Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][CH2:4][CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:14]=[CH:15][C:16]3[S:22](=[O:24])(=[O:23])[CH2:21][CH2:20][C:19]([C:25]([O:27]C)=[O:26])=[CH:18][C:17]=3[CH:29]=2)=[CH:9][CH:8]=1)[CH3:2].Cl>COCCOC>[CH2:1]([O:3][CH2:4][CH2:5][O:6][C:7]1[CH:8]=[CH:9][C:10]([C:13]2[CH:14]=[CH:15][C:16]3[S:22](=[O:23])(=[O:24])[CH2:21][CH2:20][C:19]([C:25]([OH:27])=[O:26])=[CH:18][C:17]=3[CH:29]=2)=[CH:11][CH:12]=1)[CH3:2]
Reactant: CCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)OC)CCS3(=O)=O)cc1
Agent: Cl
Solvent: COCCOC
Product: CCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)O)CCS3(=O)=O)cc1
Temperature: 100 °C
Yield: 88 %

Procedure:
To methyl 7-[4-(2-ethoxyethoxy)phenyl]-1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxylate (4.35 g) were added 1,2-dimethoxyethane (87 ml) and 6N hydrochloric acid (43.5 ml), and the mixture was refluxed at 100° C. for 16 hours and cooled to room temperature. The mixture was extracted with ethyl acetate, washed with saturated brine and dried with magnesium sulfate. Under reduced pressure, the solvent was evaporated to give 7-[4-(2-ethoxyethoxy)phenyl]-1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxylic acid (3.7 g).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:17])[CH:5]=[C:6]([O:8][C:9]1[CH:14]=[C:13]([F:15])[CH:12]=[CH:11][C:10]=1[F:16])[CH3:7])[CH3:2].[Br:18]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>[CH2:1]([O:3][C:4](=[O:17])[CH:5]=[C:6]([O:8][C:9]1[CH:14]=[C:13]([F:15])[CH:12]=[CH:11][C:10]=1[F:16])[CH2:7][Br:18])[CH3:2]
Reactant: CCOC(=O)C=C(C)Oc1cc(F)ccc1F
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: CCOC(=O)C=C(CBr)Oc1cc(F)ccc1F
Temperature: 105 °C
Yield: 87.2 %

Procedure:
A solution of 3-(2,5-difluoro-phenoxy)-but-2-enoic acid ethyl ester (1.35 g, 5.57 mmol) in carbon tetrachloride (30.9 mL) was treated with N-bromosuccinimide (1.09 g, 6.13 mmol) and benzoyl peroxide (108 mg, 0.44 mmol). The reaction was then heated to reflux (105° C.) for 5 h. At this time, the reaction was cooled to 25° C. and then was placed in the refrigerator overnight. At this time, the reaction was removed from the refrigerator. The resulting precipitate was removed by filtration and was rinsed with carbon tetrachloride (25 mL). The filtrate was concentrated in vacuo. Purification by Analogix flash chromatography (40 g, 2% ethyl acetate/hexanes) afforded impure 4-bromo-3-(2,5-difluoro-phenoxy)-but-2-enoic acid ethyl ester (1.56 g, 87%) as a clear oil. The material was used without further purification.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:16]3[N:17]=[C:18]([NH2:20])[N:19]=[C:15]3[CH:14]=[CH:13][CH:12]=2)=[CH:7][CH:6]=1)(=[O:4])=[O:3].Br[C:22]1[CH:23]=[C:24]([CH:33]=[CH:34][CH:35]=1)[CH2:25][N:26]1[CH2:31][CH2:30][N:29]([CH3:32])[CH2:28][CH2:27]1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)CCCCC1>>[CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:16]3[N:17]=[C:18]([NH:20][C:34]4[CH:35]=[CH:22][CH:23]=[C:24]([CH2:25][N:26]5[CH2:31][CH2:30][N:29]([CH3:32])[CH2:28][CH2:27]5)[CH:33]=4)[N:19]=[C:15]3[CH:14]=[CH:13][CH:12]=2)=[CH:7][CH:6]=1)(=[O:3])=[O:4]
Reactant: CN1CCN(Cc2cccc(Br)c2)CC1
Reactant: CS(=O)(=O)c1ccc(-c2cccc3nc(N)nn23)cc1
Agent: c1ccc(P(C2CCCCC2)C2CCCCC2)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c1
Product: CN1CCN(Cc2cccc(Nc3nc4cccc(-c5ccc(S(C)(=O)=O)cc5)n4n3)c2)CC1

