Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:8][C:9]1[CH:10]=[CH:11][C:12]([C@@H:20]([OH:66])[CH2:21][NH:22][CH2:23][CH2:24][C:25]2[CH:30]=[CH:29][C:28]([NH:31][C:32]([C:34]3[CH:35]=[C:36]([S:40]([C:43]4[CH:44]=[C:45]5[C:50](=[C:51]([CH3:53])[CH:52]=4)[N:49]=[CH:48][C:47]([C:54]([NH2:56])=[O:55])=[C:46]5[NH:57][C:58]4[CH:63]=[CH:62][CH:61]=[C:60]([O:64][CH3:65])[CH:59]=4)(=[O:42])=[O:41])[CH:37]=[CH:38][CH:39]=3)=[O:33])=[CH:27][CH:26]=2)=[C:13]2[C:18]=1[NH:17][C:16](=[O:19])[CH:15]=[CH:14]2)C1C=CC=CC=1>CCO.C1COCC1.[Pd]>[OH:66][C@H:20]([C:12]1[CH:11]=[CH:10][C:9]([OH:8])=[C:18]2[C:13]=1[CH:14]=[CH:15][C:16](=[O:19])[NH:17]2)[CH2:21][NH:22][CH2:23][CH2:24][C:25]1[CH:26]=[CH:27][C:28]([NH:31][C:32]([C:34]2[CH:35]=[C:36]([S:40]([C:43]3[CH:44]=[C:45]4[C:50](=[C:51]([CH3:53])[CH:52]=3)[N:49]=[CH:48][C:47]([C:54]([NH2:56])=[O:55])=[C:46]4[NH:57][C:58]3[CH:63]=[CH:62][CH:61]=[C:60]([O:64][CH3:65])[CH:59]=3)(=[O:41])=[O:42])[CH:37]=[CH:38][CH:39]=2)=[O:33])=[CH:29][CH:30]=1
Reactant: COc1cccc(Nc2c(C(N)=O)cnc3c(C)cc(S(=O)(=O)c4cccc(C(=O)Nc5ccc(CCNC[C@H](O)c6ccc(OCc7ccccc7)c7[nH]c(=O)ccc67)cc5)c4)cc23)c1
Agent: [Pd]
Solvent: CCO
Solvent: C1CCOC1
Product: COc1cccc(Nc2c(C(N)=O)cnc3c(C)cc(S(=O)(=O)c4cccc(C(=O)Nc5ccc(CCNC[C@H](O)c6ccc(O)c7[nH]c(=O)ccc67)cc5)c4)cc23)c1
Yield: 60.7 %

Procedure:
Intermediate 144 (119 mg) was dissolved in a mixture of EtOH (2 mL) and THF (3.5 mL) and hydrogenated in the presence of 10% Pd/C at rt and ambient pressure. After completion, the reaction was filtered and the filtrate purified by reverse-phase preparatory-LC to give the title compound as a yellow solid (65 mg).
Reaction SMILES: [CH:1]([NH:4][C:5]1[NH:10][C:9]2[CH:11]=[CH:12][C:13]([N+:15]([O-])=O)=[CH:14][C:8]=2[S:7](=[O:19])(=[O:18])[N:6]=1)([CH3:3])[CH3:2].[H][H]>CO.[Pd]>[NH2:15][C:13]1[CH:12]=[CH:11][C:9]2[NH:10][C:5]([NH:4][CH:1]([CH3:3])[CH3:2])=[N:6][S:7](=[O:18])(=[O:19])[C:8]=2[CH:14]=1
Reactant: CC(C)NC1=NS(=O)(=O)c2cc([N+](=O)[O-])ccc2N1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: CC(C)NC1=NS(=O)(=O)c2cc(N)ccc2N1

