Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[CH2:2][C:3]1[N:4]=[C:5]([C:9]2[CH:18]=[CH:17][C:12]([C:13]([O:15][CH3:16])=[O:14])=[CH:11][CH:10]=2)[O:6][C:7]=1[CH3:8].[CH3:19][C:20]1[CH:25]=[CH:24][C:23]([SH:26])=[CH:22][CH:21]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C=O.O>[CH3:8][C:7]1[O:6][C:5]([C:9]2[CH:18]=[CH:17][C:12]([C:13]([O:15][CH3:16])=[O:14])=[CH:11][CH:10]=2)=[N:4][C:3]=1[CH2:2][S:26][C:23]1[CH:24]=[CH:25][C:20]([CH3:19])=[CH:21][CH:22]=1
Reactant: COC(=O)c1ccc(-c2nc(CCl)c(C)o2)cc1
Reactant: Cc1ccc(S)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1ccc(-c2nc(CSc3ccc(C)cc3)c(C)o2)cc1
Yield: 77.5 %

Procedure:
A solution of methyl 4-(4-(chloromethyl)-5-methyloxazol-2-yl)benzoate (6 g, 22.64 mmol, 1.00 equiv), 4-methylbenzenethiol (4.2 g, 33.87 mmol) and cesium carbonate (8.8 g, 26.99 mmol, 1.19 equiv) in N,N-dimethylformamide (120 mL) was stirred under nitrogen overnight at 50° C. The reaction mixture was diluted with 100 mL of water and extracted with 3×150 mL of ethyl acetate. The combined organic layers was washed with 3×50 mL of brine, dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was triturated with 2×50 mL of hexane. The solid was collected by filtration and dried in vacuum to yield 6.2 g (78%) of methyl 4-(5-methyl-4-(p-tolylthiomethyl)oxazol-2-yl)benzoate as a yellow solid. LC-MS: (ES, m/z): 395 [M+CH3CN+H]+, 354 [M+H]+, 271, 203, 126, 120.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([O:12][C:13]2[CH:18]=[CH:17][N:16]=[C:15]3[NH:19][C:20](=[O:22])[NH:21][C:14]=23)=[CH:4][CH:3]=1.[N:23]([C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([C:32]([F:35])([F:34])[F:33])[CH:27]=1)=[C:24]=[O:25]>>[O:22]=[C:20]1[NH:19][C:15]2=[N:16][CH:17]=[CH:18][C:13]([O:12][C:5]3[C:6]4[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=4)[C:2]([NH:1][C:24]([NH:23][C:26]4[CH:31]=[CH:30][CH:29]=[C:28]([C:32]([F:33])([F:34])[F:35])[CH:27]=4)=[O:25])=[CH:3][CH:4]=3)=[C:14]2[NH:21]1
Reactant: Nc1ccc(Oc2ccnc3[nH]c(=O)[nH]c23)c2ccccc12
Reactant: O=C=Nc1cccc(C(F)(F)F)c1
Product: O=C(Nc1cccc(C(F)(F)F)c1)Nc1ccc(Oc2ccnc3[nH]c(=O)[nH]c23)c2ccccc12
Yield: 64.7 %

Procedure:
Method H2 was used with 7-(4-aminonaphthalen-1-yl-oxy)-1H-imidazo[4,5-b]pyridin-2(3H)-one (30 mg, 0.10 mmol) and 1-isocyanato-3-(trifluoromethyl)benzene (21 mg, 0.11 mmol) to afford the title compound as a brown solid (31 mg, 65%). 1H-NMR (δ, ppm, DMSO-d6): 6.21 (d, 1H, HPy,5, J=5.5 Hz), 7.32 (m, 2H, Harom,Naph), 7.53-7.71 (m, 5H, Harom,naph+Ph′), 7.96 (t, 2H, Harom,naph), 8.09 (s, 1H, Harom,Ph), 8.19 (d, 1H, HPy,6, J=5.5 Hz), 8.96 and 9.46 (bs, 2H, NHurea) 11.39 (s, NH, NHPy), 11.44 (s, NH, NHPy). LC-MS (m/z): 480 (M+H, 100).
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([O:8][C:9]([F:12])([F:11])[F:10])[CH:5]=[CH:4][C:3]=1[O:13][C@H:14]([CH2:16][CH:17]=[CH2:18])[CH3:15].FC1C(F)=CC([B:27]2[O:34][C:33](=[O:35])[CH2:32][N:31]([CH3:36])[CH2:30][C:29](=[O:37])[O:28]2)=C(O[C@H](CC=C)C)C=1>>[CH3:36][N:31]1[CH2:32][C:33](=[O:35])[O:34][B:27]([C:2]2[CH:7]=[C:6]([O:8][C:9]([F:12])([F:11])[F:10])[CH:5]=[CH:4][C:3]=2[O:13][C@H:14]([CH2:16][CH:17]=[CH2:18])[CH3:15])[O:28][C:29](=[O:37])[CH2:30]1
Reactant: C=CC[C@H](C)Oc1cc(F)c(F)cc1B1OC(=O)CN(C)CC(=O)O1
Reactant: C=CC[C@H](C)Oc1ccc(OC(F)(F)F)cc1Br
Product: C=CC[C@H](C)Oc1ccc(OC(F)(F)F)cc1B1OC(=O)CN(C)CC(=O)O1
Yield: 68 %

