Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:6][CH2:7][CH3:8])(=S)[C:2]([NH2:4])=O.F[B-](F)(F)F.C[O+:15](C)C.[CH:18]([NH:21][NH:22][C:23](=O)[CH3:24])([CH3:20])[CH3:19]>C(Cl)Cl>[CH2:7]([O:6][C:1]([C:2]1[N:21]([CH:18]([CH3:20])[CH3:19])[N:22]=[C:23]([CH3:24])[N:4]=1)=[O:15])[CH3:8]
Reactant: CCOC(=S)C(N)=O
Reactant: C[O+](C)C
Reactant: CC(=O)NNC(C)C
Agent: F[B-](F)(F)F
Solvent: ClCCl
Product: CCOC(=O)c1nc(C)nn1C(C)C
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of ethyl thiooxamate (29.6 g, 0.22 mol) in DCM (260 mL) at RT was added trimethyloxonium tetrafluoroborate (34.5 g, 0.23 mol) and the mixture stirred at RT for 2 h. During this time the yellow colour faded and a thick white precipitate was formed. Acetic acid N′-isopropylhydrazide (27.1 g, 0.23 mol) and TEA (30.9 mL, 0.22 mol) were added as a solution in DCM (75 mL) causing the precipitate to dissolve. The reaction mixture was stirred at reflux for 5 h then at RT for 10 h. The reaction mixture was washed with water, and the aqueous layer extracted with DCM (2×50 mL). The combined organic extracts were washed with brine, dried (MgSO4) and concentrated in vacuo. The resultant residue was subjected to flash chromatography (SiO2, gradient 0-100% ethyl acetate in cyclohexane) to give 2-Isopropyl-5-methyl-2H-[1,2,4]triazole-3-carboxylic acid ethyl ester as a pale yellow oil which crystallised on standing (15.6 g, 32%). 1H NMR 400 MHz (CDCl3) δ: 5.49 (1H, sept, J=6.7 Hz), 4.45 (2H, t, J=7.2 Hz), 2.43 (3H, s), 1.50 (6H, d, J=6.7 Hz), 1.44 (3H, t, J=7.2 Hz)
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5]1[C:14]2[N:13]=[CH:12][NH:11][C:10]=2[CH2:9][CH2:8][CH2:7][CH2:6]1)=[O:4].C(N(CC)CC)C.[C:22]1([C:28](Cl)([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>ClCCl>[CH3:1][O:2][C:3]([CH:5]1[C:14]2[N:13]=[CH:12][N:11]([C:28]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)([C:35]3[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=3)[C:29]3[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=3)[C:10]=2[CH2:9][CH2:8][CH2:7][CH2:6]1)=[O:4]
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: COC(=O)C1CCCCc2[nH]cnc21
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)C1CCCCc2c1ncn2C(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 20 °C
Reaction time: 8 h
Yield: 28 %

Procedure:
To a solution of crude 1,4,5,6,7,8-hexahydrocycloheptaimidazole-4-carboxylic acid methyl ester (8.75 g, approx. 45.0 mmol, J. Am. Chem. Soc. 1976, 98, 984) in dichloromethane (100 ml) were added triethylamine (15.4 ml, 111 mmol) and a solution of triphenylmethyl chloride (18.5 g, 66.4 mmol) in dichloromethane (100 ml). The resulting mixture was stirred at 20° C. overnight. The mixture was washed with water and dried with magnesium sulfate. Filtration, concentration, and column chromatography (silica gel, gradient elution with heptane/ethyl acetate 9:1 to 1:1) yielded 5.5 g (28%) of the title compound as a solid.
Reaction SMILES: [Cl:1][C:2]1[C:7]([CH2:8][NH:9][CH2:10][CH3:11])=[CH:6][C:5]([CH3:12])=[CH:4][N:3]=1.[CH:13]1([C:16]([OH:18])=O)[CH2:15][CH2:14]1.Cl.C(N=C=NCCCN(C)C)C.O.ON1C2C=CC=CC=2N=N1.C(N(CC)CC)C>C(Cl)Cl>[Cl:1][C:2]1[C:7]([CH2:8][N:9]([CH2:10][CH3:11])[C:16]([CH:13]2[CH2:15][CH2:14]2)=[O:18])=[CH:6][C:5]([CH3:12])=[CH:4][N:3]=1
Reactant: CCNCc1cc(C)cnc1Cl
Reactant: O=C(O)C1CC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCN(Cc1cc(C)cnc1Cl)C(=O)C1CC1
Temperature: 25 °C

