Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]2[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][S:17][C:18]3[NH:19][CH:20]=[C:21]([CH2:25][C:26]4[CH:27]=[N:28][CH:29]=[N:30][CH:31]=4)[C:22](=[O:24])[N:23]=3)=[CH:11][CH:10]=2)=[CH:4][C:3]=1[C:32]([F:35])([F:34])[F:33].[CH3:36]CN(C(C)C)C(C)C.CI>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]2[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][S:17][C:18]3[N:19]([CH3:36])[CH:20]=[C:21]([CH2:25][C:26]4[CH:31]=[N:30][CH:29]=[N:28][CH:27]=4)[C:22](=[O:24])[N:23]=3)=[CH:11][CH:10]=2)=[CH:4][C:3]=1[C:32]([F:34])([F:35])[F:33]
Reactant: CCN(C(C)C)C(C)C
Reactant: O=c1nc(SCCc2ccc(Oc3ccc(Cl)c(C(F)(F)F)c3)cc2)[nH]cc1Cc1cncnc1
Solvent: ClCCl
Solvent: CI
Product: Cn1cc(Cc2cncnc2)c(=O)nc1SCCc1ccc(Oc2ccc(Cl)c(C(F)(F)F)c2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 16.8 %

Procedure:
To the solution of 2-{[2-(4-{[4-chloro-3-(trifluoromethyl)phenyl]oxy}phenyl)ethyl]thio}-5-(5-pyrimidinylmethyl)-4(1H)-pyrimidinone (75 mg, 0.145 mmol) and DIPEA (0.08 mL, 0.458 mmol) in DCM (2 ml) was added MeI (0.014 mL, 0.217 mmol). The solution was stirred at room temperature overnight. Purification via MDAP then afforded the title compound (13 mg, 16.88% yield). LCMS: rt=3.45 min, [M+H+]=533
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([N:8]2[CH2:13][CH2:12][O:11][CH2:10][CH:9]2[CH2:14][OH:15])[C:5]([O:16]C)=[C:4]([Cl:18])[N:3]=1.[Cl-].[Li+]>CN(C=O)C>[Cl:1][C:2]1[N:3]=[C:4]([Cl:18])[C:5]([OH:16])=[C:6]([N:8]2[CH2:13][CH2:12][O:11][CH2:10][CH:9]2[CH2:14][OH:15])[N:7]=1
Reactant: COc1c(Cl)nc(Cl)nc1N1CCOCC1CO
Agent: [Cl-]
Agent: [Li+]
Solvent: CN(C)C=O
Product: OCC1COCCN1c1nc(Cl)nc(Cl)c1O
Temperature: 160 °C

Procedure:
A mixture of [4-(2,6-dichloro-5-methoxy-pyrimidin-4-yl)-morpholin-3-yl]-methanol (614 mg, 2.09 mmol) and lithium chloride (246 mg, 5.80 mmol) in anhydrous DMF (5 mL) was heated at 160° C. for 10 mins in a microwave reactor, then concentrated in vacuo to give 2,4-dichloro-6-(3-hydroxymethyl-morpholin-4-yl)-pyrimidin-5-ol. DIAD (452 μL, 2.3 mmol) was added to a solution of 2,4-dichloro-6-(3-hydroxymethyl-morpholin-4-yl)-pyrimidin-5-ol (2 mmol) and triphenyl phosphine (603 mg, 2.3 mmol) in 1,4-dioxane (5 mL) and the mixture stirred at RT for 1 h, then concentrated in vacuo. The resulting residue was purified by column chromatography (SiO2, 0 to 50% ethyl acetate in cyclohexane) affording 1,3-Dichloro-5,6,8a,9-tetrahydro-8H-7,10-dioxa-2,4,4b-triaza-phenanthrene (200 mg, 37%). LCMS (method A): RT=2.91 min, [M+H]−=262/264.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH:7]=[O:8])[CH:2]=1.[CH2:9](O)[CH2:10][OH:11].O>C1(C)C=CC=CC=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>[O:8]1[CH2:9][CH2:10][O:11][CH:7]1[C:3]1[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=1
Reactant: OCCO
Reactant: O=Cc1cccnc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: c1cncc(C2OCCO2)c1
Yield: 88.8 %

