Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:7]([NH:8][C:9]2[N:14]=[C:13]([N:15]([CH:25]3[CH2:27][CH2:26]3)CC3C=CC(OC)=CC=3)[C:12]3=[N:28][CH:29]=[C:30]([C:31]#[N:32])[N:11]3[N:10]=2)=[CH:6][C:5]([C:33]#[N:34])=[CH:4][C:3]=1[N:35]1[CH2:40][CH2:39][C@@H:38]([NH:41][C:42](=[O:45])[O:43][CH3:44])[C@H:37]([O:46][P:47]([OH:50])([OH:49])=[O:48])[CH2:36]1.C1(OC)C=CC=CC=1.C(O)(C(F)(F)F)=O>ClCCCl>[Cl:1][C:2]1[C:7]([NH:8][C:9]2[N:14]=[C:13]([NH:15][CH:25]3[CH2:27][CH2:26]3)[C:12]3=[N:28][CH:29]=[C:30]([C:31]#[N:32])[N:11]3[N:10]=2)=[CH:6][C:5]([C:33]#[N:34])=[CH:4][C:3]=1[N:35]1[CH2:40][CH2:39][C@@H:38]([NH:41][C:42](=[O:45])[O:43][CH3:44])[C@H:37]([O:46][P:47]([OH:50])([OH:49])=[O:48])[CH2:36]1
Reactant: COC(=O)N[C@@H]1CCN(c2cc(C#N)cc(Nc3nc(N(Cc4ccc(OC)cc4)C4CC4)c4ncc(C#N)n4n3)c2Cl)C[C@H]1OP(=O)(O)O
Solvent: ClCCCl
Solvent: O=C(O)C(F)(F)F
Solvent: COc1ccccc1
Product: COC(=O)N[C@@H]1CCN(c2cc(C#N)cc(Nc3nc(NC4CC4)c4ncc(C#N)n4n3)c2Cl)C[C@H]1OP(=O)(O)O
Yield: 55.2 %

Procedure:
To a solution of methyl ((3R,4R)-1-(2-chloro-5-cyano-3-((7-cyano-4-(cyclopropyl(4-methoxybenzyl)amino)imidazo[2,1-f][1,2,4]triazin-2-yl)amino)phenyl)-3-(phosphonooxy)piperidin-4 yl)carbamate (0.007 g, 0.009 mmol) in DCE (1 mL) was added anisole (0.006 mL, 0.055 mmol) followed by TFA (25% in DCE) (1.1 mL, 3.57 mmol) and at 35° C. for overnight. After completion of starting material (by LCMS), reaction mixture was concentrated and residue was taken in DCM (5 mL) concentrated under vacuum, the same thing was repeated one more time with 5 mL DCM. The resultant mixture was purified by reverse phase preparative HPLC and collected fractions were lyophilized to give methyl ((3R,4R)-1-(2-chloro-5-cyano-3-((7-cyano-4 (cyclopropylamino)imidazo[2,1-f][1,2,4]triazin-2-yl)amino)phenyl)-3-(phosphonooxy)piperidin-4 yl)carbamate (0.003 g, 4.97 μmol, 51.28% yield) as white solid.
Reaction SMILES: [Br:1][C:2]1[N:3]=[C:4]([CH:26]([NH:38][C:39]2[CH:40]=[C:41]3[C:46](=[CH:47][CH:48]=2)[C:45]([N:49]([C:57]([O:59][C:60]([CH3:63])([CH3:62])[CH3:61])=[O:58])[C:50]([O:52][C:53]([CH3:56])([CH3:55])[CH3:54])=[O:51])=[N:44][CH:43]=[CH:42]3)[C:27]2[CH:32]=[C:31]([CH2:33][CH3:34])[CH:30]=[C:29](OC)[C:28]=2[F:37])[N:5]([C:7]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=1.BrC1N=C(C(O)C2C(F)=C([N:98]3[CH2:102][CH2:101][CH2:100][C:99]3=[O:103])C=C(CC)C=2)N(C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)C=1.BrC1N=C(C(Cl)C2C=C(CC)C=C(OC)C=2F)N(C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)C=1.NC1C=C2C(=CC=1)C(N(C(OC(C)(C)C)=O)C(OC(C)(C)C)=O)=NC=C2>>[Br:1][C:2]1[N:3]=[C:4]([CH:26]([NH:38][C:39]2[CH:40]=[C:41]3[C:46](=[CH:47][CH:48]=2)[C:45]([N:49]([C:50]([O:52][C:53]([CH3:56])([CH3:55])[CH3:54])=[O:51])[C:57]([O:59][C:60]([CH3:62])([CH3:63])[CH3:61])=[O:58])=[N:44][CH:43]=[CH:42]3)[C:27]2[CH:32]=[C:31]([CH2:33][CH3:34])[CH:30]=[C:29]([N:98]3[CH2:102][CH2:101][CH2:100][C:99]3=[O:103])[C:28]=2[F:37])[N:5]([C:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)([C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:6]=1
Reactant: CCc1cc(C(O)c2nc(Br)cn2C(c2ccccc2)(c2ccccc2)c2ccccc2)c(F)c(N2CCCC2=O)c1
Reactant: CCc1cc(OC)c(F)c(C(Nc2ccc3c(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)nccc3c2)c2nc(Br)cn2C(c2ccccc2)(c2ccccc2)c2ccccc2)c1
Agent: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)c1nccc2cc(N)ccc12
Agent: CCc1cc(OC)c(F)c(C(Cl)c2nc(Br)cn2C(c2ccccc2)(c2ccccc2)c2ccccc2)c1
Product: CCc1cc(C(Nc2ccc3c(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)nccc3c2)c2nc(Br)cn2C(c2ccccc2)(c2ccccc2)c2ccccc2)c(F)c(N2CCCC2=O)c1

