Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(O)(=O)C(O)=O.[F:7][C:8]([F:21])([F:20])[C:9]1[CH:10]=[C:11]([CH:17]=[CH:18][CH:19]=1)[O:12][CH:13]1[CH2:16][NH:15][CH2:14]1.C(N(CC)CC)C.[CH3:29][N:30]([CH3:34])[C:31](Cl)=[O:32].[Cl-].[Ca+2].[Cl-]>O1CCCC1.O>[CH3:29][N:30]([CH3:34])[C:31]([N:15]1[CH2:16][CH:13]([O:12][C:11]2[CH:17]=[CH:18][CH:19]=[C:9]([C:8]([F:7])([F:20])[F:21])[CH:10]=2)[CH2:14]1)=[O:32]
Reactant: FC(F)(F)c1cccc(OC2CNC2)c1
Reactant: CN(C)C(=O)Cl
Agent: O=C(O)C(=O)O
Agent: [Ca+2]
Agent: [Cl-]
Solvent: C1CCOC1
Solvent: O
Solvent: CCN(CC)CC
Product: CN(C)C(=O)N1CC(Oc2cccc(C(F)(F)F)c2)C1
Reaction time: 15 h
Yield: 76.6 %

Procedure:
A stirred slurry of 5 g (0.0163 mole) of 3-[3-(trifluoromethyl)phenoxy]azetidine oxalate in 50 ml of tetrahydrofuran was treated with 5 ml of triethylamine and after 1 hr, 1.95 g (0.018 mole) of dimethylcarbamoyl chloride was added. After stirring an additional 15 hr, the reaction mixture was treated with 20 ml of water and 10 g of calcium chloride. The tetrahydrofuran layer was decanted and the residue triturated with 20 ml of ethyl acetate, then decanted. The combined tetrahydrofuran and ethyl acetate solution was concentrated in vacuo. The crude residue was chromatographed on a Waters Prep-LC using 50% ethyl acetate/toluene as the eluent. After concentration of the main fractions, 3.6 g (76.6%) of pale yellow oil was obtained.
Reaction SMILES: O[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([C:12]([O:14][CH3:15])=[O:13])[CH:3]=1.[C:16]1([CH3:28])[CH:21]=[CH:20][C:19]([S:22]([N:25]=C=O)(=[O:24])=[O:23])=[CH:18][CH:17]=1.C(=O)=O>C(#N)C>[C:16]1([CH3:28])[CH:17]=[CH:18][C:19]([S:22]([N:25]=[C:2]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[NH:5][C:4]([C:12]([O:14][CH3:15])=[O:13])=[CH:3]2)(=[O:23])=[O:24])=[CH:20][CH:21]=1
Reactant: COC(=O)c1cc(O)c2ccccc2n1
Reactant: Cc1ccc(S(=O)(=O)N=C=O)cc1
Agent: O=C=O
Solvent: CC#N
Product: COC(=O)c1cc(=NS(=O)(=O)c2ccc(C)cc2)c2ccccc2[nH]1
Temperature: 25 °C
Yield: 82.3 %

Procedure:
According to the procedure of Wright, Synthesis, 1984, 1058, methyl 4-hydroxy-2-quinolinecarboxylate (2.03 g, 0.01 m) and p-toluenesulfonyl isocyanate (1.97 g, 0.01 m) were mixed in reagent grade acetonitrile at RT. The heterogeneous mixture was heated at reflux until the evolution of CO2 had ceased (ca 2-3 hours). During this time a yellow solid formed. After cooling to RT, the yellow solid was collected by filtration, washed with acetonitrile, and dried to give methyl 4-(p-toluenesulfonylimino)-1,4-dihydroquinoline-2-carboxylate (2.93 g, 82%), melting point of 264°-265° C. (dec.), as a yellow solid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][C@@H:9]1[CH2:13][O:14][C:15]1[CH:20]=[C:19]([N+:21]([O-])=O)[CH:18]=[CH:17][C:16]=1[C:24]([F:27])([F:26])[F:25])=[O:7])([CH3:4])([CH3:3])[CH3:2]>CO.O1CCOCC1>[NH2:21][C:19]1[CH:18]=[CH:17][C:16]([C:24]([F:27])([F:25])[F:26])=[C:15]([CH:20]=1)[O:14][CH2:13][C@H:9]1[CH2:10][CH2:11][CH2:12][N:8]1[C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7]
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H]1COc1cc([N+](=O)[O-])ccc1C(F)(F)F
Solvent: C1COCCO1
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCC[C@@H]1COc1cc(N)ccc1C(F)(F)F
Temperature: 25 °C
Reaction time: 42 h

