Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH:2]([CH2:5][OH:6])[CH2:3][OH:4].[O-2].[Mg+2].[Cl:9][C:10]1[S:14][C:13]([S:15](Cl)(=[O:17])=[O:16])=[CH:12][C:11]=1[N+:19]([O-:21])=[O:20]>O.C1COCC1>[OH:4][CH2:3][CH:2]([NH:1][S:15]([C:13]1[S:14][C:10]([Cl:9])=[C:11]([N+:19]([O-:21])=[O:20])[CH:12]=1)(=[O:17])=[O:16])[CH2:5][OH:6]
Reactant: O=[N+]([O-])c1cc(S(=O)(=O)Cl)sc1Cl
Reactant: NC(CO)CO
Agent: [Mg+2]
Agent: [O-2]
Solvent: C1CCOC1
Solvent: O
Product: O=[N+]([O-])c1cc(S(=O)(=O)NC(CO)CO)sc1Cl
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 43.7 %

Procedure:
To a stirred solution of 2-amino-1,3-propanediol (0.5 g, 5.49 mmol) in water (2 ml) was added at room temperature magnesium oxide (1.11 g, 27.5 mmol) and THF (6 ml). The suspension was stirred at room temperature for 30 min and a solution of 5-chloro-4-nitrothiophene-2-sulfonyl chloride (2.88 g, 10.9 mmol) in THF (2 ml) was added. The light yellow suspension was stirred at room temperature for 1 h and, after filtration on Dicalit, evaporated. Water (60 ml) was added and the mixture was extracted with ethyl acetate (3×50 ml). The combined organic layers were washed with brine (70 ml), dried (MgSO4) and evaporated. The crude product was further purified by column chromatography on silica gel (heptane/ethyl acetate 1:1) and subsequent crystallization from ethyl acetate/hexane to yield 5-chloro-4-nitro-thiophene-2-sulfonic acid (2-hydroxy-1-hydroxymethyl-ethyl)-amide (0.76 g, 44%) as a light yellow solid. MS (ISP) 314.9 [(M−H)−], mp 142° C.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([C:20](=[O:26])[CH:21](OCC)O)[C:12]2[O:17][CH2:16][C:15](=[O:18])[NH:14][C:13]=2[CH:19]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:27][C:28]([CH3:48])([CH3:47])[CH2:29][CH2:30][N:31]1[C:36]2[CH:37]=[C:38]([F:41])[CH:39]=[CH:40][C:35]=2[C:34]([CH2:44][CH3:45])([CH2:42][CH3:43])[O:33][C:32]1=[O:46].C1COCC1.[BH4-].[Li+]>O.ClCCl>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:20]([OH:26])[CH2:21][NH:27][C:28]([CH3:48])([CH3:47])[CH2:29][CH2:30][N:31]2[C:36]3[CH:37]=[C:38]([F:41])[CH:39]=[CH:40][C:35]=3[C:34]([CH2:44][CH3:45])([CH2:42][CH3:43])[O:33][C:32]2=[O:46])[C:12]2[O:17][CH2:16][C:15](=[O:18])[NH:14][C:13]=2[CH:19]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(O)C(=O)c1cc(OCc2ccccc2)cc2c1OCC(=O)N2
Reactant: CCC1(CC)OC(=O)N(CCC(C)(C)N)c2cc(F)ccc21
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Solvent: ClCCl
Product: CCC1(CC)OC(=O)N(CCC(C)(C)NCC(O)c2cc(OCc3ccccc3)cc3c2OCC(=O)N3)c2cc(F)ccc21
Temperature: 5 °C
Reaction time: 1 h

Procedure:
A solution of 232 mg (0.649 mmol) 6-benzyloxy-8-(2-ethoxy-2-hydroxy-acetyl)-4H-benzo[1,4]oxazin-3-one and 200 mg (0.649 mmol) 1-(3-amino-3-methyl-butyl)-4,4-diethyl-7-fluoro-1,4-dihydro-benzo[d][1,3]oxazin-2-one in abs. THF (5 mL) is stirred for 2.5 h at RT. The mixture is cooled to 5° C., combined with 60 mg (2.755 mmol) lithium borohydride, heated to RT and stirred for 1 h. The mixture is again cooled to 5° C. and slowly diluted with 15 ml water and 20 mL dichloromethane. The phases are separated and the aqueous phase is extracted with dichloromethane. The combined org. phases are dried with sodium sulphate and concentrated by evaporation in vacuo. The residue is purified by column chromatography (silica gel, dichloromethane/MeOH 95:5).
