Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([NH:11][C@H:12]([C:17]([N:19]([C:24]1[CH:25]=[N:26][CH:27]=[CH:28][CH:29]=1)[CH2:20][C:21]([OH:23])=[O:22])=[O:18])[C@H:13]([CH2:15][CH3:16])[CH3:14])(OCC1C=CC=CC=1)=O.[BrH:30]>C(O)(=O)C>[BrH:30].[NH2:11][C@H:12]([C:17]([N:19]([C:24]1[CH:25]=[N:26][CH:27]=[CH:28][CH:29]=1)[CH2:20][C:21]([OH:23])=[O:22])=[O:18])[C@H:13]([CH2:15][CH3:16])[CH3:14]
Reactant: CC[C@H](C)[C@H](NC(=O)OCc1ccccc1)C(=O)N(CC(=O)O)c1cccnc1
Agent: Br
Solvent: CC(=O)O
Product: CC[C@H](C)[C@H](N)C(=O)N(CC(=O)O)c1cccnc1

Procedure:
In a manner described in example 5B, N-carbobenzyloxy-L-isoleucyl-N-(3-pyridyl)-glycine was treated with anhydrous hydrogen bromide in acetic acid to yield L-isoleucyl-N-(3-pyridyl) glycine hydrobromide.
Reaction SMILES: N(OCCCC)=O.[Br:8][C:9]1[N:10]([CH3:29])[N:11]=[C:12]2[C:17](=[O:18])[NH:16][C:15]([C:19]3[C:20]([O:26][CH2:27][CH3:28])=[N:21][CH:22]=[C:23](N)[CH:24]=3)=[N:14][C:13]=12.[I:30]CI>>[Br:8][C:9]1[N:10]([CH3:29])[N:11]=[C:12]2[C:17](=[O:18])[NH:16][C:15]([C:19]3[C:20]([O:26][CH2:27][CH3:28])=[N:21][CH:22]=[C:23]([I:30])[CH:24]=3)=[N:14][C:13]=12
Reactant: CCOc1ncc(N)cc1-c1nc2c(Br)n(C)nc2c(=O)[nH]1
Reactant: ICI
Agent: CCCCON=O
Product: CCOc1ncc(I)cc1-c1nc2c(Br)n(C)nc2c(=O)[nH]1
Temperature: 45 °C
Yield: 23 %

Procedure:
Butyl nitrite (282 mg, 2.74 mmol) was added dropwise to a stirred suspension of the title compound of Example 54 (200 mg, 0.55 mmol) in diiodomethane (2 mL) at room temperature. After 1 h the reaction was warmed for 2 h at 40-50° C. The mixture was cooled and purified directly by flash column chromatography (gradient elution from dichloromethane to 98% dichloromethane/5% methanol) to give the product as a brown solid (60 mg, 23%).
Reaction SMILES: [OH-].[Na+].[CH3:3][C:4]1[CH:5]=[C:6]([CH2:11][C:12]([NH:14][CH:15]([CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:16]([O:18]C)=[O:17])=[O:13])[CH:7]=[C:8]([CH3:10])[CH:9]=1>>[CH3:3][C:4]1[CH:5]=[C:6]([CH2:11][C:12]([NH:14][CH:15]([CH2:20][C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)[C:16]([OH:18])=[O:17])=[O:13])[CH:7]=[C:8]([CH3:10])[CH:9]=1
Reactant: COC(=O)C(Cc1ccccc1)NC(=O)Cc1cc(C)cc(C)c1
Agent: [Na+]
Agent: [OH-]
Product: Cc1cc(C)cc(CC(=O)NC(Cc2ccccc2)C(=O)O)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of NaOH 1N (7.8 ml, 7.83 mmol) was added to a methanolic solution (40 ml) of (S) methyl 2-[2-(3,5-dimethylphenyl)acetamido]-3-phenyl-propanoate (635 mg, 1.95 mmol) and the reaction mixture was stirred for 1 h at rt, then concentrated under reduced pressure and residue diluted with H2O (40 ml) and HCl 1N to obtain a pH value equal to 2. The crude organic product was extracted with ethyl acetate (3×40 ml) and the organic phase was dried with anhydrous Na2SO4. The solvent was removed under reduced pressure to afford (S) 2-[2-(3,5-dimethylphenyl)acetamido]-3-phenyl-propionic acid as white solid with nearly quantitative yield.
Reaction SMILES: [C:1]([CH2:3][CH2:4][C:5]([OH:13])([P:9]([OH:12])([OH:11])=[O:10])[C:6]([OH:8])=[O:7])#[N:2].[H][H]>N.[Rh]>[NH2:2][CH2:1][CH2:3][CH2:4][C:5]([OH:13])([P:9]([OH:12])([OH:11])=[O:10])[C:6]([OH:8])=[O:7]
Reactant: N#CCCC(O)(C(=O)O)P(=O)(O)O
Reactant: [H][H]
Agent: [Rh]
Agent: N
Product: NCCCC(O)(C(=O)O)P(=O)(O)O

