Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][C:7]([CH:10]=O)=[CH:6][CH:5]=1.[NH:13]1[CH2:17][CH2:16][CH2:15][CH2:14]1.C(O)(=O)C.[B-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C(Cl)Cl>[CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][C:7]([CH2:10][N:13]2[CH2:17][CH2:16][CH2:15][CH2:14]2)=[CH:6][CH:5]=1
Reactant: C1CCNC1
Reactant: COC(=O)c1ccc(C=O)cc1
Agent: CC(=O)O[B-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Product: COC(=O)c1ccc(CN2CCCC2)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A solution of 4-formyl-benzoic acid methyl ester (10 g), pyrrolidine (5.6 mL), and acetic acid (3.5 mL) in DCM (200 mL) was treated with sodium triacetoxyborohyride (20.65 g) and stirred at rt for 16 hours. The reaction mixture was then quenched with 3N NaOH (70 mL). The organic layer was dried over sodium sulfate and concentrated to yield the titled compound without purification.
Reaction SMILES: [C:1]1([C@@H:7]2[CH2:9][C@H:8]2[NH:10][CH2:11][CH2:12][CH:13]2[CH2:18][CH2:17][N:16](C(OC(C)(C)C)=O)[CH2:15][CH2:14]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.O1CCOCC1>C(Cl)(Cl)Cl>[C:1]1([C@@H:7]2[CH2:9][C@H:8]2[NH:10][CH2:11][CH2:12][CH:13]2[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CC(C)(C)OC(=O)N1CCC(CCN[C@@H]2C[C@H]2c2ccccc2)CC1
Agent: Cl
Solvent: C1COCCO1
Solvent: ClC(Cl)Cl
Product: c1ccc([C@@H]2C[C@H]2NCCC2CCNCC2)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 30.7 %

Procedure:
Chloroform (50 mL) was added to a 200 mL round-bottomed flask containing tert-butyl 4-(2-((trans-2-phenylcyclopropyl)amino)ethyl)piperidine-1-carboxylate (161 mg, 0.467 mmol). HCl/1,4-Dioxane (1 mL, 4.00 mmol) was added and the mixture stirred 18 hours at room temperature. Upon completion, the residue was adsorbed directly onto silica and purified via column chromatography on the ISCO Companion (gradient 0-100% 80:20:2 [CHCl3/MeOH/NH4OH]/CHCl3; 4 g column) Fractions were collected, solvents removed and the resulting residue was taken up in MeOH (2 mL). Excess 2M HCl in Et2O was added and the solution stirred for 10 minutes. The solvent was removed to yield the 2HCl of the desired product (35 mg, 22% yield) as a brown solid: LC-MS (ES) m/z=245 (M+H)+, 1H NMR (400 MHz, MeOH-d4) δ ppm 1.39 (br. s., 1H) 1.51 (br. s., 4H) 1.79 (br. s., 3H) 2.00 (br. s., 2H) 2.61 (br. s., 1H) 3.02 (br. s., 3H) 3.29 (br. s., 1H) 3.35-3.53 (m, 2H) 7.17-7.28 (m, 3H) 7.28-7.36 (m, 2H).
Reaction SMILES: Cl.CN(C)CCCN=C=NCC.[C:13]1([CH2:19][O:20][N:21]2[C:27](=[O:28])[N:26]3[CH2:29][C@H:22]2[CH2:23][CH2:24][C@H:25]3[C:30]([OH:32])=[O:31])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.O[CH2:34][CH:35]1[CH2:40][CH2:39][N:38]([C:41]([O:43][C:44]([CH3:47])([CH3:46])[CH3:45])=[O:42])[CH2:37][CH2:36]1>CN(C)C1C=CN=CC=1.ClCCl>[CH2:19]([O:20][N:21]1[C:27](=[O:28])[N:26]2[CH2:29][C@H:22]1[CH2:23][CH2:24][C@H:25]2[C:30]([O:32][CH2:34][CH:35]1[CH2:40][CH2:39][N:38]([C:41]([O:43][C:44]([CH3:45])([CH3:47])[CH3:46])=[O:42])[CH2:37][CH2:36]1)=[O:31])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: O=C(O)[C@@H]1CC[C@@H]2CN1C(=O)N2OCc1ccccc1
Reactant: CC(C)(C)OC(=O)N1CCC(CO)CC1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC(COC(=O)[C@@H]2CC[C@@H]3CN2C(=O)N3OCc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (109 mg, 0.57 mmol) and 4-dimethylaminopyridine (69.6 mg, 0.57 mmol) were added sequentially to a solution of (2S,5R)-6-(phenylmethoxy)-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carboxylic acid (105 mg, 0.38 mmol) in dry dichloromethane at room temperature. tert-Butyl 4-(hydroxymethyl)piperidine-1-carboxylate (123 mg, 0.57 mmol) was then added and the reaction mixture was stirred at room temperature overnight, and then concentrated under vacuum. The residue was purified by preparative HPLC to afford the title compound.
Reaction SMILES: [N+:1]([CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])([O-:3])=O.C[Si](C)(C)[O:19][C:20]#[C:21][CH3:22].C1(N=C=O)C=CC=CC=1.C(N(CC)CC)C>C1C=CC=CC=1>[CH2:5]([C:4]1[CH:22]=[C:21]([CH2:20][OH:19])[O:3][N:1]=1)[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: CC#CO[Si](C)(C)C
Reactant: CCCCCCCCCCCCC[N+](=O)[O-]
Solvent: O=C=Nc1ccccc1
Solvent: c1ccccc1
Solvent: CCN(CC)CC
Product: CCCCCCCCCCCCc1cc(CO)on1
Temperature: 60 °C
Reaction time: 0.5 h
Yield: 85.8 %