Procedure:
(2-Chloro-5-methyl-pyridin-3-ylmethyl)-ethyl-amine (0.126 g, 0.69 mmol), cyclopropanecarboxylic acid (0.08 mL, 1.03 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.197 g, 1.03 mmol), 1-hydroxybenzotriazole hydrate (0.139 g, 1.03 mmol), and triethylamine (0.29 mL, 2.05 mmol) were combined in CH2Cl2 and stirred at room temperature over the weekend. The mixture was concentrated and purified by silica gel chromatography (0-70% EtOAc in hexanes) to give the title compound.
Reaction SMILES: [CH3:1][C:2]1[C:10]([S:11][CH3:12])=[C:9]([C:13]([F:19])([F:18])[C:14]([F:17])([F:16])[F:15])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].C(Cl)(=O)C(Cl)=O.[CH:26]12[CH2:33][CH:30]([CH2:31][CH2:32]1)[C:29](=[O:34])[CH2:28][C:27]2=O.C(N(CC)CC)C.Cl>CN(C)C=O.CN(C1C=CN=CC=1)C.ClCCl>[CH3:1][C:2]1[C:10]([S:11][CH3:12])=[C:9]([C:13]([F:19])([F:18])[C:14]([F:16])([F:15])[F:17])[CH:8]=[CH:7][C:3]=1[C:4]([O:6][C:27]1[CH:26]2[CH2:33][CH:30]([C:29](=[O:34])[CH:28]=1)[CH2:31][CH2:32]2)=[O:5]
Reactant: O=C1CC(=O)C2CCC1C2
Reactant: CSc1c(C(F)(F)C(F)(F)F)ccc(C(=O)O)c1C
Agent: CN(C)c1ccncc1
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CSc1c(C(F)(F)C(F)(F)F)ccc(C(=O)OC2=CC(=O)C3CCC2C3)c1C
Temperature: 25 °C
Reaction time: 16 h

Procedure:
235 mg (0.783 mmol) of 2-methyl-3-(methylthio)-4-(pentafluoroethyl)benzoic acid were introduced into 20 ml of dry dichloromethane and admixed in succession with 129 mg (1.02 mmol) of oxalyl chloride and also with two drops of N,N-dimethyl-formamide. After the end of evolution of gas, the mixture was heated under reflux for another 10 minutes. Then, the contents were cooled and concentrated on a rotary evaporator. The residue was taken up in 20 ml of dry dichloromethane and admixed with 119 mg (0.861 mmol) of bicyclo[3.2.1]octane-2,4-dione and a catalytic amount of DMAP. Then 158 mg (1.57 mmol) of triethylamine were added dropwise. The mixture was stirred at RT for 16 hours. For working up, 3 ml of 1N hydrochloric acid were added. Following phase separation, the organic phase was freed from the solvent and the residue, finally, was purified by chromatography. This gave 280 mg of product with a purity of 90% by weight.
Reaction SMILES: [C:1](Cl)(Cl)=[O:2].[Cl:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([Cl:12])[C:7]=1[NH:13][CH2:14][C:15]1[C:16]([NH:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[N:17][C:18]([S:21][CH3:22])=[N:19][CH:20]=1.C(N(CC)CC)C.[Cl-].[NH4+]>O1CCCC1>[Cl:12][C:8]1[CH:9]=[CH:10][CH:11]=[C:6]([Cl:5])[C:7]=1[N:13]1[CH2:14][C:15]2[C:16](=[N:17][C:18]([S:21][CH3:22])=[N:19][CH:20]=2)[N:23]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:1]1=[O:2]
Reactant: CSc1ncc(CNc2c(Cl)cccc2Cl)c(Nc2ccccc2)n1
Reactant: O=C(Cl)Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CSc1ncc2c(n1)N(c1ccccc1)C(=O)N(c1c(Cl)cccc1Cl)C2
Temperature: 25 °C
Reaction time: 72 h
Yield: 100 %

