Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl-].[Al+3].[Cl-].[Cl-].[CH3:12][S:13](Cl)(=[O:15])=[O:14]>CO>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:13]([CH3:12])(=[O:15])=[O:14])=[CH:4][CH:3]=1
Reactant: Clc1ccccc1
Reactant: CS(=O)(=O)Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: CO
Product: CS(=O)(=O)c1ccc(Cl)cc1
Temperature: 15 °C

Procedure:
To 600 ml of chlorobenzene were added 272 g of anhydrous aluminum chloride and 229 g of methanesulfonyl chloride and the mixture was heated on a steam bath for 6 hours with stirring. The solution thus formed was poured into ice-water, and then the produce was extracted with 400 ml of methylene chloride. Methylene chloride was distilled off from the extract under reduced pressure. To the residue thus formed was added 300 ml of methanol, the mixture was cooled to 15° C., and crystals thus deposited were collected by filtration to provide 212 g 1-chloro-4-methylsulfonyl benzene having a melting point of 92° to 94° C.
Reaction SMILES: C([O:5][C:6](=[O:16])[CH2:7][O:8][C:9]1[N:10]=[N:11][C:12]([Br:15])=[CH:13][CH:14]=1)(C)(C)C.C(O)(C(F)(F)F)=O>>[Br:15][C:12]1[N:11]=[N:10][C:9]([O:8][CH2:7][C:6]([OH:16])=[O:5])=[CH:14][CH:13]=1
Reactant: CC(C)(C)OC(=O)COc1ccc(Br)nn1
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)COc1ccc(Br)nn1
Reaction time: 3 h

Procedure:
To the crude (6-bromo-pyridazin-3-yloxy)-acetic acid tert-butyl ester obtained in step (a) 5 ml of 90% aqueous TFA were added, and the mixture was allowed to stand at room temperature for 3 h. After evaporation, a sodium hydrogencarbonate solution was added, and the solution extracted with ethyl acetate. The aqueous phase was acidified to pH=4 and extracted with ethyl acetate. The combined extracts were dried and evaporated. Yield: 147 mg.
Reaction SMILES: [CH2:1]([C@H:3]1[CH2:8][C@H:7]2[C@H:9]3[C@H:18]([CH2:19][CH2:20][C@:5]2([CH3:6])[C@H:4]1[O:22][C:23](=[O:26])[CH2:24]Br)[C@@H:17]1[C:12](=[CH:13][C:14](=[O:21])[CH2:15][CH2:16]1)[CH2:11][CH2:10]3)[CH3:2].[C:27]([OH:36])(=[O:35])[CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34]>CC(C)=O.[OH-].[Na+].O>[CH2:1]([C@H:3]1[CH2:8][C@H:7]2[C@H:9]3[C@H:18]([CH2:19][CH2:20][C@:5]2([CH3:6])[C@H:4]1[O:22][C:23](=[O:26])[CH2:24][O:36][C:27](=[O:35])[CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34])[C@@H:17]1[C:12](=[CH:13][C:14](=[O:21])[CH2:15][CH2:16]1)[CH2:11][CH2:10]3)[CH3:2]
Reactant: CC[C@H]1C[C@H]2[C@@H]3CCC4=CC(=O)CC[C@@H]4[C@H]3CC[C@]2(C)[C@H]1OC(=O)CBr
Reactant: CCCCCCCC(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)=O
Solvent: O
Product: CCCCCCCC(=O)OCC(=O)O[C@H]1[C@@H](CC)C[C@H]2[C@@H]3CCC4=CC(=O)CC[C@@H]4[C@H]3CC[C@@]21C

