Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [ClH:1].Cl.[NH2:3][CH2:4][CH2:5][C:6]1[N:10]=[CH:9][NH:8][CH:7]=1.[OH-].[K+].O.[F:14][C:15]([F:19])([F:18])[CH:16]=O.Cl>O>[ClH:1].[F:14][C:15]([F:19])([F:18])[CH:16]1[C:7]2[N:8]=[CH:9][NH:10][C:6]=2[CH2:5][CH2:4][NH:3]1
Reactant: NCCc1c[nH]cn1
Reactant: O=CC(F)(F)F
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: FC(F)(F)C1NCCc2[nH]cnc21
Temperature: 25 °C
Reaction time: 6 h

Procedure:
A suspension of histamine dihydrochloride (1.0 g, 5.3 mmol) in H2O (20 mL) was cooled in an ice bath. To this suspension was added solid KOH (85%) (0.9 g, 16 mmol) followed by trifluoroacetaldehyde hydrate (0.5 g, 5.3 mmol). The reaction was allowed to warm to rt and heated to 80° C. After 6 h, the reaction was cooled to rt, acidified using 6N HCl, and concentrated. The resulting residue was dissolved in hot EtOH and filtered through Celite©. The solvent was evaporated to give the product as the HCl salt. This was purified by dissolving in minimal water and loading on silica (SiO2; MeOH(NH3):DCM) to give the title compound (0.6 g, 45%).
Reaction SMILES: FC(F)(F)C(O)=O.C([SiH](CC)CC)C.C1(C([O:28][C:29]([C:31]2[N:32]3[CH:35]([CH2:36][CH2:37][C:38]=2[S:39][C:40]2[S:41][CH:42]=[N:43][N:44]=2)[C@@H:34]([NH:45][C:46](=[O:76])/[C:47](/[C:69]2[N:70]=[C:71]([NH2:75])[S:72][C:73]=2[Cl:74])=[N:48]\[O:49]C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[C:33]3=[O:77])=[O:30])C2C=CC=CC=2)C=CC=CC=1>ClCCl>[NH2:75][C:71]1[S:72][C:73]([Cl:74])=[C:69](/[C:47](=[N:48]/[OH:49])/[C:46]([NH:45][C@H:34]2[C:33](=[O:77])[N:32]3[CH:35]2[CH2:36][CH2:37][C:38]([S:39][C:40]2[S:41][CH:42]=[N:43][N:44]=2)=[C:31]3[C:29]([OH:30])=[O:28])=[O:76])[N:70]=1
Reactant: Nc1nc(/C(=N/OC(c2ccccc2)(c2ccccc2)c2ccccc2)C(=O)N[C@H]2C(=O)N3C(C(=O)OC(c4ccccc4)c4ccccc4)=C(Sc4nncs4)CCC23)c(Cl)s1
Agent: CC[SiH](CC)CC
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Nc1nc(/C(=N/O)C(=O)N[C@H]2C(=O)N3C(C(=O)O)=C(Sc4nncs4)CCC23)c(Cl)s1
Temperature: 0 °C
Reaction time: 3 h
Yield: 76.2 %

Procedure:
A solution of trifluoroacetic acid (5 mL), triethylsilane (3 mL) and dichloromethane (8 mL) was cooled to 0° C. and (7R)-7-[(Z)-2-(2-amino-5-chlorothiazol-4-yl)-2-(triphenylmethoxyimino]acetamido]-3-[1,3,4-thiadiazol-2-ylthio]-8-oxo-1-aza-bicyclo-[4.2.0]oct-2-ene-2-carboxylate diphenylmethyl ester (1.5 g) was added in portions. The reaction mixture was stirred at 0° C. for 3 hours, was allowed to warm up to room temp. and was evaporated to dryness. The residue was treated with diethyl ether (50 mL), and the solid that formed was filtered and dried to give the crude product. The crude product was purified on HP 20 initially with water elution until the pH was neutral, and thereafter with acetonitrile:water 80:20 to give the title compound (0.63 g.)