Procedure:
[5-(4-Methanesulfonyl-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl]-[3-(4-methyl-piperazin-1-ylmethyl)-phenyl]-amine was prepared from 5-(4-methanesulfonyl-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-ylamine (75.0 mg, 0.260 mmol) and 1-(3-bromo-benzyl)-4-methyl-piperazine (77.0 mg, 0.286 mmol) with 2,2′-bis-dicyclohexylphosphanyl-biphenyl (25.0 mg, 0.0457 mmol) as the ligand in a manner analogous to Example 2d. Product isolated as a yellow foam (0.043, 35%). 1H NMR (400 MHz, CDCl3, δ, ppm): 8.27 (d, J=8.6 Hz, 2H), 8.13 (d, J=8.6 Hz, 2H), 7.59-7.51 (m, 3H), 7.45-7.43 (m, 1H), 7.28 (t, J=7.8 Hz, 1H), 7.06 (dd, J=5.1, 3.3 Hz, 1H), 6.98-6.94 (m, 2H), 3.50 (s, 2H), 3.15 (s, 3H), 2.70-2.32 (m, 8H), 2.28 (s, 3H). MS=477 (MH)+.
Reaction SMILES: [O:1]=[C:2]1[CH:7]=[CH:6][N:5]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([F:17])([F:16])[F:15])[CH:9]=2)[N:4]=[C:3]1[C:18]([O:20]C)=[O:19].[OH-].[Na+].Cl>CO>[O:1]=[C:2]1[CH:7]=[CH:6][N:5]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([F:17])([F:16])[F:15])[CH:9]=2)[N:4]=[C:3]1[C:18]([OH:20])=[O:19]
Reactant: COC(=O)c1nn(-c2cccc(C(F)(F)F)c2)ccc1=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)c1nn(-c2cccc(C(F)(F)F)c2)ccc1=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 97.2 %

Procedure:
To a suspension of methyl 4-oxo-1-[3-(trifluoromethyl)phenyl]-1,4-dihydropyridazine-3-carboxylate (10.0 g, 33.5 mmol) in MeOH (150 mL) was added 1 M NaOH aqueous solution (50 mL) at 0° C. The mixture was stirred at room temperature for 30 min. To the suspension was added 1 M HCl aqueous solution (50 mL) at 0° C. The mixture was concentrated in vacuo. The precipitates were collected by filtration, washed with water and dried in vacuo at 50° C. to yield the title compound (9.25 g, 97% yield) as a pale yellow solid: 1H NMR (DMSO-d6, 300 MHz): δ ppm 7.02 (1H, d, J=7.7 Hz), 7.81-7.96 (2H, m), 8.06-8.21 (2H, m), 9.16 (1H, d, J=7.7 Hz).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:13]=[C:14]([Cl:25])[C:15]=1[O:16][C:17]1[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=1)[CH:5]=[C:6]1[S:10][C:9](=[O:11])[NH:8][C:7]1=[O:12].[H][H]>C(OCC)(=O)C.CO.[Pd]>[Cl:1][C:2]1[CH:3]=[C:4]([CH:13]=[C:14]([Cl:25])[C:15]=1[O:16][C:17]1[CH:18]=[CH:19][C:20]([O:23][CH3:24])=[CH:21][CH:22]=1)[CH2:5][CH:6]1[S:10][C:9](=[O:11])[NH:8][C:7]1=[O:12]
Reactant: COc1ccc(Oc2c(Cl)cc(C=C3SC(=O)NC3=O)cc2Cl)cc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Solvent: CCOC(C)=O
Product: COc1ccc(Oc2c(Cl)cc(CC3SC(=O)NC3=O)cc2Cl)cc1
Yield: 55.6 %

