Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:9]1[CH:10]=[N:11][N:12]2[C:17]([C:18]3[CH:19]=[C:20]([N:24]([CH3:29])[C:25](=[O:28])[CH2:26]Br)[CH:21]=[CH:22][CH:23]=3)=[CH:16][CH:15]=[N:14][C:13]=12)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:30][NH:31][CH3:32].C.CCCCCC>C(O)C>[C:1]([C:9]1[CH:10]=[N:11][N:12]2[C:17]([C:18]3[CH:19]=[C:20]([N:24]([CH3:29])[C:25](=[O:28])[CH2:26][N:31]([CH3:32])[CH3:30])[CH:21]=[CH:22][CH:23]=3)=[CH:16][CH:15]=[N:14][C:13]=12)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CN(C(=O)CBr)c1cccc(-c2ccnc3c(C(=O)c4ccccc4)cnn23)c1
Reactant: CNC
Solvent: CCCCCC
Solvent: CCO
Product: CN(C)CC(=O)N(C)c1cccc(-c2ccnc3c(C(=O)c4ccccc4)cnn23)c1
Temperature: -10 °C
Reaction time: 16 h

Procedure:
A suspension of 1.7 g of N-[3-(3-benzoylpyrazolo[1,5-a]pyrimidin-7-yl)phenyl]-2-bromo-N-methylacetamide in 100 ml of ethanol was treated with gaseous dimethylamine until a solution resulted. This was then placed in a pressure bottle and kept at room temperature for 16 hours. The ethanol was removed in vacuo and the residue partitioned between 50 ml of saturated aqueous sodium bicarbonate solution and 100 ml of methylene chloride. The methylene chloride layer was separated, dried over magnesium sulfate, and the methylene chloride removed in vacuo. The residue was dissolved in 50 ml of methylene chloride, the solution then treated with hexane at the boiling point until turbidity was present. Cooling at -10° C. gave a low yield of tacky solid. The cold mixture was treated with activated charcoal, clarified and the filtrate again treated at the boiling point with hexane until turbidity occurred. Cooling at -10° C. gave 0.3 g of the desired compound as a bright yellow solid, mp 166°-168° C.
Reaction SMILES: [N:1]1([CH2:6][CH2:7][CH2:8][NH2:9])[CH:5]=[CH:4][N:3]=[CH:2]1.O1CCCC1.[Cl:15][C:16]1[CH:21]=[CH:20][C:19]([N:22]=[C:23]=[O:24])=[CH:18][CH:17]=1>C1(C)C=CC=CC=1>[Cl:15][C:16]1[CH:21]=[CH:20][C:19]([NH:22][C:23]([NH:9][CH2:8][CH2:7][CH2:6][N:1]2[CH:5]=[CH:4][N:3]=[CH:2]2)=[O:24])=[CH:18][CH:17]=1
Reactant: O=C=Nc1ccc(Cl)cc1
Reactant: NCCCn1ccnc1
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: O=C(NCCCn1ccnc1)Nc1ccc(Cl)cc1
Reaction time: 8 h

Procedure:
A 2.5 g. portion of 1H-imidazole-1-propanamine was added to 20 ml. of toluene and then 7 ml. of tetrahydrofuran was added to produce solution. A solution of 3.1 g. of distilled p-chlorophenyl isocyanate in 20 ml. of toluene was added, the mixture was stirred overnight and then evaporated to a waxy solid. This solid was triturated with ether and the resulting crystals recrystallized from chilled acetone, giving 2.3 g. of the desired product as colorless crystals, mp. 123°-125° C.
Reaction SMILES: [C:1]([OH:5])(=O)[CH2:2][CH3:3].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CN1CCOCC1.[Cl:37][C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][C:39]=1[C:44]1[O:48][C:47]([C:49]2[CH:54]=[CH:53][N:52]=[C:51]([NH2:55])[CH:50]=2)=[N:46][C:45]=1[C:56]1[N:60](COCC[Si](C)(C)C)[CH:59]=[N:58][N:57]=1>C(Cl)Cl.CN(C1C=CN=CC=1)C>[Cl:37][C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][C:39]=1[C:44]1[O:48][C:47]([C:49]2[CH:54]=[CH:53][N:52]=[C:51]([NH:55][C:1](=[O:5])[CH2:2][CH3:3])[CH:50]=2)=[N:46][C:45]=1[C:56]1[NH:60][CH:59]=[N:58][N:57]=1
Reactant: C[Si](C)(C)CCOCn1cnnc1-c1nc(-c2ccnc(N)c2)oc1-c1ccccc1Cl
Reactant: CCC(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: CN(C)c1ccncc1
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: CCC(=O)Nc1cc(-c2nc(-c3nnc[nH]3)c(-c3ccccc3Cl)o2)ccn1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 20.6 %

