Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[Na+].S(O[CH:16]([CH:21]([CH3:24])[CH2:22][CH3:23])[C:17]([O:19][CH3:20])=[O:18])(C1C=CC(C)=CC=1)(=O)=O>CN(C=O)C>[N:1]([C@H:16]([C@@H:21]([CH3:24])[CH2:22][CH3:23])[C:17]([O:19][CH3:20])=[O:18])=[N+:2]=[N-:3]
Reactant: CCC(C)C(OS(=O)(=O)c1ccc(C)cc1)C(=O)OC
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC[C@H](C)[C@@H](N=[N+]=[N-])C(=O)OC
Reaction time: 24 h
Yield: 80.9 %

Procedure:
Sodium azide (1.20 g, 18.6 mmol) was added to a stirred solution of methyl 2-tosyloxy-3-methylpentanoate (3.29 g, 10.9 mmol) in DMF (30 mL). The solution was kept at 50° C. for 24 h, then partitioned between EtOAc and water. The aqueous layer was separated and extracted with EtOAc (3×50 mL). The combined organic layers were dried over MgSO4 and concentrated in vacuo to give a deep yellow oil (1.51 g, 81%), IR (neat) v 3500-3000 (very br m), 2970 (s), 2939 (br m), 2111 (s), 1736 (s), 1472 (w), 1387 (w), 1225 (br m), 1175 (w), 1086 (w), 732 (s) cm−1; 1H NMR (300 MHz, CDCl3) δ 0.93 (t, 3H), 0.97 (d, 3H), 1.22 & 1.43 (m, 1H), 1.96 (m, 1H), 3.78 (s, 3H), 3.85 (d, 2H); CIMS 172.1 (M+H).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([CH2:21][O:22][C:23]([C:25]3[S:26][C:27]([CH3:30])=[CH:28][CH:29]=3)=[O:24])=[C:10]3[C:15](=[CH:16][CH:17]=2)[NH:14][C:13]([CH3:19])([CH3:18])[CH:12]=[C:11]3[CH3:20])=[C:4]([O:31][CH3:32])[CH:3]=1.C(N(CC)CC)C.[N:40]1[CH:45]=[CH:44][CH:43]=[C:42]([N:46]=[C:47]=[O:48])[CH:41]=1>C(Cl)Cl>[CH3:32][O:31][C:4]1[CH:3]=[C:2]([O:1][C:47]([NH:46][C:42]2[CH:41]=[N:40][CH:45]=[CH:44][CH:43]=2)=[O:48])[CH:7]=[CH:6][C:5]=1[C:8]1[C:9]([CH2:21][O:22][C:23]([C:25]2[S:26][C:27]([CH3:30])=[CH:28][CH:29]=2)=[O:24])=[C:10]2[C:15](=[CH:16][CH:17]=1)[NH:14][C:13]([CH3:18])([CH3:19])[CH:12]=[C:11]2[CH3:20]
Reactant: O=C=Nc1cccnc1
Reactant: COc1cc(O)ccc1-c1ccc2c(c1COC(=O)c1ccc(C)s1)C(C)=CC(C)(C)N2
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1cc(OC(=O)Nc2cccnc2)ccc1-c1ccc2c(c1COC(=O)c1ccc(C)s1)C(C)=CC(C)(C)N2
Temperature: 25 °C
Reaction time: 3 h
Yield: 55.5 %

