Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=O)[CH:9]([C:11]1[CH:16]=[CH:15][C:14]([S:17][CH3:18])=[CH:13][CH:12]=1)Br.[Cl:20][C:21]1[CH:29]=[CH:28][CH:27]=[CH:26][C:22]=1[C:23]([NH2:25])=[S:24].CO>C(O)C>[Cl:20][C:21]1[CH:29]=[CH:28][CH:27]=[CH:26][C:22]=1[C:23]1[S:24][C:9]([C:11]2[CH:16]=[CH:15][C:14]([S:17][CH3:18])=[CH:13][CH:12]=2)=[C:8]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[F:1])[N:25]=1
Reactant: NC(=S)c1ccccc1Cl
Reactant: CSc1ccc(C(Br)C(=O)c2ccccc2F)cc1
Solvent: CCO
Solvent: CO
Product: CSc1ccc(-c2sc(-c3ccccc3Cl)nc2-c2ccccc2F)cc1
Temperature: 25 °C
Yield: 79.3 %

Procedure:
A solution of 1-(2-fluorophenyl)-2-(4-methylthiophenyl)-2-bromo-ethanone from Step 3 (1.39 g, 4.1 mmol) and 2-chlorothiobenzamide (0.71 g, 4.1 mmol) in 10 mL of ethanol was heated to reflux for 4.4 hours. The solution was cooled to room temperature and poured into 25 mL of methanol, chilled with an ice bath whereupon crystals of pure product formed which were isolated by filtration and air dried to afford the thiazole (1.34 g, 79%): mp 117°-119° C. 1H NMR (CDCl3) 300 MHz 8.37 (m, 1H), 7.62 (m, 2H), 7.49 (d, J=7.7Hz,1H), 7.32 (m, 7H), 7.22 (d, J=8.5Hz, 2H), 2.51 (s, 3H). Mass spectrum M+ +H=412.
Reaction SMILES: C(OC([NH:8][C@@:9]1([CH3:16])[C:13]2([CH2:15][CH2:14]2)[CH2:12][NH:11][CH2:10]1)=O)(C)(C)C.F[C:18]1([N:21]2[C:30]3[C:25](=[CH:26][CH:27]=[C:28](F)[C:29]=3[CH3:31])[C:24](=[O:33])[C:23]([C:34]([OH:36])=[O:35])=[CH:22]2)[CH2:20][CH2:19]1.C(N(CC)CC)C.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>Cl.CS(C)=O>[NH2:8][C@@:9]1([CH3:16])[C:13]2([CH2:14][CH2:15]2)[CH2:12][N:11]([C:28]2[C:29]([CH3:31])=[C:30]3[C:25]([C:24](=[O:33])[C:23]([C:34]([OH:36])=[O:35])=[CH:22][N:21]3[CH:18]3[CH2:19][CH2:20]3)=[CH:26][CH:27]=2)[CH2:10]1
Reactant: CC(C)(C)OC(=O)N[C@]1(C)CNCC12CC2
Reactant: Cc1c(F)ccc2c(=O)c(C(=O)O)cn(C3(F)CC3)c12
Agent: Cl
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: Cc1c(N2CC3(CC3)[C@](C)(N)C2)ccc2c(=O)c(C(=O)O)cn(C3CC3)c12
Temperature: 75 °C
Reaction time: 120 h