Procedure:
To a solution of 1-nitrotridecane (10.5 g) and O-trimethylsilyl-propynol (5.88 g) in dry benzene (100 ml) was added dropwise a solution of freshly distilled phenylisocyanate (10.9 g) and triethylamine (5.56 g) in dry benzene (40 ml) at 40 ° C., with mechanical stirring. The mixture was heated to 60° C. for 3.5 hr, cooled, and filtered. The filtrate was evaporated, taken up in tetrahydrofuran (300 ml) and 1.0M tetrabutylammonium fluoride (8 ml) was added. After 30 mins, the mixture was evaporated and the residue was purified by flash chromatography (silica gel, 2% methanol:dichloromethane). The appropriate fractions were collected and evaporated to give 10.5 g (86%) of product, mp 61°-63° C.
Reaction SMILES: [N:1]1[C:8](Cl)=[N:7][C:5](Cl)=[N:4][C:2]=1Cl.[Cl-].[Al+3].[Cl-].[Cl-].[CH3:14][C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][C:20]=1[CH3:21]>>[CH3:14][C:15]1[CH:16]=[C:17]([C:2]2[N:4]=[C:5]([C:17]3[CH:18]=[CH:19][C:20]([CH3:21])=[C:15]([CH3:14])[CH:16]=3)[N:7]=[C:8]([C:17]3[CH:18]=[CH:19][C:20]([CH3:21])=[C:15]([CH3:14])[CH:16]=3)[N:1]=2)[CH:18]=[CH:19][C:20]=1[CH3:21]
Reactant: Clc1nc(Cl)nc(Cl)n1
Reactant: Cc1ccccc1C
Agent: [Al+3]
Agent: [Cl-]
Product: Cc1ccc(-c2nc(-c3ccc(C)c(C)c3)nc(-c3ccc(C)c(C)c3)n2)cc1C
Temperature: 25 °C

