Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[C:10]([O:11][C@@H:12]2[CH2:17][CH2:16][CH2:15][C@H:14]([NH2:18])[CH2:13]2)=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[N:5][N:6]2[CH:19]1[CH2:24][CH2:23][CH2:22][CH2:21][O:20]1.Br[CH2:26][CH2:27][CH2:28][CH2:29]Br.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C(=O)C>[CH3:1][C:2]1[C:10]([O:11][C@H:12]2[CH2:17][CH2:16][CH2:15][C@@H:14]([N:18]3[CH2:29][CH2:28][CH2:27][CH2:26]3)[CH2:13]2)=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[N:5][N:6]2[CH:19]1[CH2:24][CH2:23][CH2:22][CH2:21][O:20]1
Reactant: Cc1c(O[C@@H]2CCC[C@H](N)C2)ccc2c1cnn2C1CCCCO1
Reactant: BrCCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Solvent: O
Product: Cc1c(O[C@H]2CCC[C@@H](N3CCCC3)C2)ccc2c1cnn2C1CCCCO1
Temperature: 25 °C
Yield: 54.9 %

Procedure:
Under nitrogen, the cis-3-[(4-methyl-1-tetrahydro-2H-pyran-2-yl-1H-indazol-5-yl)oxy]cyclohexanamine (100 mg, 0.304 mmol) obtained in Example 724 was dissolved in N,N-dimethylacetamide (3 ml), followed by adding thereto 1,4-dibromobutane (36 μl, 0.304 mmol) and potassium carbonate (105 mg, 0.759 mmol), and the resulting mixture was stirred at 80° C. for 1.5 hours. The reaction solution was cooled to room temperature and water was added thereto, followed by extraction with chloroform (twice). The combined chloroform layer was washed with a saturated aqueous sodium chloride solution, dried by the addition of anhydrous magnesium sulfate, and then filtered. The solvent was distilled off under reduced pressure and the resulting concentration residue was purified by a silica gel column chromatography (eluent: acetonitrile/aqueous ammonia=100/0, 100/2) to obtain 4-methyl-5-[(cis-3-pyrrolidin-1-ylcyclohexyl)oxy]-1-tetrahydro-2H-pyran-2-yl-1H-indazole (64 mg, yield 55.0%) as light-yellow tar.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([NH:8][NH2:9])=[O:7])=[CH:4][CH:3]=1.[CH2:12]([OH:14])[CH3:13]>>[Br:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([NH:8][N:9]2[C:12](=[O:14])[CH:13]3[CH:5]([CH2:4][CH2:3][CH2:2][CH2:11]3)[C:6]2=[O:7])=[O:7])=[CH:4][CH:3]=1
Reactant: CCO
Reactant: NNC(=O)c1ccc(Br)cc1
Product: O=C(NN1C(=O)C2CCCCC2C1=O)c1ccc(Br)cc1
Yield: 52 %

Procedure:
A mixture of cis-cyclohexanedicarboxylic anhydride (150 mg, 0.97 mmol) and 4-bromobenzoic hydrazide (220 mg, 1.02 mmol) in ethanol (10 mL) was heated under argon overnight. The solvent was removed via rotary evaporation. Purification by column chromatography on silica gel using 1/1 hexane/ethyl acetate as eluent provided 179 mg (52%) of the desired product as a white solid.
Reaction SMILES: [CH2:1]([C@@H:8]1[CH2:13][C@@H:12]([NH2:14])[CH2:11][CH2:10][N:9]1[C:15](=[O:24])[C:16]1[CH:21]=[C:20]([Cl:22])[CH:19]=[C:18]([Cl:23])[CH:17]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:25]1([C:35](Cl)=[O:36])[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH:28]=[CH:27][CH:26]=1.C(N(CC)CC)C>>[CH2:1]([C@@H:8]1[CH2:13][C@@H:12]([NH:14][C:35]([C:25]2[C:34]3[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=3)[CH:28]=[CH:27][CH:26]=2)=[O:36])[CH2:11][CH2:10][N:9]1[C:15](=[O:24])[C:16]1[CH:21]=[C:20]([Cl:22])[CH:19]=[C:18]([Cl:23])[CH:17]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(Cl)c1cccc2ccccc12
Reactant: N[C@H]1CCN(C(=O)c2cc(Cl)cc(Cl)c2)[C@H](Cc2ccccc2)C1
Solvent: CCN(CC)CC
Product: O=C(N[C@H]1CCN(C(=O)c2cc(Cl)cc(Cl)c2)[C@H](Cc2ccccc2)C1)c1cccc2ccccc12

