Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([CH2:7][NH:8][C:9]([NH:11][C:12]2[CH:13]=[C:14]([C:18]([NH:20][CH2:21][C:22]([NH:24][CH:25]([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)[CH2:26][C:27]([O:29]CC)=[O:28])=[O:23])=[O:19])[CH:15]=[CH:16][CH:17]=2)=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[Li+].FC(F)(F)C(O)=O>O.C(#N)C>[C:1]1([CH2:7][NH:8][C:9]([NH:11][C:12]2[CH:13]=[C:14]([C:18]([NH:20][CH2:21][C:22]([NH:24][CH:25]([C:32]3[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=3)[CH2:26][C:27]([OH:29])=[O:28])=[O:23])=[O:19])[CH:15]=[CH:16][CH:17]=2)=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CCOC(=O)CC(NC(=O)CNC(=O)c1cccc(NC(=O)NCc2ccccc2)c1)c1ccccc1
Agent: [Li+]
Agent: [OH-]
Solvent: O=C(O)C(F)(F)F
Solvent: CC#N
Solvent: O
Product: O=C(O)CC(NC(=O)CNC(=O)c1cccc(NC(=O)NCc2ccccc2)c1)c1ccccc1
Temperature: 25 °C
Yield: 448.4 %

Procedure:
The product of Example 118 (400 mg, 0.094 mmol) was dissolved in water/acetonitrile (1:1), followed by the addition of lithium hydroxide (100 mg, 0.4 mmol). The reaction mixture was stirred at 25° C., and monitored by HPLC. After complete hydrolysis (1-2 hours) trifluoroacetic acid was added until pH=2. The product was purified by reverse phase chromatography (water/acetonitrile) and lyophilized to result in a white solid (200 mg). MS and 1H-NMR were consistent with the proposed structure.
Reaction SMILES: [H-].[Na+].[OH:3][CH2:4][C:5]([CH3:10])([CH3:9])[C:6]([O-:8])=[O:7].I[CH3:12].O.[OH-].[Li+]>C1COCC1>[CH3:12][O:3][CH2:4][C:5]([CH3:10])([CH3:9])[C:6]([OH:8])=[O:7]
Reactant: CI
Reactant: CC(C)(CO)C(=O)[O-]
Agent: [H-]
Agent: [Li+]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: COCC(C)(C)C(=O)O
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 91 %

Procedure:
Sodium hydride (1.16 g, 48.4 mmol) was dissolved in THF (48 mL) and cooled to 0° C. 3-Hydroxy-2,2-dimethylpropanoate (6.4 g, 48.4 mmol) was added dropwise and the mixture was stirred at 0° C. for 30 min, allowed to warm to RT, and stirred an additional 1 h. The mixture was cooled back to 0° C. and iodomethane (3.0 mL), 48.4 mmol) was added. The reaction mixture was allowed to warm to RT and stirred for 16 h. The reaction mixture was filtered through a pad of diatomaceous earth and the filter cake was washed with THF (2×35 mL). The filtrates were combined and diluted with water (150 mL). Lithium hydroxide hydrate (8.13 g, 194 mmol) was added and the reaction mixture was stirred at RT for 16 h. The aqueous phase was collected and the organic phase was extracted with 0.5 N NaOH (aq) (3×50 mL). The combined aqueous phases were washed with Et2O (20 mL) and hexanes (2×100 mL), saturated with solid NaCl, and the pH of the solution was adjusted to ˜2 by the careful addition of conc. HCl (aq). The acidic solution was extracted with EtOAc (4×100 mL) and the combined organics were dried (Na2SO4) and concentrated in vacuo to afford 3-methoxy-2,2-dimethylpropanoic acid (5.8 g, 91%) as a red oil. 1H NMR (400 MHz, DMSO-d6): δ 12.02 (s, 1H), 3.29 (s, 2H), 3.23 (s, 3H), 1.06 (s, 6H).
Reaction SMILES: [F:1][C:2]([F:34])([F:33])[CH2:3][NH:4][C:5]([NH:7][C:8]1[CH:9]=[C:10]([C:14]2[N:18]3[N:19]=[CH:20][C:21]([C:23]4[CH:24]=[N:25][N:26]([CH:28]([CH3:32])[C:29]([OH:31])=O)[CH:27]=4)=[CH:22][C:17]3=[N:16][CH:15]=2)[CH:11]=[CH:12][CH:13]=1)=[O:6].[CH3:35][NH:36][CH:37]1[CH2:42][CH2:41][O:40][CH2:39][CH2:38]1>>[CH3:35][N:36]([CH:37]1[CH2:42][CH2:41][O:40][CH2:39][CH2:38]1)[C:29](=[O:31])[CH:28]([N:26]1[CH:27]=[C:23]([C:21]2[CH:20]=[N:19][N:18]3[C:14]([C:10]4[CH:11]=[CH:12][CH:13]=[C:8]([NH:7][C:5]([NH:4][CH2:3][C:2]([F:33])([F:1])[F:34])=[O:6])[CH:9]=4)=[CH:15][N:16]=[C:17]3[CH:22]=2)[CH:24]=[N:25]1)[CH3:32]
Reactant: CNC1CCOCC1
Reactant: CC(C(=O)O)n1cc(-c2cnn3c(-c4cccc(NC(=O)NCC(F)(F)F)c4)cnc3c2)cn1
Product: CC(C(=O)N(C)C1CCOCC1)n1cc(-c2cnn3c(-c4cccc(NC(=O)NCC(F)(F)F)c4)cnc3c2)cn1

