Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[C:3]([OH:12])=[C:4]([C:9](=O)[CH3:10])[CH:5]=[C:6]([F:8])[CH:7]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:20][C:21]([CH:23]1[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1)=[O:22]>CN(C)C=O>[CH:23]1([C:21]([C:20]2[O:12][C:3]3[C:2]([F:1])=[CH:7][C:6]([F:8])=[CH:5][C:4]=3[C:9]=2[CH3:10])=[O:22])[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1
Reactant: O=C(CBr)C1CCCCC1
Reactant: CC(=O)c1cc(F)cc(F)c1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1c(C(=O)C2CCCCC2)oc2c(F)cc(F)cc12
Temperature: 25 °C
Reaction time: 16 h
Yield: 68.5 %

Procedure:
To a solution (50 mL) of 1-(3,5-difluoro-2-hydroxyphenyl)ethanone (2.8 g) in N,N-dimethylformamide were added potassium carbonate (6.7 g) and 2-bromo-1-cyclohexylethanone (4.0 g) synthesized in Example A51(1) at room temperature, and the mixture was stirred at room temperature for 16 hr. The reaction mixture was allowed to cool to room temperature, and filtered through celite. Water was added to the filtrate, and the mixture was extracted with diethyl ether. The extract was washed with saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The obtained residue was dissolved in N,N-dimethylformamide (50 mL) again, 1,8-diazabicyclo[5.4.0]undec-7-ene (2.6 mL) was added to the solution, and the mixture was stirred at 110° C. 1 hr with heating. After cooling to room temperature, the reaction mixture was quenched with 1N hydrochloric acid, and the reaction mixture was extracted with diethyl ether. The extract was concentrated under reduced pressure, and the precipitated compound was recrystallized from diisopropyl ether-hexane to give the title object compound (3.1 g, 70%) as a colorless solid.
Reaction SMILES: Cl.[NH2:2][C:3]1[C:12]2[C:7](=[CH:8][C:9]([C:13]([OH:15])=O)=[CH:10][CH:11]=2)[CH:6]=[CH:5][N:4]=1.OC1C2N=NNC=2C=CC=1.CN1CCOCC1.Cl.[C:34]([C@H:38]([O:42][CH:43]1[CH2:48][CH2:47][N:46]([C:49](=[O:53])[CH:50]([NH2:52])[CH3:51])[CH2:45][CH2:44]1)[C:39]([OH:41])=[O:40])([CH3:37])([CH3:36])[CH3:35].CN(C)CCCN=C=NCC>CN(C)C=O>[C:34]([C@H:38]([O:42][CH:43]1[CH2:48][CH2:47][N:46]([C:49](=[O:53])[CH:50]([NH:52][C:13]([C:9]2[CH:8]=[C:7]3[C:12](=[CH:11][CH:10]=2)[C:3]([NH2:2])=[N:4][CH:5]=[CH:6]3)=[O:15])[CH3:51])[CH2:45][CH2:44]1)[C:39]([OH:41])=[O:40])([CH3:36])([CH3:35])[CH3:37]
Reactant: CC(N)C(=O)N1CCC(O[C@H](C(=O)O)C(C)(C)C)CC1
Reactant: Nc1nccc2cc(C(=O)O)ccc12
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: Oc1cccc2[nH]nnc12
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: CC(NC(=O)c1ccc2c(N)nccc2c1)C(=O)N1CCC(O[C@H](C(=O)O)C(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 72 h
Yield: 92.3 %

