Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.Cl.[N:3]12[CH2:10][CH2:9][CH:6]([CH2:7][CH2:8]1)[C@@H:5]([NH:11][C:12]([C:14]1[S:15][C:16]3[CH:22]=[CH:21][C:20]([NH2:23])=[CH:19][C:17]=3[CH:18]=1)=[O:13])[CH2:4]2.C(N(CC)CC)C.[C:31]([Cl:39])(=[O:38])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>CN(C=O)C>[ClH:39].[N:3]12[CH2:8][CH2:7][CH:6]([CH2:9][CH2:10]1)[C@@H:5]([NH:11][C:12]([C:14]1[S:15][C:16]3[CH:22]=[CH:21][C:20]([NH:23][C:31](=[O:38])[C:32]4[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=4)=[CH:19][C:17]=3[CH:18]=1)=[O:13])[CH2:4]2
Reactant: O=C(Cl)c1ccccc1
Reactant: Nc1ccc2sc(C(=O)N[C@H]3CN4CCC3CC4)cc2c1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=C(Nc1ccc2sc(C(=O)N[C@H]3CN4CCC3CC4)cc2c1)c1ccccc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
30 mg (0.08 mmol) of N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-5-amino-1-benzo-thiophene-2-carboxamide dihydrochloride are dissolved in 1 ml of DMF, and 33.5 μl (0.24 mmol) of triethylamine are added. At 0° C., 16.9 mg (0.12 mmol) of benzoyl chloride are added. After 3 h of stirring at RT, the reaction mixture is separated by preparative HPLC. The product fraction is concentrated under reduced pressure and codistilled with 4M HCl in dioxane. 9 mg (25.4% of theory) of the title compound are obtained.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C@H:10]([NH:13][S@](C(C)(C)C)=O)[CH2:11][CH3:12])[CH:5]=[CH:6][C:7]=1[O:8][CH3:9].[ClH:20].CO>CCOCC>[ClH:20].[F:1][C:2]1[CH:3]=[C:4]([C@H:10]([NH2:13])[CH2:11][CH3:12])[CH:5]=[CH:6][C:7]=1[O:8][CH3:9]
Reactant: CC[C@@H](N[S@@](=O)C(C)(C)C)c1ccc(OC)c(F)c1
Agent: Cl
Solvent: CCOCC
Solvent: CO
Product: CC[C@@H](N)c1ccc(OC)c(F)c1
Reaction time: 1.5 h
Yield: 78.8 %

Procedure:
To a solution of 68 (1.5 g, 5.2 mmol) in Et2O (20 mL) at 0° C. was added 3N HCl/MeOH (5.0 mL, 15 mmol). After being stirred for 1.5 h, the solid was filtered and dried in vacuo to afford 900 mg (80%) of 70a. 1H NMR (500 MHz, DMSO-d6) δ 8.56 (s, 3H), 7.44 (dd, J=12.5, 2.0 Hz, 1H), 7.29-7.20 (m, 2H), 4.08 (m, 1H), 3.84 (s, 3H), 1.97 (m, 1H), 1.78 (m, 1H), 0.73 (t, J=7.0 Hz, 3H). LCMS (ESI) m/z: 167.1 [M+H−17]+.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH2:8][O:9][Si:10]([C:23]([CH3:26])([CH3:25])[CH3:24])([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[C:4]([Cl:27])[CH:3]=1.C([Li])CCC.CCCCCC.[CH:39](N1CCCCC1)=[O:40].[Cl-].[NH4+]>O1CCCC1>[O:9]([CH2:8][C:5]1[CH:6]=[CH:7][C:2]([CH:39]=[O:40])=[CH:3][C:4]=1[Cl:27])[Si:10]([C:23]([CH3:26])([CH3:25])[CH3:24])([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: O=CN1CCCCC1
Reactant: CC(C)(C)[Si](OCc1ccc(Br)cc1Cl)(c1ccccc1)c1ccccc1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CC(C)(C)[Si](OCc1ccc(C=O)cc1Cl)(c1ccccc1)c1ccccc1
Temperature: 10 °C
Reaction time: 0.25 h
Yield: 42.4 %

