Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([C:7]2[CH:37]=[CH:36][C:10]([CH2:11][O:12][C:13]3[CH:18]=[CH:17][C:16]([C:19]4[N:20]=[C:21]([NH:24][CH2:25][C:26]5[CH:35]=[CH:34][C:29]([C:30]([O:32][CH3:33])=[O:31])=[CH:28][CH:27]=5)[S:22][CH:23]=4)=[CH:15][CH:14]=3)=[CH:9][CH:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.S(OC)(O[CH3:42])(=O)=O.[H-].[Na+].C(OC(C)C)(C)C>CN(C)C=O.O>[CH:1]1([C:7]2[CH:37]=[CH:36][C:10]([CH2:11][O:12][C:13]3[CH:18]=[CH:17][C:16]([C:19]4[N:20]=[C:21]([N:24]([CH2:25][C:26]5[CH:27]=[CH:28][C:29]([C:30]([O:32][CH3:33])=[O:31])=[CH:34][CH:35]=5)[CH3:42])[S:22][CH:23]=4)=[CH:15][CH:14]=3)=[CH:9][CH:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COS(=O)(=O)OC
Reactant: COC(=O)c1ccc(CNc2nc(-c3ccc(OCc4ccc(C5CCCCC5)cc4)cc3)cs2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CC(C)OC(C)C
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(CN(C)c2nc(-c3ccc(OCc4ccc(C5CCCCC5)cc4)cc3)cs2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 83.7 %

Procedure:
Under an argon atmosphere, a suspension of methyl 4-(4-(4-(4-cyclohexylbenzyloxy)phenyl)-2-thiazolylaminomethyl)benzoate (65.0 g, 0.127 mol) obtained in Example 2(3) in N,N-dimethylformamide (130 ml) and dimethyl sulfate (15.0 ml, 0.159 mol) were successively added dropwise to a suspension of sodium hydride (content 60%, 6.09 g, 0.152 mol) in N,N-dimethylformamide (130 ml) at 10° C. or below and the mixture was stirred at room temperature for 1 hr. Diisopropyl ether (195 ml) and water (130 ml) were successively added dropwise at 10° C. or below, and the mixture was stirred at room temperature for 30 min. The precipitated crystals were collected by filtration, washed successively with diisopropyl ether (195 ml) and water (130 ml) and dried to give the title compound (56.0 g, 83.7%).
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[CH:12][C:11]([S:14][C:15]2[CH:20]=[CH:19][C:18]([C:21](=[O:30])[NH:22][C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([Br:29])[CH:24]=3)=[CH:17][C:16]=2[NH:31][C:32]2[C:33]3[CH:41]=[CH:40][CH:39]=[N:38][C:34]=3[N:35]=[CH:36][N:37]=2)=[CH:10][CH:9]=1)(C)(C)C.[F:43][C:44]([F:49])([F:48])[C:45]([OH:47])=[O:46]>C(Cl)Cl>[NH2:7][C:8]1[CH:13]=[CH:12][C:11]([S:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]([NH:22][C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([Br:29])[CH:24]=3)=[O:30])=[CH:17][C:16]=2[NH:31][C:32]2[C:33]3[CH:41]=[CH:40][CH:39]=[N:38][C:34]=3[N:35]=[CH:36][N:37]=2)=[CH:10][CH:9]=1.[F:43][C:44]([F:49])([F:48])[C:45]([OH:47])=[O:46]
Reactant: CC(C)(C)OC(=O)Nc1ccc(Sc2ccc(C(=O)Nc3cccc(Br)c3)cc2Nc2ncnc3ncccc23)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Nc1ccc(Sc2ccc(C(=O)Nc3cccc(Br)c3)cc2Nc2ncnc3ncccc23)cc1