Procedure:
A mixture of propanoic acid (0.0095 mL, 0.13 mmol), HATU (0.019 g, 0.051 mmol) and N-methylmorpholine (0.014 mL, 0.13 mmol) in DCM (1 mL) was allowed to stir at rt for 30 min. Solid 4-[5-(2-chlorophenyl)-4-(4-{[2-(trimethylsilyl)ethoxy]methyl}-4H-1,2,4-triazol-3-yl)-1,3-oxazol-2-yl]pyridine-2-amine (0.020 g, 0.043 mmol) and DMAP (0.016 g, 0.13 mmol) were then added and the reaction mixture was allowed to stir at 80° C. overnight. The reaction mixture was allowed to cool to rt and was diluted with DCM (3 mL) and washed with saturated aqueous NaHCO3 (2 mL). The organic solution was separated and the aqueous solution was extracted with DCM. The organic solutions were combined and concentrated. The residue was redissolved in DCM (0.5 mL) and to this solution was added TFA (0.5 mL). The reaction mixture was allowed to stir at rt for 12 h and then concentrated to dryness. The residue was purified by column chromatography to give N-{4-[5-(2-chlorophenyl)-4-(4H-1,2,4-triazol-3-yl)-1,3-oxazol-2-yl]pyridine-2-yl}propanamide (Compound I-75) (3.5 mg, 21%). LCMS (FA): m/z=395 (M+H). 1H NMR (400 MHz, DMSO) δ 10.72 (s, 1H), 8.79 (s, 1H), 8.51 (d, J=5.2 Hz, 1H), 7.79 (d, J=7.6 Hz, 1H), 7.67 (dd, J=5.2, 1.5 Hz, 1H), 7.64 (dd, J=8.1, 1.2 Hz, 1H), 7.58 (td, J=7.7, 1.7 Hz, 1H), 7.50 (td, J=7.5, 1.3 Hz, 1H), 2.44 (q, J=7.5 Hz, 3H), 1.08 (t, J=7.5 Hz, 3H).
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].C(OC(=O)[NH:14][CH:15]([CH2:34][C:35]1[CH:40]=[CH:39][C:38]([O:41][CH3:42])=[CH:37][C:36]=1[OH:43])[C:16]([N:18]1[CH2:21][C:20]([O:29][CH2:30][CH2:31][CH2:32][CH3:33])([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2[CH3:28])[CH2:19]1)=[O:17])(C)(C)C>ClCCl>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[NH2:14][CH:15]([CH2:34][C:35]1[CH:40]=[CH:39][C:38]([O:41][CH3:42])=[CH:37][C:36]=1[OH:43])[C:16]([N:18]1[CH2:21][C:20]([O:29][CH2:30][CH2:31][CH2:32][CH3:33])([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2[CH3:28])[CH2:19]1)=[O:17]
Reactant: CCCCOC1(c2ccccc2C)CN(C(=O)C(Cc2ccc(OC)cc2O)NC(=O)OC(C)(C)C)C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCCCOC1(c2ccccc2C)CN(C(=O)C(N)Cc2ccc(OC)cc2O)C1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
1 ml of trifluoroacetic acid is added to 220 mg (0.4 mmol) of tert-butyl[2-(3-butoxy-3-o-tolyl-azetidin-1-yl)-1-(2-hydroxy-4-methoxybenzyl)-2-oxo-ethyl]carbamate in 2 ml of dichloromethane. After stirring for 1 hour at ambient temperature, the reaction medium is concentrated under vacuum. 250 mg of 2-amino-1-(3-butoxy-3-o-tolylazetidin-1-yl)-3-(2-hydroxy-4-methoxyphenyl)propan-1-one trifluoroacetate are obtained in the form of a yellow oil with a quantitative yield.
Reaction SMILES: [CH2:1]([N:8]1[C:12]2[CH:13]=[C:14]([O:17][S:18]([C:21]3[CH:26]=[CH:25][C:24](F)=[CH:23][CH:22]=3)(=[O:20])=[O:19])[CH:15]=[CH:16][C:11]=2[N:10]=[C:9]1[NH:28][C:29]1[CH:34]=[CH:33][C:32]([O:35][CH3:36])=[C:31]([O:37][CH3:38])[CH:30]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:39]1([NH2:44])[CH2:43][CH2:42][CH2:41][CH2:40]1.O>CN1CCCC1=O>[CH2:1]([N:8]1[C:12]2[CH:13]=[C:14]([O:17][S:18]([C:21]3[CH:26]=[CH:25][C:24]([NH:44][CH:39]4[CH2:43][CH2:42][CH2:41][CH2:40]4)=[CH:23][CH:22]=3)(=[O:20])=[O:19])[CH:15]=[CH:16][C:11]=2[N:10]=[C:9]1[NH:28][C:29]1[CH:34]=[CH:33][C:32]([O:35][CH3:36])=[C:31]([O:37][CH3:38])[CH:30]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NC1CCCC1
Reactant: COc1ccc(Nc2nc3ccc(OS(=O)(=O)c4ccc(F)cc4)cc3n2Cc2ccccc2)cc1OC
Solvent: O
Solvent: CN1CCCC1=O
Product: COc1ccc(Nc2nc3ccc(OS(=O)(=O)c4ccc(NC5CCCC5)cc4)cc3n2Cc2ccccc2)cc1OC

