Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C:7]2[CH:8]=[C:9]([O:19][CH2:20][C@H:21]3[CH2:25][CH2:24][CH2:23][N:22]3C(OC(C)(C)C)=O)[CH:10]=[N:11][C:12]=2[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[ClH:33]>O1CCOCC1>[ClH:33].[ClH:33].[C:1]1([C:7]2[CH:8]=[C:9]([O:19][CH2:20][C@H:21]3[CH2:25][CH2:24][CH2:23][NH:22]3)[CH:10]=[N:11][C:12]=2[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H]1COc1cnc(-c2ccccc2)c(-c2ccccc2)c1
Agent: Cl
Solvent: C1COCCO1
Product: c1ccc(-c2cc(OC[C@H]3CCCN3)cnc2-c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 40 h

Procedure:
To the 5,6-diphenyl-3-(1-BOC-2-(R)-pyrrolidinylmethoxy)pyridine compound from Example 69b (140 mg) was added HCl in dioxane (3 mL). The mixture was stirred at room temperature for 40 hours. The solvent was removed under vacuum at 50° C., and the residue was triturated with ether. The solid was dried under high vacuum to afford the title compound. MS (DCI/NH3) m/z 331 (M+H)+. 1 H NMR (D2O, 300 MHz) δ: 1.97.-2.20 (m, 3H), 2.33 (m, 1H), 3.43 (t, J=7.2 Hz, 1H), 3.74 (m, 1H), 4.21 (m, 1H), 4.48 (m, 1H), 4.68 (dd, J=3.4, 10.5 Hz, 1H), 7.27-7.55 (m, 10H), 8.23 (d, J=2.7 Hz, 1H), 8.55 (d, J=2.7 Hz, 1H). Anal. Calcd for C22H22N2O·2.4 HCl·0.5 H2O: C, 61.89; H, 6.00; N, 6.56. Found: C, 62.04; H, 6.17; N, 6.03. [α]25D =-2.36° (c 1.95, MeOH).
Reaction SMILES: [Si]([O:8][C@H:9]([C:57]1[CH:62]=[CH:61][C:60]([F:63])=[CH:59][CH:58]=1)[CH2:10][S:11][C@H:12]1[C:15](=[O:16])[N:14]([C:17]2[CH:22]=[CH:21][C:20]([C:23]#[C:24][CH2:25][NH:26][S:27]([CH3:30])(=[O:29])=[O:28])=[CH:19][CH:18]=2)[C@@H:13]1[C:31]1[CH:56]=[CH:55][C:34]([O:35][CH2:36][C:37]([NH:39][CH2:40][C:41]([NH:43][C@@H:44]([C:52]([OH:54])=[O:53])[CH2:45][CH:46]2[CH2:51][CH2:50][CH2:49][CH2:48][CH2:47]2)=[O:42])=[O:38])=[CH:33][CH:32]=1)(C(C)(C)C)(C)C.O.[Li+].[Cl-].C1(C)C=CC=CC=1>C(O)(=O)C>[F:63][C:60]1[CH:61]=[CH:62][C:57]([C@@H:9]([OH:8])[CH2:10][S:11][C@H:12]2[C:15](=[O:16])[N:14]([C:17]3[CH:18]=[CH:19][C:20]([C:23]#[C:24][CH2:25][NH:26][S:27]([CH3:30])(=[O:28])=[O:29])=[CH:21][CH:22]=3)[C@@H:13]2[C:31]2[CH:32]=[CH:33][C:34]([O:35][CH2:36][C:37]([NH:39][CH2:40][C:41]([NH:43][C@@H:44]([C:52]([OH:54])=[O:53])[CH2:45][CH:46]3[CH2:47][CH2:48][CH2:49][CH2:50][CH2:51]3)=[O:42])=[O:38])=[CH:55][CH:56]=2)=[CH:58][CH:59]=1
Reactant: CC(C)(C)[Si](C)(C)O[C@@H](CS[C@H]1C(=O)N(c2ccc(C#CCNS(C)(=O)=O)cc2)[C@@H]1c1ccc(OCC(=O)NCC(=O)N[C@H](CC2CCCCC2)C(=O)O)cc1)c1ccc(F)cc1
Agent: [Cl-]
Agent: [Li+]
Solvent: CC(=O)O
Solvent: Cc1ccccc1
Solvent: O
Product: CS(=O)(=O)NCC#Cc1ccc(N2C(=O)[C@H](SC[C@H](O)c3ccc(F)cc3)[C@H]2c2ccc(OCC(=O)NCC(=O)N[C@H](CC3CCCCC3)C(=O)O)cc2)cc1
Reaction time: 8 h

