Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([CH2:4][CH2:5][O:6][C:7]2[CH:19]=[CH:18][C:10]([C:11]([NH:13][CH2:14][C:15]([OH:17])=[O:16])=[O:12])=[CH:9][CH:8]=2)[CH2:3][CH2:2]1.O[C:21]1[CH:30]=CC(C(OC)=O)=C[CH:22]=1.C1(CCO)C=CC=CC=1>>[C:1]1([CH2:4][CH2:5][O:6][C:7]2[CH:8]=[CH:9][C:10]([C:11]([NH:13][CH2:14][C:15]([OH:17])=[O:16])=[O:12])=[CH:18][CH:19]=2)[CH:3]=[CH:2][CH:30]=[CH:21][CH:22]=1
Reactant: COC(=O)c1ccc(O)cc1
Reactant: O=C(O)CNC(=O)c1ccc(OCCC2CC2)cc1
Solvent: OCCc1ccccc1
Product: O=C(O)CNC(=O)c1ccc(OCCc2ccccc2)cc1
Yield: 74 %

Procedure:
The same reactions as in Example 9 (9a) and (9b) were conducted using methyl 4-hydroxybenzoate (2.23 g, 14.7 mmol) and 2-phenylethanol (1.80 mL, 15.1 mmol) to give 3.23 g of the title compound (light yellow powder, yield: 74%).
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[N:14]=C(C)O[N:11]=2)=[CH:6][C:5]=1[NH:16][CH2:17][C:18]([O:20]CC1C=CC=CC=1)=[O:19].[CH2:28]([C:30]1[CH:31]=[C:32]([CH:36]=[CH:37][CH:38]=1)[C:33](O)=[O:34])[CH3:29]>>[C:10]([C:7]1[CH:8]=[CH:9][C:4]([CH2:3][NH:2][C:33](=[O:34])[C:32]2[CH:36]=[CH:37][CH:38]=[C:30]([CH2:28][CH3:29])[CH:31]=2)=[C:5]([NH:16][CH2:17][C:18]([OH:20])=[O:19])[CH:6]=1)(=[NH:11])[NH2:14]
Reactant: CCc1cccc(C(=O)O)c1
Reactant: Cc1nc(-c2ccc(CN)c(NCC(=O)OCc3ccccc3)c2)no1
Agent: Cl
Product: CCc1cccc(C(=O)NCc2ccc(C(=N)N)cc2NCC(=O)O)c1

Procedure:
Compound 58d was reacted with 3-ethylbenzoic acid and subsequently hydrogenated according to the procedure described in Example 58, to give Example 59. ESI-MS m/e 355.5 (M+1).
Reaction SMILES: [Na].Br[CH2:3][C:4]([O:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=O>C1(C)C=CC=CC=1.[Br-].C([N+](CCCC)(CCCC)CCCC)CCC>[CH3:12][CH2:13][CH2:8][CH2:9][CH2:10][CH3:11].[CH3:3][CH2:4][O:6][CH2:7][CH3:8]
Reactant: O=C(CBr)OCc1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [Na]
Solvent: Cc1ccccc1
Product: CCCCCC
Product: CCOCC
Yield: 141 %

Procedure:
Sodium salt H-1a (1.13 g; 3.15 mmol) was suspended in 5 mL dry toluene and tetra-n-butyl ammonium bromide (0.10 g; 0.3 mmol) and benzyl bromoacetate (0.79 g; 3.45 mmol) were added and the solution was refluxed for 24 h. The solvent was removed and methylene chloride added to the residue. The solution was filtered through silica gel, the filtrate was evaporated and the crude product E-1k purified by flash chromatography using silica gel and a hexane/ether gradient (0.39 g; 26% yield). 1H NMR (CDCl3): δ0.95 (dd,6H), 1.45 (s,9H), 1.78 (m,2H), 1.92 (m,1H), 3.28-3.55 (m,4H), 4.08 (t,1H), 4.32 (s,2H), 5.07 (br t, 1H), 5.21 (s,2H), 7.34 (m,5H). 13C NMR: δ22.36, 24.34, 28.26, 39.03, 39.64, 40.42, 47.87, 64.77, 67.89, 79.71, 128.28, 128.37, 128.57, 134.59, 155.78, 165.38, 166.84. This derivative of E-1, E-1k, can be readily deblocked and elaborated further to yield additional inhibitors.
Reaction SMILES: [C:1](O)([C:3]([F:6])([F:5])[F:4])=[O:2].[O:8]=[C:9]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[C:11]2([CH2:16][CH2:15][N:14](C(OC(C)(C)C)=O)[CH2:13][CH2:12]2)[CH2:10]1.C(N(CC)CC)C.FC(F)(F)C(OC(=O)C(F)(F)F)=O>ClCCl.CN(C1C=CN=CC=1)C>[F:4][C:3]([F:6])([F:5])[C:1]([N:14]1[CH2:15][CH2:16][C:11]2([C:24]3[C:29](=[CH:28][CH:27]=[CH:26][CH:25]=3)[C:9](=[O:8])[CH2:10]2)[CH2:12][CH2:13]1)=[O:2]
Reactant: O=C(O)C(F)(F)F
Reactant: CC(C)(C)OC(=O)N1CCC2(CC1)CC(=O)c1ccccc12
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Product: O=C1CC2(CCN(C(=O)C(F)(F)F)CC2)c2ccccc21
Temperature: 25 °C
Reaction time: 2 h
Yield: 92 %