Procedure:
In 60 ml of acetone is dissolved 1.0 ml of n-octanoic acid, and 3.0 ml of 2N-NaOH, 15 ml of water and 1.8 g of 16β-ethyl-17β-bromoacetoxy-4-estren-3-one are serially added to the above solution. The mixture is refluxed for 4 hours. The solvent is distilled off under reduced pressure and the residue is extracted with 150 ml of ethyl acetate. The organic layer is separated, washed with water and saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate. The solvent is then distilled off under reduced pressure and the residue is subjected to column chromatography. Following passage of 50 ml of diisopropyl ether, elution is carried out with 300 ml of the same solvent. The eluate is evaporated under reduced pressure to remove the solvent, giving 1.7 g of the above-identified compound as a colorless oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N+:10]([O-:11])=[N:9][C:8](=[O:12])[NH:7][C:6]=2[CH:13]=1.[H-].[Na+].CS(O[CH2:21][CH2:22][N:23]1[CH2:28][CH2:27][CH:26]([NH:29][C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH2:25][CH2:24]1)(=O)=O.C(OC(=O)NC1CCN(CCN2C3C(=CC=C(OC)C=3)C=CC2=O)CC1)(C)(C)C>C(OCC)C>[C:33]([O:32][C:30](=[O:31])[NH:29][CH:26]1[CH2:27][CH2:28][N:23]([CH2:22][CH2:21][N:7]2[C:6]3[CH:13]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]=3[N+:10]([O-:11])=[N:9][C:8]2=[O:12])[CH2:24][CH2:25]1)([CH3:36])([CH3:35])[CH3:34]
Reactant: CC(C)(C)OC(=O)NC1CCN(CCOS(C)(=O)=O)CC1
Reactant: O=c1n[n+]([O-])c2ccc(Cl)cc2[nH]1
Agent: COc1ccc2ccc(=O)n(CCN3CCC(NC(=O)OC(C)(C)C)CC3)c2c1
Agent: [H-]
Agent: [Na+]
Solvent: CCOCC
Product: CC(C)(C)OC(=O)NC1CCN(CCn2c(=O)n[n+]([O-])c3ccc(Cl)cc32)CC1

Procedure:
6-Chloro-1,2,4-benzotriazin-3(4H)-one 1-oxide (FR 2621583, 1.50 g) was deprotonated with sodium hydride (0.42 g, 60% in oil) and alkylated with 2-{4-[(tert-butoxycarbonyl)amino]piperidin-1-yl}ethyl methanesulfonate (Intermediate 6) (1 equivalent) as described for Intermediate 2. The residue obtained after aqueous work up was suspended in diethyl ether and filtered to yield 1.30 g of product.
Reaction SMILES: ClCCl.[C:4]([NH:12][C:13]([NH:15][C@@:16]1([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=2[F:32])[CH2:21][C@@H:20]([O:22][CH3:23])[CH2:19][CH2:18][C@H:17]1[CH2:24]O)=[S:14])(=[O:11])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.FC(F)(F)S(OS(C(F)(F)F)(=O)=O)(=O)=O.C(=O)(O)[O-].[Na+]>C(OCC)(=O)C.N1C=CC=CC=1>[F:32][C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=1[C@:16]12[CH2:21][C@@H:20]([O:22][CH3:23])[CH2:19][CH2:18][C@H:17]1[CH2:24][S:14][C:13]([NH:12][C:4](=[O:11])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[N:15]2
Reactant: CO[C@H]1CC[C@@H](CO)[C@](NC(=S)NC(=O)c2ccccc2)(c2ccccc2F)C1
Agent: O=C([O-])O
Agent: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Agent: [Na+]
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CO[C@H]1CC[C@H]2CSC(NC(=O)c3ccccc3)=N[C@@]2(c2ccccc2F)C1
Temperature: -78 °C
Reaction time: 0.25 h

Procedure:
Dichloromethane (20 mL) and pyridine (264 μL, specific gravity: 0.978 g/cm3) were added to (±)-1-benzoyl-3-[(1S*,2R*,5S*)-1-(2-fluorophenyl)-2-hydroxymethyl-5-methoxycyclohexyl]thiourea obtained in Preparation Example 57-(6) (453 mg) according to the method of Preparation Example 18-(5). The mixture was cooled to −78° C. under a nitrogen atmosphere and stirred for 15 minutes. Trifluoromethanesulfonic anhydride (358 μL, specific gravity: 1.72 g/cm3) was slowly added to the reaction solution. After completion of the addition, the mixture was stirred for 15 minutes and then further stirred for one hour while warming to 0° C. After adding ethyl acetate, a saturated sodium bicarbonate solution was added, followed by extraction with ethyl acetate. The organic layer was sequentially washed with water and brine and dried over anhydrous magnesium sulfate. The solid was removed by filtration. After concentration under reduced pressure, the residue was purified by silica gel column chromatography to obtain the title compound (268 mg).
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4](=[O:12])[O:5][C:6]2=[O:11].C(N(CC)C(C)C)(C)C.[CH3:22][O:23][CH2:24]Cl>CN(C)C=O>[CH3:22][O:23][CH2:24][O:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4](=[O:12])[O:5][C:6]2=[O:11]
Reactant: COCCl
Reactant: O=C1OC(=O)c2c(O)cccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COCOc1cccc2c1C(=O)OC2=O
Temperature: 25 °C
Yield: 95.1 %