Procedure:
A stirred solution, cooled in ice, of 0.25 ml (0.48 ml) of phosgene (20% in toluene) in 5 ml of tetrahydrofuran was treated dropwise with a solution of 100 mg (0.26 mmol) of 5-(2,6-dichlorophenyl)aminomethyl-4-phenylamino-2-methylthiopyrimidine and 0.1 ml (0.7 mmol) of triethylamine in 10 ml of tetrahydrofuran. The mixture was stirred at room temperature for 3 days. 20 ml of tetrahydrofuran and 20 ml of saturated aqueous ammonium chloride solution were added, the phases were separated and the organic phase was dried over magnesium sulfate, filtered and evaporated to give 110 mg (100%) of 3-(2,6-dichlorophenyl)-7-methylthio-3,4-dihydro-1-phenylpyrimido[4,5-d]pyrimidin-2(1H)-one as a white solid.
Reaction SMILES: CC1C=C(N2CCN(CCOC3C=CC=CC=3)C2=O)SC=1C(O)=O.[F:25][C:26]1[CH:47]=[CH:46][C:29]([CH2:30][N:31]2[CH2:35][CH2:34][N:33]([C:36]3[S:40][C:39]([C:41]([OH:43])=O)=[C:38]([CH3:44])[CH:37]=3)[C:32]2=[O:45])=[CH:28][CH:27]=1.[CH3:48][C:49]1[N:50]=[CH:51][C:52]([CH2:55][NH2:56])=[N:53][CH:54]=1>>[F:25][C:26]1[CH:27]=[CH:28][C:29]([CH2:30][N:31]2[CH2:35][CH2:34][N:33]([C:36]3[S:40][C:39]([C:41]([NH:56][CH2:55][C:52]4[CH:51]=[N:50][C:49]([CH3:48])=[CH:54][N:53]=4)=[O:43])=[C:38]([CH3:44])[CH:37]=3)[C:32]2=[O:45])=[CH:46][CH:47]=1
Reactant: Cc1cc(N2CCN(Cc3ccc(F)cc3)C2=O)sc1C(=O)O
Reactant: Cc1cnc(CN)cn1
Agent: Cc1cc(N2CCN(CCOc3ccccc3)C2=O)sc1C(=O)O
Product: Cc1cnc(CNC(=O)c2sc(N3CCN(Cc4ccc(F)cc4)C3=O)cc2C)cn1
Yield: 78 %

Procedure:
Following the procedures as described in Example 55, making variations as required to replace 3-methyl-5-(2-oxo-3-(2-phenoxyethyl)imidazolidin-1-yl)thiophene-2-carboxylic acid with 5-(3-(4-fluorobenzyl)-2-oxoimidazolidin-1-yl)-3-methylthiophene-2-carboxylic acid to react with (5-methylpyrazin-2-yl)methanamine, the title compound was obtained as a colorless solid in 78% yield: 1H NMR (300 MHz, CDCl3) δ 7.52 (s, 1H), 8.40 (s, 1H), 7.31-7.23 (m, 2H), 7.08-6.99 (m, 2H), 6.72 (t, J=4.6 Hz, 1H), 6.12 (s, 1H), 4.70 (d, J=4.6 Hz, 2H), 4.44 (s, 2H), 3.84-3.76 (m, 2H), 3.48-3.39 (m, 2H), 2.57 (s, 3H), 2.50 (s, 3H); MS (ES+) m/z 440.2 (M+1).
Reaction SMILES: Cl[C:2]([O:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([N+:12]([O-:14])=[O:13])=[CH:8][CH:7]=1)=[O:3].[CH3:15][S:16]([N:19]([CH2:34][CH2:35][Cl:36])[N:20]([S:30]([CH3:33])(=[O:32])=[O:31])C(OC1C=CC=CC=1)=O)(=[O:18])=[O:17]>>[CH3:15][S:16]([N:19]([CH2:34][CH2:35][Cl:36])[N:20]([S:30]([CH3:33])(=[O:32])=[O:31])[C:2]([O:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([N+:12]([O-:14])=[O:13])=[CH:8][CH:7]=1)=[O:3])(=[O:17])=[O:18]
Reactant: CS(=O)(=O)N(CCCl)N(C(=O)Oc1ccccc1)S(C)(=O)=O
Reactant: O=C(Cl)OCc1ccc([N+](=O)[O-])cc1
Product: CS(=O)(=O)N(CCCl)N(C(=O)OCc1ccc([N+](=O)[O-])cc1)S(C)(=O)=O

