Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([N:6]1[C:14]2[C:9](=[C:10]([CH3:17])[C:11]([OH:16])=[C:12]([CH3:15])[CH:13]=2)[CH:8]([CH3:18])[CH2:7]1)(=[O:5])[CH:2]([CH3:4])[CH3:3].N1C=CC=CC=1.[C:25](OC(=O)C)(=[O:27])[CH3:26]>C(Cl)Cl>[C:1]([N:6]1[C:14]2[C:9](=[C:10]([CH3:17])[C:11]([O:16][C:25](=[O:27])[CH3:26])=[C:12]([CH3:15])[CH:13]=2)[CH:8]([CH3:18])[CH2:7]1)(=[O:5])[CH:2]([CH3:4])[CH3:3]
Reactant: Cc1cc2c(c(C)c1O)C(C)CN2C(=O)C(C)C
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(=O)Oc1c(C)cc2c(c1C)C(C)CN2C(=O)C(C)C
Temperature: 0 °C
Reaction time: 17 h
Yield: 77.8 %

Procedure:
To an ice-cold solution of N-isobutyryl-5-hydroxy-3,4,6-trimethylindoline (11b, 49 mg, 0.2 mmol) dissolved in methylene chloride (2 mL) were added sequentially pyridine (0.16 mL, 2 mmol) and acetic anhydride (0.1 mL, 1 mmol). The mixture was stirred over the range of 0° C. to room temperature for 17 h. The mixture was diluted with methylene chloride, transferred to a separatory funnel and washed sequentially with 10% hydrochloric acid, saturated aq. sodium bicarbonate and brine. Removal of solvents after drying (MgSO4) gave a viscous liquid, which was purified by flash column chromatography, using 1:4 ethyl acetate:hexanes as eluent, to afford the N-isobutyryl-5-acetoxy-3,4,6-trimethylindoline (12b, 45 mg, 77% yield) as a colorless solid, mp 118°-120° C. Spectral data: 1H NMR: δ 2.0 (s, 3H), 2.06 (s, 3H), 2.26 (s, 3H), 2.7 (quintet, 1H, J=6.7 Hz), 3.3 (t, 1H, J=6.7 Hz), 3.7 (dd, 1H, J=10.2, 1.2 Hz), 4.1 (t, 1H, J=9.3 Hz), 8.0 (s, 1H); CI-HRMS: calcd. for C17H24NO3 (M+H+) 290.1756, fnd. 290.1756.
Reaction SMILES: FC(F)(F)C(O)=O.[Cl:8][C:9]1[CH:10]=[CH:11][C:12]([CH2:15][O:16][C:17]2[CH:22]=[CH:21][N:20]([C:23]3[CH:28]=[CH:27][C:26]([O:29][C@@H:30]4[CH2:34][CH2:33][N:32](C(OC(C)(C)C)=O)[CH2:31]4)=[CH:25][CH:24]=3)[C:19](=[O:42])[CH:18]=2)=[N:13][CH:14]=1>C(Cl)(Cl)Cl>[Cl:8][C:9]1[CH:10]=[CH:11][C:12]([CH2:15][O:16][C:17]2[CH:22]=[CH:21][N:20]([C:23]3[CH:24]=[CH:25][C:26]([O:29][C@@H:30]4[CH2:34][CH2:33][NH:32][CH2:31]4)=[CH:27][CH:28]=3)[C:19](=[O:42])[CH:18]=2)=[N:13][CH:14]=1
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](Oc2ccc(-n3ccc(OCc4ccc(Cl)cn4)cc3=O)cc2)C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClC(Cl)Cl
Product: O=c1cc(OCc2ccc(Cl)cn2)ccn1-c1ccc(O[C@@H]2CCNC2)cc1
Temperature: 25 °C
Yield: 105.6 %

