Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([C:4]2[CH:9]=[CH:8][C:7]([NH:10][C:11]3[C:12]4[N:13]([CH:20]=[N:21][CH:22]=4)[CH:14]=[CH:15][C:16]=3[C:17]([OH:19])=O)=[C:6]([F:23])[CH:5]=2)[CH2:3][CH2:2]1.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C.Cl.[NH2:55][O:56][C:57]([CH3:61])([CH3:60])[CH2:58][OH:59]>CN(C=O)C>[OH:59][CH2:58][C:57]([CH3:61])([CH3:60])[O:56][NH:55][C:17]([C:16]1[CH:15]=[CH:14][N:13]2[CH:20]=[N:21][CH:22]=[C:12]2[C:11]=1[NH:10][C:7]1[CH:8]=[CH:9][C:4]([CH:1]2[CH2:3][CH2:2]2)=[CH:5][C:6]=1[F:23])=[O:19]
Reactant: CC(C)(CO)ON
Reactant: O=C(O)c1ccn2cncc2c1Nc1ccc(C2CC2)cc1F
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(CO)ONC(=O)c1ccn2cncc2c1Nc1ccc(C2CC2)cc1F
Temperature: 25 °C
Reaction time: 18 h
Yield: 7.9 %

Procedure:
A suspension of 8-(4-cyclopropyl-2-fluoro-phenylamino)-imidazo[1,5-a]pyridine-7-carboxylic acid (0.11 g, 0.35 mmol), EDCI (0.081 g, 0.42 mmol), HOBt (0.057 g, 0.42 mmol), DIPEA (0.085 mL, 0.88 mmol) and 2-aminooxy-2-methyl-propan-1-ol hydrochloride (0.055 g, 0.39 mmol) in DMF (1.5 mL) was stirred at room temperature for 18 hours. The reaction mixture was partitioned between DCM (5 mL) and saturated aqueous NaHCO3 (5 ml). The organic layer was washed with water (5 mL), followed by brine (5 mL), then dried (MgSO4), filtered and concentrated in vacuo. The resultant residue was subjected to flash chromatography (Si-PPC, gradient 0% to 40%, ethyl actetate in DCM) to give a yellow solid, which was further purified by preparative HPLC (Gemini 5 micron C18 250×21.20 mm column, 0.1% formic acid, gradient acetonitrile/water, 5 to 98%, ramp time 20 minutes) to afford the title compound as a yellow solid (11 mg, 8%). LCMS (method A): RT=7.57 min, [M+H]+=399. 1H NMR (DMSO-d6): 10.37 (1H, s), 8.28 (1H, s), 7.79 (1H, dd, J=7.35, 0.95 Hz), 7.14 (1H, s), 7.02-6.93 (1H, m), 6.91 (1H, d, J=8.28 Hz), 6.82 (1H, s), 6.27 (1H, s), 1.99-1.90 (1H, m), 1.15 (6H, s), 0.99-0.92 (2H, m), 0.73-0.67 (2H, m).