Procedure:
To a solution of 4-hydroxy-isobenzofuran-1,3-dione (0.5 g, 3.03 mmol) in anhydrous N,N-dimethylformamide (6 ml) under nitrogen was added N,N-diisopropylethylamine (1.05 ml, 6.06 mmol). The solution was stirred with cooling in an ice bath and chloromethyl methyl ether (0.46 ml, 6.06 mmol) was added. The reaction was allowed to slowly warm to ambient temperature and then stirred for an additional 7 hours. The mixture was concentrated in vacuo to a small volume and diluted with ethyl acetate (75 ml). The organic layer was washed with water (2×40 ml), brine (20 ml), dried (Na2SO4), filtered, and the solvent evaporated in vacuo to give 0.6 g (95%) of 4-methoxymethoxy-isobenzofuran-1,3-dione as a solid.
Reaction SMILES: [CH2:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14](=[O:50])[C@@H:15]([NH:20][C:21]([C:23]2[CH:27]=[C:26]([O:28][CH2:29][C:30]([N:32]3[CH2:36][CH2:35][CH2:34][C@H:33]3[C:37](=[O:43])[NH:38][CH:39]3[CH2:42][CH2:41][CH2:40]3)=[O:31])[N:25]([C:44]3[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=3)[N:24]=2)=[O:22])[CH2:16][CH2:17][CH2:18][OH:19])[CH2:10][CH2:9]1)=[O:7])[CH2:2][CH2:3][CH3:4].N1C=CC=CC=1.[C:57](OC(=O)C)(=[O:59])[CH3:58]>ClCCl.CN(C1C=CN=CC=1)C>[CH2:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14](=[O:50])[C@@H:15]([NH:20][C:21]([C:23]2[CH:27]=[C:26]([O:28][CH2:29][C:30]([N:32]3[CH2:36][CH2:35][CH2:34][C@H:33]3[C:37](=[O:43])[NH:38][CH:39]3[CH2:42][CH2:41][CH2:40]3)=[O:31])[N:25]([C:44]3[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=3)[N:24]=2)=[O:22])[CH2:16][CH2:17][CH2:18][O:19][C:57](=[O:59])[CH3:58])[CH2:10][CH2:9]1)=[O:7])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOC(=O)N1CCN(C(=O)[C@H](CCCO)NC(=O)c2cc(OCC(=O)N3CCC[C@H]3C(=O)NC3CCC3)n(-c3ccccc3)n2)CC1
Reactant: CC(=O)OC(C)=O
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCCCOC(=O)N1CCN(C(=O)[C@H](CCCOC(C)=O)NC(=O)c2cc(OCC(=O)N3CCC[C@H]3C(=O)NC3CCC3)n(-c3ccccc3)n2)CC1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a solution of 65 mg 4-[(S)-2-({5-[2-((S)-2-Cyclobutylcarbamoyl-pyrrolidin-1-yl)-2-oxo-ethoxy]-1-phenyl-1H-pyrazole-3-carbonyl}-amino)-5-hydroxy-pentanoyl]-piperazine-1-carboxylic acid butyl ester in 4 ml dichloromethane were added 15 l pyridine, 10 l acetic anhydride and a catalytic amount of DMAP. After stirring for 24 h at room temperature the reaction mixture was concentrated and the crude product thus obtained was purified by preparative HPLC (C18 reverse phase column, elution with a water/MeCN gradient with 0.1% TFA) to give the title compound.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:14]=[CH:13][C:8]([C:9]([O:11][CH3:12])=[O:10])=[CH:7][CH:6]=1)=[O:4].[BH4-].[Na+].C([O-])([O-])=O.[K+].[K+].O>CO>[O:4]1[CH2:2][CH:3]1[C:5]1[CH:14]=[CH:13][C:8]([C:9]([O:11][CH3:12])=[O:10])=[CH:7][CH:6]=1
Reactant: COC(=O)c1ccc(C(=O)CBr)cc1
Agent: O=C([O-])[O-]
Agent: [BH4-]
Agent: [K+]
Solvent: O
Solvent: CO
Product: COC(=O)c1ccc(C2CO2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 90.3 %