Procedure:
This compound was prepared by using procedures analogous to those described for the synthesis of Example 54, Step 3 starting from 2-(4-{3-[3-({[(2,2,2-trifluoroethyl)amino]carbonyl}amino)phenyl]imidazo[1,2-b]pyridazin-7-yl}-1H-pyrazol-1-yl)propanoic acid and N-methyltetrahydro-2H-pyran-4-amine (Peakdale and Cat. No. 2006971). LCMS (M+H)+: m/z=571.3.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[C:4]([Cl:12])[N:3]=1.CCN(C(C)C)C(C)C.[CH3:22][N:23]1[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1>CN(C=O)C>[Cl:12][C:4]1[N:3]=[C:2]([N:26]2[CH2:27][CH2:28][N:23]([CH3:22])[CH2:24][CH2:25]2)[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=1
Reactant: FC(F)(F)c1cc(Cl)nc(Cl)c1
Reactant: CN1CCNCC1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CN1CCN(c2cc(C(F)(F)F)cc(Cl)n2)CC1
Temperature: 25 °C
Yield: 90.5 %

Procedure:
Dissolve 2,6-dichloro-4-(trifluoromethyl)pyridine (215 mg, 1 mmol) and DIEA (129 mg, 1 mmol) in DMF (2 mL), add 1-methyl piperazine (100 mg, 1 mmol). Stir the reaction at 120° C. overnight. Cool to room temperature; concentrate under reduced pressure to give the crude product. Purification by chromatography (silica gel, MeOH:DCM=1:10) affords the product (253 mg, 91%). MS: (M+1): 280.
Reaction SMILES: [Cl:1][C:2]1[C:6]([Cl:7])=[C:5]([CH3:8])[NH:4][C:3]=1[C:9]([NH:11][CH:12]1[CH2:17][CH2:16][N:15]([C:18]2[S:19][C:20]([C:25]([O:27][CH2:28][CH3:29])=[O:26])=[C:21]([CH:23]=O)[N:22]=2)[CH2:14][CH:13]1[O:30][CH3:31])=[O:10].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[NH:46]1[CH2:51][CH2:50][O:49][CH2:48][CH2:47]1>C(Cl)Cl.Cl>[Cl:1][C:2]1[C:6]([Cl:7])=[C:5]([CH3:8])[NH:4][C:3]=1[C:9]([NH:11][C@H:12]1[CH2:17][CH2:16][N:15]([C:18]2[S:19][C:20]([C:25]([O:27][CH2:28][CH3:29])=[O:26])=[C:21]([CH2:23][N:46]3[CH2:51][CH2:50][O:49][CH2:48][CH2:47]3)[N:22]=2)[CH2:14][C@H:13]1[O:30][CH3:31])=[O:10]
Reactant: C1COCCN1
Reactant: CCOC(=O)c1sc(N2CCC(NC(=O)c3[nH]c(C)c(Cl)c3Cl)C(OC)C2)nc1C=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: ClCCl
Product: CCOC(=O)c1sc(N2CC[C@H](NC(=O)c3[nH]c(C)c(Cl)c3Cl)[C@H](OC)C2)nc1CN1CCOCC1
Temperature: 25 °C
Yield: 52.4 %

