Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([N:6]2[CH2:12][C:11]3([CH2:14][CH2:13]3)[C:10](=[O:15])[N:9]([CH3:16])[C:8]3[CH:17]=[N:18][C:19]([NH:21][C:22]4[CH:30]=[CH:29][C:25]([C:26]([OH:28])=O)=[CH:24][C:23]=4[O:31][CH3:32])=[N:20][C:7]2=3)[CH2:5][CH2:4][CH2:3][CH2:2]1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.[NH2:64][N:65]1[CH2:70][CH2:69][N:68]([CH2:71][CH2:72][OH:73])[CH2:67][CH2:66]1>C(Cl)Cl>[CH:1]1([N:6]2[CH2:12][C:11]3([CH2:14][CH2:13]3)[C:10](=[O:15])[N:9]([CH3:16])[C:8]3[CH:17]=[N:18][C:19]([NH:21][C:22]4[CH:30]=[CH:29][C:25]([C:26]([NH:64][N:65]5[CH2:70][CH2:69][N:68]([CH2:71][CH2:72][OH:73])[CH2:67][CH2:66]5)=[O:28])=[CH:24][C:23]=4[O:31][CH3:32])=[N:20][C:7]2=3)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: NN1CCN(CCO)CC1
Reactant: COc1cc(C(=O)O)ccc1Nc1ncc2c(n1)N(C1CCCC1)CC1(CC1)C(=O)N2C
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COc1cc(C(=O)NN2CCN(CCO)CC2)ccc1Nc1ncc2c(n1)N(C1CCCC1)CC1(CC1)C(=O)N2C
Temperature: 25 °C
Reaction time: 16 h
Yield: 38.6 %

Procedure:
4-(9′-Cyclopentyl-5′-methyl-6′-oxo-5′,6′,8′,9′-tetrahydrospiro[cyclopropane-1,7′-pyrimido[4,5-b][1,4]diazepine]-2′-ylamino)-3-methoxybenzoic acid (Intermediate 5) (48 mg, 0.11 mmol, 1 eq), DIPEA (36 μL, 0.22 mmol, 2 eq) and TBTU (39 mg, 0.12 mmol, 1.1 eq) were added to 5 mL DCM and the resulting solution stirred at rt for 15 min before the addition of 2-(4-aminopiperazin-1-yl)ethanol (19 mg, 0.13 mmol, 1.2 eq). The RM was then stirred at rt for 16 hours before concentrating in vacuo and purifying by preparative RP-HPLC-MS (Preparative—1) to provide 4-(9′-cyclopentyl-5′-methyl-6′-oxo-5′,6′,8′,9′-tetrahydrospiro[cyclopropane-1,7′-pyrimido[4,5-b][1,4]diazepine]-2′-ylamino)-N-(4-(2-hydroxyethyl)piperazin-1-yl)-3-methoxybenzamide (24 mg, 39%).
Reaction SMILES: [F:1][CH:2]([F:22])[O:3][C:4]1[CH:12]=[CH:11][C:10]([B:13]2[O:17][C:16]([CH3:19])([CH3:18])[C:15]([CH3:21])([CH3:20])[O:14]2)=[CH:9][C:5]=1[C:6]([NH2:8])=[O:7].Br[C:24]1C=CC(OC(F)F)=C(C=1)C(NC)=O>>[F:22][CH:2]([F:1])[O:3][C:4]1[CH:12]=[CH:11][C:10]([B:13]2[O:17][C:16]([CH3:18])([CH3:19])[C:15]([CH3:21])([CH3:20])[O:14]2)=[CH:9][C:5]=1[C:6]([NH:8][CH3:24])=[O:7]
Reactant: CC1(C)OB(c2ccc(OC(F)F)c(C(N)=O)c2)OC1(C)C
Reactant: CNC(=O)c1cc(Br)ccc1OC(F)F
Product: CNC(=O)c1cc(B2OC(C)(C)C(C)(C)O2)ccc1OC(F)F

