Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br-].[CH2:2]([P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9].[Li]CCCC.[CH3:34][O:35][C@H:36]1[C@@H:41]([CH3:42])[CH2:40][O:39][C@H:38]([CH:43]=O)[C@@H:37]1[O:45][Si:46]([C:49]([CH3:52])([CH3:51])[CH3:50])([CH3:48])[CH3:47]>C1COCC1.CN(P(N(C)C)(N(C)C)=O)C>[Si:46]([O:45][C@@H:37]1[C@@H:36]([O:35][CH3:34])[C@@H:41]([CH3:42])[CH2:40][O:39][C@H:38]1/[CH:43]=[CH:2]\[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9])([C:49]([CH3:52])([CH3:51])[CH3:50])([CH3:47])[CH3:48]
Reactant: CCCCCCCC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CO[C@@H]1[C@@H](O[Si](C)(C)C(C)(C)C)[C@@H](C=O)OC[C@@H]1C
Agent: [Br-]
Agent: [Li]CCCC
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: C1CCOC1
Product: CCCCCCC/C=C\[C@@H]1OC[C@H](C)[C@H](OC)[C@H]1O[Si](C)(C)C(C)(C)C
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 90.8 %

Procedure:
To a stirred solution of n-octyltriphenylphosphonium bromide (2124 mg) in dry THF (10 ml) and dry HMPA (5 ml), there was added n-BuLi (4.0 ml, 1.6M in n-hexane) at 0° C. After the mixture was stirred at 0° C. for 30 min, a solution of (2S,3R,4S,5S)-4-methoxy-5-methyl-3-(tert-butyldimethylsilyloxy)tetrahydro-2H-pyran-2-carbaldehyde (497 mg) in dry THF (3 ml) was added to the resulting orange solution. The mixture was stirred at 0° C. for 30 min, and at room temperature for 2 hours. The reaction was quenched by addition of saturated aqueous ammonium chloride solution. The mixture was extracted with diethyl ether, and the combined ethereal extracts were washed with brine, dried over sodium sulfate, filtered, and concentrated. Purification of the residue by silica gel chromatography gave (2S,3R,4S,5S)-3-(tert-butyldimethylsilyloxy)-4-methoxy-5-methyl-2-[(Z)-1-nonenyl]tetrahydro-2H-pyran (602 mg, 72% yield).
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:14]([F:17])([F:16])[F:15])=[N:4][N:5]([CH:8]([CH2:12][CH3:13])[C:9]([OH:11])=O)[C:6]=1[CH3:7].[F:18][C:19]1[CH:24]=[CH:23][C:22]([N:25]2[C:33]3[CH2:32][CH2:31][CH2:30][NH:29][C:28]=3[CH:27]=[N:26]2)=[CH:21][CH:20]=1>>[Cl:1][C:2]1[C:3]([C:14]([F:17])([F:16])[F:15])=[N:4][N:5]([CH:8]([CH2:12][CH3:13])[C:9]([N:29]2[CH2:30][CH2:31][CH2:32][C:33]3[N:25]([C:22]4[CH:23]=[CH:24][C:19]([F:18])=[CH:20][CH:21]=4)[N:26]=[CH:27][C:28]2=3)=[O:11])[C:6]=1[CH3:7]
Reactant: CCC(C(=O)O)n1nc(C(F)(F)F)c(Cl)c1C
Reactant: Fc1ccc(-n2ncc3c2CCCN3)cc1
Product: CCC(C(=O)N1CCCc2c1cnn2-c1ccc(F)cc1)n1nc(C(F)(F)F)c(Cl)c1C
Yield: 69 %