Procedure:
N-({4-[(2R,3R)-3-{[(2R)-2-{[tert-butyl(dimethyl)silyl]oxy}-2-(4-fluorophenyl)ethyl]thio}-1-(4-{3-[(methylsulfonyl)amino]prop-1-yn-1-yl}phenyl)-4-oxoazetidin-2-yl]phenoxy}acetyl)glycyl-3-cyclohexyl-D-alanine (16.7 mg, 0.018 mmol) (Method 1) was dissolved in acetic acid (1 ml). Water (0.100 ml) and LiCl (50 mg, 1.18 mmol) were added and the reaction mixture was stirred overnight. The acetic acid was co-evaporated with toluene. The residue was purified with preparative HPLC on a C8 column, UV 235/285 nm. A gradient from 20 to 60% MeCN in 0.1M NH4OAc buffer was used as eluent. The pure fractions were collected and some of MeCN was removed under reduced pressure. The residue was lyophilised to give the title compound. H-NMR (500 MHz, DMSO-d6): 0.73-0.92 (m, 2H), 1.05-1.19 (m, 3H), 1.30 (b, 1H), 1.40-1.70 (m, 7H), 2.93 (d, 2H), 2.97 (s, 3H), 3.76 (d, 2H), 4.00 (s, 2H), 4.14 (bs, 1H), 4.31 (d, 1H), 4.52 (s, 2H), 4.71 (t, 1H), 5.10 (d, 1H), 5.74 (bs, 1H), 6.99 (d, 2H), 7.08-7.13 (m, 2H), 7.20 (d, 2H), 7.32-7.41 (m, 6H), 7.60 (b, 1H), 7.94 (b, 1H), 8.26 (t, 1H). M/z: 809 (M+1) and 807 (M−1).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7]2[C:15](I)=[N:14][N:13]([CH:17]3[CH2:22][CH2:21][CH2:20][CH2:19][O:18]3)[C:8]=2[N:9]=[C:10]([Cl:12])[CH:11]=1)=[O:5])[CH3:2].[CH2:23]([Sn](CCCC)(CCCC)C=C)[CH2:24]CC>O1CCCC1.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>[CH2:1]([O:3][C:4]([C:6]1[C:7]2[C:15]([CH:23]=[CH2:24])=[N:14][N:13]([CH:17]3[CH2:22][CH2:21][CH2:20][CH2:19][O:18]3)[C:8]=2[N:9]=[C:10]([Cl:12])[CH:11]=1)=[O:5])[CH3:2]
Reactant: C=C[Sn](CCCC)(CCCC)CCCC
Reactant: CCOC(=O)c1cc(Cl)nc2c1c(I)nn2C1CCCCO1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: C1CCOC1
Product: C=Cc1nn(C2CCCCO2)c2nc(Cl)cc(C(=O)OCC)c12
Temperature: 80 °C
Yield: 84.1 %

