Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[C:3]([Cl:18])=[C:4]([NH:10][C:11](=[O:17])[O:12][C:13]([CH3:16])([CH3:15])[CH3:14])[CH:5]=[C:6]([C:8]#[N:9])[CH:7]=1.C1(CNCC2CCCCC2)CCCCC1.[CH2:34]([OH:37])[CH:35]=[CH2:36]>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].C(P(C(C)(C)C)C1C=CC=CC=1C1C=CC=CC=1C)(C)(C)C.C(#N)C>[Cl:18][C:3]1[C:2]([CH2:36][CH2:35][CH:34]=[O:37])=[CH:7][C:6]([C:8]#[N:9])=[CH:5][C:4]=1[NH:10][C:11](=[O:17])[O:12][C:13]([CH3:16])([CH3:15])[CH3:14]
Reactant: C=CCO
Reactant: CC(C)(C)OC(=O)Nc1cc(C#N)cc(Br)c1Cl
Agent: [Pd]
Agent: C1CCC(CNCC2CCCCC2)CC1
Agent: Cc1ccccc1-c1ccccc1P(C(C)(C)C)C(C)(C)C
Solvent: CC#N
Product: CC(C)(C)OC(=O)Nc1cc(C#N)cc(CCC=O)c1Cl
Temperature: 90 °C
Yield: 39.5 %

Procedure:
Tert-butyl (3-bromo-2-chloro-5-cyanophenyl)carbamate (500 mg, 1.508 mmol), 2-(di-t-butylphosphino)-2′-methylbiphenyl (14.13 mg, 0.045 mmol), and Pd2(dba)3 (13.81 mg, 0.015 mmol) were combined in a 40 dram vial which was evacuated and backfilled 3× with N2. To this was added acetonitrile (3 mL), N,N-dicyclohexylmethylamine (0.388 mL, 1.809 mmol), and prop-2-en-1-ol (0.154 mL, 2.262 mmol). The vial was again evacuated and backfilled with N2 3×, and heated at 90° C. for 3 h. The reaction mixture was cooled to room temperature and the solvent removed in vacuo. The material was purified by flash column chromatography (0%-50% EtOAc/Hex; 80 g column). Tert-butyl (2-chloro-5-cyano-3-(3-oxopropyl)phenyl)carbamate (184 mg) was obtained as a yellow glass.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]=[C:8]([C@H:13]([CH3:28])[C:14]([O:16][CH2:17][CH2:18][N:19](OC(C)(C)C)[C:20](C)=O)=[O:15])[CH:7]=[CH:6]2.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]=[C:8]([C@H:13]([CH3:28])[C:14]([O:16][CH2:17][CH2:18][NH:19][CH3:20])=[O:15])[CH:7]=[CH:6]2
Reactant: COc1ccc2cc([C@H](C)C(=O)OCCN(OC(C)(C)C)C(C)=O)ccc2c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CNCCOC(=O)[C@@H](C)c1ccc2cc(OC)ccc2c1
Temperature: 0 °C
Reaction time: 8 h

Procedure:
The product of the Example 45b (17.1 g, 50 mmol) was dissolved in CH2Cl2 (400 mL). The solution was cooled to 0° C. and TFA (80 mL) was added drop-wise. The ice bath was removed and the reaction mixture was stirred at room temperature overnight, then the solvent. was evaporated. The residue was treated with aqueous sodium carbonate (10%) and extracted with EtOAc. The combined organic extracts were washed with water, brine, dried over sodium sulfate, and the solvent was evaporated. Trituration of the resulting solid with hexane gave the pure product as a white solid. Mp 64-68° C. 1HNMR (300 MHz, CDCl3) δ 7.67 (d, J=8.5 Hz, 2H), 7.66 (d, J=1.3, 1H), 7.4 (dd, J=8.5 and 1.8 Hz, 1H), 7.18-7.08 (m, 2H), 4.18 (t, J=5.4 Hz, 2H), 3.89 (s, 3H), 3.80 (q, J=7.1 Hz, 1H), 2.73 (t, J=5.4 Hz, 2H), 2.31 (s, 3H), 1.56 (d, J=7.1 Hz, 3H); 13C NMR (75 MHz, CDCl3) δ 174.5, 157.6, 135.6, 133.6, 129.2, 128.8, 127.1, 126.1, 125.8, 118.9, 105.5, 63.9, 55.2, 50.0, 45.3, 36.0, 18.4.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]2[CH:18]=[C:17]3[C:12]([C:13]([OH:34])=[C:14]([C:29](OCC)=[O:30])[C:15](=[O:28])[N:16]3[CH2:19][C:20](=[O:27])[N:21]3[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]3)=[N:11][CH:10]=2)=[CH:4][CH:3]=1.[NH2:35][CH2:36][CH:37]([OH:39])[CH3:38]>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]2[CH:18]=[C:17]3[C:12]([C:13]([OH:34])=[C:14]([C:29]([NH:35][CH2:36][CH:37]([OH:39])[CH3:38])=[O:30])[C:15](=[O:28])[N:16]3[CH2:19][C:20](=[O:27])[N:21]3[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26]3)=[N:11][CH:10]=2)=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2n(CC(=O)N2CCCCC2)c1=O
