Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1([C:10]2[C@:11]3([CH2:28][CH2:27][C@H:26]4[C@@H:16]([CH2:17][CH2:18][C:19]5[C@:24]4([CH3:25])[CH2:23][CH2:22][C:21](=[O:29])[CH:20]=5)[C@@H:13]3[CH2:14][CH:15]=2)[CH3:12])[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1.[Li][CH3:31]>C1COCC1>[CH3:31][C:21]1([OH:29])[CH2:22][CH2:23][C@@:24]2([CH3:25])[C:19]([CH2:18][CH2:17][C@@H:16]3[C@@H:26]2[CH2:27][CH2:28][C@@:11]2([CH3:12])[C@H:13]3[CH2:14][CH:15]=[C:10]2[N:1]2[C:5]3[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=3[N:3]=[CH:2]2)=[CH:20]1
Reactant: [Li]C
Reactant: C[C@]12CCC(=O)C=C1CC[C@@H]1[C@@H]2CC[C@]2(C)C(n3cnc4ccccc43)=CC[C@@H]12
Solvent: C1CCOC1
Product: CC1(O)C=C2CC[C@@H]3[C@H](CC[C@]4(C)C(n5cnc6ccccc65)=CC[C@@H]34)[C@@]2(C)CC1
Temperature: 0 °C
Reaction time: 1 h
Yield: 47.8 %

Procedure:
To a solution of ketone (32) (0.1 g, 0.26 mmol) in dry THF (3 mL) was added MeLi (1.6 M solution in ether, 0.41 mL, 0.60 mmol) at −60° C., and the resulting mixture was stirred at 0° C. for 1 h then room temperature for 3 h. The reaction was quenched with saturated aqueous NH4Cl and was extracted with EtOAc. The organic layer was washed with brine and dried over Na2SO4, and the solvent was removed under vacuum. The residue was purified by short FCC [petroleum ether, EtOAc, TEA (60:40:0.5)] to afford product 40 (0.05 g, 48%); mp 95-97° C.; IR (Neat) 3329, 2827, 2853, 1489, 1453, 1376, 1292, 1226, 1133, 918, 741 cm−1; 1H NMR (500 MHz, CDCl3) δ 1.00 (s, 3H, 18-CH3), 1.07 (s, 3H, 19-CH3), 1.27 (s, 3H, C3-CH3), 5.25 (t, J=1.6 Hz, 1H, 6-H), 5.96 (t, 1H, J=1.52 Hz, 16-H), 7.29 (m, 2H, aromatic-Hs), 7.49 (m, 1H, aromatic-H), 7.82 (dd, J=7.0, 2.6 Hz, 1H, aromatic-H), and 7.95 (s, 1H, 2′-H); 13C NMR (500 MHz, CDCl3) δ 145.3, 127.6, 124.4, 123.6, 122.7, 120.4, 111.4, 70.1, 55.7, 54.8, 37.8, 35.6, 35.3, 34.7, 32.5, 30.4, 28.5, 21.1, 18.8, 16.3. HRMS calcd 425.2563 (C27H34ON2.Na+). found 425.2570.
Reaction SMILES: [O-:1][S:2]([C:5]([F:8])([F:7])[F:6])(=[O:4])=[O:3].[C:9]1([C:15]2[CH:20]=[C:19]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[CH:18]=[C:17]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[O+]=2)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[CH2:33]([C:41]1[CH:47]=[CH:46][C:44]([NH2:45])=[CH:43][CH:42]=1)[CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH3:40]>C(O)C>[O-:4][S:2]([C:5]([F:8])([F:7])[F:6])(=[O:3])=[O:1].[CH2:33]([C:41]1[CH:42]=[CH:43][C:44]([N+:45]2[C:15]([C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=3)=[CH:20][C:19]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[CH:18][C:17]=2[C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[CH:46][CH:47]=1)[CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH3:40]
Reactant: CCCCCCCCc1ccc(N)cc1
Reactant: c1ccc(-c2cc(-c3ccccc3)[o+]c(-c3ccccc3)c2)cc1
Agent: O=S(=O)([O-])C(F)(F)F
Solvent: CCO
Product: CCCCCCCCc1ccc(-[n+]2c(-c3ccccc3)cc(-c3ccccc3)cc2-c2ccccc2)cc1

