Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[C:3]([NH:12][C:13]2[CH:18]=[CH:17][C:16]([C:19]#[C:20][CH2:21][O:22][CH3:23])=[CH:15][C:14]=2[F:24])=[C:4]([CH:8]=[CH:9][C:10]=1[F:11])[C:5]([OH:7])=[O:6]>C(O)C.[Pd]>[F:1][C:2]1[C:3]([NH:12][C:13]2[CH:18]=[CH:17][C:16]([CH2:19][CH2:20][CH2:21][O:22][CH3:23])=[CH:15][C:14]=2[F:24])=[C:4]([CH:8]=[CH:9][C:10]=1[F:11])[C:5]([OH:7])=[O:6]
Reactant: COCC#Cc1ccc(Nc2c(C(=O)O)ccc(F)c2F)c(F)c1
Agent: [Pd]
Solvent: CCO
Product: COCCCc1ccc(Nc2c(C(=O)O)ccc(F)c2F)c(F)c1
Yield: 65 %

Procedure:
The product of Example 25, Step B, 3,4-difluoro-2-[[2-fluoro-4-(3-methoxy-1-propynyl)phenyl]amino]benzoic acid, was hydrogenated in absolute ethanol in the presence of 5% Pd/C as above in Example 1, Step D. The resulting crude solid was purified by filtration through a plug of silica gel (50% EtOAc/hexanes as eluant) to give 3,4-difluoro-2-[[2-fluoro-4-(3-methoxypropyl)phenyl]amino]benzoic acid as a white solid (65%); m.p. (Et2O/hexanes) 125-127° C. 1H NMR [400 MHz, (CD3)2SO] δ 13.35 (br s, 1 H), 9.27 (br s, 1 H), 7.82 (ddd, J=8.3, 6.1, 1.9 Hz, 1 H), 7.08 (dd, J=12.4, 1.7 Hz, 1 H), 7.05-6.96 (m, 2 H), 6.93 (dd, J=8.2, 1.8 Hz, 1 H), 3.33 (t, J=6.4 Hz, 2 H), 3.23 (s, 3 H), 2.59 (t, J=7.7 Hz, 2 H), 1.83-1.73 (m, 2 H). Anal. Calcd for C17H16F3NO3: C, 60.2; H, 4.8; N, 4.1. Found: C, 60.2; H, 4.7; N, 4.1.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[C:13](I)[CH:12]=[CH:11][C:10]=1[N:16]1[S:20](=[O:22])(=[O:21])[N:19]([CH2:23][CH2:24][Si:25]([CH3:28])([CH3:27])[CH3:26])[C:18](=[O:29])[CH2:17]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:30]([O:34][C:35]([N:37]1[CH2:42][CH2:41][CH2:40][CH2:39][CH:38]1[CH:43]=[CH2:44])=[O:36])([CH3:33])([CH3:32])[CH3:31].C(N(CC)CC)C.C(P(C(C)(C)C)C1C=CC=CC=1C1C=CC=CC=1P(C(C)(C)C)C(C)(C)C)(C)(C)C>CC#N.CC([O-])=O.CC([O-])=O.[Pd+2]>[C:30]([O:34][C:35]([N:37]1[CH2:42][CH2:41][CH2:40][CH2:39][CH:38]1/[CH:43]=[CH:44]/[C:13]1[CH:12]=[CH:11][C:10]([N:16]2[CH2:17][C:18](=[O:29])[N:19]([CH2:23][CH2:24][Si:25]([CH3:28])([CH3:27])[CH3:26])[S:20]2(=[O:22])=[O:21])=[C:9]([O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH:14]=1)=[O:36])([CH3:33])([CH3:32])[CH3:31]
Reactant: C[Si](C)(C)CCN1C(=O)CN(c2ccc(I)cc2OCc2ccccc2)S1(=O)=O
Reactant: C=CC1CCCCN1C(=O)OC(C)(C)C
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)P(c1ccccc1-c1ccccc1P(C(C)(C)C)C(C)(C)C)C(C)(C)C
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CC(C)(C)OC(=O)N1CCCCC1/C=C/c1ccc(N2CC(=O)N(CC[Si](C)(C)C)S2(=O)=O)c(OCc2ccccc2)c1
Temperature: 100 °C
Reaction time: 4 h

