Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[C:14]([F:17])([F:16])[F:15])[N:5]=[C:4]([NH:18][C:19]([C:21]2[O:25][N:24]=[C:23]([C:26]([CH3:29])([CH3:28])[CH3:27])[CH:22]=2)=[O:20])[C:3]=1[N+:30]([O-])=O.[Cl-].[NH4+]>CCO.O.[Fe]>[NH2:30][C:3]1[C:4]([NH:18][C:19]([C:21]2[O:25][N:24]=[C:23]([C:26]([CH3:29])([CH3:28])[CH3:27])[CH:22]=2)=[O:20])=[N:5][C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[C:14]([F:15])([F:16])[F:17])=[CH:7][C:2]=1[Cl:1]
Reactant: CC(C)(C)c1cc(C(=O)Nc2nc(-c3ccccc3C(F)(F)F)cc(Cl)c2[N+](=O)[O-])on1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Solvent: O
Product: CC(C)(C)c1cc(C(=O)Nc2nc(-c3ccccc3C(F)(F)F)cc(Cl)c2N)on1
Temperature: 50 °C
Reaction time: 3 h

Procedure:
A solution of 3-tert-butyl-isoxazole-5-carboxylic acid [4-chloro-3-nitro-6-(2-trifluoromethyl-phenyl)-pyridin-2-yl]-amide (40.7 mg, 0.0868 mmol, prepared as described in STEP A above) in EtOH (5 mL) and water (2.5 mL) was treated with ammonium chloride (46.4 mg, 0.868 mmol) and iron powder (24.2 mg, 0.434 mmol), and the mixture was stirred at 50° C. for 3 h. The cooled mixture was concentrated in vacuo and partitioned between EtOAc (25 mL) and water (20 mL). The aqueous layer was extracted with EtOAc (20 mL). The combined organic extracts were dried over MgSO4 and concentrated in vacuo. The residue was purified on a 12-g SEPRA Si 50 SPE column (Flow rate=20 mL/min; Eluent=EtOAc-hexanes, 1:99 for 10 min, then 1:99 to 1:3 over 40 min) to yield 3-tert-butyl-isoxazole-5-carboxylic acid [3-amino-4-chloro-6-(2-trifluoromethyl-phenyl)-pyridin-2-yl]-amide as a yellow solid. Mass Spectrum (LCMS, ESI pos.): Calculated for C21H18N4O2ClF3: 439.1 (M+H). Measured: 439.1.
Reaction SMILES: I[C:2]1[C:3]([NH2:14])=[CH:4][C:5]([N:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)=[N:6][CH:7]=1.N1C2C(=CC=C3C=2N=CC=C3)C=CC=1.[C:29](=O)([O-])[O-:30].[Cs+].[Cs+]>CO.[Cu]I>[CH3:29][O:30][C:2]1[C:3]([NH2:14])=[CH:4][C:5]([N:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)=[N:6][CH:7]=1
Reactant: Nc1cc(N2CCOCC2)ncc1I
Reactant: O=C([O-])[O-]
Agent: [Cu]I
Agent: [Cs+]
Agent: c1cnc2c(c1)ccc1cccnc12
Solvent: CO
Product: COc1cnc(N2CCOCC2)cc1N
Temperature: 130 °C
Yield: 49.6 %

Procedure:
A stirred suspension of 81.4 g (267 mmol) 5-iodo-2-morpholin-4-yl-pyridin-4-ylamine, 4.06 g (21.3 mmol) copper(I) iodide, 5.77 g (32.0 mmol) 1,10-phenanthroline and 174 g (533 mmol) cesium carbonate in 600 ml methanol was heated at 130° C. for 30 min in a microwave oven. The resulting mixture was then cooled to room temperature and filtered. The filtrate was concentrated in vacuo and the residue purified by flash chromatography (1/7 methanol/dichloromethane) to afford 27.7 g (50%) 5-methoxy-2-morpholin-4-yl-pyridin-4-ylamine as a dark brown crystalline solid. ES-MS m/e (%): 210 (M+H+, 100).
Reaction SMILES: [CH2:1]([N:8]([CH2:12][C@H:13]1[NH:17][C:16](=[O:18])[CH2:15][CH2:14]1)[CH2:9][CH2:10][OH:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:19][S:20](Cl)(=[O:22])=[O:21]>C(O)C.C(Cl)Cl>[CH2:1]([N:8]([CH2:12][C@@H:13]1[CH2:14][CH2:15][C:16](=[O:18])[NH:17]1)[CH2:9][CH2:10][O:11][S:20]([CH3:19])(=[O:22])=[O:21])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CS(=O)(=O)Cl
Reactant: O=C1CC[C@@H](CN(CCO)Cc2ccccc2)N1
Solvent: CCO
Solvent: ClCCl
Product: CS(=O)(=O)OCCN(Cc1ccccc1)C[C@@H]1CCC(=O)N1
Temperature: 25 °C
Reaction time: 20 h
Yield: 63 %

