Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:20])[C:4]1[CH:9]=[CH:8][C:7]([N+:10]([O-])=O)=[C:6]([O:13][CH2:14][CH2:15][CH2:16][N:17]([CH3:19])[CH3:18])[CH:5]=1>CO.[Cl-].[NH4+].C(OCC)(=O)C.[Zn]>[CH3:1][O:2][C:3](=[O:20])[C:4]1[CH:9]=[CH:8][C:7]([NH2:10])=[C:6]([O:13][CH2:14][CH2:15][CH2:16][N:17]([CH3:18])[CH3:19])[CH:5]=1
Reactant: COC(=O)c1ccc([N+](=O)[O-])c(OCCCN(C)C)c1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Solvent: CCOC(C)=O
Solvent: CO
Product: COC(=O)c1ccc(N)c(OCCCN(C)C)c1
Reaction time: 12 h
Yield: 88 %

Procedure:
To a stirred, cooled (about 0° C.) solution of 3-(3-dimethylamino-propoxy)-4-nitro-benzoic acid methyl ester (282 mg, 1.0 mmol) in methanol (2 mL) and saturated aqueous ammonium chloride (1 mL) was added zinc dust (2.0 mmol). After stirring for 12 hours, the reaction was diluted with 30 mL of ethyl acetate and washed with 30 mL of 10% aqueous sodium carbonate (2×30 mL), brine (1×30 mL), then dried (MgSO4), and filtered. The filtered solution was concentrated under reduced pressure to yield the desired product as a tan solid (88% yield). 1H-NMR (400 MHz, CDCl3) δ7.52 (d, 1H), 7.48 (s, 1H), 7.25 (s, 1H), 6.65 (d, 1H), 4.29 (br s, 1H), 4.09 (t, 2H), 3.85 (s, 3H), 2.49 (t, 2H), 2.25 (s, 6H), 2.00 (m, 2H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[NH2:12])[NH:8][C:7](=[O:13])[CH2:6][C:5]2([CH3:15])[CH3:14].[CH:16](=O)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C(O)C>C(O)(=O)C>[CH3:14][C:5]1([CH3:15])[C:4]2[CH:3]=[C:2]3[NH:1][C:16]([C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=4)=[N:12][C:11]3=[CH:10][C:9]=2[NH:8][C:7](=[O:13])[CH2:6]1
Reactant: O=Cc1ccccc1
Reactant: CC1(C)CC(=O)Nc2cc(N)c(N)cc21
Solvent: CC(=O)O
Solvent: CCO
Product: CC1(C)CC(=O)Nc2cc3nc(-c4ccccc4)[nH]c3cc21

