Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([Li])CCC.[S:6]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[N:8]=[CH:7]1.[C:15](=[O:17])=[O:16].O>O1CCCC1>[S:6]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[N:8]=[C:7]1[C:15]([OH:17])=[O:16]
Reactant: c1ccc2scnc2c1
Reactant: O=C=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)c1nc2ccccc2s1
Yield: 47 %

Procedure:
A precooled (-78° C.) solution of 7.7 ml (19.2 mmol) of n-butyllithium in 50 ml of dry tetrahydrofuran was treated dropwise with 2.0 ml (18.3 mmol) of benzothiazole. After the addition was complete, the solution was poured into a mixture of excess dry ice in 100 ml of tetrahydrofuran. After being allowed to warm, the resulting solution was treated with water, washed with ether, acidified with HCl, and filtered to give a yellow solid. Digestion with boiling ether followed by filtration gave 1.55 g (47%) of the desired compound as a nearly white solid.
Reaction SMILES: O.[OH-].[Li+].C[O:5][C:6]([C:8]1[CH:46]=[CH:45][C:11]([CH2:12][CH:13](/[CH:26]=[CH:27]/[C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=2[O:34][CH2:35][CH2:36][CH2:37][CH2:38][N:39]2[CH2:43][CH2:42][CH2:41][C:40]2=[O:44])[CH2:14][CH2:15][C:16]2[CH:25]=[CH:24][C:19]([C:20]([O:22]C)=[O:21])=[CH:18][CH:17]=2)=[CH:10][CH:9]=1)=[O:7].Cl>O1CCOCC1.[OH-].[Na+]>[C:6]([C:8]1[CH:9]=[CH:10][C:11]([CH2:12][CH:13](/[CH:26]=[CH:27]/[C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=2[O:34][CH2:35][CH2:36][CH2:37][CH2:38][N:39]2[CH2:43][CH2:42][CH2:41][C:40]2=[O:44])[CH2:14][CH2:15][C:16]2[CH:25]=[CH:24][C:19]([C:20]([OH:22])=[O:21])=[CH:18][CH:17]=2)=[CH:45][CH:46]=1)([OH:7])=[O:5]
Reactant: COC(=O)c1ccc(CCC(/C=C/c2ccccc2OCCCCN2CCCC2=O)Cc2ccc(C(=O)OC)cc2)cc1
Agent: Cl
Agent: [Li+]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: O=C(O)c1ccc(CCC(/C=C/c2ccccc2OCCCCN2CCCC2=O)Cc2ccc(C(=O)O)cc2)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
13.7 mg (325 μmol) of lithium hydroxide monohydrate are added to a solution of 19 mg (32.5 μmol) of methyl 4-[(4E)-3-[4-(methoxycarbonyl)benzyl]-5-{2-[4-(2-oxopyrrolidin-1-yl)butoxy]-phenyl}pent-4-en-1-yl]benzoate (Example 36A) in 0.5 ml of dioxane and 0.5 ml of 2 M aqueous sodium hydroxide solution, and the mixture is stirred at room temperature for 16 h. The mixture is then adjusted to pH 2 using 1 M hydrochloric acid and extracted twice with ethyl acetate. The combined organic phases are dried over sodium sulfate, filtered and concentrated. The residue obtained is purified by preparative HPLC. This gives 1.8 mg (3.2 μmol, 10.0% of theory) of the title compound.
