Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][C@@H:10]([C:14]([OH:16])=O)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N1C=CN=C1)(N1C=CN=C1)=O.[NH:29]1[CH2:33][CH2:32][CH2:31][CH2:30]1.C(=O)([O-])[O-].[K+].[K+]>O1CCCC1.C1CCCCC1>[N:29]1([C:14]([C@@H:10]2[CH2:11][CH2:12][CH2:13][N:8]([C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[CH2:9]2)=[O:16])[CH2:33][CH2:32][CH2:31][CH2:30]1
Reactant: C1CCNC1
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H](C(=O)O)C1
Agent: O=C([O-])[O-]
Agent: O=C(n1ccnc1)n1ccnc1
Agent: [K+]
Solvent: C1CCCCC1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC[C@@H](C(=O)N2CCCC2)C1
Temperature: 21.5 °C
Reaction time: 3 h

Procedure:
(R)-1-(tert-Butoxycarbonyl)piperidine-3-carboxylic acid (6.0 kg, 26 mol) was added in portions to a mixture of 1,1′-carbonyldiimidazole (5.1 kg, 31 mol) in tetrahydrofuran (48 L) at a temperature of 18-22° C. The mixture was held at this temperature for 3 h, then pyrrolidine (2.28 kg, 32 mol) was added while maintaining a temperature of 18-25° C., and the resulting reaction mixture was held at this temperature for 2 h. Cyclohexane (48 L) and aqueous potassium carbonate solution (prepared from 4.8 kg potassium carbonate and 48 L water) were then added sequentially, and the mixture was stirred for 30 min before separation of the layers. The organic layer was then washed with another portion of aqueous potassium carbonate solution (prepared from 4.8 kg potassium carbonate and 48 L water). The combined aqueous layers were extracted with cyclohexane (30 L). The combined organic layers were then washed with aqueous sodium chloride solution (prepared from 3.0 kg sodium chloride and 30 L water). The organic layer was dried over sodium sulfate (2.0 kg), then the cyclohexane was removed by distillation under reduced pressure at 45° C. Isopropanol (43 L) was added and the mixture was stirred for 30 min. The presence of (R)-tert-butyl 3-(pyrrolidine-1-carbonyl)piperidine-1-carboxylate was confirmed by HPLC analysis: HPLC retention time: 5.98 min (Column: Halo C18, 4.6×150 mm, 2.7 μm; Mobile Phase A: 0.1% orthophosphoric acid and 2% acetonitrile in water, Mobile Phase B: acetonitrile; Gradient: 20% B to 90% B over 7 min, then held for 3 min; Flow: 0.8 mL/min; Temperature: 25° C.; UV detection at 210 and 226 nM). This material was used in the next step without further purification.
Reaction SMILES: [OH:1][CH2:2][C:3]1[N:8]=[C:7]([C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH:6]=[C:5]([I:14])[CH:4]=1.[O:15]1[CH:20]=[CH:19][CH2:18][CH2:17][CH2:16]1.C1(C)C=CC(S(O)(=O)=O)=CC=1.N1C=CC=CC=1>C(Cl)Cl>[O:15]1[CH2:20][CH2:19][CH2:18][CH2:17][CH:16]1[O:1][CH2:2][C:3]1[N:8]=[C:7]([C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH:6]=[C:5]([I:14])[CH:4]=1
Reactant: C1=COCCC1
Reactant: CCOC(=O)c1cc(I)cc(CO)n1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCOC(=O)c1cc(I)cc(COC2CCCCO2)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 86.5 %

