Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O1C2C=CC(C3(C(O)=O)CCC3)=CC=2OC1.Cl[C:18]([Cl:20])=O.[CH3:21][O:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[C:29]1([C:33](O)=[O:34])[CH2:32][CH2:31][CH2:30]1>>[Cl:20][CH2:18][C:33]([C:29]1([C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=2[O:22][CH3:21])[CH2:32][CH2:31][CH2:30]1)=[O:34]
Reactant: O=C(Cl)Cl
Reactant: COc1ccccc1C1(C(=O)O)CCC1
Agent: O=C(O)C1(c2ccc3c(c2)OCO3)CCC1
Product: COc1ccccc1C1(C(=O)CCl)CCC1

Procedure:
1-Benzo[1,3]dioxol-5-yl-cyclobutanecarboxylic acid was converted to the corresponding chloroketone following the same procedure used for the conversion of 1-(2-Methoxy-phenyl)-cyclobutanecarboxylic acid to give 2-Chloro-1-[1-(2-methoxy-phenyl)-cyclobutyl]-ethanone. 300 mg of 1-benzo[1,3]dioxol-5-yl-cyclobutanecarboxylic acid thus provided 285 mg (83%) of 1-(1-Benzo[1,3]dioxol-5-yl-cyclobutyl)-2-chloro-ethanone. Data for this chloride: 1H NMR (300 MHz, CDCl3): δ 6.7-6.85 (m, 3H), 5.98 (s, 2H), 4.03 (s, 2H), 2.75-2.85 (m, 2H), 2.35-2.45 (m, 2H), 1.85-2.0 (m, 2H); 13C NMR (75 MHz, CDCl3): δ 201.9, 148.6, 147.1, 135.8, 119.8, 108.9, 107.0, 101.6, 57.7, 45.4, 31.2, 16.2.
Reaction SMILES: [C:1]([C:3]1[CH:10]=[CH:9][C:6]([CH2:7][NH2:8])=[CH:5][CH:4]=1)#[N:2].[C:11](=N)([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>C(Cl)Cl>[C:12]1([C:11]([C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)=[N:2][CH2:1][C:3]2[CH:10]=[CH:9][C:6]([C:7]#[N:8])=[CH:5][CH:4]=2)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: N=C(c1ccccc1)c1ccccc1
Reactant: N#Cc1ccc(CN)cc1
Solvent: ClCCl
Product: N#Cc1ccc(CN=C(c2ccccc2)c2ccccc2)cc1
Reaction time: 8 h
Yield: 164.8 %

Procedure:
33.73 g (0.2 mol) of 4-cyanobenzylamine and 36.25 g (0.2 mol) of benzophenone imine were dissolved in 540 ml of DCM at room temperature and stirred overnight. The reaction mixture was subsequently washed with 2×90 ml of water and dried with Na2SO4, and the solvent was removed in a rotary evaporator. 55.59 g (93.7%) of the crude product remained. Recrystallization from 550 ml of iPrOH resulted in 97.67 g (80.4%) of pure product. 1H-NMR (CDCl3, δ in ppm): 7.7-7.15 (m, 9H, Ar—H); 4.65 (s, 2H, CH2—N)
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:27])[C@@H:5]([NH:8][C:9]([C:11]1[CH:16]=[CH:15][C:14]([C:17]2[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:19][CH:18]=2)=[CH:13][CH:12]=1)=[O:10])[CH2:6][NH2:7].[C:28]1([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[CH:33]=[CH:32][C:31]([CH:34]=O)=[CH:30][CH:29]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>>[CH3:2][O:3][C:4](=[O:27])[C@@H:5]([NH:8][C:9]([C:11]1[CH:16]=[CH:15][C:14]([C:17]2[CH:22]=[CH:21][C:20]([C:23]([F:25])([F:24])[F:26])=[CH:19][CH:18]=2)=[CH:13][CH:12]=1)=[O:10])[CH2:6][NH:7][CH2:34][C:31]1[CH:32]=[CH:33][C:28]([C:36]2[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=2)=[CH:29][CH:30]=1
Reactant: O=Cc1ccc(-c2ccccc2)cc1
Reactant: COC(=O)[C@H](CN)NC(=O)c1ccc(-c2ccc(C(F)(F)F)cc2)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Product: COC(=O)[C@H](CNCc1ccc(-c2ccccc2)cc1)NC(=O)c1ccc(-c2ccc(C(F)(F)F)cc2)cc1

