Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[O:11][CH2:10][CH2:9][N:8]3[CH:12]=[C:13]([C:15]4[N:19]([CH:20]([CH3:22])[CH3:21])[N:18]=[CH:17][N:16]=4)[N:14]=[C:7]3[C:6]=2[CH:23]=1.[C:24]1(B(O)O)[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.C([O-])([O-])=O.[Cs+].[Cs+].O>O1CCOCC1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH:20]([N:19]1[C:15]([C:13]2[N:14]=[C:7]3[C:6]4[CH:23]=[C:2]([C:24]5[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=5)[CH:3]=[CH:4][C:5]=4[O:11][CH2:10][CH2:9][N:8]3[CH:12]=2)=[N:16][CH:17]=[N:18]1)([CH3:22])[CH3:21]
Reactant: CC(C)n1ncnc1-c1cn2c(n1)-c1cc(Br)ccc1OCC2
Reactant: OB(O)c1ccccc1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Solvent: O
Product: CC(C)n1ncnc1-c1cn2c(n1)-c1cc(-c3ccccc3)ccc1OCC2
Temperature: 130 °C
Reaction time: 0.5 h
Yield: 10.7 %

Procedure:
A mixture of 10-bromo-2-(1-isopropyl-1H-1,2,4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine (0.5 mmol), phenylboronic acid (200 mg, 0.75 mmol), Cs2CO3 (490 mg, 1.5 mmol) was stirred in dioxane and water (5:1, 3.0 mL) followed by the addition of Pd(dppf)Cl2 (30 mg). The reaction mixture was bubbled with N2 gas for 10 min, the reaction tube was sealed, and the contents were stirred at 130° C. under microwave irradiation for 30 min. The mixture was filtered through celite and the filtrate was concentrated and purified with prep-HPLC to give 555 (19.8 mg, 12%). 1H-NMR (DMSO, 400 MHz): δ 8.70 (s, 1H), 7.93 (d, J=14.4 Hz, 2H), 7.61-7.66 (m, 3H), 7.46-7.50 (m, 2H), 7.34-7.38 (m, 1H), 7.14 (d, J=8.4 Hz, 2H), 5.75-5.79 (m, 1H), 4.54-4.56 (m, 4H), 1.50 (d, J=7.6 Hz, 6H)
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][NH2:11])=[CH:6][CH:5]=1)([O-:3])=[O:2].[CH2:12]([S:14](Cl)(=[O:16])=[O:15])[CH3:13]>N1C=CC=CC=1>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([CH2:10][NH:11][S:14]([CH2:12][CH3:13])(=[O:16])=[O:15])=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: CCS(=O)(=O)Cl
Reactant: NCc1ccc([N+](=O)[O-])cc1
Solvent: c1ccncc1
Product: CCS(=O)(=O)NCc1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 67.6 %

Procedure:
(4-Nitrophenyl)methanamine (715 mg, 4.7 mmol) was dissolved in pyridine (4 mL). The reaction mixture was added ethane sulfonyl chloride (0.58 mL, 6.11 mmol) and stirred for 1 h at room temperature. TLC showed complete consumption of starting material. The mixture was diluted with 1N HCl and extracted with ethyl acetate. The extract was dried over magnesium sulfate and concentrated under reduced pressure. The crude was purified by column chromatography to give N-(4-nitrobenzyl)ethanesulfonamide (776 mg, 68%).
Reaction SMILES: [C:1]1([CH:7]=[CH:8][CH:9]([OH:18])[CH2:10][C:11](=[O:17])[CH2:12][C:13]([O:15][CH3:16])=[O:14])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([BH3-])#N.[Na+].O.Cl>CO.CC(C)[O-].CC(C)[O-].CC(C)[O-].[Cl-].[Ti+4]>[C:1]1([CH:7]=[CH:8][CH:9]([OH:18])[CH2:10][CH:11]([OH:17])[CH2:12][C:13]([O:15][CH3:16])=[O:14])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: COC(=O)CC(=O)CC(O)C=Cc1ccccc1
Agent: [Ti+4]
Agent: CC(C)[O-]
Agent: Cl
Solvent: O
Solvent: CO
Product: COC(=O)CC(O)CC(O)C=Cc1ccccc1
Temperature: -10 °C
Reaction time: 0.33 h
Yield: 65.2 %

