Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C:7]2[N:12]=[CH:11][C:10]([NH2:13])=[CH:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Br:14]N1C(=O)CCC1=O>CN(C=O)C.O>[Br:14][C:11]1[C:10]([NH2:13])=[CH:9][CH:8]=[C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[N:12]=1
Reactant: Nc1ccc(-c2ccccc2)nc1
Reactant: O=C1CCC(=O)N1Br
Solvent: O
Solvent: CN(C)C=O
Product: Nc1ccc(-c2ccccc2)nc1Br
Temperature: 25 °C
Reaction time: 16 h
Yield: 80.3 %

Procedure:
To a solution of 1B (85 mg, 0.5 mmol) in DMF (1 mL) at RT was added N-bromosuccinimide (89 mg, 0.5 mmol). The reaction was stirred at RT for 16 h. After this time, no starting material was detected by LC-MS. The reaction was diluted with water (10 mL) and extracted with EtOAc (3×10 mL). The combined organic layers were washed with saturated NaCl, dried over Na2SO4, filtered, and evaporated under reduced pressure. The residue was purified by silica gel (10 g) column chromatography, eluting with a gradient of EtOAc (0-60%) in hexane to give the title compound as a light brown foam (100 mg, 80%). LC/MS (method A): retention time=2.96 min, (M+H)+=249. 1H NMR (CDCl3, 400 MHz): δ 7.80-7.91(m, 2H), 7.50 (d, J=8.2 Hz, 1H), 7.38-7.44 (m, 2H), 7.31-7.35 (m, 1H), 7.05 (d, J=8.2 Hz, 1H), 4.15 (s, 2H).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[O:12][CH2:13][CH3:14])[O:8][C:7]([CH3:16])([CH3:15])[CH:6]=[C:5]2[CH2:17][CH3:18].C([Sn](CCCC)(CCCC)[C:24]([O:26]CC)=[CH2:25])CCC>C1COCC1>[CH2:13]([O:12][C:11]1[CH:10]=[C:9]2[C:4]([C:5]([CH2:17][CH3:18])=[CH:6][C:7]([CH3:16])([CH3:15])[O:8]2)=[CH:3][C:2]=1[C:24](=[O:26])[CH3:25])[CH3:14]
Reactant: CCOc1cc2c(cc1Br)C(CC)=CC(C)(C)O2
Reactant: C=C(OCC)[Sn](CCCC)(CCCC)CCCC
Solvent: C1CCOC1
Product: CCOc1cc2c(cc1C(C)=O)C(CC)=CC(C)(C)O2

Procedure:
Following General Procedure H, a solution of 6-bromo-4-ethyl-7-ethoxy-2,2-dimethyl-2H-chromene (Compound 16, 595 mg, 2.08 mmol) in THF was treated with tributyl(1-ethoxyvinyl)tin (1.50 g, 4.17 mmol) to give the title compound as a yellow solid.
Reaction SMILES: [CH2:1]([Sn:5]([Li])([CH2:10][CH2:11][CH2:12][CH3:13])[CH2:6][CH2:7][CH2:8][CH3:9])[CH2:2][CH2:3][CH3:4].Cl[C:16]1[N:21]=[CH:20][CH:19]=[CH:18][N:17]=1>>[CH2:1]([Sn:5]([CH2:10][CH2:11][CH2:12][CH3:13])([CH2:6][CH2:7][CH2:8][CH3:9])[C:16]1[N:21]=[CH:20][CH:19]=[CH:18][N:17]=1)[CH2:2][CH2:3][CH3:4]
Reactant: Clc1ncccn1
Reactant: [Li][Sn](CCCC)(CCCC)CCCC
Product: CCCC[Sn](CCCC)(CCCC)c1ncccn1

Procedure:
Reaction of tri-n-butylstannyl lithium with 2-chloropyrimidine affords 2-(tributylstannyl)pyrimidine which can be condensed the an acid chloride such as 5 under palladium catalysis to afford these desired ketones.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N+:9]([O-])=O)=[CH:5][C:4]=1[OH:12].Cl.Cl[CH2:15][CH2:16][N:17]1[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1>>[N:17]1([CH2:16][CH2:15][O:12][C:4]2[CH:5]=[C:6]([CH:7]=[CH:8][C:3]=2[O:2][CH3:1])[NH2:9])[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1
Reactant: ClCCN1CCCCC1
Reactant: COc1ccc([N+](=O)[O-])cc1O
Agent: Cl
Product: COc1ccc(N)cc1OCCN1CCCCC1

