Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O[CH:2]=[C:3]1[C:11]2[C:6](=[CH:7][C:8]([C:12]([C:14]3[CH:15]=[C:16]([NH:20][C:21]([C:23]4[CH:27]=[C:26]([CH2:28][CH3:29])[N:25]([CH3:30])[N:24]=4)=[O:22])[CH:17]=[CH:18][CH:19]=3)=[O:13])=[CH:9][CH:10]=2)[NH:5][C:4]1=[O:31].[CH3:32][N:33]1[CH2:38][CH2:37][N:36]([C:39]2[CH:44]=[CH:43][C:42]([NH2:45])=[CH:41][CH:40]=2)[CH2:35][CH2:34]1>C1COCC1>[CH3:32][N:33]1[CH2:34][CH2:35][N:36]([C:39]2[CH:44]=[CH:43][C:42]([NH:45][CH:2]=[C:3]3[C:11]4[C:6](=[CH:7][C:8]([C:12]([C:14]5[CH:15]=[C:16]([NH:20][C:21]([C:23]6[CH:27]=[C:26]([CH2:28][CH3:29])[N:25]([CH3:30])[N:24]=6)=[O:22])[CH:17]=[CH:18][CH:19]=5)=[O:13])=[CH:9][CH:10]=4)[NH:5][C:4]3=[O:31])=[CH:41][CH:40]=2)[CH2:37][CH2:38]1
Reactant: CCc1cc(C(=O)Nc2cccc(C(=O)c3ccc4c(c3)NC(=O)C4=CO)c2)nn1C
Reactant: CN1CCN(c2ccc(N)cc2)CC1
Solvent: C1CCOC1
Product: CCc1cc(C(=O)Nc2cccc(C(=O)c3ccc4c(c3)NC(=O)C4=CNc3ccc(N4CCN(C)CC4)cc3)c2)nn1C
Temperature: 65 °C
Reaction time: 24 h
Yield: 12 %

Procedure:
A small screw cap test tube was charged with 5-Ethyl-1-methyl-1H-pyrazole-3-carboxylic acid [3-(3-hydroxymethylene-2-oxo-2,3-dihydro-1H-indole-6-carbonyl)-phenyl]-amide (prepared below, 61 mg, 0.1465 mmol) and THF (2.0 mL). To the resulting solution was added 4-(4-methyl-piperazin-1-yl)-phenylamine (27.7 mg, 0.145 mmol), and the mixture was stirred for 24 h at 65° C. Subsequently, the reaction mixture was cooled to room temperature and concentrated in vacuo. The solid residue was recrystallized with ˜5 mL of i-prOH affording the title compound in 12% yield (0.010 g, 0.017 mmol).
Reaction SMILES: Cl[C:2]1[CH:7]=[N:6][CH:5]=[C:4]([F:8])[N:3]=1.[Si:9]([O:26][C:27]1[CH:32]=[CH:31][C:30](B(O)O)=[CH:29][CH:28]=1)([C:22]([CH3:25])([CH3:24])[CH3:23])([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>>[F:8][C:4]1[CH:5]=[N:6][CH:7]=[C:2]([C:30]2[CH:29]=[CH:28][C:27]([O:26][Si:9]([C:22]([CH3:25])([CH3:24])[CH3:23])([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)=[CH:32][CH:31]=2)[N:3]=1
Reactant: Fc1cncc(Cl)n1
Reactant: CC(C)(C)[Si](Oc1ccc(B(O)O)cc1)(c1ccccc1)c1ccccc1
Product: CC(C)(C)[Si](Oc1ccc(-c2cncc(F)n2)cc1)(c1ccccc1)c1ccccc1
Yield: 69.5 %

