Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH3:23])=[C:4]([N:8]([S:13]([C:16]2[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][CH:17]=2)(=[O:15])=[O:14])[CH2:9][C:10](O)=[O:11])[CH:5]=[CH:6][CH:7]=1.[CH3:24][O:25][C:26]1[CH:33]=[CH:32][C:29]([CH2:30][NH2:31])=[CH:28][CH:27]=1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C>CN(C=O)C.O>[Cl:1][C:2]1[C:3]([CH3:23])=[C:4]([N:8]([S:13]([C:16]2[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][CH:17]=2)(=[O:15])=[O:14])[CH2:9][C:10]([NH:31][CH2:30][C:29]2[CH:32]=[CH:33][C:26]([O:25][CH3:24])=[CH:27][CH:28]=2)=[O:11])[CH:5]=[CH:6][CH:7]=1
Reactant: COc1ccc(CN)cc1
Reactant: Cc1ccc(S(=O)(=O)N(CC(=O)O)c2cccc(Cl)c2C)cc1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc(CNC(=O)CN(c2cccc(Cl)c2C)S(=O)(=O)c2ccc(C)cc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 93.2 %

Procedure:
707 mg of N-(3-chloro-2-methylphenyl)-N-[(4-methylphenyl)sulfonyl]glycine was dissolved in 8.00 mL of DMF, and 302 mg of 4-methoxybenzylamine, 324 mg of HOBt, and 460 mg of WSC were added thereto, followed by stirring at room temperature overnight. To the reaction liquid was added water, followed by extraction with ethyl acetate, and the organic layer was washed with saturated brine, and then dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (hexane:ethyl acetate=4:1) to obtain 881 mg of N2-(3-chloro-2-methylphenyl)-N-(4-methoxybenzyl)-N2-[(4-methylphenyl)sulfonyl] glycinamide.
Reaction SMILES: [Cl:1][C:2]1[C:3]([NH:18][C:19](=[O:30])[C:20]2[CH:25]=[CH:24][C:23]([O:26][CH2:27][CH3:28])=[C:22]([Br:29])[CH:21]=2)=[CH:4][CH:5]=[C:6]2[C:11]=1[CH2:10][N:9](C(=O)C(F)(F)F)[CH2:8][CH2:7]2.C(=O)([O-])[O-].[K+].[K+]>CO.O.ClCCl>[Cl:1][C:2]1[C:3]([NH:18][C:19](=[O:30])[C:20]2[CH:25]=[CH:24][C:23]([O:26][CH2:27][CH3:28])=[C:22]([Br:29])[CH:21]=2)=[CH:4][CH:5]=[C:6]2[C:11]=1[CH2:10][NH:9][CH2:8][CH2:7]2
Reactant: CCOc1ccc(C(=O)Nc2ccc3c(c2Cl)CN(C(=O)C(F)(F)F)CC3)cc1Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CO
Solvent: O
Product: CCOc1ccc(C(=O)Nc2ccc3c(c2Cl)CNCC3)cc1Br
Reaction time: 12 h
Yield: 79.4 %

Procedure:
A solution of N-(8-chloro-2-trifluoroacetyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-3-bromo-4-ethoxybenzamide (0.28 g) in methanol/water (5 ml 9:1) was treated with potassium carbonate (0.38 g) and stirred 12 h. The mixture was diluted with dichloromethane and washed with water. The organic phase was dried (MgSO4) solvent removed at reduced pressure. The residue was chromatographed (silica gel, dichloromethane/methanol/ammonia up to 9:1:0.1 eluant) to give the title compound (0.18 g) as a colourless solid.
Reaction SMILES: [CH2:1]([C:5]1[N:6]=[C:7]([CH3:27])[NH:8][C:9](=[O:26])[C:10]=1[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[C:19]([C:24]#[N:25])=[CH:20][CH:21]=[CH:22][CH:23]=2)=[CH:14][CH:13]=1)[CH2:2][CH2:3][CH3:4].N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O.C(P(CCCC)CCCC)CCC.[S:59]1[C:63]2[CH:64]=[CH:65][CH:66]=[CH:67][C:62]=2[N:61]=[C:60]1[CH2:68]O>C(OCC)(=O)C.O1CCCC1>[S:59]1[C:63]2[CH:64]=[CH:65][CH:66]=[CH:67][C:62]=2[N:61]=[C:60]1[CH2:68][N:8]1[C:9](=[O:26])[C:10]([CH2:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]3[C:19]([C:24]#[N:25])=[CH:20][CH:21]=[CH:22][CH:23]=3)=[CH:14][CH:13]=2)=[C:5]([CH2:1][CH2:2][CH2:3][CH3:4])[N:6]=[C:7]1[CH3:27]
Reactant: CCCCc1nc(C)[nH]c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Reactant: OCc1nc2ccccc2s1
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCCCc1nc(C)n(Cc2nc3ccccc3s2)c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 44.6 %

