Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][N:9]1[CH2:14][CH2:13][CH:12]([C:15]2[CH:25]=[C:18]3[N:19]=[C:20]([Cl:24])[CH:21]=[C:22](Cl)[N:17]3[N:16]=2)[CH2:11][C:10]1=[C:26]=[O:27])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:28]1[CH2:33][CH2:32][O:31][CH2:30][CH2:29]1>O1CCOCC1.O>[CH2:1]([O:8][N:9]1[CH2:14][CH2:13][CH:12]([C:15]2[CH:25]=[C:18]3[N:19]=[C:20]([Cl:24])[CH:21]=[C:22]([N:28]4[CH2:33][CH2:32][O:31][CH2:30][CH2:29]4)[N:17]3[N:16]=2)[CH2:11][C:10]1=[C:26]=[O:27])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C1COCCN1
Reactant: O=C=C1CC(c2cc3nc(Cl)cc(Cl)n3n2)CCN1OCc1ccccc1
Solvent: O
Solvent: C1COCCO1
Product: O=C=C1CC(c2cc3nc(Cl)cc(N4CCOCC4)n3n2)CCN1OCc1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 88 %

Procedure:
There was dissolved, in 1,4-dioxane (5 mL), 2-(1-benzyloxy-carbonyl-piperidin-4-yl)-5,7-dichloro-pyrazolo[1,5-a]-pyrimidine (192 mg, 0.474 mM), then morpholine (82.7 μL, 0.948 mM) was added to the solution and the mixture was stirred at room temperature for one hour. The solvent was distilled off from this reaction mixture, the residue thus obtained was diluted with water and then the mixture was extracted with ethyl acetate. The resulting extracts were combined, dried over anhydrous sodium sulfate, the solvent was distilled off and the resulting solid was washed with diethyl ether to thus give the title compound (191 mg, yield: 88%).
Reaction SMILES: [N:1]1([CH2:6][C@@H:7]([O:14][C:15]2[CH:24]=[CH:23][C:22]3[C:21](=[O:25])[CH2:20][CH2:19][CH2:18][C:17]=3[C:16]=2[CH2:26][S:27]([C:30]2[CH:38]=[CH:37][C:33]([C:34](O)=[O:35])=[CH:32][CH:31]=2)(=[O:29])=[O:28])[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:5]=[CH:4][N:3]=[CH:2]1.[NH2:39][CH2:40][CH2:41][OH:42]>>[OH:42][CH2:41][CH2:40][NH:39][C:34](=[O:35])[C:33]1[CH:32]=[CH:31][C:30]([S:27]([CH2:26][C:16]2[C:17]3[CH2:18][CH2:19][CH2:20][C:21](=[O:25])[C:22]=3[CH:23]=[CH:24][C:15]=2[O:14][C@@H:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH2:6][N:1]2[CH:5]=[CH:4][N:3]=[CH:2]2)(=[O:28])=[O:29])=[CH:38][CH:37]=1
Reactant: O=C(O)c1ccc(S(=O)(=O)Cc2c(O[C@H](Cn3ccnc3)c3ccccc3)ccc3c2CCCC3=O)cc1
Reactant: NCCO
Product: O=C(NCCO)c1ccc(S(=O)(=O)Cc2c(O[C@H](Cn3ccnc3)c3ccccc3)ccc3c2CCCC3=O)cc1
Yield: 47.1 %

Procedure:
Using the method in Example 172, 4-{[(2-{[(1S)-2-(1H-imidazol-1-yl)-1-phenylethyl]oxy}-5-oxo-5,6,7,8-tetrahydro-1-naphthalenyl)methyl]sulfonyl}benzoic acid (53 mg, 0.10 mmol, 0.20M in DMF) and 2-aminoethanol (31 mg, 0.50 mmol, 1.0M in DMF) were combined to give 27 mg of the desired compound: Low resolution mass spectrum (LC-MS, APCI) m/z 574 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[C:10]2[O:9][CH:8]([CH3:11])[CH2:7][C:6]=2[C:5]([NH:12][C:13]([N:15]2[CH2:20][CH2:19][CH2:18][CH2:17][CH:16]2[C:21]([O:23]CC)=O)=[O:14])=[CH:4][CH:3]=1.Cl>C(O)C>[Cl:1][C:2]1[C:10]2[O:9][CH:8]([CH3:11])[CH2:7][C:6]=2[C:5]([N:12]2[C:21](=[O:23])[CH:16]3[CH2:17][CH2:18][CH2:19][CH2:20][N:15]3[C:13]2=[O:14])=[CH:4][CH:3]=1
Reactant: CCOC(=O)C1CCCCN1C(=O)Nc1ccc(Cl)c2c1CC(C)O2
Agent: Cl
Solvent: CCO
Product: CC1Cc2c(N3C(=O)C4CCCCN4C3=O)ccc(Cl)c2O1

