Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1O)=[CH:13][CH:12]=[C:11]([N+:17]([O-:19])=[O:18])[CH:10]=2)=[O:5])[CH3:2].C(Cl)(=O)C([Cl:23])=O.[OH-].[Na+]>C(Cl)(Cl)Cl.CN(C)C=O>[CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1[Cl:23])=[CH:13][CH:12]=[C:11]([N+:17]([O-:19])=[O:18])[CH:10]=2)=[O:5])[CH3:2]
Reactant: O=C(Cl)C(=O)Cl
Reactant: CCOC(=O)c1cnc2cc([N+](=O)[O-])ccc2c1O
Agent: [Na+]
Agent: [OH-]
Solvent: ClC(Cl)Cl
Solvent: CN(C)C=O
Product: CCOC(=O)c1cnc2cc([N+](=O)[O-])ccc2c1Cl
Reaction time: 0.5 h
Yield: 93.4 %

Procedure:
4-Hydroxy-7-nitro-quinoline-3-carboxylic acid ethyl ester (15.6 g, 59.5 mmol) was suspended in chloroform (250 ml) and oxalyl chloride (20.7 ml, 30.2 g, 238 mmol) was added, followed by dimethyl formamide (0.4 ml, 0.38 g, 5.2 mmol). After heating at reflux for 2.5 h, the mixture was added to 300 ml of a 2N aqueous sodium hydroxide solution cooled in an ice/water bath. After stirring vigorously for 30 minutes, the aqueous layer was extracted with chloroform (200 ml). The combined organic phases were washed with water, brine and then dried over anhydrous magnesium sulfate. After vacuum filtration, the solution was concentrated under vacuum to provide 15.6 g of a fluffy brown solid. This solid was transferred to a Soxleht thimble and extracted with dichloromethane for 4 h employing a Soxleht extractor. Concentration of the dichloromethane solution under vacuum yielded 14.68 g of a tan solid. This solid was crystallized by dissolving in 400 ml of hot acetone and cooling to 0° C. overnight. The solid was collected by filtration, rinsing with ice-cold acetone, to yield 9.91 g of the title product as light yellow needles.
Reaction SMILES: C([O:8][C@H:9]1[C@H:15]([O:16]CC2C=CC=CC=2)[C@@H:14]([O:24]CC2C=CC=CC=2)[C@:13]2([C:33]3[CH:38]=[CH:37][C:36]([Cl:39])=[C:35]([CH2:40][C:41]4[CH:46]=[CH:45][C:44]([O:47][CH3:48])=[C:43]([F:49])[C:42]=4[F:50])[CH:34]=3)[O:32][C@@:10]1([CH2:51][OH:52])[CH2:11][O:12]2)C1C=CC=CC=1.ClC1C=CC=CC=1Cl>[Pd]>[Cl:39][C:36]1[CH:37]=[CH:38][C:33]([C@@:13]23[O:32][C@@:10]([CH2:51][OH:52])([CH2:11][O:12]2)[C@@H:9]([OH:8])[C@H:15]([OH:16])[C@H:14]3[OH:24])=[CH:34][C:35]=1[CH2:40][C:41]1[CH:46]=[CH:45][C:44]([O:47][CH3:48])=[C:43]([F:49])[C:42]=1[F:50]
Reactant: COc1ccc(Cc2cc([C@]34OC[C@](CO)(O3)[C@@H](OCc3ccccc3)[C@H](OCc3ccccc3)[C@H]4OCc3ccccc3)ccc2Cl)c(F)c1F
Agent: [Pd]
Solvent: Clc1ccccc1Cl
Product: COc1ccc(Cc2cc([C@]34OC[C@](CO)(O3)[C@@H](O)[C@H](O)[C@H]4O)ccc2Cl)c(F)c1F
Reaction time: 3 h
Yield: 95.3 %