Procedure:
Trifluoroacetic acid (20 mL) was added to chloroform solution (20 mL) of 4-[(5-chloro-2-pyridinyl)methoxy]-1-(4-{[(3R)-1-(tert-butoxycarbonyl)-3-pyrrolidinyl]oxy}phenyl)-1H-pyridin-2-one (3.14 g, Example 121), and stirred at room temperature for an hour. After concentrating the reaction liquid, 1N sodium hydroxide solution was added thereto, followed by extraction with chloroform two times. The organic layer was washed with saturated brine, dried over anhydrous potassium carbonate, and the solvent was concentrated under reduced pressure to provide the title compound (2.65 g, 83%).
Reaction SMILES: [N:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[NH:3][CH:2]=1.[OH-].[Na+].O.S(OCC)(O[CH2:17][CH3:18])(=O)=O>O1CCCC1>[CH2:17]([N:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1)[CH3:18]
Reactant: CCOS(=O)(=O)OCC
Reactant: c1ccc2[nH]cnc2c1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CCn1cnc2ccccc21
Reaction time: 2 h
Yield: 88.4 %

Procedure:
To a flask were added 100 g benzimidazole, 44 g Sodium hydroxide, 320 ml water and 480 ml tetrahydrofuran and the mixture was stirred under nitrogen. 157 g Diethyl sulfate were added slowly, maintaining a temperature of 40 C. After 2 hrs at 40 C, the reaction was quenched with slow addition of 100 ml concentrated hydrochloric acid. After washing with 150 ml hexane, the mixture was basified with 50 g Sodium hydroxide and extracted with 275 ml ethyl acetate, then 225 ml ethyl acetate. The solvent was removed, leaving an orange oil, which was distilled under full vacuum to give 109.4 g clear colorless oil.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH:8]=[CH:9][C:10]([O:12][CH3:13])=[O:11])=[C:4]([F:14])[CH:3]=1.[CH2:15]([NH:22][C:23](=[O:41])[N:24]([CH3:40])[C:25]1[CH:30]=[CH:29][CH:28]=[C:27](B2OC(C)(C)C(C)(C)O2)[CH:26]=1)[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21].O>CN(C)C=O.P([O-])([O-])([O-])=O.[K+].[K+].[K+].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:14][C:4]1[CH:3]=[C:2]([C:29]2[CH:28]=[CH:27][CH:26]=[C:25]([N:24]([CH3:40])[C:23]([NH:22][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])=[O:41])[CH:30]=2)[CH:7]=[CH:6][C:5]=1[CH:8]=[CH:9][C:10]([O:12][CH3:13])=[O:11]
Reactant: CCCCCCCNC(=O)N(C)c1cccc(B2OC(C)(C)C(C)(C)O2)c1
Reactant: COC(=O)C=Cc1ccc(Br)cc1F
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCCCCCNC(=O)N(C)c1cccc(-c2ccc(C=CC(=O)OC)c(F)c2)c1
Temperature: 90 °C
Reaction time: 2 h
Yield: 42 %

Procedure:
44 mg (5 mol %) of tetrakis(triphenylphosphine)palladium are added to a solution of 200 mg (0.77 mmol, 1.0 eq) of methyl 3-(4-bromo-2-fluorophenyl)acrylate and 430 mg (1.15 mmol, 1.5 eq) of 3-heptyl-1-methyl-1-[3-(4,4,5,5-tetramethyl[1,3,2]dioxaborolan-2-yl)phenyl]urea (prepared as in 1e) in a mixture of dimethylformamide and 2M potassium phosphate solution (8/2). The reaction mixture is stirred for 2 hours at 90° C. The reaction is stopped by addition of 10 mL of water and then extracted with ethyl acetate. The organic phases are combined and dried over sodium sulfate. The solvents are evaporated off and the residue is then chromatographed on silica gel (70/30 heptane/ethyl acetate). 138 mg of methyl 3-[3-fluoro-3′-(3-heptyl-1-methylureido)biphenyl-4-yl]acrylate are obtained. Yield=42%
Reaction SMILES: [CH3:1][NH:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].CCN(C(C)C)C(C)C.[N:18]([C:21]([CH3:27])([CH3:26])[CH2:22][C:23](Cl)=[O:24])=[N+:19]=[N-:20]>ClCCCl>[N:18]([C:21]([CH3:27])([CH3:26])[CH2:22][C:23]([N:2]([CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8])[CH3:1])=[O:24])=[N+:19]=[N-:20]
Reactant: CC(C)(CC(=O)Cl)N=[N+]=[N-]
Reactant: CCCCCCNC
Solvent: ClCCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCCCCCN(C)C(=O)CC(C)(C)N=[N+]=[N-]
Temperature: 25 °C
Reaction time: 1 h
Yield: 69.2 %

