Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[C:3]2[C:8]([CH:9]=[C:10]([O:14][CH3:15])[C:11]=1[O:12][CH3:13])=[N:7][C:6](=[O:16])[C:5](=[O:17])[N:4]=2.C(N(CC)CC)C.[C:25]1([CH2:31][C:32](Cl)=[O:33])[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>C(Cl)Cl>[C:25]1([CH2:31][C:32]([O:1][C:2]2[C:3]3[C:8]([CH:9]=[C:10]([O:14][CH3:15])[C:11]=2[O:12][CH3:13])=[N:7][C:6](=[O:16])[C:5](=[O:17])[N:4]=3)=[O:33])[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: O=C(Cl)Cc1ccccc1
Reactant: COc1cc2c(c(O)c1OC)=NC(=O)C(=O)N=2
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1cc2c(c(OC(=O)Cc3ccccc3)c1OC)=NC(=O)C(=O)N=2
Temperature: 25 °C
Reaction time: 12 h
Yield: 77 %

Procedure:
To a suspension of 5-hydroxy-6,7-dimethoxy-2,3-quinoxalinedione (48) (50 mg, 0.22 mmol) in 3 mL of methylene dichloride was added 0.14 mL of triethylamine and phenylacetyl chloride (77.5 mg, 0.5 mmol, Aldrich) at 0° C. The resulting mixture was stirred at room temperature for 12 hr. The reaction mixture was then poured into ice-water (5 g). A white solid precipitated and was collected by suction filtration, washed with water (3×5 mL) and ethyl acetate (3×2 mL), and dried in vacuo, giving 60 mg (77%) of the product as a white solid; mp 298°-300° C.; 1H NMR (DMSO-d6, 300 MHz) δ3.405 (s, 3H), 3.728 (s, 3H), 4.024 (s, 2H), 6.653 (s, 1H), 7.359 (m, 5H), 11.773 (s, 1H), 11.846 (s, 1H). EIMS m/e 356 (25, M+), 238 (100). (HPLC 100%).
Reaction SMILES: [F:1][C:2]([F:22])([F:21])[S:3]([O:6][C:7]1[C:15]2[N:11]([CH:12]=[CH:13][CH:14]=2)[C:10]([C:16](OCC)=[O:17])=[CH:9][CH:8]=1)(=[O:5])=[O:4].[BH4-].[Na+].O>CO>[F:22][C:2]([F:1])([F:21])[S:3]([O:6][C:7]1[C:15]2[N:11]([CH:12]=[CH:13][CH:14]=2)[C:10]([CH2:16][OH:17])=[CH:9][CH:8]=1)(=[O:4])=[O:5]
Reactant: CCOC(=O)c1ccc(OS(=O)(=O)C(F)(F)F)c2cccn12
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: O=S(=O)(Oc1ccc(CO)n2cccc12)C(F)(F)F
Temperature: 25 °C
Reaction time: 8 h
Yield: 190.3 %

Procedure:
To a solution of ethyl 8-(((trifluoromethyl)sulfonyl)oxy)indolizine-5-carboxylate (30 g, 89 mmol) in MeOH (300 mL) was added NaBH4 (13.5 g, 0.356 mol) at 0° C. under N2. The reaction mixture was stirred at rt overnight. After the completion, to the reaction was added water, extracted with EtOAc, washed with brine, dried and concentrated to give the desired product 5-(hydroxymethyl)indolizin-8-yl trifluoromethanesulfonate (50 g, crude).
Reaction SMILES: ClC1C=CC2SC=C(CN3CCN(C4SC(C(O)=O)=C(C)N=4)C3=O)C=2C=1.[F:27][C:28]1[CH:49]=[CH:48][C:31]([CH2:32][N:33]2[CH2:37][CH2:36][N:35]([C:38]3[S:39][C:40]([C:44]([OH:46])=O)=[C:41]([CH3:43])[N:42]=3)[C:34]2=[O:47])=[CH:30][CH:29]=1.[N:50]1[CH:55]=[CH:54][C:53]([CH2:56][NH2:57])=[CH:52][CH:51]=1>>[F:27][C:28]1[CH:49]=[CH:48][C:31]([CH2:32][N:33]2[CH2:37][CH2:36][N:35]([C:38]3[S:39][C:40]([C:44]([NH:57][CH2:56][C:53]4[CH:54]=[CH:55][N:50]=[CH:51][CH:52]=4)=[O:46])=[C:41]([CH3:43])[N:42]=3)[C:34]2=[O:47])=[CH:30][CH:29]=1
Reactant: Cc1nc(N2CCN(Cc3ccc(F)cc3)C2=O)sc1C(=O)O
Reactant: NCc1ccncc1
Agent: Cc1nc(N2CCN(Cc3csc4ccc(Cl)cc34)C2=O)sc1C(=O)O
Product: Cc1nc(N2CCN(Cc3ccc(F)cc3)C2=O)sc1C(=O)NCc1ccncc1
Yield: 60 %

