Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(=O)([O-])[O-].[Li+].[Li+].[Br-].[Li+].Br[CH:10]1[CH2:16][CH2:15][CH2:14][C:13]2[CH:17]=[CH:18][C:19]([N+:21]([O-:23])=[O:22])=[CH:20][C:12]=2[C:11]1=[O:24]>CN(C)C=O>[N+:21]([C:19]1[CH:18]=[CH:17][C:13]2[CH2:14][CH2:15][CH:16]=[CH:10][C:11](=[O:24])[C:12]=2[CH:20]=1)([O-:23])=[O:22]
Reactant: O=C1c2cc([N+](=O)[O-])ccc2CCCC1Br
Agent: O=C([O-])[O-]
Agent: [Br-]
Agent: [Li+]
Solvent: CN(C)C=O
Product: O=C1C=CCCc2ccc([N+](=O)[O-])cc21
Temperature: 100 °C
Reaction time: 0.08 h
Yield: 73.2 %

Procedure:
A mixture of 548 g of lithium carbonate, 548 g of lithium bromide and 5.480 liters of dimethylformamide was heated to 100° C. and 548 g of the product of Step A was added thereto over 5 minutes. The mixture was held at 100° C. for 45 minutes and was then poured into 25 liters of a water-ice-mixture. The mixture was vacuum filtered and the insolubles were extracted 8 times with one liter of methylene chloride. The organic phase was washed with water, dried over sodium sulfate and evaporated to dryness under reduced pressure. The red crystalline mass was empasted successively 3 times with 400 ml of ether, once with 400 ml of ethanol and once with 400 ml of ether and was dried at 40° C. to obtain 286.7 g of 3-nitro-8,9-dihydro [5H] benzocycloheptene-5-one in the form of red-orange crystals melting at 128° C.
Reaction SMILES: [O:1]=[C:2]([C@@H:8]([C:10]1[CH:15]=[CH:14][C:13]([NH:16][C:17]2[S:18][CH:19]=[C:20]([C:22]([F:25])([F:24])[F:23])[N:21]=2)=[CH:12][CH:11]=1)[CH3:9])[CH2:3][C:4]([O:6]C)=[O:5]>CC(O)=O.Cl>[O:1]=[C:2]([C@@H:8]([C:10]1[CH:11]=[CH:12][C:13]([NH:16][C:17]2[S:18][CH:19]=[C:20]([C:22]([F:25])([F:24])[F:23])[N:21]=2)=[CH:14][CH:15]=1)[CH3:9])[CH2:3][C:4]([OH:6])=[O:5]
Reactant: COC(=O)CC(=O)[C@H](C)c1ccc(Nc2nc(C(F)(F)F)cs2)cc1
Agent: Cl
Solvent: CC(=O)O
Product: C[C@@H](C(=O)CC(=O)O)c1ccc(Nc2nc(C(F)(F)F)cs2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 79 %

Procedure:
A solution of methyl (4R)-3-oxo-4-(4-{[4-(trifluoromethyl)-1,3-thiazol-2-yl]amino}phenyl)pentanoate (372 mg, 1 mmol) in AcOH (10 ml) and 37% HCl (1.5 ml) was refluxed for 12 h. After cooling at room temperature and solvents evaporation, the crude product was diluted with CH2Cl2 (10 ml), washed with water (3×5 ml) and brine (3×5 ml) and dried over anhydrous Na2SO4. After solvent evaporation the resulting pale yellow oil was pulped overnight in n-hexane. Pure (4R)-3-oxo-4-(4-{[4-(trifluoromethyl)-1,3-thiazol-2-yl]amino}phenyl)pentanoic acid (283 mg, 0.79 mmol) was isolated as a white solid by filtration (79%).
Reaction SMILES: [CH3:1]C(C)([O-])C.[K+].[F:7][C:8]([F:25])([F:24])[C:9]([NH:11][C@@H:12]1[C:20]2[C:15](=[CH:16][CH:17]=[C:18]([O:21][CH3:22])[CH:19]=2)[C:14](=O)[CH2:13]1)=[O:10].O>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C1COCC1>[F:7][C:8]([F:25])([F:24])[C:9]([NH:11][C@@H:12]1[C:20]2[C:15](=[CH:16][CH:17]=[C:18]([O:21][CH3:22])[CH:19]=2)[C:14](=[CH2:1])[CH2:13]1)=[O:10]
Reactant: CC(C)(C)[O-]
Reactant: COc1ccc2c(c1)[C@@H](NC(=O)C(F)(F)F)CC2=O
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: C=C1C[C@H](NC(=O)C(F)(F)F)c2cc(OC)ccc21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 92.7 %

