Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Mg].[F:2][C:3]([F:12])([F:11])[C:4]1[CH:9]=[CH:8][C:7](Br)=[CH:6][CH:5]=1.[CH3:13][O:14][C:15]([C:17]12[CH:25]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[CH2:24][CH2:23][C:22](=[O:32])[CH:21]1[CH2:20][N:19]([CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[CH2:18]2)=[O:16].[Cl-].[NH4+]>C(OCC)C>[CH3:13][O:14][C:15]([C:17]12[CH:25]([C:26]3[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=3)[CH2:24][CH2:23][C:22]([OH:32])([C:7]3[CH:8]=[CH:9][C:4]([C:3]([F:12])([F:11])[F:2])=[CH:5][CH:6]=3)[CH:21]1[CH2:20][N:19]([CH2:33][C:34]1[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=1)[CH2:18]2)=[O:16]
Reactant: COC(=O)C12CN(Cc3ccccc3)CC1C(=O)CCC2c1ccccc1
Reactant: FC(F)(F)c1ccc(Br)cc1
Agent: [Cl-]
Agent: [Mg]
Agent: [NH4+]
Solvent: CCOCC
Product: COC(=O)C12CN(Cc3ccccc3)CC1C(O)(c1ccc(C(F)(F)F)cc1)CCC2c1ccccc1
Temperature: 10 °C
Yield: 66.2 %

Procedure:
0.8 g of magnesium turnings was added to a solution of 7.2 g of 4-(trifluoromethyl)bromobenzene in 40 cm3 of dry diethyl ether. The reaction mixture was spontaneously brought to reflux for ten minutes and was then heated at reflux for twenty minutes. The reaction mixture was subsequently cooled and a solution of 5.6 g of methyl(3aRS,4SR,7aRS)-2-benzyl-7-oxo-4-phenyloctahydroisoindole-3a-carboxylate in 40 cm3 of dry diethyl ether was added over fifteen minutes at a temperature in the region of 10° C. The reaction mixture was stirred for ten minutes at a temperature in the region of 10° C. and then poured into 150 cm3 of a saturated aqueous ammonium chloride solution. The aqueous phase was separated by settling and extracted with three times 75 cm3 of diethyl ether. The organic phases were combined, washed successively with three times 75 cm3 of distilled water, dried over magnesium sulphate in the presence of 3S charcoal and concentrated under reduced pressure. After crystallization from 25 cm3 of pentane, 5.2 g of methyl(3aRS,4SR,7RS,7aRS)-2-benzyl-7-hydroxy-7-[4-(trifluoromethyl)phenyl]-4-phenyloctahydroisoindole-3a-carboxylate were obtained in the form of a beige solid, the characteristic of which was as follows:
Reaction SMILES: [Br-].[C:2]([CH2:7][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)([O:4][CH2:5][CH3:6])=[O:3].CC(C)([O-])C.[Na+].[Cl:33][C:34]1[CH:35]=[C:36]([NH:41][C:42]([C:44]2[C:48]([CH:49]=O)=[N:47][O:46][N:45]=2)=[O:43])[CH:37]=[CH:38][C:39]=1[F:40]>C1(C)C=CC=CC=1.C1COCC1>[Cl:33][C:34]1[CH:35]=[C:36]([NH:41][C:42]([C:44]2[C:48](/[CH:49]=[CH:7]/[C:2]([O:4][CH2:5][CH3:6])=[O:3])=[N:47][O:46][N:45]=2)=[O:43])[CH:37]=[CH:38][C:39]=1[F:40]
Reactant: O=Cc1nonc1C(=O)Nc1ccc(F)c(Cl)c1
Reactant: CCOC(=O)C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CC(C)(C)[O-]
Agent: [Br-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: CCOC(=O)/C=C/c1nonc1C(=O)Nc1ccc(F)c(Cl)c1
Temperature: 80 °C
Reaction time: 0.5 h

