Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:3]([C:22]2[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][CH:23]=2)=[C:4]([C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=2)[C:5]2[N:6]([C:8]([C:11]([F:14])([F:13])[F:12])=[N:9][N:10]=2)[N:7]=1.[Si]([O:33][K])(C)(C)C>>[Cl:28][C:25]1[CH:26]=[CH:27][C:22]([C:3]2[C:2](=[O:33])[NH:7][N:6]3[C:8]([C:11]([F:13])([F:12])[F:14])=[N:9][N:10]=[C:5]3[C:4]=2[C:15]2[CH:16]=[CH:17][C:18]([Cl:21])=[CH:19][CH:20]=2)=[CH:23][CH:24]=1
Reactant: FC(F)(F)c1nnc2c(-c3ccc(Cl)cc3)c(-c3ccc(Cl)cc3)c(Cl)nn12
Reactant: C[Si](C)(C)O[K]
Product: O=c1[nH]n2c(C(F)(F)F)nnc2c(-c2ccc(Cl)cc2)c1-c1ccc(Cl)cc1

Procedure:
The title compound was synthesized by reacting 6-chloro-7,8-bis(4-chlorophenyl)-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine with TMSOK using the procedures described above. 1HNMR (DMSO, 400 Hz): 7.48 (2H, d), 7.38-7.7.42 (4H, m), 7.25 (2H, d). 13CNMR (DMSO, 400 Hz) 160.88, 145.91, 137.00, 135.11, 133.90, 132.94, 132.10, 131.07, 129.98, 128.00 127.13, 118.30(q).
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:5]2[CH:6](O)[CH2:7][O:8][C:4]=2[CH:3]=1.Cl>C1COCC1.[Cl-].[Na+].O>[O:8]1[C:4]2[CH:3]=[C:2]([OH:1])[CH:11]=[CH:10][C:5]=2[CH:6]=[CH:7]1
Reactant: Oc1ccc2c(c1)OCC2O
Agent: Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: Oc1ccc2ccoc2c1
Temperature: 65 °C
Reaction time: 2 h

Procedure:
To a stirred solution of 6-hydroxy-2,3-dihydrobenzofuran-3-ol (35.2 g, 0.2 mol) in THF (1.3 L) was added hydrochloric acid (323 mL, 1.0 N). The mixture was stirred at 65° C. for 2 h. After cooling to room temperature, it was diluted with brine (2.0 L), extracted with ethyl acetate (4.0 L), dried over magnesium sulfate, filtered and concentrated. The crude product was purified on a silica gel column, eluting with ethyl acetate (1-30%) in heptane. The final product was collected as light brown solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=O)[CH2:9][CH2:10][CH2:11][N:12]2[CH:16]=[CH:15][N:14]=[CH:13]2)=[CH:4][CH:3]=1.[ClH:18].Cl.[NH2:20][CH2:21][CH2:22][O:23][NH2:24].N1C=CC=CC=1>C(O)C>[ClH:18].[ClH:18].[NH2:20][CH2:21][CH2:22][O:23][N:24]=[C:8]([C:5]1[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=1)[CH2:9][CH2:10][CH2:11][N:12]1[CH:16]=[CH:15][N:14]=[CH:13]1
Reactant: O=C(CCCn1ccnc1)c1ccc(F)cc1
Reactant: NCCON
Agent: Cl
Solvent: CCO
Solvent: c1ccncc1
Product: NCCON=C(CCCn1ccnc1)c1ccc(F)cc1
Reaction time: 4 h
Yield: 113.7 %

Procedure:
A mixture of 1-(4-fluorophenyl)-4-(1-(1H)-imidazolyl)-1-butanone (3.00 g), O-(2-aminoethyl)hydroxylamine dihydrochloride (2.31 g), 3 equivalents of pyridine, and absolute ethanol (75 ml) was heated under reflux, under nitrogen, with stirring, for four hrs. The reaction mixture was evaporated, toluene was added and evaporated. The residue was partitioned between 10% sodium hydroxide solution and ethyl acetate. The layers were separated and the aqueous phase extracted with ethyl acetate. The combined organic extracts were dried over anhydrous sodium sulfate, filtered, and the filtrate was evaporated. The residue was purified by flash chromatography (180:19:1 dichloromethane/methanol/ammonium hydroxide). The appropriate fractions were collected and concentrated. The residue was dissolved in absolute ethanol and treated with ethereal hydrogen chloride. Diethyl ether was added. The precipitate was collected and recrystallized from absolute ethanol to give 3.2 g (68%) of product, mp 237°-238° C. (dec).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:9]=[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][N:11]2[CH:16]=1.C([Li])CCC.[CH3:22][S:23]SC>CCOCC>[CH3:22][S:23][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:9]=[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][N:11]2[CH:16]=1
Reactant: CSSC
Reactant: Brc1ccccc1-c1cn2ccccc2n1
Agent: [Li]CCCC
Solvent: CCOCC
Product: CSc1ccccc1-c1cn2ccccc2n1
Temperature: 25 °C

