Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:3]([C:21]1[S:25][C:24]([C:26](O)=[O:27])=[C:23]([CH3:29])[CH:22]=1)([C:6]1[CH:11]=[CH:10][C:9]([O:12][CH2:13][CH:14]([OH:19])[C:15]([CH3:18])([CH3:17])[CH3:16])=[C:8]([CH3:20])[CH:7]=1)[CH2:4][CH3:5])[CH3:2].Cl.[CH3:31][O:32][C:33](=[O:38])[C:34]([NH2:37])([CH3:36])[CH3:35]>>[CH3:31][O:32][C:33](=[O:38])[C:34]([NH:37][C:26]([C:24]1[S:25][C:21]([C:3]([CH2:4][CH3:5])([C:6]2[CH:11]=[CH:10][C:9]([O:12][CH2:13][CH:14]([OH:19])[C:15]([CH3:18])([CH3:17])[CH3:16])=[C:8]([CH3:20])[CH:7]=2)[CH2:1][CH3:2])=[CH:22][C:23]=1[CH3:29])=[O:27])([CH3:36])[CH3:35]
Reactant: CCC(CC)(c1ccc(OCC(O)C(C)(C)C)c(C)c1)c1cc(C)c(C(=O)O)s1
Reactant: COC(=O)C(C)(C)N
Agent: Cl
Product: CCC(CC)(c1ccc(OCC(O)C(C)(C)C)c(C)c1)c1cc(C)c(C(=O)NC(C)(C)C(=O)OC)s1
Yield: 81.3 %

Procedure:
Using the procedure analogous to Example 52, enantiomer 1 of 5-{1-Ethyl-1-[4-(2-hydroxy-3,3-dirnethyl-butoxy)-3-methyl-phenyl]-propyl}-3-methyl-thiophene-2-carboxylic acid (Example 7) (0.2 g, 0.48 mmol) and 2-amino-2-methyl-propionic acid methyl ester hydrochloride salt (0.018 g, 0.53 mmol) to give the title compound (0.20 g, 0.39 mmol, 71%). 1HNMR (CDC3), δ 0.69 (t, J=7.0 Hz, 6H), 1.01 (s, 9H), 1.60 (s, 6H), 2.02-2.13 (m, 4H), 2.19 (s, 3H), 2.44 (s, 3H), 3.70 (dd, J=8.9, 2.6 Hz, 1H), 3.76 (s, 3H), 3.86 (t, J=8.7, 1H), 4.09 (dd, J=9.4, 2.6 Hz, 1H), 6.28 (s, 1H), 6.59 (s, 1H), 6.73 (d, J=8.4 Hz, 1H), 6.99 (d, J=2.2 Hz, 1H), 7.04 (dd, J=8.4, 2.2 Hz, 1H). LC/MS (m/z): calcd. for C29H44NO5S (M+H)+: 518.7; found: 518.2.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[C:4]([Cl:10])[N:3]=1.C([Li])CCC.[C:16](=[O:18])=[O:17].Cl>C1COCC1>[Cl:1][C:2]1[C:7]([C:16]([OH:18])=[O:17])=[C:6]([O:8][CH3:9])[CH:5]=[C:4]([Cl:10])[N:3]=1
Reactant: O=C=O
Reactant: COc1cc(Cl)nc(Cl)c1
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COc1cc(Cl)nc(Cl)c1C(=O)O
Temperature: 25 °C
Yield: 70 %

Procedure:
To a solution of 4.0 g (22.5 mmol) 2,6-dichloro-4-methoxy-pyridine in THF (20 ml) was added 10.0 ml (2.47 M in hexane, 24.7 mmol) n-butyllithium at −78° C. After stirring for 1 h at −78° C. excess dry ice was added and the mixture was allowed to warm to RT. Then the mixture was acidified with 6N aqueous hydrochlorid acid to pH 3-4 followed by extraction with EtOAc. The organic layer was dried over Na2SO4 and concentrated in vacuo. Purification of the residue by CC (hexane/EtOAc 4:1) provided 3.5 g (15.8 mmol, 70%) 2,6-dichloro-4-methoxy-pyridine-3-carboxylic acid.
Reaction SMILES: [CH2:1]([C:3]([C:8]1[C:9]([CH2:14][OH:15])=[N:10][CH:11]=[CH:12][CH:13]=1)([O:6][CH3:7])[CH2:4][CH3:5])[CH3:2]>O=[Mn]=O.C(Cl)Cl>[CH2:1]([C:3]([C:8]1[C:9]([CH:14]=[O:15])=[N:10][CH:11]=[CH:12][CH:13]=1)([O:6][CH3:7])[CH2:4][CH3:5])[CH3:2]
Reactant: CCC(CC)(OC)c1cccnc1CO
Agent: O=[Mn]=O
Solvent: ClCCl
Product: CCC(CC)(OC)c1cccnc1C=O
Reaction time: 16 h
Yield: 46 %