Procedure:
TFA (25 mL) was added to a solution of commercially available tert-butyl 3-oxo-2,3-dihydrospiro[indene-1,4′-piperidine]-1′-carboxylate (5.0 g, 16.6 mmol) in dichloromethane (25 mL) at 0° C. The reaction was then allowed to warm to rt for 30 min. The reaction was evaporated and dried under high vacuum for 30 min. The crude amine was dissolved in dichloromethane (25 mL) and triethylamine (6.9 mL, 49.8 mmol), trifluoroacetic anhydride (2.6 mL, 18.3 mmol) and DMAP (20 mg, 0.17 mmol) were added in that order. The reaction was stirred at rt for 2 h and then diluted in dichloromethane and washed with water, sat. NH4Cl solution and brine. The organics were then dried (MgSO4), filtered and evaporated to give 19a as a light yellow solid (4.55 g, 92%). (M+H)+=298. 1H NMR (400 MHz, CDCl3) δ ppm 7.75 (d, J=7.6 Hz, 1H); 7.66 (t, J=7.0 Hz, 1H); 7.48 (d, J=7.9 Hz, 1H); 7.44 (t, J=7.5 Hz, 1H); 4.69 (d, J=15.9 Hz, 1H); 4.13 (d, J=14.1 Hz, 1H); 3.30 (t, J=11.8 Hz, 1H); 2.90 (t, J=13.4 Hz, 1H); 2.68 (m, 2H); 2.05 (dt, J=13.6, 3.8 Hz, 2H); 1.66 (d, J=13.9 Hz, 2H).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([N:11]2[C@@H:15]([C:16](=O)[CH:17]=[N+]=[N-])[CH2:14][CH2:13][C@@H:12]2C(=O)C=[N+]=[N-])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].Br.O.[NH2:28][C:29]([NH2:31])=[S:30].CCO[CH2:35][CH3:36]>>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([N:11]2[C@@H:15]([C:16]3[N:28]=[C:29]([NH2:31])[S:30][CH:17]=3)[CH2:14][CH2:13][C@@H:12]2[C:35]2[N:28]=[C:29]([NH2:31])[S:30][CH:36]=2)=[CH:7][CH:6]=1)([CH3:2])([CH3:4])[CH3:3]
Reactant: NC(N)=S
Reactant: CCOCC
Reactant: CC(C)(C)c1ccc(N2[C@@H](C(=O)C=[N+]=[N-])CC[C@@H]2C(=O)C=[N+]=[N-])cc1
Agent: Br
Solvent: O
Product: CC(C)(C)c1ccc(N2[C@@H](c3csc(N)n3)CC[C@@H]2c2csc(N)n2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 77 %