Procedure:
The title compound was prepared from 2-(4-chloro-5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl)butanoic acid and 1-(4-fluorophenyl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-b]pyridine using General Method B. The product mixture was washed with 2×1 M NaHSO4. The reaction slurry was purified by flash chromatography (SiO2, 24 g column, eluting with 5-50% EtOAc in hexanes) to provide 81 mg (69%) of the title compound as a white solid. 1H NMR (400 MHz, CDCl3) δ 8.43 (s, 1H), 7.44 (m, 2H), 7.16 (m, 2H), 5.30 (dd, J=6.7, 8.6 Hz, 1H), 3.81 (ddd, J=3.2, 8.6, 11.5 Hz, 1H), 3.50 (ddd, J=3.1, 7.4, 10.2 Hz, 1H), 2.79 (dt, J=2.8, 6.3 Hz, 2H), 2.33 (m, 1H), 2.30 (s, 3H), 2.22 (m, 1H), 1.96 (m, 1H), 1.86 (m, 1H), 0.98 (t, J=7.0 Hz, 3H); MS: (ES) m/z calculated for C20H19ClF4N5O [M+H]+ 470.1, found 470.1.
Reaction SMILES: [N+:1]([C:4]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:5]=1[CH:6]=[CH:7][C:8](Cl)=[N:9]2)([O-])=O.[F:15][C:16]1[CH:17]=[C:18]2[C:22](=[CH:23][CH:24]=1)[CH:21]([NH2:25])[CH2:20][CH2:19]2>>[F:15][C:16]1[CH:17]=[C:18]2[C:22](=[CH:23][CH:24]=1)[CH:21]([NH:25][C:8]1[CH:7]=[CH:6][C:5]3[C:4]([NH2:1])=[CH:13][CH:12]=[CH:11][C:10]=3[N:9]=1)[CH2:20][CH2:19]2
Reactant: NC1CCc2cc(F)ccc21
Reactant: O=[N+]([O-])c1cccc2nc(Cl)ccc12
Product: Nc1cccc2nc(NC3CCc4cc(F)ccc43)ccc12

Procedure:
The title compound, light yellow foam, MS: m/e=294.1 (M+H+), was prepared in accordance with the general method of example 16 from 5-nitro-2-chloroquinoline (example 16, CAS 13067-94-2) and commercially available (RS)-5-fluoro-indane-1-ylamine.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5](/[CH:8]=[CH:9]/[C:10]([O:12][C:13]2[CH:18]=[CH:17][C:16]([O:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])=[CH:15][CH:14]=2)=[O:11])=[CH:4][CH:3]=1.[Cl:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31]O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(OC(N=NC(OCC)=O)=O)C>O1CCCC1.C1(C)C=CC=CC=1>[Cl:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][O:1][C:2]1[CH:3]=[CH:4][C:5](/[CH:8]=[CH:9]/[C:10]([O:12][C:13]2[CH:14]=[CH:15][C:16]([O:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])=[CH:17][CH:18]=2)=[O:11])=[CH:6][CH:7]=1
Reactant: CCCCCOc1ccc(OC(=O)/C=C/c2ccc(O)cc2)cc1
Reactant: OCCCCCCCl
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: CCCCCOc1ccc(OC(=O)/C=C/c2ccc(OCCCCCCCl)cc2)cc1
Temperature: 0 °C
Reaction time: 0.42 h
Yield: 74.9 %

Procedure:
7.35 g (22.5 mmol) 4-pentoxyphenyl (2E)-3-{4-hydroxyphenyl}acrylate, 3.36 g (24.6 mmol) 6-chloro-1-hexanol and 6.45 g (24.6 mmol) of triphenylphosphine were dissolved in 100 ml of tetrahydrofurane. The colourless solution was subsequently cooled to 0° C. and 4.28 g (24.6 mmol) of a 40% solution of azodicarboxylic acid diethyl ester in toluene were added dropwise thereto over a period of 25 minutes. The mixture was subsequently allowed to react for 4 h at 0° C. The reaction mixture was reduced in volume by evaporation. The resulting residue was added to a mixture of methanol and water (3:2) and was then extracted with a mixture of tert.-butyl-methylether:hexane 1:1. The tert.-butyl-methylether:hexane phase was washed repeatedly with water, dried over magnesium sulphate, filtered and concentrated by rotary evaporation to yield 7.5 g 4-pentoxyphenyl (2E)-3-{4-(6-chlorohexyloxy)phenyl}acrylate as yellowish crystals.
Reaction SMILES: [CH2:1]([N:3]([CH2:11][CH3:12])[C:4](=[O:10])/[CH:5]=[CH:6]/[CH:7](O)[CH3:8])[CH3:2].[Cl:13]P(Cl)(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>C(Cl)Cl>[Cl:13][CH:7]([CH3:8])/[CH:6]=[CH:5]/[C:4]([N:3]([CH2:11][CH3:12])[CH2:1][CH3:2])=[O:10]
Reactant: ClP(Cl)(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CCN(CC)C(=O)/C=C/C(C)O
Solvent: ClCCl
Product: CCN(CC)C(=O)/C=C/C(C)Cl
Temperature: 25 °C