Procedure:
Activated MnO2 (0.458 g, 5.26 mmol) was added to a stirred solution of [3-(1-ethyl-1-methoxy-propyl)-pyridin-2-yl]-methanol (0.110 g, 0.526 mmolbin CH2Cl2 (3 mL). The mixture was stirred for 16 h, and then filtered through a celite cake. The filtrate was concentrated by evaporation under vacuum, and the residue was purified by flash chromatography on a silica gel column (CH2Cl2), affording 3-(1-ethyl-1-methoxy-propyl)-pyridine-2-carbaldehyde as yellow oil (0.086 g, 46%). 1H NMR (CDCl3) δ 0.71 (t, 6H, J=7.5 Hz), 1.83-2.09 (m, 4H) 3.16 (s, 3H), 7.37 (dd, 1H, J=7.7, 4.8 Hz), 7.62 (dd, 1H, J=7.8, 1.5 Hz), 8.65 (dd, 1H, J=4.8, 1.5 Hz), 10.57 (s, 1H).
Reaction SMILES: [C:1]1(=[O:11])[NH:5][C:4](=[O:6])[C:3]2=[CH:7][CH:8]=[CH:9][CH:10]=[C:2]12.NN.[F:14][C:15](=[C:19]([F:21])[F:20])[CH2:16][CH2:17]N.Br>>[F:14][C:15](=[C:19]([F:21])[F:20])[CH2:16][CH2:17][N:5]1[C:1](=[O:11])[C:2]2=[CH:10][CH:9]=[CH:8][CH:7]=[C:3]2[C:4]1=[O:6]
Reactant: NCCC(F)=C(F)F
Reactant: O=C1NC(=O)c2ccccc21
Agent: Br
Agent: NN
Product: O=C1c2ccccc2C(=O)N1CCC(F)=C(F)F
Yield: 80 %

Procedure:
The compounds of the formula above wherein X, Y, and Z are F and Q is a --CH2N-- derivative are generally prepared by first obtaining the desired trifluoroalkenylamine, which when n equals 1 is 3,4,4-trifluoro-3-butene-1-amine. One method of preparing this compound is disclosed in Example 6 of U.S. Pat. No. 4,952,580, the full text of which is incorporated herein by reference. The present invention provides an improved and novel method of making this compound. Surprisingly, 4-bromo-1,1,2-trifluoro-1-butene, which is commercially available, may be directly converted by first reacting it with a tosylate salt, for example, silver tosylate, a mesylate salt, or other sulfonic acid leaving group. The resulting intermediate, for example, 3,4,4-trifluoro-3-butene-1-tosylate or 3,4,4-trifluoro-3-butene-1-mesylate, is a novel compound. This step is followed by conversion to the phthalimide derivative using a phthalimide salt, such as potassium. Advantageously, this may be accomplished without first isolating the tosylate or mesylate intermediate. The phthalimide is then converted to the desired amine by reaction with hydrazine. This novel process for preparing 3,4,4-trifluoro-3-butene-1-amine has the advantage of having an improved yield compared to the prior reported synthesis method, which is at least partially attributable to avoiding the elimination of hydrogen bromide during the conversion of the bromo compound. N-(3,4,4-trifluoro-3-butenyl)phthalimide is thus produced in greater than 80 percent yield and converted to the desired amine in greater than 85 percent yield. Also, advantageously, when silver tosylate is the reactant chosen to provide the leaving group, the silver ions may be recovered and silver tosylate regenerated.
Reaction SMILES: [NH2:1][C:2]1[C:7]2[C:8]([C:11]3[CH:16]=[CH:15][C:14]([NH:17][C:18]([C:20]4[N:21]([CH3:29])[C:22]5[C:27]([CH:28]=4)=[CH:26][CH:25]=[CH:24][CH:23]=5)=[O:19])=[C:13]([O:30][CH3:31])[CH:12]=3)=[CH:9][S:10][C:6]=2[C:5]([C:32]2[S:33][C:34]([CH:37]=O)=[CH:35][CH:36]=2)=[CH:4][N:3]=1.[NH:39]1[CH2:44][CH2:43][O:42][CH2:41][CH2:40]1>>[NH2:1][C:2]1[C:7]2[C:8]([C:11]3[CH:16]=[CH:15][C:14]([NH:17][C:18]([C:20]4[N:21]([CH3:29])[C:22]5[C:27]([CH:28]=4)=[CH:26][CH:25]=[CH:24][CH:23]=5)=[O:19])=[C:13]([O:30][CH3:31])[CH:12]=3)=[CH:9][S:10][C:6]=2[C:5]([C:32]2[S:33][C:34]([CH2:37][N:39]3[CH2:44][CH2:43][O:42][CH2:41][CH2:40]3)=[CH:35][CH:36]=2)=[CH:4][N:3]=1
Reactant: COc1cc(-c2csc3c(-c4ccc(C=O)s4)cnc(N)c23)ccc1NC(=O)c1cc2ccccc2n1C
Reactant: C1COCCN1
Product: COc1cc(-c2csc3c(-c4ccc(CN5CCOCC5)s4)cnc(N)c23)ccc1NC(=O)c1cc2ccccc2n1C