Procedure:
3.0 g. 6,7-diamino-4,4-dimethyl-1,2,3,4-tetrahydroquinolin-2-one and 1.5 ml. benzaldehyde were stirred for 20 hours in 50 ml. ethanol and 5 ml. glacial acetic acid. Half of the solvent was removed in a vacuum and the remainder was mixed with 50 ml. water and filtered off with suction. After recrystallisation from ethyl acetate, there were obtained 2.4 g. of the title compound; m.p. 296 -298° C.
Reaction SMILES: [OH-].[Na+:2].[Cl:3][C:4]1[C:9]2[O:10][C:11]3[C:20]([CH3:21])=[CH:19][C:18]([C:22]([OH:24])=[O:23])=[CH:17][C:12]=3[S:13](=[O:16])(=[O:15])[CH2:14][C:8]=2[CH:7]=[C:6]([NH:25][CH:26]=[O:27])[CH:5]=1>O.CO>[Na+:2].[Cl:3][C:4]1[C:9]2[O:10][C:11]3[C:20]([CH3:21])=[CH:19][C:18]([C:22]([O-:24])=[O:23])=[CH:17][C:12]=3[S:13](=[O:15])(=[O:16])[CH2:14][C:8]=2[CH:7]=[C:6]([NH:25][CH:26]=[O:27])[CH:5]=1
Reactant: Cc1cc(C(=O)O)cc2c1Oc1c(Cl)cc(NC=O)cc1CS2(=O)=O
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: Cc1cc(C(=O)[O-])cc2c1Oc1c(Cl)cc(NC=O)cc1CS2(=O)=O
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
A solution of sodium hydroxide (0.0108 g, 0.27 mmol) in water (0.1 mL) was added to the solution of Example 7 (0.104 g, 0.27 mmol) in methanol (5 mL) and stirred at 25° C. for 15 min, the solvent was removed and dried to obtain the title compound. Yield: 0.11 g, (100%); 1H NMR (DMSO-d6, 300 MHz): δ 2.58 (s, 3H, CH3), 5.16 (s, 2H, CH2), 7.69 (d, 1H, Ar), 7.87 (d, 1H, Ar), 7.95 (s, 1H, Ar), 8.11 (s, 1H, Ar), 8.30 (s, 1H, CHO), 10.78 (s, 1H, NH); MS: m/e (ES−) 380 (M−Na); analysis: C16H11ClNNaO6S.2H2O requires C, 43.70; H, 3.44; N, 3.81; Cl, 8.06; S, 7.29. found: C, 42.88; H, 3.19; N, 3.04; Cl, 8.69; S, 7.67%.
Reaction SMILES: [NH2:1][C:2]1[S:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][C:10]([N+:13]([O-:15])=[O:14])=[CH:9][CH:8]=2)[C:3]=1[C:16]#[N:17].C(N(CC)C(C)C)(C)C.Cl[C:28]([O:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)=[O:29]>CN(C1C=CN=CC=1)C.ClCCCl>[C:16]([C:3]1[C:4]([C:7]2[CH:8]=[CH:9][C:10]([N+:13]([O-:15])=[O:14])=[CH:11][CH:12]=2)=[N:5][S:6][C:2]=1[NH:1][C:28](=[O:29])[O:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)#[N:17]
Reactant: N#Cc1c(-c2ccc([N+](=O)[O-])cc2)nsc1N
Reactant: O=C(Cl)Oc1ccccc1
Agent: CN(C)c1ccncc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCCl
Product: N#Cc1c(-c2ccc([N+](=O)[O-])cc2)nsc1NC(=O)Oc1ccccc1
Temperature: 25 °C
Reaction time: 22 h

Procedure:
To a mixture of 5-amino-3-(4-nitrophenyl)isothiazole-4-carbonitrile (394 mg, 1.60 mmol), N,N-diisopropylethylamine (0.836 mL, 4.8 mmol), and catalytic DMAP in 20 mL 1,2-dichloroethane at rt was added phenyl chloroformate (0.301 mL, 2.40 mmol) drop wise over 1 minute. The reaction mixture was stirred at rt for 22 hours, then added directly to a dry packed silica gel column eluting with CHCl3, then gradient 10% to 50% EtOAc in CHCl3. The title compound was obtained as a beige solid (131 mg, 22%) and used as is for the next step.
Reaction SMILES: Cl.C(OC(=O)[NH:11][C:12]1([CH3:18])[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1)C1C=CC=CC=1.Br[C:21]1[CH:26]=[CH:25][C:24]([S:27]([CH3:30])(=[O:29])=[O:28])=[CH:23][N:22]=1.C(N(C(C)C)CC)(C)C>O1CCOCC1>[CH3:30][S:27]([C:24]1[CH:25]=[CH:26][C:21]([N:15]2[CH2:14][CH2:13][C:12]([NH2:11])([CH3:18])[CH2:17][CH2:16]2)=[N:22][CH:23]=1)(=[O:29])=[O:28]
Reactant: CC1(NC(=O)OCc2ccccc2)CCNCC1
Reactant: CS(=O)(=O)c1ccc(Br)nc1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: CC1(N)CCN(c2ccc(S(C)(=O)=O)cn2)CC1
Yield: 72.6 %