Procedure:
The title compound of Step C (93 mg) was dissolved in ethyl acetate/methanol (4 ml/2 ml) and then 10% palladium on carbon (70 mg) was added. The reaction mixture was placed on Parr shaker for four hours under 50 psi hydrogen at room temperature. The solution was filtered through diatomaceous earth, and concentrated. The residue was purified by preparative TLC (3% methanol in dichloromethane) to afford the title compound (52 mg) as a solid. MS (APCI−) Calc: 397.0, Found: 396.0 (M−1).
Reaction SMILES: O[CH:2]=[C:3]1[C:11]2[C:6](=[CH:7][C:8]([C:12]([C:14]3[CH:19]=[CH:18][C:17]([NH:20][C:21]([C:23]4[N:24]([CH2:29][CH3:30])[N:25]=[C:26]([CH3:28])[CH:27]=4)=[O:22])=[CH:16][CH:15]=3)=[O:13])=[CH:9][CH:10]=2)[NH:5][C:4]1=[O:31].[CH3:32][N:33]1[CH2:38][CH2:37][N:36]([C:39]2[CH:44]=[CH:43][C:42]([NH2:45])=[CH:41][CH:40]=2)[CH2:35][CH2:34]1>C1COCC1>[CH3:32][N:33]1[CH2:34][CH2:35][N:36]([C:39]2[CH:44]=[CH:43][C:42]([NH:45][CH:2]=[C:3]3[C:11]4[C:6](=[CH:7][C:8]([C:12]([C:14]5[CH:15]=[CH:16][C:17]([NH:20][C:21]([C:23]6[N:24]([CH2:29][CH3:30])[N:25]=[C:26]([CH3:28])[CH:27]=6)=[O:22])=[CH:18][CH:19]=5)=[O:13])=[CH:9][CH:10]=4)[NH:5][C:4]3=[O:31])=[CH:41][CH:40]=2)[CH2:37][CH2:38]1
Reactant: CN1CCN(c2ccc(N)cc2)CC1
Reactant: CCn1nc(C)cc1C(=O)Nc1ccc(C(=O)c2ccc3c(c2)NC(=O)C3=CO)cc1
Solvent: C1CCOC1
Product: CCn1nc(C)cc1C(=O)Nc1ccc(C(=O)c2ccc3c(c2)NC(=O)C3=CNc2ccc(N3CCN(C)CC3)cc2)cc1
Temperature: 65 °C
Reaction time: 24 h
Yield: 60 %

Procedure:
A small screw cap test tube was charged with 2-Ethyl-5-methyl-2H-pyrazole-3-carboxylic acid [4-(3-hydroxymethylene-2-oxo-2,3-dihydro-1H-indole-6-carbonyl)-phenyl]-amide (as prepared in Example 15, 100 mg, 0.240 mmol) and THF (2 mL). To the resulting solution was added 4-(4-methyl-piperazin-1-yl)-phenylamine (50.5 mg, 0.264 mmol), and the mixture was stirred for 24 h at 65° C. Subsequently, the reaction mixture was cooled to room temperature. Hexanes were added to the reaction mixture. The solid precipitate that formed was washed with ˜1 mL of i-prOH yielding 60% (85 mg, 0.144 mmol) of the title compound.
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][C:8]([C@H:11]2[CH2:16][CH2:15][CH2:14][N:13]([C:17]([C:19]3[S:23][C:22]([C:24]4[CH:29]=[CH:28][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:26][CH:25]=4)=[N:21][C:20]=3[CH3:34])=[O:18])[CH2:12]2)=[CH:7][C:3]=1[C:4]([OH:6])=O.C(Cl)(=O)C(Cl)=O.C[N:42](C)C=O.N>C(Cl)Cl.C(OCC)C.C1COCC1>[CH3:1][C:2]1[CH:10]=[CH:9][C:8]([CH:11]2[CH2:16][CH2:15][CH2:14][N:13]([C:17]([C:19]3[S:23][C:22]([C:24]4[CH:29]=[CH:28][C:27]([C:30]([F:33])([F:31])[F:32])=[CH:26][CH:25]=4)=[N:21][C:20]=3[CH3:34])=[O:18])[CH2:12]2)=[CH:7][C:3]=1[C:4]([NH2:42])=[O:6]
Reactant: CN(C)C=O
Reactant: Cc1ccc([C@H]2CCCN(C(=O)c3sc(-c4ccc(C(F)(F)F)cc4)nc3C)C2)cc1C(=O)O
Agent: N
Agent: O=C(Cl)C(=O)Cl
Solvent: C1CCOC1
Solvent: ClCCl
Solvent: CCOCC
Product: Cc1ccc(C2CCCN(C(=O)c3sc(-c4ccc(C(F)(F)F)cc4)nc3C)C2)cc1C(N)=O
Reaction time: 1 h
Yield: 72 %