Procedure:
Following the procedure as described in Example 32, making variations as required to replace 2-(3-((5-chlorobenzo[b]thiophen-3-yl)methyl)-2-oxoimidazolidin-1-yl)-4-methylthiazole-5-carboxylic acid with 2-(3-(4-fluorobenzyl)-2-oxoimidazolidin-1-yl)-4-methylthiazole-5-carboxylic acid to react with pyridin-4-ylmethanamine, the title compound was obtained as a colorless solid in 60% yield: mp 146-149° C.; 1H NMR (300 MHz, CDCl3) δ 8.51 (d, J=6.0 Hz, 2H), 7.29-7.24 (m, 4H), 7.07-7.01 (m, 2H), 6.21 (br s, 1H), 4.59 (d, J=6.0 Hz, 2H), 4.45 (s, 2H), 4.08 (t, J=9.0 Hz, 2H), 3.46 (t, J=9.0 Hz, 2H), 2.61 (s, 3H); MS (ES+) m/z 426.3 (M+1).
Reaction SMILES: Br[C:2]1[C:3]([O:21][CH3:22])=[CH:4][C:5]([Cl:20])=[C:6]([CH:19]=1)[CH2:7][O:8][Si](C(C)C)(C(C)C)C(C)C.[CH2:23]([O:30][C@@H:31]1[C@@H:37]([O:38][CH2:39][C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)[C@H:36]([O:46][CH2:47][C:48]2[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=2)[C@@H:35]([CH2:54][O:55][CH2:56][C:57]2[CH:62]=[CH:61][CH:60]=[CH:59][CH:58]=2)[O:34][CH:32]1O)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>>[Cl:20][C:5]1[CH:4]=[C:3]([O:21][CH3:22])[C:2]([CH:32]2[C@H:31]([O:30][CH2:23][C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=3)[C@@H:37]([O:38][CH2:39][C:40]3[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=3)[C@H:36]([O:46][CH2:47][C:48]3[CH:49]=[CH:50][CH:51]=[CH:52][CH:53]=3)[C@@H:35]([CH2:54][O:55][CH2:56][C:57]3[CH:58]=[CH:59][CH:60]=[CH:61][CH:62]=3)[O:34]2)=[CH:19][C:6]=1[CH2:7][OH:8]
Reactant: OC1O[C@H](COCc2ccccc2)[C@@H](OCc2ccccc2)[C@H](OCc2ccccc2)[C@H]1OCc1ccccc1
Reactant: COc1cc(Cl)c(CO[Si](C(C)C)(C(C)C)C(C)C)cc1Br
Product: COc1cc(Cl)c(CO)cc1C1O[C@H](COCc2ccccc2)[C@@H](OCc2ccccc2)[C@H](OCc2ccccc2)[C@H]1OCc1ccccc1

Procedure:
With similar method described in Step 3 of Example 92, (5-bromo-2-chloro-4-methoxybenzyloxy)triisopropylsilane (compound 89, 27.2 g, 66.7 mmol) and 2,3,4,6-tetra-O-benzyl-D-glucopyranose (compound 2, 30.0 g, 55.6 mmol) were converted to title compound (22.6 g, 59%, ca. 8:1 mixture of anomers (13:0) as a white solid.
Reaction SMILES: [CH3:1][N:2]1[C:7]2[CH:8]=[CH:9][C:10]([C:12](=O)[CH:13]([CH3:19])[CH2:14][C:15](OC)=[O:16])=[CH:11][C:6]=2[O:5][CH2:4][C:3]1=[O:21].[NH2:22][NH2:23]>>[CH3:1][N:2]1[C:7]2[CH:8]=[CH:9][C:10]([C:12]3[CH:13]([CH3:19])[CH2:14][C:15](=[O:16])[NH:22][N:23]=3)=[CH:11][C:6]=2[O:5][CH2:4][C:3]1=[O:21]
Reactant: COC(=O)CC(C)C(=O)c1ccc2c(c1)OCC(=O)N2C
Reactant: NN
Product: CC1CC(=O)NN=C1c1ccc2c(c1)OCC(=O)N2C

