Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5]/[CH:6]=[CH:7]/[C:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([F:17])[CH:15]=2)[N:10]([CH2:18][CH2:19][CH2:20][O:21][C:22]2[C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[CH:25]=[CH:24][CH:23]=2)[C:9]=1[C:32]([O:34][CH2:35][CH3:36])=[O:33].[O:37]=[C:38]1[C:46]2[C:41](=[CH:42][CH:43]=[CH:44][CH:45]=2)[C:40](=[O:47])[N-:39]1.[K+]>CN(C)C=O.C(OCC)(=O)C>[O:37]=[C:38]1[C:46]2[C:41](=[CH:42][CH:43]=[CH:44][CH:45]=2)[C:40](=[O:47])[N:39]1[CH2:2][CH2:3][CH2:4][CH2:5]/[CH:6]=[CH:7]/[C:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([F:17])[CH:15]=2)[N:10]([CH2:18][CH2:19][CH2:20][O:21][C:22]2[C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[CH:25]=[CH:24][CH:23]=2)[C:9]=1[C:32]([O:34][CH2:35][CH3:36])=[O:33]
Reactant: O=C1[N-]C(=O)c2ccccc21
Reactant: CCOC(=O)c1c(/C=C/CCCCCl)c2cc(F)ccc2n1CCCOc1cccc2ccccc12
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOC(=O)c1c(/C=C/CCCCN2C(=O)c3ccccc3C2=O)c2cc(F)ccc2n1CCCOc1cccc2ccccc12

Procedure:
A mixture of EXAMPLE 160A (531 mg) and potassium 1,3-dioxoisoindolin-2-ide (213 mg) in N,N-dimethylformamide (10 ml) was heated at 80° C. for 8 hours. The reaction was diluted with ethyl acetate and washed with water. The organic layer was dried over sodium sulfate and was concentrated. The residue was purified by flash chromatography, eluting with 0-100% ethyl acetate in dichloromethane to give (E)-ethyl 3-(6-(1,3-dioxoisoindolin-2-yl)hex-1-enyl)-5-fluoro-1-(3-(naphthalen-1-yloxy)propyl)-1H-indole-2-carboxylate. This ester was dissolved in a mixture of tetrahydrofuran and methanol and 5 equivalents of aqueous NaOH (10%) was added. The mixture was heated at 50° C. for 5 hours. The reaction mixture was concentrated and the residue was dissolved in dimethyl sulfoxide and trifluoroacetic acid-methanol (3:1), and purified by RPHPLC to provide the title compound. 1H NMR (400 MHz, dimethyl sulfoxide-d6) δ 13.06 (s, 2H), 8.25 (t, J=5.52 Hz, 1H), 8.19 (dd, J=7.83, 1.38 Hz, 1H), 7.86 (dd, J=7.21, 1.99 Hz, 1H), 7.74 (dd, J=7.52, 1.38 Hz, 1H), 7.60-7.69 (m, 2H), 7.43-7.58 (m, 5H), 7.34-7.41 (m, 2H), 6.99-7.16 (m, 2H), 6.85 (d, J=7.36 Hz, 1H), 6.15-6.32 (m, 1H), 4.65-4.96 (m, 2H), 4.13 (t, J=5.68 Hz, 2H), 3.20-3.29 (m, 2H), 2.20-2.36 (m, 4H), 1.49-1.67 (m, 4H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([C:8]2([CH3:20])[CH:13]3[CH:9]2[CH2:10][N:11]([CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])[CH2:12]3)[CH:5]=[CH:4][C:3]=1[NH2:21].[F:22][C:23]([F:28])([F:27])[C:24](O)=O>>[CH2:14]([N:11]1[CH2:10][CH:9]2[CH:13]([C:8]2([C:6]2[CH:5]=[CH:4][C:3]3[NH:21][C:24]([C:23]([F:28])([F:27])[F:22])=[N:1][C:2]=3[CH:7]=2)[CH3:20])[CH2:12]1)[CH2:15][CH2:16][CH2:17][CH2:18][CH3:19]
Reactant: O=C(O)C(F)(F)F
Reactant: CCCCCCN1CC2C(C1)C2(C)c1ccc(N)c(N)c1
Product: CCCCCCN1CC2C(C1)C2(C)c1ccc2[nH]c(C(F)(F)F)nc2c1
Yield: 54 %