Procedure:
1,2-Bis(methylsulfonyl)-1-(2-chloroethyl)-2-[(4-nitrobenzyloxy)carbonyl]hydrazine (compound 10h) was prepared by reacting compound 2 with 4-nitrobenzyl chloroformate using a procedure similar to that employed for compound 10d. The product was recrystallized from ethanol, and the yield was approximately 22.9% by weight. The Mp was approximately 132-133° C. 1H NMR (acetone-d6): δ 8.3 and 7.8 (4H, 2d, aromatic H), 5.6 (2H, s, ArCH2), 3.6-4.2 (4H, m, CH2CH2Cl), 3.6 and 3.3 (6H, 2s, 2 CH3SO2).
Reaction SMILES: C(OC([NH:8][C:9]1[CH:17]=[CH:16][CH:15]=[C:14]2[C:10]=1[CH:11]=[N:12][N:13]2[C:18]([C:28]1[O:32][N:31]=[C:30]([C:33]([O:35][CH2:36][CH3:37])=[O:34])[N:29]=1)([C:21]1[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][CH:22]=1)[CH2:19][CH3:20])=O)(C)(C)C.C1(OC)C=CC=CC=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:8][C:9]1[CH:17]=[CH:16][CH:15]=[C:14]2[C:10]=1[CH:11]=[N:12][N:13]2[C:18]([C:28]1[O:32][N:31]=[C:30]([C:33]([O:35][CH2:36][CH3:37])=[O:34])[N:29]=1)([C:21]1[CH:22]=[CH:23][C:24]([Cl:27])=[CH:25][CH:26]=1)[CH2:19][CH3:20]
Reactant: CCOC(=O)c1noc(C(CC)(c2ccc(Cl)cc2)n2ncc3c(NC(=O)OC(C)(C)C)cccc32)n1
Solvent: O=C(O)C(F)(F)F
Solvent: COc1ccccc1
Solvent: ClCCl
Product: CCOC(=O)c1noc(C(CC)(c2ccc(Cl)cc2)n2ncc3c(N)cccc32)n1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of the product from Step C above (0.083 g, 0.16 mmol) and anisole (0.068 g, 0.63 mmol) in DCM (1.0 mL) was added TFA (0.18 g, 1.58 mmol). After stirred overnight at RT, the reaction mixture was concentrated to dryness under reduced pressure. The resulting residue was re-dissolved in a mixture of acetonitrile and water followed by addition of 1 N HCl aqueous solution (0.16 mL). The solution was dried in a lyophilized to give crude title compound. LC/MS m/z=426.1[M+H]+.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([CH:7]=O)=[CH:3][CH:2]=1.C([Li])CCC.[CH3:14][C:15]([C:17]12[CH2:26][CH:21]3[CH2:22][CH:23]([CH2:25][CH:19]([CH2:20]3)[CH2:18]1)[CH2:24]2)=[O:16]>C1COCC1.C(NC(C)C)(C)C>[C:17]12([C:15](=[O:16])/[CH:14]=[CH:7]/[C:4]3[CH:3]=[CH:2][N:1]=[CH:6][CH:5]=3)[CH2:24][CH:23]3[CH2:22][CH:21]([CH2:20][CH:19]([CH2:25]3)[CH2:18]1)[CH2:26]2
Reactant: CC(=O)C12CC3CC(CC(C3)C1)C2
Reactant: O=Cc1ccncc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: O=C(/C=C/c1ccncc1)C12CC3CC(CC(C3)C1)C2
Yield: 65.9 %