Procedure:
(R)-2-(5-Nitro-2-trifluoromethyl-phenoxymethyl)-pyrrolidine-1-carboxylic acid tert-butyl ester (2.19 g, 5.60 mmol) was dissolved in 40 mL MeOH and 10 mL dioxane. To the nitrogen-degassed solution was added 10% Pd/C (0.3 g). The reaction was stirred vigorously at RT under 1 atm H2 gas for 42 h. The reaction was filtered through Celite® and concentrated in vacuo to yield the title compound as a white foam. MS (MNa+)=383.3; Calc'd 360.38 for C17H23F3N2O3.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:17]3[S:16][CH:15]=[CH:14][C:13]=3[CH:12]=[CH:11][CH:10]=2)=[CH:5][CH:4]=1.[Br:18]Br>C(Cl)Cl>[Br:18][C:12]1[C:13]2[CH:14]=[CH:15][S:16][C:17]=2[C:9]([C:6]2[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)=[CH:10][CH:11]=1
Reactant: BrBr
Reactant: COc1ccc(-c2cccc3ccsc23)cc1
Solvent: ClCCl
Product: COc1ccc(-c2ccc(Br)c3ccsc23)cc1
Reaction time: 0.5 h
Yield: 99.4 %

Procedure:
To a −20° C. solution of 7-(4-methoxyphenyl)-1-benzothiophene (500 mg, 2.08 mmol) in CH2Cl2 (15 ml) was added Br2 (8.33 ml of 0.25 M stock in CH2Cl2, 2.08 mmol) over 45 minutes. The reaction was stirred for an additional 0.5 h, washed with water, dried over Na2SO4, passed through a silica plug and concentrated to give 660 mg (100%) of product as a yellow solid. Further purification was done by recrystalization from 3% EtOAc in hexanes: mp 103–104° C.; 1H NMR (300 MHz, DMSO-d6): δ 3.84 (3H, s), 7.12 (2H, d, J=8.7 Hz), 7.31 (1H, d, J=7.9 Hz), 7.54 (1H, d, J=5.6 Hz), 7.65 (2H, d, J=8.7 Hz), 7.72 (1H, d, J=7.9 Hz), 7.98 (1H, d, J=5.6 Hz).
Reaction SMILES: C(OC([N:8]=[S:9]([CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])([CH3:11])=[O:10])=O)(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[CH2:16]([O:15][C:13](=[O:14])[CH2:12][S:9]([CH3:11])(=[NH:8])=[O:10])[CH3:17]
Reactant: CCOC(=O)CS(C)(=O)=NC(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCOC(=O)CS(C)(=N)=O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of ethyl [N-(tert-butoxycarbonyl)-S-methylsulfonimidoyl]acetate in dichloromethane (2.5 mL) was cooled to 0° C. followed by a dropwise addition of trifluoroacetic acid (0.79 mL). The reaction was then stirred at RT for 2 hours. The excess TFA was removed under reduced pressure and the oily residue was partitioned between EtOAc and saturated aq NaHCO3/brine. The organic layer was separated, washed with brine (1×), and dried over Na2SO4. The upper solution layer was decanted and concentrated yielding the title compound as a brown oil (49 mg).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH2:7][CH2:8][C:9]([CH3:15])([CH3:14])[CH:10]2[OH:13])=[CH:5][CH:4]=1.C(N(CC)CC)C.[C:23](OC(=O)C)(=[O:25])[CH3:24]>CN(C1C=CN=CC=1)C.ClCCl.C(OCC)(=O)C>[CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH2:7][CH2:8][C:9]([CH3:15])([CH3:14])[CH:10]2[O:13][C:23](=[O:25])[CH3:24])=[CH:5][CH:4]=1
Reactant: CC(=O)OC(C)=O
Reactant: COc1ccc2c(c1)C(O)C(C)(C)CC2
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: COc1ccc2c(c1)C(OC(C)=O)C(C)(C)CC2
Reaction time: 0.75 h

