Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:7](=[O:8])[NH:6][CH:5]=[C:4]([C:9](=[O:15])[CH2:10][CH2:11][C:12]([OH:14])=[O:13])[CH:3]=1.S(=O)(=O)(O)O.[CH3:21]O>>[Cl:1][C:2]1[C:7](=[O:8])[NH:6][CH:5]=[C:4]([C:9](=[O:15])[CH2:10][CH2:11][C:12]([O:14][CH3:21])=[O:13])[CH:3]=1
Reactant: O=C(O)CCC(=O)c1c[nH]c(=O)c(Cl)c1
Reactant: CO
Agent: O=S(=O)(O)O
Product: COC(=O)CCC(=O)c1c[nH]c(=O)c(Cl)c1
Temperature: 2 °C

Procedure:
43 g of 4-(5-chloro-1,6-dihydro-6-oxopyridin-3-yl)-4-oxobutyric acid (crude product, prepared as described in Example 6) was suspended in 730 ml of methanol, and 16 ml of concentrated sulfuric acid was added. The mixture was heated in such a way that approximately 100 ml of methanol distilled off in the course of 4 hours. The reaction mixture which remained was then concentrated to half its volume under reduced pressure and the resulting solution was cooled to 2° C. The product was removed by filtration, washed using 20 ml of cold methanol and dried. The product yield was 38.1 g (83%) of white crystals. The product melting point was 211.5° to 213.5° C. Other data concerning the product was:
Reaction SMILES: Cl[Si](C)(C)C.[O:6]=[C:7]1[N:12]2[CH:13]=[C:14]([C:17]([OH:19])=[O:18])[CH:15]=[CH:16][C:11]2=[N:10][C:9]2[CH2:20][S:21][CH2:22][C:8]1=2.ClN1C(=O)CCC1=O>N1C=CC=CC=1.O>[O:6]=[C:7]1[N:12]2[CH:13]=[C:14]([C:17]([OH:19])=[O:18])[CH:15]=[CH:16][C:11]2=[N:10][C:9]2=[CH:20][S:21][CH:22]=[C:8]12
Reactant: O=C(O)c1ccc2nc3c(c(=O)n2c1)CSC3
Agent: C[Si](C)(C)Cl
Agent: O=C1CCC(=O)N1Cl
Solvent: O
Solvent: c1ccncc1
Product: O=C(O)c1ccc2nc3cscc3c(=O)n2c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Chlorotrimethylsilane (2.6 ml, 0.02 mol) is added to a cooled (icebath) solution of 3,10-dihydro-10-oxo-1H-pyrido[1,2-a]thieno-[3,4-d]pyrimidine-7-carboxylic acid (5.0 g., 0.02 mol) in pyridine (40 ml) under nitrogen. The mixture is stirred at ice bath temperature for one hour and then allowed to warm to room temperature. N-Chlorosuccinimide (2.74 g., 0.02 mol) is added and the mixture is heated at 90°-95° C. for 20 minutes. The mixture is cooled, diluted with water (5 ml) and stirred for 15 minutes. The precipitate is filtered off, dried, washed with boiling acetone (3×100 ml) and recrystallized from dimethylformamide to give the product (3.9 g.), mp 320° C. (dec).
Reaction SMILES: [B:1]1([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[CH2:16]O)[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH2:3][O:2]1.[CH2:18]([N:20](CC)[CH2:21]C)C.CS(Cl)(=O)=O.CNC>ClCCl.O>[B:1]1([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[CH2:16][N:20]([CH3:21])[CH3:18])[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH2:3][O:2]1
Reactant: CCN(CC)CC
Reactant: OCc1ccccc1B1OCc2ccccc21
Agent: CNC
Agent: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: O
Product: CN(C)Cc1ccccc1B1OCc2ccccc21
Reaction time: 0.5 h
Yield: 55 %