Procedure:
2-Difluoromethoxy-N-methyl-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzamide was prepared in a similar way as 2-Difluoromethoxy-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzamide using 5-bromo-2-difluoromethoxy-N-methyl-benzamide as the starting material.
Reaction SMILES: [CH:1]1([NH:6][C:7]2[CH:8]=[CH:9][CH:10]=[C:11]3[C:15]=2[NH:14][C:13]([C:16]2[S:17][CH2:18][CH:19]([CH2:21][CH2:22][OH:23])[N:20]=2)=[CH:12]3)[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:24][O-].[Na+]>>[CH:1]1([NH:6][C:7]2[CH:8]=[CH:9][CH:10]=[C:11]3[C:15]=2[NH:14][C:13]([C:16]2[S:17][CH2:18][C@@H:19]([CH2:21][CH2:22][O:23][CH3:24])[N:20]=2)=[CH:12]3)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: OCCC1CSC(c2cc3cccc(NC4CCCC4)c3[nH]2)=N1
Reactant: C[O-]
Agent: [Na+]
Product: COCC[C@@H]1CSC(c2cc3cccc(NC4CCCC4)c3[nH]2)=N1

Procedure:
2-[2-(7-Cyclopentylamino-1H-indol-2-yl)-4,5-dihydro-thiazol-4-yl]-ethanol prepared in Example 77 and sodium methoxide were reacted according to the same procedure as Example 165 to give the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[CH:4][C:3]=1[C:10]1[N:11]=[C:12]([NH:16][C:17]2[CH:18]=[C:19]3[C:23](=[CH:24][CH:25]=2)[N:22](C2CCCCO2)[CH:21]=[CH:20]3)[S:13][C:14]=1[CH3:15].[H-].[Na+].[CH2:34](Br)[CH2:35][CH3:36].O>CN(C)C=O>[Cl:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[CH:4][C:3]=1[C:10]1[N:11]=[C:12]([N:16]([C:17]2[CH:18]=[C:19]3[C:23](=[CH:24][CH:25]=2)[NH:22][CH:21]=[CH:20]3)[CH2:34][CH2:35][CH3:36])[S:13][C:14]=1[CH3:15]
Reactant: COc1ccc(-c2nc(Nc3ccc4c(ccn4C4CCCCO4)c3)sc2C)c(Cl)c1
Reactant: CCCBr
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCN(c1ccc2[nH]ccc2c1)c1nc(-c2ccc(OC)cc2Cl)c(C)s1
Temperature: 25 °C
Reaction time: 16 h
Yield: 85 %

Procedure:
10.9 g of 4-(2-chloro-4-methoxyphenyl)-5-methyl-2-[N-(1-(tetrahydropyran-2-yl)indol-5-yl)amino]-thiazole are dissolved in 110 ml of dimethylformamide. 1.06 g of 60% sodium hydride in oil and then 3.2 ml of propyl bromide are added at 0° C. After stirring for 16 hours at room temperature, the reaction mixture is poured onto 500 ml of water and extracted 3 times with 250 ml ethyl acetate. The organic phase is washed with 3 times 200 ml of water, dried over sodium sulphate and evaporated to dryness. The residue is purified by flash chromatography on silica gel eluted with a 3/1 (v/v) cyclohexane/ethyl acetate mixture. 10.17 g of the expected product (85%) are obtained. 1H NMR (CDCl3): 0.90 (m, 3H), 1.57-1.75 (m, 6H), 2.02 (s, 3H), 1.95-2.25 (m, 2H), 3.70-4.17 (m, 7H), 5.50 (dd, J=2.6, 10.0, 1H), 6.54-7.61 (m, 8H).
Reaction SMILES: C([O-])([O-])=O.[K+].[K+].[NH:7]1[CH:11]=[N:10][CH:9]=[N:8]1.[F:12][C:13]1[CH:18]=[C:17]([F:19])[CH:16]=[CH:15][C:14]=1[C@@:20]1([O:25][CH2:24]1)[C@H:21]([OH:23])[CH3:22]>CN(C)C=O>[F:12][C:13]1[CH:18]=[C:17]([F:19])[CH:16]=[CH:15][C:14]=1[C@@:20]([OH:25])([C@H:21]([OH:23])[CH3:22])[CH2:24][N:7]1[CH:11]=[N:10][CH:9]=[N:8]1
Reactant: C[C@@H](O)[C@]1(c2ccc(F)cc2F)CO1
Reactant: c1nc[nH]n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: C[C@@H](O)[C@@](O)(Cn1cncn1)c1ccc(F)cc1F
Temperature: 80 °C
Yield: 38 %