Procedure:
Methyl 4-(3,4-dihydro-4-methyl-3-oxo-1,4(2H)-benzoxazin-7-yl)-4-oxo-3-methylbutyrate was treated with hydrazine as in example 1 to give the title compound, mp 188°-190° C.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.Cl[C:8]1[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][N:9]=1.[OH-].[Na+]>>[Cl:14][C:11]1[CH:12]=[CH:13][C:8]([N:1]2[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]2)=[N:9][CH:10]=1
Reactant: Clc1ccc(Cl)nc1
Reactant: C1CNCCN1
Agent: [Na+]
Agent: [OH-]
Product: Clc1ccc(N2CCNCC2)nc1
Temperature: 145 °C
Reaction time: 1 h
Yield: 73.4 %

Procedure:
To piperazine (29.0 g) dissolved at 115° C. was added 2,5-dichloropyridine (5.1 g) and the mixture was stirred at 140-150° C. for 1 hr. The reaction mixture was poured into a 1N aqueous sodium hydroxide solution and extracted with ethyl acetate. The extract was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated to give the title compound (5.0 g) as a pale-brown solid.
Reaction SMILES: Cl.[NH:2]1[CH2:5][CH:4]([N:6]2[CH:10]=[C:9]([C:11]3[C:19]4[C:14](=[CH:15][C:16]([F:20])=[CH:17][CH:18]=4)[N:13]([S:21]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)(=[O:23])=[O:22])[CH:12]=3)[CH:8]=[N:7]2)[CH2:3]1.CCN(CC)CC.[Si]([N:41]=[C:42]=[O:43])(C)(C)C>>[F:20][C:16]1[CH:15]=[C:14]2[C:19]([C:11]([C:9]3[CH:8]=[N:7][N:6]([CH:4]4[CH2:3][N:2]([C:42]([NH2:41])=[O:43])[CH2:5]4)[CH:10]=3)=[CH:12][N:13]2[S:21]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)(=[O:22])=[O:23])=[CH:18][CH:17]=1
Reactant: C[Si](C)(C)N=C=O
Reactant: O=S(=O)(c1ccccc1)n1cc(-c2cnn(C3CNC3)c2)c2ccc(F)cc21
Agent: Cl
Solvent: CCN(CC)CC
Product: NC(=O)N1CC(n2cc(-c3cn(S(=O)(=O)c4ccccc4)c4cc(F)ccc34)cn2)C1
Reaction time: 1.5 h
Yield: 99.7 %

Procedure:
A mixture of 3-(1-(azetidin-3-yl)-1H-pyrazol-4-yl)-6-fluoro-1-(phenylsulfonyl)-1H-indole hydrochloride (Intermediate 24; 350 mg; 0.81 mmol), Et3N (0.34 ml; 2.44 mmol) and TMSNCO (121 mg; 1.05 mmol) was stirred for 1.5 hours. The reaction mixture was concentrated to afford 355 mg (100%) of the title compound as a brown solid, which was used directly without further purification.
Reaction SMILES: [N:1]([C@H:4]1[C@@H:9]([NH:10][C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:8][CH2:7][C@@H:6]([C:18]([O:20]CC2C=CC=CC=2)=[O:19])[CH2:5]1)=[N+:2]=[N-:3].[OH-].[Li+]>O1CCCC1.O>[N:1]([C@H:4]1[C@@H:9]([NH:10][C:11]([O:13][C:14]([CH3:17])([CH3:15])[CH3:16])=[O:12])[CH2:8][CH2:7][C@@H:6]([C:18]([OH:20])=[O:19])[CH2:5]1)=[N+:2]=[N-:3]
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@@H](C(=O)OCc2ccccc2)C[C@H]1N=[N+]=[N-]
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N[C@H]1CC[C@@H](C(=O)O)C[C@H]1N=[N+]=[N-]
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 125.7 %