Reaction SMILES: C12(COC3C(C4CC4)=CC(C(O)=O)=C(F)C=3)CC3CC(CC(C3)C1)C2.[CH:26]1([C:29]2[C:30]([O:39][CH2:40][C:41]34[CH2:50][CH:45]5[CH2:46][CH:47]([CH2:49][C:43]([OH:51])([CH2:44]5)[CH2:42]3)[CH2:48]4)=[CH:31][C:32]([F:38])=[C:33]([CH:37]=2)[C:34](O)=[O:35])[CH2:28][CH2:27]1.C([CH:54]1[CH2:57][N:56]([S:58]([NH2:61])(=[O:60])=[O:59])[CH2:55]1)#N.N1(S(N)(=O)=O)CCC1>>[N:56]1([S:58]([NH:61][C:34](=[O:35])[C:33]2[CH:37]=[C:29]([CH:26]3[CH2:28][CH2:27]3)[C:30]([O:39][CH2:40][C:41]34[CH2:50][CH:45]5[CH2:46][CH:47]([CH2:49][C:43]([OH:51])([CH2:44]5)[CH2:42]3)[CH2:48]4)=[CH:31][C:32]=2[F:38])(=[O:59])=[O:60])[CH2:55][CH2:54][CH2:57]1
Reactant: O=C(O)c1cc(C2CC2)c(OCC23CC4CC(CC(O)(C4)C2)C3)cc1F
Reactant: N#CC1CN(S(N)(=O)=O)C1
Agent: NS(=O)(=O)N1CCC1
Agent: O=C(O)c1cc(C2CC2)c(OCC23CC4CC(CC(C4)C2)C3)cc1F
Product: O=C(NS(=O)(=O)N1CCC1)c1cc(C2CC2)c(OCC23CC4CC(CC(O)(C4)C2)C3)cc1F

Procedure:
Following the procedure as described in Example 230 and making variations as required to replace 4-(adamantan-1-ylmethoxy)-5-cyclopropyl-2-fluorobenzoic acid with 5-cyclopropyl-2-fluoro-4-((3-hydroxyadamantan-1-yl)methoxy)benzoic acid and to replace 3-cyanoazetidine-1-sulfonamide with azetidine-1-sulfonamide, the title compound was obtained as colorless solid (0.08 g, 65%): 1H NMR (300 MHz, DMSO-d6) δ 11.60 (s, 1H), 7.15 (d, J=8.3 Hz, 1H), 6.94 (d, J=12.9 Hz, 1H), 4.47 (s, 1H), 4.04 (t, J=7.7 Hz, 4H), 3.70 (s, 2H), 2.21-2.11 (m, 4H), 2.07-1.98 (m, 1H), 1.58-1.53 (m, 12H), 0.95-0.88 (m, 2H), 0.71-0.66 (m, 2H); MS (ES+) m/z 479.1 (M+1); MS (ES−) m/z 477.2 (M−1).
Reaction SMILES: [Si:1]([O:8][CH:9]([CH:13]([CH3:15])[CH3:14])[C:10]([OH:12])=O)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].C(N1C=CN=C1)(N1C=CN=C1)=O.[C:28]([O:31][CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)(=[O:30])[CH3:29].[Li+].CC([N-]C(C)C)C>C1COCC1>[Si:1]([O:8][CH:9]([CH:13]([CH3:15])[CH3:14])[C:10](=[O:12])[CH2:29][C:28]([O:31][CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)=[O:30])([C:4]([CH3:5])([CH3:6])[CH3:7])([CH3:2])[CH3:3]
Reactant: CC(=O)OCc1ccccc1
Reactant: CC(C)C(O[Si](C)(C)C(C)(C)C)C(=O)O
Agent: CC(C)[N-]C(C)C
Agent: O=C(n1ccnc1)n1ccnc1
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C)C(O[Si](C)(C)C(C)(C)C)C(=O)CC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 27.4 %

Procedure:
To a solution of 2-{[tert-butyl(dimethyl)silyl]oxy}-3-methylbutanoic acid (1.0 g, 4.3 mmol) in THF (14.3 mL) at 0° C. were added carbonyldiimidazole (1.05 g, 6.45 mmol). After 15 min, the mixture was allowed to warm to ambient temperature and stirred for 48 h. This solution was cooled to −78° C. and added to a solution of preformed enolate by mixing benzyl acetate (2.18 mL, 15.1 mmol) and LDA (2.0 M in THF; 7.53 mL, 15.1 mmol) in THF (15 mL) at −78° C. The mixture was stirred at −78° C. for 1 h then warmed to −10° C. for 30 min. The mixture was cooled back to −78° C. and quenched with sat. NH4Cl. The mixture was extracted with dichloromehtane (3×). The combined organic extracts was dried over MgSO4, filtered and concentrated. Purification by silica gel chromatography (100% hexanes→75% hexanes/ethyl acetate) gave the title compound (0.43 g).