Procedure:
To a solution of 5-(2-benzyloxy-4-iodophenyl)-1,1-dioxo-2-(2-trimethylsilanylethyl)-1,2,5-thiadiazolidin-3-one (120 mg, 0.22 mmol) in MeCN (2 mL) is added 2-vinylpiperidine-1-carboxylic acid tert-butyl ester (51 mg, 0.242 mmol), triethylamine (33 mg, 0.33 mmol), 2,2′-bis(di-t-butylphosphino)biphenyl (2.6 mg) and Pd(OAc)2 (1.0 mg). The vessel is flushed with nitrogen and the mixture is stirred at 100° C. for 4 h. The mixture is partitioned between EtOAc/water and the organic phase is washed with water, brine and dried over sodium sulfate. The solvent is removed under reduced pressure and the residue is purified by flash chromatography using a gradient of EtOAc/hexane (5 to 25%) as eluent to give the title compound.
Reaction SMILES: S(Cl)([Cl:3])=O.[ClH:5].Cl.[CH3:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([CH3:14])[C:9]=1[NH:15][CH2:16][CH:17]([NH:19][CH2:20][CH2:21]O)[CH3:18]>C1(C)C=CC=CC=1>[ClH:3].[ClH:5].[CH3:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([CH3:14])[C:9]=1[NH:15][CH2:16][CH:17]([NH:19][CH2:20][CH2:21][Cl:5])[CH3:18]
Reactant: Cc1cccc(C)c1NCC(C)NCCO
Reactant: O=S(Cl)Cl
Agent: Cl
Solvent: Cc1ccccc1
Product: Cc1cccc(C)c1NCC(C)NCCCl
Temperature: 80 °C
Reaction time: 3 h
Yield: 92 %

Procedure:
4 ml of thionyl chloride are added to a suspension of 10.0 g (35.1 mmoles) of 1-(2,6-dimethylphenyl-amino)-2-(2hydroxyethylamino)-propane dihydrochloride, prepared as des ribed in Example 49, in 100 ml of dry toluene, and the mixture is stirred at 80° C. for 3 hours and then at 100° C. for one hour. The mixture is cooled, the separated precipitate is filtered off, washed with toluene and dried. 10.1 g (92%) of 1-(2,6-dimethylphenyl-amino)-2-(2-chloro-ethylamino)-propane dihydrochloride are obtained; m.p.: 163°-168° C.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[CH3:7][C@H:8]([O:12][C:13]1[CH:14]=[C:15]([CH:19]=[C:20]([O:22][C:23]2[CH:35]=[CH:34][C:26]3[C:27](=[O:33])[N:28]([CH3:32])[CH2:29][CH2:30][O:31][C:25]=3[CH:24]=2)[CH:21]=1)[C:16]([OH:18])=O)[CH2:9][O:10][CH3:11].[NH2:36][C:37]1[CH:42]=[N:41][C:40]([CH3:43])=[CH:39][N:38]=1.N1C=CC=CC=1>CN(C=O)C.C(Cl)Cl>[CH3:7][C@H:8]([O:12][C:13]1[CH:14]=[C:15]([CH:19]=[C:20]([O:22][C:23]2[CH:35]=[CH:34][C:26]3[C:27](=[O:33])[N:28]([CH3:32])[CH2:29][CH2:30][O:31][C:25]=3[CH:24]=2)[CH:21]=1)[C:16]([NH:36][C:37]1[CH:42]=[N:41][C:40]([CH3:43])=[CH:39][N:38]=1)=[O:18])[CH2:9][O:10][CH3:11]
Reactant: COC[C@H](C)Oc1cc(Oc2ccc3c(c2)OCCN(C)C3=O)cc(C(=O)O)c1
Reactant: Cc1cnc(N)cn1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: c1ccncc1
Product: COC[C@H](C)Oc1cc(Oc2ccc3c(c2)OCCN(C)C3=O)cc(C(=O)Nc2cnc(C)cn2)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 45.8 %