Procedure:
150 mg (0.431 mmol) of (2R*,4S*)-2-benzyl-1-(3,5-dichlorobenzoyl)-4-piperidinamine are reacted in analogy to Example 39a with 75 μl (0.495 mmol) of 1-naphthoyl chloride and 81 μl (0.578 mmol) of triethylamine. The title compound ##STR89## is obtained (208 mg, 97%) as oil. TLC:methylene chloride/methanol/conc. ammonia (1000:50:1) Rf =0.85, FD-MS:M+ =516, 518; IR:3680, 3400, 1620 cm-1.
Reaction SMILES: [CH:1](=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:9][C:10]1[CH:11]=[CH:12][CH:13]=[C:14]2[C:19]=1[CH:18]=[N:17][CH:16]=[C:15]2[Br:20].C([BH3-])#N.[Na+]>CCO.CCOC(C)=O>[CH2:1]([NH:9][C:10]1[CH:11]=[CH:12][CH:13]=[C:14]2[C:19]=1[CH:18]=[N:17][CH:16]=[C:15]2[Br:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=Cc1ccccc1
Reactant: Nc1cccc2c(Br)cncc12
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CCO
Product: Brc1cncc2c(NCc3ccccc3)cccc12
Temperature: 90 °C

Procedure:
Under argon, benzaldehyde (584 μl, 5.75 mmol) is added to a solution of 8-amino-4-bromoisoquinoline (Intermediate 23.2, 1.11 g, 5 mmol) in absolute EtOH (60 ml). The mixture is heated at 90° C. for 24 h. It is cooled to 0° C. and then sodium cyanoborohydride (NaBH3CN, 3.3 g, 50 mmol) is added in small portions. The stirring is maintained for 2 h at room temperature. The reaction mixture is diluted with AcOEt (600 ml) and is then washed with water. The organic phase is dried over Na2SO4 and then evaporated. The residue is purified on silica gel, eluting with an AcOEt/petroleum ether (1/4) mixture.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH:12]([C:14]3[CH:21]=[C:20]([Cl:22])[C:17]([C:18]#[N:19])=[C:16]([CH:23]4[CH2:26][NH:25][CH2:24]4)[C:15]=3[O:27][CH2:28][CH3:29])[CH3:13])[N:9]=[C:10]([CH3:11])[C:3]=12.C(=O)([O-])[O-].[K+].[K+].Br[C:37]([CH3:46])([CH3:45])[C:38]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:39].O>CN(C)C=O>[NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH:12]([C:14]3[C:15]([O:27][CH2:28][CH3:29])=[C:16]([CH:23]4[CH2:24][N:25]([C:37]([CH3:46])([CH3:45])[C:38]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:39])[CH2:26]4)[C:17]([C:18]#[N:19])=[C:20]([Cl:22])[CH:21]=3)[CH3:13])[N:9]=[C:10]([CH3:11])[C:3]=12
Reactant: CCOc1c(C(C)n2nc(C)c3c(N)ncnc32)cc(Cl)c(C#N)c1C1CNC1
Reactant: CC(C)(C)OC(=O)C(C)(C)Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOc1c(C(C)n2nc(C)c3c(N)ncnc32)cc(Cl)c(C#N)c1C1CN(C(C)(C)C(=O)OC(C)(C)C)C1
Temperature: 60 °C
Yield: 84.4 %

