Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:23])=[C:4]([CH:20]=[CH:21][CH:22]=1)[C:5]([C@@H:7]1[CH2:12][CH2:11][CH2:10][N:9]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:8]1)=[O:6].[BH4-].[Na+]>CO>[Cl:1][C:2]1[C:3]([F:23])=[C:4]([CH:5]([OH:6])[C@@H:7]2[CH2:12][CH2:11][CH2:10][N:9]([C:13]([O:15][C:16]([CH3:17])([CH3:18])[CH3:19])=[O:14])[CH2:8]2)[CH:20]=[CH:21][CH:22]=1
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H](C(=O)c2cccc(Cl)c2F)C1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCC[C@@H](C(O)c2cccc(Cl)c2F)C1
Temperature: 25 °C
Reaction time: 3 h
Yield: 55.7 %

Procedure:
To a solution of (R)-tert-butyl 3-(3-chloro-2-fluorobenzoyl)piperidine-1-carboxylate (7.75 g, 22.7 mmol) in MeOH (160 mL) was added NaBH4 (6.9 g, 182 mmol) in portions such that the temperature remained below 40° C. After addition, the mixture was stirred at rt for 3 h. TLC showed the start material had disappeared. The solvent was removed in vacuo and the residue was partitioned between water and EtOAc. The organic layer was washed with H2O and brine, dried over Na2SO4 and evaporated to give (R)-tert-butyl 3-((3-chloro-2-fluorophenyl)(hydroxy)methyl)piperidine-1-carboxylate (4.35 g, 56%) which was used in the next step without purification. MS (E/Z): 344 (M+H+).
Reaction SMILES: Cl[C:2]1[O:3][C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1.[CH3:11][N:12]1[CH2:18][CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1>ClCCl>[CH3:11][N:12]1[CH2:18][CH2:17][CH2:16][N:15]([C:2]2[O:3][C:4]3[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=3[N:6]=2)[CH2:14][CH2:13]1
Reactant: Clc1nc2ccccc2o1
Reactant: CN1CCCNCC1
Solvent: ClCCl
Product: CN1CCCN(c2nc3ccccc3o2)CC1

Procedure:
A 1.54 g portion of 2-chlorobenzoxazole was dissolved in 5 ml of dichloromethane. Under cooling with ice, to this was added dropwise 2.28 g of N-methylhomopiperazine which had been dissolved in 10 ml of dichloromethane, followed by 1 hour of reaction. The reaction solution was concentrated under a reduced pressure, and the resulting residue was dissolved in 500 ml of dichloromethane, washed with water, dehydrated with sodium sulfate and then concentrated under a reduced pressure. Thereafter, the resulting residue was purified by a silica gel column chromatography (chloroform:methanol=10:1) to obtain 1.87 g of the title compound.
Reaction SMILES: [C:1]([C:4]1[S:25][C:7]2[CH2:8][CH2:9][CH2:10][CH:11]3[CH2:16][C:15](=[O:17])[N:14]([C:18]4[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=4)[N:13]=[C:12]3[C:6]=2[CH:5]=1)(=[O:3])[CH3:2].CS(C)=O.S([O-])(O)=O.[Na+]>Br.C(O)(=O)C>[C:1]([C:4]1[S:25][C:7]2[CH2:8][CH2:9][CH2:10][C:11]3[C:12](=[N:13][N:14]([C:18]4[CH:19]=[CH:20][C:21]([Cl:24])=[CH:22][CH:23]=4)[C:15](=[O:17])[CH:16]=3)[C:6]=2[CH:5]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)c1cc2c(s1)CCCC1CC(=O)N(c3ccc(Cl)cc3)N=C21
Agent: Br
Agent: O=S([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CS(C)=O
Product: CC(=O)c1cc2c(s1)CCCc1cc(=O)n(-c3ccc(Cl)cc3)nc1-2
Yield: 33.5 %