Procedure:
To a solution of ethyl 2-(4-{[(3,4-dichloro-5-methyl-1H-pyrrol-2-yl)carbonyl]amino}-3-methoxypiperidin-1-yl)-4-formyl-1,3-thiazole-5-carboxylate (0.15 g, 0.31 mmol, Example 252) in methylene chloride (20 mL) was added sodium triacetoxyborohydride (0.1 g, 0.47 mmol) and morpholine (0.03 mL, 0.34 mmol). Reaction was stirred at room temperature and monitored by LCMS. Upon completion, the reaction mixture was diluted with 1N HCl and then partitioned with EtOAc/sat. sodium bicarbonate. Washing with brine, drying with MgSO4 and concentrating yielded a solid. Purification by silica gel flash column (gradient elution 70-100% EtOAc/CH2Cl2) afforded pure product (0.091 g) MS (ES) M+H+: 560 for C23H31Cl2N5O5S; NMR: 1.24 (t, 3 H) 1.75 (s, 2 H) 2.18 (s, 3 H) 3.32 (s, 2 H) 3.36 (s, 3 H) 3.52 (s, 2 H) 3.54 (d, 4 H) 3.65-3.75 (m, 2 H) 3.76-3.86 (m, 2 H) 3.93 (s, 1 H) 4.18 (q, 2 H) 4.27 (s, 1 H) 7.16 (d, 1 H) 12.16 (s, 1 H).
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].Cl[C:11]1[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][C:12]=1[N+:18]([O-:20])=[O:19]>CN(C=O)C>[Cl:17][C:14]1[CH:15]=[CH:16][C:11]([O:7][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)=[C:12]([N+:18]([O-:20])=[O:19])[CH:13]=1
Reactant: O=[N+]([O-])c1cc(Cl)ccc1Cl
Reactant: Oc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1cc(Cl)ccc1Oc1ccccc1
Reaction time: 16 h
Yield: 96.4 %

Procedure:
To a stirred solution of phenol (36.6 g, 0.39 mol) in DMF (250 mL) was added sodium hydride (10 g, 0.42 mol) in portions. To the resulting solution was added a solution of 2,5-dichloronitrobenzene (68 g, 0.35 mol) in DMF (500 mL), and the mixture was stirred for 16 hours. The solvent was removed under reduced pressure, and the residue was takene up in EtOAc (400 mL) and extracted with brine (saturated, 400 mL). The product was distilled to yield a yellow liquid (84.2 g, 95%), which had a boiling point of 245°-265° C./1.5 mmHg. This material was employed in Example 9 without further purification.
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:9]=[C:8]([O:10][CH3:11])[C:7]([O:12][CH3:13])=[C:6]([O:14][CH3:15])[CH:5]=1)=[O:3].[N:16]1[CH:21]=[CH:20][CH:19]=[C:18]([CH:22]=O)[CH:17]=1.N1CCCCC1.C(O)(=O)C>C(OCC)(=O)C.C(O)C>[CH3:15][O:14][C:6]1[CH:5]=[C:4]([C:2](=[O:3])[CH:1]=[CH:22][C:18]2[CH:17]=[N:16][CH:21]=[CH:20][CH:19]=2)[CH:9]=[C:8]([O:10][CH3:11])[C:7]=1[O:12][CH3:13]
Reactant: O=Cc1cccnc1
Reactant: COc1cc(C(C)=O)cc(OC)c1OC
Solvent: CCO
Solvent: CC(=O)O
Solvent: C1CCNCC1
Product: COc1cc(C(=O)C=Cc2cccnc2)cc(OC)c1OC
Yield: 23.4 %