Procedure:
To a solution of 4-bromo-1-((tert-butyldiphenylsiloxy)methyl)-2-chlorobenzene (8.65 g) in tetrahydrofuran (22 ml) was added 1-butyl lithium/hexane solution (1.54M, 13.5 ml) at −75° C. in a nitrogen atmosphere, and the mixture was stirred for 15 min. The reaction mixture was once heated to 10° C. and again cooled to −75° C. and 1-formyl piperidine (2.55 g) was added dropwise over 10 min. The reaction mixture was heated to room temperature over 3 hr. To the reaction mixture was added aqueous ammonium chloride solution and the resulting product was extracted twice with hexane. The organic layers were combined, washed successively with dil. hydrochloric acid, saturated aqueous sodium hydrogencarbonate solution and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated and the residue was applied to silica gel column chromatography (hexane/ethyl acetate=40/1) to give 4-((tert-butyldiphenylsiloxy)methyl)-3-chlorobenzaldehyde (3.26 g) as a pale-yellow oil.
Reaction SMILES: [CH:1]1[C:9]2[C:8]3[CH:10]=[CH:11][CH:12]=[CH:13][C:7]=3[O:6][C:5]=2[C:4](B(O)O)=[CH:3][CH:2]=1.Cl[C:18]1[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][N:19]=1.C(=O)([O-])[O-].[K+].[K+].C(COC)OC>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O>[Cl:24][C:21]1[CH:22]=[CH:23][C:18]([C:4]2[C:5]3[O:6][C:7]4[CH:13]=[CH:12][CH:11]=[CH:10][C:8]=4[C:9]=3[CH:1]=[CH:2][CH:3]=2)=[N:19][CH:20]=1
Reactant: Clc1ccc(Cl)nc1
Reactant: OB(O)c1cccc2c1oc1ccccc12
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: COCCOC
Solvent: O
Product: Clc1ccc(-c2cccc3c2oc2ccccc23)nc1
Yield: 75.8 %

Procedure:
Dibenzo[b,d]furan-4-ylboronic acid (9.5 g, 44.8 mmol), 2,5-dichloropyridine (7.0 g, 47.0 mmol), Pd(PPh3)4 (2.6 g, 2.2 mmol) and potassium carbonate (18.6 g, 134 mmol) were added to dimethoxyethane (75 mL) and water (75 mL). The reaction mixture was degassed with nitrogen before being heated to reflux overnight. EtOAc and water were added, the organic layer separated and the aqueous layer was extracted with 3×50 mL dichloromethane and dried over sodium sulfate. After removing the solvent under reduced pressure, the crude product was chromatographed on silica gel with dichloromethane to yield 11.7 g of crude product. The product was crystallized from hexane to give 9.5 g (76%) of 5-chloro-2-(dibenzo[b,d]furan-4-yl)pyridine as white needles. The product was confirmed by GC/MS.
Reaction SMILES: [C:1]([C:4]1[C:22]([OH:23])=[CH:21][CH:20]=[CH:19][C:5]=1[O:6][CH2:7][CH:8]([OH:18])[CH2:9][O:10][C:11]1[CH:16]=[CH:15][C:14]([Br:17])=[CH:13][CH:12]=1)(=[O:3])[CH3:2].[C:24](OCC)(=O)[C:25]([O:27]CC)=[O:26].[O-]CC.[Na+]>CCOCC>[C:25]([C:24]1[O:23][C:22]2[C:4]([C:1](=[O:3])[CH:2]=1)=[C:5]([O:6][CH2:7][CH:8]([OH:18])[CH2:9][O:10][C:11]1[CH:16]=[CH:15][C:14]([Br:17])=[CH:13][CH:12]=1)[CH:19]=[CH:20][CH:21]=2)([OH:27])=[O:26]
Reactant: CCOC(=O)C(=O)OCC
Reactant: CC(=O)c1c(O)cccc1OCC(O)COc1ccc(Br)cc1
Agent: CC[O-]
Agent: [Na+]
Solvent: CCOCC
Product: O=C(O)c1cc(=O)c2c(OCC(O)COc3ccc(Br)cc3)cccc2o1

