Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6](Cl)[CH:5]=[C:4]([CH:9]=[C:10]([Cl:12])[Cl:11])[N:3]=1.[CH3:13][O-:14].[Na+].[Na]>CO>[NH2:1][C:2]1[N:3]=[C:4]([CH:9]=[C:10]([Cl:12])[Cl:11])[CH:5]=[C:6]([O:14][CH3:13])[N:7]=1
Reactant: C[O-]
Reactant: Nc1nc(Cl)cc(C=C(Cl)Cl)n1
Agent: [Na+]
Agent: [Na]
Solvent: CO
Product: COc1cc(C=C(Cl)Cl)nc(N)n1
Reaction time: 4 h

Procedure:
22.0 Parts of 2-amino-4-chloro-6-(2,2-dichlorovinyl)pyrimidine was dissolved in 500 parts of dry methanol and stirred whilst a solution of sodium methoxide, prepared by dissolving 4.6 parts of sodium in 200 parts of dry methanol, was added dropwise, over 30 minutes at ambient temperature. The resulting solution was stirred for 4 hours by which time all the starting material had been consumed. The product was precipitated by the addition of water, filtered and dried. The solid obtained was purified by chromatography on silica using diethyl ether as eluent. Final purification was effected by recrystallisation from carbon tetrachloride to give 2-amino-4-(2,2-dichlorovinyl)-6-methoxypyrimidine m.p. 90°-91° C.
Reaction SMILES: [O:1]=[C:2]1[C:6]2([CH2:11][CH2:10][NH:9][CH2:8][CH2:7]2)[N:5]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:4][N:3]1[CH2:18][C:19]1[CH:20]=[C:21]([CH:26]=[CH:27][CH:28]=1)[C:22]([O:24][CH3:25])=[O:23].[F:29][C:30]1[CH:35]=[CH:34][C:33]([C:36](=[O:41])[CH2:37][CH2:38][CH2:39]I)=[CH:32][CH:31]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[F:29][C:30]1[CH:31]=[CH:32][C:33]([C:36](=[O:41])[CH2:37][CH2:38][CH2:39][N:9]2[CH2:10][CH2:11][C:6]3([N:5]([C:12]4[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=4)[CH2:4][N:3]([CH2:18][C:19]4[CH:20]=[C:21]([CH:26]=[CH:27][CH:28]=4)[C:22]([O:24][CH3:25])=[O:23])[C:2]3=[O:1])[CH2:7][CH2:8]2)=[CH:34][CH:35]=1
Reactant: COC(=O)c1cccc(CN2CN(c3ccccc3)C3(CCNCC3)C2=O)c1
Reactant: O=C(CCCI)c1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)c1cccc(CN2CN(c3ccccc3)C3(CCN(CCCC(=O)c4ccc(F)cc4)CC3)C2=O)c1
Temperature: 65 °C
Yield: 10 %

Procedure:
A mixture of methyl 3-((4-oxo-1-phenyl-1,3,8-triazaspiro[4.5]decan-3-yl)methyl)benzoate (500 mg, 1.2 mmol, 1 equiv), 1-(4-fluorophenyl)-4-iodobutan-1-one (351.1 mg, 1.2 mmol, 1 equiv), and potassium carbonate (497.6 mg, 3.6 mmol, 3 equiv) in N,N-dimethylformamide was heated at 65° C. for 16 h. The reaction was cooled to ambient temperature and partitioned between ethyl acetate and water. The organic layer was dried over MgSO4, and concentrated in vacuo. The crude was purified using preparatory thin layer chromatography in 10% methanol in dichloromethane followed by a purification using preparatory high performance liquid chromatography to afford the acetate salt of the title compound as a yellow powder (65 mg, ˜10%); 1H NMR (400 MHz, DMSO-d6): δ 1.58 (d, 2H, J=14 Hz), 1.81-1.88 (m, 2H); 2.39-2.47 (m, 4H); 2.67-2.75 (m, 4H); 3.04 (t, 2H, J=6.4 and 7.2 Hz); 3.84 (s, 3H); 4.57 (s, 2H); 4.61 (s, 2H); 6.74-6.77 (m, 3H); 7.14-7.18 (m, 2H); 7.32-7.37 (m, 2H); 7.52-7.58 (m, 2H); 7.88-7.90 (m, 2H); 8.05-8.08 (m, 2H); 10.82 (s, 1H); MS for C32H34FN3O4 m/z 544.02 (M+H)+.
Reaction SMILES: Cl.[O:2]=[S:3]1(=[O:22])[CH2:8][CH2:7][CH2:6][CH2:5][N:4]1[C:9]1[CH:17]=[C:16]([C:18]([O:20][CH3:21])=[O:19])[CH:15]=[C:14]2[C:10]=1[CH2:11][CH2:12][NH:13]2.CCN(CC)CC.[C:30](OC(=O)C)(=[O:32])[CH3:31]>CCOC(C)=O>[C:30]([N:13]1[C:14]2[C:10](=[C:9]([N:4]3[CH2:5][CH2:6][CH2:7][CH2:8][S:3]3(=[O:2])=[O:22])[CH:17]=[C:16]([C:18]([O:20][CH3:21])=[O:19])[CH:15]=2)[CH2:11][CH2:12]1)(=[O:32])[CH3:31]
Reactant: COC(=O)c1cc2c(c(N3CCCCS3(=O)=O)c1)CCN2
Reactant: CC(=O)OC(C)=O
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: COC(=O)c1cc2c(c(N3CCCCS3(=O)=O)c1)CCN2C(C)=O
Temperature: 50 °C
Reaction time: 0.5 h

