Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[N:9]([C:13]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[N:8]=[C:7]2[C:32]([OH:34])=O)([O-:3])=[O:2].CN([C:38]([O:42][N:43]1N=NC2C=CC=N[C:44]1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.Cl.CNOC.CCN(C(C)C)C(C)C>CN(C=O)C.O>[CH3:38][O:42][N:43]([CH3:44])[C:32]([C:7]1[C:6]2[C:10](=[CH:11][CH:12]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=2)[N:9]([C:13]([C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)([C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)[C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[N:8]=1)=[O:34]
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Reactant: O=C(O)c1nn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c2ccc([N+](=O)[O-])cc12
Agent: CNOC
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: O
Product: CON(C)C(=O)c1nn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c2ccc([N+](=O)[O-])cc12
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
5-nitro-1-trityl-1H-indazole-3-carboxylic acid 20AP (12.06 g, 26.85 mmol) and HATU (10.2 g, 26.85 mmol) was dissolved in DMF (100 ml). After stirring for 10 min at room temperature, N,O-dimethylhydroxylamine hydrochloride 21AP (2.62 g, 26.85 mmol) and DIEA (14.1 ml, 80.55 mmol) was added. It was stirred further for 1 hr at room temperature. Reaction mixture was poured into 300 ml of water. Solid was collected by filtration. This solid was redissolved in EtOAc (300 ml) and 75 ml of sat. NaHCO3 was added. Organic fraction was washed with water (2×75 ml), brine (75 ml) and dried over MgSO4. Solvent was removed under reduced pressure to give desired 5-nitro-1-trityl-1H-indazole-3-carboxylic acid methoxy-methyl-amide 22AP (12.56 g, 95%).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:9]2[N:10]=[C:11]([C:15]3[CH:20]=[CH:19][C:18]([F:21])=[CH:17][C:16]=3[F:22])[N:12]=[N:13][CH:14]=2)[CH:5]=[CH:6][C:7]=1[F:8].[F:23][C:24]1[C:25](B2OC(C)(C)C(C)(C)O2)=[C:26]([CH:29]=[CH:30][CH:31]=1)[C:27]#[N:28]>O1CCOCC1.C(=O)([O-])[O-].[Na+].[Na+].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:23][C:24]1[CH:31]=[CH:30][CH:29]=[C:26]([C:27]#[N:28])[C:25]=1[C:2]1[CH:3]=[C:4]([C:9]2[N:10]=[C:11]([C:15]3[CH:20]=[CH:19][C:18]([F:21])=[CH:17][C:16]=3[F:22])[N:12]=[N:13][CH:14]=2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: CC1(C)OB(c2c(F)cccc2C#N)OC1(C)C
Reactant: Fc1ccc(-c2nncc(-c3ccc(F)c(Br)c3)n2)c(F)c1
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: [Na+]
Solvent: C1COCCO1
Product: N#Cc1cccc(F)c1-c1cc(-c2cnnc(-c3ccc(F)cc3F)n2)ccc1F
Temperature: 80 °C
Yield: 6.3 %

Procedure:
To a degassed mixture of 5-(3-bromo-4-fluorophenyl)-3-(2,4-difluorophenyl)-[1,2,4]triazine (0.2 g, 0.55 mmol) and 3-fluoro-2-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)benzonitrile (0.270 g, 1.1 mmol) in 1,4-dioxane (6 ml) and sodium carbonate (2 ml, 2N solution) was added tetrakis(triphenylphosphine)palladium(0), and the mixture heated at 80° C. Fog 24 h. The mixture was cooled to ambient temperature and partitioned between water (30 ml) and dichloromethane (40 ml). The aqueous layer was extracted with dichloromethane (2×40 ml) and the combined organics dried over Mg2SO4, filtered and the solvent removed at reduced pressure. The crude product was chromatographed on silica gel, eluent 5% ethyl acetate in dichloromethane, to give the product as a pale yellow solid (0.014 g): δH (400 MHz, CDCl3) 6.99-7.10 (2H, m), 7.49 (4H, m), 8.30-8.44 (3H, m), 9.69 (1H, dd, J 0.8, 2.0 Hz); m/z (ES+) 407.
Reaction SMILES: [OH:1][C@H:2]1[CH2:6][N:5]([S:7]([C:10]2[CH:19]=[CH:18][C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[CH:11]=2)(=[O:9])=[O:8])[C@H:4]([C:20]([OH:22])=[O:21])[CH2:3]1.Cl.[CH3:24]O>>[CH3:24][O:21][C:20]([C@@H:4]1[CH2:3][C@@H:2]([OH:1])[CH2:6][N:5]1[S:7]([C:10]1[CH:19]=[CH:18][C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH:11]=1)(=[O:8])=[O:9])=[O:22]
Reactant: CO
Reactant: O=C(O)[C@@H]1C[C@@H](O)CN1S(=O)(=O)c1ccc2ccccc2c1
Agent: Cl
Product: COC(=O)[C@@H]1C[C@@H](O)CN1S(=O)(=O)c1ccc2ccccc2c1

