Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]([CH:4]=[N:5][C:6]1[C:11]2[C:12]([C:15]3[CH:20]=[CH:19][C:18]([NH:21][C:22]([C:24]4[N:25]([CH3:33])[C:26]5[C:31]([CH:32]=4)=[CH:30][CH:29]=[CH:28][CH:27]=5)=[O:23])=[C:17]([O:34][CH3:35])[CH:16]=3)=[CH:13][S:14][C:10]=2[C:9]([N:36]=C(C2C=CC=CC=2)C2C=CC=CC=2)=[CH:8][N:7]=1)[CH3:3].Cl>O1CCCC1.CO.ClCCl>[NH2:36][C:9]1[C:10]2[S:14][CH:13]=[C:12]([C:15]3[CH:20]=[CH:19][C:18]([NH:21][C:22]([C:24]4[N:25]([CH3:33])[C:26]5[C:31]([CH:32]=4)=[CH:30][CH:29]=[CH:28][CH:27]=5)=[O:23])=[C:17]([O:34][CH3:35])[CH:16]=3)[C:11]=2[C:6]([N:5]=[CH:4][N:2]([CH3:3])[CH3:1])=[N:7][CH:8]=1
Reactant: COc1cc(-c2csc3c(N=C(c4ccccc4)c4ccccc4)cnc(N=CN(C)C)c23)ccc1NC(=O)c1cc2ccccc2n1C
Agent: Cl
Solvent: C1CCOC1
Solvent: ClCCl
Solvent: CO
Product: COc1cc(-c2csc3c(N)cnc(N=CN(C)C)c23)ccc1NC(=O)c1cc2ccccc2n1C
Temperature: 25 °C
Reaction time: 12 h
Yield: 96 %

Procedure:
N-(4-{4-{[(dimethylamino)methylene]amino}-7-[(diphenylmethylene)amino]thieno[3,2-c]pyridin-3-yl}-2-methoxyphenyl)-1-methyl-1H-indole-2-carboxamide (0.117 g, 0.177 mmol) was dissolved in tetrahydrofuran (5 mL), and aqueous hydrochloric acid (1 M, 0.24 mL) was added, and the mixture was stirred at ambient temperature for 12 h. The mixture was diluted with methanol/dichloromethane (1:19, 50 mL) the resulting solution was extracted with aqueous sodium bicarbonate (1 M, 10 mL). The organic layer was dried over magnesium sulfate, filtered, and concentrated. Purification of the residue by flash column chromatography on silica gel which had been deactivated with triethylamine (10% by volume of silica gel used) using methanol/dichloromethane (1:19) as the mobile phase afforded the title compound (0.085 g, 0.17 mmol) as a tan powder: 1H NMR (DMSO-d6, 400 MHz) δ 9.40 (s, 1H), 8.13 (s, 1H), 7.79 (d, 1H), 7.70 (d, 1H), 7.58 (d, 1H), 7.56 (s, 1H), 7.49 (s, 1H), 7.33 (m, 2H), 7.15 (t, 1H), 7.06 (m, 1H), 7.01 (d, 1H), 5.07 (br, 2H), 4.04 (s, 3H), 3.88 (s, 3H), 2.94 (s, 3H), 2.47 (s, 3H); MS: (MH)+ 499.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10]([O:23][CH3:24])=[CH:11][C:12]([C:17]2[N:21]=[C:20]([CH3:22])[O:19][N:18]=2)=[C:13]([CH:16]=1)[CH:14]=[O:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CS(C)=[O:27].S(=O)(=O)(O)O.Cl([O-])=O.[Na+]>O.C(#N)C>[CH2:1]([O:8][C:9]1[C:10]([O:23][CH3:24])=[CH:11][C:12]([C:17]2[N:21]=[C:20]([CH3:22])[O:19][N:18]=2)=[C:13]([CH:16]=1)[C:14]([OH:27])=[O:15])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1cc(-c2noc(C)n2)c(C=O)cc1OCc1ccccc1
Reactant: CS(C)=O
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [O-][Cl+][O-]
Solvent: CC#N
Solvent: O
