Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]2[CH:11]=[C:12]3[C:16](=[CH:17][CH:18]=2)[NH:15][CH:14]=[C:13]3[C:19]2[CH2:24][CH2:23][N:22]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:21][CH:20]=2)=[C:5]([N+:32]([O-])=O)[CH:4]=1)#[N:2].[CH2:35](OC=C(C#N)C#N)C.C(OCC)(=O)C>C(Cl)Cl>[C:1]([C:3]1[CH:8]=[CH:7][C:6]2[N:9]([C:10]3[CH:11]=[C:12]4[C:16](=[CH:17][CH:18]=3)[NH:15][CH:14]=[C:13]4[CH:19]3[CH2:24][CH2:23][N:22]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:21][CH2:20]3)[CH:35]=[N:32][C:5]=2[CH:4]=1)#[N:2]
Reactant: CCOC=C(C#N)C#N
Reactant: CC(C)(C)OC(=O)N1CC=C(c2c[nH]c3ccc(Nc4ccc(C#N)cc4[N+](=O)[O-])cc23)CC1
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC(c2c[nH]c3ccc(-n4cnc5cc(C#N)ccc54)cc23)CC1
Yield: 10 %

Procedure:
5-(4-Cyano-2-nitrophenyl)amino-3-(N-t-butoxycarbonyl-1,2,5,6-tetrahydropyrid-4-yl)-1H-indole was used. Reduction was by catalytic hydrogenation, the cyclization reaction used ethoxymethylene malononitrile, and the cyclization reaction was heated for 48 hours. Chromatography using 10% ethyl acetate in methylene chloride afforded the title compound (10%) as a brown foam: Rf =0.2 in 10% ethyl acetate in methylene chloride; HRMS calculated for C26H27N5O2 441.2167, found 441.2169.
Reaction SMILES: C1(C2OC(C)=C(COC3C=CC(CO[C:20]4[C:24]([CH:25]=O)=[CH:23][N:22]([C:27]5[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=5)[N:21]=4)=CC=3)N=2)C=CC=CC=1.Cl.NO.[N:39]1C=CC=CC=1.C(O)C>O>[C:27]1([N:22]2[CH:23]=[C:24]([C:25]#[N:39])[CH:20]=[N:21]2)[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: c1ccncc1
Reactant: Cc1oc(-c2ccccc2)nc1COc1ccc(COc2nn(-c3ccccc3)cc2C=O)cc1
Agent: Cl
Agent: NO
Solvent: O
Solvent: CCO
Product: N#Cc1cnn(-c2ccccc2)c1
Yield: 137.6 %