Procedure:
To a solution of 0.33 g (1-amino-6-isoquinolinyl)carboxylic acid hydrochloride in 20 mL of N,N-dimethylformamide were added 0.34 g hydroxybenztriazole, 0.504 mL N-methylmorpholine, 0.525 g tert-butyl (S)-[[1-(2-amino-1-oxopropyl)piperidin-4-yl]oxy]acetic acid hydrochloride and 0.425 g 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide. After stirring at room temperature for three days the mixture was concentrated. Dichloromethane and 1% aqueous sodium hydrogencarbonate were added to the residue and the organic layer was separated. The aqueous layer was washed four times with dichloromethane, the combined organic layers dried (sodium sulfate) and concentrated. The residue was purified by chromatography (silica gel, dichloromethane/methanol: 10/1 v/v followed by a purification using silica gel, ethyl acetate/methanol: 10/1 v/v) to give 0.619 g of the title compound.
Reaction SMILES: C([O:8][CH2:9][CH2:10][O:11][C:12]1[CH:17]=[CH:16][C:15]([CH:18]2[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]2)=[CH:14][CH:13]=1)C1C=CC=CC=1.[H][H]>C(O)C.[OH-].[Pd+2].[OH-]>[CH:18]1([C:15]2[CH:14]=[CH:13][C:12]([O:11][CH2:10][CH2:9][OH:8])=[CH:17][CH:16]=2)[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23]1
Reactant: [H][H]
Reactant: c1ccc(COCCOc2ccc(C3CCCCC3)cc2)cc1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCO
Product: OCCOc1ccc(C2CCCCC2)cc1
Yield: 103 %

Procedure:
1-[2-(Benzyloxy)ethoxy]-4-cyclohexylbenzene (3.2 g) was dissolved in ethanol (100 mL). The resulting solution was added with 20% palladium hydroxide (300 mg) and then stirred in a hydrogen atmosphere at room temperature for 25 hours. The catalyst was filtered off, and washed with ethyl acetate. The filtrate was evaporated, and the residue was azeotroped with toluene (×2) to give the title compound as a colorless solid (2.34 g).
Reaction SMILES: [F:1][C:2]1[CH:23]=[CH:22][C:5]2[NH:6][C:7]([CH:9]3[CH2:14][CH2:13][N:12](C(OC(C)(C)C)=O)[CH2:11][CH2:10]3)=[N:8][C:4]=2[CH:3]=1.Cl>C(Cl)Cl.O1CCOCC1>[F:1][C:2]1[CH:23]=[CH:22][C:5]2[NH:6][C:7]([CH:9]3[CH2:10][CH2:11][NH:12][CH2:13][CH2:14]3)=[N:8][C:4]=2[CH:3]=1
Reactant: CC(C)(C)OC(=O)N1CCC(c2nc3cc(F)ccc3[nH]2)CC1
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: Fc1ccc2[nH]c(C3CCNCC3)nc2c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 133.4 %

Procedure:
To a stirred solution of tert-butyl 4-(5-fluoro-1H-benzimidazol-2-yl)piperidine-1-carboxylate (0.81 g, 2.53 mmol) in DCM (8 mL) is added a solution of 4M HCl in dioxane (2 mL). The reaction mixture is stirred at room temperature for 18 h. The reaction mixture is concentrated under reduced pressure to give 0.74 g of 5-fluoro-2-(piperidin-4-yl)-1H-benzimidazole. This product is used in the next step without further purification.
Reaction SMILES: Br[C:2]1[CH:35]=[CH:34][C:5]([CH2:6][C:7]2[N:8]([C:20]3[CH:25]=[CH:24][C:23]([N:26]4[S:30](=[O:32])(=[O:31])[NH:29][C:28](=[O:33])[CH2:27]4)=[CH:22][CH:21]=3)[CH:9]=[C:10]([C:12]3[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][C:13]=3[Cl:19])[N:11]=2)=[CH:4][CH:3]=1.[CH2:36]([CH:38]1[CH2:41][CH:40]([C:42]2[CH:47]=[CH:46][C:45](B(O)O)=[CH:44][CH:43]=2)[CH2:39]1)[CH3:37].BrC1C=CC(C2CC(=O)C2)=CC=1.BrC1C=CC=CC=1C=O>>[Cl:19][C:13]1[CH:14]=[C:15]([Cl:18])[CH:16]=[CH:17][C:12]=1[C:10]1[N:11]=[C:7]([CH2:6][C:5]2[CH:34]=[CH:35][C:2]([C:45]3[CH:44]=[CH:43][C:42]([CH:40]4[CH2:41][CH:38]([CH2:36][CH3:37])[CH2:39]4)=[CH:47][CH:46]=3)=[CH:3][CH:4]=2)[N:8]([C:20]2[CH:21]=[CH:22][C:23]([N:26]3[S:30](=[O:32])(=[O:31])[NH:29][C:28](=[O:33])[CH2:27]3)=[CH:24][CH:25]=2)[CH:9]=1
Reactant: CCC1CC(c2ccc(B(O)O)cc2)C1
Reactant: O=C1CN(c2ccc(-n3cc(-c4ccc(Cl)cc4Cl)nc3Cc3ccc(Br)cc3)cc2)S(=O)(=O)N1
Agent: O=C1CC(c2ccc(Br)cc2)C1
Agent: O=Cc1ccccc1Br
Product: CCC1CC(c2ccc(-c3ccc(Cc4nc(-c5ccc(Cl)cc5Cl)cn4-c4ccc(N5CC(=O)NS5(=O)=O)cc4)cc3)cc2)C1

