Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:42])([F:41])[C@H:3]([N:28]1[CH2:32][CH2:31][C@H:30]([NH:33][C:34](=[O:40])[O:35][C:36]([CH3:39])([CH3:38])[CH3:37])[CH2:29]1)[C:4]1[CH:5]=[N:6][C:7]([NH:10]/[N:11]=[CH:12]/[C:13]2[CH:22]=[CH:21][C:20]3[C:15](=[C:16]([O:24][CH:25]([CH3:27])[CH3:26])[CH:17]=[C:18]([F:23])[CH:19]=3)[N:14]=2)=[CH:8][CH:9]=1.C(O)(=O)C.C(O)(=O)C.I(C1C=CC=CC=1)=O>C(Cl)Cl>[F:42][C:2]([F:1])([F:41])[C@H:3]([N:28]1[CH2:32][CH2:31][C@H:30]([NH:33][C:34](=[O:40])[O:35][C:36]([CH3:37])([CH3:39])[CH3:38])[CH2:29]1)[C:4]1[CH:9]=[CH:8][C:7]2[N:6]([C:12]([C:13]3[CH:22]=[CH:21][C:20]4[C:15](=[C:16]([O:24][CH:25]([CH3:27])[CH3:26])[CH:17]=[C:18]([F:23])[CH:19]=4)[N:14]=3)=[N:11][N:10]=2)[CH:5]=1
Reactant: CC(C)Oc1cc(F)cc2ccc(/C=N/Nc3ccc([C@@H](N4CC[C@H](NC(=O)OC(C)(C)C)C4)C(F)(F)F)cn3)nc12
Agent: O=Ic1ccccc1
Solvent: ClCCl
Solvent: CC(=O)O
Product: CC(C)Oc1cc(F)cc2ccc(-c3nnc4ccc([C@@H](N5CC[C@H](NC(=O)OC(C)(C)C)C5)C(F)(F)F)cn34)nc12
Temperature: 25 °C
Reaction time: 2 h
Yield: 79.2 %

Procedure:
To tert-butyl (S)-1-((R)-2,2,2-trifluoro-1-(6-((E)-2-((6-fluoro-8-isopropoxyquinolin-2-yl)methylene)hydrazinyl)pyridin-3-yl)ethyl)pyrrolidin-3-ylcarbamate (157 mg, 0.266 mmol) in DCM (10 mL) was added iodosobenzene diacetate (94.2 mg, 0.292 mmol) and the reaction was stirred at ambient temperature for 2 hours. The reaction was concentrated to dryness and the residue purified by reverse phase chromatography (SP4, 12M, eluting with a gradient of water/ACN 100:0 to 0:100, 20 column volumes) to yield tert-butyl (S)-1-((R)-2,2,2-trifluoro-1-(3-(6-fluoro-8-isopropoxyquinolin-2-yl)-[1,2,4]triazolo[4,3-a]pyridin-6-yl)ethyl)pyrrolidin-3-ylcarbamate (124 mg, 79.3% yield) as a beige solid.
Reaction SMILES: [N:1]([CH2:4][C:5]([C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([O:13][C:14]2[CH:19]=[CH:18][C:17]([C:20](=[O:25])[CH2:21][N:22]=[N+]=[N-])=[CH:16][CH:15]=2)[CH:8]=1)=[O:6])=[N+]=[N-].[ClH:26]>CO.[Pd]>[ClH:26].[ClH:26].[NH2:1][CH2:4][C:5]([C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([O:13][C:14]2[CH:15]=[CH:16][C:17]([C:20](=[O:25])[CH2:21][NH2:22])=[CH:18][CH:19]=2)[CH:8]=1)=[O:6]
Reactant: [N-]=[N+]=NCC(=O)c1ccc(Oc2cccc(C(=O)CN=[N+]=[N-])c2)cc1
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: NCC(=O)c1ccc(Oc2cccc(C(=O)CN)c2)cc1