Procedure:
N-{4-[4-amino-7-(5-formylthien-2-yl)thieno[3,2-c]pyridin-3-yl]-2-methoxyphenyl}-1-methyl-1H-indole-2-carboxamide (80.0 mg, 0.149 mmol) and morpholine (51.7 μL, 0.595 mmol) were reacted according to General Procedure B followed by flash chromatography purification to furnish the title compound as a light yellow powder. (1.3 mg, 0.0021 mmol): LCMS (Conditions a): MH−=608.0, RT =4.35 minutes; 1H NMR (DMSO-d6, 400 MHz) δ 9.50 (s, 1H), 8.08 (s, 1H), 8.00 (d, J=8.2 Hz, 1H), 7.70 (d, J=8.0 Hz, 1H), 7.63 (s, 1H), 7.59 (dd, J=8.5, 0.70 Hz, 1H), 7.34 (m, 1H), 7.31 (m, 1H), 7.22 (d, J=1.8 Hz, 1H), 7.14 (d, J=7.8 Hz, 2H), 7.08–7.12 (m, 1H), 7.05 (d, J=3.5 Hz, 1H), 5.69 (br, 2H), 4.04 (s, 3H), 3.92 (s, 3H), 3.72 (s, 2H), 3.61 (t, J=4.5 Hz, 4H), 2.46 (m, 4H).
Reaction SMILES: [CH2:1](O)[CH2:2][CH2:3]/[CH:4]=[CH:5]\[CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1C(=O)N([Br:38])C(=O)C1>CN(C=O)C>[Br:38][CH2:1][CH2:2][CH2:3]/[CH:4]=[CH:5]\[CH2:6][CH2:7][CH2:8][CH2:9][CH3:10]
Reactant: O=C1CCC(=O)N1Br
Reactant: CCCCC/C=C\CCCO
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Product: CCCCC/C=C\CCCBr
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 87.6 %

Procedure:
To a solution of cis-dec-4-en-1-ol (1.00 g, 6.41 mmol) in DMF (15 mL) was added triphenylphosphine (1.87 g, 7.13 mmol). The solution was cooled to 0° C. and NBS (1.23 g, 6.91 mmol) was added in portions. After stirring for 30 min at room temperature, the reaction was quenched with methanol (0.6 mL). The solution was diluted with ether (60 mL), washed with water, saturated aqueous NaHCO3 and brine successively. The organic layer was dried and concentrated. The residue was purified by flash chromatography on silica gel, eluting with hexane to afford cis-1-bromo-dec-4-ene (1.23 g, 96%) as a colorless oil: 1H NMR (300 MHz, CDCl3) δ 5.38 (1H, m), 5.29 (1H, m), 3.39 (2H, t, J=6.9 Hz), 2.17 (2H, m), 2.03 (2H, m), 1.88 (2H, m), 1.28 (6H, m), 0.87 (3H, t, J=6.6 Hz); 13C NMR (75 MHz, CDCl3) δ 131.87, 127.39, 33.65, 32.90, 31.76, 29.63, 27.51, 25.87, 22.83, 14.35.
Reaction SMILES: C[O:2][C:3](=O)[CH2:4][CH2:5][CH2:6][N:7]1[CH2:11][CH2:10][CH2:9][C@H:8]1[CH2:12][O:13][C:14]1[CH:19]=[CH:18][C:17]([CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[CH:16][CH:15]=1.[H-].C([Al+]CC(C)C)C(C)C.CC(O)=O>C1(C)C=CC=CC=1>[CH2:20]([C:17]1[CH:18]=[CH:19][C:14]([O:13][CH2:12][C@@H:8]2[CH2:9][CH2:10][CH2:11][N:7]2[CH2:6][CH2:5][CH2:4][CH2:3][OH:2])=[CH:15][CH:16]=1)[C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1
Reactant: COC(=O)CCCN1CCC[C@H]1COc1ccc(Cc2ccccc2)cc1
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: CC(=O)O
Solvent: Cc1ccccc1
Product: OCCCCN1CCC[C@H]1COc1ccc(Cc2ccccc2)cc1
Yield: 64.8 %

