Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([Br:5])(Br)(Br)Br.OC[C:8]1[CH:9]=[C:10]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH:15]=2)[CH:11]=[CH:12][CH:13]=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>C(Cl)Cl>[Br:5][CH2:1][C:12]1[CH:11]=[C:10]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH:15]=2)[CH:9]=[CH:8][CH:13]=1
Reactant: BrC(Br)(Br)Br
Reactant: CCOC(=O)c1cccc(-c2cccc(CO)c2)c1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CCOC(=O)c1cccc(-c2cccc(CBr)c2)c1
Temperature: 25 °C

Procedure:
A mixture of ethyl-3-bromobenzoate (3.0 g, 13 mmol), [3-(hydroxymethyl)-phenyl]boronic acid (3.0 g, 20 mmol), PdCl2(PPh3)2 (0.46 g, 0.66 mmol), K2CO3 (3.6 g, 26 mmol), methanol (4 mL), and toluene (36 mL) was heated at 80° C. for 18 h under N2 and then allowed to cool to rt. The reaction mixture was filtered through Celite and then poured into a mixture of ethyl acetate and brine. The two layers were separated and the aqueous layer was extracted with ethyl acetate (×3). The organic extracts were dried (Na2SO4), filtered, concentrated and purified by silica gel chromatography to give ethyl 3′-(hydroxymethyl)biphenyl-3-carboxylate as an orange oil. A solution of CBr4 (5.8 g, 17 mmol) and CH2Cl2 (20 mL) was added dropwise to a solution of the above alcohol, PPh3 (4.6 g, 18 mmol), and CH2Cl2 (50 mL) at 0° C. under N2. The reaction was allowed to warm to rt, maintained for 2 h, concentrated, and purified by silica gel chromatography to give ethyl 3′-(bromomethyl)biphenyl-3-carboxylate as a clear oil. Ethyl 3′-(bromomethyl)biphenyl-3-carboxylate was used to alkylate 1-(2,2-dimethylpropyl)-4-propyl-1H-indol-5-ol following the procedure outlined in example 1. A mixture of the above indole (0.66 g, 1.4 mmol), 1 N LiOH (8 mL), and THF (8 mL) was heated at 40° C. for 2 d and then cooled to 0° C.—acetone can used in place of THF if faster reaction rates are desired. The reaction was acidified to pH=1 with conc. HCl and extracted with ethyl acetate (×3). The organic extracts were dried (Na2SO4), filtered, concentrated and purified by silica gel chromatography to give a yellow oil. 1H NMR (CDCl3, 500 MHz) δ 8.39 (s, 1H), 8.11 (d, 1H), 7.85 (d, 1H), 7.76 (s, 1H), 7.59-7.48 (m, 4H), 7.12 (d, 1H), 7.05 (d, 1H), 6.96 (d, 1H), 6.46 (d, 1H), 5.16 (s, 2H), 3.84 (s, 2H), 2.95 (t, 2H), 1.76 (m, 2H), 1.01 (t, 3H), 0.99 (s, 9H). MS (ESI): 456 (M+H).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[C:9]([SH:11])[CH:8]=[C:7]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:6]=1[OH:16])([CH3:4])([CH3:3])[CH3:2].