Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[C:10]2[C:9]([NH2:11])=[N:8][CH:7]=[N:6][C:5]=2[N:4]([CH:12]2[CH2:15][O:14][CH2:13]2)[CH:3]=1.CC1(C)C(C)(C)OB([C:24]2[CH:25]=[C:26]3[C:30](=[CH:31][CH:32]=2)[N:29]([C:33](=[O:45])[CH2:34][C:35]2[CH:40]=[CH:39][CH:38]=[C:37]([C:41]([F:44])([F:43])[F:42])[CH:36]=2)[CH2:28][CH2:27]3)O1.O1CCOCC1.C([O-])(O)=O.[Na+]>O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[O:14]1[CH2:15][CH:12]([N:4]2[C:5]3[N:6]=[CH:7][N:8]=[C:9]([NH2:11])[C:10]=3[C:2]([C:24]3[CH:25]=[C:26]4[C:30](=[CH:31][CH:32]=3)[N:29]([C:33](=[O:45])[CH2:34][C:35]3[CH:40]=[CH:39][CH:38]=[C:37]([C:41]([F:44])([F:42])[F:43])[CH:36]=3)[CH2:28][CH2:27]4)=[CH:3]2)[CH2:13]1
Reactant: Nc1ncnc2c1c(Br)cn2C1COC1
Reactant: CC1(C)OB(c2ccc3c(c2)CCN3C(=O)Cc2cccc(C(F)(F)F)c2)OC1(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: Nc1ncnc2c1c(-c1ccc3c(c1)CCN3C(=O)Cc1cccc(C(F)(F)F)c1)cn2C1COC1
Temperature: 100 °C
Yield: 50.1 %

Procedure:
To 5-bromo-7-(3-oxetanyl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine (50 mg, 0.186 mmol) and 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-{[3-(trifluoromethyl)phenyl]acetyl}-2,3-dihydro-1H-indole (112 mg, 0.260 mmol) were added 1,4-Dioxane (2 mL) and sat. NaHCO3 (1 mL) into a 5 ml sealable. The mixture was then bubbled with N2 gas for 5 minutes. Pd(Ph3P)4 (21.47 mg, 0.019 mmol) was added and the vessel was capped and heated at 100° C. overnight. The reaction was then diluted with water (2 ml) and extracted with EtOAc (3×3 ml). The organics were then combined and washed with brine, dried over MgSO4, filtered, concentrated. The crude was dissolved in 3 mL of DMSO and purified by HPLC: (HPLC condition: Gilson using Trilution software with a Sunfire 5u C18(2) 100A. 50×30.00 mm 5 micron. 7.3-minute run (47 ml/min, 20% ACN/H2O, 0.1% TFA to 45% ACN/H2O, 0.1% TFA) with UV detection at 254 nm). Product fractions were combined and the volume was reduced to remove most of the MeCN. To the water left behind was added saturated NaHCO3 and then the mixture was extracted with EtOAc (3×15 mL). The organics were combined wash with saturated NaCl solution, dried over MgSO4, filtered and concentrated. The material was transferred into a 40 mL vial with MeCN then water was added and the solution was freeze-dried to give 7-(3-oxetanyl)-5-(1-{[3-(trifluoromethyl)phenyl]acetyl}-2,3-dihydro-1H-indol-5-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine (46 mg, 50.2% yield) as a white solid. LC-MS (ES) m/z=494.4 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 8.11-8.17 (m, 2H), 7.67-7.72 (m, 2H), 7.56-7.67 (m, 3H), 7.40 (s, 1H), 7.29 (d, J=8.08 Hz, 1H), 6.16 (br. s., 2H), 5.88 (quin, J=7.14 Hz, 1H), 4.95-5.04 (m, 4H), 4.28 (t, J=8.34 Hz, 2H), 4.04 (s, 2H), 3.27 (t, J=8.34 Hz, 2H).
Reaction SMILES: N1C=CC=CC=1.[CH3:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14]/[CH:15]=[CH:16]\[CH2:17][CH2:18][OH:19]>C(Cl)Cl.CCOCC.[O-2].[O-2].[O-2].[Cr+6]>[CH:18](=[O:19])/[CH:17]=[CH:16]\[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH3:7]
Reactant: CCCCCCCC/C=C\CCO
Agent: [Cr+6]
Agent: [O-2]
Solvent: CCOCC
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCCCCCCCC/C=C\C=O
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 94.8 %