Procedure:
To a solution of (2-(benzo[c][1,2]oxaborol-1(3H)-yl)phenyl)methanol (300 mg, 1.34 mmol) in dichloromethane (10 mL) were added sequentially triethylamine (0.373 mL, 2.7 mmol) and methanesulfonyl chloride (0.125 mL, 1.60 mmol) at 0° C. After stirring for 30 min, dimethylamine (2M in tetrahydrofuran; 3 mL) was added, and the mixture was stirred for another 30 min. Water was added and the mixture was extracted with ethyl acetate. The organic layer was washed with brine and dried on anhydrous sodium sulfate. The solvent was removed under reduced pressure and the residue was purified by silica gel column chromatography (1:2 hexane/ethyl acetate) followed by recrystallization from diisopropyl ether/hexane to give the title compound (185 mg, 55%): 1H NMR (300 MHz, DMSO-d6) δ 2.25 (s, 3H), 2.41 (s, 3H), 4.09 (br d, J=8.5 Hz, 2H), 4.87 (d, J=13.2 Hz, 1H), 5.05 (d, J=13.2 Hz, 1H), 7.0-7.3 (m, 8H); ESI-MS m/z 252 (positive); C16H18BNO=251
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[NH2:8].O=[CH:10][CH2:11][C:12]1([C:25]([O:27][CH2:28][CH3:29])=[O:26])[CH2:17][CH2:16][CH2:15][N:14]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:13]1.ClCCCl.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>O>[CH3:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[NH:8][CH2:10][CH2:11][C:12]1([C:25]([O:27][CH2:28][CH3:29])=[O:26])[CH2:17][CH2:16][CH2:15][N:14]([C:18]([O:20][C:21]([CH3:23])([CH3:24])[CH3:22])=[O:19])[CH2:13]1
Reactant: Cc1ccncc1N
Reactant: CCOC(=O)C1(CC=O)CCCN(C(=O)OC(C)(C)C)C1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Solvent: O
Product: CCOC(=O)C1(CCNc2cnccc2C)CCCN(C(=O)OC(C)(C)C)C1
Reaction time: 24 h

Procedure:
4-Methylpyridin-3-amine (36.0 mg, 0.000333 mol) was added to a solution of 1-tert-butyl 3-ethyl 3-(2-oxoethyl)piperidine-1,3-dicarboxylate (0.095 g, 0.00032 mol) in 1,2-dichloroethane (1.9 mL, 0.025 mol) and followed by sodium triacetoxyborohydride (0.20 g, 0.00095 mol) and the mixture was stirred for 24 h. The mixture was poured into pre-cooled water, extracted with ethyl acetate. The organic layer was separated, dried and concentrated. The product was purified by CombiFlash using CH2Cl2/EtOAc (max EtOAc 50%). LC-MS: 392.3 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[C:20]([N+:21]([O-])=O)=[CH:19][C:5]([C:6]([NH:8][C@H:9]2[CH2:14][CH2:13][C@H:12]([C:15]([F:18])([F:17])[F:16])[CH2:11][CH2:10]2)=[O:7])=[C:4]([O:24][CH2:25][CH:26]([F:28])[F:27])[N:3]=1>[Ni].C1COCC1>[NH2:21][C:20]1[C:2]([NH2:1])=[N:3][C:4]([O:24][CH2:25][CH:26]([F:27])[F:28])=[C:5]([CH:19]=1)[C:6]([NH:8][C@H:9]1[CH2:14][CH2:13][C@H:12]([C:15]([F:17])([F:16])[F:18])[CH2:11][CH2:10]1)=[O:7]
Reactant: Nc1nc(OCC(F)F)c(C(=O)N[C@H]2CC[C@H](C(F)(F)F)CC2)cc1[N+](=O)[O-]
Agent: [Ni]
Solvent: C1CCOC1
Product: Nc1cc(C(=O)N[C@H]2CC[C@H](C(F)(F)F)CC2)c(OCC(F)F)nc1N
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of 6-amino-2-(2,2-difluoro-ethoxy)-5-nitro-N-(trans-4-trifluoromethyl-cyclohexyl)-nicotinamide (250 mg, 0.61 mmol), Ra—Ni (30 mg) and THF (10 mL) is stirred at rt for 2 h under a hydrogen atmosphere (3.0 bar). The catalyst is removed by filtration and the filtrate is concentrated.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:11][N:10](C(C3C=CC=CC=3)C3C=CC=CC=3)[CH2:9]2)=[CH:4][CH:3]=1.[C:25](Cl)(Cl)=[O:26]>ClCCl.C1(C)C=CC=CC=1>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]2[CH2:9][N:10]([C:25]([NH:10][CH2:9][C:8]#[CH:5])=[O:26])[CH2:11]2)=[CH:6][CH:7]=1
Reactant: O=C(Cl)Cl
Reactant: Fc1ccc(C2CN(C(c3ccccc3)c3ccccc3)C2)cc1
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: C#CCNC(=O)N1CC(c2ccc(F)cc2)C1
Reaction time: 1.5 h