Procedure:
[(1S,2S,3S,4R,5S)-2,3,4-tribenzyloxy-5-[4-chloro-3-[(2,3-difluoro-4-methoxy-phenyl)methyl]phenyl]-6,8-dioxabicyclo[3.2.1]octan-1-yl]methanol 2p (350 mg, 0.48 mmol) was dissolved in 10 mL of mixed solution (THF and MeOH, v:v=1:1), followed by addition of o-dichlorobenzene (0.55 mL, 4.8 mmol) and Palladium/carbon (300 mg, 10%) in turn. The mixture was exchanged with H2 three times and stirred for 3 hours, filtered with silica gel and the filtrate was concentrated under reduced pressure and the resulting residue was purified by silica gel chromatography with elution system A to obtain the title compound (1S,2S,3S,4R,5S)-5-[4-chloro-3-[(2,3-difluoro-4-methoxy-phenyl)methyl]phenyl]-1-(hydroxymethyl)-6,8-dioxabicyclo[3.2.1]octane-2,3,4-triol 2 (210 mg, white solid), yield: 95.5%. MS m/z (ESI): 459.1 [M+1];
Reaction SMILES: [NH2:1][CH:2]([CH2:24][C:25]1[CH:30]=[CH:29][C:28]([CH3:31])=[CH:27][CH:26]=1)[C:3]([NH:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[N:13]=[C:14]3[N:18]([CH:19]=2)[C:17]2[CH:20]=[CH:21][CH:22]=[CH:23][C:16]=2[S:15]3)=[CH:8][CH:7]=1)=[O:4].[CH3:32][C:33]1[CH:34]=[C:35]([CH2:40][C:41](O)=[O:42])[CH:36]=[C:37]([CH3:39])[CH:38]=1.CC(C)N=C=NC(C)C>C(Cl)Cl.CN(C1C=CN=CC=1)C>[CH3:32][C:33]1[CH:34]=[C:35]([CH2:40][C:41]([NH:1][C@@H:2]([CH2:24][C:25]2[CH:26]=[CH:27][C:28]([CH3:31])=[CH:29][CH:30]=2)[C:3]([NH:5][C:6]2[CH:11]=[CH:10][C:9]([C:12]3[N:13]=[C:14]4[N:18]([CH:19]=3)[C:17]3[CH:20]=[CH:21][CH:22]=[CH:23][C:16]=3[S:15]4)=[CH:8][CH:7]=2)=[O:4])=[O:42])[CH:36]=[C:37]([CH3:39])[CH:38]=1
Reactant: Cc1cc(C)cc(CC(=O)O)c1
Reactant: Cc1ccc(CC(N)C(=O)Nc2ccc(-c3cn4c(n3)sc3ccccc34)cc2)cc1
Agent: CC(C)N=C=NC(C)C
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: Cc1ccc(C[C@H](NC(=O)Cc2cc(C)cc(C)c2)C(=O)Nc2ccc(-c3cn4c(n3)sc3ccccc34)cc2)cc1

Procedure:
HATU (258 mg, 0.68 mmol) and DIPEA (197 μl, 1.13 mmol) were added to a solution of 4-[(imidazo[2,1-b]benzothiazol-2-yl)]aniline (150 mg, 0.56 mmol) and N-Boc-4-methylphenylalanine (158 mg, 0.56 mmol) in dry THF (11 ml). After 48 h at room temperature the solvent was removed under reduced pressure and the crude mixture was purified by flash chromatography (DCM containing 1% MeOH) to afford the desired N-Boc derivative that was dissolved in dry DCM (5 ml). TFA (5 ml) was then added and the reaction mixture was stirred at room temperature for 4 hours. Then the solvent was removed under reduced pressure and the crude mixture was purified by flash chromatography (DCM containing 10% EtOH) to afford 2-amino-3-(4-methylphenyl)-N-[4-(imidazo[2,1-b]benzothiazol-2-yl)phenyl]-propanamide in nearly quantitative yield. A suspension of 2-amino-3-(4-methylphenyl)-N-[4-(imidazo[2,1-b]benzothiazol-2-yl]phenyl]propanamide (150 mg, 0.35 mmol) in dry DCM (4 ml) was then mixed to 3,5-dimethylphenylacetic acid (60.6 mg, 0.37 mmol) and DMAP (21.5 mg, 0.17 mmol). Once the solution was obtained, DIC (83 l, 0.53 mmol) was added. After 4.5 h at room temperature the solvent was removed under reduced pressure and the crude mixture was purified by flash chromatography (DCM containing 2% EtOH) to afford (S)-2-(3,5-dimethylphenylacetamido)-3-(4-methylphenyl)-N-[4-(imidazo[2,1-b]benzothiazol-2-yl]phenyl]propanamide that was further on purified by crystallization in CHCl3 (32% c.y.)
Reaction SMILES: [C:1]([O:5][C:6](=[O:9])[NH:7][NH2:8])([CH3:4])([CH3:3])[CH3:2].[N:10]([O-])=O.[Na+]>C(O)(=O)C.O>[C:6]([N:7]=[N+:8]=[N-:10])(=[O:9])[O:5][C:1]([CH3:4])([CH3:3])[CH3:2]
Reactant: O=N[O-]
Reactant: CC(C)(C)OC(=O)NN
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)N=[N+]=[N-]
Reaction time: 0.5 h

