Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br-].[O:2]1[CH2:6][CH2:5][O:4][CH:3]1[CH2:7][CH2:8][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O=[C:29]1[CH2:34][CH2:33][CH:32]([C:35]2[CH:43]=[CH:42][C:38]([C:39]([NH2:41])=[O:40])=[CH:37][CH:36]=2)[CH2:31][CH2:30]1.C(OCC)C>O1CCCC1>[O:4]1[CH2:5][CH2:6][O:2][CH:3]1[CH2:7][CH:8]=[C:29]1[CH2:34][CH2:33][CH:32]([C:35]2[CH:43]=[CH:42][C:38]([C:39]([NH2:41])=[O:40])=[CH:37][CH:36]=2)[CH2:31][CH2:30]1
Reactant: NC(=O)c1ccc(C2CCC(=O)CC2)cc1
Reactant: c1ccc([P+](CCC2OCCO2)(c2ccccc2)c2ccccc2)cc1
Agent: [Br-]
Solvent: C1CCOC1
Solvent: CCOCC
Product: NC(=O)c1ccc(C2CCC(=CCC3OCCO3)CC2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 61.3 %

Procedure:
140.9 g of 2-(1,3-dioxolan-2-yl)ethyl-triphenylphosphonium bromide were suspended in 4.5 l of tetrahydrofuran while gassing with nitrogen and the suspension was treated at 0° C. within 5 minutes with 36.8 g of potassium tert.butylate. The orange suspension was stirred at room temperature for a further 1 hour and treated within 5 minutes with 46.1 g of 4-(4-oxocyclohexyl)benzamide. The reaction mixture was stirred at room temperature for a further 4.5 hours and then concentrated in a vacuum. The yellowish crystals obtained (212.5 g) were treated with 1.2 l of diethyl ether. The mixture was stirred at room temperature for 30 minutes and then suction filtered. The residue was washed with diethyl ether and then suspended in 700 ml of water. The mixture was stirred for 15 minutes and then suction filtered. The residue was washed with water and dissolved while heating in 600 ml of dioxan. The solution was left to cool to room temperature. The separated crystals were removed by filtration under suction, washed with a small amount of dioxan and hexane and dried at 60° C. in a vacuum, whereby there were obtained 39.2 g of crystalline 4-[4-[2-(1,3-dioxolan-2-yl)ethylidene]cyclo-hexyl]benzamide with m.p. 209°-212° C. Working-up of the mother liquor (72.6 g) gave a further 7.7 g of product and 64.2 g of a second mother liquor.
Reaction SMILES: Cl.[NH:2]([C:6]1[S:7][CH:8]=[C:9]([CH2:11][S:12][CH2:13][CH2:14][NH2:15])[N:10]=1)[C:3]([NH2:5])=[NH:4].C(N(CC)CC)C.[CH3:23][N:24]=[C:25]=[S:26].[C:27]([OH:34])(=[O:33])/[CH:28]=[CH:29]\[C:30]([OH:32])=[O:31]>CO.CC(C)=O>[C:27]([OH:34])(=[O:33])/[CH:28]=[CH:29]\[C:30]([OH:32])=[O:31].[NH:2]([C:6]1[S:7][CH:8]=[C:9]([CH2:11][S:12][CH2:13][CH2:14][NH:15][C:25]([NH:24][CH3:23])=[S:26])[N:10]=1)[C:3]([NH2:5])=[NH:4]
Reactant: CN=C=S
Reactant: N=C(N)Nc1nc(CSCCN)cs1
Agent: Cl
Agent: O=C(O)/C=C\C(=O)O
Solvent: CO
Solvent: CCN(CC)CC
Solvent: CC(C)=O
Product: CNC(=S)NCCSCc1csc(NC(=N)N)n1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A suspension of 2-guanidino-4-[(2-aminoethyl)thiomethyl]thiazole hydrochloride (1.52 g.) in methanol (30 ml.) was treated with triethylamine (1.01 g.) to give a pale yellow solution. Methyl isothiocyanate (0.365 g.) was added and the solution stirred for 16 hours at room temperature. Evaporation of the solvent gave a gum which was dissolved in acetone (20 ml.) and treated with maleic acid (1 g.) in acetone (20 ml.). The precipitate was filtered off and recrystallized from ethanol to give 2-guanidino-4-[2-(3-methylthioureido)ethylthiomethyl]thiazole hydrogen maleate as a pale brown solid (0.420 g.). Found: C, 37.4; H, 4.7; N, 19.8; S, 22.7. C13H20N6S3O4 requires C, 37.14; H, 4.76; N, 20.00; S, 22.85%.
Reaction SMILES: [NH2:1][C:2]1[CH:20]=[CH:19][C:5]2[N:6]([CH2:14][C:15]([F:18])([F:17])[F:16])[CH:7]([C:10]([F:13])([F:12])[F:11])[CH2:8][O:9][C:4]=2[CH:3]=1.[CH3:21][C:22]([CH3:27])([CH3:26])[C:23](Cl)=O.N1C=CC=CC=1.C[CH2:35][O:36]C(C)=O>>[F:16][C:15]([F:18])([F:17])[CH2:14][N:6]1[C:5]2[CH:19]=[CH:20][C:2]([NH:1][C:35](=[O:36])[CH2:23][C:22]([CH3:27])([CH3:26])[CH3:21])=[CH:3][C:4]=2[O:9][CH2:8][CH:7]1[C:10]([F:11])([F:12])[F:13]
Reactant: CCOC(C)=O
Reactant: CC(C)(C)C(=O)Cl
Reactant: Nc1ccc2c(c1)OCC(C(F)(F)F)N2CC(F)(F)F
Solvent: c1ccncc1
Product: CC(C)(C)CC(=O)Nc1ccc2c(c1)OCC(C(F)(F)F)N2CC(F)(F)F
Temperature: 25 °C
Reaction time: 12 h
Yield: 89 %

