Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: I[C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[C:4]([O:9][C:10]([F:13])([F:12])[F:11])[CH:3]=1.[CH3:14][PH:15](=[O:17])[CH3:16].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>CN(C=O)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH3:14][P:15]([C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[C:4]([O:9][C:10]([F:13])([F:12])[F:11])[CH:3]=1)([CH3:16])=[O:17]
Reactant: C[PH](C)=O
Reactant: Nc1ccc(I)cc1OC(F)(F)F
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Solvent: CN(C)C=O
Product: CP(C)(=O)c1ccc(N)c(OC(F)(F)F)c1
Reaction time: 0.33 h

Procedure:
To a solution of 4-iodo-2-(trifluoromethoxy)aniline (0.606 g, 2.00 mmol) in 8 mL DMF was added dimethylphosphine oxide (0.171 g, 2.20 mmol), palladium acetate (22.4 mg, 0.0100 mmol), XANTPHOS (69.4 mg, 0.120 mmol), and potassium phosphate (0.467 g, 2.20 mmol). The mixture was purged with nitrogen, and subjected to microwaves at 150° C. for 20 minutes. The reaction mixture was concentrated and purified by silica gel chromatography (0-20% 7N ammonia in methanol:dichloromethane) and acidified with HCl in methanol to afford the desired product as its hydrochloride salt (0.573 g, 98% yield).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:24])[C@@H:4]1[CH2:8][CH2:7][CH2:6][N:5]1[C:9](=[O:23])[C@H:10]([CH2:19][CH:20]([CH3:22])[CH3:21])[NH:11][C:12]1[S:16][N:15]=[C:14]([CH2:17]Cl)[N:13]=1.[N:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[N:31]1[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]1.C(N(CC)CC)C>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.CN(C=O)C.O.C(OCC)(=O)C>[CH3:1][O:2][C:3](=[O:24])[C@@H:4]1[CH2:8][CH2:7][CH2:6][N:5]1[C:9](=[O:23])[C@H:10]([CH2:19][CH:20]([CH3:22])[CH3:21])[NH:11][C:12]1[S:16][N:15]=[C:14]([CH2:17][N:34]2[CH2:35][CH2:36][N:31]([C:26]3[CH:27]=[CH:28][CH:29]=[CH:30][N:25]=3)[CH2:32][CH2:33]2)[N:13]=1
Reactant: COC(=O)[C@@H]1CCCN1C(=O)[C@H](CC(C)C)Nc1nc(CCl)ns1
Reactant: c1ccc(N2CCNCC2)nc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: COC(=O)[C@@H]1CCCN1C(=O)[C@H](CC(C)C)Nc1nc(CN2CCN(c3ccccn3)CC2)ns1
Temperature: 25 °C
Reaction time: 24 h
Yield: 91.4 %

Procedure:
A mixture of N-(3-chloromethyl-[1,2,4]thiadiazol-5-yl)-L-leucyl-L-proline methyl ester (0.45 g, 1.2 mmol), 1-(2-pyridyl)piperazine (0.62 mL, 4 mmol), triethylamine (1.2 mL, 8 mmol) and tetra-butylammonium bromide (100 mg) in DMF (20 mL) was stirred at room temperature for 24 h. The reaction mixture was diluted with water and ethyl acetate. The organic layer was collected, washed with water, dried (sodium sulfate), filtered and concentrated in vacuo to give a light yellow oil. Purification by column chromatography on silica gel using a solvent mixture of 5% methanol in dichloromethane afforded N-{3-[1-[4-(2-pyridyl)piperazinyl]-methyl]-[1,2,4]thiadiazol-5-yl}-L-leucyl-L-proline methyl ester as a white foam (0.55 g, 91.7 %). 