Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:8]([C:10]([CH3:30])([CH3:29])[CH2:11][CH2:12][C:13]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:14]([NH2:16])=[O:15])C)C1C=CC=CC=1>CO.C(O)=O.[Pd]>[C:17]1([C:13]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)([CH2:12][CH2:11][C:10]([CH3:30])([NH:8][CH3:1])[CH3:29])[C:14]([NH2:16])=[O:15])[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: CN(Cc1ccccc1)C(C)(C)CCC(C(N)=O)(c1ccccc1)c1ccccc1
Agent: [Pd]
Solvent: CO
Solvent: O=CO
Product: CNC(C)(C)CCC(C(N)=O)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
10% Palladium-on-carbon was added to a solution of 5-(N-benzyl-N-methylamino)-2,2-diphenyl-5-methylhexanamide (0.6 g--see Example 3) in methanol (19 ml) and formic acid (1 ml). The mixture was stirred at room temperature for 16 hours then filtered and the filtrate concentrated in vacuo to give the title compound as a gum, yield 0.4 g.
Reaction SMILES: C([O:3][C:4](=[O:31])[C:5]([CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)([S:13]([C:16]1[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=1)(=[O:15])=[O:14])[CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)C>CO.[OH-].[Na+]>[CH2:24]([C:5]([S:13]([C:16]1[CH:17]=[CH:18][C:19]([O:22][CH3:23])=[CH:20][CH:21]=1)(=[O:14])=[O:15])([CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[C:4]([OH:31])=[O:3])[C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1
Reactant: CCOC(=O)C(Cc1ccccc1)(Cc1ccccc1)S(=O)(=O)c1ccc(OC)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COc1ccc(S(=O)(=O)C(Cc2ccccc2)(Cc2ccccc2)C(=O)O)cc1

Procedure:
2-Benzyl-2-(4-methoxy-benzenesulfonyl)-3-phenyl-propionic acid was prepared starting from 2-benzyl-2-(4-methoxy-benzenesulfonyl)-3-phenyl-propionic acid ethyl ester (1.0 g, 2.2 mmol) dissolved in methanol (50 ml) and 10 N NaOH (30 ml). The resulting reaction mixture was worked up as outlined in Example 9. Yield: 580 mg, 62%; Waxy solid; MS: 409 (M−H)−.
Reaction SMILES: I[C:2]1[C-:3]([N:7]([CH3:9])[CH3:8])[CH:4]=[CH:5][CH:6]=1.[CH-:10]1[CH:14]=[CH:13][CH:12]=[CH:11]1.[Fe+2:15].[Br:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1B(O)O.[OH-].[Na+]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.COCCOC>[Br:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[C:2]1[C-:3]([N:7]([CH3:9])[CH3:8])[CH:4]=[CH:5][CH:6]=1.[CH-:10]1[CH:14]=[CH:13][CH:12]=[CH:11]1.[Fe+2:15]
Reactant: CN(C)[c-]1cccc1I
Reactant: OB(O)c1ccccc1Br
Agent: [Fe+2]
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Na+]
Solvent: COCCOC
Product: CN(C)[c-]1cccc1-c1ccccc1Br
Temperature: 25 °C
Yield: 46.1 %

