Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]([C:10]2[C:18]3[CH:17]=[N:16][CH:15]=[N:14][C:13]=3[N:12]([CH:19]([CH3:21])[CH3:20])[CH:11]=2)=[O:9])[CH:5]=[N:6][CH:7]=1.[C:22]([C:30]1[CH:35]=[CH:34][C:33]([CH2:36][C:37](O)=[O:38])=[CH:32][CH:31]=1)(=[O:29])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>>[C:22]([C:30]1[CH:31]=[CH:32][C:33]([CH2:36][C:37]([NH:1][C:2]2[CH:7]=[N:6][CH:5]=[C:4]([C:8]([C:10]3[C:18]4[CH:17]=[N:16][CH:15]=[N:14][C:13]=4[N:12]([CH:19]([CH3:21])[CH3:20])[CH:11]=3)=[O:9])[CH:3]=2)=[O:38])=[CH:34][CH:35]=1)(=[O:29])[C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1
Reactant: O=C(O)Cc1ccc(C(=O)c2ccccc2)cc1
Reactant: CC(C)n1cc(C(=O)c2cncc(N)c2)c2cncnc21
Product: CC(C)n1cc(C(=O)c2cncc(NC(=O)Cc3ccc(C(=O)c4ccccc4)cc3)c2)c2cncnc21

Procedure:
The title compound was prepared according to the method described for Example 34 starting from (5-aminopyridin-3-yl)(7-isopropyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)methanone (Preparation 95) and 2-(4-benzoylphenyl)acetic acid (JOC, 1961, 1635) to afford the title compound in 94% yield, 34 mg. LCMS (system 3): Rt=3.12 min; m/z 504 [M+H]+.
Reaction SMILES: [OH:1][CH2:2][C@H:3]([NH:8][C:9](=[O:18])[C:10]1[CH:15]=[CH:14][C:13]([CH3:16])=[C:12]([CH3:17])[CH:11]=1)[CH2:4][CH:5]([CH3:7])[CH3:6].[OH-].[Na+].I[CH3:22]>CN(C=O)C>[CH3:22][O:1][CH2:2][C@H:3]([NH:8][C:9](=[O:18])[C:10]1[CH:15]=[CH:14][C:13]([CH3:16])=[C:12]([CH3:17])[CH:11]=1)[CH2:4][CH:5]([CH3:7])[CH3:6]
Reactant: Cc1ccc(C(=O)N[C@@H](CO)CC(C)C)cc1C
Reactant: CI
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: COC[C@@H](CC(C)C)NC(=O)c1ccc(C)c(C)c1
Temperature: 0 °C
Reaction time: 2 h
Yield: 73.1 %

Procedure:
To a solution of (R)—N-(1-hydroxy-4-methylpentan-2-yl)-3,4-dimethylbenzamide (1.59 g, 6.39 mmol) (example 18a) in dry DMF (20 mL) was added powdered NaOH (281 mg, 7 mmol) an the solution was stirred at 0° C. for 2 hrs. Iodomethane (1 eq, 6.39 mmol) was added in DMF (10 ml) drop-wise over period of 1 hr. The temperature was kept at 0° C. and the mixture was stirred for 1 hr. The reaction was quenched by adding 300 ml of water. The aqueous layer was extracted with dichloromethane, dried over MgSO4 and evaporated. The residue was purified by flash chromatography on silica-gel (toluene-ethyl acetate; 5-20% gradient) to give 1.23 g (R)—N-(1-methoxy-4-methylpentan-2-yl)-3,4-dimethylbenzamide (73%). 1H NMR (500 MHz, CDCl3): ÿ 0.94-0.97 (t, 6H), 1.41-1.47 (M, 1H), 1.54-1.60 (m, 1H), 1.64-1.68 (m, 1H), 2.29 (d, 6H)5 3.36 (s3 3H), 3.45-3.50 (m, 2H), 4.34-4.39 (m, 1H), 6.23-6.25 (d, 1H), 7.16-7.17 (d, 1H), 7.47-7.49 (dd, 1H), 7.56 (s, 1H). MS (M+H, 264.3).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6](Cl)=[O:7].[CH3:9][O:10][C:11]1[CH:12]=[C:13]([CH:15]=[CH:16][CH:17]=1)[NH2:14].CCN(C(C)C)C(C)C>C(Cl)Cl>[CH3:9][O:10][C:11]1[CH:12]=[C:13]([NH:14][C:6]([C:2]2[S:1][CH:5]=[CH:4][CH:3]=2)=[O:7])[CH:15]=[CH:16][CH:17]=1
Reactant: O=C(Cl)c1cccs1
Reactant: COc1cccc(N)c1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COc1cccc(NC(=O)c2cccs2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 70.1 %

