Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([CH2:7][N:8]2[CH:12]=[CH:11][C:10]([S:13]([NH:16][CH:17]3[CH2:19][CH2:18]3)(=[O:15])=[O:14])=[C:9]2[CH3:20])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C1C(=O)N([Br:28])C(=O)C1.O>C1COCC1>[Br:28][C:12]1[N:8]([CH2:7][CH:1]2[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]2)[C:9]([CH3:20])=[C:10]([S:13]([NH:16][CH:17]2[CH2:19][CH2:18]2)(=[O:15])=[O:14])[CH:11]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1c(S(=O)(=O)NC2CC2)ccn1CC1CCCCC1
Solvent: O
Solvent: C1CCOC1
Product: Cc1c(S(=O)(=O)NC2CC2)cc(Br)n1CC1CCCCC1
Temperature: -78 °C
Reaction time: 2 h
Yield: 85.3 %

Procedure:
To a solution of compound 3c (3.0 g, 10.0 mmol) in THF (80 mL) at −78° C. was added a solution of NBS (1.78 g, 10.0 mmol) in THF (50 mL) and the solution was stirred for 2 h at −78° C. Water was added and the solution was extracted with EA twice. The combined organic layers were dried over Na2SO4, filtered, concentrated and purified CC (EA/PE=1/5) to give compound 3d (3.2 g, 85%) as a white solid.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH:6]=[C:5]([C:8]2[O:9][C:10]3[C:16]([O:17][CH3:18])=[CH:15][CH:14]=[CH:13][C:11]=3[CH:12]=2)[CH2:4][CH2:3]1.CO.Br>[Pt](=O)=O.O>[CH3:1][N:2]1[CH2:7][CH2:6][CH:5]([C:8]2[O:9][C:10]3[C:16]([O:17][CH3:18])=[CH:15][CH:14]=[CH:13][C:11]=3[CH:12]=2)[CH2:4][CH2:3]1
Reactant: COc1cccc2cc(C3=CCN(C)CC3)oc12
Agent: O=[Pt]=O
Agent: Br
Solvent: O
Solvent: CO
Product: COc1cccc2cc(C3CCN(C)CC3)oc12
Temperature: 25 °C
Reaction time: 6 h
Yield: 100.9 %

Procedure:
A mixture of 1-methyl-4-(7-methoxy-2-benzofuranyl)-1,2,3,6-tetrahydropyridine (58.0 g), methanol (1.5 l), water (200 ml), 48% HBr (42.0 g), and platinum dioxide were shaken under hydrogen at room temperature for 6 hours. The mixture was filtered; the filtrate was concentrated in vacuo to the aqueous phase, neutralized with 5% Na2CO3 and extracted with CH2 Cl2. The organic phase was washed with water, dried (Na2 SO4) and concentrated in vacuo to give 59 g of the crude product, which was crystallized from methanol/water, m.p. 74°-75° C.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:14])[CH2:5]P(OCC)(OCC)=O)[CH3:2].[H-].[Na+].[Cl:17][C:18]1[CH:40]=[CH:39][C:21]([C:22]([N:24]2[CH2:29][CH2:28][CH:27]([NH:30][C:31]3[CH:38]=[CH:37][C:34]([CH:35]=O)=[CH:33][N:32]=3)[CH2:26][CH2:25]2)=[O:23])=[CH:20][CH:19]=1.C(OCC)(C)=O.O>C1COCC1>[Cl:17][C:18]1[CH:19]=[CH:20][C:21]([C:22]([N:24]2[CH2:25][CH2:26][CH:27]([NH:30][C:31]3[N:32]=[CH:33][C:34](/[CH:35]=[CH:5]/[C:4]([O:3][CH2:1][CH3:2])=[O:14])=[CH:37][CH:38]=3)[CH2:28][CH2:29]2)=[O:23])=[CH:39][CH:40]=1
Reactant: O=Cc1ccc(NC2CCN(C(=O)c3ccc(Cl)cc3)CC2)nc1
Reactant: CCOC(=O)CP(=O)(OCC)OCC
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: O
Product: CCOC(=O)/C=C/c1ccc(NC2CCN(C(=O)c3ccc(Cl)cc3)CC2)nc1
Temperature: 15 °C
Yield: 75.2 %