Procedure:
Benzyl (1R,3R,4S)-3-azido-4-(N-tert-butoxycarbonylamino)cyclohexane-1-carboxylate (3.5 g) was dissolved in tetrahydrofuran (130 ml) and water (16 ml), and lithium hydroxide (291 mg) was added under ice cooling. After 10 minutes, the mixture was heated to room temperature to continue stirring. After 20 hours, the reaction was stopped, the solvent was distilled off under reduced pressure, and the resultant residue was subjected to column chromatography on silica gel (methanol:dichloromethane=1:20) to obtain (1R,3R,4S)-3-azido-4-(N-tert-butoxycarbonylamino)cyclohexane-1-carboxylic acid (3.34 g) as a pale yellow oil. This product was dissolved in methanol (18 ml) and toluene (64 ml), trimethylsilyldiazomethane (2 M solution, 6.1 ml) was added under ice cooling, and the mixture was heated to room temperature and stirred. After 2 hours, the reaction was stopped, the solvent was distilled off under reduced pressure, and the residue was purified by column chromatography on silica gel (ethyl acetate:hexane=1:4) to obtain the title compound (3.35 g) as a colorless oil.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8](F)=[C:7]([Cl:12])[CH:6]=1)(=[O:4])=[O:3].[Cl:13][C:14]1[CH:15]=[CH:16][C:17]([O:21][CH3:22])=[C:18]([OH:20])[CH:19]=1>>[CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([O:20][C:18]2[CH:19]=[C:14]([Cl:13])[CH:15]=[CH:16][C:17]=2[O:21][CH3:22])=[C:7]([Cl:12])[CH:6]=1)(=[O:4])=[O:3]
Reactant: CS(=O)(=O)c1ccc(F)c(Cl)c1
Reactant: COc1ccc(Cl)cc1O
Product: COc1ccc(Cl)cc1Oc1ccc(S(C)(=O)=O)cc1Cl

Procedure:
The subtitle compound was prepared by the method of example 1 step (ii) using the product from example 7 step (ii) and 5-chloro-2-methoxy phenol. Yield 4.0 g
Reaction SMILES: [CH2:1]([O:4][C:5]1[N:10]=[C:9]([C:11]([OH:13])=[O:12])[CH:8]=[N:7][C:6]=1[N:14]1[CH2:18][CH2:17][CH2:16][CH2:15]1)[CH2:2][CH3:3].[CH3:19]OC(C1C=NC(Cl)=C(Br)N=1)=O.N1CCCC1.[OH-].[K+]>C(O)CCC>[CH2:1]([O:4][C:5]1[N:10]=[C:9]([C:11]([OH:13])=[O:12])[CH:8]=[N:7][C:6]=1[N:14]1[CH2:18][CH2:17][CH2:16][CH2:15]1)[CH2:2][CH2:3][CH3:19]
Reactant: CCCOc1nc(C(=O)O)cnc1N1CCCC1
Reactant: COC(=O)c1cnc(Cl)c(Br)n1
Agent: [K+]
Agent: [OH-]
Solvent: CCCCO
Solvent: C1CCNC1
Product: CCCCOc1nc(C(=O)O)cnc1N1CCCC1
Yield: 8 %

Procedure:
In analogy to the procedure described for the synthesis of 6-propoxy-5-pyrrolidin-1-yl-pyrazine-2-carboxylic acid (example 10, step c), the title compound was synthesized from 6-Bromo-5-chloro-pyrazine-2-carboxylic acid methyl ester, butanol (commercially available), pyrrolidine (commercially available) and subsequent saponification with KOH in 8% yield. m/z (ES+): 266.0 (M+H).
Reaction SMILES: [F:1][C:2]([F:41])([F:40])[C:3]1[CH:4]=[C:5]([CH:33]=[C:34]([C:36]([F:39])([F:38])[F:37])[CH:35]=1)[CH2:6][N:7]([CH2:12][C:13]1[CH:18]=[C:17]([N+:19]([O-])=O)[CH:16]=[CH:15][C:14]=1[C:22]1[CH:27]=[C:26]([CH:28]([CH3:30])[CH3:29])[CH:25]=[CH:24][C:23]=1[O:31][CH3:32])[C:8](=[O:11])[O:9][CH3:10].[H][H]>CO.[Pd]>[NH2:19][C:17]1[CH:16]=[CH:15][C:14]([C:22]2[CH:27]=[C:26]([CH:28]([CH3:30])[CH3:29])[CH:25]=[CH:24][C:23]=2[O:31][CH3:32])=[C:13]([CH2:12][N:7]([CH2:6][C:5]2[CH:33]=[C:34]([C:36]([F:37])([F:38])[F:39])[CH:35]=[C:3]([C:2]([F:1])([F:40])[F:41])[CH:4]=2)[C:8](=[O:11])[O:9][CH3:10])[CH:18]=1
Reactant: COC(=O)N(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)Cc1cc([N+](=O)[O-])ccc1-c1cc(C(C)C)ccc1OC
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: COC(=O)N(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)Cc1cc(N)ccc1-c1cc(C(C)C)ccc1OC