Procedure:
According to Scheme 1 Method A: A solution of thiophene-2-carbonyl chloride (2.92 mmol, 0.31 mL) in DCM (1 mL) was added to solution of 3-methoxyaniline (2.44 mmol, 0.27 mL) and DIEA (4.87 mmol, 0.87 mL) in DCM (4 mL) at 0° C. The reaction mixture was stirred at room temperature for 1 hour. The organic phase was washed with HCl 1 M solution, then with a saturated solution of NaHCO3, was dried over MgSO4, was filtered and was concentrated under reduced pressure to yield N-(3-methoxyphenyl)thiophene-2-carboxamide (1.71 mmol, 0.40 g, 70%) as a white solid.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][N:5]([C:8]2[CH:16]=[CH:15][C:14]3[C:10](=[C:11]([CH3:19])[N:12]([CH2:17][CH3:18])[N:13]=3)[CH:9]=2)[C:4](=[O:20])[CH:3]=1.[F:21][C:22]([F:31])([F:30])[C:23]1[N:24]=[C:25]([CH2:28][OH:29])[S:26][CH:27]=1.CC(C)([O-])C.[K+].O>C1(C)C=CC=CC=1>[CH2:17]([N:12]1[C:11]([CH3:19])=[C:10]2[C:14]([CH:15]=[CH:16][C:8]([N:5]3[CH:6]=[CH:7][C:2]([O:29][CH2:28][C:25]4[S:26][CH:27]=[C:23]([C:22]([F:31])([F:30])[F:21])[N:24]=4)=[CH:3][C:4]3=[O:20])=[CH:9]2)=[N:13]1)[CH3:18]
Reactant: CCn1nc2ccc(-n3ccc(Br)cc3=O)cc2c1C
Reactant: OCc1nc(C(F)(F)F)cs1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: O
Product: CCn1nc2ccc(-n3ccc(OCc4nc(C(F)(F)F)cs4)cc3=O)cc2c1C
Temperature: 100 °C
Reaction time: 2 h
Yield: 16.4 %

Procedure:
To a solution of 4-bromo-1-(2-ethyl-3-methyl-2H-indazol-5-yl)pyridin-2(1H)-one (350 mg) and [4-(trifluoromethyl)-1,3-thiazol-2-yl]methanol (289 mg) in toluene (5 ml) was added potassium tert-butoxide (355 mg) at room temperature, and the mixture was stirred at 100° C. for 2 hr. The reaction mixture was cooled to room temperature, water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (NH, hexane/ethyl acetate) and recrystallized from ethanol-water to give the title compound (75 mg).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:18])[C@@H:5]([O:15][CH2:16][CH3:17])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][C:8]=1[CH3:14])C.Cl[CH2:20][C:21]1[N:22]=[C:23]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[O:24][CH:25]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[I-].[K+]>>[CH3:1][O:3][C:4](=[O:18])[C@@H:5]([O:15][CH2:16][CH3:17])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:20][C:21]2[N:22]=[C:23]([C:26]3[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=3)[O:24][CH:25]=2)=[CH:9][C:8]=1[CH3:14]
Reactant: CCOC(=O)[C@H](Cc1ccc(O)cc1C)OCC
Reactant: ClCc1coc(-c2ccccc2)n1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Agent: [I-]
Product: CCO[C@@H](Cc1ccc(OCc2coc(-c3ccccc3)n2)cc1C)C(=O)OC