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C.Br.[CH2:35]1[C:38]2([CH:42]([NH:43][C:44]3[C:45]4[N:46]([CH:53]=[C:54]([C:56]5[CH:57]=[N:58][N:59]([CH3:61])[CH:60]=5)[CH:55]=4)[N:47]=[CH:48][C:49]=3[C:50]([NH2:52])=[O:51])[CH2:41][NH:40][CH2:39]2)[CH2:37][CH2:36]1.[CH:62]1([C:65]([O-])=[O:66])[CH2:64][CH2:63]1>CN(C=O)C>[CH:62]1([C:65]([N:40]2[CH2:41][C@@H:42]([NH:43][C:44]3[C:45]4[N:46]([CH:53]=[C:54]([C:56]5[CH:57]=[N:58][N:59]([CH3:61])[CH:60]=5)[CH:55]=4)[N:47]=[CH:48][C:49]=3[C:50]([NH2:52])=[O:51])[C:38]3([CH2:37][CH2:36][CH2:35]3)[CH2:39]2)=[O:66])[CH2:64][CH2:63]1
Reactant: Cn1cc(-c2cc3c(NC4CNCC45CCC5)c(C(N)=O)cnn3c2)cn1
Reactant: O=C([O-])C1CC1
Agent: Br
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: CN(C)C=O
Product: Cn1cc(-c2cc3c(N[C@@H]4CN(C(=O)C5CC5)CC45CCC5)c(C(N)=O)cnn3c2)cn1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A 200 uL aliquot of HATU (23.41 mg, 0.062 mmol) and diisopropylethylamine (21.51 μl, 0.123 mmol) were added to a 200 uL aliquot of 4-(6-azaspiro[3.4]octan-8-ylamino)-6-(1-methyl-1H-pyrazol-4-yl)pyrrolo[1,2-b]pyridazine-3-carboxamide HBr (from Step 6, 15 mg, 0.041 mmol) and cyclopropane carboxylate (1.5 equiv.) in DMF. The reaction was stirred for 3 h at room temperature. The crude material was purified via preparative LC/MS with the following conditions: Column: Waters XBridge C18, 19×250 mm, 5-μm particles; Guard Column: Waters XBridge C18, 19×10 mm, 5-μm particles; Mobile Phase A: 5:95 acetonitrile:water with 10-mM ammonium acetate; Mobile Phase B: 95:5 acetonitrile:water with 10-mM ammonium acetate; Gradient: 0-100% B over 25 minutes, then a 5-minute hold at 100% B; Flow: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation to afford the title compound (3.9 mg). 1H NMR (500 MHz, METHANOL-d4/CDCl3) δ 8.11 (d, J=11.9 Hz, 1H), 7.80 (d, J=9.9 Hz, 1H), 7.78-7.71 (m, 2H), 6.91 (dd, J=14.1, 1.7 Hz, 1H), 4.83-4.75 (m, 1H), 4.13 (dd, J=10.4, 5.0 Hz, 1H), 4.07-3.99 (m, 1H), 3.96 (s, 1.5H), 3.94 (s, 1.5H), 3.98-3.76 (m, 2H), 2.37 (dd, J=11.1, 7.2 Hz, 1H), 2.28-1.95 (m, 5H), 1.12-0.70 (m, 4H)
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]1[CH2:7][C@@H:6]([O:8][Si:9]([C:12]([CH3:15])([CH3:14])[CH3:13])([CH3:11])[CH3:10])[CH2:5][N:4]1[C:16]([O:18][CH2:19][C:20]1[CH:25]=[CH:24][C:23]([N+:26]([O-:28])=[O:27])=[CH:22][CH:21]=1)=[O:17].C(N(CC)CC)C.Br[CH2:37][C:38]([O:40][CH2:41][CH3:42])=[O:39].[Cl-].[Na+]>CN(C)C=O>[Si:9]([O:8][C@H:6]1[CH2:5][N:4]([C:16]([O:18][CH2:19][C:20]2[CH:25]=[CH:24][C:23]([N+:26]([O-:28])=[O:27])=[CH:22][CH:21]=2)=[O:17])[C@H:3]([CH2:2][NH:1][CH2:37][C:38]([O:40][CH2:41][CH3:42])=[O:39])[CH2:7]1)([C:12]([CH3:15])([CH3:14])[CH3:13])([CH3:11])[CH3:10]
Reactant: CCOC(=O)CBr
Reactant: CC(C)(C)[Si](C)(C)O[C@@H]1C[C@@H](CN)N(C(=O)OCc2ccc([N+](=O)[O-])cc2)C1
Agent: [Cl-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCOC(=O)CNC[C@@H]1C[C@@H](O[Si](C)(C)C(C)(C)C)CN1C(=O)OCc1ccc([N+](=O)[O-])cc1
Reaction time: 6 h

Procedure:
To a solution of (2S, 4R)-2-aminomethyl-4-t-butyldimethylsilyloxy-1-(4-nitrobenzyloxycarbonyl)pyrrolidine (5 g) and triethylamine (1.87 ml) in N,N-dimethylformamide (50 ml) was dropwise added ethyl bromoacetate (1.49 ml) at ambient temperature with stirring. The mixture was stirred at 40° C. for 30 minutes and then allowed to stand at ambient temperature for 6 hours. The reaction mixture was poured into saturated aqueous sodium chloride (100 ml) and extracted twice with ethyl acetate (100 ml). The extract was washed with saturated aqueous sodium chloride, dried over magnesium sulfate and evaporated in vacuo. The resulting residue was subjected to a column chromatography on silica gel (100 g) eluting with a mixture of dichloromethane and acetone (20:1 v/v). The fractions containing the desired compound were collected and evaporated in vacuo to give (2S, 4R)-4-t-butyldimethylsilyloxy-2-[(ethoxycarbonylmethyl)aminomethyl]-1-(4-nitrobenzyloxycarbonyl)pyrrolidine (3.52 g).
