Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH3:30])[CH2:9][CH2:10][CH2:11][N:12]([CH3:29])[C:13]([C:15]1[CH:20]=[CH:19][C:18]([NH:21][CH2:22][CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25])=[CH:17][CH:16]=1)=[O:14])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:31]=O>CO.[C].[Pd]>[C:1]([O:5][C:6]([N:8]([CH3:30])[CH2:9][CH2:10][CH2:11][N:12]([CH3:29])[C:13]([C:15]1[CH:16]=[CH:17][C:18]([N:21]([CH3:31])[CH2:22][CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25])=[CH:19][CH:20]=1)=[O:14])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: C=O
Reactant: CCOC(=O)CCNc1ccc(C(=O)N(C)CCCN(C)C(=O)OC(C)(C)C)cc1
Agent: [Pd]
Solvent: CO
Product: CCOC(=O)CCN(C)c1ccc(C(=O)N(C)CCCN(C)C(=O)OC(C)(C)C)cc1
Temperature: 60 °C
Reaction time: 18 h
Yield: 69.3 %

Procedure:
The compound (239 mg, 0.57 mmol) obtained in Example 94a was dissolved in methanol (15 mL), paraformaldehyde (179 mg, 5.67 mmol) and 10% palladium-carbon (48 mg, 20% by weight) were added, and the mixture was stirred at 60° C. under a hydrogen atmosphere for 18 hours. After the reaction was completed, the reaction mixture was filtered through celite, the filtrate was washed with methanol, and the solvent was evaporated under reduced pressure. The residue was purified by NH silica gel column chromatography (hexane:ethyl acetate, 10:1, v/v) to give the title compound (172 mg; yield, 70%) as a pale pink oily substance.
Reaction SMILES: [CH:1]1([CH2:6][C@@H:7]([C:20]([N:22]2[C@H:26]([C:27]([N:29]3[CH2:34][CH2:33][O:32][CH2:31][CH2:30]3)=[O:28])[CH2:25][CH:24]=[N:23]2)=[O:21])[CH2:8][C:9]([NH:11][O:12]CC2C=CC=CC=2)=[O:10])[CH2:5][CH2:4][CH2:3][CH2:2]1>CO.[OH-].[OH-].[Pd+2]>[CH:1]1([CH2:6][C@@H:7]([C:20]([N:22]2[C@H:26]([C:27]([N:29]3[CH2:34][CH2:33][O:32][CH2:31][CH2:30]3)=[O:28])[CH2:25][CH:24]=[N:23]2)=[O:21])[CH2:8][C:9]([NH:11][OH:12])=[O:10])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C(C[C@@H](CC1CCCC1)C(=O)N1N=CC[C@H]1C(=O)N1CCOCC1)NOCc1ccccc1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Product: O=C(C[C@@H](CC1CCCC1)C(=O)N1N=CC[C@H]1C(=O)N1CCOCC1)NO
Reaction time: 1 h
Yield: 39.2 %

Procedure:
To a solution of (3R)-3-(cyclopentylmethyl)-4-[(5S)-5-(4-morpholinylcarbonyl)-4,5-dihydro-1H-pyrazol-1-yl]-4-oxo-N-[(phenylmethyl)oxy]butanamide (57 mg, 0.12 mmol) in methanol (5 mL) was added Pearlman's catalyst (17 mg, 0.024 mmol). The mixture then was stirred under 1 atm of H2 for 1 hour. After 1 hour, the mixture was filtered, concentrated, and purified by Gilson HPLC (Sunfire Column 19×50 mm, flowrate 25 mL/min, 10 min, 5-65% MeCN:H2O) to afford (3R)-3-(cyclopentylmethyl)-N-hydroxy-4-[(5S)-5-(4-morpholinylcarbonyl)-4,5-dihydro-1H-pyrazol-1-yl]-4-oxobutanamide (19 mg, 0.047 mmol, 39% yield) as a white solid. MS: 381 ([M+H]+). 1H NMR (400 MHz, METHANOL-d4) δ ppm 1.07-1.29 (m, 2H) 1.36-1.48 (m, 1H) 1.50-1.69 (m, 4H) 1.72-2.03 (m, 5H) 2.19-2.30 (m, 1H) 2.36-2.53 (m, 1H) 2.77-3.01 (m, 2H) 3.46-3.98 (m, 10H) 5.15-5.29 (m, 1H) 7.03-7.07 (m, 1H).
Reaction SMILES: [SH:1][C:2]1[CH:3]=[C:4]([OH:9])[CH:5]=[C:6]([OH:8])[CH:7]=1.CN(C=O)C.Cl[CH2:16][C:17](=[O:23])[CH2:18][C:19]([O:21][CH3:22])=[O:20]>O>[OH:9][C:4]1[CH:3]=[C:2]([S:1][CH2:16][C:17](=[O:23])[CH2:18][C:19]([O:21][CH3:22])=[O:20])[CH:7]=[C:6]([OH:8])[CH:5]=1
Reactant: COC(=O)CC(=O)CCl
Reactant: Oc1cc(O)cc(S)c1
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)CC(=O)CSc1cc(O)cc(O)c1
Temperature: 70 °C
Reaction time: 4 h

