Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1](=O)[CH2:2][CH2:3][C:4]#[CH:5].[NH2:7][C:8]([CH3:19])([CH3:18])[CH2:9][NH:10][C:11](=[O:17])[O:12][C:13]([CH3:16])([CH3:15])[CH3:14].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)([O-])O.[Na+]>C(Cl)Cl.C(OCC)(=O)C.C(O)(=O)C>[CH3:19][C:8]([NH:7][CH2:1][CH2:2][CH2:3][C:4]#[CH:5])([CH3:18])[CH2:9][NH:10][C:11](=[O:17])[O:12][C:13]([CH3:15])([CH3:14])[CH3:16]
Reactant: CC(C)(N)CNC(=O)OC(C)(C)C
Reactant: C#CCCC=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: C#CCCCNC(C)(C)CNC(=O)OC(C)(C)C
Reaction time: 2 h

Procedure:
To a solution of 4-pentynal (631 mg) synthesized according to the method described in U.S. Pat. No. 4,877,779 A1 and tert-butyl (2-amino-2-methylpropyl)carbamate (328 mg) in methylene chloride (10 mL), sodium triacetoxyborohydride (921 mg) and acetic acid (99 μL) were added at room temperature, and the mixture was stirred at the same temperature for 2 hours. To the reaction mixture, ethyl acetate and saturated aqueous sodium hydrogencarbonate were added. The organic layer was separated, washed with saturated aqueous sodium chloride, and then dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent, 100 to 80% ethyl acetate in methanol) to obtain tert-butyl (2-methyl-2-((4-pentyn-1-yl)amino)propyl)carbamate (G7, 172 mg).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C@:15]3([CH2:19][O:18][C:17]([NH2:20])=[N:16]3)[C:14]3[C:9](=[CH:10][CH:11]=[C:12](I)[CH:13]=3)[O:8][C:5]2=[N:6][CH:7]=1.[N:22]1[CH:27]=[C:26](B(O)O)[CH:25]=[N:24][CH:23]=1.C1COCC1.C(=O)([O-])[O-].[K+].[K+]>O>[Br:1][C:2]1[CH:3]=[C:4]2[C@:15]3([CH2:19][O:18][C:17]([NH2:20])=[N:16]3)[C:14]3[C:9](=[CH:10][CH:11]=[C:12]([C:26]4[CH:27]=[N:22][CH:23]=[N:24][CH:25]=4)[CH:13]=3)[O:8][C:5]2=[N:6][CH:7]=1
Reactant: OB(O)c1cncnc1
Reactant: NC1=N[C@@]2(CO1)c1cc(I)ccc1Oc1ncc(Br)cc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: NC1=N[C@@]2(CO1)c1cc(-c3cncnc3)ccc1Oc1ncc(Br)cc12
Temperature: 110 °C

Procedure:
A 10-20 mL microwave vial was charged with (S)-3-bromo-7-iodo-5′H-spiro[chromeno[2,3-b]pyridine-5,4′-oxazol]-2′-amine (503 mg, 1.098 mmol), pyrimidin-5-ylboronic acid (143 mg, 1.153 mmol), pd(ph3p)4 (127 mg, 0.110 mmol). The vial was flushed with Ar(g), then THF (5489 μL, 1.098 mmol) and potassium carbonate (1.5 M) (1464 μL, 2.195 mmol) (aq. solution) were added in sequence. The vial was sealed and heated at 110° C. for 2 hours. The mixture was diluted with water and extracted with 10% i-PrOH/EtOAc (3×). The combined organic extracts were dried over sodium sulfate, filtered, and evaporated. The residue was purified by chromatography on a 100-g SNAP column, eluting with 0-100% of a 90:10:1 mixture of DCM/MeOH/NH4OH in DCM to provide (S)-3-bromo-7-(pyrimidin-5-yl)-5′H-spiro[chromeno[2,3-b]pyridine-5,4′-oxazol]-2′-amine as an off-white solid.
Reaction SMILES: [OH:1][C:2]([C:30]1[CH:31]=[C:32]([C:36]2[CH:41]=[CH:40][C:39]([C:42]#[N:43])=[CH:38][CH:37]=2)[CH:33]=[CH:34][CH:35]=1)([C:6]1[N:7]=[CH:8][N:9](C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[CH:10]=1)[CH:3]([CH3:5])[CH3:4].Cl.N1C=CC=CC=1>>[OH:1][C:2]([C:30]1[CH:31]=[C:32]([C:36]2[CH:37]=[CH:38][C:39]([C:42]#[N:43])=[CH:40][CH:41]=2)[CH:33]=[CH:34][CH:35]=1)([C:6]1[N:7]=[CH:8][NH:9][CH:10]=1)[CH:3]([CH3:4])[CH3:5]
Reactant: CC(C)C(O)(c1cccc(-c2ccc(C#N)cc2)c1)c1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Agent: Cl
Solvent: c1ccncc1
Product: CC(C)C(O)(c1cccc(-c2ccc(C#N)cc2)c1)c1c[nH]cn1
Yield: 78 %