Procedure:
The product of Example 68 was treated with trifluoroacetic acid (3 mL) in methylene chloride (3 mL) at room temperature for 30 minutes. The solvents were removed under vacuum to provide the title compound as a trifluoroacetic acid salt. 1H NMR (300 MHz, DMSO-D6) δ ppm: 6.65 (d, J=8.82 Hz, 2 H) 6.97 (d, J=8.46 Hz, 1 H) 7.17 (d, J=8.46 Hz, 2 H) 7.30 (m, 2 H) 7.72 (m, 1 H) 7.91 (m, 3 H) 8.05 (s, 1 H) 8.91 (s, 1 H) 9.12 (d, J=8.46 Hz, 1 H) 9.19 (d, J=3.68 Hz, 1 H) 10.36 (s, 1 H) 11.72 (s, 1 H); MS (ESI+) m/z 543/545 (M+H)+.
Reaction SMILES: [ClH:1].[OH:2][CH:3]([C:18]1[CH:19]=[CH:20][C:21]([O:28][CH3:29])=[C:22]([CH:27]=1)[C:23](OC)=[O:24])[CH2:4][N:5]1[CH2:10][CH2:9][N:8]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[CH3:17])[CH2:7][CH2:6]1.Cl.OC(C1C=CC(OC)=C(C=1)C(OC)=O)[CH2:33][N:34]1CCN(C2C=CC=CC=2OC)CC1>>[ClH:1].[OH:2][CH:3]([C:18]1[CH:19]=[CH:20][C:21]([O:28][CH3:29])=[C:22]([CH:27]=1)[C:23]([NH:34][CH3:33])=[O:24])[CH2:4][N:5]1[CH2:6][CH2:7][N:8]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[CH3:17])[CH2:9][CH2:10]1
Reactant: COC(=O)c1cc(C(O)CN2CCN(c3ccccc3C)CC2)ccc1OC
Reactant: COC(=O)c1cc(C(O)CN2CCN(c3ccccc3OC)CC2)ccc1OC
Agent: Cl
Product: CNC(=O)c1cc(C(O)CN2CCN(c3ccccc3C)CC2)ccc1OC

Procedure:
Following essentially the same procedure but substituting methyl 5-[1-hydroxy-2-[4-(2-methylphenyl)-1-piperazinyl]ethyl]-2-methoxybenzoate hydrochloride for the methyl 5-[1-hydroxy-2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl]-2-methoxybenzoate hydrochloride above results in the preparation of 5-[1-hydroxy-2-[4-(2-methylphenyl)-1-piperazinyl]ethyl]-2-methoxy-N-methylbenzamide hydrochloride, having a m.pt. of 226°-7° C. (dec.).
Reaction SMILES: Cl[C:2]1[C:3](=[O:11])[O:4][C:5]([CH2:9][CH3:10])=[C:6]([Cl:8])[N:7]=1.[CH3:12][OH:13]>C(Cl)Cl>[Cl:8][C:6]1[N:7]=[C:2]([O:13][CH3:12])[C:3](=[O:11])[O:4][C:5]=1[CH2:9][CH3:10]
Reactant: CCc1oc(=O)c(Cl)nc1Cl
Reactant: CO
Solvent: ClCCl
Product: CCc1oc(=O)c(OC)nc1Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 46 %

Procedure:
To solution of 3,5-dichloro-6-ethyl-2H-1,4-oxazin-2-one (10.0 g, 52.0 mmol) in DCM (10 mL) was added dry MeOH (10.4 mL, 257 mmol). The reaction was stirred overnight at room temperature. The mixture was purified via column chromatography using EtOAc/hexanes (gradient 0-10%) to afford 5-chloro-6-ethyl-3-methoxy-2H-1,4-oxazin-2-one (4.54 g, 55%) as an oil.
Reaction SMILES: F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.[NH2:28][C@H:29]1[CH2:35][O:34][C:33]2[CH:36]=[CH:37][CH:38]=[CH:39][C:32]=2[N:31]([CH2:40][C:41]2[C:49]3[C:44](=[CH:45][CH:46]=[CH:47][CH:48]=3)[N:43]([C:50]3[CH:57]=[CH:56][CH:55]=[CH:54][C:51]=3[C:52]#[N:53])[N:42]=2)[C:30]1=[O:58].[C:59]([O:63][C:64]([NH:66][C@@H:67]([CH3:71])[C:68](O)=[O:69])=[O:65])([CH3:62])([CH3:61])[CH3:60].CCN(C(C)C)C(C)C>C1COCC1.[Cl-].[Na+].O>[C:52]([C:51]1[CH:54]=[CH:55][CH:56]=[CH:57][C:50]=1[N:43]1[C:44]2[C:49](=[CH:48][CH:47]=[CH:46][CH:45]=2)[C:41]([CH2:40][N:31]2[C:30](=[O:58])[C@@H:29]([NH:28][C:68](=[O:69])[C@@H:67]([NH:66][C:64](=[O:65])[O:63][C:59]([CH3:61])([CH3:60])[CH3:62])[CH3:71])[CH2:35][O:34][C:33]3[CH:36]=[CH:37][CH:38]=[CH:39][C:32]2=3)=[N:42]1)#[N:53]
Reactant: N#Cc1ccccc1-n1nc(CN2C(=O)[C@@H](N)COc3ccccc32)c2ccccc21
Reactant: C[C@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: [Cl-]
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: C[C@H](NC(=O)OC(C)(C)C)C(=O)N[C@H]1COc2ccccc2N(Cc2nn(-c3ccccc3C#N)c3ccccc23)C1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 89.3 %