Procedure:
3-Amino-(2S)-[(4′-trifluoromethyl-biphenyl-4-carbonyl)-amino]-propionic acid methyl ester hydrochloride (0.200 g, 0.493 mmol) was subjected to reductive amination as per general procedure E with biphenyl-4-carbaldehyde (0.080 g, 0.444 mmol) and sodium triacetoxyborohydride (0.208 g, 0.986 mmol) to yield the 3-[(biphenyl-4-ylmethyl)-amino]-(2S)-[(4′-trifluoromethyl-biphenyl-4-carbonyl)-amino]-propionic acid methyl ester which was further hydrolyzed as per general procedure C to yield 3-[(biphenyl-4-ylmethyl)-amino]-(2S)-[(4′-trifluoromethyl-biphenyl-4-carbonyl)-amino]-propionic acid (0.190 g, 70%).
Reaction SMILES: C([O:3][C:4](=[O:37])[CH:5]([C:10]1[CH:11]=[C:12]([C:27]2[CH:32]=[CH:31][C:30]([C:33]([F:36])([F:35])[F:34])=[CH:29][CH:28]=2)[CH:13]=[C:14]([CH:16]2[CH2:21][CH2:20][CH2:19][N:18]([CH:22]([CH2:25][CH3:26])[CH2:23][CH3:24])[CH2:17]2)[CH:15]=1)[CH2:6][CH:7]([CH3:9])[CH3:8])C.[OH-].[K+]>CCO>[CH2:23]([CH:22]([N:18]1[CH2:19][CH2:20][CH2:21][CH:16]([C:14]2[CH:15]=[C:10]([CH:5]([CH2:6][CH:7]([CH3:9])[CH3:8])[C:4]([OH:37])=[O:3])[CH:11]=[C:12]([C:27]3[CH:28]=[CH:29][C:30]([C:33]([F:36])([F:34])[F:35])=[CH:31][CH:32]=3)[CH:13]=2)[CH2:17]1)[CH2:25][CH3:26])[CH3:24]
Reactant: CCOC(=O)C(CC(C)C)c1cc(-c2ccc(C(F)(F)F)cc2)cc(C2CCCN(C(CC)CC)C2)c1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: CCC(CC)N1CCCC(c2cc(-c3ccc(C(F)(F)F)cc3)cc(C(CC(C)C)C(=O)O)c2)C1
Temperature: 78 °C

Procedure:
To a solution of compound 33c, 2-{5-[1-(1-Ethyl-propyl)-piperidin-3-yl]-4′-trifluoromethyl-biphenyl-3-yl}-4-methyl-pentanoic acid ethyl ester (30.7 mg, 59.3 μmol) in EtOH (3 ml) was added 2M KOH (119 μl, 0.24 mmol). The reaction was heated to 78° C. for 2.5 hours, cooled to room temperature, and concentrated in vacuo. Purification via Gilson HPLC, followed by salt exchange with aqueous 1N HCl, gave the product as a white solid. (10.2 mg, 35% ) 1H NMR (300 MHz, MeOD) δ ppm 0.85 (d, J=6.78 Hz, 6 H) 0.99 (td, J=7.35, 3.77 Hz, 6 H) 1.35-1.49 (m, 1 H) 1.56-1.70 (m, 3 H) 1.79-1.93 (m, 4 H) 1.94-2.08 (m, 4H) 2.99 (dd, J=7.91, 4.14 Hz, 1 H) 3.05-3.15 (m, 2 H) 3.41 (s, 2 H) 3.68 (t, J=7.72 Hz, 1 H) 7.27 (s, 1 H) 7.47 (d, J=9.80 Hz, 2 H) 7.64-7.75 (m, 4 H) Calcd for C29H38F3NO2 (M+H) 489.61, Found 490.4.
Reaction SMILES: [F:1][CH:2]([F:12])[C:3]1[N:4]=[C:5]([CH3:11])[S:6][C:7]=1[C:8]([OH:10])=O.[CH3:13][Si:14]([CH3:22])([CH3:21])[CH2:15][CH2:16][CH2:17][CH:18]([NH2:20])[CH3:19].C1CN([P+](Br)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F>C(#N)C>[F:12][CH:2]([F:1])[C:3]1[N:4]=[C:5]([CH3:11])[S:6][C:7]=1[C:8]([NH:20][CH:18]([CH3:19])[CH2:17][CH2:16][CH2:15][Si:14]([CH3:22])([CH3:21])[CH3:13])=[O:10]
Reactant: Cc1nc(C(F)F)c(C(=O)O)s1
Reactant: CC(N)CCC[Si](C)(C)C
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: F[P-](F)(F)(F)(F)F
Solvent: CC#N
Product: Cc1nc(C(F)F)c(C(=O)NC(C)CCC[Si](C)(C)C)s1
Yield: 56.4 %