Procedure:
By the reaction in the same manner as in Example 4-(iii) using 3′-[1-hydroxy-2-methyl-1-(1-trityl-1H-imidazol-4-yl)-1-propyl][1,1′-biphenyl]-4-carbonitrile (590 mg) and pyridine hydrochloride (111 mg), the title compound (261 mg) was obtained as colorless needle crystals.
Reaction SMILES: Cl.Cl.[NH2:3][C:4]1[CH:5]=[CH:6][C:7]2[S:11][C:10]([CH3:12])=[N:9][C:8]=2[CH:13]=1.C(=O)(O)[O-].[Na+].[N:19]#[C:20][NH2:21].[N+:22]([O-:25])([OH:24])=[O:23]>C(O)C.O.ClCCl>[N+:22]([O-:25])([OH:24])=[O:23].[NH:3]([C:4]1[CH:5]=[CH:6][C:7]2[S:11][C:10]([CH3:12])=[N:9][C:8]=2[CH:13]=1)[C:20]([NH2:21])=[NH:19]
Reactant: Cc1nc2cc(N)ccc2s1
Reactant: N#CN
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Solvent: O=[N+]([O-])O
Solvent: ClCCl
Product: Cc1nc2cc(NC(=N)N)ccc2s1
Temperature: 25 °C
Yield: 47.9 %

Procedure:
5-Amino-2-methylbenzothiazole dihydrochloride (2.50 g, 10.54 mmol) was partitioned between dichloromethane and saturated aqueous sodium bicarbonate solution. The organic phase was dried (MgSO4) and evaporated to afford the free base which was dissolved in ethanol (5 ml). A solution of cyanamide (660 mg, 15.71 mmol) in water (1 ml) was added followed by concentrated nitric acid (69%, 0.68 ml, 10.54 mmol) and the resulting mixture was refluxed for 18 h. The solid which formed on cooling to room temperature was collected and washed with cold ethanol then diethyl ether to give the title compound (1.36 g) as a beige solid m.p. 260-261° (dec.). δH (d6DMSO) 2.80 (3H, s), 7.26 (1H, m), 7.37 (4H, s), 7.78 (1H, s), 8.08 (1H, d, J 8.6 Hz) and 9.67 (1H, br s).
Reaction SMILES: ClC1C=CC2SC=C(CN3CCN(C4SC(C(O)=O)=C(C)N=4)C3=O)C=2C=1.[CH3:27][C:28]1[N:29]=[C:30]([N:36]2[CH2:40][CH2:39][N:38]([CH2:41][C:42]3[CH:46]=[C:45]([CH3:47])[O:44][N:43]=3)[C:37]2=[O:48])[S:31][C:32]=1[C:33]([OH:35])=O.[NH2:49][CH2:50][C:51]1[CH:52]=[N:53][CH:54]=[CH:55][CH:56]=1>>[CH3:27][C:28]1[N:29]=[C:30]([N:36]2[CH2:40][CH2:39][N:38]([CH2:41][C:42]3[CH:46]=[C:45]([CH3:47])[O:44][N:43]=3)[C:37]2=[O:48])[S:31][C:32]=1[C:33]([NH:49][CH2:50][C:51]1[CH:52]=[N:53][CH:54]=[CH:55][CH:56]=1)=[O:35]
Reactant: NCc1cccnc1
Reactant: Cc1cc(CN2CCN(c3nc(C)c(C(=O)O)s3)C2=O)no1
Agent: Cc1nc(N2CCN(Cc3csc4ccc(Cl)cc34)C2=O)sc1C(=O)O
Product: Cc1cc(CN2CCN(c3nc(C)c(C(=O)NCc4cccnc4)s3)C2=O)no1
Yield: 57 %

