Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:10])=CC=1.[CH3:23][O:24][C:25]1[CH:26]=[C:27]2[C:35](=[CH:36][CH:37]=1)[NH:34][C:33]1[CH:32]([CH3:38])[N:31]([C:39](=O)[CH3:40])[CH2:30][CH2:29][C:28]2=1>C1(C)C=CC=CC=1>[CH3:23][O:24][C:25]1[CH:26]=[C:27]2[C:35](=[CH:36][CH:37]=1)[NH:34][C:33]1[CH:32]([CH3:38])[N:31]([C:39](=[S:10])[CH3:40])[CH2:30][CH2:29][C:28]2=1
Reactant: COc1ccc2[nH]c3c(c2c1)CCN(C(C)=O)C3C
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: Cc1ccccc1
Product: COc1ccc2[nH]c3c(c2c1)CCN(C(C)=S)C3C
Yield: 40 %

Procedure:
Lawesson's reagent (520 mg) is added portionwise, at 110° C., to a solution of 1-(6-methoxy-1-methyl-2,3,4,9-tetrahydro- 1H-β-carbolin-2-yl)-1 -ethanone (500 mg) in anhydrous toluene (25 mL). After refluxing for 1 h and evaporation of the toluene, the product is chromatographed on silica gel (99/1 chlorofomvmethanol eluent) and the 1-(6-methoxy-1-methyl-2,3,4,9-tetrahydro- 1H-β-carbolin-2-yl)-1 -ethanethione is thus recovered (40% yield).
Reaction SMILES: Cl[C:2]1[N:3]=[N:4][C:5]([C:8]2[S:12][N:11]=[C:10]([CH3:13])[N:9]=2)=[CH:6][CH:7]=1.Cl.[NH:15]1[CH2:20][CH2:19][C:18]2([C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=3[CH2:22][O:21]2)[CH2:17][CH2:16]1.C(=O)([O-])[O-].[K+].[K+]>>[CH3:13][C:10]1[N:9]=[C:8]([C:5]2[N:4]=[N:3][C:2]([N:15]3[CH2:20][CH2:19][C:18]4([C:24]5[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=5[CH2:22][O:21]4)[CH2:17][CH2:16]3)=[CH:7][CH:6]=2)[S:12][N:11]=1
Reactant: c1ccc2c(c1)COC21CCNCC1
Reactant: Cc1nsc(-c2ccc(Cl)nn2)n1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Product: Cc1nsc(-c2ccc(N3CCC4(CC3)OCc3ccccc34)nn2)n1

Procedure:
The object product (66 mg, 26%) was obtained in the same manner as in Example 1 and using 3-chloro-6-(3-methyl-1,2,4-thiadiazol-5-yl)pyridazine (150 mg), 3H-spiro[2-benzofuran-1,4′-piperidine] hydrochloride (159 mg) and potassium carbonate (244 mg).
Reaction SMILES: [Na].C(OC([NH:7][N:8]=[C:9]([C:15]1[O:19][C:18]2[CH:20]=[CH:21][CH:22]=[CH:23][C:17]=2[CH:16]=1)[CH2:10][O:11][C:12](=[O:14])C)=O)C.C(O)(=O)C>C(O)C.O>[O:19]1[C:15]([C:9]2[CH2:10][O:11][C:12](=[O:14])[NH:7][N:8]=2)=[CH:16][C:17]2[CH:23]=[CH:22][CH:21]=[CH:20][C:18]1=2
Reactant: CCOC(=O)NN=C(COC(C)=O)c1cc2ccccc2o1
Agent: [Na]
Solvent: O
Solvent: CC(=O)O
Solvent: CCO
Product: O=C1NN=C(c2cc3ccccc3o2)CO1
Reaction time: 48 h

Procedure:
A solution of sodium (0.45 g.) in ethanol (30 ml.) was added to a stirred solution of acetoxymethyl 2-benzo[b]furyl ketone ethoxycarbonylhydrazone (5.48 g.) in ethanol (30 ml.) and the mixture was stirred at laboratory temperature for 2 days. Further sodium (0.45g.) in ethanol (30 ml.) was added and the mixture was stirred at laboratory temperature for a further 30 hours, diluted with water (300 ml.), adjusted to pH 5 with acetic acid and extracted with 100 ml. and then 50 ml. of ethyl acetate. The combined extracts were washed with saturated aqueous sodium chloride solution, dried and evaporated to dryness and the residue was purified by chromatography on a silica gel column (Merck 7734; 400 g.) using initially a 3:2 v/v mixture of petroleum ether (b.p. 60°-80° C.) and ethyl acetate as eluant. 