Procedure:
To a solution of 6-chloro-3-iodo-1-(tetrahydro-pyran-2-yl)-1H-pyrazolo[3,4-b]pyridine-4-carboxylic acid ethyl ester (5.00 g, 11.48 mmol) in anhydrous tetrahydrofuran (115 ml) was added tributyl(vinyl)stannane (3.52 ml, 12.05 mmol). The mixture was degassed for 15 minutes using argon, dichlorobis(triphenylphosphine)palladium (0.40 g, 0.57 mmol) was then added. The resulting solution was heated at 80° C. overnight under argon, then evaporated under reduced pressure. Ethyl acetate and a 5% aqueous potassium fluoride solution were added to the residue, the resulting precipitate was filtered. The filtrate was recovered and the two layers separated, the organic phase was washed with brine, dried (Na2SO4), filtered and concentrated under vacuum. The crude product was purified on a silica gel column chromatography using a gradient of ethyl acetate (0-10%) in cyclohexane to afford the title compound as a yellow solid (3.24 g, 84%).
Reaction SMILES: [C:1]([O:5][C:6](=[O:27])[C@H:7]([CH2:19][C:20]1[CH:25]=[CH:24][C:23]([OH:26])=[CH:22][CH:21]=1)[NH:8][C:9]([O:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:10])([CH3:4])([CH3:3])[CH3:2].[C:28]([O:32][C:33](=[O:36])[CH2:34]Br)([CH3:31])([CH3:30])[CH3:29]>>[C:1]([O:5][C:6](=[O:27])[C@H:7]([CH2:19][C:20]1[CH:21]=[CH:22][C:23]([O:26][CH2:34][C:33]([O:32][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:36])=[CH:24][CH:25]=1)[NH:8][C:9]([O:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:10])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)OCc1ccccc1
Reactant: CC(C)(C)OC(=O)CBr
Product: CC(C)(C)OC(=O)COc1ccc(C[C@H](NC(=O)OCc2ccccc2)C(=O)OC(C)(C)C)cc1

Procedure:
5.57 g (15 mmol) of N-benzyloxycarbonyl-tyrosine-tert-butyl ester is reacted with bromoacetic acid-tert-butyl ester to alkylated phenol analogously to Example 1a).
Reaction SMILES: [CH3:1][NH:2][C:3]1[CH:8]=[CH:7][C:6]([N+:9]([O-:11])=[O:10])=[CH:5][CH:4]=1.[Br:12]Br.C([O-])(O)=O.[Na+]>CC(O)=O.C(Cl)(Cl)Cl>[Br:12][C:4]1[CH:5]=[C:6]([N+:9]([O-:11])=[O:10])[CH:7]=[CH:8][C:3]=1[NH:2][CH3:1].[Br:12][C:4]1[CH:5]=[C:6]([N+:9]([O-:11])=[O:10])[CH:7]=[CH:8][C:3]=1[NH:2][CH3:1]
Reactant: CNc1ccc([N+](=O)[O-])cc1
Reactant: BrBr
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: CC(=O)O
Product: CNc1ccc([N+](=O)[O-])cc1Br
Temperature: 10 °C
Reaction time: 1 h
Yield: 99.5 %

Procedure:
To a solution of methyl-(4-nitro-phenyl)-amine (15.2 g, 0.1 mol) in AcOH (150 mL) and CHCl3 (50 mL) was added Br2 (16.0 g, 0.1 mol) dropwise at 5° C. The mixture was stirred at 10° C. for 1 h and then basified with sat. aq. NaHCO3. The resulting mixture was extracted with EtOAc (100 mL×3), and the combined organics were dried over anhydrous Na2SO4 and evaporated under vacuum to give (2-bromo-4-nitro-phenyl)-methyl-amine (2-bromo-4-nitro-phenyl)-methyl-amine (23.0 g, 99%), which was used in the next step without further purification. 1H NMR (300 MHz, CDCl3) δ 8.37 (d, J=2.4 Hz, 1H), 8.13 (dd, J=2.4, 9.0 Hz, 1H), 6.58 (d, J=9.0 Hz, 1H), 5.17 (brs, 1H), 3.01 (d, J=5.4 Hz, 3H).
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:7]=[C:8]2[C:17](=[CH:18][C:19]=1[CH3:20])[C:16]1[N:12]([CH:13]=[C:14]([C:21]3[N:25]([CH:26]([CH3:28])[CH3:27])[N:24]=[CH:23][N:22]=3)[N:15]=1)[CH2:11][CH2:10][O:9]2)=[CH2:5])C.C1(C)C=CC(S(O)(=O)=O)=CC=1>CC(C)=O>[CH3:20][C:19]1[CH:18]=[C:17]2[C:8]([O:9][CH2:10][CH2:11][N:12]3[C:16]2=[N:15][C:14]([C:21]2[N:25]([CH:26]([CH3:28])[CH3:27])[N:24]=[CH:23][N:22]=2)=[CH:13]3)=[CH:7][C:6]=1[C:4](=[O:3])[CH3:5]
Reactant: C=C(OCC)c1cc2c(cc1C)-c1nc(-c3ncnn3C(C)C)cn1CCO2
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CC(C)=O
Product: CC(=O)c1cc2c(cc1C)-c1nc(-c3ncnn3C(C)C)cn1CCO2
Temperature: 60 °C
Reaction time: 1.25 h
Yield: 77.6 %