1H-NMR (CDCl3) δ8.19 (m, 1H), 7.48-7.52 (m, 1H), 7.14 (br. m, 1H, NH), 6.64-6.67 (m, 2H), 4.67 (m, 1H, CHCO), 4.57 (dd, J=8.4 and 4.6 Hz, 1H, CHCO2), 3.92 (m, 1H, NCHpro), 3.62-3.78 (m, 1OH, OMe, NCHpro, N=CCH2, 2NCH2), 2.83 (m, 4H, 2NCH2), 1.62-2.30 (m, 6H, 2CH2 pro and CH2), 0.90-1.03 (2d, J=6.5 and 6.6 Hz, 7H, 2Me and 1CH); MS (m/z) 502 (M+ +1), 459, 408, 382, 300, 253, 225, 176, 147, 121, 95.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[CH:19]=[CH:18][C:17]([NH:20][C:21]([C:23]3[NH:24][CH:25]=[C:26]([C:28]#[N:29])[CH:27]=3)=[O:22])=[C:16]([C:30]3[CH2:35][CH2:34][CH2:33][CH2:32][CH:31]=3)[CH:15]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.[C:36]([OH:42])([C:38]([F:41])([F:40])[F:39])=[O:37].CO>C(Cl)Cl.CO>[F:39][C:38]([F:41])([F:40])[C:36]([OH:42])=[O:37].[C:30]1([C:16]2[CH:15]=[C:14]([CH:11]3[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]3)[CH:19]=[CH:18][C:17]=2[NH:20][C:21]([C:23]2[NH:24][CH:25]=[C:26]([C:28]#[N:29])[CH:27]=2)=[O:22])[CH2:35][CH2:34][CH2:33][CH2:32][CH:31]=1
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(NC(=O)c3cc(C#N)c[nH]3)c(C3=CCCCC3)c2)CC1
Solvent: CO
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: N#Cc1c[nH]c(C(=O)Nc2ccc(C3CCNCC3)cc2C2=CCCCC2)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 59 %

Procedure:
A solution of 36.0 mg (0.0759 mmol) 4-{4-[(4-cyano-1H-pyrrole-2-carbonyl)-amino]-3-cyclohex-1-enyl-phenyl}-piperidine-1-carboxylic acid tert-butyl ester (as prepared in the previous step) in 5 mL CH2Cl2 was treated with 4 drops MeOH and 1 mL TFA and stirred at RT for 2 h. MeOH (5 mL) was added, and solvents were evaporated in vacuo. Purification of the residue by RP-HPLC (C18) with 10-80% CH3CN in 0.1% TFA/H2O over 30 min afforded 22.0 mg (59%) of the title compound as a white solid: Mass spectrum (ESI, m/z): Calcd. for C23H26N4O, 375.2 (M+H), found 375.2.
Reaction SMILES: [NH2:1][N:2]1[N:11]=[C:10]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]1=[O:18].[O:19]1[C:23]2[CH:24]=[CH:25][C:26]([CH2:28][C:29](O)=[O:30])=[CH:27][C:22]=2[O:21][CH2:20]1>>[O:19]1[C:23]2[CH:24]=[CH:25][C:26]([CH2:28][C:29]([NH:1][N:2]3[N:11]=[C:10]([N:12]4[CH2:17][CH2:16][O:15][CH2:14][CH2:13]4)[C:9]4[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=4)[C:3]3=[O:18])=[O:30])=[CH:27][C:22]=2[O:21][CH2:20]1
Reactant: Nn1nc(N2CCOCC2)c2ccccc2c1=O
Reactant: O=C(O)Cc1ccc2c(c1)OCO2
Product: O=C(Cc1ccc2c(c1)OCO2)Nn1nc(N2CCOCC2)c2ccccc2c1=O

Procedure:
The product of Example 1B and 2-(1,3-benzodioxol-5-yl)acetic acid were treated using a method similar to that described in Example 111 to give the title compound. 1H NMR (500 MHz, DMSO-d6/Deuterium Oxide) δ ppm 8.31 (dd, J=7.9, 1.3 Hz, 1H), 8.03 (d, J=8.0 Hz, 1H), 7.97-8.01 (m, 1H), 7.89-7.93 (m, 1H), 6.96 (d, J=1.7 Hz, 1H), 6.89 (d, J=7.9 Hz, 1H), 6.84 (dd, J=7.9, 1.7 Hz, 1H), 6.00 (s, 2H), 3.81-3.83 (m, 4H), 3.58 (s, 2H), 3.08-3.10 (m, 4H); MS (ESI+) M/Z 409 (M+H)+.
