Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[NH:7][C:6]([C:8]2[O:9][CH:10]=[CH:11][CH:12]=2)=[C:5]([C:13]#[N:14])[C:4](=[O:15])[CH:3]=1.Cl.[N:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[CH2:23]Cl.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C>[NH2:1][C:2]1[CH:3]=[C:4]([O:15][CH2:23][C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][N:17]=2)[C:5]([C:13]#[N:14])=[C:6]([C:8]2[O:9][CH:10]=[CH:11][CH:12]=2)[N:7]=1
Reactant: ClCc1ccccn1
Reactant: N#Cc1c(-c2ccco2)[nH]c(N)cc1=O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: N#Cc1c(OCc2ccccn2)cc(N)nc1-c1ccco1

Procedure:
From 6-amino-2-furan-2-yl-4-oxo-1,4-dihydro-pyridine-3-carbonitrile, 2-picolyl chloride hydrochloride and cesium carbonate in DMF. ES-MS m/e (%): 293 (M+H+, 100).
Reaction SMILES: [NH2:1][C:2]1[CH:33]=[CH:32][C:5]2[S:6][C:7]([C:9]3[C:10]([NH2:31])=[N:11][CH:12]=[C:13]([C:15]4[N:19]([CH2:20][CH2:21][CH2:22][O:23][Si:24]([C:27]([CH3:30])([CH3:29])[CH3:28])([CH3:26])[CH3:25])[N:18]=[N:17][N:16]=4)[CH:14]=3)=[CH:8][C:4]=2[CH:3]=1.[Cl:34][C:35]1[CH:40]=[CH:39][C:38]([N:41]=[C:42]=[O:43])=[CH:37][C:36]=1[C:44]([F:47])([F:46])[F:45]>O1CCCC1.C(OCC)(=O)C>[NH2:31][C:10]1[C:9]([C:7]2[S:6][C:5]3[CH:32]=[CH:33][C:2]([NH:1][C:42]([NH:41][C:38]4[CH:39]=[CH:40][C:35]([Cl:34])=[C:36]([C:44]([F:46])([F:45])[F:47])[CH:37]=4)=[O:43])=[CH:3][C:4]=3[CH:8]=2)=[CH:14][C:13]([C:15]2[N:19]([CH2:20][CH2:21][CH2:22][O:23][Si:24]([C:27]([CH3:28])([CH3:29])[CH3:30])([CH3:25])[CH3:26])[N:18]=[N:17][N:16]=2)=[CH:12][N:11]=1
Reactant: CC(C)(C)[Si](C)(C)OCCCn1nnnc1-c1cnc(N)c(-c2cc3cc(N)ccc3s2)c1
Reactant: O=C=Nc1ccc(Cl)c(C(F)(F)F)c1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(C)(C)[Si](C)(C)OCCCn1nnnc1-c1cnc(N)c(-c2cc3cc(NC(=O)Nc4ccc(Cl)c(C(F)(F)F)c4)ccc3s2)c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To the stirring solution of 3-(5-aminobenzo[b]thiophen-2-yl)-5-(1-(3-((tert-butyldimethylsilyl)oxy)propyl)-1H-tetrazol-5-yl)pyridin-2-amine (123 mg, 0.256 mmol, 1 eq) in anhydrous tetrahydrofuran (3 mL) under nitrogen atmosphere was added 4-chloro-3-(trifluoromethyl)phenyl isocyanate (58 mg, 1 eq) and the reaction mixture was stirred at room temperature for three hours. The reaction was then diluted with ethyl acetate, washed sequentially with aqueous ammonium chloride, saturated aqueous sodium bicarbonate, and brine, and dried with anhydrous sodium sulfate. The upper clear solution was decanted and concentrated under reduced pressure and loaded onto silica. The mixture was subject to a gradient column chromatography (EtOAc-Hex 1:5 to 2:1) to give 1-(2-(2-amino-5-(1-(3-((tert-butyldimethylsilyl)oxy)propyl)-1H-tetrazol-5-yl)pyridin-3-yl)benzo[b]thiophen-5-yl)-3-(4-chloro-3-(trifluoromethyl)phenyl)urea as a white solid in the amount of 130 mg.
Reaction SMILES: Cl[CH2:2][C:3]#[C:4][CH2:5][N:6]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[N:7]1.Cl.[O:15]1CCCC1>CN(C)C=O.C(OCC)(=O)C>[N+:11]([C:8]1[CH:9]=[CH:10][N:6]([CH2:5][C:4]#[C:3][CH2:2][OH:15])[N:7]=1)([O-:13])=[O:12]
Reactant: C1CCOC1
Reactant: O=[N+]([O-])c1ccn(CC#CCCl)n1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccn(CC#CCO)n1
Temperature: 100 °C
Reaction time: 36 h
Yield: 61 %

