Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([CH:7]([CH:12]([C:14]([OH:16])=O)[CH3:13])[CH2:8][C:9]([OH:11])=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.S(=O)(=O)(O)O>>[CH3:13][CH:12]1[CH:7]([CH2:8][C:9]([OH:11])=[O:10])[C:1]2[C:2](=[CH:3][CH:4]=[CH:5][CH:6]=2)[C:14]1=[O:16]
Reactant: CC(C(=O)O)C(CC(=O)O)c1ccccc1
Agent: O=S(=O)(O)O
Product: CC1C(=O)c2ccccc2C1CC(=O)O
Temperature: 0 °C
Yield: 79.4 %

Procedure:
2-Phenylbutane-1,3-dicarboxylic acid (Swan, J. Chem. Soc., 1955, 1039) (20.0 g, 90.0 mmol) was dissolved in 300 ml. concentrated sulfuric acid and heated at 100° for 24 hr. The hot solution was poured onto 1 kg ice and the mixture extracted with 5×250 ml. ether. The ether phases were washed with brine, dried over magnesium sulfate, filtered, and vacuum evaporated to yield a pale yellow syrup 14.6 g. (79%), m/e 222. The NMR spectrum indicated the presence of only one major isomer as evidenced by a single upfieled doublet, assigned to the 2-methyl substituent, and small amounts of three other isomers.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:20]=[CH:19][C:18]2[C@@H:17]3[C@H:8]([C@H:9]4[C@@:13]([CH2:15][CH2:16]3)([CH3:14])[CH2:12][C@@H:11](OS(C3C=CC(C)=CC=3)(=O)=O)[CH2:10]4)[CH2:7][CH2:6][C:5]=2[CH:4]=1.[N-:32]=[N+:33]=[N-:34].[Li+]>CS(C)=O>[N:32]([C@@H:11]1[CH2:10][C@H:9]2[C@H:8]3[C@H:17]([CH2:16][CH2:15][C@:13]2([CH3:14])[CH2:12]1)[C:18]1[CH:19]=[CH:20][C:3]([O:2][CH3:1])=[CH:4][C:5]=1[CH2:6][CH2:7]3)=[N+:33]=[N-:34]
Reactant: COc1ccc2c(c1)CC[C@@H]1[C@@H]2CC[C@]2(C)C[C@@H](OS(=O)(=O)c3ccc(C)cc3)C[C@@H]12
Reactant: [N-]=[N+]=[N-]
Agent: [Li+]
Solvent: CS(C)=O
Product: COc1ccc2c(c1)CC[C@@H]1[C@@H]2CC[C@]2(C)C[C@H](N=[N+]=[N-])C[C@@H]12

Procedure:
3.3 g (7.5 mmol) of 3-methoxy-16β-tosyloxy-estra-1,3,5(10)-triene and 0.99 g (15.7 mmol) lithium azide in 66 ml of DMSO are reacted as described above. Yield: 2.15 g (92%), F=80-89° C., after recrystallization from acetone: F=89-92° C.
Reaction SMILES: Br[C:2]1[C:3]([NH2:19])=[N:4][CH:5]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([S:14]([CH2:17][CH3:18])(=[O:16])=[O:15])=[CH:10][CH:9]=2)[CH:7]=1.[O:20]=[C:21]1[C:30]2[C:25](=[CH:26][C:27](B(O)O)=[CH:28][CH:29]=2)[CH2:24][CH2:23][NH:22]1.C([O-])([O-])=O.[Na+].[Na+].CC#N>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O>[NH2:19][C:3]1[C:2]([C:27]2[CH:26]=[C:25]3[C:30](=[CH:29][CH:28]=2)[C:21](=[O:20])[NH:22][CH2:23][CH2:24]3)=[CH:7][C:6]([C:8]2[CH:13]=[CH:12][C:11]([S:14]([CH2:17][CH3:18])(=[O:16])=[O:15])=[CH:10][CH:9]=2)=[CH:5][N:4]=1
Reactant: O=C1NCCc2cc(B(O)O)ccc21
Reactant: CCS(=O)(=O)c1ccc(-c2cnc(N)c(Br)c2)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Solvent: O
Product: CCS(=O)(=O)c1ccc(-c2cnc(N)c(-c3ccc4c(c3)CCNC4=O)c2)cc1
Temperature: 150 °C
Yield: 40.6 %