Reaction SMILES: FC(F)(F)C([O-])=O.[F:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[C:20]([CH2:21][P+](CCCC)(CCCC)CCCC)=[C:19]([CH:35]([CH3:37])[CH3:36])[N:18]=[C:17]([N:38]([CH3:43])[S:39]([CH3:42])(=[O:41])=[O:40])[N:16]=2)=[CH:11][CH:10]=1.C[Si](C)(C)N[Si](C)(C)C.[Na].[Si:54]([O:61][C@H:62]1[CH2:67][C:66](=[O:68])[O:65][C@H:64]([CH:69]=O)[CH2:63]1)([C:57]([CH3:60])([CH3:59])[CH3:58])([CH3:56])[CH3:55].[Cl-].[NH4+]>C1(C)C=CC=CC=1.O>[Si:54]([O:61][C@H:62]1[CH2:67][C:66](=[O:68])[O:65][C@H:64](/[CH:69]=[CH:21]/[C:20]2[C:15]([C:12]3[CH:13]=[CH:14][C:9]([F:8])=[CH:10][CH:11]=3)=[N:16][C:17]([N:38]([CH3:43])[S:39]([CH3:42])(=[O:41])=[O:40])=[N:18][C:19]=2[CH:35]([CH3:36])[CH3:37])[CH2:63]1)([C:57]([CH3:60])([CH3:59])[CH3:58])([CH3:56])[CH3:55]
Reactant: CC(C)(C)[Si](C)(C)O[C@H]1CC(=O)O[C@H](C=O)C1
Reactant: CCCC[P+](CCCC)(CCCC)Cc1c(-c2ccc(F)cc2)nc(N(C)S(C)(=O)=O)nc1C(C)C
Agent: C[Si](C)(C)N[Si](C)(C)C
Agent: O=C([O-])C(F)(F)F
Agent: [Cl-]
Solvent: O
Solvent: Cc1ccccc1
Product: CC(C)c1nc(N(C)S(C)(=O)=O)nc(-c2ccc(F)cc2)c1/C=C/[C@@H]1C[C@@H](O[Si](C)(C)C(C)(C)C)CC(=O)O1
Reaction time: 1 h
Yield: 45 %

Procedure:
To a stirred suspension of ((4-(4-fluorophenyl)-6-isopropyl-2-(N-methylmethyl-sulfonamido)pyrimidin-5-yl)methyl)tributylphosphonium 2,2,2-trifluoro-acetate (260 mg, 0.4 mmol) at room temperature in dry toluene (4 mL) is added sodium hexamethyldisilazane in toluene (0.67 mL of 0.6 M, 0.4 mmol) portionwise in 10 minutes. The reaction mixture is stirred for 60 min and treated at room temperature with a solution of (2S,4R)-4-(tert-butyldimethylsilyloxy)-6-oxo-tetrahydro-2H-pyran-2-carbaldehyde (9) (105 mg, 0.40 mmol) in 13 mL of dry toluene. After 24 hours of stirring at room temperature the solution is treated with saturated ammonium chloride solution or water. The aqueous phase is extracted with t-BuMeO (2×10 mL), and the combined organic layers dried and concentrated. The residue is purified by silica gel chromatography (elution with t-BuMeO/hexane mixture) to give 104 mg (45%) of N-(5-((E)-2-((2S,4R)-4-(tert-butyldimethylsilyloxy)-6-oxo-tetrahydro-2H-pyran-2-yl)vinyl)-4-(4-fluorophenyl)-6-isopropylpyrimidin-2-yl)-N-methylmethanesulfonamide (10) as white amorphous solid.