Procedure:
To a solution of (±)-7-amino-3,4-dihydro-4-(2,2,2-trifluoroethyl)-3-(trifluoromethyl)-2H-1,4-benzoxazine (140 mg, 0.47 mmol) in 5 mL EtOAc was added trimethylacetyl chloride (0.085 mL, 0.70 mmol) and anhydrous pyridine (0.056 mL, 0.70 mmol). The solution was allowed to stir at rt for 12 h. The solution was then washed sequentially with saturated sodium bisulfate (2×10 mL), copper sulfate (10 mL) and brine (10 mL). The organic phase was dried with anhydrous magnesium sulfate, filtered and the solvent was evaporated under reduced pressure to yield an oil. The oil was purified via flash chromatography (7:3 hexanes:EtOAc) to afford 160 mg (89%) of (±)-3,4-dihydro-4-(2,2,2-trifluoroethyl)-3-(trifluoromethyl)-7-(trimethylpropionamido)-2H-1,4-benzoxazine. 1H NMR (CDCl3, 400 MHz) d 1.25 (s, 9H), 3.78 (sext, J=8.0 Hz, 1H), 3.88 (m, 1H), 4.02 (m, 1H), 4.22 (sext. J=8.3 Hz, 1H), 4.59 (d, J=11.6 Hz, 1H), 6.77 (d, J=8.8 Hz, 1H), 7.05 (dd, J=2.4 Hz, 8.8 Hz, 1H), 7.11 (d, J=2.44 Hz, 1H), 7.15 (s, 1H).
Reaction SMILES: [C:1]([Si:5]([CH3:24])([CH3:23])[O:6][CH:7]([C:20]([CH3:22])=[CH2:21])[CH2:8][CH2:9]/[C:10](/[CH3:19])=[CH:11]/[CH2:12][CH2:13][C:14]([CH3:18])=[CH:15][CH:16]=[O:17])([CH3:4])([CH3:3])[CH3:2].[CH3:25][Mg]I.[Mg].CI.[Cl-].[NH4+]>CCOCC>[C:1]([Si:5]([CH3:23])([CH3:24])[O:6][CH:7]([C:20]([CH3:22])=[CH2:21])[CH2:8][CH2:9]/[C:10](/[CH3:19])=[CH:11]/[CH:12]=[CH:13][C:14]([CH3:18])=[CH:15][C:16]([OH:17])=[CH2:25])([CH3:4])([CH3:3])[CH3:2]
Reactant: C=C(C)C(CC/C(C)=C/CCC(C)=CC=O)O[Si](C)(C)C(C)(C)C
Reactant: C[Mg]I
Agent: [Cl-]
Agent: [Mg]
Agent: [NH4+]
Solvent: CCOCC
Solvent: CI
Product: C=C(O)C=C(C)C=C/C=C(\C)CCC(O[Si](C)(C)C(C)(C)C)C(=C)C
Reaction time: 2 h