Procedure:
A solution of 133 mg of 4-(difluoromethyl)-2-methyl-1,3-thiazole-5-carboxylic acid, 110 mg 5-(trimethylsilyl)pentan-2-amine, 354 mg of PyBroP [bromo-tris-pyrrolidino-phosphonium hexafluorophosphate], and 142 mg N,N′-diisopropylamine in 10 mL acetonitrile was stirred over night at room temperature. Aqueous work-up [extraction with 1.0M NaOH], and silica gel chromatography yielded 130 mg (53%) of a colourless oil.
Reaction SMILES: [NH:1]([CH:3]([CH2:5][CH2:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[CH3:4])[NH2:2].C(N(CC)CC)C.[CH3:21][O:22][C:23](OC)=[C:24]([C:27]#[N:28])[C:25]#[N:26].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>CO.O>[NH2:28][C:27]1[N:1]([CH:3]([CH2:5][CH2:6][CH2:7][C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH3:4])[N:2]=[C:23]([O:22][CH3:21])[C:24]=1[C:25]#[N:26]
Reactant: COC(OC)=C(C#N)C#N
Reactant: CC(CCCc1ccccc1)NN
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: CCN(CC)CC
Solvent: CO
Solvent: O
Product: COc1nn(C(C)CCCc2ccccc2)c(N)c1C#N
Temperature: 20 °C
Reaction time: 1.5 h
Yield: 80.1 %

Procedure:
3.6 g of 2-hydrazino-5-phenylpentane are dissolved in 40 ml of methanol, and 2.8 ml of triethylamine are added. Then, 2.8 g of 1,1-dimethoxy-2,2-dicyanoethylene are added at approx. 0° C. The reaction solution is warmed to approx. 20° C. and stirred for 1.5 hours at approx. 20° C. For work-up, the mixture is diluted with water, acidified with citric acid and extracted twice with dichloromethane. The combined dichloromethane phases are dried with magnesium sulphate and evaporated in vacuo. This gives 5.1 g of a yellow oil, which crystallizes slowly. The oil is chromatographed on silica gel (Merck Si 60 0.04-0.063 mm) with a petroleum ether/ethyl acetate mixture in a ratio of 5:1 to 1:1. This gives a fraction which, after evaporation in vacuo, affords 4.6 g (=80.9% of theory) of 5-amino-4-cyano-3-methoxy-1-[(5-phenyl)-pent-2-yl]-pyrazole.
Reaction SMILES: [Si]([O:8][CH2:9][CH2:10][O:11][C:12](=[O:28])[C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([F:19])[C:14]=1[NH:20][C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])(C(C)(C)C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.[Cl-].[NH4+]>C1COCC1>[OH:8][CH2:9][CH2:10][O:11][C:12](=[O:28])[C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([F:19])[C:14]=1[NH:20][C:21]([O:23][C:24]([CH3:26])([CH3:25])[CH3:27])=[O:22]
Reactant: CC(C)(C)OC(=O)Nc1c(F)cccc1C(=O)OCCO[Si](C)(C)C(C)(C)C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Cl-]
Agent: [F-]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)Nc1c(F)cccc1C(=O)OCCO
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of 2-tert-butoxycarbonylamino-3-fluorobenzoic acid 2-(tert-butyldimethylsilanyloxy)ethyl ester from Example 19B (1.2 g, 2.9 mmol) in THF (25 ml) was added a solution tetrabutylammonium fluoride (1.0M, 5.8 ml, 5.8 mmol) in THF while cooling in an ice/water bath. The mixture was allowed to warm to room temperature and stirred for 18 h. Saturated ammonium chloride solution (20 ml) was added and the mixture was stirred for 1 h and evaporated in vacuo. The residue was partitioned between chloroform and water and the organic phase was dried and evaporated in vacuo. The residue was purified by flash chromatography on silica (eluant EtOAc:pet.ether 90:10) to give a colourless gum; yield 180 mg, 21%.
Reaction SMILES: [CH3:1][C:2]1[S:3][C:4]([CH:7]=[CH:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[O:15][CH2:16][CH:17]2[O:19][CH2:18]2)=[N:5][N:6]=1.[C:20]([NH2:24])([CH3:23])([CH3:22])[CH3:21]>C1(C)C=CC=CC=1>[CH3:1][C:2]1[S:3][C:4]([CH:7]=[CH:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[O:15][CH2:16][CH:17]([OH:19])[CH2:18][NH:24][C:20]([CH3:23])([CH3:22])[CH3:21])=[N:5][N:6]=1
Reactant: Cc1nnc(C=Cc2ccccc2OCC2CO2)s1
Reactant: CC(C)(C)N
Solvent: Cc1ccccc1
Product: Cc1nnc(C=Cc2ccccc2OCC(O)CNC(C)(C)C)s1

