Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CC(OC(=O)[NH:7][CH2:8][CH2:9][C@@H:10]([O:16][C:17]1[CH:22]=[C:21]([Cl:23])[C:20]([F:24])=[CH:19][C:18]=1[C:25]#[N:26])[C:11]1[CH:15]=[CH:14][O:13][CH:12]=1)(C)C.C(=O)(O)[O-].[Na+].[C:33]([OH:40])(=[O:39])/[CH:34]=[CH:35]/[C:36]([OH:38])=[O:37]>Cl.O1CCOCC1>[C:33]([OH:40])(=[O:39])/[CH:34]=[CH:35]/[C:36]([OH:38])=[O:37].[NH2:7][CH2:8][CH2:9][C@@H:10]([O:16][C:17]1[CH:22]=[C:21]([Cl:23])[C:20]([F:24])=[CH:19][C:18]=1[C:25]#[N:26])[C:11]1[CH:15]=[CH:14][O:13][CH:12]=1
Reactant: CC(C)(C)OC(=O)NCC[C@@H](Oc1cc(Cl)c(F)cc1C#N)c1ccoc1
Agent: Cl
Agent: O=C(O)/C=C/C(=O)O
Agent: O=C([O-])O
Solvent: C1COCCO1
Product: N#Cc1cc(F)c(Cl)cc1O[C@H](CCN)c1ccoc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 40 %

Procedure:
The product from step (c) (150 mg, 0.3 mmol) was dissolved in 4M HCl in dioxan (10 ml) and stirred at room temperature for 10 minutes. The reaction was placed in an ice-bath and aqueous saturated sodium bicarbonate solution (30 ml) added cautiously. The mixture wa extracted with ethyl acetate (3×50 ml) and the combined extracts were washed with water (20 ml), dried (sodium sulphate) and evaporated in vacuo. The residue was chromatographed on flash silica, eluting with 5% 7N ammonia in methanol in dichloromethane. The product was dissolved in methanol (5 ml) and treated with one equivalent of fumaric acid. Stirred for 10 minutes then removed the solvent in vacuo and triturated the solid residue with a little ethyl acetate. The white solid was filtered off and dried to give the title compound (50 mg, 40%).
Reaction SMILES: I[C:2]1[C:3]([NH:11][CH:12]([CH3:14])[CH3:13])=[N:4][C:5]([S:9][CH3:10])=[N:6][C:7]=1[CH3:8].[C:15]([O:19][CH2:20][CH3:21])(=[O:18])[CH:16]=[CH2:17].C(N(CC)CC)C.C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.CC(N(C)C)=O>[CH:12]([NH:11][C:3]1[C:2](/[CH:17]=[CH:16]/[C:15]([O:19][CH2:20][CH3:21])=[O:18])=[C:7]([CH3:8])[N:6]=[C:5]([S:9][CH3:10])[N:4]=1)([CH3:14])[CH3:13]
Reactant: C=CC(=O)OCC
Reactant: CSc1nc(C)c(I)c(NC(C)C)n1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CC(=O)N(C)C
Solvent: CCN(CC)CC
Product: CCOC(=O)/C=C/c1c(C)nc(SC)nc1NC(C)C
Temperature: 100 °C
Reaction time: 8 h
Yield: 32.3 %