Procedure:
Racemic iodide 12i (355 mg, 1.00 mmol), 2-bromophenylboronic acid (210 mg, 1.05 mmol) and Pd(PPh3)4 (115 mg, 0.10 mmol) were added to a dry Schlenk flask, followed by DME (10 mL) and an aqueous solution of 3 M aqueous NaOH (0.50 mL, 1.50 mmol). Argon was bubbled through the resulting mixture for 10 minutes, and the system was heated at reflux for 15 h. The reaction mixture was allowed to cool to room temperature, diluted with Et2O, washed with water (1×5 mL), brine (1×5 mL), dried over Na2SO4, filtered, and all volatiles were removed in vacuo. Gradient flash column chromatography (silica gel, 97:3→95:5 t-BuOMe/hexane) afforded 58 (177 mg, 46%) as an orange oil: Rf 0.38 (90:10 hex/EtOAc); IR (KBr, CHCl3) vmax 3091, 2947, 2846, 2783, 1587, 1502, 1485, 1416 cm−1; 1H NMR (300 MHz, CDCl3) δ 8.12 (dd, 1H, J=7.7, 1.5 Hz), 7.26 (dd, 1H, J=8.1, 1.2 Hz), 7.34 (td, 1H, J=7.5, 1.2 Hz), 7.13 (td, 1H, J=7.8, 1.8 Hz), 4.32 (s, 5H), 4.13 (t, 1H, J=1.8 Hz), 4.10-4.05 (m, 2H), 2.41 (s, 6H); 13C NMR (75 MHz, CDCl3) δ 157.5, 132.6, 127.5, 127.0, 120.0, 113.1, 110.5, 75.5, 68.9, 66.8, 62.0, 56.8, 55.6, 44.1; EIMS [m/z (%)] 385 (81Br M+, 91), 383 (79Br M+, 100), 182 (62); HRMS (EI) calcd for C18H18N56Fe79Br: 382.9972. Found 382.9974.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:12]2[CH:13]=[C:14]([CH:17]=[O:18])[CH:15]=[CH:16][C:11]=2[N:10]=[C:9]1[C:19]1[C:24]([CH3:25])=[CH:23][CH:22]=[CH:21][C:20]=1[CH3:26])=[O:7])([CH3:4])([CH3:3])[CH3:2].[F:27][C:28]([Si](C)(C)C)([F:30])[F:29].CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C1COCC1>[C:1]([O:5][C:6]([N:8]1[C:12]2[CH:13]=[C:14]([CH:17]([OH:18])[C:28]([F:30])([F:29])[F:27])[CH:15]=[CH:16][C:11]=2[N:10]=[C:9]1[C:19]1[C:24]([CH3:25])=[CH:23][CH:22]=[CH:21][C:20]=1[CH3:26])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1cccc(C)c1-c1nc2ccc(C=O)cc2n1C(=O)OC(C)(C)C
Reactant: C[Si](C)(C)C(F)(F)F
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: Cc1cccc(C)c1-c1nc2ccc(C(O)C(F)(F)F)cc2n1C(=O)OC(C)(C)C
Temperature: -30 °C
Reaction time: 0.75 h

Procedure:
To 2-(2,6-dimethylphenyl)-6-formyl-benzoimidazole-1-carboxylic acid tert-butyl ester (565 mg) was added 16 mL of a 0.5 M solution of trifluoromethyltrimethylsilane in THF. When a solution formed the mixture was cooled to −30° C. then a solution of TBAF (1.76 mL of a 1.0M solution in THF) was added dropwise. The mixture was stirred at −30° C. for 45 min then was allowed to warm to 5° C. The mixture was extracted with EtOAc (2×) and the combined organic layers were dried over sodium sulfate. The solvent was removed under reduced pressure and the resulting foam was purified by flash chromatography using 10% EtOAc/methylene chloride as eluent to give 2-(2,6-dimethyl-phenyl)-6-(2,2,2-trifluoro-1-hydroxyethyl)-benzoimidazole-1-carboxylic acid tert-butyl ester as a waxy solid. MS (ESI)m/z 421 (M+H).
Reaction SMILES: [F:1][C:2]([F:32])([F:31])[C:3]1[CH:4]=[C:5]([N:13]([CH2:21][CH2:22][O:23][Si](C(C)(C)C)(C)C)[C:14](=[O:20])[O:15][C:16]([CH3:19])([CH3:18])[CH3:17])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1>C(O)(=O)C.O.C1COCC1>[F:1][C:2]([F:31])([F:32])[C:3]1[CH:4]=[C:5]([N:13]([CH2:21][CH2:22][OH:23])[C:14](=[O:20])[O:15][C:16]([CH3:17])([CH3:18])[CH3:19])[CH:6]=[C:7]([C:9]([F:11])([F:10])[F:12])[CH:8]=1
Reactant: CC(C)(C)OC(=O)N(CCO[Si](C)(C)C(C)(C)C)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Solvent: O
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)N(CCO)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Yield: 88.8 %