Procedure:
A solution of 4-[1-(4-amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-2-azetidin-3-yl-6-chloro-3-ethoxybenzonitrile (0.38 g, 0.92 mmol, chiral intermediate from Example 212) in N,N-dimethylformamide (4.6 mL) was treated with potassium carbonate (0.51 g, 3.7 mmol) followed by tert-butyl 2-bromo-2-methylpropanoate (0.86 mL, 4.6 mmol) and heated at 60° C. for 3 h. The reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was separated, dried with magnesium sulfate, filtered, and concentrated to a crude oil. The crude material was purified by flash column chromatography using methanol in dichloromethane (0%-10%) to give the desired product (0.43 g, 83%). The product was isolated as a single enantiomer. 1H NMR (300 MHz, DMSO-d6) δ 8.10 (s, 1H), 7.44 (s, 1H), 6.22 (q, J=6.8 Hz, 1H), 4.12-3.97 (m, 1H), 3.88-3.70 (m, 4H), 3.62-3.48 (m, 2H), 2.54 (s, 3H), 1.70 (d, J=7.0 Hz, 3H), 1.33 (t, J=6.9 Hz, 3H), 1.17 (s, 9H), 1.05 (s, 6H). LCMS for C28H37ClN7O3 (M+H)+: m/z=554.3; Found: 554.3.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[C:13]3[C:18]([CH:19]=2)=[CH:17][C:16]([CH2:20][N:21]2[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]2)=[CH:15][CH:14]=3)=[C:7]2[C:3]=1[CH2:4][NH:5][C:6]2=[O:34].C(N(CC)CC)C.[CH3:42][O:43][C:44]1[CH:45]=[C:46]([S:50](Cl)(=[O:52])=[O:51])[CH:47]=[CH:48][CH:49]=1>C(#N)C>[CH3:42][O:43][C:44]1[CH:45]=[C:46]([S:50]([O:1][C:2]2[CH:10]=[CH:9][C:8]([C:11]3[N:12]([C:27]([O:29][C:30]([CH3:31])([CH3:33])[CH3:32])=[O:28])[C:13]4[C:18]([CH:19]=3)=[CH:17][C:16]([CH2:20][N:21]3[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]3)=[CH:15][CH:14]=4)=[C:7]3[C:3]=2[CH2:4][NH:5][C:6]3=[O:34])(=[O:52])=[O:51])[CH:47]=[CH:48][CH:49]=1
Reactant: COc1cccc(S(=O)(=O)Cl)c1
Reactant: CC(C)(C)OC(=O)n1c(-c2ccc(O)c3c2C(=O)NC3)cc2cc(CN3CCCCC3)ccc21
Solvent: CC#N
Solvent: CCN(CC)CC
Product: COc1cccc(S(=O)(=O)Oc2ccc(-c3cc4cc(CN5CCCCC5)ccc4n3C(=O)OC(C)(C)C)c3c2CNC3=O)c1
Yield: 44.5 %

Procedure:
In a similar manner to Step 1 of Example 233, 4-hydroxy-7-[1-(tert-butoxycarbonyl)-5-(piperidinomethyl)indol-2-yl]isoindolinone (0.0314 g, 0.0680 mmol) was dissolved in acetonitrile (0.650 mL), and the solution was treated with triethylamine (0.0540 mL, 0.390 mmol) and 3-methoxybenzenesulfonyl chloride (0.0403 g, 0.195 mmol) to obtain 4-(3-methoxybenzenesulfonyloxy)-7-[1-(tert-butoxycarbonyl)-5-(piperidinomethyl)indol-2-yl]isoindolinone (0.0191 g, yield 44%).
Reaction SMILES: [CH3:1][C:2]1([CH3:17])[CH2:11][CH2:10][C:9]([CH3:13])([CH3:12])[C:8]2[CH:7]=[C:6]([C:14](=[O:16])C)[CH:5]=[CH:4][C:3]1=2.Cl[O-].[Na+].[OH-:21].[Na+]>O1CCOCC1>[CH3:1][C:2]1([CH3:17])[CH2:11][CH2:10][C:9]([CH3:12])([CH3:13])[C:8]2[CH:7]=[C:6]([C:14]([OH:16])=[O:21])[CH:5]=[CH:4][C:3]1=2
Reactant: CC(=O)c1ccc2c(c1)C(C)(C)CCC2(C)C
Reactant: [OH-]
Agent: [Na+]
Agent: [O-]Cl
Solvent: C1COCCO1
Product: CC1(C)CCC(C)(C)c2cc(C(=O)O)ccc21

