Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [BH4-].[Na+].[I:3][C:4]1[C:5]([CH3:12])=[N:6][N:7]([CH3:11])[C:8]=1[CH:9]=[O:10].[Cl-].[NH4+]>CO>[I:3][C:4]1[C:5]([CH3:12])=[N:6][N:7]([CH3:11])[C:8]=1[CH2:9][OH:10]
Reactant: Cc1nn(C)c(C=O)c1I
Agent: [BH4-]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CO
Product: Cc1nn(C)c(CO)c1I
Reaction time: 3 h
Yield: 37.2 %

Procedure:
Sodium borohydride (45 mg) was added to a methanol (10 mL) solution of 4-iodo-1,3-dimethyl-1H-pyrazol-5-carbaldehyde (200 mg) at a room temperature, and the obtained solution was then stirred for 3 hour. Thereafter, a saturated ammonium chloride aqueous solution was added to the reaction solution, and the obtained mixture was then extracted with ethyl acetate. The organic layer was washed with water, and was then dried over anhydrous sodium sulfate, followed by vacuum concentration, so as to obtain the title compound (75 mg) in the form of a light yellow solid.
Reaction SMILES: O[C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[N:5]2[N:12]=[CH:13][C:14]([C:15]([O:17][CH3:18])=[O:16])=[C:4]2[N:3]=1.P(Cl)(Cl)([Cl:21])=O>CN(C)C1C=CN=CC=1>[Cl:21][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[N:5]2[N:12]=[CH:13][C:14]([C:15]([O:17][CH3:18])=[O:16])=[C:4]2[N:3]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: COC(=O)c1cnn2c(C(F)(F)F)cc(O)nc12
Agent: CN(C)c1ccncc1
Product: COC(=O)c1cnn2c(C(F)(F)F)cc(Cl)nc12

Procedure:
A mixture of 2.70 g of methyl 5-hydroxy-7-(trifluoromethyl)pyrazolo[1,5-a]pyrimidine-3-carboxylate and 1.26 g of 4-dimethylaminopyridine was heated to 100° for 2.5 hours in 50 ml of phosphorus oxychloride. The resulting solution was concentrated in a vacuum and then partitioned between ethyl acetate and saturated sodium chloride solution. The organic phase was washed in succession with 1N hydrochloric acid and saturated sodium chloride solution, dried over sodium sulphate, freed from solvent in a vacuum and the residue was crystallized from ethyl acetate/petroleum ether. There was obtained methyl 5-chloro-7-(tri-fluoromethyl)pyrazolo[1,5-a]pyrimidine-3-carboxylate as white crystals of m.p. 126°-127°.
Reaction SMILES: Cl.[S:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[CH:4]=[C:3]1[C:11]1[CH2:12][CH2:13][NH:14][CH2:15][CH:16]=1.Cl[CH2:18][C:19]1[NH:20][C:21]2[CH:27]=[CH:26][CH:25]=[CH:24][C:22]=2[N:23]=1.N>>[S:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[CH:4]=[C:3]1[C:11]1[CH2:12][CH2:13][N:14]([CH2:18][C:19]2[NH:20][C:21]3[CH:27]=[CH:26][CH:25]=[CH:24][C:22]=3[N:23]=2)[CH2:15][CH:16]=1
Reactant: C1=C(c2cc3ccccc3s2)CCNC1
Reactant: ClCc1nc2ccccc2[nH]1
Agent: Cl
Agent: N
Product: C1=C(c2cc3ccccc3s2)CCN(Cc2nc3ccccc3[nH]2)C1

