Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]([C:17]2[CH:22]=[CH:21][N:20]=[CH:19][CH:18]=2)([C:14](O)=[O:15])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH3:23]>>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][C:11]([C:17]2[CH:22]=[CH:21][N:20]=[CH:19][CH:18]=2)([C:14]([NH2:23])=[O:15])[CH2:12][CH2:13]1)=[O:7])([CH3:3])([CH3:4])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)O)(c2ccncc2)CC1
Reactant: N
Product: CC(C)(C)OC(=O)N1CCC(C(N)=O)(c2ccncc2)CC1

Procedure:
Prepare by the method of example 20.8 using 1-tert-butoxycarbonyl-4-(pyridin-4-yl)-piperidine-4-carboxylic acid (4.0 mmol) and NH3 (gas). Purify to give the title compound.
Reaction SMILES: Br.[Br:2][CH2:3][CH2:4][CH2:5][NH2:6].C(N(CC)CC)C.CO[C:16]1[C:25](=[O:26])[C:20]2[N:21]=[C:22]([CH3:24])[S:23][C:19]=2[C:18](=[O:27])[CH:17]=1>CO>[Br:2][CH2:3][CH2:4][CH2:5][NH:6][C:16]1[C:25](=[O:26])[C:20]2[N:21]=[C:22]([CH3:24])[S:23][C:19]=2[C:18](=[O:27])[CH:17]=1
Reactant: COC1=CC(=O)c2sc(C)nc2C1=O
Reactant: NCCCBr
Agent: Br
Solvent: CO
Solvent: CCN(CC)CC
Product: Cc1nc2c(s1)C(=O)C=C(NCCCBr)C2=O
Temperature: 60 °C
Reaction time: 2 h

Procedure:
1.57 g (7.17 mmol; 1.5 equivalent) of 3-bromopropylamine hydrobromide and 1.02 ml (7.17 mmol; 1.5 equivalent) of triethylamine are added to 1 g (4.78 mmol) of 5-methoxy-2-methyl-1,3-benzothiazole-4,7-dione in solution in 100 ml of methanol. The reaction mixture is maintained under stirring for 2 hours at 60° C., then the solvent is evaporated off under reduced pressure and the residue is purified by chromatography on a silica column (eluent: dichloromethane/methanol: 97/3). The 5-[(3-bromopropyl)amino]-2-methyl-1,3-benzothiazole-4,7-dione is obtained in the form of a red oil.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][C:5]1[CH:10]=[CH:9][C:8]([C@H:11]2[CH2:16][CH2:15][C@H:14]([NH:17][CH3:18])[CH2:13][CH2:12]2)=[C:7]([CH2:19][NH:20][CH3:21])[CH:6]=1.[CH2:22]1[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH2:25][CH2:24][CH:23]1[C:32](Cl)=[O:33]>>[OH:1][CH2:2][CH2:3][CH2:4][C:5]1[CH:10]=[CH:9][C:8]([C@H:11]2[CH2:16][CH2:15][C@H:14]([N:17]([CH3:18])[C:32]([CH:23]3[CH2:24][CH2:25][C:26]4[C:31](=[CH:30][CH:29]=[CH:28][CH:27]=4)[CH2:22]3)=[O:33])[CH2:13][CH2:12]2)=[C:7]([CH2:19][NH:20][CH3:21])[CH:6]=1
Reactant: CNCc1cc(CCCO)ccc1[C@H]1CC[C@H](NC)CC1
Reactant: O=C(Cl)C1CCc2ccccc2C1
Product: CNCc1cc(CCCO)ccc1[C@H]1CC[C@H](N(C)C(=O)C2CCc3ccccc3C2)CC1