Procedure:
(Benzotriazol-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate (BOP, 486 mg, 1.1 mmol, Eq: 1.5) was added to a mixture of (S)-2-(3-((3-amino-4-oxo-3,4-dihydrobenzo[b][1,4]oxazepin-5(2H)-yl)methyl)-1H-indazol-1-yl)benzonitrile (300 mg, 733 μmol, Eq: 1.00), (S)-2-(tert-butoxycarbonylamino)propanoic acid (208 mg, 1.1 mmol, Eq: 1.5) and DIEA (284 mg, 383 μl, 2.2 mmol, Eq: 3) in THF (10.0 mL) and the mixture was stirred at RT overnight. The mixture was diluted with brine and extracted with EtOAc, then the combined extracts were dried over Na2SO4. The mixture was filtered, concentrated and the residue was purified by silica gel chromatographyto give tert-butyl (S)-1-((S)-5-((1-(2-cyanophenyl)-1H-indazol-3-yl)methyl)-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl amino)-1-oxopropan-2-ylcarbamate (380 mg, 89%).
Reaction SMILES: [CH:1]1([CH:7]([NH:19][C:20]2[CH:28]=[CH:27][C:23]([C:24]([OH:26])=O)=[CH:22][CH:21]=2)[C:8]2[O:9][C:10]3[CH:17]=[C:16]([F:18])[CH:15]=[CH:14][C:11]=3[C:12]=2[CH3:13])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:29][NH:30][CH2:31][CH2:32][C:33]([O:35][CH2:36][CH3:37])=[O:34].O.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C.Cl>CN(C)C=O.C(N(CC)CC)C>[CH:1]1([CH:7]([NH:19][C:20]2[CH:28]=[CH:27][C:23]([C:24]([N:30]([CH3:29])[CH2:31][CH2:32][C:33]([O:35][CH2:36][CH3:37])=[O:34])=[O:26])=[CH:22][CH:21]=2)[C:8]2[O:9][C:10]3[CH:17]=[C:16]([F:18])[CH:15]=[CH:14][C:11]=3[C:12]=2[CH3:13])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: Cc1c(C(Nc2ccc(C(=O)O)cc2)C2CCCCC2)oc2cc(F)ccc12
Reactant: CCOC(=O)CCNC
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: O
Product: CCOC(=O)CCN(C)C(=O)c1ccc(NC(c2oc3cc(F)ccc3c2C)C2CCCCC2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 95.2 %

Procedure:
To a mixture of 4-{[cyclohexyl(6-fluoro-3-methyl-1-benzofuran-2-yl)methyl]amino}benzoic acid (350 mg) synthesized in Example A96(5), ethyl 3-(methylamino)propanoate (181 mg), 1-hydroxybenzotriazole monohydrate (211 mg), triethylamine (383 μL) and N,N-dimethylformamide (10 mL) was added 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (265 mg), and the mixture was stirred overnight at room temperature. 1N Hydrochloric acid was added to quench the reaction, and the mixture was extracted with ethyl acetate. The extract was washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (50% ethyl acetate/hexane) to give the title object compound (432 mg, 95%) as a yellow oil.
Reaction SMILES: [CH2:1]([N:3]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([NH:12][C:13](=[O:26])[C:14]3[CH:19]=[CH:18][C:17]([N:20]4[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]4)=[N:16][CH:15]=3)[CH:10]=2)[CH:5]=[CH:4]1)[CH3:2].Br[C:28]1[CH:36]=[CH:35][C:31]([C:32]([OH:34])=[O:33])=[C:30]([Cl:37])[CH:29]=1.C(C1C=C(NC(C2C=CC(N3CCN(C4C=CC(C(O)=O)=CC=4)CC3)=C(F)C=2)=O)C=CC=1)(C)(C)C>>[Cl:37][C:30]1[CH:29]=[C:28]([N:23]2[CH2:24][CH2:25][N:20]([C:17]3[CH:18]=[CH:19][C:14]([C:13](=[O:26])[NH:12][C:9]4[CH:10]=[C:11]5[C:6]([CH:5]=[CH:4][N:3]5[CH2:1][CH3:2])=[CH:7][CH:8]=4)=[CH:15][N:16]=3)[CH2:21][CH2:22]2)[CH:36]=[CH:35][C:31]=1[C:32]([OH:34])=[O:33]
Reactant: O=C(O)c1ccc(Br)cc1Cl
Reactant: CCn1ccc2ccc(NC(=O)c3ccc(N4CCNCC4)nc3)cc21
Agent: CC(C)(C)c1cccc(NC(=O)c2ccc(N3CCN(c4ccc(C(=O)O)cc4)CC3)c(F)c2)c1
Product: CCn1ccc2ccc(NC(=O)c3ccc(N4CCN(c5ccc(C(=O)O)c(Cl)c5)CC4)nc3)cc21