Procedure:
A mixed solution of the compound (0.50 g) obtained in step 3 in acetic acid (6 mL), water (2 mL) and THF (2 mL) was stirred at 50° C. for 14 hr, poured into water, and extracted with diethyl ether. The extract was washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried and concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (solvent gradient; 10→33% ethyl acetate/hexane) to give tert-butyl [3,5-bis(trifluoromethyl)phenyl](2-hydroxyethyl)carbamate (0.34 g, 87%) as a colorless oil.
Reaction SMILES: [CH2:1]([C@H:9]1[CH2:14][O:13][C@H:12]([C:15]2[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][CH:16]=2)[O:11][C@@H:10]1[CH3:22])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[F:23][C@@H:24]([CH2:28][CH2:29][CH2:30][CH3:31])[C:25](O)=[O:26].C1(N=C=NC2CCCCC2)CCCCC1>CN(C)C1C=CN=CC=1.C(Cl)Cl>[CH2:1]([C@H:9]1[CH2:14][O:13][C@H:12]([C:15]2[CH:20]=[CH:19][C:18]([O:21][C:25](=[O:26])[C@@H:24]([F:23])[CH2:28][CH2:29][CH2:30][CH3:31])=[CH:17][CH:16]=2)[O:11][C@@H:10]1[CH3:22])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: CCCC[C@H](F)C(=O)O
Reactant: CCCCCCCC[C@H]1CO[C@H](c2ccc(O)cc2)O[C@@H]1C
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CCCCCCCC[C@H]1CO[C@H](c2ccc(OC(=O)[C@@H](F)CCCC)cc2)O[C@@H]1C
Temperature: 25 °C
Reaction time: 16.5 h
Yield: 76.3 %

Procedure:
A mixture of 380 mg of 4-[(2S,4R,5S)-5-octyl-4-methyl-1,3-dioxan-2-yl]phenol, 185 mg of (S)-2-fluorocaproic acid, 333 mg of N,N'-dicyclohexylcarbodiimide, 20 mg of 4-(dimethylamino)pyridine and 40 ml methylene chloride was stirred at room temperature under nitrogen for 16.5 hours. Subsequently, the suspension was filtered and the filtrate was evaporated on a rotary evaporator. The crude product (1.0 g) was suspended in 50 ml of methylene chloride, the suspension was filtered and the filtrate was evaporated. Recrystallization of the white, solid residue (0.5 g) from hexane gave 0.4 g of 0.4 g of 1-[(2S,4R,5S)-5-octyl-4-methyl-1,3-dioxan-2-yl]-4-[(S)-2-fluorohexanoyloxy]benzene as white crystals with m.p. (C-I) 58.8° C. and [a]D =+16.7° (c=1% in chloroform).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([NH2:9])[C:5]([NH2:8])=[CH:6][CH:7]=1.[CH:10]([CH:12]=O)=O>C(O)(C)C>[CH3:1][C:2]1[CH:3]=[C:4]2[C:5](=[CH:6][CH:7]=1)[N:8]=[CH:12][CH:10]=[N:9]2
Reactant: O=CC=O
Reactant: Cc1ccc(N)c(N)c1
Solvent: CC(C)O
Product: Cc1ccc2nccnc2c1
Temperature: 80 °C
Yield: 93 %

Procedure:
To a solution of 4-methylbenzene-1,2-diamine (50.0 g, 0.41 mol) in isopropanol (300 mL) was added a solution of glyoxal (40% in water, 65.3 g, 0.45 mol) at room temperature. The reaction mixture was heated at 80° C. for 2 hours and evaporated under vacuum to give 6-methylquinoxaline (55 g, 93%), which was used directly in the next step. 1H NMR (300 MHz, CDCl3) δ 8.77 (dd, J=1.5, 7.2 Hz, 2 H), 7.99 (d, J=8.7 Hz, 1 H), 7.87 (s, 1 H), 7.60 (dd, J=1.5, 8.4 Hz, 1 H), 2.59 (s, 3 H).
Reaction SMILES: Br[CH:2]([C:4]1[O:5][C:6](=[O:21])[C:7]2[C:12]([C:13]=1[C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([F:20])[CH:15]=1)=[CH:11][CH:10]=[CH:9][CH:8]=2)[CH3:3].[N:22]1[C:30]([NH2:31])=[C:29]2[C:25]([NH:26][CH:27]=[N:28]2)=[N:24][CH:23]=1.C([O-])([O-])=O.[K+].[K+]>>[NH2:31][C:30]1[N:22]=[CH:23][N:24]=[C:25]2[C:29]=1[N:28]=[CH:27][N:26]2[CH:2]([C:4]1[O:5][C:6](=[O:21])[C:7]2[C:12]([C:13]=1[C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([F:20])[CH:15]=1)=[CH:11][CH:10]=[CH:9][CH:8]=2)[CH3:3]
Reactant: CC(Br)c1oc(=O)c2ccccc2c1-c1cccc(F)c1
Reactant: Nc1ncnc2[nH]cnc12
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CC(c1oc(=O)c2ccccc2c1-c1cccc(F)c1)n1cnc2c(N)ncnc21
Yield: 37 %

