Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)C(Cl)=O.C(Cl)(=O)C1C=CC=CC=1.Br[C:21]1[CH:39]=[CH:38][C:24]([C:25]([CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][C:33]([O:35]CC)=O)=[O:26])=[CH:23][CH:22]=1.C(CCCCCCC(OCC)=O)(=O)C1C=CC=CC=1.[NH2:59][OH:60].Cl>C(N(CC)CC)C>[OH:60][NH:59][C:33](=[O:35])[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][C:25]([C:24]1[CH:38]=[C:39]([C:10]2[CH:9]=[CH:8][CH:4]=[CH:3][CH:2]=2)[CH:21]=[CH:22][CH:23]=1)=[O:26]
Reactant: CCOC(=O)CCCCCCC(=O)c1ccc(Br)cc1
Reactant: O=C(Cl)c1cccc(Br)c1
Reactant: NO
Agent: CCOC(=O)CCCCCCC(=O)c1ccccc1
Agent: Cl
Solvent: O=C(Cl)c1ccccc1
Solvent: CCN(CC)CC
Product: O=C(CCCCCCC(=O)c1cccc(-c2ccccc2)c1)NO
Yield: 35 %

Procedure:
Following the procedure described in Example 18, step 1, 2, but substituting respectively 3-bromobenzoyl chloride for benzoyl chloride, the resulting ester was substituted for 49d in Example 67, step 1. Then, following the procedure described in Example 18, step 3, but substituting the final ester for ester 49a, the resulting acid was substituted in Example 14, step 3, using 1.1 equivalent of NH2OH.HCl and triethylamine each, to afford the title compound 131 in 35% yield. 1H NMR (300 MHz, CDCl3): δ 8.13 (s, 1H), 7.88-7.30 (m, 8H), 2.96 (br t, 2H), 2.17 (m, 2H), 1.77-1.58 (m, 4H), 1.35 (m, 4H). 13C NMR (75 MHz, CDCl3) δ623.93, 25.12, 28.71(2), 32.73, 38.48, 126.61, 126.88, 127.08, 127.72, 128.85, 128.99, 131.58, 137.30, 140.06, 141.57, 171.82, 200.75.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[F:7][C:8]([F:18])([F:17])[C:9]1[S:10][CH:11]=[C:12]([C:14]([O-:16])=O)[N:13]=1.[Li+].[NH2:20][C:21]1[C:26]([Cl:27])=[C:25]([O:28][CH3:29])[CH:24]=[CH:23][C:22]=1[C:30](=[O:32])[CH3:31]>C(Cl)Cl.CN(C=O)C.O1CCOCC1>[C:30]([C:22]1[C:21]([NH:20][C:14]([C:12]2[N:13]=[C:9]([C:8]([F:7])([F:18])[F:17])[S:10][CH:11]=2)=[O:16])=[C:26]([Cl:27])[C:25]([O:28][CH3:29])=[CH:24][CH:23]=1)(=[O:32])[CH3:31]
Reactant: COc1ccc(C(C)=O)c(N)c1Cl
Reactant: O=C([O-])c1csc(C(F)(F)F)n1
Agent: O=C(Cl)C(=O)Cl
Agent: [Li+]
Solvent: CN(C)C=O
Solvent: C1COCCO1
Solvent: ClCCl
Product: COc1ccc(C(C)=O)c(NC(=O)c2csc(C(F)(F)F)n2)c1Cl
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 69 %