Procedure:
A mixture of 3-[{4-[(2-phenyl-5-methyl-1,3-oxazol-4-yl)methoxy]benzyl}oxy]-1-phenyl-1H-pyrazole-4-carbaldehyde (0.70 g), hydroxylamine hydrochloride (0.16 g), pyridine (0.30 g) and ethanol (30 mL) was heated under reflux for 2 hrs. Water was poured into the reaction mixture, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated. Acetic anhydride (20 mL) was added to residue, and the mixture was heated under reflux for 2 hrs. The reaction mixture was concentrated and ethyl acetate was added to the residue. The ethyl acetate layer was washed successively with water and saturated brine, dried over anhydrous magnesium sulfate and concentrated. The residue was subjected to silica gel column chromatography to give 3-({4-[(2-phenyl-5-methyl-1,3-oxazol-4-yl)methoxy]benzyl}oxy)}-1-phenyl-1H-pyrazole-4-carbonitrile as colorless crystals (0.35 g, 51%) from a fraction eluted with ethyl acetate-hexane (1:1, v/v). Recrystallization from ethyl acetate-hexane gave colorless prism crystals. melting point: 162-163° C.
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:8][CH:7]=[CH:6][C@@H:5]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[N:4]([CH:15]2[CH2:19][CH2:18][CH2:17][CH2:16]2)[C:3]1=[O:20].[F:21][C:22]1[CH:23]=[C:24]([CH2:29][C:30]([NH:32][C@H:33]([C:35](O)=[O:36])[CH3:34])=[O:31])[CH:25]=[C:26]([F:28])[CH:27]=1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.CN1CCOCC1>C(Cl)Cl>[CH:15]1([N:4]2[C@H:5]([C:9]3[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=3)[CH:6]=[CH:7][CH2:8][C@@H:2]([NH:1][C:35](=[O:36])[C@H:33]([CH3:34])[NH:32][C:30](=[O:31])[CH2:29][C:24]3[CH:25]=[C:26]([F:28])[CH:27]=[C:22]([F:21])[CH:23]=3)[C:3]2=[O:20])[CH2:19][CH2:18][CH2:17][CH2:16]1
Reactant: C[C@H](NC(=O)Cc1cc(F)cc(F)c1)C(=O)O
Reactant: N[C@@H]1CC=C[C@@H](c2ccccc2)N(C2CCCC2)C1=O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: C[C@H](NC(=O)Cc1cc(F)cc(F)c1)C(=O)N[C@@H]1CC=C[C@@H](c2ccccc2)N(C2CCCC2)C1=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of (3R,7S)-3-amino-1-cyclopentyl-7-phenyl-1,3,4,7-tetrahydro-2H-azepin-2-one (8f) (65 mg) in DCM (4 ml) at RT under N2 was added N-[(3,5-difluorophenyl)acetyl]-L-alanine (59 mg), HOBt (65 mg), EDAC.HCl (69 mg), and N-methylmorpholine (24 mg). The reaction was stirred at RT overnight, then diluted with DCM (10 ml) and washed with 1N HCl, 1N K2CO3, dried (Na2SO4), filtered and evaporated. The crude product was purified by flash chromatography (2% MeOH/DCM) to afford the title compound as an off white solid (60 mg, 50%). 1H NMR (300 MHz, CDCl3) δ 1.28 (d, 3H, J=7 Hz), 1.37-1.70 (m, 6H), 1.94-2.16 (m, 3H), 2.50-2.60 (m, 1H), 3.48 (s, 2H), 4.36-4.55 (m, 2H), 4.96 (d, 1H, J=8 Hz), 5.20 (tt, 1H, J=9 Hz, J=9 Hz), 5.87-5.94 (m, 1H), 6.18-6.33 (m, 2H), 6.67-6.80 (m, 3H), 7.00 (d, 1H, J=6 Hz), 7.25-7.38 (m, 5H). MS APCI, m/z=496 (M+1), LC/MS, 2.54 min.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][N:24]=[C:23]([CH3:26])[C:22]=4[NH2:27])=[CH:17][CH:16]=3)=[CH:11][CH:10]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2].Br[C:29]1[CH:30]=[N:31][CH:32]=[C:33]([C:35]2[CH:40]=[CH:39][CH:38]=[C:37]([F:41])[CH:36]=2)[CH:34]=1>>[CH2:1]([O:3][C:4]([C:6]1([C:9]2[CH:10]=[CH:11][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][N:24]=[C:23]([CH3:26])[C:22]=4[NH:27][C:29]4[CH:30]=[N:31][CH:32]=[C:33]([C:35]5[CH:40]=[CH:39][CH:38]=[C:37]([F:41])[CH:36]=5)[CH:34]=4)=[CH:17][CH:16]=3)=[CH:13][CH:14]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4N)cc3)cc2)CC1
Reactant: Fc1cccc(-c2cncc(Br)c2)c1
Product: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4Nc4cncc(-c5cccc(F)c5)c4)cc3)cc2)CC1