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][CH:9]([NH:16][C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([C:23]2[N:27]3[CH:28]=[CH:29][N:30]=[C:31]([N:32]4[CH2:37][CH2:36][N:35]([CH3:38])[CH2:34][CH2:33]4)[C:26]3=[N:25][CH:24]=2)[N:18]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)(C)(C)C.Cl>C(O)C>[CH3:38][N:35]1[CH2:34][CH2:33][N:32]([C:31]2[C:26]3[N:27]([C:23]([C:19]4[N:18]=[C:17]([NH:16][CH:9]([C:10]5[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=5)[CH2:8][NH2:7])[CH:22]=[CH:21][CH:20]=4)=[CH:24][N:25]=3)[CH:28]=[CH:29][N:30]=2)[CH2:37][CH2:36]1
Reactant: CN1CCN(c2nccn3c(-c4cccc(NC(CNC(=O)OC(C)(C)C)c5ccccc5)n4)cnc23)CC1
Agent: Cl
Solvent: CCO
Product: CN1CCN(c2nccn3c(-c4cccc(NC(CN)c5ccccc5)n4)cnc23)CC1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
The mixture of (2-{6-[8-(4-methyl-piperazin-1-yl)-imidazo[1,2-a]pyrazin-3-yl]-pyridin-2-ylamino}-2-phenyl-ethyl)-carbamic acid tert-butyl ester (30 mg, 0.06 mmol) and concentrated HCl (3 mL) in ethanol (3 mL) was stirred at room temperature for 15 hours. The reaction mixture was then concentrated under reduced pressure to give N1-{6-[8-(4-methyl-piperazin-1-yl)-imidazo[1,2-a]pyrazin-3-yl]-pyridin-2-yl}-1-phenyl-ethane-1,2-diamine; hydrochloride. (Yield 40 mg). 1HNMR (300 MHz, CD3OD): δ 8.54 (brs, 1H), 8.13 (s, 1H), 7.64-7.46 (m, 3H), 7.31-7.10 (m, 5H), 6.92 (d, 1H, J=8.1 Hz), 5.44 (brs, 3H), 3.93 (brs, 2H), 3.72-3.69 (m, 2H), 3.52-3.34 (m, 4H), 2.92 (s, 3H). LC-MS: [M+H]+ 429.
Reaction SMILES: [CH3:1][C:2]1([CH3:32])[CH2:5][CH:4]([CH:6]([NH:20][C:21]2[CH:22]=[N:23][C:24]3[C:29]([CH:30]=2)=[CH:28][C:27]([F:31])=[CH:26][CH:25]=3)[C:7]2[CH:19]=[CH:18][C:10]([C:11]([O:13]C(C)(C)C)=[O:12])=[CH:9][CH:8]=2)[CH2:3]1.FC(F)(F)C(O)=O>C(Cl)Cl>[CH3:1][C:2]1([CH3:32])[CH2:3][CH:4]([CH:6]([NH:20][C:21]2[CH:22]=[N:23][C:24]3[C:29]([CH:30]=2)=[CH:28][C:27]([F:31])=[CH:26][CH:25]=3)[C:7]2[CH:19]=[CH:18][C:10]([C:11]([OH:13])=[O:12])=[CH:9][CH:8]=2)[CH2:5]1
Reactant: CC1(C)CC(C(Nc2cnc3ccc(F)cc3c2)c2ccc(C(=O)OC(C)(C)C)cc2)C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC1(C)CC(C(Nc2cnc3ccc(F)cc3c2)c2ccc(C(=O)O)cc2)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 96.9 %

Procedure:
To a flask containing tert-butyl 4-((3,3-dimethylcyclobutyl)(6-fluoroquinolin-3-ylamino)methyl)benzoate (13.0 mg, 0.0300 mmol) was added anhydrous methylene chloride (0.150 mL) and trifluoroacetic acid (0.150 mL, 0.0300 mmol). The reaction was stirred at room temperature for 1 h. The mixture was concentrated and azeotrophed with toluene to provide crude 4-((3,3-dimethylcyclobutyl)(6-fluoroquinolin-3-ylamino)methyl)benzoic acid (11 mg, 96% yield) as an oil. (M+1): 379.2.