Procedure:
2-Chloro-4-{4-[5-(1-ethyl-1H-indol-6-ylcarbamoyl)-pyridin-2-yl]-piperazin-1-yl}-benzoic acid was synthesized from N-(1-ethyl-1H-indol-6-yl)-6-piperazin-1-yl-nicotinamide and 4-bromo-2-chloro-benzoic acid in a manner similar to the one described in the synthesis of 4-{4-[4-(3-tert-butyl-phenylcarbamoyl)-2-fluoro-phenyl]-piperazin-1-yl}-benzoic acid above. LCMS calcd for C27H26ClN5O3 (m/e) 503, obsd 504 (M+H).
Reaction SMILES: [CH3:1][OH:2].[CH3:3][C:4]([CH3:14])=[CH:5][CH:6]1[CH:8]([C:9](Cl)=[O:10])[C:7]1([CH3:13])[CH3:12]>N1C=CC=CC=1>[CH3:3][C:4]([CH3:14])=[CH:5][CH:6]1[CH:8]([C:9]([O:2][CH3:1])=[O:10])[C:7]1([CH3:13])[CH3:12]
Reactant: CO
Reactant: CC(C)=CC1C(C(=O)Cl)C1(C)C
Solvent: c1ccncc1
Product: COC(=O)C1C(C=C(C)C)C1(C)C
Yield: 86.9 %

Procedure:
To a mixture containing 430 g of methanol and 265 g of pyridine, under ice cooled conditions, 501.9 g of 3-(2-methyl-1-propenyl)-2,2-dimethylcyclopropanecarboxylic chloride {wherein the molar ratio of the (1R)-trans compound: (1R)-cis compound: (1S)-trans compound: (1S)-cis compound was 93.9:2.5:3.5:0.1} was added over 2.5 hours while stirring the reaction mixture. Subsequently, the reaction mixture was further stirred at room temperature over 4 hours. After concentrating the reaction mixture under reduced pressure to about half of its volume, the reaction mixture was eye-dropped into 500 ml of 3.5% hydrochloric acid. The resulting mixture was extracted 3 times with 200 ml of methyl-t-butyl ether and then concentrated to provide a residue. The resulting residue was distilled under reduced pressure (84 to 89° C./7 mmHg) to provide 426 g of methyl 3-(2-methyl-1-propenyl)-2,2-dimethylcyclopropanecarboxylate.
Reaction SMILES: [Mg].[CH2:2](Br)[CH:3]([CH3:5])[CH3:4].[F:7][C:8]1[CH:15]=[CH:14][CH:13]=[CH:12][C:9]=1[CH:10]=[O:11]>CCOCC>[CH3:4][CH:3]([CH3:5])[CH2:2][CH:10]([OH:11])[C:9]1[CH:12]=[CH:13][CH:14]=[CH:15][C:8]=1[F:7]
Reactant: O=Cc1ccccc1F
Reactant: CC(C)CBr
Agent: [Mg]
Solvent: CCOCC
Product: CC(C)CC(O)c1ccccc1F
Reaction time: 0.33 h
Yield: 53.5 %