Procedure:
To a solution of 2-azido-1-(3-(4-(2-azidoacetyl)phenoxy)phenyl)ethanone (9 g, 26.4 mmol) in methanol (400 mL) was added HCl (1M in methanol, 53 mL) and the mixture was hydrogenated using Pd/C (10%) under hydrogen atmosphere (1 bar) during 2 hours. The solution was filtered over celite and concentrated under reduced pressure. The crude was dissolved in dichloromethane and after addition of HCl (6N in isopropanol) the hydrochloride salt precipitated. Filtration and drying in vacuo afforded 2-amino-1-(3-(4-(2-aminoacetyl)phenoxy)phenyl)ethanone dihydrochloride.
Reaction SMILES: [CH3:1][O:2][CH:3]([O:8][CH3:9])[C:4](OC)=[O:5].[CH3:10][CH:11]([NH2:18])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>CCCCCC>[CH3:1][O:2][CH:3]([O:8][CH3:9])[C:4]([NH:18][CH:11]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[CH3:10])=[O:5]
Reactant: CC(N)c1ccccc1
Reactant: COC(=O)C(OC)OC
Solvent: CCCCCC
Product: COC(OC)C(=O)NC(C)c1ccccc1
Temperature: 40 °C
Reaction time: 96 h

Procedure:
A mixture of methyl dimethoxyacetate (2.10 g, 15.6 mmol) and α-methylbenzylamine (1.90 g, 15.7 mmol) was stirred at ambient temperature for 5 d and at 40° C. for 4 d. To the reaction mixture was added hexane (5 mL), and the mixture was sonicated. Two layers formed, but no solid precipitated, even upon cooling, and the hexane layer was withdrawn with a pipette. This was repeated twice. The residue was dissolved in EtOAc (≈100 mL), and the solution was washed with aqueous solutions of NH4Cl, NaHCO3, and brine, and dried over MgSO4. The solution was filtered and dried in vacuo overnight to give the title compound as pale yellow oil. 1H NMR (CDCl3, 400 MHz): δ=7.38-7.30 (m, 4H), 7.29-7.24 (m, 1H), 6.80 (brs, 1H), 5.16 (dq, J=8.0, 6.8 Hz, 1H), 4.70 (s, 1H), 3.42 (s, 3H), 3.36 (s, 3H), 1.52 (d, J=6.8 Hz, 3H). MS(ES+): m/z=246.07 (64) [MNa+], 224.11 (78) [MH+], 192.11 (52) [MH+-MeOH], 160.10 (60) [MH+-2 MeOH]. HPLC: tR=2.76 min (polar—5 min, ZQ3).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:19])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([O:10][CH3:11])[C:5]=1[O:12][S:13]([N:16]=[C:17]=[O:18])(=[O:15])=[O:14].[NH2:20][C:21]1[N:26]=[C:25]([O:27][CH3:28])[CH:24]=[C:23]([O:29][CH3:30])[N:22]=1>C(Cl)Cl>[CH3:30][O:29][C:23]1[CH:24]=[C:25]([O:27][CH3:28])[N:26]=[C:21]([NH:20][C:17](=[O:18])[NH:16][S:13]([O:12][C:5]2[C:6]([O:10][CH3:11])=[CH:7][CH:8]=[CH:9][C:4]=2[C:3]([O:2][CH3:1])=[O:19])(=[O:15])=[O:14])[N:22]=1
Reactant: COc1cc(OC)nc(N)n1
Reactant: COC(=O)c1cccc(OC)c1OS(=O)(=O)N=C=O
Solvent: ClCCl
Product: COC(=O)c1cccc(OC)c1OS(=O)(=O)NC(=O)Nc1nc(OC)cc(OC)n1
Temperature: 25 °C
Reaction time: 24 h
Yield: 76.9 %

Procedure:
A solution of 5.4 g (0.02 mol) of the product from Example 1 in 10 ml of methylene chloride is added dropwise to 3.1 g (0.02 mol) of 2-amino-4,6-dimethoxypyrimidine in 50 ml of methylene chloride at 0° C. The mixture is subsequently stirred at 25° C. for 24 hours and diluted with 50 ml of methylene chloride and the organic phase is washed twice with 50 ml of 2N hydrochloric acid each time and once with 50 ml of water. After drying with sodium sulfate and removing the solvent on a rotary evaporator, an oily product remains, which crystallizes on trituration with diethylether. 6.8 g (77% of theory) of methyl 2-[3-(4,6-dimethoxypyrimidin-2-yl)-ureidosulfonyloxy]-3-methoxy-benzoate of melting point 169°-170° C. are obtained.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:31])[CH2:5][NH:6][C:7](=[O:30])[NH:8][C:9]1[CH:14]=[C:13]([O:15][C:16]2[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[C:18]([Cl:26])[CH:17]=2)[CH:12]=[CH:11][C:10]=1[N+:27]([O-:29])=[O:28])[CH3:2].[C:32](=[O:37])=[N:33][C:34](Cl)=[O:35]>C1(C)C=CC=CC=1>[Cl:26][C:18]1[CH:17]=[C:16]([O:15][C:13]2[CH:12]=[CH:11][C:10]([N+:27]([O-:29])=[O:28])=[C:9]([N:8]3[C:34](=[O:35])[NH:33][C:32](=[O:37])[N:6]([CH2:5][C:4]([O:3][CH2:1][CH3:2])=[O:31])[C:7]3=[O:30])[CH:14]=2)[CH:21]=[CH:20][C:19]=1[C:22]([F:23])([F:24])[F:25]
Reactant: O=C=NC(=O)Cl
Reactant: CCOC(=O)CNC(=O)Nc1cc(Oc2ccc(C(F)(F)F)c(Cl)c2)ccc1[N+](=O)[O-]
Solvent: Cc1ccccc1
Product: CCOC(=O)Cn1c(=O)[nH]c(=O)n(-c2cc(Oc3ccc(C(F)(F)F)c(Cl)c3)ccc2[N+](=O)[O-])c1=O
Temperature: 60 °C

