Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([NH:8][C:9]([C:11]2[CH:33]=[CH:32][C:14]([O:15][C:16]3[CH:25]=[C:24]4[C:19]([CH:20]([C:26]([O:28][CH3:29])=[O:27])[CH2:21][CH2:22][O:23]4)=[CH:18][C:17]=3[C:30]#[N:31])=[CH:13][CH:12]=2)=[O:10])[CH:5]=[CH:4][CH:3]=1.[CH3:34][C:35]1[CH:36]=[C:37](B(O)O)[CH:38]=[CH:39][C:40]=1[CH3:41].C([O-])([O-])=O.[Na+].[Na+].C1(C)C=CC=CC=1>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.O>[C:30]([C:17]1[CH:18]=[C:19]2[C:24](=[CH:25][C:16]=1[O:15][C:14]1[CH:32]=[CH:33][C:11]([C:9](=[O:10])[NH:8][C:6]3[CH:5]=[CH:4][CH:3]=[C:2]([C:37]4[CH:38]=[CH:39][C:40]([CH3:41])=[C:35]([CH3:34])[CH:36]=4)[N:7]=3)=[CH:12][CH:13]=1)[O:23][CH2:22][CH2:21][CH:20]2[C:26]([O:28][CH3:29])=[O:27])#[N:31]
Reactant: COC(=O)C1CCOc2cc(Oc3ccc(C(=O)Nc4cccc(Br)n4)cc3)c(C#N)cc21
Reactant: Cc1ccc(B(O)O)cc1C
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: O
Solvent: Cc1ccccc1
Product: COC(=O)C1CCOc2cc(Oc3ccc(C(=O)Nc4cccc(-c5ccc(C)c(C)c5)n4)cc3)c(C#N)cc21
Temperature: 100 °C
Yield: 95.6 %

Procedure:
A vial was charged with methyl 7-(4-(6-bromopyridin-2-ylcarbamoyl)phenoxy)-6-cyanochroman-4-carboxylate (51 mg, 0.100 mmol), 3,4-dimethylphenylboronic acid (19.5 mg, 0.130 mmol), Na2CO3 (31.9 mg, 0.300 mmol), toluene (1 mL) and water (0.1 mL). The mixture was degassed with Argon for few minutes, and then Pd(PPh3)4 (5.8 mg, 0.005 mmol) was added. The vial was sealed and heated at 100° C. for 16 hours. The reaction was cooled and the crude material was purified by silica gel column chromatography to provide the desired product (0.051 g, 95%).
Reaction SMILES: [NH2:1][C@@H:2]([CH2:6][S:7][C:8]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:3]([OH:5])=[O:4].CCN(C(C)C)C(C)C.[F:36][C:37]([F:55])([F:54])[C@H:38](OS(C(F)(F)F)(=O)=O)[C:39]1[CH:44]=[CH:43][C:42]([F:45])=[CH:41][CH:40]=1>C(Cl)Cl>[F:55][C:37]([F:36])([F:54])[C@@H:38]([NH:1][C@@H:2]([CH2:6][S:7][C:8]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1)[C:3]([OH:5])=[O:4])[C:39]1[CH:40]=[CH:41][C:42]([F:45])=[CH:43][CH:44]=1
Reactant: O=S(=O)(O[C@H](c1ccc(F)cc1)C(F)(F)F)C(F)(F)F
Reactant: N[C@@H](CSC(c1ccccc1)(c1ccccc1)c1ccccc1)C(=O)O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=C(O)[C@H](CSC(c1ccccc1)(c1ccccc1)c1ccccc1)N[C@@H](c1ccc(F)cc1)C(F)(F)F
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 77.7 %