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[C:3]1[CH:12]=[CH:11][C:10]2[C:5](=[CH:6][C:7]([CH2:13][C:14]([OH:16])=O)=[CH:8][CH:9]=2)[N:4]=1.[Br:19][C:20]1[C:21]([C:26]2[NH:30][CH:29]=[N:28][N:27]=2)=[C:22]([NH2:25])[S:23][CH:24]=1.C1C=NC2N(O)N=NC=2C=1>>[Br:19][C:20]1[C:21]([C:26]2[NH:30][CH:29]=[N:28][N:27]=2)=[C:22]([NH:25][C:14](=[O:16])[CH2:13][C:7]2[CH:6]=[C:5]3[C:10]([CH:11]=[CH:12][C:3]([C:2]([F:1])([F:18])[F:17])=[N:4]3)=[CH:9][CH:8]=2)[S:23][CH:24]=1
Reactant: O=C(O)Cc1ccc2ccc(C(F)(F)F)nc2c1
Reactant: Nc1scc(Br)c1-c1nnc[nH]1
Agent: On1nnc2cccnc21
Product: O=C(Cc1ccc2ccc(C(F)(F)F)nc2c1)Nc1scc(Br)c1-c1nnc[nH]1

Procedure:
The title compound was synthesized via protocol B from 2-(2-(trifluoromethyl)quinolin-7-yl)acetic acid and 4-bromo-3-(4H-1,2,4-triazol-3-yl)thiophen-2-amine, using HOAt instead of HOBt. HPLC purification afforded the product as a white solid. HPLC method [7], retention time 8.68 min; MS (ESI) 484.2 (MH+, 81Br); 1H NMR (300 MHz, CD3OD) δ 8.76 (d, J=9.5 Hz, 1H), 8.25 (d, J=9.0 Hz, 1H), 7.96 (dd, J=8.7, 7.3 Hz, 1H), 7.92-7.81 (m, 1H), 7.11-6.97 (m, 1H), 4.45 (s, 2H).
Reaction SMILES: [F:1][C:2]([F:21])([F:20])[C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]2[C:11]3[CH2:19][CH2:18][NH:17][CH2:16][C:12]=3[N:13]=[CH:14][N:15]=2)=[CH:5][CH:4]=1.Cl[C:23]1[C:28]([Cl:29])=[CH:27][CH:26]=[CH:25][N:24]=1.C(N(CC)C(C)C)(C)C>O1CCOCC1.CN(C)C(=O)C>[Cl:29][C:28]1[C:23]([N:17]2[CH2:18][CH2:19][C:11]3[C:10]([NH:9][C:6]4[CH:5]=[CH:4][C:3]([C:2]([F:1])([F:20])[F:21])=[CH:8][CH:7]=4)=[N:15][CH:14]=[N:13][C:12]=3[CH2:16]2)=[N:24][CH:25]=[CH:26][CH:27]=1
Reactant: Clc1cccnc1Cl
Reactant: FC(F)(F)c1ccc(Nc2ncnc3c2CCNC3)cc1
Solvent: C1COCCO1
Solvent: CC(=O)N(C)C
Solvent: CCN(C(C)C)C(C)C
Product: FC(F)(F)c1ccc(Nc2ncnc3c2CCN(c2ncccc2Cl)C3)cc1
Temperature: 150 °C
Yield: 24.6 %

Procedure:
N-(4-(Trifluoromethyl)phenyl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-amine (700 mg, 3.4 mmol) was dissolved in a mixture of dioxane/N,N-dimethylacetamide (4:1) (2 mL). To the mixture was added 2,3-dichloropyridine (1.5 g, 10.2 mmol) and N,N-diisopropylethylamine (0.87 mL, 5.1 mmol). The mixture was heated in a sealed tube at 150° C. in microwave (Model, Personal Chemistry) for 16 h. The solvents were removed under vacuum and the residue was dissolved in ethyl acetate and washed with sat. NaHCO3 and brine. The organic layer was dried over Na2SO4, filtered and evaporated to give a brown residue. The residue was purified using a gradient of ethyl acetate:hexane (0-100%) to give the desired compound as an off-white powder (340 mg, 26%).