Procedure:
To (E)-N,N-Diethyl-4-hydroxy-2-pentenamide (0.67 g, 3.93 mmol) in methylene chloride cooled to -15° C. in a flame dried flask is added dichlorotriphenylphosphorane (1.40 g, 4.33 mmol). The reaction is warmed to ambient temperature, quenched by addition of ice (10 ml), extracted with methylene chloride (3×20 ml), washed with saline (30 ml), dried over sodium sulfate, concentrated in vacuo, and chromatographed on silica gel (230-400 mesh, 100 ml), eluting with hexane/ethyl acetate (75/25). The appropriate fractions are combined (Rf =0.48, TLC, hexane/ethyl acetate, 25/75) and concentrated in vacuo to give (E)-4-chloro-N,N-diethyl-2-pentenamide. 4-Amino-6-chloro-2-mercaptopyrimidine mesylate (0.56 g, 2.19 mmol) is dissolved in DMF (4 ml) and sodium hydride (0.12 g, 4.82 mmol) at ambient temperature followed by the addition of (E)-4-chloro-N,N-diethyl-2-pentenamide (0.41 g, 2.19 mmol). The reaction is stirred for 15 hours, quenched with excess water, extracted with ethyl acetate (3×25 ml). The extracts are combined, washed with saline (25 ml), dried over sodium sulfate, concentrated in vacuo and chromatographed on silica gel (230-400 mesh, 100 ml), eluting with a gradient of hexane/ethyl acetate (80/20-60/40). The appropriate fractions are combined (Rf =0.27, TLC, hexane/ethyl acetate, 25/75) and concentrated in vacuo to give the title compound, mp 152-153° C.
Reaction SMILES: OCCNS([C:8]1[CH:16]=[CH:15][C:11]([C:12](O)=[O:13])=[CH:10][CH:9]=1)(=O)=O.ClC1C=CC([NH2:22])=CC=1C1C=CC=CN=1>>[C:12]([NH2:22])(=[O:13])[C:11]1[CH:15]=[CH:16][CH:8]=[CH:9][CH:10]=1
Reactant: Nc1ccc(Cl)c(-c2ccccn2)c1
Reactant: O=C(O)c1ccc(S(=O)(=O)NCCO)cc1
Product: NC(=O)c1ccccc1

Procedure:
Procedure G was used to couple 4-(2-hydroxyethylsulfamoyl)benzoic acid with 4-chloro-3-(pyridin-2-yl)aniline (42 mg) to yield N-(4-chloro-3-(pyridin-2-yl)phenyl)-4-[(2-hydroxyethyl)amino]sulfonyl]-benzamide. MS (Q1) 431.9 (M)+.
Reaction SMILES: [Cr](Cl)([O-])(=O)=O.[NH+]1C=CC=CC=1.C([O-])(=O)C.[Na+].[CH3:17][O:18][C:19]([C:21]1([CH:24]([OH:37])[CH2:25][CH2:26][CH2:27][CH2:28][O:29][C:30]2[CH:35]=[CH:34][C:33]([Cl:36])=[CH:32][CH:31]=2)[CH2:23][O:22]1)=[O:20].CCCCCC.C(OCC)C>C(Cl)Cl.C(OCC)C>[CH3:17][O:18][C:19]([C:21]1([C:24](=[O:37])[CH2:25][CH2:26][CH2:27][CH2:28][O:29][C:30]2[CH:35]=[CH:34][C:33]([Cl:36])=[CH:32][CH:31]=2)[CH2:23][O:22]1)=[O:20]
Reactant: COC(=O)C1(C(O)CCCCOc2ccc(Cl)cc2)CO1
Agent: O=[Cr](=O)([O-])Cl
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CCCCCC
Solvent: CCOCC
Product: COC(=O)C1(C(=O)CCCCOc2ccc(Cl)cc2)CO1
Reaction time: 4 h
Yield: 23.9 %

