Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[CH:9]=[N:10][N:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=23)[C:5]([Cl:17])=[CH:4][N:3]=1.[F:18][C:19]1[C:25]([N+:26]([O-:28])=[O:27])=[CH:24][C:22]([NH2:23])=[C:21]([O:29][CH3:30])[CH:20]=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>CC(O)CCC>[Cl:17][C:5]1[C:6]([C:8]2[CH:9]=[N:10][N:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=23)=[N:7][C:2]([NH:23][C:22]2[CH:24]=[C:25]([N+:26]([O-:28])=[O:27])[C:19]([F:18])=[CH:20][C:21]=2[O:29][CH3:30])=[N:3][CH:4]=1
Reactant: Clc1ncc(Cl)c(-c2cnn3ccccc23)n1
Reactant: COc1cc(F)c([N+](=O)[O-])cc1N
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCCC(C)O
Solvent: O
Product: COc1cc(F)c([N+](=O)[O-])cc1Nc1ncc(Cl)c(-c2cnn3ccccc23)n1
Yield: 79 %

Procedure:
A mixture of 3-(2,5-dichloropyrimidin-4-yl)pyrazolo[1,5-a]pyridine (Intermediate 21, 1.4 g, 5.28 mmol), 4-fluoro-2-methoxy-5-nitroaniline (Intermediate 23, 1.032 g, 5.55 mmol) and p-toluenesulfonic acid monohydrate (1.105 g, 5.81 mmol) was heated at 125° C. in 2-pentanol (40 mL) for 18 h. The mixture was then cooled and a solid was collected by filtration. The solid was washed with CH3OH and diethyl ether, and was then dried on the filter to give the title compound (1.73 g, 79%) as a yellow powder; 1H NMR: 3.98 (3H, s), 7.16 (1H, td), 7.33-7.48 (2H, m), 8.49 (1H, d), 8.53 (1H, d), 8.66 (1H, d), 8.86 (1H, d), 8.90 (1H, s), 8.96 (1H, s).
Reaction SMILES: Cl[C:2]1[C:7]([N:8]2[CH:12]=[CH:11][CH:10]=[N:9]2)=[CH:6][CH:5]=[CH:4][N:3]=1.C([Li])CCC.[O:18]=[C:19]1[CH2:24][CH2:23][N:22]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:21][CH2:20]1.O>C1COCC1>[N:9]1[N:8]2[C:7]3[CH:6]=[CH:5][CH:4]=[N:3][C:2]=3[O:18][C:19]3([CH2:20][CH2:21][N:22]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:23][CH2:24]3)[C:12]2=[CH:11][CH:10]=1
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Reactant: Clc1ncccc1-n1cccn1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC2(CC1)Oc1ncccc1-n1nccc12
Temperature: 70 °C
Yield: 5.4 %

Procedure:
To a solution of 2-chloro-3-pyrazol-1-yl-pyridine (338 mg, 1.88 mmol) in THF (3.4 mL) at −78° C. was added butyllithium (979 μL of 2.5 M, 2.45 mmol) dropwise over 5 minutes. The reaction mixture was then stirred at the temperature for 15 minutes before the addition of tert-butyl 4-oxopiperidine-1-carboxylate (562.5 mg, 2.82 mmol). The reaction was allowed to come to 25° C., then heated at 70° C. for 4 hours. The reaction mixture was poured into water, and extracted with EtOAc (3×). The organics were combined, washed with brine, dried (Na2SO4) and evaporated to dryness to yield a crude mixture that was purified by column chromatography (5 to 30% EtOAC in hexanes) to give the title product (35 mg, 5%) that was used in the next step without further purification. ESI-MS m/z calc. 342.2. found 343.3 (M+1)+. Retention time: 1.46 minutes (3 min run).
Reaction SMILES: Br[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1.[NH:10]1[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]1.C(=O)([O-])[O-].[K+].[K+].C(O)CCC.[ClH:27]>C(OCC)(=O)C>[ClH:27].[N:10]1([C:2]2[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=2)[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]1
Reactant: C1CNCCN1
Reactant: N#Cc1ccc(Br)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCCCO
Solvent: CCOC(C)=O
Product: N#Cc1ccc(N2CCNCC2)cc1