Procedure:
Oxalyl chloride (0.17 mL, 1.94 mmol) and DMF (1 drop) were added to a solution of 3-{[(1S)-1-methyl-2-(methyloxy)ethyl]oxy}-5-[(4-methyl-5-oxo-2,3,4,5-tetrahydro-1,4-benzoxazepin-8-yl)oxy]benzoic acid (625 mg, 1.56 mmol) in DCM (15 mL) and the mixture stirred at RT for 4 hours. The solvent was evaporated in vacuo to a residue which was added to a solution of 2-amino-5-methylpyrazine (255 mg, 2.34 mmol) and pyridine (0.64 mL, 7.8 mmol) in DCM (5 mL). The resultant mixture was heated at 60° C. in a microwave reactor for 5 minutes. The mixture was cooled to RT and pressure, the DCM was evaporated in vacuo to a residue which was partitioned between ethyl acetate (50 mL) and 1N citric acid (25 mL). The organic layer was washed with 1N citric acid (25 mL), brine, dried (MgSO4) and evaporated in vacuo to a residue which was chromatographed on silica, eluting with ethyl acetate, to give the desired compound (352 mg).
Reaction SMILES: CON(C)[C:4](=[O:18])[C@H:5]([CH2:14][CH:15]([CH3:17])[CH3:16])[NH:6][C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8].[CH:20]([Mg]Br)=[CH2:21].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>O1CCCC1>[C:10]([O:9][C:7]([NH:6][C@@H:5]([CH2:14][CH:15]([CH3:16])[CH3:17])[C:4](=[O:18])[CH:20]=[CH2:21])=[O:8])([CH3:11])([CH3:12])[CH3:13]
Reactant: C=C[Mg]Br
Reactant: CON(C)C(=O)[C@H](CC(C)C)NC(=O)OC(C)(C)C
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: C1CCOC1
Product: C=CC(=O)[C@H](CC(C)C)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 53.9 %

Procedure:
A solution of 1.01 g (3.69 mmol) of the resultant compound of Example 29 in 50 ml of anhydrous tetrahydrofuran was cooled under N2 atmosphere to -78° C. and treated with 16 ml (9.6 mmol) of vinylmagnesium bromide (0.6M in tetrahydrofuran). The resulting solution was allowed to warm to ambient temperature, stirred for 1.5 h, and poured over a mixture of ice and 10% aqueous citric acid. The mixture was extracted with ether, washed with saturated brine, dried over MgSO4, and concentrated in vacuo. Silica gel chromatography of the residue using 12% ethyl acetate in hexane provided 0.48 g (58%) of the desired compound (Rf 0.48, 7:3 hexane:ethyl acetate). 1H NMR (CDCl3) δ 0.93 (d, J=7 Hz, 3 H), 1.00 (d, J=7 Hz, 1 H), 1.3-1.45 (m, 2 H), 1.43 (s, 9 H), 1.74 (m, 1 H), 4.65 (td, J=9, 4 H, 1 H), 5.09 (br d, 1 H), 5.88 (dd, J=10, 2 Hz, 1 H), 6.38 (dd, J=18, 2 Hz, 1 H), 6.48 (dd, J=18, 10 Hz, 1 H). Mass spectrum: (M+H)+ =242.
Reaction SMILES: [NH2:1][C@H:2]([C:4]1[N:8]([C:9]2[CH:10]=[C:11]([CH:14]=[CH:15][CH:16]=2)[C:12]#[N:13])[C:7]2[CH:17]=[CH:18][CH:19]=[CH:20][C:6]=2[N:5]=1)[CH3:3].Cl[C:22]1[N:30]=[CH:29][N:28]=[C:27]2[C:23]=1[N:24]=[CH:25][N:26]2C1CCCCO1.CCN(C(C)C)C(C)C>C(O)CCC>[N:30]1[C:22]([NH:1][C@H:2]([C:4]2[N:8]([C:9]3[CH:10]=[C:11]([CH:14]=[CH:15][CH:16]=3)[C:12]#[N:13])[C:7]3[CH:17]=[CH:18][CH:19]=[CH:20][C:6]=3[N:5]=2)[CH3:3])=[C:23]2[C:27]([NH:26][CH:25]=[N:24]2)=[N:28][CH:29]=1
Reactant: Clc1ncnc2c1ncn2C1CCCCO1
Reactant: C[C@H](N)c1nc2ccccc2n1-c1cccc(C#N)c1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCCCO
Product: C[C@H](Nc1ncnc2[nH]cnc12)c1nc2ccccc2n1-c1cccc(C#N)c1
Temperature: 90 °C
Yield: 36.3 %