Procedure:
A 4.58-g portion (0.01 mole) of 2,4,6-triphenylpyrylium triflate is added to 200 ml of ethanol. To this solution, 2.05 g (0.01 mole) of p-n-octylaniline is added. The mixture is refluxed for about 20 hours. Upon removing the ethanol by rotating evaporation, an orange oil remains. To remove the last of the ethanol the oil is placed under high vacuum.
Reaction SMILES: Cl[C:2]1[C:3]2[CH:10]=[CH:9][N:8]([C@@H:11]3[O:27][C@H:26]([CH2:28][O:29][CH2:30][C:31]4[CH:36]=[CH:35][C:34]([Cl:37])=[CH:33][C:32]=4[Cl:38])[C@@H:15]([O:16][CH2:17][C:18]4[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][C:19]=4[Cl:25])[C@@:12]3([CH3:39])[O:13][CH3:14])[C:4]=2[N:5]=[CH:6][N:7]=1.[NH3:40]>>[NH2:40][C:2]1[C:3]2[CH:10]=[CH:9][N:8]([C@@H:11]3[O:27][C@H:26]([CH2:15][O:16][CH2:17][C:18]4[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][C:19]=4[Cl:25])[C@@H:28]([O:29][CH2:30][C:31]4[CH:36]=[CH:35][C:34]([Cl:37])=[CH:33][C:32]=4[Cl:38])[C@@:12]3([CH3:39])[O:13][CH3:14])[C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: CO[C@]1(C)[C@H](OCc2ccc(Cl)cc2Cl)[C@@H](COCc2ccc(Cl)cc2Cl)O[C@H]1n1ccc2c(Cl)ncnc21
Reactant: N
Product: CO[C@]1(C)[C@H](OCc2ccc(Cl)cc2Cl)[C@@H](COCc2ccc(Cl)cc2Cl)O[C@H]1n1ccc2c(N)ncnc21

Procedure:
To the compound from Step A (735 mg, 1.16 mmol) was added methanolic ammonia (saturated at 0° C.) (20 mL). The mixture was heated in a stainless steel autoclave at 80° C. overnight, then cooled and the content evaporated in vacuo. The crude mixture was purified on silica gel using ethyl acetate/hexane as the eluent. Fractions containing the product were pooled and evaporated in vacuo to give the desired product (504 mg) as colorless foam.
Reaction SMILES: [CH2:1]([N:3]([CH2:51][CH3:52])[C@H:4]([C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1)[C:5]([N:7]1[CH2:11][CH2:10][CH2:9][C@H:8]1[C:12]([NH:14][C:15]1[CH:20]=[CH:19][C:18]([CH2:21][N:22]([C:38]2[CH:43]=[CH:42][C:41]([F:44])=[CH:40][CH:39]=2)[CH2:23][C:24]2[CH:29]=[CH:28][C:27]([NH:30][C:31]([C@@H:33]3[CH2:37][CH2:36][CH2:35][NH:34]3)=[O:32])=[CH:26][CH:25]=2)=[CH:17][CH:16]=1)=[O:13])=[O:6])[CH3:2].[CH3:53][O:54][C:55]([NH:57][C@@H:58]([C@H:62]1[CH2:66][CH2:65][O:64][CH2:63]1)[C:59](O)=[O:60])=[O:56]>>[CH2:51]([N:3]([CH2:1][CH3:2])[C@H:4]([C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1)[C:5]([N:7]1[CH2:11][CH2:10][CH2:9][C@H:8]1[C:12]([NH:14][C:15]1[CH:16]=[CH:17][C:18]([CH2:21][N:22]([CH2:23][C:24]2[CH:29]=[CH:28][C:27]([NH:30][C:31]([C@@H:33]3[CH2:37][CH2:36][CH2:35][N:34]3[C:59](=[O:60])[C@@H:58]([NH:57][C:55](=[O:56])[O:54][CH3:53])[C@H:62]3[CH2:66][CH2:65][O:64][CH2:63]3)=[O:32])=[CH:26][CH:25]=2)[C:38]2[CH:39]=[CH:40][C:41]([F:44])=[CH:42][CH:43]=2)=[CH:19][CH:20]=1)=[O:13])=[O:6])[CH3:52]
Reactant: CCN(CC)[C@@H](C(=O)N1CCC[C@H]1C(=O)Nc1ccc(CN(Cc2ccc(NC(=O)[C@@H]3CCCN3)cc2)c2ccc(F)cc2)cc1)c1ccccc1
Reactant: COC(=O)N[C@H](C(=O)O)[C@H]1CCOC1
Product: CCN(CC)[C@@H](C(=O)N1CCC[C@H]1C(=O)Nc1ccc(CN(Cc2ccc(NC(=O)[C@@H]3CCCN3C(=O)[C@@H](NC(=O)OC)[C@H]3CCOC3)cc2)c2ccc(F)cc2)cc1)c1ccccc1
Yield: 61.8 %