Procedure:
The method essentially followed that described in Example 17a but using 4-pyridinecarboxaldehyde (0.48 ml, 5.0 mmol) in THF (6 ml), diisopropylamine in THF (20 ml), butyllithium (3.13 g, 5.0 mmol) and 1-adamantyl methyl ketone (0.48 ml, 5.0 mmol). Chromatography, on elution with petrol-ether-triethylamine 100:100:1, gave the title compound (881 mg, 66%), which crystallised from hexane, m.p. 128°-129° C., IR νmax 1690 cm-1 ; 1H-NMR (CDCl3) δ1.72-1.89 (12H, adamantyl CH2) 2.12 (3H, s, adamantyl CH), 7.36 (1H, d, J 15.6 Hz, COCHCH), 7.56 (1H, d, J 15.6 Hz, COCHCH), 7.71 (2H, d, J 5.5 Hz, Py 3-H and 5-H), 8.71 (2H, d, J 5.5 Hz, Py 2-H and 6-H); MS m/z 267 (M+). Anal. Calcd: C, 80.86; H, 7.92; N, 5.24. Found: C, 80.96; H, 8.13; N, 5.04 %.
Reaction SMILES: S([O-])(O[O-])(=O)=[O:2].[K+].[K+].[C:9]([C:12]1[CH:35]=[CH:34][C:15]([O:16][CH2:17][C:18]2[CH:19]=[C:20]([S:24][C:25]3[CH:26]=[N:27][CH:28]=[C:29]([CH:33]=3)[C:30]([OH:32])=[O:31])[CH:21]=[CH:22][CH:23]=2)=[C:14]([CH3:36])[C:13]=1[OH:37])(=[O:11])[CH3:10].Cl>O.CO>[C:9]([C:12]1[CH:35]=[CH:34][C:15]([O:16][CH2:17][C:18]2[CH:19]=[C:20]([S:24]([C:25]3[CH:26]=[N:27][CH:28]=[C:29]([CH:33]=3)[C:30]([OH:32])=[O:31])=[O:2])[CH:21]=[CH:22][CH:23]=2)=[C:14]([CH3:36])[C:13]=1[OH:37])(=[O:11])[CH3:10]
Reactant: CC(=O)c1ccc(OCc2cccc(Sc3cncc(C(=O)O)c3)c2)c(C)c1O
Reactant: O=S(=O)([O-])O[O-]
Agent: Cl
Agent: [K+]
Solvent: O
Solvent: CO
Product: CC(=O)c1ccc(OCc2cccc(S(=O)c3cncc(C(=O)O)c3)c2)c(C)c1O
Temperature: 25 °C
Reaction time: 36 h
Yield: 14.6 %

Procedure:
Add a 0.5 M solution of potassium peroxymonosulfate (0.61 g, 1.00 mmol) in water (2.0 mL) to a solution of 5-(3-((4-acetyl-3-hydroxy-2-methylphenoxy)methyl)phenylthio)nicotinic acid (205 mg, 0.50 mmol) in methanol (7.5 mL) at 0° C. Allow the solution to warm to room temperature and stir for 1.5 d. Add water and 2.2 mL of 2.0 M HCl to the mixture. Extract the mixture with EtOAc. Dry, filter and concentrate. Recrystallize the residue from a mixture of CH2Cl2 and hexanes to give a light yellow solid. Purify the yellow solid by flash chromatograhpy on silica gel eluting with a mixture of acetone, hexanes, and acetic acid (50:50:1 to 90:10) to afford the title compound (31 mg, 15%): 1H NMR (d6-DMSO) δ 2.01 (s, 3H), 2.58 (s, 3H), 5.33 (s, 2H), 6.67 (d, J=9.0 Hz, 1H), 7.61-7.63 (m, 2H), 7.77 (d, J=9.0 Hz, 1H), 7.81-7.83 (m, 1H), 7.88 (s, 1H), 8.49 (t, J=2.0 Hz, 1H), 9.08 (d, J=2.0 Hz, 1H), 9.12 (d, J=2.0 Hz, 1H), 12.84 (s, 1H); MS (APCI-neg mode) m/z (rel intensity): 424 (M−H, 100%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH2:14][CH2:13][O:12][CH2:11][CH2:10]2)=[CH:5][C:4]=1[NH:15][C:16]([C:18]1[NH:19][CH:20]=[CH:21][N:22]=1)=O.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:32])=CC=1.O>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH2:14][CH2:13][O:12][CH2:11][CH2:10]2)=[CH:5][C:4]=1[NH:15][C:16]([C:18]1[NH:19][CH:20]=[CH:21][N:22]=1)=[S:32]
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: COc1ccc(N2CCOCC2)cc1NC(=O)c1ncc[nH]1
Solvent: Cc1ccccc1
Solvent: O
Product: COc1ccc(N2CCOCC2)cc1NC(=S)c1ncc[nH]1
Temperature: 25 °C
Yield: 59.5 %