Procedure:
To a solution of methyl 4-(1,1-dioxidotetrahydro-2H-1,2-thiazin-2-yl)-2,3-dihydro-1H-indole-6-carboxylate hydrochloride salt (D234) (350 mg, 1.0 mmol, 1 equiv) in AcOEt (5 ml) were added NEt3 (140 ml, 1.0 mmol, 1 equiv) and acetic anhydride (0.5 ml, 5.6 mmol, 5.6 equiv) and the resulting mixture was stirred at 50° C. for 30 min then cooled to room temperature and washed with a 2N aqueous HCl solution followed by a saturated aqueous NaHCO3 solution, then dried over MgSO4 and concentrated in vacuo to give methyl 1-acetyl-4-(1,1-dioxidotetrahydro-2H-1,2-thiazin-2-yl)-2,3-dihydro-1H-indole-6-carboxylate (D235) as a white solid which was used in the next step without further purification. [M+H]+=353.2, RT=2.24 min.
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[F:25][C:26]1[CH:27]=[C:28]([NH:37][C:38]([C@H:40]2[C:49]3[C:44](=[CH:45][C:46]([O:50][CH3:51])=[CH:47][CH:48]=3)[CH2:43][CH2:42][NH:41]2)=[O:39])[CH:29]=[C:30]([F:36])[C:31]=1[Si:32]([CH3:35])([CH3:34])[CH3:33].[C:52]([O:56][C:57](=[O:66])[CH2:58][C@H:59]1[CH2:62][C@H:61]([C:63](O)=[O:64])[CH2:60]1)([CH3:55])([CH3:54])[CH3:53].CCN(C(C)C)C(C)C>CN(C=O)C.O>[F:25][C:26]1[CH:27]=[C:28]([NH:37][C:38]([C@H:40]2[C:49]3[C:44](=[CH:45][C:46]([O:50][CH3:51])=[CH:47][CH:48]=3)[CH2:43][CH2:42][N:41]2[C:63]([C@H:61]2[CH2:60][C@H:59]([CH2:58][C:57]([O:56][C:52]([CH3:55])([CH3:54])[CH3:53])=[O:66])[CH2:62]2)=[O:64])=[O:39])[CH:29]=[C:30]([F:36])[C:31]=1[Si:32]([CH3:33])([CH3:35])[CH3:34]
Reactant: CC(C)(C)OC(=O)C[C@H]1C[C@H](C(=O)O)C1
Reactant: COc1ccc2c(c1)CCN[C@H]2C(=O)Nc1cc(F)c([Si](C)(C)C)c(F)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc2c(c1)CCN(C(=O)[C@H]1C[C@H](CC(=O)OC(C)(C)C)C1)[C@H]2C(=O)Nc1cc(F)c([Si](C)(C)C)c(F)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
HATU (55.7 mg, 0.15 mmol) was added to a solution of (R)—N-(3,5-difluoro-4-(trimethylsilyl)phenyl)-6-methoxy-1,2,3,4-tetrahydroisoquinoline-1-carboxamide (52 mg, 0.13 mmol), trans-3-(2-(tert-butoxy)-2-oxoethyl)cyclobutanecarboxylic acid (30.0 mg, 0.14 mmol) and DIEA (0.026 mL, 0.15 mmol) in DMF (2 mL) at room temperature, and the mixture was stirred overnight at room temperature. To the reaction mixture was added water, and the precipitate was collected by filtration, and washed with water to give tert-butyl 2-(trans-3-((R)-1-((3,5-difluoro-4-(trimethylsilyl)phenyl)carbamoyl)-6-methoxy-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)cyclobutyl)acetate (64.0 mg, 0.109 mmol, 82%) as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4](B2OC(C)(C)C(C)(C)O2)[CH:5]=[CH:6][C:7]=1[C:8]([F:11])([F:10])[F:9].Br[C:22]1[CH:23]=[N:24][CH:25]=[C:26]([CH:31]=1)[C:27]([O:29][CH3:30])=[O:28]>>[F:1][C:2]1[CH:3]=[C:4]([C:22]2[CH:23]=[N:24][CH:25]=[C:26]([CH:31]=2)[C:27]([O:29][CH3:30])=[O:28])[CH:5]=[CH:6][C:7]=1[C:8]([F:9])([F:10])[F:11]
Reactant: COC(=O)c1cncc(Br)c1
Reactant: CC1(C)OB(c2ccc(C(F)(F)F)c(F)c2)OC1(C)C
Product: COC(=O)c1cncc(-c2ccc(C(F)(F)F)c(F)c2)c1

