Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:12]([N+:13]([O-:15])=[O:14])=[CH:11][CH:10]=[CH:9][C:3]=1[O:4][CH2:5][CH:6]([NH2:8])[CH3:7].C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[CH3:7][CH:6]1[NH:8][C:2]2[C:12]([N+:13]([O-:15])=[O:14])=[CH:11][CH:10]=[CH:9][C:3]=2[O:4][CH2:5]1
Reactant: CC(N)COc1cccc([N+](=O)[O-])c1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC1COc2cccc([N+](=O)[O-])c2N1
Reaction time: 8 h
Yield: 79.2 %

Procedure:
6 g (0.026 mol) of 1-(2-chloro-3-nitrophenoxy)propan-2-amine, 3.6 g (0.026 mol) of potassium carbonate and 20 ml of N,N-dimethylformamide are heated at 110° C. with stirring overnight. The reaction mixture is poured into water and extracted 3 times with ether. The organic phase is recovered, washed with water, dried and the solvent evaporated to dryness. There are obtained 4 g of product in the form of a crystalline residue which is used as is in the following stage.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]2[CH2:13][CH2:12][C:11](=O)[CH2:10][CH2:9][C:8]=2[CH:15]=1)([O-:3])=[O:2].[CH3:16][N:17]1[CH2:22][CH2:21][N:20]([CH:23]2[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]2)[CH2:19][CH2:18]1>>[CH3:16][N:17]1[CH2:22][CH2:21][N:20]([CH:23]2[CH2:28][CH2:27][N:26]([CH:11]3[CH2:10][CH2:9][C:8]4[CH:15]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=[CH:6][C:7]=4[CH2:13][CH2:12]3)[CH2:25][CH2:24]2)[CH2:19][CH2:18]1
Reactant: CN1CCN(C2CCNCC2)CC1
Reactant: O=C1CCc2ccc([N+](=O)[O-])cc2CC1
Product: CN1CCN(C2CCN(C3CCc4ccc([N+](=O)[O-])cc4CC3)CC2)CC1

Procedure:
1-Methyl-4-[1-(2-nitro-6,7,8,9-tetrahydro-5H-benzocyclohepten-7-yl)-piperidin-4-yl]-piperazine was prepared from 2-nitro-5,6,8,9-tetrahydrobenzocyclohepten-7-one and 1-methyl-4-piperidin-4-yl-piperazine in an analogous manner to Example 178a. Product was isolated as a tan solid. 1H NMR (CDCl3, 400 MHz) δ 7.98 (s, 1H), 7.97 (d, 1H, J=8.08 Hz), 7.24 (d, 1H, J=8.08 Hz), 2.95 (dd, 2H, J=7.32, 12 Hz), 2.84 (d, 2H, J=12 Hz), 2.74 (m, 3H), 2.60 (broad s, 4H), 2.47 (m, 3H), 2.29 (s, 5H), 2.11 (m, 2H), 1.82 (d, 2H, J=12 Hz), 1.67 (m, 2H), 1.54 (m, 2H), 1.40 (m, 2H).
Reaction SMILES: [S:1]([CH2:5][CH2:6][CH2:7][C:8]([OH:10])=[O:9])(=[O:4])(=[O:3])[NH2:2].C(=O)([O-])[O-].[Cs+].[Cs+].[CH2:17](Br)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.O>CN(C=O)C>[S:1]([CH2:5][CH2:6][CH2:7][C:8]([O:10][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:9])(=[O:4])(=[O:3])[NH2:2]
Reactant: NS(=O)(=O)CCCC(=O)O
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: NS(=O)(=O)CCCC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 61 %