Procedure:
To a stirred solution of 3-(4fluorophenyl)-1-(diphenylmethyl)azetidine (17) (0.38 g) in dichloromethane (5 mL) at 0° C. was added dropwise a solution of 20% phosgene in toluene (1.4 mL). The mixture was stirred for 90 minutes then concentrated in vacuo. To the concentrate was added dichloromethane (5 mL) and to this solution at 0° C. was added, dropwise, with stirring propargylaminc (0.3 mL). The mixture was stirred for 18 hrs at room temperature, diluted with dichworomethane (20 mL), washed (water, brine), dried (Na2SO4) and concentrated in vacuo. The crude material was purified by flash column chromatography (50% ethyl acetate hexane) and then crystallised from diisopropyl ether to give 3-(4-fluoropenyl)-N-(2-propynyl)azetidine-1-carboxamide (19) (0.14 g), m.p. 141° C. (diisopropyl ether). Found: C, 67.32; H, 5.65; N, 11.93. C13Hi3FN2O requires C, 67.23; H, 5.64; N, 12.06%.
Reaction SMILES: [C:1]([O:4][C@H:5]1[C@H:10]([O:11][C:12](=[O:14])[CH3:13])[C@@H:9]([O:15][C:16](=[O:18])[CH3:17])[C@H:8]([C:19]2[CH:24]=[CH:23][C:22]([Cl:25])=[C:21]([CH2:26][C:27]3[CH:32]=[CH:31][C:30]([CH2:33][CH3:34])=[CH:29][CH:28]=3)[CH:20]=2)[O:7][C@@H:6]1[CH2:35][O:36][C:37](=[O:39])[CH3:38])(=[O:3])[CH3:2].[Cr]([O-])([O-])(=O)=[O:41].[K+].[K+]>C(O)(=O)C>[C:1]([O:4][C@H:5]1[C@H:10]([O:11][C:12](=[O:14])[CH3:13])[C@@H:9]([O:15][C:16](=[O:18])[CH3:17])[C@H:8]([C:19]2[CH:24]=[CH:23][C:22]([Cl:25])=[C:21]([CH2:26][C:27]3[CH:28]=[CH:29][C:30]([C:33](=[O:41])[CH3:34])=[CH:31][CH:32]=3)[CH:20]=2)[O:7][C@@H:6]1[CH2:35][O:36][C:37](=[O:39])[CH3:38])(=[O:3])[CH3:2]
Reactant: O=[Cr](=O)([O-])[O-]
Reactant: CCc1ccc(Cc2cc([C@@H]3O[C@H](COC(C)=O)[C@@H](OC(C)=O)[C@H](OC(C)=O)[C@H]3OC(C)=O)ccc2Cl)cc1
Agent: [K+]
Solvent: CC(=O)O
Product: CC(=O)OC[C@H]1O[C@@H](c2ccc(Cl)c(Cc3ccc(C(C)=O)cc3)c2)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Temperature: 120 °C
Reaction time: 22 h
Yield: 37 %