Procedure:
A solution of 7.3 g of (6E)-10-(tert.-butyldimethylsiloxy)-3,7,11-trimethyl-2,6,11-dodecatrienal in 10 ml of ether is added dropwise at -20° to a methylmagnesium iodide solution prepared from 0.56 g of magnesium shavings and 3.1 g of methyl iodide in 80 ml of ether. After stirring at -20° for 2 hours the reaction mixture is poured into a mixture of ice and saturated ammonium chloride solution and extracted twice with ether. The combined organic extracts are washed with saturated sodium chloride solution, dried over sodium sulphate, filtered and evaporated. The oil which remains behind as the residue is chromatographed on silica gel with hexane-ethyl acetate-triethylamine 90:10:0.1, whereby (7E)-11-(tert.-butyldimethylsiloxy)-4,8,12-trimethyl-3,7,12-tridecadien-trien-2-ol is obtained as a colourless oil. NMR (250 MHz, CDCl3): 5.2 (d, J=8 H-C(3)); 5.1 (t, J=6.5, H-C(7)); 4.84 and 4.75 (2m, 2H-C(13)); 4.57 (m, H-C(2)); 4.0 (t, J=6.5, H-C(11)); 2.25-1.4 (m, 4CH2, 3CH3); 1.22 (d, J=6.5, 3H-C(1)); 0.89 (s, SiC(CH3)3); 0.04 and 0.0 (2s, Si(CH3)2).
Reaction SMILES: [NH:1]([C:53]([O:55][CH2:56][C:57]1[CH:62]=[CH:61][CH:60]=[CH:59][CH:58]=1)=[O:54])[C@H:2]([C:11]([NH:13][C@H:14]([C:18]([NH:20][C@H:21]([C:34]([NH:36][C@H:37]([C:43]([NH:45][C@H:46]([C:49](OC)=[O:50])[CH2:47][OH:48])=[O:44])[CH2:38][CH2:39][C:40](=[O:42])[NH2:41])=[O:35])[CH2:22][CH2:23][CH2:24][CH2:25][NH:26][C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])=[O:19])[C@@H:15]([CH3:17])[OH:16])=[O:12])[CH2:3][C:4]1[CH:9]=[CH:8][C:7](O)=[CH:6][CH:5]=1.[NH2:63][NH2:64].[OH2:65]>CO>[NH:1]([C:53]([O:55][CH2:56][C:57]1[CH:62]=[CH:61][CH:60]=[CH:59][CH:58]=1)=[O:54])[C@H:2]([C:11]([NH:13][C@H:14]([C:18]([NH:20][C@H:21]([C:34]([NH:36][C@H:37]([C:43]([NH:45][C@H:46]([C:47]([NH:63][NH2:64])=[O:48])[CH2:49][OH:50])=[O:44])[CH2:38][CH2:39][C:40](=[O:42])[NH2:41])=[O:35])[CH2:22][CH2:23][CH2:24][CH2:25][NH:26][C:27]([O:29][C:30]([CH3:32])([CH3:33])[CH3:31])=[O:28])=[O:19])[C@@H:15]([CH3:17])[OH:16])=[O:12])[CH2:3][C:4]1[CH:5]=[CH:6][C:7]([OH:65])=[CH:8][CH:9]=1
Reactant: O
Reactant: COC(=O)[C@H](CO)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@H](CCCCNC(=O)OC(C)(C)C)NC(=O)[C@@H](NC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)OCc1ccccc1)[C@@H](C)O
Reactant: NN
Solvent: CO
Product: C[C@@H](O)[C@H](NC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)OCc1ccccc1)C(=O)N[C@@H](CCCCNC(=O)OC(C)(C)C)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CO)C(=O)NN
Reaction time: 48 h

