Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([S:3]([C:6]1[N:7]=[CH:8][N:9]2[CH:13]=[CH:12][S:11][C:10]=12)(=[O:5])=[O:4])[CH3:2].C([Li])CCC.CCCCCC.[CH2:25]([Sn:29](Cl)([CH2:34][CH2:35][CH2:36][CH3:37])[CH2:30][CH2:31][CH2:32][CH3:33])[CH2:26][CH2:27][CH3:28].[Cl-].[NH4+]>C1COCC1>[CH2:1]([S:3]([C:6]1[N:7]=[CH:8][N:9]2[CH:13]=[C:12]([Sn:29]([CH2:30][CH2:31][CH2:32][CH3:33])([CH2:34][CH2:35][CH2:36][CH3:37])[CH2:25][CH2:26][CH2:27][CH3:28])[S:11][C:10]=12)(=[O:4])=[O:5])[CH3:2]
Reactant: CCS(=O)(=O)c1ncn2ccsc12
Reactant: CCCC[Sn](Cl)(CCCC)CCCC
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CCCC[Sn](CCCC)(CCCC)c1cn2cnc(S(=O)(=O)CC)c2s1
Reaction time: 0.25 h

Procedure:
A solution of 669 mg of 7-ethanesulfonylimidazo[5,1-b]thiazole in 30 ml of THF was cooled to −40° C. in an argon atmosphere. A 1.6 N n-butyllithium/n-hexane solution (4.3 ml) was added dropwise thereto at the same temperature. The mixture was stirred for 15 min. Tri-n-butylstannyl chloride (0.88 ml) was added thereto, followed by stirring at the same temperature for 10 min. A saturated aqueous ammonium chloride solution was added thereto. The mixture was extracted twice with ethyl acetate. The extract was dried over anhydrous magnesium sulfate. The solvent was removed by distillation under the reduced pressure. The residue was purified by column chromatography on silica gel (hexane:ethyl acetate=1:1). The title compound (1.54 g) was obtained from the fraction of Rf=0.2.
Reaction SMILES: [OH-].[Na+].[Cl:3][C:4]1[C:5]([NH:10][CH2:11][C:12]([O:14]CC)=[O:13])=[N:6][CH:7]=[CH:8][N:9]=1.Cl>C(O)C>[Cl:3][C:4]1[C:5]([NH:10][CH2:11][C:12]([OH:14])=[O:13])=[N:6][CH:7]=[CH:8][N:9]=1
Reactant: CCOC(=O)CNc1nccnc1Cl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)CNc1nccnc1Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 22.5 %

Procedure:
A 2N aqueous sodium hydroxide solution (0.6 mL) was added to an ethanol solution (0.3 mL) of Compound 22 (194 mg) and the mixture was stirred at room temperature for 1 hour. 2N hydrochloric acid was then added to the reaction mixture while cooled with ice, and the mixture was neutralized. The product was extracted with chloroform (5 times). The organic layer was dried over sodium sulfate, filtered, and concentrated under reduced pressure to give 38 mg (23% yield) of the desired product.
Reaction SMILES: [C:1]1([C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[OH:4])[OH:2].[CH2:9]([C:11]1([O:15][CH2:14]1)[CH2:12]Cl)[CH3:10].[OH-].[Na+]>O>[OH:15][CH2:14][C:11]1([CH2:9][CH3:10])[O:4][C:3]2[CH:5]=[CH:6][CH:7]=[CH:8][C:1]=2[O:2][CH2:12]1
Reactant: Oc1ccccc1O
Reactant: CCC1(CCl)CO1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CCC1(CO)COc2ccccc2O1
Yield: 43.8 %

Procedure:
A stirred mixture of catechol (14.0 g), 2-ethyl-epichlorohydrin (15.3 g), sodium hydroxide (5.1 g) and water (50 ml) was heated at 90° under an atmosphere of nitrogen for 4 hours. On cooling water was added and the product was extracted with methylene chloride. The combined extracts were washed with 2 N aqueous sodium hydroxide solution, water and brine, dried and evaporated to leave an oil (10.8 g); IR νmax 3650-3200, 3000-2850 cm-1.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[CH3:8].N.[Cl-].[NH4+].[CH3:12][N:13](C=O)C>>[C:12]([C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[CH3:8])#[N:13]
Reactant: Cc1ccncc1Br
Reactant: CN(C)C=O
Agent: N
Agent: [Cl-]
Agent: [NH4+]
Product: Cc1ccncc1C#N