Procedure:
7 g (0.025 mole) of 2-methyl-5-[2-(2,3-epoxy-propoxy)-styryl]-1,3,4-thiadiazole and 2.1 g (0.028 mole) of tert.-butylamine are reacted by the method described in Example 1. 3.8 g (44% of theory) of yellow crystals are obtained from toluene; melting point 110°-112° C.
Reaction SMILES: C(O)(C(F)(F)F)=O.C(O[C:13](=O)[N:14]([C:16]1[N:21]=[C:20]([N:22]2[CH2:27][CH2:26][CH:25]([N:28]3[C:36]4[C:31](=[N:32][CH:33]=[CH:34][CH:35]=4)[NH:30][C:29]3=[O:37])[CH2:24][CH2:23]2)[CH:19]=[C:18]([C:38]([C:40]2[CH:50]=[C:49]([CH3:51])[C:43]3[N:44]([CH3:48])[C:45](=[O:47])[O:46][C:42]=3[CH:41]=2)=[O:39])[CH:17]=1)C)(C)(C)C>C(Cl)Cl>[CH3:48][N:44]1[C:43]2[C:49]([CH3:51])=[CH:50][C:40]([C:38]([C:18]3[CH:17]=[C:16]([NH:14][CH3:13])[N:21]=[C:20]([N:22]4[CH2:27][CH2:26][CH:25]([N:28]5[C:36]6[C:31](=[N:32][CH:33]=[CH:34][CH:35]=6)[NH:30][C:29]5=[O:37])[CH2:24][CH2:23]4)[CH:19]=3)=[O:39])=[CH:41][C:42]=2[O:46][C:45]1=[O:47]
Reactant: Cc1cc(C(=O)c2cc(N3CCC(n4c(=O)[nH]c5ncccc54)CC3)nc(N(C)C(=O)OC(C)(C)C)c2)cc2oc(=O)n(C)c12
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CNc1cc(C(=O)c2cc(C)c3c(c2)oc(=O)n3C)cc(N2CCC(n3c(=O)[nH]c4ncccc43)CC2)n1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
1.00 mL TFA were added to 59 mg (0.096 mmol) tert-butyl[4′-(3,4-dimethyl-2-oxo-2,3-dihydro-benzoxazole-6-carbonyl)-4-(2-oxo-2,3-dihydro-imidazo[4,5-b]pyridin-1-yl)-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-6′-yl]-methyl-carbamate in 5.00 mL DCM and the mixture was stirred for 3 h at RT. Then the reaction mixture was evaporated down, the residue was dissolved in DMF and purified by preparative HPLC-MS. The fractions containing the product were combined and freeze-dried.
Reaction SMILES: C([O:3][C:4]([C:6]1([C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][N:24]=[C:23]([CH3:26])[C:22]=4[CH:27]([C:29]4[CH:30]=[C:31]([C:35]5[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=5)[CH:32]=[CH:33][CH:34]=4)[OH:28])=[CH:17][CH:16]=3)=[CH:11][CH:10]=2)[CH2:8][CH2:7]1)=[O:5])C.CCO.[OH-].[Na+]>C1COCC1>[C:31]1([C:35]2[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=2)[CH:32]=[CH:33][CH:34]=[C:29]([CH:27]([OH:28])[C:22]2[C:23]([CH3:26])=[N:24][O:25][C:21]=2[C:18]2[CH:17]=[CH:16][C:15]([C:12]3[CH:13]=[CH:14][C:9]([C:6]4([C:4]([OH:5])=[O:3])[CH2:8][CH2:7]4)=[CH:10][CH:11]=3)=[CH:20][CH:19]=2)[CH:30]=1
Reactant: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4C(O)c4cccc(-c5ccccc5)c4)cc3)cc2)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: Cc1noc(-c2ccc(-c3ccc(C4(C(=O)O)CC4)cc3)cc2)c1C(O)c1cccc(-c2ccccc2)c1
Temperature: 60 °C
Reaction time: 8 h