Procedure:
To a solution of 4-[(S)-2-(4-benzyl-phenoxymethyl)-pyrrolidin-1-yl]-butyric acid methyl ester (0.37 g, 1 mmol) in toluene (2 mL) was added 1.5M diisobutylaluminum hydride in toluene (2 mL, 3 mmol) at −60° C. and then stirred the reaction at −30 to −20° C. for 2 h, followed by addition of 15% AcOH dropwise. The reaction was stirred at room temperature for 30 minutes and formed white solid was filtered and washed with acetone. The filtrate was concentrated in vacuo to yield the title compound as a white solid (0.22 g, 79%); MS; m/z 340.8 (M+H). 1H NMR (400 HMz, CDCl3) δ 1.61-2.26 (m, 8H), 2.79 (m, 1H), 2.85 (m, 1H), 3.25 (m, 2H), 3.42 (m, 2H), 3.54 (m, 1H). 3.68 (m, 1H), 3.75 (m, 1H), 3.92 (s, 2H), 6.82 (d, J=8.8 Hz, 2H), 7.09-7.21 (m, 5H), 7.28 (m, 2H).
Reaction SMILES: [CH3:1][CH:2]1[CH2:7][CH2:6][CH2:5][CH2:4][N:3]1[C:8]1[C:9](=[O:22])[NH:10][C:11]2[C:16]([N:17]=1)=[CH:15][C:14]([C:18]([O:20][CH3:21])=[O:19])=[CH:13][CH:12]=2.N1C=CC=CC=1.[O:29](S(C(F)(F)F)(=O)=O)[S:30]([C:33]([F:36])([F:35])[F:34])(=O)=[O:31]>ClCCl>[CH3:1][CH:2]1[CH2:7][CH2:6][CH2:5][CH2:4][N:3]1[C:8]1[C:9]([O:22][S:30]([C:33]([F:36])([F:35])[F:34])(=[O:31])=[O:29])=[N:10][C:11]2[C:16]([N:17]=1)=[CH:15][C:14]([C:18]([O:20][CH3:21])=[O:19])=[CH:13][CH:12]=2
Reactant: COC(=O)c1ccc2[nH]c(=O)c(N3CCCCC3C)nc2c1
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: ClCCl
Solvent: c1ccncc1
Product: COC(=O)c1ccc2nc(OS(=O)(=O)C(F)(F)F)c(N3CCCCC3C)nc2c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of methyl 3-(2-methylpiperidin-1-yl)-2-oxo-1,2-dihydroquinoxaline-6-carboxylate (520 mg, 1.73 mmol) in dichloromethane (60 ml) was added pyridine (690 mg, 8.72 mmol) followed by the addition of Tf2O (1.22 g, 4.32 mmol), and the resulting solution was stirred overnight at room temperature. The reaction was quenched by the addition of ice-water (200 ml) and extracted with dichloromethane (2×30 ml). The organic layers were combined, dried over anhydrous magnesium sulfate and concentrated in vacuo to afford methyl 3-(2-methylpiperidin-1-yl)-2-(trifluoromethylsulfonyloxy)quinoxaline-6-carboxylate as red oil (880 mg, crude).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[CH3:10].C(Cl)(Cl)(Cl)Cl.C1C(=O)N([Br:23])C(=O)C1>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[CH2:10][Br:23]
Reactant: O=C1CCC(=O)N1Br
Reactant: COc1ccc(Br)c(C)c1
Solvent: ClC(Cl)(Cl)Cl
Product: COc1ccc(Br)c(CBr)c1
Temperature: 25 °C