Procedure:
A mixture of 2.0 g of 34B, 25 mL of ethanol and 25 mL of 2N hydrochloric acid was stirred and refluxed for 2 hours. Then the solvent was evaporated, the residue was mixed with 50 mL of water, and the resulting mixture was extracted with methylene chloride. The extract was dried (MgSO4) and the solvent was evaporated. The residue was purified by filtration through a short pad of silica gel, with a 1:1 v:v mixture ethyl acetate and hexane as eluent, to give the title compound, as a solid, m.p.: 145°-148° C.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[N:6][C:5](Br)=[CH:4][N:3]=1.[Br:9][C:10]1[CH:15]=[CH:14][C:13](B(O)O)=[C:12]([F:19])[CH:11]=1>COCCOC>[Br:9][C:10]1[CH:15]=[CH:14][C:13]([C:10]2[CH:15]=[CH:14][C:13]([C:5]3[N:6]=[CH:7][C:2]([NH2:1])=[N:3][CH:4]=3)=[C:12]([F:19])[CH:11]=2)=[C:12]([F:19])[CH:11]=1
Reactant: Nc1cnc(Br)cn1
Reactant: OB(O)c1ccc(Br)cc1F
Solvent: COCCOC
Product: Nc1cnc(-c2ccc(-c3ccc(Br)cc3F)cc2F)cn1
Temperature: 100 °C

Procedure:
The title compound was prepared in a manner similar to that described for Intermediate D with DME as a solvent, heating at 100° Celsius for 16 hours and using 2-amino-5-bromopyrazine and 4-bromo-2-fluorobenzeneboronic acid. MS (ESI): mass calcd. for C16H10BrF2N3, 361.00; m/z found, 362.0, 364.0 [M+H]+. 1H NMR (400 MHz, CDCl3) δ 8.47 (s, 1H), 8.30 (d, J=1.4, 1H), 8.12-8.02 (m, 1H), 7.49-7.32 (m, 5H), 6.37-5.94 (m, 1H), 6.15 (s, 2H).
Reaction SMILES: S(OCC)(O[CH2:5][CH3:6])(=O)=O.[NH2:10][C:11]1[CH:16]=[C:15]([N+:17]([O-:19])=[O:18])[CH:14]=[CH:13][C:12]=1[O:20][CH2:21][CH2:22][O:23][CH3:24].N>C1(C)C=CC=CC=1>[CH2:5]([NH:10][C:11]1[CH:16]=[C:15]([N+:17]([O-:19])=[O:18])[CH:14]=[CH:13][C:12]=1[O:20][CH2:21][CH2:22][O:23][CH3:24])[CH3:6]
Reactant: CCOS(=O)(=O)OCC
Reactant: COCCOc1ccc([N+](=O)[O-])cc1N
Agent: N
Solvent: Cc1ccccc1
Product: CCNc1cc([N+](=O)[O-])ccc1OCCOC
Temperature: 80 °C
Reaction time: 5 h
Yield: 89.5 %