Procedure:
To a suspension of 1.0 g of imidazole-2-carboxylic acid (8.9 mmol) in 15 ml DMF was added 1.6 g of CDI (9.8 mmol) and stirred at ambient temperature for 1 h. Then the mixture was refluxed for 30 min. After cooling to ambient temperature, 2.0 g of 2-methoxy-5-morpholin-4-yl-phenylamine (9.8 mmol) were added and the reaction mixture was heated to reflux for 16 h. The mixture was evaporated and the residue taken up in water (40 ml) and extracted 3 times with ethyl acetate. The combined organic phases were dried on sodium carbonate, evaporated and the residue subjected to column chromatography (silica gel, ethyl acetate/hexanes 2:1). 0.25 g 1H-imidazole-2-carboxylic acid (2-methoxy-5-morpholin-4-yl-phenyl)-amide (9%) were obtained as a white solid; M.p.: 227–230° C. 0.2 g of 1H-Imidazole-2-carboxylic acid (2-methoxy-5-morpholin-4-yl-phenyl)-amide (0.66 mmol) were taken up in toluene (8.0 ml) and treated with 0.8 g of Lawesson reagent (2.0 mmol). The reaction mixture was heated to reflux for 22 h. After cooling to ambient temperature, water (25 ml) was added and the mixture was extracted 3 times with ethyl acetate. The combined organic phases were dried on sodium carbonate, evaporated and the residue subjected to column chromatography (silica gel, ethyl acetate/hexanes 1:1). 0.125 g of 1H-imidazole-2-carbothioic acid (2-methoxy-5-morpholin-4-yl-phenyl)-amide (59%) was obtained as a yellow foam; MS (ISP): m/e=319 (M+H+).
Reaction SMILES: [CH2:1]([C:5]1[CH:6]=[C:7]([CH:15]=[CH:16][CH:17]=1)[NH:8][C:9](=[O:14])[CH2:10][C:11](=[O:13])[CH3:12])[CH2:2][CH2:3][CH3:4].[CH:18]([O-])([O-])OC.CO.N1C2C(=CC=CC=2)C=CC=1>C1(C)C=CC(S(O)(=O)=O)=CC=1.C1(C)C=CC=CC=1>[CH2:1]([C:5]1[CH:6]=[C:7]([CH:15]=[CH:16][CH:17]=1)[NH:8][C:9](=[O:14])/[CH:10]=[C:11](\[O:13][CH3:18])/[CH3:12])[CH2:2][CH2:3][CH3:4]
Reactant: COC([O-])[O-]
Reactant: CCCCc1cccc(NC(=O)CC(C)=O)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: c1ccc2ncccc2c1
Solvent: CO
Product: CCCCc1cccc(NC(=O)/C=C(/C)OC)c1
Temperature: 20 °C
Reaction time: 16 h
Yield: 69.9 %

Procedure:
A mixture of 8.5 g of m-(n-butyl)-acetylacetanilide, 5.7 g of methyl orthoformate, 80 ml of methanol and 0.3 g of p-toluene sulfonic acid was stirred at 20° C for 16 hours and after the addition of 100 ml of toluene and 0.6 ml of quinoline, the mixture was heated at 140° C for one hour while distilling the toluene-methanol azeotrope. After refluxing for 30 minutes, another 100 ml of toluene were added thereto and the reaction was completed when the solvent was evaporated. The residue was chromatographed over silica gel and elution with an 8-2 mixture of methylene chloride and ethyl acetate yielded 6.3 g of m-(n-butyl)-3-methoxy-crotonanilide melting at 36° C.
Reaction SMILES: O(Cl)[Cl:2].[P+5].[Cl:5][C:6]1[CH:7]=[C:8]([C:12]2[NH:21][C:20](=O)[C:19]3[CH2:18][CH2:17][CH2:16][CH2:15][C:14]=3[N:13]=2)[CH:9]=[CH:10][CH:11]=1>>[Cl:2][C:20]1[C:19]2[CH2:18][CH2:17][CH2:16][CH2:15][C:14]=2[N:13]=[C:12]([C:8]2[CH:9]=[CH:10][CH:11]=[C:6]([Cl:5])[CH:7]=2)[N:21]=1
Reactant: O=c1[nH]c(-c2cccc(Cl)c2)nc2c1CCCC2
Reactant: ClOCl
Agent: [P+5]
Product: Clc1cccc(-c2nc(Cl)c3c(n2)CCCC3)c1
Temperature: 100 °C
Reaction time: 2 h
Yield: 88.5 %