Procedure:
A mixture of 1-(2-acetyl-3-hydroxyphenoxy)-2-hydroxy-3-p-bromophenoxypropane (15.2 g) and diethyl oxalate (15 ml) was added to a suspension of sodium ethoxide (prepared from 3.0 sodium) in absolute ether. The mixture was heated under reflux for 1.5 hours and then poured onto ice (100 g). After acidification with a solution of acetic acid (12 ml) in water (80 ml), the ether layer was separated and the aqueous layer was extracted with ether (3 × 25 ml). The combined ether solutions were evaporated and the residue was dissolved in a mixture of acetic acid (80 ml) and hydrochloric acid (30 ml) and heated under reflux for 1 hour. Recrystallization from acetic acid yielded crude 1-(2-carboxychromon-5-yloxy)-2-hydroxy-3-p-bromophenoxypropane, (14.7 g), as a white solid, m.p. 188°-190°, which was converted to the ethyl ester employing absolute ethyl alcohol and concentrated sulphuric acid as catalyst. 1-(2-carbethoxychromon-5-yloxy)-2-hydroxy-2-p-bromophenoxypropane was obtained as white crystals, m.p. 79°-80° after recrystallization from aqueous dioxane.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[Cl:11])[CH:7](O)[CH2:6][CH2:5]2.C1(C)C=CC=CC=1.C1(C)C=CC(S(O)(=O)=O)=CC=1.[OH-].[Na+]>O>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[Cl:11])[CH2:7][CH:6]=[CH:5]2
Reactant: OC1CCc2cc(Cl)c(Cl)cc21
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Solvent: O
Product: Clc1cc2c(cc1Cl)CC=C2
Yield: 56.5 %

Procedure:
A mixture of 17.48 g of the product of Step B, 470 ml of toluene, 0.57 g of 4-tert.-butyl-chatechol and 1.63 g of p-toluene sulfonic acid was refluxed for 2 hours and then was diluted with water. 10 ml of N sodium hydroxide solution were added and the mixture was extracted with toluene. The organic phase was evaporated to dryness under reduced pressure and the residue was taken up in hexane. The mixture was vacuum filtered and the crystalline product was dried to obtain 9 g of the desired product melting at 76° C.
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[CH2:3][O:4][C:5]1[CH:10]=[CH:9][N:8]=[C:7]([C:11](=O)[CH3:12])[CH:6]=1.[CH3:16][C:17]([S@:20]([NH2:22])=[O:21])([CH3:19])[CH3:18]>>[CH3:16][C:17]([S@:20]([NH:22][CH:11]([C:7]1[CH:6]=[C:5]([O:4][CH2:3][C:2]([F:15])([F:14])[F:1])[CH:10]=[CH:9][N:8]=1)[CH3:12])=[O:21])([CH3:19])[CH3:18]
Reactant: CC(C)(C)[S@](N)=O
Reactant: CC(=O)c1cc(OCC(F)(F)F)ccn1
Product: CC(N[S@](=O)C(C)(C)C)c1cc(OCC(F)(F)F)ccn1
Yield: 35 %

Procedure:
The title compound is prepared in 35% yield (60 mg, colorless oil) from 1-(4-(2,2,2-trifluoroethoxy)pyridin-2-yl)ethanone (120 mg, 0.53 mmol, Step-3) and (R)-2-methylpropane-2-sulfinamide by the similar manner in Step-4 of Amine-1.
Reaction SMILES: [C:1]([O:5][C:6](=[O:28])[C:7]1[CH:12]=[CH:11][C:10]([CH2:13][N:14]([C:17](=[O:27])[CH:18]=[C:19]2[C:23](=O)[O:22]C(C)(C)[O:20]2)[O:15][CH3:16])=[CH:9][CH:8]=1)([CH3:4])([CH3:3])[CH3:2].C=O.CN.ClC1C=C(C=CC=1Cl)[CH2:37][N:38](C)[C:39](C1CN(C)C(=O)C=1O)=O>CO>[C:1]([O:5][C:6](=[O:28])[C:7]1[CH:12]=[CH:11][C:10]([CH2:13][N:14]([C:17]([C:18]2[CH2:37][N:38]([CH3:39])[C:23](=[O:22])[C:19]=2[OH:20])=[O:27])[O:15][CH3:16])=[CH:9][CH:8]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CN1CC(C(=O)N(C)Cc2ccc(Cl)c(Cl)c2)=C(O)C1=O
Reactant: CON(Cc1ccc(C(=O)OC(C)(C)C)cc1)C(=O)C=C1OC(C)(C)OC1=O
Agent: C=O
Agent: CN
Solvent: CO
Product: CON(Cc1ccc(C(=O)OC(C)(C)C)cc1)C(=O)C1=C(O)C(=O)N(C)C1
Yield: 40 %