Procedure:
from trans-4-[4-(3-hydroxypropyl)methylaminomethyl-phenyl]-N-methylcyclohexylamine and 1,2,3,4-tetrahydronaphthalene-2-carboxylic acid chloride. Melting point: 93°-95° C.
Reaction SMILES: [Cl:1]C(OC(Cl)C)=O.C([N:21]1[CH2:24][CH:23]([O:25][CH2:26][CH2:27][CH2:28][C:29]([F:32])([F:31])[F:30])[CH2:22]1)(C1C=CC=CC=1)C1C=CC=CC=1.C(O)C>ClCCl>[ClH:1].[F:32][C:29]([F:30])([F:31])[CH2:28][CH2:27][CH2:26][O:25][CH:23]1[CH2:22][NH:21][CH2:24]1
Reactant: CC(Cl)OC(=O)Cl
Reactant: FC(F)(F)CCCOC1CN(C(c2ccccc2)c2ccccc2)C1
Solvent: CCO
Solvent: ClCCl
Product: Cl
Product: FC(F)(F)CCCOC1CNC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
1-Chloroethyl chloroformate (65 μL, 0.60 mmol) was added to a solution of 1-benzhydryl-3-(4,4,4-trifluorobutoxy)-azetidine (200 mg, 0.57 mmol) in dichloromethane (5 mL) at 0° C. The reaction mixture was stirred for 3 hours and 30 minutes at room temperature. Ethanol (5 mL) was then added and the mixture was stirred for an additional 2 hours at 0° C. and 2 hours at 70° C. The reaction mixture was concentrated under vacuum and the residue was triturated in petroleum ether (2×20 mL) to give a colorless oil (130 mg, quantitative) which was used without further purification.
Reaction SMILES: Cl.[NH2:2][C@@H:3]1[CH2:8][CH2:7][C@H:6]([NH:9][C:10](=[O:27])[C:11]2[CH:16]=[C:15]([F:17])[CH:14]=[N:13][C:12]=2[O:18][C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([S:25][CH3:26])[CH:20]=2)[CH2:5][CH2:4]1.C(N(CC)CC)C.[CH:35]1([C:38](O)=[O:39])[CH2:37][CH2:36]1.Cl.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1>CN(C)C=O>[CH:35]1([C:38]([NH:2][C@@H:3]2[CH2:8][CH2:7][C@H:6]([NH:9][C:10](=[O:27])[C:11]3[CH:16]=[C:15]([F:17])[CH:14]=[N:13][C:12]=3[O:18][C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([S:25][CH3:26])[CH:20]=3)[CH2:5][CH2:4]2)=[O:39])[CH2:37][CH2:36]1
Reactant: O=C(O)C1CC1
Reactant: CSc1cccc(Oc2ncc(F)cc2C(=O)N[C@H]2CC[C@@H](N)CC2)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CSc1cccc(Oc2ncc(F)cc2C(=O)N[C@H]2CC[C@@H](NC(=O)C3CC3)CC2)c1
Temperature: 25 °C
Reaction time: 64 h
Yield: 98.3 %

Procedure:
N-(cis-4-Amino-cyclohexyl)-5-fluoro-2-(3-methylsulfanyl-phenoxy)-nicotinamide hydrochloride (100 mg, 0.243 mmol) was dissolved in dimethylformamide (1 ml) and triethylamine (100 μl, 0.729 mmol) was added followed by cyclopropanecarboxylic acid (23 μl, 0.291 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (56 mg, 0.291 mmol) and 1-hydroxybenzotriazole (39 mg, 0.291 mmol). The reaction was stirred under nitrogen at room temperature for 64 h and the solvent was removed under reduced pressure. The residue was partitioned between sat. sodium bicarbonate solution (5 ml) and ethyl acetate (10 ml) and the aqueous phase was extracted with ethyl acetate (3×10 ml). The combined organic extracts were washed with water (2×5 ml), brine (5 ml), dried over MgSO4 and the solvent was removed under reduced pressure. The residue was triturated with diethylether (5 ml) to give N-[cis-4-(Cyclopropanecarbonyl-amino)-cyclohexyl]-5-fluoro-2-(3-methylsulfanyl-phenoxy)-nicotinamide (106 mg) as a white solid.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8](/[C:11](=[C:14](\[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)/[CH2:15][OH:16])/[CH2:12][OH:13])=[CH:7][CH:6]=1)(=[O:4])=[O:3].N1C=CN=C1.[CH3:28][C:29]([Si:32](Cl)([CH3:34])[CH3:33])([CH3:31])[CH3:30]>C1COCC1.ClCCl.[Cl-].[Na+].O>[Si:32]([O:16][CH2:15]/[C:14](/[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1)=[C:11](/[C:8]1[CH:7]=[CH:6][C:5]([S:2]([CH3:1])(=[O:3])=[O:4])=[CH:10][CH:9]=1)\[CH2:12][OH:13])([C:29]([CH3:31])([CH3:30])[CH3:28])([CH3:34])[CH3:33]
Reactant: CS(=O)(=O)c1ccc(/C(CO)=C(/CO)c2ccccc2)cc1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: [Cl-]
Agent: [Na+]
Agent: c1c[nH]cn1
Solvent: C1CCOC1
Solvent: ClCCl
Solvent: O
Product: CC(C)(C)[Si](C)(C)OC/C(=C(\CO)c1ccc(S(C)(=O)=O)cc1)c1ccccc1
Temperature: -78 °C
Yield: 17.5 %