Reaction SMILES: [CH2:1]([O:5][C:6]([C:8]1[N:9]=[C:10]([O:26][CH3:27])[C:11]2[C:16]([C:17]=1[O:18]CC1C=CC=CC=1)=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:7])[CH2:2][CH2:3][CH3:4]>[Pd].CCOC(C)=O>[CH2:1]([O:5][C:6]([C:8]1[N:9]=[C:10]([O:26][CH3:27])[C:11]2[C:16]([C:17]=1[OH:18])=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:7])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOC(=O)c1nc(OC)c2ccccc2c1OCc1ccccc1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CCCCOC(=O)c1nc(OC)c2ccccc2c1O
Reaction time: 16 h
Yield: 92.8 %

Procedure:
A mixture of 4-benzyloxy-1-methoxy-isoquinoline-3-carboxylic acid butyl ester (164 mg, 0.45 mmol), Pd/C (50 mg, 10 wt % Pd) and EtOAc (15 ml) was stirred under a H2-atmosphere at ambient pressure and temperature for 16 h. Then the mixture was filtered through a pad of celite. Celite and filter cake were washed thoroughly with EtOAc and the combined organic phases were concentrated in vacuo to give the title compound as a white solid (115 mg); 1H NMR (CDCl3): δ=11.48 (s, 1H), 8.27 to 8.32 (m, 1H), 8.17 to 8.21 (m, 1H), 7.65 to 7.78 (m, 2H), 4.43 (t, 2H), 4.10 (s, 3H), 1.87 (m, 2H), 1.54 (m, 2H), 1.02 (t, 3H).
Reaction SMILES: FC1C=C(CC(N[C@H](C(O)=O)C)=O)C=C(F)C=1.CCN=C=NCCCN(C)C.Cl.CN1CCOCC1.[F:37][C:38]1[CH:39]=[C:40]([CH2:45][C:46]([NH:48][C@H:49]([C:51]([NH:53][C@H:54]2[C:60](=[O:61])[NH:59][C:58]3[CH:62]=[CH:63][CH:64]=[CH:65][C:57]=3[S:56][C@H:55]2[C:66]2[CH:71]=[C:70]([F:72])[CH:69]=[CH:68][C:67]=2[F:73])=[O:52])[CH3:50])=[O:47])[CH:41]=[C:42]([F:44])[CH:43]=1>ClCCl>[F:37][C:38]1[CH:39]=[C:40]([CH2:45][C:46]([NH:48][C@H:49]([C:51]([NH:53][C@@H:54]2[C:60](=[O:61])[NH:59][C:58]3[CH:62]=[CH:63][CH:64]=[CH:65][C:57]=3[S:56][C@@H:55]2[C:66]2[CH:71]=[C:70]([F:72])[CH:69]=[CH:68][C:67]=2[F:73])=[O:52])[CH3:50])=[O:47])[CH:41]=[C:42]([F:44])[CH:43]=1
Reactant: C[C@H](NC(=O)Cc1cc(F)cc(F)c1)C(=O)N[C@H]1C(=O)Nc2ccccc2S[C@H]1c1cc(F)ccc1F
Agent: CCN=C=NCCCN(C)C
Agent: C[C@H](NC(=O)Cc1cc(F)cc(F)c1)C(=O)O
Agent: Cl
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: C[C@H](NC(=O)Cc1cc(F)cc(F)c1)C(=O)N[C@@H]1C(=O)Nc2ccccc2S[C@@H]1c1cc(F)ccc1F
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a solution of racemic 2,3-cis-3-amino-2-(2,5-difluorophenyl)-2,3-dihydro-1,5-benzothiazepin-4(5H)-one (1d) (300 mg) in dichloromethane (40 mL) at 0° C. under nitrogen was added N-[(3,5-difluorophenyl)acetyl]-L-alanine (1e) (238 mg), HOBt-hydrate (330 mg), EDAC-HCl (282 mg) and NMM (165 mg). The reaction mixture was stirred 1 h at 0° C., concentrated in vacuo and partitioned between water (100 mL) and ethyl acetate (125 mL). The organic phase was collected and consecutively washed with water, saturated aqueous sodium bicarbonate, and brine, dried, filtered and evaporated to yield a mixture of the title compound and N2-[(3,5-difluorophenyl)acetyl]-N1-[(2S,3S)-2-(2,5-difluorophenyl)-4-oxo-2,3,4,5-tetrahydro-1,5-benzothiazepin-3-yl]-L-alaninamide. The crude product (500 mg) was purified by flash chromatography (50% ethyl acetate/hexanes) to afford the title compound (180 mg, 69%) as an off-white solid. 