Procedure:
To an ice cooled suspension of anhydrous K2CO3 (0.691 g, 0.005 mole) in N,N-dimethylformamide (7 ml), 1H-1,2,4-triazole (0.345, 0.005 mole) was added in small portions under art atmosphere of nitrogen. The mixture was slowly brought to room temperature and a solution of compound 7c (2R, 3S)-3-(2,4-Difluorophenyl)-3,4-epoxy-2-butanol (0.5 g, 0.0025 mole) in N,N-dimethylformamide (1 ml) was added. The resulting mixture was heated at 80° C. for 2 hours. The solvent was removed under reduced pressure and 25 g of crushed ice was added to the residue. The so formed mixture was extracted with ethyl acetate (50 ml, 2×25 ml). The combined organic layers were washed with water (10 ml) brine (25 ml) and dried over MgSO4. The solvent was removed in vacuo and the residue was chromatographed on silica gel. Elution with methanol in chloroform (0% -3%) gave the title compound 9c as an amorphous solid (0.26 g, 38%).
Reaction SMILES: O[CH:2]1[CH2:5][CH:4]([NH:6][C:7](=[O:13])[O:8][C:9]([CH3:12])([CH3:11])[CH3:10])[CH2:3]1.C(N(CC)CC)C.[S:21](Cl)([C:24]1[CH:30]=[CH:29][C:27]([CH3:28])=[CH:26][CH:25]=1)(=[O:23])=[O:22]>C(Cl)(Cl)Cl>[S:21]([CH:2]1[CH2:5][CH:4]([NH:6][C:7](=[O:13])[O:8][C:9]([CH3:12])([CH3:11])[CH3:10])[CH2:3]1)([C:24]1[CH:30]=[CH:29][C:27]([CH3:28])=[CH:26][CH:25]=1)(=[O:23])=[O:22]
Reactant: CC(C)(C)OC(=O)NC1CC(O)C1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: Cc1ccc(S(=O)(=O)C2CC(NC(=O)OC(C)(C)C)C2)cc1

Procedure:
18.7 g (100 mmol) tert.butyl (3-hydroxy-cyclobutyl)-carbamate and 12.1 g (120 mmol) triethylamine are placed in 500 ml chloroform. 20.5 g (105 mmol) tosyl chloride, dissolved in 150 ml chloroform, is added dropwise to this solution at 0° C. with stirring. Then the mixture is left to come up to ambient temperature and stirred for 2 h. The organic phase is washed successively with water, dilute hydrochloric acid, sodium hydrogen carbonate solution and water. The organic phase is dried with magnesium sulphate and the solvent is eliminated in vacuo.
Reaction SMILES: [CH3:1][NH:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[Cl:9][CH2:10][CH2:11][C:12](Cl)=[O:13]>O1CCCC1>[Cl:9][CH2:10][CH2:11][C:12]([N:2]([CH3:1])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1)=[O:13]
Reactant: CNc1ccccc1
Reactant: O=C(Cl)CCCl
Solvent: C1CCOC1
Product: CN(C(=O)CCCl)c1ccccc1
Yield: 92.6 %