Procedure:
In an analogous reaction to Example 1b, 8.86 g (66.85 mmol) of 2-chloro-6-fluoropyrazine (prepared as described in Example 1a) and 25.13 g (66.85 mmol) of 4-tert-butyldiphenylsilyloxyphenylboronic acid give 19.90 g of 2-fluoro-6-(4-tert-butyldiphenylsilyloxyphenyl)pyrazine. ##STR22## 4b
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([C:7](Cl)=[O:8])[CH2:3][CH2:2]1.C(N(C(C)C)C(C)C)C.C1(C)C=CC(S(O)(=O)=O)=CC=1.[CH2:30]([O:37][C:38](=[O:44])[C@H:39]([CH:41]([CH3:43])[CH3:42])[NH2:40])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>C(Cl)Cl.C(OCC)(=O)C>[CH2:30]([O:37][C:38](=[O:44])[C@H:39]([CH:41]([CH3:42])[CH3:43])[NH:40][C:7]([N:4]1[CH2:5][CH2:6][O:1][CH2:2][CH2:3]1)=[O:8])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1
Reactant: O=C(Cl)N1CCOCC1
Reactant: CC(C)[C@H](N)C(=O)OCc1ccccc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)[C@H](NC(=O)N1CCOCC1)C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
0.8 ml (8.1 mmol) of (morpholinocarbonyl)chloride (preparation: J. Med. Chem. 31, 2277 (1988)) and 4.1 ml (24.1 mmol) of N-ethyldiisopropylamine are added to a solution of 4 g (10.5 mmol) of (L)-valine-benzyl ester 4-toluenesulfonate in 56 ml of methylene chloride and the mixture is stirred at RT for 24 h. The reaction mixture is diluted with ethyl acetate and washed in succession with 1N hydrochloric acid, water, saturated sodium hydrogen carbonate solution and brine. The organic phase is dried over sodium sulfate and concentrated by evaporation. Chromatography on silica gel with ethyl acetate yields N-morpholinocarbonyl-(L)-valine-benzyl ester in the form of a colourless oil. The ester is directly further used in a).
Reaction SMILES: [CH2:1]([C:3]1([CH2:17][CH3:18])[C:8]2[CH:9]=[C:10]([B:13]([OH:15])[OH:14])[CH:11]=[CH:12][C:7]=2[NH:6][C:5](=[O:16])[O:4]1)[CH3:2].[H-].[Na+].[CH3:21]I>C1COCC1>[CH2:17]([C:3]1([CH2:1][CH3:2])[C:8]2[CH:9]=[C:10]([B:13]([OH:14])[OH:15])[CH:11]=[CH:12][C:7]=2[N:6]([CH3:21])[C:5](=[O:16])[O:4]1)[CH3:18]
Reactant: CI
Reactant: CCC1(CC)OC(=O)Nc2ccc(B(O)O)cc21
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCC1(CC)OC(=O)N(C)c2ccc(B(O)O)cc21
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 77.4 %

Procedure:
To a stirred solution of 4,4-diethyl-2-oxo-1,4-dihydro-2H-3,1-benzoxazin-6-ylboronic acid (4.85 g, 19.50 mmol) in THF (100 mL) at 0° C. was added sodium hydride (3.12 g-60%, 78 mmol). After 10 minutes, methyl iodide (9.7 mL, 156.0 mmol) was added and the reaction was allowed to warm to room temperature After one week the reaction was quenched with ammonium chloride solution (sat.) and extracted with ethyl acetate several times. The organic layers were washed with brine, dried over magnesium sulfate and concentrated. Trituration with ether gave 4,4-diethyl-1-methyl-2-oxo-1,4-dihydro-2H-3,1-benzoxazin-6-ylboronic acid as a yellow solid (3.97 g, 77%). 1H NMR (DMSO-d6): δ 8.03 (s, 2H), 7.78 (dd, J=8.2, 1.3 Hz, 1H), 7.60 (d, J=1.3 Hz, 1H), 7.05 (d, J=8.3 Hz, 1H), 3.28 (s, 3H), 1.99 (m, 4H), 0.78 (t, J=7.4 Hz, 6H). MS (ESI) m/z 264 ([M+H]+); MS (ESI) m/z 262 ([M−H]−); Anal. calcd for C13H18BNO4: C, 59.35; H, 6.90; N, 5.32. Found: C, 58.97; H, 6.98; N, 4.73.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([CH2:10]O)=[C:7]([CH3:12])[C:6]=2[CH:13]=1.P(Br)(Br)[Br:15].CN(C=O)C>CCOCC>[Br:15][CH2:10][C:8]1[O:9][C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:13][C:6]=2[C:7]=1[CH3:12]
Reactant: Cc1c(CO)oc2ccc(Cl)cc12
Reactant: BrP(Br)Br
Solvent: CN(C)C=O
Solvent: CCOCC
Product: Cc1c(CBr)oc2ccc(Cl)cc12
Reaction time: 3 h