Procedure:
185 g of diethyl sulfate (1.2 mole) are added dropwise to a mixture of 577 g of toluene and 212 g of 2-amino-4-nitro-β-methoxyethoxybenzene (1 mole). The mixture is stirred at 80° C. for 5 hours and then neutralized with 169 g of 14% strength aqueous ammonia. The toluene is removed by azeotropic distillation and the aqueous residue is adjusted to pH 0.4 with 165 g of concentrated hydrochloric acid. 10 g of keiselguhr and 0.5 g of zinc dust are added to the mixture. It is then boiled under reflux for 30 minutes and finally filtered hot. The filtrate is adjusted to pH 2 with 120 ml of concentrated sodium hydroxide solution. The precipitate is filtered off with suction and dried in vacuo. 215 g of 2-ethylamino-4-nitro-β-methoxyethoxybenzene are obtained, which corresponds to a yield of 76% of theory.
Reaction SMILES: [CH3:1][N:2]([CH2:13][CH2:14][C:15]1[O:16][C:17]([C:26]2[CH:31]=[CH:30][C:29]([S:32]([NH2:35])(=[O:34])=[O:33])=[CH:28][CH:27]=2)=[C:18]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[N:19]=1)C(OCC1C=CC=CC=1)=O.C(O)(=O)C>CO.[Pd]>[CH3:1][NH:2][CH2:13][CH2:14][C:15]1[O:16][C:17]([C:26]2[CH:27]=[CH:28][C:29]([S:32]([NH2:35])(=[O:33])=[O:34])=[CH:30][CH:31]=2)=[C:18]([C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)[N:19]=1
Reactant: CN(CCc1nc(-c2ccccc2)c(-c2ccc(S(N)(=O)=O)cc2)o1)C(=O)OCc1ccccc1
Agent: [Pd]
Solvent: CC(=O)O
Solvent: CO
Product: CNCCc1nc(-c2ccccc2)c(-c2ccc(S(N)(=O)=O)cc2)o1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A solution of 4-[2-[2-(N-methyl-N-phenylmethoxycarbonylamino)ethyl]-4-phenyloxazol-5-yl]benzenesulfonamide and 4-[2-[2-(N-methyl-N-phenyl-methoxycarbonylamino)ethyl]-5-phenyloxazol-4-yl]benzenesulfonamide (0.7 g, 1.4 mmol) from Step 3, in MeOH (15 mL) containing acetic acid (0.1 mL) was treated with 10% Pd on carbon (0.4 g) and stirred under an atmosphere of hydrogen at 50 psi at room temperature for 3 h. The catalyst was removed by filtration, the filtrate was concentrated under reduced pressure, and the resulting substance was purified by reverse-phase HPLC using a gradient of 5-70% CH3CN in water to give 0.42 g of 4-[2-[2-(N-methylamino)ethyl]-4-phenyloxazol-5-yl]benzenesulfonamide and 4-[2-[2-(N-methylamino)ethyl]-5-phenyloxazol-4-yl]benzenesulfonamide trifluoroacetate salts as a white powder: 1H NMR (CD3OD/300 MHz) δ 7.88 (d, 2H, J=8.7 Hz), 7.74 (d, 2H, J=8.7 Hz), 7.6 (m, 2H), 7.43 (m, 3H), 3.55 (t, 2H, J=6.6 Hz), 3.36 (t, 2H, J=6.6 Hz), 2.82 (s, 3H); FABMS m/z =358 (M+H).
Reaction SMILES: [Cl:1][C:2]1[NH:3][C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1.[H-].[Na+].Cl[CH2:14][C:15]1[O:19][C:18]([C:20]([O:22][CH2:23][CH3:24])=[O:21])=[CH:17][CH:16]=1>C(OCC)(=O)C>[CH2:23]([O:22][C:20]([C:18]1[O:19][C:15]([CH2:14][N:3]2[C:4]3[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=3[N:6]=[C:2]2[Cl:1])=[CH:16][CH:17]=1)=[O:21])[CH3:24]
Reactant: CCOC(=O)c1ccc(CCl)o1
Reactant: Clc1nc2ccccc2[nH]1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Product: CCOC(=O)c1ccc(Cn2c(Cl)nc3ccccc32)o1
Reaction time: 24 h