Procedure:
A mixture of 3-[2-((S)-1-aminoethyl)benzoimidazol-1-yl]benzonitrile (54 mg, 0.21 mmol), 6-chloro-9-(tetrahydropyran-2-yl)-9H-purine (69 mg, 0.29 mmol) and DIPEA (65 mL, 0.37 mmol) in n-butanol (0.5 mL) was heated at 90° C. in a sealed vial for 16 h. After cooling to RT, the crude reaction mixture was loaded onto an Isolute® SCX-2 cartridge and washed with MeOH followed by 2M NH3/MeOH. The basic fractions were combined and concentrated in vacuo. The resulting residue was purified by column chromatography (Si—PCC, gradient 0-10% 2M NH3/MeOH in DCM) then by preparative HPLC (Phenomenex Gemini 5 μm C18 on a gradient 20-98%, 0.1% HCO2H in acetonitrile/water) to afford 170 as a white solid (29 mg, 37%). LCMS (Method K): RT 3.03 min [M+H]+ 381.0. 1H NMR (DMSO-d6, 400 MHz): δ 12.90 (1H, s), 8.25-7.49 (8H, m), 7.32-7.17 (2H, m), 7.09 (1H, d, J=7.84 Hz), 5.60 (1H, s), 1.64 (3H, d, J=6.81 Hz)
Reaction SMILES: [NH:1]1[CH2:8][CH2:7][CH2:6][C@H:2]1[C:3]([OH:5])=[O:4].C([O-])(O)=O.[Na+].[CH2:14]([O:21][C:22]([NH:24][C@@H:25]([CH2:29][CH3:30])[C:26](O)=[O:27])=[O:23])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.Cl>O.C(COC)OC>[CH2:14]([O:21][C:22]([NH:24][C@@H:25]([CH2:29][CH3:30])[C:26]([N:1]1[CH2:8][CH2:7][CH2:6][C@H:2]1[C:3]([OH:5])=[O:4])=[O:27])=[O:23])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: O=C(O)[C@@H]1CCCN1
Reactant: CC[C@H](NC(=O)OCc1ccccc1)C(=O)O
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: CC[C@H](NC(=O)OCc1ccccc1)C(=O)N1CCC[C@H]1C(=O)O
Reaction time: 5 h

Procedure:
A solution of 2.1395 g of L-proline (18.6 mmol) and 1.56 g of NaHCO3 (18.6 mmol) in water (20 ml) is treated with a solution of 4.138 g of the succinimide ester of N-benzyloxycarbonyl-2(S)-aminobutyric acid (12.4 mmol) prepared as in Example 3 b), in dimethoxyethane (25 ml). After 5 hours, 12.4 ml of water are added, the resulting mixture is acidified to pH=2 with concentrated HCl and is extracted with ethyl acetate. The extracts are dried and are evaporated, which leads to a syrup.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH:4]([CH:7]=[CH:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH2:3][CH2:2]1>C(O)C.[C].[Pd]>[O:1]1[CH2:6][CH2:5][CH:4]([CH2:7][CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH2:3][CH2:2]1
Reactant: CCOC(=O)C=CC1CCOCC1
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)CCC1CCOCC1
Yield: 87.3 %

Procedure:
A solution of ethyl 3-(3,4,5,6-tetrahydro-2H-pyran-4-yl)acrylate (17 g) in ethanol (200 ml) is catalytically hydrogenated over 10% palladium-carbon (4 g, 50% wet) at room temperature under atmospheric pressure. After the absorption of hydrogen has ceased, the catalyst is removed by filtration and the filtrate is concentrated in vacuo. The oily residue is purified by vacuum distillation to give ethyl 3-(3,4,5,6-tetrahydro-2H-pyran-4-yl)propionate (15 g) as an oil.
Reaction SMILES: [C:1]1([C:7]2[N:8]=[C:9]([CH2:18][CH2:19][CH:20]=O)[O:10][C:11]=2[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.[CH2:23]([O:30][NH2:31])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>>[CH2:23]([O:30][N:31]=[CH:20][CH2:19][CH2:18][C:9]1[O:10][C:11]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[C:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[N:8]=1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: NOCc1ccccc1
Reactant: O=CCCc1nc(-c2ccccc2)c(-c2ccccc2)o1
Agent: Cl
Product: C(CCc1nc(-c2ccccc2)c(-c2ccccc2)o1)=NOCc1ccccc1