Procedure:
The product from Example 81A (0.042 g, 0.060 mmol) and (S)-2-(methoxycarbonylamino)-2-((R)-tetrahydrofuran-3-yl)acetic acid (0.013 g, 0.066 mmol) were processed as in Example 81A to give 0.033 g (62%) of the title compound as an off-white solid. MS (AA, ELSD+) m/z 890 (M+H)+.
Reaction SMILES: [OH2:1].[F-].C([N+](CCCC)(CCCC)CCCC)CCC.[Si]([CH2:27][CH2:28][CH:29]([OH:35])[C:30]([CH3:34])([CH3:33])[C:31]#[N:32])(C(C)(C)C)(C)C>O1CCCC1>[OH:1][CH2:27][CH2:28][CH:29]([OH:35])[C:30]([CH3:34])([CH3:33])[C:31]#[N:32]
Reactant: O
Reactant: CC(C)(C#N)C(O)CC[Si](C)(C)C(C)(C)C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: CC(C)(C#N)C(O)CCO
Temperature: 25 °C
Reaction time: 16 h

Procedure:
12.18 g (46.61 mmol) of tetrabutylammonium fluoride hydrate is added to a solution that consists of 3 g (11.65 mmol) of 5-tert-butyldimethylsilyl-2,2-dimethyl-3(R,S)-hydroxy-pentane-nitrile of the title compound of Example 6a, dissolved in 40 ml of tetrahydrofuran, and it is stirred for 16 hours at room temperature. Then, it is evaporated to the dry state in a vacuum. The residue is purified by RP-18 chromatography (mobile solvent: acetonitrile/water gradient).
Reaction SMILES: ClCC[CH:4]([S:10]([CH:13]([C:17]1[O:18][CH:19]=[CH:20][CH:21]=1)CCCl)(=[O:12])=[O:11])[C:5]1OC=CC=1.[CH:22]([NH2:25])([CH3:24])[CH3:23]>>[O:18]1[CH:19]=[CH:20][CH:21]=[C:17]1[CH2:13][S:10]([CH2:4][CH2:5][NH:25][CH:22]([CH3:24])[CH3:23])(=[O:11])=[O:12]
Reactant: CC(C)N
Reactant: O=S(=O)(C(CCCl)c1ccco1)C(CCCl)c1ccco1
Product: CC(C)NCCS(=O)(=O)Cc1ccco1

Procedure:
A solution of 2-chloroethyl-2-furanylmethyl sulfone in isopropylamine is stirred at room temperature for about 72 hr. The isopropylamine is removed by evaporation and the residue is dissolved with agitation in a mixture of methylene chloride and dilute sodium hydroxide. The methylene chloride layer is extracted with dilute sodium hydroxide and dried over magnesium sulfate. The solvent is removed by evaporation to give the free base of the title compound, which is converted to the hydrochloride salt and is then recrystallized from methanol-diethyl ether.
Reaction SMILES: [C:1]1([C:7]([C:9]2[O:10][C:11]([C:14]([O:16][CH3:17])=[O:15])=[CH:12][CH:13]=2)=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:18]([NH:25][NH2:26])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C(O)(=O)C>CO>[CH2:18]([NH:25][N:26]=[C:7]([C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[C:9]1[O:10][C:11]([C:14]([O:16][CH3:17])=[O:15])=[CH:12][CH:13]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: NNCc1ccccc1
Reactant: COC(=O)c1ccc(C(=O)c2ccccc2)o1
Solvent: CO
Solvent: CC(=O)O
Product: COC(=O)c1ccc(C(=NNCc2ccccc2)c2ccccc2)o1

