc1ccccc1N
Reactant: CC(C)(C=O)NC(=O)OC(C)(C)C
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Product: Cc1ccccc1NCC(C)(C)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 16 h
Yield: 87.4 %

Procedure:
2.5 g of sodium triacetoxyborohydride (12.0 mmol) was added to a solution of 1.87 g of (1,1-dimethyl-2-oxoethyl)carbamic acid t-butyl ester obtained in Reference Example 3 (10.0 mmol), 10.7 g of 2-methylaniline (10.0 mmol) and 0.57 ml of acetic acid (10.0 mmol) in methylene chloride (100 ml) under ice-cooling, and the mixture was stirred at room temperature for 16 hours. A saturated sodium bicarbonate aqueous solution was added to the reaction mixture, followed by extraction with methylene chloride. Then, the organic layer was washed with brine and dried over anhydrous sodium sulfate. After filtration, the solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (elution solvent:hexane/ethyl acetate=5/1) to obtain 2.43 g of the title compound (yield: 87%).
Reaction SMILES: [CH3:1][O:2][CH:3](O)[CH3:4].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[OH:25][C:26]1[CH:35]=[CH:34][C:29]([C:30]([O:32][CH3:33])=[O:31])=[CH:28][CH:27]=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O.Cl>C1COCC1.O>[CH3:1][O:2][CH2:3][CH2:4][O:25][C:26]1[CH:27]=[CH:28][C:29]([C:30]([O:32][CH3:33])=[O:31])=[CH:34][CH:35]=1
Reactant: COC(=O)c1ccc(O)cc1
Reactant: COC(C)O
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: O
Product: COCCOc1ccc(C(=O)OC)cc1
Temperature: 10 °C
Reaction time: 18 h
Yield: 104.6 %

Procedure:
4.3 mL (37.5 mmol) of methoxyethanol and 10.1 g (37.5 mmol) of triphenylphosphine are added to a solution of 61 g (30 mmol) of methyl 4-hydroxybenzoate in 120 ml of THF at room temperature. 7.7 mL (37.5 mmol) of diisopropyl azodicarboxylate (DIAD) in 110 mL of THF are incorporated slowly so that the temperature is maintained to 10° C. After 18 hours at room temperature, the reaction mixture is poured onto icy water and acidified with a 1N HCl solution. The aqueous phase is extracted with ethyl acetate and the organic phase is then washed repeatedly with water, dried over sodium sulfate, filtered and concentrated by rotary evaporation. Chromatography of the residue using cyclohexane: ethyl acetate 4:1 yielded 6.6 g (98%) of pure methyl 4-(2-methoxyethoxy)benzoate as a white powder.
Reaction SMILES: [C:1]([C:4]1[C:9]([C:10]([O-:12])=[O:11])=[CH:8][N:7]=[CH:6][N:5]=1)(=[O:3])[CH3:2].O.[OH-].[Li+].Cl>>[C:1]([C:4]1[C:9]([C:10]([OH:12])=[O:11])=[CH:8][N:7]=[CH:6][N:5]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)c1ncncc1C(=O)[O-]
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Product: CC(=O)c1ncncc1C(=O)O

Procedure:
Following the procedure of Example 30, 4-acetyl-5-pyrimidinecarboxylate is reacted with lithium hydroxide monohydrate and with hydrochloric acid to give 4-acetyl-5-pyrimidinecarboxylic acid.
Reaction SMILES: BrBr.[S-:3][C:4]#[N:5].[NH4+].[CH3:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][C:10]=1[OH:17].O>C(O)(=O)C>[CH3:7][O:8][C:9]1[CH:14]=[C:13]([S:3][C:4]#[N:5])[C:12]([O:15][CH3:16])=[CH:11][C:10]=1[OH:17]
Reactant: N#C[S-]
Reactant: COc1ccc(OC)c(O)c1
Agent: BrBr
Agent: [NH4+]
Solvent: O
Solvent: CC(=O)O
Product: COc1cc(SC#N)c(OC)cc1O
Reaction time: 0.5 h
Yield: 66.3 %