Procedure:
In 270 ml of MeOH were dissolved 3.93 g of Z-Tyr-Thr-Lys(Boc)-Gln-Ser-OMe, and 2.5 ml of NH2NH2.H2O was added to the solution, followed by allowing the mixture to stand at room temperature for 48 hours. The resulting crystals were recovered by filtration and recrystallized from MeOH. Yield 3.4 g (86.5%); m.p. 204°-205° C. (decomp.); [α]D22 -9.0° (c=0.5, DMF); Rf2 =0.36.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:6]2[CH:7]=[CH:8][N:9]([CH:16]([CH3:18])[CH3:17])[C:10]=2[CH:11]=[C:12]([O:14]C)[CH:13]=1)=[O:4].[Cl-].[Al+3].[Cl-].[Cl-]>C1(C)C=CC=CC=1.O>[CH3:1][O:2][C:3]([C:5]1[C:6]2[CH:7]=[CH:8][N:9]([CH:16]([CH3:18])[CH3:17])[C:10]=2[CH:11]=[C:12]([OH:14])[CH:13]=1)=[O:4]
Reactant: COC(=O)c1cc(OC)cc2c1ccn2C(C)C
Agent: [Al+3]
Agent: [Cl-]
Solvent: O
Solvent: Cc1ccccc1
Product: COC(=O)c1cc(O)cc2c1ccn2C(C)C
Yield: 83.6 %

Procedure:
To a stirred solution of 1-isopropyl-6-methoxy-1H-indole-4-carboxylic acid methyl ester (1.9 g, 7.69 mmol) in toluene (20 mL) was added anhydrous aluminum chloride (5.11 g, 38.4 mmol) at room temperature and then heated to reflux for 2 h. The reaction mixture was diluted with water and extracted with ethyl acetate (2×20 mL). The combined organic layer was dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by column chromatography by eluting 3-15% Ethyl acetate in petroleum ether to afford the title compound 6-hydroxy-1-isopropyl-1H-indole-4-carboxylic acid methyl ester (1.5 g, 83%) as yellow colored gum. 1H NMR (400 MHz, DMSO-d6): δ 1.43 (d, J=6.8 Hz, 6H), 3.86 (s, 3H), 4.65-4.61 (m, 1H), 6.81 (d, J=2.8 Hz, 1H), 7.11 (s, 1H), 7.29 (s, 1H), 7.44 (d, J=2.8 Hz, 1H), 9.32 (bs, 1H). LCMS (ES+): m/z=234.09 [M+H]
Reaction SMILES: C[O:2][C:3]([C@@H:5]1[CH2:9][C@H:8]([OH:10])[CH2:7][N:6]1[S:11](=[O:24])(=[O:23])[NH:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]#[N:20])=[C:15]([Cl:21])[C:14]=1[CH3:22])=[O:4].Cl>[OH-].[Na+]>[Cl:21][C:15]1[C:14]([CH3:22])=[C:13]([NH:12][S:11]([N:6]2[CH2:7][C@@H:8]([OH:10])[CH2:9][C@H:5]2[C:3]([OH:4])=[O:2])(=[O:23])=[O:24])[CH:18]=[CH:17][C:16]=1[C:19]#[N:20]
Reactant: COC(=O)[C@@H]1C[C@H](O)CN1S(=O)(=O)Nc1ccc(C#N)c(Cl)c1C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: Cc1c(NS(=O)(=O)N2C[C@@H](O)C[C@H]2C(=O)O)ccc(C#N)c1Cl
Yield: 100.8 %

Procedure:
A solution of 4A (60 mg, 0.160 mmol) in 4 mL of 1.6 N NaOH was stirred at rt for 1 h. The reaction mixture was acidified to pH 2 with 10% HCl. A solid precipitated which was filtered, washed with water and dried to afford the title compound (58 mg) as an orange solid. 1H NMR (CD3OD) δ 2.38-2.42 (m, 5H) 3.31-3.34 (m, 1H), 3.62-3.65 (m, 1H), 4.40-4.42 (m, 1H), 4.49-4.52 (m, 1H), 7.60 (d, J=8.8, 1H), 7.71 (d, J=8.8, 1H); 13C NMR (CD3OD) δ 15.28, 39.89, 57.29, 61.95, 71.03, 109.61, 117.42, 121.42, 130.55, 132.93, 137.84, 143.77, 175.99; HPLC a) column: Phenominex ODS C18 4.6×50 mm, 4 min gradient, 10% MeOH/90% H2O/0.1% TFA to 90% MeOH/10% H2O/0.1% TFA; 1 min hold, 4 mL/min UV detection at 220 nm, 2.40 min retention time; HPLC b) column: Shimadzu Shim-Pack VP-ODS C18 4.6×50 mm, 4 min gradient, 10% MeOH/90% H2O/0.1% TFA to 90% MeOH/10% H2O/0.1% TFA, 1 min hold; 4 mL/min, UV detection at 220 nm, 2.23 min retention time (63%); MS (ES) m/z 360 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:14]=[CH:13][C:5]2[S:6][CH:7]=[C:8]([CH2:9][CH:10]([CH3:12])[CH3:11])[C:4]=2[CH:3]=1.[Cl:15][S:16](O)(=[O:18])=[O:17]>C(Cl)(Cl)Cl>[F:1][C:2]1[CH:14]=[CH:13][C:5]2[S:6][C:7]([S:16]([Cl:15])(=[O:18])=[O:17])=[C:8]([CH2:9][CH:10]([CH3:11])[CH3:12])[C:4]=2[CH:3]=1
Reactant: CC(C)Cc1csc2ccc(F)cc12
Reactant: O=S(=O)(O)Cl
Solvent: ClC(Cl)Cl
Product: CC(C)Cc1c(S(=O)(=O)Cl)sc2ccc(F)cc12
Temperature: 25 °C
Reaction time: 3 h
Yield: 60.5 %