Procedure:
700 mg of methyl 7-phenyl-5-hydroxy-3-oxo-6-heptenoate (2.82 mmol) are dissolved in 25 cm3 of methanol and then cooled to -10° C. 0.71 cm3 of titanium chloride triisopropoxide (2.82 mmol) is added. The mixture is stirred for 20 minutes at -10° C. 207.8 mg of sodium cyanoborohydride (3.1 mmol) are then added and the mixture is then stirred for 3 hours 45 minutes at a temperature between -5° and 0° C. 5 cm3 of water and 1 cm3 of concentrated hydrochloric acid are added. After evaporation of the methanol under reduced pressure, the mixture is taken up in 50 cm3 of dichloromethane. The organic phase is washed with 25 cm3 of a saturated sodium bicarbonate solution and then with 25 cm3 of water and is then dried over sodium sulphate. After filtration and concentration to dryness, the residue obtained is treated with methanol. There is thus obtained, with a yield of 55%, 460 mg of methyl 7-phenyl-3,5-dihydroxy-6-heptenoate for which the syn/anti ratio is equal to 80/20.
Reaction SMILES: [CH2:1]([O:3][C:4]([C@@H:6]1[CH2:10][CH:9]([OH:11])[CH2:8][C@H:7]1[C:12](=[O:19])[NH:13][C:14]1([C:17]#[N:18])[CH2:16][CH2:15]1)=[O:5])[CH3:2].[S:20]([O-])(=[O:23])(=[O:22])[CH3:21]>>[CH2:1]([O:3][C:4]([C@@H:6]1[CH2:10][CH:9]([O:11][S:20]([CH3:21])(=[O:23])=[O:22])[CH2:8][C@H:7]1[C:12](=[O:19])[NH:13][C:14]1([C:17]#[N:18])[CH2:16][CH2:15]1)=[O:5])[CH3:2]
Reactant: CS(=O)(=O)[O-]
Reactant: CCOC(=O)[C@@H]1CC(O)C[C@H]1C(=O)NC1(C#N)CC1
Product: CCOC(=O)[C@@H]1CC(OS(C)(=O)=O)C[C@H]1C(=O)NC1(C#N)CC1

Procedure:
The mixture of (1R,2R,4R) and (1R,2R,4S)-2-(1-cyano-cyclopropylcarbamoyl)-4-hydroxy-cyclopentanecarboxylic acid ethyl ester from step 2 was converted to the corresponding mesylate according to the procedure from example 1, step 4 to give (1R,2R)-2-(1-cyano-cyclopropylcarbamoyl)-4-methanesulfonyloxy-cyclopentanecarboxylic acid ethyl ester as a 2:1 mixture of epimers as a colorless solid. MS: 345.0 (M+H)+.
Reaction SMILES: Br[C:2]1[S:3][CH:4]=[CH:5][N:6]=1.C([Sn](CCCC)(CCCC)[C:12]1[N:16]2[CH:17]=[CH:18][C:19]([C:21]([F:24])([F:23])[F:22])=[N:20][C:15]2=[N:14][CH:13]=1)CCC>>[S:3]1[CH:4]=[CH:5][N:6]=[C:2]1[C:12]1[N:16]2[CH:17]=[CH:18][C:19]([C:21]([F:22])([F:23])[F:24])=[N:20][C:15]2=[N:14][CH:13]=1
Reactant: Brc1nccs1
Reactant: CCCC[Sn](CCCC)(CCCC)c1cnc2nc(C(F)(F)F)ccn12
Product: FC(F)(F)c1ccn2c(-c3nccs3)cnc2n1
Yield: 33.3 %