Procedure:
To a solution of (S)-(+)-5-((benzyl(2-hydroxyethyl)amino)methyl)pyrrolidin-2-one (3.5 g, 14.1 mmol) in ethanol-free CHCl3 (55 ml), TEA (2.85 g, 28.22 mmol) and methanesulfonyl chloride (3.23 g, 28.22 mmol, in 10 ml of CHCl3) were added at 0° C. The mixture was allowed to warm to room temperature and left stirring for 20 hours, then it was diluted with DCM (60 ml) and washed with a saturated solution of NaHCO3 (3×50 ml). After drying (Na2SO4) and removal of the solvent, the crude was purified by flash chromatography (DCM/abs EtOH/Petroleum Ether/33% NH4OH/Et2O 300/180/900/9.9/360 respectively) to afford the title compound (2.9 g, 63% yield).
Reaction SMILES: [F:1][CH:2]([F:30])[CH2:3][O:4][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[N:11]([CH:15]1[CH2:20][CH2:19][N:18](C(OC(C)(C)C)=O)[CH2:17][CH2:16]1)[C:10](=[O:28])[NH:9][C:8]2=[O:29]>C(O)=O>[F:30][CH:2]([F:1])[CH2:3][O:4][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[N:11]([CH:15]1[CH2:16][CH2:17][NH:18][CH2:19][CH2:20]1)[C:10](=[O:28])[NH:9][C:8]2=[O:29]
Reactant: CC(C)(C)OC(=O)N1CCC(n2c(=O)[nH]c(=O)c3cc(OCC(F)F)ccc32)CC1
Solvent: O=CO
Product: O=c1[nH]c(=O)n(C2CCNCC2)c2ccc(OCC(F)F)cc12
Yield: 142.4 %

Procedure:
A solution of 5.63 g of 1,1-dimethylethyl 4-[6-(2,2-difluoroethoxy)-2,4-dioxo-3,4-dihydroquinazolin-1(2H)-yl]piperidine-1-carboxylate obtained in stage 3.5 in 70 ml of formic acid is stirred at AT for 2 h 00. The solvent is evaporated under reduced pressure to give 6.13 g of the expected product in the form of the formic acid salt.
Reaction SMILES: [C:1](Cl)(=[O:4])[CH:2]=[CH2:3].[NH2:6][C:7]1[C:8]([N:34]2[CH2:38][CH2:37][C@@H:36]([N:39]([CH3:41])[CH3:40])[CH2:35]2)=[CH:9][C:10]([O:32][CH3:33])=[C:11]([NH:13][C:14]2[N:19]=[C:18]([C:20]3[C:28]4[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=4)[N:22]([CH3:29])[CH:21]=3)[C:17]([C:30]#[N:31])=[CH:16][N:15]=2)[CH:12]=1.CCN(C(C)C)C(C)C>C1COCC1.O.C(Cl)Cl.C(OCC)C>[C:30]([C:17]1[C:18]([C:20]2[C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[N:22]([CH3:29])[CH:21]=2)=[N:19][C:14]([NH:13][C:11]2[C:10]([O:32][CH3:33])=[CH:9][C:8]([N:34]3[CH2:38][CH2:37][C@@H:36]([N:39]([CH3:40])[CH3:41])[CH2:35]3)=[C:7]([NH:6][C:1](=[O:4])[CH:2]=[CH2:3])[CH:12]=2)=[N:15][CH:16]=1)#[N:31]
Reactant: COc1cc(N2CC[C@@H](N(C)C)C2)c(N)cc1Nc1ncc(C#N)c(-c2cn(C)c3ccccc23)n1
Reactant: C=CC(=O)Cl
Solvent: O
Solvent: CCOCC
Solvent: CCN(C(C)C)C(C)C
Product: C=CC(=O)Nc1cc(Nc2ncc(C#N)c(-c3cn(C)c4ccccc34)n2)c(OC)cc1N1CC[C@@H](N(C)C)C1
Temperature: 0 °C
Reaction time: 1 h
Yield: 45.8 %