Procedure:
According to General Method 1A, 18.2 g (approx. 62.81 mmol) of the compound from Example 80A and 5.4 g (25.1 mmol) of methyl 5-bromonicotinate were reacted. Yield: 7.0 g (36% of theory)
Reaction SMILES: ClC(Cl)(Cl)[C:3]([N:5]1[C:9]([C:10]2[CH:15]=[CH:14][C:13]([F:16])=[C:12]([F:17])[CH:11]=2)=[C:8]([C:18]([O:20][CH3:21])=[O:19])[NH:7][C:6]1=[O:22])=[O:4].[NH2:25][CH2:26][CH2:27][CH2:28][N:29]1[CH2:34][CH2:33][C:32]([C:41]([O:43][CH3:44])=[O:42])([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[CH2:31][CH2:30]1.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1>[F:17][C:12]1[CH:11]=[C:10]([C:9]2[N:5]([C:3]([NH:25][CH2:26][CH2:27][CH2:28][N:29]3[CH2:30][CH2:31][C:32]([C:41]([O:43][CH3:44])=[O:42])([C:35]4[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=4)[CH2:33][CH2:34]3)=[O:4])[C:6](=[O:22])[NH:7][C:8]=2[C:18]([O:20][CH3:21])=[O:19])[CH:15]=[CH:14][C:13]=1[F:16]
Reactant: COC(=O)C1(c2ccccc2)CCN(CCCN)CC1
Reactant: COC(=O)c1[nH]c(=O)n(C(=O)C(Cl)(Cl)Cl)c1-c1ccc(F)c(F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: COC(=O)c1[nH]c(=O)n(C(=O)NCCCN2CCC(C(=O)OC)(c3ccccc3)CC2)c1-c1ccc(F)c(F)c1
Yield: 1.8 %

Procedure:
A mixture of 1-trichloroacetyl-5-(3,4-difluorophenyl)-2,3-dihydro-4-methoxycarbonyl-2(1H)-imidazolone (583 mg, 1.46 mmol), 1-(3-aminopropyl)-4-methoxycarbonyl-4-phenylpiperidine (808 mg, 2.92 mmol) and potassium carbonate (809 mg, 5.85 mmol) in dioxane (15 mL) was heated at reflux for 24 hours and then concentrated. The residue was partitioned between EtOAc and water. The organic layer was dried over Na2SO4, filtered and concentrated to give the crude product which was flash chromatographed over silica gel to give the product (15 mg, 2% yield). Hydrochloride salt: light brown solid; m.p. 134-136° C.
Reaction SMILES: [BH4-].[Li+].[Cl:3][C:4]1[CH:5]=[CH:6][C:7]([C:26](OC)=[O:27])=[C:8]2[C:12]=1[N:11]=[C:10]1[N:13]([C:17]3[C:22]([CH3:23])=[CH:21][C:20]([Cl:24])=[CH:19][C:18]=3[Cl:25])[CH2:14][CH2:15][CH2:16][N:9]21>O1CCCC1>[Cl:3][C:4]1[C:12]2[N:11]=[C:10]3[N:13]([C:17]4[C:22]([CH3:23])=[CH:21][C:20]([Cl:24])=[CH:19][C:18]=4[Cl:25])[CH2:14][CH2:15][CH2:16][N:9]3[C:8]=2[C:7]([CH2:26][OH:27])=[CH:6][CH:5]=1
Reactant: COC(=O)c1ccc(Cl)c2nc3n(c12)CCCN3c1c(C)cc(Cl)cc1Cl
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Product: Cc1cc(Cl)cc(Cl)c1N1CCCn2c1nc1c(Cl)ccc(CO)c12
Temperature: 50 °C
Reaction time: 13 h
Yield: 83 %

