Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([OH:20])[CH2:13][CH2:12][N:11]([CH:14]3[CH:18]([OH:19])[CH2:17][NH:16][CH2:15]3)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.Cl[C:22]1[C:31]2[C:26](=[CH:27][C:28]([Cl:32])=[CH:29][CH:30]=2)[N:25]=[CH:24][N:23]=1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([OH:20])[CH2:13][CH2:12][N:11]([C@@H:14]3[C@@H:18]([OH:19])[CH2:17][N:16]([C:22]4[C:31]5[C:26](=[CH:27][C:28]([Cl:32])=[CH:29][CH:30]=5)[N:25]=[CH:24][N:23]=4)[CH2:15]3)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1
Reactant: Clc1ccc2c(Cl)ncnc2c1
Reactant: OC1CNCC1N1CCC(O)(c2ccc(Cl)cc2)CC1
Product: O[C@H]1CN(c2ncnc3cc(Cl)ccc23)C[C@@H]1N1CCC(O)(c2ccc(Cl)cc2)CC1

Procedure:
The title compound was prepared following general procedures described above from 4-(4-Chlorophenyl)-1-(4-hydroxy-pyrrolidin-3-yl)-piperidin-4-ol and 4,7-dichloroquinazoline. 1H-NMR (300 MHz, DMSO): δ 1.57 (2H, m), 1.90 (2H, m), 2.60-2.70 (3H, m), 2.96 (2H, m), 3.70 (1H, m), 3.85 (1H, m), 4.10 (2H, m), 4.36 (1H, m), 4.90 (1H, s), 5.32 (1H, d), 7.40 (4H, dd), 7.48 (1H, m), 7.73 (1H, d), 8.30 (1H, d), 8.45 (1H, s). Retention Time (LC, method, AA standard): 1.48 min MS (M+H+): 459.
Reaction SMILES: [CH3:1][C:2]([C:22]1[CH:27]=[CH:26][C:25]([O:28][C:29]2[CH:34]=[CH:33][C:32]3[C:35](O[C:38](=[O:39])[C:31]=3[CH:30]=2)=[O:36])=[CH:24][CH:23]=1)([C:4]1[CH:9]=[CH:8][C:7]([O:10][C:11]2[CH:16]=[CH:15][C:14]3[C:17](O[C:20](=[O:21])[C:13]=3[CH:12]=2)=[O:18])=[CH:6][CH:5]=1)[CH3:3].[NH2:40][C:41]1[CH:46]=[CH:45][C:44]([OH:47])=[CH:43][CH:42]=1>CN(C=O)C>[CH3:3][C:2]([C:22]1[CH:27]=[CH:26][C:25]([O:28][C:29]2[CH:30]=[C:31]3[C:32](=[CH:33][CH:34]=2)[C:35](=[O:36])[N:40]([C:41]2[CH:46]=[CH:45][C:44]([OH:47])=[CH:43][CH:42]=2)[C:38]3=[O:39])=[CH:24][CH:23]=1)([C:4]1[CH:9]=[CH:8][C:7]([O:10][C:11]2[CH:12]=[C:13]3[C:14](=[CH:15][CH:16]=2)[C:17](=[O:18])[N:40]([C:41]2[CH:46]=[CH:45][C:44]([OH:47])=[CH:43][CH:42]=2)[C:20]3=[O:21])=[CH:6][CH:5]=1)[CH3:1]
Reactant: Nc1ccc(O)cc1
Reactant: CC(C)(c1ccc(Oc2ccc3c(c2)C(=O)OC3=O)cc1)c1ccc(Oc2ccc3c(c2)C(=O)OC3=O)cc1
Solvent: CN(C)C=O
Product: CC(C)(c1ccc(Oc2ccc3c(c2)C(=O)N(c2ccc(O)cc2)C3=O)cc1)c1ccc(Oc2ccc3c(c2)C(=O)N(c2ccc(O)cc2)C3=O)cc1