Procedure:
The title compound was prepared in a analogous manner to Example 1 using 4-(benzothiophen-2-yl)-1,2,3,6-tetrahydropyridine hydrochloride and 2-chloromethylbenzimidazole, m.p. 241° C. (dec.); (Found: C, 72.44; H, 5.41; N, 11.83. C12H19N3S.0.1H2O requires C, 72.63; H, 5.57; N, 2.10%); δH (DMSO-d6) 2.62 (2H, br s, tetrahydropyridinyl CH2), 2.77 (2H, m, tetrahydropyridinyl CH2), 3.24 (2H, d, J 2.8 Hz, tetrahydropyridinyl CH2), 3.87 (2H, s, NCH2Ar), 6.23 (1H, br s, CH=CR), 7.10-7.42 (1H, m, ArH), 7.45 (1H, d, J 8 Hz, ArH), 7.74 (1H, d, J 8 Hz, ArH), 7.76 (1H, dd, J 8, 2 Hz, ArH), 7.86 (1H, dd, J 8, 2 Hz, ArH), and 12.32 (1H, br s, NH); m/z (CI+, NH3) 346 (M+1)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:10]=[C:11]([NH2:15])[S:12][C:13]=2[CH3:14])=[CH:5][CH:4]=1.[N:16]1([C:21](N2C=CN=C2)=[S:22])[CH:20]=[CH:19][N:18]=[CH:17]1>C(#N)C>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:9]2[N:10]=[C:11]([NH:15][C:21]([N:16]3[CH:20]=[CH:19][N:18]=[CH:17]3)=[S:22])[S:12][C:13]=2[CH3:14])=[CH:7][CH:8]=1
Reactant: S=C(n1ccnc1)n1ccnc1
Reactant: COc1ccc(-c2nc(N)sc2C)cc1
Solvent: CC#N
Product: COc1ccc(-c2nc(NC(=S)n3ccnc3)sc2C)cc1
Temperature: 50 °C
Reaction time: 3 h
Yield: 87 %

Procedure:
To 4-(4-methoxyphenyl)-5-methylthiazol-2-amine (0.98 g, 4.45 mmol) in acetonitrile (25 mL) was added di(1H-imidazol-1-yl)methanethione (1.03 g, 5.78 mmol). The reaction was stirred at 50° C. for 3 hours. The reaction was cooled to room temperature and the precipitate was filtered. The powder was washed with acetonitrile (2×10 mL) and dried to yield racemic N-(4-(4-methoxyphenyl)-5-methylthiazol-2-yl)-1H-imidazole-1-carbothioamide (1.28 g, 3.87 mmol, 87% yield) as a yellow powder. The product was taken directly to the next step.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:13]([C:14]([O:16]CC)=[O:15])=[C:12]([Br:19])[N:11]([CH:20]([CH3:22])[CH3:21])[N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+].Cl>O1CCOCC1>[CH2:1]([O:8][C:9]1[C:13]([C:14]([OH:16])=[O:15])=[C:12]([Br:19])[N:11]([CH:20]([CH3:22])[CH3:21])[N:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)c1c(OCc2ccccc2)nn(C(C)C)c1Br
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: CC(C)n1nc(OCc2ccccc2)c(C(=O)O)c1Br
Temperature: 100 °C
Reaction time: 8 h
Yield: 64.7 %

Procedure:
Ethyl 3-benzyloxy-5-bromo-1-isopropylpyrazole-4-carboxylate (7.7 g) was suspended in 1,4-dioxane (19 mL) and 20% sodium hydroxide aqueous solution (19 mL) was added to the suspension. The mixture was stirred at 100° C. for 8 hours. After the reaction mixture was cooled, the reaction mixture was poured into 2 mol/L hydrochloric acid (100 mL) and the mixture was extracted with ethyl acetate. The organic layer was washed with brine and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure to give 4.6 g of the title compound.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([OH:9])=[CH:5][CH:4]=1)#[N:2].C([O-])([O-])=O.[K+].[K+].[I:16][C:17]1[CH:24]=[CH:23][C:20]([CH2:21]Br)=[CH:19][CH:18]=1>CC(C)=O.O>[I:16][C:17]1[CH:24]=[CH:23][C:20]([CH2:21][O:9][C:6]2[CH:7]=[CH:8][C:3]([C:1]#[N:2])=[CH:4][CH:5]=2)=[CH:19][CH:18]=1
Reactant: BrCc1ccc(I)cc1
Reactant: N#Cc1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: O
Product: N#Cc1ccc(OCc2ccc(I)cc2)cc1
Temperature: 70 °C
Reaction time: 6 h
Yield: 24.9 %