Procedure:
To a solution of 173 g (0.86 mol) of 1-bromo-4-methoxy-2-methylbenzene in 850 ml of CCl4 153 g (0.86 mol) of NBS and 1.0 g of (PhCOO)2 were added at room temperature. This mixture was refluxed for 16 h, cooled to room temperature, and then filtered through glass frit (G2). The precipitate was additionally washed by 2×150 ml of CCl4. The combined filtrate was evaporated to dryness, and the residue was triturated with 600 ml of n-hexane. The precipitate was filtered off (G3 glass frit), washed by 50 ml of n-hexane, and dried in vacuum. This procedure gave 121 g of the title product. Additional amount of the product was obtained by evaporation of a mother liquor followed by crystallization of the residue from 200 ml of n-hexane at −25° C. In total, 157 g (65%; or 56% overall yield for two stages) of 1-bromo-2-(bromomethyl)-4-methoxybenzene has been isolated.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][CH:6]=1)(=[O:3])[CH3:2].[H-].[Na+].S(O[CH2:25][CH:26]1[CH2:31][CH2:30][CH:29]=[CH:28][O:27]1)(C1C=CC(C)=CC=1)(=O)=O.O>CN(C)C=O>[C:1]([NH:4][C:5]1[CH:10]=[CH:9][C:8]([O:11][CH2:25][CH:26]2[CH2:31][CH2:30][CH:29]=[CH:28][O:27]2)=[CH:7][CH:6]=1)(=[O:3])[CH3:2]
Reactant: Cc1ccc(S(=O)(=O)OCC2CCC=CO2)cc1
Reactant: CC(=O)Nc1ccc(O)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(=O)Nc1ccc(OCC2CCC=CO2)cc1
Reaction time: 4.5 h
Yield: 78.1 %

Procedure:
A solution of 831 mg of 4-acetamidophenol in 5 ml of dimethylformamide was stirred for 30 minutes at room temperature with 240 mg of 55% sodium hydride. 1.34 g of 2-tosyloxymethyl-3,4-dihydro-2H-pyran was then added and the mixture was heated, with stirring, at 90°-95° C. for 4.5 hours. The mixture was then poured into water and extracted with diethyl ether. The ethereal extract was washed with water and dried over anhydrous magnesium sulphate, after which the solvent was evaporated off. The residue was purified by column chromatography through silica gel, to give 965 mg of the title compound, melting at 114°-116° C.
Reaction SMILES: [CH3:1][C:2]1[S:3][C:4]([C:8]([OH:10])=O)=[C:5]([CH3:7])[N:6]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.ClN1C(=O)CCC1=O.[CH:38]1([CH2:41][N:42]2[C:50]3[N:49]=[C:48]([CH2:51][C:52]4[CH:57]=[CH:56][C:55]([NH:58][CH3:59])=[CH:54][CH:53]=4)[NH:47][C:46]=3[C:45](=[O:60])[N:44]([CH2:61][C:62]3[CH:67]=[CH:66][CH:65]=[CH:64][C:63]=3[F:68])[C:43]2=[O:69])[CH2:40][CH2:39]1>ClCCl>[CH:38]1([CH2:41][N:42]2[C:50]3[N:49]=[C:48]([CH2:51][C:52]4[CH:53]=[CH:54][C:55]([N:58]([CH3:59])[C:8]([C:4]5[S:3][C:2]([CH3:1])=[N:6][C:5]=5[CH3:7])=[O:10])=[CH:56][CH:57]=4)[NH:47][C:46]=3[C:45](=[O:60])[N:44]([CH2:61][C:62]3[CH:67]=[CH:66][CH:65]=[CH:64][C:63]=3[F:68])[C:43]2=[O:69])[CH2:40][CH2:39]1
Reactant: CNc1ccc(Cc2nc3c([nH]2)c(=O)n(Cc2ccccc2F)c(=O)n3CC2CC2)cc1
Reactant: Cc1nc(C)c(C(=O)O)s1
Agent: O=C1CCC(=O)N1Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: Cc1nc(C)c(C(=O)N(C)c2ccc(Cc3nc4c([nH]3)c(=O)n(Cc3ccccc3F)c(=O)n4CC3CC3)cc2)s1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 47.9 %