Procedure:
Bromine (8 g, 2.5 ml) in glacial acetic acid (10 ml) was added dropwise with vigorous stirring over 15 minutes to a mixture of ammonium thiocyanate (8 g), 2,5-dimethoxyphenol (7.7 g), and glacial acetic acid (50 ml) kept at 15°-20°. The mixture was left at room temperature for 30 minutes and then poured into water (400 ml). A solid separated which was filtered off, washed with water and dried in vacuo to give the thiocyanatophenol (7 g). RfE 0.36.
Reaction SMILES: Cl.[CH3:2][C:3]([CH3:48])([CH3:47])[CH2:4][C:5]1[N:6]=[C:7]([CH2:29][C:30]([C:35]2[CH:40]=[CH:39][C:38]([C:41]3[N:45]([CH3:46])[N:44]=[CH:43][CH:42]=3)=[CH:37][CH:36]=2)([OH:34])[CH:31]([F:33])[F:32])[N:8](C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[CH:9]=1>CO>[CH3:2][C:3]([CH3:48])([CH3:47])[CH2:4][C:5]1[N:6]=[C:7]([CH2:29][C:30]([C:35]2[CH:40]=[CH:39][C:38]([C:41]3[N:45]([CH3:46])[N:44]=[CH:43][CH:42]=3)=[CH:37][CH:36]=2)([OH:34])[CH:31]([F:32])[F:33])[NH:8][CH:9]=1
Reactant: Cn1nccc1-c1ccc(C(O)(Cc2nc(CC(C)(C)C)cn2C(c2ccccc2)(c2ccccc2)c2ccccc2)C(F)F)cc1
Agent: Cl
Solvent: CO
Product: Cn1nccc1-c1ccc(C(O)(Cc2nc(CC(C)(C)C)c[nH]2)C(F)F)cc1
Temperature: 70 °C
Reaction time: 1 h

Procedure:
Hydrogen chloride (4 M in 1,4-dioxane) (1 mL, 0.25 mmol) was added to an ambient temperature solution of 3-[4-(2,2-dimethylpropyl)-1-trityl-1H-imidazol-2-yl]-1,1-difluoro-2-[4-(1-methyl-1H-pyrazol-5-yl)phenyl]propan-2-ol (30 mg, 0.05 mmol) in methanol (1 mL). After stirring at 70° C. for 1 h, volatiles were removed in vacuo. The residue was partitioned between diethyl ether and 1 N hydrochloric acid. The aqueous phase was washed with diethyl ether, basified with 2.5 N aqueous sodium hydroxide and extracted with ethyl acetate. Combined extracts were washed with brine, dried (sodium sulfate) and concentrated in vacuo to afford the title compound. 1H NMR (500 MHz, CD3OD) δ 7.58 (d, J=8.0 Hz, 2H), 7.46 (d, J=1.5 Hz, 1H), 7.39 (d, J=8.0 Hz, 2H), 6.51 (s, 1H), 6.30 (d, J=1.5 Hz, 1H), 5.98 (t, J=55.7 Hz, 1H), 3.81 (s, 3H), 3.42-3.28 (m, 2H), 2.31 (s, 2H), 0.76 (s, 9H).
Reaction SMILES: C(O)(C(F)(F)F)=O.[C:8]12([C:18]3[CH:19]=[C:20]([C:44]4[CH:49]=[CH:48][C:47](/[CH:50]=[CH:51]/[C:52]([O:54]C(C)(C)C)=[O:53])=[CH:46][CH:45]=4)[CH:21]=[CH:22][C:23]=3[O:24][C:25](=[O:43])[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH:33]=[CH:34][CH2:35][CH:36]=[CH:37][CH2:38][CH2:39][CH2:40][CH2:41][CH3:42])[CH2:17][CH:12]3[CH2:13][CH:14]([CH2:16][CH:10]([CH2:11]3)[CH2:9]1)[CH2:15]2>C(Cl)Cl>[C:8]12([C:18]3[CH:19]=[C:20]([C:44]4[CH:45]=[CH:46][C:47]([CH:50]=[CH:51][C:52]([OH:54])=[O:53])=[CH:48][CH:49]=4)[CH:21]=[CH:22][C:23]=3[O:24][C:25](=[O:43])[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32]/[CH:33]=[CH:34]/[CH2:35][CH:36]=[CH:37][CH2:38][CH2:39][CH2:40][CH2:41][CH3:42])[CH2:9][CH:10]3[CH2:11][CH:12]([CH2:13][CH:14]([CH2:16]3)[CH2:15]1)[CH2:17]2
Reactant: CCCCCC=CCC=CCCCCCCCC(=O)Oc1ccc(-c2ccc(/C=C/C(=O)OC(C)(C)C)cc2)cc1C12CC3CC(CC(C3)C1)C2
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCCCCC=CC/C=C/CCCCCCCC(=O)Oc1ccc(-c2ccc(C=CC(=O)O)cc2)cc1C12CC3CC(CC(C3)C1)C2
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 98.7 %