Procedure:
A mixture of 3.8 g (16.5 mmol) of 5,5,8,8-tetramethyl-2-acetyl-5,6,7,8-tetrahydronaphthalene from the preceeding Example 3, 70 ml of 5.25% aqueous sodium hypochlorite (49 mmol), 25 ml of aqueous 2N NaOH and 30 ml of dioxane was heated at 60°-70° C. for 2 hours. The mixture was allowed to cool and the oily organic layer removed. Then the aqueous layer was washed with two portions of ether. The aqueous layer was then treated with sodium metabisulfite solution until the solution was negative to the potassium iodide.starch test. The aqueous layer was then cooled and acidified with H2SO4. The resultant white precipitate was collected by filtration and washed with water. This crude product was further purified by recrystallization from an ethanol/water mixture to give the title compound as a white, crystalline solid. PMR (CDCl3): δ 1.31 (6H, s), 1.32 (6H, s), 1.71 (4H, s), 7.40 (1H, d, J~8.8 Hz), 7.85 (1H, dd, J~8.8 Hz, 1.8 Hz), 8.08 (1H, d, J~1.8 Hz).
Reaction SMILES: [BrH:1].C(O)(=O)C.[Cl:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[C:13](=O)[CH2:14][S:15][C:16]#[N:17].O>C(O)(=O)C>[Br:1][C:16]1[S:15][CH:14]=[C:13]([C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[Cl:6])[N:17]=1
Reactant: Br
Reactant: N#CSCC(=O)c1ccccc1Cl
Solvent: CC(=O)O
Solvent: O
Product: Clc1ccccc1-c1csc(Br)n1
Temperature: 130 °C
Reaction time: 2 h
Yield: 67.1 %

Procedure:
A 25% hydrogen bromide/acetic acid (50 ml) solution was added to a solution of 2-(2-chlorophenyl)-2-oxoethyl thiocyanate (5.15 g, 24.3 mmol) in acetic acid (50 ml), and the mixture was stirred at 130° C. for 2 hours. Water (100 ml) was poured to the reaction mixture, and crystals were collected by filtration and washed with water to give 4.48 g (67.1%) of the desired product as a solid.
Reaction SMILES: [Cl:1][C:2]1[CH:22]=[C:21]([O:23][CH2:24][CH:25]=[C:26]([Cl:28])[Cl:27])[CH:20]=[C:19]([Cl:29])[C:3]=1[O:4][CH2:5][C:6](=[CH2:18])[CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15](=O)[CH3:16])=[CH:11][CH:10]=1.Cl.[CH3:31][O:32][NH2:33].CO.C([O-])(=O)C.[Na+]>C(OCC)(=O)C>[CH3:31][O:32][N:33]=[C:15]([C:12]1[CH:11]=[CH:10][C:9]([O:8][CH2:7][C:6]([CH2:5][O:4][C:3]2[C:2]([Cl:1])=[CH:22][C:21]([O:23][CH2:24][CH:25]=[C:26]([Cl:27])[Cl:28])=[CH:20][C:19]=2[Cl:29])=[CH2:18])=[CH:14][CH:13]=1)[CH3:16]
Reactant: C=C(COc1ccc(C(C)=O)cc1)COc1c(Cl)cc(OCC=C(Cl)Cl)cc1Cl
Reactant: CON
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CO
Product: C=C(COc1ccc(C(C)=NOC)cc1)COc1c(Cl)cc(OCC=C(Cl)Cl)cc1Cl
Temperature: 25 °C
Reaction time: 24 h

Procedure:
286 mg of 1-(4-{2-[2,6-dichloro-4-(3,3-dichloro-allyloxy)-phenoxymethyl]-allyloxy}-phenyl)-ethanone and 56 mg of O-methyl-hydroxylamine hydrochloride are introduced into 4 ml of methanol. 55 mg of sodium acetate are then added and the mixture is stirred for 24 hours at 25° C. The reaction mixture is diluted with 12 ml of ethyl acetate and washed twice with water. After concentration of the organic phase and purification over silica gel, the title compound is obtained.
Reaction SMILES: [NH2:1][C:2]1[S:6][C:5]2[CH2:7][CH2:8][CH2:9][CH2:10][C:4]=2[C:3]=1[C:11]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:12].N1C=CC=CC=1.[C:25](OC(=O)C)(=[O:27])[CH3:26]>>[C:11]([C:3]1[C:4]2[CH2:10][CH2:9][CH2:8][CH2:7][C:5]=2[S:6][C:2]=1[NH:1][C:25](=[O:27])[CH3:26])(=[O:12])[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: CC(=O)OC(C)=O
Reactant: Nc1sc2c(c1C(=O)c1ccccc1)CCCC2
Solvent: c1ccncc1
Product: CC(=O)Nc1sc2c(c1C(=O)c1ccccc1)CCCC2
Temperature: 50 °C
Yield: 78 %