Procedure:
A mixture of the 3-bromo-5-(4-(ethylsulfonyl)phenyl)pyridin-2-amine (100 mg, 0.29 mmol), 1-oxo-1,2,3,4-tetrahydroisoquinolin-6-ylboronic acid (75 mg, 0.29 mmol), PdCl2(PPh3)2 (7.0 mg, 0.01 mmol) and Na2CO3 in 3:1 MeCN:H2O was microwave heated at 150° C. for 3 min. At completion, the reaction mixture was filtered, then purified by preparatory HPLC to provide 6-(2-amino-5-(4-(ethylsulfonyl)phenyl)pyridin-3-yl)-3,4-dihydroisoquinolin-1(2H)-one as a pale yellow solid (48 mg, 41% yield) after reverse phase preparatory HPLC purification. 1H NMR (400 MHz, MeOD) δ ppm 8.37 (d, J=2.5 Hz, 1H), 8.06 (d, J=8.0 Hz, 1H), 7.94 (d, J=8.5 Hz, 2H), 7.89 (d, J=8.5 Hz, 2H), 7.81 (d, J=2.5 Hz, 1H), 7.53 (d, J=7.8 Hz, 1H), 7.49 (s, 1H), 3.56 (t, J=6.7 Hz, 2H), 3.19-3.27 (m, 2H), 3.07 (q, J=6.5 Hz, 2H), 1.25 (t, J=7.3 Hz, 3 H); MS (EI) m/z: 408 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[CH:37]=[CH:36][C:5]2[NH:6][C:7](=[O:35])[C@H:8]([CH2:27][C:28]3[CH:33]=[CH:32][C:31]([OH:34])=[CH:30][CH:29]=3)[N:9]([CH2:12][C:13]([NH:15][CH:16]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[CH2:17][C:18]([OH:20])=[O:19])=[O:14])[C:10](=[O:11])[C:4]=2[CH:3]=1.[CH2:38]([N:45]=[C:46]=[O:47])[C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1>CN(C=O)C>[CH2:38]([NH:45][C:46](=[O:47])[NH:1][C:2]1[CH:37]=[CH:36][C:5]2[NH:6][C:7](=[O:35])[C@H:8]([CH2:27][C:28]3[CH:33]=[CH:32][C:31]([OH:34])=[CH:30][CH:29]=3)[N:9]([CH2:12][C:13]([NH:15][CH:16]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[CH2:17][C:18]([OH:20])=[O:19])=[O:14])[C:10](=[O:11])[C:4]=2[CH:3]=1)[C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1
Reactant: Nc1ccc2c(c1)C(=O)N(CC(=O)NC(CC(=O)O)c1ccccc1)[C@@H](Cc1ccc(O)cc1)C(=O)N2
Reactant: O=C=NCc1ccccc1
Solvent: CN(C)C=O
Product: O=C(O)CC(NC(=O)CN1C(=O)c2cc(NC(=O)NCc3ccccc3)ccc2NC(=O)[C@@H]1Cc1ccc(O)cc1)c1ccccc1
Temperature: 45 °C
Yield: 31.5 %

Procedure:
To a solution of 3-(R,S)-{2-[7-amino-3-(S)-(4-hydroxy-benzyl)-2,5-dioxo-1,2,3,5-tetrahydro-benzo[e][1,4]diazepin-4-yl]-acetylamino}-3-phenyl-propionic acid (0.1 mmol, 50mg) in DMF (2.5 mL) was added benzylisocyanate (31 μl 0.25 mmol). The mixture was shaken at 45° C. over night until no starting material was detected by HPLC. Afterwards the solution was concentrated in vacuo. The crude product was purified by RP-HPLC to give 3-(R,S)-{2-[7-(3-benzyl-ureido)-3-(S)-(4-hydroxy-benzyl)-2,5-dioxo-1,2,3,5-tetrahydro-benzo[e][1,4]diazepin-4-yl]-acetylamino}-3-phenyl-propionic acid (20 mg): MS 634 (M−H)−.
Reaction SMILES: [C:1]1([O-:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Na+].[C:9]([O-:18])(=[O:17])C1C(=CC=CC=1)O.[Na+]>>[CH:3]1[C:4]([C:9]([OH:18])=[O:17])=[CH:5][CH:6]=[C:1]([OH:7])[CH:2]=1
Reactant: O=C([O-])c1ccccc1O
Reactant: [O-]c1ccccc1
Agent: [Na+]
Product: O=C(O)c1ccc(O)cc1