Procedure:
5-Methoxycarbonyl-2-furyl phenyl ketone (5.5 g, 0.024 mole) was dissolved in methanol (60 mL), added with benzylhydrazine (9 g, 0.07 mole) and acetic acid (0.5 mL) and then heated under reflux till the reaction was completed. After cooling, the solvent was evaporated. The resultant residue was extracted with chloroform and washed with dilute HCl solution, then water, and then dried over anhydrous magnesium sulfate and filtered. The solvent of the filtrate was removed to give 5-methoxycarbonylfuryl phenyl ketone benzylhydrazone.
Reaction SMILES: Br[CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([Cl:10])=[CH:6][CH:5]=1.[NH:11]([C:13]1[CH:22]=[CH:21][C:16]([C:17]([O:19]C)=[O:18])=[CH:15][CH:14]=1)N.[CH3:23][N:24]1[CH2:29][CH2:28][C:27](=O)[CH2:26][CH2:25]1>C(N(CC)CC)C>[Cl:10][C:7]1[CH:8]=[CH:9][C:4]([CH2:3][CH2:2][CH:25]2[C:26]3[C:14]4[CH:15]=[C:16]([C:17]([OH:19])=[O:18])[CH:21]=[CH:22][C:13]=4[NH:11][C:27]=3[CH2:28][CH2:29][N:24]2[CH3:23])=[CH:5][CH:6]=1
Reactant: CN1CCC(=O)CC1
Reactant: COC(=O)c1ccc(NN)cc1
Reactant: Clc1ccc(CCBr)cc1
Solvent: CCN(CC)CC
Product: CN1CCc2[nH]c3ccc(C(=O)O)cc3c2C1CCc1ccc(Cl)cc1

Procedure:
The title compound is prepared by following Method 8 by using 1-(2-bromoethyl)-4-chlorobenzene, methyl 4-hydrazinobenzoate, triethylamine and N-methyl-4-piperidone
Reaction SMILES: C(OC(NC1C=C(C2C(C3C=CC=CC=3[F:35])=NN(C3C=CC4N(C=NN=4)N=3)C=2)C=CN=1)=O)(C)(C)C.C(OC([NH:43][C:44]1[CH:49]=[C:48]([C:50]2[C:51]([C:64]3[CH:69]=[CH:68][CH:67]=[CH:66][CH:65]=3)=[N:52][N:53]([C:55]3[CH:56]=[CH:57][C:58]4[N:59]([CH:61]=[N:62][N:63]=4)[N:60]=3)[CH:54]=2)[CH:47]=[CH:46][N:45]=1)=O)(C)(C)C>>[NH2:43][C:44]1[CH:49]=[C:48]([C:50]2[C:51]([C:64]3[CH:69]=[CH:68][CH:67]=[C:66]([F:35])[CH:65]=3)=[N:52][N:53]([C:55]3[CH:56]=[CH:57][C:58]4[N:59]([CH:61]=[N:62][N:63]=4)[N:60]=3)[CH:54]=2)[CH:47]=[CH:46][N:45]=1
Reactant: CC(C)(C)OC(=O)Nc1cc(-c2cn(-c3ccc4nncn4n3)nc2-c2ccccc2F)ccn1
Reactant: CC(C)(C)OC(=O)Nc1cc(-c2cn(-c3ccc4nncn4n3)nc2-c2ccccc2)ccn1
Product: Nc1cc(-c2cn(-c3ccc4nncn4n3)nc2-c2cccc(F)c2)ccn1
Yield: 86 %