Procedure:
3-Bromo-4-methylpyridine (20.0 g, 116 mmol) is dissolved in DMF (100 ml), and thereto is added cuprous cyanide (11.6 g, 30 mmol), and the mixture is heated under reflux for 18 hours. After cooling, a 25% aqueous ammonia (200 ml) and a saturated aqueous ammonium chloride solution (200 ml) are added to the reaction solution, and the mixture is extracted with ethyl acetate (200 ml×5). The organic layer is washed with a saturated brine (100 ml), dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue is purified by silica gel column chromatography (eluent: ethyl acetate/hexane) to give the title compound (11.0 g) as colorless crystals, m.p. 75-78° C.
Reaction SMILES: [CH2:1]([N:8]([CH3:28])[C:9]1[NH:10][C:11](=[O:27])[C:12]2[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15][CH2:14][C:13]=2[N:26]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.F[B-](F)(F)F.[CH3:34][O+](C)C>C(Cl)Cl>[CH2:1]([N:8]([CH3:28])[C:9]1[N:10]=[C:11]([O:27][CH3:34])[C:12]2[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:23])([CH3:24])[CH3:25])=[O:20])[CH2:15][CH2:14][C:13]=2[N:26]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C[O+](C)C
Reactant: CN(Cc1ccccc1)c1nc2c(c(=O)[nH]1)CCN(C(=O)OC(C)(C)C)CC2
Agent: F[B-](F)(F)F
Solvent: ClCCl
Product: COc1nc(N(C)Cc2ccccc2)nc2c1CCN(C(=O)OC(C)(C)C)CC2
Reaction time: 2 h
Yield: 41 %

Procedure:
To a solution of tert-butyl 2-[benzyl(methyl)amino]-4-oxo-3,4,5,6,8,9-hexahydro-7H-pyrimido[4,5,d]azepine-7-carboxylate of Preparation 16, Step A (70 mg, 0.19 mmol) in DCM (2 ml) was added trimethyloxonium tetrafluoroborate (3 eq., 84.1 mg, 0.57 mmol) and the mixture was stirred for 2 h. The combined organic layers were combined, dried over MgSO4, filtered and concentrated in vacuo. The residue was purified by column chromatography eluting with ethyl actate/pentane (1:3 to 1:1). The relevant fractions were combined and concentrated in vacuo to afford the title compound as a colourless oil (31 mg, 41% yield).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([N:12]2[CH2:17][CH2:16][N:15]([S:18]([CH3:21])(=[O:20])=[O:19])[CH2:14][CH2:13]2)[CH:6]=[CH:7][C:8]=1[N+:9]([O-])=O.CO.[BH4-].[Na+]>C1COCC1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([N:12]2[CH2:17][CH2:16][N:15]([S:18]([CH3:21])(=[O:20])=[O:19])[CH2:14][CH2:13]2)[CH:6]=[CH:7][C:8]=1[NH2:9]
Reactant: COc1cc(N2CCN(S(C)(=O)=O)CC2)ccc1[N+](=O)[O-]
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: COc1cc(N2CCN(S(C)(=O)=O)CC2)ccc1N