Procedure:
Following the procedure as described in Example 32, making variations as required to replace 2-(3-((5-chlorobenzo[b]thiophen-3-yl)methyl)-2-oxoimidazolidin-1-yl)-4-methylthiazole-5-carboxylic acid with 4-methyl-2-(3-((5-methylisoxazol-3-yl)methyl)-2-oxoimidazolidin-1-yl)thiazole-5-carboxylic acid to react with 3-(aminomethyl)pyridine, the title compound was obtained as a colorless solid in 57% yield: mp 185-188° C. (dichloromethane/hexanes); 1H NMR (300 MHz, CDCl3) δ 8.59-8.58 (m, 1H), 8.51 (d, J=4.7 Hz, 1H), 7.69 (d, J=7.8 Hz, 1H), 7.29-7.25 (m, 1H), 6.22-6.19 (m, 1H), 5.98 (s, 1H), 4.58 (d, J=5.8 Hz, 2H), 4.49 (s, 2H), 4.12-4.06 (m, 2H), 3.61-3.55 (m, 2H), 2.60 (s, 3H), 2.40 (s, 3H); MS (ES+) m/z 413.2 (M+1).
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([N:11]2[C:15]3=[N:16][CH:17]=[N:18][C:19](O)=[C:14]3[CH:13]=[N:12]2)=[CH:7][CH:6]=1)(=[O:4])=[O:3].CN(C)C1C=CC=CC=1.O=P(Cl)(Cl)[Cl:32]>>[Cl:32][C:19]1[N:18]=[CH:17][N:16]=[C:15]2[N:11]([C:8]3[CH:9]=[CH:10][C:5]([S:2]([CH3:1])(=[O:4])=[O:3])=[CH:6][CH:7]=3)[N:12]=[CH:13][C:14]=12
Reactant: CS(=O)(=O)c1ccc(-n2ncc3c(O)ncnc32)cc1
Reactant: O=P(Cl)(Cl)Cl
Solvent: CN(C)c1ccccc1
Product: CS(=O)(=O)c1ccc(-n2ncc3c(Cl)ncnc32)cc1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 27 %

Procedure:
Into a 50 mL round-bottomed equipped with a reflux condenser and N2 inlet septum was place a stir bar, 1-(4-methanesulfonyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-ol (93 mg, 0.32 mmol), dimethylaniline (0.3 mL) and POCl3 (10 mL). The reaction mixture was stirred at room temperature under N2 for 5 minutes and brought to reflux for 6 hrs. After cooling down to room temperature, the reaction mixture was poured into ice and extracted with CH2Cl2 quickly. The crude product was then purified by flash chromatography (EtOAc:Hex=1:1), 24 mg of product was obtained (27% yield). 1H NMR (DMSO-d6, 400 MHz) δ 3.29 (s, 3H), 8.19 (d, 2H), 8.53 (d, 2H), 8.89 (s, 1H), 9.08 (s, 1H). LCMS calculated C12H9ClN4O2S 308.01, observed 309.1 (MH+).
Reaction SMILES: [CH:1]([Mg]Cl)([CH3:3])[CH3:2].[C:6]([O:10][C:11]([NH:13][C@@H:14]([CH2:27][C:28]1[CH:33]=CC=C[CH:29]=1)[C@H:15](OS(C)(=O)=O)/[CH:16]=[CH:17]/[C:18]([O:20][CH3:21])=[O:19])=[O:12])([CH3:9])([CH3:8])[CH3:7].C(OC(N[C@@H](CC(C)C)[C@H](OS(C)(=O)=O)/C=C/C(OC)=O)=O)(C)(C)C>>[C:6]([O:10][C:11]([NH:13][C@@H:14]([CH2:27][CH:28]([CH3:29])[CH3:33])/[CH:15]=[CH:16]/[C@H:17]([C:18]([O:20][CH3:21])=[O:19])[CH:1]([CH3:3])[CH3:2])=[O:12])([CH3:7])([CH3:8])[CH3:9]
Reactant: CC(C)[Mg]Cl
Reactant: COC(=O)/C=C/[C@@H](OS(C)(=O)=O)[C@H](Cc1ccccc1)NC(=O)OC(C)(C)C
Agent: COC(=O)/C=C/[C@@H](OS(C)(=O)=O)[C@H](CC(C)C)NC(=O)OC(C)(C)C
Product: COC(=O)[C@@H](/C=C/[C@H](CC(C)C)NC(=O)OC(C)(C)C)C(C)C