Procedure:
In analogy to the procedure described in example 1 f], (S)-2-ethoxy-3-(4-hydroxy-2-methyl-phenyl)-propionic acid ethyl ester (example 1 d]) was reacted with 4-chloromethyl-2-phenyl-oxazole [prepared from benzamide and 1,3-dichloroacetone as described in Bioorg. Med. Chem. Lett. (2000), 10(17), 2041-2044] in the presence of cesium carbonate and potassium iodide to yield (S)-2-ethoxy-3-[2-methyl-4-(2-phenyl-oxazol-4-ylmethoxy)-phenyl]-propionic acid methyl ester as colorless liquid.
Reaction SMILES: [F:1][C:2]1[C:3]([C:9]2[CH:10]=[C:11](B(O)O)[CH:12]=[CH:13][CH:14]=2)=[N:4][CH:5]=[C:6]([F:8])[CH:7]=1.Br[C:19]1[N:23]2[N:24]=[CH:25][C:26]([C:28]([OH:31])([CH3:30])[CH3:29])=[N:27][C:22]2=[N:21][CH:20]=1>Cl>[F:1][C:2]1[C:3]([C:9]2[CH:10]=[C:11]([C:19]3[N:23]4[N:24]=[CH:25][C:26]([C:28]([OH:31])([CH3:29])[CH3:30])=[N:27][C:22]4=[N:21][CH:20]=3)[CH:12]=[CH:13][CH:14]=2)=[N:4][CH:5]=[C:6]([F:8])[CH:7]=1
Reactant: CC(C)(O)c1cnn2c(Br)cnc2n1
Reactant: OB(O)c1cccc(-c2ncc(F)cc2F)c1
Agent: Cl
Product: CC(C)(O)c1cnn2c(-c3cccc(-c4ncc(F)cc4F)c3)cnc2n1
Temperature: 0 °C

Procedure:
3-(3,5-Difluoropyridin-2-yl)phenylboronic acid (25 mg, 0.11 mmol) was coupled to 2-(7-bromoimidazo[1,2-b][1,2,4]triazin-3-yl)propan-2-ol (27 mg, 0.11 mmol) using the method of Example 20. Purification by chromatography (silica gel, 3% MeOH/CH2Cl2) gave impure product as a yellow solid. The product was then dissolved in hydrochloric acid (2 N, 50 ml), filtered and washed with diethyl ether (2×20 ml). The acid solution was cooled to 0° C. and neutralised with saturated aqueous sodium hydrogencarbonate and extracted with ethyl acetate (3×20 ml). The combined organic phases were dried over anhydrous magnesium sulphate, filtered and evaporated to give the title compound as a yellow solid: 1H. NMR (400 MHz, CDCl3) δ 1.72 (6H, s), 3.35 (1H, s), 7.32-7.38 (1H, m), 7.64 (1H, t, J 8 Hz), 7.95-7.98 (1H, m), 8.10-8.13 (1H, m), 8.33 (1H, 8), 8.48 (1H, d, J 3 Hz), 8.60-8.61 (1H, m), 8.79 (1H, s); MS (ES+) m/z 368 [M+H]+.
Reaction SMILES: [ClH:1].O1CCOCC1.C(OC([N:15]1[CH2:20][CH2:19][CH:18]([CH2:21][C:22]2[CH:27]=[C:26]([O:28][CH3:29])[CH:25]=[CH:24][C:23]=2[Br:30])[CH2:17][CH2:16]1)=O)(C)(C)C>C(O)(=O)C>[ClH:1].[Br:30][C:23]1[CH:24]=[CH:25][C:26]([O:28][CH3:29])=[CH:27][C:22]=1[CH2:21][CH:18]1[CH2:17][CH2:16][NH:15][CH2:20][CH2:19]1
Reactant: COc1ccc(Br)c(CC2CCN(C(=O)OC(C)(C)C)CC2)c1
Agent: Cl
Solvent: CC(=O)O
Solvent: C1COCCO1
Product: COc1ccc(Br)c(CC2CCNCC2)c1
Temperature: 60 °C
Reaction time: 1 h