Procedure:
A solution of 4-fluoro-benzenesulfonic acid 3-benzyl-2-(3,4-dimethoxy-phenylamino)-3H-benzoimidazol-5-yl ester (151 mg) and cyclopentylamine (118 μl) in N-methylpyrrolidinone (1.5 ml) was heated at 110° C. in a sealed tube for 3 hours. The reaction mixture was allowed to cool then poured into water (30 ml) and extracted three times with ethyl acetate. The combined extracts were dried over magnesium sulfate then evaporated. The residue was subjected to flash chromatography on silica eluting with a mixture of ethyl acetate and heptane (1:1, v/v) to give 4-cyclopentylamino-benzenesulfonic acid 3-benzyl-2-(3,4-dimethoxy-phenylamino)-3H-benzoimidazol-5-yl ester (122 mg) as a brown solid. Mass spectrum: 599 [M+H]+, retention time=4.0 minutes.
Reaction SMILES: [NH:1]([C:8]1[C:13](I)=[CH:12][N:11]=[C:10]([Cl:15])[N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:16]1([CH2:22][CH2:23][C:24]#[CH:25])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C(N(CC)CC)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>[NH:1]([C:8]1[C:13]([C:25]#[C:24][CH2:23][CH2:22][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[CH:12][N:11]=[C:10]([Cl:15])[N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C#CCCc1ccccc1
Reactant: Clc1ncc(I)c(Nc2ccccc2)n1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: Clc1ncc(C#CCCc2ccccc2)c(Nc2ccccc2)n1
Reaction time: 20 h
Yield: 74.9 %

Procedure:
A solution of 4-anilino-2-chloro-5-iodopyrimidine (Method 59; 662 mg, 2.0 mmol), 4-phenyl-1-butyne (260 mg, 2.0 mmol) and triethylamine (0.56 ml, 4.0 mmol) in THF (20 ml) was purged with nitrogen. Tetrakis(triphenylphosphine)palladium(0) (25 mg) and cuprous iodide (12.5 mg) were added and the mixture was stirred for 20 hours. Insoluble material was removed by filtration and washed with diethyl ether (50 ml). The filtrate and washings were combined and concentrated, and the residue was purified by bond elute chromatography, eluting with 25% ethyl acetate in isohexane, to give the product (0.5 g). NMR (CDCl3): 2.85 (m, 2H), 2.95 (m, 2H), 7.05 (m, 2H), 7.1-7.4 (m, 7H), 7.45 (dd, 2H), 8.2 (s, 1H); MS (MH+): 334, 336.
Reaction SMILES: CO[C:3]1[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][N:9]=1.[CH3:10][O:11][C:12]1[CH:20]=[CH:19][C:15]([CH2:16][C:17]#[N:18])=[CH:14][CH:13]=1.N12CCCCC1C=NCCC2>>[C:17]([C:16](=[C:3]1[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][NH:9]1)[C:15]1[CH:19]=[CH:20][C:12]([O:11][CH3:10])=[CH:13][CH:14]=1)#[N:18]
Reactant: COC1=NCCCCC1
Reactant: COc1ccc(CC#N)cc1
Agent: C1=NCCCN2CCCCC12
Product: COc1ccc(C(C#N)=C2CCCCCN2)cc1