Procedure:
2-Bromothiazole (341 μl, 3.78 mmol) was coupled to 3-tributylstannyl-7-trifluoromethylimidazo[1,2-α]pyrimidine (1.8 mmol) by the method of Example 1 to give 3-(thiazol-2-yl)-7-trifluoromethyl-imidazo[1,2-α]pyrimidine (162 mg) as an off-white solid: δH (400 MHz, CDCl3) 7.40 (2H, dd, J 4 and 3), 7.93 (1H, d, J 3), 8.48 (1H, s), 10.22 (1H, d, J 8); m/z (ES+) 271 (M++H).
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[OH:11])[CH:4]=[CH:3]1.Cl[CH2:13][C:14]([N:16]([CH3:18])[CH3:17])=[O:15].C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>CC(C)=O>[CH3:17][N:16]([CH3:18])[C:14](=[O:15])[CH2:13][O:11][C:9]1[CH:8]=[CH:7][CH:6]=[C:5]2[C:10]=1[N:2]([CH3:1])[CH:3]=[CH:4]2
Reactant: CN(C)C(=O)CCl
Reactant: Cn1ccc2cccc(O)c21
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC(C)=O
Product: CN(C)C(=O)COc1cccc2ccn(C)c12
Yield: 83.2 %

Procedure:
To a solution of 1-methyl-1-H-indol-7-ol (Chemstep, CAS: 47577-33-4, 2.2 g, 15 mmol) and 2-chloro-N,N-dimethylacetamide (Fluka, CAS: 2675-89-0, 2.0 g, 17 mmol) in acetone (25 mL) were added potassium carbonate (2.5 g, 18 mmol) and potassium iodide, (0.25 g, 1.5 mmol). The reaction mixture was stirred at reflux for 4 h, quenched with ice/water, and extracted with ethyl acetate. The organics were washed, dried and concentrated. The residue was chromatographed on silica gel using heptane/ethyl acetate as eluent to obtain the desired compound (2.9 g) as a creamy solid. MS (ISP): m/e 233.1 (M+H)+
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:12])[C@H:5]([CH2:7][CH2:8][S:9][CH2:10][CH3:11])[NH2:6])[CH3:2].[C:13]([S:16][CH2:17][CH:18]([CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:19](O)=[O:20])(=[O:15])[CH3:14]>CO>[CH2:1]([O:3][C:4](=[O:12])[C@H:5]([CH2:7][CH2:8][S:9][CH2:10][CH3:11])[NH:6][C:19](=[O:20])[CH:18]([CH2:22][C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1)[CH2:17][S:16][C:13](=[O:15])[CH3:14])[CH3:2]
Reactant: CC(=O)SCC(Cc1ccccc1)C(=O)O
Reactant: CCOC(=O)[C@@H](N)CCSCC
Solvent: CO
Product: CCOC(=O)[C@H](CCSCC)NC(=O)C(CSC(C)=O)Cc1ccccc1

Procedure:
React L-ethionine ethyl ester (3.51 g) and 3-acetylthio-2-benzylpropionic acid (4.37 g) in a manner similar to that described in Example 1, Step 1 to give a yellow residue. Chromatograph the yellow residue on the Waters Prep 500 (2 silica gel cartridges) and elute with ethyl acetate:hexane 2:18 (16 L), then ethyl acetate:hexane 3:17. Repeat chromatography of the fractions using ethyl acetate:hexane as eluant to give Isomer A, a white solid (0.89 g), m.p. 84°-90°, [α]D26 =-60.6° (MeOH) and Isomer B (0.82 g), m.p. 79°-84°, [α]D26 =-0.3° (MeOH).
Reaction SMILES: [ClH:1].Cl.[F:3][C:4]1[CH:5]=[C:6]([CH:22]([C:31]2([OH:37])[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]2)[CH2:23][N:24]2[CH2:29][CH2:28][N:27](C)[CH2:26][CH2:25]2)[CH:7]=[CH:8][C:9]=1[O:10][CH2:11][C:12]1[CH:17]=[CH:16][C:15]([C:18](F)(F)F)=[CH:14][CH:13]=1.FC1C=C(C(C2(O)CCCCC2)C(N2CCN(C(OC(C)(C)C)=O)CC2)=O)C=CC=1OCC1C=CC(C)=CC=1>>[ClH:1].[ClH:1].[F:3][C:4]1[CH:5]=[C:6]([CH:22]([C:31]2([OH:37])[CH2:32][CH2:33][CH2:34][CH2:35][CH2:36]2)[CH2:23][N:24]2[CH2:25][CH2:26][NH:27][CH2:28][CH2:29]2)[CH:7]=[CH:8][C:9]=1[O:10][CH2:11][C:12]1[CH:13]=[CH:14][C:15]([CH3:18])=[CH:16][CH:17]=1
Reactant: CN1CCN(CC(c2ccc(OCc3ccc(C(F)(F)F)cc3)c(F)c2)C2(O)CCCCC2)CC1
Agent: Cc1ccc(COc2ccc(C(C(=O)N3CCN(C(=O)OC(C)(C)C)CC3)C3(O)CCCCC3)cc2F)cc1
Agent: Cl
Product: Cc1ccc(COc2ccc(C(CN3CCNCC3)C3(O)CCCCC3)cc2F)cc1