Procedure:
A mixture of N-{{5-[(2-chloro-α,α,α-trifluoro-p-tolyl)oxy]-2-nitrophenyl}carbamoyl}glycine ethyl ester (75.0 g, 0.162 mol) and N-(chlorocarbonyl) isocyanate (35.0 g, 0.332 mol) in toluene is heated at 60° C. overnight, treated with additional N-(chlorocarbonyl) isocyanate (4.25 g), heated at 60° C. for 4 hours, cooled to room temperature and filtered to obtain a solid. The solid is washed with petroleum ether and dried to give the title product as a white solid which is identified by 1H and 13CNMR spectral analyses.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([S:8]([O-:10])=[O:9])[CH:5]=[CH:6][CH:7]=1.[Na+].Br[C:13]1[CH:21]=[CH:20][C:19]2[N:18]([CH3:22])[C:17]3[CH2:23][CH:24]4[NH:28][CH:27]([C:16]=3[C:15]=2[C:14]=1[C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH2:26][CH2:25]4>>[Cl:1][C:2]1[CH:3]=[C:4]([S:8]([C:13]2[CH:21]=[CH:20][C:19]3[N:18]([CH3:22])[C:17]4[CH2:23][CH:24]5[NH:28][CH:27]([C:16]=4[C:15]=3[C:14]=2[C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH2:26][CH2:25]5)(=[O:10])=[O:9])[CH:5]=[CH:6][CH:7]=1
Reactant: O=S([O-])c1cccc(Cl)c1
Reactant: Cn1c2c(c3c(C(=O)OC(C)(C)C)c(Br)ccc31)C1CCC(C2)N1
Agent: [Na+]
Product: Cn1c2c(c3c(C(=O)OC(C)(C)C)c(S(=O)(=O)c4cccc(Cl)c4)ccc31)C1CCC(C2)N1
Yield: 35 %

Procedure:
Intermediate 1 was coupled with the product of Example 27, step B following the procedure of Example 27, step C. The crude material was purified by flash column chromatography (SiO2, 8:2 hexanes/ethyl acetate) to give tert-butyl 2-(3-chlorophenyl)sulfonyl-5-methyl-5,6,7,8,9,10-hexahydro-7,10-epiminocyclohepta[b]indole-carboxylate (110 mg, 35%) as an off-white solid: 1H NMR (CDCl3, 300 MHz) δ 8.17-8.23 (m, 1H), 7.92-7.96 (m, 1H), 7.83-7.88 (m, 1H), 7.65-7.73 (m, 1H), 7.46-7.50 (m, 1H), 7.41 (t, J=7.8 Hz, 1H), 7.34 (d, J=8.7 Hz, 1H), 5.20-5.36 (m, 1H), 4.60-4.73 (m, 1H), 3.63 (s, 3H), 3.30-3.50 (m, 1H), 2.52 (d, J=16.2 Hz, 1H), 2.15-2.42 (m, 2H), 1.90-2.01 (m, 1H), 1.58-1.60 (m, 1H), 1.39 (br s, 9H)
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][CH:11]=1)[C:6]([NH2:8])=[NH:7].[Cl:14][C:15]1[CH:26]=[C:25]([Cl:27])[CH:24]=[CH:23][C:16]=1[CH:17]=[C:18]([C:21]#[N:22])[C:19]#[N:20]>>[NH2:22][CH2:21][C:18]1[C:19]([NH2:20])=[N:7][C:6]([C:5]2[CH:9]=[CH:10][CH:11]=[C:3]([C:2]([F:12])([F:13])[F:1])[CH:4]=2)=[N:8][C:17]=1[C:16]1[CH:23]=[CH:24][C:25]([Cl:27])=[CH:26][C:15]=1[Cl:14]
Reactant: N#CC(C#N)=Cc1ccc(Cl)cc1Cl
Reactant: N=C(N)c1cccc(C(F)(F)F)c1
Product: NCc1c(N)nc(-c2cccc(C(F)(F)F)c2)nc1-c1ccc(Cl)cc1Cl