Procedure:
Acryloyl chloride (0.373 mL, 1M in THF, 0.37 mmol) was added dropwise to a mixture of 2-({5-amino-4-[(3R)-3-dimethylaminopyrrolidin-1-yl]-2-methoxyphenyl}amino)-4-(1-methylindol-3-yl)pyrimidine-5-carbonitrile (Intermediate 89, 180 mg, 0.37 mmol) and DIPEA (0.072 mL, 0.41 mmol) in THF (15 mL) at 0° C. under N2. The resulting suspension was stirred at 0° C. for 1 h, then allowed to warm to r.t. The mixture was diluted with water (15 mL) and then concentrated in vacuo. The resulting material was dissolved in a mixture of CH2Cl2 (20 mL) and CH3OH (5 mL). The resulting solution was washed with water and sat. brine. The organic solution was dried (MgSO4) and concentrated in vacuo. Purification by FCC, eluting with 1-8% 7M methanolic ammonia in CH2Cl2 gave a yellow dry film after concentration of the appropriate fractions in vacuo. This material was dissolved in CH2Cl2 and the resulting solution was diluted with diethyl ether. A yellow gelatinous solid then precipitated from the solution. Concentration of the mixture in vacuo gave the title compound (91 mg, 46%) as a yellow solid; 1H NMR: (100° C.) 1.82 (1H, dq), 2.04-2.11 (1H, m), 2.22 (6H, d), 2.85 (1H, dd), 3.20-3.39 (4H, m), 3.79 (3H, s), 3.90 (3H, s), 5.62 (1H, d), 6.16 (1H, dd), 6.45 (1H, dd), 6.62 (1H, s), 7.10 (1H, t), 7.25 (1H, t), 7.49 (1H, d), 7.65 (1H, s), 8.26 (1H, d), 8.42 (1H, s), 8.59 (1H, s), 8.72 (1H, s), 8.93 (1H, s); m/z: ES+ MH+ 537.61.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6](Cl)[C:5]([C:9]#[N:10])=[C:4]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[N:3]=1.[CH:17]([Sn](CCCC)(CCCC)CCCC)=[CH2:18].C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Pd]>[NH2:1][C:2]1[N:3]=[C:4]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:5]([C:9]#[N:10])=[C:6]([CH:17]=[CH2:18])[N:7]=1
Reactant: C=C[Sn](CCCC)(CCCC)CCCC
Reactant: N#Cc1c(Cl)nc(N)nc1-c1ccccc1
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Product: C=Cc1nc(N)nc(-c2ccccc2)c1C#N
Yield: 8.1 %

Procedure:
To a stirred solution of 515 mg (2.23 mmol) 2-amino-4-chloro-6-phenyl-pyrimidine-5-carbonitrile in 20 ml dioxane under argon at room temperature were added 0.65 ml (2.23 mmol) vinyltributylstannane, 258 mg (0.22 mmol) tetrakis(triphenylphosphine)palladium(O) and 4.5 ml (9.0 mmol) 2M aqueous sodium carbonate solution. The reaction mixture was heated at reflux for 16 h, then concentrated in vacuo. The residue was partitioned between ethyl acetate and water and the organic phase washed with brine, dried over sodium sulfate, and concentrated in vacuo. Flash chromatography (1/1 ethyl acetate/hexane) followed by trituration in ether afforded 40 mg (8%) 2-Amino-4-phenyl-6-vinyl-pyrimidine-5-carbonitrile as a yellow crystalline solid. EI-MS m/e (%): 222 (M+, 85), 221 ([M—H]+, 100).
Reaction SMILES: [C:1]([OH:9])(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)C(C)C)(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH2:43][CH2:44][CH2:45][NH:46][C:47]1[N:52]=[C:51]([C:53]2[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=2)[N:50]=[C:49]([NH:59][CH2:60][CH2:61][NH:62][C:63](=[O:65])[CH3:64])[C:48]=1[CH3:66]>CN1C(=O)CCC1>[C:63]([NH:62][CH2:61][CH2:60][NH:59][C:49]1[N:50]=[C:51]([C:53]2[CH:54]=[CH:55][CH:56]=[CH:57][CH:58]=2)[N:52]=[C:47]([NH:46][CH2:45][CH2:44][NH:43][C:1](=[O:9])[C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[C:48]=1[CH3:66])(=[O:65])[CH3:64]
Reactant: O=C(O)c1ccccc1
Reactant: CC(=O)NCCNc1nc(-c2ccccc2)nc(NCCN)c1C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN1CCCC1=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)NCCNc1nc(-c2ccccc2)nc(NCCNC(=O)c2ccccc2)c1C
Temperature: 25 °C
Reaction time: 16 h
Yield: 27.3 %