Procedure:
To a stirred solution of methyl 4-(2-bromoacetyl)benzoate (0.59 g, 2.3 mmol) in MeOH (6 mL) at 0° C. was added NaBH4 (92 mg, 2.4 mmol) in portions. The cooling bath was removed and the mixture was stirred at room temperature for 1 h. K2CO3 (317 mg, 2.30 mmol) was added and the mixture was stirred at room temperature for 72 h. The mixture was poured into water and was extracted with Et2O (3×). The organics were combined, washed with water, brine, dried (MgSO4) and evaporated to dryness to give methyl 4-(oxiran-2-yl)benzoate (370 mg, 90%) as a white solid. ESI-MS m/z calc. 178.2, found 179.1 (M+1)+; Retention time: 1.14 minutes (3 min run).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[C:4]([C:12]([O:14]C)=[O:13])=[CH:5][N:6]=[CH:7]2.[OH-].[K+].Cl>CO.O>[Cl:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[C:4]([C:12]([OH:14])=[O:13])=[CH:5][N:6]=[CH:7]2
Reactant: COC(=O)c1cncc2cccc(Cl)c12
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C(O)c1cncc2cccc(Cl)c12

Procedure:
To a stirred solution of methyl 5-chloroisoquinolin-4-carboxylate (Intermediate-42) (3.8 g, 17.1 mmol) in MeOH (30 mL) was added, KOH (9.62 g, 171 mmol) solution in H2O (20 mL) and the reaction mixture was heated to 70° C. for 3 h. After completion (TLC), it was concentrated under vacuum to give crude product (3.5 g) that was diluted with water, acidified with 1N HCl (pH=3) and the aqueous phase was extracted with EtOAc, dried and concentrated under vacuum to afford the desired acid derivative (3 g, 84%) as an off white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH3:13])[CH:6]=[C:7]([O:11][CH3:12])[C:8]=1[O:9][CH3:10].[CH3:14][O:15][C:16]1[CH:24]=[CH:23][CH:22]=[C:21]([CH3:25])[C:17]=1[C:18](Cl)=[O:19].[Cl-].[Al+3].[Cl-].[Cl-].Cl>C(OCC)(=O)C.ClCCl>[CH3:25][C:21]1[C:17]([C:18]([C:4]2[C:5]([CH3:13])=[CH:6][C:7]([O:11][CH3:12])=[C:8]([O:9][CH3:10])[C:3]=2[O:2][CH3:1])=[O:19])=[C:16]([O:15][CH3:14])[CH:24]=[CH:23][CH:22]=1
Reactant: COc1cc(C)cc(OC)c1OC
Reactant: COc1cccc(C)c1C(=O)Cl
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: COc1cc(C)c(C(=O)c2c(C)cccc2OC)c(OC)c1OC
Temperature: 0 °C