Procedure:
4-({[2-(2,2-dimethyl-5-oxo-[1,3]-dioxolan-4-ylidene)-acetyl]-methoxyamino}-methyl)-benzoic acid tert-butyl ester, prepared using the methods described in the previous examples, was treated in methanol with paraformaldehyde and methylamine as described in the preparation of Compound 12 to give the title compound as a white solid (40% yield); mp 157–160° C. 1HNMR 400 MHz (CDCl3) δ (ppm): 1.58 (9H, s, t-Bu), 3.11 (3H, s, NCH3), 3.72 (3H, s, OCH3), 4.16 (2H, s, NCH2), 4.92 (2H, s, NCH2), 7.37 (2H, d, J=8 Hz, aromatics), 7.97 (2H, d, J=8 Hz, aromatics), 11.55 (1H, broad s, OH).
Reaction SMILES: [CH3:1][S:2][C:3]1[NH:8][C:7]2=[N:9][C:10]([CH2:12][CH3:13])=[CH:11][C:6]2=[C:5]([Cl:14])[N:4]=1.[CH2:15](Br)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.[H-].[Na+]>O1CCCC1>[CH3:1][S:2][C:3]1[N:4]=[C:5]([Cl:14])[C:6]2[CH:11]=[C:10]([CH2:12][CH3:13])[N:9]([CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[C:7]=2[N:8]=1
Reactant: BrCc1ccccc1
Reactant: CCc1cc2c(Cl)nc(SC)[nH]c-2n1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCc1cc2c(Cl)nc(SC)nc2n1Cc1ccccc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 86.8 %

Procedure:
A solution of 5.30 g (23.2 mmol) of 2-(methylthio)-4-chloro-6-ethyl-1H-pyrrolo[2,3-d]pyrimidine in 160 mL of tetrahydrofuran (THF) was added to a 0° C. slurry of 7.96 g (46.5 mmol) of benzylbromide and 1.12 g (46.5 mmol) of sodium hydride in 40 mL of THF. The reaction was allowed to warm to ambient temperature and stirred for 18 hours. The reaction was quenched by the addition of 70 mL of brine. The organic phase was dried with sodium sulfate and concentrated to 12.0 g of brown oil. The oil was purified by flash chromatography using 1 Kg of silica gel and methylene chloride as an eluent to provide 6.40 g (87%) of 2-(methylthio)-4-chloro-6-ethyl-7-(phenylmethyl)-7H-pyrrolo[2,3-d]pyrimidine as a light yellow solid. nmr (500 MHz, CDCl3) δ1.29 (t, J=7.5 Hz, 3H), 2.60 (s, 3H), 2.61 (q, J=7.5 Hz, 2H), 5.41 (s, 2H), 6.28 (s, 1H), 7.07 (d, J=6.8 Hz, 2H), 7.28 (m, 3H)
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][C:5]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([N+:14]([O-:16])=[O:15])[CH:12]=2)[NH:7][CH:6]=1.[N:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[N:23]1[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1.C([O-])([O-])=O.[K+].[K+]>C(#N)C>[N:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[N:23]1[CH2:24][CH2:25][N:26]([CH2:2][CH2:3][CH2:4][C:5]2[C:13]3[C:8](=[CH:9][CH:10]=[C:11]([N+:14]([O-:16])=[O:15])[CH:12]=3)[NH:7][CH:6]=2)[CH2:27][CH2:28]1
Reactant: c1ccc(N2CCNCC2)nc1
Reactant: O=[N+]([O-])c1ccc2[nH]cc(CCCBr)c2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: O=[N+]([O-])c1ccc2[nH]cc(CCCN3CCN(c4ccccn4)CC3)c2c1
Yield: 39.1 %