Procedure:
The title compound was made in a similar way as that of the compound of example 1, using 3-(1-bromoethyl)-4-(3-fluorophenyl)-1H-isochromen-1-one (intermediate C6, 70 mg, 0.202 mmol), 9H-purin-6-amine (54.5 mg, 0.403 mmol) and K2CO3 (55.7 mg, 0.403 mmol) to give the title compound (30 mg, 37.1%).
Reaction SMILES: C([O:3][C:4]([C:6]1[O:7][C:8]2[CH:16]=[C:15]([NH:17][S:18]([CH3:21])(=[O:20])=[O:19])[C:14]([O:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)=[CH:13][C:9]=2[C:10](=[O:12])[CH:11]=1)=[O:5])C.Cl.O>C(O)(=O)C>[C:4]([C:6]1[O:7][C:8]2[CH:16]=[C:15]([NH:17][S:18]([CH3:21])(=[O:20])=[O:19])[C:14]([O:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)=[CH:13][C:9]=2[C:10](=[O:12])[CH:11]=1)([OH:5])=[O:3]
Reactant: CCOC(=O)c1cc(=O)c2cc(Oc3ccccc3)c(NS(C)(=O)=O)cc2o1
Agent: Cl
Solvent: O
Solvent: CC(=O)O
Product: CS(=O)(=O)Nc1cc2oc(C(=O)O)cc(=O)c2cc1Oc1ccccc1
Yield: 92.1 %

Procedure:
3.5 g of 2-ethoxycarbonyl-7-methylsulfonylamino-6-phenoxy-4H-1-benzopyran-4-one was suspended in 30 ml of acetic acid. Thereto was added 20 ml of concentrated hydrochloric acid. The mixture was refluxed for 1 hour. To the reaction mixture was added 100 ml of water. The resulting crystal was collected by filtration and then recrystallized from ethanol to obtain 3.0 g (yield: 91%) of 2-carboxy-7-methylsulfonylamino-6-phenoxy-4H-1-benzopyran-4-one having a melting point of >250° C.
Reaction SMILES: [O:1]1[C:6]2=[C:7]3[C:12](=[CH:13][CH:14]=[C:5]2[O:4][CH2:3][CH2:2]1)[NH:11][CH:10]=[CH:9][C:8]3=[O:15].[Cl:16]N1C(=O)CCC1=O>C(O)(=O)C>[Cl:16][C:9]1[CH:10]=[N:11][C:12]2[C:7]([C:8]=1[OH:15])=[C:6]1[O:1][CH2:2][CH2:3][O:4][C:5]1=[CH:14][CH:13]=2
Reactant: O=C1CCC(=O)N1Cl
Reactant: O=c1cc[nH]c2ccc3c(c12)OCCO3
Solvent: CC(=O)O
Product: Oc1c(Cl)cnc2ccc3c(c12)OCCO3
Temperature: 35 °C
Yield: 73.2 %

Procedure:
2,3-Dihydro-7H-[1,4]dioxino[2,3-f]quinolin-10-one (6.93 g, 34.1 mmol, 1 eq) in acetic acid (95.9 mL) was sonicated and warmed until all had dissolved, and then it was treated with N-chlorosuccinimide (5.01 g, 37.5 mmol, 1.1 eq) and the mixture was heated at 35° C. for 18 hr, cooled and the solid collected and washed with acetic acid and dried in vacuo at 40 oC overnight, to give a white solid (5.93 g, 73%). LC/MS (ES) m/z 237 (MH+ 84%); 1H-NMR (400 MHz, d6-DMSO), 8.17 (1H, d, J=6.28, CHNHC), 7.21 (1H, d, J=8.96 Hz, CHCO), 7.01 (1H, d, J=9, CHCN), 4.29-4.25 (4H, m, 2×(CH2O)).
Reaction SMILES: [CH2:1]1[CH2:7][S:4](=[O:6])(=O)[O:3][CH2:2]1.[CH3:8][C:9]1[CH:14]=[N:13][CH:12]=[CH:11][N:10]=1>CCOCC.C(OCC)(=O)C>[S:4](=[CH:7][CH2:1][CH2:2][N:13]1[CH:12]=[CH:11][N:10]=[C:9]([CH3:8])[CH2:14]1)(=[O:6])=[O:3]
Reactant: O=S1(=O)CCCO1
Reactant: Cc1cnccn1
Solvent: CCOCC
Solvent: CCOC(C)=O
Product: CC1=NC=CN(CCC=S(=O)=O)C1

