Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:3][C:4]([CH:6]1[CH2:9][C:8](=[O:10])[N:7]1[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][C:13]=1[O:20][CH3:21])=O)C.Cl>CO>[CH3:21][O:20][C:13]1[CH:14]=[C:15]([O:18][CH3:19])[CH:16]=[CH:17][C:12]=1[CH2:11][N:7]1[CH:6]([CH2:4][OH:3])[CH2:9][C:8]1=[O:10]
Reactant: CCOC(=O)C1CC(=O)N1Cc1ccc(OC)cc1OC
Agent: Cl
Solvent: CO
Product: COc1ccc(CN2C(=O)CC2CO)c(OC)c1
Temperature: 0 °C

Procedure:
47.6 g. (0.162 moles) of ethyl-1-(2,4-dimethoxybenzyl)-4-oxo-2-azetidine-carboxylate prepared according to Example 10 are reacted with 12.4 g. (0.327 moles) of sodium tetrahydrido-borate(III), in 200 ml. of methanol, under outer cooling with ice water for about half an hour. The solution is neutralized with a dilute aqueous hydrochloric acid solution and the oil precipitated from the aqueous mixture is shaken with five 50-ml. portions of ethyl acetate.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]([N:13]2[CH:17]=[CH:16][CH:15]=[CH:14]2)=[C:8]([CH:12]=1)[C:9](O)=[O:10])([O-:3])=[O:2].O>O1CCCC1>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([N:13]2[CH:14]=[CH:15][CH:16]=[CH:17]2)=[C:8]([CH:12]=1)[CH2:9][OH:10])([O-:3])=[O:2]
Reactant: O=C(O)c1cc([N+](=O)[O-])ccc1-n1cccc1
Solvent: C1CCOC1
Solvent: O
Product: O=[N+]([O-])c1ccc(-n2cccc2)c(CO)c1
Yield: 70 %

Procedure:
To a solution in anhydrous tetrahydrofuran (10 ml) of the compound (392 mg) obtained in Example 1a, a borane-tetrahydrofuran complex (1.0 M, 2.2 ml) was added dropwise under a nitrogen atmosphere. After heating the reaction mixture under reflux for 3 hours, water was added and the mixture was concentrated at reduced pressure. Brine was added to the resulting residue and the mixture was extracted with ethyl acetate. The organic layer was dried with anhydrous sodium sulfate and concentrated at reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent; ethyl acetate:dichloromethane=1:19) to give the titled compound (yield, 70%).
Reaction SMILES: C(C(C1C2NC3C(=CC(F)=CC=3S(C)(=O)=O)C=2CCC1)C([O-])=O)C.C([O:27][C:28](=[O:57])[CH2:29][C@@H:30]1[C:42]2[N:41]([C@H:43]([C:45]3[CH:50]=[CH:49][C:48]([Cl:51])=[CH:47][CH:46]=3)[CH3:44])[C:40]3[C:35](=[CH:36][C:37]([F:56])=[CH:38][C:39]=3[S:52]([CH3:55])(=[O:54])=[O:53])[C:34]=2[CH2:33][CH2:32][CH2:31]1)C.C(OC(=O)C[C@H]1C2N([C@H](C3C=CC(Cl)=CC=3)C)C3C(=CC(F)=CC=3S(C)(=O)=O)C=2CCC1)C>>[Cl:51][C:48]1[CH:47]=[CH:46][C:45]([C@@H:43]([N:41]2[C:42]3[C@@H:30]([CH2:29][C:28]([OH:57])=[O:27])[CH2:31][CH2:32][CH2:33][C:34]=3[C:35]3[C:40]2=[C:39]([S:52]([CH3:55])(=[O:53])=[O:54])[CH:38]=[C:37]([F:56])[CH:36]=3)[CH3:44])=[CH:50][CH:49]=1
Reactant: CCOC(=O)C[C@H]1CCCc2c1n([C@@H](C)c1ccc(Cl)cc1)c1c(S(C)(=O)=O)cc(F)cc21
Agent: CCC(C(=O)[O-])C1CCCc2c1[nH]c1c(S(C)(=O)=O)cc(F)cc21
Agent: CCOC(=O)C[C@@H]1CCCc2c1n([C@@H](C)c1ccc(Cl)cc1)c1c(S(C)(=O)=O)cc(F)cc21
Product: C[C@@H](c1ccc(Cl)cc1)n1c2c(c3cc(F)cc(S(C)(=O)=O)c31)CCC[C@@H]2CC(=O)O