Procedure:
A solution of 9.5 ml of pyridine in 150 ml of methylene chloride was treated in one portion with 6.0 g of chromium trioxide. The mixture was stirred for 15 minutes at room temperature and then 1.60 g of 3Z-dodecen-1-ol in 3 ml of methylene chloride was added. After 5 minutes the reaction mixture was diluted with 200 ml of ether and then filtered through celite. The filtrate was washed three times with 100 ml of 5% aqueous sodium hydroxide, then with ice-cold 5% hydrochloric acid, saturated sodium bicarbonate and finally with brine. After drying over sodium sulfate, the solvent was evaporated giving 1.5 g of 3Z-dodecen-1-al.
Reaction SMILES: [O:1]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[CH2:14][C:15]([O:17]C)=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.[NH2:20][NH2:21]>CO.O>[O:1]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[CH2:14][C:15]([NH:20][NH2:21])=[O:17])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NN
Reactant: COC(=O)Cc1ccccc1Oc1ccccc1
Solvent: O
Solvent: CO
Product: NNC(=O)Cc1ccccc1Oc1ccccc1
Reaction time: 2 h
Yield: 96 %

Procedure:
A solution of methyl (2-phenoxyphenyl)acetate (6.0 g) in methanol (100 ml) was added dropwise with stirring to hydrazine hydrate (12 ml). The resulting mixture was stirred for 2 hours, then diluted with water and extracted with ether. The extracts were washed with water, dried and concentrated to give almost pure (2-phenoxyphenyl)acetohydrazide (5.8 g, 96% yield) as a waxy solid with amp of about 65° C., 1H NMR (CDCl3): delta 3.60 (2H,s) ppm. Concentrated sulphuric acid (4 drops) was added to a mixture of this hydrazide and triethyl orthoformate (20 ml) and the resulting mixture was heated at 90° C. for one hour. After cooling, water was added to the mixture and it was extracted with ether. The extracts were washed, dried, concentrated and chromatographed using increasing proportions (up to 50%) of ethyl acetate in hexane as eluant to give 2-(2-phenoxyphenylmethyl)oxa-1,3,4-diazole (3.14 g, 52% yield) as a yellow oil, IH NMR (CDCl3): delta 4.31 (2H,s) and 8.28 (1H,s) ppm.
Reaction SMILES: [C:1]1([CH:7]([CH2:11][C:12]([OH:14])=[O:13])[C:8]([OH:10])=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(Cl)(=O)C>C1(C)C=CC=CC=1>[C:1]1([CH:7]2[CH2:11][C:12](=[O:13])[O:14][C:8]2=[O:10])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C(O)CC(C(=O)O)c1ccccc1
Solvent: Cc1ccccc1
Solvent: CC(=O)Cl
Product: O=C1CC(c2ccccc2)C(=O)O1
Temperature: 25 °C
Yield: 69.3 %