Procedure:
To a solution of 1.2 g of 9-acetyl-2-(4-chlorophenyl)-2,4,4a,5,6,7-hexahydro-3H-thieno-[2',3':6,7]cyclohepta[1,2-c]pyridazin-3-one in 15% hydrogen bromide-acetic acid solution was added 0.23 ml of dimethylsulfoxide at room temperature with stirring. After stirring at the same temperature for 15 minutes, the mixture was poured into 0.5% sodium hydrogensulfite solution and extracted with chloroform. The extract was washed with water, dried over anhydrous magnesium sulfate and concentrated. The residue was chromatographed on a silica gel column using chloroform as an eluent. The resulting solid was recrystallized from ethanol to give 0.4 g of 9-acetyl-2-(4-chlorophenyl)-2,5,6,7-tetrahydro-3H-thieno-[2',3':6,7]cyclohepta[1,2-c]pyridazin-3-one as a white crystal, melting at 164°-166° C.
Reaction SMILES: O=[C:2]([C:13]1[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=1)[CH2:3][N:4]1[CH:8]=[CH:7][CH:6]=[C:5]1[C:9]([O:11]C)=O.[CH2:19]([NH2:22])[CH2:20][NH2:21]>O1CCOCC1>[N:15]1[CH:16]=[CH:17][CH:18]=[C:13]([C:2]23[NH:22][CH2:19][CH2:20][N:21]2[C:9](=[O:11])[C:5]2[N:4]([CH:8]=[CH:7][CH:6]=2)[CH2:3]3)[CH:14]=1
Reactant: NCCN
Reactant: COC(=O)c1cccn1CC(=O)c1cccnc1
Solvent: C1COCCO1
Product: O=C1c2cccn2CC2(c3cccnc3)NCCN12
Yield: 86.7 %

Procedure:
To a solution of methyl 1-[2-oxo-2-(pyridin-3-yl)ethyl]-1H-pyrrole-2-carboxylate (84 mg, 0.34 mmol) in 1,4-dioxane (15 mL) was added ethane-1,2-diamine (0.65 mL, 9.7 mmol). The solution was heated at reflux for 3 days. The mixture was then concentrated in vacuo to give an oily solid. The material was purified by flash chromatography (Silica gel, gradient 5-9% methanol in CH2Cl2) to yield 10a-(pyridin-3-yl)-2,3,10,10a-tetrahydro-1H,5H-imidazo[1,2-a]pyrrolo[1,2-d]pyrazin-5-one (102) as an off-white solid (75 mg, yield 86%).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][C:3]=1[NH:12]C(=O)C.O.S(=O)(=O)(O)O>C(O)C>[CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][C:3]=1[NH2:12]
Reactant: CC(=O)Nc1cc([N+](=O)[O-])c(C)cc1C
Agent: O=S(=O)(O)O
Solvent: CCO
Solvent: O
Product: Cc1cc(C)c([N+](=O)[O-])cc1N

Procedure:
A mixture of N-(2,4-dimethyl-5-nitrophenyl)acetamide, water (24 mL), concentrated sulfuric acid (12 mL), and ethanol (120 mL) was heated at reflux under an atmosphere of nitrogen for 4 hours. The ethanol was evaporated under reduced pressure and the residue partitioned between ethyl acetate (250 mL) and brine (150 mL). The brine solution was reextracted with ethyl acetate. The combined ethyl acetate extracts were then dried over magnesium sulfate. Evaporation afforded a crude product which was flash chromatographed on silica and eluted with ethyl acetate:hexane (1:4) to afford 4.63 g as a pale yellow solid.
Reaction SMILES: O=[CH:2][CH2:3][C:4]1([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[O:9][CH2:8][CH2:7][N:6]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:5]1.Cl.Cl.[C@@H:25]12[NH:32][C@@H:29]([CH2:30][CH2:31]1)[CH2:28][CH:27]([N:33]1[C:37]3[CH:38]=[CH:39][CH:40]=[CH:41][C:36]=3[N:35]=[C:34]1[CH3:42])[CH2:26]2.C(N(C(C)C)CC)(C)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl>[CH3:42][C:34]1[N:33]([CH:27]2[CH2:28][C@H:29]3[N:32]([CH2:2][CH2:3][C:4]4([C:17]5[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=5)[O:9][CH2:8][CH2:7][N:6]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:5]4)[C@H:25]([CH2:31][CH2:30]3)[CH2:26]2)[C:37]2[CH:38]=[CH:39][CH:40]=[CH:41][C:36]=2[N:35]=1
Reactant: Cc1nc2ccccc2n1C1C[C@H]2CC[C@@H](C1)N2
Reactant: CC(C)(C)OC(=O)N1CCOC(CC=O)(c2ccccc2)C1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cc1nc2ccccc2n1C1C[C@H]2CC[C@@H](C1)N2CCC1(c2ccccc2)CN(C(=O)OC(C)(C)C)CCO1
Temperature: 25 °C
Reaction time: 2 h
Yield: 84 %

