Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3](=O)[C:4]1[C:9]([Cl:10])=[CH:8][C:7]([Cl:11])=[CH:6][C:5]=1[NH:12][C:13](=[O:30])[CH:14]([C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([O:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH:17]=1)[CH3:15].[Li+].C[Si]([N-][Si](C)(C)C)(C)C.CCCCCC>CCOC(C)=O>[CH2:23]([O:22][C:18]1[CH:17]=[C:16]([C:14]2([CH3:15])[C:3](=[O:2])[C:4]3[C:5](=[CH:6][C:7]([Cl:11])=[CH:8][C:9]=3[Cl:10])[NH:12][C:13]2=[O:30])[CH:21]=[CH:20][CH:19]=1)[C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: COC(=O)c1c(Cl)cc(Cl)cc1NC(=O)C(C)c1cccc(OCc2ccccc2)c1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: CC1(c2cccc(OCc3ccccc3)c2)C(=O)Nc2cc(Cl)cc(Cl)c2C1=O
Yield: 69.6 %

Procedure:
The objective compound was prepared by the same procedure for the example 1, using a 4,6-dichloro-2-[2-(3-benzyloxy-phenyl)-propionylamino]-benzoic acid methyl ester (2.80 g, 6.40 mmol) and LiHMDS (19.0 mmol, 1M THF solution). After normal workup, the objective compound (1.90 g, 71%) was obtained as pale yellow solid by a flash column chromatography (n-hexane:EtOAc=9:1): 1H NMR (200 MHz, DMSO-d6) δ 1.55 (s, 3H, CH3), 5.02 (s, 2H, OCH2), 6.69-7.02 (m, 2H, ArH), 7.22-7.38 (m, 7H, ArH), 11.28 (br s, 1H, NH); m.p. 201-203° C.; MS(EI) m/e 426 [M++1], 160, 91.
Reaction SMILES: [CH2:1]([CH:3]([CH2:19][CH3:20])[CH:4]([NH2:18])[C:5]1[N:9]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=2)[N:8]=[CH:7][N:6]=1)[CH3:2].CCN(CC)CC.[Cl:28][C:29]1[S:33][C:32]([S:34](Cl)(=[O:36])=[O:35])=[CH:31][CH:30]=1>C(Cl)Cl>[Cl:28][C:29]1[S:33][C:32]([S:34]([NH:18][CH:4]([C:5]2[N:9]([CH2:10][C:11]3[CH:12]=[CH:13][C:14]([F:17])=[CH:15][CH:16]=3)[N:8]=[CH:7][N:6]=2)[CH:3]([CH2:1][CH3:2])[CH2:19][CH3:20])(=[O:36])=[O:35])=[CH:31][CH:30]=1
Reactant: CCC(CC)C(N)c1ncnn1Cc1ccc(F)cc1
Reactant: O=S(=O)(Cl)c1ccc(Cl)s1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCC(CC)C(NS(=O)(=O)c1ccc(Cl)s1)c1ncnn1Cc1ccc(F)cc1
Reaction time: 18 h
Yield: 60 %

Procedure:
To a stirred solution of the {2-ethyl-1-[1-(4-fluorobenzyl)-1H-1,2,4-triazol-5-yl]butyl}amine (0.133 g, 0.481 mmol) in CH2Cl2 (10 mL) was added Et3N (0.10 mL, 0.72 mmol) followed by 5-chlorothiophene-2-sulfonyl chloride (0.115 g, 0.529 mmol). The reaction mixture was stirred for 18 h, concentrated in vacuo, partitioned between 0.1N HCl and EtOAc. The organic extracts were dried (MgSO4), filtered and concentrated in vacuo. Column chromatography (SiO2, EtOAc/hexane, 3:7) provided pure material as a yellow solid in 60% yield.
Reaction SMILES: [CH:1]1([CH2:4][N:5]2[CH2:9][CH2:8][N:7]([C:10]3[S:11][C:12]([C:15]([OH:17])=O)=[CH:13][N:14]=3)[C:6]2=[O:18])[CH2:3][CH2:2]1.C(N(CC)C(C)C)(C)C.Cl.C(N=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1.[N:50]1[CH:55]=[CH:54][CH:53]=[C:52]([CH2:56][NH2:57])[CH:51]=1>CN(C)C=O>[CH:1]1([CH2:4][N:5]2[CH2:9][CH2:8][N:7]([C:10]3[S:11][C:12]([C:15]([NH:57][CH2:56][C:52]4[CH:51]=[N:50][CH:55]=[CH:54][CH:53]=4)=[O:17])=[CH:13][N:14]=3)[C:6]2=[O:18])[CH2:2][CH2:3]1
Reactant: O=C(O)c1cnc(N2CCN(CC3CC3)C2=O)s1
Reactant: NCc1cccnc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NCc1cccnc1)c1cnc(N2CCN(CC3CC3)C2=O)s1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 40 %