Procedure:
(R)-2-methyl-5-{1-[4-methyl-2-(4-trifluoromethyl-phenyl)-thiazole-5-carbonyl]-piperidin-3-yl}-benzoic acid (Example 9-1; 1.026 g, 2.10 mmol) was dissolved in 20 mL CH2Cl2 and treated with oxalyl chloride (0.22 mL, 2.52 mmol) and 10 mL of dimethyl formamide. The mixture was allowed to stir for 1 h until all solids had dissolved. 10 mL of THF saturated with ammonia was added slowly. A thick white precipitate formed. The slurry was stirred for 20 min then diluted with diethyl ether (100 mL), washed with 100 mL of each of H2O, 0.2 N aqueous HCl, saturated aqueous NaHCO3, and brine. The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The resultant oil was flash chromatographed with 50% ethyl acetate/hexanes to yield 740 mg (72%) of the desired 2-methyl-5-{1-[4-methyl-2-(4-trifluoromethyl-phenyl)-thiazole-5-carbonyl]-piperidin-3-yl}-benzamide as a clear oil.
Reaction SMILES: [C:1]([C:5]1[O:6][C:7]([C:10]2[C:14]([CH:15]=[C:16](Br)Br)=[C:13]([C:19]3[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=3)[N:12]([C:26]3[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][C:27]=3[Cl:33])[N:11]=2)=[N:8][N:9]=1)([CH3:4])([CH3:3])[CH3:2].C[Si]([N-][Si](C)(C)C)(C)C.[K+]>O1CCCC1>[C:1]([C:5]1[O:6][C:7]([C:10]2[C:14]([C:15]#[CH:16])=[C:13]([C:19]3[CH:20]=[CH:21][C:22]([Cl:25])=[CH:23][CH:24]=3)[N:12]([C:26]3[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][C:27]=3[Cl:33])[N:11]=2)=[N:8][N:9]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1nnc(-c2nn(-c3ccc(Cl)cc3Cl)c(-c3ccc(Cl)cc3)c2C=C(Br)Br)o1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [K+]
Solvent: C1CCOC1
Product: C#Cc1c(-c2nnc(C(C)(C)C)o2)nn(-c2ccc(Cl)cc2Cl)c1-c1ccc(Cl)cc1
Temperature: 78 °C
Reaction time: 0.33 h
Yield: 88.3 %

Procedure:
To a solution of 2-tert-butyl-5-(5-(4-chlorophenyl)-4-(2,2-dibromovinyl)-1-(2,4-dichlorophenyl)-1H-pyrazol-3-yl)-1,3,4-oxadiazole (230 mg, 0.36 mmol) in tetrahydrofuran (10 ml) at 78° C., potassium bis(trimethysilyl)amide (1.46 ml, 0.5 M solution in tetahydrofuran, 0.73 mmol) was added slowly. After stirring for 20 minutes at 78° C., the resulting solution was quenched with saturated ammonium chloride (5 ml). After warming up to room temperature, the solution was diluted with ethyl ether, and then the organic layer was extracted with ethyl acetate (50 ml twice). After evaporation, crude residue was purified with silica gel column (hexane/ethyl acetate=5/1) to obtain title compound (150 mg, 91% yield) as light yellow solid.
Reaction SMILES: [F:1][C:2]([C:5]1[CH:9]=[C:8]([NH:10][C:11]([NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([OH:20])[CH:15]=2)=[O:12])[O:7][N:6]=1)([CH3:4])[CH3:3].Cl[C:22]1[C:31]2[C:26](=[CH:27][C:28]([O:40][CH3:41])=[C:29]([O:32][CH2:33][CH2:34][CH2:35][S:36]([CH3:39])(=[O:38])=[O:37])[CH:30]=2)[N:25]=[CH:24][N:23]=1>>[F:1][C:2]([C:5]1[CH:9]=[C:8]([NH:10][C:11]([NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([O:20][C:22]3[C:31]4[C:26](=[CH:27][C:28]([O:40][CH3:41])=[C:29]([O:32][CH2:33][CH2:34][CH2:35][S:36]([CH3:39])(=[O:37])=[O:38])[CH:30]=4)[N:25]=[CH:24][N:23]=3)[CH:15]=2)=[O:12])[O:7][N:6]=1)([CH3:3])[CH3:4]
Reactant: CC(C)(F)c1cc(NC(=O)Nc2cccc(O)c2)on1
Reactant: COc1cc2ncnc(Cl)c2cc1OCCCS(C)(=O)=O
Product: COc1cc2ncnc(Oc3cccc(NC(=O)Nc4cc(C(C)(C)F)no4)c3)c2cc1OCCCS(C)(=O)=O
Yield: 60.9 %

