Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[CH:6][C:3]=1[CH:4]=[O:5].[CH:13](I)([CH3:15])[CH3:14].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.C(OCC)(=O)C>[CH:13]([O:1][C:2]1[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[CH:6][C:3]=1[CH:4]=[O:5])([CH3:15])[CH3:14]
Reactant: O=Cc1cc([N+](=O)[O-])ccc1O
Reactant: CC(C)I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)Oc1ccc([N+](=O)[O-])cc1C=O
Temperature: 95 °C
Yield: 89.2 %

Procedure:
To commercially available 2-hydroxy-5-nitrobenzaldehyde (500 mg, 3.0 mmol) in DMF (10 mL) in a sealable tube was added isopropyl iodide (1.02 g, 6.0 mmol) and potassium carbonate (1.7 g, 12 mmol). The tube was sealed and heated to 95° C. overnight. After cooling to rt, the reaction was diluted with ethyl acetate. The layers were separated, and the organic layer was washed with brine, then concentrated and purified via silica gel chromatography (10-20% ethyl acetate/hexane) to provide 8A (560 mg, 89%). 1H NMR (400 MHz, CDCl3) δ ppm 1.48 (d, J=6.15 Hz, 6H) 4.69-4.96 (m, 1H) 7.10 (d, J=9.23 Hz, 1H) 8.40 (dd, J=9.23, 3.08 Hz, 1H) 8.70 (d, J=3.08 Hz, 1H) 10.46 (s, 1H).
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH3:8])=[C:6]([O:9][CH2:10][C:11]([F:17])([F:16])[C:12]([F:15])([F:14])[F:13])[CH:5]=[CH:4][N+:3]=1[O-].C(OC(=O)C)(=[O:21])C>S(=O)(=O)(O)O>[OH:21][CH2:1][C:2]1[C:7]([CH3:8])=[C:6]([O:9][CH2:10][C:11]([F:17])([F:16])[C:12]([F:15])([F:14])[F:13])[CH:5]=[CH:4][N:3]=1
Reactant: CC(=O)OC(C)=O
Reactant: Cc1c(OCC(F)(F)C(F)(F)F)cc[n+]([O-])c1C
Agent: O=S(=O)(O)O
Product: Cc1c(OCC(F)(F)C(F)(F)F)ccnc1CO
Temperature: 110 °C
Reaction time: 2 h

Procedure:
Concentrated sulfuric acid (2 drops) was added to a solution of 2,3-dimethyl-4-(2,2,3,3,3-pentafluoropropoxy)pyridine-1-oxide (2.5 g) in acetic anhydride (8 ml) and the mixture was stirred at 110° C. for 2 hours and then concentrated. The residue was dissolved in methanol (30 ml), 2N aqueous sodium hydroxide (20 ml) was added, and the mixture was stirred at room temperature for 2 hours. After concentration, water was added to the residue and the mixture was extracted with ethyl acetate. The extract was dried over magnesium sulfate, the solvent was then distilled off, and the residue was applied to a silica gel (50 g) column. Elution with chloroform-methanol (10:1) and recrystallization from isopropyl ether gave 1.6 g of 2-hydroxymethyl-3-methyl-4-(2,2,3,3,3-pentafluoropropoxy)pyridine as a brown oil.
Reaction SMILES: ClC1C=C(Cl)C=CC=1C1N=C(CC)C(N[C@H]2[C@@H](OCC)CN(C3SC=CN=3)C2)=NC=1CC.Br[C:34]1[N:39]=[CH:38][CH:37]=[CH:36][N:35]=1.[Cl:40][C:41]1[CH:46]=[C:45]([O:47][CH3:48])[CH:44]=[CH:43][C:42]=1[C:49]1[N:50]=[C:51]([CH2:66][CH3:67])[C:52]([NH:57][C@H:58]2[C@@H:62]([O:63][CH2:64][CH3:65])[CH2:61][NH:60][CH2:59]2)=[N:53][C:54]=1[CH2:55][CH3:56]>>[Cl:40][C:41]1[CH:46]=[C:45]([O:47][CH3:48])[CH:44]=[CH:43][C:42]=1[C:49]1[N:50]=[C:51]([CH2:66][CH3:67])[C:52]([NH:57][C@H:58]2[C@@H:62]([O:63][CH2:64][CH3:65])[CH2:61][N:60]([C:34]3[N:39]=[CH:38][CH:37]=[CH:36][N:35]=3)[CH2:59]2)=[N:53][C:54]=1[CH2:55][CH3:56]
Reactant: CCO[C@H]1CNC[C@H]1Nc1nc(CC)c(-c2ccc(OC)cc2Cl)nc1CC
Reactant: Brc1ncccn1
Agent: CCO[C@H]1CN(c2nccs2)C[C@H]1Nc1nc(CC)c(-c2ccc(Cl)cc2Cl)nc1CC
Product: CCO[C@H]1CN(c2ncccn2)C[C@H]1Nc1nc(CC)c(-c2ccc(OC)cc2Cl)nc1CC