Procedure:
A mixture of 27.3 g (0.15 mol) of p-bromobenzonitrile, 38.7 g (0.45 mol) of piperazine and 42.0 g (0.30 mol) of solid potassium carbonate in a total volume of 60 mL of n-butanol was heated at reflux for 6 h under a nitrogen atmosphere. The mixture was concentrated under reduced pressure and the slurry partitioned between 10% sodium hydroxide and chloroform. The chloroform layer was separated, dried (MgSO4) and concentrated under reduced pressure to give an oil. The oil was eluted through a 400 g silica gel column with a 10% methanol in methylene chloride mixture. The appropriate fractions were concentrated under reduced pressure to give a golden oil. Trituration of this oil with ethyl acetate gave a white powder. The collected white powder was stirred for 15 min in ethereal HCl and recrystallized from methanol-water to give 1.5 g (4.5%)* of white solid, mp>160° C. with decomposition.
Reaction SMILES: [O:1]([CH2:8][C:9]1[CH:18]=[CH:17][C:12]([C:13]([O:15]C)=[O:14])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.[OH-].[Li+].O1CCC[CH2:23]1.Cl>O.CO>[CH3:23][C:17]1[CH:18]=[C:9]([CH2:8][O:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH:10]=[CH:11][C:12]=1[C:13]([OH:15])=[O:14]
Reactant: COC(=O)c1ccc(COc2ccccc2)cc1
Reactant: C1CCOC1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: Cc1cc(COc2ccccc2)ccc1C(=O)O
Temperature: 25 °C
Reaction time: 5 h
Yield: 81 %

Procedure:
A mixture of methyl 4-(phenoxymethyl)benzoate (1.1 g, 4.55 mmol), lithium hydroxide monohydrate (955 mg, 22.8 mmol), tetrahydrofuran (20 mL), methanol (7 mL) and water (7 mL) were stirred at room temperature for 5 hours. The mixture was neutralized to pH to 1 with concentrated hydrochloric acid and then extracted with ethyl acetate (15 mL×3). The combined organic phase was separated, dried over sodium sulfate, and then filtered. The filtrate was concentrated in vacuo to give methyl 4-(phenoxymethyl)benzoic acid as a white solid (840 mg, 81%). LRMS (M+H)− m/z: calcd 228.08. found 228.
Reaction SMILES: [CH3:1][N:2]([CH3:23])[C:3]1[CH:8]=[C:7]([NH:9][C:10]2[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][CH:11]=2)[N:6]=[C:5]([N:17]2[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]2)[N:4]=1.Cl[CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[O:32][CH3:33].C(N(CC)CC)C.C([O-])(O)=O.[Na+]>CN(C=O)C>[CH3:33][O:32][C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=1[CH2:25][N:20]1[CH2:19][CH2:18][N:17]([C:5]2[N:4]=[C:3]([N:2]([CH3:1])[CH3:23])[CH:8]=[C:7]([NH:9][C:10]3[CH:11]=[CH:12][C:13]([CH3:16])=[CH:14][CH:15]=3)[N:6]=2)[CH2:22][CH2:21]1
Reactant: Cc1ccc(Nc2cc(N(C)C)nc(N3CCNCC3)n2)cc1
Reactant: COc1ccccc1CCl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COc1ccccc1CN1CCN(c2nc(Nc3ccc(C)cc3)cc(N(C)C)n2)CC1
Temperature: 200 °C
Yield: 26.9 %