Procedure:
Alternatively (+/−) ethyl[6-fluoro-8-(methylsulfonyl)-2,3,4,9-tetrahydro-1H-carbazol-1-yl]acetate was used for the alkylation reaction in step 5 to give a mixture of 2 diastereomers: ethyl[(1R)-9-[(1S)-1-(4-chlorophenyl)ethyl]-6-fluoro-8-(methylsulfonyl)-2,3,4,9-tetrahydro-1H-carbazol-1-yl]acetate and ethyl[(1S)-9-[(1S)-1-(4-chlorophenyl)ethyl]-6-fluoro-8-(methylsulfonyl)-2,3,4,9-tetrahydro-1H-carbazol-1-yl]acetate. The diastereomeric mixture was resolved by selective hydrolysis using the following procedure to give the desired [(1R)-9-[(1S)-1-(4-chlorophenyl)ethyl]-6-fluoro-8-(methylsulfonyl)-2,3,4,9-tetrahydro-1H-carbazol-1-yl]acetic acid.
Reaction SMILES: [CH:1]([N:4]=[C:5]=[O:6])([CH3:3])[CH3:2].[NH2:7][C:8]([CH3:28])([CH3:27])[CH2:9][C:10]1[N:11]([CH2:24][CH2:25][CH3:26])[N:12]=[C:13]2[C:22]=1[C:21]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[N:15]=[C:14]2[NH2:23]>ClCCl>[NH2:23][C:14]1[C:13]2=[N:12][N:11]([CH2:24][CH2:25][CH3:26])[C:10]([CH2:9][C:8]([NH:7][C:5]([NH:4][CH:1]([CH3:3])[CH3:2])=[O:6])([CH3:27])[CH3:28])=[C:22]2[C:21]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[N:15]=1
Reactant: CCCn1nc2c(N)nc3ccccc3c2c1CC(C)(C)N
Reactant: CC(C)N=C=O
Solvent: ClCCl
Product: CCCn1nc2c(N)nc3ccccc3c2c1CC(C)(C)NC(=O)NC(C)C
Temperature: 25 °C
Reaction time: 4 h
Yield: 11.3 %

Procedure:
Isopropyl isocyanate (255 mg, 3.00 mmol) was added to a 0° C. stirred solution of 1-(2-amino-2-methylpropyl)-2-propyl-2H-pyrazolo[3,4-c]quinolin-4-amine (prepared as described in Example 64, 892 mg, 3.00 mmol) in dichloromethane (26.7 mL). After 4 hours at 0° C., the solution was stirred overnight at ambient temperature. The solution was concentrated to afford a colorless resin that was purified by IFC (silica gel, elution with CMA in chloroform). The appropriate fractions were combined and concentrated to yield a solid that was recrystallized from ethyl acetate in hexanes. The solid was isolated by filtration, washed with ethyl acetate/hexanes, and dried to yield 130 mg of N-[2-(4-amino-2-propyl-2H-pyrazolo[3,4-c]quinolin-1-yl)-1,1-dimethylethyl]-N′-isopropylurea as a white solid, mp 190-191° C.
Reaction SMILES: [C:1]([N:4]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[NH:6][C:5]1=[O:13])([CH3:3])=[CH2:2]>[Pd].CO>[CH:1]([N:4]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[NH:6][C:5]1=[O:13])([CH3:3])[CH3:2]
Reactant: C=C(C)n1c(=O)[nH]c2ccccc21
Agent: [Pd]
Solvent: CO
Product: CC(C)n1c(=O)[nH]c2ccccc21
Reaction time: 2 h
Yield: 99.9 %