Reaction SMILES: [OH:1][C:2]1[CH:12]=[CH:11][C:5]2[C:6](=[O:10])[CH2:7][CH2:8][O:9][C:4]=2[C:3]=1[CH2:13][CH2:14][CH3:15].[CH3:16][O:17][C:18](=[O:46])[CH2:19][CH2:20][C:21]1[CH:26]=[C:25]([O:27][CH2:28][CH2:29][CH2:30][C:31]([O:33][CH3:34])=[O:32])[CH:24]=[CH:23][C:22]=1[CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40]OS(C)(=O)=O>>[CH3:16][O:17][C:18](=[O:46])[CH2:19][CH2:20][C:21]1[CH:26]=[C:25]([O:27][CH2:28][CH2:29][CH2:30][C:31]([O:33][CH3:34])=[O:32])[CH:24]=[CH:23][C:22]=1[CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][O:1][C:2]1[CH:12]=[CH:11][C:5]2[C:6](=[O:10])[CH2:7][CH2:8][O:9][C:4]=2[C:3]=1[CH2:13][CH2:14][CH3:15]
Reactant: CCCc1c(O)ccc2c1OCCC2=O
Reactant: COC(=O)CCCOc1ccc(CCCCCCOS(C)(=O)=O)c(CCC(=O)OC)c1
Product: CCCc1c(OCCCCCCc2ccc(OCCCC(=O)OC)cc2CCC(=O)OC)ccc2c1OCCC2=O
Yield: 86.7 %

Procedure:
Using the procedure of example 11 and starting with 0.28 g (1.4 mmol) of 2,3-dihydro-7-hydroxy-8-propyl-4H-1-benzopyran-4-one and 0.64 g (1.4 mmol) of 2-[6-[(methylsulfonyl)oxy]hexyl]-5-(4-methoxy-4-oxobutoxy)benzenepropanoic acid methyl ester (from example 53), 5-(4-methoxy-4-oxobutoxy)-2-[6-[(3,4-dihydro-4-oxo-8-propyl-2H-1-benzopyran-7-yl)oxy]hexyl]benzenepropanoic acid methyl ester was obtained in 86.7% yield (0.69 g) as an oil. This diester (1.21 mmol) was saponified with 2 mL of 3N aqueous lithium hydroxide in 20 mL of tetrahydrofuran, at room temperature, for 24 hr. Work-up as in example 4 gave a light-brown oily acid which was flash-chromatographed on silica gel, eluting with 95:5:1 chloroform-methanol-acetic acid. There was obtained 0.6 g (91.8%) of pure 5-(3-carboxypropoxy)-2-[6-[(3,4-dihydro-4-oxo-8-propyl-2H-1-benzopyran-7-yl)oxy]hexyl]benzenepropanoic acid. Recrystallization from hexane-ethyl acetate gave 0.49 g (75%) of a colorless solid, mp 119°-120° C.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7]([CH2:18]Br)=[N:8][N:9]([C:11]2[C:16]([F:17])=[CH:15][CH:14]=[CH:13][N:12]=2)[CH:10]=1)=[O:5])[CH3:2].[I-].[K+].[C:22](=O)([O-])[O-:23].[K+].[K+].CO>CC(C)=O>[F:17][C:16]1[C:11]([N:9]2[CH:10]=[C:6]([C:4]([O:3][CH2:1][CH3:2])=[O:5])[C:7]([CH2:18][O:23][CH3:22])=[N:8]2)=[N:12][CH:13]=[CH:14][CH:15]=1
Reactant: O=C([O-])[O-]
Reactant: CCOC(=O)c1cn(-c2ncccc2F)nc1CBr
Agent: [I-]
Agent: [K+]
Solvent: CO
Solvent: CC(C)=O
Product: CCOC(=O)c1cn(-c2ncccc2F)nc1COC
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To a solution of 3-bromomethyl-1-(3-fluoro-pyridin-2-yl)-1H-pyrazole-4-carboxylic acid ethyl ester (1.13 g, 3.44 mmol) in acetone (23 mL), potassium iodide (200.1 mg), potassium carbonate (865.33 mg) and methanol (4.18 mL) are added. The mixture is stirred at room temperature for 48 hours. Methyl and ethyl ester of the desired compound are detected. Solvents are evaporated. Residue is diluted with dichloromethane and washed with water. Organic layer is decanted, dried over magnesium sulfate and solvent evaporated. Crude is purified by normal phase Isco chromatography using as eluent ethyl acetate and hexane to yield 599 mg of a mixture of both methyl and ethyl esters. MS (m/z): 266 (M+1) and 280 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:20][C:21]([OH:23])=O)[CH:6]=[CH:7][C:8]=1[NH:9][C:10]([NH:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[F:19])=[O:11].[Cl:24][C:25]1[CH:26]=[C:27]([CH:32]=[CH:33][C:34]=1[O:35][CH2:36][C@@H:37]([NH:39][CH3:40])[CH3:38])[C:28]([O:30][CH3:31])=[O:29].C1C=CC2N(O)N=NC=2C=1>CN(C1C=CN=CC=1)C.CN(C=O)C.CCOC(C)=O>[Cl:24][C:25]1[CH:26]=[C:27]([CH:32]=[CH:33][C:34]=1[O:35][CH2:36][C@@H:37]([N:39]([CH3:40])[C:21](=[O:23])[CH2:20][C:5]1[CH:6]=[CH:7][C:8]([NH:9][C:10]([NH:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[F:19])=[O:11])=[C:3]([O:2][CH3:1])[CH:4]=1)[CH3:38])[C:28]([O:30][CH3:31])=[O:29]
