Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH:2]([CH3:18])[C:3]([O:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])=[O:4].C(=O)(O)[O-].[Na+].[CH:24]([NH2:27])([CH3:26])[CH3:25]>C(#N)C>[CH:24]([NH:27][CH:2]([CH3:18])[C:3]([O:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])=[O:4])([CH3:26])[CH3:25]
Reactant: CC(C)N
Reactant: CCCCCCCCCCCCOC(=O)C(C)Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Product: CCCCCCCCCCCCOC(=O)C(C)NC(C)C
Temperature: 57.5 °C
Reaction time: 12 h
Yield: 75.2 %

Procedure:
To a stirred solution of 59 (10 g, 31.2 mmol) in acetonitrile (30 mL) was added sodium bicarbonate (2.62 g, 31.2 mmol) and followed by isopropyl amine (50% in water) (30 mL, 3 vol) at 25-30° C. The reaction mixture was stirred for 12 h at 55-60° C. and the reaction was monitored by TLC. The solid obtained in the reaction mixture was filtered under vacuum. The solvent was concentrated, diluted with ethyl acetate/water and stirred for 15 minutes at 25-30° C. The aqueous and organic layers were separated, and the aqueous layer was extracted with ethyl acetate (2×10 mL). The combined organic layers were washed with brine solution. The organic layer was dried over Na2SO4 and concentrated under vacuum to afford crude 62 (7 g, yield: 75.2%) as a liquid.
Reaction SMILES: C(N)CN.ClCC1SC=CN=1.[S:12]1[CH:16]=[CH:15][N:14]=[C:13]1[CH2:17][NH:18][CH2:19][CH2:20][NH2:21].[C:22]([NH:24][C:25](=[N:28][CH3:29])SC)#[N:23]>>[C:22]([NH:24][C:25]([NH:28][CH3:29])=[N:21][CH2:20][CH2:19][NH:18][CH2:17][C:13]1[S:12][CH:16]=[CH:15][N:14]=1)#[N:23]
Reactant: CN=C(NC#N)SC
Reactant: NCCNCc1nccs1
Agent: ClCc1nccs1
Solvent: NCCN
Product: CNC(=NCCNCc1nccs1)NC#N

Procedure:
Reacting ethylenediamine with 2-chloromethylthiazole by the procedure of Example 34, then reacting the resulting N-(2-thiazolylmethyl)ethylenediamine with N-cyano-N',S-dimethylisothiourea by the procedure of Example 3(a), gives N-cyano-N'-methyl-N"-[2-(2-thiazolylmethylamino)ethyl]guanidine. Hydrolysis of this compound by the procedure of Example 3(e) gives N-methyl-N'-[2-(2-thiazolylmethylamino)ethyl]guanidine trihydrochloride.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:4]=[N:5][N:6]([CH2:28][CH2:29][CH3:30])[C:7]=1[NH:8]C(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[ClH:31]>C(OCC)(=O)C.CO>[ClH:31].[ClH:31].[NH2:1][CH2:2][C:3]1[CH:4]=[N:5][N:6]([CH2:28][CH2:29][CH3:30])[C:7]=1[NH2:8]
Reactant: CCCn1ncc(CN)c1NC(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: Cl
Solvent: CO
Solvent: CCOC(C)=O
Product: CCCn1ncc(CN)c1N
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 4-aminomethyl-1-propyl-5-tritylaminopyrazole (9.6 g) in a mixture of ethyl acetate (150 ml) and methanol (30 ml) was added 4N hydrochloric acid in ethyl acetate (24.2 ml), and the mixture was stirred at room temperature for 2 hours. The resulting precipitate was collected by filtration and dried in vacuo to give 4-aminomethyl-1-propyl-5-aminopyrazole dihydrochloride (3.3 g).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:12])[CH2:5][N:6]1[CH:10]=[N:9][C:8]([NH2:11])=[N:7]1)[CH3:2].[Cl:13][C:14]1[S:18][C:17]([C:19](O)=[O:20])=[CH:16][CH:15]=1>>[CH2:1]([O:3][C:4](=[O:12])[CH2:5][N:6]1[CH:10]=[N:9][C:8]([NH:11][C:19]([C:17]2[S:18][C:14]([Cl:13])=[CH:15][CH:16]=2)=[O:20])=[N:7]1)[CH3:2]
Reactant: CCOC(=O)Cn1cnc(N)n1
Reactant: O=C(O)c1ccc(Cl)s1
Product: CCOC(=O)Cn1cnc(NC(=O)c2ccc(Cl)s2)n1