Procedure:
1-[3-(Methyloxy)-4-nitrophenyl]-4-(methylsulfonyl)piperazine (1.09 g, 3.46 mmol) was suspended in 5 mL THF and 10 mL MeOH in a 100 mL round bottom flask. NiCl2-6H2O (0.247 g, 1.04 mmol) was added, followed by slow addition of NaBH4 (0.392 g, 10.38 mmol). The reaction mixture was adsorbed on SiO2 and purified via column chromatography to afford 2-(methyloxy)-4-[4-(methylsulfonyl)-1-piperazinyl]aniline. (0.925 g, 3.24 mmol, 93%). 1H NMR (400 MHz, DMSO-d6) δ ppm 2.91 (s, 3 H) 2.99-3.07 (m, 4 H) 3.19-3.27 (m, 4 H) 3.75 (s, 3 H) 4.28 (s, 2 H) 6.33 (dd, J=8.39, 2.43 Hz, 1 H) 6.49-6.58 (m, 2 H). ESIMS M+H)+=285.
Reaction SMILES: [CH2:1]([N:8]1[C:13](=[O:14])[CH:12]=[C:10]([CH3:11])[C:9]1=[O:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:16]([NH2:23])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>O1CCCC1>[CH2:1]([N:8]1[C:13](=[O:14])[CH2:12][C:10]([NH:23][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)([CH3:11])[C:9]1=[O:15])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC1=CC(=O)N(Cc2ccccc2)C1=O
Reactant: NCc1ccccc1
Solvent: C1CCOC1
Product: CC1(NCc2ccccc2)CC(=O)N(Cc2ccccc2)C1=O
Yield: 38 %

Procedure:
120.6 g (0.6 mol) of N-benzylcitraconimide and 65.2 g (0.6 mol) of benzylamine are heated to reflux in 600 ml of tetrahydrofuran for 16 hours. The solvent is then distilled off, and the residue is chromatographed on silica gel using ethyl acetate-petrol ether 1:1. This gives 76.2 g of an oil, which is 93% strength after analysis by gas chromatography (yield 38% of theory).
Reaction SMILES: Br[C:2]1[C:3]([O:21][CH2:22][CH3:23])=[C:4]([CH:11]([NH:13][C:14](=[O:20])[O:15][C:16]([CH3:19])([CH3:18])[CH3:17])[CH3:12])[CH:5]=[C:6]([Cl:10])[C:7]=1[C:8]#[N:9].[CH3:24][S:25]([C:28]1[CH:29]=[N:30][CH:31]=[C:32](B2OC(C)(C)C(C)(C)O2)[CH:33]=1)(=[O:27])=[O:26].C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1.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>[Cl:10][C:6]1[C:7]([C:8]#[N:9])=[C:2]([C:32]2[CH:31]=[N:30][CH:29]=[C:28]([S:25]([CH3:24])(=[O:27])=[O:26])[CH:33]=2)[C:3]([O:21][CH2:22][CH3:23])=[C:4]([CH:11]([NH:13][C:14](=[O:20])[O:15][C:16]([CH3:19])([CH3:18])[CH3:17])[CH3:12])[CH:5]=1
Reactant: CCOc1c(C(C)NC(=O)OC(C)(C)C)cc(Cl)c(C#N)c1Br
Reactant: CC1(C)OB(c2cncc(S(C)(=O)=O)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: C1COCCO1
Solvent: O
Product: CCOc1c(C(C)NC(=O)OC(C)(C)C)cc(Cl)c(C#N)c1-c1cncc(S(C)(=O)=O)c1
Temperature: 100 °C
Yield: 62.5 %