Procedure:
16.0 g of 1,3-propane sultone was dissolved in 200 ml of 1:1 ether/ethyl acetate and 15.1 g of 2-methylpyrazine added. It was then stored and the solvent allowed to evaporate.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([N+:9]([O-])=O)=[CH:7][C:6]([C:12]([F:15])([F:14])[F:13])=[CH:5][C:4]=1[N+:16]([O-])=O.CO.C([O-])=O.[NH4+]>CCOC(C)=O.[Pd]>[CH3:1][O:2][C:3]1[C:8]([NH2:9])=[CH:7][C:6]([C:12]([F:13])([F:15])[F:14])=[CH:5][C:4]=1[NH2:16]
Reactant: COc1c([N+](=O)[O-])cc(C(F)(F)F)cc1[N+](=O)[O-]
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CO
Solvent: CCOC(C)=O
Product: COc1c(N)cc(C(F)(F)F)cc1N
Yield: 92 %

Procedure:
2-Methoxy-1,3-dinitro-5-trifluoromethylbenzene (3.0 g, 11.3 mmol) was dissolved in 100 mL 50:50 EtOAc:MeOH. Ammonium formate (7.06 g, 112 mmol) was added followed by palladium-on-carbon catalyst (1.0 g). The reaction was heated to a gentle reflux for 45 min, then allowed to cool, and filtered through a plug of diatomaceous earth. The calalyst was washed with EtOAc repeatedly, and the filtrate was in vacuo. The residue was taken up in 500 ml 50% EtOAc in hexanes and filtered through a short plug of silica gel. The filtrate was concentrated in vacuo, providing 2.15 g (10.4 mmol, 95%) of 2-methoxy-5-trifluoromethyl-benzene-1,3-diamine as a brown oil.
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[C:8]([N:10]([CH3:12])[CH3:11])[CH:7]=[CH:6][C:3]=1[CH:4]=O.[CH3:13][O:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[CH2:21][CH2:22][C:23]#[N:24]>>[CH3:13][O:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[CH2:21][C:22]1[C:23]([NH2:24])=[N:1][C:2]2[C:3]([CH:4]=1)=[CH:6][CH:7]=[C:8]([N:10]([CH3:12])[CH3:11])[CH:9]=2
Reactant: COc1ccccc1CCC#N
Reactant: CN(C)c1ccc(C=O)c(N)c1
Product: COc1ccccc1Cc1cc2ccc(N(C)C)cc2nc1N

Procedure:
The title compound was synthesized according to EXAMPLE 11 from 2-amino-4-dimethylaminobenzaldehyde and 3-(2-methoxyphenyl)propionitrile. The reaction was performed thermally (45 min, 70-80° C.).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:13][C:14]1[CH:15]=[N:16][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:18][CH:19]=1)[C:10]([OH:12])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:24][C:25]1([CH3:33])[O:30][C:29](=[O:31])[CH2:28][C:27](=[O:32])[O:26]1.C1(N=C=NC2CCCCC2)CCCCC1>CN(C)C1C=CN=CC=1.C(Cl)Cl>[CH3:24][C:25]1([CH3:33])[O:30][C:29](=[O:31])[CH:28]([C:10](=[O:12])[C@@H:9]([NH:8][C:6](=[O:7])[O:5][C:1]([CH3:2])([CH3:3])[CH3:4])[CH2:13][C:14]2[CH:15]=[N:16][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:18][CH:19]=2)[C:27](=[O:32])[O:26]1
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(C(F)(F)F)nc1)C(=O)O
Reactant: CC1(C)OC(=O)CC(=O)O1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(C(F)(F)F)nc1)C(=O)C1C(=O)OC(C)(C)OC1=O
Temperature: 25 °C
Reaction time: 16 h
Yield: 90.5 %