Procedure:
247.2 g of 4,4′-(4,4′-isopropylidenediphenoxy)bis(phthalic anhydride) (0.47 mol) are dissolved in 200 ml of DMF in a 3 l three-necked flask with reflux divider, reflux condenser and distillation bridge. 105.8 g of 4-aminophenol (0.095 mol) are slowly added dropwise. The mixture is heated at reflux for 2 hours. Water is continuously removed by distillation during this process. The mixture is then cooled, diluted with 500 ml of dichloromethane, and washed twice with water. Finally, the product is washed with saturated NaCl solution. The organic phase is concentrated, and the residue is brought to the boil in 300 ml of methanol. After cooling, the residue is isolated by suction filtration and then washed with 200 ml of methanol.
Reaction SMILES: [CH3:1][S:2]([NH:5][C:6]1[CH:7]=[C:8]([C:12]2[CH:13]=[C:14]3[C:18](=[C:19]([C:21]([NH2:23])=[O:22])[CH:20]=2)[NH:17][N:16]=[C:15]3[CH:24]2[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]2)[CH:9]=[CH:10][CH:11]=1)(=[O:4])=[O:3].C(N(C(C)C)CC)(C)C.[CH3:39][N:40]1[CH:44]=[C:43]([S:45](Cl)(=[O:47])=[O:46])[N:42]=[C:41]1[CH3:49]>CN(C1C=CN=CC=1)C>[CH3:39][N:40]1[CH:44]=[C:43]([S:45]([N:27]2[CH2:28][CH2:29][CH:24]([C:15]3[C:14]4[C:18](=[C:19]([C:21]([NH2:23])=[O:22])[CH:20]=[C:12]([C:8]5[CH:9]=[CH:10][CH:11]=[C:6]([NH:5][S:2]([CH3:1])(=[O:4])=[O:3])[CH:7]=5)[CH:13]=4)[NH:17][N:16]=3)[CH2:25][CH2:26]2)(=[O:47])=[O:46])[N:42]=[C:41]1[CH3:49]
Reactant: CS(=O)(=O)Nc1cccc(-c2cc(C(N)=O)c3[nH]nc(C4CCNCC4)c3c2)c1
Reactant: Cc1nc(S(=O)(=O)Cl)cn1C
Agent: CN(C)c1ccncc1
Solvent: CCN(C(C)C)C(C)C
Product: Cc1nc(S(=O)(=O)N2CCC(c3n[nH]c4c(C(N)=O)cc(-c5cccc(NS(C)(=O)=O)c5)cc34)CC2)cn1C
Yield: 12.5 %

Procedure:
Following the general procedure of Example 11, 5-{3-[(methylsulfonyl)-amino]phenyl}-3-(4-piperidinyl)-1H-indazole-7-carboxamide (Example 67) (0.07 mmol), diisopropylethylamine (100 uL, 0.56 mmol), DMAP (25 mg, 0.014 mmol) and 1,2-dimethyl-1H-imidazole-4-sulfonyl chloride (33 mg, 0.17 mmol) were reacted to give the title compound (5 mg, 13% for 3 steps).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([N:14]([CH2:25][C:26](O)=[O:27])[C:15]2[CH:16]=[C:17]3[C:22](=[CH:23][CH:24]=2)[N:21]=[CH:20][CH:19]=[CH:18]3)(=[O:13])=[O:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH2:29]([NH:36][CH2:37][CH3:38])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>>[CH2:29]([N:36]([CH2:37][CH3:38])[C:26](=[O:27])[CH2:25][N:14]([S:11]([C:8]1[CH:9]=[CH:10][C:5]([C:1]([CH3:2])([CH3:4])[CH3:3])=[CH:6][CH:7]=1)(=[O:13])=[O:12])[C:15]1[CH:16]=[C:17]2[C:22](=[CH:23][CH:24]=1)[N:21]=[CH:20][CH:19]=[CH:18]2)[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: CCNCc1ccccc1
Reactant: CC(C)(C)c1ccc(S(=O)(=O)N(CC(=O)O)c2ccc3ncccc3c2)cc1
Product: CCN(Cc1ccccc1)C(=O)CN(c1ccc2ncccc2c1)S(=O)(=O)c1ccc(C(C)(C)C)cc1