Procedure:
3-Pyridinecarboxaldehyde (3.00 mL, 31.8 mmol), ethylene glycol (2.66 mL, 47.7 mmol) and p-toluenesulfonic acid (302 mg, 1.59 mmol) were suspended in toluene (100 mL). The mixture was heated to reflux under a nitrogen atmosphere for 2 hours, during which produced water was removed by use of a Dean-Stark trap. Then, a saturated aqueous potassium carbonate solution was added to the reaction mixture, and extraction with ethyl acetate was performed, followed by washing with brine and drying over anhydrous sodium sulfate. The solvent was evaporated off under reduced pressure, and the residue was purified by column chromatography (hexane/ethyl acetate=1/1) to give 3-(1,3-dioxolan-2-yl)pyridine (4.27 g, yield: 89%).
Reaction SMILES: I[C:2]1[CH:3]=[CH:4][C:5]([N:8]2[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH2:9]2)=[N:6][CH:7]=1.[CH3:21][Si:22]([C:25]#[CH:26])([CH3:24])[CH3:23].C(N(CC)CC)C>CC(N(C)C)=O>[CH3:21][Si:22]([C:25]#[C:26][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH2:9]2)=[N:6][CH:7]=1)([CH3:24])[CH3:23]
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(I)cn2)CC1
Reactant: C#C[Si](C)(C)C
Solvent: CCN(CC)CC
Solvent: CC(=O)N(C)C
Product: CC(C)(C)OC(=O)N1CCN(c2ccc(C#C[Si](C)(C)C)cn2)CC1
Reaction time: 0.17 h
Yield: 70.4 %

Procedure:
To a stirred solution of tert-butyl 4-(5-iodopyridin-2-yl)piperazine-1-carboxylate (1.0 g, 2.57 mmol, prepared as in Example 1), trimethylsilyl acetylene (0.73 mL, 5.14 mmol), triethylamine (1.11 mL, 7.71 mmol), and cuprous iodide (196 mg, 1.03 mmol) in DMA (20 mL) at 25° C. was added tetrakistriphenylphosphine palladium (0) (149 mg, 5 mol %). The reaction was stirred for 10 minutes. Volatiles were removed in vacuo. The residue was then dissolved in ethyl acetate (250 mL) and washed with water (100 mL). The layers were then separated and the aqueous phase extracted with ethyl acetate (250 mL). The combined organic extracts were then dried, (MgSO4), filtered and concentrated in vacuo. The residue was then purified by flash chromatography (silica gel, 10% EtOAc in hexanes) to give tert-butyl 4-{5-[(trimethylsilyl)ethynyl]pyridin-2-yl}piperazine-1-carboxylate as a pale brown solid (652 mg, 1.81 mmol, 70%).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:14]([O:15][CH3:16])=[CH:13][C:12]2=[C:17]3[C:4]=1[CH2:5][CH:6](O)[N:7]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:8]3=[N:9][CH:10]=[N:11]2.C(N(CC)CC)C.CS(Cl)(=O)=O>ClCCl>[CH3:1][O:2][C:3]1[C:14]([O:15][CH3:16])=[CH:13][C:12]2=[C:17]3[C:4]=1[CH:5]=[CH:6][N:7]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:8]3=[N:9][CH:10]=[N:11]2
Reactant: COc1cc2ncnc3c2c(c1OC)CC(O)N3c1ccccc1
Agent: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1cc2ncnc3c2c(c1OC)C=CN3c1ccccc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 7,8-dimethoxy-4-phenyl-5,6-dihydro-4H-1,3,4-triaza-phenalen-5-ol (91 mg, 0.28 mmol) (from Example 20, Step A, supra) and triethylamine (0.23 mL, 1.69 mmol) in dichloromethane (50 mL) at 0° C. was added methanesulfonyl chloride (0.087 mL, 1.12 mmol) (Aldrich). The reaction solution was the stirred at room temperature for 2 hours. The solution was then concentrated, the residue was purified by chromatography using EtOAc/CH2Cl2/NEt3 (1:4:0.05) as eluent to give the desired 7,8-dimethoxy-4-phenyl-4H-1,3,4-triaza-phenalene as a white solid. (Yield 47 mg, 55%).
Reaction SMILES: [N+:1]([C:4]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:5]=1[CH:6]=[CH:7][C:8]([C:14]([F:17])([F:16])[F:15])=[N:9]2)([O-])=O.C(=O)([O-])[O-].[K+].[K+]>CO.[Pd]>[NH2:1][C:4]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:5]=1[CH:6]=[CH:7][C:8]([C:14]([F:17])([F:15])[F:16])=[N:9]2
Reactant: O=[N+]([O-])c1cccc2nc(C(F)(F)F)ccc12
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: Nc1cccc2nc(C(F)(F)F)ccc12
Temperature: 25 °C
Reaction time: 20 h