Procedure:
To a suspension of 9.05 g (42 mmol) of pyridinium chlorochromate and 3.4 g (42 mmol) of sodium acetate in 150 ml of methylene chloride is added 2.2 g (7 mmol) of 2-[5-(4-chlorophenoxy)-1-hydroxypentyl]-2-oxiranecarboxylic acid methyl ester of Example 2, part 2. The mixture is stirred for 4 hours, is diluted with ethyl ether and is filtered through Florisil. The solution is rotoevaporated and is chromatographed preparatively on silica gel using hexane:ethyl ether (3:2) as eluting solvent. The appropriate fractions are combined, washed with aqueous copper sulfate and brine and dried over magnesium sulfate. Filtration and rotoevaporation gives crude product. Column chromatography (silica gel; hexane:ethyl ether (3:2)) affords 523 mg (23.9%) of the title compound: IR (film) 1746, 1717 cm-1 ; NMR (CDCl3) δ 1.80 (4H, m), 2.66 (2H, m), 3.08 (1H, d, J=6 Hz), 3.34 (1H, d, J=6 Hz), 3.84 (3H, s), 3.94 (2H, t, J=6 Hz), 6.82 (2H, d, J=10 Hz) and 7.24 (2H, d, J=10 Hz).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]([N+:9]([O-:11])=[O:10])=[C:6]([NH2:8])[CH:7]=1.[H-].[Na+].I[CH3:15]>CN(C=O)C>[CH3:15][NH:8][C:6]1[CH:7]=[C:2]([CH3:1])[CH:3]=[CH:4][C:5]=1[N+:9]([O-:11])=[O:10]
Reactant: Cc1ccc([N+](=O)[O-])c(N)c1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CNc1cc(C)ccc1[N+](=O)[O-]
Reaction time: 0.17 h

Procedure:
To a solution of 5-methyl-2-nitro-phenylamine (3.04 g, 20.0 mmol) in anhydrous DMF (20 mL) at 0° C. was portionwise added 95% NaH (528 mg, 22.0 mmol) and stirred for 10 min. A solution of iodomethane (1.25 mL, 20.0 mmol) in anhydrous DMF (10 mL) was then added. The ice bath was removed and the resulting mixture was stirred at room temperature overnight. The resulting mixture was then diluted with water, and the resulting solid was collected by filtration, washed with H2O and hexanes to yield methyl-(5-methyl-2-nitro-phenyl)-amine MS 167 (M+1)+.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]2[CH2:7][C:8]3[CH:14]=[C:13]([CH:15]([CH3:19])[C:16]([OH:18])=[O:17])[CH:12]=[CH:11][C:9]=3[O:10][C:2]=12.CC(C)[O-].[Al+3:24].CC(C)[O-].CC(C)[O-].O>C(O)(C)C>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]2[CH2:7][C:8]3[CH:14]=[C:13]([CH:15]([CH3:19])[C:16]([O-:18])=[O:17])[CH:12]=[CH:11][C:9]=3[O:10][C:2]=12.[Al+3:24].[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]2[CH2:7][C:8]3[CH:14]=[C:13]([CH:15]([CH3:19])[C:16]([O-:18])=[O:17])[CH:12]=[CH:11][C:9]=3[O:10][C:2]=12.[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]2[CH2:7][C:8]3[CH:14]=[C:13]([CH:15]([CH3:19])[C:16]([O-:18])=[O:17])[CH:12]=[CH:11][C:9]=3[O:10][C:2]=12
Reactant: CC(C(=O)O)c1ccc2c(c1)Cc1cccnc1O2
Agent: CC(C)[O-]
Agent: [Al+3]
Solvent: CC(C)O
Solvent: O
Product: CC(C(=O)[O-])c1ccc2c(c1)Cc1cccnc1O2