Procedure:
To a solution of 2-(3-(cyclopropylmethyl)-2-oxoimidazolidin-1-yl)thiazole-5-carboxylic acid (0.10 g, 0.37 mmol) in anhydrous N,N-dimethylformamide (10 mL) was added N,N-diisopropylethylamine (0.17 mL, 1.34 mmol), followed by the addition of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.11 g, 0.59 mmol). The reaction was stirred at ambient temperature for 0.5 hours, 1-Hydroxybenzotriazole (0.07 g, 0.52 mmol) was added, followed by the addition of pyridin-3-ylmethanamine (0.06 g, 0.56 mmol). The reaction mixture was stirred at ambient temperature for 18 hours. The solvent was concentrated in vacuo. The residue was diluted with dichloromethane (150 mL), washed with water (100 mL) and brine (50 mL). The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was crystallized in dichloromethane and hexane to yield the title compound as a colorless solid in 40% yield (0.065 g): mp 190-192° C. (dichloromethane/hexanes); 1H NMR (300 MHz, DMSO-d6) δ 8.98 (t, J=5.8 Hz 1H), 8.49 (m, 1H), 8.43-8.39 (m, 1H), 7.98 (s, 1H), 7.68-7.65 (m, 1H), 7.34-7.30 (m, 1H), 4.40 (d, J=5.8 Hz, 2H), 4.01-3.95 (m, 2H), 3.65-3.59 (m, 2H), 3.07 (d, J=7.1 Hz, 2H), 1.01-0.85 (m, 1H), 0.53-0.39 (m, 2H), 0.21-0.16 (m, 2H); 13C NMR (75 MHz, DMSO-d6) δ 161.5, 161.3, 155.1, 149.3, 148.6, 140.1, 135.7, 135.3, 127.1, 123.9, 48.2, 42.5, 42.3, 9.31, 3.63; MS (ES+) m/z 358.2 (M+1).
Reaction SMILES: CC([O-])(C)C.[K+].F[C:8]1[CH:13]=[CH:12][C:11]([N+:14]([O-:16])=[O:15])=[CH:10][CH:9]=1.[Cl:17][CH2:18][CH2:19][CH2:20][SH:21]>CS(C)=O.O>[Cl:17][CH2:18][CH2:19][CH2:20][S:21][C:8]1[CH:13]=[CH:12][C:11]([N+:14]([O-:16])=[O:15])=[CH:10][CH:9]=1
Reactant: O=[N+]([O-])c1ccc(F)cc1
Reactant: SCCCCl
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: O=[N+]([O-])c1ccc(SCCCCl)cc1
Temperature: 10 °C
Yield: 33.4 %