Procedure:
Step AF (2): To a solution of methyltriphenylphosphonium bromide (1.6 g) in THF (5 mL) was added potassium t-butoxide (700 mg), and the mixture was stirred at rt for 30 min to form a deep yellow solution. A solution of (S)-2,2,2-trifluoro-N-(6-methoxy-3-oxo-2,3-dihydro-1H-inden-1-yl)acetamide (500 mg) in THF (2 mL) was added, and the reaction was continued for 40 min. Water was added, the aqueous layer was extracted with EtOAc (×3), and the combined organic layers were washed with brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was evaporated in vacuo, and the residue was purified by Biotage chromatography eluting with 1-10% EtOAc/hexanes to give (S)-2,2,2-trifluoro-N-(6-methoxy-3-methylene-2,3-dihydro-1H-inden-1-yl)-acetamide as a white solid (460 mg). 1H NMR (400 MHz, CDCl3) δ 7.45 (1H, d), 6.91 (1H, dd), 6.83 (1H, d), 6.45 (1H, br. S), 5.38 (1H, dt), 5.38 (1H, t), 4.99 (1H, t), 3.81 (3H, s), 3.45 (1H, m), and 2.62 (1H, m).
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([N+:10]([O-:12])=[O:11])[CH:5]=1)=[O:3].[N+:13]([C:16]1[CH:17]=[C:18]([CH:21]=[CH:22][CH:23]=1)[CH:19]=O)([O-:15])=[O:14].[OH-].[Na+]>CO>[N+:10]([C:6]1[CH:5]=[C:4]([C:2](=[O:3])/[CH:1]=[CH:19]/[C:18]2[CH:21]=[CH:22][CH:23]=[C:16]([N+:13]([O-:15])=[O:14])[CH:17]=2)[CH:9]=[CH:8][CH:7]=1)([O-:12])=[O:11]
Reactant: O=Cc1cccc([N+](=O)[O-])c1
Reactant: CC(=O)c1cccc([N+](=O)[O-])c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(/C=C/c1cccc([N+](=O)[O-])c1)c1cccc([N+](=O)[O-])c1
Reaction time: 16 h
Yield: 89.4 %

Procedure:
3-Nitroacetophenone (2.23 g, 0.0135 mol) [Aldrich] and 3-nitrobenzaldehyde (2.04 g, 0.0135 mol) [Aldrich] were dissolved in methanol (20 mL), and sodium hydroxide (1.3 g, 0.032 mol) was added. The mixture was stirred for 16 hours. The solid formed was filtered and washed with water to give the desired product (3.6 g, 89%). LCMS for C15H11N2O5 (M+H)+: m/z=299.1.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[N:18]([CH2:19][C:20]([OH:22])=O)[C:13]3=[N:14][CH:15]=[CH:16][CH:17]=[C:12]3[N:11]=2)=[CH:6][CH:5]=1)([O-:3])=[O:2].[C:23](N1C=CN=C1)([N:25]1C=CN=C1)=O.CN>O1CCCC1>[CH3:23][NH:25][C:20](=[O:22])[CH2:19][N:18]1[C:13]2=[N:14][CH:15]=[CH:16][CH:17]=[C:12]2[N:11]=[C:10]1[C:7]1[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:9][CH:8]=1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: O=C(O)Cn1c(-c2ccc([N+](=O)[O-])cc2)nc2cccnc21
Agent: CN
Solvent: C1CCOC1
Product: CNC(=O)Cn1c(-c2ccc([N+](=O)[O-])cc2)nc2cccnc21
Temperature: 25 °C
Reaction time: 3 h
Yield: 13.4 %