Procedure:
Alternately, combine 2-chlorobenzimidazole (20 mmol) and sodium hydride (20 mmol) in dimethylformamidle (30 mL). After gas evolution ceases, add ethyl 5-chloromethyl-2-furoate (20 mmol) and stir. After 1 day, evaporate in vacuo to give a residue. Combine the residue and ethyl acetate. Extract with water and brine. Dry the the organic layer over Na2SO4, filter, and evaporate in vacuo to give 1-(5-(ethoxycarbonyl)fur-2-ylmethyl)-2-chloro-1H-benzimidazole.
Reaction SMILES: [C:1]([NH:4][C:5]1[S:6][C:7]([C:11]2[CH:12]=[C:13]([S:17](Cl)(=[O:19])=[O:18])[S:14][C:15]=2[Br:16])=[C:8]([CH3:10])[N:9]=1)(=[O:3])[CH3:2].C(N(CC)CC)C.CC1(C)[O:33][CH:32]([CH2:34][NH2:35])[CH2:31][O:30]1>C(Cl)Cl>[Br:16][C:15]1[S:14][C:13]([S:17](=[O:19])(=[O:18])[NH:35][CH2:34][CH:32]([OH:33])[CH2:31][OH:30])=[CH:12][C:11]=1[C:7]1[S:6][C:5]([NH:4][C:1](=[O:3])[CH3:2])=[N:9][C:8]=1[CH3:10]
Reactant: CC(=O)Nc1nc(C)c(-c2cc(S(=O)(=O)Cl)sc2Br)s1
Reactant: CC1(C)OCC(CN)O1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)Nc1nc(C)c(-c2cc(S(=O)(=O)NCC(O)CO)sc2Br)s1
Temperature: 25 °C
Reaction time: 8 h
Yield: 94 %

Procedure:
4-[2-(acetylamino)-4-methyl-1,3-thiazol-5-yl]-5-bromothiophene-2-sulfonyl chloride, prepared as in Step III of Example 23 (500 mg; 1.2 mmol; 1 eq), is dissolved in anhydrous DCM (30 ml). The reaction is put under nitrogen. Triethylamine (0.34 ml; 2.41 mmol; 2 eq) and 2,2-dimethyl-1,3-dioxolane-4-methanamine (0.31 ml; 2.41 mmol; 2 eq) are added successively and the reaction mixture is stirred overnight at room temperature. It is then washed with water, NH4Cl sat., brine and dried over MgSO4, affording the title compound (3650 mg; 94%).
Reaction SMILES: [NH2:1][C:2]1[CH:23]=[CH:22][C:5]([O:6][C:7]2[CH:12]=[CH:11][N:10]=[C:9]([NH:13][C:14]([N:16]3[CH2:21][CH2:20][O:19][CH2:18][CH2:17]3)=[O:15])[CH:8]=2)=[CH:4][CH:3]=1.[F:24][C:25]1[CH:30]=[CH:29][C:28]([NH:31][C:32]([C:34]2([C:37](O)=[O:38])[CH2:36][CH2:35]2)=[O:33])=[CH:27][CH:26]=1.C(N(C(C)C)CC)(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C)C=O>[F:24][C:25]1[CH:26]=[CH:27][C:28]([NH:31][C:32]([C:34]2([C:37]([NH:1][C:2]3[CH:23]=[CH:22][C:5]([O:6][C:7]4[CH:12]=[CH:11][N:10]=[C:9]([NH:13][C:14]([N:16]5[CH2:17][CH2:18][O:19][CH2:20][CH2:21]5)=[O:15])[CH:8]=4)=[CH:4][CH:3]=3)=[O:38])[CH2:36][CH2:35]2)=[O:33])=[CH:29][CH:30]=1
Reactant: Nc1ccc(Oc2ccnc(NC(=O)N3CCOCC3)c2)cc1
Reactant: O=C(O)C1(C(=O)Nc2ccc(F)cc2)CC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(Nc1cc(Oc2ccc(NC(=O)C3(C(=O)Nc4ccc(F)cc4)CC3)cc2)ccn1)N1CCOCC1
Reaction time: 4 h
Yield: 53.6 %