Procedure:
A solution of 107.2 g (1.00 mole) of N-methylaniline in 150 ml of tetrahydrofuran was added dropwise to a solution of 90.4 g (0.71 mole) of 3-chloropropionyl chloride in 250 ml of tetrahydrofuran. The reaction temperature was maintained between 5° and 15° C. throughout the addition. After the final addition, the solution was filtered to remove a solid precipitate, and the filtrate was concentrated under reduced pressure to yield 130.0 g (91%) of a dark oil. An analytical sample was prepared by filtering the oil through a small bed of silica gel and eluting with ethyl acetate-hexane (1:5). The fractions containing the desired product were combined and concentrated under reduced pressure to give a light-yellow liquid. The liquid was partitioned between ethyl acetate and a saturated sodium bicarbonate solution. The ethyl acetate layer was washed with water and brine, dried (MgSO4), and concentrated under reduced pressure to give the title compound as a light-yellow oil.
Reaction SMILES: [C:1](Cl)(Cl)=[O:2].[Cl:5][C:6]1[CH:7]=[C:8]([CH:18]=[C:19]([Cl:21])[CH:20]=1)[O:9][CH:10]([C:12]1[S:16][C:15]([NH2:17])=[N:14][N:13]=1)[CH3:11]>C(OCC)(=O)C>[Cl:5][C:6]1[CH:7]=[C:8]([CH:18]=[C:19]([Cl:21])[CH:20]=1)[O:9][CH:10]([C:12]1[S:16][C:15]([N:17]=[C:1]=[O:2])=[N:14][N:13]=1)[CH3:11]
Reactant: O=C(Cl)Cl
Reactant: CC(Oc1cc(Cl)cc(Cl)c1)c1nnc(N)s1
Solvent: CCOC(C)=O
Product: CC(Oc1cc(Cl)cc(Cl)c1)c1nnc(N=C=O)s1
Reaction time: 64 h

Procedure:
A 500 milliliter, 3-neck flask equipped with a magnetic stirrer, thermometer, dry ice condenser/drying tube and inlet from a phosgene (COCl2) tank via a calibrated rotameter was charged with 50 milliliters of ethyl acetate saturated with phosgene at 20° C. (approximately 0.5 mole of phosgene). An additional 50 milliliters of ethylacetate was added, and 7.9 grams of 5-[1-(3,5-dichorophenoxy)ethyl]-2-amino-1,3,4-thiadiazole, (prepared above) in 30 milliliters of ethyl acetate was added. The resulting solution was stirred for 64 hours, and then purged with nitrogen until no COCl2 was detected. The solution was filtered and then topped at 70° C. in a roto-vac to form 10.0 grams of a viscous yellow oil of 5-[1-(3,5-dichlorophenoxy)ethyl]-1,3,4-thiadiazol-2-yl isocyanate dimer.
Reaction SMILES: Cl.[NH2:2][C:3]1[N:11]=[CH:10][N:9]=[C:8]2[C:4]=1[N:5]=[CH:6][N:7]2[C:12]1[CH:17]=[CH:16][C:15]([NH:18][C:19]([NH:21][C:22]2[CH:27]=[CH:26][C:25]([Cl:28])=[C:24]([C:29]([F:32])([F:31])[F:30])[CH:23]=2)=[O:20])=[CH:14][CH:13]=1.[CH3:33][S:34](Cl)(=[O:36])=[O:35]>>[Cl:28][C:25]1[CH:26]=[CH:27][C:22]([NH:21][C:19]([NH:18][C:15]2[CH:14]=[CH:13][C:12]([N:7]3[CH:6]=[N:5][C:4]4[C:8]3=[N:9][CH:10]=[N:11][C:3]=4[N:2]([S:34]([CH3:33])(=[O:36])=[O:35])[S:34]([CH3:33])(=[O:36])=[O:35])=[CH:17][CH:16]=2)=[O:20])=[CH:23][C:24]=1[C:29]([F:31])([F:32])[F:30]
Reactant: CS(=O)(=O)Cl
Reactant: Nc1ncnc2c1ncn2-c1ccc(NC(=O)Nc2ccc(Cl)c(C(F)(F)F)c2)cc1
Agent: Cl
Product: CS(=O)(=O)N(c1ncnc2c1ncn2-c1ccc(NC(=O)Nc2ccc(Cl)c(C(F)(F)F)c2)cc1)S(C)(=O)=O

