Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1(N=C=NC2CCCCC2)CCCCC1.[CH3:16][C:17]1([CH3:33])[C@@H:19]([C:20]#[C:21][C:22]([O:24][CH2:25][C:26]([Cl:29])([Cl:28])[Cl:27])=[O:23])[C@H:18]1[C:30]([OH:32])=[O:31].C(Cl)Cl.[C:37]([C@@H:39](O)[C:40]1[CH:45]=[CH:44][CH:43]=[C:42]([O:46][C:47]2[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=2)[CH:41]=1)#[N:38]>N1C=CC=CC=1>[CH3:16][C:17]1([CH3:33])[C@@H:19]([C:20]#[C:21][C:22]([O:24][CH2:25][C:26]([Cl:28])([Cl:29])[Cl:27])=[O:23])[C@H:18]1[C:30]([O:32][C@H:39]([C:37]#[N:38])[C:40]1[CH:45]=[CH:44][CH:43]=[C:42]([O:46][C:47]2[CH:48]=[CH:49][CH:50]=[CH:51][CH:52]=2)[CH:41]=1)=[O:31]
Reactant: N#C[C@@H](O)c1cccc(Oc2ccccc2)c1
Reactant: CC1(C)[C@H](C(=O)O)[C@@H]1C#CC(=O)OCC(Cl)(Cl)Cl
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC1(C)[C@H](C(=O)O[C@H](C#N)c2cccc(Oc3ccccc3)c2)[C@@H]1C#CC(=O)OCC(Cl)(Cl)Cl
Reaction time: 0.5 h

Procedure:
6.2 g of dicyclohexylcarbodiimide were added to a mixture of 9.5 g of the product of Step B, 30 ml of methylene chloride and 3 ml of pyridine and after stirring for 30 minutes, 6.8 g of (S)α-cyano-3-phenoxy-benzyl alcohol were added to the mixture. The mixture was stirred for 90 minutes and was filtered and the filtrate was washed with N hydrochloric acid and then with water until the wash water was neutral, dried and evaporated to dryness. The 16.3 g of oil residue were chromatographed over silica gel and eluted with a 97-3 benzene-ethyl acetate mixture to obtain 12 of (S)α-cyano-3-phenoxy-benzyl (1R,cis) 2,2-dimethyl-3-(2,2,2-trichloroethoxycarbonyl-ethynyl]-cyclopropane-carboxylate melting at 101° C.
Reaction SMILES: [F:1][C:2]1([F:25])[CH2:7][CH2:6][C:5]([CH2:9][NH:10][C:11]([C:13]2[C:14]3[CH:15]=[CH:16][C:17](Cl)=[N:18][C:19]=3[CH:20]=[CH:21][C:22]=2[Cl:23])=[O:12])([OH:8])[CH2:4][CH2:3]1.CCN(C(C)C)C(C)C.[CH3:35][N:36]([CH3:42])[CH:37]1[CH2:41][CH2:40][NH:39][CH2:38]1>>[F:1][C:2]1([F:25])[CH2:7][CH2:6][C:5]([CH2:9][NH:10][C:11]([C:13]2[C:14]3[CH:15]=[CH:16][C:17]([N:39]4[CH2:40][CH2:41][CH:37]([N:36]([CH3:42])[CH3:35])[CH2:38]4)=[N:18][C:19]=3[CH:20]=[CH:21][C:22]=2[Cl:23])=[O:12])([OH:8])[CH2:4][CH2:3]1
Reactant: CN(C)C1CCNC1
Reactant: O=C(NCC1(O)CCC(F)(F)CC1)c1c(Cl)ccc2nc(Cl)ccc12
Solvent: CCN(C(C)C)C(C)C
Product: CN(C)C1CCN(c2ccc3c(C(=O)NCC4(O)CCC(F)(F)CC4)c(Cl)ccc3n2)C1