Procedure:
To a solution of tert-butyl 2-(2-oxoethyl)-2-phenylmorpholine-4-carboxylate (226.1 mg, 0.74 mmol), 1-[(1R,5S)8-azabicyclo[3.2.1]oct-3-yl]-2-methyl-1H-benzimidazole dihydrochloride (272.7 mg, 0.74 mmol) and diisopropylethylamine (0.27 mL, 1.48 mmol) in 3 mL CH2Cl2 was added sodium triacetoxyborohydride (235.4 mg, 1.11 mmol) and the reaction mixture was stirred for 2 h at room temperature. After evaporation, the residue was chromatographed (5% (2M NH3/MeOH) in CHCl3) to provide tert-butyl 2-{2-[(1R,5S)-3-(2-methyl-1H-benzimidazol-1-yl)-8-azabicyclo[3.2.1]oct-8-yl]ethyl}-2-phenylmorpholine-4-carboxylate (329.9 mg, 84%) as an off-white foam: 1H NMR (400 MHz, CDCl3), δ 7.65 (m, 1H), 7.49-7.40 (br., 2H), 7.39-7.34 (m, 2H), 7.31 (m, 1H), 7.27 (m, 1H), 7.19-7.11 (m, 2H), 4.75-4.16 (m, 2H), 3.76-3.47 (m, 3H), 3.40-3.13 (m, 4H), 2.58 (s, 3H), 2.46-2.32 (m, 2H), 2.17-1.82 (m 8H), 1.63 (m, 2H), 1.53-1.40 (br., 9H); ESI-MS 531 (M+H), 553 (M+Na).
Reaction SMILES: [CH:1]1([N:7]2[CH:15]=[N:14][C:13]3[C:8]2=[N:9][C:10]([O:17][CH2:18][CH3:19])=[N:11][C:12]=3[NH2:16])[CH2:6][CH2:5][CH2:4][CH:3]=[CH:2]1>C(O)C.[Pd]>[CH2:18]([O:17][C:10]1[N:9]=[C:8]2[C:13]([N:14]=[CH:15][N:7]2[CH:1]2[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]2)=[C:12]([NH2:16])[N:11]=1)[CH3:19]
Reactant: CCOc1nc(N)c2ncn(C3C=CCCC3)c2n1
Agent: [Pd]
Solvent: CCO
Product: CCOc1nc(N)c2ncn(C3CCCCC3)c2n1
Yield: 40 %