Procedure:
A mixture of (7S)-7-(tert-butoxycarbonylamino)-7-methyl-5-azaspiro[2.4]heptane (524 mg, 2.31 mmol), 1-fluorocyclopropyl-7-fluoro-8-methyl-1,4-dihydro-4-oxoquinoline-3-carboxylic acid (503 mg, 1.925 mmol), triethylamine (0.537 mL, 3.85 mmol), and dimethyl sulfoxide (6 mL) was stirred in nitrogen atmosphere in an oil bath at 75° C. for 5 days, and in an oil bath at 85° C. for 2 days. To the reaction mixture was added 10% aqueous solution of citric acid (10 mL), and the mixture was extracted with ethyl acetate (50 mL). The organic layer was washed with water (10 mL×2) and saturated aqueous solution of sodium chloride (10 mL), and dried with anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (silica gel, 10 g; elusion by chloroform→chloroform:methanol, 98:2) to obtain a pale yellow foam solid. The purified pale yellow foam solid was dissolved in concentrated hydrochloric acid (8 mL) at room temperature, and after transferring the resulting acidic aqueous solution to a separatory funnel while washing with 6N hydrochloric acid, the solution was washed with chloroform (50 mL×8). To the aqueous layer was added 10 mol/l aqueous solution of sodium hydroxide to pH 12.0 in an ice bath, and hydrochloric acid was added to adjust the pH to 7.4. The solution was extracted with a mixed solvent of chloroform and methanol (chloroform:methanol, 9:1) (100 mL×3), and the organic layer was dried with anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The concentrate was purified by recrystallization from ethanol, and dried under reduced pressure to obtain 268 mg (0.641 mmol, 2 steps, 33%) of the title compound as a pale yellow powder.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:33])[CH:5]([NH2:32])[CH2:6][C:7]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]([O:17][CH2:18][CH2:19][C:20]2[N:21]=[C:22]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[O:23][C:24]=2[CH3:25])=[CH:9][CH:8]=1)[CH3:2].[C:34]([CH:42]1[CH2:47][CH2:46][CH2:45][CH2:44][C:43]1=O)(=[O:41])[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1>C1(OC)C=CC=CC=1.[Pd]>[CH2:1]([O:3][C:4](=[O:33])[CH:5]([NH:32][C:36]1[CH:37]=[CH:38][CH:39]=[CH:40][C:35]=1[C:34](=[O:41])[C:42]1[CH:43]=[CH:44][CH:45]=[CH:46][CH:47]=1)[CH2:6][C:7]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]([O:17][CH2:18][CH2:19][C:20]2[N:21]=[C:22]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[O:23][C:24]=2[CH3:25])=[CH:9][CH:8]=1)[CH3:2]
Reactant: O=C1CCCCC1C(=O)c1ccccc1
Reactant: CCOC(=O)C(N)Cc1ccc(OCCc2nc(-c3ccccc3)oc2C)c2ccccc12
Agent: [Pd]
Solvent: COc1ccccc1
Product: CCOC(=O)C(Cc1ccc(OCCc2nc(-c3ccccc3)oc2C)c2ccccc12)Nc1ccccc1C(=O)c1ccccc1
Temperature: 182.5 °C
Reaction time: 3.5 h
Yield: 15.5 %

