Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[C:5]2=[CH:6][N:7]=[CH:8][CH:9]=[C:4]2[CH:3]=[C:2]1[CH:10]=[O:11].[CH3:12][Mg]Cl>C1COCC1>[NH:1]1[C:5]2=[CH:6][N:7]=[CH:8][CH:9]=[C:4]2[CH:3]=[C:2]1[CH:10]([OH:11])[CH3:12]
Reactant: O=Cc1cc2ccncc2[nH]1
Reactant: C[Mg]Cl
Solvent: C1CCOC1
Product: CC(O)c1cc2ccncc2[nH]1
Reaction time: 0.75 h
Yield: 75.5 %

Procedure:
To a solution of 1H-pyrrolo[2,3-c]pyridine-2-carboxaldehyde (0.80 g, 5.47 mmol) in THF (27.4 mL) was slowly added methylmagnesium chloride (22% by weight in THF, 5.0 mL, 15.3 mmol) at 0° C. under a nitrogen atmosphere. The ice/water bath was removed, and the reaction mixture was stirred for 45 min. The reaction mixture was quenched with methanol and concentrated to dryness. The solid residue was treated with water (50 mL) and sonicated. The solids were filtered and collected, but they were shown to be undesired material. The water filtrate was concentrated to dryness, treated with 6 N HCl (2.55 mL) and concentrated to dryness again. The resulting orange solid was diluted with EtOAc and treated with saturated NaHCO3. The aqueous layer was extracted with EtOAc (3×). The combined organic extracts were washed with saturated NaCl and dried over Na2SO4. The organic extract was filtered and concentrated to provide 1-(1H-pyrrolo[2,3-c]pyridin-2-yl)ethanol (0.67 g, 75%) as a tan solid: 1H NMR (300 MHz, CD3OD) δ1.59 (3H, d, J=6.6 Hz), 5.05 (1H, q, J=6.6 Hz), 6.41 (1H, s), 7.49-7.51 (1H, m), 8.00 (1H, d, J=5.6 Hz), 8.60 (1H, s); ESI MS m/z 163 [C9H10N2O+H]+; HPLC (Method A) 89.0% (AUC), tR=9.34 min.
Reaction SMILES: [F:1][CH:2]([F:24])[O:3][CH2:4][C@@H:5]([O:7][C:8]1[CH:9]=[C:10]([CH:20]=[C:21]([OH:23])[CH:22]=1)[C:11]([NH:13][C:14]1[CH:18]=[CH:17][N:16]([CH3:19])[N:15]=1)=[O:12])[CH3:6].[N:25]1([C:29]([C:31]2[CH:32]=[C:33]([Cl:38])[C:34](Cl)=[N:35][CH:36]=2)=[O:30])[CH2:28][CH2:27][CH2:26]1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[N:25]1([C:29]([C:31]2[CH:32]=[C:33]([Cl:38])[C:34]([O:23][C:21]3[CH:20]=[C:10]([CH:9]=[C:8]([O:7][C@@H:5]([CH3:6])[CH2:4][O:3][CH:2]([F:1])[F:24])[CH:22]=3)[C:11]([NH:13][C:14]3[CH:18]=[CH:17][N:16]([CH3:19])[N:15]=3)=[O:12])=[N:35][CH:36]=2)=[O:30])[CH2:28][CH2:27][CH2:26]1
Reactant: O=C(c1cnc(Cl)c(Cl)c1)N1CCC1
Reactant: C[C@@H](COC(F)F)Oc1cc(O)cc(C(=O)Nc2ccn(C)n2)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: C[C@@H](COC(F)F)Oc1cc(Oc2ncc(C(=O)N3CCC3)cc2Cl)cc(C(=O)Nc2ccn(C)n2)c1
Temperature: 160 °C
Reaction time: 3 h
Yield: 53.6 %