Procedure:
To a solution of 110 g of (2Z)-2-[4-(methylsulfonyl)phenyl]-3-phenylbut-2-ene-1,4-diol and 50 g of imidazole in 1 L of THF stirred at −78° C., a solution 51 g of TBSCl in 250 mL of dichloromethane was added dropwise. The resulting mixture was stirred at −78° C. 0.5 hr. Brine was then added and then warmed to room temperature. The organic phase was separated and the aqueous phase was extracted with EtOAc. The organic phases were combined and dried over Na2SO4 and evaporated. The resulting crude material was purified by flash chromatography to afford 25.6 g of the title compound as a white solid. 1H NMR (acetone-d6, 500 M Hz): δ 7.69 (d, 2 H), 7.37 (d, 2 H), 7.18–7.04 (m, 5 H), 4,77 (s, 2 H), 4.65 (d, 2 H), 3.96 (t, 1H, OH), 3.03 (s, 3 H), 0.84 (s, 9 H), 0.01 (s, 6 H).
Reaction SMILES: [F:1][C:2]1[C:7]([O:8]C)=[C:6]([F:10])[CH:5]=[CH:4][C:3]=1[NH:11][C:12]([NH:26][C:27]1[NH:31][N:30]=[C:29]([C:32]2[CH:37]=[CH:36][C:35]([O:38]C)=[C:34]([F:40])[CH:33]=2)[CH:28]=1)=[N:13][C:14]([C:16]1[C:17]([C:22]([F:25])([F:24])[F:23])=[N:18][N:19]([CH3:21])[CH:20]=1)=[O:15].B(Br)(Br)Br.CCOC(C)=O>ClCCl>[F:1][C:2]1[C:7]([OH:8])=[C:6]([F:10])[CH:5]=[CH:4][C:3]=1[NH:11][C:12]([NH:26][C:27]1[NH:31][N:30]=[C:29]([C:32]2[CH:37]=[CH:36][C:35]([OH:38])=[C:34]([F:40])[CH:33]=2)[CH:28]=1)=[N:13][C:14]([C:16]1[C:17]([C:22]([F:25])([F:23])[F:24])=[N:18][N:19]([CH3:21])[CH:20]=1)=[O:15]
Reactant: COc1ccc(-c2cc(NC(=NC(=O)c3cn(C)nc3C(F)(F)F)Nc3ccc(F)c(OC)c3F)[nH]n2)cc1F
Agent: BrB(Br)Br
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: Cn1cc(C(=O)N=C(Nc2cc(-c3ccc(O)c(F)c3)n[nH]2)Nc2ccc(F)c(O)c2F)c(C(F)(F)F)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 27.7 %