Procedure:
The title compound was synthesized according to the procedure described in example 1 using 2,6-dichloro-quinoline-5-carboxylic acid (4,4-difluoro-1-hydroxycyclohexylmethyl)-amide, DIPEA and N,N-dimethylpyrrolidin-3-amine. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.73 (m, 1H), 7.85 (1H), 7.48 (m, 2H), 6.69 (1H), 4.66 (s, 1H), 3.89 (m, 1H), 3.70 (m, 1H), 3.45 (m, 1H), 3.26 (m, 2H), 2.85 (m, 1H), 2.54 (m, 4H), 2.22 (s, 6H), 2.15 (m, 1H), 2.06 (m, 2H), 1.85 (m, 3H), 1.74-1.76 (m, 5H). m/z: 467 [M+H]
Reaction SMILES: [C:1]([C:4]1[CH2:9][CH2:8][CH2:7][NH:6][CH:5]=1)(=[O:3])[CH3:2].[H-].[Na+].O1CCCC1.Br[CH2:18][CH:19]([CH2:24][CH3:25])[CH2:20][CH2:21][CH2:22][CH3:23]>O>[CH2:24]([CH:19]([CH2:20][CH2:21][CH2:22][CH3:23])[CH2:18][N:6]1[CH2:7][CH2:8][CH2:9][C:4]([C:1]([CH3:2])=[O:3])=[CH:5]1)[CH3:25]
Reactant: CCCCC(CC)CBr
Reactant: CC(=O)C1=CNCCC1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CCCCC(CC)CN1C=C(C(C)=O)CCC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
3-acetyl-1,4,5,6-tetrahydropyridine (20.0 g, 0.16 mole) was added under nitrogen to a mixture of sodium hydride (5.76 g, 0.24 mole) and dry tetrahydrofuran (50 ml) stirring at room temperature. After one hour, 1-bromo-2-ethyl hexane (33.8 g, 0.175 mole) was added dropwise over 15 minutes and the mixture stirred overnight at room temperature. The reaction mixture was cautiously added to iced water (100 g) under nitrogen and extracted with diethyl ether (3×100 ml). The combined organic phase was dried over magnesium sulphate, concentrated under reduced pressure and the residue distilled to give methyl 1-(2-ethylhexyl)-1,4,5,6-tetrahydro-3-pyridyl ketone (5) as a pale yellow oil (b.pt 140°-142° C./0.1 mm Hg).
Reaction SMILES: C(O[C:6](=[O:34])[NH:7][C@H:8]([C:13](=[O:33])[NH:14][C@H:15]([B:20]1[O:28][C@H:27]2[C@:22]([CH3:32])([C@H:23]3[CH2:29][C@@H:25]([CH2:26]2)[C:24]3([CH3:31])[CH3:30])[O:21]1)[CH2:16][CH:17]([CH3:19])[CH3:18])[CH2:9][CH:10]([CH3:12])[CH3:11])(C)(C)C.[C:35]1([C:57]2[CH:62]=[CH:61][CH:60]=[CH:59][CH:58]=2)[CH:40]=[CH:39][CH:38]=[C:37]([NH:41][C@@H:42]([CH2:46][C:47]2[CH:52]=[CH:51][C:50]([O:53][CH3:54])=[C:49]([O:55][CH3:56])[CH:48]=2)C(O)=O)[CH:36]=1>>[CH3:18][CH:17]([CH3:19])[CH2:16][C@H:15]([NH:14][C:13](=[O:33])[C@@H:8]([NH:7][C:6](=[O:34])[C@@H:42]([NH:41][C:37]1[CH:36]=[C:35]([C:57]2[CH:62]=[CH:61][CH:60]=[CH:59][CH:58]=2)[CH:40]=[CH:39][CH:38]=1)[CH2:46][C:47]1[CH:52]=[CH:51][C:50]([O:53][CH3:54])=[C:49]([O:55][CH3:56])[CH:48]=1)[CH2:9][CH:10]([CH3:12])[CH3:11])[B:20]1[O:28][C@H:27]2[C@:22]([CH3:32])([C@H:23]3[CH2:29][C@@H:25]([CH2:26]2)[C:24]3([CH3:30])[CH3:31])[O:21]1
Reactant: CC(C)C[C@H](NC(=O)[C@H](CC(C)C)NC(=O)OC(C)(C)C)B1O[C@@H]2C[C@@H]3C[C@@H](C3(C)C)[C@]2(C)O1
Reactant: COc1ccc(C[C@H](Nc2cccc(-c3ccccc3)c2)C(=O)O)cc1OC
Product: COc1ccc(C[C@H](Nc2cccc(-c3ccccc3)c2)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC(C)C)B2O[C@@H]3C[C@@H]4C[C@@H](C4(C)C)[C@]3(C)O2)cc1OC