Procedure:
The 1-(4-chloro-but-2-ynyl)-3-nitro-1H-pyrazole (300 mg, 1.50 mmol) was dissolved in tetrahydrofuran (2 mL) and N,N-dimethylformamide (6 mL). 1.0 M aqueous hydrochloric acid solution (8 mL) was added and the solution was heated to 100° C. while stirring for 36 h in a sealed vial. The solution was diluted with ethyl acetate (100 mL), washed with water (2×50 mL), saturated aqueous brine solution (2×25 mL), dried over magnesium sulfate and concentrated in vacuo to give a waxy yellow solid. Purification by ISCO flash column chromatography (Teledyne Isco RediSep Flash Column 40 g; 15% ethyl acetate/hexanes to 100% ethyl acetate/hexanes) afforded 4-(3-nitro-pyrazol-1-yl)-but-2-yn-1-ol (166 mg, 61%) as an off white solid: H1-NMR (400 MHz, DMSO-d6) δ 4.12 (2H, d, J=6.0 Hz), 5.23 (2H, s), 7.06 (1H, d, J=2.8 Hz), 8.08 (2H, d, J=3.6 Hz).
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([CH:11]=O)[CH:9]=2)[CH:4]=[CH:3][CH:2]=1.N1C=CC=CC=1C1C=C[C:22]([CH:23]=[O:24])=CC=1>>[N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8](/[CH:11]=[CH:22]/[CH:23]=[O:24])[CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: O=Cc1ccc2cccnc2c1
Reactant: O=Cc1ccc(-c2ccccn2)cc1
Product: O=C/C=C/c1ccc2cccnc2c1

Procedure:
The title compound was prepared by a procedure analogous to Reference Example 31 by substituting 7-quinolinecarboxaldehyde (prepared as described in J. Med. Chem. 1993, 36, 3308) for the 4-(2-pyridinyl)-benzaldehyde of Reference Example 31. MS 184 (M+H)+.
Reaction SMILES: C([Li])CCC.C(NC(C)C)(C)C.[CH:13]1([CH2:19][C:20]([O:22][CH3:23])=[O:21])[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1.[Cl:24][CH2:25][CH2:26][CH2:27]I>C1COCC1.C(OCC)(=O)C.O>[Cl:24][CH2:25][CH2:26][CH2:27][CH:19]([CH:13]1[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1)[C:20]([O:22][CH3:23])=[O:21]
Reactant: COC(=O)CC1CCCCC1
Reactant: ClCCCI
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Solvent: CCOC(C)=O
Product: COC(=O)C(CCCCl)C1CCCCC1
Temperature: -78 °C
Reaction time: 0.17 h