Procedure:
Lithium borohydride (205 mg, 9.42 mmol) was added to a stirred solution of methyl 9-chloro-1-(2,4-dichloro-6-methylphenyl)-1,2,3,4-tetrahydropyrimido[1,2-a]benzimidazole-6-carboxylate (800 mg, 1.88 mmol) in tetrahydrofuran (4.0 mL) at room temperature, and the mixture was stirred at 50° C. for 13 hr. The reaction was quenched by aqueous saturated ammonium chloride at 0° C. and the mixture was extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo. The residue was washed with ethyl acetate/diisopropyl ether to give the title compound as a colorless powder (620 mg, 1.56 mmol, 83%).
Reaction SMILES: [C:1]([C:3]1[C:11]2[C:6](=[N:7][CH:8]=[CH:9][C:10]=2[O:12][C:13]2[CH:18]=[CH:17][C:16]([NH:19]C(=O)C)=[CH:15][C:14]=2[F:23])[N:5](S(C2C=CC(C)=CC=2)(=O)=O)[CH:4]=1)#[N:2].[OH-].[Na+]>C(O)C.C1COCC1>[NH2:19][C:16]1[CH:17]=[CH:18][C:13]([O:12][C:10]2[CH:9]=[CH:8][N:7]=[C:6]3[NH:5][CH:4]=[C:3]([C:1]#[N:2])[C:11]=23)=[C:14]([F:23])[CH:15]=1
Reactant: CC(=O)Nc1ccc(Oc2ccnc3c2c(C#N)cn3S(=O)(=O)c2ccc(C)cc2)c(F)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: N#Cc1c[nH]c2nccc(Oc3ccc(N)cc3F)c12
Temperature: 90 °C
Reaction time: 6 h

Procedure:
30 mg (0.065 mmol) of N-[4-({3-cyano-1-[(4-methylphenyl)sulfonyl]-1H-pyrrolo[2,3-b]pyridin-4-yl}oxy)-3-fluorophenyl]acetamide are dissolved in a mixture of 3 ml of ethanol and 3 ml of THF. 1.5 ml of 20% strength aqueous sodium hydroxide solution are added, and the mixture is heated at 90° C. overnight. Another 1 ml of 20% strength-aqueous sodium hydroxide solution is then added, and a further ml after 6 hours. The mixture is again stirred overnight. The reaction mixture is then partitioned between ethyl acetate and water. The aqueous phase is extracted with ethyl acetate. The combined organic phases are dried over magnesium sulfate and the solvent is removed under reduced pressure. The crude product is reacted without further purification.
Reaction SMILES: C([O:8][C:9]1[CH:10]=[C:11]([CH:16]=[C:17]([O:19][CH:20]([CH3:24])[CH2:21][O:22][CH3:23])[CH:18]=1)[C:12]([O:14][CH3:15])=[O:13])C1C=CC=CC=1>CO.[Pd]>[OH:8][C:9]1[CH:10]=[C:11]([CH:16]=[C:17]([O:19][CH:20]([CH3:24])[CH2:21][O:22][CH3:23])[CH:18]=1)[C:12]([O:14][CH3:15])=[O:13]
Reactant: COCC(C)Oc1cc(OCc2ccccc2)cc(C(=O)OC)c1
Agent: [Pd]
Solvent: CO
Product: COCC(C)Oc1cc(O)cc(C(=O)OC)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 98.2 %