Procedure:
The product of step (a) above (546 mg) was dissolved in dry ether (10 ml) and stirred under a nitrogen atmosphere at -60°. A solution of n-butyl lithium (1.25 ml of 1.6 M) was added dropwise. After stirring for 5 minutes methyl disulphide (179 ml) was added dropwise and the mixture stirred for a further 45 minutes. The mixture was allowed to warm up to room temperature then quenched with water. The layers were separated and the aqueous layer extracted with ethyl acetate. The combined organic solution was washed with water and brine then dried and evaporated to leave the sub-title compound as a gum. MS MW 240 bp 207.
Reaction SMILES: [ClH:1].[NH:2]1[CH2:7][CH2:6][CH2:5]NN1.C(N)CCC.[S:13]1[CH:17]=[CH:16][CH:15]=[C:14]1CCN>CN(C)C=O>[ClH:1].[S:13]1[C:14]2[CH2:15][CH2:16][NH:2][CH2:7][C:6]=2[CH:5]=[CH:17]1
Reactant: NCCc1cccs1
Reactant: C1CNNNC1
Agent: Cl
Solvent: CCCCN
Solvent: CN(C)C=O
Product: c1cc2c(s1)CCNC2
Temperature: 45 °C
Yield: 65 %

Procedure:
To 73 ml dimethylformamide heated at 45° C. in which are dissolved 0.45 mole gaseous hydrochloric acid, is added, over 25 minutes, a mixture of 17 g (0.2 M) s.hexahydrotriazine of n. n.butylamine/and 26 g 2-(2-thienyl)ethylamine. The temperature of the medium is maintained at 45° C. throughout the addition by means of a cold water bath. The desired product precipitates out at the end of the addition. Filtration gives 22.16 g 4,5,6,7-tetrahydrothieno[3,2-c]pyridine hydrochloride (Yield: 65%).
Reaction SMILES: [CH3:1][C:2]1[C:7]([NH2:8])=[CH:6][CH:5]=[C:4]([N:9]2[CH2:13][CH2:12][C@H:11]([N:14]3[CH2:18][CH2:17][CH2:16][C@@H:15]3[CH3:19])[CH2:10]2)[N:3]=1.[F:20][C:21]1[CH:22]=[C:23]([S:28](Cl)(=[O:30])=[O:29])[CH:24]=[CH:25][C:26]=1[F:27]>ClCCl.N1C=CC=CC=1>[F:20][C:21]1[CH:22]=[C:23]([S:28]([NH:8][C:7]2[C:2]([CH3:1])=[N:3][C:4]([N:9]3[CH2:13][CH2:12][C@H:11]([N:14]4[CH2:18][CH2:17][CH2:16][C@@H:15]4[CH3:19])[CH2:10]3)=[CH:5][CH:6]=2)(=[O:29])=[O:30])[CH:24]=[CH:25][C:26]=1[F:27]
Reactant: O=S(=O)(Cl)c1ccc(F)c(F)c1
Reactant: Cc1nc(N2CC[C@H](N3CCC[C@@H]3C)C2)ccc1N
Solvent: c1ccncc1
Solvent: ClCCl
Product: Cc1nc(N2CC[C@H](N3CCC[C@@H]3C)C2)ccc1NS(=O)(=O)c1ccc(F)c(F)c1
Yield: 35.8 %