Procedure:
A solution of 5-chloro-3-methyl benzofuran 2-methanol (18.3 mmol, 3.6 g) in ether (200 mL) was cooled to 0° C. To this was added drop-wise phosphorus tribromide (29.3 mmol, 7.9 g) and then DMF (2 mL). After allowing the reaction mixture to come to room temperature over three hours, the reaction was quenched with ice water (100 mL). The ether layer was collected, dried, filtered and the filtrate was evaporated to a yellow solid: 2-bromomethyl-5-chloro-3-methyl benzofuran (88%, 4.2 g); mp 81° C.-82° C.
Reaction SMILES: [CH3:1][N:2]1[CH2:8][CH2:7][CH:6]([OH:9])[C:5]2[CH:10]=[CH:11][O:12][C:4]=2[CH2:3]1.[Cl:13][C:14]1[C:19]([Cl:20])=[CH:18][CH:17]=[CH:16][C:15]=1F>>[ClH:13].[Cl:13][C:14]1[C:19]([Cl:20])=[CH:18][CH:17]=[CH:16][C:15]=1[O:9][CH:6]1[CH2:7][CH2:8][N:2]([CH3:1])[CH2:3][C:4]2[O:12][CH:11]=[CH:10][C:5]1=2
Reactant: Fc1cccc(Cl)c1Cl
Reactant: CN1CCC(O)c2ccoc2C1
Product: CN1CCC(Oc2cccc(Cl)c2Cl)c2ccoc2C1
Product: Cl

Procedure:
The same method as in Example 3 was conducted using 7-methyl-5,6,7,8-tetrahydro-4H-furo[2,3-c]azepin-4-ol (Reference Example 19) instead of 6-methyl-4,5,6,7-tetrahydrothieno[2,3-c]pyridin-4-ol (Reference Example 6) and was conducted using 2,3-dichloro-1-fluorobenzene instead of 1,3-difluorobenzene to give the objective compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[C:18]([CH3:23])[C:17]=1[CH3:24].ClC(Cl)(O[C:29](=[O:35])[O:30][C:31](Cl)(Cl)Cl)Cl.[CH3:37][O:38][C:39]1[CH:44]=[CH:43][CH:42]=[C:41]([O:45][CH3:46])C=1O.C(=O)(O)[O-].[Na+]>C(Cl)Cl.C(N(CC)CC)C.C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH:20][C:29](=[O:35])[O:30][C:31]2[C:39]([O:38][CH3:37])=[CH:44][CH:43]=[CH:42][C:41]=2[O:45][CH3:46])=[C:18]([CH3:23])[C:17]=1[CH3:24]
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: COc1cc2nccc(Oc3ccc(N)c(C)c3C)c2cc1OC
Reactant: COc1cccc(OC)c1O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1cc2nccc(Oc3ccc(NC(=O)Oc4c(OC)cccc4OC)c(C)c3C)c2cc1OC
Yield: 95.2 %