Procedure:
In an analogous manner to Example 1, step 2 1-[1-(3-fluoro-4-{[4-(trifluoromethyl)benzyl]oxy}phenyl)-2-(4-methylpiperazin-1-yl)ethyl]cyclohexanol dihydrochloride was prepared from tert-butyl 4-[(3-fluoro-4-{[4-(methyl)benzyl]oxy}phenyl)(1-hydroxycyclohexyl)acetyl]piperazine-1-carboxylate. MS (ESI) m/z 427; HRMS: calcd for C26H35FN2O2+H+, 427.27553; found (ESI, [M+H]+), 427.2776.
Reaction SMILES: C([S@@]([NH:7][C@H:8]([C:19]1[CH:24]=[C:23]([F:25])[CH:22]=[C:21]([F:26])[CH:20]=1)[CH2:9][CH2:10][C:11]([CH3:18])([CH3:17])[C:12]([O:14][CH2:15][CH3:16])=[O:13])=O)(C)(C)C.Cl>CO>[NH2:7][C@H:8]([C:19]1[CH:20]=[C:21]([F:26])[CH:22]=[C:23]([F:25])[CH:24]=1)[CH2:9][CH2:10][C:11]([CH3:17])([CH3:18])[C:12]([O:14][CH2:15][CH3:16])=[O:13]
Reactant: CCOC(=O)C(C)(C)CC[C@H](N[S@@](=O)C(C)(C)C)c1cc(F)cc(F)c1
Agent: Cl
Solvent: CO
Product: CCOC(=O)C(C)(C)CC[C@H](N)c1cc(F)cc(F)c1
Reaction time: 0.5 h

Procedure:
To a solution of ethyl (5S)-5-{[(S)-tert-butylsulfinyl]amino}-5-(3,5-difluorophenyl)-2,2-dimethylpentanoate (113 mg, 0.289 mmol, prepared by direct analogy to the methyl ester version according to U.S. Patent Application Publication No. US 2007/0265225) in MeOH (6 mL), cooled to 0° C., was added excess anhydrous, gaseous HCl over 1 minute via a rapid stream of bubbles. After 30 min, a stream of nitrogen was passed over the solution to remove some HCl. The reaction was then concentrated in vacuo. The residue was diluted with DCM (20 mL) and washed with saturated sodium bicarbonate (10 mL). The bicarbonate layer was subsequently extracted twice with DCM (10 mL). The combined organics were dried over sodium sulfate, filtered and concentrated in vacuo, to yield a residue, containing about 30% methyl ester, which was used without further purification. MS: m/z=286 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[C@H:4]([CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[NH2:5].C(N(CC)CC)C.[CH3:21][O:22][C:23]1[CH:28]=[C:27]([CH3:29])[C:26]([S:30](Cl)(=[O:32])=[O:31])=[C:25]([CH3:34])[C:24]=1[CH3:35]>C(Cl)Cl.CN(C1C=CN=CC=1)C>[CH3:1][O:2][C:3](=[O:13])[CH:4]([NH:5][S:30]([C:26]1[C:27]([CH3:29])=[CH:28][C:23]([O:22][CH3:21])=[C:24]([CH3:35])[C:25]=1[CH3:34])(=[O:32])=[O:31])[CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: COC(=O)[C@@H](N)Cc1ccccc1
Reactant: COc1cc(C)c(S(=O)(=O)Cl)c(C)c1C
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)C(Cc1ccccc1)NS(=O)(=O)c1c(C)cc(OC)c(C)c1C
Temperature: 25 °C
Reaction time: 12 h