Procedure:
The process described in Method A was followed. 3-(4,5-Diphenyl-1,3-oxazol-2-yl)propanal (416 mg, 1.5 mmol, see Pridgen L. N. et al in Tetrahedron Lett., 25(27), 2835 (1984)) and O-benzylhydroxylamine hydrochloride (319 mg, 2.0 mmol) were used to obtain the title compound.
Reaction SMILES: [C:1]([CH2:3][C:4]([OH:6])=O)#[N:2].C(OC(=O)C)(=O)C.[Cl:14][C:15]1[CH:16]=[C:17]([CH:23]=[CH:24][CH:25]=1)[CH2:18][NH:19][C:20]([NH2:22])=[O:21]>C1COCC1>[Cl:14][C:15]1[CH:16]=[C:17]([CH:23]=[CH:24][CH:25]=1)[CH2:18][NH:19][C:20]([NH:22][C:4](=[O:6])[CH2:3][C:1]#[N:2])=[O:21]
Reactant: NC(=O)NCc1cccc(Cl)c1
Reactant: N#CCC(=O)O
Solvent: CC(=O)OC(C)=O
Solvent: C1CCOC1
Product: N#CCC(=O)NC(=O)NCc1cccc(Cl)c1
Reaction time: 4 h
Yield: 84.8 %

Procedure:
3.76 g of 98% cyanoacetic acid and 14 ml of acetic anhydride were heated for 1 hour at 65° C. A solution of 7.73 g of (3-chlorobenzyl)urea in 55 ml THF was added and the mixture kept for 4 hours at 65° C. The THF was removed in vacuo and the residue diluted with 50 ml of toluene. The solid was collected and washed to give the title compound (8.94 g) as a white solid.
Reaction SMILES: [C:1]([O:5][C:6](=[O:18])[CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][C:10]=1[C:16]#[CH:17])([CH3:4])([CH3:3])[CH3:2].Br[C:20]1[CH:25]=[C:24]([CH2:26][O:27][CH3:28])[CH:23]=[CH:22][C:21]=1[F:29]>>[C:1]([O:5][C:6](=[O:18])[CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][C:10]=1[C:16]#[C:17][C:20]1[CH:25]=[C:24]([CH2:26][O:27][CH3:28])[CH:23]=[CH:22][C:21]=1[F:29])([CH3:4])([CH3:3])[CH3:2]
Reactant: COCc1ccc(F)c(Br)c1
Reactant: C#Cc1cc(Cl)ccc1OCC(=O)OC(C)(C)C
Product: COCc1ccc(F)c(C#Cc2cc(Cl)ccc2OCC(=O)OC(C)(C)C)c1

Procedure:
Following the general method as outlined in Intermediate 19, starting from tert-butyl(4-chloro-2-ethynylphenoxy)acetate (Intermediate 3) and 2-bromo-1-fluoro-4-(methoxymethyl)benzene (Intermediate 15), the title compound was obtained as a dark yellow sticky solid after purification by flash column chromatography (silica), eluting with cyclohexane containing increasing amounts of EtOAc.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[C:4]([F:20])=[C:5]([O:10][C:11]2[CH:12]=[C:13]([CH:16]=[C:17]([Cl:19])[CH:18]=2)[C:14]#[N:15])[C:6]([Cl:9])=[CH:7][CH:8]=1.CCN(C(C)C)C(C)C.[CH3:30][C:31]1[N:32]=[N:33][S:34][C:35]=1[C:36](O)=[O:37].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C.CO>[Cl:9][C:6]1[CH:7]=[CH:8][C:3]([CH2:2][NH:1][C:36]([C:35]2[S:34][N:33]=[N:32][C:31]=2[CH3:30])=[O:37])=[C:4]([F:20])[C:5]=1[O:10][C:11]1[CH:12]=[C:13]([C:14]#[N:15])[CH:16]=[C:17]([Cl:19])[CH:18]=1
Reactant: Cc1nnsc1C(=O)O
Reactant: N#Cc1cc(Cl)cc(Oc2c(Cl)ccc(CN)c2F)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CO
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1nnsc1C(=O)NCc1ccc(Cl)c(Oc2cc(Cl)cc(C#N)c2)c1F
Reaction time: 8 h
Yield: 40 %