Procedure:
A solution of (4-methyl-piperidin-4-yl)-carbamic acid benzyl ester hydrochloride salt (0.37 g, 1.3 mmol, Example 30B), 2-bromo-5-(methylsulfonyl)pyridine (0.27 g, 1.15 mmol) and diisopropylethylamine (0.7 mL) in dioxane (4 mL) in a sealed tube was heated to 80° C. for 16 hours. The mixture was cooled, concentrated under reduced pressure and purified by chromatography (silica gel, eluting with 5% hexane/ethyl acetate to 25% ethyl acetate/hexane) to provide the titled compound (0.225 g) as a white solid. MS (CI) m/z 404 (M+1)+; 1H NMR (300 MHz, CDCl3) δ ppm 8.63 (d, 1H), 7.86 (dd, 1H), 7.37 (m, 5H), 6.65 (d, 1H), 5.07 (s, 2H), 4.67 (s, 1H), 4.04-3.96 (m, 2H), 3.49-3.39 (m, 2H), 3.03 (s, 3H), 2.19-2.12 (m, 2H), 1.71-1.61 (m, 2H), 1.41 (s, 3H).
Reaction SMILES: Cl.[NH2:2][C:3]1[N:4]=[CH:5][NH:6][C:7]=1[C:8]([NH2:10])=[O:9].CN(C)[CH:13]=[CH:14][C:15]([C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([O:23][CH3:24])[CH:18]=1)=O.C([O-])(=O)C.[Na+]>C(O)(=O)C>[CH3:24][O:23][C:19]1[CH:18]=[C:17]([C:15]2[N:4]3[CH:5]=[N:6][C:7]([C:8]([NH2:10])=[O:9])=[C:3]3[N:2]=[CH:13][CH:14]=2)[CH:22]=[CH:21][CH:20]=1
Reactant: NC(=O)c1[nH]cnc1N
Reactant: COc1cccc(C(=O)C=CN(C)C)c1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CC(=O)O
Product: COc1cccc(-c2ccnc3c(C(N)=O)ncn23)c1

Procedure:
A mixture of 1.62 g. of 4-amino-5-imidazolecarboxamide hydrochloride, 3-dimethylamino-3'-methoxyacrylophenone, 0.82 g. of sodium acetate and 25 ml. of glacial acetic acid is refluxed for 10 hours. The mixture is evaporated to dryness and the residue worked up to give 4-(m-methoxyphenyl)imidazo[1,5-a]pyrimidine-8-carboxamide. This compound is treated as for Example 29 with trifluoroacetic anhydride to give the product of the example.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH2:11])(=[O:10])=[O:9])=[CH:4][CH:3]=1.O1CCCC1.[C:17](Cl)(=[O:21])[C:18]([CH3:20])=[CH2:19]>O>[NH2:11][S:8]([C:5]1[CH:6]=[CH:7][C:2]([NH:1][C:17](=[O:21])[C:18]([CH3:20])=[CH2:19])=[CH:3][CH:4]=1)(=[O:9])=[O:10]
Reactant: C=C(C)C(=O)Cl
Reactant: Nc1ccc(S(N)(=O)=O)cc1
Solvent: C1CCOC1
Solvent: O
Product: C=C(C)C(=O)Nc1ccc(S(N)(=O)=O)cc1
Temperature: 60 °C
Reaction time: 0.5 h

Procedure:
To a 1 l three-necked flask equipped with a stirring machine, a condenser and a dropping funnel, there were introduced 170.2 g (1.0 mole) of p-aminobenzenesulfonamide and 700 ml of tetrahydrofuran, and the mixture was stirred while cooling it in an ice-water bath. 52.3 g (0.5 mole) of methacrylic acid chloride was dropwise added to the mixture through the dropping funnel over about one hour. After the dropwise addition, the flask was removed from the ice-water bath and the content thereof was stirred at room temperature for 30 minutes and further stirred for additional one hour while heating it to 60° C. in an oil bath. After completion of the reaction, the reaction mixture was poured into 3 l of water while stirring. The stirring was continued for 30 minutes and then the mixture was filtered to give white solid of N-(p-aminosulfonylphenyl) methacrylamide. The white solid thus obtained was purified by recrystallization from ethanol-acetone mixed solvent (yield 39.3 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[CH:6]=[CH:5][C:4]=1[NH:11][CH2:12][C:13]1[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=1.C(=O)([O-])[O-].[K+].[K+].[CH3:25][S:26](Cl)(=[O:28])=[O:27]>ClCCl>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[CH:6]=[CH:5][C:4]=1[N:11]([CH2:12][C:13]1[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=1)[S:26]([CH3:25])(=[O:28])=[O:27]
Reactant: CS(=O)(=O)Cl
Reactant: COc1ccc(NCc2cccnc2)c(OC)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Product: COc1ccc(N(Cc2cccnc2)S(C)(=O)=O)c(OC)c1