Procedure:
To a cooled (10° C.), stirred suspension of KOtBu (8.9 g, 0.080 mol) in DMSO (40 mL) was added a solution of 4-fluoronitrobenzene (11.2 g, 0.080 mol) and 3-chloropropanethiol (8.8 g, 0.080 mol) in DMSO (40 mL) over 10 minutes. The mixture was stirred at room temperature for 3.5 hours, diluted with water (1000 ml), and extracted with ether. The extracts were washed with brine, dried (MgSO4), and concentrated. Purification by flash chromatography (10% EtOAc/hexane) gave 6.2 g (34%) of product as a yellow solid m.p. 45°-48° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C@@H:11]([CH2:13][NH:14][CH:15]([CH3:17])[CH3:16])[C@H:10]([C:18]([CH3:26])([CH3:25])[O:19][SiH2:20][C:21]([CH3:24])([CH3:23])[CH3:22])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:27][O:28][CH2:29][CH2:30][CH2:31][N:32]1[C:40]2[C:35](=[CH:36][CH:37]=[C:38]([C:41](O)=[O:42])[CH:39]=2)[C:34]([CH3:44])=[CH:33]1.O=C1N(P(Cl)(N2CCOC2=O)=O)CCO1.C(N(CC)CC)C>C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:12][C@@H:11]([CH2:13][N:14]([CH:15]([CH3:16])[CH3:17])[C:41]([C:38]2[CH:39]=[C:40]3[C:35]([C:34]([CH3:44])=[CH:33][N:32]3[CH2:31][CH2:30][CH2:29][O:28][CH3:27])=[CH:36][CH:37]=2)=[O:42])[C@H:10]([C:18]([CH3:26])([CH3:25])[O:19][SiH2:20][C:21]([CH3:24])([CH3:23])[CH3:22])[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)NC[C@@H]1CN(C(=O)OC(C)(C)C)C[C@H]1C(C)(C)O[SiH2]C(C)(C)C
Reactant: COCCCn1cc(C)c2ccc(C(=O)O)cc21
Agent: O=C1OCCN1P(=O)(Cl)N1CCOC1=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COCCCn1cc(C)c2ccc(C(=O)N(C[C@@H]3CN(C(=O)OC(C)(C)C)C[C@H]3C(C)(C)O[SiH2]C(C)(C)C)C(C)C)cc21
Reaction time: 3 h

Procedure:
A mixture of (3S,4R)-3-(tert-butyl-dimethyl-silanyloxymethyl)-4-(isopropylamino-methyl)-pyrrolidine-1-carboxylic acid tert-butyl ester (8.5 g, 22 mmol), 1-(3-methoxy-propyl)-3-methyl-1H-indole-6-carboxylic acid (7.6 g, 30.8 mmol), bis(2-oxo-3-oxazolidinyl)phosphinic chloride (7.84 g, 30.8 mmol) and triethylamine (12.3 mL, 88 mmol) in CH2Cl2 (425 mL) is refluxed overnight under a nitrogen atmosphere and then quenched by the addition of an aqueous saturated solution of NaHCO3. The organic layer is separated, and the aqueous phase is extracted 3 times with AcOEt. The combined organic extracts are concentrated in vacuo. The residual oil is taken up in a mixture of THF and MeOH, NaOH 1N is added to cleave the anhydride side product and the mixture stirred for 3 h. The solvents are concentrated, CH2Cl2 is added and the layers are separated. The aqueous one is then back extracted twice with CH2Cl2 and the combined organic extracts are washed with brine, dried over Na2SO4, filtered and concentrated. The crude product is used in the next step without further purification. TLC, Rf (AcOEt)=0.6. MS (LC-MS): 516.3 [M-Boc+H]+; tR (HPLC, Macherey-Nagel Nucleosil C18 column, 10-100% CH3CN/H2O/5 min, 100% CH3CN/3 min, CH3CN an H2O containing 0.1% TFA, flow: 1.5 mL/min): 8.60 min.
Reaction SMILES: [O:1]1[CH2:20][CH:2]1[CH2:3][N:4]1[CH2:9][CH2:8][CH:7]([C:10]2[C:14]3[CH:15]=[CH:16][C:17]([F:19])=[CH:18][C:13]=3[O:12][N:11]=2)[CH2:6][CH2:5]1.[CH2:21]1[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[CH2:24][CH2:23][NH:22]1.[C:31]([OH:38])(=[O:37])/[CH:32]=[CH:33]/[C:34]([OH:36])=[O:35]>C(O)(C)C.C(O)C>[C:31]([OH:38])(=[O:37])/[CH:32]=[CH:33]/[C:34]([OH:36])=[O:35].[C:31]([OH:38])(=[O:37])/[CH:32]=[CH:33]/[C:34]([OH:36])=[O:35].[F:19][C:17]1[CH:16]=[CH:15][C:14]2[C:10]([CH:7]3[CH2:8][CH2:9][N:4]([CH2:3][CH:2]([OH:1])[CH2:20][N:22]4[CH2:23][CH2:24][C:25]5[C:30](=[CH:29][CH:28]=[CH:27][CH:26]=5)[CH2:21]4)[CH2:5][CH2:6]3)=[N:11][O:12][C:13]=2[CH:18]=1
Reactant: c1ccc2c(c1)CCNC2
Reactant: Fc1ccc2c(C3CCN(CC4CO4)CC3)noc2c1
Agent: O=C(O)/C=C/C(=O)O
Solvent: CCO
Solvent: CC(C)O
Product: OC(CN1CCC(c2noc3cc(F)ccc23)CC1)CN1CCc2ccccc2C1