Procedure:
The title compound was synthesized substantially in the same manner as Example 3 by coupling of 2-methyl-6-((2S,3′S)-2-methyl-[1,3′]bipyrrolidinyl-1′-yl)-pyridin-3-ylamine (0.025 g, 0.096 mmol) with 3,4-difluorobenzenesulfonyl chloride (0.061 g, 0.288 mmol) in dichloromethane (3 mL) and pyridine (0.5 mL) to obtain 0.015 g (36%) of the title compound.
Reaction SMILES: Cl[CH2:2][C:3]1[O:4][C:5]2[CH:11]=[CH:10][C:9]([C:12]([F:15])([F:14])[F:13])=[CH:8][C:6]=2[N:7]=1.Cl.[N+:17]([C:20]1[CH:25]=[CH:24][C:23]([NH:26][CH:27]2[CH2:32][CH2:31][CH:30]([O:33][CH2:34][C:35]([N:37]3[CH2:42][CH2:41][NH:40][CH2:39][CH2:38]3)=[O:36])[CH2:29][CH2:28]2)=[CH:22][C:21]=1[C:43]([F:46])([F:45])[F:44])([O-:19])=[O:18].C(=O)([O-])[O-].[K+].[K+].CN(C=O)C>CCOC(C)=O>[N+:17]([C:20]1[CH:25]=[CH:24][C:23]([NH:26][CH:27]2[CH2:28][CH2:29][CH:30]([O:33][CH2:34][C:35]([N:37]3[CH2:42][CH2:41][N:40]([CH2:2][C:3]4[O:4][C:5]5[CH:11]=[CH:10][C:9]([C:12]([F:15])([F:14])[F:13])=[CH:8][C:6]=5[N:7]=4)[CH2:39][CH2:38]3)=[O:36])[CH2:31][CH2:32]2)=[CH:22][C:21]=1[C:43]([F:46])([F:45])[F:44])([O-:19])=[O:18]
Reactant: FC(F)(F)c1ccc2oc(CCl)nc2c1
Reactant: O=C(COC1CCC(Nc2ccc([N+](=O)[O-])c(C(F)(F)F)c2)CC1)N1CCNCC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: O=C(COC1CCC(Nc2ccc([N+](=O)[O-])c(C(F)(F)F)c2)CC1)N1CCN(Cc2nc3cc(C(F)(F)F)ccc3o2)CC1
Temperature: 100 °C

Procedure:
A mixture of 2-chloromethyl-5-trifluoromethyl-benzoxazole (50 mg, 0.214 mmol), 2-[4-(4-Nitro-3-trifluoromethyl-phenylamino)-cyclohexyloxy]-1-piperazin-1-yl-ethanone hydrochloride (100 mg, 0.214 mmol), potassium carbonate (60 mg, 0.428 mmol), and DMF (1 mL) was heated at 100° C. for two hours before the reaction mixture was cooled, diluted with EtOAc (60 mL), washed with water (2×40 mL), washed with brine (1×40 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure to an orange residue that was purified by silica gel chromatography, eluting with a gradient of 0 to 100% EtOAc in heptanes, to provide 2-[4-(4-nitro-3-trifluoromethyl-phenylamino)-cyclohexyloxy]-1-[4-(5-trifluoromethyl-benzooxazol-2-ylmethyl)-piperazin-1-yl]-ethanone as a stiff, orange solid (69 mg, 51%). (CI, m/z): [M+H]+ 360; 1H NMR (400 MHz, DMSO-d6): δ 8.17 (s, 1H), 8.05 (d, J=9.23 Hz, 1H), 7.97 (d, J=8.54 Hz, 1H), 7.77 (dd, J=8.57, 1.44 Hz, 1H), 7.43 (d, J=7.71 Hz, 1H), 7.06 (s, 1H), 6.84 (dd, J=9.30, 2.51 Hz, 1H), 3.99 (s, 2H) 4.12 (s, 2H), 3.45 (br s, 5H), 2.52-2.64 (m, 4H), 1.95-2.04 (m, 2H), 1.92 (d, J=10.59 Hz, 2H), 1.28-1.40 (m, 2H), 1.19-1.27 (m, 2H); 19F NMR (376 MHz, DMSO-d6): δ ppm −59.45 (s, 3F)-59.17 (s, 3F).
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[Cl:25][C:26]1[CH:30]=[C:29]([CH:31]=[O:32])[NH:28][C:27]=1[C:33]([OH:35])=O.[NH2:36][CH2:37][C:38]1[C:39]([F:55])=[C:40]([O:45][C:46]2[CH:47]=[C:48]([CH:51]=[C:52]([Cl:54])[CH:53]=2)[C:49]#[N:50])[C:41]([Cl:44])=[CH:42][CH:43]=1.CCN(C(C)C)C(C)C>CN(C=O)C>[Cl:25][C:26]1[CH:30]=[C:29]([CH:31]=[O:32])[NH:28][C:27]=1[C:33]([NH:36][CH2:37][C:38]1[CH:43]=[CH:42][C:41]([Cl:44])=[C:40]([O:45][C:46]2[CH:47]=[C:48]([C:49]#[N:50])[CH:51]=[C:52]([Cl:54])[CH:53]=2)[C:39]=1[F:55])=[O:35]
Reactant: N#Cc1cc(Cl)cc(Oc2c(Cl)ccc(CN)c2F)c1
Reactant: O=Cc1cc(Cl)c(C(=O)O)[nH]1
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: CN(C)C=O
Product: N#Cc1cc(Cl)cc(Oc2c(Cl)ccc(CNC(=O)c3[nH]c(C=O)cc3Cl)c2F)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 16 %

