Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][CH2:2][CH2:3][C:4]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)([OH:7])[CH:5]=[CH2:6].B.C1C[O:18]CC1.[OH-].[Na+].OO>C1COCC1>[Cl:1][CH2:2][CH2:3][C:4]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)([OH:7])[CH2:5][CH2:6][OH:18]
Reactant: C=CC(O)(CCCl)c1ccccc1
Reactant: C1CCOC1
Agent: B
Agent: OO
Agent: [Na+]
Product: OCCC(O)(CCCl)c1ccccc1
Temperature: 0 °C
Reaction time: 3 h
Yield: 64.4 %

Procedure:
To a 0° C. solution of 5-chloro-3-phenylpent-1-en-3-ol (6.12 g, 31.12 mmol) in 125 mL THF was added a 1M solution of BH3.THF (62.2 mL, 62.2 mmol) dropwise. The reaction mixture was stirred for 3 h at 0° C., and 5M NaOH (38 mL, 190 mmol) was slowly added, followed by 30% H2O2 (56 mL, 495 mmol). After stirring for 90 min at room temperature, the organic layer was isolated and the aqueous layer extracted with EtOAc. The organic layers were pooled, washed with saturated aqueous Na2S2O3 and saturated aqueous NH4Cl, dried (Na2SO4), filtered, and passed through a silica plug to provide 5-chloro-3-phenylpentane-1,3-diol (4.3 g, 64%) as an oil. 1H NMR (400 MHz, CDCl3): δ 7.43-7.34 (m, 5H), 7.27 (m, 1H), 3.80 (td, 1H, J=10.8, 4.2 Hz), 3.67-3.52 (m, 2H), 3.22 (td, 1H, J=10.5, 5.1 Hz), 2.38 (ddd, 1H, J=13.7, 10.3, 5.9 Hz), 2.28 (ddd, 1H, J=13.7, 10.4, 5.1 Hz), 2.23 (m, 1H), 2.03 (ddd, 1H, J=14.8, 4.6, 2.9 Hz).
Reaction SMILES: [OH:1][CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1.Br[CH2:12][C:13]1[CH:22]=[CH:21][CH:20]=[CH:19][C:14]=1[C:15]([O:17][CH3:18])=[O:16].C(=O)([O-])[O-].[K+].[K+].C(O)C(N)(CO)CO>C(#N)C>[OH:1][CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:12][C:13]2[CH:22]=[CH:21][CH:20]=[CH:19][C:14]=2[C:15]([O:17][CH3:18])=[O:16])=[CH:6][CH:5]=1
Reactant: COC(=O)c1ccccc1CBr
Reactant: OCCc1ccc(O)cc1
Agent: NC(CO)(CO)CO
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COC(=O)c1ccccc1COc1ccc(CCO)cc1
Reaction time: 8 h
Yield: 90 %

Procedure:
4-(2-Hydroxyethyl)phenol (2 g, 14.48 mmol) and methyl 2-(bromomethyl)benzoate (3.48 g, 15.20 mmol) were dissolved in acetonitrile (20 ml). Potassium carbonate anhydrous (4.0 g, 28.95 mmol) was added. After stirring at 60° C. for three hours PS-trisamine was added (0.2 eq) and the mixture was stirred overnight. The PS-trisamine was filtered off and the acetonitrile was removed by evaporation. EtOAc (10 ml) was added and the organic layer was washed with 3 portions of water (3×10 ml). The organic phase was dried (MgSO4) and the solvent was removed by evaporation to give 3.732 g of methyl 2-{[4-(2-hydroxyethyl)phenoxy]methyl}benzoate (yield 90%).
Reaction SMILES: [NH:1]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:2][C:3]([NH:5][C@H:6]([C:8]([NH:10][CH2:11][C:12]([OH:14])=O)=[O:9])[CH3:7])=[O:4].C1C=CC2N(O)N=NC=2C=1.O.CCN=C=NCCCN(C)C.Cl.[NH2:45][C@@H:46]([C:48]([NH:50][CH2:51][C:52]([O:54][CH2:55][C:56]1[CH:61]=[CH:60][CH:59]=[CH:58][CH:57]=1)=[O:53])=[O:49])[CH3:47].Cl>CN(C=O)C>[NH:1]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:2][C:3]([NH:5][C@H:6]([C:8]([NH:10][CH2:11][C:12]([NH:45][C@@H:46]([C:48]([NH:50][CH2:51][C:52]([O:54][CH2:55][C:56]1[CH:57]=[CH:58][CH:59]=[CH:60][CH:61]=1)=[O:53])=[O:49])[CH3:47])=[O:14])=[O:9])[CH3:7])=[O:4]
Reactant: C[C@@H](N)C(=O)NCC(=O)OCc1ccccc1
Reactant: C[C@H](NC(=O)CNC(=O)OC(C)(C)C)C(=O)NCC(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Product: C[C@H](NC(=O)CNC(=O)OC(C)(C)C)C(=O)NCC(=O)N[C@H](C)C(=O)NCC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 70 %