Procedure:
Stir 6.5 g of caprolactim methyl ether, 5.0 g of 4-methoxybenzyl cyanide and 0.5 g of 1,5-diazabicyclo[5.4.0]-undec-5-ene together under nitrogen for 18 hours at 125°. Then remove volatile components from the resulting reaction mixture under a high vacuum to obtain 2-(α-cyano-4-methoxybenzylidene)perhydroazepine as a viscous dark residue. Boil this residue with 50 ml of concentrated hydrochloric acid under reflux until the evolution of carbon dioxide ceases. Cool the refluxed material to ambient temperature, and then alkalize it (while cooling), extract the produced base with diethyl ether, dry the ether extract over sodium sulfate and concentrate the dried extract to obtain 2-(4-methoxybenzyl)-4,5,6,7-tetrahydro-3H-azepine. Hydrogenate this intermediate with platinum/active carbon/hydrogen in ethyl alcohol, filter off the catalyst, concentrate and then distil the filtrate to obtain the title compound with a BP of 100° to 106° at 0.01 mm of Hg.
Reaction SMILES: [CH2:1]([N:8]1[C:12](=[O:13])[C:11](=[C:14]2[N:18]([CH3:19])[C:17]3[CH:20]=[CH:21][C:22]([NH:24][C:25]([NH:34]C(OC(C)(C)C)=O)=[N:26]C(OC(C)(C)C)=O)=[CH:23][C:16]=3[S:15]2)[S:10][C:9]1=[N:42][C:43]1[CH:48]=[C:47]([C:49]#[N:50])[CH:46]=[CH:45][C:44]=1[NH:51][CH2:52][CH3:53])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH2:1]([N:8]1[C:12](=[O:13])[C:11](=[C:14]2[N:18]([CH3:19])[C:17]3[CH:20]=[CH:21][C:22]([NH:24][C:25]([NH2:34])=[NH:26])=[CH:23][C:16]=3[S:15]2)[S:10][C:9]1=[N:42][C:43]1[CH:48]=[C:47]([C:49]#[N:50])[CH:46]=[CH:45][C:44]=1[NH:51][CH2:52][CH3:53])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCNc1ccc(C#N)cc1N=C1SC(=C2Sc3cc(NC(=NC(=O)OC(C)(C)C)NC(=O)OC(C)(C)C)ccc3N2C)C(=O)N1Cc1ccccc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCNc1ccc(C#N)cc1N=C1SC(=C2Sc3cc(NC(=N)N)ccc3N2C)C(=O)N1Cc1ccccc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 30 %

Procedure:
To a stirred solution of the product of Example 273 (116 mg, 0.15 mmol) in anhydrous DCM (6 mL) was added TFA (3 mL) at 0° C. The reaction mixture was stirred at 0° C. for 30 min, then at ambient temperature for 14 h. The solvent was removed in vacuo, and the residue was purified by reverse-phase HPLC (C18 column), eluting with 0.05% TFA in MeCN—H2O (1:9 to 9:1) to afford the title compound (25 mg, 30%) as a yellow solid. 1H-NMR (DMSO-d6): δ 9.65 (1H, s), 7.72 (1H, d), 7.48 (1H, d), 7.41-7.25 (8H, m), 7.15 (1H, d), 6.65 (1H, d), 5.14 (2H, s), 3.84 (3H, s), 3.07 (2H, m), 1.01 (3H, t); MS(ESI): 555 (MH+).
Reaction SMILES: [O:1]=[S:2]1(=[O:18])[CH2:7][CH2:6][N:5]([C:8]2[CH:9]=[C:10]([CH:15]=[CH:16][CH:17]=2)[C:11](OC)=[O:12])[CH2:4][CH2:3]1.[NH2:19][NH2:20]>CO>[O:1]=[S:2]1(=[O:18])[CH2:7][CH2:6][N:5]([C:8]2[CH:9]=[C:10]([CH:15]=[CH:16][CH:17]=2)[C:11]([NH:19][NH2:20])=[O:12])[CH2:4][CH2:3]1
Reactant: COC(=O)c1cccc(N2CCS(=O)(=O)CC2)c1
Reactant: NN
Solvent: CO
Product: NNC(=O)c1cccc(N2CCS(=O)(=O)CC2)c1
Temperature: 65 °C
Yield: 30.9 %