Procedure:
5-Iodo-N-isopropyl-6-methyl-2-(methylthio)pyrimidin-4-amine (8.1 g, 26.2 mmol), ethyl acrylate (5.24 g, 52.4 mmol), triethylamine (10.6 g, 105 mmol), palladium (II) acetate (1.17 g, 5.23 mmol), and tri-o-tolyl phosphine (1.59 g, 5.23 mmol) were added in that order to 10.8 mL of DMA in a pressure tube and sealed. The reaction mixture was heated to 100° C. and allowed to stir overnight. The reaction was quenched by filtration through a short silica plug washing with ACN. The solvent was evaporated and diluted with ethyl acetate then extracted with 10% aqueous LiCl, followed by water and brine. NOTE: Extraction is necessary to remove all DMA giving resolution in chromatography. The sample was purified by silica gel column chromatography using 20% ethyl acetate/hexane as eluent. Desired fractions were combined and reduced to afford 2.5 g (34% yield) of ethyl (2E)-3-[4-(isopropylamino)-6-methyl-2-(methylthio)pyrimidin-5-yl]acrylate as a yellow/orange oil.
Reaction SMILES: [C:1]1(/[CH:7]=[CH:8]/[S:9]([NH:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[S:19]([NH2:22])(=[O:21])=[O:20])(=[O:11])=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H][H]>CO.[Pd]>[CH2:8]([S:9]([NH:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[S:19]([NH2:22])(=[O:20])=[O:21])(=[O:10])=[O:11])[CH2:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: [H][H]
Reactant: NS(=O)(=O)c1ccccc1NS(=O)(=O)/C=C/c1ccccc1
Agent: [Pd]
Solvent: CO
Product: NS(=O)(=O)c1ccccc1NS(=O)(=O)CCc1ccccc1
Yield: 7.8 %

Procedure:
2-[[(E)-2-Phenylethenyl]sulfonylamino]benzenesulfonamide (0.052 g, 0.15 mmol) was dissolved in MeOH (5 mL) followed by the addition of 10% Pd/C (30 mg). The solution was subjected to hydrogen overnight at 40° C. After filtration, the crude product was purified by preparative HPLC (XTerra MS C8 column, acetonitrile/ammonium acetate buffer) to give the title compound (4 mg, 8%) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]([OH:10])=[O:9])=[CH:6][N:5]=[CH:4][C:3]=1[F:11].[CH2:12]1CCN2C(=NCCC2)CC1.IC>C(#N)C>[Cl:1][C:2]1[C:7]([C:8]([O:10][CH3:12])=[O:9])=[CH:6][N:5]=[CH:4][C:3]=1[F:11]
Reactant: C1CCC2=NCCCN2CC1
Reactant: O=C(O)c1cncc(F)c1Cl
Solvent: CC#N
Solvent: CI
Product: COC(=O)c1cncc(F)c1Cl
Reaction time: 0.5 h
Yield: 65.4 %

Procedure:
To a solution of 4-chloro-5-fluoronicotinic acid (1.7 g, 9.68 mmol) in acetonitrile (18 mL) cooled to 0° C. was added DBU (3.65 mL, 24.21 mmol) dropwise. The reaction mixture was stirred for 30 min. To this mixture iodomethane (3.03 mL, 48.4 mmol) was added dropwise and stirred at rt for 12 h. The volatiles were removed under reduced pressure. The residue was purified via silica gel column chromatography (hexane and ethyl acetate) to afford methyl 4-chloro-5-fluoronicotinate (1.2 g, 6.33 mmol, 65% yield) as a yellow solid. LC/MS (ESI) m/e 190.0 [(M+H)+, calcd for C7H6ClFNO2 189.9]; LC/MS retention time (method D): tR=0.77 min.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:26]=[CH:25][C:24]([C:27]2[CH:28]=[N:29][C:30]([CH3:33])=[CH:31][CH:32]=2)=[CH:23][C:5]=1[CH2:6][NH:7][CH:8]1[CH2:13][CH2:12][CH:11]([N:14]([CH3:22])[C:15](=[O:21])[O:16][C:17]([CH3:20])([CH3:19])[CH3:18])[CH2:10][CH2:9]1)[CH3:2].[Cl:34][C:35]1[C:36]2[CH:46]=[CH:45][CH:44]=[CH:43][C:37]=2[S:38][C:39]=1[C:40](Cl)=[O:41]>>[Cl:34][C:35]1[C:36]2[CH:46]=[CH:45][CH:44]=[CH:43][C:37]=2[S:38][C:39]=1[C:40]([N:7]([CH2:6][C:5]1[CH:23]=[C:24]([C:27]2[CH:28]=[N:29][C:30]([CH3:33])=[CH:31][CH:32]=2)[CH:25]=[CH:26][C:4]=1[O:3][CH2:1][CH3:2])[CH:8]1[CH2:13][CH2:12][CH:11]([N:14]([CH3:22])[C:15](=[O:21])[O:16][C:17]([CH3:19])([CH3:20])[CH3:18])[CH2:10][CH2:9]1)=[O:41]
Reactant: CCOc1ccc(-c2ccc(C)nc2)cc1CNC1CCC(N(C)C(=O)OC(C)(C)C)CC1
Reactant: O=C(Cl)c1sc2ccccc2c1Cl
Product: CCOc1ccc(-c2ccc(C)nc2)cc1CN(C(=O)c1sc2ccccc2c1Cl)C1CCC(N(C)C(=O)OC(C)(C)C)CC1