Procedure:
61.2 Using general method A, (3-amino-[1,2,4]triazol-1-yl)-acetic acid ethyl ester was coupled with 5-chlorothiophene-2-carboxylic acid to give {3-[(5-chloro-thiophene-2-carbonyl)-amino]-[1,2,4]triazol-1-yl}-acetic acid ethyl ester. Off-white solid. MS 315.1 ([M+H]+)
Reaction SMILES: [C:1]([CH:5]([NH:8][CH:9]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:10]([OH:12])=O)[CH:6]=[CH2:7])([O:3][CH3:4])=[O:2].O1CCCC1.ClC(OC)=O.[NH2:29][CH:30]1[C:56](=[O:57])[N:32]2[CH:33]([C:40]([O:42][CH:43]([C:50]3[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=3)[C:44]3[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=3)=[O:41])[C:34]([C:37](=[O:39])[CH3:38])=[CH:35][S:36][C@H:31]12>CN(CC1C=CC=CC=1)C.C(OCC)(=O)C>[C:1]([CH:5]([NH:8][CH:9]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:10]([NH:29][CH:30]1[C:56](=[O:57])[N:32]2[CH:33]([C:40]([O:42][CH:43]([C:50]3[CH:51]=[CH:52][CH:53]=[CH:54][CH:55]=3)[C:44]3[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=3)=[O:41])[C:34]([C:37](=[O:39])[CH3:38])=[CH:35][S:36][C@H:31]12)=[O:12])[CH:6]=[CH2:7])([O:3][CH3:4])=[O:2]
Reactant: C=CC(NC(C(=O)O)c1ccccc1)C(=O)OC
Reactant: CC(=O)C1=CS[C@@H]2C(N)C(=O)N2C1C(=O)OC(c1ccccc1)c1ccccc1
Agent: CN(C)Cc1ccccc1
Agent: COC(=O)Cl
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: C=CC(NC(C(=O)NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)C(C(C)=O)=CS[C@H]12)c1ccccc1)C(=O)OC
Temperature: -15 °C
Yield: 68 %

Procedure:
To a cooled (-15° C.), stirred slurry of 0.381 g. of 2-(1-carbomethoxy-2-propenylamino)-2-phenylacetic acid and 25 ml. of tetrahydrofuran was added three drops of N,N-dimethylbenzylamine and 0.109 ml. of methyl chloroformate. The reaction mixture was allowed to stir with cooling under an argon atmosphere for 10 minutes. The reaction mixture was then cooled to -20° C. and a solution of 0.521 g. of benzhydryl 7-amino-3-acetyl-2-cephem-4-carboxylate in 5 ml. of tetrahydrofuran was added dropwise. The resulting mixture was allowed to stir under argon with cooling for approximately one hour, after which time the mixture was transferred to a separatory funnel with the aid of cold ethyl acetate. The organic solution was washed with cold 1N.HCl, and brine, and then dried over anhydrous sodium sulfate. Evaporation in vacuo to dryness gave a product which was chromatographed on silica gel using a toluene-ethyl acetate gradient to give 0.556 g. (68 percent) of the title product as a tan froth:
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[C:5]([C:10]3[N:11]=[C:12]([N:35]4[CH2:40][CH2:39][O:38][CH2:37][CH2:36]4)[C:13]4[S:18][C:17]([CH2:19][N:20]([CH2:32][CH2:33][OH:34])[C:21]5[N:26]=[CH:25][C:24]([C:27](OCC)=[O:28])=[CH:23][N:22]=5)=[CH:16][C:14]=4[N:15]=3)[CH:6]=[CH:7][CH:8]=2)[CH:3]=[N:2]1.CO.[NH2:43][OH:44]>>[NH:1]1[C:9]2[C:4](=[C:5]([C:10]3[N:11]=[C:12]([N:35]4[CH2:36][CH2:37][O:38][CH2:39][CH2:40]4)[C:13]4[S:18][C:17]([CH2:19][N:20]([CH2:32][CH2:33][OH:34])[C:21]5[N:26]=[CH:25][C:24]([C:27]([NH:43][OH:44])=[O:28])=[CH:23][N:22]=5)=[CH:16][C:14]=4[N:15]=3)[CH:6]=[CH:7][CH:8]=2)[CH:3]=[N:2]1
Reactant: CCOC(=O)c1cnc(N(CCO)Cc2cc3nc(-c4cccc5[nH]ncc45)nc(N4CCOCC4)c3s2)nc1
Reactant: NO
Solvent: CO
Product: O=C(NO)c1cnc(N(CCO)Cc2cc3nc(-c4cccc5[nH]ncc45)nc(N4CCOCC4)c3s2)nc1