Procedure:
In contrast to published information, it has been found that the degree of conversion of sodium phenolate to sodium salicylate is practically independent of the reaction temperature. At 165° C. and at 200° C., 85-88% conversion is easily obtained, but by-product formation is reduced as the temperature is increased. For instance, reaction at 140°-150° C. gives about 9% non-salicylic acids mostly 4-HBA in the crude product mixture whereas reaction at 190°-195° C. (at 5 bar co-pressure) gives less than 0.5% non-salicylic acids in the reaction product mixture.
Reaction SMILES: [OH:1][CH2:2][C@H:3]1[CH2:7][CH2:6][C@H:5]([OH:8])[CH2:4]1.N1C=CN=C1.[Si:14](Cl)([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:16])[CH3:15]>CN(C=O)C>[Si:14]([O:1][CH2:2][C@H:3]1[CH2:7][CH2:6][C@H:5]([OH:8])[CH2:4]1)([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:16])[CH3:15]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: OC[C@H]1CC[C@H](O)C1
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)OC[C@H]1CC[C@H](O)C1
Reaction time: 1.25 h
Yield: 31 %

Procedure:
To a solution of (1S,3S)-3-(hydroxymethyl)cyclopentanol (453.0 mg, 0.003276 mol) and 1H-imidazole (669 mg, 0.00983 mol) in DMF (35.8 mL) under an atmosphere of nitrogen was added tert-butyldimethylsilyl chloride (494 mg, 0.00328 mol). The mixture was stirred for 1.25 hours, then tert-butyldimethylsilyl chloride (49 mg, 0.00033 mol) was added. After an additional hour of stirring, the reaction was quenched with water, extracted with ethyl acetate (3×), dried with anhydrous Na2SO4, filtered, and concentrated. The residue was filtered through a plug of silica with 30% EtOAc/hexanes to obtain 234.1 mg (31%) of the title compound.
Reaction SMILES: [NH2:1][C:2]1[C:3]2[C:10]([C:11]3[CH:16]=[CH:15][C:14]([O:17][C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)=[CH:13][CH:12]=3)=[CH:9][N:8]([C@@H:24]3[CH2:29][CH2:28][C@H:27]([N:30]4[CH2:35][CH2:34][N:33](C(OC(C)(C)C)=O)[CH2:32][CH2:31]4)[CH2:26][CH2:25]3)[C:4]=2[N:5]=[CH:6][N:7]=1.FC(F)(F)C(O)=O.ClCCl.[C:53]([OH:60])(=[O:59])/[CH:54]=[CH:55]\[C:56]([OH:58])=[O:57]>C(OCC)(=O)C>[C:53]([OH:60])(=[O:59])/[CH:54]=[CH:55]\[C:56]([OH:58])=[O:57].[C:53]([OH:60])(=[O:59])/[CH:54]=[CH:55]\[C:56]([OH:58])=[O:57].[C:53]([OH:60])(=[O:59])/[CH:54]=[CH:55]\[C:56]([OH:58])=[O:57].[O:17]([C:14]1[CH:15]=[CH:16][C:11]([C:10]2[C:3]3[C:2]([NH2:1])=[N:7][CH:6]=[N:5][C:4]=3[N:8]([C@H:24]3[CH2:29][CH2:28][C@@H:27]([N:30]4[CH2:31][CH2:32][NH:33][CH2:34][CH2:35]4)[CH2:26][CH2:25]3)[CH:9]=2)=[CH:12][CH:13]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: CC(C)(C)OC(=O)N1CCN([C@H]2CC[C@@H](n3cc(-c4ccc(Oc5ccccc5)cc4)c4c(N)ncnc43)CC2)CC1
Agent: O=C(O)/C=C\C(=O)O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: CCOC(C)=O
Product: Nc1ncnc2c1c(-c1ccc(Oc3ccccc3)cc1)cn2[C@H]1CC[C@@H](N2CCNCC2)CC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
The cis-tert-butyl 4-{4-[4-amino-5-(4-phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl]cyclohexyl}-1-piperazinecarboxylate (1.85 g, 3.27 mmol) was treated with a 20% trifluoroacetic acid/dichloromethane solution (60 ml) and stirred for 30 minutes at ambient temperature. The solvents were removed under reduced pressure then the residue was partitioned between dichloromethane (200 ml) and aqueous saturated sodium bicarbonate solution (30 ml). The organic solution was dried over magnesium sulfate, filtered and the filtrate evaporated to a residue (1.55 g). A portion of this material (1.0 g, 2.15 mmol) was dissolved in warm ethyl acetate (220 ml) then treated with maleic acid (0.75 g, 0.44 mmol) in warm ethyl acetate (75 ml). The mixture was cooled to ambient temperature then the solid was collected by filtration and dried to give Cis-5-(4-phenoxyphenyl)-7-(4-piperazinocyclohexyl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine trimaleate salt (1.15 g) as a white solid: 1H NMR (DMSO-d6, 400 MHz) δ 8.5 (bs, 1H), 8.23 (s, 1H), 7.41-7.51 (m, 5H), 7.08-7.19 (m, 5H), 6.65 (bs, 2H), 6.16 (s, 6H), 4.74 (m, 1H), 1.16-3.2 (m, 17H); RP—HPLC (Hypersil CPS, 5 μm, 100 A, 250×4.6 mm; 25-100% acetonitrile-0.1 M ammonium acetate over 10 min, 1 ml/min) tr=8.63 min; MS: MH+469.
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:12]=[C:11]2[C:6]([N:7]=[CH:8][C:9](=O)[NH:10]2)=[CH:5][CH:4]=1.P(Cl)(Cl)([Cl:16])=O>ClCCl>[Cl:16][C:9]1[CH:8]=[N:7][C:6]2[C:11](=[CH:12][C:3]([S:2][CH3:1])=[CH:4][CH:5]=2)[N:10]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: CSc1ccc2ncc(=O)[nH]c2c1
Solvent: ClCCl
Product: CSc1ccc2ncc(Cl)nc2c1
Temperature: 25 °C
Yield: 33.7 %