Procedure:
38.97 g (121.4 mmol) (2S,4R)-4-hydroxy-1-(naphthalene-2-sulfonyl)-pyrrolidine-2-carboxylic acid were dissolved in 97 ml MeOH and 64.5 ml 1.75 M (112.8 mmol) HCl in MeOH were added and the solution heated to reflux for 3 h and concentrated. Trituration with hexane yielded 41.4 g (quant.) (2S,4R)-4-hydroxy-1-(naphthalene-2-sulfonyl)-pyrrolidine-2-carboxylic acid methyl ester as brown solid, MS: 335 (MH+).
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[CH:7][C:6]=1[CH:13]1[C:18](=[O:19])[N:17]([CH3:20])[C:16]2[CH:21]=[CH:22][CH:23]=[CH:24][C:15]=2[S:14]1.Br[CH2:26][CH2:27][CH2:28][Cl:29].C(OCC)(=O)C>CN(C)C=O.O>[Cl:29][CH2:28][CH2:27][CH2:26][C:13]1([C:6]2[CH:7]=[C:8]([O:11][CH3:12])[CH:9]=[CH:10][C:5]=2[O:4][CH3:3])[C:18](=[O:19])[N:17]([CH3:20])[C:16]2[CH:21]=[CH:22][CH:23]=[CH:24][C:15]=2[S:14]1
Reactant: COc1ccc(OC)c(C2Sc3ccccc3N(C)C2=O)c1
Reactant: ClCCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOC(C)=O
Product: COc1ccc(OC)c(C2(CCCCl)Sc3ccccc3N(C)C2=O)c1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 86.9 %

Procedure:
To a stirred suspension of 60% sodium hydride (0.7 g) in anhydrous dimethylformamide (10 ml), 3,4-dihydro-2-(2,5-dimethoxyphenyl)-4-methyl-3-oxo-2H-1,4-benzothiazine (5.0 g) dissolved in anhydrous dimethylformamide (15 ml) is added under nitrogen atmosphere and ice-cooling, and the mixture is stirred for 20 minutes at room temperature. 1-Bromo-3-chloropropane (3.0 g) dissolved in dimethylformamide (5 ml) is added to a reaction mixture, and the mixture is stirred for 1.5 hours at 50° C. The mixture is poured into a mixture of ethyl acetate and water. The organic layer is washed with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate and concentrated in vacuo. The residue is purified by silica gel column chromatography to give 5.4 g (86.9%) of the titled compound as an oily form.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]2[CH:16]3[CH2:17][CH2:18][CH2:19][CH:12]2[C:13](=[CH:21]O)[C:14](=O)[CH2:15]3)(=[O:10])=[O:9])=[CH:4][CH:3]=1.C(O)(=O)C.[CH:27]([NH2:29])=[NH:28]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]2[CH:16]3[CH2:17][CH2:18][CH2:19][CH:12]2[C:13]2[CH:21]=[N:28][CH:27]=[N:29][C:14]=2[CH2:15]3)(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: O=C1CC2CCCC(C1=CO)N2S(=O)(=O)c1ccc(Cl)cc1
Reactant: N=CN
Solvent: CC(=O)O
Product: O=S(=O)(c1ccc(Cl)cc1)N1C2CCCC1c1cncnc1C2