Procedure:
The title compound 86 was prepared (42 mg, 36%) as an off-white solid from 0505-86 (120 mg, 0.21 mmol) and freshly prepared hydroxylamine methanol solution (8.0 mL) using a procedure similar to that described for compound 3 (Example 1): m.p. 190-194° C. LCMS: 548 [M+1]+; 1H NMR (400 MHz, DMSO-d6): δ 3.64 (dd, J1=10.8 Hz, J2=5.6 Hz, 2H), 3.79 (dd, J1=8.4 Hz, J2=4.4 Hz, 6H), 3.95 (t, J=4.4 Hz, 4H), 4.85 (t, J=5.2 Hz, 1H), 5.25 (s, 2H), 7.46 (t, J=7.8 Hz, 1H), 7.57 (s, 1H), 7.66 (d, J=8.4 Hz, 1H), 8.21 (d, J=6.8 Hz, 1H), 8.74 (s, 2H), 8.87 (s, 1H), 9.07 (s, 1H), 11.13 (s, 1H), 13.20 (s, 1H).
Reaction SMILES: Cl[C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[C@@H:11]2[O:15][C@H:14]([CH2:16][OH:17])[C@H:13]([OH:18])[C@@H:12]2[OH:19])=[C:4]([NH:20][CH:21]2[CH2:25][CH2:24][CH2:23][CH2:22]2)[N:3]=1.O.[NH2:27][NH2:28]>>[NH:27]([C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[C@H:11]2[C@H:12]([OH:19])[C@H:13]([OH:18])[C@@H:14]([CH2:16][OH:17])[O:15]2)=[C:4]([NH:20][CH:21]2[CH2:25][CH2:24][CH2:23][CH2:22]2)[N:3]=1)[NH2:28]
Reactant: OC[C@H]1O[C@@H](n2cnc3c(NC4CCCC4)nc(Cl)nc32)[C@@H](O)[C@H]1O
Reactant: NN
Solvent: O
Product: NNc1nc(NC2CCCC2)c2ncn([C@@H]3O[C@H](CO)[C@@H](O)[C@H]3O)c2n1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
(4S,2R,3R,5R) 5-[2-chloro-6-(cyclopentylamino)purin-9-yl]-2-(hydroxymethyl)oxolane-3,4-diol, a compound of formula (2) as prepared in Example 1A, was suspended in hydrazine hydrate (5 mL), and the mixture was allowed to stir at room temperature for 24 hours. The hydrazine was removed by filtration and the residue triturated with ethanol and filtered, to afford (4S,2R,3R,5R)-2-[2-hydrazino-6-(cyclopentylamino)purin-9-yl]-5-(hydroxymethyl)oxolane-3,4-diol, a compound of formula (3), as a white solid.
Reaction SMILES: [CH3:1][C:2]([N:9]1[CH:13]=[CH:12][CH:11]=[N:10]1)([CH3:8])[C:3]([O:5][CH2:6][CH3:7])=[O:4].[Br:14]N1C(=O)CCC1=O>CC1CCCO1>[Br:14][C:12]1[CH:11]=[N:10][N:9]([C:2]([CH3:1])([CH3:8])[C:3]([O:5][CH2:6][CH3:7])=[O:4])[CH:13]=1
Reactant: CCOC(=O)C(C)(C)n1cccn1
Reactant: O=C1CCC(=O)N1Br
Solvent: CC1CCCO1
Product: CCOC(=O)C(C)(C)n1cc(Br)cn1