Procedure:
A mixture of 2,4-dimethyl-thiazole-5-carboxylic acid (18.1 mg, 0.11 mmol) in dichloromethane (3.0 mL) at 25° C. was treated with triphenylphosphine (33 mg, 0.13 mmol). The reaction was cooled to 0° C. and was treated with N-chlorosuccinimide (19.9 mg, 0.15 mmol). This mixture was stirred at 0° C. for 20 min and then was warmed to 25° C. for 20 min. At this time, the reaction was treated with N-chlorosuccinimide (5.0 mg, 0.04 mmol) and 3-cyclopropylmethyl-1-(2-fluoro-benzyl)-8-(4-methylamino-benzyl)-3,7-dihydro-purine-2,6-dione (100 mg, 0.23 mmol) and was stirred at 25° C. for 2 d. At this time, the reaction was diluted with dichloromethane (100 mL) and then was washed with a saturated aqueous sodium bicarbonate solution (1×20 mL). The organics were dried over magnesium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230–400 mesh, 5:95 methanol/dichloromethane) afforded impure product. The resulting residue was purified by HPLC (15–60% acetonitrile/water (0.075% trifluoroacetic acid in both solvents) over 40 min). Fractions with the desired product were combined and concentrated in vacuo. The resulting residue was diluted with chloroform (100 mL) and was washed with a saturated aqueous sodium bicarbonate solution (25 mL). The aqueous layer was re-extracted with chloroform (1×50 mL). The combined organics were dried over magnesium sulfate, filtered, and concentrated in vacuo. The resulting solid was dried in vacuo for 24 h to afford 2,4-dimethyl-thiazole-5-carboxylic acid {4-[3-cyclopropylmethyl-1-(2-fluoro-benzyl)-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-ylmethyl]-phenyl}-methyl-amide (30.2 mg, 45.8%) as a white solid: EI-HRMS m/e calcd for C30H29N6O3FS (M+H)+ 573.2079, found 573.2083.
Reaction SMILES: [CH3:1][N:2]1[C:11]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=2[C:5](=[O:12])[N:4]2[N:13]=[C:14]([C:16]([NH2:18])=O)[CH:15]=[C:3]12.S(Cl)(Cl)=O>CN(C)C=O>[CH3:1][N:2]1[C:11]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=2[C:5](=[O:12])[N:4]2[N:13]=[C:14]([C:16]#[N:18])[CH:15]=[C:3]12
Reactant: Cn1c2ccccc2c(=O)n2nc(C(N)=O)cc12
Solvent: O=S(Cl)Cl
Solvent: CN(C)C=O
Product: Cn1c2ccccc2c(=O)n2nc(C#N)cc12
Temperature: 57 °C

Procedure:
A mixture of 5.3 g of 4,9-dihydro-4-methyl-9-oxo-pyrazolo[5,1-b]quinazoline-2-carboxamide, 5.2 g of thionyl chloride and 65 ml of dimethylformamide is stirred and heated at 57° C. for 18 hrs, then evaporated at reduced pressure. The residue is stirred with 600 ml of water and the resulting solid 4,9-dihydro-4-methyl-9-oxo-pyrazolo[5,1-b]quinazoline-2-carbonitrile is collected by filtration, washed with water and dried; mp 307°-310° C., after crystallization from dimethylformamide/ethanol.
Reaction SMILES: [CH2:1]([OH:5])[CH:2]([CH3:4])[CH3:3].[C:6](Cl)(=[O:10])[C:7]([Cl:9])=[O:8]>>[CH2:1]([O:5][C:6](=[O:10])[C:7]([Cl:9])=[O:8])[CH:2]([CH3:4])[CH3:3]
Reactant: CC(C)CO
Reactant: O=C(Cl)C(=O)Cl
Product: CC(C)COC(=O)C(=O)Cl
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Isobutanol (191 μL, 2.1 mmol, 1.0 eq.) was added dropwise over 5 minutes to oxalyl chloride (350 μL, 4.14 mmol, 2.0 eq.) at 0° C., and the resulting mixture was stirred at room temperature for 2 hours. The excess oxalyl chloride was removed by rotary evaporation (40° C., 40 mmHg) and used without further purification.
Reaction SMILES: [NH2:1][C:2]([CH3:17])([CH2:5][N:6]1[CH:16]=[C:9]2[N:10]=[C:11]([Br:15])[C:12]([Br:14])=[CH:13][C:8]2=[N:7]1)[C:3]#[N:4].[F:18][C:19]([F:30])([F:29])[C:20]1[CH:28]=[CH:27][C:23]([C:24](Cl)=[S:25])=[CH:22][CH:21]=1>>[C:3]([C:2]([NH:1][C:24](=[S:25])[C:23]1[CH:22]=[CH:21][C:20]([C:19]([F:18])([F:29])[F:30])=[CH:28][CH:27]=1)([CH3:17])[CH2:5][N:6]1[CH:16]=[C:9]2[N:10]=[C:11]([Br:15])[C:12]([Br:14])=[CH:13][C:8]2=[N:7]1)#[N:4]
Reactant: CC(N)(C#N)Cn1cc2nc(Br)c(Br)cc2n1
Reactant: FC(F)(F)c1ccc(C(=S)Cl)cc1
Product: CC(C#N)(Cn1cc2nc(Br)c(Br)cc2n1)NC(=S)c1ccc(C(F)(F)F)cc1