Procedure:
A solution of 2-amino-4-(3-hexyl-6-methyl-3-azabicyclo[3.1.0]hex-6-yl)phenylamine (Preparation 48, 99.0 mg, 0.345 mmol) in trifluoroacetic acid (2.0 ml) was heated under reflux for 1 hour. The mixture was cooled and the solvent was removed in vacuo. The residue was suspended in 2N sodium hydroxide (5 ml) and the aqueous layer was extracted with diethyl ether (3×5 ml). The combined extracts were dried (MgSO4), filtered and concentrated in vacuo. The crude residue was purified by silica column chromatography ieluting with ethyl acetate to afford the title compound (67 mg, 54%) as a colourless oil.
Reaction SMILES: [C:1](Cl)(=[O:5])[CH2:2][CH2:3][CH3:4].[C:7]([C:9]1[CH:10]=[N:11][C:12]([N:15]2[CH2:20][CH2:19][C@@H:18]([NH:21][C:22]3[C:23]4[N:24]([CH:31]=[C:32]([N:34]5[CH2:38][CH2:37][C@H:36]([OH:39])[C:35]5=[O:40])[CH:33]=4)[N:25]=[CH:26][C:27]=3[C:28]([NH2:30])=[O:29])[C:17]([CH3:42])([CH3:41])[CH2:16]2)=[N:13][CH:14]=1)#[N:8].C(N(CC)CC)C.N1C=CC=CC=1>O1CCCC1.CN(C1C=CN=CC=1)C>[C:1]([O:39][C@H:36]1[CH2:37][CH2:38][N:34]([C:32]2[CH:33]=[C:23]3[C:22]([NH:21][C@@H:18]4[CH2:19][CH2:20][N:15]([C:12]5[N:13]=[CH:14][C:9]([C:7]#[N:8])=[CH:10][N:11]=5)[CH2:16][C:17]4([CH3:42])[CH3:41])=[C:27]([C:28](=[O:29])[NH2:30])[CH:26]=[N:25][N:24]3[CH:31]=2)[C:35]1=[O:40])(=[O:5])[CH2:2][CH2:3][CH3:4]
Reactant: CC1(C)CN(c2ncc(C#N)cn2)CC[C@H]1Nc1c(C(N)=O)cnn2cc(N3CC[C@H](O)C3=O)cc12
Reactant: CCCC(=O)Cl
Agent: CN(C)c1ccncc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: c1ccncc1
Product: CCCC(=O)O[C@H]1CCN(c2cc3c(N[C@@H]4CCN(c5ncc(C#N)cn5)CC4(C)C)c(C(N)=O)cnn3c2)C1=O
Reaction time: 2 h
Yield: 22.5 %