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:5]2[C:6](=[O:9])[CH2:7][O:8][C:4]=2[C:3]=1[CH2:12][N:13]1[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15][CH2:14]1.[Br:26][C:27]1[CH:28]=[C:29]2[C:33](=[CH:34][CH:35]=1)[NH:32][N:31]=[C:30]2[CH:36]=O.N1CCCCC1>CO>[OH:1][C:2]1[CH:11]=[CH:10][C:5]2[C:6](=[O:9])/[C:7](=[CH:36]/[C:30]3[C:29]4[C:33](=[CH:34][CH:35]=[C:27]([Br:26])[CH:28]=4)[NH:32][N:31]=3)/[O:8][C:4]=2[C:3]=1[CH2:12][N:13]1[CH2:14][CH2:15][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:17][CH2:18]1
Reactant: O=Cc1n[nH]c2ccc(Br)cc12
Reactant: CC(C)(C)OC(=O)N1CCN(Cc2c(O)ccc3c2OCC3=O)CC1
Solvent: CO
Solvent: C1CCNCC1
Product: CC(C)(C)OC(=O)N1CCN(Cc2c(O)ccc3c2O/C(=C\c2n[nH]c4ccc(Br)cc24)C3=O)CC1
Temperature: 60 °C
Reaction time: 2 h
Yield: 43.9 %

Procedure:
A solution of tert-butyl 4-[1-(6-hydroxy-3-oxo-2,3-dihydrobenzofuran-7-yl)methyl]piperazine-1-carboxylate (0.100 g, 0.287 mmol) in methanol (1.2 mL) was added with 5-bromo-1H-indazole-3-carbaldehyde (0.0646 g, 0.287 mmol), and piperidine (0.00244 g, 0.0287 mmol) at room temperature, and the mixture was stirred at 60° C. for 2 hours. The reaction mixture was added with methanol (4 mL), suspended in methanol and thereby washed, and then the solid was collected by filtration to obtain tert-butyl (Z)-4-({6-hydroxy-3-oxo-2-[(5-bromo-1H-indazol-3-yl)methylene]-2,3-dihydrobenzofuran-7-yl}methyl)piperazine-1-carboxylate (0.0700 g, 44%).
Reaction SMILES: [C:1]([N:8]1[CH2:14][CH2:13][CH2:12][C@@H:9]1[CH2:10][OH:11])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[C:15]1([CH3:25])[CH:20]=[CH:19][C:18]([S:21](Cl)(=[O:23])=[O:22])=[CH:17][CH:16]=1.C(N(CC)CC)C>CN(C)C1C=CN=CC=1.ClCCl>[CH3:25][C:15]1[CH:20]=[CH:19][C:18]([S:21]([O:11][CH2:10][C@H:9]2[CH2:12][CH2:13][CH2:14][N:8]2[C:1]([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2])(=[O:23])=[O:22])=[CH:17][CH:16]=1
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H]1CO
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1ccc(S(=O)(=O)OC[C@H]2CCCN2C(=O)OC(C)(C)C)cc1
Temperature: 40 °C
Yield: 45 %

Procedure:
A mixture of Boc-D-prolinol (201 mg, 1.0 mmol), p-toluenesulfonyl chloride (400 mg, 2.1 mmol), triethylamine (420 μL, 3.0 mmol), and 4-(dimethylamino)pyridine (12 mg, 0.1 mmol) in dichloromethane (10 mL) was heated at 40° C. for 48 hours, cooled to room temperature, concentrated under vacuum, diluted with ethyl acetate, washed with water and brine, dried (MgSO4), filtered, and concentrated. The residue was purified by column chromatography on silica gel to provide 160 mg (45%) of the desired product.