Procedure:
To a solution of 5-fluoro-3-isobutyl-benzo[b]thiophene 0.55 g) in chloroform (10 ml) was added chlorosulfonic acid (1.54 g), and the resulting mixture was stirred at rt for 3 h, quenched with ice/water, and extracted with methylene chloride. The organic phases were washed with water and aqueous sodium bicarbonate solution, dried and concentrated. The residue was chromatographed on silica gel using heptane/ethyl acetate as eluent to obtain the title compound (0.49 g) as a colorless oil. MS (EI): 306.8 (M)
Reaction SMILES: [C:1]([C:5]1[O:6][C:7](=[O:15])[C:8]2[CH:14]=[CH:13][CH:12]=[N:11][C:9]=2[N:10]=1)([CH3:4])([CH3:3])[CH3:2].O1CCC[CH2:17]1.C[Mg]Br.[Cl-].[NH4+]>O>[C:7]([C:8]1[C:9]([NH:10][C:5](=[O:6])[C:1]([CH3:4])([CH3:3])[CH3:2])=[N:11][CH:12]=[CH:13][CH:14]=1)(=[O:15])[CH3:17]
Reactant: CC(C)(C)c1nc2ncccc2c(=O)o1
Reactant: C1CCOC1
Agent: C[Mg]Br
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Product: CC(=O)c1cccnc1NC(=O)C(C)(C)C
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
To a mixture of 2-tert-butyl-4H-pyrido[2,3-d][1,3]oxazin-4-one (10.2 g, 50 mmol) and tetrahydrofuran (50 mL) was added methyl magnesium bromide (0.97M tetrahydrofuran solution, 100 mL, 97 mmol) dropwise at −78° C., after the dropwise addition was finished, which was stirred at −78° C. for 30 minutes. To the reaction mixture were added a saturated aqueous solution of ammonium chloride and water, which was extracted with ethyl acetate, and the organic layer was washed with an aqueous solution of ammonium chloride. The solvent was evaporated under a reduced pressure and the precipitated solid was filtered, so as to obtain the title compound (9.1 g).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:17]=[CH:18][CH:19]=1)[CH2:5][NH:6][C:7]([NH:9][C:10]1[S:11][CH:12]=[C:13]([CH2:15]O)[N:14]=1)=[O:8].[NH2:20][C:21]1SC=C(COC(=O)C)N=1.FC1C=C(C=CC=1)[CH2:35][N:36]=C=O.[OH-].[Na+]>C1COCC1.CCOC(C)=O.CO>[C:21]([CH:15]([NH:36][CH3:35])[C:13]1[N:14]=[C:10]([NH:9][C:7]([NH:6][CH2:5][C:4]2[CH:17]=[CH:18][CH:19]=[C:2]([F:1])[CH:3]=2)=[O:8])[S:11][CH:12]=1)#[N:20]
Reactant: O=C=NCc1cccc(F)c1
Reactant: CC(=O)OCc1csc(N)n1
Reactant: O=C(NCc1cccc(F)c1)Nc1nc(CO)cs1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: CCOC(C)=O
Product: CNC(C#N)c1csc(NC(=O)NCc2cccc(F)c2)n1
Temperature: 60 °C