[C:17]([O:21][C:22]([N:24]1[CH2:29][CH2:28][C:27](=[CH:30][C:31]([O:33][CH2:34][CH3:35])=[O:32])[CH2:26][CH2:25]1)=[O:23])([CH3:20])([CH3:19])[CH3:18]>N1CCCCC1.C(OCC)(=O)C>[C:17]([O:21][C:22]([N:24]1[CH2:29][CH2:28][C:27]([S:11][C:9]2[CH:8]=[C:7]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:6]([OH:16])=[C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])[CH:10]=2)([CH2:30][C:31]([O:33][CH2:34][CH3:35])=[O:32])[CH2:26][CH2:25]1)=[O:23])([CH3:20])([CH3:19])[CH3:18]
Reactant: CC(C)(C)c1cc(S)cc(C(C)(C)C)c1O
Reactant: CCOC(=O)C=C1CCN(C(=O)OC(C)(C)C)CC1
Solvent: C1CCNCC1
Solvent: CCOC(C)=O
Product: CCOC(=O)CC1(Sc2cc(C(C)(C)C)c(O)c(C(C)(C)C)c2)CCN(C(=O)OC(C)(C)C)CC1
Temperature: 90 °C
Yield: 94 %

Procedure:
A suspension of 2,6-di-tert-butyl-4-mercapto-phenol (1.2 g, 5.2 mmol) and 4-ethoxycarbonylmethylene-piperidine-1-carboxylic acid tert-butyl ester (1.2 g, 4.4 mmol) in 5 mL of piperidine was degassed and then heated to 90° C. for 15 h. The reaction was cooled to room temperature, toluene (10 mL) was added, and the mixture was concentrated under reduced pressure. The residue obtained was diluted with ethyl acetate (40 mL), washed with 1 N HCl (2×30 mL) and water (40 mL), dried over Na2SO4, and concentrated under reduced pressure. Chromatography (2-20% ethyl acetate/hexanes) afforded 4-(3,5-di-tert-butyl-4-hydroxy-phenylsulfanyl)-4-ethoxycarbonylmethyl-piperidine-1-carboxylic acid tert-butyl ester as a foamy solid (2.1 g, 94%). ESI/CI-MS m/z 506 ([M−H]−).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[C:11](=[O:26])[NH:12][C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[C:15]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=2)[CH:14]=1)[C:5](O)=[O:6].[NH2:27][C@@H:28]1[C:36]2[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=2)[CH2:30][C@@H:29]1[OH:37]>>[Cl:1][C:2]1[CH:3]=[C:4]([C:5]([NH:27][C@@H:28]2[C:36]3[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=3)[CH2:30][C@@H:29]2[OH:37])=[O:6])[CH:8]=[CH:9][C:10]=1[C:11]([NH:12][C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[C:15]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=2)[CH:14]=1)=[O:26]
Reactant: O=C(O)c1ccc(C(=O)Nc2ccc(Cl)c(-c3ccccn3)c2)c(Cl)c1
Reactant: N[C@@H]1c2ccccc2C[C@@H]1O
Product: O=C(N[C@@H]1c2ccccc2C[C@@H]1O)c1ccc(C(=O)Nc2ccc(Cl)c(-c3ccccn3)c2)c(Cl)c1

Procedure:
60 mg of 3-chloro-4-(4-chloro-3-(pyridin-2-yl)phenylcarbamoyl)benzoic acid was coupled to (1R,2S)-1-amino-2,3-dihydro-1H-inden-2-ol via Procedure G. The crude product was purified on reverse phase HPLC to yield 2-chloro-N1-(4-chloro-3-(pyridin-2-yl)phenyl)-N4-((1R,2S)-2-hydroxy-2,3-dihydro-1H-inden-1-yl)terephthalamide. MS (Q1) 518.2 (M)+.