Procedure:
0.345 g of 2-Amino-3-{4-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-naphthalen-1-yl}-propionic acid ethyl ester was dissolved in 6 ml of anisole and treated successively with 0.181 g (1.15 eq.) of 2-benzoyl-cyclohexanone and 60 mg of Pd/C (10%) and heated under Ar to 180-185° C. After 80 Min., additional 60 mg of fresh catalyst was added and heating continued for another 3.5 h. Cooling to RT, pouring onto crashed ice, twofold extraction with AcOEt, washing with water, drying over sodium sulfate, and purification by flash chromatography (SiO2, hexane/AcOEt 7/3) produced 0.075 g of the title compound in the less polar fractions and 0.285 g of intermediate enamine, which was processed once again as just described. Final purification left a combined crop of 0.221 g of 2-(2-benzoyl-phenylamino)-3-{4-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-naphthalen-1-yl}-propionic acid ethyl ester as yellow, sticky oil.
Reaction SMILES: F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.[Br:25][C:26]1[C:34]2[C:29](=[CH:30][CH:31]=[C:32]([C:35](O)=[O:36])[CH:33]=2)[N:28]([C:38]([C:51]2[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=2)([C:45]2[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=2)[C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)[N:27]=1.[NH2:57][CH:58]1[CH:63]([C:64]2[CH:69]=[CH:68][CH:67]=[C:66]([F:70])[CH:65]=2)[CH2:62][CH2:61][N:60]([C:71]([O:73][C:74]([CH3:77])([CH3:76])[CH3:75])=[O:72])[CH2:59]1.C(N(C(C)C)CC)(C)C>CN(C=O)C>[Br:25][C:26]1[C:34]2[C:29](=[CH:30][CH:31]=[C:32]([C:35]([NH:57][CH:58]3[CH:63]([C:64]4[CH:69]=[CH:68][CH:67]=[C:66]([F:70])[CH:65]=4)[CH2:62][CH2:61][N:60]([C:71]([O:73][C:74]([CH3:77])([CH3:76])[CH3:75])=[O:72])[CH2:59]3)=[O:36])[CH:33]=2)[N:28]([C:38]([C:51]2[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=2)([C:39]2[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=2)[C:45]2[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=2)[N:27]=1
Reactant: O=C(O)c1ccc2c(c1)c(Br)nn2C(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CC(C)(C)OC(=O)N1CCC(c2cccc(F)c2)C(N)C1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1CCC(c2cccc(F)c2)C(NC(=O)c2ccc3c(c2)c(Br)nn3C(c2ccccc2)(c2ccccc2)c2ccccc2)C1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
2-(7-Aza-1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium hexafluoro-phosphate (HATU) (88 mg, 0.231 mmol) was added to a suspension of 3-bromo-1-trityl-1H-indazole-5-carboxylic acid (100 mg, 0.21 mmol) in DMF (0.5 mL) and was stirred at room temperature for 15 minutes. A solution of tert-butyl 3-amino-4-(3-fluorophenyl)piperidine-1-carboxylate (62 mg, 0.21 mmol) in DMF (0.5 mL) was added to the reaction and followed by diisopropyl ethyl amine (DIEA) (0.1 mL). The mixture was stirred at room temperature for an additional 30 minutes. The reaction was quenched with water (5 mL) and extracted with ethyl acetate (3×10 mL). The extracts were combined, dried using anhydrous sodium sulfate, filtered, and concentrated in vacuo. The crude product was progressed to the next step without purification.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([OH:11])[CH:8]=[CH:9][CH:10]=1)([CH3:4])([CH3:3])[CH3:2].[CH2:12]([CH:14]1[O:16][CH2:15]1)Cl>>[C:1]([C:5]1[CH:6]=[C:7]([CH:8]=[CH:9][CH:10]=1)[O:11][CH2:12][CH:14]1[CH2:15][O:16]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1cccc(O)c1
Reactant: ClCC1CO1
Product: CC(C)(C)c1cccc(OCC2CO2)c1

Procedure:
The title compound was prepared from 3-tert-butyl-phenol and epichlorohydrin employing the procedures as set forth in Step 1 of Example 2.
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[CH:17][C:5]([O:6][C:7]2[C:12]([CH3:13])=[CH:11][C:10]([N+:14]([O-])=O)=[CH:9][N:8]=2)=[C:4]([CH3:19])[CH:3]=1.[H][H]>C(O)C.[OH-].[OH-].[Pd+2]>[Cl:1][C:2]1[CH:18]=[CH:17][C:5]([O:6][C:7]2[C:12]([CH3:13])=[CH:11][C:10]([NH2:14])=[CH:9][N:8]=2)=[C:4]([CH3:19])[CH:3]=1
Reactant: Cc1cc(Cl)ccc1Oc1ncc([N+](=O)[O-])cc1C
Reactant: [H][H]
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCO
Product: Cc1cc(Cl)ccc1Oc1ncc(N)cc1C