Procedure:
n-Butyl lithium (2.64 M solution in hexane, 3.8 ml) was added dropwise to a solution of diisopropylamine (1.55 ml) in THF (15 ml) under ice-cooling, and the reaction solution was stirred at the same temperature for 10 minutes. The reaction solution was cooled to −78° C. Then, a solution of methyl cyclohexylacetate (CAS No. 14352-61-5, 500 mg) in THF (3 ml) was added dropwise and the reaction solution was stirred at the same temperature for 30 minutes. Then, 1-chloro-3-iodopropane (CAS No. 6940-76-7, 1.1 ml) was added dropwise to the reaction solution. The reaction solution was stirred at the same temperature for 20 minutes and then gradually heated to room temperature. Water and ethyl acetate were added to the reaction solution, and the organic layer was separated. The organic layer was sequentially washed with 1 N hydrochloric acid, water, a saturated sodium bicarbonate solution and brine, dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (elution solvent: hexane-diethyl ether system) to obtain 1.00 g of the title compound. The property value of the compound is as follows.
Reaction SMILES: [CH:1]([NH2:4])([CH3:3])[CH3:2].[CH3:5][C:6]1[C:10]([C:11]([O:13][CH2:14]C)=[O:12])=[C:9]([C:16](OCC)=[O:17])[O:8][N:7]=1>CO>[CH:1]([NH:4][C:16]([C:9]1[O:8][N:7]=[C:6]([CH3:5])[C:10]=1[C:11]([O:13][CH3:14])=[O:12])=[O:17])([CH3:3])[CH3:2]
Reactant: CC(C)N
Reactant: CCOC(=O)c1onc(C)c1C(=O)OCC
Solvent: CO
Product: COC(=O)c1c(C)noc1C(=O)NC(C)C

Procedure:
2.9 g of isopropylamine are added dropwise to 10 g of diethyl 3-methylisoxazole-4,5-dicarboxylate, dissolved in 100 ml of methanol, and the mixture is then refluxed. After 7 hours the mixture is evaporated down and the remaining oil is chromatographed over silica gel (using 9:1 toluene/acetone). Methyl 5-isopropylaminocarbonyl-3-methylisoxazole-4-carboxylate is obtained as colorless crystals of melting point 64°-66° C. (compound No. 1005).
Reaction SMILES: [C:1]([N:8]([C:21]1[NH:25][C:24]2[C:26]([C@H:41]3[CH2:45][CH2:44][CH2:43][O:42]3)=[C:27]([F:40])[C:28]([C:30]3[CH:31]=[N:32][C:33]([C:36]([OH:39])([CH3:38])[CH3:37])=[N:34][CH:35]=3)=[CH:29][C:23]=2[N:22]=1)[C:9](=[O:20])[N:10]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:11][CH3:12])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].N1C=NN=N1.CC(N([P:58]([O:67][CH2:68][C:69]1[CH:74]=[CH:73][CH:72]=[CH:71][CH:70]=1)[O:59]CC1C=CC=CC=1)C(C)C)C.C1C=C(Cl)C=C(C(OO)=[O:83])C=1>C(Cl)Cl>[CH2:68]([O:67][P:58]([OH:59])([O:42][CH2:41][C:26]1[CH:24]=[CH:23][CH:29]=[CH:28][CH:27]=1)=[O:83])[C:69]1[CH:70]=[CH:71][CH:72]=[CH:73][CH:74]=1.[C:1]([N:8]([C:21]1[NH:25][C:24]2[C:26]([C@H:41]3[CH2:45][CH2:44][CH2:43][O:42]3)=[C:27]([F:40])[C:28]([C:30]3[CH:31]=[N:32][C:33]([C:36]([OH:39])([CH3:38])[CH3:37])=[N:34][CH:35]=3)=[CH:29][C:23]=2[N:22]=1)[C:9](=[O:20])[N:10]([C:13]([O:15][C:16]([CH3:17])([CH3:19])[CH3:18])=[O:14])[CH2:11][CH3:12])([O:3][C:4]([CH3:5])([CH3:6])[CH3:7])=[O:2]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CC(C)N(C(C)C)P(OCc1ccccc1)OCc1ccccc1
Agent: CCN(C(=O)OC(C)(C)C)C(=O)N(C(=O)OC(C)(C)C)c1nc2cc(-c3cnc(C(C)(C)O)nc3)c(F)c([C@H]3CCCO3)c2[nH]1
Agent: c1nnn[nH]1
Solvent: ClCCl
Product: O=P(O)(OCc1ccccc1)OCc1ccccc1
Temperature: 0 °C
Reaction time: 18 h