Procedure:
To a stirred solution of 4-cyano phenol (1 g, 8.4 mmol) in acetone (15 ml) was added K2CO3 (3.48 g, 25.0 mmol), followed by 4-iodobenzyl bromide (2.7 g, 9.2 mmol) at 20-35° C. and the reaction mixture was stirred at 70° C. for 6 h. The progress of the reaction was monitored by TLC. After 6 h of stirring, the mixture was cooled to 20-35° C., diluted with water (50 ml) and extracted with ethyl acetate (2×50 ml). The combined organic layers were washed with brine (50 ml), followed by drying over anhydrous Na2SO4 and filtering. The filtrate was rotary evaporated to get residue which was purified by column chromatography using a mixture of 5% ethyl acetate/hexane as an eluent to get the desired compound as a white solid (700 mg, 35%). 1H NMR (400 MHz, DMSO-d6) δ 7.80-7.75 (m, 4H), 7.26 (d, J=8.3 Hz, 2H), 7.19-7.15 (m, 2H), 5.18 (s, 2H).
Reaction SMILES: [Cl:1][C:2]1[C:3]([Cl:13])=[CH:4][C:5]2[O:10][CH2:9][CH2:8][C:7](=O)[C:6]=2[CH:12]=1.CO.C(=O)([O-])[O-].[K+].[K+].Cl.[NH2:23][OH:24]>O>[Cl:1][C:2]1[C:3]([Cl:13])=[CH:4][C:5]2[O:10][CH2:9][CH2:8][C:7](=[N:23][OH:24])[C:6]=2[CH:12]=1
Reactant: NO
Reactant: O=C1CCOc2cc(Cl)c(Cl)cc21
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CO
Product: ON=C1CCOc2cc(Cl)c(Cl)cc21
Temperature: 0 °C

Procedure:
A mixture of 6,7-dichloro-2,3-dihydro-4H-1-benzopyran-4-one (59.7 g), methanol (750 ml), water (75 ml), potassium carbonate (76 g), hydroxylamine HCl (76.4 g) was heated at reflux for 4 hours, then poured into ice-water: the oxime of 6,7-dichloro-2,3-dihydro-4H-1-benzopyran-4-one was filtered off, washed with water, with a small volume of ether, then dried in air. Yield: 62.7 g; m.p. 192°-193°.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:12](=[O:13])[CH2:11][CH2:10][CH:9]1[CH2:14][O:15][Si:16]([C:19]([CH3:22])([CH3:21])[CH3:20])([CH3:18])[CH3:17])=[O:7])([CH3:4])([CH3:3])[CH3:2].C[Si]([N-][Si](C)(C)C)(C)C.[Li+].C1([Se][Br:40])C=CC=CC=1.BrC(Cl)(Cl)C(Cl)(Cl)Br>O1CCCC1>[C:1]([O:5][C:6]([N:8]1[C@@H:9]([CH2:14][O:15][Si:16]([C:19]([CH3:22])([CH3:21])[CH3:20])([CH3:17])[CH3:18])[CH:10]=[C:11]([Br:40])[C:12]1=[O:13])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1C(=O)CCC1CO[Si](C)(C)C(C)(C)C
Reactant: Br[Se]c1ccccc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: ClC(Cl)(Br)C(Cl)(Cl)Br
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1C(=O)C(Br)=C[C@@H]1CO[Si](C)(C)C(C)(C)C
Reaction time: 2 h
Yield: 59.1 %