Procedure:
According to the procedure for the preparation of Intermediate 206.4, Intermediate 398.3 (65 mg, 0.104 mmol) was converted to the chloro intermediate, then displaced with di-tert-butyl (6-aminoisoquinolin-1-yl)imidodicarbonate (rt for 14 h) to afford after flash chromatography (0 to 100% EtOAc/hexanes gradient) 53.3 mg of Intermediate 398.4 as a colorless solid. LCMS (2 min gradient) RT=2.14 min, 723.1 (M+(H−Tr)+H)+.
Reaction SMILES: C([O:5][C:6]1[CH:7]=[C:8]([C:12]2[C:13]3[CH2:26][CH2:25][N:24]([C:27](=[O:29])[CH3:28])[C:14]=3[N:15]=[C:16]([N:18]3[CH2:23][CH2:22][O:21][CH2:20][CH2:19]3)[N:17]=2)[CH:9]=[CH:10][CH:11]=1)(C)(C)C>FC(F)(F)C(O)=O>[OH:5][C:6]1[CH:7]=[C:8]([C:12]2[C:13]3[CH2:26][CH2:25][N:24]([C:27](=[O:29])[CH3:28])[C:14]=3[N:15]=[C:16]([N:18]3[CH2:19][CH2:20][O:21][CH2:22][CH2:23]3)[N:17]=2)[CH:9]=[CH:10][CH:11]=1
Reactant: CC(=O)N1CCc2c(-c3cccc(OC(C)(C)C)c3)nc(N3CCOCC3)nc21
Solvent: O=C(O)C(F)(F)F
Product: CC(=O)N1CCc2c(-c3cccc(O)c3)nc(N3CCOCC3)nc21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 64.1 %

Procedure:
1-[4-(3-t-Butoxyphenyl)-2-morpholin-4-yl-5,6-dihydro-pyrrolo[2,3-d]pyrimidin-7-yl]-ethanone (20 mg) prepared according to Step E in Example 1-J-01 described later was dissolved in trifluoroacetic acid (500 μl), followed by stirring at room temperature for 30 minutes. The reaction mixture was concentrated under reduced pressure, and to the resulting residue, water (5 ml) and methanol (1 ml) were added, followed by neutralization with aqueous saturated sodium bicarbonate solution. The deposited precipitate was filtered off, followed by drying under reduced pressure, to obtain a colorless powder (11 mg, 64%).
Reaction SMILES: Cl.[NH2:2][OH:3].[CH3:4][C:5]1[C:6](=[O:14])[C:7]([CH3:13])=[C:8]([CH3:12])[C:9](=O)[CH:10]=1>O.CO>[CH3:13][C:7]1[C:6](=[O:14])[C:5]([CH3:4])=[CH:10][C:9](=[N:2][OH:3])[C:8]=1[CH3:12]
Reactant: CC1=CC(=O)C(C)=C(C)C1=O
Reactant: NO
Agent: Cl
Solvent: O
Solvent: CO
Product: CC1=CC(=NO)C(C)=C(C)C1=O
Reaction time: 2 h
Yield: 66.9 %