Procedure:
2.5 G of 2-(5H-[1]benzopyrano[2,3-b]pyridin-7-yl)propionic acid is dissolved in 80 ml of isopropyl alcohol. A solution of 2.1 g of aluminum isopropoxide in 25 ml of isopropyl alcohol is added dropwise to the solution with stirring, white crystals being immediately yielded. After refluxing the mixture for 1 hour, 3 ml of water is added, and then the whole mixture is further refluxed for 1 hour. After cooling, the crystals are filtered off, washed with isopropyl alcohol, and dried to give aluminum 2-(5H-[1]-benzopyrano[2,3-b]pyridin-7-yl)propionate as white crystals melting at above 250°C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[S:11][CH2:10][CH2:9][CH:8]=[C:7]([OH:12])[C:6]=2[CH:13]=1.I([O-])(=O)(=O)=[O:15].[Na+]>CO.O1CCOCC1.O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[S:11](=[O:15])[CH2:10][CH2:9][CH:8]=[C:7]([OH:12])[C:6]=2[CH:13]=1
Reactant: OC1=CCCSc2ccc(Cl)cc21
Reactant: [O-][I+3]([O-])([O-])[O-]
Agent: [Na+]
Solvent: CO
Solvent: O
Solvent: C1COCCO1
Product: O=S1CCC=C(O)c2cc(Cl)ccc21
Temperature: 25 °C
Reaction time: 2 h

Procedure:
The starting material is prepared as follows: The solution of 6.4 g of 7-chloro-5-hydroxy-2,3-dihydro-1-benzothiepin in 65 ml of dry methanol and 65 ml of dry dioxane is treated dropwise at 0° in 1 hour with the solution of 7.0 g of sodium metaperiodate in 65 ml water. The mixture is stirred at 0° for two hours after the addition period and then allowed to warm to room temperature for overnight. It is filtered and the solid rinsed with 30 ml of methanol. The combined filtrate and wash is concentrated to a smaller volume and treated with 40 ml of water. The mixture is extracted with chloroform, the extract separated, washed with water, dried and evaporated, to yield the 7-chloro-5-hydroxy-2,3-dihydro-1-benzothiepin-1-oxide boiling at 154-157/0.25 mmHg.
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][N:5]([C:8]2[S:9][CH:10]=[C:11]([CH:13]([N:18]3[CH2:24][CH2:23][CH2:22][N:21]([C:25]4[C:26]([O:35][CH3:36])=[CH:27][CH:28]=[C:29]5[C:34]=4[N:33]=[CH:32][CH:31]=[CH:30]5)[CH2:20][CH2:19]3)[CH2:14][C:15](O)=[O:16])[N:12]=2)[CH2:4][CH2:3]1.[CH3:37][N:38]1[CH2:43][CH2:42][NH:41][CH2:40][CH2:39]1.CCN(CC)CC.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C(Cl)Cl.CN(C=O)C>[OH:1][CH:2]1[CH2:3][CH2:4][N:5]([C:8]2[S:9][CH:10]=[C:11]([CH:13]([N:18]3[CH2:24][CH2:23][CH2:22][N:21]([C:25]4[C:26]([O:35][CH3:36])=[CH:27][CH:28]=[C:29]5[C:34]=4[N:33]=[CH:32][CH:31]=[CH:30]5)[CH2:20][CH2:19]3)[CH2:14][C:15]([N:41]3[CH2:42][CH2:43][N:38]([CH3:37])[CH2:39][CH2:40]3)=[O:16])[N:12]=2)[CH2:6][CH2:7]1
Reactant: COc1ccc2cccnc2c1N1CCCN(C(CC(=O)O)c2csc(N3CCC(O)CC3)n2)CC1
Reactant: CN1CCNCC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COc1ccc2cccnc2c1N1CCCN(C(CC(=O)N2CCN(C)CC2)c2csc(N3CCC(O)CC3)n2)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 34.2 %