Procedure:
To a solution of (carbethoxymethyl)triphenylphosphonium bromide (3.14 g, 7.32 mmol) in toluene (37 mL) was added sodium tert-butoxide (723 mg, 7.52 mmol) at rt under a nitrogen atmosphere. After stirring for 30 min, a solution of N-(3-chloro-4-fluorophenyl)-4-formyl-1,2,5-oxadiazole-3-carboxamide (811 mg, 3.01 mmol) in THF (10 mL) was cannulated into reaction flask. The resulting solution was heated at 80° C. for 3 h, then cooled to rt overnight. The reaction was quenched with a 1 N HCl solution, the aqueous solution was then extracted with ethyl acetate. The combined organic solutions were washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified with flash chromatography (30% ethyl acetate/hexane) to give the desired product as a white solid. 1H NMR (400 MHz, CD3OD): δ 7.92 (m, 2H), 7.65 (m, 1H), 7.26 (m, 1H), 7.01 (m, 1H), 4.27 (m, 2H), 1.33 (m, 3H); LCMS for C14H12ClFN3O4(M+H)+: m/z=340.
Reaction SMILES: [CH3:1][C:2]12[CH2:12][C:6]3([CH2:13][N:14]4[C:18]([CH3:19])=[CH:17][CH:16]=[N:15]4)[CH2:7][C:8]([CH3:11])([CH2:10][C:4]([O:20][CH2:21][CH2:22][OH:23])([CH2:5]3)[CH2:3]1)[CH2:9]2.[I:24]N1C(=O)CCC1=O>CN(C)C=O.C(OCC)(=O)C>[CH3:1][C:2]12[CH2:3][C:4]3([O:20][CH2:21][CH2:22][OH:23])[CH2:10][C:8]([CH3:11])([CH2:7][C:6]([CH2:13][N:14]4[C:18]([CH3:19])=[C:17]([I:24])[CH:16]=[N:15]4)([CH2:5]3)[CH2:12]1)[CH2:9]2
Reactant: O=C1CCC(=O)N1I
Reactant: Cc1ccnn1CC12CC3(C)CC(C)(C1)CC(OCCO)(C3)C2
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Cc1c(I)cnn1CC12CC3(C)CC(C)(C1)CC(OCCO)(C3)C2
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a solution of the 2-({3,5-dimethyl-7-[(5-methyl-1H-pyrazol-1-yl)methyl]tricyclo[3.3.1.13,7]dec-1-yl}oxy)ethanol (3.5 g, 11 mmol) in N,N-dimethylformamide (30 ml) was added N-iodosuccinimide (3.2 g, 14.22 mmol). The mixture was stirred at room temperature for 1.5 hours. The reaction mixture was then diluted with ethyl acetate and washed with aqueous sodium thiosulfate, water and brine. After drying over anhydrous sodium sulfate, the mixture was filtered and concentrated. The residue was purified by normal phase chromatography to give the title compound.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14](Cl)[CH:15]=2)[C:10]([CH3:19])([CH3:18])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cl-].[CH3:21][Zn+]>>[C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([CH3:21])[CH:15]=2)[C:10]([CH3:19])([CH3:18])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: C[Zn+]
Reactant: CC(C)(C)OC(=O)N1CC(C)(C)c2ccc(Cl)cc21
Agent: [Cl-]
Product: Cc1ccc2c(c1)N(C(=O)OC(C)(C)C)CC2(C)C

Procedure:
The title compound was prepared from 6-chloro-3,3-dimethyl-2,3-dihydro-indole-1-carboxylic acid tert-butyl ester and methylzinc chloride following similar methods to those described in Preparation 117, MS: [M+H]+=206 (-tBu).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[CH:4][C:3]=1[N:16]1[C:21]2[N:22]=[C:23]([S:26][CH3:27])[N:24]=[CH:25][C:20]=2[CH:19]=[CH:18][C:17]1=[O:28].C1C=C(Cl)C=C(C(OO)=[O:37])C=1.O.C([O-])([O-])=O.[Na+].[Na+]>C(Cl)Cl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[CH:4][C:3]=1[N:16]1[C:21]2[N:22]=[C:23]([S:26]([CH3:27])=[O:37])[N:24]=[CH:25][C:20]=2[CH:19]=[CH:18][C:17]1=[O:28]
Reactant: CSc1ncc2ccc(=O)n(-c3cc(NC(=O)OC(C)(C)C)ccc3F)c2n1
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: CS(=O)c1ncc2ccc(=O)n(-c3cc(NC(=O)OC(C)(C)C)ccc3F)c2n1
Temperature: 0 °C
Reaction time: 1 h
Yield: 131.6 %