Procedure:
A solution of the methyl [3,5-bis(trifluoromethyl)benzyl][(5′-isopropyl-2′-methoxy-4-nitrobiphenyl-2-yl)methyl]carbamate from Example 8 (0.31 g, 0.53 mmol) in MeOH (10 ml) was charged with a catalytic amount Pd/C and hydrogen at 40 psi for 1 h. The mixture was filtered through Celite and the filtrate was concentrated. The title compound was obtained by flash column chromatography using 3:7 EtOAc/hexane as the eluant. 1H NMR (CDCl3, 500 MHz) δ 7.72 (m, 1H), 7.50 (s, 1H), 7.30 (s, 1H), 7.16 (m, 1H), 7.03 (d, J=8.0 Hz, 1H), 6.94 (s, 1H), 6.82 (m, 1H), 6.69 (dd, J=8.5, 2.5 Hz, 1H), 6.58 (m, 1H), 4.18-4.30 (m, 4H), 3.75 (s, 3H), 3.65 (s, 3H), 2.83 (m, 1H), 1.20 (s, 6H). LC-MS (M+1): 555.3 (3.58 min).
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10]([C:30](O)=[O:31])=[N:11][C:12]([CH2:16][C:17]2([C:22]3[CH:27]=[CH:26][C:25]([Cl:28])=[C:24]([Cl:29])[CH:23]=3)[CH2:21][CH2:20][CH2:19][CH2:18]2)=[N:13][C:14]=1[OH:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Si:33]([O:40][CH2:41][CH2:42][NH:43][CH:44]([CH3:46])[CH3:45])([C:36]([CH3:39])([CH3:38])[CH3:37])([CH3:35])[CH3:34].[Si](OCCN(C(C)C)C(C1C(OCC2C=CC=CC=2)=C(O)N=C(CC2(C3C=CC(C(F)(F)F)=CC=3)CCCC2)N=1)=O)(C(C)(C)C)(C)C>>[CH2:1]([O:8][C:9]1[C:10]([C:30]([N:43]([CH2:42][CH2:41][O:40][Si:33]([C:36]([CH3:38])([CH3:37])[CH3:39])([CH3:34])[CH3:35])[CH:44]([CH3:45])[CH3:46])=[O:31])=[N:11][C:12]([CH2:16][C:17]2([C:22]3[CH:27]=[CH:26][C:25]([Cl:28])=[C:24]([Cl:29])[CH:23]=3)[CH2:18][CH2:19][CH2:20][CH2:21]2)=[N:13][C:14]=1[OH:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(O)c1nc(CC2(c3ccc(Cl)c(Cl)c3)CCCC2)nc(O)c1OCc1ccccc1
Reactant: CC(C)NCCO[Si](C)(C)C(C)(C)C
Agent: CC(C)N(CCO[Si](C)(C)C(C)(C)C)C(=O)c1nc(CC2(c3ccc(C(F)(F)F)cc3)CCCC2)nc(O)c1OCc1ccccc1
Product: CC(C)N(CCO[Si](C)(C)C(C)(C)C)C(=O)c1nc(CC2(c3ccc(Cl)c(Cl)c3)CCCC2)nc(O)c1OCc1ccccc1