Procedure:
A mixture of 4′-[(4-butyl-2-methyl-6-oxo-1,6-dihydropyrimidin-5-yl)methyl]biphenyl-2-carbonitrile (1 g), 1,1′-(azodicarbonyl)dipiperidine (1.41 g), tributylphosphine (1.56 mL), 1,3-benzothiazol-2-ylmethanol (0.69 g) and tetrahydrofuran (50 mL) was stirred at room temperature for 4 hr. The reaction mixture was diluted with ethyl acetate, washed with water and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography to give the title compound as a colorless solid (0.63 g, 45%).
Reaction SMILES: [CH:1]([C:5]1[CH:6]=[CH:7][C:8]([NH2:11])=[N:9][CH:10]=1)([CH2:3][CH3:4])[CH3:2].C(N(CC)C(C)C)(C)C.ClC(Cl)(Cl)[C:23](Cl)=[O:24].C([O-])(O)=O.[Na+].[N:33]1([C:40]([CH:42]2[CH2:47][CH2:46][O:45][CH2:44][CH2:43]2)=[O:41])[CH2:39][CH2:38][CH2:37][NH:36][CH2:35][CH2:34]1.C([O-])([O-])=O.[Na+].[Na+]>C(Cl)Cl>[CH:1]([C:5]1[CH:6]=[CH:7][C:8]([NH:11][C:23]([N:36]2[CH2:37][CH2:38][CH2:39][N:33]([C:40]([CH:42]3[CH2:47][CH2:46][O:45][CH2:44][CH2:43]3)=[O:41])[CH2:34][CH2:35]2)=[O:24])=[N:9][CH:10]=1)([CH2:3][CH3:4])[CH3:2]
Reactant: CCC(C)c1ccc(N)nc1
Reactant: O=C(C1CCOCC1)N1CCCNCC1
Reactant: O=C(Cl)C(Cl)(Cl)Cl
Agent: O=C([O-])O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCC(C)c1ccc(NC(=O)N2CCCN(C(=O)C3CCOCC3)CC2)nc1
Temperature: 100 °C
Reaction time: 18 h
Yield: 9 %

Procedure:
To a solution of 90 mg (0.6 mmol) of 5-sec-butyl-pyridin-2-ylamine in DCM (2 mL) was added N,N-diisopropylethylamine (348 μL, 1.2 mmol), followed by 67 μL (0.6 mmol) of trichloroacetylchloride. The reaction mixture was shaken on an orbital shaker for 18 h. Saturated aqueous NaHCO3 solution (3 mL) was added to the reaction mixture. The organic layer was dried over Na2SO4, filtered and the filtrate was concentrated under reduced pressure. The residue was dissolved in DMF (2 mL) and added to 332 mg (0.6 mmol) of [1,4]diazepan-1-yl-(tetrahydro-pyran-4-yl)-methanone (triple trifluoroacetic acid salt). To this solution 254 mg (2.4 mmol) of Na2CO3 were added and the mixture was heated in a sealed tube at 100° C. for 18 h. The reaction was cooled to room temperature, filtered and the filtrate was concentrated under reduced pressure. The residue was purified by mass-triggered preparative LC-MS to afford 21 mg of 4-(tetrahydro-pyran-4-carbonyl)-[1,4]diazepane-1-carboxylic acid (5-sec-butyl-pyridin-2-yl)-amide. ES−MS: m/z 389;
Reaction SMILES: [CH3:1][N:2]([CH2:4][C:5]1([C:11]2[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=2)[CH2:10][CH2:9][O:8][CH2:7][CH2:6]1)[CH3:3].Cl[CH2:19][CH2:20][CH2:21][N:22]1[C@@H:26]([CH3:27])[CH2:25][CH2:24][C@@H:23]1[CH3:28].C([O-])([O-])=O.[K+].[K+].N>CO.C(Cl)Cl.CN(C=O)C>[CH3:28][CH:23]1[CH2:24][CH2:25][CH:26]([CH3:27])[N:22]1[CH2:21][CH2:20][CH2:19][O:17][C:14]1[CH:15]=[CH:16][C:11]([C:5]2([CH2:4][N:2]([CH3:1])[CH3:3])[CH2:6][CH2:7][O:8][CH2:9][CH2:10]2)=[CH:12][CH:13]=1
Reactant: CN(C)CC1(c2ccc(O)cc2)CCOCC1
Reactant: C[C@H]1CC[C@H](C)N1CCCCl
Agent: N
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: CO
Product: CC1CCC(C)N1CCCOc1ccc(C2(CN(C)C)CCOCC2)cc1
Yield: 38.1 %