Procedure:
To tert-butyl [-1-(3-bromo-5-chloro-4-cyano-2-ethoxyphenyl)ethyl]carbamate (50 mg, 0.1 mmol, from Example 179, Step 3) and 3-(methylsulfonyl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (30. mg, 0.11 mmol, Peptech, catalog #BE358) in 1,4-dioxane (4 mL) was added potassium carbonate (30 mg, 0.2 mmol) in water (2 mL). The reaction was degassed with N2. Tetrakis(triphenylphosphine)palladium(0) (40 mg, 0.04 mmol) was added and degassed again with N2. The reaction was heated at 100° C. overnight. The reaction was allowed to cool to room temperature and was partitioned between EtOAc and water. The combined organic layer was washed with brine, dried over MgSO4, filtered and concentrated to give crude product. The product was purified by chromatography on silica gel eluting with a hexane:EtOAc gradient to give tert-butyl (1-{5-chloro-4-cyano-2-ethoxy-3-[5-(methylsulfonyl)pyridin-3-yl]phenyl}ethyl)carbamate as a yellow oil (0.030 g, 60%). LCMS calculated for C22H27ClN3O5S (M+H)+: m/z=480.1. found: 480.1.
Reaction SMILES: [NH2:1][C@H:2]([CH2:29][C:30]1[C:38]2[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=2)[N:32]([CH3:39])[CH:31]=1)[C:3]([NH:5][CH:6]1[CH2:15][C:14]2[C:9](=[C:10]([N:16]3[CH2:20][CH2:19][CH2:18][C:17]3=[O:21])[CH:11]=[CH:12][CH:13]=2)[N:8]([CH2:22][C:23]2[CH:27]=[CH:26][S:25][CH:24]=2)[C:7]1=[O:28])=[O:4].[C:40]([O:44][C:45]([NH:47][C@:48]([CH3:54])([CH2:52][CH3:53])[C:49](O)=[O:50])=[O:46])([CH3:43])([CH3:42])[CH3:41]>>[CH3:54][C@@:48]([NH:47][C:45](=[O:46])[O:44][C:40]([CH3:43])([CH3:42])[CH3:41])([CH2:52][CH3:53])[C:49]([NH:1][C@H:2]([CH2:29][C:30]1[C:38]2[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=2)[N:32]([CH3:39])[CH:31]=1)[C:3](=[O:4])[NH:5][CH:6]1[CH2:15][C:14]2[C:9](=[C:10]([N:16]3[CH2:20][CH2:19][CH2:18][C:17]3=[O:21])[CH:11]=[CH:12][CH:13]=2)[N:8]([CH2:22][C:23]2[CH:27]=[CH:26][S:25][CH:24]=2)[C:7]1=[O:28])=[O:50]
Reactant: CC[C@@](C)(NC(=O)OC(C)(C)C)C(=O)O
Reactant: Cn1cc(C[C@@H](N)C(=O)NC2Cc3cccc(N4CCCC4=O)c3N(Cc3ccsc3)C2=O)c2ccccc21
Product: CC[C@@](C)(NC(=O)OC(C)(C)C)C(=O)N[C@H](Cc1cn(C)c2ccccc12)C(=O)NC1Cc2cccc(N3CCCC3=O)c2N(Cc2ccsc2)C1=O
Yield: 89.4 %

Procedure:
The procedure of Example 14(a) was repeated, except that (2R)-2-amino-3-(1-methyl-1H-indol-3-yl)-N-[2-oxo-8-(2-oxopyrrolidin-1-yl)-1-(thiophen-3-ylmethyl)-1,2,3,4-tetrahydroquinolin-3-yl]propanamide obtained in Example 8(b) (5.4 g) and (R)-2-(tert-butoxycarbonylamino)-2-methylbutanoic acid (2.4 g) were used, whereby the title compound (6.6 g) was yielded.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[CH:15]([C:16]3[C:17]([S:23]C)=[N:18][C:19](=[O:22])[NH:20][CH:21]=3)[C:10]3[N:11]=[C:12]([CH3:14])[S:13][C:9]=3[CH:8]=[CH:7][C:6]=2[CH:25]=1.CI.[CH3:28]C(C)([O-])C.[K+]>O1CCCC1.CN(C)C=O.C(OCC)(=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[CH:15]([C:16]3[C:17](=[S:23])[NH:18][C:19](=[O:22])[N:20]([CH3:28])[CH:21]=3)[C:10]3[N:11]=[C:12]([CH3:14])[S:13][C:9]=3[CH:8]=[CH:7][C:6]=2[CH:25]=1
Reactant: CC(C)(C)[O-]
Reactant: CSc1nc(=O)[nH]cc1C1c2ccc(Cl)cc2C=Cc2sc(C)nc21
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CI
Product: Cc1nc2c(s1)C=Cc1cc(Cl)ccc1C2c1cn(C)c(=O)[nH]c1=S