Procedure:
DMF (3.0 mL) was added to the product from step 2 (309 mg, 0.60 mmol), followed by N-methylpiperazine (0.08 mL, 0.72 mmol), and Et3N (0.17 mL, 1.20 mmol). HATU (274 mg, 0.72 mmol) was then added to the mixture, and the reaction was stirred for 2 h at room temperature. The solution was then diluted with CH2Cl2 and washed with H2O (4×50 mL), then brine. The organic was dried over MgSO4, filtered, and concentrated to give the crude. This was purified by silica gel chromatography (99:1 to 90:10 CH2Cl2:(9:1 MeOH:NH4OH)) and lyophilized from MeCN/H2O to give the product (122 mg, 34% yield) as a pale yellow solid. 1H NMR (400 MHz, CDCl3) δ 8.84 (dd, 1H, J=1.4, 4.2 Hz), 8.02 (dd, 1H, J=2.0, 8.0 Hz), 7.51 (d, 1H, J=8.8 Hz), 7.29 (d, 1H, J=8.8 Hz), 7.21 (dd, 1H, J=4.2, 8.2 Hz), 6.44 (s, 1H), 4.35 (bs, 1H), 3.95 (s, 3H), 3.95-3.76 (m, 2H), 3.67-3.45 (m, 7H), 3.24-2.78 (m, 8H), 2.42-2.33 (m, 2H), 2.28 (s, 3H), 2.32-2.10 (m, 5H), 2.02-1.92 (m, 4H), 1.68-1.58 (m, 2H). MS (ES) m/z 594.5 (M+H+).
Reaction SMILES: [H][H].[N:3]([CH2:6][C@@H:7]1[C@@H:11]([F:12])[CH2:10][N:9]([C:13]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[O:14])[CH2:8]1)=[N+]=[N-].N(CC1CN(C(OCC2C=CC=CC=2)=O)CC=1)=[N+]=[N-]>C(O)C.[Pt](=O)=O>[NH2:3][CH2:6][C@@H:7]1[C@@H:11]([F:12])[CH2:10][N:9]([C:13]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[O:14])[CH2:8]1
Reactant: [H][H]
Reactant: [N-]=[N+]=NC[C@H]1CN(C(=O)OCc2ccccc2)C[C@@H]1F
Agent: O=[Pt]=O
Agent: [N-]=[N+]=NCC1=CCN(C(=O)OCc2ccccc2)C1
Solvent: CCO
Product: NC[C@H]1CN(C(=O)OCc2ccccc2)C[C@@H]1F
Yield: 62.7 %

Procedure:
Platinum (IV) oxide (50.0 mg) was suspended in ethanol (7 mL) and the suspension was stirred at room temperature under a stream of hydrogen gas (blown by a balloon) for 30 min. Subsequently, a mixture (551 mg) of (3R,4R)-3-azidomethyl-1-benzyloxycarbonyl-4-fluoropyrrolidine and 3-azidomethyl-1-benzyloxycarbonyl-3-pyrroline in ethanol (3 mL) was added and the mixture was stirred at room temperature under a stream of hydrogen gas (blown by a balloon) for 5 hours. The catalyst in the reaction mixture was filtered and was washed with ethanol. The filtrate and the washings were combined and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluant: ethyl acetate->ethyl acetate:methanol=10:1) to give a mixture (313 mg) of (3S,4R)-3-aminomethyl-1-benzyloxycarbonyl-4-fluoropyrrolidine and 3-aminomethyl-1-benzyloxycarbonyl-3-pyrroline.
Reaction SMILES: Br[C:2]1[N:6]=[C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[N:4]([CH2:13][C:14]([N:16]2[CH2:21][CH2:20][N:19]([C:22]3[N:27]=[CH:26][CH:25]=[CH:24][N:23]=3)[CH2:18][CH2:17]2)=[O:15])[N:3]=1.C(OC([O-])=O)([O-])=O.[Na+].[Na+].[F:37][C:38]1[CH:43]=[CH:42][C:41](B(O)O)=[CH:40][C:39]=1[CH3:47]>O1CCOCC1.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>[F:37][C:38]1[CH:43]=[CH:42][C:41]([C:2]2[N:6]=[C:5]([C:7]3[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=3)[N:4]([CH2:13][C:14]([N:16]3[CH2:21][CH2:20][N:19]([C:22]4[N:27]=[CH:26][CH:25]=[CH:24][N:23]=4)[CH2:18][CH2:17]3)=[O:15])[N:3]=2)=[CH:40][C:39]=1[CH3:47]
Reactant: Cc1cc(B(O)O)ccc1F
Reactant: O=C(Cn1nc(Br)nc1-c1ccccc1)N1CCN(c2ncccn2)CC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])OC(=O)[O-]
Agent: [Na+]
Solvent: C1COCCO1
Product: Cc1cc(-c2nc(-c3ccccc3)n(CC(=O)N3CCN(c4ncccn4)CC3)n2)ccc1F
Temperature: 120 °C
Yield: 30 %

