Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([S:9][C:10]2[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][C:11]=2[NH2:17])=[CH:5][CH:4]=1.C([C:20]1[C:21]([N:29]=[CH:30][N:31]([CH3:33])C)=[N:22][C:23]([CH:26]2[CH2:28][CH2:27]2)=[CH:24][CH:25]=1)#N.NC1C=C(C)C=CC=1SC1C=CC(O)=CC=1.C(C1C(N=CN(C)C)=NC(C)=CC=1)#N>>[CH:26]1([C:23]2[CH:24]=[CH:25][C:20]3[C:33]([NH:17][C:11]4[CH:12]=[C:13]([CH3:16])[CH:14]=[CH:15][C:10]=4[S:9][C:6]4[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=4)=[N:31][CH:30]=[N:29][C:21]=3[N:22]=2)[CH2:27][CH2:28]1
Reactant: CN(C)C=Nc1nc(C2CC2)ccc1C#N
Reactant: COc1ccc(Sc2ccc(C)cc2N)cc1
Agent: Cc1ccc(C#N)c(N=CN(C)C)n1
Agent: Cc1ccc(Sc2ccc(O)cc2)c(N)c1
Product: COc1ccc(Sc2ccc(C)cc2Nc2ncnc3nc(C4CC4)ccc23)cc1

Procedure:
2-(4-Methoxy-phenylsulfanyl)-5-methyl-phenylamine (Example 118) was reacted with the product from Example 119A using the procedure from Example 102 substituting 2-(4-Methoxy-phenylsulfanyl)-5-methyl-phenylamine for the product from Example 6c and substituting the product from Example 119A for the product from Example 10B to provide the crude residue which was purified by trituration with methanol to provide the title compound. 1H NMR (300 MHz, DMSO-D6) δ ppm: 0.96-1.30 (m, J=5.52 Hz, 4H), 2.21-2.42 (m, 1H), 2.31 (s, 3H), 3.71 (s, 3H), 6.85 (d, J=8.82 Hz, 2H), 6.99-7.12 (m, 2H), 7.24 (d, J=8.82 Hz, 2H), 7.63 (d, J=8.46 Hz, 1H), 8.53 (s, 1H), 8.72 (d, J=8.46 Hz, 1H), 10.33 (s, 1H); MS (ESI)+ m/z 415 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]=[CH:5][C:4]=1[C:13]([OH:15])=O.S(Cl)([Cl:18])=O>>[CH3:1][O:2][C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]=[CH:5][C:4]=1[C:13]([Cl:18])=[O:15]
Reactant: COc1c(C(=O)O)ccc2ccccc12
Reactant: O=S(Cl)Cl
Product: COc1c(C(=O)Cl)ccc2ccccc12

Procedure:
Using 1-methoxy-2-naphthoic acid (1 g) and thionyl chloride (3 ml), a reaction as that described in Example 24 is carried out to give 1-methoxy-2-naphthoyl chloride, which is allowed to react with 1-(3,4,5-trimethoxybenzyl)piperazine dihydrochloride (1.8 g). The product is purified by silica gel column chromatography (hexane:acetone=3:2-1:2) and then converted to the hydrochloride in a mixture of ethyl acetate and ethyl ether. Thus-obtained powder is recrystallized from ethyl acetate to afford 1-(1-methoxy-2-naphthoyl)-4-(3,4,5-trimethoxybenzyl) piperazine hydrochloride (1.7 g) as colorless crystals, m.p. 194°-197° C. (decomp.).
Reaction SMILES: [C:1]([N:8]1[CH:12]=[CH:11]N=C1)(N1C=CN=C1)=[O:2].[CH:13]1([CH2:16][OH:17])[CH2:15][CH2:14]1.CCCCCC.C(OC(=O)C)C.NCC[C:33]1[C:41]2[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=2)[NH:35][CH:34]=1>C1COCC1>[CH:13]1([CH2:16][O:17][C:1]([NH:8][CH2:12][CH2:11][C:33]2[C:41]3[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=3)[NH:35][CH:34]=2)=[O:2])[CH2:15][CH2:14]1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: NCCc1c[nH]c2ccccc12
Reactant: OCC1CC1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CCCCCC
Product: O=C(NCCc1c[nH]c2ccccc12)OCC1CC1
Reaction time: 8 h
Yield: 76 %