Procedure:
6-(4-Hydroxy-2-methoxyphenyl)-5-(5-methylthiophen-2-ylcarbonyloxymethyl)-2,2,4-trimethyl-1,2-dihydroquinoline (Reference Compound No. 3-2, 31.0 mg, 0.0690 mmol) was dissolved in anhydrous methylene dichloride (1 mL), triethylamine (27 μL, 0.19 mmol) and 3-pyridyl isocyanate (17.0 mg, 0.142 mmol) were added thereto, and then the mixture was stirred at room temperature for 3 hours. The reaction mixture was purified by silica gel column chromatography (hexane-ethyl acetate) to give the titled compound (21.8 mg) as a pale yellow amorphous product. (Yield 57%)
Reaction SMILES: [Cl-].[CH3:2][C:3]1([CH3:34])[C:11]2[C:6](=[CH:7][C:8]([CH2:12][P+](C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)=[CH:9][CH:10]=2)[C:5]([CH3:33])([CH3:32])[CH2:4]1.[CH2:35]([O:37][C:38]([C:40]1[CH:47]=[CH:46][C:43]([CH:44]=O)=[CH:42][CH:41]=1)=[O:39])[CH3:36]>>[CH2:35]([O:37][C:38](=[O:39])[C:40]1[CH:47]=[CH:46][C:43](/[CH:44]=[CH:12]/[C:8]2[CH:7]=[C:6]3[C:11](=[CH:10][CH:9]=2)[C:3]([CH3:34])([CH3:2])[CH2:4][C:5]3([CH3:33])[CH3:32])=[CH:42][CH:41]=1)[CH3:36]
Reactant: CC1(C)CC(C)(C)c2cc(C[P+](c3ccccc3)(c3ccccc3)c3ccccc3)ccc21
Reactant: CCOC(=O)c1ccc(C=O)cc1
Agent: [Cl-]
Product: CCOC(=O)c1ccc(/C=C/c2ccc3c(c2)C(C)(C)CC3(C)C)cc1

Procedure:
In a manner analogous to that described in Example 1, from [(1,1,3,3-tetramethyl-5-indanyl)methyl]-triphenylphosphonium chloride and 4-ethoxycarbonyl-benzaldehyde there can be obtained p-[(E)-2-(1,1,3,3-tetramethyl-5-indanyl)vinyl]-benzoic acid ethyl ester of melting point 151°-152° C.
Reaction SMILES: COC([CH:5]1[C:13](=[O:14])[C:9]2([CH2:12][CH2:11][CH2:10]2)[CH2:8][NH:7][C:6]1=[O:15])=O>C(#N)C.O>[CH2:12]1[C:9]2([C:13](=[O:14])[CH2:5][C:6](=[O:15])[NH:7][CH2:8]2)[CH2:10][CH2:11]1
Reactant: COC(=O)C1C(=O)NCC2(CCC2)C1=O
Solvent: CC#N
Solvent: O
Product: O=C1CC(=O)C2(CCC2)CN1

Procedure:
7,9-Dioxo-6-aza-spiro[3.5]nonane-8-carboxylic acid methyl ester (1.30 g, 6.2 mmol) in 30 ml acetonitrile/water (10:1) is refluxed for 1 hour. The reaction mixture is evaporated and the product purified by chromatography on silica. 1H-NMR (400 MHz; DMSO-d6): 8.02 (s, 1H), 3.40 (brs, 2H), 3.25 (s, 2H), 2.30-2.15 (m, 2H), 2.04-1.88 (m, 1H), 1.86-1.70 (m, 3H); LC-MS (m/z, ES+): 153 (MH+), retention time: 0.86 mins (LC-MS method 2)
Reaction SMILES: I[C:2]1[CH:7]=[N:6][CH:5]=[CH:4][N:3]=1.[Li]CCCC.[CH:13](=[O:18])[CH2:14][CH:15]([CH3:17])[CH3:16].[NH4+].[Cl-]>C(OCC)C>[CH3:16][CH:15]([CH3:17])[CH2:14][CH:13]([C:2]1[CH:7]=[N:6][CH:5]=[CH:4][N:3]=1)[OH:18]
Reactant: Ic1cnccn1
Reactant: CC(C)CC=O
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CCOCC
Product: CC(C)CC(O)c1cnccn1