Procedure:
Following the procedure for the preparation of 5-(2,4-dichlorophenyl)-N-[(3R,4S)-4-ethoxy-1-(1,3-thiazol-2-yl)pyrrolidin-3-yl]-3,6-diethylpyrazin-2-amine but substituting 2-bromopyrimidine and starting with 5-(2-chloro-4-methoxyphenyl)-N-[(3R,4S)-4-ethoxypyrrolidin-3-yl]-3,6-diethylpyrazin-2-amine provided the title compound as an amorphous solid. 1H NMR (CDCl3) δ 1.17, 1.26–1.34, 2.51, 2.76, 3.54, 3.78, 3.86, 3.97, 4.27, 4.91, 5.25, 6.61, 6.90, 7.02, 7.25, 8.40; IR (diffuse reflectance) 2971, 2392 (w), 2352 (w), 2307 (w), 2265 (w), 2170 (w), 1583 (s), 1569, 1549 (s), 1508 (s), 1481 (s), 1475 (s), 1397, 1392, 1384 cm−1 HRMS (EI) calcd for C25H31ClN6O2 482.2197. found 482.2192.
Reaction SMILES: C([O:8][C@H:9]1[C@H:27]([O:28][CH3:29])[C@@H:26]([CH2:30][OH:31])[O:25][C@H:11]([O:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][C:21]([O:23][CH3:24])=[O:22])[C@@H:10]1[O:32][C@H:33]1[O:62][C@H:61]([CH2:63][O:64]CC2C=CC=CC=2)[C@@H:52]([O:53]CC2C=CC=CC=2)[C@H:43]([O:44]CC2C=CC=CC=2)[C@H:34]1[O:35]CC1C=CC=CC=1)C1C=CC=CC=1.[C@H]1(O[C@@H]2[C@@H](O)[C@H](O)[C@@H](CO)O[C@@H]2OCCCCCCCCC(OC)=O)O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O>>[CH3:29][O:28][C@@H:27]1[C@@H:26]([CH2:30][OH:31])[O:25][C@H:11]([O:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][C:21]([O:23][CH3:24])=[O:22])[C@H:10]([O:32][C@H:33]2[O:62][C@H:61]([CH2:63][OH:64])[C@@H:52]([OH:53])[C@H:43]([OH:44])[C@H:34]2[OH:35])[C@H:9]1[OH:8]
Reactant: COC(=O)CCCCCCCCO[C@H]1O[C@H](CO)[C@@H](OC)[C@H](OCc2ccccc2)[C@H]1O[C@H]1O[C@H](COCc2ccccc2)[C@@H](OCc2ccccc2)[C@H](OCc2ccccc2)[C@H]1OCc1ccccc1
Agent: COC(=O)CCCCCCCCO[C@H]1O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O[C@H]1O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O
Product: COC(=O)CCCCCCCCO[C@H]1O[C@H](CO)[C@@H](OC)[C@H](O)[C@H]1O[C@H]1O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O
Yield: 89.6 %

Procedure:
Compound 41 (52 mg, 0.053 mmol) was hydrogenated as described for the preparation of 44 to provide 61 (25 mg, 89.2%) as a white powder after lyophilization; ›α!D +115 (c 0.28, water); 1H-n.m.r. (D2O): δ 5.20(d, 1H, J1',2' 3.8 Hz, H-1'), 5.13(d, 1H, J1,2 3.8 Hz, H-1), 3.75, 3.46(s, 3H each, 2×OCH3) 2.39(t, 2H J 7.5 Hz, CH2COO).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][CH2:10][CH2:11][CH2:12][O:13][C:14]2[CH:23]=[CH:22][C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH:15]=2)=[CH:5][CH:4]=1.Br[CH2:25][C:26]([O:28][CH2:29][CH3:30])=[O:27]>CC(C)=O>[CH2:29]([O:28][C:26](=[O:27])[CH2:25][N:9]([CH2:10][CH2:11][CH2:12][O:13][C:14]1[CH:23]=[CH:22][C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH:15]=1)[C:6]1[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=1)[CH3:30]
Reactant: COc1ccc(NCCCOc2ccc3ccccc3c2)cc1
Reactant: CCOC(=O)CBr
Solvent: CC(C)=O
Product: CCOC(=O)CN(CCCOc1ccc2ccccc2c1)c1ccc(OC)cc1