Procedure:
prepared by reaction of [(4-tert-butyl-benzenesulfonyl)-quinolin-6-yl-amino]-acetic acid with benzyl-ethyl-amine
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([CH2:7][C:8]([N:10]2[CH2:15][CH2:14][N:13]([CH2:16][C:17](=[O:23])[N:18]3[CH2:22][CH2:21][CH2:20][CH2:19]3)[CH2:12][CH2:11]2)=[O:9])[N:6]=1.[Cl:24][C:25]1[CH:26]=[CH:27][C:28]([C:31](O)=[O:32])=[N:29][CH:30]=1>>[O:9]=[C:8]([N:10]1[CH2:15][CH2:14][N:13]([CH2:16][C:17](=[O:23])[N:18]2[CH2:19][CH2:20][CH2:21][CH2:22]2)[CH2:12][CH2:11]1)[CH2:7][C:5]1[N:6]=[C:2]([NH:1][C:31]([C:28]2[CH:27]=[CH:26][C:25]([Cl:24])=[CH:30][N:29]=2)=[O:32])[S:3][CH:4]=1
Reactant: Nc1nc(CC(=O)N2CCN(CC(=O)N3CCCC3)CC2)cs1
Reactant: O=C(O)c1ccc(Cl)cn1
Product: O=C(Nc1nc(CC(=O)N2CCN(CC(=O)N3CCCC3)CC2)cs1)c1ccc(Cl)cn1

Procedure:
In analogy to example 37.5, 2-(2-amino-thiazol-4-yl)-1-[4-(2-oxo-2-pyrrolidin-1-yl-ethyl)-piperazin-1-yl]-ethanone (example 37.4) was coupled with 5-chloro-pyridine-2-carboxylic acid, using general method D, to give 5-chloro-pyridine-2-carboxylic acid (4-{2-oxo-2-[4-(2-oxo-2-pyrrolidin-1-yl-ethyl)-piperazin-1-yl]-ethyl}-thiazol-2-yl)-amide. Yellow solid. MS 477.3 ([M+H]+)
Reaction SMILES: [C:1](=O)([O-])[O-].[K+].[K+].[C:7]([O:11][C:12]([NH:14][C@H:15]1[CH2:20][CH2:19][C@H:18]([C:21]([OH:23])=[O:22])[CH2:17][CH2:16]1)=[O:13])([CH3:10])([CH3:9])[CH3:8].CI>CN(C)C=O>[CH3:1][O:22][C:21]([C@H:18]1[CH2:17][CH2:16][C@H:15]([NH:14][C:12]([O:11][C:7]([CH3:10])([CH3:8])[CH3:9])=[O:13])[CH2:20][CH2:19]1)=[O:23]
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@H](C(=O)O)CC1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Product: COC(=O)[C@H]1CC[C@H](NC(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
Potassium carbonate (877 mg, 6.34 mmol, 1.05 eq) is added at room temperature to a stirred solution of trans-4-tert-butoxycarbonylamino-cyclohexanecarboxylic acid (1.50 g, 6.04 mmol, 1.0 eq) in N,N-dimethylformamide (30 mL), followed by methyl iodide (395 μL, 6.34 mmol, 1.05 eq). After 5 hours stirring at room temperature, solvent is evaporated and the residue is extracted with ethyl acetate (3×30 mL) and water (30 mL). The combined organic layers are washed with brine (30 mL), dried over sodium sulfate, filtered and concentrated to afford trans-4-tert-butoxycarbonylamino-cyclohexanecarboxylic acid methyl ester as a yellow solid (1.60 g, 98% yield).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:17])/[CH:5]=[CH:6]/[C:7]1[CH:12]=[C:11]([O:13][CH3:14])[C:10]([Cl:15])=[CH:9][C:8]=1[NH2:16])[CH3:2].[CH3:18][S:19](Cl)(=[O:21])=[O:20]>N1C=CC=CC=1>[CH2:1]([O:3][C:4](=[O:17])/[CH:5]=[CH:6]/[C:7]1[CH:12]=[C:11]([O:13][CH3:14])[C:10]([Cl:15])=[CH:9][C:8]=1[NH:16][S:19]([CH3:18])(=[O:21])=[O:20])[CH3:2]
Reactant: CS(=O)(=O)Cl
Reactant: CCOC(=O)/C=C/c1cc(OC)c(Cl)cc1N
Solvent: c1ccncc1
Product: CCOC(=O)/C=C/c1cc(OC)c(Cl)cc1NS(C)(=O)=O

