Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH2:2][C:3]1[CH:4]=[C:5]2[N:11]=[C:10]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[N+:18]([O-:20])=[O:19])[S:9][C:6]2=[N:7][CH:8]=1.[C:21]([N:28]1[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]1)([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22].CCN(CC)CC>C(#N)C>[N+:18]([C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=1[C:10]1[S:9][C:6]2[C:5]([N:11]=1)=[CH:4][C:3]([CH2:2][N:31]1[CH2:30][CH2:29][N:28]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:33][CH2:32]1)=[CH:8][N:7]=2)([O-:20])=[O:19]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: O=[N+]([O-])c1ccccc1-c1nc2cc(CBr)cnc2s1
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCN(Cc2cnc3sc(-c4ccccc4[N+](=O)[O-])nc3c2)CC1
Reaction time: 60 h
Yield: 74 %

Procedure:
A solution of crude 6-(bromomethyl)-2-(2-nitrophenyl)thiazolo[5,4-b]pyridine (4.0 g), Boc-piperazine (1.99 g, 10.7 mmol), Et3N (1.5 mL, 10.7 mmol) and acetonitrile (100 mL) was stirred at 50° C. for 4 h and then at room temperature for 60 h. TLC demonstrated that the reaction was complete. The mixture was concentrated in vacuo and purified by silica gel chromatography (petroleum ether: ethyl acetate: Et3N=100:10:1) to afford tert-butyl 4-((2-(2-nitrophenyl)thiazolo[5,4-b]pyridin-6-yl)methyl)piperazine-1-carboxylate as a yellow solid (3.6 g, yield: 74% over 2 steps).
Reaction SMILES: C1C2C(COC([NH:18][C:19]3[CH:24]=[CH:23][C:22]([S:25][C:26]4[S:30][C:29]([C:31]([O:33]CC)=[O:32])=[CH:28][C:27]=4[NH:36][C:37]4[C:38]5[CH:46]=[CH:45][C:44]([CH:47]([CH3:49])[CH3:48])=[N:43][C:39]=5[N:40]=[CH:41][N:42]=4)=[CH:21][CH:20]=3)=O)C3C(=CC=CC=3)C=2C=CC=1.O.[OH-].[Li+].Cl>O1CCOCC1.O>[NH2:18][C:19]1[CH:24]=[CH:23][C:22]([S:25][C:26]2[S:30][C:29]([C:31]([OH:33])=[O:32])=[CH:28][C:27]=2[NH:36][C:37]2[C:38]3[CH:46]=[CH:45][C:44]([CH:47]([CH3:49])[CH3:48])=[N:43][C:39]=3[N:40]=[CH:41][N:42]=2)=[CH:21][CH:20]=1
Reactant: CCOC(=O)c1cc(Nc2ncnc3nc(C(C)C)ccc23)c(Sc2ccc(NC(=O)OCC3c4ccccc4-c4ccccc43)cc2)s1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: CC(C)c1ccc2c(Nc3cc(C(=O)O)sc3Sc3ccc(N)cc3)ncnc2n1
Yield: 72.5 %

Procedure:
The product of Example 90E (0.245 g, 0.356 mmol) in 1,4-dioxane (3 mL), was treated with a solution of lithium hydroxide monohydrate (0.0747 g, 1.78 mmol) in water (1.5 mL) at room temperature, the resulting mixture was heated at 60° for 25 minutes. The reaction mixture was cooled, diluted with water (10 mL), adjusted the pH to 3 with 1N aqueous HCl, and the resulting precipitate was collected by vacuum filtration. Washing of the crude product with small volumes of 1,4-dioxane afforded the title compound (0.113 g, 0.258 mmol, 72%). MS (ESI+) m/z 438 (M+H)+, MS (ESI−) m/z 436 (M−H)−.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][N:5]1[C:14]2[C:9](=[CH:10][C:11]([CH3:16])=[C:12]([F:15])[CH:13]=2)[CH2:8][CH2:7][C:6]1=[O:17].[CH2:18]([CH:22]1[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1)[CH2:19][CH2:20][CH3:21].[Na+].[I-].C([O-])([O-])=O.[K+].[K+]>CC#N>[CH2:18]([CH:22]1[CH2:27][CH2:26][N:25]([CH2:2][CH2:3][CH2:4][N:5]2[C:14]3[C:9](=[CH:10][C:11]([CH3:16])=[C:12]([F:15])[CH:13]=3)[CH2:8][CH2:7][C:6]2=[O:17])[CH2:24][CH2:23]1)[CH2:19][CH2:20][CH3:21]
Reactant: CCCCC1CCNCC1
Reactant: Cc1cc2c(cc1F)N(CCCCl)C(=O)CC2
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC#N
Product: CCCCC1CCN(CCCN2C(=O)CCc3cc(C)c(F)cc32)CC1
Reaction time: 20 h
Yield: 33.9 %