Procedure:
A suspension of crude 2-(4-nitrophenyl)-3H-imidazo[4,5-b]pyridine-3-acetic acid (3.0 g, 0.0101 mole), 1,1'-carbonyldiimidazole (1.63 g, 0.0101 mole) and dry tetrahydrofuran (100 ml) was stirred at room temperature for three hours with a stream of nitrogen bubbling through it and then refluxed overnight under nitrogen. It was cooled to room temperature and a solution of methylamine (0.94 g, 0.0302 mole) in tetrahydrofuran (10 ml) was added and the reaction mixture was stirred at room temperature over the weekend. The solvents were removed under reduced pressure and the resulting solid was triturated in water, collected by filtration, rinsed once with water, once with 5% potassium hydroxide solution and once with water. The solid was dissolved in hot isopropyl alcohol, filtered hot and cooled in the refrigerator to precipitate a solid. Water was added and the solid was collected by filtration and dried under high vacuum at 70° C. to give 0.42 g (13%) of title compound, mp. >260° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]([NH:13][C:14](=[O:18])OCC)=[N:11][C:10]2[C:5](=[CH:6][CH:7]=[C:8]([O:19][CH3:20])[CH:9]=2)[N:4]=1.[CH3:21][O:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[N:29]1[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]1>>[CH3:1][O:2][C:3]1[C:12]([NH:13][C:14]([N:32]2[CH2:31][CH2:30][N:29]([C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=3[O:22][CH3:21])[CH2:34][CH2:33]2)=[O:18])=[N:11][C:10]2[C:5](=[CH:6][CH:7]=[C:8]([O:19][CH3:20])[CH:9]=2)[N:4]=1
Reactant: COc1ccccc1N1CCNCC1
Reactant: CCOC(=O)Nc1nc2cc(OC)ccc2nc1OC
Product: COc1ccc2nc(OC)c(NC(=O)N3CCN(c4ccccc4OC)CC3)nc2c1
Yield: 84 %

Procedure:
Ethyl N-(2,6-dimethoxyquinoxalin-3-yl)carbamate and 1-(2-methoxyphenyl)piperazine were reacted by the same way with the example 64 to obtain the titled compound (yield, 84%). 1H NMR (300 MHz, CDCl3): δ 3.15 (s, 4H), 3.83-3.89 (m, 9H), 4.12-4.17 (m, 4H), 6.88-6.95 (m, 3H), 7.02-7.05 (m, 1H), 7.14 (d, J=8.7 Hz, 1H), 7.31 (s, 1H), 7.51 (d, J=8.7 Hz, 1H), 7.63 (d, J=9.0 Hz, 1H).
Reaction SMILES: C1(N)C(F)=C(F)C(F)=C(N)C=1F.Cl.Cl.[CH2:15]([C@@H:17]1[CH2:26][C:25]2[N:24]=[CH:23][N:22]=[C:21]([N:27]3[CH2:33][C:32]4[CH:34]=[C:35](B(O)O)[CH:36]=[CH:37][C:31]=4[O:30][CH2:29][CH2:28]3)[C:20]=2[CH2:19][CH2:18]1)[CH3:16].[NH2:41][C:42]1[C:47]([S:48]([N:51]2[CH2:56][C@@H:55]3[CH2:57][C@H:52]2[CH2:53][N:54]3C(OC(C)(C)C)=O)(=[O:50])=[O:49])=[CH:46][C:45](Br)=[CH:44][N:43]=1>>[C@H:52]12[CH2:57][C@H:55]([NH:54][CH2:53]1)[CH2:56][N:51]2[S:48]([C:47]1[C:42]([NH2:41])=[N:43][CH:44]=[C:45]([C:35]2[CH:36]=[CH:37][C:31]3[O:30][CH2:29][CH2:28][N:27]([C:21]4[C:20]5[CH2:19][CH2:18][C@H:17]([CH2:15][CH3:16])[CH2:26][C:25]=5[N:24]=[CH:23][N:22]=4)[CH2:33][C:32]=3[CH:34]=2)[CH:46]=1)(=[O:49])=[O:50]
Reactant: CC[C@H]1CCc2c(ncnc2N2CCOc3ccc(B(O)O)cc3C2)C1
Reactant: CC(C)(C)OC(=O)N1C[C@@H]2C[C@H]1CN2S(=O)(=O)c1cc(Br)cnc1N
Agent: Cl
Agent: Nc1c(F)c(N)c(F)c(F)c1F
Product: CC[C@H]1CCc2c(ncnc2N2CCOc3ccc(-c4cnc(N)c(S(=O)(=O)N5C[C@@H]6C[C@H]5CN6)c4)cc3C2)C1