Procedure:
Biaryl amine 75 (373 mg, 0.82 mmol) is treated with 3-chlorobenzo-[b]thiophene-2-carbonyl chloride (227 mg, 1.80 mmol) using Method D to give the title compound.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8]([CH3:13])([CH3:12])[CH2:7][CH2:6][C:5]2([CH3:15])[CH3:14].[NH2:16][C:17]1[CH:24]=[CH:23][C:20]([C:21]#[N:22])=[CH:19][C:18]=1[N+:25]([O-:27])=[O:26].CC([O-])(C)C.[Na+].C(PC1C=CC=CC=1C1C=CC=CC=1)(C)(C)C>C1COCC1>[N+:25]([C:18]1[CH:19]=[C:20]([CH:23]=[CH:24][C:17]=1[NH:16][C:2]1[CH:11]=[CH:10][C:9]2[C:8]([CH3:13])([CH3:12])[CH2:7][CH2:6][C:5]([CH3:15])([CH3:14])[C:4]=2[CH:3]=1)[C:21]#[N:22])([O-:27])=[O:26]
Reactant: CC1(C)CCC(C)(C)c2cc(Br)ccc21
Reactant: N#Cc1ccc(N)c([N+](=O)[O-])c1
Agent: CC(C)(C)Pc1ccccc1-c1ccccc1
Agent: CC(C)(C)[O-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC1(C)CCC(C)(C)c2cc(Nc3ccc(C#N)cc3[N+](=O)[O-])ccc21
Temperature: 80 °C

Procedure:
To a solution of 6-bromo-1,1,4,4-tetramethyl-1,2,3,4-tetrahydronaphthalene (61.3 mmol) and 4-amino-3-nitrobenzonitrile (61.3 mmol) in THF (150 mL) are added NaOtBu (67.4 mmol), 2-(t-butylphosphino)biphenyl (6.13 mmol), and Pd2(bda)3 (3.06 mmol) at room temperature. The reaction mixture is heated at 80° C. for 2 h. After cooling, the mixture is filtered through Celite. The filtrate is diluted with H2O and extracted with EtOAc. The organic layer is dried over MgSO4 and evaporated in vacuo. The resulting solid is washed with a mixture of hexane and EtOAc (8:1) to give (30).
Reaction SMILES: C([O:5][C:6](=[O:15])[C:7]1[CH:12]=[C:11]([CH3:13])[N:10]=[C:9](Cl)[CH:8]=1)(C)(C)C.CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.[CH3:58][NH:59][CH3:60]>C1COCC1.Cl.CC([O-])=O.CC([O-])=O.[Pd+2]>[CH3:58][N:59]([CH3:60])[C:9]1[CH:8]=[C:7]([CH:12]=[C:11]([CH3:13])[N:10]=1)[C:6]([OH:5])=[O:15]
Reactant: Cc1cc(C(=O)OC(C)(C)C)cc(Cl)n1
Reactant: CNC
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Solvent: C1CCOC1
Product: Cc1cc(C(=O)O)cc(N(C)C)n1
Temperature: 25 °C