Procedure:
To a solution of 2-iodopyrazine (10.0 g, 48.5 mmol) in diethyl ether at −50° C. was added dropwise n-BuLi (2.5 M in hexanes, 25 mL, 60.7 mmol), immediately followed by addition of isovaleraldehyde (8.13 mL, 6.48 g, 75 mmol) over 5 minutes. The mixture was allowed to reach room temperature and was added to a saturated NH4Cl solution. The aqueous phase was extracted with TBME (3×100 mL) and the combined organic extracts were washed with brine, dried over MgSO4 and concentrated in vacuo. The resulting oil was filtered over a plug of silica to afford 3-methyl-1-(pyrazin-2-yl)butan-1-ol as a yellow-brownish oil (5.5 g; 68%).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:13]=[C:12]([OH:14])[C:11]([Cl:15])=[C:10]([CH3:16])[N:9]=2)=[N:6][CH:7]=1.[H-].[Na+].[CH2:19](Br)[CH:20]=[CH2:21]>CN(C=O)C>[CH2:21]([O:14][C:12]1[C:11]([Cl:15])=[C:10]([CH3:16])[N:9]=[C:8]([C:5]2[N:6]=[CH:7][C:2]([NH2:1])=[CH:3][CH:4]=2)[N:13]=1)[CH:20]=[CH2:19]
Reactant: C=CCBr
Reactant: Cc1nc(-c2ccc(N)cn2)nc(O)c1Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C=CCOc1nc(-c2ccc(N)cn2)nc(C)c1Cl
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of compound of example 16 (0.275 g, 1.1620 mmol) in DMF (3 mL) at 0° C., was added NaH (0.046 g, 1.1620 mmol) and allyl bromide (0.14 g, 1016 mmol) slowly and the reaction mixture was stirred at 25° C. for 4 hours. DMF was removed under vacuum, and the reaction mass quenched by water, extracted with ethyl acetate (3×20 mL), dried over sodium sulfate and concentrated to obtain the crude product, which was purified by column chromatography using silica gel and 8% methanol in chloroform as an eluent to obtain the title compound.
Reaction SMILES: C[Si](C)(C(C)(C)C)[O:3][CH2:4][C:5]1[CH:24]=[CH:23][C:8]2[N:9]([CH2:14][C:15]3[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=3)[C:10](=[O:13])[CH2:11][O:12][C:7]=2[CH:6]=1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1>[OH:3][CH2:4][C:5]1[CH:24]=[CH:23][C:8]2[N:9]([CH2:14][C:15]3[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=3)[C:10](=[O:13])[CH2:11][O:12][C:7]=2[CH:6]=1
Reactant: COc1ccc(CN2C(=O)COc3cc(CO[Si](C)(C)C(C)(C)C)ccc32)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: COc1ccc(CN2C(=O)COc3cc(CO)ccc32)cc1
Reaction time: 8 h

Procedure:
A solution of 7-(dimethyl-t-butylsilyl)oxymethyl-4-p-methoxybenzyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazine in tetrahydrofuran is treated with a solution of tetrabutylammonium fluoride in tetrahydrofuran and the reaction mixture left standing overnight. The solvent is evaporated, the residue is treated with aqueous hydrochloric acid and extracted with dichloromethane. The organic phase is washed with a solution of sodium bicarbonate, brine and then dried on sodium sulfate. Evaporation of the solvent and filtration through a small pad of silica gel yields the pure 7-hydroxymethyl-4-p-methoxybenzyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazine. To a solution of 7-hydroxymethyl-4-p-methoxybenzyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazine in dichloromethane is added triphenylphosphine and carbonium tetrabromide. Then a solution of diethyl azodicarboxylate in dichloromethane is added dropwise and the reaction mixture stirred at room temperature for 6 hours. The solvent is evaporated and the product isolated by flash chromatography.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:25])=[C:6]([CH:24]=1)[NH:7][C:8]1[CH:13]=[C:12]([C:14]([F:17])([F:16])[F:15])[N:11]=[C:10]([C:18]2[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=2)[N:9]=1.[C:26]1([CH3:35])[CH:31]=[CH:30][C:29]([C:32](Cl)=[O:33])=[CH:28][CH:27]=1.O>N1C=CC=CC=1>[CH3:35][C:26]1[CH:31]=[CH:30][C:29]([C:32]([NH:1][C:2]2[CH:3]=[CH:4][C:5]([CH3:25])=[C:6]([NH:7][C:8]3[CH:13]=[C:12]([C:14]([F:16])([F:17])[F:15])[N:11]=[C:10]([C:18]4[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=4)[N:9]=3)[CH:24]=2)=[O:33])=[CH:28][CH:27]=1
Reactant: Cc1ccc(N)cc1Nc1cc(C(F)(F)F)nc(-c2ccncc2)n1
Reactant: Cc1ccc(C(=O)Cl)cc1
Solvent: O
Solvent: c1ccncc1
Product: Cc1ccc(C(=O)Nc2ccc(C)c(Nc3cc(C(F)(F)F)nc(-c4ccncc4)n3)c2)cc1
Temperature: 25 °C
Reaction time: 15 h
Yield: 94 %