Procedure:
A solution of 7.04 g of hydroxylamine hydrochloride in 30 ml of water was added at room temperature to a solution of 16.9 g of trimethylbenzoquinone [prepared as described in step (a) above] in 150 ml of methanol, and the resulting mixture was stirred for 2 hours, after which it was allowed to stand for 2 days. At the end of this time, the reaction mixture was diluted with 1000 ml of water. The precipitate which separated out was collected by filtration and recrystallized from a mixture of ethyl acetate and hexane, to give 11.2 g of the title compound, melting at 188-190° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5](F)=[N:6][CH:7]=1.[NH2:9][C@H:10]1[CH2:15][CH2:14][C@H:13]([OH:16])[CH2:12][CH2:11]1>CC(O)C>[Br:1][C:2]1[CH:3]=[N:4][C:5]([NH:9][C@H:10]2[CH2:15][CH2:14][C@H:13]([OH:16])[CH2:12][CH2:11]2)=[N:6][CH:7]=1
Reactant: Fc1ncc(Br)cn1
Reactant: N[C@H]1CC[C@H](O)CC1
Solvent: CC(C)O
Product: O[C@H]1CC[C@H](Nc2ncc(Br)cn2)CC1

Procedure:
As shown in step 6-i of Scheme 6, to a mixture of 5-bromo-2-fluoro-pyrimidine (1 g, 5.651 mmol) in iPrOH (10 mL) was added TEA (1.143 g, 1.574 mL, 11.30 mmol) and trans-4-aminocyclohexan-1-ol (650.8 mg, 5.651 mmol). The mixture was microwaved for 20 min at 150° C., concentrated under reduced pressure, diluted with EtOAc, washed with water, and dried over Na2SO4. After removal of the volatiles under reduced pressure, the residue was purified by medium pressure silica gel chromatography (0-80% EtOAc/hexanes gradient) to provide (trans)-4-((5-bromopyrimidin-2-yl)amino)cyclohexanol (compound 1013, 1.2 g): 1H-NMR (300 MHz, CDCl3) δ 8.28 (s, 2H), 5.03 (d, J=8.1 Hz, 1H), 3.91-3.49 (m, 2H), 2.31-1.90 (m, 4H), 1.56-1.19 (m, 4H).
Reaction SMILES: [H-].C([Al+]CC(C)C)C(C)C.CON(C)[C:14]([C:16]1[O:17][C:18]([Br:22])=[C:19]([Br:21])[CH:20]=1)=[O:15]>O1CCCC1>[Br:21][C:19]1[CH:20]=[C:16]([CH:14]=[O:15])[O:17][C:18]=1[Br:22]
Reactant: CON(C)C(=O)c1cc(Br)c(Br)o1
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: C1CCOC1
Product: O=Cc1cc(Br)c(Br)o1
Temperature: -78 °C
Reaction time: 1.5 h
Yield: 80.1 %

Procedure:
Diisobutylaluminum hydride (80 ml, 1M solution in toluene) was added to a solution of the product from Step 2 (20 g, 63.4 mmol) in tetrahydrofuran (160 ml) at −78° C. The mixture was stirred at −78° C. for 1.5 hours and was then quenched with a saturated aqueous solution of ammonium chloride (40 ml). The reaction was allowed to warm to room temperature, diluted with ethyl acetate and 5M hydrochloric acid (20 ml) and stirred for 30 minutes. The organic layer was separated, washed twice with water and then brine, dried and concentrated in vacuo to yield the title compound (12.9 g, 81%); 1H NMR (CDCl3) 9.52 (1H, s), 7.21 (1H, s).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:12]=[C:11]([C:13]3[C:18]([Cl:19])=[CH:17][CH:16]=[CH:15][C:14]=3[Cl:20])[O:10][N:9]=2)[CH:5]=[CH:6][CH:7]=1.C(N(CC)CC)C.[Cl:28][CH:29]([Cl:33])[C:30](Cl)=[O:31]>O1CCCC1>[Cl:28][CH:29]([Cl:33])[C:30]([NH:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([C:8]2[CH:12]=[C:11]([C:13]3[C:14]([Cl:20])=[CH:15][CH:16]=[CH:17][C:18]=3[Cl:19])[O:10][N:9]=2)[CH:3]=1)=[O:31]
Reactant: O=C(Cl)C(Cl)Cl
Reactant: Nc1cccc(-c2cc(-c3c(Cl)cccc3Cl)on2)c1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=C(Nc1cccc(-c2cc(-c3c(Cl)cccc3Cl)on2)c1)C(Cl)Cl
Temperature: 25 °C
Reaction time: 12 h