Procedure:
Morpholine-4-carboxylic acid [4-(4-aminophenoxy)pyridin-2-yl]amide (121 mg) and 1-(4-fluorophenylcarbamoyl)cyclopropanecarboxylic acid (92.0 mg) were dissolved in N,N-dimethylformamide (4 ml), and diisopropylethylamine (0.358 ml) and HBTU (O-benzotriazol-1-yl-N,N,N′,N′-tetramethyluronium hexafluorophosphate; 213 mg) were added under a nitrogen atmosphere at room temperature, followed by stirring for 4 hr. The reaction mixture was partitioned after addition of ethyl acetate (50 ml) and a saturated aqueous solution of sodium hydrogencarbonate (20 ml). The separated organic layer was washed with a saturated aqueous solution of sodium hydrogencarbonate (30 ml) and brine (30 ml), and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure, and the resultant residue was purified by silica gel column chromatography (eluent; heptane:ethyl acetate=1:7, then ethyl acetate). Fractions containing the target compound were concentrated under reduced pressure, and to the residue (131.9 mg) were added tert-butyl methyl ether (4 ml) and heptane (4 ml) to suspend a solid. The solid was collected by filtration, and dried under aeration to provide a titled compound as pale yellow powder (107.1 mg, 55.1%).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4](=[O:20])[N:5]([CH:12]1[CH2:17][CH2:16][C:15](=[O:18])[NH:14][C:13]1=[O:19])[C:6]2=[O:11].[C:21](Cl)(=[O:28])[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27]>C1COCC1>[O:19]=[C:13]1[CH:12]([N:5]2[C:4](=[O:20])[C:3]3[C:7](=[CH:8][CH:9]=[CH:10][C:2]=3[NH:1][C:21](=[O:28])[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])[C:6]2=[O:11])[CH2:17][CH2:16][C:15](=[O:18])[NH:14]1
Reactant: Nc1cccc2c1C(=O)N(C1CCC(=O)NC1=O)C2=O
Reactant: CCCCCCC(=O)Cl
Solvent: C1CCOC1
Product: CCCCCCC(=O)Nc1cccc2c1C(=O)N(C1CCC(=O)NC1=O)C2=O
Yield: 79.1 %

Procedure:
To a stirred suspension of 4-amino-2-(2,6-dioxo(3-piperidyl))isoindoline-1,3-dione (0.55 g, 2.0 mmol) in THF (30 ml) was added heptanoyl chloride (0.59 g, 4.0 mmol). The mixture was heated to reflux for 18 hours. The solvent was evaporated in vacuo and the resulting solid was slurried in diethyl ether (20 ml) and filtered to give 0.61 g (79%) of product as an off-white solid: mp 200–202° C.; 1H NMR (DMSO-d6) δ 11.16 (s, 1H), 9.65 (s, 1H), 8.48 (d, J=8.3 Hz, 1H), 7.81 (t, J=7.7 Hz, 1H), 7.58 (d, J=7.2 Hz, 1H), 5.15 (dd, J=4.8 and 12.2 Hz, 1H), 2.97–2.87 (m, 1H), 2.65–2.43 (m, 4H), 2.10–2.06 (m, 1H), 1.61–1.58 (m, 2H), 1.28 (bs, 6H), 0.85 (bs, 3H); 13C NMR (DMSO-d6) δ 172.67, 171.96, 169.69, 167.78, 166.61, 136.62, 136.04, 131.36, 125.97, 118.13, 116.67, 48.93, 36.56, 30.95, 28.16, 24.69, 21.94, 13.84; Anal. Calcd. For C20H23N3O5: C, 62.3 3; H, 6.02; N, 10.90. Found: C, 62.14; H, 6.05; N, 10.72.
Reaction SMILES: C(OC(=O)[NH:7][C@H:8]([C:10]1[N:18]([C:19]2[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=2)[C:13]2=[N:14][CH:15]=[CH:16][CH:17]=[C:12]2[N:11]=1)[CH3:9])(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[Cl:25][C:22]1[CH:23]=[CH:24][C:19]([N:18]2[C:13]3=[N:14][CH:15]=[CH:16][CH:17]=[C:12]3[N:11]=[C:10]2[C@@H:8]([NH2:7])[CH3:9])=[CH:20][CH:21]=1
Reactant: C[C@H](NC(=O)OC(C)(C)C)c1nc2cccnc2n1-c1ccc(Cl)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: C[C@H](N)c1nc2cccnc2n1-c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 96.4 %