Procedure:
Ethyl 2-methyl-2-(1H-pyrazol-1-yl)propanoate 17 was reacted with N-bromosuccinimide (NBS) in 2-methyltetrahydrofuran to give IV (CAS Reg. No. 1040377-17-0).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([CH:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)=[O:9])=[CH:4][CH:3]=1.[CH2:16]([O:18][C:19](=[O:22])[CH2:20]Br)[CH3:17].C(N(CC)CC)C>C(#N)C>[CH2:16]([O:18][C:19](=[O:22])[CH2:20][N:13]1[CH2:14][CH2:15][CH:10]([C:8](=[O:9])[C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)[CH2:11][CH2:12]1)[CH3:17]
Reactant: O=C(c1ccc(Cl)cc1)C1CCNCC1
Reactant: CCOC(=O)CBr
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CCOC(=O)CN1CCC(C(=O)c2ccc(Cl)cc2)CC1
Temperature: 85 °C
Reaction time: 15 h
Yield: 81.6 %

Procedure:
To a suspension of (4-chloro-phenyl)-piperidin-4-yl-methanone (1.0 g, 3.8 mmol) and bromo-acetic acid ethyl ester (0.71 g, 4.2 mmol) in acetonitrile (10 mL) was added triethylamine (0.78 g, 7.7 mmol), the reaction mixture was stirred at 85° C. for 15 h. The reaction mixture was cooled to ambient temperature, the solvent was removed, the residue was redissolved in DCM (20 mL), washed with water (20 mL), the organic layers were then washed with brine (20 mL) and dried over Na2SO4. Purification by flash chromatography gave the title compound as a white solid (1.01 g, 3.10 mmol, 81% yield). MS (ESI) m/z 310.3 (M+H+); HPLC (Novapak 150×3.9 mm C-18 column: mobile phase: 35-90% acetonitrile/water with 0.1% TFA, at 2 mL/min over 2 min.) t 1.45 min.
Reaction SMILES: CO[C:3]([C:5]1[CH:10]=[C:9]([Cl:11])[CH:8]=[CH:7][N:6]=1)=[O:4].[Mg+2].[Cl-].[Cl-].[NH:15]1[CH2:19][CH2:18][CH2:17][CH2:16]1.Cl>C1COCC1.C(OCC)(=O)C>[Cl:11][C:9]1[CH:8]=[CH:7][N:6]=[C:5]([C:3]([N:15]2[CH2:19][CH2:18][CH2:17][CH2:16]2)=[O:4])[CH:10]=1
Reactant: C1CCNC1
Reactant: COC(=O)c1cc(Cl)ccn1
Agent: Cl
Agent: [Cl-]
Agent: [Mg+2]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: O=C(c1cc(Cl)ccn1)N1CCCC1
Reaction time: 0.08 h

Procedure:
4-Chloro-pyridine-2-carboxylic acid methylester (200 mg, 1.17 mmol) and MgCl2 (555 mg, 0.58 mmol) are suspended in THF (5 mL) at rt. The mixture is stirred for 5 min and then pyrrolidine (193 μL, 2.33 mmol) is added and the mixture stirred for an additional 15 min. It is worked up by addition of aqueous HCl solution (1M, 1.2 mL) and extraction with ethyl acetate. The combined organic extracts are washed with brine dried over MgSO4. The volatiles are removed under reduced pressure to give the title compound as a yellow oil: C10H11ClN2O: M+=211.3; 1H-NMR (DMSO-d6): 8.55 (d, 1H), 7.82 (s, 1H), 7.59 (d, 1H), 3.62-3.42 (m, 4H), 1.93-1.75 (m, 4H).
Reaction SMILES: [PH2](O)=O.C(N1CCCCC1)C.[CH2:12]=[CH:13][S:14]([O:17][C:18]1[C:23]([F:24])=[C:22]([F:25])[C:21]([F:26])=[C:20]([F:27])[C:19]=1[F:28])(=[O:16])=[O:15].I[CH2:30][C@@H:31]1[CH2:35][CH2:34][CH2:33][N:32]1[C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37].C(B(CC)CC)C>C(Cl)Cl>[F:24][C:23]1[C:22]([F:25])=[C:21]([F:26])[C:20]([F:27])=[C:19]([F:28])[C:18]=1[O:17][S:14]([CH2:13][CH2:12][CH2:30][C@@H:31]1[CH2:35][CH2:34][CH2:33][N:32]1[C:36]([O:38][C:39]([CH3:40])([CH3:42])[CH3:41])=[O:37])(=[O:16])=[O:15]
Reactant: C=CS(=O)(=O)Oc1c(F)c(F)c(F)c(F)c1F
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1CI
Agent: CCB(CC)CC
Agent: CCN1CCCCC1
Agent: O=[PH2]O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC[C@H]1CCCS(=O)(=O)Oc1c(F)c(F)c(F)c(F)c1F
Temperature: 0 °C
Reaction time: 0 h