Procedure:
A solution of 3-isopropylamino-7-nitro-4H-1,2,4-benzothiadiazine 1,1-dioxide (0.6 g) in hot methanol (25 mL) was supplemented with 10% Pd/C (0.06 g) and submitted to hydrogen under pressure (4 bars) for 1 h at 40° C. The insoluble material was removed by filtration and the filtrate was concentrated to dryness by evaporation under reduced pressure. The residue of the crude title compound was recrystallized from methanol-water (yield: 0.45 g); m.p.: 278-283° C.; IR (KBr): 3455, 3363, 3216, 2972, 1618, 1575, 1510, 1298, 1255, 1174, 1146, 1113 cm−1; 1H-NMR (DMSO-d6, HMDS; d ppm): 1.10 (d, 6H, 2×CH3), 3.85 (m, 1H, NH—CH), 5.15 (bs, 2H, NH2), 6.50-6.95 (bm, 4H, 5-H+6-H+8-H+NH—CH), 9.75 (bs, 1H, NH).
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:4]=[N:5][CH:6]=[CH:7][CH:8]=1.[F:9][C:10]([F:17])([F:16])[C:11](OCC)=[O:12].C(N(CC)CC)C>ClCCl>[N:5]1[CH:6]=[CH:7][CH:8]=[C:3]([CH2:2][NH:1][C:11](=[O:12])[C:10]([F:17])([F:16])[F:9])[CH:4]=1
Reactant: NCc1cccnc1
Reactant: CCOC(=O)C(F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(NCc1cccnc1)C(F)(F)F
Yield: 93 %

Procedure:
22.87 g of 3-(aminomethyl)pyridine was dissolved in 100 ml dichloromethane and stirred with 50.4 ml ethyl trifluoroacetate and 29.5 ml triethylamine at room temperature for 2 hours. The solvent was evaporated under reduced pressure to give a residue, which was then recrystallized from ethyl acetate to provide N-(3-pyridylmethyl)trifluoroacetic acid amide (40.15 g, 93%).
Reaction SMILES: N.CC(C)([O-:5])C.[K+].[Cl:8][C:9]1[CH:14]=[C:13]([N+:15]([O-:17])=[O:16])[CH:12]=[C:11]([N+:18]([O-:20])=[O:19])[C:10]=1[Cl:21].C(OO)(C)(C)C>CN1CCCC1=O>[Cl:8][C:9]1[C:10]([Cl:21])=[C:11]([N+:18]([O-:20])=[O:19])[CH:12]=[C:13]([N+:15]([O-:17])=[O:16])[C:14]=1[OH:5]
Reactant: O=[N+]([O-])c1cc(Cl)c(Cl)c([N+](=O)[O-])c1
Reactant: CC(C)(C)[O-]
Agent: CC(C)(C)OO
Agent: N
Agent: [K+]
Solvent: CN1CCCC1=O
Product: O=[N+]([O-])c1cc([N+](=O)[O-])c(Cl)c(Cl)c1O
Temperature: -33 °C

Procedure:
A 100 mL round-bottomed flask with stir bar is charged with 10 milliliters (mL) of liquid ammonia and 5.6 grams (g) (0.050 mol) of potassium t-butoxide. The resulting mixture is refluxed at -33° C. under a dry ice/acetone condenser and a nitrogen atmosphere. A solution of 2.4 g (0.010 mol) 1,2-dichloro-3,5-dinitrobenzene and 1.1 g (1.1 eq.) of 90% t-butyl hydroperoxide in 30 mL of N-methylpyrrolidinone is added dropwise over approximately 1 hour to the agitated refluxing liquid ammonia reaction mixture. Upon completion of the addition, the dry ice/acetone condenser is removed and the ammonia is allowed to evaporate under a stream of dry nitrogen. The crude 2,3-dichloro-4,6-dinitrophenol is isolated by pouring the reaction mixture into 50 mL of aqueous hydrochloric acid, extracted with ethyl acetate and the organic solvents evaporated under reduced pressure (15 mm). The yield of the product is 2.2 g (89%). This product is of sufficient purity to be used without further refinement.
Reaction SMILES: [NH2:1][C:2]1[O:6][N:5]=[C:4]([CH3:7])[C:3]=1[Br:8].[CH:9]([C:12]1[CH:17]=[CH:16][C:15]([N:18]2[CH:22]=[CH:21][CH:20]=[C:19]2[S:23](Cl)(=[O:25])=[O:24])=[CH:14][CH:13]=1)([CH3:11])[CH3:10].C(C1C=CC(N2C=CC(S(Cl)(=O)=O)=C2)=CC=1)(C)C.C(O)(C(F)(F)F)=O.[Br:52][C:53]1[C:54]([CH3:76])=[N:55][O:56][C:57]=1[NH:58][S:59]([C:62]1[CH:66]=[CH:65][N:64]([C:67]2[CH:72]=[CH:71][C:70]([CH:73]([CH3:75])[CH3:74])=[CH:69][CH:68]=2)[CH:63]=1)(=[O:61])=[O:60]>O.C(#N)C>[Br:8][C:3]1[C:4]([CH3:7])=[N:5][O:6][C:2]=1[NH:1][S:23]([C:19]1[N:18]([C:15]2[CH:16]=[CH:17][C:12]([CH:9]([CH3:11])[CH3:10])=[CH:13][CH:14]=2)[CH:22]=[CH:21][CH:20]=1)(=[O:24])=[O:25].[Br:52][C:53]1[C:54]([CH3:76])=[N:55][O:56][C:57]=1[NH:58][S:59]([C:62]1[CH:66]=[CH:65][N:64]([C:67]2[CH:72]=[CH:71][C:70]([CH:73]([CH3:74])[CH3:75])=[CH:69][CH:68]=2)[CH:63]=1)(=[O:61])=[O:60]
Reactant: CC(C)c1ccc(-n2cccc2S(=O)(=O)Cl)cc1
Reactant: Cc1noc(N)c1Br
Agent: CC(C)c1ccc(-n2ccc(S(=O)(=O)Cl)c2)cc1
Agent: Cc1noc(NS(=O)(=O)c2ccn(-c3ccc(C(C)C)cc3)c2)c1Br
Solvent: CC#N
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: Cc1noc(NS(=O)(=O)c2cccn2-c2ccc(C(C)C)cc2)c1Br