Procedure:
Prepared as dihydrochloride salt according to the method of example 5 by using {4-[(7S)-7-ethyl-5,6,7,8-tetrahydroquinazolin-4-yl]-2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl}boronic acid (reagent preparation 23) and (1S,4S)-tert-butyl 5-(2-amino-5-bromopyridin-3-ylsulfonyl)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate (reagent preparation 25) in step 1 followed by Boc deprotection. 1H NMR (400 MHz, methanol-d4): 8.65 (s, 1H), 8.52 (s, 2H), 7.74 (s, 1H), 7.53 (d, 1H), 7.08 (d, 1H), 5.24 (d, 1H), 5.14 (d, 1H), 4.56 (m, 2H), 4.46 (m, 1H), 4.36 (m, 1H), 4.21 (m, 1H), 3.69 (m, 3H), 3.53 (m, 1H), 3.38 (m, 1H), 2.99 (m, 2H), 2.74 (m, 1H), 2.42 (m, 1H), 2.05 (m, 3H), 1.83 (m, 1H), 1.47 (m, 2H), 1.24 (m, 1H), 1.01 (t, 3H); MS (EI) for C29H35N7O3S: 562 (MH+).
Reaction SMILES: [F:1][CH:2]([F:26])[C:3]1[N:8]2[N:9]=[CH:10][C:11]([C:12]([OH:14])=O)=[C:7]2[N:6]=[C:5]([C:15]2[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[C:17]([CH3:25])[CH:16]=2)[CH:4]=1.[N:27]1([S:33]([C:36]2[CH:37]=[C:38]([NH2:42])[CH:39]=[CH:40][CH:41]=2)(=[O:35])=[O:34])[CH2:32][CH2:31][O:30][CH2:29][CH2:28]1>>[N:27]1([S:33]([C:36]2[CH:37]=[C:38]([NH:42][C:12]([C:11]3[CH:10]=[N:9][N:8]4[C:3]([CH:2]([F:1])[F:26])=[CH:4][C:5]([C:15]5[CH:20]=[CH:19][C:18]([C:21]([F:22])([F:24])[F:23])=[C:17]([CH3:25])[CH:16]=5)=[N:6][C:7]=34)=[O:14])[CH:39]=[CH:40][CH:41]=2)(=[O:35])=[O:34])[CH2:28][CH2:29][O:30][CH2:31][CH2:32]1
Reactant: Nc1cccc(S(=O)(=O)N2CCOCC2)c1
Reactant: Cc1cc(-c2cc(C(F)F)n3ncc(C(=O)O)c3n2)ccc1C(F)(F)F
Product: Cc1cc(-c2cc(C(F)F)n3ncc(C(=O)Nc4cccc(S(=O)(=O)N5CCOCC5)c4)c3n2)ccc1C(F)(F)F

Procedure:
The title compound was prepared from 7-difluoromethyl-5-(3-methyl-4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (example C.5) and 3-(morpholine-4-sulfonyl)-phenylamine [CAS 22184-97-0; commercially available] according to general procedure II. Yellow solid. MS (ISP) 595.2 [(M+H)+]; mp 261° C.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:38]=[CH:37][C:12]([O:13][C:14]2[CH:22]=[CH:21][C:17]([C:18](Cl)=[O:19])=[CH:16][C:15]=2[NH:23][C:24]2[C:25]3[CH:33]=[CH:32][C:31]([CH:34]([CH3:36])[CH3:35])=[N:30][C:26]=3[N:27]=[CH:28][N:29]=2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:39][C:40]1[CH:48]=[CH:47][CH:46]=[CH:45][C:41]=1[C:42]([NH2:44])=[O:43]>>[CH2:1]([O:8][C:9]1[CH:38]=[CH:37][C:12]([O:13][C:14]2[CH:22]=[CH:21][C:17]([C:18]([NH:39][C:40]3[CH:48]=[CH:47][CH:46]=[CH:45][C:41]=3[C:42](=[O:43])[NH2:44])=[O:19])=[CH:16][C:15]=2[NH:23][C:24]2[C:25]3[CH:33]=[CH:32][C:31]([CH:34]([CH3:36])[CH3:35])=[N:30][C:26]=3[N:27]=[CH:28][N:29]=2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)c1ccc2c(Nc3cc(C(=O)Cl)ccc3Oc3ccc(OCc4ccccc4)cc3)ncnc2n1
Reactant: NC(=O)c1ccccc1N
Product: CC(C)c1ccc2c(Nc3cc(C(=O)Nc4ccccc4C(N)=O)ccc3Oc3ccc(OCc4ccccc4)cc3)ncnc2n1