Procedure:
A mixture of 12-(1-ethoxyethenyl)-13-methyl-4-[1-(propan-2-yl)-1H-1,2,4-triazol-5-yl]-9-oxa-3,6-diazatricyclo[8.4.0.02,6]tetradeca1(14),2,4,10,12-pentaene (160 mg, 0.440 mmol) and p-toluenesulfonic acid (7.5 mg, 0.044 mmol) in acetone (10 mL) was stirred at 60° C. for 75 min. The solid was filtered off and the filtrate was concentrated. The residue was purified by reverse phase Combiflash eluting with a 0-40% gradient of CH3CN in 0.3% NH4HCO3 to afford 1-{13-methyl-4-[1-(propan-2-yl)-1H-1,2,4-triazol-5-yl]-9-oxa-3,6-diazatricyclo[8.4.0.02,6]tetradeca1(14),2,4,10,12-pentaen-12-yl}ethan-1-one (120 mg, 81% yield). LCMS (ESI) m/z: 352.2 [M+H+].
Reaction SMILES: [NH2:1][C:2]1[C:7]([CH:8]=O)=[CH:6][CH:5]=[CH:4][N:3]=1.[CH3:10][C:11]([CH3:13])=O>C(O)C>[CH3:13][C:11]1[CH:10]=[CH:8][C:7]2[C:2](=[N:3][CH:4]=[CH:5][CH:6]=2)[N:1]=1
Reactant: Nc1ncccc1C=O
Reactant: CC(C)=O
Solvent: CCO
Product: Cc1ccc2cccnc2n1
Temperature: 25 °C
Yield: 70.2 %

Procedure:
The compound was prepared according to the procedure as described by E. M. Hawes and D. G. Wibberley, J. Chem. Soc. (C), 1966, 315. To a solution of 2-amino-3-pyridinecarboxaldehyde (2 g, 16 mmol) in ethanol 3 ml) was added acetone (1.9 g, 32 mmol) and peperidine (0,34 g, 4 mmol) and the reaction mixture was refluxed 24 hours. Reaction mixture was cooled to room temperature then concentrated in vacuum. Ether was added to concentrated residue. Solid was filtered and dried to give 1.62 g (69%) yellow solid. NMR (CD3OD) δ 2.76 (s, 3H), 7.52-7.58 (m, 2H), 8.30 (d, 2H, J=8.33 Hz), 8.36-8.39 (m, 1H), 8.39-8.99 (m, 1H).
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[C:3]1[CH:4]=[C:5]([NH2:13])[C:6]2[CH:7]=[CH:8][N:9]=[CH:10][C:11]=2[CH:12]=1.[F:16][C:17]([F:30])([F:29])[O:18][C:19]1[CH:28]=[CH:27][C:22]([CH2:23][N:24]=[C:25]=[O:26])=[CH:21][CH:20]=1>>[F:15][C:2]([F:1])([F:14])[C:3]1[CH:12]=[C:11]2[C:6]([CH:7]=[CH:8][N:9]=[CH:10]2)=[C:5]([NH:13][C:25]([NH:24][CH2:23][C:22]2[CH:21]=[CH:20][C:19]([O:18][C:17]([F:16])([F:30])[F:29])=[CH:28][CH:27]=2)=[O:26])[CH:4]=1
Reactant: O=C=NCc1ccc(OC(F)(F)F)cc1
Reactant: Nc1cc(C(F)(F)F)cc2cnccc12
Product: O=C(NCc1ccc(OC(F)(F)F)cc1)Nc1cc(C(F)(F)F)cc2cnccc12