Procedure:
N-(4-bromo-3-methyl-5-isoxazolyl) 1-(4'-isopropylphenyl)pyrrole-2-sulfonamide and N-(4-bromo-3-methyl-5-isoxazolyl) 1-(4'-isopropylphenyl)pyrrole-3-sulfonamide were prepared in the same manner as described in Example 2 from 5-amino-4-bromo-3-methylisoxazole and a mixture of 1-(4'-isopropylphenyl)pyrrole-2-sulfonyl chloride and 1-(4'-isopropylphenyl)pyrrole-3-sulfonyl chloride in 65% combined yield. The 22.85 min, 5% to 95% acetonitrile in water with 0.1 % TFA over 30 min period, C18 analytical column) and N-(4-bromo-3-methyl-5-isoxazolyl) 1-(4'-isopropylphenyl)pyrrole-3-sulfonamide (retention time 24.56 min, 5% to 95% acetonitrile in water with 0.1% TFA over 30 min period, C18 analytical column) as oils.
Reaction SMILES: C(=[N:14][C:15]1[S:16][C:17]([C:21]2[CH:26]=[CH:25][C:24]([N:27]3[CH:31]=[CH:30][CH:29]=[N:28]3)=[CH:23][CH:22]=2)=[C:18]([CH3:20])[N:19]=1)(C1C=CC=CC=1)C1C=CC=CC=1.NC1SC(C2C=CC(C(=O)C)=CC=2)=C(C)N=1>>[CH3:20][C:18]1[N:19]=[C:15]([NH2:14])[S:16][C:17]=1[C:21]1[CH:26]=[CH:25][C:24]([N:27]2[CH:31]=[CH:30][CH:29]=[N:28]2)=[CH:23][CH:22]=1
Reactant: Cc1nc(N=C(c2ccccc2)c2ccccc2)sc1-c1ccc(-n2cccn2)cc1
Agent: CC(=O)c1ccc(-c2sc(N)nc2C)cc1
Product: Cc1nc(N)sc1-c1ccc(-n2cccn2)cc1

Procedure:
This compound is prepared from benzhydrylidene-[4-methyl-5-(4-pyrazol-1-yl-phenyl)-thiazol-2-yl]-amine analogously to 1-[4-(2-amino-4-methyl-thiazol-5-yl)-phenyl]-ethanone (Intermediate A1 step 4).
Reaction SMILES: [NH3:1].[Cl:2][C:3]1[N:4]=[N:5][CH:6]=[C:7]([Cl:10])[C:8]=1Cl>C(O)C>[NH2:1][C:8]1[C:7]([Cl:10])=[CH:6][N:5]=[N:4][C:3]=1[Cl:2]
Reactant: Clc1cnnc(Cl)c1Cl
Reactant: N
Solvent: CCO
Product: Nc1c(Cl)cnnc1Cl
Temperature: 25 °C