Procedure:
4-Sulfamoylbutanoic acid (1.00 g, 5.98 mmol) was dissolved in DMF (6.00 mL). To this, cesium carbonate (994 mg, 3.05 mmol) and benzyl bromide (0.711 mL, 5.98 mmol) were added and the mixture was stirred at room temperature for 18 hours. The reaction was stopped by addition of water, and the organic layer was extracted with dichloromethane, washed with a saturated aqueous sodium bicarbonate solution and dried over anhydrous magnesium sulfate. The solvent was evaporated off under reduced pressure, and the residue was subjected to slurry purification using diethyl ether, to give Compound GM (940 mg, yield: 61%).
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][C:10](C)=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:14][CH2:15][O:16][C:17]1[CH:22]=[CH:21][C:20]([CH2:23][C@H:24]([NH:30][CH2:31]C2C=CC(F)=CC=2)[C:25]([O:27][CH2:28]C)=[O:26])=[CH:19][CH:18]=1.[F:39][C:40]1[C:47]([F:48])=[CH:46][CH:45]=[CH:44][C:41]=1C=O>>[CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:14][CH2:15][O:16][C:17]1[CH:22]=[CH:21][C:20]([CH2:23][C@H:24]([NH:30][CH2:31][C:46]2[CH:45]=[CH:44][CH:41]=[C:40]([F:39])[C:47]=2[F:48])[C:25]([O:27][CH3:28])=[O:26])=[CH:19][CH:18]=1
Reactant: O=Cc1cccc(F)c1F
Reactant: CCOC(=O)[C@H](Cc1ccc(OCCc2nc(-c3ccc(C)cc3)oc2C)cc1)NCc1ccc(F)cc1
Product: COC(=O)[C@H](Cc1ccc(OCCc2nc(-c3ccccc3)oc2C)cc1)NCc1cccc(F)c1F

Procedure:
In the same manner as in Example 7, 253.2 mg of the title compound was obtained as colorless oil from 510.0 mg of Referential Compound 3 and 191 μL of 2,3-difluorobenzaldehyde.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:16]=[C:15]([CH:17]([O:23][CH2:24][CH2:25][C:26]3[N:30]([CH3:31])[CH:29]=[N:28][CH:27]=3)[C:18]3[S:19][CH:20]=[CH:21][N:22]=3)[CH:14]=[CH:13][C:9]=2[C:10]([OH:12])=O)=[CH:4][CH:3]=1.Cl.[C:33]([O:37][C:38](=[O:45])[C@H:39]([CH2:41][CH2:42][S:43][CH3:44])[NH2:40])([CH3:36])([CH3:35])[CH3:34].C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.Cl>CN(C1C=CN=CC=1)C.CN(C=O)C.C(OCC)(=O)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:16]=[C:15]([CH:17]([O:23][CH2:24][CH2:25][C:26]3[N:30]([CH3:31])[CH:29]=[N:28][CH:27]=3)[C:18]3[S:19][CH:20]=[CH:21][N:22]=3)[CH:14]=[CH:13][C:9]=2[C:10]([NH:40][C@@H:39]([CH2:41][CH2:42][S:43][CH3:44])[C:38]([O:37][C:33]([CH3:34])([CH3:35])[CH3:36])=[O:45])=[O:12])=[CH:6][CH:7]=1
Reactant: Cn1cncc1CCOC(c1ccc(C(=O)O)c(-c2ccc(F)cc2)c1)c1nccs1
Reactant: CSCC[C@H](N)C(=O)OC(C)(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCOC(C)=O
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: CSCC[C@H](NC(=O)c1ccc(C(OCCc2cncn2C)c2nccs2)cc1-c1ccc(F)cc1)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A mixture of 2-(4-fluorophenyl)-4-[1-(thiazol-2-yl)-2-(1-methylimidazol-5-yl)ethoxymethyl]benzoic acid (0.44 g, 1.07 mmol) (from Example 65), DMAP (0.62 g, 5.03 mmol), L-methionine tert-butyl ester HCl (0.62 g, 5.03 mmol), EDC (0.39 g, 2.01 mmol) and HOBT (0.138 g, 1.01 mmol) in DMF (25 ml) was stirred at ambient temperature under a nitrogen atmosphere for 16 hours. The reaction was evaporated to dryness, the residue treated with aqueous citric acid (1M, 10 ml) and then extracted with dichloromethane (20 ml). The extracts were washed with saturated brine, dried and applied directly to a silica flash column eluting with dichloromethane/methanol (95:5, 9:1 and 85:15) to give a gum. This was dissolved in ethyl acetate and treated with ethereal 1M HCl (10 ml). The resulting solid was isolated by centrifuging, further washing with diethyl ether and drying under high vacuum to give tert-butyl (2S)-2-{2-(4-fluorophenyl)-4-[1-(thiazol-2-yl)-2-(1-methylimidazol-5-yl)ethoxymethyl]benzoylamino}-4-methylsulfanylbutyrate as a white solid, (0.373 g, 59%).
Reaction SMILES: [CH2:1]([N:5]1[C:13]2[C:12](=[O:14])[NH:11][C:10](=[O:15])[N:9]([CH3:16])[C:8]=2[N:7]=[CH:6]1)[C:2]#[C:3][CH3:4].[Cl:17]N1C(=O)CCC1=O>CN(C)C=O.C(OCC)(=O)C>[CH2:1]([N:5]1[C:13]2[C:12](=[O:14])[NH:11][C:10](=[O:15])[N:9]([CH3:16])[C:8]=2[N:7]=[C:6]1[Cl:17])[C:2]#[C:3][CH3:4]
Reactant: CC#CCn1cnc2c1c(=O)[nH]c(=O)n2C
Reactant: O=C1CCC(=O)N1Cl
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC#CCn1c(Cl)nc2c1c(=O)[nH]c(=O)n2C
Temperature: 25 °C
Reaction time: 3 h
Yield: 73.1 %