Procedure:
Prepared in 68% yield from (S)-2-bromo-1-(pent-4-en-2-yloxy)-4-(trifluoromethoxy)benzene following the same procedure as (S)-2-(4,5-difluoro-2-(pent-4-en-2-yloxy)phenyl)-6-methyl-1,3,6,2-dioxazaborocane-4,8-dione. 1H NMR (400 MHz, CDCl3) δ 7.57 (d, J=3.0 Hz, 1H), 7.23 (dd, J=8.8, 3.0 Hz, 1H), 6.93 (d, J=8.8 Hz, 1H), 5.90-5.77 (m, 1H), 5.19-5.11 (m, 2H), 4.69-4.60 (m, 1H), 4.12 (d, J=16.1 Hz, 1H), 4.01-3.85 (m, 3H), 2.71 (s, 3H), 2.53 (dt, J=14.4, 7.1 Hz, 1H), 2.44-2.34 (m, 1H), 1.32 (d, J=6.0 Hz, 3H); 19F NMR (376 MHz, CDCl3) δ −58.20 (s, 3F).
Reaction SMILES: C([C:4]1([OH:16])[CH:15]=[CH:14][C:7]([CH2:8][C@@H:9]([C:11]([OH:13])=[O:12])[NH2:10])=[CH:6][CH2:5]1)C=C.N[C@H:18]([C:27](O)=O)[CH2:19]C1C=CC(O)=CC=1.C(Br)C=C>>[CH2:27]([NH:10][C@H:9]([C:11]([OH:13])=[O:12])[CH2:8][C:7]1[CH:6]=[CH:5][C:4]([OH:16])=[CH:15][CH:14]=1)[CH:18]=[CH2:19]
Reactant: N[C@@H](Cc1ccc(O)cc1)C(=O)O
Reactant: C=CCC1(O)C=CC(C[C@H](N)C(=O)O)=CC1
Solvent: C=CCBr
Product: C=CCN[C@@H](Cc1ccc(O)cc1)C(=O)O

Procedure:
The compound of Formula II, 4-ally-L-tyrosine, is synthesized according to the scheme set forth in FIG. 13. A protected tyrosine, e.g., an Nboc or Fmoc protected tyrosine, is reacted with allyl bromide, resulting in a protected allyl tyrosine, which is then typically deprotected to yield 4-allyl-L-tyrosine. For example, N-(tert-Butoxycarbonyl)-L-tyrosine (2.95 g, 10 mmole) was dissolved in 80 ml of DMF. The solution was chilled to 5° C. and NaH (0.63 g, 26 mmole) was added. The reaction mixture was allowed to warm up to 10° C. and stirred for additional 2 hours. After that, allyl bromide (1.33 g, 11 mmole) was added to the mixture and reaction was warmed to room temperature. The reaction mixture was stirred for 4 hours. Water was added to work up the reaction. The aqueous layer was extracted with ethyl acetate and CH2Cl2. The organic layer was dried over anhydrous MgSO4. The organic solvent was removed to give white solid. This compound was then refluxed in 4M HCl in 1.4-dioxane for 4 hours. All the solvent was evaporated to give the desired product as white solid (1.9 g, 86%). 1HNMR (CD3OD): d ppm 3.1(m, 2H), 4.1 (t, 1H), 4.5 (d, 2H), 5.3 (q, 1H), 5.9 (m, 1H), 6.9 (d, 2H), 7.1 (d, 2H). Calculated molecular weight: 221, obtained molecular weight: 222.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:6]=[N:7][C:8]([OH:12])=[C:9]([Br:11])[CH:10]=1)=[O:4].[CH3:13][N:14]1[CH:18]=[CH:17][N:16]=[C:15]1[CH2:19]O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(OC(N=NC(OC(C)C)=O)=O)(C)C>O1CCCC1>[CH3:1][O:2][C:3](=[O:4])[C:5]1[CH:10]=[C:9]([Br:11])[C:8]([O:12][CH2:19][C:15]2[N:14]([CH3:13])[CH:18]=[CH:17][N:16]=2)=[N:7][CH:6]=1
Reactant: COC(=O)c1cnc(O)c(Br)c1
Reactant: Cn1ccnc1CO
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COC(=O)c1cnc(OCc2nccn2C)c(Br)c1
Reaction time: 1 h
Yield: 27.1 %