Procedure:
A solution of the product from Example 214D (0.50 g, 1.47 mmol) in Et2O (10 mL) was treated dropwise with 48% aq. hydrogen bromide (0.500 mL, 4.42 mmol). The resulting mixture was stirred at rt for 30 min. Water (1 mL) was added, and the mixture was extracted with Et2O (3×10 mL). The combined organic layers were dried over Na2SO4, filtered, and concentrated in vacuo. The residue was dissolved in EtOH (15 mL). To the resulting solution was added thiourea (0.45 g, 5.89 mmol), and the resulting mixture was stirred at rt for 1 h and then concentrated to ca. 1 mL. Water (10 mL) was added, and the pH was neutralized using saturated aq. NaHCO3. The resulting solid was collected by filtration and dried in vacuo to give the title compound (0.455 g, 77%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[C:18]([CH3:23])[C:17]=1[CH3:24].Cl[C:26](Cl)([O:28][C:29](=[O:35])OC(Cl)(Cl)Cl)Cl.OC1[CH:45]=[CH:44][C:41]([C:42]#[N:43])=[CH:40][CH:39]=1.C(=O)(O)[O-].[Na+]>C(Cl)Cl.C(N(CC)CC)C.C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH:20][C:29](=[O:35])[O:28][C:26]2[CH:45]=[CH:44][C:41]([C:42]#[N:43])=[CH:40][CH:39]=2)=[C:18]([CH3:23])[C:17]=1[CH3:24]
Reactant: COc1cc2nccc(Oc3ccc(N)c(C)c3C)c2cc1OC
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: N#Cc1ccc(O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: COc1cc2nccc(Oc3ccc(NC(=O)Oc4ccc(C#N)cc4)c(C)c3C)c2cc1OC
Yield: 55.3 %

Procedure:
4-[(6,7-Dimethoxy-4-quinolyl)oxy]-2,3-dimethylaniline (50 mg) was added to toluene (5 ml) and triethylamine (0.5 ml), and the mixture was heated under reflux to prepare a solution. A solution of triphosgene (68 mg) in methylene chloride was then added thereto, and the mixture was heated under reflux for 10 min. Next, 4-hydroxybenzonitrile (27 mg) was added thereto, and the mixture was further stirred with heating under reflux for 3 hr. A saturated aqueous sodium bicarbonate solution was added to stop the reaction, and the reaction solution was then extracted with chloroform, followed by washing with a 1 N aqueous hydrochloric acid solution, water, and saturated brine in that order. The extract was dried over sodium sulfate and was then concentrated. The residue was purified on a column using chloroform/methanol to give the title compound (40 mg, yield 53%).
Reaction SMILES: [Cl-].[In+3].[Cl-].[Cl-].FC(F)(F)C(O)=O.[Cl:12][C:13]1[CH:18]=[CH:17][C:16]([CH:19](O)[CH:20]2[CH2:22][CH:21]2[C:23]#[N:24])=[C:15]([F:26])[CH:14]=1.[F:27][C:28]1[CH:29]=[C:30]2[C:34](=[C:35]([CH2:37][S:38]([CH3:41])(=[O:40])=[O:39])[CH:36]=1)[NH:33][CH:32]=[CH:31]2>ClCCl>[Cl:12][C:13]1[CH:18]=[CH:17][C:16]([CH:19]([C:31]2[C:30]3[C:34](=[C:35]([CH2:37][S:38]([CH3:41])(=[O:39])=[O:40])[CH:36]=[C:28]([F:27])[CH:29]=3)[NH:33][CH:32]=2)[CH:20]2[CH2:22][CH:21]2[C:23]#[N:24])=[C:15]([F:26])[CH:14]=1
Reactant: N#CC1CC1C(O)c1ccc(Cl)cc1F
Reactant: CS(=O)(=O)Cc1cc(F)cc2cc[nH]c12
Agent: [Cl-]
Agent: [In+3]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CS(=O)(=O)Cc1cc(F)cc2c(C(c3ccc(Cl)cc3F)C3CC3C#N)c[nH]c12