Procedure:
5-{4-[2-(4-Bromo-benzyl)-4-(2,4-dichloro-phenyl)-imidazol-1-yl]-phenyl}-1,2,5-thiadiazolidine-3-one-1,1-dioxide (59 mg, 0.1 mmol) was treated as described in general procedure G using 4-(3-ethyl-cyclobutyl)phenylboronic acid (41 mg, 0.2 mmol, prepared according to general procedure Y using 3-(4-bromophenyl)cyclobutan-1-one in stead of bromobenzaldehyde) to give 5-(4-{4-(2,4-dichloro-phenyl)-2-[4′-(3-ethyl-cyclobutyl)-biphenyl-4-ylmethyl]-imidazol-1-yl}-phenyl)-1,2,5-thiadiazolidine-3-one-1,1-dioxide.
Reaction SMILES: [C:1]1([C:7]2[CH:8]=[CH:9][C:10]([C:13](=[N:15][O:16][CH2:17][CH2:18][OH:19])[CH3:14])=[N:11][CH:12]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.O[C:21]1[CH:53]=[CH:52][C:24]([CH2:25][CH:26]2[S:30][C:29](=[O:31])[N:28]([C:32]([C:45]3[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=3)([C:39]3[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=3)[C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)[C:27]2=[O:51])=[CH:23][CH:22]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>>[C:1]1([C:7]2[CH:8]=[CH:9][C:10]([C:13](=[N:15][O:16][CH2:17][CH2:18][O:19][C:21]3[CH:53]=[CH:52][C:24]([CH2:25][CH:26]4[S:30][C:29](=[O:31])[N:28]([C:32]([C:45]5[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=5)([C:39]5[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=5)[C:33]5[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=5)[C:27]4=[O:51])=[CH:23][CH:22]=3)[CH3:14])=[N:11][CH:12]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C1SC(Cc2ccc(O)cc2)C(=O)N1C(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CC(=NOCCO)c1ccc(-c2ccccc2)cn1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: CC(=NOCCOc1ccc(CC2SC(=O)N(C(c3ccccc3)(c3ccccc3)c3ccccc3)C2=O)cc1)c1ccc(-c2ccccc2)cn1
Yield: 99.4 %

Procedure:
Following a procedure similar to that described in Example 1(a), but using 513 mg of 2-[1-(5-phenyl-2-pyridyl)ethylideneaminooxy]ethanol (prepared as described in Preparation 39), 1.02 g of 5-(4-hydroxybenzyl)-3-tritylthiazolidine-2,4-dione, 577 mg of triphenylphosphine and 383 mg of diethyl azodicarboxylate, 1.40 g of the title compound were obtained as a foam-like solid.
Reaction SMILES: Br[C:2]1[C:3]([N:22]2[CH2:26][CH2:25][C@@H:24]([OH:27])[CH2:23]2)=[N:4][CH:5]=[C:6]([CH:21]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=1)=[O:8].CC1(C)C(C)(C)OB([C:36]2[CH:37]=[N:38][O:39][CH:40]=2)O1>>[OH:27][C@@H:24]1[CH2:25][CH2:26][N:22]([C:3]2[C:2]([C:36]3[CH:37]=[N:38][O:39][CH:40]=3)=[CH:21][C:6]([C:7]([NH:9][C:10]3[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=3)=[O:8])=[CH:5][N:4]=2)[CH2:23]1
Reactant: O=C(Nc1ccc(OC(F)(F)F)cc1)c1cnc(N2CC[C@@H](O)C2)c(Br)c1
Reactant: CC1(C)OB(c2cnoc2)OC1(C)C
Product: O=C(Nc1ccc(OC(F)(F)F)cc1)c1cnc(N2CC[C@@H](O)C2)c(-c2cnoc2)c1