Reaction SMILES: C[O:2][C:3]([C@@H:5]1[CH2:10][CH2:9][CH2:8][CH2:7][C@@H:6]1[NH2:11])=O.[OH-].[NH4+:13]>C1(C)C=CC=CC=1>[NH2:11][C@H:6]1[CH2:7][CH2:8][CH2:9][CH2:10][C@H:5]1[C:3]([NH2:13])=[O:2]
Reactant: [NH4+]
Reactant: COC(=O)[C@@H]1CCCC[C@@H]1N
Agent: [OH-]
Solvent: Cc1ccccc1
Product: NC(=O)[C@@H]1CCCC[C@@H]1N
Temperature: 25 °C
Reaction time: 16 h

Procedure:
cis-2-Aminocyclohexanecarboxylic acid methyl ester (2.20 g, 14.0 mmol) was treated with aqueous ammonium hydroxide (40 mL) in toluene (40 mL) and stirred vigorously at room temperature for 16 h. The reaction was concentrated to dryness in vacuo and azeotroped with toluene (50 mL). The crude product, cis-2-aminocyclohexanecarboxylic acid amide, was used in the next reaction without purification: 1H NMR (400 MHz, DMSO-d6) δ 7.78 (2 H, s br), 7.67 (s, 1 H), 7.25 (s, 1 H), 1.87 (m, 2 H), 1.60 (m, 4 H), 1.41 (m, 4 H).
Reaction SMILES: [SH:1][CH2:2][CH:3]([OH:6])[CH2:4][OH:5].[CH3:7][C:8]([CH3:12])([CH3:11])[CH:9]=[CH2:10].N(C(C)(C)C#N)=NC(C)(C)C#N>CCCCCC>[CH3:7][C:8]([CH3:12])([CH3:11])[CH2:9][CH2:10][S:1][CH2:2][CH:3]([OH:6])[CH2:4][OH:5]
Reactant: OCC(O)CS
Reactant: C=CC(C)(C)C
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: CCCCCC
Product: CC(C)(C)CCSCC(O)CO
Reaction time: 20 h

Procedure:
A mixture of 3-mercapto-1,2-propanediol (10.8 g), 3,3-dimethyl-1-butene (9.6 g) and 2,2'-azobis(2-methylpropionitrile) (0.5 g) is heated under reflux with vigorous stirring for 20 hours, then is diluted with hexane, extracted with water and stripped to give 3-(3,3-dimethylbutylthio)-1,2propanediol.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]2[CH:8]=[C:9]([CH3:20])[N:10]([S:11]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)(=[O:13])=[O:12])[C:5]2=[CH:4][CH:3]=1.[NH:21]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[NH:22][C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24].C([O-])([O-])=O.[Cs+].[Cs+]>C1(C)C=CC=CC=1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C(C(C)C)=CC(C(C)C)=CC=2C(C)C)CCCCC1.NC1C=CC=CC=1C1C=CC=CC=1[Pd]Cl>[CH3:20][C:9]1[N:10]([S:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)(=[O:13])=[O:12])[C:5]2[C:6](=[N:7][C:2]([N:21]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[NH:22][C:23]([O:25][C:26]([CH3:27])([CH3:28])[CH3:29])=[O:24])=[CH:3][CH:4]=2)[CH:8]=1
Reactant: CC(C)(C)OC(=O)NNC(=O)OC(C)(C)C
Reactant: Cc1cc2nc(Cl)ccc2n1S(=O)(=O)c1ccccc1
Agent: Nc1ccccc1-c1ccccc1[Pd]Cl
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Product: Cc1cc2nc(N(NC(=O)OC(C)(C)C)C(=O)OC(C)(C)C)ccc2n1S(=O)(=O)c1ccccc1
Temperature: 100 °C
Yield: 9.4 %

Procedure:
A mixture of 5-chloro-2-methyl-1-(phenylsulfonyl)-1H-pyrrolo[3,2-b]pyridine (16.29 g, 53.10 mmol, from Step 2), di-tert-butyl hydrazine-1,2-dicarboxylate (12 g, 53 mmol, Aldrich), dicyclohexyl(2′,4′,6′-triisopropylbiphenyl-2-yl)phosphine-(2′-amino biphenyl-2-yl)(chloro)palladium (1:1) (4.2 g, 5.3 mmol, Aldrich), and Cs2CO3 (17.3 g, 53.1 mmol) in toluene (170 mL) was degassed and heated at 100° C. overnight. Upon cooling to room temperature, the solid product was isolated by filtration and washed with several portions of DCM. The solid was then triturated with DCM, and again isolated by filtration, and dried at 40° C. under vacuum (19.5 g). Flash chromatography of the filtrate (eluting with a gradient from 0-40% EtOAc in hexanes) afforded an additional 2.5 g of product. Yield: (22 g, 82%).