Procedure:
A solution of the product from Example 43D and 2-Amino-benzamide was reacted to provide 4-(4-Benzyloxy-phenoxy)-N-(2-carbamoyl-phenyl)-3-(7-isopropyl-pyrido[2,3-d]pyrimidin-4-ylamino)-benzamide using the procedure from Example 43E. The material was then deprotected using the procedure from Example 43F to provide the crude title compound which was purified by HPLC with TFA to provide the title compound as a trifluoroacetic acid salt (18 mg, 34%). 1H NMR (300 MHz, DMSO-D6) δ ppm: 1.35 (d, J=6.99 Hz, 6 H) 3.28 (m, 1 H) 6.76 (m, 2 H) 6.96 (m, 3 H) 7.18 (m, 1 H) 7.57 (m, 1 H) 7.85 (m, 4 H) 8.10 (d, J=2.21 Hz, 1 H) 8.43 (s, 1 H) 8.68 (d, J=8.46 Hz, 1 H) 8.91 (s, 1 H) 9.00 (d, J=8.82 Hz, 1 H) 9.48 (s, 1 H) 11.50 (s, 1 H) 12.99 (s, 1 H); MS (ESI+) m/z 535 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:21]=[CH:20][C:5]([O:6][CH2:7][CH2:8][CH2:9][N:10]2[C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=3[NH:12][C:11]2=[NH:19])=[CH:4][CH:3]=1.[Br:22][C:23]1[CH:30]=[CH:29][C:26]([CH2:27]Br)=[CH:25][CH:24]=1>CC(=O)CC>[Br:22][C:23]1[CH:30]=[CH:29][C:26]([CH2:27][N:12]2[C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[N:10]([CH2:9][CH2:8][CH2:7][O:6][C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:21][CH:20]=3)[C:11]2=[NH:19])=[CH:25][CH:24]=1
Reactant: N=c1[nH]c2ccccc2n1CCCOc1ccc(F)cc1
Reactant: BrCc1ccc(Br)cc1
Solvent: CCC(C)=O
Product: N=c1n(CCCOc2ccc(F)cc2)c2ccccc2n1Cc1ccc(Br)cc1
Temperature: 90 °C
Reaction time: 0.17 h
Yield: 83.6 %

Procedure:
To a solution of 1-[3-(4-fluoro-phenoxy)-propyl]-1,3-dihydro-benzoimidazol-2-ylideneamine (0.40 g, 1.40 mmol) in 2-butanone (30 ml) was added 4-bromobenzyl bromide (0.52 g, 2.1 mmol). The reaction was heated to 90° C. for 16 h. After this time, the resulting suspension was cooled to rt and filtered. The collected solid was washed with additional 2-butanone and then the solid was partitioned between dichloromethane and a saturated solution of NaHCO3. The biphasic mixture was stirred at rt for 10 min and then the organic layer was separated. The aqueous phase was extracted with additional dichloromethane and the combined organic fractions were washed with H2O, dried (Na2SO4), filtered and concentrated under reduced pressure to provide 1-(4-bromo-benzyl)-3-[3-(4-fluoro-phenoxy)-propyl]-1,3-dihydro-benzoimidazol-2-ylideneamine as a white solid (0.532 g, 83%). HPLC-MS 454, 456 [M+1]+.
Reaction SMILES: [C:1]([O:5][CH:6]([C:11]1[C:12]([CH3:30])=[N:13][C:14]([N:24]2[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]2)=[N:15][C:16]=1[C:17]1[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][CH:18]=1)[C:7]([O:9]C)=[O:8])([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+]>ClCCl.CO>[C:1]([O:5][CH:6]([C:11]1[C:12]([CH3:30])=[N:13][C:14]([N:24]2[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29]2)=[N:15][C:16]=1[C:17]1[CH:18]=[CH:19][C:20]([CH3:23])=[CH:21][CH:22]=1)[C:7]([OH:9])=[O:8])([CH3:4])([CH3:3])[CH3:2]
Reactant: COC(=O)C(OC(C)(C)C)c1c(C)nc(N2CCCCC2)nc1-c1ccc(C)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CO
Product: Cc1ccc(-c2nc(N3CCCCC3)nc(C)c2C(OC(C)(C)C)C(=O)O)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 68.9 %