Procedure:
A solution of 2-(tert-butyldimethylsilanyloxymethyl)-5-oxopyrrolidine-l-carboxylic acid tert-butyl ester (16.5 grams, 50 mmol) in tetrahydrofuran (800 mL) was cooled in bath at -78° C. A 1M solution of lithium bis(trimethylsilyl)amide in tetrahydrofuran (100 mL, 100 mmol) was added slowly. After stirring for 2 hours, a solution of phenylselenylbromide (14.16 grams, 60 mmol) in tetrahydrofuran (100 mL) was added and, after 15 minutes, a solution of 1,2-dibromotetrachloroethane (19.5 grams, 60 mmol) in tetrahydrofuran (100 mL) was added. The reaction mixture was stirred for an additional 1.5 hours while cooling at -78° and was quenched by addition of saturated ammonium chloride solution. Water and diethyl ether were added. The aqueous phase was separated and extracted with diethyl ether. The combined organic layers were concentrated to an orange oil which was dissolved in methylene chloride (1000 mL). A 30% w/v aqueous solution of hydrogen peroxide (20 mL) was added and the mixture was stirred vigorously overnight. Water (50 mL) was added. The aqueous layer was separated and extracted with methylene chloride. The combined organic layers were dried over magnesium sulfate and concentrated to an orange oil. The title compound (12.0 grams, 59%) was isolated by flash chromatography on silica gel eluting first with a 1:1 mixture of hexane and methylene chloride and then with methylene chloride alone.
Reaction SMILES: C[O:2][C:3]([C:5]1[S:6][C:7]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[CH:8][C:9]=1[N:10]([CH:20]([CH3:22])[CH3:21])[C:11]([CH:13]1[CH2:18][CH2:17][C:16](=[CH2:19])[CH2:15][CH2:14]1)=[O:12])=[O:4].[Li+].[OH-]>C1COCC1.CO.O>[CH:20]([N:10]([C:11]([CH:13]1[CH2:14][CH2:15][C:16](=[CH2:19])[CH2:17][CH2:18]1)=[O:12])[C:9]1[CH:8]=[C:7]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[S:6][C:5]=1[C:3]([OH:4])=[O:2])([CH3:22])[CH3:21]
Reactant: C=C1CCC(C(=O)N(c2cc(-c3ccccc3)sc2C(=O)OC)C(C)C)CC1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: C=C1CCC(C(=O)N(c2cc(-c3ccccc3)sc2C(=O)O)C(C)C)CC1
Temperature: 25 °C
Reaction time: 12 h
Yield: 51.7 %

Procedure:
3-[Isopropyl-(4-methylene-cyclohexanecarbonyl)-amino]-5-phenyl-thiophene-2-carboxylic acid methyl ester (50 mg, 0.126 mmol) was taken in a mixture of THF:MeOH:H2O (3:2:1, 3 mL) and then 1N aqueous solution of LiOH.H20 (0.8 mL, 0.800 mmol) was added. The reaction mixture was stirred at room temperature for 12 h. Solvents were removed and the residue was partitioned between water and ethyl acetate. The aqueous layer was acidified using 10% KHSO4 solution. The organic layer was separated, dried (Na2SO4) and concentrated. The residue was purified by silica gel column chromatography using chloroform and methanol (8:2) to obtain 3-[Isopropyl-(4-methylene-cyclohexanecarbonyl)-amino]-5-phenyl-thiophene-2-carboxylic acid (compound 28) (25 mg, 52%) as a white solid. 1H NMR (CDCl3, 400 MHz): δ7.61 (d, J=7 Hz, 2H), 7.40-7.38 (m, 3H), 7.04 (s, 1H), 4.92 (m, 1H), 4.50 (d, J=7.6 Hz, 2H), 2.21-1.43 (m, 9H), 1.15 (bd, 3H), 0.93 (bd, 3H).
Reaction SMILES: N1C=CC=CC=1.[CH3:7][S:8](Cl)(=[O:10])=[O:9].[F:12][C:13]1[CH:23]=[CH:22][C:16]([O:17][CH2:18][CH2:19][CH2:20][NH2:21])=[C:15]([N+:24]([O-:26])=[O:25])[CH:14]=1.Cl>O.ClCCl>[F:12][C:13]1[CH:23]=[CH:22][C:16]([O:17][CH2:18][CH2:19][CH2:20][NH:21][S:8]([CH3:7])(=[O:10])=[O:9])=[C:15]([N+:24]([O-:26])=[O:25])[CH:14]=1
Reactant: NCCCOc1ccc(F)cc1[N+](=O)[O-]
Reactant: CS(=O)(=O)Cl
Agent: Cl
Solvent: O
Solvent: c1ccncc1
Solvent: ClCCl
Product: CS(=O)(=O)NCCCOc1ccc(F)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 24 h
Yield: 44 %