Procedure:
To a stirred ice cold solution of N-methylhexan-1-amine (4.69 mL, 1.0 equiv, 30.9 mmol) and DIEA (7.0 mL, 1.3 equiv, 40.2 mmol) in anhydrous DCE (150 mL) was added 3-azido-3-methylbutanoyl chloride (5.0 g, 30.9 mmol) in small portions over 5 min. The reaction was removed from the ice bath and stirred at room temperature for 1 h. The reaction mixture was poured into a separatory funnel and washed with 1 M HCl (3×100 mL) and saturated sodium hydrogen carbonate (2×100 mL). The organic layer was separate and dried over anhydrous MgSO4, filtered, concentrated and dried under high vacuum to give a yellow oil (5.14 g, 72.0%). This material was used without further purification. 1H NMR (CDCl3, 400 MHz): δ 0.88-0.94 (m, 3H), 1.2-1.35 (m, 6H), 1.47 (d, 6H), 1.47-1.66 (m, 2H), 2.51 (s, 2H), 2.94-3.04 (d, J=40 Hz, 3 H), 3.30-3.40 (m, 2H). LRMS (ESI+) for C12H24N4O (240.2); Found: 241 (MH+).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([OH:9])[CH:5]=[CH:6][C:7]=1[CH3:8].FC(F)(F)C(O)=O.[N:17]([O-:19])=[O:18].[Na+]>O>[CH3:8][C:7]1[C:2]([CH3:1])=[CH:3][C:4]([OH:9])=[C:5]([N+:17]([O-:19])=[O:18])[CH:6]=1
Reactant: O=N[O-]
Reactant: Cc1ccc(O)cc1C
Agent: [Na+]
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc(O)c([N+](=O)[O-])cc1C
Temperature: 25 °C
Reaction time: 14 h
Yield: 80 %

Procedure:
To 3,4-dimethylphenol(12.1 g, 0.1 mol), trifluoroacetic acid(250 ml) was added, and in water bath sodium nitrite(12.4 g, 0.18 mol) was added slowly. The resulting mixture was stirred at room temperature for 14 hours and concentrated under the reduced pressure to remove trifluoroacetic acid, followed by addition of water(150 ml), extracted with ether and purified by column chromatography to obtain the titled compound.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][N:3]=1.[Cl:9][CH2:10][C:11](Cl)=[O:12]>>[Cl:9][CH2:10][C:11]([NH:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][N:3]=1)=[O:12]
Reactant: Cc1ccnc(N)c1
Reactant: O=C(Cl)CCl
Product: Cc1ccnc(NC(=O)CCl)c1
Yield: 74 %

Procedure:
The sub-titled compound (1.3 g, 74%, solid) was prepared by a similar procedure to that used to prepare Example 14f using 2-amino-4-methylpyridine in place of 2-amino-pyridine and adding the chloroacetyl chloride at room temperature rather than at 0° C.
Reaction SMILES: [H-].[Na+].CCCCCC.[CH3:9][O:10][C:11]1[CH:17]=[CH:16][CH:15]=[C:14]([N+:18]([O-:20])=[O:19])[C:12]=1[NH2:13].[Br:21][CH2:22][C:23](Br)=[O:24]>C1COCC1>[Br:21][CH2:22][C:23]([NH:13][C:12]1[C:14]([N+:18]([O-:20])=[O:19])=[CH:15][CH:16]=[CH:17][C:11]=1[O:10][CH3:9])=[O:24]
Reactant: O=C(Br)CBr
Reactant: COc1cccc([N+](=O)[O-])c1N
Agent: [H-]
Agent: [Na+]
Solvent: CCCCCC
Solvent: C1CCOC1
Product: COc1cccc([N+](=O)[O-])c1NC(=O)CBr
Temperature: 25 °C
Reaction time: 3 h
Yield: 83.6 %