Procedure:
A solution of 11.7 g (69.3 mmol) of carbonyldiimidazole and 5.0 g (69.3 mmol) of cyclopropylmethanol in 150 mL of THF was stirred, under nitrogen and later at room temperature for 4-5 hours or the time until the TLC (silica gel; hexane-ethylacetate, 4:1) analysis indicated a complete disappearance of cyclopropylmethanol in the mixture. To this reaction mixture, a solution of tryptamine (11.12 g, 69.3 mmol) in THF (5 mL) was added and stirred overnight. The TLC analysis indicated a complete disappearence of tryptamine. The solvent was removed and the residue was redissolved in methylene chloride (450 mL), washed with 5% HCl (4×100 mL), water, dried over MgSO4, filtered. The filtrate was swirled with 50 g of silica gel, filtered and concentracted under vacuum. The solid was crystallized from hexane-methylene chloride to furnish 13.6 g of N-cyclopropylmethyloxycarbonyltryptamine (75% yield). mp 88°-90° C.
Reaction SMILES: [N+:1]([C:4]1[NH:8][C:7]([C:9]#[N:10])=[CH:6][CH:5]=1)([O-:3])=[O:2].CC(C)([O-])C.[K+].Cl[CH2:18][O:19][CH2:20][CH3:21]>C1COCC1.CCOCC.O>[CH2:20]([O:19][CH2:18][N:8]1[C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=[C:7]1[C:9]#[N:10])[CH3:21]
Reactant: N#Cc1ccc([N+](=O)[O-])[nH]1
Reactant: CCOCCl
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: CCOCC
Solvent: C1CCOC1
Product: CCOCn1c(C#N)ccc1[N+](=O)[O-]
Reaction time: 4 h
Yield: 76.9 %

Procedure:
To a solution of 560 mg of 5-nitropyrrole-2-carbonitrile (4 mmol) in 20 mL of dry THF, is added 515 mg of potassium tert-butoxide (4.6 mmol). After the addition of 0.45 mL of chloromethylethylether (4.8 mmol) to the mixture, the mixture is stirred for 4 hours, then diluted with ether (30 mL) and water (50 mL). The organic layer is separated, washed with water MgSO4 (20 mL) and dried over MgSO4. After evaporation of the solvent a red oil is obtained (600 mg, 75%) 1-(ethoxymethyl)-5-nitropyrrole-2-carbonitrile.
Reaction SMILES: [F:1][C:2]1[C:3]([CH3:37])=[C:4]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([CH2:21][O:22][C:23]3[CH:36]=[CH:35][C:26]4[C@H:27]([CH2:30][C:31]([O:33]C)=[O:32])[CH2:28][O:29][C:25]=4[CH:24]=3)[CH:16]=2)[C:5]([CH3:14])=[CH:6][C:7]=1[O:8][C@H:9]1[CH2:13][CH2:12][O:11][CH2:10]1.[OH-].[Li+]>CO.O1CCCC1>[F:1][C:2]1[C:3]([CH3:37])=[C:4]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([CH2:21][O:22][C:23]3[CH:36]=[CH:35][C:26]4[C@H:27]([CH2:30][C:31]([OH:33])=[O:32])[CH2:28][O:29][C:25]=4[CH:24]=3)[CH:16]=2)[C:5]([CH3:14])=[CH:6][C:7]=1[O:8][C@H:9]1[CH2:13][CH2:12][O:11][CH2:10]1
Reactant: COC(=O)C[C@@H]1COc2cc(OCc3cccc(-c4c(C)cc(O[C@H]5CCOC5)c(F)c4C)c3)ccc21
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: Cc1cc(O[C@H]2CCOC2)c(F)c(C)c1-c1cccc(COc2ccc3c(c2)OC[C@H]3CC(=O)O)c1
Reaction time: 2 h
Yield: 57.5 %