Procedure:
Oxalyl chloride (1.9 mL, 1.4 eq.) was added dropwise under nitrogen at 0° C. to a suspension of compound 252 (4 g, 1.2 eq.) in DCM (120 mL) and DMF (few drops). The reaction mixture was stirred at 0° C. for 30 min and then at room temperature for additional 3 hrs. The solid was removed by filtration under nitrogen and the filtrate was evaporated to give a yellow oil. This oil was solubilised in dioxane (30 mL) and added under nitrogen to a solution of 6-acetyl-2-chloro-3-methoxy aniline 201d (3.26 g, 1 eq.) in 1,4-dioxane (60 mL). The reaction mixture was stirred at room temperature for 3 days. The solvent was removed under reduced pressure, the residue was solubilised in dichloromethane, washed with water, dried over Na2SO4 and concentrated in vacuum. The crude oil was triturated in MeOH/Et2O mixture to give the compound 254a as a white solid in 69% yield. 1H NMR (CDCl3, 400 MHz): δ (ppm) 2.59 (s, 3H), 4 (s, 3H), 6.90 (d, J=8.75 Hz, 1H), 7.70 (d, J=8.75 Hz, 1H), 8.44 (s, 1H), 10.28 (s, 1H); 19F NMR (CDCl3, 376 MHz): δ (ppm) −61.08 (s, 3F).
Reaction SMILES: Cl[CH2:2][C:3]1[CH:22]=[CH:21][C:6]([O:7][CH2:8][C:9]2[N:10]=[C:11]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[O:12][C:13]=2[CH3:14])=[CH:5][CH:4]=1.[OH:23][C:24]1[CH:29]=[CH:28][C:27]([O:30][CH2:31][O:32][CH3:33])=[CH:26][C:25]=1[CH2:34][C:35]#[N:36].CN(C)C=O.[H-].[Na+]>O>[CH3:33][O:32][CH2:31][O:30][C:27]1[CH:28]=[CH:29][C:24]([O:23][CH2:2][C:3]2[CH:22]=[CH:21][C:6]([O:7][CH2:8][C:9]3[N:10]=[C:11]([C:15]4[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=4)[O:12][C:13]=3[CH3:14])=[CH:5][CH:4]=2)=[C:25]([CH2:34][C:35]#[N:36])[CH:26]=1
Reactant: Cc1oc(-c2ccccc2)nc1COc1ccc(CCl)cc1
Reactant: COCOc1ccc(O)c(CC#N)c1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COCOc1ccc(OCc2ccc(OCc3nc(-c4ccccc4)oc3C)cc2)c(CC#N)c1
Temperature: 80 °C
Reaction time: 1 h
Yield: 57.5 %

Procedure:
To a mixture of 4-(4-chloromethylphenoxymethyl)-5-methyl-2-phenyloxazole (1.95 g), 2-(2-hydroxy-5-methoxymethoxyphenyl)acetonitrile (1.0 g) and N,N-dimethylformamide (50 mL) was added sodium hydride (60%, oil, 0.23 g) under ice-cooling, and the mixture was stirred at 80° C. for 1 hr. The reaction mixture was poured into water and extracted with ethyl acetate. The organic, layer was washed successively with water, 2N aqueous sodium hydroxide solution and saturated brine, and dried over anhydrous magnesium sulfate. After concentration of the organic layer, the residue was subjected to silica gel column chromatography to give crystals (1.40 g, 57%) of 2-[5-methoxymethoxy-2-[4-[(5-methyl-2-phenyl-4-oxazolyl)methoxy]benzyloxy]phenyl]acetonitrile from a fraction eluted with ethyl acetate-hexane (1:3, v/v). Recrystallization from ethyl acetate-hexane gave colorless prism crystals. melting point: 123-124° C.
Reaction SMILES: [BH4-].[Na+].[CH3:3][NH2:4].[F:5][C:6]1[CH:7]=[C:8]([CH:24]=[CH:25][CH:26]=1)[CH2:9][NH:10][C:11]([NH:13][C:14]1[S:15][C:16]([CH:21]([CH3:23])[CH3:22])=[C:17]([CH:19]=O)[N:18]=1)=[O:12]>>[F:5][C:6]1[CH:7]=[C:8]([CH:24]=[CH:25][CH:26]=1)[CH2:9][NH:10][C:11]([NH:13][C:14]1[S:15][C:16]([CH:21]([CH3:23])[CH3:22])=[C:17]([CH2:19][NH:4][CH3:3])[N:18]=1)=[O:12]
Reactant: CN
Reactant: CC(C)c1sc(NC(=O)NCc2cccc(F)c2)nc1C=O
Agent: [BH4-]
Agent: [Na+]
Product: CNCc1nc(NC(=O)NCc2cccc(F)c2)sc1C(C)C
Reaction time: 6 h