Procedure:
To a solution of Boc-Gly-Ala-Gly prepared as in Example 34B (11.0 g, 36.5 mmol) in anhydrous DMF (270 ml), was added HOBT.H2O (5.46 g, 40.4 mmol), EDC.HCl (7.74 g, 40.4 mmol), and DAla-Gly-OBzl.HCl prepared as in Example 34A (9.95 g, 36.5 mmol). The pH of the resulting solution was adjusted to ~8 (measured by spotting the reaction mixture on moistened Hydrion paper) and the reaction mixture was allowed to stir at room temperature for 12 h thereafter. The solution was concentrated in vacuo and the residue was dissolved in water (50 ml). This solution was extracted with ethyl acetate (3×100 ml). The combined ethyl acetate layers were washed with 1 N sodium bisulfate (50 ml), saturated sodium bicarbonate (50 ml) and brine (50 ml). The ethyl acetate solution was dried (magnesium sulfate), filtered and allowed to sit for 12 h undisturbed. Collection of the crystals by filtration and drying at high vacuum afforded 13.4 g (70% yield) of pure product: 1H NMR (DMSO-d6) δ 1.22 (d, J=7.2 Hz, 3 H), 1.23 (d, J=7.2 Hz, 3 H), 1.38 (s, 9 H), 3.58 (d, J=6.0 Hz, 2 H), 3.73 (d, J=4.8 Hz, 2 H), 3.91 (dd, J=6.0, 3.0 Hz, 2 H), 4.32 (m, 2 H), 5.14 (s, 2 H), 6.91 (t, J=4.8 Hz, 1 H), 7.38 (s, 5 H), 7.97 (d, J=8.1 Hz, 1 H), 8.02 (d, J=6.9 Hz, 1 H), 8.19 (t, J=5.4 Hz, 1 H), 8.33 (t, J=5.4 Hz, 1 H).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:18]=[C:17]2[C:12]([C:13]([NH:20][CH2:21][CH:22]([CH3:24])[CH3:23])=[C:14]([NH2:19])[CH:15]=[N:16]2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:25]([O:27][CH2:28][C:29](Cl)=O)[CH3:26].C1(C)C=CC=CC=1>N1C=CC=CC=1.C(N(CC)CC)C>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]2[C:13]3[N:20]([CH2:21][CH:22]([CH3:24])[CH3:23])[C:26]([CH2:25][O:27][CH2:28][CH3:29])=[N:19][C:14]=3[CH:15]=[N:16][C:17]=2[CH:18]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)CNc1c(N)cnc2cc(OCc3ccccc3)ccc12
Reactant: CCOCC(=O)Cl
Solvent: c1ccncc1
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CCOCc1nc2cnc3cc(OCc4ccccc4)ccc3c2n1CC(C)C
Temperature: 25 °C