Procedure:
2-(4-chloro-2-methyl-phenoxy)-3-methyl-5-nitropyridine (5.8 g, 20.8 mmol) was dissolved in 95% ethanol (50 mL) and treated with 20% palladium hydroxide on carbon (350 mg). The reaction mixture was shaken in a hydrogen atmosphere (40 psi) for 1 hour. The solution was filtered through celite and concentrated in vacuo followed by chromatography on SiO2 using 1:1 ethyl acetate/hexanes as eluant. MS (m/z): 248/250 (M+H)+; C13H13N2OCl requires 248.7.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([NH:15][C:16](=[O:33])[C@@H:17]([NH:25][C:26](=[O:32])[O:27][C:28]([CH3:31])([CH3:30])[CH3:29])[CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:5]=[C:6]([C:8]2[CH:13]=[CH:12][N:11]=[C:10]([CH3:14])[CH:9]=2)[CH:7]=1.C(N(CC)CC)C.[CH3:41][S:42](Cl)(=[O:44])=[O:43].C([O-])(O)=O.[Na+]>C(Cl)Cl.O>[CH3:14][C:10]1[CH:9]=[C:8]([C:6]2[CH:5]=[C:4]([NH:15][C:16](=[O:33])[C@@H:17]([NH:25][C:26](=[O:32])[O:27][C:28]([CH3:30])([CH3:29])[CH3:31])[CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH:3]=[C:2]([NH:1][S:42]([CH3:41])(=[O:44])=[O:43])[CH:7]=2)[CH:13]=[CH:12][N:11]=1
Reactant: Cc1cc(-c2cc(N)cc(NC(=O)[C@H](Cc3ccccc3)NC(=O)OC(C)(C)C)c2)ccn1
Reactant: CS(=O)(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Solvent: CCN(CC)CC
Product: Cc1cc(-c2cc(NC(=O)[C@H](Cc3ccccc3)NC(=O)OC(C)(C)C)cc(NS(C)(=O)=O)c2)ccn1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 47.3 %

Procedure:
To a 0° C. solution of 51.1D (512 mg, 1.16 mmol) and triethylamine (478 μl, 3.44 mmol) in CH2Cl2 (10 mL) under N2 was added methanesulfonyl chloride (available from Aldrich) (84.3 μl, 1.08 mmol) drop wise over 10 min. After stirring at 0° C. for 30 min, the reaction mixture was treated with saturated aqueous NaHCO3 (1 mL), diluted with water (10 mL), and extracted with CH2Cl2 (3×10 mL). Organic layers were combined, dried over MgSO4, and concentrated under reduced pressure. Purification of the residue by flash chromatography on silica gel using 0-70% EtOAc/CH2Cl2 provided title product 51.1E as white solid (268 mg, 43%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([S:9]([NH2:12])(=[O:11])=[O:10])[CH:5]=[CH:6][C:7]=1C.[C:13](=[O:16])([O-])[O-:14].[Na+].[Na+].[Mn]([O-])(=O)(=O)=O.[K+].C(O)=O>O>[NH2:12][S:9]([C:4]1[CH:5]=[CH:6][C:7]([C:13]([OH:14])=[O:16])=[C:2]([F:1])[CH:3]=1)(=[O:11])=[O:10]
Reactant: Cc1ccc(S(N)(=O)=O)cc1F
Reactant: O=C([O-])[O-]
Agent: O=[Mn](=O)(=O)[O-]
Agent: [K+]
Agent: [Na+]
Solvent: O
Solvent: O=CO
Product: NS(=O)(=O)c1ccc(C(=O)O)c(F)c1

Procedure:
To a stirred solution of 3-fluoro-4-methyl-benzenesulfonamide (prepared above) in 50 mL of water was added sodium carbonate (0.53 g, 5 mmol) and potassium permanganate (3.16 g, 20 mmol) portionwise over three hours at 50˜60° C. The resulting mixture was stirred for further 8 hours at this temperature before 0.2 mL of formic acid was added to quench the excess of potassium permanganate. The mixture was then filtered through celite while it was still hot and further washed with the hot water. The filtrate was concentrated to ˜30 mL and adjusted to pH 9˜10. The filtration was applied again to remove non-oxidized starting material. The final filtrate was acidified with HCl (conc.) to ˜pH 1 and 4-(aminosulfonyl)-2-fluorobenzoic acid was precipitated and collected by filtration as white solid (1.10 g, 50%).
Reaction SMILES: [Li]CCCC.Cl[C:7]1[S:8][C:9]([CH2:13][N:14]([CH2:21][CH:22]([CH3:24])[CH3:23])[CH:15]2[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]2)=[C:10]([Cl:12])[N:11]=1>O1CCCC1.C([O-])(O)=O.[Na+]>[CH3:23][CH:22]([CH3:24])[CH2:21][N:14]([CH2:13][C:9]1[S:8][CH:7]=[N:11][C:10]=1[Cl:12])[CH:15]1[CH2:16][CH2:17][NH:18][CH2:19][CH2:20]1
Reactant: CC(C)CN(Cc1sc(Cl)nc1Cl)C1CCNCC1
Agent: O=C([O-])O
Agent: [Li]CCCC
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)CN(Cc1scnc1Cl)C1CCNCC1
Temperature: -78 °C
Reaction time: 1 h
Yield: 79.9 %