Procedure:
A mixture of 3-[3-bromopropyl]-5-nitro-1H-indole (1.4 g, 4.2 mmol), 1-(2-pyridinyl)-piperazine, (0.98 g, 5.09 mmol) and K2CO3 (1.4 g, 10.2 mmol) in 30 mL of acetonitrile was heated to reflux for 4 h. The reaction mixture was cooled, the solvent was removed and the residue dissolved in ethyl acetate and water. The aqueous layer was separated and extracted with ethyl acetate. The organic extracts were dried (MgSO4) and concentrated, and the gummy residue purified by flash silica gel chromatography (5% methanol in dichloromethane) to give 3-[3-[4-(2-pyridinyl)-1-piperazinyl]propyl]-5-nitro-1H-indole, (0.6 g, 36%) as a yellow solid: IR(KBr) 3182, 1520, 1330 cm-1 ; 1H NMR (DMSO-d6, 300 MHz) δ8.52 (d, J=2.24 Hz, 1H), 8.80 (dd, J=1.8, 4.8 Hz, 1H), 7.95 (dd, J=2.25, 9.0 Hz, 1H), 7.52-7.49 (m, 2H), 7.41 (s, 1H), 6.79 (d, J=8.6 Hz, 1H), 6.60 (t, J=6.6 Hz, 1H), 3.46 (t, J=4.7 Hz, 4H), 2.78 (t, J=7.4 Hz, 2H), 2.42 (t, J=5.0 Hz, 4H), 2.34 (t, J=6.9 HZ, 4H), 1.82 (dt, J=7.4, 6.9 Hz, 2H); MS (m/e) 365 (M+). Anal. Calcd for C20H23N5O2 : C, 65.73, H, 6.34, N 19.16; found C, 65.35, H, 6.26, N, 18.87.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:18](=[O:23])[NH:19][CH:20]2[CH2:22][CH2:21]2)=[CH:4][C:5]2[N:9]=[C:8]([C:10]([O:12]C)=[O:11])[N:7]([CH:14]3[CH2:16][CH2:15]3)[C:6]=2[CH:17]=1.[OH-].[Li+]>C1COCC1.O>[Cl:1][C:2]1[C:3]([C:18](=[O:23])[NH:19][CH:20]2[CH2:21][CH2:22]2)=[CH:4][C:5]2[N:9]=[C:8]([C:10]([OH:12])=[O:11])[N:7]([CH:14]3[CH2:16][CH2:15]3)[C:6]=2[CH:17]=1
Reactant: COC(=O)c1nc2cc(C(=O)NC3CC3)c(Cl)cc2n1C1CC1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(NC1CC1)c1cc2nc(C(=O)O)n(C3CC3)c2cc1Cl
Temperature: 25 °C
Reaction time: 18 h