Procedure:
The title compound was prepared from 2-methoxy-5-nitrophenol and 1-(2-chloroethyl)piperidine hydrochloride using a similar procedure to Descriptions 1 and 2 (40%).
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[CH:11]=[CH:10][C:6]([C:7](Cl)=[O:8])=[CH:5][CH:4]=1.[CH3:14][C:15]1[C:19]([NH2:20])=[C:18]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[NH:17][N:16]=1>N1C=CC=CC=1>[CH3:14][C:15]1[C:19]([NH:20][C:7](=[O:8])[C:6]2[CH:10]=[CH:11][C:3]([C:2]([F:13])([F:12])[F:1])=[CH:4][CH:5]=2)=[C:18]([C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)[NH:17][N:16]=1
Reactant: Cc1n[nH]c(-c2ccccc2)c1N
Reactant: O=C(Cl)c1ccc(C(F)(F)F)cc1
Solvent: c1ccncc1
Product: Cc1n[nH]c(-c2ccccc2)c1NC(=O)c1ccc(C(F)(F)F)cc1
Reaction time: 16 h

Procedure:
361 mg of 4-trifluoromethylbenzoyl chloride were added dropwise to a solution of 300 mg of 3-methyl-5-phenyl-1H-pyrazol-4-ylamine in 5 ml of pyridine at room temperature. The reaction mixture was stirred for 16 h and then concentrated. The residue was extracted into dichloromethane and washed with 0.5M hydrochloric acid, at which point the title compound precipitated.
Reaction SMILES: [CH2:1]([N:13]([C:15]([CH2:17][N:18]1[CH:23]=[C:22]([CH2:24][C:25]2[CH:26]=[N:27][C:28](=[O:37])[N:29]([CH2:31][C:32]([O:34]CC)=[O:33])[CH:30]=2)[C:21](=[O:38])[N:20]=[C:19]1[S:39][CH2:40][C:41]1[CH:46]=[CH:45][C:44]([F:47])=[CH:43][CH:42]=1)=[O:16])[CH3:14])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].[OH-].[Na+]>O1CCOCC1.O>[CH2:1]([N:13]([C:15]([CH2:17][N:18]1[CH:23]=[C:22]([CH2:24][C:25]2[CH:26]=[N:27][C:28](=[O:37])[N:29]([CH2:31][C:32]([OH:34])=[O:33])[CH:30]=2)[C:21](=[O:38])[N:20]=[C:19]1[S:39][CH2:40][C:41]1[CH:46]=[CH:45][C:44]([F:47])=[CH:43][CH:42]=1)=[O:16])[CH3:14])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: CCCCCCCCCCCCN(C)C(=O)Cn1cc(Cc2cnc(=O)n(CC(=O)OCC)c2)c(=O)nc1SCc1ccc(F)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: CCCCCCCCCCCCN(C)C(=O)Cn1cc(Cc2cnc(=O)n(CC(=O)O)c2)c(=O)nc1SCc1ccc(F)cc1
Reaction time: 1 h