Procedure:
Using the procedure of Example 8 but replacing benzylmagnesium chloride with isopropylmagnesium chloride and replacing the resultant compound of Example 7 with the resultant compound of Example 33 provided the desired compound.
Reaction SMILES: CC1C=CC(S(O[CH2:12][C@H:13]2[CH2:22][CH2:21][C:20]3[C:15](=[C:16]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=4[CH3:30])[C:17]([Cl:23])=[CH:18][CH:19]=3)[O:14]2)(=O)=O)=CC=1.[N-:31]=[N+:32]=[N-:33].[Na+]>CS(C)=O>[N:31]([CH2:12][C@H:13]1[CH2:22][CH2:21][C:20]2[C:15](=[C:16]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=3[CH3:30])[C:17]([Cl:23])=[CH:18][CH:19]=2)[O:14]1)=[N+:32]=[N-:33]
Reactant: Cc1ccc(S(=O)(=O)OC[C@H]2CCc3ccc(Cl)c(-c4ccccc4C)c3O2)cc1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CS(C)=O
Product: Cc1ccccc1-c1c(Cl)ccc2c1O[C@@H](CN=[N+]=[N-])CC2
Temperature: 60 °C
Yield: 88.5 %

Procedure:
To a solution of ((2R)-7-chloro-8-o-tolylchroman-2-yl)methyl 4-methylbenzenesulfonate (0.8 g, 1.8 mmol) in DMSO (50 mL) was added sodium azide (1.2 g, 18.4 mmol) and the resulting mixture was heated at 60° C. overnight. The mixture was extracted with ethyl acetate, washed with water and saturated sodium chloride, dried with anhydrous sodium sulfate and concentrated under reduced pressure. Purification by ISCO using a solvent gradient of 0 to 20% ethyl acetate in hexanes provided 0.5 g (88%) of (2R)-2-(azidomethyl)-7-chloro-8-o-tolylchroman as a colorless oil.
Reaction SMILES: [NH:1]1[C@@H:10]2[C@@H:5]([CH2:6][CH2:7][CH2:8][CH2:9]2)[NH:4][CH2:3][CH2:2]1.C(N(CC)CC)C.Cl[C:19]([O:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)=[O:20]>ClCCl>[N:1]1([C:19]([O:21][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[O:20])[CH:10]2[CH:5]([CH2:6][CH2:7][CH2:8][CH2:9]2)[NH:4][CH2:3][CH2:2]1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: C1CC[C@H]2NCCN[C@H]2C1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(OCc1ccccc1)N1CCNC2CCCCC21
Temperature: 25 °C
Reaction time: 2 h
Yield: 84.6 %

Procedure:
To (4aR,8aS)-decahydroquinoxaline (1.4 g, 10 mmol) in dichloromethane (50 mL) was added triethylamine (1.7 mL, 12 mmol) followed by dropwise benzyl chloroformate (1.71 g, 10 mmol). The reaction mixture was stirred at room temperature for 2 h before being diluted with dichloromethane and washed with 1N NaOH followed by sat. aq. NH4Cl. The combined organic layers were washed with brine, dried (MgSO4) and concentrated to provide the crude product, which was purified via Combiflash to yield phenylmethyl octahydro-1(2H)-quinoxalinecarboxylate (enantiomeric mixture, cis) (2.32 g, 85%). LCMS: (M+H)+: 275.1.
Reaction SMILES: [CH:1]12[CH2:7][CH:6]1[CH2:5][CH2:4][C@H:3]([C:8]([NH:10][C@H:11]([C:13]1[CH:22]=[CH:21][C:16]([C:17]([O:19][CH3:20])=[O:18])=[CH:15][CH:14]=1)[CH3:12])=[O:9])[NH:2]2.[F:23][C:24]([F:34])([F:33])[C:25]1[CH:32]=[CH:31][C:28]([CH2:29]Br)=[CH:27][CH:26]=1.C([O-])([O-])=O.[Cs+].[Cs+]>>[F:23][C:24]([F:33])([F:34])[C:25]1[CH:32]=[CH:31][C:28]([CH2:29][N:2]2[C@@H:3]([C:8]([NH:10][C@H:11]([C:13]3[CH:14]=[CH:15][C:16]([C:17]([O:19][CH3:20])=[O:18])=[CH:21][CH:22]=3)[CH3:12])=[O:9])[CH2:4][CH2:5][CH:6]3[CH:1]2[CH2:7]3)=[CH:27][CH:26]=1
Reactant: COC(=O)c1ccc([C@H](C)NC(=O)[C@H]2CCC3CC3N2)cc1
Reactant: FC(F)(F)c1ccc(CBr)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: COC(=O)c1ccc([C@H](C)NC(=O)[C@H]2CCC3CC3N2Cc2ccc(C(F)(F)F)cc2)cc1