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[F:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([C:20]2[CH:25]=[CH:24][C:23]([C@H:26]3[CH2:31][CH2:30][C@H:29]([CH2:32][CH2:33][CH2:34][CH2:35][CH3:36])[CH2:28][CH2:27]3)=[CH:22][CH:21]=2)[N:15]=1.B(OC(C)C)(OC(C)C)[O:38]C(C)C.Cl.[Cl-].[Na+]>O1CCCC1.CCCCCC.CCOCC>[F:13][C:14]1[C:19]([OH:38])=[CH:18][CH:17]=[C:16]([C:20]2[CH:21]=[CH:22][C:23]([C@H:26]3[CH2:31][CH2:30][C@H:29]([CH2:32][CH2:33][CH2:34][CH2:35][CH3:36])[CH2:28][CH2:27]3)=[CH:24][CH:25]=2)[N:15]=1
Reactant: CC(C)OB(OC(C)C)OC(C)C
Reactant: CCCCC[C@H]1CC[C@H](c2ccc(-c3cccc(F)n3)cc2)CC1
Agent: Cl
Agent: [Cl-]
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: CCOCC
Solvent: C1CCOC1
Product: CCCCC[C@H]1CC[C@H](c2ccc(-c3ccc(O)c(F)n3)cc2)CC1
Temperature: -78 °C
Reaction time: 4 h

Procedure:
0.49 ml (3.50 mmol) of diisopropylamine in 10 ml of tetrahydrofuran are stirred with 2.20 ml (3.50 mmol) of a 1.6-molar n-butyllithium solution in hexane at 0° C. for one hour. After cooling to -78° C., 0.94 g (2.90 mmol) of 2-fluoro-6-[4-(trans-4-pentylcyclohexyl)phenyl]pyridine in 120 ml of tetrahydrofuran is added dropwise, and the mixture is stirred at -78° C. for 4 hours. 1.31 g (6.96 mmol) of triisopropyl borate are then added dropwise at -78° C., and the reaction mixture is stirred overnight, during which it warms to room temperature. Addition of 4.40 ml of 10% hydrochloric acid and one hour of stirring at room temperature is followed by addition of sodium chloride solution, extraction with ether, washing of the ether phase with sodium chloride solution, drying over sodium sulfate, filtration and concentration. The residue is taken up in 50 ml of tetrahydrofuran, and the resulting mixture is refluxed together with 8.80 ml of a 17.5% hydrogen peroxide solution for 4 hours. After addition of sodium chloride solution, extraction with ether, washing of the organic phase with sodium sulfite solution and sodium chloride solution, drying over sodium sulfate, filtration, evaporation to dryness and purification of the residue by chromatography (silica gel, 9:1 hexane/ethyl acetate), 0.31 g of 2-fluoro-3-hydroxy-6-[4-(trans-4-pentylcyclohexyl)phenyl]pyridine is obtained. ##STR51##
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[O:10])=[CH:4][CH:3]=1.N1C(C)=CC=CC=1C.[Si:27](OS(C(F)(F)F)(=O)=O)([CH:34]([CH3:36])[CH3:35])([CH:31]([CH3:33])[CH3:32])[CH:28]([CH3:30])[CH3:29]>C(Cl)Cl>[CH:28]([Si:27]([CH:34]([CH3:36])[CH3:35])([CH:31]([CH3:33])[CH3:32])[O:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][C:9]([O:11][CH2:12][C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)=[O:10])=[CH:6][CH:7]=1)([CH3:30])[CH3:29]
Reactant: O=C(Cc1ccc(O)cc1)OCc1ccccc1
Reactant: CC(C)[Si](OS(=O)(=O)C(F)(F)F)(C(C)C)C(C)C
Solvent: Cc1cccc(C)n1
Solvent: ClCCl
Product: CC(C)[Si](Oc1ccc(CC(=O)OCc2ccccc2)cc1)(C(C)C)C(C)C
Temperature: 0 °C
Reaction time: 2.5 h

Procedure:
To benzyl 2-(4-hydroxyphenyl)acetate (E301) in CH2Cl2 at 0° C. was added 2,6-lutidine and TIPS-OTf and the solution stirred for 2.5 h at 0° C. The mixture was poured into NH4Cl(sat) and extracted with CH2Cl2. The combined organics were dried (Na2SO4), filtered, and evaporated. Column chromatography (SiO2, 0-15% EtOAc/Hex) gave pure benzyl 2-(4-(triisopropylsiloxy)phenyl)acetate (E302).