Procedure:
To a stirred solution of (2R,3R,4R,5S,6S)-2-(acetoxymethyl)-6-(4-chloro-3-(4-ethylbenzyl)phenyl)tetrahydro-2H-pyran-3,4,5-triyl triacetate (10 g, 10.8 mmol) (prepared using methods analogous to those described in US20040138439) in acetic acid (130 mL) at 120° C. was added potassium chromate (6.3 g, 21.4 mmol) in one portion. The mixture was stirred for 22 hours at 120° C. The solvents were removed under reduced pressure, ethyl acetate was added, and the solid was filtered. The organic layer was washed with saturated aqueous sodium bicarbonate and then with brine, and then dried over sodium sulfate. The sample was concentrated, and the resulting residue was purified by silica gel chromatography (3:1 petroleum ether:ethyl acetate) to give pure product 47 as a solid (2.3 g). 1H-NMR (CDCl3, 400 MHz): δ 7.90 (d, J=8.0 Hz, 2H), 7.39 (d, J=8.4 Hz, 1H), 7.26 (d, J=8.4 Hz, 2H), 7.22 (dd, J=8.4, 2.2 Hz, 1H), 7.17 (d, J=2.0 Hz, 1H), 5.31 (t, J=9.4 Hz, 1H), 5.22 (t, J=9.8 Hz, 1H), 5.09 (t, J=9.4 Hz, 1H), 4.35 (d, J=10.0 Hz, 1H), 4.29 (dd, J=12.4, 4.8 Hz, 1H), 4.18-4.13 (m, 3H), 3.85-3.81 (m, 1H), 2.60 (s, 3H), 2.09 (s, 3H), 2.07 (s, 3H), 2.01 (s, 3H), 1.75 (s, 3H); MS ESI: 575 [M+H]+, 619 [M+HCO2]−.
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:11]=[CH:10][C:8]([NH2:9])=[CH:7][CH:6]=1)([CH3:3])[CH3:2].Cl.C(N=C=NCCCN(C)C)C.CCN=C=NCCCN(C)C.[C:35]([O:39][C:40]([N:42]1[CH2:47][C@H:46]2[CH2:48][CH2:49][C@@H:43]1[C@H:44]([C:50](O)=[O:51])[CH2:45]2)=[O:41])([CH3:38])([CH3:37])[CH3:36]>N1C=CC=CC=1>[CH:1]([O:4][C:5]1[CH:11]=[CH:10][C:8]([NH:9][C:50]([C@H:44]2[C@H:43]3[CH2:49][CH2:48][C@H:46]([CH2:47][N:42]3[C:40]([O:39][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:41])[CH2:45]2)=[O:51])=[CH:7][CH:6]=1)([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1C[C@H]2CC[C@@H]1[C@H](C(=O)O)C2
Reactant: CC(C)Oc1ccc(N)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: c1ccncc1
Product: CC(C)Oc1ccc(NC(=O)[C@@H]2C[C@@H]3CC[C@H]2N(C(=O)OC(C)(C)C)C3)cc1
Temperature: 25 °C
Reaction time: 14 h

Procedure:
4-Isopropoxyaniline (1.49 g, 9.87 mmol), and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (hereinafter, “WSC”; 1.89 g, 9.87 mmol) were added to a pyridine (20 mL) solution of the compound (1.68 g, 6.58 mmol) synthesized in (2), and the mixture was stirred at room temperature for 14 hours. The reaction mixture was concentrated under reduced pressure, and, after addition of ethyl acetate, washed once with distilled water, once with 1 N-hydrochloric acid aqueous solution, and once with 1N-sodium hydroxide aqueous solution. The organic layer was dried over magnesium sulfate, and concentrated under reduced pressure. The resulting residue was then purified using silica gel column chromatography to obtain the target (1.26 g, 49%).
Reaction SMILES: [C:1]1(B(O)O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:10][C:11]1[N:12]=[CH:13][C:14]([C:21]2[CH:22]=[N:23][N:24]([CH:26]3[CH2:31][CH2:30][N:29]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:28][CH2:27]3)[CH:25]=2)=[C:15]2[C:19]([Cl:20])=[CH:18][O:17][C:16]=12.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1.O>[NH2:10][C:11]1[N:12]=[CH:13][C:14]([C:21]2[CH:22]=[N:23][N:24]([CH:26]3[CH2:27][CH2:28][N:29]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:30][CH2:31]3)[CH:25]=2)=[C:15]2[C:19]([Cl:20])=[C:18]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[O:17][C:16]=12
Reactant: CC(C)(C)OC(=O)N1CCC(n2cc(-c3cnc(N)c4occ(Cl)c34)cn2)CC1
Reactant: OB(O)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC(n2cc(-c3cnc(N)c4oc(-c5ccccc5)c(Cl)c34)cn2)CC1