Procedure:
The hydrogenation of 4-cyano-2-hydroxy-2-phosphonobutanoic acid is carried out using the hydrogenation technique of Freifelder (J. Am. Chem. Soc., 8, 2386 (1960)). The cyano compound (2.09 g; 0.01 mole) is placed in 20 ml of 10% methanolic ammonia. Rhodium on alumina (5%) catalyst (0.5 g) is added, and the mixture is hydrogenated at 40 PSI on a Parr apparatus for several hours (until uptake of hydrogen is complete). The catalyst is filtered off, and the filtrate is evaporated dry. The residue treated with cation exchange resin in H+ form to convert the material to acid form. The solution containing it is evaporated to dryness under vacuum. The product is purified by dissolving the residue in water, adding ethanol to give a precipitate, and collecting the solids by filtration. Further purification is accomplished by again recrystallizing from water/ethanol.
Reaction SMILES: [CH3:1][N:2]([CH3:7])[CH2:3][CH:4]([NH2:6])[CH3:5].C(=O)([O-])[O-].[K+].[K+].F[C:15]1[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[CH:17][CH:16]=1>CN(C=O)C>[CH3:1][N:2]([CH3:7])[CH2:3][CH:4]([NH:6][C:15]1[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[CH:17][CH:16]=1)[CH3:5]
Reactant: CC(N)CN(C)C
Reactant: O=[N+]([O-])c1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(CN(C)C)Nc1ccc([N+](=O)[O-])cc1
Temperature: 110 °C
Reaction time: 8 h
Yield: 81.4 %

Procedure:
A solution of N1,N1-Dimethyl-propane-1,2-diamine (10 mL, 77.4 mmol) in DMF (40 mL) at room temperature was treated with potassium carbonate (15.26 g, 1.5 equiv.) and 1-fluoro-4-nitrobenzene (8.2 mL, 1 equiv.). The reaction mixture was stirred at 110° C. overnight. The reaction mixture was cooled to room temperature, filtered to remove remaining solid potassium carbonate and diluted with CH2Cl2 (500 mL). The reaction mixture was extracted with H2O (3×500 mL) and dried over anhydrous MgSO4. Following filtration and concentration in vacuo the gelatinous red residue was purified by flash silica gel chromatography (CHCl3 to 1:4 MeOH:CHCl3 gradient eluant) to give N1,N1-Dimethyl-N2-(4-nitro-phenyl)-propane-1,2-diamine as a light brown oil (81.4%).
Reaction SMILES: Br[CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][C:6]=1[O:14][CH3:15].[NH:16]1[CH2:20][CH2:19][CH2:18][C@H:17]1[CH2:21][OH:22]>ClCCl.CO>[CH3:15][O:14][C:6]1[CH:7]=[C:8]([N+:11]([O-:13])=[O:12])[CH:9]=[CH:10][C:5]=1[O:4][CH2:3][CH2:2][N:16]1[CH2:20][CH2:19][CH2:18][C@H:17]1[CH2:21][OH:22]
Reactant: OC[C@@H]1CCCN1
Reactant: COc1cc([N+](=O)[O-])ccc1OCCBr
Solvent: CO
Solvent: ClCCl
Product: COc1cc([N+](=O)[O-])ccc1OCCN1CCC[C@H]1CO