Procedure:
4-(4-Dimethylaminomethyl-tetrahydro-pyran-4-yl)-phenol (330 mg, 1.43 mmol), 1-(3-chloro-propyl)-2,5-trans-dimethyl-pyrrolidine (221 mg, 1.26 mmol), DMF (7.6 ml) and K2CO3 (790 mg, 5.72 mmol) were reacted together according to general procedure B. The isolated material was subjected to chromatography on silica, eluant 95:4:1 (DCM, MeOH, NH3) to give the title compound as a yellow oil (180 mg, 34%). 1H NMR (400 MHz, CDCl3) δ7.20 (d, 2H), 6.87 (d, 2H), 4.08-3.95 (m, 2H), 3.79-3.70 (m, 2H), 3.59-3.49 (m, 2H), 3.11-3.00 (m, 2H), 2.77 (m, 1H), 2.54 (m, 1H), 2.40 (s, 2H), 2.14-1.81 (m, 8H), 1.96 (s, 6H), 1.44-1.31 (m, 2H), 0.97 (d, 6H).
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:14])[C@H:5]([CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[NH2:6].CN1CCOCC1.[N:22]1[CH:27]=[CH:26][N:25]=[CH:24][C:23]=1[C:28](O)=[O:29].C1(N=C=NC2CCCCC2)CCCCC1.C1C=CC2N(O)N=NC=2C=1>C1COCC1>[CH3:2][O:3][C:4](=[O:14])[C@H:5]([CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[NH:6][C:28]([C:23]1[CH:24]=[N:25][CH:26]=[CH:27][N:22]=1)=[O:29]
Reactant: O=C(O)c1cnccn1
Reactant: COC(=O)[C@@H](N)Cc1ccccc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN1CCOCC1
Solvent: C1CCOC1
Product: COC(=O)[C@H](Cc1ccccc1)NC(=O)c1cnccn1
Reaction time: 2 h
Yield: 98 %

Procedure:
The product L-phenylalanine methyl ester hydrochloride of Preparation example 1 (1.12 g, 5.2 mmol) was dissolved in 20 ml of THF, and neutralized with N-methyl morpholine (NMM) (0.7 ml, 6.2 mmol), then cooled with an ice bath for later use. Pyrazinecarboxylic acid (0.65 g, 5.2 mmol) was added to another reaction flask, dissolved with 20 ml of THF, cooled with an ice water bath, dicyclohexylcarbodiimide (DCC) (1.07 g, 5.2 mmol) and HOBt (0.84 g, 6.2 mmol) were added at 0° C. and reacted for 40 min at 0° C., to which the solution of L-phenylalanine methyl ester hydrochloride in THF prepared, cooled and neutralized according to the above was added, the reaction was monitored by TLC and completed after 2 h, insoluble N,N′-dicyclohexylurea (DCU) was removed by filtration, to the filtrate was added 150 ml of ethyl acetate, washed with 5% sodium bicarbonate solution, 10% citric acid solution, 5% sodium bicarbonate solution, saturated salt solution (2×20 ml) successively. The ethyl acetate layer was dried over anhydrous sodium sulfate, filtered, and evaporated the solvent under reduced pressure, 1.37 g of white solid was obtained with a yield of 98%, m.p.: 152-155° C. 1H-NMR (CDCl3, 300 MHz): δ 3.26 (—CH2, m, 2H), 3.75 (—CH3, s, 3H), 5.09 (—CH, m, 1H), 7.15˜7.32 (-Ph, m, 5H), 8.23 (—CONH, d, 1H), 8.52 (-Pyz, d, 1H), 8.74 (-Pyz, d, 1H), 9.37 (-Pyz, s, 1H).
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[N:20]([CH:23]([C:25]1[O:26][C:27]2[CH:39]=[CH:38][CH:37]=[CH:36][C:28]=2[C:29]=1[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[CH3:24])=[N+]=[N-]>C1COCC1.O>[C:30]1([C:29]2[C:28]3[CH:36]=[CH:37][CH:38]=[CH:39][C:27]=3[O:26][C:25]=2[CH:23]([NH2:20])[CH3:24])[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1
Reactant: CC(N=[N+]=[N-])c1oc2ccccc2c1-c1ccccc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: C1CCOC1
Product: CC(N)c1oc2ccccc2c1-c1ccccc1
Temperature: 60 °C