Procedure:
Preparation of -(3-fluoro-benzyl)-3-(4-hydroxymethyl-thiazol-2-yl)-urea. To a solution of acetic acid 2-amino-thiazol-4-ylmethyl ester (6.89 g) in THF (50 mL) were 3-fluorobenzylisocyanate (5.50 g) and TEA (5.03 mL) added. The resultant solution was heated at 70° C. over 2 h. Then, MeOH (30 mL) and NaOH (6N, 15 mL) were added to the above solution. The reaction mixture was heated at 60° C. for 30 min After cooling down, the reaction mixture was diluted with EtOAc (150 mL) and was washed with water. The organic solvents were concentrated and the residue was purified by silica-gel column chromatography to afford 8.29 g of the desired product-1-(3-fluoro-benzyl)-3-(4-hydroxymethyl-thiazol-2-yl)-urea.
Reaction SMILES: Cl[CH2:2][CH2:3][O:4][CH2:5][CH2:6][O:7][CH2:8][CH2:9][OH:10].[C:11]1(=[O:21])[NH:15][C:14](=[O:16])[C:13]2=[CH:17][CH:18]=[CH:19][CH:20]=[C:12]12.[K]>CN(C)C=O>[C:11]1(=[O:21])[N:15]([CH2:2][CH2:3][O:4][CH2:5][CH2:6][O:7][CH2:8][CH2:9][OH:10])[C:14](=[O:16])[C:13]2=[CH:17][CH:18]=[CH:19][CH:20]=[C:12]12
Reactant: OCCOCCOCCCl
Reactant: O=C1NC(=O)c2ccccc21
Agent: [K]
Solvent: CN(C)C=O
Product: O=C1c2ccccc2C(=O)N1CCOCCOCCO

Procedure:
188 g of 2-[2-(2-Chloroethoxy)ethoxy]ethanol and 146 g of potassium phtalimide in 700 ml of dimethylformamide are brought to 95° C. for 17 hours.
Reaction SMILES: CO.[S-2:3].[CH3:4][Na].Cl[C:7]1[CH:8]=[CH:9][C:10]([N+:13]([O-:15])=[O:14])=[N:11][CH:12]=1>O>[CH3:4][S:3][C:7]1[CH:8]=[CH:9][C:10]([N+:13]([O-:15])=[O:14])=[N:11][CH:12]=1
Reactant: O=[N+]([O-])c1ccc(Cl)cn1
Reactant: C[Na]
Reactant: [S-2]
Solvent: O
Solvent: CO
Product: CSc1ccc([N+](=O)[O-])nc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 83.8 %

Procedure:
The methanol solution (2000 mL) of methyl sodium sulfide (150 g) was added dropwise into the methanol solution (4000 mL) of 5-chloro-2-nitropyridine (300 g), and the reaction temperature was kept below 0° C. After completing the dropping, the reactant was heated to room temperature, and stirred overnight. The solvent of the reaction mixture was discarded and 5 liters of water was added into the residue, then extracted with ethyl acetate. The organic layer was washed with saturated NaCl solution, and dried with anhydrous sodium sulfate. The yellow and solid target compound (270 g) was obtained by filtration and concentration under reduced pressure. 1H-NMR (300 MHz, CDCl3) δ 2.61 (3H, s), 7.73 (1H, dd), 8.18 (1H, d), 8.40 (1H, d). LC-MS m/z: 171 [M++1].
Reaction SMILES: S1C=CN=[CH:2]1.[NH2:6][C:7]1[N:12]=[CH:11][N:10]=[C:9]2[N:13]([C@H:30]3[CH2:35][CH2:34][C@@H:33]([N:36]4[CH2:41][CH2:40][N:39]([CH3:42])[CH2:38][CH2:37]4)[CH2:32][CH2:31]3)[N:14]=[C:15]([C:16]3[CH:21]=[CH:20][C:19]([NH:22][C:23]4[S:24][CH:25]=[C:26]([CH2:28][CH3:29])[N:27]=4)=[CH:18][CH:17]=3)[C:8]=12.Br[CH:44]([CH3:53])[C:45]([C:47]1C=CC=CC=1)=O>>[NH2:6][C:7]1[N:12]=[CH:11][N:10]=[C:9]2[N:13]([C@H:30]3[CH2:35][CH2:34][C@@H:33]([N:36]4[CH2:41][CH2:40][N:39]([CH3:42])[CH2:38][CH2:37]4)[CH2:32][CH2:31]3)[N:14]=[C:15]([C:16]3[CH:17]=[CH:18][C:19]([NH:22][C:23]4[S:24][C:25]([CH3:2])=[C:26]([C:28]5[CH:47]=[CH:45][CH:44]=[CH:53][CH:29]=5)[N:27]=4)=[CH:20][CH:21]=3)[C:8]=12
Reactant: CCc1csc(Nc2ccc(-c3nn([C@H]4CC[C@@H](N5CCN(C)CC5)CC4)c4ncnc(N)c34)cc2)n1
Reactant: CC(Br)C(=O)c1ccccc1
Reactant: c1cscn1
Product: Cc1sc(Nc2ccc(-c3nn([C@H]4CC[C@@H](N5CCN(C)CC5)CC4)c4ncnc(N)c34)cc2)nc1-c1ccccc1
Reaction time: 24 h