Procedure:
5-(Benzyloxy)-N-(2-((tert-butyldimethylsilyl)oxy)ethyl)-2-((1-(3,4-dichlorophenyl)cyclo-pentyl)methyl)-6-hydroxy-N-isopropylpyrimidine-4-carboxamide (489) was synthesized from 5-(benzyloxy)-2-((1-(3,4-dichlorophenyl)cyclopentyl)methyl)-6-hydroxypyrimidine-4-carboxylic acid (488) and [2-(tert-butyl-dimethylsilanyloxy)-ethyl]-isopropyl-amine (8b) following the procedure described for 5-benzyloxy-2-[1-(4-trifluoromethyl-phenyl)-cyclopentylmethyl]-6-hydroxypyrimidine-4-carboxylic acid [2-(tert-butyl-dimethylsilanyloxy)-ethyl]isopropylamide (245).
Reaction SMILES: [C:1]([NH:9][C:10]1[N:18]=[CH:17][N:16]=[C:15]2[C:11]=1[N:12]=[CH:13][N:14]2[C@@H:19]1[O:24][C@H:23]([CH2:25][O:26][C:27](=[O:34])[C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[C@H:21](O)[CH2:20]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Li][N:55]=[N+:56]=[N-:57].CCOC(/N=N/C(OCC)=O)=O>CN(C=O)C>[C:27]([O:26][CH2:25][C@H:23]1[O:24][C@@H:19]([N:14]2[C:15]3[N:16]=[CH:17][N:18]=[C:10]([NH:9][C:1](=[O:8])[C:2]4[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=4)[C:11]=3[N:12]=[CH:13]2)[CH2:20][C@@H:21]1[N:55]=[N+:56]=[N-:57])(=[O:34])[C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1
Reactant: [Li]N=[N+]=[N-]
Reactant: O=C(Nc1ncnc2c1ncn2[C@H]1C[C@@H](O)[C@@H](COC(=O)c2ccccc2)O1)c1ccccc1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Product: [N-]=[N+]=N[C@H]1C[C@H](n2cnc3c(NC(=O)c4ccccc4)ncnc32)O[C@@H]1COC(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
N6 -Benzoyl-9-(5-O-benzoyl-2-deoxy-β-D-threo-pentofuranosyl)adenine (7.0 g, 15.3 mmol), triphenylphosphine (6.0 g, 22.9 mmol), and LiN3 (2.8 g, 56.4 mmol) were dissolved in DMF (100 mL). To this stirring mixture was added diethylazodicarboxylate (3.6 mL, 22.9 mmol) in one portion, the reaction was stirred for 2.5 h at RT, and the reaction was quenched with H2O (10 mL). The solvents were removed in vacuo, the residual oil was redissolved in EtOAc (300 mL) and extracted with H2O (2×200 mL) and saturated. aq. NaCl (200 mL). The organic layer was dried over Na2SO4, filtered, and concentrated in vacuo. The resulting residual oil was purified on SiO2 (2-5% MeOH/CH2 Cl2) to afford 5'-O-Benzoyl-N6 -benzoyl-3'-azido-2',3'-dideoxyadenosine, 1a, as an amber foam, which was taken on directly to hydrogenation.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:11][C:12]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[N:15]=[CH:14][N:13]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[CH3:22]I.[H-].[Na+]>CN(C=O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([N:11]([C:12]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[N:15]=[CH:14][N:13]=2)[CH3:22])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: CI
Reactant: COc1ccc(Nc2ncnc3ccccc23)cc1OC
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc(N(C)c2ncnc3ccccc23)cc1OC

Procedure:
The title compound was prepared from (3,4-dimethoxy-phenyl)-quinazolin-4-yl-amine (130 mg, 0.46 mmol), methyl iodide (0.043 ml, 0.7 mmol), sodium hydride (28 mg, 0.7 mmol, 60% oil dispersion) in DMF similar to example 21 to give 2.0 mg (2%) of white solids. 1H NMR (CDCl3): 7.88 (s, 1H), 7.55-7.45 (m, 2H), 7.31 (d, J=7.2 Hz, 1H), 6.97 (t, J=7.2 Hz, 1H), 6.86 (d, J=8.4 Hz, 1H), 6.45 (d, J=2.1 Hz, 1H), 6.37 (d, J=2.4 Hz, J=8.1 Hz, 1H), 3.91 (s, 3H), 3.82 (s, 3H), 3.53 (s, 3H).
Reaction SMILES: Cl.Cl.[NH2:3][C:4]1[CH:11]=[C:10]([CH2:12][N:13]2[CH2:18][CH2:17][CH:16]([CH2:19][C:20]3[NH:24][C:23]4[CH:25]=[C:26]([Cl:29])[CH:27]=[CH:28][C:22]=4[N:21]=3)[CH2:15][C:14]2=[O:30])[CH:9]=[CH:8][C:5]=1[C:6]#[N:7].[C:31](#[N:33])[CH3:32]>O1CCOCC1>[NH2:7][C:6]1[C:5]2[C:4](=[CH:11][C:10]([CH2:12][N:13]3[CH2:18][CH2:17][CH:16]([CH2:19][C:20]4[NH:24][C:23]5[CH:25]=[C:26]([Cl:29])[CH:27]=[CH:28][C:22]=5[N:21]=4)[CH2:15][C:14]3=[O:30])=[CH:9][CH:8]=2)[N:3]=[C:31]([CH3:32])[N:33]=1
Reactant: CC#N
Reactant: N#Cc1ccc(CN2CCC(Cc3nc4ccc(Cl)cc4[nH]3)CC2=O)cc1N
Agent: Cl
Solvent: C1COCCO1
Product: Cc1nc(N)c2ccc(CN3CCC(Cc4nc5ccc(Cl)cc5[nH]4)CC3=O)cc2n1
Temperature: 0 °C
Yield: 17.8 %