Procedure:
A solution of 7-methylsulfanyl-1H-quinoxalin-2-one (9.23 g, 48.0 mmol, 1.0 eq) in phosphorus oxychloride (36 mL, 384.0 mmol, 8.0 eq) is heated under reflux for 30 minutes. Then the reaction mixture is cooled down to room temperature and the solvent is evaporated. The residue is poured into ice water, the resulting mixture is basified with saturated sodium hydrogen carbonate to pH=8˜9 and extracted with ethyl acetate (3×50 mL). The combined organic layers are dried over sodium sulfate, filtered and concentrated to give a crude product that is purified by column chromatography (silica gel, eluent: petroleum ether:dichloromethane, 4:1 to 1:1, v/v) to afford 2-chloro-7-methylsulfanyl-quinoxaline as a green solid (3.41 g, 33% yield).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][CH2:15][C:16]([N:18]2[CH2:23][CH2:22][CH2:21][C@@H:20]([C:24]([NH:26][CH:27]([C:32]3[CH:37]=[CH:36][CH:35]=[C:34]([O:38][CH2:39][CH2:40][F:41])[CH:33]=3)[CH2:28][C:29]([OH:31])=[O:30])=[O:25])[CH2:19]2)=[O:17])[CH2:10][CH2:9]1)=O)(C)(C)C.Cl>O1CCOCC1>[F:41][CH2:40][CH2:39][O:38][C:34]1[CH:35]=[CH:36][CH:37]=[C:32]([C@@H:27]([NH:26][C:24]([C@@H:20]2[CH2:21][CH2:22][CH2:23][N:18]([C:16](=[O:17])[CH2:15][CH2:14][CH:11]3[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]3)[CH2:19]2)=[O:25])[CH2:28][C:29]([OH:31])=[O:30])[CH:33]=1
Reactant: CC(C)(C)OC(=O)N1CCC(CCC(=O)N2CCC[C@@H](C(=O)NC(CC(=O)O)c3cccc(OCCF)c3)C2)CC1
Agent: Cl
Solvent: C1COCCO1
Product: O=C(O)C[C@H](NC(=O)[C@@H]1CCCN(C(=O)CCC2CCNCC2)C1)c1cccc(OCCF)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 20.2 %