Procedure:
The title compound is prepared as described in example 1 but using {(S)-3-Methyl-1-[(R)-3-methyl-1-((1S,2S,6R,8S)-2,9,9-trimethyl-3,5-dioxa-4-bora-tricyclo[6.1.1.02,6]dec-4-yl)-butylcarbamoyl]-butyl}-carbamic acid tert-butyl ester and (S)-2-(Biphenyl-3-ylamino)-3-(3,4-dimethoxy-phenyl)-propionic acid.
Reaction SMILES: [H-].[Na+].[OH:3][CH:4]1[CH2:9][CH2:8][N:7]([CH3:10])[CH2:6][CH2:5]1.Cl[CH2:12][C:13](=[O:20])[CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16].C(O)C>CN(C)C=O>[CH3:10][N:7]1[CH2:8][CH2:9][CH:4]([O:3][CH2:12][C:13](=[O:20])[CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH2:5][CH2:6]1
Reactant: CN1CCC(O)CC1
Reactant: CCOC(=O)CC(=O)CCl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCO
Product: CCOC(=O)CC(=O)COC1CCN(C)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 85 %

Procedure:
Sodium hydride (5.0 g of 50% dispersion in mineral oil) was added portionwise to a stirred solution of 4-hydroxy-1-methyl-piperidine (11.5 g) in dry dimethylformamide (80 ml). The mixture was stirred at room temperature for 1 hour and then cooled to 10° C. A solution of ethyl 4-chloroacetoacetate (8.2 g) in dry dimethylformamide (20 ml) was added dropwise with stirring and stirring was continued for a further 20 hours at room temperature. Ethanol (10 ml) was added and the solution was evaporated to dryness. The residue was partitioned between dichloromethane and dilute hydrochloric acid. The organic layer was separated, dried over sodium sulphate and evaporated to given an oil which was partitioned between acetonitrile and petrol to remove mineral oil. The acetonitrile extract was evaporated to give the title compound as an oil (10.3 g) which was used without further purification.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([CH3:8])[N:5]=[C:4]([NH2:9])[N:3]=1.[Cl:10][C:11]1[CH:12]=[C:13](B(O)O)[C:14]([F:17])=[N:15][CH:16]=1.C([O-])(=O)C.[K+]>CCO.O>[Cl:10][C:11]1[CH:12]=[C:13]([C:2]2[N:7]=[C:6]([CH3:8])[N:5]=[C:4]([NH2:9])[N:3]=2)[C:14]([F:17])=[N:15][CH:16]=1
Reactant: OB(O)c1cc(Cl)cnc1F
Reactant: Cc1nc(N)nc(Cl)n1
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: O
Solvent: CCO
Product: Cc1nc(N)nc(-c2cc(Cl)cnc2F)n1
Temperature: 100 °C
Yield: 56.3 %

Procedure:
To a 20 mL microwave reaction tube was added 4-chloro-6-methyl-1,3,5-triazin-2-amine (Example 9, 1.00 g, 6.94 mmol), 5-chloro-2-fluoropyridin-3-ylboronic acid (Combi-Blocks, 1.62 g, 9.22 mmol), potassium acetate (Aldrich, 2.07 g, 21.1 mmol) and Am-Phos (Aldrich, 0.247 g, 0.349 mmol) in EtOH (12 mL) and water (1.2 mL). The mixture was degassed by bubbling argon through for 5 min. The tube was heated in an microwave reactor (Biotage) at 100° C. for 20 min. The reaction mixture was partitioned between water (100 mL) and 25% IPA in chloroform with 1% NH4OH (60 mL). The aqueous phase was extracted with 25% IPA in chloroform with 1% NH4OH (2×50 mL). The combined organic phases were washed with saturated aqueous sodium chloride (40 mL). The organic phase was dried over sodium sulfate, filtered and concentrated in vacuo. Adding DCM to the residue resulted in precipitate formation. The solid was collected via filtration and washed with MeOH to afford 4-(5-chloro-2-fluoropyridin-3-yl)-6-methyl-1,3,5-triazin-2-amine (0.937 g) as a light yellow powder. The filtrate and the wash were combined and concentrated, then purified by column chromatography (eluent: iPrOH (w/10% NH4OH) in CHCl3 0.25% to 6.25%) followed by washing with MeOH to afford additional product (0.149 g) as a white solid. The total yield is 1.08 g (65%). 1H NMR (400 MHz, DMSO-d6) δ ppm 8.54 (dd, J=8.02, 2.74 Hz, 1H) 8.46-8.51 (m, 1H) 7.73 (s, 2H) 2.37 (s, 3H). m/z (ESI, positive ion) m/z: 240.1 (M+H)+.
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[CH3:15][O:16][P:17]([O:20]C)[O:18][CH3:19]>C1(C)C=CC=CC=1>[CH3:15][O:16][P:17]([CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)(=[O:20])[O:18][CH3:19]
Reactant: COP(OC)OC
Reactant: BrCc1ccccc1-c1ccccc1
Solvent: Cc1ccccc1
Product: COP(=O)(Cc1ccccc1-c1ccccc1)OC
Yield: 96.9 %