Procedure:
NaBH4 (100 mg, 3 mmol) was added in portions to a mixture of MeNH2 (5 mL, 30% in EtOH) and 1-(3-fluorobenzyl)-3-(4-formyl-5-isopropylthiazol-2-yl)urea (322 mg, 1 mmol) at 0 C. The mixture was stirred for 6 hours then quenched with dilute HCl solution. Basic aqueous work-up with CH2Cl2 followed by flash chromatography afforded 1-(3-fluorobenzyl)-3-(5-isopropyl-4-((methylamino)methyl)thiazol-2-yl)urea. MS (ES+): M/Z 337 (M+H)+.
Reaction SMILES: C([O:8][C:9]1[C:14](=[O:15])[N:13]2[CH:16]=[CH:17][N:18]([CH2:19][C:20](=[O:27])[N:21]3[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]3)[C:12]2=[N:11][C:10]=1[C:28]1[O:29][C:30]([CH2:33][C:34]2[CH:39]=[CH:38][C:37]([F:40])=[CH:36][CH:35]=2)=[CH:31][N:32]=1)C1C=CC=CC=1.[Si](I)(C)(C)C.CO.[O-]S([O-])(=S)=O.[Na+].[Na+]>C(#N)C>[F:40][C:37]1[CH:36]=[CH:35][C:34]([CH2:33][C:30]2[O:29][C:28]([C:10]3[N:11]=[C:12]4[N:18]([CH2:19][C:20](=[O:27])[N:21]5[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]5)[CH:17]=[CH:16][N:13]4[C:14](=[O:15])[C:9]=3[OH:8])=[N:32][CH:31]=2)=[CH:39][CH:38]=1
Reactant: O=C(Cn1ccn2c(=O)c(OCc3ccccc3)c(-c3ncc(Cc4ccc(F)cc4)o3)nc12)N1CCCCC1
Agent: C[Si](C)(C)I
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: CO
Solvent: CC#N
Product: O=C(Cn1ccn2c(=O)c(O)c(-c3ncc(Cc4ccc(F)cc4)o3)nc12)N1CCCCC1
Reaction time: 8 h
Yield: 24.1 %

Procedure:
To a solution of the product of example 6 (50 mg, 0.092 mmol) in acetonitrile (2 ml) was added TMSI (150 mg, 0.75 mmol) drop-wise at room temperature. The mixture was stirred for 8 hours, after which methanol (0.1 ml) was added to quench the reaction. Then saturated solution of Na2S2O3 was added drop-wise till a yellow solid was precipitated. The resulting solids were collected by filtration, washed with ethyl acetate to give the desired product (10 mg, 24% yield).
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8]C)=[O:7])=[C:4]([NH:12][C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=2)[CH:3]=1.[F:20][C:21]1[CH:26]=[CH:25][C:24](B(O)O)=[CH:23][CH:22]=1.C(=O)([O-])[O-].[Na+].[Na+]>CN(C)C(=O)C>[F:19][C:16]1[CH:17]=[CH:18][C:13]([NH:12][C:4]2[CH:3]=[C:2]([C:24]3[CH:25]=[CH:26][C:21]([F:20])=[CH:22][CH:23]=3)[CH:11]=[CH:10][C:5]=2[C:6]([OH:8])=[O:7])=[CH:14][CH:15]=1
Reactant: COC(=O)c1ccc(Br)cc1Nc1ccc(F)cc1
Reactant: OB(O)c1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Product: O=C(O)c1ccc(-c2ccc(F)cc2)cc1Nc1ccc(F)cc1
Temperature: 90 °C
Reaction time: 12 h
Yield: 11.1 %