Procedure:
Prepared analogously to Example 1.1.c. from 1-(2-bromoethoxy)-2-methoxy-4-nitrobenzene and (S)-1-pyrrolidin-2-ylmethanol. Yield: 0.2 g (25% of theory); C14H20N2O5 (M=296.32); calc.: molecular ion peak (M+H)+: 297; found: molecular ion peak (M+H)+: 297; Rf value: 0.55 (silica gel, dichloromethane/methanol (9:1)).
Reaction SMILES: [CH3:1][N:2]([CH3:29])[CH2:3][CH2:4][N:5]1[C:26]([CH2:27][CH3:28])=[C:8]2[N:9]=[C:10]([C:14]3[C:15]([O:23][CH2:24][CH3:25])=[N:16][CH:17]=[C:18]([CH:22]=3)[C:19](O)=[O:20])[NH:11][C:12](=[O:13])[C:7]2=[N:6]1.O.ON1C2C=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C.Cl.CN(C)CCCN=C=NCC.Cl.[CH3:63][NH:64][O:65][CH3:66].C(=O)([O-])O.[Na+]>ClCCl>[CH3:29][N:2]([CH3:1])[CH2:3][CH2:4][N:5]1[C:26]([CH2:27][CH3:28])=[C:8]2[N:9]=[C:10]([C:14]3[C:15]([O:23][CH2:24][CH3:25])=[N:16][CH:17]=[C:18]([CH:22]=3)[C:19]([N:64]([O:65][CH3:66])[CH3:63])=[O:20])[NH:11][C:12](=[O:13])[C:7]2=[N:6]1
Reactant: CNOC
Reactant: CCOc1ncc(C(=O)O)cc1-c1nc2c(CC)n(CCN(C)C)nc2c(=O)[nH]1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: O=C([O-])O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: ClCCl
Product: CCOc1ncc(C(=O)N(C)OC)cc1-c1nc2c(CC)n(CCN(C)C)nc2c(=O)[nH]1
Yield: 72.2 %

Procedure:
The title compound of Example 86 (710 mg, 1.8 mmol) was dissolved in dichloromethane (150 mL), 1-hydroxybenzotriazole hydrate (263 mg, 1.95 mmol), N,N-diisopropylethylamine (1.26 mL, 7 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (374 mg, 1.95 mmol) were added followed by N,O-dimethylhydroxylamine hydrochloride (173 mg, 1.8 mmol), and the resultant mixture stirred at room temperature for 14 h. Saturated aq. sodium hydrogen carbonate (80 mL) and dichloromethane (50 mL) were added, the organic phase removed and the aqueous phase extracted with dichloromethane (2×50 mL). The combined organic phases were dried over MgSO4, concentrated and purified by column chromatography (dichloromethane to 10% methanol in dichloromethane as eluant) to afford the title compound as a yellow oil (590 mg, 1.3 mmol).
Reaction SMILES: [C:1]([O:5][C:6]([CH:8]1[CH2:13][CH2:12][CH:11]([C:14](=O)[CH2:15][C:16]([O:18]CC)=O)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH2:22][C:23]1[CH:27]=[CH:26][NH:25][N:24]=1>ClCCl>[C:1]([O:5][C:6]([CH:8]1[CH2:9][CH2:10][CH:11]([C:14]2[CH:15]=[C:16]([OH:18])[N:24]3[N:25]=[CH:26][CH:27]=[C:23]3[N:22]=2)[CH2:12][CH2:13]1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CCOC(=O)CC(=O)C1CCC(C(=O)OC(C)(C)C)CC1
Reactant: Nc1cc[nH]n1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)C1CCC(c2cc(O)n3nccc3n2)CC1
Temperature: 100 °C

Procedure:
4-(2-Ethoxycarbonyl-acetyl)-cyclohexanecarboxylic acid t-butyl ester (8.5 g) and 3-amino-1H-pyrazole (Int-7a, 26.5 mmol, 2.2 g) were mixed and heated neat at 100° C. for 16 hours. The resulting residue was dissolved in dichloromethane (100 mL) and concentrated in vacuo to remove water formed during cyclization. This solid was taken forward without further purification. LC-MS: 318 [M+H].
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C@H:9]2[CH2:13][CH2:12][CH2:11][N:10]2[C:14]2[CH:19]=[CH:18][N:17]3[N:20]=[CH:21][C:22]([C:23]([O:25][CH2:26][CH3:27])=[O:24])=[C:16]3[N:15]=2)[CH:5]=[C:6]([OH:8])[CH:7]=1.Br[CH2:29][CH2:30][O:31][CH3:32].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[F:1][C:2]1[CH:3]=[C:4]([C@H:9]2[CH2:13][CH2:12][CH2:11][N:10]2[C:14]2[CH:19]=[CH:18][N:17]3[N:20]=[CH:21][C:22]([C:23]([O:25][CH2:26][CH3:27])=[O:24])=[C:16]3[N:15]=2)[CH:5]=[C:6]([O:8][CH2:29][CH2:30][O:31][CH3:32])[CH:7]=1
Reactant: CCOC(=O)c1cnn2ccc(N3CCC[C@@H]3c3cc(O)cc(F)c3)nc12
Reactant: COCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1cnn2ccc(N3CCC[C@@H]3c3cc(F)cc(OCCOC)c3)nc12
Temperature: 25 °C
Reaction time: 15 h
Yield: 90.9 %