Procedure:
A solution of the product of example 39 step (i) (0.1 g) together with methyl iodide (0.040 ml) and a 1M solution of potassium tert-butoxide in tetrahydrofuran (0.52 ml) in N,N-dimethylformamide (10 ml) was heated at 80° C. for 2 h. The reaction mixture was cooled, diluted with ethyl acetate and washed with saturated aqueous ammonium chloride and brine. The organic phase was dried over magnesium sulphate, filtered and evaporated. The crude product was purified by chromatography eluting with 5% ethanol in ethyl acetate to give a yellow oil (86 mg). This material was dissolved in a saturated blue solution of sodium hydrosulphide in N,N-dimethylformamide (3 ml) and heated at 80° C. for 3 h. The reaction mixture was cooled, diluted with dichloromethane and washed with water. The organic phase was dried over magnesium sulphate, filtered and evaporated. The crude product was purified by chromatography eluting with 30% isohexane in ethyl acetate to give the title compound as a yellow solid.
Reaction SMILES: [C:1]1([S:7]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([C:17](=O)[CH3:18])=[CH:13][CH:12]=2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.[NH2:21][O:22][CH2:23][CH2:24][O:25][C:26]1[CH:39]=[CH:38][C:29]([CH2:30][CH:31]2[S:35][C:34](=[O:36])[NH:33][C:32]2=[O:37])=[CH:28][CH:27]=1>>[C:1]1([S:7]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([C:17](=[N:21][O:22][CH2:23][CH2:24][O:25][C:26]3[CH:27]=[CH:28][C:29]([CH2:30][CH:31]4[S:35][C:34](=[O:36])[NH:33][C:32]4=[O:37])=[CH:38][CH:39]=3)[CH3:18])=[CH:13][CH:12]=2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: NOCCOc1ccc(CC2SC(=O)NC2=O)cc1
Reactant: CC(=O)c1ccc(NS(=O)(=O)c2ccccc2)cc1
Agent: Cl
Product: CC(=NOCCOc1ccc(CC2SC(=O)NC2=O)cc1)c1ccc(NS(=O)(=O)c2ccccc2)cc1
Yield: 51 %

Procedure:
Following a procedure similar to that described in Example 40(f), 170 mg of 4'-(phenylsulfonylamino)acetophenone were reacted with 197 mg of 5-[4-(2-aminooxyethoxy)benzyl]thiazolidine-2,4-dione hydrochloride [prepared as described in Example 40(e)]. The reaction mixture was then concentrated by evaporation under reduced pressure, and the resulting residue was extracted with ethyl acetate. The extract was washed with water and the solvent was removed by distillation under reduced pressure. The residue was purified by column chromatography through silica gel, using a 2:98 by volume mixture of methanol and methylene chloride as the eluent, to give 170 mg of the title compound, melting at 213°-215° C.
Reaction SMILES: [Cl:1][C:2]1[S:3][C:4]([S:8](Cl)(=[O:10])=[O:9])=[C:5]([CH3:7])[N:6]=1.Cl.[NH:13]1[CH2:16][CH2:15][CH2:14]1.C(N(CC)CC)C>C(Cl)Cl>[N:13]1([S:8]([C:4]2[S:3][C:2]([Cl:1])=[N:6][C:5]=2[CH3:7])(=[O:10])=[O:9])[CH2:16][CH2:15][CH2:14]1
Reactant: Cc1nc(Cl)sc1S(=O)(=O)Cl
Reactant: C1CNC1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1nc(Cl)sc1S(=O)(=O)N1CCC1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
A solution of 2-chloro-4-methylthiazole-5-sulphonylchloride (462 mg; 2.0 mmol) in DCM (5 mL) was added to an ice-cold solution of azetidine hydrochloride (196 mg; 2.1 mmol) and triethylamine (1.0 mL; 7.2 mmol) in DCM (15 mL) and the mixture stirred at 0° C. for 30 minutes. The DCM was removed in vacuo to give a residue which was partitioned between water (50 mL) and ethyl acetate (75 mL). The organic layer was washed with brine, dried (MgSO4) and evaporated to a residue which was chromatographed on silica, eluting with 10% ethyl acetate in isohexane, to give the desired material as a solid which was crystallised from ethyl acetate and isohexane (100 mg).
Reaction SMILES: F[C:2](F)(F)[C:3]1[N:4]=[C:5]2[CH2:10][NH:9][CH2:8][CH2:7][N:6]2[CH:11]=1.Br[CH2:15][C:16]([C:18]1C=CC=[CH:20][CH:19]=1)=O.C(O)C>[Pt](=O)=O.CO>[C:2]1([C:3]2[N:4]=[C:5]3[CH2:10][NH:9][CH2:8][CH2:7][N:6]3[CH:11]=2)[CH:20]=[CH:19][CH:18]=[CH:16][CH:15]=1
Reactant: FC(F)(F)c1cn2c(n1)CNCC2
Reactant: O=C(CBr)c1ccccc1
Agent: O=[Pt]=O
Solvent: CCO
Solvent: CO
Product: c1ccc(-c2cn3c(n2)CNCC3)cc1