Procedure:
A mixture of 36.8 g. (0.20 mole) of cyanuric chloride, 88.0 g. (0.66 mole) of anhydrous aluminum chloride and 250 ml. of o-xylene was heated at 45°C for 1.5 hours. After cooling to room temperature, the mixture was poured into ice water, and then steam distilled to remove the excess o-xylene. The water was decanted from the pot residue and the remaining solid filtered, washed with acetone and dried to yield 58.1 g. of product, m.p. 220°-230°. Recrystallization from benzene gave an analytically pure sample, m.p. 235°-236°.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]2[C:9]([CH:10]([CH2:14][CH2:15][CH3:16])[CH2:11][CH2:12][CH3:13])=[CH:8][C:7]([CH3:17])=[N:6][N:5]2[CH:18]=1.Br[C:20]1[S:24][C:23]([C:25]2[N:29]([CH3:30])[N:28]=[CH:27][N:26]=2)=[CH:22][C:21]=1[Cl:31].CC([O-])=O.[K+].N#N>CCCC[N+](CCCC)(CCCC)CCCC.[Br-].CCOC(C)=O.CC([O-])=O.CC([O-])=O.[Pd+2].C(OP(OCC(Br)CBr)(OCC(Br)CBr)=O)C(Br)CBr.CN1C(=O)CCC1>[Cl:31][C:21]1[CH:22]=[C:23]([C:25]2[N:29]([CH3:30])[N:28]=[CH:27][N:26]=2)[S:24][C:20]=1[C:18]1[N:5]2[N:6]=[C:7]([CH3:17])[CH:8]=[C:9]([CH:10]([CH2:14][CH2:15][CH3:16])[CH2:11][CH2:12][CH3:13])[C:4]2=[N:3][C:2]=1[CH3:1]
Reactant: CCCC(CCC)c1cc(C)nn2cc(C)nc12
Reactant: Cn1ncnc1-c1cc(Cl)c(Br)s1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: CCOC(C)=O
Solvent: CN1CCCC1=O
Product: CCCC(CCC)c1cc(C)nn2c(-c3sc(-c4ncnn4C)cc3Cl)c(C)nc12
Temperature: 125 °C
Yield: 55.7 %

Procedure:
A slurry of 2,6-dimethyl-8-(1-propyl-butyl)-imidazo[1,2-b]pyridazine (below) (0.30 g, 1.22 mmol), 5-(5-bromo-4-chloro-thiophen-2-yl)-1-methyl-[1,2,4]triazole (below) (0.41 g, 1.47 mmol), KOAc (0.60 g, 6.11 mmol), TBABr (0.39 g, 1.22 mmol), and NMP (3 mL) is de-gassed with N2 for 30 minutes. Pd(OAc)2 (0.014 g, 0.061 mmol) and TDBPP (0.040 g, 0.061 mmol) are added and the solution heated at 125° C. for 2.5 hours. The solution is diluted with EtOAc (50 mL), washed with water (3×50 mL), brine (50 mL), dried over MgSO4, filtered and concentrated. The residue is purified by ISCO flash chromatography (20%-40% EtOAc gradient) furnish the title compound (0.30 g, 0.68 mmol, 56%). 1H NMR (CDCl3) δ 0.89 (t, J=7.4 Hz, 6H), 1.14-1.39 (m, 4H), 1.76 (q, J=16.3, 7.7 Hz, 4H), 2.51 (s, 3H), 2.52 (s, 3H), 3.41-3.50 (m, 1H), 4.15 (s, 3H), 6.73 (s, 1H), 7.48 (s, 1H), 7.90 (s, 1H). LC/MS (m/z): calcd. for C22H27ClN6S (M+H)+: 443.2; found: 443.3.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][CH2:15][C:16]([N:18]2[CH2:23][CH2:22][CH2:21][C@@H:20]([C:24]([NH:26][CH2:27][C@H:28]([NH2:32])[C:29]([OH:31])=[O:30])=[O:25])[CH2:19]2)=[O:17])[CH2:10][CH2:9]1)=O)(C)(C)C.[OH-].[Na+].Cl[C:36]([O:38][CH3:39])=[O:37].S([O-])(O)(=O)=O.[K+]>O1CCCC1>[NH:8]1[CH2:9][CH2:10][CH:11]([CH2:14][CH2:15][C:16]([N:18]2[CH2:23][CH2:22][CH2:21][C@@H:20]([C:24]([NH:26][CH2:27][C@H:28]([NH:32][C:36]([O:38][CH3:39])=[O:37])[C:29]([OH:31])=[O:30])=[O:25])[CH2:19]2)=[O:17])[CH2:12][CH2:13]1
Reactant: COC(=O)Cl
Reactant: CC(C)(C)OC(=O)N1CCC(CCC(=O)N2CCC[C@@H](C(=O)NC[C@H](N)C(=O)O)C2)CC1
Agent: O=S(=O)([O-])O
Agent: [K+]
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(=O)N[C@@H](CNC(=O)[C@@H]1CCCN(C(=O)CCC2CCNCC2)C1)C(=O)O
Reaction time: 0.25 h
Yield: 71.4 %