Procedure:
Under argon, a solution of 2-chloro-6-methyl-isonicotinic acid tert.-butyl ester (625 mg 2.75 mmol), Na tert.-butylate (396 mg, 4.10 mmol), Xantphos (173 mg, 0.30 mmol) and Pd(OAc)2 (83 mg, 0.37 mmol) in 2 M dimethylamine in THF (35 mL) is stirred at 110° C. for 18 h. The dark reaction mixture is cooled to rt, diluted with 6 N aq. HCl and extracted with diethyl ether (4×60 mL). The org. extracts are concentrated, the residue is dissolved in 6N aq. HCl and heated to 100° C. for 18 h. The orange suspension is concentrated, dissolved in 1 N aq. NaOH (40 mL) and concentrated again. The residue is dissolved in 1 N aq. NaOH (3 mL) and methanol and separated by MPLC on RP-C18 silica gel to give 2-dimethylamino-6-methyl-isonicotinic acid (1.1 g) as a beige oil; LC-MS: tR=0.44 min, [M+H]+=181.07.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([C:16]([CH3:24])([CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])[CH3:17])[CH:12]=[CH:13][C:14]=1Br)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Mg].CN(C)[CH:28]=[O:29]>O1CCCC1>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([C:16]([CH3:24])([CH3:17])[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])[CH:12]=[CH:13][C:14]=1[CH:28]=[O:29])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCCCCCC(C)(C)c1ccc(Br)c(OCc2ccccc2)c1
Reactant: CN(C)C=O
Agent: [Mg]
Solvent: C1CCOC1
Product: CCCCCCC(C)(C)c1ccc(C=O)c(OCc2ccccc2)c1
Temperature: 25 °C

Procedure:
2-(3-benzyloxy-4-bromophenyl)-2-methyloctane (100 g., 0.257 mole) in tetrahydrofuran (500 ml.) was slowly added to 70-80 mesh magnesium (12.3 g., 0.514 mole) at such a rate that reflux was maintained. Upon completion of addition, the reaction mixture was stirred until it cooled to room temperature. It was then further cooled to 0° C. Dimethylformamide (29.8 ml., 0.385 mole) was added dropwise to the reaction mixture over a 25 minute period (reaction temperature <10° C.). The reaction mixture was then allowed to warm and was stirred for 40 minutes at room temperature. The reaction mixture was quenched by addition to a saturated aqueous solution of cold ammonium chloride (1800 ml.) and the product extracted with ether (one liter). The ether extract was washed twice with saturated sodium chloride (1500 ml.), dried over magnesium sulfate and evaporated to a quantitative yield of the title compound as an oil.
Reaction SMILES: [Cl:1][C:2]([Cl:26])([Cl:25])[CH2:3][O:4][C:5]([C@@H:7]1[CH2:12][CH2:11][CH2:10][N:9]([C:13](=[O:24])[C@@H:14]([NH:16][C:17](=[O:23])[C@@H:18]([NH2:22])[CH:19]([CH3:21])[CH3:20])[CH3:15])[NH:8]1)=[O:6].[OH:27][C@@H:28]([C:30]1[CH:39]=[CH:38][C:37]2[C:32](=[CH:33][C:34](/[CH:40]=[CH:41]/[C@@:42]([CH2:47][O:48][CH3:49])([CH3:46])[C:43](O)=[O:44])=[CH:35][CH:36]=2)[N:31]=1)[CH3:29].F[P-](F)(F)(F)(F)F.CN(C(N(C)C)=[N+]1C2C(=NC=CC=2)[N+]([O-])=N1)C.C(N(CC)C(C)C)(C)C>ClCCl>[Cl:26][C:2]([Cl:25])([Cl:1])[CH2:3][O:4][C:5]([C@@H:7]1[CH2:12][CH2:11][CH2:10][N:9]([C:13](=[O:24])[C@@H:14]([NH:16][C:17](=[O:23])[C@@H:18]([NH:22][C:43](=[O:44])[C@:42]([CH2:47][O:48][CH3:49])([CH3:46])/[CH:41]=[CH:40]/[C:34]2[CH:33]=[C:32]3[C:37]([CH:38]=[CH:39][C:30]([C@H:28]([OH:27])[CH3:29])=[N:31]3)=[CH:36][CH:35]=2)[CH:19]([CH3:21])[CH3:20])[CH3:15])[NH:8]1)=[O:6]
Reactant: COC[C@@](C)(/C=C/c1ccc2ccc([C@@H](C)O)nc2c1)C(=O)O
Reactant: CC(C)[C@H](N)C(=O)N[C@@H](C)C(=O)N1CCC[C@@H](C(=O)OCC(Cl)(Cl)Cl)N1
Agent: CN(C)C(N(C)C)=[N+]1N=[N+]([O-])c2ncccc21
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COC[C@@](C)(/C=C/c1ccc2ccc([C@@H](C)O)nc2c1)C(=O)N[C@H](C(=O)N[C@@H](C)C(=O)N1CCC[C@@H](C(=O)OCC(Cl)(Cl)Cl)N1)C(C)C
Temperature: 0 °C
Yield: 52.6 %