1H NMR (300 MHz, CDCl3) δ1.22 (d, 3H), 3.48 (s, 2H), 4.29 (m, 1H), 4.93 (t, 1H), 5.68 (d, 1H), 6.01 (d, 1H), 6.50 (d, 1H), 6.73-6.80 (m, 3H), 6.93-7.02 (m, 2H), 7.15 (d, 1H), 7.30 (t, 1H), 7.43 (t, 1H), 7.5-7.6 (m, 1H), 7.73 (d, 1H), 7.74 (s, 1H). MS APCI, m/z=532 (M+1). LC/MS: 2.53 min.
Reaction SMILES: [CH2:1]([N:8]1[C:12](=[O:13])[C:11](=[C:14]2[N:18]([CH3:19])[C:17]3[CH:20]=[CH:21][CH:22]=[CH:23][C:16]=3[S:15]2)[S:10][C:9]1=[N:24][C:25]1[CH:26]=[C:27]([NH:34][C:35]([CH2:37][O:38]C(=O)C)=[O:36])[CH:28]=[CH:29][C:30]=1[NH:31][CH2:32][CH3:33])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CO.O.C(=O)([O-])[O-].[K+].[K+]>C(Cl)(Cl)Cl>[CH2:1]([N:8]1[C:12](=[O:13])[C:11](=[C:14]2[N:18]([CH3:19])[C:17]3[CH:20]=[CH:21][CH:22]=[CH:23][C:16]=3[S:15]2)[S:10][C:9]1=[N:24][C:25]1[CH:26]=[C:27]([NH:34][C:35](=[O:36])[CH2:37][OH:38])[CH:28]=[CH:29][C:30]=1[NH:31][CH2:32][CH3:33])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCNc1ccc(NC(=O)COC(C)=O)cc1N=C1SC(=C2Sc3ccccc3N2C)C(=O)N1Cc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClC(Cl)Cl
Solvent: CO
Solvent: O
Product: CCNc1ccc(NC(=O)CO)cc1N=C1SC(=C2Sc3ccccc3N2C)C(=O)N1Cc1ccccc1
Yield: 21.2 %

Procedure:
To a 50 mL flask was added the product of Example 157 (0.19 g, 0.32 mmol), CHCl3 (5 mL), MeOH (10 mL), water (2 mL), and potassium carbonate (0.22 g, 1.6 mmol). After 4 h the reaction mixture was diluted with CHCl3 (40 mL), and the organic phase was partitioned, washed with water (20 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude sample was chromatographed (silica gel, 0–10% MeOH/DCM) to afford the title compound (37 mg, 21%). 1H-NMR (CDCl3): δ 8.14 (1H, s), 7.42–7.48 (3H, m), 7.27–7.33 (5H, m), 7.15 (1H, t), 7.09 (1H, dd), 6.99 (1H, d), 6.56 (1H, d), 5.15 (2H, s), 4.14 (2H, s), 3.71 (3H, s), 2.95 (2H, q), 0.99 (3H, t); MS(ESI): 546(MH+).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[CH:10][C:11]3[O:17][CH2:16][CH2:15][C:14]([C:18](O)=[O:19])=[CH:13][C:12]=3[CH:21]=2)=[CH:4][CH:3]=1.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C.Cl.Cl.[NH2:46][CH:47]1[CH2:52][CH2:51][N:50]([CH2:53][CH2:54][N:55]([CH3:62])[CH:56]2[CH2:61][CH2:60][O:59][CH2:58][CH2:57]2)[CH2:49][CH2:48]1>C(#N)C.C(N(CC)CC)C>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[CH:10][C:11]3[O:17][CH2:16][CH2:15][C:14]([C:18]([NH:46][CH:47]4[CH2:48][CH2:49][N:50]([CH2:53][CH2:54][N:55]([CH3:62])[CH:56]5[CH2:61][CH2:60][O:59][CH2:58][CH2:57]5)[CH2:51][CH2:52]4)=[O:19])=[CH:13][C:12]=3[CH:21]=2)=[CH:4][CH:3]=1
Reactant: Cc1ccc(-c2ccc3c(c2)C=C(C(=O)O)CCO3)cc1
Reactant: CN(CCN1CCC(N)CC1)C1CCOCC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: CC#N
Product: Cc1ccc(-c2ccc3c(c2)C=C(C(=O)NC2CCN(CCN(C)C4CCOCC4)CC2)CCO3)cc1
Reaction time: 1 h
Yield: 36.7 %

Procedure:
Into a solution of 7-(4-methylphenyl)-2,3-dihydro-1-benzooxepine-4-carboxylic acid (150 mg) and 1-hydroxybenzotriazole (0.14 g) in acetonitrile (10 ml) was added at room temperature 1-ethyl-3-(3′-dimethylaminopropyl)carbodiimide hydrochloride (0.20 g), and the resulting mixture was stirred for one hour. Into the reaction mixture was added a solution of 4-amino-1-[2-[N-methyl-N-(tetrahydropyran-4-yl)amino]ethyl]piperidine dihydrochloride (282 mg), triethylamine (0.15 ml.) and diazabicyclo[5,4,0]-7-undecene (0.37 g) in acetonitrile (15 ml), and the resulting mixture was stirred for 18 hours. After the reaction mixture was concentrated under reduced pressure, water was added to the residue and the resulting mixture was extracted with ethyl acetate. The organic layer was washed with an aqueous saturated solution of sodium chloride and was dried with magnesium sulfate. The resulting organic layer was evaporated to remove the solvent, and then the residue was subjected to purification using column chromatography (triethylamine/ethanol/ethyl acetate 1:10:10) and further to recrystallization (ethyl acetate/hexane) to obtain 7-(4-methylphenyl)-N-[1-[2-[N-methyl-N-(tetrahydropyran-4-yl)amino]ethyl]piperidin-4-yl]-2,3-dihydro-1-benzooxepine-4-carboxamide (compound 62) (99 mg) as colorless crystals.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([O:29][C@H:30]2[CH2:34][CH2:33][O:32][CH2:31]2)[C:5]2[C:10]([C:11]3[CH:20]=[CH:19][C:14]4[N:15]=[C:16]([CH3:18])[O:17][C:13]=4[CH:12]=3)=[CH:9][N:8]([CH2:21][O:22][CH2:23][CH2:24][Si:25]([CH3:28])([CH3:27])[CH3:26])[C:6]=2[N:7]=1.[NH2:35][C:36]1[CH:45]=[CH:44][C:39]([C:40]([NH:42][CH3:43])=[O:41])=[CH:38][C:37]=1[CH3:46].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.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]>[CH3:43][NH:42][C:40](=[O:41])[C:39]1[CH:44]=[CH:45][C:36]([NH:35][C:2]2[N:3]=[C:4]([O:29][C@H:30]3[CH2:34][CH2:33][O:32][CH2:31]3)[C:5]3[C:10]([C:11]4[CH:20]=[CH:19][C:14]5[N:15]=[C:16]([CH3:18])[O:17][C:13]=5[CH:12]=4)=[CH:9][N:8]([CH2:21][O:22][CH2:23][CH2:24][Si:25]([CH3:26])([CH3:27])[CH3:28])[C:6]=3[N:7]=2)=[C:37]([CH3:46])[CH:38]=1
Reactant: CNC(=O)c1ccc(N)c(C)c1
Reactant: Cc1nc2ccc(-c3cn(COCC[Si](C)(C)C)c4nc(Cl)nc(O[C@H]5CCOC5)c34)cc2o1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: CNC(=O)c1ccc(Nc2nc(O[C@H]3CCOC3)c3c(-c4ccc5nc(C)oc5c4)cn(COCC[Si](C)(C)C)c3n2)c(C)c1
Temperature: 150 °C
Yield: 63.6 %

Procedure:
To a solution of (S)-6-(2-chloro-4-((tetrahydrofuran-3-yl)oxy)-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-2-methylbenzo[d]oxazole (1 equiv), 4-amino-N,3-dimethylbenzamide (1 equiv), tris(dibenzylideneacetone)dipalladium(0) (0.1 equiv), xantphos (0.2 equiv) in 1,4-dioxane (0.1 M) was added cesium carbonate (1.4 equiv). The reaction was heated, under with microwave irradiation, in a microwave reactor at 150° C. for 2 h. The reaction mixture was quenched with saturated aqueous sodium chloride and then washed with ethyl acetate. The organic phase was combined and washed with saturated aqueous sodium chloride. The organic layer was dried (magnesium sulfate), filtered, and concentrated. The crude was purified by silica gel column chromatography (20-80% ethyl acetate, with 10% 1N ammonia in MeOH in hexane). Concentration of the desired fractions afforded the title compound (63.6% yield) as a yellow solid; MS (ESI) m/z 629.4 [M+1]+.