Procedure:
Prepared according to the procedure described in Example 68, Step 2, using 1-[4′-(4-amino-3-methyl-isoxazol-5-yl)-biphenyl-4-yl]-cyclopropanecarboxylic acid ethyl ester and 3-bromo-5-(3-fluoro-phenyl)-pyridine.
Reaction SMILES: Cl([O-])(=O)(=O)=O.[CH2:6]([C:8]1[C:12]2[C:13]([F:17])=[CH:14][CH:15]=[CH:16][C:11]=2[S:10][C:9]=1[C:18]1[C:30]2[C:22](=[CH:23][C:24]3[NH:25][C:26](=[O:31])[O:27][C:28]=3[CH:29]=2)[CH:21]=[C:20]([CH3:32])[O+]=1)[CH3:7].C(C1C2C(F)=CC=CC=2SC=1C=O)C.O.[NH2:48][NH2:49]>CC(O)C>[CH2:6]([C:8]1[C:12]2[C:13]([F:17])=[CH:14][CH:15]=[CH:16][C:11]=2[S:10][C:9]=1[C:18]1[C:30]2[CH:29]=[C:28]3[O:27][C:26](=[O:31])[NH:25][C:24]3=[CH:23][C:22]=2[CH2:21][C:20]([CH3:32])=[N:49][N:48]=1)[CH3:7]
Reactant: NN
Reactant: CCc1c(-c2[o+]c(C)cc3cc4[nH]c(=O)oc4cc23)sc2cccc(F)c12
Agent: CCc1c(C=O)sc2cccc(F)c12
Agent: [O-][Cl+3]([O-])([O-])[O-]
Solvent: O
Solvent: CC(C)O
Product: CCc1c(C2=NN=C(C)Cc3cc4[nH]c(=O)oc4cc32)sc2cccc(F)c12
Temperature: 25 °C
Reaction time: 20 h

Procedure:
To a suspension of 5-(3-ethyl-4-fluoro-1-benzothien-2-yl)-7-methyl-2-oxo-1H,2H-isochromeno[6,7-d][1,3]oxazol-6-ium perchlorate (51 mmol) (obtained according to Steps A and B described in Example 1 using 3-ethyl-4-fluoro-1-benzothiophene-2-carbaldehyde instead of 2-naphthaldehyde) in 2-propanol (468 mL) there is added hydrazine hydrate (6.68 mL; 133 mmol), with vigorous stirring, at ambient temperature. The reaction mixture is stirred for 20 hours at ambient temperature. The crystals obtained are then filtered off and then stirred in warm water (1900 mL) for 30 minutes. After filtration and drying, the solid is purified by chromatography over a silica gel column (eluant: dichloromethane/acetonitrile) to yield the title product.
Reaction SMILES: [N:1]([C@@H:4]1[CH2:9][C@H:8]2[C@H:10]3[C@H:19]([CH2:20][CH2:21][C@:6]2([CH3:7])[C@H:5]1[OH:24])[C:18]1[CH:17]=[CH:16][C:15]([O:22][CH3:23])=[CH:14][C:13]=1[CH2:12][CH2:11]3)=[N+:2]=[N-:3].CC(C)=O.C(O)(C)C>S(=O)(=O)(O)O.[O-2].[O-2].[O-2].[Cr+6]>[N:1]([C@@H:4]1[CH2:9][C@H:8]2[C@H:10]3[C@H:19]([CH2:20][CH2:21][C@:6]2([CH3:7])[C:5]1=[O:24])[C:18]1[CH:17]=[CH:16][C:15]([O:22][CH3:23])=[CH:14][C:13]=1[CH2:12][CH2:11]3)=[N+:2]=[N-:3]
Reactant: COc1ccc2c(c1)CC[C@@H]1[C@@H]2CC[C@]2(C)[C@@H](O)[C@H](N=[N+]=[N-])C[C@@H]12
Agent: [Cr+6]
Agent: O=S(=O)(O)O
Agent: [O-2]
Solvent: CC(C)O
Solvent: CC(C)=O
Product: COc1ccc2c(c1)CC[C@@H]1[C@@H]2CC[C@]2(C)C(=O)[C@H](N=[N+]=[N-])C[C@@H]12
Reaction time: 2 h