Procedure:
A mixture of 3-({(1S)-2-[(difluoromethyl)oxy]-1-methylethyl}oxy)-5-hydroxy-N-(1-methyl-1H-pyrazol-3-yl)benzamide (110 mg, 0.32 mmol), 5-(azetidin-1-ylcarbonyl)-2,3-dichloropyridine (75 mg, 0.32 mmol) and potassium carbonate (89 mg, 0.64 mmol) in acetonitrile (5 mL) was stirred in a ‘Biotage initiator Microwave’ at 160° C. for 3 hours. The solvent was removed in vacuo and ethyl acetate (50 mL) added to the residue which was washed with water (20 mL), brine (50 mL), dried (MgSO4), filtered and the solvent removed in vacuo to give a yellow oil. The residue was chromatographed on silica, eluting with a gradient of 50-100% ethyl acetate in isohexane, to give the desired compound (92 mg). 1H NMR δ (CDCl3): 1.40 (d, 3H), 2.41 (quin, 2H), 3.81 (s, 3H), 4.01 (mult, 2H), 4.26 (t, 2H), 4.38 (t, 2H), 4.67 (sextet, 1H), 6.29 (t, 1H), 6.82 (d, 1H), 6.96 (t, 1H), 7.27 (t, 1H), 7.31 (d, 1H), 7.38 (t, 1H), 8.18 (d, 1H), 8.26 (d, 1H), 8.77 (s, 1H), m/z 536 (M+H)+
Reaction SMILES: [C:1]1([CH2:11][C:12]([OH:14])=[O:13])([CH2:7][C:8]([OH:10])=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[C:15](OC(=O)C)(=O)C>>[CH3:15][O:9][C:8]([CH2:7][C:1]1([CH2:11][C:12]([OH:14])=[O:13])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1)=[O:10]
Reactant: O=C(O)CC1(CC(=O)O)CCCCC1
Reactant: CC(=O)OC(C)=O
Product: COC(=O)CC1(CC(=O)O)CCCCC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of 1,1-cyclohexanediacetic acid (5.0 g) in acetic anhydride (8.0 mL) was stirred under reflux for 5 hours. The solution was then concentrated under reduced pressure and distilled with toluene azeotropically. To a solution of the resulting residue in methanol (15.2 mL) was added boron trifluoride diethyl ether complex (1.58 mL) at room temperature. The solution was stirred at room temperature for 2 hours. Saturated aqueous sodium carbonate solution was added to the solution and it was washed with diethyl ether. The aqueous layer was neutralized by addition of conc. hydrochloric acid and then extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride solution, and then, dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to give the title compound (4.21 g).
Reaction SMILES: [CH:1]1([N:4]([CH:12]2[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)[CH2:5][C:6]2[CH:11]=[CH:10][N:9]=[CH:8][CH:7]=2)[CH2:3][CH2:2]1.Cl[C:19]([O:21][C:22]1[CH:27]=[CH:26][C:25]([O:28][C:29]2[CH:34]=[CH:33][C:32]([C:35]([F:38])([F:37])[F:36])=[CH:31][N:30]=2)=[CH:24][CH:23]=1)=[O:20].C(NC(C)C)(C)C>CN(C)C=O>[F:37][C:35]([F:36])([F:38])[C:32]1[CH:33]=[CH:34][C:29]([O:28][C:25]2[CH:26]=[CH:27][C:22]([O:21][C:19]([N:15]3[CH2:16][CH2:17][CH:12]([N:4]([CH:1]4[CH2:2][CH2:3]4)[CH2:5][C:6]4[CH:7]=[CH:8][N:9]=[CH:10][CH:11]=4)[CH2:13][CH2:14]3)=[O:20])=[CH:23][CH:24]=2)=[N:30][CH:31]=1
Reactant: c1cc(CN(C2CCNCC2)C2CC2)ccn1
Reactant: O=C(Cl)Oc1ccc(Oc2ccc(C(F)(F)F)cn2)cc1
Solvent: CN(C)C=O
Solvent: CC(C)NC(C)C
Product: O=C(Oc1ccc(Oc2ccc(C(F)(F)F)cn2)cc1)N1CCC(N(Cc2ccncc2)C2CC2)CC1