Procedure:
A solution of diethylphosphonoacetic acid ethyl ester (274 mg) in THF (10 ml) was added dropwise to a mixture of 60% sodium hydride in oil (55 mg) in THF (10 mL) with stirring at 10-20° C. under atmospheric pressure of nitrogen, and the reaction mixture was stirred at ambient temperature for 30 minutes. A solution of 6-{[1-(4-chlorobenzoyl)-4-piperidyl]amino}nicotinaldehyde (210 mg) in THF (10 ml) solution was added to the above mixture and resultant mixture was stirred at ambient temperature for 1.5 hour. The reaction mixture was poured into a mixture of AcOEt-H2O and the organic layer was washed with brine and dried over MgSO4. The solvent was evaporated in vacuo and the residue was chromatographed on silicagel eluting with AcOEt-MeOH (95:5). The eluted fractions containing the desired product were collected and evaporated in vacuo to give ethyl (2E)-3-(6-{[1-(4-chlorobenzoyl)-4-piperidyl]amino}-3-pyridyl)acrylate (190 mg)
Reaction SMILES: COC1C=CC(C[O:8][C:9](=[O:14])[C:10]([CH3:13])([CH3:12])[CH3:11])=CC=1.[C:17]([NH:27][C@@H:28]([C:32]([OH:34])=[O:33])[CH:29]([CH3:31])[CH3:30])([O:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:18].C1CCC(N=C=NC2CCCCC2)CC1>ClCCl.CN(C)C1C=CN=CC=1>[CH3:11][C:10]([CH3:13])([CH2:12][O:33][C:32](=[O:34])[C@@H:28]([CH:29]([CH3:30])[CH3:31])[NH:27][C:17]([O:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:18])[C:9]([OH:14])=[O:8]
Reactant: CC(C)[C@@H](NC(=O)OCc1ccccc1)C(=O)O
Reactant: COc1ccc(COC(=O)C(C)(C)C)cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CC(C)[C@@H](NC(=O)OCc1ccccc1)C(=O)OCC(C)(C)C(=O)O
Reaction time: 18 h

Procedure:
To a solution of 2,2-dimethyl propionic acid 4methoxybenzyl ester (4.7 g, 20 mmole) and N-CBz-D-valine (5.5 g, 22 mmole) in dichloromethane (100 ml) were added 4-dimethyaminopyridine (305 mg, 2.5 mmole) and DCC (5.15 g, 25 mmole). After 18 hr, the solution was washed successively with sodium bicarbonate aqueous solution, citric acid solution and water. The organic phase was dried and the residue was dissolved in dichloromethane (100 ml). To the solution was added trifluoroacetic acid (10 ml). After 3 hr, it was evaporated and the product was isolated with silica gel column chromatography. 4.5 g. The compound may be activated and esterified to a drug or further modified as described below.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:13]([NH2:15])=[O:14])=[N:4][C:5]([C:9](O)([CH3:11])[CH3:10])=[C:6]([Cl:8])[N:7]=1.N1C=CC=CC=1.S(Cl)(C)(=O)=O.[H][H]>[Pd].C1COCC1.C(O)C>[Cl:1][C:2]1[C:3]([C:13]([NH2:15])=[O:14])=[N:4][C:5]([CH:9]([CH3:11])[CH3:10])=[C:6]([Cl:8])[N:7]=1
Reactant: [H][H]
Reactant: CC(C)(O)c1nc(C(N)=O)c(Cl)nc1Cl
Agent: [Pd]
Agent: CS(=O)(=O)Cl
Solvent: c1ccncc1
Solvent: CCO
Solvent: C1CCOC1
Product: CC(C)c1nc(C(N)=O)c(Cl)nc1Cl
Temperature: 25 °C
Reaction time: 5 h
Yield: 25.6 %