Procedure:
Methyl 3-(1,1-dioxidothiomorpholino)benzoate (95 mg, 0.353 mmol) was added to the hydrazine (22.61 mg, 0.705 mmol) in methanol and refluxed for 12 h at 65° C. Following cooling, Reaction was monitored by TLC. After completion of the reaction, the solvent was removed by vacuum and then compound was purified by column chromatography (2% CH3OH/CH2Cl2) afforded the title compound 3-(1,1-dioxidothiomorpholino)benzohydrazide (32 mg, 0.109 mmol, 31.0% yield) as a solid. 1H NMR (CDCl3, 400 MHz): δ 7.34 (m, 1H), 7.29 (t, 1H, J=8.4 Hz), 7.18 (d, 1H, J=7.6 Hz), 6.70 (dd, 1H, J=4.8 & 8.0 Hz), 3.85 (m, 4H), 3.05 (m, 4H). Mass [M+H]+: 270.1
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([OH:10])[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].Br[CH2:12][CH2:13][CH2:14][N:15]1[C:19](=[O:20])[C:18]2=[CH:21][CH:22]=[CH:23][CH:24]=[C:17]2[C:16]1=[O:25].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.O>[N+:1]([C:4]1[CH:5]=[C:6]([CH:7]=[CH:8][CH:9]=1)[O:10][CH2:12][CH2:13][CH2:14][N:15]1[C:19](=[O:20])[C:18]2=[CH:21][CH:22]=[CH:23][CH:24]=[C:17]2[C:16]1=[O:25])([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1cccc(O)c1
Reactant: O=C1c2ccccc2C(=O)N1CCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: O=C1c2ccccc2C(=O)N1CCCOc1cccc([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 70 h
Yield: 75.8 %

Procedure:
A partial suspension of m-nitrophenol (6.0 g; 43.0 mmoles), N-(3-bromopropyl)phthalimide (10.0 g; 37.0 mmoles) and potassium carbonate (8.0 g; 58.0 mmoles) in 50 ml of DMF was stirred at ambient temperature for 70 hours. The reaction mixture was diluted with 80 ml of water and filtered to give product. Recrystallization from 2-methoxyethanol yielded 9.15 g of the title compound, mp 149°-152°.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:8][CH:9]([C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=2)[C:10]([OH:12])=O)[CH:5]=[CH:6][CH:7]=1.O>CCCCCC>[F:1][C:2]1[CH:3]=[C:4]2[C:5](=[CH:6][CH:7]=1)[C:10](=[O:12])[CH:9]([C:13]1[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=1)[CH2:8]2
Reactant: O=C(O)C(Cc1cccc(F)c1)c1ccc(F)cc1
Solvent: O
Solvent: CCCCCC
Product: O=C1c2ccc(F)cc2CC1c1ccc(F)cc1
Temperature: 110 °C