Reactant: CC(O)CN
Product: CC(O)CNC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2n(CC(=O)N2CCCCC2)c1=O

Procedure:
This compound was prepared from ethyl 7-[(4-fluorophenyl)methyl]-4-hydroxy-2-oxo-1-[2-oxo-2-(1-piperidinyl)ethyl]-1,2-dihydro-1,5-naphthyridine-3-carboxylate and (±)-1-amino-2-propanol employing methods similar to those those described in Example 9 and was purified by reverse phase preparative HPLC (C-18 stationary phase; 10-100% CH3CN/water/0.1% formic acid mobile phase). The product was obtained as a white solid: 1H NMR (CDCl3) δ 10.32 (1H, m), 8.55 (1H, s), 7.16 (2H, dd, J=8.5, 5.5 Hz), 7.03 (2H, t, J=8.5 Hz), 6.97 (1H, s), 4.94 (2H, m), 4.11 (2H, s), 4.04 (1H, m), 3.62 (1H, m), 3.50 (2H, t, J=5.5 Hz), 3.44 (2H, t, J=5.5 Hz), 3.35 (1H, m), 2.21 (1H, d, J=4 Hz), 1.69 (2H, m), 1.54 (4H, m), 1.26 (3H, d, J=6 Hz); HRMS calcd for C26H29FN4O5+H+: 497.2200. Found: 497.2189.
Reaction SMILES: [Cl:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([O:10][CH3:11])=[CH:4][C:3]=1[NH2:12].[CH2:13]([NH:15][C:16]1[C:21]([CH:22]=O)=[CH:20][N:19]=[C:18]([S:24][CH3:25])[N:17]=1)[CH3:14]>C1(C)C=CC=CC=1.S(=O)(=O)(O)O>[Cl:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([O:10][CH3:11])=[CH:4][C:3]=1[N:12]=[CH:22][C:21]1[C:16]([NH:15][CH2:13][CH3:14])=[N:17][C:18]([S:24][CH3:25])=[N:19][CH:20]=1
Reactant: CCNc1nc(SC)ncc1C=O
Reactant: COc1cc(N)c(Cl)c(OC)c1
Agent: O=S(=O)(O)O
Solvent: Cc1ccccc1
Product: CCNc1nc(SC)ncc1C=Nc1cc(OC)cc(OC)c1Cl
Reaction time: 3 h
Yield: 99.6 %

Procedure:
Into a solution of 3.78 g (20.2 mmol) of 2-chloro-3,5-dimethoxy-phenylamine in 110 mL of toluene was added 3.97 g (20.15 mmol) of 4-ethylamino-2-methylsulfanyl-pyrimidine-5-carbaldehyde. The reaction vessel was equipped with a Dean-Stark trap, and the reaction was warmed to reflux. After 3 hours, two drops of concentrated sulfuric acid were added to the reaction. The reaction was refluxed overnight then concentrated in vacuo to give 7.36 g (93%) of the title compound, which was used as is in the following example:
Reaction SMILES: C([O-])([O-])=O.[K+].[K+].[CH3:7][C:8]1[N:12]([CH2:13][C:14]2[CH:15]=[C:16]([OH:20])[CH:17]=[CH:18][CH:19]=2)[N:11]=[C:10]([C:21]2[O:25][N:24]=[C:23]([C:26]3[CH:31]=[CH:30][C:29]([O:32][C:33]([F:36])([F:35])[F:34])=[CH:28][CH:27]=3)[N:22]=2)[N:9]=1.Br[CH2:38][CH2:39][O:40][CH3:41]>CN(C=O)C.O>[CH3:41][O:40][CH2:39][CH2:38][O:20][C:16]1[CH:15]=[C:14]([CH2:13][N:12]2[C:8]([CH3:7])=[N:9][C:10]([C:21]3[O:25][N:24]=[C:23]([C:26]4[CH:31]=[CH:30][C:29]([O:32][C:33]([F:36])([F:34])[F:35])=[CH:28][CH:27]=4)[N:22]=3)=[N:11]2)[CH:19]=[CH:18][CH:17]=1
Reactant: Cc1nc(-c2nc(-c3ccc(OC(F)(F)F)cc3)no2)nn1Cc1cccc(O)c1
Reactant: COCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COCCOc1cccc(Cn2nc(-c3nc(-c4ccc(OC(F)(F)F)cc4)no3)nc2C)c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A mixture of K2CO3 (19.9 mg, 0.144 mmol), 3-((5-methyl-3-(3-(4-(trifluoromethoxy)phenyl)-1,2,4-oxadiazol-5-yl)-1H-1,2,4-triazol-1-yl)methyl)phenol (Example 59; 30.0 mg, 0.072 mmol) and 1-bromo-2-methoxyethane (19.9 mg, 0.144 mmol) in DMF (0.36 mL) was stirred at RT for 16 h. The mixture was diluted with H2O and extracted with 4:1 CHCl3:i-PrOH. The organic layer was separated, dried with MgSO4 and concentrated under reduced pressure. The residue was dissolved in DMSO and purified using Prep-HPLC to furnish the title compound. MS (ES+) C22H20F3N5O4 requires: 475. found 476 [M+H]+; 1H-NMR (600 MHz, CD3OD) δ ppm 8.29 (d, J=8.8 Hz, 2H), 7.35 (d, J=8.1 Hz, 2H), 7.28 (m, 1H), 6.91 (m, 1H), 6.83 (d, J=7.6 Hz, 1H), 6.81 (m, 1H), 5.42 (s, 2H), 4.09 (m, 2H), 3.73 (m, 2H), 3.43 (s, 3H), 2.52 (s, 3H).