Procedure:
To a mixture of 5-sulfanylbenzene-1,3-diol (12.2 g) and DMF (dry) (100 mL) was added methyl 4-chloroacetoacetate (10.0 mL) at room temperature, and the mixture was stirred at 70° C. for 4 h. The mixture was poured into water at room temperature and extracted with EtOAc. The organic layer was separated, washed successively with 1N HCl and brine, dried over MgSO4 and concentrated in vacuo. The residue was purified by silica gel column chromatography (EtOAc/hexane) to give the title compound (15.1 g).
Reaction SMILES: Cl.Cl[CH2:3][C:4]1[C:5]([NH2:11])=[N:6][C:7]([CH3:10])=[N:8][CH:9]=1.C(=O)([O-])[O-].[K+].[K+].Cl.Cl.[C:20]1([CH3:32])[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[N:26]1[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1>CN(C)C=O>[CH3:10][C:7]1[N:6]=[C:5]([NH2:11])[C:4]([CH2:3][N:29]2[CH2:30][CH2:31][N:26]([C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=3[CH3:32])[CH2:27][CH2:28]2)=[CH:9][N:8]=1
Reactant: Cc1ccccc1N1CCNCC1
Reactant: Cc1ncc(CCl)c(N)n1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1ncc(CN2CCN(c3ccccc3C)CC2)c(N)n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 21 %

Procedure:
A suspension of 7.7 g (0.040 mol) of 5-chloromethyl-2-methyl-pyrimidin-4-ylamine hydrochloride in 6 ml of dimethyl-formamide was treated with 15 g (0.11 mol) of dry potassium carbonate. At the same time a suspension of 10 g (0.040 mol) of 1-o-tolyl-piperazine dihydrochloride was treated with 15 g (0.11 mol) of dry potassium carbonate in 60 ml of dimethylformamide. After stirring at room temperature for 1/2 hr both solutions were combined and stirred for a further 4 hours. The reaction mixture was suction filtered, the residue was chromatographed over silica gel with dichloromethane/ethyl acetate 1:1 as the eluent and recrystallized from ethanol/ethyl acetate. 2.5 g of 2-methyl-5-(4-o-tolyl-piperazin-1-ylmethyl)-pyrimidin-4-ylamine were obtained as beige crystals; m.p. 189°-190°.
Reaction SMILES: [OH:1][N:2]=[C:3](Cl)[C:4]1[CH:9]=[N:8][CH:7]=[CH:6][N:5]=1.[C:11]([C:13]1[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=1)#[CH:12].N>>[F:19][C:16]1[CH:17]=[CH:18][C:13]([C:11]2[O:1][N:2]=[C:3]([C:4]3[CH:9]=[N:8][CH:7]=[CH:6][N:5]=3)[CH:12]=2)=[CH:14][CH:15]=1
Reactant: C#Cc1ccc(F)cc1
Reactant: ON=C(Cl)c1cnccn1
Agent: N
Product: Fc1ccc(-c2cc(-c3cnccn3)no2)cc1