Procedure:
n-BuLi (1.6M in hexanes, 0.50 mL, 0.8 mmol) is added to a cold (−78° C.) solution of (2,4-dichloro-thiazol-5-ylmethyl)-isobutyl-piperdin-4-yl-amine (0.0995 g, 0.3 mmol) in anhydrous tetrahydrofuran. After stirring for 1 h at −78° C., aqueous saturated NaHCO3 is added, then poured in 100 mL aqueous saturated NaHCO3, extracted with ethyl acetate (3×100 mL). The layers are separated and the organic layer dried over Na2SO4, filtered, and concentrated. The crude material is purified on silica gel eluting with 1% NH4OH/10% ethanol/chloroform to yield (0.069 g, 78%) N-(2-methylpropyl)-N-[(4-chloro-1,3-thiazol-5-yl)methyl]piperidin-4-amine: mass spectrum (ion spray): m/z=288.1 (M+1); 1H NMR (CDCl3): δ=8.64 (1H, s), 3.81 (2H, s), 3.16 (2 H, brd), 2.60-2.49 (3H, m), 2.32 (2H, d), 1.82-1.62 (4H, m), 1.53-1.39 (2H, m), 0.91 (6H, d).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH:8]=[CH2:9])[CH:3]=1.C(C1C=NC=CC=1)#N.OO.S([O-])([O-])=[O:21].[Na+].[Na+].C(=O)(O)[O-].[Na+]>C(Cl)Cl.C[Re](=O)(=O)=O>[Br:1][C:2]1[CH:3]=[C:4]([CH:8]2[CH2:9][O:21]2)[CH:5]=[CH:6][CH:7]=1
Reactant: C=Cc1cccc(Br)c1
Reactant: O=S([O-])[O-]
Agent: C[Re](=O)(=O)=O
Agent: N#Cc1cccnc1
Agent: O=C([O-])O
Solvent: ClCCl
Product: Brc1cccc(C2CO2)c1
Reaction time: 18 h

Procedure:
1-Bromo-3-vinyl-benzene (5 g, 27.3 mmol) and 3-cyanopyridine (551 mg, 2.7 mmol) were added in CH2Cl2 (25 mL), Methyltrioxorhenium (VII) (34 mg, 0.137 mmol) and hydrogen peroxide (30%) (6.2 mL, 54.6 mmol) were added and the reaction mixture was stirred at room temperaute for 18 h. Sodium sulfite 1M (10 mL) and saturated sodium bicarbonate were added, the aqueous layer was extracted with CH2Cl2, and the combined organic layers were dried over anhydrous magnesium sulfate, filtered. The filtrate was concentrated in vacuo to provide the title compound as clear oil ((5.05 g, 93%).
Reaction SMILES: [CH3:1][C:2]1[CH:31]=[CH:30][CH:29]=[C:28]([CH3:32])[C:3]=1[CH2:4][NH:5][C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][C:15]=1[F:16])[N:12]=[C:11]([N:17]1[CH:21]=[C:20]([C:22]([O:24]CC)=[O:23])[CH:19]=[N:18]1)[NH:10][C:9]2=O.[CH3:33][NH:34][CH2:35][CH3:36]>>[CH3:1][C:2]1[CH:31]=[CH:30][CH:29]=[C:28]([CH3:32])[C:3]=1[CH2:4][NH:5][C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][C:15]=1[F:16])[N:12]=[C:11]([N:17]1[CH:21]=[C:20]([C:22]([OH:24])=[O:23])[CH:19]=[N:18]1)[N:10]=[C:9]2[N:34]([CH2:35][CH3:36])[CH3:33]
Reactant: CCOC(=O)c1cnn(-c2nc3cc(F)c(NCc4c(C)cccc4C)cc3c(=O)[nH]2)c1
Reactant: CCNC
Product: CCN(C)c1nc(-n2cc(C(=O)O)cn2)nc2cc(F)c(NCc3c(C)cccc3C)cc12