Procedure:
471 mg (2.13 mmol) of indium(III) chloride and 0.25 ml (3.19 mmol) of trifluoroacetic acid were added to 400 mg (1.77 mmol) of the compound from Example 165A and 483 mg (2.13 mmol) of the compound from Example 87A under argon in 18 ml of dichloromethane, and the mixture was heated under reflux for 3 days. It was concentrated and the residue was taken up in ethyl acetate, washed with saturated aqueous sodium bicarbonate solution and saturated aqueous sodium chloride solution, dried over sodium sulfate, filtered and concentrated. The residue was purified by preparative HPLC (RP18 column; mobile phase: acetonitrile/water gradient with addition of 0.1% formic acid) and another RP18 separation with acetonitrile/water 55:45 to result in 131 mg (17% of theory) of diastereomer 1 and 127 mg (17% of theory) of diastereomer 2 of the title compound.
Reaction SMILES: [O:1]=[C:2]([N:19]1[CH2:23][CH2:22][CH2:21][CH2:20]1)[CH2:3][CH:4]([CH2:8][S:9]([CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)(=[O:11])=[O:10])[C:5]([OH:7])=O.O[C:25](C(F)(F)F)=O.[NH2:31][CH:32]([CH3:43])[CH:33]([C:35]1[O:36][C:37]([CH2:40][O:41][CH3:42])=[N:38][N:39]=1)[OH:34].C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl.CN1CCOCC1>C(Cl)Cl>[OH:34][CH:33]([C:35]1[O:36][C:37]([CH2:40][O:41][CH3:42])=[N:38][N:39]=1)[CH:32]([NH:31][C:5](=[O:7])[CH:4]([CH2:8][S:9]([CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)(=[O:11])=[O:10])[CH2:3][C:2](=[O:1])[N:19]1[CH2:23][CH2:22][CH2:21][CH2:20]1)[CH2:43][CH3:25]
Reactant: COCc1nnc(C(O)C(C)N)o1
Reactant: O=C(O)C(F)(F)F
Reactant: O=C(O)C(CC(=O)N1CCCC1)CS(=O)(=O)Cc1ccccc1
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CN1CCOCC1
Solvent: ClCCCl
Product: CCC(NC(=O)C(CC(=O)N1CCCC1)CS(=O)(=O)Cc1ccccc1)C(O)c1nnc(COC)o1
Reaction time: 14 h
Yield: 24.7 %

Procedure:
To a stirred mixture of 4-oxo-2-benzylsulfonylmethyl-4-pyrrolidin-1-yl-butyric acid (220 mg, 0.65 mmol), 2-amino-1-(5-methoxymethyl-1,3,4-oxadiazole-2-yl)-1-propanol TFA salt (204 mg), prepared as in reference 15, and HOBt (119 mg, 0.78 mmol) in MeCl2 (5 ml), was added EDC (187 mg, 0.98 mmol) and N-methylmorpholine (0.35 ml) at room temperature. After stirring for 14 hours, the reaction mixture was extracted with ethyl acetate. The organic layer was washed with saturated NaHCO3, brine, dried with MgSO4 and concentrated to yield 84 mg of N-{1-[Hydroxy-(5-methoxymethyl-[1,3,4]oxadiazol-2-yl)-methyl]-propyl}-4-oxo-2-benzylsulfonylmethyl-4-pyrrolidin-1-yl-butyramide. Without further purification, the crude product was used for next reaction; MS: 521.6(M−1), 523.2(M+1).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8](=[NH:10])[NH2:9])[CH:5]=[CH:6][CH:7]=1.CN(C)[CH:13]=[O:14].[OH2:16]>>[F:1][C:2]1[CH:3]=[C:4]([C:8]2[N:9]=[CH:5][C:4]([C:8]([O:14][CH3:13])=[O:16])=[CH:3][N:10]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: CN(C)C=O
Reactant: O
Reactant: N=C(N)c1cccc(F)c1
Product: COC(=O)c1cnc(-c2cccc(F)c2)nc1
Temperature: 100 °C
Yield: 59 %

Procedure:
To a solution of methyl 3,3-dimethoxypropionate (304 g, 2.05 mol) in dimethoxyethane (1.5 L) was added methyl formate (580 g, 9.44 mol). Sodium hydride (98.5 g, 60% suspension in mineral oil, 2.46 mol) was added portion-wise and the mixture was stirred at 50° C. for 5 hours and then at room temperature overnight. Diethyl ether (1.5 L) was added and the reaction was filtered under an atmosphere of nitrogen. The solid residue was washed with diethyl ether (300 mL ×2) and dried to give 200 g (68.9%) of [methyl-2-(dimethoxymethyl)-3-(hydroxyl-kappaO)acrylatato]sodium. A mixture of this compound (63.5 g, 0.32 mol), 3-fluorobenzenecarboximidamide (38 g, 0.27 mol) and dimethylformamide (400 mL) was heated at 100° C. for 2 h. After this time the reaction was cooled to room temperature and water (400 mL) was added. The reaction was filtered and the residue was washed with water (100 mL x2) and dried to give 37 g (yield 59%) of methyl 2-(3-fluorophenyl)pyrimidine-5-carboxylate.
Reaction SMILES: [C:1]([O:7][CH2:8][N:9]1[C:13]2[N:14]=[CH:15][N:16]=[C:17](Cl)[C:12]=2[CH:11]=[CH:10]1)(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3].[CH:19]1([CH:24]([N:28]2[CH:32]=[C:31](B3OC(C)(C)C(C)(C)O3)[CH:30]=[N:29]2)[CH2:25][C:26]#[N:27])[CH2:23][CH2:22][CH2:21][CH2:20]1.COCCOC.O.C(=O)([O-])[O-].[K+].[K+]>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>[C:1]([O:7][CH2:8][N:9]1[C:13]2[N:14]=[CH:15][N:16]=[C:17]([C:31]3[CH:30]=[N:29][N:28]([CH:24]([CH:19]4[CH2:23][CH2:22][CH2:21][CH2:20]4)[CH2:25][C:26]#[N:27])[CH:32]=3)[C:12]=2[CH:11]=[CH:10]1)(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3]
Reactant: CC(C)(C)C(=O)OCn1ccc2c(Cl)ncnc21
Reactant: CC1(C)OB(c2cnn(C(CC#N)C3CCCC3)c2)OC1(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: COCCOC
Solvent: O
Product: CC(C)(C)C(=O)OCn1ccc2c(-c3cnn(C(CC#N)C4CCCC4)c3)ncnc21
Temperature: 82 °C
Reaction time: 6 h
Yield: 88.4 %