Procedure:
15 mg tetrakis(triphenylphosphine)palladium(0) was added to 100 mg 2-(3-bromo-5-phenyl-(1,2,4)triazol-1-yl)-1-(4-pyrimidin-2-yl-piperazin-1-yl)-ethanone, 500 μL 2 mol/L aqueous sodiumdicarbonate solution and 43 mg 4-fluoro-3-methylphenylboronic acid in 10 mL dioxane under nitrogen. The reaction was stirred over night at 120° C. The reaction was filltered and evaporated. The residue was purified by HPLC to give 32 mg of the desired product.
Reaction SMILES: CS(OCC)(=O)=O.C(#N)C.[Cl:11][C:12]1[CH:13]=[CH:14][C:15]([CH2:18][O:19][C:20]2[CH:25]=[CH:24][N:23]([C:26]3[CH:31]=[CH:30][C:29]([O:32][C@@H:33]4[CH2:37][CH2:36][N:35]([CH:38](C)[CH3:39])[CH2:34]4)=[CH:28][CH:27]=3)[C:22](=[O:41])[CH:21]=2)=[N:16][CH:17]=1>C(Cl)(Cl)Cl>[Cl:11][C:12]1[CH:13]=[CH:14][C:15]([CH2:18][O:19][C:20]2[CH:25]=[CH:24][N:23]([C:26]3[CH:27]=[CH:28][C:29]([O:32][C@@H:33]4[CH2:37][CH2:36][N:35]([CH2:38][CH3:39])[CH2:34]4)=[CH:30][CH:31]=3)[C:22](=[O:41])[CH:21]=2)=[N:16][CH:17]=1
Reactant: CC(C)N1CC[C@@H](Oc2ccc(-n3ccc(OCc4ccc(Cl)cn4)cc3=O)cc2)C1
Agent: CCOS(C)(=O)=O
Solvent: ClC(Cl)Cl
Solvent: CC#N
Product: CCN1CC[C@@H](Oc2ccc(-n3ccc(OCc4ccc(Cl)cn4)cc3=O)cc2)C1
Temperature: 80 °C
Reaction time: 2 h
Yield: 41.3 %

Procedure:
Ethyl methanesulfonate (0.45 mL) was added to acetonitrile solution of 4-[(5-chloro-2-pyridinyl)methoxy]-1-(4-{[(3R)-3-pyrrolidinyl]oxy}phenyl)-1H-pyridin-2-one (1.65 g, Example 122), and stirred at 80° C. for 2 hours. Additional ethyl methanesulfonate (0.45 mL) was added and stirred at 80° C. for further 2 hours, followed by cooling to room temperature. Chloroform was added to the reaction liquid which then was washed with saturated aqueous sodium hydrogencarbonate solution and saturated brine, and dried over anhydrous potassium carbonate. Concentrating the solvent under reduced pressure, the residue was purified on silica gel column chromatography (C-300; methanol:chloroform=1:100-1:10-1:4). The residue was crystallized from mixed solvent of ethyl acetate and heptane to provide the title compound (660 mg).
Reaction SMILES: BrC1C=CC=CC=1C=O.C([O-])(=O)CC(C)=O.C(=O)C1C=CC=CC=1.[OH-].[Na+].Cl.[Br:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=1[CH:35]([CH2:40][C:41]([OH:43])=[O:42])[CH2:36][C:37]([OH:39])=O>C(OCC)(=O)CC(C)=O.C(O)C.C(Cl)(=O)C>[Br:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=1[CH:35]1[CH2:36][C:37](=[O:39])[O:43][C:41](=[O:42])[CH2:40]1
Reactant: O=C(O)CC(CC(=O)O)c1ccccc1Br
Agent: CC(=O)CC(=O)[O-]
Agent: Cl
Agent: O=Cc1ccccc1Br
Solvent: CCO
Solvent: O=Cc1ccccc1
Solvent: CC(=O)Cl
Product: O=C1CC(c2ccccc2Br)CC(=O)O1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
To a solution of commercial 2-bromobenzaldehyde (5 g) in ethyl acetoacetate (7 g) piperidine (0.5 ml) was added with stirring at rt. The cloudy solution was kept at rt for 3 d. The yellowish amorphous solid (the bis-adduct of acetoacetate to the benzaldehyde) was dissolved in ethanol (20 ml). This solution was added in portions to 40% NaOH (150 g) with stirring. The resulting orange slurry was stirred at reflux for 2 h. After cooling in an ice bath the now yellowish mixture was acidified by portionwise addition of conc. HCl (150 ml) to give a white, partly resinous precipitate. The solid was collected by suction filtration and washed with water. After drying in vacuo 3-(2-bromophenyl)glutaric acid (5.7 g) was obtained. The suspension of finely divided 3-(2-bromophenyl)glutaric acid in acetyl chloride (7 ml) was heated to reflux with stirring for 1 h. After cooling to rt precipitation was induced by addition of petrol ether (50 ml). From the oily precipitate the mother liquor was removed by decantation and the residue was dried in vacuo to afford 3-(2-bromophenyl)glutaric anhydride (4.6 g) as light yellow solid in sufficient purity.
Reaction SMILES: C[C:2]1([N:8]2[C:12]([C:13]3[S:25][C:16]4[N:17]=[CH:18][N:19]=[C:20]([S:21]([CH3:24])(=[O:23])=[O:22])[C:15]=4[CH:14]=3)=[CH:11][N:10]=[CH:9]2)C=CC=CC1.[Br:26][C:27]1[CH:32]=[CH:31][C:30](C2N=CN(C)C=2C2SC3N=CN=C(SC)C=3C=2)=[CH:29][CH:28]=1>>[Br:26][C:27]1[CH:32]=[CH:31][C:30]([C:11]2[N:10]=[CH:9][N:8]([CH3:2])[C:12]=2[C:13]2[S:25][C:16]3[N:17]=[CH:18][N:19]=[C:20]([S:21]([CH3:24])(=[O:22])=[O:23])[C:15]=3[CH:14]=2)=[CH:29][CH:28]=1
Reactant: CC1(n2cncc2-c2cc3c(S(C)(=O)=O)ncnc3s2)C=CC=CC1
Reactant: CSc1ncnc2sc(-c3c(-c4ccc(Br)cc4)ncn3C)cc12
Product: Cn1cnc(-c2ccc(Br)cc2)c1-c1cc2c(S(C)(=O)=O)ncnc2s1