Reaction SMILES: F[C:2](F)(F)[C:3](O)=O.[CH3:8][O:9][C:10]1[CH:11]=[C:12]([NH:22][C:23]2[N:24]=[C:25](CCC3CCCO3)[C:26]3[CH2:32][N:31](C(OC(C)(C)C)=O)[CH2:30][CH2:29][C:27]=3[N:28]=2)[CH:13]=[CH:14][C:15]=1[N:16]1[CH:20]=[C:19]([CH3:21])[N:18]=[CH:17]1>C(Cl)Cl>[CH3:8][O:9][C:10]1[CH:11]=[C:12]([NH:22][C:23]2[N:24]=[CH:25][C:26]3[CH2:32][NH:31][CH2:30][CH:29]([C:3]4[CH:2]=[CH:14][CH:15]=[CH:10][CH:11]=4)[C:27]=3[N:28]=2)[CH:13]=[CH:14][C:15]=1[N:16]1[CH:20]=[C:19]([CH3:21])[N:18]=[CH:17]1
Reactant: O=C(O)C(F)(F)F
Reactant: COc1cc(Nc2nc(CCC3CCCO3)c3c(n2)CCN(C(=O)OC(C)(C)C)C3)ccc1-n1cnc(C)c1
Solvent: ClCCl
Product: COc1cc(Nc2ncc3c(n2)C(c2ccccc2)CNC3)ccc1-n1cnc(C)c1
Temperature: 25 °C
Yield: 193.2 %

Procedure:
Trifluoroacetic acid (0.238 mL, 3.09 mmol) was added dropwise to a stirred solution of tert-butyl 2-(3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenylamino)-4-(2-(tetrahydrofuran-2-yl)ethyl)-7,8-dihydropyrido[4,3-d]pyrimidine-6(5H)-carboxylate (0.330 g, 0.62 mmol) in DCM (3 mL) at rt. The reaction mixture was stirred under reflux for 1 hr. Five equivalents of trifluoroacetic acid were added and the reaction mixture was stirred at reflux for 1 hour. The reaction mixture was allowed to cool to room temperature. The organic mixture was washed with potassium carbonate (aq) and the organic layer was separated, dried (MgSO4) and concentrated giving 0.247 g (92%) of N-(3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl)-8-phenyl-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-2-amine.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([N:10]2[C:18]([NH:19][CH:20]3[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]3)=[C:17]3[C:12]([CH:13]=[CH:14][CH:15]=[CH:16]3)=[N:11]2)=[CH:6][CH:5]=1.[C:26]1([CH2:32][C:33](Cl)=[O:34])[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.C(OC(C)=O)(C)C.[Cl-].[Na+].O>CN(C=O)C>[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([N:10]2[C:18]([N:19]([CH:20]3[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]3)[C:33](=[O:34])[CH2:32][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)=[C:17]3[C:12]([CH:13]=[CH:14][CH:15]=[CH:16]3)=[N:11]2)=[CH:6][CH:5]=1
Reactant: O=C(Cl)Cc1ccccc1
Reactant: Clc1ccc(-n2nc3ccccc3c2NC2CCCCC2)cc1
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CC(=O)OC(C)C
Product: O=C(Cc1ccccc1)N(c1c2ccccc2nn1-c1ccc(Cl)cc1)C1CCCCC1
Temperature: 0 °C
Reaction time: 1 h
Yield: 7.4 %

Procedure:
To an ice cold suspension of NaH (13 mg, 320 umol) in DMF (3 ml) under an argon atmosphere was added a solution of [2-(4-chloro-phenyl)-2H-indazol-3-yl]-cyclohexyl-amine (100 mg, 310 μmol; example 11.1) in DMF (1 ml) within 10 min. The suspension was stirred for 1 h at 0° C. A solution of phenyl-acetyl chloride (40 μl, 340 μmol; [103-80-0]) in DMF (1 ml) was added within 5 min. The reaction mixture was stirred for 14 h at ambient temperature, poured onto ice water/brine 1/1 and extracted two times with iPrOAc. The combined extracts were washed with ice water/brine 1/1 and dried over Na2SO4. The solvent was removed under reduced pressure and the residue was purified by preparative thin layer chromatography (silica gel, iPrOAc/heptane) to give the title compound (10 mg, 23 μmol; 7%) as off-white solid. MS: m/e=444.1 [M+H+].