Procedure:
A mixture of N4,N4-dimethyl-N6-(4-methylphenyl)-2-(1-piperazinyl)-4,6-pyrimidinediamine (30 mg, 0.086 mmol), 1-(chloromethyl)-2-methoxybenzene (17 mg, 0.1 mmol) and triethylamine (200 mg, 2 mmol) in 1 DMF (1 mL) heated by microwave at 200° C. for 12 minutes. The crude product was treated with saturated NaHCO3 (50 mL) and extracted with EtOAC (3×50 mL). The organic layer was washed with brine (2×100 mL), dried over Na2SO4, filtered, and concentrated in vacuo. The crude product was purified by chromatography on silica using hexane/EtOAc (1:3), giving the desired product (10 mg, 27%).
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]=1[CH2:13][O:14][C:15]1[N:20]=[CH:19][C:18]([C:21]([NH:23][CH:24]2[CH2:29][CH2:28][CH2:27][N:26]([CH2:30][C:31]([OH:33])=O)[CH2:25]2)=[O:22])=[CH:17][CH:16]=1.[NH2:34][CH:35]1[CH2:40][CH2:39][O:38][CH2:37][CH2:36]1>>[CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:3]=1[CH2:13][O:14][C:15]1[CH:16]=[CH:17][C:18]([C:21]([NH:23][CH:24]2[CH2:29][CH2:28][CH2:27][N:26]([CH2:30][C:31](=[O:33])[NH:34][CH:35]3[CH2:40][CH2:39][O:38][CH2:37][CH2:36]3)[CH2:25]2)=[O:22])=[CH:19][N:20]=1
Reactant: Cc1onc(-c2ccccc2)c1COc1ccc(C(=O)NC2CCCN(CC(=O)O)C2)cn1
Reactant: NC1CCOCC1
Product: Cc1onc(-c2ccccc2)c1COc1ccc(C(=O)NC2CCCN(CC(=O)NC3CCOCC3)C2)cn1
Yield: 74 %

Procedure:
As described for example 42, (3-{[6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-pyridine-3-carbonyl]-amino}-piperidin-1-yl)-acetic acid (70 mg, 0.16 mmol) was converted, using 4-aminotetrahydropyran instead of methylamine, to the title compound (61 mg, 74%) which was obtained as an off white solid. MS: m/e=534.2 [M+H]+.
Reaction SMILES: [CH3:1][N:2]([CH3:15])[CH2:3][CH2:4][NH:5][C:6]1[CH:11]=[CH:10][C:9]([N+:12]([O-:14])=[O:13])=[CH:8][CH:7]=1.[C:16](Cl)(=[O:20])[CH2:17][CH2:18][CH3:19]>>[CH3:1][N:2]([CH3:15])[CH2:3][CH2:4][N:5]([C:6]1[CH:11]=[CH:10][C:9]([N+:12]([O-:14])=[O:13])=[CH:8][CH:7]=1)[C:16](=[O:20])[CH2:17][CH2:18][CH3:19]
Reactant: CCCC(=O)Cl
Reactant: CN(C)CCNc1ccc([N+](=O)[O-])cc1
Product: CCCC(=O)N(CCN(C)C)c1ccc([N+](=O)[O-])cc1

Procedure:
Prepared from 4-(2-dimethylamino-ethylamino)-nitrobenzene and butyryl chloride
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:6]([O:13][N:14]1[C:23](=[O:24])[C:22]2[C:17](=[CH:18][C:19](F)=[C:20]([F:25])[CH:21]=2)[N:16]([CH2:27][CH2:28][F:29])[C:15]1=[O:30])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.C(N(CC)CC)C>C(#N)C>[CH2:6]([O:13][N:14]1[C:23](=[O:24])[C:22]2[C:17](=[CH:18][C:19]([N:1]3[CH2:5][CH2:4][CH2:3][CH2:2]3)=[C:20]([F:25])[CH:21]=2)[N:16]([CH2:27][CH2:28][F:29])[C:15]1=[O:30])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: O=c1c2cc(F)c(F)cc2n(CCF)c(=O)n1OCc1ccccc1
Reactant: C1CCNC1
Solvent: CCN(CC)CC
Solvent: CC#N
Product: O=c1c2cc(F)c(N3CCCC3)cc2n(CCF)c(=O)n1OCc1ccccc1
Yield: 83 %