Procedure:
(E)-3-(2-Amino-4-chloro-5-methoxyphenyl)-acrylic acid ethyl ester (250 mg; 0.98 mmol) in pyridine (2 ml) was treated with methanesulfonyl chloride (0.15 ml; 2 mmol) for 15 min. at room temperature. The reaction mixture was poured on water and extracted with TBME three times. The combined organic phases were evaporated to dryness and purified via chromatography (SiO2; acetone/hexanes 2/8) to yield the title compound as slightly yellow crystals (216 mg; 66%)
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([C:7](=[O:20])[N:8]3[C:15]4[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=4[NH:13][C:9]3=[N:10]2)=[CH:5][CH:4]=1.Cl[CH2:22][CH2:23][N:24]([CH2:28][CH2:29][CH3:30])[CH2:25][CH2:26][CH3:27]>>[CH2:25]([N:24]([CH2:28][CH2:29][CH3:30])[CH2:23][CH2:22][N:13]1[C:9]2=[N:10][C:11]3[C:6]([C:7](=[O:20])[N:8]2[C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][C:14]1=2)=[CH:5][CH:4]=[C:3]([O:2][CH3:1])[CH:12]=3)[CH2:26][CH3:27]
Reactant: COc1ccc2c(=O)n3c(nc2c1)[nH]c1ccccc13
Reactant: CCCN(CCC)CCCl
Product: CCCN(CCC)CCn1c2ccccc2n2c(=O)c3ccc(OC)cc3nc12

Procedure:
6-(2-di(n-Propyl)aminoethyl)-3-methoxybenzimidazo[2,1-b]-quinazolin-12(6H)one is prepared with 3-methoxybenzimidazo[2,1-b]-quinazolin-12(6H)one and 2-chlorodi(n-propyl)aminoethane.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([OH:14])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].O[C:16]1[CH:23]=[CH:22][C:19]([CH:20]=[O:21])=[CH:18][CH:17]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(OCC)(=O)C>C1COCC1>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:16]2[CH:23]=[CH:22][C:19]([CH:20]=[O:21])=[CH:18][CH:17]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Reactant: O=Cc1ccc(O)cc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCC(Oc2ccc(C=O)cc2)CC1
Reaction time: 8 h

Procedure:
770 mg (3.83 mmol) of 1-t-butoxycarbonyl-4-hydroxypiperidine and 467 mg (3.83 mmol) of 4-hydroxybenzaldehyde were dissolved in 20 ml of THF. 1.2 g (4.6 mmol) of triphenylphosphine and 790 mg (4.6 mmol) of N,N,N′,N′-tetramethylazodicarboxyamide were added to the obtained solution, and they were stirred overnight. After the treatment with ethyl acetate as the extracting solvent by an ordinary method, the obtained crude product was purified by the silica gel column chromatography to obtain the title compound.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][N:4]=[CH:3][C:2]=1[C:7]([OH:9])=O.C(Cl)[Cl:11].S(Cl)(Cl)=O>N1C=CC=CC=1>[N:1]1[CH:6]=[CH:5][N:4]=[CH:3][C:2]=1[C:7]([Cl:11])=[O:9]
Reactant: ClCCl
Reactant: O=C(O)c1cnccn1
Solvent: O=S(Cl)Cl
Solvent: c1ccncc1
Product: O=C(Cl)c1cnccn1
Temperature: 30 °C

Procedure:
A mixture of 68.2 g (0.55 moles) 2-pyrazine carboxylic acid and methylene chloride (about 200 ml) containing a catalytic amount of pyridine was warmed (to about 30° C.). To that mixture, 78.5 g (0.66 mole) thionyl chloride was added dropwise. The reaction mixture was refluxed for 24 hours. The methylene chloride was removed under reduced pressure and heat to give the 2-pyrazine carboxylic acid chloride which was used in step (b) without further isolation.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][C@H:9]1[CH2:13][NH:14][C:15]1[C:16]([O:27][C:28]2[CH:33]=[CH:32][C:31]([O:34][CH3:35])=[CH:30][CH:29]=2)=[N:17][C:18]([C:21]2[CH:22]=[N:23][CH:24]=[N:25][CH:26]=2)=[N:19][CH:20]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:36](Cl)(=[O:38])[CH3:37].N1C=CC=CC=1>C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][C@H:9]1[CH2:13][N:14]([C:36](=[O:38])[CH3:37])[C:15]1[C:16]([O:27][C:28]2[CH:29]=[CH:30][C:31]([O:34][CH3:35])=[CH:32][CH:33]=2)=[N:17][C:18]([C:21]2[CH:26]=[N:25][CH:24]=[N:23][CH:22]=2)=[N:19][CH:20]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(=O)Cl
Reactant: COc1ccc(Oc2nc(-c3cncnc3)ncc2NC[C@@H]2CCCN2C(=O)OC(C)(C)C)cc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: COc1ccc(Oc2nc(-c3cncnc3)ncc2N(C[C@@H]2CCCN2C(=O)OC(C)(C)C)C(C)=O)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of Compound 8b (89 mg; 0.19 mmol) in CH2Cl2 (7 mL) was added acetyl chloride (0.1 mL) and pyridine (0.1 mL) at ambient temperature. The mixture was stirred at room temperature for 3 h. Diluted the resulted mixture with CH2Cl2. The organic phase was washed sequentially with H2O and brine, and then dried over Na2SO4. The mixture was filtered and the filtrate was evaporated under reduced pressure to afford Compound 9a. The crude product was used in the next reaction without further purification. MS: m/z 521.3 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[CH:6]=[C:5]([C:7]([CH3:10])([CH3:9])[CH3:8])[NH:4][N:3]=1.Cl[C:12]([O:14][CH2:15][CH3:16])=[O:13]>O1CCOCC1>[C:7]([C:5]1[NH:4][N:3]=[C:2]([NH:1][C:12](=[O:13])[O:14][CH2:15][CH3:16])[CH:6]=1)([CH3:10])([CH3:9])[CH3:8]
Reactant: CCOC(=O)Cl
Reactant: CC(C)(C)c1cc(N)n[nH]1
Solvent: C1COCCO1
Product: CCOC(=O)Nc1cc(C(C)(C)C)[nH]n1
Yield: 25.9 %