Procedure:
4-[(6,7-Dimethoxy-4-quinolyl)oxy]-2,3-dimethylaniline (50 mg) was added to toluene (5 ml), and triethylamine (0.5 ml), and the mixture was heated under reflux to prepare a solution. A solution of triphosgene (68 mg) in methylene chloride was then added thereto, and the mixture was heated under reflux for 10 min. Next, 2,6-dimethoxyphenol (35 mg) was added thereto, and the mixture was further stirred with heating under reflux for 3 hr. A saturated aqueous sodium bicarbonate solution was added to stop the reaction, and the reaction solution was then extracted with chloroform, followed by washing with a 1 N aqueous hydrochloric acid solution, water, and saturated brine in that order. The extract was dried over sodium sulfate and was then concentrated. The residue was purified on a column using chloroform/methanol to give the title compound (74 mg, yield 91%).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[N:5][C:6]([NH2:9])=[N:7][CH:8]=1)#[CH:2].I[C:11]1[CH:12]=[C:13]([CH:27]=[CH:28][C:29]=1[CH3:30])[C:14]([NH:16][C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([C:23]([F:26])([F:25])[F:24])[CH:18]=1)=[O:15].CC#N>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I.CCN(CC)CC>[NH2:9][C:6]1[N:7]=[CH:8][C:3]([C:1]#[C:2][C:28]2[CH:27]=[C:13]([CH:12]=[CH:11][C:29]=2[CH3:30])[C:14]([NH:16][C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([C:23]([F:25])([F:26])[F:24])[CH:18]=2)=[O:15])=[CH:4][N:5]=1
Reactant: Cc1ccc(C(=O)Nc2cccc(C(F)(F)F)c2)cc1I
Reactant: C#Cc1cnc(N)nc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Solvent: CC#N
Product: Cc1ccc(C(=O)Nc2cccc(C(F)(F)F)c2)cc1C#Cc1cnc(N)nc1
Temperature: 90 °C

Procedure:
To a sealable tube containing 5-ethynylpyrimidin-2-amine (172 mg, 1.44 mmol), PdCl2(PPh3)2 (25 mg, 0.036 mmol), 3-iodo-4-methyl-N-(3-(trifluoromethyl)phenyl)benzamide (292 mg, 0.72 mmol) was added MeCN (10 mL) and Et3N (3 mL) followed by CuI (6.8 mg, 0.036 mmol). The tube was sealed and heated at 90° C. for 1 h. The reaction was allowed to cool to room temperature and concentrated under reduced pressure. The resulting brown solid was reconstituted in MeOH:CH2Cl2 (1:1, 10 mL) and silica gel was added and reconcentrated. The silica-gel combined crude mixture was purified via automated flash chromatography (silica gel, 0 to 5% MeOH in CH2Cl2, gradient elution) to afford 3-(2-(2-aminopyrimidin-5-yl)ethynyl)-4-methyl-N-(3-(trifluoromethyl)phenyl)benzamide. MS m/z=397 [M+H]+. Calc'd for C21H15F3N4O: 396
Reaction SMILES: [Cl-].[CH2:2]([O:9][C:10]([C@@H:12]1[CH2:17][CH2:16][CH2:15][CH2:14][NH2+:13]1)=[O:11])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[C:18]([O:21][C:22]1[CH:31]=[CH:30][C:25]2[N:26]=[C:27](Cl)[O:28][C:24]=2[CH:23]=1)(=[O:20])[CH3:19]>>[C:18]([O:21][C:22]1[CH:31]=[CH:30][C:25]2[N:26]=[C:27]([N:13]3[CH2:14][CH2:15][CH2:16][CH2:17][C@H:12]3[C:10]([O:9][CH2:2][C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=3)=[O:11])[O:28][C:24]=2[CH:23]=1)(=[O:20])[CH3:19]
Reactant: O=C(OCc1ccccc1)[C@@H]1CCCC[NH2+]1
Reactant: CC(=O)Oc1ccc2nc(Cl)oc2c1
Agent: [Cl-]
Product: CC(=O)Oc1ccc2nc(N3CCCC[C@H]3C(=O)OCc3ccccc3)oc2c1