Procedure:
A solution of L-phenylalanine methyl ester (300 mg, 1.68 mmol) in anhydrous CH2Cl2 (10 mL) was cooled to 0° C. in an ice bath, then triethylamine (0.35 mL), 4-methoxy-2,3,6-trimethyl-benzenesulfonyl chloride (438 mg, 1.76 mmol) and catalytic amount of DMAP (25 mg) were added under a N2 atmosphere. The reaction mixture was stirred at room temperature for 12 h. After that period of time, the mixture was partitioned between water and CH2Cl2, the organic layer was separated, dried (Na2SO4) and concentrated. The residue was purified by silica gel column chromatography using ethyl acetate and hexane (1:2) as eluent to obtain 2-(4-Methoxy-2,3,6-trimethyl-benzenesulfonylamino)-3-phenyl-propionic acid methyl ester as a white solid, 500 mg (77%). 1H NMR (CDCl3, 400 MHz): δ7.26-7.18 (m, 3H), 7.02-6.99 (m, 2H), 6.53 (s, 1H), 5.12 (d, 1H), 4.09-4.04 (m, 1H), 3.84 (s, 3H), 3.55 (s, 3H), 3.05 (dd, 1H), 3.03 (dd, 1H), 2.64, 2.38, 2.08 (3s, 9H).
Reaction SMILES: [Cl:1][C:2]1[C:8]2[CH:9]=[CH:10][C:11]([C:13](Cl)=[O:14])=[CH:12][C:7]=2[S:6][C:5]2[CH:16]=[CH:17][CH:18]=[CH:19][C:4]=2[N:3]=1.O1CCOCC1.[NH3:26]>ClCCl>[Cl:1][C:2]1[C:8]2[CH:9]=[CH:10][C:11]([C:13]([NH2:26])=[O:14])=[CH:12][C:7]=2[S:6][C:5]2[CH:16]=[CH:17][CH:18]=[CH:19][C:4]=2[N:3]=1
Reactant: N
Reactant: O=C(Cl)c1ccc2c(c1)Sc1ccccc1N=C2Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: NC(=O)c1ccc2c(c1)Sc1ccccc1N=C2Cl
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 11-chloro-dibenzo[b,f][1,4]thiazepine-3-carbonyl chloride, prepared as described in the previous step, (ca 1.5 mmol) in dichloromethane (10 mL) was treated with a 1,4-dioxane solution of ammonia (0.5 M, 9 mL) under ice bath. The resulting suspension was stirred at room temperature for 1 hour, and the reaction was quenched with water (10 mL). The resulting precipitate was filtered, washed with water and dichloromethane, and dried. The organic layer of the filtrate was washed with saturated aqueous sodium bicarbonate solution and concentrated to additional off white product, which was used in the next step without additional purification. LC-MS: m/z 289 (M+1). 1H NMR (DMSO-d6, 400 MHz): δ (ppm) 8.19 (br, 1H), 8.00-7.96 (m, 2H), 7.90 (d, 1H), 7.64 (br, 1H), 7.56 (m, 1H), 7.47 (m, 1H), 7.31 (m, 2H).
Reaction SMILES: Cl.[NH:2]1[CH2:7][CH2:6][CH:5]([N:8]2[CH:17]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[NH:10][C:9]2=[O:24])[CH2:4][CH2:3]1.[CH:25](=O)[C:26]1[O:30][CH:29]=[CH:28][CH:27]=1.C([BH3-])#N.[Na+]>CO>[O:30]1[CH:29]=[CH:28][CH:27]=[C:26]1[CH2:25][N:2]1[CH2:3][CH2:4][CH:5]([N:8]2[CH:17]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[NH:10][C:9]2=[O:24])[CH2:6][CH2:7]1
Reactant: O=Cc1ccco1
Reactant: O=C1Nc2ccccc2C(c2ccccc2)N1C1CCNCC1
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Product: O=C1Nc2ccccc2C(c2ccccc2)N1C1CCN(Cc2ccco2)CC1
Temperature: 25 °C
Reaction time: 12 h
Yield: 85 %