Procedure:
(R)-ethyl 5-(2-(3-fluoro-5-hydroxyphenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidine-3-carboxylate (Example 76 Step B, 174 mg, 0.470 mmol), 1-bromo-2-methoxyethane (196 mg, 1.41 mmol), and K2CO3 (325 mg, 2.35 mmol) were suspended in DMF (5 mL) and stirred at ambient temperature for 15 hours. The crude reaction mixture was purified by reverse phase HPLC (0-60% acetonitrile/water) to provide yield the title compound (183 mg, 91% yield). MS (apci) m/z=429.0 (M+H).
Reaction SMILES: C(OC(=O)NC1C=CC(N2C=[C:20]([S:22][CH3:23])[N:19]=N2)=C(F)C=1)C1C=CC=CC=1.[Li+].C[Si]([N-][Si](C)(C)C)(C)C.[F:36][C:37]1[CH:38]=[C:39]([N:49]2[CH2:53][C@H:52]([CH2:54][OH:55])[O:51][C:50]2=[O:56])[CH:40]=[CH:41][C:42]=1[N:43]1[CH:47]=NC(C)=[N:44]1>>[F:36][C:37]1[CH:38]=[C:39]([N:49]2[CH2:53][C@H:52]([CH2:54][OH:55])[O:51][C:50]2=[O:56])[CH:40]=[CH:41][C:42]=1[N:43]1[CH:47]=[C:20]([S:22][CH3:23])[N:19]=[N:44]1
Reactant: CSc1cn(-c2ccc(NC(=O)OCc3ccccc3)cc2F)nn1
Reactant: Cc1ncn(-c2ccc(N3C[C@H](CO)OC3=O)cc2F)n1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Product: CSc1cn(-c2ccc(N3C[C@H](CO)OC3=O)cc2F)nn1

Procedure:
[3-Fluoro-4-[4-(methylthio)-1H-1,2,3-triazol-1-yl]phenyl] carbamic acid benzyl ester (Intermediate 49) (27.4 g, 76.5 mmol), LiHMDS (1M in THF, 91 ml) and R-(−)-glycidyl butyrate (11.5 g, 79.7 mmol) were reacted following the procedure for Intermediate 25 to give the crude title compound (19.4 g), which was used without further purification.
Reaction SMILES: [CH2:1]([C:5]1[NH:9][C:8]2[CH:10]=[CH:11][CH:12]=[CH:13][C:7]=2[N:6]=1)[CH2:2][CH2:3][CH3:4].Br[CH2:15][C:16]1[CH:23]=[CH:22][C:19]([C:20]#[N:21])=[CH:18][CH:17]=1>>[CH2:1]([C:5]1[N:6]([CH2:15][C:16]2[CH:23]=[CH:22][C:19]([C:20]#[N:21])=[CH:18][CH:17]=2)[C:7]2[CH:13]=[CH:12][CH:11]=[CH:10][C:8]=2[N:9]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nc2ccccc2[nH]1
Reactant: N#Cc1ccc(CBr)cc1
Product: CCCCc1nc2ccccc2n1Cc1ccc(C#N)cc1
Yield: 117 %

