Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:3][C:4]([C:6]1[NH:13][N:12]=[C:11]2[C:7]=1[CH2:8][CH:9]1[C:14]([CH3:16])([CH3:15])[CH:10]12)=O)C.[NH3:17]>>[CH3:15][C:14]1([CH3:16])[CH:9]2[CH2:8][C:7]3[C:11]([CH:10]12)=[N:12][NH:13][C:6]=3[C:4]([NH2:17])=[O:3]
Reactant: N
Reactant: CCOC(=O)c1[nH]nc2c1CC1C2C1(C)C
Product: CC1(C)C2Cc3c(n[nH]c3C(N)=O)C21
Temperature: 100 °C

Procedure:
(±)-1,1-Dimethyl-1a,3,5,5a-tetrahydro-1H-2,3-diaza-cyclopropa[a]pentalene-4-carboxylic acid ethyl ester (1.280 g, 5.81 mmol) was taken up in 7M methanolic ammonia (60 mL) in a sealed flask and heated to 100° C. for 18 hours. The resulting suspension was collected by vacuum filtration to give 1,1-dimethyl-1a,3,5,5a-tetrahydro-1H-2,3-diaza-cyclopropa[a]pentalene-4-carboxylic acid amide as a cream solid. Solvent was removed from the mother liquor and the residue purified by preparative HPLC to give further (±)-1,1-dimethyl-1a,3,5,5a-tetrahydro-1H-2,3-diaza-cyclopropa[a]pentalene-4-carboxylic acid amide as a cream solid. m/z (ES+): 192 [M+H]+, 175 [M−NH2]+; 1H NMR (CD3OD): δ 2.9-2.65 (m, 1H), 2.55 (t, 1H, J=19.9), 2.0-1.8 (m, 2H), 1.03 (s, 3H), 0.63 (s, 3H).
Reaction SMILES: [Si]([O:18][C:19]1[CH:56]=[CH:55][C:22]([O:23][CH2:24][C@@H:25]([OH:54])[CH2:26][NH:27][CH2:28][CH2:29][C:30]2[CH:53]=[CH:52][C:33]([O:34][CH:35]3[CH2:40][CH2:39][N:38]([C:41]([NH:43][CH2:44][C:45]4[CH:50]=[CH:49][C:48]([F:51])=[CH:47][CH:46]=4)=[O:42])[CH2:37][CH2:36]3)=[CH:32][CH:31]=2)=[CH:21][CH:20]=1)(C(C)(C)C)(C1C=CC=CC=1)C1C=CC=CC=1>C(Cl)(Cl)Cl.CO>[F:51][C:48]1[CH:47]=[CH:46][C:45]([CH2:44][NH:43][C:41]([N:38]2[CH2:37][CH2:36][CH:35]([O:34][C:33]3[CH:52]=[CH:53][C:30]([CH2:29][CH2:28][NH:27][CH2:26][C@H:25]([OH:54])[CH2:24][O:23][C:22]4[CH:21]=[CH:20][C:19]([OH:18])=[CH:56][CH:55]=4)=[CH:31][CH:32]=3)[CH2:40][CH2:39]2)=[O:42])=[CH:50][CH:49]=1
Reactant: CC(C)(C)[Si](Oc1ccc(OC[C@@H](O)CNCCc2ccc(OC3CCN(C(=O)NCc4ccc(F)cc4)CC3)cc2)cc1)(c1ccccc1)c1ccccc1
Solvent: ClC(Cl)Cl
Solvent: CO
Product: O=C(NCc1ccc(F)cc1)N1CCC(Oc2ccc(CCNC[C@H](O)COc3ccc(O)cc3)cc2)CC1
Yield: 33.7 %