Procedure:
To a mixture of {(S)-1-[3-(4-chlorophenyl)-3H-imidazo[4,5-b]pyridin-2-yl]ethyl}carbamic acid tert-butyl ester (99 mg, 0.27 mmol) in DCM (1 mL) was added TFA (1 mL) and the reaction mixture was stirred at RT for 3 h. The crude mixture was loaded onto an Isolute® SCX-2 cartridge and washed with MeOH followed by 2M NH3/MeOH. The basic fractions were combined and concentrated in vacuo to afford (S)-1-[3-(4-chlorophenyl)-3H-imidazo[4,5-b]pyridin-2-yl]ethylamine as an orange oil (71 mg).
Reaction SMILES: [CH2:1]([NH:8][C:9]([NH:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:19](O)(=[O:24])[CH2:20][C:21](O)=[O:22].C(OC(=O)C)(=O)C>>[CH2:1]([N:8]1[C:19](=[O:24])[CH2:20][C:21](=[O:22])[N:11]([CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:9]1=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)CC(=O)O
Reactant: O=C(NCc1ccccc1)NCc1ccccc1
Solvent: CC(=O)OC(C)=O
Product: O=C1CC(=O)N(Cc2ccccc2)C(=O)N1Cc1ccccc1
Yield: 95.4 %

Procedure:
Heated was a mixture of N,N′-dibenzylurea 12.02 g (50.0 mmol) and malonic acid 5.20 g (50.0 mmol) in acetic anhydride 50.0 mL (530 mmol, 10.6 equivalents) at 70° C.-75° C. for 14 hours under a nitrogen atmosphere. Then, removed were the volatile materials under the reduced pressure and distributed the residue between layers of 2 M sodium hydroxide 250 mL and ether 200 mL. Separated was the alkaline aqueous layer and after washing with ether, neutralized with concentrated hydrochloric acid under cooling in ice-water bath (pH 2-3). Extracted was the neutrallized aqueous solution with chloroform, washed with water, and dried over sodium sulfate. Removal of the solvent under reduced pressure gave 1,3-dibenzylbarbituric acid 14.7 g as pale yellow crystalline powder (95.6% yield).
Reaction SMILES: [NH2:1][C:2]1[CH:24]=[CH:23][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][CH:12]=[C:13]([F:16])[CH:14]=3)[C:9]([CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])=[N:8]2)=[CH:4][CH:3]=1.C(N(CC)CC)C.[F:32][C:33]1[CH:41]=[C:40]([F:42])[CH:39]=[CH:38][C:34]=1[C:35](Cl)=[O:36].C(=O)(O)[O-].[Na+]>ClCCl>[F:32][C:33]1[CH:41]=[C:40]([F:42])[CH:39]=[CH:38][C:34]=1[C:35]([NH:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][CH:12]=[C:13]([F:16])[CH:14]=3)[C:9]([CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])=[N:8]2)=[CH:23][CH:24]=1)=[O:36]
Reactant: CCOC(=O)Cc1nn(Cc2ccc(N)cc2)c2cc(F)ccc12
Reactant: O=C(Cl)c1ccc(F)cc1F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)Cc1nn(Cc2ccc(NC(=O)c3ccc(F)cc3F)cc2)c2cc(F)ccc12
Yield: 45.6 %

Procedure:
The crude ethyl 2-[1-(4-aminobenzyl)-6-fluoro-1H-indazol-3-yl]acetate (about 1.0 mmol) obtained in the last step and triethylamine (0.5 mL) were dissolved in dichloromethane (15 mL), and in an ice bath dichloromethane solution (10 mL) of 2,4-difluorobenzoyl chloride (177 mg, 1.0 mmol) was added dropwise slowly. Upon completion of the dropwise addition, it was reacted at room temperature for 16 hours. An aqueous solution of sodium bicarbonate was added to quench, and extracted with ethyl acetate. The organic phase was dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduce pressure, chromatographed on a silica gel column (petroleum ether:ethyl acetate=2:1) to obtain a white solid 213 mg, at a total yield over two steps of reactions of 45.6%.
Reaction SMILES: C([O:8][C:9](=[O:37])[N:10]([CH2:12][C:13](=[O:36])[NH:14][CH2:15][CH:16]1[C:25]2[C:20](=[CH:21][C:22]([S:26]([C:29]3[CH:34]=[CH:33][CH:32]=[C:31]([F:35])[CH:30]=3)(=[O:28])=[O:27])=[CH:23][CH:24]=2)[CH2:19][CH2:18][CH2:17]1)C)C1C=CC=CC=1>CO.C(O)=O.[Pd]>[CH:9]([OH:37])=[O:8].[F:35][C:31]1[CH:30]=[C:29]([S:26]([C:22]2[CH:21]=[C:20]3[C:25](=[CH:24][CH:23]=2)[CH:16]([CH2:15][NH:14][C:13](=[O:36])[CH2:12][NH:10][CH3:9])[CH2:17][CH2:18][CH2:19]3)(=[O:28])=[O:27])[CH:34]=[CH:33][CH:32]=1
Reactant: CN(CC(=O)NCC1CCCc2cc(S(=O)(=O)c3cccc(F)c3)ccc21)C(=O)OCc1ccccc1
Agent: [Pd]
Solvent: O=CO
Solvent: CO
Product: CNCC(=O)NCC1CCCc2cc(S(=O)(=O)c3cccc(F)c3)ccc21
Reaction time: 3 h
Yield: 144.2 %