Procedure:
A 7.3 g. portion of 3-(2,4-dimethoxyphenylaminomethyl)pyridine was dissolved in 25 ml. of dichloromethane, and 5.5 g. of potassium carbonate and 3.1 ml. of methanesulfonyl chloride were added. The mixture was stirred under reflux overnight. Then it was cooled, diluted with 25 ml. of dichloromethane and washed with 25 ml. of aqueous sodium bicarbonate. The organic layer was separated, washed with water, dried over magnesium sulfate and evaporated under vacuum. The residue was suspended in ethyl acetate, and filtered. The filtrate was evaporated, and the residue was triturated with diethyl ether, filtered and dried under vacuum to obtain 6.7 g. of the desired product, m.p. 117°-119°.
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:13][CH2:14][O:15][C:16]1[CH:23]=[CH:22][C:19]([CH:20]=O)=[CH:18][CH:17]=1.[C:24]([O:32][CH2:33][CH3:34])(=[O:31])[CH2:25][C:26]([O:28][CH2:29][CH3:30])=[O:27].N1CCCCC1>C(O)(=O)C>[CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:13][CH2:14][O:15][C:16]1[CH:23]=[CH:22][C:19]([CH:20]=[C:25]([C:26]([O:28][CH2:29][CH3:30])=[O:27])[C:24]([O:32][CH2:33][CH3:34])=[O:31])=[CH:18][CH:17]=1
Reactant: Cc1oc(-c2ccccc2)nc1CCOc1ccc(C=O)cc1
Reactant: CCOC(=O)CC(=O)OCC
Solvent: CC(=O)O
Solvent: C1CCNCC1
Product: CCOC(=O)C(=Cc1ccc(OCCc2nc(-c3ccccc3)oc2C)cc1)C(=O)OCC
Yield: 81.7 %

Procedure:
4-[2-(5-Methyl-2-phenyl-4-oxazolyl)ethoxy]benzaldehyde (8.0 g, 26.0 mmol) synthesized according to the method described in WO95/18125, diethyl malonate (4.79 g, 29.9 mmol), acetic acid (1.04 ml) and piperidine (1.03 ml) were mixed. While removing water through Dean-Stark trap, the mixture was refluxed under heating. Three and a half hours later, toluene was evaporated and the obtained residue was recrystallized from ethyl acetate-hexane to give the title compound (9.55 g, yield 82%) as pale-brown white crystals.
Reaction SMILES: Cl[C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:8])[CH:7]=1.[S:9]1[CH:13]=[CH:12][CH:11]=[C:10]1B(O)O>>[Cl:8][C:6]1[CH:7]=[C:2]([C:10]2[S:9][CH:13]=[CH:12][CH:11]=2)[CH:3]=[N:4][CH:5]=1
Reactant: Clc1cncc(Cl)c1
Reactant: OB(O)c1cccs1
Product: Clc1cncc(-c2cccs2)c1
Yield: 16 %

Procedure:
The title compound (0.21 g, 1.08 mmol) was prepared from 3,5-dichloropyridine (1.0 g, 6.76 mmol) and 2-thiophene boronic acid (0.95 g, 7.43 mmol) as described in EXAMPLE 48, Part B.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:15]2[S:14][C:13]([NH2:16])=[N:12][C:11]=2[NH:10][N:9]=1.Cl.[N:18]1([CH2:24][C:25]2[O:29][C:28]([C:30](Cl)=[O:31])=[CH:27][CH:26]=2)[CH2:23][CH2:22][O:21][CH2:20][CH2:19]1.C(O)C(N)(CO)CO>CN(C1C=CN=CC=1)C.C1COCC1>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:15]2[S:14][C:13]([NH:16][C:30]([C:28]3[O:29][C:25]([CH2:24][N:18]4[CH2:19][CH2:20][O:21][CH2:22][CH2:23]4)=[CH:26][CH:27]=3)=[O:31])=[N:12][C:11]=2[NH:10][N:9]=1
Reactant: O=C(Cl)c1ccc(CN2CCOCC2)o1
Reactant: Nc1nc2[nH]nc(-c3ccccc3Br)c2s1
Agent: CN(C)c1ccncc1
Agent: Cl
Agent: NC(CO)(CO)CO
Solvent: C1CCOC1
Product: O=C(Nc1nc2[nH]nc(-c3ccccc3Br)c2s1)c1ccc(CN2CCOCC2)o1
Temperature: 70 °C
Reaction time: 17 h
Yield: 27.3 %