Procedure:
The titled compound was prepared according to Method CB using the product of Example 83D (79 mg, 0.5 mmol) and 1-ethynyl-4-fluorobenzene (Aldrich, 60 mg, 0.5 mmol). 1H NMR (300 MHz, MeOH-d4) δ 5.70-5.81 (m, 2H), 5.85 (s, 1 H), 6.35-6.55 (m, 2H), 7.15 (d, J=2.4 Hz, 1H), 7.19-7.26 (m, 1H), 7.75 (d, J=1.6 Hz, 1H) ppm; MS (DCI/NH3) m/z 242 (M+H)+.
Reaction SMILES: Cl[C:2]1([C:14]2[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=2)[C:7](=[O:8])[N:6]([CH3:9])[C:5]2[CH:10]=[CH:11][CH:12]=[CH:13][C:4]=2[S:3]1.C(OCC)(=[O:23])C>O1CCCC1.O>[OH:23][C:2]1([C:14]2[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=2)[C:7](=[O:8])[N:6]([CH3:9])[C:5]2[CH:10]=[CH:11][CH:12]=[CH:13][C:4]=2[S:3]1
Reactant: CCOC(C)=O
Reactant: CN1C(=O)C(Cl)(c2ccc(O)cc2)Sc2ccccc21
Solvent: C1CCOC1
Solvent: O
Product: CN1C(=O)C(O)(c2ccc(O)cc2)Sc2ccccc21
Reaction time: 8 h

Procedure:
2-Chloro-3,4-dihydro-2-(4-hydroxyphenyl)-4-methyl-3-oxo-2H-1,4-benzothiazine (0.1 g, compound No. 2) is dissolved in a mixture of tetrahydrofuran (2 ml) and water (1 ml), and the solution is standed overnight at room temperature. The mixture is poured into a mixture of ethyl acetate and water. The organic layer is dried over anhydrous sodium sulfate, and concentrated in vacuo to give 0.1 g (quant. yield) of the titled compound as amorphous powder.
Reaction SMILES: [CH2:1]([O:4][C:5]([N:7]1[CH2:11][C@H:10](O)[CH2:9][C@H:8]1[CH2:13][CH2:14][N:15]1[CH:19]=[N:18][CH:17]=[N:16]1)=[O:6])[CH:2]=[CH2:3].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O.[C:51]([OH:59])(=[S:58])[C:52]1[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=1>O1CCCC1>[CH2:1]([O:4][C:5]([N:7]1[CH2:11][C@@H:10]([S:58][C:51](=[O:59])[C:52]2[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=2)[CH2:9][C@H:8]1[CH2:13][CH2:14][N:15]1[CH:19]=[N:18][CH:17]=[N:16]1)=[O:6])[CH:2]=[CH2:3]
Reactant: OC(=S)c1ccccc1
Reactant: C=CCOC(=O)N1C[C@H](O)C[C@H]1CCn1cncn1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: C=CCOC(=O)N1C[C@@H](SC(=O)c2ccccc2)C[C@H]1CCn1cncn1

Procedure:
(2R,4R)-1-Allyloxycarbonyl-4-hydroxy-2-[2-(1,2, 4-triazol-1-yl)ethyl]pyrrolidine (5.82 g) was reacted with triphenylphosphine (8.62 g), diethyl azodicarboxylate (5.17 ml) and thiobenzoic acid (4.64 ml) in tetrahydrofuran (58 ml) in the same manner as Preparation 3-6) to give (2R,4S)-1-allyloxycarbonyl-4-benzoylthio-2-[2-(1,2, 4-triazol-1-yl)ethyl]pyrrolidine (7.92 g) as a yellow paste.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[N+:10]([O-])=O)[CH2:5][OH:6]>C(O)C.[Pd]>[OH:6][CH2:5][C:4]1[CH:7]=[CH:8][C:9]([NH2:10])=[C:2]([CH3:1])[CH:3]=1
Reactant: Cc1cc(CO)ccc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CCO
Product: Cc1cc(CO)ccc1N
Yield: 98.8 %