7500 ml. of this eluant were used, the eluate being discarded, and elution was continued with ethyl acetate (1000 ml.). The eluate was evaporated to dryness under reduced pressure and the residue was stirred with a mixture of methanol and diethyl ether. The mixture was filtered and the solid residue was purified by chromatography on a silica gel column (Merck 9385; column size 25 cm. long and 20 mm. diameter) using a 1:1 v/v mixture of petroleum ether (b.p. 60°-80° C.) and ethyl acetate as eluant. The first 40 ml. of eluate were discarded and the next 90 ml. of eluate were evaporated to dryness under reduced pressure. The residue was stirred with a mixture of diethyl ether and petroleum ether (b.p. 60°-80° C.) and the mixture was filtered. There was thus obtained as solid product 5-(2-benzo[b]furyl)-3H,6H-1,3,4-oxadiazin-2-one, m.p. 209°-211° C.
Reaction SMILES: [CH2:1]([Si:4]1(Cl)[N:8]([CH3:9])[C@@H:7]([CH3:10])[C@H:6]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[O:5]1)[CH:2]=[CH2:3].C(N(CC)CC)C.[CH3:25][CH:26]([OH:28])[CH3:27]>C(Cl)Cl>[CH2:1]([Si:4]1([O:28][CH:26]([CH3:27])[CH3:25])[N:8]([CH3:9])[C@@H:7]([CH3:10])[C@H:6]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[O:5]1)[CH:2]=[CH2:3]
Reactant: CC(C)O
Reactant: C=CC[Si]1(Cl)O[C@@H](c2ccccc2)[C@H](C)N1C
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C=CC[Si]1(OC(C)C)O[C@@H](c2ccccc2)[C@H](C)N1C
Reaction time: 12 h
Yield: 47.5 %

Procedure:
To a solution of (4S,5S)-2-Allyl-2-chloro-3,4-dimethyl-5-phenyl-[1,3,2]oxazasilolidine (2.08 g, 7.8 mmol) in methylene chloride (25 mL) was added triethylamine (1.2 mL, 8.6 mmol). 2-Propanol (0.6 mL, 7.8 mmol) was added slowly by syringe and the mixture was allowed to stir for 12 hours. The methylene chloride was removed by distillation and pentane (20 ml) was added to the residue. The mixture was stirred for 3 hours. The mixture was then filtered through a pad of celite. The filtrate was concentrated to afford an oil which was distilled under reduced pressure (b.p. ˜72° C., ˜0.2 mm Hg) to yield 1.08 g (48%) of (4S,5S)-2-Allyl-2-isopropoxy-3,4-dimethyl-5-phenyl-[1,3,2]oxazasilolidine as a ˜2:1 mixture of diastereomers.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[C:18]([N+:19]([O-:21])=[O:20])=[CH:17][CH:16]=[CH:15][C:10]=1[C:11]([O:13][CH3:14])=[O:12])=[O:7])([CH3:4])([CH3:3])[CH3:2].Br[CH2:23][C:24]1[CH:29]=[CH:28][C:27]([C:30]2[C:31]([C:36]([NH2:38])=[O:37])=[CH:32][CH:33]=[CH:34][CH:35]=2)=[CH:26][CH:25]=1.C([O-])([O-])=O.[K+].[K+].O>C(#N)C>[C:1]([O:5][C:6]([N:8]([C:9]1[C:18]([N+:19]([O-:21])=[O:20])=[CH:17][CH:16]=[CH:15][C:10]=1[C:11]([O:13][CH3:14])=[O:12])[CH2:23][C:24]1[CH:29]=[CH:28][C:27]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=2[C:36](=[O:37])[NH2:38])=[CH:26][CH:25]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)c1cccc([N+](=O)[O-])c1NC(=O)OC(C)(C)C
Reactant: NC(=O)c1ccccc1-c1ccc(CBr)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: COC(=O)c1cccc([N+](=O)[O-])c1N(Cc1ccc(-c2ccccc2C(N)=O)cc1)C(=O)OC(C)(C)C
Yield: 74.9 %

Procedure:
A mixture of methyl 2-(N-tert-butoxycarbonylamino)-3-nitrobenzoate (1.8 g), 4'-bromomethylbiphenyl-2-carboxamide (1.8 g) and K2CO3 (0.86 g) in acetonitrile (25 ml) was heated for 6 hours under reflux. To the reaction mixture was added water, and the mixture was extracted with ethyl acetate. The extract was washed with water and dried over MgSO4. The solvent was removed in vacuo., and the residue was purified by column chromatography on silica gel to afford a yellow syrup (2.3 g, 90%).