Procedure:
To a stirred solution of N-[(3R)-1-{3-(1-tert-butoxycarbonyl-4-piperidyl)propionyl}-3-piperidylcarbonyl]-2(S)-amino-β-alanine (250 mg) in a mixture of tetrahydrofuran (5 mL) and 1 N-aqueous sodium hydroxide solution (1.16 mL) was added dropwise methyl chloroformate (45 μL) at 4° C. After 15 minutes, the reaction mixture was acidified with 5% aqueous potassium hydrogensulfate solution and extracted with ethyl acetate. The organic layer was washed with brine and dried over sodium sulfate. The organic layer was evaporated and the residue was treated with 4 N-hydrogen chloride in ethyl acetate. The resulting insoluble material was collected by filtration and dried. The dry material was dissolved in water. Thus obtained solution was neutralized with an aqueous saturated sodium hydrogencarbonate solution and lyophilized. The residue was purified by ODS column chromatography (Daisogel-120sp®) eluting with 2, 5 and 8% CH3CN/H2O and lyophilized to give N-[(3R)-1-{3-(4-piperidyl)propionyl}-3-piperidylcarbonyl]-2(S)-methoxycarbonylamino-β-alanine (162 mg, 71.4%) as an amorphous powder.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[N+:11]([O-])=O)[C:7](=[O:14])[NH:6][C:5]2=[O:15].[Sn](Cl)Cl.[OH-].[Na+]>Cl>[NH2:11][C:10]1[CH:9]=[C:8]2[C:4](=[CH:3][C:2]=1[F:1])[C:5](=[O:15])[NH:6][C:7]2=[O:14]
Reactant: O=C1NC(=O)c2cc([N+](=O)[O-])c(F)cc21
Agent: Cl
Agent: Cl[Sn]Cl
Agent: [Na+]
Product: Nc1cc2c(cc1F)C(=O)NC2=O
Temperature: 60 °C
Yield: 80 %

Procedure:
To a suspension of 99.9 mmol 5-fluoro-6-nitro-isoindole-1,3-dione in 400 ml concentrated hydrochloric acid was added 350 mmol tin(II) chloride dehydrate and the resulting mixture was heated at 60° C. for 2 h. The reaction mixture was then poured onto ice-water and then 28% aq sodium hydroxide was added with stirring until a suspension was formed. The crystals were collected by filtration and dried in vacuo to afford the title compound as a yellow solid (80% yield). MS (m/e): 179.1 ([M−H]−, 100%).
Reaction SMILES: [CH2:1]([S:5]([NH:8][C:9]1[CH:17]=[CH:16][C:12]([C:13](O)=[O:14])=[CH:11][CH:10]=1)(=[O:7])=[O:6])[CH2:2][CH2:3][CH3:4].O=S(Cl)[Cl:20]>>[CH2:1]([S:5]([NH:8][C:9]1[CH:17]=[CH:16][C:12]([C:13]([Cl:20])=[O:14])=[CH:11][CH:10]=1)(=[O:7])=[O:6])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCS(=O)(=O)Nc1ccc(C(=O)O)cc1
Reactant: O=S(Cl)Cl
Product: CCCCS(=O)(=O)Nc1ccc(C(=O)Cl)cc1

Procedure:
In a manner similar to Preparation 10 react 4-[(1-butylsulfonyl)amino]benzoic acid with SOCl2 to obtain the title compound.
Reaction SMILES: Cl[C:2](=[CH2:5])[C:3]#[N:4].Cl.[CH:7]([NH:10][NH2:11])([CH3:9])[CH3:8].C(=O)([O-])[O-].[K+].[K+]>O>[CH3:8][CH:7]([N:10]1[CH:5]=[CH:2][C:3]([NH2:4])=[N:11]1)[CH3:9]
Reactant: CC(C)NN
Reactant: C=C(Cl)C#N
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: CC(C)n1ccc(N)n1
Temperature: 45 °C
Yield: 57.8 %