Procedure:
The title compound was prepared by a similar process to that described for Intermediate 17 but using 6-[4-(4-bromophenyl)-1-methyl-1H-imidazol-5-yl]4-(methylthio)thieno[2,3-d]pyrimidine (Intermediate 67) in place of 6-(1-methyl-4-phenyl-1H-imidazol-5-yl)-4-(methylthio)thieno[2,3-d]pyrimidine (example 7). Pale yellow solid (715 mg, 79%);
Reaction SMILES: [S:1]1[CH:5]=[CH:4][N:3]=[C:2]1[CH:6]([CH3:12])[C:7](OCC)=[O:8].[H-].[H-].[H-].[H-].[Li+].[Al+3].[O-]S([O-])(=O)=O.[Na+].[Na+]>CCOCC>[S:1]1[CH:5]=[CH:4][N:3]=[C:2]1[CH:6]([CH3:12])[CH2:7][OH:8]
Reactant: CCOC(=O)C(C)c1nccs1
Agent: O=S(=O)([O-])[O-]
Agent: [Al+3]
Agent: [H-]
Solvent: CCOCC
Product: CC(CO)c1nccs1
Reaction time: 1 h
Yield: 80.8 %

Procedure:
To a stirred solution of ethyl 2-(thiazol-2-yl)propanoate (418 mg, 2.3 mmol) in ether (15 ml) at -10° C. was added LiAlH4 (2.2 ml of a 1.0M solution in ether, 2.2 mmol) dropwise. After 2 h at -10° C. more LiAlH4 (0.5 ml of a 1.0M solution in ether, 0.5 mmol) was added. After a further 1 h more LiAlH4 (0.5 ml of a 1.0M solution in ether, 0.5 mmol) was added. Stirring was continued for 1 h then Na2SO4 (sat., 3 ml) was added and the mixture stirred at room temperature for 10 min. The mixture was filtered and the filtrate evaporated. The residue was chromatographed on silica, eluting with CH2Cl2 :MeOH (95:5), to give the alcohol (266 mg, 82%) as a colourless oil. 1H NMR (250 MHz, CDCl3) δ 1.42 (3H, d, J=7.1 Hz), 3.31-3.44 (1H, m), 3.64 (1H, br s), 3.80-3.93 (2H, m), 7.25 (1H, d, J=3.3 Hz), 7.70 (1H, d, J=3.3 Hz).