Procedure:
A solution of 3-methyl-4-nitrobenzyl alcohol (compound 12-1, 8.5 g, 50.9 mmol) in ethanol (100 mL) was stirred at room temperature, while 10% Pd/C (1.0 g) was added in one portion. The resulting suspension was hydrogenated (10 psi) in a Parr apparatus at room temperature for 1.5 hours. The catalyst was removed by filtration, and solvent was evaporated under vacuum to give the title compound (12-2, 6.9 g, 99%). MS (electrospray) 138 (M+1); 1H N MR (CDCl3) δ 2.16 (s, 3H), 2.72 (br s, 3H), 4.52 (s, 2H), 6.64 (d, 1H, J=8.0 Hz), 7.02 (d, 1H, J=8.0 Hz), 7.05 (s, 1H).
Reaction SMILES: [CH3:1][N:2]1[N:6]=[N:5][C:4]([C:7]2[S:11][C:10]([NH2:12])=[N:9][C:8]=2[C:13]2[S:14][CH:15]=[CH:16][CH:17]=2)=[N:3]1.[CH3:18][O:19][C:20]1[CH:21]=[C:22]([CH2:28][C:29](Cl)=[O:30])[CH:23]=[CH:24][C:25]=1[O:26][CH3:27]>>[CH3:18][O:19][C:20]1[CH:21]=[C:22]([CH2:28][C:29]([NH:12][C:10]2[S:11][C:7]([C:4]3[N:5]=[N:6][N:2]([CH3:1])[N:3]=3)=[C:8]([C:13]3[S:14][CH:15]=[CH:16][CH:17]=3)[N:9]=2)=[O:30])[CH:23]=[CH:24][C:25]=1[O:26][CH3:27]
Reactant: COc1ccc(CC(=O)Cl)cc1OC
Reactant: Cn1nnc(-c2sc(N)nc2-c2cccs2)n1
Product: COc1ccc(CC(=O)Nc2nc(-c3cccs3)c(-c3nnn(C)n3)s2)cc1OC

Procedure:
Prepared from 5-(2-methyl-2H-tetrazol-5-yl)-4-thiophen-2-yl-thiazol-2-ylamine and (3,4-dimethoxy-phenyl)-acetyl chloride.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[C:8]([C:10]2[CH2:14][C:13]([C:19]3[CH:24]=[C:23]([Cl:25])[CH:22]=[C:21]([Cl:26])[CH:20]=3)([C:15]([F:18])([F:17])[F:16])[O:12][N:11]=2)[CH:7]=[CH:6][C:3]=1[CH:4]=O.Cl.[NH2:28][OH:29].Cl>CO>[Cl:1][C:2]1[CH:9]=[C:8]([C:10]2[CH2:14][C:13]([C:19]3[CH:24]=[C:23]([Cl:25])[CH:22]=[C:21]([Cl:26])[CH:20]=3)([C:15]([F:18])([F:17])[F:16])[O:12][N:11]=2)[CH:7]=[CH:6][C:3]=1[CH:4]=[N:28][OH:29]
Reactant: NO
Reactant: O=Cc1ccc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)cc1Cl
Agent: Cl
Solvent: CO
Product: ON=Cc1ccc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)cc1Cl
Temperature: 70 °C
Reaction time: 3 h
Yield: 97 %

Procedure:
To a solution of 2-chloro-4-[5-(3,5-dichloro-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]-benzaldehyde (i.e. the product of Step 2, 1.20 g) in methanol (5 mL) was added hydroxylamine hydrochloride (296 mg) and a catalytic amount of concentrated hydrochloric acid. The mixture was stirred at 70° C. for 3 h and concentrated in vacuum. Water was added and the mixture was extracted with ethyl acetate. Combined organic layers were dried (Na2SO4) and evaporated to obtain the title compound (1.2 g, 97%).
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4](=O)[C:5]2[S:10][CH:9]=[CH:8][C:6]=2[N:7]=1.O=P(Cl)(Cl)[Cl:14]>>[Cl:14][C:4]1[C:5]2[S:10][CH:9]=[CH:8][C:6]=2[N:7]=[C:2]([CH3:1])[N:3]=1
Reactant: Cc1nc2ccsc2c(=O)[nH]1
Reactant: O=P(Cl)(Cl)Cl
Product: Cc1nc(Cl)c2sccc2n1
Yield: 88 %