Procedure:
Butyryl chloride (4 μl, 0.034 mmol) was added to a stirred suspension of 4-(((R)-1-(5-cyanopyrimidin-2-yl)-3,3-dimethylpiperidin-4-yl)amino)-6-((S)-3-hydroxy-2-oxopyrrolidin-1-yl)pyrrolo[1,2-b]pyridazine-3-carboxamide (15 mg, 0.031 mmol, from Example 115) and triethylamine (0.013 mL, 0.092 mmol) in tetrahydrofuran (0.5 mL). After 2 h at room temperature, no reaction was observed. Pyridine (5.0 μl, 0.061 mmol), DMAP (0.5 mg, 4.09 μmol) and additional butyryl chloride (3.5 μl, 0.034 mmol) were added. After 24 h at room temperature, the crude material was purified via preparative LC/MS with the following conditions: Column: Waters XBridge C18, 19×250 mm, 5-μm particles; Guard Column: Waters XBridge C18, 19×10 mm, 5-μm particles; Mobile Phase A: 5:95 acetonitrile:water with 0.05% TFA; Mobile Phase B: 95:5 acetonitrile:water with 0.05% TFA; Gradient: 15-100% B over 25 minutes, then a 5-minute hold at 100% B; Flow: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The material was further purified via preparative LC/MS with the following conditions: Column: Waters XBridge C18, 19×250 mm, 5-μm particles; Guard Column: Waters XBridge C18, 19×10 mm, 5-μm particles; Mobile Phase A: 5:95 acetonitrile:water with 10-mM ammonium acetate; Mobile Phase B: 95:5 acetonitrile:water with 10-mM ammonium acetate; Gradient: 15-55% B over 25 minutes, then a 10-minute hold at 55% B; Flow: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation to give the title compound (3.9 mg, 22% yield). 1H NMR (500 MHz, 1:1 mixture of chloroform-d/methanol-d4) δ ppm 8.51 (s, 2H), 8.12 (s, 1H), 7.79 (d, J=1.5 Hz, 1H), 7.32 (d, J=1.5 Hz, 1H), 5.54 (t, J=8.4 Hz, 1H), 4.45 (d, J=13.4 Hz, 1H), 4.17 (dd, J=10.2, 3.7 Hz, 1H), 3.95 (td, J=9.7, 2.5 Hz, 1H), 3.87-3.79 (m, 1H), 3.52-3.44 (m, 1H), 3.22 (d, J=13.4 Hz, 1H), 2.80-2.70 (m, 1H), 2.47-2.35 (m, 2H), 2.25-2.15 (m, 2H), 1.87-1.77 (m, 1H), 1.69 (sxt, J=7.3 Hz, 2H), 1.08 (s, 3H), 1.05 (s, 3H), 0.97 (t, J=7.4 Hz, 3H); MS (ES+) m/z: 560.4 (M+H); LC retention time: 1.98 min (analytical LCMS Method I).
Reaction SMILES: [Al].[CH3:2][C:3]([CH3:5])=[O:4].C(OCCOC)(=[O:8])C.[CH2:14]([C:16](C)=[O:17])[CH3:15]>>[C:3]1([CH:5]=[CH:15][CH:14]=[C:16]([OH:17])[C:2]=1[OH:8])[OH:4]
Reactant: CCC(C)=O
Reactant: COCCOC(C)=O
Reactant: CC(C)=O
Agent: [Al]
Product: Oc1cccc(O)c1O
Temperature: 70 °C

Procedure:
Both surfaces of a 0.24 mm thick aluminum plate were sand-grained using a nylon brush and an aqueous dispersion of 400 mesh pumice stone and thoroughly washed with water. This aluminum plate was dipped in a 5% aqueous solution of sodium triphosphate maintained at 70° C. for 3 minutes, washed with water, and dried. A photo-sensitive solution as described in British Pat. No. 1,113,759 was prepared by dissolving 1 part by weight of a naphthoquinone-1,2-diazido-5-sulfonic acid ester of polyhydroxyphenyl obtained by polycondensation of acetone and pyrogallol and 2 parts by weight of a novolak type phenol-formaldehyde resin in a mixed solvent of 20 parts by weight of 2-methoxyethyl acetate and 20 parts by weight of methyl ethyl ketone. This photo-sensitive solution was coated on one surface of the above-prepared plate and then on the other surface to produce a pre-sensitized printing plate which has photo-sensitive layers on both surfaces of the plate. The thus-produced printing plate was cut in three 1,003 mm×800 mm pieces to produce Samples A, B and C.
Reaction SMILES: [N+:1]([C:4]1[CH:11]=[CH:10][C:7]([CH:8]=O)=[CH:6][CH:5]=1)([O-:3])=[O:2].[CH2:12]([O:14][C:15](=[O:31])[CH2:16][C:17]([CH2:19][N:20]1[C:24](=[O:25])[C:23]2=[CH:26][CH:27]=[CH:28][CH:29]=[C:22]2[C:21]1=[O:30])=O)[CH3:13].[NH3:32]>C(O)C>[CH2:12]([O:14][C:15]([C:16]1[CH:8]([C:7]2[CH:10]=[CH:11][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=2)[C:16]([C:15]([O:14][CH2:12][CH3:13])=[O:31])=[C:17]([CH2:19][N:20]2[C:21](=[O:30])[C:22]3=[CH:29][CH:28]=[CH:27][CH:26]=[C:23]3[C:24]2=[O:25])[NH:32][C:17]=1[CH2:19][N:20]1[C:24](=[O:25])[C:23]2=[CH:26][CH:27]=[CH:28][CH:29]=[C:22]2[C:21]1=[O:30])=[O:31])[CH3:13]
Reactant: O=Cc1ccc([N+](=O)[O-])cc1
Reactant: N
Reactant: CCOC(=O)CC(=O)CN1C(=O)c2ccccc2C1=O
Solvent: CCO
Product: CCOC(=O)C1=C(CN2C(=O)c3ccccc3C2=O)NC(CN2C(=O)c3ccccc3C2=O)=C(C(=O)OCC)C1c1ccc([N+](=O)[O-])cc1