Procedure:
2(R)-Amino-3-tritylsulfanylpropionic acid (78 g, 214.6mmol) was dissolved in CH2Cl2 and DIPEA (112 mL, 643.8 mmol) was added and the reaction mixture was stirred for 10 min at room temperature. Trifluoromethanesulfonic acid 2,2,2-trifluoro-1(R)-(4-fluorophenyl)ethyl ester (70 g, 214.6 mmol) in CH2Cl2 was added and the reaction mixture was stirred overnight at room temperature. Solvent was removed under the reduced pressure and the residue was dissolved in Et2O and washed with IN HCl, brine and dried over MgSO4. Solvent was removed give 2(R)-[2,2,2-trifluoro-1(S)-(4-fluorophenyl)ethylamino]-3-tritylsulfanylpropionic acid (90 g) as a yellow solid.
Reaction SMILES: [C:1]([C:4]1[CH2:9][CH2:8][CH2:7][NH:6][CH:5]=1)(=[O:3])[CH3:2].[C:10](Cl)(=[O:17])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>>[C:10]([N:6]1[CH2:7][CH2:8][CH2:9][C:4]([C:1]([CH3:2])=[O:3])=[CH:5]1)(=[O:17])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: CC(=O)C1=CNCCC1
Product: CC(=O)C1=CN(C(=O)c2ccccc2)CCC1

Procedure:
Methyl 1-benzoyl-1,4,5,6-tetrahydro-3-pyridyl ketone was prepared from 3-acetyl-1,4,5,6-tetrahydropyridine and benzoyl chloride according to the procedure of Part b) of Example 1. The product was recrystallised from ethanol/water m.pt. 93°-95° C.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[N:11][N:12]([C:15]3[CH:23]=[CH:22][C:18]([C:19](O)=[O:20])=[CH:17][N:16]=3)[C:13]=2[OH:14])=[C:5]([CH3:24])[CH:4]=1)#[N:2].[CH3:25][C@H:26]([NH2:29])[CH2:27][CH3:28]>>[C@@H:26]([NH:29][C:19](=[O:20])[C:18]1[CH:22]=[CH:23][C:15]([N:12]2[C:13]([OH:14])=[C:9]([C:6]3[CH:7]=[CH:8][C:3]([C:1]#[N:2])=[CH:4][C:5]=3[CH3:24])[CH:10]=[N:11]2)=[N:16][CH:17]=1)([CH2:27][CH3:28])[CH3:25]
Reactant: CC[C@H](C)N
Reactant: Cc1cc(C#N)ccc1-c1cnn(-c2ccc(C(=O)O)cn2)c1O
Product: CC[C@H](C)NC(=O)c1ccc(-n2ncc(-c3ccc(C#N)cc3C)c2O)nc1

Procedure:
The title compound was prepared in a manner similar to Example 112 using 6-(4-(4-cyano-2-methylphenyl)-5-hydroxy-1H-pyrazol-1-yl)nicotinic acid and (S)-butan-2-amine. 1H NMR (400 MHz, DMSO-d6) δ ppm 0.90 (t, J=7.33 Hz, 3H) 1.17 (d, J=6.57 Hz, 3H) 1.46-1.63 (m, 2H) 2.44 (s, 3H) 3.95 (dt, J=13.83, 7.11 Hz, 1H) 7.67 (dd, J=8.08, 1.26 Hz, 1H) 7.74 (s, 1H) 7.78 (br. s., 1H) 8.17 (br. s., 1H) 8.32-8.58 (m, 3H) 8.87-8.95 (m, 1H) 13.18 (br. s., 1H). MS m/z [M+H]+ 376.2.
Reaction SMILES: [CH3:1][C:2]1[C:7]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[C:6]([CH3:16])[N:5]=[C:4]([O:17][CH2:18][C:19]([N:21]([CH3:28])[CH:22]2[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]2)=[O:20])[N:3]=1.[CH:29]1([C:32](Cl)=[O:33])[CH2:31][CH2:30]1>>[CH:29]1([C:32]([N:25]2[CH2:24][CH2:23][CH:22]([N:21]([CH3:28])[C:19](=[O:20])[CH2:18][O:17][C:4]3[N:3]=[C:2]([CH3:1])[C:7]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:12])[CH3:13])=[C:6]([CH3:16])[N:5]=3)[CH2:27][CH2:26]2)=[O:33])[CH2:31][CH2:30]1
Reactant: O=C(Cl)C1CC1
Reactant: Cc1nc(OCC(=O)N(C)C2CCNCC2)nc(C)c1NC(=O)OC(C)(C)C
Product: Cc1nc(OCC(=O)N(C)C2CCN(C(=O)C3CC3)CC2)nc(C)c1NC(=O)OC(C)(C)C