Procedure:
Using a procedure similar to that described in Example 1, except using 2-amino-3-(5,6-dibromo-2H-pyrazolo[4,3-b]pyridin-2-yl)-2-methylpropionitrile (60 mg, described in Example 195) and 4-trifluoromethylthiobenzoyl chloride (28 μL), the title compound was isolated as a white solid (44 mg, 47%). MS (ES): M/Z [M+H]=562. 1H NMR: (400 MHz, DMSO-d6): 1.68 (s, 3H), 5.13 (d, J=13.2 Hz, 1H), 5.18 (d, J=13.2 Hz, 1H), 7.88 (d, J=8.4 Hz, 2H), 7.94 (d, J=8.4 Hz, 2H), 8.74 (s, 1H), 8.79 (s, 1H) and 9.04 (s, 1H). 19F NMR (376 MHz, DMSO-d6): −41.9 (s, 3F).
Reaction SMILES: [CH:1]1([NH:4][C:5](=[O:31])[C:6]2[CH:11]=[C:10]([F:12])[C:9]([CH3:13])=[C:8]([C:14]3[CH:15]=[C:16]4[C:21](=[CH:22][CH:23]=3)[C:20](=[O:24])[N:19]([CH2:25][CH:26]3[CH2:28][CH2:27]3)[CH:18]=[C:17]4[CH:29]=O)[CH:7]=2)[CH2:3][CH2:2]1.[OH:32][CH2:33][C@@H:34]1[NH:38][CH2:37][C@@H:36]([NH:39]C(=O)OC(C)(C)C)[CH2:35]1>>[NH2:39][C@@H:36]1[CH2:37][N:38]([CH2:29][C:17]2[C:16]3[C:21](=[CH:22][CH:23]=[C:14]([C:8]4[CH:7]=[C:6]([CH:11]=[C:10]([F:12])[C:9]=4[CH3:13])[C:5]([NH:4][CH:1]4[CH2:3][CH2:2]4)=[O:31])[CH:15]=3)[C:20](=[O:24])[N:19]([CH2:25][CH:26]3[CH2:27][CH2:28]3)[CH:18]=2)[C@@H:34]([CH2:33][OH:32])[CH2:35]1
Reactant: Cc1c(F)cc(C(=O)NC2CC2)cc1-c1ccc2c(=O)n(CC3CC3)cc(C=O)c2c1
Reactant: CC(C)(C)OC(=O)N[C@@H]1CN[C@@H](CO)C1
Product: Cc1c(F)cc(C(=O)NC2CC2)cc1-c1ccc2c(=O)n(CC3CC3)cc(CN3C[C@@H](N)C[C@@H]3CO)c2c1

Procedure:
The title compound was prepared as a solid according to the method of Example 81 using the product of Example 75 step i) and ((3S,5R)-5-hydroxymethyl-pyrrolidin-3-yl)-carbamic acid, tert-butyl ester.
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:6]=[N:7][C:8]([O:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[N:9][CH:10]=1)=[O:4].[Li+].[OH-]>C1COCC1.O>[O:11]([C:8]1[N:7]=[CH:6][C:5]([C:3]([OH:4])=[O:2])=[CH:10][N:9]=1)[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: COC(=O)c1cnc(Oc2ccccc2)nc1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)c1cnc(Oc2ccccc2)nc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 72.5 %