Procedure:
The title compound, MS: m/e=412.9 (M+H+), was prepared from 3-trifluoromethyl-benzamidine and 2-(2,4-dichloro-benzylidene)-malononitrile in analogy to the process described in Example 11 as a solid.
Reaction SMILES: Cl[C:2]1[CH:16]=[CH:15][C:5]2[N:6]=[C:7]([N:9]3[CH2:13][CH2:12][C@H:11]([OH:14])[CH2:10]3)[S:8][C:4]=2[CH:3]=1.[C:17]([C:19]1[CH:24]=[CH:23][C:22](B(O)O)=[CH:21][CH:20]=1)#[N:18].C1(P(C2CCCCC2)C2C=CC=CC=2C2C(OC)=CC=CC=2OC)CCCCC1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>C1(C)C=CC=CC=1.C(O)(C)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[OH:14][C@H:11]1[CH2:12][CH2:13][N:9]([C:7]2[S:8][C:4]3[CH:3]=[C:2]([C:22]4[CH:23]=[CH:24][C:19]([C:17]#[N:18])=[CH:20][CH:21]=4)[CH:16]=[CH:15][C:5]=3[N:6]=2)[CH2:10]1
Reactant: N#Cc1ccc(B(O)O)cc1
Reactant: O[C@H]1CCN(c2nc3ccc(Cl)cc3s2)C1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: COc1cccc(OC)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Solvent: CC(C)O
Solvent: Cc1ccccc1
Product: N#Cc1ccc(-c2ccc3nc(N4CC[C@H](O)C4)sc3c2)cc1
Temperature: 150 °C

Procedure:
A mixture of (S)-1-(6-chlorobenzo[d]thiazol-2-yl)pyrrolidin-3-ol (Reference Example 13a, 0.2547 g, 1.0 mmol), 4-cyanophenylboronic acid (CAS #126747-14-6, 0.2204 g, 1.5 mmol), palladium (II) acetate (2.2 mg, 0.01 mmol), 2-dicyclohexylphosphino-2′,6′-dimethoxybiphenyl (CAS #657408-07-6, 0.0102 g, 0.025 mmol), and potassium phosphate (0.4246 g, 2.0 mmol) in toluene/isopropanol (2 mL/2 mL) was heated under microwave irradiation at 150° C. for 10 minutes. The reaction mixture was then cooled to room temperature and concentrated under reduced pressure. This residue was partitioned between ethyl acetate and saturated aqueous sodium carbonate. The organic layer was dried (MgSO4) and filtered. The filtrate was concentrated under reduced pressure and the residue was purified by silica gel chromatography (80:20 to 60:40 hexane/isopropanol). Fractions containing product were combined and concentrated under reduced pressure to provide (S)-4-(2-(3-hydroxypyrrolidin-1-yl)benzo[d]thiazol-6-yl)benzonitrile. 1H NMR (300 MHz, DMSO-d6) δ ppm 1.91-2.02 (m, 1H), 2.06-2.19 (m, 1H), 3.38-3.46 (m, 1H), 3.56-3.68 (m, 3H), 4.41-4.48 (m, 1H), 5.14 (d, J=4 Hz, 1H), 7.54 (d, J=8 Hz, 1H), 7.68 (dd, J=2, 8 Hz, 1H), 7.89 (s, 1H), 8.23 (d, J=2 Hz, 1H); MS (DCI/NH3) m/z 322 (M+H)+.
Reaction SMILES: [C:1]([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([F:13])[CH:11]=2)[C:6]([CH3:14])=[N:5]1)(=[O:3])[CH3:2].C1C(=O)N([Br:22])C(=O)C1.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[C:1]([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([F:13])[CH:11]=2)[C:6]([CH2:14][Br:22])=[N:5]1)(=[O:3])[CH3:2]
Reactant: O=C1CCC(=O)N1Br
Reactant: CC(=O)n1nc(C)c2ccc(F)cc21
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: CC(=O)n1nc(CBr)c2ccc(F)cc21
Temperature: 70 °C
Yield: 54.8 %