Procedure:
Prepared as described in Example 5 using 9-(4-chlorophenylsulfonyl)-2-(hydroxymethylene)-9-azabicyclo[3.3.1]nonan-3-one which was prepared as described in Example 34 and formamidine acetate. See also: Hajos, Gyorgy; Snatzke, Guenther Liebigs Annalen der Chemie 1989, (1), 31-3.
Reaction SMILES: [CH:1]1[C:13]2[CH:12]([CH2:14][O:15]C(Cl)=O)[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.[NH2:19][C@H:20]1[CH2:43][CH2:42][C@@:41]2([CH3:44])[C@H:22]([CH2:23][C@@H:24]([OH:47])[C@@H:25]3[C@@H:40]2[CH2:39][C@H:38]([OH:45])[C@@:37]2([CH3:46])[C@H:26]3[CH2:27][CH2:28][C@@H:29]2[C@H:30]([CH3:36])[CH2:31][CH2:32][C:33]([OH:35])=[O:34])[CH2:21]1.O>O1CCOCC1.C([O-])([O-])=O.[Na+].[Na+]>[CH:1]1[C:13]2[CH:12]([CH2:14][O:15][NH:19][C@H:20]3[CH2:43][CH2:42][C@@:41]4([CH3:44])[C@H:22]([CH2:23][C@@H:24]([OH:47])[C@@H:25]5[C@@H:40]4[CH2:39][C@H:38]([OH:45])[C@@:37]4([CH3:46])[C@H:26]5[CH2:27][CH2:28][C@@H:29]4[C@H:30]([CH3:36])[CH2:31][CH2:32][C:33]([OH:35])=[O:34])[CH2:21]3)[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: O=C(Cl)OCC1c2ccccc2-c2ccccc21
Reactant: C[C@H](CCC(=O)O)[C@H]1CC[C@H]2[C@@H]3[C@H](O)C[C@@H]4C[C@@H](N)CC[C@]4(C)[C@H]3C[C@H](O)[C@]12C
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: C[C@H](CCC(=O)O)[C@H]1CC[C@H]2[C@@H]3[C@H](O)C[C@@H]4C[C@@H](NOCC5c6ccccc6-c6ccccc65)CC[C@]4(C)[C@H]3C[C@H](O)[C@]12C
Temperature: 0 °C
Yield: 71 %

Procedure:
A solution of 9-fluorenylmethoxycarbonyl chloride (1.4 g; 5.4 mmol) in 1,4-dioxane (18 mL) was added dropwise to a suspension of (3β,5β,7α,12α)-3-amino-7,12-dihydroxycholan-24-oic acid A (2.0 g; 4.9 mmol) (3) in 10% aq. Na2CO3 (30 mL) and 1,4-dioxane (18 mL) stirred at 0° C. After 6 h stirring at room temperature H2O (100 mL) was added, the aqueous phase washed with Et2O (2×90 mL) and then 2 M HCl (15 mL) was added (final pH: 1.5). The precipitated solid was filtered, washed with H2O (3×100 mL), vacuum dried and then purified by flash chromatography (4) to give B as a white solid (2.2 g; 3.5 mmol). Yield 71%.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:14](=[O:15])[N:13]([CH3:16])[C:12]([O:17][CH2:18][CH3:19])=[N:11][C:10]=1[C:20]([OH:22])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:23][C:24]1[CH:29]=[CH:28][C:27]([CH2:30][C:31](=[NH:34])[NH:32]O)=[CH:26][CH:25]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>O1CCOCC1.CCOC(C)=O>[CH2:1]([O:8][C:9]1[C:14](=[O:15])[N:13]([CH3:16])[C:12]([O:17][CH2:18][CH3:19])=[N:11][C:10]=1[C:20]1[O:22][N:34]=[C:31]([CH2:30][C:27]2[CH:28]=[CH:29][C:24]([F:23])=[CH:25][CH:26]=2)[N:32]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOc1nc(C(=O)O)c(OCc2ccccc2)c(=O)n1C
Reactant: N=C(Cc1ccc(F)cc1)NO
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CCOc1nc(-c2nc(Cc3ccc(F)cc3)no2)c(OCc2ccccc2)c(=O)n1C
Temperature: 100 °C