Procedure:
2.8 g of Compound [II] was dissolved in 30 ml of dioxane, and 2.2 g of ethyl chloroformate was added to the solution. The mixture was then allowed to react for 5 hours under refluxing. After completion of the reaction, the solvent was distilled off, and hexane and a potassium carbonate aqueous solution were added to the residue to form crystals. The crystals were collected by filtration and washed with water and hexane to obtain 1.1 g of ethyl N-(5-t-butyl-3-pyrazolyl)carbamate.
Reaction SMILES: Cl.[F:2][C:3]1[CH:4]=[C:5]([CH:28]=[CH:29][CH:30]=1)[CH2:6][N:7]1[C:15]2[C:10](=[CH:11][C:12]([NH:16][C:17]3[C:26]4[C:21](=[CH:22][CH:23]=[C:24](I)[CH:25]=4)[N:20]=[CH:19][N:18]=3)=[CH:13][CH:14]=2)[CH:9]=[N:8]1.[C:31]([O:35][C:36](=[O:41])[NH:37][CH2:38][C:39]#[CH:40])([CH3:34])([CH3:33])[CH3:32].N(C(C)C)C(C)C>C1COCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Cu]I>[C:31]([O:35][C:36](=[O:41])[NH:37][CH2:38][C:39]#[C:40][C:24]1[CH:25]=[C:26]2[C:21](=[CH:22][CH:23]=1)[N:20]=[CH:19][N:18]=[C:17]2[NH:16][C:12]1[CH:11]=[C:10]2[C:15](=[CH:14][CH:13]=1)[N:7]([CH2:6][C:5]1[CH:28]=[CH:29][CH:30]=[C:3]([F:2])[CH:4]=1)[N:8]=[CH:9]2)([CH3:34])([CH3:33])[CH3:32]
Reactant: Fc1cccc(Cn2ncc3cc(Nc4ncnc5ccc(I)cc45)ccc32)c1
Reactant: C#CCNC(=O)OC(C)(C)C
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: Cl
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NCC#Cc1ccc2ncnc(Nc3ccc4c(cnn4Cc4cccc(F)c4)c3)c2c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 89.3 %

Procedure:
[1-(3-Fluoro-benzyl)-1 H-indazol-5-yl]-(6-iodo-quinazolin-4-yl)-amine hydrochloride (0.334 g, 0.628 mmol) and Prop-2-ynyl-carbamic acid tert-butyl ester (113 mg, 1.16 equiv.) is treated with i-Pr2NH (2 equiv.) in dry THF (4 ml) under N2. Pd(PPh3)4 (25 mg, 0.0356 mmol, 5.7 mol %) and solid CuI (5 mol %) are added next, and the mixture is stirred at r.t. for 3 hours. Workup: THF is removed under reduced pressure and DCM (10 ml) is added. The organic layer is washed with sat. aq. NH4Cl solution and brine, dried and concentrated. Chromatography on silica (EtOAc/hexanes) affords the desired pure product (293 mg, 89%).
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]1([CH3:17])[CH2:9][NH:8][C:7]2[CH:10]=[CH:11][C:12]([N+:14]([O-:16])=[O:15])=[CH:13][C:6]=2[O:5]1.Cl.Br[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][N+:21]=1[O-:26]>CN(C)C=O>[CH3:3][C:4]1([CH3:17])[CH2:9][N:8]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][N+:21]=2[O-:26])[C:7]2[CH:10]=[CH:11][C:12]([N+:14]([O-:16])=[O:15])=[CH:13][C:6]=2[O:5]1
Reactant: [O-][n+]1ccccc1Br
Reactant: CC1(C)CNc2ccc([N+](=O)[O-])cc2O1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC1(C)CN(c2cccc[n+]2[O-])c2ccc([N+](=O)[O-])cc2O1
Temperature: 70 °C
Reaction time: 16 h
Yield: 23.5 %