Procedure:
A mixture of (4-methoxyphenyl)-(3-(naphthalen-2-yloxy)propyl)amine (0.5 gm, 0.002 mole) and ethyl bromoacetate (0.62 ml, 0.003 mole) was taken in dry acetone (40 ml). It was refluxed for 10 hrs and the progress of reaction checked by TLC. Reaction mixture was filtered and the filtrate was concentrated to get the oily compound {N-(4-methoxy phenyl)-(3-(naphthalen-2-yloxy)propyl)amino}acetic acid ethyl ester, oil (yield 0.75 ml, 96%).
Reaction SMILES: [C:1](N1C=CN=C1)([N:3]1[CH:7]=[CH:6][N:5]=[CH:4]1)=[O:2].[NH2:13][C:14]1[C:15]([Cl:29])=[N:16][C:17]2[C:22]([C:23]=1[NH:24][CH2:25][CH2:26][CH2:27][OH:28])=[CH:21][CH:20]=[CH:19][CH:18]=2.N1C=CC=CC=1.O.C1C[O:40][CH2:39]C1>>[N:3]1([C:1]([O:28][CH2:27][CH2:26][CH2:25][N:24]2[C:23]3[C:22]4[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=4[N:16]=[C:15]([Cl:29])[C:14]=3[N:13]=[C:39]2[OH:40])=[O:2])[CH:7]=[CH:6][N:5]=[CH:4]1
Reactant: C1CCOC1
Reactant: Nc1c(Cl)nc2ccccc2c1NCCCO
Reactant: O=C(n1ccnc1)n1ccnc1
Solvent: c1ccncc1
Solvent: O
Product: O=C(OCCCn1c(O)nc2c(Cl)nc3ccccc3c21)n1ccnc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
1,1′-Carbonyldiimidazole (25 g, 155 mmol) was added to a solution of 3-[(3-amino-2-chloroquinolin-4-yl)amino]propan-1-ol (26 g, 0.010 mol) in THF (140 mL), and the reaction was stirred for three hours at room temperature. Additional 1,1′-carbonyldiimidazole (25 g) and pyridine (50 mL) were added, and the reaction was heated at 90° C. for three hours and allowed to cool. The reaction was cooled to 0° C., and water (300 mL) was added. The resulting mixture was stirred for 30 minutes, and a precipitate formed. The precipitate was isolated by filtration and washed with water to provide 38 g of 3-(4-chloro-2-hydroxy-1H-imidazo[4,5-c]quinolin-1-yl)propyl 1H-imidazole-1-carboxylate as a white solid.
Reaction SMILES: C(N(CC)C(C)C)(C)C.Cl.[NH2:11][CH:12]([C:38]1[CH:43]=[CH:42][CH:41]=[C:40]([C:44]([F:47])([F:46])[F:45])[CH:39]=1)[CH2:13][NH:14][C:15](=[O:37])[CH2:16][N:17]1[C:21](=[O:22])[N:20]([CH2:23][C@H:24]([OH:29])[C:25]([F:28])([F:27])[F:26])[C:19]([C:30]2[CH:35]=[CH:34][C:33]([Cl:36])=[CH:32][CH:31]=2)=[N:18]1.[CH:48](OC1C=CC([N+]([O-])=O)=CC=1)=[O:49].[OH-].[Li+]>C1COCC1.O>[Cl:36][C:33]1[CH:32]=[CH:31][C:30]([C:19]2[N:20]([CH2:23][C@H:24]([OH:29])[C:25]([F:28])([F:27])[F:26])[C:21](=[O:22])[N:17]([CH2:16][C:15]([NH:14][CH2:13][CH:12]([NH:11][CH:48]=[O:49])[C:38]3[CH:43]=[CH:42][CH:41]=[C:40]([C:44]([F:47])([F:46])[F:45])[CH:39]=3)=[O:37])[N:18]=2)=[CH:35][CH:34]=1
Reactant: O=COc1ccc([N+](=O)[O-])cc1
Reactant: NC(CNC(=O)Cn1nc(-c2ccc(Cl)cc2)n(C[C@H](O)C(F)(F)F)c1=O)c1cccc(C(F)(F)F)c1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: O=CNC(CNC(=O)Cn1nc(-c2ccc(Cl)cc2)n(C[C@H](O)C(F)(F)F)c1=O)c1cccc(C(F)(F)F)c1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
20 μl (112 μmol) of N,N-diisopropylethylamine were added to a solution of 60 mg (102 μmol) of the compound of Example 58A in 1 ml of THF. The mixture was cooled to 0° C., 18 mg (107 μmol) of 4-nitrophenyl formate were then added a little at a time and stirring was continued at 0° C. for 1 h. Since LC/MS analysis of the reaction mixture indicated the additional formation of an O-formylated byproduct, 408 μl of a 1 N solution of lithium hydroxide in water were added to the reaction mixture. Stirring of the mixture was then continued at RT overnight. The volatile components were then removed on a rotary evaporator. The residue was dissolved in a little DMSO and separated by preparative HPLC [Method 8]. The product-containing fraction was freed from the solvent on a rotary evaporator and the residue was dried under high vacuum. This gave 35 mg (59% of theory) of the title compound.
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[N:6][N:5]=[C:4]2[NH:14][N:15]=C(C3C=CC=CC=3)[C:3]=12.[CH3:23][C:24]1[CH:25]=[C:26]([CH:29]=[CH:30][CH:31]=1)[CH:27]=O.[CH3:32]NN>>[Cl:1][C:2]1[C:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[N:6][N:5]=[C:4]2[N:14]([CH3:32])[N:15]=[C:27]([C:26]3[CH:25]=[C:24]([CH3:23])[CH:31]=[CH:30][CH:29]=3)[C:3]=12
Reactant: CNN
Reactant: Clc1c(-c2ccccc2)nnc2[nH]nc(-c3ccccc3)c12
Reactant: Cc1cccc(C=O)c1
Product: Cc1cccc(-c2nn(C)c3nnc(-c4ccccc4)c(Cl)c23)c1
Reaction time: 16 h