Procedure:
A solution of 2-(bromomethyl)biphenyl (4.94 g, 0.020 M) and trimethylphosphite (5.0 mL, 5.26 g, 0.042 M) in toluene (25 mL) is heated at reflux temperature for 24 hours Toluene and excess trimethylphosphite are removed under reduced pressure and the oily residue is chromatographed over silica gel (195 g, 40-63 pm, EtOAc, 50 mL fractions) using EtOAc to elute the column. The title compound (5.35 g, 0.0194 M, 97%) is obtained in fractions 10-19 and is a colorless viscous oil.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]2C(C#N)[C:8]3[CH:15]=[CH:14][CH:13]=[CH:12][C:9]=3[O:10][CH2:11][C:2]=12.Cl.[C:19]([OH:22])(=[O:21])[CH3:20].[OH-].[Na+]>ClCCl.O>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]2[CH:20]([C:19]([OH:22])=[O:21])[C:12]3[CH:13]=[CH:14][CH:15]=[CH:8][C:9]=3[O:10][CH2:11][C:2]=12
Reactant: CC(=O)O
Reactant: N#CC1c2ccccc2OCc2ncccc21
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: ClCCl
Product: O=C(O)C1c2ccccc2OCc2ncccc21

Procedure:
A mixture of 2.03 g of 5,11-dihydrobenzoxepino[3,4-b]pyridin-5-carbonitrile, 30 ml of hydrochloric acid and 30 ml of acetic acid was heated under reflux for 19 hours. The reaction mixture was allowed to stand at room temperature. Water and dichloromethane were added to the reaction mixture and the pH was adjusted to 3.4 with 10N sodium hydroxide. The organic layer was dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated to dryness under reduced pressure to obtain 1.95 g of Compound U.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:13]#[CH:14])[CH:6]=[C:7]([O:11][CH3:12])[C:8]=1[O:9][CH3:10].C#CCCCCCC.I[C:24]1[CH:25]=[C:26]([C:30]#[C:31][C:32]2([NH:40][C:41](=[O:47])[O:42][C:43]([CH3:46])([CH3:45])[CH3:44])[CH2:37][O:36][C:35]([CH3:39])([CH3:38])[O:34][CH2:33]2)[CH:27]=[CH:28][CH:29]=1.IC1C=C2C(=CC=1)CN(C(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)C2>>[C:43]([O:42][C:41](=[O:47])[NH:40][C:32]1([C:31]#[C:30][C:26]2[CH:27]=[CH:28][CH:29]=[C:24]([C:14]#[C:13][C:5]3[CH:6]=[C:7]([O:11][CH3:12])[C:8]([O:9][CH3:10])=[C:3]([O:2][CH3:1])[CH:4]=3)[CH:25]=2)[CH2:33][O:34][C:35]([CH3:39])([CH3:38])[O:36][CH2:37]1)([CH3:44])([CH3:45])[CH3:46]
Reactant: C#Cc1cc(OC)c(OC)c(OC)c1
Reactant: CC(C)(C)OC(=O)NC1(C#Cc2cccc(I)c2)COC(C)(C)OC1
Agent: C#CCCCCCC
Agent: Ic1ccc2c(c1)CN(C(c1ccccc1)(c1ccccc1)c1ccccc1)C2
Product: COc1cc(C#Cc2cccc(C#CC3(NC(=O)OC(C)(C)C)COC(C)(C)OC3)c2)cc(OC)c1OC
Yield: 64 %