Procedure:
390 mg (1.61 mmol) of 5-nitro-2-(trifluoromethyl)quinoline is dissolved in 13 ml of methanol. After the addition of 39 mg of palladium on carbon and 19 mg of potassium carbonate, the reaction mixture is allowed to stir for 20 hours at room temperature under hydrogen atmosphere. It is then filtered on Celite and washed with ethyl acetate. After the solvent is removed in a vacuum and after chromatography on silica gel with hexane-ethyl acetate (0–100%), 250 mg (73% of theory) of the product is obtained.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]([OH:17])=O)=[N:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:18][C:19]1[CH:20]=[C:21]([CH:28]=[CH:29][C:30]=1[CH3:31])[C:22]([NH:24][CH:25]1[CH2:27][CH2:26]1)=[O:23]>>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]([NH:18][C:19]2[CH:20]=[C:21]([C:22]([NH:24][CH:25]3[CH2:26][CH2:27]3)=[O:23])[CH:28]=[CH:29][C:30]=2[CH3:31])=[O:17])=[N:13][CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)c1ccc(OCc2ccccc2)cn1
Reactant: Cc1ccc(C(=O)NC2CC2)cc1N
Product: Cc1ccc(C(=O)NC2CC2)cc1NC(=O)c1ccc(OCc2ccccc2)cn1

Procedure:
The title compound was prepared from 5-(benzyloxy)pyridine-2-carboxylic acid and 3-amino-N-cyclopropyl-4-methylbenzamide according to the method described for Example 1; NMR Spectrum: (DMSOd6) 0.58 (m, 2H), 0.69 (m, 2H), 2.32 (s, 3H), 2.86 (m, 1H), 5.32 (s, 2H), 7.39 (m, 4H), 7.51 (m, 2H), 7.57 (m, 1H), 7.71 (m, 1H), 8.13 (m, 1H), 8.22 (m, 1H), 8.36 (m, 1H), 8.48 (s, 1H), 10.16 (s, 1H); Mass Spectrum: M+Na+ 424.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][CH:11]=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:13]([O:17][C:18]([CH:20]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)=[O:19])([CH3:16])([CH3:15])[CH3:14]>C1COCC1>[C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][CH:11]=[CH:20][C:18]([O:17][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:19])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=CCCCCc1ccccc1
Reactant: CC(C)(C)OC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)C=CCCCCc1ccccc1
Reaction time: 2.5 h
Yield: 79.4 %