Procedure:
To a vial charged with 3-(2-bromo-phenyl)-1H-pyrazolo[3,4-d]thiazol-5-ylamine (30 mg, 0.135 mmol), PS-DMAP (Argonaut resin, 0.54 g, 6 equiv.), and a stirring bar was added THF (1.5 mL) and 5-morpholin-4-ylmethyl-furan-2-carbonyl chloride hydrochloride (180 mg, 0.675 mmol). The reaction mixture was stirred at 70° C. for 17 hours, then cooled to room temperature and treated with PS-trisamine (Argonaut resin, 0.76 g, 20 equiv.) at 50° C. for 8 hours. The resin was filtered, washed with DMF and the solvent was evaporated. Purification on silica gel with 0-8% MeOH in CH2Cl2 as eluent provided 18 mg (27% yield) of 5-morpholin-4-ylmethyl-furan-2-carboxylic acid [3-(2-bromo-phenyl)-1H-pyrazolo[3,4-d]thiazol-5-yl]-amide as a white solid. 1H-NMR (d6-DMSO) δ: 13.7 and 13.5 (2 broad s, 1H, NH+tautomer), 12.8 (broad s, 1H, NH), 7.65-7.82 (m, 3H), 7.49 and 7.55 (2 t, 1H, tautomers), 7.36 and 7.41 ( 2 t, 1H, tautomers), 6.58 (d, 1H), 3.59 (s, 2H), 3.56 (t, 4H), 2.41 (broad s, 4H); HPLC/MS m/z: 488.0, 490.0 [MH]+.
Reaction SMILES: [C:1]([CH2:6][C:7]([O:9][CH3:10])=[O:8])(=[O:5])[CH:2]([CH3:4])[CH3:3].C[O-].[Na+].CO.[Cl:16][C:17]1[C:22]([C:23](Cl)=[N:24]O)=[C:21]([Cl:27])[CH:20]=[CH:19][N:18]=1>C1COCC1>[Cl:16][C:17]1[C:22]([C:23]2[C:6]([C:7]([O:9][CH3:10])=[O:8])=[C:1]([CH:2]([CH3:4])[CH3:3])[O:5][N:24]=2)=[C:21]([Cl:27])[CH:20]=[CH:19][N:18]=1
Reactant: ON=C(Cl)c1c(Cl)ccnc1Cl
Reactant: COC(=O)CC(=O)C(C)C
Agent: C[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: COC(=O)c1c(-c2c(Cl)ccnc2Cl)noc1C(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 60.2 %

Procedure:
A solution of methyl isobutyrylacetate (1.37 mL, 10.2 mmol) in THF (2.1 mL) was stirred at 0° C. as a 0.5 N solution of sodium methoxide in methanol (20.3 mL, 10.2 mmol) was added. A solution of 2,4-dichloro-N-hydroxy-3-pyridinecarboximidoyl chloride (1.94 g, 8.64 mmol) in THF (19 mL) was added and the resulting solution was allowed to warm to room temperature and stir overnight. The mixture was concentrated and the residue partitioned between ethyl acetate and brine. The organic layer was dried with MgSO4, filtered and concentrated. The residue was purified by chromatography (silica gel, hexanes to 3:7 ethyl acetate:hexanes gradient elution) and fractions containing the product concentrated. The residue was azetroped with methanol then dichloromethane to provide methyl 3-(2,4-dichloro-3-pyridinyl)-5-(1-methylethyl)-4-isoxazolecarboxylate (1.64 g, 66% as 0.15 dichloromethane). 1H NMR (400 MHz, DMSO-d6): δ 8.65 (d, J=5 Hz, 1H), 7.82 (d, J=5 Hz, 1H), 3.79 (septet, J=7 Hz, 1H), 3.63 (s, 3H), 1.34 (m, 6H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].I[C:23]1[CH:28]=[CH:27][C:26]([N+:29]([O-:31])=[O:30])=[CH:25][CH:24]=1.N#N>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C1(C)C=CC=CC=1>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]([CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:23]2[CH:28]=[CH:27][C:26]([N+:29]([O-:31])=[O:30])=[CH:25][CH:24]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC(NCc2ccccc2)CC1
Reactant: O=[N+]([O-])c1ccc(I)cc1
Agent: [Pd]
Agent: N#N
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N1CCC(N(Cc2ccccc2)c2ccc([N+](=O)[O-])cc2)CC1
Temperature: 100 °C
Yield: 37 %