Procedure:
To a mixture of 3,5-dichloro-6-(1-hydroxy-1-methylethyl)pyrazine-2-carboxamide (2.64 g) and pyridine (30 mL), mesyl chloride (2.45 mL) was added under ice cooling. After stirring at room temperature for 5 hours, pyridine was distilled off under reduced pressure, and the resulting residue was partitioned using ethyl acetate and water. The resulting organic layer was washed with 10% aqueous citric acid, saturated aqueous sodium hydrogen carbonate and saturated aqueous sodium chloride, and dried over anhydrous magnesium sulfate, and the solvent was distilled off to give a light brown syrup. To the light brown syrup, ethanol (60 mL) and THF (30 mL) were added, and then 10% palladium on carbon (0.7 g) was added and stirred at room temperature for 14 hours under 3 atmospheric pressure of hydrogen. After filtration through celite, the filtrate was distilled off under reduced pressure, and the residue was diluted with ethyl acetate and then washed with saturated aqueous sodium hydrogen carbonate and saturated aqueous sodium chloride. After the solvent was distilled off, the residue was purified by silica gel column chromatography (eluent; chloroform:methanol=100:0 to 40:1). The resulting crude product was washed with diisopropyl ether to give 3,5-di-chloro-6-isopropylpyrazine-2-carboxamide (632 mg) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[C:7](Cl)=[N:6][C:5]([C:9]#[N:10])=[C:4]([C:11]#[N:12])[N:3]=1.[NH3:13].O>O1CCCC1>[NH2:13][C:7]1[C:2]([Cl:1])=[N:3][C:4]([C:11]#[N:12])=[C:5]([C:9]#[N:10])[N:6]=1
Reactant: N
Reactant: N#Cc1nc(Cl)c(Cl)nc1C#N
Solvent: C1CCOC1
Solvent: O
Product: N#Cc1nc(N)c(Cl)nc1C#N
Reaction time: 1 h
Yield: 93.6 %

Procedure:
5.0 g (0.025 mol) of 2,3-dichloro-5,6-dicyanopyrazine was dissolved in 50 ml of dry tetrahydrofuran, and 6.1 g (0.050 mol) of 28% aqueous ammonia was dropwise added at a temperature of from -15°to 0° C. After completion of the dropwise addition, the mixture was stirred for 1 hour, and the reaction solution was poured into 500 ml of water. The precipitated solid was collected by filtration and recrystallized from a solvent mixture of toluene and ethyl acetate to obtain 4.2 g of slightly yellow crystals (yield: 93.6%, melting point: 205-208° C.).
Reaction SMILES: [C:1]([C:6]1[NH:7][C:8]([CH3:17])=[C:9]([CH3:16])[C:10]=1[O:11][CH2:12][CH2:13][CH2:14][Cl:15])([O:3][CH2:4][CH3:5])=[O:2].[OH:18][C:19]1([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1.C(=O)([O-])[O-].[Na+].[Na+]>CN(C)C=O>[ClH:15].[CH2:4]([O:3][C:1]([C:6]1[NH:7][C:8]([CH3:17])=[C:9]([CH3:16])[C:10]=1[O:11][CH2:12][CH2:13][CH2:14][N:22]1[CH2:21][CH2:20][C:19]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)([OH:18])[CH2:24][CH2:23]1)=[O:2])[CH3:5]
Reactant: CCOC(=O)c1[nH]c(C)c(C)c1OCCCCl
Reactant: OC1(c2ccccc2)CCNCC1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1[nH]c(C)c(C)c1OCCCN1CCC(O)(c2ccccc2)CC1
Product: Cl
Yield: 66.6 %