Procedure:
2-Phenyl-5,6,7,8-tetrahydroimidazo[1,2-a]pyrazine was prepared in an analogous manner to that described above for 2-(trifluoromethyl)-5,6,7,8-tetrahydroimidazo[1,2-a]pyrazine (Intermediate 4) but starting from 2-bromo-1-phenylethanone instead of 3-bromo-1,1,1-trifluoro-2-propanone and using platinum (IV) oxide and ethanol in the place of 10% palladium on carbon paste and methanol for the hydrogenation step.
Reaction SMILES: CO[C:3](=[O:18])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([C:10]2[NH:11][C:12]([CH:15]([CH3:17])[CH3:16])=[N:13][CH:14]=2)[CH:5]=1.[C:19]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])(=[O:21])[CH3:20].[Li]>>[C:23]([O:22][C:19](=[O:21])[CH2:20][C:3]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([C:10]2[NH:11][C:12]([CH:15]([CH3:16])[CH3:17])=[N:13][CH:14]=2)[CH:5]=1)=[O:18])([CH3:26])([CH3:25])[CH3:24]
Reactant: COC(=O)c1cccc(-c2cnc(C(C)C)[nH]2)c1
Reactant: CC(=O)OC(C)(C)C
Agent: [Li]
Product: CC(C)c1ncc(-c2cccc(C(=O)CC(=O)OC(C)(C)C)c2)[nH]1

Procedure:
3-(2-Isopropyl-3H-imidazol-4-yl)-benzoic acid methyl ester was treated with lithium tert.-butyl acetate according to the general procedure K (method b) to give crude 3-[3-(2-isopropyl-3H-imidazol-4-yl)-phenyl]-3-oxo-propionic acid tert-butyl ester (0.25 g) as a pale-yellow oil.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[CH:6]2)#[N:2].[CH3:12][N:13]1[CH2:18][CH2:17][C:16](=O)[CH2:15][CH2:14]1.N1CCCC1.N>C(O)C.CO>[CH3:12][N:13]1[CH2:14][CH:15]=[C:16]([C:6]2[C:5]3[C:9](=[CH:10][CH:11]=[C:3]([C:1]#[N:2])[CH:4]=3)[NH:8][CH:7]=2)[CH2:17][CH2:18]1
Reactant: CN1CCC(=O)CC1
Reactant: N#Cc1ccc2[nH]ccc2c1
Agent: N
Solvent: CCO
Solvent: C1CCNC1
Solvent: CO
Product: CN1CC=C(c2c[nH]c3ccc(C#N)cc23)CC1
Temperature: 25 °C
Reaction time: 44 h