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[N:15]=[CH:16][C:17]3[NH:18][C:19](=[O:25])[CH2:20][CH2:21][CH2:22][C:23]=3[N:24]=2)[CH2:10][CH2:9]1)C1C=CC=CC=1.[H][H]>[Pd].C(O)C>[N:11]1([C:14]2[N:15]=[CH:16][C:17]3[NH:18][C:19](=[O:25])[CH2:20][CH2:21][CH2:22][C:23]=3[N:24]=2)[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]1
Reactant: O=C1CCCc2nc(N3CCN(Cc4ccccc4)CC3)ncc2N1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: O=C1CCCc2nc(N3CCNCC3)ncc2N1
Yield: 99.7 %

Procedure:
Added to 20 ml of ethanol were 0.1 g (0.3 mmol, Referential Example 51) of 2-(4-benzylpiperazino)-6-oxo-6,7,8,9-tetrahydro(5H)pyrimido[5,4-b]azepine and 0.01 g of 10% Pd-C. In a hydrogen atmosphere, they were reacted at 50° C. for 4 hours. After filtering off the Pd-C, the filtrate was dried to solid to obtain 0.074 g of colorless crystals in a quantitative yield.
Reaction SMILES: [NH2:1][C@H:2]([C:15]([O:17]C)=O)[CH2:3][C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[C:6]([C:11]([CH3:14])([CH3:13])[CH3:12])[CH:5]=1.[CH3:19][NH2:20].[C-]#N.[Na+]>CO>[NH2:1][C@H:2]([C:15]([NH:20][CH3:19])=[O:17])[CH2:3][C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[C:6]([C:11]([CH3:14])([CH3:13])[CH3:12])[CH:5]=1
Reactant: CN
Reactant: COC(=O)[C@@H](N)Cc1ccc(O)c(C(C)(C)C)c1
Agent: [C-]#N
Agent: [Na+]
Solvent: CO
Product: CNC(=O)[C@@H](N)Cc1ccc(O)c(C(C)(C)C)c1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of 10.6 g (42.0 mmol) of Tyr(3-tBu)-OMe in 80 ml of methanol, 80 ml of a solution of 40% methylamine in methanol and 0.41 g of sodium cyanide were added and the mixture was stirred at room temperature for 4 hours. The reaction mixture was concentrated under reduced pressure and the resulting residue was dissolved in methylene chloride, followed by washing first with water, then with saturated brine. The organic layer was dried with anhydrous sodium sulfate and concentrated under reduced pressure; the resulting residue was subjected to silica gel column chromatography (eluting solvent consisting of chloroform, methanol and aqueous ammonia at a ratio of 20:1:0.1) to give Tyr(3-tBu)-NHMe in the amount of 7.3 g (70%).
Reaction SMILES: CC(C)([O-])C.[Na+].Cl.[OH:8][CH:9]1[CH2:12][NH:11][CH2:10]1.Br[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C1(P(C2C=CC=CC=2)C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1(C)C=CC=CC=1>[C:14]1([N:11]2[CH2:12][CH:9]([OH:8])[CH2:10]2)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: Brc1ccccc1
Reactant: OC1CNC1
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [Na+]
Solvent: Cc1ccccc1
Product: OC1CN(c2ccccc2)C1

Procedure:
The mixture of 1.053 g of sodium tert-butoxide, 0.500 g of 3-hydroxyazetidine hydrochloride, 0.864 g of bromobenzene and 9 ml of toluene is initially charged under argon with stirring in a Schlenk apparatus. The mixture is admixed with a solution of 0.234 g of (+,−)-2,2′-bis(diphenylphosphino)-1,1′-binaphthyl and dipalladiumtris(dibenzylidenacetone)-chloroform complex in 2 ml of toluene (prepared in a Schlenk apparatus under argon) and the reaction mixture is stirred at 70° C. for 5 hours. The reaction mixture is cooled, poured onto ice-water (50 ml) and extracted with tert-butyl methyl ether (2×100 ml). The organic phases are washed with brine (50 ml), dried over sodium sulphate and concentrated by evaporation. The title compound is obtained as a reddish oil from the residue by means of flash chromatography (SiO2 60F). Rf=0.25 (1:1 EtOAc-heptane). Rt=2.01.