Procedure:
50 g of 1-(2-carboethoxy-4,5-dimethyl-pyrrol-3-oxy)-3-chloropropane, 35 g of 4-hydroxy-4-phenyl-piperidine and 50 g of sodium carbonate in 300 ml of N,N-dimethylformamide are heated for 20 hours at 100° C. When the mixture has cooled, it is partitioned between water and methylene chloride, the organic phase is evaporated under reduced pressure, the residue which remains in dissolved in a small amount of methanol, and a solution of hydrogen chloride in ether is added dropwise. The crystals which precipitate are filtered off, washed with ether and dried. 56 g of 3-[3-(4-phenyl-4-hydroxy-piperidino)-propoxy]-4,5-dimethylpyrrole-2-carboxylic acid ethyl ester hydrochloride, of melting point 165°-169° C., are obtained.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[C:8]([C@@H:10]2[CH2:15][CH:14]=[CH:13][CH2:12][C@H:11]2[N+:16]([O-:18])=[O:17])[CH:7]=[CH:6][C:5]=1[O:19][CH3:20])[CH3:2].[OH-].[K+].S(=O)(=O)(O)O>C(O)C>[CH2:1]([O:3][C:4]1[CH:9]=[C:8]([C@@H:10]2[CH2:15][CH:14]=[CH:13][CH2:12][C@@H:11]2[N+:16]([O-:18])=[O:17])[CH:7]=[CH:6][C:5]=1[O:19][CH3:20])[CH3:2]
Reactant: CCOc1cc([C@@H]2CC=CC[C@H]2[N+](=O)[O-])ccc1OC
Agent: O=S(=O)(O)O
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: CCOc1cc([C@@H]2CC=CC[C@@H]2[N+](=O)[O-])ccc1OC
Temperature: 0 °C
Reaction time: 1 h

Procedure:
89.25 of (+/−)-trans-2-ethoxy-1-methoxy-4-(2-nitrocyclohex-4-enyl)benzene (compound D1) and 37 g of potassium hydroxide are dissolved in 500 ml of absolute ethanol. A solution of 23.5 ml of conc. sulfuric acid in 120 ml of absolute ethanol is then added dropwise such that the internal temperature does not exceed −2° C. After stirring for 1 h, the mixture is added to 4 l of ice water, and the precipitate is filtered off with suction, washed with water and dried, M.p.: 66-67° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:18])[C:7]=1[CH2:8][C@H:9]1[CH2:13][C:12]2([CH2:17][CH:16]=[CH:15][CH2:14]2)[CH2:11][NH:10]1.CO>CCOC(C)=O.C(Cl)Cl.[Pd]>[Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:18])[C:7]=1[CH2:8][C@H:9]1[CH2:13][C:12]2([CH2:17][CH2:16][CH2:15][CH2:14]2)[CH2:11][NH:10]1
Reactant: Clc1cncc(Cl)c1C[C@H]1CC2(CC=CC2)CN1
Agent: [Pd]
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: CO
Product: Clc1cncc(Cl)c1C[C@H]1CC2(CCCC2)CN1
Temperature: 25 °C
Reaction time: 3 h
Yield: 58.5 %

Procedure:
A mixture of (R)-3-((3,5-dichloropyridin-4-yl)methyl)-2-azaspiro[4.4]non-7-ene (0.090 g, 0.318 mmol) and palladium 10 wt. % on activated carbon (0.034 g, 0.032 mmol) in EtOAc (4 ml) was stirred under hydrogen balloon at room temperature for 3 h. Starting material was converted to the desired project with mono-chloro product (˜4:1). The crude material was absorbed onto a plug of silica gel and purified by chromatography through a REDISEP™ pre-packed silica gel column (12 g), eluting with a gradient of 5% to 50% 1 M NH3.MeOH in DCM, to provide (R)-3-((3,5-dichloropyridin-4-yl)methyl)-2-azaspiro[4.4]nonane (0.053 g, 0.186 mmol, 58.5% yield) as a brown oil. 1H NMR (400 MHz, CDCl3) δ 8.42-8.50 (m, 2H), 3.63-3.83 (m, 1H), 3.28 (br. s., 2H), 3.02 (d, J=10.37 Hz, 1H), 2.87 (br. s., 1H), 1.73-1.83 (m, 1H), 1.54-1.72 (m, 9H), 1.42-1.53 (m, 1H); LCMS (ESI) m/z 285.0 (M+H)+.
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[C:5]([CH:10]=[CH:11][CH:12]=1)[C:6]([O:8][CH3:9])=[O:7])=O.[F:13][C:14]1[CH:20]=[CH:19][CH:18]=[CH:17][C:15]=1[NH2:16].C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl.O>[F:13][C:14]1[CH:20]=[CH:19][CH:18]=[CH:17][C:15]=1[NH:16][CH2:1][C:3]1[CH:4]=[C:5]([CH:10]=[CH:11][CH:12]=1)[C:6]([O:8][CH3:9])=[O:7]
Reactant: Nc1ccccc1F
Reactant: COC(=O)c1cccc(C=O)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Solvent: CC(=O)O
Product: COC(=O)c1cccc(CNc2ccccc2F)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 99.4 %