Procedure:
Method B. Into a 50 ml round bottom flask equipped with a stir bar, condenser and 3-way valve connected to nitrogen and vacuum was charged (4-chloro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl pivalate (3f, 700 mg, 2.61 mmol), 3-cyclopentyl-3-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl]propanenitrile (23, 935 mg, 2.97 mmol, 1.13 equiv), 1,2-dimethoxyethane (DME, 10 mL, 96 mmol), water (5 mL, 0.28 mol) and potassium carbonate (K2CO3, 1.82 g, 7.84 mmol, 3.0 equiv) at room temperature. The resulting reaction mixture was degassed three times back filling with nitrogen each time before being charged tetrakis(triphenylphosphine)palladium(0) (30 mg, 0.026 mmol, 0.010 equiv). The resulting reaction mixture was degassed four times back filling with nitrogen each time and then warmed to 82° C. The reaction mixture was stirred at 82° C. for 6 hours. When the reaction was deemed complete, the reaction mixture was cooled to room temperature before being diluted with ethyl acetate (45 mL) and water (10 mL). The resulting mixture was stirred until the majority of solids had gone into solution. The two layers were separated, and the aqueous layer was extracted with ethyl acetate (1×25 mL). The combined organic fractions were washed with aqueous brine (2×25 mL), dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by flash chromatography (SiO2, 0-50% ethyl acetate/hexane gradient elution) to afford racemic 4-(1-(2-cyano-1-cyclopentylethyl)-1H-pyrazol-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl pivalate (20, 0.97 g, 1.1 g theoretical, 88.6% yield) as colorless oil, which solidified upon standing at room temperature in vacuo. For 20: 1H NMR (CDCl3, 300 MHz) δ 8.85 (s, 1H), 8.29 (s, 1H), 8.27 (s, 1H), 7.45 (d, 1H, J=3.8 Hz), 6.73 (d, 1H, J=3.8 Hz), 6.22 (s, 2H), 4.23 (ddd, 1H, J=10.0, 8.6, 4.0 Hz), 3.10 (dd, 1H, J=17.0, 8.6 Hz), 2.92 (dd, 1H, J=17.0, 4.0 Hz), 2.56 (m, 1H), 2.0-1.25 (m, 8H), 1.12 (s, 9H); C23H28N6O2 (MW, 420.51), LCMS (EI) m/e 421 (M++H).
Reaction SMILES: C(NC(C)C)(C)C.[Li][CH2:9][CH2:10][CH2:11][CH3:12].[N:13]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH:17]=CC=1C.CI>C1COCC1>[CH2:11]([C:10]1[CH:9]=[CH:17][C:18]2[C:23](=[CH:22][CH:21]=[CH:20][CH:19]=2)[N:13]=1)[CH3:12]
Reactant: [Li]CCCC
Reactant: Cc1ccc2ccccc2n1
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Solvent: CI
Product: CCc1ccc2ccccc2n1
Temperature: -78 °C
Reaction time: 0.17 h