Procedure:
In a 3 necked round bottom flask (100 ml), equipped with a dropping funnel reflux condenser and thermometer pocket, placed magnesium turnings (1.45 gm 0.0604 mole) and flame dried the apparatus. Dry diethyl ether (15 ml.) was added to Mg. Turning, Isobutyl bromide (6.57 ml, 8.28 gm, 0.0645 mole) was taken in 5 ml of dry ether and added drop wise to the Mg turnings. As soon as ether starts boiling (in a few minutes) the reaction was cooled using ice-salt and continued the addition of isobutyl bromide. After complete addition of isobutyl bromide continued for another 20 minutes. o-Fluro benzaldehyde (4.25 ml, 5.0 gm, 0.0403 mole) in 10 ml of ether was added drop wise at −10° C. (around ½ hr). After the completion of addition of fluoro benzaldehyde continued the stirring for 1 hr and the reaction was quenched with ice-cooled saturated ammonium chloride solution (30 ml), the solid separated is filtered off, the filtrate is extracted with ethyl acetate (20×1, 10×2 ml) dried over sodium sulphate and concentrated to yield 6.54 gm of crude product (GC showed area of 85% purity). The crude product on vacuum distillation gave 3.93 gm (54.2%) of pure 3-methyl-1-(2-fluoro phenyl)butylalcohol (12) and impure product ˜2.87 gm containing 3-methyl-1-(2-fluoro phenyl)butylalcohol (12) 60% and byproduct (o-fluoro benzylalcohol) 40%. 1HNMR CDCl3 (spectrum 11): 0.96(d, 6H), 1.55(m, 1H), 1.75(m, 2H), 1.95 (bs, 1H), 5.05(m, 1H), 7.0(m, 1H), 7.20(m, 2H), 7.45(m, 1H)
Reaction SMILES: ON1C2C=CC=CC=2N=N1.[C:11]1([CH2:17][CH2:18][NH2:19])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.CN1CCOCC1.Cl.[CH3:28][N:29]([CH3:46])[C:30]1([C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)[CH2:35][CH2:34][C:33](=[CH:36][C:37]([OH:39])=O)[CH2:32][CH2:31]1.C1(N=C=NC2CCCCC2)CCCCC1.[OH-].[Na+]>CN(C)C=O.O>[CH3:46][N:29]([CH3:28])[C:30]1([C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)[CH2:31][CH2:32][C:33](=[CH:36][C:37]([NH:19][CH2:18][CH2:17][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:39])[CH2:34][CH2:35]1
Reactant: CN(C)C1(c2ccccc2)CCC(=CC(=O)O)CC1
Reactant: NCCc1ccccc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Solvent: O
Product: CN(C)C1(c2ccccc2)CCC(=CC(=O)NCCc2ccccc2)CC1
Temperature: 0 °C
Reaction time: 240 h
Yield: 62 %

Procedure:
1-Hydroxybenzotriazole (273 mg, 2.0 mmol), 2-phenylethylamine (0.125 ml, 1.0 mmol) and N-methylmorpholine (0.222 ml, 2.0 mmol) were added to a solution of (4-dimethylamino-4-phenylcyclohexylidene)acetic acid hydrochloride (296 mg, 1.0 mmol) in dry dimethylformamide (10 ml) under argon. The solution was cooled to 0° C. and dicyclohexylcarbodiimide (417 mg, 2.0 mmol) was added. The reaction mixture was stirred at RT for 10 d. Working up of the mixture was carried out by separating off the urea which had precipitated out and introducing the filtrate into a mixture of saturated NaCl solution (40 ml) and saturated NaHCO3 solution (10 ml). Still further urea thereby precipitated out and was separated off. 5 M sodium hydroxide solution (4 ml, 20 mmol) was added to the aqueous phase and the mixture was diluted with water (300 ml) and stored at 5° C. for 3 d. The product thereby precipitated out as a colourless solid in a yield of 62% (223 mg) and with an m.p. of 153-155° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:24])[C:7]=1[S:8][C:9]1[S:13][C:12]([C:14]([NH:16][CH2:17][CH2:18][CH:19]=O)=[O:15])=[CH:11][C:10]=1[N+:21]([O-:23])=[O:22].[NH:25]1[CH2:30][CH2:29][CH:28]([C:31]([NH2:33])=[O:32])[CH2:27][CH2:26]1>>[Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:24])[C:7]=1[S:8][C:9]1[S:13][C:12]([C:14]([NH:16][CH2:17][CH2:18][CH2:19][N:25]2[CH2:30][CH2:29][CH:28]([C:31]([NH2:33])=[O:32])[CH2:27][CH2:26]2)=[O:15])=[CH:11][C:10]=1[N+:21]([O-:23])=[O:22]
Reactant: O=CCCNC(=O)c1cc([N+](=O)[O-])c(Sc2c(Cl)cncc2Cl)s1
Reactant: NC(=O)C1CCNCC1
Product: NC(=O)C1CCN(CCCNC(=O)c2cc([N+](=O)[O-])c(Sc3c(Cl)cncc3Cl)s2)CC1