Procedure:
1.65 g (4.9 mmol) of methyl 6-chloro-1-cyclopropyl-5-(cyclopropylcarbamoyl)-1H-benzimidazole-2-carboxylate were dissolved in 82 ml of THF and admixed at 0° C. with 0.24 g (9.89 mmol) of lithium hydroxide predissolved in 18 ml of water, and the reaction mixture was stirred at room temperature for 18 hours. The THF was distilled off and the aqueous phase was extracted three times with ethyl acetate; the aqueous phase was adjusted to pH=3 with HCl. The solid which precipitates out was filtered off with suction. Due to its relative instability, the acid was used for subsequent reactions without further purification.
Reaction SMILES: C(N(CC)CC)C.[F:8][C:9]1[CH:17]=[CH:16][CH:15]=[C:14]([F:18])[C:10]=1[C:11](Cl)=[O:12].[CH3:19][O:20][C:21](=[O:41])[CH:22]([NH2:40])[CH2:23][CH:24]=[CH:25][C:26]1[CH:31]=[CH:30][C:29]([N:32]([CH3:39])[C:33]2[N:38]=[CH:37][CH:36]=[CH:35][N:34]=2)=[CH:28][CH:27]=1.C(=O)([O-])O.[Na+]>ClCCl>[CH3:19][O:20][C:21](=[O:41])[CH:22]([NH:40][C:11](=[O:12])[C:10]1[C:9]([F:8])=[CH:17][CH:16]=[CH:15][C:14]=1[F:18])[CH2:23]/[CH:24]=[CH:25]/[C:26]1[CH:27]=[CH:28][C:29]([N:32]([CH3:39])[C:33]2[N:38]=[CH:37][CH:36]=[CH:35][N:34]=2)=[CH:30][CH:31]=1
Reactant: O=C(Cl)c1c(F)cccc1F
Reactant: COC(=O)C(N)CC=Cc1ccc(N(C)c2ncccn2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)C(C/C=C/c1ccc(N(C)c2ncccn2)cc1)NC(=O)c1c(F)cccc1F
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Under an argon atmosphere, triethylamine (0.028 ml) and 2,6-difluorobenzoyl chloride (0.015 ml) were added to a solution of 2-amino-5-[4-(methyl-pyrimidin-2-ylamino)phenyl]pent-4-enoic acid methyl ester (31.7 mg) in dichloromethane (2 ml), and the resulting mixture was stirred at room temperature for 2 hours. Saturated aqueous sodium hydrogen carbonate solution was added to the reaction solution and the resulting mixture was extracted with ethyl acetate. Organic layer was washed twice with water and once with saturated brine, and dried over anhydrous sodium sulfate. After removing anhydrous sodium sulfate by filtration, the filtrate was concentrated. The residue was purified by thin layer chromatography (silica gel, mobile phase: cyclohexane/ethyl acetate=3/2) to obtain (E)-2-(2,6-difluorobenzamido)-5-[4-(methyl-pyrimidin-2-ylamino)phenyl]pent-4-enoic acid methyl ester (42 mg).
Reaction SMILES: [C:1]1([C:7]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[N:10]=[C:9]([O:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][C:23](O)=[O:24])[CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N1C=CN=C1)(N1C=CN=C1)=O.[NH:38]1[CH2:42][CH2:41][CH2:40][CH2:39]1>O1CCCC1>[C:1]1([C:7]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[N:10]=[C:9]([O:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][C:23]([N:38]3[CH2:42][CH2:41][CH2:40][CH2:39]3)=[O:24])[CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: C1CCNC1
Reactant: O=C(O)CCCCCOc1cc(-c2ccccc2)c2ccccc2n1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: O=C(CCCCCOc1cc(-c2ccccc2)c2ccccc2n1)N1CCCC1

Procedure:
To a solution of 5 g of 6-[(4-phenyl-2-quinolyl)oxy]hexanoic acid in 120 cc of tetrahydrofuran is added 2.9 g of 1,1'-carbonyldiimidazole. The mixture is stirred for 2 hours to 50° C. After cooling, 1.3 g of pyrrolidine is added and the mixture is stirred at room temperature overnight. The tetrahydrofuran is removed in vacuo and the residue partitioned between ethyl acetate and water. The ethyl acetate solution is washed with water, dried (Na2SO4), filtered and concentrated in vacuo. The resultant residue is then purified by flash chromatography on silica gel (30-60mm; eluent: 3:7 cyclohexane/ethyl acetate) to give 1-[6-(4-phenyl-2-quinolyloxy)hexanoyl]pyrrolidine as a white solid m.p.=52°-54° C.)
Reaction SMILES: [F:1][C:2]([F:32])([F:31])[O:3][C:4]1[CH:9]=[CH:8][C:7]([S:10]([N:13]2[CH2:18][CH2:17][CH:16]([O:19][N:20]3C(=O)C4C(=CC=CC=4)C3=O)[CH2:15][CH2:14]2)(=[O:12])=[O:11])=[CH:6][CH:5]=1.O.NN>CCO>[F:32][C:2]([F:1])([F:31])[O:3][C:4]1[CH:5]=[CH:6][C:7]([S:10]([N:13]2[CH2:18][CH2:17][CH:16]([O:19][NH2:20])[CH2:15][CH2:14]2)(=[O:11])=[O:12])=[CH:8][CH:9]=1
Reactant: O=C1c2ccccc2C(=O)N1OC1CCN(S(=O)(=O)c2ccc(OC(F)(F)F)cc2)CC1
Agent: NN
Solvent: CCO
Solvent: O
Product: NOC1CCN(S(=O)(=O)c2ccc(OC(F)(F)F)cc2)CC1
Reaction time: 1 h
Yield: 100 %