Procedure:
Prepared from 7-(trifluoromethyl)isoquinolin-5-amine (Description 99) and [4-(trifluoromethoxy)benzyl]isocyanate (Description 59) according to Description 61. m/z (ES+) 414 (M+H)+.
Reaction SMILES: C([O:9][C:10]1[C:19](=[O:20])[C:18]2[C:13](=[CH:14][CH:15]=[C:16]([F:21])[CH:17]=2)[N:12]([CH3:22])[CH:11]=1)(=O)C1C=CC=CC=1.N1CCCCC1>ClCCl>[F:21][C:16]1[CH:17]=[C:18]2[C:13](=[CH:14][CH:15]=1)[N:12]([CH3:22])[CH:11]=[C:10]([OH:9])[C:19]2=[O:20]
Reactant: Cn1cc(OC(=O)c2ccccc2)c(=O)c2cc(F)ccc21
Solvent: ClCCl
Solvent: C1CCNCC1
Product: Cn1cc(O)c(=O)c2cc(F)ccc21
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A mixture of 6-fluoro-1 -methyl-4-oxo-1 ,4-dihydro-quinol-3-yl benzoate (1.90 g), piperidine (0.9 ml) and dry dichloromethane (50 ml) was stirred under nitrogen for 24 hours at ambient temperature. The solvent was removed by distillation and the residue triturated with diethyl ether (100 ml). The resultant solid was collected by filtration to give the novel compound 6-fluoro-3-hydroxy-1-methyl-4-quinolone, m.pp. 104°-106°.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[C:10]3[CH2:18][CH2:17][NH:16][CH2:15][C:11]=3[N:12]=[CH:13][N:14]=2)=[CH:4][CH:3]=1.Cl[C:20]1[C:25]([Cl:26])=[CH:24][CH:23]=[CH:22][N:21]=1.C(N(CC)C(C)C)(C)C>O1CCOCC1.CN(C)C(=O)C>[Cl:26][C:25]1[C:20]([N:16]2[CH2:17][CH2:18][C:10]3[C:9]([NH:8][C:5]4[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=4)=[N:14][CH:13]=[N:12][C:11]=3[CH2:15]2)=[N:21][CH:22]=[CH:23][CH:24]=1
Reactant: Fc1ccc(Nc2ncnc3c2CCNC3)cc1
Reactant: Clc1cccnc1Cl
Solvent: CC(=O)N(C)C
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: Fc1ccc(Nc2ncnc3c2CCN(c2ncccc2Cl)C3)cc1
Temperature: 150 °C
Yield: 29.3 %

Procedure:
N-(4-Fluorophenyl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-amine (0.47 g, 1.92 mmol) was dissolved in a mixture of dioxane/N,N-dimethylacetamide (4:1) (3 mL). To the mixture was added 2,3-dichloropyridine (420 mg, 2.86 mmol) and N,N-diisopropylethylamine (0.38 mL, 2.2 mmol). The mixture was heated at 150° C. in a Personal Chemistry microwave 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 by silica gel chromatography using a gradient of ethyl acetate:hexane (0-100%) to give the desired compound as an off-white powder (200 mg, 30%).
Reaction SMILES: [F:1][C:2]1([F:20])[CH2:7][CH2:6][C:5]([C:9]2[CH:10]=[N:11][N:12]([CH:14]3[CH2:19][CH2:18][CH2:17][CH2:16][O:15]3)[CH:13]=2)(O)[CH2:4][CH2:3]1.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[F:20][C:2]1([F:1])[CH2:7][CH2:6][C:5]([C:9]2[CH:10]=[N:11][N:12]([CH:14]3[CH2:19][CH2:18][CH2:17][CH2:16][O:15]3)[CH:13]=2)=[CH:4][CH2:3]1
Reactant: OC1(c2cnn(C3CCCCO3)c2)CCC(F)(F)CC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: FC1(F)CC=C(c2cnn(C3CCCCO3)c2)CC1
Yield: 53.4 %