Procedure:
The above compound may be made analogous to Example 1 using ethyl 1-(6-((2,6-dimethylbenzyl)amino)-7-fluoro-4-oxo-3,4-dihydroquinazolin-2-yl)-1H-pyrazole-4-carboxylate in step D and N-methylethanamine in step E. MS (ESI): predicted mass calcd. for C24H25FN6O2, 448.2
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[C:8]([O:10]C)[C:7]([O:12]C)=[CH:6][C:3]=1[C:4]#[N:5].B(Br)(Br)Br.O>ClCCl>[NH2:1][C:2]1[CH:9]=[C:8]([OH:10])[C:7]([OH:12])=[CH:6][C:3]=1[C:4]#[N:5]
Reactant: COc1cc(N)c(C#N)cc1OC
Agent: BrB(Br)Br
Solvent: ClCCl
Solvent: O
Product: N#Cc1cc(O)c(O)cc1N
Temperature: 25 °C
Reaction time: 8 h
Yield: 142.2 %

Procedure:
To a solution of 15.65 g (87.83 mmol) of 2-amino-4,5-dimethoxybenzonitrile in 440 ml of dry dichloromethane was added dropwise at -78° C., 66.0 g (263.5 mmol) of boron tribromide. The mixture was stirred overnight while the mixture was allowed to warm to room temperature. After the addition of 180 ml of water, the resulting precipitate was filtered off and dried in vacuo (37.6 g). The crude material was dissolved in 570 ml of methanol, 0.5 ml of concentrated hydrochloric acid was added and the mixture was refluxed for 1 hour. Evaporation to dryness yielded 18.75 g of 2-amino-4,5-dihydroxybenzonitrile as the hydrobromide salt.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:30]=[CH:31][CH:32]=1)[CH2:5][N:6]1[C:15]2[C:10](=[CH:11][C:12]([O:16][CH2:17][C:18]#[CH:19])=[CH:13][CH:14]=2)[C:9]([C:20]2[CH:25]=[CH:24][C:23]([CH:26]([CH3:28])[CH3:27])=[CH:22][CH:21]=2)=[N:8][C:7]1=[O:29].[H-].[Na+].Br[CH2:36][CH2:37][O:38][CH3:39]>CN(C=O)C>[CH:26]([C:23]1[CH:24]=[CH:25][C:20]([C:9]2[C:10]3[C:15](=[CH:14][CH:13]=[C:12]([O:16][CH2:17][C:18]#[CH:19])[CH:11]=3)[N:6]([CH2:5][C:4]3[CH:30]=[CH:31][CH:32]=[C:2]([O:1][CH2:36][CH2:37][O:38][CH3:39])[CH:3]=3)[C:7](=[O:29])[N:8]=2)=[CH:21][CH:22]=1)([CH3:27])[CH3:28]
Reactant: C#CCOc1ccc2c(c1)c(-c1ccc(C(C)C)cc1)nc(=O)n2Cc1cccc(O)c1
Reactant: COCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C#CCOc1ccc2c(c1)c(-c1ccc(C(C)C)cc1)nc(=O)n2Cc1cccc(OCCOC)c1
Temperature: 60 °C