Procedure:
A mixture of 2 (2.89 g, 9.4 mmol), 3,4-dihydro-2H-pyran (1.19 g, 14.1 mmol), pyridine p-toluenesulfonate (0.236 g, 0.94 mmol) and CH2Cl2 (50 ml) was stirred overnight at r.t. The solvent was evaporated and the product purified on silica gel (petroleum ether, by 40-60° C./ethyl acetate 2:5), yielding 3.18 g (86%) of the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:40]=[CH:39][C:6]([CH2:7][N:8]([CH2:30][C:31]2[CH:36]=[CH:35][C:34]([O:37][CH3:38])=[CH:33][CH:32]=2)[C:9]2[N:14]=[CH:13][C:12]([C:15]3[C:16]4[CH2:29][CH2:28][NH:27][C:17]=4[N:18]=[C:19]([N:21]4[CH2:26][CH2:25][O:24][CH2:23][CH2:22]4)[N:20]=3)=[CH:11][N:10]=2)=[CH:5][CH:4]=1.Br[C:42]1[CH:47]=[CH:46][C:45]([C:48]([N:50]2[CH2:55][CH2:54][N:53]([CH2:56][CH2:57][OH:58])[CH2:52][CH2:51]2)=[O:49])=[CH:44][C:43]=1[CH3:59]>>[CH3:38][O:37][C:34]1[CH:33]=[CH:32][C:31]([CH2:30][N:8]([CH2:7][C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:40][CH:39]=2)[C:9]2[N:10]=[CH:11][C:12]([C:15]3[C:16]4[CH2:29][CH2:28][N:27]([C:42]5[CH:47]=[CH:46][C:45]([C:48]([N:50]6[CH2:51][CH2:52][N:53]([CH2:56][CH2:57][OH:58])[CH2:54][CH2:55]6)=[O:49])=[CH:44][C:43]=5[CH3:59])[C:17]=4[N:18]=[C:19]([N:21]4[CH2:26][CH2:25][O:24][CH2:23][CH2:22]4)[N:20]=3)=[CH:13][N:14]=2)=[CH:36][CH:35]=1
Reactant: Cc1cc(C(=O)N2CCN(CCO)CC2)ccc1Br
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)c2ncc(-c3nc(N4CCOCC4)nc4c3CCN4)cn2)cc1
Product: COc1ccc(CN(Cc2ccc(OC)cc2)c2ncc(-c3nc(N4CCOCC4)nc4c3CCN4c3ccc(C(=O)N4CCN(CCO)CC4)cc3C)cn2)cc1

Procedure:
Using bis-(4-methoxy-benzyl)-[5-(2-morpholin-4-yl-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-4-yl)-pyrimidin-2-yl]-amine (100 mg) and (4-bromo-3-methyl-phenyl)-[4-(2-hydroxy-ethyl)-piperazin-1-yl]-methanone (168 mg) instead of 4-chloropicolinic acid t-butylamide, in the same manner as Example 1-D-07, a crude product of [4-(4-{2-[bis-(4-methoxy-benzyl)-amino]-pyrimidin-5-yl}-2-morpholin-4-yl-5,6-dihydro-pyrrolo[2,3-d]pyrimidin-7-yl)-3-methyl-phenyl]-[4-(2-hydroxy-ethyl)-piperazin-1-yl]-methanone was obtained, and then the PMB groups were removed according to the above Deprotection method 3, to obtain the desired compound (D-147) as a pale yellow powder (28 mg, 28%).
Reaction SMILES: [CH:1]1([CH2:6][NH:7][C:8]([C:10]2[CH:18]=[C:17]3[C:13]([C:14]([CH2:31][CH2:32][C:33](=[O:36])[NH:34][CH3:35])=[CH:15][N:16]3[CH2:19][C:20]3[CH:28]=[CH:27][C:23]([C:24](O)=[O:25])=[CH:22][C:21]=3[O:29][CH3:30])=[CH:12][CH:11]=2)=[O:9])[CH2:5][CH2:4][CH2:3][CH2:2]1.Cl.CN(C)CCCN=C=NCC.[C:49]1([CH3:59])[C:50]([S:55]([NH2:58])(=[O:57])=[O:56])=[CH:51][CH:52]=[CH:53][CH:54]=1>CN(C)C1C=CN=CC=1.C(Cl)Cl>[CH:1]1([CH2:6][NH:7][C:8]([C:10]2[CH:18]=[C:17]3[C:13]([C:14]([CH2:31][CH2:32][C:33](=[O:36])[NH:34][CH3:35])=[CH:15][N:16]3[CH2:19][C:20]3[CH:28]=[CH:27][C:23]([C:24]([NH:58][S:55]([C:50]4[CH:51]=[CH:52][CH:53]=[CH:54][C:49]=4[CH3:59])(=[O:57])=[O:56])=[O:25])=[CH:22][C:21]=3[O:29][CH3:30])=[CH:12][CH:11]=2)=[O:9])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: CNC(=O)CCc1cn(Cc2ccc(C(=O)O)cc2OC)c2cc(C(=O)NCC3CCCC3)ccc12
Reactant: Cc1ccccc1S(N)(=O)=O
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: CNC(=O)CCc1cn(Cc2ccc(C(=O)NS(=O)(=O)c3ccccc3C)cc2OC)c2cc(C(=O)NCC3CCCC3)ccc12
Yield: 18.3 %