Reaction SMILES: [C:1](=[O:4])([O-])[O-].[K+].[K+].[CH3:7][CH:8]1[CH:12]([CH3:13])[O:11][C:10]([C:14]2([C:20]3[CH:21]=[C:22]([S:26][C:27]4[CH:32]=[CH:31][C:30]([N:33]5[C:37](=O)[NH:36][C:35]([CH3:39])=[N:34]5)=[CH:29][CH:28]=4)[CH:23]=[CH:24][CH:25]=3)[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)=[N:9]1.CI>CN(C)C=O>[CH3:7][CH:8]1[CH:12]([CH3:13])[O:11][C:10]([C:14]2([C:20]3[CH:21]=[C:22]([S:26][C:27]4[CH:28]=[CH:29][C:30]([N:33]5[C:1](=[O:4])[N:36]([CH3:37])[C:35]([CH3:39])=[N:34]5)=[CH:31][CH:32]=4)[CH:23]=[CH:24][CH:25]=3)[CH2:15][CH2:16][O:17][CH2:18][CH2:19]2)=[N:9]1
Reactant: Cc1nn(-c2ccc(Sc3cccc(C4(C5=NC(C)C(C)O5)CCOCC4)c3)cc2)c(=O)[nH]1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Product: Cc1nn(-c2ccc(Sc3cccc(C4(C5=NC(C)C(C)O5)CCOCC4)c3)cc2)c(=O)n1C
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
Solid potassium carbonate (4.5 mmol) is added to a solution of 2-[4-({3-[4-(4,5-dimethyl-4,5-dihydro-1,3-oxazol-2-yl)tetrahydro-2H-pyran-4-yl]phenyl}thio)phenyl]-5-methyl-2,4-dihydro-3H-1,2,4-traizol-3-one (1.0 mmol) (example 21) in dry dimethylformamide. The reaction mixture is stirred a room temperature for about 15 minutes. Methyl iodide (3.0 mmol) is added and the reaction mixture is heated at about 100° C. for about 12 hours. The solvent is evaporated under vacuum, water is added and the reaction mixture is extracted with ethyl acetate. The organic layer is washed with water, dried over anhydrous sodium sulphate, filtered and the solvent is evaporated to afford the residue. Column chromatography of the residue over silica gel affords the title compound.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([O:10][CH3:11])=[O:9])=[N:6][CH:7]=1.[CH2:12](O)[C:13]#[C:14][CH3:15].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>C1COCC1.C(Cl)Cl>[CH2:12]([O:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([O:10][CH3:11])=[O:9])=[N:6][CH:7]=1)[C:13]#[C:14][CH3:15]
Reactant: COC(=O)c1ccc(O)cn1
Reactant: CC#CCO
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: ClCCl
Product: CC#CCOc1ccc(C(=O)OC)nc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of methyl 5-hydroxypyridine-2-carboxylate (1.5 g, 9.8 mmol, Molbridge) in THF (39 ml) under argon was cooled to 0° C. and 2-butyn-1-ol (1.5 ml, 20 mmol, Aldrich), triphenyl phosphine (2.95 g, 11.2 mmol, Aldrich) and diisopropyl azodicarboxylate (2.2 ml, 11.2 mmol, Aldrich) were added consecutively. The reaction mixture was stirred at room temperature for 2 h. Additional diisopropyl azodicarboxylate (1 ml) was added and the reaction mixture was stirred at room temperature for another 1 h. The reaction mixture was diluted with CH2Cl2 and washed with saturated NaHCO3 solution; the aqueous layer was back-extracted with CH2Cl2. The combined organic extracts were dried over MgSO4 and concentrated in vacuo. Purification by silica gel chromatography (0% to 50% EtOAc/Hexanes) afforded the title compound as a light tan solid. MS