Procedure:
The reaction and aftertreatment were conducted in the same manner as in Example 99b by using the 4,4-difluoro-1-[1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl]cyclohexanol (1.10 g, 3.84 mmol) prepared in Example 103a, p-toluenesulfonic acid (0.33 g, 1.92 mmol) and toluene (20 mL), to yield the title compound (0.55 g, 70%) as a colorless oil.
Reaction SMILES: [NH2:1][C:2]1[C:3]([CH3:18])=[C:4]2[C:8](=[CH:9][C:10]=1[CH3:11])[N:7]([CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])[CH2:6][CH2:5]2.C(N(CC)CC)C.[C:26](Cl)(=[O:31])[C:27]([CH3:30])([CH3:29])[CH3:28].O>C(Cl)(Cl)Cl>[CH2:12]([N:7]1[C:8]2[C:4](=[C:3]([CH3:18])[C:2]([NH:1][C:26](=[O:31])[C:27]([CH3:30])([CH3:29])[CH3:28])=[C:10]([CH3:11])[CH:9]=2)[CH2:5][CH2:6]1)[CH2:13][CH2:14][CH2:15][CH2:16][CH3:17]
Reactant: CCCCCCN1CCc2c1cc(C)c(N)c2C
Reactant: CC(C)(C)C(=O)Cl
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CCCCCCN1CCc2c1cc(C)c(NC(=O)C(C)(C)C)c2C
Temperature: 25 °C
Reaction time: 1 h
Yield: 55.1 %

Procedure:
5-Amino-4,6-dimethyl-1-hexylindoline (880 mg) was dissolved in chloroform (20 ml), and triethylamine (370 mg) and pivaloyl chloride (430 mg) were added, which was followed by stirring at room temperature for 1 hour. Water was added to the reaction mixture, and the mixture was washed with saturated brine and dried over sodium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (developing solvent:chloroform-methanol=1:0-50:1) and recrystallized from ethanol to give 650 mg of the title compound.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6](B(O)O)[CH:7]=[CH:8][CH:9]=1)[CH3:2].Br[C:14]1[CH:15]=[CH:16][C:17]([F:23])=[C:18]([N+:20]([O-:22])=[O:21])[CH:19]=1.C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1.C(O)C.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>[F:23][C:17]1[CH:16]=[CH:15][C:14]([C:6]2[CH:7]=[CH:8][CH:9]=[C:4]([O:3][CH2:1][CH3:2])[CH:5]=2)=[CH:19][C:18]=1[N+:20]([O-:22])=[O:21]
Reactant: O=[N+]([O-])c1cc(Br)ccc1F
Reactant: CCOc1cccc(B(O)O)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCO
Product: CCOc1cccc(-c2ccc(F)c([N+](=O)[O-])c2)c1
Yield: 89.3 %