Procedure:
The title compound can be synthesized from 1-[4-(6-aminopurin-9-yl)phenyl]-3-(4-chloro-3-(trifluoromethyl)phenyl)urea hydrochloride and methanesulfonyl chloride by using the same method as in Example 107.
Reaction SMILES: [OH-].[Na+].[OH:3][C:4]1[CH:14]=[CH:13][C:7]([CH:8]=[CH:9][C:10]([OH:12])=[O:11])=[CH:6][CH:5]=1.Br[CH2:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.Cl>C(O)C.O>[CH2:16]([O:3][C:4]1[CH:5]=[CH:6][C:7]([CH:8]=[CH:9][C:10]([OH:12])=[O:11])=[CH:13][CH:14]=1)[CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: O=C(O)C=Cc1ccc(O)cc1
Reactant: BrCCc1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: O=C(O)C=Cc1ccc(OCCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 65.4 %

Procedure:
Aqueous 1N Sodium hydroxide solution (6.0 mL, 12.0 mmol) was added to a solution of 4-hydroxycinnamic acid (536.0 mg, 3.2 mmol) in ethanol (10.0 mL). 2-Bromoethylbenzene (575.0 mg, 3.1 mmol) was then added to the reaction mixture and the resulting reaction mixture was stirred at room temperature overnight. The solvent was evaporated under reduced pressure to afford a white residue, which was taken up in water. The aqueous phase was then acidified with concentrated hydrochloric acid to produce a white precipitate which was isolated by filtration and washed with water, then dried to afford (544.0 mg, 66.8%) of the desired 4-phenethyloxycinnamic acid as a white powder. 1H NMR (300 MHz, DMSO) δ 3.82 (3H, s, OCH3), 4.78 (2H, s, CH2), 6.92 (2H, d, 2×ArH, J=7.5 Hz), 7.16 (2H, d, 2×ArH, J=7.5 Hz), 7.52-7.60 (1H, m, ArH), 7.62-7.72 (1H, m, ArH), 7.98 (1H, m, ArH).
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7]2[CH:8]=[C:9]([C:12]([OH:14])=[O:13])[S:10][CH:11]=2)=[CH:5][CH:4]=[N:3]1.[Cl:15]N1C(=O)CCC1=O>C1COCC1>[Cl:15][C:5]1[CH:4]=[N:3][N:2]([CH3:1])[C:6]=1[C:7]1[CH:8]=[C:9]([C:12]([OH:14])=[O:13])[S:10][CH:11]=1
Reactant: O=C1CCC(=O)N1Cl
Reactant: Cn1nccc1-c1csc(C(=O)O)c1
Solvent: C1CCOC1
Product: Cn1ncc(Cl)c1-c1csc(C(=O)O)c1
Reaction time: 1 h

Procedure:
A solution of 4-(1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxylic acid (600 mg, 2.88 mmol) and N-chlorosuccinimide (384 mg, 2.88 mmol) in THF (14 mL) was stirred in a sealed tube at 70° C. After 1 h, the solution was partitioned between H2O-DCM, the aqueous phase was adjusted to pH 3 and the aqueous phase was washed several times with DCM. The combined organic fractions were dried (Na2SO4), concentrated under vacuum and used directly without further purification (698 mg, quant.): LCMS (ES) m/z=243 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([C:11]2[CH:12]=[N:13][C:14](S(C)=O)=[N:15][CH:16]=2)=[O:10])=[CH:4][CH:3]=1.[C:20]([O:25][CH3:26])(=[O:24])[C@@H:21]([CH3:23])[OH:22].C1CCN2C(=NCCC2)CC1>C1COCC1>[CH3:26][O:25][C:20](=[O:24])[C@@H:21]([O:22][C:14]1[N:13]=[CH:12][C:11]([C:9](=[O:10])[NH:8][C:5]2[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=2)=[CH:16][N:15]=1)[CH3:23]
Reactant: COC(=O)[C@@H](C)O
Reactant: CS(=O)c1ncc(C(=O)Nc2ccc(F)cc2)cn1
Solvent: C1CCOC1
Solvent: C1CCC2=NCCCN2CC1
Product: COC(=O)[C@H](C)Oc1ncc(C(=O)Nc2ccc(F)cc2)cn1
Reaction time: 48 h
Yield: 44.5 %