Procedure:
A mixture of 1-isopropenyl-1,3-dihydro-benzoimidazol-2-one (J. Davoll, J. Chem. Soc. 1960, 308) (6.90 g, 39.6 mmol) and 10% palladium on carbon (1.0 g) in MeOH (50 mL) was placed in a Parr shaker under hydrogen (40 psi) for 2 h. The reaction mixture was filtered through celite and evaporated to give 6.97 g (100%) of 1-isopropyl-1,3-dihydro-benzoimidazol-2-one as a white solid.
Reaction SMILES: C(OC(=O)[NH:7][CH:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH:9]1[C:14](=[O:19])[NH:15][CH2:16][C:17]#[N:18])(C)(C)C>C(O)=O>[C:17]([CH2:16][NH:15][C:14]([CH:9]1[CH2:10][CH2:11][CH2:12][CH2:13][CH:8]1[NH2:7])=[O:19])#[N:18]
Reactant: CC(C)(C)OC(=O)NC1CCCCC1C(=O)NCC#N
Solvent: O=CO
Product: N#CCNC(=O)C1CCCCC1N
Yield: 61.7 %

Procedure:
A solution of [2-(cyanomethyl-carbamoyl)-cyclohexyl]-carbamic acid tert-butyl ester (7.3 g, 25.95 mmol) in formic acid (100 ml) and solution was stirred for four hours. Reaction was concentrated and then dissolved in 10% MeOH/dichloromethane solution (150 ml) Potassium carbonate was added until pH reached 9 and subsequent slurry was stirred vigorously before being filtered through Celite plug. The filtrate was concentrated in vacuo yielding 2-amino-cyclohexanecarboxylic acid cyanomethyl-amide (2.9 g, 62%).
Reaction SMILES: Cl.Cl.[Cl:3][C:4]1[C:5]([CH3:40])=[C:6]([NH:10][C:11]([C:13]2[C:21]3[N:20]=[C:19]([C@@H:22]4[CH2:26][CH2:25][CH2:24][NH:23]4)[NH:18][C:17]=3[CH:16]=[C:15]([NH:27][C:28]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=3[C:36]([F:39])([F:38])[F:37])=[O:29])[CH:14]=2)=[O:12])[CH:7]=[CH:8][CH:9]=1.N1C=CC=CC=1.[C:47](Cl)(=[O:49])[CH3:48]>C1COCC1>[C:47]([N:23]1[CH2:24][CH2:25][CH2:26][C@H:22]1[C:19]1[NH:18][C:17]2[CH:16]=[C:15]([NH:27][C:28]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=3[C:36]([F:39])([F:37])[F:38])=[O:29])[CH:14]=[C:13]([C:11]([NH:10][C:6]3[CH:7]=[CH:8][CH:9]=[C:4]([Cl:3])[C:5]=3[CH3:40])=[O:12])[C:21]=2[N:20]=1)(=[O:49])[CH3:48]
Reactant: CC(=O)Cl
Reactant: Cc1c(Cl)cccc1NC(=O)c1cc(NC(=O)c2ccccc2C(F)(F)F)cc2[nH]c([C@@H]3CCCN3)nc12
Agent: Cl
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: CC(=O)N1CCC[C@H]1c1nc2c(C(=O)Nc3cccc(Cl)c3C)cc(NC(=O)c3ccccc3C(F)(F)F)cc2[nH]1
Temperature: 0 °C

Procedure:
To a solution of N-(3-chloro-2-methylphenyl)-2-[(2S)-pyrrolidin-2-yl]-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide (Example 71) (26 mg) in THF solution (0.5 mL), was added pyridine (12 μL), and the mixture was stirred under ice-cooling. To the mixture was added acetyl chloride (5.1 μL), and it was stirred at room temperature for 1 hour. To the reaction mixture was added ice water, and the mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. The residue was purified on column chromatography to obtain the titled compound (15 mg) as white powder.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][CH:11]=1)[C:5](OC)=O.S(C1C=CC(C)=CC=1)(O)(=O)=O.[NH2:23][CH2:24][CH2:25][NH2:26].[OH-].[Na+]>>[OH:1][C:2]1[CH:3]=[C:4]([C:5]2[NH:23][CH2:24][CH2:25][N:26]=2)[CH:9]=[CH:10][CH:11]=1
Reactant: NCCN
Reactant: COC(=O)c1cccc(O)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: [Na+]
Agent: [OH-]
Product: Oc1cccc(C2=NCCN2)c1
Temperature: 210 °C
Yield: 22.3 %