Procedure:
Prepared according to the procedure described for step D of example 223 from 5-((3,5-dichloropyridin-4-yl)thio)-4-nitro-N-(3-oxopropyl)thiophene-2-carboxamide (100 mg, 0.23 mmol) and piperidine-4-carboxamide (36.0 mg, 0.28 mmol). The title compound was afforded as a solid (20.0 mg, 17% yield). 1H NMR (400 MHz, d6-DMSO) δ: 8.99 (2H, m), 8.85 (1H, m), 8.42 (1H, s), 7.21 (1H, m), 6.73 (1H, m), 3.19 (2H, m), 2.84 (2H, m), 2.25 (1H, m), 2.0 (1H, m), 1.8 (2H, m), 1.64 (4H, m), 1.53 (2H, m), 1.23 (1H, m). MS m/z: 518.33, 520.35 [M+H]+.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([O:10][CH3:11])=[O:9])=[C:6]([C:12]([Cl:15])([F:14])[F:13])[N:5]=[C:4]([C:16]([F:19])([F:18])[F:17])[C:3]=1[C:20]([O:22][CH2:23][CH3:24])=[O:21].[NH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.C(N(CC)CC)C>CN(C=O)C>[Cl:15][C:12]([F:13])([F:14])[C:6]1[N:5]=[C:4]([C:16]([F:18])([F:19])[F:17])[C:3]([C:20]([O:22][CH2:23][CH3:24])=[O:21])=[C:2]([NH:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:7]=1[C:8]([O:10][CH3:11])=[O:9]
Reactant: Nc1ccccc1
Reactant: CCOC(=O)c1c(C(F)(F)F)nc(C(F)(F)Cl)c(C(=O)OC)c1Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCOC(=O)c1c(C(F)(F)F)nc(C(F)(F)Cl)c(C(=O)OC)c1Nc1ccccc1
Temperature: 35 °C

Procedure:
This compound was prepared as described in Example 37: 5.0 g (0.013 mol) of product of Example 28, 3.6 ml (0.039 mol) of aniline, 1.3 g (0.013 mol) of triethylamine in 30 ml of DMF were reacted at room temperature for 16 hours and heated to 35° C. for 20 minutes. The residue was recrystallized in hot hexane affording 4.0 g (68.0%) of product as a beige solid; mp 91°-92° C.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[Cl:8][C:9]1[CH:10]=[C:11]2[C:15](=[C:16]([CH:18]([O:23][CH2:24][C:25]3([C:32]4[CH:37]=[CH:36][C:35]([F:38])=[CH:34][CH:33]=4)[CH2:30][CH2:29][N:28]([CH3:31])[CH2:27][CH2:26]3)[C:19]([O:21]C)=[O:20])[CH:17]=1)[NH:14][N:13]=[CH:12]2.C(OC(N1CCC(COC(C2C=C(Cl)C=C3C=2NN=C3)C(O)=O)(C2C=CC(F)=CC=2)CC1)=O)(C)(C)C>>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[Cl:8][C:9]1[CH:10]=[C:11]2[C:15](=[C:16]([CH:18]([O:23][CH2:24][C:25]3([C:32]4[CH:37]=[CH:36][C:35]([F:38])=[CH:34][CH:33]=4)[CH2:30][CH2:29][N:28]([CH3:31])[CH2:27][CH2:26]3)[C:19]([OH:21])=[O:20])[CH:17]=1)[NH:14][N:13]=[CH:12]2
Reactant: COC(=O)C(OCC1(c2ccc(F)cc2)CCN(C)CC1)c1cc(Cl)cc2cn[nH]c12
Agent: CC(C)(C)OC(=O)N1CCC(COC(C(=O)O)c2cc(Cl)cc3cn[nH]c23)(c2ccc(F)cc2)CC1
Solvent: O=C(O)C(F)(F)F
Product: CN1CCC(COC(C(=O)O)c2cc(Cl)cc3cn[nH]c23)(c2ccc(F)cc2)CC1