Reactant: CN[C@@H](C)COc1ccc(C(=O)OC)cc1Cl
Reactant: COc1cc(CC(=O)O)ccc1NC(=O)Nc1ccccc1F
Agent: CN(C)c1ccncc1
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc(OC[C@H](C)N(C)C(=O)Cc2ccc(NC(=O)Nc3ccccc3F)c(OC)c2)c(Cl)c1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 100.2 %

Procedure:
A mixture of 3-methoxy-4-[N′-(2-fluorophenyl)ureido]phenylacetic acid (296 mg, 0.93 mmol), methyl (S)-3-chloro-4-(2-methylamino-1-propoxy)benzoate (240 mg, 0.93 mmol), EDC(hydrochloride) (268 mg, 1.40 mmol), HOBt (189 mg, 1.40 mmol), and DMAP (23 mg, 0.19 mmol) in DMF (8 mL) was stirred at room temp for 1.5 hr. The mixture was diluted with EtOAc, washed with 0.5 N HCl, brine, dried over Na2SO4 and evaporated. The residue was purified by column chromatography on silica-gel with 5% MeOH in CHCl3 as eluent to give 520 mg (100%) methyl (S)-3-chloro-4-[2-[N-methyl-N-[3-methoxy-4-[N′-(2-fluorophenyl)ureido]phenylacetyl]amino]-1-propoxy]benzoate as a red-brown amorphous solid.
Reaction SMILES: ClC1C=CC=[C:4]([C:8]([O:10]O)=O)[CH:3]=1.C(O[C:16]1[CH:21]=[CH:20][C:19]([C:22]2[CH:27]=[CH:26][C:25]([C:28]#[N:29])=[CH:24][CH:23]=2)=[CH:18][CH:17]=1)C=C>C(Cl)Cl>[C:28]([C:25]1[CH:24]=[CH:23][C:22]([C:19]2[CH:18]=[CH:17][C:16]([CH2:3][CH:4]3[O:10][CH2:8]3)=[CH:21][CH:20]=2)=[CH:27][CH:26]=1)#[N:29]
Reactant: C=CCOc1ccc(-c2ccc(C#N)cc2)cc1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: N#Cc1ccc(-c2ccc(CC3CO3)cc2)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 68.4 %

Procedure:
20 g of m-chloroperbenzoic acid divided into portions was added in a few times to a solution prepared by dissolving 19 g of 4-allyloxy-4′-cyanobiphenyl in 150 ml of methylene chloride, and stirred at room temperature for 24 hours. The deposited insoluble was filtered away, water was added to it for liquid-liquid separation, and the organic layer was washed with an aqueous saturated sodium hydrosulfite solution and then dried with anhydrous magnesium sulfate. The solvent was evaporated away, and the residue was purified through silica gel column chromatography and further recrystallized from ethanol to obtain 13 g of 4-cyano-4′-glycidylbiphenyl.
Reaction SMILES: [Cl:1][CH2:2][C:3](Cl)=[O:4].[CH3:6][CH:7]([CH2:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[CH2:8][CH2:9][OH:10].N1C=CC=CC=1>ClCCl>[Cl:1][CH2:2][C:3]([O:10][CH2:9][CH2:8][CH:7]([CH3:6])[CH2:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:4]
Reactant: O=C(Cl)CCl
Reactant: CC(CCO)CCc1ccccc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(CCOC(=O)CCl)CCc1ccccc1
Reaction time: 2 h
Yield: 84.9 %

Procedure:
A 127.05 g (1.125 mol) of chloroacetyl chloride and 200 ml of dichloromethane were put into a flask and, while stirring under ice-cooling, a mixture consisting of 199.6 g (1.12 mol) of 3-methyl-5-phenylpentanol and 88.59 g (1.12 mol) of pyridine was added dropwise thereto spending 2 hours (reaction temperature 5 to 15° C.). After completion of the dropwise addition, this was further stirred at room temperature for 3 hours, and white crystals of the thus precipitated pyridine hydrochloride were removed by filtration. The reaction mixture was washed with water (3×300 ml), the organic phase was dehydrated with anhydrous magnesium sulfate and then the solvent was evaporated under a reduced pressure. By distilling the remained yellow oil under a reduced pressure, the title compound was obtained as a light yellow transparent oil. Yield 242.25 g (0.849 mol; yield 84.9%, boiling point 148-151° C./0.2 kPa).