Procedure:
A solution of phenylboronic acid (35.0 mg, 287 μmol), tert-butyl 4-[4-(7-amino-3-chlorofuro[2,3-c]pyridin-4-yl)-1H-pyrazol-1-yl]piperidine-1-carboxylate (65 mg, 144 μmol), (1,1′-bis(diphenylphosphino)ferrocene)palladium dichloride (10.5 mg, 14.4 μmol), potassium carbonate (29.8 mg, 216 μmol) in 1,4-dioxane (785 μL) and H2O (259 μL) was evacuated and filled with argon three times. The mixture was irradiated in a microwave reactor at 100° C. for 40 min. The reaction mixture was partitioned between EtOAc and brine/water and separated. The aqueous layer was extracted with EtOAc (3×) and the combined organic extracts were washed with brine, dried over sodium sulfate, filtered, and concentrated. The residue was purified by flash chromatography (60 to 100% EtOAc:hexanes) to afford tert-butyl 4-[4-(7-amino-3-chloro-2-phenylfuro[2,3-c]pyridin-4-yl)-1H-pyrazol-1-yl]piperidine-1-carboxylate. MS (ESI): 494.16 [M+H]+; HPLC tR=3.11 min.
Reaction SMILES: [H-].[Na+].[CH3:3][N:4]1[CH:11]=[CH:10][C:8](=[O:9])[NH:7][C:5]1=[O:6].Br[CH:13]([CH2:19][CH2:20][CH3:21])[CH2:14][CH2:15][CH2:16][CH:17]=[CH2:18].O>CS(C)=O>[CH3:3][N:4]1[CH:11]=[CH:10][C:8](=[O:9])[N:7]([CH2:21][CH2:20][CH2:19][CH2:13][CH2:14][CH2:15][CH2:16][CH:17]=[CH2:18])[C:5]1=[O:6]
Reactant: C=CCCCC(Br)CCC
Reactant: Cn1ccc(=O)[nH]c1=O
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: C=CCCCCCCCn1c(=O)ccn(C)c1=O
Reaction time: 0.25 h
Yield: 92.9 %

Procedure:
This example illustrates a synthesis of 1-Methyl-3-(8,9-oxidononyl)uracil (inventive compound no. 1804). Sodium hydride (365 mg, 16 mmol) was added to a stirring solution of 1-methyluracil (2.00 g, 16 mmol) in dimethyl sulfoxide (40 mL). After 15 minutes, 6-bromo-1-nonene (3.26 g, 16 mmol) was added and the mixture stirred for 3 days. The reaction was then poured into water (50 mL) and extracted with dichloromethane (3×60 mL). The combined organic layers were washed with water (50 mL), and aqueous saturated salt solution (30 mL) was then dried over sodium sulfate. The solvent was evaporated under vacuum to yield 3.72 g (94%) 1-methyl-3-(8-nonenyl)uracil (inventive compound no. 1817) as a colorless oil which solidified upon standing.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:25])[CH2:5][C:6]1[CH:7]=[C:8]([C:14]2[CH:19]=[C:18]([CH3:20])[CH:17]=[CH:16][C:15]=2[CH2:21][NH:22][CH2:23][CH3:24])[C:9]([O:12][CH3:13])=[CH:10][CH:11]=1)[CH3:2].[CH:26]1([C:29](Cl)=[O:30])[CH2:28][CH2:27]1>>[CH2:1]([O:3][C:4](=[O:25])[CH2:5][C:6]1[CH:7]=[C:8]([C:14]2[CH:19]=[C:18]([CH3:20])[CH:17]=[CH:16][C:15]=2[CH2:21][N:22]([C:29]([CH:26]2[CH2:28][CH2:27]2)=[O:30])[CH2:23][CH3:24])[C:9]([O:12][CH3:13])=[CH:10][CH:11]=1)[CH3:2]
Reactant: CCNCc1ccc(C)cc1-c1cc(CC(=O)OCC)ccc1OC
Reactant: O=C(Cl)C1CC1
Product: CCOC(=O)Cc1ccc(OC)c(-c2cc(C)ccc2CN(CC)C(=O)C2CC2)c1