Procedure:
To a stirring solution of 1-(N-(1-dodecyl)-N-methylaminocarbonylmethyl)-2-(4-fluorobenzyl)thio-5-(1-ethoxycarbonylmethyl-2-oxopyrimid-5-ylmethyl)pyrimidin-4-one in 1,4-dioxan (8 ml) was added 0.5M sodium hydroxide (1.56 ml). After 1 h, water (3 ml) was added. After a further hour, the mixture was diluted with water, extracted with ethyl acetate and acidified to pH 3 with aq. sodium bisulphate. The solid which precipitated was filtered, washed with water and ether, heated briefly with acetone and filtered again to give the product as a white solid, yield 0.28 g. 1H-NMR (d6-DMSO) δ0.85 (3H, t), 1.22 (18H, m), 1.35-1.61 (2H, m,), 2.78, 2.95 (3H, 2xs), 3.20-3.35 (2H, m), 3.58 (2H, s), 4.40 (2H, s), 4.55 (2H, s), 4.83 (2H, m), 7.10 (2H, m), 7.44 (2H, m), 7.54 and 7.57 (1H, 2xs), 8.03 (1H, m), 8.54 (1H, m) 13.10 (1H, br. s); MS (APCI+) found (M+1)=642, C33H44FN5O5S requires 641.
Reaction SMILES: [CH:1]1([CH2:4][NH:5][CH2:6][CH2:7][C:8]([OH:10])=[O:9])[CH2:3][CH2:2]1.[CH:11]([C:13]1[CH:21]=[CH:20][C:16]([C:17](O)=[O:18])=[CH:15][CH:14]=1)=[O:12].F[P-](F)(F)(F)(F)F.Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1>CN(C=O)C.C(N(C(C)C)CC)(C)C>[CH:1]1([CH2:4][N:5]([C:17](=[O:18])[C:16]2[CH:20]=[CH:21][C:13]([CH:11]=[O:12])=[CH:14][CH:15]=2)[CH2:6][CH2:7][C:8]([OH:10])=[O:9])[CH2:3][CH2:2]1
Reactant: O=Cc1ccc(C(=O)O)cc1
Reactant: O=C(O)CCNCC1CC1
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=Cc1ccc(C(=O)N(CCC(=O)O)CC2CC2)cc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To the above resin bound N-(cyclopropylmethyl) 3-aminopropionic acid (50 mg) was added 200 μmol 4-formylbenzoic acid (30 mg) dissolved in a mixture of 430 μL DMF and 70 μL diisopropylethylamine followed by 200 μmol bromo-tris-pyrrolidinophosphonium hexafluorophosphate (PyBrOP, 93 mg) dissolved in 500 μL DMF. The mixture was shaken at 25° C. for 4 hours followed by filtration and washing of the resin with 3×1 mL DMF and 1 mL trimethylorthoformate.
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5]([C:7]1[S:8][C:9]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[CH:10][C:11]=1[NH:12][C:13](=[O:22])[C:14]1[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][C:15]=1[Cl:21])=[O:6].N#N.I[CH:32]([CH3:34])[CH3:33]>CN(C)C=O>[CH3:3][O:4][C:5]([C:7]1[S:8][C:9]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[CH:10][C:11]=1[N:12]([C:13](=[O:22])[C:14]1[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][C:15]=1[Cl:21])[CH:32]([CH3:34])[CH3:33])=[O:6]
Reactant: CC(C)I
Reactant: COC(=O)c1sc(-c2ccccc2)cc1NC(=O)c1ccc(Cl)cc1Cl
Agent: N#N
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)c1sc(-c2ccccc2)cc1N(C(=O)c1ccc(Cl)cc1Cl)C(C)C
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 54.9 %

Procedure:
Sodium Hydride (60% dispersion in oil, 190 mg, 5,2 mmol) was added to an ice-cold solution of 3-(2,4-Dichloro-benzoylamino)-5-phenyl-thiophene-2-carboxylic acid methyl ester (2) (1.5 g, 3.69 mmol) in 350 ml of N,N-dimethylformamide in an atmosphere of N2. After 5 min, 2-Iodo-propane (941 mg, 5.54 mmol) was added to the solution and then the reaction mixture was stirred for 30 min at 0° C. and 64 h at room temperature. The mixture was partitioned between ether (200 mL) and water (350 mL) and the organic layer was separated. The aqueous phase was washed twice with ether (2×70 mL) and the combined ether layer was dried (MgSO4), concentrated and the residue was purified by flash chromatography (10% EtOAc/Hexane) to obtain 908 mg (55%) of 3-[(2,4-Dichloro-benzoyl)-isopropyl-amino]-5-phenyl-thiophene-2-carboxylic acid methyl ester. NMR 1H (CDCl3, 400 MHz): Rotamere 95/05: 7.54 ppm (dd, 2H, Haro); 7.49-7.35 ppm (m, 3H, Haro); 7.29-7.25 ppm (m, 2H, Haro); 7.15 ppm (d, 1H, Haro); 7.05 ppm (d, 1H, Haro) 5.09 ppm (hex, 1H, N—CH(CH3), major rotamere); 3.99 ppm (hex, N—CH(CH3), minor rotamere); 3.89 ppm (s, 3H); 1.40 ppm (d, 3H, N—CH(CH3), major rotamere); 1.28 ppm (d, N—CH(CH3), minor rotamere); 1.09 ppm (d, 3H, N—CH(CH3), major rotamere); 1.01 ppm (d, N—CH(CH3), minor rotamere).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=O)[CH2:9][CH2:10][CH2:11][CH2:12][N:13]1[CH2:18][CH2:17][CH:16]([C:19]2[CH:20]=[C:21]([NH:25][C:26](=[O:30])[CH:27]([CH3:29])[CH3:28])[CH:22]=[CH:23][CH:24]=2)[CH2:15][CH2:14]1.Cl.[C:33]1([N:39]([C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)N)[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1>>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:39]([C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)[C:33]2[C:34]([C:9]=1[CH2:10][CH2:11][CH2:12][N:13]1[CH2:18][CH2:17][CH:16]([C:19]3[CH:20]=[C:21]([NH:25][C:26](=[O:30])[CH:27]([CH3:29])[CH3:28])[CH:22]=[CH:23][CH:24]=3)[CH2:15][CH2:14]1)=[CH:35][CH:36]=[CH:37][CH:38]=2
Reactant: NN(c1ccccc1)c1ccccc1
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CCCCC(=O)c3ccccc3Br)CC2)c1
Agent: Cl
Product: CC(C)C(=O)Nc1cccc(C2CCN(CCCc3c(-c4ccccc4Br)n(-c4ccccc4)c4ccccc34)CC2)c1