Procedure:
To a solution of 5-phenylpentanal (60 mmol) in anhydrous THF (100 mL) at room temperature is added (t-butoxycarbonylmethylene)triphenyl-phosphorane (27.5 g, 72 mmol). The resulting orange solution is stirred for 2.5 hours, after which TLC analysis indicated complete reaction. The reaction mixture is concentrated in vacuo to afford a crude product which is chromatographed on silica gel (hexane/EtOAc, 19:1) to afford 12.4 g of t-butyl 7-phenyl-2-heptenoate (80%) as a colorless oil. TLC [pet-ether/EtOAc, 9:1, Rf (aldehyde)=0.60, Rf (ester)=0.80]. 1H NMR (300 MHz, CDCl3) δ 1.45 (s, 9H), 1.65 (m, 4H), 2.18 (q, 2H), 2.61 (t, 2H), 5.70 (d, 1H), 6.82 (dt, 1H), 7.10-7.30 (m, 5H) ppm.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([OH:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10](=[O:15])[C:11]([F:14])([F:13])[F:12].C([O-])([O-])=O.[K+].[K+].Br[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30].Cl>CN(C=O)C>[OH:1][C:2]1[CH:7]=[C:6]([O:8][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])[CH:5]=[CH:4][C:3]=1[NH:9][C:10](=[O:15])[C:11]([F:12])([F:13])[F:14]
Reactant: CCCCCCCCBr
Reactant: O=C(Nc1ccc(O)cc1O)C(F)(F)F
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCCCCCCOc1ccc(NC(=O)C(F)(F)F)c(O)c1
Temperature: 25 °C
Reaction time: 48 h
Yield: 82.5 %

Procedure:
To a solution of N-(2,4-dihydroxy phenyl)-2,2,2-trifluoro-acetamide (0.44 g; 2 mmol) in DMF (4 mL) was added K2CO3 and 1-bromooctane (0.37 mL; 2.1 mmol). The slurry was stirred for 2 days at room temperature, poured onto 0.1 M HCl (aq.; 50 mL) and then extracted with diethylether (30 mL). The organic phase was dried (MgSO4), filtered and the eluate evaporated to leave 550 mg of black solid which was purified by chromatography (SiO2; PE80-100° C./EtOAc=4:1) to leave 100 mg (15%) of a pure white solid. Mp. 114-116° C.; MS (GC-MS; Cl): 334 (MH+).
Reaction SMILES: Cl[C:2]1[N:7]=[N:6][C:5]([C:8]([NH2:10])=[O:9])=[C:4]([NH:11][C:12]2[N:17]=[C:16]3[CH2:18][CH2:19][CH2:20][C:15]3=[CH:14][CH:13]=2)[CH:3]=1.[NH2:21][C@@H:22]1[CH2:27][CH2:26][CH2:25][CH2:24][C@@H:23]1[NH:28][C:29](=[O:35])[O:30][C:31]([CH3:34])([CH3:33])[CH3:32]>CN1CCCC1=O>[C:8]([C:5]1[N:6]=[N:7][C:2]([NH:21][C@@H:22]2[CH2:27][CH2:26][CH2:25][CH2:24][C@@H:23]2[NH:28][C:29](=[O:35])[O:30][C:31]([CH3:33])([CH3:32])[CH3:34])=[CH:3][C:4]=1[NH:11][C:12]1[N:17]=[C:16]2[CH2:18][CH2:19][CH2:20][C:15]2=[CH:14][CH:13]=1)(=[O:9])[NH2:10]
Reactant: NC(=O)c1nnc(Cl)cc1Nc1ccc2c(n1)CCC2
Reactant: CC(C)(C)OC(=O)N[C@H]1CCCC[C@H]1N
Solvent: CN1CCCC1=O
Product: CC(C)(C)OC(=O)N[C@H]1CCCC[C@H]1Nc1cc(Nc2ccc3c(n2)CCC3)c(C(N)=O)nn1
Temperature: 120 °C
Yield: 73.6 %