Reaction SMILES: [F:1][C:2]1[C:7]([Sn](CCCC)(CCCC)CCCC)=[CH:6][CH:5]=[CH:4][N:3]=1.[Br:21][C:22]1[C:26](Br)=[CH:25][S:24][CH:23]=1.[F-].[K+]>CN1CCCC1=O.C(OCC)(=O)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[Br:21][C:22]1[C:26]([C:7]2[C:2]([F:1])=[N:3][CH:4]=[CH:5][CH:6]=2)=[CH:25][S:24][CH:23]=1
Reactant: CCCC[Sn](CCCC)(CCCC)c1cccnc1F
Reactant: Brc1cscc1Br
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [F-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN1CCCC1=O
Product: Fc1ncccc1-c1cscc1Br
Temperature: 100 °C
Yield: 27.6 %

Procedure:
A mixture of 2-fluoro-3-tributylstannylpyridine (1.9 g), 3, 4-dibromothiophene (1.5 g) and Pd(Ph3P)2Cl2 (0.175 g) in N-methylpyrrolidinone (7.5 mL), in a sealed tube, was heated at 100° C. for 16 hours. The mixture was cooled and stirred with aqueous potassium fluoride for 6 hours. The mixture was diluted with ethyl acetate, washed with water, dried filtered and evaporated. The residue was fractionated by chromatography to give 3-bromo-4-(2-fluoropyridin-3-yl)thiophene (0.35 g), mp 48-50° C.
Reaction SMILES: F[C:2]1[C:11]([N:12]2[CH2:17][CH2:16][N:15]([CH3:18])[CH2:14][CH2:13]2)=[CH:10][C:9]2[N:4]([C:5](=[O:26])[C:6]([C:21]([O:23]CC)=[O:22])=[CH:7][C:8]=2NC)[CH:3]=1.[OH-].[Na+].[ClH:29]>C1COCC1>[ClH:29].[CH3:18][N:15]1[CH2:16][CH2:17][N:12]([C:11]2[CH:2]=[CH:3][N:4]3[C:9]([CH:10]=2)=[CH:8][CH:7]=[C:6]([C:21]([OH:23])=[O:22])[C:5]3=[O:26])[CH2:13][CH2:14]1
Reactant: CCOC(=O)c1cc(NC)c2cc(N3CCN(C)CC3)c(F)cn2c1=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CN1CCN(c2ccn3c(=O)c(C(=O)O)ccc3c2)CC1
Temperature: 75 °C
Reaction time: 8 h

Procedure:
A mixture of 1 g (2.75 mmol) of ethyl 7-fluoro-1-methylamino-8-(4-methylpiperazin-1-yl)-4H-quinolizin-4-one-3-carboxylate, from Step 7, in 12 mL of THF and 16.5 mL of a 0.5N aqueous solution of sodium hydroxide is heated, with stirring, at 75° C. for 8 hours. The THF is removed from the reaction mixture by distillation during the reaction. The concentrated reaction mixture is cooled to ambient temperature and adjusted to pH 2.0 with 10.5 mL of 1N aqueous hydrochloric acid solution. The aqueous solution is concentrated in vacuo to remove ~80% of the water and the concentrate is diluted with 50 mL of 95% ethyl alcohol. The solid is collected by filtration, washed with 2×5 mL of ethyl alcohol and dried in vacuo to afford the desired product.