Procedure:
4-[4-(2-{[(2S)-3-(4-{[tert-butyl(diphenyl)silyl]oxy}phenoxy)-2-hydroxy-propyl]amino}ethyl)phenoxy]-N-(4-fluorobenzyl)-1-piperidinecarboxamide (0.335 g, 0.43 mmol) was reacted according to Procedure H (eluant: 8:1 chloroform-methanol) to give the title compound (0.09 g, 0.145 mmol). The free base was treated with a solution of anhydrous hydrogen chloride in methanol, followed by diethyl ether and hexane. The precipitate was filtered and, after drying in vacuo overnight, yielded the title compound (0.17 g, 0.3 mmol)
Reaction SMILES: [H-].[Na+].C(OP([CH2:11][C:12]([N:14]1[CH2:19][CH2:18][CH2:17][CH2:16][CH:15]1[CH2:20][CH3:21])=[O:13])(OCC)=O)C.[CH3:22][C:23]1[C:24]2[N:25]([N:29]=[C:30]([C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)[C:31]=2[CH:32]=O)[CH:26]=[CH:27][CH:28]=1>O1CCCC1>[CH3:22][C:23]1[C:24]2[N:25]([N:29]=[C:30]([C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)[C:31]=2[CH:32]=[CH:11][C:12]([N:14]2[CH2:19][CH2:18][CH2:17][CH2:16][CH:15]2[CH2:20][CH3:21])=[O:13])[CH:26]=[CH:27][CH:28]=1
Reactant: Cc1cccn2nc(-c3ccccc3)c(C=O)c12
Reactant: CCOP(=O)(CC(=O)N1CCCCC1CC)OCC
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCC1CCCCN1C(=O)C=Cc1c(-c2ccccc2)nn2cccc(C)c12
Temperature: 25 °C
Reaction time: 1 h
Yield: 99.7 %

Procedure:
Sodium hydride (60%, 110 mg) was added to a solution of 1-(2-diethoxyphosphorylacetyl)-2-ethylpiperidine (0.80 g) in tetrahydrofuran (5 ml) at 7° C. under nitrogen atmosphere. A solution of 4-methyl-2-phenylpyrazolo-[1,5-a]pyridine-3-carbaldehyde (0.50 g) in tetrahydrofuran (5 ml) was added dropwise to the above solution at 10° C., and then stirred at room temperature for 1 hour. After evaporating the solvent, in vacuo saturated sodium chloride aqueous solution (20 ml) was added to the residue and extracted with ethyl acetate (20 ml×2). Combined extracts were washed with saturated sodium chloride aqueous solution (20 ml), dried over magnesium sulfate and evaporated in vacuo. The residue was chromatographed on silica gel (20 g) with chloroform as an eluent. The fractions containing the objective compound were combined and evaporated in vacuo to give 1-[3-(4-methyl-2-phenylpyrazolo[1,5-a]pyridin-3-yl)acryloyl]-2-ethylpiperidine (trans isomer) (788 mg) as an oil.
Reaction SMILES: N[C:2]1[C:11]2[C:6](=[N:7][CH:8]=[C:9]([CH3:12])[N:10]=2)[N:5]=[C:4]([CH2:13][O:14][CH2:15][CH3:16])[N:3]=1.C(O)(=[O:19])C>[OH-].[Na+]>[CH2:15]([O:14][CH2:13][C:4]1[NH:3][C:2](=[O:19])[C:11]2[C:6](=[N:7][CH:8]=[C:9]([CH3:12])[N:10]=2)[N:5]=1)[CH3:16]
Reactant: CC(=O)O
Reactant: CCOCc1nc(N)c2nc(C)cnc2n1
Agent: [Na+]
Agent: [OH-]
Product: CCOCc1nc2ncc(C)nc2c(=O)[nH]1
Reaction time: 1 h

Procedure:
A suspension of 7.4 g (0.0338 mole) of 4-amino-2-ethoxymethyl-6-methylpteridine in 148 ml of 5% aqueous sodium hydroxide is brought slowly to 85° C. and maintained at this temperature for 2 hours. A further 592 ml of 5% aqueous sodium hydroxide are then added and heating is contained at 85° C. for 1 hour. After cooling, the solution obtained is acidified with acetic acid to pH 5.5, and is then extracted with dichloromethane. The organic extracts are dried over sodium sulphate and concentrated to dryness under reduced pressure. The solid residue is recrystallized from acetone in the presence of Norit. Yld: 4.9 g (66%), m.p. 181°-183° C.
Reaction SMILES: C([Li])(C)(C)C.[OH:6][CH:7]([C:20]1[CH:21]=[C:22]([Si:25]([CH3:28])([CH3:27])[CH3:26])[O:23][CH:24]=1)[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19].[C:29]1([CH2:35][CH2:36][CH2:37][C:38](Cl)=[O:39])[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>CCCCC.O1CCCC1>[C:29]1([CH2:35][CH2:36][CH2:37][C:38]([O:6][CH:7]([C:20]2[CH:21]=[C:22]([Si:25]([CH3:28])([CH3:27])[CH3:26])[O:23][CH:24]=2)[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])=[O:39])[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: CCCCCCCCCCCCC(O)c1coc([Si](C)(C)C)c1
Reactant: O=C(Cl)CCCc1ccccc1
Agent: [Li]C(C)(C)C
Solvent: CCCCC
Solvent: C1CCOC1
Product: CCCCCCCCCCCCC(OC(=O)CCCc1ccccc1)c1coc([Si](C)(C)C)c1
Reaction time: 0.17 h