Procedure:
5-Bromo-6-hydroxy-3-pyridinecarboxylic acid methyl ester (1.0 g, 4.3 mmol) was suspended in tetrahydrofurane, 1-methyl-1H-imidazole-2-methanol (0.72 g, 6.5 mmol) and triphenylphosphine was added (1.70 g, 6.5 mmol). To this mixture was added with stirring diisopropyl-azodicarboxylate (1.35 mL, 6.5 mmol) at room temperature. Stirring was continued for 1 h at room temperature, solvent was removed and the residue was purified by chromatography with heptane/ethylacetate/methanol on silica gel to yield 0.38 g of the title compound as a colorless solid, MS (ISP) 326.0, 328.0 (M+H)+.
Reaction SMILES: [CH3:1][N:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][C:5](=[O:12])[N:4]([C:13]2[C:14]([F:35])=[CH:15][C:16]3[O:20][N:19]=[C:18]([C:21]4[CH:26]=[C:25]([O:27][CH2:28][C:29]([O:31]C)=[O:30])[CH:24]=[CH:23][C:22]=4[CH3:33])[C:17]=3[CH:34]=2)[C:3]1=[O:36].Cl.C(O)(=O)C>O>[CH3:1][N:2]1[C:7]([C:8]([F:10])([F:11])[F:9])=[CH:6][C:5](=[O:12])[N:4]([C:13]2[C:14]([F:35])=[CH:15][C:16]3[O:20][N:19]=[C:18]([C:21]4[CH:26]=[C:25]([O:27][CH2:28][C:29]([OH:31])=[O:30])[CH:24]=[CH:23][C:22]=4[CH3:33])[C:17]=3[CH:34]=2)[C:3]1=[O:36]
Reactant: COC(=O)COc1ccc(C)c(-c2noc3cc(F)c(-n4c(=O)cc(C(F)(F)F)n(C)c4=O)cc23)c1
Agent: Cl
Solvent: O
Solvent: CC(=O)O
Product: Cc1ccc(OCC(=O)O)cc1-c1noc2cc(F)c(-n3c(=O)cc(C(F)(F)F)n(C)c3=O)cc12
Temperature: 90 °C
Reaction time: 2 h
Yield: 66.1 %

Procedure:
A mixture of {{2-{5-[3,6-dihydro-3-methyl-2,6-dioxo-4-(trifluoromethyl)-1(2H)-pyrimidinyl]-6-fluoro-1,2-benzisoxazol-3-yl}-p-tolyl}oxy}acetic acid, methyl ester (10.9 g, 0.0190 mol), 10% hydrochloric acid and acetic acid is stirred two hours at 90° C., cooled, poured into water and extracted with ethyl acetate. The organic layers are combined, washed with water and brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to a foam. The foam is recrystallized from ethyl acetate to afford the title compound as a white solid (6.20 g, 66.2%, mp 123-126° C.).
Reaction SMILES: [CH3:1][NH2:2].[CH3:3][S:4][C:5]1[C:6]2[S:13][C:12]([CH:14]=O)=[CH:11][C:7]=2[N:8]=[CH:9][N:10]=1.N1[CH2:21][CH2:20][NH:19][CH2:18]C1.O>C(Cl)Cl>[CH3:1][N:2]1[C:14]([C:12]2[S:13][C:6]3[C:5]([S:4][CH3:3])=[N:10][CH:9]=[N:8][C:7]=3[CH:11]=2)=[C:20]([C:21]2[CH:12]=[CH:11][CH:7]=[CH:6][CH:5]=2)[N:19]=[CH:18]1
Reactant: C1CNCCN1
Reactant: CN
Reactant: CSc1ncnc2cc(C=O)sc12
Solvent: O
Solvent: ClCCl
Product: CSc1ncnc2cc(-c3c(-c4ccccc4)ncn3C)sc12
Reaction time: 72 h