Reaction SMILES: C[Si](CC[O:7][C:8]([C:10]1[C:11]([NH:21][C:22]([O:24][CH2:25][C:26]2[O:27][C:28]3[CH:34]=[CH:33][C:32]([C:35]4[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=4)=[CH:31][C:29]=3[CH:30]=2)=[O:23])=[N:12][N:13]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:14]=1)=[O:9])(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>CN(C=O)C>[C:15]1([N:13]2[CH:14]=[C:10]([C:8]([OH:9])=[O:7])[C:11]([NH:21][C:22]([O:24][CH2:25][C:26]3[O:27][C:28]4[CH:34]=[CH:33][C:32]([C:35]5[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=5)=[CH:31][C:29]=4[CH:30]=3)=[O:23])=[N:12]2)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: C[Si](C)(C)CCOC(=O)c1cn(-c2ccccc2)nc1NC(=O)OCc1cc2cc(-c3ccccc3)ccc2o1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CN(C)C=O
Product: O=C(Nc1nn(-c2ccccc2)cc1C(=O)O)OCc1cc2cc(-c3ccccc3)ccc2o1
Reaction time: 2 h
Yield: 65.9 %

Procedure:
To a solution of 1-phenyl-3-(5-phenyl-benzofuran-2-ylmethoxycarbonylamino)-1H-pyrazole-4-carboxylic acid trimethylsilylethyl ester (1.27 g, 2.29 mmol) in 10 mL DMF under N2, was added tetra-n-butylammonium fluoride (2.75 mL of 1M THF solution, 2.75 mmol). The mixture was allowed to stir at room temp. for 2 hrs. The solvent was evaporated under high vacuum (60° C. max). Water was added and the mixture was extracted. After addition of 4 mL 1N HCl a white precipitate separated which was filtered off. This material was triturated in 10 mL boiling EtOH to afford 684 mg of 1-phenyl-3-(5-phenyl-benzofuran-2-ylmethoxycarbonylamino)-1H-pyrazole-4-carboxylic acid as a white solid, mp 220.6°-220.8° C.
Reaction SMILES: [CH:1](=[CH:8][C:9](=[O:13])[C:10]([OH:12])=[O:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H][H]>C(O)C.[PdH2]>[C:2]1([CH2:1][CH2:8][C:9](=[O:13])[C:10]([OH:12])=[O:11])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(O)C(=O)C=Cc1ccccc1
Reactant: [H][H]
Agent: [PdH2]
Solvent: CCO
Product: O=C(O)C(=O)CCc1ccccc1
Reaction time: 2 h

Procedure:
Benzalpyruvic acid (2-oxo-4-phenyl-3-butenoic acid) prepared as in step B of Example 2 (26.4 g, 0.15 mol) was dissolved in 150 ml ethanol. The catalyst from Example 1 was then added to the unsaturated acid. The reactor was pressurized to 10 psi with hydrogen and aged with good agitation for two hours. The catalyst was then removed by filtration and the titled product isolated in quantitative yield following vacuum concentration. 1H NMR (CDCl3, DMSO-d6) δ: 3.9 (m, 4H), 7.3 (s, 5H), 10.9 (s, 1H). IR (KBr) cm-1 : 3500m, 3000m, 1725s, 1700s, 1600m, 1200s, 970m.