Procedure:
Compound 19 was synthesised following similar procedures outlined in Example 22 (Compound 9), using 3-methylbenzaldehyde instead of benzaldehyde in Step 1 and methyl hydrazine instead of hydrazine hydrate in Step 3. As a slightly modified procedure, Step 3 was performed at 60° C. for 16 h in a sealed tube. Subsequently, the reaction mixture was partitioned between CH2Cl2 and water. The organic phase was separated using a phase separating cartridge and concentrated in vacuo. The crude residue was purified by column chromatography (silica gel, gradient 5 to 20% ethyl acetate/isohexane) yielding Compound 19 as a solid.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([N:8]([CH:20]2[CH2:24][CH2:23][CH2:22][CH2:21]2)[CH2:9][C:10]([CH3:19])([CH3:18])[C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[C:5]([N+:25]([O-:27])=[O:26])=[CH:4][N:3]=1.N[C:29]1[CH:38]=[CH:37][C:32]([C:33]([O:35][CH3:36])=[O:34])=[CH:31][C:30]=1[O:39][CH3:40].[CH3:41]CN(C(C)C)C(C)C>CC(C)CC(O)C>[C:14]([O:13][C:11](=[O:12])[C:10]([CH3:19])([CH3:18])[CH2:9][N:8]([CH:20]1[CH2:24][CH2:23][CH2:22][CH2:21]1)[C:6]1[C:5]([N+:25]([O-:27])=[O:26])=[CH:4][N:3]=[C:2]([NH:7][C:29]2[CH:38]=[CH:37][C:32]([C:33]([O:35][CH3:36])=[O:34])=[CH:31][C:30]=2[O:39][CH3:40])[CH:41]=1)([CH3:17])([CH3:16])[CH3:15]
Reactant: CCN(C(C)C)C(C)C
Reactant: CC(C)(C)OC(=O)C(C)(C)CN(c1nc(Cl)ncc1[N+](=O)[O-])C1CCCC1
Reactant: COC(=O)c1ccc(N)c(OC)c1
Solvent: CC(C)CC(C)O
Product: COC(=O)c1ccc(Nc2cc(N(CC(C)(C)C(=O)OC(C)(C)C)C3CCCC3)c([N+](=O)[O-])cn2)c(OC)c1
Yield: 61.3 %