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[C:10]([CH:19]([OH:28])[CH2:20][Si](OC(C)C)(C)C)=[CH:11][C:12]3[NH:16][CH:15]=[N:14][C:13]=3[C:17]=2[F:18])=[C:4]([Cl:29])[CH:3]=1.[F-].[K+].[OH:32]O>CO.C1COCC1.O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[C:10]([CH:19]([OH:28])[CH2:20][OH:32])=[CH:11][C:12]3[NH:16][CH:15]=[N:14][C:13]=3[C:17]=2[F:18])=[C:4]([Cl:29])[CH:3]=1
Reactant: CC(C)O[Si](C)(C)CC(O)c1cc2[nH]cnc2c(F)c1Nc1ccc(Br)cc1Cl
Reactant: OO
Agent: [F-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: OCC(O)c1cc2[nH]cnc2c(F)c1Nc1ccc(Br)cc1Cl
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 34 %

Procedure:
To the crude 1-[6-(4-bromo-2-chloro-phenylamino)-7-fluoro-3H-benzoimidazol-5-yl]-2-(isopropoxy-dimethyl-silanyl)-ethanol 10v in MeOH-THF (5 mL-5 mL) is added KHCO3 (54 mg, 0.54 mmol), and KF (74 mg, 1.27 mmol), and 30% aqueous H2O2 (0.20 mL) at room temperature. After stirring for 3.5 hours at room temperature, the reaction mixture is diluted with water, and extracted with EtOAc. The organic layer is dried over MgSO4, filtered, concentrated in vacuo, and purified by flash chromatography (8% to 10% MeOH in CH2Cl2) to give the desired product (74 mg, 34%): MS APCI (+) m/z 400, 402 (M+, Br pattern) detected; 1H NMR (400 MHz, CD3OD) δ 8.20 (s, 1H), 7.62 (broad s, 1H), 7.47 (d, 1H), 7.14 (dd, 1H), 6.30 (d, 1H), 4.96 (t, 1H), 3.64 (m, 2H); 19F NMR (376 MHz, CD3OD) −136.87 (s).