Procedure:
A mixture of methyl 3-hydroxybenzoate (5.48 g, 36.0 mmol) and 1,2-diaminoethane monotosylate (9.85 g, 42.4 mmol) is heated at 210° C. for 7 hours. After cooling, the mixture is stirred with aqueous 2N sodium hydroxide and extracted with ethyl acetate. The precipitate which formed and is present in the aqueous layer is collected by filtration and dried in vacuo to give 1.3 g (22%) of 2-(3-hydroxyphenyl)imidazoline.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]([OH:11])([CH3:10])[CH3:9])=[C:4]([O:12][CH3:13])[CH:3]=1.[Cl:14][C:15]1[CH:23]=[C:22]2[C:18]([C:19]([C:24]([O:26][CH3:27])=[O:25])=[CH:20][NH:21]2)=[CH:17][C:16]=1B1OCC(C)(C)CO1.C(O)C.C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].O1CCCC1>[Cl:14][C:15]1[CH:23]=[C:22]2[C:18]([C:19]([C:24]([O:26][CH3:27])=[O:25])=[CH:20][NH:21]2)=[CH:17][C:16]=1[C:2]1[CH:7]=[CH:6][C:5]([C:8]([OH:11])([CH3:10])[CH3:9])=[C:4]([O:12][CH3:13])[CH:3]=1
Reactant: COc1cc(Br)ccc1C(C)(C)O
Reactant: COC(=O)c1c[nH]c2cc(Cl)c(B3OCC(C)(C)CO3)cc12
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: CCO
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: COC(=O)c1c[nH]c2cc(Cl)c(-c3ccc(C(C)(C)O)c(OC)c3)cc12
Temperature: 115 °C
Yield: 60.2 %

Procedure:
To a solution of 2-(4-bromo-2-methoxyphenyl)propan-2-ol (50.0 mg, 0.20 mmol) in toluene (0.81 mL) was added methyl 6-chloro-5-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)-1H-indole-3-carboxylate (72 mg, 0.22 mmol), ethanol (0.43 mL), and tetrahydrofuran (0.43 mL). This was followed by the addition of 2M potassium carbonate aqueous (0.58 mL, 1.2 mmol). The reaction was evacuated and back filled with nitrogen (3×) then Pd(dppf)Cl2 (19.0 mg, 0.023 mmol) was added and the reaction heated to 115° C. for 3 hours. The reaction was then cooled to room temperature and filtered through a pad of celite washing with ethyl acetate. The filtrate was concentrated under reduced pressure and purified via column chromatography (0-40% ethyl acetate/heptanes) to provide the title compound (45 mg, 59% yield) as a solid.
Reaction SMILES: [C:1]1([CH3:10])[CH:6]=[CH:5][C:4]([N:7]=[C:8]=[O:9])=[CH:3][CH:2]=1.[CH3:11][O:12][C:13]1[CH:19]=[CH:18][C:17]([S:20]([C:23]([F:26])([F:25])[F:24])(=[O:22])=[O:21])=[CH:16][C:14]=1[NH2:15]>CCOC(C)=O>[CH3:11][O:12][C:13]1[CH:19]=[CH:18][C:17]([S:20]([C:23]([F:24])([F:25])[F:26])(=[O:21])=[O:22])=[CH:16][C:14]=1[NH:15][C:8]([NH:7][C:4]1[CH:5]=[CH:6][C:1]([CH3:10])=[CH:2][CH:3]=1)=[O:9]
Reactant: COc1ccc(S(=O)(=O)C(F)(F)F)cc1N
Reactant: Cc1ccc(N=C=O)cc1
Solvent: CCOC(C)=O
Product: COc1ccc(S(=O)(=O)C(F)(F)F)cc1NC(=O)Nc1ccc(C)cc1
Reaction time: 18 h
Yield: 55.9 %