Procedure:
At room temperature, 4N-hydrogen chloride/dioxane (35 mL) was added dropwise to a solution of the crude product (18.3 g) of N-tert-butoxycarbonyl-4-(2-bromo-5-methoxy-benzyl)piperidine in acetic acid (50 mL), and the resulting mixture was stirred at 60° C. for 1 hour. The solvent was distilled off and ethyl acetate was added to the residue to effect crystallization. The crystals were collected by filtration, washed with ethyl acetate and then dried to obtain 12.9 g (40.2 mmol) of 4-(2-bromo-5-methoxybenzyl)piperidine hydrochloride.
Reaction SMILES: [OH:1][CH2:2][C@@:3]1([O:12][C@H:11]([CH2:13][OH:14])[C@@H:9]([OH:10])[C@@H:7]1[OH:8])[CH2:4][CH:5]=C.S(=O)(=O)(O)[OH:16].[BH4-].[Na+].P(Cl)(=O)(OC1C=CC=CC=1)OC1C=CC=CC=1>CC(C)=O.N1C=CC=CC=1.ClCCl.C(O)C.CO.C(O)(=O)C.[Pd].CO.S([O-])([O-])(=O)=O.[Cu+2].[Pt]=O>[OH:1][CH2:2][C@@:3]1([O:12][C@H:11]([CH2:13][OH:14])[C@@H:9]([OH:10])[C@@H:7]1[OH:8])[CH2:4][CH2:5][OH:16]
Reactant: O=S(=O)(O)O
Reactant: C=CC[C@@]1(CO)O[C@H](CO)[C@@H](O)[C@@H]1O
Agent: O=[Pt]
Agent: [Cu+2]
Agent: [Pd]
Solvent: CC(C)=O
Solvent: CCO
Solvent: ClCCl
Product: OCC[C@@]1(CO)O[C@H](CO)[C@@H](O)[C@@H]1O

Procedure:
In accordance with Flowchart H, D-fructofuranose, pentabenzoate and allyltrimethylsilane are reacted in acetonitrile at reduced temperature, in the presence of borontrifluoride etherate, giving 4,7-anhydro-4-C-[(benzoyloxy)methyl]-1,2,3-trideoxy-D-arabino-oct-1-enitol, 5,6,8-tribenzoate 56, which is reacted with sodium methoxide in methanol, giving 4,7-anhydro-1,2,3-trideoxy-4-C-(hydroxymethyl)-D-manno-oct-1-enitol 57. Compound 57 is reacted with copper sulfate and sulfuric acid in acetone, then neutralized giving 41,1,5:4,7-dianhydro-1,2,3-trideoxy-4-C-[(1-hydroxy-1-methylethoxy)methyl]-6,8-bis-O-(phenylmethyl)-D-manno-oct-1-enitol 58, which is first subjected to ozonolysis in a mixture of pyridine and dichloromethane and then reduced with sodium borohydride in ethanol, giving 3,6:31,4-dianhydro-2-deoxy-3-C-[(1-hydroxy-1-methylethoxy)methyl]-5,7-bis-O-(phenylmethyl)-D-manno-heptitol 59. Compound 59 is hydrogenated in methanol/acetic acid over palladium on carbon, giving 3,6:31,4-dianhydro-2-deoxy-3-C-[(1-hydroxy-1-methylethoxy)methyl]-D-manno-heptitol 60, which is reacted with diphenyl phosphorochloridate in pyridine at reduced temperature, giving the product 3,6:31,4-dianhydro-2-deoxy-3-C-[( 1-hydroxy-1-methylethoxy)methyl]-D-manno-heptitol, 1.7-bis-(diphenyl phosphate) 61, which is hydrogenated in methanol over platinum oxide, giving the product 3,6-anhydro-2-deoxy-3-C-(hydroxymethyl)-D-manno-heptitol, 1,7-bis(dihydrogen phosphate) 62. ##STR21##
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@@H:12]([CH2:17][C:18]1[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=1)[C:13](=[O:16])[CH2:14][Cl:15])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O)=O.C(N(CC)CC)C>C(OCC)(=O)C.C1(C)C=CC(S(N[C@@H](C2C=CC=CC=2)[C@H](C2C=CC=CC=2)N)(=O)=O)=CC=1.Cl[Rh+]C1(C)C(C)=C(C)C(C)=C1C>[CH2:1]([O:8][C:9]([NH:11][C@@H:12]([CH2:17][C:18]1[CH:19]=[CH:20][C:21]([F:24])=[CH:22][CH:23]=1)[C@H:13]([OH:16])[CH2:14][Cl:15])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(N[C@@H](Cc1ccc(F)cc1)C(=O)CCl)OCc1ccccc1
Agent: CC1=C(C)C(C)([Rh+]Cl)C(C)=C1C
Agent: Cc1ccc(S(=O)(=O)N[C@@H](c2ccccc2)[C@@H](N)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: O=CO
Product: O=C(N[C@@H](Cc1ccc(F)cc1)[C@H](O)CCl)OCc1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 91 %