Procedure:
1-Acetyl-6-fluoro-3-methyl-1H-indazole (5.77 g, 33.1 mmol) in CCl4 (100 mL) was treated with NBS (3.64 g, 20 mmol) and benzoyl peroxide (0.388 g, 1.6 mmol) and the mixture was heated at 70° C. for 6 h. The mixture was concentrated and the residue quickly filtered through a plug of flash silica eluting with 2%→7% EtOAc in hexane to give the crude title compound (2.97 g, 65%) contaminated with traces of dibromide and starting material. This was conveniently used directly in subsequent reactions without further purification.
Reaction SMILES: [CH3:1][N:2]([CH2:10][CH2:11][O:12][C:13]1[CH:18]=[CH:17][C:16]([O:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[C:15]([C:27]([NH:29][C:30]2[CH:31]=[N:32][CH:33]=[CH:34][CH:35]=2)=[O:28])[CH:14]=1)C(=O)OC(C)(C)C.FC(F)(F)C(O)=O.C([O-])(O)=O.[Na+]>ClCCl>[CH3:1][NH:2][CH2:10][CH2:11][O:12][C:13]1[CH:18]=[CH:17][C:16]([O:19][CH2:20][C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)=[C:15]([CH:14]=1)[C:27]([NH:29][C:30]1[CH:31]=[N:32][CH:33]=[CH:34][CH:35]=1)=[O:28]
Reactant: CN(CCOc1ccc(OCc2ccccc2)c(C(=O)Nc2cccnc2)c1)C(=O)OC(C)(C)C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CNCCOc1ccc(OCc2ccccc2)c(C(=O)Nc2cccnc2)c1
Temperature: 30 °C
Reaction time: 2 h

Procedure:
To the solution of 1,1-dimethylethyl methyl[2-({4-[(phenylmethyl)oxy]-3-[(3-pyridinylamino)carbonyl]phenyl}oxy)ethyl]carbamate (may be prepared as described in Description 75; 140 mg, 0.17 mmol) in dichloromethane (10 ml) was added trifluoroacetic acid (3.0 ml, 38.9 mmol) dropwise. After stirring at 30° C. for 2 h, the pH of the solution was adjusted to 7-8 by adding aqueous NaHCO3 solution. The mixture was extracted with dichloromethane. The dichloromethane layer was washed with brine, dried over Na2SO4, and concentrated to obtain a crude product. The crude product was purified by prep-HPLC (Gilson GX-281, waters X-Bridge 5 μm, 100*30 mm; A: 0.04% NH3.H2O/water, B: CH3CN; 0-6.0 min, 30%-55%; 6-12 min, 95%, RT=7.3 min) to yield the title compound as a white solid. 20 mg.
Reaction SMILES: [OH:1][CH:2]1[CH:7]([C:8]2[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=2)[CH2:6][CH2:5][N:4]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:3]1.[CH2:22](Cl)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>>[CH2:22]([O:14][C:11]1[CH:10]=[CH:9][C:8]([CH:7]2[CH2:6][CH2:5][N:4]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:3][CH:2]2[OH:1])=[CH:13][CH:12]=1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(O)cc2)C(O)C1
Reactant: ClCc1ccccc1
Product: CC(C)(C)OC(=O)N1CCC(c2ccc(OCc3ccccc3)cc2)C(O)C1

Procedure:
Analogously to Method I, 9.89 g of tert-butyl 3-hydroxy-4-(4-hydroxyphenyl)piperidine-1-carboxylate and 4.84 ml of benzyl chloride are reacted. The title compound is obtained as a white solid. Rf=0.53 (1:1 EtOAc-heptane); Rt=4.96.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[CH:4][C:3]=1[F:11].[C:12]([NH:16][C:17](=[O:31])[C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([CH2:24][N:25]2[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]2)[CH:19]=1)([CH3:15])([CH3:14])[CH3:13].Cl.CN(C)CCCN=C=NCC.C(N(CC)CC)C>C(#N)C>[NH2:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([N:28]2[CH2:27][CH2:26][N:25]([CH2:24][C:20]3[CH:19]=[C:18]([CH:23]=[CH:22][CH:21]=3)[C:17]([NH:16][C:12]([CH3:14])([CH3:15])[CH3:13])=[O:31])[CH2:30][CH2:29]2)=[O:8])=[CH:4][C:3]=1[F:11]
Reactant: CC(C)(C)NC(=O)c1cccc(CN2CCNCC2)c1
Reactant: Nc1ccc(C(=O)O)cc1F
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CC(C)(C)NC(=O)c1cccc(CN2CCN(C(=O)c3ccc(N)c(F)c3)CC2)c1
Yield: 26.7 %