Procedure:
Triphenylphosphine (231 mg, 0.883 mmol) was added to a solution of 2-(1-azidoethyl)-3-phenylbenzofuran (186 mg, 0.706 mmol) in THF (9 mL) and water (1 mL). The mixture was heated at 60° C. for 2 h and then cooled to RT. Volatiles were removed under reduced pressure and the resulting residue was purified by column chromatography (Si—PCC, gradient 0-10% MeOH in EtOAc) affording 1-(3-phenylbenzofuran-2-yl)ethanamine as an oil (327 mg, quantitative). LCMS: RT 2.21 min [M−NH2]+ 221.1
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:14]2[CH:45]=[CH:44][C:17]([C:18]([NH:20][C@@H:21]([C:37]3[CH:42]=[CH:41][CH:40]=[C:39]([Cl:43])[CH:38]=3)[CH2:22][N:23]([CH3:36])S(C3C=CC=CC=3[N+]([O-])=O)(=O)=O)=[O:19])=[C:16]([F:46])[CH:15]=2)=[N:4][C:5]([CH:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)=[CH:6][N:7]=1.SC1C=CC(C(O)=O)=CC=1.C([O-])([O-])=O.[K+].[K+].O>CN(C=O)C>[NH2:1][C:2]1[C:3]([C:14]2[CH:45]=[CH:44][C:17]([C:18]([NH:20][C@@H:21]([C:37]3[CH:42]=[CH:41][CH:40]=[C:39]([Cl:43])[CH:38]=3)[CH2:22][NH:23][CH3:36])=[O:19])=[C:16]([F:46])[CH:15]=2)=[N:4][C:5]([CH:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)=[CH:6][N:7]=1
Reactant: CN(C[C@@H](NC(=O)c1ccc(-c2nc(C3CCOCC3)cnc2N)cc1F)c1cccc(Cl)c1)S(=O)(=O)c1ccccc1[N+](=O)[O-]
Agent: O=C(O)c1ccc(S)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CNC[C@@H](NC(=O)c1ccc(-c2nc(C3CCOCC3)cnc2N)cc1F)c1cccc(Cl)c1
Temperature: 40 °C
Reaction time: 0.5 h
Yield: 67.1 %