Procedure:
A solution of the above amine (500 mg, 1.72 mmol), 1-iodo-4-nitrobenzene (408 mg, 1.64 mmol), Pd2(dba)3, (±)BINAP and toluene was purged with N2 and then heated to 100° C. for 24 h to afford 4-[benzyl-(4-nitro-phenyl)-amino]-piperidine-1-carboxylic acid tert-butyl ester as a yellow foam (250 mg, 37%) following aqueous work-up and purification.
Reaction SMILES: [CH3:1][S:2][C:3]1[S:7][C:6]([N:8]2[CH:13]([OH:14])[CH2:12][CH2:11][N:10]([CH2:15][CH2:16][CH3:17])[C:9]2=[O:18])=[N:5][N:4]=1.Cl[C:20]([O:22][CH2:23][CH:24]=[CH2:25])=[O:21]>N1C=CC=CC=1>[CH3:1][S:2][C:3]1[S:7][C:6]([N:8]2[CH:13]([O:14][C:20]([O:22][CH2:23][CH:24]=[CH2:25])=[O:21])[CH2:12][CH2:11][N:10]([CH2:15][CH2:16][CH3:17])[C:9]2=[O:18])=[N:5][N:4]=1
Reactant: CCCN1CCC(O)N(c2nnc(SC)s2)C1=O
Reactant: C=CCOC(=O)Cl
Solvent: c1ccncc1
Product: C=CCOC(=O)OC1CCN(CCC)C(=O)N1c1nnc(SC)s1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
Tetrahydro-1-(5-methylthio-1,3,4-thiadiazol-2-yl)-3-propyl-6-hydroxy-2(1H)-pyrimidinone (0.05 mole) dissolved in pyridine (80 ml) is charged into a glass reaction vessel equipped with a mechanical stirrer and thermometer. The solution is cooled to a temperature of about 10° C and allyl chloroformate (0.06 mole) dissolved in pyridine (25 ml) is slowly added with stirring over a period of about 15 minutes. After the addition is completed, the reaction mixture is warmed to room temperature and is stirred for an additional period of about 20 minutes to ensure completion of the reaction. After this time the reaction mixture is filtered. The filtrate is then combined with water (100 ml) resulting in the formation of a precipitate. This precipitate is recovered by filtration and is dissolved in ether. The ether solution is washed with dilute aqueous sodium carbonate, is dried over anhydrous magnesium sulfate and is filtered. The filtrate is then stripped of ether to yield the desired product tetrahydro-1-(5-methylthio-1,3,4-thiadiazol-2-yl)-3-propyl-6-allyloxycarbonyloxy-2(1H)-pyrimidinone as the residue.
Reaction SMILES: [Si](C=[N+]=[N-])(C)(C)[CH3:2].[CH2:8]([C@H:15]([C:42]([NH:44][C@H:45]1[CH2:51][CH2:50][S:49][C@H:48]2[CH2:52][CH2:53][CH2:54][C@@H:55]([C:56]([O:58][CH3:59])=[O:57])[N:47]2[C:46]1=[O:60])=[O:43])[CH2:16][CH2:17][C@@H:18]([C:23](=[O:41])[NH:24][C@H:25]1[CH2:31][CH2:30][S:29][C@H:28]2[CH2:32][CH2:33][CH2:34][C@@H:35]([C:36]([O:38][CH3:39])=[O:37])[N:27]2[C:26]1=[O:40])[CH2:19][C:20]([OH:22])=[O:21])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>C(Cl)Cl.CO>[CH2:8]([C@H:15]([C:42]([NH:44][C@H:45]1[CH2:51][CH2:50][S:49][C@H:48]2[CH2:52][CH2:53][CH2:54][C@@H:55]([C:56]([O:58][CH3:59])=[O:57])[N:47]2[C:46]1=[O:60])=[O:43])[CH2:16][CH2:17][C@H:18]([CH2:19][C:20]([O:22][CH3:2])=[O:21])[C:23]([NH:24][C@H:25]1[CH2:31][CH2:30][S:29][C@H:28]2[CH2:32][CH2:33][CH2:34][C@@H:35]([C:36]([O:38][CH3:39])=[O:37])[N:27]2[C:26]1=[O:40])=[O:41])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: C[Si](C)(C)C=[N+]=[N-]
Reactant: COC(=O)[C@@H]1CCC[C@@H]2SCC[C@H](NC(=O)[C@H](CC[C@H](Cc3ccccc3)C(=O)N[C@H]3CCS[C@H]4CCC[C@@H](C(=O)OC)N4C3=O)CC(=O)O)C(=O)N21
Solvent: ClCCl
Solvent: CO
Product: COC(=O)C[C@@H](CC[C@H](Cc1ccccc1)C(=O)N[C@H]1CCS[C@H]2CCC[C@@H](C(=O)OC)N2C1=O)C(=O)N[C@H]1CCS[C@H]2CCC[C@@H](C(=O)OC)N2C1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 52.5 %