Procedure:
tert-Butyl lithium (a 1.7 M solution in pentane; 0.47 ml, 0.79 mmol) was added dropwise to a solution of 4-(1-hydroxytridecyl)-2-trimethylsilylfuran (256.4 mg, 0.76 mmol), prepared as in Example 38, in tetrahydrofuran (5 ml) at -78 degrees under argon. After 10 minutes, a solution of 4-phenylbutyryl chloride (145 mg, 0.79 mmol) was added. Stirring was continued at room temperature for 2 days and the mixture was quenched with water. Extraction and evaporation of the dried (magnesium sulphate) extracts gave an oil, which was purified by preparative thin-layer chromatography (20×20 cm, 1000 micron silica plate; developed with 10% ethyl ether/hexane) The title ester was obtained as a light yellow oil.
Reaction SMILES: [C:1]1([CH2:7][N:8]2[CH2:13][CH2:12][CH2:11][CH2:10][C:9]2=[O:14])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:15](Br)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C([N-]C(C)C)(C)C.[Li+].CN(P(N(C)C)(N(C)C)=O)C>C1COCC1>[C:1]1([CH2:7][N:8]2[CH2:13][CH2:12][CH2:11][CH:10]([CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[C:9]2=[O:14])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C1CCCCN1Cc1ccccc1
Reactant: BrCc1ccccc1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: O=C1C(Cc2ccccc2)CCCN1Cc1ccccc1
Temperature: -78 °C
Reaction time: 2 h