Procedure:
To a solution of 7-methoxy-2,2-dimethyl-3,4-dihydro-2H-naphthalen-1-ol (1.40 g, 6.52 mmol) and DMAP (0.16 g, 1.30 mmol) in dichloromethane (30 mL) is added triethylamine (1.99 g, 19.55 mmol) and acetic anhydride (1.68 g, 16.29 mmol). After 45 min, the mixture is diluted with ethyl acetate and washed successively with 1M aqueous sodium bisulfate, saturated aqueous sodium bicarbonate, and brine. The organic phase is dried over magnesium sulfate, filtered, and concentrated to give acetic acid 7-methoxy-2,2-dimethyl-1,2,3,4-tetrahydro-naphthalen-1-yl ester, which is used in the next step without further purification.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][C:17]#[CH:18].C([Li])CCC.Br[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH3:44]>C1COCC1.CN(C)P(=O)(N(C)C)N(C)C.CCCCCC>[O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][C:17]#[C:18][CH2:44][CH2:43][CH2:42][CH2:41][CH2:40][CH2:39][CH2:38][CH2:37][CH2:36][CH2:35][CH2:34][CH2:33][CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH3:25]
Reactant: CCCCCCCCCCCCCCCCCCCCBr
Reactant: C#CCCCCCCCCCOC1CCCCO1
Agent: [Li]CCCC
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CCCCCCCCCCCCCCCCCCCCC#CCCCCCCCCCOC1CCCCO1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 61.6 %

Procedure:
5 g (0.0198 mol) of 11-tetrahydropyranyloxyundecyne of Example 7 were placed in a mixture of 50 ml of THF and 25 ml of hexamethylphosphoric triamide under an argon atmosphere. At -60° C., 12.4 ml (0.0198 mol) of n-butyllithium in hexane were added dropwise. After 30 min at -60° C., a solution of 9.0 g (0.0248 mol) of 1-bromoeicosane in 25 ml of THF was added dropwise at -60° C. The mixture was left to warm up to room temperature. After 18 h at room temperature, it was poured into 25% aqueous NaH2PO4 solution and extracted with n-heptane (3×). The combined organic phases were dried (Na2SO4) and the solvent was removed. Flash chromatography on silica gel (n-heptane/ethyl acetate =15:1) gave 6.5 g (61.3% of theory) of 1-tetrahydropyranyloxy-hentriacont-10-yne.
Reaction SMILES: Br[C:2]1[N:6]([S:7]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[C:16]#[N:17])(=[O:9])=[O:8])[CH:5]=[C:4]([CH2:18][N:19]([CH3:27])[C:20](=[O:26])[O:21][C:22]([CH3:25])([CH3:24])[CH3:23])[CH:3]=1.[N:28]1[CH:33]=[CH:32][CH:31]=[C:30](B(O)O)[CH:29]=1.C(=O)([O-])[O-].[Na+].[Na+]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:16]([C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=1[S:7]([N:6]1[C:2]([C:30]2[CH:29]=[N:28][CH:33]=[CH:32][CH:31]=2)=[CH:3][C:4]([CH2:18][N:19]([CH3:27])[C:20](=[O:26])[O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[CH:5]1)(=[O:9])=[O:8])#[N:17]
Reactant: OB(O)c1cccnc1
Reactant: CN(Cc1cc(Br)n(S(=O)(=O)c2ccccc2C#N)c1)C(=O)OC(C)(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: CN(Cc1cc(-c2cccnc2)n(S(=O)(=O)c2ccccc2C#N)c1)C(=O)OC(C)(C)C
Yield: 63.4 %