Reaction SMILES: C(OC([NH:8][C:9]1[CH:10]=[C:11]([C:15]2([OH:21])[CH2:20][CH2:19][O:18][CH2:17][CH2:16]2)[CH:12]=[CH:13][CH:14]=1)=O)(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[NH2:8][C:9]1[CH:10]=[C:11]([C:15]2([OH:21])[CH2:20][CH2:19][O:18][CH2:17][CH2:16]2)[CH:12]=[CH:13][CH:14]=1
Reactant: CC(C)(C)OC(=O)Nc1cccc(C2(O)CCOCC2)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Nc1cccc(C2(O)CCOCC2)c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 76.9 %

Procedure:
To an ice-cooled solution of 4-(3-t-butyloxycarbonylaminophenyl)-4-hydroxytetrahydropyran (2.0 g, 6.8 mmol), prepared as in step 2, in dichloromethane (14 mL) was added trifluoroacetic acid (14, mL). The resulting solution was stirred for 0.25 hours at 0° C. and 1 hour at ambient temperature. The volatiles were removed in vacuo and the resulting solution was basified with saturated aqueous potassium carbonate. The resulting mixture was diluted with dichloromethane and the layers separated. The aqueous layer was extracted (4×, dichloromethane). The combined organic layers were dried (MgSO4), and concentrated in vacuo to provide a solid. Trituration with hexanes provided 4-(3-aminophenyl)-4-hydroxytetrahydropyran as a colorless solid (1.01 g, 77%). mp 154°-155° C. 1H NMR (300 MHz, CDCl3) δ7.17 (1H, dt, J=7.5, 1 Hz), 6.84-6.88 (2H, m), 6.62 (1H, br d, J=7.5 Hz), 3.93 (2H, td, J=12, 12, 2.5 Hz), 3.84 (2H, ddd, J=12, 5, 1.5 Hz), 2.05-32 (4H, m). MS m/e 193 (M+NH4 --H2O)+, 211 (M+NH4)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:10]([C:11]3[N:16]=[C:15]([NH:17][C@H:18]4[CH2:23][CH2:22][CH2:21][C@@H:20]([OH:24])[C@H:19]4[OH:25])[C:14]([F:26])=[CH:13][N:12]=3)=[CH:9][N:8]([S:27]([C:30]3[CH:36]=[CH:35][C:33]([CH3:34])=[CH:32][CH:31]=3)(=[O:29])=[O:28])[C:5]2=[N:6][CH:7]=1.ClC1N=C(N[C@H]2CCC[C@H](O)[C@H]2O)C(F)=CN=1>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:10]([C:11]3[N:16]=[C:15]([NH:17][C@H:18]4[CH2:23][CH2:22][CH2:21][C@H:20]([OH:24])[C@H:19]4[OH:25])[C:14]([F:26])=[CH:13][N:12]=3)=[CH:9][N:8]([S:27]([C:30]3[CH:31]=[CH:32][C:33]([CH3:34])=[CH:35][CH:36]=3)(=[O:29])=[O:28])[C:5]2=[N:6][CH:7]=1
Reactant: Cc1ccc(S(=O)(=O)n2cc(-c3ncc(F)c(N[C@H]4CCC[C@@H](O)[C@H]4O)n3)c3cc(Cl)cnc32)cc1
Agent: O[C@H]1[C@@H](Nc2nc(Cl)ncc2F)CCC[C@@H]1O
Product: Cc1ccc(S(=O)(=O)n2cc(-c3ncc(F)c(N[C@H]4CCC[C@H](O)[C@H]4O)n3)c3cc(Cl)cnc32)cc1

Procedure:
According to the method for compound 31c, except use compound 32b (0.03 g, 0.11 mmol), to give compound 32c (0.06 g, 0.11 mmol).
Reaction SMILES: [NH2:1][C:2]1[C:54]([C:55]([F:58])([F:57])[F:56])=[CH:53][C:5]([CH2:6][C@@H:7]([CH2:32][C:33](=[O:52])[N:34]2[CH2:39][CH2:38][CH:37]([N:40]3[CH2:46][CH2:45][C:44]4[CH:47]=[CH:48][CH:49]=[CH:50][C:43]=4[NH:42][C:41]3=[O:51])[CH2:36][CH2:35]2)[C:8]([N:10]2[CH2:15][CH2:14][CH:13]([N:16]3[CH2:21][CH2:20][N:19](C(OCC4C=CC=CC=4)=O)[CH2:18][CH2:17]3)[CH2:12][CH2:11]2)=[O:9])=[CH:4][C:3]=1[Cl:59]>[Ni].CO>[NH2:1][C:2]1[C:54]([C:55]([F:57])([F:56])[F:58])=[CH:53][C:5]([CH2:6][C@@H:7]([CH2:32][C:33]([N:34]2[CH2:35][CH2:36][CH:37]([N:40]3[CH2:46][CH2:45][C:44]4[CH:47]=[CH:48][CH:49]=[CH:50][C:43]=4[NH:42][C:41]3=[O:51])[CH2:38][CH2:39]2)=[O:52])[C:8]([N:10]2[CH2:15][CH2:14][CH:13]([N:16]3[CH2:17][CH2:18][NH:19][CH2:20][CH2:21]3)[CH2:12][CH2:11]2)=[O:9])=[CH:4][C:3]=1[Cl:59]
Reactant: Nc1c(Cl)cc(C[C@@H](CC(=O)N2CCC(N3CCc4ccccc4NC3=O)CC2)C(=O)N2CCC(N3CCN(C(=O)OCc4ccccc4)CC3)CC2)cc1C(F)(F)F
Agent: [Ni]
Solvent: CO
Product: Nc1c(Cl)cc(C[C@@H](CC(=O)N2CCC(N3CCc4ccccc4NC3=O)CC2)C(=O)N2CCC(N3CCNCC3)CC2)cc1C(F)(F)F
Temperature: 25 °C
Reaction time: 5 h

Procedure:
100 mg Raney nickel were added to a solution of 250 mg (0.30 mmol) benzyl 4-(1-{(S)-2-(4-amino-3-chloro-5-trifluoromethyl-benzyl)-4-oxo-4-[4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidin-1-yl]-butyryl}-piperidin-4-yl)-piperazin-1-carboxylate in 30 mL MeOH and the reaction mixture was stirred for 5 h at RT and 50 psi H2. To complete the reaction another 100 mg of Raney nickel were added and the mixture was stirred for a further 10 h at RT. The catalyst was suction filtered, the solvent eliminated i. vac. and the residue purified by HPLC.