Procedure:
To diBoc-1-ethyl-3-[6-fluoro-5-[2-(1-hydroxy-1-methyl-ethyl)pyrimidin-5-yl]-7-[(2R)-tetrahydrofuran-2-yl]-1H-benzimidazol-2-yl]urea (28) (1.13 g, 1.797 mmol) and tetrazole (251.8 mg, 3.594 mmol) at 23° C. under N2 was added DCM (30 mL) followed by N-dibenzyloxyphosphanyl-N-isopropyl-propan-2-amine (744.7 mg, 724.4 μA, 2.156 mmol). After stirring for 18 h, the reaction was cooled to 0° C. then treated with mCPBA (531.5 mg, 2.156 mmol). The reaction was stirred for 15 min at 0° C., then for 30 min at 23° C. The resulting solution was then partitioned between EtOAc and saturated aqueous sodium bicarbonate (300 mL each), the organic layer separated, then washed with 10% aqueous sodium bisulfite, saturated aqueous sodium bicarbonate and brine (300 mL each), then dried over magnesium sulfate filtered and concentrated. The residue was purified by MPLC using an ISCO COMBIFLASH brand flash chromatography purification system (80 g silica column) eluting with a 0-80% EtOAc in hexanes linear gradient over 20 column volumes at 60 mL/min flow rate. Desired product fractions were combined and evaporated to give diBoc-1-ethyl-3-[6-fluoro-5-[2-(1-hydroxy-1-methyl-ethyl)pyrimidin-5-yl]-7-[(2R)-tetrahydrofuran-2-yl]-1H-benzimidazol-2-yl]urea dibenzyl phosphate (29) (1.03 g, 1.159 mmol, 64.50%) as a clear, glassy oil. ESMS (M+1)=889.5; 1H NMR (300.0 MHz, CDCl3) δ 8.93 (d, J=1.5 Hz, 2H), 8.31 (s, 1H), 8.04 (d, J=6.4 Hz, 1H), 7.36-7.26 (m, 10H), 5.83-5.70 (m, 1H), 5.16-5.05 (m, 4H), 4.24-4.18 (m, 1H), 4.03-3.97 (m, 1H), 3.42-3.36 (m, 2H), 2.43-2.05 (m, 4H), 1.98 (s, 6H), 1.64 (s, 9H), 1.40 (s, 9H) and 1.26 (t, J7.2 Hz, 3H) ppm.
Reaction SMILES: Cl[C:2]1[C:7]([NH2:8])=[C:6]([Cl:9])[N:5]=[C:4]([CH3:10])[N:3]=1.[C:11]1(B(O)O)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C(=O)([O-])[O-].[Na+].[Na+]>C(COC)OC.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:9][C:6]1[C:7]([NH2:8])=[C:2]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[N:3]=[C:4]([CH3:10])[N:5]=1
Reactant: Cc1nc(Cl)c(N)c(Cl)n1
Reactant: OB(O)c1ccccc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: Cc1nc(Cl)c(N)c(-c2ccccc2)n1

Procedure:
The title compound was prepared from 4,6-dichloro-2-methyl-pyrimidin-5-ylamine (500 mg, 2.8 mmol), phenylboronic acid (340 mg, 2.8 mmol), sodium carbonate (920 mg, 8.7 mmol, dissolved in minimal amount of water) and Pd(PPh3)4 (160 mg, 0.14 mmol) in 30 mL of glyme by a procedure similar to example 17, step 1 yielding 380 mg (61%) of a solid.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH:10]([O:27][C:28]2[CH:29]=[C:30]3[C:34](=[CH:35][CH:36]=2)[C:33](=[O:37])[NH:32][C:31]3=[O:38])[C:11]([NH:13][S:14]([C:17]2[CH:22]=[CH:21][C:20]([C:23]([CH3:26])([CH3:25])[CH3:24])=[CH:19][CH:18]=2)(=[O:16])=[O:15])=[O:12])=[CH:6][CH:5]=1)([O-])=O>CO.[Ni]>[NH2:1][C:4]1[CH:5]=[CH:6][C:7]([CH:10]([O:27][C:28]2[CH:29]=[C:30]3[C:34](=[CH:35][CH:36]=2)[C:33](=[O:37])[NH:32][C:31]3=[O:38])[C:11]([NH:13][S:14]([C:17]2[CH:18]=[CH:19][C:20]([C:23]([CH3:26])([CH3:24])[CH3:25])=[CH:21][CH:22]=2)(=[O:16])=[O:15])=[O:12])=[CH:8][CH:9]=1
Reactant: CC(C)(C)c1ccc(S(=O)(=O)NC(=O)C(Oc2ccc3c(c2)C(=O)NC3=O)c2ccc([N+](=O)[O-])cc2)cc1
Agent: [Ni]
Solvent: CO
Product: CC(C)(C)c1ccc(S(=O)(=O)NC(=O)C(Oc2ccc3c(c2)C(=O)NC3=O)c2ccc(N)cc2)cc1