Procedure:
To a suspension of 0.38 g sodium hydride (60% in paraffin composition) in 14 ml dimethylformamide, was added 1.00 g 3,4-dihydro-2,2-dimethyl-7-nitro-2H-1,4-benzoxazine, and 1.01 g 2-bromopyridine N-oxide hydrochloride was further added under ice-cooling, and the mixture was stirred for 16 hours at 70° C. The reaction mixture was poured to ice water, the resulting mixture was extracted with ethyl acetate, and the extract was washed with an aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate. The solvent was distilled off from the dried solution under reduced pressure, the residue was subjected to column chromatography on silica gel, and elution was conducted by the use of a 3:1 mixture of chloroform and acetone, thus giving 0.34 g of 2-(3,4-dihydro-2,2-dimethyl-7-nitro-2H-1,4-benzoxazin-4-yl)pyridine N-oxide. Ethanolic solution of hydrogen chloride (a mixture of 1 ml concentrated hydrochloric acid and 5 ml ethanol) was then added to the product obtained above, the solvent was distilled off from the mixture, and the residue was recrystallized from acetone, thus giving 182 mg of 2-(3,4-dihydro-2,2-dimethyl-7-nitro-2H-1,4-benzoxazin-4-yl)pyridine N-oxide hydrochloride.
Reaction SMILES: [CH:1]([O:4][C:5](=[O:28])[NH:6][C@@H:7]1[CH2:27][C:10]2[N:11]([CH2:20][C@@H:21]3[C@@H:25]([OH:26])[CH2:24][CH2:23][NH:22]3)[C:12]3[CH:13]=[CH:14][C:15]([C:18]#[N:19])=[CH:16][C:17]=3[C:9]=2[CH2:8]1)([CH3:3])[CH3:2].[CH:29](=O)[CH3:30].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)(O)[O-].[Na+]>C(#N)C.ClCCl>[CH:1]([O:4][C:5](=[O:28])[NH:6][C@@H:7]1[CH2:27][C:10]2[N:11]([CH2:20][C@@H:21]3[C@@H:25]([OH:26])[CH2:24][CH2:23][N:22]3[CH2:29][CH3:30])[C:12]3[CH:13]=[CH:14][C:15]([C:18]#[N:19])=[CH:16][C:17]=3[C:9]=2[CH2:8]1)([CH3:3])[CH3:2]
Reactant: CC(C)OC(=O)N[C@H]1Cc2c(n(C[C@H]3NCC[C@@H]3O)c3ccc(C#N)cc23)C1
Reactant: CC=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC#N
Product: CCN1CC[C@H](O)[C@H]1Cn1c2c(c3cc(C#N)ccc31)C[C@H](NC(=O)OC(C)C)C2
Temperature: 25 °C
Reaction time: 8 h
Yield: 31.1 %