Procedure:
A stream of hydrogen chloride gas is bubbled intermittently through an ice-cold mixture of 2-amino-4-[4-(6-chloro-1H-benzoimidazol-2-ylmethyl)-2-oxo-piperidin-1-ylmethyl]-benzonitrile hydrochloric acid salt (57 mg, 0.123 mmol), EXAMPLE 814, Part E, and acetonitrile (0.03 mL, 0.93 mmol) in 1.5 mL of dioxane for six hours. The dioxane is removed; the residue is purified by reverse phase HPLC (0-40% ACN/H2O). The desired product (9.5 mg, 12% yield) is isolated as a clear wax. C23H23ClN6O MS m/z: 435, 437.
Reaction SMILES: [C:1]1([CH3:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:8]([O:11][C:12](=[O:14])[CH3:13])(=O)[CH3:9].Cl>CN(C)C1C=CN=CC=1.N1C=CC=CC=1>[C:12]([O:11][CH:8]([CH3:9])[CH2:7][C:1]1[CH:6]=[CH:5][C:4]2[C:3](=[CH:6][CH:1]=[CH:2][CH:3]=2)[CH:2]=1)(=[O:14])[CH3:13]
Reactant: Cc1ccccc1
Reactant: CC(=O)OC(C)=O
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: c1ccncc1
Product: CC(=O)OC(C)Cc1ccc2ccccc2c1
Reaction time: 4 h

Procedure:
In a four-necked flask equipped with a thermometer and stirrer, were placed 15.1 g (0.08 mole) of the compound (XII-1) obtained in Preparation Example 1, 50 ml of toluene and 20 ml of pyridine, thereafter 10.2 g (0.1 mole) of acetic anhydride and 0.1 g of 4-dimethylaminopyridine was added thereto, and the resulting mixture was stirred at 40°-50° C. for 4 hours. After completion of the reaction, the reaction mixture was poured into 50 ml of 4N hydrochloric acid to conduct extraction and layer separation. The organic layer obtained was washed successively with 1N hydrochloric acid, water, 5% aqueous sodium bicarbonate solution and water. The organic layer was then concentrated under reduced pressure to obtain 18.2 g of 2-(2-acetoxypropyl)naphthalene (XIII-1). Yield: 99 0%, nD20 1,5413
Reaction SMILES: [C:1](N1C=CN=C1)(N1C=CN=C1)=[O:2].[F:13][C:14]1[CH:39]=[C:38]([F:40])[C:37]([F:41])=[CH:36][C:15]=1[NH:16][C:17]1[CH:33]=[C:32]([F:34])[C:31]([F:35])=[CH:30][C:18]=1[C:19]([NH:21][O:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[O:20]>>[F:13][C:14]1[CH:39]=[C:38]([F:40])[C:37]([F:41])=[CH:36][C:15]=1[N:16]1[C:17]2[C:18](=[CH:30][C:31]([F:35])=[C:32]([F:34])[CH:33]=2)[C:19](=[O:20])[N:21]([O:22][CH2:23][C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)[C:1]1=[O:2]
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: O=C(NOCc1ccccc1)c1cc(F)c(F)cc1Nc1cc(F)c(F)cc1F
Product: O=c1c2cc(F)c(F)cc2n(-c2cc(F)c(F)cc2F)c(=O)n1OCc1ccccc1
Yield: 5.3 %