Procedure:
3-Methylxanthine (1.1 g) was dissolved in N,N-dimethylformamide (15 ml), and potassium carbonate (1.0 g) and 1-bromo-2-butyne (0.64 ml) were added thereto. After stirring at room temperature overnight, the reaction mixture was diluted with ethyl acetate, and washed with water. Insoluble white solid was collected by filtration, and washed with ethyl acetate to give 1.3 g of 7-(2-butynyl)-3-methyl-3,7-dihydropurine-2,6-dione. Then, the resulting 7-(2-butynyl)-3-methyl-3,7-dihydropurine-2,6-dione (1.3 g) was dissolved in N,N-dimethylformamide (15 ml), and N-chlorosuccinimide (0.89 g) was added while cooling on ice. After stirring at room temperature for 3 hours, the reaction mixture was diluted with ethyl acetate, and washed with water. Insoluble white solid was collected by filtration, and washed with ethyl acetate to give 1.1 g of 7-(2-butynyl)-8-chloro-3-methyl-3,7-dihydropurine-2,6-dione. The resulting 7-(2-butynyl)-8-chloro-3-methyl-3,7-dihydropurine-2,6-dione (1.4 g) and 1-piperazine carboxylic acid tert-butyl ester (2.8 g) were stirred at 150° C. for 1 hour. After cooling to room temperature, the reaction mixture was extracted with ethyl acetate, then the organic layer was washed with water and saturate brine, and was dried over anhydrous magnesium sulfate. The solvent was removed by distillation at reduced pressure. The residue was purified by silica gel column chromatography to obtain 1.1 g of the title compound from a fraction eluted with hexane-ethyl acetate (1:4).
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:6]=[C:7]([CH:11]=[C:12]([O:14][CH2:15][CH2:16][C:17]2[CH:21]=[CH:20][S:19][CH:18]=2)[CH:13]=1)[C:8]([OH:10])=O)([CH3:3])[CH3:2].[CH2:22]([N:29]1[CH:33]=[CH:32][C:31]([NH2:34])=[N:30]1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>S(Cl)(Cl)=O>[CH2:22]([N:29]1[CH:33]=[CH:32][C:31]([NH:34][C:8](=[O:10])[C:7]2[CH:11]=[C:12]([O:14][CH2:15][CH2:16][C:17]3[CH:21]=[CH:20][S:19][CH:18]=3)[CH:13]=[C:5]([O:4][CH:1]([CH3:2])[CH3:3])[CH:6]=2)=[N:30]1)[C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1
Reactant: Nc1ccn(Cc2ccccc2)n1
Reactant: CC(C)Oc1cc(OCCc2ccsc2)cc(C(=O)O)c1
Solvent: O=S(Cl)Cl
Product: CC(C)Oc1cc(OCCc2ccsc2)cc(C(=O)Nc2ccn(Cc3ccccc3)n2)c1
Temperature: 70 °C
Reaction time: 21 h
Yield: 45 %