Procedure:
A solution of 1 g of 2-(4-nitrophenyl)-2-(1,3-dihydro-1,3-dioxoisoindol-5-yloxy)-N-(4-tertbutylphenylsulfonyl)acetamide in 25 ml of methanol is hydrogenated to completion at normal pressure and 20° on 1 g of Raney nickel. The mixture is filtered, the solvent is removed and 2-(4-aminophenyl)-2-(1,3-dihydro-1,3-dioxoisoindol-5-yloxy)-N-(4-tert-butylphenylsulfonyl)acetamide is obtained.
Reaction SMILES: OCCC1C2C=CC(C#N)=CC=2CCO1.[CH3:16][S:17]([O:20][CH2:21][CH2:22][C@H:23]1[C:28]2[CH:29]=[CH:30][C:31]([C:33]([NH2:35])=O)=[CH:32][C:27]=2[CH2:26][CH2:25][O:24]1)(=[O:19])=[O:18]>>[CH3:16][S:17]([O:20][CH2:21][CH2:22][CH:23]1[C:28]2[CH:29]=[CH:30][C:31]([C:33]#[N:35])=[CH:32][C:27]=2[CH2:26][CH2:25][O:24]1)(=[O:18])=[O:19]
Reactant: CS(=O)(=O)OCC[C@@H]1OCCc2cc(C(N)=O)ccc21
Agent: N#Cc1ccc2c(c1)CCOC2CCO
Product: CS(=O)(=O)OCCC1OCCc2cc(C#N)ccc21

Procedure:
Prepared from 1-(2-hydroxyethyl)-3,4-dihydro-1H-2-benzopyran-6-carbonitrile, as described for the preparation of 2-[(1S)-6-(aminocarbonyl)-3,4-dihydro-1H-2-benzopyran-1-yl]ethyl methanesulfonate.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:11][C:10](=[S:12])[CH2:9][N:8]=[C:7]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[C:6]=2[CH:19]=1.C[O-].[Na+].[CH2:23](Br)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.O>CO>[CH2:23]([S:12][C:10]1[CH2:9][N:8]=[C:7]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:6]2[CH:19]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]=2[N:11]=1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: S=C1CN=C(c2ccccc2)c2cc(Cl)ccc2N1
Reactant: BrCc1ccccc1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: Clc1ccc2c(c1)C(c1ccccc1)=NCC(SCc1ccccc1)=N2
Reaction time: 0.5 h