Procedure:
(3S)-3-Benzyloxycarbonylamino-1-chloro-4-(p-fluorophenyl)-2-butanone (174.9 mg, 0.5 mmol) and a formic acid/triethylamine azeotropic mixture (0.1 ml) were added to a solution of chloro(pentamethylcyclopentadienyl)rhodium (III) (1S,2S)-N-(p-toluenesulfonyl)-1,2-diphenylethylenediamine (0.34 mg, 0.0005 mmol, s/c=1000) in ethyl acetate (1.0 ml), followed by stirring at room temperature for 2 hours. After completion of the reaction, the reaction mixture was purified by silica gel column chromatography to give a desired compound, (2S,3S)-3-benzyloxycarbonylamino-1-chloro-2-hydroxy-4-(p-fluorophenyl)butane (160.1 mg; yield: 91.0%). As a result of HPLC analysis, the production ratio of the desired (2S,3S)-form to the isomeric (2R,3S)-form, (2S,3S):(2R,3S), was 18.3:1. The results of elementary analysis were as follows.
Reaction SMILES: [Br-].C1([P+](C2C=CC=CC=2)(C2C=CC=CC=2)[CH2:9][C:10]2[C:15]([F:16])=[CH:14][CH:13]=[C:12]([F:17])[C:11]=2[F:18])C=CC=CC=1.CC(C)([O-])C.[K+].[F:37][C:38]1[CH:43]=[CH:42][C:41]([N:44]2[C:48]([C:49]([O:51][CH2:52][CH3:53])=[O:50])=[CH:47][N:46]=[C:45]2[CH:54]=O)=[CH:40][CH:39]=1>C1COCC1>[F:37][C:38]1[CH:39]=[CH:40][C:41]([N:44]2[C:48]([C:49]([O:51][CH2:52][CH3:53])=[O:50])=[CH:47][N:46]=[C:45]2/[CH:54]=[CH:9]/[C:10]2[C:15]([F:16])=[CH:14][CH:13]=[C:12]([F:17])[C:11]=2[F:18])=[CH:42][CH:43]=1
Reactant: Fc1ccc(F)c(C[P+](c2ccccc2)(c2ccccc2)c2ccccc2)c1F
Reactant: CCOC(=O)c1cnc(C=O)n1-c1ccc(F)cc1
Agent: CC(C)(C)[O-]
Agent: [Br-]
Agent: [K+]
Solvent: C1CCOC1
Product: CCOC(=O)c1cnc(/C=C/c2c(F)ccc(F)c2F)n1-c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of triphenyl(2,3,6-trifluorobenzyl)phosphonium bromide (428 mg, 0.88 mmol) in THF at 0° C. was added potassium tert-butoxide (99 mg, 0.88 mmol). After the reaction was stirred for 1 h, it was warmed to room temperature and a solution of ethyl 1-(4-fluorophenyl)-2-formyl-1H-imidazole-5-carboxylate (16) (210 mg, 0.80) in THF (1 mL) was added. The mixture was refluxed for 6 h, cooled to room temperature, filtered, and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel (0-40% EtOAc in hexanes, Rf=0.2 in 80/20 hexanes/ethyl acetate) to yield (E)-ethyl 1-(4-fluorophenyl)-2-(2,3,6-trifluorostyryl)-1H-imidazole-5-carboxylate (17) as the only stereoisomer.
Reaction SMILES: [CH2:1]([NH:8][C:9]1[NH:14][CH2:13][C:12]2=[C:15]([CH3:21])[N:16]=[C:17]([CH2:18][CH2:19][CH3:20])[N:11]2[N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O)(=O)/C=C\C([O-])=O>>[CH2:1]([NH:8][C:9]1[N:14]=[CH:13][C:12]2=[C:15]([CH3:21])[N:16]=[C:17]([CH2:18][CH2:19][CH3:20])[N:11]2[N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCCc1nc(C)c2n1N=C(NCc1ccccc1)NC2
Agent: O=C([O-])/C=C\C(=O)O
Product: CCCc1nc(C)c2cnc(NCc3ccccc3)nn12