Procedure:
Benzoic acid (55.8 mg), N,N-diisopropylethylamine (80 μl) and HATU (160 mg) were stirred in NMP (6851 μl) for 30 min. After this time N-[2-({6-[(2-aminoethyl)amino]-5-methyl-2-phenylpyrimidin-4-yl}amino)ethyl]acetamide (150 mg) was added and the mixture stirred for 16 hrs at room temperature. Purification via SCX resin furnished the title compound (54 mg).
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[CH:14]=[CH:13][C:9]([C:10]([OH:12])=O)=[CH:8][CH:7]=2)[CH2:3][CH2:2]1.[C:15]([NH:18][C@@H:19]([CH3:43])[CH2:20][O:21][C:22]1[CH:27]=[C:26]([S:28][CH2:29][CH2:30][C:31]([O:33][CH2:34][CH:35]([CH2:40][CH3:41])[CH2:36][CH2:37][CH2:38][CH3:39])=[O:32])[C:25]([NH2:42])=[CH:24][N:23]=1)(=[O:17])[CH3:16].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C>O.CN(C=O)C>[C:15]([NH:18][C@@H:19]([CH3:43])[CH2:20][O:21][C:22]1[CH:27]=[C:26]([S:28][CH2:29][CH2:30][C:31]([O:33][CH2:34][CH:35]([CH2:40][CH3:41])[CH2:36][CH2:37][CH2:38][CH3:39])=[O:32])[C:25]([NH:42][C:10](=[O:12])[C:9]2[CH:8]=[CH:7][C:6]([O:5][CH2:4][CH:1]3[CH2:2][CH2:3]3)=[CH:14][CH:13]=2)=[CH:24][N:23]=1)(=[O:17])[CH3:16]
Reactant: O=C(O)c1ccc(OCC2CC2)cc1
Reactant: CCCCC(CC)COC(=O)CCSc1cc(OC[C@H](C)NC(C)=O)ncc1N
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CN(C)C=O
Product: CCCCC(CC)COC(=O)CCSc1cc(OC[C@H](C)NC(C)=O)ncc1NC(=O)c1ccc(OCC2CC2)cc1
Temperature: 70 °C
Reaction time: 120 h
Yield: 52.5 %

Procedure:
A mixture of 4-(cyclopropylmethoxy)benzoic acid (452 mg), 2-ethylhexyl 3-((2-(((2S)-2-acetamidopropyl)oxy)-5-aminopyridin-4-yl)sulfanyl)propanoate (1.00 g), HATU (0.893 g), N,N-diisopropylethylamine (0.821 mL) and DMF (10 mL) was stirred at 70° C. for 5 days. To the reaction mixture was added water, and the mixture was extracted with ethyl acetate. The combined organic layer were washed with saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give the title compound (0.740 g).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1Cl)=[CH:13][C:12]([Br:17])=[CH:11][CH:10]=2)=[O:5])[CH3:2].Cl.[CH3:19][O:20][C@@H:21]([CH3:24])[CH2:22][NH2:23].C(N(C(C)C)CC)(C)C>C(O)C>[Br:17][C:12]1[CH:13]=[C:14]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:4]([O:3][CH2:1][CH3:2])=[O:5])=[C:15]2[NH:23][CH2:22][C@@H:21]([O:20][CH3:19])[CH3:24]
Reactant: CO[C@@H](C)CN
Reactant: CCOC(=O)c1cnc2ccc(Br)cc2c1Cl
Agent: Cl
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)c1cnc2ccc(Br)cc2c1NC[C@H](C)OC
Reaction time: 16 h