Procedure:
To a mixture of methyl 2-tert-butoxy-2-(4-methyl-2-(piperidin-1-yl)-6-p-tolylpyrimidin-5-yl)acetate (0.030 g; 0.073 mmol) in a mixture dichloromethane-methanol (10:1) (0.55 ml) was added a solution of sodium hydroxide (2N in methanol) (0.075 ml; 0.150 mmol) and the reaction was stirred at room temperature for 24 h. The solvent was removed under reduced pressure, the residue diluted with water and washed with diethyl ether. The pH of the aqueous layer was adjusted to 2 with a solution of hydrochloric acid 2N and the suspension was extracted twice with dichloromethane. The combined organic layers were dried over sodium sulphate, filtered and concentrated under reduced pressure to furnish 0.020 g (65%) of the title compound as a white solid.
Reaction SMILES: [F:1][CH:2]([F:24])[C:3]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([S:14][CH3:15])=[CH:10][CH:9]=2)[N:5]([C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=2)[N:4]=1.ClC1C=CC=C(C(OO)=[O:33])C=1>ClCCl>[F:24][CH:2]([F:1])[C:3]1[CH:7]=[C:6]([C:8]2[CH:9]=[CH:10][C:11]([S:14]([CH3:15])=[O:33])=[CH:12][CH:13]=2)[N:5]([C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=2)[N:4]=1
Reactant: COc1ccc(-n2nc(C(F)F)cc2-c2ccc(SC)cc2)cc1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: COc1ccc(-n2nc(C(F)F)cc2-c2ccc(S(C)=O)cc2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 78.4 %

Procedure:
A mixture of 3-(difluoromethyl)-1-(4-methoxyphenyl)-5-[4-(methylthio)phenyl]pyrazole (1 g) and m-chloroperbenzoic acid (0.56 g) in dichloromethane (23 ml) was stirred at ambient temperature for 1 hour. The mixture was washed with an aqueous solution of sodium bicarbonate, dried over magnesium sulfate, and concentrated. The oily residue was crystallized from ethanol to give crystals of 3-(difluoromethyl)-1-(4-methoxyphenyl)-5-[4-(methylsulfinyl)phenyl]pyrazole (0.82 g).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[N:5]=[C:4]([N:9]([CH3:11])[CH3:10])[N:3]=1.C(=O)([O-])[O-].[K+].[K+].[NH:18]1[CH:22]=[CH:21][N:20]=[CH:19]1>CN(C=O)C>[Cl:1][C:2]1[N:7]=[C:6]([N:18]2[CH:22]=[CH:21][N:20]=[CH:19]2)[N:5]=[C:4]([N:9]([CH3:11])[CH3:10])[N:3]=1
Reactant: CN(C)c1nc(Cl)nc(Cl)n1
Reactant: c1c[nH]cn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CN(C)c1nc(Cl)nc(-n2ccnc2)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 38860.4 %