Reaction SMILES: [N:1]1([C:9]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[O:10])[CH2:8][CH2:7][CH2:6][C@H:2]1[C:3]([OH:5])=[O:4].CN1CCOCC1.[C:26]([C:28]1[CH:35]=[CH:34][C:31]([CH2:32][NH2:33])=[CH:30][CH:29]=1)#[N:27]>C1COCC1>[N:1]1([C:9]([O:11][CH2:12][C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)=[O:10])[CH2:8][CH2:7][CH2:6][C@H:2]1[C:3]([OH:5])=[O:4].[C:26]([C:28]1[CH:35]=[CH:34][C:31]([CH2:32][NH-:33])=[CH:30][CH:29]=1)#[N:27]
Reactant: N#Cc1ccc(CN)cc1
Agent: O=C(O)[C@@H]1CCCN1C(=O)OCc1ccccc1
Solvent: C1CCOC1
Solvent: CN1CCOCC1
Product: N#Cc1ccc(C[NH-])cc1
Temperature: -15 °C
Reaction time: 0.17 h

Procedure:
7.27 g (29.16 mmol) Z-Pro-OH and 3.2 ml (29.16 mmol) NMM were dissolved under stirring in 200 ml THF. Then the mixture was cooled to −15° C. and 3.79 ml (29.16 mmol) CKIBE were added. After about 10 minutes at −15° C., 4.24 g (32 mmol) 4-(cyano)benzylamine were added and stirring was continued for one hour at −15° C. and for another 12 hours at room temperature. The solvent was removed under vacuum; the residue was dissolved in 500 ml EE, and washed three times with 5% KHSO4 solution, one time with an NaCl-saturated solution, three times with an NaHCO3-saturated solution and three times with an NaCl-saturated solution, dried with Na2SO4 and concentrated in a vacuum.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:39]([O:40][CH3:41])=[CH:38][C:6]2[CH2:7][C:8](=[O:37])[N:9]([CH2:12][CH2:13][CH2:14][N:15](CC3C=CC=CC=3)[CH:16]3[CH2:25][CH2:24][C:23]4[C:18](=[CH:19][C:20]([O:28][CH3:29])=[C:21]([O:26][CH3:27])[CH:22]=4)[CH2:17]3)[CH2:10][CH2:11][C:5]=2[CH:4]=1>C(O)(=O)C.[Pd]>[CH3:1][O:2][C:3]1[C:39]([O:40][CH3:41])=[CH:38][C:6]2[CH2:7][C:8](=[O:37])[N:9]([CH2:12][CH2:13][CH2:14][NH:15][CH:16]3[CH2:25][CH2:24][C:23]4[C:18](=[CH:19][C:20]([O:28][CH3:29])=[C:21]([O:26][CH3:27])[CH:22]=4)[CH2:17]3)[CH2:10][CH2:11][C:5]=2[CH:4]=1
Reactant: COc1cc2c(cc1OC)CC(=O)N(CCCN(Cc1ccccc1)C1CCc3cc(OC)c(OC)cc3C1)CC2
Agent: [Pd]
Solvent: CC(=O)O
Product: COc1cc2c(cc1OC)CC(=O)N(CCCNC1CCc3cc(OC)c(OC)cc3C1)CC2

Procedure:
Here, 1-[7,8-dimethoxy-1,3,4,5-tetrahydro-2H-3-benzazepin-2-on-3-yl]-3-[N-benzyl-N-(6,7-dimethoxy-1,2,3,4-tetrahydronaphth-2-yl)-amino]-propane (0.78 g, 0.0014 mol) is hydrogenated in glacial acetic acid (20 ml) in the presence of 10% palladium/charcoal (0.1 g) for 3 hours at ambient temperature under pressure (5 bar). The catalyst is removed by suction filtering, the glacial acetic acid is distilled off in vacuo, the residue is taken up in methylene chloride/saturated potassium carbonate solution, the organic phase is washed with water, dried over magnesium sulphate, evaporated again and purified over alumina (100 g), neutral, activity II, with methylene chloride and then with increasing amounts of ethanol (up to 40%). The hydrochloride is precipitated from a solution in acetone with ethereal hydrochloric acid. Yield: 0.45 g Mp: 222°-223° C.