Procedure:
To a stirred solution of methyl 3-formylbenzoate (1 g, 6.092 mmol) in anhydrous DCM (30 mL) was added 2-fluoroaniline (0.620 mL, 6.396 mmol) followed by glacial acetic acid (0.350 mL, 6.092 mmol). The reaction was stirred at room temperature for 18 hours. Sodium triacetoxyborohydride (3.23 g, 15.23 mmol) was added, and the reaction was stirred at room temperature for 3 hours. Water was added to quench the reaction, and the mixture was diluted with DCM. The organic layer was washed with brine, passed through a hydrophobic fit and the solvent was removed in vacuo to afford the title compound as a yellow oil (1.57 g, quantitative yield).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][CH:8]=1)[NH2:5].[N:9]([O-])=O.[Na+].C([O-])(=O)C.[Na+].[C:18]([CH2:21][C:22](=[O:24])[CH3:23])(=[O:20])[CH3:19]>O.Cl.C(O)C>[Cl:1][C:2]1[CH:3]=[C:4]([NH:5][N:9]=[C:21]([C:22](=[O:24])[CH3:23])[C:18](=[O:20])[CH3:19])[CH:6]=[CH:7][CH:8]=1
Reactant: O=N[O-]
Reactant: Nc1cccc(Cl)c1
Reactant: CC(=O)CC(C)=O
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CC(=O)C(=NNc1cccc(Cl)c1)C(C)=O
Temperature: 0 °C
Reaction time: 1 h
Yield: 24 %

Procedure:
To a solution of 3-chloroaniline (1000 mg, 7.87 mmol) in 5 mL of water and 5 mL of concentrated hydrochloride solution, sodium nitrite (652 mg, 9.45 mmol) in 4 mL of water was added dropwise at 0° C., and the mixture was stirred at 0° C. for 1 h. Then to the reaction mixture was added dropwise a solution of sodium acetate (1936 mg, 23.61 mmol) and acetylacetone (866 mg, 8.66 mmol) in 10 mL of ethanol and 6 mL of water. The mixture was stirred at room temperature overnight, filtered, washed with water, EtOH/H2O (1:1) and hexane, and dried to give 3-[(3-chlorophenyl)hydrazono]pentane-2,4-dione (450 mg, 24%).
Reaction SMILES: [C:1]1(=[O:11])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH2:2]1.[N+:12]([C:15]1[CH:16]=[C:17]([CH:20]=[CH:21][CH:22]=1)[CH:18]=O)([O-:14])=[O:13].O.C1(C)C=CC(S(O)(=O)=O)=CC=1.O>C1(C)C=CC=CC=1>[N+:12]([C:15]1[CH:16]=[C:17]([CH:20]=[CH:21][CH:22]=1)[CH:18]=[C:2]1[CH2:3][CH2:4][C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[C:1]1=[O:11])([O-:14])=[O:13]
Reactant: O=C1CCCc2ccccc21
Reactant: O=Cc1cccc([N+](=O)[O-])c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: O=C1C(=Cc2cccc([N+](=O)[O-])c2)CCc2ccccc21