Procedure:
3-(3-Aminophenyl)-5-(2,6-dichlorophenyl)isoxazole (60 mg, 0.2 mmol) was dissolved in anhydrous tetrahydrofuran (10 mL) with triethylamine (33 mL, 0.24 mmol). The mixture was cooled in an ice-bath under nitrogen, then a solution of dichloroacetyl chloride (23 mL, 0.24 mmol) in anhydrous tetrahydrofuran (5 mL) was added dropwise. After the addition was completed the ice-bath was removed and the mixture was stirred at room temperature for 12 h. The solvent was removed under reduced pressure. The residue was dissolved in ethyl acetate and washed successively with water and brine. The ethyl acetate solution was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The resulting solid was purified by column chromatography on silica gel, eluting with 8:2 hexanes-ethyl acetate. The appropriate fractions were combined to give the title compound as a tan solid, 74 mg.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[C:12]([P:15](=[O:22])([O:19][CH2:20][CH3:21])[O:16][CH2:17][CH3:18])([F:14])[F:13])[N:8]=[C:7]([CH:23]=O)[CH:6]=[CH:5]2.Cl.[NH2:26][OH:27].C([O-])(=O)C.[Na+].C(=O)([O-])O.[Na+]>C(O)C>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[C:12]([P:15](=[O:22])([O:16][CH2:17][CH3:18])[O:19][CH2:20][CH3:21])([F:13])[F:14])[N:8]=[C:7](/[CH:23]=[N:26]/[OH:27])[CH:6]=[CH:5]2
Reactant: CCOP(=O)(OCC)C(F)(F)c1cc2nc(C=O)ccc2cc1Br
Reactant: NO
Agent: CC(=O)[O-]
Agent: Cl
Agent: O=C([O-])O
Solvent: CCO
Product: CCOP(=O)(OCC)C(F)(F)c1cc2nc(/C=N/O)ccc2cc1Br
Temperature: 70 °C
Reaction time: 1 h