Procedure:
N-(((2,4-Difluoro-3-methoxyphenyl)amino)((3-(3-fluoro-4-methoxyphenyl)-1H-pyrazol-5-yl)amino)methylene)-1-methyl-3-(trifluoromethyl)-1H-pyrazole-4-carboxamide (110 mg, 0.194 mmol) was suspended in dichloromethane (4 mL), and a solution of boron tribromide in DCM (1 mL of 1 M, 5 equivalents) was added carefully. The mixture was stirred at room temperature overnight. Then, the reaction was quenched by the addition of ice, and the resulting slurry was then treated with aqueous sodium bicarbonate (pH approximately neutral). The mixture was stirred for 30 minutes, and then partitioned between water and EtOAc. Next, the organic phase was dried over sodium sulfate, and concentrated onto silica gel. The crude product was purified by chromatography (gradient: 8:2 hexanes:EtOAc to 2:8 hexanes:EtOAc to provide the title compound as a white solid (29 mg, 28% yield). 1H NMR (DMSO-d6) δ 13.16 (s, 1H), 12.69 (s, 1H), 10.72 (s, 1H), 10.32 (s, 1H), 10.23 (s, 1H), 8.09 (s, 1H), 7.56 (m, 2H), 7.40 (d, 1H), 7.04 (m, 2H), 6.62 (s, 1H), 3.89 (s, 3H). MS: calc.=539.39; obs. M+H=540.03. HPLC (Method E): retention time was 4.828 minutes.
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[O:13][N:12]=[CH:11][C:10]=2[C:14]([OH:16])=O)=[CH:5][CH:4]=1.[CH2:19]1[CH2:24][NH:23][CH2:22][CH:21]([C:25]([F:28])([F:27])[F:26])[CH2:20]1>>[F:26][C:25]([F:28])([F:27])[CH:21]1[CH2:20][CH2:19][CH2:24][N:23]([C:14]([C:10]2[CH:11]=[N:12][O:13][C:9]=2[C:6]2[CH:5]=[CH:4][C:3]([C:2]([F:1])([F:18])[F:17])=[CH:8][CH:7]=2)=[O:16])[CH2:22]1
Reactant: O=C(O)c1cnoc1-c1ccc(C(F)(F)F)cc1
Reactant: FC(F)(F)C1CCCNC1
Product: O=C(c1cnoc1-c1ccc(C(F)(F)F)cc1)N1CCCC(C(F)(F)F)C1

Procedure:
The title compound was prepared from 5-(4-trifluoromethylphenyl)isoxazole-4-carboxylic acid (12.9 mg, 0.050 mmol) and DL-3-(trifluoromethyl)piperidine (9.2 mg, 0.060 mmol) as described in synthetic method C and thereafter purified by preparative HPLC method B to give a solid (11.8 mg). Calcd for C17H14F6N2O2: 392.0959, found 392.0959.
Reaction SMILES: [CH2:1]([N:4]1[CH2:9][CH2:8][CH2:7][CH2:6][C:5]1=[O:10])[CH2:2][CH3:3].C([N-]C(C)C)(C)C.[Li+].[Br:19][C:20]1[C:21](=O)[CH2:22][CH2:23][CH2:24][C:25]=1[O:26]C>C1C=CC=CC=1.C1COCC1>[Br:19][C:20]1[C:25](=[O:26])[CH2:24][CH2:23][CH2:22][C:21]=1[CH:6]1[CH2:7][CH2:8][CH2:9][N:4]([CH2:1][CH2:2][CH3:3])[C:5]1=[O:10]
Reactant: COC1=C(Br)C(=O)CCC1
Reactant: CCCN1CCCCC1=O
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: c1ccccc1
Solvent: C1CCOC1
Product: CCCN1CCCC(C2=C(Br)C(=O)CCC2)C1=O

Procedure:
A solution of 1-propyl-2-piperidone (50 mM) in benzene (40 ml) was added dropwise to a solution of lithium di-isopropylamide [ex n-butyl lithium in hexane (32.3 ml, 50 mM), di-isopropylamine (7 ml, 50 mM) and THF (33 ml)]. A solution of 2-bromo-3-methoxycyclohex-2-en-1-one (10.25 g, 50 mM) in THF (40 ml) was added, and after 5 minutes the mixture was quenched by pouring on to excess aqueous hydrochloric acid. Ether extraction followed by passage through a short silica pad using ethyl acetate as eluant gave the title compound as a colourless oil (10.75 g).
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[CH2:11]([C:14]1[N:15]([CH2:27][CH2:28][CH2:29][CH:30]([OH:32])[CH3:31])[C:16]2[C:25]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[N:19]=[CH:18][C:17]=2[N:26]=1)[CH2:12][CH3:13].C(N(CC)CC)C.C(=O)(O)[O-].[Na+]>ClCCl>[CH2:11]([C:14]1[N:15]([CH2:27][CH2:28][CH2:29][C:30](=[O:32])[CH3:31])[C:16]2[C:25]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[N:19]=[CH:18][C:17]=2[N:26]=1)[CH2:12][CH3:13]
Reactant: CCCc1nc2cnc3ccccc3c2n1CCCC(C)O
Agent: O=C(Cl)C(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CS(C)=O
Product: CCCc1nc2cnc3ccccc3c2n1CCCC(C)=O
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 75.9 %