Procedure:
A solution of 6-chloro-4-(6,7-dihydro-5H-cyclopenta[b]pyridin-2-ylamino)pyridazine-3-carboxamide (375 mg, 1.29 mmol) and tert-butyl (1S,2R)-2-aminocyclohexylcarbamate (555 mg, 2.59 mmol) in N-methyl-2-pyrrolidinone (3 mL) was treated with tert-butyl (1S,2R)-2-aminocyclohexylcarbamate (555 mg, 2.59 mmol), The reaction mixture was heated at 120° C. for 72 h, then cooled to room temperature, concentrated under high vacuum and the residue obtained was purified by chromatography (spherical silica 20-45 μM, 80 g, Versaflash Supelco, 0 to 5% of a 9:1 MeOH:NH4OH solution in CH2Cl2, 20 min) to give tert-butyl (1S,2R)-2-(6-carbamoyl-5-(6,7-dihydro-5H-cyclopenta[b]pyridin-2-ylamino)pyridazin-3-ylamino)cyclohexylcarbamate (444 mg, 73%) as a light brown foam. 1H NMR (CHLOROFORM-d) δ: 11.30 (s, 1H), 8.19 (s, 1H), 8.06 (d, J=3.4 Hz, 1H), 7.40 (d, J=8.3 Hz, 1H), 6.75-7.10 (m, 1H), 6.61 (d, J=8.3 Hz, 1H), 5.77-6.14 (m, 2H), 3.99 (m, 1H), 3.55-3.74 (m, 1H), 2.67-3.05 (m, 4H), 2.11 (quin, J=7.5 Hz, 2H), 1.18-2.01 (m, 17H); LC-MS 468.2 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH:7]=[CH:8][C:9](=[O:29])[N:10]2[CH2:13][CH2:14][N:15]2[CH2:20][CH2:19][CH:18]([NH:21]C(=O)OC(C)(C)C)[CH2:17][CH2:16]2)=[N:5][CH:4]=1>C(Cl)(Cl)Cl.FC(F)(F)C(O)=O>[NH2:21][CH:18]1[CH2:17][CH2:16][N:15]([CH2:14][CH2:13][N:10]2[C:11]3[C:6](=[N:5][CH:4]=[C:3]([O:2][CH3:1])[CH:12]=3)[CH:7]=[CH:8][C:9]2=[O:29])[CH2:20][CH2:19]1
Reactant: COc1cnc2ccc(=O)n(CCN3CCC(NC(=O)OC(C)(C)C)CC3)c2c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClC(Cl)Cl
Product: COc1cnc2ccc(=O)n(CCN3CCC(N)CC3)c2c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 65.9 %

Procedure:
To a solution of 4.36 g of tert-butyl (1-(2-(7-methoxy-2-oxo-1,5-naphthyridin-1(2H)-yl)ethyl)piperidin-4-yl)carbamate in 50 mL of chloroform, 10 mL of trifluoroacetic acid was added, and the mixture was stirred at room temperature for 1 hour. After the solvent was distilled off under reduced pressure, the reaction mixture was alkalified with a saturated aqueous sodium hydrogen carbonate solution, the solvent was then distilled off under reduced pressure, and the resultant residue was purified by silica gel column chromatography using silica gel; Chromatorex-NH made by Fuji Silysia Chemical Ltd., and an eluent of chloroform:methanol=10:1 to obtain 2.16 g of 1-(2-(4-aminopiperidin-1-yl)ethyl)-7-methoxy-1,5-naphthyridin-2(1H)-one as a yellow oily substance.
Reaction SMILES: [CH2:1]([C:5]1[N:6]([CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[Cl:25])[C:7](/[C:10](/[CH3:17])=[CH:11]/[C:12]([O:14]CC)=[O:13])=[CH:8][N:9]=1)[CH2:2][CH2:3][CH3:4]>C(OCC)(=O)C.CO>[CH2:1]([C:5]1[N:6]([CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[Cl:25])[C:7](/[C:10](/[CH3:17])=[CH:11]/[C:12]([OH:14])=[O:13])=[CH:8][N:9]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1ncc(/C(C)=C/C(=O)OCC)n1Cc1ccccc1Cl
Solvent: CCOC(C)=O
Solvent: CO
Product: CCCCc1ncc(/C(C)=C/C(=O)O)n1Cc1ccccc1Cl