Procedure:
A solution of 4-[6-(N-cyclopentylmethylcarbamoyl)-3-[2-(N-methylcarbamoyl)ethyl]indol-1-ylmethyl]-3-methoxybenzoic acid (0.25 g) (prepared as described in Example 1), 4-(dimethylamino)pyridine (0.07 g), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.12 g), and ortho-toluenesulphonamide (0.09 g) in methylene chloride (3.0 ml) was stirred under a nitrogen atmosphere for 24 hours. The mixture was diluted with methylene chloride, washed sequentially with 10% (v/v) hydrochloric acid, water, and brine, and evaporated. The resulting ivory solid was purified by flash chromatography on silica gel (10 ml), eluting with 1:9 methanol:chloroform, to give the title compound (0.06 g, 17%) as an ivory powder; mp 211°-212°.
Reaction SMILES: C(OC([N:8]1[CH2:12][CH2:11][CH:10]([N:13]([CH2:17][C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=2)[CH2:14][CH2:15][OH:16])[CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[Cl:24][C:21]1[CH:20]=[CH:19][C:18]([CH2:17][N:13]([CH:10]2[CH2:11][CH2:12][NH:8][CH2:9]2)[CH2:14][CH2:15][OH:16])=[CH:23][CH:22]=1
Reactant: CC(C)(C)OC(=O)N1CCC(N(CCO)Cc2ccc(Cl)cc2)C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: OCCN(Cc1ccc(Cl)cc1)C1CCNC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of 3-[(4-chloro-benzyl)-(2-hydroxy-ethyl)-amino]-pyrrolidine-1-carboxylic acid tert-butyl ester (0.22 g, 0.6 mmol) in dichloromethane cooled at 0° C. was treated with trifluoroacetic acid (20%). The resulting mixture was warmed to room temperature and stirred for 2 h. The reaction mixture was concentrated in vacuo, diluted with ethyl acetate and free based with 10% aqueous sodium bicarbonate. The combined organics were dried over sodium sulfate. The product was used without any further purification. ESI-MS m/z: 255 (M+1), UV retention time: 0.34 min.
Reaction SMILES: [C:1]1([N:7]2[C:11]([C:12]3[S:13][CH:14]=[CH:15][CH:16]=3)=[CH:10][C:9]([CH2:17][CH2:18][CH:19]=O)=[N:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:21]1([N:27]2[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]2)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.CCN(C(C)C)C(C)C.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>>[C:21]1([N:27]2[CH2:32][CH2:31][N:30]([CH2:19][CH2:18][CH2:17][C:9]3[CH:10]=[C:11]([C:12]4[S:13][CH:14]=[CH:15][CH:16]=4)[N:7]([C:1]4[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=4)[N:8]=3)[CH2:29][CH2:28]2)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: c1ccc(N2CCNCC2)cc1
Reactant: O=CCCc1cc(-c2cccs2)n(-c2ccccc2)n1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Product: c1ccc(N2CCN(CCCc3cc(-c4cccs4)n(-c4ccccc4)n3)CC2)cc1