Procedure:
To a stirred solution of 1.04 g (4.04 mmol) (2-Amino-4,5,6,7-tetrahydro-benzo[b]thiophen-3-yl)-phenyl-methanone in 25 ml acetic anhydride was added 0.2 ml pyridine. The mixture was heated at 50° C. for 35 minutes and then poured onto water and extracted three times with ethyl acetate. The combined organic phases were dried over sodium sulfate and concentrated in vacuo to afford 1.35 g (78%) N-(3-benzoyl-4,5,6,7-tetrahydro-benzo[b]thiophen-2-yl)-acetamide as an orange oil. ES-MS m/e (%): 300 (M+H+, 100).
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[C:8](Cl)[C:5]([C:6]#[N:7])=[CH:4][N:3]=1.[O:11]1[CH2:16][CH2:15][CH2:14][CH2:13][CH:12]1[CH2:17][OH:18]>>[NH2:1][C:2]1[CH:9]=[C:8]([O:18][CH2:17][CH:12]2[CH2:13][CH2:14][CH2:15][CH2:16][O:11]2)[C:5]([C:6]#[N:7])=[CH:4][N:3]=1
Reactant: N#Cc1cnc(N)cc1Cl
Reactant: OCC1CCCCO1
Product: N#Cc1cnc(N)cc1OCC1CCCCO1

Procedure:
From intermediate 16 and (tetrahydro-2H-pyran-2-yl)methanol, reacted in an analogous manner to the preparation of intermediate 34. (UPLC-MS 3) tR 0.69 min; ESI-MS 234.1 [M+H]+.
Reaction SMILES: [Cl-:1].[NH2:2][C:3]([CH3:14])([CH3:13])[CH2:4][CH2:5][N+:6]([CH2:9][CH2:10][O:11][CH3:12])([CH3:8])[CH3:7].C(O[Cl:20])(C)(C)C>CO>[Cl-:20].[Cl:1][N:2]([Cl:20])[C:3]([CH3:14])([CH3:13])[CH2:4][CH2:5][N+:6]([CH2:9][CH2:10][O:11][CH3:12])([CH3:7])[CH3:8]
Reactant: COCC[N+](C)(C)CCC(C)(C)N
Reactant: CC(C)(C)OCl
Agent: [Cl-]
Solvent: CO
Product: COCC[N+](C)(C)CCC(C)(C)N(Cl)Cl
Temperature: 0 °C
Reaction time: 0.75 h
Yield: 168.4 %

Procedure:
A solution of 3-amino-N-(2-methoxyethyl)-N,N,3-trimethylbutan-1-aminium chloride (830 mg, 3.5 mmol) in methanol (14 ml) was cooled to 0° C. tert-Butylhypochlorite (984 μl, 2.5 mmol) was added. The resulting solution was stirred for 45 minutes at 0° C. and then concentrated under reduced pressure. The residue was purified by reverse phase high pressure liquid chromatography eluting from a C18 column with a gradient of 5 to 95% CH3CN in water (with 0.01% acetic acid) to give 618 mg of a clear oil. 1H NMR (D2O, 400 MHz) δ 1.33 (s, 6H), 2.15-2.20 (m, 2H), 3.08 (s, 6H), 3.40 (s, 3H), 3.40-3.44 (m, 2H), 3.49-3.51 (m, 2H), 3.80-3.82 (m, 2H). 13C NMR (D2O, 100 MHz) δ 73.1, 65.5, 62.9, 62.9, 62.8, 60.8, 60.8, 60.7, 58.2, 51.5, 51.4, 51.4, 31.3, 22.8; LRMS (ESI/APCI) m/z 257 [M]+.
Reaction SMILES: [CH2:1]([C:3]1[N:7]([CH2:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[C:21]3[NH:25][N:24]=[N:23][N:22]=3)=[CH:11][CH:10]=2)[C:6]2[C:26]([C:30]([O:32]CC)=[O:31])=[CH:27][CH:28]=[CH:29][C:5]=2[N:4]=1)[CH3:2]>CO.[OH-].[Na+]>[CH2:1]([C:3]1[N:7]([CH2:8][C:9]2[CH:10]=[CH:11][C:12]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[C:21]3[NH:25][N:24]=[N:23][N:22]=3)=[CH:13][CH:14]=2)[C:6]2[C:26]([C:30]([OH:32])=[O:31])=[CH:27][CH:28]=[CH:29][C:5]=2[N:4]=1)[CH3:2]
Reactant: CCOC(=O)c1cccc2nc(CC)n(Cc3ccc(-c4ccccc4-c4nnn[nH]4)cc3)c12
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCc1nc2cccc(C(=O)O)c2n1Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1