Procedure:
To a 0.40 M solution of diisopropyl amine in THF at −10° C. was added slowly 1.0 equiv of a solution of n-BuLi (2.5 M/hexane). After 10 min, the mixture was cooled to −78° C. and 0.9 equiv of quinaldine was added dropwise. The red/orange solution was then stirred at 0° C. for 1 h. MeI was then added and the reaction was stirred at room temperature for 2 h. The reaction was quenched with aqueous NH4Cl solution, and then extracted with EtOAc. The organic phase was washed with H2O and brine. The solution was then dried (MgSO4), filtered, and evaporated. The crude material was purified by flash chromatography with 1:10 EtOAc:hexanes to give the title compound as a pale yellow oil.
Reaction SMILES: [CH:1](NC(C)C)(C)C.C([Li])CCC.[CH2:13]([N:20]1[CH2:25][CH2:24][CH:23]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:22][CH2:21]1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.CI>O1CCCC1>[CH2:13]([N:20]1[CH2:25][CH2:24][C:23]([CH3:1])([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:22][CH2:21]1)[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: CC(C)NC(C)C
Reactant: CC(C)(C)OC(=O)C1CCN(Cc2ccccc2)CC1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CI
Product: CC(C)(C)OC(=O)C1(C)CCN(Cc2ccccc2)CC1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
To a solution of N,N-diisopropylamine (3.1 mL, 22 mmol) in tetrahydrofuran (60 mL) cooled at −78° C. was added n-butyllithium (2.5N solution in hexanes, 8.9 mL, 22 mmol) dropwise over 5 minutes and the mixture was stirred for 30 minutes at −78° C. A solution of tert-butyl 1-benzylpiperidine-4-carboxylate (5.0 g, 20 mmol) in tetrahydrofuran (40 mL) was then added to the reaction mixture dropwise over 10 min and the temperature was maintained at −78° C. for 30 minutes before methyl iodide (1.3 mL, 21 mmol) was added in one portion. The reaction mixture was warmed to ambient temperature and stirred for 1 hour. The reaction was quenched with water (100 mL) and diluted with ethyl acetate (50 mL). The organic layer was separated and the aqueous layer was extracted with ethyl acetate (3×50 mL). The combined organic portions were dried over sodium sulfate, filtered, concentrated in vacuo, and purified flash chromatography (silica, 40 g, ISCO, 0-100% ethyl acetate in heptanes) to afford the title compound as a colorless oil, which was used in the next step without any further purification (5.3 g, 90%).
Reaction SMILES: Br[C:2]1[C:10]2[C:5](=[CH:6][N:7]=[C:8]([C:11]3[C:16]([CH2:17][CH3:18])=[CH:15][CH:14]=[CH:13][C:12]=3[CH2:19][CH3:20])[CH:9]=2)[N:4]([C:21]2[CH:26]=[CH:25][C:24]([CH:27]([CH3:29])[CH3:28])=[CH:23][CH:22]=2)[CH:3]=1.C([Sn](CCCC)(CCCC)[C:35]1[S:36][CH:37]=[CH:38][N:39]=1)CCC.CN(C=O)C>CCOC(C)=O.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>[CH2:19]([C:12]1[CH:13]=[CH:14][CH:15]=[C:16]([CH2:17][CH3:18])[C:11]=1[C:8]1[CH:9]=[C:10]2[C:2]([C:35]3[S:36][CH:37]=[CH:38][N:39]=3)=[CH:3][N:4]([C:21]3[CH:22]=[CH:23][C:24]([CH:27]([CH3:29])[CH3:28])=[CH:25][CH:26]=3)[C:5]2=[CH:6][N:7]=1)[CH3:20]
Reactant: CCc1cccc(CC)c1-c1cc2c(Br)cn(-c3ccc(C(C)C)cc3)c2cn1
Reactant: CCCC[Sn](CCCC)(CCCC)c1nccs1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCc1cccc(CC)c1-c1cc2c(-c3nccs3)cn(-c3ccc(C(C)C)cc3)c2cn1
Temperature: 100 °C
Reaction time: 18 h