Procedure:
A mixture of 5-(benzyloxy)-2-ethoxy-1-methyl-6-oxo-1,6-dihydropyrimidine-4-carboxylic acid (0.5045 g, 3 mmol), 2-(4-fluorophenyl)-N-hydroxyacetimidamide (0.9190, 3.02 mmol), HATU (1.255 g, 3.3 mmol) and DIEA (0.5 mL) in 1,4-dioxane (20 mL) was heated at 100° C. for 6 h. The mixture was cooled, diluted with EtOAc (50 mL), washed with water (10 mL), sat. NaHCO3 (10 mL), brine (10 mL), then dried (Na2SO4), filtered and concentrated to give a brown residue. This residue was purified by flash chromatography on a silica gel column using 7:3 Hexanes/EtOAc as eluant to afford the title compound product (0.68 g, 52% yield) as a yellow solid. 1HNMR (500 MHz, CDCl3) δ: 7.41-7.38 (2H, m), 7.30 (2H, dd, J=8.6, 5.2 Hz), 7.27-7.24 (3H, m), 6.99 (2H, t, J=8.6 Hz), 5.24 (2H, s), 4.52 (2H, q, J=7.0 Hz), 4.13 (2H, s), 3.47 (3H, s), 1.44 (3H, t, J=7.0 Hz). HRMS (M+H) calcd for C23H22N4O4F: 437.1625. found: 437.4719. Anal calcd for C23H21N4O4F: C, 63.29; H, 4.85; N, 12.83. found: C, 62.76; H, 4.84; N, 12.81.
Reaction SMILES: [CH3:1][N:2]1[CH2:6][CH2:5][CH:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[O:3]1.[OH-].[Na+]>C(O)(=O)C.[Zn]>[CH3:1][NH:2][CH2:6][CH2:5][CH:4]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[OH:3]
Reactant: CN1CCC(c2ccccc2)O1
Agent: [Na+]
Agent: [OH-]
Agent: [Zn]
Solvent: CC(=O)O
Product: CNCCC(O)c1ccccc1

Procedure:
2-Methyl-5-phenylisoxazolidine (2.0 g, 12.3 mmol) and Zn powder (1.2 g, 18.3 mmol) in 10 molar aqueous acetic acid are heated to 65-70° C. for 4 hours. Additional Zn powder (0.4 g, 6.1 mmol) is added and heating is continued for one more hour. The reaction mixture is neutralized with sodium hydroxide and extracted with chloroform. The extract is dried (K2CO)3 and concentrated to give N-methyl-3-phenyl-3-hydroxypropylamine.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:10]=[CH:11][C:12]=1[Cl:13])[CH:5]=[CH:6][C:7]([OH:9])=[O:8].[CH3:14]OS(OC)(=O)=O.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:10]=[CH:11][C:12]=1[Cl:13])[CH:5]=[CH:6][C:7]([O:9][CH3:14])=[O:8]
Reactant: COS(=O)(=O)OC
Reactant: O=C(O)C=Cc1ccc(Cl)c(Cl)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COC(=O)C=Cc1ccc(Cl)c(Cl)c1
Yield: 57.9 %

Procedure:
3,4-Dichlorocinnamic acid (6.5g) (Ex.Aldrich), dimethylsulphate (3.77 g), potassium carbonate (4.13 g) and anhydrous acetone heated together under reflux. After cooling and filtration the acetone was removed and the residue recrystallised (80:20-hexane: ether) to give methyl 3,4-dichlorocinnamate as a colourless solid (4 g).
Reaction SMILES: [Na+].[C:2]([O:5][C:6]1[C:15]([O:16][C:17](=[O:19])[CH3:18])=[CH:14][C:13]2[C:8](=[CH:9][C:10]([S:20]([O-:23])(=O)=[O:21])=[CH:11][CH:12]=2)[CH:7]=1)(=[O:4])[CH3:3].S(Cl)([Cl:26])=O>CN(C=O)C>[C:2]([O:5][C:6]1[C:15]([O:16][C:17](=[O:19])[CH3:18])=[CH:14][C:13]2[C:8](=[CH:9][C:10]([S:20]([Cl:26])(=[O:23])=[O:21])=[CH:11][CH:12]=2)[CH:7]=1)(=[O:4])[CH3:3]
Reactant: CC(=O)Oc1cc2ccc(S(=O)(=O)[O-])cc2cc1OC(C)=O
Reactant: O=S(Cl)Cl
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(=O)Oc1cc2ccc(S(=O)(=O)Cl)cc2cc1OC(C)=O
Temperature: 25 °C