Procedure:
To 3-({[(3R)-1-{3-[1-(tert-butoxycarbonyl)piperidin-4-yl]propanoyl}piperidin-3-yl]carbonyl}amino)-3-[3-(2-fluoroethoxy)phenyl]propanoic acid (65 mg, 90 μmol) in dioxane was added a 4 M solution of hydrochloric acid in dioxane (0.23 ml, 900 μmol) and stirred for 3 hours at room temperature. The solution was concentrated under reduced pressure and the residue was purified by preparative HPLC to yield 8.7 mg of (3S)-3-[5-(2-fluoroethoxy)phenyl]-3-[({(3R)-1-[3-(piperidin-4-yl)propanoyl]piperidin-3-yl}carbonyl)amino]propanoic acid.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:23]=[CH:24][CH:25]=1)[CH:5]=[N:6][NH:7][C:8]1[CH:13]=[C:12]([N:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)[N:11]=[C:10]([CH2:20][CH2:21][OH:22])[N:9]=1.C(N(C(C)C)CC)(C)C.[CH3:35][S:36](Cl)(=[O:38])=[O:37]>C(Cl)Cl>[CH3:1][C:2]1[CH:3]=[C:4]([CH:23]=[CH:24][CH:25]=1)[CH:5]=[N:6][NH:7][C:8]1[CH:13]=[C:12]([N:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)[N:11]=[C:10]([CH2:20][CH2:21][O:22][S:36]([CH3:35])(=[O:38])=[O:37])[N:9]=1
Reactant: Cc1cccc(C=NNc2cc(N3CCOCC3)nc(CCO)n2)c1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cc1cccc(C=NNc2cc(N3CCOCC3)nc(CCOS(C)(=O)=O)n2)c1
Temperature: 0 °C
Yield: 35 %

Procedure:
Compound 93, 2-{4-[N′-(3-methyl-benzylidene)-hydrazino]-6-morpholin-4-yl-pyrimidin-2-yl}-ethanol (680 mg., 2 mmol) was dissolved in methylene chloride (10 mL) and to the reaction mixture was added diisopropylethylamine (0.6 mL, 3 mmol). The reaction was chilled to 0° C. To the reaction was added methanesulfonyl chloride (251 mg., 2.2 mmol). After fifteen minutes, the reaction was washed with saturated aqueous ammonium chloride (2×2 mL), dried with sodium sulfate, and purified by column chromatography to give Compound 95, methanesulfonic acid 2-{4-[N′-(3-methyl-benzylidene)-hydrazino]-6-morpholin-4-yl-pyrimidin-2-yl}-ethyl ester (290 mg., 0.7 mmol).
Reaction SMILES: [CH3:1][N:2]([CH3:15])[C:3](=[O:14])[CH2:4][CH2:5][CH:6]([N+:11]([O-])=O)[CH:7]([OH:10])[CH2:8][F:9]>CO.[Ni]>[CH3:15][N:2]([CH3:1])[C:3](=[O:14])[CH2:4][CH2:5][CH:6]([NH2:11])[CH:7]([OH:10])[CH2:8][F:9]
Reactant: CN(C)C(=O)CCC(C(O)CF)[N+](=O)[O-]
Agent: [Ni]
Solvent: CO
Product: CN(C)C(=O)CCC(N)C(O)CF
Reaction time: 6 h
Yield: 87 %

Procedure:
To a solution of 6-fluoro-5-hydroxy-4-nitro-hexanoic acid dimethylamide (1.22 g, 5.5 mmol) in MeOH (20 mL) was added Ranny Ni (about 500 mg), and the mixture was hydrogenated under 40-45 psi H2 at room temperature for 6 h. The catalyst was removed. The MeOH solution was evaporated and the residue oil (0.92 g, yield 87%) was used without further purification. MS m/e 193 (M+1).
Reaction SMILES: [CH3:1][N:2]([CH2:4][CH2:5][NH2:6])[CH3:3].[C:7]1([N:13]=[C:14]=[O:15])[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1>C1(C)C=CC=CC=1>[C:7]1([NH:13][C:14]([NH:6][CH2:5][CH2:4][N:2]([CH3:3])[CH3:1])=[O:15])[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: CN(C)CCN
Reactant: O=C=Nc1ccccc1
Solvent: Cc1ccccc1
Product: CN(C)CCNC(=O)Nc1ccccc1

Procedure:
88 g of dimethylaminoethylamine are dissolved in 500 l of toluene and then 119 g of phenyl isocyanate are added dropwise in the course of 10 minutes, whereupon the temperature rises to 97° C. The mixture is refluxed for 4 hours. On cooling, the product crystallises and is filtered with suction. The moist product is recrystallised from 1000 ml of ethyl acetate. Yield: 135 g (65.1%); m.p. 141°-142° C.
Reaction SMILES: [Cl:1]Cl.[CH2:3]([N:5]1[CH:9]=[N:8][C:7]([OH:10])=[N:6]1)[CH3:4].C(N(CC)CC)C>C(O)C>[CH2:3]([N:5]1[C:9]([Cl:1])=[N:8][C:7]([OH:10])=[N:6]1)[CH3:4]
Reactant: CCn1cnc(O)n1
Reactant: ClCl
Solvent: CCO
Solvent: CCN(CC)CC
Product: CCn1nc(O)nc1Cl
Reaction time: 2 h