Procedure:
At 0° C., a suspension of tert-butyl (4-fluoro-3-(2-(methylthio)-7-oxopyrido[2,3-d]pyrimidin-8(7H)-yl)phenyl)carbamate (59) (270 mg, 0.67 mmol) in DCM (10 mL) was treated with MCPBA (77 wt. %, 161 mg, 0.72 mmol) in one portion and stirred at 0° C. for 1 h. The reaction mixture was diluted with DCM (50 mL), and treated with ice and water (30 mL) followed by 10% Na2CO3 (ca. 10 mL). The DCM layer was separated and the aqueous layer was extracted with an additional amount of DCM (2×50 mL), dried over Na2SO4 and concentrated to give crude tert-butyl (4-fluoro-3-(2-(methylsulfinyl)-7-oxopyrido[2,3-d]pyrimidin-8(7H)-yl)phenyl)carbamate (60) (369 mg) as a light yellow solid. m/z (ESI, +ve ion) 440.9 (M+Na)+. 1H NMR (400 MHz, DMSO-d6) δ ppm 9.63 (1H, br. s.), 8.24 (1H, d, J=9.6 Hz), 7.68 (1H, d, J=3.5 Hz), 7.44-7.52 (1H, m), 7.33-7.41 (1H, m), 6.95-7.01 (1H, m), 5.76 (1H, s), 2.72-2.78 (3H, m), 1.47 (9H, s). 19F NMR (376 MHz, DMSO-d6) δ ppm-129.58 (1F, s).
Reaction SMILES: Br[CH2:2][C:3](=[O:6])[CH2:4][CH3:5].[OH:7][C:8]1[CH:15]=[CH:14][C:11]([C:12]#[N:13])=[CH:10][CH:9]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CC(C)=O>[O:6]=[C:3]([CH2:4][CH3:5])[CH2:2][O:7][C:8]1[CH:15]=[CH:14][C:11]([C:12]#[N:13])=[CH:10][CH:9]=1
Reactant: CCC(=O)CBr
Reactant: N#Cc1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(C)=O
Product: CCC(=O)COc1ccc(C#N)cc1
Temperature: 60 °C
Yield: 96 %

Procedure:
1-Bromo-2-butanone (1.51 g, 10 mmol) was added to a solution of 4-hydroxybenzonitrile (1.19 g, 10 mmol) and caesium carbonate (3.25 g, 10 mmol), in acetone (50 ml). The reaction mixture was then heated at 60° C. for 2 hours. After cooling, it was concentrated under reduced pressure. Water (25 ml) was added and the mixture was extracted with ethyl acetate (2×50 ml). The combined organic layers were washed with brine, dried over magnesium sulphate, filtered and concentrated under reduced pressure to give crude 4-(2-oxobutoxy)benzonitrile intermediate (1.83 g) (9.6 mmol). Ethyl formate (407 mg, 5.5 mmol) was added to a solution of the crude intermediate (945 mg, 5 mmol) in ethanol (5 ml). The reaction mixture was then cooled to 0° C. and sodium ethoxide (21% wt solution in ethanol, 1.78 ml, 5.5 mmol) was added dropwise over 2 minutes at 0° C. under nitrogen. The reaction mixture was then warmed to room temperature and stirred for 18 hours, after which time 0.5N hydrochloric acid (25 ml) was added and the mixture was extracted with diethyl ether (2×50 ml). The combined organic layers were washed with brine, dried over magnesium sulphate and concentrated under reduced pressure to provide crude 4-(1-formyl-2-oxobutoxy)benzonitrile (820 mg, 3.78 mmol). This intermediate was then dissolved in acetic acid (10 ml), and then hydrazine hydrate (320 mg, 6.4 mmol) was added. The reaction mixture was stirred at room temperature for 2 hours, under nitrogen. It was then concentrated under reduced pressure, and the residue was purified by flash chromatography on silica gel, eluting with ethyl acetate:pentane (30:70 to 40:60, by volume), to provide the title compound (118 mg, 15%) as a solid.
Reaction SMILES: [OH-].[Na+].[C:3]1([P:9]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[CH2:16][PH:17](=[O:23])[O:18]CC(C)C)[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1>O.C1COCC1.Cl>[C:24]1([P:9]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[CH2:16][PH:17](=[O:18])[OH:23])[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: CC(C)CO[PH](=O)Cc1ccccc1P(c1ccccc1)c1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=[PH](O)Cc1ccccc1P(c1ccccc1)c1ccccc1
Temperature: 23 °C
Reaction time: 0.33 h