Procedure:
To N,N-dimethylacetamide 2.5 mL solution of methyl 4-bromo-2-(4-fluoroanilino)benzoate 70 mg were added 4-fluorophenylboronic acid 45 mg, sodium carbonate 57 mg and polymer-carried bis(acetato)triphenylphosphine palladium (II) 31 mg at room temperature, and it was stirred at 90° C. for 12 hours. After the reaction mixture was cooled to room temperature, insoluble matter was filtrated, and ethyl acetate and 1.0 mol/L hydrochloric acid were added to it. The organic layer was separated and collected,dried over anhydrous magnesium sulfate after sequential washing with 1.0 mol/L hydrochloric acid and saturated sodium chloride aqueous solution, and the solvent was removed under reduced pressure. 1.0 mol/L Sodium hydroxide aqueous solution 1.0 mL and ethanol 3.0 mL were added to the obtained residue, and it was stirred at room temperature for 1 hour. 6.0 mol/L Hydrochloric acid was added to the reaction mixture, solid matter was filtrated, and it was refined by silica gel column chromatography [Trikonex company, Flash Tube,2008, eluent; hexane:ethyl acetate:acetic acid=20:10:1] to give 2-(4-fluoroanilino)-4-(4-fluorophenyl)benzoic acid 7.8 mg of pale yellow solid.
Reaction SMILES: [Br:1][C:2]1[S:6][C:5]2[CH2:7][CH2:8][CH2:9][CH:10]([NH:11]C=O)[C:4]=2[CH:3]=1.[ClH:14]>>[ClH:14].[Br:1][C:2]1[S:6][C:5]2[CH2:7][CH2:8][CH2:9][CH:10]([NH2:11])[C:4]=2[CH:3]=1
Reactant: O=CNC1CCCc2sc(Br)cc21
Agent: Cl
Product: NC1CCCc2sc(Br)cc21

Procedure:
Acid hydrolysis of 2-bromo-N-formyl-4,5,6,7-tetrahydrobenzo[b]thien-4-amine (Example 35 ) with 1N hydrochloric acid after refluxing for one hour and evaporating to dryness affords 2-bromo-4,5,6,7-tetrahydrobenzo[b]thiophen-4-amine hydrochloride.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][OH:4].[Cl:5][C:6]1[CH:35]=[CH:34][C:9](/[CH:10]=[C:11]2\[N:12]=[C:13]([C:17]3[CH:22]=[CH:21][C:20]([O:23][CH2:24][CH2:25][C:26]4[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[CH:28][CH:27]=4)=[CH:19][CH:18]=3)[O:14][C:15]\2=[O:16])=[CH:8][CH:7]=1>C(O)C>[Cl:5][C:6]1[CH:7]=[CH:8][C:9](/[CH:10]=[C:11](\[NH:12][C:13](=[O:14])[C:17]2[CH:22]=[CH:21][C:20]([O:23][CH2:24][CH2:25][C:26]3[CH:27]=[CH:28][C:29]([O:32][CH3:33])=[CH:30][CH:31]=3)=[CH:19][CH:18]=2)/[C:15]([NH:1][CH2:2][CH2:3][OH:4])=[O:16])=[CH:34][CH:35]=1
Reactant: COc1ccc(CCOc2ccc(C3=N/C(=C\c4ccc(Cl)cc4)C(=O)O3)cc2)cc1
Reactant: NCCO
Solvent: CCO
Product: COc1ccc(CCOc2ccc(C(=O)N/C(=C\c3ccc(Cl)cc3)C(=O)NCCO)cc2)cc1
Temperature: 60 °C
Reaction time: 3 h
Yield: 71.1 %

Procedure:
2-Aminoethanol (18 μL, 0.30 mmol) was added to a solution of ethanol (0.7 mL) containing (4Z)-4-(4-chlorobenzylidene)-2-{-4-[2-(4-methoxyphenyl)ethoxy]phenyl}-1,3-oxazol-5(4H)-one prepared in Example 1 (1c) (108 mg, 0.25 mmol). The mixture was stirred at 60° C. for 3 hours. The solvent was evaporated, and the residue was purified by thin layer chromatography for separation (ethyl acetate:methanol, 30:1, v/v, developed three times) to give 88 mg of the title compound (white amorphous solid, yield: 71%).
Reaction SMILES: [CH:1]([C:4]1[O:8][N:7]=[C:6]([CH:9](O)[CH3:10])[CH:5]=1)([CH3:3])[CH3:2].C1(C)C=CC(S([Cl:21])(=O)=O)=CC=1.O>N1C=CC=CC=1>[Cl:21][CH:9]([C:6]1[CH:5]=[C:4]([CH:1]([CH3:3])[CH3:2])[O:8][N:7]=1)[CH3:10]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CC(C)c1cc(C(C)O)no1
Solvent: c1ccncc1
Solvent: O
Product: CC(C)c1cc(C(C)Cl)no1
Reaction time: 5 h
Yield: 57.3 %