Procedure:
2-Methylthieno[3,2-d]pyrimidin-4(3H)-one (compound 32b, 0.18 g, 1.13 mmol) was heated to 110° C. in POCl3 overnight. The solvent was removed under reduced pressure, and the residue was neutralized with saturated NaHCO3 solution. The product was extracted into CH2Cl2, and the organic phase separated, washed with brine, and dried (MgSO4). After removal of the solvent compound 32c was obtained as a yellow-orange solid (0.21 g, 88%). Compound 32c was used without further purification. Rf=0.16 (10% EtOAc/hexane). 1H NMR (400 MHz, DMSO-d6): δ 2.71 (s, 3H), 7.66 (d, J=5.6 Hz, 1H), 8.54 (d, J=5.6 Hz, 1H). LCMS 185 (M+H). Anal. (C23H29N8OF.0.35H2O.0.35 hexane) C, H, N. HPLC>98% purity.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([N:8]2[C:12](=[O:13])[CH2:11][CH:10]([C:14]([NH:16][CH:17]([C:24]3[CH:25]=[N:26][CH:27]=[CH:28][CH:29]=3)[CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20])=[O:15])[CH2:9]2)[CH:5]=[CH:6][CH:7]=1.C([O-])(O)=O.[Na+].Br[CH2:36][C:37]([NH:39][C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1)=[O:38]>C(Cl)Cl>[O:13]=[C:12]1[N:8]([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([NH:1][CH2:36][C:37](=[O:38])[NH:39][C:40]3[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=3)[CH:3]=2)[CH2:9][CH:10]([C:14]([NH:16][CH:17]([C:24]2[CH:25]=[N:26][CH:27]=[CH:28][CH:29]=2)[CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20])=[O:15])[CH2:11]1
Reactant: O=C(CBr)Nc1ccccc1
Reactant: CCOC(=O)CC(NC(=O)C1CC(=O)N(c2cccc(N)c2)C1)c1cccnc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CCOC(=O)CC(NC(=O)C1CC(=O)N(c2cccc(NCC(=O)Nc3ccccc3)c2)C1)c1cccnc1
Temperature: 25 °C

Procedure:
To a suspension of ethyl 3-{(1-(3-aminophenyl)-5-oxopyrrolidin-3-yl)carbonylamino}-3-(3-pyridyl)propanoate (100 mg, 0.25 mmol, 1.1 eq), NaHCO3 (20 mg, 0.23 mmol, 1.0 eq), and CH2Cl2 (4 mL), was added 2-bromo-N-phenyl acetamide (50 mg, 0.23 mmol, 1.0 eq) in 2 mL CH2Cl2 dropwise. The reaction mixture was heated up to reflux for 5 hours, then cooled to room temperature.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][C:11]([NH:13][NH2:14])=[O:12])=[CH:6][CH:5]=1)([O-:3])=[O:2].[C:15](OC)(OC)(OC)[CH2:16][CH2:17][CH3:18].CS(O)(=O)=O.O1CCCC1>O>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([CH2:10][C:11]2[O:12][C:15]([CH2:16][CH2:17][CH3:18])=[N:14][N:13]=2)=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: NNC(=O)Cc1ccc([N+](=O)[O-])cc1
Reactant: CCCC(OC)(OC)OC
Agent: CS(=O)(=O)O
Solvent: C1CCOC1
Solvent: O
Product: CCCc1nnc(Cc2ccc([N+](=O)[O-])cc2)o1

Procedure:
A mixture of 2-(4-nitrophenyl)acetohydrazide (7.0 g), trimethyl orthobutyrate (16.01 g), methanesulfonic acid (0.69 g) and tetrahydrofuran (200 mL) was heated under reflux for 2 hrs. Water was poured into the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed successively with saturated aqueous sodium hydrogen carbonate and saturated brine, dried over anhydrous magnesium sulfate and concentrated. The residue was subjected to silica gel column chromatography, and 2-(4-nitrobenzyl)-5-propyl-1,3,4-oxadiazole was obtained as a colorless oil (7.73 g, yield 87%) from a fraction eluted with hexane-ethyl acetate (3:2-1:2, v/v).
Reaction SMILES: [Cl:1][C:2]1[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[C:3]=1[CH2:4][O:5][C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[N:11]([CH2:15][CH2:16][CH2:17][C:18]#[N:19])[CH:10]=[C:9]2[C:20](=[O:23])[CH2:21][CH3:22].[N:29]([Si](C)(C)C)=[N+:30]=[N-:31].C([Sn](=O)CCCC)CCC>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[C:3]=1[CH2:4][O:5][C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[N:11]([CH2:15][CH2:16][CH2:17][C:18]1[NH:31][N:30]=[N:29][N:19]=1)[CH:10]=[C:9]2[C:20](=[O:23])[CH2:21][CH3:22]
Reactant: C[Si](C)(C)N=[N+]=[N-]
Reactant: CCC(=O)c1cn(CCCC#N)c2ccc(OCc3c(Cl)cccc3Cl)cc12
Agent: CCCC[Sn](=O)CCCC
Solvent: Cc1ccccc1
Product: CCC(=O)c1cn(CCCc2nnn[nH]2)c2ccc(OCc3c(Cl)cccc3Cl)cc12
Yield: 46.4 %