Procedure:
To a solution of (S)-4-(3-amino-6-(tetrahydro-2H-pyran-4-yl)pyrazin-2-yl)-N-(1-(3-chlorophenyl)-2-(N-methyl-2-nitrophenylsulfonamido)ethyl)-2-fluorobenzamide (2.68 g, 4.01 mmol) in DMF (20 mL) was added 4-mercaptobenzoic acid (1.235 g, 8.01 mmol) and K2CO3 (2.214 g, 16.02 mmol). The reaction mixture was heated at 40° C. overnight under nitrogen. Water (50 mL) was added, and the mixture turned into homogenous. The reaction was stirred at room temperature for 30 min, and then water (150 mL) was added slowly. Light yellow solid was precipitated out. The mixture was stirred for another 30 min, and the suspension was filtered out. The solid was washed well with water, followed by heptane, and air dried for 1 h. The solid was suspended in water and stirred at room temperature for 1 h, and then filtered. To the solid was added EtOAc, and slowly rotated on rotavap to remove excess ethyl acetate until about 20 mL of EtOAc left, the white solid was filtered, and redissolved in acetonitrile and water, lyophilized. The solution was dried on lyophilizer to afford (S)-4-(3-amino-6-(tetrahydro-2H-pyran-4-yl)pyrazin-2-yl)-N-(1-(3-chlorophenyl)-2-(methylamino)ethyl)-2-fluorobenzamide (1.31 g, 2.69 mmol, 67.2%). LCMS (m/z): 484.3 (MH+), 0.66 min; 1H NMR (500 MHz, METHANOL-d4) δ ppm 7.90 (s, 1H), 7.83 (t, J=7.7 Hz, 1H), 7.70 (dd, J=1.1, 8.0 Hz, 1H), 7.63 (d, J=10.7 Hz, 1H), 7.48 (s, 1H), 7.38 (d, J=5.4 Hz, 2H), 7.32 (dt, J=1.9, 4.6 Hz, 1H), 5.33 (dd, J=5.2, 9.0 Hz, 1H), 4.05 (dd, J=3.5, 11.0 Hz, 2H), 3.57 (dt, J=1.9, 11.8 Hz, 2H), 3.12-3.04 (m, 1H), 3.04-2.88 (m, 2H), 2.48 (s, 3H), 1.89-1.88 (m, 1H), 1.96-1.76 (m, 4H).
Reaction SMILES: [N:1]1([C:5](=[O:25])[CH2:6][C:7]2[CH:12]=[CH:11][C:10]([C:13]3[CH:14]=[C:15]4[C:19](=[CH:20][C:21]=3[Cl:22])[NH:18][CH:17]=[C:16]4[CH:23]=[O:24])=[CH:9][CH:8]=2)[CH2:4][CH2:3][CH2:2]1.CC(=CC)C.Cl([O-])=[O:32].[Na+].O.O.OP([O-])(O)=O.[Na+]>C(#N)C.C(O)(C)(C)C.O>[N:1]1([C:5](=[O:25])[CH2:6][C:7]2[CH:12]=[CH:11][C:10]([C:13]3[CH:14]=[C:15]4[C:19](=[CH:20][C:21]=3[Cl:22])[NH:18][CH:17]=[C:16]4[C:23]([OH:32])=[O:24])=[CH:9][CH:8]=2)[CH2:4][CH2:3][CH2:2]1
Reactant: O=Cc1c[nH]c2cc(Cl)c(-c3ccc(CC(=O)N4CCC4)cc3)cc12
Reactant: [O-][Cl+][O-]
Agent: CC=C(C)C
Agent: O=P([O-])(O)O
Agent: [Na+]
Solvent: CC#N
Solvent: CC(C)(C)O
Solvent: O
Product: O=C(O)c1c[nH]c2cc(Cl)c(-c3ccc(CC(=O)N4CCC4)cc3)cc12
Temperature: 0 °C
Reaction time: 2 h
Yield: 15 %

Procedure:
To a solution of 5-{4-[2-(azetidin-1-yl)-2-oxoethyl]phenyl}-6-chloro-1H-indole-3-carbaldehyde (0.16 g, 0.453 mmol) in acetonitrile (8 mL) and tert-butanol (8 mL) was added 2-methyl-2-butene (8 mL). The reaction mixture was cooled to 0° C. and treated with a solution of sodium chlorite (456 mg, 5 mmol) and sodium phosphate monobasic dihydrate (1.06 g, 6.8 mmol) in water (6 mL). The reaction mixture was stirred for 2 hours at room temperature, and treated with additional sodium chlorite (607 mg, 6.67 mmol), sodium phosphate monobasic dihydrate (1.41 g, 9.04 mmol) and 2-methyl-2-butene (1 mL). The resulting mixture was stirred at room temperature overnight. The reaction mixture was partially evaporated in vacuo and extracted with EtOAc (30 mL×3). The combined organic layers were dried over sodium sulfate and concentrated in vacuo. The residue was purified via prep-HPLC to give 5-{4-[2-(azetidin-1-yl)-2-oxoethyl]phenyl}-6-chloro-1H-indole-3-carboxylic acid (25 mg) as a yellow solid.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([OH:8])[CH:5]=[CH:4][C:3]=1[CH:9]=[CH:10][C:11]([C:13]1[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[C:15]([O:21][CH3:22])[CH:14]=1)=O.[BH4-].[Na+].C(O)(=[O:27])C>C(O)CC>[OH:1][C:2]1[CH:7]=[C:6]([OH:8])[CH:5]=[CH:4][C:3]=1[CH:9]([OH:27])[CH2:10][CH2:11][C:13]1[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[C:15]([O:21][CH3:22])[CH:14]=1
Reactant: CC(=O)O
Reactant: COc1ccc(C(=O)C=Cc2ccc(O)cc2O)cc1OC
Agent: [BH4-]
Agent: [Na+]
Solvent: CCCO
Product: COc1ccc(CCC(O)c2ccc(O)cc2O)cc1OC
Temperature: 80 °C