Reaction SMILES: C([O:8][C:9]1[C:14](=[O:15])[N:13]=[C:12]([CH2:16][C:17]2([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH2:21][CH2:20][CH2:19][CH2:18]2)[N:11]2[CH2:28][CH2:29][N:30]([CH:33]3[CH2:35][CH2:34]3)[C:31](=[O:32])[C:10]=12)C1C=CC=CC=1>C(O)C.[Pd]>[CH:33]1([N:30]2[CH2:29][CH2:28][N:11]3[C:12]([CH2:16][C:17]4([C:22]5[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=5)[CH2:21][CH2:20][CH2:19][CH2:18]4)=[N:13][C:14](=[O:15])[C:9]([OH:8])=[C:10]3[C:31]2=[O:32])[CH2:34][CH2:35]1
Reactant: O=C1c2c(OCc3ccccc3)c(=O)nc(CC3(c4ccccc4)CCCC3)n2CCN1C1CC1
Agent: [Pd]
Solvent: CCO
Product: O=C1c2c(O)c(=O)nc(CC3(c4ccccc4)CCCC3)n2CCN1C1CC1
Reaction time: 1 h
Yield: 97.1 %

Procedure:
A solution of 9-benzyloxy-2-cyclopropyl-6-(1-phenyl-cyclopentylmethyl)-3,4-dihydro-2H-pyrazino[1,2-c]pyrimidine-1,8-dione (286) (180 mg, 0.38 mmol) in ethanol (20 mL) was degassed, Pd—C (10%) (15 mg) added and hydrogenated for 1 h. The catalyst was filtered off, washed with ethanol (3×20 mL) and dichloromethane (2×15 mL), The combined solvent was concentrated and the solid was washed with n-pentane to get pure 2-cyclopropyl-9-hydroxy-6-(1-phenyl-cyclopentylmethyl)-3,4-dihydro-2H-pyrazino[1,2-c]pyrimidine-1,8-dione (287) (140 mg, 96.25%) as a white solid.
Reaction SMILES: [CH3:1][C@@H:2]([CH2:24][CH3:25])[C@H:3]([N:11]1[CH2:15][CH2:14][N:13]([CH2:16][C:17]2[N:18]=[C:19]([CH3:22])[S:20][CH:21]=2)[C:12]1=[O:23])[C:4]([O:6]C(C)(C)C)=[O:5].[F:26][C:27]([F:32])([F:31])[C:28]([OH:30])=[O:29]>ClCCl>[CH3:1][C@@H:2]([CH2:24][CH3:25])[C@H:3]([N:11]1[CH2:15][CH2:14][N:13]([CH2:16][C:17]2[N:18]=[C:19]([CH3:22])[S:20][CH:21]=2)[C:12]1=[O:23])[C:4]([OH:6])=[O:5].[F:26][C:27]([F:32])([F:31])[C:28]([OH:30])=[O:29]
Reactant: CC[C@H](C)[C@@H](C(=O)OC(C)(C)C)N1CCN(Cc2csc(C)n2)C1=O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC[C@H](C)[C@@H](C(=O)O)N1CCN(Cc2csc(C)n2)C1=O
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A solution containing the product from Example 11C (2.0 g, 5.4 mmol) in dichloromethane (14 mL) was treated with trifluoracetic acid (7 mL), stirred at 25° C. for 3 hours and concentrated to give the title compound as a trifluoroacetic acid salt.
Reaction SMILES: Br.[N:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH2:8][CH2:9][CH2:10]Br)[CH:3]=1.CN(C)C=O.[C:17]1(=[O:27])[NH:21][C:20](=[O:22])[C:19]2=[CH:23][CH:24]=[CH:25][CH:26]=[C:18]12.[K].[OH-].[K+]>O>[N:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH2:8][CH2:9][CH2:10][N:21]2[C:17](=[O:27])[C:18]3[C:19](=[CH:23][CH:24]=[CH:25][CH:26]=3)[C:20]2=[O:22])[CH:3]=1
Reactant: BrCCCc1cccnc1
Reactant: O=C1NC(=O)c2ccccc21
Agent: Br
Agent: [K+]
Agent: [K]
Solvent: O
Solvent: CN(C)C=O
Product: O=C1c2ccccc2C(=O)N1CCCc1cccnc1
Yield: 147.5 %

Procedure:
To 7.9 g (28 mmoles) of 3-(3-pyridyl)-1-bromopropane HBr was added 150 mL of dimethylformamide and 27.0 g (145 moles) of potassium phthalimide. The reaction mixture was heated under reflux for 3 hours. The mixture was cooled, diluted with water, and made basic with aqueous potassium hydroxide. The product was then extracted with ethyl acetate, and the extracts were washed with saturated solutions of sodium bicarbonate and sodium chloride, dried and evaporated to give 11.0 g of 2-[3-(3-pyridinyl)propyl]-1H-isoindole-1,3(2H)-dione, m.p. 88°-90°; NMR (CDCl3) δ8.36-8.50 (m, 2H); 7.75-7.90 (m, 2H); 7.57-7.75 (m, 2H); 7.47-7.56 (d, 1H); 7.13-7.32 (m, 1H); 3.63-3.29 (t, 2H); 2.53-2.71 (t, 2H); 1.94-2.10 (m, 2H) .