Procedure:
HATU (0.061 g, 0.161 mmol) was added to a solution of 3-chloro-5-formyl-1H-pyrrole-2-carboxylic acid (0.028 g, 0.161 mmol), 3-{[3-(aminomethyl)-6-chloro-2-fluorophenyl]oxy}-5-chlorobenzonitrile (0.050 g, 0.161 mmol) and DIPEA (0.028 mL, 0.161 mmol) in DMF (2 mL). The solution was stirred overnight at RT. The reaction mixture was partitioned between water and EtOAc. The organic layer was washed with a 15% Na2CO3 solution and dried over MgSO4. The solid was filtered off and the solvent was evaporated. Purification was accomplished by silica gel column chromatography (EtOAc/hexanes) to give an orange film which was triturated in acetone to afford the title compound (0.012 g, 15%) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 12.88 (s, 1H), 9.57 (s, 1H), 8.53-8.71 (m, 1H), 7.74-7.86 (m, 1H), 7.47-7.52 (m, 2H), 7.38-7.46 (m, 2H), 7.04 (s, 1H), 4.52 (d, 1H). LCMS: m/z 466.2 (M+1).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:12]([CH2:13][CH2:14][C:15]3[S:16][C:17]([C:20]([OH:22])=O)=[CH:18][N:19]=3)=[C:11]([CH3:23])[O:10][N:9]=2)=[N:6][CH:7]=1.[CH2:24]([CH2:26][NH2:27])[OH:25]>>[OH:25][CH2:24][CH2:26][NH:27][C:20]([C:17]1[S:16][C:15]([CH2:14][CH2:13][C:12]2[C:8]([C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:7][N:6]=3)=[N:9][O:10][C:11]=2[CH3:23])=[N:19][CH:18]=1)=[O:22]
Reactant: NCCO
Reactant: Cc1onc(-c2ccc(F)cn2)c1CCc1ncc(C(=O)O)s1
Product: Cc1onc(-c2ccc(F)cn2)c1CCc1ncc(C(=O)NCCO)s1
Yield: 41 %

Procedure:
As described for example 40c, 2-{2-[3-(5-fluoro-pyridin-2-yl)-5-methyl-isoxazol-4-yl]-ethyl}-thiazole-5-carboxylic acid (67 mg, 0.20 mmol) was converted, using ethanolamine instead of 4-aminotetrahydropyran, to the title compound (65 mg, 41%) which was obtained as a white solid. MS: m/e=377.2 [M+H]+.
Reaction SMILES: [CH2:1]([CH:3]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([F:17])[CH:15]=2)[C:10]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=2[N:4]1[S:18]([C:21]1[CH:26]=[CH:25][C:24]([OH:27])=[CH:23][CH:22]=1)(=[O:20])=[O:19])[CH3:2].N1C=CC=CC=1.[C:34](Cl)(=[O:37])[CH2:35][CH3:36]>ClCCl>[C:34]([O:27][C:24]1[CH:23]=[CH:22][C:21]([S:18]([N:4]2[CH:3]([CH2:1][CH3:2])[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([F:17])[CH:15]=3)[C:10]3[CH:9]=[CH:8][CH:7]=[CH:6][C:5]2=3)(=[O:20])=[O:19])=[CH:26][CH:25]=1)(=[O:37])[CH2:35][CH3:36]
Reactant: CCC(=O)Cl
Reactant: CCC1c2cc(F)ccc2-c2ccccc2N1S(=O)(=O)c1ccc(O)cc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCC(=O)Oc1ccc(S(=O)(=O)N2c3ccccc3-c3ccc(F)cc3C2CC)cc1
Temperature: 25 °C
Yield: 77 %