Procedure:
The title compound was prepared by a similar method to Preparation 2 from (2S)-2-[(benzyloxy)carbonyl]piperidinium chloride [see EP 530167 A1 930303] and 2-chloro-1,3-benzoxazol-6-yl acetate [see Preparation 35]. The crude product was purified by column chromatography on silica gel eluting with a solvent gradient of 80:10 changing to 40:10, by volume, hexane:ethyl acetate to afford benzyl (2S)-1-[6-(acetyloxy)-1,3-benzoxazol-2-yl]-2-piperidinecarboxylate as a gum.
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]1[CH:9]=[C:8]([F:10])[C:7]([NH:11][S:12]([CH3:15])(=[O:14])=[O:13])=[C:6]([C:16]#[CH:17])[CH:5]=1.C(N(CC)CC)C.[N:25]1([C:31]2[N:36]=[CH:35][C:34]([CH:37]=[CH:38][C:39](O)=[O:40])=[CH:33][CH:32]=2)[CH2:30][CH2:29][O:28][CH2:27][CH2:26]1.C[N+]1(C2N=C(OC)N=C(OC)N=2)CCOCC1.[Cl-]>C1COCC1.CCOC(C)=O>[C:16]([C:6]1[CH:5]=[C:4]([CH:9]=[C:8]([F:10])[C:7]=1[NH:11][S:12]([CH3:15])(=[O:14])=[O:13])[CH2:3][NH:2][C:39](=[O:40])[CH:38]=[CH:37][C:34]1[CH:35]=[N:36][C:31]([N:25]2[CH2:26][CH2:27][O:28][CH2:29][CH2:30]2)=[CH:32][CH:33]=1)#[CH:17]
Reactant: C#Cc1cc(CN)cc(F)c1NS(C)(=O)=O
Reactant: O=C(O)C=Cc1ccc(N2CCOCC2)nc1
Agent: COc1nc(OC)nc([N+]2(C)CCOCC2)n1
Agent: Cl
Agent: [Cl-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: C#Cc1cc(CNC(=O)C=Cc2ccc(N3CCOCC3)nc2)cc(F)c1NS(C)(=O)=O
Reaction time: 0.17 h
Yield: 24.2 %

Procedure:
N-(4-Aminomethyl-2-ethynyl-6-fluoro-phenyl)-methanesulfonamide HCl salt (20 mg, 0.072 mmol) was suspended in THF and treated with triethylamine (11 mg, 0.108 mmol) and then the resulting mixture was stirred for 10 mins. 3-(6-morpholin-4-yl-pyridin-3-yl)-acrylic acid (17 mg, 0.072 mmol) was added to the reaction mixture followed by DMTMM (22 mg, 0.08 mmol) after 10 mins. The resulting mixture was stirred overnight at ambient temperature and then diluted with EtOAc. The resulting solution was washed successively with water, sat'd NaHCO3 (×2), brine, and then dried over anh. Na2SO4, filtered and concentrated under reduced pressure. The crude residue was recrystallized (CH2Cl) to yield the title compound (8 mg, 24%).
Reaction SMILES: [C:1]([N:9]1[CH2:15][CH2:14][CH2:13][C:12]([Cl:17])([Cl:16])[CH2:11][C:10]1=[O:18])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:19](Cl)(=O)[CH2:20]CCCCCCC>>[C:1]([N:9]1[CH2:15][CH2:14][CH2:13][C:12]([Cl:16])([Cl:17])[CH2:11][C:10]1=[O:18])(=[O:8])[CH2:2][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:19][CH3:20]
Reactant: CCCCCCCCC(=O)Cl
Reactant: O=C1CC(Cl)(Cl)CCCN1C(=O)c1ccccc1
Product: CCCCCCCCC(=O)N1CCCC(Cl)(Cl)CC1=O