m/z=206.0 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([N:10]2[CH2:15][CH2:14][C@:13]([CH2:23][CH2:24][C:25](O)=[O:26])([C:16]3[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=3)[CH2:12][C:11]2=[O:28])[CH3:9])=[CH:4][CH:3]=1.CC[N:31]=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C.N>C(Cl)Cl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([N:10]2[CH2:15][CH2:14][C@:13]([CH2:23][CH2:24][C:25]([NH2:31])=[O:26])([C:16]3[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=3)[CH2:12][C:11]2=[O:28])[CH3:9])=[CH:4][CH:3]=1
Reactant: CCN=C=NCCCN(C)C
Reactant: C[C@@H](c1ccc(Br)cc1)N1CC[C@](CCC(=O)O)(c2ccc(F)cc2)CC1=O
Agent: N
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: C[C@@H](c1ccc(Br)cc1)N1CC[C@](CCC(N)=O)(c2ccc(F)cc2)CC1=O
Reaction time: 8 h

Procedure:
The solution of 3-((S)-1-((S)-1-(4-bromophenyl)ethyl)-4-(4-fluorophenyl)-2-oxopiperidin-4-yl)propanoic acid (28 mg, 0.063 mmol), EDCI (38 mg, 0.189 mmol), HOBt (26 mg, 0.189 mmol), and DIEA (82 mg, 0.63 mmol) in CH2Cl2 was filled with NH3 at 0° C. The mixture was stirred overnight, and washed with water. The organic phase was separated and concentrated to give the crude product, which was purified by preparative HPLC to afford 3-((S)-1-((S)-1-(4-bromophenyl)ethyl)-4-(4-fluorophenyl)-2-oxopiperidin-4-yl)propanamide (6 mg, 21%□. LC-MS Method 2, tR=1.869 min, m/z=447. 1H NMR (CDCl3): δ 1.46 (d, 3H), 1.77 (m, 1H), 1.92 (m, 1H), 1.96 (m, 1H), 2.08 (m, 1H), 2.14 (m, 3H), 2.24 (m, 1H), 2.51 (d, 1H), 3.02 (m, 1H), 3.12 (m, 1H), 5.32 (m, 1H), 5.71 (m, 1H), 5.94 (q, 1H), 6.76 (m, 2H), 6.99 (m, 2H), 7.16 (m, 2H), 7.24 (m, 2H).
Reaction SMILES: [CH2:1]([C:3]1[S:7][C:6]([NH:8][C:9]([NH:11][S:12]([C:15]2[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=2)(=[O:14])=[O:13])=[S:10])=[N:5][C:4]=1[C:22]1[CH:31]=[CH:30][C:29]2[CH2:28][CH2:27][CH2:26][CH2:25][C:24]=2[CH:23]=1)[CH3:2].S(Cl)(Cl)(=O)=O>C(Cl)(Cl)Cl>[CH2:1]([C:3]1[S:7][C:6]2[N:5]([S:10][C:9](=[N:11][S:12]([C:15]3[CH:16]=[CH:17][C:18]([CH3:21])=[CH:19][CH:20]=3)(=[O:14])=[O:13])[N:8]=2)[C:4]=1[C:22]1[CH:31]=[CH:30][C:29]2[CH2:28][CH2:27][CH2:26][CH2:25][C:24]=2[CH:23]=1)[CH3:2]
Reactant: CCc1sc(NC(=S)NS(=O)(=O)c2ccc(C)cc2)nc1-c1ccc2c(c1)CCCC2
Solvent: ClC(Cl)Cl
Solvent: O=S(=O)(Cl)Cl
Product: CCc1sc2nc(=NS(=O)(=O)c3ccc(C)cc3)sn2c1-c1ccc2c(c1)CCCC2
Temperature: 25 °C
Reaction time: 2 h
Yield: 71.7 %

Procedure:
To a mixture of 1-[5-ethyl-4-(5,6,7,8-tetrahydro-2-naphthyl)-2-thiazolyl]-3-(4-methylphenyl)sulfonyl-2-thiourea (1.40 g) and chloroform (10 ml), sulfuryl chloride (420 mg) was added. After being stirred at room temperature for 2 hours, the reaction mixture was concentrated; the residue was treated with ethanol, and the resulting crystal was collected by filtration and recrystallized from dichloromethane-ethanol to yield 5-ethyl-2-(4-methylphenyl)sulfonylimino-6-(5,6,7,8-tetrahydro-2-naphthyl)-2H-thiazolo[3,2- b][1,2,4]thiadiazole (1.00 g, yield 72%) as a colorless needle.