Procedure:
A stirred solution of 4-[(6-ethyl-8-fluorophenanthridin-5(6H)-yl)sulfonyl]phenol (Example 40, Step d, 0.06 g, 0.16 mmol) in dichloromethane (2 mL) was treated sequentially with pyridine (0.05 mL, 0.63 mmol) and propionyl chloride (0.03 mL, 0.3 mmol). After stirring for twelve hours at room temperature, the reaction was quenched with a saturated, aqueous, sodium bicarbonate solution (50 mL). The separated aqueous phase was extracted with dichloromethane (3×10 mL). The combined organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to a crude product. The crude product was purified by flash column chromatography on silica gel, eluting with a mixture of ethyl acetate-hexane (1:9 to 1:4 gradient) to yield the title compound as a white solid (0.05, 77%), m.p. 111-112° C.;
Reaction SMILES: C([Li])CCC.[CH3:6][O:7][C:8]([CH2:10]P(OC)(OC)=O)=[O:9].[CH2:17]([C@H:21]1[CH2:26][CH2:25][C@H:24]([C:27]2[CH:32]=[CH:31][C:30]([C:33]3[CH:38]=[CH:37][C:36]([CH:39]=O)=[CH:35][CH:34]=3)=[CH:29][CH:28]=2)[CH2:23][CH2:22]1)[CH2:18][CH:19]=[CH2:20]>O1CCCC1>[CH2:17]([C@H:21]1[CH2:22][CH2:23][C@H:24]([C:27]2[CH:32]=[CH:31][C:30]([C:33]3[CH:38]=[CH:37][C:36](/[CH:39]=[CH:10]/[C:8]([O:7][CH3:6])=[O:9])=[CH:35][CH:34]=3)=[CH:29][CH:28]=2)[CH2:25][CH2:26]1)[CH2:18][CH:19]=[CH2:20]
Reactant: C=CCC[C@H]1CC[C@H](c2ccc(-c3ccc(C=O)cc3)cc2)CC1
Reactant: COC(=O)CP(=O)(OC)OC
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: C=CCC[C@H]1CC[C@H](c2ccc(-c3ccc(/C=C/C(=O)OC)cc3)cc2)CC1
Temperature: 0 °C
Reaction time: 1.5 h

Procedure:
27.6 ml of a 1.6N butyllithium solution were added dropwise at 0° C. within 10 minutes to a solution of 6.4 ml of trimethyl phosphonoacetate in 50 ml of dry tetrahydrofuran. The mixture was stirred at 0° C. for 1.5 hours and thereafter a solution of 11.5 g of crude trans-4'-[4-(3-butenyl)cyclohexyl]biphenyl-4-carboxaldehyde in 50 ml of dry tetrahydrofuran was added dropwise within 5 minutes at the same temperature. Subsequently, the mixture was warmed slowly to room temperature and left to react for 15 hours. The reaction mixture was then partitioned between methylene chloride and 1N hydrochloric acid and the organic phase was washed with saturated sodium bicarbonate solution and water, dried over magnesium sulphate and evaporated. Chromatography on silica gel with ethyl acetate/hexane (1:9) and subsequent repeated recrystallization from hexane/ethyl acetate gave methyl trans-(E)-3-{4'-[4-(3-butenyl)cyclohexyl]biphenyl-4-yl}acrylate.
Reaction SMILES: IC.[Br:3][C:4]1[CH:9]=[C:8]([C:10]2[C:19]3[C:20]4[CH:26]=[CH:25][CH:24]=[CH:23][C:21]=4[S:22][C:18]=3[C:17](Br)=[C:16]3[C:11]=2[CH:12]=[CH:13][CH:14]=[CH:15]3)[CH:7]=[C:6]([Br:28])[C:5]=1[OH:29].[K].[CH3:31]N(C=O)C>O>[Br:3][C:4]1[CH:9]=[C:8]([C:10]2[C:19]3[C:20]4[CH:26]=[CH:25][CH:24]=[CH:23][C:21]=4[S:22][C:18]=3[CH:17]=[C:16]3[C:11]=2[CH:12]=[CH:13][CH:14]=[CH:15]3)[CH:7]=[C:6]([Br:28])[C:5]=1[O:29][CH3:31]
Reactant: CN(C)C=O
Reactant: Oc1c(Br)cc(-c2c3ccccc3c(Br)c3sc4ccccc4c23)cc1Br
Agent: [K]
Solvent: CI
Solvent: O
Product: COc1c(Br)cc(-c2c3ccccc3cc3sc4ccccc4c23)cc1Br
Reaction time: 3 h
Yield: 91 %