Procedure:
The title compound was prepared in an analogous fashion to that described in Example 7 using (R)-5-bromo-6-(3-hydroxypyrrolidin-1-yl)-N-(4-(trifluoromethoxy)phenyl)nicotinamide (Stage 6.1) and 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoxazole to afford a white solid. LC-MS (Condition 2) tR=1.80 min, m/z=435.2-436.2 [M+H]+, m/z=433 [M−H]−; 1H-NMR (400 MHz, DMSO-d6) δ ppm 1.74-1.82 (m, 1H) 1.84-1.94 (m, 1H) 3.01 (d, J=11.25 Hz, 1H) 3.29-3.53 (m, 3H) 4.22-4.28 (m, 1H) 7.35 (d, J=8.80 Hz, 2H) 7.86 (d, J=9.05 Hz, 2H) 8.03 (d, J=2.20 Hz, 1H) 8.75 (d, J=2.20 Hz, 1H) 8.85 (s, 1H) 9.12 (s, 1H) 10.17 (s, 1H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([C:11]2[CH:12]=[N:13][C:14]([O:17][CH2:18][C:19]([OH:21])=[O:20])=[N:15][CH:16]=2)=[O:10])=[CH:4][CH:3]=1.[CH:22]1(O)[CH2:26][CH2:25][CH2:24][CH2:23]1.CO>ClCCl>[CH:22]1([O:20][C:19](=[O:21])[CH2:18][O:17][C:14]2[N:13]=[CH:12][C:11]([C:9](=[O:10])[NH:8][C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=3)=[CH:16][N:15]=2)[CH2:26][CH2:25][CH2:24][CH2:23]1
Reactant: OC1CCCC1
Reactant: O=C(O)COc1ncc(C(=O)Nc2ccc(F)cc2)cn1
Solvent: CO
Solvent: ClCCl
Product: O=C(COc1ncc(C(=O)Nc2ccc(F)cc2)cn1)OC1CCCC1
Yield: 77 %

Procedure:
The titled compound was prepared from [5-(4-fluorophenylcarbamoyl)pyrimidin-2-yloxy]acetic acid using cyclopentanol (31 μL, 0.34 mmol) as the coupling partner. Chromatography (1:1 methanol:dichloromethane) through SiO2 yielded 47 mg (77%) of the titled compound as fine white needles. ESI-MS m/z 360 (MH+), 358 (M−H−).
Reaction SMILES: [CH2:1]([N:8]([CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C:9]1[CH:14]=[CH:13][C:12]([C:15]([F:18])([F:17])[F:16])=[C:11](Cl)[N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:27][O:28][Na]>C1COCC1.O>[CH2:1]([N:8]([CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C:9]1[CH:14]=[CH:13][C:12]([C:15]([F:18])([F:17])[F:16])=[C:11]([O:28][CH3:27])[N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CO[Na]
Reactant: FC(F)(F)c1ccc(N(Cc2ccccc2)Cc2ccccc2)nc1Cl
Solvent: C1CCOC1
Solvent: O
Product: COc1nc(N(Cc2ccccc2)Cc2ccccc2)ccc1C(F)(F)F
Temperature: 25 °C
Yield: 89.5 %