Procedure:
A mixture of 3-bromo-5-(2,6-diethyl-phenyl)-1-(4-isopropyl-phenyl)-1H-pyrrolo[2,3-c]pyridine (50 mg, 0.11 mmol), 2-tributylstannanyl-thiazole (83 mg, 0.22 mmol), Pd(PPh3)4 (20 mg, 0.017 mmol), and DMF (3 mL) is stirred under nitrogen at 100° C. for 18 h. The mixture is diluted with EtOAc (15 mL) and washed with water and brine, dried (Na2SO4), and concentrated under reduced pressure. Chromatography of the residue gives 5-(2,6-diethyl-phenyl)-1-(4-isopropyl-phenyl)-3-thiazol-2-yl-1H-pyrrolo[2,3-c]pyridine as colorless oil: 1H NMR (CDCl3) 9.03 (s, 1H), 8.15 (s, 1H), 7.84 (d, J=1 Hz, 1H), 7.56 (d, J=12 Hz, 2H), 7.46 (d, J=12 Hz, 2H), 7.32 (t, J=7 Hz, 1H), 7.31-7.26 (m, 3H), 7.20 (s, 1H), 3.05 (m, 1H), 2.39 (m, 4H), 1.35 (d, J=8 Hz, 6H), 1.09 (t, J=8 Hz, 6H); LCMS m/z 452.23 (2.93 min).
Reaction SMILES: [C:1]([C:5]1[C:17]([N:18]([CH3:20])[CH3:19])=[CH:16][C:8]([CH:9](O)CS(C)(=O)=O)=[CH:7][C:6]=1[N:21]([CH3:23])[CH3:22])([CH3:4])([CH3:3])[CH3:2].C[O-].[Na+].[NH:27]([CH2:34][CH2:35][C:36]#[N:37])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>CS(C)=O>[NH:27]([CH:34]=[C:35]([CH2:9][C:8]1[CH:7]=[C:6]([N:21]([CH3:23])[CH3:22])[C:5]([C:1]([CH3:4])([CH3:2])[CH3:3])=[C:17]([N:18]([CH3:19])[CH3:20])[CH:16]=1)[C:36]#[N:37])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: CN(C)c1cc(C(O)CS(C)(=O)=O)cc(N(C)C)c1C(C)(C)C
Reactant: N#CCCNc1ccccc1
Agent: C[O-]
Agent: [Na+]
Solvent: CS(C)=O
Product: CN(C)c1cc(CC(C#N)=CNc2ccccc2)cc(N(C)C)c1C(C)(C)C

Procedure:
A mixture of 4.66 g. of 4-tert. butyl-3,5-bis(dimethylamino)-α-[(methylsulfonyl)methyl]benzyl alcohol, 1.28 g. of sodium methylate and 3.3 g. of β-anilinopropionitrile in 35 ml. of dimethylsulfoxide was stirred at room temperature under nitrogen for 60 minutes. The mixture was poured into 200 ml. of ice water, the separated oil extracted with ethyl acetate, the ethyl acetate solution dried over sodium sulfate and then evaporated. By purification of the residue over aluminum oxide with benzene and recrystallization from ethanol, there was obtained α-(anilinomethylene)-4 -tert. butyl-3,5-bis(dimethylamino)hydrocinnamonitrile having a melting point of 150° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([C:11](=[C:14]([NH:17][C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([C:24]#[N:25])[CH:19]=2)SC)[C:12]#[N:13])(=[O:10])=[O:9])=[CH:4][CH:3]=1.[CH:26]1([NH2:31])[CH2:30][CH2:29][CH2:28][CH2:27]1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([C:11](=[C:14]([NH:17][C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([C:24]#[N:25])[CH:19]=2)[NH:31][CH:26]2[CH2:30][CH2:29][CH2:28][CH2:27]2)[C:12]#[N:13])(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: CSC(Nc1cccc(C#N)c1)=C(C#N)S(=O)(=O)c1ccc(Cl)cc1
Reactant: NC1CCCC1
Product: N#CC(=C(Nc1cccc(C#N)c1)NC1CCCC1)S(=O)(=O)c1ccc(Cl)cc1
Yield: 16 %

Procedure:
2-(4-Chlorophenylsulfonyl)-3-(3-cyanophenylamino)-3-methylsulfanyl-2-propenenitrile(0.300 g, 0.6 mmol) was stirred in cyclopentylamine(1 ml) for 48 h at 100° C. under nitrogen in a sealed flask. Work up as described in Example 1, 2) gave 51 mg (16%) of the title compound as light brown crystals. 1H NMR (200 MHz, CDCl3): δ=1.43-1.54 (m, 4H), 1.68-1.78 (m, 4H), 3.64 (sextet, 1H), 7.07 (d, 1H), 7.21 (s, 1H), 7.40-7.55 (m, 6H), 7.77 (dd, 2H)