Procedure:
A mixture of 3,4-dihydro-1(2H)-naphthalenone (21.9 G), 3-nitrobenzaldehyde (22.6 g) and p-toluenesulphonic acid monohydrate (50 mg) in toluene (250 ml) was stirred at reflux with separation of water for 4.5 hours. The brown solution was allowed to cool overnight. The resulting yellow-orange deposited solid was filtered off, washed well with toluene and dried in vacuo yielding 2-(3-nitrobenzylidene)-3,4-dihydro-1(2H)-naphthalenone as crisp yellow needles.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([C:9]2[NH:10][C:11]3[C:16]([CH:17]=2)=[CH:15][C:14]([C:18]([NH:20][CH2:21][CH2:22][CH2:23][N:24]2[CH2:29][CH2:28][O:27][CH2:26][CH2:25]2)=[O:19])=[CH:13][CH:12]=3)=[CH:7][CH:6]=[CH:5][N:4]=1.[Br:30]N1C(=O)CCC1=O>C1COCC1>[Br:30][C:17]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([C:18]([NH:20][CH2:21][CH2:22][CH2:23][N:24]3[CH2:25][CH2:26][O:27][CH2:28][CH2:29]3)=[O:19])[CH:15]=2)[NH:10][C:9]=1[C:8]1[C:3]([O:2][CH3:1])=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: COc1ncccc1-c1cc2cc(C(=O)NCCCN3CCOCC3)ccc2[nH]1
Solvent: C1CCOC1
Product: COc1ncccc1-c1[nH]c2ccc(C(=O)NCCCN3CCOCC3)cc2c1Br
Temperature: 60 °C
Reaction time: 1.5 h

Procedure:
A suspension of 2-(2-methoxypyridin-3-yl)-N-(3-morpholinopropyl)-1H-indole-5-carboxamide (0.850 g, 0.215 mmol) in 100 ml THF was heated to 60° C. until dissolved. To the solution was added N-bromosuccinimide (0.406 g, 0.263 mmol) and the reaction was allowed to stir for 1.5 hours. The reaction was not complete, so more N-bromosuccinimide (0.062 g, 0.35 mmol; 0.040 g, 0.022 mmol) was added sequentially and the reaction stirred for 10 more minutes after each addition. Upon completion, the reaction was concentrated and to the residue was added 50 ml EtOAC and 100 ml water. The organics were separated, washed with water (50 ml) and brine (25 ml) and concentrated. The crude product was used with no further purification. LCMS: 473 [M+H].
Reaction SMILES: [H-].[Na+].[C:3]([O:7][C:8]([N:10]([CH3:28])[CH2:11][CH2:12][C:13]1[CH:14]=[C:15]([CH:19](C(OC)=O)[C:20]([O:22][CH3:23])=[O:21])[CH:16]=[CH:17][CH:18]=1)=[O:9])([CH3:6])([CH3:5])[CH3:4]>O1CCCC1.CO>[C:3]([O:7][C:8]([N:10]([CH3:28])[CH2:11][CH2:12][C:13]1[CH:14]=[C:15]([CH2:19][C:20]([O:22][CH3:23])=[O:21])[CH:16]=[CH:17][CH:18]=1)=[O:9])([CH3:5])([CH3:4])[CH3:6]
Reactant: COC(=O)C(C(=O)OC)c1cccc(CCN(C)C(=O)OC(C)(C)C)c1
Agent: [H-]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: COC(=O)Cc1cccc(CCN(C)C(=O)OC(C)(C)C)c1
Temperature: 22 °C