Procedure:
Dry ethanol is saturated with ammonia gas and placed in a sealed tube with 8.0 grams of 3,4,5-trichloropyridazine. The reaction mixture is heated at 120°-130° C. for five hours. The tube is opened and the reaction mixture concentrated under reduced pressure. The residue is dissolved in 20 ml of chloroform and the solution heated under reflux for 20 minutes. The solution is allowed to cool to ambient temperature for several hours in place. A solid precipitate is collected by filtration and repeatedly recrystallized from water to yield 2.8 grams of 4-amino-3,5-dichloropyridazine; m.p. 176°-178° C. The filtrate is concentrated under reduced pressure and the residue recrystallized from water to yield 2.0 grams of 4-amino-5,6-dichloropyridazine; m.p. 150°-151° C.
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7]#[C:8][Si](C)(C)C)=[CH:5][N:4]=[CH:3]1.[Li]CCCC.C[Si]([N:22]=[C:23]=[O:24])(C)C.O>C1COCC1.CCOC(C)=O>[C:7]([C:6]1[N:2]([CH3:1])[C:3]([C:23]([NH2:22])=[O:24])=[N:4][CH:5]=1)#[CH:8]
Reactant: Cn1cncc1C#C[Si](C)(C)C
Reactant: C[Si](C)(C)N=C=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Solvent: CCOC(C)=O
Product: C#Cc1cnc(C(N)=O)n1C
Reaction time: 1 h
Yield: 26 %

Procedure:
To a solution of 1-methyl-5-trimethylsilanylethynyl-1H-imidazole (1.78 g, 10 mmol) in THF (30 mL) was slowly added a solution of nBuLi in hexanes (2.5M, 4.4 mL) at −78° C. and the resulting suspension was stirred at the same temperature for 1 h. Trimethylsilyl isocyanate (from Aldrich, 85% pure. 11.76 mmol, 1.6 mL) was slowly added to this suspension at −78° C. After stirring at −78° C. for another 30 minutes the reaction mixture was allowed to warm up slowly by removing the cooling bath. Water (2 mL) and MeOH (1 mL) was added to quench the reaction and the mixture was stirred overnight. More water and EtOAc was added to facilitate the extraction. The combined organic layers were dried over Na2SO4, filtered, and then concentrated on a rotavap and the residue was purified on a silica gel column (eluent: 40-60% EtOAc in hexanes) to give the desired product as a white solid in 26% yield (387 mg).
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[CH:3]=1.[CH3:12][O:13][C:14]1[CH:15]=[C:16]([CH:19]=[CH:20][CH:21]=1)[CH:17]=O.Cl>CO>[CH3:12][O:13][C:14]1[CH:15]=[C:16]([CH:17]=[C:7]2[C:6](=[O:9])[C:5]3[CH:10]=[CH:11][C:2]([OH:1])=[CH:3][C:4]=3[O:8]2)[CH:19]=[CH:20][CH:21]=1
Reactant: COc1cccc(C=O)c1
Reactant: O=C1COc2cc(O)ccc21
Agent: Cl
Solvent: CO
Product: COc1cccc(C=C2Oc3cc(O)ccc3C2=O)c1
Temperature: 25 °C
Yield: 68.3 %