Procedure:
Suspend ethyl-6-bromo-4-chloro-quinoline-3-carboxylate (389 g, 1.24 mol) and (2S)-2-methoxypropan-1-amine, hydrochloride (171 g, 1.36 mol, 1.1 eq.) in ethanol (5.84 L). Add diisopropylethylamine (474 mL) and heat the mixture at 50° C. overnight. After 16 hours, cool the reaction to room temperature and concentrate in vacuo. Add methyl tert-butyl ether (2 L) to the residue and stir for 20 min. Filter the precipitate and wash it with methyl tert-butyl ether (2×250 mL). Concentrate the filtrate in vacuo to afford the titled compound in almost quantitative yield. The compound will be used in the next step without further purification. MS (ESI) m/z (M+H)+ 367.0, 369.0.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5]([C:8]2[CH:9]=[CH:10][C:11]([O:31][CH3:32])=[C:12]([CH:30]=2)[CH2:13][NH:14][CH:15]2[CH2:20][CH2:19][CH:18]([N:21]([CH3:29])[C:22](=[O:28])[O:23][C:24]([CH3:27])([CH3:26])[CH3:25])[CH2:17][CH2:16]2)=[CH:4][CH:3]=1.[Cl:33][C:34]1[C:35]2[C:45]([F:46])=[CH:44][CH:43]=[C:42]([F:47])[C:36]=2[S:37][C:38]=1[C:39](Cl)=[O:40]>>[NH2:1][C:2]1[N:7]=[CH:6][C:5]([C:8]2[CH:9]=[CH:10][C:11]([O:31][CH3:32])=[C:12]([CH:30]=2)[CH2:13][N:14]([C:39]([C:38]2[S:37][C:36]3[C:42]([F:47])=[CH:43][CH:44]=[C:45]([F:46])[C:35]=3[C:34]=2[Cl:33])=[O:40])[CH:15]2[CH2:16][CH2:17][CH:18]([N:21]([CH3:29])[C:22](=[O:28])[O:23][C:24]([CH3:26])([CH3:27])[CH3:25])[CH2:19][CH2:20]2)=[CH:4][CH:3]=1
Reactant: O=C(Cl)c1sc2c(F)ccc(F)c2c1Cl
Reactant: COc1ccc(-c2ccc(N)nc2)cc1CNC1CCC(N(C)C(=O)OC(C)(C)C)CC1
Product: COc1ccc(-c2ccc(N)nc2)cc1CN(C(=O)c1sc2c(F)ccc(F)c2c1Cl)C1CCC(N(C)C(=O)OC(C)(C)C)CC1

Procedure:
Crude biaryl amine 142 (300 mg, 0.68 mmol) is treated with acid chloride 8 (182 mg, 0.68 mmol) using Method D to give the title compound.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][C:9]([OH:11])=[O:10].[CH3:12][O:13][C:14]1[CH:19]=[CH:18][C:17]([S:20](Cl)(=[O:22])=[O:21])=[CH:16][CH:15]=1>[OH-].[Na+]>[CH3:12][O:13][C:14]1[CH:15]=[CH:16][C:17]([S:20]([NH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][C:9]([OH:11])=[O:10])(=[O:22])=[O:21])=[CH:18][CH:19]=1
Reactant: NCCCCCCCC(=O)O
Reactant: COc1ccc(S(=O)(=O)Cl)cc1
Agent: [Na+]
Agent: [OH-]
Product: COc1ccc(S(=O)(=O)NCCCCCCCC(=O)O)cc1

Procedure:
A solution of 8-aminooctanoic acid in 10% sodium hydroxide solution was treated with 4-methoxybenzenesulphonylchloride in the manner of Example 2 to give the title compound which, on recrystallisation from aqueous 2-propanol, had a melting point of 102°-103° C.
Reaction SMILES: [CH:1]12[O:8][CH:5]([CH2:6][CH2:7]1)[CH2:4][N:3]([C:9]1[N:14]=[C:13]([N:15]3[CH2:20][CH2:19][C:18](=O)[CH2:17][CH2:16]3)[N:12]=[C:11]([C:22]3[CH:27]=[CH:26][C:25]([NH:28][C:29]([NH:31][C:32]4[CH:37]=[CH:36][N:35]=[CH:34][CH:33]=4)=[O:30])=[CH:24][CH:23]=3)[N:10]=1)[CH2:2]2.C(O)(C(F)(F)F)=O.Cl.[C:46]([O:50][C:51](=[O:54])[CH2:52][NH2:53])([CH3:49])([CH3:48])[CH3:47]>C(N(CC)CC)C>[CH:5]12[O:8][CH:1]([CH2:7][CH2:6]1)[CH2:2][N:3]([C:9]1[N:10]=[C:11]([C:22]3[CH:27]=[CH:26][C:25]([NH:28][C:29]([NH:31][C:32]4[CH:33]=[CH:34][N:35]=[CH:36][CH:37]=4)=[O:30])=[CH:24][CH:23]=3)[N:12]=[C:13]([N:15]3[CH2:16][CH2:17][CH:18]([NH:53][CH2:52][C:51]([O:50][C:46]([CH3:49])([CH3:48])[CH3:47])=[O:54])[CH2:19][CH2:20]3)[N:14]=1)[CH2:4]2
Reactant: O=C1CCN(c2nc(-c3ccc(NC(=O)Nc4ccncc4)cc3)nc(N3CC4CCC(C3)O4)n2)CC1
Reactant: CC(C)(C)OC(=O)CN
Agent: Cl
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)CNC1CCN(c2nc(-c3ccc(NC(=O)Nc4ccncc4)cc3)nc(N3CC4CCC(C3)O4)n2)CC1