Procedure:
71.5 g of chlorine is passed into a solution of 75.5 g of 1-ethyl-3-hydroxy-1,2,4-triazole and 185 ml of triethylamine in 800 ml of absolute ethanol. The exothermic reaction is kept at 20° to 30°C while cooling. Triethylamine hydrochloride is precipitated. The batch is further stirred for 2 hours after the chlorine has been passed in. Triethylamine hydrochloride is filtered off and the filtrate concentrated. The residue is dissolved in 500 ml of ether and 500 ml of water. The phases are separated and the aqueous phase is extracted 3 times with 300 ml of ether each time. The ethereal extracts are dried over sodium sulphate. The drying agent is filtered off and the filtrate concentrated. The residue is recrystallised from a mixture of 400 ml of xylene and 250 ml of ligroin and dried in vacuo. Yield: 28.7 g (29 % of theory); m.p. 108°-110°C.
Reaction SMILES: [N:1]1[CH2:6][CH2:5][CH2:4][NH:3][C:2]=1[SH:7].Br[CH2:9][CH2:10][CH2:11]Br>>[S:7]1[CH2:11][CH2:10][CH2:9][N:1]2[CH2:6][CH2:5][CH2:4][N:3]=[C:2]12
Reactant: BrCCCBr
Reactant: SC1=NCCCN1
Product: C1CN=C2SCCCN2C1

Procedure:
3,4,7,8-Tetrahydro-2H,6H-pyrimido[2,1-b]-[1,3]-thiazine was prepared by the above-described reaction scheme wherein n=2 and m=2. The starting materials were 3,4,5,6-tetrahydro-2-pyrimidinethiol and 1,3-dibromopropane (both obtained from Aldrich Chemical Company, Milwaukee, Wis.), and the remainder of the preparation process was essentially the same as described above. The resulting crude product was 93 percent (%) pure and was used directly for catalysis.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]2[CH2:13][CH2:12][CH:11]([N:14]3[CH2:18][CH2:17][CH2:16][CH2:15]3)[CH2:10][CH2:9][C:8]=2[CH:19]=1)([O-])=O>[Pd].CO>[NH2:1][C:4]1[CH:5]=[CH:6][C:7]2[CH2:13][CH2:12][CH:11]([N:14]3[CH2:18][CH2:17][CH2:16][CH2:15]3)[CH2:10][CH2:9][C:8]=2[CH:19]=1
Reactant: O=[N+]([O-])c1ccc2c(c1)CCC(N1CCCC1)CC2
Agent: [Pd]
Solvent: CO
Product: Nc1ccc2c(c1)CCC(N1CCCC1)CC2
Reaction time: 1 h

Procedure:
A mixture of 1-(2-nitro-6,7,8,9-tetrahydro-5H-benzo[7]annulene-7-yl)pyrrolidine (2.0 g; 7.69 mmol) and 10% palladium on carbon (0.2 g, ˜50% water) in methanol (150 mL) was shaken under hydrogen (40 psi) for 1 h. After this time the reaction mixture was filtered through diatomaceous earth and the filtrate was concentrated under reduced pressure to afford 1-(2-amino-6,7,8,9-tetrahydro-5H-benzo[7]annulene-7-yl)pyrrolidine as an oil (quantitative yield); MS (m/e): 231 (M+H+).
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5]1[CH2:11][N:10](CC2C=CC=CC=2)[CH2:9][CH2:8][CH2:7][N:6]1[S:19]([C:22]1[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=1)(=[O:21])=[O:20])=[O:4].[H][H]>C(O)C.[OH-].[OH-].[Pd+2]>[CH3:1][O:2][C:3]([CH:5]1[CH2:11][NH:10][CH2:9][CH2:8][CH2:7][N:6]1[S:19]([C:22]1[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=1)(=[O:21])=[O:20])=[O:4]
Reactant: COC(=O)C1CN(Cc2ccccc2)CCCN1S(=O)(=O)c1ccc(OC)cc1
Reactant: [H][H]
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCO
Product: COC(=O)C1CNCCCN1S(=O)(=O)c1ccc(OC)cc1