Procedure:
To a solution of 2-methanesulfinylpyrimidine-5-carboxylic acid (4-fluorophenyl)amide (40 mg, 0.14 mmol) in THF (1 mL) was added (R)-(+)-methyl lactate (20 μL, 0.21 mmol) followed by DBU (34 μL, 0.23 mmol). The solution was stirred for 2 days, quenched with 3% HCl and extracted with ethyl acetate. The organic layers were combined, washed successively with 5% NaHCO3, water, and brine, dried and concentrated in vacuo to afford 19.9 mg (46% yield) of the titled compound as a white solid shown to be 94% pure by HPLC. ESI-MS m/z 320 (MH+), 318 (M−H)−.
Reaction SMILES: Cl.[CH:2]([NH2:4])=[NH:3].CC[O-].[Na+].[CH3:9][O:10][CH:11]([C:16](OC)=[O:17])[C:12](OC)=[O:13].C(O)(=O)C>C(O)C>[CH3:9][O:10][C:11]1[C:12]([OH:13])=[N:3][CH:2]=[N:4][C:16]=1[OH:17]
Reactant: COC(=O)C(OC)C(=O)OC
Reactant: N=CN
Agent: CC[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Solvent: CC(=O)O
Product: COc1c(O)ncnc1O
Temperature: 25 °C

Procedure:
5 g (6.2 mmoles) of formamidine hydrochloride is added at 0° C. and in small quantities into a single-necked flask containing 30 ml of absolute ethanol and 90 ml of a solution of sodium ethylate at a concentration of 1.7 mol/l in ethanol. Stirring is maintained at ambient temperature for about twenty minutes, then 8.5 ml of dimethyl methoxymalonate is added dropwise. Stirring is maintained for 16 hours. The reaction mixture is then acidified with pure acetic acid to a pH between 4 and 5, then concentrated to dryness in the presence of cyclohexane. After impasting the crude product obtained is chromatographed on silicagel eluting with a mixture of methylene chloride-methanol (85-15) and 2% water-acetic acid (1-1). 9.5 g of the expected product is obtained containing a small quantity of sodium acetate salts.
Reaction SMILES: C([BH3-])#N.[Na+].[F:5][C:6]1[C:11]([F:12])=[CH:10][CH:9]=[CH:8][C:7]=1[C@H:13]1[CH2:19][N:18]2[C:20]([CH2:23][CH:24]=O)=[CH:21][N:22]=[C:17]2[C@H:16]([NH:26][C:27](=[O:33])[O:28][C:29]([CH3:32])([CH3:31])[CH3:30])[CH2:15][CH2:14]1.[CH3:34][NH:35][CH3:36].C(O)(=O)C>CO>[F:5][C:6]1[C:11]([F:12])=[CH:10][CH:9]=[CH:8][C:7]=1[C@H:13]1[CH2:19][N:18]2[C:20]([CH2:23][CH2:24][N:35]([CH3:36])[CH3:34])=[CH:21][N:22]=[C:17]2[C@H:16]([NH:26][C:27](=[O:33])[O:28][C:29]([CH3:32])([CH3:30])[CH3:31])[CH2:15][CH2:14]1
Reactant: CC(C)(C)OC(=O)N[C@@H]1CC[C@@H](c2cccc(F)c2F)Cn2c(CC=O)cnc21
Reactant: CNC
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: CN(C)CCc1cnc2n1C[C@H](c1cccc(F)c1F)CC[C@H]2NC(=O)OC(C)(C)C
Reaction time: 2 h
Yield: 84.2 %