Reaction SMILES: [CH2:1]([C:8]1[CH:18]=[CH:17][CH:16]=[CH:15][C:9]=1[C:10]([O:12][CH2:13][CH3:14])=[O:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl-].[Na+].[CH3:21][O:22]C(Cl)Cl>ClCCl>[CH2:13]([O:12][C:10]([C:9]1[CH:15]=[CH:16][CH:17]=[CH:18][C:8]=1[CH2:1][C:2]1[CH:3]=[CH:4][C:5]([CH:21]=[O:22])=[CH:6][CH:7]=1)=[O:11])[CH3:14]
Reactant: COC(Cl)Cl
Reactant: CCOC(=O)c1ccccc1Cc1ccccc1
Agent: [Cl-]
Agent: [Na+]
Solvent: ClCCl
Product: CCOC(=O)c1ccccc1Cc1ccc(C=O)cc1
Temperature: 0 °C
Yield: 71.8 %

Procedure:
Ethyl 2-benzylbenzoate (54.0 g) was dissolved in 100 ml of dichloromethane, and with stirring, 121.3 g of stannic chloride was added while cooling the solution with a mixture of ice and sodium chloride. The mixture was stirred for 1 hour. Subsequently, 86 g of α,α-dichloromethyl methyl ether was added dropwise over 1 hour, and then the mixture was stirred at room temperature for 3 hours. After the reaction, the reaction mixture was poured into 1 liter of ice water, and stirred. The dichloromethane layer was separated, washed with water, a saturated aqueous solution of sodium carbonate and subsequently with a saturated aqueous solution of sodium chloride, and dried over anhydrous magnesium sulfate. The dichloromethane was distilled off. To the residue was added 250 ml of a saturated aqueous solution of sodium bisulfite, and the mixture was vigorously stirred. The precipitated crystals were collected by filtration, and washed with 100 ml of a saturated aqueous solution of sodium chloride and then with 100 ml of ether. The crystals were then suspended in 500 ml of water, and with stirring, 120 g of sodium carbonate was added little by little over the course of 15 minutes. The mixture was stirred for 2 hours. The separated oily substance was extracted with 300 ml of ether. The ethereal layer was washed with water and dried over anhydrous magnesium sulfate. The ether was distilled off to afford 43.3 g of 4-(2-ethoxycarbonylbenzyl)benzaldehyde as a red oily substance.
Reaction SMILES: [C:1]([C:5]1[N:10]=[C:9]([N:11]2[CH2:16][CH2:15][N:14]([CH2:17][CH2:18][CH2:19][CH2:20][N:21]3[CH:26]=[C:25]([CH3:27])[C:24](=S)[NH:23][C:22]3=[O:29])[CH2:13][CH2:12]2)[CH:8]=[C:7]([C:30]([F:33])([F:32])[F:31])[N:6]=1)([CH3:4])([CH3:3])[CH3:2].[NH:34]1[CH2:37][CH2:36][CH2:35]1>C(O)C>[N:34]1([C:24]2[C:25]([CH3:27])=[CH:26][N:21]([CH2:20][CH2:19][CH2:18][CH2:17][N:14]3[CH2:15][CH2:16][N:11]([C:9]4[CH:8]=[C:7]([C:30]([F:33])([F:32])[F:31])[N:6]=[C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])[N:10]=4)[CH2:12][CH2:13]3)[C:22](=[O:29])[N:23]=2)[CH2:37][CH2:36][CH2:35]1
Reactant: Cc1cn(CCCCN2CCN(c3cc(C(F)(F)F)nc(C(C)(C)C)n3)CC2)c(=O)[nH]c1=S
Reactant: C1CNC1
Solvent: CCO
Product: Cc1cn(CCCCN2CCN(c3cc(C(F)(F)F)nc(C(C)(C)C)n3)CC2)c(=O)nc1N1CCC1
Temperature: 60 °C
Reaction time: 1 h
Yield: 65.7 %

Procedure:
A mixture of 1-{4-[4-(2-tert-butyl-6-trifluoromethylpyrimidin-4-yl)piperazin-1-yl]butyl}-5-methyl-4-thioxo-3,4-dihydro-1H-pyrimidin-2-one from Example 2 (0.24 mmol, 0.12 g) and azetidine (5.81 mmol, 0.33 g) in ethanol (1.9 ml) was stirred at 60° C. in a microwave (Milestone Ethos 1600) for 1 hour. The reaction mixture was then concentrated and the resulting residue was purified by column chromatography on silica gel (eluent: CH2Cl2/methanol 95/5), resulting in 0.08 g of the title compound.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:21])[C:4]([CH3:20])([CH3:19])[NH:5][C:6](=[O:18])[C:7]([CH3:17])([CH3:16])[NH:8]C(OC(C)(C)C)=O.[C:22]([OH:28])([C:24]([F:27])([F:26])[F:25])=[O:23]>C(Cl)Cl>[F:25][C:24]([F:27])([F:26])[C:22]([OH:28])=[O:23].[CH3:1][O:2][C:3](=[O:21])[C:4]([CH3:20])([CH3:19])[NH:5][C:6](=[O:18])[C:7]([CH3:17])([CH3:16])[NH2:8]
Reactant: COC(=O)C(C)(C)NC(=O)C(C)(C)NC(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COC(=O)C(C)(C)NC(=O)C(C)(C)N
Reaction time: 8 h
Yield: 90 %

Procedure:
N-tert-butoxycarbonyl α,α-dimethylglycyl α,α-dimethylglycine methyl ester 3 (10.79 g, 35.69 mmol) was dissolved in 50% (v/v) TFA in CH2Cl2 (100 mL). The reaction mixture was stirred for 2 h 30 min at room temperature before the solvent and bulk of excess TFA were evaporated at 50° C. over 1 h 30 min. The residue was left standing overnight, dissolved in CH2Cl2 (100 mL) and the bulk of solvent evaporated. More CH2Cl2 (2×100 mL) was added and evaporated. The residue was washed with Et2O (3×60 mL) and the Et2O decanted off. The residue was dissolved in CH2Cl2 (30 mL). Upon standing a solid precipitated and was collected by filtration. The residue was washed with Et2O (3×60 mL) under suction and dried under vacuum affording the title compound as a white solid (10.17 g, 90%), with spectral characteristics in accordance with literature data5,6; 1H NMR (300 MHz, DMSO-d6) δ 8.45 (s, 1H, NH), 8.20 (br s, 3H, NH3+), 3.57 (s, 3H, OCH3), 1.47 (s, 6H, CH3), 1.39 (s, 6H, CH3); 13C NMR (75 MHz, DMSO-d6) δ 174.1, 171.4, 158.3 (q, JCF=33 Hz), 116.7 (q, JCF=295 Hz), 56.4, 55.9, 52.1, 24.8, 23.3; HRMS (m/z): M+ calcd. for C9H19N2O3, 203.1395. found, 203.1396; Anal. Calcd. for C11H19F3N2O5: C, 41.77; H, 6.06; N, 8.86. Found: C, 41.8; H, 6.1; N, 8.7.
Reaction SMILES: [CH3:1][NH2:2].C([O:5][C:6](=O)[CH2:7][N:8]1[CH:13]=[CH:12][C:11]([N:14]2[CH:18]=[C:17]([C:19]#[C:20][C:21]3[CH:22]=[C:23]([CH3:27])[CH:24]=[CH:25][CH:26]=3)[N:16]=[C:15]2[CH3:28])=[CH:10][C:9]1=[O:29])C>C(O)C>[CH3:1][NH:2][C:6](=[O:5])[CH2:7][N:8]1[CH:13]=[CH:12][C:11]([N:14]2[CH:18]=[C:17]([C:19]#[C:20][C:21]3[CH:22]=[C:23]([CH3:27])[CH:24]=[CH:25][CH:26]=3)[N:16]=[C:15]2[CH3:28])=[CH:10][C:9]1=[O:29]
Reactant: CCOC(=O)Cn1ccc(-n2cc(C#Cc3cccc(C)c3)nc2C)cc1=O
Reactant: CN
Solvent: CCO
Product: CNC(=O)Cn1ccc(-n2cc(C#Cc3cccc(C)c3)nc2C)cc1=O
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To 2 ml of a 8M solution of methylamine in ethanol were added 67 mg (0.18 mmol) of [4-(2-methyl-4-m-tolylethynyl-imidazol-1-yl)-2-oxo-2H-pyridin-1-yl]-acetic acid ethyl ester (Example 13). The reaction vessel was closed and the yellow solution was stirred for 16 h at room temperature. The solution was then evaporated to dryness yielding 63 mg of the title compound as a light brown solid, MS: m/e=361.2 (M+H+).