Procedure:
Methyl 2-((S)-6-((3′-fluoro-2′,6′-dimethyl-4′-(((S)-tetrahydrofuran-3-yl)oxy) biphenyl-3-yl)methoxy)-2,3-dihydrobenzofuran-3-yl)acetate 19d (150 mg, 0.30 mmol) was dissolved in 4 mL of a mixture of the solvents of methanol and tetrahydrofuran (V/V=1:1), followed by addition of 1M aqueous lithium hydroxide solution (1.5 mL, 1.50 mmol). The reaction solution was stirred for 2 hours. The resulting solution was concentrated under reduced pressure, mixed with 10 mL of water, 1M hydrochloric acid was added dropwise to adjust the pH to 2˜3, and extracted with ethyl acetate (20 mL×2). The combined organic extracts were washed with saturated sodium chloride solution (30 mL), dried with anhydrous magnesium sulphate, and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by TLC with elution system A to obtain the title compound 2-((S)-6-((3′-fluoro-2′,6′-dimethyl-4′-(((S)-tetrahydrofuran-3-yl)oxy)biphenyl-3-yl)methoxy)-2,3-dihydrobenzofuran-3-yl)acetic acid 19 (85 mg, yield 57.8%) as a white solid.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([C:22]([C:25]#[N:26])([CH3:24])[CH3:23])[C:8]([O:20][CH3:21])=[C:9]([NH:11][C:12](=[O:19])OCC(Cl)(Cl)Cl)[CH:10]=1)([CH3:4])([CH3:3])[CH3:2].[NH2:27][C@@H:28]1[CH2:36][C:35]2[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=2)[C@@H:29]1[OH:37].C(O)(=O)[C@@H]([C@H](C(O)=O)O)O.C(N(CC)C(C)C)(C)C>C(#N)C>[C:1]([C:5]1[CH:6]=[C:7]([C:22]([C:25]#[N:26])([CH3:23])[CH3:24])[C:8]([O:20][CH3:21])=[C:9]([NH:11][C:12]([NH:27][C@@H:28]2[CH2:36][C:35]3[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=3)[C@@H:29]2[OH:37])=[O:19])[CH:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: N[C@@H]1Cc2ccccc2[C@@H]1O
Reactant: COc1c(NC(=O)OCC(Cl)(Cl)Cl)cc(C(C)(C)C)cc1C(C)(C)C#N
Agent: O=C(O)[C@H](O)[C@@H](O)C(=O)O
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: COc1c(NC(=O)N[C@@H]2Cc3ccccc3[C@@H]2O)cc(C(C)(C)C)cc1C(C)(C)C#N
Temperature: 110 °C
Reaction time: 8 h
Yield: 51 %

Procedure:
To a solution of 2,2,2-trichloroethyl 5-tert-butyl-3-(2-cyanopropan-2-yl)-2-methoxyphenylcarbamate (0.086 g, 0.203 mmol) and (1S,2R)-2-amino-2,3-dihydro-1H-indene-1-ol.L-tartaric acid salt (0.067 g, 0.223 mmol) in acetonitrile (0.8 mL), N,N-diisopropylethylamine (0.058 mL, 0.333 mmol) was added, the mixture was stirred overnight at 110° C. The reaction mixture was evaporated under reduced pressure and the obtained residue was purified by silica gel column chromatography (ethyl acetate/n-hexane=10/90-60/40) to obtain 0.044 g of the captioned compound (51% yield).
Reaction SMILES: [C:1]([O:5][C:6](=[O:19])[NH:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]1[CH:17]=[CH:16][C:15]([NH2:18])=[CH:14][CH:13]=1)([CH3:4])([CH3:3])[CH3:2].Br.Br[CH2:22][CH2:23][NH2:24]>C1(C)C=CC=CC=1>[C:1]([O:5][C:6](=[O:19])[NH:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]1[CH:13]=[CH:14][C:15]([NH:18][CH2:22][CH2:23][NH2:24])=[CH:16][CH:17]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NCCCCc1ccc(N)cc1
Reactant: NCCBr
Agent: Br
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)NCCCCc1ccc(NCCN)cc1
Temperature: 100 °C
Reaction time: 72 h
Yield: 56.3 %