Procedure:
4-Amino-3-fluorobenzoic acid (500 mg, 3.22 mmol), N-tert-butyl-3-(piperazin-1-ylmethyl)benzamide (888 mg, 3.22 mmol), N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (926 mg, 4.83 mmol, EDCl) and triethylamine (984 mg, 898 μl, 6.44 mmol) were combined and stirred in acetonitrile (10 mL) at room temperature overnight (under nitrogen). The reaction was concentrated under reduced pressure. The residue was taken up in dichloromethane (30 mL) and washed with water. The organic phase was dried over sodium sulfate and concentrated under vacuum. The residue was purified by silica chromatography (eluting with a solvent gradient from dichloromethane to 4% methanol/dichloromethane) to give the title compound (355 mg).
Reaction SMILES: C([O:3][C:4](=[O:45])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[C:8]([O:14][C:15]2[CH:20]=[CH:19][C:18]([NH:21][C:22](=[O:30])[C:23]3[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=3)=[CH:17][C:16]=2[CH2:31][N:32]([C:35]([O:37][CH2:38][C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)=[O:36])[CH2:33][CH3:34])[CH:7]=1)C.[OH-].[Li+]>CO.O>[CH2:38]([O:37][C:35]([N:32]([CH2:31][C:16]1[CH:17]=[C:18]([NH:21][C:22](=[O:30])[C:23]2[CH:24]=[CH:25][C:26]([Cl:29])=[CH:27][CH:28]=2)[CH:19]=[CH:20][C:15]=1[O:14][C:8]1[CH:7]=[C:6]([CH2:5][C:4]([OH:45])=[O:3])[CH:11]=[CH:10][C:9]=1[O:12][CH3:13])[CH2:33][CH3:34])=[O:36])[C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1
Reactant: CCOC(=O)Cc1ccc(OC)c(Oc2ccc(NC(=O)c3ccc(Cl)cc3)cc2CN(CC)C(=O)OCc2ccccc2)c1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CCN(Cc1cc(NC(=O)c2ccc(Cl)cc2)ccc1Oc1cc(CC(=O)O)ccc1OC)C(=O)OCc1ccccc1
Temperature: 60 °C
Reaction time: 0.33 h

Procedure:
To a solution of {3-[2-[(benzyloxycarbonyl-ethyl-amino)-methyl]-4-(4-chloro-benzoylamino)-phenoxy]-4-methoxy-phenyl}-acetic acid ethyl ester (0.18 mmol) in MeOH and H2O was added lithium hydroxide (0.100 g, 2.4 mmol), and the reaction was stirred at 60° C. for 20 minutes. After work-up, the crude material was purified by preparative HPLC to give the title compound. M+H=603.
Reaction SMILES: [C:1]([N:5]1[C:9]([C:10]([F:13])([F:12])[F:11])=[C:8]([NH:14][C:15]([NH:17][C:18]2[CH:23]=[C:22]([C:24]3[C:35](=[O:36])[N:34]([CH3:37])[C:27]4[N:28]=[C:29](SC)[N:30]=[CH:31][C:26]=4[CH:25]=3)[CH:21]=[CH:20][C:19]=2[F:38])=[O:16])[CH:7]=[N:6]1)([CH3:4])([CH3:3])[CH3:2].[CH3:39][NH2:40].C1COCC1>>[C:1]([N:5]1[C:9]([C:10]([F:13])([F:12])[F:11])=[C:8]([NH:14][C:15]([NH:17][C:18]2[CH:23]=[C:22]([C:24]3[C:35](=[O:36])[N:34]([CH3:37])[C:27]4[N:28]=[C:29]([NH:40][CH3:39])[N:30]=[CH:31][C:26]=4[CH:25]=3)[CH:21]=[CH:20][C:19]=2[F:38])=[O:16])[CH:7]=[N:6]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CN
Reactant: CSc1ncc2cc(-c3ccc(F)c(NC(=O)Nc4cnn(C(C)(C)C)c4C(F)(F)F)c3)c(=O)n(C)c2n1
Solvent: C1CCOC1
Product: CNc1ncc2cc(-c3ccc(F)c(NC(=O)Nc4cnn(C(C)(C)C)c4C(F)(F)F)c3)c(=O)n(C)c2n1
Yield: 63 %