Procedure:
When 3,4,5-trimethoxyphenyl-acetylene was substituted for 1-octyne and the product of Step A was substituted for 5-iodo-2-tritylisoindoline in Example 2, Step D, the similar process afforded the title compound in 64% yield, as pale paste. 1H-NMR (CDCl3) 1.43 (s, 3H); 1.47 (s, 9H); 1.49 (5, 3H); 3.84 (s, 3H); 3.87 (s, 6H); 4.00 (d, 2H, J=11.4 Hz); 4.10 (d, 2H, J=11.33 Hz); 5.19 (broad s, 1H), 6.74 (s, 2H); 6.74-6.76 (m, 1H); 7.26-7.38 (m, 1H); 7.43 (d, 1H, J=7.67 Hz); 7.60 (broad s, 1H).
Reaction SMILES: [NH:1]([C:5]1[NH:6][CH2:7][CH2:8][CH2:9][N:10]=1)[N+]([O-])=O.N[CH2:12][CH:13]([OH:20])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C1(C)C(C)=CC=CC=1>O>[NH:6]1[CH2:7][CH2:8][CH2:9][N:10]=[C:5]1[NH:1][CH2:12][CH:13]([OH:20])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: O=[N+]([O-])NC1=NCCCN1
Reactant: NCC(O)c1ccccc1
Solvent: O
Solvent: Cc1ccccc1C
Product: OC(CNC1=NCCCN1)c1ccccc1

Procedure:
A mixture of 7.2 parts of 1,4,5,6-tetrahydro-2-nitraminopyrimidine, 7.55 parts of α-(aminomethyl)benzyl alcohol and 12 parts of xylene is stirred and refluxed for 4 hours on a water-tap. The xylene is evaporated and the residue is dissolved in 20 parts of acetone. The product is crystallized at room temperature. It is filtered off and dried, yielding α-(1,4,5,6-tetrahydro-2-pyrimidinylaminomethyl)benzyl alcohol.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][CH:6]=1)=[O:4].[C-:14]#[N:15].[Na+].Cl>C(O)C.O>[C:14]([CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][CH:6]=1)=[O:4])#[N:15]
Reactant: [C-]#N
Reactant: O=C(CBr)c1ccc([N+](=O)[O-])cc1
Agent: Cl
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: N#CCC(=O)c1ccc([N+](=O)[O-])cc1
Temperature: 0 °C

Procedure:
To a solution of 2-bromo-4′-nitroacetophenone (30 g, 0.123 mol) in ethanol (200 mL) at 0° C. was added a solution of NaCN (18 g, 0.368 mol) in H2O (60 mL) dropwise over 1 h. Upon completion of the addition, the mixture was stirred at 0° C. for an additional hour and then diluted with H2O (200 mL). The solution was treated with 1N aq. HCl solution, to a pH of 2, and extracted with CH2Cl2 (2×500 ML). The combined organic layers were dried over Na2SO4 and concentrated by rotary evaporation. The residue was purified by flash chromatography on silica gel eluting with 1:1 hexane/EtOAc to obtain 2-cyano-4′nitroacetophenone as an orange solid.
Reaction SMILES: C(O[CH:5]1[S:9][C@H:8]([CH2:10][O:11][Si:12]([C:25]([CH3:28])([CH3:27])[CH3:26])([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH2:7][CH2:6]1)(=O)C.[Cl:29][C:30]1[N:38]=[C:37]2[C:33]([NH:34][CH:35]=[N:36]2)=[C:32]([Cl:39])[N:31]=1.C1(C)C=CC=CC=1.[Cl-].C([Al+]CC)C>C(#N)C>[Si:12]([O:11][CH2:10][C@H:8]1[S:9][CH:5]([N:36]2[CH:35]=[N:34][C:33]3[C:37]2=[N:38][C:30]([Cl:29])=[N:31][C:32]=3[Cl:39])[CH2:6][CH2:7]1)([C:25]([CH3:27])([CH3:26])[CH3:28])([C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1)[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: CC(=O)OC1CC[C@@H](CO[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)S1
Reactant: Clc1nc(Cl)c2[nH]cnc2n1
Agent: CC[Al+]CC
Agent: [Cl-]
Solvent: Cc1ccccc1
Solvent: CC#N
Product: CC(C)(C)[Si](OC[C@@H]1CCC(n2cnc3c(Cl)nc(Cl)nc32)S1)(c1ccccc1)c1ccccc1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 30 %