Procedure:
Using the procedure of Step B of Example 1, 3.5 g of 2-butyl -1H-benzimidazol [POOL et al., Am. Soc., Vol. 59, p. 178 (1937)] and 4.3 g of 4-bromomethyl benzonitrile were reacted to obtain 6.8 g of the desired product melting at 130° C. which was dissolved in methylene chloride, treated with activated charcoal, filtered and evaporated to dryness to obtain 6 g of product melting at 130° C. which was crystallized from isopropyl ether to obtain 4.7 g of the expected product melting at 148° C. The analytical sample was obtained by two successive crystallizations of 1.2 g of the product from isopropyl ether to obtain 700 mg of purified product melting at 150° C.
Reaction SMILES: [CH:1]1([C:6]2[CH:11]=[CH:10][CH:9]=[C:8]([CH3:12])[C:7]=2O)[CH2:5][CH2:4][CH2:3][CH2:2]1.[NH3:14].[O-2].[Pr+3].[O-2].[O-2].[Pr+3]>[Pd]>[CH:1]1([CH:6]2[CH2:11][CH2:10][CH2:9][CH:8]([CH3:12])[CH:7]2[NH2:14])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: Cc1cccc(C2CCCC2)c1O
Reactant: N
Agent: [Pd]
Agent: [O-2]
Agent: [Pr+3]
Product: CC1CCCC(C2CCCC2)C1N
Yield: 97 %

Procedure:
In a 5 l stirred autoclave, a mixture of 485 g of 2-cyclopentyl-6-methylphenol and 551 g of ammonia is subjected to reductive amination in the presence of a powder catalyst containing 10% by weight of palladium and 5% by weight of praseodymium oxide on alumina at 230° C. and under a hydrogen pressure of 300 bar until the pressure remains constant. After the catalyst has been separated off, 484 g (95% yield) of crude 2-cyclopentyl-6-methylcyclohexylamine are obtained, and can be used without further purification in the next stage.
Reaction SMILES: [CH:1]1([CH:4]([O:24][C:25]2[CH:30]=[CH:29][C:28]([F:31])=[CH:27][C:26]=2[N+:32]([O-])=O)[CH:5]([N:9]([CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:6]([OH:8])=[O:7])[CH2:3][CH2:2]1>CO.[Ni]>[NH2:32][C:26]1[CH:27]=[C:28]([F:31])[CH:29]=[CH:30][C:25]=1[O:24][CH:4]([CH:1]1[CH2:3][CH2:2]1)[CH:5]([N:9]([CH2:10][C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1)[CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:6]([OH:8])=[O:7]
Reactant: O=C(O)C(C(Oc1ccc(F)cc1[N+](=O)[O-])C1CC1)N(Cc1ccccc1)Cc1ccccc1
Agent: [Ni]
Solvent: CO
Product: Nc1cc(F)ccc1OC(C1CC1)C(C(=O)O)N(Cc1ccccc1)Cc1ccccc1

Procedure:
1.47 g (3.17 mmol) racemic (2R,3S and 2S,3R)-3-Cyclopropyl-2-dibenzylamino-3-(4-fluoro-2-nitro-phenoxy)-propionic acid in 50 ml methanol were hydrogenated with 0.37 g Raney-Nickel. Filtration and removal of the solvent by distillation yielded 1.22 g (89%) racemic (2R,3S and 2S,3R)-3-(2-amino-4-fluoro-phenoxy)-3-cyclopropyl-2-dibenzylamino-propionic acid as light grey foam, MS m/e (%): 435.1 (M+H+, 100).
Reaction SMILES: C1(C2C=C(C3N4N=CC(C5C=C(C=CC=5)C(O)=O)=CC4=NC=3)C=CN=2)C=CC=CC=1.C([O:33][C:34](=[O:59])[C:35]1[CH:40]=[CH:39][CH:38]=[C:37]([C:41]2[CH:46]=[N:45][N:44]3[C:47]([C:50]4[CH:55]=[CH:54][C:53]([OH:56])=[C:52]([O:57][CH3:58])[CH:51]=4)=[CH:48][N:49]=[C:43]3[CH:42]=2)[CH:36]=1)C>>[OH:56][C:53]1[CH:54]=[CH:55][C:50]([C:47]2[N:44]3[N:45]=[CH:46][C:41]([C:37]4[CH:36]=[C:35]([CH:40]=[CH:39][CH:38]=4)[C:34]([OH:59])=[O:33])=[CH:42][C:43]3=[N:49][CH:48]=2)=[CH:51][C:52]=1[O:57][CH3:58]
Reactant: CCOC(=O)c1cccc(-c2cnn3c(-c4ccc(O)c(OC)c4)cnc3c2)c1
Agent: O=C(O)c1cccc(-c2cnn3c(-c4ccnc(-c5ccccc5)c4)cnc3c2)c1
Product: COc1cc(-c2cnc3cc(-c4cccc(C(=O)O)c4)cnn23)ccc1O