Procedure:
In a 1 dram vial, 3-{[3-(aminomethyl)-6-chloro-2-fluorophenyl]oxy}-5-chlorobenzonitrile (25 mg, 0.080 mmol), DIPEA (0.014 mL, 0.080 mmol) and 4-methyl-1,2,3-thiadiazole-5-carboxylic acid (11.58 mg, 0.080 mmol) were dissolved in DMF (1 mL). HATU was added (30.6 mg, 0.080 mmol) and the solution stirred overnight. The reaction mixture was diluted to 2 mL with MeOH. Purification was accomplished by Reverse-Phase HPLC (water/acetonitrile with 0.1% TFA) to afford the title compound (0.014 g, 39%) as a white solid. 1H NMR (400 MHz, Acetone-d6): δ ppm 8.50 (br. s., 1H), 7.64 (t, 1H), 7.48-7.55 (m, 1H), 7.42-7.46 (m, 1H), 7.36-7.41 (m, 2H), 4.68 (d, 2H), 2.81-2.86 (m, 3H). LCMS m/z 436.8 (M+1).
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10]([OH:12])=[O:11])=[CH:5][CH:4]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Na+].C1COCC1.[Cl:28][CH2:29][CH2:30][CH2:31][CH2:32]I>>[Cl:28][CH2:29][CH2:30][CH2:31][CH2:32][CH:9]([C:6]1[CH:5]=[CH:4][C:3]([S:2][CH3:1])=[CH:8][CH:7]=1)[C:10]([OH:12])=[O:11]
Reactant: CSc1ccc(CC(=O)O)cc1
Reactant: ClCCCCI
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: C1CCOC1
Product: CSc1ccc(C(CCCCCl)C(=O)O)cc1
Yield: 90.9 %

Procedure:
Step AAL (1): 2-(4-(Methylthio)phenyl)acetic acid (1.00 g, 5.49 mmol) was deprotonated with NaHMDS 2.0 M in THF (5.49 mL, 11.0 mmol) and reacted with 1-chloro-4-iodobutane (0.672 mL, 5.49 mmol) using a procedure analogous to Step AC (1) to afford 6-chloro-2-(4-(methylthio)phenyl)hexanoic acid (1.36 g, 4.99 mmol, 91% yield) as a pale-yellow oil. LC-MS (M−H)− 271.1. 1H NMR (500 MHz, CHLOROFORM-d) δ ppm 8.95 (1 H, br. s.), 7.12-7.28 (4 H, m), 3.39-3.55 (3 H, m), 2.39-2.50 (3 H, m), 1.97-2.19 (1 H, m), 1.59-1.86 (3 H, m), 1.28-1.51 (2 H, m).
Reaction SMILES: [CH2:1]([NH:3][CH2:4][CH3:5])[CH3:2].[O:6]1[CH2:10][CH:7]1[CH:8]=[CH2:9]>C1COCC1.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH2:1]([N:3]([CH2:9][CH:8]=[CH:7][CH2:10][OH:6])[CH2:4][CH3:5])[CH3:2]
Reactant: C=CC1CO1
Reactant: CCNCC
Agent: [Pd]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCN(CC)CC=CCO
Temperature: 25 °C
Reaction time: 36 h
Yield: 80 %

Procedure:
0.4 g of polymer-bound triphenylphosphine palladium(0) from Aldrich Chemical Co., Inc., Milwaukee, Wisconsin, Catalogue No. 24815-0 was suspended in 20 ml of THF, followed by 1.42 ml (14.3 mmol) diethylamine and 1.15 ml (14.3 mmol) 3,4-epoxy-1-butene. The reaction mixture was stirred at room temperature for 36 hours. The catalyst was removed by filtration and the filtrate was concentrated by evaporation at reduced pressure. The residue was distilled at reduced pressure. The reaction resulted in an 80% yield of 4-(N,N-diethylamino)-2-buten-1-ol. None of the isomeric 1,2 adduct was detected. The increased ratio of 4-(N,N-diethylamino)-2-buten-1-ol produced as compared to the approximately 1:1 ratio seen in Example 1 (with an unbound catalyst) has tremendous manufacturing advantages when extrapolated out to production scale synthesis.
Reaction SMILES: Cl[C:2]1[C:3]2[N:4]([C:15]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[N:16][N:17]=2)[CH:5]=[C:6]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH:7]=1.[Br-].[CH3:25][C:26]1[CH:27]=[CH:28][C:29]([Zn+])=[N:30][CH:31]=1>O1CCOCC1.CC(C)([P](C(C)(C)C)([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)C(C)(C)C)C>[CH3:25][C:26]1[CH:27]=[CH:28][C:29]([C:2]2[C:3]3[N:4]([C:15]([C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)=[N:16][N:17]=3)[CH:5]=[C:6]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH:7]=2)=[N:30][CH:31]=1
Reactant: CC(C)(C)OC(=O)c1cc(Cl)c2nnc(-c3ccccc3)n2c1
Reactant: Cc1ccc([Zn+])nc1
Agent: CC(C)(C)[P]([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)(C(C)(C)C)C(C)(C)C
Agent: [Br-]
Solvent: C1COCCO1
Product: Cc1ccc(-c2cc(C(=O)OC(C)(C)C)cn3c(-c4ccccc4)nnc23)nc1
Temperature: 75 °C
Yield: 26.6 %