Procedure:
To a solution of Methyl 3-(benzyloxy)-5-(1-methoxypropan-2-yloxy)benzoate (Intermediate 4) (11.2 g, 33.93 mmol) in methanol (150 mL) was added Pd/C (1.12°g, 10% w/w), and the resulting suspension was stirred at ambient temperature overnight under hydrogen atmosphere. The catalyst was filtered off and washed with methanol and THF, and filtrate was evaporated to give methyl 3-hydroxy-5-(1-methoxypropan-2-yloxy)benzoate (8 g, 33.33 mmol, 98%) as white solid.
Reaction SMILES: [N:1]1([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[C:9]2[C:4](=[N:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.CC(O)=O>CCOC(C)=O.[Pt](=O)=O>[N:1]1([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH:9]2[CH:4]([NH:5][CH2:6][CH2:7][CH2:8]2)[CH2:3][CH2:2]1
Reactant: CC(C)(C)OC(=O)n1ccc2ncccc21
Agent: O=[Pt]=O
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCC2NCCCC21
Reaction time: 24 h

Procedure:
The product of Step 3 (2.66 g, 12.2 mmol) was added to a Parr shaker pressure vessel that was subsequently purged with nitrogen. Platinum (IV) oxide (0.277 g, 1.22 mmol) was added, followed by AcOH (27 mL). The vessel was placed on a Parr shaker apparatus and was sealed and evacuated and refilled with nitrogen 4 times (with shaking in between cycles). The vessel was then evacuated and refilled with hydrogen 4 times (with shaking in between cycles). The reaction was shaken under hydrogen pressure (approximately 60 psi; the vessel was recharged up to 60 psi as needed) for 48 hours. An additional amount of platinum (IV) oxide (0.277 g, 1.22 mmol) was added in order to drive the reaction to completion. After 24 hours, the reaction mixture was diluted with EtOAc (50 mL) and filtered through a Celite cartridge (Celite 545 Isolute®SPE column; Biotage, Inc.), rinsing the filter cake with additional EtOAc. The filtrate was concentrated in vacuo to a crude oil which was azeotroped with heptane several times until a constant weight was achieved, affording the desired product (HOAc salt). LRMS calc'd for C12H23N2O2 [M+H]+, 227; found 227.
Reaction SMILES: Br[C:2]1([CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([Cl:20])[CH:15]=2)[C:10]2[C:5](=[CH:6][C:7]([Cl:11])=[CH:8][CH:9]=2)[NH:4][C:3]1=[O:12].[NH2:21][C:22]1[CH:23]=[C:24]([CH:28]=[CH:29][CH:30]=1)[C:25]([OH:27])=[O:26].C([O-])([O-])=O.[K+].[K+].O>CN(C=O)C.C(O)(=O)C>[Cl:11][C:7]1[CH:6]=[C:5]2[C:10]([C:2]([NH:21][C:22]3[CH:23]=[C:24]([CH:28]=[CH:29][CH:30]=3)[C:25]([OH:27])=[O:26])([CH2:13][C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([Cl:20])[CH:15]=3)[C:3](=[O:12])[NH:4]2)=[CH:9][CH:8]=1
Reactant: Nc1cccc(C(=O)O)c1
Reactant: O=C1Nc2cc(Cl)ccc2C1(Br)Cc1cccc(Cl)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CC(=O)O
Solvent: O
Product: O=C(O)c1cccc(NC2(Cc3cccc(Cl)c3)C(=O)Nc3cc(Cl)ccc32)c1
Reaction time: 0.5 h

Procedure:
The mixture of rac-3-bromo-6-chloro-3-(3-chloro-benzyl)-1,3-dihydro-indol-2-one (740 mg, 2 mmol), 3-amino-benzoic acid (301 mg, 2.2 mmol) and K2CO3 (552 mg, 4 mmol) in DMF (5 mL) was stirred for 0.5 h and then poured into water (100 mL). The resulting solution was acidified by acetic acid and filtered. The filter cake was washed by water and dried to give rac-3-[6-chloro-3-(3-chloro-benzyl)-2-oxo-2,3-dihydro-1H-indol-3-ylamino]-benzoic acid as a pale yellow solid. MS m/z 425 (M−H)−.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH:10]([CH3:14])[C:11]([OH:13])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl.C(N(CC)CC)C.Cl.[CH3:37][NH:38][O:39][CH3:40]>C(#N)C>[CH3:40][O:39][N:38]([CH3:37])[C:11](=[O:13])[CH:10]([CH3:14])[CH2:9][NH:8][C:6](=[O:7])[O:5][C:1]([CH3:2])([CH3:3])[CH3:4]
Reactant: CNOC
Reactant: CC(CNC(=O)OC(C)(C)C)C(=O)O
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CC#N
Solvent: ClCCCl
Solvent: CCN(CC)CC
Product: CON(C)C(=O)C(C)CNC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 2 h