Procedure:
A mixture of ethyl 2-ethyl-1-[[2'-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl]benzimidazole-7-carboxylate (0.5 g) in methanol (10 ml) and 2N NaOH was heated under reflux for 4 hours. The reaction mixture was concentrated to dryness. The concentrate was dissolved in water, followed by neutralization with 1N-HCl to give crystals. Recrystallization from DMF-ethanol-water afforded colorless prisms (0.27 g, 58%), m.p. 261°-262° C.
Reaction SMILES: [C:1]([CH2:4][O:5][CH:6]1[CH:11]([C:12]2[CH:17]=[CH:16][C:15]([O:18][CH2:19][CH2:20][CH2:21][O:22][CH2:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=3[O:30][CH3:31])=[CH:14][CH:13]=2)[CH2:10][CH2:9][N:8]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:7]1)(O)=[O:2].[NH2:39][C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][C:41]=1[CH2:46][CH2:47][NH:48][C:49](=[O:51])[CH3:50]>>[C:49]([NH:48][CH2:47][CH2:46][C:41]1[CH:42]=[CH:43][CH:44]=[CH:45][C:40]=1[NH:39][C:1]([CH2:4][O:5][CH:6]1[CH:11]([C:12]2[CH:17]=[CH:16][C:15]([O:18][CH2:19][CH2:20][CH2:21][O:22][CH2:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=3[O:30][CH3:31])=[CH:14][CH:13]=2)[CH2:10][CH2:9][N:8]([C:32]([O:34][C:35]([CH3:38])([CH3:36])[CH3:37])=[O:33])[CH2:7]1)=[O:2])(=[O:51])[CH3:50]
Reactant: CC(=O)NCCc1ccccc1N
Reactant: COc1ccccc1COCCCOc1ccc(C2CCN(C(=O)OC(C)(C)C)CC2OCC(=O)O)cc1
Product: COc1ccccc1COCCCOc1ccc(C2CCN(C(=O)OC(C)(C)C)CC2OCC(=O)Nc2ccccc2CCNC(C)=O)cc1

Procedure:
Analogously to Example 3a, 0.138 g of tert-butyl 3-carboxymethoxy-4-{4-[3-(2-methoxybenzyloxy)propoxy]phenyl}piperidine-1-carboxylate and 0.061 g of N-[2-(2-aminophenyl)ethyl]acetamide. The title compound is obtained as a yellow oil. Rf=0.21 (95:5 dichloromethane-methanol); Rt=5.22.
Reaction SMILES: [F:1][C:2]1[CH:20]=[C:19]([F:21])[CH:18]=[CH:17][C:3]=1[O:4][C:5]1[CH:6]=[C:7]([CH:11]=[CH:12][C:13]=1[N+:14]([O-:16])=[O:15])[C:8](Cl)=[O:9].[Cl-].[Al+3].[Cl-].[Cl-]>C1C=CC=CC=1>[F:1][C:2]1[CH:20]=[C:19]([F:21])[CH:18]=[CH:17][C:3]=1[O:4][C:5]1[CH:6]=[C:7]([CH:11]=[CH:12][C:13]=1[N+:14]([O-:16])=[O:15])[C:8]([C:2]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:3]=1)=[O:9]
Reactant: O=C(Cl)c1ccc([N+](=O)[O-])c(Oc2ccc(F)cc2F)c1
Agent: [Al+3]
Agent: [Cl-]
Solvent: c1ccccc1
Product: O=C(c1ccccc1)c1ccc([N+](=O)[O-])c(Oc2ccc(F)cc2F)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 184.6 %