Procedure:
Pyridine (1.5 ml, 18.6 mmol) and methanesulfonyl chloride (0.8 ml, 10.3 mmol) were added, while being cooled with ice, to a dichloromethane solution of 3-(4-fluoro-2-nitrophenoxy)propylamine (2.0 g, 9.33 mmol), and dichloromethane (4 ml) was further added. The resulting mixture was stirred at room temperature for 24 hours, and methanesulfonyl chloride (0.12 ml, 1.5 mmol) was further added thereto, and then the mixture was stirred at room temperature for 15 hours. 2N hydrochloric acid (9.5 ml) was added to the reaction mixture, and the mixture was stirred. Water was added to the mixture, and the resulting mixture was extracted with dichloromethane. After being washed with a saturated sodium chloride aqueous solution, the organic layer was concentrated under reduced pressure, and the residue was then purified by silica gel column chromatography (n-hexane:ethyl acetate=4:1→1:1). The purified product was concentrated under reduced pressure to thereby obtain 1.2 g of oily yellow orange N-[3-(4-fluoro-2-nitrophenoxy)propyl]methansulfonamide (yield: 44%).
Reaction SMILES: [Br:1]Br.[NH:3]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:12]3[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][CH:13]=3)[CH:10]=2)[CH:5]=[CH:4]1.O.S([O-])([O-])(=O)=S.[Na+].[Na+]>CN(C=O)C>[Br:1][C:5]1[C:6]2[C:11](=[CH:10][C:9]([C:12]3[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][CH:13]=3)=[CH:8][CH:7]=2)[NH:3][CH:4]=1
Reactant: BrBr
Reactant: Oc1ccc(-c2ccc3cc[nH]c3c2)cc1
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Oc1ccc(-c2ccc3c(Br)c[nH]c3c2)cc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 98.3 %

Procedure:
A mixture solution of bromine (25 μL, 0.48 mmol) in DMF (1 mL) was added to a mixture solution of 4-(1H-indol-6-yl)phenol (100 mg, 0.48 mmol) in DMF (1 mL) at room temperature. After stirring for 1.5 hours at room temperature, followed by addition of icy water and addition of sodium thiosulfate, the mixture was stirred for 1 hour. Thus produced solid was filtered, washed with water and dried at room temperature. The target compound (136 mg) was obtained as white solid.
Reaction SMILES: Cl[S:2]([N:5]=C=O)(=[O:4])=[O:3].[CH:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH:11]=[CH:10][C:9]=1[OH:18].C(N(CC)CC)C>C(#N)C.C(OCC)(=O)C.O>[CH:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH:11]=[CH:10][C:9]=1[O:18][S:2](=[O:3])(=[O:4])[NH2:5]
Reactant: Oc1ccc2ccccc2c1
Reactant: O=C=NS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: CC#N
Solvent: CCOC(C)=O
Product: NS(=O)(=O)Oc1ccc2ccccc2c1
Reaction time: 0.08 h
Yield: 107.5 %