Procedure:
The title compound was synthesized from Compound 31 and cyclopropanecarbonyl chloride in the same manner as in Example 32.
Reaction SMILES: [C:1]1([O:11][CH2:12][CH:13]([OH:16])[CH2:14]Cl)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[C:17]([NH:25][CH:26]1[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1)(=[O:24])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C(=O)([O-])[O-].[K+].[K+]>C(O)(C)C>[C:1]1([O:11][CH2:12][CH:13]([OH:16])[CH2:14][N:29]2[CH2:30][CH2:31][CH:26]([NH:25][C:17](=[O:24])[C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH2:27][CH2:28]2)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: OC(CCl)COc1cccc2ccccc12
Reactant: O=C(NC1CCNCC1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)O
Product: O=C(NC1CCN(CC(O)COc2cccc3ccccc23)CC1)c1ccccc1

Procedure:
3-(α-Naphthoxy)-1-chloropropan-2-ol (1.18 g.) was refluxed for 16 hours in isopropyl alcohol (100 ml.) with 4-benzamidopiperidine (1.032 g.) and anhydrous potassium carbonate (1.037 g.). The mixture was filtered hot, cooled and evaporated to dryness. The gum so obtained gave the title compound as a solid on triturating in ether, m.p. 139°-141° C. (Found: C, 74.1; H, 7.1; N, 6.9. C25H28N2O3 requires C, 74.2; H, 7.0; N, 6.9%).
Reaction SMILES: [CH3:1][O:2][CH:3]1[O:8][CH2:7][CH:6]([CH2:9][O:10][C:11]2[CH:16]=[CH:15][N+:14]([O-])=[C:13]([CH3:18])[C:12]=2[CH3:19])[CH2:5][O:4]1.C(OC(=O)C)(=[O:22])C>>[CH3:1][O:2][CH:3]1[O:8][CH2:7][CH:6]([CH2:9][O:10][C:11]2[CH:16]=[CH:15][N:14]=[C:13]([CH2:18][OH:22])[C:12]=2[CH3:19])[CH2:5][O:4]1
Reactant: COC1OCC(COc2cc[n+]([O-])c(C)c2C)CO1
Reactant: CC(=O)OC(C)=O
Product: COC1OCC(COc2ccnc(CO)c2C)CO1
Temperature: 100 °C
Reaction time: 2 h
Yield: 22.8 %