Procedure:
To a solution of 2-phenoxy-pyrimidine-5-carboxylic acid methyl ester (0.5 g, 2.17 mmol) in THF (10 mL) and water (5 mL) is added LiOH (105 mg, 4.35 mmol). The reaction is stirred at 0° C. for 1 h. The THF is evaporated and the aqueous reissue is washed with ether, acidified with 2 M aqueous HCl. The resulting precipitate is filtered and dried to afford 2-phenoxy-pyrimidine-5-carboxylic acid (0.34 g, 73%) as a solid. MS: 217 (M+H); 1H NMR (300 MHz, CDCl3): δ 7.20-7.35 (m, 3H), 7.47 (t, 2H) 9.16 (s, 2H).
Reaction SMILES: [C:1]([CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:15](Br)[CH2:16]Br.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[C:1]([C:9]1([C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH2:16][CH2:15]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: BrCCBr
Reactant: CCOC(=O)CC(=O)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCOC(=O)C1(C(=O)c2ccccc2)CC1
Yield: 68.3 %

Procedure:
To 1370 ml of acetonitrile were added ethyl benzoylacetate (49.9 g, 0.26 mol), 1,2-dibromomethane (48.8 g, 0.26 g) and anhydrous potassium carbonate (143.6 g, 1.04 mol) and the mixture was stirred under reflux for 18 h. After cooling, the reaction mixture was filtrated and concentrated. The residual solution (56.3 g) was purified by silica gel column chromatography (ethyl acetate/hexane=1/5) to give the title compound (38.7 g) as a colorless oil (yield 68%).
Reaction SMILES: [CH3:1][NH:2][C:3](=[N:6][N+:7]([O-:9])=[O:8])[S:4][CH3:5].[C:10]([O:13]C(=O)C)(=O)[CH3:11].Cl>N1C=CC=CC=1>[C:10]([N:2]([CH3:1])[C:3](=[N:6][N+:7]([O-:9])=[O:8])[S:4][CH3:5])(=[O:13])[CH3:11]
Reactant: CC(=O)OC(C)=O
Reactant: CNC(=N[N+](=O)[O-])SC
Agent: Cl
Solvent: c1ccncc1
Product: CSC(=N[N+](=O)[O-])N(C)C(C)=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 93.6 %

Procedure:
To a mixture of 0.50 g of 1,2-dimethyl-3-nitroisothiourea and 10 ml of pyridine was dropwise added 1.03 g of acetic anhydride at room temperature. The mixture was stirred at room temperature for 1 hour, and then poured onto 150 ml of 2N hydrochloric acid followed by extraction with 100 ml of chloroform. The chloroform layer was washed with 50 ml of 2N hydrochloric acid and then concentrated to give 0.60 g of 1-acetyl-1,2-dimethyl-3-nitroisothiourea as pale yellow liquid. NMR (CDCl3):2.23(3H, s), 2.52(3H, s), 3.17(3H, s).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:13]=[C:12]([N:14]3[CH:23]([CH3:24])[CH2:22][C:21]4[C:16](=[CH:17][C:18](B5OC(C)(C)C(C)(C)O5)=[CH:19][CH:20]=4)[CH2:15]3)[N:11]=[C:10]([NH2:34])[N:9]=2)[CH2:4][CH2:3]1.Br[C:36]1[N:37]=[C:38]([O:41][CH2:42][CH3:43])[S:39][CH:40]=1>>[CH2:42]([O:41][C:38]1[S:39][CH:40]=[C:36]([C:18]2[CH:17]=[C:16]3[C:21]([CH2:22][CH:23]([CH3:24])[N:14]([C:12]4[CH:13]=[C:8]([N:5]5[CH2:4][CH2:3][N:2]([CH3:1])[CH2:7][CH2:6]5)[N:9]=[C:10]([NH2:34])[N:11]=4)[CH2:15]3)=[CH:20][CH:19]=2)[N:37]=1)[CH3:43]
Reactant: CCOc1nc(Br)cs1
Reactant: CC1Cc2ccc(B3OC(C)(C)C(C)(C)O3)cc2CN1c1cc(N2CCN(C)CC2)nc(N)n1
Product: CCOc1nc(-c2ccc3c(c2)CN(c2cc(N4CCN(C)CC4)nc(N)n2)C(C)C3)cs1

Procedure:
This compound was prepared by using procedures analogous to those described for the synthesis of Example 116 starting from 4-(4-methylpiperazin-1-yl)-6-[3-methyl-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,4-dihydroisoquinolin-2(1H)-yl]pyrimidin-2-amine and 4-bromo-2-ethoxy-1,3-thiazole (Indofine, Cat. No. 08-932). LCMS (M+H)+: m/z=466.2.