Procedure:
The reaction was carried out in the same manner as in Example 37-2) except for using 4.00 g (8.47 mmol) of 4-(2-t-butoxycarbonylaminopyridin-4-yl)-3-(2-fluorophenyl)-1-([1,2,4]triazolo[4,3-b]pyridazin-6-yl)-1H-pyrazole obtained in Example 42-1) in place of 4-(2-t-butoxycarbonylaminopyridin-4-yl)-3-phenyl-1-([1,2,4]triazolo[4,3-b]pyridazin-6-yl)-1H-pyrazole to obtain 2.71 g of the title compound as a pale beige powder. (Yield: 86%)
Reaction SMILES: [S:1]1[CH:5]=[C:4]([C:6]([OH:8])=O)[C:3]2[CH:9]=[CH:10][CH:11]=[CH:12][C:2]1=2.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[CH2:46]([O:48][C:49]([C:51]1([NH2:60])[CH2:59][C:58]2[C:53](=[CH:54][CH:55]=[CH:56][CH:57]=2)[CH2:52]1)=[O:50])[CH3:47]>CO.C(Cl)Cl.C(Cl)Cl>[CH2:46]([O:48][C:49]([C:51]1([NH:60][C:6]([C:4]2[C:3]3[CH:9]=[CH:10][CH:11]=[CH:12][C:2]=3[S:1][CH:5]=2)=[O:8])[CH2:59][C:58]2[C:53](=[CH:54][CH:55]=[CH:56][CH:57]=2)[CH2:52]1)=[O:50])[CH3:47]
Reactant: CCOC(=O)C1(N)Cc2ccccc2C1
Reactant: O=C(O)c1csc2ccccc12
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CO
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)C1(NC(=O)c2csc3ccccc23)Cc2ccccc2C1
Yield: 77.4 %

Procedure:
To a 40 mL vial containing a stirring bar, benzo[b]thiophene-3-carboxylic acid ([5381-25-9], 434 g, 2.44 mmol) is charged with dry DCM (7 mL). Stirring is initiated. HBTU (922 mg, 2.43 mmol) and DIPEA (0.95 mL, 8.0 mmol) are added. The 2-aminoindane-2-carboxylic acid ethyl ester (500 mg, 2.44 mmol) is added. The reaction is allowed to stir for 20 h. Analysis by tlc of the reaction mixture (silica, 10% MeOH/DCM) indicates complete consumption of the starting amine. The contents of the reaction flask are diluted with EtOAc (50 mL) and transferred to a reparatory funnel. This is washed consecutively with dilute aqueous NaHCO3 (25 mL) and brine (25 mL), dried over MgSO4, filtered and evaporated in vacuo to provide 1.64 g of off white solid. This material is purified utilizing an ISCO Companion with a 40 g cartridge of silica. The gradient is 20% EtOAc in heptanes over 3 column volumes followed by a linear gradient to 50% over 8 column volumes and then 90% EtOAc for 2 column volumes with a ramp of 1 column volume. 25 mL fractions are collected. Fractions 4 through 16 are combined and evaporated in vacuo. Pumping to a constant weight gives amorphous white solid 0.69 g.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:16]=[CH:17][CH:18]=1)[C:12](OC)=[S:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N+:19]([CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23])#[C-:20]>>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([C:12]2[S:13][CH:20]=[N:19][C:21]=2[C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH:16]=[CH:17][CH:18]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=S)c1cccc(OCc2ccccc2)c1
Reactant: [C-]#[N+]CC(=O)OCC
Product: CCOC(=O)c1ncsc1-c1cccc(OCc2ccccc2)c1
Yield: 92.9 %

Procedure:
In an analogous manner to that described in Example 1(C), 21.7 g of O-methyl 3-(benzyloxy)thiobenzoate (44.13 mmol) were reacted with ethyl isocyanoacetate, whereby there were obtained 26.5 g (92.9%) of ethyl 5-[3-(benzyloxy)phenyl]-4-thiazolecarboxylate as an orange oil.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([OH:12])[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:10])=[O:9].[N+:13]([O-])([OH:15])=[O:14].O>C(Cl)Cl>[CH3:1][C:2]1[C:7]([S:8]([CH3:11])(=[O:10])=[O:9])=[CH:6][C:5]([N+:13]([O-:15])=[O:14])=[C:4]([OH:12])[CH:3]=1
Reactant: O=[N+]([O-])O
Reactant: Cc1cc(O)ccc1S(C)(=O)=O
Solvent: O
Solvent: ClCCl
Product: Cc1cc(O)c([N+](=O)[O-])cc1S(C)(=O)=O
Yield: 19.5 %