Procedure:
To a stirred solution of diethyl [(6-bromo-2-formylquinolin-7-yl)(difluoro)methyl]phosphonate (525 mg, 1.244 mmol) [Example 8, Step 4] in ethanol (12 mL) at room temperature were added hydroxylamine hydrochloride (130 mg, 1.865 mmol) and sodium acetate (508 mg. 3.73 mmol). The reaction mixture was stirred at 70° C. for 1 hour. It was then poured into aqueous sodium hydrogen carbonate and extracted with ethyl acetate (100 mL), washed with aqueous sodium hydrogen carbonate (2×), brine, dried with MgSO4, and concentrated in vacuo to give crude diethyl [(6-bromo-2-[(E)-(hydroxyimino)methyl]quinolin-7-yl)(difluoro)methyl]phosphonate.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:29](O)=[O:30])=[N:4][C:5]([Cl:28])=[C:6]([N:8]2[CH2:13][CH2:12][C:11](=[N:14][O:15][CH:16]3[CH2:21][CH2:20][N:19]([C:22]([O:24][CH:25]([CH3:27])[CH3:26])=[O:23])[CH2:18][CH2:17]3)[CH2:10][CH2:9]2)[N:7]=1.C(N(CC)CC)C.ClC(OCC)=O.[BH4-].[Na+]>C1COCC1.O>[CH:25]([O:24][C:22]([N:19]1[CH2:18][CH2:17][CH:16]([O:15][N:14]=[C:11]2[CH2:12][CH2:13][N:8]([C:6]3[C:5]([Cl:28])=[N:4][C:3]([CH2:29][OH:30])=[C:2]([Cl:1])[N:7]=3)[CH2:9][CH2:10]2)[CH2:21][CH2:20]1)=[O:23])([CH3:27])[CH3:26]
Reactant: CC(C)OC(=O)N1CCC(ON=C2CCN(c3nc(Cl)c(C(=O)O)nc3Cl)CC2)CC1
Agent: CCOC(=O)Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(C)OC(=O)N1CCC(ON=C2CCN(c3nc(Cl)c(CO)nc3Cl)CC2)CC1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
The crude 56c obtained in the previous step was combined with triethylamine (50 μL, 0.36 mmol) in 2 mL of THF and treated at 0° C. with ethyl chloroformate (30 μL, 0.31 mmol). The mixture was stirred at room temperature for 4 h then it was added to a stirred suspension of sodium borohydride (32 mg, 0.84 mmol) in water and the stirring was continued for 3 h. The mixture was quenched with aqueous NaHCO3 (5 mL) and water (5 mL) and extracted with EtOAc (3×5 mL). The combined extracts were dried and concentrated and the residue was purified by reparative TLC(eluent: EtOAc) to afford 56-1: LC-MS 442.0 (MH+-18), tR=7.43 (Method 2). EC50: 35 nM.
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[NH:11][C:12](=[O:26])/[CH:13]=[CH:14]/[C:15]1[CH:24]=[CH:23][C:22]2[C:17](=[CH:18][CH:19]=[C:20]([F:25])[CH:21]=2)[CH:16]=1)=[O:4].[OH-].[Na+]>CO>[C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[NH:11][C:12](=[O:26])/[CH:13]=[CH:14]/[C:15]1[CH:24]=[CH:23][C:22]2[C:17](=[CH:18][CH:19]=[C:20]([F:25])[CH:21]=2)[CH:16]=1)([OH:4])=[O:2]
Reactant: COC(=O)c1ccccc1NC(=O)/C=C/c1ccc2cc(F)ccc2c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(/C=C/c1ccc2cc(F)ccc2c1)Nc1ccccc1C(=O)O

Procedure:
Prepared analogously to Example 2 from trans-3-(6-fluoro-naphth-2-yl)-acrylic acid-N-(2-methoxycarbonyl-phenyl)-amide and sodium hydroxide solution in methanol.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][C:5]=1[C:11]([F:14])([F:13])[F:12])([O-])=O>CO.[Pd]>[NH2:1][C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][C:5]=1[C:11]([F:12])([F:13])[F:14]
Reactant: O=[N+]([O-])c1ccc(O)cc1C(F)(F)F
Agent: [Pd]
Solvent: CO
Product: Nc1ccc(O)cc1C(F)(F)F
Reaction time: 12 h
Yield: 98.8 %

Procedure:
A solution of 4-nitro-3-(trifluoromethyl)phenol (Aldrich, 414 mg, 2.0 mmol) in 10 mL of MeOH was added 10% Pd/C (100 mg). The suspension was stirred under H2 atmosphere for 12 h and it was then filtered and concentrated in vacuo to give 4-amino-3-(trifluoromethyl)phenol (350 mg, 95% yield), which was sufficiently pure to use in the next step. MS (ESI+): m/z 178.02 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([N:25]2[CH2:30][CH2:29][O:28][CH2:27][CH2:26]2)[C:5]2[S:10][C:9]([CH2:11][N:12]3[CH2:15][C:14]4([CH2:20][CH2:19][N:18](S(C)(=O)=O)[CH2:17][CH2:16]4)[CH2:13]3)=[CH:8][C:6]=2[N:7]=1.[CH3:31][N:32]([CH3:36])[C:33](Cl)=[O:34]>>[CH3:31][N:32]([CH3:36])[C:33]([N:18]1[CH2:19][CH2:20][C:14]2([CH2:13][N:12]([CH2:11][C:9]3[S:10][C:5]4[C:4]([N:25]5[CH2:26][CH2:27][O:28][CH2:29][CH2:30]5)=[N:3][C:2]([Cl:1])=[N:7][C:6]=4[CH:8]=3)[CH2:15]2)[CH2:16][CH2:17]1)=[O:34]
Reactant: CS(=O)(=O)N1CCC2(CC1)CN(Cc1cc3nc(Cl)nc(N4CCOCC4)c3s1)C2
Reactant: CN(C)C(=O)Cl
Product: CN(C)C(=O)N1CCC2(CC1)CN(Cc1cc3nc(Cl)nc(N4CCOCC4)c3s1)C2