Procedure:
To a degassed solution of tert-butyl 8-chloro-3-phenyl[1,2,4]triazolo[4,3-a]pyridine-6-carboxylate (0.22 g, 0.67 mmol) and bis(tri-tert-butylphosphine)palladium(0) (17.1 mg, 33 μmol) in dioxane (2 mL) was added 5-methyl-2-pyridylzinc bromide (0.5 M in THF; 4.0 mL, 2.0 mmol). The mixture was heated 75° C. After 181, the mixture was cooled to ambient temperature and concentrated. Saturated aqueous sodium bicarbonate was added and the mixture was extracted with dichloromethane (3×). The combined organic layer was washed with brine, dried over sodium sulfate, filtered and concentrated. Purification by silica gel chromatography (100% hexanes→75% hexanes/ethyl acetate) gave the title compound (69 mg): LC-MS [M+1]=387.1.
Reaction SMILES: Br[C:2]1[CH:17]=[CH:16][C:5]([O:6][C:7]2[N:8]=[C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][N:10]3[CH:15]=2)=[CH:4][CH:3]=1.[NH:18]1[C:22]2=[N:23][CH:24]=[CH:25][CH:26]=[C:21]2[CH2:20][C:19]1=[O:27].CN[C@@H]1CCCC[C@H]1NC.C([O-])([O-])=O.[K+].[K+]>[Cu]I.C1COCC1>[N:8]1[C:7]([O:6][C:5]2[CH:16]=[CH:17][C:2]([N:18]3[C:22]4=[N:23][CH:24]=[CH:25][CH:26]=[C:21]4[CH2:20][C:19]3=[O:27])=[CH:3][CH:4]=2)=[CH:15][N:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=12
Reactant: Brc1ccc(Oc2cn3ccccc3n2)cc1
Reactant: O=C1Cc2cccnc2N1
Agent: [Cu]I
Agent: CN[C@@H]1CCCC[C@H]1NC
Agent: O=C([O-])[O-]
Solvent: C1CCOC1
Product: O=C1Cc2cccnc2N1c1ccc(Oc2cn3ccccc3n2)cc1
Temperature: 180 °C
Yield: 17.2 %