Procedure:
To a stirring solution of ({[6-(3-Fluoro-benzenesulfonyl)-1,2,3,4-tetrahydro-naphthalen-1-ylmethyl]-carbamoyl}-methyl)-methyl-carbamic acid benzyl ester (0.15 g) in 20 ml methanol and 2 ml formic acid at room temperature was added 0.1 gms of 10% palladium on carbon. After stirring for three hours the mixture was filtered thru Celite and the clear filtrate was concentrated to dryness. The residue was recrystallized from ethyl acetate and diethyl ether to give 0.090 gms of N-[6-(3-Fluoro-benzenesulfonyl)-1,2,3,4-tetrahydro-naphthalen-1-ylmethyl]-2-methylamino-acetamide formate salt: M+H=391.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([F:16])[CH:11]=1.CC(O)=O.S(=O)(=O)(O)O.C1C(=O)N([I:33])C(=O)C1>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[C:6]([I:33])[C:5]([O:8][CH3:9])=[CH:4][C:3]=1[C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([F:16])[CH:11]=1
Reactant: O=C1CCC(=O)N1I
Reactant: COc1ccc(Cl)c(-c2cccc(F)c2)c1
Agent: O=S(=O)(O)O
Solvent: ClCCl
Solvent: CC(=O)O
Product: COc1cc(-c2cccc(F)c2)c(Cl)cc1I
Reaction time: 7 h
Yield: 85.1 %

Procedure:
A round-bottom flask was charged with 2-chloro-3′-fluoro-5-methoxy-1,1′-biphenyl (1.288 g, 5.44 mmol), DCM (8.00 ml), AcOH (8.00 ml), and sulfuric acid (0.160 ml, 2.99 mmol) to give a clear solution. n-Iodosuccinimide (1.224 g, 5.44 mmol) was added in one portion to give a maroon-colored solution. After 7 h, the mixture was diluted with DCM, washed with water, washed with saturated aq. sodium thiosulfate, dried over sodium sulfate, filtered, and concentrated. The residue was purified by chromatography on silica gel (40-g Redi-Sep Gold column, 25-g silica gel column, 0-5% EtOAc/Heptane) give 2-chloro-3′-fluoro-4-iodo-5-methoxy-1,1′-biphenyl (1.68 g, 4.63 mmol, 85% yield) as a clear oil. m/z (ESI) 362.0 (M+H)+.
Reaction SMILES: C[O:2][C:3](=[O:44])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][CH2:12][CH2:13][O:14]/[N:15]=[CH:16]/[C:17]2[CH:22]=[CH:21][C:20]([C:23]([CH3:26])([CH3:25])[CH3:24])=[CH:19][CH:18]=2)=[CH:6][C:5]=1[NH:27][C:28](=[O:43])[C:29]1[CH:34]=[C:33]([C:35]([F:38])([F:37])[F:36])[CH:32]=[C:31]([C:39]([F:42])([F:41])[F:40])[CH:30]=1.[OH-].[Na+].O>C(O)C>[F:36][C:35]([F:37])([F:38])[C:33]1[CH:34]=[C:29]([CH:30]=[C:31]([C:39]([F:41])([F:40])[F:42])[CH:32]=1)[C:28]([NH:27][C:5]1[CH:6]=[C:7]([O:10][CH2:11][CH2:12][CH2:13][O:14]/[N:15]=[CH:16]/[C:17]2[CH:22]=[CH:21][C:20]([C:23]([CH3:24])([CH3:25])[CH3:26])=[CH:19][CH:18]=2)[CH:8]=[CH:9][C:4]=1[C:3]([OH:44])=[O:2])=[O:43]
Reactant: COC(=O)c1ccc(OCCCO/N=C/c2ccc(C(C)(C)C)cc2)cc1NC(=O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CC(C)(C)c1ccc(/C=N/OCCCOc2ccc(C(=O)O)c(NC(=O)c3cc(C(F)(F)F)cc(C(F)(F)F)c3)c2)cc1
Temperature: 25 °C
Yield: 44.4 %