Procedure:
0.30 g (7.6 mmol) of NaOH in 5 ml of water are added dropwise at 23° C. to a solution of 1.50 g (3.8 mmol) of isobutyl (2-diphenylphosphinophenyl)methylphosphinate in 5 ml of THF. After refluxing for 6 hours, the mixture is diluted with a further 5 ml of THF, 3.0 ml of 2N hydrochloric acid are added dropwise at 23° C. and the mixture is stirred for 20 min at 23° C. After phase separation, the aqueous phase is extracted twice, each time with 20 ml of dichloromethane, and the combined organic phases are washed with 20 ml of water. After drying over Na2SO4, complete evaporation under reduced pressure and drying in high vacuum, 1.17 g of (2-diphenylphosphinophenyl)methylphosphinic acid (92% of theory) are obtained in the form of a pale yellow solid having an m.p. of 167° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[C:10]1[S:11][C:12]2[C:17]([N:18]=1)=[CH:16][CH:15]=[C:14]([C:19]1([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH2:21][CH2:20]1)[N:13]=2)[CH:5]=O.[ClH:28].[NH2:29][C@H:30]([CH3:35])[CH2:31][C:32]([OH:34])=[O:33]>>[ClH:28].[F:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[C:10]1[S:11][C:12]2[C:17]([N:18]=1)=[CH:16][CH:15]=[C:14]([C:19]1([C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=3)[CH2:20][CH2:21]1)[N:13]=2)[CH2:5][NH:29][C@H:30]([CH3:35])[CH2:31][C:32]([OH:34])=[O:33]
Reactant: O=Cc1ccc(-c2nc3ccc(C4(c5ccccc5)CC4)nc3s2)c(F)c1
Reactant: C[C@@H](N)CC(=O)O
Agent: Cl
Product: C[C@H](CC(=O)O)NCc1ccc(-c2nc3ccc(C4(c5ccccc5)CC4)nc3s2)c(F)c1

Procedure:
Reaction of 3-fluoro-4-(5-(1-phenylcyclopropyl)thiazolo[5,4-b]pyridin-2-yl)benzaldehyde (0.040 g, 0.11 mmol) and (R)-3-aminobutanoic acid hydrochloride (0.056 g, 0.40 mmol) according to Reference R and general procedure for reductive amination afforded (R)-3-(3-fluoro-4-(5-(1-phenylcyclopropyl)thiazolo[5,4-b]pyridin-2-yl)benzylamino)butanoic acid hydrochloride. MS (ESI) m/z: calculated: 461.2; Observed: 462.1 (M++1).
Reaction SMILES: [Br:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([C:12]3[N:13]=[C:14]([C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=4)[S:15][CH:16]=3)=[CH:9][CH:10]=2)[CH:5]=[CH:4][C:3]=1[OH:23].Br[CH2:25][C:26]([O:28][CH3:29])=[O:27].C(=O)([O-])[O-].[Cs+].[Cs+]>CC(C)=O>[Br:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([C:12]3[N:13]=[C:14]([C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=4)[S:15][CH:16]=3)=[CH:9][CH:10]=2)[CH:5]=[CH:4][C:3]=1[O:23][CH2:25][C:26]([O:28][CH3:29])=[O:27]
Reactant: Oc1ccc2cc(-c3csc(-c4ccccc4)n3)ccc2c1Br
Reactant: COC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(C)=O
Product: COC(=O)COc1ccc2cc(-c3csc(-c4ccccc4)n3)ccc2c1Br
Temperature: 25 °C
Reaction time: 19 h
Yield: 94.8 %