Procedure:
The title product was prepared from cyclopropyl-piperidine-4-yl-pyridin-4-ylmethyl-amine and 4-(5-trifluoromethyl-pyridin-2-yloxy)-phenyl chloroformate, 3 equivalent of diisopropylamine was added, solvent: dimethylformamide. The crude reaction mixture was evaporated without addition of acetic acid, preparative HPLC (method C) (19%, yellow oil). HPLC-MS m/z=(M+1), Rt: 2.82 min.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][C@H:13]([O:17][CH3:18])[C:14]([OH:16])=[O:15])=[CH:8][CH:7]=1.O[C:20]1[CH:21]=[C:22]2[C:27](=[CH:28][CH:29]=1)[O:26][CH:25]([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[CH2:24][C:23]2=[O:36]>>[CH3:18][O:17][C@@H:13]([CH2:12][C:9]1[CH:10]=[CH:11][C:6]([O:5][CH2:4][CH2:3][CH2:2][O:1][C:20]2[CH:21]=[C:22]3[C:27](=[CH:28][CH:29]=2)[O:26][CH:25]([C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=2)[CH2:24][C:23]3=[O:36])=[CH:7][CH:8]=1)[C:14]([OH:16])=[O:15]
Reactant: CO[C@@H](Cc1ccc(OCCCO)cc1)C(=O)O
Reactant: O=C1CC(c2ccccc2)Oc2ccc(O)cc21
Product: CO[C@@H](Cc1ccc(OCCCOc2ccc3c(c2)C(=O)CC(c2ccccc2)O3)cc1)C(=O)O

Procedure:
The title compound was prepared from (2S)-3-[4-(3-Hydroxy-propoxy)-phenyl]-2-methoxy-propionic acid linked to Wang's Resin (Example 94, Step D) via Mitsunobu coupling with 6-hydroxyflavanone and cleavage from the resin (Standard Procedure G) gave an oily solid.
Reaction SMILES: COC1C=CC(C([O:22][CH2:23][C@H:24]2[O:28][C@@H:27]([N:29]3[CH:37]=[N:36][C:35]4[C:30]3=[N:31][CH:32]=[N:33][C:34]=4[NH:38][C:39](=[O:46])[C:40]3[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=3)[C@@H:26]([F:47])[C@@H:25]2[OH:48])(C2C=CC=CC=2)C2C=CC(OC)=CC=2)=CC=1.[Si:51](O[C@@H]1[C@@H](CO)O[C@@H](N2C3N=CN=C(NC(=O)C4C=CC=CC=4)C=3N=C2)C1)([C:54]([CH3:57])([CH3:56])[CH3:55])([CH3:53])[CH3:52]>>[Si:51]([O:48][C@@H:25]1[C@@H:24]([CH2:23][OH:22])[O:28][C@@H:27]([N:29]2[CH:37]=[N:36][C:35]3[C:30]2=[N:31][CH:32]=[N:33][C:34]=3[NH:38][C:39](=[O:46])[C:40]2[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=2)[C@H:26]1[F:47])([C:54]([CH3:57])([CH3:56])[CH3:55])([CH3:53])[CH3:52]
Reactant: CC(C)(C)[Si](C)(C)O[C@H]1C[C@H](n2cnc3c(NC(=O)c4ccccc4)ncnc32)O[C@@H]1CO
Reactant: COc1ccc(C(OC[C@H]2O[C@@H](n3cnc4c(NC(=O)c5ccccc5)ncnc43)[C@@H](F)[C@@H]2O)(c2ccccc2)c2ccc(OC)cc2)cc1
Product: CC(C)(C)[Si](C)(C)O[C@H]1[C@H](F)[C@H](n2cnc3c(NC(=O)c4ccccc4)ncnc32)O[C@@H]1CO

Procedure:
This compound is prepared from 9-[2-deoxy-5-O-(4,4'-dimethoxytrityl)-2-fluoro-β-D-arabinofuranosyl]-N6 -benzoyladenine by the same procedure used for the preparation of 3'-O-t-butyldimethylsilyl-N6 -benzoyl-2'-deoxyadenosine.
Reaction SMILES: [CH3:1][NH:2][C:3](=[N:6][N+:7]([O-:9])=[O:8])[S:4][CH3:5].C(=O)([O-])[O-].[K+].[K+].[C:16]([O:19]C(=O)C)(=O)[CH3:17].Cl>C(#N)C>[C:16]([N:2]([CH3:1])[C:3](=[N:6][N+:7]([O-:9])=[O:8])[S:4][CH3:5])(=[O:19])[CH3:17]
Reactant: CNC(=N[N+](=O)[O-])SC
Reactant: CC(=O)OC(C)=O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CSC(=N[N+](=O)[O-])N(C)C(C)=O
Temperature: 25 °C
Reaction time: 5 h
Yield: 93.6 %