Procedure:
63 mg (96%) of target compound was obtained by using a method same as in Example 1 by using 3-(1-phenyl-5-(thiophene2-yl)-1H-pyrazol-3-yl)-propanal (40 mg, 0.142 mmol), 1-phenylpiperazine (0.021 mL, 0.142 mmol), DIPEA (0.040 mL, 0.213 mmol) and NaBH(OAc)3 (90 mg, 0.426 mmol).
Reaction SMILES: [C:1]1(=[O:11])[NH:5][C:4](=[O:6])[C:3]2=[CH:7][CH:8]=[CH:9][CH:10]=[C:2]12.[K].Br[CH2:14][CH2:15][CH:16]=[C:17]([CH3:19])[CH3:18].O>CN(C)C=O>[CH3:18][C:17]([CH3:19])=[CH:16][CH2:15][CH2:14][N:5]1[C:1](=[O:11])[C:2]2=[CH:10][CH:9]=[CH:8][CH:7]=[C:3]2[C:4]1=[O:6]
Reactant: CC(C)=CCCBr
Reactant: O=C1NC(=O)c2ccccc21
Agent: [K]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)=CCCN1C(=O)c2ccccc2C1=O
Temperature: 90 °C
Reaction time: 4 h

Procedure:
To a suspension of phthalimide, potassium derivative (11.5 g, 0.062 mol) in dry dimethylformamide (60 mL) was added 1-bromo-4-methyl-3-pentene (10.0 g, 0.061 mol) and the suspension was stirred under N2 at 90° C. for 4 h. The reaction mixture was poured into water (300 mL) and the precipitated solid was filtered and washed with water and the solid was dried under vacuum. Yield: 12.8 g (91%). mp 95-97° C. MS: (M+H)+=229.9.
Reaction SMILES: Cl.[C:2]([N:10]1[CH2:16][CH2:15][NH:14][CH2:13][CH2:12][N:11]1[C:17](=[O:24])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)(=[O:9])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.C(=O)([O-])[O-].[Na+].[Na+].[F:31][C:32]1[CH:37]=[CH:36][C:35]([CH:38]([C:43]2[CH:48]=[CH:47][C:46]([F:49])=[CH:45][CH:44]=2)[CH2:39][CH2:40][CH2:41]Br)=[CH:34][CH:33]=1>CN(C)C=O>[C:2]([N:10]1[CH2:16][CH2:15][N:14]([CH2:41][CH2:40][CH2:39][CH:38]([C:35]2[CH:34]=[CH:33][C:32]([F:31])=[CH:37][CH:36]=2)[C:43]2[CH:48]=[CH:47][C:46]([F:49])=[CH:45][CH:44]=2)[CH2:13][CH2:12][N:11]1[C:17](=[O:24])[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1)(=[O:9])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: Fc1ccc(C(CCCBr)c2ccc(F)cc2)cc1
Reactant: O=C(c1ccccc1)N1CCNCCN1C(=O)c1ccccc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C(c1ccccc1)N1CCN(CCCC(c2ccc(F)cc2)c2ccc(F)cc2)CCN1C(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
To a stirred mixture of 1,2-dibenzoylhexahydro-1H-1,2,5-triazepine hydrochloride (13.0 g), powdered anhydrous sodium carbonate (17.8 g) in N,N-dimethylformamide (100 ml, dried over 4A molecular sieves) under a purging nitrogen atmosphere was added 4,4-bis(4-fluorophenyl)butyl bromide (13.66 g) in N,N-dimethylformamide (30 ml) over a period of 40 minutes. The mixture was stirred under a purging nitrogen atmosphere at room temperature for 3 days. The mixture was filtered through sintered glass and the filter pad washed with N,N-dimethylformamide. The filtrate and washings were evaporated at 30° under oil pump vacuum. The residual oil was extracted with ether and the extract was filtered. The solution was slurried with 200 g of silica gel for 20 minutes. The mixture was then filtered through a sintered glass filter. The silica gel was stirred repeatedly with fresh ether (10-15 times) until no more product was removed from the silica gel. The filtrate and washings were evaporated to an oil. To the oil dissolved in 2-propanol (125 ml) was added 75 ml of a saturated solution of etheral hydrogen chloride. The hydrochloride salt of the titled product crystallized slowly on standing at room temperature; wt. 18.8 g (76%), mp=211°-212°.
Reaction SMILES: [ClH:1].[CH2:2]([O:4][C:5]1[CH:6]=[C:7]2[C:12](=[N:13][C:14]=1[CH3:15])[N:11]=[CH:10][C:9]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[C:8]2[NH:21][C:22]1[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=1)[CH3:3].[C:30]([OH:34])(=[O:33])[CH:31]=O.C(=O)(O)[O-].[Na+].Cl>O.C(O)(=O)C>[ClH:1].[CH2:2]([O:4][C:5]1[C:14]([CH:15]=[CH:31][C:30]([OH:34])=[O:33])=[N:13][C:12]2[C:7]([CH:6]=1)=[C:8]([NH:21][C:22]1[CH:23]=[CH:24][C:25]([O:28][CH3:29])=[CH:26][CH:27]=1)[C:9]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:10][N:11]=2)[CH3:3].[CH2:2]([O:4][C:5]1[C:14]([CH:15]=[CH:31][C:30]([OH:34])=[O:33])=[N:13][C:12]2[C:7]([CH:6]=1)=[C:8]([NH:21][C:22]1[CH:23]=[CH:24][C:25]([O:28][CH3:29])=[CH:26][CH:27]=1)[C:9]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:10][N:11]=2)[CH3:3]
Reactant: O=CC(=O)O
Reactant: CCOC(=O)c1cnc2nc(C)c(OCC)cc2c1Nc1ccc(OC)cc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: CCOC(=O)c1cnc2nc(C=CC(=O)O)c(OCC)cc2c1Nc1ccc(OC)cc1