Procedure:
The preparation of 7-benzyloxy-N4-(2-methylpropyl)quinoline-3,4-diamine is described in Parts A-F of Example 1. A concentrated solution of ethoxyacetyl chloride (12.2 g, 99.2 mmol) was added dropwise to a solution of 7-benzyloxy-N4-(2-methylpropyl)quinoline-3,4-diamine (29 g, 90 mmol) in 50:50 toluene:pyridine. The temperature of the reaction reached 40° C., and a precipitate formed. Triethylamine (15-20 g) and pyridine were added to help dissolve the precipitate. The reaction was heated at reflux for three hours and then allowed to cool to ambient temperature overnight. The solvents were removed under reduced pressure, and the black residue was dissolved in dichloromethane. The resulting solution was washed several times with aqueous sodium carbonate (150 mL), dried over magnesium sulfate, filtered, and concentrated under reduced pressure to provide 29.2 g of 7-benzyloxy-2-ethoxymethyl-1-(2-methylpropyl)-1H-imidazo[4,5-c]quinoline as a tan solid.
Reaction SMILES: CS[CH2:3][P:4](=[O:11])([O:8][CH2:9][CH3:10])[O:5][CH2:6][CH3:7].C[O-:13].[Na+].CO>>[CH2:6]([O:5][P:4]([CH:3]=[O:13])([O:8][CH2:9][CH3:10])=[O:11])[CH3:7]
Reactant: CCOP(=O)(CSC)OCC
Reactant: C[O-]
Agent: [Na+]
Solvent: CO
Product: CCOP(=O)(C=O)OCC

Procedure:
Oxydation of diethyl methylthiomethylphosphonate include anodic oxidation in NaOMe/MeOH (saturated with CO2) to give the O, S-acetal of diethoxyphosphinylformaldehyde, which upon oxidation may give the corresponding sulfone as Diethyl methoxy(methylsulfone)phenyl phosphonate (Shankaran, K et al. 2001).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:7]([C:10]#[C:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[Cl:18])=[CH:8][N:9]=1)[CH:5]=O.C([O-])(=O)C.[Na+].Cl.[NH2:25][OH:26]>C(O)C.ClC(Cl)C.C(OCC)(=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([C:7]([C:10]#[C:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[Cl:18])=[CH:8][N:9]=1)[CH:5]=[N:25][OH:26]
Reactant: NO
Reactant: O=Cc1cc(Cl)ncc1C#Cc1ccccc1Cl
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CC(Cl)Cl
Solvent: CCOC(C)=O
Solvent: CCO
Product: ON=Cc1cc(Cl)ncc1C#Cc1ccccc1Cl
Temperature: 50 °C

Procedure:
A mixture of 2-chloro-5-((2-chlorophenyl)ethynyl)isonicotinaldehyde (1.1 g, 4.0 mmol), sodium acetate (490 mg, 6 mmol), and hyroxylamine hydrochloride (415 mg, 6 mmol) in ethanol (23 mL) and dichloroethane (13 mL) was heated at 50° C. for 15 minutes. The cooled reaction mixture was evaporated in vacuo to afford a residue that was redissolved in ethyl acetate (150 mL) and washed with water (100 mL). The organic layer was separated, dried over sodium sulfate, filtered, and evaporated in vacuo to afford a white solid that was used in the next step without further purification.
Reaction SMILES: [CH3:1][C:2]1[NH:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][C:10]([CH3:13])=[C:9]([N+:14]([O-])=O)[CH:8]=2)[CH:3]=1>C(O)C.[Pd]>[CH3:13][C:10]1[CH:11]=[CH:12][C:7]([C:4]2[NH:5][N:6]=[C:2]([CH3:1])[CH:3]=2)=[CH:8][C:9]=1[NH2:14]
Reactant: Cc1cc(-c2ccc(C)c([N+](=O)[O-])c2)n[nH]1
Agent: [Pd]
Solvent: CCO
Product: Cc1cc(-c2ccc(C)c(N)c2)[nH]n1
Reaction time: 5 h
Yield: 5.9 %