Procedure:
A mixture of 1-bromo-6-(2-phenyl-1,3-thiazol-4-yl)-2-naphthol (356 mg, 0.931 mmol), prepared in step 1 of Example 3, methyl bromoacetate (106 μL, 1.12 mmol) and cesium carbonate (457 mg, 1.40 mmol) in 25 mL of acetone was stirred under nitrogen at room temperature for 19 h. The reaction was concentrated under reduced pressure to remove the acetone. The residue was partitioned between methylene chloride and water. The aqueous layer was separated and extracted multiple times with methylene chloride. The combined organic extracts were dried (MgSO4), filtered and the solvent removed under reduced pressure to give methyl {[1-bromo-6-(2-phenyl-1,3-thiazol-4-yl)-2-naphthyl]oxy}acetate (401 mg, 95%) as an off-white solid, mp 156-159° C. Elemental Analysis for C22H16BrNO3S Calc'd: C, 58.16; H, 3.55; N, 3.08. Found: C, 57.87; H, 3.43; N, 2.94.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([N:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)[CH:5]=[N:6][CH:7]=1.C[CH2:15][O:16]CC.C([Li])CCC.CN(C=O)C>CCCCCC>[N:8]1([C:4]2[CH:5]=[N:6][CH:7]=[C:2]([CH:3]=2)[CH:15]=[O:16])[CH2:13][CH2:12][O:11][CH2:10][CH2:9]1
Reactant: Brc1cncc(N2CCOCC2)c1
Reactant: CCOCC
Agent: [Li]CCCC
Solvent: CN(C)C=O
Solvent: CCCCCC
Product: O=Cc1cncc(N2CCOCC2)c1
Reaction time: 1 h
Yield: 91 %

Procedure:
A solution of 4-(5-bromopyridin-3-yl)morpholine (100 mg, 0.0004 mol) in ether (2 mL, 0.02 mol) cooled at −78° C. was treated with 2.5 M n-butyllithium in hexane (0.2 mL) and was stirred for 1 h. To this mixture was added DMF (0.5 mL, 0.006 mol) dropwise. The reaction was quenched with water and extracted with ethyl acetate. The combined organic layers were washed with saturated sodium chloride, dried over magnesium sulfate, filtered and concentrated to give 5-morpholin-4-ylnicotinaldehyde (70 mg, 90%) as a crude product. 1H NMR (400 MHz, CDCl3): δ□ 10.1 (s, 1H), 8.0 (s, 2H), 7.6 (s, 1H), 3.8 (m, 4H), 3.2 (m, 4H).
Reaction SMILES: Cl.Cl.[CH2:3]([O:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]2[CH:22]=[C:21]([O:23][CH2:24][CH:25]3[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]3)[N:20]=[N:19][C:18]=2[CH2:31][CH2:32][CH2:33][CH3:34])=[CH:13][CH:12]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.C=O.[C:37](O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl>[CH2:3]([O:10][C:11]1[CH:12]=[CH:13][C:14]([C:17]2[CH:22]=[C:21]([O:23][CH2:24][CH:25]3[CH2:30][CH2:29][N:28]([CH3:37])[CH2:27][CH2:26]3)[N:20]=[N:19][C:18]=2[CH2:31][CH2:32][CH2:33][CH3:34])=[CH:15][CH:16]=1)[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: CCCCc1nnc(OCC2CCNCC2)cc1-c1ccc(OCc2ccccc2)cc1
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: C=O
Agent: Cl
Agent: [Na+]
Solvent: ClCCl
Product: CCCCc1nnc(OCC2CCN(C)CC2)cc1-c1ccc(OCc2ccccc2)cc1
Reaction time: 0.33 h