Procedure:
The title compound was prepared from 1-(3-(2-fluoropropan-2-yl)isoxazol-5-yl)-3-(3-hydroxyphenyl)urea (84 mg, 0.3 mmol) and 4-chloro-7-methoxy-6-(3-(methylsulfonyl)propoxy)quinazoline from Example 41B Step 1 (76 mg, 0.23 mmol) using the procedure described in Example 16C. The crude product was purified by chromatography on silica gel (25-100% EtOAc/hexanes) to afford 1-(3-(2-fluoropropan-2-yl)isoxazol-5-yl)-3-(3-(7-methoxy-6-(3-(methylsulfonyl)propoxy)quinazolin-4-yloxy)phenyl)urea (81 mg, 0.14 mmol, 61%). 1H NMR (300 MHz, DMSO-d6) δ 10.42 (br s, 1H), 9.11 (s, 1H), 8.57 (s, 1H), 7.63-7.58 (m, 2H), 7.47-7.40 (m, 2H), 7.32 (d, 1H), 7.00 (d, 1H), 6.15 (s, 1H), 4.32 (t, 2H), 4.02 (s, 3H), 3.41-3.29 (m, 2H), 3.06 (s, 3H), 2.31-2.22 (m, 2H), 1.66 (d, 6H); LC-MS (ESI) m/z 574 (M+H)+.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([OH:12])[CH:6]=[CH:5]2.C[Li].C([Li])(C)(C)C.[CH:20](=[O:25])[CH2:21][CH2:22][CH2:23][CH3:24]>CCOCC>[OH:25][CH:20]([C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([OH:12])[CH:6]=[CH:5]2)[CH2:21][CH2:22][CH2:23][CH3:24]
Reactant: Oc1ccc2cc(Br)ccc2c1
Reactant: CCCCC=O
Agent: [Li]C
Agent: [Li]C(C)(C)C
Solvent: CCOCC
Product: CCCCC(O)c1ccc2cc(O)ccc2c1
Reaction time: 0.08 h
Yield: 57.2 %