Procedure:
5-Methyl-3-(4-methyl-3-nitro-phenyl)-1H-pyrazole (8.2 g) was dissolved in ethanol and Palladium (10%) on activated carbon was added. The mixture was subject to barometric hydrogenation under balloon pressure for five hours at room temperature. The mixture was filtered and the filtrate was concentrated under reduced pressure to give 414 mg of crude 2-methyl-5-(5-methyl-2H-pyrazol-3-yl)-phenylamine as a white solid, which was used directly without further purification.
Reaction SMILES: [H-].[Na+].[CH2:3]([N:5]([CH2:15][CH3:16])[C:6](=[O:14])[CH2:7]P(=O)([O-])OCC)[CH3:4].[CH2:17]([C:20]1[CH:21]=[C:22]([C:35](=O)[CH3:36])[CH:23]=[CH:24][C:25]=1[O:26][CH:27]([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[CH3:28])[CH:18]=[CH2:19]>C1COCC1>[CH2:15]([N:5]([CH2:3][CH3:4])[C:6](=[O:14])/[CH:7]=[C:35](/[C:22]1[CH:23]=[CH:24][C:25]([O:26][CH:27]([C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=2)[CH3:28])=[C:20]([CH2:17][CH:18]=[CH2:19])[CH:21]=1)\[CH3:36])[CH3:16]
Reactant: C=CCc1cc(C(C)=O)ccc1OC(C)c1ccccc1
Reactant: CCOP(=O)([O-])CC(=O)N(CC)CC
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: C=CCc1cc(/C(C)=C/C(=O)N(CC)CC)ccc1OC(C)c1ccccc1
Reaction time: 0.08 h

Procedure:
A solution of 3′-allyl-4′-hydroxyacetophenone (3.46 g, 19.66), (1-bromoethyl)-benzene (3.05 mL, 21.63 mmol)), and K2CO3 (4.07 g, 29.49 mmol) in acetone (100 mL) is refluxed 20 hours. The mixture is then filtered and the filtrate is concentrated in vacuo. The residue is dissolved in EtOAc (100 mL) and then washed with H2O (1×100 mL) and brine (1×100 mL), dried over MgSO4, and concentrated in vacuo. Chromatography (5:1 hexane/EtOAc) yields 3′-allyl-4′-(1-phenylethoxy)-acetopbenone. To a solution of sodium hydride (0.54 g, 13.5 mmol) in THF (20 mL) is added a solution of ethyl [2-(diethylamino)-2-oxoethyl]-phosphonate (3.13 g. 12.5 mmol) in THF (20 ml). After stirring this mixture for 5 minutes. at room temperature, a solution of 3′-allyl-4′-(1-phenylethoxy)-acetophenone (2.91 g, 10.4 mmol) in ThF (30 mL) is added, and the solution is refluxed 18 hours. After cooling, the mixture is then quenched with saturated aqueous ammonium chloride (50 mL), and extracted with ethyl acetate (4×75 mL). The combined organic phase is washed with water (1×100 mL) and brine (1×100 mL), dried over MgSO4, concentrated in vacuo, chromatographed (silica, 2:1 EtOAc/hexane) to yield N,N-diethyl (E)-3-[3-allyl 4-(1-phenylethoxy)-phenyl)-but-2-enamide.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][O:11][NH:12][C:13]([C@@H:15]1[CH2:20][CH2:19][C@@H:18]([NH:21][O:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH2:17][N:16]1C(=O)C(F)(F)F)=[O:14])=[O:7])([CH3:4])([CH3:3])[CH3:2].O.[OH-].[Na+].C(O)(=O)C>O1CCOCC1>[C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][O:11][NH:12][C:13]([C@@H:15]1[CH2:20][CH2:19][C@@H:18]([NH:21][O:22][CH2:23][C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)[CH2:17][NH:16]1)=[O:14])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NCCONC(=O)[C@@H]1CC[C@@H](NOCc2ccccc2)CN1C(=O)C(F)(F)F
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)NCCONC(=O)[C@@H]1CC[C@@H](NOCc2ccccc2)CN1
Yield: 95.1 %