Procedure:
A mixture of N-[3-(2,3-epoxy)propyl]-4-(6-fluoro-1,2-benzisoxaz-3-yl)piperidine (3.56 g, 12.9 mmol) and 1,2,3,4-tetrahydroisoquinoline (2.06 g, 15.4 mmol) in isopropyl alcohol (150 ml) was heated at reflux for 4 hours. At the end of the reaction, the solvent was removed. The residual oil was purified by flash chromatography over a silica gel column (SiO2, 45 g, eluted with 1% CH3OH: 99% methylene chloride). The product thus purified as a light oil, weighed 4.15 g. The oil was treated with a solution of fumaric acid (1.98 gm, 17 mmol) in ethanol. The white crystals so obtained were recrystallized in a large volume of hot ethanol (~150 ml). The recrystallized crystals weighed 2.75 g, m.p. 179°-181° C.
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:5]=[CH:6][C:7]([OH:10])=[CH:8][CH:9]=1)=[O:3].[C:11]([O:15][C:16]([NH:18][CH2:19][CH2:20]Br)=[O:17])([CH3:14])([CH3:13])[CH3:12].[I-].[K+].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[C:2]([C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:20][CH2:19][NH:18][C:16](=[O:17])[O:15][C:11]([CH3:14])([CH3:13])[CH3:12])=[CH:6][CH:5]=1)(=[O:3])[CH3:1]
Reactant: CC(C)(C)OC(=O)NCCBr
Reactant: CC(=O)c1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(=O)c1ccc(OCCNC(=O)OC(C)(C)C)cc1

Procedure:
To a solution of 4-hydroxyacetophenone (10 g) and 2-tert-butoxycarbonylaminoethylbromide (24.7 g) in N,N-dimethylformamide (50 ml) was added potassium iodide (12.2 g) and potassium carbonate (15.2 g).
Reaction SMILES: [Br:1][C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][C:3]=1[OH:13].[C:14]([O:17][CH2:18][CH2:19][CH2:20][CH2:21]I)(=[O:16])[CH3:15].[H-].[Na+]>CN(C=O)C>[C:14]([O:17][CH2:18][CH2:19][CH2:20][CH2:21][O:13][C:3]1[CH:4]=[C:5]([CH:11]=[CH:12][C:2]=1[Br:1])[C:6]([O:8][CH2:9][CH3:10])=[O:7])(=[O:16])[CH3:15]
Reactant: CCOC(=O)c1ccc(Br)c(O)c1
Reactant: CC(=O)OCCCCI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1ccc(Br)c(OCCCCOC(C)=O)c1
Temperature: 80 °C
Reaction time: 3 h

Procedure:
Ethyl 4-bromo-3-hydroxybenzoate (200 mg) was dissolved in DMF (10 ml) and 4-iodo-butyl acetate (195 μl) and sodium hydride (56 mg, 60% dispersion in mineral oil) were added and the reaction stirred at 80° C. under nitrogen for 3 hours. The reaction was quenched with water (5 ml) and the solvents evaporated under vacuum. The residue was partitioned between ethyl acetate/chloroform (1:1) and water. The organic phase was dried using a hydrophobic filter and the solvent evaporated in vacuo to give ethyl 3-{[4-(acetyloxy)butyl]oxy}-4-bromobenzoate as a yellow gel (318 mg).
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([O:10][CH2:11][CH3:12])[N:5]=[C:4]([NH2:13])[CH:3]=1.[S:14]1[CH:18]=[CH:17][CH:16]=[C:15]1[CH2:19][C:20](Cl)=[O:21].O>N1C=CC=CC=1>[NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([O:10][CH2:11][CH3:12])[N:5]=[C:4]([NH:13][C:20](=[O:21])[CH2:19][C:15]2[S:14][CH:18]=[CH:17][CH:16]=2)[CH:3]=1
Reactant: CCOc1nc(N)cc(N)c1C#N
Reactant: O=C(Cl)Cc1cccs1
Solvent: c1ccncc1
Solvent: O
Product: CCOc1nc(NC(=O)Cc2cccs2)cc(N)c1C#N
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 9.4 %