Procedure:
A solution of phenylsuccinic acid (20.0 g, 0.10 mol), acetyl chloride, and 200 mL of toluene was stirred at reflux for 5.5 hours, removing H2O azeotropically during the reaction. After cooling to room temperature, toluene was evaporated in vacuo, and the residue was crystallized from ether to obtain 12.2 g of phenyl succinic anhydride as a white solid.
Reaction SMILES: [NH2:1][C:2]1[C:31]([Cl:32])=[CH:30][C:5]([C:6]([NH:8][CH2:9][CH:10]2[CH2:15][CH2:14][N:13]([CH2:16][CH2:17][CH2:18][CH2:19][NH:20][CH2:21][C:22]3[CH:27]=[CH:26][C:25]([Cl:28])=[C:24]([Cl:29])[CH:23]=3)[CH2:12][CH2:11]2)=[O:7])=[C:4]([O:33][CH3:34])[CH:3]=1.[CH:35](=O)[CH3:36].C([BH3-])#N.[Na+]>>[NH2:1][C:2]1[C:31]([Cl:32])=[CH:30][C:5]([C:6]([NH:8][CH2:9][CH:10]2[CH2:11][CH2:12][N:13]([CH2:16][CH2:17][CH2:18][CH2:19][N:20]([CH2:21][C:22]3[CH:27]=[CH:26][C:25]([Cl:28])=[C:24]([Cl:29])[CH:23]=3)[CH2:35][CH3:36])[CH2:14][CH2:15]2)=[O:7])=[C:4]([O:33][CH3:34])[CH:3]=1
Reactant: COc1cc(N)c(Cl)cc1C(=O)NCC1CCN(CCCCNCc2ccc(Cl)c(Cl)c2)CC1
Reactant: CC=O
Agent: [BH3-]C#N
Agent: [Na+]
Product: CCN(CCCCN1CCC(CNC(=O)c2cc(Cl)c(N)cc2OC)CC1)Cc1ccc(Cl)c(Cl)c1

Procedure:
4-Amino-5-chloro-N-((1-(4-(3,4-dichlorobenzylamino)butyl)piperidin-4-yl)methyl)-2-methoxybenzamide (1.9 g) as starting compound, acetaldehyde (0.26 ml) and sodium cyanoborohydride (0.3 g) were reacted and treated in the same manner as in Example 136 to give 1.1 g of 4-amino-5-chloro-N-((1-(4-(N-(3,4-dichlorobenzyl)-N-ethylamino)butyl)-piperidin-4-yl)methyl)-2-methoxybenzamide.
Reaction SMILES: [K+].[C:2]([C@@H:4]([CH2:14][CH:15]([CH3:17])[CH3:16])[CH:5]([C:9]([O:11]CC)=[O:10])[C:6]([O-])=[O:7])#[N:3].[H][H]>[Ni]>[CH2:14]([CH:4]1[CH2:2][NH:3][C:6](=[O:7])[C@H:5]1[C:9]([OH:11])=[O:10])[CH:15]([CH3:17])[CH3:16]
Reactant: CCOC(=O)C(C(=O)[O-])[C@@H](C#N)CC(C)C
Reactant: [H][H]
Agent: [Ni]
Agent: [K+]
Product: CC(C)CC1CNC(=O)[C@H]1C(=O)O

Procedure:
A vessel was charged with an aqueous solution containing (3S)-3-cyano-2-ethoxycarbonyl-5-methyl-hexanoic acid potassium salt (Formula 23, 411 L from Example 2). Raney Nickel (50% aq solution, Sigma-Aldrich) was added to the mixture, and hydrogen gas was introduced into the vessel over a 20 h period to maintain a pressure of 50 psig in the vessel headspace throughout reaction. The hydrogenation reaction was monitored by H2 uptake and HPLC analysis (C18 column, 4.6 mm×150 mm, detection at 200 nm) of the vessel contents. Following reaction, the aqueous mixture was filtered to remove the Raney Ni catalyst. The pH of the concentrated solution was adjusted to 3.0 using 37% HCl (about 14 L). The resulting solution was extracted three times with EtOAc (50% v/v). The combined organic layers were concentrated under vacuum to afford (S)-4-isobutyl-2-oxo-pyrrolidine-3-carboxylic acid (Formula 10). MS m/z [M+H]+186.1130. 13C NMR (75 ppm, CDCl3) δ 175.67, 172.23, 54.09, 47.62, 43.69, 37.22, 26.31, 23.34, 22.54. Yield 40-42%; 97% ee.
Reaction SMILES: O.[OH-].[Li+].[CH3:4][O:5]/[C:6](=[CH:11]\[C:12]1[CH:17]=[CH:16][C:15]([O:18][S:19]([C:22]([F:25])([F:24])[F:23])(=[O:21])=[O:20])=[C:14]([O:26][CH2:27][CH2:28][CH2:29][CH3:30])[CH:13]=1)/[C:7]([O:9]C)=[O:8].Cl>O1CCCC1.O>[CH2:27]([O:26][C:14]1[CH:13]=[C:12](/[CH:11]=[C:6](\[O:5][CH3:4])/[C:7]([OH:9])=[O:8])[CH:17]=[CH:16][C:15]=1[O:18][S:19]([C:22]([F:25])([F:23])[F:24])(=[O:21])=[O:20])[CH2:28][CH2:29][CH3:30]
Reactant: CCCCOc1cc(/C=C(\OC)C(=O)OC)ccc1OS(=O)(=O)C(F)(F)F
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CCCCOc1cc(/C=C(\OC)C(=O)O)ccc1OS(=O)(=O)C(F)(F)F
Temperature: 68 °C
Reaction time: 5 h
Yield: 64.8 %