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([CH:8]=[O:9])[CH:5]=[CH:4][CH:3]=1.[CH:10]#[C:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20].C(N(CC)CC)C>O1CCCC1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl.[Cu]I>[C:10]([C:2]1[N:7]=[C:6]([CH:8]=[O:9])[CH:5]=[CH:4][CH:3]=1)#[C:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20]
Reactant: O=Cc1cccc(Br)n1
Reactant: C#CCCCCCCCCC
Agent: Cl[Pd]Cl
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCCCCCCCCC#Cc1cccc(C=O)n1
Yield: 84.3 %

Procedure:
A solution of 6-bromopyridine-2-caboxaldehyde (15.0 g), 1-undecyne (12.9 g), triethylamine (24.5 g), bis(triphenylphosphine)palladium(II)chloride (1.1 g, 2%), and copper(I)iodide (0.15g, 1%) in dry tetrahydrofuran (60 ml) was heated under nitrogen at 55° C. for 10 hrs. The reaction mixture was filtered, the filter cake was washed with ethyl acetate, and the filtrate was evaporated. The residue was dissolved in ethyl acetate, and the solution was washed with half-saturated sodium chloride solution, dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated. The residue was flash chromatographed on silica gel, eluting with 0%-2%-ethyl acetate:hexane. The appropriate fractions were collected and evaporated to yield 17.5 g (84.0%) of product.
Reaction SMILES: [CH2:1]([O:5][C:6]([C:8]1[N:9]=[C:10](Cl)[C:11]2[C:16]([C:17]=1[OH:18])=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:7])[CH2:2][CH2:3][CH3:4].[CH:20]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH:23]=[CH:22][C:21]=1[OH:30]>>[CH2:1]([O:5][C:6]([C:8]1[N:9]=[C:10]([O:30][C:21]2[CH:22]=[CH:23][C:24]3[C:29](=[CH:28][CH:27]=[CH:26][CH:25]=3)[CH:20]=2)[C:11]2[C:16]([C:17]=1[OH:18])=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:7])[CH2:2][CH2:3][CH3:4]
Reactant: Oc1ccc2ccccc2c1
Reactant: CCCCOC(=O)c1nc(Cl)c2ccccc2c1O
Product: CCCCOC(=O)c1nc(Oc2ccc3ccccc3c2)c2ccccc2c1O

Procedure:
Synthesized from 1-chloro-4-hydroxy-isoquinoline-3-carboxylic acid butyl ester and Naphthalen-2-ol in analogy to Example D-20 d); MS-(+)-ion: M+1=388.1.
Reaction SMILES: [CH:1]([C:3]1[CH:18]=[CH:17][C:6]([O:7][C:8]2[N:9]=[CH:10][C:11]([C:14]([NH2:16])=[O:15])=[N:12][CH:13]=2)=[C:5]([O:19][CH3:20])[CH:4]=1)=O.[CH:21]([O:24][CH2:25][CH2:26][NH2:27])([CH3:23])[CH3:22].[BH4-].[Na+]>CO>[CH:21]([O:24][CH2:25][CH2:26][NH:27][CH2:1][C:3]1[CH:18]=[CH:17][C:6]([O:7][C:8]2[N:9]=[CH:10][C:11]([C:14]([NH2:16])=[O:15])=[N:12][CH:13]=2)=[C:5]([O:19][CH3:20])[CH:4]=1)([CH3:23])[CH3:22]
Reactant: CC(C)OCCN
Reactant: COc1cc(C=O)ccc1Oc1cnc(C(N)=O)cn1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: COc1cc(CNCCOC(C)C)ccc1Oc1cnc(C(N)=O)cn1
Reaction time: 8 h
Yield: 55.5 %

Procedure:
Place 5-(4-formyl-2-methoxyphenoxy)pyrazine-2-carboxamide (Example 719, Part A) (0.700 g, 2.56 mmol), 2-isopropoxyethylamine (0.278 g, 2.69 mmol) and 3 {acute over (Å)} molecular sieves in a vial. Add methanol (12.8 mL), cap and stir overnight. Add NaBH4 (0.0969 g, 2.56 mmol) and stir until the gasses stop evolving. Load the reaction mixture directly onto a 25 g ISCO® pre-load column. Dry the column in a vacuum oven at room temperature. Purify by eluting through a 40 g ISCO® column with 5% to 20% (2.0 M NH3 in methanol) in ethyl acetate over 45 minutes. Concentrate the fraction containing the product, then take it up in EtOAc (100 mL). Wash the organic solution with 1.0 N NaOH (2×25 mL), dry it over Na2SO4, filter and concentrate to give the title compound (0.512 g, 55.5%): TOF MS ES+ 361.2 (M+H)+, HRMS calcd for C18H25N4O4 361.1876 (M+H)+, found 361.1891, time 0.38 min; HPLC [YMC-Pro pack C-18 (150×4.6 mm, S-5 microm), 0.05% TFA/acetonitrile in 0.05% TFA/water at 1.0 mL/min, 10-20% over 5 min, 20-95% over 18], tR=9.4 min, 100% purity.