Procedure:
To a stirred solution of N,N-dibenzyl-6-chloro-5-(trifluoromethyl)pyridin-2-amine (100 mg, 0.27 mmol) in THF (5 mL) was added freshly produced CH3ONa (42 mg, 0.78 mmol) at room temperature. The mixture was heated to reflux for 10 h and then cooled to the room temperature, diluted with water (5 mL) and extracted with CH2Cl2 (6 mL×3). The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated under vacuum. The residue was purified by silica gel column chromatography using 2%-10% EtOAc in petroleum ether as eluant to obtain N,N-dibenzyl-6-methoxy-5-(trifluoromethyl)pyridin-2-amine (90 mg, 91%). 1H NMR (400 MHz, CDCl3) δ 7.53 (d, J=8.4 Hz, 1H), 7.35-7.22 (m, 10H), 6.02 (d, J=8.4 Hz, 1H), 4.79 (s, 4H), 3.90 (s, 3H).
Reaction SMILES: [OH:1][CH2:2][C@@H:3]1[CH2:7][CH2:6][CH2:5][N:4]1[C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9].[F:15][C:16]1[C:24]([O:25][C:26]2[C:35]3[C:30](=[CH:31][C:32](O)=[C:33]([O:36][CH3:37])[CH:34]=3)[N:29]=[CH:28][N:27]=2)=[CH:23][CH:22]=[C:21]2[C:17]=1[CH:18]=[C:19]([CH3:39])[NH:20]2>>[F:15][C:16]1[C:24]([O:25][C:26]2[C:35]3[C:30](=[CH:31][C:32]([O:1][CH2:2][C@@H:3]4[CH2:7][CH2:6][CH2:5][N:4]4[C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])=[C:33]([O:36][CH3:37])[CH:34]=3)[N:29]=[CH:28][N:27]=2)=[CH:23][CH:22]=[C:21]2[C:17]=1[CH:18]=[C:19]([CH3:39])[NH:20]2
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1CO
Reactant: COc1cc2c(Oc3ccc4[nH]c(C)cc4c3F)ncnc2cc1O
Product: COc1cc2c(Oc3ccc4[nH]c(C)cc4c3F)ncnc2cc1OC[C@@H]1CCCN1C(=O)OC(C)(C)C
Yield: 57.7 %

Procedure:
Using an analogous procedure to that described for the preparation of the starting material in Example 11, tert-butyl (2S)-2-(hydroxymethyl)pyrrolidine-1-carboxylate (142 mg, 0.71 mmol) was reacted with 4-(4-fluoro-2-methylindol-5-yloxy)-7-hydroxy-6-methoxyquinazoline (200 mg, 0.59 mmol), (prepared as described for the starting material in Example 7), and the product purified by column chromatography, eluting with methanol/methylene chloride (1/9) containing 0.1% triethylamine to give tert-butyl (2S)-2-[(4-[(4-fluoro-2-methyl-1H-indol-5-yl)oxy]-6-methoxyquinazolin-7-yloxy)methyl]pyrrolidine 1-carboxylate (178 mg, 58%).
Reaction SMILES: [CH:1]1([NH:6][C:7]2[C:12]([CH:13]=O)=[CH:11][N:10]=[C:9]([S:15][CH3:16])[N:8]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].CCCCCC.[CH3:33][S:34](Cl)(=[O:36])=[O:35]>C1COCC1>[CH:1]1([N:6]2[C:7]3[C:12](=[CH:11][N:10]=[C:9]([S:15][CH3:16])[N:8]=3)[CH:13]=[CH:33][S:34]2(=[O:36])=[O:35])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CS(=O)(=O)Cl
Reactant: CSc1ncc(C=O)c(NC2CCCC2)n1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CSc1ncc2c(n1)N(C1CCCC1)S(=O)(=O)C=C2
Temperature: -70 °C
Reaction time: 0.5 h
Yield: 18.7 %