Procedure:
A 4 mL vial was charged with 1-(3-chloropropyl)-7-fluoro-6-methyl-3,4-dihydro-1H-quinolin-2-one (112KK01) (0.047 g, 0.18 mmol), 4-butylpiperidine (0.039 g, 0.28 mmol), NaI (0.100 g, 0.67 mmol), and K2CO3 (0.075 g, 0.54 mmol) in MeCN (2 mL) and shaken at 50° for 20 h. The reaction mixture was quenched with water, and the product extracted into EtOAc. The combined organic layers were purified by cation exchange CC followed by purification by flash CC (SiO2; MeOH/DCM 1:10) to give the title compound (112KK06) (0.022 g, 34%). 1H NMR (CD3OD) d 7.05 (d, J=8.4 Hz, 1H), 6.93 (d, J=11.7 Hz, 1H), 3.93 (t, J=7.2 Hz, CH2), 2.93 (d, J=11.1 Hz, 2H), 2.83 (t, J=6.9 Hz, CH2), 2.60-2.56 (m, 2H), 2.44-2.40 (m, 2H), 2.19 (D, J=1.8 Hz, CH3) 2.03-1.98 (m, 2H), 1.86-1.79 (m, 2H), 1.69 (d, J=11.0 Hz, 2H), 1.31-1.19 (m, 9H), 0.89 (t, J=6.6 Hz, CH3); 13C NMR (CD3OD) d 172.4, 161.7 (d, J=241.0 Hz), 139.5 (d, J=10.0 Hz), 131.7 (d, J=6.1 Hz), 123.5 (d, J=3.6 Hz), 119.9 (d, J=17.4 Hz), 104.0 (d, J=28.1 Hz), 56.8, 55.0, 41.5, 37.3, 36.7, 33.0, 32.8, 30.1, 25.5, 25.3, 23.9, 14.4, 13.7.
Reaction SMILES: [CH3:1][NH:2][C:3]1[C:4]([NH2:13])=[CH:5][C:6]([C:9]([F:12])([F:11])[F:10])=[CH:7][CH:8]=1.[F:14][C:15]1[CH:16]=[N:17][CH:18]=[CH:19][C:20]=1[CH:21]=O.S(=O)(O)[O-].[Na+].[Cl-].[NH4+]>CN(C=O)C>[F:14][C:15]1[CH:16]=[N:17][CH:18]=[CH:19][C:20]=1[C:21]1[N:2]([CH3:1])[C:3]2[CH:8]=[CH:7][C:6]([C:9]([F:10])([F:11])[F:12])=[CH:5][C:4]=2[N:13]=1
Reactant: O=Cc1ccncc1F
Reactant: CNc1ccc(C(F)(F)F)cc1N
Agent: O=S([O-])O
Agent: [Cl-]
Agent: [NH4+]
Solvent: CN(C)C=O
Product: Cn1c(-c2ccncc2F)nc2cc(C(F)(F)F)ccc21
Temperature: 80 °C
Reaction time: 1.5 h
Yield: 62 %

Procedure:
A mixture of 1.90 g of N1-methyl-4-trifluoromethylbenzene-1,2-diamine, 1.49 g of 3-fluoropyridine-4-carbaldehyde, 3.12 g of sodium bisulfite and 20 ml of DMF was stirred for 1.5 hours while heating at 80° C., then, was stirred for 2 hours while heating at 120° C. After cooling down to room temperature, a saturated ammonium chloride aqueous solution was poured, and the mixture was extracted three times with ethyl acetate. The combined organic layers were dried over magnesium sulfate, then, concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to obtain 1.83 g of 2-(3-fluoropyridin-4-yl)-1-methyl-5-trifluoromethyl-1H-benzimidazole (hereinafter, referred to as present active compound 4).
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[CH2:23][CH2:22][C:10]2[C:11]3[C:12](O)([CH3:20])[C:13]([F:19])([F:18])[CH2:14][C:15]=3[CH:16]=[CH:17][C:9]=2[CH2:8][CH2:7]1)=[O:5])[CH3:2].N1C=CC=CC=1.O=S(Cl)[Cl:32]>>[CH2:1]([O:3][C:4]([N:6]1[CH2:23][CH2:22][C:10]2[C:11]3[C:12]([Cl:32])([CH3:20])[C:13]([F:19])([F:18])[CH2:14][C:15]=3[CH:16]=[CH:17][C:9]=2[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)N1CCc2ccc3c(c2CC1)C(C)(O)C(F)(F)C3
Reactant: O=S(Cl)Cl
Solvent: c1ccncc1
Product: CCOC(=O)N1CCc2ccc3c(c2CC1)C(C)(Cl)C(F)(F)C3
Temperature: 50 °C