Procedure:
Using tert-butyl {[5-bromo-1-(2-cyanophenyl)sulfonyl-1H-pyrrol-3-yl]methyl}methylcarbamate (296 mg), 3-pyridineboronic acid (162 mg), sodium carbonate (208 mg) and tetrakis(triphenylphosphine)palladium (38.2 mg), a procedure as in Reference Example 267 was performed to give the title compound as a white solid (yield 187 mg, 63%).
Reaction SMILES: [CH2:1]([N:8]1[CH:12]=[C:11]([C:13]2[CH:17]=[C:16]([C:18]([OH:20])=O)[NH:15][N:14]=2)[N:10]=[CH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:21][C@@H:22]([CH3:38])[CH2:23][N:24]1[CH:28]=[CH:27][C:26]([C:29]2[CH:36]=[CH:35][C:32]([C:33]#[N:34])=[C:31]([Cl:37])[CH:30]=2)=[N:25]1>>[CH2:1]([N:8]1[CH:12]=[C:11]([C:13]2[CH:17]=[C:16]([C:18]([NH:21][C@@H:22]([CH3:38])[CH2:23][N:24]3[CH:28]=[CH:27][C:26]([C:29]4[CH:36]=[CH:35][C:32]([C:33]#[N:34])=[C:31]([Cl:37])[CH:30]=4)=[N:25]3)=[O:20])[NH:15][N:14]=2)[N:10]=[CH:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)c1cc(-c2cn(Cc3ccccc3)cn2)n[nH]1
Reactant: C[C@H](N)Cn1ccc(-c2ccc(C#N)c(Cl)c2)n1
Product: C[C@@H](Cn1ccc(-c2ccc(C#N)c(Cl)c2)n1)NC(=O)c1cc(-c2cn(Cc3ccccc3)cn2)n[nH]1
Yield: 44.9 %

Procedure:
The title compound was prepared using the method of Example 34(d) starting from 3-(1-benzyl-1H-imidazol-4-yl)-1H-pyrazole-5-carboxylic acid (0.268 g, 0.997 mmol) and (S)-4-(1-(2-aminopropyl)-1H-pyrazol-3-yl)-2-chlorobenzonitrile (0.2 g, 0.767 mmol). The product was purified with flash chromatography. Yield 44.9%. 1H-NMR (400 MHz; CDCl3): δ 1.23 (d, 3H), 4.27 (dd, 1H), 4.41 (dd, 1H), 4.53-4.63 (m, 1H), 5.26 (s, 2H), 6.61 (d, 1H), 6.76 (s, 1H), 7.00-7.05 (m, 2H), 7.28-7.36 (m, 5H), 7.49 (d, 1H), 7.58-7.63 (m, 2H), 7.78 (dd, 1H), 8.03 (s, 1H), 11.75 (bs, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH2:19])[CH:5]=[N:6][C:7]=1[O:8][C:9]1[CH:10]=[N:11][C:12]2[C:17]([CH:18]=1)=[CH:16][CH:15]=[CH:14][CH:13]=2.[CH3:20][C:21]1[CH:26]=[C:25]([CH3:27])[CH:24]=[C:23]([CH3:28])[C:22]=1[S:29](Cl)(=[O:31])=[O:30]>>[Cl:1][C:2]1[CH:3]=[C:4]([NH:19][S:29]([C:22]2[C:23]([CH3:28])=[CH:24][C:25]([CH3:27])=[CH:26][C:21]=2[CH3:20])(=[O:31])=[O:30])[CH:5]=[N:6][C:7]=1[O:8][C:9]1[CH:10]=[N:11][C:12]2[C:17]([CH:18]=1)=[CH:16][CH:15]=[CH:14][CH:13]=2
Reactant: Cc1cc(C)c(S(=O)(=O)Cl)c(C)c1
Reactant: Nc1cnc(Oc2cnc3ccccc3c2)c(Cl)c1
Product: Cc1cc(C)c(S(=O)(=O)Nc2cnc(Oc3cnc4ccccc4c3)c(Cl)c2)c(C)c1