Procedure:
7.5 g of 4-nitrobenzaldehyde, 28 g of γ-phthalimidoacetoacetic acid ethyl ester and 7 ccs of concentrated ammonia in 120 ccs of ethanol are heated to the boil under reflux for 60 hours and the product is filtered off after cooling on ice.
Reaction SMILES: Cl[C:2]1[C:3]2[CH:14]=[CH:13][CH:12]=[CH:11][C:4]=2[N:5]([CH3:10])[C:6](=[O:9])[CH2:7][N:8]=1.[CH3:15][O:16][C:17]([C:19]1[CH:24]=[CH:23][C:22](B(O)O)=[CH:21][CH:20]=1)=[O:18].[C:28](=O)([O-])[O-].[Na+].[Na+].C(OCC)(=O)C>COCCOC.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH3:10][N:5]1[C:4]2[CH:11]=[CH:12][CH:13]=[CH:14][C:3]=2[C:2]([C:22]2[CH:23]=[CH:24][C:19]([C:17]([O:16][CH2:15][CH3:28])=[O:18])=[CH:20][CH:21]=2)=[N:8][CH2:7][C:6]1=[O:9]
Reactant: COC(=O)c1ccc(B(O)O)cc1
Reactant: CN1C(=O)CN=C(Cl)c2ccccc21
Reactant: O=C([O-])[O-]
Agent: [Pd]
Agent: [Na+]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: COCCOC
Solvent: CCOC(C)=O
Product: CCOC(=O)c1ccc(C2=NCC(=O)N(C)c3ccccc32)cc1
Temperature: 90 °C
Reaction time: 1 h
Yield: 57.7 %

Procedure:
Title compound 468 (1.69 g, 8.10 mmol) was dissolve in DME (50 mL) and 4-(methoxycarbonyl)phenylboronic acid (1.47 g, 7.58 mmol) was added followed by tetrakis(triphenylphosphine) palladium (0) (0.301 g, 0.260 mmol) and then sodium carbonate (2M in water, 12 mL, 24.00 mmol). The reaction mixture was stirred at 90° C. for 1 h, cooled at room temperature and poured into ethyl acetate. The organic layer was washed with water and brine, dried over sodium sulfate, filtered and concentrated. The crude was purified by flash chromatography (10% ethyl acetate in hexanes) to afford title compound 469 (1.41 g, 54%) as a red foam. MS (ESI): 323.42 (MH)+.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([C:11]1[CH:19]=[CH:18][C:14]([C:15]([OH:17])=O)=[CH:13][CH:12]=1)[CH:6]=[CH:5]2.[CH:20]1([NH2:23])[CH2:22][CH2:21]1.[OH:24][CH2:25][CH2:26][N:27]1[C:35]2[C:30](=[CH:31][C:32]([C:36](O)=[O:37])=[CH:33][CH:34]=2)[CH:29]=[CH:28]1>>[CH:20]1([NH:23][C:15]([C:14]2[CH:18]=[CH:19][C:11]([N:7]3[C:8]4[C:4](=[CH:3][C:2]([NH:1][C:36]([C:32]5[CH:31]=[C:30]6[C:35](=[CH:34][CH:33]=5)[N:27]([CH2:26][CH2:25][OH:24])[CH:28]=[CH:29]6)=[O:37])=[CH:10][CH:9]=4)[CH:5]=[CH:6]3)=[CH:12][CH:13]=2)=[O:17])[CH2:22][CH2:21]1
Reactant: NC1CC1
Reactant: Nc1ccc2c(ccn2-c2ccc(C(=O)O)cc2)c1
Reactant: O=C(O)c1ccc2c(ccn2CCO)c1
Product: O=C(Nc1ccc2c(ccn2-c2ccc(C(=O)NC3CC3)cc2)c1)c1ccc2c(ccn2CCO)c1