Procedure:
(2S,5R)—N-(2-tert-butoxycarbonylaminoethoxy)-5-(benzyloxyamino)-1-(2,2,2-trifluoroacetyl)piperidine-2-carboxamide (1.07 g, 2.06 mmol) was dissolved in 1,4-dioxane (4.2 mL), to which was added water (1.1 mL), and followed by ice cooling. To this was added 1M sodium hydroxide aqueous solution (6.3 mL), and followed by reaction at the same temperature for 2.5 h. pH was adjusted to ca. pH 7 by the addition of acetic acid to the reaction mixture. The organic solvent was distilled off under reduced pressure. The resulting aqueous solution was extracted with ethyl acetate. After the organic layer was washed with saturated brine, and dehydrated with anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The resulting oil residue was purified by silica gel column chromatography (ethyl acetate/methanol=9/1) to afford 0.80 g of the title compound (yield 93%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:25])[CH:4]([N:11]1[CH2:16][CH2:15][N:14]([C:17]2[CH:22]=[CH:21][C:20]([NH2:23])=[CH:19][C:18]=2[F:24])[CH2:13][CH2:12]1)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[CH3:26][CH:27]([CH3:33])[CH2:28][CH2:29][C:30](Cl)=[O:31]>C(Cl)Cl>[CH3:1][O:2][C:3](=[O:25])[CH:4]([N:11]1[CH2:12][CH2:13][N:14]([C:17]2[CH:22]=[CH:21][C:20]([NH:23][C:30](=[O:31])[CH2:29][CH2:28][CH:27]([CH3:33])[CH3:26])=[CH:19][C:18]=2[F:24])[CH2:15][CH2:16]1)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: CC(C)CCC(=O)Cl
Reactant: COC(=O)C(c1ccccc1)N1CCN(c2ccc(N)cc2F)CC1
Solvent: ClCCl
Product: COC(=O)C(c1ccccc1)N1CCN(c2ccc(NC(=O)CCC(C)C)cc2F)CC1
Reaction time: 16 h
Yield: 74.7 %

Procedure:
A solution of [4-(4-amino-2-fluoro-phenyl)-piperazin-1-yl]-phenyl-acetic acid methyl ester (35 mg, 0.10 mmol) in DCM (2 mL) was treated with 4-methylvaleroyl chloride (15 mg, 0.11 mmol) followed by TEA (16 μL, 0.11 mmol). After 16 h, the mixture was purified directly by PTLC to give a beige solid (33 mg, 73%). MS (ESI): mass calcd. for C25H32FN3O3, 441.55; m/z found, 442.5 [M+H]+. 1H NMR (CDCl3): 7.46-7.44 (m, 2H), 7.42-7.39 (m, 1H), 7.36-7.32 (m, 3H), 7.05-7.03 (m, 1H), 6.98 (br s, 1H), 6.88-6.84 (m, 1H), 4.06 (s, 1H), 3.70 (s, 3H), 3.10-3.06 (m, 4H), 2.34-2.31 (m, 4H), 2.35-2.31 (m, 2H), 1.62-1.60 (m, 3H), 0.92 (d, J=6.1, 6H).
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5]1[CH:12]=[CH:11][CH:10]=[CH:9][C:6]=1[CH:7]=O.[CH3:13]S(C)=O>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:3][O:4][C:5]1[CH:12]=[CH:11][CH:10]=[CH:9][C:6]=1[CH:7]=[CH2:13]
Reactant: CS(C)=O
Reactant: COc1ccccc1C=O
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Agent: [H-]
Product: C=Cc1ccccc1OC
Temperature: 85 °C
Reaction time: 0.5 h
Yield: 61.1 %