Procedure:
Pyrrolidine (0.04 mL, 0.52 mmol) was added to a solution of 3-benzyloxy-1-(2-fluoroethyl)-6,7-difluoro-1H-quinazoline-2,4-dione (Example D-4, 0.15 g, 0.42 mmol) and triethylamine (0.36 mL, 2.6 mmol) in 20 mL of acetonitrile. The solution was warmed to reflux for 17 hours, cooled, and concentrated to a solid. The solid was dissolved in chloroform washed with 1N HCl, saturated NaHCO3, brine and dried over magnesium sulfate. The solution was concentrated to give 0.14 g of the title compound as a solid.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([S:8]([NH:11][C:12]2[C:21](Cl)=[N:20][C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[N:13]=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[CH3:23][O:24][C:25]1[CH:26]=[C:27]([CH:29]=[C:30]([O:32][CH3:33])[CH:31]=1)[NH2:28].C1(C)C=CC=CC=1>CCOCC>[Cl:1][C:2]1[N:7]=[CH:6][C:5]([S:8]([NH:11][C:12]2[C:21]([NH:28][C:27]3[CH:29]=[C:30]([O:32][CH3:33])[CH:31]=[C:25]([O:24][CH3:23])[CH:26]=3)=[N:20][C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[N:13]=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: COc1cc(N)cc(OC)c1
Reactant: O=S(=O)(Nc1nc2ccccc2nc1Cl)c1ccc(Cl)nc1
Solvent: Cc1ccccc1
Solvent: CCOCC
Product: COc1cc(Nc2nc3ccccc3nc2NS(=O)(=O)c2ccc(Cl)nc2)cc(OC)c1
Temperature: 125 °C
Reaction time: 8 h
Yield: 88.6 %

Procedure:
6-Chloro-N-(3-chloroquinoxalin-2-yl)pyridine-3-sulfonamide (775 mg, 2.2 mmol), 3,5-dimethoxyaniline (355 mg, 2.3 mmol) and toluene (12 mL) were combined and heated to 125° C. with stirring overnight. The reaction was allowed to cool to room temperature and diluted with Et2O with vigorous stirring. The resulting solids were filtered, washed with Et2O and dried to give 6-chloro-N-(3-(3,5-dimethoxy-phenylamino)quinoxalin-2-yl)pyridine-3-sulfonamide (920 mg, 89%). 1H NMR (400 MHz, DMSO-d6) δ 12.20 (br s, 1H), 9.12 (d, 1H), 9.01 (br s, 1H), 8.53 (dd, 1H), 7.91 (br d, 1H), 7.77 (d, 1H), 7.60 (dd, 1H), 7.40 (m, 4H), 6.26 (m, 1H), 3.78 (s, 6H). MS (EI) m/z for C21H18ClN5O4S: 472.0 (MH+).
Reaction SMILES: [CH3:1][Si:2]([CH3:35])([CH3:34])[CH2:3][CH2:4][O:5][CH2:6][N:7]1[C:11]2[N:12]=[CH:13][N:14]=[C:15]([C:16]3[CH:17]=[N:18][N:19]([CH:21]([CH2:28][C:29](OCC)=[O:30])[CH2:22][C:23](OCC)=[O:24])[CH:20]=3)[C:10]=2[CH:9]=[CH:8]1.[AlH4-].[Li+]>C1COCC1>[CH3:35][Si:2]([CH3:1])([CH3:34])[CH2:3][CH2:4][O:5][CH2:6][N:7]1[C:11]2[N:12]=[CH:13][N:14]=[C:15]([C:16]3[CH:17]=[N:18][N:19]([CH:21]([CH2:22][CH2:23][OH:24])[CH2:28][CH2:29][OH:30])[CH:20]=3)[C:10]=2[CH:9]=[CH:8]1
Reactant: CCOC(=O)CC(CC(=O)OCC)n1cc(-c2ncnc3c2ccn3COCC[Si](C)(C)C)cn1
Agent: [AlH4-]
Agent: [Li+]
Solvent: C1CCOC1
Product: C[Si](C)(C)CCOCn1ccc2c(-c3cnn(C(CCO)CCO)c3)ncnc21
Reaction time: 1 h
Yield: 76 %