Procedure:
Starting from 1-(4-(4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-6-(4-oxopiperidin-1-yl)-1,3,5-triazin-2-yl)phenyl)-3-(pyridin-4-yl)urea.TFA (60 mg) and glycine tert-butyl ester hydrochloride (33 mg) and triethylamine (10 drops) and following the procedure as outlined in example 118, the title compound was isolated as its di-TFA salt after HPLC purification; MS (ES+) 616.9 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([SH:8])[CH:3]=1.Cl[CH2:10][CH2:11][CH2:12][C:13]([C:15]1[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=1)=[O:14].C(N(CC)CC)C>O1CCCC1>[F:21][C:18]1[CH:17]=[CH:16][C:15]([C:13](=[O:14])[CH2:12][CH2:11][CH2:10][S:8][C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([CH3:1])[CH:3]=2)=[CH:20][CH:19]=1
Reactant: O=C(CCCCl)c1ccc(F)cc1
Reactant: Cc1cccc(S)c1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: Cc1cccc(SCCCC(=O)c2ccc(F)cc2)c1
Yield: 98.8 %

Procedure:
A solution of 3-thiocresol (25.0 g, 0.2 mole) and 4-chloro-4'-fluorobutyrophenone (40.1 g, 0.2 mole) in tetrahydrofuran (200 ml) was treated with triethylamine (22.3 g, 0.22 mole) and refluxed for six hours under nitrogen. The mixture was concentrated in vacuo, and the residue was partitioned between diethyl ether (200 ml) and water (200 ml). The organic layer was washed three times with sodium hydroxide (1N), water, and brine; dried over anhydrous magnesium sulfate, filtered, and concentrated to a pure oil by tlc (n-butyl chloride) to yield the title compound (57.0 g, 99%); IR(nujol): C=O @ 1686 cm-1 ; NMR(CDCl3, TMS): δ2.08(m,2H,CH2), 2.30(s,3H,ArCH3), 3.00(t,2H,CH2 --CO), 3.10(t,2H,S--CH2), 6.9-7.17(m,4H, 1,3-substituted phenyl), [7.10(d of d, 2H) and 7.97(m,2H) p-F-phenyl]; Anal. Calcd. for C17H17FNOS, MW 288.38: C,70.80; H,7.97; S,11.12. Found: C,70.79; H,6.01; S,11.18. Mass spectrum m/e 288,150.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([N:11]2[CH:16]=[CH:15][C:14]([O:17][CH:18]3C[CH2:22][N:21]([C:24]([O:26][C:27]([CH3:30])(C)[CH3:28])=[O:25])[CH2:20][CH2:19]3)=[CH:13][C:12]2=[O:31])=[CH:7][CH:6]=1)(=[O:4])=[O:3].ClC(OC1C=[CH:40][C:39]([Cl:42])=[CH:38]C=1)=O.ClC(OC(C)C(F)(F)F)=O>>[CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([N:11]2[CH:16]=[CH:15][C:14]([O:17][CH2:18][CH:19]3[CH2:22][N:21]([C:24]([O:26][C:27]4[CH:28]=[CH:40][C:39]([Cl:42])=[CH:38][CH:30]=4)=[O:25])[CH2:20]3)=[CH:13][C:12]2=[O:31])=[CH:7][CH:6]=1)(=[O:4])=[O:3]
Reactant: O=C(Cl)Oc1ccc(Cl)cc1
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2ccn(-c3ccc(S(C)(=O)=O)cc3)c(=O)c2)CC1
Agent: CC(OC(=O)Cl)C(F)(F)F
Product: CS(=O)(=O)c1ccc(-n2ccc(OCC3CN(C(=O)Oc4ccc(Cl)cc4)C3)cc2=O)cc1