Procedure:
The title compound was prepared by reacting 5-chloro-6-(quinolin-3-yloxy)pyridin-3-amine (obtained as per procedure described in preparation 1) and 2,4,6-trimethylbenzene-1-sulfonyl chloride.
Reaction SMILES: [ClH:1].Cl.[CH3:3][N:4]([CH3:13])[CH2:5][CH2:6][CH:7]1[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]1.[CH3:14][C:15]1[CH:20]=[CH:19][C:18]([O:21][CH2:22][CH2:23]Br)=[CH:17][CH:16]=1.C(N(CC)CC)C.[OH-].[Na+]>CN(C=O)C>[ClH:1].[ClH:1].[CH3:13][N:4]([CH3:3])[CH2:5][CH2:6][CH:7]1[CH2:12][CH2:11][N:10]([CH2:23][CH2:22][O:21][C:18]2[CH:19]=[CH:20][C:15]([CH3:14])=[CH:16][CH:17]=2)[CH2:9][CH2:8]1
Reactant: CN(C)CCC1CCNCC1
Reactant: Cc1ccc(OCCBr)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Cc1ccc(OCCN2CCC(CCN(C)C)CC2)cc1
Temperature: 0 °C

Procedure:
A mixture of 4-(2-dimethylaminoethyl)piperidine dihydrochloride (7.0 g), 2-bromoethyl 4-methylphenyl ether (6.6 g), triethylamine (12.75 ml) and DMF (50 ml) was heated on a steam bath for 16 hours. The mixture was poured into ice/water (500 ml), basified with 2M sodium hydroxide solution and extracted with dichloromethane. The combined organic extracts were washed with water and then extracted with 2M hydrochloric acid. The combined acidic layers were basified with 2M sodium hydroxide solution and then extracted with dichloromethane to give an oil. The oil was distilled at 120° C. at 0.05 mbar and the distillate was dissolved in ether, acidified with ethereal hydrogen chloride solution and filtered. The solid obtained was washed with ether and recrystallised from absolute ethanol to give 4-(2-dimethylaminoethyl)-1-[2-(4-methylphenoxy)ethyl]piperidine dihydrochloride m.p. 281°-283° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]([CH2:11][C:12]([O:14][CH3:15])=[O:13])[NH2:10])=[CH:5][C:4]=1[CH3:16].[O-:17][C:18]#[N:19].[Na+].FC(F)(F)C(O)=O.C(=O)(O)[O-].[Na+]>C1(C)C=CC=CC=1>[NH2:19][C:18]([NH:10][N:9]([CH2:11][C:12]([O:14][CH3:15])=[O:13])[C:6]1[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[C:4]([CH3:16])[CH:5]=1)=[O:17]
Reactant: N#C[O-]
Reactant: COC(=O)CN(N)c1ccc(OC)c(C)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: Cc1ccccc1
Product: COC(=O)CN(NC(N)=O)c1ccc(OC)c(C)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 52.2 %

Procedure:
A mixture of methyl [1-[4-methoxy-3-methylphenyl]hydrazino]acetate (Intermediate 97, 380 mg, 0.0017 mol), sodium cyanate (380 mg, 0.0058 mol) and trifluoroacetic acid (0.4 ml, 0.0052 mol) in dry toluene (10 ml) was stirred under nitrogen and at room temperature for 31/2 hours. It was poured into 8% sodium bicarbonate solution (20 ml) and extracted with ethyl acetate (2×20 ml). The organic extract was dried (MgSO4) and evaporated to give a yellow solid which was triturated with ether and filtered to give the title compound as a yellow solid (237 mg, 52%) m.p. 174°-176° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:10]=[C:11]([F:39])[C:12]=1[CH2:13][S:14][C:15]1[N:16]([C:32]2[CH:37]=[CH:36][C:35]([F:38])=[CH:34][CH:33]=2)[C:17]([C:20]([C:23]2[CH:28]=[CH:27][C:26]([F:29])=[C:25]([O:30][CH3:31])[CH:24]=2)([CH3:22])[CH3:21])=[CH:18][N:19]=1)[O:5][CH2:6][CH2:7][CH2:8][OH:9].CCN(C(C)C)C(C)C.[CH3:49][S:50](Cl)(=[O:52])=[O:51]>C(Cl)Cl>[CH3:49][S:50]([O:9][CH2:8][CH2:7][CH2:6][O:5][C:4]1[CH:10]=[C:11]([F:39])[C:12]([CH2:13][S:14][C:15]2[N:16]([C:32]3[CH:33]=[CH:34][C:35]([F:38])=[CH:36][CH:37]=3)[C:17]([C:20]([C:23]3[CH:28]=[CH:27][C:26]([F:29])=[C:25]([O:30][CH3:31])[CH:24]=3)([CH3:22])[CH3:21])=[CH:18][N:19]=2)=[C:2]([Cl:1])[CH:3]=1)(=[O:52])=[O:51]
Reactant: COc1cc(C(C)(C)c2cnc(SCc3c(F)cc(OCCCO)cc3Cl)n2-c2ccc(F)cc2)ccc1F
Reactant: CS(=O)(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COc1cc(C(C)(C)c2cnc(SCc3c(F)cc(OCCCOS(C)(=O)=O)cc3Cl)n2-c2ccc(F)cc2)ccc1F
Reaction time: 0.5 h
Yield: 98.3 %