Reaction SMILES: C[O:2][C:3](=[O:20])[C:4]1[CH:9]=[C:8]([CH2:10][C:11]([F:14])([F:13])[CH3:12])[N:7]=[C:6]([NH:15][C@H:16]([CH2:18][CH3:19])[CH3:17])[CH:5]=1.[OH-].[Li+].Cl>C1COCC1>[C@@H:16]([NH:15][C:6]1[CH:5]=[C:4]([CH:9]=[C:8]([CH2:10][C:11]([F:14])([F:13])[CH3:12])[N:7]=1)[C:3]([OH:20])=[O:2])([CH2:18][CH3:19])[CH3:17]
Reactant: CC[C@H](C)Nc1cc(C(=O)OC)cc(CC(C)(F)F)n1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CC[C@H](C)Nc1cc(C(=O)O)cc(CC(C)(F)F)n1

Procedure:
Dissolve (S)-2-sec-butylamino-6-(2,2-difluoropropyl)-isonicotinic acid methyl ester (100 mg, 0.34 mmol) in THF (3 mL). Slowly add 1 N lithium hydroxide (0.52 mL) and stir overnight at room temperature. Acidify the mixture to about pH=6 by 5 N HCl and concentrate to near dryness. Dilute with ethyl acetate (20 mL) and wash the organic layer with saturated aqueous sodium chloride, dry (magnesium sulfate) and concentrate to give the title compound as a solid.
Reaction SMILES: C(OC(N1CC2C(COC3C=C4C(C(OC5C=CC=CC=5N[C:40]([NH:42][C:43](=[O:51])[CH2:44][C:45]5[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=5)=[S:41])=NC(F)=N4)=CC=3OC)CCC2C1)=O)C1C=CC=CC=1.C1(CC(Cl)=O)C=CC=CC=1.[CH2:64]([O:71][C:72]([N:74]1[CH2:78][CH:77]2[CH2:79][CH:80]([CH2:82][O:83][C:84]3[CH:93]=[C:92]4[C:87]([C:88]([O:94][C:95]5[CH:100]=[CH:99][C:98]([NH2:101])=[CH:97][C:96]=5[F:102])=[N:89][CH:90]=[N:91]4)=[CH:86][C:85]=3[O:103][CH3:104])[CH2:81][CH:76]2[CH2:75]1)=[O:73])[C:65]1[CH:70]=[CH:69][CH:68]=[CH:67][CH:66]=1.CCO>C1(C)C=CC=CC=1.CCOC(C)=O.C([S-])#N.[Ag+]>[CH2:64]([O:71][C:72]([N:74]1[CH2:75][CH:76]2[CH2:81][CH:80]([CH2:82][O:83][C:84]3[CH:93]=[C:92]4[C:87]([C:88]([O:94][C:95]5[CH:100]=[CH:99][C:98]([NH:101][C:40]([NH:42][C:43](=[O:51])[CH2:44][C:45]6[CH:46]=[CH:47][CH:48]=[CH:49][CH:50]=6)=[S:41])=[CH:97][C:96]=5[F:102])=[N:89][CH:90]=[N:91]4)=[CH:86][C:85]=3[O:103][CH3:104])[CH2:79][CH:77]2[CH2:78]1)=[O:73])[C:65]1[CH:70]=[CH:69][CH:68]=[CH:67][CH:66]=1
Reactant: COc1cc2c(Oc3ccccc3NC(=S)NC(=O)Cc3ccccc3)nc(F)nc2cc1OCC1CCC2CN(C(=O)OCc3ccccc3)CC12
Reactant: COc1cc2c(Oc3ccc(N)cc3F)ncnc2cc1OCC1CC2CN(C(=O)OCc3ccccc3)CC2C1
Agent: [Ag+]
Agent: N#C[S-]
Agent: O=C(Cl)Cc1ccccc1
Solvent: CCO
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: COc1cc2c(Oc3ccc(NC(=S)NC(=O)Cc4ccccc4)cc3F)ncnc2cc1OCC1CC2CN(C(=O)OCc3ccccc3)CC2C1
Temperature: 25 °C
Yield: 49 %

Procedure:
5-{4-[2-Fluoro-4-(3-phenylacetyl-thioureido-phenoxy]-6-methoxy-quinazolin-7-yloxymethyl}-hexahydro-cyclopenta[c]pyrrole-2-carboxylic acid benzyl ester. Phenylacetyl chloride (2.65 ml, 20.00 mmol) and AgSCN (4.92 g, 29.6 mmol) were combined in dry toluene (50 ml) and heated to reflux for 2 hrs. The reaction mixture was allowed to cool to room temperature, the solids were filtered through celite and the filtrate concentrated in vacuo. The