Procedure:
To a cold (ice-acetone bath) solution of 11.3 ml (0.13 mole, 18.4 g) of chlorosulfonyl isocyanate in 50 ml of acetonitrile was added dropwise a solution of 2.3 g (0.13 mole) of water in 10 ml of acetonitrile at such a rate that the temperature was maintained between -2° to 7° C. (ca. 45 min). After the addition was complete, the solution was stirred for 5 min and then treated dropwise with a solution of 14.4 g (0.1 mole) of β-naphthol, 20.9 ml (0.15 mole, 15.2 g) of triethylamine and 100 ml of acetonitrile at such a rate that the temperature did not exceed 10° C. (ca. 30 min). The mixture was stirred at ambient temperature for 3.5 h and then diluted with 100 ml of ethyl acetate and 50 ml of water. The layers were separated and the organic layer was washed once with 50 ml of water and once with 100 ml of brine, dried (sodium sulfate), and concentrated to give 24 g of dark gum. The gum was purified by column chromatography on 400 g of silica gel eluted with methylene chloride. Fractions containing the desired product were combined and concentrated to yield 5.7 g (26%) of the title compound as a white solid, mp 114°-115° C. (benzene).
Reaction SMILES: [NH2:1][C@H:2]([CH2:33][CH:34]([CH3:36])[CH3:35])[CH2:3][N:4]1[C:9](=[O:10])[C:8]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([O:17][CH3:18])[C:12]=2[Cl:19])=[CH:7][N:6]([CH2:20][C:21]2[C:26]([C:27]([F:30])([F:29])[F:28])=[CH:25][CH:24]=[CH:23][C:22]=2[F:31])[C:5]1=[O:32].C([O-])([O-])=O.[K+].[K+].Br[CH2:44][CH2:45][CH2:46][C:47]([O:49][CH2:50][CH3:51])=[O:48]>CN(C=O)C>[CH2:50]([O:49][C:47]([CH2:46][CH2:45][CH2:44][NH:1][C@H:2]([CH2:33][CH:34]([CH3:36])[CH3:35])[CH2:3][N:4]1[C:9](=[O:10])[C:8]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([O:17][CH3:18])[C:12]=2[Cl:19])=[CH:7][N:6]([CH2:20][C:21]2[C:26]([C:27]([F:28])([F:30])[F:29])=[CH:25][CH:24]=[CH:23][C:22]=2[F:31])[C:5]1=[O:32])=[O:48])[CH3:51]
Reactant: CCOC(=O)CCCBr
Reactant: COc1cccc(-c2cn(Cc3c(F)cccc3C(F)(F)F)c(=O)n(C[C@H](N)CC(C)C)c2=O)c1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)CCCN[C@H](CC(C)C)Cn1c(=O)c(-c2cccc(OC)c2Cl)cn(Cc2c(F)cccc2C(F)(F)F)c1=O
Temperature: 95 °C

Procedure:
To a solution of compound 8b (25 mg, 0.048 mmol) in DMF (1 mL) was added K2CO3 (21 mg, 0.15 mmol) followed by ethyl 4-bromobutyrate (0.015 mL, 0.1 mmol). The mixture was heated at 95° C. for 16 hours, cooled to room temperature, and partitioned between ethyl acetate and H2O. The organic layer was washed with brine, dried over Na2SO4 and concentrated. The residue was purified by column chromatography on silica gel with ethyl acetate/hexanes/triethylamine 500/500/5 to afford compound 8c . MS (CI) m/z 642.2, 644.2 (MH+).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:13])[C@@H:5]1[CH2:9][CH:8]([OH:10])[CH2:7][N:6]1[CH2:11][CH3:12])[CH3:2].C(N(CC)CC)C.[S:21](Cl)([CH3:24])(=[O:23])=[O:22]>C(Cl)(Cl)Cl>[CH2:1]([O:3][C:4](=[O:13])[C@@H:5]1[CH2:9][CH:8]([O:10][S:21]([CH3:24])(=[O:23])=[O:22])[CH2:7][N:6]1[CH2:11][CH3:12])[CH3:2]
Reactant: CCOC(=O)[C@@H]1CC(O)CN1CC
Reactant: CS(=O)(=O)Cl
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CCOC(=O)[C@@H]1CC(OS(C)(=O)=O)CN1CC
Temperature: 25 °C
Reaction time: 2 h
Yield: 102.7 %