Procedure:
To an argon-purged round bottom flask fitted with a magnetic stirbar containing an orange solution of 5-cyanoindole (48) (250 mg, 1.76 mmol) dissolved in absolute ethanol (10 mL) were added 1-methyl-4-piperidone (0.43 mL, 3.50 mmol) and pyrrolidine (0.44 mL, 5.27 mmol). The reaction vessel was fitted with a condenser and transferred to an oil bath preheated to 80° C. The reaction was stirred at this temperature for 44 hrs. As no starting material remained (TLC 5% 2M NH3 in methanol/95% CH2Cl2) the reaction was cooled to room temperature followed by additional cooling in the fridge. As no precipitate formed, the reaction was concentrated under reduced pressure to afford an orange oil. The oil was redissolved in ethanol (20 mL) and the solvent removed under reduced pressure. This was repeated once more, and then the final residue was treated with ethanol and left in the fridge for 2 hrs. The precipitate which formed was collected by vacuum filtration and washed with hexanes (205 mg of pale yellow solid, compound 49, 48.7%) 1H NMR (DMSO) δ 11.90 (br s, NH), 8.51 (s, 1H), 7.80 (s, 1H), 7.77-7.74 (d, J=8.7 Hz, 1H), 7.68-7.65 (d, J=8.1 Hz, 1H), 6.41 (s, 1H), 3.53 (s, 2H), 3.27-3.26 (d, J=2.4 Hz, 2H), 2.79-2.77 (d, J=4.5 Hz, 2H), 2.72-2.71 (d, J=1.5 Hz, 3H).
Reaction SMILES: [Si](OCC1C=C([NH:20][C:21]([CH:23]2[CH2:32][CH2:31][C:30]3[C:25](=[CH:26][C:27](OC4C=CN=C(NC(C5CC5)=O)C=4)=[CH:28][CH:29]=3)[CH2:24]2)=[O:22])C=C(C(F)(F)F)C=1)(C(C)(C)C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.O>C1COCC1>[CH2:24]1[C:25]2[C:30](=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH2:31][CH2:32][CH:23]1[C:21]([NH2:20])=[O:22]
Reactant: CC(C)(C)[Si](C)(C)OCc1cc(NC(=O)C2CCc3ccc(Oc4ccnc(NC(=O)C5CC5)c4)cc3C2)cc(C(F)(F)F)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: O
Solvent: C1CCOC1
Product: NC(=O)C1CCc2ccccc2C1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a solution of N-[3-({[tert-butyl(dimethyl)silyl]oxy}methyl)-5-(trifluoromethyl)-phenyl]-7-({2-[(cyclopropylcarbonyl)amino]pyridin-4-yl}oxy)-1,2,3,4-tetrahydronaphthalene-2-carboxamide (0.250 g, 0.39 mol) in THF (5 mL) at 0° C. was added 1.0 M tetra-n-butylammonium fluoride in THF (0.43 mL). The reaction mixture was allowed to stir at 0° C. for 1 h and then at rt overnight. Water was added and the reaction mixture was extracted with EtOAc. The organic solutions were combined, dried over Na2SO4, filtered and concentrated. The residue was purified by column chromatography to give 7-({2-[(cyclopropylcarbonyl)amino]pyridin-4-yl}-oxy)-N-3(hydroxymethyl)-5-(trifluoromethyl)phenyl]-1,2,3,4-tetrahydronaphthalene-2-carboxamide I-206 (199 mg, 88%) as a white solid. 1H NMR (400 MHz, d6-DMSO, HCl salt) δ: 11.48 (br s, 1H), 10.46 (s, 1H), 8.21 (d, 1H), 8.02 (s, 1H), 7.79 (s, 1H), 7.35 (br s, 1H), 7.31 (s, 1H), 7.22 (d, 1H), 6.93-7.02 (m, 2H), 6.81-6.86 (m, 1H), 4.54 (s, 2H), 2.76-2.97 (m, 5H), 2.07-2.15 (m, 1H), 1.90-1.98 (m, 1H), 1.73-1.85 (m, 1H), and 0.81-0.89 (m, 4H). LCMS: (FA) ES+526.4, ES−524.5.
Reaction SMILES: COCC[S](F)(F)([F:10])CCOC.O[C:14]([CH3:44])([CH3:43])[CH2:15][N:16]1[CH2:21][CH2:20][C:19]2([CH2:24][C:23]3([O:42][C:27]4=[CH:28][N:29]=[C:30]([C:32]5[CH:37]=[CH:36][C:35]([S:38]([CH3:41])(=[O:40])=[O:39])=[CH:34][CH:33]=5)[CH:31]=[C:26]4[CH2:25]3)[CH2:22]2)[CH2:18][CH2:17]1.O>ClCCl.CO>[F:10][C:14]([CH3:44])([CH3:43])[CH2:15][N:16]1[CH2:21][CH2:20][C:19]2([CH2:24][C:23]3([O:42][C:27]4=[CH:28][N:29]=[C:30]([C:32]5[CH:37]=[CH:36][C:35]([S:38]([CH3:41])(=[O:40])=[O:39])=[CH:34][CH:33]=5)[CH:31]=[C:26]4[CH2:25]3)[CH2:22]2)[CH2:18][CH2:17]1
Reactant: CC(C)(O)CN1CCC2(CC1)CC1(Cc3cc(-c4ccc(S(C)(=O)=O)cc4)ncc3O1)C2
Reactant: COCC[S](F)(F)(F)CCOC
Solvent: CO
Solvent: ClCCl
Solvent: O
Product: CC(C)(F)CN1CCC2(CC1)CC1(Cc3cc(-c4ccc(S(C)(=O)=O)cc4)ncc3O1)C2
Reaction time: 3 h