Procedure:
Methylamine (2M in THF, 2.5 mL) was added to a solution of 4- (methylthio)thieno[3,2-d]pyrimidine-6-carbaldehyde (intermediate 21) (105 mg) in DCM (10 mL) containing 4 Å molecular sieves (1 g). The reaction mixture was stirred for 2.5 hours, at which point PhTosMIC (149 mg) and piperazine (90 mg) were added. The reaction was stirred for a further 72 hours then additional PhTosMIC (30 mg) was added. After stirring for a further 1.5 hours the mixture was poured into water and extracted into DCM, washed with water and brine, dried, and the solvent removed. Purification by flash chromatography on silica eluting with EtOAc:hexane (25:75 to 0:1Q0) gave the title compound as a pale solid foam (95 mg, 56%);
Reaction SMILES: CO[C:3]([C:5]1[S:6][C:7]([C:11](=[O:13])[CH3:12])=[C:8]([OH:10])[CH:9]=1)=[O:4].[CH3:14][C:15]1[CH:16]=[C:17]([CH2:21][CH2:22]O)[CH:18]=[CH:19][CH:20]=1.Cl.C[O:26][C:27]([C:29]1([NH2:38])[CH2:37][C:36]2[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=2)[CH2:30]1)=[O:28]>>[C:11]([C:7]1[S:6][C:5]([C:3]([NH:38][C:29]2([C:27]([OH:28])=[O:26])[CH2:30][C:31]3[C:36](=[CH:35][CH:34]=[CH:33][CH:32]=3)[CH2:37]2)=[O:4])=[CH:9][C:8]=1[O:10][CH2:22][CH2:21][C:17]1[CH:16]=[C:15]([CH3:14])[CH:20]=[CH:19][CH:18]=1)(=[O:13])[CH3:12]
Reactant: COC(=O)C1(N)Cc2ccccc2C1
Reactant: Cc1cccc(CCO)c1
Reactant: COC(=O)c1cc(O)c(C(C)=O)s1
Agent: Cl
Product: CC(=O)c1sc(C(=O)NC2(C(=O)O)Cc3ccccc3C2)cc1OCCc1cccc(C)c1

Procedure:
The title compound was synthesized by reaction of 5-acetyl-4-hydroxy-thiophene-2-carboxylic acid methyl ester with 2-(3-methylphenyl)-ethanol in analogy to step 1 of example 1, subsequent ester hydrolysis in analogy to example 2, reaction with 2-amino-indane-2-carboxylic acid methyl ester hydrochloride in analogy to step 1 of example 15, and ester hydrolysis in analogy to example 2.
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C@@:5]([CH3:17])([CH2:12][CH2:13][CH:14]([CH3:16])[CH3:15])[C:4](=[O:18])[C:3]=1[C:19]1[NH:24][C:23]2[CH:25]=[CH:26][C:27]([NH:29][S:30]([CH3:33])(=[O:32])=[O:31])=[CH:28][C:22]=2[S:21](=[O:35])(=[O:34])[N:20]=1.[OH-].[Na+:37].[CH3:38]I>O.CN(C)C=O>[CH3:17][C@@:5]1([CH2:12][CH2:13][CH:14]([CH3:16])[CH3:15])[C:6]2[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=2)[C:2]([O-:1])=[C:3]([C:19]2[NH:24][C:23]3[CH:25]=[CH:26][C:27]([N:29]([CH3:38])[S:30]([CH3:33])(=[O:32])=[O:31])=[CH:28][C:22]=3[S:21](=[O:35])(=[O:34])[N:20]=2)[C:4]1=[O:18].[Na+:37]
Reactant: CI
Reactant: CC(C)CC[C@@]1(C)C(=O)C(C2=NS(=O)(=O)c3cc(NS(C)(=O)=O)ccc3N2)=C(O)c2ccccc21
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)CC[C@@]1(C)C(=O)C(C2=NS(=O)(=O)c3cc(N(C)S(C)(=O)=O)ccc3N2)=C([O-])c2ccccc21
Reaction time: 2 h