Procedure:
To a mixture of N,S-dimethyl-N'-nitroisothiourea (500 mg), potassium carbonate (695 mg) and acetonitrile (10 ml) was added 376 mg of acetic anhydride at room temperature. After stirring at room temperature for 5 hours, 10 ml of 2N hydrochloric acid was added to the mixture which was then extracted with 40 ml of dichloromethane. The resultant organic layers were washed with aqueous saturated sodium bicarbonate, then dried over anhydrous magnesium sulfate and concentrated to afford 600 mg of N-acetyl-N,S-dimethyl-N'-nitroisothiourea as a white crystal, mp 40-41° C.
Reaction SMILES: [C:1]([O:5][C:6](=[O:24])[NH:7][CH2:8][C:9]1[C:14]([C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=2[Cl:22])=[CH:13][N:12]=[C:11](N)[CH:10]=1)([CH3:4])([CH3:3])[CH3:2].C(Cl)(Cl)[Cl:26]>>[C:1]([O:5][C:6](=[O:24])[NH:7][CH2:8][C:9]1[C:14]([C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=2[Cl:22])=[CH:13][N:12]=[C:11]([Cl:26])[CH:10]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: ClC(Cl)Cl
Reactant: CC(C)(C)OC(=O)NCc1cc(N)ncc1-c1ccc(Cl)cc1Cl
Product: CC(C)(C)OC(=O)NCc1cc(Cl)ncc1-c1ccc(Cl)cc1Cl
Temperature: 25 °C
Reaction time: 72 h
Yield: 62 %

Procedure:
A mixture of [2-amino-5-(2,4-dichloro-phenyl)-pyridin-4-ylmethyl]-carbamic acid tert-butyl ester (1.78 g, 4.82 mmol, prepared according to Example 6, Step 3.2), tBuONO (1.05 mL, 8.0 mmol), and CuCl2 (1.01 g, 7.51 mmol) in CHCl3 (6 mL) was stirred at RT for 3 days with exclusion of light. The reaction mixture was concentrated under vacuum, then the remaining residue was suspended in a 2.0 M aqueous Na2CO3 solution (200 mL) and extracted with AcOEt (2×100 mL). The combined organic fractions were dried over Na2SO4, filtered, and evaporated. The residue was purified by Combi-Flash Companion™ (Isco Inc.) column chromatography (SiO2; gradient elution, [hexane/DCM 1:1]/TBME 95:5→4:6) to yield the title compound (1.17 g, 3.0 mmol, 62%) as a colorless solid. MS: 388 [M+1]+; HPLC: AtRet=2.89; TLC: RF 0.36 ([hexane/DCM 1:1]/TBME 95:5).
Reaction SMILES: [O:1]([CH2:8][CH2:9][CH2:10][CH2:11][NH2:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:13]([N:17]1[C:21](=[O:22])[C:20](Cl)=[C:19]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[S:18]1(=[O:31])=[O:30])([CH3:16])([CH3:15])[CH3:14]>>[C:13]([N:17]1[C:21](=[O:22])[C:20]([NH:12][CH2:11][CH2:10][CH2:9][CH2:8][O:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[C:19]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[S:18]1(=[O:30])=[O:31])([CH3:16])([CH3:14])[CH3:15]
Reactant: NCCCCOc1ccccc1
Reactant: CC(C)(C)N1C(=O)C(Cl)=C(c2ccccc2)S1(=O)=O
Product: CC(C)(C)N1C(=O)C(NCCCCOc2ccccc2)=C(c2ccccc2)S1(=O)=O
Yield: 80 %