Procedure:
2-Chloroacrylonitrile (3.41 mL, 42.59 mmol) was added at RT to a stirring solution of N-isopropylhydrazine hydrochloride (4.71 g, 42.6 mmol), potassium carbonate (11.8 g, 85.2 mmol) in water (50 mL). The reaction was warmed to 45° C. for 4 hours before cooling back to RT. The aqueous layer was then extracted with ethyl acetate (5×30 mL) and the combined organic layers were dried (MgSO4), treated with activated charcoal, filtered and evaporated. The residue was purified by chromatography, eluting with 67%-100% ethyl acetate in hexanes, to afford the title compound (3.08 g, 58%) as a 6:1 mixture of authentic product to regioisomeric product as an oil. The material was used without further purification. 1H NMR δ (CDCl3): 1.42 (m, 6H), 3.58 (br. s, 2H), 4.25 (sept, 1H), 5.58 (d, 1H), 7.15 (d, 1H).
Reaction SMILES: C(OC(=O)[NH:7][C@H:8]([C:17](=[O:39])[NH:18][C:19]1[CH:20]=[C:21]2[C:37](=[O:38])[NH:36][N:35]=[CH:34][C:23]3=[C:24]([C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)[NH:25][C:26]([CH:27]=1)=[C:22]23)[CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)(C)(C)C.[C:41]([OH:47])([C:43]([F:46])([F:45])[F:44])=[O:42]>C(Cl)Cl>[F:44][C:43]([F:46])([F:45])[C:41]([OH:47])=[O:42].[NH2:7][C@@H:8]([CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[C:17]([NH:18][C:19]1[CH:20]=[C:21]2[C:37](=[O:38])[NH:36][N:35]=[CH:34][C:23]3=[C:24]([C:28]4[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=4)[NH:25][C:26]([CH:27]=1)=[C:22]23)=[O:39]
Reactant: CC(C)(C)OC(=O)N[C@@H](CCc1ccccc1)C(=O)Nc1cc2c3c(c(-c4ccccc4)[nH]c3c1)C=NNC2=O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: N[C@@H](CCc1ccccc1)C(=O)Nc1cc2c3c(c(-c4ccccc4)[nH]c3c1)C=NNC2=O
Yield: 84 %

Procedure:
Preparation of example 54 from the title compound of Example 53 (30 mg, 0.056 mmol) and 45% TFA in CH2Cl2 (1 mL) was carried out analogously to Example 20. Isolation, also in an analogous manner, afforded the title compound (26 mg, 0.047 mmol) as a yellow powder in 84% yield.
Reaction SMILES: C([O:3][C:4](=O)[CH2:5][N:6]1[C:10](=[O:11])[CH2:9][C@@H:8]2[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][C@H:7]12)C.[NH3:19].C(OCC)C>CO>[O:11]=[C:10]1[N:6]([CH2:5][C:4]([NH2:19])=[O:3])[C@H:7]2[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][C@H:8]2[CH2:9]1
Reactant: CCOC(=O)CN1C(=O)C[C@@H]2CCCCCC[C@@H]21
Reactant: N
Solvent: CCOCC
Solvent: CO
Product: NC(=O)CN1C(=O)C[C@@H]2CCCCCC[C@@H]21
Reaction time: 18 h

Procedure:
A solution of cis-decahydro-2-oxo-1H-cycloocta[b]pyrrole-1-acetic acid ethyl ester (4.0 g, 0.0157 mole) in methanol (30 ml) is saturated with anhydrous ammonia. The solution is stirred 18 hours. The solution is concentrated at reduced pressure to yield a solid. Trituration with anhydrous diethyl ether yields pure cis-decahydro-2-oxo-1H-cycloocta[b]pyrrole-1-acetamide with mp 110°-112° C.
Reaction SMILES: [NH2:1][C:2]1[C:3]2[CH:15]=[CH:14][CH:13]=[CH:12][C:4]=2[S:5][C:6]=1[C:7](OCC)=[O:8].[CH:16]([NH2:18])=O>>[N:1]1[C:2]2[C:3]3[CH:15]=[CH:14][CH:13]=[CH:12][C:4]=3[S:5][C:6]=2[C:7](=[O:8])[NH:18][CH:16]=1
Reactant: NC=O
Reactant: CCOC(=O)c1sc2ccccc2c1N
Product: O=c1[nH]cnc2c1sc1ccccc12
Temperature: 190 °C
Yield: 61.2 %