Procedure:
1.53 g (36.3 mmol) of lithium hydroxide monohydrate are added to a solution of 7.5 g (18.2 mmol) of methyl (Z)-2-methoxy-3-(3-butoxy-4-(trifluoromethanesulphonyloxy)phenyl)acrylate in 50 ml of a tetrahydrofuran/water 10/1 mixture. The reaction mixture is stirred at 68° C. for 5 hours. The reaction mixture is acidified with a 2N hydrochloric acid solution down to pH=1. The reaction mixture is extracted with two times 100 ml of a heptane/ethyl acetate 1/2 mixture. The organic phases are combined and then dried over sodium sulphate. The solvents are evaporated and then the residue is taken up in 30 ml of pentane. 4.7 g of (Z)-3-(3-Butoxy-4-(trifluoromethane-sulphonyloxy)phenyl)-2-methoxyacrylic acid are obtained in the form of a white solid.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][C:9]2[CH:17]=[CH:16][C:12]([C:13](O)=[O:14])=[CH:11][CH:10]=2)=[C:4]([N+:18]([O-:20])=[O:19])[CH:3]=1.C[N:22]1CCOCC1.N.O>C1COCC1>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][C:9]2[CH:17]=[CH:16][C:12]([C:13]([NH2:22])=[O:14])=[CH:11][CH:10]=2)=[C:4]([N+:18]([O-:20])=[O:19])[CH:3]=1
Reactant: Cc1ccc(Sc2ccc(C(=O)O)cc2)c([N+](=O)[O-])c1
Reactant: CN1CCOCC1
Agent: N
Solvent: O
Solvent: C1CCOC1
Product: Cc1ccc(Sc2ccc(C(N)=O)cc2)c([N+](=O)[O-])c1
Temperature: 25 °C

Procedure:
The product from Example 84a (0.3 g, 1.04 mmol) was dissolved in THF (15 mL) and treated with N-methylmorpholine (0.131 mL, 1.19 mmol) followed by cooling in an ice bath and addition of isobutylchloroforamte (0.148 mL, 1.14 mmol). The resulting mixture was allowed warm to room temperature with stirring for thirty minutes. Subsequent cooling in an ice bath was followed by addition of ammonia gas and warming to room temperature. The title compound was isolated by the addition of water and collection of the solid by vacuum filtration was used without further purification (0.289 g, 96%).
Reaction SMILES: C(C1OC1)Cl.C(C(CCCC)CO)C.Cl[CH2:16][CH:17]([OH:28])[CH2:18][O:19][CH2:20][CH:21]([CH2:26][CH3:27])[CH2:22][CH2:23][CH2:24][CH3:25].CC(C)([O-])C.[K+]>O1CCCC1>[CH2:18]([O:19][CH2:20][CH:21]([CH2:26][CH3:27])[CH2:22][CH2:23][CH2:24][CH3:25])[CH:17]1[O:28][CH2:16]1
Reactant: CCCCC(CC)COCC(O)CCl
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CCCCC(CC)CO
Solvent: ClCC1CO1
Product: CCCCC(CC)COCC1CO1
Temperature: 90 °C
Reaction time: 18 h