Product: COc1cc(-c2noc(C)n2)c(C(=O)O)cc1OCc1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a mixture of 5-benzyloxy-4-methoxy-2-(5-methyl-[1,2,4]oxadiazol-3-yl)benzaldehyde (reference example 15-1) (5.38 g), dimethyl sulfoxide (5.89 mL), concentrated sulfuric acid (0.506 mL), water (8 mL) and acetonitrile (41 mL) was added a mixture of sodium chlorite (2.25 g) and water (10 mL). After stirring at room temperature for 30 minutes, water was added to the mixture. The solid was collected by filtration to give the title compound (3.58 g).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([NH2:8])[C:3]=1[C:9]1[CH:14]=[CH:13][C:12]([O:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[CH:11][CH:10]=1.[H-].[Na+].Cl[CH2:25][CH2:26][S:27](Cl)(=[O:29])=[O:28].O>C1COCC1.CCCCCC>[Cl:1][C:2]1[CH:7]=[CH:6][N:5]2[C:4](=[N:8][S:27](=[O:29])(=[O:28])[CH2:26][CH2:25]2)[C:3]=1[C:9]1[CH:14]=[CH:13][C:12]([O:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[CH:11][CH:10]=1
Reactant: Nc1nccc(Cl)c1-c1ccc(Oc2ccccc2)cc1
Reactant: O=S(=O)(Cl)CCCl
Agent: [H-]
Agent: [Na+]
Solvent: CCCCCC
Solvent: O
Solvent: C1CCOC1
Product: O=S1(=O)CCN2C=CC(Cl)=C(c3ccc(Oc4ccccc4)cc3)C2=N1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 4-chloro-3-(4-phenoxyphenyl)pyridin-2-amine (124 mg) in THF (dry) (5 ml) was added to a suspension of NaH (60%, 84.0 mg) and 2-chloroethanesulfonyl chloride (0.131 mL) in THF (dry) (5 mL) at 0° C. The mixture was stirred at room temperature overnight. Water and hexane were added to give a white precipitate. The precipitate was collected by filtration and washed with water and EtOAc, and then crystallized from THF-IPE to give the title compound (60.0 mg) as a white solid.
Reaction SMILES: [CH:1]1([O:6][C:7]2[CH:8]=[C:9]([C@H:15]3[C@H:19]([C:20]([O:22][CH3:23])=[O:21])[CH2:18][NH:17][CH2:16]3)[CH:10]=[CH:11][C:12]=2[O:13][CH3:14])[CH2:5][CH2:4][CH2:3][CH2:2]1.Cl[C:25]([O:27][CH:28]([CH3:30])[CH3:29])=[O:26].C1(C)C=CC=CC=1>C(Cl)Cl.CN(C)C1C=CN=CC=1>[CH:1]1([O:6][C:7]2[CH:8]=[C:9]([C@H:15]3[C@H:19]([C:20]([O:22][CH3:23])=[O:21])[CH2:18][N:17]([C:25]([O:27][CH:28]([CH3:30])[CH3:29])=[O:26])[CH2:16]3)[CH:10]=[CH:11][C:12]=2[O:13][CH3:14])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: COC(=O)[C@@H]1CNC[C@H]1c1ccc(OC)c(OC2CCCC2)c1
Reactant: CC(C)OC(=O)Cl
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: COC(=O)[C@@H]1CN(C(=O)OC(C)C)C[C@H]1c1ccc(OC)c(OC2CCCC2)c1
Yield: 44 %

Procedure:
To a solution of trans-3-(3-cyclopentoxy-4-methoxyphenyl)-4-(methoxycarbonyl)pyrrolidine (500 mg, 1.57 mmol) in 4 mL of CH2Cl2 was added at 0° C. 4-dimethylaminopyridine (250 mg, 2.04 mmol), followed by isopropyl chloroformate (1.7 mL of a 1M toluene solution). After 16 hr the reaction was diluted with CH2Cl2 and washed with 1M H3PO4. The organic layer was dried over MgSO4, filtered, and concentrated under reduced pressure. Silica gel chromatography (2:1, hexanes:ethyl acetate) provided trans-3-(3-cyclopentoxy-4-methoxyphenyl)-4-methoxycarbonyl-1-(methylethoxycarbonyl)pyrrolidine as a white solid (280 mg, 44%). Anal. Calcd for C22H29NO6 : C, 65.17; H, 7.71; N, 3.45. Found: C, 65.16; H, 7.69; N, 3.43.