Procedure:
To 429 μL (10.6 mmol) of methanol was slowly added 85 mg (2.1 mmol) of sodium hydride (60% dispersion in mineral oil). This mixture was then added to a separate solution of 387 mg (1.06 mmol) of dimethyl 2-(3-(2-(tert-butoxycarbonyl(methyl)amino)ethyl)phenyl)malonate in 5 mL of tetrahydrofuran. The resulting solution was refluxed for 2 h then cooled to 22° C. An additional 85 mg of NaH in 429 ml of methanol was added and the solution was again heated to reflux for about 16 h. The solvent was evaporated and the residue partitioned between saturated NH4Cl and ethyl acetate. The organic layer was washed with brine, dried (Na2SO4), filtered and evaporated. The residue was purified by flash chromatography on silica gel, eluting first with hexane and then gradually increasing to 15% ethyl acetate/hexane to give methyl 2-(3-(2-(tert-butoxycarbonyl(methyl)amino)ethyl)phenyl)acetate.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C@@H:9]2[CH2:13][NH:12][C:11](=[O:14])[CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8].C(N(C(C)C)CC)(C)C.[Cl:24][C:25]1[CH:26]=[C:27]([S:32](Cl)(=[O:34])=[O:33])[CH:28]=[CH:29][C:30]=1[Cl:31].Cl.Cl.NC[C@@H](C1C=CC(Cl)=C(Br)C=1)CC(O)=[O:43]>C(Cl)Cl.CN(C1C=CN=CC=1)C>[NH2:12][CH2:13][C@@H:9]([C:4]1[CH:5]=[CH:6][C:7]([Cl:8])=[C:2]([NH:1][S:32]([C:27]2[CH:28]=[CH:29][C:30]([Cl:31])=[C:25]([Cl:24])[CH:26]=2)(=[O:34])=[O:33])[CH:3]=1)[CH2:10][C:11]([OH:14])=[O:43]
Reactant: O=S(=O)(Cl)c1ccc(Cl)c(Cl)c1
Reactant: NC[C@H](CC(=O)O)c1ccc(Cl)c(Br)c1
Reactant: Nc1cc([C@@H]2CNC(=O)C2)ccc1Cl
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: NC[C@H](CC(=O)O)c1ccc(Cl)c(NS(=O)(=O)c2ccc(Cl)c(Cl)c2)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
(4R)-4-(3-Amino-4-chlorophenyl)pyrrolidin-2-one (0.105 g, 0.5 mmol) was dissolved in 2 mL of methylene chloride (2 mL). Diisopropylethylamine (0.14 mL, 0.75 mmol) was added followed by 3,4-dichlorobenzenesulfonyl chloride (0.134 g, 0.55 mmol) and a catalytic amount of DMAP (0.05 mmol). The mixture was stirred overnight at room temperature. The mixture was then diluted with methylene chloride (50 mL), washed with water, then brine, and concentrated to give the product, which was treated with HCl as described for the preparation of (3R)-4-amino-3-(3-bromo-4-chlorophenyl)butanoic acid hydrochloride to provide the title compound (21). MS (ESI) m/z 438.89 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C@H:3]([CH3:7])[C:4]([OH:6])=O.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[OH:41][C:42]([C:44]([F:47])([F:46])[F:45])=[O:43].[F:48][CH:49]([F:77])[CH2:50][NH:51][C:52]1[N:57]=[C:56]2[CH2:58][NH:59][CH2:60][CH2:61][C:55]2=[N:54][C:53]=1[N:62]1[CH2:67][CH2:66][CH:65]([O:68][C:69]2[CH:74]=[CH:73][C:72]([F:75])=[CH:71][C:70]=2[F:76])[CH2:64][CH2:63]1>CN(C=O)C>[F:77][CH:49]([F:48])[CH2:50][NH:51][C:52]1[N:57]=[C:56]2[CH2:58][N:59]([C:4](=[O:6])[C@H:3]([O:2][CH3:1])[CH3:7])[CH2:60][CH2:61][C:55]2=[N:54][C:53]=1[N:62]1[CH2:63][CH2:64][CH:65]([O:68][C:69]2[CH:74]=[CH:73][C:72]([F:75])=[CH:71][C:70]=2[F:76])[CH2:66][CH2:67]1.[C:42]([OH:43])([C:44]([F:47])([F:46])[F:45])=[O:41]
Reactant: CO[C@H](C)C(=O)O
Reactant: Fc1ccc(OC2CCN(c3nc4c(nc3NCC(F)F)CNCC4)CC2)c(F)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CO[C@H](C)C(=O)N1CCc2nc(N3CCC(Oc4ccc(F)cc4F)CC3)c(NCC(F)F)nc2C1
Reaction time: 8 h