Procedure:
Compound 947 was prepared according to the procedure described in Scheme IV from 4-(5-amino-1H-indol-1-yl)benzoic acid, cyclopropaneamine, and 1-(2-hydroxy ethyl)-1H-indole-5-carboxylic acid. [M+H]+ calcd for C29H26N4O3: 479.20; found: 479.01.
Reaction SMILES: [CH3:1][SH:2].C(N(CC)CC)C.O.[NH2:11][C:12]1[C:17]([CH:18]=[O:19])=[N:16][C:15]([Cl:20])=[C:14](Cl)[N:13]=1>CN(C)C=O>[NH2:11][C:12]1[C:17]([CH:18]=[O:19])=[N:16][C:15]([Cl:20])=[C:14]([S:2][CH3:1])[N:13]=1
Reactant: CS
Reactant: Nc1nc(Cl)c(Cl)nc1C=O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: O
Product: CSc1nc(N)c(C=O)nc1Cl
Temperature: 0 °C

Procedure:
In 3 ml of dimethylformamide there was dissolved 2-amino-5,6-dichloro-3-formylpyrazine prepared as described in Example 1, Steps A and B. The solution was cooled in an ice bath, and there was then bubbled therethrough methane thiol, for 2 minutes followed by addition of triethylamine (223 mg; 2.2 mMol), followed by methane thiol addition for another 3 minutes. The reaction mixture was stirred for 30 minutes at the ice bath temperature and for 30 minutes at room temperature. The methane thiol and dimethylformamide were then blown off, the residue was treated with water, and the product precipitated, was filtered and washed (333 mg). Elemental Analysis for C6H6N3OSCl:
Reaction SMILES: [CH2:1]([N:5]1[C:9]([CH2:10][N:11]([CH2:17][C:18]2[CH:19]=[C:20]3[C:24](=[CH:25][CH:26]=2)[NH:23][CH:22]=[CH:21]3)[CH2:12][CH2:13][CH:14]([CH3:16])[CH3:15])=[C:8]([Cl:27])[N:7]=[C:6]1[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1[CH3:34])[CH2:2][CH2:3][CH3:4].ClS([N:39]=[C:40]=O)(=O)=O.CN(C=O)C.[OH-].[NH4+]>C(#N)C>[CH2:1]([N:5]1[C:9]([CH2:10][N:11]([CH2:17][C:18]2[CH:19]=[C:20]3[C:24](=[CH:25][CH:26]=2)[NH:23][CH:22]=[C:21]3[C:40]#[N:39])[CH2:12][CH2:13][CH:14]([CH3:15])[CH3:16])=[C:8]([Cl:27])[N:7]=[C:6]1[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1[CH3:34])[CH2:2][CH2:3][CH3:4]
Reactant: O=C=NS(=O)(=O)Cl
Reactant: CCCCn1c(-c2ccccc2C)nc(Cl)c1CN(CCC(C)C)Cc1ccc2[nH]ccc2c1
Agent: [NH4+]
Agent: [OH-]
Solvent: CC#N
Solvent: CN(C)C=O
Product: CCCCn1c(-c2ccccc2C)nc(Cl)c1CN(CCC(C)C)Cc1ccc2[nH]cc(C#N)c2c1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 6 %

Procedure:
To an ice-cooled solution of 5-{[(3-butyl-5-chloro-2-o-tolyl-3H-imidazol-4-ylmethyl)-(3-methyl-butyl)-amino]-methyl}-1H-indole (173 mg, 0.363 mmol) in 5 ml of anhydrous acetonitrile under nitrogen is added a solution of chlorosulfonyl isocyanate (69.5 mg, 0.491 mmol, 1.35 eq.) in 1 ml of acetonitrile, after stirring for 20 min, a solution of DMF (30.1 mg) in 2 ml of acetonitrile is added dropwise, stirred for additional 1 h. The reaction mixture is poured into ice water and basified with diluted ammonium hydroxide solution; the mixture is extracted with dichloromethane, dried over sodium sulfate. The solvent is evaporated; the residue is purified through flash chromatography to give 11 mg of 5-{[(3-butyl-5-chloro-2-o-tolyl-3H-imidazol-4-ylmethyl)-(3-methyl-butyl)-amino]-methyl}-1H-indole-3-carbonitrile as white solid. 1H NMR (400 MHz, CDCl3) δ 7.63 (1H, s), 7.38 (1H, d, J=3 Hz), 7.15˜7.36 (4H, m), 7.07 (1H, dd, J=1.2, 8.4 Hz), 6.89˜6.93 (2H, m), 3.73 (2H, t, J=7.5 Hz), 3.65 (2H, s), 3.57 (2H, s), 2.55 (2H, d, J=6.9 Hz), 2.02 (3H, s), 1.62 (1H, m), 1.46 (2H, q, J=6.6 Hz), 1.14 (2H,m), 0.85 (6H, d, J=6.6 Hz), 0.75 (2H, m), 0.51 (3H, t, J=7.2 Hz); MS (+VE) m/z 502 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:21])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][NH:12][C:13]1[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=1.C(N(CC)CC)C.[Cl:29][C:30]1[CH:38]=[CH:37][C:33]([C:34](Cl)=[O:35])=[CH:32][CH:31]=1>CCOCC>[CH3:1][O:2][C:3](=[O:21])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][N:12]([C:13]1[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=1)[C:34](=[O:35])[C:33]1[CH:37]=[CH:38][C:30]([Cl:29])=[CH:31][CH:32]=1
Reactant: O=C(Cl)c1ccc(Cl)cc1
Reactant: COC(=O)CCCCCCCCNc1ccc(OC)cc1
Solvent: CCN(CC)CC
Solvent: CCOCC
Product: COC(=O)CCCCCCCCN(C(=O)c1ccc(Cl)cc1)c1ccc(OC)cc1