Procedure:
To a mixture of 2.50 g of N-ethyl-4-hydroxy-L-proline ethylester, 1.76 g of triethylamine and 10 ml of chloroform were dropwise added 1.84 g of mesyl chloride while cooling with ice-water and the combined was stirred at room temperature for 2 hours and then poured into ice-water. The mixture was extracted with chloroform and the extract was washed with an aqueous sodium bicarbonate solution and then with water, dried over magnesium sulfate and concentrated under reduced pressure to obtain 3.64 g of N-ethyl-4-mesyloxy-L-proline ethylester.
Reaction SMILES: FC(F)(F)C([O-])=O.[C:8]([C:10]1[C:11]([CH3:27])=[C:12]([C@@H:17]2[O:22][CH2:21][C@@H:20]3[CH2:23][NH2+:24][CH2:25][CH2:26][N:19]3[CH2:18]2)[CH:13]=[CH:14][C:15]=1[F:16])#[N:9].CN1CCOCC1.[N:35]1([C:40]2[N:45]=[CH:44][C:43]([CH2:46][C:47](O)=[O:48])=[CH:42][CH:41]=2)[CH:39]=[N:38][N:37]=[N:36]1.C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl>C(Cl)Cl>[F:16][C:15]1[C:10]([C:8]#[N:9])=[C:11]([CH3:27])[C:12]([C@@H:17]2[O:22][CH2:21][C@@H:20]3[CH2:23][N:24]([C:47](=[O:48])[CH2:46][C:43]4[CH:44]=[N:45][C:40]([N:35]5[CH:39]=[N:38][N:37]=[N:36]5)=[CH:41][CH:42]=4)[CH2:25][CH2:26][N:19]3[CH2:18]2)=[CH:13][CH:14]=1
Reactant: O=C(O)Cc1ccc(-n2cnnn2)nc1
Reactant: Cc1c([C@H]2CN3CC[NH2+]C[C@H]3CO2)ccc(F)c1C#N
Agent: O=C([O-])C(F)(F)F
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CN1CCOCC1
Solvent: ClCCCl
Product: Cc1c([C@H]2CN3CCN(C(=O)Cc4ccc(-n5cnnn5)nc4)C[C@H]3CO2)ccc(F)c1C#N
Temperature: 25 °C
Reaction time: 4 h