Procedure:
A solution of 4-cyclopentylamino-2-methylsulfanyl-pyrimidine-5-carbaldehyde (prepared as described in WO 98/33798 (incorporated herein by reference)) (30 g, 126 mmol) was suspended in dry THF (700 mL) under argon, and the mixture was cooled to −70° C. A solution of lithium bis(trimethylsilyl) amide, 1.0M in hexane (316 mL, 316 mmol) was added dropwise with stirring over 30 minutes. A solution of methanesulfonylchloride (10.5 ml, 136 mmol) in dry THF (25 mL) was added over 5 minutes, and then the reaction mixture was left to stir at −55° C. for at least 1 hour. An additional portion of methanesulfonylchloride (9 ml, 78 mmol) was added over 2 hours as the temperature was allowed to reach 0° C. The reaction was then cooled to −70° C. and left undisturbed overnight. The reaction mixture was then evaporated in vacuo to an oil and poured into a mixture of diethyl ether (1 L) and 1N citric acid solution (375 ml). The pH of the mixture was adjusted to 8 by addition of 4N NaOH, agitated, and the ether phase was decanted. The aqueous phase was extracted with diethylether, the organic phases were combined, washed with water, brine, and dried over anhydrous magnesium sulfate. After removal of the drying agent and evaporation of the solvent, the crude product was purified by chromatography on 300 g silica gel (10%–20% ethyl acetate in hexanes) to yield 7.01 g (18.7% yield) 1-Cyclopentyl-7-methylsulfanyl-1H-2-thia-1,6,8-triaza-naphthalene 2,2-dioxide as a colorless solid. MS: APCI: M+1: 298.1 (M: 297.4).
Reaction SMILES: [C:1]([O:5][C:6](=[O:18])[NH:7][C@@H:8]1[CH2:13][CH2:12][C@H:11]([NH2:14])[C@H:10]([CH2:15][CH2:16][CH3:17])[CH2:9]1)([CH3:4])([CH3:3])[CH3:2].[C:19]([NH:29][C@H:30]([C:35](O)=[O:36])[CH2:31][CH2:32][S:33][CH3:34])([O:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)=[O:20].C(N(C(C)C)CC)C.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>C(Cl)Cl.CN(C=O)C>[C:1]([O:5][C:6](=[O:18])[NH:7][C@@H:8]1[CH2:13][CH2:12][C@H:11]([NH:14][C:35](=[O:36])[C@@H:30]([NH:29][C:19]([O:21][CH2:22][C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)=[O:20])[CH2:31][CH2:32][S:33][CH3:34])[C@H:10]([CH2:15][CH2:16][CH3:17])[CH2:9]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CSCC[C@H](NC(=O)OCc1ccccc1)C(=O)O
Reactant: CCC[C@@H]1C[C@H](NC(=O)OC(C)(C)C)CC[C@@H]1N
Agent: CCN(CC)C(C)C
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CCC[C@@H]1C[C@H](NC(=O)OC(C)(C)C)CC[C@@H]1NC(=O)[C@H](CCSC)NC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 37.8 %

Procedure:
A sample of (1R,3R,4S)-(4-amino-3-propyl-cyclohexyl)-carbamic acid tert-butyl ester (1.9 mmol) was dissolved in 1:1 CH2Cl2/DMF (40 mL), and the resultant solution was charged with N-Cbz methionine (591 mg, 2.1 mmol), N,N-diethylisopropylamine (1 mL, 5.7 mmol), and BOP (1.0 g, 2.3 mmol). The reaction was stirred for 12 h at RT and then partitioned between EtOAc and sat. NaHCO3; the aqueous phase was back extracted with EtOAc (1×). The organic phases were combined, washed with brine, dried (Na2SO4), filtered, and concentrated in vacuo. The residue was purified by flash chromatography to afford (1R,3R,4S)-[4-((2S)-2-benzyloxycarbonylamino-4-methylsulfanyl-butyrylamino)-3-propyl-cyclohexyl]-carbamic acid tert-butyl ester (375 mg). MS found: (M+H)+=522.3.
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[CH2:14][N:13]([C:15]([N:17]3[CH2:22][CH2:21][S:20][CH2:19][CH2:18]3)=[O:16])[CH2:12][CH:11]([C:23](O)=[O:24])[CH2:10]2)=[CH:5][C:4]=1[F:26])[CH3:2].O[N:28]=[C:29]([O:31][CH2:32][CH3:33])[NH2:30].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C>CN(C=O)C>[CH2:32]([O:31][C:29]1[N:30]=[C:23]([CH:11]2[CH2:10][CH:9]([C:6]3[CH:7]=[CH:8][C:3]([CH2:1][CH3:2])=[C:4]([F:26])[CH:5]=3)[CH2:14][N:13]([C:15]([N:17]3[CH2:22][CH2:21][S:20][CH2:19][CH2:18]3)=[O:16])[CH2:12]2)[O:24][N:28]=1)[CH3:33]
Reactant: CCc1ccc(C2CC(C(=O)O)CN(C(=O)N3CCSCC3)C2)cc1F
Reactant: CCOC(N)=NO
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCOc1noc(C2CC(c3ccc(CC)c(F)c3)CN(C(=O)N3CCSCC3)C2)n1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
309 mg (0.81 mmol) of the compound from Example 36A and 169 mg (1.62 mmol) of ethyl N′-hydroxyimidocarbamate [G. Zinner, G. Nebel, Arch. Pharm. 1970, 303, 385-390] were initially charged in 3.1 ml of DMF and reacted with 463 mg (1.22 mmol) of HATU and 0.42 ml (315 mg, 2.44 mmol) of N,N-diisopropylethylamine. The mixture was stirred at RT for 15 minutes; the reaction mixture was partitioned between water and ethyl acetate. The organic phase was washed repeatedly with water, dried over sodium sulphate and concentrated under reduced pressure. The residue was taken up in 3.0 ml of DMF and converted at 180° C. for two minutes in the microwave (Emrys Optimizer). The reaction mixture was purified by means of preparative HPLC. Yield: 108 mg (30% of theory)
Reaction SMILES: C([O:8][C:9]1[CH:17]=[C:16]2[C:12]([CH:13]=[C:14]([C:27]([O:29][CH2:30][CH3:31])=[O:28])[N:15]2[CH2:18][CH2:19][CH2:20][CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23])=[C:11]([Cl:32])[CH:10]=1)C1C=CC=CC=1.Cl.C(O)(=O)C>[C].[Pd].CN(C)C=O>[Cl:32][C:11]1[CH:10]=[C:9]([OH:8])[CH:17]=[C:16]2[C:12]=1[CH:13]=[C:14]([C:27]([O:29][CH2:30][CH3:31])=[O:28])[N:15]2[CH2:18][CH2:19][CH2:20][CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23]
Reactant: CCOC(=O)CCCCn1c(C(=O)OCC)cc2c(Cl)cc(OCc3ccccc3)cc21
Agent: [Pd]
Agent: Cl
Solvent: CC(=O)O
Solvent: CN(C)C=O
Product: CCOC(=O)CCCCn1c(C(=O)OCC)cc2c(Cl)cc(O)cc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 54.5 %