Procedure:
A 100 mL RBF was charged with ethyl 3-aminobenzo[b]thiophene-2-carboxylate (17.7 g, 80 mmol), treated with formamide (60.6 mL, 1520 mmol) and heated to 190° C. for 2 hrs. Precipitate formed upon cooling. The solid precipitate was collected by filtration and washed with ether, then recrystallized from ethanol/tetrahydrofuran. Benzo[4,5]thieno[3,2-d]pyrimidin-4(3H)-one (9.9 g, 61% yield) was obtained.
Reaction SMILES: [CH3:1][Si:2]([CH3:16])([CH3:15])[C:3]1[S:4][C:5]2[CH:14]=[CH:13][CH:12]=[CH:11][C:6]=2[C:7]=1[C:8]([OH:10])=O.S(Cl)(Cl)=O.Cl.[CH:22]([NH:25][OH:26])([CH3:24])[CH3:23].C(=O)(O)[O-].[Na+]>C(Cl)Cl.O>[OH:26][N:25]([CH:22]([CH3:24])[CH3:23])[C:8]([C:7]1[C:6]2[CH:11]=[CH:12][CH:13]=[CH:14][C:5]=2[S:4][C:3]=1[Si:2]([CH3:1])([CH3:16])[CH3:15])=[O:10]
Reactant: CC(C)NO
Reactant: C[Si](C)(C)c1sc2ccccc2c1C(=O)O
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=S(Cl)Cl
Solvent: ClCCl
Solvent: O
Product: CC(C)N(O)C(=O)c1c([Si](C)(C)C)sc2ccccc12
Temperature: 25 °C
Reaction time: 2 h
Yield: 66.1 %

Procedure:
A mixture of 2-(trimethylsilyl)-3-benzothiophenecarboxylic acid (0.8 g, 3.2 mmol), made as in Example 14, and thionyl chloride (6 mL) was refluxed for 2 h. The excess thionyl chloride was removed under reduced pressure. The crude acid chloride was dissolved in 20 mL methylene chloride and added to a mixture of N-isopropylhydroxylamine hydrochloride (0.4 g, 3.6 mmol) and 4 g sodium bicarbonate in 20 mL methylene chloride and 20 mL water at 0° C. The resulting mixture was stirred at RT for 2 h. The organic layer was separated, washed with brine, dried, and concentrated in vacuo. The crude product was chromatographed on a silica gel column with 10% ethyl acetate/hexane to give 0.65 g of the title compound as a yellow solid, a 66.1% yield. m.p. 115-118° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:19])[CH:4]([O:16][CH2:17][CH3:18])[CH2:5][C:6]1[C:14]2[CH:13]=[CH:12][S:11][C:10]=2[C:9]([OH:15])=[CH:8][CH:7]=1.[CH3:20][C:21]1[S:25][C:24]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[N:23][C:22]=1[CH2:32][CH2:33]O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>O1CCCC1>[CH3:1][O:2][C:3](=[O:19])[CH:4]([O:16][CH2:17][CH3:18])[CH2:5][C:6]1[C:14]2[CH:13]=[CH:12][S:11][C:10]=2[C:9]([O:15][CH2:33][CH2:32][C:22]2[N:23]=[C:24]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[S:25][C:21]=2[CH3:20])=[CH:8][CH:7]=1
Reactant: CCOC(Cc1ccc(O)c2sccc12)C(=O)OC
Reactant: Cc1sc(-c2ccccc2)nc1CCO
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCOC(Cc1ccc(OCCc2nc(-c3ccccc3)sc2C)c2sccc12)C(=O)OC