Procedure:
Under nitrogen atmosphere, in dry dimethylsulfoxide (15 mL) was suspended 1.92 g (48.0 mmol) of 60% sodium hydride washed with hexane, after stirring the suspension at 85° C. for 30 minutes, it was cooled to room temperature and then, in an ice bath, a dry dimethylsulfoxide (35 mL) solution containing 17.2 g (48.2 mmol) of methyl(triphenyl)phosphonium bromide was gradually added dropwise thereto. After stirring at room temperature for 20 minutes, 4.83 mL (40.1 mmol) of commercially available 2-methoxybenzaldehyde was added dropwise thereto, and the resulting mixture was stirred at room temperature for 1 hour and then at 65° C. for 3 hours. The reaction mixture was poured into ice water, and extracted with ethyl acetate. The organic layer was successively washed with water and brine, and dried over anhydrous magnesium sulfate. The solvent was removed, and the obtained residue was purified by silica gel column chromatography (Wako gel C-100, hexane-ethyl acetate, gradient) to obtain 3.29 g (24.5 mmol, Yield: 61.1%) of 1-methoxy-2-vinylbenzene.
Reaction SMILES: [NH2:1][C@@H:2]([C:6]1[CH:21]=[CH:20][C:9]([C:10]([NH:12][O:13][CH:14]2[CH2:19][CH2:18][CH2:17][CH2:16][O:15]2)=[O:11])=[CH:8][CH:7]=1)[CH:3]([CH3:5])[CH3:4].C(N(CC)C(C)C)(C)C.C([N:48]=[C:49]=[S:50])(OCC1C2C(=CC=CC=2)C2C1=CC=CC=2)=O.N1CCCCC1>C(Cl)Cl>[CH3:4][CH:3]([CH3:5])[C@H:2]([C:6]1[CH:7]=[CH:8][C:9]([C:10]([NH:12][O:13][CH:14]2[CH2:19][CH2:18][CH2:17][CH2:16][O:15]2)=[O:11])=[CH:20][CH:21]=1)[NH:1][C:49]([NH2:48])=[S:50]
Reactant: O=C(N=C=S)OCC1c2ccccc2-c2ccccc21
Reactant: CC(C)[C@@H](N)c1ccc(C(=O)NOC2CCCCO2)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCNCC1
Solvent: ClCCl
Product: CC(C)[C@@H](NC(N)=S)c1ccc(C(=O)NOC2CCCCO2)cc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A solution of 4-((R)-1-amino-2-methylpropyl)-N-(tetrahydro-2H-pyran-2-yloxy)benzamide (0.1643 g, 0.562 mmol) and N,N-diisopropylethylamine (0.1 mL, 0.6 mmol) in DCM (2.5 mL) was cooled in an ice bath and added to a solution of Fmoc-isothiocyanate (0.173 g, 0.616 mmol) in DCM (2.5 mL, 38 mmol) cooled at 0° C. in an ice bath. The reaction solution was stirred at rt for 1 h. Piperidine (1.0 mL, 2.0 mmol, 2.0 M in MeOH) was then added and the reaction stirred at rt for an additional 2 h. The reaction was concentrated and the residue was purified by flash chromatography (EtOAc:hex, 7:3 to 1:0) to afford 4-((R)-2-methyl-1-thioureidopropyl)-N-(tetrahydro-2H-pyran-2-yloxy)benzamide as a white solid. LC-MS: (FA) ES+ 352.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][N:6]=[C:5]2[NH:11][S:12]([CH3:15])(=[O:14])=[O:13].[F:16][C:17]1[CH:18]=[C:19]([S:23](Cl)(=[O:25])=[O:24])[CH:20]=[CH:21][CH:22]=1>N1C=CC=CC=1>[F:16][C:17]1[CH:18]=[C:19]([S:23]([NH:1][C:2]2[CH:3]=[C:4]3[C:8](=[CH:9][CH:10]=2)[NH:7][N:6]=[C:5]3[NH:11][S:12]([CH3:15])(=[O:14])=[O:13])(=[O:25])=[O:24])[CH:20]=[CH:21][CH:22]=1
Reactant: O=S(=O)(Cl)c1cccc(F)c1
Reactant: CS(=O)(=O)Nc1n[nH]c2ccc(N)cc12
Solvent: c1ccncc1
Product: CS(=O)(=O)Nc1n[nH]c2ccc(NS(=O)(=O)c3cccc(F)c3)cc12
Yield: 18.3 %