Procedure:
To a solution of 344 mg (1.0 mmol) of 3-(piperidin-4-yl)-4-phenyl-3,4-dihydro-2(1H)-quinazolinone HCl salt and 384 mg (4.0 mmol) of furfural in 40 mL of methanol was added 123 mg (2.0 mmol) of sodium cyano-borohydride under ice-cooling. After being stirred for 12 hours at ambient temperature, the reaction mixture was concentrated in vacuo. The residue was diluted with water, and the mixture was adjusted to pH 10 with aqueous ammonia, and then extracted with chloroform. The organic layer separated was dried on potassium carbonate and then concentrated in vacuo. The residue was purified by means of column chromatography (silica gel, 1:9 methanol:chloroform) to give 329 mg (0.85 mmol) of the title compound.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[CH2:14]([O:16][C:17](=[O:22])[C:18](Br)([F:20])[F:19])[CH3:15]>[Cu].CS(C)=O>[CH2:14]([O:16][C:17](=[O:22])[C:18]([C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[CH:4][CH:3]=1)([F:20])[F:19])[CH3:15]
Reactant: CCOC(=O)C(F)(F)Br
Reactant: Ic1ccc(-c2ccccc2)cc1
Agent: [Cu]
Solvent: CS(C)=O
Product: CCOC(=O)C(F)(F)c1ccc(-c2ccccc2)cc1
Temperature: 55 °C
Reaction time: 24 h