Procedure:
3-[(tert-Butoxycarbonyl)amino]-2-methylpropanoic acid (2.0 g, 9.9 mmol) was dissolved in acetonitrile (50 mL). To this solution was added HOBT (1.6 g, 11.85 mmol) and EDC (2.0 g, 10.4 mmol). The reaction was stirred at room temperature for 2 hr, and then treated with triethylamine (2.8 mL, 20 mmol) and N,O-dimethylhydroxyamine hydrochloride (2.0 g, 20 mmol). The reaction mixture was stirred at room temperature overnight. The reaction was quenched with water and extracted with ethyl acetate (3×). The combined organic extract was washed sequentially with 0.5N hydrochloric acid, 1N aqueous sodium bicarbonate solution and brine, dried over sodium sulfate, filtered and evaporated. The crude product was purified by flash chromatography on a Biotage® system (silica, 40-100% ethyl acetate in hexanes) to yield tert-butyl {3-[methoxy(methyl)amino]-2-methyl-3-oxopropyl}carbamate as white solid. MS (M+1−Boc): 147.
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]([CH3:11])[C:8]([F:12])=[CH:7][C:3]=1[C:4](O)=[O:5].C(N=C=NCCCN(C)C)C.Cl.C(N(CC)C(C)C)(C)C.[CH3:34][N:35]([CH3:40])[S:36]([NH2:39])(=[O:38])=[O:37]>ClCCCl.CN(C)C1C=CN=CC=1>[CH3:34][N:35]([CH3:40])[S:36]([NH:39][C:4](=[O:5])[C:3]1[CH:7]=[C:8]([F:12])[C:9]([CH3:11])=[CH:10][C:2]=1[F:1])(=[O:38])=[O:37]
Reactant: Cc1cc(F)c(C(=O)O)cc1F
Reactant: CN(C)S(N)(=O)=O
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc(F)c(C(=O)NS(=O)(=O)N(C)C)cc1F
Temperature: 60 °C
Yield: 862.5 %

Procedure:
To a suspension of 2,5-difluoro-4-methylbenzoic acid (6.0 g, 3.5 mmol) in 1,2-dichloroethane (100 mL) was added 4-dimethylaminopyridine (10.65 g, 8.7 mmol), 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide:hydrochloride (16.65 g, 8.7 mmol) in 1,2-dichloroethane (60 mL) and N,N-diisopropylethylamine (15 mL, 8.60 mmol) and the mixture stirred at room temperature for 20 minutes. N,N-Dimethylsulfamide (8.64 g, 6.9 mmol) was added to the solution and the mixture heated at 60° C. under nitrogen. After 3 hours the mixture was cooled to room temperature and extracted with dichloromethane (100 mL). The extract was washed successively with 2M hydrochloric acid (2×300 mL), brine (100 mL), dried over magnesium sulfate, filtered and evaporated to afford an oil (8.40 g) which solidified at room temperature. The crude product was purified by silica gel column chromatography eluting with ethyl acetate/heptane 1:4 as eluent to afford the title compound (7.17 g, 79%) as a white solid.
Reaction SMILES: Cl.[CH:2]([N:5]1[CH2:10][CH2:9][CH:8]([O:11][C:12]2[CH:13]=[C:14]3[C:18](=[CH:19][C:20]=2[CH3:21])[NH:17][C:16]([C:22]([OH:24])=O)=[CH:15]3)[CH2:7][CH2:6]1)([CH3:4])[CH3:3].[CH2:25]([O:27][C:28]([N:30]1[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]1)=[O:29])[CH3:26]>>[CH2:25]([O:27][C:28]([N:30]1[CH2:31][CH2:32][N:33]([C:22]([C:16]2[NH:17][C:18]3[C:14]([CH:15]=2)=[CH:13][C:12]([O:11][CH:8]2[CH2:7][CH2:6][N:5]([CH:2]([CH3:3])[CH3:4])[CH2:10][CH2:9]2)=[C:20]([CH3:21])[CH:19]=3)=[O:24])[CH2:34][CH2:35]1)=[O:29])[CH3:26]
Reactant: CCOC(=O)N1CCNCC1
Reactant: Cc1cc2[nH]c(C(=O)O)cc2cc1OC1CCN(C(C)C)CC1
Agent: Cl
Product: CCOC(=O)N1CCN(C(=O)c2cc3cc(OC4CCN(C(C)C)CC4)c(C)cc3[nH]2)CC1
Yield: 65 %