Procedure:
3-Methyl-4-(methylsulfonyl)phenol (D85, 503 mg, 2.29 mmol) was dissolved in DCM (5 mL) and 70% nitric acid (0.16 mL, 3.58 mmol) was added dropwise to the reaction. The mixture was stirred o/n. A further 2 mL of 70% nitric acid was then added. The reaction was stirred for 4 h, then H2O (20 mL) was added and the 2 phases were separated. The aqueous layer was extracted with DCM and the combined organics were dried (Na2SO4) and concentrated by rotary evaporation to give a yellow solid, which was purified via flash column chromatography (silica, iso-hexane to 50% EtOAc/50% iso-hexane) to give a yellow solid. This solid was triturated with Et2O (2×) to give 5-methyl-4-(methylsulfonyl)-2-nitrophenol (D86, 103 mg, 19%) as a yellow solid.
Reaction SMILES: [F:1][C:2]1[CH:36]=[CH:35][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:9]3[C:16]([C:28]4[CH:33]=[CH:32][C:31]([CH3:34])=[CH:30][CH:29]=4)=[C:17]([CH:22]([OH:27])[C:23]([O:25][CH3:26])=[O:24])[N:18]([CH3:21])[C:19](=[O:20])[C:8]2=3)=[CH:4][CH:3]=1.Cl(O)(=O)(=O)=O>C(OC(C)(C)C)(=O)C.C(OCC)(=O)C>[C:5]([O:27][CH:22]([C:17]1[N:18]([CH3:21])[C:19](=[O:20])[C:8]2[N:7]([CH2:6][C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:36][CH:35]=3)[C:15]3[C:10]([C:9]=2[C:16]=1[C:28]1[CH:29]=[CH:30][C:31]([CH3:34])=[CH:32][CH:33]=1)=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:23]([O:25][CH3:26])=[O:24])([CH3:35])([CH3:6])[CH3:4]
Reactant: COC(=O)C(O)c1c(-c2ccc(C)cc2)c2c3ccccc3n(Cc3ccc(F)cc3)c2c(=O)n1C
Agent: [O-][Cl+3]([O-])([O-])O
Solvent: CCOC(C)=O
Solvent: CC(=O)OC(C)(C)C
Product: COC(=O)C(OC(C)(C)C)c1c(-c2ccc(C)cc2)c2c3ccccc3n(Cc3ccc(F)cc3)c2c(=O)n1C
Temperature: 25 °C
Reaction time: 1 h
Yield: 126.4 %