Reaction SMILES: CO[C:3](=[O:40])[CH:4]([NH:20][C:21]([N:23]1[CH2:28][CH2:27][CH:26]([N:29]2[CH2:38][C:37]3[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=3)[NH:31][C:30]2=[O:39])[CH2:25][CH2:24]1)=[O:22])[CH2:5][C:6]1[CH:7]=[N:8][C:9]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:10][CH:11]=1.O.[OH-].[Li+].[N:44]1([CH:50]2[CH2:55][CH2:54][NH:53][CH2:52][CH2:51]2)[CH2:49][CH2:48][CH2:47][CH2:46][CH2:45]1.C(N(CC)CC)C.[PH2](Cl)=O>CO.O>[CH2:13]([O:12][C:9]1[N:8]=[CH:7][C:6]([CH2:5][CH:4]([NH:20][C:21]([N:23]2[CH2:24][CH2:25][CH:26]([N:29]3[CH2:38][C:37]4[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=4)[NH:31][C:30]3=[O:39])[CH2:27][CH2:28]2)=[O:22])[C:3]([N:53]2[CH2:54][CH2:55][CH:50]([N:44]3[CH2:49][CH2:48][CH2:47][CH2:46][CH2:45]3)[CH2:51][CH2:52]2)=[O:40])=[CH:11][CH:10]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: COC(=O)C(Cc1ccc(OCc2ccccc2)nc1)NC(=O)N1CCC(N2Cc3ccccc3NC2=O)CC1
Reactant: C1CCN(C2CCNCC2)CC1
Agent: O=[PH2]Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CCN(CC)CC
Solvent: CO
Product: O=C(NC(Cc1ccc(OCc2ccccc2)nc1)C(=O)N1CCC(N2CCCCC2)CC1)N1CCC(N2Cc3ccccc3NC2=O)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a stirred solution of 3-(6-benzyloxy-pyridin-3-yl)-2-{[4-(2-oxo-1,4-dihydro-2H-quinazolin-3-yl)-piperidine-1-carbonyl]-amino}-propionic acid methyl ester (59 mg, 0.11 mmol) in methanol (3 mL) was added a solution of lithium hydroxide monohydrate (9.1 mg, 2 equiv) in water (0.5 mL). The reaction was stirred 2 h at room temperature, cooled to 0° C., quenched by addition of 1N hydrochloric acid (0.15 mL), and concentrated. The crude product was used without purification. The crude acid was dissolved in methylene chloride (2 mL, 0° C.), and treated sequentially with 4-piperidino-piperidine (34 mg, 1.8 equiv), triethylamine (35 μL, 2.3 equiv.), and bis-2-oxo-3-oxazolidinyl)phosphinic chloride (34 mg, 1.2 equiv). The ice bath was removed and the reaction allowed to stir overnight. The reaction was concentrated and purified by Prep TLC to give 30.3 mg (41%). LC/MS: tR=1.49 min, 680.29 (MH)+.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:20])[CH2:5][C:6]1[CH:7]=[C:8]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([Cl:18])[C:13]=2[Cl:19])[CH:9]=[CH:10][CH:11]=1)[CH3:2].[C:21](=O)([O:25]CC)[O:22][CH2:23][CH3:24].[H-].[Na+]>>[CH2:1]([O:3][C:4](=[O:20])[CH:5]([C:6]1[CH:7]=[C:8]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([Cl:18])[C:13]=2[Cl:19])[CH:9]=[CH:10][CH:11]=1)[C:21]([O:22][CH2:23][CH3:24])=[O:25])[CH3:2]
Reactant: CCOC(=O)Cc1cccc(-c2cccc(Cl)c2Cl)c1
Reactant: CCOC(=O)OCC
Agent: [H-]
Agent: [Na+]
Product: CCOC(=O)C(C(=O)OCC)c1cccc(-c2cccc(Cl)c2Cl)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 2′,3′-dichloro-[1,1′-biphenyl]-3-acetic acid ethyl ester (i.e. the product of Step A, 0.45 g, 1.45 mmol) and diethyl carbonate (5 mL) was added sodium hydride (60% dispersion in oil, 0.23 g, 5.8 mmol). The reaction mixture was stirred overnight at room temperature, and then quenched with saturated aqueous ammonium chloride solution. The reaction mixture was then extracted with ethyl acetate, and the organic layer was dried over sodium sulfate and concentrated under reduced pressure to yield the title compound (0.50 g).