Procedure:
TFA (1.6 ml) was dropped into an ice-cooled solution of octadeca-9,12-dienoic acid (E)-3-adamantan-1-yl-4′-(2-tert-butoxycarbonylvinyl)biphenyl-4-yl ester (110 mg, 0.159 mmol) in DCM (1.6 ml) and the resulting solution was stirred for 30 min at 0° C. The solvent was removed under reduced pressure to obtain the title compound as a white solid (100 mg, 99%).
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=[O:5].C[Si]([C:14]([F:17])([F:16])[F:15])(C)C>O.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.Cl>[Br:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]([OH:5])[C:14]([F:17])([F:16])[F:15]
Reactant: O=Cc1ccccc1Br
Reactant: C[Si](C)(C)C(F)(F)F
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: Cl
Agent: [F-]
Solvent: O
Product: OC(c1ccccc1Br)C(F)(F)F
Temperature: 25 °C
Reaction time: 16 h
Yield: 71.8 %

Procedure:
The title compound was prepared by an adaptation of the method described in Xue, Y. et al. (Bioorg. Med. Chem. 2007, 15, 2156-2166). Tetrabutylammonium fluoride hydrate (0.05 eq., 131 mg, 0.050 mmol) was placed in a 40 mL vial equipped with a magnetic stir bar, and the vial was evacuated and backflushed with Ar. Dry THF (25 mL) was added via syringe, and 2-bromobenzaldehyde (1.16 mL, 10.0 mmol) and trimethylsilyltrifluoromethane (1.3 eq., 1.90 mL, 13.0 mmol) were sequentially added via syringe. The reaction was stirred at RT for 16 h, and additional CF3 TMS (1 mL) was added. After stirring for 2 h, the reaction was poured into 3 M aq HCl (30 mL) and stirred at RT for 2 h. The reaction mixture was extracted three times with DCM (30 mL), and the combined organic extracts were dried over anhydrous MgSO4, filtered, and the solvent removed under reduced pressure, yielding 1.83 g (72%) of the title compound. 1H-NMR (400 MHz, CDCl3) δ: 7.69 (d, J=7.8 Hz, 1H), 7.60 (dd, J=8.1, 1.3 Hz, 1H), 7.40 (td, J=7.6, 1.1 Hz, 1H), 7.27 (td, J=7.7, 1.8 Hz, 1H), 5.56-5.68 (m, 1H), 2.77 (d, J=4.8 Hz, 1H).
Reaction SMILES: C(OC([NH:8][CH:9]([CH3:31])[CH2:10][CH2:11][N:12]1[C:20]2[C:15](=[CH:16][CH:17]=[C:18]([C:21]([O:23][CH2:24][CH3:25])=[O:22])[CH:19]=2)[CH:14]=[C:13]1[C:26](OCC)=[O:27])=O)(C)(C)C.N1C2C(=CC=C(C(OCC)=O)C=2)C=C1C(OCC)=O.C(O)(C(F)(F)F)=O.C([O-])([O-])=O.[K+].[K+].C(N(CC)CC)C>C(Cl)Cl.C(O)C.O>[CH3:31][CH:9]1[CH2:10][CH2:11][N:12]2[C:20]3[CH:19]=[C:18]([C:21]([O:23][CH2:24][CH3:25])=[O:22])[CH:17]=[CH:16][C:15]=3[CH:14]=[C:13]2[C:26](=[O:27])[NH:8]1
Reactant: CCOC(=O)c1ccc2cc(C(=O)OCC)n(CCC(C)NC(=O)OC(C)(C)C)c2c1
Agent: CCOC(=O)c1ccc2cc(C(=O)OCC)[nH]c2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCO
Solvent: CCN(CC)CC
Product: CCOC(=O)c1ccc2cc3n(c2c1)CCC(C)NC3=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 15 %