Procedure:
A mixture of ethyl 6-benzyloxy-4-chloro-1-(4-ethoxycarbonylbutyl)-1H-indolecarboxylate (15.0 g, 32.8 mmol), 35% hydrochloric acid (3.3 ml), acetic acid (240 ml), 10% palladium-carbon (1.5 g) and N,N-dimethylformamide (60 ml) was stirred under a hydrogen atmosphere at room temperature for about 1 hour. The catalyst was filtered off and the filtrate was poured into a cooled 5% aqueous sodium chloride solution and extracted twice with ethyl acetate. The extract solution was washed three times with a 5% aqueous sodium chloride solution and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure and the resulting residue was crystallized from toluene to obtain 6.57 g of ethyl 4-chloro-1-(4-ethoxycarbonylbutyl)-6-hydroxy-1H-indolecarboxylate.
Reaction SMILES: [C:1]([O:5][N:6]=[C:7]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14](Br)[CH:15]=2)[O:10][C:9]([C:18]2[N:19]=[CH:20][C:21]3[C:26]([CH:27]=2)=[CH:25][CH:24]=[CH:23][CH:22]=3)=[CH:8]1)([CH3:4])([CH3:3])[CH3:2].[CH2:28]([Sn](CCCC)(CCCC)C=C)[CH2:29]CC>C1(C)C=CC=CC=1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:1]([O:5][N:6]=[C:7]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([CH:28]=[CH2:29])[CH:15]=2)[O:10][C:9]([C:18]2[N:19]=[CH:20][C:21]3[C:26]([CH:27]=2)=[CH:25][CH:24]=[CH:23][CH:22]=3)=[CH:8]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: C=C[Sn](CCCC)(CCCC)CCCC
Reactant: CC(C)(C)ON=c1cc(-c2cc3ccccc3cn2)oc2ccc(Br)cc12
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: C=Cc1ccc2oc(-c3cc4ccccc4cn3)cc(=NOC(C)(C)C)c2c1
Temperature: 120 °C
Reaction time: 0.08 h
Yield: 96.1 %