Procedure:
Prepared according to the procedure used to prepare methyl 2-(5-chloro-1H-indazol-7-yl)-2-((4-(4-fluorophenyl)-1-methylpiperidin-4-yl)methoxy)acetate trifluoroacetic acid salt using 2-((1-(tert-butoxycarbonyl)-4-(4-fluorophenyl)piperidin-4-yl)methoxy)-2-(5-chloro-1H-indazol-7-yl)acetic acid as the starting material. 1H-NMR (CD3OD, 500 MHz) δ 8.06 (m, 1H), 7.78 (m, 1H), 7.35-7.53)m, 2H), 7.27 (d, J=1.5 Hz, 0.8H), 7.20 (d, J=1.5 Hz, 0.2H), 7.14 (m, 1.5H), 7.04 (m, 0.5H), 5.20 (s, 1H), 4.05 (d, J=9.5 Hz, 0.2H), 3.66 (d, J=9.2 Hz, 1H), 3.35-3.55 (m, 5H), 2.60-2.97 (m, 8H), 2.00-2.40 (m, 2.6H). Mass spec.: 432.21 (MH)+.
Reaction SMILES: [Cl:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([O:10][CH3:11])=[C:4]([Cl:12])[C:3]=1[C:13]1[N:18]=[C:17]2[NH:19][N:20]=[C:21](I)[C:16]2=[CH:15][N:14]=1.[OH:23][C@@H:24]1[CH2:29][CH2:28][C@H:27]([N:30]2[CH2:38][C:37]3[C:32](=[CH:33][CH:34]=[C:35](B4OC(C)(C)C(C)(C)O4)[CH:36]=3)[C:31]2=[O:48])[CH2:26][CH2:25]1>>[Cl:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([O:10][CH3:11])=[C:4]([Cl:12])[C:3]=1[C:13]1[N:18]=[C:17]2[NH:19][N:20]=[C:21]([C:35]3[CH:36]=[C:37]4[C:32](=[CH:33][CH:34]=3)[C:31](=[O:48])[N:30]([C@H:27]3[CH2:26][CH2:25][C@@H:24]([OH:23])[CH2:29][CH2:28]3)[CH2:38]4)[C:16]2=[CH:15][N:14]=1
Reactant: CC1(C)OB(c2ccc3c(c2)CN([C@H]2CC[C@@H](O)CC2)C3=O)OC1(C)C
Reactant: COc1cc(OC)c(Cl)c(-c2ncc3c(I)n[nH]c3n2)c1Cl
Product: COc1cc(OC)c(Cl)c(-c2ncc3c(-c4ccc5c(c4)CN([C@H]4CC[C@@H](O)CC4)C5=O)n[nH]c3n2)c1Cl

Procedure:
This compound was prepared by using procedures analogous to those described for the synthesis of Example 1, Step 7 starting from 6-(2,6-dichloro-3,5-dimethoxyphenyl)-3-iodo-1H-pyrazolo[3,4-d]pyrimidine and 2-(cis-4-hydroxycyclohexyl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoindolin-1-one. LCMS (M+H)+=553.9/555.9. 1H NMR (300 MHz, DMSO-d6) δ: 9.90 (s, 1H), 8.40 (s, 1H), 8.28 (d, J=7.9 Hz, 1H), 7.83 (d, J=7.9 Hz, 1H), 7.08 (s, 1H), 4.57 (s, 2H), 4.48 (d, J=3.1 Hz, 1H), 4.13-4.01 (m, 1H), 4.00 (s, 6H), 3.91-3.85 (m, 1H), 2.03-1.91 (m, 2H), 1.85-1.73 (m, 2H), 1.67-1.42 (m, 4H).
Reaction SMILES: [C:1]12([CH2:11][O:12][C:13]([NH:15][C@@H:16]([CH2:24][C:25]3[CH:30]=[CH:29][C:28]([O:31][CH2:32][CH2:33][CH2:34][C:35]([O:37]CC)=O)=[CH:27][CH:26]=3)[C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])=[O:14])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.Cl.[NH2:41][C:42]1[NH:43][CH2:44][CH2:45][N:46]=1.CC(C)([O-])C.[K+]>CN(C=O)C>[C:1]12([CH2:11][O:12][C:13]([NH:15][C@@H:16]([CH2:24][C:25]3[CH:26]=[CH:27][C:28]([O:31][CH2:32][CH2:33][CH2:34][C:35](=[O:37])[NH:41][C:42]4[NH:46][CH2:45][CH2:44][N:43]=4)=[CH:29][CH:30]=3)[C:17]([O:19][C:20]([CH3:22])([CH3:21])[CH3:23])=[O:18])=[O:14])[CH2:8][CH:7]3[CH2:9][CH:3]([CH2:4][CH:5]([CH2:6]3)[CH2:10]1)[CH2:2]2
Reactant: NC1=NCCN1
Reactant: CCOC(=O)CCCOc1ccc(C[C@H](NC(=O)OCC23CC4CC(CC(C4)C2)C3)C(=O)OC(C)(C)C)cc1
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)[C@H](Cc1ccc(OCCCC(=O)NC2=NCCN2)cc1)NC(=O)OCC12CC3CC(CC(C3)C1)C2
Reaction time: 8 h
Yield: 40 %