Procedure:
To a flame dried, 500 mL round bottomed flask equipped with an addition funnel charged with epichlorohydrin (15.62 g, 0.17 moles), is added 2-ethylhexanol (16.5 g, 0.127 moles) and stannic chloride (0.20 g, 0.001 moles). The reaction is kept under an argon atmosphere and warmed to 90° C. using an oil bath. Epichlorohydrin is dripped into the stirring solution over 60 minutes followed by stirring at 90° C. for 18 hours. The reaction is fitted with a vacuum distillation head and 1-chloro-3-(2-ethyl-hexyloxy)-propan-2-ol is distilled under 0.2 mm Hg. The 1-chloro-3-(2-ethyl-hexyloxy)-propan-2-ol (4.46 g, 0.020 moles) is dissolved in tetrahydrofuran (50 mL) and stirred at room temperature under an argon atmosphere. To the stirring solution is added potassium tert-butoxide (2.52 g, 0.022 moles) and the suspension is stirred at room temperature for 18 hours. The reaction is then evaporated to dryness, residue dissolved in hexanes and washed with water (100 mL). The hexanes phase is separated, dried with Na2SO4, filtered and evaporated to dryness to yield the crude 2-ethylhexyl glycidyl ether, which can be further purified by vacuum distillation.
Reaction SMILES: C([O:3][C:4](=[O:13])[CH:5]([CH2:9][CH2:10][CH2:11][CH3:12])[C:6](O)=[O:7])C.C(O)(C)C.[BH4-].[Li+]>O1CCCC1>[CH2:9]([CH:5]([CH2:6][OH:7])[C:4]([OH:13])=[O:3])[CH2:10][CH2:11][CH3:12]
Reactant: CCCCC(C(=O)O)C(=O)OCC
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CC(C)O
Product: CCCCC(CO)C(=O)O
Temperature: 16.5 °C
Reaction time: 3 h
Yield: 543.8 %

Procedure:
A 12 L, 4-necked, round-bottomed flaks, equipped with a mechanical stirrer, digital thermometer, and nitrogen inlet-outlet is charged with 2-butyl-propanedioic acid monoethyl ester (3, 450.0 g, 2.39 mol) and isopropanol (4.5 L). The solution is cooled to an internal temperature at 15-18° C. and a 2 M solution of lithium borohydride (2.4 L, 4.8 mol) in tetrahydrofuran is added over a period of 1.5 hours while maintaining the internal temperature at 15-25° C. The stirring is continued for an additional 3 h. The reaction mixture is cooled to an internal temperature at 10-13° C. and quenched by the addition of 2 N HCl (2.4 L) over a period of 1 hour while maintaining the internal temperature at 10-25° C. The reaction mixture is concentrated at 35-40° C. (20 mbar) to collect ˜7.5 L of the solvent to obtain a suspension (˜1.9 kg). This suspension is diluted with water (2.0 L) and ethyl acetate (2.5 L) and the biphasic mixture is stirred for 1 hour. The organic layer is separated and the aqueous layer is extracted with ethyl acetate (2.0 L). The combined organic layers are washed with 20% aqueous solution of sodium chloride (1.0 L) and concentrated under vacuum (20 mbar) until no further solvent distills to afford crude (±)-2-butyl-3-hydroxypropionic acid (4, 349.4 g, 100%) as a colorless liquid, which is used as such in the next step.
Reaction SMILES: [NH2:1][CH2:2][CH:3]([NH:10][C:11](=[O:24])[C:12]1[CH:17]=[CH:16][C:15]([C:18]2[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=2)=[CH:14][CH:13]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1>CCCCCC.CCO.CO>[NH2:1][CH2:2][C@H:3]([NH:10][C:11](=[O:24])[C:12]1[CH:17]=[CH:16][C:15]([C:18]2[CH:19]=[CH:20][N:21]=[CH:22][CH:23]=2)=[CH:14][CH:13]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: NCC(NC(=O)c1ccc(-c2ccncc2)cc1)c1ccccc1
Solvent: CCO
Solvent: CO
Solvent: CCCCCC
Product: NC[C@H](NC(=O)c1ccc(-c2ccncc2)cc1)c1ccccc1