Procedure:
p-Tolyl isocyanate (0.19 mL, 1.55 mmol) was added to a solution of 2-methoxy-5-(trifluoromethanesulfonyl)aniline (0.330 g, 1.29 mmol) in EtOAc (5 mL), and the reaction mixture was stirred at room temp. for 18 h. The resulting precipitate was collected by filtration and washed with Et2O to give a white solid (0.28 g). This material was then purified by HPLC (C-18 column, 50% CH3CN/50% H2O) and the resulting solids were triturated with Et2O to provide the title compound (0.198 g): 1H-NMR (CDCl3) δ 7.08 (d, J=8.5 Hz, 2H), 7.33 (d, J=8.5 Hz, 2H), 7.40 (d, J=8.8 Hz, 1H), 7.71 (dd, J=2.6, 8.8 Hz, 1H), 8.66 (s, 1H), 8.90 (d, J=2.6 Hz, 1H), 9.36 (s, 1H); FAB-MS m/z 389 ((M+1)+). B1c. General Method for the Reaction of an Aryl Amine with an Aryl Isocyanate
Reaction SMILES: C(C1C=CC(C(NC2C=CC(C3C=C4C(CN([C@@H](C(C)C)C(O)=O)C4=O)=CC=3)=NC=2)=O)=CC=1)(C)(C)C.[CH3:37][CH:38]([CH3:74])[C@H:39]([N:44]1[CH2:52][C:51]2[C:46](=[CH:47][C:48]([C:53]3[N:54]=[N:55][C:56]([NH:59][C:60](=[O:72])[C:61]4[CH:66]=[CH:65][C:64]([CH2:67][CH2:68][CH2:69][CH2:70][CH3:71])=[CH:63][CH:62]=4)=[CH:57][CH:58]=3)=[CH:49][CH:50]=2)[C:45]1=[O:73])[C:40]([O:42]C)=[O:41]>>[CH3:74][CH:38]([CH3:37])[C@H:39]([N:44]1[CH2:52][C:51]2[C:46](=[CH:47][C:48]([C:53]3[N:54]=[N:55][C:56]([NH:59][C:60](=[O:72])[C:61]4[CH:62]=[CH:63][C:64]([CH2:67][CH2:68][CH2:69][CH2:70][CH3:71])=[CH:65][CH:66]=4)=[CH:57][CH:58]=3)=[CH:49][CH:50]=2)[C:45]1=[O:73])[C:40]([OH:42])=[O:41]
Reactant: CCCCCc1ccc(C(=O)Nc2ccc(-c3ccc4c(c3)C(=O)N([C@H](C(=O)OC)C(C)C)C4)nn2)cc1
Agent: CC(C)[C@@H](C(=O)O)N1Cc2ccc(-c3ccc(NC(=O)c4ccc(C(C)(C)C)cc4)cn3)cc2C1=O
Product: CCCCCc1ccc(C(=O)Nc2ccc(-c3ccc4c(c3)C(=O)N([C@H](C(=O)O)C(C)C)C4)nn2)cc1
Yield: 70 %

Procedure:
The compound of example 500 was prepared analogous to the compound of example 404 by hydrolysis of the compound of example 499.
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[C:3]1[CH:4]=[C:5]([C:9]2[N:14]=[C:13]([NH2:15])[N:12]=[C:11]([NH2:16])[CH:10]=2)[CH:6]=[CH:7][CH:8]=1.C1C(=O)N([I:26])C(=O)C1>>[I:26][C:10]1[C:11]([NH2:16])=[N:12][C:13]([NH2:15])=[N:14][C:9]=1[C:5]1[CH:6]=[CH:7][CH:8]=[C:3]([C:2]([F:1])([F:17])[F:18])[CH:4]=1
Reactant: Nc1cc(-c2cccc(C(F)(F)F)c2)nc(N)n1
Reactant: O=C1CCC(=O)N1I
Product: Nc1nc(N)c(I)c(-c2cccc(C(F)(F)F)c2)n1