Procedure:
To a stirred solution of 3-(3-chloro-5-fluoro-4-((5-(2-(4-fluoro-3-methoxyphenyl)propan-2-yl)-1-(4-fluorophenyl)-1H-imidazol-2-ylthio)methyl)phenoxy)propan-1-ol (420 mg, 0.73 mmol) and DIPEA (0.32 mL, 1.83 mmol) in DCM (10 mL) at 0° C. was added dropwise methanesulfonylchloride (113 μL, 1.45 mmol). After stirring 30 min, the reaction mixture was partitioned in DCM (20 mL) and water (20 mL). The aqueous layer was re-extracted with DCM (20 mL×2). The combined organic layers were dried over MgSO4, concentrated and purified by column chromatography (EtOAc/Hex=1:2) to give 3-(3-chloro-5-fluoro-4-((5-(2-(4-fluoro-3-methoxyphenyl)propan-2-yl)-1-(4-fluorophenyl)-1H-imidazol-2-ylthio)methyl)phenoxy)propyl methanesulfonate (470 mg, 99% yield) as a white solid. 1H NMR (400 MHz, CDCl3) δ 7.25 (d, J=8.65 Hz, 1H), 6.87 (dd, J=11.04, 8.48 Hz, 1H), 6.81-6.73 (m, 2H), 6.69-6.66 (m, 1H), 6.58 (dd, J=8.13, 2.23 Hz, 1H), 6.50-6.43 (m, 2H), 6.38-6.31 (m, 1H), 4.42 (t, J=6.04 Hz, 2H), 4.18 (s, 2H), 4.03 (t, J=5.88 Hz, 2H), 3.77 (d, J=5.83 Hz, 2H), 3.68 (s, 4H), 3.10-2.98 (m, 3H), 2.22 (p, J=5.94 Hz, 2H), 1.51 (t, J=4.73 Hz, 5H).
Reaction SMILES: C(O)(C(F)(F)F)=O.[NH2:8][C:9]1[CH:10]=[C:11]([C:16]2[C:17](=[O:38])[N:18]([CH2:36][CH3:37])[C:19]3[C:24]([CH:25]=2)=[CH:23][N:22]=[C:21]([NH:26]CC2C=CC(OC)=CC=2)[CH:20]=3)[CH:12]=[CH:13][C:14]=1[F:15].C([O-])(O)=O.[Na+]>C(Cl)Cl>[NH2:26][C:21]1[CH:20]=[C:19]2[C:24]([CH:25]=[C:16]([C:11]3[CH:12]=[CH:13][C:14]([F:15])=[C:9]([NH2:8])[CH:10]=3)[C:17](=[O:38])[N:18]2[CH2:36][CH3:37])=[CH:23][N:22]=1
Reactant: CCn1c(=O)c(-c2ccc(F)c(N)c2)cc2cnc(NCc3ccc(OC)cc3)cc21
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCn1c(=O)c(-c2ccc(F)c(N)c2)cc2cnc(N)cc21
Temperature: 50 °C
Reaction time: 8 h
Yield: 31.6 %