Procedure:
To a flask was added sodium hydride (60% dispersion in mineral oil, 610 mg, 15 mmol) and hexane (2 mL) at 0° C. The supernatant liquid was decanted and the residue was dried under reduced pressure. To this was added THF (20 mL) and a solution of 2-methoxy-6-nitroaniline (2 g, 12 mmol, Kubo, K. et al. J. Med. Chem. 1993, 36, 1772-1784) in THF (20 mL) at 0° C. and stirred at rt for 2 h. To this mixture was added bromoacetyl bromide (1.2 mL, 14 mmol) at 0° C. and stirred at rt for 3 h. Then the reaction mixture was quenched by addition of water (100 mL) and extracted with ethyl acetate (100 mL×2). The combined organic layers were washed with brine (100 mL), dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography on silica gel eluting with hexane/ethyl acetate (2/1-1/1) to afford 2.9 g (85%) of the title compound.
Reaction SMILES: O[CH2:2]/[CH:3]=[CH:4]\[CH2:5][CH2:6][CH2:7][C:8]([O:10][CH3:11])=[O:9].P(Br)(Br)[Br:13]>>[Br:13][CH2:2]/[CH:3]=[CH:4]\[CH2:5][CH2:6][CH2:7][C:8]([O:10][CH3:11])=[O:9]
Reactant: COC(=O)CCC/C=C\CO
Reactant: BrP(Br)Br
Product: COC(=O)CCC/C=C\CBr

Procedure:
To 23.7 g of cis-7-hydroxy-5-heptenoic acid, methyl ester and 150 ml of hexanes under nitrogen at 0° C. was added dropwise, 7.05 ml of phosphorous tribromide. After 2 hours the reaction was quenched with ice, diluted with hexanes, washed once with water and once with saturated aqueous bicarbonate, dried and stripped at reduced pressure. The crude product was dissolved in ether and filtered through a plug of silica gel. Removal of the ether at reduced pressure gave 31.4 g of the desired compound. NMR: 5.95-5.35 ppm (2H, m, olefins), 3.95 ppm (2H, d, 7 Hz, BrCH2), 3.65 ppm (3H, s, OMe), 2.45-2.05 ppm (4H, m, CH2 --CH2), 1.8 ppm (2H, q, 7 Hz, CH2).
Reaction SMILES: [NH2:1][C:2]1[NH:6][N:5]=[C:4]([CH3:7])[C:3]=1[C:8]1[S:9][C:10]2[CH:16]=[C:15]([S:17](Cl)(=[O:19])=[O:18])[C:14]([F:21])=[CH:13][C:11]=2[N:12]=1.FC1C=CC2SC(C3C(C)=NNC=3N)=NC=2C=1.[N:39]1[CH:44]=[CH:43][C:42]([CH2:45][NH2:46])=[CH:41][CH:40]=1.C(N(CC)CC)C>C(Cl)(Cl)Cl>[N:39]1[CH:44]=[CH:43][C:42]([CH2:45][NH:46][S:17]([C:15]2[C:14]([F:21])=[CH:13][C:11]3[N:12]=[C:8]([C:3]4[C:4]([CH3:7])=[N:5][NH:6][C:2]=4[NH2:1])[S:9][C:10]=3[CH:16]=2)(=[O:19])=[O:18])=[CH:41][CH:40]=1
Reactant: NCc1ccncc1
Reactant: Cc1n[nH]c(N)c1-c1nc2cc(F)c(S(=O)(=O)Cl)cc2s1
Agent: Cc1n[nH]c(N)c1-c1nc2cc(F)ccc2s1
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: Cc1n[nH]c(N)c1-c1nc2cc(F)c(S(=O)(=O)NCc3ccncc3)cc2s1
Yield: 24 %