Procedure:
Using a procedure analogous to Example A1, 1-(1-tert-butyl-5-(trifluoromethyl)-1H-pyrazol-4-yl)-3-(2-fluoro-5-(8-methyl-2-(methylthio)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-6-yl)phenyl)urea (247 mg, 0.449 mmol) and 2.0N methylamine in THF (2.25 mL, 4.49 mmol) were combined to afford 1-(1-tert-butyl-5-(trifluoromethyl)-1H-pyrazol-4-yl)-3-(2-fluoro-5-(8-methyl-2-(methylamino)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-6-yl)phenyl)urea (152 mg, 63% yield). 1H NMR (300 MHz, acetone-d6) δ 1.64 (s, 9H), 2.82 (s, 3H), 3.06 (m, 3H), 6.80-6.95 (m, 1H), 7.14-7.19 (m, 1H), 7.38-7.42 (m, 1H), 7.85 (s, 1H), 8.06 (s, 1H), 8.11 (br. s, 1H), 8.50 (br. s, 1H), 8.57-8.59 (m, 1H), 8.60-8.63 (m, 1H); MS (ESI) m/z: 533.3 (M+H+).
Reaction SMILES: [CH2:1]([C:5]1([CH2:20][C:21](=[O:23])[CH3:22])[CH2:14][CH2:13][C:12]2[C:7](=[CH:8][C:9]([F:18])=[C:10]([O:16][CH3:17])[C:11]=2[Cl:15])[C:6]1=O)[CH2:2][CH2:3][CH3:4].[OH-].[K+]>CCO.ClCCl>[CH2:1]([C:5]12[CH2:20][C:21](=[O:23])[CH:22]=[C:6]1[C:7]1[C:12]([CH2:13][CH2:14]2)=[C:11]([Cl:15])[C:10]([O:16][CH3:17])=[C:9]([F:18])[CH:8]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCC1(CC(C)=O)CCc2c(cc(F)c(OC)c2Cl)C1=O
Agent: [K+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CCO
Product: CCCCC12CCc3c(cc(F)c(OC)c3Cl)C1=CC(=O)C2
Temperature: 90 °C

Procedure:
To a solution of 2-butyl-5-chloro-7-fluoro-6-methoxy-2-(2-oxo-propyl)-3,4-dihydro-2H-naphthalen-1-one (28 mg, 0.08 mmol) in EtOH (0.4 mL) was added potassium hydroxide (2M solution in EtOH, 0.05 mL, 0.1 mmol). The reaction mixture was heated at 90° C. in a sealed flask for two hours. The reaction was cooled to room temperature, diluted with dichloromethane (5 mL) and filtered through a pad of MgSO4 atop a pad of SiO2. The filter pad was washed with 5% MeOH in CH2Cl2 and the combined filtrates concentrated under vacuum to give 3a-butyl-6-chloro-8-fluoro-7-methoxy-3,3a,4,5-tetrahydro-2H-cyclopenta[a]naphthalen-2-one as an oil which solidified on standing.
Reaction SMILES: [C:1]12([CH2:11][NH:12][CH2:13][CH:14]([C:16]3[CH:21]=[CH:20][C:19]([OH:22])=[CH:18][CH:17]=3)[OH:15])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.CCN(CC)CC.Cl[C:31](Cl)([O:33]C(=O)OC(Cl)(Cl)Cl)Cl>C(Cl)Cl>[C:1]12([CH2:11][N:12]3[CH2:13][CH:14]([C:16]4[CH:17]=[CH:18][C:19]([OH:22])=[CH:20][CH:21]=4)[O:15][C:31]3=[O:33])[CH2:10][CH:5]3[CH2:4][CH:3]([CH2:9][CH:7]([CH2:6]3)[CH2:8]1)[CH2:2]2
Reactant: Oc1ccc(C(O)CNCC23CC4CC(CC(C4)C2)C3)cc1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C1OC(c2ccc(O)cc2)CN1CC12CC3CC(CC(C3)C1)C2
Temperature: 0 °C
Reaction time: 8 h
Yield: 11.1 %