Procedure:
A mixture of N-[4-(4-aminophenyl)butyl]carbamic acid tert-butyl ester (4.5 g, 17 mmol) and 2-bromoethylamine hydrobromide (1.75 g, 8.5 mmol) in toluene was stirred at 100° C. for 3 days. The solvent was removed under reduced pressure and the residue was purified by flash chromatography (silica gel, chloroform/methanol/ammonium hydroxide, 8:1:0.1, v/v) to give 660 (1.47 g, 56%) as a white powder. 1H NMR (300 MHz, CD3OD) δ 1.42 (s, 9H), 1.51 (m, 4H), 2.48 (t, 2H), 2.85 (t, 2H), 3.03 (t, 2H), 3.17 (m, 2H), 6.59 (d, 2H), 6.94 (d, 2H). m/z (ESI) 308 [C17H29lN3O2+H].
Reaction SMILES: F[C:2]1[C:7]([C:8]2[N:13]=[C:12]([CH3:14])[N:11]=[C:10]([N:15]([CH2:25][C:26]3[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[CH:28][CH:27]=3)[CH2:16][C:17]3[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=3)[N:9]=2)=[CH:6][C:5]([CH:34]2[CH2:39][CH2:38][O:37][CH2:36][CH2:35]2)=[CH:4][N:3]=1.[F:40][C:41]1[CH:42]=[C:43]([NH2:49])[CH:44]=[N:45][C:46]=1[O:47][CH3:48].C[Si]([N-][Si](C)(C)C)(C)C.[Na+]>C1COCC1>[F:40][C:41]1[CH:42]=[C:43]([NH:49][C:2]2[C:7]([C:8]3[N:13]=[C:12]([CH3:14])[N:11]=[C:10]([N:15]([CH2:25][C:26]4[CH:27]=[CH:28][C:29]([O:32][CH3:33])=[CH:30][CH:31]=4)[CH2:16][C:17]4[CH:18]=[CH:19][C:20]([O:23][CH3:24])=[CH:21][CH:22]=4)[N:9]=3)=[CH:6][C:5]([CH:34]3[CH2:35][CH2:36][O:37][CH2:38][CH2:39]3)=[CH:4][N:3]=2)[CH:44]=[N:45][C:46]=1[O:47][CH3:48]
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)c2nc(C)nc(-c3cc(C4CCOCC4)cnc3F)n2)cc1
Reactant: COc1ncc(N)cc1F
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1ccc(CN(Cc2ccc(OC)cc2)c2nc(C)nc(-c3cc(C4CCOCC4)cnc3Nc3cnc(OC)c(F)c3)n2)cc1
Reaction time: 0.25 h
Yield: 85 %

Procedure:
A mixture of 4-(2-fluoro-5-(tetrahydro-2H-pyran-4-yl)pyridin-3-yl)-N,N-bis(4-methoxybenzyl)-6-methyl-1,3,5-triazin-2-amine (210 mg, 0.397 mmol) and 5-fluoro-6-methoxypyridin-3-amine (85 mg, 0.595 mmol) in 1.5 mL of THF at 0° C. was treated with sodium bis(trimethylsilyl)amide (0.99 mL of 1.0 M solution in tetrahydrofuran, 0.99 mmol). It was stirred at this temperature for 15 min, then quenched with sat NH4Cl (5 mL) and extracted with 2×10 mL of EtOAc. The combined organic solution was dried with sodium sulfate and concentrated. The residue was purified on a silica gel column and eluted with 10-30% EtOAc in DCM to give the title compound (220 mg, 85% yield) as a brown amorphous solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 11.65 (s, 1H), 8.56 (d, J=2.6 Hz, 1H), 8.26 (d, J=2.4 Hz, 1H), 8.07 (m, 2H), 7.29 (d, J=8.6 Hz, 2H), 7.22 (d, J=8.4 Hz, 2H), 6.91 (d, J=8.6 Hz, 2H), 6.85 (d, J=8.6 Hz, 2H), 4.87 (s, 2H), 4.80 (s, 2H), 3.96 (m, 2H), 3.91 (s, 3H), 3.74 (s, 3H), 3.69 (s, 3H), 3.45 (m, 2H), 2.78 (m, 1H), 2.57 (s, 3H), 1.67 (m, 4H). m/z (ESI, positive ion) 652.0 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]([CH3:12])[C:10](=[O:13])[C:9]([CH3:15])([CH3:14])[N:8]=[C:7]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[F:22])[C:6]=2[CH:23]=1.Cl.[NH2:25][C:26]([CH3:31])([CH3:30])[C:27](Cl)=[O:28].C(=O)([O-])[O-].[K+].[K+].C(Cl)Cl>O1CCCC1.O>[NH2:25][C:26]([CH3:31])([CH3:30])[C:27]([NH:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]([CH3:12])[C:10](=[O:13])[C:9]([CH3:15])([CH3:14])[N:8]=[C:7]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[F:22])[C:6]=2[CH:23]=1)=[O:28]
Reactant: CC(C)(N)C(=O)Cl
Reactant: CN1C(=O)C(C)(C)N=C(c2ccccc2F)c2cc(N)ccc21
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: ClCCl
Solvent: O
Product: CN1C(=O)C(C)(C)N=C(c2ccccc2F)c2cc(NC(=O)C(C)(C)N)ccc21
Reaction time: 0.25 h