Procedure:
A mixture of 3-(2,4-difluorophenoxy)-4-nitrobenzoic acid (2.1 g) and phosphorus pentachloride (1.6 g) in benzene (20 ml) was stirred for 2 hours at room temperature. The mixture was concentrated under reduced pressure to give crystals of 3-(2,4-difluorophenoxy)-4-nitrobenzoyl chloride (2.2 g). A solution of 3-(2,4-difluorophenoxy)-4-nitrobenzoyl chloride (2.2 g) in benzene (20 ml) was added to a mixture of aluminum chloride (2.4 g) in benzene (20 ml). The mixture was stirred overnight at ambient temperature and concentrated under reduced pressure. The residue was dissolved in chloroform, washed with diluted hydrochloric acid and water successively, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was recrystallized from a mixture of hexane and ethanol to give crystals of 3-(2,4-difluorophenoxy)-4-nitrobenzophenone (2.3 g).
Reaction SMILES: [Cl:1][C:2]1[CH:19]=[CH:18][C:5]([C:6]([NH:8][C:9]2[S:10][CH:11]=[C:12]([CH2:14][C:15]([OH:17])=O)[N:13]=2)=[O:7])=[CH:4][CH:3]=1.[CH2:20]([O:22][C:23]([CH2:25][N:26]1[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1)=[O:24])[CH3:21]>>[CH2:20]([O:22][C:23](=[O:24])[CH2:25][N:26]1[CH2:31][CH2:30][N:29]([C:15](=[O:17])[CH2:14][C:12]2[N:13]=[C:9]([NH:8][C:6](=[O:7])[C:5]3[CH:4]=[CH:3][C:2]([Cl:1])=[CH:19][CH:18]=3)[S:10][CH:11]=2)[CH2:28][CH2:27]1)[CH3:21]
Reactant: CCOC(=O)CN1CCNCC1
Reactant: O=C(O)Cc1csc(NC(=O)c2ccc(Cl)cc2)n1
Product: CCOC(=O)CN1CCN(C(=O)Cc2csc(NC(=O)c3ccc(Cl)cc3)n2)CC1

Procedure:
22.1 Using general procedure A, [2-(4-chloro-benzoylamino)-thiazol-4-yl]-acetic acid (example 1.2) was coupled with 1-(ethoxycarbonylmethyl)-piperazine to give (4-{2-[2-(4-chloro-benzoylamino)-thiazol-4-yl]-acetyl}-piperazin-1-yl)-acetic acid ethyl ester. Off-white solid. MS 473.1 ([M+Na]+)
Reaction SMILES: C1(C)C=CC(S(O)(=O)=O)=CC=1.[CH2:12]([O:19][C:20]([C@@H:22]1[CH2:30][C@H:29]2[C@H:24]([CH2:25][CH2:26][CH2:27][CH2:28]2)[NH:23]1)=[O:21])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[CH3:31][CH2:32][CH2:33][C@H:34]([NH:40][C@H:41]([C:43](O)=[O:44])[CH3:42])[C:35]([O:37][CH2:38][CH3:39])=[O:36].ON1C2C=CC=CC=2N=N1.C1(N=C=NC2CCCCC2)CCCCC1>C(OCC)(=O)C.C(N(CC)CC)C>[CH2:38]([O:37][C:35]([C@@H:34]([NH:40][C@@H:41]([CH3:42])[C:43]([N:23]1[C@@H:24]2[C@@H:29]([CH2:28][CH2:27][CH2:26][CH2:25]2)[CH2:30][C@H:22]1[C:20]([O:19][CH2:12][C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1)=[O:21])=[O:44])[CH2:33][CH2:32][CH3:31])=[O:36])[CH3:39]
Reactant: CCC[C@H](N[C@@H](C)C(=O)O)C(=O)OCC
Reactant: O=C(OCc1ccccc1)[C@@H]1C[C@@H]2CCCC[C@@H]2N1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CCC[C@H](N[C@@H](C)C(=O)N1[C@H](C(=O)OCc2ccccc2)C[C@@H]2CCCC[C@@H]21)C(=O)OCC
Temperature: 0 °C
Reaction time: 3 h
Yield: 92 %

Procedure:
There are introduced into a reactor, with stirring, 1 kg of (2S,3aS,7aS)-octahydroindole-2-carboxylic acid benzyl ester para-toluenesulfonate, 0.06 kg of triethylamine, 4.6 liters of ethyl acetate and then, after stirring for 10 minutes at ambient temperature, 0.52 kg of N-[(S)-ethoxycarbonyl-1-butyl]-(S)-alanine, 0.15 kg of 1-hydroxybenzotriazole and 0.5 kg of dicylohexylcarbodiimide. The heterogeneous mixture is then brought to 30° C. for 3 hours while stirring well, and is subsequently cooled to 0° C. and filtered. The filtrate is then washed and subsequently evaporated to dryess to produce the expected product in a yield of 92%.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][C:8]=1[C:9]1[CH2:18][CH2:17][C:12]2([O:16][CH2:15][CH2:14][O:13]2)[CH2:11][CH:10]=1)[NH2:5].[C:19]([O:22][CH2:23][CH3:24])(=[O:21])C>[Pt]=O>[Cl:1][C:2]1[CH:3]=[C:4]([NH:5][C:19](=[O:21])[O:22][CH2:23][C:24]2[CH:4]=[CH:3][CH:2]=[CH:8][CH:7]=2)[CH:6]=[CH:7][C:8]=1[CH:9]1[CH2:18][CH2:17][C:12]2([O:13][CH2:14][CH2:15][O:16]2)[CH2:11][CH2:10]1
Reactant: Nc1ccc(C2=CCC3(CC2)OCCO3)c(Cl)c1
Reactant: CCOC(C)=O
Agent: O=[Pt]
Product: O=C(Nc1ccc(C2CCC3(CC2)OCCO3)c(Cl)c1)OCc1ccccc1
Temperature: 25 °C
Reaction time: 9 h