Procedure:
The title compound (D143) (10 mg) was prepared according to the general procedure for substituted benzyl amines preparation starting from methyl 4-((1S)-1-((3R)-2-azabicyclo[4.1.0]heptane-3-carboxamido)ethyl)benzoate (diastereoisomers mixture) (D102) (20 mg) and 4-(trifluoromethyl)-benzylbromide (0.012 ml). (Cs2CO3: 1.5 eq; Reaction time: 20 hrs; RT).
Reaction SMILES: CO[CH2:3][C:4]1[CH:5]=[C:6]([N:10]([CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([O:25][C:26]([F:31])([F:30])[CH:27]([F:29])[F:28])[CH:20]=2)[CH2:11][CH:12]([OH:17])[C:13]([F:16])([F:15])[F:14])[CH:7]=[CH:8][CH:9]=1.B(Br)(Br)[Br:33].COC>ClCCl>[Br:33][CH2:3][C:4]1[CH:5]=[C:6]([N:10]([CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([O:25][C:26]([F:31])([F:30])[CH:27]([F:29])[F:28])[CH:20]=2)[CH2:11][CH:12]([OH:17])[C:13]([F:16])([F:15])[F:14])[CH:7]=[CH:8][CH:9]=1
Reactant: BrB(Br)Br
Reactant: COCc1cccc(N(Cc2cccc(OC(F)(F)C(F)F)c2)CC(O)C(F)(F)F)c1
Agent: COC
Solvent: ClCCl
Product: OC(CN(Cc1cccc(OC(F)(F)C(F)F)c1)c1cccc(CBr)c1)C(F)(F)F
Temperature: -50 °C
Reaction time: 1 h
Yield: 59 %

Procedure:
EX -514D) The 3-[[3-(methoxymethyl)phenyl][[3-(1,1,2,2-tetrafluoroethoxy) phenyl]-methyl]amino]-1,1,1-trifluoro-2-propanol from EX-514C (1 g, 2.2 mmol) was dissolved in 10 mL of dichloromethane. The solution was cooled to −50° C. and a 1 M solution of BBr3 in dichloromethane (2.3 mL, 2.3 mmol) was added. The solution was stirred at −50° C. for 1 hour and warmed to room temperature over 1 hour, at which time HPLC analysis indicated that no methyl ether starting material remained. The reaction mixture was quenched with aqueous saturated sodium bicarbonate and diluted in dichloromethane. The organic layer was washed with brine, then dried over MgSO4, and concentrated in vacuo. The crude product was purified by flash column chromatography on silica gel eluting with ethyl acetate:hexane 1:7 to give 0.65 g (59%) of the desired 3-[[3-(bromomethyl)pheny][[3-(1,1,2,2-tetrafluoroethoxy)phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol product as a brown oil. HRMS calcd. for C19H18BrF7NO2: 504.0409 [M+H]+, found: 504.0361. 1H NMR (CDCl3) δ3.3 (s, 1H), 3.6 (dd, 1H), 3.9 (dd, 1H), 4.3 (m, 1H), 4.4 (s, 2H), 4.8 (m, 2H), 5.9 (tt, 1H), 6.7 (d, 1H), 6.8-6.9 (m, 2H), 7.1-7.3 (m, 4H), 7.4 (t, 1H).
Reaction SMILES: [CH2:1]([NH:8][C:9]([NH2:11])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:12][CH:13]([C:19](OCC)=[O:20])[C:14](OCC)=[O:15].C[O-].[Na+]>CO>[CH2:1]([N:8]1[C:14](=[O:15])[CH:13]([CH3:12])[C:19](=[O:20])[NH:11][C:9]1=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NC(=O)NCc1ccccc1
Reactant: CCOC(=O)C(C)C(=O)OCC
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: CC1C(=O)NC(=O)N(Cc2ccccc2)C1=O