Procedure:
According to the Kumadaki method (supra) and the above-described scheme, 4-iodobiphenyl (Compound 1g; 840.3 mg, 3.0 mmol), bromodifluoroacetic acid ethyl ester (609.0 mg, 3.0 mmol), copper powder (381.0 mg, 6.0 mmol) and DMSO (6.0 mL) were put into a two-neck reaction tube, and the mixture was stirred under argon atmosphere at 55° C. for 24 hours. The reaction mixture was extracted with ethyl acetate and washed with water, and an organic layer was dried with anhydrous sodium sulfate. Ethyl acetate was distilled away under reduced pressure, and by carrying out purification by silica gel column chromatography, 2-(biphenyl-4-yl)-2,2-difluoroacetic acid ethyl ester (Compound 2g) was obtained with a yield of 65%.
Reaction SMILES: Cl.Cl.Cl.[O:4]1[C:12]2[CH:11]=[CH:10][N:9]=[C:8]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([NH2:27])[CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[C:7]=2[CH2:6][CH2:5]1.C(N(CC)CC)C.[CH3:35][S:36](Cl)(=[O:38])=[O:37].[OH-].[Na+]>ClCCl>[O:4]1[C:12]2[CH:11]=[CH:10][N:9]=[C:8]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([NH:27][S:36]([CH3:35])(=[O:38])=[O:37])[CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[C:7]=2[CH2:6][CH2:5]1
Reactant: N[C@H]1CC[C@H](CCN2CCN(c3nccc4c3CCO4)CC2)CC1
Reactant: CS(=O)(=O)Cl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)N[C@H]1CC[C@H](CCN2CCN(c3nccc4c3CCO4)CC2)CC1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a stirred mixture of trans-4-{2-[4-(2,3-dihydrofuro[3,2-c]pyridin-4-yl)-piperazin-1-yl]-ethyl}-cyclohexanamine trihydrochloride (intermediate C) (110 mg, 0.25 mmol) in dichloromethane (1.6 ml) was added at room temperature triethylamine (139 mg, 192 μl, 1.38 mmol) and methanesulfonyl chloride (43.0 mg, 29.2 μl, 375 μmol). The mixture was allowed to stir at room temperature for 4 h, poured into ice/water (5 ml) and 1N sodium hydroxide solution (5 ml) and extracted with dichloromethane (2×20 ml). The combined organic layers were washed with brine (20 ml), dried (MgSO4) and evaporated. The crude material (0.1 g) was triturated with dichloromethane (1 ml) and heptane (5 mL) for 30 min. The precipitate was collected by filtration, washed with heptane and dried to yield the title compound as a white solid (90 mg, 88%), MS (ISP) m/z=409.4 [(M+H)+], mp 220° C.
Reaction SMILES: Br[C:2]1[N:6]2[CH:7]=[CH:8][C:9]([C:11]([O:15][CH3:16])([O:13][CH3:14])[CH3:12])=[N:10][C:5]2=[N:4][CH:3]=1.C([Mg]Cl)(C)C.C([Sn](Cl)(CCCC)CCCC)CCC.Cl[C:37]1[CH:42]=[CH:41][N:40]=[C:39]([C:43]2[CH:48]=[CH:47][N:46]=[CH:45][CH:44]=2)[N:38]=1>C1COCC1.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>[CH3:14][O:13][C:11]([C:9]1[CH:8]=[CH:7][N:6]2[C:2]([C:41]3[CH:42]=[CH:37][N:38]=[C:39]([C:43]4[CH:48]=[CH:47][N:46]=[CH:45][CH:44]=4)[N:40]=3)=[CH:3][N:4]=[C:5]2[N:10]=1)([O:15][CH3:16])[CH3:12]
Reactant: COC(C)(OC)c1ccn2c(Br)cnc2n1
Reactant: Clc1ccnc(-c2ccncc2)n1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CC(C)[Mg]Cl
Agent: CCCC[Sn](Cl)(CCCC)CCCC
Solvent: C1CCOC1
Product: COC(C)(OC)c1ccn2c(-c3ccnc(-c4ccncc4)n3)cnc2n1
Temperature: -45 °C
Reaction time: 0.25 h
Yield: 18.5 %

Procedure:
To a solution of 3-bromo-7-(1,1-dimethoxyethyl)imidazo[1,2-α]pyrimidine (1.0 g, 3.5 mmol) at −45° C. was added isopropylmagnesium chloride (2.6 ml of a 2M solution in THF, 5.2 mmol) dropwise. After stirring at −45° C. for 1.5 h tri-n-butylstannyl chloride (1.52 ml, 5.6 mmol) was added dropwise. The solution was stirred at −45° C. for 15 min then the cooling bath was removed and the solution stirred at room temperature for 1.5 h. After this time half of the solution was taken and degassed with N2 for 15 min. 4-Chloro-2-(pyridin-4-yl)pyrimidine (prepared according to J. Med. Chem., 1982, 25(7), 837-842) (487 mg, 2.55 mmol) and tetrakis(triphenylphosphine)palladium(0) (294 mg, 0.26 mmol) were then added and the mixture heated at reflux for 18 h. After this time the solvent was evaporated and the residue partitioned between dichloromethane (2×40 ml) and water (40 ml). The combined organic layers were washed with brine (40 ml), dried (MgSO4) and evaporated. The residue was chromatographed on silica gel, eluting with 1:1 isohexane:ethyl acetate followed by dichloromethane:MeOH (97:3), to afford 7-(1,1-dimethoxyethyl)-3-[2-(pyridin-4-yl)pyrimidin-4-yl]imidazo[1,2-α]pyrimidine (171 mg, 28%) as an off-white solid: δH (360 MHz, CDCl3) 1.76 (3H, s), 3.33 (6H, s), 7.66-7.69 (2H, m), 8.28 (2H, dd, J 4.6 and 1.5), 8.60 (1H, s), 8.80-8.90 (3H, m), 10.30 (1H, d, J 7.3); m/z (ES+) 363 (M++H).
Reaction SMILES: [Br-].[C:2]([CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)([OH:4])=[O:3].[S:31]1[CH:35]=[CH:34][CH:33]=[C:32]1[CH:36]=O>C1COCC1>[S:31]1[CH:35]=[CH:34][CH:33]=[C:32]1[CH:36]=[CH:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][C:2]([OH:4])=[O:3]
Reactant: O=Cc1cccs1
Reactant: O=C(O)CCCCCCC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Solvent: C1CCOC1
Product: O=C(O)CCCCCCC=Cc1cccs1
Yield: 58.5 %