Reaction SMILES: S(Cl)(Cl)=O.[I:5][C:6]1[CH:7]=[C:8]([CH:12]=[C:13]([I:15])[CH:14]=1)[C:9]([NH2:11])=O>>[I:5][C:6]1[CH:7]=[C:8]([CH:12]=[C:13]([I:15])[CH:14]=1)[C:9]#[N:11]
Reactant: NC(=O)c1cc(I)cc(I)c1
Solvent: O=S(Cl)Cl
Product: N#Cc1cc(I)cc(I)c1
Yield: 60 %

Procedure:
To a stirred solution of 3,5-diiodbenzoic acid (1.7 g, 4.5 mmol) in dichloromethane (DCM; 10 mL) was added oxalyl chloride (2.9 g, 23 mmol). After 5 hours, the volatile contents were removed under reduced pressure. The resulting residue was poured with caution into cold ammonium hydroxide (50 mL, 28%) and stirred for 2 h. The amide product was removed by filtration and the collected residue was dissolved in DCM and washed with 1 M HCl, 1 M NaOH, water and brine. The organic layer was dried with MgSO4. Removal of DCM in vacuo afforded 3,5-diiodobenzamide which was used without further purification. Thionyl chloride (8.2 g, 69 mmol) was added to the collected amide and the mixture was heated under reflux for 18 h. The reaction mixture was allowed to cool and excess thionyl chloride removed under reduced pressure. The resulting residue was dissolved in EtOAc and washed with a saturated solution of NaHCO3 (3×10 mL), water (2×10 mL), brine and dried over anhydrous MgSO4. Concentration of the organic solution followed by column chromatography purification yielded the titled compound as an off white solid in 60% yield; mp 129-131° C.; 1H-NMR (300 MHz, CDCl3) δ (ppm): δ 8.30 (t, J=1.4 Hz, 1H), 7.94 (d, J=1.5 Hz, 2H). 13C-NMR (75 MHz, CDCl3) δ (ppm): 149.7, 139.6, 115.6, 115.5, 94.5 HRMS (m/z): [M+H]+ calc. for C7H4I2N, 355.8428. found 355.8439.
Reaction SMILES: [CH3:1][C:2]1[C:11]2[C:6](=[C:7]([NH2:12])[CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][N:3]=1.[C:13]1([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH:18]=[CH:17][C:16]([C:19](O)=[O:20])=[CH:15][CH:14]=1.Cl.CN(C)CCCN=C=NCC>C(Cl)Cl.CN(C)C1C=CN=CC=1>[CH3:1][C:2]1[C:11]2[C:6](=[C:7]([NH:12][C:19]([C:16]3[CH:17]=[CH:18][C:13]([C:22]4[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=4)=[CH:14][CH:15]=3)=[O:20])[CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][N:3]=1
Reactant: Cc1nccc2c(N)cccc12
Reactant: O=C(O)c1ccc(-c2ccccc2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: Cc1nccc2c(NC(=O)c3ccc(-c4ccccc4)cc3)cccc12
Temperature: 38 °C
Reaction time: 72 h

Procedure:
To a solution of 1-methyl-5-aminoisoquinoline (94 (75 mg, 0.47 mmol) in DCM (4 ml) was added 4-biphenylcarboxylic acid (141 mg, 0.71 mmol), 1-(3-dimethylaminopropyl)-3-ethyl-carbodiimide hydrochloride (135 mg, 0.71 mmol) and 4-dimethylaminopyridine (10 mg, 0.08 mmol) and the reaction stirred at 38° C. for 3 days. The mixture was diluted with DCM, washed with sat. aqueous sodium bicarbonate solution and water, dried over MgSO4 and concentrated in vacuo to give the crude product which was triturated with methanol. The resulting precipitate was collected by filtration, washed with ether and dried in vacuo giving the title compound as an off-white solid. 1H NMR (400 MHz, CDCl3) δ (ppm): 8.48 (d, 1H), 8.33 (d, 1H), 8.21 (br, 1H), 8.06 (m, 3H), 7.78 (d, 2H), 7.68 (m, 3H), 7.58 (d, 1H), 7.51 (t, 2H), 7.41 (t, 1H), 3.02 (s, 3H).