Procedure:
The 4-((2-methoxy-1,3-dioxan-5-yl)methoxy)-2,3-dimethylpyridine 1-oxide (1.8 g, 6.68 ml) obtained in the step (6b) was mixed with acetic anhydride (8 ml). The mixture was stirred at 100° C. for 2 hours. After cooled to room temperature, the reaction mixture was concentrated under reduced pressure. To the residue, methanol (10 ml) and a 5N aqueous sodium hydroxide solution (5 ml) were added and the mixture was stirred at room temperature for 15 hours. The reaction mixture was concentrated and the residue was separated with a saturated saline solution and ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, filtered, concentrated and the residue was purified by silica gel column chromatography (elution solvent: heptane/ethyl acetate, ethyl acetate/methanol) to obtain the title compound (0.41 g, yield: 22.8%), which is a cis and trans (1:1) mixture, as a yellow oil.
Reaction SMILES: C[O:2][C:3](=[O:29])[CH2:4][N:5]([S:15]([C:18]1[CH:23]=[CH:22][C:21]([O:24][CH2:25][CH2:26][CH2:27][Cl:28])=[CH:20][CH:19]=1)(=[O:17])=[O:16])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[CH:9][CH:8]=1.[Li+].[OH-]>CO.C1COCC1.O>[Cl:28][CH2:27][CH2:26][CH2:25][O:24][C:21]1[CH:20]=[CH:19][C:18]([S:15]([N:5]([CH2:4][C:3]([OH:29])=[O:2])[CH2:6][C:7]2[CH:8]=[CH:9][C:10]([O:13][CH3:14])=[CH:11][CH:12]=2)(=[O:17])=[O:16])=[CH:23][CH:22]=1
Reactant: COC(=O)CN(Cc1ccc(OC)cc1)S(=O)(=O)c1ccc(OCCCCl)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: COc1ccc(CN(CC(=O)O)S(=O)(=O)c2ccc(OCCCCl)cc2)cc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of 59.7 g (0.135 mol) of ([4-(3-chloro-propoxy)-benzenesulfonyl]-(4-methoxybenzyl)-amino)-acetic acid methyl ester in 500 ml of MeOH, 500 ml of THF and 200 ml of H2O, 11.3 g of LiOH:H2O (0.27 mol) is added at 0-5° C. The mixture is allowed to warm to r.t. and stirred for 4 h. The reaction mixture is concentrated under reduced pressure and diluted with H2O and AcOEt. After acidifying with 2N HCl at 0-5° C., the mixture is extracted with AcOEt. The combined extracts are washed with brine and concentrated under reduced pressure to give {[4-(3-chloro-propoxy)-benzenesulfonyl]-(4-methoxy-benzyl)-amino]-acetic acid; NMR (CDCl3): 2.25-2.29 (m, 2H), 3.75 (t, 2H, J=6 Hz), 3.79 (s, 3H), 3.91 (s, 2H), 4.19 (t, 2H, J=6 Hz), 4.38 (s, 2H), 6.84 (d, 2H, J=8.56 Hz), 6.99 (d, 2H, J=8.56 Hz), 7.13 (d, 2H, J=9.04 Hz), 7.82 (d, 2H, J=9.04 Hz).
Reaction SMILES: [CH3:1][C:2]([N+:22]([O-])=O)([CH3:21])[CH2:3][C:4]1[C:12]2[C:7](=[C:8]([O:13][CH2:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[CH:9]=[CH:10][CH:11]=2)[NH:6][CH:5]=1.C(O)C>[Ni].O1CCCC1>[CH3:21][C:2]([NH2:22])([CH3:1])[CH2:3][C:4]1[C:12]2[C:7](=[C:8]([O:13][CH2:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[CH:9]=[CH:10][CH:11]=2)[NH:6][CH:5]=1
Reactant: CC(C)(Cc1c[nH]c2c(OCc3ccccc3)cccc12)[N+](=O)[O-]
Agent: [Ni]
Solvent: CCO
Solvent: C1CCOC1
Product: CC(C)(N)Cc1c[nH]c2c(OCc3ccccc3)cccc12
Temperature: 60 °C
Reaction time: 1 h

Procedure:
A mixture of 3-(2-methyl-2-nitropropyl)-7-(benzyloxy)indole (25.0 g, 77.1 mmol), Raney Nickel® (9.5 g wet lump), and 3A ethanol (250 mL) is pressurized to 50 psig with H2 and is heated to 60° C. After 1 hour, the mixture is cooled to ambient temperature. The mixture is diluted with tetrahydrofuran (100 mL) and is warmed to 50° C. The catalyst is removed by filtration and the cake is rinsed with 50° C. tetrahydrofuran (4×50 mL). The filtrate is concentrated to a solid which is dried in a 50° C. vacuum oven to provide 22.41 (99%) of 2-methyl-1-[7-(benzyloxy)indol-3-yl]prop-2-ylamine. MS (ES+) m/z 295 (100%).
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([O:14][C:15]2[N:20]=[C:19]3[S:21][C:22]([NH:24][C:25](=[O:28])[CH2:26][CH3:27])=[N:23][C:18]3=[CH:17][CH:16]=2)[C:11]([Cl:29])=[CH:10][C:9]=1[F:30])(C)(C)C>FC(F)(F)C(O)=O>[NH2:7][C:8]1[C:9]([F:30])=[CH:10][C:11]([Cl:29])=[C:12]([CH:13]=1)[O:14][C:15]1[N:20]=[C:19]2[S:21][C:22]([NH:24][C:25](=[O:28])[CH2:26][CH3:27])=[N:23][C:18]2=[CH:17][CH:16]=1
Reactant: CCC(=O)Nc1nc2ccc(Oc3cc(NC(=O)OC(C)(C)C)c(F)cc3Cl)nc2s1
Solvent: O=C(O)C(F)(F)F
Product: CCC(=O)Nc1nc2ccc(Oc3cc(N)c(F)cc3Cl)nc2s1
Temperature: 25 °C
Reaction time: 2 h
Yield: 79.5 %