Reaction SMILES: [H-].[Na+].[C:3]([O:9][CH3:10])(=[O:8])[CH2:4][C:5]([CH3:7])=[O:6].Cl[CH2:12][C:13]1[CH:14]=[C:15]([C:19]#[N:20])[CH:16]=[N:17][CH:18]=1.Cl>COCCOC.[I-].C([N+](CCCC)(CCCC)CCCC)CCC.O>[C:19]([C:15]1[CH:14]=[C:13]([CH2:12][CH:4]([C:5](=[O:6])[CH3:7])[C:3]([O:9][CH3:10])=[O:8])[CH:18]=[N:17][CH:16]=1)#[N:20]
Reactant: N#Cc1cncc(CCl)c1
Reactant: COC(=O)CC(C)=O
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: Cl
Agent: [H-]
Solvent: COCCOC
Solvent: O
Product: COC(=O)C(Cc1cncc(C#N)c1)C(C)=O
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 56.9 %

Procedure:
To a suspension of 84 mg (2.11 mmol) of sodium hydride (60% in oil) in 3 mL of anhydrous DME is added, under argon at 0° C., 0.23 ml (2.11 mmol) of methyl acetoacetate. The reaction medium is stirred for 30 minutes at 0° C. and for 30 minutes at room temperature, followed by addition of 161 mg (1.06 mmol) of 5-(chloromethyl)pyridine-3-carbonitrile diluted in 1 mL of DME and 29 mg (0.11 mmol) of tetrabutylammonium iodide. The medium is then heated at 65° C. for 4 hours. After cooling to room temperature, the medium is taken up in 10 mL or water, neutralized by adding 0.1N HCl, and then extracted with EtOAc (2×40 mL), dried over Na2SO4, concentrated under reduced pressure and purified by chromatography on a column of silica gel, eluting with a cyclohexane/EtOAc mixture (8/2). 140 mg of methyl 2-[(5-cyanopyridin-3-yl)methyl]-3-oxobutanoate are obtained in the form of a colourless oil.
Reaction SMILES: [OH-].[Li+].C([O:5][C:6](=[O:29])/[CH:7]=[CH:8]/[C:9]1[C:18]2[C:13](=[CH:14][C:15]([C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([O:25][CH3:26])[CH:20]=3)=[CH:16][CH:17]=2)[CH:12]=[CH:11][C:10]=1[O:27][CH3:28])C>C1COCC1.O>[CH3:28][O:27][C:10]1[CH:11]=[CH:12][C:13]2[C:18](=[CH:17][CH:16]=[C:15]([C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([O:25][CH3:26])[CH:20]=3)[CH:14]=2)[C:9]=1/[CH:8]=[CH:7]/[C:6]([OH:29])=[O:5]
Reactant: CCOC(=O)/C=C/c1c(OC)ccc2cc(-c3cccc(OC)c3)ccc12
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: COc1cccc(-c2ccc3c(/C=C/C(=O)O)c(OC)ccc3c2)c1
Yield: 99.8 %

Procedure:
Lithium hydroxide (407.7 mg, 9.94 mmol, 6 eq) is added to a solution, cooled at 0° C., of (E)-3-(2-methoxy-6-(3-methoxyphenyl)naphthalene-1-yl)acrylic acid ethyl ester (600 mg, 1.66 mmol, 1 eq) in a mixture of THF/water 3/1 (20 ml), and the reaction mixture is boiled under reflux over night. The solvent is removed in vacuum on a rotary evaporator, and 2 N HCl is added to the residue. This phase is extracted with dichloromethane. The combined organic phases are dried over magnesium sulfate, filtered and concentrated in vacuum on a rotary evaporator. The residual solid is the desired product (quantitative yield, 554 mg).