Procedure:
Example 21 was prepared according to procedures described in Example 2, Step A and Step C, substituting tert-butyl 3-((1-(4-(methylsulfonyl)phenyl)-2-oxo-1,2-dihydropyridin-4-yloxy)methyl)azetidine-1-carboxylate for tert-butyl 4-(1-(4-(methylsulfonyl)phenyl)-2-oxo-1,2-dihydropyridin-4-yloxy)piperidine-1-carboxylate in Step A and 4-chlorophenyl chloroformate for 1,1,1-trifluoropropan-2-yl chloroformate in Step C. 1H NMR (500 MHz, CDCl3) δ 8.09 (d, J=8.25 Hz, 2 H), 7.62 (d, J=8.80 Hz, 2 H), 7.29-7.36 (m, 3 H), 7.05-7.12 (m, 2 H), 6.16-6.25 (m, 2 H), 4.38 (app br. s, 1 H), 4.28 (app br. s, 1 H), 4.21 (d, J=6.05 Hz, 2 H), 4.09 (app br. s, 1 H), 4.00 (app br. s, 1 H), 3.14-3.23 (m, 1 H), 3.11 (s, 3 H). MS (ESI) 489 (M+H).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([C:10]2[N:11]=[N:12][N:13]([C:15]3[CH:23]=[CH:22][C:18]([C:19](O)=[O:20])=[CH:17][CH:16]=3)[CH:14]=2)=[N:2]1.[CH3:24][N:25]([CH3:31])[CH:26]1[CH2:30][CH2:29][NH:28][CH2:27]1>>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([C:10]2[N:11]=[N:12][N:13]([C:15]3[CH:16]=[CH:17][C:18]([C:19]([N:28]4[CH2:29][CH2:30][CH:26]([N:25]([CH3:31])[CH3:24])[CH2:27]4)=[O:20])=[CH:22][CH:23]=3)[CH:14]=2)=[N:2]1
Reactant: CN(C)C1CCNC1
Reactant: O=C(O)c1ccc(-n2cc(-c3n[nH]c4ccccc34)nn2)cc1
Product: CN(C)C1CCN(C(=O)c2ccc(-n3cc(-c4n[nH]c5ccccc45)nn3)cc2)C1

Procedure:
The title compound was obtained following procedure described for example 26, but starting from 4-[4-(1H-indazol-3-yl)-1H-1,2,3-triazol-1-yl]benzoic acid (100 mg; 0.33 mmol; 1.0 eq.) and 3-dimethylamino pyrrolidine (56 mg, 0.49, 1.5 eq.). Purification by flash chomatography on silica (DCM:MeOH:NH4OH, gradient from 100:0:0 to 90:10:0.1) afforded the title compound as a yellow powder. 1H NMR (300 Mz, DMSO-d6) δ 13.37 (s, 1H), 9.39 (s, 1H), 8.36 (d, J=8.2 Hz, 1H), 8.13 (d, J=8.3 Hz, 2H), 7.83-7.72 (m, 2H), 7.61 (d, J=8.4 Hz, 1H), 7.53-7.36 (m, 1H), 7.33-7.19 (m, 1H), 3.77-3.18 (m, 5H), 2.78-2.60 (m, 1H), 2.24-1.92 (m, 6H), 1.82-1.69 (m, 1H). HPLC (Condition A): Rt 2.20 min (purity 90.1%). MS (ESI+): 402.3, MS (ESI−): 400.3.
Reaction SMILES: [CH2:1]([O:6][C:7]1[CH:19]=[CH:18][C:17]2[C:16]3[C:11](=[CH:12][C:13]([CH2:20][CH2:21][C:22]4[CH:27]=[CH:26][C:25]([OH:28])=[C:24]([F:29])[CH:23]=4)=[CH:14][CH:15]=3)[CH2:10][C:9]=2[CH:8]=1)[CH2:2][CH2:3][CH2:4][CH3:5].[C:30](O)(=[O:33])[CH:31]=[CH2:32].Cl.C(N=C=NCCCN(C)C)C.O>C(Cl)(Cl)Cl.CN(C)C1C=CN=CC=1>[CH2:1]([O:6][C:7]1[CH:19]=[CH:18][C:17]2[C:16]3[C:11](=[CH:12][C:13]([CH2:20][CH2:21][C:22]4[CH:27]=[CH:26][C:25]([O:28][C:30](=[O:33])[CH:31]=[CH2:32])=[C:24]([F:29])[CH:23]=4)=[CH:14][CH:15]=3)[CH2:10][C:9]=2[CH:8]=1)[CH2:2][CH2:3][CH2:4][CH3:5]
Reactant: C=CC(=O)O
Reactant: CCCCCOc1ccc2c(c1)Cc1cc(CCc3ccc(O)c(F)c3)ccc1-2
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: O
Solvent: ClC(Cl)Cl
Product: C=CC(=O)Oc1ccc(CCc2ccc3c(c2)Cc2cc(OCCCCC)ccc2-3)cc1F
Temperature: 0 °C
Reaction time: 24 h
Yield: 17.6 %