Procedure:
To a solution of 1.43 parts of 7-chloro-5phenyl-3-H-1,4-benzodiazepine-2-thione in 12.5 parts by volume of 0.4 N sodium methoxide in methanol is added dropwise with stirring 0.6 part by volume of benzyl bromide and the stirring is continued for an additional 30 minutes. Water is added to the reaction mixture and the resulting oil is extracted with ethyl acetate. The ethyl acetate layer is washed with water and dried over sodium sulfate. Evaporation of the solvent yields 2-benzylmercapto-7-chloro-5-phenyl-3H-1,4-benzodiazepine as an oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:12]2[CH:17]=[C:16]([CH:18]([F:20])[F:19])[N:15]3[N:21]=[CH:22][C:23]([C:24](O)=[O:25])=[C:14]3[N:13]=2)[CH:5]=[CH:6][C:7]=1[C:8]([F:11])([F:10])[F:9].[NH2:27][C:28]1[CH:37]=[CH:36][C:31]([C:32]([NH:34]O)=[NH:33])=[CH:30][N:29]=1>>[Cl:1][C:2]1[CH:3]=[C:4]([C:12]2[CH:17]=[C:16]([CH:18]([F:20])[F:19])[N:15]3[N:21]=[CH:22][C:23]([C:24]4[O:25][N:34]=[C:32]([C:31]5[CH:36]=[CH:37][C:28]([NH2:27])=[N:29][CH:30]=5)[N:33]=4)=[C:14]3[N:13]=2)[CH:5]=[CH:6][C:7]=1[C:8]([F:11])([F:10])[F:9]
Reactant: O=C(O)c1cnn2c(C(F)F)cc(-c3ccc(C(F)(F)F)c(Cl)c3)nc12
Reactant: N=C(NO)c1ccc(N)nc1
Product: Nc1ccc(-c2noc(-c3cnn4c(C(F)F)cc(-c5ccc(C(F)(F)F)c(Cl)c5)nc34)n2)cn1

Procedure:
The title compound was prepared from 5-(3-chloro-4-trifluoromethyl-phenyl)-7-difluoromethyl-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (example C.15) (196 mg, 0.5 mmol) and 6-amino-N-hydroxy-nicotinamidine (example B.4) (114 mg, 0.75 mmol) according to general procedure II. Obtained after flash chromatography on silica gel (ethyl acetate/heptane) and further purification by crystallization (dichloromethane/hexane) as a yellow solid (97 mg, 38%). MS (ISP) 508.2 [(M+H)+]; mp 252° C.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[N:16]=[CH:15][C:14]3[C:9](=[C:10]([C:17]([OH:19])=O)[CH:11]=[CH:12][CH:13]=3)[N:8]=2)[CH:2]=1.[S:20]1[CH:24]=[CH:23][N:22]=[C:21]1[NH2:25].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C.O>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[N:16]=[CH:15][C:14]3[C:9](=[C:10]([C:17]([NH:25][C:21]4[S:20][CH:24]=[CH:23][N:22]=4)=[O:19])[CH:11]=[CH:12][CH:13]=3)[N:8]=2)[CH:2]=1
Reactant: O=C(O)c1cccc2cnc(-c3cccnc3)nc12
Reactant: Nc1nccs1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CN(C)C=O
Product: O=C(Nc1nccs1)c1cccc2cnc(-c3cccnc3)nc12
Temperature: 50 °C
Reaction time: 12 h
Yield: 45 %

Procedure:
A mixture of 2-(pyridin-3-yl)quinazoline-8-carboxylic acid (250 g, 1.0 mmol), thiazole-2-amine (94 mg, 1.0 mmol), HATU (760 mg, 2.0 mmol) and DIPEA (260 mg, 2.0 mmol) in DMF (15 mL) was stirred at 50° C. for 12 hours. Water (20 mL) was added and the precipitate was collected by filtration, washed with water (3×10 mL) and methanol (3×5 mL) to obtain 2-(pyridin-3-yl)-N-(thiazol-2-yl)quinazoline-8-carboxamide (150 mg, 46% yield). MS (ESI) calcd for C17H11N5OS (m/z): 333.07. found: 334 [M+1].
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:11]([OH:13])=O)[CH:5]=[C:6]2[C:10]=1[NH:9][CH:8]=[CH:7]2.Cl.[NH2:15][CH2:16][CH:17]([C:19]1[CH:24]=[C:23]([O:25][CH3:26])[C:22]([O:27][CH3:28])=[C:21]([O:29][CH3:30])[CH:20]=1)[OH:18].C(Cl)CCl.C(N(CC)CC)C>CN(C=O)C.CN(C1C=CN=CC=1)C.O>[OH:18][CH:17]([C:19]1[CH:20]=[C:21]([O:29][CH3:30])[C:22]([O:27][CH3:28])=[C:23]([O:25][CH3:26])[CH:24]=1)[CH2:16][NH:15][C:11]([C:4]1[CH:5]=[C:6]2[C:10](=[C:2]([F:1])[CH:3]=1)[NH:9][CH:8]=[CH:7]2)=[O:13]
Reactant: COc1cc(C(O)CN)cc(OC)c1OC
Reactant: O=C(O)c1cc(F)c2[nH]ccc2c1
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: O
Solvent: ClCCCl
Solvent: CCN(CC)CC
Product: COc1cc(C(O)CNC(=O)c2cc(F)c3[nH]ccc3c2)cc(OC)c1OC
Temperature: 50 °C