Procedure:
25 g (0.19 mol) of t-butylcarbazate was dissolved in 80 mL of acetic acid and 160 mL of water, and 15 g (0.22 mol) of sodium nitrite was added in small portions under cooling with ice. The reaction solution was stirred for 30 minutes under cooling with ice and extracted with 250 ml of diisopropyl ether. The organic layer was washed with 200 mL of saturated aqueous sodium hydrogen carbonate twice and with 100 mL of saturated aqueous sodium chloride once successively, dried over anhydrous sodium sulfate and filtered to give a solution of t-butyl carbonazidate in diethyl ether.
Reaction SMILES: C([N:4]1[C:12]2[C:7](=[CH:8][C:9]([O:15][CH3:16])=[C:10]([O:13][CH3:14])[CH:11]=2)[C:6](=[C:17](OCC)[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:5]1=[O:27])(=O)C.[CH2:28]([N:35]([CH2:37][C:38]1[CH:44]=[CH:43][C:41]([NH2:42])=[CH:40][CH:39]=1)[CH3:36])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>>[CH2:28]([N:35]([CH2:37][C:38]1[CH:39]=[CH:40][C:41]([NH:42]/[C:17](=[C:6]2\[C:5](=[O:27])[NH:4][C:12]3[C:7]\2=[CH:8][C:9]([O:15][CH3:16])=[C:10]([O:13][CH3:14])[CH:11]=3)/[C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)=[CH:43][CH:44]=1)[CH3:36])[C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1
Reactant: CCOC(=C1C(=O)N(C(C)=O)c2cc(OC)c(OC)cc21)c1ccccc1
Reactant: CN(Cc1ccccc1)Cc1ccc(N)cc1
Product: COc1cc2c(cc1OC)/C(=C(/Nc1ccc(CN(C)Cc3ccccc3)cc1)c1ccccc1)C(=O)N2

Procedure:
Prepared from 1-acetyl-3-(1-ethoxy-1-phenyl-methylidene)-5,6-dimethoxy-2-indolinone and 4-[(N-benzyl-N-methyl-amino)-methyl]-aniline
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:9])[CH2:5][C:6](=O)[CH3:7])[CH3:2].[NH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C(O)(=O)C>CCO>[CH2:1]([O:3][C:4](=[O:9])[CH:5]=[C:6]([NH:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[CH3:7])[CH3:2]
Reactant: CCOC(=O)CC(C)=O
Reactant: Nc1ccccc1
Solvent: CC(=O)O
Solvent: CCO
Product: CCOC(=O)C=C(C)Nc1ccccc1
Temperature: 25 °C
Yield: 63.5 %

Procedure:
A mixture of 3-oxo-butyric acid ethyl ester (7 mL, 53.7 mmol), aniline (5 g, 53.7 mmol), acetic acid (0.060 mL) and 4 Å molecular sieves (5 g) in EtOH (20 mL) was refluxed for 5 h. After cooling to r.t., the mixture was filtered. EtOAc was added to rinse the solids, and the filtrate was concentrated to give a reddish oil, which was purified by silica gel chromatography (0-10% EtOAc/hexanes) to give 7 g of the title compound as a pale yellow oil. 1H NMR (CDCl3, 200 MHz): δ=10.38 (br s, 1H), 7.00-7.40 (m, 5H), 4.69 (s, 1H), 4.15 (q, 2H, J=7.0 Hz), 2.00 (s, 3H), 1.29 (t, 3H, J=7.0 Hz).
Reaction SMILES: [C:1]1([S:7]([CH2:10][C:11]2[CH:16]=[C:15]([Br:17])[CH:14]=[CH:13][C:12]=2[N+:18]([O-])=O)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H][H]>[Ni].C(OCC)(=O)C>[Br:17][C:15]1[CH:14]=[CH:13][C:12]([NH2:18])=[C:11]([CH2:10][S:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)(=[O:8])=[O:9])[CH:16]=1
Reactant: O=[N+]([O-])c1ccc(Br)cc1CS(=O)(=O)c1ccccc1
Reactant: [H][H]
Agent: [Ni]
Solvent: CCOC(C)=O
Product: Nc1ccc(Br)cc1CS(=O)(=O)c1ccccc1
Yield: 100.6 %