Procedure:
A mixture of 9-(2-cyclohexenyl)-2-ethoxy-9H-adenine (0.5 mmole) and 10% palladium-on-charcoal (35 mg.) in ethanol (6 ml.) was hydrogenated at room temperature and under atmospheric pressure. The reaction mixture was filtered and the filtrate was evaporated. The residue was lyophilized to give the title product in 40% yield; m.p. 134°-136° C. IR(KBr): 3280, 2995, 1705, 1615, 1525, 1415, 1310, 1010 cm-1. UV: λmaxEtOH 253 nm(ε 6800), 269 nm(ε , 10200). NMR(CDCl3): 1.44(3H, t, J=7 Hz), 2.00(10H, m), 4.45(2H, q, J=7 Hz), 4.50(1H, m), 8.07(1H, s), 8.60(2H, s).
Reaction SMILES: [S:1]([C:5]1[CH:13]=[CH:12][C:8]([C:9]([OH:11])=[O:10])=[CH:7][CH:6]=1)(=[O:4])(=[O:3])[NH2:2].C(=O)(O)[O-].[Na+].[CH2:19](I)[CH:20]=[CH2:21]>CN(C=O)C>[CH2:21]([O:10][C:9](=[O:11])[C:8]1[CH:7]=[CH:6][C:5]([S:1](=[O:3])(=[O:4])[NH2:2])=[CH:13][CH:12]=1)[CH:20]=[CH2:19]
Reactant: NS(=O)(=O)c1ccc(C(=O)O)cc1
Reactant: C=CCI
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Product: C=CCOC(=O)c1ccc(S(N)(=O)=O)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a suspension of 4-Sulfamoyl-benzoic acid (2.0 g, 9.94 mmol) and sodium bicarbonate (0.84 g, 9.94 mmol) in DMF (20 mL) was added allyl iodide (0.91 mL, 9.94 mmol) and stirred at room temperature overnight under argon. The reaction was quenched with water, extracted with EtOAc and dried over Na2SO4. After removing the solvent under reduced pressure, the crude product was used in the next reaction without further purification. 1H NMR (400 MHz, CDCl3) δ8.20 (d, 2H), 8.00 (d, 2H), 6.06 (m, 1H), 5.40 dd, 2H), 5.02 (s, 2H), 4.96 (d, 2H). MH+ 243.
Reaction SMILES: CS[C:3]1[N:4]=[N:5][C:6]([C:20]#[N:21])=[C:7]([N:9]2[CH2:15][CH2:14][C:13]3[CH:16]=[CH:17][CH:18]=[CH:19][C:12]=3[CH2:11][CH2:10]2)[N:8]=1.[CH2:22]([CH2:24][NH2:25])[OH:23]>O1CCOCC1>[OH:23][CH2:22][CH2:24][NH:25][C:3]1[N:4]=[N:5][C:6]([C:20]#[N:21])=[C:7]([N:9]2[CH2:15][CH2:14][C:13]3[CH:16]=[CH:17][CH:18]=[CH:19][C:12]=3[CH2:11][CH2:10]2)[N:8]=1
Reactant: CSc1nnc(C#N)c(N2CCc3ccccc3CC2)n1
Reactant: NCCO
Solvent: C1COCCO1
Product: N#Cc1nnc(NCCO)nc1N1CCc2ccccc2CC1

Procedure:
In analogy to the procedure as described in example 4 the 3-methylsulfanyl-5-(1,2,4,5-tetrahydro-benzo[d]azepin-3-yl)-[1,2,4]triazine-6-carbonitrile was reacted with ethanolamine in dioxane at 140° C. overnight to give 3-(2-hydroxy-ethylamino)-5 -(1,2,4,5-tetrahydro-benzo[d]azepin-3-yl)-[1,2,4]triazine-6-carbonitrile as a light yellow solid; MS: 311 (M+H)+.
Reaction SMILES: C(O[C:6]1[C:7](=[O:18])[C:8](=[O:17])[C:9]=1[NH:10][CH:11]([CH3:16])[C:12]([CH3:15])([CH3:14])[CH3:13])CCC.[Cl:19][C:20]1[CH:27]=[C:26]([C:28]#[N:29])[CH:25]=[CH:24][C:21]=1[CH2:22][NH2:23]>O1CCCC1>[Cl:19][C:20]1[CH:27]=[C:26]([CH:25]=[CH:24][C:21]=1[CH2:22][NH:23][C:6]1[C:7](=[O:18])[C:8](=[O:17])[C:9]=1[NH:10][CH:11]([CH3:16])[C:12]([CH3:13])([CH3:14])[CH3:15])[C:28]#[N:29]
Reactant: N#Cc1ccc(CN)c(Cl)c1
Reactant: CCCCOc1c(NC(C)C(C)(C)C)c(=O)c1=O
Solvent: C1CCOC1
Product: CC(Nc1c(NCc2ccc(C#N)cc2Cl)c(=O)c1=O)C(C)(C)C
Reaction time: 62 h
Yield: 44.6 %