Procedure:
To a mixture of diethyl 1-{3-[(tert-butoxycarbonyl)amino]butyl}-1H-indole-2,6-dicarboxylate and diethyl 1H-indole-2,6-dicarboxylate (600 mg) in CH2Cl2 (10 mL) is added TFA (5 mL). The reaction mixture is stirred for 2 h at room temperature. The solvent is evaporated and the residue dried in vacuo. To a solution of the residue in ethanol (10 mL) is added K2CO3 (500 mg, 3.6 mmol) and triethylamine (0.02 mL, 0.14 mmol). The reaction mixture is heated to 80° C. for 36 h. The mixture is diluted with water (10 mL) and is extracted with EtOAc. The organic layers are dried (Na2SO4) and concentrated and the residue is purified by flash column chromatography using EtOAc in heptane to afford the title compound (120 mg, 15% for 3 steps).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][NH:8][C:9]([C:11]2[S:15][C:14]([C:16]3[NH:17][N:18]=[CH:19][CH:20]=3)=[N:13][C:12]=2[CH3:21])=[O:10])[CH:2]=1.Br[CH2:23][C:24]1[CH:29]=[CH:28][C:27]([C:30]([CH3:33])([CH3:32])[CH3:31])=[CH:26][CH:25]=1>>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][NH:8][C:9]([C:11]2[S:15][C:14]([C:16]3[CH:20]=[CH:19][N:18]([CH2:23][C:24]4[CH:29]=[CH:28][C:27]([C:30]([CH3:33])([CH3:32])[CH3:31])=[CH:26][CH:25]=4)[N:17]=3)=[N:13][C:12]=2[CH3:21])=[O:10])[CH:2]=1
Reactant: Cc1nc(-c2ccn[nH]2)sc1C(=O)NCc1cccnc1
Reactant: CC(C)(C)c1ccc(CBr)cc1
Product: Cc1nc(-c2ccn(Cc3ccc(C(C)(C)C)cc3)n2)sc1C(=O)NCc1cccnc1

Procedure:
The title compound was prepared from 4-methyl-2-(2H-pyrazol-3-yl)-thiazole-5-carboxylic acid (pyridin-3-ylmethyl)-amide and 1-bromomethyl-4-tert-butyl-benzene as described in Example 49 and isolated as a yellow solid (0.080 g, 53% yield). 1H NMR (400 MHz, CDCl3) δ 8.61 (s, 1H), 8.56 (d, J=4 Hz, 1H), 7.71 (d, J=8 Hz, 1H), 7.36-7.40 (m, 3H), 7.26-7.30 (m, 1H), 7.20 (d, J=8 Hz, 2H), 6.82 (d, J=2 Hz, 1H), 6.09-6.14 (m, 1H), 5.31 (s, 2H), 4.63 (d, J=8 Hz, 2H), 2.75 (s, 3H), 1.30 (s, 9H); MS (M+H)+=445.9; Rt=1.47 min; HRMS (M+H)+=446.20.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]([NH:12][C:13](=[O:35])[CH2:14][N:15]1[C:19](=[O:20])[N:18]([CH2:21][C@H:22](O)[C:23](F)(F)F)[C:17]([C:28]2[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][CH:29]=2)=[N:16]1)[CH2:9][CH2:10][OH:11].ClC1C=CC(C2N(C3CC3)C(=O)N(CC(O)=O)N=2)=CC=1>>[Cl:34][C:31]1[CH:30]=[CH:29][C:28]([C:17]2[N:18]([CH:21]3[CH2:23][CH2:22]3)[C:19](=[O:20])[N:15]([CH2:14][C:13]([NH:12][CH:8]([C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=3[Cl:1])[CH2:9][CH2:10][OH:11])=[O:35])[N:16]=2)=[CH:33][CH:32]=1
Reactant: O=C(Cn1nc(-c2ccc(Cl)cc2)n(C[C@H](O)C(F)(F)F)c1=O)NC(CCO)c1ccccc1Cl
Agent: O=C(O)Cn1nc(-c2ccc(Cl)cc2)n(C2CC2)c1=O
Product: O=C(Cn1nc(-c2ccc(Cl)cc2)n(C2CC2)c1=O)NC(CCO)c1ccccc1Cl

Procedure:
In the same way as for the compound from Example 82, 30 mg (0.10 mmol) of [3-(4-chlorophenyl)-4-cyclopropyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl]acetic acid (for preparation see WO 2007/134862, Example 88A) were reacted. This gave 14 mg (30% of theory) of the target compound.