Reaction SMILES: [H-].[Na+].[CH2:3]([O:5][C:6]([C:8]1[CH:12]=[C:11]([C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][CH:14]=2)[NH:10][N:9]=1)=[O:7])[CH3:4].[F:23][C:24]([F:35])([F:34])[CH2:25]OS(C(F)(F)F)(=O)=O.ClCCl>CN(C=O)C>[CH2:3]([O:5][C:6]([C:8]1[N:9]([CH2:25][C:24]([F:35])([F:34])[F:23])[N:10]=[C:11]([C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:21])([F:22])[F:20])=[CH:15][CH:14]=2)[CH:12]=1)=[O:7])[CH3:4]
Reactant: CCOC(=O)c1cc(-c2ccc(C(F)(F)F)cc2)[nH]n1
Reactant: O=S(=O)(OCC(F)(F)F)C(F)(F)F
Agent: [H-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CCOC(=O)c1cc(-c2ccc(C(F)(F)F)cc2)nn1CC(F)(F)F
Temperature: 0 °C
Reaction time: 0.67 h
Yield: 56.8 %

Procedure:
Sodium hydride (55% dispersion in mineral oil, 203 mg, 5 mmol) was added to an ice cooled solution of 5-(4-trifluoromethyl-phenyl)-1H-pyrazole-3-carboxylic acid ethyl ester (1 g, 4 mmol; PCT Int. Appl. (2003), WO 2004000785 A2) in DMF (60 ml) under an argon atmosphere. The solution was stirred for 10 min at 0° C. and for 40 min at ambient temperature. Trifluoroethyltriflate (1.07 g, 5 mmol) was added and the mixture was stirred for 3 h at ambient temperature. The solution was cooled to 0° C., 1 N HCl/ice water 1/2 and dichloromethane were added. The aqueous layer was extracted two times with dichloromethane, the combined extracts were washed with brine/ice water 1/1 and dried over sodium sulfate. Evaporation of the solvent under reduced pressure gave yellow crystals which were purified by column chromatography (silica gel, n-heptane/AcOEt) to yield 833 mg (2.27 mmol, 65%) of the title compound as colorless crystals.
Reaction SMILES: [C:1]([NH:4][C:5]1[C:6]([O:8][C@@H:9]([CH3:16])[C:10]=1[C:11]([O:13][CH2:14][CH3:15])=[O:12])=[O:7])(=[O:3])[CH3:2]>C(OCC)(=O)C.C(Cl)(Cl)Cl>[C:1]([NH:4][C@@H:5]1[C@H:10]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[C@H:9]([CH3:16])[O:8][C:6]1=[O:7])(=[O:3])[CH3:2]
Reactant: CCOC(=O)C1=C(NC(C)=O)C(=O)O[C@H]1C
Solvent: CCOC(C)=O
Solvent: ClC(Cl)Cl
Product: CCOC(=O)[C@@H]1[C@H](C)OC(=O)[C@@H]1NC(C)=O
Reaction time: 21 h

Procedure:
0.45 g of rhodium/Al2O3 catalyst is added to 15 g of (S)-2-acetamido-3-ethoxycarbonyl-2-penten-4-olide dissolved in 100 ml of ethyl acetate and the whole is hydrogenated at 50° C. and 50 bars for 21 hours and worked up as in Example 14. The ratio of the diastereoisomers of the crude product exhibited by HPLC analysis is (2R,3S,4S):(2S,3R,4S):(2R,3R,4S)=approximately 85:13:2. Diastereoisomerically pure title compound is obtained by crystallisation from ethyl acetate, [α]D20 =-183.2° (3% in CHCl3), m.p. 165°-167° C.