Procedure:
Into a glass vial containing the product from step (a) (231 mg, 0.710 mmol) dissolved in SOCl2 (2 ml), pyridine (1 μL, 0.0071 mmol) was added. The stirred reaction mixture was heated to 50° C. for 30 minutes. The volatiles were evaporated in vacuo and the residue diluted with water (50 ml). The aqueous mixture was extracted with EtOAc (3×). The combined EtOAc extracts were washed with brine, dried over Na2SO4, and solvent evaporated in vacuo to give the sub-title compound as a dark yellow oil (214 mg) that was used without further purification. MS: ESI (positive): 344 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5](I)=[CH:4][C:3]=1[F:9].C(=O)([O-])[O-].[Cs+].[Cs+].[CH2:16]([O:18][C:19](=[O:22])[C:20]#[CH:21])[CH3:17]>[Pd](Cl)Cl.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Cu]I.C1COCC1>[CH2:16]([O:18][C:19](=[O:22])[C:20]#[C:21][C:5]1[CH:6]=[CH:7][C:2]([Cl:1])=[C:3]([F:9])[CH:4]=1)[CH3:17]
Reactant: Fc1cc(I)ccc1Cl
Reactant: C#CC(=O)OCC
Agent: Cl[Pd]Cl
Agent: [Cu]I
Agent: O=C([O-])[O-]
Solvent: C1CCOC1
Product: CCOC(=O)C#Cc1ccc(Cl)c(F)c1
Temperature: 35 °C
Reaction time: 48 h

Procedure:
Under argon atmosphere, a four neck flask was charged with 1-chloro-2-fluoro-4-iodo-benzene (50.5 g, 0.20 mol), bis(triphenylphosphine) palladium(II) chloride (2.76 g, 3.94 mmol, 2 mol %), copper(I) iodide (1.50 g, 7.80 mol, 4 mol %) and dry THF (600 ml). At r.t., cesium carbonate (128.3 g, 0.39 mol, 2 eq.) was added over 5 min. Finally, propynoic acid ethyl ester (38.6 g, 0.39 mol, 2 eq.) was added, and the reaction was stirred for 48 h at 35° C. The reaction mixture was evaporated to dryness, and the residue was taken up in toluene (50 ml) and heptane (100 ml). The resulting suspension was stirred at 40° C. for 1 h and filtered afterward over celite. The filtrate was concentrated, and the product was purified by silica gel filtration (toluene/heptane 1:2) to yield 38.8 g (87%) of the Vd as a light yellow solid.
Reaction SMILES: C(OC(=O)C)C.Cl.[CH3:8][N:9]([CH2:17][CH2:18][N:19]([CH2:41][C:42]1[CH:47]=[CH:46][N:45]=[CH:44][CH:43]=1)[CH2:20][CH2:21][CH2:22][O:23][C:24]1[CH:40]=[CH:39][C:27]2[N:28]([CH3:38])[C:29](=[O:37])[C:30]([CH3:36])([CH3:35])[C:31](=[O:34])[N:32]([CH3:33])[C:26]=2[CH:25]=1)C(=O)OC(C)(C)C>C(OCC)(=O)C>[CH3:38][N:28]1[C:29](=[O:37])[C:30]([CH3:35])([CH3:36])[C:31](=[O:34])[N:32]([CH3:33])[C:26]2[CH:25]=[C:24]([O:23][CH2:22][CH2:21][CH2:20][N:19]([CH2:18][CH2:17][NH:9][CH3:8])[CH2:41][C:42]3[CH:43]=[CH:44][N:45]=[CH:46][CH:47]=3)[CH:40]=[CH:39][C:27]1=2
Reactant: CN(CCN(CCCOc1ccc2c(c1)N(C)C(=O)C(C)(C)C(=O)N2C)Cc1ccncc1)C(=O)OC(C)(C)C
Agent: Cl
Solvent: CCOC(C)=O
Product: CNCCN(CCCOc1ccc2c(c1)N(C)C(=O)C(C)(C)C(=O)N2C)Cc1ccncc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 127 %