Procedure:
A mixture of 4-(5-amino-2-methylanilino)-2-(4-pyridinyl)-6-(trifluoromethyl)pyrimidine (20 mg, 0.058 mmol) and p-toluoyl chloride in pyridine (5 ml) was stirred at room temperature for 15 h. Then water was added to the mixture. The resulting precipitate was filtered, washed with excess water and dried to give a tan solid (26 mg, 94%). 1H NMR (CDCl3): 8.77 (dd, J=1.8, 4.5 Hz, 2H), 8.29 (dd, J=1.8, 4.5 Hz, 2H), 8.00 (s, 1H), 7.83 (s, 1H), 7.78 (d, J=8.1 Hz, 2H), 7.38 (dd, J=2.1, 8.4 Hz, 1H), 7.34 (s, 1H), 7.31 (d, J=7.5 Hz, 2H), 7.01 (s, 1H), 6.73 (s, 1H), 2.44 (s, 3H), 2.29 (s, 3H).
Reaction SMILES: [CH2:1]([O:4][C:5]1([CH3:52])[CH2:10][CH2:9][N:8]([C:11]2[N:16]3[CH:17]=[C:18]([C:20]4[CH:21]=[C:22]([C:26]5[C:31]([O:32][C@H:33]([CH2:35]C=C)[CH3:34])=[CH:30][C:29]([F:38])=[CH:28][C:27]=5[F:39])[CH:23]=[CH:24][CH:25]=4)[N:19]=[C:15]3[C:14]([CH3:40])=[C:13]([CH3:41])[C:12]=2[C@H:42]([O:47][C:48]([CH3:51])([CH3:50])[CH3:49])[C:43]([O:45][CH3:46])=[O:44])[CH2:7][CH2:6]1)[CH:2]=[CH2:3].C(O[C@@H](C1C(C)=CC2=NC3=CN2C=1N1CCC(C)(OCC=CC[C@H](C)OC2C=C(F)C=CC=2C2C=C3C=CC=2)CC1)C(OC)=O)(C)(C)C>>[C:48]([O:47][C@@H:42]([C:12]1[C:13]([CH3:41])=[C:14]([CH3:40])[C:15]2=[N:19][C:18]3=[CH:17][N:16]2[C:11]=1[N:8]1[CH2:9][CH2:10][C:5]([CH3:52])([O:4][CH2:1][CH:2]=[CH:3][CH2:34][C@H:33]([CH3:35])[O:32][C:31]2[CH:30]=[C:29]([F:38])[CH:28]=[C:27]([F:39])[C:26]=2[C:22]2[CH:21]=[C:20]3[CH:25]=[CH:24][CH:23]=2)[CH2:6][CH2:7]1)[C:43]([O:45][CH3:46])=[O:44])([CH3:50])([CH3:51])[CH3:49]
Reactant: C=CCOC1(C)CCN(c2c([C@H](OC(C)(C)C)C(=O)OC)c(C)c(C)c3nc(-c4cccc(-c5c(F)cc(F)cc5O[C@@H](C)CC=C)c4)cn23)CC1
Agent: COC(=O)[C@@H](OC(C)(C)C)c1c(C)c(C)c2nc3cn2c1N1CCC(C)(CC1)OC/C=C\C[C@H](C)Oc1cc(F)cc(F)c1-c1cccc-3c1
Agent: COC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2nc3cn2c1N1CCC(C)(CC1)OCC=CC[C@H](C)Oc1cc(F)ccc1-c1cccc-3c1
Product: COC(=O)[C@@H](OC(C)(C)C)c1c(C)c(C)c2nc3cn2c1N1CCC(C)(CC1)OCC=CC[C@H](C)Oc1cc(F)cc(F)c1-c1cccc-3c1