Procedure:
As described in example 3(b) the reaction is carried out with 2 g. (6.8 mmol) of 9-(4-methoxyphenylamino)-pelargonic acid methyl ester, 0.75 g (7.5 mmol) of triethylamine, 1.2 g (6.8 mmol) of 4-chlorobenzoic acid chloride and 80 cc. of ether. The crude product is used in the next reaction step without further purification.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([CH:10]=[C:11]([C:14]([CH3:17])([CH3:16])[CH3:15])[C:12]=1[OH:13])[CH:8]=O)([CH3:4])([CH3:3])[CH3:2].[N:18]1[CH:23]=[CH:22][CH:21]=[C:20]([CH2:24][C:25]([O:27][CH2:28][CH3:29])=[O:26])[CH:19]=1.N1CCCCC1>C(O)C>[C:14]([C:11]1[CH:10]=[C:7]([CH:8]=[C:24]([C:20]2[CH:19]=[N:18][CH:23]=[CH:22][CH:21]=2)[C:25]([O:27][CH2:28][CH3:29])=[O:26])[CH:6]=[C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])[C:12]=1[OH:13])([CH3:17])([CH3:16])[CH3:15]
Reactant: CCOC(=O)Cc1cccnc1
Reactant: CC(C)(C)c1cc(C=O)cc(C(C)(C)C)c1O
Solvent: CCO
Solvent: C1CCNCC1
Product: CCOC(=O)C(=Cc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1)c1cccnc1
Temperature: 25 °C
Yield: 46.6 %

Procedure:
Here, 3,5-di-t-butyl-4-hydroxybenzaldehyde (223 g, 0.952 mol), Ethyl 3-pyridylacetate (157.2 g, 0.952 mol), piperidine (81 g, 0.952 mol) and p-tolunesulfonic acid (0.5 g) are combined in ethanol (2,400 ml) and heated at reflux for 48 hours. The reaction mixture is allowed to cool to room temperature and then stirred on an ice bath, whereupon the product begins to crystallize. The mixture is stored in the freezer overnight, filtered and rinsed with cold ethanol-water (1:1). The product is dried, giving ethyl 3-(3,5-di-t-butyl-4-hydroxyphenyl)-2-(3-pyridyl)propenoate (169.1 g) Mp 119.5°-120.5° C.
Reaction SMILES: [CH3:1][N:2]([CH2:9][C:10]1[CH:15]=[CH:14][C:13]([NH:16][C:17](=[O:34])/[CH:18]=[CH:19]/[C:20]2[S:21][C:22]([C:25]3[CH:30]=[CH:29][C:28]([CH:31]([CH3:33])[CH3:32])=[CH:27][CH:26]=3)=[CH:23][CH:24]=2)=[CH:12][CH:11]=1)[CH:3]1[CH2:8][CH2:7][O:6][CH2:5][CH2:4]1.[CH3:35][I:36]>CN(C=O)C>[I-:36].[CH3:1][N+:2]([CH:3]1[CH2:8][CH2:7][O:6][CH2:5][CH2:4]1)([CH3:35])[CH2:9][C:10]1[CH:11]=[CH:12][C:13]([NH:16][C:17](=[O:34])/[CH:18]=[CH:19]/[C:20]2[S:21][C:22]([C:25]3[CH:26]=[CH:27][C:28]([CH:31]([CH3:32])[CH3:33])=[CH:29][CH:30]=3)=[CH:23][CH:24]=2)=[CH:14][CH:15]=1
Reactant: CI
Reactant: CC(C)c1ccc(-c2ccc(/C=C/C(=O)Nc3ccc(CN(C)C4CCOCC4)cc3)s2)cc1
Solvent: CN(C)C=O
Product: CC(C)c1ccc(-c2ccc(/C=C/C(=O)Nc3ccc(C[N+](C)(C)C4CCOCC4)cc3)s2)cc1
Product: [I-]
Reaction time: 72 h