Procedure:
To a solution of 100 mg (0.236 mmol) of 1-(3-hydroxy-benzyl)-4-(4-isopropyl-phenyl)-6-prop-2-ynyloxy-1H-quinazolin-2-one in anhydrous DMF (5 ml) is added NaH (11 mg, 0.471 mmol) and the solution is allowed to stir until evolution of gas ceases. 1-Bromo-2-methoxy-ethane (34 μl, 0.236 mmol) is added and the mixture is heated for 2 days at 60° C. After cooling to room temperature, the reaction mixture is quenched with water and the mixture is acidified to pH 3 with 10% citric acid. The mixture is extracted with ether (2×20 ml). The combined organic layers are washed with brine, dried (Na2SO4), filtered and evaporated in vacuo to provide a yellow solid which is purified by flash chromatography on silica gel using petroleum ether/ethyl acetate (9:1 to 1:1) to provide the title compound as a yellow oil. Yield:56 mg (49%).
Reaction SMILES: [OH-].[Na+].C[O:4][C:5](=[O:41])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:18]=[CH:17][C:16]([C:19]([CH2:37][CH3:38])([C:22]3[CH:27]=[CH:26][C:25]([C:28]#[C:29][C:30]4([OH:35])[CH2:34][CH2:33][CH2:32][CH2:31]4)=[C:24]([CH3:36])[CH:23]=3)[CH2:20][CH3:21])=[CH:15][C:14]=2[CH3:39])=[CH:9][C:8]=1[F:40].[Cl-].[NH4+]>CO>[CH2:20]([C:19]([C:16]1[CH:17]=[CH:18][C:13]([C:10]2[CH:11]=[CH:12][C:7]([CH2:6][C:5]([OH:41])=[O:4])=[C:8]([F:40])[CH:9]=2)=[C:14]([CH3:39])[CH:15]=1)([C:22]1[CH:27]=[CH:26][C:25]([C:28]#[C:29][C:30]2([OH:35])[CH2:34][CH2:33][CH2:32][CH2:31]2)=[C:24]([CH3:36])[CH:23]=1)[CH2:37][CH3:38])[CH3:21]
Reactant: CCC(CC)(c1ccc(C#CC2(O)CCCC2)c(C)c1)c1ccc(-c2ccc(CC(=O)OC)c(F)c2)c(C)c1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CO
Product: CCC(CC)(c1ccc(C#CC2(O)CCCC2)c(C)c1)c1ccc(-c2ccc(CC(=O)O)c(F)c2)c(C)c1
Reaction time: 3 h
Yield: 98.5 %

Procedure:
A 2 N sodium hydroxide aqueous solution (0.24 mL) was added to a solution of (4′-{1-ethyl-1-[4-(1-hydroxy-cyclopentylethynyl)-3-methyl-phenyl]-propyl}-3-fluoro-2′-methyl-biphenyl-4-yl)acetic acid methyl ester (Example 93-(2); 41.1 mg, 0.078 mmol) in methanol (1.3 mL), and the mixture was stirred for three hours. A saturated aqueous ammonium chloride solution was added to the reaction mixture, followed by extraction with ethyl acetate. The organic layer was washed with water, dried over anhydrous sodium sulfate and concentrated under reduced pressure to give the title compound (39.4 mg, 98%).
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:17]2[C:16](=[O:18])[N:15]([CH2:19][C:20]3[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=3)[N:14]=[C:13]([OH:27])[C:12]=2[N:11]2[CH2:28][CH2:29][N:30]([CH3:33])[C:31](=[O:32])[C:10]=12)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[CH2:35]Cl.CO.C[Si](C=[N+]=[N-])(C)C>CCCCCC.C(O)(=O)C>[CH2:1]([O:8][C:9]1[C:17]2[C:16](=[O:18])[N:15]([CH2:19][C:20]3[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=3)[N:14]=[C:13]([O:27][CH3:35])[C:12]=2[N:11]2[CH2:28][CH2:29][N:30]([CH3:33])[C:31](=[O:32])[C:10]=12)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CN1CCn2c(c(OCc3ccccc3)c3c(=O)n(Cc4ccc(F)cc4)nc(O)c32)C1=O
Reactant: ClCCl
Agent: C[Si](C)(C)C=[N+]=[N-]
Solvent: CCCCCC
Solvent: CC(=O)O
Solvent: CO
Product: COc1nn(Cc2ccc(F)cc2)c(=O)c2c(OCc3ccccc3)c3n(c12)CCN(C)C3=O
Reaction time: 0.5 h