Procedure:
3-Isopropoxy-5-(2-thiophen-3-yl-ethoxy)-benzoic acid (0.672 mmol) is dissolved in thionylchloride (1.2 ml) and heated to 70° C. for 1 hour. After cooling to room temperature, the solvent is removed in vacuo. The residue is dissolved in dichloromethane (1.2 ml) and ethyldiisopropyl-amine (167 μl) is added and 1-benzyl-1H-pyrazol-3-ylamine (1.2 eq) is added. The solution is stirred 21 hours at room temperature. The reaction solution is extracted with water. The organic layer is washed with brine and dried over MgSO4 and the solvent is removed in vacuo. N-(1-Benzyl-1H-pyrazol-3-yl)-3-isopropoxy-5-(2-thiophen-3-yl-ethoxy)-benzamide is isolated after column chromatography (heptan /ethylacetate) as yellow oil in a yield of 45%; HPLC (method B): 3.63 min; LC-MS (method B): 2.74 min, 462.2 (MH+); 1H-NMR (DMSO-d5, 500 MHz): δ [ppm] 10.78 (s, 1), 7.79 (d, 1H, J=2.2 Hz), 7.468 (dd, 1H, J=3 Hz, J=4.9 Hz), 7.359-7.269 (m, 4H), 7.245-7228 (m, 2H), 7.174-7.139 (m, 2H), 7.11 (dd, 1H, J=1.1 Hz, J=4.9 Hz), 6.648 (d, 1H, J=2.2 Hz), 5.256 (s, 2H), 4.678 (sep, 1H, J=6 Hz), 4.223 (t, 2H, J=6.9 Hz), 3.049 (t, 2H, J=6.9 Hz), 1.262 (d, 6H, J=6 Hz).
Reaction SMILES: Cl.[Cl:2][CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][O:8][CH2:7][CH2:6]1.C(=O)([O-])[O-].[K+].[K+].[F:17][C:18]1[CH:57]=[CH:56][C:21]([CH2:22][N:23]2[C:32](=[O:33])[C:31]3[C:26](=[CH:27][CH:28]=[C:29]([C:34]([C:36]4[N:40]5[CH:41]=[CH:42][CH:43]=[CH:44][C:39]5=[C:38]([C:45]5[CH:46]=[C:47]([CH:51]=[CH:52][CH:53]=5)[C:48]([OH:50])=[O:49])[N:37]=4)=[O:35])[CH:30]=3)[N:25]([CH3:54])[C:24]2=[O:55])=[CH:20][CH:19]=1.O>CN(C=O)C.CCOCC>[ClH:2].[F:17][C:18]1[CH:57]=[CH:56][C:21]([CH2:22][N:23]2[C:32](=[O:33])[C:31]3[C:26](=[CH:27][CH:28]=[C:29]([C:34]([C:36]4[N:40]5[CH:41]=[CH:42][CH:43]=[CH:44][C:39]5=[C:38]([C:45]5[CH:46]=[C:47]([CH:51]=[CH:52][CH:53]=5)[C:48]([O:50][CH2:3][CH2:4][N:5]5[CH2:10][CH2:9][O:8][CH2:7][CH2:6]5)=[O:49])[N:37]=4)=[O:35])[CH:30]=3)[N:25]([CH3:54])[C:24]2=[O:55])=[CH:20][CH:19]=1
Reactant: ClCCN1CCOCC1
Reactant: Cn1c(=O)n(Cc2ccc(F)cc2)c(=O)c2cc(C(=O)c3nc(-c4cccc(C(=O)O)c4)c4ccccn34)ccc21
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOCC
Solvent: CN(C)C=O
Solvent: O
Product: Cn1c(=O)n(Cc2ccc(F)cc2)c(=O)c2cc(C(=O)c3nc(-c4cccc(C(=O)OCCN5CCOCC5)c4)c4ccccn34)ccc21
Temperature: 25 °C
Reaction time: 18 h
Yield: 77.6 %