Procedure:
436 mg (0.8 mmol) of tert-butyl (2S)-2-(1-adamantylmethyloxycarbonylamino)-3-(4-(3-ethoxycarbonylpropyloxy)phenyl)propionate were added to a solution of 388 mg (3.2 mmol) of 2-amino-4,5-dihydroimidazole hydrochloride and 359 mg (3.2 mmol) of potassium tert-butoxide in 10 ml of DMF. The mixture was stirred overnight. After the reaction had ended, it was worked up analogously to Example 4c and chromatographed on silica gel using the same eluent mixture. 188 mg (0.32 mmol) of (5.1) were obtained.
Reaction SMILES: C([S:9][CH:10]([CH2:21][C:22](OC)=O)[C:11]([N:13]1[CH2:20][CH2:19][CH2:18][C@H:14]1[C:15]([OH:17])=[O:16])=[O:12])(=O)C1C=CC=CC=1.C(SCC(C[C:43]([O:45][CH3:46])=[O:44])C(N1CCC[C@H]1C(O)=O)=O)(=O)C>>[SH:9][CH:10]([CH2:21][CH2:22][C:43]([O:45][CH3:46])=[O:44])[C:11]([N:13]1[CH2:20][CH2:19][CH2:18][C@H:14]1[C:15]([OH:17])=[O:16])=[O:12]
Reactant: COC(=O)CC(SC(=O)c1ccccc1)C(=O)N1CCC[C@H]1C(=O)O
Reactant: COC(=O)CC(CSC(C)=O)C(=O)N1CCC[C@H]1C(=O)O
Product: COC(=O)CCC(S)C(=O)N1CCC[C@H]1C(=O)O

Procedure:
By substituting 1-[2-(benzoylthio)-3-(methoxycarbonyl)propanoyl]-L-proline for the 1-[3-(acetylthio)-2-(methoxycarbonylmethyl)propanoyl]-L-proline in the procedure of Example 4, 1-[2-mercapto-3-(methoxycarbonylmethyl)propanoyl]-L-proline is obtained.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[C:10](=[O:23])[CH2:11][CH2:12][C:13]1[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][C:14]=1[O:21][CH3:22].[BH4-].[Na+].C(O)(=O)C>C(O)CC>[OH:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[CH:10]([OH:23])[CH2:11][CH2:12][C:13]1[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][C:14]=1[O:21][CH3:22]
Reactant: COc1ccc(CCC(=O)c2cc(OC)ccc2O)c(OC)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CCCO
Product: COc1ccc(CCC(O)c2cc(OC)ccc2O)c(OC)c1

Procedure:
1-(2-hydroxy-5-methoxyphenyl)-3-(2′,4′-dimethoxyphenyl)-1-propanone (6) (5 mg) was dissolved in 1-propanol (1 ml), followed by the addition of sodium borohydride (2 mg) and the mixture was allowed to react at room temperature for 5 hours. Upon completion of the reaction, 20% acetic acid (0.2 ml) was added to neutralize the excess sodium borohydride. The reaction mixture was then separated on a pre-packed C18 column eluting with a MeOH/H2O gradient to provide 1-(2-hydroxy-5-methoxyphenyl)-3-(2′,4′-dimethoxyphenyl)-1-propanol (7).
Reaction SMILES: [Cl:1][C:2]1[CH:16]=[CH:15][C:5]([O:6][CH2:7][C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])=[C:4]([CH:17]=[O:18])[CH:3]=1.[BH4-].[Na+]>C(O)C>[Cl:1][C:2]1[CH:16]=[CH:15][C:5]([O:6][CH2:7][C:8]([O:10][C:11]([CH3:14])([CH3:12])[CH3:13])=[O:9])=[C:4]([CH2:17][OH:18])[CH:3]=1
Reactant: CC(C)(C)OC(=O)COc1ccc(Cl)cc1C=O
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: CC(C)(C)OC(=O)COc1ccc(Cl)cc1CO
Reaction time: 0.17 h
Yield: 94.5 %

Procedure:
To a solution of (4-chloro-2-formylphenoxy)-acetic acid, 1,1-dimethylethyl ester (2.1 g) in ethanol (20 ml) was added sodium borohydride (0.29 g). After stirring for 10 minutes the reaction was concentrated in vacuo and water added to the residue. The organics were extracted into ethylacetate, washed with brine, dried (MgSO4) and concentrated in vacuo to give the subtitle compound as an oil (2 g).