Procedure:
A solution of (R)-2-methoxypropanoic acid (2.9 mg, 0.028 mmol), DIPEA (10.8 mg, 0.083 mmol), and HATU (10.6 mg, 0.028 mmol) in DMF (278 μL) was stirred at room temperature for 10 min followed by the addition of N-(2,2-difluoroethyl)-2-(4-(2,4-difluorophenoxyl)piperidin-1-yl)-5,6,7,8-tetrahydropyrido[3,4-b]pyrazin-3-amine TFA salt (15 mg, 0.028 mmol) and stirring overnight. The crude reaction mixture was diluted in DMF, filtered through a hydrophilic PTFE 0.45 μm filter (Millipore® Millex-LCR), and purified via HPLC Method A to give the title compound as a TFA salt (3 mg) as a clear oil. 1H NMR (400 MHz, methanol-d4, mixture of rotamers) δ ppm 1.32 (d, J=6.8 Hz, 1.3H), 1.38 (d, J=6.6 Hz, 1.6H), 1.90-2.04 (m, 2H), 2.09-2.18 (m, 2H), 2.76 (t, J=6.6 Hz, 0.9H), 2.84 (t, J=6.1 Hz, 1.1H), 3.00 (ddd, J=12.3, 8.6, 3.3 Hz, 2H), 3.33 (s, 3H), 3.34-3.43 (m, 2H), 3.72-3.84 (m, 2H), 3.84-3.98 (m, 2H), 4.32-4.41 (m, 1H), 4.42-4.50 (m, 1H), 4.51-4.55 (m, 0.6H), 4.62-4.69 (m, 1.4H), 5.89-6.22 (m, 1H), 6.84-6.91 (m, 1H), 6.98 (ddd, J=11.2, 8.5, 3.0 Hz, 1H), 7.17 (td, J=9.2, 5.6 Hz, 1H); ESI-MS m/z [M+H]+ 512.4.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:21]2[C:26]([Cl:27])=[CH:25][CH:24]=[CH:23][C:22]=2[Cl:28])=[CH:4][C:5]2[CH:10]=[N:9][C:8]([NH:11][CH2:12][CH2:13][CH2:14][N:15]([CH2:18][CH3:19])[CH2:16][CH3:17])=[N:7][C:6]=2[N:20]=1.[H-].[Na+].[C:31]([N:35]=[C:36]=[O:37])([CH3:34])([CH3:33])[CH3:32].C>CN(C=O)C.O>[C:31]([NH:35][C:36]([NH:1][C:2]1[C:3]([C:21]2[C:26]([Cl:27])=[CH:25][CH:24]=[CH:23][C:22]=2[Cl:28])=[CH:4][C:5]2[CH:10]=[N:9][C:8]([NH:11][CH2:12][CH2:13][CH2:14][N:15]([CH2:18][CH3:19])[CH2:16][CH3:17])=[N:7][C:6]=2[N:20]=1)=[O:37])([CH3:34])([CH3:33])[CH3:32]
Reactant: CC(C)(C)N=C=O
Reactant: CCN(CC)CCCNc1ncc2cc(-c3c(Cl)cccc3Cl)c(N)nc2n1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCN(CC)CCCNc1ncc2cc(-c3c(Cl)cccc3Cl)c(NC(=O)NC(C)(C)C)nc2n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 27.9 %

Procedure:
To a solution of 7-amino-6-(2,6-dichlorophenyl)-2-(3-diethylamino-propylamino)-pyrido[2,3-d]pyrimidine (0.48 g) from Example 20 in DMF (5 mL) was added 60% sodium hydride suspension (46 mg), and the mixture was stirred for 1 hour at room temperature. To the reaction mixture was added t-butyl isocyanate (0.113 g), and the mixture was stirred for 18 hours. The reaction mixture was diluted with water and the insoluble material was collected by filtration. The solid was suspended in water (20 mL) and acidified with 1.ON HCl to form a solution. Activated charcoal was added to the solution, and the suspension filtered through celite, washing with water. The filtrate was made basic with 1.0 N NaOH, and the insoluble product was collected by filtration and washed with water. A 180-mg sample of the product was further purified by reverse phase preparative HPLC on a C18 reverse phase column, eluting with a solvent gradient starting from 86% of 0.1% trifluoroacetic acid in water/14% acetonitrile to 14% of 0.1% trifluoroacetic acid in water/86% acetonitrile over a 22-minute time period to afford 165 mg of 1-tert-butyl-3-[6-(2,6-dichlorophenyl)-2-(3-diethylamino-propylamino)-pyrido[2,3-d]pyrimidin-7-yl]-urea, mp dec >80° C.