Procedure:
This example is prepared by an analogous method to 3-[3-(2-Phenyl-pyridin-4-yl)imidazo[1,2-b]pyridazin-7-yl]benzoic acid (Ex. 52) by replacing 3-[3-(2-Phenyl-pyridin-4-yl)-imidazo[1,2-b]pyridazin-7-yl]-benzoic acid ethyl ester (Ex 42) with 3-[3-(4-Hydroxy-3-methoxy-phenyl)-imidazo[1,2-b]pyridazin-7-yl]-benzoic acid ethyl ester (Ex. 40).
Reaction SMILES: [F:1][C:2]1[CH:29]=[CH:28][C:5]([CH2:6][C:7]2[N:11]([CH2:12][C:13]([N:15]3[CH2:20][CH2:19][CH:18]([NH2:21])[CH2:17][CH2:16]3)=[O:14])[N:10]=[C:9]([C:22]3[CH:27]=[CH:26][N:25]=[CH:24][CH:23]=3)[CH:8]=2)=[CH:4][CH:3]=1.[CH:30]([N:33]=[C:34]=[O:35])([CH3:32])[CH3:31]>C1COCC1>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][C:7]2[N:11]([CH2:12][C:13]([N:15]3[CH2:16][CH2:17][CH:18]([NH:21][C:34]([NH:33][CH:30]([CH3:32])[CH3:31])=[O:35])[CH2:19][CH2:20]3)=[O:14])[N:10]=[C:9]([C:22]3[CH:23]=[CH:24][N:25]=[CH:26][CH:27]=3)[CH:8]=2)=[CH:28][CH:29]=1
Reactant: NC1CCN(C(=O)Cn2nc(-c3ccncc3)cc2Cc2ccc(F)cc2)CC1
Reactant: CC(C)N=C=O
Solvent: C1CCOC1
Product: CC(C)NC(=O)NC1CCN(C(=O)Cn2nc(-c3ccncc3)cc2Cc2ccc(F)cc2)CC1
Temperature: 50 °C
Reaction time: 16 h

Procedure:
To a solution of 1-{[5-(4-fluorobenzyl)-3-pyridin-4-yl-1H-pyrazol-1-yl]acetyl}piperidin-4-amine (635 mg, 1.61 mmol) in THF (10 mL) at room temperature was added isopropyl isocyanate (164 mg, 1.93 mmol) and the solution stirred 50° C. for 16 h. The volatiles were removed under vacuum and the residue was triturated with water to afford a white solid, 627 mg, 82%.1H NMR (400 MHz, DMSO-d6) δ ppm 1.02 (d, J=6.55 Hz, 6 H), 1.08-1.21 (m, J=7.18, 7.18 Hz, 1 H), 1.23-1.39 (m, 1 H), 1.65-1.90 (m, 2 H), 2.81 (t, J=10.95 Hz, 1 H), 3.05-3.25 (m, J=11.33, 11.33 Hz, 1 H), 3.50-3.72 (m, 2 H), 3.80 (d, J=13.60 Hz, 1 H), 3.95 (s, 2 H), 4.07 (d, J=13.35 Hz, 1 H), 5.03-5.33 (m, 2 H), 5.58 (d, J=7.81 Hz, 1 H), 5.75 (d, J=7.81 Hz, 1 H), 6.56 (s, 1 H), 7.02-7.26 (m, 2 H), 7.22-7.40 (m, 2 H), 7.64-7.79 (m, 2 H), 8.56 (d, J=6.04 Hz, 2 H); m/z (APCI+) for C26H31FN6O2 479.6 (M+H)+.
Reaction SMILES: [O:1]1[CH2:10][CH:2]1[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[CH2:11]([NH2:15])[CH:12]([CH3:14])[CH3:13]>O>[C:4]1([CH2:3][CH:2]([OH:1])[CH2:10][NH:15][CH2:11][CH:12]([CH3:14])[CH3:13])[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: c1ccc(CC2CO2)cc1
Reactant: CC(C)CN
Solvent: O
Product: CC(C)CNCC(O)Cc1ccccc1
Temperature: 110 °C
Reaction time: 8 h
Yield: 42.1 %