Procedure:
Diethyl 3-[4-(7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]pentanedioate, prepared substantially as described in Example 407 (0.80 g, 0.0016 mol), was dissolved in THF (40 mL, 0.49 mol) and cooled in an ice bath under a nitrogen atmosphere. To this mixture, 1.0 M lithium tetrahydroaluminate in THF (3.2 mL) was added slowly. The reaction was stirred for 1 h, quenched with ice and partitioned between ethyl acetate and 1 N HCl. The organic layer was washed with brine, dried over magnesium sulfate and concentrated to give an amber oil. The product was purified by FCC on silica gel eluting with an ethyl acetate:methanol gradient to give 3-[4-(7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]pentane-1,5-diol as a clear viscous oil (0.51 gm, 76%), LC/MS (M+H)+: 418, 1H NMR (DMSO-d6) δ, 8.85 (s, 1H), 8.41 (s, 1H), 8.37 (s, 1H), 7.45 (d, 1H), 6.83 (d, 1H), 5.73 (s, 2H), 4.91 (m, 1H), 3.75 (m, 2H), 3.59 (m, 2H), 3.45 (m, 2H), 2.18 (m, 4H), 0.95 (m, 2H), 0.1 (s, 9H).
Reaction SMILES: Cl.[NH2:2][C:3]1[CH:7]=[C:6]([Cl:8])[S:5][C:4]=1[S:9]([NH2:12])(=[O:11])=[O:10].[CH2:13]([N:19]=[C:20]=[S:21])[C:14]1[O:18][CH:17]=[CH:16][CH:15]=1>>[NH2:2][C:3]1[CH:7]=[C:6]([Cl:8])[S:5][C:4]=1[S:9]([NH:12][C:20]([NH:19][CH2:13][C:14]1[O:18][CH:17]=[CH:16][CH:15]=1)=[S:21])(=[O:10])=[O:11]
Reactant: S=C=NCc1ccco1
Reactant: Nc1cc(Cl)sc1S(N)(=O)=O
Agent: Cl
Product: Nc1cc(Cl)sc1S(=O)(=O)NC(=S)NCc1ccco1

Procedure:
The title compound was prepared from 3-amino-5-chlorothiophene-2-sulfonamide hydrochloride and furfuryl isothiocyanate by a procedure analogous to the procedure described in example 3-a (yield of crude product: 92%).
Reaction SMILES: [CH:1]([O:4][CH2:5][CH2:6][OH:7])([CH3:3])[CH3:2].C(N(CC)C(C)C)(C)C.[CH3:17][S:18](Cl)(=[O:20])=[O:19]>ClCCl>[S:18]([O:7][CH2:6][CH2:5][O:4][CH:1]([CH3:3])[CH3:2])(=[O:20])(=[O:19])[CH3:17]
Reactant: CC(C)OCCO
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)OCCOS(C)(=O)=O
Reaction time: 2 h

Procedure:
Combine 2-isopropoxyethanol (1.0 g, 9.6 mmol), N,N-diisopropylethylamine (2.73 g, 21.12 mmol), and dichloromethane (20 mL). Cool in an ice bath. Add dropwise methanesulfonyl chloride (1.43 g, 9.6 mmol). After 2 hours, dilute the reaction mixture with dichloromethane and extract with 1 M hydrochloric acid solution, a saturated solution of sodium bicarbonate, and then brine. Dry the organic layer over Na2SO4, filter, and evaporate in vacuo to give a residue. Distill the residue to give 2-(isopropoxy)ethyl mesylate: bp; 84° C. at 0.1 mm Hg.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([C:11]([F:16])([F:15])[CH2:12][O:13][CH3:14])=[N:9][N:10]=2)[CH:7]=1.[C:17]([C:19]1[CH:24]=[CH:23][C:22]([C:25]([F:28])([F:27])[F:26])=[CH:21][CH:20]=1)#[CH:18]>C1COCC1.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[F:15][C:11]([C:8]1[N:6]2[CH:7]=[C:2]([C:18]#[C:17][C:19]3[CH:24]=[CH:23][C:22]([C:25]([F:26])([F:27])[F:28])=[CH:21][CH:20]=3)[CH:3]=[CH:4][C:5]2=[N:10][N:9]=1)([F:16])[CH2:12][O:13][CH3:14]
Reactant: COCC(F)(F)c1nnc2ccc(Br)cn12
Reactant: C#Cc1ccc(C(F)(F)F)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: C1CCOC1
Product: COCC(F)(F)c1nnc2ccc(C#Cc3ccc(C(F)(F)F)cc3)cn12
Temperature: 70 °C
Reaction time: 8 h