Procedure:
This compound was prepared by catalytic hydrogenation of 5-bromo-2-nitrobenzyl phenyl sulfone (0.23 g, 0.64 mmol) in the presence of Raney nickel and hydrogen (45 psi) in ethyl acetate (30 ml) for 1 hour. The reaction mixture is filtered through celite and concentrated in vacuo to give the title compound as a light brown solid (0.21 g, 99%). Mp: 140-141° C. MS (ES+): 326 (M+H).
Reaction SMILES: [C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([O:14][CH3:15])=[CH:11][CH:12]=2)[CH2:7][CH2:6][CH2:5]1)(=[O:3])[CH3:2].[N:16]([O-:18])=[O:17].[Na+]>FC(F)(F)C(O)=O>[C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([O:14][CH3:15])=[C:11]([N+:16]([O-:18])=[O:17])[CH:12]=2)[CH2:7][CH2:6][CH2:5]1)(=[O:3])[CH3:2]
Reactant: O=N[O-]
Reactant: COc1ccc2c(c1)CCCN2C(C)=O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Product: COc1cc2c(cc1[N+](=O)[O-])N(C(C)=O)CCC2
Reaction time: 2 h
Yield: 59 %

Procedure:
A solution of 1-acetyl-6-(methyloxy)-1,2,3,4-tetrahydroquinoline (500 mg, 2.44 mmol, Aldrich) in trifluoroacetic acid (4 mL, Aldrich) was treated with sodium nitrite (169 mg, 2.45 mmol, added slowly in about 4 portions, Aldrich). The dark brown reaction was stirred for 2 h and then poured over ice. The mixture was extracted with ethyl acetate and the organic layer was separated, dried over magnesium sulfate, filtered, concentrated, and purified by chromatography on SiO2 (0 to 100% ethyl acetate/hexanes) to give 1-acetyl-6-(methyloxy)-7-nitro-1,2,3,4-tetrahydroquinoline (357 mg, 59%). 1H NMR (400 MHz, DMSO-d6) is complicated due to amide rotomers δ ppm 1.83-1.94 (m, 2 H), 2.14-2.25 (m, 3 H), 2.76-2.85 (m, 2 H), 3.64-3.73 (m, 2 H), 3.86-3.92 (m, 3 H), 7.14-7.25 (m, 1 H), 8.38 (very broad singlet, 1H).
Reaction SMILES: [CH3:1][NH:2][NH2:3].[Cl:4][C:5]1[C:18]2[C:17](=[O:19])[C:16]3[CH:15]=[N:14][CH:13]=[CH:12][C:11]=3[C:10](=O)[C:9]=2[C:8](F)=[CH:7][CH:6]=1>N1C=CC=CC=1>[Cl:4][C:5]1[CH:6]=[CH:7][C:8]2[N:2]([CH3:1])[N:3]=[C:10]3[C:11]4[CH:12]=[CH:13][N:14]=[CH:15][C:16]=4[C:17](=[O:19])[C:18]=1[C:9]=23
Reactant: O=C1c2ccncc2C(=O)c2c(Cl)ccc(F)c21
Reactant: CNN
Solvent: c1ccncc1
Product: Cn1nc2c3c(c(Cl)ccc31)C(=O)c1cnccc1-2
Reaction time: 0.1 h
Yield: 71 %