Procedure:
0.022 g (0.61 mmol) of 4-(2-chloroethyl)morpholine hydrochloride and 0.189 g (1.37 mmol) of potassium carbonate are added, under an inert atmosphere, to 0.3 g (0.55 mmol) of 3-(3-{[3-(4-fluorobenzyl)-1-methyl-2,4-dioxo-1,2,3,4-tetrahydroquinazolin-6-yl]carbonyl}imidazo[1,5-a]pyridin-1-yl)benzoic acid in 8 ml of DMF. After stirring for 18 h at ambient temperature and then for 8 hours at 50° C., the reaction medium is hydrolysed with water, and extracted with ethyl acetate. The organic phase is washed with water, dried over sodium sulphate, filtered, and then concentrated under reduced pressure. The yellow solid obtained is purified by silica gel column chromatography, elution being carried out with a dichloromethane/methanol (95/5) mixture. 0.61 ml of a 1N aqueous solution of hydrochloric acid is added to 0.334 g of the yellow solid obtained, in 5 ml of methanol. The reaction medium is stirred for 1 hour at ambient temperature. Dyethyl ether is added and then the reaction medium is filtered. The precipitate obtained is rinsed with dyethyl ether and then dried under reduced pressure at 50° C. overnight. 0.298 g of a yellow solid is obtained.
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:7]([F:10])=[CH:6][C:3]=1[CH:4]=[O:5].[BH4-].[Na+]>CO>[Br:1][C:2]1[CH:9]=[CH:8][C:7]([F:10])=[CH:6][C:3]=1[CH2:4][OH:5]
Reactant: O=Cc1cc(F)ccc1Br
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: OCc1cc(F)ccc1Br
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 2-bromo-5-fluoro-benzaldehyde (21.34 g, 105 mmole) in methanol (170 mL) was added at 0-5° C. portionwise NaBH4 (3.99 g, 105 mmole). At the end of the addition, the cooling bath was removed and the reaction mixture was stirred at room temperature for 2 h. On concentration, the solution generated a white solid that was added with water, filtered and dried under vacuum to yield compound PRE7 (19.23 g; white powder) (Yield=91 Rt: 10.64 min.
Reaction SMILES: [N:1]1([C:7]2[CH:12]=[CH:11][C:10]([C:13]3[N:22]=[C:21]([NH:23][CH2:24][C@@H:25]4[O:30][CH2:29][CH2:28][N:27]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH2:26]4)[C:20]4[C:15](=[N:16][CH:17]=[CH:18][N:19]=4)[CH:14]=3)=[CH:9][CH:8]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[CH:38]1([S:41](Cl)(=[O:43])=[O:42])[CH2:40][CH2:39]1.CCN(CC)CC>C(Cl)Cl>[CH:38]1([S:41]([N:4]2[CH2:5][CH2:6][N:1]([C:7]3[CH:8]=[CH:9][C:10]([C:13]4[N:22]=[C:21]([NH:23][CH2:24][C@@H:25]5[O:30][CH2:29][CH2:28][N:27]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH2:26]5)[C:20]5[C:15](=[N:16][CH:17]=[CH:18][N:19]=5)[CH:14]=4)=[CH:11][CH:12]=3)[CH2:2][CH2:3]2)(=[O:43])=[O:42])[CH2:40][CH2:39]1
Reactant: CC(C)(C)OC(=O)N1CCO[C@@H](CNc2nc(-c3ccc(N4CCNCC4)cc3)cc3nccnc23)C1
Reactant: O=S(=O)(Cl)C1CC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCO[C@@H](CNc2nc(-c3ccc(N4CCN(S(=O)(=O)C5CC5)CC4)cc3)cc3nccnc23)C1
Yield: 42.6 %

Procedure:
A solution of (S)-tert-butyl 2-((7-(4-(piperazin-1-yl)phenyl)pyrido[4,3-b]pyrazin-5-ylamino)methyl)morpholine-4-carboxylate (100 mg, 0.20 mmol), cyclopropanesulfonyl chloride (33 mg, 0.24 mmol) and Et3N (41 mg, 0.40 mmol) in 5 mL of DCM at 0° C. was stirred at room temperature for 1 hour. The volatiles were removed in vacuo, and the residues was purified by chromatography with PE/EA (1:2˜1:10) to give 52 mg of title compound.
Reaction SMILES: [CH:1]([C:3]1[C:12](OS(C(F)(F)F)(=O)=O)=[CH:11][C:10]([O:21][CH3:22])=[CH:9][C:4]=1[C:5]([O:7]C)=[O:6])=[O:2].[C:23]1(B(O)O)[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.C(=O)([O-])[O-].[Na+].[Na+].O>C1(C)C=CC=CC=1.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.[Pd]>[CH:1]([C:3]1[C:12]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[CH:11][C:10]([O:21][CH3:22])=[CH:9][C:4]=1[C:5]([OH:7])=[O:6])=[O:2]
Reactant: OB(O)c1ccccc1
Reactant: COC(=O)c1cc(OC)cc(OS(=O)(=O)C(F)(F)F)c1C=O
Agent: [Pd]
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Solvent: O
Solvent: Cc1ccccc1
Product: COc1cc(C(=O)O)c(C=O)c(-c2ccccc2)c1
Temperature: 110 °C
Reaction time: 6 h