Procedure:
After 6-hydroxy-2H-benzofuran-3-one 1 g and 3-methoxybenzaldehyde 1.125 g were dissolved in methanol 75 ml, concentrated hydrochloric acid 50 ml was added, and the mixture was refluxed for 1.5 hours. The solution was cooled to room temperature, and precipitated crystals were filtered and dried over phosphorous pentoxide at a temperature of 60° C. for four hours under reduced pressure to obtain the desired compound 1.22 g.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[CH:16]=[CH:15][C:9]3=[N:10][CH:11]=[C:12]([Cl:14])[CH:13]=[C:8]3[C:7](=[O:17])[C:6]=2[CH:18]=1.[O:19]1[CH2:24][CH2:23][O:22][CH2:21][C@H:20]1[CH2:25][N:26]([CH3:31])[S:27]([NH2:30])(=[O:29])=[O:28].CC(C)([O-])C.[Na+].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].O>[Cl:14][C:12]1[CH:13]=[C:8]2[C:7](=[O:17])[C:6]3[CH:18]=[C:2]([NH:30][S:27]([N:26]([CH2:25][C@@H:20]4[CH2:21][O:22][CH2:23][CH2:24][O:19]4)[CH3:31])(=[O:28])=[O:29])[CH:3]=[CH:4][C:5]=3[CH:16]=[CH:15][C:9]2=[N:10][CH:11]=1
Reactant: O=c1c2cc(Br)ccc2ccc2ncc(Cl)cc12
Reactant: CN(C[C@@H]1COCCO1)S(N)(=O)=O
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Solvent: O
Solvent: Cc1ccccc1
Product: CN(C[C@@H]1COCCO1)S(=O)(=O)Nc1ccc2ccc3ncc(Cl)cc3c(=O)c2c1
Temperature: 60 °C

Procedure:
A stirred solution of 7-bromo-3-chloro-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-5-one (10 g, 1.0 equiv), {[((2R)1,4-dioxan-2-ylmethyl)(methyl)amino]-sulfonyl}amine (6.9 g, 1.05 equiv), sodium tert-butoxide (6.6 g, 2.2 equiv), Pd2(dba)3 (0.29 g, 0.01 equiv), and Xantphos (0.36 g, 0.02 equiv) in toluene (250 mL) was thoroughly de-gassed, and then put under a nitrogen atmosphere. The resulting reaction mixture was then heated to 60° C., and left to age at this temperature until the reaction was complete (typically 1.5 h). The batch was then cooled to ambient temperature, and water (150 mL) was added. The resulting biphasic mixture was allowed to settle, and the aqueous layer was collected. The organic layer was extracted with 0.2 M aqueous NaOH (150 mL), the aqueous layers were combined and then washed twice with DCM (100 mL, then 50 mL). To the resulting aqueous layer was added DCM (200 mL) followed by concentrated hydrochloric acid (˜10 mL). After mixing thoroughly, the two layers were separated and the aqueous layer was extracted twice with DCM (100 mL, then 50 mL). The combined DCM layers were washed with water (100 mL), and then solvent-switched into toluene (to a final volume of ˜150 mL). The resulting slurry was aged at ˜20° C. for at least 1 h and then filtered, washing the filter-cake with toluene (30 mL, then 20 mL). The resulting solid was dried under vacuum at 40° C. to afford the title compound.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:15]2[CH2:20][CH2:19][O:18][CH2:17][CH2:16]2)[C:5]2[N:10]=[C:9]([C:11]([OH:14])([CH3:13])[CH3:12])[S:8][C:6]=2[N:7]=1.C(=O)([O-])[O-].[Na+].[Na+].[C:27](#[N:29])[CH3:28]>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[NH2:7][C:2]1[N:3]=[CH:4][C:28]([C:2]2[N:3]=[C:4]([N:15]3[CH2:20][CH2:19][O:18][CH2:17][CH2:16]3)[C:5]3[N:10]=[C:9]([C:11]([OH:14])([CH3:13])[CH3:12])[S:8][C:6]=3[N:7]=2)=[CH:27][N:29]=1
Reactant: CC#N
Reactant: CC(C)(O)c1nc2c(N3CCOCC3)nc(Cl)nc2s1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: CC(C)(O)c1nc2c(N3CCOCC3)nc(-c3cnc(N)nc3)nc2s1