Procedure:
To a solution of 1.00 g (4.48 mmol, Aldrich) of 6-bromo-2-naphthol in 40 ml of dry ether at -78° was added dropwise 3.2 ml (1.4M in ether, 5.0 mmol) of methyllithium solution. The reaction mixture was stirred for 5 minutes then 5.0 ml (1.8M in pentane, 9.0 mmol) of t-butyllithium solution was added over 5 minutes. The resulting slurry was stirred at -78° C. for 30 minutes then at 0° for 15 minutes, re-cooled to -78° and a solution of 0.50 ml (4.7 mmol) of distilled valeraldehyde in 3 ml of ether was added dropwise over several minutes. After 5 minutes the reaction mixture was warmed to 0°, quenched with 1 ml of H2O, added to 100 ml of ice-cold saturated aqueous NH4Cl solution. The organic layer was separated, washed with 100 ml of H2O, dried (MgSO4) and concentrated in vacuo to give a dark oil. The crude oil was purified by flash chromatography (10×5.0 cm, 1:3 EtOAc/petroleum ether) to afford 590 mg (57%) of title compound as a pale yellow solid, m.p. 109°-111°.
Reaction SMILES: [OH:1][CH:2]1[CH2:5][N:4]([C:6](=[O:8])[CH3:7])[CH2:3]1.[O:9]1[CH:14]=[CH:13][CH2:12][CH2:11][CH2:10]1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C(=O)([O-])O.[Na+]>C(Cl)Cl.O>[O:9]1[CH2:14][CH2:13][CH2:12][CH2:11][CH:10]1[O:1][CH:2]1[CH2:5][N:4]([C:6](=[O:8])[CH3:7])[CH2:3]1
Reactant: CC(=O)N1CC(O)C1
Reactant: C1=COCCC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: CC(=O)N1CC(OC2CCCCO2)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
In 10 mL of methylene chloride was dissolved 1.00 g of 1-(3-hydroxy-1-azetidinyl)-1-ethanone, and 1.19 mL of 3,4-dihydro-2H-pyran and 0.08 g of p-toluenesulfonic acid monohydrate were added to the solution, after which the resulting mixture was stirred overnight at room temperature. To the reaction mixture was added 10 mL of water and the pH was adjusted to 8 with a saturated aqueous sodium hydrogencarbonate solution, after which the organic layer was separated. The organic layer was dried over anhydrous magnesium sulfate and distilled under reduced pressure to remove the solvent. The residue was purified by a column chromatography (eluent; chloroform˜chloroform:methanol=25:1) to obtain 1.79 g of 1-[3-(tetrahydro-2H-pyran-2-yloxy)-1-azetidinyl]-1-ethanone as a yellow oil.
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH2:10][CH2:11][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:13][CH:14]=2)O1.C([O-])([O-])=O.[K+].[K+].Br[C:30]1[CH:35]=[C:34]([N+:36]([O-:38])=[O:37])[CH:33]=[CH:32][C:31]=1[O:39][CH3:40].O>CN(C=O)C>[CH3:40][O:39][C:31]1[CH:32]=[CH:33][C:34]([N+:36]([O-:38])=[O:37])=[CH:35][C:30]=1[C:9]1[CH2:10][CH2:11][N:12]([C:15]([O:17][C:18]([CH3:19])([CH3:20])[CH3:21])=[O:16])[CH2:13][CH:14]=1
Reactant: CC(C)(C)OC(=O)N1CC=C(B2OC(C)(C)C(C)(C)O2)CC1
Reactant: COc1ccc([N+](=O)[O-])cc1Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc([N+](=O)[O-])cc1C1=CCN(C(=O)OC(C)(C)C)CC1
Temperature: 80 °C
Yield: 45.2 %

Procedure:
To a 250-mL RB-flask containing tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydro-1(2H)-pyridinecarboxylate (3.09 g, 10.0 mmol), K2CO3 (4.14 g, 30.0 mmol) and PdCl2dppf (419 mg) was added a solution of 2-bromo-4-nitroanisole (2.30 g, 10 mmol) in DMF (10.0 mL) at room temperature under argon. The mixture was heated to 80° C. under argon overnight. After cooled to room temperature, water (500 mL) was added to the mixture. The aqueous layer was extracted with EtOAc (2×200 mL) and the combined organic extracts were dried over K2CO3, filtered and concentrated in vacuo. The crude material was purified on flash chromatography (20% EtOAc/hexane) to give tert-butyl 4-(2-methoxy-5-nitrophenyl)-3,6-dihydro-1(2H)-pyridinecarboxylate (1.51 g, 46%): ESMS m/e: 334.9 (M+H)+.
Reaction SMILES: [CH3:1][S:2][C:3]1[N:8]=[C:7](Cl)[CH:6]=[CH:5][N:4]=1.[OH-].[Na+].[CH2:12]([OH:15])[C:13]#[CH:14].O>C1C=CC=CC=1.[Cl-].C([N+](CC)(CC)CC1C=CC=CC=1)C>[CH3:1][S:2][C:3]1[N:8]=[C:7]([O:15][CH2:12][C:13]#[CH:14])[CH:6]=[CH:5][N:4]=1
Reactant: C#CCO
Reactant: CSc1nccc(Cl)n1
Agent: CC[N+](CC)(CC)Cc1ccccc1
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: c1ccccc1
Product: C#CCOc1ccnc(SC)n1
Reaction time: 4 h