Procedure:
A 4N-hydrogen chloride ethyl acetate solution (3.2 ml) was added to an ethyl acetate solution (30 ml) of tert-butyl methyl-(2-{pyridin-4-ylmethyl-[3-(1,3,3,5-tetramethyl-2,4-dioxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-7-yloxy)propyl]amino}ethyl)carbamate (1.43 g, 2.5 mmol) and stirred at room temperature overnight. The reaction mixture was concentrated under reduced pressure. The residue was dissolved in dichloromethane, and trifluoroacetic acid (3 ml) was added thereto. Stirring was conducted at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure, and the residue was dissolved in a dichloromethane-methanol mixture solvent. Polymer-bonded quaternary ammonium carbonate (PL-HcO3MP) was added thereto to neutralize the mixture. The resulting reaction mixture was filtered. The filtrate was concentrated under reduced pressure to thereby obtain 1.44 g (yield: quantitative) of 1,3,3,5-tetramethyl-7-{3-[(2-methylaminoethyl)pyridin-4-ylmethylamino]propoxy}-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione as a pale brown oil.
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([S:7](Cl)(=[O:9])=[O:8])=[CH:4][CH:3]=1.[C:11]([NH2:15])([CH3:14])([CH3:13])[CH3:12]>C1COCC1.C(OCC)C>[C:11]([NH:15][S:7]([C:5]1[S:6][C:2]([Cl:1])=[CH:3][CH:4]=1)(=[O:9])=[O:8])([CH3:14])([CH3:13])[CH3:12]
Reactant: O=S(=O)(Cl)c1ccc(Cl)s1
Reactant: CC(C)(C)N
Solvent: C1CCOC1
Solvent: CCOCC
Product: CC(C)(C)NS(=O)(=O)c1ccc(Cl)s1
Yield: 91.7 %

Procedure:
A solution of 5.5 g (27.5 mmol) of 5-chlorothiophenesulfonyl chloride in dry THF at 0° C. was treated with a solution of 5.7 mL (75.5 mmol) of t-butylamine. After warning to 23° C., the reaction mixture was diluted with 125 mL of diethyl ether, filtered, and washed with 1 N HCl, brine, and dried (MgSO4). Concentration in vacuo affords 6.4 g (98%) of the named compound as an oil.
Reaction SMILES: [CH3:1][O:2][C:3]([C@H:5]1[O:16][C@H:15]([CH2:17][O:18]CC2C=CC=CC=2)[C@@H:6]1[O:7]CC1C=CC=CC=1)=[O:4].[H][H]>[OH-].[OH-].[Pd+2].CO>[CH3:1][O:2][C:3]([C@H:5]1[O:16][C@H:15]([CH2:17][OH:18])[C@@H:6]1[OH:7])=[O:4]
Reactant: COC(=O)[C@H]1O[C@H](COCc2ccccc2)[C@@H]1OCc1ccccc1
Reactant: [H][H]
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Product: COC(=O)[C@H]1O[C@H](CO)[C@@H]1O
Yield: 96.2 %