Procedure:
A mixture of ethyl 6-ethoxy-4-(4-methoxyanilino)-7-methyl-1,8-naphthyridine-3-carboxylate hydrochloride (4.76 g), glyoxylic acid (1.73 g) and glacial acetic acid (50 ml) was boiled under reflux for 24 hours. The mixture was cooled and a solid was collected by filtration. The filtrate was acidified with concentrated hydrochloric acid and filtered to give a second crop of solid. The two crops of solid were combined, stirred in water and the mixture basified with sodium bicarbonate. The pH of the mixture was adjusted to pH 6 with concentrated hydrochloric acid and the mixture was extracted with ethyl acetate and then with dichloromethane. The combined organic extracts were washed with water, dried and evaporated. The residue was triturated with ethyl acetate and then filtered to give 3-[3-ethoxy-6-ethoxycarbonyl-5-(4-methoxyanilino)-1,8-naphthyridin-2-yl]acrylic acid hemihydrochloride, m.p. 259°-261° C.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:26])[CH2:5][CH2:6][C:7]1[C:12]([CH2:13][OH:14])=[CH:11][N:10]=[C:9]([CH3:15])[C:8]=1[O:16][CH2:17][C:18]1[CH:23]=[CH:22][C:21]([C:24]#[N:25])=[CH:20][CH:19]=1)[CH3:2].[C:27]([C:29]1[CH:34]=[CH:33][C:32](O)=[CH:31][CH:30]=1)#[N:28]>>[CH2:1]([O:3][C:4](=[O:26])[CH2:5][CH2:6][C:7]1[C:12]([CH2:13][O:14][C:32]2[CH:33]=[CH:34][C:29]([C:27]#[N:28])=[CH:30][CH:31]=2)=[CH:11][N:10]=[C:9]([CH3:15])[C:8]=1[O:16][CH2:17][C:18]1[CH:19]=[CH:20][C:21]([C:24]#[N:25])=[CH:22][CH:23]=1)[CH3:2]
Reactant: CCOC(=O)CCc1c(CO)cnc(C)c1OCc1ccc(C#N)cc1
Reactant: N#Cc1ccc(O)cc1
Product: CCOC(=O)CCc1c(COc2ccc(C#N)cc2)cnc(C)c1OCc1ccc(C#N)cc1
Yield: 93.2 %