Procedure:
A mixture of 10 (0.25 g, 0.6 mmol), 2,6-dichloropurine (0.142 g, 0.75 mmol) in 10 mL acetonitrile was cooled to 0° C. and a 1.8M toluene solution of diethyl aluminum chloride (0.345 mL, 0.62 mmol) was added over 1 min. Stirring was continued at 0° C. for 5 minutes and at 25° C. for 10 minutes. The reaction mixture was quenched by pouring into a mixture of 20 mL dichloromethane and 10 mL saturated NaHCO3. The organic phase was dried (MgSO4) and concentrated in vacuo. The residue was flash chromatographed with 15:1 toluene/ethyl acetate. Solvent removal gave 98 mg (30%) of 12. FAB MS 543 (M+H)+ ; 1H NMR (CDCl3) δ 8.47 (s, 1, H-8), 7.7 (m, 4, ArH), 7.45 (m, 6, ArH), 6.22 (m, 1, 1'-H), 3.96 (m, 1, 5'-H), 3.85 (m, 2, 4'-H, 5'-H), 2.45 (m, 2, 2'-H's), 2.25 (m, 1, 3'-H), 1.82 (m, 1, 3'-H), 1.1 (s, 9, t-butyl).
Reaction SMILES: [F:1][C:2]1[CH:3]=[N:4][C:5]([N:8]2[CH2:17][CH2:16][N+:11]3([CH2:15][CH2:14][CH2:13][CH2:12]3)[CH2:10][CH2:9]2)=[N:6][CH:7]=1.[Cl:18][C:19]1[N:20]=[C:21]([CH3:25])[NH:22][C:23]=1[Cl:24].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[Cl:18][C:19]1[N:20]=[C:21]([CH3:25])[N:22]([CH2:12][CH2:13][CH2:14][CH2:15][N:11]2[CH2:10][CH2:9][N:8]([C:5]3[N:6]=[CH:7][C:2]([F:1])=[CH:3][N:4]=3)[CH2:17][CH2:16]2)[C:23]=1[Cl:24]
Reactant: Fc1cnc(N2CC[N+]3(CCCC3)CC2)nc1
Reactant: Cc1nc(Cl)c(Cl)[nH]1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1nc(Cl)c(Cl)n1CCCCN1CCN(c2ncc(F)cn2)CC1
Yield: 85.2 %

Procedure:
A mixture of 3.17 g (0.01 mol) of 8-(5-fluoro-2-pyrimidinyl)-8-aza-5-azoniaspiro[4.5]decane, 2.26 g (0.015 mol) of 4,5-dichloro-2-methyl-1H-imidazole and 76 g (0.02 mol) of potassium carbonate in 80 ml of dimethylformamide is maintained at reflux for 12 hours. The mixture is subsequently evaporated to dryness and the resulting crude product is redissolved in chloroform and washed repeatedly with water. The organic phase is dried and evaporated, and then the resulting crude product is purified by chromatography on a column of silica gel. 3.3 g (85% yield) of 2-{4-[4-(4,5-dichloro-2-methylimidazol-1-yl)butyl]piperazin-1-yl}-5-fluoropyrimidine are obtained in the form of an oil.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([CH2:7][NH:8][C:9]2[C:10]([OH:15])=[N:11][CH:12]=[CH:13][N:14]=2)[CH2:3][CH2:2]1.C(N(CC)CC)C.[CH2:23]([O:30][C:31](ON1C(=O)CCC1=O)=[O:32])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>CN(C=O)C>[CH2:23]([O:30][C:31]([N:1]1[CH2:6][CH2:5][CH:4]([CH2:7][NH:8][C:9]2[C:10]([OH:15])=[N:11][CH:12]=[CH:13][N:14]=2)[CH2:3][CH2:2]1)=[O:32])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: Oc1nccnc1NCC1CCNCC1
Reactant: O=C(OCc1ccccc1)ON1C(=O)CCC1=O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=C(OCc1ccccc1)N1CCC(CNc2nccnc2O)CC1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a solution of 3-[(piperidin-4-ylmethyl)-amino]-pyrazin-2-ol from Step 1 above (0.287 g, 1.021 mmol) in DMF (5 mL) was added triethylamine (0.356 mL, 2.55 mmol), followed by N-(benzyloxycarbonyloxy)succinimide (0.305 g, 1.23 mmol). The resulting reaction mixture was stirred at rt for 15 min, then partitioned between EtOAc and water. The organic layer was washed with water and brine, dried over anhydrous sodium sulfate and the crude product purified by flash column chromatography (50% EtOAc hexane to 5% MeOH EtOAc) to give an oil which solidified on standing. M.S (M+1): 343.24.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[CH:14]=[CH:13][C:12]([CH:15](C)[CH2:16]C#N)=[CH:11][CH:10]=1.Cl.[C:21]([OH:24])(=[O:23])[CH3:22]>>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[CH:14]=[CH:13][C:12]([CH:15]([CH3:16])[CH2:22][C:21]([OH:24])=[O:23])=[CH:11][CH:10]=1
Reactant: CC(=O)O
Reactant: CC(CC#N)c1ccc(-c2ccc(F)cc2F)cc1
Agent: Cl
Product: CC(CC(=O)O)c1ccc(-c2ccc(F)cc2F)cc1