Procedure:
2-Pentyloxy-7-(2-(3-fluoro-4-hydroxyphenyl)ethyl)fluorene (0.7 g) and acrylic acid (0.14 g) were dissolved in chloroform (30 mL) and cooled down to 0° C. 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.44 g) and 4-dimethylaminopyridine (0.01 g) were added thereto, and then the temperature was allowed to come back to a room temperature, followed by stirring for 24 hours. Water was added to separate the solution, and the chloroform layer was dried on anhydrous magnesium sulfate. A residue obtained by distilling chloroform off was purified by means of column chromatography (silica gel, eluting solvent: toluene), and it was further recrystallized to obtain 2-pentyloxy-7-(2-(3-fluoro-4-acryloyloxyphenyl)ethyl)fluorene (0.14 g) of the intended product.
Reaction SMILES: [CH2:1]([N:3]([CH:46]1[CH2:51][CH2:50][O:49][CH2:48][CH2:47]1)[C:4]1[CH:5]=[C:6]([C:26]2[CH:27]=[CH:28][C:29]([N:32]3[CH2:37][CH2:36][CH:35]([NH:38]C(=O)OC(C)(C)C)[CH2:34][CH2:33]3)=[N:30][CH:31]=2)[CH:7]=[C:8]([C:11](=[O:25])[NH:12][CH2:13][C:14]2[C:15](=[O:24])[NH:16][C:17]([CH3:23])=[CH:18][C:19]=2[CH:20]([CH3:22])[CH3:21])[C:9]=1[CH3:10])[CH3:2].C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:38][CH:35]1[CH2:34][CH2:33][N:32]([C:29]2[N:30]=[CH:31][C:26]([C:6]3[CH:5]=[C:4]([N:3]([CH2:1][CH3:2])[CH:46]4[CH2:47][CH2:48][O:49][CH2:50][CH2:51]4)[C:9]([CH3:10])=[C:8]([CH:7]=3)[C:11]([NH:12][CH2:13][C:14]3[C:15](=[O:24])[NH:16][C:17]([CH3:23])=[CH:18][C:19]=3[CH:20]([CH3:22])[CH3:21])=[O:25])=[CH:27][CH:28]=2)[CH2:37][CH2:36]1
Reactant: CCN(c1cc(-c2ccc(N3CCC(NC(=O)OC(C)(C)C)CC3)nc2)cc(C(=O)NCc2c(C(C)C)cc(C)[nH]c2=O)c1C)C1CCOCC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCN(c1cc(-c2ccc(N3CCC(N)CC3)nc2)cc(C(=O)NCc2c(C(C)C)cc(C)[nH]c2=O)c1C)C1CCOCC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 98.4 %

Procedure:
tert-butyl (1-(5-(3-(ethyl(tetrahydro-2H-pyran-4-yl)amino)-5-(((4-isopropyl-6-methyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)carbamoyl)-4-methylphenyl)pyridin-2-yl)piperidin-4-yl)carbamate (0.31 g, 0.44 mmol) was taken in DCM (5 mL) and TFA (1 mL) was added to it and stirred at rt for 2 h. After completion of reaction, solvent was removed under reduced pressure and saturated NaHCO3 solution was added to it. Extraction was carried out using 10% MeOH/DCM; the combined organic layers were washed with water and brine; dried over anhydrous Na2SO4; filtered and concentrated under reduced pressure to give the title compound (0.26 g, 98.11%)