Procedure:
To a solution of 4-[5-(2,6-dichlorobenzyloxy)-3-propionyl-indol-1-yl]butyronitrile (0.034 g, 0.08 mmol) in toluene (3 mL) was added azidotrimethylsilane (0.033 mL, 0.25 mmol) and dibutyltin oxide (0.006 g, 0.02 mmol). The reaction was refluxed for 16 h. The solvent was removed under reduced pressure and the crude product was purified by HPLC to yield a white solid (0.017 g, 46%). MS(ES) m/e 458.0 [M+H]+.
Reaction SMILES: Cl.Cl.[F:3][C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)=[CH:6][CH:5]=1.[CH3:16][S:17](Cl)(=[O:19])=[O:18].O>C(Cl)Cl>[F:3][C:4]1[CH:5]=[CH:6][C:7]([N:10]2[CH2:15][CH2:14][N:13]([S:17]([CH3:16])(=[O:19])=[O:18])[CH2:12][CH2:11]2)=[CH:8][CH:9]=1
Reactant: Fc1ccc(N2CCNCC2)cc1
Reactant: CS(=O)(=O)Cl
Agent: Cl
Solvent: ClCCl
Solvent: O
Product: CS(=O)(=O)N1CCN(c2ccc(F)cc2)CC1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 76.7 %

Procedure:
To a suspension of 1-(4-fluorophenyl)piperazine dihydrochloride (2.53 g; 10.0 mmol; 1.0 eq.) in anhydrous DCM (50 mL) was added TEA (3.33 g; 33.0 mmol; 3.3 eq.) and the resulting mixture was chilled at 0° C. A 1N solution of methanesulfonyl chloride (1.26 g; 11.0 mmol; 1.1 eq.) in DCM (11 mL) was added dropwise. After 20 min at 0° C., the reaction mixture was stirred at rt for 3 h. Water was added and the mixture extracted with DCM. The combined organic layers were washed with an aqueous saturated solution of NaHCO3, water, brine then dried over MgSO4, filtered and evaporated to give a white powder. Crystallization from EtOAc gave a white solid (1.98 g, 76% yield). HPLC, Rt: 2.3 min (purity: 100%). 1H NMR (CDCl3) δ: 7.08-6.83 (m, 4H), 3.41 (m, 4H), 3.22 (m, 4H), 2.85 (s, 3H).
Reaction SMILES: C[O:2][C:3]([C:5]1[N:6]([CH2:31][CH:32]=O)[CH:7]=[C:8]([C:20](=[O:30])[NH:21][CH2:22][C:23]2[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=2)[C:9](=[O:19])[C:10]=1[O:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=O.[NH2:34][C@H:35]([CH3:43])[CH2:36][CH2:37][NH:38][CH2:39][CH:40]([CH3:42])[CH3:41].C(O)(=O)C>ClCCl>[F:29][C:26]1[CH:25]=[CH:24][C:23]([CH2:22][NH:21][C:20]([C:8]2[C:9](=[O:19])[C:10]([O:11][CH2:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)=[C:5]3[C:3](=[O:2])[N:34]4[C@H:35]([CH3:43])[CH2:36][CH2:37][N:38]([CH2:39][CH:40]([CH3:42])[CH3:41])[C@H:32]4[CH2:31][N:6]3[CH:7]=2)=[O:30])=[CH:28][CH:27]=1
Reactant: CC(C)CNCC[C@@H](C)N
Reactant: COC(=O)c1c(OCc2ccccc2)c(=O)c(C(=O)NCc2ccc(F)cc2)cn1CC=O
Solvent: CC(=O)O
Solvent: ClCCl
Product: CC(C)CN1CC[C@@H](C)N2C(=O)c3c(OCc4ccccc4)c(=O)c(C(=O)NCc4ccc(F)cc4)cn3C[C@H]12
Yield: 58.9 %