Procedure:
To a stirred solution of 6-bromo-3-(1,1-difluoro-2-methoxyethyl)[1,2,4]triazolo[4,3-a]pyridine (46 mg, 0.16 mmol) in THF (5 mL) was added catalytical amount of dichlorobis(triphenylphosphine)palladium(II) (11 mg) and copper(I) iodide (3 mg), followed by 1-ethynyl-4-(trifluoromethyl)benzene (41 mg, 0.24 mmol). The resulting mixture was flushed with N2 and Et3N (2 mL) was added. The reaction mixture was stirred at 70° C. overnight and purified by prep-TLC (EtOAc:hexanes=2:3) followed by HPLC to give 3-(1,1-difluoro-2-methoxyethyl)-6-((4-(trifluoromethyl)phenyl)ethynyl)-[1,2,4]triazolo[4,3-a]pyridine.
Reaction SMILES: C(=O)([O-])O.[Na+].[CH3:6][N:7]1[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([O:16][CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH:14]=2)[C:9]([NH2:24])=[N:8]1.Cl[C:26]([O:28][CH2:29][CH3:30])=[O:27]>O1CCCC1.O>[CH3:6][N:7]1[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([O:16][CH2:17][C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=3)[CH:14]=2)[C:9]([NH:24][C:26](=[O:27])[O:28][CH2:29][CH3:30])=[N:8]1
Reactant: CCOC(=O)Cl
Reactant: Cn1nc(N)c2ccc(OCc3ccccc3)cc21
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CCOC(=O)Nc1nn(C)c2cc(OCc3ccccc3)ccc12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 79.2 %

Procedure:
9.8 g of sodium hydrogen carbonate (0.117 mol) are added to a solution of 19.7 g (0.078 mol) of 1-methyl-6-(phenylmethoxy)-1H-indazol-3-amine in 200 ml of a 9:1 mixture of tetrahydrofuran/water, and then 8.9 ml (0.093 mol) of ethyl chloroformate are added dropwise while maintaining the temperature at 25° C. A milky suspension is obtained which is left with stirring for 30 minutes, and then the solvent is evaporated off under reduced pressure. The residue is treated with dichloromethane and water. The organic phase is decanted off, dried over sodium sulphate and concentrated under reduced pressure. The product is crystallized from diisopropyl ether. 20.1 g of product are obtained.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([S:9]([CH:12]2[S:16][C:15](=[O:17])[NH:14][C:13]2=[O:18])(=[O:11])=[O:10])=[CH:5][CH:4]=1.Br[CH2:20][C:21]1[CH:26]=[CH:25][C:24]([C:27]2[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][C:28]=2[Cl:34])=[CH:23][CH:22]=1>CN(C)C=O>[Cl:34][C:28]1[CH:29]=[C:30]([Cl:33])[CH:31]=[CH:32][C:27]=1[C:24]1[CH:23]=[CH:22][C:21]([CH2:20][C:12]2([S:9]([C:6]3[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=3)(=[O:10])=[O:11])[S:16][C:15](=[O:17])[NH:14][C:13]2=[O:18])=[CH:26][CH:25]=1
Reactant: COc1ccc(S(=O)(=O)C2SC(=O)NC2=O)cc1
Reactant: Clc1ccc(-c2ccc(CBr)cc2)c(Cl)c1
Solvent: CN(C)C=O
Product: COc1ccc(S(=O)(=O)C2(Cc3ccc(-c4ccc(Cl)cc4Cl)cc3)SC(=O)NC2=O)cc1