Procedure:
To freshly prepared (S)-1-[(S)-2-((S)-2-amino-3-methyl-butyrylamino)-propionyl]-hexahydro-pyridazine-3-carboxylic acid 2,2,2-trichloro-ethyl ester (139 mg, 0.321 mmol) in dichloromethane (25 mL) was added (E)-(R)-4-[2-((R)-1-hydroxy-ethyl)-quinolin-7-yl]-2-methoxymethyl-2-methyl-but-3-enoic acid (101 mg, 0.321 mmol) and the mixture was evaporated. The residue was dissolved in anhydrous acetonitrile (6.4 mL) and the mixture cooled to 0° C. with stirring under nitrogen. 1-[Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate (146 mg, 0.38 mmol) and N,N-diisopropylethylamine (168 μL, 0.963 mmol) were added and the reaction mixture stirred for 5 minutes and then allowed to warm to ambient temperature. The mixture was stirred for 19 h and evaporated and the residue dissolved in dichloromethane and washed sequentially with saturated sodium bicarbonate solution, water, saturated ammonium chloride solution, brine then was dried over anhydrous sodium sulfate, filtered and evaporated. The residue was purified on silica eluting with ethyl acetate to afford the title compound (123 mg, 53%) as a yellow gum. 1H NMR (300 MHz, CDCl3) δ 0.91 (d, J=6.7 Hz, 3H), 0.97 (d, J=6.7 Hz, 3H), 1.33 (d, J=6.7 Hz, 3H), 1.45 (s, 3H), 1.59 (d, J=6.5 Hz, 3H), 1.67-1.78 (m, 2H), 1.90-2.00 (m, 1H), 2.15-2.33 (m, 2H), 2.82-2.91 (m, 1H), 3.47-3.54 (m, 1H), 3.51 (s, 3H), 3.60 (d, J=9.2 Hz, 1H), 3.68-3.76 (m, 1H), 3.73 (d, J=11.4 Hz, 1H), 3.85 (d, J=9.2 Hz, 1H), 4.33-4.45 (m, 2H), 4.72 (d, J=12.0 Hz, 1H), 4.96 (d, J=12.0 Hz, 1H), 4.99-5.08 (m, 2H), 5.27-5.37 (m, 1H), 6.70 (ABq, J=16.5 Hz, 1H), 6.80 (d, J=16.5 Hz, 1H), 6.80 (d, J=8.0 Hz, 1H), 7.31 (d, J=8.3 Hz, 1H), 7.66 (dd, J=8.6, 1.2 Hz, 1H), 7.77 (d, J=8.3 Hz, 1H), 8.01 (s, 1H), 8.12 (d, J=8.7 Hz, 1H). LCMS (m/z) 728.3, 730.3 [M+H], Tr=2.25 min.
Reaction SMILES: [F:1][C:2]1([F:10])[CH2:7][CH2:6][CH:5]([CH:8]=O)[CH2:4][CH2:3]1.O1CCCC1.[NH:16]1[CH2:21][CH2:20][CH:19]([NH:22][C:23](=[O:29])[O:24][C:25]([CH3:28])([CH3:27])[CH3:26])[CH2:18][CH2:17]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>[Cl-].[Na+].O>[F:1][C:2]1([F:10])[CH2:7][CH2:6][CH:5]([CH2:8][N:16]2[CH2:17][CH2:18][CH:19]([NH:22][C:23](=[O:29])[O:24][C:25]([CH3:27])([CH3:26])[CH3:28])[CH2:20][CH2:21]2)[CH2:4][CH2:3]1
Reactant: CC(C)(C)OC(=O)NC1CCNCC1
Reactant: O=CC1CCC(F)(F)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NC1CCN(CC2CCC(F)(F)CC2)CC1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 20.7 %