Procedure:
In analogy to the procedure described in example 1 d], [rac]-2-ethoxy-3-(7-hydroxy-benzo[b]thiophen-4-yl)-propionic acid methyl ester was reacted with 2-(5-methyl-2-phenyl-thiazol-4-yl)-ethanol [PCT Int. Appl. (2002), WO 02/18355 A1] in tetrahydrofuran in the presence of triphenylphosphine and DIAD (diisopropyl azodicarboxylate) to yield [rac]-2-ethoxy-3-{7-[2-(5-methyl-2-phenyl-thiazol-4-yl)-ethoxy]-benzo[b]thiophen-4-yl}-propionic acid methyl ester as colorless viscous oil.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:30]=[CH:31][CH:32]=1)[CH2:7][NH:8][C:9]([C:11]1[NH:12][C:13]2[C:18]([C:19]=1[S:20]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)(=[O:22])=[O:21])=[CH:17][C:16]([Cl:29])=[CH:15][CH:14]=2)=[O:10])([O-])=O.[H][H]>O1CCCC1.CO.[Pt]=O>[NH2:1][C:4]1[CH:5]=[C:6]([CH:30]=[CH:31][CH:32]=1)[CH2:7][NH:8][C:9]([C:11]1[NH:12][C:13]2[C:18]([C:19]=1[S:20]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)(=[O:21])=[O:22])=[CH:17][C:16]([Cl:29])=[CH:15][CH:14]=2)=[O:10]
Reactant: [H][H]
Reactant: O=C(NCc1cccc([N+](=O)[O-])c1)c1[nH]c2ccc(Cl)cc2c1S(=O)(=O)c1ccccc1
Agent: O=[Pt]
Solvent: C1CCOC1
Solvent: CO
Product: Nc1cccc(CNC(=O)c2[nH]c3ccc(Cl)cc3c2S(=O)(=O)c2ccccc2)c1

Procedure:
A solution of N-(3-nitrobenzyl) 3-phenylsulfonyl-5-chloroindole-2-carboxamide (353 mg, 0.75 mmol) in tetrahydrofuran (25 mL) and methanol (10 mL) containing platinum oxide (70 mg) was hydrogenated with an atmospheric pressure of hydrogen for 3 hours. The degassed solution was filtered to remove catalyst and the solvents evaporated. The residue was triturated with diethyl ether to give the product. Crystallization from acetonitrile gave analytically pure product, mp 247°-249° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[O:9][N:10]=[C:11]3[CH:16]=[CH:15][C:14]([CH:17]4OCC[O:18]4)=[CH:13][C:12]=23)[CH:5]=[CH:6][CH:7]=1>Cl.CO>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[O:9][N:10]=[C:11]3[CH:16]=[CH:15][C:14]([CH:17]=[O:18])=[CH:13][C:12]=23)[CH:5]=[CH:6][CH:7]=1
Reactant: Clc1cccc(-c2onc3ccc(C4OCCO4)cc23)c1
Agent: Cl
Solvent: CO
Product: O=Cc1ccc2noc(-c3cccc(Cl)c3)c2c1
Yield: 89.9 %

Procedure:
A mixture of intermediate (12) (0.0941 mol) in HCl 6N (200 ml) and methanol (100 ml) was stirred and refluxed for 6 hours, cooled and poured out on ice. The precipitate was filtered off, washed with diethyl ether and dried, yielding 21.8 g (90%) of 3-(3-chlorophenyl)-2,1-benzisoxazole-5-carboxaldehyde (intermediate 13), mp. 148° C.
Reaction SMILES: [F:1][C:2]([F:45])([F:44])[C:3]1[CH:4]=[C:5]([CH:37]=[C:38]([C:40]([F:43])([F:42])[F:41])[CH:39]=1)[CH2:6][N:7]([CH2:12][C:13]1[CH:18]=[C:17]([C:19]([F:22])([F:21])[F:20])[CH:16]=[CH:15][C:14]=1[C:23]1[CH:28]=[C:27]([C:29]([C:31]([F:34])([F:33])[F:32])=[CH2:30])[CH:26]=[CH:25][C:24]=1[O:35][CH3:36])[C:8](=[O:11])[O:9][CH3:10]>CO.[Pd]>[F:1][C:2]([F:44])([F:45])[C:3]1[CH:4]=[C:5]([CH:37]=[C:38]([C:40]([F:41])([F:42])[F:43])[CH:39]=1)[CH2:6][N:7]([CH2:12][C:13]1[CH:18]=[C:17]([C:19]([F:22])([F:21])[F:20])[CH:16]=[CH:15][C:14]=1[C:23]1[CH:28]=[C:27]([CH:29]([CH3:30])[C:31]([F:32])([F:33])[F:34])[CH:26]=[CH:25][C:24]=1[O:35][CH3:36])[C:8](=[O:11])[O:9][CH3:10]
Reactant: C=C(c1ccc(OC)c(-c2ccc(C(F)(F)F)cc2CN(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)C(=O)OC)c1)C(F)(F)F
Agent: [Pd]
Solvent: CO
Product: COC(=O)N(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)Cc1cc(C(F)(F)F)ccc1-c1cc(C(C)C(F)(F)F)ccc1OC