resulting oil was combined with 5-[4-(4-amino-2-fluoro-phenoxy)-6-methoxy-quinazolin-7-yloxymethyl]-hexahydro-cyclopenta[c]pyrrole-2-carboxylic acid benzyl ester (5.6 g, 10 mmol) in 1:1 EtOH:toluene (100 ml) and the mixture stirred at room temperature for 1-2 hrs. The reaction mixture was diluted with EtOAc and washed with sat'd NaHCO3 (3×), H2O (1×), sat'd NaCl (1×), dried (Na2SO4), and concentrated in vacuo. The resulting oil was purified by flash chromatography (3:1 EtOAc:hexanes) to give 5-{4-[2-fluoro-4-(3-phenylacetyl-thioureido)-phenoxy]-6-methoxy-quinazolin-7-yloxymethyl}-hexahydrocyclopenta[c]pyrrole-2-carboxylic acid benzyl ester (3.61 g, 49%) as a dark brown foam. 1H-NMR (400 MHz, DMSO): 12.44 (s, 1H), 11.80 (s, 1H), 8.54 (s, 1H), 7.90 (m, 1H), 7.53 (s, 1H), 7.48 (m, 2H), 7.38 (s, 1H), 7.34 (m, 7H), 7.28 (m, 3H), 5.05 (s, 2H), 4.16 (d, 2H), 3.94 (s, 3H), 3.72 (s, 2H), 3.48 (m, 2H), 3.30 (m, 2H), 2.65 (m, 2H), 2.52 (m, 1H), 2.10 (m, 2H), 1.30 (m, 2H). LC/MS Calcd for [M+H]+ 736.2, found 736.0.
Reaction SMILES: C(OC([NH:8][C:9]1[CH:10]=[C:11]([N:15]([CH2:18][C:19]2[C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[CH:22]=[CH:21][CH:20]=2)[CH:16]=[O:17])[CH:12]=[CH:13][CH:14]=1)=O)(C)(C)C.Cl.NC1C=CC=CC=1.[Cl:37][C:38]1[CH:39]=[C:40]([CH:44]=[C:45]([Cl:47])[CH:46]=1)[C:41](Cl)=[O:42]>ClCCl.CCOCC.CC(N(C)C)=O.C(N(CC)CC)C>[Cl:37][C:38]1[CH:39]=[C:40]([C:41]([NH:8][C:9]2[CH:10]=[C:11]([N:15]([CH2:18][C:19]3[C:28]4[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=4)[CH:22]=[CH:21][CH:20]=3)[CH:16]=[O:17])[CH:12]=[CH:13][CH:14]=2)=[O:42])[CH:44]=[C:45]([Cl:47])[CH:46]=1
Reactant: CC(C)(C)OC(=O)Nc1cccc(N(C=O)Cc2cccc3ccccc23)c1
Reactant: O=C(Cl)c1cc(Cl)cc(Cl)c1
Agent: Cl
Solvent: CC(=O)N(C)C
Solvent: Nc1ccccc1
Solvent: ClCCl
Product: O=CN(Cc1cccc2ccccc12)c1cccc(NC(=O)c2cc(Cl)cc(Cl)c2)c1
Reaction time: 8 h

Procedure:
{3-[(tert-Butoxy)carbonylamino]phenyl}-N-(naphthylmethyl) formamide (270 mg, 0.72 mmol) was dissolved in 25 ml of dichloromethane and treated with 7 ml of 2N HCl in ether. After stirring overnight, the precipitate was collected by filtration and dried under vacuum. The aniline (190 mg, 0.61 mmol) was dissolved in dimethylacetamide (10 ml), and 3,5-dichlorobenzoyl chloride (130 mg, 0.61 mmol) and triethylamine (0.5 mL) were added and the resulting mixture was stirred overnight. The product was worked up as described above and recrystallized from ethyl acetate to provide compound 16 as a white crystalline solid, Mp=205-208° C., and 1H NMR (DMSO, 400 MHz) peaks of: δ 4.97 (d, 2H, J=5.76); 7.45-8.26 (m, 14H); 9.10 (t, 1H, J=5.76); 10.57 (s, 1H). The theoretical atomic composition for C25H18N2O2Cl2 [C, 66.83; H, 4.04; N, 6.23; Cl, 15.78] compares favorably with that found experimentally [C, 66.73; H, 4.15; N, 6.16; Cl, 15.81].