Procedure:
A mixture of 3,4,5-trimethoxytoluene (1.86 g; 10.2 mmol), 1B (10.2 mmol), aluminium chloride (1.33 g, 10 mmol) and dichloromethane (20 ml) is stirred at 0° C. Subsequently, the reaction mixture is stirred for another 4 hours at room temperature. A mixture of dilute hydrochloric acid and ethyl acetate (1:1 v/v; 100 ml) is then slowly added at 0° C. The organic phase is concentrated and the residue is recrystallized from methanol. The solid material is collected by vacuum filtration, three times washed with methanol/water (3:1 v/v; 100 ml each) and dried yielding white crystals, 1.0 g (30.3%), mp 84° C.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][C:9]=1[NH:18][C:19](=[O:37])[CH2:20][C:21]([C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([C:29]2[CH:34]=[C:33]([CH3:35])[N:32]=[C:31]([CH3:36])[CH:30]=2)[CH:24]=1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:36][C:31]1[CH:30]=[C:29]([C:25]2[CH:24]=[C:23]([C:21]3[CH2:20][C:19](=[O:37])[NH:18][C:9]4[CH:10]=[C:11]([C:14]([F:15])([F:17])[F:16])[CH:12]=[CH:13][C:8]=4[N:7]=3)[CH:28]=[CH:27][CH:26]=2)[CH:34]=[C:33]([CH3:35])[N:32]=1
Reactant: Cc1cc(-c2cccc(C(=O)CC(=O)Nc3cc(C(F)(F)F)ccc3NC(=O)OC(C)(C)C)c2)cc(C)n1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc(-c2cccc(C3=Nc4ccc(C(F)(F)F)cc4NC(=O)C3)c2)cc(C)n1

Procedure:
The title compound was prepared from (2-{3-[3-(2,6-dimethyl-pyridin-4-yl)-phenyl]-3-oxo-propionylamino}-4-trifluoromethyl-phenyl)-carbamic acid tert-butyl ester (Example M109) (0.26 g, 0.49 mmol) by treatment with TFA in CH2Cl2 according to the general procedure N. Obtained as a light yellow solid (110 mg, 55%).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:18])[CH2:5][CH2:6][C:7]1[C:16]2[CH2:15][CH2:14][CH2:13][CH2:12][C:11]=2[C:10]([OH:17])=[CH:9][CH:8]=1)[CH3:2].Cl[CH2:20][C:21]1[C:22]([CH:37]2[CH2:39][CH2:38]2)=[N:23][C:24]([C:27]2[CH:32]=[CH:31][C:30]([C:33]([F:36])([F:35])[F:34])=[CH:29][CH:28]=2)=[N:25][CH:26]=1>>[CH2:1]([O:3][C:4](=[O:18])[CH2:5][CH2:6][C:7]1[C:16]2[CH2:15][CH2:14][CH2:13][CH2:12][C:11]=2[C:10]([O:17][CH2:20][C:21]2[C:22]([CH:37]3[CH2:39][CH2:38]3)=[N:23][C:24]([C:27]3[CH:28]=[CH:29][C:30]([C:33]([F:35])([F:36])[F:34])=[CH:31][CH:32]=3)=[N:25][CH:26]=2)=[CH:9][CH:8]=1)[CH3:2]
Reactant: CCOC(=O)CCc1ccc(O)c2c1CCCC2
Reactant: FC(F)(F)c1ccc(-c2ncc(CCl)c(C3CC3)n2)cc1
Product: CCOC(=O)CCc1ccc(OCc2cnc(-c3ccc(C(F)(F)F)cc3)nc2C2CC2)c2c1CCCC2

Procedure:
In analogy to the procedures described in example 5C] and 5D], 3-(4-hydroxy-5,6,7,8-tetrahydro-naphthalen-1-yl)-propionic acid ethyl ester (example 5B]) was reacted with 5-chloromethyl-4-cyclopropyl-2-(4-trifluoromethyl-phenyl)-pyrimidine (example 9E]) to give 3-{4-[4-cyclopropyl-2-(4-trifluoromethyl-phenyl)-pyrimidin-5-ylmethoxy]-5,6,7,8-tetrahydro-naphthalen-1-yl}-propionic acid ethyl ester, which was subsequently saponified to yield the title compound as colorless solid.
Reaction SMILES: [ClH:1].[NH:2]1[CH2:7][CH2:6][CH:5]([O:8][C:9]2[CH:10]=[C:11]3[C:16](=[CH:17][CH:18]=2)[CH:15]=[N:14][CH:13]=[CH:12]3)[CH2:4][CH2:3]1.C(O[C:22]1(O[Si](C)(C)C)[CH2:24][CH2:23]1)C.C([BH3-])#N.[Na+].[OH-].[Na+]>CO.C(O)(=O)C.C(N(CC)CC)C>[ClH:1].[CH:22]1([N:2]2[CH2:7][CH2:6][CH:5]([O:8][C:9]3[CH:10]=[C:11]4[C:16](=[CH:17][CH:18]=3)[CH:15]=[N:14][CH:13]=[CH:12]4)[CH2:4][CH2:3]2)[CH2:24][CH2:23]1
Reactant: c1cc2cc(OC3CCNCC3)ccc2cn1
Reactant: CCOC1(O[Si](C)(C)C)CC1
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CC(=O)O
Solvent: CO
Product: c1cc2cc(OC3CCN(C4CC4)CC3)ccc2cn1
Temperature: 25 °C