Procedure:
To a solution of TFA in CH2Cl2 (10%, 50 mL) was added 3-(3-amino-4-fluoro-phenyl)-1-ethyl-7-(4-methoxy-benzylamino)-1H-[1,6]naphthyridin-2-one (2.0 g, 4.78 mmol). The resulting mixture was stirred at 50° C. overnight. The reaction mixture was poured saturated aq NaHCO3 solution (100 mL), and was extracted with CH2Cl2 (3×75 mL). The combined organic layer was dried (MgSO4) and concentrated in vacuo. The residue was purified by silica gel column chromatography to give 7-amino-3-(3-amino-4-fluorophenyl)-1-ethyl-1,6-naphthyridin-2(1H)-one (0.45 g, 32% yield). 1H NMR (300 MHz, DMSO-d6): δ 8.35 (s, 1 H), 7.76 (s, 1 H), 7.09 (dd, J=9.0, 2.1 Hz, 1 H), 6.97 (dd, J=11.4, 8.4 Hz, 1 H), 6.75 (m, 1 H), 6.44 (s, 2 H), 6.31 (s, 1 H), 5.09 (s, 2 H), 4.08 (q, J=7.2 Hz, 2 H), 1.20 (t, J=7.2 Hz, 3 H), MS (ESI) m/z (M+H+): 299.3.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:13]=[CH:12][C:11]([NH:14][C:15]3[C:16]4[N:17]([N:29]=[CH:30][N:31]=4)[C:18](C4C=C(C(N)=O)SC=4)=[CH:19][N:20]=3)=[CH:10][CH:9]=2)[CH2:4][CH2:3]1.BrC1N2N=CN=C2C(NC2C=CC(N3CCN(C)CC3)=CC=2)=NC=1.[CH3:56][C:57]1[NH:61][N:60]=[CH:59][C:58]=1B1OC(C)(C)C(C)(C)O1.C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:56][C:57]1[NH:61][N:60]=[CH:59][C:58]=1[C:18]1[N:17]2[N:29]=[CH:30][N:31]=[C:16]2[C:15]([NH:14][C:11]2[CH:12]=[CH:13][C:8]([N:5]3[CH2:4][CH2:3][N:2]([CH3:1])[CH2:7][CH2:6]3)=[CH:9][CH:10]=2)=[N:20][CH:19]=1
Reactant: CN1CCN(c2ccc(Nc3ncc(-c4csc(C(N)=O)c4)n4ncnc34)cc2)CC1
Reactant: Cc1[nH]ncc1B1OC(C)(C)C(C)(C)O1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CN1CCN(c2ccc(Nc3ncc(Br)n4ncnc34)cc2)CC1
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Product: Cc1[nH]ncc1-c1cnc(Nc2ccc(N3CCN(C)CC3)cc2)c2ncnn12
Yield: 7 %