Procedure:
The title compound was prepared as described for Example 24 from 1 equivalent of (4-phenoxybutyl)amine, 2-tert-butyl-4-chloro-5-phenylisothiazol-3(2H)-one 1,1-dioxide and 1 equivalent TEA at 100° C. The residue was purified by silica gel column chromatography (Horizons Biotage) using 10-20% EtOAc in hexane as eluent giving the title compound (0.172 g, 80%) as a solid. 1H NMR (500 MHz CDCl3): 1H NMR (500 MHz CDCl3): δ 7.54-7.50 (m, 2H), 7.44-7.38 (m, 3H), 7.32-7.25 (m, 2H), 6.96 (t, 1H), 6.83 (d, 2H), 5.34 (t, 1H), 3.81 (t, 2H), 2.98-2.90 (m, 2H), 1.75 (s, 9H), 1.64-1.53 (m, 4H); 13C NMR (125 MHz CDCl3): δ 159.9, 158.9, 135.2, 131.8, 129.8, 129.7, 128.8, 125.3, 121.0, 114.6, 107.2, 67.1, 61.7, 43.9, 27.9, 26.6, 26.4; Mass Spectrum: M+H+ 429.
Reaction SMILES: C[O:2][C:3]([C:5]1[C:6]([C:11]2[CH:16]=[C:15]([O:17][CH3:18])[C:14]([O:19][CH3:20])=[C:13]([O:21][CH3:22])[CH:12]=2)=[CH:7][CH:8]=[CH:9][CH:10]=1)=[O:4].[Li+].[OH-]>CO>[CH3:22][O:21][C:13]1[CH:12]=[C:11]([C:6]2[C:5]([C:3]([OH:4])=[O:2])=[CH:10][CH:9]=[CH:8][CH:7]=2)[CH:16]=[C:15]([O:17][CH3:18])[C:14]=1[O:19][CH3:20]
Reactant: COC(=O)c1ccccc1-c1cc(OC)c(OC)c(OC)c1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Product: COc1cc(-c2ccccc2C(=O)O)cc(OC)c1OC
Yield: 70.5 %

Procedure:
Dissolve 3′,4′,5′-Trimethoxy-biphenyl-2-carboxylic acid methyl ester (55) (626 mg, 2.08 mmol) in MeOH (14 mL) at rt and add 1M aqu LiOH (4.2 mL, 4.20 mmol). Stir reaction mixture for 8 h under reflux. Remove solvent and partition the residue between 1M aqu. HCl and EtOAc, separate layers, extract the aqu. layer with EtOAc (3×), wash the combined organic layer with brine and dry with Na2SO4. Remove solvent and recrystallize residue from EtOAc/CyH 1+2 to obtain 3′,4′,5′-Trimethoxy-biphenyl-2-carboxylic acid (56) as a white solid (423 mg, 79%). 1H NMR (400 MHz, CD3OD: 3.84 (s, 3H); 3.89 (s, 6H); 6.68 (s, 2H); 7.42-7.49 (m, 2H); 7.57 (t, 1H, J=7.5 Hz); 7.76 (d, 1H, J=8.0 Hz).
Reaction SMILES: Cl[CH2:2][C:3]1[N:4]=[C:5](/[CH:8]=[CH:9]/[C:10]2[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][CH:11]=2)[O:6][CH:7]=1.[CH3:17][S:18]([CH2:21][C:22]1[N:23]([CH2:27][CH2:28][CH2:29][CH2:30][C:31]2[CH:36]=[CH:35][C:34]([OH:37])=[CH:33][CH:32]=2)[CH:24]=[CH:25][N:26]=1)(=[O:20])=[O:19].[H-].[Na+]>>[Cl:16][C:13]1[CH:14]=[CH:15][C:10](/[CH:9]=[CH:8]/[C:5]2[O:6][CH:7]=[C:3]([CH2:2][O:37][C:34]3[CH:33]=[CH:32][C:31]([CH2:30][CH2:29][CH2:28][CH2:27][N:23]4[CH:24]=[CH:25][N:26]=[C:22]4[CH2:21][S:18]([CH3:17])(=[O:20])=[O:19])=[CH:36][CH:35]=3)[N:4]=2)=[CH:11][CH:12]=1
Reactant: CS(=O)(=O)Cc1nccn1CCCCc1ccc(O)cc1
Reactant: ClCc1coc(/C=C/c2ccc(Cl)cc2)n1
Agent: [H-]
Agent: [Na+]
Product: CS(=O)(=O)Cc1nccn1CCCCc1ccc(OCc2coc(/C=C/c3ccc(Cl)cc3)n2)cc1
Yield: 75.5 %