Procedure:
Combine 3,4,5-trimethoxyacetophenone (5.25 g, 25 mmol), 3-pyridinecarboxaldehyde (2.35 mL, 25 mmol), piperidine (4.93 mL, 50 mmol), acetic acid (2.86 mL, 50 mmol) and ethanol (25 mL). Heat at reflux for 6 hour s, passing the distillate through a column of 3 Å molecular si eves (25 g). Dilute with ethyl acetate (600 mL), wash with IN sodium hydroxide (200 mL), then water, then saturated sodium chloride. Dry (MgSO4) and evaporate the solvent. Purify by silica gel chromatography (90% ethyl acetate/hexane). Recrystallize (methylene chloride/ethyl ether/hexane) to yield 1.75 g of the title compound; mp 137°-8° C.
Reaction SMILES: [OH:1][C:2]1[C:3]([CH3:12])=[C:4]([CH:8]=[C:9](O)[CH:10]=1)[C:5]([OH:7])=[O:6].[Cl-].[NH4+:14]>N>[NH2:14][C:9]1[CH:10]=[C:2]([OH:1])[C:3]([CH3:12])=[C:4]([CH:8]=1)[C:5]([OH:7])=[O:6]
Reactant: [NH4+]
Reactant: Cc1c(O)cc(O)cc1C(=O)O
Agent: N
Agent: [Cl-]
Product: Cc1c(O)cc(N)cc1C(=O)O
Temperature: 180 °C
Yield: 35.9 %

Procedure:
A mixture of 7.00 g of 3,5-dihydroxy-2-methylbenzoic acid, 5.40 g of ammonium chloride, and 20 ml of 25% aqueous ammonia was heated to 180° C. for 40 hours in a pressure vessel. After cooling, the mixture was evaporated in vacuo. The residue was taken up in 230 ml of 6N hydrochloric acid, and the mixture was heated at reflux for 16 hours. After cooling, unsoluble material was removed by filtration, and the filtrate was evaporated in vacuo. The residue was supended in 100 ml of water, the pH of the suspension was adjusted to 4.5 by the addition of 3N sodium hydroxide, and the mixture was cooled to 0° C. for 30 minutes. The precipitate was isolated by filtration and dried to give 2.50 g of 5-amino-3-hydroxy-2-methylbenzoic acid as white crystals, m.p. >250° C.
Reaction SMILES: [C:1]1([N:7]2[CH:11]=[CH:10][CH:9]=[N:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(O[CH:16]=[CH:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)(=O)C.C1(C)C=CC=CC=1>CCN(CC)CC.CCOC(C)=O.CCCCCC>[CH:16]([C:6]1[CH:5]=[CH:4][CH:3]=[CH:2][C:1]=1[N:7]1[CH:11]=[CH:10][CH:9]=[N:8]1)=[CH:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: CC(=O)OC=Cc1ccccc1
Reactant: c1ccc(-n2cccn2)cc1
Solvent: CCN(CC)CC
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: C(=Cc1ccccc1-n1cccn1)c1ccccc1
Temperature: 25 °C
Reaction time: 50 h
Yield: 56 %