Procedure:
1-Phenylmethyl-2-piperidinone (See: Yamaguchi M, Hirao 1 (1985) "A direct synthesis of [(tert-butoxycarbonyl)methylidene]-azacycloalkanes from N-alkyllactams" J. Org. Chem., 50, 1975-1977) (3.40 g, 18 mmol) was reacted with benzyl bromide (4.84 g, 28.3 mmol) in the presence of lithium diisopropylamide (prepared by treating diisopropylamine (2.73 g, 27 mmol) with butyllithium in hexanes (2.5 M, 10.3 mL, 25.7 mmol)) in THF (45 mL) and HMPA (2.7 mL, 15.5 mmol) as described above in the preparation of Example 7. After the addition of benzyl bromide, the reaction mixture was stirred for 2 h at -78° C., and then quenched with saturated NH4Cl (50 mL). The reaction mixture was extracted with ether (3×40 mL) and the combined ether extract washed with brine (40 mL) and dried over MgSO4. The solvent was removed in vacuo, and the residue (8.40 g) thus obtained, was chromatographed over silica gel (hexanes-CHCl3 -EtOAC, 15:4:1 and then 7:2:1) to give the product lactam (3.14 g, 63%) as a colorless solid: mp 94-95° C. (CH2Cl2 -hexanes).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]([F:12])([F:11])[F:10])=[CH:4][C:3]=1[C@H:13]1[CH2:17][O:16][C@:15]2([CH2:23][CH2:22][C@@H:21]3[NH:24][C@@:18]2([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[CH2:19][C@H:20]3[S:25]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)(=[O:27])=[O:26])[CH2:14]1.N(C(OCC)=O)=N[C:42](OCC)=O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CO>O1CCCC1>[CH3:42][O:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]([F:12])([F:10])[F:11])=[CH:4][C:3]=1[C@H:13]1[CH2:17][O:16][C@:15]2([CH2:23][CH2:22][C@@H:21]3[NH:24][C@@:18]2([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[CH2:19][C@H:20]3[S:25]([C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=2)(=[O:27])=[O:26])[CH2:14]1
Reactant: CCOC(=O)N=NC(=O)OCC
Reactant: O=S(=O)(c1ccccc1)[C@@H]1C[C@]2(c3ccccc3)N[C@H]1CC[C@@]21C[C@@H](c2cc(OC(F)(F)F)ccc2O)CO1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CO
Solvent: C1CCOC1
Product: COc1ccc(OC(F)(F)F)cc1[C@H]1CO[C@]2(CC[C@@H]3N[C@@]2(c2ccccc2)C[C@H]3S(=O)(=O)c2ccccc2)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
The mixture of (1R*,2R*,4S*,5S*,6R*)-2′,3′,4′,5′-tetrahydro-4′-(2-hydroxy-5-trifluoromethoxyphenyl)-1-phenyl-6-phenylsulphonylspiro[8-azabicyclo[3.2.1]octane-2,2′-furan] (Example 10; 60 mg, 0.11 mmol), diethyl azodicarboxylate (0.04 ml, 0.25 mmol), triphenylphosphine (68 mg, 0.26 mmol), methanol (0.2 ml) and tetrahydrofuran (2 ml) was stirred at room temperature overnight then concentrated in vacuo and treated with methanol (2 ml) followed by 4M aqueous Na
Reaction SMILES: [C:1]([NH:4][C:5]1[C:6]2[N:7]=[CH:8][N:9]([C:42]=2[N:43]=[CH:44][N:45]=1)[C@@H:10]1[O:41][C@H:15]([CH2:16][O:17][C:18]([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)([C:27]2[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[CH:29][CH:28]=2)[C:19]2[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=2)[C@@H:13]([OH:14])[C@H:11]1[OH:12])(=[O:3])[CH3:2].C(N(C(C)C)CC)(C)C.[C:55]([CH2:57][CH2:58][O:59][CH2:60]Cl)#[N:56].C(=O)(O)[O-].[Na+]>ClCCCl>[C:1]([NH:4][C:5]1[C:6]2[N:7]=[CH:8][N:9]([C:42]=2[N:43]=[CH:44][N:45]=1)[C@@H:10]1[O:41][C@H:15]([CH2:16][O:17][C:18]([C:35]2[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=2)([C:19]2[CH:20]=[CH:21][C:22]([O:25][CH3:26])=[CH:23][CH:24]=2)[C:27]2[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[CH:29][CH:28]=2)[C@@H:13]([OH:14])[C@H:11]1[O:12][CH2:60][O:59][CH2:58][CH2:57][C:55]#[N:56])(=[O:3])[CH3:2]
Reactant: COc1ccc(C(OC[C@H]2O[C@@H](n3cnc4c(NC(C)=O)ncnc43)[C@H](O)[C@@H]2O)(c2ccccc2)c2ccc(OC)cc2)cc1
Reactant: N#CCCOCCl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCCl
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(C(OC[C@H]2O[C@@H](n3cnc4c(NC(C)=O)ncnc43)[C@H](OCOCCC#N)[C@@H]2O)(c2ccccc2)c2ccc(OC)cc2)cc1
Temperature: 80 °C
Reaction time: 1 h
Yield: 29.9 %

Procedure:
N6-Acetyl-5′-O-(4,4′-dimethoxytrityl)adenosine (22.0 g, 36.0 mmol) was dissolved in 170 mL of 1,2-dichloroethane, and 16.3 g of diisopropylethylamine (126 mmol) was added, and 12.1 g of dibutylstannyl dichloride (39.7 mmol) was added subsequently. Then, the reaction was performed at room temperature for 1 hour. Then, the reaction solution was heated up to 80° C., and 4.30 g of chloromethyl 2-cyanoethyl ether (36.0 mmol) was added dropwise, and the solution was stirred for 30 minutes. After the reaction completed, the reaction solution was added to an aqueous saturated sodium bicarbonate solution, and was subjected to extraction with methylene chloride. The extract was dried over anhydrous magnesium sulfate, and the solvent was distilled off. The obtained mixture was purified by silica gel column chromatography to obtain N6-acetyl-5′-O-(4,4′-dimethoxytrityl)-2′-O-(2-cyanoethoxymethyl) adenosine (7.47 g, yield 33%).
Reaction SMILES: [C:1]([N:4]1[CH2:7][CH:6]([C:8]2[N:12]3[CH:13]4[CH2:23][CH:15]([C:16]5[CH:21]=[CH:20][C:19](Br)=[CH:18][C:17]=5[C:11]3=[N:10][C:9]=2[C:24]([NH2:26])=[O:25])[CH2:14]4)[CH2:5]1)(=[O:3])[CH3:2].[C:27]([C:29]1([OH:34])[CH2:33][CH2:32][CH2:31][CH2:30]1)#[CH:28]>>[C:1]([N:4]1[CH2:7][CH:6]([C:8]2[N:12]3[CH:13]4[CH2:23][CH:15]([C:16]5[CH:21]=[CH:20][C:19]([C:28]#[C:27][C:29]6([OH:34])[CH2:33][CH2:32][CH2:31][CH2:30]6)=[CH:18][C:17]=5[C:11]3=[N:10][C:9]=2[C:24]([NH2:26])=[O:25])[CH2:14]4)[CH2:5]1)(=[O:3])[CH3:2]
Reactant: CC(=O)N1CC(c2c(C(N)=O)nc3n2C2CC(C2)c2ccc(Br)cc2-3)C1
Reactant: C#CC1(O)CCCC1
Product: CC(=O)N1CC(c2c(C(N)=O)nc3n2C2CC(C2)c2ccc(C#CC4(O)CCCC4)cc2-3)C1