Procedure:
A slurry of 1.01 g of 2,4-anhydro-3,5-bis-O-(phenylmethyl)-D-lyxonic acid methyl ester (prepared by the procedure in Tetrahedron Letters, Vol 31, No. 33, p4787, 1990), 0.253 g of palladium hydroxide on carbon, and 30 ml of methyl alcohol is hydrogenated under a balloon of hydrogen (1 atm.) for 2.5 hours. The mixture is filtered through diatomaceous earth, washed with ethyl acetate and ethyl alcohol, and concentrated in vacuo to give 0.460 g of the desired product.
Reaction SMILES: Cl[CH:2]([SiH3:4])Cl.[S:5]([C:21]1[CH:26]=[C:25]([C:27]([CH3:30])([CH3:29])[CH3:28])[CH:24]=[C:23]([C:31]([CH3:34])([CH3:33])[CH3:32])[C:22]=1[OH:35])[C:6]1[CH:11]=[C:10]([C:12]([CH3:15])([CH3:14])[CH3:13])[CH:9]=[C:8]([C:16]([CH3:19])([CH3:18])[CH3:17])[C:7]=1[OH:20].C(N(CC)CC)C>>[C:27]([C:25]1[CH:24]=[C:23]([C:31]([CH3:34])([CH3:33])[CH3:32])[C:22]2[O:35][SiH:4]([CH3:2])[O:20][C:7]3[C:8]([C:16]([CH3:18])([CH3:17])[CH3:19])=[CH:9][C:10]([C:12]([CH3:15])([CH3:14])[CH3:13])=[CH:11][C:6]=3[S:5][C:21]=2[CH:26]=1)([CH3:30])([CH3:29])[CH3:28]
Reactant: [SiH3]C(Cl)Cl
Reactant: CC(C)(C)c1cc(Sc2cc(C(C)(C)C)cc(C(C)(C)C)c2O)c(O)c(C(C)(C)C)c1
Solvent: CCN(CC)CC
Product: C[SiH]1Oc2c(cc(C(C)(C)C)cc2C(C)(C)C)Sc2cc(C(C)(C)C)cc(C(C)(C)C)c2O1
Yield: 48.7 %

Procedure:
Utilizing the procedure of Example 1, this compound is prepared from 5.7 grams (0.05 mole) dichloromethylsilane, 22.1 grams (0.05 mole) 2,2'-thiobis(4,6-di-t-butylphenol), and 10.1 grams (0.10 mole) triethylamine. Recrystallization twice from acetone-toluene gives 11.8 grams (48% yield) of white crystals, mp 178°-180° C.
Reaction SMILES: C([O:4][C:5]1[CH:6]=[C:7]([CH:20]=[CH:21][C:22]=1[O:23]C(=O)C)/[CH:8]=[C:9]1\[CH2:10][CH2:11][CH2:12][C:13]2[CH:14]=[C:15]([CH3:19])[CH:16]=[N:17][C:18]\1=2)(=O)C.[ClH:27]>>[OH:4][C:5]1[CH:6]=[C:7]([CH:20]=[CH:21][C:22]=1[OH:23])/[CH:8]=[C:9]1\[CH2:10][CH2:11][CH2:12][C:13]2[CH:14]=[C:15]([CH3:19])[CH:16]=[N:17][C:18]\1=2.[ClH:27]
Reactant: CC(=O)Oc1ccc(/C=C2\CCCc3cc(C)cnc32)cc1OC(C)=O
Agent: Cl
Product: Cc1cnc2c(c1)CCC/C2=C\c1ccc(O)c(O)c1

Procedure:
A solution of E-8-(3,4-diacetoxybenzylidene)-5,6,7,8-tetrahydro-3-methylquinoline (prepared according to Example 5) (3 g) in 2N HCl (50 ml) was heated at 80° for 11/2 hours. The precipitated crystals were removed by filtration and dried to give the title compound as the hydrochloride, quarterhydrate (2.6 g) m.p. 265° C. decomp.
Reaction SMILES: [CH3:1][Mg+].[Br-].[F:4][C:5]1[CH:10]=[C:9]([I:11])[CH:8]=[CH:7][C:6]=1[N:12]1[CH:17]=[C:16]([O:18][CH3:19])[C:15](=[O:20])[C:14]([C:21](N(OC)C)=[O:22])=[N:13]1>C1COCC1>[C:21]([C:14]1[C:15](=[O:20])[C:16]([O:18][CH3:19])=[CH:17][N:12]([C:6]2[CH:7]=[CH:8][C:9]([I:11])=[CH:10][C:5]=2[F:4])[N:13]=1)(=[O:22])[CH3:1]
Reactant: COc1cn(-c2ccc(I)cc2F)nc(C(=O)N(C)OC)c1=O
Reactant: C[Mg+]
Agent: [Br-]
Solvent: C1CCOC1
Product: COc1cn(-c2ccc(I)cc2F)nc(C(C)=O)c1=O
Reaction time: 1 h
Yield: 23 %