Procedure:
A suspension of 10-(benzyloxy)-2-(4-fluorobenzyl)-4-hydroxy-8-methyl-7,8-dihydropyrazino[1′,2′:1,5]-pyrrolo[2,3-d]pyridazine-1,9(2H,6H)-dione (0.50 g, 1.11 mmol) in mixture of dichloromethane (20 mL) and methanol (1 mL) at room temperature was treated with a solution of (trimethylsilyl)diazomethane in hexane. After stirring for 30 minutes, the resultant homogeneous solution was treated with a few drops of acetic acid, and the mixture was concentrated under vacuum. The residue was partitioned between chloroform and brine. The organic extract was dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. The residue was subject to column chromatography on silica gel eluting with 2% methanol in chloroform. Collection and concentration of the faster eluting major product provide the titled compound.
Reaction SMILES: [F:1][C:2]1[C:3]([CH2:13][NH:14][C:15]2[C:20]([N+:21]([O-])=O)=[CH:19][CH:18]=[CH:17][N:16]=2)=[CH:4][C:5]2[S:9][C:8]([S:10][CH3:11])=[N:7][C:6]=2[CH:12]=1.BrC1C(OC)=CC(NCC2C=CC3N=C(SC)SC=3C=2)=C([N+]([O-])=O)C=1>>[F:1][C:2]1[C:3]([CH2:13][NH:14][C:15]2[C:20]([NH2:21])=[CH:19][CH:18]=[CH:17][N:16]=2)=[CH:4][C:5]2[S:9][C:8]([S:10][CH3:11])=[N:7][C:6]=2[CH:12]=1
Reactant: CSc1nc2cc(F)c(CNc3ncccc3[N+](=O)[O-])cc2s1
Agent: COc1cc(NCc2ccc3nc(SC)sc3c2)c([N+](=O)[O-])cc1Br
Product: CSc1nc2cc(F)c(CNc3ncccc3N)cc2s1

Procedure:
N2-((5-Fluoro-2-(methylthio)benzo[d]thiazol-6-yl)methyl)pyridine-2,3-diamine was synthesized as a yellow solid (200 mg) using a procedure analogous to that described in Step 2 of Example 41, substituting N-((5-fluoro-2-(methylthio)benzo[d]thiazol-6-yl)methyl)-3-nitropyridin-2-amine from the previous step for 4-bromo-5-methoxy-N-((2-(methylthio)benzo[d]thiazol-6-yl)methyl)-2-nitroaniline used in Example 41. LCMS (ESI) m/z 321 (M+H)+.
Reaction SMILES: [O:1]=[C:2]1[NH:10][CH:9]=[N:8][C:7]2[N:6]([CH2:11][CH2:12][C:13]([O:15]CC)=O)[CH:5]=[N:4][C:3]1=2.[NH2:18][CH:19]1[CH2:24][CH2:23][N:22]([CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH2:21][CH2:20]1.C(#N)C>CCOCC>[O:1]=[C:2]1[NH:10][CH:9]=[N:8][C:7]2[N:6]([CH2:11][CH2:12][C:13]([NH:18][CH:19]3[CH2:24][CH2:23][N:22]([CH2:25][C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)[CH2:21][CH2:20]3)=[O:15])[CH:5]=[N:4][C:3]1=2
Reactant: NC1CCN(Cc2ccccc2)CC1
Reactant: CCOC(=O)CCn1cnc2c(=O)[nH]cnc21
Solvent: CCOCC
Solvent: CC#N
Product: O=C(CCn1cnc2c(=O)[nH]cnc21)NC1CCN(Cc2ccccc2)CC1
Temperature: 120 °C
Reaction time: 17 h
Yield: 95.5 %

Procedure:
250 mg. (1.06 mmol) 3-(1,6-dihydro-6-oxo-9H-purin-9-yl) propionic acid, ethyl ester (AIT-0027) was added to a 10 ml round bottom flask equipped with a magnetic stirring bar, reflux condenser and CaCl2 drying tube. Then, 604 mg (3.17 mmol) 4-amino-1-benzyl-piperidine and 1 ml acetonitrile were added and the solution was brought to reflux. Reflux was continued for 17 hours. Aacetonitrile was evaporated and the mixture was heated at 120° C. for eight hours to yield a dark viscous oil. The oil was treated with ether while stirring. The solution was filtered and the orangebrown solid was washed with additional ether. Upon drying, 385 mg of a brown solid was obtained. The solid was stirred in acetone, filtered, washed with acetone and then with ether. This yielded 200 mg of 3-(1,6-dihydro-6-oxo-9H-purin-9-yl)-N-(1-benzylpiperidin-4-yl)propanamide (AIT-0033) as a tan solid. Analysis by HPLC indicated that the product was 65% pure.