Procedure:
To a suspension of 21.83 g (145 mmol) of benzylurea and 25 ml (145 mmol) of diethyl methylmalonate in 74 ml of methanol, 35.4 ml (145 mmol) of a 4.1M sodium methylate solution was added at room temperature, followed by refluxing for 16 hours. After the reaction mixture was cooled, the solvent was distilled off. After the residue was dissolved in water and insoluble substances were filtered out, the filtrate was adjusted to pH 3-4 by adding concentrated hydrochloric acid. The resulting precipitate was collected by filtration, washed with water and n-hexane-diethyl ether and dried to yield 30.11 g (84.8%, white crystal) of the desired product.
Reaction SMILES: C1(C(C2C=CC=CC=2)(C2C=CC=CC=2)[N:8]2[CH:12]=[C:11]([C:13]3[CH:14]=[CH:15][C:16]4[N:17]([CH:19]=[C:20]([C:22]([NH:24][C:25]5[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=5)=[O:23])[N:21]=4)[CH:18]=3)[N:10]=[CH:9]2)C=CC=CC=1.[Cl:43]CCl>Cl.CO>[ClH:43].[NH:8]1[CH:12]=[C:11]([C:13]2[CH:14]=[CH:15][C:16]3[N:17]([CH:19]=[C:20]([C:22]([NH:24][C:25]4[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=4)=[O:23])[N:21]=3)[CH:18]=2)[N:10]=[CH:9]1
Reactant: ClCCl
Reactant: O=C(Nc1ccccc1)c1cn2cc(-c3cn(C(c4ccccc4)(c4ccccc4)c4ccccc4)cn3)ccc2n1
Agent: Cl
Solvent: CO
Product: O=C(Nc1ccccc1)c1cn2cc(-c3c[nH]cn3)ccc2n1
Temperature: 70 °C
Reaction time: 60 h