Procedure:
Sodium cyanoborohydride (12 mg, 0.185 mmol) was added to a solution of tert-butyl (6S,9R)-6-(2,3-difluorophenyl)-3-(2-oxoethyl)-6,7,8,9-tetrahydro-5H-imidazo[1,2-a]azepin-9-ylcarbamate (50 mg, 0.123 mmol) and dimethylamine (2.0 M in tetrahydrofuran; 0.185 mL, 0.370 mmol) in methanol (5 mL) adjusted to pH 5 with acetic acid. After 2 h, the solution was concentrated. Purification by silica gel chromatography (100% dichloromethane→92% dichloromethane/methanol) gave the title compound (45 mg). MS 435.2 (M+1).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([C:7]2[CH:12]=[CH:11][C:10]([NH:13][C:14]([C:16]3[S:17][CH:18]=[C:19]([C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)[CH:20]=3)=[O:15])=[CH:9][CH:8]=2)[CH2:3][CH2:2]1.F[C:28]1[CH:36]=[CH:35][C:31]([C:32]([OH:34])=[O:33])=[CH:30][N:29]=1.C(N(C(C)C)CC)(C)C>O1CCOCC1>[C:21]1([C:19]2[CH:20]=[C:16]([C:14]([NH:13][C:10]3[CH:11]=[CH:12][C:7]([CH:4]4[CH2:5][CH2:6][N:1]([C:28]5[CH:36]=[CH:35][C:31]([C:32]([OH:34])=[O:33])=[CH:30][N:29]=5)[CH2:2][CH2:3]4)=[CH:8][CH:9]=3)=[O:15])[S:17][CH:18]=2)[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1
Reactant: O=C(O)c1ccc(F)nc1
Reactant: O=C(Nc1ccc(C2CCNCC2)cc1)c1cc(-c2ccccc2)cs1
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: O=C(O)c1ccc(N2CCC(c3ccc(NC(=O)c4cc(-c5ccccc5)cs4)cc3)CC2)nc1
Temperature: 175 °C
Yield: 47.1 %

Procedure:
A mixture of 4-phenyl-thiophene-2-carboxylic acid (4-piperidin-4-yl-phenyl)-amide (181 mg, 0.5 mmol) and 6-fluoronicotinic acid (141 mg, 1 mmol) in dioxane (3 mL) containing diisopropylethylamine (0.5 mL, 2.7 mmol) was heated in a microwave at 175° C. for 30 minutes. The mixture was evaporated and extracted with ethyl acetate (containing THF and methanol) and 0.2N hydrochloric acid. The organic layer was dried and evaporated. The residue was crystallized from methanol and ethyl acetate to give a pale yellow solid as 4-{4-[(4-phenyl-thiophene-2-carbonyl)-amino]-phenyl}-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-5′-carboxylic acid (114 mg). LC-MS for C28H25N3O3S (in/e) calcd 483, obsd 484 (M+H). 1H-NMR is consistent with the desired structure.
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=1.[Cu](C#N)[C:12]#[N:13].O>CN(C=O)C>[C:12]([C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=1)#[N:13]
Reactant: N#C[Cu]C#N
Reactant: O=[N+]([O-])c1cccnc1Cl
Solvent: O
Solvent: CN(C)C=O
Product: N#Cc1ncccc1[N+](=O)[O-]
Temperature: 100 °C

Procedure:
To a solution of 2-chloro-3-nitropyridine (5 g, 31.6 mmol, 1.0 eq.) in 50 mL of DMF was added copper cyanide (2.47 g, 38 mmol, 1.2 eq.) and the reaction heated to 100° C. for 16 hours. The reaction mixture was cooled to ambient temperature and poured into 100 mL of water. The mixture was extracted with ethyl acetate (3×50 mL) and the combined ethyl acetate portions were dried over sodium sulfate and concentrated. The crude material was chromatographed on silica with 3:7 ethyl acetate/hexanes to give 2-cyano-3-nitropyridine as a yellow solid.
Reaction SMILES: [C:1]1([NH:7][CH2:8][C:9]([OH:11])=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:12]([N:16]=[C:17]=[O:18])([CH3:15])([CH3:14])[CH3:13]>C1(C)C=CC=CC=1>[C:1]1([N:7]2[CH2:8][C:9](=[O:11])[N:16]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:17]2=[O:18])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CC(C)(C)N=C=O
Reactant: O=C(O)CNc1ccccc1
Solvent: Cc1ccccc1
Product: CC(C)(C)N1C(=O)CN(c2ccccc2)C1=O
Yield: 60 %