Procedure:
Synthesized as for N-benzoyl-3,3-chlorocaprolactam (Example IX) using nonanoyl chloride (Aldrich) in place of benzoyl chloride.
Reaction SMILES: O.[OH-].[Li+].C[O:5][C:6]([C:8]1[CH:47]=[CH:46][C:11]([CH2:12][CH:13](/[CH:26]=[CH:27]/[C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=2[O:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][N:40]2[CH2:44][CH2:43][O:42][C:41]2=[O:45])[CH2:14][CH2:15][C:16]2[CH:25]=[CH:24][C:19]([C:20]([O:22]C)=[O:21])=[CH:18][CH:17]=2)=[CH:10][CH:9]=1)=[O:7].Cl>C1COCC1.O>[C:6]([C:8]1[CH:9]=[CH:10][C:11]([CH2:12][CH:13](/[CH:26]=[CH:27]/[C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=2[O:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][N:40]2[CH2:44][CH2:43][O:42][C:41]2=[O:45])[CH2:14][CH2:15][C:16]2[CH:17]=[CH:18][C:19]([C:20]([OH:22])=[O:21])=[CH:24][CH:25]=2)=[CH:46][CH:47]=1)([OH:7])=[O:5]
Reactant: COC(=O)c1ccc(CCC(/C=C/c2ccccc2OCCCCCN2CCOC2=O)Cc2ccc(C(=O)OC)cc2)cc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)c1ccc(CCC(/C=C/c2ccccc2OCCCCCN2CCOC2=O)Cc2ccc(C(=O)O)cc2)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
8.75 mg (208 mmol) of lithium hydroxide monohydrate are added to a solution of 25 mg (41.7 μmol) of methyl 4-[(4E)-3-[4-(methoxycarbonyl)benzyl]-5-(2-{[5-(2-oxo-1,3-oxazolidin-3-yl)-pentyl]oxy}phenyl)pent-4-en-1-yl]benzoate (Example 33A) in 0.5 ml of THF and 0.5 ml of water, and the mixture is stirred at room temperature for 16 h. The mixture is then adjusted to pH 2 using 1 M hydrochloric acid and extracted twice with ethyl acetate. The combined organic phases are dried over sodium sulfate, filtered and concentrated. The residue obtained is purified by preparative HPLC. This gives 1.5 mg (2.62 μmol, 6.3% of theory) of the title compound.
Reaction SMILES: [C:1]([C:9]1[CH:10]=[C:11]([CH:15]([CH3:20])[C:16]([O:18][CH3:19])=[O:17])[CH:12]=[CH:13][CH:14]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[BH4-].[Na+].C(Cl)(Cl)Cl>CO>[C:2]1([CH:1]([OH:8])[C:9]2[CH:10]=[C:11]([CH:15]([CH3:20])[C:16]([O:18][CH3:19])=[O:17])[CH:12]=[CH:13][CH:14]=2)[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)C(C)c1cccc(C(=O)c2ccccc2)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: CO
Product: COC(=O)C(C)c1cccc(C(O)c2ccccc2)c1
Temperature: 0 °C
Reaction time: 2 h
Yield: 97 %

Procedure:
To a solution of 164 g of methyl 2-(3-benzoylphenyl)propionate in 1100 mL methanol at a 0° C., 14 of sodium borohydride were added, keeping the temperature between 7 and 10° C. After 2 hours of stirring at 0° C., TLC (silica-gel/chloroform) showed total consumption of starting material. The solvent was evaporated under vacuum. The residue was dissolved in 400 mL of methylene chloride. The solution was washed three times with 250 ml of 1% hydrochloric acid, until acid pH, and then with saturated sodium chloride solution, until neutral pH. After evaporation of the solvent, the oily colourless residue wheighted 160,0 g (97% yield) and was identified as the title compound. IR Spectrum (film), cm-1 : 3480 (broad), 3080-2880, 1730, 1455, 1200, 1175, 1110, 700. In the 200 MHz 1H-NMR apparatus the signal of CH3 appears as two doublets of similar intensity, indicating the presence of the two possible diasteromers. By following analogous procedures, compounds IVc of Table 2 were obtained.
Reaction SMILES: [CH3:1][N:2](/[CH:4]=C/C(C1C=NC=CN=1)=O)[CH3:3].N1C=CN=CC=1C(=O)C.[C:23]([N:30]([C:40]([O:42][C:43]([CH3:46])([CH3:45])[CH3:44])=[O:41])[C:31]1[S:32][C:33]([C:37](=[O:39])[CH3:38])=[C:34]([CH3:36])[N:35]=1)([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24]>>[C:40]([N:30]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[C:31]1[S:32][C:33]([C:37](=[O:39])/[CH:38]=[CH:1]/[N:2]([CH3:4])[CH3:3])=[C:34]([CH3:36])[N:35]=1)([O:42][C:43]([CH3:46])([CH3:45])[CH3:44])=[O:41]
Reactant: CC(=O)c1sc(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)nc1C
Reactant: CN(C)/C=C/C(=O)c1cnccn1
Agent: CC(=O)c1cnccn1
Product: Cc1nc(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)sc1C(=O)/C=C/N(C)C
Yield: 16 %