Reaction SMILES: [CH2:1]([NH:8][C:9]1[CH:17]=[C:16]([N:18]2[CH2:23][CH2:22][N:21]([C:24](=[O:31])[C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[CH2:20][CH2:19]2)[CH:15]=[CH:14][C:10]=1[C:11](O)=[O:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[CH2:33]([NH2:35])[CH3:34].CCN(C(C)C)C(C)C.C1(P(N=[N+]=[N-])(C2C=CC=CC=2)=O)C=CC=CC=1>C1COCC1>[CH2:1]([NH:8][C:9]1[CH:17]=[C:16]([N:18]2[CH2:23][CH2:22][N:21]([C:24](=[O:31])[C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=3)[CH2:20][CH2:19]2)[CH:15]=[CH:14][C:10]=1[C:11]([NH:35][CH2:33][CH3:34])=[O:12])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)c1ccc(N2CCN(C(=O)c3ccccc3)CC2)cc1NCc1ccccc1
Reactant: CCN
Agent: Cl
Agent: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CCNC(=O)c1ccc(N2CCN(C(=O)c3ccccc3)CC2)cc1NCc1ccccc1
Yield: 28.2 %

Procedure:
A solution of 2-(benzylamino)-4-(4-benzoylpiperazin-1-yl)benzoic acid (50 mg, 0.12 mmol), ethylamine hydrochloride (36 mg, 0.36 mmol), DIPEA (0.20 ml, 1.2 mmol) and diphenylphosphoryl azide (0.026 ml, 0.12 mmol) in 15 ml THF was stirred for 16 hours. The run was quenched with 1 ml water and all the solvents were evaporated under vacuum. 2-(benzylamino)-N-ethyl-4-(4-benzoylpiperazin-1-yl)benzamide (15 mg, 33%) was obtained by flash column chromatograph (60% ethyl acetate in hexanes), and its hydrochloride was made by bubbling HCL gas in ether solution. 1H NMR (500 MHz, DMSO-d6) δ (ppm) 1.10 (t, J=7.2 Hz, 3H), 3.19-3.47 (m, br, 10H), 4.40 (s, 2H), 6.43 (t, J=8.3 Hz, 2H), 7.27-7.59 (m, 13H), 8.26 (s, 1H). 13C NMR (125 MHz, DMSO-d6): δ (ppm) 14.8, 33.6, 47.5, 127.0, 127.2, 127.8, 128.4, 128.5, 129.4, 129.6, 135.7, 168.3, 169.0.
Reaction SMILES: Cl.[NH2:2][CH:3]1[CH2:8][CH2:7][N:6]([CH2:9][CH2:10][C:11]2[CH:12]=[CH:13][CH:14]=[C:15]3[C:20]=2[O:19][C:18](=[O:21])[CH:17]=[CH:16]3)[CH2:5][CH2:4]1.CCN(CC)CC.[O:29]=[C:30]1[CH2:35][S:34][C:33]2[CH:36]=[CH:37][C:38]([CH:40]=O)=[N:39][C:32]=2[NH:31]1.[BH4-].[Na+]>CO.C(Cl)Cl>[O:21]=[C:18]1[CH:17]=[CH:16][C:15]2[C:20](=[C:11]([CH2:10][CH2:9][N:6]3[CH2:7][CH2:8][CH:3]([NH:2][CH2:40][C:38]4[CH:37]=[CH:36][C:33]5[S:34][CH2:35][C:30](=[O:29])[NH:31][C:32]=5[N:39]=4)[CH2:4][CH2:5]3)[CH:12]=[CH:13][CH:14]=2)[O:19]1
Reactant: NC1CCN(CCc2cccc3ccc(=O)oc23)CC1
Reactant: O=Cc1ccc2c(n1)NC(=O)CS2
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CO
Product: O=C1CSc2ccc(CNC3CCN(CCc4cccc5ccc(=O)oc45)CC3)nc2N1
Temperature: 25 °C
Reaction time: 16 h
Yield: 50.3 %

Procedure:
To a solution of 8-[2-(4-amino-1-piperidinyl)ethyl]-2H-chromen-2-one hydrochloride (41 mg, 0.15 mmol), Et3N (0.10 mL), in 10% methanol/CH2Cl2 (5 mL) was added 3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]thiazine-6-carboxaldehyde (32 mg, 0.17 mmol). The solution was allowed to stir at RT for 16 h, then sodium borohydride (7 mg, 0.17 mmol) was added. The solution was stirred for an additional 30 min then was concentrated under reduced pressure. Flash chromatography on silica gel (90:9:1 CHCl3/MeOH/conc NH4OH) gave the title compound (34 mg, 51%) as a yellow solid: 1H NMR (400 MHz, DMSO-d6) δ 7.99 (d, J=9.6 Hz, 1H), 7.79 (d, J=7.8 Hz, 1H), 7.50-7.62 (m, 2H), 7.32 (m, 1H), 7.11 (d, J=7.8 Hz, 1H), 6.47 (d, J=9.6 Hz, 1H), 4.17 (s, 2H), 3.57 (s, 2H), 3.36-3.04 (m, 5H), 3.00-2.84 (m, 2H), 2.62-2.38 (m, 2H), 2.33-2.10 (m, 2H), 1.87-1.62 (m, 2H); MS (ES) m/e 451.1 (M+H)+.