Procedure:
3 grams of 2-methylthio-4-chloro pyrimidine in 30 ml of benzene was reacted with 3 ml of an aqueous 40% sodium hydroxide solution, 0.3 grams of triethyl benzyl ammonium chloride and 2 ml of propargyl alcohol. The resultant reaction mixture was refluxed with stirring for a period of 4 hours. Following, the mixture was cooled and 20 milliliters of water added, so resulting in separation of the benzene layer. Then, the solvent was evaporated under reduced pressure to yield 4.1 grams of 2-methylthio-4-propargyloxy pyrimidine melting at a temperature within the range of 70°-71° C. in ethanol.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([N:17]3[CH2:22][CH2:21][N:20]([CH:23]([CH3:25])[CH3:24])[CH2:19][CH2:18]3)=[CH:13][N:12]=2)[C:5](=[O:9])[N:6]([CH3:8])[CH:7]=1.C([O-])(=O)C.[K+].C(Cl)Cl.[C:34]([O:37][CH2:38][C:39]1[C:44]([N:45]2[CH2:56][CH2:55][N:54]3[C:47](=[CH:48][C:49]4[CH2:50][C:51]([CH3:58])([CH3:57])[CH2:52][C:53]=43)[C:46]2=[O:59])=[CH:43][C:42]([F:60])=[CH:41][C:40]=1Br)(=[O:36])[CH3:35].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.O1CCOCC1>[F:60][C:42]1[CH:41]=[C:40]([C:2]2[CH:3]=[C:4]([NH:10][C:11]3[CH:16]=[CH:15][C:14]([N:17]4[CH2:22][CH2:21][N:20]([CH:23]([CH3:25])[CH3:24])[CH2:19][CH2:18]4)=[CH:13][N:12]=3)[C:5](=[O:9])[N:6]([CH3:8])[CH:7]=2)[C:39]([CH2:38][O:37][C:34](=[O:36])[CH3:35])=[C:44]([N:45]2[CH2:56][CH2:55][N:54]3[C:47](=[CH:48][C:49]4[CH2:50][C:51]([CH3:57])([CH3:58])[CH2:52][C:53]=43)[C:46]2=[O:59])[CH:43]=1
Reactant: CC(C)N1CCN(c2ccc(Nc3cc(Br)cn(C)c3=O)nc2)CC1
Reactant: CC(=O)OCc1c(Br)cc(F)cc1N1CCn2c(cc3c2CC(C)(C)C3)C1=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: ClCCl
Solvent: C1COCCO1
Product: CC(=O)OCc1c(-c2cc(Nc3ccc(N4CCN(C(C)C)CC4)cn3)c(=O)n(C)c2)cc(F)cc1N1CCn2c(cc3c2CC(C)(C)C3)C1=O
Temperature: 105 °C
Reaction time: 6 h
Yield: 35.9 %

Procedure:
A 44-mL sealed tube equipped with a magnetic stirrer was charged with 220a (400 mg, 1.0 mmol), 7 (508 mg, 2.0 mmol), potassium acetate (392 mg, 4.0 mmol) and 1,4-dioxane (10 mL). After the mixture was degassed for 30 minutes, Pd(dppf)Cl2.CH2Cl2 (82 mg, 0.10 mmol) was added. The resulting reaction mixture was stirred at 105° C. for 6 h. Then, it was cooled to room temperature and filtered through a pad of Celite. The filtrate was concentrated, and the crude mixture was redissolved in DME (2 mL) and transferred into a 10-mL microwave reaction vessel. To this solution was added 10-[2-(acetoxymethyl)-3-bromo-5-fluorophenyl]-4,4-dimethyl-1,10-diazatricyclo-[6.4.0.02,6]dodeca-2(6),7-dien-9-one (189a) (270 mg, 0.60 mmol), Pd(PPh3)4 (50 mg, 0.050 mmol), and 2 N Na2CO3 (2 mL). Then, the reaction mixture was degassed for 5 minutes and placed into the microwave cavity. After the reaction mixture was stirred at 125° C. for 7 min., it was purified by flash chromatography (dichloromethane:methanol, 85:15) to give 49% (150 mg) of 245a.
Reaction SMILES: [NH2:1][CH2:2][CH:3]([OH:18])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:6][CH:5]=1.Br[CH2:20][CH2:21][O:22][C:23]1[CH:24]=[CH:25][C:26]2[O:31]C(C)(C)[NH:29][C:28](=[O:34])[C:27]=2[CH:35]=1>>[CH2:11]([O:10][C:7]1[CH:8]=[CH:9][C:4]([CH:3]([OH:18])[CH2:2][NH:1][CH2:20][CH2:21][O:22][C:23]2[CH:24]=[CH:25][C:26]([OH:31])=[C:27]([C:28](=[O:34])[NH2:29])[CH:35]=2)=[CH:5][CH:6]=1)[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: CC1(C)NC(=O)c2cc(OCCBr)ccc2O1
Reactant: NCC(O)c1ccc(OCc2ccccc2)cc1
Product: NC(=O)c1cc(OCCNCC(O)c2ccc(OCc3ccccc3)cc2)ccc1O
Reaction time: 1 h