Procedure:
This compound was synthesized from 7-carboxyheptyltriphenylphosphonium bromide (9.71 g, 20 mmol) and 2-thiophenecarboxaldehyde (2.24 g, 20 mmol) in THF (100 mL) by a Wittig reaction. Crystallization afforded the product (2.79 g, 59%) as white crystals (mp 45°-46° C.). IR: 3400-2500, 1720, 710 cm-1 ; 1H-NMR: 1.45 (m, 8H), 2.35 (m, 4H), 5.55 (m, 1H), 6.50 (d, 1H), 7.00 (m, 3H), 11.00 (bs, 1H). Anal. Calcd. for C13H18SO2 : C, 65.51, H, 7.61%; Found: C, 65.58, H, 7.63%. Z:E=75:25.
Reaction SMILES: C([O:4][C@@H:5]1[C@@H:10]([O:11]C(=O)C)[C@H:9]([O:15]C(=O)C)[C@@H:8]([CH2:19][O:20]C(=O)C)[O:7][C@H:6]1[O:24][C:25]1[C:29]([CH2:30][C:31]2[CH:36]=[CH:35][C:34]([O:37][CH2:38][CH2:39][CH2:40][NH:41][C:42](=[N:45][C:46]#[N:47])SC)=[CH:33][CH:32]=2)=[C:28]([CH:48]([CH3:50])[CH3:49])[NH:27][N:26]=1)(=O)C.[NH2:51][CH2:52][CH2:53][OH:54].C[O-].[Na+]>CO>[C:46]([N:45]=[C:42]([NH:51][CH2:52][CH2:53][OH:54])[NH:41][CH2:40][CH2:39][CH2:38][O:37][C:34]1[CH:33]=[CH:32][C:31]([CH2:30][C:29]2[C:25]([O:24][C@@H:6]3[O:7][C@H:8]([CH2:19][OH:20])[C@@H:9]([OH:15])[C@H:10]([OH:11])[C@H:5]3[OH:4])=[N:26][NH:27][C:28]=2[CH:48]([CH3:50])[CH3:49])=[CH:36][CH:35]=1)#[N:47]
Reactant: NCCO
Reactant: CSC(=NC#N)NCCCOc1ccc(Cc2c(O[C@@H]3O[C@H](COC(C)=O)[C@@H](OC(C)=O)[C@H](OC(C)=O)[C@H]3OC(C)=O)n[nH]c2C(C)C)cc1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: CC(C)c1[nH]nc(O[C@@H]2O[C@H](CO)[C@@H](O)[C@H](O)[C@H]2O)c1Cc1ccc(OCCCNC(=NC#N)NCCO)cc1
Temperature: 50 °C
Reaction time: 8 h

Procedure:
To a solution of 3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-4-[(4-{3-[N′-(cyano)-S-(methyl)isothioureido]propoxy}phenyl)methyl]-5-isopropyl-1H-pyrazole (30 mg) in methanol (1 mL) was added 2-aminoethanol (0.5 mL), and the mixture was stirred at 50° C. overnight. After cooling to room temperature, to the reaction mixture was added sodium methoxide (28% methanol solution, 0.02 mL), and the mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure, and the residue was purified by solid phase extraction on ODS (washing solvent: distilled water, eluent: methanol) to give the title compound (15 mg).