Procedure:
A Teflon-coated magnetic stirring rod was placed in a 10 mL two-necked flask which was then equipped with a reflux condenser. The reflux condenser was connected to a pressure reduced/nitrogen line, and the whole apparatus was dried with heating under reduced pressure. Thereafter, N2 gas was charged in the reaction apparatus and the whole reaction apparatus was purged with nitrogen. The reaction vessel was left to cool to room temperature, then, Ru(cod)(cot) complex (0.05 mmol, 15.8 mg), 1-phenyl-1H-pyrazole (1 mmol, 144.2 mg), styryl acetate (3 mmol, 486.6 mg) and toluene (1.5 mL) were added. The mixture was heated by an oil bath and reacted under reflux condition for 50 hours. 50 hours after, the reaction solution was left to cool to room temperature, then, triethylamine (0.3 mL) was added. Isolation of the product was carried out by silica gel column chromatography (i.d.=30 mm; length=170-250 mm; hexane:EtOAc:Et3N=9:1:0.1; 25 mL each). A subject substance 1-(2-styrylphenyl)-1H-pyrazole was obtained with a yield of 56%.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[C:10]([C:11](=[O:24])[C:12]3[CH:17]=[C:16]([O:18][CH3:19])[C:15]([O:20][CH3:21])=[C:14]([O:22][CH3:23])[CH:13]=3)=[C:9]([CH3:25])[S:8][C:7]=2[C:26]=1[O:27]S(C1C=CC(C)=CC=1)(=O)=O.CO.C(C(O)=O)(F)(F)F>C1COCC1.[OH-].[Na+]>[OH:27][C:26]1[C:7]2[S:8][C:9]([CH3:25])=[C:10]([C:11](=[O:24])[C:12]3[CH:17]=[C:16]([O:18][CH3:19])[C:15]([O:20][CH3:21])=[C:14]([O:22][CH3:23])[CH:13]=3)[C:6]=2[CH:5]=[CH:4][C:3]=1[O:2][CH3:1]
Reactant: COc1cc(C(=O)c2c(C)sc3c(OS(=O)(=O)c4ccc(C)cc4)c(OC)ccc23)cc(OC)c1OC
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O=C(O)C(F)(F)F
Product: COc1cc(C(=O)c2c(C)sc3c(O)c(OC)ccc23)cc(OC)c1OC
Temperature: 30 °C
Reaction time: 8 h
Yield: 279.4 %

Procedure:
A mixture of the product of Example 41 (0.035 g; 0.00645 mmol) in THF (0.5 ml) and 1% NaOH in MeOH (0.52 ml; 0.0129 mmol) was stirred overnight at 30° C. under N2 and acidified with the drop of CF3CO2H. This was evaporated to dryness and diluted to 15 ml with diethyl ether, washed with 0.1 M HCl (2 ml), 5% NaHCO3 (2 ml), brine, dried over anhydrous MgSO4, filtered and filtrate evaporated to dryness under reduced pressure. The residue was purified by flash column chromatography (SiO2, CH2Cl2) to give pure title compound (0.007 g; 28%), as a colourless crystals. 1H-NMR (CDCl3) 2.47 (s, 3H); 3.83 (s, 6H); 3.92 (s, 6H); 5.94 (s, 1H); 6.93 (d, 1H, J=8.69 Hz); 7.05 (d, 1H, J=8.69 Hz); 7.1 (s, 2H).
Reaction SMILES: [C:1]([NH:8][CH2:9][C:10]1[S:11][C:12]([C:16]([NH2:18])=O)=[C:13]([CH3:15])[N:14]=1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].C(N(C(C)C)C(C)C)C.FC(F)(F)C(OC(=O)C(F)(F)F)=O>ClCCl>[C:1]([NH:8][CH2:9][C:10]1[S:11][C:12]([C:16]#[N:18])=[C:13]([CH3:15])[N:14]=1)([O:3][C:4]([CH3:6])([CH3:7])[CH3:5])=[O:2]
Reactant: Cc1nc(CNC(=O)OC(C)(C)C)sc1C(N)=O
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cc1nc(CNC(=O)OC(C)(C)C)sc1C#N
Temperature: 0 °C
Reaction time: 1 h

Procedure:
2-(N-BOC-Aminomethyl)-4-methylthiazole-5-carboxamide [sic] (11.13 g, 41.02 mmol) was suspended in dichloromethane (75 ml) and cooled to 0° C. At this temperature, ethyldiisopropylamine (17.86 ml, 102.55 mmol) was first added, and then, slowly, a solution of trifluoroacetic anhydride (6.56 ml, 47.17 mmol) in dichloromethane (20 ml). After stirring for 1 hour, the mixture was diluted with dichloromethane and washed with 5% strength citric acid solution. After drying (MgSO4), the solvent was removed on a rotary evaporator and the crude product was purified by flash chromatography.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]([OH:25])([CH:16]([C:18]1[CH:23]=[CH:22][N+:21]([O-])=[CH:20][N:19]=1)[CH3:17])[CH2:10][N:11]1[CH:15]=[N:14][CH:13]=[N:12]1.[CH3:26][N:27](C)C(Cl)=O.C[Si](C#N)(C)C>ClCCl>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]([OH:25])([CH:16]([C:18]1[CH:23]=[C:22]([C:26]#[N:27])[N:21]=[CH:20][N:19]=1)[CH3:17])[CH2:10][N:11]1[CH:15]=[N:14][CH:13]=[N:12]1
Reactant: CN(C)C(=O)Cl
Reactant: CC(c1cc[n+]([O-])cn1)C(O)(Cn1cncn1)c1ccc(F)cc1F
Agent: C[Si](C)(C)C#N
Solvent: ClCCl
Product: CC(c1cc(C#N)ncn1)C(O)(Cn1cncn1)c1ccc(F)cc1F
Temperature: 25 °C
Reaction time: 2 h
Yield: 3.7 %