Reaction SMILES: [CH:1]([NH:4]C(C)C)(C)[CH3:2].C([Li])CCC.[CH3:13][O:14][C:15]1[CH:16]=[C:17]([CH:20]=[CH:21][C:22]=1[O:23][CH3:24])[CH:18]=[O:19].[Cl-].[NH4+]>O1CCCC1.C(#N)C.CCCCCC>[CH3:13][O:14][C:15]1[CH:16]=[C:17]([CH:18]([OH:19])[CH2:2][C:1]#[N:4])[CH:20]=[CH:21][C:22]=1[O:23][CH3:24]
Reactant: COc1ccc(C=O)cc1OC
Reactant: CC(C)NC(C)C
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CC#N
Solvent: CCCCCC
Solvent: C1CCOC1
Product: COc1ccc(C(O)CC#N)cc1OC
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of diisopropylamine (0.67 g, 6.62 mM) in dried tetrahydrofuran (5 ml) was cooled to −78° C. A hexane solution of n-butyllithium (6.62 mM) was dropped into this solution, then this was stirred at that temperature for 30 minutes. Next, acetonitrile (0.27 g, 6.62 mM) was dropped into this solution and the result stirred for a further 30 minutes, then a solution of 3,4-dimethoxybenzaldehyde (1.00 g, 6.02 mM) in dried tetrahydrofuran (5 ml) was added and the mixture stirred at that temperature for 4 hours. An aqueous ammonium chloride was poured into the obtained solution, which was warmed to room temperature and extracted with diethyl ether. The organic layer was dried over anhydrous magnesium sulfate, then the solvent was removed in vacuo to obtain a crude product (1.25 g) of 3-(3,4-dimethoxyphenyl)-3-hydroxypropiononitrile as a yellow oil. The crude product thus obtained had sufficient purity without purification, therefore could be used for the next reaction as it was.
Reaction SMILES: Cl[C:2]1[C:11]([N:12]([CH:14]([CH3:16])[CH3:15])[CH3:13])=[N:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:17]([O:19][CH3:20])=[O:18])[CH:8]=2)[N:3]=1.CC1(C)C(C)(C)OB([C:29]2[CH:33]=[C:32]([C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)OC=2)O1.[C:41]([O-])([O-])=[O:42].[Na+].[Na+]>O1CCOCC1.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>[CH:14]([N:12]([CH3:13])[C:11]1[C:2]([C:29]2[O:42][CH:41]=[C:32]([C:34]3[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=3)[CH:33]=2)=[N:3][C:4]2[C:9]([N:10]=1)=[CH:8][C:7]([C:17]([O:19][CH3:20])=[O:18])=[CH:6][CH:5]=2)([CH3:16])[CH3:15]
Reactant: CC1(C)OB(c2coc(-c3ccccc3)c2)OC1(C)C
Reactant: COC(=O)c1ccc2nc(Cl)c(N(C)C(C)C)nc2c1
Reactant: O=C([O-])[O-]
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Na+]
Solvent: C1COCCO1
Product: COC(=O)c1ccc2nc(-c3cc(-c4ccccc4)co3)c(N(C)C(C)C)nc2c1
Temperature: 90 °C
Reaction time: 1 h
Yield: 68.4 %

Procedure:
To a solution of methyl 2-chloro-3-(isopropyl(methyl)amino)quinoxaline-6-carboxylate (150 mg, 0.51 mmol) in dioxane (5 mL) was added 4,4,5,5-tetramethyl-2-(5-phenylfuran-3-yl)-1,3,2-dioxaborolane (276 mg, 1.02 mmol), Na2CO3 (54 mg, 0.51 mmol), Pd(PPh3)4 (30 mg, 0.03 mmol). The resulting solution was stirred for 1 h at 90° C. and then concentrated in vacuo to give a residue, which was purified by silica gel column chromatography (3.3% ethyl acetate in petroleum ether) to afford methyl 3-(isopropyl(methyl)amino)-2-(4-phenylfuran-2-yl)quinoxaline-6-carboxylate as a red solid (140 mg, 68%).