Procedure:
MeMgBr (1 M solution in THF, 70 mL, 70 mmol) was added dropwise at −78° C. to a solution of 1-(2-fluoro-4-iodophenyl)-N,5-dimethoxy-N-methyl-4-oxo-1,4-dihydropyridazine-3-carboxamide (9.96 g, 23 mmol) in THF (250 mL). After stirring for 1 h, the reaction mixture was quenched with 1 M HCl aqueous solution and extracted with AcOEt. The extract was washed with brine, dried over MgSO4, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with AcOEt and recrystallized from MeOH to give the title compound (2.05 g, 23% yield) as pale yellow crystals: mp 196-198° C.; 1H NMR (300 MHz, CDCl3): δ ppm 2.67 (3H, s), 3.90 (3H, s), 7.36-7.41 (1H, m), 7.66-7.71 (2H, m), 7.73 (1H, d, J=2.6 Hz). Anal. Calcd for C13H10FIN2O3: C, 40.23; H, 2.60; N, 7.22. Found: C, 40.25; H, 2.87; N, 7.28.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2(O)[O:19]C[N:17]([C:20]([O:22][CH2:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)=[O:21])[C@H:16]2[CH:30]([CH3:32])[CH3:31])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.Cl>O1CCCC1.C1(C)C=CC=CC=1>[CH2:23]([O:22][C:20]([NH:17][C@@H:16]([CH:30]([CH3:32])[CH3:31])[C:15]([C:12]1[CH:11]=[CH:10][C:9]([O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[CH:14][CH:13]=1)=[O:19])=[O:21])[C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: CC(C)[C@@H]1N(C(=O)OCc2ccccc2)COC1(O)c1ccc(OCc2ccccc2)cc1
Agent: Cl
Solvent: O
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: CC(C)[C@H](NC(=O)OCc1ccccc1)C(=O)c1ccc(OCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 36.2 %

Procedure:
In tetrahydrofuran (4 mL) was dissolved (4S)-N-benzyloxycarbonyl-5-(4-benzyloxyphenyl)-4-isopropyl-5-hydroxyoxazolidine (1.38 g) prepared in Example 8, and to the solution were added water (5 mL) and conc. hydrochloric acid (2 mL). The mixture was stirred at room temperature for 24 hours. The reaction was diluted with toluene and the aqueous layer was discarded. The organic layer was washed with water three times. The organic layer was dried over anhydrous magnesium sulfate and then concentrated in vacuo. The residue was purified by silica column chromatography (eluent: hexane/ethyl acetate=2/1) to give the title compound (466 mg) as pale yellow crystals in a yield of 36%.
Reaction SMILES: [C:1]1([CH2:11][CH2:12][C@H:13]2[CH2:18][NH:17][CH2:16][CH2:15][NH:14]2)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[CH3:19][C:20]1[S:29][C:28]2[NH:27][C:26]3[CH:30]=[CH:31][CH:32]=[CH:33][C:25]=3[N:24]=[C:23](N)[C:22]=2[CH:21]=1.C1(C)C=CC=CC=1.CS(C)=O>C(O)(=O)C.C(OCC)(=O)C.O>[CH3:19][C:20]1[S:29][C:28]2[NH:27][C:26]3[CH:30]=[CH:31][CH:32]=[CH:33][C:25]=3[N:24]=[C:23]([N:17]3[CH2:16][CH2:15][NH:14][C@@H:13]([CH2:12][CH2:11][C:1]4[C:10]5[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=5)[CH:4]=[CH:3][CH:2]=4)[CH2:18]3)[C:22]=2[CH:21]=1
Reactant: c1ccc2c(CC[C@H]3CNCCN3)cccc2c1
Reactant: Cc1cc2c(s1)Nc1ccccc1N=C2N
Solvent: CS(C)=O
Solvent: Cc1ccccc1
Solvent: CC(=O)O
Product: Cc1cc2c(s1)Nc1ccccc1N=C2N1CCN[C@@H](CCc2cccc3ccccc23)C1
Temperature: 105 °C
Reaction time: 48 h
Yield: 21.4 %