Procedure:
To a solution of Example 39I (104 mg, 0.193 mmol) in 3 mL of water was added 0.997 N NaOH (0.194 mL, 0.193 mmol). After stirring for 2 hours, the reaction mixture was concentrated to dryness. To a solution of the resulting residue in 3 mL of dimethylformamide was added methyl iodide (0.012 mL, 0.193 mmol). After stirring at room temperature overnight, the reaction solution was concentrated and chromatographed on silica gel eluting with hexane followed by 60% and 80% ethyl acetate in hexane. The resulting yellow solid was suspended in 3 mL of water and 0.997 N NaOH was added (0.160 mL, 0.160 mmol). After stirring for 4 hours, the suspension was lyophilized to 84 mg (79%) of a yellow solid. 1H NMR (300 MHz, DMSO-d6): δ ppm 0.46 (m, 1H) 0.69 (t, J=7.17 Hz, 6H) 0.82 (m, 1H) 1.28 (m, 1H) 1.39 (s, 3H) 1.73 (m, 1H) 2.15 (m, 1H) 2.97 (s, 3H) 3.27 (s, 3H) 7.33 (m, 2H) 7.46 (m, 2H) 7.57 (dd, J=8.82, 2.21 Hz, 1H) 7.66 (d, J=2.57 Hz, 1H) 8.05 (d, J=7.72 Hz, 1H) 15.64 (s, 1H). MS (ESI−) m/z 530 (M−H)−.
Reaction SMILES: [Na].[CH:2]([N:4]1[CH2:9][CH2:8][CH2:7][CH2:6][CH:5]1[C:10]([O-])=O)=O.C1(C)C=CC(S(Cl)(=O)=O)=CC=1.[C:24](#[N:27])C=C.[CH2:28](N(CC)CC)C>ClCCl>[C:10]1([C:24]#[N:27])[CH:28]=[CH:2][N:4]2[C:5]=1[CH2:6][CH2:7][CH2:8][CH2:9]2
Reactant: CCN(CC)CC
Reactant: C=CC#N
Reactant: O=CN1CCCCC1C(=O)[O-]
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: [Na]
Solvent: ClCCl
Product: N#Cc1ccn2c1CCCC2
Reaction time: 0.17 h

Procedure:
To a solution of sodium-1-formyl-piperidine-2-carboxylate (2.0 g) (Reference Example 7) in dichloromethane (50 mL) at ambient temperature under nitrogen was added para-toluenesulfonyl chloride (2.31 g). After stirring for 10 minutes the mixture was treated dropwise with acrylonitrile (0.88 mL) and triethylamine (1.5 mL) and stirring was continued for a further 1 hour when a second portion of triethylamine (1.0 mL) was added. The reaction mixture was stirred for 18 hours and the dichloromethane removed in vacuo. The residue was taken up in water (50 mL) and extracted with ethyl acetate (200 mL). The combined organic extracts were evaporated in vacuo and the residue was subjected to flash column chromatography on silica eluting with a mixture of ethyl acetate and pentane (1:4, v/v) to give the title compound (1.38 g) as an orange oil, MS: 147(MH+). 1H NMR(CDCl3): δ 6.48 (1H, d, J=3.1 Hz); 6.36 (1H, d, J=3.1 Hz); 3.91 (2H, t, J=6.0 Hz); 2.89 (2H, t, J=6.0 Hz); 1.98 (2H, m); 1.88 (2H, m).
Reaction SMILES: [Na].[F:2][C:3]1[CH:8]=[CH:7][C:6]([C:9](=[O:16])[CH2:10][C:11](OCC)=O)=[CH:5][CH:4]=1.[CH3:17][C:18]1([O:27][CH2:28][CH2:29][CH2:30][CH3:31])[CH2:23][CH2:22][N:21]([CH2:24]C[Cl:26])[CH2:20][CH2:19]1>C1(C)C=CC=CC=1>[ClH:26].[CH3:17][C:18]1([O:27][CH2:28][CH2:29][CH2:30][CH3:31])[CH2:23][CH2:22][N:21]([CH2:24][CH2:11][CH2:10][C:9]([C:6]2[CH:5]=[CH:4][C:3]([F:2])=[CH:8][CH:7]=2)=[O:16])[CH2:20][CH2:19]1
Reactant: CCOC(=O)CC(=O)c1ccc(F)cc1
Reactant: CCCCOC1(C)CCN(CCCl)CC1
Agent: [Na]
Solvent: Cc1ccccc1
Product: CCCCOC1(C)CCN(CCCC(=O)c2ccc(F)cc2)CC1
Product: Cl
Temperature: 50 °C