Procedure:
The title compound is synthesized according to general procedure GP1 starting from 1.8 g (7.1 mmol) 6-(3-trifluoromethyl-phenyl)-pyrimidine-2,4-diamine and 1.8 g (7.8 mmol) NIS. Yield: 2.0 g (74%).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[N:9]([CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=1)[N:8]=[CH:7]2)([O-])=O>CO.[Pt](=O)=O>[N:15]1[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=1[CH2:13][N:9]1[C:10]2[C:6](=[CH:5][C:4]([NH2:1])=[CH:12][CH:11]=2)[CH:7]=[N:8]1
Reactant: O=[N+]([O-])c1ccc2c(cnn2Cc2ccccn2)c1
Agent: O=[Pt]=O
Solvent: CO
Product: Nc1ccc2c(cnn2Cc2ccccn2)c1
Yield: 95.2 %

Procedure:
A mixture of 5-nitro-1-(pyridin-2-ylmethyl)-1H-indazole (34 g, 134 mmol) and platinum(IV) oxide (1 g) in methanol (500 ml) was hydrogenated under a 1 bar pressure. After 4 hours (when absorption of hydrogen had stopped), the mixture was filtered on celite. The filtrate was evaporated under reduced pressure. The residue was triturated in ether to give 1-(pyridin-2-ylmethyl)-1H-indazol-5-amine as an off-white solid (28.6 g, 95%); NMR Spectrum (CDCl3) 3.61 (m, 2H), 5.67 (m, 2H), 6.78 (d, 1H), 6.82 (dd, 1H), 6.95 (d, 1H), 7.16 (m, 1H), 7.20 (d, 1H), 7.53 (m, 1H), 7.87 (s, 1H), 8.57 (d, 1H); Mass spectrum MH+ 225.
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]=1[C:13]([NH:15][NH2:16])=[O:14].N1([C:22]([C:24]2[CH:33]=[CH:32][C:27]3[NH:28][C:29](=[O:31])[NH:30][C:26]=3[CH:25]=2)=O)C=CN=C1.P(Cl)(Cl)(Cl)=O.O>ClC1C=CC=CC=1>[CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]=1[C:13]1[O:14][C:22]([C:24]2[CH:33]=[CH:32][C:27]3[NH:28][C:29](=[O:31])[NH:30][C:26]=3[CH:25]=2)=[N:16][N:15]=1
Reactant: O=C(c1ccc2[nH]c(=O)[nH]c2c1)n1ccnc1
Reactant: Cc1onc(-c2ccccc2)c1C(=O)NN
Solvent: Clc1ccccc1
Solvent: O
Solvent: O=P(Cl)(Cl)Cl
Product: Cc1onc(-c2ccccc2)c1-c1nnc(-c2ccc3[nH]c(=O)[nH]c3c2)o1
Temperature: 100 °C
Reaction time: 18 h
Yield: 77.7 %

Procedure:
To a suspension of 5-methyl-3-phenyl-isoxazole-4-carboxylic acid hydrazide (200 mg, 0.92 mmol) in chlorobenzene (2 mL) was added 5-(imidazole-1-carbonyl)-1,3-dihydro-benzoimidazol-2-one (315 mg, 1.38 mmol) and stirred for 18 h at 100° C. After cooling to ambient temperature phosphorus oxychloride (126 μL, 1.38 mmol) was added and the suspension was stirred for 4 h at 100° C. It was then cooled to ambient temperature and water (2 mL) was added, stirred for 15 min, and the resulting precipitate filtered off and washed with water (5 mL) and tert-butylmethylether (5 mL). Recrystallisation from ethanol afforded the title compound (257 mg, 78%) which was obtained as a light-grey solid. MS: m/e=360.1 [M+H]+.
Reaction SMILES: [H-].[Li+].[CH2:3]([P:7](=[O:14])([O:11][CH2:12][CH3:13])[O:8][CH2:9][CH3:10])[C:4]([CH3:6])=[O:5].[Cl:15][C:16]1[CH:30]=[C:29]([O:31][CH3:32])[CH:28]=[CH:27][C:17]=1[O:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25]I>>[C:4]([CH:3]([P:7](=[O:14])([O:8][CH2:9][CH3:10])[O:11][CH2:12][CH3:13])[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][O:18][C:17]1[CH:27]=[CH:28][C:29]([O:31][CH3:32])=[CH:30][C:16]=1[Cl:15])(=[O:5])[CH3:6]
Reactant: COc1ccc(OCCCCCCCI)c(Cl)c1
Reactant: CCOP(=O)(CC(C)=O)OCC
Agent: [H-]
Agent: [Li+]
Product: CCOP(=O)(OCC)C(CCCCCCCOc1ccc(OC)cc1Cl)C(C)=O
Yield: 18.4 %