Procedure:
tert-butyl 3-[(2-chloro-5-nitro-pyrimidin-4-yl)-cyclopentyl-amino]-2,2-dimethyl-propanoate (1.5 g, 3.760 mmol), methyl 4-amino-3-methoxy-benzoate (817.5 mg, 4.512 mmol) and DIPEA (728.9 mg, 982.3 μL, 5.640 mmol) in 4-methylpentan-2-ol were treated under microwave at 140 C for 2 hours. The mixture was concentrated and purification by flash chromatography, eluting with 5% ethylacetate/petether to remove impurities followed by 10% ethylacetate/pet ether to elute product, gave methyl 4-(4-((3-tert-butoxy-2,2-dimethyl-3-oxopropyl) (cyclopentyl)amino)-5-nitropyridin-2-ylamino)-3-methoxybenzoate as a yellow oil (1.25 g, 61%). NMR CDCl3 1.18 (6H, s), 1.46 (9H, s), 1.52-1.58 (2H, m), 1.63-1.70 (2H, m), 1.72-1.80 (2H, m), 1.92-1.98 (2H, m), 3.62-3.68 (1H, m), 3.85-4.0 (8H, m), 7.55 (1H, s), 7.72-7.75 (1H, m), 8.12 (1H, brs), 8.5 (1H, d), 8.97 (1H, s); MS (ES+) 544.1 (ES−) 542.1
Reaction SMILES: [C:1](Cl)(Cl)=[O:2].[O:5]=[C:6]1[NH:10][CH2:9][CH2:8][N:7]1[CH2:11][C:12]#[N:13].N1C=CC=CC=1.[CH3:20][N:21]1[CH:25]=[C:24]([C:26]2[CH:31]=[C:30]([O:32][C:33]3[CH:34]=[CH:35][C:36]([NH2:39])=[N:37][CH:38]=3)[CH:29]=[CH:28][N:27]=2)[CH:23]=[N:22]1>C(Cl)Cl>[C:12]([CH2:11][N:7]1[CH2:8][CH2:9][N:10]([C:6]([NH:39][C:36]2[CH:35]=[CH:34][C:33]([O:32][C:30]3[CH:29]=[CH:28][N:27]=[C:26]([C:24]4[CH:23]=[N:22][N:21]([CH3:20])[CH:25]=4)[CH:31]=3)=[CH:38][N:37]=2)=[O:5])[C:1]1=[O:2])#[N:13]
Reactant: O=C(Cl)Cl
Reactant: Cn1cc(-c2cc(Oc3ccc(N)nc3)ccn2)cn1
Reactant: N#CCN1CCNC1=O
Solvent: c1ccncc1
Solvent: ClCCl
Product: Cn1cc(-c2cc(Oc3ccc(NC(=O)N4CCN(CC#N)C4=O)nc3)ccn2)cn1
Temperature: 25 °C
Reaction time: 2 h
Yield: 23 %

Procedure:
A 0° C. solution of phosgene (15% in toluene, 1.37 mL, 1.948 mmol) in DCM (5 mL) was treated drop-wise with a solution of 2-(2-oxoimidazolidin-1-yl)acetonitrile (0.065 g, 0.519 mmol) and pyridine (0.2 mL, 2.473 mmol) in DCM (5 mL), warmed to RT, stirred for 2 h, then concentrated to dryness. The residue was dissolved in DCM (5 mL), cooled to 0° C., treated with a solution of Example A2 (0.069 g, 0.260 mmol) and pyridine (0.2 mL) in DCM (5 mL), warmed to RT and stirred for 3 h. The mixture was treated with satd. NaHCO3, extracted with DCM (3×) and the combined organics were dried over Na2SO4, concentrated to dryness and purified via silica gel chromatography (MeOH/EtOAc) to afford 3-(cyanomethyl)-N-(5-((2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yl)oxy)pyridin-2-yl)-2-oxoimidazolidine-1-carboxamide (25 mg, 22%). 1H NMR (400 MHz, DMSO-d6): δ 10.69 (s, 1 H), 8.37 (d, J=5.7 Hz, 1 H), 8.25-8.24 (m, 2 H), 8.07 (d, J=9.0 Hz, 1 H), 7.96 (d, J=0.7 Hz, 1 H), 7.74 (dd, J=9.0, 2.9 Hz, 1 H), 7.23 (d, J=2.4 Hz, 1 H), 6.70 (dd, J=5.7, 2.4 Hz, 1H), 4.47 (s, 2 H), 3.93-3.84 (m, 5 H), 3.54 (t, J=8.2 Hz, 2H); MS (ESI) m/z: 419.2 (M+H+).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]([S:10][CH2:11][CH2:12][O:13][C:14](=[O:22])[C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([Cl:21])[CH:16]=2)=[N:8][CH:9]=1)([O-])=O>C1(C)C=CC=CC=1.CO.[Pd]>[NH2:1][C:4]1[CH:5]=[CH:6][C:7]([S:10][CH2:11][CH2:12][O:13][C:14](=[O:22])[C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([Cl:21])[CH:16]=2)=[N:8][CH:9]=1
Reactant: O=C(OCCSc1ccc([N+](=O)[O-])cn1)c1cccc(Cl)c1
Agent: [Pd]
Solvent: CO
Solvent: Cc1ccccc1
Product: Nc1ccc(SCCOC(=O)c2cccc(Cl)c2)nc1
Reaction time: 1 h