Procedure:
8 g (0.026 mol) of 7-amino-5-(o-fluorophenyl)-1,3-dihydro-1,3,3-trimethyl-2H-1,4-benzodiazepin-2-one are stirred at room temperature for 1 hour with 5 g of α-aminoisobutyric acid chloride hydrochloride in 30 ml of tetrahydrofuran, 8 g of potassium carbonate are subsequently added thereto and, after a further 15 minutes, the mixture is treated with methylene chloride and water. The organic phase is separated and the aqueous phase is extracted four times with methylene chloride. The combined organic extracts are dried and evaporated. The residue is purified on 350 g of silica gel with methylene chloride/ethyl acetate (1:1) and ethyl acetate as the elution agent. From ethyl acetate/ether there is obtained 2-amino-N-[5-(o-fluorophenyl)-2,3-dihydro-1,3,3-trimethyl-2-oxo-1H-1,4-benzodiazepin-7-yl]-2-methylpropionamide of melting point 250°.
Reaction SMILES: [CH2:1]([O:3][C:4]1[C:5]([F:14])=[C:6]([CH:9]=[C:10]([CH2:12][CH3:13])[CH:11]=1)[CH:7]=[O:8])[CH3:2].[C-:15]#[N:16].[K+].OS([O-])=O.[Na+]>C(OCC)(=O)C.O>[CH2:1]([O:3][C:4]1[C:5]([F:14])=[C:6]([CH:7]([OH:8])[C:15]#[N:16])[CH:9]=[C:10]([CH2:12][CH3:13])[CH:11]=1)[CH3:2]
Reactant: [C-]#N
Reactant: CCOc1cc(CC)cc(C=O)c1F
Agent: O=S([O-])O
Agent: [K+]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Product: CCOc1cc(CC)cc(C(O)C#N)c1F
Reaction time: 8 h
Yield: 88.7 %

Procedure:
To 118D (630 mg, 3.46 mmol) in ethyl acetate (10 mL) was added a solution of KCN (676 mg) and NaHSO3 (1.08 g) dissolved in H2O (10 mL). It was left stirring overnight before extracted with ethyl acetate (2×50 mL). The combined organic extracts were dried and concentrated. The crude producte was purified by column chromatography to give 118E (685 mg, 92% yield) as an oil. 1H NMR (400 MHz, CDCl3) δ ppm 1.23 (t, J=7.69 Hz, 3H) 1.44 (t, J=7.03 Hz, 3H) 2.62 (q, J=7.76 Hz, 2H) 4.11 (q, J=7.03 Hz, 2H) 5.75 (s, 1H) 6.85 (dd, J=7.91, 2.20 Hz, 1H) 6.96 (dd, J=5.93, 1.98 Hz, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([C:28]([F:31])([F:30])[F:29])[O:13][N:12]=[C:11]([C:14]3[CH:23]=[CH:22][C:17]([C:18]([O:20]C)=[O:19])=[C:16]([C:24]([CH3:27])([CH3:26])[NH2:25])[CH:15]=3)[CH2:10]2)[CH:5]=[C:6]([Cl:8])[CH:7]=1.[OH-].[K+].Cl>C(O)C.O>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([C:28]([F:30])([F:29])[F:31])[O:13][N:12]=[C:11]([C:14]3[CH:23]=[CH:22][C:17]([C:18]([OH:20])=[O:19])=[C:16]([C:24]([CH3:27])([CH3:26])[NH2:25])[CH:15]=3)[CH2:10]2)[CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: COC(=O)c1ccc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)cc1C(C)(C)N
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CC(C)(N)c1cc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)ccc1C(=O)O
Temperature: 25 °C
Yield: 80.1 %