Procedure:
A solution of [(S)-7-cyano-4-((2R,3S)-3-hydroxy-pyrrolidin-2-ylmethyl)-1,2,3,4-tetrahydro-cyclopenta[b]indol-2-yl]-carbamic acid isopropyl ester (300 mg, 784.4 μmol) in acetonitrile (20 mL) is treated with acetaldehyde (1.0 mL, 17.80 mmol) and sodium triacetoxyborohydride (520 mg, 2.35 mmol) and stirred at room temperature overnight. The suspension is treated with saturated sodium bicarbonate solution (40 mL) and stirred for 30 min. The resulting suspension is diluted with dichloromethane (100 mL) and washed with water (3×100 mL) and brine. The organic portion is dried over sodium sulfate, filtered, and concentrated to dryness. The resulting residue is purified by medium pressure liquid chromatography, eluting with methanol:chloroform (5:95). Fractions containing pure product are combined and concentrated to afford 0.1 g (31%) of the title compound. LC-ES/MS m/z 144.2 [M+H]+, TR=1.94 min.
Reaction SMILES: [Br:1][C:2]1[N:6]([CH2:7][C:8]([O:10]CC)=[O:9])[N:5]=[C:4]([C:13]([F:16])([F:15])[F:14])[CH:3]=1.[OH-].[Na+].Cl>O1CCCC1>[Br:1][C:2]1[N:6]([CH2:7][C:8]([OH:10])=[O:9])[N:5]=[C:4]([C:13]([F:16])([F:14])[F:15])[CH:3]=1
Reactant: CCOC(=O)Cn1nc(C(F)(F)F)cc1Br
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: O=C(O)Cn1nc(C(F)(F)F)cc1Br
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of ethyl 5-bromo-3-(trifluoromethyl)-1H-pyrazole-1-acetate (i.e. the product of Example 11, Step C) (2.84 g, 9.4 mmol) in tetrahydrofuran (10 mL) was treated with a 50 wt. % aqueous solution of sodium hydroxide solution (1.0 mL). The reaction mixture was stirred at room temperature for 2 h. The reaction mixture was treated with concentrated aqueous hydrochloric acid to lower the pH to 1, and then extracted with ethyl acetate. The extract was dried (MgSO4) and concentrated under pressure to give 2.26 g of the title compound as a light brown solid. Recrystallization from 1-chlorobutane (20 mL) gave 0.68 g of the title compound as lustrous light pink plates.
Reaction SMILES: [Br:1][CH:2]([Br:15])[C:3]1[N:11]=[CH:10][C:9]([N+:12]([O-:14])=[O:13])=[CH:8][C:4]=1[C:5]([NH2:7])=[O:6].[C:16](OC(=O)C)(=[O:18])[CH3:17].C(=O)(O)[O-].[Na+]>S(=O)(=O)(O)O>[C:16]([NH:7][C:5](=[O:6])[C:4]1[CH:8]=[C:9]([N+:12]([O-:14])=[O:13])[CH:10]=[N:11][C:3]=1[CH:2]([Br:1])[Br:15])(=[O:18])[CH3:17]
Reactant: CC(=O)OC(C)=O
Reactant: NC(=O)c1cc([N+](=O)[O-])cnc1C(Br)Br
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Product: CC(=O)NC(=O)c1cc([N+](=O)[O-])cnc1C(Br)Br
Temperature: 0 °C

Procedure:
A mixture of 0.48 g of 2-dibromomethyl-5-nitronicotinamide and acetic anhydride was stirred with 3 drops of conc. sulfuric acid at room temperature for 1 hour. The reaction mixture was poured into ice-water, made alkaline with 5% sodium bicarbonate and extracted with ethyl acetate. The extract was dried and the solvent was distilled off to give 0.35 g of crystalline substance, which was then recrystallized from ethyl acetate-n-hexane to give the desired product as yellow needles. mp 168° C. (with decomp.)
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([CH2:16][NH:17][C:18]2[CH:23]=[CH:22][C:21]([CH:24]([CH3:26])[CH3:25])=[CH:20][CH:19]=2)[CH:8]=[C:9]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:10]=1[OH:11])([CH3:4])([CH3:3])[CH3:2].[CH:27]([C:30]1[CH:35]=[CH:34][CH:33]=[C:32]([CH:36]([CH3:38])[CH3:37])[C:31]=1[N:39]=[C:40]=[O:41])([CH3:29])[CH3:28]>>[C:1]([C:5]1[CH:6]=[C:7]([CH2:16][N:17]([C:18]2[CH:23]=[CH:22][C:21]([CH:24]([CH3:26])[CH3:25])=[CH:20][CH:19]=2)[C:40]([NH:39][C:31]2[C:30]([CH:27]([CH3:28])[CH3:29])=[CH:35][CH:34]=[CH:33][C:32]=2[CH:36]([CH3:38])[CH3:37])=[O:41])[CH:8]=[C:9]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:10]=1[OH:11])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)c1ccc(NCc2cc(C(C)(C)C)c(O)c(C(C)(C)C)c2)cc1
Reactant: CC(C)c1cccc(C(C)C)c1N=C=O
Product: CC(C)c1ccc(N(Cc2cc(C(C)(C)C)c(O)c(C(C)(C)C)c2)C(=O)Nc2c(C(C)C)cccc2C(C)C)cc1