Procedure:
Phosphorus(V) oxychloride (17.6 g, 114.7 mmol) was slowly added to 2-(3-chlorophenyl)-5,6,7,8-tetrahydroquinazolin-4(3H)-one (2.2 g, 8.5 mmol) at 0° C. The reaction mixture was warmed to 100° C. and held at that temperature for 2 h. After this time, the mixture was cooled, quenched with saturated sodium hydroxide, and extracted with ethyl acetate. The combined organic layer was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The residue was purified by column chromatography (silica, hexanes/dichloromethane) to afford the title compound (2.1 g, 23%) as a white solid. MW=279.16. 1H NMR (CDCl3, 300 MHz) δ 8.43-8.37 (m, 1H), 8.32-8.24 (m, 1H), 7.49-7.33 (m, 2H), 3.03-2.87 (m, 2H), 2.86-2.70 (m, 2H), 1.98-1.83 (m, 4H); APCI MS m/z 279 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[CH:5][S:4][C:3]=1[C:7](=[O:12])[C:8]([O:10][CH3:11])=[O:9].[Br:13]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl.N(C(C)(C)C#N)=NC(C)(C)C#N>[Br:13][CH2:1][C:2]1[CH:6]=[CH:5][S:4][C:3]=1[C:7](=[O:12])[C:8]([O:10][CH3:11])=[O:9]
Reactant: O=C1CCC(=O)N1Br
Reactant: COC(=O)C(=O)c1sccc1C
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: COC(=O)C(=O)c1sccc1CBr
Yield: 52.1 %

Procedure:
A solution of 135.7 g (0.73 mol) of methyl 3-methylthien-2-ylglyoxylate, 131.2 g (0.73 mol) of N-bromosuccinimide and 1.35 g of azobisisobutyronitrile in 1000 ml of carbon tetrachloride is refluxed for 3 hours. Thereafter, the mixture is filtered and the filtrate is evaporated down. The residue is taken up in diethyl ether and the solution is washed with water, dried and evaporated down. 166.4 g of crude product are obtained, which is recrystallized from methanol. 100 g of the abovementioned compound are obtained as a yellow solid.
Reaction SMILES: [CH2:1]([NH:3][C:4]([C:6]1[C:10](Br)=[C:9]([C:12]2[CH:17]=[C:16]([Cl:18])[C:15]([O:19][CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[CH:14][C:13]=2[O:27][CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[O:8][N:7]=1)=[O:5])[CH3:2].[CH3:35][N:36]1[CH2:41][CH2:40][N:39]([C:42]2[CH:47]=[CH:46][CH:45]=[C:44](B3OC(C)(C)C(C)(C)O3)[CH:43]=2)[CH2:38][CH2:37]1>>[CH2:1]([NH:3][C:4]([C:6]1[C:10]([C:44]2[CH:45]=[CH:46][CH:47]=[C:42]([N:39]3[CH2:40][CH2:41][N:36]([CH3:35])[CH2:37][CH2:38]3)[CH:43]=2)=[C:9]([C:12]2[CH:17]=[C:16]([Cl:18])[C:15]([O:19][CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[CH:14][C:13]=2[O:27][CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[O:8][N:7]=1)=[O:5])[CH3:2]
Reactant: CN1CCN(c2cccc(B3OC(C)(C)C(C)(C)O3)c2)CC1
Reactant: CCNC(=O)c1noc(-c2cc(Cl)c(OCc3ccccc3)cc2OCc2ccccc2)c1Br
Product: CCNC(=O)c1noc(-c2cc(Cl)c(OCc3ccccc3)cc2OCc2ccccc2)c1-c1cccc(N2CCN(C)CC2)c1
Yield: 83 %