Procedure:
The procedure for thiazole synthesis, described in the preparation of cis-N2-(4-{4-amino-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-3-yl}phenyl)-4-ethyl-1,3-thiazol-2-amine, was employed with the exception that 2-bromopropiophenone (0.081 mL, 0.532 mmol) was used as the alkylating agent, and the alkylation reaction was conducted at 50° C. for 24 h. Purification of the product by preparative HPLC (25 to 100% acetonitrile in 0.1 M aqueous ammonium acetate over 20 min at 21 mL/min using an 8μ Hypersil HS C18, 250×21 mm column, Rt 9.1-10.3 min) afforded cis-N2-(4-{4-amino-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-3-yl}phenyl)-5-methyl-4-phenyl-1,3-thiazol-2-amine as a white powder (0.015 g, 0.026 mmol); RP-HPLC (25 to 100% acetonitrile in 0.1 M aqueous ammonium acetate over 10 min at 1 mL/min using a 5μ Hypersil HS C18, 250×4.6 mm column) Rt 8.67 min; MS (MH)+ 580.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][N:6]=[C:5]2[NH:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([Br:19])[CH:14]=1.[C:20]1(=[O:26])[O:25][C:23](=[O:24])[CH:22]=[CH:21]1>CN(C=O)C.O>[Br:19][C:15]1[CH:14]=[C:13]([NH:12][C:5]2[C:4]3[C:9](=[CH:10][CH:11]=[C:2]([NH:1][C:20]([CH:21]=[CH:22][C:23]([OH:25])=[O:24])=[O:26])[CH:3]=3)[N:8]=[CH:7][N:6]=2)[CH:18]=[CH:17][CH:16]=1
Reactant: Nc1ccc2ncnc(Nc3cccc(Br)c3)c2c1
Reactant: O=C1C=CC(=O)O1
Solvent: O
Solvent: CN(C)C=O
Product: O=C(O)C=CC(=O)Nc1ccc2ncnc(Nc3cccc(Br)c3)c2c1
Temperature: 70 °C
Reaction time: 2.5 h
Yield: 84.2 %

Procedure:
To a solution of 6-amino-4-[(3-bromophenyl)amino]-quinazoline (0.78 g, 2.5 mmol) in 8 mL of DMF was added maleic anhydride (0.266 g, 2.7 mmol), and the mixture was heated with stirring in a 70° C. oil bath for 2.5 hours. The resulting suspension was cooled to room temperature and then diluted with water. The solid was collected, washed sequentially with a mixture of toluene/DMF (1:1), water, and IPA. The solid was dried in vacuo at 60° C. for 16 hours to afford 3-[4-(3-bromo-phenylamino)-quinazolin-6-ylcarbamoyl]-acrylic acid (Z) (0.87 g, 86%) as a pale yellow powder, mp 224-225° C. (decomposition with gas evolution).
Reaction SMILES: [NH2:1][CH:2]([P:6](=[O:11])([O:9][CH3:10])[O:7][CH3:8])[CH:3]([CH3:5])[CH3:4].C(N(C(C)C)CC)(C)C.CN(C1C=CC=CN=1)C.[C:30]([CH2:34][CH2:35][C:36](Cl)=[O:37])([O:32][CH3:33])=[O:31]>N1C=CC=CC=1>[C:30]([CH2:34][CH2:35][C:36]([NH:1][CH:2]([P:6](=[O:11])([O:7][CH3:8])[O:9][CH3:10])[CH:3]([CH3:5])[CH3:4])=[O:37])([O:32][CH3:33])=[O:31]
Reactant: COP(=O)(OC)C(N)C(C)C
Reactant: COC(=O)CCC(=O)Cl
Agent: CN(C)c1ccccn1
Solvent: c1ccncc1
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)CCC(=O)NC(C(C)C)P(=O)(OC)OC
Temperature: 0 °C