Procedure:
Bis(2-methoxyethyl)sulfur trifluoride (50% in toluene; 40 μL) is added to a solution of 1″-(2-hydroxy-2-methyl-propyl)-5-(4-methylsulfonyl-phenyl)-dispiro[2,3-dihydrofuro[2,3-c]pyridine-2,1′-cyclobutane-3′,4″-piperidine] (20 mg) in dichloromethane (5 mL) chilled in an ice bath. The solution is stirred in the cooling bath for 2 h before another portion of bis(2-methoxyethyl)sulfur trifluoride (50% in toluene; 20 μL) is added. After stirring for 3 h, a few drops of methanol and water are added. The resulting solution is concentrated and the residue is purified by HPLC on reversed phase (acetonitrile/water/trifluoroacetic acid) to give the title compound as bis(trifluoroacetic acid) salt. LC (method 1): tR=0.76 min; Mass spectrum (ESI+): m/z=459 [M+H]+.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH2:15][CH2:16][CH2:17][N:18]3[CH2:22][CH2:21][CH2:20][CH2:19]3)=[C:9](C#N)[CH:10]=2)[N:5]=[CH:4][CH:3]=1.[OH:23][C:24]1[CH:25]=[C:26]2[C:30](=[CH:31][CH:32]=1)[NH:29][C:28]([CH3:33])=[CH:27]2.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C>[CH3:33][C:28]1[NH:29][C:30]2[C:26]([CH:27]=1)=[CH:25][C:24]([O:23][C:4]1[CH:3]=[CH:2][C:11]3[C:6](=[CH:7][C:8]([O:14][CH2:15][CH2:16][CH2:17][N:18]4[CH2:19][CH2:20][CH2:21][CH2:22]4)=[CH:9][CH:10]=3)[N:5]=1)=[CH:32][CH:31]=2
Reactant: N#Cc1cc2c(Cl)ccnc2cc1OCCCN1CCCC1
Reactant: Cc1cc2cc(O)ccc2[nH]1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: Cc1cc2cc(Oc3ccc4ccc(OCCCN5CCCC5)cc4n3)ccc2[nH]1
Temperature: 95 °C
Yield: 58.1 %

Procedure:
A suspension of 4-chloro-6-cyano-7-(3-(pyrrolidin-1-yl)propoxy)quinoline (150 mg, 0.48 mmol), (prepared as described for the starting material in Example 11), 5-hydroxy-2-methylindole (84 mg, 0.57 mmol) and cesium carbonate (200 mg, 0.72 mmol) in DMF (6 ml) was heated at 95° C. for 2 hours. After cooling, the mixture was filtered and the filtrate was evaporated under vacuum. The residue was purified by column chromatography eluting with methylene chloride, followed by ethyl acetate, followed by methanol/methylene chloride (1/9) followed by methylene chloride/methanol saturated with ammonia (9/1 followed by 85/15) to give 6-cyano-((2-methylindol-5-yloxy)-7-(3-(pyrrolidin-1-yl)propoxy)quinoline (112 mg, 46%).