Procedure:
Iodomethane (0.383 mL, 6.16.mmol) was added to a stirred suspension of 2,6-dibromo-4-(6-bromo-benzo[b]naphtho[2,3-d]thiophen-11-yl)-phenol (2.13 g, 4.4 mmol), potassium carbobnate (0.669 g, 4.34 mmol) and DMF (15 mL) at room temperature under a dry nitrogen atmosphere. After 3 h, the reaction mixture was diluted with water and the resulting solid was filtered and washed with water. The solid was taken up in dichloromethane and silica gel (40 mL) was added. The solvent was removed and the adsorbate was flash chromatographed (90:10 petroleum ether:dichloromethane) to provide the title compound as a white solid (2.0 g, 91%): mp 238.5-239.5° C.: NMR (CDCl3); δ 8.36 (ddd, J=8, 1, 1 Hz, 1H), 7.84 (ddd, J=8, 1, 1 Hz, 1H), 7.67 (ddd, J=8, 7, 1 Hz, 1H), 7.60 (s, 2H), 7.58 (ddd, J=8, 1, 1 Hz, 1H), 7.50 (ddd, J=8, 7, 1 Hz, 1H), 7.45 (ddd, J=8, 7, 1 Hz, 1H), 7.20 (ddd, J=8, 7, 1 Hz, 1H), 6.80 (ddd, J=8, 1, 1 Hz, 1H), 4.11 (s, 3H, CH3); MS (EI): [M+], 3 bromine isotope pattern, 574 (35%), 576 (95%) 578 (100%) 580 (45%); Anal. Calc. for C23H13Br3OS: C, 47.87, H, 2.27, N, 0.00. Found: C, 47.73, H, 1.88, N, 0.03.
Reaction SMILES: [NH2:1][C:2]1[NH:3][C:4](=[O:12])[C:5]2[S:10][C:9](=[O:11])[NH:8][C:6]=2[N:7]=1.[CH3:13][CH:14]([CH3:34])[C:15]([O:17][C@H:18]([C@@H:21]1[CH2:25][C@@H:24]([O:26][C:27](=[O:29])[CH3:28])[C@@H:23](OC(=O)C)[O:22]1)[CH2:19][CH3:20])=[O:16].[Si](OS(C(F)(F)F)(=O)=O)(C)(C)C>C(#N)C>[CH3:34][CH:14]([CH3:13])[C:15]([O:17][C@H:18]([C@@H:21]1[CH2:25][C@@H:24]([O:26][C:27](=[O:29])[CH3:28])[C@H:23]([N:8]2[C:6]3[N:7]=[C:2]([NH2:1])[NH:3][C:4](=[O:12])[C:5]=3[S:10][C:9]2=[O:11])[O:22]1)[CH2:19][CH3:20])=[O:16]
Reactant: CC[C@H](OC(=O)C(C)C)[C@@H]1C[C@@H](OC(C)=O)[C@@H](OC(C)=O)O1
Reactant: Nc1nc2[nH]c(=O)sc2c(=O)[nH]1
Agent: C[Si](C)(C)OS(=O)(=O)C(F)(F)F
Solvent: CC#N
Product: CC[C@H](OC(=O)C(C)C)[C@@H]1C[C@@H](OC(C)=O)[C@H](n2c(=O)sc3c(=O)[nH]c(N)nc32)O1
Temperature: 70 °C
Reaction time: 0.5 h
Yield: 50.1 %