Procedure:
The title compounds were prepared by subjecting the compound of Example 4 to a column chromatography with a chiral stationary phase (Prep HPLC; column: Whelk O 2.5 cm ID×25 cm; mobile phase: hexane/EtOH/MeOH/DEA=50/25/25/0.1; flow rate: 40 ml/min; detector: UV 270 nm; column temp: RT; sample preparation: 10 mg/ml; load: 10 ml (100 mg))
Reaction SMILES: [F:1][CH:2]([F:24])[C:3]1[N:8]2[CH:9]=[N:10][C:11]([C:12]#[CH:13])=[C:7]2[N:6]=[C:5]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=2)[CH:4]=1.Br[C:26]1[CH:31]=[CH:30][C:29]([S:32]([NH2:35])(=[O:34])=[O:33])=[CH:28][CH:27]=1>>[F:24][CH:2]([F:1])[C:3]1[N:8]2[CH:9]=[N:10][C:11]([C:12]#[C:13][C:26]3[CH:31]=[CH:30][C:29]([S:32]([NH2:35])(=[O:34])=[O:33])=[CH:28][CH:27]=3)=[C:7]2[N:6]=[C:5]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=2)[CH:4]=1
Reactant: NS(=O)(=O)c1ccc(Br)cc1
Reactant: C#Cc1ncn2c(C(F)F)cc(-c3ccc(C(F)(F)F)cc3)nc12
Product: NS(=O)(=O)c1ccc(C#Cc2ncn3c(C(F)F)cc(-c4ccc(C(F)(F)F)cc4)nc23)cc1

Procedure:
The title compound was prepared from 4-difluoromethyl-8-ethynyl-2-(4-trifluoromethyl-phenyl)-imidazo[1,5-a]pyrimidine (example C.31) (190 mg, 0.56 mmol) and commercially available 4-bromo-benzenesulfonamide (133 mg, 0.56 mmol) according to general procedure II. Obtained as a brown solid (184 mg, 66%). MS (ISN) 491.2 [(M−H)−]; mp 282° C.
Reaction SMILES: [Cl:1][C:2]1[C:7](I)=[CH:6][N:5]=[C:4]([NH:9][C:10]2[CH:17]=[CH:16][C:13]([C:14]#[N:15])=[CH:12][CH:11]=2)[N:3]=1.[C:18]([O:22][C:23](=[O:30])[NH:24][CH2:25][CH2:26][CH2:27][C:28]#[CH:29])([CH3:21])([CH3:20])[CH3:19].C(N(CC)CC)C.[Cl-].[NH4+]>CN(C)C=O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I.C(OCC)(=O)C>[Cl:1][C:2]1[C:7]([C:29]#[C:28][CH2:27][CH2:26][CH2:25][NH:24][C:23](=[O:30])[O:22][C:18]([CH3:20])([CH3:19])[CH3:21])=[CH:6][N:5]=[C:4]([NH:9][C:10]2[CH:17]=[CH:16][C:13]([C:14]#[N:15])=[CH:12][CH:11]=2)[N:3]=1
Reactant: C#CCCCNC(=O)OC(C)(C)C
Reactant: N#Cc1ccc(Nc2ncc(I)c(Cl)n2)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Agent: [Cl-]
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)NCCCC#Cc1cnc(Nc2ccc(C#N)cc2)nc1Cl
Reaction time: 1 h
Yield: 63.2 %

Procedure:
To a solution of 4-((4-chloro-5-iodopyrimidin-2-yl)amino)benzonitrile (J12, 100 mg) and tert-butyl(4-pentynyl)carbamate (77 mg) in N,N-dimethylformamide (3 mL), bis(triphenylphosphine)palladium(II) dichloride (20 mg), triethylamine (195 μL) and copper(I) iodide (11 mg) were added at room temperature, and the mixture was stirred at the same temperature for 1 hour. To the reaction mixture, saturated aqueous ammonium chloride and ethyl acetate were added. The organic layer was separated, washed with saturated aqueous sodium chloride, and then dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The obtained solid matter was washed with a mixture of hexane and ethyl acetate (5:1), and then air-dried to obtain tert-butyl (5-(4-chloro-2-((4-cyanophenyl)amino)pyrimidin-5-yl)-4-pentyn-1-yl)carbamate (T5, 73 mg) as pale yellow solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([C:11]([OH:13])=O)=[CH:5]2.[CH3:14][C:15]([NH:18][CH:19]1[NH:24][CH2:23][CH2:22][NH:21][CH:20]1C1C=NC=CN=1)([CH3:17])[CH3:16]>>[CH3:17][C:15]([NH:18][C:19]1[C:20]([N:21]2[CH2:22][CH2:23][N:24]([C:11]([C:6]3[NH:7][C:8]4[CH:9]=[CH:10][C:2]([F:1])=[CH:3][C:4]=4[CH:5]=3)=[O:13])[CH2:19][CH2:20]2)=[N:21][CH:22]=[CH:23][N:24]=1)([CH3:14])[CH3:16]
Reactant: CC(C)(C)NC1NCCNC1c1cnccn1
Reactant: O=C(O)c1cc2cc(F)ccc2[nH]1
Product: CC(C)(C)Nc1nccnc1N1CCN(C(=O)c2cc3cc(F)ccc3[nH]2)CC1