Procedure:
Prepared according to the method used in the preparation of 2-chloro-6-(7-methanesulfonyl-2,7-diaza-spiro[3.5]non-2-ylmethyl)-4-morpholin-4-yl-thieno[3,2-d]pyrimidine using dimethylcarbamoyl chloride in place of methanesulfonyl chloride. The title compound was obtained as a yellow oil (39 mg, 42%).
Reaction SMILES: C(OC(=O)COC1C=CC(SCC2C=C(C3C=CC(C(F)(F)F)=CC=3)OC=2)=CC=1C)C.[CH2:32]([O:34][C:35](=[O:46])[CH2:36][O:37][C:38]1[CH:43]=[CH:42][C:41]([SH:44])=[CH:40][C:39]=1[CH3:45])[CH3:33].[CH3:47][C:48]1[CH:52]=[C:51]([C:53]2[CH:58]=[CH:57][C:56]([O:59][C:60]([F:63])([F:62])[F:61])=[CH:55][CH:54]=2)[S:50][C:49]=1[CH2:64]O>>[CH2:32]([O:34][C:35](=[O:46])[CH2:36][O:37][C:38]1[CH:43]=[CH:42][C:41]([S:44][CH2:64][C:49]2[S:50][C:51]([C:53]3[CH:54]=[CH:55][C:56]([O:59][C:60]([F:62])([F:63])[F:61])=[CH:57][CH:58]=3)=[CH:52][C:48]=2[CH3:47])=[CH:40][C:39]=1[CH3:45])[CH3:33]
Reactant: Cc1cc(-c2ccc(OC(F)(F)F)cc2)sc1CO
Reactant: CCOC(=O)COc1ccc(S)cc1C
Agent: CCOC(=O)COc1ccc(SCc2coc(-c3ccc(C(F)(F)F)cc3)c2)cc1C
Product: CCOC(=O)COc1ccc(SCc2sc(-c3ccc(OC(F)(F)F)cc3)cc2C)cc1C

Procedure:
The title compound was prepared by a method analogous to that used for the preparation of ethyl{2-methyl-4-[({5-[4-(trifluoromethyl)phenyl]-3-furyl}methyl)thio]phenoxy}acetate (example 1) using ethyl(4-mercapto-2-methylphenoxy)acetate (intermediate 4) and {3-methyl-5-[4-(trifluoromethoxy)phenyl]thien-2-yl}methanol (intermediate 118).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[S:9][N:8]=[C:7]([NH:10][CH2:11][CH2:12][CH2:13][NH2:14])[C:6]=2[CH:15]=1.[CH3:16][O:17][C:18]1[CH:23]=[CH:22][C:21]([C:24]2[CH:29]=[CH:28][C:27]([CH:30]=O)=[CH:26][CH:25]=2)=[CH:20][CH:19]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl.C(O)(=O)C.C(OCC)(=O)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[S:9][N:8]=[C:7]([NH:10][CH2:11][CH2:12][CH2:13][NH:14][CH2:30][C:27]3[CH:26]=[CH:25][C:24]([C:21]4[CH:22]=[CH:23][C:18]([O:17][CH3:16])=[CH:19][CH:20]=4)=[CH:29][CH:28]=3)[C:6]=2[CH:15]=1
Reactant: COc1ccc(-c2ccc(C=O)cc2)cc1
Reactant: NCCCNc1nsc2ccc(Br)cc12
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: COc1ccc(-c2ccc(CNCCCNc3nsc4ccc(Br)cc34)cc2)cc1
Yield: 40.8 %