Procedure:
The title compound was prepared according to Example 1(v) by using ethyl (E)-3-[2-n-butyl-1-{(2-chlorophenyl)methyl}-1H-imidazol-5-yl]-3-methyl-2-propenoate in place of ethyl-(E)-3-[2-n-butyl-1-{(2-chlorgphenyl)methyl}-1H-imidazol-5-yl]-2-methyl-2-propenoate. The title compound was a white solid, and was converted to the hydrochloride salt to give 82 mg (41%); mp 198°-199.5° C. (from ethyl acetate/methanol).
Reaction SMILES: C([O:8][C:9]1[CH:10]=[CH:11][C:12]2[CH2:18][CH:17]([NH:19][C:20]([N:22]3[CH2:27][CH2:26][CH:25]([N:28]4[CH2:37][C:36]5[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=5)[NH:30][C:29]4=[O:38])[CH2:24][CH2:23]3)=[O:21])[C:16](=[O:39])[N:15]([CH3:40])[CH2:14][C:13]=2[CH:41]=1)C1C=CC=CC=1.[H][H]>CO.[Pd]>[OH:8][C:9]1[CH:10]=[CH:11][C:12]2[CH2:18][CH:17]([NH:19][C:20]([N:22]3[CH2:27][CH2:26][CH:25]([N:28]4[CH2:37][C:36]5[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=5)[NH:30][C:29]4=[O:38])[CH2:24][CH2:23]3)=[O:21])[C:16](=[O:39])[N:15]([CH3:40])[CH2:14][C:13]=2[CH:41]=1
Reactant: CN1Cc2cc(OCc3ccccc3)ccc2CC(NC(=O)N2CCC(N3Cc4ccccc4NC3=O)CC2)C1=O
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: CN1Cc2cc(O)ccc2CC(NC(=O)N2CCC(N3Cc4ccccc4NC3=O)CC2)C1=O
Reaction time: 12 h

Procedure:
To a stirred solution of 4-(2-oxo-1,4-dihydro-2H-quinazolin-3-yl)-piperidine-1-carboxylic acid (8-benzyloxy-2-methyl-3-oxo-2,3,4,5-tetrahydro-1H-benzo[c]azepin-4-yl)-amide (187 mg, 0.34 mmol) in methanol (30 mL) followed by 10% palladium on carbon (30 mg) under nitrogen. The reaction mixture was brought to 1 atmosphere of hydrogen and stirred for 12 h. The catalyst was filtered and the solvent was evaporated to give 4-(2-Oxo-1,4-dihydro-2H-quinazolin-3-yl)-piperidine-1-carboxylic acid (8-hydroxy-2-methyl-3-oxo-2,3,4,5-tetrahydro-1H-benzo[c]azepin-4-yl)-amide in quantitative yield. MS (ESI) 464 (M+H); Rf=1.34.
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[C:11]([S:13]([CH3:16])(=[O:15])=[O:14])[CH:10]=[CH:9][C:5]=1[C:6](Cl)=[O:7])([O-:3])=[O:2].[CH3:17][N:18]1[C:22]([CH2:23][C:24]#[N:25])=[N:21][CH:20]=[N:19]1.C(N(C(C)C)CC)(C)C.Cl>CO>[N+:1]([C:4]1[CH:12]=[C:11]([S:13]([CH3:16])(=[O:15])=[O:14])[CH:10]=[CH:9][C:5]=1[C:6]([CH:23]([C:22]1[N:18]([CH3:17])[N:19]=[CH:20][N:21]=1)[C:24]#[N:25])=[O:7])([O-:3])=[O:2]
Reactant: CS(=O)(=O)c1ccc(C(=O)Cl)c([N+](=O)[O-])c1
Reactant: Cn1ncnc1CC#N
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CO
Product: Cn1ncnc1C(C#N)C(=O)c1ccc(S(C)(=O)=O)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 16 h