Procedure:
1 g. of 3-(2',4'-difluoro-4-biphenylyl)butyronitrile and 6 ml. of acetic acid and 6 ml. of concentrated hydrochloric acid are heated under reflux for 2 hours under nitrogen. The mixture is evaporated. The residue is dissolved in dilute NaOH and the solution is washed with ether and worked up in the customary manner to give 3-(2',4'-difluoro-4-biphenylyl)butyric acid, m.p. 109°-110°.
Reaction SMILES: IC.[H-].[Na+].[C:5]([CH:9]1[CH:13]([C:14]([OH:16])=[O:15])[CH2:12][C:11](=[O:17])[N:10]1[C@@H:18]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[CH3:19])([CH3:8])([CH3:7])[CH3:6].[C:26](O)(=O)CC(CC(O)=O)(C(O)=O)O>CN(C=O)C>[C:5]([CH:9]1[C@@:13]([CH3:26])([C:14]([OH:16])=[O:15])[CH2:12][C:11](=[O:17])[N:10]1[C@@H:18]([C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1)[CH3:19])([CH3:6])([CH3:7])[CH3:8]
Reactant: C[C@H](c1ccccc1)N1C(=O)CC(C(=O)O)C1C(C)(C)C
Reactant: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [H-]
Agent: [Na+]
Solvent: CI
Solvent: CN(C)C=O
Product: C[C@H](c1ccccc1)N1C(=O)C[C@](C)(C(=O)O)C1C(C)(C)C
Temperature: 30 °C
Yield: 33.7 %

Procedure:
Under a nitrogen gas atmosphere, iodomethane (26.0 mL, 59.28 g, 0.418 mol) and sodium hydride (oil content: 55%, 11.35 g, 0.260 mol) were sequentially added at room temperature to a solution of t-butyl 5-oxo-1-[(1R)-1-phenylethyl]pyrrolidine-3-carboxylic acid (30.05 g, 0.104 mol) in N,N′-dimethylformamide (210 mL) with stirring. When the internal temperature reached to about 50° C., the mixture was cooled to 30° C. in an ice-water bath. Subsequently, the bath was changed to a water bath having an external temperature of 17° C., followed by stirring for 23 hours. The reaction mixture was poured into cold aqueous citric acid (a mixture of 10% citric acid (1 L) and ice (500 g)), followed by stirring for 30 minutes and extracting with ethyl acetate (800 mL, 500 mL). The organic layers were combined. The combined organic layer was washed with saturated brine, followed by drying over sodium sulfate anhydrate and filtration. The filtrate was evaporated to dryness under reduced pressure. The residue was purified through flash silica gel column chromatography (eluent; hexane:ethyl acetate=5:1 to 4:1), to thereby yield the title compound as white solid (10.63 g, 33.7%) as a high-polar isomer. In addition, t-butyl (3R)-3-methyl-5-oxo-1-[(1R)-1-phenylethyl]pyrrolidine-3-carboxylic acid (14.91 g, 47.3%) was produced as a low-polar isomer.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[N:6]=[C:5]([SH:11])[N:4]=1.[OH-].[K+].[N+]([N:17]1[CH:21]=[C:20]([N+:22]([O-:24])=[O:23])[C:19]([CH3:25])=[N:18]1)([O-])=O>O.C(O)C>[CH3:10][O:9][C:7]1[CH:8]=[C:3]([O:2][CH3:1])[N:4]=[C:5]([S:11][C:21]2[NH:17][N:18]=[C:19]([CH3:25])[C:20]=2[N+:22]([O-:24])=[O:23])[N:6]=1
Reactant: Cc1nn([N+](=O)[O-])cc1[N+](=O)[O-]
Reactant: COc1cc(OC)nc(S)n1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: COc1cc(OC)nc(Sc2[nH]nc(C)c2[N+](=O)[O-])n1
Reaction time: 0.75 h
Yield: 78.5 %