Procedure:
A mixture of 2-(1-(4-(trifluoromethoxy)phenylsulfonyl)piperidin-4-yloxy)isoindoline-1,3-dione (390 mg, 0.82 mmol) and hydrazine monohydrate (0.044 ml, 0.90 mmol) in EtOH (4 ml) was stirred for 1 hour. The precipitated materials were filtered off and washed with EtOH (2 ml×2), then the filtrate was evaporated under reduced pressure to give O-(1-(4-(trifluoromethoxy)phenylsulfonyl)piperidin-4-yl)hydroxylamine (279 mg, 100%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([C:11]([OH:13])=O)=[CH:5]2.CCN=C=NCCCN(C)C.[NH2:25][CH2:26][CH2:27][CH2:28][OH:29]>C(Cl)Cl.CN(C1C=CN=CC=1)C>[OH:29][CH2:28][CH2:27][CH2:26][NH:25][C:11]([C:6]1[NH:7][C:8]2[C:4]([CH:5]=1)=[CH:3][C:2]([F:1])=[CH:10][CH:9]=2)=[O:13]
Reactant: O=C(O)c1cc2cc(F)ccc2[nH]1
Reactant: NCCCO
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: O=C(NCCCO)c1cc2cc(F)ccc2[nH]1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a solution of 5-fluoro-1H-indole-2-carboxylic acid (2.27 g, 12.7 mmol) in CH2Cl2 (100 mL) is added DMAP (4.64 g, 38 mmol), EDCI (3.64 g, 19 mmol), 3-amino-propan-1-ol (1.90 g, 25 mmol). The mixture is stirred at room temperature for 24 hours. After the solvent is removed under vacuum, 5% HCl (100 mL) is added to the mixture. It is extracted with EtOAc (100 mL×3). The combined organic layers are washed with saturated aqueous NaHCO3 (100 mL), brine (100 mL) and dried with Na2SO4. Solvent is removed to give 5-fluoro-1H-indole-2-carboxylic acid (3-hydroxy-propyl)-amide; 1H NMR (DMSO-d6) δ 1.69 (quint, 2H, J=6.4 Hz), 3.34 (q, 2H, J=6.0 Hz), 3.48 (t, 2H, J=6.4 Hz), 4.48 (bs, 1H), 6.99-7.10 (m, 2H), 7.36-7.44 (m, 2H), 8.47 (t, 1H, J=5.6 Hz), 11.63 (s, 1H); m/z [M++1] 237.1.
Reaction SMILES: C([O:4][CH2:5][C:6]1[CH:26]=[CH:25][CH:24]=[CH:23][C:7]=1[CH2:8][O:9][C:10]1[C:11]2[N:12]([C:16]([CH2:20][C:21]#[CH:22])=[C:17]([CH3:19])[N:18]=2)[CH:13]=[CH:14][CH:15]=1)(=O)C.C(=O)([O-])[O-].[K+].[K+]>O.CO>[OH:4][CH2:5][C:6]1[CH:26]=[CH:25][CH:24]=[CH:23][C:7]=1[CH2:8][O:9][C:10]1[C:11]2[N:12]([C:16]([CH2:20][C:21]#[CH:22])=[C:17]([CH3:19])[N:18]=2)[CH:13]=[CH:14][CH:15]=1
Reactant: C#CCc1c(C)nc2c(OCc3ccccc3COC(C)=O)cccn12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: O
Product: C#CCc1c(C)nc2c(OCc3ccccc3CO)cccn12
Temperature: 25 °C
Reaction time: 1.2 h
Yield: 56.5 %