Procedure:
Prepared by Procedure E and Scheme M using N-(3-{1-[5-(2-bromophenyl)-5-oxopentyl]-4-piperidinyl}phenyl)-2-methylpropanamide and 1,1-diphenylhydrazine hydrochloride: ESMS m/e: 634 (M+H)+.
Reaction SMILES: [C:1]1([C:7]2[CH:12]=[CH:11][C:10]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)=[CH:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Al].Cl[CH:21](Cl)[CH2:22][Si:23]([Cl:26])([Cl:25])[Cl:24]>C(=S)=S.CCCCCC>[Cl:24][Si:23]([CH2:22][CH:21]1[C:8]2[CH:9]=[C:10]([C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH:11]=[CH:12][C:7]=2[C:1]2[C:2]1=[CH:3][CH:4]=[CH:5][CH:6]=2)([Cl:26])[Cl:25]
Reactant: ClC(Cl)C[Si](Cl)(Cl)Cl
Reactant: c1ccc(-c2ccc(-c3ccccc3)cc2)cc1
Agent: [Al]
Solvent: CCCCCC
Solvent: S=C=S
Product: Cl[Si](Cl)(Cl)CC1c2ccccc2-c2ccc(-c3ccccc3)cc21
Yield: 10 %

Procedure:
In the same apparatus and procedures as Example 1 above, 5.0 g (21.7 mmol) of para-terphenyl and 0.30 g (11.1 mmol) of aluminum were alkylated in CS2 (50 ml) solution with (2,2-dichloroethyl)trichlorosilane 6.68 g (21.7 mmol) under dry nitrogen atmospheric pressure for 24 hrs at reflux temperature. Freshly distilled hexane (100 ml) was added to the reaction mixture and insoluble solids in hexane were filtered from the organic solution. After hexane and CS2 were distilled, recrystallization from ether yielded 0.85 g of 9-(trichlorosilyl)methyl-2-phenylfluorene (yield; 10%).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:24])[C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([S:11][C:12]2[C:20]3[C:15](=[C:16]([F:22])[C:17]([Cl:21])=[CH:18][CH:19]=3)[NH:14][C:13]=2[CH3:23])[CH:6]=1)[CH3:2].[CH2:25]([N:27]1[CH:31]=[CH:30][C:29](I)=[N:28]1)[CH3:26]>>[CH2:1]([O:3][C:4](=[O:24])[C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([S:11][C:12]2[C:20]3[C:15](=[C:16]([F:22])[C:17]([Cl:21])=[CH:18][CH:19]=3)[N:14]([C:29]3[CH:30]=[CH:31][N:27]([CH2:25][CH3:26])[N:28]=3)[C:13]=2[CH3:23])[CH:6]=1)[CH3:2]
Reactant: CCn1ccc(I)n1
Reactant: CCOC(=O)c1cccc(Sc2c(C)[nH]c3c(F)c(Cl)ccc23)c1
Product: CCOC(=O)c1cccc(Sc2c(C)n(-c3ccn(CC)n3)c3c(F)c(Cl)ccc23)c1