Procedure:
300 mg (1.13 mmol) 6-(Piperidine-4-yloxy)-isoquinoline hydrochloride (124) are dissolved in 10 mL of methanol. 202 mg of triethylamine, molecular sieves 4A, 600 mg of glacial acetic acid, 871 mg of (1-Ethoxy-cyclopropyloxy)-trimethyl-silane and 101 mg of sodium cyanoborohydride are added successively and the reaction mixture is heated under reflux for 6 hours. The reaction mixture is cooled to room temperature, 6 mL of 2N sodium hydroxide are added and the reaction mixture is filtered. The filtrate is evaporated, the residue is taken up in dichloromethane, extracted with 2 N sodium hydroxide and brine, dried with sodium sulfate, evaporated to dryness and the crude material is purified by preparative HPLC. The product fractions are evaporated, the product is taken up in 2 N hydrochloric acid and lyophilized.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[S:10]([N:13]1[CH2:17][CH:16]=[CH:15][CH2:14]1)(=[O:12])=[O:11])([O-])=O.[In].Cl>O.O1CCCC1>[N:13]1([S:10]([C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[NH2:1])(=[O:12])=[O:11])[CH2:14][CH:15]=[CH:16][CH2:17]1
Reactant: O=[N+]([O-])c1ccccc1S(=O)(=O)N1CC=CC1
Agent: Cl
Agent: [In]
Solvent: O
Solvent: C1CCOC1
Product: Nc1ccccc1S(=O)(=O)N1CC=CC1
Reaction time: 24 h

Procedure:
A 250 mL round bottom flask was equipped with a magnetic stirrer and charged with 1-(2-nitrobenzenesulfonyl)-2,5-dihydro-1H-pyrrole (Example 87, 9.32 mmol, followed by 3:1 water/tetrahydrofuran v/v (50 mL). Indium powder (37.3 mmol) was added, followed by concentrated HCl (55.9 mmol). The reaction gives a slight exotherm and the indium forms a solid metal chunk. After 24 hours, TLC (dichloromethane/silica) indicated the reaction was mostly complete. The indium was removed with a pair of tweesers to a separate waste stream and the reaction was neutralized with sodium bicarbonate. The aqueous mixture was extracted with ethyl acetate (150 mL), the organic layer dried (Na2SO4), filtered, and the solvent was removed under reduced pressure. The residue was dissolved in dichloromethane (20 mL) and loaded onto a 600 mL sintered glass funnel charged with silica gel (400 g). The silica plug was eluted with 9:1 dichloromethane:ethyl acetate, collecting 100 mL fractions. Fractions containing the desired product were combined and the solvent was removed under diminished pressure to afford 2-(2,5-dihydropyrrole-1-sulfonyl)-aniline as a pale yellow, crystalline solid. 1.66 g, (62%). m.p.: 104-105° C. LC/MS: m/z 225.2 [C10H12N2O2S+H]+. 1H-NMR (CDCl3): δ 4.20 (s, 4H); 5.05 (b, 2H); 5.69 (s, 2H); 6.71-6.79 (m, 2H); 7.26-7.32 (t, 1H, J=8.1 Hz); 7.64-7.67 (d, 1H, J=7.9 Hz).
Reaction SMILES: [H-].[Na+].[CH3:3][N:4]1[C:8]2=[C:9]3[CH:15]=[CH:14][NH:13][C:10]3=[N:11][CH:12]=[C:7]2[CH:6]=[N:5]1.[C:16]1([CH3:26])[CH:21]=[CH:20][C:19]([S:22](Cl)(=[O:24])=[O:23])=[CH:18][CH:17]=1.O>CN(C=O)C>[CH3:3][N:4]1[C:8]2=[C:9]3[CH:15]=[CH:14][N:13]([S:22]([C:19]4[CH:20]=[CH:21][C:16]([CH3:26])=[CH:17][CH:18]=4)(=[O:24])=[O:23])[C:10]3=[N:11][CH:12]=[C:7]2[CH:6]=[N:5]1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: Cn1ncc2cnc3[nH]ccc3c21
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1ccc(S(=O)(=O)n2ccc3c2ncc2cnn(C)c23)cc1
Reaction time: 2 h
Yield: 43.8 %