Procedure:
2,4-Dihydroxy-3′,4′-dimethoxychalcone (4) (40 mg) was dissolved in 1-propanol (5 ml), followed by the addition of sodium borohydride (15 mg) and the mixture was allowed to react at room temperature for 2 hours. Upon completion of the reaction, 20% acetic acid (0.2 ml) was added and the mixture was heated at 80° C. for 5 minutes and cooled down. The mixture was then separated on a pre-packed C18 column eluting with a MeOH/H2O gradient to provide 1-(2,4-dihydroxyphenyl)-3-(3,4-dimethoxyphenyl)-1-propanol (5). The structure of compound (5) was confirmed by MS, UV spectroscopy, 1D and 2D 1H-NMR.
Reaction SMILES: C([O:3][C:4]([CH:6]1[CH2:9][C:8]([F:34])([C:10]2[CH:15]=[CH:14][C:13]([C:16]3[CH2:20][C:19]([C:25]4[CH:30]=[C:29]([Cl:31])[C:28]([Cl:32])=[C:27]([Cl:33])[CH:26]=4)([C:21]([F:24])([F:23])[F:22])[O:18][N:17]=3)=[CH:12][CH:11]=2)[CH2:7]1)=[O:5])C.[OH-].[Li+]>CCO.O>[F:34][C:8]1([C:10]2[CH:15]=[CH:14][C:13]([C:16]3[CH2:20][C:19]([C:25]4[CH:26]=[C:27]([Cl:33])[C:28]([Cl:32])=[C:29]([Cl:31])[CH:30]=4)([C:21]([F:22])([F:23])[F:24])[O:18][N:17]=3)=[CH:12][CH:11]=2)[CH2:7][CH:6]([C:4]([OH:5])=[O:3])[CH2:9]1
Reactant: CCOC(=O)C1CC(F)(c2ccc(C3=NOC(c4cc(Cl)c(Cl)c(Cl)c4)(C(F)(F)F)C3)cc2)C1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: O=C(O)C1CC(F)(c2ccc(C3=NOC(c4cc(Cl)c(Cl)c(Cl)c4)(C(F)(F)F)C3)cc2)C1
Temperature: 25 °C
Reaction time: 16 h
Yield: 72 %

Procedure:
To a stirred solution of 3-fluoro-3-{4-[5-(3,4,5-trichloro-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]-phenyl}-cyclobutanecarboxylic acid ethyl ester (polar spot of Preparation 5, 1.2 g, 2.23 mmol) in EtOH:H2O (1:1, 80 mL) was added lithium hydroxide (0.469 g, 11.17 mmol) at 0° C. Resulting reaction mixture was stirred at room temperature for 16 hours. After consumption of starting material, reaction mixture was concentrated in vacuo, diluted with water (50 mL) and acidified using 1M HCl up to pH=2 at 0° C., solid was precipitated out. Resulting solid was filtered on Whatmann filter paper. Solid was dissolved in EtOAc (50 mL), dried over sodium sulphate, filtered and evaporated to afford solid, which was washed with n-pentane (3×3 mL) to afford white solid (0.820 g, 72%). 1H NMR (400 MHz, DMSO-d6) δ: 2.75-2.84 (m, 5H), 4.30-4.42 (m, 2H), 7.65 (d, J=8.20 Hz, 2H), 7.77 (d, J=8.16 Hz, 2H), 7.85 (s, 2H), 12.52 (bs, 1H); LC-MS (m/z): 507.90 (M−H).
Reaction SMILES: [OH:1][CH:2]1[CH2:15][C@@H:14]2[C@@H:5]([C@@H:6]3[C@@H:11]([CH2:12][CH2:13]2)[CH2:10][C@@:9]2([CH3:20])[C:16](=[O:19])[CH2:17][CH2:18][C@@H:8]2[CH2:7]3)[CH2:4][CH2:3]1.[I-].[CH3:22][S+](C)C.CC(C)([O-])C.[K+]>O>[CH3:20][C@:9]12[C@@:16]3([CH2:22][O:19]3)[CH2:17][CH2:18][C@@H:8]1[CH2:7][C@H:6]1[C@@H:11]([CH2:12][CH2:13][C@H:14]3[C@@H:5]1[CH2:4][CH2:3][C@@H:2]([OH:1])[CH2:15]3)[CH2:10]2
Reactant: C[C@@]12C[C@@H]3CC[C@@H]4CC(O)CC[C@@H]4[C@H]3C[C@H]1CCC2=O
Reactant: C[S+](C)C
Agent: CC(C)(C)[O-]
Agent: [I-]
Agent: [K+]
Solvent: O
Product: C[C@@]12C[C@@H]3CC[C@@H]4C[C@H](O)CC[C@@H]4[C@H]3C[C@H]1CC[C@]21CO1
Reaction time: 3 h
Yield: 64.6 %