Procedure:
Prepared in 85% yield from (S)-methyl 2-(5-(4-(allyloxy)-4-methylpiperidin-1-yl)-2-(2′,4′-difluoro-6′-((S)-pent-4-en-2-yloxy)-[1,1′-biphenyl]-3-yl)-7,8-dimethylimidazo[1,2-a]pyridin-6-yl)-2-(tert-butoxy)acetate following the procedure for methyl(2S)-2-(tert-butoxy)-2-[(22S)-18-fluoro-4,22,28-trimethyl-21,27-dioxa-1,7,34-triazahexacyclo[26.2.2.16,9.110,14.02,7.015,20]tetratriaconta-2,4,6(34),8,10(33),11,13,15(20),16,18,24-undecaen-3-yl]acetate. LCMS (ESI, M+1): 688.4.
Reaction SMILES: C[O:2][C:3](=O)[CH2:4][NH:5][C:6](=[O:37])[C:7]1[CH:12]=[C:11]([Cl:13])[C:10]([O:14][C:15]2[CH:20]=[CH:19][N:18]=[CH:17][C:16]=2[C:21]([N:23]2[C:32]3[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=3)[N:26]([CH:33]3[CH2:35][CH2:34]3)[CH2:25][CH2:24]2)=[O:22])=[CH:9][C:8]=1[Cl:36].NCCO>>[Cl:36][C:8]1[CH:9]=[C:10]([O:14][C:15]2[CH:20]=[CH:19][N:18]=[CH:17][C:16]=2[C:21]([N:23]2[C:32]3[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=3)[N:26]([CH:33]3[CH2:35][CH2:34]3)[CH2:25][CH2:24]2)=[O:22])[C:11]([Cl:13])=[CH:12][C:7]=1[C:6]([NH:5][CH2:4][CH2:3][OH:2])=[O:37]
Reactant: COC(=O)CNC(=O)c1cc(Cl)c(Oc2ccncc2C(=O)N2CCN(C3CC3)c3ccccc32)cc1Cl
Solvent: NCCO
Product: O=C(NCCO)c1cc(Cl)c(Oc2ccncc2C(=O)N2CCN(C3CC3)c3ccccc32)cc1Cl
Yield: 60 %

Procedure:
The title compound was prepared in analogy to Example 1, from 2,5-dichloro-4-[3-(4-cyclopropyl-3,4-dihydro-2H-quinoxaline-1-carbonyl)-pyridin-4-yloxy]-benzoic acid (Example 29, intermediate) and 2-amino-ethanol (commercially available, CAS RN 141-43-5). The product was purified on a preparative HPLC system (Phenomenex Gemini column) using a gradient of acetonitrile:water (containing 0.05% formic acid) (10:90 to 98:2) to give the desired compound as a light brown foam (60%). MS (ESI): m/z=527.124 [M+H]+.
Reaction SMILES: Cl.[NH2:2][CH:3]([CH2:6][OH:7])[CH2:4][OH:5].[NH2:8][C:9]1[N:17]=[C:16]2[C:12]([N:13]=[CH:14][N:15]2[C@@H:18]2[CH2:22][C@H:21]([CH2:23][OH:24])[CH:20]=[CH:19]2)=[C:11](Cl)[N:10]=1.[OH-].[Na+]>CO>[NH2:8][C:9]1[N:17]=[C:16]2[C:12]([N:13]=[CH:14][N:15]2[C@@H:18]2[CH2:22][C@H:21]([CH2:23][OH:24])[CH:20]=[CH:19]2)=[C:11]([NH:2][CH:3]([CH2:6][OH:7])[CH2:4][OH:5])[N:10]=1
Reactant: NC(CO)CO
Reactant: Nc1nc(Cl)c2ncn([C@H]3C=C[C@@H](CO)C3)c2n1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Nc1nc(NC(CO)CO)c2ncn([C@H]3C=C[C@@H](CO)C3)c2n1
Temperature: 80 °C
Reaction time: 8 h

Procedure:
A solution of serinol hydrochloride (0.765 g, 6.00 mmol) in methanol (20 mL) was stirred with basic ion exchange resin for 10 minutes. The resin was filtered off and the filtrate concentrated to a colorless oil. To this was added (±)-cis-4-(2-amino-6-chloro-9H-purin-9-yl)-2-cyclopentene-1-methanol (0.544 g, 2.00 mmol) and methanol (10 mL). The resulting solution was stirred in a Parr bomb at 80° C. overnight. 1N NaOH (2 mL) was added and the solvent evaporated. The residue was chromatrographed on silica gel. Title compound eluted with 20% methanol-chloroform; white powder after crystallization from acetonitrile-methanol (0.404 g, 63%), m.p. 160-162° C.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH3:19])[N:9]=[C:10]([C:11]3[O:12][C:13]([N+:16]([O-:18])=[O:17])=[CH:14][CH:15]=3)[C:3]=12.[OH:20]O>C(O)(=O)C>[NH2:1][C:2]1[N+:7]([O-:20])=[CH:6][N:5]=[C:4]2[N:8]([CH3:19])[N:9]=[C:10]([C:11]3[O:12][C:13]([N+:16]([O-:18])=[O:17])=[CH:14][CH:15]=3)[C:3]=12
Reactant: Cn1nc(-c2ccc([N+](=O)[O-])o2)c2c(N)ncnc21
Reactant: OO
Solvent: CC(=O)O
Product: Cn1nc(-c2ccc([N+](=O)[O-])o2)c2c(N)[n+]([O-])cnc21
Reaction time: 72 h