Procedure:
A solution of about 2.3 mmol of methyl 2-formyl-5-methoxy-3-trifluoromethanesulfonyloxybenzoate in 10 mL of toluene is stirred under argon, and 330 mg (2.7 mmol) of phenylboronic acid, 84 mg of tetrakis palladium and 2.5 mL of aqueous 2N sodium carbonate solution are added. The mixture is stirred at 110° C. for 6 hours in a stoppered tube under argon. Water is added to the cooled reaction medium, and the mixture is washed with ethyl acetate and, after acidification (1N HCl), is then extracted with dichloromethane. The organic phase is dried over anhydrous sodium sulfate, filtered and evaporated under reduced pressure. The product, in the form of a brown solid, is used without purification in the following reaction.
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[CH:6][N:5]=[C:4]2[N:14](S(C3C=CC=CC=3)(=O)=O)[CH:15]=[CH:16][C:3]=12.C1COCC1.O.[Li+].[OH-]>C(Cl)Cl>[Cl:1][C:2]1[C:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[CH:6][N:5]=[C:4]2[NH:14][CH:15]=[CH:16][C:3]=12
Reactant: O=S(=O)(c1ccccc1)n1ccc2c(Cl)c(-c3ccccc3)cnc21
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: ClCCl
Solvent: C1CCOC1
Product: Clc1c(-c2ccccc2)cnc2[nH]ccc12
Temperature: 65 °C
Yield: 95.8 %

Procedure:
4-Chloro-5-phenyl-1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridine (1.70 g, 4.61 mmol) was placed in 1:1 THF:water (30 mL). 3M LiOH (aq., 15.4 mL, 46.1 mmol) was then added, and the reaction was heated to 65° C. for 18 hours. The reaction was cooled to room temperature, diluted with DCM (50 mL) and poured into water. The organic fraction was dried, filtered, and concentrated to give the crude product 4-chloro-5-phenyl-1H-pyrrolo[2,3-b]pyridine (1.01 g, 95.8% yield), which was used without further purification.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[NH2:6][C:7]1[CH:12]=[C:11]([Cl:13])[CH:10]=[CH:9][C:8]=1[OH:14].C(N(CC)CC)C>C(Cl)Cl>[CH3:1][S:2]([O:14][C:8]1[CH:9]=[CH:10][C:11]([Cl:13])=[CH:12][C:7]=1[NH2:6])(=[O:4])=[O:3]
Reactant: CS(=O)(=O)Cl
Reactant: Nc1cc(Cl)ccc1O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)Oc1ccc(Cl)cc1N
Temperature: 25 °C
Reaction time: 18 h