Procedure:
Tetrakis(triphenylphosphine)palladium (0.8 g) was added to a mixture of 4.2 g of 3-ethoxyphenylboronic acid, 5.0 g of 5-bromo-2-fluoronitrobenzene and 22 mL of 2 M sodium carbonate solution in 50 mL of toluene and 50 mL of ethanol. The mixture was refluxed for 2 hours, concentrated, water was added and the mixture was extracted twice with ethyl acetate. The ethyl acetate layer was washed with water and brine, then dried, and concentrated. The residue was chromatographed on silica gel (5% ethyl acetate in hexane) to give 5.3 g (90% yield) of crude 4-fluoro-3′-ethoxy-3-nitrobiphenyl as a yellow oil.
Reaction SMILES: [CH3:1][CH:2]([CH3:31])[CH2:3][C@H:4]([NH:21][C:22]1[CH:30]=[CH:29][C:25]([C:26]([OH:28])=O)=[CH:24][N:23]=1)[C:5]1[CH:6]=[N:7][C:8]([C:11]2[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][CH:12]=2)=[N:9][CH:10]=1.Cl.CN(C)CCCN=C=NCC.Cl.[CH2:45]([O:47][C:48](=[O:52])[CH2:49][CH2:50][NH2:51])[CH3:46].C(N(CC)CC)C>ClCCl>[CH2:45]([O:47][C:48](=[O:52])[CH2:49][CH2:50][NH:51][C:26]([C:25]1[CH:24]=[N:23][C:22]([NH:21][C@H:4]([C:5]2[CH:6]=[N:7][C:8]([C:11]3[CH:12]=[CH:13][C:14]([C:17]([F:19])([F:20])[F:18])=[CH:15][CH:16]=3)=[N:9][CH:10]=2)[CH2:3][CH:2]([CH3:31])[CH3:1])=[CH:30][CH:29]=1)=[O:28])[CH3:46]
Reactant: CC(C)C[C@H](Nc1ccc(C(=O)O)cn1)c1cnc(-c2ccc(C(F)(F)F)cc2)nc1
Reactant: CCOC(=O)CCN
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)CCNC(=O)c1ccc(N[C@@H](CC(C)C)c2cnc(-c3ccc(C(F)(F)F)cc3)nc2)nc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
6-{(S)-3-Methyl-1-[2-(4-trifluoromethyl-phenyl)-pyrimidin-5-yl]-butylamino}-nicotinic acid (31.1 g wet with ethyl acetate, theoretical 65.8 mmol) was dissolved in dichloromethane (270 mL). 1-Hydroxybenotriazole hydrate (15.1 g, 98.7 mmol) was added followed by N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (18.9 g, 98.7 mmol). beta-Alanine ethyl ester hydrochloride (12.1 g, 79.0 mmol) was added and the reaction was placed in an ice bath. When only slightly cool, triethylamine (18.3 mL, 132 mmol) was added over 3 min. The bath was then removed and the reaction was stirred at room temperature as a solution. At 16 h, most of the dichloromethane was rotovapped off. The residue was partitioned between ethyl acetate and sat. NH4Cl. The aqueous was extracted with additional ethyl acetate and the combined organics were washed with sat. NaHCO3 two times. The first aqueous was back extracted with ethyl acetate to remove a small amount of product. The combined organics were washed with brine and dried over MgSO4. The material was purified by silica gel flash chromatography (ethyl acetate/heptane) and then further purified by chiral SFC. Column: Chiralcel OJ-H. Dimensions: 21 mm×250 mm. Mobile Phase: 80/20 CO2/ethanol. Flow Rate: 65 ml/min. The purified material was taken up in ethyl acetate, filtered through a course frit and concentrated in vacuo to give 3-[(6-{(S)-3-methyl-1-[2-(4-trifluoromethyl-phenyl)-pyrimidin-5-yl]-butylamino}-pyridine-3-carbonyl)-amino]-propionic acid ethyl ester with ethyl acetate (29.2 g) as a white foam. 1H NMR (400 MHz, CDCl3, δ): 8.83 (s, 2H) 8.54 (d, J=8.0 Hz, 2H) 8.46 (d, J=2.0 Hz, 1H) 7.81 (dd, J=8.7, 2.2 Hz, 1H) 7.73 (d, J=8.4 Hz, 2H) 6.64 (t, J=5.8 Hz, 1H) 6.36 (d, J=8.6 Hz, 1H) 5.13 (d, J=6.7 Hz, 1H) 4.97-5.08 (m, 1H) 4.09-4.21 (m, 2H) 3.68 (q, J=5.9 Hz, 2H) 2.60 (t, J=5.9 Hz, 2H) 1.81-1.95 (m, 1H) 1.67-1.81 (m, 2H) 1.26 (t, J=7.1 Hz, 3H) 1.03 (d, J=6.1 Hz, 3H) 1.00 (d, J=6.1 Hz, 3H); MS (M+1): 530.2. Analytical chiral SFC: Column—Chiralcel OJ-H. Dimensions: 4.6 mm×25 cm. Mobile Phase: 80/20 CO2/ethanol. Flow Rate: 2.5 mL/min. Retention time: 5.18 minutes.
Reaction SMILES: C(OC([NH:8][C@@H:9]([C:39]([CH3:42])([CH3:41])[CH3:40])[C:10]([N:12]1[C@H:21]([C:22](=[O:34])[NH:23][C@H:24]2[C:33]3[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=3)[CH2:27][CH2:26][CH2:25]2)[CH2:20][C:19]2[C:14](=[CH:15][C:16]([C:35]([O:37][CH3:38])=[O:36])=[CH:17][CH:18]=2)[CH2:13]1)=[O:11])=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:8][C@@H:9]([C:39]([CH3:42])([CH3:41])[CH3:40])[C:10]([N:12]1[C@H:21]([C:22](=[O:34])[NH:23][C@H:24]2[C:33]3[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=3)[CH2:27][CH2:26][CH2:25]2)[CH2:20][C:19]2[C:14](=[CH:15][C:16]([C:35]([O:37][CH3:38])=[O:36])=[CH:17][CH:18]=2)[CH2:13]1)=[O:11]
Reactant: COC(=O)c1ccc2c(c1)CN(C(=O)[C@@H](NC(=O)OC(C)(C)C)C(C)(C)C)[C@H](C(=O)N[C@@H]1CCCc3ccccc31)C2
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)c1ccc2c(c1)CN(C(=O)[C@@H](N)C(C)(C)C)[C@H](C(=O)N[C@@H]1CCCc3ccccc31)C2
Reaction time: 0.67 h
Yield: 96.7 %