Procedure:
2-(5-Chloro-7-morpholinothiazolo[5,4-d]pyrimidin-2-yl)propan-2-ol, 5-pyrimidine-2-amine boronic acid 68 (1.2 eq), and trans-dichlorobis(triphenylphosphine)palladium(II) (0.1 eq) were slurried with equal parts 1M sodium carbonate aqueous solution (3 eq) and acetonitrile. The solution was microwaved at 130° C. for 15 minutes. The solution was evaporated to dryness and purified by reverse phase silica gel chromatography to give the product 130.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]#[N:9])=[C:6]([CH:10]2[CH2:15][CH2:14][CH2:13][O:12][CH2:11]2)[C:5]([C:16]#[N:17])=[C:4]([S:18][CH2:19][C:20]2[N:21]=[C:22]([C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=3)[O:23][CH:24]=2)[N:3]=1.Cl.[CH3:33][O:34][C:35](=[O:39])[CH2:36][NH:37][CH3:38].C(N(CC)CC)C>C1COCC1>[Cl:31][C:28]1[CH:29]=[CH:30][C:25]([C:22]2[O:23][CH:24]=[C:20]([CH2:19][S:18][C:4]3[N:3]=[C:2]([N:37]([CH3:38])[CH2:36][C:35]([O:34][CH3:33])=[O:39])[C:7]([C:8]#[N:9])=[C:6]([CH:10]4[CH2:15][CH2:14][CH2:13][O:12][CH2:11]4)[C:5]=3[C:16]#[N:17])[N:21]=2)=[CH:26][CH:27]=1
Reactant: N#Cc1c(Cl)nc(SCc2coc(-c3ccc(Cl)cc3)n2)c(C#N)c1C1CCCOC1
Reactant: CNCC(=O)OC
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COC(=O)CN(C)c1nc(SCc2coc(-c3ccc(Cl)cc3)n2)c(C#N)c(C2CCCOC2)c1C#N
Temperature: 25 °C
Reaction time: 10 h

Procedure:
239 mg (0.42 mmol) of the compound from Example 43A are dissolved in 6 ml of dry THF, and 116 mg (0.83 mmol) of sarcosine methyl ester hydrochloride and 126 mg (1.25 mmol) of triethylamine are then added in succession. The reaction mixture is stirred at RT for 10 h. The solvent is then removed on a rotary evaporator and the residue is purified by preparative HPLC (column: YMC GEL ODS-AQ S-5, 15 μm; mobile phase gradient: acetonitrile/water 10:90→95:5).
Reaction SMILES: I[C:2]1[C:3]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[N:4][N:5]([CH2:8][C:9]2[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][CH:10]=2)[C:6]=1[CH3:7].[Cl:22][C:23]1[CH:30]=[CH:29][C:26]([CH:27]=[O:28])=[CH:25][CH:24]=1>C1COCC1>[Cl:22][C:23]1[CH:30]=[CH:29][C:26]([CH:27]([OH:28])[C:2]2[C:3]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[N:4][N:5]([CH2:8][C:9]3[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][CH:10]=3)[C:6]=2[CH3:7])=[CH:25][CH:24]=1
Reactant: CCOC(=O)c1nn(Cc2ccc(OC)cc2)c(C)c1I
Reactant: O=Cc1ccc(Cl)cc1
Solvent: C1CCOC1
Product: CCOC(=O)c1nn(Cc2ccc(OC)cc2)c(C)c1C(O)c1ccc(Cl)cc1
Reaction time: 0.25 h
Yield: 69.7 %

Procedure:
To a stirred solution of ethyl 4-iodo-1-(4-methoxybenzyl)-5-methyl-1H-pyrazole-3-carboxylate (Step 1.2) (6.23 g, 15.57 mmol) in THF (100 mL) under Ar was added TurboGrignard (15.57 mL, 20.24 mmol) at −10° C. After 15 min, 4-chlorobenzaldehyde (2.188 g, 15.57 mmol) was added. The reaction mixture was stirred for 30 min at this temperature, quenched with a saturated aqueous solution of NH4Cl (50 mL), extracted with EtOAc (2×50 mL). The combined organic layers were washed with a saturated aqueous solution of NH4Cl (75 mL), dried over Na2SO4 and evaporated. The crude material was purified by silica gel column chromatography (hexane/EtOAc 20-50%) to afford the title product (4.50 g, 10.85 mmol, 70% yield) as a colorless oil. tR: 5.34 min (HPLC 1); tR: 1.15 min (LC-MS 2); ESI-MS: 415 [M+H]+ (LC-MS 2); Rf=0.40 (hexane/EtOAc 1:1).
Reaction SMILES: Cl[CH2:2][C@H:3]([C@H:5]1[CH2:14][CH2:13][C:12]2[C:7](=[CH:8][CH:9]=[C:10]([F:15])[CH:11]=2)[O:6]1)[OH:4].[OH-].[Na+]>CC(O)C.C1(C)C=CC=CC=1.O>[F:15][C:10]1[CH:11]=[C:12]2[C:7](=[CH:8][CH:9]=1)[O:6][C@@H:5]([C@H:3]1[CH2:2][O:4]1)[CH2:14][CH2:13]2
Reactant: O[C@H](CCl)[C@H]1CCc2cc(F)ccc2O1
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)O
Solvent: O
Solvent: Cc1ccccc1
Product: Fc1ccc2c(c1)CC[C@H]([C@H]1CO1)O2
Temperature: 0 °C
Reaction time: 2 h