Procedure:
To a solution of a compound of formula 3, preferably dimethyl (1-amino-2-methylpropyl)phosphonate, in an anhydrous polar aprotic solvent, preferably pyridine, is added a tertiary amine, preferably a mixture of tertiary amines, and most preferably, a mixture of diisopropylethylamine and dimethylaminopyridine. The mixture is cooled, preferably to 0° C, and a carboalkoxyalkyl halide, preferably carbomethoxypropionyl chloride is added. The reaction is allowed to stir until the reaction is complete. The product, a compound of Formula 4, preferably dimethyl [1-[N-(3-carbomethoxypropionyl)amino]-2-methylpropyl]phosphonate, may be isolated and purified by conventional means.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]([NH:12][C:13]([CH3:18])([CH3:17])[CH2:14][CH2:15][CH3:16])=S)[CH:5]=[C:6]([Cl:8])[CH:7]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Cl)(Cl)(Cl)Cl.C(N(CC)CC)C>ClCCl>[Cl:1][C:2]1[CH:3]=[C:4]([N:9]=[C:10]=[N:12][C:13]([CH3:17])([CH3:18])[CH2:14][CH2:15][CH3:16])[CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: CCCC(C)(C)NC(=S)Nc1cc(Cl)cc(Cl)c1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClC(Cl)(Cl)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCC(C)(C)N=C=Nc1cc(Cl)cc(Cl)c1

Procedure:
To a solution of 3.0 g of N-(3,5-dichlorophenyl)-N'-(1,1-dimethylbutyl)thiourea produced in Example A-3 in 50 ml of dichloromethane were added 5.2 g of triphenylphosphine, 3.1 g of carbon tetrachloride and 2.0 g of triethylamine. The mixture was refluxed for 6 hours, and then evaporated in vacuo. The residue was extracted with petroleum ether. The extract was evaporated in vacuo to give N-(3,5-dichlorophenyl)-N'-(1,1-dimethylbutyl)carbodiimide as an oil. To a solution of this oil in 20 ml of DMF were added 1.6 g of cyanamide and 0.1 ml of diisopropylethylamine. The mixture was stirred at 100° C. for 6 hours, cooled to room temperature and poured into 400 ml of water. The resulting crystals were filtered off, washed with small amount of cyclohexane, and purified by silica gel column chromatography using chloroform as a solvent to give 1.2 g of the title compound. Recrystallization from cyclohexane gave 1.1 g of colorless platelets melting at 115.0°-117.0° C.
Reaction SMILES: [C:1]1([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:6]=[CH:5][C:4](B(O)O)=[CH:3][CH:2]=1.[CH3:16][C:17]1[CH:21]=[C:20]([C:22]([O:24][CH2:25][CH3:26])=[O:23])[NH:19][N:18]=1.N1C=CC=CC=1>C(Cl)Cl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[CH3:16][C:17]1[CH:21]=[C:20]([C:22]([O:24][CH2:25][CH3:26])=[O:23])[N:19]([C:4]2[CH:5]=[CH:6][C:1]([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)=[CH:2][CH:3]=2)[N:18]=1
Reactant: CCOC(=O)c1cc(C)n[nH]1
Reactant: OB(O)c1ccc(-c2ccccc2)cc1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCOC(=O)c1cc(C)nn1-c1ccc(-c2ccccc2)cc1
Yield: 26 %

Procedure:
To a solution of 4-biphenylboronic acid (1.0 g, 5.1 mmol) and ethyl 3-methylpyrazole-5-carboxylate (0.78 g, 5.1 mmol) in 25 mL dry DCM were added pyridine (1.2 mL, 15 mmol) and anhydrous powder of copper(II) acetate (1.84 g, 10 mmol). Some activated molecular sieve powder was added afterwards. The resulting slurry was refluxed for 2 days under argon. The mixture was diluted with DCM, filtered through celite. The blue filtrate was washed with water (×2), dried, concentrated, purified with flush column to yield ethyl 3-methyl-1-(4-phenylphenyl)-1H-pyrazole-5-carboxylate (26%), Rf 0.67 (1:2 EtOAc:hexane), ES-MS: (M+H)+307; and its regioisomer, ethyl 5-methyl-1-(4-phenylphenyl)-1H-pyrazole-3-carboxylate (31%), Rf 0.50 (1:2 EtOAc:hexane), ES-MS: (M+H)+307.