Procedure:
2,3-Epoxypropyl benzene (10 g, 74.5 mmol) and isobutylamine (5.4 g, 74.5 mmol) were mixed then treated with water (2 mL). The mixture was stirred overnight at 110° C., then distilled to yield N-(3-phenyl-2-hydroxypropyl)N-isobutylamine (6.5 g): bp 115-117° C. (1 mmHg).
Reaction SMILES: Br[C:2]1[C:3]2[C:8]([C:9]([C:16]3[CH:21]=[CH:20][C:19]([CH:22]=[CH:23][C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)=[CH:18][CH:17]=3)=[C:10]3[C:15]=1[CH:14]=[CH:13][CH:12]=[CH:11]3)=[CH:7][CH:6]=[CH:5][CH:4]=2.[C:30]1([C:36]([C:47]2[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=2)=[CH:37][C:38]2[CH:43]=[CH:42][C:41](B(O)O)=[CH:40][CH:39]=2)[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.C(=O)([O-])[O-].[Na+].[Na+]>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.C1(C)C=CC=CC=1>[C:30]1([C:36]([C:47]2[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=2)=[CH:37][C:38]2[CH:43]=[CH:42][C:41]([C:2]3[C:3]4[C:8]([C:9]([C:16]5[CH:21]=[CH:20][C:19]([CH:22]=[CH:23][C:24]6[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=6)=[CH:18][CH:17]=5)=[C:10]5[C:15]=3[CH:14]=[CH:13][CH:12]=[CH:11]5)=[CH:7][CH:6]=[CH:5][CH:4]=4)=[CH:40][CH:39]=2)[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: OB(O)c1ccc(C=C(c2ccccc2)c2ccccc2)cc1
Reactant: Brc1c2ccccc2c(-c2ccc(C=Cc3ccccc3)cc2)c2ccccc12
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: C(=Cc1ccc(-c2c3ccccc3c(-c3ccc(C=C(c4ccccc4)c4ccccc4)cc3)c3ccccc23)cc1)c1ccccc1
Yield: 87.6 %

Procedure:
Under an atmosphere of argon, 9-bromo-10-(4-(2-phenylvinyl)phenyl)anthracene (3.1 g, 7.1 mmole), 4-(2,2-diphenylvinyl)phenylboronic acid (2.4 g, 8.0 mmole, 1.1 eq) and tetrakis(triphenylphosphine)palladium(0) (0.16 g, 0.14 mmole, 2% Pd) were suspended into toluene (25 ml). To the obtained suspension, a 2 M aqueous solution of sodium carbonate (2.5 g, 24 mmole, 3 eq/12 ml) was added and the resultant mixture was heated under refluxing for 10 hours. The reaction mixture was filtered and washed with water and methanol and a yellow solid was obtained. The obtained solid was suspended in boiling toluene (50 ml), cooled while being left standing, filtered and washed with toluene and a light yellow solid (3.8 g, 88%) was obtained.
Reaction SMILES: [CH3:1][C:2]1[C:7]([C:8]([OH:10])=O)=[CH:6][CH:5]=[CH:4][N:3]=1.ClC(OCC)=O.[NH2:17][CH2:18][CH:19]1[CH2:24][CH2:23][N:22]([CH2:25][C@@H:26]2[O:31][C:30]3[CH:32]=[C:33]([Cl:36])[CH:34]=[CH:35][C:29]=3[O:28][CH2:27]2)[CH2:21][CH2:20]1>ClCCl.C(N(CC)CC)C.CO>[Cl:36][C:33]1[CH:34]=[CH:35][C:29]2[O:28][CH2:27][C@H:26]([CH2:25][N:22]3[CH2:21][CH2:20][CH:19]([CH2:18][NH:17][C:8]([C:7]4[C:2]([CH3:1])=[N:3][CH:4]=[CH:5][CH:6]=4)=[O:10])[CH2:24][CH2:23]3)[O:31][C:30]=2[CH:32]=1
Reactant: Cc1ncccc1C(=O)O
Reactant: NCC1CCN(C[C@H]2COc3ccc(Cl)cc3O2)CC1
Agent: CCOC(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CO
Product: Cc1ncccc1C(=O)NCC1CCN(C[C@H]2COc3ccc(Cl)cc3O2)CC1
Temperature: 25 °C
Reaction time: 24 h
Yield: 23.7 %