Procedure:
2-Benzylamino-5-methyl-7-propylimidazo[5,1-f]-as-triazine was prepared from 2-benzylamino-3,4-dihydro-5-methyl-7-propylimidazo[5,1-f]-as-triazine (Example 12b). It was converted into its hydrogen maleate which had m.p. 141°-142°.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[CH:9]=[C:10]([CH:26]=[CH:27][C:28]=2[O:29][CH3:30])[CH2:11][N:12]2[CH2:17][CH2:16][N:15](C(OC(C)(C)C)=O)[CH2:14][C@@H:13]2[CH3:25])[CH:5]=[CH:4][N:3]=1.[NH2:31][CH2:32][CH2:33][C:34]1[CH:39]=[CH:38][C:37]([OH:40])=[C:36]([Cl:41])[CH:35]=1>>[Cl:41][C:36]1[CH:35]=[C:34]([CH2:33][CH2:32][NH:31][C:2]2[N:7]=[C:6]([C:8]3[CH:9]=[C:10]([CH2:11][N:12]4[CH2:17][CH2:16][NH:15][CH2:14][C@@H:13]4[CH3:25])[CH:26]=[CH:27][C:28]=3[O:29][CH3:30])[CH:5]=[CH:4][N:3]=2)[CH:39]=[CH:38][C:37]=1[OH:40]
Reactant: COc1ccc(CN2CCN(C(=O)OC(C)(C)C)C[C@@H]2C)cc1-c1ccnc(Cl)n1
Reactant: NCCc1ccc(O)c(Cl)c1
Product: COc1ccc(CN2CCNC[C@@H]2C)cc1-c1ccnc(NCCc2ccc(O)c(Cl)c2)n1

Procedure:
Intermediate 146 from above was coupled with 4-(2-aminoethyl)-2-chlorophenol following procedure F. The product was deprotected by procedure G2. LC-MS showed the product had the expected M+H+ of 468. 1H NMR (Varian 300 MHz, DMSO-d6, shifts relative to the solvent peak at 2.49 ppm) δ 8.4 (d, 1H) 7.8 (d, 1H) 7.4-7.2 (m, 3H) 7.1 (m, 2H), 6.1 (d, 1H), 3.9 (s, 3H) 3.7-3.6 (m, 4H) 3.5 (d, 2H) 3.4-3.3 (m, 4H), 3.2 (m, 1H), 2.8 (t, 2H), 1.6 (d, 3H).
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([N:8]2[C:12]3=[N:13][CH:14]=[CH:15][N:16]=[C:11]3[N:10]([CH:17]3[CH2:19][CH2:18]3)[C:9]2=[O:20])[CH2:4][CH2:3]1.Cl[C:22]1[CH:31]=[CH:30][C:29]2[C:24](=[CH:25][CH:26]=[CH:27][N:28]=2)[N:23]=1.C(N(C(C)C)CC)(C)C>CS(C)=O>[N:23]1[C:24]2[C:29](=[N:28][CH:27]=[CH:26][CH:25]=2)[CH:30]=[CH:31][C:22]=1[NH:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([N:8]2[C:12]3=[N:13][CH:14]=[CH:15][N:16]=[C:11]3[N:10]([CH:17]3[CH2:19][CH2:18]3)[C:9]2=[O:20])[CH2:4][CH2:3]1
Reactant: Clc1ccc2ncccc2n1
Reactant: N[C@H]1CC[C@H](n2c(=O)n(C3CC3)c3nccnc32)CC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Product: O=c1n(C2CC2)c2nccnc2n1[C@H]1CC[C@H](Nc2ccc3ncccc3n2)CC1
Temperature: 120 °C