Procedure:
The title compound (15 mg) was prepared from crude 2-(5-amino-3-methyl-1H-pyrazol-4-yl)-5-fluorobenzothiazole-6-sulfonyl chloride, which had been derived from the chlorosulfonation of 90 mg of 4-(5-fluorobenzothiazol-2-yl)-5-methyl-2H-pyrazol-3-ylamine, 32 mg (0.30 mmol) of C-pyridin-4-ylmethylamine, and triethylamine (0.50 mL) in chloroform. MS (m/z, ES+): 419.1 (M+1, 100%), 210.0 (100%). Yield=24%.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[C:16]3[O:15][CH:14]([CH2:17][NH2:18])[CH2:13][C:12]=3[CH:11]=[CH:10][CH:9]=2)[CH:5]=[CH:6][CH:7]=1.C(N(C(C)C)CC)(C)C.Cl[C:29]([O:31][CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)=[O:30]>>[CH2:32]([O:31][C:29](=[O:30])[NH:18][CH2:17][CH:14]1[CH2:13][C:12]2[CH:11]=[CH:10][CH:9]=[C:8]([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=3)[C:16]=2[O:15]1)[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: NCC1Cc2cccc(-c3cccc(Cl)c3)c2O1
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NCC1Cc2cccc(-c3cccc(Cl)c3)c2O1)OCc1ccccc1
Yield: 74.8 %

Procedure:
Treatment of (±)-1-[7-(3-chlorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methanamine (1.6 g, 5.4 mmol) with diisopropylethylamine (1.197 g, 9.26 mmol) and benzyl chloroformate (1.02 g, 5.96 mmol) generally according to the procedure described for Intermediate 12 afforded 1.59 g (75%) of (±)-benzyl[7-(3-chlorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methylcarbamate as a colorless oil. Rf=0.56 (silica, ethyl acetate:hexanes 1:9); Anal. calcd. for C23H20ClNO3: C, 70.14; H, 5.12; N, 3.56. Found: C, 69.11; H, 5.07; N, 3.37. Chiral HPLC separation of (±)-benzyl[7-(3-chlorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methylcarbamate (Chiralcel OD, hexane:isopropanol 9:1) provided two fractions. Fraction 1 (Rt=15.935 min Chiralcel OD, hexane:isopropanol 9:1); Fraction 2 (Rt=18.546 min, Chiralcel OD, hexane:isopropanol 9:1).
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH:12]=[CH:11][C:10]([N:13]2[CH:18]=[C:17]([O:19][CH3:20])[C:16](=[O:21])[C:15]([C:22]3[N:26]([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)[N:25]=[CH:24][CH:23]=3)=[N:14]2)=[C:9]([F:33])[CH:8]=1)(=O)=O.[CH3:36][C:37]1[C:41](B(O)O)=[C:40]([CH3:45])[O:39][N:38]=1.C([O-])([O-])=O.[Na+].[Na+].COCCOC>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.O>[CH3:36][C:37]1[C:41]([C:7]2[CH:12]=[CH:11][C:10]([N:13]3[CH:18]=[C:17]([O:19][CH3:20])[C:16](=[O:21])[C:15]([C:22]4[N:26]([C:27]5[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=5)[N:25]=[CH:24][CH:23]=4)=[N:14]3)=[C:9]([F:33])[CH:8]=2)=[C:40]([CH3:45])[O:39][N:38]=1
Reactant: COc1cn(-c2ccc(OS(=O)(=O)C(F)(F)F)cc2F)nc(-c2ccnn2-c2ccccc2)c1=O
Reactant: Cc1noc(C)c1B(O)O
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: O
Solvent: COCCOC
Product: COc1cn(-c2ccc(-c3c(C)noc3C)cc2F)nc(-c2ccnn2-c2ccccc2)c1=O
Temperature: 25 °C
Yield: 58.8 %