Procedure:
A mixture of the crude product of 4,4-difluorocyclohexane-1-carbaldehyde obtained in Example 2b (1.4 g) and tetrahydrofuran (100 ml) was cooled to 0° C., tert-butyl N-(piperidin-4-yl)carbamate (2.27 g, 11.3 mmol) was added thereto, followed by stirring for 20 minutes. Sodium triacetoxyborohydride (2.2 g, 10.4 mmol) was then added to the reaction mixture, which was stirred at mom temperature for eight hours. Brine was added to the reaction mixture, which was extracted with ethyl acetate. The organic layer was dried over magnesium sulfate, and the solvent was distilled off. The residue was purified by silica gel column chromatography (elution solvent: ethyl acetate/heptane). The resulting residue was dissolved in ethyl acetate and washed with a saturated aqueous sodium bicarbonate solution, and the solvent was then distilled off to give the title compound (650 mg, yield 20.7%).
Reaction SMILES: [Cl:1][C:2]1[C:3]([NH:23][C:24]2[CH:28]=[C:27]([CH3:29])[NH:26][N:25]=2)=[N:4][C:5]([NH:8][C:9]2[CH:14]=[C:13]([CH3:15])[C:12]([CH:16]3[CH2:21][CH2:20][CH2:19][CH2:18][NH:17]3)=[CH:11][C:10]=2[CH3:22])=[N:6][CH:7]=1.C(N(CC)CC)C.Br[CH2:38][C:39]([NH2:41])=[O:40]>CN(C=O)C>[Cl:1][C:2]1[C:3]([NH:23][C:24]2[CH:28]=[C:27]([CH3:29])[NH:26][N:25]=2)=[N:4][C:5]([NH:8][C:9]2[C:10]([CH3:22])=[CH:11][C:12]([CH:16]3[CH2:21][CH2:20][CH2:19][CH2:18][N:17]3[CH2:38][C:39]([NH2:41])=[O:40])=[C:13]([CH3:15])[CH:14]=2)=[N:6][CH:7]=1
Reactant: NC(=O)CBr
Reactant: Cc1cc(Nc2nc(Nc3cc(C)c(C4CCCCN4)cc3C)ncc2Cl)n[nH]1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Cc1cc(Nc2nc(Nc3cc(C)c(C4CCCCN4CC(N)=O)cc3C)ncc2Cl)n[nH]1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a mixture of 5-Chloro-N2-(2,5-dimethyl-4-(piperidin-2-yl)phenyl)-N4-(5-methyl-1H-pyrazol-3-yl)pyrimidine-2,4-diamine (0.12 mmol) and triethylamine (83 uL, 0.6 mmol) in DMF (1.5 mL), was added 2-bromoacetamide (35 mg, 0.24 mmol). The mixture was stirred at room temperature for 3 h. The reaction was filtered and the filtrate was purified by RP-HPLC to afford 2-(2-(4-(5-chloro-4-(5-methyl-1H-pyrazol-3-ylamino)pyrimidin-2-ylamino)-2,5-dimethylphenyl)piperidin-1-yl)acetamide as a white solid; 1H NMR (400 MHz, MeOD-d4) 8.09 (s, 1H), 7.65 (d, 1H), 7.43 (s, 1H), 6.41 (s, 1H), 4.79-4.74 (m, 2H), 3.83-3.48 (m, 2H), 2.71 (s, 3H), 2.42 (s, 3H), 2.34 (s, 6H), 2.15-1.84 (m, 7H); ESMS m/z 469.2 (M+H+).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]([C:20]3[C:25]([F:26])=[CH:24][CH:23]=[CH:22][C:21]=3[Cl:27])[NH:11][C:12]=2[C:13]2[CH:18]=[CH:17][NH:16][C:15](=[O:19])[CH:14]=2)=[CH:4][CH:3]=1>ClCCCl.C(O)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]2=[C:8]3[N:9]=[C:10]([C:20]4[C:25]([F:26])=[CH:24][CH:23]=[CH:22][C:21]=4[Cl:27])[NH:11][C:12]3=[C:13]3[C:14]([C:15](=[O:19])[NH:16][CH:17]=[CH:18]3)=[C:4]2[CH:3]=1
Reactant: O=c1cc(-c2[nH]c(-c3c(F)cccc3Cl)nc2-c2ccc(Br)cc2)cc[nH]1
Solvent: CCO
Solvent: ClCCCl
Product: O=c1[nH]ccc2c3[nH]c(-c4c(F)cccc4Cl)nc3c3ccc(Br)cc3c12