Procedure:
1-{4′-[4-(biphenyl-3-yl-hydroxy-methyl)-3-methyl-isoxazol-5-yl]-biphenyl-4-yl}-cyclopropanecarboxylic acid ethyl ester (1 equivalent) was dissolved in THF then EtOH and NaOH (3N aq., 3 equivalents) was added and the reaction stirred at 60° C. overnight. The reaction was worked up and purified via preparatory HPLC (0.1% TFA/H2O/ACN).
Reaction SMILES: Cl[C:2]1[N:7]2[N:8]=[C:9]([C:11]([F:14])([F:13])[CH3:12])[N:10]=[C:6]2[N:5]=[C:4]([CH3:15])[CH:3]=1.[NH2:16][C:17]1[CH:22]=[C:21]([F:23])[C:20]([C:24]([F:27])([F:26])[F:25])=[C:19]([F:28])[CH:18]=1>C(O)C>[F:13][C:11]([C:9]1[N:10]=[C:6]2[N:5]=[C:4]([CH3:15])[CH:3]=[C:2]([NH:16][C:17]3[CH:18]=[C:19]([F:28])[C:20]([C:24]([F:27])([F:25])[F:26])=[C:21]([F:23])[CH:22]=3)[N:7]2[N:8]=1)([F:14])[CH3:12]
Reactant: Nc1cc(F)c(C(F)(F)F)c(F)c1
Reactant: Cc1cc(Cl)n2nc(C(C)(F)F)nc2n1
Solvent: CCO
Product: Cc1cc(Nc2cc(F)c(C(F)(F)F)c(F)c2)n2nc(C(C)(F)F)nc2n1

Procedure:
A solution of Intermediate 3 (0.1 g, 0.43 mmol) and 4-amino-2,6-difluorobenzotrifluoride (FLUOROCHEM, 0.085 g, 0.43 mmol) in ethanol (7 mL) was stirred at room temperature overnight. Solvent was removed in vacuo and the residue was taken up in DCM. The resulting solution was washed with 1N Na2CO3, then with brine and dried over anhydrous Na2SO4 to yield a yellow oil which was purified by flash chromatography (Si, eluting with Hexane/EtOAc mixtures from 100:0 to 50:50%) to afford the title compound as a pale yellow solid.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]([N+:9]([O-:11])=[O:10])=[C:6]([OH:8])[CH:7]=1.C(=O)([O-])[O-].[K+].[K+].C[CH2:19][O:20][CH2:21][CH3:22]>CN(C=O)C.C(C1OC1)Br>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([N+:9]([O-:11])=[O:10])=[C:6]([CH:7]=1)[O:8][CH2:22][CH:21]1[CH2:19][O:20]1
Reactant: CCOCC
Reactant: Cc1ccc([N+](=O)[O-])c(O)c1
Agent: BrCC1CO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1ccc([N+](=O)[O-])c(OCC2CO2)c1
Temperature: 100 °C
Reaction time: 2.5 h
Yield: 83 %