Procedure:
A solution of 500 g of polyphosphoric acid was heated to 60° C. and 43.0 g of the acid from step A was added. The mixture was then heated to 110° C. for 1 hour. After this time, the reaction was cooled to about 60° C. and 400 mL of water was added rapidly with externalcooling. The mixture was then partitioned between toluene and water, washed twice with toluene and the combined toluene extracts were then washed with 5% aqueous NaHCO3. The toluene extracts were then dried over MgSO4, filtered, concentrated and chromatographed on silica gel with 10% ethyl acetate in hexane as the eluent to afford, after trituration with hexane, 26.98 g of a yellow solid; mp 72°-74° C. 1H NMR (CDCl3) δ: 3.22 (dd, 1H), 3.70 (dd, 1H), 3.94 (dd, 1H), 7.0-7.3 (m, 5H), 7.82 (dd, 1H).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:24]=[C:23]([N:25]([CH2:41][C:42]2[CH:47]=[CH:46][C:45](Br)=[CH:44][CH:43]=2)[C:26](=[O:40])[CH2:27][N:28]([CH3:39])[S:29]([C:32]2[CH:37]=[CH:36][C:35]([CH3:38])=[CH:34][CH:33]=2)(=[O:31])=[O:30])[CH:22]=[CH:21][C:10]=1[C:11]([O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:49][O:50][C:51]([C:53]1[CH:58]=[CH:57][C:56](B(O)O)=[CH:55][CH:54]=1)=[O:52]>>[CH2:1]([O:8][C:9]1[CH:24]=[C:23]([N:25]([CH2:41][C:42]2[CH:47]=[CH:46][C:45]([C:56]3[CH:57]=[CH:58][C:53]([C:51]([O:50][CH3:49])=[O:52])=[CH:54][CH:55]=3)=[CH:44][CH:43]=2)[C:26](=[O:40])[CH2:27][N:28]([CH3:39])[S:29]([C:32]2[CH:37]=[CH:36][C:35]([CH3:38])=[CH:34][CH:33]=2)(=[O:31])=[O:30])[CH:22]=[CH:21][C:10]=1[C:11]([O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1ccc(S(=O)(=O)N(C)CC(=O)N(Cc2ccc(Br)cc2)c2ccc(C(=O)OCc3ccccc3)c(OCc3ccccc3)c2)cc1
Reactant: COC(=O)c1ccc(B(O)O)cc1
Product: COC(=O)c1ccc(-c2ccc(CN(C(=O)CN(C)S(=O)(=O)c3ccc(C)cc3)c3ccc(C(=O)OCc4ccccc4)c(OCc4ccccc4)c3)cc2)cc1

Procedure:
Aryl halide 9 was coupled to 4-(methoxycarbonyl)phenylboronic acid to give 31, on a 0.1 mmol scale via General Procedure H (53 mg, 52%): δH (400 MHz, CDCl3) 2.39 (s, 3H, CH3), 2.82 (s, 3H, CH3), 3.68 (s, 2H, CH2), 3.93 (s, 3H, CH3), 4.84 (s, 2H, CH2), 5.03 (s, 2H, CH2), 5.34 (s, 2H, CH2), 6.64 (s, 1H, CH), 6.68 (dd, J=8.4 and 1.2 Hz, 1H, CH), 7.19 (d, J=8.0 Hz, 2H, CH), 7.23-7.34 (m, 8H, CH), 7.37-7.40 (m, 2H, CH), 7.50-7.54 (m, 3H, CH), 7.60 (d, J=8.0 Hz, 2H, CH), 7.22 (d, J=8.4 Hz, 2H, CH), 7.70 (dd, J=5.6 and 3.2 Hz, 1H, CH), 7.83 (d, J=8.0 Hz, 1H, CH) 8.09 (d, 2H, J=8.4 Hz, CH); δC (100 MHz, CDCl3) 21.4, 36.0, 51.4, 52.1, 52.8, 67.0, 70.7, 114.1, 120.0, 120.9, 126.8, 126.9, 127.3, 127.4, 128.0, 128.2, 128.2, 128.5, 128.6, 128.7, 129.0, 129.4, 129.5, 130.1, 132.4, 133.1, 135.3, 135.7, 135.7, 136.5, 139.3, 143.3, 144.8, 144.9, 158.8, 166.8, 167.0, 167.7; LRMS (ES+) calcd for [C46H42N2O8S+H] 783.27 found 783.26.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:9]=[C:8]([Cl:10])[C:7]([Cl:11])=[CH:6][C:5]=1[N:12]1[C:16](=[O:17])[NH:15][N:14]=[N:13]1.I[CH2:19][CH2:20][CH3:21]>CN(C)C=O.O1CCOCCOCCOCCOCCOCC1>[CH2:19]([N:15]1[C:16](=[O:17])[N:12]([C:5]2[CH:6]=[C:7]([Cl:11])[C:8]([Cl:10])=[CH:9][C:4]=2[Cl:3])[N:13]=[N:14]1)[CH2:20][CH3:21]
Reactant: CCCI
Reactant: O=c1[nH]nnn1-c1cc(Cl)c(Cl)cc1Cl
Agent: C1COCCOCCOCCOCCOCCO1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCn1nnn(-c2cc(Cl)c(Cl)cc2Cl)c1=O
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 19.5 %