Procedure:
A mixture of 2.0 grams of 4-amino-1-methyl-3-(5-nitro-2-furyl)-1H-pyrazolo[3,4-d]pyrimidine dissolved in 100 milliliters of glacial acetic acid and 10 milliliters of 30 % w/v hydrogen peroxide solution (100 volumes) was allowed to stand at room temperature for 3 days. The reaction mixture was evaporated to dryness and the solid product was collected, washed with acetic acid and dried. Recrystallisation from water gave 4-amino-1-methyl-3-(5-nitro-2-furyl)-1H-pyrazolo[3,4-d]pyrimidin-5-oxide, having melting point 285°C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:6]([CH:7]=O)=[CH:5][CH:4]=1.[S:11]1[CH2:15][C:14](=[O:16])[NH:13][C:12]1=[O:17].N1CCCCC1>C(O)C>[CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:6]([CH:7]=[C:15]2[S:11][C:12](=[O:17])[NH:13][C:14]2=[O:16])=[CH:5][CH:4]=1
Reactant: COc1ccc(C=O)cc1
Reactant: O=C1CSC(=O)N1
Solvent: C1CCNCC1
Solvent: CCO
Product: COc1ccc(C=C2SC(=O)NC2=O)cc1
Yield: 31.7 %

Procedure:
4-Methoxybenzaldehyde (20.4 g, 150 mmol), thiazolidine-2,4-dione (21.1 g, 180 mmol), piperidine (12.8 g, 150 mmol) and ethanol (150 mL) were mixed and refluxed for 18 hours. After allowed to stand for cooling, the precipitated crystals were collected by filtration. These were washed with ethanol, and then dried to obtain 11.2 g (32%) of the title compound as yellow crystals. Moreover, the filtrate was made acidic with concentrated hydrochloric acid, and the precipitated crystals were collected by filtration, washed with ethanol and water, and then dried to additionally obtain 18.1 g (51%, totally 83%) of the title compound as yellow crystals.
Reaction SMILES: [ClH:1].C(OC([N:9]1[CH2:14][CH2:13][CH:12]([CH2:15][CH2:16][CH2:17][CH2:18][C@H:19]([NH:25][C@H:26]2[CH2:32][S:31][C@H:30]([C:33]3[S:34][CH:35]=[CH:36][CH:37]=3)[CH2:29][N:28]([CH2:38][C:39]([O:41]C(C)(C)C)=[O:40])[C:27]2=[O:46])[C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH2:11][CH2:10]1)=O)(C)(C)C>O1CCOCC1>[ClH:1].[ClH:1].[CH2:23]([O:22][C:20]([C@@H:19]([NH:25][C@H:26]1[CH2:32][S:31][C@H:30]([C:33]2[S:34][CH:35]=[CH:36][CH:37]=2)[CH2:29][N:28]([CH2:38][C:39]([OH:41])=[O:40])[C:27]1=[O:46])[CH2:18][CH2:17][CH2:16][CH2:15][CH:12]1[CH2:13][CH2:14][NH:9][CH2:10][CH2:11]1)=[O:21])[CH3:24]
Reactant: CCOC(=O)[C@H](CCCCC1CCN(C(=O)OC(C)(C)C)CC1)N[C@H]1CS[C@H](c2cccs2)CN(CC(=O)OC(C)(C)C)C1=O
Agent: Cl
Solvent: C1COCCO1
Product: CCOC(=O)[C@H](CCCCC1CCNCC1)N[C@H]1CS[C@H](c2cccs2)CN(CC(=O)O)C1=O
Reaction time: 8 h