Procedure:
3.1 g (0.127 m) of sodium is granulated in 200 ml of boiling toluene. After cooling, 26.5 g (0.126 m) of ethyl beta-(p-fluorophenyl)-beta-oxopropionate is added drop by drop and then the solution is stirred for one-half hour at 50° C. The yellow solution which forms is cooled and 30 g (0.30 m) of beta-(4-methyl-4-butoxy-piperidino)-ethyl-chloride is added rapidly thereto. The reaction mixture is stirred for four hours at 60° C and for five hours at 85° C. After evaporation on a steam bath and addition of 500 ml of 2.5-N sulphonic acid, the solution is refluxed for sixteen hours, cooled, alkalized with an excess of potassium carbonate, and extracted with ether. The solution is evaporated and the residue distilled at 124-130/0.01 mm Hg. Yield 19.5 g. The hydrochloride has the m.p. 167°-169° C.
Reaction SMILES: C(N(CC)CC)C.[CH3:8][N:9]1[C:14](=[O:15])[CH2:13][C:12]2[CH:16]=[C:17]3[C:22](=[CH:23][C:11]=2[S:10]1(=O)=O)[CH2:21][CH2:20][CH2:19][CH2:18]3.FC1C=CC(N=C=O)=CC=1>CS(C)=O>[CH3:8][N:9]1[C:14](=[O:15])[CH2:13][C:12]2[CH:16]=[C:17]3[C:22](=[CH:23][C:11]=2[S:10]1)[CH2:21][CH2:20][CH2:19][CH2:18]3
Reactant: CN1C(=O)Cc2cc3c(cc2S1(=O)=O)CCCC3
Agent: O=C=Nc1ccc(F)cc1
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: CN1Sc2cc3c(cc2CC1=O)CCCC3
Reaction time: 1 h
Yield: 97.1 %

Procedure:
0.76 g (7.5 mmol) triethylamin were added to a solution of 2 g (7.5 mmol) 3,4,6,7,8,9-hexahydro-2-methyl-3-oxo-2H-naphtho[2,3-e]-1,2-thiazine 1,1-dioxide and 1.03 g (7.5 mmol) p-fluor-phenylisocyanate dissolved in 50 mL DMSO (dimethyl sulfoxide) at room temperature. After stirring for 1 hr the resulting mixture was quenched with dilute HCl in an ice bath and then extracted with ether (2 times). The combined ether extracts were washed, dried and concentrated to give 2.3 g crude product. This material was recrystallized from ethanol to give 1.7 g 3,4,6,7,8,9-hexahydro-2-methyl-3-oxo-2H-naphtho[2,3-e]-1,2-thiazine-4-(4-fluor)carboxanilide 1,1-dioxide.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:10]=[CH:9][C:8]([NH2:11])=[CH:7][N:6]=1)(=[O:3])[CH3:2].C([O:14][C:15](=O)[C:16](=[CH:19]OCC)[C:17]#[N:18])C>C1(C)C=CC=CC=1>[C:1]([NH:4][C:5]1[N:6]=[C:7]2[C:8](=[CH:9][CH:10]=1)[N:11]=[CH:19][C:16]([C:17]#[N:18])=[C:15]2[OH:14])(=[O:3])[CH3:2]
Reactant: CC(=O)Nc1ccc(N)cn1
Reactant: CCOC=C(C#N)C(=O)OCC
Solvent: Cc1ccccc1
Product: CC(=O)Nc1ccc2ncc(C#N)c(O)c2n1
Temperature: 257.5 °C

Procedure:
A solution of 2-acetamido-5-aminopyridine (1.6 g, 10.7 mmol) and ethyl(ethoxymethylene)cyanoacetate (3.6 g, 21.3 mmol) in toluene (50 ml) was heated at reflux for 10 hrs under argon. After cooling, the white solid was collected and dried. A solution of this solid in Dowtherm (250 ml) was heated at 255-260° C. for 6 hrs under nitrogen. During this process, ethanol was distilled off. The mixture was heated at 260° C. for an additional 5 hrs. After cooling, the mixture was poured in hexane. The solid was collected, dissolved in a 1:1 mixture of DMF and ethyl acetate, and ether was added to give the title compound as a solid. mass spectrum (electrospray, m/e): 228.7 (M+H); IR cm-1: 2228, 1682.; H-NMR δ (DMSO-d6): 2.182 (3H, s, CH3), 7.96 (1H, s, OH), 8.09 (1H, d, C7-H), 8.49 (1H, d, C8-H), 8.71 (1H, s, C2-H), 11.20 (1H, s, NH).
Reaction SMILES: [CH2:1]([C:3]1[C:8](=[O:9])[NH:7][C:6]([CH3:10])=[C:5]([C:11]2[S:15][C:14]([S:16]([Cl:19])(=[O:18])=[O:17])=[CH:13][CH:12]=2)[CH:4]=1)[CH3:2].[NH:20]1[C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=2[N:22]=[C:21]1[CH2:29][NH2:30]>>[ClH:19].[NH:20]1[C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=2[N:22]=[C:21]1[CH2:29][NH:30][S:16]([C:14]1[S:15][C:11]([C:5]2[CH:4]=[C:3]([CH2:1][CH3:2])[C:8](=[O:9])[NH:7][C:6]=2[CH3:10])=[CH:12][CH:13]=1)(=[O:18])=[O:17]
Reactant: NCc1nc2ccccc2[nH]1
Reactant: CCc1cc(-c2ccc(S(=O)(=O)Cl)s2)c(C)[nH]c1=O
Product: CCc1cc(-c2ccc(S(=O)(=O)NCc3nc4ccccc4[nH]3)s2)c(C)[nH]c1=O
Product: Cl
Yield: 44 %