Procedure:
A suspension of 4-(4-benzyloxy-phenyl)-3-butyl-6-(piperidin-4-ylmethoxy)-pyridazine dihydro chloride (0.37 mmol, 190 mg) and paraformaldehyde (6.7 mmol, 611 mg) in DCM was stirred for 20 min then sodium triacetoxyborohydride (6.7 mmol, 1.41 g) was added. Stirring was continued overnight. Solvent was evaporated, and to the residue was added saturated NaHCO3. The mixture was extracted with ethyl acetate. The organic layer was washed with water, brine, dried (Na2SO4), filtered and concentrated under reduced pressure. The resultant product was purified by column chromatography using 5% methanolic solution of ammonia (2.0 M ammonia in methanol) in DCM to provide 4-(4-benzyloxy-phenyl)-3-butyl-6-(1-methyl-piperidin-4-ylmethoxy)-pyridazine.
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[C:3]1[C:11]([C:12]#[N:13])=[CH:10][CH:9]=[C:8]2[C:4]=1[CH:5]=[CH:6][NH:7]2.Br[CH:17]([CH2:22][CH3:23])[C:18]([O:20][CH3:21])=[O:19]>>[C:12]([C:11]1[C:3]([C:2]([F:14])([F:1])[F:15])=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH:17]([CH2:22][CH3:23])[C:18]([O:20][CH3:21])=[O:19])[CH:6]=[CH:5]2)#[N:13]
Reactant: CCC(Br)C(=O)OC
Reactant: N#Cc1ccc2[nH]ccc2c1C(F)(F)F
Product: CCC(C(=O)OC)n1ccc2c(C(F)(F)F)c(C#N)ccc21

Procedure:
Synthesized in a manner similar to Example 1 using 4-(trifluoromethyl)-1H-indole-5-carbonitrile and methyl 2-bromobutanoate: MS (ESI): m/z 311 (MH+).
Reaction SMILES: [Cl:1][C:2]1[C:15]2[O:14][C:13]3[C:8](=[C:9]([F:16])[CH:10]=[CH:11][CH:12]=3)[C:7](=[O:17])[C:6]=2[CH:5]=[CH:4][C:3]=1[OH:18].C(=O)([O-])[O-].Br[CH2:24][C:25]([O:27][CH2:28][CH3:29])=[O:26].CN(C)C=O>O>[Cl:1][C:2]1[C:15]2[O:14][C:13]3[C:8](=[C:9]([F:16])[CH:10]=[CH:11][CH:12]=3)[C:7](=[O:17])[C:6]=2[CH:5]=[CH:4][C:3]=1[O:18][CH2:24][C:25]([O:27][CH2:28][CH3:29])=[O:26]
Reactant: O=c1c2ccc(O)c(Cl)c2oc2cccc(F)c12
Reactant: CCOC(=O)CBr
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)COc1ccc2c(=O)c3c(F)cccc3oc2c1Cl

Procedure:
A mixture of 2.6 g of 4-chloro-8-fluoro-3-hydroxy-9-oxo-9H-xanthene, 2.8 g of postassium carbonate, 3.3. g of ethyl bromoacetate and 40 ml of N,N-dimethylformamide (DMF) was stirred at 60°-70° C. for 4 hours. After cooling the mixture, water was added thereto and the resulting crystal was recovered by filtration, washed with water and dried. Recrystallization from ethanol gave 3.4 g of ethyl 4-chloro-8-fluoro-9-oxo-9H-xanthene-3-yloxyacetate. A mixture of this ester (3.3 g), sodium hydroxide (1.9 g) and water (100 ml) was refluxed for 30 minutes. After cooling, the mixture was rendered acidic with concentrated hydrochloric acid and the resulting crystal was recovered by filtration and dried. Recrystallization from DMF gave 2.5 g of 4-chloro-8-fluoro-9-oxo-9H-xanthene-3-yloxyacetic acid. m.p. 300° C.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([C:19]2[S:23][C:22]([CH:24]=O)=[N:21][CH:20]=2)[CH:5]=[C:6]([NH:8][C:9]2[N:14]=[C:13]([C:15]([F:18])([F:17])[F:16])[CH:12]=[CH:11][N:10]=2)[CH:7]=1.[NH2:26][CH2:27][CH:28]1[NH:32][C:31](=[O:33])[CH2:30][CH2:29]1.CN(C=O)C.C([BH3-])#N.[Na+]>C(O)(=O)C>[CH3:1][C:2]1[CH:3]=[C:4]([C:19]2[S:23][C:22]([CH2:24][NH:26][CH2:27][CH:28]3[NH:32][C:31](=[O:33])[CH2:30][CH2:29]3)=[N:21][CH:20]=2)[CH:5]=[C:6]([NH:8][C:9]2[N:14]=[C:13]([C:15]([F:17])([F:16])[F:18])[CH:12]=[CH:11][N:10]=2)[CH:7]=1
Reactant: NCC1CCC(=O)N1
Reactant: Cc1cc(Nc2nccc(C(F)(F)F)n2)cc(-c2cnc(C=O)s2)c1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CN(C)C=O
Product: Cc1cc(Nc2nccc(C(F)(F)F)n2)cc(-c2cnc(CNCC3CCC(=O)N3)s2)c1
Reaction time: 8 h
Yield: 24.7 %