Procedure:
To a solution of 20 g 16α-azido-3-methoxy-estra-1,3,5(10)-triene-17β-ol in 11 acetone, 40 ml of 8 N chromium trioxide solution in conc. sulfuric acid is added dropwise at 0° C. and under stirring. After 2 h, 2 ml isopropanol are added and the reaction product is precipitated in crystalline form by dropwise addition of water. The product is filtered off, washed with water, dried and recrystallized from acetone/water. Yield: 16 g (81%), F=118-122° C.; [α]D+405°. IR: 1747 cm (CO), 2095 (N3).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][C:10]=1[O:11][CH2:12][CH2:13][O:14][CH3:15])[CH:6]=O.[S:16]1[CH2:22][C:20](=[O:21])[NH:19][C:17]1=[S:18].CC([O-])=O.[Na+].CC(O)=O>O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:6]=[C:22]2[S:16][C:17](=[S:18])[NH:19][C:20]2=[O:21])[CH:8]=[CH:9][C:10]=1[O:11][CH2:12][CH2:13][O:14][CH3:15]
Reactant: O=C1CSC(=S)N1
Reactant: COCCOc1ccc(C=O)cc1OC
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: COCCOc1ccc(C=C2SC(=S)NC2=O)cc1OC
Temperature: 90 °C
Yield: 71.1 %

Procedure:
To a N2-purged flask was added 3-methoxy-4-(2-methoxy-ethoxy)-benzaldehyde from Step A (162 mg, 771 mmol), rhodanine (103 mg, 1 equiv), NaOAc (190 mg, 2.31 mmol) and HOAc (3 mL). The mixture was stirred and heated at 90° C. for 14 h under a condenser, resulting in a yellow precipitate. The reaction mixture was diluted with water (100 mL) and the solid precipitate was filtered in a Buchner funnel. The solid was washed with water, washed with hexane, and dried under high vacuum to yield the intermediate compound (179 mg, 72% yield).
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.N1C=CC=CC=1.[C:14]1([CH:20]([CH3:25])[CH2:21][C:22](Cl)=[O:23])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.Cl>CN(C)C1C=CN=CC=1.C1(C)C=CC=CC=1>[C:14]1([CH:20]([CH3:25])[CH2:21][C:22]([O:7][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)=[O:23])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: CC(CC(=O)Cl)c1ccccc1
Reactant: Oc1ccccc1
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: c1ccncc1
Solvent: Cc1ccccc1
Product: CC(CC(=O)Oc1ccccc1)c1ccccc1
Temperature: 10 °C
Reaction time: 24 h
Yield: 83.8 %

Procedure:
To the solution of phenol (8.62 g, 92 mmol) and 4-dimethylaminopyridine (400 mg) in toluene (110 ml) was added pyridine (18.1 g, 229 mmol) and the resulting solution was cooled to 10° C. Then a solution of 3-phenylbutanoyl chloride (20.1 g, 110 mmol) was added dropwise. The resulting mixture was stirred at room temperature for 24 h, and then cooled to 5° C. before the careful addition of 2N aq. HCl-solution (225 ml). The mixture was stirred intensely for 15 min, then diluted with toluene and transferred into a separatory funnel. The aqueous layer was separated and the organic layer washed 4 times with water, then brine and dried over MgSO4. The solvent was removed in a rotary evaporator and the residue short-path distilled at 125-128° C./0.07 mbar to yield 18.52 g (70%) of colourless oil.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][C:3]([N:6]2C(=O)C3C(=CC=CC=3)C2=O)=[N:2]1.[H-].[Na+].[CH2:19](Br)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>CN(C=O)C>[CH2:19]([N:1]1[CH:5]=[CH:4][C:3]([NH2:6])=[N:2]1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: O=C1c2ccccc2C(=O)N1c1cc[nH]n1
Reactant: BrCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Nc1ccn(Cc2ccccc2)n1
Temperature: 50 °C
Reaction time: 15 h
Yield: 32 %

Procedure:
3.1 2-(1H-Pyrazole-3-yl)-isoindole-1,3-dione (11.7 mmol) is added to a suspension of NaH (2 eq.) in DMF at 0° C. Benzylbromide (1 eq.) is added and the reaction is stirred 15 h at 50° C. The solvent is removed in vacuo. Hydrazine hydroxide (10 ml) and ethanol (20 ml) are added and the reaction is stirred 17 hours at 120° C. The precipitate is filtered and the solvent is removed in vacuo. The residue is suspended in dichloromethane and filtrated. The solvent of the filtrate is removed in vacuo. The remaining residue is purified via column chromatography (Ethyl acetate/methanol). 1-Benzyl-1H-pyrazole-3-ylamine is isolated as a yellow powder in a yield of 32%; HPLC (Method B): 2.45 min; LC-MS (Method B): 1.203 min, 174.15 (M+H+);
Reaction SMILES: [C:1]([O:5][C:6](=[O:14])[CH2:7][CH:8]([CH2:12][SH:13])[C:9]([OH:11])=[O:10])([CH3:4])([CH3:3])[CH3:2].[C:15]1([C:21](Cl)([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>C1COCC1>[C:1]([O:5][C:6](=[O:14])[CH2:7][CH:8]([CH2:12][S:13][C:21]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)([C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1)[C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1)[C:9]([OH:11])=[O:10])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)CC(CS)C(=O)O
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)CC(CSC(c1ccccc1)(c1ccccc1)c1ccccc1)C(=O)O
Temperature: 25 °C
Reaction time: 24 h
Yield: 20.6 %