Procedure:
To a stirred mixture of 0.24 g (0.005 mole) of sodium hydride (60% oil suspension) in 45 mL of N,N-dimethylformamide was added 1.3 g (0.005 mole) of 1,4-dihydro-1-(2,4,5-trichlorophenyl)-5H-tetrazol-5-one. The mixture was stirred at room temperature for 15 minutes, then 0.85 g (0.005 mole) of 1-iodopropane and several drops of 1,4,7,10,13,16-hexaoxacyclooctadecane (18-crown-6) were added. After complete addition, the reaction mixture was stirred at room temperature for 4 days. The reaction mixture was poured into ice water and the resulting mixture extracted with diethyl ether. The ether extract was dried over anhydrous magnesium sulfate, filtered, and the filtrate evaporated under reduced pressure to leave a solid. The solid was purified by column chromatography on silica gel, eluting with methylene chloride. Recrystallization from ethanol gave 0.3 g of 1,4-dihydro-4-propyl-1-(2,4,5-trichlorophenyl)-5H-tetrazol-5-one as a solid, mp 89°-90° C.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([NH:15][C:16](=[O:25])[C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([Cl:23])[C:18]=2[OH:24])[CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH2:7]1)=[O:5])[CH3:2].C([O-])([O-])=O.[Cs+].[Cs+].Br[CH2:33][CH:34]=[CH2:35]>CN(C=O)C>[CH2:1]([O:3][C:4]([C:6]1([NH:15][C:16](=[O:25])[C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([Cl:23])[C:18]=2[O:24][CH:34]([CH3:35])[CH3:33])[CH2:7][C:8]2[C:13](=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH2:14]1)=[O:5])[CH3:2]
Reactant: C=CCBr
Reactant: CCOC(=O)C1(NC(=O)c2cccc(Cl)c2O)Cc2ccccc2C1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CCOC(=O)C1(NC(=O)c2cccc(Cl)c2OC(C)C)Cc2ccccc2C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 81.2 %

Procedure:
To a suspension of 2-(3-chloro-2-hydroxy-benzoylamino)-indan-2-carboxylic acid ethyl ester (14) (150 mg, 0.42 mmol), anhydrous Cs2CO3 (274 mg, 0.84 mmol), and KI (13 mg, 0.08 mmol) in DMF (7 mL) is added 3-bromo-propene (237 μL, 2.52 mmol). The resulting reaction suspension is stirred at RT overnight. After the removal of DMF in vacuo, the residue is dissolved in EtOAc (20 mL) and washed with water (1×5 mL) and brine (2×5 mL). The organic layer is dried over anhydrous Na2SO4 and concentrated in vacuo. The residue is purified by flash column chromatography (80 g silica gel, gradient elution: 10-40% EtOAc in heptane) to give a pure product (15) as white solid (137 mg, 81%).
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.[CH3:9][O:10][C:11]1[C:16]2[N:17]=[C:18]([S:20][CH3:21])[O:19][C:15]=2[CH:14]=[CH:13][CH:12]=1>C(#N)C>[Br:1][C:14]1[C:15]2[O:19][C:18]([S:20][CH3:21])=[N:17][C:16]=2[C:11]([O:10][CH3:9])=[CH:12][CH:13]=1
Reactant: COc1cccc2oc(SC)nc12
Reactant: O=C1CCC(=O)N1Br
Solvent: CC#N
Product: COc1ccc(Br)c2oc(SC)nc12
Reaction time: 18 h
Yield: 33.8 %

Procedure:
N-Bromosuccinimide (2.4 g) was added to a solution of 4-methoxy-2-methylsulfanylbenzooxazole (2.63 g) in acetonitrile (80 ml) and the mixture stirred for 18 hours. It was then partitioned between dichloromethane (200 ml) and water (200 ml). The organics were washed with water (200 ml), dried over magnesium sulphate, filtered and the solvent removed in vacuo. Purification by column chromatography on silica eluting with 10% ethyl acetate in heptane afforded the title compound as a white solid (1.25 g).
Reaction SMILES: [CH2:1]([O:3][P:4]([C:9]1[C:14]([N+:15]([O-])=O)=[CH:13][C:12]([C:18]([O:20][CH3:21])=[O:19])=[CH:11][C:10]=1[N+:22]([O-])=O)(=[O:8])[O:5][CH2:6][CH3:7])[CH3:2]>[Ni].C(O)C>[CH2:6]([O:5][P:4]([C:9]1[C:14]([NH2:15])=[CH:13][C:12]([C:18]([O:20][CH3:21])=[O:19])=[CH:11][C:10]=1[NH2:22])(=[O:8])[O:3][CH2:1][CH3:2])[CH3:7]
Reactant: CCOP(=O)(OCC)c1c([N+](=O)[O-])cc(C(=O)OC)cc1[N+](=O)[O-]
Agent: [Ni]
Solvent: CCO
Product: CCOP(=O)(OCC)c1c(N)cc(C(=O)OC)cc1N