Procedure:
A solution of methyl 2-(9-(4-fluorobenzyl)-2-methyl-1-oxo-4-(p-tolyl)-2,9-dihydro-1H-pyrido[3,4-b]indol-3-yl)-2-hydroxyacetate (42 mg, 0.087 mmol) in t-Butyl acetate (1 mL) was treated with perchloric acid (6.22 μL, 0.103 mmol) and then stirred at room temperature for 1 hour. The mixture was diluted with Ethyl acetate, washed with NaHCO3 and brine, dried over Na2SO4, filtered and concentrated. The residue was purified on silica gel (0-70% ethyl acetate/hexanes) to afford methyl 2-(tert-butoxy)-2-(9-(4-fluorobenzyl)-2-methyl-1-oxo-4-(p-tolyl)-2,9-dihydro-1H-pyrido[3,4-b]indol-3-yl)acetate as a white solid (30 mg, 0.055 mmol, 64% yield). 1H NMR (400 MHz, CHLOROFORM-d) ppm 7.25-7.47 (m, 8H) 6.88-7.00 (m, 3H) 6.57-6.63 (m, 1H) 6.19-6.22 (m, 1H) 6.11-6.17 (m, 1H) 5.29 (s, 1H) 3.79 (s, 3H) 3.78 (s, 3H) 2.54 (s, 3H) 1.04 (s, 9H); LCMS (m/z) ES+=541 (M+1).
Reaction SMILES: [Cl:1][C:2]1[C:3](Cl)=[C:4]2[N:10]=[C:9]([C:11]3[CH:16]=[CH:15][C:14]([O:17][CH2:18][CH2:19][N:20]4[CH2:25][CH2:24][O:23][CH2:22][CH2:21]4)=[CH:13][CH:12]=3)[NH:8][C:5]2=[N:6][CH:7]=1.[NH:27]1[CH2:31][CH2:30][CH2:29][CH2:28]1>CN(C=O)C>[Cl:1][C:2]1[C:3]([N:27]2[CH2:31][CH2:30][CH2:29][CH2:28]2)=[C:4]2[N:10]=[C:9]([C:11]3[CH:12]=[CH:13][C:14]([O:17][CH2:18][CH2:19][N:20]4[CH2:21][CH2:22][O:23][CH2:24][CH2:25]4)=[CH:15][CH:16]=3)[NH:8][C:5]2=[N:6][CH:7]=1
Reactant: Clc1cnc2[nH]c(-c3ccc(OCCN4CCOCC4)cc3)nc2c1Cl
Reactant: C1CCNC1
Solvent: CN(C)C=O
Product: Clc1cnc2[nH]c(-c3ccc(OCCN4CCOCC4)cc3)nc2c1N1CCCC1
Temperature: 150 °C
Yield: 18.7 %

Procedure:
6,7-Dichloro-2-[4-(2-morpholin-4-ylethoxy)phenyl]-3H-imidazo[4,5-b]pyridine (Example 206) (0.010 g, 0.025 mmol) and pyrrolidine (0.03 ml, 0.4 mmol) were dissolved in DMF (1 ml) and heated in a sealed vial at 150° C. for 3 h. The excess amine and the solvent were removed under reduced pressure, and the solid residue was washed with CH3CN, giving the title product (0.002 g, 19%).
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:23])[CH2:10][CH2:11][C@H:12]([NH:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:13][OH:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.[C:25]1(C)[CH:30]=CC(S(O)(=O)=O)=C[CH:26]=1.COC=CC>C(Cl)Cl>[C:19]([O:18][C:16]([N:15]1[C@@H:12]([CH2:11][CH2:10][C:9]([O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[O:23])[CH2:13][O:14][C:25]1([CH3:30])[CH3:26])=[O:17])([CH3:20])([CH3:22])[CH3:21]
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: CC(C)(C)OC(=O)N[C@H](CO)CCC(=O)OCc1ccccc1
Agent: CC=COC
Solvent: ClCCl
Solvent: O
Product: CC(C)(C)OC(=O)N1[C@@H](CCC(=O)OCc2ccccc2)COC1(C)C
Temperature: 0 °C
Reaction time: 3 h

Procedure:
To a solution of 52.46 g of 4(S)-tert-butoxycarbonylamino-5-hydroxy-pentanoic acid benzyl ester [9069-62-8] and 895 mg of p-toluenesulfonic acid hydrate in 125 ml of methylene chloride at 0° C. under argon are added 31 ml of methoxypropene over 15 minutes. The mixture is stirred at 0° C. for 3 hours, then at room temperature for 9 hours. The mixture is washed with saturated sodium bicarbonate solution and dried over sodium sulphate, filtered and concentrated. The title compound is obtained as a yellow oil from the residue by means of flash chromatography (SiO2 60 F). Rf=0.32 (1:3 EtOAc-heptane); Rt=5.32 (gradient I).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11](=[CH:14][CH2:15][OH:16])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(Cl)(Cl)Cl>CCCCCC.[O-2].[O-2].[Mn+4]>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11](=[CH:14][CH:15]=[O:16])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCC(=CCO)CC1
Agent: [Mn+4]
Agent: [O-2]
Solvent: CCCCCC
Solvent: ClC(Cl)Cl
Product: CC(C)(C)OC(=O)N1CCC(=CC=O)CC1
Reaction time: 10 h
Yield: 88.8 %