Procedure:
To a stirring solution of the compound of example 25 (8.10 g; 36.77 mmoles) in dry THF (25 mL) at room temperature, was transferred dropwise a solution of triphenylmethyl chloride (12.30 g; 44.13 mmoles) in dry THF (25 mL). The mixture was stirred at room temperature for 24 hours. The solvent was then evaporated under vacuum and the residue was directly subjected to flash chromatography (SiO2, gradient of 15% ethyl acetate in hexanes to 50% ethyl acetate in hexanes) to give 3.50 g (20.6% yield) of the pure desired protected compound: 1H NMR (CDCl3, 400 MHz) 7.50 (d, 6H), 7.29 (m, 9H), 2.58 (m, 5H), 1.45 (S, 9H); 13C NMR (CDCl3, 100 MHz) □ 179.31, 170.32, 144.34, 129.47, 127.93, 127.81, 126.75, 81.03, 66.93, 40.73, 36.13, 32.66, 27.90.
Reaction SMILES: [F:1][C:2]([F:29])([F:28])[C:3]1[CH:4]=[C:5]([CH:21]=[C:22]([C:24]([F:27])([F:26])[F:25])[CH:23]=1)[CH2:6][N:7]1[CH2:14][CH2:13][CH2:12][O:11][C:10]2[N:15]=[CH:16][CH:17]=[C:18](I)[C:9]=2[C:8]1=[O:20].[CH3:30][O:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=1B(O)O>>[F:1][C:2]([F:29])([F:28])[C:3]1[CH:4]=[C:5]([CH:21]=[C:22]([C:24]([F:27])([F:26])[F:25])[CH:23]=1)[CH2:6][N:7]1[CH2:14][CH2:13][CH2:12][O:11][C:10]2[N:15]=[CH:16][CH:17]=[C:18]([C:33]3[CH:34]=[CH:35][CH:36]=[CH:37][C:32]=3[O:31][CH3:30])[C:9]=2[C:8]1=[O:20]
Reactant: O=C1c2c(I)ccnc2OCCCN1Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: COc1ccccc1B(O)O
Product: COc1ccccc1-c1ccnc2c1C(=O)N(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)CCCO2
Yield: 85.7 %

Procedure:
In a similar manner to Reference Example 5, 5-[3,5-bis(trifluoromethyl)benzyl]-7-iodo6-oxo-2,3,4,5-tetrahydro-6H-pyrido[2,3-b][1,5]oxazocine (compound of Reference Example 3; 2.00 g) was reacted with 2-methoxyphenylboronic acid (690 mg) to obtain 5-[3,5-bis(trifluoromethyl)benzyl]-7-(2-methoxyphenyl)-6-oxo-2,3,4,5-tetrahydro-6H-pyrido[2,3-b][1,5]oxazocine (1.65 g, 86%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:11])=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8].[C:12]([O-])([O-])=O.[K+].[K+].CI>CN(C=O)C>[CH3:12][O:8][C:7](=[O:9])[C:6]1[CH:10]=[C:2]([Br:1])[CH:3]=[CH:4][C:5]=1[CH3:11]
Reactant: O=C([O-])[O-]
Reactant: Cc1ccc(Br)cc1C(=O)O
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Product: COC(=O)c1cc(Br)ccc1C
Temperature: 25 °C
Reaction time: 4 h
Yield: 81.6 %