Procedure:
Oxalyl chloride (4.99 mL, 57.28 mmol) was added to a mixture of methyl sulfoxide (DMSO) (5.54 g, 71.46 mmol) in dichloromethane (50 mL) at −78° C. and stirred for 5 minutes. 5-(2-Propyl-1H-imidazo[4,5-c]quinolin-1-yl)pentan-2-ol (14.2 g, 47.74 mmol) was added dropwise, followed by the addition of triethylamine (19.96 mL, 143.2 mmol). The reaction was allowed to warm to ambient temperature and the reaction was stirred for 2 hours. Saturated aqueous sodium bicarbonate solution was added and the layers were separated. The organic layer was washed with saturated aqueous sodium bicarbonate and brine, filtered over magnesium sulfate, and concentrated under reduced pressure to afford 10.7 g of 5-(2-propyl-1H-imidazo[4,5-c]quinolin-1-yl)pentan-2-one as a brown oil.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[C:15]1[N:16]([CH2:27][CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[C:17](=[O:26])[C:18]2[C:24](Cl)=[N:23][CH:22]=[CH:21][C:19]=2[N:20]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].C1C[O:40][CH2:39]C1>>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[C:15]1[N:16]([CH2:27][CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[C:17](=[O:26])[C:18]2[C:24]([O:40][CH3:39])=[N:23][CH:22]=[CH:21][C:19]=2[N:20]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C1CCOC1
Reactant: O=c1c2c(Cl)nccc2nc(-c2ccccc2OCc2ccccc2)n1CCc1ccccc1
Agent: [H-]
Agent: [Na+]
Product: COc1nccc2nc(-c3ccccc3OCc3ccccc3)n(CCc3ccccc3)c(=O)c12
Temperature: 70 °C

Procedure:
A mixture of 2-(2-benzyloxy-phenyl)-5-chloro-3-phenethyl-3H-pyrido[4,3-d]pyrimidin-4-one, sodium hydride (60% suspension in mineral oil) (1.5 equiv.), and corresponding alcohol (1.5 equiv.) in THF was heated at 70° C. overnight. The reaction was cooled to RT, solvent removed, water and ethyl acetate were added and phases separated. The aqueous phase was washed with ethyl acetate (2×), organic portions combined, washed with water, brine, dried over anhydrous MgSO4, filtered and concentrated. The residue was purified on preparative TLC plate using 1:1 ethyl acetate:heptane.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH2:8])=[O:7])=[C:4]([OH:11])[CH:3]=1.N1C=CC=CC=1.Cl[C:19](OCC)=[O:20]>C(#N)C>[Cl:1][C:2]1[CH:10]=[CH:9][C:5]2[C:6](=[O:7])[NH:8][C:19](=[O:20])[O:11][C:4]=2[CH:3]=1
Reactant: NC(=O)c1ccc(Cl)cc1O
Reactant: CCOC(=O)Cl
Solvent: c1ccncc1
Solvent: CC#N
Product: O=c1[nH]c(=O)c2ccc(Cl)cc2o1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 93.1 %