Procedure:
To a solution of compound 55 (40 mg, 0.144 mmol) in DSMO (3 mL) was added trimethylsulfonium iodide (204 mg, 1.0 mmol) and potassium tert-butoxide (112 mg, 1.0 mmol) at room temperature. After 3 h, water (20 mL) was added and the product extracted into EtOAc (50 mL×3). The combined extracts were dried, filtered and concentrated. The residue was purified by flash column chromatography (silica gel eluted with 30% EtOAc in hexanes) to give compound 56 (27 mg, 65%) as a white solid: mp 163-165° C.; [α]D25 +16.7 (c 0.12, CHCl3); 1H NMR (CDCl3) δ 3.64-3.60 (m, 1H), 2.90 (d, J=15.0 Hz, 1H), 2.61 (d, J=15.2 Hz, 1H), 0.86 (s, 3H); 13C NMR (CDCl3) δ 71.7, 70.5, 53.6, 47.1, 41.6, 40.7, 39.1, 38.6, 38.1, 36.2, 35.1, 35.0, 33.6, 33.0, 30.4, 29.8, 28.9, 25.6, 14.5; IR νmax 3379, 1443, 1375 cm−1. MS (FAB) for [C19H30O2]+: 290.2246. Found: 290.2243.
Reaction SMILES: [F:1][CH:2]([F:25])[C:3]1[N:8]2[N:9]=[CH:10][C:11]([C:12](O)=[O:13])=[C:7]2[N:6]=[C:5]([C:15]2[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=2)[CH:4]=1.[CH3:26][S:27]([C:30]1[CH:31]=[C:32]([NH2:36])[CH:33]=[CH:34][CH:35]=1)(=[O:29])=[O:28].Cl>>[CH3:26][S:27]([C:30]1[CH:31]=[C:32]([NH:36][C:12]([C:11]2[CH:10]=[N:9][N:8]3[C:3]([CH:2]([F:1])[F:25])=[CH:4][C:5]([C:15]4[CH:16]=[CH:17][C:18]([C:21]([F:23])([F:22])[F:24])=[CH:19][CH:20]=4)=[N:6][C:7]=23)=[O:13])[CH:33]=[CH:34][CH:35]=1)(=[O:28])=[O:29]
Reactant: O=C(O)c1cnn2c(C(F)F)cc(-c3ccc(C(F)(F)F)cc3)nc12
Reactant: CS(=O)(=O)c1cccc(N)c1
Agent: Cl
Product: CS(=O)(=O)c1cccc(NC(=O)c2cnn3c(C(F)F)cc(-c4ccc(C(F)(F)F)cc4)nc23)c1