Procedure:
The title compound was synthesized in analogy to example 1, from 5-(1-isopropyl-piperidin-4-yloxy)-6-methyl-1H-indole-2-carboxylic acid hydrochloride and 1-ethoxycarbonylpiperazine to afford the title compound as a light-yellow foam (65%).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH:4]([CH2:7][OH:8])[CH2:3][CH2:2]1.[OH-].[Na+].[C:11]1([CH3:21])[CH:16]=[CH:15][C:14]([S:17](Cl)(=[O:19])=[O:18])=[CH:13][CH:12]=1.Cl.CC1CCCCC1>CC1CCCO1>[O:1]1[CH2:6][CH2:5][CH:4]([CH2:7][O:8][S:17]([C:14]2[CH:15]=[CH:16][C:11]([CH3:21])=[CH:12][CH:13]=2)(=[O:19])=[O:18])[CH2:3][CH2:2]1
Reactant: OCC1CCOCC1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CC1CCCO1
Solvent: CC1CCCCC1
Product: Cc1ccc(S(=O)(=O)OCC2CCOCC2)cc1
Temperature: 32.5 °C
Reaction time: 18 h
Yield: 98.6 %

Procedure:
To 97 g (810 mmol) of (tetrahydro-pyran-4-yl)-methanol in 2-methyltetrahydrofuran (190 mL) are added 165 mL of 50% aq. NaOH solution. To this stirred suspension is added dropwise with cooling a solution of p-toluene-sulfonylchloride (283 g, 1.46 mol) in 2-methyltetrahydrofuran (280 mL). The reaction is stirred at 30-35° C. for 18 h. The suspension is poured into a mixture of ice-water (280 mL) and aq. HCl solution (37%, 203 mL). After addition of methylcyclohexane (1.4 L) and further ice-water (0.2 L), the reaction mixture is stirred for 2 h in an ice-bath. The resulting crystalline precipitate is isolated by filtration and washed with methylcyclohexane (0.5 L) and water (0.5 L). Drying under reduced pressure at 40° C. gave 216 g of toluene-4-sulfonic acid tetrahydro-pyran-4-ylmethyl ester. Yield: 99%; ESI-MS: 271 [M+H]+
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12](=[O:13])[C:11]([CH2:14][CH:15]=[CH2:16])=[C:10]([C:17]([F:20])([F:19])[F:18])[NH:9]2)=[CH:4][C:3]=1[Cl:21].[Cl:22]Cl>C(Cl)(Cl)(Cl)Cl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12](=[O:13])[C:11]([CH2:14][CH:15]=[CH2:16])([Cl:22])[C:10]([C:17]([F:18])([F:19])[F:20])=[N:9]2)=[CH:4][C:3]=1[Cl:21]
Reactant: C=CCc1c(C(F)(F)F)[nH]n(-c2ccc(Br)c(Cl)c2)c1=O
Reactant: ClCl
Solvent: ClC(Cl)(Cl)Cl
Product: C=CCC1(Cl)C(=O)N(c2ccc(Br)c(Cl)c2)N=C1C(F)(F)F
Temperature: 0 °C
Reaction time: 15 h