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][C:11]([NH:15][C:16]([C:18]2[N:22]3[CH:23]=[CH:24][CH:25]=[C:26]([O:27][CH2:28][CH:29]4[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]4)[C:21]3=[N:20][C:19]=2[CH3:35])=[O:17])([CH3:14])[CH2:10][CH2:9]1)C1C=CC=CC=1.ClC(OC(Cl)C)=O.ClC(Cl)C>>[CH:29]1([CH2:28][O:27][C:26]2[C:21]3[N:22]([C:18]([C:16]([NH:15][C:11]4([CH3:14])[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]4)=[O:17])=[C:19]([CH3:35])[N:20]=3)[CH:23]=[CH:24][CH:25]=2)[CH2:30][CH2:31][CH2:32][CH2:33][CH2:34]1
Reactant: Cc1nc2c(OCC3CCCCC3)cccn2c1C(=O)NC1(C)CCN(Cc2ccccc2)CC1
Agent: CC(Cl)OC(=O)Cl
Solvent: CC(Cl)Cl
Product: Cc1nc2c(OCC3CCCCC3)cccn2c1C(=O)NC1(C)CCNCC1
Temperature: 25 °C
Yield: 45.7 %

Procedure:
A mixture of 1.15 g of N-(1-benzyl-4-methylpiperidin-4-yl)-8-(cyclohexylmethoxy)-2-methylimidazolo[1,2-a]pyridine-3-carboxamide, 0.4 mL of 1-chloroethyl chloroformate, and 15 mL of dichloroethane was heated to reflux overnight. After leaving to be cooled at room temperature, the solvent was evaporated under reduced pressure, and to the residue was added 15 mL of methanol, followed by heating to reflux for 6 hours. After leaving to be cooled at room temperature, the solvent was evaporated under reduced pressure, and to the residue were added a saturated aqueous sodium hydrogen carbonate solution and chloroform to carry out a layer separation operation. The organic layer was dried over anhydrous magnesium sulfate and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography to obtain 426 mg of 8-(cyclohexylmethoxy)-2-methyl-N-(4-methylpiperidin-4-yl)imidazolo[1,2-a]pyridine-3-carboxamide.
Reaction SMILES: [C:1]([C:3]1[CH:26]=[CH:25][C:6]([C:7]([NH:9][C:10](=[O:24])[NH:11][C:12]2[CH:23]=[CH:22][C:15]([O:16][CH2:17][C:18]([O:20][CH3:21])=[O:19])=[CH:14][CH:13]=2)=[O:8])=[CH:5][CH:4]=1)#[N:2].[SH2:27]>N1C=CC=CC=1.C(N(CC)CC)C>[C:1]([C:3]1[CH:4]=[CH:5][C:6]([C:7]([NH:9][C:10](=[O:24])[NH:11][C:12]2[CH:23]=[CH:22][C:15]([O:16][CH2:17][C:18]([O:20][CH3:21])=[O:19])=[CH:14][CH:13]=2)=[O:8])=[CH:25][CH:26]=1)(=[S:27])[NH2:2]
Reactant: S
Reactant: COC(=O)COc1ccc(NC(=O)NC(=O)c2ccc(C#N)cc2)cc1
Solvent: c1ccncc1
Solvent: CCN(CC)CC
Product: COC(=O)COc1ccc(NC(=O)NC(=O)c2ccc(C(N)=S)cc2)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A solution of the product of step (a) (850 mg) in pyridine (48 ml) and triethylamine (7 ml) was covered with a blanket of H2S gas and stirred at ambient temperature for 16 hours. The reaction mixture was evaporated to dryness and the residue was triturated with dry ether. The resultant solid was washed thoroughly with ether to give methyl 4-[3-(4-thiocarbamoylbenzoyl)ureido]phenoxyacetate (880 mg) as a yellow solid: NMR Spectrum (DMSO-d6) 3.72 (3H, s), 4.78 (2H, s), 6.95 (2H, d), 7.48 (2H, m), 7.93 (2H, d), 8.06 (2H, d), 9.65 (1H, br s), 10.05 (1H, br s), 10.62 (1H, s).