Procedure:
The coupling of 3-[3-(4-cyano-benzyloxy)-5-hydroxymethyl-2-methyl-pyridin-4-yl]-propionic acid ethyl ester (36) (3.5 g, 9.89 mmol) and 4-cyanophenol (1.2 g, 9.9 mmol), as described in Example 9, gave 3-[3-(4-cyano-benzyloxy)-5-(4-cyano-phenoxymethyl)-2-methyl-pyridin-4-yl]-propionic acid ethyl ester (37) (4.2 g, 91% yield).
Reaction SMILES: [CH:1]([O:4][CH2:5][CH2:6][CH2:7][NH2:8])([CH3:3])[CH3:2].[C:9]([N:12]1[C:21]2[C:16](=[CH:17][C:18]([C:22](O)=[O:23])=[CH:19][CH:20]=2)[C:15]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)([CH3:25])[CH2:14][C:13]1([CH3:33])[CH3:32])(=[O:11])[CH3:10].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C>ClCCl>[C:9]([N:12]1[C:21]2[C:16](=[CH:17][C:18]([C:22]([NH:8][CH2:7][CH2:6][CH2:5][O:4][CH:1]([CH3:3])[CH3:2])=[O:23])=[CH:19][CH:20]=2)[C:15]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)([CH3:25])[CH2:14][C:13]1([CH3:33])[CH3:32])(=[O:11])[CH3:10]
Reactant: CC(=O)N1c2ccc(C(=O)O)cc2C(C)(c2ccccc2)CC1(C)C
Reactant: CC(C)OCCCN
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(=O)N1c2ccc(C(=O)NCCCOC(C)C)cc2C(C)(c2ccccc2)CC1(C)C

Procedure:
Condensation of 3-isopropoxypropylamine (5.2 mg) with 1-acetyl-4-phenyl-1,2,3,4-tetrahydro-2,2,4-trimethylquinoline-6-carboxylic acid (10 mg), under the agency of HATU (23 mg) and N,N-diisopropylethylamine (19 μl) in dichloromethane (2 ml) was performed according to the method described in example 11.
Reaction SMILES: [Br:1][C:2]1[O:3][C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([CH2:13]Br)[CH:8]=2)=[CH:5][CH:6]=1.[C:15]([O-:18])(=[O:17])[CH3:16].[K+]>C(O)(=O)C.O>[C:15]([O:18][CH2:13][C:9]1[CH:10]=[CH:11][CH:12]=[C:7]([C:4]2[O:3][C:2]([Br:1])=[CH:6][CH:5]=2)[CH:8]=1)(=[O:17])[CH3:16]
Reactant: BrCc1cccc(-c2ccc(Br)o2)c1
Reactant: CC(=O)[O-]
Agent: [K+]
Solvent: O
Solvent: CC(=O)O
Product: CC(=O)OCc1cccc(-c2ccc(Br)o2)c1
Reaction time: 19 h
Yield: 56 %

Procedure:
A stirred solution of 7.3 g (0.023 mol) of 2-bromo-5-(3-bromomethylphenyl)furan in 50 mL of acetic acid was cooled in an ice-water bath, and 3.4 g (0.035 mol) of potassium acetate was added. Upon complete addition, the reaction mixture was heated to reflux temperature and stirred for 19 hours. The reaction mixture was transferred to a separatory funnel, diluted with 100 mL of water, then extracted with two portions of 150 mL each of chloroform. The combined extracts were washed with one portion of 150 mL of a saturated aqueous solution of sodium chloride, two portions of 150 mL each of a saturated aqueous solution of sodium bicarbonate, and finally with one portion of 200 mL of a saturated aqueous solution of sodium chloride. The organic layer was dried with magnesium sulfate, filtered, and the filtrate concentrated under reduced pressure to give a residual oil. The oil was subjected to column chromatography on silica gel, eluting with hexane: chloroform (2:1). The appropriate fractions were combined to give 3.8 g of 3-(2-bromo-5-furanyl)phenylmethyl acetate.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:27])[C:7]=1[NH:8][C:9]([C:11]1[C:19]2[C:18]3[CH:20]=[C:21]([NH2:24])[CH:22]=[CH:23][C:17]=3[O:16][C:15]=2[C:14]([O:25][CH3:26])=[CH:13][CH:12]=1)=[O:10].[C:28]([O:32][CH2:33][CH3:34])(=[O:31])[CH:29]=O.C1(C)C=CC=CC=1>C(O)C.[Ni]>[Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:27])[C:7]=1[NH:8][C:9]([C:11]1[C:19]2[C:18]3[CH:20]=[C:21]([NH:24][CH2:29][C:28]([O:32][CH2:33][CH3:34])=[O:31])[CH:22]=[CH:23][C:17]=3[O:16][C:15]=2[C:14]([O:25][CH3:26])=[CH:13][CH:12]=1)=[O:10]
Reactant: CCOC(=O)C=O
Reactant: COc1ccc(C(=O)Nc2c(Cl)cncc2Cl)c2c1oc1ccc(N)cc12
Agent: [Ni]
Solvent: CCO
Solvent: Cc1ccccc1
Product: CCOC(=O)CNc1ccc2oc3c(OC)ccc(C(=O)Nc4c(Cl)cncc4Cl)c3c2c1