Procedure:
Similar to as described in General Procedure E, 3-(1-acetylazetidin-3-yl)-10-bromo-6,7-dihydro-5H-5,7-methanobenzo[c]imidazo[1,2-a]azepine-2-carboxamide was reacted with 1-ethynylcyclopentanol to give the titled compound.
Reaction SMILES: [CH3:1][C@@:2]1([CH2:13][N:14]2[CH2:19][CH2:18][N:17]([C:20]([O:22][CH2:23][C:24]3[CH:25]=[C:26]4[C:30](=[CH:31][CH:32]=3)[NH:29][C:28](=[O:33])[C:27]4([CH3:35])[CH3:34])=[O:21])[CH2:16][CH2:15]2)[O:6][C:5]2=[N:7][C:8]([N+:10]([O-:12])=[O:11])=[CH:9][N:4]2[CH2:3]1.[CH3:36]N(C=O)C.[H-].[Na+].CI>O>[CH3:1][C@@:2]1([CH2:13][N:14]2[CH2:15][CH2:16][N:17]([C:20]([O:22][CH2:23][C:24]3[CH:25]=[C:26]4[C:30](=[CH:31][CH:32]=3)[N:29]([CH3:36])[C:28](=[O:33])[C:27]4([CH3:35])[CH3:34])=[O:21])[CH2:18][CH2:19]2)[O:6][C:5]2=[N:7][C:8]([N+:10]([O-:12])=[O:11])=[CH:9][N:4]2[CH2:3]1
Reactant: CN(C)C=O
Reactant: CC1(C)C(=O)Nc2ccc(COC(=O)N3CCN(C[C@@]4(C)Cn5cc([N+](=O)[O-])nc5O4)CC3)cc21
Agent: [H-]
Agent: [Na+]
Solvent: CI
Solvent: O
Product: CN1C(=O)C(C)(C)c2cc(COC(=O)N3CCN(C[C@@]4(C)Cn5cc([N+](=O)[O-])nc5O4)CC3)ccc21
Reaction time: 0.5 h
Yield: 45 %

Procedure:
To a mixture of 3,3-dimethyl-2-oxo-2,3-dihydro-1H-indol-5-ylmethyl (S)-4-(2-methyl-6-nitro-2,3-dihydroimidazo[2,1-b]oxazol-2-ylmethyl)piperazine-1-carboxylate (300 mg, 0.62 mmol) and DMF (3 ml), sodium hydride (27 mg, 0.68 mmol) was added followed by stirring for 30 minutes with cooling on ice-bath. To the reaction mixture, methyl iodide (97 mg, 0.68 mmol) was added followed by stirring at room temperature for 2 hours. To the reaction mixture, water was added, and the mixture was extracted with ethyl acetate twice. The organic phases were combined, washed with water twice and a saturated saline solution, dried over sodium sulfate and then filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate) to afford 1,3,3-trimethyl-2-oxo-2,3-dihydro-1H-indol-5-ylmethyl (S)-4-(2-methyl-6-nitro-2,3-dihydroimidazo[2,1-b]oxazol-2-ylmethyl)piperazine-1-carboxylate (140 mg, 45%) as a light yellow powder.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[C:7]([NH:12][C:13](=[O:22])[C:14]3[C:19]([Cl:20])=[CH:18][CH:17]=[CH:16][C:15]=3[Cl:21])[CH:8]=[CH:9][CH:10]=2)[N:5]=[CH:4][C:3]=1[C:23](OCC)=[O:24].[SH:28][C:29]1[NH:30][CH:31]=[CH:32][N:33]=1.O>CN1CCCC1=O>[Cl:21][C:15]1[CH:16]=[CH:17][CH:18]=[C:19]([Cl:20])[C:14]=1[C:13]([NH:12][C:7]1[CH:8]=[CH:9][CH:10]=[C:11]2[C:6]=1[N:5]=[CH:4][C:3]1[C:23](=[O:24])[N:30]3[CH:31]=[CH:32][N:33]=[C:29]3[S:28][C:2]2=1)=[O:22]
Reactant: CCOC(=O)c1cnc2c(NC(=O)c3c(Cl)cccc3Cl)cccc2c1Cl
Reactant: Sc1ncc[nH]1
Solvent: O
Solvent: CN1CCCC1=O
Product: O=C(Nc1cccc2c1ncc1c(=O)n3ccnc3sc12)c1c(Cl)cccc1Cl
Temperature: 65 °C
Reaction time: 1 h
Yield: 94.9 %