Reaction SMILES: [C:1](#[N:5])[CH2:2][C:3]#[N:4].[H-].[Na+].Br[C:9]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=1)([CH3:14])[C:10]([O:12][CH3:13])=[O:11].C(=O)=O.CO.CC#N>CN(C=O)C>[C:3]([CH:2]([C:1]#[N:5])[C:9]([CH3:14])([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=1)[C:10]([O:12][CH3:13])=[O:11])#[N:4]
Reactant: N#CCC#N
Reactant: COC(=O)C(C)(Br)c1ccccn1
Agent: O=C=O
Agent: [H-]
Agent: [Na+]
Solvent: CO
Solvent: CC#N
Solvent: CN(C)C=O
Product: COC(=O)C(C)(c1ccccn1)C(C#N)C#N
Temperature: 0 °C
Reaction time: 8 h

Procedure:
A DMF (7 mL) solution of malononitrile (0.413 g, 6.24 mmol) was added to a suspension of NaH (0.252 g, 6.30 mmol, 60%) in DMF (9 mL) cooled to 0° C. After 10 minutes a DMF (7 mL) solution of the intermediate from Step B (1.438 g, 5.89 mmol) was added. The reaction solution was then stirred overnight at room temperature. The solution was then partitioned between EtOAc and water. The organic layer was washed with brine, dried over MgSO4, filtered and concentrated. The residue was purified by silica gel chromatography using a hexanes/EtOAc gradient to give the indicated product. 1H NMR (400 MHz, CHCl3-d): δ 8.59 (d, J=4.8 Hz, 1H); 7.79 (td, J=7.7, 1.8 Hz, 1H); 7.50 (d, J=8.0 Hz, 1H); 7.32 (dd, J=7.6, 4.8 Hz, 1H); 5.25 (s, 1H); 3.77 (s, 3H); 2.01 (s, 3H). m/z=230.2 (M+H). The racemic material was resolved on a Berger SFC II preparative instrument using a ChiralCel IA-H, 250×30 mm I.D. column and a SFC CO2/Methanol/MeCN eluent.
Reaction SMILES: N12CCCNC1=NCCC2.[CH3:11]/[C:12](/[N+]([O-])=O)=[CH:13]\[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.[CH2:23]([O:25][C:26](=[O:30])[CH2:27][N+:28]#[C-:29])[CH3:24]>C(O)(C)C.C1COCC1>[CH2:23]([O:25][C:26]([C:27]1[NH:28][CH:29]=[C:12]([CH3:11])[C:13]=1[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:30])[CH3:24]
Reactant: C/C(=C\c1ccccc1)[N+](=O)[O-]
Reactant: [C-]#[N+]CC(=O)OCC
Agent: C1CN=C2NCCCN2C1
Solvent: C1CCOC1
Solvent: CC(C)O
Product: CCOC(=O)c1[nH]cc(C)c1-c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 89.2 %

Procedure:
1,5,7-Triazabicyclo[4.4.0]dec-5-ene on polystyrene (4.7 g, 2.6 mmol/g, 12.2 mmol) was added to a reaction mixture of trans-β-methyl-β-nitrostyrene (997 mg, 6.11 mmol) and isocyanoacetic acid ethyl ester (691 mg, 6.11 mmol) in isopropanol (5 mL) and THF (5 mL) and the reaction mixture was stirred overnight at RT under nitrogen as protective gas. The reaction mixture was filtered out and the residue washed with isopropanol and THF. The desired product 4-methyl-3-phenyl-1H-pyrrole-2-carboxylic acid ethyl ester (1.25 g, 89% of theoretical) was obtained.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[OH:11][CH2:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[C:25]#[N:26])=[CH:15][CH:14]=1.C(N(CC)CC)C>C(Cl)Cl.O>[C:25]([C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=1[C:16]1[CH:15]=[CH:14][C:13]([CH:12]=[O:11])=[CH:18][CH:17]=1)#[N:26]
Reactant: N#Cc1ccccc1-c1ccc(CO)cc1