Procedure:
Cyanuric chloride (11.0 g, 59.6 mmol) was dissolved in ethylene glycol dimethyl ether (100 ml), cooled to -5° C. and gradually added dropwise with 50% aqueous dimethylamine solution (10.8 ml, 120 mmol). This reaction mixture was stirred at the same temperature for 2 hours and then stirred at room temperature overnight. The reaction mixture was evaporated under reduced pressure. The obtained residue was added with dichloromethane and water, and then shaken for mixing. The organic layer was separated from the mixture, washed with water and dried over anhydrous magnesium sulfate. The solvent was removed to obtain 11.0 g (yield: 95.4%) of 2,4-dichloro-6-dimethylamino-1,3,5-triazine as colorless crystals having melting point of 122.5° C.-123° C. (2) The obtained 2,4-dichloro-6-dimethylamino-1,3,5-triazine (1.93 g, 10.0 mmol) was dissolved in DMF (8 ml), added with anhydrous potassium carbonate (1.40 g, 10.1 mmol) and cooled to -5° C.-0° C. This mixture was gradually added with imidazole (695 mg, 10.2 mmol). The reaction mixture was stirred at room temperature overnight and evaporated under reduced pressure. The residue was added with ethyl acetate and water, and then shaken for mixing. The organic layer was separated from the mixture, washed with water, dried over anhydrous magnesium sulfate and evaporated. The obtained residue was purified by silica gel column chromatography, using ethyl acetate and methanol (95:5) as eluant, to obtain 873 g (yield: 38.8%) of 2-chloro-4-(1-imidazolyl)-6-dimethylamino-1,3,5-triazine as colorless crystals having melting point of 88° C.-92° C.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[N:13]=[C:14]3[CH:19]=[C:18]([CH3:20])[CH:17]=[CH:16][N:15]3[CH:21]=2)=[C:8]([CH3:22])[CH:7]=1.[NH:23]1[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1>>[N:23]1([CH2:2][CH2:3][CH2:4][O:5][C:6]2[CH:11]=[CH:10][C:9]([C:12]3[N:13]=[C:14]4[CH:19]=[C:18]([CH3:20])[CH:17]=[CH:16][N:15]4[CH:21]=3)=[C:8]([CH3:22])[CH:7]=2)[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1
Reactant: Cc1ccn2cc(-c3ccc(OCCCCl)cc3C)nc2c1
Reactant: C1CCNCC1
Product: Cc1ccn2cc(-c3ccc(OCCCN4CCCCC4)cc3C)nc2c1
Temperature: 25 °C