Procedure:
To a solution of 4-chloro-8-(2,6-dichlorobenzoylamino)-3-ethoxycarbonylquinoline (251 mg) in N-methylpyrrolidone (2 ml) was added 2-mercaptoimidazole (89 mg), and the mixture was stirred for 1 hour at 65° C. The mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with saturated ammonium chloride solution, saturated sodium bicarbonate solution and brine, dried over magnesium sulfate and evaporated in vacuo. The residue was crystallized from ethanol to give 4-(2,6-dichlorobenzoylamino)-7H-imidazo[2',1':2,3][1,3]thiazino-[5,6-c]quinolin-7-one (248.2 mg).
Reaction SMILES: [Al+3].[Cl-].[Cl-].[Cl-].[F:5][C:6]1[CH:19]=[CH:18][CH:17]=[CH:16][C:7]=1[CH2:8][C:9]1[CH:10]=[CH:11][C:12](=[O:15])[NH:13][N:14]=1.[Cl:20][C:21]1[CH:29]=[C:28]([Cl:30])[CH:27]=[C:26]([Cl:31])[C:22]=1[C:23](Cl)=[O:24].C(Cl)(=O)C(Cl)=O.C(Cl)Cl>C(Cl)Cl.CN(C=O)C>[Cl:20][C:21]1[CH:29]=[C:28]([Cl:30])[CH:27]=[C:26]([Cl:31])[C:22]=1[C:23]([C:17]1[CH:16]=[C:7]([C:6]([F:5])=[CH:19][CH:18]=1)[CH2:8][C:9]1[CH:10]=[CH:11][C:12](=[O:15])[NH:13][N:14]=1)=[O:24]
Reactant: O=c1ccc(Cc2ccccc2F)n[nH]1
Reactant: O=C(Cl)c1c(Cl)cc(Cl)cc1Cl
Agent: O=C(Cl)C(=O)Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=C(c1ccc(F)c(Cc2ccc(=O)[nH]n2)c1)c1c(Cl)cc(Cl)cc1Cl
Reaction time: 8 h

Procedure:
AlCl3 (1.75 g, 13.1 mmol) was added to a solution of 6-(2-fluorobenzyl)-2H-pyridazin-3-one (0.9 g, 4.4 mmol) [prepared as described above] in methylene chloride (20 ml) at ambient temperature and under a nitrogen atmosphere. 2,4,6-trichlorobenzoyl chloride [(1.98 g, 8.78 mmol) prepared from the corresponding acid by treatment with oxalyl chloride/ methylene chloride with a trace of DMF] was added to the slurry. After stirring overnight, the reaction was quenched with ice. The product was extracted into ethyl acetate, and dried over MgSO4. The solvent was removed in vacuo and the crude product was chromatographed on a silica gel column (ether) to give impure 6-[3-(2,4,6-trichlorobenzoyl)-6-fluorobenzyl)-2H-pyridazin-3-one (0.43 g). Recrystallization from acetone/hexanes mixture gave pure 6-[3-(2,4,6-trichlorobenzoyl)-6-fluorobenzyl)-2H-pyridazin-3-one (0.34 g, 18% yield) as a solid, mp 185.0°-185.3° C.
Reaction SMILES: [NH2:1][C:2]1[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][C:3]=1[C:4]([NH:6][CH2:7][C:8]([NH:10][CH2:11][CH:12]1[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1)=[O:9])=[O:5].[Cl:26][C:27]1[CH:34]=[CH:33][C:30]([CH2:31]Cl)=[C:29]([N+:35]([O-])=O)[CH:28]=1.C(#N)C>C(Cl)(Cl)Cl>[NH2:1][C:2]1[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:23])[F:24])=[CH:18][C:3]=1[C:4]([NH:6][CH2:7][C:8]([NH:10][CH2:11][CH:12]1[CH2:13][CH2:14][N:15]([CH2:31][C:30]2[CH:33]=[CH:34][C:27]([Cl:26])=[CH:28][C:29]=2[NH2:35])[CH2:16][CH2:17]1)=[O:9])=[O:5]
Reactant: Nc1ccc(C(F)(F)F)cc1C(=O)NCC(=O)NCC1CCNCC1
Reactant: O=[N+]([O-])c1cc(Cl)ccc1CCl
Solvent: CC#N
Solvent: ClC(Cl)Cl
Product: Nc1cc(Cl)ccc1CN1CCC(CNC(=O)CNC(=O)c2cc(C(F)(F)F)ccc2N)CC1
Temperature: 50 °C
Reaction time: 8 h