Procedure:
[II; Ar is 2-Cl-4-CH3OC6H3, Y is O(CH2)7, R is C2H5, R' is CH3CO] was prepared from 0.57 g of lithium hydride, 13.9 g of diethyl acetonylphosphonate and 27.8 g of 7-(2-chloro-4-methoxyphenoxy)-heptyl iodide according to the procedure of Example 2(b). The product was chromatographed on Florisil and further purified by preparative thin layer chromatography (TLC) on silica gel to give 5.9 g of diethyl [1-acetyl-8-(2-chloro-4-methoxyphenoxy)-octyl]phosphonate as a yellow oil; MIC vs. herpes simplex type 2=6 mcg/ml. The NMR spectrum was consistent with the assigned structure.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([CH3:15])=[CH:11][CH:10]=2)[C:5]([N+:16]([O-])=O)=[CH:4][CH:3]=1.O.O.[Sn](Cl)Cl.C([O-])([O-])=O.[K+].[K+]>Cl.C(OCC)(=O)C>[NH2:16][C:5]1[C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([CH3:15])=[CH:11][CH:10]=2)=[N:7][C:2]([Cl:1])=[CH:3][CH:4]=1
Reactant: Cc1ccc(Nc2nc(Cl)ccc2[N+](=O)[O-])cc1
Agent: Cl
Agent: Cl[Sn]Cl
Agent: O=C([O-])[O-]
Solvent: CCOC(C)=O
Solvent: O
Product: Cc1ccc(Nc2nc(Cl)ccc2N)cc1
Temperature: 90 °C
Yield: 102.5 %

Procedure:
A mixture of 6-chloro-3-nitro-pyridin-2-yl-p-tolyl-amine (527 mg, 2 mmol) and tin(II) chloride dihydrate (2.72 g, 12 mmol) in 4 mL conc. HCl was heated at 90° C. for 2 h. After cooling down the yellow suspension was diluted with ethyl acetate and treated with aq. K2CO3 at 0° C. under vigorous stirring to pH 10. The emulsion was extracted with 5×30 mL EtOAc. The combined organic phase was dried over Na2SO4. Evaporation gave 479 mg (yield: quantitative) of the title compound, which was pure by LC-MS and used for further reaction without any purification. Calculated mass=233. Observed mass=234.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[N:11]=[C:10]([NH2:12])[N:9]=[C:8]([NH2:13])[C:7]=1[N+:14]([O-:16])=[O:15].[Cl:17][C:18]1[CH:26]=[CH:25][C:21]([C:22](Cl)=[O:23])=[CH:20][N:19]=1.O>N1C=CC=CC=1>[NH2:12][C:10]1[N:9]=[C:8]([NH:13][C:22]([C:21]2[CH:20]=[N:19][C:18]([Cl:17])=[CH:26][CH:25]=2)=[O:23])[C:7]([N+:14]([O-:16])=[O:15])=[C:6]([C:2]2[O:1][CH:5]=[CH:4][CH:3]=2)[N:11]=1
Reactant: Nc1nc(N)c([N+](=O)[O-])c(-c2ccco2)n1
Reactant: O=C(Cl)c1ccc(Cl)nc1
Solvent: O
Solvent: c1ccncc1
Product: Nc1nc(NC(=O)c2ccc(Cl)nc2)c([N+](=O)[O-])c(-c2ccco2)n1
Temperature: 80 °C
Reaction time: 16 h
Yield: 52.7 %