Procedure:
To 50 mg (0.28 mmol) of 4,6-diamino-2-ethoxy-nicotinonitrile in 1 mL of pyridine was added 150 μL (1.21 mmol) of 2-thiopheneacetyl chloride, dropwise. The mixture was stirred for 5 min at ambient temperature, then 1 mL of water was added. The mixture was stirred for an additional 30 minutes then concentrated under reduced pressure. The residue was taken up in 10 mL of ethyl acetate, extracted with water (2×5 mL), 1M HCl(aq.) (1×5 mL), saturated NaHCO3(aq.) (2×5 mL), and brine (1×5 mL), dried over MgSO4, filtered, and concentrated to an oil. This was partially purified via silica gel chromatography, eluting with 30% ethyl acetate:hexanes to provide a sticky, yellow solid. This was triturated with methanol to provide 8 mg (9%) of a white solid. 1H NMR (300 MHz, d6-DMSO) δ 10.33 (s, 1H), 7.38 (m, 1H), 7.18 (s, 1H), 6.97 (m, 2H), 6.92 (s, 2H), 4.34 (q, 2H, J=7.1 Hz), 3.94 (s, 2H), 1.30 (t, 3H, J=7.1 Hz); MS (ESI) m/e=275 (M−Et+H)+, 303 (M+H)+, 301 (M−H)−.
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[Na+].Br[CH2:6][CH2:7][CH2:8][O:9][C:10]1[CH:11]=[C:12]2[CH:15]([C:16]([N:18]3[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]3)=[O:17])[CH2:14][C:13]2=[CH:24][CH:25]=1.O>C(O)C.O>[N:1]([CH2:6][CH2:7][CH2:8][O:9][C:10]1[CH:11]=[C:12]2[CH:15]([C:16]([N:18]3[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23]3)=[O:17])[CH2:14][C:13]2=[CH:24][CH:25]=1)=[N+:2]=[N-:3]
Reactant: O=C(C1Cc2ccc(OCCCBr)cc21)N1CCCCC1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: [N-]=[N+]=NCCCOc1ccc2c(c1)C(C(=O)N1CCCCC1)C2

Procedure:
Sodium azide (2.4 g) is added to a stirred solution of 5-(3-bromopropoxy)-1-(1-piperidinylcarbonyl)benzocyclobutene (12.8 g) in ethanol/water (13 ml/130 ml). The reaction mixture is refluxed overnight, poured into water, washed with methylene chloride and the organic extract washed, dried, filtered and evaporated in vacuo affording the desired azide product as an oil, which is used in the next step without further purification.
Reaction SMILES: Cl[CH:2]1[C:11]2[C:6](=[C:7]([Cl:18])[CH:8]=[C:9]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[C:10]=2[CH3:12])[S:5][CH2:4][CH2:3]1.[CH2:19]([SH:21])[CH3:20].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[CH2:19]([S:21][CH:2]1[C:11]2[C:6](=[C:7]([Cl:18])[CH:8]=[C:9]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[C:10]=2[CH3:12])[S:5][CH2:4][CH2:3]1)[CH3:20]
Reactant: CCOC(=O)c1cc(Cl)c2c(c1C)C(Cl)CCS2
Reactant: CCS
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)c1cc(Cl)c2c(c1C)C(SCC)CCS2
Temperature: 25 °C
Reaction time: 48 h
Yield: 139.5 %