Procedure:
A solution of 3-butoxy-4-(1,2,2-trimethyl-propylamino)cyclobut-3-ene-1,2-dione (1.27 g, 5.0 mmol, Example 5), 2-chloro-4-cyanobenzylamine (0.833 g, 5.0 mmol, Example 2, Step 3) and tetrahydrofuran (8 mL) was stirred at room temperature for 23 hours, refluxed for 4 hours and allowed to stand at room temperature for approximately 62 hours. The mixture was freed of solvent and the residue was triturated with diethyl ether and dried. The resulting white solid (1.096 g) was recrystallized three times from methanol to yield 771 mg (45%) of the title compound as a faintly pink solid: mp 250.0°-251.5° C. (softens 248.0° C.); 1H NMR (DMSO-d6) δ8.10 (d, 1H), 7.88 (m, 1H), 7.70 (br m, 1H), 7.61 (d, 1H), 7.37 (br m, 1H), 4.88 (m, 1H), 3.91 (br m, 1H), 1.11 (d, 3H), 0.86 (s, 9H) ppm IR (KBr): 3200, 2230, 1790, 1635 cm-1 ; MS (m/z) 345/347 (M+). HPLC indicates a major component (98.7%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@H:8]([NH:10][CH2:11][CH:12]2[CH2:16][N:15]([C:17]3[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=3)[C:14](=O)[CH2:13]2)[CH3:9])[CH:5]=[CH:6][CH:7]=1.B.C1COCC1>C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]([C@H:8]([NH:10][CH2:11][CH:12]2[CH2:13][CH2:14][N:15]([C:17]3[CH:18]=[CH:19][C:20]([F:23])=[CH:21][CH:22]=3)[CH2:16]2)[CH3:9])[CH:5]=[CH:6][CH:7]=1
Reactant: C[C@@H](NCC1CC(=O)N(c2ccc(F)cc2)C1)c1cccc(Cl)c1
Agent: B
Solvent: C1CCOC1
Product: C[C@@H](NCC1CCN(c2ccc(F)cc2)C1)c1cccc(Cl)c1
Temperature: 0 °C

Procedure:
A 100 mL round-bottomed flask was charged with 4-({[(1R)-1-(3-chlorophenyl)ethyl]amino}methyl)-1-(4-fluorophenyl)pyrrolidin-2-one 56 (0.400 g, 1.0 mmol) as a 1:1 mixture of diastereomers and 10 mL of THF. To this solution was added BH3.THF (1 M in THF, 5.2 mL, 5.2 mmol). The mixture was heated to reflux for 3 h then cooled to 0° C. The reaction was quenched with saturated aqueous NaHCO3 and extracted with CH2Cl2. The extracts were dried and concentrated to give an oil, which was purified by column chromatography on silica gel (2% to 7% MeOH in DCM) to give (1R)-1-(3-chlorophenyl)-N-{[1-(4-fluorophenyl)pyrrolidin-3-yl]methyl}ethanamine 58 as a 1:1 mixture of diastereomers. Mass spectrum, calculated for C19H22ClFN2 332.1; found 333.2 (M++1).
Reaction SMILES: [C:1]([C:3]1[C:7]2[CH2:8][CH2:9][C:10](=O)[CH2:11][C:6]=2[S:5][C:4]=1[NH:13][C:14](=[O:20])[CH:15]([CH2:18][CH3:19])[CH2:16][CH3:17])#[N:2].[Cl:21][C:22]1[CH:27]=[C:26]([Cl:28])[CH:25]=[CH:24][C:23]=1[CH2:29][NH2:30].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(=O)C>ClCCl>[C:1]([C:3]1[C:7]2[CH2:8][CH2:9][CH:10]([NH:30][CH2:29][C:23]3[CH:24]=[CH:25][C:26]([Cl:28])=[CH:27][C:22]=3[Cl:21])[CH2:11][C:6]=2[S:5][C:4]=1[NH:13][C:14](=[O:20])[CH:15]([CH2:18][CH3:19])[CH2:16][CH3:17])#[N:2]
Reactant: CCC(CC)C(=O)Nc1sc2c(c1C#N)CCC(=O)C2
Reactant: NCc1ccc(Cl)cc1Cl
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Product: CCC(CC)C(=O)Nc1sc2c(c1C#N)CCC(NCc1ccc(Cl)cc1Cl)C2
Reaction time: 16 h