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([O:10][CH2:11][CH:12]2[CH2:17][CH2:16][N:15]([C:18](=[O:26])[C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([OH:25])[CH:20]=3)[CH2:14][CH2:13]2)[C:3]=1[C:4]#[N:5].O=[C:28]([CH3:35])[CH2:29][C:30]([O:32][CH2:33][CH3:34])=[O:31]>>[NH2:5][C:4]1[C:3]2[C:2](=[CH:9][CH:8]=[CH:7][C:6]=2[O:10][CH2:11][CH:12]2[CH2:13][CH2:14][N:15]([C:18](=[O:26])[C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([OH:25])[CH:20]=3)[CH2:16][CH2:17]2)[N:1]=[C:28]([CH3:35])[C:29]=1[C:30]([O:32][CH2:33][CH3:34])=[O:31]
Reactant: CCOC(=O)CC(C)=O
Reactant: N#Cc1c(N)cccc1OCC1CCN(C(=O)c2cccc(O)c2)CC1
Product: CCOC(=O)c1c(C)nc2cccc(OCC3CCN(C(=O)c4cccc(O)c4)CC3)c2c1N

Procedure:
Prepared as in Example 2a from 2-amino-6-((1-(3-hydroxybenzoyl)piperidin-4-yl)methoxy)benzonitrile (Example 34b) and ethyl 3-oxobutanoate as a yellow solid (49%). 1H NMR (400 MHz, DMSO-d6) δ 1.24 (m, 2H), 1.31 (t, J=4.0 Hz, 3H), 1.77-1.89 (m, 2H), 2.22 (brs, 1H), 2.55 (s, 3H), 2.79 (brs, 1H), 3.04 (brs, 1H), 3.64 (brs, 1H), 4.10 (m, 2H), 4.32 (q, J=8.0 Hz, 2H), 4.49 (brs, 1H), 6.71-6.82 (m, 3H), 6.93 (d, J=8.0 Hz, 1H), 7.19-7.25 (m, 2H), 7.52 (t, J=8.0 Hz, 1H), 8.06 (brs, 2H), 9.64 (s, 1H). MS 464 (MH+).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[C:4]([N+:13]([O-:15])=[O:14])[CH:3]=1.CC1(C)C(C)(C)OB([C:24]2[CH:25]=[N:26][C:27]([NH2:30])=[N:28][CH:29]=2)O1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.O.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:9]([NH:8][C:5]1[CH:6]=[CH:7][C:2]([C:24]2[CH:25]=[N:26][C:27]([NH2:30])=[N:28][CH:29]=2)=[CH:3][C:4]=1[N+:13]([O-:15])=[O:14])([CH3:12])([CH3:11])[CH3:10]
Reactant: CC(C)(C)Nc1ccc(Br)cc1[N+](=O)[O-]
Reactant: CC1(C)OB(c2cnc(N)nc2)OC1(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: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)Nc1ccc(-c2cnc(N)nc2)cc1[N+](=O)[O-]
Temperature: 100 °C

Procedure:
To a solution of (4-bromo-2-nitro-phenyl)-tert-butyl-amine (7.2 g, 0.026 mol) in DMF (100 mL) and H2O (10 mL) are added 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-pyrimidin-2-ylamine (8.7 g, 0.04 mol), Pd(PPh3)4 (3 g, 0.003 mol) and K2CO3 (7.3 g, 0.053 mol) at room temperature. The solution is heated to 100° C. for 2 hours. The solution is cooled down, washed with H2O (100 mL) and extracted with EtOAc (3×50 mL). The combined organic layer is dried with MgSO4 and filtered. The filtrate is concentrated and the residue is re-crystallized in CH2Cl2 (10 mL) to afford 5-(4-tert-butylamino-3-nitro-phenyl)-pyrimidin-2-ylamine as a scarlet solid (6.3 g, 83%).