Procedure:
A solution of methyl hydrazine (0.76M; 0.021 g) in pyridine (0.6 mL) is added dropwise over two min to a stirred solution of 9-chloro-6-fluorobenzo[g]isoquinoline-5,10-dione of Preparative Example 13 in pyridine (0.5 mL) cooled with an ice-bath. A yellow precipitate appears in the dark solution after 6 min. After 1.3 h the reaction mixture is reduced to half its volume by a gentle stream of nitrogen and quenched with ice (5 g). The pale yellow precipitate is collected by suction filtration and washed with ice-water (2×1 mL) and dried under vacuum. The yellow solid is purified by silica gel column chromatography (eluant: chloroform/methanol 96/4 v/v) to yield 5-chloro-2-methylisoquino[5,6,7-cd]indazole-6(2H)-one (0.033 g; 71% yield) as a yellow solid.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]=[C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([N:19]4[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]4)[N:14]3[CH:25]=2)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[N:26]1[CH:31]=[C:30]([CH:32]=O)[N:29]=[C:28]2[N:34]=[CH:35][CH:36]=[CH:37][C:27]=12.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>CN1C(=O)CCC1.C(O)(=O)C>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]=[C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([N:19]4[CH2:24][CH2:23][N:22]([CH2:32][C:30]5[N:29]=[C:28]6[N:34]=[CH:35][CH:36]=[CH:37][C:27]6=[N:26][CH:31]=5)[CH2:21][CH2:20]4)[N:14]3[CH:25]=2)=[CH:7][CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: O=Cc1cnc2cccnc2n1
Reactant: CC(C)(C)c1ccc(-c2cn3c(N4CCNCC4)cccc3n2)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CN1CCCC1=O
Solvent: CC(=O)O
Product: CC(C)(C)c1ccc(-c2cn3c(N4CCN(Cc5cnc6cccnc6n5)CC4)cccc3n2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 10.9 %

Procedure:
Crude 2-(4-tert-Butyl-phenyl)-5-piperazin-1-yl-imidazo[1,2-a]pyridine (0.100 g, 0.298 mmol) and pyrido[2,3-b]pyrazine-3-carbaldehyde (0.062 g, 0.378 mmol) was dissolved in NMP (5 mL). The mixture was treated with 3 drops of glacial acetic acid, followed by sodium triacetoxyborohydride (0.126 g, 0.596 mmol.) The mixture was stirred at room temperature overnight and then purified by semipreparative RP-HPLC (Method C) followed by basification as in example 18 to obtain 0.0155 g of the title compound (11%). HPLC (Method B): r.t.=9.0 min., purity 85.2% at 210-370 nm, 81.1% at 252 nm. HRMS: calcd for C29H31N7+H+, 478.27137; found (ESI, [M+H]+), 478.271.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[N:16]([CH3:17])[C:15](=[O:18])[N:14]([CH3:19])[C:13](=S)[CH:12]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].CI.[CH3:23][C:24]1[CH:30]=[C:29]([CH3:31])[CH:28]=[C:27]([CH3:32])[C:25]=1[NH2:26]>O1CCCC1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[N:16]([CH3:17])[C:15](=[O:18])[N:14]([CH3:19])[C:13](=[N:26][C:25]3[C:27]([CH3:32])=[CH:28][C:29]([CH3:31])=[CH:30][C:24]=3[CH3:23])[CH:12]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: Cc1cc(C)c(N)c(C)c1
Reactant: COc1ccc(-c2cc(=S)n(C)c(=O)n2C)cc1OC
Solvent: C1CCOC1
Solvent: CI
Product: COc1ccc(-c2cc(=Nc3c(C)cc(C)cc3C)n(C)c(=O)n2C)cc1OC
Yield: 70.9 %