Procedure:
To a solution of the intermediate isolated in Step C in 100 mL of dichloromethane was added 1.41 mL (12.0 mL) of 1-(2,4-dichlorophenyl)methanamine, followed by 2.54 g (12.0 mmol) of sodium triacetoxyborohydride, and 0.960 mL (16.0 mmol) of acetic acid. After 16 h at ambient temperature, the reaction was quenched with an equal volume of saturated aqueous NaHCO3. The mixture was extracted twice with dichloromethane, and the combined organic layers were dried (Na2SO4), and concentrated in vacuo, affording a yellow solid. Purification by flash chromatography (15% EtOAc in hexane) afforded the title compound as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([C:8](O)([CH3:12])[C:9]([OH:11])=[O:10])[CH:5]=[CH:4][C:3]=1[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>O>[F:1][C:2]1[CH:7]=[C:6]([C:8](=[CH2:12])[C:9]([OH:11])=[O:10])[CH:5]=[CH:4][C:3]=1[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: CC(O)(C(=O)O)c1ccc(-c2ccccc2)c(F)c1
Solvent: O
Product: C=C(C(=O)O)c1ccc(-c2ccccc2)c(F)c1
Temperature: 100 °C
Yield: 91 %

Procedure:
The product of Example 1 (2 g.) was mixed with polyphosphoric acid (10 g.) and heated at 100° C. for 30 minutes. Water was added and the mixture stirred and extracted with ether. The extract was dried, filtered and evaporated to give crude 2-(2-fluoro-4-biphenylyl)acrylic acid in a yield of 91%, m.p. 169°-172° C. This was recrystallised from a mixture of ether and light petroleum (b.p. 40°-60° C.) to give pure material, m.p. 176°-177° C.
Reaction SMILES: [C:1]([C:7]1[CH:8]=[C:9]([CH:12]=[CH:13][CH:14]=1)[CH2:10][OH:11])(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3].[OH-].[K+].[O-:17][Mn](=O)(=O)=O.[K+]>O1CCOCC1.O>[C:1]([C:7]1[CH:8]=[C:9]([CH:12]=[CH:13][CH:14]=1)[C:10]([OH:17])=[O:11])(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3]
Reactant: CC(C)(C)C(=O)c1cccc(CO)c1
Reactant: O=[Mn](=O)(=O)[O-]
Agent: [K+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: CC(C)(C)C(=O)c1cccc(C(=O)O)c1
Temperature: 25 °C
Yield: 93.2 %

Procedure:
3-Pivaloylbenzyl alcohol (0.80 g, 4.16 mmol) was dissolved in dioxane (20 ml). A solution of KOH (0.35 g, 6.30 mmol) in water (5 ml) was added followed by KMnO4 (145 g, 9.17 mmol). The mixture was stirred at room temperature over the weekend. The solution was filtered through Celite and extracted with ether. The aqueous phase was acidified with dil. HCl and extracted with ether (3×50 ml). The organic layer was dried over magnesium sulphate and concentrated in vacuo to afford the title compound as a white solid (0.80 g).
Reaction SMILES: [H-].[Na+].[NH2:3][C@H:4]([C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([F:13])[CH:8]=1)[CH2:5][OH:6].Cl[CH2:15][C:16](OCC)=[O:17]>C1COCC1>[F:13][C:9]1[CH:8]=[C:7]([C@H:4]2[NH:3][C:16](=[O:17])[CH2:15][O:6][CH2:5]2)[CH:12]=[CH:11][CH:10]=1
Reactant: N[C@@H](CO)c1cccc(F)c1
Reactant: CCOC(=O)CCl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: O=C1COC[C@@H](c2cccc(F)c2)N1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 33.6 %

Procedure:
To a stirring mixture of NaH (900 mg, 37.5 mmol) in THF (25 mL) at room temperature under N2 atmosphere was added dropwise a solution of (R)-2-amino-2-(3-fluoro-phenyl)-ethanol (4.0 g, 26.4 mmol) in THF (25 mL). The reaction mixture was stirred at room temperature for 30 minutes, then cooled to 0° C. A solution of ethyl chloroacetate (3.31 g g, 27 mmol) in THF (10 mL) was added dropwise, and the reaction mixture was stirred for 25 minutes at 0° C., then stirred at room temperature for two hours. The reaction mixture was concentrated under reduced pressure, and the residue was partitioned between ethyl acetate and a 1:1 mixture of brine and water. The organic layer was separated, dried (Na2SO4), filtered and concentrated under reduced pressure. The residue was recrystallized from diethyl ether to give 1.73 g (34%) of (R)-5-(3-fluoro-phenyl)-morpholin-3-one, MP=119-121° C.
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.[CH2:9]([O:16][C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:18]=1[C:31]([F:34])([F:33])[F:32])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.O>CN(C)C=O>[CH2:24]([O:23][C:19]1[CH:20]=[CH:21][C:22]([Br:1])=[C:17]([O:16][CH2:9][C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:18]=1[C:31]([F:33])([F:32])[F:34])[C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: FC(F)(F)c1c(OCc2ccccc2)cccc1OCc1ccccc1
Solvent: CN(C)C=O
Solvent: O
Product: FC(F)(F)c1c(OCc2ccccc2)ccc(Br)c1OCc1ccccc1
Yield: 97.8 %