Procedure:
1-Ethylpiperidine hypophosphite (30 g, 168 mmol) were weighed into the reaction flask under an inert gas, and methylene chloride (100 ml) was added. The solution was cooled with ice-water and 2,3,4,5,6-pentafluorophenyl 1-ethylenesulfonate (5.06 g, 18.5 mmol) [Org. Lett.; 2002; 4(15); 2549-2551] and (S)-tert-butyl 2-(iodomethyl)pyrrolidine-1-carboxylate (5.22 g, 16.8 mmol) was added at 10° C. Triethylborane solution (1.6 ml, 1 mol/l) was added and compressed air was then passed through the mixture for 5 sec. After stirring for min the addition of triethylborane solution-compressed air was repeated with the same amount. The cooling bath was removed, the mixture was stirred for 10 min and the reaction mixture was then washed with water (20 ml) and saturated sodium chloride solution (20 ml), dried over sodium sulfate and concentrated in vacuo. The crude product was purified by column chromatography (silica gel) with hexane/diethyl ether (2:1). Yield: 2.81 g (36%)
Reaction SMILES: [CH3:1][N:2]([CH3:15])[CH2:3][CH2:4][CH2:5][C:6]#[C:7][C:8]1[CH:9]=[N:10][C:11]([NH2:14])=[N:12][CH:13]=1.[F:16][C:17]([F:29])([F:28])[C:18]1[CH:23]=[CH:22][C:21]([S:24](Cl)(=[O:26])=[O:25])=[CH:20][CH:19]=1>N1C=CC=CC=1>[CH3:15][N:2]([CH3:1])[CH2:3][CH2:4][CH2:5][C:6]#[C:7][C:8]1[CH:9]=[N:10][C:11]([NH:14][S:24]([C:21]2[CH:20]=[CH:19][C:18]([C:17]([F:16])([F:28])[F:29])=[CH:23][CH:22]=2)(=[O:26])=[O:25])=[N:12][CH:13]=1
Reactant: CN(C)CCCC#Cc1cnc(N)nc1
Reactant: O=S(=O)(Cl)c1ccc(C(F)(F)F)cc1
Solvent: c1ccncc1
Product: CN(C)CCCC#Cc1cnc(NS(=O)(=O)c2ccc(C(F)(F)F)cc2)nc1
Temperature: 70 °C
Yield: 33.9 %

Procedure:
A solution of 102 mg (0.5 mmol) of 5-(5-Dimethylamino-pent-1-ynyl)-pyrimidin-2-ylamine in 3.9 ml pyridine was treated with 257 mg (1.05 mmol) 4-(trifluoromethyl)benzenesulfonyl chloride. The reaction was stirred over night at 70° C., evaporated and extracted with aqueous saturated NaHCO3(2×)/CH2Cl2 (3×). The organic phases were washed with aqueous 10% NaCl solution, dried (Na2SO4) and evaporated. Flash column chromatography on silica gel with CH2Cl2/MeOH (95:5 to 9:1) yielded 70 mg (34%) of N-[5-(5-Dimethylamino-pent-1-ynyl)-pyrimidin-2-yl]-4-trifluoromethyl-benzenesulfonamide, mp: 194-202° C.,slowly dec.; MS: 413 (MH+).
Reaction SMILES: [C:1]([O:5][C:6](=[O:36])[NH:7][C:8]1([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[C:27](=[O:28])[C:26]4[C:21](=[CH:22][CH:23]=[C:24](F)[CH:25]=4)[O:20][C:19]=3[C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)=[CH:14][CH:13]=2)[CH2:11][CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].IC1C(=O)C2C(=CC=C(OC)C=2)[O:40][C:39]=1C1C=CC=CC=1>>[C:1]([O:5][C:6](=[O:36])[NH:7][C:8]1([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[C:27](=[O:28])[C:26]4[C:21](=[CH:22][CH:23]=[C:24]([O:40][CH3:39])[CH:25]=4)[O:20][C:19]=3[C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)=[CH:14][CH:13]=2)[CH2:11][CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: COc1ccc2oc(-c3ccccc3)c(I)c(=O)c2c1
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(-c3c(-c4ccccc4)oc4ccc(F)cc4c3=O)cc2)CCC1
Product: COc1ccc2oc(-c3ccccc3)c(-c3ccc(C4(NC(=O)OC(C)(C)C)CCC4)cc3)c(=O)c2c1
Yield: 44 %