Procedure:
To a solution of 3,4-dihydro-6-(3,4-dimethoxyphenyl)-1,3-dimethyl-4-thioxo-2(1H)-pyrimidinone (1.51 g) in tetrahydrofuran (150 ml) was added methyl iodide (30 ml) and the mixture was refluxed for 90 minutes. The precipitate was added to 2,4,6-trimethylaniline (6 g) and the mixture was heated at 110°-120° C. for 3 hours. The reaction mixture was washed with a mixture of hexane and diisopropyl ether to remove excess 2,4,6-trimethylaniline. The resulting precipitate was collected by filtration and then dissolved in chloroform. The solution was washed with an aqueous solution of sodium bicarbonate, dried over magnesium sulfate and evaporated under reduced pressure to give crude product, which was purified by silica gel column chromatography to give 3,4-dihydro-6-(3,4-dimethoxyphenyl)-1,3-dimethyl-4-(2,4,6-trimethylphenylimino)-2(1H)-pyrimidinone (1.44 g); mp 68°-70° C. Thus obtained compound was recrystallized from a mixture of methanol and water (5:1) to give the desired compound as crystals. mp 96°-98° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:17]=[CH:18][CH:19]=1)[NH:5][C:6]1[C:7]2[CH:15]=[CH:14][C:13](F)=[N:12][C:8]=2[N:9]=[CH:10][N:11]=1.Cl.CN.C[CH2:24][N:25](CC)CC>CCO>[Br:1][C:2]1[CH:3]=[C:4]([CH:17]=[CH:18][CH:19]=1)[NH:5][C:6]1[C:7]2[CH:15]=[CH:14][C:13]([NH:25][CH3:24])=[N:12][C:8]=2[N:9]=[CH:10][N:11]=1
Reactant: CCN(CC)CC
Reactant: Fc1ccc2c(Nc3cccc(Br)c3)ncnc2n1
Agent: CN
Agent: Cl
Solvent: CCO
Product: CNc1ccc2c(Nc3cccc(Br)c3)ncnc2n1
Temperature: 100 °C

Procedure:
A solution of 4-(3-bromoanilino)-7-fluoropyrido[2,3-d]pyrimidine (see a previous experimental) (0.20 g, 0.63 mmol), methylamine hydrochloride (0.13 g, 1.88 mmol) and Et3N (0.30 mL) 2.19 mmol) in EtOH (15 mL) is heated at 100° C. in a pressure vessel for 18 h. The solvent is removed under reduced pressure, and the residue is partitioned between EtOAc and water. Workup of the organic layer gives 4-(3-bromoanilino)-7-(methylamino)pyrido[2,3-d]pyrimidine (0.16 g, 770.). 1H NMR (DMSO) δ 9.53 (1H, s), 8.54 (1H, s), 8.41 (1H, d, J=8.1 Hz), 8.17 (1H, t, J=1.8 Hz), 7.83 (1H, dd, J=8.0, 1.9 Hz), 7.66 (1H, brs), 7.32 (1H, t, J=8.0 Hz), 7.24 (1H, dd, J=8.0, 1.8 Hz), 6.77 (1H, d, J=8.1 Hz), 2.92 (3H, d, J=4.8 Hz).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH:16]([C:21](=O)[CH2:22][CH2:23][CH2:24][CH3:25])[C:17](OC)=[O:18])=[CH:11][CH:10]=1)#[N:2].[O:27]1[C:31]2([CH2:36][CH2:35][CH:34]([NH:37][C:38]3[NH:42][CH:41]=[N:40][N:39]=3)[CH2:33][CH2:32]2)[O:30][CH2:29][CH2:28]1>>[CH2:22]([C:21]1[N:39]2[N:40]=[CH:41][N:42]=[C:38]2[N:37]([CH:34]2[CH2:33][CH2:32][C:31]3([O:27][CH2:28][CH2:29][O:30]3)[CH2:36][CH2:35]2)[C:17](=[O:18])[C:16]=1[CH2:15][C:12]1[CH:11]=[CH:10][C:9]([C:4]2[C:3]([C:1]#[N:2])=[CH:8][CH:7]=[CH:6][CH:5]=2)=[CH:14][CH:13]=1)[CH2:23][CH2:24][CH3:25]
Reactant: CCCCC(=O)C(Cc1ccc(-c2ccccc2C#N)cc1)C(=O)OC
Reactant: c1nnc(NC2CCC3(CC2)OCCO3)[nH]1
Product: CCCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n(C2CCC3(CC2)OCCO3)c2ncnn12
Temperature: 250 °C
Reaction time: 0.33 h
Yield: 53.5 %