Reaction SMILES: C(O[C:9]([N:11]([C:13]1[CH:14]=[CH:15][C:16]2[O:20][C:19]([C:21]([NH:23][C:24]3[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][N:25]=3)=[O:22])=[C:18]([NH:31][C:32]([C@H:34]3[CH2:39][CH2:38][C@H:37]([N:40]([CH3:42])[CH3:41])[CH2:36][CH2:35]3)=[O:33])[C:17]=2[CH:43]=1)C)=O)C1C=CC=CC=1.Br.C(OCC)C>C(O)(=O)C>[CH3:42][N:40]([CH3:41])[C@H:37]1[CH2:36][CH2:35][C@H:34]([C:32]([NH:31][C:18]2[C:17]3[CH:43]=[C:13]([NH:11][CH3:9])[CH:14]=[CH:15][C:16]=3[O:20][C:19]=2[C:21]([NH:23][C:24]2[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][N:25]=2)=[O:22])=[O:33])[CH2:39][CH2:38]1
Reactant: CN(C(=O)OCc1ccccc1)c1ccc2oc(C(=O)Nc3ccc(Cl)cn3)c(NC(=O)[C@H]3CC[C@H](N(C)C)CC3)c2c1
Agent: Br
Solvent: CC(=O)O
Solvent: CCOCC
Product: CNc1ccc2oc(C(=O)Nc3ccc(Cl)cn3)c(NC(=O)[C@H]3CC[C@H](N(C)C)CC3)c2c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To trans-5-[N-(benzyloxycarbonyl)-N-methylamino]-3-[4-(dimethylamino)cyclohexylcarbonylamino]-N-(5-chloropyridin-2-yl)benzofuran-2-carboxamide (100 mg) obtained in Example 22 is added 30% hydrogen bromide in acetic acid (2 ml), and the mixture is stirred at room temperature for 2 hours. To the reaction solution is added diethyl ether (20 ml), and the precipitates are collected by filtration, and suspended in a saturated aqueous sodium hydrogen carbonate solution, and extracted with ethyl acetate. The organic layer is washed with a saturated brine, dried over sodium sulfate, and the solvent is evaporated under reduced pressure to give trans-3-[4-(dimethylamino)cyclohexylcarbonylamino]-5-methylamino-N-(5-chloropyridin-2-yl)benzofuran-2-carboxamide. Subsequently, this product is dissolved in ethanol, and treated with 4N hydrogen chloride in ethyl acetate to give the title compound (88 mg).
Reaction SMILES: C[O:2][C:3](=[O:31])[C@H:4]([N:8]([S:16]([C:19]1[CH:30]=[CH:29][C:22]2[N:23]=[C:24]([S:26][CH2:27][CH3:28])[S:25][C:21]=2[CH:20]=1)(=[O:18])=[O:17])[CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[CH:5]([CH3:7])[CH3:6].[Li+].[OH-]>C1COCC1.O>[CH3:7][CH:5]([CH3:6])[C@@H:4]([N:8]([S:16]([C:19]1[CH:30]=[CH:29][C:22]2[N:23]=[C:24]([S:26][CH2:27][CH3:28])[S:25][C:21]=2[CH:20]=1)(=[O:17])=[O:18])[CH2:9][C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1)[C:3]([OH:31])=[O:2]
Reactant: CCSc1nc2ccc(S(=O)(=O)N(Cc3ccccc3)[C@@H](C(=O)OC)C(C)C)cc2s1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CCSc1nc2ccc(S(=O)(=O)N(Cc3ccccc3)[C@@H](C(=O)O)C(C)C)cc2s1

Procedure:
(2R)-3-methyl-2-[(ethylthio-6-benzthiazolsulfonyl) benzylamino]butanoic acid methylester (180 mg, 0.376 mmol) prepared in Example 26 was dissolved in THF/H2O (2 mL/2 mL), and LiOH (0.08 g, 5 equi.) was added. After reflux for 6 days, the reaction solution was distilled under reduced pressure and treated with 1N HCl, and ethylacetate (10 mL) was added to extract the product. The separated organic phase containing product was washed with NaCl solution, dried over MgSO4 and distilled under reduced pressure. The remaining material was purified on silica gel chromatography using ethylacetate/n-hexane (1/1) and ethylacetate/dichloromethane/acetate (1/1/trace amount) as solvent and dried under vacuum to prepare the titled compound, (2R)-3-methyl-2-[(ethylthio-6-benzthiazolsulfonyl)benzylamino]butanoic acid (0.1 g, 57%).