Agent: O=C(Cl)C(=O)Cl
Solvent: O
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: N#Cc1ccccc1-c1ccc(C=O)cc1
Reaction time: 0.03 h

Procedure:
53 ml of oxalyl chloride in 2 litres of methylene chloride are cooled to -60°. A solution of 88 ml of dimethyl sulfoxide in 150 ml of methylene chloride is added dropwise at this temperature and the mixture is then stirred for 2 minutes. After this, 117 g of 4-hydroxymethyl-2'-cyanobiphenyl in 1 litre of methylene chloride are added dropwise at -60°. After addition has ended (about 5 minutes), the mixture is subsequently stirred for 15 minutes. After this, 390 ml of triethylamine are added dropwise. The mixture is then stirred at -60° for 2 minutes and allowed to wann to room temperature. The reaction mixture is poured into water, extracted with methylene chloride, and the organic phase is washed with dilute hydrochloric acid and brine, dried and concentrated. The product is stirred in hexane, filtered off with suction, washed and dried at 600 in a high vacuum. Elemental analysis: C 80.7%, H 4.5%, N 6.7%, O 7.7%.
Reaction SMILES: [CH2:1]([O:3][C:4]1[N:12]=[CH:11][C:10]([S:13]([N:16]2[CH2:21][CH2:20][N:19]([CH2:22][CH3:23])[CH2:18][CH2:17]2)(=[O:15])=[O:14])=[CH:9][C:5]=1[C:6]([OH:8])=O)[CH3:2].[NH2:24][C:25]1[C:26]([C:36]([NH2:38])=[O:37])=[N:27][N:28]([CH2:32][CH2:33][O:34][CH3:35])[C:29]=1[CH2:30][CH3:31].O>C(OCC)(=O)C>[C:36]([C:26]1[C:25]([NH:24][C:6](=[O:8])[C:5]2[CH:9]=[C:10]([S:13]([N:16]3[CH2:17][CH2:18][N:19]([CH2:22][CH3:23])[CH2:20][CH2:21]3)(=[O:14])=[O:15])[CH:11]=[N:12][C:4]=2[O:3][CH2:1][CH3:2])=[C:29]([CH2:30][CH3:31])[N:28]([CH2:32][CH2:33][O:34][CH3:35])[N:27]=1)(=[O:37])[NH2:38]
Reactant: CCc1c(N)c(C(N)=O)nn1CCOC
Reactant: CCOc1ncc(S(=O)(=O)N2CCN(CC)CC2)cc1C(=O)O
Solvent: O
Solvent: CCOC(C)=O
Product: CCOc1ncc(S(=O)(=O)N2CCN(CC)CC2)cc1C(=O)Nc1c(C(N)=O)nn(CCOC)c1CC
Temperature: 45 °C
Reaction time: 1 h

Procedure:
2-ethoxy-5-(4-ethyl-1-piperazinylsulfonyl)nicotinic acid (27.5 g, 0.08 Mol) was suspended in ethyl acetate (0.193 L) and 1,1-carbonyidimidazole (13.3 g, 0.082 Mol) was added at room temperature. The reaction mixture was heated at 45° C. for 15 minutes and then the reaction was stirred for a further 60 minutes at reflux. After cooling to ambient temperature 4-amino-5-ethyl-1-(2-methoxyethyl)-1H-pyrazole-3-carboxamide (16.5 g, 0.078 Mol) was added to the cooled mixture, and the reaction stirred for a further 17 hours under reflux. The solution was cooled and water (0.07 L) and ethyl acetate (0.17 L) added. The slurry was warmed to 40° C. and the organic separated. The organic was concentrated to by evaporating 0.23 L solvent. The slurry was cooled, granulated at 0-−10° C. filtered and the filter cake was washed with 90% water/10% ethyl acetate, (2 mL/g) to afford N-[3-carbamoyl-5-ethyl-1-(2-methoxyethyl)-1H-pyrazol-4-yl}-2-ethoxy-5-(4-ethyl-1-piperazinyl sulfonyl)nicotinamide as an off white crystalline solid, 38.7 g, 89%. m.p.=159-161° C.