Procedure:
80 g (0.221 mol) of 2,6-dinitro-4-carbomethoxy-benzene-phosphonic acid diethylester, 1000 ml of ethanol and 15 g of Raney nickel.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([NH:8][CH2:9][C:10]2[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][C:11]=2[C:17]2[CH:18]=[CH:19][C:20]([C:23]([NH:25][CH2:26][CH2:27][C:28]([O:30][CH2:31][CH3:32])=[O:29])=[O:24])=[N:21][CH:22]=2)=[C:4]([F:33])[CH:3]=1.[Cl:34][C:35]1[CH:40]=[C:39]([Cl:41])[CH:38]=[CH:37][C:36]=1B(O)O.C([O-])([O-])=O.[K+].[K+].O>O1CCOCC1.CCOC(C)=O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[Cl:16][C:13]1[CH:14]=[CH:15][C:10]([CH2:9][NH:8][C:5]2[CH:6]=[CH:7][C:2]([C:38]3[CH:37]=[CH:36][C:35]([Cl:34])=[CH:40][C:39]=3[Cl:41])=[CH:3][C:4]=2[F:33])=[C:11]([C:17]2[CH:18]=[CH:19][C:20]([C:23]([NH:25][CH2:26][CH2:27][C:28]([O:30][CH2:31][CH3:32])=[O:29])=[O:24])=[N:21][CH:22]=2)[CH:12]=1
Reactant: OB(O)c1ccc(Cl)cc1Cl
Reactant: CCOC(=O)CCNC(=O)c1ccc(-c2cc(Cl)ccc2CNc2ccc(Br)cc2F)cn1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1COCCO1
Product: CCOC(=O)CCNC(=O)c1ccc(-c2cc(Cl)ccc2CNc2ccc(-c3ccc(Cl)cc3Cl)cc2F)cn1
Temperature: 25 °C

Procedure:
Ethyl 3-(5-(2-(((4-bromo-2-fluorophenyl)amino)methyl)-5-chlorophenyl)picolinamido)propanoate (138 mg, 0.26 mmol), (2,4-dichlorophenyl)boronic acid (57 mg, 0.30 mmol), Pd(dppf)Cl2 (21 mg, 0.03 mmol), and K2CO3 (71 mg, 0.52 mmol) were dissolved in 1,4-dioxane (1.0 mL) and water (0.25 mL) and the resulting mixture was heated to 80° C. After 3 h the resulting mixture was cooled to room temperature, diluted with EtOAc, washed with water and brine, dried (Na2SO4), and dry packed onto silica gel. Column chromatography yielded the title compound.
Reaction SMILES: Cl[S:2]([C:5]1[CH:13]=[CH:12][C:8]([C:9]([OH:11])=[O:10])=[CH:7][CH:6]=1)(=[O:4])=[O:3].[CH2:14]([NH2:16])[CH3:15].CN>>[CH2:14]([NH:16][S:2]([C:5]1[CH:13]=[CH:12][C:8]([C:9]([OH:11])=[O:10])=[CH:7][CH:6]=1)(=[O:4])=[O:3])[CH3:15]
Reactant: CCN
Reactant: O=C(O)c1ccc(S(=O)(=O)Cl)cc1
Agent: CN
Product: CCNS(=O)(=O)c1ccc(C(=O)O)cc1
Yield: 64 %

Procedure:
A reaction was carried out following the conditions of Example 32 using 4.4 g (20 mmol) of 4-chlorosulfonylbenzoic acid and an ethylamine solution instead of the 40% aqueous solution of methylamine. The reaction product was post-treated to obtain 2.92 g of 4-ethylaminosulfonylbenzoic acid (yield 64%).