Procedure:
A mixture of 5-Methyl-2-nitrophenol (7.7 g, 50 mmol), potassium carbonate (13.8 g, 0.1 mmol) and epibromohydrine (8.25 mL, 0.1 mmol) was dissolved in DMF (100 mL) and stirred 2-3 h at 100° C. under an atmosphere of nitrogen. The mixture was diluted with ether (0.5 L) and extracted with water until pH=7. The organic phase was evaporated and the residue was purified by flash-chromatography on silica (DCM) to give the sub-title compound as a yellow solid (8.65 g, 83%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:15][C:16]2[N:21]=[C:20]([CH:22]=O)[CH:19]=[C:18]([CH2:24][O:25][CH2:26][C:27]([F:30])([F:29])[F:28])[N:17]=2)[CH:6]=[CH:7][C:8]=1[N:9]1[CH:13]=[C:12]([CH3:14])[N:11]=[CH:10]1.[CH3:31][NH:32][CH3:33].C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl.O>[CH3:31][N:32]([CH2:22][C:20]1[CH:19]=[C:18]([CH2:24][O:25][CH2:26][C:27]([F:30])([F:28])[F:29])[N:17]=[C:16]([NH:15][C:5]2[CH:6]=[CH:7][C:8]([N:9]3[CH:13]=[C:12]([CH3:14])[N:11]=[CH:10]3)=[C:3]([O:2][CH3:1])[CH:4]=2)[N:21]=1)[CH3:33]
Reactant: CNC
Reactant: COc1cc(Nc2nc(C=O)cc(COCC(F)(F)F)n2)ccc1-n1cnc(C)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Solvent: ClCCCl
Product: COc1cc(Nc2nc(COCC(F)(F)F)cc(CN(C)C)n2)ccc1-n1cnc(C)c1
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
2-(3-Methoxy-4-(4-methyl-1H-imidazol-1-yl)phenylamino)-6-((2,2,2-trifluoroethoxy)methyl)-pyrimidine-4-carbaldehyde (100 mg, 0.24 mmol) was dissolved in DCE (4 mL). Dimethylamine (2 M in THF, 0.142 mL, 0.28 mmol) and acetic acid (0.014 mL, 0.24 mmol) were added followed by sodium triacetoxyborohydride (80 mg, 0.38 mmol). The mixture was stirred at rt under nitrogen atmosphere for 1 hour 45 min. Water was added and the mixture was stirred for 3 minutes then the phases were separated. The water phase was extracted by DCM. The combined organic layer was dried over anhydrous sodium sulfate, filtered and concentrated on silica then subjected to column chromatography eluting with a gradient of methanol in DCM. The solvents were evaporated and the residue was purified by preparative HPLC to give the title compound as a dry film, 22 mg (21%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[C:9]1(O)[CH2:14][CH2:13][CH2:12][CH2:11][N:10]1C(OC(C)(C)C)=O.C(O)(C(F)(F)F)=O>C(Cl)Cl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[C:9]1[CH2:14][CH2:13][CH2:12][CH2:11][N:10]=1
Reactant: CC(C)(C)OC(=O)N1CCCCC1(O)c1cc(F)ccc1F
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Fc1ccc(F)c(C2=NCCCC2)c1
Reaction time: 2 h
Yield: 93.9 %

Procedure:
To a stifled solution of tert-butyl 2-(2,5-difluorophenyl)-2-hydroxypiperidine-1-carboxylate (9.4 g, 30 mmol) in DCM was added TFA (34.2 g, 300 mmol) and stifled at room temperature for 2 h. After completion of reaction, solvent was removed under vacuum and residue was quenched with sat.NaHCO3 and extracted with DCM. Organic layer was washed with water, brine and dried over anhydrous Na2SO4 and concentration to afford crude product as brown liquid (5.5 g), this crude was directly used for next step without any purification.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][N:5]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=1)[CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[N+](N[C:23]1[NH:28][C:27](=[O:29])[C:26]([CH2:30][C:31]2[CH:32]=[N:33][C:34]([CH3:38])=[C:35]([CH3:37])[CH:36]=2)=[CH:25][N:24]=1)([O-])=O>N1C=CC=CC=1>[CH2:6]([N:5]([CH2:4][CH2:3][CH2:2][NH:1][C:23]1[NH:28][C:27](=[O:29])[C:26]([CH2:30][C:31]2[CH:32]=[N:33][C:34]([CH3:38])=[C:35]([CH3:37])[CH:36]=2)=[CH:25][N:24]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: Cc1cc(Cc2cnc(N[N+](=O)[O-])[nH]c2=O)cnc1C
Reactant: NCCCN(Cc1ccccc1)c1ccccn1
Solvent: c1ccncc1
Product: Cc1cc(Cc2cnc(NCCCN(Cc3ccccc3)c3ccccn3)[nH]c2=O)cnc1C