Procedure:
To a suspension of 5-amino-3,6-dihydrothiazolo[4,5-d]pyrimidine-2,7-dione (63 mg, 0.34 mmol) in ACN (5 mL) was added BSA (252 μL, 1.02 mmol). The resulting reaction mixture was then stirred at 70° C. under argon for 0.5 hour to form a clear solution. After the solution was cooled to room temperature, [(1S)-1-[(2S,4R,5R)-4,5-diacetoxytetrahydrofuran-2-yl]propyl] 2-methylpropanoate (compound 42b, 105 mg, 0.34 mmol) and TMSOTf (113 μL, 0.51 mmol) were added in sequence. After being heated with stirring at 70° C. for 14 hours, the resulting mixture was concentrated in vacuo to remove the solvent and the residue was purified by column chromatography on silica gel (eluting with 0-5% methanol in DCM) to afford 75 mg of [(1S)-1-[(2S,4R,5R)-4-acetoxy-5-(5-amino-2,7-dioxo-6H-thiazolo[4,5-d]pyrimidin-3-yl)tetrahydrofuran-2-yl]propyl] 2-methylpropanoate (compound 42c) as a light yellow solid.
Reaction SMILES: Cl[C:2]1[C:3]2[N:4]([CH:15]=[N:16][N:17]=2)[CH:5]=[C:6]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH:7]=1.[CH3:18][C:19]1[CH:24]=[CH:23][C:22](B(O)O)=[CH:21][CH:20]=1.C(=O)([O-])[O-].[K+].[K+]>C(O)CC.O.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>[CH3:18][C:19]1[CH:24]=[CH:23][C:22]([C:2]2[C:3]3[N:4]([CH:15]=[N:16][N:17]=3)[CH:5]=[C:6]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH:7]=2)=[CH:21][CH:20]=1
Reactant: Cc1ccc(B(O)O)cc1
Reactant: CC(C)(C)OC(=O)c1cc(Cl)c2nncn2c1
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: [K+]
Solvent: CCCO
Solvent: O
Product: Cc1ccc(-c2cc(C(=O)OC(C)(C)C)cn3cnnc23)cc1
Temperature: 85 °C
Reaction time: 18 h
Yield: 16.9 %

Procedure:
To a solution of tert-butyl 8-chloro[1,2,4]triazolo[4,3-a]pyridine-6-carboxylate (1.7 g, 6.7 mmol) in n-propanol (53.6 mL) and water (13.4 mL) were added (4-methylphenyl)boronic acid (1.37 g, 10.1 mmol), tetrakistriphenylphosphinepalladium (0) (0.39 g, 0.34 mmol) and potassium carbonate (2.78 g, 20.1 mmol). The mixture was purged with nitrogen and heated to 85° C. After 18 h, the mixture was cooled to ambient temperature and filtered with Celite. The filtrate was concentrated to remove n-propanol. The aqueous mixture was extracted with ethyl acetate (3×). The combined organic layer was washed with brine, dried over sodium sulfate, filtered and concentrated. Purification by silica gel chromatography (100% dichloromethane→95% dichloromethane/methanol). The product obtained was purified again by reverse phase HPLC (C-18, 95% water/acetonitrile→5% water/acetonitrile with 0.025% trifluoroacetic acid) gave the title compound (0.35 g): LC-MS [M+1]=310.2.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[N:4][C:5]2[C:6](=O)[CH2:7][CH2:8][CH2:9][C:10]=2[CH:11]=1.Cl.[NH2:14][OH:15].[OH-].[Na+].C(O)C>O>[CH3:1][C:2]1[CH:3]=[N:4][C:5]2[C:6](=[N:14][OH:15])[CH2:7][CH2:8][CH2:9][C:10]=2[CH:11]=1
Reactant: NO
Reactant: Cc1cnc2c(c1)CCCC2=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: Cc1cnc2c(c1)CCCC2=NO

Procedure:
The quinoline (30g), hydroxylamine hydrochloride (14g), sodium hydroxide (9g), ethanol (165ml) and water (65ml) were stirred and refluxed for 2 hours. Water (100ml) was added and the product was allowed to crystallise overnight. The crystals were removed by filtration and washed with water and dried to give 3-methyl-8-oximino-5,6,7,8-tetrahydroquinoline (27.5g) mp 188° C.
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:28])=[C:4]([NH:8][C:9]2[C:18]3[C:13](=[CH:14][C:15]([O:26][CH3:27])=[C:16]([CH2:19][NH:20][CH2:21][CH2:22][N:23]([CH3:25])[CH3:24])[CH:17]=3)[N:12]=[CH:11][N:10]=2)[CH:5]=[CH:6][CH:7]=1.CC[O:31][C:32]([C@H:34](OS(C(F)(F)F)(=O)=O)[CH3:35])=[O:33]>>[Cl:1][C:2]1[C:3]([F:28])=[C:4]([NH:8][C:9]2[C:18]3[C:13](=[CH:14][C:15]([O:26][CH3:27])=[C:16]([CH2:19][N:20]([CH2:21][CH2:22][N:23]([CH3:24])[CH3:25])[C@H:34]([C:32]([OH:33])=[O:31])[CH3:35])[CH:17]=3)[N:12]=[CH:11][N:10]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)[C@@H](C)OS(=O)(=O)C(F)(F)F
Reactant: COc1cc2ncnc(Nc3cccc(Cl)c3F)c2cc1CNCCN(C)C
Product: COc1cc2ncnc(Nc3cccc(Cl)c3F)c2cc1CN(CCN(C)C)[C@@H](C)C(=O)O