Procedure:
5-(2,4-Bis-benzyloxy-5-chloro-phenyl)-4-bromo-isoxazole-3-carboxylic acid ethylamide (38 mg, 0.07 mmol) and 1-Methyl-4-[3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-piperazine (31 mg, 2 equiv.) were coupled together using the suzuki method previously described to provide 37 mg (83% yield) of the crude as a brown oil which was taken on to the deprotection step.
Reaction SMILES: [C:1]([N:5]1[C:9](=[O:10])[C:8]([NH:11][CH2:12][C:13]([OH:15])=[O:14])=[C:7]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[S:6]1(=[O:23])=[O:22])([CH3:4])([CH3:3])[CH3:2].[CH3:24][O:25][C:26]1[CH:31]=[CH:30][C:29]([CH2:32]O)=[CH:28][CH:27]=1.C(Cl)CCl.C([O-])([O-])=O.[K+].[K+]>CN(C1C=CN=CC=1)C.C(Cl)Cl.CN(C=O)C>[C:1]([N:5]1[C:9](=[O:10])[C:8]([NH:11][CH2:12][C:13]([O:15][CH2:32][C:29]2[CH:30]=[CH:31][C:26]([O:25][CH3:24])=[CH:27][CH:28]=2)=[O:14])=[C:7]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[S:6]1(=[O:23])=[O:22])([CH3:4])([CH3:2])[CH3:3]
Reactant: COc1ccc(CO)cc1
Reactant: CC(C)(C)N1C(=O)C(NCC(=O)O)=C(c2ccccc2)S1(=O)=O
Agent: CN(C)c1ccncc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCCl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: COc1ccc(COC(=O)CNC2=C(c3ccccc3)S(=O)(=O)N(C(C)(C)C)C2=O)cc1
Temperature: 40 °C
Yield: 16.7 %

Procedure:
[(2-tert-Butyl-1,1-dioxido-3-oxo-5-phenyl-2,3-dihydroisothiazol-4-yl)amino]acetic acid (100 mg, 0.30 mmol), (4-methoxyphenyl)methanol (204 mg, 1.48 mmol), TEA (123 μL) and DMAP (9 mg, 0.074 mmol) were dissolved in DCM (10 mL). DMF 81 mL) and EDC (113 mg, 0.59 mmol) was added and the solution was stirred at 40° C. over night. Aqueous K2CO3 (1M, 50 mL) was added and the reaction mixture was extracted with DCM. The organic phases were combined, dried over MgSO4, filtered and evaporated. The residue was purified by preparative HPLC affording the title compound (23 mg, 17%). 1H NMR (CDCl3, 400 MHz) δ 1.69 (s, 9H), 3.54 (s, 2H), 3.77 (s, 3H), 4.98 (s, 2H), 5.79 (t, 1H), 6.83 (d, 2H), 7.17 (d, 2H), 7.32-7.40 (m, 5H). 13C NMR (CDCl3, 100 MHz) δ 27.7, 45.4, 55.5, 61.8, 67.6, 109.6, 114.2, 124.4, 127.0, 128.9, 130.1, 130.7, 131.5, 134.8, 159.2, 160.2, 168.7.
Reaction SMILES: [NH2:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[C:4](Cl)[N:3]=1.[SH:12][CH2:13][CH2:14][NH:15][C:16](=[O:22])[O:17][C:18]([CH3:21])([CH3:20])[CH3:19].N12CCCN=C1CCCCC2>>[NH2:1][C:2]1[N:3]=[C:4]([S:12][CH2:13][CH2:14][NH:15][C:16](=[O:22])[O:17][C:18]([CH3:20])([CH3:19])[CH3:21])[CH:5]=[CH:6][C:7]=1[N+:8]([O-:10])=[O:9]
Reactant: Nc1nc(Cl)ccc1[N+](=O)[O-]
Reactant: CC(C)(C)OC(=O)NCCS
Solvent: C1CCC2=NCCCN2CC1
Product: CC(C)(C)OC(=O)NCCSc1ccc([N+](=O)[O-])c(N)n1

Procedure:
tert-Butyl {2-[(6-amino-5-nitropyridin-2-yl)thio]ethyl}carbamate (Example 43A) is prepared in analogy to Example 42A from 2-amino-6-chloro-3-nitropyridine (500 mg, 2.9 mmol), tert-butyl (2-mercaptoethyl)carbamate (255 mg, 1.4 mmol) and 1,8-diazabicyclo(5.4.0)undec-7-ene (439 mg, 2.9 mmol). 422 mg (93% of theory) of product are obtained.