Procedure:
Following the procedure used to prepare {1-[4-(6-fluoro-4-oxo-2-phenyl-4H-chromen-3-yl)-phenyl]-cyclobutyl}-carbamic acid tert-butyl ester, 3-iodo-6-methoxy-2-phenyl-chromen-4-one (76 mg, 0.20 mmol) was reacted to give the title compound (42 mg, 44%). 1H NMR (400 MHz, CDCl3): δ 7.68-7.64 (d, 1H), 7.51-7.16 (m, 11H), 5.05 (s, 1H), 3.92 (s, 3H), 2.61-2.45 (m, 4H), 2.16-1.75 (m, 2H), 1.52-1.00 (m, 9H).
Reaction SMILES: [CH:1]1([NH2:6])[CH2:5][CH2:4][CH2:3][CH2:2]1.Cl[C:8]1[CH:13]=[CH:12][C:11]([N+:14]([O-:16])=[O:15])=[CH:10][N:9]=1>CN(C=O)C>[CH:1]1([NH:6][C:8]2[CH:13]=[CH:12][C:11]([N+:14]([O-:16])=[O:15])=[CH:10][N:9]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=[N+]([O-])c1ccc(Cl)nc1
Reactant: NC1CCCC1
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccc(NC2CCCC2)nc1
Temperature: 200 °C

Procedure:
To a 20 mL vial containing cyclopentylamine (300 mg, 3.53 mmol) was added DMF (5 mL), 2-chloro-5-nitro-pyridine (559 mg, 3.53 mmol), and the TEA (0.98 mL). The vessel was purged with argon, sealed, and heat by microwave at 200° C. for 5 min (Personal Chemistry, Emrys Optimizer). The reaction mixture was concentrated, diluted with water (100 mL) and extracted with ethyl acetate. The organic layer was washed with saturated sodium bicarbonate (100 mL) and brine (100 mL), dried over sodium sulfate, and evaporated to give cyclopentyl-(5-nitro-pyridin-2-yl)-amine. LCMS calcd. C10H13N3O2 (m/e) 207, observed 208 (M+H). This intermediate nitropyridyl compound was transferred to a PARR vessel with MeOH (5 mL), Pd/C (10%) was added and the vessel was pressurized with H2 at 55 psi and shaken for 2.5 hr. The mixture was then filtered through a bed of celite and concentrated to dryness twice from CH2Cl2. The purple black material was used immediately for amide coupling (LCMS calcd. for C10H15N3 (m/e) 177, observed 178 (M+H).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH:7]=O)[CH:2]=1.[CH3:9][O:10][C:11]1[CH:12]=[C:13]([CH:17]=[CH:18][C:19]=1[O:20][CH3:21])[CH2:14][C:15]#[N:16]>>[CH3:9][O:10][C:11]1[CH:12]=[C:13](/[C:14](=[CH:7]/[C:3]2[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=2)/[C:15]#[N:16])[CH:17]=[CH:18][C:19]=1[O:20][CH3:21]
Reactant: O=Cc1cccnc1
Reactant: COc1ccc(CC#N)cc1OC
Product: COc1ccc(/C(C#N)=C/c2cccnc2)cc1OC
Yield: 90 %