Procedure:
A mixture of 21 g of α-(aminomethyl)-4-benzyloxybenzyl alcohol and 12 g of 6-(2-bromoethoxy)-2,3-dihydro-2,2-dimethyl-4H-1,3-benzoxazin-4-one is stirred in an oil bath at 130° for 1 hour. The reaction mixture is partitioned between 500 ml of ethyl acetate and 50 ml of 2N aqueous ammonia solution, the organic phase is separated off and evaporated and the residue is recrystallised from isopropanol. 4-Benzyloxy-α-[N-[2-(3-carbamoyl-4-hydroxy-phenoxy)-ethyl]-aminomethyl]-benzyl alcohol with a melting point of 160°-162° is obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]#[N:10].[NH2:11][C:12]1[C:17]([CH:18]=O)=[CH:16][N:15]=[C:14]([CH3:20])[N:13]=1.[Na]>C(OCCO)C>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:9]([NH2:10])=[N:11][C:12]2[N:13]=[C:14]([CH3:20])[N:15]=[CH:16][C:17]=2[CH:18]=1
Reactant: N#CCc1ccccc1Cl
Reactant: Cc1ncc(C=O)c(N)n1
Agent: [Na]
Solvent: CCOCCO
Product: Cc1ncc2cc(-c3ccccc3Cl)c(N)nc2n1

Procedure:
2-Chlorophenylacetonitrile 4.0 g and 4-amino-2-methylpyrimidine-5-carboxaldehyde 3.6 g are added to a solution prepared by dissolving 0.2 g of sodium metal in 40 ml of 2-ethoxy-ethanol. The mixture is heated at reflux for 2 hours, and then cooled. The crude product precipitates as a solid and is collected by filtration. After recrystallization from aqueous dimethylformamide, 3.4 g of 6-(2-chlorophenyl)-2-methylpyrido[2,3-d]pyrimidin-7-amine, mp 259°-260° C. is obtained.
Reaction SMILES: C(=O)(OC(C)(C)C)[O:2][C:3]1[N:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=2)[N:6]=[C:5]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[C:20]2[CH:28]=[CH:27][C:23]3[O:24][CH2:25][O:26][C:22]=3[CH:21]=2)[CH:4]=1.C(=O)(OC(C)(C)C)OC1N(C2C=CC=CN=2)N=C(C2C=CC(C3C=CC=CC=3)=CC=2)C=1>>[O:24]1[C:23]2[CH:27]=[CH:28][C:20]([C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=3[C:5]3[CH:4]=[C:3]([OH:2])[N:7]([C:8]4[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=4)[N:6]=3)=[CH:21][C:22]=2[O:26][CH2:25]1
Reactant: CC(C)(C)OC(=O)Oc1cc(-c2ccccc2-c2ccc3c(c2)OCO3)nn1-c1ccccn1
Agent: CC(C)(C)OC(=O)Oc1cc(-c2ccc(-c3ccccc3)cc2)nn1-c1ccccn1
Product: Oc1cc(-c2ccccc2-c2ccc3c(c2)OCO3)nn1-c1ccccn1
Yield: 84 %

Procedure:
The title compound was prepared in the same manner as in Example D-1, except that an equimolar amount of Compound 32 of Example C-6 was used in place of Compound 27 of Example C-1.