Procedure:
Using 4-(chloromethyl)-2-[(E)-2-(4-chlorophenyl)ethenyl]-1,3-oxazole (227 mg), 4-[4-[2-[(methylsulfonyl)methyl]-1H-imidazol-1-yl]butyl]phenol (250 mg) and 65% sodium hydride (32.9 mg), the same reaction as Example 11-(i) was carried out to yield the titled compound (322 mg) as a colorless crystal powder.
Reaction SMILES: [C:1]1([CH3:8])[CH:6]=[CH:5][CH:4]=[C:3]([CH3:7])[CH:2]=1.[C:9](Cl)(=[O:12])[CH:10]=[CH2:11].[Cl-].[Al+3].[Cl-].[Cl-]>ClCCl>[CH3:8][C:1]1[CH:2]=[C:3]([CH3:7])[CH:4]=[CH:5][C:6]=1[C:9](=[O:12])[CH:10]=[CH2:11]
Reactant: C=CC(=O)Cl
Reactant: Cc1cccc(C)c1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: C=CC(=O)c1ccc(C)cc1C
Yield: 16 %

Procedure:
Metaxylene (128 mg), acryloyl chloride (154 mg), and aluminium chloride (160 mg) were reacted in dichloromethane (1.5 mL) at from 0° C. to room temperature for 4 hours. The resultant was treated in the same manner as described in Example 1 to obtain the title compound (31 mg).
Reaction SMILES: [N:1]1([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[CH3:14][C:15]1[C:23]([CH3:24])=[CH:22][CH:21]=[CH:20][C:16]=1[C:17](O)=[O:18].ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C>>[CH3:14][C:15]1[C:23]([CH3:24])=[CH:22][CH:21]=[CH:20][C:16]=1[C:17]([N:4]1[CH2:5][CH2:6][N:1]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:2][CH2:3]1)=[O:18]
Reactant: Cc1cccc(C(=O)O)c1C
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Product: Cc1cccc(C(=O)N2CCN(C(=O)OC(C)(C)C)CC2)c1C
Reaction time: 2 h

Procedure:
tert-Butyl piperazine-1-carboxylate(0.50 g, 2.6 mmol), 2,3-dimethylbenzoic acid (0.44 g, 2.9 mmol), 1-hydroxybenzotriazole (HOBT) (0.45 g, 2.9 mmol) and 1-ethyl-3-(3-dimethylamino- propyl)carbodiimide hydrochloride (EDC.HCl) (0.56 g, 2.9 mmol) were added to dry, degassed dimethylformamide (7 mL). The pH of the reaction was adjusted to 7 with triethylamine, and the reaction stirred for 2 h. The dimethylformamide (DMF) was distilled in vacuo, and the residue partitioned between ethyl acetate and water. The organic phase was washed with 2% aqueous potassium hydrogen sulfate, saturated sodium bicarbonate solution, saturated sodium chloride solution, and dried over magnesium sulfate. The crude product was chromatographed on silica gel using 30% ethyl acetate in hexane as eluant. The title compound was obtained as a white solid, NMR (CDCl3, 300 MHz) δ 7.17 (1H, d, J=7 Hz), 7.13 (1H, t, J=7 Hz), 6.98 (1H, d, J=7 Hz), 3.77 (2H, m), 3.51 (2H, m), 3.32 (2H, t, J=5 Hz), 3.19 (2H, m), 2.28 (3H, s), 2.18 (3H, s), 1.45 (9H, s).
Reaction SMILES: [OH-].[Na+].[F:3][C:4]([F:18])([F:17])[CH2:5][O:6][C:7]1[CH:16]=[CH:15][C:10]2[S:11]C(=O)[O:13][C:9]=2[CH:8]=1>C1COCC1>[F:18][C:4]([F:3])([F:17])[CH2:5][O:6][C:7]1[CH:16]=[CH:15][C:10]([SH:11])=[C:9]([OH:13])[CH:8]=1
Reactant: O=c1oc2cc(OCC(F)(F)F)ccc2s1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: Oc1cc(OCC(F)(F)F)ccc1S