Procedure:
A mixture of 8-(2-acetoxymethylbenzyloxy)-2-methyl-3-(2-propynyl)imidazo [1,2-a]pyridine (0.36 g) and potassium carbonate (0.214 g) in water (1.8 ml) and methanol (10 ml) was stirred at room temperature for 1.2 hours and then diluted with water. The resulting precipitates were collected by filtration and recrystallized from ethyl acetate to give 8-(2-hydroxymethylbenzyloxy)-2-methyl-3-(2-propynyl)imidazo[1,2-a]pyridine (0.179 g).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([O:8][CH2:9][CH2:10][CH2:11][Cl:12])[CH:5]=[CH:4][C:3]=1[C:13](=[O:15])[CH3:14].[Br:16]Br.C(=O)(O)[O-].[Na+]>CCOCC>[Br:16][CH2:14][C:13]([C:3]1[CH:4]=[CH:5][C:6]([O:8][CH2:9][CH2:10][CH2:11][Cl:12])=[CH:7][C:2]=1[CH3:1])=[O:15]
Reactant: BrBr
Reactant: CC(=O)c1ccc(OCCCCl)cc1C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOCC
Product: Cc1cc(OCCCCl)ccc1C(=O)CBr
Reaction time: 17 h

Procedure:
A solution of the product of Step A (9.33 g) in ether (42 mL) was treated with bromine (2.1 mL) and the mixture stirred for approximately 17 hours. The mixture was slowly poured into saturated sodium bicarbonate solution (100 mL) and then the organic layer was separated. The aqueous layer was washed with a fresh portion of ether (100 mL). The combined organic layers were washed with a fresh portion of water (100 mL), dried over magnesium sulfate, filtered and evaporated to give the title compound (11 g).
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:6][O:7][C@@H:8]1[CH2:16][N:15]2[C@H:10]([CH2:11][C:12](=O)[CH2:13][C:14]2=[O:17])[CH2:9]1>C(O)C>[CH3:6][O:7][C@@H:8]1[CH2:16][N:15]2[C@@H:10]([CH2:11][C:12]([N:1]3[CH2:5][CH2:4][CH2:3][CH2:2]3)=[CH:13][C:14]2=[O:17])[CH2:9]1
Reactant: CO[C@H]1C[C@H]2CC(=O)CC(=O)N2C1
Reactant: C1CCNC1
Solvent: CCO
Product: CO[C@H]1C[C@@H]2CC(N3CCCC3)=CC(=O)N2C1
Reaction time: 0.5 h
Yield: 98 %

Procedure:
3.07 ml (36.8 mmol) of pyrrolidine were added to a solution of 3.38 g (18.4 mmol) of (2S,8aS)-2-methoxy-1,2,3,5,6,7,8,8a-octahydroindolizine-5,7-dione [obtained as described in Preparative Example 10(iii)′ above] in 34 ml of ethanol, and the resulting mixture was left to stand for 30 minutes at room temperature. At the end of this time, the solvent and any excess pyrrolidine were distilled off under reduced pressure to afford 4.26 g (yield: 98%) of the title compound as a brown oil.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]([CH3:17])([CH3:16])[CH2:9][C:10](=[O:15])[C:11]([F:14])([F:13])[F:12].[BH4-].[Na+]>CO.C1COCC1>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]([CH3:17])([CH3:16])[CH2:9][CH:10]([OH:15])[C:11]([F:13])([F:14])[F:12]
Reactant: CC(C)(CC(=O)C(F)(F)F)c1ccccc1Br
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)(CC(O)C(F)(F)F)c1ccccc1Br
Temperature: 25 °C
Reaction time: 24 h
Yield: 58.3 %

Procedure:
To a round bottom flask was added 4-(2-bromophenyl)-1,1,1-trifluoro-4-methylpentan-2-one (3.0 g, 9.7 mmol) in 70 mL of MeOH and 70 mL of THF at 0° C., followed by the slow addition of NaBH4 (1.1 g, 29.1 mmol). The reaction mixture was stirred at room temperature for 24 hours and then concentrated in vacuo. The residue was diluted with 1000 mL of ethyl acetate, washed with 200 mL of saturated aqueous sodium bicarbonate solution, 200 mL of brine, dried over sodium sulfate, filtered, and concentrated in vacuo. The crude mixture was purified by flash chromatography. The column was eluted with 0-20% EtOAc/hexanes to afford 1.76 g (58%) of 4-(2-bromophenyl)-1,1,1-trifluoro-4-methylpentan-2-ol.