Procedure:
Using General Method 3, the reaction of carbonyldiimidazole (4.9 g, 30.4 mmol) and crude 2-(2,4,5-trifluoro-anilino)-N-benzyloxy-4,5-difluoro-benzamide (Example A-1, 6.22 g, 15.2 mmol) provided 0.35 g of the title compound as a solid.
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.[N:28]1([CH2:34][CH2:35][NH2:36])[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]1>C(Cl)Cl>[Br:16][C:15]1[S:14][C:13]([S:17](=[O:19])(=[O:18])[NH:36][CH2:35][CH2:34][N:28]2[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]2)=[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: NCCN1CCCCC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)Nc1nc(C)c(-c2cc(S(=O)(=O)NCCN3CCCCC3)sc2Br)s1
Temperature: 0 °C
Reaction time: 2 h
Yield: 68 %

Procedure:
4-[2-(acetylamino)-4-methyl-1,3-thiazol-5-yl]-5-bromothiophene-2-sulfonyl chloride, prepared as in Step III of Example 23 (200 mg; 0.48 mmol; 1 eq), is dissolved in anhydrous DCM (10 ml). The reaction mixture is cooled down to 0° C. and put under nitrogen. Triethylamine (0.4 ml; 2.88 mmol; 6 eq) and 2-piperidin-1-yl-ethylamine (0.16 ml; 1.16 mmol; 2.4 eq) are added successively and the reaction mixture is stirred at 0° C. for 2 hours. The mixture is washed with water, NaHCO3 and dried over MgSO4, affording the title compound (170 mg; 68%).
Reaction SMILES: [ClH:1].Cl.[NH2:3][C:4]1[C:12]([F:13])=[CH:11][CH:10]=[C:9]([F:14])[C:5]=1[C:6]([NH2:8])=[NH:7].O=[C:16]1[CH2:21][CH2:20][N:19]([C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH2:18][CH2:17]1>>[ClH:1].[NH2:7][C:6]1[C:5]2[C:4](=[C:12]([F:13])[CH:11]=[CH:10][C:9]=2[F:14])[NH:3][C:16]2([CH2:21][CH2:20][N:19]([C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH2:18][CH2:17]2)[N:8]=1
Reactant: CCOC(=O)N1CCC(=O)CC1
Reactant: N=C(N)c1c(F)ccc(F)c1N
Agent: Cl
Product: CCOC(=O)N1CCC2(CC1)N=C(N)c1c(F)ccc(F)c1N2

Procedure:
This was prepared by the method of Example 173 using 2-amino-3,6-difluorobenzamidine dihydrochloride (Example G) and ethyl 4-oxopiperidine-1-carboxylate to give the title compound, m.p. 228°-229° C.
Reaction SMILES: [C:1]12([CH2:11][NH:12][C:13]3[CH:26]=[CH:25][C:24]([N+:27]([O-:29])=[O:28])=[CH:23][C:14]=3[C:15]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=O)[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.[C:30](=[O:35])(OCC)[NH2:31].C(O)C>[Cl-].[Zn+2].[Cl-].C(Cl)(Cl)Cl>[C:1]12([CH2:11][N:12]3[C:13]4[C:14](=[CH:23][C:24]([N+:27]([O-:29])=[O:28])=[CH:25][CH:26]=4)[C:15]([C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=4)=[N:31][C:30]3=[O:35])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2
Reactant: O=C(c1ccccc1)c1cc([N+](=O)[O-])ccc1NCC12CC3CC(CC(C3)C1)C2
Reactant: CCOC(N)=O
Agent: [Cl-]
Agent: [Zn+2]
Solvent: ClC(Cl)Cl
Solvent: CCO
Product: O=c1nc(-c2ccccc2)c2cc([N+](=O)[O-])ccc2n1CC12CC3CC(CC(C3)C1)C2
Reaction time: 1 h

Procedure:
A mixture of 3.9 g of 2-(1-adamantylmethyl-amino)-5-nitrobenzophenone, 6.4 g of ethyl carbamate and 0.45 g of anhydrous zinc chloride was heated at 170°- 180°C for 1 hour, and then, distillating off the produced ethanol, heating was continued at that temperature for additional 1 hour. After cooling, chloroform was added thereto and insoluble material was filtered off. The chloroform layer was washed with water and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure and the residual oil was chromatographed on silica gel using chloroform as eluting solvent to give 1-(1-adamantylmethyl)-4-phenyl-6-nitro-2(1H)-quinazolinone, m.p. 230°- 233°C, following recrystallization from a mixture of ethanol and chloroform.