Procedure:
A mixture of 2-[(5-nitro-2-pyridinyl)thio]ethyl 3-chlorobenzoate (5) (0.24 g, 0.71 mmol) and 10% Pd/C (0.10 g) in toluene or methanol was agitated under a hydrogen atmosphere (40 PSI) for 1 h. The reaction mixture was filtered through Celite® and concentrated to give 2-[(5-amino-2-pyridinyl)thio]ethyl-3-chlorobenzoate (51), LCMS: purity: 99%; MS (m/e): 309 (MH+), which was used without further purification. Acetyl chloride (4.6 μL, 0.064 mmol) was added to a room temperature solution of 2-[(5-amino-2-pyridinyl)thio]ethyl-3-chlorobenzoate (51) (18.9 mg, 0.061 mmol) and triethylamine (18 μL, 0.13 mmol) in anhydrous dichloromethane (1.0 mL), After 16 h, the reaction mixture was diluted with dichloromethane and washed with 1N HCl and brine and then dried over anhydrous MgSO4. Purification by silica gel chromatography provided 2-[(5-acetylamino-2-pyridinyl)thio]ethyl-3-chlorobenzoate (52), LCMS: purity: 99%; MS (m/e): 351 (MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH3:22])[C:7](=[O:21])[C:8]3[CH:18]=[C:17]([CH2:19]Cl)[CH:16]=[N:15][C:9]=3[N:10]([CH2:13][CH3:14])[C:11]=2[N:12]=1.[C:23]([O:32][CH3:33])(=[O:31])[C:24]1[C:25](=[CH:27][CH:28]=[CH:29][CH:30]=1)[OH:26]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH3:22])[C:7](=[O:21])[C:8]3[CH:18]=[C:17]([CH2:19][O:26][C:25]4[CH:27]=[CH:28][CH:29]=[CH:30][C:24]=4[C:23]([O:32][CH3:33])=[O:31])[CH:16]=[N:15][C:9]=3[N:10]([CH2:13][CH3:14])[C:11]=2[N:12]=1
Reactant: COC(=O)c1ccccc1O
Reactant: CCN1c2ncc(CCl)cc2C(=O)N(C)c2ccc(Cl)nc21
Product: CCN1c2ncc(COc3ccccc3C(=O)OC)cc2C(=O)N(C)c2ccc(Cl)nc21
Yield: 57 %

Procedure:
Using a procedure analogous to that described in Example 98, the title compound, m.p. 155°-156° C., was prepared from 2-chloro-8-chloromethyl-5,11-dihydro-11-ethyl-5-methyl-6H-dipyrido[3,2-b:2',3'-e][1,4]diazepin-6-one and methyl salicylate. The yield was 57% of theory.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9](=[O:13])[CH:8]([CH2:14]/[CH:15]=[CH:16]/[CH:17]=O)[CH2:7][CH2:6]2.[F:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[CH2:26][NH:27][CH:28]=[CH:29][C:30](=[O:32])[CH3:31]>>[C:30]([C:29]1[CH:15]([CH2:14][CH:8]2[CH2:7][CH2:6][C:5]3[C:10](=[CH:11][CH:12]=[C:3]([O:2][CH3:1])[CH:4]=3)[C:9]2=[O:13])[CH:16]=[CH:17][N:27]([CH2:26][C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=2[F:19])[CH:28]=1)(=[O:32])[CH3:31]
Reactant: COc1ccc2c(c1)CCC(C/C=C/C=O)C2=O
Reactant: CC(=O)C=CNCc1ccccc1F
Product: COc1ccc2c(c1)CCC(CC1C=CN(Cc3ccccc3F)C=C1C(C)=O)C2=O