Procedure:
The title compound from Step A (10 mg, 0.017 mmol) was hydrogenated at 1 atm in methanol using Pd/C as the catalyst. The solution was filtered through Celite then concentrated. The title compound was purified by preparative thin layer chromatography using 1:4 EtOAc:hexane.
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[C:5]([CH3:24])[C:6]([N:9]2[CH2:14][CH2:13][N:12]([C:15]([C:17]3[CH:22]=[CH:21][C:20](I)=[CH:19][CH:18]=3)=[O:16])[CH2:11][CH2:10]2)=[N:7][CH:8]=1)[CH3:2].[NH:25]1[CH2:29][CH2:28][CH2:27][C:26]1=[O:30]>>[CH2:1]([C:3]1[CH:4]=[C:5]([CH3:24])[C:6]([N:9]2[CH2:14][CH2:13][N:12]([C:15]([C:17]3[CH:22]=[CH:21][C:20]([N:25]4[CH2:29][CH2:28][CH2:27][C:26]4=[O:30])=[CH:19][CH:18]=3)=[O:16])[CH2:11][CH2:10]2)=[N:7][CH:8]=1)[CH3:2]
Reactant: CCc1cnc(N2CCN(C(=O)c3ccc(I)cc3)CC2)c(C)c1
Reactant: O=C1CCCN1
Product: CCc1cnc(N2CCN(C(=O)c3ccc(N4CCCC4=O)cc3)CC2)c(C)c1

Procedure:
Using [4-(5-ethyl-3-methylpyridin-2-yl)piperazin-1-yl](4-iodophenyl)methanone (435 mg) described in Preparation Example 133 and pyrrolidin-2-one (115 μL) and by the reaction and treatment in the same manner as in Example 262, the title compound (234 mg) was obtained.
Reaction SMILES: [C:1]1([N:7]2[CH2:12][CH2:11][N:10]([CH2:13][CH2:14][NH2:15])[CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CCN(CC)CC.[N+:23]([C:26]1[CH:31]=[CH:30][C:29]([CH2:32][C:33](Cl)=[O:34])=[CH:28][CH:27]=1)([O-:25])=[O:24]>C(Cl)Cl>[N+:23]([C:26]1[CH:27]=[CH:28][C:29]([CH2:32][C:33]([NH:15][CH2:14][CH2:13][N:10]2[CH2:9][CH2:8][N:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[CH2:12][CH2:11]2)=[O:34])=[CH:30][CH:31]=1)([O-:25])=[O:24]
Reactant: O=C(Cl)Cc1ccc([N+](=O)[O-])cc1
Reactant: NCCN1CCN(c2ccccc2)CC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(Cc1ccc([N+](=O)[O-])cc1)NCCN1CCN(c2ccccc2)CC1
Reaction time: 2 h
Yield: 89 %

Procedure:
To a stirred solution of 2-(4-Phenyl-piperazin-1-yl)-ethylamine 4a (0.5 g, 2.44 mmol) and Et3N (0.34 g, 3.41 mmol) in 40 mL of dry CH2Cl2 under nitrogen at 0° C. was added a solution (4-Nitro-phenyl)-acetyl chloride (0.58 g, 2.92 mmol). The temperature was allowed to rise to room temperature, the mixture was stirred for 2 h, and then washed with water. The aqueous layer was extracted with dichloromethane. The combined organic phase was washed with saturated sodium chloride, dried (Na2SO4) and concentrated. The crude product was purified by column chromatography over silica gel (EtOAc) to produce 26a: 0.8 g, (89% yield) as a white solid (mp: 138-139° C.). 1H NMR (CDCl3, 400 MHz): δ 2.52 (2H, t, J=5.6, CH2—CH2NH), 2.57 (4H, t, J=5.2, (CH2)2N—), 3.11 (4H, t, J=5.2, (CH2)2—NPh), 3.36-3.34 (2H, m, CH2—NHCO), 3.65 (2H, s, CH2Ar), 6.19 (1H, bs, NHCO), 6.86-6.91 (3H, m, ArH), 7.25-7.29 (2H, m, ArH), 7.47 (2H, d, J=8.8, ArH), 8.16-8.19 (2H, m, ArH).