Procedure:
A mixture of 3-fluoro-4-[5-methoxy-4-oxo-3-(1-phenyl-1H-pyrazol-5-yl)pyridazin-1(4H)-yl]phenyl trifluoromethanesulfonate (230 mg, 0.45 mmol); 3,5-dimethylisoxazole-4-boronic acid (70 mg, 0.50 mmol), Pd(PPh3)4 (29 mg, 0.025 mmol), Na2CO3 (106 mg, 1.0 mmol), DME (4 mL), and H2O (1 mL) was refluxed for 3 h under Ar atmosphere. After cooling to room temperature, the reaction mixture was poured into water and extracted with AcOEt. The extract was washed with brine, dried over MgSO4, and concentrated under reduced pressure. The residue was purified by basic silica gel column chromatography eluting with THF and recrystallized from MeOH/H2O to give the title compound (121 mg, 59% yield) as a white solid: mp 200-202° C.; 1H NMR (300 MHz, CDCl3): δ ppm 2.27 (3H, s), 2.42 (3H, s), 3.92 (3H, s), 6.49 (1H, t, J=8.3 Hz), 6.89 (1H, ddd, J=0.8, 1.9, 8.3 Hz), 7.08 (1H, dd, J=1.9, 12.1 Hz), 7.32 (1H, d, J=1.9 Hz), 7.35-7.47 (5H, m), 7.79 (1H, d, J=1.9 Hz), 7.85 (1H, d, J=2.3 Hz). LC-MS (ESI) m/z 458 [M+H]+. Anal. Calcd for C25H2FN5O3: C, 65.64; H, 4.41; N, 15.31. Found: C, 65.55; H, 4.32; N, 15.33.
Reaction SMILES: F[C:2]1[C:3]([CH3:15])=[C:4]([CH:8]=[CH:9][C:10]=1[C:11]([F:14])([F:13])[F:12])[C:5]([OH:7])=[O:6].[H-].[Na+].[CH2:18]([SH:20])[CH3:19].Cl>CN(C)C=O>[CH2:18]([S:20][C:2]1[C:3]([CH3:15])=[C:4]([CH:8]=[CH:9][C:10]=1[C:11]([F:14])([F:13])[F:12])[C:5]([OH:7])=[O:6])[CH3:19]
Reactant: Cc1c(C(=O)O)ccc(C(F)(F)F)c1F
Reactant: CCS
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCSc1c(C(F)(F)F)ccc(C(=O)O)c1C
Temperature: 25 °C
Reaction time: 2 h

Procedure:
3.00 g (13.5 mmol) of 3-fluoro-2-methyl-4-trifluoromethylbenzoic acid were initially charged in 50 ml of N,N-dimethylformamide. 1.68 g (purity 60% by weight, 41.9 mmol) of NaH were added a little at a time. Towards the end of the evolution of gas, 1.77 g (purity 95% by weight, 27.0 mmol) of ethanethiol were added dropwise. The mixture was stirred at RT for 2 h and then heated at 80° C. for 10 h. The reaction mixture was cooled and, for workup, poured into ice-water and then acidified with concentrated hydrochloric acid. The product precipitated out and was separated off by filtration. What was isolated were 3.7 g of the pure product.
Reaction SMILES: [OH:1][CH:2]1[C:7](=O)[CH2:6][CH2:5][N:4]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:3]1.[C:16](#[N:20])[CH2:17][C:18]#[N:19].C(NCC)C>C(O)C>[NH2:20][C:16]1[O:1][C:2]2[CH2:3][N:4]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:5][CH2:6][C:7]=2[C:17]=1[C:18]#[N:19]
Reactant: CC(C)(C)OC(=O)N1CCC(=O)C(O)C1
Reactant: N#CCC#N
Solvent: CCO
Solvent: CCNCC
Product: CC(C)(C)OC(=O)N1CCc2c(oc(N)c2C#N)C1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 47.9 %

Procedure:
tert-Butyl 3-hydroxy-4-oxopiperidine-1-carboxylate from Example 45A (3.88 g, 64% purity, 11.5 mmol) was dissolved in ethanol (10 mL), and propanedinitrile (758 mg, 11.5 mmol) was added. Within 10 min, diethylamine (0.84 g, 11.5 mmol) was added dropwise, whilst the temperature was kept below 30° C. Subsequently, the reaction mixture was stirred for 20 h at rt. The solvent was removed in vacuo, and the residue was purified by column chromatography on silica gel (eluent: cyclohexane/ethyl acetate 2:1). The product was triturated with petroleum ether/tert-butyl methyl ether (3:1) to yield 1.45 g (47%) of the title compound as yellow crystals.
Reaction SMILES: [CH2:1]([OH:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([Li:13])CCC>>[CH2:1]([O:8][Li:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OCc1ccccc1
Reactant: [Li]CCCC
Product: [Li]OCc1ccccc1
Temperature: 25 °C