Reaction SMILES: S1C=CC2C=C(C(=O)CC)C=CC1=2.[C:14]([O:18]C)(=[O:17])[CH2:15][SH:16].[Br:20][C:21]1[CH:22]=[CH:23][C:24](F)=[C:25]([CH:28]=1)[CH:26]=O>>[Br:20][C:21]1[CH:22]=[CH:23][C:24]2[S:16][C:15]([C:14]([OH:18])=[O:17])=[CH:26][C:25]=2[CH:28]=1
Reactant: COC(=O)CS
Reactant: O=Cc1cc(Br)ccc1F
Agent: CCC(=O)c1ccc2sccc2c1
Product: O=C(O)c1cc2cc(Br)ccc2s1
Yield: 95.1 %

Procedure:
In a similar manner to Example 9 Method A, 1-(benzo[b]thiophen-5-yl)propan-1-one was prepared starting from methyl thioglycolate (13.2 g) and 5-bromo-2-fluorobenzaldehyde (25.35 g) which were reacted together and the product hydrolysed to give 5-bromobenzo[b]thiophene-2-carboxylic acid (30.4 g), which was decarboxylated using copper and quinoline at 190° C. for 1.5 hours to give 5-bromobenzo[b]thiophene. This compound was reacted with magnesium and then with N-methoxy-N-methylpropionamide to give 1-(benzo[b]thiophen-5-yl)propan-1-one (1.3 g) as a cream solid which was used without further purification.
Reaction SMILES: C([O:3][CH:4](OCC)[C:5]1[CH:10]=[CH:9][C:8]([CH:11]2[NH:23][C:21]3[C:22]4[C:13](=[N:14][NH:15][C:16](=[O:24])[C:17]=4[CH:18]=[CH:19][CH:20]=3)[CH:12]2[C:25]2[CH:35]=[CH:34][C:28]([C:29]([N:31]([CH3:33])[CH3:32])=[O:30])=[CH:27][CH:26]=2)=[CH:7][CH:6]=1)C.FC(F)(F)C(O)=O>C(#N)C>[CH:4]([C:5]1[CH:6]=[CH:7][C:8]([CH:11]2[NH:23][C:21]3[C:22]4[C:13](=[N:14][NH:15][C:16](=[O:24])[C:17]=4[CH:18]=[CH:19][CH:20]=3)[CH:12]2[C:25]2[CH:26]=[CH:27][C:28]([C:29]([N:31]([CH3:33])[CH3:32])=[O:30])=[CH:34][CH:35]=2)=[CH:9][CH:10]=1)=[O:3]
Reactant: CCOC(OCC)c1ccc(C2Nc3cccc4c(=O)[nH]nc(c34)C2c2ccc(C(=O)N(C)C)cc2)cc1
Solvent: CC#N
Solvent: O=C(O)C(F)(F)F
Product: CN(C)C(=O)c1ccc(C2c3n[nH]c(=O)c4cccc(c34)NC2c2ccc(C=O)cc2)cc1
Reaction time: 0.5 h
Yield: 91.2 %

Procedure:
To a solution of 4-(8-(4-(diethoxymethyl)phenyl)-3-oxo-3,7,8,9-tetrahydro-2H-pyrido[4,3,2-de]phthalazin-9-yl)-N,N-dimethylbenzamide (180 mg, 0.35 mmol) in acetonitrile (10 mL) was added trifluoroacetic acid (5 mL), stirred for 30 min, Then the mixture was evaporated under reduced pressure to get the title compound (140 mg, yield 91%). LC-MS (ESI) m/z: 439 (M+1)+.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:7]=[C:8]([NH:11][C:12](=[O:32])[CH:13]([C:20]2[CH:25]=[CH:24][C:23]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)=[CH:22][CH:21]=2)[CH2:14][CH:15]2[CH2:19][CH2:18][CH2:17][CH2:16]2)[S:9][CH:10]=1)=[O:5])C>CO.S(=O)(=O)(O)O>[CH3:1][O:3][C:4]([C:6]1[N:7]=[C:8]([NH:11][C:12](=[O:32])[CH:13]([C:20]2[CH:21]=[CH:22][C:23]([C:26]3[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=3)=[CH:24][CH:25]=2)[CH2:14][CH:15]2[CH2:19][CH2:18][CH2:17][CH2:16]2)[S:9][CH:10]=1)=[O:5]
Reactant: CCOC(=O)c1csc(NC(=O)C(CC2CCCC2)c2ccc(-c3ccccc3)cc2)n1
Agent: O=S(=O)(O)O
Solvent: CO
Product: COC(=O)c1csc(NC(=O)C(CC2CCCC2)c2ccc(-c3ccccc3)cc2)n1
Temperature: 25 °C
Yield: 40.9 %

Procedure:
A solution of 2-(2-biphenyl-4-yl-3-cyclopentyl-propionylamino)-thiazole-4-carboxylic acid ethyl ester (prepared in Example 1B-d, 200 mg, 0.45 mmol) in methanol (4 mL) was treated with concentrated sulfuric acid (2 drops). The reaction mixture was heated under reflux for 15 h. The reaction mixture was allowed to cool to 25° C. and then concentrated in vacuo to remove methanol. The resulting residue was partitioned between water and ethyl acetate. The organic layer was dried over magnesium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230-400 mesh, 2/1 hexanes/ethyl acetate) afforded 2-(2-biphenyl-4-yl-3-cyclopentyl-propionylamino)-thiazole-4-carboxylic acid methyl ester (80 mg, 41%) as a white solid: mp 98-101° C.; FAB-HRMS m/e calcd for C25H26N2O3S (M+H)+ 435.1743, found 435.1752.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][CH:11]=1)[C:5]([O:7][CH3:8])=[O:6].[N+:12]([C:15]1[CH:21]=[CH:20][C:18]([NH2:19])=[CH:17][CH:16]=1)([O-:14])=[O:13]>>[CH3:8][O:7][C:5](=[O:6])[C:4]1[CH:9]=[CH:10][CH:11]=[C:2]([NH:19][C:18]2[CH:20]=[CH:21][C:15]([N+:12]([O-:14])=[O:13])=[CH:16][CH:17]=2)[CH:3]=1
Reactant: COC(=O)c1cccc(Br)c1
Reactant: Nc1ccc([N+](=O)[O-])cc1
Product: COC(=O)c1cccc(Nc2ccc([N+](=O)[O-])cc2)c1

Procedure:
Reaction of methyl 3-bromobenzoate with 4-nitroaniline according to general procedure A provided methyl ester of Compound 5 as an orange solid (59% yield). 1H NMR (CDCl3, 500 MHz): δ=8.16 (d, J=9.1 Hz, 2H), 7.89 (s, 1H), 7.83 (d, J=7.6 Hz, 1H), 7.47 (t, J=7.8 Hz, 1H), 7.41 (m, 1H), 6.98 (d, J=9.1 Hz, 2H), 6.31 (s, 1H), 3.94 (s, 3H). 13C NMR (CDCl3, 125 MHz): δ=166.7, 149.7, 140.7, 140.3, 132.2, 130.1, 126.5, 125.9, 125.7, 122.6, 114.4, 52.6.
Reaction SMILES: O=[C:2]1C2C(=CC=CC=2)C(=O)[N:3]1[CH2:12][C:13]([NH:15][CH2:16][C:17]1[CH:18]=[C:19]([NH:27][C:28]([CH:30]2[CH2:39][C:38]3[CH:37]=[C:36]([O:40][C:41]4[CH:46]=[CH:45][N:44]=[C:43]([C:47]([NH:49][CH3:50])=[O:48])[CH:42]=4)[CH:35]=[CH:34][C:33]=3[CH2:32][CH2:31]2)=[O:29])[CH:20]=[C:21]([C:23]([F:26])([F:25])[F:24])[CH:22]=1)=[O:14].CN.O>CCO>[CH3:50][NH:49][C:47]([C:43]1[CH:42]=[C:41]([O:40][C:36]2[CH:35]=[CH:34][C:33]3[CH2:32][CH2:31][CH:30]([C:28]([NH:27][C:19]4[CH:20]=[C:21]([C:23]([F:25])([F:26])[F:24])[CH:22]=[C:17]([CH2:16][NH:15][C:13](=[O:14])[CH2:12][NH:3][CH3:2])[CH:18]=4)=[O:29])[CH2:39][C:38]=3[CH:37]=2)[CH:46]=[CH:45][N:44]=1)=[O:48]
Reactant: CNC(=O)c1cc(Oc2ccc3c(c2)CC(C(=O)Nc2cc(CNC(=O)CN4C(=O)c5ccccc5C4=O)cc(C(F)(F)F)c2)CC3)ccn1
Agent: CN
Solvent: O
Solvent: CCO
Product: CNCC(=O)NCc1cc(NC(=O)C2CCc3ccc(Oc4ccnc(C(=O)NC)c4)cc3C2)cc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To a solution of 4-{[7-({[3-({[(1,3dioxo-1,3-dihydro-2-H-isoindol-2-yl)acetyl]-amino}methyl)-5-(trifluoromethyl)phenyl]amino}carbonyl)-5,6,7,8-tetrahydronaphthalen-2-yl]-oxy}-N-methylpyridine-2-carboxamide (0.819 g, 1.19 mmol) in EtOH (20 mL) was added a 40% aqueous solution of methyl amine in water (5.00 mL, 44.8 mmol). The reaction mixture was allowed to stir at rt for 5 h and then concentrated. The residue was purified by column chromatography to give N-methyl-4-{[7-({[3-({[(methylamino)acetyl]amino}-methyl)-5-(trifluoromethyl)phenylamino}carbonyl)-5,6,7,8-tetrahydronaphthalen-2-yl]oxy}-pyridine-2-carboxamide I-345 (0.124 g, 19%) as a white solid. 1H NMR (400 MHz, d6-DMSO, HCI salt) δ: 10.65 (s, 1H), 9.19-9.09 (br s, 1H), 8.85-8.77 (m, 1H), 8.50 (d, 1H), 8.17-8.02 (m, 2H), 7.66 (s, 1H), 7.41-7.36 (m, 1H), 7.28-7.21 (m, 1H), 7.19-7.14 (m, 1H), 7.04-6.94 (m, 2H), 4.22 (t, 2H), 3.83-3.76 (m, 2H), 3.67 (t, 2H), 3.03-2.81 (m, 5H), 2.77 (d, 3H), 2.17-2.08 (m, 1H), and 1.89-1.75 (m, 1H). LCMS: (FA) ES+543.2, ES−541.2.