Procedure:
To a solution of 4-(2-hydroxyethylidene)piperidine-1-carboxylic acid t-butyl ester (10.4 g, 46 mmol) in a mixture of hexane (300 mL)-chloroform (100 mL) was added manganese dioxide (100 g), and stirred for 10 hours. After the reaction was completed, insoluble materials were filtered off through Celite and the filtrate was concentrated under a reduced pressure to obtain 9.2 g (yield 89%) of 4-(2-oxoethylidene)piperidine-1-carboxylic acid t-butyl ester (VII-18, 20, 21, 24, 30, 41, 42, 43, 44, 45).
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].C(N(CC)CC)C.[O:12]1[CH2:17][CH2:16][N:15]([C:18]2[N:23]=[C:22]([CH2:24][CH2:25][CH3:26])[N:21]=[C:20]([NH:27][CH2:28][CH2:29][OH:30])[N:19]=2)[CH2:14][CH2:13]1>ClCCl>[C:1]([O:30][CH2:29][CH2:28][NH:27][C:20]1[N:19]=[C:18]([N:15]2[CH2:14][CH2:13][O:12][CH2:17][CH2:16]2)[N:23]=[C:22]([CH2:24][CH2:25][CH3:26])[N:21]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)Cl
Reactant: CCCc1nc(NCCO)nc(N2CCOCC2)n1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCc1nc(NCCOC(C)=O)nc(N2CCOCC2)n1
Temperature: 5 °C
Reaction time: 1 h
Yield: 60 %

Procedure:
4 3 g (0.055 mole) of acetyl chloride, dissolved in 50 ml of dichloromethane, and 5.5 g (0.055 mole) of triethylamine, dissolved in 50 ml of dichloromethane, are simultaneously introduced, between 0° and 5° C., into a solution of 13.4 g (0.05 mole) of 2-[(4-morpholino-6-propyl-1,3,5-triazin-2-yl)amino]-ethanol (compound 1 prepared in Example 1) in 200 ml of dichloromethane. The addition of these two reagents is regulated in a manner such that the acid chloride is always present in the reaction mixture in excess with respect to the triethylamine. The mixture is stirred for one hour at 5° C. and then for 12 hours at room temperature. The reaction mixture is washed successively with an aqueous solution of sodium bicarbonate and with water. It is dried over sodium sulfate and the solvent is evaporated under reduced pressure. The residue crystallizes in a mixture of toluene-hexane 1:2. The product obtained is first purified by chromatography on silica (eluent: 95:5 (v/v) dichloromethane-ethanol) and is then firstly recrystallized from a mixture of toluene-hexane 1:1. 9.3 g of 2-[[2-(acetoxy)ethyl]amino]-4-morpholino-6-propyl-1,3,5-triazine are obtained.
Reaction SMILES: [CH:1]1[NH:5][CH:4]=[C:3]2[C:6](=[O:10])[O:7][CH2:8][CH2:9][C:2]=12.CN(C)[CH:13]=[O:14].P(Cl)(Cl)(Cl)=O>ClCCl>[O:10]=[C:6]1[C:3]2[CH2:2][CH2:1][N:5]([CH:13]=[O:14])[C:4]=2[CH2:9][CH2:8][O:7]1
Reactant: O=C1OCCc2c[nH]cc21
Reactant: CN(C)C=O
Solvent: O=P(Cl)(Cl)Cl
Solvent: ClCCl
Product: O=CN1CCC2=C1CCOC2=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 58 %

Procedure:
6,7-Dihydro-2H-pyrano[3,4-c]pyrrol-4-one (5 g, 36 mmol) was formulated under standard Vilsmeier reaction using N,N-dimethylformamide (DMF, 1.2 eq.) and phosphorus oxychloride (POCl3, 1.1 eq.) in dichloromethane. The above mixture was stirred at room temperature for 1 hour. The precipitate salt was filtered, washed with dichloromethane, suspended in water and made basic with 6 N sodium hydroxide to pH=12. The mixture was stirred for 5 minutes and filtered. The solid was washed with ethanol/water mixture (1:1) to give 3.5 g (58%) of 4-oxo-2,4,6,7-tetrahydro-pyrano[3,4]pyrrole-1-carbaldehyde.