Procedure:
The title compound 55 is prepared according to the procedure reported in step D of Example 8 with aldehyde 54 (100 mg, 0.41 mmol) and enamine 56 (115 mg, 0.59 mmol) as reactants. Purification by column chromatography on SiO2 (Petroleum/EtOAc=2:1) afford the title compound 55 as a yellow solid. (Yield 0.11 g, 65%).
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[C:5]([OH:12])[CH:6]=[CH:7][CH:8]=2)[N:3]=1.C1(=O)O[CH2:16][CH2:15][O:14]1.O(C(C)(C)C)[K]>CN(C=O)C.[Cl-].[Na+].O>[NH2:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[C:5]([O:12][CH2:16][CH2:15][OH:14])[CH:6]=[CH:7][CH:8]=2)[N:3]=1
Reactant: Nc1ccc2cccc(O)c2n1
Reactant: O=C1OCCO1
Agent: CC(C)(C)O[K]
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Nc1ccc2cccc(OCCO)c2n1
Temperature: 90 °C
Reaction time: 15 h
Yield: 27.7 %

Procedure:
A mixture of 2-amino-8-quinolinol (3.20 g, 20.0 mmol), ethylene carbonate (1.76 g, 20.0 mmol) and KO-t-Bu (2.24 g, 20.0 mmol) in DMF (20 mL) was stirred at 90° C. for 15 h The mixture was poured into brine, extracted with EtOAc, dried (MgSO4), and concentrated under reduced pressure. The residue was purified by chromatography on silica gel using toluene/EtOAc/MeOH (50:50-2) as eluent to give 1.13 g (28%) of the title product as a solid HRMS m/z calcd for C11H12N2O2 (M)+ 204.0899. found 204.0906
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[C:13]2([CH:18]=[CH:17][C:16](=[O:19])[CH:15]=[CH:14]2)[N:12]=[C:11]([N:20]2[CH2:25][CH2:24][N:23]([CH2:26][C:27]3[CH:32]=[CH:31][C:30]([CH3:33])=[CH:29][CH:28]=3)[CH2:22][CH2:21]2)[CH:10]=1>ClC1C=CC(Cl)=CC=1Cl.C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[CH:10]=[C:11]([N:20]2[CH2:21][CH2:22][N:23]([CH2:26][C:27]3[CH:28]=[CH:29][C:30]([CH3:33])=[CH:31][CH:32]=3)[CH2:24][CH2:25]2)[N:12]2[CH:18]=[CH:17][C:16](=[O:19])[CH:15]=[CH:14][C:13]=12
Reactant: COc1ccccc1C1=CC(N2CCN(Cc3ccc(C)cc3)CC2)=NC12C=CC(=O)C=C2
Solvent: ClCCl
Solvent: Clc1ccc(Cl)c(Cl)c1
Product: COc1ccccc1-c1cc(N2CCN(Cc3ccc(C)cc3)CC2)n2ccc(=O)ccc12
Yield: 64.3 %

Procedure:
A solution of 4-(2-methoxyphenyl)-2-[4-(4-methylbenzyl)-1-piperazinyl]-1-azaspiro[4.5]deca-1,3,6,9-tetraen-8-one (2.8 g) in 1,2,4-trichlorobenzene (80 cc) is heated for 4 hours at a temperature of about 210° C. After evaporation to dryness under reduced pressure (1 mm Hg; 0.13 kPa) at 40° C., the residue obtained is dissolved in methylene chloride (50 cc) and the solution is poured into silica (60 g) contained in a column 2 cm in diameter. Elution is first performed with a mixture of methylene chloride and methanol (99:1 by volume) (200 cc); the corresponding eluates are rejected. Eluation is then performed with a mixture of methylene chloride and methanol (99:1 by volume) (450 cc) and the corresponding eluate is evaporated to dryness under reduced pressure (20 mm Hg; 2.7 kPa) at 40° C. After recrystallization of the residue in acetonitrile (75 cc), 1-(2-methoxyphenyl)-3-[4-(4-methylbenzyl)-1-piperazinyl]-7H-pyrrolo[1,2-a]azepin-7-one (1.8 g), m.p. 186° C., is obtained.
Reaction SMILES: [NH3:1].[Cl:2][S:3]([C:6]1[CH:15]=[CH:14][CH:13]=[C:12]([F:16])[C:7]=1[C:8](OC)=[O:9])(=[O:5])=[O:4]>O1CCCC1>[ClH:2].[F:16][C:12]1[C:7]2[C:8](=[O:9])[NH:1][S:3](=[O:5])(=[O:4])[C:6]=2[CH:15]=[CH:14][CH:13]=1
Reactant: COC(=O)c1c(F)cccc1S(=O)(=O)Cl
Reactant: N
Solvent: C1CCOC1
Product: Cl
Product: O=C1NS(=O)(=O)c2cccc(F)c21