Procedure:
A suspension of 270 mg of 6-(1-triphenylmethyl-1H-imidazol-4-yl)-N-phenyl-imidazo[1,2-a]pyridine-2-carboxamide in 4 mL of 2N hydrochloric acid is heated for 30 minutes at 70° C. and then diluted with 2 mL of methanol, heated for 45 minutes at reflux, diluted again by addition of 2 mL of dichloromethane and heated for a further 2 hours at reflux. The reaction mixture is stirred for 60 hours at room temperature. The precipitate is filtered off by suction, washed with methanol, water and then pentane and dried under reduced pressure to give 96 mg of 6-(1H-imidazol-4-yl)-N-phenylimidazo[1,2-a]pyridine-2-carboxamide hydrochloride (1:1) in the form of a white solid.
Reaction SMILES: [C:1]([O:5][C:6](=[O:20])[C@@H:7]1[CH2:11][C:10](=[CH2:12])[CH2:9][N:8]1[C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])([CH3:4])([CH3:3])[CH3:2].C(BC(C(C)C)C)(C(C)C)C.C[O:33]CCOCCOC>O1CCCC1>[C:1]([O:5][C:6](=[O:20])[C@@H:7]1[CH2:11][C@H:10]([CH2:12][OH:33])[CH2:9][N:8]1[C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])([CH3:3])([CH3:4])[CH3:2]
Reactant: COCCOCCOC
Reactant: C=C1C[C@@H](C(=O)OC(C)(C)C)N(C(=O)OC(C)(C)C)C1
Agent: CC(C)C(C)BC(C)C(C)C
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)[C@@H]1C[C@H](CO)CN1C(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
To an oven-dried 100-mL 2-necked round-bottomed flask was added a solution of 1-(tert-butyloxycarbonyl)-4-C-methylene-L-proline tert-butyl ester (519 mg, 1.83 mmol) in 2-methoxyethyl ether (diglyme) (5 mL) followed at 0° C. by a solution of disiamylborane (12.8 ML of a 0.5M solution in tetrahydrofuran, 6.41 mmol) in diglyme (15 mL). After stirring for 15 minutes at 0° C., the cooling bath was removed, and the mixture was allowed to warm up for 15 minutes. The reaction was then quenched by the careful addition of water (25 mL). The reaction mixture was again cooled to 0° C., and the pH was adjusted to 8 with 3N sodium hydroxide. 30% Hydrogen peroxide (4 mL) was added dropwise slowly with the temperature maintained at 0° C. for 10 minutes. The cooling bath was removed for 10 minutes, and an additional 1.3 mL of 30% hydrogen peroxide was added, while maintaining the pH at 8 by addition of 3N sodium hydroxide. The pH was then adjusted to ~6 by the addition of glacial acetic acid. The mixture was partitioned between diethyl ether (100 mL) and water (50 mL), and the aqueous layer extracted with ether. The combined ethereal layers were washed with water, dried (MgSO4), and evaporated. Flash silica gel chromatography eluting with 20% acetone/hexane afforded the title compound as a colorless oil; yield 376 mg (68%).
Reaction SMILES: [N:1]1([CH2:6][CH2:7][C:8]([C:10]2[CH:15]=[CH:14][C:13]([C:16]([F:19])([F:18])[F:17])=[CH:12][CH:11]=2)=O)[CH:5]=[CH:4][N:3]=[CH:2]1.[ClH:20].Cl.[NH2:22][CH2:23][CH2:24][O:25][NH2:26].N1C=CC=CC=1.C(O)C>[OH-].[Na+].C(OCC)(=O)C>[ClH:20].[ClH:20].[NH2:22][CH2:23][CH2:24][O:25][N:26]=[C:8]([C:10]1[CH:15]=[CH:14][C:13]([C:16]([F:19])([F:18])[F:17])=[CH:12][CH:11]=1)[CH2:7][CH2:6][N:1]1[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: O=C(CCn1ccnc1)c1ccc(C(F)(F)F)cc1
Reactant: NCCON
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Solvent: CCO
Product: NCCON=C(CCn1ccnc1)c1ccc(C(F)(F)F)cc1
Reaction time: 2 h
Yield: 67.4 %

Procedure:
A mixture of 3-(1-(1H)-imidazolyl)-1-(4-trifluoromethylphenyl)-1-propanone (4.65 g), O-(2-aminoethyl)hydroxylamine dihydrochloride (3.10 g), 3 equivalents of pyridine, and absolute ethanol (75 ml) was heated under reflux, under nitrogen, with stirring, for two hrs. The reaction mixture was diluted with 10% sodium hydroxide solution and ethyl acetate. The layers were separated. The aqueous phase was extracted with ethyl acetate, the organic layers were dried over anhydrous sodium sulfate, filtered, and the filtrate was evaporated. The residue was taken up in toluene and evaporated. The residue was flash chromatographed (180:19:1 dichloromethane/methanol/ammonium hydroxide). The appropriate fractions were collected and concentrated. The residue was dissolved in absolute ethanol and treated with ethereal hydrogen chloride. Diethyl ether was added to the solution. The solid was collected and recrystallized twice from absolute ethanol/ether to give 2.8 g (40%) of product, mp 213°-214° C. (dec).
Reaction SMILES: Cl[C:2]1[C:7]([C:8]#[N:9])=[N:6][CH:5]=[CH:4][N:3]=1.Cl.[CH2:11]([O:13][C:14](=[O:18])[CH2:15][NH:16][CH3:17])[CH3:12].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[CH3:17][N:16]1[C:2]2[N:3]=[CH:4][CH2:5][NH:6][C:7]=2[C:8]([NH2:9])=[C:15]1[C:14]([O:13][CH2:11][CH3:12])=[O:18]
Reactant: N#Cc1nccnc1Cl
Reactant: CCOC(=O)CNC
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1c(N)c2c(n1C)N=CCN2
Yield: 31.1 %