Procedure:
TMS-diazomethane (2.0 M in ether, 0.0061 mL, 0.012 mmol) was added to a solution of (3R,6R)-6-benzyl-7-((4S,7S,10aS)-7-(methoxycarbonyl)-5-oxooctahydro-2H-pyrido[2,1-b][1,3]thiazepin-4-ylamino)-3-((4S,7S,10aS)-7-(methoxycarbonyl)-5-oxooctahydro-2H-pyrido[2,1-b][1,3]thiazepin-4-ylcarbamoyl)-7-oxoheptanoic acid (5.4 mg, 7.0 mmol) in DCM (0.06 mL) and MeOH (0.0062 mL). Gas evolution occurred. The reaction was stirred at rt for 1 hr. The reaction mixture was concentrated and triturated with hexanes. The solid was dried over vacuum to give methyl (4S,7S,10aS)-4-(((2R,5R)-5-benzyl-6-(((4S,7S,10aS)-7-(methoxycarbonyl)-5-oxooctahydro-7H-pyrido[2,1-b][1,3]thiazepin-4-yl)amino)-2-(2-methoxy-2-oxoethyl)-6-oxohexanoyl)amino)-5-oxooctahydro-7H-pyrido[2,1-b][1,3]thiazepine-7-carboxylate (5.0 mg, 0.0063 mmol, 91% yield) as a white solid. Anal. Calcd. for C38H52N4O10S2 m/z 788.7. found: 789.2 (M+H)+; 1H NMR (400 MHz, CDCl3) δ ppm 7.32 (1H, d), 7.25-7.21 (2H, m), 7.19-7.11 (3H, m), 7.00 (1H, d), 5.39 (1H, t, J=4.7 Hz), 5.36 (1H, t, J=4.7 Hz), 5.21-5.16 (1H, m), 5.16-5.12 (1H, m), 5.10-4.98 (2H, m), 3.72 (3H, s), 3.69 (3H, s), 3.65 (3H, s), 3.28-3.10 (2H, m), 2.98-2.81 (3H, m), 2.77-2.62 (3H, m), 2.47-2.37 (3H, m), 2.34 (1H, dd, J=15.7, 3.6 Hz), 2.27-2.19 (1H, m), 2.08-1.95 (4H, m), 1.88 (1H, ddd, J=10.9, 7.0, 3.6 Hz), 1.76-1.47 (12H, m).
Reaction SMILES: [O-:1][CH2:2][CH3:3].[Na+].[Na].F[C:7]1[C:8]([CH:14]([N:16]2[C:20]([CH3:21])=[CH:19][CH:18]=[C:17]2[CH3:22])[CH3:15])=[N:9][CH:10]=[CH:11][C:12]=1[I:13]>C(O)C.O>[I:13][C:12]1[CH:11]=[CH:10][N:9]=[C:8]([CH:14]([N:16]2[C:20]([CH3:21])=[CH:19][CH:18]=[C:17]2[CH3:22])[CH3:15])[C:7]=1[O:1][CH2:2][CH3:3]
Reactant: CC[O-]
Reactant: Cc1ccc(C)n1C(C)c1nccc(I)c1F
Agent: [Na+]
Agent: [Na]
Solvent: CCO
Solvent: O
Product: CCOc1c(I)ccnc1C(C)n1c(C)ccc1C
Yield: 8.5 %