Procedure:
The title compound was made in two steps using a similar process to that described in example Z-2. 16 (40 mg, 0.09 mmol) and [(3R)-3-aminobutyl](2-methylpropyl)amine (65 mg, 0.45 mmol) were reacted in dichloromethane (2 mL) with acetic acid to give (4R,12aR)—N-[(4-fluorophenyl)methyl]-4-methyl-1-(2-methylpropyl)-6,8-dioxo-7-[(phenylmethyl)oxy]-1,2,3,4,6,8,12,12a-octahydropyrido[1′,2′:4,5]pyrazino[1,2-a]pyrimidine-9-carboxamide (29 mg, 60%). This material was hydrogenated in a second step as described in example Z-2 to give (4R,12aR)—N-[(4-fluorophenyl)methyl]-7-hydroxy-4-methyl-1-(2-methylpropyl)-6,8-dioxo-1,2,3,4,6,8,12,12a-octahydropyrido[1′,2′:4,5]pyrazino[1,2-a]pyrimidine-9-carboxamide (18 mg, 75%) as a tan solid. 1H NMR (400 MHz, CDCl3) δ 0.77 (d, J=6.4 Hz, 3H), 0.84 (d, J=6.4 Hz, 3H), 1.32 (d, J=7.2 Hz), 1.45-1.49 (m, 1H), 1.57-1.67 (m, 1H), 2.03-2.12 (m, 2H), 2.21-2.27 (m, 1H), 2.73-2.79 (m, 1H), 2.87-2.92 (m, 1H), 4.16-4.24 (m, 2H), 4.45 (s, 1H), 4.54-4.64 (m, 2H), 4.96-4.99 (m, 1H), 6.96-7.00 (m, 2H), 7.29-7.32 (m, 2H), 8.27 (s, 1H), 10.46 (s, 1H), 12.55 (s, 1H); ES+ MS: 456 (M+1).
Reaction SMILES: [H-].[Na+].[N+:3]([C:6]1[C:11]([CH3:12])=[CH:10][C:9]([SH:13])=[C:8]([CH3:14])[CH:7]=1)([O-:5])=[O:4].Br[C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([O:22][CH:23]([F:25])[F:24])[CH:17]=1>CN(C)C=O.Cl[Cu]>[N+:3]([C:6]1[CH:7]=[C:8]([CH3:14])[C:9]([S:13][C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([O:22][CH:23]([F:25])[F:24])[CH:17]=2)=[CH:10][C:11]=1[CH3:12])([O-:5])=[O:4]
Reactant: FC(F)Oc1cccc(Br)c1
Reactant: Cc1cc([N+](=O)[O-])c(C)cc1S
Agent: Cl[Cu]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1cc([N+](=O)[O-])c(C)cc1Sc1cccc(OC(F)F)c1
Reaction time: 1 h

Procedure:
4.36 g (0.109 moles) of sodium hydride are suspended in 80 ml of N,N-dimethylformamide at 0° C. 20 g of 4-nitro-2,5-dimethylthiophenol (0.109 moles) dissolved in 67 ml of N,N-dimethylformamide are added dropwise under stirring. 24.4 g of 1-bromo-3-(difluoromethoxy)benzene (0.109 moles) dissolved in 20 ml of N,N-dimethylformamide are then added dropwise; catalytic Cu° and CuCl are subsequently added and the reaction temperature is brought to 150° C. for 1 h.
Reaction SMILES: P(Cl)(Cl)([Cl:3])=O.[Cl:6][C:7]1[C:12](=O)[NH:11][C:10]([CH:14]2[CH2:16][CH2:15]2)=[N:9][C:8]=1[C:17]([OH:19])=[O:18].O>C(O)(C)(C)C>[Cl:6][C:7]1[C:8]([C:17]([OH:19])=[O:18])=[N:9][C:10]([CH:14]2[CH2:16][CH2:15]2)=[N:11][C:12]=1[Cl:3]
Reactant: O=P(Cl)(Cl)Cl
Reactant: O=C(O)c1nc(C2CC2)[nH]c(=O)c1Cl
Solvent: O
Solvent: CC(C)(C)O
Product: O=C(O)c1nc(C2CC2)nc(Cl)c1Cl
Temperature: 90 °C
Reaction time: 1 h
Yield: 84.7 %