Procedure:
Following the procedure described for the synthesis of enamino ketone 23a (scheme 6) but substituting 1-(pyrazin-2-yl)-ethanone for the ketone 336, title compound was obtained in 16% yield. 1H NMR (DMSO-d6) δ (ppm): 7.65 (d, J=12.1 Hz, 1H), 5.34 (d, J=12.1 Hz, 1H), 3.14 (s, 3H), 2.87 (s, 3H), 2.50 (s, 3H), 1.51 (s, 18H). MS (m/z): 411.52 (calc) 412.3 (MH+) (found).
Reaction SMILES: [C:1]([O:5][C:6](=[O:47])[N:7]([CH2:30][CH:31]([C:33]1[CH:38]=[C:37]([C:39]([F:42])([F:41])[F:40])[CH:36]=[C:35]([C:43]([F:46])([F:45])[F:44])[CH:34]=1)[OH:32])[CH2:8][C:9]1[CH:14]=[C:13]([C:15]([F:18])([F:17])[F:16])[CH:12]=[CH:11][C:10]=1[C:19]1[CH:24]=[C:23]([CH:25]([CH3:27])[CH3:26])[CH:22]=[CH:21][C:20]=1[O:28][CH3:29])([CH3:4])([CH3:3])[CH3:2].CCN(C(C)C)C(C)C.[CH3:57][S:58](Cl)(=[O:60])=[O:59]>C(Cl)Cl.CCOC(C)=O>[CH3:57][S:58]([O:32][CH:31]([C:33]1[CH:38]=[C:37]([C:39]([F:42])([F:41])[F:40])[CH:36]=[C:35]([C:43]([F:44])([F:45])[F:46])[CH:34]=1)[CH2:30][N:7]([C:6]([O:5][C:1]([CH3:3])([CH3:4])[CH3:2])=[O:47])[CH2:8][C:9]1[CH:14]=[C:13]([C:15]([F:18])([F:17])[F:16])[CH:12]=[CH:11][C:10]=1[C:19]1[CH:24]=[C:23]([CH:25]([CH3:27])[CH3:26])[CH:22]=[CH:21][C:20]=1[O:28][CH3:29])(=[O:60])=[O:59]
Reactant: CS(=O)(=O)Cl
Reactant: COc1ccc(C(C)C)cc1-c1ccc(C(F)(F)F)cc1CN(CC(O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1)C(=O)OC(C)(C)C
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: COc1ccc(C(C)C)cc1-c1ccc(C(F)(F)F)cc1CN(CC(OS(C)(=O)=O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1)C(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 0.75 h

Procedure:
To a solution of tert-butyl{2-[3,5-bis(trifluoromethyl)phenyl]-2-hydroxyethyl}{[5′-isopropyl-2′-methoxy-4-(trifluoromethyl)biphenyl-2-yl]methyl}carbamate (350.1 mg, 0.516 mmol) in CH2Cl2 (15 mL) was added DIPEA (450 μL, 2.58 mmol). The solution was cooled to 0° C. and MsCl (100 μL, 1.29 mmol) was added. After 45 minutes of stirring at 0° C., the reaction was diluted with EtOAc (100 mL) and washed with saturated NaHCO3 (25 mL), brine (25 mL), 1N HCl (25 mL), and brine (2×25 mL). The organic layer was dried over Na2SO4, filtered, and concentrated. The residue was put through a short plug of silica gel with 25% EtOAc/hexanes and concentrated. The product, 1-[3,5-bis(trifluoromethyl)phenyl]-2-((tert-butoxycarbonyl){[5′-isopropyl-2′-methoxy-4-(trifluoromethyl)biphenyl-2-yl]methyl}amino)ethyl methanesulfonate, was used immediately in the next reaction without further characterization. Rf=0.33 (25% EtOAc/hexanes).
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[O:4][CH2:3][C@@H:2]1[C:11]1[CH:24]=[CH:23][C:14]([CH2:15][N:16]2[CH2:21][CH2:20][CH:19]([NH2:22])[CH2:18][CH2:17]2)=[CH:13][CH:12]=1.[Cl:25][CH2:26][CH2:27][CH2:28][S:29](Cl)(=[O:31])=[O:30].N1C=CC=CC=1>C1COCC1.C([O-])(O)=O.[Na+]>[O:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[O:4][CH2:3][C@@H:2]1[C:11]1[CH:12]=[CH:13][C:14]([CH2:15][N:16]2[CH2:17][CH2:18][CH:19]([NH:22][S:29]([CH2:28][CH2:27][CH2:26][Cl:25])(=[O:31])=[O:30])[CH2:20][CH2:21]2)=[CH:23][CH:24]=1
Reactant: O=S(=O)(Cl)CCCCl
Reactant: NC1CCN(Cc2ccc([C@H]3COc4ccccc4O3)cc2)CC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: O=S(=O)(CCCCl)NC1CCN(Cc2ccc([C@H]3COc4ccccc4O3)cc2)CC1
Reaction time: 18 h