Reaction SMILES: Cl.[O:2]1[C:10]2[CH2:9][CH2:8][NH:7][CH2:6][C:5]=2[CH:4]=[CH:3]1.[C:11]([C:19]1[CH:27]=[CH:26][CH:25]=[CH:24][C:20]=1[C:21](O)=[O:22])(=[O:18])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(N(CC)CC)C.C(P(=O)(OCC)OCC)#N>ClCCl.O>[C:11]([C:19]1[CH:27]=[CH:26][CH:25]=[CH:24][C:20]=1[C:21]([N:7]1[CH2:8][CH2:9][C:10]2[O:2][CH:3]=[CH:4][C:5]=2[CH2:6]1)=[O:22])(=[O:18])[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: O=C(O)c1ccccc1C(=O)c1ccccc1
Reactant: c1cc2c(o1)CCNC2
Agent: CCOP(=O)(C#N)OCC
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O
Product: O=C(c1ccccc1)c1ccccc1C(=O)N1CCc2occc2C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 0.160 g (1.000 mmol) of 4,5,6,7-tetrahydrofuro[3,2-c]pyridine hydrochloride, 0.27 g (1.2 mmol) of 2-benzoylbenzoic acid and 0.55 ml (4.0 mmol) of triethylamine in 30 ml of dichloromethane, 0.24 g (1.5 mmol) of diethyl cyanophosphonate was added dropwise under ice-cooling, followed by overnight stirring at room temperature. The reaction mixture was poured into water and extracted with dichloromethane 2 times. The combined organic layer was washed with water and dried over anhydrous sodium sulfate; the solvent was distilled off under reduced pressure. The resulting crude product was purified by silica gel column chromatography (hexane/ethyl acetate=5/1 to 3/1) to yield the desired product.
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[CH2:13]([O:15][C:16]([C:18]1[S:19][CH:20]=[CH:21][CH:22]=1)=[O:17])[CH3:14].CN(C)[CH:25]=[O:26]>C1COCC1>[CH2:13]([O:15][C:16]([C:18]1[S:19][C:20]([CH:25]=[O:26])=[CH:21][CH:22]=1)=[O:17])[CH3:14]
Reactant: CN(C)C=O
Reactant: CCOC(=O)c1cccs1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: CCOC(=O)c1ccc(C=O)s1
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 55.1 %

Procedure:
A solution of diisopropylamine (0.588 mL, 60 mmol) in THF (20 mL) under N2 is cooled to −78° C. and treated with n-butyllithium (2.5 M in hexanes, 1.66 mL). The mixture is then warmed to 0° C. for 10 min, cooled back to −78° C., treated dropwise with a solution of thiophene-2-carboxylic acid ethyl ester (0.5 g, 3.2 mmol) in THF (12 mL), and stirred 5 min. N,N-dimethylformamide (0.324 mL, 4.16 mmol) is then added, and the reaction is allowed to warm to rt, while stirring overnight. Aqueous buffer (pH=7) is added, and the product is extracted into ethyl acetate (3×). Combined organic layers are dried, filtered, and concentrated. The resulting residue is applied to silica gel and eluted using hexanes with an ethyl acetate gradient from 0% to 40% to give 5-formyl-thiophene-2-carboxylic acid ethyl ester (325 mg).