Procedure:
(S)-2-(tert-Butoxycarbonylamino)-3-(6-(trifluoromethyl)pyridin-3-yl)propanoic acid (2.4 g, 7.2 mmol), 2,2-dimethyl-1,3-dioxane-4,6-dione (1.1 g, 7.9 mmol), and N,N-dimethylpyridin-4-amine (1.4 g, 11 mmol) in 30 mL DCM were cooled in an ice-water-sodium chloride bath (−5° C.). N-((cyclohexylimino)methylene)cyclohexanamine (1.6 g, 7.9 mmol) in 50 mL DCM was added dropwise in about 40 minutes. The reaction mixture was stirred for 16 hours at room temperature. The suspension was filtered, and the solid was washed with DCM. The filtrate was washed with 5% KHSO4 (4×50 mL) and once with brine, and dried over MgSO4. After removing the solvent, the product was obtained as a white solid (3.0 g, 91%). LCMS (API-ES) m/z (%): 461.0 (100%, M+H+).
Reaction SMILES: [NH2:1][O:2][CH2:3][CH2:4][CH2:5][O:6][CH2:7][P:8](=[O:15])([O:12][CH2:13][CH3:14])[O:9][CH2:10][CH3:11].[Cl:16][C:17]1[C:22]([NH:23][CH:24]=[O:25])=[C:21](Cl)[N:20]=[CH:19][N:18]=1.C(N(C(C)C)CC)(C)C>COCCOCCOC>[Cl:16][C:17]1[C:22]([NH:23][CH:24]=[O:25])=[C:21]([NH:1][O:2][CH2:3][CH2:4][CH2:5][O:6][CH2:7][P:8]([O:12][CH2:13][CH3:14])([O:9][CH2:10][CH3:11])=[O:15])[N:20]=[CH:19][N:18]=1
Reactant: CCOP(=O)(COCCCON)OCC
Reactant: O=CNc1c(Cl)ncnc1Cl
Solvent: COCCOCCOC
Solvent: CCN(C(C)C)C(C)C
Product: CCOP(=O)(COCCCONc1ncnc(Cl)c1NC=O)OCC
Temperature: 100 °C
Yield: 67 %

Procedure:
A mixture of diethyl 3-aminooxypropoxymethylphosphonate (1.0 g, 4.15 mmol), 4,6-dichloro-5-formamidopyrimidine (0.80 g, 4.15 mmol) and diisopropylethylamine (2.16 ml, 12.45 mmol) in diglyme (25 ml) was heated at 100° C. for 2 h. The solvent was then removed in vacuo and the residue chromatographed in chloroform/methanol (50:1) to give 4-chloro-6-[3-(diethoxyphosphorylmethoxy)propoxyamino]-5-formamidopyrimidine (1.lg, 67%) as a brown oil; νmax (film) 1600, 1570, 1220, 1030 cm-1 ; δH [(CD3)2SO] 1.23(6H, t, J7.2 Hz, (CH3CH2O)2), 1.85(2H, m, CH2CH2CH2), 3.63(2H, t, J6 Hz, CH2OCH2P), 3.79(2H, d, J8.3 Hz, CH2P), 3.94(2H, t, J6.1Hz, CH2ON), 4.04(4 H, m, (CH3CH2O)2), 8.15(1H, s, H-2), 9.50(1H, br s, D2O exchangeable, NH), 10.50-12.00(1H, br s, NH); Found: C, 39.37; H, 5.69; N, 13.82%; M+ 396.0963; C13H22ClN4O6P requires: C, 39.35; H, 5.59; N, 14.12%; M+ 396.0966.
Reaction SMILES: [CH:1]1([C:5]([N:7]2[CH2:16][CH2:15][C:14]3[C:9](=[CH:10][CH:11]=[C:12]([C:17]([NH:19][O:20]C4CCCCO4)=[O:18])[CH:13]=3)[CH2:8]2)=[O:6])[CH2:4][CH2:3][CH2:2]1.Cl>O.CO>[CH:1]1([C:5]([N:7]2[CH2:16][CH2:15][C:14]3[C:9](=[CH:10][CH:11]=[C:12]([C:17]([NH:19][OH:20])=[O:18])[CH:13]=3)[CH2:8]2)=[O:6])[CH2:2][CH2:3][CH2:4]1
Reactant: O=C(NOC1CCCCO1)c1ccc2c(c1)CCN(C(=O)C1CCC1)C2
Agent: Cl
Solvent: CO
Solvent: O
Product: O=C(NO)c1ccc2c(c1)CCN(C(=O)C1CCC1)C2