Procedure:
A glass microwave reaction vessel was charged with 1-(trans-4-aminocyclohexyl)-3-cyclopropyl-1H-imidazo[4,5-b]pyrazin-2(3H)-one (0.1050 g, 0.339 mmol), 2-chloro-1,5-naphthyridine (0.067 g, 0.407 mmol, 00358), and diisopropylethylamine (0.177 ml, 1.017 mmol, Sigma-Aldrich Chemical Company, Inc.) in DMSO (0.484 ml) and heated to 120° C. for 2 days. The crude product was purified by reverse-phase preparative HPLC using a Phenomenex Gemini column, 10 micron, 100×50 mm, 0.1% TFA in CH3CN/H2O, gradient 10% to 90% over 15 min. Fractions containing product were collected and concentrated. The product was taken up in DCM and loaded onto a Silicycle Si-carbonate cartridge and washed with DCM and MeOH to remove any salts to give the title compound (6.4 mg, 0.016 mmol, 4.7% yield). LCMS showed product peak at 1.434 min (m+1=402.0). 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.09-1.24 (m, 4 H) 1.37-1.53 (m, 2 H) 1.94 (d, J=11.93 Hz, 2 H) 2.39 (d, J=12.13 Hz, 2 H) 2.68 (qd, J=12.91, 3.13 Hz, 2 H) 2.97-3.09 (m, 1 H) 4.08-4.24 (m, 1 H) 4.47 (tt, J=12.32, 3.91 Hz, 1 H) 6.85 (d, J=9.19 Hz, 1 H) 7.45 (dd, J=8.41, 4.30 Hz, 1 H) 7.91-7.96 (m, 2 H) 7.97 (d, J=8.61 Hz, 1 H) 8.03 (d, J=9.19 Hz, 1 H) 8.60 (d, J=3.33 Hz, 1 H)
Reaction SMILES: [C:1]([C:5]1[C:10]2[NH:11][C:12]3[C:17]([C:9]=2[C:8]([OH:18])=[CH:7][N:6]=1)=[CH:16][CH:15]=[CH:14][CH:13]=3)([O:3][CH3:4])=[O:2].[C:19](OC(=O)C)(=[O:21])[CH3:20]>N1C=CC=CC=1>[C:1]([C:5]1[C:10]2[NH:11][C:12]3[C:17]([C:9]=2[C:8]([O:18][C:19](=[O:21])[CH3:20])=[CH:7][N:6]=1)=[CH:16][CH:15]=[CH:14][CH:13]=3)([O:3][CH3:4])=[O:2]
Reactant: CC(=O)OC(C)=O
Reactant: COC(=O)c1ncc(O)c2c1[nH]c1ccccc12
Solvent: c1ccncc1
Product: COC(=O)c1ncc(OC(C)=O)c2c1[nH]c1ccccc12
Reaction time: 8 h

Procedure:
Four grams of 1-carbomethoxy-4-hydroxy-9H-pyrido[3,4-b]-indole were dissolved in a mixture of 20 ml pyridine and 24 ml acetic anhydride and the solution was allowed to stand at room temperature overnight. The resultant crystals were collected by filtration and recrystallized from methanol to yield 2.9 g of the title compound. Yield 61.8% colorless prisms, m.p. 220°-221° C. Elemental analysis--found: C, 63.23%; H, 3.94%, N, 9.59%; calculated for C15H12N2O4 (mol. wt. 284): C, 63.38%; H, 4.26%; N, 9.86%. Mol. wt. (based on mass spectrum) 284. NMR (DMSO-d6): δ2.62 ppm, 3H (COCH3), 4.07 ppm, 3H (COOCH3), 8.37 ppm, 1H (3-H), 7.20-8.20 ppm, 4H, 11.85 ppm; 1H (NH). UV spectrum (methanol): 360, 300, 264, 243, 212 mμ. IR spectrum: 3380, 1760, 1675, 1242, 1222 cm-1.
Reaction SMILES: [CH3:1][C:2]1([CH3:16])[C:6]([CH3:8])([CH3:7])[O:5][B:4]([C:9]2[CH:14]=[CH:13][C:12]([NH2:15])=[CH:11][CH:10]=2)[O:3]1.[C:17]1([S:23](Cl)(=[O:25])=[O:24])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>>[CH3:8][C:6]1([CH3:7])[C:2]([CH3:16])([CH3:1])[O:3][B:4]([C:9]2[CH:14]=[CH:13][C:12]([NH:15][S:23]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)(=[O:25])=[O:24])=[CH:11][CH:10]=2)[O:5]1
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: CC1(C)OB(c2ccc(N)cc2)OC1(C)C
Product: CC1(C)OB(c2ccc(NS(=O)(=O)c3ccccc3)cc2)OC1(C)C

Procedure:
Intermediate 23 was prepared in analogy to GP 4 by reaction of 4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenylamine with benzenesulfonyl chloride.
Reaction SMILES: Cl[C:2]1[N:7]([CH2:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]3[C:16]([C:21]#[N:22])=[CH:17][CH:18]=[CH:19][CH:20]=3)=[CH:11][CH:10]=2)[C:6](=[O:23])[NH:5][C:4](=[O:24])[CH:3]=1.[Na]>C(O)CC>[O:23]=[C:6]1[NH:5][C:4](=[O:24])[CH:3]=[C:2]([O:24][CH2:4][CH2:3][CH3:2])[N:7]1[CH2:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[C:16]([C:21]#[N:22])=[CH:17][CH:18]=[CH:19][CH:20]=2)=[CH:11][CH:10]=1
Reactant: N#Cc1ccccc1-c1ccc(Cn2c(Cl)cc(=O)[nH]c2=O)cc1
Agent: [Na]
Solvent: CCCO
Product: CCCOc1cc(=O)[nH]c(=O)n1Cc1ccc(-c2ccccc2C#N)cc1
Temperature: 100 °C
Reaction time: 4 h
Yield: 95.1 %