Procedure:
N1-(5-Bromobenzo[d]isothiazol-3-yl)propane-1,3-diamine (190 mg, 0.66 mmol) and 4′-methoxybiphenyl-4-carbaldehyde (140 mg, 0.66 mmol) were combined in 1,2-dichloroethane (30 mL) and treated with sodium triacetoxyborohydride (280 mg, 1.32 mmol) and acetic acid (one drop). The mixture was sonicated at room temperature for 18 h. The reaction was diluted with ethyl acetate and then washed with water, brine and saturated sodium bicarbonate solution. The organic solution was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The resulting residue was purified by flash column chromatography, on silica gel, eluting with 98:2 methylene chloride:methanol to yield N1-(5-bromobenzo[d]isothiazol-3-yl)-N3-((4′-methoxybiphenyl-4-yl)methyl)propane-1,3-diamine (130 mg) as a yellow solid. MW=482 confirmed by LC-MS, tr=3.24 min (Method B) MH+=481-483.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([CH2:14][OH:15])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.N1C=CN=C1.[C:21]([Si:25]([CH3:28])([CH3:27])Cl)([CH3:24])([CH3:23])[CH3:22].O>O1CCCC1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:13]=[CH:12][C:11]([CH2:14][O:15][Si:25]([C:21]([CH3:24])([CH3:23])[CH3:22])([CH3:28])[CH3:27])=[CH:10][CH:9]=2)=[CH:6][CH:7]=1
Reactant: OCc1ccc(-c2ccc(Br)cc2)cc1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)[Si](C)(C)OCc1ccc(-c2ccc(Br)cc2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 88.9 %

Procedure:
(4′-Bromobiphenyl-4-yl)methanol (0.70 g, 2.7 mmol) and imidazole (0.54 g, 8.0 mmol) were dissolved in tetrahydrofuran (20 mL), and tert-butyldimethylchlorosilane (1.2 g, 8.0 mmol) was added under a nitrogen atmosphere, followed by stirring at room temperature for 1 hour. Water was added to the reaction solution, which was extracted with ethyl acetate, and subsequently washed sequentially with a saturated sodium hydrogencarbonate solution, water and a saturated aqueous sodium chloride solution. After the organic layer was concentrated under reduced pressure, the resulting residue was purified by chromatography on a silica gel column (Moritex Corporation, elution solvent: hexane/ethyl acetate), and a fraction corresponding to the Rf value=0.90 (hexane/ethyl acetate=9/1) by thin layer chromatography was concentrated under reduced pressure to afford the title compound (0.92 g, 2.4 mmol) as a white solid (yield 91%).
Reaction SMILES: [CH2:1]([CH2:3][NH2:4])[OH:2].Cl[CH2:6][CH2:7][S:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[C:15]([NH:18][C:19]1[C:20](=[O:39])[N:21]([C:25]2[CH:26]=[C:27]([CH:34]=[C:35]([F:38])[C:36]=2[CH3:37])[C:28]([NH:30][CH:31]2[CH2:33][CH2:32]2)=[O:29])[CH:22]=[CH:23][N:24]=1)([CH3:17])[CH3:16]>>[CH:31]1([NH:30][C:28](=[O:29])[C:27]2[CH:26]=[C:25]([N:21]3[CH:22]=[CH:23][N:24]=[C:19]([NH:18][C:15]([C:10]4[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=4[S:8][CH2:7][CH2:6][NH:4][CH2:3][CH2:1][OH:2])([CH3:17])[CH3:16])[C:20]3=[O:39])[C:36]([CH3:37])=[C:35]([F:38])[CH:34]=2)[CH2:32][CH2:33]1
Reactant: NCCO
Reactant: Cc1c(F)cc(C(=O)NC2CC2)cc1-n1ccnc(NC(C)(C)c2ccccc2SCCCl)c1=O
Product: Cc1c(F)cc(C(=O)NC2CC2)cc1-n1ccnc(NC(C)(C)c2ccccc2SCCNCCO)c1=O