Reaction SMILES: C([O-])(=O)C.C([O-])(=O)C.C([O-])(=O)C.[Cl:13][C:14]1[CH:28]=[CH:27][C:17]([C:18]2[CH:19]=[CH:20][C:21]([CH2:25][CH3:26])=[C:22]([Pb+3])[CH:23]=2)=[CH:16][CH:15]=1.[CH:29]12[CH2:36][CH:33]([CH:34]=[CH:35]1)[C:32](=[O:37])[CH2:31][C:30]2=[O:38].C1(C)C=CC=CC=1>C(Cl)(Cl)Cl.CN(C)C1C=CN=CC=1>[Cl:13][C:14]1[CH:28]=[CH:27][C:17]([C:18]2[CH:19]=[CH:20][C:21]([CH2:25][CH3:26])=[C:22]([CH:31]3[C:32](=[O:37])[CH:33]4[CH2:36][CH:29]([CH:35]=[CH:34]4)[C:30]3=[O:38])[CH:23]=2)=[CH:16][CH:15]=1
Reactant: O=C1CC(=O)C2C=CC1C2
Reactant: CCc1ccc(-c2ccc(Cl)cc2)cc1[Pb+3]
Agent: CC(=O)[O-]
Agent: CN(C)c1ccncc1
Solvent: ClC(Cl)Cl
Solvent: Cc1ccccc1
Product: CCc1ccc(-c2ccc(Cl)cc2)cc1C1C(=O)C2C=CC(C2)C1=O
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
To a solution of 4′-chloro-4-ethylbiphen-3-yllead triacetate (0.478 g, 0.80 mmol) in chloroform (5 ml) is added bicyclo[3.2.1]oct-6-ene-2,4-dione (0.097 g, 0.72 mmol) (preparation described by R. Beaudegnies et al., WO2005/123667) and 4-dimethylaminopyridine (0.36 g, 2.86 mmol), and the reaction mixture is stirred at room temperature for 5 minutes. Next toluene (1 ml) is added, and the mixture is stirred at 80° C. for 2 hours (pre-heated oil bath). The reaction mixture is allowed to cool to room temperature, quenched with 2M hydrochloric acid and the inorganic precipitate removed by filtration. The organic phase is separated, and the aqueous phase is further washed with dichloromethane (×2), and again the phases are separated. All organics are combined then evaporated under reduced pressure to give a brown gum. This crude product is first purified by preparative reverse-phase HPLC, then also by flash column chromatography on silica gel (20% to 100% ethyl acetate/hexane eluant ratio) to afford 3-(4′-chloro-4-ethylbiphen-3-yl)bicyclo[3.2.1]oct-6-ene-2,4-dione.
Reaction SMILES: CON(C)[C:4]([C:6]1[N:7]=[CH:8][N:9]([C:11]2[CH:12]=[C:13]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[O:23][CH3:24])[CH:14]=[CH:15][CH:16]=2)[CH:10]=1)=[O:5].[S:26]1[CH:30]=[CH:29][N:28]=[CH:27]1>>[CH3:24][O:23][C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=1[C:13]1[CH:14]=[CH:15][CH:16]=[C:11]([N:9]2[CH:10]=[C:6]([C:4]([C:27]3[S:26][CH:30]=[CH:29][N:28]=3)=[O:5])[N:7]=[CH:8]2)[CH:12]=1
Reactant: c1cscn1
Reactant: COc1ccccc1-c1cccc(-n2cnc(C(=O)N(C)OC)c2)c1
Product: COc1ccccc1-c1cccc(-n2cnc(C(=O)c3nccs3)c2)c1

Procedure:
This compound is prepared by method C using compound 12c and thiazole
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5]([CH:12]1[NH:17][CH2:16][CH2:15][CH2:14][CH2:13]1)[C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1)=[O:4].Cl.[OH-].[NH4+]>O>[CH3:1][O:2][C:3]([C@H:5]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[C@@H:12]1[NH:17][CH2:16][CH2:15][CH2:14][CH2:13]1)=[O:4]
Reactant: COC(=O)C(c1ccccc1)C1CCCCN1
Agent: Cl
Agent: [NH4+]
Agent: [OH-]
Solvent: O
Product: COC(=O)[C@H](c1ccccc1)[C@H]1CCCCN1
Yield: 98 %

Procedure:
To a 200 mL beaker was charged 10.0 g (37.1 mmol) racemic-methylphenidate hydrochloride and 135 mL water. Ammonium hydroxide (3.40 g; 96.8 mmol) was then added to bring the pH to approximately 9 upon which an oily semi-solid formed. The product was extracted with three 100 mL portions of ethyl acetate, the combined organic layers were dried over sodium sulfate, filtered and concentrated under reduce pressure at 40° C. to provide 8.5 g of a clear, colorless viscous oil (98% yield). The free base was characterized by FTIR and found to be consistent with the anticipated structure
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH3:7][NH:8][N:9]=[C:10]([CH3:16])[C:11]([O:13][CH2:14][CH3:15])=[O:12].[CH2:17]([C:19]1[CH:24]=[C:23]([CH3:25])[CH:22]=[C:21]([CH2:26][CH3:27])[C:20]=1[CH2:28][C:29](Cl)=[O:30])[CH3:18].C(OCC)(=O)C>C(#N)C.CCCCCC>[CH2:17]([C:19]1[CH:24]=[C:23]([CH3:25])[CH:22]=[C:21]([CH2:26][CH3:27])[C:20]=1[CH2:28][C:29]([N:8]([CH3:7])[N:9]=[C:10]([CH3:16])[C:11]([O:13][CH2:14][CH3:15])=[O:12])=[O:30])[CH3:18]
Reactant: CCOC(=O)C(C)=NNC
Reactant: CCc1cc(C)cc(CC)c1CC(=O)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCCCCC
Solvent: CC#N
Solvent: CCOC(C)=O
Product: CCOC(=O)C(C)=NN(C)C(=O)Cc1c(CC)cc(C)cc1CC
Temperature: 0 °C
Yield: 49.4 %

Procedure:
1.5 g of potassium carbonate was added to a solution of 2.0 g of ethyl 2-(methylhydrazono)propanoate in 35 mL of acetonitrile. The mixture was stirred under cooling with ice, to which a solution of 2.6 g of 2,6-diethyl-4-methylphenylacetyl chloride in 10 mL of acetonitrile was added dropwise over about 20 minutes. The resulting mixture was further stirred for 3.5 hours at room temperature, and then concentrated under reduced pressure. To the residue obtained was added 20 mL of ice-water, which was extracted with ethyl acetate (20 mL×3). The extracts were combined, washed with a saturated sodium chloride aqueous solution (20 mL×2), dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue obtained was subjected to basic alumina column chromatography (ethyl acetate:hexane=1:3 as eluent) to yield 1.9 g of the title compound as white crystals.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]12[CH2:16][CH:15]3[CH2:17][C:11]([C:18]([OH:20])=O)([CH2:12][CH:13]1[CH2:14]3)[CH2:10]2)=[O:7])([CH3:4])([CH3:3])[CH3:2].CC[N:23](C(C)C)C(C)C.N.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[C:1]([O:5][C:6](=[O:7])[NH:8][C:9]12[CH2:16][CH:15]3[CH2:17][C:11]([C:18](=[O:20])[NH2:23])([CH2:12][CH:13]1[CH2:14]3)[CH2:10]2)([CH3:4])([CH3:3])[CH3:2]
Reactant: CCN(C(C)C)C(C)C
Reactant: CC(C)(C)OC(=O)NC12CC3CC1CC(C(=O)O)(C3)C2
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: N
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NC12CC3CC1CC(C(N)=O)(C3)C2
Temperature: 25 °C
Reaction time: 2 h

Procedure:
3a-tert-Butoxycarbonylaminohexahydro-2,5-methanopentalene-2-carboxylic acid was dissolved in DMF (200 ml), and DIPEA (10.6 g) and ammonia (6.1 ml, 7M in MeOH) were added. Subsequently, HATU (14.8 g) was added and the mixture was stirred at room temperature for 2 h. The reaction solution was concentrated by rotary evaporation down to volume 50 ml, poured into 400 ml of dilute NaHCO3 solution (300 ml of H2O+100 ml of saturated NaHCO3 solution) and extracted 3 times with 100 ml of EtOAc. Then dried over MgSO4, filtered and concentrated by rotary evaporation.