Procedure:
To a solution of 5-bromo-2-methyl-benzoic acid (9.9 g, 46 mmol) in DMF (100 mL) was added K2CO3 (7.6 g, 55 mmol) and CH3I (20 g, 140 mmol) slowly. After stirring at room temperature for 4 h, the solvent was removed under vacuum. The residue was partitioned between ethyl acetate and water. The organic layer was washed with brine and dried over Na3SO4. The solvent was removed under vacuum to afford 5-bromo-2-methylbenzoic acid methyl ester (8.6 g, 82%), which was used in next step without further purification. 1H NMR (300 MHz, CDCl3) δ 8.04 (d, J=2.1, 1H), 7.50 (d, J=2.1, 1H), 7.50 (dd, J=8.1, 2.1, 1H), 7.12 (d, J=8.1, 1H), 3.89 (s, 3H), 2.53 (s, 3H).
Reaction SMILES: CO[C:3]([C:5]1[NH:6][N:7]=[C:8]([O:10][CH2:11][C:12]2[C:13]([CH2:18][CH2:19][CH2:20][CH3:21])=[N:14][O:15][C:16]=2[CH3:17])[CH:9]=1)=[O:4].[NH2:22][C@@H:23]([CH2:25][OH:26])[CH3:24]>>[OH:26][CH2:25][C@H:23]([NH:22][C:3]([C:5]1[NH:6][N:7]=[C:8]([O:10][CH2:11][C:12]2[C:13]([CH2:18][CH2:19][CH2:20][CH3:21])=[N:14][O:15][C:16]=2[CH3:17])[CH:9]=1)=[O:4])[CH3:24]
Reactant: CCCCc1noc(C)c1COc1cc(C(=O)OC)[nH]n1
Reactant: C[C@@H](N)CO
Product: CCCCc1noc(C)c1COc1cc(C(=O)N[C@H](C)CO)[nH]n1
Yield: 90 %

Procedure:
As described for example 27, 5-(3-butyl-5-methyl-isoxazol-4-ylmethoxy)-2H-pyrazole-3-carboxylic acid methyl ester (100 mg, 0.34 mmol) was converted, using D-alaninol instead of L-alaninol, to the title compound (103 mg, 90%) which was obtained as a colorless oil.
Reaction SMILES: [NH2:1][C:2]1([C:15]([O:17][CH3:18])=[O:16])[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][CH2:3]1.N1C=CC=CC=1.[Cl:25][CH2:26][CH2:27][CH2:28][C:29](Cl)=[O:30]>C(Cl)Cl>[CH3:18][O:17][C:15]([C:2]1([NH:1][C:29](=[O:30])[CH2:28][CH2:27][CH2:26][Cl:25])[CH2:3][CH2:4][N:5]([C:8]([O:10][C:11]([CH3:12])([CH3:13])[CH3:14])=[O:9])[CH2:6][CH2:7]1)=[O:16]
Reactant: COC(=O)C1(N)CCN(C(=O)OC(C)(C)C)CC1
Reactant: O=C(Cl)CCCCl
Solvent: c1ccncc1
Solvent: ClCCl
Product: COC(=O)C1(NC(=O)CCCCl)CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of methyl 4-amino-1-BOC-piperidine-4-carboxylate (2.0 g, 6.78 mmol) in DCM (15 mL) and pyridine (2.10 mL, 20.35 mmol), 4-chlorobutyryl chloride (0.84 mL, 7.5 mmol) in DCM (5 mL) was added slowly at 0° C. The reaction mixture was gradually warmed to room temperature and stirred for 16 hours. The reaction mixture was diluted with DCM (40 mL), and quenched with saturated NaHCO3 (30 mL). The organic layer was separated and the aqueous layer was extracted twice with DCM. The combined organic layers were then washed with saturated aqueous NaHCO3 and brine, dried over MgSO4, filtered and concentrated to give 4-(4-chloro-butyrylamino)-piperidine-1,4-dicarboxylic acid 1-tert-butyl ester 4-methyl ester which was used further without purification.
Reaction SMILES: Cl.[C:2]([N:5]1[CH2:10][CH2:9][CH:8]([NH2:11])[CH2:7][CH2:6]1)(=[O:4])[CH3:3].C(N(C(C)C)CC)(C)C.[F:21][C:22]1[CH:27]=[CH:26][C:25]([S:28](Cl)(=[O:30])=[O:29])=[CH:24][CH:23]=1>ClCCl>[C:2]([N:5]1[CH2:10][CH2:9][CH:8]([NH:11][S:28]([C:25]2[CH:26]=[CH:27][C:22]([F:21])=[CH:23][CH:24]=2)(=[O:30])=[O:29])[CH2:7][CH2:6]1)(=[O:4])[CH3:3]
Reactant: O=S(=O)(Cl)c1ccc(F)cc1
Reactant: CC(=O)N1CCC(N)CC1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)N1CCC(NS(=O)(=O)c2ccc(F)cc2)CC1
Reaction time: 6.5 h
Yield: 67058.9 %