Procedure:
0.8 Gram (2.6 mmol) of 4,8-dichloro-5-methyl-6-ethoxycarbonylthiochroman was dissolved in 5 ml of N,N-dimethylformamide, and 0.15 ml (3.1 mmol) of ethanethiol and 0.43 g (3.1 mmol) of potassium carbonate were added. The mixture was stirred at room temperature for 2 days. After the completion of the reaction, 20 ml of water was added, and the reaction mixture was extracted with ethyl acetate twice. An organic layer was washed with water and with a saturated sodium chloride aqueous solution and dried over anhydrous sodium sulfate, and the solvent was distilled off to give 1.2 g (yield 100%) of 4-ethylthio-5-methyl-6-ethoxycarbonyl-8-chlorothiochroman.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:9]2[CH:17]=[CH:16][CH:15]=[C:14]3[C:10]=2[CH2:11][C:12](=[O:18])[NH:13]3)[CH:6]=[CH:7][CH:8]=1.[N:19]1([CH2:24][CH2:25][NH:26][C:27]([C:29]2[C:33]([CH3:34])=[C:32]([CH:35]=O)[NH:31][C:30]=2[CH3:37])=[O:28])[CH2:23][CH2:22][CH2:21][CH2:20]1>C(O)C.N1CCCCC1>[N:19]1([CH2:24][CH2:25][NH:26][C:27]([C:29]2[C:33]([CH3:34])=[C:32]([CH:35]=[C:11]3[C:10]4[C:14](=[CH:15][CH:16]=[CH:17][C:9]=4[C:5]4[CH:6]=[CH:7][CH:8]=[C:3]([O:2][CH3:1])[CH:4]=4)[NH:13][C:12]3=[O:18])[NH:31][C:30]=2[CH3:37])=[O:28])[CH2:23][CH2:22][CH2:21][CH2:20]1
Reactant: COc1cccc(-c2cccc3c2CC(=O)N3)c1
Reactant: Cc1[nH]c(C=O)c(C)c1C(=O)NCCN1CCCC1
Solvent: C1CCNCC1
Solvent: CCO
Product: COc1cccc(-c2cccc3c2C(=Cc2[nH]c(C)c(C(=O)NCCN4CCCC4)c2C)C(=O)N3)c1
Temperature: 25 °C
Reaction time: 72 h
Yield: 80.1 %

Procedure:
To a solution of 4-(3-methoxy-phenyl)-1,3-dihydro-indol-2-one (59.8 mg, 0.25 mmol) and 5-formyl-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (2-pyrrolidin-1-yl-ethyl)-amide (68.5 mg, 0.25 mmol) in ethanol (2 mL) was added piperidine (3 drops). The reaction mixture was stirred at room temperature for three days. The reaction solution was evaporated, and purified on a silica gel column eluting with MeOH—CH2Cl2 5:95 to provide pure product 5-[4-(3-Methoxy-phenyl)-2-oxo-1,2-dihydro-indol-3-ylidenemethyl]-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (2-pyrrolidin-1-yl-ethyl)-amide as a yellow solid (97 mg, 80%).
Reaction SMILES: [CH:1]([N:4]1[CH2:9][CH2:8][CH:7]([OH:10])[CH2:6][CH2:5]1)([CH3:3])[CH3:2].C(N(CC)CC)C.[S:18](Cl)([CH3:21])(=[O:20])=[O:19]>C(Cl)Cl>[CH:1]([N:4]1[CH2:9][CH2:8][CH:7]([O:10][S:18]([CH3:21])(=[O:20])=[O:19])[CH2:6][CH2:5]1)([CH3:3])[CH3:2]
Reactant: CC(C)N1CCC(O)CC1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)N1CCC(OS(C)(=O)=O)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 100.3 %