Procedure:
174.5 g (1.52 mol) of methanesulfonyl chloride were added dropwise at 10°-15° C. to a solution of 218.7 g (1.52 mol) of 2-amino-4-chlorophenol and 153.8 g (1.52 mol) of triethylamine in 400 ml of methylene chloride. The mixture was stirred for 18 hours at 25° C. and was introduced into ice water, and the organic phase was separated off, washed twice with water and dried over Na2SO4. After the solvent had been distilled off, a gradually crystallizing residue of the product remained, which was sufficiently pure for further reaction (329.5 g, 98% of theory). The product could be recrystallized from methanol/water (mp. 70°-71° C.).
Reaction SMILES: Cl.FC1C=CC2NC3C=CC(C)=CC=3C(N)=NC=2C=1.[F:20][C:21]1[CH:26]=[CH:25][C:24]([NH:27][C:28]2[CH:35]=[CH:34][C:33]([CH:36]([CH3:38])[CH3:37])=[CH:32][C:29]=2[C:30]#[N:31])=[C:23]([N+:39]([O-])=O)[CH:22]=1.[Sn](Cl)[Cl:43]>>[ClH:43].[F:20][C:21]1[CH:26]=[CH:25][C:24]2[NH:27][C:28]3[CH:35]=[CH:34][C:33]([CH:36]([CH3:38])[CH3:37])=[CH:32][C:29]=3[C:30]([NH2:31])=[N:39][C:23]=2[CH:22]=1
Reactant: CC(C)c1ccc(Nc2ccc(F)cc2[N+](=O)[O-])c(C#N)c1
Reactant: Cl[Sn]Cl
Agent: Cc1ccc2c(c1)C(N)=Nc1cc(F)ccc1N2
Agent: Cl
Product: CC(C)c1ccc2c(c1)C(N)=Nc1cc(F)ccc1N2
Yield: 73.8 %

Procedure:
Using a similar procedure as found for 8-fluoro-2-methyl-5H-dibenzo[b,e][1,4]diazepin-11-ylamine hydrochloride, using 2-(4-fluoro-2-nitro-phenylamino)-5-isopropyl-benzonitrile (0.559 g, 1.87 mmol), tin (II) chloride(1.06 g, 5.60 mmol) to obtain the title compound (0.422 g, 1.38 mmol, 74% yield) as a yellow amorphous solid: Mass Spectrum (m/e): 270(M+1).
Reaction SMILES: O.[OH-].[Li+].C[O:5][C:6](=[O:34])[CH2:7][C:8]1[C:17]([CH3:18])=[C:16]([C:19]2[CH:24]=[CH:23][C:22]([S:25](=[O:32])(=[O:31])[N:26]([CH2:29][CH3:30])[CH2:27][CH3:28])=[CH:21][CH:20]=2)[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([Cl:33])[CH:14]=2)[CH:9]=1.C1COCC1.O>CCCCCC>[Cl:33][C:13]1[CH:14]=[C:15]2[C:10](=[CH:11][CH:12]=1)[CH:9]=[C:8]([CH2:7][C:6]([OH:34])=[O:5])[C:17]([CH3:18])=[C:16]2[C:19]1[CH:24]=[CH:23][C:22]([S:25](=[O:31])(=[O:32])[N:26]([CH2:29][CH3:30])[CH2:27][CH3:28])=[CH:21][CH:20]=1
Reactant: CCN(CC)S(=O)(=O)c1ccc(-c2c(C)c(CC(=O)OC)cc3ccc(Cl)cc23)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: CCCCCC
Solvent: O
Solvent: C1CCOC1
Product: CCN(CC)S(=O)(=O)c1ccc(-c2c(C)c(CC(=O)O)cc3ccc(Cl)cc23)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 92.2 %