Procedure:
In a solution of 1.35 g of methyl 4-[5-(3,5-dichlorophenyl)-5-trifluoromethyl-4,5-dihydroisoxazole-3-yl]-2-(dimethyl-aminomethyl)benzoate in 30 mL of ethanol, a solution of 0.48 g of potassium hydroxide in 15 mL of water was added, and stirred under reflux with heating for 30 minutes. After the completion of the reaction, the reaction mixture was left and cooled to room temperature, and 10 mL of 2N hydrochloric acid was added, and the solvent was distilled off under reduced pressure. The residue was dissolved in 20 mL of ethyl acetate, insoluble material was filtered off, and the solvent was distilled off under reduced pressure to obtain 1.05 g of the crude aimed product as white crystal. The resulting product was used as such without purification for the next step.
Reaction SMILES: [CH2:1]([C:4]1[CH:12]=[CH:11][C:7]([C:8](O)=[O:9])=[CH:6][CH:5]=1)[CH2:2][CH3:3].O.ON1C2C=CC=CC=2N=N1.ClCCl.Cl.[CH3:28][NH:29][O:30][CH3:31]>O.C(N(CC)CC)C>[CH3:31][O:30][N:29]([CH3:28])[C:8](=[O:9])[C:7]1[CH:11]=[CH:12][C:4]([CH2:1][CH2:2][CH3:3])=[CH:5][CH:6]=1
Reactant: CCCc1ccc(C(=O)O)cc1
Reactant: CNOC
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O
Product: CCCc1ccc(C(=O)N(C)OC)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 85.6 %

Procedure:
A mixture of 4-n-propylbenzoic acid (10.0 g), 1-hydroxybenzotriazole hydrate (8.20 g), 1-(3-N,N-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (21.5 g) and dichloromethane (1000 ml) was treated dropwise with triethylamine (42.6 ml) and N,O-dimethylhydroxylamine hydrochloride (6.6 g). The mixture was stirred overnight at room temperature and then treated with water (700 ml). The organic layer was separated, washed with 2N aqueous hydrochloric acid (4×500 ml) and then saturated aqueous sodium bicarbonate solution (4×500 ml). The organic phase was dried (MgSO4) and concentrated to give the title compound as a clear oil (10.8 g).
Reaction SMILES: [O:1]1[C:5]([CH2:6][OH:7])=[CH:4][C:3]2[CH2:8][CH2:9][CH2:10][C:2]1=2>O=[Mn]=O.C(Cl)(Cl)Cl>[O:1]1[C:5]([CH:6]=[O:7])=[CH:4][C:3]2[CH2:8][CH2:9][CH2:10][C:2]1=2
Reactant: OCc1cc2c(o1)CCC2
Agent: O=[Mn]=O
Solvent: ClC(Cl)Cl
Product: O=Cc1cc2c(o1)CCC2