Reaction SMILES: CO[C:3](=[O:26])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][C:12]2[C:13]([C:18]3[CH:23]=[CH:22][C:21]([F:24])=[C:20]([F:25])[CH:19]=3)=[N:14][O:15][C:16]=2[CH3:17])=[N:6][CH:5]=1.[NH2:27][CH2:28][C:29]([CH3:33])([CH3:32])[CH2:30][OH:31]>>[F:25][C:20]1[CH:19]=[C:18]([C:13]2[C:12]([CH2:11][O:10][C:7]3[CH:8]=[CH:9][C:4]([C:3]([NH:27][CH2:28][C:29]([CH3:33])([CH3:32])[CH2:30][OH:31])=[O:26])=[CH:5][N:6]=3)=[C:16]([CH3:17])[O:15][N:14]=2)[CH:23]=[CH:22][C:21]=1[F:24]
Reactant: COC(=O)c1ccc(OCc2c(-c3ccc(F)c(F)c3)noc2C)nc1
Reactant: CC(C)(CN)CO
Product: Cc1onc(-c2ccc(F)c(F)c2)c1COc1ccc(C(=O)NCC(C)(C)CO)cn1
Yield: 48 %

Procedure:
As described for example 125f, 6-[3-(3,4-difluoro-phenyl)-5-methyl-isoxazol-4-ylmethoxy]-nicotinic acid methyl ester (200 mg, 0.56 mmol) was converted, using 3-amino-2,2-dimethyl-1-propanol instead of 2,2,2-trifluoroethylamine, to the title compound (120 mg, 48%) which was obtained as a colourless oil. MS: m/e=432.2 [M+H]+.
Reaction SMILES: [CH2:1]([C:3]([CH2:15][OH:16])([CH3:14])[C:4]([O:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:5])[OH:2].N1C=CC=CC=1.[C:23](=O)=[O:24].CC(C)=O.ClC(Cl)(OC(=O)OC(Cl)(Cl)Cl)Cl>C(Cl)Cl>[CH3:14][C:3]1([C:4]([O:6][CH2:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[O:5])[CH2:15][O:16][C:23](=[O:24])[O:2][CH2:1]1
Reactant: CC(CO)(CO)C(=O)OCc1ccccc1
Reactant: O=C=O
Agent: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: CC(C)=O
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC1(C(=O)OCc2ccccc2)COC(=O)OC1
Temperature: 25 °C
Yield: 86 %

Procedure:
Benzyl 2,2-bis(methylol)propionate (BnMPA) (11.2 g, 0.05 mol) was dissolved in CH2Cl2 (150 mL) and pyridine (25 mL, 0.3 mol) and the solution was chilled to −75° C. with dry ice/acetone under N2 atmosphere. A solution of triphosgene (7.5 g, 25 mmol) in CH2Cl2 (150 mL) was added dropwise over 1 hours, and then the reaction mixture was allowed to warm to room temperature for 2 hours. The reaction was quenched by addition of saturated aqueous NH4Cl (75 mL), after which the organic layer was washed with 1 M aqueous HCl (3×100 mL), saturated aqueous NaHCO3 (1×100 mL), dried over MgSO4, filtered and evaporated. The resulting solid was recrystallized from ethyl acetate (15 mL) to give MTCOBn as a white solid (10.7 g, 86%). 1H NMR (400 MHz, CDCl3, 22° C.): delta 7.37 (m, 5H, PhH), 5.20 (s, 2H, —OCH2Ph), 4.69 (d, 2H, —CH2OCOO), 4.23 (d, 2H, —CH2OCOO), 1.31 (s, 3H, —CH3).