Procedure:
A 22 L, five neck, round bottom flask was equipped with an overhead stirrer, reflux condenser, addition funnel, thermocouple temperature read out, and a heating mantle. The reactor was purged with nitrogen. Acetonitrile (4700 mL) and 4-chloro-2-hydroxybenzamide (1782 g, 10.4 mol) were charged to the reaction flask and the stirring was started. Pyridine (1133 mL, 14.0 mol) was charged to the reactor. The resulting reaction slurry was cooled to less than 10° C. with an ice bath. Ethyl chloroformate (1091 mL, 1237 g, 11.4 mol) was placed in the addition funnel and charged slowly to the stirred reaction mixture such that the temperature of the reaction mixture did not exceed 15° C. during the addition. The temperature of the reaction mixture was held between 10 and 15° C. for 30 minutes after the ethyl chloroformate addition was complete. The ice bath was removed, and the reaction mixture was warmed to ambient temperature. The reaction mixture was then slowly heated to reflux and held at that temperature for 18 hours Liquid chromatographic analysis of the reaction mixture indicated that the reaction was only 80% complete. Approximately half of the solvent was removed by atmospheric distillation. The reaction mixture was cooled first to ambient temperature and then to <10° C. with an ice bath. Additional pyridine (215 mL, 2.65 mol) was added to the reaction mixture. Ethyl chloroformate (235 g, 2.17 mol) was added slowly via an addition funnel to the cold reaction mixture. The reaction mixture was held between 10 and 15° C. for 30 minutes after the ethyl chloroformate addition was complete. The ice bath was removed, and the reaction mixture was warmed to ambient temperature. The reaction mixture was then slowly heated to reflux and held at that temperature for 18 hours, after which time liquid chromatographic analysis indicated that the reaction was complete. The reaction mixture was cooled first to ambient temperature and then to <10° C. with an ice bath. Water (1600 mL) was added slowly via an addition funnel and the resulting slurry held at <10° C. for 90 minutes. The solid product was collected by vacuum filtration through a large sintered glass funnel. The product filter cake was washed with deionized water and vacuum dried at 50° C. for 18 hours to give 1914 g of 7-chloro-2H-1,3-benzoxazine-2,4 (3H)-dione as a tan solid. The yield was 83%.
Reaction SMILES: C(OC([C:6]1[N:10]=[C:9]([C:11]2[CH:16]=[CH:15][N:14]=[CH:13][C:12]=2[NH:17][C:18]2[CH:23]=[CH:22][C:21]([I:24])=[CH:20][C:19]=2[F:25])[O:8][N:7]=1)=O)C.[Li+].[OH-].Cl>C1COCC1.O.O>[F:25][C:19]1[CH:20]=[C:21]([I:24])[CH:22]=[CH:23][C:18]=1[NH:17][C:12]1[CH:13]=[N:14][CH:15]=[CH:16][C:11]=1[C:9]1[O:8][N:7]=[CH:6][N:10]=1
Reactant: CCOC(=O)c1noc(-c2ccncc2Nc2ccc(I)cc2F)n1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: Fc1cc(I)ccc1Nc1cnccc1-c1ncno1
Temperature: 25 °C
Reaction time: 2 h
Yield: 92.5 %

Procedure:
To a solution of 5-[3-(2-Fluoro-4-iodo-phenylamino)-pyridin-4-yl]-[1,2,4]oxadiazole-3-carboxylic acid ethyl ester (1.8 g, 3.96 mmol) in THF-H2O (1:1)(20 mL) LiOH (0.19 g, 7.93 mmL) was added. The reaction mixture was stirred for 2 hrs at RT. The pH was adjusted to 5 with 1N HCl and the mixture was diluted with water. A solid precipitated and was filtered to give the product (1.4 g). LC/MS (Method A) [4.39 min; 383(M+1)]
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.C1COCC1.[F:12][C:13]([F:54])([F:53])[C:14]1[CH:15]=[C:16]([C@H:24]2[O:28][C:27](=[O:29])[N:26]([CH2:30][C:31]3[C:36]([C:37]4[C:38]([O:46][CH3:47])=[N:39][CH:40]=[C:41]([CH:43]([CH3:45])[CH3:44])[CH:42]=4)=[CH:35][N:34]=[C:33](S(C)(=O)=O)[N:32]=3)[C@H:25]2[CH3:52])[CH:17]=[C:18]([C:20]([F:23])([F:22])[F:21])[CH:19]=1.C(#N)C.O>CC#N>[F:22][C:20]([F:21])([F:23])[C:18]1[CH:17]=[C:16]([C@H:24]2[O:28][C:27](=[O:29])[N:26]([CH2:30][C:31]3[C:36]([C:37]4[C:38]([O:46][CH3:47])=[N:39][CH:40]=[C:41]([CH:43]([CH3:45])[CH3:44])[CH:42]=4)=[CH:35][N:34]=[C:33]([N:1]4[CH2:6][CH2:5][O:4][CH2:3][CH2:2]4)[N:32]=3)[C@H:25]2[CH3:52])[CH:15]=[C:14]([C:13]([F:12])([F:54])[F:53])[CH:19]=1
Reactant: C1COCCN1
Reactant: COc1ncc(C(C)C)cc1-c1cnc(S(C)(=O)=O)nc1CN1C(=O)O[C@H](c2cc(C(F)(F)F)cc(C(F)(F)F)c2)[C@@H]1C
Solvent: CC#N
Solvent: C1CCOC1
Solvent: O
Product: COc1ncc(C(C)C)cc1-c1cnc(N2CCOCC2)nc1CN1C(=O)O[C@H](c2cc(C(F)(F)F)cc(C(F)(F)F)c2)[C@@H]1C
Temperature: 90 °C