Procedure:
(3S,9aS)-3-(3-Cyano-4-fluoro-2-methylphenyl)octahydropyrazino[2,1-c][1,4]oxazin-8-ium trifluoroacetate (1.44 g, 3.70 mmol) and N-methylmorpholine (1.220 mL, 11.10 mmol) was added to DCM (25 mL). Then [6-(1H-tetrazol-1-yl)pyridin-3-yl]acetic acid (0.911 g, 4.44 mmol), HOBT (0.850 g, 5.55 mmol) and EDC (1.418 g, 7.40 mmol) were added in that order. The reaction mixture was stirred at RT for 4 h. The reaction mixture was washed with brine and saturated aq. NaHCO3 solution. The DCM layer was separated and dried over Na2SO4, filtered, and evaporated to dryness. The residue was purified by preparative TLC eluting with a 5% (10% NH4OH in Methanol): 95% chloroform solvent system to yield the title compound: 1H-NMR (500 MHz, DMSO): δ ppm 10.17 (s, 1H), 8.48 (s, 1H), 8.22 (t, J=7.35 Hz, 1H), 8.01 (s, 2H), 7.37 (s, 1H), 4.93 (s, 1H), 4.21 (dd, J=13.3, 60.75 Hz, 1H), 3.89-3.99 (m, 3H), 3.57 (dd, J=11, 23.5 Hz, 1H), 3.29 (s, 1H), 3.10-3.24 (m, 2H), 2.80-3.0 (m, 2H), 2.68 (d, J=11 Hz, 1H), 2.53 (s, 3H), 2.23-2.48 (2H).
Reaction SMILES: [C:1]1([C:7]2[CH:12]=[C:11]([C:13]3[N:17]4[CH:18]=[CH:19][C:20]([C:22]5[CH2:23][CH2:24][NH:25][CH2:26][CH:27]=5)=[CH:21][C:16]4=[N:15][CH:14]=3)[CH:10]=[CH:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:28][C:29]([CH3:31])=O.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>CO.C(Cl)Cl>[CH:29]([N:25]1[CH2:24][CH:23]=[C:22]([C:20]2[CH:19]=[CH:18][N:17]3[C:13]([C:11]4[CH:10]=[CH:9][N:8]=[C:7]([C:1]5[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=5)[CH:12]=4)=[CH:14][N:15]=[C:16]3[CH:21]=2)[CH2:27][CH2:26]1)([CH3:31])[CH3:28]
Reactant: C1=C(c2ccn3c(-c4ccnc(-c5ccccc5)c4)cnc3c2)CCNC1
Reactant: CC(C)=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Solvent: CO
Product: CC(C)N1CC=C(c2ccn3c(-c4ccnc(-c5ccccc5)c4)cnc3c2)CC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 3-(2-Phenyl-pyridin-4-yl)-7-(1,2,3,6-tetrahydro-pyridin-4-yl)-imidazo[1,2-a]pyridine (Ex. 1.190) (1.0 eq, 0.2 mmol, 90 mg) in MeOH (2 ml) is added acetone (10 eq, 1.04, 0.76 ml) and acetic acid (2 eq, 0.21 mmol, 0.1 ml) and the reaction mixture is stirred at room temperature for 30 min. After this time sodium triacetoxyborohydride (5 eq, 0.52 mmol, 116 mg) is added to the reaction mixture and is stirred for a further 2 h. The reaction is diluted with CH2Cl2 and the organic phase is washed with NaHCO3. The aqueous layer is further extracted with EtOAc. The combined organic layers are washed with brine, dried over MgSO4, filtered and the solvent removed in vacuo. The reaction mixture is purified by flash column chromatography eluting with 8:2 DCM/MeOH to yield 7-(1-isopropyl-1,2,3,6-tetrahydro-pyridin-4-yl)-3-(2-phenyl-pyridin-4-yl)-imidazo[1,2-a]pyridine as a light yellow solid; [M+H]+=395
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1I.C([Mg]Br)C.[Cl:13][C:14]1[CH:21]=[CH:20][CH:19]=[CH:18][C:15]=1[CH:16]=[O:17].Cl>C1COCC1.CC(OC)(C)C>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:16]([C:15]1[CH:18]=[CH:19][CH:20]=[CH:21][C:14]=1[Cl:13])[OH:17]
Reactant: O=Cc1ccccc1Cl
Reactant: Clc1ccccc1I
Agent: CC[Mg]Br
Agent: Cl
Solvent: C1CCOC1
Solvent: COC(C)(C)C
Product: OC(c1ccccc1Cl)c1ccccc1Cl
Temperature: -12.5 °C
Reaction time: 0.5 h

Procedure:
Under N2, 1-chloro-2-iodobenzene (40 ml, 0.33 mol) was dissolved in THF (360 ml) and cooled to −10 to −15° C. Within 30 min, a 1M solution of ethyl magnesium bromide (344 ml, 0.34 mol) in TBME was added at this temperature. The mixture was stirred at −10 to −15° C. and the reaction was followed by HPLC. After the reaction was complete (15 to 30 min), a solution of 2-chloro benzaldehyde (40.7 ml, 0.36 mol) in TBME (160 ml) was added at −10 to −15° C. within 30 min and the reaction was followed by HPLC. After complete reaction (15 to 30 min), the mixture was hydrolized with dilute HCl until all solids were dissolved at a final temperature of 20 to 25° C. The organic phase was washed with water (2×40 ml) and evaporated to dryness at a temperature of 45 to 50° C. The residue was co-evaporated twice with heptane (80 ml each) and crystallized from hot n-heptane (280 ml at 95 to 100° C.). The product was isolated by filtration after stirring for 1 h at 0 to 5° C. and washed with cold n-heptane (40 ml at 0 to 5° C.). The product was dried under vacuum at 50° C. to constant weight. Yield: 73.4 g (88%). Assay (HPLC): 100% pure vs. standard.