Procedure:
4,6-Dimethoxy-2-mercaptopyrimidine (4.65 g) was dissolved in water containing potassium hydroxide (1.7 g in 75 mls of water). 1,4-Dinitro-3-methylpyrazole (4.65 g) dissolved in the minimum of ethanol was then added dropwise. After the exothermic reaction had subsided, the mixture was stirred for 45 minutes. The precipitated solid was filtered off, washed with fresh water, and dried to give 6.3 g of the desired product, mp 175°-6° C.
Reaction SMILES: C(N(CC)CC)C.[CH3:8][NH:9][NH2:10].[CH2:11]([N:13]1[C:18](S(C)=O)=[C:17]([C:22]#[N:23])[C:16](=[O:24])[N:15]2[N:25]=[CH:26][CH:27]=[C:14]12)[CH3:12]>C(O)C>[NH2:23][C:22]1[C:17]2[C:16](=[O:24])[N:15]3[N:25]=[CH:26][CH:27]=[C:14]3[N:13]([CH2:11][CH3:12])[C:18]=2[N:9]([CH3:8])[N:10]=1
Reactant: CNN
Reactant: CCn1c(S(C)=O)c(C#N)c(=O)n2nccc12
Solvent: CCO
Solvent: CCN(CC)CC
Product: CCn1c2c(c(N)nn2C)c(=O)n2nccc12
Temperature: 60 °C
Reaction time: 0.5 h
Yield: 64 %

Procedure:
Triethylamine (1.44 g) and methylhydrazine (1.44 g) were added to a solution of 3.2 g of 4-ethyl-5-methanesulfinyl-7-oxo-4,7-dihydropyrazolo[1,5-a]pyrimidine-6-carbonitrile in 100 ml of ethanol and stirred at 60° C. for 30 minutes. The reaction mixture was cooled and the crystals precipitated were collected by filtration and sequentially washed with ethanol, methanol and diethyl ether to provide 1.9 g of the title compound as colorless crystals. The structure and melting point of the compound obtained are shown in Table 1.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([N:9]2[CH2:14][CH2:13][CH2:12][C@@H:11]([C:15]([OH:17])=[O:16])[CH2:10]2)=[N:6][C:7]=1[NH2:8].CN(C)C=O.[CH:23]1([C:26]2[N:31]=[C:30]([CH:32]=O)[CH:29]=[CH:28][N:27]=2)[CH2:25][CH2:24]1.C(O)(=O)C>>[CH:23]1([C:26]2[N:31]=[C:30]([C:32]3[NH:8][C:7]4=[N:6][C:5]([N:9]5[CH2:14][CH2:13][CH2:12][C@@H:11]([C:15]([OH:17])=[O:16])[CH2:10]5)=[CH:4][CH:3]=[C:2]4[N:1]=3)[CH:29]=[CH:28][N:27]=2)[CH2:25][CH2:24]1
Reactant: O=Cc1ccnc(C2CC2)n1
Reactant: Nc1ccc(N2CCC[C@@H](C(=O)O)C2)nc1N
Solvent: CC(=O)O
Solvent: CN(C)C=O
Product: O=C(O)[C@@H]1CCCN(c2ccc3nc(-c4ccnc(C5CC5)n4)[nH]c3n2)C1
Temperature: 60 °C
Reaction time: 16 h

Procedure:
To a solution of (R)-1-(5,6-diaminopyridin-2-yl)piperidine-3-carboxylic acid in N,N-dimethylformamide (49 mL, 12.25 mmol, 0.25M) was added a solution of 2-cyclopropylpyrimidine-4-carbaldehyde in N,N-dimethylformamide (49 mL, 12.25 mmol, 0.25M) followed by acetic acid (7.35 mL, 122.5 mmol). The reaction mixture was stirred at 60° C. for 16 h. The solvent was removed under reduced pressure and the residue was purified via HPLC to afford (R)-1-(2-(2-cyclopropylpyrimidin-4-yl)-3H-imidazo[4,5-b]pyridin-5-yl)piperidine-3-carboxylic acid.