Procedure:
A mixture of the product of part (i) (0.80 g) and N,N-dimethylcarbamoyl chloride (0.50 g) in dichloromethane (10 ml) was stirred at room temperature for 2 hours. Trimethylsilyl cyanide (0.50 g) was added and stirring was continued for a further 6 days. The solution was evaporated and the residue was chromatographed on silica gel. Elution with dichloromethane/methanol (100:1) gave a product which was rechromatographed on silica gel. Elution was commenced with ether and the polarity of the eluant was gradually increased by the addition of up to 6% (by volume) of methanol. Combination and evaporation of the initial product-containing fractions gave 2-(2,4-difluorophenyl)-3-(6-cyanopyrimidin-4-yl)-1-(1H-1,2,4-triazol-1-yl)butan-2-ol, (30 mg), m.p. 148°-149°.
Reaction SMILES: [C:1]([OH:4])(=[O:3])[CH3:2].Br.C(OC([NH:16][C@H:17]([C:24]([N:26]1[CH2:36][CH2:35][CH2:34][C@H:27]1[C:28]([NH:30][CH2:31][CH2:32]O)=[O:29])=[O:25])[CH2:18][C:19]1[N:23]=[CH:22][NH:21][CH:20]=1)=O)C1C=CC=CC=1>CCOCC>[NH2:16][C@H:17]([C:24]([N:26]1[CH2:36][CH2:35][CH2:34][C@H:27]1[C:28]([NH:30][CH2:31][CH2:32][O:3][C:1](=[O:4])[CH3:2])=[O:29])=[O:25])[CH2:18][C:19]1[N:23]=[CH:22][NH:21][CH:20]=1
Reactant: O=C(N[C@@H](Cc1c[nH]cn1)C(=O)N1CCC[C@H]1C(=O)NCCO)OCc1ccccc1
Reactant: CC(=O)O
Agent: Br
Solvent: CCOCC
Product: CC(=O)OCCNC(=O)[C@@H]1CCCN1C(=O)[C@@H](N)Cc1c[nH]cn1
Temperature: 25 °C

Procedure:
To 37.5 ml of ice-cooled acetic acid solution of 25% hydrobromic acid was added 3.22 g of compound (54) and the reaction was maintained for 3 hours at room temperature. The reaction mixture was added to 375 ml of dry ether and the precipitates thus formed were quickly collected by filtration and dried overnight in a desiccator containing potassium hydroxide to provide 4.43 g of L-histidyl-N-(2-acetoxyethyl)-L-prolinamide.2-hydrobromide.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([F:9])[C:5]([Cl:8])=[N:6][CH:7]=1.[CH3:10][C:11]1(C)CC(C)OB(C=C)O1.C([O-])([O-])=O.[K+].[K+]>CCCC[N+](CCCC)(CCCC)CCCC.[F-].C1COCC1.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.O>[Cl:8][C:5]1[C:4]([F:9])=[CH:3][C:2]([CH:10]=[CH2:11])=[CH:7][N:6]=1
Reactant: C=CB1OC(C)CC(C)(C)O1
Reactant: Fc1cc(Br)cnc1Cl
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])[O-]
Solvent: O
Solvent: C1CCOC1
Product: C=Cc1cnc(Cl)c(F)c1
Temperature: 60 °C
Reaction time: 16 h
Yield: 94.9 %