Procedure:
3-Fluoro-N-(3-methylsulfonylamino-1H-indazol-5-yl)benzenesulfonamide can be obtained as described in Example 2 from 0.1 g of 5-amino-3-methylsulfonylamino-1H-indazole, 5 ml of pyridine and 83 mg of 3-fluorobenzenesulfonyl chloride. 30 mg of 3-fluoro-N-(3-methylsulfonylamino-1H-indazol-5-yl)benzenesulfonamide are thus obtained in the form of a beige solid melting at 230° C. (analysis C14H13FN4O4S2.0.57H2O % calculated C, 43.75; H, 3.41; F, 4.94; N, 14.57; O, 16.65; S, 16.68. % found C, 43.75; H, 2.86; N, 14.77; S, 15.93).
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[C:5]([NH2:12])=[C:4]([N+:13]([O-:15])=[O:14])[CH:3]=1.[Cl:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1B(O)O.C(Cl)Cl>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]>[Cl:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[C:2]1[CH:3]=[C:4]([N+:13]([O-:15])=[O:14])[C:5]([NH2:12])=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1
Reactant: OB(O)c1ccccc1Cl
Reactant: Nc1c([N+](=O)[O-])cc(Br)cc1C(F)(F)F
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Solvent: ClCCl
Product: Nc1c([N+](=O)[O-])cc(-c2ccccc2Cl)cc1C(F)(F)F
Temperature: 90 °C
Reaction time: 18 h
Yield: 93.4 %

Procedure:
4-Bromo-2-nitro-6-trifluoromethyl-phenylamine (1.01 g, 3.55 mmol), 2-chlorophenylboronic acid (1.5 eq., 833 mg, 5.33 mmol), and (dppf)PdCl2.DCM (0.05 eq., 145 mg, 0.178 mmol) were placed in a 40 mL vial equipped with a magnetic stir bar. The vial was evacuated and backflushed with Ar, and DME (15 mL) and 2M aq Na2 CO3 (5 mL) were added via syringe. The vial was capped tightly and placed in a heating block where the reaction was stirred at 90° C. for 18 h. The mixture was cooled to rt, diluted with EtOAc, and washed with water. The aqueous layers were combined and extracted with EtOAc. The combined organic extracts were dried over anhydrous MgSO4, filtered, and the solvent was removed under reduced pressure. The crude product was purified by column chromatography using a 24-g SiO2 pre-packed column eluting with EtOAc/hexanes, 0 to 1:4, v/v over 20 min, yielding 1.05 g (94%) of the desired compound. 1H-NMR (400 MHz, CDCl3) δ: 8.47 (d, J=2.0 Hz, 1H), 7.89 (d, J=2.0 Hz, 1H), 7.47-7.53 (m, 1H), 7.30-7.37 (m, 3H), 6.76 (br. s., 2H).
Reaction SMILES: CC1C=CC(S(O[CH2:12][C@@H:13]2[O:18][C:17]3[CH:19]=[C:20]([S:24]([CH3:27])(=[O:26])=[O:25])[CH:21]=[C:22]([Cl:23])[C:16]=3[O:15][CH2:14]2)(=O)=O)=CC=1.[CH3:28][O:29][CH2:30][CH2:31][NH2:32]>C(#N)C>[Cl:23][C:22]1[C:16]2[O:15][CH2:14][C@H:13]([CH2:12][NH:32][CH2:31][CH2:30][O:29][CH3:28])[O:18][C:17]=2[CH:19]=[C:20]([S:24]([CH3:27])(=[O:25])=[O:26])[CH:21]=1
Reactant: Cc1ccc(S(=O)(=O)OC[C@H]2COc3c(Cl)cc(S(C)(=O)=O)cc3O2)cc1
Reactant: COCCN
Solvent: CC#N
Product: COCCNC[C@H]1COc2c(Cl)cc(S(C)(=O)=O)cc2O1

Procedure:
Preparation according to Example 57 using [(2R)-5-chloro-7-(methylsulfonyl)-2,3-dihydro-1,4-benzodioxin-2-yl]methyl 4-methylbenzenesulfonate (0.027 g, 0.062 mmol), 2-methoxyethanamine (0.5 ml), ACN (3 ml). MS m/z (rel. intensity, 70 eV) 335 (M+, 1), 290 (18), 88 (bp), 70 (8), 58 (8), 56 (12).
Reaction SMILES: S([O-])(OCCCCCCCCCCCC)(=O)=O.[Na+].O.[C:20]1([CH3:30])[C:21]([S:26]([OH:29])(=[O:28])=[O:27])=[CH:22][CH:23]=[CH:24][CH:25]=1.[OH-].[NH4+:32]>O>[C:20]1([CH3:30])[C:21]([S:26]([O-:29])(=[O:28])=[O:27])=[CH:22][CH:23]=[CH:24][CH:25]=1.[NH4+:32]
Reactant: Cc1ccccc1S(=O)(=O)O
Agent: CCCCCCCCCCCCOS(=O)(=O)[O-]
Agent: [NH4+]
Agent: [Na+]
Solvent: O
Product: Cc1ccccc1S(=O)(=O)[O-]