Procedure:
The compound (S*)-2-chloro-1-((R*)-6-fluoro-3,4-dihydro-2H-chromen-2-yl)-ethanol obtained in Example 1 (320 mg, 1.387 mmoles) is dissolved in i-PrOH (2 ml) under nitrogen and the reaction mixture is cooled to 0° C. On the magnetically stirred mixture is added a 2M aqueous solution of sodium hydroxide (1.39 ml) in 10 min. The mixture is stirred for 2 hours at 0° C., then diluted with toluene (5 ml) and transferred in a separator funnel. The biphasic mixture is further diluted with toluene (5 ml) and demi water (5 ml) and the phases are separated. The organic phase is washed with demi water (10 ml) and concentrated under vacuum to yield (R*)-6-fluoro-3,4-dihydro((R*)-oxiran-2-yl)-2H-chromen as yellow oil (200 mg, 74%, 98% de via GC).
Reaction SMILES: [O:1]([CH2:8][C:9]1[NH:10][CH:11]=[C:12]([C:14]2[CH:27]=[CH:26][C:17]([O:18][C:19]3[CH:25]=[CH:24][C:22]([NH2:23])=[CH:21][CH:20]=3)=[CH:16][CH:15]=2)[N:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.CI.[CH2:37]([OH:39])[CH3:38]>>[O:1]([CH2:8][C:9]1[NH:10][CH:11]=[C:12]([C:14]2[CH:27]=[CH:26][C:17]([O:18][C:19]3[CH:20]=[CH:21][C:22]([NH:23][C:37](=[O:39])[CH3:38])=[CH:24][CH:25]=3)=[CH:16][CH:15]=2)[N:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCO
Reactant: Nc1ccc(Oc2ccc(-c3c[nH]c(COc4ccccc4)n3)cc2)cc1
Solvent: CI
Solvent: CCN(CC)CC
Product: CC(=O)Nc1ccc(Oc2ccc(-c3c[nH]c(COc4ccccc4)n3)cc2)cc1
Reaction time: 20 h

Procedure:
4-{4-[2-(phenoxymethyl)-1H-imidazol-4-yl]phenoxy}aniline (600 mg, 0.00168 mol), (prepared according to a method analogous to that described in Example 28) is suspended in ethanol (30 ml) at 0° C. Triethylamine (0.235 ml, 0.00168 mol) and methyl iodide (0.136 ml, 0.0022 mol) are added. The mixture is stirred for 20 hours then evaporated to dryness. The residue obtained is adsorbed on silica then purified by chromatography on a Biotage-type silica column (eluent: ethyl acetate-heptane: 4-6 to 5-5). After washing with diethyl ether and isopentane, a beige-coloured powder is obtained.
Reaction SMILES: [OH:1][C:2]([CH3:35])([CH3:34])[CH2:3][C@@:4]1([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[O:9][C:8](=[O:10])[N:7]([C@H:11]([C:13]2[CH:18]=[CH:17][C:16](B3OC(C)(C)C(C)(C)O3)=[CH:15][CH:14]=2)[CH3:12])[CH2:6][CH2:5]1.[F:36][CH:37]([F:46])[N:38]1[CH:43]=[CH:42][C:41](I)=[CH:40][C:39]1=[O:45].C([O-])([O-])=O.[Cs+].[Cs+].O>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].O1CCOCC1>[F:36][CH:37]([F:46])[N:38]1[CH:43]=[CH:42][C:41]([C:16]2[CH:17]=[CH:18][C:13]([C@@H:11]([N:7]3[CH2:6][CH2:5][C@:4]([CH2:3][C:2]([OH:1])([CH3:35])[CH3:34])([C:28]4[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=4)[O:9][C:8]3=[O:10])[CH3:12])=[CH:14][CH:15]=2)=[CH:40][C:39]1=[O:45]
Reactant: O=c1cc(I)ccn1C(F)F
Reactant: C[C@@H](c1ccc(B2OC(C)(C)C(C)(C)O2)cc1)N1CC[C@](CC(C)(C)O)(c2ccccc2)OC1=O
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: O
Solvent: C1COCCO1
Product: C[C@@H](c1ccc(-c2ccn(C(F)F)c(=O)c2)cc1)N1CC[C@](CC(C)(C)O)(c2ccccc2)OC1=O
Temperature: 110 °C
Yield: 29.7 %