Reaction SMILES: C([O:3][C:4]([CH:6]1[C:11]2[N:12]=[CH:13][S:14][C:10]=2[CH2:9][CH2:8][CH2:7]1)=O)C>O1CCCC1>[OH:3][CH2:4][CH:6]1[C:11]2[N:12]=[CH:13][S:14][C:10]=2[CH2:9][CH2:8][CH2:7]1
Reactant: CCOC(=O)C1CCCc2scnc21
Solvent: C1CCOC1
Product: OCC1CCCc2scnc21
Reaction time: 0.5 h
Yield: 70 %

Procedure:
To a solution of 1.14 g (30 mmoles) of AlLiH4 in 50 ml anhydrous tetrahydrofuran, cooled to -20° C. and maintained at that temperature, are slowly added 6.66 g (30 mmoles) of the above derivative (III) dissolved in 30 ml anhydrous THF. After 30 minutes at -20° C., excess AlLiH4 is destroyed by addition of isopropanol at -20° C. followed by 5 ml saturated aqueous sodium chloride, and is then stirred for 2 hrs. The resulting precipitate is filtered off and washed with ethyl acetate; the filtrate is evaporated and the oily residue is taken up in the hot with hexane; product (IV) crystallizes on cooling. Yield: 70%. M.p.=74°-75° C.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]=[C:9]=[O:10])=[CH:4][C:3]=1[S:11]([F:16])([F:15])([F:14])([F:13])[F:12].[NH2:17][C:18]1[CH:34]=[CH:33][C:21]([O:22][C:23]2[CH:28]=[CH:27][N:26]=[C:25]([C:29]([NH:31][CH3:32])=[O:30])[CH:24]=2)=[CH:20][C:19]=1[F:35]>C(Cl)Cl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([NH:17][C:18]2[CH:34]=[CH:33][C:21]([O:22][C:23]3[CH:28]=[CH:27][N:26]=[C:25]([C:29]([NH:31][CH3:32])=[O:30])[CH:24]=3)=[CH:20][C:19]=2[F:35])=[O:10])=[CH:4][C:3]=1[S:11]([F:16])([F:12])([F:13])([F:14])[F:15]
Reactant: O=C=Nc1ccc(Br)c(S(F)(F)(F)(F)F)c1
Reactant: CNC(=O)c1cc(Oc2ccc(N)c(F)c2)ccn1
Solvent: ClCCl
Product: CNC(=O)c1cc(Oc2ccc(NC(=O)Nc3ccc(Br)c(S(F)(F)(F)(F)F)c3)c(F)c2)ccn1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
The crude 1-bromo-4-isocyanato-2-(pentafluoro-λ6-sulfanyl)benzene was dissolved in DCM (70 mL). 4-(4-amino-3-fluorophenoxy)-N-methylpicolinamide (1.75 g, 6.71 mmol, 0.8 eq) was added at room temperature under N2. The mixture was stirred at room temperature for about 30 min, a lot of solid precipitated. DCM (30 mL) was added and made the mixture stirred at room temperature for 18 hrs. The solid was collected by filtration, washed with DCM (50 mL), and dried under high vacuum to afford 2.9 g of the title compound as a white solid.