Procedure:
A mixture of 4-[{N-(2-amino-5-trifluoromethylbenzoyl)glycyl}aminomethyl]piperidine (0.050 mmol), 4-chloro-2-nitrobenzyl chloride (0.050 mmol), piperidinomethylpolystyrene (60 mg), acetonitrile (1.0 mL) and chloroform (0.7 mL) was stirred overnight at 50° C. The reaction mixture was cooled, loaded onto Variant™ SCX column and washed with 50% CHCl3/CH3OH (10 mL) and CH3OH (10 mL). Product was eluted using 2 N NH3 in CH3OH (5 mL) and concentrated. To the resulting material was added ethanol (3 mL) and 10% Pd—C (15 mg), and the mixture was stirred under H2 at room temperature for 1.5 h. Filtration, concentration, and preparative TLC afforded 4-[{N-(2-amino-5-trifluoromethylbenzoyl)glycyl}aminomethyl]-1-(2-amino-4-chlorobenzyl)piperidine (Compound No. 1919) (5.1 mg, 14%): The purity was determined by RPLC/MS (90%); 1H NMR (400 MHz, CDCl3) δ1.09-1.32 (m, 4H), 1.41-1.59 (m, 1H), 1.66 (d, J=12.5 Hz, 2H), 1.88 (t, J=11.5 Hz, 2H), 2.82 (d, J=11.5 Hz, 2H), 3.17 (t, J=6.5 Hz, 2H), 3.42 (s, 2H), 4.05 (d, J=5.5 Hz, 2H), 4.85 (br s, 1H), 5.92 (br s, 2H), 6.25-6.36 (m, 1H), 6.55-6.66 (m, 1H), 6.70 (d, J=8.5 Hz, 1H), 6.85 (d, J=8.5 Hz, 1H), 7.26 (s, 1H), 7.42 (d, J=8.5 Hz, 1H), 7.68 (s, 1H); ESI/MS m/e 498.2 (M++H, C23H27ClF3N5O3).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11](=[CH:14][CH2:15][OH:16])[C:10]([CH3:18])([CH3:17])[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])[C:10]([CH3:18])([CH3:17])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCC(=CCO)C(C)(C)C1
Agent: [Mn+4]
Agent: [O-2]
Solvent: CCCCCC
Solvent: ClC(Cl)Cl
Product: CC(C)(C)OC(=O)N1CCC(=CC=O)C(C)(C)C1
Reaction time: 10 h
Yield: 71.1 %

Procedure:
Manganese dioxide (10 g) was added to a solution of 4-(2-hydroxyethylidene)-3,3-dimethylpiperidine-1-carboxylic acid t-butyl ester (0.9 g, 3.5 mmol) in a mixture of hexane (30 mL)-chloroform (10 mL) 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 0.63 g (yield 70.8%) of 3,3-dimethyl-4-(2-oxoethylidene)piperidine-1-carboxylic acid t-butyl ester (VII-141, 142). Its physical property is shown below.
Reaction SMILES: [NH2:1][C:2]1[C:3]2[S:10][CH:9]=[C:8]([C:11]([NH:13][C:14]3[CH:15]=[C:16]([CH:20]=[CH:21][C:22]=3[CH3:23])[C:17](O)=[O:18])=[O:12])[C:4]=2[N:5]=[CH:6][N:7]=1.[CH3:24][O:25][C:26]1[CH:27]=[C:28]([CH:30]=[CH:31][CH:32]=1)[NH2:29]>>[NH2:1][C:2]1[C:3]2[S:10][CH:9]=[C:8]([C:11]([NH:13][C:14]3[CH:15]=[C:16]([C:17](=[O:18])[NH:29][C:28]4[CH:30]=[CH:31][CH:32]=[C:26]([O:25][CH3:24])[CH:27]=4)[CH:20]=[CH:21][C:22]=3[CH3:23])=[O:12])[C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: Cc1ccc(C(=O)O)cc1NC(=O)c1csc2c(N)ncnc12
Reactant: COc1cccc(N)c1
Product: COc1cccc(NC(=O)c2ccc(C)c(NC(=O)c3csc4c(N)ncnc34)c2)c1