Procedure:
2-Chloro-3-cyanopyrazine (0.808 g, 5.79 mmol), prepared by the method of Shneller, et. al., J. Het. Chem., 12:513 (1975), was dissolved in 30 ml DMF under nitrogen and treated with sarcosine ethyl ester hydrochloride (0.978 g, 6.37 mmol) followed by K2CO3 (1.68 g, 12.16 mmol) at rt. The reaction mixture was gently refluxed for 36 h after which the cooled solution was partitioned between water and CHCl3. The aqueous phase was extracted with CHCl3 and the combined organics washed with water then brine and dried over Na2SO4. Concentration gave a green-black oil that was purified by chromatography on silica gel eluting with a gradient from 3:1 to 1:1 hexanes:ethyl acetate to give 0.40 g (31%) of the title compound as an orange solid. mp: 119°-121° C. 1H NMR (300 MHz, CDCl3) δ1.47 (t, 3H), 4.01 (s, 3H), 4.46 (q, 2H), 5.65 (br s, 2H), 8.32 (d, 1H), 8.38 (d, 1H). MS (DCI/NH3) m/e 220 (M+H)+. Analysis calc'd. for C10H12N4O2: C, 54.54; H, 5.49; N, 25.44; Found: C, 54.29; H, 5.52; N, 25.42.
Reaction SMILES: [CH:1]1([N:6]2[C:11]3[N:12]=[C:13](S(C)=O)[N:14]=[CH:15][C:10]=3[C:9]([CH3:19])=[CH:8][C:7]2=[O:20])[CH2:5][CH2:4][CH2:3][CH2:2]1.[C:21]([O:25][C:26]([N:28]1[CH2:33][CH2:32][N:31]([C:34]2[CH:35]=[N:36][C:37]([NH2:40])=[CH:38][CH:39]=2)[CH2:30][CH2:29]1)=[O:27])([CH3:24])([CH3:23])[CH3:22]>C1(C)C=CC=CC=1>[C:21]([O:25][C:26]([N:28]1[CH2:33][CH2:32][N:31]([C:34]2[CH:35]=[N:36][C:37]([NH:40][C:13]3[N:14]=[CH:15][C:10]4[C:9]([CH3:19])=[CH:8][C:7](=[O:20])[N:6]([CH:1]5[CH2:5][CH2:4][CH2:3][CH2:2]5)[C:11]=4[N:12]=3)=[CH:38][CH:39]=2)[CH2:30][CH2:29]1)=[O:27])([CH3:24])([CH3:22])[CH3:23]
Reactant: Cc1cc(=O)n(C2CCCC2)c2nc(S(C)=O)ncc12
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(N)nc2)CC1
Solvent: Cc1ccccc1
Product: Cc1cc(=O)n(C2CCCC2)c2nc(Nc3ccc(N4CCN(C(=O)OC(C)(C)C)CC4)cn3)ncc12
Temperature: 25 °C
Yield: 14.4 %

Procedure:
8-Cyclopentyl-2-methanesulfinyl-5-methyl-8H-pyrido[2,3-d]pyrimidin-7-one (0.40 g, 1.37 mmol) and 4-(6-amino-pyridin-3-yl)-piperazine-1-carboxylic acid tert-butyl ester (0.497 g, 1.78 mmol) were heated to reflux in toluene (4 mL) for 16 hours. The reaction mixture was cooled to room temperature and the precipitate that formed was collected by filtration and washed on the funnel with toluene (3×10 mL) to give 4-[6-(8-cyclopentyl-5-methyl-7-oxo-7,8-dihydro-pyrido[2,3-d]pyrimidin-2-ylamino)-pyridin-3-yl]-piperazine-1-carboxylic acid tert-butyl ester as a dark brown-gray solid (0.100 g, 16.2%). 1H NMR δ(400 MHz, DMSO-d6) 9.92 (s, 1H), 8.78 (s,1H), 8.02 (d, J=2.9 Hz, 1H), 7.87 (d, J=9.3 Hz, 1H), 7.50 (dd, J=2.9, 9.0 Hz, 1H), 6.18 (s, 1H), 5.77 (m, 1H), 3.44 (m, 4H), 3.07 (m, 4H), 2.39 (s, 3H), 2.20 (m, 2H), 1.85 (m, 2H), 1.71 (m, 2H), 1.55 (m, 2H), 1.39 (s, 9H).