Procedure:
A mixture of 14.4 g. (0.0416 mole) of 2,3-diacetoxy-7-naphthalenesulfonic acid sodium salt, 150 ml. of thionyl chloride and 1 ml. of DMF was stirred 1 hr. at room temperature and 1 hr. at reflux, cooled to room temperature and poured into 1 l. of petroleum ether. The solid was collected, washed with petroleum ether and dried to give 11.3 g. (79.9%) of cream-colored product, m.p. 158°-167° C.
Reaction SMILES: F[B-](F)(F)F.[CH2:6]([O+](CC)CC)[CH3:7].[CH3:13][C:14]1([CH3:21])[NH:17][C:16](=[S:18])[C:15]1([CH3:20])[CH3:19].C([O-])([O-])=O.[K+].[K+]>C(Cl)Cl>[CH2:6]([S:18][C:16]1[C:15]([CH3:20])([CH3:19])[C:14]([CH3:21])([CH3:13])[N:17]=1)[CH3:7]
Reactant: CC1(C)NC(=S)C1(C)C
Reactant: CC[O+](CC)CC
Agent: F[B-](F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Product: CCSC1=NC(C)(C)C1(C)C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 10.5 ml of triethyloxonium tetrafluoroborate as a 1M solution in CH2Cl2, a solution of 1 g (7 mmol) of tetramethylazetidinethione in 3 ml of dry CH2Cl2 was added under an inert atmosphere. The mixture was stirred at room temperature for 1 hour and then at reflux for 1 hour. After cooling, it was added dropwise to 10 ml of a 50% K2CO3 solution at -10° C. After filtration, the organic phase was separated out and immediately dried over MgSO4. Filtration was followed by removal of the solvent under vacuum and the oily residue was subjected to flash silica chromatography (pet. ether: ethyl acetate; 8:2) to obtain the product as a colorless oil.
Reaction SMILES: O.C1(C)C=CC(S(O)(=O)=O)=CC=1.[CH2:13]([O:15][C:16](=[O:37])[CH2:17][O:18][CH2:19]/[CH:20]=[CH:21]\[CH2:22][N:23]1[C:28](=[O:29])[CH2:27][CH2:26][CH2:25][C@@H:24]1[CH2:30][O:31]C(OCC)C)C>CO>[CH3:13][O:15][C:16](=[O:37])[CH2:17][O:18][CH2:19]/[CH:20]=[CH:21]\[CH2:22][N:23]1[C:28](=[O:29])[CH2:27][CH2:26][CH2:25][C@@H:24]1[CH2:30][OH:31]
Reactant: CCOC(=O)COC/C=C\CN1C(=O)CCC[C@@H]1COC(C)OCC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CO
Product: COC(=O)COC/C=C\CN1C(=O)CCC[C@@H]1CO
Reaction time: 17 h
Yield: 64.4 %