Procedure:
The procedure of Step 5 of Example 1 was repeated except for using 3-(4-aminothieno[3,2-d]pyrimidine-7-carboxamido)-4-methylbenzoic acid obtained in Step 4 of Example 8 and 3-methoxyaniline to obtain the title compound (see Table 1).
Reaction SMILES: [F:1][CH:2]([F:14])[O:3][C:4]1[CH:8]=[C:7]([C:9]([O:11][CH3:12])=[O:10])[N:6]([CH3:13])[N:5]=1.[Br:15]Br.O.S(=O)(O)[O-].[Na+]>C(Cl)(Cl)Cl>[Br:15][C:8]1[C:4]([O:3][CH:2]([F:1])[F:14])=[N:5][N:6]([CH3:13])[C:7]=1[C:9]([O:11][CH3:12])=[O:10]
Reactant: BrBr
Reactant: COC(=O)c1cc(OC(F)F)nn1C
Agent: O=S([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: O
Product: COC(=O)c1c(Br)c(OC(F)F)nn1C
Temperature: 25 °C
Reaction time: 72 h
Yield: 82 %

Procedure:
A solution of 700 mg (3.39 mmol) of methyl 3-(difluoromethoxy)-1-methyl-1H-pyrazole-5-carboxylate in 20 ml of chloroform is admixed dropwise with a solution of 570 mg (3.56 mmol) of bromine in 10 ml of chloroform and then stirred for three days at room temperature. The reaction mixture is added to 80 ml of water with some sodium bisulfite and shaken. The organic phase is separated off, dried over magnesium sulphate, filtered and concentrated by evaporation in vacuo: 792 mg of methyl 4-bromo-3-(difluoromethoxy)-1-methyl-1H-pyrazole-5-carboxylate (82%) are produced as white crystals.
Reaction SMILES: [CH:1]1([N:6]2[C:11]3[N:12]=[C:13]([S:17][CH3:18])[N:14]=[C:15]([CH3:16])[C:10]=3[CH:9]=[C:8]([C:19]3[CH:20]=[N:21][NH:22][CH:23]=3)[C:7]2=[O:24])[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:25][C:26]1([CH3:29])[CH2:28][O:27]1.C(=O)([O-])[O-].[K+].[K+]>CS(C)=O>[CH:1]1([N:6]2[C:11]3[N:12]=[C:13]([S:17][CH3:18])[N:14]=[C:15]([CH3:16])[C:10]=3[CH:9]=[C:8]([C:19]3[CH:20]=[N:21][N:22]([CH2:25][C:26]([OH:27])([CH3:29])[CH3:28])[CH:23]=3)[C:7]2=[O:24])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CSc1nc(C)c2cc(-c3cn[nH]c3)c(=O)n(C3CCCC3)c2n1
Reactant: CC1(C)CO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: CSc1nc(C)c2cc(-c3cnn(CC(C)(C)O)c3)c(=O)n(C3CCCC3)c2n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 12 %

Procedure:
To the solution of 8-Cyclopentyl-4-methyl-2-methylsulfanyl-6-(1H-pyrazol-4-yl)-8H-pyrido[2,3-d]pyrimidin-7-one (100 mg, 0.29 mmol) in 5 ml of DMSO were added 2,2-Dimethyl-oxirane (0.03 ml, 1.20 eq.), and potassium carbonate (40.5 mg, 1.00 eq.) under nitrogen. The reaction mixture was stirred at room temperature. After two hours, no reaction. The reaction mixture was heated to 100° C. for 30 min. Some product was formed. It was continued heating for 1 hour. Starting material was gone. The reaction mixture was partitioned in EA/brine. EA layer was dried and concentrated. It was further purified by chromatography (10% MeOH/DCM). 15 mg of product was obtained at yield of 12%.