Procedure:
Activated MnO2 (9.3 g) was added to the CHCl3 (135 mL) solution of (5,6-dihydro-4H-cyclopenta[b]furan-2-yl)methanol (1.86 g) and refluxed for 1 h under a nitrogen atmosphere. The reaction mixture was filtered through a pad of Celite. The filtrate was concentrated under reduced pressure. The residue was applied to silica gel column chromatography, then the column was eluted with n-hexane-AcOEt (9/1–7/1). The titled compound was obtained as yellow crystals (1.51 g, 77%).
Reaction SMILES: [CH3:1][N:2]1[C:7]([NH:8][CH2:9][CH2:10][CH2:11]Cl)=[C:6]([CH3:13])[C:5](=[O:14])[N:4]([CH3:15])[C:3]1=[O:16].CN1C(NCCCO)=C(C)C(=O)N(C)C1=O.S(Cl)(Cl)=O.[OH:37][C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][C:39]=1[N:44]1[CH2:49][CH2:48][NH:47][CH2:46][CH2:45]1>C1(C)C(C)=CC=CC=1.C(N(CCC)CCC)CC>[CH3:1][N:2]1[C:7]([NH:8][CH2:9][CH2:10][CH2:11][N:47]2[CH2:46][CH2:45][N:44]([C:39]3[CH:40]=[CH:41][CH:42]=[CH:43][C:38]=3[OH:37])[CH2:49][CH2:48]2)=[C:6]([CH3:13])[C:5](=[O:14])[N:4]([CH3:15])[C:3]1=[O:16]
Reactant: Oc1ccccc1N1CCNCC1
Reactant: Cc1c(NCCCCl)n(C)c(=O)n(C)c1=O
Agent: CCCN(CCC)CCC
Agent: Cc1c(NCCCO)n(C)c(=O)n(C)c1=O
Solvent: Cc1ccccc1C
Solvent: O=S(Cl)Cl
Product: Cc1c(NCCCN2CCN(c3ccccc3O)CC2)n(C)c(=O)n(C)c1=O

Procedure:
The 1,3,5-trimethyl-6-(3-chloropropylamino)-2,4(1H,3H)-pyrimidinedione prepared from 6.8 g (30 mmol) of 1,3,5-trimethyl-6-(3-hydroxypropylamino)-2,4(1H,3H)pyrimidinedione with thionyl chloride is refluxed for 15 h with 4.5 g (25 mmol) of 1-(2-hydroxyphenyl)piperazine in 140 ml of xylene and 20 ml of tripropylamine. The dark oil obtained after customary work-up is purified by column chromatography on silica gel using dichloromethane/methanol (1-10%). From the product fractions, the fumarate is precipitated from ethyl acetate/ethanol using fumaric acid, yield 5.9 g (47%), m.p. 203-205° C.
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:10]=[N:9][C:8]([Cl:11])=[CH:7][N:6]=1)=[O:4].[OH-].[Na+]>C1COCC1.CO.C(Cl)Cl>[Cl:11][C:8]1[N:9]=[CH:10][C:5]([C:3]([OH:4])=[O:2])=[N:6][CH:7]=1
Reactant: COC(=O)c1cnc(Cl)cn1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: ClCCl
Product: O=C(O)c1cnc(Cl)cn1
Temperature: 0 °C

Procedure:
Dissolve 5-chloro-pyrazine-2-carboxylic acid methyl ester (10.0 g, 57.9 mmol) in THF (65 mL) and MeOH (65 mL). Cool the solution to 0° C. before adding 1N NaOH (63.7 mL) with stirring. Warm the mixture to room temperature and stir for 5 h. Concentrate the mixture in vacuo to 1/3 volume. Quench with 1N HCl (75 mL) to form a white precipitate. Dilute with CH2Cl2 (200 mL) and filter. Wash the filter cake with water and CH2Cl2. Separate the phases, dry the organic phase over MgSO4, filter, and concentrate. Add the aqueous layer to the concentrated organic residue and concentrate. Purify by silica gel flash column chromatography, eluting with 40% ethyl acetate/n-hexane, followed by 10% MeOH, 3% acetic acid and 87%
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:27])[C@@H:10]([C:23]([CH3:26])([CH3:25])[CH3:24])[NH:11][S:12]([C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([O:21][CH3:22])[CH:16]=1)(=[O:14])=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].I[CH2:35][CH2:36][CH:37]([CH3:39])[CH3:38].Cl>CN(C=O)C>[CH2:1]([O:8][C:9](=[O:27])[C@@H:10]([C:23]([CH3:24])([CH3:26])[CH3:25])[N:11]([CH2:35][CH2:36][CH:37]([CH3:39])[CH3:38])[S:12]([C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([O:21][CH3:22])[CH:16]=1)(=[O:14])=[O:13])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1cccc(S(=O)(=O)N[C@@H](C(=O)OCc2ccccc2)C(C)(C)C)c1
Reactant: CC(C)CCI
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1cccc(S(=O)(=O)N(CCC(C)C)[C@@H](C(=O)OCc2ccccc2)C(C)(C)C)c1
Temperature: 70 °C
Yield: 64.7 %