Procedure:
To a mixture of 4′-[(6-chloro-2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)methyl]biphenyl-2-carbonitrile (2.3 g) and n-propanol (70 mL) was added a solution of sodium (0.24 g) in n-propanol (10 mL), and the mixture was stirred at 100° C. for 4 hr. The reaction mixture was concentrated under reduced pressure, and the obtained residue was dissolved in water (100 mL). 1N Hydrochloric acid was added to adjust to pH 4, and the precipitated solid was recrystallized from methanol to give the title compound as colorless crystals (1.17 g, 47%).
Reaction SMILES: [Br:1][C:2]1[C:3]([CH2:10][CH3:11])=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=O.[NH:12]1[CH2:15][CH:14]([C:16]([O:18][CH3:19])=[O:17])[CH2:13]1.C([O-])(=O)C.[Na+].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl>[Br:1][C:2]1[C:3]([CH2:10][CH3:11])=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH2:5][N:12]1[CH2:15][CH:14]([C:16]([O:18][CH3:19])=[O:17])[CH2:13]1
Reactant: COC(=O)C1CNC1
Reactant: CCc1c(Br)cccc1C=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: ClCCl
Product: CCc1c(Br)cccc1CN1CC(C(=O)OC)C1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 78 %

Procedure:
To a solution of 3-bromo-2-ethylbenzaldehyde (2.66 g, 12.48 mmol) in Dichloromethane (DCM) (30 mL) were added methyl 3-azetidinecarboxylate (1.987 g, 13.11 mmol) and sodium acetate (1.536 g, 18.73 mmol). The mixture was stirred for 30 min at rt then sodium triacetoxyborohydride (3.97 g, 18.73 mmol) was added to above solution. The obtained mixture was stirred for an hour at rt. The solvent was removed under the reduced pressure, water (30 mL) was added to the above residue and the mixture was adjusted to pH value around 3 with HCl (1.0 N) then extracted with EtOAc (10 mL). Acidic phase was adjusted to pH value around 8 with NaOH (1.0 N) solution then extracted with EtOAc (30 mL). The organic phase was dried over anhydrous sodium sulfate, concentrated under the reduced pressure and dried in vacuum to give methyl 1-(3-bromo-2-ethylbenzyl)azetidine-3-carboxylate (3.04 g) as pale yellow oil
Reaction SMILES: [NH2:1][C:2]1[N:6]([CH2:7][CH2:8][OH:9])[N:5]=[CH:4][C:3]=1[C:10]#[N:11].[ClH:12].O>CO.[Pd]>[ClH:12].[ClH:12].[NH2:1][C:2]1[N:6]([CH2:7][CH2:8][OH:9])[N:5]=[CH:4][C:3]=1[CH2:10][NH2:11]
Reactant: N#Cc1cnn(CCO)c1N
Agent: [Pd]
Agent: Cl
Solvent: CO
Solvent: O
Product: NCc1cnn(CCO)c1N
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Under a nitrogen atmosphere, 10% palladium on active carbon (125 g) and methanol (3.75 L) were placed in a 5.0 L of three-necked flask. To the mixture was added 5-amino-4-cyano-1-(2-hydroxyethyl)-1H-pyrazole (250 g). The mixture was stirred at room temperature for 1 hour under a hydrogen atmosphere. To the reaction mixture was added 4N hydrogen chloride solution in methanol (1.65 L), and the mixture was stirred at room temperature for 1.5 hours under a hydrogen atmosphere. To the reaction mixture was added water (1.2 L). The catalyst was filtered off and washed with 50% aqueous methanol, and the filtrate was evaporated in vacuo. The residue was triturated with isopropanol/ethyl acetate (1:1). The precipitate was collected by filtration on a glass filter, washed with ethyl acetate and dried in vacuo to give 5-amino-4-aminomethyl-1-(2-hydroxyethyl)-1H-pyrazole dihydrochloride (358 g) as a white solid.