Procedure:
A solution of Example 63D in DMF (10 mL)was treated sequentially with 2-amino-1-(3,4,5-trimethoxyphenyl)ethanol hydrochloric acid salt (0.343 g, 1.30 mmol), EDC (0.325 g, 1.7 mmol), triethylamine, DMAP (catalytic), heated at 50° C. for 15 hours, cooled to room temperature, poured into water (100 ml), and extracted with ethyl acetate. The extract was washed with brine, dried (MgSO4), filtered, and concentrated. The concentrate was purified by flash chromatography on silica gel with 8:2 ethyl acetate/hexanes to provide 0.24 g of the desired product.
Reaction SMILES: C([N:8]1[CH2:12][CH2:11][CH2:10][C@H:9]1[CH2:13][CH2:14][O:15][C:16]1[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=1)(OC(C)(C)C)=O.[ClH:22].N.CO>C(O)C>[ClH:22].[ClH:22].[NH:8]1[CH2:12][CH2:11][CH2:10][C@H:9]1[CH2:13][CH2:14][O:15][C:16]1[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=1
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1CCOc1cccnc1
Agent: Cl
Agent: N
Solvent: CCO
Solvent: CO
Product: c1cncc(OCC[C@@H]2CCCN2)c1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a solution of the compound from step 102b above (60 mg, 0.20 mmol) in 3 mL of ethanol at 0° C. was added saturated HCl in ethanol (10 mL), and the reaction mixture was stirred for 30 minutes at 0° C. The volatiles were removed under vacuum, and the residue was purified on a column of silica gel, eluting with methanol/methylene chloride (5:95). The product was treated with a saturated solution of HCl/EtOH and held under vacuum for 24 hours to afford a white solid. MS (DCI/NH3) m/e: 193 (M+H)+, 210 (M+NH4)+. 1H NMR (D2O, 300 MHz) δ: 1.69-1.86 (m, 1H), 1.91-2.20 (m, 3H), 2.26-2.43 (m, 2H), 3.28-3.47 (m, 2H), 3.70-3.85 (m, 1H), 4.27-4.45 (m, 2H), 7.82 (dd, J=8.5, 5.0 Hz, 1H), 7.98 (dd, J=9.0, 4.0 Hz, 1H), 8.35 (d, J=6.0 Hz, 1H), 8.45 (d, J=2.0 Hz, 1H). Anal. Calc. for C11H16N2O.2.3 HCl: C, 47.84; H, 6.68; N, 10.14; Found C, 47.48; H, 6.92; N, 9.94. [α]25D =+41.62° (c=0.41, methanol).
Reaction SMILES: [NH2:1][C:2]1[S:6][N:5]=[C:4]([C:7]([Cl:10])([Cl:9])[Cl:8])[N:3]=1.[C:11]1([CH3:20])[C:12]([C:17](Cl)=[O:18])=[CH:13][CH:14]=[CH:15][CH:16]=1.C1(C)C=CC=CC=1>C1(C)C(C)=CC=CC=1>[C:11]1([CH3:20])[C:12]([C:17]([NH:1][C:2]2[S:6][N:5]=[C:4]([C:7]([Cl:10])([Cl:9])[Cl:8])[N:3]=2)=[O:18])=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: Nc1nc(C(Cl)(Cl)Cl)ns1
Reactant: Cc1ccccc1C(=O)Cl
Solvent: Cc1ccccc1C
Solvent: Cc1ccccc1
Product: Cc1ccccc1C(=O)Nc1nc(C(Cl)(Cl)Cl)ns1
Temperature: 25 °C
Yield: 35.1 %