Procedure:
Add N-bromosuccinimide (4.67 g, 26.23 mmol) to a solution of 1,3-bis-benzyloxy-2-trifluoromethyl-benzene (9.40 g, 26.2 mmol) in dimethylformamide (100 mL) and stir. After 18 hours add water and extract with diethyl ether. Combine organic layers, dry with sodium sulfate, filter and concentrate under reduced pressure to yield the title compound as an orange oil (11.20 g, 98%): 1H NMR (CD3CN) δ 4.97 (2, 2H), 5.18 (s, 2H), 6.99 (d, 1H), 7.33-7.55 (m, 10H), 7.79 (d, 1H).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[C:9]([C:11]1[CH:12]=[N:13][N:14]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:15]=1)=[O:10].Br[CH2:23][C:24]([O:26]CC)=[O:25]>>[CH3:8][C:5]1[CH:6]=[CH:7][C:2]([O:1][CH2:23][C:24]([OH:26])=[O:25])=[C:3]([C:9]([C:11]2[CH:12]=[N:13][N:14]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH:15]=2)=[O:10])[CH:4]=1
Reactant: CCOC(=O)CBr
Reactant: Cc1ccc(O)c(C(=O)c2cnn(-c3ccccc3)c2)c1
Product: Cc1ccc(OCC(=O)O)c(C(=O)c2cnn(-c3ccccc3)c2)c1

Procedure:
Prepared from (2-hydroxy-5-methylphenyl)-(1-phenyl-1H-pyrazol-4-yl)-methanone and ethyl bromoacetate according to GP2 and GP3: LC/MS (an 10p8): Rt 3.08 min, m/z 356.6 [M+1]+; 1H NMR (CDCl3): δ2.37 (s, 3H), 4.78 (s, 2H), 6.97 (d, J=9.0 Hz, 1H), 7.33-7.51 (m, 5H), 7.73 (d, J=6 Hz, 2H), 8.16 (s, 1H), 8.51 (s, 1H), 11.21 (br s, 1H)
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[Br:6][C:7]1[N:8]([C:17]2[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[C:20]([CH:27]3[CH2:29][CH2:28]3)=[CH:19][CH:18]=2)[C:9]([S:12][CH2:13][C:14]([OH:16])=[O:15])=[N:10][N:11]=1.[OH:30][CH:31]1[O:37][C@H:36]([C@@H:38]([CH2:40][OH:41])[OH:39])[C@H:34](O)[C@H:32]1[OH:33]>N1C=CC=CC=1>[Br:6][C:7]1[N:8]([C:17]2[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[C:20]([CH:27]3[CH2:29][CH2:28]3)=[CH:19][CH:18]=2)[C:9]([S:12][CH2:13][C:14]([O:16][CH:34]2[CH:32]([OH:33])[CH:31]([OH:30])[O:37][CH:36]2[CH:38]([OH:39])[CH2:40][OH:41])=[O:15])=[N:10][N:11]=1
Reactant: OC[C@@H](O)[C@H]1OC(O)[C@H](O)[C@H]1O
Reactant: O=C(O)CSc1nnc(Br)n1-c1ccc(C2CC2)c2ccccc12
Solvent: c1ccncc1
Solvent: O=P(Cl)(Cl)Cl
Product: O=C(CSc1nnc(Br)n1-c1ccc(C2CC2)c2ccccc12)OC1C(O)C(O)OC1C(O)CO
Temperature: 0 °C
Reaction time: 1 h