Procedure:
To a solution of (E)-N-[4-[N-methyl-N-(tetrahydropyran-4-yl)aminomethyl]phenyl]-3-[5-(4-isopropylphenyl)thiophen-2-yl]acrylamide (80 mg) in DMF (5 ml) was added at room temperature methyl iodide (0.04 ml), and the mixture was stirred for 3 days. Under reduced pressure, the solvent was evaporated, and to the residue was added acetonitrile. The resulting crystals were collected by filtration to give yellow crystals of N,N-dimethyl-N-[4-[[(E)-3-[5-(4-isopropylphenyl)thiophen-2-yl]-2-propenoyl]amino]benzyl]-4-tetrahydropyranyl ammonium iodide (Compound 280) (76.9 mg).
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:18](=[O:19])[N:17]2[C:12]([C:13]([CH3:21])([CH3:20])[O:14][CH2:15][CH2:16]2)=[N:11][C:10]=1[C:22]([OH:24])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:25][C:26]1[CH:31]=[CH:30][C:29]([CH2:32][NH2:33])=[C:28]([C:34]2[N:35]=[N:36][S:37][CH:38]=2)[CH:27]=1>>[F:25][C:26]1[CH:31]=[CH:30][C:29]([CH2:32][NH:33][C:22]([C:10]2[N:11]=[C:12]3[N:17]([C:18](=[O:19])[C:9]=2[O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH2:16][CH2:15][O:14][C:13]3([CH3:20])[CH3:21])=[O:24])=[C:28]([C:34]2[N:35]=[N:36][S:37][CH:38]=2)[CH:27]=1
Reactant: CC1(C)OCCn2c1nc(C(=O)O)c(OCc1ccccc1)c2=O
Reactant: NCc1ccc(F)cc1-c1csnn1
Product: CC1(C)OCCn2c1nc(C(=O)NCc1ccc(F)cc1-c1csnn1)c(OCc1ccccc1)c2=O

Procedure:
The title compound can be prepared from intermediate 27, 3-(benzyloxy)-9,9-dimethyl-4-oxo-4,6,7,9-tetrahydropyrimido-[2,1-c][1,4]oxazine-2-carboxylic acid and (4-fluoro-2-(1,2,3-thiadiazol-4-yl)phenyl)methanamine. 1HNMR 400 MHz (CDCl3) δ (ppm): 1.66 (6H, s, 2×CH3), 4.02 (4H, m, 2×CH2), 4.57 (2H, d, J=6.6 Hz, NCH2), 5.32 (2H, s, OCH2), 7.18 (1H, m, aromatic), 7.27–7.34 (4H, m, aromatics), 7.54 (2H, m, aromatics), 7.74 (1H, dd, J=6.2 Hz and J=8.6 Hz, aromatic), 8.71 (1H, s, CH), 8.80 (1H, broad t, NH). HRMS (ESI+) calculated for C26H25FN5O4S [M+H+]: 522.1611. found: 522.1601.
Reaction SMILES: [N:1]([C:4]1[CH:14]=[CH:13][C:7]([C:8]([NH:10][CH2:11][CH3:12])=[O:9])=[CH:6][CH:5]=1)=[N+:2]=[N-:3].[C:15]1([CH2:21][C:22](=O)[CH2:23][C:24]([O:26]CC)=[O:25])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.[O-]CC.[Na+].C(=O)([O-])[O-].[Na+].[Na+]>C(O)C>[CH2:21]([C:22]1[N:1]([C:4]2[CH:5]=[CH:6][C:7]([C:8]([NH:10][CH2:11][CH3:12])=[O:9])=[CH:13][CH:14]=2)[N:2]=[N:3][C:23]=1[C:24]([OH:26])=[O:25])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: CCOC(=O)CC(=O)Cc1ccccc1
Reactant: CCNC(=O)c1ccc(N=[N+]=[N-])cc1
Agent: CC[O-]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Product: CCNC(=O)c1ccc(-n2nnc(C(=O)O)c2Cc2ccccc2)cc1
Temperature: 80 °C
Reaction time: 2 h
Yield: 75.7 %