Procedure:
To a solution 2-{[3,5-bis(trifluoromethyl)benzoyl]amino}-4-[3-({[(1E)-(4-tert-butylphenyl)methylidene]amino}oxy)propoxy]benzoic acid methyl ester (0.30 g, 0.48 mmol) in ethanol (20 mL) was added 1.0 N, sodium hydroxide solution (4 mL). This mixture was heated to reflux for 20 minutes and then allowed to cool back to room temperature. Water (5 mL) was added to the mixture, it was concentrated to approximately ¼ volume and then partitioned between ethyl acetate and water. The aqueous layer was acidified to approximately pH 3 using 1 N hydrochloric acid. The layers were then separated. The aqueous layer was extracted with two additional portions of ethyl acetate. The organics were combined, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The crude material was purified by flash chromatography through silica gel using ethyl acetate/hexanes (10/90 with 1% formic acid gradient to 20/80 with 1% formic acid) and then recrystallized one time from chloroform/hexanes (1/20) to give 2-{[3,5-bis(trifluoromethyl)benzoyl]amino}-4-[3-({[(1E)-(4-tert-butylphenyl)methylidene]amino}oxy)propoxy]benzoic acid (0.13 g, 45%) as a white powder. mp=157.5-158.5° C. 1H NMR (500 MHz, DMSO-d6); δ 13.54 (bs, 1H), 12.54 (s, 1H), 8.51 (s, 2H), 8.45 (s, 1H), 8.32 (d, 1H), 8.21 (s, 1H), 8.00 (d, 1H), 7.50-7.37 (AA′BB′, 4H), 6.83 (dd, 1H), 4.27 (t, 2H), 4.21 (t, 2H), 2.16 (m, 2H), 1.23 (s, 9H). Mass spec (MW 610.55); (ES−) m/z 609.2. Elemental analysis; Calculated for C30H28F6N2O5: C, 59.02; H, 4.62; N, 4.59. Found: C, 58.78; H, 4.52; N, 4.46.
Reaction SMILES: [CH3:1][C:2]1[C:6]([C:7]2[C:16]3[O:15][CH2:14][CH:13]([C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=4)[N:12]4[C:23](=O)[NH:24][C:10]([C:11]=34)=[CH:9][CH:8]=2)=[C:5]([CH3:26])[O:4][N:3]=1.COC1C=CC(P2(=S)SP(C3C=CC(OC)=CC=3)(=S)[S:36]2)=CC=1>O1CCOCC1>[CH3:1][C:2]1[C:6]([C:7]2[C:16]3[O:15][CH2:14][CH:13]([C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=4)[N:12]4[C:23](=[S:36])[NH:24][C:10]([C:11]=34)=[CH:9][CH:8]=2)=[C:5]([CH3:26])[O:4][N:3]=1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: Cc1noc(C)c1-c1ccc2[nH]c(=O)n3c2c1OCC3c1ccccn1
Solvent: C1COCCO1
Product: Cc1noc(C)c1-c1ccc2[nH]c(=S)n3c2c1OCC3c1ccccn1
Temperature: 100 °C

Procedure:
7-(3,5-Dimethylisoxazol-4-yl)-4-pyridin-2-yl-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazin-2(1H)-one (50 mg, 0.1 mmol) from Example 13 was stirred in 1,4-dioxane (2 mL) and 2,4-bis(4-methoxyphenyl)-2,4-dithioxo-1,3,2,4-dithiadiphosphetane [Aldrich #: 227439](58 mg, 0.14 mmol) was added. The mixture was heated to 100° C. for 3 h and concentrated. Purification by preparative LCMS (pH 10) afforded the title compound. LCMS calc. for C19H17N4O2S (M+H)+: m/z=365.1. found: 365.1.