Procedure:
2-[N-(3-aminopropyl)-N-benzylamino]pyridine (1 g) and 2-nitroamino-5-(5,6-dimethylpyrid-3-ylmethyl)pyrimid-4-one (0.94 g) were heated together under reflux in pyridine (5 ml) for 20 hrs. After stripping the resulting solid was recrystallized from ethanol/water to give 2-[3-(N-benzyl-N-pyrid-2-ylamino)propylamino]-5-(5,6-dimethylpyrid-3-ylmethyl)pyrimid-4-one 0.75 H2O, 0.61 g (38%) m.p. 95°-99° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([S:15][CH3:16])[CH2:9][CH2:10][C:11](OC)=[O:12])=[CH:4][CH:3]=1.CO.[NH2:19][OH:20].[C-]#N.[K+]>C1COCC1.O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([S:15][CH3:16])[CH2:9][CH2:10][C:11]([NH:19][OH:20])=[O:12])=[CH:4][CH:3]=1
Reactant: NO
Reactant: COC(=O)CCC(SC)c1ccc(F)cc1
Agent: [C-]#N
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: CSC(CCC(=O)NO)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
To a solution of methyl 4-(4-fluorophenyl)-4-(methylthio)butanoate (30.0 mg, 0.12 mmol) dissolved in 2 mL of THF, methanol, and 50 wt % NH2OH in H2O (2:2:1) was added KCN (4.0 mg, 0.06) and the resulting mixture stirred for 3 days at room temperature. The reaction was quenched by the addition of aqueous 1M HCl (10 mL) and the resulting mixture extracted with ethyl acetate (3×10 mL). The combined organic layers were washed with brine (2×5 mL). The product was isolated by flash column chromatography eluting with 0% to 10% methanol/DCM to give the title compound (27 mg) as a colorless oil.
Reaction SMILES: [C@@H:1]1([N:9]2[C:18]3[N:17]=[CH:16][N:15]=[C:13]([NH2:14])[C:12]=3[N:11]=[CH:10]2)[O:8][C@H:5]([CH2:6][OH:7])[C@@H:3]([OH:4])[CH2:2]1.[Br:19]Br.S(S([O-])=O)([O-])(=O)=O.[Na+].[Na+].[OH-].[Na+]>C([O-])(=O)C.[Na+]>[Br:19][C:10]1[N:9]([C:18]2[N:17]=[CH:16][N:15]=[C:13]([NH2:14])[C:12]=2[N:11]=1)[C@@H:1]1[O:8][C@H:5]([CH2:6][OH:7])[C@@H:3]([OH:4])[CH2:2]1
Reactant: BrBr
Reactant: Nc1ncnc2c1ncn2[C@H]1C[C@H](O)[C@@H](CO)O1
Agent: CC(=O)[O-]
Agent: O=S([O-])S(=O)(=O)[O-]
Agent: [Na+]
Product: Nc1ncnc2c1nc(Br)n2[C@H]1C[C@H](O)[C@@H](CO)O1
Temperature: 30 °C
Reaction time: 6 h
Yield: 64 %

Procedure:
2′-deoxyadenosine (7 gm, 25.9 mmol) was dissolved in sodium acetate buffer (150 mL, 1 M, pH 5.0) by worming it to about 50° C., then was cooled dawn to 30° C., then 3 mL of bromine in 100 mL of the same buffer was added drop wise at RT for 15 min, to the reaction. After 6 hrs the TLC on silica gel (20% MeOH in CH2Cl2) showed that all starting material was converted to a new product. The reaction was discolored by adding some sodium metabisulfite (Na2S2O5) while stirring. The color changed to a white solution, and the pH of the reaction was neutralized by adding 1 M NaOH. The reaction mixture was kept at 4° C. (refrigerator) for 16 hrs. The solid material was then filtered, washed with cold water, then acetone to give a solid yellow powder product (5.75 gm, 64%). The structure of this product was confirmed by H-NMR and ES-MS.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][NH2:9])=[CH:4][CH:3]=1.[C:10]([C:12](=[C:18](OCC)[CH3:19])[C:13]([O:15][CH2:16][CH3:17])=[O:14])#[N:11]>C(O)C>[NH2:11][C:10]1[N:8]([C:5]2[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=2)[N:9]=[C:18]([CH3:19])[C:12]=1[C:13]([O:15][CH2:16][CH3:17])=[O:14]
Reactant: NNc1ccc(F)cc1
Reactant: CCOC(=O)C(C#N)=C(C)OCC
Solvent: CCO
Product: CCOC(=O)c1c(C)nn(-c2ccc(F)cc2)c1N
Yield: 23.3 %