Procedure:
To a solution of 11.0 g (0.026 mol) of the product of Example 45 in 50 mL of ethanol was added 4.40 g of 20% palladium hydroxide on carbon (Pearlman's catalyst) and the resulting suspension was shaken at room temperature in a Parr reactor under 44 psi of hydrogen for 4 h. The reaction mixture was then filtered through Celite and the filter cake was washed with 100 mL of methanol. The filtrate was concentrated in vacuo and the residue was diluted with ethyl acetate. The solution was washed with water, dried over Na2SO4, filtered and concentrated in vacuo. The resulting oil was pure enough for use in the next step. Electrospray Mass Spec: 328.9 (M+H)+
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3](=[S:5])[NH2:4].CC(O)(C)C.Cl[CH:14]([C:20](=O)[CH3:21])[C:15]([O:17][CH2:18][CH3:19])=[O:16]>CCOC(C)=O>[CH3:21][C:20]1[N:4]=[C:3]([C:2]([F:7])([F:6])[F:1])[S:5][C:14]=1[C:15]([O:17][CH2:18][CH3:19])=[O:16]
Reactant: NC(=S)C(F)(F)F
Reactant: CCOC(=O)C(Cl)C(C)=O
Solvent: CCOC(C)=O
Solvent: CC(C)(C)O
Product: CCOC(=O)c1sc(C(F)(F)F)nc1C

Procedure:
To a mixture of 2,2,2-trifluoroethanethioamide (200 mg) and t-BuOH (10 mL) was added ethyl 2-chloro-3-oxobutanoate (0.217 mL) at room temperature. The mixture was refluxed for 2 days. After cooling, EtOAc was poured into the mixture, and the mixture was washed successively with water and brine, dried over Na2SO4 and concentrated in vacuo. The residue was purified by silica gel column chromatography (NH, EtOAc/hexane) to give the title compound (133 mg).
Reaction SMILES: C(O[C:6](=[O:25])[NH:7][CH2:8][CH2:9][NH:10][C:11]([NH:13][C:14]1[S:15][C:16]2[N:17]=[CH:18][N:19]=[C:20]([O:23][CH3:24])[C:21]=2[N:22]=1)=[O:12])(C)(C)C.FC(F)(F)C(O)=O.COC1C2N=C(NC(N3CCC(N)C3)=O)SC=2N=CN=1.[F:53][C:54]1[CH:62]=[CH:61][C:57](C(Cl)=O)=[CH:56][C:55]=1[C:63]([F:66])([F:65])[F:64]>C(Cl)Cl>[F:53][C:54]1[CH:62]=[CH:61][C:57]([C:6]([NH:7][CH2:8][CH2:9][NH:10][C:11]([NH:13][C:14]2[S:15][C:16]3[N:17]=[CH:18][N:19]=[C:20]([O:23][CH3:24])[C:21]=3[N:22]=2)=[O:12])=[O:25])=[CH:56][C:55]=1[C:63]([F:64])([F:65])[F:66]
Reactant: COc1ncnc2sc(NC(=O)NCCNC(=O)OC(C)(C)C)nc12
Reactant: O=C(Cl)c1ccc(F)c(C(F)(F)F)c1
Agent: COc1ncnc2sc(NC(=O)N3CCC(N)C3)nc12
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1ncnc2sc(NC(=O)NCCNC(=O)c3ccc(F)c(C(F)(F)F)c3)nc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 11.9 %