Procedure:
The intermediate from Example 1 Step D (2.9 g, 6.55 mmol) was dissolved in 200 mL of a 60:40 mixture of 1,2-dichloroethane-ethanol. The mixture was irradiated under a high intensity light for 3 days. The volatiles were removed in vacuo and the crude material was triturated with DCM and filtered. The product was triturated twice more with EtOAc and filtered. 1 NMR 400 MHz, DMSO-d6: δ14.12 (br, 1H), 11.82 (m, 1H), 10.55(m, 1H), 7.40˜7.90(m, 7H): [M+1]+ 442.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[CH2:15][CH:14]([CH2:16][N:17]3C(=O)C4=CC=CC=C4C3=O)[N:6]3[C:7](=[O:13])[C:8](=[O:12])[NH:9][C:10]([CH:11]=1)=[C:5]23.[ClH:28]>C(O)(=O)C>[ClH:28].[Br:1][C:2]1[CH:3]=[C:4]2[CH2:15][CH:14]([CH2:16][NH2:17])[N:6]3[C:7](=[O:13])[C:8](=[O:12])[NH:9][C:10]([CH:11]=1)=[C:5]23
Reactant: O=C1c2ccccc2C(=O)N1CC1Cc2cc(Br)cc3[nH]c(=O)c(=O)n1c23
Agent: Cl
Solvent: CC(=O)O
Product: NCC1Cc2cc(Br)cc3[nH]c(=O)c(=O)n1c23
Yield: 60 %

Procedure:
A solution of 8-bromo-5-phthalimidomethyl-5,6-dihydro-1H-pyrrolo[1,2,3-de]quinoxaline-2,3-dione (100 mg)in a mixture of acetic acid (6 mL) and concentrated HCl (6 mL) was refluxed for 4.5 h and concentrated. The residue was triturated with methylenechloride containing a small amount of methanol. The precipitates were collected by filtration, rinsed with methylenechloride, and dried in vacuo to give 60 mg of the title compound (60%): mp 268° C. (dec); 1H NMR (270 MHz, DMSO-d6) δ11.98 (s, 1H), 8.07 (br, 3H), 7.23 (d, 1H, J=1 Hz), 7.07 (d, 1H, J=1 Hz), 5.02~5.12 (m, 1H), 3.56 (dd, 1H, J=17, 10 Hz), 3.28~3.48 (m, 2H), 3.11 (dd, 1H, J=17, 3 Hz).
Reaction SMILES: [Br:1][C:2]1[C:6]([C:7]2[C:8](F)=[N:9][CH:10]=[CH:11][CH:12]=2)=[CH:5][S:4][CH:3]=1.[CH2:14]([NH2:16])[CH3:15]>O1CCOCC1.C(OCC)(=O)C>[Br:1][C:2]1[C:6]([C:7]2[C:8]([NH:16][CH2:14][CH3:15])=[N:9][CH:10]=[CH:11][CH:12]=2)=[CH:5][S:4][CH:3]=1
Reactant: CCN
Reactant: Fc1ncccc1-c1cscc1Br
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: CCNc1ncccc1-c1cscc1Br
Yield: 83.7 %