Procedure:
4-Fluorophenylhydrazine (25 g) and ethyl 2-cyano-3-ethoxy-3-methylacrylate (32 g) were stirred in ethanol (130 ml) at a refluxing temperature for 3 h. The solvent was evaporated and diisopropyl ether was added to the residue to allow crystallization. The crystals were recrystallized from a mixed solvent of ethyl acetate-n-hexane to give the title compound (10.7 g), melting point: 129–131° C.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]([CH3:13])=[N:11][N:12]=2)=[CH:4][CH:3]=1.[CH3:14][C:15]1[CH:20]=[CH:19][C:18]([NH:21][C:22]([C:24]2[CH:28]=[CH:27][S:26][CH:25]=2)=[O:23])=[CH:17][C:16]=1B1OC(C)(C)C(C)(C)O1>CC(O)C>[CH3:14][C:15]1[C:16]([C:2]2[CH:7]=[CH:6][C:5]([C:8]3[O:9][C:10]([CH3:13])=[N:11][N:12]=3)=[CH:4][CH:3]=2)=[CH:17][C:18]([NH:21][C:22]([C:24]2[CH:28]=[CH:27][S:26][CH:25]=2)=[O:23])=[CH:19][CH:20]=1
Reactant: Cc1ccc(NC(=O)c2ccsc2)cc1B1OC(C)(C)C(C)(C)O1
Reactant: Cc1nnc(-c2ccc(I)cc2)o1
Solvent: CC(C)O
Product: Cc1nnc(-c2ccc(-c3cc(NC(=O)c4ccsc4)ccc3C)cc2)o1

Procedure:
Example 34 was prepared using 2-(4-iodophenyl)-5-methyl-[1,3,4]oxadiazole (Intermediate 15) and N-[4-methyl-3-(4,4,5,5, -tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]thiophene-3-amide (Intermediate 27) with propan-2-ol as the solvent.
Reaction SMILES: [CH:1]1([S:4]([C:7]2[CH:12]=[CH:11][C:10]([CH:13]([C:21](=[O:25])[CH:22]=[CH:23][CH3:24])[CH2:14][CH:15]3[CH2:20][CH2:19][O:18][CH2:17][CH2:16]3)=[CH:9][CH:8]=2)(=[O:6])=[O:5])[CH2:3][CH2:2]1.C(O)C.O1CCCC1.[N:34]1[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=1[CH:40]=[O:41]>[Cl-].C([N+]1C(C)=C(CCO)SC=1)C1C=CC=CC=1.C(OCC)(=O)C.C(N(CC)CC)C>[CH:1]1([S:4]([C:7]2[CH:8]=[CH:9][C:10]([CH:13]([CH2:14][CH:15]3[CH2:20][CH2:19][O:18][CH2:17][CH2:16]3)[C:21](=[O:25])[CH2:22][CH:23]([CH3:24])[C:40]([C:35]3[CH:36]=[CH:37][CH:38]=[CH:39][N:34]=3)=[O:41])=[CH:11][CH:12]=2)(=[O:6])=[O:5])[CH2:2][CH2:3]1
Reactant: O=Cc1ccccn1
Reactant: CC=CC(=O)C(CC1CCOCC1)c1ccc(S(=O)(=O)C2CC2)cc1
Agent: Cc1c(CCO)sc[n+]1Cc1ccccc1
Agent: [Cl-]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: CCO
Product: CC(CC(=O)C(CC1CCOCC1)c1ccc(S(=O)(=O)C2CC2)cc1)C(=O)c1ccccn1
Temperature: 80 °C
Reaction time: 3 h
Yield: 69.5 %

Procedure:
To a solution of 2-[4-(cyclopropylsulfonyl)phenyl]-1-(tetrahydro-2H-pyran-4-yl)hex-4-en-3-one (200 mg) in a mixed solvent of ethanol (3 mL) and tetrahydrofuran (3 mL) were added pyridine-2-carbaldehyde (71.0 mg), 3-benzyl-5-(2-hydroxyethyl)-4-methyl-1,3-thiazol-3-ium chloride (16.0 mg) and triethylamine (33 μL), and the mixture was stirred under argon atmosphere at 80° C. for 3 hr. After cooling to room temperature, the reaction mixture was diluted with ethyl acetate and washed with water. The ethyl acetate layer was washed with saturated brine, dried (MgSO4) and concentrated. The residue was subjected to silica gel column chromatography, and the title compound (180 mg, yield 69%) was obtained as a pale-yellow oil from a fraction eluted with ethyl acetate-hexane (4:1, volume ratio). MS: 470 (MH+).