Procedure:
1-Isopropyl-4-hydroxypiperidine (1 g, 6.98 mmol), DCM (10 ml) and triethylamine (1.08 ml, 7.68 mmol) were cooled to 0-5° C. and mesyl chloride (0.54 ml, 6.98 mmol) was added dropwise under N2. The reaction was allowed to warm to room temperature and stirred for 1 hour. The reaction was quenched with sat. NaHCO3 (20 ml) and the aqueous phase extracted with DCM (2×5 ml). The combined organic extracts were dried over MgSO4, filtered, washed with DCM and concentrated in vacuo to give the title compound (1.55 g, 100%) as a pale yellow oil.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([S:23][CH3:24])=[C:8]([S:10]([C:13]2[CH:21]=[C:20]([Br:22])[C:16]3[N:17]=[CH:18][NH:19][C:15]=3[CH:14]=2)(=[O:12])=[O:11])[CH:9]=1)=[O:4].[C:25]1(B(O)O)[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.[N+]1([O-])C=CC=CC=1.C(N(CC)CC)C>C(Cl)Cl.CC([O-])=O.CC([O-])=O.[Cu+2]>[CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([S:23][CH3:24])=[C:8]([S:10]([C:13]2[CH:21]=[C:20]([Br:22])[C:16]3[N:17]=[CH:18][N:19]([C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)[C:15]=3[CH:14]=2)(=[O:11])=[O:12])[CH:9]=1)=[O:4]
Reactant: OB(O)c1ccccc1
Reactant: COC(=O)c1cc(S(=O)(=O)c2cc(Br)c3nc[nH]c3c2)c(SC)s1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Agent: [O-][n+]1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)c1cc(S(=O)(=O)c2cc(Br)c3ncn(-c4ccccc4)c3c2)c(SC)s1
Yield: 51.3 %

Procedure:
4-(7-Bromo-3-phenyl-3H-benzoimidazole-5-sulfonyl)-5-methylsulfanyl-thiophene-2-carboxylic acid methyl ester was prepared according to literature (Lam, P. Y. S. et al., Tetrahedron Letters, 42:3415 (2001)) using 4-(7-bromo-3H-benzoimidazole-5-sulfonyl)-5-methylsulfanyl-thiophene-2-carboxylic acid methyl ester (20 mg, 44.7 μmol, Example 38: step e), phenylboronic acid (11.4 mg, 93.5 μmol), Cu(OAc)2 (8.5 mg, 46.8 μmol), pyridine N-oxide (4.7 mg, 49.2 μmol), triethylamine (13 μL, 93.3 μmol), and CH2Cl2 (1.5 mL) in a loosely-capped, 1-dram vial. The reaction mixture was diluted in CH2Cl2 and washed with water and brine. The organic layer was dried over magnesium sulfate. Removal of solvents in vacuo followed by preparative TLC afforded the title compound as a brown oil (12 mg, 51%). ESI-MS (m/z): Calcd. for C20H15N2O4S3: 522.9 (M+1); found: 525.0.
Reaction SMILES: [F:1][C:2]([F:45])([F:44])[C:3]1[CH:4]=[C:5]([C:13]([CH3:43])([CH3:42])[C:14]([N:16]([C:18]2[CH:19]=[N:20][C:21]([N:32]3[CH2:36][CH2:35][C@@H:34]([NH:37][S:38]([CH3:41])(=[O:40])=[O:39])[CH2:33]3)=[CH:22][C:23]=2[C:24]2[CH:29]=[CH:28][C:27]([F:30])=[CH:26][C:25]=2[CH3:31])[CH3:17])=[O:15])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[H-].[Na+].IC.[C:50](OCC)(=O)C>CN(C)C=O>[F:11][C:9]([F:10])([F:12])[C:7]1[CH:6]=[C:5]([C:13]([CH3:43])([CH3:42])[C:14]([N:16]([C:18]2[CH:19]=[N:20][C:21]([N:32]3[CH2:36][CH2:35][C@@H:34]([N:37]([S:38]([CH3:41])(=[O:40])=[O:39])[CH3:50])[CH2:33]3)=[CH:22][C:23]=2[C:24]2[CH:29]=[CH:28][C:27]([F:30])=[CH:26][C:25]=2[CH3:31])[CH3:17])=[O:15])[CH:4]=[C:3]([C:2]([F:1])([F:44])[F:45])[CH:8]=1
Reactant: CCOC(C)=O
Reactant: Cc1cc(F)ccc1-c1cc(N2CC[C@@H](NS(C)(=O)=O)C2)ncc1N(C)C(=O)C(C)(C)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CI
Product: Cc1cc(F)ccc1-c1cc(N2CC[C@@H](N(C)S(C)(=O)=O)C2)ncc1N(C)C(=O)C(C)(C)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 78 %