Procedure:
Phosphorus oxychloride (363 g, 221 mL, 2.37 mol) and 5-chloro-2-cyclopropyl-1,6-dihydro-6-oxo-4-pyrimidinecarboxylic acid (169 g, 0.79 mol) were added to a 1-L flask and heated at 90° C. for 5 h. The reaction mixture was cooled to 30° C. and added over 60 minutes into a 2-L jacketed reactor containing a well-stirred mixture of t-butanol (280 mL) and water (750 mL) while maintaining the temperature at 5-10° C. After the addition of the reaction mixture was about 70% complete, the aqueous t-butanol mixture was seeded to initiate crystallization, and the addition of the reaction mixture was continued. At the end of the addition, water (750 mL) was added gradually at 10-15° C., and the mixture was stirred for an additional 1 h. The resulting mixture was cooled to 5° C., filtered, and the collected solid was washed with water (3×50 mL). The resulting wet cake was dried in a vacuum-oven at 60° C. to give 156 g (85% yield) of the title compound as a solid melting at 126-127° C.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[NH:12][C:13]([C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=3)([CH3:24])[C:14]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)([CH3:16])[N:15]=2)=[C:7]([O:32][CH2:33][CH3:34])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[C:35]([C:37]1[CH:45]=[CH:44][C:40]([C:41](Cl)=[O:42])=[CH:39][CH:38]=1)#[N:36]>>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:15]([C:41]([C:40]3[CH:44]=[CH:45][C:37]([C:35]#[N:36])=[CH:38][CH:39]=3)=[O:42])[C@@:14]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)([CH3:16])[C@@:13]([C:25]3[CH:26]=[CH:27][C:28]([Cl:31])=[CH:29][CH:30]=3)([CH3:24])[N:12]=2)=[C:7]([O:32][CH2:33][CH3:34])[CH:6]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: N#Cc1ccc(C(=O)Cl)cc1
Reactant: CCOc1cc(C(C)(C)C)ccc1C1=NC(C)(c2ccc(Cl)cc2)C(C)(c2ccc(Cl)cc2)N1
Product: CCOc1cc(C(C)(C)C)ccc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)c1ccc(C#N)cc1

Procedure:
In a manner analogous to the method described in example 5, rac-(4S*,5R*)-2-(4-tert-butyl-2-ethoxy-phenyl)-4,5-bis-(4-chloro-phenyl)-4,5-dimethyl-4,5-dihydro-1H-imidazole was reacted with 4-cyano-benzoyl chloride (Aldrich) to give the title compound. HR-MS (ES, m/z) calculated for C37H36N3O2Cl2 [(M+H)+] 624.2179, observed 624.2177.
Reaction SMILES: [CH:1]([NH2:3])=O.C(O)(=O)C.[NH2:8][C:9]1[CH:17]=[C:16]([F:18])[C:15]([F:19])=[CH:14][C:10]=1[C:11](O)=[O:12]>O>[F:19][C:15]1[CH:14]=[C:10]2[C:9](=[CH:17][C:16]=1[F:18])[N:8]=[CH:1][N:3]=[C:11]2[OH:12]
Reactant: NC=O
Reactant: Nc1cc(F)c(F)cc1C(=O)O
Solvent: O
Solvent: CC(=O)O
Product: Oc1ncnc2cc(F)c(F)cc12
Temperature: 125 °C
Reaction time: 8 h
Yield: 84 %

Procedure:
To a stirring mixture of formamide (10 mL) and glacial acetic acid (2.5 mL) was added 2-amino-4,5-difluorobenzoic acid (2.0 g, 11.6 mmol) and the solution stirred at 125° C. for 8 hours. After cooling to room temperature, the reaction was diluted with H2O (100 mL) and the resulting solid filtered and dried under vacuum to give 6,7-difluoro-4-hydroxyquinazoline (1.77 g, 9.7 mmol, 84%). 1H NMR (300 MHz, DMSO-d6) δ 12.49 (br s, 1H), 8.15 (s, 1H), 8.04 (dd, 1H), 7.76 (dd, 1H); LC-MS (ESI) m/z 183 (M+H)+.