Reaction SMILES: Br[C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][N:3]=1.[C:10]1(B(O)O)[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH:13]=[CH:12][CH:11]=1>>[C:18]1([C:2]2[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][N:3]=2)[C:19]2[C:14](=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:15]=[CH:16][CH:17]=1
Reactant: O=Cc1ccc(Br)nc1
Reactant: OB(O)c1cccc2ccccc12
Product: O=Cc1ccc(-c2cccc3ccccc23)nc1

Procedure:
Synthesized using compound 43c (720 mg, 3.87 mmol) and 1-naphthaleneboronic acid (1.00 g, 5.81 mmol) according to Method C. Crude product was purified by flash chromatography on silica-gel using a mixture of hexane/ethyl acetate (8:1) as eluent. Orange solid. Yield: 733 mg, 81%. 1H NMR (CDCl3, 500 MHz): δH (ppm)=7.50-7.62 (m, 3H), 7.65-7.69 (m, 1H), 7.77-7.81 (m, 1H), 7.92-8.00 (m, 2H), 8.10-8.14 (m, 1H), 8.31 (dd, J=7.9, 2.2 Hz, 1H), 9.25 (dd, J=2.2, 0.9 Hz, 1H), 10.22 (s, 1H); 13C NMR (CDCl3, 125 MHz): δC (ppm)=125.1, 125.2, 125.4, 126.2, 127.0, 128.0, 128.5, 129.7, 130.0, 130.7, 134.0, 136.1, 137.2, 152.1, 164.6, 190.5; MS (ESI): m/z=234.29 [M+H]+.
Reaction SMILES: C(S([NH:7][CH:8]([C:10]1[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][C:11]=1[CH2:12][OH:13])[CH3:9])=O)(C)(C)C.Cl.O1CCOCC1>CO>[NH2:7][CH:8]([C:10]1[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][C:11]=1[CH2:12][OH:13])[CH3:9]
Reactant: CC(NS(=O)C(C)(C)C)c1ccc(Cl)cc1CO
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: CC(N)c1ccc(Cl)cc1CO
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a stirred solution of 2-(1-tert-butylsulfinamidylethyl)-5-chlorobenzyl alcohol from step 2 of the L-519,502 synthesis (isomer 2, 0.654 g, 2.23 mmol) in MeOH (10 mL) at ambient temperature was added 4M HCl in dioxane (1.12 mL, 4.46 mmol). The resulting solution was stirred at ambient temperature for 0.5 h, then concentrated in vacuo. The residue was partitioned between EtOAc and water basified to pH=8 with saturated NaHCO3 solution. The EtOAc layer was separated, dried over anhydrous Na2SO4, and filtered. The filtrate solvent was removed under reduced pressure. 2-(1-aminoethyl)-5-chlorobenzyl alcohol was obtained as a pink oil that crystallizes on sitting (0.3 g; HPLC RT=2.07 min, method A; 1H NMR, 400 MHz, CDCl3, 7.32 ppm (d, 1H), 7.29 ppm (d, 1H), 7.24 ppm (dd, 1H), 4.76 ppm (d, 1H), 4.65 ppm (d, 1H), 4.34 ppm (q, 1H), 3.4 ppm (br s, 3H), 1.7 ppm (d, 3H).