Procedure:
To a suspension of 1-acetyl-4-aminopiperidine hydrochloride (715 mg) in dichloromethane (7 ml) were added diisopropylethylamine (1.83 ml) and a solution of 4-fluorobenzenesulfonyl chloride (0.83 mg) in dichloromethane (2 ml) at ambient temperature. After stirring for 6.5 hours, the reaction mixture was diluted with dichloromethane and washed with water, saturated aqueous sodium hydrogen carbonate, and brine. After drying with magnesium sulfate, the solvents were removed under reduced pressure. A residue was purified by column chromatography (silica gel 50 ml, dichloromethane:methanol=50:1 to 20:1). After rinse with diisopropyl ether, N-(1-acetylpiperidin-4-yl)-4-fluorobenzenesulfonamide (859 mg) was obtained.
Reaction SMILES: [S:1]1[C:5]2[C:6]([C:10]3[O:30][C:13]4=[C:14]([NH2:29])[N:15]=[CH:16][C:17]([C:18]5[CH:19]=[N:20][N:21]([CH:23]6[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]6)[CH:22]=5)=[C:12]4[CH:11]=3)=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[N:2]1.C(N(C(C)C)CC)(C)C.[CH2:40]([N:44]=[C:45]=[O:46])[CH:41]([CH3:43])[CH3:42]>CN(C=O)C>[CH2:40]([NH:44][C:45]([N:26]1[CH2:25][CH2:24][CH:23]([N:21]2[CH:22]=[C:18]([C:17]3[CH:16]=[N:15][C:14]([NH2:29])=[C:13]4[O:30][C:10]([C:6]5[C:5]6[S:1][N:2]=[CH:3][C:4]=6[CH:9]=[CH:8][CH:7]=5)=[CH:11][C:12]=34)[CH:19]=[N:20]2)[CH2:28][CH2:27]1)=[O:46])[CH:41]([CH3:43])[CH3:42]
Reactant: Nc1ncc(-c2cnn(C3CCNCC3)c2)c2cc(-c3cccc4cnsc34)oc12
Reactant: CC(C)CN=C=O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)CNC(=O)N1CCC(n2cc(-c3cnc(N)c4oc(-c5cccc6cnsc56)cc34)cn2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 2-benzo[d]isothiazol-7-yl-4-(1-piperidin-4-yl-1H-pyrazol-4-yl)-furo[2,3-c]pyridin-7-ylamine (20.8 mg, 0.05 mmol) in DMF (0.5 mL) was added diisopropylethylamine (0.05 mL, 6.5 mmol) and isobutyl isocyanate (0.06 mmol). The resulting solution stirred at room temperature overnight. The mixture was concentrated and then purified by MDP to afford the title compound as an off-white solid. 1H NMR (400 MHz, CD3OD): δ 9.51 (s, 1H), 9.12 (d, J=1.5 Hz, 1H), 8.84 (d, J=7.3 Hz, 1H), 8.72 (d, J=7.3 Hz, 1H), 8.35 (s, 1H), 8.07 (s, 1H), 7.92 (s, 1H), 7.88 (s, 1H), 4.53 (m, 1H), 3.03 (m, 4H), 2.18 (m, 2H), 2.06 (m, 4H), 1.83 (m, 1H), 1.76 (d, J=5.8 Hz, 6H); MS (ESI): MS (ESI): 516.64 [M+H]+; HPLC tR=0.86 min (HPLC: Analytical—2 min).
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[C:7]2[C:12]1[O:13][C:14]([CH3:17])=[N:15][N:16]=1.[C:18]([C:21]1[CH:26]=[CH:25][C:24](B(O)O)=[CH:23][CH:22]=1)([OH:20])=[O:19].C(=O)([O-])[O-].[Na+].[Na+]>C(COC)OC.O>[C:18]([C:21]1[CH:26]=[CH:25][C:24]([C:2]2[C:3]3[C:8](=[C:7]([C:12]4[O:13][C:14]([CH3:17])=[N:15][N:16]=4)[CH:6]=[CH:5][CH:4]=3)[CH:9]=[CH:10][CH:11]=2)=[CH:23][CH:22]=1)([OH:20])=[O:19]
Reactant: O=C(O)c1ccc(B(O)O)cc1
Reactant: Cc1nnc(-c2cccc3c(Br)cccc23)o1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: Cc1nnc(-c2cccc3c(-c4ccc(C(=O)O)cc4)cccc23)o1