Procedure:
p-Toluenesulfonic acid hydrate (620 mg, 3.26 mmol) was added to a solution of {(Z)-4-[(R)-2-(1-ethoxyethoxymethyl)-6-oxo-piperidin-1-yl]-but-2-enyloxy}-acetic acid ethyl ester (1.10 g, 3.08 mmol) in MeOH (10 mL). After 17 h at rt, the reaction was quenched with saturated aqueous NaHCO3 (20 mL) and the mixture was extracted with CH2Cl2 (3×30 mL). The combined organic phase was dried (Na2SO4), filtered and concentrated in vacuo. Purification of the residue by flash column chromatography on silica gel (40% EtOAc/CH2Cl2→60% EtOAc/CH2Cl2, gradient, then 7% MeOH/CH2Cl2) afforded 538 mg (64%) of [(Z)-4-((R)-2-hydroxymethyl-6-oxo-piperidin-1-yl)-but-2-enyloxy]-acetic acid methyl ester.
Reaction SMILES: [CH2:1]([N:3]([Si](C)(C)C)[CH2:4][CH3:5])C.[CH3:10][O:11][S:12]([O-:15])(=[O:14])=[O:13].[CH3:16][NH+:17]1[CH2:21][CH2:20][N:19](C)[CH:18]1Cl>C(Cl)(Cl)Cl>[CH3:10][O:11][S:12]([O-:15])(=[O:14])=[O:13].[CH3:1][NH+:3]1[CH2:4][CH2:5][N:19]([CH3:20])[CH:18]1[N:17]([CH3:21])[CH3:16]
Reactant: CCN(CC)[Si](C)(C)C
Reactant: CN1CC[NH+](C)C1Cl
Agent: COS(=O)(=O)[O-]
Solvent: ClC(Cl)Cl
Product: CN(C)C1N(C)CC[NH+]1C
Yield: 85.1 %

Procedure:
1.33 g (11.34 mmol) of N,N-diethyltrimethylsilylamine are added over the course of 5 minutes at room temperature and with vigorous stirring to 2.50 g (10.22 mmol) of 1,3-dimethyl-2-chloroimidazolidinium methylsulfate in 10 ml of dry chloroform. The solvent is distilled off, and the residue is washed three times with 5 ml of diethyl ether and subsequently dried under a reduced pressure of 7.0 Pa and at 50° C. for 1 hour. The product is crystallised from a mixture of tetrahydrofuran:diethyl ether (1:1), giving 2.22 g of 1,3-dimethyl-2-dimethylaminoimidazolidinium methylsulfate, corresponding to a yield of 85.7%.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:24])[NH:10][C@H:11]([C:18](=[O:23])N(OC)C)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:25][O:26][C:27]1[CH:32]=[CH:31][C:30]([Mg]Br)=[CH:29][CH:28]=1.CCOC(C)=O>C1COCC1>[CH2:1]([O:8][C:9](=[O:24])[NH:10][C@@H:11]([C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1)[C:18]([C:30]1[CH:31]=[CH:32][C:27]([O:26][CH3:25])=[CH:28][CH:29]=1)=[O:23])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1ccc([Mg]Br)cc1
Reactant: CON(C)C(=O)[C@@H](NC(=O)OCc1ccccc1)c1ccccc1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COc1ccc(C(=O)[C@@H](NC(=O)OCc2ccccc2)c2ccccc2)cc1
Reaction time: 3 h

Procedure:
To a cold (0° C.) solution of the amide 482 (328 mg, 1.0 mmol) in THF (20 mL) is added 0.5M 4-methoxyphenylmagnesium bromide in THF (8.0 mL, 4.0 mmol), and the mixture is allowed to come to rt and stirred at this temperature for 3 h. The reaction mixture is poured into a mixture of ammonium chloride/ice followed by the addition of EtOAc. The organic layer is separated, washed with brine, dried (MgSO4), and filtered. The filtrate is evaporated, and the residue purified by chromatography on silica gel; elution with heptane:EtOAc (85:15) gives 2.12 g of the product 483. 1H NMR (CDCl3) δ 7.95 (d, 2H), 7.45-7.20 (m, 10H), 6.88 (d, 2H), 6.50-6.20 (m, 2H), 5.25-5.00 (m, 2H), 3.81 (s, 3H)
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:11]=[CH:10][C:9]([C:12]2[N:17]3[CH:18]=[N:19][CH:20]=[C:16]3[CH:15]=[CH:14][CH:13]=2)=[CH:8][CH:7]=1)=O)C.[H-].C([Al+]CC(C)C)C(C)C.C1(C)C=CC=CC=1.CO>C(Cl)Cl>[OH:3][CH2:4][C:6]1[CH:7]=[CH:8][C:9]([C:12]2[N:17]3[CH:18]=[N:19][CH:20]=[C:16]3[CH:15]=[CH:14][CH:13]=2)=[CH:10][CH:11]=1
Reactant: CCOC(=O)c1ccc(-c2cccc3cncn23)cc1
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: Cc1ccccc1
Solvent: CO
Solvent: ClCCl
Product: OCc1ccc(-c2cccc3cncn23)cc1
Reaction time: 1 h