Procedure:
3-Pyridinecarboxaldehyde (2.14 g) was condensed with 3,4-dimethoxybenzyl cyanide (3.54 g) through Method A (production step 2), to thereby yield the target product (yield: 4.79 g, 90%).
Reaction SMILES: [Na].[OH:2][CH:3]([C:9]([C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([C:17](=[O:24])[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:12]=1)=[CH2:10])[C:4]([O:6][CH2:7][CH3:8])=[O:5].C(O)(=O)C>C(O)C>[CH3:10][CH:9]([C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([C:17](=[O:24])[C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH:12]=1)[C:3](=[O:2])[C:4]([O:6][CH2:7][CH3:8])=[O:5]
Reactant: C=C(c1cccc(C(=O)c2ccccc2)c1)C(O)C(=O)OCC
Agent: [Na]
Solvent: CC(=O)O
Solvent: CCO
Product: CCOC(=O)C(=O)C(C)c1cccc(C(=O)c2ccccc2)c1
Yield: 73.3 %

Procedure:
To a solution of 0.5 g of metallic sodium in 50 ml of anhydrous ethanol was added a solution of 3.0 g of ethyl 2-hydroxy-3-(3-benzoylphenyl)-3-butenoate in 20 ml of anhydrous ethanol. The resulting mixture was refluxed for 20 minutes and then cooled. The reaction liquid was charged with 5 ml of glacial acetic acid, and the ethanol was removed therefrom by distillation at a low temperature and under reduced pressure. The residue was charged with ethyl acetate and water, thereby effecting ethyl acetate extraction. The ethyl acetate layer was successively washed with water, aqueous sodium bicarbonate solution and water, and then dried over anhydrous magnesium sulfate. Thereafter, the ethyl acetate was removed by distillation under reduced pressure to obtain 2.2 g of ethyl 3-methyl-3-(3-benzoylphenyl)-pyruvate. The yield was 73%.
Reaction SMILES: [C:1]1([CH:7]([OH:11])[CH2:8][CH2:9][OH:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1(C)C=CC(S(Cl)(=O)=O)=CC=1.C(N(CC)CC)C.[C:30]1(O)[C:39]2[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=2)[CH:33]=[CH:32][CH:31]=1.[OH-].[Na+]>>[C:38]1([O:10][CH2:9][CH2:8][C@H:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[OH:11])[C:39]2[C:34](=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH:35]=[CH:36][CH:37]=1
Reactant: Oc1cccc2ccccc12
Reactant: OCCC(O)c1ccccc1
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCN(CC)CC
Product: O[C@H](CCOc1cccc2ccccc12)c1ccccc1
Yield: 87 %

Procedure:
Using (R) 3-phenyl-1,3-dihydroxypropane, 1.05 equivalents of 4-toluenesulfonyl chloride, 0.05 equivalents of poly-DMAP™, and 2.0 equivalents of triethylamine, 1.0 equivalents of 1-naphthol, and 1.1 equivalents of 50% sodium hydroxide as in example I.C.1, an 87% yield of (R)-(-)-3-(1-naphthalenyloxy)-1-phenyl-1-propanol was obtained. (HPLC chiral purity, 98.6% ee)
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[CH:4]=[CH:5][C:6]([C:9]([OH:11])=O)=[N:7][CH:8]=1.[CH3:14][C:15]1[C:16]([NH2:30])=[N:17][C:18]2([C:28]3[C:23](=[CH:24][CH:25]=[C:26]([NH2:29])[CH:27]=3)[O:22][CH2:21][CH2:20]2)[N:19]=1>>[NH2:30][C:16]1[C:15]([CH3:14])=[N:19][C:18]2([C:28]3[C:23](=[CH:24][CH:25]=[C:26]([NH:29][C:9](=[O:11])[C:6]4[CH:5]=[CH:4][C:3]([C:2]([F:1])([F:13])[F:12])=[CH:8][N:7]=4)[CH:27]=3)[O:22][CH2:21][CH2:20]2)[N:17]=1
Reactant: O=C(O)c1ccc(C(F)(F)F)cn1
Reactant: CC1=NC2(CCOc3ccc(N)cc32)N=C1N
Product: CC1=NC2(CCOc3ccc(NC(=O)c4ccc(C(F)(F)F)cn4)cc32)N=C1N
Yield: 47.4 %