Procedure:
To a flask was added 4 Å molecular sieves (200 mgs) and the product from Step 1 (0.050 g, 0.14 mmol), 5-(aminomethyl)pyrrolidin-2-one (0.016 g, 0.21 mmol) and a 95:5 solution of DMF: acetic acid (1.4 mL). The mixture was stirred overnight. Resin-bound sodium cyanoborohydride (0.44 g, 0.41 mmol, 0.93 mmol/g loading) was added and the reaction was stirred for 72 hours. The mixture was filtered and purified by reverse phase HPLC (12-100% acetonitrile gradient with water over 6 minutes with 0.1% formic acid buffer) to yield 5-[({[5-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)-1,3-thiazol-2-yl]methyl}amino)-methyl]pyrrolidin-2-one (0.016 g, 25%). MS ESI: [M+H]+ m/z 463.1. 1H NMR (600 MHz, DMSO-d6) δ 10.22 (s, 1H), 8.81 (d, J=5.2, 1H), 7.96 (s, 2H), 7.61 (s, 1H), 7.42 (s, 1H), 7.26 (d, J=5.1, 1H), 7.14 (s, 1H), 4.03 (s, 2H), 3.63 (s, 1H), 2.74-2.53 (m, 1H), 2.47 (m, 1H), 2.29 (s, 3H), 2.20-1.98 (m, 3H), 1.80-1.59 (m, 1H). rhSYK activity=+++
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][CH:11]([OH:14])[CH:10]([CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:9]1)C1C=CC=CC=1>CO.[H][H].[OH-].[Pd+2].[OH-]>[OH:14][CH:11]1[CH2:12][CH2:13][NH:8][CH2:9][CH:10]1[CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: [H][H]
Reactant: OC1CCN(Cc2ccccc2)CC1Cc1ccccc1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Product: OC1CCNCC1Cc1ccccc1