Reaction SMILES: [Cl:1][C:2]1[CH:19]=[CH:18][CH:17]=[C:16]([Cl:20])[C:3]=1[CH2:4][N:5]1[CH2:10][CH2:9][NH:8][C:7]2[N:11]=[CH:12][C:13](I)=[CH:14][C:6]1=2.[N:21]1([CH:26]2[CH2:31][CH2:30][N:29]([C:32]([C:34]3[CH:39]=[CH:38][C:37](B4OC(C)(C)C(C)(C)O4)=[CH:36][CH:35]=3)=[O:33])[CH2:28][CH2:27]2)[CH2:25][CH2:24][CH2:23][CH2:22]1>>[Cl:1][C:2]1[CH:19]=[CH:18][CH:17]=[C:16]([Cl:20])[C:3]=1[CH2:4][N:5]1[CH2:10][CH2:9][NH:8][C:7]2[N:11]=[CH:12][C:13]([C:37]3[CH:38]=[CH:39][C:34]([C:32]([N:29]4[CH2:28][CH2:27][CH:26]([N:21]5[CH2:22][CH2:23][CH2:24][CH2:25]5)[CH2:31][CH2:30]4)=[O:33])=[CH:35][CH:36]=3)=[CH:14][C:6]1=2
Reactant: Clc1cccc(Cl)c1CN1CCNc2ncc(I)cc21
Reactant: CC1(C)OB(c2ccc(C(=O)N3CCC(N4CCCC4)CC3)cc2)OC1(C)C
Product: O=C(c1ccc(-c2cnc3c(c2)N(Cc2c(Cl)cccc2Cl)CCN3)cc1)N1CCC(N2CCCC2)CC1
Yield: 10 %

Procedure:
1-(2,6-Dichlorobenzyl)-7-iodo-1,2,3,4-tetrahydropyrido[2,3-b]pyrazine (56 mg) was reacted with (4-(pyrrolidin-1-yl)piperidin-1-yl)-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)phenyl]methanone as in General Procedure 4B to give the title compound as a yellow solid (10% yield). LCMS: m/z=470.05 (M+H+), 1H-NMR (CDCl3, 400 MHz) δ 1.56 (3H, m), 1.90 (11H, m), 2.17 (1H, s), 2.28 (1H, m), 2.59 (5H, m), 2.98 (3H, m), 3.14 (2H, t, J=4.7 Hz), 3.50 (2H, m), 3.85 (1H, bs), 4.61 (3H, s), 4.92 (1H, bs), 7.12 (1H, s), 7.23 (1H, m), 7.48 (6H, m), 7.75 (1H, d, J=1.5 Hz).