Procedure:
The title compound was prepared from 7-difluoromethyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (example C.1) and 3-methanesulfonyl-phenylamine [commercially available as hydrochloride] according to general procedure II. Yellow solid. MS (ISP) 511.4 [(M+H)+]; mp 251° C.
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][CH:5]([NH2:8])[CH2:4][CH2:3]1.C1C(=O)N([O:16][C:17]([CH2:19][CH2:20][CH2:21][CH2:22][CH:23]2[S:27][CH2:26][CH:25]3[NH:28][C:29]([NH:31][CH:24]23)=[O:30])=O)C(=O)C1.CCOCC>CN(C=O)C>[NH2:1][CH:2]1[CH2:7][CH2:6][CH:5]([NH:8][C:17](=[O:16])[CH2:19][CH2:20][CH2:21][CH2:22][CH:23]2[CH:24]3[CH:25]([NH:28][C:29](=[O:30])[NH:31]3)[CH2:26][S:27]2)[CH2:4][CH2:3]1
Reactant: NC1CCC(N)CC1
Reactant: O=C1NC2CSC(CCCCC(=O)ON3C(=O)CCC3=O)C2N1
Solvent: CCOCC
Solvent: CN(C)C=O
Product: NC1CCC(NC(=O)CCCCC2SCC3NC(=O)NC32)CC1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
1,4-Diaminocyclohexane (37.6 mg, 0.33 mmol) was dissolved in dry DMF (3 mL) under nitrogen. Solution of NHS-Biotin (102.3 mg, 0.3 mmol) in dry DMF (3 mL) was added to stirred solution of diamine over a 15 min period. Reaction mixture was stirred for 16 h at ambient temperature. Dilution of reaction mixture with dry Et2O (50 mL) produced white precipitate. Precipitated 19b was filtered, washed with EtOAc (3×20 mL) for removing of NHS and dried in high vacuum.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH:16]=[C:17]([OH:20])[C:18]=1I)[CH2:7][C:8]1[C:9]([NH2:15])=[N:10][C:11]([NH2:14])=[N:12][CH:13]=1)[CH3:2].C[C:22]([O-])([CH3:24])[CH3:23].[K+].[O:27]1[CH2:32][CH2:31][CH:30]([S:33](Cl)(=[O:35])=[O:34])[CH2:29][CH2:28]1>O1CCCC1>[NH2:10][C:9]1[CH:8]=[C:7]([C:18]2[C:4]([O:3][CH2:1][CH3:2])=[CH:5][C:6]([CH2:7][C:8]3[C:9]([NH2:15])=[N:10][C:11]([NH2:14])=[N:12][CH:13]=3)=[CH:16][C:17]=2[O:20][S:33]([CH:30]2[CH2:31][CH2:32][O:27][CH2:28][CH2:29]2)(=[O:35])=[O:34])[CH:24]=[CH:22][CH:23]=1
Reactant: CCOc1cc(Cc2cnc(N)nc2N)cc(O)c1I
Reactant: CC(C)(C)[O-]
Reactant: O=S(=O)(Cl)C1CCOCC1
Agent: [K+]
Solvent: C1CCOC1
Product: CCOc1cc(Cc2cnc(N)nc2N)cc(OS(=O)(=O)C2CCOCC2)c1-c1cccc(N)c1
Temperature: -20 °C
Reaction time: 1 h

Procedure:
5-(3-Ethoxy-5-hydroxy-4-iodo-benzyl)-pyrimidine-2,4-diamine (see example 32 stage a) (2,300 mg; 5.96 mmol) is dissolved in tetrahydrofuran (70 ml), potassium tert-butylate (1,000 mg; 8.9 mmol) is added and the mixture is cooled to −20° C. Tetrahydropyran-4-sulphonyl chloride (2.2 g; 11.9 mmol) is added at this temperature and the mixture is then stirred for one hour at −20° C. The reaction mixture is poured on to ice-water and extracted twice with ethyl acetate. The organic phase is dried over sodium sulphate, the salts are filtered off and the solvent is evaporated off. The residue is chromatographed over silica gel with methylene chloride 1 methanol (19/1) and 0.5% ammonia. The pure fractions are co mbidand the solvent is evaporated off.
Reaction SMILES: [C:1](=[O:4])([O-])[O-].[K+].[K+].CI.[C:9]([N:13]1[C:17](O)=[CH:16][C:15]([C:19]([F:22])([F:21])[F:20])=[N:14]1)([CH3:12])([CH3:11])[CH3:10].O>CN(C)C=O>[C:9]([N:13]1[C:17]([O:4][CH3:1])=[CH:16][C:15]([C:19]([F:21])([F:22])[F:20])=[N:14]1)([CH3:12])([CH3:10])[CH3:11]
Reactant: CC(C)(C)n1nc(C(F)(F)F)cc1O
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc(C(F)(F)F)nn1C(C)(C)C
Reaction time: 15 h
Yield: 99.7 %

Procedure:
15.0 g (108.4 mmoles) of anhydrous potassium carbonate and 19.3 g (135.5 mmoles) of methyl iodide were added, at room temperature, to a solution of 18.8 g (90.3 mmoles) of 1-tert-butyl-3-trifluoromethyl-1H-pyrazol-5-ol dissolved in 100 ml of N,N-dimethylformamide. The mixture was stirred for 15 hours to give rise to a reaction. After the completion of the reaction, the reaction mixture was poured into water, followed by extraction with diethyl ether. The resulting organic layer was washed with water and an aqueous sodium chloride solution in this order and then dried over anhydrous magnesium sulfate. The resulting solution was subjected to vacuum distillation to remove the solvent contained therein, to obtain 20.0 g (yield: 99.8%) of 1-tert-butyl-5-methoxy-3-trifluoromethyl-1H-pyrazole.