Procedure:
N-(3,5-dichloropyrid-4-yl)-4-methoxy-8-amino dibenzo[b,d]furan-1-carboxamide (500 mg, 1.24 mmol) was suspended in ethanol and a 50% solution of ethyl glyoxalate in toluene (384 mg, 3.72 mmol) was added to the suspension. The reaction mixture was hydrogenated at 40 psi in presence of pre-activated raney nickel (50% w/w) for 24 h-48 h. The reaction was filtered and the filterate was concentrated in vacuo. The residue was purified by silica gel (100-200) column chromatography using 0.5% methanol in dichloromethane to obtain the compound as a pale yellow solid (180 mg). mp: >270° C.
Reaction SMILES: [C:1]1([C@@H:7]2[O:12][CH2:11][CH2:10][NH:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl:13][C:14]1[N:19]=[CH:18][C:17]([CH:20]=O)=[CH:16][CH:15]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)(O)[O-].[Na+]>ClC(Cl)C>[Cl:13][C:14]1[N:19]=[CH:18][C:17]([CH2:20][N:9]2[CH2:10][CH2:11][O:12][C@@H:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[CH2:8]2)=[CH:16][CH:15]=1
Reactant: c1ccc([C@H]2CNCCO2)cc1
Reactant: O=Cc1ccc(Cl)nc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(Cl)Cl
Product: Clc1ccc(CN2CCO[C@@H](c3ccccc3)C2)cn1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 63.5 %

Procedure:
10 g of (S)-2-Phenyl-morpholine was dissolved in 610 mL of dichloroethane. 10.407 g of 6-Chloropyridine-3-carboxaldehyde was added and the reaction stirred at room temperature for 30 minutes followed by addition of 23.4 g of sodium triacetoxyborohydride. After stirring overnight at room temperature, the solution was poured into an aqueous saturated sodium bicarbonate solution and the layers separated. The organic layer was washed several times with aqueous saturated sodium bicarbonate solution followed by brine. It was then dried over sodium sulfate, filtered and concentrated in vacuo. Purification was accomplished by flash chromatography to afford 11.23 g of product. 63.5% yield. EI m/z 289=MH+
Reaction SMILES: [N+:1]([C:4]1[CH:20]=[CH:19][C:7]([CH2:8][O:9][C:10]([N:12]2[CH2:17][CH2:16][CH:15]([OH:18])[CH2:14][CH2:13]2)=[O:11])=[CH:6][CH:5]=1)([O-:3])=[O:2].[C:21]1([CH3:31])[CH:26]=[CH:25][C:24]([S:27](Cl)(=[O:29])=[O:28])=[CH:23][CH:22]=1>N1C=CC=CC=1.O>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([CH2:8][O:9][C:10]([N:12]2[CH2:13][CH2:14][CH:15]([O:18][S:27]([C:24]3[CH:25]=[CH:26][C:21]([CH3:31])=[CH:22][CH:23]=3)(=[O:29])=[O:28])[CH2:16][CH2:17]2)=[O:11])=[CH:19][CH:20]=1)([O-:3])=[O:2]
Reactant: O=C(OCc1ccc([N+](=O)[O-])cc1)N1CCC(O)CC1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: c1ccncc1
Solvent: O
Product: Cc1ccc(S(=O)(=O)OC2CCN(C(=O)OCc3ccc([N+](=O)[O-])cc3)CC2)cc1
Temperature: 25 °C
Reaction time: 23 h