Procedure:
A solution of 3-bromo-4-(2-fluoropyridin-3-yl)thiophene (0.344 g) and ethylamine (0.2 g) in dioxane (1 mL), in a sealed tube, was heated at 100° C. for four days. The mixture was cooled, diluted with ethyl acetate, washed with water, dried, filtered, and evaporated. The residue was fractionated by chromatography to give 3-bromo-4-(2-ethylaminopyridin-3-yl)thiophene (0.316 g) as an oil.
Reaction SMILES: Cl[C:2]([O:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:3].[OH:12][P:13]([CH2:25]C(O)=O)([CH2:15][CH2:16][CH2:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:14].C(N(CC)CC)C.OS([O-])(=O)=O.[K+]>O1CCCC1.C(OCC)(=O)C>[OH:14][P:13]([CH2:25][C:2]([O:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:3])([CH2:15][CH2:16][CH2:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:12]
Reactant: O=C(O)CP(=O)(O)CCCCc1ccccc1
Reactant: O=C(Cl)OCc1ccccc1
Agent: O=S(=O)([O-])O
Agent: [K+]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: O=C(CP(=O)(O)CCCCc1ccccc1)OCc1ccccc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A solution of benzyl chloroformate (1.8 ml, 12.6 mmol) in 5 ml of dry tetrahydrofuran was added dropwise to a solution of [hydroxy(4-phenylbutyl)phosphinyl]acetic acid (2.55 g, 10 mmol) and triethylamine (2.0 ml, 14.5 mmol) in 30 ml of dry tetrahydrofuran at 0° C. After addition was complete, the mixture was stirred at 0° C. for 30 minutes and at room temperature for 1 hour. The mixture was positioned between ethyl acetate and 5% KHSO4 and the ethyl acetate layer was evaporated to a residue. The residue was taken up in aqueous NaHCO3, washed with ethyl acetate, and the aqueous solution acidified to pH 1 and extracted with ethyl acetate. The extracts were dried (Na2SO4) and evaporated to give the crude product which was triturated with pentane to yield a solid, melting point 64°-67° C. (3.30 g).
Reaction SMILES: [OH-].[Na+].[CH3:3][O:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([CH:11]([Cl:16])[C:12](Cl)([Cl:14])[Cl:13])[CH:6]=1>CO>[CH3:3][O:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([C:11]([Cl:16])=[C:12]([Cl:13])[Cl:14])[CH:6]=1
Reactant: COc1cccc(C(Cl)C(Cl)(Cl)Cl)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COc1cccc(C(Cl)=C(Cl)Cl)c1
Reaction time: 3 h

Procedure:
To a magnetically stirred solution of 0.228 g (5.7 mmol) of sodium hydroxide in 2.0 mL methanol was slowly added a solution of 1.2 g (4.4 mmol) of the product of Step B in 1.0 mL methanol. A white precipitate was deposited and the reaction mixture was stirred for an additional 3 h. At this point the reaction mixture was evaporated in vacuo and the residue was purified on a silica gel flash chromatography column eluted with hexane. Evaporation of the purified fractions afforded the title compound.
Reaction SMILES: [CH2:1]([NH:13][CH2:14][CH2:15][OH:16])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].I[CH2:18][CH3:19].C(N(CC)C(C)C)(C)C>C(O)(C)C>[CH2:1]([N:13]([CH2:14][CH2:15][OH:16])[CH2:18][CH3:19])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: CCCCCCCCCCCCNCCO
Reactant: CCI
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)O
Product: CCCCCCCCCCCCN(CC)CCO
Yield: 73.4 %

Procedure:
2-[Dodecylamino]ethanol (2.0 g, 8.73 mmol), 1-iodoethane (1.63 g, 10.48 mmol) and N,N-diisopropylethylamine (2.51 g, 17.5 mmol) in isopropanol (25 ml )were heated under reflux for 4 h. The solvent was then evaporated in vacuo and the residue was diluted with ethyl acetate washed with aqueous sodium bicarbonate, brine and dried (magnesium sulfate). Evaporation of the solvent followed by chromatography on silica gel (ethyl acetate/methanol 90:10 to 80:20) afforded the title compound (1.65 g, 73%) as a white solid.