Reaction SMILES: [CH:1]1([O:5][C:6]2[C:14]([CH3:15])=[CH:13][CH:12]=[CH:11][C:7]=2[C:8]([OH:10])=O)[CH2:4][CH2:3][CH2:2]1.[CH2:16]([O:18][C:19]([C:21]1([NH2:31])[CH:29](F)[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH2:22]1)=[O:20])[CH3:17].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.[F:49][P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[CH2:16]([O:18][C:19]([C:21]1([NH:31][C:8](=[O:10])[C:7]2[CH:11]=[CH:12][CH:13]=[C:14]([CH3:15])[C:6]=2[O:5][CH:1]2[CH2:2][CH2:3][CH2:4]2)[CH2:29][C:28]2[C:23](=[CH:24][CH:25]=[CH:26][C:27]=2[F:49])[CH2:22]1)=[O:20])[CH3:17]
Reactant: F[P-](F)(F)(F)(F)F
Reactant: Cc1cccc(C(=O)O)c1OC1CCC1
Reactant: CCOC(=O)C1(N)Cc2ccccc2C1F
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCOC(=O)C1(NC(=O)c2cccc(C)c2OC2CCC2)Cc2cccc(F)c2C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 83.7 %

Procedure:
To a solution of 2-cyclobutoxy-3-methyl-benzoic acid (127 mg, 0.61 mmol), 2-Amino-3-fluoro-indan-2-carboxylic acid ethyl ester (265) (165 mg, 0.74 mmol), HATU 352 mg, 0.93 mmol) in anhydrous DMF (10 mL) is added DIPEA (204 μL, 1.23 mmol). The resulting solution is stirred at RT overnight. After the removal of DMF in vacuo, the residue is suspended in H2O (50 mL) and washed with EtOAc (3×50 mL). Organics are combined and washed successively with NaHCO3 and brine, and then the organic layer is dried over anhydrous Na2SO4 and concentrated in vacuo. The residue is purified by flash column chromatography (12 g silica gel, gradient elution: 0%-20% EtOAc in heptane) to give a pure product (266) as a colorless oil (210 mg, 84%).
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([NH:17][C:18](=[O:48])[N:19]([CH2:29][C:30]2[CH:35]=[C:34]([F:36])[CH:33]=[CH:32][C:31]=2[O:37][C:38]2[CH:39]=[C:40]3[C:44](=[CH:45][CH:46]=2)[N:43]([CH3:47])[N:42]=[CH:41]3)[CH2:20][C:21]2[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][CH:22]=2)[N:8]([C:10]2[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][CH:11]=2)[N:9]=1)([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[CH3:51]I>CN(C=O)C>[C:1]([C:5]1[CH:6]=[C:7]([N:17]([CH3:51])[C:18]([N:19]([CH2:29][C:30]2[CH:35]=[C:34]([F:36])[CH:33]=[CH:32][C:31]=2[O:37][C:38]2[CH:39]=[C:40]3[C:44](=[CH:45][CH:46]=2)[N:43]([CH3:47])[N:42]=[CH:41]3)[CH2:20][C:21]2[CH:22]=[CH:23][C:24]([O:27][CH3:28])=[CH:25][CH:26]=2)=[O:48])[N:8]([C:10]2[CH:11]=[CH:12][C:13]([CH3:16])=[CH:14][CH:15]=2)[N:9]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CI
Reactant: COc1ccc(CN(Cc2cc(F)ccc2Oc2ccc3c(cnn3C)c2)C(=O)Nc2cc(C(C)(C)C)nn2-c2ccc(C)cc2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc(CN(Cc2cc(F)ccc2Oc2ccc3c(cnn3C)c2)C(=O)N(C)c2cc(C(C)(C)C)nn2-c2ccc(C)cc2)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 87 %

Procedure:
Intermediate (30t) (150 mg, 0.23 mmol) was dissolved in DMF (2 mL) and cooled to 0° C. Sodium hydride (60% in oil, 14 mg, 0.36 mmol) and methyl iodide (73.8 μL, 168 mg, 1.19 mmol) were added to the solution at 0° C. and the reaction mixture was stirred at 0° C. for 1 hour. The reaction mixture was quenched by addition of 5 mL of water at 0° C., and then extracted three times with 50 mL of Et2O. The combined organic layer was washed with 5 mL of water twice and with brine once, dried over MgSO4, filtered and evaporated under reduced pressure. The residue was purified on silica gel with EtOAc/hexane (1:2) to obtain compound (31t) as a pale yellow amorphous (134 mg, 87% yield). 1HNMR (400 MHz, CDCl3) δ 7.82 (s, 1H), 7.37 (d, J=8.6 Hz, 2H), 7.28 (d, J=9.4 Hz, 1H), 7.15-7.02 (m, 2H), 7.00-6.81 (m, 6H), 6.80-6.60 (m, 3H), 5.85 (s, 1H), 4.21 (s, 2H), 4.20 (s, 2H), 4.05 (s, 3H), 3.76 (s, 3H), 2.98 (s, 3H), 2.29 (s, 3H), 1.23 (s, 9H) ppm.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[CH:18]=[CH:17][CH:16]=[CH:15][C:8]=1[CH2:9][CH:10]([CH3:14])[C:11]([OH:13])=O.S(Cl)(Cl)=O.[Al+3].[Cl-].[Cl-].[Cl-].Cl>C1(C)C=CC=CC=1>[CH3:14][CH:10]1[CH2:9][C:8]2[C:15](=[CH:16][CH:17]=[CH:18][C:7]=2[C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=2)[C:11]1=[O:13]