Procedure:
Combine (S)-2-(2-naphthalen-1-yl-ethyl)-piperazine (720 mg, 3.0 mmol), 2-methyl-4H-3-thia-4,9-diaza-benzo[f]azulen-10-ylamine (686 mg, 3.0 mmol), toluene (6 mL), DMSO (1.5 mL) and glacial acetic acid (1 drop). Heat at 105° C. After 48 h, cool to ambient temperature and dilute with ethyl acetate and water. Extract with ethyl acetate. Wash the extracts with water and brine, dry over sodium sulfate, filter and concentrate the filtrate. Purify by silica gel chromatography using 2N ammonia in methanol-methylene chloride (2.5%–3%) as the eluent to give 290 mg (21%)of the title compound: mass spectrum (ion spray): m/z=453 (M+1), 451 (M−1).
Reaction SMILES: [N:1]([CH2:4][C:5]1[C:14](=[O:15])[C:13]2[C:8](=[CH:9][C:10]([Cl:16])=[CH:11][CH:12]=2)[N:7]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[Cl:23])[CH:6]=1)=[N+]=[N-]>[Pt](=O)=O.C(OCC)(=O)C>[NH2:1][CH2:4][C:5]1[C:14](=[O:15])[C:13]2[C:8](=[CH:9][C:10]([Cl:16])=[CH:11][CH:12]=2)[N:7]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[Cl:23])[CH:6]=1
Reactant: [N-]=[N+]=NCc1cn(-c2ccccc2Cl)c2cc(Cl)ccc2c1=O
Agent: O=[Pt]=O
Solvent: CCOC(C)=O
Product: NCc1cn(-c2ccccc2Cl)c2cc(Cl)ccc2c1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 76.4 %

Procedure:
To a 100 mL round-bottom flask was added 3-azidomethyl-7-chloro-1-(2-chloro-phenyl)-1H-quinolin-4-one (215 mg, 0.623 mmol), ethyl acetate (20 mL) followed by platinum (IV) oxide (18.0 mg, 0.079 mmol). The reaction vessel was evacuated and back-filled with hydrogen gas via a balloon. Almost immediately the reddish color of the PtO2 turned black. The reaction mixture was stirred under a balloon of hydrogen gas at room temp overnight. The reaction mixture was filtered through a bed of celite. The filtrate was concentrated to give the crude 3-aminomethyl-7-chloro-1-(2-chloro-phenyl)-1H-quinolin-4-one (152 mg, 76.4%, 81% purity by HPLC). 1H NMR (DMSO-d6) δ ppm 8.23 (d, J=8.7 Hz, 1H) 7.80-7.92 (m, 2H) 7.59-7.79 (m, 3H) 7.41 (dd, J=8.7, 1.8 Hz, 1H) 6.66 (d, J=1.8 Hz, 1H) 3.58 (s, 2H) 1.69 (br. s., 2H). MS calcd. for C16H12Cl2N2O [(M+H)+] 320.0, obsd. 318.9, [(M-NH2)+] 303.0, obsd. 301.9.
Reaction SMILES: [C:1]1([C:11]([CH2:13][C:14]#[N:15])=O)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[NH2:16][NH2:17]>C(O)C>[C:1]1([C:11]2[CH:13]=[C:14]([NH2:15])[NH:17][N:16]=2)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: N#CCC(=O)c1cccc2ccccc12
Reactant: NN
Solvent: CCO
Product: Nc1cc(-c2cccc3ccccc23)n[nH]1
Temperature: 25 °C

Procedure:
1-Naphthoylacetonitrile (161 mg, 0.825 mmol) and hydrazine (0.11 mL, 3.5 mmol) are heated in ethanol (1.1 mL) at 70° C. in a sealed vial for 60 hr. The reaction is cooled to room temperature and the solvent is removed. The crude material is taken up in 5 ml of ethyl acetate and washed with water and brine. The organic layer is concentrated in vacuo to give 3-(1-naphthyl)-1H-pyrazol-5-amine which is dissolved in acetic acid (0.375 mL, 6.60 mmol). Diethyl ethoxymethylenemalonate (0.182 mL, 0.907 mmol) is added and the mixture is heated at 120° C. for 3 hr in a sealed vial. During the reaction, a precipitate forms. The reaction is cooled to room temperature and the solid is collected in a Buchner funnel and washed with reagent grade alcohol to provide ethyl 2-(1-naphthyl)-7-oxo-4,7-dihydropyrazolo[1,5-a]pyrimidine-6-carboxylate (166 mg, yield 60%). 1H NMR (300 MHz, DMSO) δ 8.73-8.66 (m, 1H), 8.64 (s, 1H), 8.02 (dd, J=8.9, 3.4 Hz, 2H), 7.87-7.78 (m, 1H), 7.68-7.52 (m, 3H), 6.71 (s, 1H), 4.25 (q, J=7.1 Hz, 2H), 1.30 (t, J=7.1 Hz, 3H).
Reaction SMILES: [C:1]([C:3]1[CH:10]=[CH:9][C:6]([CH:7]=[O:8])=[CH:5][CH:4]=1)#[N:2].[BH4-].[Na+]>C(O)C>[C:1]([C:3]1[CH:10]=[CH:9][C:6]([CH2:7][OH:8])=[CH:5][CH:4]=1)#[N:2]
Reactant: N#Cc1ccc(C=O)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: N#Cc1ccc(CO)cc1
Reaction time: 96 h
Yield: 91.1 %