Procedure:
To a solution of 101 (5.00 g, 23.8 mmol) and 4,4,6-trimethyl-2-vinyl-1,3,2-dioxaborinane (111, 3.29 g, 21.39 mmol, Sigma-Aldrich) in a mixture of TBAF (30.0 mL) and THF (64.0 mL) under an argon atmosphere was added bis(triphenylphosphine)dichloropalladium(II) catalyst (Pd(PPh3)2Cl2, 1.33 g, 1.90 mmol, Sigma-Aldrich) and K2CO3 (8.20 g, 59.4 mmol). The resulting reaction mixture was heated to 60° C. and held for 16 hrs in a sealed bottle. The mixture was cooled to a temperature of about 25° C., diluted with water, and extracted with EtOAc. The organic layer was separated, washed with brine, and concentrated. The residue was chromatographed on a silica gel column eluted with EtOAc:hexanes to provide 3.2 g of 112 as a colorless oil (85% yield). 1H NMR (CDCl3) δ: 5.48 (1H, d, J=10.97 Hz), 5.83 (1H, d, J=17.62 Hz), 6.68 (1H, dd, J=10.97, 17.62 Hz), 7.52 (1H, d, J=1.60 Hz), 8.20 (1H, d, J=1.60 Hz). LC/MS (M+1): m/z=158.
Reaction SMILES: [C:1]([SiH2:5][O:6][C:7]([CH3:19])([CH3:18])[C:8]1[CH:9]=[C:10]([CH2:15][CH2:16][NH2:17])[CH:11]=[CH:12][C:13]=1[Cl:14])([CH3:4])([CH3:3])[CH3:2].[CH:20](=O)[CH3:21].[BH4-].[Na+]>CO>[C:1]([SiH2:5][O:6][C:7]([CH3:19])([CH3:18])[C:8]1[CH:9]=[C:10]([CH2:15][CH2:16][NH:17][CH2:20][CH3:21])[CH:11]=[CH:12][C:13]=1[Cl:14])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)[SiH2]OC(C)(C)c1cc(CCN)ccc1Cl
Reactant: CC=O
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CCNCCc1ccc(Cl)c(C(C)(C)O[SiH2]C(C)(C)C)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 27.9 %

Procedure:
A mixture of 2-[3-(tert-butyl-dimethyl-silanyloxymethyl)-4-chloro-phenyl]-ethylamine (1.05 g, 3.50 mmol) and acetaldehyde (1.19 mL, 21.0 mmol) in MeOH (35 mL) was heated to reflux for 4 h. The mixture was allowed to cool to rt and NaBH4 (198 mg, 5.25 mmol) was added in portions. The mixture was stirred at rt for 1 h, and the solvents were removed under reduced pressure. The resulting oil was diluted with EtOAc, and the mixture was washed with aq. sat. NaHCO3 and brine. The org. layer was dried over MgSO4, filtered, and the solvents were removed under reduced pressure. Purification of the crude by FC (CH2Cl2/MeOH 19:1→9:1) yielded the title compound (320 mg, 28%). LC-MS: tR=0.90 min; ES+: 369.22.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([O:8][CH3:9])[CH:5]=[C:4]([O:10][CH3:11])[N:3]=1.C(N(CC)CC)C.[C:19]1([C:25]#[CH:26])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.CCCCCC>[N+](CCCC)(CCCC)(CCCC)CCCC.[I-].CN(C=O)C.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>[CH3:11][O:10][C:4]1[CH:5]=[C:6]([O:8][CH3:9])[N:7]=[C:2]([C:26]#[C:25][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[N:3]=1
Reactant: COc1cc(OC)nc(Cl)n1
Reactant: C#Cc1ccccc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: COc1cc(OC)nc(C#Cc2ccccc2)n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 45.9 %