Procedure:
5.66 g of 1-(5-i-propyl-isoxazol-3-yl)ethanol was dissolved in 30 ml of pyridine, and 7.20 g of 4-toluenesulfonyl chloride was then added under ice-cooling. The mixture was stirred for 5 hours under ice-cooling. After water was added, the reaction mixture was extracted with ethyl acetate. The organic layer was washed with water, dried over anhydrous magnesium sulfate, filtered and then concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to obtain 3.63 g of 3-(1-chloroethyl)-5-i-propylisoxazole.
Reaction SMILES: CCO[C:4](/[N:6]=N/C(OCC)=O)=O.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O[CH2:33][CH2:34][C:35]1[O:36][C:37]([CH2:40][CH2:41][O:42][CH2:43][C:44]2[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=2)=[CH:38][CH:39]=1.CC(C)(O)C#N>C1COCC1>[C:44]1([CH2:43][O:42][CH2:41][CH2:40][C:37]2[O:36][C:35]([CH2:34][CH2:33][C:4]#[N:6])=[CH:39][CH:38]=2)[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1
Reactant: CCOC(=O)/N=N/C(=O)OCC
Reactant: OCCc1ccc(CCOCc2ccccc2)o1
Agent: CC(C)(O)C#N
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: N#CCCc1ccc(CCOCc2ccccc2)o1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 25.9 %

Procedure:
DEAD (1.285 mL, 8.17 mmol) was added to a stirred solution of Ph3P (2.14 g, 8.17 mmol) in 12 mL of dry THF at 0° C. The solution was stirred for 30 min at rt and compound 255E (670 mg, 2.72 mmol) was added. The reaction was stirred for 15 min and acetone cyanohydrin (0.745 mL, 8.17 mmol) was added at −15° C. The reaction was stirred for 30 min at −15° C., then at rt overnight. The mixture was then concentrated under reduced pressure. Purification by flash chromatography on silica gel eluting with 100% CH2Cl2 gave 180 mg (0.705 mmol, 26%) of compound 255F as a colorless oil.
Reaction SMILES: [F:1][CH:2]([F:5])[CH2:3]Cl.[C:6]1(=[O:16])[NH:10][C:9](=[O:11])[C:8]2=[CH:12][CH:13]=[CH:14][CH:15]=[C:7]12.[K]>CN(C)C=O>[F:1][CH:2]([F:5])[CH2:3][N:10]1[C:6](=[O:16])[C:7]2[C:8](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:9]1=[O:11]
Reactant: FC(F)CCl
Reactant: O=C1NC(=O)c2ccccc21
Agent: [K]
Solvent: CN(C)C=O
Product: O=C1c2ccccc2C(=O)N1CC(F)F
Temperature: 120 °C
Reaction time: 12 h
Yield: 99.6 %

Procedure:
An amount of 21.4 g (0.214 mol) of 2,2-difluoro-1-chloroethane and 20 g (0.107 mol) of potassium phthalimide are dissolved in 95 g of N,N-dimethylformamide. The reaction mixture is stirred in an autoclave under pressure at 120° C. for 12 h. After the end of the reaction, cooling is carried out to ambient temperature and the solvent is exhaustively removed under vacuum. The remaining residue is treated with 100 ml of water and the solid is filtered off. The filter residue is washed twice with water and the product is dried under vacuum. An amount of 22.5 g of 2-(2,2-difluoroethyl)-1H-isoindole-1,3(2H)-dione with a purity of only 59% is obtained. This corresponds to a yield of 59% of theory.
Reaction SMILES: [O-:1]CC.[K+].[CH3:5][C:6]1[N:10]([C:11]2[CH:12]=[N:13][CH:14]=[CH:15][C:16]=2[C:17]([O:19]CC)=O)[N:9]=[N:8][N:7]=1.CN(C)C=O>C(O)(=O)C>[OH2:1].[N:9]1[N:10]2[C:11]3[C:16]([C:17]([OH:19])=[CH:5][C:6]2=[N:7][N:8]=1)=[CH:15][CH:14]=[N:13][CH:12]=3
Reactant: CCOC(=O)c1ccncc1-n1nnnc1C
Reactant: CC[O-]
Agent: [K+]
Solvent: CC(=O)O
Solvent: CN(C)C=O
Product: O
Product: Oc1cc2nnnn2c2cnccc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 90.9 %