Reactant: CC(Cc1ccccc1-c1ccccn1)C(=O)O
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: O=S(Cl)Cl
Solvent: Cc1ccccc1
Product: CC1Cc2c(cccc2-c2ccccn2)C1=O
Temperature: 80 °C

Procedure:
A solution of 193 g (0.80 mol) of 2-(2-(2-(pyridyl)benzyl)propionic acid in 81 cm3 (1.2 mol) of thionyl chloride was stirred at room temperature for 18 hours. Excess thionyl chloride was removed at 10 mbar and the acid chloride was taken up in 400 cm3 of toluene. The solution was added dropwise at 10° C. to a suspension of 113 g (0.85 mol) of AlCl3 in 1500 cm3 of toluene and heated at 80° C. for 1 hour. The reaction mixture was poured onto 2000 g of ice and acidified with concentrated aqueous HCl to a pH of 1. The organic phase was separated off and the aqueous phase was further extracted 3 times with 200 cm3 each time of Et2O. The combined organic phases were washed with saturated aqueous NaHCO3 solution and saturated aqueous NaCl solution and subsequently dried (MgSO4). This gave 132 g (74%) of 2-methyl-4-(2-pyridyl)-1-indanone which was further reacted without further purification.
Reaction SMILES: O[CH2:2][C:3]1[C:4]([C:9]2[N:13]([CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])[N:12]=[CH:11][CH:10]=2)=[N:5][CH:6]=[CH:7][CH:8]=1.O=S(Cl)[Cl:22]>C(Cl)Cl>[ClH:22].[Cl:22][CH2:2][C:3]1[C:4]([C:9]2[N:13]([CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])[N:12]=[CH:11][CH:10]=2)=[N:5][CH:6]=[CH:7][CH:8]=1
Reactant: CCOC(=O)Cn1nccc1-c1ncccc1CO
Reactant: O=S(Cl)Cl
Solvent: ClCCl
Product: CCOC(=O)Cn1nccc1-c1ncccc1CCl
Product: Cl
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To ethyl 2-(5-(3-(hydroxymethyl)pyridin-2-yl)-1H-pyrazol-1-yl)acetate (182 mg, 0.70 mmol) in DCM (10 mL) was added SOCl2 (3.0 mL) at rt. The reaction mixture was stirred at rt for 4 h and concentrated to dryness. The crude solid was suspended in toluene and concentrated to dryness. The process was repeated three times and dried under vacuum to give ethyl 2-(5-(3-(chloromethyl)pyridin-2-yl)-1H-pyrazol-1-yl)acetate hydrochloride (220 mg) as an off-white solid, which was used for next step without further purification.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([F:11])=[CH:7][CH:6]=1.[CH3:13][Si](C)(C)[N-][Si](C)(C)C.[Li+].CI>O1CCCC1>[F:11][C:8]1[CH:9]=[CH:10][C:5]([CH:4]([CH3:13])[C:3]([O:2][CH3:1])=[O:12])=[CH:6][CH:7]=1
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Reactant: COC(=O)Cc1ccc(F)cc1
Agent: [Li+]
Solvent: CI
Solvent: C1CCOC1
Product: COC(=O)C(C)c1ccc(F)cc1
Temperature: -78 °C
Reaction time: 1 h
Yield: 87.1 %

Procedure:
A solution of the compound of Example 14A (23.2 g, 0.138 mol) in dry tetrahydrofuran (30 mL) was added dropwise over 30 min to a −78° C. solution of lithium hexamethyldisilazide (prepared from hexamethyldisilazane (35 mL, 0.165 mol) and n-butyllithium in hexane (2.5 M, 58 mL, 0.145 mol)) in dry tetrahydrofuran (100 mL). The solution was stirred at −78° C. for 1 h, and then a large excess of methyl iodide was added. The solution was stirred at −78° C. for 30 min and was then warmed to ambient temperature for 18 h. The solution was quenched by addition of saturated ammonium chloride solution and diluted with water. The mixture was concentrated in vacuo to remove tetrahydrofuran and then extracted with ethyl acetate. The organic layer was extracted with water (2×) and saturated NaCl solution, followed by drying (Na2SO4) and concentration in vacuo. The residue was distilled under reduced pressure (70-75° C./0.5 mm Hg) to afford the title compound (21.9 g, 87%) as a colorless oil. 1H NMR (300 MHz, CDCl3): δ 1.49 (d, J=7.35 Hz, 3 H) 3.70 (m, 4 H) 7.01 (m, 2 H) 7.27 (m, 2 H).