Procedure:
A mixture of tert-butyl(4-chloro-2-fluoro-5-{[2-(propanoylamino)[1,3]thiazolo[5,4-b]pyridin-5-yl]oxy}phenyl)carbamate (1.26 g, 2.70 mmol) and trifluoroacetic acid (10 mL) was stirred at room temperature for 2 hr. The reaction mixture was concentrated under reduced pressure, and the residue was dissolved in ethyl acetate (100 mL). The solution was washed with aqueous sodium hydrogen carbonate solution (30 mL×2) and saturated brine (10 mL), dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=67/33→0/100) to give the title compound (787 mg, 79%) as white crystals.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:8]=[C:7]([C:9]2[CH:14]=[C:13]([Cl:15])[CH:12]=[CH:11][C:10]=2[Cl:16])[N:6]=[C:5]2[CH2:17][CH2:18][CH2:19][C:4]=12.[NH2:20][C:21]1[CH:26]=[CH:25][C:24]([CH2:27][C:28]([NH2:30])=[O:29])=[CH:23][CH:22]=1>>[ClH:2].[Cl:16][C:10]1[CH:11]=[CH:12][C:13]([Cl:15])=[CH:14][C:9]=1[C:7]1[N:6]=[C:5]2[CH2:17][CH2:18][CH2:19][C:4]2=[C:3]([NH:20][C:21]2[CH:22]=[CH:23][C:24]([CH2:27][C:28]([NH2:30])=[O:29])=[CH:25][CH:26]=2)[CH:8]=1
Reactant: Clc1ccc(Cl)c(-c2cc(Cl)c3c(n2)CCC3)c1
Reactant: NC(=O)Cc1ccc(N)cc1
Agent: Cl
Product: NC(=O)Cc1ccc(Nc2cc(-c3cc(Cl)ccc3Cl)nc3c2CCC3)cc1
Yield: 6.1 %