Procedure:
Potassium ethoxide (20.2 g) was added to a mixture of ethyl 3-(5-methyl-1H-tetrazol-1-yl)pyridine-4-carboxylate (28 g) and dimethylformamide (280 mL). The reaction mixture was allowed to stir at ambient temperature overnight then poured into cold dilute acetic acid. The resulting precipitate was collected, washed with water and dried to provide 22.4 g of tetrazolo[1,5-a][1,7]naphthyridin-5-ol hydrate as a solid, m.p. 247-248° C. (decomposition). Analysis: Calculated for C8H5N5O: % C, 46.83; % H, 3.44; % N, 34.13; Found: % C, 46.48; % H, 3.42; % N, 34.03.
Reaction SMILES: P(Cl)(Cl)([Cl:3])=O.CN([CH:9]=[O:10])C.[C:11]1([N:17]2[C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[CH2:19][C:18]2=O)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.N1C=CC=CC=1>ClCCl.C(Cl)(Cl)Cl>[Cl:3][C:18]1[N:17]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:25]2[C:20]([C:19]=1[CH:9]=[O:10])=[CH:21][CH:22]=[CH:23][CH:24]=2
Reactant: O=C1Cc2ccccc2N1c1ccccc1
Reactant: O=P(Cl)(Cl)Cl
Reactant: CN(C)C=O
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: O=Cc1c(Cl)n(-c2ccccc2)c2ccccc12
Temperature: 5 °C
Reaction time: 0.5 h
Yield: 39.25 %

Procedure:
Phosphorous oxychloride (50 mL, 538 mmol) is added slowly to a solution of DMF (50 mL) in dichloromethane (50 mL) maintaining the temperature at 5° C. After 30 min, a solution of 1-phenyl-1H-indol-2-one (25 g, 120 mmol) and pyridine (25 mL, 309 mmol) in chloroform (125 mL) is added and the reaction is stirred 48 hr at room temperature. The reaction is poured into ice water (600 mL) and the aqueous layer is separated and extracted with chloroform (3×200 mL). The combined organic layer and extracts is dried, filtered and concentrated. The solid residue is crystallized from ethanol to afford 2-chloro-1-phenyl-1H-indole-3-carboxaldehyde (12.0 g, 39.25% yield) as an orange solid. NMR (CDCl3) 10.21 (1H, s), 8.37 (1H, d), 7.60 (3H, m), 7.41 (2H, m), 7.38 (1H, t), 7.28 (1H, m), 7.10 (1H, d). A second crop (7.5 g, 24.5% yield) is obtained by concentration of the filtrate and chromatography the residue eluting with dichloromethane.
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[NH:9][C:10]1[N:15]2[N:16]=[CH:17][C:18]([C:19](O)=[O:20])=[C:14]2[N:13]=[CH:12][C:11]=1[C:22]([N:24]1[CH2:29][CH2:28][CH:27]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[CH2:26][CH2:25]1)=[O:23].[CH2:36]([S:38]([NH2:41])(=[O:40])=[O:39])[CH3:37]>>[CH3:1][S:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[NH:9][C:10]1[N:15]2[N:16]=[CH:17][C:18]([C:19]([NH:41][S:38]([CH2:36][CH3:37])(=[O:40])=[O:39])=[O:20])=[C:14]2[N:13]=[CH:12][C:11]=1[C:22]([N:24]1[CH2:29][CH2:28][CH:27]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[CH2:26][CH2:25]1)=[O:23]
Reactant: CCS(N)(=O)=O
Reactant: CSc1ccccc1Nc1c(C(=O)N2CCC(c3ccccc3)CC2)cnc2c(C(=O)O)cnn12
Product: CCS(=O)(=O)NC(=O)c1cnn2c(Nc3ccccc3SC)c(C(=O)N3CCC(c4ccccc4)CC3)cnc12
Yield: 43.2 %