Procedure:
This compound may be prepared using methods as described for Compound 6, step 4 using (5-bromo-[1,2,4]triazolo[1,5-a]pyrazin-8-yl)-[4-(4-methyl-piperazin-1-yl)-phenyl]-amine (132 mg, 0.340 mmol), 5-methyl-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-pyrazole (141 mg, 0.68 mmol), Pd(PPh3)4 (98 mg, 0.085 mmol) and 1.5N Na2CO3 (1.81 mL, 2.72 mmol) in dioxane (5.4 mL). The crude product is purified by silica gel column chromatography eluting with 95:5 DCM:NH3 (7M in MeOH) followed by trituration with diethyl ether and petroleum ether to afford the title compound (9 mg, 7%) as a pale green solid. 1H-NMR (400 MHz, d6-DMSO) δ (ppm) 2.27 (3H, s), 2.38-2.49 (7H, m), 3.14 (4H, m), 6.97 (2H, d), 7.70 (1H, s), 7.88 (2H, d), 7.99 and 8.43 (1H, br s), 8.68 (1H, s), 9.71 (1H, s), 12.92 and 12.98 (1H, br s).
Reaction SMILES: C(OC([N:8]1[CH2:12][CH:11]([C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[C:15]([O:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[CH3:28])[CH:14]=2)[CH2:10][C:9]1=[O:29])=O)(C)(C)C.C(O)(C(F)(F)F)=O.C(Cl)Cl>>[CH3:20][O:19][C:16]1[CH:17]=[CH:18][C:13]([CH:11]2[CH2:12][NH:8][C:9](=[O:29])[CH2:10]2)=[CH:14][C:15]=1[O:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[CH3:28]
Reactant: COc1ccc(C2CC(=O)N(C(=O)OC(C)(C)C)C2)cc1Oc1ccccc1C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc(C2CNC(=O)C2)cc1Oc1ccccc1C
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
The deprotection of 4-(4-methoxy-3-o-tolyloxyphenyl)-2-oxo-pyrrolidine-1-carboxylic acid tert-butyl ester was performed in a 25% TFA/DCM solution. This solution was stirred for 30 min at r.t. After neutralization and extraction in EtOAc, the mixture was concentrated under reduced pressure to give the desired compound without purification.
Reaction SMILES: [F:1][C:2]1[CH:14]=[CH:13][C:5]([C:6]([CH:8](Br)[CH2:9][CH2:10][Cl:11])=[O:7])=[CH:4][CH:3]=1.[C:15]1([OH:25])[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH:18]=[CH:17][CH:16]=1.[I-].[Na+].C([O-])([O-])=O.[K+].[K+]>CC(C)=O>[F:1][C:2]1[CH:14]=[CH:13][C:5]([C:6]([CH:8]([O:25][C:15]2[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[CH:18]=[CH:17][CH:16]=2)[CH2:9][CH2:10][Cl:11])=[O:7])=[CH:4][CH:3]=1
Reactant: O=C(c1ccc(F)cc1)C(Br)CCCl
Reactant: Oc1cccc2ccccc12
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC(C)=O
Product: O=C(c1ccc(F)cc1)C(CCCl)Oc1cccc2ccccc12

Procedure:
The 1-p-Fluorobenzoyl-1-(alpha-naphthoxy)-3-chloropropane is prepared as follows. A solution of 20 g. of 1-p-fluorobenzoyl-1-bromo-3-chloropropane in 60 cc. anhydrous acetone is added slowly over half an hour while stirring to a suspension of 10.4 g. of α-naphthol, 0.72 g. of sodium iodide and 16.8 g. of K2CO3 in 300 cc. anhydrous acetone. When the addition is complete, the mixture is refluxed for 10 hours and then cooled. The solid therein is filtered off and the solvent is removed from the filtrate at reduced pressure. The residue melts at 147°C (from benzene).
Reaction SMILES: [P:1]([O-:39])([O:35][CH2:36][CH2:37]Br)([O:3][CH2:4][CH:5]([O:29][C:30]1[CH:34]=[CH:33][O:32][N:31]=1)[CH2:6][O:7][C:8]1[CH:12]=[C:11]([CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])[O:10][N:9]=1)=[O:2].[S:40]1[CH:44]=[CH:43][N:42]=[CH:41]1>>[P:1]([O-:39])([O:35][CH2:36][CH2:37][C:41]1[S:40][CH:44]=[CH:43][NH+:42]=1)([O:3][CH2:4][CH:5]([O:29][C:30]1[CH:34]=[CH:33][O:32][N:31]=1)[CH2:6][O:7][C:8]1[CH:12]=[C:11]([CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])[O:10][N:9]=1)=[O:2]
Reactant: c1cscn1
Reactant: CCCCCCCCCCCCCCCCc1cc(OCC(COP(=O)([O-])OCCBr)Oc2ccon2)no1
Product: CCCCCCCCCCCCCCCCc1cc(OCC(COP(=O)([O-])OCCc2[nH+]ccs2)Oc2ccon2)no1

Procedure:
0.779 g of (2RS)-3-(5-hexadecyl-3-isoxazolyloxy)-2-(3-isoxazolyloxy)propyl 2-bromoethyl phosphate [prepared as described in Example 21(a)] was reacted with 0.86 ml of thiazole in a similar manner to that described in Example 13, to give 0.288 g of the title compound as a white powder melting at 94°-100° C.