Procedure:
2-Chloro-4,6-dimethoxypyrimidine (500 mg, 2.9 mmol), PdCl2(PPh3)2 (200 mg, 0.28 mmol), CuI (160 mg, 0.84 mmol), triethylamine (4.8 mL, 34 mmol), and n-Bu4NI (3.2 g, 8.7 mmol) were combined in DMF (24 mL). The mixture was cooled in an ice bath and then phenylacetylene (1.25 mL, 11.4 mmol) was added. The reaction mixture was allowed to warm to ambient temperature. After 2.5 h at ambient temperature the reaction mixture was heated to 45-50° C. After 2 h, additional phenylacetylene (1.0 mL, 9.1 mmol) was added. After an additional 17 h stirring at 45-50° C., the reaction mixture was filtered through a pad of Celite™, and the filter pad was washed thoroughly with ethyl acetate. The combined filtrates were washed with brine (4×20 mL), dried over MgSO4, filtered and concentrated in vacuo. The resulting black oil was purified by column chromatography eluting with hexane, 90:10, then 85:15 hexane:ethyl acetate to afford product contaminated with an impurity. Careful column chromatography of this impure material eluting with hexane then 90:10 hexane:ethyl acetate afforded 4,6-dimethoxy-2-(phenylethynyl)pyrimidine (320 mg, 46% yield) as a yellow solid. This material was carried on to the salt formation without further purification.
Reaction SMILES: Cl[C:2]1[C:3]([C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=2)=[N:4][C:5]2[C:10]([N:11]=1)=[CH:9][C:8]([C:12]([O:14][CH3:15])=[O:13])=[CH:7][CH:6]=2.[O:23]1[CH2:28][CH2:27][CH:26]([NH2:29])[CH2:25][CH2:24]1.CCN(C(C)C)C(C)C>CS(C)=O.ClCCl>[F:22][C:19]1[CH:20]=[CH:21][C:16]([C:3]2[C:2]([NH:29][CH:26]3[CH2:27][CH2:28][O:23][CH2:24][CH2:25]3)=[N:11][C:10]3[C:5](=[CH:6][CH:7]=[C:8]([C:12]([O:14][CH3:15])=[O:13])[CH:9]=3)[N:4]=2)=[CH:17][CH:18]=1
Reactant: NC1CCOCC1
Reactant: COC(=O)c1ccc2nc(-c3ccc(F)cc3)c(Cl)nc2c1
Solvent: CS(C)=O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)c1ccc2nc(-c3ccc(F)cc3)c(NC3CCOCC3)nc2c1
Temperature: 100 °C
Reaction time: 8 h
Yield: 74.9 %

Procedure:
To a solution of methyl 3-chloro-2-(4-fluorophenyl)quinoxaline-6-carboxylate (200.0 mg, 0.63 mmol) in DMSO (1.5 mL) was added tetrahydro-2H-pyran-4-amine (127.8 mg, 1.26 mmol), DIEA (163.3 mg, 1.27 mmol) under nitrogen atmosphere. After stirring overnight at 100° C., the reaction mixture was dissolved in dichloromethane (30 mL), washed with water (3×10 mL), dried over anhydrous magnesium sulfate and concentrated under reduced pressure to afford a residue, which was purified by a silica gel column with 0.01%-0.1% ethyl acetate in petroleum ether to afford methyl 2-(4-fluorophenyl)-3-(tetrahydro-2H-pyran-4-ylamino)quinoxaline-6-carboxylate as a light yellow solid (180.0 mg, 75%).
Reaction SMILES: [N:1]1([C:7]([N:9]2[CH2:14][CH:13]([C:15]3[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=3)[CH2:12][CH:11]([C:25]([O:27]C)=[O:26])[CH2:10]2)=[O:8])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.CC(C)([O-])C.[K+]>>[N:1]1([C:7]([N:9]2[CH2:14][CH:13]([C:15]3[CH:20]=[CH:19][C:18]([C:21]([F:23])([F:24])[F:22])=[CH:17][CH:16]=3)[CH2:12][CH:11]([C:25]([OH:27])=[O:26])[CH2:10]2)=[O:8])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1
Reactant: COC(=O)C1CC(c2ccc(C(F)(F)F)cc2)CN(C(=O)N2CCOCC2)C1
Agent: CC(C)(C)[O-]
Agent: [K+]
Product: O=C(O)C1CC(c2ccc(C(F)(F)F)cc2)CN(C(=O)N2CCOCC2)C1

Procedure:
According to General Method 4A, 22.19 g (39.90 mmol) of the compound from Example 3A and 44.78 g (399.0 mmol) of potassium tert-butoxide were reacted. The reaction led selectively to the cis isomer. Yield: 18.29 g (100% of theory)