Procedure:
In the same manner as in Example 1, step 6 and using 7-(2-methylthiophenylamino)-6-(4-phenylpiperidine-1-carbonyl)pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (0.077 g, 0.16 mmol) obtained in step 2 and ethanesulfonamide (0.084 g, 0.80 mmol), the title compound (0.040 g, 43%) was obtained.
Reaction SMILES: [OH:1][CH:2]1[CH:9]2[CH2:10][C:5]3([C:12]([OH:14])=O)[CH2:6][CH:7]([CH2:11][CH:3]1[CH2:4]3)[CH2:8]2.C(N1C=CN=C1)(N1C=CN=C1)=O.[C:27]([OH:32])(=[O:31])[C:28]([OH:30])=[O:29].C(O)(=O)C(O)=O.[NH2:39][CH:40]1[CH2:45][CH2:44][N:43]([CH2:46][CH2:47][NH:48][C:49]([C:51]2[C:59]3[C:54](=[CH:55][CH:56]=[CH:57][CH:58]=3)[N:53]([CH:60]([CH3:62])[CH3:61])[N:52]=2)=[O:50])[CH2:42][CH2:41]1>CN(C)C=O>[C:27]([OH:32])(=[O:31])[C:28]([OH:30])=[O:29].[OH:1][CH:2]1[CH:9]2[CH2:10][C:5]3([C:12]([NH:39][CH:40]4[CH2:41][CH2:42][N:43]([CH2:46][CH2:47][NH:48][C:49]([C:51]5[C:59]6[C:54](=[CH:55][CH:56]=[CH:57][CH:58]=6)[N:53]([CH:60]([CH3:62])[CH3:61])[N:52]=5)=[O:50])[CH2:44][CH2:45]4)=[O:14])[CH2:6][CH:7]([CH2:11][CH:3]1[CH2:4]3)[CH2:8]2
Reactant: O=C(O)C12CC3CC(C1)C(O)C(C3)C2
Reactant: CC(C)n1nc(C(=O)NCCN2CCC(N)CC2)c2ccccc21
Agent: O=C(O)C(=O)O
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Product: CC(C)n1nc(C(=O)NCCN2CCC(NC(=O)C34CC5CC(C3)C(O)C(C5)C4)CC2)c2ccccc21
Temperature: 25 °C
Reaction time: 2 h
Yield: 46.6 %