Procedure:
Prepared analogously to Example 9 from from 5-(4-methoxybenzenesulfonyl)thiazolidine-2,4-dione and 4′-bromomethyl-2,4-dichlorobiphenyl in N,N-dimethylformamide. Column chromatography provided an off-white solid. 1H NMR: δ 8.01 (v br s, 1H), 7.93 (dm, J=9.0 Hz, 2H), 7.47 (d, J=2.0 Hz, 1H), 7.22-7.35 (m, 6H), 7.07 (dm, J=9.0 Hz, 2H), 3.98 (a of ab, J=13.7 Hz, 1H), 3.93 (s, 3H), 3.40 (b of ab, J=13.7 Hz, 1H). MS (m/e): 519.9 (M−H)−. Anal: Calc for C23H17Cl2NO5S2.0.75 C4H10O: 54.03% C, 4.27% H, 2.42% N; Found: 53.63% C, 4.33% H, 2.23% N. MP: 104-107° C.
Reaction SMILES: [C:1]1([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:6]=[CH:5][C:4]([CH2:7][C@H:8]2[NH:12][C:11](=[O:13])[CH2:10][CH2:9]2)=[CH:3][CH:2]=1.C([Li])CCC.[C:25](Cl)(=[O:30])[C:26]([CH3:29])([CH3:28])[CH3:27]>O1CCCC1>[C:1]1([C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:2]=[CH:3][C:4]([CH2:7][C@H:8]2[N:12]([C:25](=[O:30])[C:26]([CH3:29])([CH3:28])[CH3:27])[C:11](=[O:13])[CH2:10][CH2:9]2)=[CH:5][CH:6]=1
Reactant: O=C1CC[C@@H](Cc2ccc(-c3ccccc3)cc2)N1
Reactant: CC(C)(C)C(=O)Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(C)(C)C(=O)N1C(=O)CC[C@H]1Cc1ccc(-c2ccccc2)cc1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
20 g of (S)-5-biphenyl-4-ylmethylpyrrolidin-2-one (1-a, R1=H) of example 3 were dissolved in 200 ml tetrahydrofuran. The mixture was cooled to about −78° C. and 55 ml n-butyllithium (1.6 M) were added. After about 0.5 hours, 11.8 ml of pivaloyl chloride were added. After 1 hour, the mixture was quenched with 210 ml ammonium chloride solution and extracted with 70 ml ethyl acetate. The mixture was concentrated to dryness to obtain 26/g of (S)-5-biphenyl-4-ylmethyl-1-(2,2-dimethylpropionyl)pyrrolidin-2-one (1, R1=pivaloyl). 1H-NMR (CDCl3): 1.40 (9H, s, C(CH3)3); 1.91 (1H, m, 4-CHH); 2.03 (1H, m, 4-CHH); 2.47 (1H, m, 3-CHH); 2.55 (1H, m, 3-CHH); 2.74 (1H, dd, 1-CHH); 3.18 (1H, dd, 1-CHH); 4.67 (1H, m, 5-CH); 7.34 (2H, m, aromatic); 7.36 (1H, m, aromatic); 7.46 (2H, m, aromatic); 7.58 (4H, m, aromatic). m/z: 336 (MH+, 100%).
Reaction SMILES: [C:1]1([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[CH:6]=[CH:5][C:4]([CH2:7][CH2:8][NH:9][C:10]([C:12]2[CH:32]=[CH:31][C:15]([O:16][C:17]3[CH:26]=[C:25]4[C:20]([CH:21]([C:27]([OH:29])=[O:28])[CH2:22][CH2:23][O:24]4)=[CH:19][C:18]=3[Cl:30])=[CH:14][CH:13]=2)=[O:11])=[CH:3][CH:2]=1.C[O-].[Na+:41].CO>CO.C1COCC1>[C:1]1([C:33]2[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=2)[CH:2]=[CH:3][C:4]([CH2:7][CH2:8][NH:9][C:10]([C:12]2[CH:13]=[CH:14][C:15]([O:16][C:17]3[CH:26]=[C:25]4[C:20]([CH:21]([C:27]([O-:29])=[O:28])[CH2:22][CH2:23][O:24]4)=[CH:19][C:18]=3[Cl:30])=[CH:31][CH:32]=2)=[O:11])=[CH:5][CH:6]=1.[Na+:41]
Reactant: O=C(NCCc1ccc(-c2ccccc2)cc1)c1ccc(Oc2cc3c(cc2Cl)C(C(=O)O)CCO3)cc1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: O=C(NCCc1ccc(-c2ccccc2)cc1)c1ccc(Oc2cc3c(cc2Cl)C(C(=O)[O-])CCO3)cc1
Yield: 102 %