Procedure:
To a stirred solution of compound 217 (535 mg, 1.65 mmol) in THF (10 mL) is added 3-chloro-propane-1-sulfonyl chloride (0.40 mL, 3.3 mmol) and pyridine (0.27 mL). After 18 h, the mixture is diluted with saturated NaHCO3 and extracted with EtOAc. The organic layer is dried over Na2SO4, filtered, and concentrated. The residue is purified by flash chromatography eluting with a gradient of 0-10% MeOH in DCM to provide 3-chloro-propane-1-sulfonic acid {1-[(S)-4-(2,3-dihydro-benzo[1,4]dioxin-2-yl)-benzyl]-piperidin-4-yl}-amide. LC/MS method 1: ES+ m/z 465.2 [M]+, Rt=0.68 min).
Reaction SMILES: [CH2:1]([NH2:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O)(=O)C.C([BH3-])#N.[Na+].[Cl:17][C:18]1[N:19]=[C:20]([C:25]([NH:27][CH:28]2[CH2:33][CH2:32][N:31]([C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[CH2:30][C:29]2=O)=[O:26])[NH:21][C:22]=1[CH2:23][CH3:24]>O1CCCC1.CO>[C:37]([O:36][C:34]([N:31]1[CH2:30][CH2:29][C@@H:28]([NH:27][C:25]([C:20]2[NH:21][C:22]([CH2:23][CH3:24])=[C:18]([Cl:17])[N:19]=2)=[O:26])[C@H:33]([NH:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH2:32]1)=[O:35])([CH3:40])([CH3:39])[CH3:38].[CH2:1]([NH:8][C@H:29]1[C@@H:28]([NH:27][C:25]([C:20]2[NH:21][C:22]([CH2:23][CH3:24])=[C:18]([Cl:17])[N:19]=2)=[O:26])[CH2:33][CH2:32][N:31]([C:34]([O:36][C:37]([CH3:38])([CH3:40])[CH3:39])=[O:35])[CH2:30]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCc1[nH]c(C(=O)NC2CCN(C(=O)OC(C)(C)C)CC2=O)nc1Cl
Reactant: NCc1ccccc1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: CCc1[nH]c(C(=O)N[C@@H]2CCN(C(=O)OC(C)(C)C)C[C@H]2NCc2ccccc2)nc1Cl
Product: CCc1[nH]c(C(=O)N[C@H]2CCN(C(=O)OC(C)(C)C)C[C@H]2NCc2ccccc2)nc1Cl
Temperature: 25 °C
Reaction time: 15 h
Yield: 41 %

Procedure:
Benzylamine (70 μL, 0.64 mmol), acetic acid (68.7 μL, 1.20 mmol) and sodium cyanoborohydride (42 mg, 0.667 mmol) were added to a mixed solution of tert-butyl 4-{[(4-chloro-5-ethyl-1H-imidazol-2-yl)carbonyl]amino}-3-oxopiperidine-1-carboxylate obtained in Example (201c) (99 mg, 0.267 mmol) in tetrahydrofuran (3 mL) and methanol (3 mL) under ice-cooling, and the mixture was stirred at room temperature for 15 hours. The reaction solution was concentrated under reduced pressure. Saturated aqueous sodium bicarbonate solution was added to the residue, followed by extraction with ethyl acetate. The resulting organic layer was washed with brine and dried over anhydrous sodium sulfate, and then the insoluble matter was separated by filtration. The filtrate was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (eluent: chloroform:methanol=10:1 v/v) to obtain 26 mg of the cis isomer of the title compound (21%) as a colorless solid and 50 mg of the trans isomer of the title compound (41%) as a colorless solid. cis-form