Procedure:
160 mg of 2-(cyclobutylcarbonyl)-N-(tetrahydro-2H-pyran-2-yloxy)-1,2,3,4-tetrahydroisoquinoline-6-carboxamide and 2 ml of a 0.1M solution of HCl in water in 2 ml methanol are stirred overnight at ambient temperature. The reaction mixture is evaporated and the residue is treated with acetonitrile. 53 mg of nearly colorless crystals are obtained. MH+=275.1
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1B(O)O.Br[C:12]1[N:16]([CH3:17])[C:15]([CH3:18])=[N:14][C:13]=1[C:19]#[N:20].C(O)CC.C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O>[NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:12]1[N:16]([CH3:17])[C:15]([CH3:18])=[N:14][C:13]=1[C:19]#[N:20]
Reactant: Nc1ccccc1B(O)O
Reactant: Cc1nc(C#N)c(Br)n1C
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: CCCO
Solvent: Cc1ccccc1
Solvent: O
Product: Cc1nc(C#N)c(-c2ccccc2N)n1C
Temperature: 100 °C
Yield: 98.9 %

Procedure:
2-Aminophenylboronic acid (238 mg, 1.74 mmol), 5-bromo-1,2-dimethyl-1H-imidazole-4-carbonitrile (0.200 g, 1.00 mmol), and n-propanol (1.75 mL) were combined and placed under a nitrogen atmosphere. Palladium (II) acetate (134 μL of a 5 mg/mL solution in toluene, 0.003 mmol), triphenylphosphine (2.4 mg, 0.009 mmol), aqueous sodium carbonate (0.600 mL of 2 M) and water (0.350 mL) were added, and the vessel was evacuated and filled with nitrogen three times. The reaction was sealed and heated under a nitrogen atmosphere at 100° C. for four hours, allowed to cool to room temperature, further cooled with ice, and then partitioned between 2M aqueous sodium carbonate and dichloromethane. The aqueous layer was separated and extracted twice with chloroform. The combined organic fractions were dried over magnesium sulfate, filtered, and concentrated under reduced pressure to provide 210 mg of 5-(2-aminophenyl)-1,2-dimethyl-1H-imidazole-4-carbonitrile as a brown oil that crystallized upon standing.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]([N:19]3[CH2:24][CH2:23][O:22][CH2:21][CH2:20]3)=[O:18])=[CH:13][N:12]=2)[C:5](=[O:9])[N:6]([CH3:8])[N:7]=1.[C:25]([O:28][CH2:29][C:30]1[C:31]([N:45]2[CH2:57][CH2:56][N:48]3[C:49]4[CH2:50][CH2:51][CH2:52][CH2:53][C:54]=4[CH:55]=[C:47]3[C:46]2=[O:58])=[N:32][CH:33]=[CH:34][C:35]=1B1OC(C)(C)C(C)(C)O1)(=[O:27])[CH3:26].C1(P(C2CCCCC2)C2CCCCC2)CCCCC1.C(=O)([O-])[O-].[Cs+].[Cs+]>O.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].O1CCOCC1>[C:25]([O:28][CH2:29][C:30]1[C:31]([N:45]2[CH2:57][CH2:56][N:48]3[C:49]4[CH2:50][CH2:51][CH2:52][CH2:53][C:54]=4[CH:55]=[C:47]3[C:46]2=[O:58])=[N:32][CH:33]=[CH:34][C:35]=1[C:2]1[CH:3]=[C:4]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]([N:19]3[CH2:24][CH2:23][O:22][CH2:21][CH2:20]3)=[O:18])=[CH:13][N:12]=2)[C:5](=[O:9])[N:6]([CH3:8])[N:7]=1)(=[O:27])[CH3:26]
Reactant: CC(=O)OCc1c(B2OC(C)(C)C(C)(C)O2)ccnc1N1CCn2c(cc3c2CCCC3)C1=O
Reactant: Cn1nc(Cl)cc(Nc2ccc(C(=O)N3CCOCC3)cn2)c1=O
Agent: [Pd]
Agent: C1CCC(P(C2CCCCC2)C2CCCCC2)CC1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: O
Solvent: C1COCCO1
Product: CC(=O)OCc1c(-c2cc(Nc3ccc(C(=O)N4CCOCC4)cn3)c(=O)n(C)n2)ccnc1N1CCn2c(cc3c2CCCC3)C1=O
Temperature: 110 °C
Reaction time: 4 h
Yield: 63.5 %