Procedure:
Following the general procedure of EXAMPLE 16 and making non-critical variations but starting with 5-fluoroindole-2-carboxylic acid (0.44 g) and 3-(1,1-dimethylethylamino)-2-pyrazinylpiperazine (2.50 mmol), a solid is obtained which is recrystallized from ethyl acetate to give the title compound.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[CH3:11])[C:7](=O)[N:6]([C:13]1[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=1)[CH:5]2[OH:19].[O:20]=[C:21]([CH2:42][CH2:43][CH3:44])[CH:22]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>C1(C)C=CC=CC=1>[CH3:11][C:10]1[CH:9]=[C:8]2[C:4](=[CH:3][C:2]=1[CH3:1])[C:5](=[O:19])[N:6]([C:13]1[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=1)[CH:7]2[CH2:22][C:21](=[O:20])[CH2:42][CH2:43][CH3:44]
Reactant: CCCC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: Cc1cc2c(cc1C)C(O)N(c1cccnc1)C2=O
Solvent: Cc1ccccc1
Product: CCCC(=O)CC1c2cc(C)c(C)cc2C(=O)N1c1cccnc1
Yield: 36.2 %

Procedure:
5,6-dimethyl-3-hydroxy-2-(3-pyridyl)isoindolin-1-one (0.30 g, 1.2 mmol) and 2-oxo-1-triphenylphosphoranylidene-pentane (0.61 g, 1.8 mmol) was heated under reflux in toluene (20 ml) under an argon atmosphere for 20 hrs. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel chromatography (chloroform:acetone=10:1) to give 0.14 g of the title compound.
Reaction SMILES: [CH:1]([NH:4][CH:5]([CH3:7])[CH3:6])([CH3:3])[CH3:2].[Cl:8][CH:9]([C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=1)[C:10](Cl)=[O:11].Cl>O1CCOCC1>[CH:1]([N:4]([CH:5]([CH3:7])[CH3:6])[C:10](=[O:11])[CH:9]([Cl:8])[C:13]1[CH:14]=[CH:15][C:16]([Cl:19])=[CH:17][CH:18]=1)([CH3:3])[CH3:2]
Reactant: CC(C)NC(C)C
Reactant: O=C(Cl)C(Cl)c1ccc(Cl)cc1
Agent: Cl
Solvent: C1COCCO1
Product: CC(C)N(C(=O)C(Cl)c1ccc(Cl)cc1)C(C)C
Temperature: 0 °C
Yield: 86.1 %