Procedure:
Prepared according to the procedure described in Example 55, Step 2 using the following starting materials: 3-(6-chloro-7-fluoro-2-methyl-1H-indol-3-ylsulfanyl)-benzoic acid ethyl ester and 1-ethyl-3-iodo-1H-pyrazole.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:9]2[C:14](=[O:15])[C:13]([O:16][CH2:17][C:18]([OH:21])([CH3:20])[CH3:19])=[C:12]([C:22]3[CH:27]=[CH:26][C:25]([S:28]([NH2:31])(=[O:30])=[O:29])=[CH:24][CH:23]=3)[CH:11]=[N:10]2)[CH:5]=[CH:6][C:7]=1[F:8].[C:32](OC(=O)C)(=[O:34])[CH3:33].C(N(CC)CC)C>CN(C)C1C=CN=CC=1>[F:1][C:2]1[CH:3]=[C:4]([N:9]2[C:14](=[O:15])[C:13]([O:16][CH2:17][C:18]([OH:21])([CH3:20])[CH3:19])=[C:12]([C:22]3[CH:27]=[CH:26][C:25]([S:28]([NH:31][C:32](=[O:34])[CH3:33])(=[O:30])=[O:29])=[CH:24][CH:23]=3)[CH:11]=[N:10]2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: CC(=O)OC(C)=O
Reactant: CC(C)(O)COc1c(-c2ccc(S(N)(=O)=O)cc2)cnn(-c2ccc(F)c(F)c2)c1=O
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Product: CC(=O)NS(=O)(=O)c1ccc(-c2cnn(-c3ccc(F)c(F)c3)c(=O)c2OCC(C)(C)O)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A mixture of 2-(3,4-difluorophenyl)-4-(2-hydroxy-2-methyl-1-propoxy)-5-[4-(aminosulfonyl)phenyl]-3(2H)-pyridazinone (Example 459, 1 equivalent), acetic anhydride (3 equivalents), 4-(dimethylamino)pyridine (0.3 equivalents), and triethylamine (1.2 equivalents) is stirred at room temperature for 16 hours. The reaction mixture is partitioned between ethyl acetate and water. The organic layer is washed with brine then dried over MgSO4 and filtered. The filtrate is concentrated in vacuo to give the title compound.
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[Na+].[C:5]([O:9][C:10]([N:12]([C:20]1[S:29][CH2:28][C@H:27]2[C@:22]([C:30]3[S:31][CH:32]=[C:33](B4OC(C)(C)C(C)(C)O4)[CH:34]=3)([CH2:23][O:24][CH2:25][CH2:26]2)[N:21]=1)[C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])=[O:11])([CH3:8])([CH3:7])[CH3:6]>CO.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[C:5]([O:9][C:10]([N:12]([C:20]1[S:29][CH2:28][C@H:27]2[C@:22]([C:30]3[S:31][CH:32]=[C:33]([N:1]=[N+:2]=[N-:3])[CH:34]=3)([CH2:23][O:24][CH2:25][CH2:26]2)[N:21]=1)[C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])=[O:11])([CH3:6])([CH3:7])[CH3:8]
Reactant: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)C1=N[C@@]2(c3cc(B4OC(C)(C)C(C)(C)O4)cs3)COCC[C@H]2CS1
Reactant: [N-]=[N+]=[N-]
Agent: [Cu+2]
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CO
Product: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)C1=N[C@@]2(c3cc(N=[N+]=[N-])cs3)COCC[C@H]2CS1
Temperature: 25 °C
Reaction time: 8 h
Yield: 74.6 %