Procedure:
A solution of {2-[3-(7-methoxy-thiazolo[5,4-d]pyrimidin-2-yl)-ureido]-ethyl}-carbamic acid tert-butyl ester (170 mg, 0.46 mmol) was treated with trifluoroacetic acid (80 μL, 0.57 mmol). The reaction was stirred at 25° C. for 1 h. The reaction was then concentrated in vacuo, triturated with diethyl ether, collected by filtration and dried in vacuo. A portion of the resulting trifluoroacetic acid salt of 3-amino-pyrrolidine-1-carboxylic acid (7-methoxy-thiazolo[5,4-d]pyrimidin-2-yl)-amide (88 mg, 0.23 mmol) in methylene chloride at 25° C. was treated with 4-fluoro-3-(trifluoromethyl)benzoyl chloride (70 mL, 0.46 mmol). The resulting solution was stirred at 25° C. overnight. Flash chromatography (Merck Silica gel 60, 230-400 mesh, gradient elution 3:1 ethyl acetate/hexanes to 100% ethyl acetate) afforded 4-fluoro-N-{2-[3-(7-methoxy-thiazolo[5,4-d]pyrimidin-2-yl)-ureido]-ethyl}-3-trifluoromethyl-benzamide (25 mg, 11.8%) as a white solid; ES-HRMS m/e calcd for C17H14F4N6O3S (M+H)+ 459.0857, found 459.0862.
Reaction SMILES: [SH:1][CH2:2][CH:3]([CH2:14][C:15]([O:17]C)=[O:16])[C:4]([N:6]1[CH2:13][CH2:12][CH2:11][C@H:7]1[C:8]([OH:10])=[O:9])=[O:5].[H][H]>CO.[OH-].[Na+]>[C:15]([CH2:14][CH:3]([CH2:2][SH:1])[C:4]([N:6]1[CH2:13][CH2:12][CH2:11][C@H:7]1[C:8]([OH:10])=[O:9])=[O:5])([OH:17])=[O:16]
Reactant: COC(=O)CC(CS)C(=O)N1CCC[C@H]1C(=O)O
Reactant: [H][H]
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)CC(CS)C(=O)N1CCC[C@H]1C(=O)O
Reaction time: 4 h
Yield: 80.8 %

Procedure:
To a solution of the product from Example 62, Step (d) (3.0 g) in methanol (60 ml), 1N sodium hydroxide (60 ml) is added. After 4 hours, the solution is applied to a column of Dowex 50 ion exchange resin in the hydrogen cycle, and the desired material is eluted with water to yield 2.3 g of the named product, Rf =0.2 (silica gel-benzene:acetic acid, 75:25).
Reaction SMILES: IC.[CH3:3][C:4]1[CH:5]=[C:6]([OH:13])[C:7](=[CH:11][CH:12]=1)[C:8]([OH:10])=[O:9].[C:14](=O)([O-])[O-].[Li+].[Li+]>CN(C)C=O>[OH:13][C:6]1[CH:5]=[C:4]([CH3:3])[CH:12]=[CH:11][C:7]=1[C:8]([O:10][CH3:14])=[O:9]
Reactant: O=C([O-])[O-]
Reactant: Cc1ccc(C(=O)O)c(O)c1
Agent: [Li+]
Solvent: CI
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(C)cc1O
Temperature: 60 °C
Reaction time: 3.5 h

Procedure:
Iodomethane (22.6 mL, 362 mmol, 1.1 equiv) was added to a suspension of 4-methylsalicylic acid (50.0 g, 329 mmol, 1 equiv) and lithium carbonate (26.8 g, 362 mmol, 1.1 equiv) in dimethylformamide (450 mL) at 23° C. The reaction flask was heated in an oil bath at 60° C. After 3.5 h, the warm suspension was partitioned carefully between ice water (500 mL) and ethyl acetate (800 mL). The layers were separated. The aqueous layer was extracted with ethyl acetate (800 mL). The organic layers were combined. The combined solution was washed sequentially with water (2×500 mL) then saturated aqueous sodium chloride solution (500 mL) and the washed solution was dried over sodium sulfate. The dried solution was filtered and the filtrate was concentrated. A small sample of the product (˜50 mg) was purified by flash-column chromatography (2% ethyl acetate-hexanes) and was characterized by 1H NMR, 13C NMR, IR, and HRMS. The balance of the product, methyl 2-hydroxy-4-methylbenzoate, was used directly in the next reaction without purification. TLC: (2% ethyl acetate-hexanes) Rf=0.15 (CAM); 1H NMR (500 MHz, CDCl3) δ: 10.70 (s, 1H), 7.70 (d, 1H, J=8.4 Hz), 6.79 (s, 1H), 6.69 (d, 1H, J=7.7 Hz), 3.92 (s, 3H), 2.34 (s, 3H); 13C NMR (125 MHz, CDCl3) δ: 170.5, 161.5, 147.0, 129.6, 120.4, 117.7, 109.8, 52.0, 21.8; FTIR (neat), cm−1: 3186 (m), 2956 (m), 1672 (s), 1623 (m), 1579 (m), 1504 (m), 1441 (s), 1338 (s), 1298 (s), 1250 (s), 1215 (s), 1157 (s), 1096 (s), 906 (s), 780 (s); HRMS (ESI): Calcd for (C9H10O3+H)+ 167.0703, found 167.0698.