Procedure:
Following General Procedure A1, 4-chloro-2-(2,5-dichlorophenyl)-6,7-dihydro-5H-cyclopenta[b]pyridine hydrochloride (0.100 g, 0.33 mmol) was reacted with 2-(4-aminophenyl)acetamide (0.060 g, 0.40 mmol), followed by the formation of the hydrochloride salt to afford the title compound (0.009 g, 10%) as a tan solid. MW=448.77. 1H NMR (DMSO-d6, 500 MHz) δ 14.18 (s, 1H), 10.16 (s, 1H), 7.79 (s, 1H), 7.71-7.64 (m, 2H), 7.50 (d, J=8.5 Hz, 1H), 7.42 (d, J=8.5 Hz, 1H), 7.31 (d, J=8.0 Hz, 1H), 7.16 (d, j=8.5 Hz, 1H), 6.91 (s, 1H), 3.66 (s, 2H), 3.30 (s, 2H), 3.15-3.06 (m, 2H), 3.0-2.89 (m, 2H), 2.31-2.19 (m, 2H); APCI MS m/z 412 [M+H]+.
Reaction SMILES: [CH:1]1[C:12]2[CH2:11][C:10]3[CH:13]=[CH:14][CH:15]=[CH:16][C:9]=3[O:8][CH:7]([C:17]([OH:19])=[O:18])[O:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.S(=O)(=O)(O)O>C(O)CCC.C1(C)C=CC=CC=1>[CH:13]1[C:10]2[CH2:11][C:12]3[CH:1]=[CH:2][CH:3]=[CH:4][C:5]=3[O:6][CH:7]([C:17]([O:19][CH2:12][CH2:1][CH2:2][CH3:3])=[O:18])[O:8][C:9]=2[CH:16]=[CH:15][CH:14]=1
Reactant: O=C(O)C1Oc2ccccc2Cc2ccccc2O1
Agent: O=S(=O)(O)O
Solvent: CCCCO
Solvent: Cc1ccccc1
Product: CCCCOC(=O)C1Oc2ccccc2Cc2ccccc2O1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
Into a 500 ml round bottom flask fitted with a stir bar and a Dean-Stark apparatus is placed 111.4 grams of crude (87 percent) 12H-dibenzo[d,g][1,3]dioxocin-6-carboxylic acid in 300 ml of 2:1 n-butanol:toluene. The mixture is stirred at room temperature for 15 minutes to effect the complete dissolution of the acid. Concentrated sulfuric acid (4.0 ml) is then added and the reaction mixture is heated to reflux Immediately upon attaining reflux, an aqueous layer begins to separate out in the Dean-Stark apparatus. After 2 hours at reflux, no additional water formation is observed and the reaction is cooled to room temperature with a cold water bath. A total of 10 ml of water is collected, the majority of this water being formed in the initial 30 minutes of reflux. The cooled reddish-yellow reaction solution is diluted with 200 ml of toluene, washed with 300 ml of water, 300 ml of saturated aqueous NaHCO3, ml of brine and then concentrated under reduced pressure on a rota-vap. Toluene (200 ml) is added to the residue and the solution again is concentrated under reduced pressure This evaporation with toluene facilitates the removal of n-butanol. The residue obtained is taken up into 300 ml of 2:1 toluene:ether and washed with 200 ml of 5 percent NaOH. Brine, 50 ml, is added to break up the emulsion that forms with the 5 percent NaOH wash. The organic solution is then washed with 200 ml of brine, dried over MgSO4 and concentrated under reduced pressure to afford a thick light reddish-yellow liquid (130 grams). This liquid is then subjected to vacuum distillation, using a Claisen adapter as the distillation head and an oil bath for heating. Care is taken during the course of the distillation to avoid solidification of the product in the distillation condenser. A forerun (11 grams) is collected having a b.p. 70° C. to 170° C. at 0.25 mm. Pure n-butyl ester, 84.3 grams (62 percent), is then collected from 171° C. to 180° C. at 0.25 mm as a thick clear liquid which readily solidifies on cooling to afford a white solid: mp 63°-66° C. (softening at 60° C.); greater than 99 percent purity as determined by L.C. bp 189°-195° C./0.4mm; IR (neat) 3.45, 5.75, 6.95, 8.35, 10.4 cm-1 ; H NRM (60 MHz, CDCl3) δ 0.9-1.9 (m, 7, OCH2CH2CH2CH3), 3.42 and 4.6 (2d, 2, CH2), 4.35, (t, 2, OCH2CH2CH2CH 3), 5.05 (s, 1, CH), 7.0-7.4 (m, 8, Ar--H)).
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH:5]1[CH2:9][CH2:8][CH:7]([C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=2)[N:6]1[S:17]([C:20]1[CH:25]=[CH:24][C:23]([CH3:26])=[CH:22][CH:21]=1)(=[O:19])=[O:18].[CH3:27][C:28]1[N:29]=[CH:30][NH:31][CH:32]=1>>[F:16][C:13]1[CH:14]=[CH:15][C:10]([CH:7]2[N:6]([S:17]([C:20]3[CH:25]=[CH:24][C:23]([CH3:26])=[CH:22][CH:21]=3)(=[O:18])=[O:19])[CH:5]([CH2:4][CH2:3][CH2:2][N:31]3[CH:32]=[C:28]([CH3:27])[N:29]=[CH:30]3)[CH2:9][CH2:8]2)=[CH:11][CH:12]=1
Reactant: Cc1c[nH]cn1
Reactant: Cc1ccc(S(=O)(=O)N2C(CCCCl)CCC2c2ccc(F)cc2)cc1
Product: Cc1ccc(S(=O)(=O)N2C(CCCn3cnc(C)c3)CCC2c2ccc(F)cc2)cc1