Procedure:
5-(5-Ethyl-2-methyl-6-oxo-1,6-dihydropyridin-3-yl)thiophene-2-sulfonyl chloride is reacted with (1H-benzoimidazol-2-yl)methylamine as described in Step 5, Example 24 to give the title compound as a yellow solid (44% yield). LC/MS: RT 2.10 min; m/e 429 (M+H); 1H NMR (δ, ppm): 11.80 (1H, br), 9.17 (1H, t), 7.80 (2H, m), 7.70 (1H, d), 7.50 (2H, m), 7.21 (1H, s), 7.12 (1H, d), 4.65 (3H, m), 2.40 (2H, q), 2.28 (3H, s), 1.10 (3H, t).
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:22]=[CH:21][C:7]([CH2:8][N:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:12]([CH3:19])=[CH:11][C:10]2=[O:20])=[CH:6][CH:5]=1.[C:23](OCC)(=[O:29])[C:24]([O:26][CH2:27][CH3:28])=[O:25].CCOCC>CN(C)C=O>[Cl:3][C:4]1[CH:5]=[CH:6][C:7]([CH2:8][N:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:12]([CH2:19][C:23](=[O:29])[C:24]([O:26][CH2:27][CH3:28])=[O:25])=[CH:11][C:10]2=[O:20])=[CH:21][CH:22]=1
Reactant: CCOC(=O)C(=O)OCC
Reactant: Cc1cc(=O)n(Cc2ccc(Cl)cc2)c2ccccc12
Agent: [H-]
Agent: [Na+]
Solvent: CCOCC
Solvent: CN(C)C=O
Product: CCOC(=O)C(=O)Cc1cc(=O)n(Cc2ccc(Cl)cc2)c2ccccc12
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
Sodium hydride (18 g.; 60% w/w dispersion in oil, washed as described in Example 1) was stirred in dry dimethylformamide (300 ml.), and 1-(4-chlorobenzyl)-1,2-dihydro-4-methyl-2-oxoquinoline (64.7 g.) was added, followed by diethyl oxalate (55 g.). The mixture was stirred at room temperature for 2.5 hours with occasional external cooling to keep the temperature below 25° C. Ether (2 l.) was added, and the mixture was filtered. The solid residue was washed with ether (500 ml.), and then suspended in dimethylformamide (200 ml.) and acidified to pH 2 by the addition of concentrated hydrochloric acid. The resultant mixture was added to water (3 l.), and the mixture filtered, and the solid residue washed with water (2 l.), drained well, and crystallised from ethanol to give ethyl 1-(4-chlorobenzyl)-1,2-dihydro-2-oxoquinol-4-ylpyruvate, m.p. 180°-182° C.
Reaction SMILES: [H-].[Na+].[CH2:3]([CH2:10][S:11]([NH:14][CH2:15][CH2:16][OH:17])(=[O:13])=[O:12])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.Cl[C:19]1[N:24]2[CH:25]=[CH:26][N:27]=[C:23]2[CH:22]=[CH:21][CH:20]=1.O>CN(C)C=O>[CH2:3]([CH2:10][S:11]([NH:14][CH2:15][CH2:16][O:17][C:19]1[N:24]2[CH:25]=[CH:26][N:27]=[C:23]2[CH:22]=[CH:21][CH:20]=1)(=[O:13])=[O:12])[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: O=S(=O)(CCc1ccccc1)NCCO
Reactant: Clc1cccc2nccn12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: O=S(=O)(CCc1ccccc1)NCCOc1cccc2nccn12
Yield: 39.4 %