Procedure:
2 ml of a 4N solution of hydrochloric acid in dioxane were added to 264 mg of t-butyl α-{6(R)[5-(1-t-butoxycarbonyl-4-piperidyl)-1(S)-ethoxycarbonylpentylamino]-5-oxo-2(S)-(2-thienyl)perhydro-1,4-thiazepin-4-yl}acetate (prepared as described in Example 18), and the mixture was allowed to stand at room temperature overnight. The solvent was then removed from the reaction mixture by evaporation under reduced pressure, and the residue was pulverized in diethyl ether and collected by filtration, to afford 208 mg of the title compound.
Reaction SMILES: C([O-])=O.[NH4+].[C:5]([C:9]1[CH:10]=[C:11]([N+:25]([O-])=O)[C:12]([O:23][CH3:24])=[C:13]([S:15]([NH:18][C:19]([CH3:22])([CH3:21])[CH3:20])(=[O:17])=[O:16])[CH:14]=1)([CH3:8])([CH3:7])[CH3:6]>[Pd].CO>[C:5]([C:9]1[CH:10]=[C:11]([NH2:25])[C:12]([O:23][CH3:24])=[C:13]([S:15]([NH:18][C:19]([CH3:22])([CH3:21])[CH3:20])(=[O:16])=[O:17])[CH:14]=1)([CH3:8])([CH3:6])[CH3:7]
Reactant: COc1c([N+](=O)[O-])cc(C(C)(C)C)cc1S(=O)(=O)NC(C)(C)C
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CO
Product: COc1c(N)cc(C(C)(C)C)cc1S(=O)(=O)NC(C)(C)C
Yield: 94.5 %

Procedure:
Ammonium formate (8.0 g) was added to a stirred and cooled mixture of 5-t-butyl-2-methoxy-3-nitrophenyl N-t-butyl-sulfonamide (8.0 g) and 10% Palladium on charcoal (1.1 g) in dry methanol (80 ml) under nitrogen. The mixture was stirred at ambient temperature for 1 hour and then filtered through diatomaceous earth. The filtrate was concentrated and taken up into a mixture of ethyl acetate and water. The organic layer was separated and dried over sodium sulphate. After removal of solvent and recrystallization from aqueous ethanol the title compound was obtained as white crystals (6.9 g).
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[O:13][N:12]=[CH:11][C:10]=2[C:14]([OH:16])=O)=[CH:5][CH:4]=1.[B-](F)(F)(F)F.CN(C(ON1N=NC2C1=CC=CC=2)=[N+](C)C)C.N1C=CC=CC=1.Cl.Cl.Cl.[NH:50]1[CH2:54][CH2:53][CH:52]([C:55]2[CH:60]=[N:59][CH:58]=[CH:57][N:56]=2)[CH2:51]1>C(#N)C>[F:17][C:2]([F:1])([F:18])[C:3]1[CH:4]=[CH:5][C:6]([C:9]2[O:13][N:12]=[CH:11][C:10]=2[C:14]([N:50]2[CH2:54][CH2:53][CH:52]([C:55]3[CH:60]=[N:59][CH:58]=[CH:57][N:56]=3)[CH2:51]2)=[O:16])=[CH:7][CH:8]=1
Reactant: c1cnc(C2CCNC2)cn1
Reactant: O=C(O)c1cnoc1-c1ccc(C(F)(F)F)cc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CC#N
Solvent: c1ccncc1
Product: O=C(c1cnoc1-c1ccc(C(F)(F)F)cc1)N1CCC(c2cnccn2)C1
Temperature: 60 °C
Reaction time: 0.5 h
Yield: 55.8 %