Procedure:
The title compound, colorless oil, MS: m/e=442.2 (M+H+), was prepared in accordance with the general method of example 82b from (2RS,5RS)-2-(3-chloro-propyl)-5-(4-fluoro-phenyl)-1-(toluene-4-sulfonyl)-pyrrolidine and 4-methyl-1H-imidazole.
Reaction SMILES: Br[C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH3:14])([CH3:13])[C:7](=[O:12])[N:8]2[CH3:11])=[CH:4][C:3]=1[F:15].C1(P(C2C=CC=CC=2)C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH2:62]([NH2:69])[C:63]1[CH:68]=[CH:67][CH:66]=[CH:65][CH:64]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+]>O1CCCC1.C(OCC)(=O)C.O.C([O-])([O-])=O.[Na+].[Na+].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]>[CH2:62]([NH:69][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH3:14])([CH3:13])[C:7](=[O:12])[N:8]2[CH3:11])=[CH:4][C:3]=1[F:15])[C:63]1[CH:68]=[CH:67][CH:66]=[CH:65][CH:64]=1
Reactant: NCc1ccccc1
Reactant: CN1C(=O)C(C)(C)c2cc(F)c(Br)cc21
Agent: [Pd]
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1CCOC1
Solvent: O
Solvent: CCOC(C)=O
Product: CN1C(=O)C(C)(C)c2cc(F)c(NCc3ccccc3)cc21
Temperature: 80 °C

Procedure:
To a solution of 6-bromo-5-fluoro-1,3,3-trimethylindolin-2-one (2.8 g, 10.3 mmol) in tetrahydrofuran (280 ml) under an argon atmosphere were added 2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (320 mg, 514 μmol), tris(dibenzylideneacetone)dipalladium(0) (471 mg, 514 μmol), benzylamine (2.21 g, 2.25 ml, 20.6 mmol) and a 1 M solution of lithium bis(trimethylsilyl)amide (25.7 ml, 25.7 mmol). The reaction mixture was heated to 80° C. in the microwave for 45 minutes and then diluted with ethyl acetate, water and 2 N aqueous Na2CO3 solution. The aqueous phase was extracted with ethyl acetate. The combined organic phases were washed with brine, dried over sodium sulfate. The solvent was evaporated and the residue purified by silica gel chromatography using ethyl acetate/heptane as eluent. The title compound was obtained as light yellow powder (1.57 g).
Reaction SMILES: [NH2:1][C:2]1[CH:20]=[CH:19][C:5]([O:6][C:7]2[N:12]=[CH:11][N:10]=[C:9]([NH:13][C:14]([CH:16]3[CH2:18][CH2:17]3)=[O:15])[CH:8]=2)=[CH:4][C:3]=1[CH3:21].[F:22][C:23]1[CH:28]=[CH:27][C:26]([NH:29][C:30](=O)[O:31]C2C=CC=CC=2)=[CH:25][C:24]=1[C:39]([F:42])([F:41])[F:40].CCN(C(C)C)C(C)C>C1COCC1>[F:22][C:23]1[CH:28]=[CH:27][C:26]([NH:29][C:30]([NH:1][C:2]2[CH:20]=[CH:19][C:5]([O:6][C:7]3[N:12]=[CH:11][N:10]=[C:9]([NH:13][C:14]([CH:16]4[CH2:17][CH2:18]4)=[O:15])[CH:8]=3)=[CH:4][C:3]=2[CH3:21])=[O:31])=[CH:25][C:24]=1[C:39]([F:40])([F:41])[F:42]
Reactant: O=C(Nc1ccc(F)c(C(F)(F)F)c1)Oc1ccccc1
Reactant: Cc1cc(Oc2cc(NC(=O)C3CC3)ncn2)ccc1N
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc(Oc2cc(NC(=O)C3CC3)ncn2)ccc1NC(=O)Nc1ccc(F)c(C(F)(F)F)c1
Temperature: 80 °C
Reaction time: 2 h
Yield: 77.1 %