Procedure:
The title compound was prepared from ethanolamine and 3-{3-[(1-{2-[(2-chloroethyl)sulfanyl]phenyl}-1-methylethyl)amino]-2-oxopyrazin-1(2H)-yl}-N-cyclopropyl-5-fluoro-4-methylbenzamide (Example 321a) using a similar method to that described for Example 252l. The crude product was purified by preparative HPLC (X-Bridge column eluting with 95-5% gradient of aqueous 0.2% ammonia in acetonitrile) to give the title compound as a solid.
Reaction SMILES: C([O:3][C:4]([CH:6]1[O:11][CH2:10][C:9]2[S:12][C:13]([NH2:22])=[C:14]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[C:8]=2[CH2:7]1)=[O:5])C.[OH-].[Na+].Cl>C(O)C.O1CCCC1>[C:18]([O:17][C:15]([C:14]1[C:8]2[CH2:7][CH:6]([C:4]([OH:5])=[O:3])[O:11][CH2:10][C:9]=2[S:12][C:13]=1[NH2:22])=[O:16])([CH3:21])([CH3:19])[CH3:20]
Reactant: CCOC(=O)C1Cc2c(sc(N)c2C(=O)OC(C)(C)C)CO1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)c1c(N)sc2c1CC(C(=O)O)OC2
Temperature: 25 °C
Reaction time: 5 h

Procedure:
The above 2-amino-4,7-dihydro-5H-thieno[2,3-c]pyran-3,5-dicarboxylic acid 3-tert-butyl ester 5-ethyl ester (275 mg, 0.84 mmol) was dissolved in a mixture of ethanol (4 ml) and tetrahydrofuran (1 ml). Sodium hydroxide (1N, 1.6 ml, 1.68 mmol) was added and the reaction stirred at ambient temperature for 5 hours after which TLC analysis indicated that the reaction was complete. The reaction was monitored with a pH meter and neutralized with 1N hydrochloric acid until pH=6.9. The solution was concentrated in vacuo to give 2-amino-4,7-dihydro-5H-thieno[2,3-c]pyran-3,5-dicarboxylic acid 3-tert-butyl ester as a solid. Sodium chloride remained as an impurity.
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH2:11][C:12]([NH2:14])=[O:13])=[CH:7][NH:8]2)=[CH:4][CH:3]=1.C[O:16][C:17](=O)[C:18]([C:20]1[C:30]2=[C:31]3[C:26](=[CH:27][C:28]([F:32])=[CH:29]2)[C:25]([CH3:34])([CH3:33])[CH2:24][CH2:23][N:22]3[CH:21]=1)=O>>[CH3:33][C:25]1([CH3:34])[C:26]2[C:31]3=[C:30]([C:20]([C:18]4[C:17](=[O:16])[NH:14][C:12](=[O:13])[C:11]=4[C:6]4[C:5]5[C:9](=[CH:10][C:2]([F:1])=[CH:3][CH:4]=5)[NH:8][CH:7]=4)=[CH:21][N:22]3[CH2:23][CH2:24]1)[CH:29]=[C:28]([F:32])[CH:27]=2
Reactant: NC(=O)Cc1c[nH]c2cc(F)ccc12
Reactant: COC(=O)C(=O)c1cn2c3c(cc(F)cc13)C(C)(C)CC2
Product: CC1(C)CCn2cc(C3=C(c4c[nH]c5cc(F)ccc45)C(=O)NC3=O)c3cc(F)cc1c32

Procedure:
Beginning with (6-fluoroindol-3-yl)acetamide and (6,6-dimethyl-8-fluoro-5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-1-yl)oxoacetic acid methyl ester, the title compound was prepared essentially as described in Example 1.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([N+:11]([O-:13])=[O:12])=[C:6]([CH:10]=1)[C:7](O)=[O:8]>CO>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N+:11]([O-:13])=[O:12])=[C:6]([CH2:7][OH:8])[CH:10]=1
Reactant: O=C(O)c1cc(F)ccc1[N+](=O)[O-]
Solvent: CO
Product: O=[N+]([O-])c1ccc(F)cc1CO
Temperature: 70 °C
Yield: 103.9 %

Procedure:
To 5-fluoro-2-nitrobenzoic acid (0.5 g, 2.7 mmol) was added a solution of borane-tetrahydrofuran complex (5 mL, 1.0 M, 5 mmol) and the resulting solution was heated to 70° C. for 3 hours. The reaction was then cooled to room temperature and methanol was added. The mixture was concentrated and methanol was added two additional times to provide 0.48 g (100%) of a white solid. mp 82-86° C. Anal Calc'd for C7H6N3O3F: C, 49.13; H, 3.52; N, 8.18. Found: C, 48.76; H, 3.56; N, 7.88.