Procedure:
A solution of (S)-methyl 2-((S)-2-((tert-butoxycarbonyl)amino)-3,3-dimethylbutanoyl)-3-(((R)-1,2,3,4-tetrahydronaphthalen-1-yl)carbamoyl)-1,2,3,4-tetrahydroisoquinoline-7-carboxylate (1.21 g, 2.09 mmol) in CH2Cl2 (13.9 mL) was charged with TFA (3.49 mL) at room temperature. After 40 min, the reaction mixture was quenched carefully with sat. NaHCO3 and then extracted with EtOAc (3×). The combined extracts were washed with sat. NaCl, dried over MgSO4, filtered and concentrated in vacuo to afford the title compound (0.97 g, 2.02 mmol, 97%) as a light yellow foam, which was used without further purification. MS (ESI+) m/z 478.2 (M+H)+.
Reaction SMILES: [CH2:1]1[CH:5]2[CH2:6][NH:7][CH2:8][CH:4]2[CH2:3][N:2]1[C:9]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[C:17]1[S:18][CH:19]=[CH:20][CH:21]=1)=[O:10].Cl[C:23]1[N:28]=[C:27]([C:29]2[O:30][CH:31]=[CH:32][CH:33]=2)[CH:26]=[CH:25][N:24]=1>>[O:30]1[CH:31]=[CH:32][CH:33]=[C:29]1[C:27]1[CH:26]=[CH:25][N:24]=[C:23]([N:7]2[CH2:8][CH:4]3[CH:5]([CH2:1][N:2]([C:9]([C:11]4[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=4[C:17]4[S:18][CH:19]=[CH:20][CH:21]=4)=[O:10])[CH2:3]3)[CH2:6]2)[N:28]=1
Reactant: O=C(c1ccccc1-c1cccs1)N1CC2CNCC2C1
Reactant: Clc1nccc(-c2ccco2)n1
Product: O=C(c1ccccc1-c1cccs1)N1CC2CN(c3nccc(-c4ccco4)n3)CC2C1

Procedure:
The title compound was prepared in a manner analogous to Example 15 utilizing Intermediate 37 and 2-chloro-4-furan-2-yl-pyrimidine. MS (ESI) mass calcd. for C26H22N4O2S, 442.50; m/z found, 443.2 [M+H]+.
Reaction SMILES: Br[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([F:10])[CH:3]=1.C1(C)C=CC=CC=1.[Cl-].[NH4+].[CH3:20][N:21](C=O)C>[C-]#N.[Zn+2].[C-]#N.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>[F:10][C:4]1[CH:3]=[C:2]([C:20]#[N:21])[CH:9]=[CH:8][C:5]=1[C:6]#[N:7]
Reactant: N#Cc1ccc(Br)cc1F
Reactant: CN(C)C=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Agent: [Cl-]
Solvent: Cc1ccccc1
Product: N#Cc1ccc(C#N)c(F)c1

Procedure:
A solution of 4-bromo-2-fluorobenzonitrile (20 g, 100 mmol), zinc cyanide (7 g, 60 mmol) and tetrakis(triphenylphosphine)palladium (4.6 g, 4 mmol) in DMF (100 mL) was heated at 80° C. for 4 hr. Toluene (300 mL) and saturated aqueous ammonium chloride (300 mL) were added and the layers were separated. The organic layer was washed once with saturated aqueous ammonium chloride and twice with brine. The organic phase was dried (MgSO4), filtered and concentrated. The product was purified by silica gel chromatography, eluting with a gradient of hexanes to 30% EtOAc/hexanes (11 g, 75%).