Procedure:
4-(2-((1-adamantylmethyl)amino)-1-hydroxyethyl)phenol (50 mg, 0.166 mmol) and Et3N (34 mg, 0.33 mmol) were dissolved in dry CH2Cl2 (1 mL) and the solution was cooled to 0° C. Triphosgene (19.7 mg, 0.066 mmol) in dry CH2Cl2 (1 mL) was added dropwise slowly. The mixture was allowed to warm to rt and stirred overnight. The solution was concentrated to give a residue, which was purified by preparative HPLC to afford 3-adamantan-1-ylmethyl-5-(4-hydroxy-phenyl)-oxazolidin-2-one (2.40 mg, 4.4%). 1H NMR: (CDCl3, 400 MHz): δ=1.54 (s, 6H), 1.58-1.65 (d, 3H), 1.66-1.75 (d, 3H), 1.99 (s, 3H), 2.80-2.87 (d, 1H), 3.02-3.08 (d, 1H), 3.50-3.56 (t, 1H), 3.93-4.00 (t, 1H), 5.40-5.48 (t, 1H), 6.82-6.90 (d, 1H), 7.20-7.26 (d, 1H); MS m/z=328
Reaction SMILES: Br[CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.C([Li])(C)(C)C.[Cl:15][C:16]1[N:21]=[C:20]([Cl:22])[CH:19]=[CH:18][N:17]=1>C(OCC)C>[Cl:15][C:16]1[N:21]=[C:20]([Cl:22])[CH:19]=[C:18]([CH2:2][CH2:3][C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=2)[N:17]=1
Reactant: BrCCc1ccccc1
Reactant: Clc1ccnc(Cl)n1
Agent: [Li]C(C)(C)C
Solvent: CCOCC
Product: Clc1cc(CCc2ccccc2)nc(Cl)n1
Temperature: -30 °C
Reaction time: 0.08 h

Procedure:
To a solution of 4.6 mL of (2-bromoethyl)benzene in 70 mL ethyl ether at −70° C. was added 41.5 mL of tert-butyllithium. The mixture was slowly allowed to warm to −30° C. over 2 h, then cooled to −60° C. and treated with 5.0 g of 2,4-dichloropyrimidine The reaction was again slowly allowed to warm to −30° C. over 2 h, then quenched by the addition of 1.94 mL of acetic acid and 0.30 mL of water in 5 mL tetrahydrofuran. The mixture was treated with 7.6 g of 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ) in 25 mL THF and warmed to room temperature. The reaction was cooled to 0° C. and 13.4 mL of ice-cold 3 M NaOH was added to the mixture. After 5 minutes, the organic layer was separated and dried over sodium sulfate. The solvent was evaporated and the crude residue was chromatographed (2% to 10% EtOAc in hexanes) to give 4.0 g of 2,4-dichloro-6-phenethylpyrimidine.
Reaction SMILES: [F:1][C:2]1[C:3]([C:10]2[CH:19]=[CH:18][C:13]([C:14](OC)=[O:15])=[CH:12][C:11]=2[C:20]2([CH:25]=[CH2:26])[CH2:24][CH2:23][CH2:22][CH2:21]2)=[CH:4][C:5]([O:8][CH3:9])=[N:6][CH:7]=1.[H-].[H-].[H-].[H-].[Li+].[Al+3].C(OCC)C>C1COCC1>[F:1][C:2]1[C:3]([C:10]2[CH:19]=[CH:18][C:13]([CH2:14][OH:15])=[CH:12][C:11]=2[C:20]2([CH:25]=[CH2:26])[CH2:24][CH2:23][CH2:22][CH2:21]2)=[CH:4][C:5]([O:8][CH3:9])=[N:6][CH:7]=1
Reactant: C=CC1(c2cc(C(=O)OC)ccc2-c2cc(OC)ncc2F)CCCC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Solvent: C1CCOC1
Product: C=CC1(c2cc(CO)ccc2-c2cc(OC)ncc2F)CCCC1
Temperature: 50 °C
Reaction time: 1 h

Procedure:
To a solution of methyl 4-(5-fluoro-2-methoxypyridin-4-yl)-3-(1-vinylcyclopentyl)benzoate 26.5 (51.0 mg, 143 μmol) in THF (2.0 mL) was slowly added LAH, (1.0 M solution in diethyl ether (0.30 mL, 287 μmol)) at room temperature. The resulting mixture was stirred at 50° C. for 1 hour. The product was obtained after work up and solvent removal. The desired product was used in the next step without further purification. MS ESI (pos.) m/e: 328.2 (M+H)+.