Procedure:
To a solution of N-(3 Methoxyphenylsulfonyl)D-tert-leucine benzyl ester (1.31 g, 3.35 mmol) in DMF (10 ml) is added K2CO3 (1.87 g, 13.4 mmol) followed by 1-iodo-3-methyl butane (1.33 g, 6.69 mmol) and the reaction mixture is heated to 70° C. overnight. The reaction is cooled to room temperature and then poured over 1 N HCl and extracted with Ethyl Acetate. The organics are washed with brine, dried over MgSO4 and concentrated. The crude product is purified by column chromatography eluting with a gradient of 5-40% (Hex-EtOAc) affording the title compound as a colorless oil (1.0 g, 65% yield). Mass spectrum (462.3; M+1).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5](/[C:8](=[CH:12]\[C:13]2[O:14][CH:15]=[CH:16][CH:17]=2)/[C:9](O)=[O:10])=[CH:4][CH:3]=1.C(Cl)(=O)C([Cl:21])=O.CN(C=O)C>C(Cl)Cl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[CH:12][C:13]2[O:14][CH:15]=[CH:16][CH:17]=2)[C:9]([Cl:21])=[O:10])=[CH:4][CH:3]=1
Reactant: O=C(Cl)C(=O)Cl
Reactant: O=C(O)/C(=C/c1ccco1)c1ccc(Br)cc1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=C(Cl)C(=Cc1ccco1)c1ccc(Br)cc1
Temperature: 20 °C
Reaction time: 4 h

Procedure:
A suspension of (E)-2-(4-bromophenyl)-3-furan-2-ylacrylic acid (Preparation 9, 4.10 g, 14.0 mmol) and oxalyl chloride (2.5 mL, 28.0 mmol) in anhydrous CH2Cl2 (100 mL) was treated with a catalytic amount of anhydrous DMF (25 μL). The resulting solution was stirred at 20° C. for 4 h, then the solvents were removed under reduced pressure. CH2Cl2 (50 mL) was added to the residue, then the solvents were evaporated off under reduced pressure to give 2-(4-bromophenyl)-3-furan-2-ylacryloyl chloride as a brown solid. A solution of this acid chloride (343 mg, 1.1 mmol) in anhydrous THF (1 mL) was added to a solution of 5-chlorothiazol-2-ylamine hydrochloride (171 g, 1.0 mmol) and NEt3 (0.56 mL, 4.0 mmol) in anhydrous THF (1 mL). The suspension was stirred for 16 h at 20° C., then the solvents were removed under reduced pressure. The residue was partitioned between CH2Cl2 (10 mL) and saturated aqueous NaHCO3 (5 mL). The organic layer was washed with H2O (5 mL) and brine (5 mL), before being concentrated. The resulting solid was recrystallised from MeOH to furnish the title compound: RTA=4.39 min; m/z (ES+)=410.9 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[C:4]([CH3:9])[C:3]=1[O:10][CH3:11].[N+:12]([O-])([OH:14])=[O:13]>C(O)(=O)C>[N+:12]([C:6]1[CH:5]=[C:4]([CH3:9])[C:3]([O:10][CH3:11])=[C:2]([CH3:1])[C:7]=1[CH3:8])([O-:14])=[O:13]
Reactant: O=[N+]([O-])O
Reactant: COc1c(C)ccc(C)c1C
Solvent: CC(=O)O
Product: COc1c(C)cc([N+](=O)[O-])c(C)c1C
Yield: 72 %

Procedure:
To a stirred, heated (70°-80° C.) solution of 20.3 g (0.135 mol) of 2,3,6-trimethylanisole in 200 ml of acetic acid was added dropwise 9.65 ml of conc. aqueous HNO3 in 20 ml of acetic acid. After the addition the mixture was poured onto ice, and the resulting mixture was extracted 3 times with methylene chloride. The organic phase was evaporated to remove acetic acid and methylene chloride, and the residue was dissolved in ether and washed twice with NaOH-solution and twice with NaHCO3 -solution. Drying (MgSO4) and evaporation gave 19.0 g (72%) of the product, which was used without further purification in the next step.