Procedure:
Prepared according to the procedure described in Example 1, Step 6, using the following starting materials: (2′-ethylaminomethyl-6-methoxy-5′-methyl-biphenyl-3-yl)-acetic acid ethyl ester and cyclopropanecarbonyl chloride.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:26]=[CH:27][CH:28]=1)[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([NH2:13])=[CH:9][C:8]=1[C:14]#[C:15][Si:16]([CH:23]([CH3:25])[CH3:24])([CH:20]([CH3:22])[CH3:21])[CH:17]([CH3:19])[CH3:18].Cl[C:30]1[C:39]2[C:34](=[CH:35][CH:36]=[C:37]([I:40])[CH:38]=2)[N:33]=[CH:32][N:31]=1>C(O)(C)C>[F:1][C:2]1[CH:3]=[C:4]([CH:26]=[CH:27][CH:28]=1)[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([NH:13][C:30]2[C:39]3[C:34](=[CH:35][CH:36]=[C:37]([I:40])[CH:38]=3)[N:33]=[CH:32][N:31]=2)=[CH:9][C:8]=1[C:14]#[C:15][Si:16]([CH:17]([CH3:18])[CH3:19])([CH:20]([CH3:21])[CH3:22])[CH:23]([CH3:25])[CH3:24]
Reactant: CC(C)[Si](C#Cc1cc(N)ccc1OCc1cccc(F)c1)(C(C)C)C(C)C
Reactant: Clc1ncnc2ccc(I)cc12
Solvent: CC(C)O
Product: CC(C)[Si](C#Cc1cc(Nc2ncnc3ccc(I)cc23)ccc1OCc1cccc(F)c1)(C(C)C)C(C)C

Procedure:
4-(3-fluorobenzyloxy)-3-(2-(triisopropylsilyl)ethynyl)benzenamine (900 mg, 2.27 mmol) and 4-chloro-6-iodo-quinazoline (657 mg, 2.27 mmol) were dissolved in isopropanol (50 ml). The reaction mixture was refluxed for 12 hours. The solid product was collected by filtration, washed with cold isopropanol (10 mL) and ether (20 mL), and air dried to afford the clean desired material.
Reaction SMILES: C(#N)C.O([C:11]([NH:13][C:14]1[CH:15]=[C:16]([C:20]2[N:21]([CH3:26])[N:22]=[N:23][C:24]=2[SH:25])[CH:17]=[CH:18][CH:19]=1)=[O:12])C1C=CC=CC=1.C(O)(=O)C(O)=O.[NH2:33][CH2:34][CH2:35][CH2:36][P:37](=[O:44])([O:41][CH2:42][CH3:43])[O:38][CH2:39][CH3:40]>C(N(CC)CC)C>[CH2:42]([O:41][P:37]([CH2:36][CH2:35][CH2:34][NH:33][C:11](=[O:12])[NH:13][C:14]1[CH:15]=[C:16]([C:20]2[N:21]([CH3:26])[N:22]=[N:23][C:24]=2[SH:25])[CH:17]=[CH:18][CH:19]=1)([O:38][CH2:39][CH3:40])=[O:44])[CH3:43]
Reactant: CCOP(=O)(CCCN)OCC
Reactant: Cn1nnc(S)c1-c1cccc(NC(=O)Oc2ccccc2)c1
Agent: O=C(O)C(=O)O
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CCOP(=O)(CCCNC(=O)Nc1cccc(-c2c(S)nnn2C)c1)OCC
Yield: 94 %