Procedure:
7-(4-(2-(Biphenyl-4-yl)ethylcarbamoyl)phenoxy)-6-chlorochroman-4-carboxylic acid (42 mg, 0.07955 mmol) was dissolved in MeOH-THF (1 ml-1-ml). A 0.5 M solution of NaOMe in MeOH (159.1 μl, 0.0795 mmol) was added and the mixture was stirred for few minutes. The crude mixture was concentrated and chased with EtOAc and dichloromethane to provide 44.6 mg of the title compound as a white solid (102%). MS (apci) m/z=528.1 (M+2H-Na).
Reaction SMILES: [C:1]1([S:7]([CH2:10][CH2:11][N:12]2[C:20]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[C:14]3[CH2:21][CH2:22][N:23](C(OC(C)(C)C)=O)[CH2:24][CH2:25][C:13]2=3)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.FC(F)(F)C(O)=O>C(Cl)Cl>[C:1]1([S:7]([CH2:10][CH2:11][N:12]2[C:20]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[C:14]3[CH2:21][CH2:22][NH:23][CH2:24][CH2:25][C:13]2=3)(=[O:9])=[O:8])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CC(C)(C)OC(=O)N1CCc2c(n(CCS(=O)(=O)c3ccccc3)c3ccccc23)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=S(=O)(CCn1c2c(c3ccccc31)CCNCC2)c1ccccc1
Yield: 11.3 %

Procedure:
tert-Butyl 6-[2-(phenylsulfonyl)ethyl]-1,4,5,6-tetrahydroazepino[4,5-b]indole-3(2H)-carboxylate (0.139 g, 0.306 mmol) was treated with trifluoroacetic acid (1 mL) for 5 min. CH2Cl2 was added and the reaction mixture was concentrated to dryness. The salt was partitioned between CH2Cl2 and a mixture of 1M KOH and brine. The organic layer was dried over MgSO4, filtered and concentrated. The crude product was chromatographed (SiO2, eluted with 1:1 EtOAc:hexane) to give 6-[2-(phenylsulfonyl)ethyl]-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole (0.0123 g) as a white solid. 1H NMR (300 MHz, CD3OD) δ 3.13, 3.29-3.33, 3.42, 3.50, 3.71, 4.65, 7.07, 7.14, 7.22, 7.42, 7.51, 7.66, 7.70.
Reaction SMILES: [Na].[C:2]1([C:8]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[SH:9])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:22](Br)[CH:23]=[CH2:24]>CO>[CH2:24]([S:9][C:8]([C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)([C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1)[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1)[CH:23]=[CH2:22]
Reactant: C=CCBr
Reactant: SC(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Na]
Solvent: CO
Product: C=CCSC(c1ccccc1)(c1ccccc1)c1ccccc1

Procedure:
Initially, sodium (2 g) was added to 200 mL MeOH in a reflux apparatus, stirred until the sodium was dissolved, and then 25 g of triphenylmethanethiol (TrSH) was added. The reaction mixture was refluxed for 1 hour, 10 mL allyl bromide was then added, and the mixture was refluxed for another 2 hours. The solution was allowed to cool, 19 g of particulate material, trityl allyl sulfide (TrSAll), was obtained by filtration using filter paper, and it was used directly for the next step without any purification. tert-BuOK (11 g) was added to a solution of 19 g of TrSAll in 100 mL anhydrous tetrahydrofuran (THF) and 200 mL tert-BuOH, and the reaction mixture was stirred at 20-22° C. overnight. The solvent in the reaction mixture was removed by rotary evaporation, water and CH2Cl2 was added to the residue, and the product was extracted into the CH2Cl2 phase. Trityl 1-propenyl sulfide (TrSPe) was obtained as a white color powder by purification of the CH2Cl2 extract on a silica gel column eluted with 10% CH2Cl2 in hexane.