Procedure:
A solution of 6-(2-furyl)-5-nitropyrimidine-2,4-diamine (500 mg, 2.26 mmol) in pyridine (10 mL) was treated with 6-chloronicotinoyl chloride (438 mg, 2.49 mmol), stirred for 16 h at 80° C., cooled to room temperature, poured into water (100 mL) and extracted with EtOAc (2×25 mL) and the combined organic phase was dried (MgSO4), concentrated in vacuo and purified by chromatography [SiO2; isohexane:EtOAc (3:2)] to give the title compound (430 mg, 82%) as a yellow solid; NMR δH (400 MHz, DMSO) 11.14 (1H, s), 8.86 (1H, d, J 2.5 Hz), 8.27 (1H, dd, J 8.5, 2.5 Hz), 7.93 (1H, m), 7.77 (2H, br s), 7.65 (1H, d, J 7.5 Hz), 7.09 (1H, d, J 4.5 Hz), 6.72-6.70 (1H, m); Retention time 2.41 min.
Reaction SMILES: Cl[C:2]1[C:3]2[N:10]([CH2:11][CH2:12][O:13][CH2:14][CH3:15])[CH:9]=[CH:8][C:4]=2[N:5]=[CH:6][N:7]=1.[Cl:16][C:17]1[CH:18]=[C:19]([CH:21]=[CH:22][C:23]=1[O:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([F:32])[CH:27]=1)[NH2:20]>CN1CCCC1=O.C(=O)([O-])O.[Na+]>[Cl:16][C:17]1[CH:18]=[C:19]([NH:20][C:2]2[C:3]3[N:10]([CH2:11][CH2:12][O:13][CH2:14][CH3:15])[CH:9]=[CH:8][C:4]=3[N:5]=[CH:6][N:7]=2)[CH:21]=[CH:22][C:23]=1[O:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([F:32])[CH:27]=1
Reactant: CCOCCn1ccc2ncnc(Cl)c21
Reactant: Nc1ccc(OCc2cccc(F)c2)c(Cl)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN1CCCC1=O
Product: CCOCCn1ccc2ncnc(Nc3ccc(OCc4cccc(F)c4)c(Cl)c3)c21
Temperature: 140 °C
Reaction time: 7 h
Yield: 51.2 %

Procedure:
To a solution of 4-chloro-5-(2-ethoxyethyl)-5H-pyrrolo[3,2-d]pyrimidine (90 mg) in 1-methyl-2-pyrrolidone (0.7 mL), 3-chloro-4-[(3-fluorobenzyl)oxy]aniline (151 mg) was added, and the mixture was heated to 140° C. and stirred for 7 hrs. The reaction mixture was allowed to cool to room temperature. The reaction mixture was diluted with 5% aqueous sodium hydrogen carbonate solution (20 mL) and extracted with ethyl acetate (25 mL×3). The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the obtained residue was subjected to silica gel column chromatography (basic silica gel, eluent:ethyl acetate/methanol=10/0→8/2). The object fraction was concentrated under reduced pressure. The residue was recrystallized from diisopropyl ether, collected by filtration and dried under reduced pressure to give the title compound (90 mg) as pale-yellow needle crystals.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]([CH2:19]OS(C)(=O)=O)[C:11](=[O:18])[N:12]([CH2:14][CH:15]([CH3:17])[CH3:16])[N:13]=2)=[CH:4][C:3]=1[CH3:25].[NH:26]1[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]1>C(O)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]([CH2:19][N:26]3[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]3)[C:11](=[O:18])[N:12]([CH2:14][CH:15]([CH3:17])[CH3:16])[N:13]=2)=[CH:4][C:3]=1[CH3:25]
Reactant: Cc1cc(-c2cc(COS(C)(=O)=O)c(=O)n(CC(C)C)n2)ccc1F
Reactant: C1CCNCC1
Solvent: CCO
Product: Cc1cc(-c2cc(CN3CCCCC3)c(=O)n(CC(C)C)n2)ccc1F
Temperature: 80 °C

Procedure:
6-(4-Fluoro-3-methylphenyl)-2-isobutyl-4-methane-sulfonyloxymethyl-2H-pyridazin-3-one (80 mg, 0.22 mmol) and piperidine (55 mg, 0.65 mmol) were dissolved in ethanol (0.5 mL), and the mixture was heated at 80° C. for 1 hour under stirring. The solvent was distilled off. The residue was purified by preparative thin-layer chromatography on silica gel [developing solvent: chloroform/methanol (10/1)] to yield the title compound as a slightly yellow oil (73 mg, 94.0%).