Procedure:
A mixture of 1,3-dibenzyl-4-hydroxypiperidine (1.7 g, 6.0 mmole) and 20% palladium hydroxide (0.3 g) in methanol (20 ml) was stirred in hydrogen atmosphere (1 atm.) for 12 hr at 35° C. Catalyst was filtered off, washed with methanol, filtrate was concentrated to dryness to give 4-hydroxy-3-benzylpiperidine as oil. Yield 1.0 g (91%), C12H17NO, m/z 192 (M+1) PMR (CDCl3): 1.66 (1H, m, H3), 1.94 (1H, m, H5), 2.26 (2H, m, H5, & OH, D2O exchangeable), 2.62 (1H, m, H2), 2.74 (1H, m, H6), 3.02 (1H, m, H2), 3.34 (1H, m, H6), 3.52 (1H, bs, NH, D2O exchangeable), 3.9 (1H, m, H4), 4.74 (2H, m, CH2-Ar), 7.28 (5H, m, ArH).
Reaction SMILES: [O:1]=[C:2]1[C:11]2[CH:10]=[CH:9][CH:8]=[C:7]([C:12]([OH:14])=O)[C:6]=2[CH:5]=[CH:4][NH:3]1.[C:15]12([CH2:25][NH2:26])[CH2:24][CH:19]3[CH2:20][CH:21]([CH2:23][CH:17]([CH2:18]3)[CH2:16]1)[CH2:22]2.Cl.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1.C(N(CC)CC)C.CN(C)C=O>>[C:15]12([CH2:25][NH:26][C:12]([C:7]3[C:6]4[CH:5]=[CH:4][NH:3][C:2](=[O:1])[C:11]=4[CH:10]=[CH:9][CH:8]=3)=[O:14])[CH2:22][CH:21]3[CH2:20][CH:19]([CH2:18][CH:17]([CH2:23]3)[CH2:16]1)[CH2:24]2
Reactant: NCC12CC3CC(CC(C3)C1)C2
Reactant: O=C(O)c1cccc2c(=O)[nH]ccc12
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=C(NCC12CC3CC(CC(C3)C1)C2)c1cccc2c(=O)[nH]ccc12
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A mixture of 1,2-dihydro-1-oxoisoquinoline-5-carboxylic acid (0.107 g, 0.000566 mol), 1-adamantanemethylamine (0.120 mL, 0.000679 mol), N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (0.141 g, 0.000735 mol), 1-hydroxybenzotriazole (0.099 g, 0.00074 mol) and triethylamine (0.12 mL, 0.00085 mol) in N,N-dimethylformamide (2 mL, 0.02 mol) was stirred at room temperature for 18 hours. The mixture was poured onto water (100 ml) and extracted with ethyl acetate (3×100 ml). The combined extracts were dried over sodium sulfate and reduced in vacuo to afford the title compound.
Reaction SMILES: Br[CH2:2][CH2:3][NH:4][C:5]([N:7]1[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=2[NH:11][C:10](=[O:18])[C:9]2=[CH:19][S:20][C:21]([CH3:22])=[C:8]12)=[O:6].[N:23]1([CH2:29][CH2:30][CH2:31][CH2:32][CH:33]2[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]2)[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1>>[N:23]1([CH2:29][CH2:30][CH2:31][CH2:32][CH:33]2[CH2:38][CH2:37][N:36]([CH2:2][CH2:3][NH:4][C:5]([N:7]3[C:13]4[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=4[NH:11][C:10](=[O:18])[C:9]4=[CH:19][S:20][C:21]([CH3:22])=[C:8]34)=[O:6])[CH2:35][CH2:34]2)[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28]1
Reactant: Cc1scc2c1N(C(=O)NCCBr)c1ccccc1NC2=O
Reactant: C1CCN(CCCCC2CCNCC2)CC1
Product: Cc1scc2c1N(C(=O)NCCN1CCC(CCCCN3CCCCC3)CC1)c1ccccc1NC2=O
Yield: 20 %

Procedure:
Prepared analogously to Example 109 from 4-[[[2-bromo-ethyl]amino]carbonyl]-4,9-dihydro-3-methyl-10H-thieno[3,4-b][1,5]benzodiazepin-10-one and 4-[4-(piperidin-l-yl)butyl]piperidine in a yield of 20% of theory. Colourless crystals, m.p. 186°-187° C.
Reaction SMILES: [C:1]1(/[CH:7]=[CH:8]/[C:9]2[O:10][CH:11]=[C:12]([CH2:14][O:15][C:16]3[CH:17]=[C:18]([CH2:22][CH2:23][CH2:24]O)[CH:19]=[CH:20][CH:21]=3)[N:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH:26]1[CH:30]=[N:29][CH:28]=[N:27]1>>[C:1]1(/[CH:7]=[CH:8]/[C:9]2[O:10][CH:11]=[C:12]([CH2:14][O:15][C:16]3[CH:17]=[C:18]([CH2:22][CH2:23][CH2:24][N:26]4[CH:30]=[N:29][CH:28]=[N:27]4)[CH:19]=[CH:20][CH:21]=3)[N:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: c1nc[nH]n1
Reactant: OCCCc1cccc(OCc2coc(/C=C/c3ccccc3)n2)c1
Product: C(=C/c1nc(COc2cccc(CCCn3cncn3)c2)co1)\c1ccccc1
Yield: 61 %

Procedure:
In substantially the same manner as in Working Example 1, 3-[3-[2-[(E)-2-phenylethenyl]-4-oxazolylmethoxy]phenyl]propanol was allowed to react with 1,2,4-triazole to give 1-[3-[3-[2-[(E)-2-phenylethenyl]-4-oxazolylmethoxy]phenyl]propyl]-1,2,4-triazole. The yield was 61%. Recrystallization from ethyl acetate-hexane gave colorless prisms, mp 59-60° C.