Procedure:
To a solution of 4-cyanobenzaldehyde (1.97 g, 15.0 mmol) in 50 mL of ethanol at room temperature was added sodium borohydride (0.57 g, 15.0 mmol). After 4 days, the solution was quenched with saturated ammonoum chloride solution, then poured into EtOAc, washed with sat, NaHCO3 soln. and brine, dried (Na2SO4), filtered, and concentrated in vacuo to provide the product (1.82 g, 92% yield) as a white waxy solid which was sufficiently pure for use in the next step without further purification.
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[C:8]([C:10]([OH:19])([C:15]([F:18])([F:17])[F:16])[C:11]([F:14])([F:13])[F:12])[CH:7]=[C:6]([CH:20]([CH3:22])[CH3:21])[C:5]=1[NH:23][CH2:24][C:25]([O:27]CC)=[O:26])([CH3:3])[CH3:2].[OH-].[Na+]>Cl>[C:25]([CH2:24][NH:23][C:5]1[C:4]([CH:1]([CH3:3])[CH3:2])=[CH:9][C:8]([C:10]([OH:19])([C:15]([F:17])([F:16])[F:18])[C:11]([F:14])([F:12])[F:13])=[CH:7][C:6]=1[CH:20]([CH3:22])[CH3:21])([OH:27])=[O:26]
Reactant: CCOC(=O)CNc1c(C(C)C)cc(C(O)(C(F)(F)F)C(F)(F)F)cc1C(C)C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: CC(C)c1cc(C(O)(C(F)(F)F)C(F)(F)F)cc(C(C)C)c1NCC(=O)O

Procedure:
Stir ethyl N-[2,6-diisopropyl-4-(hexafluoro-2-hydroxy-2-propyl)phenyl]glycinate (5.0 g, 12 mmol) with 50 ml 1.0 N NaOH for 1 hour. Neutralize the solution with 50 ml 1.0 N HCl. Filter the solid, dissolve in ether, dry and concentrate. Recrystallize from ether-hexane to obtain the title compound as a white solid, m.p. 130°-132° C.
Reaction SMILES: C(OC([N:8]1[CH2:15][CH:14]2[NH:16][CH:10]([CH2:11][O:12][CH2:13]2)[CH2:9]1)=O)(C)(C)C.[Br:17][C:18]1[CH:23]=[C:22]([F:24])[CH:21]=[CH:20][C:19]=1[C@H:25]1[C:30]([C:31]([O:33][CH3:34])=[O:32])=[C:29]([CH2:35]Br)[NH:28][C:27]([C:37]2[S:38][CH:39]=[CH:40][N:41]=2)=[N:26]1.COC(C1[C@H](C2C=CC(F)=CC=2Cl)N=C(C2SC=CN=2)NC=1CBr)=O>>[Br:17][C:18]1[CH:23]=[C:22]([F:24])[CH:21]=[CH:20][C:19]=1[C@H:25]1[C:30]([C:31]([O:33][CH3:34])=[O:32])=[C:29]([CH2:35][N:16]2[CH:14]3[CH2:15][NH:8][CH2:9][CH:10]2[CH2:11][O:12][CH2:13]3)[NH:28][C:27]([C:37]2[S:38][CH:39]=[CH:40][N:41]=2)=[N:26]1
Reactant: CC(C)(C)OC(=O)N1CC2COCC(C1)N2
Reactant: COC(=O)C1=C(CBr)NC(c2nccs2)=N[C@H]1c1ccc(F)cc1Br
Agent: COC(=O)C1=C(CBr)NC(c2nccs2)=N[C@H]1c1ccc(F)cc1Cl
Product: COC(=O)C1=C(CN2C3CNCC2COC3)NC(c2nccs2)=N[C@H]1c1ccc(F)cc1Br

Procedure:
Compound 53b was prepared in analogy to intermediate AC in Example 15, starting from 3-oxa-7,9-diaza-bicyclo[3.3.1]nonane-7-carboxylic acid tert-butyl ester and methyl (4R)-4-(2-bromo-4-fluoro-phenyl)-6-(bromomethyl)-2-thiazol-2-yl-1,4-dihydropyrimidine-5-carboxylate 53a, while 53a was prepared in analogy to compound C in Example 1.