Procedure:
4-Azido-N-ethylbenzamide (0.571 g, 3.00 mmol) and ethyl 4-phenyl-3-oxobutyrate (0.692 g, 3.60 mmol, 1.25 eq.) were dissolved in ethanol (15 ml), sodium ethoxide (284 mg, 3.60 mmol, 1.25 eq.) was added, and the mixture was stirred at room temperature for 30 min and at 80° C. for 2 hr. 2% aqueous sodium carbonate solution (20 ml) was added to the reaction mixture, and the mixture was further stirred for 30 min. Ethanol was evaporated, and the residue was diluted with 2% aqueous sodium carbonate solution (20 ml) and washed with ethyl acetate (40 ml). The organic layer was extracted with 2% aqueous sodium carbonate solution (20 ml). The aqueous layers were combined, concentrated to about 30 ml, acidified (pH<3) with 6N hydrochloric acid and extracted with ethyl acetate (35 ml×2). The organic layers were combined, washed with saturated brine, dried over anhydrous sodium sulfate and concentrated, and diethyl ether and ethyl acetate were added. The precipitate was collected by filtration, washed with diethyl ether and dried to give the title compound as a pale-brown powder (796 mg, 2.27 mmol, 75.7%).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[C:18]([O:20][CH3:21])[N:17]=[CH:16][N:15]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.[ClH:22]>O1CCOCC1>[ClH:22].[CH3:21][O:20][C:18]1[CH:19]=[C:14]([N:11]2[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]2)[N:15]=[CH:16][N:17]=1
Reactant: COc1cc(N2CCN(C(=O)OC(C)(C)C)CC2)ncn1
Agent: Cl
Solvent: C1COCCO1
Product: COc1cc(N2CCNCC2)ncn1

Procedure:
8.61 g 4-(6-Methoxy-pyrimidin-4-yl)-piperazine-1-carboxylic acid tert-butyl ester were stirred in 4 mol/L HCl solution in dioxane for 1 h. The precipitates was filtered, washed with dioxane and dried to yield 5.17 g of the desired compound.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C@H:10]([OH:13])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CCN(CC)CC.[CH3:21][S:22](Cl)(=[O:24])=[O:23]>C(Cl)Cl.[Cl-].[Na+].O>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH:10]([O:13][S:22]([CH3:21])(=[O:24])=[O:23])[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(C)OC(=O)N1CC[C@H](O)C1
Agent: [Cl-]
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCC(OS(C)(=O)=O)C1
Reaction time: 1 h

Procedure:
To (S)-3-hydroxy-pyrrolidine-1-carboxylic acid tert-butyl ester (2.0 g, 10.9 mmol) in CH2Cl2 (50 mL) at 0° C. was added Et3N (1.4 g, 1.9 mL, 13.4 mmol) and methanesulfonyl chloride (1.38 g, 0.94 mL, 12.1 mmol). After 1 h, brine was added and the mixture extracted with CH2Cl2 (2×). The combined organics were dried to give 3-methanesulfonyloxy-pyrrolidine-1-carboxylic acid tert-butyl ester that was used without further purification.
Reaction SMILES: [C:1]([NH:9][NH2:10])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[K+].[C:13](=S)=[S:14]>C(O)C>[C:2]1([C:1]2[O:8][C:13]([SH:14])=[N:10][N:9]=2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: S=C=S
Reactant: NNC(=O)c1ccccc1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: Sc1nnc(-c2ccccc2)o1

Procedure:
To a 100 ml flask were added 2.7 g of benzoyl hydrazine, a solution of 1.2 g potassium hydroxide in ethanol (20 ml) and 3 g of carbon disulfide. The mixture was heated under reflux for 6 hours with stirring. The solvent was distilled under reduced pressure and water was added to dissolve the solid. The pH was adjusted to 6-7 with 10% hydrochloric acid and a lot of solid was precipitated, which was filtrated, and recrystallized with anhydrous ethanol to give 5-phenyl-2-mercapto-1,3,4-oxadiazole. MP: 212-214° C.