Procedure:
A mixture of 0.50 g (2.55 mmol) of 4-hydroxy-1-adamantylcarboxylic acid and 0.44 g (2.71 mmol) of 1,1'-carbonyldiimidazole in 10 mL of dimethylformamide was stirred for 2 hours at ambient temperature. To this solution was dropwise added 0.90 g (2.75 mmol) of the product of Example 23 in 7 mL of dimethylformamide. The reaction was stirred for 18 hours and then concentrated in vacuo, diluted with dichloromethane and solids removed by filtration. The crude product was purified by chromatography (silica, 9:1 dichloromethane-methanol) to provide 0.71 g (55%) of the desired product as a foam. Further treatment of 500 mg of the product with 88 mg of oxalic acid in 15 mL of ethanol provided, upon concentration of the solution, 580 mg of the oxalate salt (LSN343032). 1H NMR (300 MHz, DMSO-d6) d 8.47 (t, 1H), 8.11 (d, 1H), 7.75 (d, 1H), 7.40 (t, 1H), 7.28 (d, 1H), 7.21 (t, 1H), 6.3 (br s, 3H), 5.04 (m, 1H), 3.74 (m, 1H), 3.59 (m, 3H), 3.40 (m, 2H), 3.13 (m, 2H), 2.95 (m, 2H), 1.95 (d, 2H), 1.69 (m, 13H), 1.47 (d, 6H), 1.25 (d, 2H).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:12])[C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([NH2:11])[CH:6]=1)[CH3:2].Cl[S:14]([OH:17])(=[O:16])=O.P(Cl)(Cl)(Cl)(Cl)Cl.[NH2:24][C:25]1[CH:53]=[CH:52][C:28]2[NH:29][C:30]([C:35]3[C:36](=[O:51])[N:37]([CH2:46][CH2:47][CH:48]([CH3:50])[CH3:49])[C:38]4[C:43]([C:44]=3[OH:45])=[CH:42][CH:41]=[CH:40][N:39]=4)=[N:31][S:32](=[O:34])(=[O:33])[C:27]=2[CH:26]=1.C(N(CC)CC)C.Cl>ClCCl>[OH:45][C:44]1[C:43]2[C:38](=[N:39][CH:40]=[CH:41][CH:42]=2)[N:37]([CH2:46][CH2:47][CH:48]([CH3:49])[CH3:50])[C:36](=[O:51])[C:35]=1[C:30]1[NH:29][C:28]2[CH:52]=[CH:53][C:25]([NH:24][S:14]([NH:11][C:7]3[CH:6]=[C:5]([CH:10]=[CH:9][CH:8]=3)[C:4]([O:3][CH2:1][CH3:2])=[O:12])(=[O:17])=[O:16])=[CH:26][C:27]=2[S:32](=[O:33])(=[O:34])[N:31]=1
Reactant: O=S(=O)(O)Cl
Reactant: CCOC(=O)c1cccc(N)c1
Reactant: CC(C)CCn1c(=O)c(C2=NS(=O)(=O)c3cc(N)ccc3N2)c(O)c2cccnc21
Agent: Cl
Agent: ClP(Cl)(Cl)(Cl)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)c1cccc(NS(=O)(=O)Nc2ccc3c(c2)S(=O)(=O)N=C(c2c(O)c4cccnc4n(CCC(C)C)c2=O)N3)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 50.7 %

Procedure:
A solution of 3-amino-benzoic acid ethyl ester (0.165 g, 1.0 mmol) in dichloromethane (6 mL ) at about 0° C. was added dropwise with chlorosulfonic acid (0.128 g, 1.1 mmol). The reaction mixture was stirred at 25° C. for 1 h and then phosphorous pentachloride (0.229 g, 1.1 mmol) was added and the reaction mixture heated under reflux for 3.5 hours. The reaction mixture was then cooled to about 25° C. and the solvent evaporated under reduced pressure. A solution of the residue in dichloromethane (10 mL) was treated with the product of Example 205 (0.214 g, 0.5 mmol), followed by triethylamine (0.152 g, 1.5 mmol). The reaction mixture was stirred at 25° C. for 3 hours and then poured into 25 mL of 1N aqueous hydrochloric acid. The reaction mixture was then extracted with dichloromethane (3×25 mL). The combined organics were dried over anhydrous magnesium sulfate, filtered, and evaporated under reduced pressure. The residue was purified by chromatography on silica gel, eluting with 0-2% methanol/dichloromethane to provide the title compound (0.166 g, 48% yield). 1H NMR (300 MHz, DMSO-d6) δ 0.98 (d, J=6.25 Hz, 6 H) 1.30 (t, J=7.17 Hz, 3 H) 1.56 (m, 2 H) 1.68 (m, 1 H) 4.29 (q, J=6.99 Hz, 2 H) 4.48 (m, 2 H) 7.44 (m, 4 H) 7.57 (d, J=2.21 Hz, 1 H) 7.62 (dt, J=7.36, 1.47 Hz, 1 H) 7.69 (d, J=8.82 Hz, 1 H) 7.74 (s, 1 H) 8.55 (dd, J=8.09, 1.84 Hz, 1 H) 8.88 (dd, J=4.41, 1.84 Hz, 1 H) 10.80 (s, 1 H) 10.88 (s, 1 H) 14.11 (s, 1 H). MS (ESI+) m/z 655.1 (M+H)+, 672.2 (M+NH4)+, 677.0 (M+Na)+, (ESI−) m/z 653.1 (M−H)−.