Procedure:
A mixture of methyl 2-[(2′-cyanobiphenyl-4-yl)methyl]-3-oxoheptanoate (1.9 g) and N-(1,4-dioxaspiro[4.5]dec-8-yl)-4H-1,2,4-triazol-3-amine (0.6 g) was stirred at 250° C. for 20 min under microwave irradiation. The obtained reaction mixture was purified by silica gel column chromatography to give the title compound as a colorless solid (0.75 g, 53%).
Reaction SMILES: [CH3:1][C@@:2]([NH:15][NH2:16])([C:12]([OH:14])=[O:13])[CH2:3][C:4]1[CH:5]=[CH:6][C:7]([OH:11])=[C:8]([OH:10])[CH:9]=1.[CH3:17][C:18]1[CH:26]=[CH:25][CH:24]=[C:23]([CH3:27])[C:19]=1[C:20](Cl)=[O:21]>FC(F)(F)C(O)=O>[C:12]([C:2]([NH:15][NH2:16])([CH3:1])[CH2:3][C:4]1[CH:5]=[CH:6][C:7]([OH:11])=[C:8]([O:10][C:20](=[O:21])[C:19]2[C:23]([CH3:27])=[CH:24][CH:25]=[CH:26][C:18]=2[CH3:17])[CH:9]=1)([OH:14])=[O:13]
Reactant: Cc1cccc(C)c1C(=O)Cl
Reactant: C[C@@](Cc1ccc(O)c(O)c1)(NN)C(=O)O
Solvent: O=C(O)C(F)(F)F
Product: Cc1cccc(C)c1C(=O)Oc1cc(CC(C)(NN)C(=O)O)ccc1O
Temperature: 25 °C
Reaction time: 1 h
Yield: 15 %

Procedure:
To a solution of carbidopa (732 mg, 3 mmol) in trifluoroacetic acid (10 mL), was slowly added 2,6-dimethyl-benzoyl chloride (504 mg, 3 mmol) at 0° C. and the mixture stirred at room temperature for 1 h. The reaction mixture was concentrated under reduced pressure. The oily residue was dissolved in acetonitrile/H2O and purified by reverse phase preparative HPLC to afford 196 mg of compound 125 [1H NMR (CD3OD, 400 MHz) 1.49 (s, 3H), 2.45 (d, 6H), 3.10 (dd, 2H), 6.82–7.25 (m, 6H). MS (ESI) m/z 359.23 (M+H+)] and 161 mg of compound 126 [1H NMR (CD3OD, 400 MHz): 1.45 (s, 3H), 2.42 (d, 6H), 3.15 (dd, 2H), 6.74–7.27 (m, 6H). MS (ESI m/z 359.23 (M+H+)].
Reaction SMILES: [OH:1][CH2:2][C@:3]1([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:7][C:6](=[O:8])[N:5]([C@@H:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH3:10])[CH2:4]1.N1C=CN=C1.[Si:29](Cl)([C:32]([CH3:35])([CH3:34])[CH3:33])([CH3:31])[CH3:30].[Cl-].[NH4+]>CN(C)C=O>[Si:29]([O:1][CH2:2][C@:3]1([C:17]([O:19][C:20]([CH3:22])([CH3:21])[CH3:23])=[O:18])[CH2:7][C:6](=[O:8])[N:5]([C@@H:9]([C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH3:10])[CH2:4]1)([C:32]([CH3:35])([CH3:34])[CH3:33])([CH3:31])[CH3:30]
Reactant: C[C@H](c1ccccc1)N1C[C@@](CO)(C(=O)OC(C)(C)C)CC1=O
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: [Cl-]
Agent: [NH4+]
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: C[C@H](c1ccccc1)N1C[C@@](CO[Si](C)(C)C(C)(C)C)(C(=O)OC(C)(C)C)CC1=O
Temperature: 25 °C
Reaction time: 4 h
Yield: 71.3 %