Procedure:
Add N-[6-(4-amino-3-methyl-phenoxy)pyrimidin-4-yl]cyclopropanecarboxamide (99 mg, 0.35 mmol), phenyl N-[4-fluoro-3-(trifluoromethyl)phenyl]carbamate (100 mg, 0.35 mmol) and DIEA (135 mg, 1.05 mmol) in THF (4 mL), stir at 80° C. for 2 hrs, Remove the volatiles, suspend the residue in DCM, filter and collect the solid to get the target compound (132 mg, 77%). MS: (M+1): 490.3.
Reaction SMILES: CN1CCOCC1.ClC(OCC(C)C)=O.[C:16]([O:20][C:21]([NH:23][C@H:24]([CH2:29][C:30]1[CH:35]=[C:34]([F:36])[C:33]([F:37])=[CH:32][C:31]=1[F:38])[CH2:25][C:26]([OH:28])=O)=[O:22])([CH3:19])([CH3:18])[CH3:17].Cl.[CH2:40]([CH:47]1[NH:53][CH2:52][CH2:51][CH2:50][N:49]([CH3:54])[C:48]1=[O:55])[C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1.C(O)C.CC1C=C(Cl)C=CC=1OCCCC(O)=O>C1COCC1.CN(C=O)C>[C:16]([O:20][C:21]([NH:23][C@H:24]([CH2:29][C:30]1[CH:35]=[C:34]([F:36])[C:33]([F:37])=[CH:32][C:31]=1[F:38])[CH2:25][C:26]([N:53]1[CH2:52][CH2:51][CH2:50][N:49]([CH3:54])[C:48](=[O:55])[C@H:47]1[CH2:40][C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1)=[O:28])=[O:22])([CH3:17])([CH3:18])[CH3:19]
Reactant: CN1CCCNC(Cc2ccccc2)C1=O
Reactant: CC(C)(C)OC(=O)N[C@@H](CC(=O)O)Cc1cc(F)c(F)cc1F
Agent: CC(C)COC(=O)Cl
Agent: Cc1cc(Cl)ccc1OCCCC(=O)O
Agent: Cl
Solvent: CN1CCOCC1
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: CN1CCCN(C(=O)C[C@@H](Cc2cc(F)c(F)cc2F)NC(=O)OC(C)(C)C)[C@H](Cc2ccccc2)C1=O
Temperature: -20 °C
Reaction time: 36 h

Procedure:
N-Methylmorpholine (0.048 mL) and isobutyl chloroformate (0.026 mL) were added to a stirred solution of (3R)-3-[(tert-butoxycarbonyl)amino]-4-(2,4,5-trifluorophenyl)butanoic acid (67 mg) in THF (1 mL) at −20° C. and the resultant mixture was stirred for 1 h. 3-Benzylhexahydro-1-methyl-2H-1,4-diazepin-2-one hydrochloride obtained in Step B above (48 mg) and N-methylmorpholine (0.024 mL) in DMF (1 mL) were added. The mixture was stirred for 30 min at −20° C. and for 36 h at ambient temperature, and then evaporated. The residue was treated with saturated aqueous ammonium chloride solution, extracted with ethyl acetate, and the organic extract evaporated. The product obtained was purified by preparative TLC (silica gel, methanol/concentrated ammonium hydroxide/dichloromethane 4.4:0.1:95.5) to obtain the coupled product as a mixture of diastereomers. The isomers were resolved by HPLC (ChiralPAK AD, 14% ethanol/bexane) and the faster eluting (R,S)-isomer and slower eluting (R,R)-isomer were collected.
Reaction SMILES: Cl[CH2:2][CH2:3][NH:4][C:5]1[CH:9]=[CH:8][NH:7][N:6]=1.[CH3:10][NH:11][CH3:12]>CO>[CH3:10][N:11]([CH3:12])[CH2:2][CH2:3][NH:4][C:5]1[CH:9]=[CH:8][NH:7][N:6]=1
Reactant: ClCCNc1cc[nH]n1
Reactant: CNC
Solvent: CO
Product: CN(C)CCNc1cc[nH]n1
Temperature: 100 °C

Procedure:
In a sealable flask, the N-(2-chloroethyl)-1H-pyrazol-3-amine (0.214 g, 1.47 mmol) were combined with 1.5 mL of dimethylamine (40% in H2O). The mixture flask was sealed, and the mixture was heated to 100° C. for 16 h. The mixture was cooled to rt, and transferred to a rb flask with MeOH. The solvent was removed under reduced pressure to give the N1,N1-dimethyl-N2-(1H-pyrazol-3-yl)ethane-1,2-diamine in quantitative yield. LCMS: m/e 155.3 (M+H)+, ret time 0.96 min (method 3).