Procedure:
40 ml of acetonitrile was added to 5.0 g of 4-(3-phenoxycarbonylaminophenyl)-3-methyl-5-mercaptotriazole (6) prepared in Step 1-5. 8.2 g of triethylamine was added to the system. 4.1 g of oxalic acid salt of diethyl 3-aminopropylphosphonate (8) prepared in Step 1-7 was added to the system. The system was then allowed to undergo reaction at a temperature of 50° C. over 4 hours. After the completion of the reaction, the solvent was distilled off under reduced pressure. 100 ml of water was added to the residue to deposit 62 g of a crystal of 4-[3-{3-(3-diethylphosphonopropyl)ureido}phenyl]-3-methyl-5-mercaptotriazole (9). (Yield: 94%; m.p. 128° C.)
Reaction SMILES: C([NH:9][C:10]([NH:12][CH2:13][CH:14]1[CH2:19][CH2:18][CH:17]([NH:20][C:21](=[O:30])[O:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH2:16][CH2:15]1)=[S:11])(=O)C1C=CC=CC=1.C([O-])([O-])=O.[K+].[K+]>CO.O>[CH2:23]([O:22][C:21](=[O:30])[NH:20][CH:17]1[CH2:16][CH2:15][CH:14]([CH2:13][NH:12][C:10]([NH2:9])=[S:11])[CH2:19][CH2:18]1)[C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: O=C(NC1CCC(CNC(=S)NC(=O)c2ccccc2)CC1)OCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: O
Product: NC(=S)NCC1CCC(NC(=O)OCc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 24 h
Yield: 94.7 %

Procedure:
To a solution of benzyl N-[4-({[(benzoylamino)carbothioyl]amino}methyl)cyclohexyl]carba mate (5.02 g, 11.4 mmol) in MeOH (110 ml) was added a solution of K2CO3 (3.5 g, 25.3 mmol) in water (30 ml). The solution was stirred for 24 hours at room temperature. The solvent was removed in vacuo with repeated additions of MeOH to azeotropically remove water. The resulting solid was treated with acetone (60 ml) and filtered. The filtrate was evaporated to yield 95% (3.47 g) of a yellow solid.
Reaction SMILES: [Cl-].[NH4+].C(O)(C)C.[N+:7]([C:10]1[CH:23]=[CH:22][C:13]([C:14]([CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18])=[O:15])=[CH:12][CH:11]=1)([O-])=O>O>[NH2:7][C:10]1[CH:11]=[CH:12][C:13]([C:14]([CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18])=[O:15])=[CH:22][CH:23]=1
Reactant: CCOC(=O)CC(=O)c1ccc([N+](=O)[O-])cc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: CC(C)O
Solvent: O
Product: CCOC(=O)CC(=O)c1ccc(N)cc1
Temperature: 5 °C
Yield: 83.1 %

Procedure:
A mixture of 224 g of reduced iron, 13.4 g of ammonium chloride, 1,000 ml of isopropyl alcohol, and 200 ml of water was prepared, and then 237 g of ethyl p-nitrobenzoylacetate was added thereto in small amounts at temperatures ranging between 50° and 70° C. They were reacted at 70° C. for 1 hour and then the reaction solution was filtered. Then, 1,000 ml of water was added to the filtrate and cooled to 5° C., and crystals precipitated were collected by filtration to yield 172 g of yellow ethyl p-aminobenzoylacetate crystals, m.p., 82°-4° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:26])/[C:4](/[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[CH2:14][O:15][C:16]1[CH:21]=[CH:20][C:19]([N+:22]([O-])=O)=[CH:18][C:17]=1[F:25])=[CH:5]/[O:6][CH3:7].[H][H]>CO.C(OCC)(=O)C.[Pd]>[CH3:1][O:2][C:3](=[O:26])/[C:4](/[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[CH2:14][O:15][C:16]1[CH:21]=[CH:20][C:19]([NH2:22])=[CH:18][C:17]=1[F:25])=[CH:5]/[O:6][CH3:7]
Reactant: [H][H]
Reactant: CO/C=C(/C(=O)OC)c1ccccc1COc1ccc([N+](=O)[O-])cc1F
Agent: [Pd]
Solvent: CO
Solvent: CCOC(C)=O
Product: CO/C=C(/C(=O)OC)c1ccccc1COc1ccc(N)cc1F
Reaction time: 18 h
Yield: 93.9 %