Procedure:
The title compound (44 mg, 46% yield) was prepared as described for Example 13a starting from 5-(trifluoromethyl)picolinic acid (45 mg, 0.23 mmol) and 5′-methylspiro[chroman-4,2′-imidazole]-4′,6-diamine (Intermediate 30, 54 mg, 0.23 mmol): 1H NMR (400 MHz, DMSO-d6) δ ppm 1.85-1.98 (m, 2 H), 2.24 (s, 3 H), 4.30-4.50 (m, 2 H), 6.56 (s, 2 H), 6.81 (d, 1 H), 7.02-7.10 (m, 1 H), 7.62-7.71 (m, 1 H), 8.28 (d, 1 H), 8.46 (dd, 1 H), 9.01-9.10 (m, 1 H), 10.57 (s, 1 H); MS (APCI+) m/z 404 [M+H]+.
Reaction SMILES: C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.N1C=CN=C1.[I:25]I.[C:27]1([CH2:33][O:34][C:35](=[O:48])[C@@H:36]([NH:40][C:41]([O:43][C:44]([CH3:47])([CH3:46])[CH3:45])=[O:42])[CH2:37][CH2:38]O)[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>C(Cl)Cl>[C:27]1([CH2:33][O:34][C:35](=[O:48])[C@@H:36]([NH:40][C:41]([O:43][C:44]([CH3:47])([CH3:46])[CH3:45])=[O:42])[CH2:37][CH2:38][I:25])[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: CC(C)(C)OC(=O)N[C@@H](CCO)C(=O)OCc1ccccc1
Reactant: II
Agent: c1c[nH]cn1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N[C@@H](CCI)C(=O)OCc1ccccc1
Reaction time: 0.08 h
Yield: 57.7 %

Procedure:
To a mixture of PPh3 (4.19 g, 16 mmol) and imidazole (1.09 g, 16 mmol) in anhydrous CH2Cl2 (40 mL) was added slowly iodine (4.07 g, 16 mmol) at rt. After 5 min, a solution of (2S)-2-[[(1,1-dimethylethoxy)carbonyl]amino]-4-hydroxy-butanoic acid phenylmethyl ester (4.12 g, 13.3 mmol) in CH2Cl2 (20 mL) was added at 0° C. After 2 h at rt, the reaction mixture was filtered through a short silica gel column. The filtrate was concentrated in vacuo, and the resulting residue was purified by flash chromatography (hexane-EtOAc, 95:5 to 9:1) to afford the product as light yellow oil (3.22 g, 58%). 1H NMR (CDCl3) δ 1.43 (s, 9H), 2.20 (m, 1H), 2.40 (m, 1H), 3.13 (m, 2H), 4.35 (br.s, 1H), 5.10 (br.s, 1H), 5.20 (AB, 2H), 7.30–7.40 (m, 5H). LC-MS: 420 (M++1).
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[N:9]2[N:10]=[C:11]([O:21][CH3:22])[C:12]([NH:13][C:14](=[O:20])[O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[C:8]2[CH:7]=[CH:6][CH:5]=1.Br[CH2:24][CH:25]1[CH2:27][CH2:26]1.C(OCC)(=O)C>CN(C)C=O>[Br:3][C:4]1[N:9]2[N:10]=[C:11]([O:21][CH3:22])[C:12]([N:13]([CH2:24][CH:25]3[CH2:27][CH2:26]3)[C:14](=[O:20])[O:15][C:16]([CH3:17])([CH3:18])[CH3:19])=[C:8]2[CH:7]=[CH:6][CH:5]=1
Reactant: COc1nn2c(Br)cccc2c1NC(=O)OC(C)(C)C
Reactant: BrCC1CC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COc1nn2c(Br)cccc2c1N(CC1CC1)C(=O)OC(C)(C)C
Reaction time: 0.5 h

Procedure:
Sodium hydride (60% in oil; 24.6 mg) was added to a solution of tert-butyl N-(7-bromo-2-methoxypyrazolo[1,5-a]pyridin-3-yl)carbamate (140 mg) in N,N-dimethylformamide (10 mL) at room temperature and the reaction mixture was stirred for 30 minutes. (Bromomethyl)cyclopropane (0.06 mL) was added thereto at the same temperature, and the reaction mixture was stirred for 1 hour at 60° C. After completion of the reaction, the reaction mixture was gradually added to ice, extraction was performed with ethyl acetate, the organic extract was washed with water and brine, dried over anhydrous magnesium sulfate and filtered, and the solvent was evaporated under reduced pressure to afford a crude product of tert-butyl N-(7-bromo-2-methoxypyrazolo[1,5-a]pyridin-3-yl)-N-cyclopropylmethylcarbamate.