Procedure:
2-(5-Bromo-1-naphthyl)-5-methyl-1,3,4-oxadiazole (D3) (1.50 g, 5.2 mmol) and 4-carboxyphenylboronic acid (0.86 g, 5.2 mmol) were stirred in dimethoxyethane (DME) (40 ml), and sodium carbonate (2.5 g, 23 mmol) in water (40 ml) was added. The mixture was purged by a stream of Ar for 15 min, when tetrakis (triphenylphosphine)palladium (0) (0.1 g, 0.008 mmol) was added. The mixture was stirred at reflux under Ar for 20 h, and then evaporated to remove DME. The grey suspension was acidified (5M HCl), and the solid was filtered off and dried in vacuo at 60° C. This material was heated at reflux in ethanol (30 ml), and filtered hot. The white solid so collected was dried in vacuo at 60° C. giving 1.32 (77%) of the title compound.
Reaction SMILES: [Cl:1][C:2]1[C:6]([Cl:7])=[C:5]([C:8]([C:11]2[CH:15]=[CH:14][S:13][CH:12]=2)=[N:9][OH:10])[S:4][N:3]=1.Cl[CH2:17][C:18]1[N:23]=[C:22]([NH2:24])[CH:21]=[CH:20][N:19]=1.[I-].[K+].N12CCCC1=NCCC2>C(#N)C>[Cl:1][C:2]1[C:6]([Cl:7])=[C:5]([C:8](=[N:9][O:10][CH2:17][C:18]2[N:23]=[C:22]([NH2:24])[CH:21]=[CH:20][N:19]=2)[C:11]2[CH:15]=[CH:14][S:13][CH:12]=2)[S:4][N:3]=1
Reactant: ON=C(c1ccsc1)c1snc(Cl)c1Cl
Reactant: Nc1ccnc(CCl)n1
Agent: C1CN=C2CCCN2C1
Agent: [I-]
Agent: [K+]
Solvent: CC#N
Product: Nc1ccnc(CON=C(c2ccsc2)c2snc(Cl)c2Cl)n1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 6.4 %

Procedure:
To a stirred suspension of 1-(3,4-dichloro-1,2-thiazol-5-yl)-N-hydroxy-1-(3-thienyl)methanimine (1.69 g, 6.06 mmol), 2-(chloromethyl)pyrimidin-4-amine (957 mg, 6.66 mmol) and potassium iodide (1.01 g, 6.06 mmol) in acetonitrile (15 mL) at 0° C. was added 1,5-diazabicyclo(4.3.0)non-5-ene (1.52 mL, 12.7 mmol). The mixture was stirred 10 min at 0° C., then overnight at room temperature. After dilution of the reaction mixture with water and extraction with ethyl acetate, the combined organic layers were dried over MgSO4, concentrated in vacuo, and the residue purified on silica gel to afford 2-[({[(3,4-dichloro-1,2-thiazol-5-yl)(3-thienyl)methylene]amino}oxy)methyl]pyrimidin-4-amine [150 mg, yield 3%].