Procedure:
Triethylamine (0.47 ml) was added to a suspension of 2-methylpyridine-3-carboxylic acid (0.46 g) in dichloromethane and the mixture cooled in ice water. Ethyl chloroformate (0.33 ml) was added with stirring and the mixture allowed to warm to ambient temperature during 18 hours. (S)-4-(Aminomethyl)-1-(7-chloro-1,4-benzodioxan-2-ylmethyl)piperidine (1.0 g) was added and stirring continued for 24 hours. The solvent was evaporated and the residue triturated with water, collected by filtration, and purified by flash chromatography over silica eluting with a 3:1, then a 2:1, then a 1:1 mixture of ethyl acetate and methanol. Appropriate fractions were combined and the solvent removed in vacuo to give still impure product. Repeat flash chromatography over silica eluting with a 10:1 mixture of dichloromethane and methanol, then an 18:1:1 mixture of dichloromethane, methanol and triethylamine, followed by removal of solvent in vacuo from the appropriate fractions, gave (S)-N-{[1-(7-chloro-1,4-benzodioxan-2-ylmethyl)-4-piperidyl]methyl}-2-methylpyridine-3-carboxamide (330 mg) as a colourless solid m.p. 133-136° C. [α]D -46.6° (c=0.837, methanol).
Reaction SMILES: [CH2:1]([O:3][C:4]1[C:8]([CH2:9][CH2:10][C:11]([O:13]CC)=[O:12])=[CH:7][N:6]([CH2:16][C:17]2[CH:22]=[CH:21][N:20]=[C:19]([O:23][CH2:24][C:25]3[N:26]=[C:27]([C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=4)[O:28][C:29]=3[CH3:30])[CH:18]=2)[N:5]=1)[CH3:2].[OH-].[Na+].O1CCCC1.Cl>C(O)C>[CH2:1]([O:3][C:4]1[C:8]([CH2:9][CH2:10][C:11]([OH:13])=[O:12])=[CH:7][N:6]([CH2:16][C:17]2[CH:22]=[CH:21][N:20]=[C:19]([O:23][CH2:24][C:25]3[N:26]=[C:27]([C:31]4[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=4)[O:28][C:29]=3[CH3:30])[CH:18]=2)[N:5]=1)[CH3:2]
Reactant: CCOC(=O)CCc1cn(Cc2ccnc(OCc3nc(-c4ccccc4)oc3C)c2)nc1OCC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: CCOc1nn(Cc2ccnc(OCc3nc(-c4ccccc4)oc3C)c2)cc1CCC(=O)O
Temperature: 25 °C
Reaction time: 3 h
Yield: 82.3 %

Procedure:
After a mixture of ethyl 3-[3-ethoxy-1-[2-(5-methyl-2-phenyl-4-oxazolylmethoxy)-4-pyridylmethyl]-1H-pyrazol-4-yl]propionate (638 mg), 1N aqueous sodium hydroxide solution (3 ml), tetrahydrofuran (6 ml) and ethanol (6 ml) was stirred at room temperature for 3 hours, 1N hydrochloric acid (3 ml) was added to the mixture, and then the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated aqueous sodium chloride solution, dried (MgSO4) and concentrated. The resulting colorless crystals were collected by filtration to obtain 3-[3-ethoxy-1-[2-(5-methyl-2-phenyl-4-oxazolylmethoxy)-4-pyridylmethyl]-1H-pyrazol-4-yl]propionic acid (495 mg, yield: 82%). This was recrystallized from ethanol-hexane. Melting point: 114–115° C.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][N:3]=1.C([Sn](CCCC)(CCCC)[C:14]1[CH:19]=[N:18][CH:17]=[CH:16][N:15]=1)CCC>>[Br:8][C:5]1[CH:6]=[CH:7][C:2]([C:14]2[CH:19]=[N:18][CH:17]=[CH:16][N:15]=2)=[N:3][CH:4]=1
Reactant: Brc1ccc(Br)nc1
Reactant: CCCC[Sn](CCCC)(CCCC)c1cnccn1
Product: Brc1ccc(-c2cnccn2)nc1
Yield: 60 %

Procedure:
Obtained (0.310 g, yield 60%) following the procedure described in Intermediate 37, starting with 2,5-dibromopyridine (2.11 mmol, 0.5 g), 2-(tributylstannyl)pyrazine (2.32 mmol, 0.857 g).