Procedure:
5-(p-Ethoxycarbonylphenyl)-imidazo[1,5-a]pyridine (1.0 g) is dissolved in 26 ml of methylene chloride at -78° under nitrogen and 6.6 ml of diisobutylaluminum hydride in toluene (11.4 mmole) is added dropwise. After stirring for 1 hour, 1.5 ml of methanol is added, the cold bath is removed and 15 ml of water is added. The salts are filtered off, the organic phase is dried over sodium sulfate and evaporated to yield 5-(p-hydroxymethylphenyl)imidazo[1,5-a]pyridine, m.p. 137°-138°.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([O:8][C@@H:9]([CH3:13])[CH2:10][O:11][CH3:12])[C:5]([Cl:14])=[CH:4][N:3]=1.COC1C=CC(C[NH2:22])=CC=1.FC(F)(F)C(O)=O>CN(C=O)C>[Cl:14][C:5]1[C:6]([O:8][C@@H:9]([CH3:13])[CH2:10][O:11][CH3:12])=[N:7][C:2]([NH2:22])=[N:3][CH:4]=1
Reactant: COC[C@H](C)Oc1nc(Cl)ncc1Cl
Reactant: COc1ccc(CN)cc1
Solvent: CN(C)C=O
Solvent: O=C(O)C(F)(F)F
Product: COC[C@H](C)Oc1nc(N)ncc1Cl
Temperature: 50 °C
Reaction time: 18 h

Procedure:
A mixture of (S)-2,5-dichloro-4-((1-methoxypropan-2-yl)oxy)pyrimidine (intermediate 91, 1.26 g, 4.15 mmol) and 4-methoxybenzylamine (0.65 ml, 4.97 mmol) in DMF (7 ml) was heated at 50° C. for 18 h. The reaction mixture was partitioned between aqueous 1M HCl and DCM, extracted with DCM (2×), the combined DCM layers were washed with water, dried over Na2SO4 and evaporated. To the residue was added trifluoroacetic acid (3.93 ml, 51.0 mmol) and the reaction mixture stood at room temperature for 18 h, heated for 5 h at 70° C., stood 3 days at room temperature, heated at 80° C. for 2 days. The reaction mixture was evaporated and purified by a combination of normal and reversed phase chromatography (RP 3) to give the title compound as a colorless oil. (UPLC-MS 7) tR 0.74; ESI-MS 218.1 and 220.1 [M+H]+.
Reaction SMILES: [F:1][CH:2]([F:16])[C:3]([O:11][Si:12]([CH3:15])([CH3:14])[CH3:13])([CH2:7][CH2:8][CH2:9][CH3:10])[CH2:4][C:5]#[CH:6].[CH2:17]([SnH:21]([CH2:26][CH2:27][CH2:28][CH3:29])[CH2:22][CH2:23][CH2:24][CH3:25])[CH2:18][CH2:19][CH3:20].N(C(C)(C)C#N)=NC(C)(C)C#N>>[F:16][CH:2]([F:1])[C:3]([O:11][Si:12]([CH3:15])([CH3:13])[CH3:14])([CH2:7][CH2:8][CH2:9][CH3:10])[CH2:4]/[CH:5]=[CH:6]/[Sn:21]([CH2:22][CH2:23][CH2:24][CH3:25])([CH2:26][CH2:27][CH2:28][CH3:29])[CH2:17][CH2:18][CH2:19][CH3:20]
Reactant: C#CCC(CCCC)(O[Si](C)(C)C)C(F)F
Reactant: CCCC[SnH](CCCC)CCCC
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Product: CCCCC(C/C=C/[Sn](CCCC)(CCCC)CCCC)(O[Si](C)(C)C)C(F)F
Temperature: 25 °C