Procedure:
Platinum oxide (250 mg) was added in one portion to a stirred solution of 3-chloro-4-(1,4-dioxaspiro[4.5]dec-7-en-8-yl)aniline (3.4 g, 12.8 mmol) in ethyl acetate (50 mL) and the mixture was stirred at room temperature under a hydrogen atmosphere for 9 h. A further portion of platinum oxide (250 mg) was added in one portion and the mixture was stirred for 8 h at room temperature under a hydrogen atmosphere. The reaction mixture was filtered and concentrated in vacuo to leave the cyclohexane-aniline product (2.1 g) as a solid, which was used with no further purification.
Reaction SMILES: S(=O)(=O)(O)O.[NH2:6][C:7]1[NH:12][C:11](=[O:13])[CH:10]=[CH:9][N:8]=1.[N+:14]([O-])([OH:16])=[O:15]>O>[NH2:6][C:7]1[NH:12][C:11](=[O:13])[C:10]([N+:14]([O-:16])=[O:15])=[CH:9][N:8]=1
Reactant: O=[N+]([O-])O
Reactant: Nc1nccc(=O)[nH]1
Agent: O=S(=O)(O)O
Solvent: O
Product: Nc1ncc([N+](=O)[O-])c(=O)[nH]1
Temperature: 70 °C

Procedure:
Concentrated sulfuric acid (2.4 mL) was added to 2-amino-3,4-dihydropyrimidin-4-one (1 g, 9.0 mmol). The mixture was stirred and cooled in ice bath before dropwise addition of concentrated nitric acid (0.56 mL). The mixture was stirred at RT for 30 min before being heated at 70° C. for 2 hr. The mixture was allowed to cool to RT and was slowly added to water (10 mL), cooled in an ice bath. The resultant precipitate was collected by suction filtration, washed with diethyl ether (5 mL) and then thoroughly dried under high vacuum to give the title compound: 1H NMR (250 MHz, DMSO) δ 7.18 (1H, br. s.), 8.61 (1H, br. s.), 8.81 (1H, s); LC-MS: m/z=+156.9 (M+H)+.
Reaction SMILES: [N:1]1([CH:6]2[CH2:20][C:9]3[C:10]4[NH:11][C:12](=[O:19])[C:13](=[O:18])[NH:14][C:15]=4[CH:16]=[CH:17][C:8]=3[CH2:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[N+:21]([O-])([OH:23])=[O:22]>FC(F)(F)C(O)=O>[N+:21]([C:17]1[C:8]2[CH2:7][CH:6]([N:1]3[CH2:5][CH2:4][CH2:3][CH2:2]3)[CH2:20][C:9]=2[C:10]2[NH:11][C:12](=[O:19])[C:13](=[O:18])[NH:14][C:15]=2[CH:16]=1)([O-:23])=[O:22]
Reactant: O=c1[nH]c2ccc3c(c2[nH]c1=O)CC(N1CCCC1)C3
Reactant: O=[N+]([O-])O
Solvent: O=C(O)C(F)(F)F
Product: O=c1[nH]c2cc([N+](=O)[O-])c3c(c2[nH]c1=O)CC(N1CCCC1)C3

Procedure:
Nitration of 8-pyrrolidin-1-yl-4,7,8,9-tetrahydro-1H-cyclopenta[f]quinoxaline-2,3-dione as described before with fuming nitric acid in trifluoroacetic acid gave the product as a yellow solid (0.1 g). C15H16N4 O4.HCL. MS M+1 (317). HPLC 99%.