Reaction SMILES: [C:1]([C:5]1[CH:16]=[CH:15][C:8]([O:9][CH2:10][CH2:11][CH2:12][CH:13]=[CH2:14])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].C1(C2CCCCCCCC2)BCCCCCCC1.[OH-:35].[Na+].OO>O1CCCC1>[C:1]([C:5]1[CH:6]=[CH:7][C:8]([O:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][OH:35])=[CH:15][CH:16]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: C=CCCCOc1ccc(C(C)(C)C)cc1
Reactant: [OH-]
Agent: B1CCCCCCCC1C1CCCCCCCC1
Agent: OO
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)(C)c1ccc(OCCCCCO)cc1
Temperature: 25 °C

Procedure:
The 5-(p-tert-butylphenoxy)-1-pentene (10.5 g) was treated with 115 ml 0.5M 9-borabicyclononane in tetrahydrofuran and the reaction mixture was stirred at reflux for one hour. The solution was cooled to room temperature and treated with 25 ml 3N sodium hydroxide, then 10 ml 30% hydrogen peroxide. After the bubbling ceased the reaction mixture was partitioned between 150 ml ether-150 ml water. The ether layer was removed, dried (MgSO4), and evaporated to a yellow oil which was chromatographed through 300 g, 90 to 200 mesh silica gel (2% MeOH/CH2Cl2 eluent) yielding a yellow oil which was vacuum distilled (126° C./0.75 mm) to a clear, colorless oil, 5-p-t-butylphenoxy-1-pentanol, 1.7 g.
Reaction SMILES: [H-].[Na+].[C:3]([O:7][C:8]([N:10]1[CH2:15][CH2:14][CH:13]([C:16]2[C:24]3[C:19](=[CH:20][CH:21]=[C:22]([F:25])[CH:23]=3)[NH:18][CH:17]=2)[CH2:12][CH2:11]1)=[O:9])([CH3:6])([CH3:5])[CH3:4].[CH3:26][Si:27]([CH3:35])([CH3:34])[CH2:28][CH2:29][S:30](Cl)(=[O:32])=[O:31]>CN(C=O)C>[C:3]([O:7][C:8]([N:10]1[CH2:11][CH2:12][CH:13]([C:16]2[C:24]3[C:19](=[CH:20][CH:21]=[C:22]([F:25])[CH:23]=3)[N:18]([S:30]([CH2:29][CH2:28][Si:27]([CH3:35])([CH3:34])[CH3:26])(=[O:32])=[O:31])[CH:17]=2)[CH2:14][CH2:15]1)=[O:9])([CH3:6])([CH3:4])[CH3:5]
Reactant: C[Si](C)(C)CCS(=O)(=O)Cl
Reactant: CC(C)(C)OC(=O)N1CCC(c2c[nH]c3ccc(F)cc23)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(c2cn(S(=O)(=O)CC[Si](C)(C)C)c3ccc(F)cc23)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 84 %

Procedure:
Sodium hydride (96 mg, 4.07 mmol) was added to a solution of N-tert-butoxycarbonyl-4-(5-fluoroindol-3-yl)piperidine (1.28 g, 4.07 mmol), [prepared as described in Step 1, above] in DMF (6 ml) at 0° C. and the reaction mixture was stirred for 30 min. 2-Trimethylsilylethanesulfonyl chloride (820 mg, 4.07 mmol) was added and the reaction mixture was slowly warmed to RT over 30 min. After 2.5 h, the reaction mixture was quenched with water (10 ml) and the product was extracted into methylene chloride. The combined organic layers were dried over MgSO4 and concentrated in vacuo. Due to incomplete reaction the above steps were repeated on the isolated crude reaction mixture. The final residue was chromatographed (PTLC, SiO2, 20% ethyl acetate/hexanes) to afford N-tert-butoxycarbonyl-4-[5-fluoro-1-(2-trimethylsilylethanesulfonyl)indol-3-yl]piperidine (84%) as a clear oil.