Reaction SMILES: C[O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[C:13]([C:14]3[CH:19]=[CH:18][C:17]([S:20]([CH3:23])(=[O:22])=[O:21])=[CH:16][CH:15]=3)=[N:12][C:11]([C:24]([F:27])([F:26])[F:25])=[N:10]2)=[CH:5][CH:4]=1.Br.C(O)(=O)C>O>[OH:2][C:3]1[CH:4]=[CH:5][C:6]([N:9]2[C:13]([C:14]3[CH:15]=[CH:16][C:17]([S:20]([CH3:23])(=[O:21])=[O:22])=[CH:18][CH:19]=3)=[N:12][C:11]([C:24]([F:25])([F:26])[F:27])=[N:10]2)=[CH:7][CH:8]=1
Reactant: COc1ccc(-n2nc(C(F)(F)F)nc2-c2ccc(S(C)(=O)=O)cc2)cc1
Agent: Br
Solvent: O
Solvent: CC(=O)O
Product: CS(=O)(=O)c1ccc(-c2nc(C(F)(F)F)nn2-c2ccc(O)cc2)cc1
Temperature: 120 °C
Yield: 77.6 %

Procedure:
A mixture of 1-(4-methoxy-phenyl)-5-(4-methylsulfonyl-phenyl)-3-trifluoromethyl-1H-1,2,4-triazole (10 g, 25.2 mmol), 48% aqueous HBr (70 ml) and acetic acid (70 ml) was heated at 120° C. for 55 h. Then HBr 48% (20 ml) and AcOH (20 ml) were added and the mixture was heated again at 120° C. for 2 h. After cooling the solution was poured into water (2 l), the precipitate was filtered, washed several times with water and dried. Recrystallization from ethanol yielded a white solid (7.5 g, 78%).
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4](C(=O)C(Cl)(Cl)Cl)[NH:5][CH:6]=1.[CH3:13][OH:14].[CH3:15][O-:16].[Na+]>O.C(OCC)C>[I:1][C:2]1[CH:3]=[C:4]([C:13]([O:16][CH3:15])=[O:14])[NH:5][CH:6]=1
Reactant: CO
Reactant: O=C(c1cc(I)c[nH]1)C(Cl)(Cl)Cl
Reactant: C[O-]
Agent: [Na+]
Solvent: CCOCC
Solvent: O
Product: COC(=O)c1cc(I)c[nH]1
Reaction time: 4 h

Procedure:
8.2 g (24 mmol) of 4-iodo-2-trichloroacetylpyrrole and 100 ml of methanol were introduced into a round-bottomed flask and 2 g (36 mmol) of sodium methoxide were added. Stirring was carried out at room temperature for four hours, the reaction mixture was evaporated to dryness and the residue obtained was taken up in water and ethyl ether. The organic phase was separated by settling, dried over magnesium sulfate and evaporated. The residue obtained was triturated in heptane and filtered. 4.9 g (81%) of the expected ester, with a melting point of 77°-78° C., were recovered.