Procedure:
A solution of sodium ethoxide was initially prepared by dissolving 2.0 g (87 mmole) of sodium metal in 300 ml of anhydrous absolute ethanol. To the stirring solution thus prepared was added 3.5 g (10.2 mmole) of N-[(3-Fluoro-4-iodopyrid-2-yl)eth-2-yl]-2,5-dimethylpyrrole and the mixture was refluxed under nitrogen for 4 days. The solution was cooled, diluted to 1 liter with water, and extracted with ethyl acetate (2×). The organic layer was dried over sodium sulfate, filtered, and concentrated to a resin. Chromatography over flash silica gel (30% ethyl acetate in hexanes) gave initially 320 mg (8.5%) of N-[(4-Iodo-3-ethoxypyrid-2-yl)-eth-2-yl]-2,5-dimethylpyrrole: 1H NMR (300 MHz, DMSO-d6) δ 7.95 (d, 1H), 7.62 (d, 1H), 5.80 (s, 2H), 4.10 (t, 2H), 4.00 (q, 2H), 3.15 (t, 2H), 2.20 (s, 6H), 1.45 (t, 3H); MS (FD) m/e 370 (Mt). Further elution provided the titled compound, 1.7 g (64%): IR (KBr, cm-1) 2991, 1608, 1495, 1309, 1075; 1H NMR (300 MHz, DMSO-d6) δ 8.22 (d, 1H), 7.15 (t, 1H), 5.60 (s, 2H), 4.20 (q, 2H), 4.10 (t, 2H), 2.98 (dt, 2H), 2.10 (s, 6H), 1.38 (t, 3H): MS (FD) m/e 262 (Mt). Anal. Calc'd. for C15H19FN2O 0.25 H2 O: C, 67.55; H, 7.31; N, 10.50. Found: C, 67.56; H, 7.35; N, 10.46.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([NH2:8])[C:5]([C:9]2[CH:14]=[C:13]([Cl:15])[CH:12]=[C:11]([Cl:16])[C:10]=2[Cl:17])=[C:4]([CH3:18])[N:3]=1.[N+:19]([O-])([O-:21])=[O:20].[K+].N>S(=O)(=O)(O)O>[NH2:1][C:2]1[N:7]=[C:6]([NH2:8])[C:5]([C:9]2[CH:14]=[C:13]([Cl:15])[C:12]([N+:19]([O-:21])=[O:20])=[C:11]([Cl:16])[C:10]=2[Cl:17])=[C:4]([CH3:18])[N:3]=1
Reactant: Cc1nc(N)nc(N)c1-c1cc(Cl)cc(Cl)c1Cl
Reactant: O=[N+]([O-])[O-]
Agent: N
Agent: O=S(=O)(O)O
Agent: [K+]
Product: Cc1nc(N)nc(N)c1-c1cc(Cl)c([N+](=O)[O-])c(Cl)c1Cl
Temperature: 25 °C
Reaction time: 8 h

Procedure:
2,4-Diamino-6-methyl-5-(2,3,5-trichlorophenyl)pyrimidine (0.152 g) (Example 6) was dissolved in concentrated sulphuric acid and potassium nitrate (50 mg) was added. The solution was stirred at room temperature overnight, then poured onto ice and basified with 0.880 ammonia. The product was extracted into ethyl acetate, bulked, dried (MgSO4) and evaporated. The residue was purified by chromatography on SiO2 gel, eluting with EtOAc to 8% MeOH/EtOAc to give the desired product, 0.13 g, mp. 313°-315° C.
Reaction SMILES: [Cl:1][C:2]1[C:8]([O:9][CH2:10][C:11]([O:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])=[O:12])=[CH:7][C:5]([NH2:6])=[C:4]([F:19])[CH:3]=1.[C:20]1(=O)[O:25][C:23](=[O:24])[C:22]2[CH2:26][CH2:27][CH2:28][CH2:29][C:21]1=2.C1(C)C=CC=CC=1>C1(C)C=CC(S(O)(=O)=O)=CC=1.O>[Cl:1][C:2]1[C:8]([O:9][CH2:10][C:11]([O:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])=[O:12])=[CH:7][C:5]([N:6]2[C:23](=[O:24])[C:22]3[CH2:26][CH2:27][CH2:28][CH2:29][C:21]=3[C:20]2=[O:25])=[C:4]([F:19])[CH:3]=1
Reactant: CCCCCOC(=O)COc1cc(N)c(F)cc1Cl
Reactant: O=C1OC(=O)C2=C1CCCC2
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: CCCCCOC(=O)COc1cc(N2C(=O)C3=C(CCCC3)C2=O)c(F)cc1Cl
Yield: 88.9 %

Procedure:
A mixture of the compound (II) (12.0 g), 3,4,5,6-tetrahydrophthalic anhydride (7.56 g), p-toluenesulfonic acid (0.4 g) and toluene (24 g) was refluxed for 10 hours, during which water was azeotropically removed. The reaction mixture was treated in the same manner as in Example 4 to give the compound (I) (15.6 g).