Procedure:
To a solution of 1-(p-nitrobenzyloxycarbonyl)-4-hydroxypiperidine (10.54 g) in dry pyridine (105 ml) was added p-toluenesulfonyl chloride (14.35 g) at 0° C., followed by stirring at 25° C. for 23 hours. The reaction mixture was diluted with water and extracted with diethyl ether-dichloromethane (9:1). The extract was washed successively with saturated aqueous sodium chloride, 1N hydrochloric acid, saturated aqueous sodium chloride and saturated aqueous sodium bicarbonate, dried over anhydrous sodium suflate and evaporated to give 1-(p-nitrobenzyloxycarbonyl)-4-(p-toluenesulfonyloxy)piperidine.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]#[N:9])=[C:6]([NH:10][C@H:11]([C:13]2[N:18]=[C:17]3[CH:19]=[CH:20][N:21]([CH3:22])[C:16]3=[CH:15][C:14]=2[C:23]2[N:27]([CH3:28])[N:26]=[CH:25][CH:24]=2)[CH3:12])[N:5]=[C:4]([S:29][CH3:30])[N:3]=1.[OH-].[NH4+:32]>>[NH2:32][C:2]1[C:7]([C:8]#[N:9])=[C:6]([NH:10][C@H:11]([C:13]2[N:18]=[C:17]3[CH:19]=[CH:20][N:21]([CH3:22])[C:16]3=[CH:15][C:14]=2[C:23]2[N:27]([CH3:28])[N:26]=[CH:25][CH:24]=2)[CH3:12])[N:5]=[C:4]([S:29][CH3:30])[N:3]=1
Reactant: CSc1nc(Cl)c(C#N)c(N[C@@H](C)c2nc3ccn(C)c3cc2-c2ccnn2C)n1
Reactant: [NH4+]
Agent: [OH-]
Product: CSc1nc(N)c(C#N)c(N[C@@H](C)c2nc3ccn(C)c3cc2-c2ccnn2C)n1
Temperature: 85 °C

Procedure:
A mixture of (S)-4-chloro-6-((1-(1-methyl-6-(1-methyl-1H-pyrazol-5-yl)-1H-pyrrolo[3,2-b]pyridin-5-yl)ethyl)amino)-2-(methylthio)pyrimidine-5-carbonitrile (1.857 g, 4.23 mmol) and ammonium hydroxide (0.494 mL, 12.69 mmol) was heated at 85° C. in a microwave reactor for 12 hours. Additional ammonium hydroxide (0.494 mL, 12.69 mmol) was added. The reaction mixture was heated at 85° C. in a microwave reactor for 6 hours and then concentrated to give the title compound, which was used without further purification. ESI-MS m/z [M+H]+ calc'd for C20H21N9S, 420.16; found 420.4.
Reaction SMILES: [Br:1][C:2]1[C:3](=[O:10])[N:4]([CH3:9])[C:5](=[O:8])[NH:6][N:7]=1.[C:11](#[N:14])[CH:12]=[CH2:13].N1C=CC=CC=1>O>[Br:1][C:2]1[C:3](=[O:10])[N:4]([CH3:9])[C:5](=[O:8])[N:6]([CH2:13][CH2:12][C:11]#[N:14])[N:7]=1
Reactant: C=CC#N
Reactant: Cn1c(=O)[nH]nc(Br)c1=O
Solvent: O
Solvent: c1ccncc1
Product: Cn1c(=O)c(Br)nn(CCC#N)c1=O
Yield: 93 %

Procedure:
2.4 g (11.6 mmol) of the triazine 2a and 7 mL (106 mmol) of acrylonitrile are placed in 24 mL of a solution of pyridine and water (1/1) under reflux for 3 h. After concentration, the reaction medium is extracted with AcOEt and then after drying on MgSO4, the organic phases are dry concentrated. After washing the obtained solid with ether, 2.8 g of intermediate 3a are obtained (yield=93%).