Procedure:
At 20° to 28° C. and while stirring, 42.5 g of ammonia was gassed into a mixture of 252.6 g (1 mol) of methyl 2-chlorosulfonyl-6-fluorobenzoate in 700 ml of anhydrous tetrahydrofuran. After the mixture had been stirred for an hour at 25° C., the precipitate was filtered off, dissolved in water, and extracted once with ethyl acetate. Acidification of the aqueous phase with concentrated hydrochloric acid gave 4% of theory of 4-fluoro-1,2-benzisothiazol-3-one-1,1-dioxide of m.p. 210° to 212° C.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[CH:10]([S:12]([N:15]=[C:16]=[O:17])(=[O:14])=[O:13])[CH3:11])([O-:3])=[O:2].[CH3:18][O:19][C:20]1[CH:25]=[C:24]([O:26][CH3:27])[N:23]=[C:22]([NH2:28])[N:21]=1>C(#N)C>[CH3:18][O:19][C:20]1[CH:25]=[C:24]([O:26][CH3:27])[N:23]=[C:22]([NH:28][C:16]([NH:15][S:12]([CH:10]([C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N+:1]([O-:3])=[O:2])[CH3:11])(=[O:14])=[O:13])=[O:17])[N:21]=1
Reactant: CC(c1ccccc1[N+](=O)[O-])S(=O)(=O)N=C=O
Reactant: COc1cc(OC)nc(N)n1
Solvent: CC#N
Product: COc1cc(OC)nc(NC(=O)NS(=O)(=O)C(C)c2ccccc2[N+](=O)[O-])n1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 4.0 g of the product from Example 15 and 2.2 g of 4,6-dimethoxy-2-aminopyrimidine in 29 ml dry acetonitrile was heated to ca. 60° C. for 11/2 hours and then stirred at room temperature overnight. The product, which had precipitated, was collected and washed with 1-chlorobutane and then dried in vacuo. The yield of N-[(4,6-dimethoxypyrimidin-2-yl)aminocarbonyl]-1-(2-nitrophenyl)ethanesulfonamide was 3.1 g white solid, m.p. 168°-170° C.
Reaction SMILES: [CH3:1][C:2](=[CH:6][C:7]1[CH:12]=[CH:11][C:10]([N+:13]([O-])=O)=[CH:9][CH:8]=1)[C:3]([OH:5])=[O:4].[CH3:16]O>CCOC(C)=O.CCOCC.CC(O)=O>[CH3:16][O:5][C:3](=[O:4])/[C:2](/[CH3:1])=[CH:6]/[C:7]1[CH:12]=[CH:11][C:10]([NH2:13])=[CH:9][CH:8]=1
Reactant: CO
Reactant: CC(=Cc1ccc([N+](=O)[O-])cc1)C(=O)O
Solvent: CC(=O)O
Solvent: CCOCC
Solvent: CCOC(C)=O
Product: COC(=O)/C(C)=C/c1ccc(N)cc1
Temperature: 25 °C

Procedure:
α-Methyl-4-nitrocinnamic acid (53 mg, 0.25 mmol) was dissolved in EtOAc and MeOH and a solution of CH2N2 in Et2O was added until a persistent yellow color was observed. A couple of drops of AcOH were added to destroy the excess CH2N2. The mixture was diluted with EtOAc and the organic layer was washed with H2O, aqueous NaOH (1N) and brine, dried over anhydrous MgSO4 and concentrated to dryness. The residue was re-dissolved in EtOH (2 mL), SnCl2-2H2O (289 mg, 1.28 mmol) was added and the reaction mixture was heated to reflux for 1 h. The mixture was cooled to RT, diluted with EtOAc and quenched by the addition of aqueous, saturated NaHCO3. The organic layer was separated, washed with brine, dried over anhydrous MgSO4 and concentrated to dryness to give the title compound (40 mg) as a yellow solid.