Procedure:
While stirring, 22.3 g of diisopropylamine is dripped into a solution of 24.5 g of α-chloro-α-(4-chlorophenyl)-acetyl chloride (see a)) in 50 ml of dioxane. After the exothermic reaction has subsided, the mixture is stirred overnight and then poured into 700 ml of ice water; the resultant mixture is acidified with dilute hydrochloric acid and the oil which separates out is extracted 8 times, each time with 100 ml of dichloromethane. The combined extracts are washed twice with sodium carbonate solution, dried over magnesium sulfate and concentrated. There is obtained 27.2 g of α-chloro-α-(4-chlorophenyl)-acetic acid diisopropyl amide as a brownish oil.
Reaction SMILES: [CH3:1][N+:2]([CH2:5][C@H:6]([NH2:11])[CH2:7][C:8]([O-:10])=[O:9])([CH3:4])[CH3:3].[CH2:12]([O:15][C:16]1[CH:31]=[CH:30][C:19]([C:20](ON2C(=O)CCC2=O)=[O:21])=[CH:18][CH:17]=1)[CH2:13][CH3:14].CN(C=O)C.C(N(C(C)C)CC)(C)C>C(OCC)C>[CH2:12]([O:15][C:16]1[CH:31]=[CH:30][C:19]([C:20]([NH:11][C@@H:6]([CH2:5][N+:2]([CH3:3])([CH3:4])[CH3:1])[CH2:7][C:8]([O-:10])=[O:9])=[O:21])=[CH:18][CH:17]=1)[CH2:13][CH3:14]
Reactant: CCCOc1ccc(C(=O)ON2C(=O)CCC2=O)cc1
Reactant: C[N+](C)(C)C[C@H](N)CC(=O)[O-]
Solvent: CCOCC
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCCOc1ccc(C(=O)N[C@H](CC(=O)[O-])C[N+](C)(C)C)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 20.9 %

Procedure:
(R)-aminocarnitine (20 mg, 0.12 mmol) and 2,5-dioxopyrrolidin-1-yl 4-propoxybenzoate (42 mg, 0.15 mmol) were dissolved into DMF (0.5 mL). Diisopropylethylamine (63 μL, 0.36 mmol) was added and the solution was stirred at room temperature for 18 h. Diethyl ether (20 mL) was added and a white precipitate was collected. The white solid was triturated with 1:1 acetone/ether and dried to give the title compound as a white powder (8.1 mg, 21%). 1H NMR (300 MHz, CD3OD) δ 7.89-7.78 (m, 2H), 7.01 (d, 2H, J=7.8 Hz), 4.75-4.63 (m, 1H), 4.02 (t, 2H, J=7.2 Hz), 3.75-3.51 (m, 2H), 3.21 (s, 9H), 2.82-2.71 (m, 2H), 1.85-1.75 (m, 2H), 1.05 (t, 3H, J=7.0 Hz); MS ESI 323.1 [M+H]+, calcd for [C17H26N2O4+H]+ 323.19.
Reaction SMILES: [Cl:1][CH:2]1[CH2:7][CH2:6][NH:5][CH2:4][CH:3]1[NH:8][P:9](=[O:16])([O:13][CH2:14][CH3:15])[O:10][CH2:11][CH3:12].Cl[C:18]1[CH:23]=[CH:22][N:21]=[CH:20][C:19]=1[N+:24]([O-:26])=[O:25].CCN(C(C)C)C(C)C>C(O)(C)C>[Cl:1][CH:2]1[CH2:7][CH2:6][N:5]([C:18]2[CH:23]=[CH:22][N:21]=[CH:20][C:19]=2[N+:24]([O-:26])=[O:25])[CH2:4][CH:3]1[NH:8][P:9](=[O:16])([O:13][CH2:14][CH3:15])[O:10][CH2:11][CH3:12]
Reactant: O=[N+]([O-])c1cnccc1Cl
Reactant: CCOP(=O)(NC1CNCCC1Cl)OCC
Solvent: CC(C)O
Solvent: CCN(C(C)C)C(C)C
Product: CCOP(=O)(NC1CN(c2ccncc2[N+](=O)[O-])CCC1Cl)OCC
Temperature: 70 °C
Yield: 69 %

Procedure:
To a solution of diethyl 4-chloropiperidin-3-ylphosphoramidate (1.0 equiv.) in isopropyl alcohol (0.1M) was added 4-chloro-3-nitropyridine (2.0 equiv.) and DIEA (1.1 equiv.). The reaction was heated to 70° C. for 18 h, then quenched with water and extracted with ethyl acetate. The organics were dried and concentrated under vacuo. The crude was purified via ISCO (ethyl acetate and hexanes then 10% methanol in DCM) to yield diethyl 4-chloro-1-(3-nitropyridin-4-yl)piperidin-3-ylphosphoramidate in 69% yield. LCMS (m/z): 393.1 (MH+), Rt=2.01 min.