Procedure:
Into a solution of benzyl alcohol (1.51 ml) in tetrahydrofran (57 ml) was added n-butyl lithium (1.6 M in hexane) (7.25 ml) at -60° C., and the mixture was warmed to 25° C. Into the solution of benzyloxy lithium thus obtained was added the product of Example 4-(1) (6.0 g) at -78° C., and the mixture was stirred at 3° C. for 17 hr. The mixture was diluted with water and ethyl acetate. The organic layer was washed, dried and evaporated. The residue was purified by silica-gel column chromatography (chloroform:n-hexane:ethylacetate=10:1:0.1) to afford 2.57 g of (2S)-phthalimido-2-[(1R)-1-tert-butyldimethylsilyloxyethyl]-propionic acid benzyl ester in colorless oil.
Reaction SMILES: [Cl:1][CH2:2][C:3]1[CH:11]=[CH:10][C:6]([CH:7]=[N:8][OH:9])=[CH:5][CH:4]=1.C1C(=O)N([Cl:19])C(=O)C1.Cl.O1CCOCC1>CN(C=O)C>[Cl:1][CH2:2][C:3]1[CH:11]=[CH:10][C:6]([C:7]([Cl:19])=[N:8][OH:9])=[CH:5][CH:4]=1
Reactant: ON=Cc1ccc(CCl)cc1
Reactant: O=C1CCC(=O)N1Cl
Agent: Cl
Solvent: CN(C)C=O
Solvent: C1COCCO1
Product: ON=C(Cl)c1ccc(CCl)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 113.9 %

Procedure:
4-(chloromethyl)benzaldehyde oxime 5 (15.8 g, 93.16 mmol) was dissolved in DMF (300 mL). NCS (13.69 g, 102.5 mmol) was added in portions and then HCl in dioxane (100 mL of 4 M, 400.0 mmol) was added slowly, cooling the mixture with an ice water bath to moderate the exotherm, keeping internal temperature below 33° C. The mixture was then stirred at room temperature for 1 hour. The solution was partitioned between EtOAc and water and the organic extract was washed with water and brine (5×200 ml), dried over MgSO4 and concentrated under reduced pressure to give a colourless solid (21.65 g, 95%). 1H NMR (400 MHz, CDCl3) δ 4.63 (2H, s), 7.45 (2H, d, J=8 Hz), 7.86 (2H, d, J=8 Hz), 8.36 (1H, s).
Reaction SMILES: [CH2:1]([NH2:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].Br[CH2:16][CH2:17][Si:18]([CH2:21][CH2:22]Br)([CH3:20])[CH3:19].O>ClCCl>[CH2:1]([N:8]1[CH2:22][CH2:21][Si:18]([CH3:20])([CH3:19])[CH2:17][CH2:16]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C[Si](C)(CCBr)CCBr
Reactant: NCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: ClCCl
Product: C[Si]1(C)CCN(Cc2ccccc2)CC1
Yield: 58.4 %