Procedure:
In a sealed tube was degassed with argon for 15 min. a solution of 6-bromo-2-isoquinolin-3-yl-chromen-4-one O-tert-butyl oxime (100 mg, 0.236 mmol) in toluene. Tributyl(vinyl)tin (76 μl, 0.26 mmol) and tetrakis(triphenylphosphine)palladium (13 mg, 0.012 mmol) were added degassing was continued for 5 min. The tube was sealed and heated at 120° C. for 8 hours. The mixture was filtered, concentrated and purified by flash chromatography over silica gel (cyclohexane/ethyl acetate: 0-10%) to yield 2-isoquinolin-3-yl-6-(vinyl)-chromen-4-one O-tert-butyl oxime (84 mg, 96%).
Reaction SMILES: OC(C(F)(F)F)=O.[NH:8]1[CH2:11][CH:10]([NH:12][C:13](=[O:31])[CH2:14][NH:15][C:16]2[C:24]3[C:19](=[CH:20][CH:21]=[C:22]([C:25]([F:28])([F:27])[F:26])[CH:23]=3)[N:18]([CH2:29][CH3:30])[N:17]=2)[CH2:9]1.[OH:32][C:33]1([C:40]2[S:44][C:43]([CH3:45])=[N:42][CH:41]=2)[CH2:38][CH2:37][C:36](=O)[CH2:35][CH2:34]1>>[CH2:29]([N:18]1[C:19]2[C:24](=[CH:23][C:22]([C:25]([F:27])([F:26])[F:28])=[CH:21][CH:20]=2)[C:16]([NH:15][CH2:14][C:13]([NH:12][CH:10]2[CH2:9][N:8]([CH:36]3[CH2:35][CH2:34][C:33]([OH:32])([C:40]4[S:44][C:43]([CH3:45])=[N:42][CH:41]=4)[CH2:38][CH2:37]3)[CH2:11]2)=[O:31])=[N:17]1)[CH3:30]
Reactant: CCn1nc(NCC(=O)NC2CNC2)c2cc(C(F)(F)F)ccc21
Reactant: Cc1ncc(C2(O)CCC(=O)CC2)s1
Solvent: O=C(O)C(F)(F)F
Product: CCn1nc(NCC(=O)NC2CN(C3CCC(O)(c4cnc(C)s4)CC3)C2)c2cc(C(F)(F)F)ccc21

Procedure:
The title compound was prepared as a white solid from reaction of N-azetidin-3-yl-2-(1-ethyl-5-trifluoromethyl-1H-indazol-3-ylamino)-acetamide TFA salt (as prepared in Example 67, Step A) and 4-hydroxy-4-(2-methyl-thiazol-5-yl)-cyclohexanone using the procedure described in Step E of Example 1.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[C:4]([O:9][CH3:10])[N:3]=1.Cl.[F:12][C:13]1([F:25])[O:17][C:16]2[CH:18]=[CH:19][C:20]([CH2:22][CH2:23][NH2:24])=[CH:21][C:15]=2[O:14]1.C(=O)(O)[O-].[Na+]>CCO>[Cl:8][C:6]1[N:5]=[C:4]([O:9][CH3:10])[N:3]=[C:2]([NH:24][CH2:23][CH2:22][C:20]2[CH:19]=[CH:18][C:16]3[O:17][C:13]([F:25])([F:12])[O:14][C:15]=3[CH:21]=2)[CH:7]=1
Reactant: NCCc1ccc2c(c1)OC(F)(F)O2
Reactant: COc1nc(Cl)cc(Cl)n1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: COc1nc(Cl)cc(NCCc2ccc3c(c2)OC(F)(F)O3)n1
Yield: 79 %

Procedure:
To a solution of 4,6-dichloro-2-methoxy-pyrimidine (0.606 g, 3.38 mmol, Intermediate (4)] and 2-(2,2-difluoro-benzo[1,3]dioxol-5-yl)-ethylamine hydrochloride (0.884 g, 3.72 mmol, Intermediate (62)]) in EtOH (11 mL) is added sodium bicarbonate (0.85 g, 10.14 mmol) and heated to reflux for 4 hours. The reaction mixture is filtered and filtrate is concentrated, residue solid is washed with small amount of EtOH to yield (6-chloro-2-methoxy-pyrimidin-4-yl)-[2-(2,2-difluoro-benzo[1,3]dioxol-5-yl)-ethyl]-amine [0.918 g, 79%, Intermediate (63)] as a solid. LC/MS: MS: 344 (M+H).