Procedure:
Sodium azide (177 mg) and copper (II) acetate (99.2 mg) were added to a solution of (±)-N,N-di(tert-butyloxycarbonyl)-[(4aR*,8aR*)-8a-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-thiophen-2-yl]-4,4a,5,6,8,8a-hexahydro-7-oxa-3-thia-1-azanaphthalen-2-yl]amine (790 mg) in methanol (88 ml). The mixture was stirred at room temperature overnight, and then the excess of methanol was evaporated under reduced pressure. An ammonium chloride solution was added to the residue, and the aqueous layer was with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by NH-silica gel column chromatography to obtain the title compound (503 mg).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[CH:15]=[C:16]([NH:20][C:21](=[O:25])[CH:22]([CH3:24])[CH3:23])[CH:17]=[CH:18][CH:19]=2)[CH2:10][CH2:9]1.[C:26]1([N:32]=[C:33]=[O:34])[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>C1COCC1>[NH:32]([C:33]([NH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[CH:15]=[C:16]([NH:20][C:21](=[O:25])[CH:22]([CH3:23])[CH3:24])[CH:17]=[CH:18][CH:19]=2)[CH2:10][CH2:9]1)=[O:34])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: O=C=Nc1ccccc1
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CCCCCCN)CC2)c1
Solvent: C1CCOC1
Product: CC(C)C(=O)Nc1cccc(C2CCN(CCCCCCNC(=O)Nc3ccccc3)CC2)c1

Procedure:
Prepared by Procedure Q1 (THF) and Scheme AT using N-{3-[1-(6-aminohexyl)-4-piperidinyl]phenyl}-2-methylpropanamide and phenyl isocyanate: ESMS m/e: 465.2 (M+H)+.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5]([C:8]#[C:9][Si:10]([CH3:13])([CH3:12])[CH3:11])=[CH:4][CH:3]=1.[CH2:14]([C:18]1[CH:23]=[CH:22][C:21]([C:24]#[CH:25])=[CH:20][CH:19]=1)[CH2:15][CH2:16][CH3:17].C(N(CC)CC)C>[Cu]I.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl.C1COCC1>[CH3:11][Si:10]([C:9]#[C:8][C:5]1[CH:6]=[CH:7][C:2]([C:25]#[C:24][C:21]2[CH:22]=[CH:23][C:18]([CH2:14][CH2:15][CH2:16][CH3:17])=[CH:19][CH:20]=2)=[CH:3][CH:4]=1)([CH3:13])[CH3:12]
Reactant: C#Cc1ccc(CCCC)cc1
Reactant: C[Si](C)(C)C#Cc1ccc(I)cc1
Agent: Cl[Pd]Cl
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCCCc1ccc(C#Cc2ccc(C#C[Si](C)(C)C)cc2)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 39.7 %

Procedure:
4-iodophenytrimethyl silylacetylene (5.0 g, 16.6 mmol), 4-n-butylphenylacetylene (2.67 g, 16.0 mmol), CuI (32 mg, 0.16 mmol), bis(triphenylphosphine)palladium(II)dichloride (0.35 g, 0.48 mmol), triethylamine (50 mL) and THF (50 mL) were added together and stirred at ambient temperature under N2 for 18 h. The reaction mixture was filtered to remove solids and concentrated to dryness, redissolved in CHCl3, washed with water (2×), brine, dried with MgSO4, filtered, concentrated and the solid recrystallized from hexanes to give 2.10 g (40%) product. The crude product could also be purified by washing with MeOH. This gave 1.94 g additional product for a total yield of 79%. 1H NMR (CDCl3) δ: 7.46 (m, 6H), 7.20 (d, J=8.11 Hz, 2H); 2.63 (t, J=7.6 Hz, 2H); 1.62 (m, 2H); 1.38 (m, 2H); 0.95 (t, J=7.2 Hz, 3H); 0.28 (s, 9H). 13C {1H} NMR (CDCl3): 143.7, 131.9, 131.6, 131.3, 128.5, 123.6, 122.7, 120.1, 104.7, 96.1, 91.6, 88.4, 35.6, 33.4, 22.3, 14.0, −0.1 ppm.
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5](=[O:16])[CH2:6][C:7]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[NH:9][CH:8]=1.[CH3:17][Si:18]([CH2:21][CH2:22][O:23][CH2:24]Cl)([CH3:20])[CH3:19]>CN(C=O)C.CS(C)=O>[CH3:3][O:4][C:5](=[O:16])[CH2:6][C:7]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[N:9]([CH2:24][O:23][CH2:22][CH2:21][Si:18]([CH3:20])([CH3:19])[CH3:17])[CH:8]=1
Reactant: COC(=O)Cc1c[nH]c2ccccc12
Reactant: C[Si](C)(C)CCOCCl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CS(C)=O
Product: COC(=O)Cc1cn(COCC[Si](C)(C)C)c2ccccc12
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 65 %