Procedure:
In some embodiments, the 5-(2,2,2-trifluoroethoxy)-2-mercaptophenol can be generated by hydrolysis of 6-(2,2,2-trifluoroethoxy)benzo[d][1,3]oxathiol-2-one and used in the aforementioned step without isolation in a solid form. In one embodiment, the 6-(2,2,2-trifluoroethoxy)benzo[d][1,3]oxathiol-2-one can be hydrolyzed with aqueous sodium hydroxide to afford 5-(2,2,2-trifluoroethoxy)-2-mercaptophenol. In an exemplary embodiment, the 6-(2,2,2-trifluoroethoxy)benzo[d][1,3]oxathiol-2-one dissolved in degassed THF can be hydrolyzed by addition of degassed aqueous sodium hydroxide; subsequently, the reaction can be quenched with acid and the resultant 5-(2,2,2-trifluoroethoxy)-2-mercaptophenol can be obtained in organic solution. In some aspects, the 5-(2,2,2-trifluoroethoxy)-2-mercaptophenol can be obtained in organic solution by partitioning the solvent mixture with degassed MTBE, extracting the remaining aqueous solution with degassed MTBE, and combining the organic layers containing 5-(2,2,2-trifluoroethoxy)-2-mercaptophenol. The 5-(2,2,2-trifluoroethoxy)-2-mercaptophenol dissolved in the organic solution (THF/MTBE) can be used directly in the ring forming reaction without isolation.
Reaction SMILES: C[O:2][C:3](=[O:13])[C:4]1[CH:9]=[C:8]([Br:10])[CH:7]=[C:6]([CH3:11])[C:5]=1[NH2:12].[F:14][C:15]1[CH:20]=[CH:19][C:18]([S:21](Cl)(=[O:23])=[O:22])=[CH:17][CH:16]=1.O>N1C=CC=CC=1>[CH3:11][C:6]1[C:5]([NH:12][S:21]([C:18]2[CH:19]=[CH:20][C:15]([F:14])=[CH:16][CH:17]=2)(=[O:23])=[O:22])=[C:4]([CH:9]=[C:8]([Br:10])[CH:7]=1)[C:3]([OH:2])=[O:13]
Reactant: O=S(=O)(Cl)c1ccc(F)cc1
Reactant: COC(=O)c1cc(Br)cc(C)c1N
Solvent: O
Solvent: c1ccncc1
Product: Cc1cc(Br)cc(C(=O)O)c1NS(=O)(=O)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 36.7 %

Procedure:
To a solution of 25.0 g (0.102 mol) of 2-amino-3-methyl-5-bromobenzoic acid methyl ester (U.S. Pat. No. 5,776,961) in 300 mL of pyridine was added 21.93 g (0.113 mol) of 4-fluorobenzenesulfonyl chloride. The reaction mixture was stirred for 18 h at 80°, cooled to room temperature and poured into water. The resulting mixture was extracted with ethyl acetate and the combined organics were then washed with 5% HCl solution and water. The organic layer was then dried over MgSO4, filtered and concentrated in vacuo. The residue was chromatographed on silica gel eluting with ethyl acetate/hexanes (1:3) to provide 14.53 g (39%) of the desired product as a tan solid. Electrospray Mass Spec: 388.0 (M−H)−
Reaction SMILES: [CH3:1][C:2]1([CH3:14])[O:6][C@H:5]([CH2:7][N:8]2[CH:12]=[CH:11][C:10]([NH2:13])=[N:9]2)[CH2:4][O:3]1.[I:15][C:16]1[CH:17]=[N:18][N:19]([CH:23]([CH2:27][CH:28]([CH3:30])[CH3:29])[C:24](O)=[O:25])[C:20](=[O:22])[CH:21]=1.Cl.CN(C)CCCN=C=NCC>CN(C)C=O.CN(C)C1C=CN=CC=1.C(OCC)(=O)C>[CH3:1][C:2]1([CH3:14])[O:6][C@H:5]([CH2:7][N:8]2[CH:12]=[CH:11][C:10]([NH:13][C:24](=[O:25])[CH:23]([N:19]3[C:20](=[O:22])[CH:21]=[C:16]([I:15])[CH:17]=[N:18]3)[CH2:27][CH:28]([CH3:30])[CH3:29])=[N:9]2)[CH2:4][O:3]1
Reactant: CC1(C)OC[C@@H](Cn2ccc(N)n2)O1
Reactant: CC(C)CC(C(=O)O)n1ncc(I)cc1=O
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)CC(C(=O)Nc1ccn(C[C@@H]2COC(C)(C)O2)n1)n1ncc(I)cc1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 51.3 %