Procedure:
263 mg (1.0 mmol) of 2-nitro-4-(methylsulfonyl)benzoyl chloride are added at 0° C. to 122 mg (1.0 mmol) of 2-(1-methyl-1,2,4-triazol-5-yl)acetonitrile and 258 mg (2 mmol) of diisopropylethylamine. The mixture is then stirred at room temperature for 16 h. 1 ml of methanol is then added and, after 15 min, 2N HCl is added. The mixture is extracted with dichloromethane, dried over Na2SO4, evaporated and purified by means of RP-HPLC (acetonitrile/water). Yield 156 mg (45%).
Reaction SMILES: [C:1]([Si:5]([CH3:13])([CH3:12])[O:6][C:7]([CH3:11])([CH3:10])[C:8]#[CH:9])([CH3:4])([CH3:3])[CH3:2].[O:14]1CCC[CH2:15]1.CN(C)C=O>CCCCCC>[C:1]([Si:5]([CH3:13])([CH3:12])[O:6][C:7]([CH3:11])([CH3:10])[C:8]#[C:9][CH:15]=[O:14])([CH3:4])([CH3:3])[CH3:2]
Reactant: C1CCOC1
Reactant: C#CC(C)(C)O[Si](C)(C)C(C)(C)C
Solvent: CN(C)C=O
Solvent: CCCCCC
Product: CC(C)(C#CC=O)O[Si](C)(C)C(C)(C)C
Temperature: -78 °C
Yield: 78 %

Procedure:
To the solution of 10 g (50 mmol) of 3-(tert.butyldimethylsilyl)oxy-3-methyl-butyne in 25 ml. of anhydrous tetrahydrofuran cooled at -78° C. in an argon atmosphere was added dropwise over a 40 minute period 40 ml (0.64 mmol) 1.6M solution of N-butyl lithium in hexane, which was followed by addition of 31 ml (400 mmol) of N,N-dimethylformamide. The reaction mixture was stirred for an additional one-half hour at -78° C., and then quenched by addition of ice and pouring into 300 ml of brine. It was then extracted with pentane. The pentane extract was washed with saturated ammonium chloride solution, water and brine, dried over anhydrous sodium sulfate and evaporated to dryness. The crude product was purified by distillation at 113°-115° C./25 mmHg. It gave 8.88 g (78%) of the title compound.
Reaction SMILES: [Cl-:1].[OH:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C@H:10]([NH3+:15])[C:11]([O:13][CH3:14])=[O:12])=[CH:5][C:4]=1[O:16][C:17](=[O:20])[NH:18][CH3:19].[CH2:21]([O:23]CC)[CH3:22]>C(O)(=O)C>[Cl-:1].[C:21]([O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C@H:10]([NH3+:15])[C:11]([O:13][CH3:14])=[O:12])=[CH:5][C:4]=1[O:16][C:17](=[O:20])[NH:18][CH3:19])(=[O:23])[CH3:22]
Reactant: CNC(=O)Oc1cc(C[C@H]([NH3+])C(=O)OC)ccc1O
Reactant: CCOCC
Agent: [Cl-]
Solvent: CC(=O)O
Product: CNC(=O)Oc1cc(C[C@H]([NH3+])C(=O)OC)ccc1OC(C)=O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
(S)-2-(4-Hydroxy-3-methylcarbamoyloxyphenyl)-1-methoxycarbonylethylammonium chloride (1.68 g, 6.26 mM) was dissolved in acetic acid (25 ml). HCl (g) was bubbled through the reaction mixture for 5 minutes before adding acetyl chloride (4.45 ml, 62.6 mM) dropwise. The reaction mixture was stirred at room temperature for 2 h. The mixture was concentrated to approximately half of its initial reaction volume. Diethyl ether was added to afford a solid. The solvent was evaporated and the residue was triturated with diethyl ether. The product was collected by filtration and dried under vacuum to constant weight to afford (S)-2-(4-Acetoxy-3-methylcarbamoyloxy-phenyl)-1-methoxycarbonyl-ethyl-ammonium chloride as a solid, 1.55 g. 1H-NMR (500 MHz, DMSO-d6): δ=2.23 (s, 3H), 2.65 (d, J=4.6 Hz, 3H), 3.08-3.11 (m, J=14.35 Hz, 7.1 Hz, 1H), 3.14-3.17 (m, J=14.15 Hz, 5.9 Hz, 1H), 3.68 (s, 3H), 4.28 (t, 1H, CH), 7.10-7.17 (m, 3H), 7.70 (q, J=4.55 Hz, 1H), 8.59 (s, 3H). HPLC/MS (Method A) retention time 2.85 min, m/z 311 (MH+).
Reaction SMILES: [CH2:1]([C@@H:8]1[CH2:12][O:11][C:10](=[O:13])[N:9]1[C:14](=[O:19])[CH2:15][CH2:16][CH:17]=[CH2:18])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Na+].Br[CH2:31][C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33]>C1COCC1>[CH2:1]([C@@H:8]1[CH2:12][O:11][C:10](=[O:13])[N:9]1[C:14]([C@@H:15]([CH2:16][CH:17]=[CH2:18])[CH2:31][C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])=[O:19])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C=CCCC(=O)N1C(=O)OC[C@H]1Cc1ccccc1
Reactant: CC(C)(C)OC(=O)CBr
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: C1CCOC1
Product: C=CC[C@@H](CC(=O)OC(C)(C)C)C(=O)N1C(=O)OC[C@H]1Cc1ccccc1
Temperature: -78 °C
Reaction time: 0.33 h
Yield: 92.7 %