Procedure:
Morpholine (0.062 mL, 0.711 mmol) was added to a THF (1 mL) solution of (4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-3-{[5-(5-isopropyl-2-methoxypyridin-3-yl)-2-(methylsulfonyl)pyrimidin-4-yl]methyl}-4-methyl-1,3-oxazolidin-2-one (INTERMEDIATE 17, 90 mg, 0.142 mmol) in a microwave vial. The vial was capped, then heated for 15 minutes at 90° C. in a BIOTAGE microwave reactor. LCMS showed complete conversion to product. The reaction was diluted with 2 mL CH3CN and loaded directly onto an X-Bridge 21.2×150 mm RP column. Using a 10-100% acetonitrile/water (0.1% NH4OH) linear gradient at 15 mL/minutes over 20 minutes, the product of interest was recovered and lyophilized to give the titled compound as a white solid. LCMS (M+H)+: 640.5. 1H NMR (CDCl3, 500 MHz): δ 8.17 (s, 1H), 8.10 (d, J=2.2 Hz, 1H), 7.91 (s, 1H), 7.75 (s, 2H), 7.35 (d, J=2.2 Hz, 1H), 5.64 (d, J=8.5 Hz, 1H), 4.72 (d, J=17.1 Hz, 1H), 4.32 (m, 1H), 4.00 (d, J=17.2 Hz, 1H), 3.94 (s, 3H), 3.88 (m, 4H), 3.83 (m, 4H), 2.96 (m, 1H), 1.29 (d, J=7.0 Hz, 6H), 0.71 (d, J=6.5 Hz, 3H). SPA IC50: 229 nM.
Reaction SMILES: Cl[C:2]([O:4][CH:5]([CH:19]1[C:31]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[C:25]2[C:20]1=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH:6]1[C:18]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[C:12]2[C:7]1=[CH:8][CH:9]=[CH:10][CH:11]=2)=[O:3].C1COCC1.[NH2:37][C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1>C1C=CC=CC=1>[C:2](=[O:3])([O:4][CH:5]([CH:19]1[C:31]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[C:25]2[C:20]1=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH:6]1[C:18]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[C:12]2[C:7]1=[CH:8][CH:9]=[CH:10][CH:11]=2)[NH:37][C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1
Reactant: O=C(Cl)OC(C1c2ccccc2-c2ccccc21)C1c2ccccc2-c2ccccc21
Reactant: Nc1ccccc1
Solvent: C1CCOC1
Solvent: c1ccccc1
Product: O=C(Nc1ccccc1)OC(C1c2ccccc2-c2ccccc21)C1c2ccccc2-c2ccccc21
Temperature: 0 °C
Reaction time: 3 h
Yield: 100 %