Procedure:
To a solution of NaH (60% dispersion in mineral oil, 0.209 g, 5.23 mmol) in DMF (10 mL) at about 0° C. was added a solution of 1-methyl-1,6-dihydropyrazolo[3,4-d]pyrrolo[2,3-b]pyridine (0.60 g, 3.5 mmol) in DMF (5 mL). The cooling bath was removed and after about 20 min, p-toluenesulfonyl chloride (0.996 g, 5.23 mmol) was added. After about 2 h at room temperature, water was added (15 mL) and the mixture was extracted with EtOAc (3×20 mL). The organic layers were combined, dried over anhydrous MgSO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with a gradient of 5-45% EtOAc in heptane to give 1-methyl-6-tosyl-1,6-dihydropyrazolo[3,4-d]pyrrolo[2,3-b]pyridine (0.50 g, 44%): LC/MS (Table 2, Method d) Rt=2.20 min; MS m/z: 327 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([O:9][CH3:10])=[CH:4][C:3]=1[CH2:11]Br.C([O-])([O-])=[O:14].[Ca+2].CCOC(C)=O>O1CCOCC1.O>[Br:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([O:9][CH3:10])=[CH:4][C:3]=1[CH2:11][OH:14]
Reactant: O=C([O-])[O-]
Reactant: COc1cc(C)c(Br)c(CBr)c1
Agent: [Ca+2]
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: COc1cc(C)c(Br)c(CO)c1
Temperature: 110 °C
Yield: 12 %

Procedure:
A solution of 2-bromo-1-bromomethyl-5-methoxy-3-methyl-benzene ((Example 192: step b) 10.8 g, 36.7 mmol) in dioxane:water (1:1, 200 mL) was treated with CaCO3 and heated to reflux (110° C.)18 h. The reaction mixture was cooled to room temperature and filtered by gravity to remove solid salts. The dioxane was removed in vacuo. Dilute HCl (10 mL) was added, and the mixture was extracted with CH2Cl2 (2×150 mL). The combined organic layers were dried over MgSO4. The solvents were removed in vacuo to afford a pale orange oil, which slowly solidified upon standing. Silica gel chromatography (25% EtOAc in hexanes) yielded the product (2-bromo-5-methoxy-3-methyl-phenyl)-methanol (1.03 g, 12%) as a yellow oil. 1H NMR (CDCl3): δ 6.905 (d, 1H, J=3.2 Hz), 6.746 (d, 1H, J=3.2 Hz), 4.720 (d, 2H, J=3.6 Hz), 3.798 (s, 3H), 2.390 (s, 3H).
Reaction SMILES: [CH:1]([N:4]1[CH2:9][CH2:8][CH:7]([O:10][C:11]2[CH:19]=[CH:18][C:17]3[N:16]4[CH2:20][C@@H:21]([CH3:25])[NH:22][C:23](=[O:24])[C:15]4=[CH:14][C:13]=3[CH:12]=2)[CH2:6][CH2:5]1)([CH3:3])[CH3:2].[CH3:26][O:27][CH2:28][CH2:29]Br.[H-].[Na+]>>[CH:1]([N:4]1[CH2:9][CH2:8][CH:7]([O:10][C:11]2[CH:19]=[CH:18][C:17]3[N:16]4[CH2:20][C@@H:21]([CH3:25])[N:22]([CH2:29][CH2:28][O:27][CH3:26])[C:23](=[O:24])[C:15]4=[CH:14][C:13]=3[CH:12]=2)[CH2:6][CH2:5]1)([CH3:3])[CH3:2]
Reactant: CC(C)N1CCC(Oc2ccc3c(c2)cc2n3C[C@@H](C)NC2=O)CC1
Reactant: COCCBr
Agent: [H-]
Agent: [Na+]
Product: COCCN1C(=O)c2cc3cc(OC4CCN(C(C)C)CC4)ccc3n2C[C@H]1C
Yield: 49 %