Procedure:
A dry round bottom flask was charged with 1a (3.2 g, 12.34 mmol) and dry THF (123 mL) and then cooled to −78° C. To this solution NaHMDS (1M in THF, 13.57 mL, 13.57 mmol) was added over a period of 10 minutes. To ensure complete enolization, the reaction mixture was stirred for an additional 20 minutes at −78° C. A solution of tert-butyl bromoacetate (2.74 mL, 18.51 mmol) in THF (6 mL) was then introduced to the reaction flask. The solution was stirred for 1 hour at −78° C. and then warmed to −48° C. while still stirring. The reaction was monitored by TLC (˜3 h) and quenched with saturated aqueous NH4Cl. The reaction mixture was concentrated by the removing the THF under reduced pressure. The residue was then diluted with dichloromethane. This solution was washed successively with water and brine, dried over Na2SO4, and concentrated under reduced pressure to give white crystals of 2a (4.27 g, 93%). 1H NMR (500 MHz, CDCl3): δ ppm 7.32-7.37 (m, 2H) 7.27-7.30 (m, 3H) 5.74-5.85 (m, 1H) 5.05-5.13 (m, 2H) 4.63-4.70 (m, 1H) 4.25-4.32 (m, 1H) 4.16 (d, J=4.9 Hz, 2H) 3.34 (dd, J=13.4, 2.7 Hz, 1H) 2.74-2.87 (m, 2H) 2.39-2.52 (m, 2H) 2.19-2.26 (m, 1H) 1.44 (s, 9H); 13C NMR (126 MHz, CDCl3): δ 175.0, 171.1, 153.0, 135.6, 134.4, 129.4, 128.8, 127.1, 117.7, 80.6, 65.8, 55.4, 39.0, 37.5, 36.6, 36.1, 28.0. HRMS calcd for C21H27NO5 (M+H) m/z 374.1967, found 374.1971.
Reaction SMILES: I[C:2]1[CH:10]=[CH:9][C:8]([O:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][C:13]=2[Cl:22])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[CH2:23]([SH:25])[CH3:24].[H-].[Na+].Cl>CN(C)C=O>[CH2:23]([S:25][C:2]1[CH:10]=[CH:9][C:8]([O:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][C:13]=2[Cl:22])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5])[CH3:24]
Reactant: O=C(O)c1cc(Oc2ccc(C(F)(F)F)cc2Cl)ccc1I
Reactant: CCS
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCSc1ccc(Oc2ccc(C(F)(F)F)cc2Cl)cc1C(=O)O

Procedure:
2-Iodo-5-(2-chloro-4-trifluoromethylphenoxy) benzoic acid (0.1 mole) in dimethylformamide (500 ml) was cooled to 0°. Cuprous oxide (0.11 mole) was added, followed by ethyl mercaptan (0.1 mole). The mixture was stirred while sodium hydride (0.25 mole) was added in portions. After 15 minutes the temperature was raised to 80° for 6 hours. The mixture was cooled and poured into hydrochloric acid (2 molar). The mixture was twice extracted with ether. The ether extract was washed with water, dried (Na2SO4) and evaporated. The residue was recrystallised from ether to give 2-ethylthio-5-(2-chloro-4-trifluoromethylphenoxy)benzoic acid, with a melting point of 153°-155°.