Procedure:
By the reaction and treatment in the same manner as in Example 2 using (3,5-di-tert-butyl-4-hydroxyphenylmethyl)(4-isopropylphenyl)amine (2.0 g) and 2,6-diisopropylphenyl isocyanate (1.8 mL) as starting materials, N-(3,5-di-tert-butyl-4-hydroxyphenylmethyl)-N′-(2,6-diisopropylphenyl)-N-(4-isopropylphenyl)urea (0.82 g) was obtained.
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:10]=[C:9]([C:11]2[CH:16]=[CH:15][C:14]([C:17]#[N:18])=[CH:13][C:12]=2[F:19])[O:8][N:7]=1)=[O:5])C.[OH-].[Na+]>O1CCCC1>[C:17]([C:14]1[CH:15]=[CH:16][C:11]([C:9]2[O:8][N:7]=[C:6]([C:4]([OH:5])=[O:3])[CH:10]=2)=[C:12]([F:19])[CH:13]=1)#[N:18]
Reactant: CCOC(=O)c1cc(-c2ccc(C#N)cc2F)on1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: N#Cc1ccc(-c2cc(C(=O)O)no2)c(F)c1

Procedure:
The title compound is prepared from 5-(4-cyano-2-fluoro-phenyl)-isoxazole-3-carboxylic acid ethyl ester by treatment with aqueous NaOH solution in tetrahydrofuran. LC (method 4): tR=0.32 min; Mass spectrum (EI): m/z=232 [M]+.
Reaction SMILES: [NH2:1][C:2]1[CH:27]=[CH:26][C:5]([O:6][C:7]2[CH:12]=[CH:11][N:10]=[C:9]([NH:13][C:14]([N:16]3[CH2:21][CH2:20][CH:19]([CH2:22][N:23]([CH3:25])[CH3:24])[CH2:18][CH2:17]3)=[O:15])[CH:8]=2)=[CH:4][CH:3]=1.C12(CS(O)(=O)=O)C(C)(C)C(CC1)CC2=O.[C:43]1([CH2:49][C:50]([N:52]=[C:53]=[S:54])=[O:51])[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1>C(O)C.C1(C)C=CC=CC=1>[CH3:25][N:23]([CH2:22][CH:19]1[CH2:20][CH2:21][N:16]([C:14]([NH:13][C:9]2[CH:8]=[C:7]([O:6][C:5]3[CH:26]=[CH:27][C:2]([NH:1][C:53]([NH:52][C:50](=[O:51])[CH2:49][C:43]4[CH:44]=[CH:45][CH:46]=[CH:47][CH:48]=4)=[S:54])=[CH:3][CH:4]=3)[CH:12]=[CH:11][N:10]=2)=[O:15])[CH2:17][CH2:18]1)[CH3:24]
Reactant: O=C(Cc1ccccc1)N=C=S
Reactant: CN(C)CC1CCN(C(=O)Nc2cc(Oc3ccc(N)cc3)ccn2)CC1
Agent: CC1(C)C2CCC1(CS(=O)(=O)O)C(=O)C2
Solvent: Cc1ccccc1
Solvent: CCO
Product: CN(C)CC1CCN(C(=O)Nc2cc(Oc3ccc(NC(=S)NC(=O)Cc4ccccc4)cc3)ccn2)CC1
Reaction time: 1 h
Yield: 46 %

Procedure:
To a solution of 4-(4-aminophenoxy)-2-{[4-(dimethylaminomethyl)piperidin-1-yl]carbonylamino}pyridine (105.6 mg) and (+)-10-camphorsulfonic acid (62 mg) in ethanol (2.5 ml) was added a solution of 2-phenylacetyl isothiocyanate in toluene (0.25 M, 2.5 ml) at room temperature, followed by stirring for 1 hour. The reaction mixture was partitioned between ethyl acetate and a saturated aqueous solution of sodium hydrogencarbonate. The organic layer was washed with a saturated aqueous solution of sodium hydrogencarbonate and brine in this order, dried over anhydrous sodium sulfate. The solvent was evaporated to give a residue, which was then purified by silica gel column chromatography (Fuji Silysia NH, eluent; ethyl acetate:heptane=1:1 to 4:1) to provide the titled compound (70.2 mg, 46%) as white powder.