Procedure:
The title compound was synthesized in analogy to example 17, from (R)-8-(1-isopropyl-piperidin-4-yloxy)-3-methyl-3,4-dihydro-2H-pyrazino[1,2-a]indol-1-one (example 14), 2-bromoethyl methyl ether and sodium hydride, to give the desired product as a colorless oil (49%).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][C:17]([C:20]3[O:21][CH:22]=[N:23][N:24]=3)=[CH:16][CH:15]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.[ClH:25].O1CCOC[CH2:27]1>>[ClH:25].[CH3:27][C:22]1[O:21][C:20]([C:17]2[CH:18]=[CH:19][C:14]([N:11]3[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]3)=[CH:15][CH:16]=2)=[N:24][N:23]=1
Reactant: C1COCCO1
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(-c3nnco3)cc2)CC1
Agent: Cl
Product: Cc1nnc(-c2ccc(N3CCNCC3)cc2)o1

Procedure:
Prepared in analogy to example 4.4(b) from 4-(4-[1,3,4]Oxadiazol-2-yl-phenyl)-piperazine-1-carboxylic acid tert-butyl ester and hydrochloric acid in dioxane. MS (m/e): 245.3 (MH+, 100%)
Reaction SMILES: [C:1]([C:3]1[CH:4]([C:28]2[CH:33]=[CH:32][CH:31]=[C:30]([N+:34]([O-:36])=[O:35])[CH:29]=2)[C:5]2[CH:21]=[CH:20][C:19]3[C:14](=[CH:15][C:16]([OH:27])=[C:17]([C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH:18]=3)[C:6]=2[O:7][C:8]=1[N:9]1[CH:13]=[CH:12][CH:11]=[CH:10]1)#[N:2].[C:37](=O)([O-])[O-].[K+].[K+].CI.O>CN(C=O)C>[C:1]([C:3]1[CH:4]([C:28]2[CH:33]=[CH:32][CH:31]=[C:30]([N+:34]([O-:36])=[O:35])[CH:29]=2)[C:5]2[CH:21]=[CH:20][C:19]3[C:14](=[CH:15][C:16]([O:27][CH3:37])=[C:17]([C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH:18]=3)[C:6]=2[O:7][C:8]=1[N:9]1[CH:10]=[CH:11][CH:12]=[CH:13]1)#[N:2]
Reactant: O=C([O-])[O-]
Reactant: CCOC(=O)c1cc2ccc3c(c2cc1O)OC(n1cccc1)=C(C#N)C3c1cccc([N+](=O)[O-])c1
Agent: [K+]
Solvent: CI
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)c1cc2ccc3c(c2cc1OC)OC(n1cccc1)=C(C#N)C3c1cccc([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
Ethyl 3-cyano-9-hydroxy-4-(3-nitrophenyl)-2-(1-pyrrolyl)-4H-naphtho[1,2-b]pyran-8-carboxylate (4 g) was dissolved in dry DMF (50 ml). Solid potassium carbonate (2.3 g) and methyl iodide (1.05 ml) were added and the mixture stirred at room temperature for 16 hours. The solution was poured into water (400 ml) and extracted with ethyl acetate (4×200 ml). The combined organic extracts were washed with water (3×250 ml), dried over magnesium suphate, then solvent was removed under reduced pressure to yield a brown solid. This was triturated with ether (10 ml), the solid collected by filtration and dried to yield ethyl 3-cyano-9-methoxy-4-(3-nitrophenyl)-2-(1-pyrrolyl)-4H-naphtho[1,2-b]pyran-8-carboxylate as a dark yellow solid, m.p. 190°-191° C.