Procedure:
To a suspension of sodium hydride (326 mg, 8.10 mmol) in DMF (13 mL) at 0° C. was added a solution of (1H-Indol-3-yl)-acetic acid methyl ester (1.0 g, 5.3 mmol) in DMSO (3 mL). The mixture was stirred at 0° C. for 30 min and then at rt for 1 h. The reaction mixture was cooled back down to 0° C., and SEMCl (1.35 mL, 8.41 mmol) was added neat. The reaction mixture was stirred at 0° C. for 15 min and then at rt for 1 h. The reaction mixture was then partitioned between water (200 mL) and diethyl ether (200 mL) followed by further extraction of the water layer with ether (2×200 mL) and drying of the combined organic layers with Na2SO4. After removal of the solvent under reduced pressure, the crude material was purified by flash chromatography (EtOAc/hexanes) giving 1.1 g (70%) of [1-(2-trimethylsilanyl-ethoxymethyl)-1H-indol-3yl]-acetic acid methyl ester. 1H NMR (400 MHz, CDCl3): 7.65 (d, J=7.8 Hz, 1H), 7.46 (d, J=8.1, 1H), 7.26 (m, 1H), 7.22 (m, 2H), 5.51 (s, 2H), 3.83 (s, 2H), 3.76 (s, 3H), 3.53 (t, J=7.9 Hz, 2H), 0.94 (t, J=7.9 Hz, 2H), 0.0 (s, 9H).
Reaction SMILES: C(OC([N:8]1[CH2:12][CH2:11][CH2:10][C@@H:9]1[CH2:13][NH:14][C:15]1[CH:20]=[CH:19][C:18]([CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[CH:17][CH:16]=1)=O)(C)(C)C.Cl>O1CCOCC1>[CH2:21]([C:18]1[CH:19]=[CH:20][C:15]([NH:14][CH2:13][C@H:9]2[CH2:10][CH2:11][CH2:12][NH:8]2)=[CH:16][CH:17]=1)[C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H]1CNc1ccc(Cc2ccccc2)cc1
Agent: Cl
Solvent: C1COCCO1
Product: c1ccc(Cc2ccc(NC[C@H]3CCCN3)cc2)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 106.9 %

Procedure:
To the product from step 1 (340 mg, 0.927 mmol) was added 4M HCl in dioxane (6 mL) and the resulting mixture was stirred at rt for 3 h. The solvent was removed in vacuo to obtain the title product as a white solid (264 mg, 84%). The solid was dried under vacuum oven at 50° C. for 15 h: MS; m/z 267 (M+H); LCMS (UV) 99%: HPLC 98.8%. 1H NMR (400 MHz, DMSO-d6) δ 1.61-1.66 (m, 1H), 1.84-1.94 (m, 2H), 2.04-2.09 (m, 1H), 3.13-3.18 (m, 2H), 3.30-3.37 (m, 2H), 3.57 (s, 1H), 3.62-3.67 (m, 1H), 3.79 (s, 2H), 6.63 (d, 2H, J=8.4 Hz), 7.0 (d, 2H, J=8.4 Hz), 7.13-7.19 (m, 3H), 7.24-7.28 (m, 2H), 8.9 (s, 1H), 9.4 (s, 1H).
Reaction SMILES: [C:1]([O:5][C:6]1[CH:11]=[C:10]([CH:12]([CH3:14])[CH3:13])[C:9]([O:15][C:16]2[CH:21]=[CH:20][C:19]([N+:22]([O-])=O)=[C:18]([OH:25])[CH:17]=2)=[C:8]([CH:26]([CH3:28])[CH3:27])[C:7]=1[CH3:29])(=[O:4])[CH2:2][CH3:3].[H][H]>[Pd].CO>[C:1]([O:5][C:6]1[CH:11]=[C:10]([CH:12]([CH3:13])[CH3:14])[C:9]([O:15][C:16]2[CH:21]=[CH:20][C:19]([NH2:22])=[C:18]([OH:25])[CH:17]=2)=[C:8]([CH:26]([CH3:28])[CH3:27])[C:7]=1[CH3:29])(=[O:4])[CH2:2][CH3:3]
Reactant: CCC(=O)Oc1cc(C(C)C)c(Oc2ccc([N+](=O)[O-])c(O)c2)c(C(C)C)c1C
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: CCC(=O)Oc1cc(C(C)C)c(Oc2ccc(N)c(O)c2)c(C(C)C)c1C
Yield: 100.9 %