Procedure:
A microwave vial equipped with a flea stir bar was charged with (S)-6-(2-hydroxy-2-methylpropyl)-6-phenyl-3-((S)-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan -2-yl)phenyl)ethyl)-1,3-oxazinan-2-one (52 mg, 0.11 mmol), 1-(difluoromethyl)-4-iodopyridin-2(1H)-one (29 mg, 0.11 mmol), Cs2CO3 (71 mg, 0.22 mmol), H2O (0.1 mL) and dry dioxane (1 mL). The mixture was sparged with N2 for 5 min and PdCl2(dppf) (5 mg, 0.007 mmol) was added. The mixture was sparged with N2 for 5 min and heated at 110° C. in the microwave for 1 h. The mixture was diluted with 5% aq HCl (0.2 mL) and MeOH (2 mL) and filtered. The filtrate was directly purified by prep HPLC to afford a brown oil (16.2 mg) which was applied to a 2-g silica SPE cartridge which was eluted sequentially with 25 and 50% EtOAc in hexanes (15 mL of each) and EtOAc (3×15 mL) to afford five fractions. Fractions 3 and 4 were pooled and concentrated to afford (S)-3-(S)-1-(4-(1-(difluoromethyl)-2-oxo-1,2-dihydropyridin-4-yl)phenyl)ethyl)-6-(2-hydroxy-2-methylpropyl)-6-phenyl-1,3-oxazinan-2-one (13.4 mg, 25%) as a colorless oil. LC-MS Method 1 tR=1.57 min, m/z=497, 439; 1H NMR (CD3OD) 0.96 (s, 3H), 1.27 (s, 3H), 1.56 (d, 3H), 2.15 (s, 2H), 2.21 (m, 1H), 2.40-2.60 (2H), 3.08 (m, 1H), 5.59 (q, 1H), 6.66 (s, 1H), 6.74 (d, 1H), 7.07 (d, 2H), 7.30-7.40 (5H), 7.45 (d, 2H), 7.77 (1H), 7.79 (t, 1H).
Reaction SMILES: C([O:5][C:6](=[O:33])[CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][CH2:17][C:18]2[N:19]=[C:20]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[O:21][C:22]=2[CH3:23])=[CH:11][C:10]=1[CH2:30][O:31][CH3:32])(C)(C)C.FC(F)(F)C(O)=O>C(Cl)Cl>[CH3:32][O:31][CH2:30][C:10]1[CH:11]=[C:12]([O:15][CH2:16][CH2:17][C:18]2[N:19]=[C:20]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[O:21][C:22]=2[CH3:23])[CH:13]=[CH:14][C:9]=1[CH2:8][CH2:7][C:6]([OH:33])=[O:5]
Reactant: COCc1cc(OCCc2nc(-c3ccccc3)oc2C)ccc1CCC(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COCc1cc(OCCc2nc(-c3ccccc3)oc2C)ccc1CCC(=O)O
Temperature: 25 °C
Reaction time: 16 h
Yield: 89.5 %

Procedure:
A 15 mL round bottomed flask was charged 3-{2-methoxymethyl-4-[2-(5-methyl-2-phenyloxazol-4-yl)ethoxy]phenyl}propionic acid tert-butyl ester (0.060 g, 0.13 mmol), CH2Cl2 (1.2 mL), and then trifluoroacetic acid (0.6 mL). The solution was stirred at ambient temperature under a nitrogen atmosphere for 16 h and was concentrated. The residue was diluted with CH2Cl2 (30 mL) and washed with brine. The organic layer was dried (Na2SO4), filtered, and concentrated to give a white solid (0.046 g, 89%). MS (ES) m/e 648 (M+1).