Reaction SMILES: Br[C:2]1[C:3]([NH2:12])=[N:4][CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.[C:13]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)#[CH:14].O>C(N(CC)CC)C.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](Br)Br>[C:15]1([C:13]#[C:14][C:2]2[C:3]([NH2:12])=[N:4][CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=2)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: C#Cc1ccccc1
Reactant: Nc1ncc(C(F)(F)F)cc1Br
Agent: Br[Cu]Br
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: O
Solvent: CCN(CC)CC
Product: Nc1ncc(C(F)(F)F)cc1C#Cc1ccccc1
Temperature: 60 °C
Reaction time: 8 h

Procedure:
Under an atmosphere of argon, to a solution of 3-bromo-5-(trifluoromethyl)pyridin-2-amine (the compound described in Bio. Org. Med. Chem., 9, 1715 (1999)) (163 mg) in triethylamine (1.5 mL), ethynylbenzene (82 μL), bis(triphenylphosphine)palladium dichloride (43 mg) and copper bromide (14 mg) were added. The reaction mixture was stirred for overnight at 60° C. To the reaction mixture, water was added and extracted with ethyl acetate. The extract was washed with a saturated aqueous solution of sodium chloride, dried with anhydrous magnesium sulfate and concentrated. The obtained residue was purified by column chromatography on silica gel (hexane:ethyl acetate=5:1) to give the title compound (26 mg) having the following physical data.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[NH:9][C:10]2[C:15]([CH:16]=1)=[CH:14][CH:13]=[CH:12][CH:11]=2.[OH:17][C:18]1[CH:28]=[CH:27][C:21]([O:22][CH2:23][C:24](O)=[O:25])=[CH:20][CH:19]=1>>[OH:17][C:18]1[CH:19]=[CH:20][C:21]([O:22][CH2:23][C:24]([NH:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=2[C:8]2[NH:9][C:10]3[C:15]([CH:16]=2)=[CH:14][CH:13]=[CH:12][CH:11]=3)=[O:25])=[CH:27][CH:28]=1
Reactant: Nc1ccccc1-c1cc2ccccc2[nH]1
Reactant: O=C(O)COc1ccc(O)cc1
Product: O=C(COc1ccc(O)cc1)Nc1ccccc1-c1cc2ccccc2[nH]1
Yield: 30 %

Procedure:
Prepared from 2-(2-aminophenyl) indole and (4-hydroxyphenoxy) acetic acid in 30% yield following procedure 1. The product was crystallized from methanol. 89% Purity by LC/MS (230 DAD), Mass-spec [M+H+]=359, 1H NMR (MeOH-d4): 4.52 s (2H), 6.55 d, 9 Hz (2H), 6.58 s (1H), 6.61 d, 9 Hz (2H), 7.09 t, 8 Hz (1H), 7.18 t, 8 Hz (1H), 7.26 t, 8 Hz (1H), 7.37–7.43 m (2H), 7.56 t, 8 Hz (2H), 8.38 d, 8 Hz (1H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]([CH2:20][C:21](O)=[O:22])[S:10]([C:13]1[C:18]([CH3:19])=[CH:17][CH:16]=[CH:15][N:14]=1)(=[O:12])=[O:11].[CH2:24]([NH:31][CH2:32][CH3:33])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>>[CH2:24]([N:31]([CH2:32][CH3:33])[C:21](=[O:22])[CH2:20][N:9]([C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=1[O:2][CH3:1])[S:10]([C:13]1[C:18]([CH3:19])=[CH:17][CH:16]=[CH:15][N:14]=1)(=[O:11])=[O:12])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: COc1ccccc1N(CC(=O)O)S(=O)(=O)c1ncccc1C
Reactant: CCNCc1ccccc1
Product: CCN(Cc1ccccc1)C(=O)CN(c1ccccc1OC)S(=O)(=O)c1ncccc1C

Procedure:
prepared by reaction of [(2-methoxy-phenyl)-(3-methyl-pyridine-2-sulfonyl)-amino]-acetic acid with benzyl-ethyl-amine