Procedure:
A solution of 22.0 g (0.1 mole) 5-amino-3-trichloromethyl-1,2,4-thiadiazole and 16.0 g (0.1 mole) 2-toluoyl chloride in 250 ml xylene was heated at reflux for 20 hours. The reaction mixture was cooled to room temperature and the resulting precipitate removed by filtration. Following recrystallization for toluene, 11.8 g (35% yield) of pure product was otained; m.p. 170° C.
Reaction SMILES: [C:1]([O:4][CH2:5][CH:6]([OH:9])[CH2:7][Cl:8])(=[O:3])[CH3:2].[O:10]1[CH:15]=[CH:14][CH2:13][CH2:12][CH2:11]1.C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1>C(Cl)Cl>[C:1]([O:4][CH2:5][CH:6]([O:9][CH:11]1[CH2:12][CH2:13][CH2:14][CH2:15][O:10]1)[CH2:7][Cl:8])(=[O:3])[CH3:2]
Reactant: C1=COCCC1
Reactant: CC(=O)OCC(O)CCl
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: CC(=O)OCC(CCl)OC1CCCCO1

Procedure:
A solution of 271.9 g (1.78 moles) of 3-chloro-2-hydroxy-1-propyl acetate, 244 ml (2.67 moles) of freshly distilled dihydropyran, and 44.7 g (0.178 moles) of pyridinium p-toluenesulfonate in 1800 mL of methylene chloride was stirred at room temperature with cooling to control the reaction exotherm. After 22 hours the reaction mixture was washed with 500 mL of water and 250 mL of sodium chloride solution, and was dried over sodium sulfate. Solvent was removed and the residue was dried at 0.03 mm for 1.5 hours to give 473.3 g of crude 3-chloro-2-tetrahydropyranyloxy-1-propyl acetate: 1H NMR (CDCl3) δ1.63 (br. s, 6 H, (CH2)3); 2.08 (s, 3H, CH3CO); 3.5-4.3 (7H, CH2CHCH2); 4.73 (br. s, 1H, --O--CH); IR (neat, NaCl) 3000, 2910 (C--H); 1740 cm- 1 (--O--CO--CH3).
Reaction SMILES: C(=S)([O-])N.[NH4+].Br[CH:7]([C:18]1[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=1)[C:8]([C:10]1[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=1)=O.[C:26](=[S:29])([S-:28])[NH2:27].[NH4+]>C(O)C>[CH3:17][O:16][C:13]1[CH:14]=[CH:15][C:10]([C:8]2[CH:7]([C:18]3[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=3)[S:29][C:26](=[S:28])[N:27]=2)=[CH:11][CH:12]=1
Reactant: COc1ccc(C(=O)C(Br)c2ccc(OC)cc2)cc1
Reactant: NC(=S)[S-]
Agent: NC([O-])=S
Agent: [NH4+]
Solvent: CCO
Product: COc1ccc(C2=NC(=S)SC2c2ccc(OC)cc2)cc1
Temperature: 0 °C
Reaction time: 3 h

Procedure:
4.92 g of ammonium thiocarbamate are suspended in 70 ml of 96% strength ethanol. The suspension is cooled to 5° and, while stirring, 15 g of 2-bromo-1,2-bis-(p-methoxyphenyl)-ethanone are added thereto in portions in the course of 10 minutes, the internal temperature being maintained at approximately 10° by cooling. The mixture is then stirred for 1 hour at 10°, a further 2.4 g of ammonium dithiocarbamate are added and stirring is carried out again for 3 hours at room temperature. The mixture is then poured into 500 ml of ice-water, the crude product is filtered off with suction and then washed with ice-water. For purification, the crude product is suspended in 50 ml of ethanol and heated under reflux, first of all dissolution occurring and, after 90 minutes, reprecipitation. The whole is allowed to cool, filtered with suction and the residue is then washed with cold ethanol. 4,5-bis-(p-methoxyphenyl)-thiazoline-2-thione having a melting point of 226°-230° is obtained.