Procedure:
A mixture of 13.0 g. of 4-difluoromethyl-4-trimethylsiloxy-1-octyne, 17.23 ml. of tri-n-butylstannane and 70 mg. of azobisisobutyronitrile is heated under nitrogen in an oil bath at 125°-135° C. for 2 hours. The reaction is cooled to room temperature and vacuum distilled through a short-path apparatus, giving, after a 5 ml. forerun, 25.6 g. of the product as an oil, containing a minor amount of the corresponding cis isomer.
Reaction SMILES: [F:1][C:2]([F:24])([F:23])[C:3]1[CH:22]=[CH:21][C:6]([O:7][C:8]2[CH:9]=[CH:10][C:11]([N+:18]([O-:20])=[O:19])=[C:12]([CH:17]=2)[C:13]([O:15][CH3:16])=[O:14])=[CH:5][CH:4]=1.[Cl:25]Cl.O>CCOCC>[Cl:25][C:5]1[CH:4]=[C:3]([C:2]([F:23])([F:24])[F:1])[CH:22]=[CH:21][C:6]=1[O:7][C:8]1[CH:9]=[CH:10][C:11]([N+:18]([O-:20])=[O:19])=[C:12]([CH:17]=1)[C:13]([O:15][CH3:16])=[O:14]
Reactant: COC(=O)c1cc(Oc2ccc(C(F)(F)F)cc2)ccc1[N+](=O)[O-]
Reactant: ClCl
Solvent: O
Solvent: CCOCC
Product: COC(=O)c1cc(Oc2ccc(C(F)(F)F)cc2Cl)ccc1[N+](=O)[O-]
Reaction time: 2.5 h

Procedure:
Methyl 5-(4-trifluoromethylphenoxy)-2-nitrobenzoate is stirred with a catalytic amount of ferric chloride. The reaction mixture was heated to 70° C. under a continuous stream of chlorine gas. After 2.5 hours, the mixture was taken up in ether, shaken with water and the organic phase was dried over MgSO4. The ether was evaporated to afford methyl 5-(2-chloro-4-trifluoromethylphenoxy)-2-nitrobenzoate. NMR (CDCl3)δ8.2-7 (m,6) 4.0 (2,3). TLC (40% ether/hexane) Rf ≈.4.
Reaction SMILES: Cl[C:2]1[C:7]([CH:8]=[O:9])=[C:6]([NH:10][C:11]2[C:16]([F:17])=[CH:15][CH:14]=[CH:13][C:12]=2[F:18])[N:5]=[C:4]([S:19][CH3:20])[N:3]=1.[F:21][C:22]1[CH:27]=[CH:26][C:25](B(O)O)=[C:24]([CH3:31])[CH:23]=1>>[F:18][C:12]1[CH:13]=[CH:14][CH:15]=[C:16]([F:17])[C:11]=1[NH:10][C:6]1[C:7]([CH:8]=[O:9])=[C:2]([C:25]2[CH:26]=[CH:27][C:22]([F:21])=[CH:23][C:24]=2[CH3:31])[N:3]=[C:4]([S:19][CH3:20])[N:5]=1
Reactant: CSc1nc(Cl)c(C=O)c(Nc2c(F)cccc2F)n1
Reactant: Cc1cc(F)ccc1B(O)O
Product: CSc1nc(Nc2c(F)cccc2F)c(C=O)c(-c2ccc(F)cc2C)n1

Procedure:
Prepared as described above in Example 2 starting from 4-chloro-6-(2,6-difluoro-phenylamino)-2-methylsulfanyl-pyrimidine-5-carbaldehyde and 4-fluoro-2-methyl-phenylboronic acid to give the title compound 4-(2,6-difluoro-phenylamino)-6-(4-fluoro-2-methyl-phenyl)-2-methylsulfanyl-pyrimidine-5-carbaldehyde. 1H-NMR: δ 2.21 (s, 3H), 2.25 (s, 3H), 6.95 (m, 4H), 7.18 (m, 4H), 9.54 (s, 1H), 10.29 (br s, 1H). LC MS (m/e)=390 (MH+).