Procedure:
Lithium hydroxide monohydrate (0.015 g, 0.34 mmol) was added to a stirred solution of [6-chloro-4-(4-diethylsulfamoyl-phenyl)-3-methyl-naphthalen-2-yl]-acetic acid methyl ester (0.040 g, 0.09 mmol) in a 3:1 mixture of THF—H2O mixture (5 mL). The reaction mixture was stirred for 16 hours at room temperature. The reaction mixture was concentrated to remove THF, and the crude material was diluted with water, acidified [pH˜2] with a 6 N aqueous solution of hydrochloric acid. The mixture was extracted twice with ethyl acetate. The collected organic layers were washed with water and brine, dried over anhydrous Na2SO4, and concentrated under reduced pressure to give the crude product. Trituration with hexane gave [6-chloro-4-(4-diethylsulfamoyl-phenyl)-3-methyl-naphthalen-2-yl]-acetic acid (0.037 g, 95%) as a solid. 1H NMR (DMSO-d6) δ: 12.49 (br. s, 1H), 7.98 (d, J=8.3 Hz, 3H), 7.91 (s, 1H), 7.49 (d, J=8.3 Hz, 3H), 7.00 (s, 1H), 3.86 (s, 2H), 3.28 (s, 4H), 2.07 (s, 3H), 1.08 (t, J=7.1 Hz, 6H). MS calcd. for C23H25ClNO4S [(M+H)+] 446, obsd. 446.4.
Reaction SMILES: ClC1C=CC=C(C(OO)=[O:9])C=1.[CH3:12][O:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]2[N:21]=[C:22]([S:33][C:34]3[CH:39]=[CH:38][C:37]([Cl:40])=[C:36]([Cl:41])[CH:35]=3)[NH:23][C:24]=2[C:25]2[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][CH:26]=2)=[CH:16][CH:15]=1>ClCCl>[CH3:12][O:13][C:14]1[CH:15]=[CH:16][C:17]([C:20]2[N:21]=[C:22]([S:33]([C:34]3[CH:39]=[CH:38][C:37]([Cl:40])=[C:36]([Cl:41])[CH:35]=3)=[O:9])[NH:23][C:24]=2[C:25]2[CH:26]=[CH:27][C:28]([O:31][CH3:32])=[CH:29][CH:30]=2)=[CH:18][CH:19]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: COc1ccc(-c2nc(Sc3ccc(Cl)c(Cl)c3)[nH]c2-c2ccc(OC)cc2)cc1
Solvent: ClCCl
Product: COc1ccc(-c2nc(S(=O)c3ccc(Cl)c(Cl)c3)[nH]c2-c2ccc(OC)cc2)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 88.6 %

Procedure:
A solution of 2.164 g of 3-chloroperbenzoic acid (80%) in 150 ml of dichloromethane is added dropwise to a solution of 4.57 g of 4,5-bis(4-methoxyphenyl)-2-(3,4-dichlorophenylthio)imidazole in 100 ml of dichloromethane. The solution is stirred for 3 hours at room temperature, washed with sodium bicarbonate solution, dried over sodium sulfate, and concentrated to dryness under vacuum. The residue is chromatographed on 150 g of silica gel with acetone/hexane 2:3, thus obtaining 4.19 g of 4,5-bis(4-methoxyphenyl)-2-(3,4-dichlorophenylsulfinyl)imidazole as an amorphous foam.
Reaction SMILES: I[C:2]1[C:10]2[C:5](=[CH:6][C:7]([CH:11]=[O:12])=[CH:8][CH:9]=2)[N:4]([CH2:13][O:14][CH2:15][CH2:16][Si:17]([CH3:20])([CH3:19])[CH3:18])[N:3]=1.[CH2:21]=[CH:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.C(N(C(C)C)CC)(C)C.CC1C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C>CC([O-])=O.CC([O-])=O.[Pd+2].CN(C=O)C>[CH:21](/[C:2]1[C:10]2[C:5](=[CH:6][C:7]([CH:11]=[O:12])=[CH:8][CH:9]=2)[N:4]([CH2:13][O:14][CH2:15][CH2:16][Si:17]([CH3:20])([CH3:19])[CH3:18])[N:3]=1)=[CH:22]\[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: C=Cc1ccccc1
Reactant: C[Si](C)(C)CCOCn1nc(I)c2ccc(C=O)cc21
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: C[Si](C)(C)CCOCn1nc(/C=C/c2ccccc2)c2ccc(C=O)cc21
Temperature: 100 °C
Yield: 66.8 %

Procedure:
A solution of 3-iodo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazole-6-carbaldehyde (100 mg, 0.249 mmol), styrene (37 uL, 0.324 mmol), diisopropylethylamine (87 uL, 0.324 mmol) and DMF (2.5 mL) was purged with Ar gas for 20 min at which time Pd(OAc)2 (2.8 mg, 0.0125 mmol) and P(o-tol)3 (11 mg, 0.0374 mmol) were added and the reaction heated to 100° C. for 20 hours. The reaction was cooled to room temperature and partitioned between EtOAc and NH4Cl. The aqueous layer was extracted 3× with EtOAc and the combined organics washed with water (2×) and brine (2×). The organic layer was dried over MgSO4 and the EtOAc removed in vacuo. The residue was purified by column chromatography (silica gel, 5:1 hexanes/EtOAc) to give the title compound (63 mg, 67%) which was used without further purification. MS ESI 379.2 [M+H]+, calcd for [C22H26N2O2Si+H]+ 379.18.