Procedure:
5-[4-(Trifluoromethyl)phenyl]isoxazole-4-carboxylic acid (30 mg, 0.12 mmol) was dissolved in acetonitrile (1.5 mL) followed by the addition of o-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate (TBTU) (52 mg, 0.16 mmol), pyridine (60 μL, 0.72 mmol) and 2-pyrrolidin-3-yl-pyrazine trihydrochloride (36 mg, 0.14 mmol), and stirred at 60° C. for 30 min. The residue was purified on reversed phase HPLC to yield the title compound (26 mg). HRMS (ESI, pos. ion) m/z calcd for C19H15F3N4O2: 388.1147, found 388.1152.
Reaction SMILES: [N+](C1C=CC(O[C:11](=[O:36])/[CH:12]=[CH:13]/[CH:14]=[C:15]([C:26]2[CH:31]=[CH:30][CH:29]=[C:28]([C:32]([F:35])([F:34])[F:33])[CH:27]=2)[C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([C:22]([F:25])([F:24])[F:23])[CH:17]=2)=CC=1)([O-])=O.[N:37]1[CH:42]=[CH:41][CH:40]=[C:39]([CH2:43][CH2:44][CH2:45][CH2:46][NH2:47])[CH:38]=1>O1CCCC1>[F:24][C:22]([F:25])([F:23])[C:18]1[CH:17]=[C:16]([C:15]([C:26]2[CH:31]=[CH:30][CH:29]=[C:28]([C:32]([F:33])([F:35])[F:34])[CH:27]=2)=[CH:14]/[CH:13]=[CH:12]/[C:11]([NH:47][CH2:46][CH2:45][CH2:44][CH2:43][C:39]2[CH:38]=[N:37][CH:42]=[CH:41][CH:40]=2)=[O:36])[CH:21]=[CH:20][CH:19]=1
Reactant: O=C(/C=C/C=C(c1cccc(C(F)(F)F)c1)c1cccc(C(F)(F)F)c1)Oc1ccc([N+](=O)[O-])cc1
Reactant: NCCCCc1cccnc1
Solvent: C1CCOC1
Product: O=C(/C=C/C=C(c1cccc(C(F)(F)F)c1)c1cccc(C(F)(F)F)c1)NCCCCc1cccnc1
Yield: 65.2 %

Procedure:
As in Example 134, a solution of (E)-5,5-bis[3-(trifluoromethyl)phenyl]-2,4-pentadienoic acid 4-nitrophenyl ester (4.8 g) and 3-pyridinebutanamine (1.5 g) in tetrahydrofuran (20 mL) was stirred for 2 hours at room temperature and was then worked up in the usual manner. The crude product was purified by HPLC (ethyl acetate) and then crystallized from ether-hexane to afford 3.2 g of (E)-5,5-bis[3-(trifluoromethyl)phenyl]-N-[4-(3-pyridinyl)butyl]-2,4-pentadienamide mp 89°-90° C.
Reaction SMILES: Br[C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][N:7]([C@@H:12]3[CH2:17][CH2:16][CH2:15][CH2:14][C@H:13]3[OH:18])[C:8]2=[O:11])=[CH:4][CH:3]=1.[Cl-].[Cl:20][C:21]1[N:26]=[CH:25][C:24]([CH2:27][Zn+])=[CH:23][CH:22]=1.C(=O)(O)[O-].[Na+].C(OCC)(=O)C>C1COCC1.CC(C)([P](C(C)(C)C)([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)C(C)(C)C)C>[Cl:20][C:21]1[N:26]=[CH:25][C:24]([CH2:27][C:2]2[CH:10]=[C:9]3[C:5]([CH2:6][N:7]([C@@H:12]4[CH2:17][CH2:16][CH2:15][CH2:14][C@H:13]4[OH:18])[C:8]3=[O:11])=[CH:4][CH:3]=2)=[CH:23][CH:22]=1
Reactant: O=C1c2cc(Br)ccc2CN1[C@@H]1CCCC[C@H]1O
Reactant: Clc1ccc(C[Zn+])cn1
Agent: CC(C)(C)[P]([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)(C(C)(C)C)C(C)(C)C
Agent: O=C([O-])O
Agent: [Cl-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: O=C1c2cc(Cc3ccc(Cl)nc3)ccc2CN1[C@@H]1CCCC[C@H]1O
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of rac-6-bromo-2-(trans-2-hydroxycyclohexyl)isoindolin-1-one (0.23 g) in THF (3.0 mL) were added ((6-chloropyridin-3-yl)methyl)zinc(II) chloride (3.66 mL) and bis(tri-tert-butylphosphine)palladium(0) (0.07 g) under ice-cooling, and the mixture was stirred at room temperature for 3 hr under argon atmosphere. To the reaction mixture were added 5% aqueous sodium bicarbonate and ethyl acetate, the mixture was stirred, and the insoluble substance was removed by filtration. The filtrate was extracted with ethyl acetate, the organic layer was washed with saturated brine, and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (0.15 g).