Procedure:
A solution of 1-((R)-2,2-dimethyl-[1,3]dioxolan-4-ylmethyl)-1H-pyrazol-3-ylamine (Intermediate 4, 708.7 mg, 3.59 mmol) in N,N-dimethylformamide was added to 2-(4-iodo-6-oxo-6H-pyridazin-1-yl)-4-methyl-pentanoic acid (Intermediate 86, 1.42 g, 4.23 mmol). At this point, the reaction was treated with 4-dimethylaminopyridine (21.9 mg, 0.18 mmol) followed by N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (823.7 mg, 4.31 mmol). The resulting reaction was stirred at 25° C. overnight. The reaction was then diluted with ethyl acetate (200 mL), was washed with water (200 mL) and a saturated aqueous sodium chloride solution (200 mL), filtered, and concentrated in vacuo onto silica gel. Chromatography (ISCO Combiflash, 10-60% ethyl acetate/hexanes) afforded 2-(4-iodo-6-oxo-6H-pyridazin-1-yl)-4-methyl-pentanoic acid [1-((R)-2,2-dimethyl-[1,3]dioxolan-4-ylmethyl)-1H-pyrazol-3-yl]-amide as a white/yellow solid (950 mg, 51%); ES+-HRMS m/e calcd for C19H26N5O4I [M+Na+] 538.0921, found 538.0921. 1H NMR (300 MHz, DMSO-d6) δ ppm 0.83 (d, J=5.7 Hz, 3H), 0.85 (d, J=5.7 Hz, 3H), 1.23 (s, 3H), 1.29 (s, 3H), 1.35 (br. s., 1H), 1.76 (ddd, J=13.3, 9.4, 4.2 Hz, 1H), 2.03-2.21 (m, 1H), 3.71 (dd, J=8.4, 6.0 Hz, 1H), 3.98 (dd, J=8.4, 6.5 Hz, 1H), 4.03-4.18 (m, 2H), 4.33 (quin, J=6.0 Hz, 1H), 5.47 (dd, J=11.0, 4.1 Hz, 1H), 6.36 (d, J=2.1 Hz, 1H), 7.58 (d, J=1.8 Hz, 1H), 7.59 (d, J=2.1 Hz, 1H), 8.23 (d, J=1.8 Hz, 1H), 10.82 (s, 1H).
Reaction SMILES: [Cl:1][C:2]1[C:3]([N:8]2[C:12]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:11][C:10](=[O:18])[NH:9]2)=[N:4][CH:5]=[CH:6][CH:7]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:25](Br)[C:26]#[CH:27].O>C(#N)C>[Cl:1][C:2]1[C:3]([N:8]2[C:12]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:11][C:10]([O:18][CH2:27][C:26]#[CH:25])=[N:9]2)=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: C#CCBr
Reactant: CCOC(=O)c1cc(=O)[nH]n1-c1ncccc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: C#CCOc1cc(C(=O)OCC)n(-c2ncccc2Cl)n1
Yield: 95 %

Procedure:
To a solution of ethyl 1-(3-chloro-2-pyridinyl)-2,3-dihydro-3-oxo-1H-pyrazole-5-carboxyate (i.e. the product of Example 1, Step B) (0.5 g, 1.9 mmol) in acetonitrile (20 mL) was added potassium carbonate (0.6 g, 3.8 mmol) and propargyl bromide (1.0 mL, 9.4 mmol). The reaction mixture was heated at reflux for 15 minutes. The mixture was then cooled and treated with water and extracted with a 1:1 mixture of diethyl ether and ethyl acetate. The organic extracts were then washed with a saturated solution of sodium chloride and dried over magnesium sulfate. The extract was concentrated to dryness on a rotary evaporator and chromatographed on silica gel using hexane/ethyl acetate (7:3) as eluent to isolate the title compound (0.45 g, 95% purity) as a red oil.