Procedure:
To a solution of 1.0 g (1.18 mmol) of bis(9-fluorenyl)-methyl chloroformate in 15 mL of freshly distilled THF and 15 mL of dry benzene was added 0.21 mL (2.3 mmol) of freshly distilled aniline in one portion at 0° C. The mixture was stirred at 0° C. for 3 hours and quenched with 10 mL of sat'd NH4Cl. The organic layer was washed with water (10mL) and the pooled aqueous layer was extracted with CHCl3 (2×10 mL). The combined organic extracts were dried over MgSO4 and the solvent was evaporated in vacuo to give 1.13 g (100%) of the crude urethane as a white solid. Recrystallization from chloroform gave 0.93 g (82.03%) of the pure α-F-Fmoc-aniline as white crystals, m.p. 225°-227° C. (dec.); IR (KBr): 3340 (NH), 1705 (C=O) cm-1 ; 1H NMR (DMSO-d6): δ 4.59 (d, 2H, ArCH), 5.70 (t, 1H, CHO), 6.80-7.95 (m, 21H, aryl), 9.38 (b, 1H, NH).
Reaction SMILES: C(N(CC)CC)C.[CH2:8]([N:10]=[C:11]=[O:12])[CH3:9].[ClH:13].[N:14]12[CH2:21][CH2:20][CH:17]([CH2:18][CH2:19]1)[C@@H:16]([NH:22][C:23]([C:25]1[S:26][C:27]3[C:33]([C:34]4[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=4[CH2:40][OH:41])=[CH:32][CH:31]=[CH:30][C:28]=3[CH:29]=1)=[O:24])[CH2:15]2.C1COCC1>CN(C=O)C>[ClH:13].[CH2:8]([NH:10][C:11](=[O:12])[O:41][CH2:40][C:35]1[CH:36]=[CH:37][CH:38]=[CH:39][C:34]=1[C:33]1[C:27]2[S:26][C:25]([C:23]([NH:22][C@@H:16]3[CH:17]4[CH2:18][CH2:19][N:14]([CH2:21][CH2:20]4)[CH2:15]3)=[O:24])=[CH:29][C:28]=2[CH:30]=[CH:31][CH:32]=1)[CH3:9]
Reactant: CCN=C=O
Reactant: O=C(N[C@H]1CN2CCC1CC2)c1cc2cccc(-c3ccccc3CO)c2s1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: CCNC(=O)OCc1ccccc1-c1cccc2cc(C(=O)N[C@H]3CN4CCC3CC4)sc12
Temperature: 25 °C
Reaction time: 18 h

Procedure:
32.5 μl (0.23 mmol) of triethylamine and 16.6 mg (0.23) mmol) of ethyl isocyanate are added to a suspension of 50 mg (0.12 mmol) of N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-7-[2-(hydroxymethyl)phenyl]-1-benzothiophene-2-carboxamide hydrochloride (Example 131) in 1 ml of a 5:1 mixture of THF and DMF. After 18 h at room temperature, a further 16.6 mg (0.23 mmol) of ethyl isocyanate and a catalytic amount of 4-N,N-dimethylaminopyridine are added. The mixture is stirred at room temperature for a further 18 h. The reaction mixture is concentrated in vacuo and purified by preparative HPLC. The product fractions are concentrated and, after addition of a 5:1 mixture of methanol and 1N hydrochloric acid, again concentrated. Drying under high vacuum results in 28 mg (47% of theory) of the title compound.
Reaction SMILES: [Si:1]([O:8][C:9]1[CH:10]=[CH:11][C:12](I)=[C:13]2[C:18]=1[N:17]=[CH:16][CH:15]=[CH:14]2)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[C:20]([O:24][C:25](=[O:28])[CH:26]=[CH2:27])([CH3:23])([CH3:22])[CH3:21].C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.C(N(CC)CC)C>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C(#N)C>[Si:1]([O:8][C:9]1[CH:10]=[CH:11][C:12](/[CH:27]=[CH:26]/[C:25]([O:24][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:28])=[C:13]2[C:18]=1[N:17]=[CH:16][CH:15]=[CH:14]2)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: C=CC(=O)OC(C)(C)C
Reactant: CC(C)(C)[Si](C)(C)Oc1ccc(I)c2cccnc12
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)/C=C/c1ccc(O[Si](C)(C)C(C)(C)C)c2ncccc12

Procedure:
A mixture of Example 201B (5.00 g, 13.0 mmol), tert-butylacrylate (2.00 g, 15.6 mmol), palladium(II) acetate (175 mg, 0.78 mmol), and tri-o-tolylphosphine (951 mg, 3.12 mmol) in a sealed tube with triethylamine (8 mL) and acetonitrile (38 mL) was heated to 120° C. for 16 hours and then concentrated. The concentrate was purified by flash column chromatography on silica gel with 10-100% ethyl acetate/hexanes to provide the desired product.