Procedure:
Ethyl 2-chloroimidazo[1,2-a]pyridine-3-carboxylate (2.00 g) was added to a solution of p-bromophenol (1.617 g) and NaH (0.427 g) in DMF (dry) (10 ml) at 100° C. The mixture was stirred at 100° C. under a dry atmosphere overnight. The reaction mixture was diluted with MeOH, and concentrated in vacuo. The residue was purified by column chromatography (silica gel, eluted with 0%-30% EtOAc in hexane) to give ethyl 2-(4-bromophenoxy)imidazo[1,2-a]pyridine-3-carboxylate (1.5 g) as a colorless solid and 2-(4-bromophenoxy)imidazo[1,2-a]pyridine (530 mg) as a colorless solid. The mixture of 2-(4-bromophenoxy)imidazo[1,2-a]pyridine (410 mg), 1,3-dihydro-2H-pyrrolo[2,3-b]pyridine-2-one (164 mg), trans-N,N′-dimethylcyclohexane-1,2-diamine (174 mg), copper(I) iodide (116 mg), K2CO3 (338 mg) and THF (dry) (5 mL) was heated at 180° C. for 3 h under microwave irradiation. The solid was removed by filtration, and the filtrate was concentrated in vacuo. The residue was purified by column chromatography (silica gel, EtOAc/hexane) to give the title compound (72 mg) as an orange solid (mixture with 1,3-dihydro-2H-pyrrolo[2,3-b]pyridine-2-one, ca. 20% purity).
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[C:5]([CH:44]=[CH:45][C:46]=1[CH2:47][CH3:48])[CH2:6][C@@H:7]([NH:23][C:24]([N:26]1[CH2:31][CH2:30][CH:29]([N:32]2[CH2:38][CH2:37][C:36]3[CH:39]=[CH:40][CH:41]=[CH:42][C:35]=3[NH:34][C:33]2=[O:43])[CH2:28][CH2:27]1)=[O:25])[C:8]([N:10]1[CH2:15][CH2:14][N:13]([CH:16]2[CH2:21][CH2:20][N:19]([CH3:22])[CH2:18][CH2:17]2)[CH2:12][CH2:11]1)=[O:9])[CH3:2].[C:49]1([S:55]([OH:58])(=[O:57])=[O:56])[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=1>C(O)(C)C>[CH2:1]([C:3]1[CH:4]=[C:5]([CH:44]=[CH:45][C:46]=1[CH2:47][CH3:48])[CH2:6][C@@H:7]([NH:23][C:24]([N:26]1[CH2:31][CH2:30][CH:29]([N:32]2[CH2:38][CH2:37][C:36]3[CH:39]=[CH:40][CH:41]=[CH:42][C:35]=3[NH:34][C:33]2=[O:43])[CH2:28][CH2:27]1)=[O:25])[C:8]([N:10]1[CH2:11][CH2:12][N:13]([CH:16]2[CH2:17][CH2:18][N:19]([CH3:22])[CH2:20][CH2:21]2)[CH2:14][CH2:15]1)=[O:9])[CH3:2].[C:49]1([S:55]([O-:58])(=[O:57])=[O:56])[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=1
Reactant: O=S(=O)(O)c1ccccc1
Agent: CCc1ccc(C[C@@H](NC(=O)N2CCC(N3CCc4ccccc4NC3=O)CC2)C(=O)N2CCN(C3CCN(C)CC3)CC2)cc1CC
Solvent: CC(C)O
Product: O=S(=O)([O-])c1ccccc1
Temperature: 50 °C
Reaction time: 24 h

Procedure:
1.0 g (1.52 mmol) 4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylic acid-{(R)-1-(3,4-diethyl-benzyl)-2-[4-(1-methyl-piperidin-4-yl)-piperazin-1-yl]-2-oxo-ethyl}-amide and 240 mg (1.52 mmol) benzenesulphonic acid are dissolved in 14 ml boiling isopropanol. The solution is stirred for 24 hours at 50° C. Then the temperature is reduced by 5° C. every 8 hours, during which time a white precipitate is formed. After 3 days and at a final temperature of 25° C. the solid formed is filtered off, washed with 5 ml isopropanol and dried for 12 hours at 50° C.
Reaction SMILES: [NH:1]1[C:5]2=[CH:6][N:7]=[CH:8][CH:9]=[C:4]2[CH:3]=[CH:2]1.[H-].[Na+].I[CH2:13][CH2:14][CH3:15]>CN(C=O)C>[CH2:13]([N:1]1[C:5]2=[CH:6][N:7]=[CH:8][CH:9]=[C:4]2[CH:3]=[CH:2]1)[CH2:14][CH3:15]
Reactant: CCCI
Reactant: c1cc2cc[nH]c2cn1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCn1ccc2ccncc21

Procedure:
A solution of 1H-pyrrolo[2,3-c]pyridine (10 mmol) in DMF cooling on an ice bath was treated with NaH (143 mmol). After stirred at room temperature for thr iodopropane (26 mmol) was added dropwise. The mixture was allowed to react at room temperature for further 3 hrs. Upon cooling on an ice bath the mixture was quenched with 20 mL H2O, followed by extraction with diethyl ether (5×50 mL). The organic layers were combined, washed with brine, dried on MgSO4 and filtered. The solvent was evaporated and dried on a high vacuum to give 1-propyl-1H-pyrrolo[2,3-c]pyridine as orange oil. MS (ESI+) m/z 161.1063 (M+H)+.