Procedure:
To a solution of 150 mg (0.227 mmol) (R)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(4-fluoro-2-methyl-phenyl)-6-(3-methanesulfonylamino-pyrrolidin-1-yl)-pyridin-3-yl]-N-methyl-isobutyramide in 1 ml dimethylformamide were added 15 mg (0.34 mmol) sodium hydride (55% dispersion in mineral oil) at room temperature. After stirring at room temperature for 30 min 39 mg (27 mmol) iodomethane were added. The reaction mixture was stirred at room temperature for 18 h, followed by dilution with 10 ml ethyl acetate and washing with 10 ml saturated sodium carbonate solution. The combined organic layers were dried over sodium sulfate, concentrated in vacuo and purified by flash chromatography to give 120 mg (78%) of the title compound as a white foam.
Reaction SMILES: C(N(CC)C(C)C)(C)C.[Br:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]2[N:18]=[C:19]([NH:22][C:23]([CH3:27])([CH3:26])[CH2:24][OH:25])[S:20][CH:21]=2)=[C:13]([F:28])[CH:12]=1.Cl[C:30](Cl)([O:32]C(=O)OC(Cl)(Cl)Cl)Cl>C(Cl)Cl>[Br:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]2[N:18]=[C:19]([N:22]3[C:23]([CH3:26])([CH3:27])[CH2:24][O:25][C:30]3=[O:32])[S:20][CH:21]=2)=[C:13]([F:28])[CH:12]=1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: CC(C)(CO)Nc1nc(-c2ccc(Br)cc2F)cs1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC1(C)COC(=O)N1c1nc(-c2ccc(Br)cc2F)cs1
Temperature: 0 °C
Reaction time: 3 h
Yield: 111.5 %

Procedure:
N,N-diisopropylethylamine (1.2 mL, 6.9 mmol) was added to a solution of 2-{[4-(4-bromo-2-fluorophenyl)-1,3-thiazol-2-yl]amino}-2-methylpropan-1-ol (1.0 g, 2.9 mmol), prepared in the previous step, in 50 mL of dry methylene chloride at 0° C. Triphosgene (1.0 g, 3.4 mmol) in 10 mL of dry methylene chloride was added drop-wise over 10 min. The orange solution was stirred at 0° C. for 3 h and then allowed to warm to room temperature. The reaction was washed with 2N HCl and the aqueous layer was extracted with methylene chloride. The organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure to give 1.2 g of a green residue. The crude product was purified on silica gel using a step-wise gradient of 5-30% ethyl acetate:hexane to give the title compound (0.9 g, 89%). MS (ES) m/z 372 [M+H]+.
Reaction SMILES: [CH2:1]([N:5]1[CH:9]=[CH:8][N:7]=[N:6]1)[CH2:2][CH:3]=[CH2:4].C([Si]([O:17][C:18]1[CH:23]=[CH:22][C:21](I)=[CH:20][CH:19]=1)(C)C)(C)(C)C.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C(N(CC)CC)C>[N:5]1([CH2:1][CH2:2][CH:3]=[CH:4][C:21]2[CH:22]=[CH:23][C:18]([OH:17])=[CH:19][CH:20]=2)[CH:9]=[CH:8][N:7]=[N:6]1
Reactant: C=CCCn1ccnn1
Reactant: CC(C)(C)[Si](C)(C)Oc1ccc(I)cc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Product: Oc1ccc(C=CCCn2ccnn2)cc1
Temperature: 25 °C

Procedure:
A mixture of 3.00 g (24.4 mmol) 1-but-3-enyl-1H-[1,2,3]triazole, 6.79 g (20.3 mmol) tert-butyl-(4-iodo-phenoxy)-dimethyl-silane, 1.07 g (4.06 mmol) triphenylphosphine, 0.685 g (3.05 mmol) palladium(II)acetate and 56 ml triethylamine was heated to reflux for 24 h. The reaction mixture was cooled to r.t., evaporated, stirred with ice and adjusted to pH=1 by addition of conc. HCl. The organic material was collected with ethyl acetate/dichloromethane 1:2, the organic phase dried over sodium sulfate and evaporated. The residue was stirred with 20.3 ml 1M solution of tetrabutylammonium fluoride solution in THF at 28° C. for 3 h. After removal of THF, the residue was dissolved in dichloromethane, washed with water, evaporated and purified by chromatography on silica gel (ethyl acetate/n-heptane 5:1). The product containing fractions were collected, evaporated and stirred with little ethyl acetate/n-heptane 3:1 to yield 1.53 g (29%).