Procedure:
A mixture of N-phenyl glycine (0.1 mole), t-butyl isocyanate (0.12 mole) and toluene (30 ml) was refluxed for 5 hours and then cooled. The product was collected by filtration and crystallized from ethanol to produce 0.06 mole of the aforedescribed product having a melting point of 116° C.
Reaction SMILES: CC([CH:5]([O:9][CH:10]1[C:19]2[N:18]([CH2:20][C:21]3[CH:26]=[CH:25][C:24]([Cl:27])=[C:23]([Cl:28])[CH:22]=3)[C:17]([CH:29]([CH3:31])[CH3:30])=[N:16][C:15]=2[CH2:14][CH2:13][CH2:12][CH2:11]1)[C:6]([O-:8])=[O:7])(C)C.O1CCOCC1>Cl>[ClH:27].[Cl:28][C:23]1[CH:22]=[C:21]([CH2:20][N:18]2[C:19]3[CH:10]([O:9][CH2:5][C:6]([OH:8])=[O:7])[CH2:11][CH2:12][CH2:13][CH2:14][C:15]=3[N:16]=[C:17]2[CH:29]([CH3:31])[CH3:30])[CH:26]=[CH:25][C:24]=1[Cl:27]
Reactant: CC(C)c1nc2c(n1Cc1ccc(Cl)c(Cl)c1)C(OC(C(=O)[O-])C(C)(C)C)CCCC2
Agent: Cl
Solvent: C1COCCO1
Product: CC(C)c1nc2c(n1Cc1ccc(Cl)c(Cl)c1)C(OCC(=O)O)CCCC2
Reaction time: 8 h

Procedure:
Intermediate 71 (0.210 g) was stirred in HCl (0.899 mL) and 1,4-Dioxane (0.9 mL) for 1 hour under an atmosphere of Nitrogen. The reaction was allowed to stir overnight. LCMS showed 60% conversion to the product. The reaction mixture was allowed to stir over a second night. LCMS showed further conversion to the product. The sample was concentrated in vacuo and then re-dissolved in 2 mL of a 1:1 mixture of ACN:H2O. An aminopropyl column was washed with 2 CV of ACN:H2O (1:1), then the sample was loaded onto the column. The column was washed with 3 CV of ACN:H2O (1:1). The product was eluted with 3CV of 2N HCl. The appropriate fraction was concentrated in vacuo to give the product. There is an impurity (about 10%) which has the m/z of the methyl ester of the product.
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]2[C:5]([NH:6][CH:7]=[N:8]2)=[C:4]([Cl:11])[N:3]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:19][C:20]([OH:22])=[O:21].Cl>CN(C=O)C.O>[NH2:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH2:19][C:20]([OH:22])=[O:21])=[C:4]([Cl:11])[N:3]=1
Reactant: O=C(O)CBr
Reactant: Nc1nc(Cl)c2[nH]cnc2n1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Nc1nc(Cl)c2ncn(CC(=O)O)c2n1
Reaction time: 20 h

Procedure:
To a suspension of 2-amino-6-chloropurine (5.02 g, 29.6 mmol) and potassium carbonate (12.91 g, 93.5 mmol) in DMF (50 mL) was added bromoacetic acid (4.7 g, 22.8 mmol). The mixture was stirred vigorously for 20 h under nitrogen. Water (150 mL) was added and the solution was filtered through celite to give a clear yellow solution. The solution was acidified to a pH of 3 with 4N hydrochloric acid. The precipitate was filtered and dried, in vacuo, over sicapent. Yield: 3.02 g (44.8%). 1H-NMR(DMSO-d6) δ: 4.88 ppm (s, 2H); 6.95 (s, 2H); 8.10 (s, 1H).