Procedure:
A 500 gallon tank containing 211 gallons of purified water was charged with 0.07 lbs. of sodium lauryl sulfate, and the aqueous solution was agitated to ensure homogeneity. A 66% aqueous solution of toluene sulfonic acid monohydrate, 500 lbs., was added followed by the addition of 5 gallons of purified water. Finally, an aqueous solution of ammonium hydroxide (17.5 gallons, 29-30% NH4OH by weight) was added. This catalyst solution had a density of 8.65 lb/gallon and a solids content of about 15±1%.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:10]([O:12][CH3:13])=[O:11])[CH:8]=2)[CH:3]=[N:2]1.Cl[CH2:15][CH2:16][CH2:17][O:18][CH3:19]>>[CH3:19][O:18][CH2:17][CH2:16][CH2:15][N:2]1[CH:3]=[C:4]2[C:9]([CH:8]=[C:7]([C:10]([O:12][CH3:13])=[O:11])[CH:6]=[CH:5]2)=[N:1]1
Reactant: COC(=O)c1ccc2cn[nH]c2c1
Reactant: COCCCCl
Product: COCCCn1cc2ccc(C(=O)OC)cc2n1

Procedure:
Analogously to Example 8c, 1.0 g of methyl 1H-indazole-6-carboxylate and 1.16 g of 1-chloro-3-methoxypropane are reacted. The title compounds are obtained as yellowish oils.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH:12]=[C:11](OS(C(F)(F)F)(=O)=O)[CH2:10][CH2:9]1)=O)(C)(C)C.[Cl:22][C:23]1[CH:24]=[C:25](OB(O)O)[CH:26]=[CH:27][C:28]=1[F:29].[Cl-].[Li+].C(=O)([O-])[O-].[Na+].[Na+].C(=O)([O-])O.[Na+]>C(COC)OC>[Cl:22][C:23]1[CH:24]=[C:25]([C:11]2[CH2:10][CH2:9][NH:8][CH2:13][CH:12]=2)[CH:26]=[CH:27][C:28]=1[F:29]
Reactant: CC(C)(C)OC(=O)N1CC=C(OS(=O)(=O)C(F)(F)F)CC1
Reactant: OB(O)Oc1ccc(F)c(Cl)c1
Agent: O=C([O-])O
Agent: O=C([O-])[O-]
Agent: [Cl-]
Solvent: COCCOC
Product: Fc1ccc(C2=CCNCC2)cc1Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 56 %

Procedure:
4-{[(Trifluoromethyl)sulfonyl]oxy}-3,6-dihydropyridine-1(2H)carboxylic acid tert-butyl ester (synthesized according to the method described in Synthesis, 1991, 993-995, 1.0 g), 3-chloro-4-fluorophenylboric acid (Aldrich Co., 790 mg), lithium chloride (380 mg), tetrakistriphenylphosphine palladium (170 mg) and a 2N sodium carbonate aqueous solution (5 ml) were added to dimethoxyethane (12 ml), and the mixture was heated under reflux for 6 hr. After completion of the reaction, the reaction mixture was washed with a sodium carbonate aqueous solution and aqueous ammonia, and the aqueous layer was extracted with ethyl acetate. The organic layers were combined and dried, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (elution solvent: hexane-ethyl acetate (20:1-10:1)). The intermediate was dissolved in methylene chloride, and trifluoroacetic acid was added. The mixture was stirred at room temperature for 8 hr. After completion of the reaction, a saturated aqueous sodium hydrogen carbonate solution was added and the mixture was extracted with chloroform. The organic layer was dried and the solvent was evaporated under reduced pressure. The precipitated solid was collected by filtration to give 4-(3-chloro-4-fluorophenyl)-1,2,3,6-tetrahydropyridine (357 mg, yield 56%).