Procedure:
Methyl(3,5-diisopropyl-4-[3-hydroxy-4-nitrophenoxy]phenyl) propionate (0.30 g), methanol (10 mL), palladium on carbon (10%) and 1–2 atmospheres of hydrogen gas was stirred at room temperature for 4 hours. After filtration, 0.28 g of methyl(3,5-diisopropyl-4-[4-amino-3-hydroxyphenoxy]phenyl) propionate was obtained.
Reaction SMILES: [SH:1][CH2:2][CH2:3][C:4]([OH:6])=[O:5].[OH-].[Na+].[C:9]1([C:14](Cl)=[O:15])[S:13][CH:12]=[CH:11][CH:10]=1.C([O-])(O)=O.[Na+]>C(OCC)C.O>[C:9]1([C:14]([S:1][CH2:2][CH2:3][C:4]([OH:6])=[O:5])=[O:15])[S:13][CH:12]=[CH:11][CH:10]=1
Reactant: O=C(O)CCS
Reactant: O=C(Cl)c1cccs1
Agent: O=C([O-])O
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Solvent: O
Product: O=C(O)CCSC(=O)c1cccs1

Procedure:
A mixture of 26.5 g (0.25 mol) of 3-mercaptopropionic acid, 150 mls of ethyl ether and 250 mls of 1-normal NaOH has been treated dropwise, the temperature being maintained between 0° C. and 5° C., with vigorous stirring, with 40.3 g of 2-thenoyl chloride (0.275 mol) in 80 mls of ethyl ether, while concurrently adding, so as to keep the pH of the reaction environment constantly alkaline, 31.5 g (0.36 mol) of NaHCO3 in 800 mls of water. On completion of dripping, stirring has been continued for 16 additional hours at room temperature. Upon separation of the organic phase, the waters have been extracted with ethyl ether again, and then made acidic with 4-normal hydrochloric acid. The as-formed precipitate has been recrystallized from 70% ethanol.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][S:10]([C:13]2[CH:14]=[C:15]3[C:19](=[CH:20][CH:21]=2)[NH:18][C:17](=[O:22])/[C:16]/3=[CH:23]\[C:24]2[NH:28][C:27]([CH3:29])=[C:26]([C:30]([OH:32])=O)[C:25]=2[CH3:33])(=[O:12])=[O:11])[CH:5]=[C:6]([Cl:8])[CH:7]=1.[N:34]1([CH:39]2[CH2:44][CH2:43][NH:42][CH2:41][CH2:40]2)[CH2:38][CH2:37][CH2:36][CH2:35]1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl>CN(C=O)C>[Cl:8][C:6]1[CH:5]=[C:4]([CH2:9][S:10]([C:13]2[CH:14]=[C:15]3[C:19](=[CH:20][CH:21]=2)[NH:18][C:17](=[O:22])/[C:16]/3=[CH:23]\[C:24]2[NH:28][C:27]([CH3:29])=[C:26]([C:30]([N:42]3[CH2:43][CH2:44][CH:39]([N:34]4[CH2:38][CH2:37][CH2:36][CH2:35]4)[CH2:40][CH2:41]3)=[O:32])[C:25]=2[CH3:33])(=[O:11])=[O:12])[CH:3]=[C:2]([Cl:1])[CH:7]=1
Reactant: Cc1[nH]c(/C=C2\C(=O)Nc3ccc(S(=O)(=O)Cc4cc(Cl)cc(Cl)c4)cc32)c(C)c1C(=O)O
Reactant: C1CCN(C2CCNCC2)C1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: Cc1[nH]c(/C=C2\C(=O)Nc3ccc(S(=O)(=O)Cc4cc(Cl)cc(Cl)c4)cc32)c(C)c1C(=O)N1CCC(N2CCCC2)CC1

Procedure:
5-[5-(3,5-Dichloro-phenylmethanesulfonyl)-2-oxo-1,2-dihydro-indol-(3Z)-ylidenemethyl]-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (120 mg, 0.24 mmol) was coupled with 4-pyrrolidin-1-yl-piperidine (45 mg, 1.2 eq.) using HOBt (1.2 eq.), EDAC.HCl (1.2 eq.) and TEA (3 eq.) in DMF (25 mL) to give the titled compound. MS m/z 639 [M−1].