Procedure:
A mixture of 4.06 g of the product of Step A and 150 ml of carbon tetrachloride was cooled to 0° C. and 17.2 ml of chlorine in solution in carbon tetrachloride (1.55 mole per liter) were added. When the reaction was complete, the product was washed with a saturated solution of sodium bicarbonate, with water, dried, treated with active charcoal and stirred for 15 hours, filtered and concentrated to obtain 51 g of 1-(4-bromo-3-chlorophenyl)-3-trifluoromethyl-4-allyl-4-chloro-5-pyrazolone.
Reaction SMILES: [F:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][CH:3]=1.C[Al](C)C.[O:13]1[C@@:23]23[C@H:18]([CH2:19][CH2:20][O:21][CH2:22]2)[CH2:17][CH2:16][CH2:15][CH:14]13>C(Cl)Cl>[F:1][C:2]1[CH:8]=[CH:7][C:5]([NH:6][C@H:14]2[C@:23]3([OH:13])[C@H:18]([CH2:19][CH2:20][O:21][CH2:22]3)[CH2:17][CH2:16][CH2:15]2)=[CH:4][CH:3]=1
Reactant: Nc1ccc(F)cc1
Reactant: C1CC2O[C@@]23COCC[C@@H]3C1
Agent: C[Al](C)C
Solvent: ClCCl
Product: O[C@]12COCC[C@@H]1CCC[C@H]2Nc1ccc(F)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture of 4-fluoroaniline (0.721 g, 6.48 mmol) in CH2Cl2 (6 mL) at 0° C. was added trimethylaluminum (2M in toluene, 3.24 mL) dropwise. The mixture was warmed and stirred to rt for 30 min. (1aS,5aS)-hexahydro-4H-oxireno[i]isochromene (0.200 g, 1.30 mmol) in CH2Cl2 2 mL+0.5 mL rinse) was then added and the mixture was stirred at rt overnight. The reaction was cooled to 0° C. and treated with 50% NaOH (1 mL) then water (1 mL) The mixture was diluted with more water and extracted 3× with CH2Cl2. The combined organics were dried (anhd. Na2SO4), filtered, and concentrated. The residue was purified by column chromatography to give the title compound. 1H NMR (500 MHz, CDCl3) δ 6.84-6.90 (m, 2H), 6.51-6.57 (m, 2H), 3.90-3.97 (m, 1H), 3.50-3.64 (m, 3H), 3.35-3.45 (m, 2H), 2.61 (s, 1H), 1.95-2.04 (m, 1H), 1.32-1.75 (m, 8H). HRMS (ES) m/z M+H cal'd: 266.1551. found: 266.1548.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([C:11]2[CH:12]=[C:13]([CH:25]=[CH:26][CH:27]=2)[CH2:14][S:15][CH2:16][CH2:17][C:18]([O:20]C(C)(C)C)=[O:19])=[O:10])=[C:4]([C:28](=[O:45])[NH:29][C:30]2[CH:34]=[CH:33][N:32]([C:35]3[CH:40]=[CH:39][CH:38]=[C:37]([C:41]([F:44])([F:43])[F:42])[CH:36]=3)[N:31]=2)[CH:3]=1>ClCCl.FC(F)(F)C(O)=O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([C:11]2[CH:12]=[C:13]([CH:25]=[CH:26][CH:27]=2)[CH2:14][S:15][CH2:16][CH2:17][C:18]([OH:20])=[O:19])=[O:10])=[C:4]([C:28](=[O:45])[NH:29][C:30]2[CH:34]=[CH:33][N:32]([C:35]3[CH:40]=[CH:39][CH:38]=[C:37]([C:41]([F:43])([F:44])[F:42])[CH:36]=3)[N:31]=2)[CH:3]=1
Reactant: CC(C)(C)OC(=O)CCSCc1cccc(C(=O)Nc2ccc(Cl)cc2C(=O)Nc2ccn(-c3cccc(C(F)(F)F)c3)n2)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)CCSCc1cccc(C(=O)Nc2ccc(Cl)cc2C(=O)Nc2ccn(-c3cccc(C(F)(F)F)c3)n2)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 35.3 %

Procedure:
Into a 50-mL round bottom flask, was placed a solution of tert-butyl 3-(3-(4-chloro-2-(1-(3-(trifluoromethyl)phenyl)-1H-pyrazol-3-ylcarbamoyl)phenylcarbamoyl)benzylthio)propanoate (150 mg, 0.23 mmol, 1.00 equiv) in dichloromethane (4 mL), trifluoroacetic acid (2 mL). The resulting solution was stirred for 2 h at room temperature. The resulting mixture was concentrated under vacuum. The crude product (100 mg) was purified by reverse phase HPLC eluting with a water/CH3CN gradient containing 0.05% TFA. The product was obtained as 48.9 mg (36%) of a white solid. 1H-NMR (300 MHz, DMSO, ppm): δ 12.21(s, 1H), 11.73(s, 1H), 11.56(s, 1H), 8.68(m, 1H), 8.49(m, 1H), 8.10(m, 3H), 7.92(s, 1H), 7.73(m, 7H), 7.01(d, J=3 Hz, 1H), 3.86(s, 2H), 2.59(m, 2H). MS (ES, m/z): 625 [M+Na]+.