Procedure:
Phosphorus oxychloride (2.4 mmol) is added dropwise over 5 mins to a solution of 2-(5-bromo-4-(1-cyclopropylnaphthalen-4-yl)-4H-1,2,4-triazol-3-ylthio)acetic acid (810 mg, 2.0 mmol) in pyridine (20 mL) at 0° C. The mixture is stirred at 0° C. for a further 1 hour and then a solution of 1,2:5,6-Di-O-isopropilydene-□-D-glucofuranose (320 mg, 2.0 mmol) in pyridine (5 mL) is added dropwise over 5 mins. The mixture is stirred at 0° C. for a further 1 hour and 1 hour at 20° C. and then is quenched by addition of water (1 mL). Volatile solvents are removed in vacuo and DCM (200 mL) added. The organic phase is washed with water (1×50 mL), saturated sodium carbonate solution (1×50 mL) and brine (1×50 mL), dried over Na2SO4 and concentrated to dryness. Ethanol and water are added to produce a solid which is collected by filtration. Additional product is recovered by extraction of the filtrate with DCM. Combined product is concentrated, dried and purified by column chromatography (acetone/DCM eluent). The combined solids are dissolved in acetic acid (25 mL) and water (5 mL) mixture, heated at 60° C. for 3 hours. Volatile solvents are removed in vacuo. Ethanol and water are added to produce a solid which is collected by filtration.
Reaction SMILES: Br[CH2:2][C:3]1[N:7]2[C:8]3[C:13]([NH:14][C:15](=[O:16])[C:6]2=[N:5][C:4]=1[C:21]([O:23][CH2:24][CH3:25])=[O:22])=[CH:12][C:11]([C:17]([F:20])([F:19])[F:18])=[CH:10][CH:9]=3.[Cl:26][C:27]1[N:28]=[CH:29][NH:30][C:31]=1[Cl:32].C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[Cl:26][C:27]1[N:28]=[CH:29][N:30]([CH2:2][C:3]2[N:7]3[C:8]4[C:13]([NH:14][C:15](=[O:16])[C:6]3=[N:5][C:4]=2[C:21]([O:23][CH2:24][CH3:25])=[O:22])=[CH:12][C:11]([C:17]([F:20])([F:19])[F:18])=[CH:10][CH:9]=4)[C:31]=1[Cl:32]
Reactant: CCOC(=O)c1nc2c(=O)[nH]c3cc(C(F)(F)F)ccc3n2c1CBr
Reactant: Clc1nc[nH]c1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCOC(=O)c1nc2c(=O)[nH]c3cc(C(F)(F)F)ccc3n2c1Cn1cnc(Cl)c1Cl
Temperature: 80 °C
Reaction time: 8 h
Yield: 22.8 %

Procedure:
A suspension of 1-bromomethyl-2-ethoxycarbonyl-7-trifluoromethylimidazo[1,2-a]quinoxalin-4(5H)-one (Example 3) (2.1 g, 5.0 mmol), 4,5-dichloroimidazole (1.5 g, 11.0 mmol) and potassium carbonate (1.5 g, 11 mmol) in acetonitril (100 ml) was stirred at 80° C. for 5 h and overnight at room temperature. The solvent was evaporated in vacuo and the residue submitted to flash chromatography on silica gel 60 eluting with dichloromethane/methanole (19:1) to give 540 mg (23%) of the title compound. M.p. 240° C.
Reaction SMILES: [C:1]([Br:5])(Br)(Br)Br.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[N+:25]([C:28]1[CH:29]=[C:30]([CH:34]=[CH:35][CH:36]=1)[CH2:31]CO)([O-:27])=[O:26]>C(Cl)Cl>[Br:5][CH2:1][CH2:31][C:30]1[CH:29]=[C:28]([N+:25]([O-:27])=[O:26])[CH:36]=[CH:35][CH:34]=1
Reactant: BrC(Br)(Br)Br
Reactant: O=[N+]([O-])c1cccc(CCO)c1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: O=[N+]([O-])c1cccc(CCBr)c1
Reaction time: 0.5 h
Yield: 114.8 %

Procedure:
Carbon tetrabromide (2.48 g) and triphenylphosphine (2.35 g) were added to a mixture of 3-nitrophenethyl alcohol (1.0 g) and methylene chloride (20 ml) under cooling with ice and stirred for 30 min under cooling with ice. The reaction mixture was distilled under reduced pressure and the resulting residue was purified by silica gel column chromatography (eluent, n-hexane:ethyl acetate=4:1) to give 1.58 g of the titled compound quantitatively.