Procedure:
Benzylamine (17.56 g, 0.16 mol) and K2CO3 (3.4 g, 24.6 mmol) are added to a solution of bis(2-bromoethyl)dimethylsilane 2(4.0 g, 16.4 mmol) in Dichloromethane (DCM). The mixture is then refluxed for 16 h. Water is added and the aqueous layer is extracted with DCM. It is then washed with 5% sodiumhydroxide (NaOH) solution, dried and concentrated. The product is purified by column chromatography on silica using hexane-ethylacetate mixtures to obtain the product as a colorless liquid 3 (2.1 g) in 59% yield.
Reaction SMILES: Cl[CH:2]([CH2:5][O:6][CH3:7])[CH:3]=[O:4].[Cl:8][CH2:9][CH2:10][NH2:11]>C1(C)C=CC=CC=1>[Cl:8][CH2:9][CH2:10][NH:11][CH:2]([CH2:5][O:6][CH3:7])[CH:3]=[O:4]
Reactant: COCC(Cl)C=O
Reactant: NCCCl
Solvent: Cc1ccccc1
Product: COCC(C=O)NCCCl
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
The dimethyl acetal of 2-chloro-3-methoxypropionaldehyde (0.1 mole) and toluene (75 ml) are charged into a glass reaction vessel equipped with a mechanical stirrer, thermometer and reflux condenser. β-Chloroethylamine (0.22 mole) is added to the reaction mixture with stirring at room temperature. Stirring is continued for a period of about 15 minutes. After this time the reaction mixture is heated at reflux for a period of about 1 hour. The reaction mixture is then cooled to room temperature and filtered. The filtrate is stripped of toluene and unreacted starting material under reduced pressure to yield the desired product the dimethyl acetal of 2-β-chloroethylamino-3-methoxypropionaldehyde as the residue.
Reaction SMILES: [CH3:1][C:2]([CH3:17])([C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([O:14][CH2:15][CH3:16])[CH:9]=1)[C:3]([O:5][CH2:6][CH3:7])=[O:4].[I:18]Cl>C(O)(=O)C.O>[CH3:17][C:2]([CH3:1])([C:8]1[CH:13]=[CH:12][C:11]([I:18])=[C:10]([O:14][CH2:15][CH3:16])[CH:9]=1)[C:3]([O:5][CH2:6][CH3:7])=[O:4]
Reactant: CCOC(=O)C(C)(C)c1cccc(OCC)c1
Reactant: ClI
Solvent: O
Solvent: CC(=O)O
Product: CCOC(=O)C(C)(C)c1ccc(I)c(OCC)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 81.8 %

Procedure:
To a cooled solution (5° C.) of ethyl dimethyl-3-ethoxyphenylacetate (5.0 g, 21.1 mmol) in acetic acid (40 mL) was added dropwise a solution of iodine monochloride (5.0 g, 30.9 mmol) in acetic acid. The reaction was stirred at room temperature for 18 h and diluted with water and extracted with methylene chloride. The combined organic layers were washed with aqueous sodium thiosulfate, aqueous sodium bicarbonate and brine. The solution was dried over anhydrous magnesium sulfate, filtered and concentrated to give ethyl dimethyl-(3-ethoxy-4-iodophenyl)acetate (6.25 g, 82%) as a yellow oil.
Reaction SMILES: [F:1][C:2]1[CH:31]=[CH:30][CH:29]=[CH:28][C:3]=1[CH2:4][C:5]1[C:6]2[CH2:27][NH:26][CH2:25][CH2:24][C:7]=2[N:8]=[C:9]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([N:18]3[CH:22]=[CH:21][N:20]=[C:19]3[CH3:23])=[CH:14][CH:13]=2)[N:10]=1.[CH:32](=O)[CH2:33][OH:34]>>[F:1][C:2]1[CH:31]=[CH:30][CH:29]=[CH:28][C:3]=1[CH2:4][C:5]1[C:6]2[CH2:27][N:26]([CH2:32][CH2:33][OH:34])[CH2:25][CH2:24][C:7]=2[N:8]=[C:9]([NH:11][C:12]2[CH:13]=[CH:14][C:15]([N:18]3[CH:22]=[CH:21][N:20]=[C:19]3[CH3:23])=[CH:16][CH:17]=2)[N:10]=1
Reactant: Cc1nccn1-c1ccc(Nc2nc3c(c(Cc4ccccc4F)n2)CNCC3)cc1
Reactant: O=CCO
Product: Cc1nccn1-c1ccc(Nc2nc3c(c(Cc4ccccc4F)n2)CN(CCO)CC3)cc1
Yield: 4.5 %

Procedure:
2-(4-(2-Fluorobenzyl)-2-(4-(2-methyl-1H-imidazol-1-yl)phenylamino)-7,8-dihydropyrido[4,3-d]pyrimidin-6(5H)-yl)ethanol (4.7 mg, 4.5%) was synthesised from 4-(2-fluorobenzyl)-N-(4-(2-methyl-1H-imidazol-1-yl)phenyl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-2-amine (Example 52a) and glycolaldehyde according to the general procedure for reductive amination. MS (ES+) m/z 459.3 (M+H)+