Procedure:
To a solution of tert-butyl (3S)-3-hydroxymethyl-5-oxo-1-[(1R)-1-phenylethyl]pyrrolidine-3-carboxylate (8.23 g, 25.8 mmol) and imidazole (2.63 g, 38.7 mmol) in N,N-dimethylformamide (150 mL), tert-butyl dimethylsilyl chloride (4.66 g, 31.0 mmol) was added in an ice bath, and the mixture was stirred at room temperature for 4 hours. To the reaction mixture, saturated aqueous solution of ammonium chloride (300 mL) was added in an ice bath, and the mixture was extracted with diethylether (300 mL×2). The organic layer was washed with water (300 mL×2) and saturated aqueous solution of sodium chloride (200 mL), and dried with anhydrous magnesium sulfate. After filtration, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (elusion by hexane:ethyl acetate, 10:1→1:1) to obtain 7.98 g (71%) of the title compound as a colorless oily substance.
Reaction SMILES: [Br-].[CH3:2][O:3][C:4]1[CH:9]=[CH:8][C:7]([CH2:10][P+](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=[CH:6][CH:5]=1.[CH:30](=O)[CH2:31][CH2:32]/[CH:33]=[CH:34]/[CH2:35][CH2:36][CH2:37][CH2:38][CH3:39]>C1COCC1>[CH3:2][O:3][C:4]1[CH:5]=[CH:6][C:7]([CH:10]=[CH:30][CH2:31][CH2:32]/[CH:33]=[CH:34]/[CH2:35][CH2:36][CH2:37][CH2:38][CH3:39])=[CH:8][CH:9]=1
Reactant: CCCCC/C=C/CCC=O
Reactant: COc1ccc(C[P+](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Br-]
Solvent: C1CCOC1
Product: CCCCC/C=C/CCC=Cc1ccc(OC)cc1
Yield: 71.6 %

Procedure:
Starting from (4-methoxyphenyl)methyltriphenylphosphonium bromide (14.0 g, 30.2 mmol, 1.0 equiv.), KtBuO (34 mL, 34.0 mmol, 1.1 equiv., 1M in THF) and (E)-dec-4-enal (5.59 g, 36.3 mmol, 1.2 equiv.), 5.59 g (72%) of the title compound was obtained after purification by flash chromatography on SiO2 (cyclohexane/EtOAc 99:1) as a light yellow oil.
Reaction SMILES: [CH2:1]([Li])CCC.[CH2:6]([O:13][C:14]1[CH:15]=[CH:16][C:17]([OH:22])=[C:18]([CH:21]=1)[CH:19]=O)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.ClCCl>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C1COCC1>[CH2:6]([O:13][C:14]1[CH:15]=[CH:16][C:17]([OH:22])=[C:18]([CH:19]=[CH2:1])[CH:21]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: O=Cc1cc(OCc2ccccc2)ccc1O
Reactant: [Li]CCCC
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Solvent: C1CCOC1
Solvent: ClCCl
Product: C=Cc1cc(OCc2ccccc2)ccc1O
Temperature: 25 °C
Reaction time: 1 h
Yield: 88.3 %

Procedure:
To a flame dried 500 mL 3-neck flask under an atmosphere of argon, was charged methyltriphenylphosphonium bromide (43.8 mmol) dissolved in anhydrous THF (120 mL), followed by the dropwise addition of n-butyllithium (21.9 mL, 35.04 mmol). The dark red mixture was stirred at ambient temperature for 1 h. Next 5-benzyloxy-2-hydroxybenzaldehyde (2.0 g, 8.76 mmol) (Acta. Chem. Scand., Ser. B, B40(5), 400-1, (1986) was added followed by the addition of anhydrous dichloromethane (40 mL). The mixture was stirred at ambient temperature for 18 h. The solvents were removed in vacuo, and the residue was partitioned between EtOAc and water (500 mL each). The organic layer was washed with brine (500 mL), dried (Na2SO4), and concentrated in vacuo. The crude product was purified using the Biotage FlashElute chromatography system using a 65M normal phase cartridge, eluting with 15% EtOAc/Hexanes to give a yellow solid (1.75 g, 88%). 1H NMR (400 MHz, CDCl3) δ 7.44-7.30, (m, 4H), 7.14 (d, J=2.9 Hz, 1H), 6.94-6.87 (m, 1H), 6.79 (dd, J=8.8, 2.9 Hz, 2H), 6.72 (d, J=8.8 Hz, 1H), 5.71 (dd, J=17.6, 1.5 Hz, 1H), 5.35 (dd, J=11.2, 0.98 Hz, 1H), 5.02 (s, 2H), 4.60 (s, 1H); MS (FIA) m/e 227 (M+1)