Procedure:
A sealed tube equipped with a magnetic stirrer was charged with 6-chloro-2-methyl-4-({5-[(morpholin-4-yl)carbonyl]pyridin-2-yl}amino)-2,3-dihydropyridazin-3-one 226a (244 mg, 0.70 mmol), 3-(acetoxymethyl)-2-(1-oxo-3,4,6,7,8,9-hexahydropyrazino[1,2-a]indol-2(1H)-yl)pyridin-4-ylboronic acid 113i (558 mg, 1.5 mmol), Pd2(dba)3 (64 mg, 0.070 mmol), tricyclohexylphospine (39 mg, 0.14 mmol), cesium carbonate (456 mg, 1.4 mmol), 1,4-dioxane (7 mL), and water (6 drops). After three cycles of vacuum/argon flush, the mixture was stirred at 110° C. for 4 h. It was then filtered and the filtrate was evaporated in vacuo. The residue was purified by silica-gel column chromatography eluting with 40:1 ethyl acetate/methanol to afford 227a as a yellow solid (290 mg, 63%). MS-ESI: [M+H]+ 653.3
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Br:8])[N:3]=1.CCN(CC)CC.[CH3:16][C:17]([CH3:22])=[CH:18][C:19](Cl)=[O:20]>C(Cl)Cl>[Br:8][C:4]1[N:3]=[C:2]([NH:1][C:19](=[O:20])[CH:18]=[C:17]([CH3:22])[CH3:16])[CH:7]=[CH:6][CH:5]=1
Reactant: Nc1cccc(Br)n1
Reactant: CC(C)=CC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)=CC(=O)Nc1cccc(Br)n1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a solution of 2-amino-6-bromopyridine (3.015 g, 0.017 mol) and Et3N (2.40 mL, 0.017 mol) in CH2Cl2 (20.0 mL), was added 3,3-dimethylacryloylchloride (1.96 mL, 0.017 mol) under N2 at 0° C. The mixture was slowly warmed to RT and stirred for 12 h. The reaction was quenched by the addition of H2O (20.0 mL), the organic layer was separated, dried over Na2SO4 and evaporated to dryness to yield crude compound which was used without purification.
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]1[C@H:8]([CH3:9])[CH2:7][CH2:6][CH2:5][N:4]1[C:10]([C:12]1[CH:17]=[C:16]([CH3:18])[CH:15]=[CH:14][C:13]=1[N:19]1[N:23]=[CH:22][CH:21]=[N:20]1)=[O:11].Cl[C:25]1[S:26][CH:27]=[C:28]([C:30]([F:33])([F:32])[F:31])[N:29]=1>>[CH3:9][C@@H:8]1[CH2:7][CH2:6][CH2:5][N:4]([C:10]([C:12]2[CH:17]=[C:16]([CH3:18])[CH:15]=[CH:14][C:13]=2[N:19]2[N:23]=[CH:22][CH:21]=[N:20]2)=[O:11])[C@@H:3]1[CH2:2][NH:1][C:25]1[S:26][CH:27]=[C:28]([C:30]([F:33])([F:32])[F:31])[N:29]=1
Reactant: FC(F)(F)c1csc(Cl)n1
Reactant: Cc1ccc(-n2nccn2)c(C(=O)N2CCC[C@@H](C)[C@H]2CN)c1
Product: Cc1ccc(-n2nccn2)c(C(=O)N2CCC[C@@H](C)[C@H]2CNc2nc(C(F)(F)F)cs2)c1

Procedure:
The title compound was prepared following the same general protocol as described for Example A1, using ((2S,3R)-2-(aminomethyl)-3-methylpiperidin-1-yl)(5-methyl-2-(2H-1,2,3-triazol-2-yl)phenyl)methanone and 2-chloro-4-(trifluoromethyl)thiazole. ESI-MS (m/z): 465 [M+1]+.