Procedure:
To a suspension of 60% sodium hydride in oil (0.20 g, 5 mmoles) in dimethylformamide (20 ml) was added 2-(N-benzylmethylsulfonylamino)-1-ethanol (1.14 g, 5 mmoles) with stirring under ice-cooling and the mixture was stirred at room temperature for 30 minutes. To this reaction mixture was added 5-chloroimidazo[1,2-a]pyridine (0.763 g, 5 mmoles) with stirring under ice-cooling, followed by stirring at 80° C. for 16 hours. After cooling, water was added to the reaction mixture, which was extracted with ethyl acetate and dried. After the solvent was distilled off, the residue was purified by column chromatography [eluent: ethyl acetate/hexane (1:1)→ethyl acetate/hexane (2:1)] to obtain 0.68 g of the desired product (39.4%, pale yellow oily product).
Reaction SMILES: [CH:1]1([CH:6]2[CH2:10][O:9][C:8](=O)[CH2:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[BrH:12].[CH3:13][CH2:14][OH:15]>O>[CH2:14]([O:15][C:8](=[O:9])[CH2:7][CH:6]([CH2:10][Br:12])[CH:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1)[CH3:13]
Reactant: O=C1CC(C2CCCC2)CO1
Reactant: CCO
Reactant: Br
Solvent: O
Product: CCOC(=O)CC(CBr)C1CCCC1
Temperature: 25 °C
Yield: 85 %

Procedure:
Preparation of 3-bromomethyl-3-cyclopentyl-propionic acid ethyl ester—A solution of 4-cyclopentyl-dihydro-furan-2-one (4.4 g, 28.5 mmol) in 100 mL of EtOH is saturated with HBr at 0° C. The mixture is warmed to room temperature overnight. It is diluted with 200 mL of H2O and extracted with Et2O (3,100 mL). The combined extracts are washed with brine (2.50 mL) and dried over MgSO4. Evaporation of Et2O gives 6.4 g (85% yield) of 3-bromomethyl-3-cyclopentyl-propionic acid ethyl ester as a clear oil. NMR (1H, 400 MHz, CDCl3) δ1.1 (2H, m); 1.2 (3H, t); 1.5 (4H, m); 1.8 (3H, m); 1.9 (1H, m); 2.4 (2H, dd); 3.5 (2H, dd); 4.1 (2H,q).
Reaction SMILES: [N+](C1C=CC(N=[N:11][C:12]2[C:13]([CH3:32])=[C:14]([CH3:31])[C:15]3[O:19][C:18]([CH3:21])([CH3:20])[CH:17]([C:22]4[CH:27]=[CH:26][C:25]([CH3:28])=[CH:24][CH:23]=4)[C:16]=3[C:29]=2[CH3:30])=CC=1)([O-])=O.S(S([O-])=O)([O-])=O.[Na+].[Na+].CO.[OH-].[Na+]>C1(C)C=CC=CC=1.O>[CH3:20][C:18]1([CH3:21])[CH:17]([C:22]2[CH:23]=[CH:24][C:25]([CH3:28])=[CH:26][CH:27]=2)[C:16]2[C:29]([CH3:30])=[C:12]([NH2:11])[C:13]([CH3:32])=[C:14]([CH3:31])[C:15]=2[O:19]1
Reactant: Cc1ccc(C2c3c(C)c(N=Nc4ccc([N+](=O)[O-])cc4)c(C)c(C)c3OC2(C)C)cc1
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: Cc1ccccc1
Solvent: O
Product: Cc1ccc(C2c3c(C)c(N)c(C)c(C)c3OC2(C)C)cc1
Temperature: 67.5 °C
Reaction time: 2 h
Yield: 84.8 %

Procedure:
The above-obtained 1-(4-nitrophenyl)-2-[2,2,4,6,7-pentamethyl-3-(4-methylphenyl)-2,3-dihydro-1-benzofuran-5-yl]diazene (6.0 g) and sodium dithionite (14.6 g) were added to a mixture of methanol (30 mL) and water (30 mL), and the mixture was stirred at 65 to 70° C. for 2 hours under a nitrogen atmosphere. The mixture was cooled to room temperature, and further stirred at 0 to 5° C. for one hour. Precipitated crystals were collected by filtration, and washed with a mixture of methanol and water again to obtained wetted crystals. The wetted crystals were added to a mixture of toluene and 2N aqueous sodium hydroxide. An organic layer was separated and concentrated. The concentrate was recrystallized from a mixture of water and methanol, and the resultant crystals were dried under reduced pressure to obtain the title compound (3.5 g., yield 86%).