Procedure:
1.0 g (2.7 mmol) of the compound obtained in Step 1 was dissolved in a mixture of 5 ml of methanol and 5 ml of ethyl acetate, and 200 mg of 10% palladium/carbon was added thereto. The resulting mixture was placed in a hydrogenation reactor, and hydrogen gas was introduced therein with stirring the mixture for 18 hours. The reaction mixture was filtered through Cellite, and concentrated under a reduced pressure. The residue was subjected to column chromatography using 40% ethyl acetate/hexane as an eluent to obtain 0.84 g (yield 92%) of (E)-methyl-2-[2-((2-fluoro-4-aminophenoxy)methyl)phenyl]-3-methoxyacrylate.
Reaction SMILES: [CH3:1][NH:2][NH2:3].[F:4][C:5]([F:12])([F:11])[C:6](=O)[CH2:7][C:8]#[N:9].Cl>CCO>[CH3:1][N:2]1[C:8]([NH2:9])=[CH:7][C:6]([C:5]([F:12])([F:11])[F:4])=[N:3]1
Reactant: CNN
Reactant: N#CCC(=O)C(F)(F)F
Agent: Cl
Solvent: CCO
Product: Cn1nc(C(F)(F)F)cc1N
Yield: 20.9 %

Procedure:
A solution of methylhydrazine (5.0 g, 60 mmol) and 4,4,4-trifluoro-3-oxo-butyronitrile (9.8 g, 71 mmol) in EtOH (50 mL) was treated with conc. HCl (5 mL) and the resultant mixture was heated to reflux overnight. The solvent was removed in vacuo and the crude product was dissolved in EtOAc washed with saturated aq. Na2CO3 solution until the washings were pH 8. The organics were concentrated and purified by prep-HPLC to provide 2-methyl-5-trifluoromethyl-2H-pyrazol-3-ylamine (2.07 g, 21% yield). 1H NMR (300 MHz, DMSO-d6), δ 5.57 (s, 1 H), 5.54 (br s, 2 H), 3.55 (s, 3 H); MS (ESI) m/z: 166.1 (M+H+).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]([CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[Cl:24])[CH:10]=[C:11]([C:13]([OH:16])([CH3:15])[CH3:14])[N:12]=2)=[CH:4][CH:3]=1.[CH3:25][S:26]([C:29]1[CH:30]=[C:31](B(O)O)[CH:32]=[CH:33][CH:34]=1)(=[O:28])=[O:27].C([O-])([O-])=O.[K+].[K+]>COCCOC>[Cl:24][C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=1[CH2:17][N:9]1[CH:10]=[C:11]([C:13]([OH:16])([CH3:15])[CH3:14])[N:12]=[C:8]1[C:5]1[CH:6]=[CH:7][C:2]([C:33]2[CH:32]=[CH:31][CH:30]=[C:29]([S:26]([CH3:25])(=[O:28])=[O:27])[CH:34]=2)=[CH:3][CH:4]=1
Reactant: CS(=O)(=O)c1cccc(B(O)O)c1
Reactant: CC(C)(O)c1cn(Cc2ccccc2Cl)c(-c2ccc(Br)cc2)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: COCCOC
Product: CC(C)(O)c1cn(Cc2ccccc2Cl)c(-c2ccc(-c3cccc(S(C)(=O)=O)c3)cc2)n1
Yield: 76.7 %

Procedure:
A mixture of 2-[2-(4-bromophenyl)-1-(2-chlorobenzyl)-1H-imidazol-4-yl]-propan-2-ol (130 mg, 0.32 mmol), 3-methanesulfonyl-phenylboronic acid (80 mg, 0.40 mmol), Cl2Pd(dppf)DCM (13 mg, 5 mol %) and a 2.8M aqueous solution of K2CO3 (0.35 mL, 0.98 mmol) in DME (2 mL) was heated in a microwave unit (Biotage Initiator™) at 120° C. for 4 min. The reaction mixture was concentrated and purified by chromatography (silica, EtOAc/Hex, 45:55 to 90:10) to give the title compound (118 mg, 77%) as a white solid. 1H-NMR. (DCM-d2): δ 8.08 (m, 1H), 7.84 (dd, 2H), 7.55-7.64 (m, 5H), 736 (m, 1H), 7.17-7.26 (m, 2H), 6.85 (d, 1H), 6.77 (s, 1H), 5.24 (s, 2H), 3.00 (s, 3H), 2.86 (br s, 1H), 1.49 (s, 6H); MS (ES): 481 [M+H]+.