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH:3]([OH:6])[CH2:2]1.C(N(CC)CC)C.Cl.[F:15][C:16]([F:50])([F:49])[C:17]1[CH:22]=[C:21]([C:23]2[CH:28]=[CH:27][C:26]([C:29]([F:32])([F:31])[F:30])=[CH:25][CH:24]=2)[N:20]=[C:19]([C:33]2[CH:38]=[CH:37][N:36]=[C:35]([C:39]3[CH:40]=[C:41]([S:45](Cl)(=[O:47])=[O:46])[CH:42]=[CH:43][CH:44]=3)[CH:34]=2)[N:18]=1>C1COCC1>[F:50][C:16]([F:15])([F:49])[C:17]1[CH:22]=[C:21]([C:23]2[CH:24]=[CH:25][C:26]([C:29]([F:32])([F:31])[F:30])=[CH:27][CH:28]=2)[N:20]=[C:19]([C:33]2[CH:38]=[CH:37][N:36]=[C:35]([C:39]3[CH:40]=[C:41]([S:45]([N:1]4[CH2:5][CH2:4][CH:3]([OH:6])[CH2:2]4)(=[O:47])=[O:46])[CH:42]=[CH:43][CH:44]=3)[CH:34]=2)[N:18]=1
Reactant: O=S(=O)(Cl)c1cccc(-c2cc(-c3nc(-c4ccc(C(F)(F)F)cc4)cc(C(F)(F)F)n3)ccn2)c1
Reactant: OC1CCNC1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=S(=O)(c1cccc(-c2cc(-c3nc(-c4ccc(C(F)(F)F)cc4)cc(C(F)(F)F)n3)ccn2)c1)N1CCC(O)C1
Temperature: 0 °C
Yield: 82.4 %

Procedure:
To a cooled (ice-water bath) and stirred mixture of (RS)-3-pyrrolidinol (0.27 g, 3.0 mmol), triethylamine (0.29 ml, 2.1 mmol) and THF (4 ml) was added drop wise a solution of 3-{4-[4-trifluoromethyl-6-(4-trifluoromethyl-phenyl)-pyrimidin-2-yl]-pyridin-2-yl}-benzenesulfonyl chloride hydrochloride (example I.1) (0.58 g, 1.0 mmol) in THF (6 ml). The mixture was allowed to stir at room temperature for 16 h. Purification of the reaction mixture by flash chromatography on silica gel (ethyl acetate/heptane) and crystallization (dichloromethane/MeOH/hexane) yielded the title compound as a white solid (0.49 g, 88%). MS (ISP) 594.6 [(M+H)+]; mp 234° C.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:5]2[C:6](=[O:9])[CH2:7][O:8][C:4]=2[C:3]=1[CH2:12][N:13]1[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15][CH2:14]1.[Cl:26][C:27]1[CH:28]=[C:29]2[C:33](=[CH:34][CH:35]=1)[NH:32][N:31]=[C:30]2[CH:36]=O.N1CCCCC1>CO>[OH:1][C:2]1[CH:11]=[CH:10][C:5]2[C:6](=[O:9])/[C:7](=[CH:36]/[C:30]3[C:29]4[C:33](=[CH:34][CH:35]=[C:27]([Cl:26])[CH:28]=4)[NH:32][N:31]=3)/[O:8][C:4]=2[C:3]=1[CH2:12][N:13]1[CH2:14][CH2:15][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:17][CH2:18]1
Reactant: CC(C)(C)OC(=O)N1CCN(Cc2c(O)ccc3c2OCC3=O)CC1
Reactant: O=Cc1n[nH]c2ccc(Cl)cc12
Solvent: C1CCNCC1
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCN(Cc2c(O)ccc3c2O/C(=C\c2n[nH]c4ccc(Cl)cc24)C3=O)CC1
Temperature: 60 °C
Reaction time: 3 h
Yield: 51.1 %

Procedure:
A solution of tert-butyl 4-[1-(6-hydroxy-3-oxo-2,3-dihydrobenzofuran-7-yl)methyl]piperazine-1-carboxylate (0.100 g, 0.287 mmol) in methanol (1.2 mL) was added with 5-chloro-1H-indazole-3-carbaldehyde (0.0518 g, 0.287 mmol), and piperidine (0.00244 g, 0.0287 mmol) at room temperature, and the mixture was stirred at 60° C. for 3 hours. The reaction mixture was added with methanol (4 mL), suspended in methanol and thereby washed, and then the solid was collected by filtration to obtain tert-butyl (Z)-4-({6-hydroxy-3-oxo-2-[(5-chloro-1H-indazol-3-yl)methylene]-2,3-dihydrobenzofuran-7-yl}methyl)piperazine-1-carboxylate (0.0750 g, 51%).