Procedure:
The product of Step C (200 mg) and piperidine (2.0 mL) were heated at 100° C. for 2.5 hours. The reaction was cooled to ambient temperature and partitioned between ethyl acetate (10 mL) and saturated sodium bicarbonate solution (10 mL). The aqueous portion was extracted with additional ethyl acetate (10 mL) and the organic portions combined, washed with brine, and evaporated. The residue was purified via silica gel chromatography (dichloromethane/methanol) to give the title compound (110 mg). 1H-NMR (CD3OD) δ 8.28 (d, J=7.0 Hz, 1H), 7.78 (s, 1H), 7.61 (d, J=8.0 Hz, 1H), 7.31 (s, 1H), 6.84 (s, 1H), 6.79 (m, 2H), 4.04 (t, J=6.0 Hz, 2H), 2.50 (m, 12H), 1.99 (m, 2H), 1.64 (m, 4H), 1.51 (m, 2H).
Reaction SMILES: CN1CCOCC1.[Br:8][C:9]1[CH:30]=[CH:29][C:12]([CH2:13][C@@:14]2([C:26]([OH:28])=O)[CH2:18][CH2:17][CH2:16][N:15]2[C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])=[CH:11][CH:10]=1.[NH2:31][CH2:32][CH:33]([OH:40])[CH2:34][C:35]([CH3:39])([CH3:38])[CH2:36][CH3:37].Cl.CN(C)CCCN=C=NCC.OC1C2N=NNC=2C=CC=1>ClCCl>[Br:8][C:9]1[CH:10]=[CH:11][C:12]([CH2:13][C:14]2([C:26]([NH:31][CH2:32][CH:33]([OH:40])[CH2:34][C:35]([CH3:39])([CH3:38])[CH2:36][CH3:37])=[O:28])[CH2:18][CH2:17][CH2:16][N:15]2[C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])=[CH:29][CH:30]=1
Reactant: CC(C)(C)OC(=O)N1CCC[C@@]1(Cc1ccc(Br)cc1)C(=O)O
Reactant: CCC(C)(C)CC(O)CN
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: Oc1cccc2[nH]nnc12
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: CCC(C)(C)CC(O)CNC(=O)C1(Cc2ccc(Br)cc2)CCCN1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
N-methylmorpholine (6.4 mL, 58.6 mmol) was added to an ambient temperature solution of 2-(4-bromobenzyl)-1-(tert-butoxycarbonyl)proline (5.0 g, 13 mmol), 1-amino-4,4-dimethylhexan-2-ol (1.89 g, 13 mmol), 1-[3-(dimethylamino) propyl]-3-ethylcarbodiimide hydrochloride (3.0 g, 15.6 mmol), and hydroxybenzotriazole (2.1 g, 15.6 mmol) in dichloromethane (51 mL). After stirring at ambient temperature overnight, the reaction mixture was quenched with water. The organic phase was dried (magnesium sulfate), filtered, and concentrated in vacuo to afford tert-butyl 2-(4-bromobenzyl)-2-{[(2-hydroxy-4,4-dimethylhexyl)amino]carbonyl}pyrrolidine-1-carboxylate.
Reaction SMILES: [F:1][C:2]1[CH:26]=[CH:25][C:5]([CH2:6][N:7]2[C:11]3=[CH:12][N:13]=[C:14]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[C:15]([C:16]#[C:17][CH2:18][OH:19])=[C:10]3[CH:9]=[CH:8]2)=[CH:4][CH:3]=1>CO.[Pd]>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][N:7]2[C:11]3=[CH:12][N:13]=[C:14]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[C:15]([CH2:16][CH2:17][CH2:18][OH:19])=[C:10]3[CH:9]=[CH:8]2)=[CH:25][CH:26]=1
Reactant: CCOC(=O)c1ncc2c(ccn2Cc2ccc(F)cc2)c1C#CCO
Agent: [Pd]
Solvent: CO
Product: CCOC(=O)c1ncc2c(ccn2Cc2ccc(F)cc2)c1CCCO
Temperature: 25 °C
Reaction time: 4 h
Yield: 87.8 %

Procedure:
To a solution of ethyl 1-(4-fluorobenzyl)-4-(3-hydroxyprop-1-yn-1-yl)-1H-pyrrolo[2,3-c]pyridine-5-carboxylate (0.46 g, 1.31 mmol) in MeOH (6 mL) was added palladium, (10 wt. % on activated carbon, 15 mg, 0.014 mmol). The resulting mixture was stirred for 4 h at room temperature under H2 at 60 psi. The mixture was filtered and concentrated to afford the title product as yellow oil (0.41 g, 88% yield). LC-MS (APCI, M+H+): 357.2. HPLC: 96% purity.
Reaction SMILES: Br[CH2:2][C@H:3]([CH3:10])[CH2:4][CH2:5][CH2:6][CH:7]([CH3:9])[CH3:8].C1(C)C=CC(S(O[CH2:21][CH2:22][C@@H:23]([CH3:30])[CH2:24][O:25][C:26]([CH3:29])([CH3:28])[CH3:27])(=O)=O)=CC=1>>[C:26]([O:25][CH2:24][C@H:23]([CH3:30])[CH2:22][CH2:21][CH2:2][C@H:3]([CH3:10])[CH2:4][CH2:5][CH2:6][CH:7]([CH3:9])[CH3:8])([CH3:27])([CH3:28])[CH3:29]
Reactant: Cc1ccc(S(=O)(=O)OCC[C@@H](C)COC(C)(C)C)cc1
Reactant: CC(C)CCC[C@@H](C)CBr
Product: CC(C)CCC[C@@H](C)CCC[C@@H](C)COC(C)(C)C

Procedure:
Reaction of the Grignard reagent, i.e., the magnesium salt of (R)-1-bromo-2,6-dimethylheptane with the (R)-(+)-4-tert. butoxy-3-methyl-1-butanol p-toluenesulfonate was carried out using the procedure described in Example 12. The desired product (2R,6R)-(+)-1-tert. butoxy-2,6,10-trimethylundecane was obtained as a colorless oil, b.p. 90° C. (bath temperature) (0.1 mm Hg.).