Procedure:
N′-({4-[(3-Chloro-2-fluorophenyl)amino]-7-methoxyquinazolin-6-yl}methyl)-N,N-dimethylethane-1,2-diamine was coupled with ethyl O-trifluoromethanesulfonyl-D-lactate and hydrolysed using analogous methods to those described for the equivalent steps in Example 46 to give N-({4-[(3-chloro-2-fluorophenyl)amino]-7-methoxyquinazolin-6-yl}methyl)-N-[2-(dimethylamino)ethyl]-L-alanine; 1H NMR Spectrum: (DMSO-d6) 1.24 (d, 3H); 2.36 (s, 6H); 2.63 (m, 2H); 2.77 (m, 1H); 2.86 (m, 1H); 3.41 (q, 1H); 3.80 (d, 1H); 3.89 (d, 1H); 3.96 (s, 3H); 7.21 (s, 1H); 7.29 (t, 1H); 7.49 (t, 1H); 7.60 (t, 1H); 8.36 (s, 1H); 8.44 (s, 1H); 9.71 (brs, 1H); Mass Spectrum: (M+H)+ 476.
Reaction SMILES: B(Br)(Br)Br.C[O:6][CH2:7][C:8]1[N:13]=[C:12]([N:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)[CH:11]=[CH:10][N:9]=1.[OH-].[Na+]>ClCCl>[OH:6][CH2:7][C:8]1[N:13]=[C:12]([N:14]2[CH2:15][CH2:16][O:17][CH2:18][CH2:19]2)[CH:11]=[CH:10][N:9]=1
Reactant: COCc1nccc(N2CCOCC2)n1
Agent: BrB(Br)Br
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: OCc1nccc(N2CCOCC2)n1
Reaction time: 0.5 h
Yield: 45.3 %

Procedure:
A solution of 24 ml of boron tribromide in 100 ml of dichloromethane was added dropwise, at -25° C. under a nitrogen atmosphere, to a solution of 13 g of 2-methoxymethyl-4-morpholinopyrimidine in 100 ml of dichloromethane. After 30 minutes at -25° C., the solution was left to stand at 0° C. for a further 2 hours and then poured onto ice. The solution was made alkaline with sodium hydroxide solution and was extracted with dichloromethane. After drying (Na2SO4) and concentration, diethyl ether was added, and 5.5 g of 2-hydroxymethyl-4-morpholinopyrimidine were obtained as a solid (melting point 76°-77° C.).
Reaction SMILES: [CH2:1]([C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6](=[O:13])[NH:5][N:4]=1)[CH3:2].Br[CH2:15][CH2:16][O:17][C:18]1[CH:25]=[CH:24][C:21]([CH:22]=[O:23])=[CH:20][CH:19]=1.C([O-])([O-])=O.[K+].[K+]>>[CH2:1]([C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6](=[O:13])[N:5]([CH2:15][CH2:16][O:17][C:18]2[CH:25]=[CH:24][C:21]([CH:22]=[O:23])=[CH:20][CH:19]=2)[N:4]=1)[CH3:2]
Reactant: CCc1n[nH]c(=O)c2ccccc12
Reactant: O=Cc1ccc(OCCBr)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CCc1nn(CCOc2ccc(C=O)cc2)c(=O)c2ccccc12
Yield: 53.7 %

Procedure:
##STR32## The title compound (450 mg, 54%) was prepared from 4-ethyl-1(2H)-phthalazinone (450 mg, 2.6 mmol) (Ref: Chemistry of Heterocyclic Compounds; Condensed Pyridazines including Cinnolines and Phthalazines, edited by R. N. Castle; John Wiley and Sons, 27, (1973) 375-441), 4-[2-bromoethoxy]benzaldehyde (600 mg, 2.6 mmol) and K2CO3 (720 mg, 5.2 mmol) by a similar procedure to that described in preparation 2. mp: 110° C.