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[C:7]([C:9]([F:18])([C:14]([F:17])([F:16])[F:15])[C:10]([F:13])([F:12])[F:11])[CH:6]=[C:5]([CH3:19])[C:4]=1[NH:20][C:21]([C:23]1[CH:24]=[C:25]2[C:29](=[CH:30][CH:31]=1)[C:28](=O)[CH2:27][CH2:26]2)=[O:22])[CH3:2].C([O-])(=O)C.[Na+].Cl.[NH2:39][OH:40]>C(O)C.O>[CH2:1]([C:3]1[CH:8]=[C:7]([C:9]([F:18])([C:10]([F:11])([F:13])[F:12])[C:14]([F:15])([F:17])[F:16])[CH:6]=[C:5]([CH3:19])[C:4]=1[NH:20][C:21]([C:23]1[CH:24]=[C:25]2[C:29](=[CH:30][CH:31]=1)[C:28](=[N:39][OH:40])[CH2:27][CH2:26]2)=[O:22])[CH3:2]
Reactant: CCc1cc(C(F)(C(F)(F)F)C(F)(F)F)cc(C)c1NC(=O)c1ccc2c(c1)CCC2=O
Reactant: NO
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CCc1cc(C(F)(C(F)(F)F)C(F)(F)F)cc(C)c1NC(=O)c1ccc2c(c1)CCC2=NO
Yield: 92.8 %

Procedure:
N-[2-Ethyl-4-(1,1,1,2,3,3,3-heptafluoropropan-2-yl)-6-methylphenyl]-1-oxoindane-5-carboxamide (2.4 g) was dissolved in ethanol (40 ml), and sodium acetate (0.85 g) and hydroxylamine hydrochloride (0.43 g) were added thereto, and then stirred and heated at reflux temperature for 2 hours. The reaction solution was brought back to room temperature and diluted with water. The resulting crystals were collected by filtration and dried to obtain N-[2-ethyl-4-(1,1,1,2,3,3,3-heptafluoropropan-2-yl)-6-methylphenyl]-1-(hydroxyimino) indane-5-carboxamide (2.3 g, yield 91%).
Reaction SMILES: [NH2:1][C:2]1[C:10]2[C:5](=[N:6][C:7]([N:15]3[CH2:20][CH2:19][CH:18]([NH:21][CH2:22][CH:23]([C:25]4[CH:30]=[CH:29][C:28](Br)=[CH:27][N:26]=4)[OH:24])[CH2:17][CH2:16]3)=[CH:8][C:9]=2[C:11]([F:14])([F:13])[F:12])[S:4][C:3]=1[C:32]([NH2:34])=[O:33].B1(B2OC(C)(C)C(C)(C)O2)OC(C)(C)C(C)(C)O1.C([O-])(=O)C.[K+].N#N.Br[C:61]1[CH:69]=[C:68]2[C:64]([CH2:65][C:66](=[O:70])[NH:67]2)=[CH:63][CH:62]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[NH2:1][C:2]1[C:10]2[C:5](=[N:6][C:7]([N:15]3[CH2:20][CH2:19][CH:18]([NH:21][CH2:22][CH:23]([OH:24])[C:25]4[CH:30]=[CH:29][C:28]([C:61]5[CH:69]=[C:68]6[C:64]([CH2:65][C:66](=[O:70])[NH:67]6)=[CH:63][CH:62]=5)=[CH:27][N:26]=4)[CH2:17][CH2:16]3)=[CH:8][C:9]=2[C:11]([F:14])([F:13])[F:12])[S:4][C:3]=1[C:32]([NH2:34])=[O:33]
Reactant: NC(=O)c1sc2nc(N3CCC(NCC(O)c4ccc(Br)cn4)CC3)cc(C(F)(F)F)c2c1N
Reactant: O=C1Cc2ccc(Br)cc2N1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CC(=O)[O-]
Agent: CC1(C)OB(B2OC(C)(C)C(C)(C)O2)OC1(C)C
Solvent: CN(C)C=O
Solvent: O
Product: NC(=O)c1sc2nc(N3CCC(NCC(O)c4ccc(-c5ccc6c(c5)NC(=O)C6)cn4)CC3)cc(C(F)(F)F)c2c1N
Temperature: 80 °C
Yield: 12.5 %

Procedure:
An N2-purged suspension of 3-Amino-6-{4-[2-(5-bromo-pyridin-2-yl)-2-hydroxy-ethylamino]-piperidin-1-yl}-4-trifluoromethyl-thieno[2,3-b]pyridine-2-carboxylic acid amide (150 mg, 0.268 mmol), bis(pinacolato)diboron (153 mg, 0.590 mmol), [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II)-CH2Cl2 complex (33 mg, 0.040 mmol), and potassium acetate (133 mg, 1.34 mmol) in dry DMF (4 ml) was heated at 80° C. for 2.5 h. The crude reaction mixture was then added directly via syringe to a stirring, N2-purged suspension of 6-bromo-2-oxindole (65 mg, 0.295 mmol), tetrakis(triphenylphosphine)palladium(0) (47 mg, 0.040 mmol), and potassium carbonate (74 mg, 0.536 mmol) in dry DMF (6 ml) and water (2 ml) at rt. The sealed mixture was heated to 85° C. for 4 h. The crude reaction was applied direcly to a SiO2 column and purified (0–25% MeOH/CH2Cl2 with NH4OH). Fractions containing desired product were pooled and concentrated. The yellow residue was dissolved in 2 ml DMF and applied to a 2 mm prep plate (Merck) eluting with 10% MeOH/CH2Cl2 with 1% NH4OH. The yellow product crystallized at the origin and the impurities were removed by being carried up the plate. The recovered yellow residue was dissolved in 1 ml DMF, 2 ml MeOH, 5 ml EtOAc, and 5 ml CH2Cl2 and crystallized by the addition of 30 ml hexanes to give 20.5 mg, 11.9% of 3-Amino-6-(4-{2-hydroxy-2-[5-(2-oxo-2,3-dihydro-1H-indol-6-yl)-pyridin-2-yl]-ethylamino}-piperidin-1-yl)-4-trifluoromethyl-thieno[2,3-b]pyridine-2-carboxylic acid amide product. ES+ 612.4 m/z (MH+).
Reaction SMILES: O=[C:2]([CH2:8][C:9](=O)[CH3:10])[C:3]([O:5][CH2:6][CH3:7])=[O:4].[CH:12]([NH:15][NH2:16])([CH3:14])[CH3:13]>C(O)(=O)C>[CH:12]([N:15]1[C:9]([CH3:10])=[CH:8][C:2]([C:3]([O:5][CH2:6][CH3:7])=[O:4])=[N:16]1)([CH3:14])[CH3:13]
Reactant: CC(C)NN
Reactant: CCOC(=O)C(=O)CC(C)=O
Solvent: CC(=O)O
Product: CCOC(=O)c1cc(C)n(C(C)C)n1
Reaction time: 2 h
Yield: 31.3 %

Procedure:
To ethyl 2,4-dioxopentanoate (20.1 g, 127 mmol) in acetic acid (100 mL) at 0° C. was added isopropylhydrazine (9.42 g, 127 mmol) dropwise. The cold bath was removed and the reaction mixture was stirred for 2 hours. The reaction mixture was diluted with EtOAc/H2O (300 mL/100 mL). The organic layer was washed with saturated NaHCO3 aqueous solution (100 mL), H2O (50 mL) and brine (50 mL). The organic layer was dried (Na2SO4) and concentrated. The residue was purified by silica gel flash chromatography (1:2 EtOAc/hexane) to give 7.8 g (31%) of the title compound.
Reaction SMILES: [CH2:1]([O:8][C:9]([C@H:11]1[CH2:16][N:15]([C:17](=[S:19])[NH2:18])[CH2:14][CH2:13][N:12]1[S:20]([C:23]1[CH:28]=[CH:27][C:26]([O:29][C:30]([F:33])([F:32])[F:31])=[CH:25][CH:24]=1)(=[O:22])=[O:21])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:34]([O:38][C:39](=[O:45])[CH:40](Br)[C:41](=O)[CH3:42])([CH3:37])([CH3:36])[CH3:35]>C(#N)C>[CH2:1]([O:8][C:9]([C@H:11]1[CH2:16][N:15]([C:17]2[S:19][C:40]([C:39]([O:38][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:45])=[C:41]([CH3:42])[N:18]=2)[CH2:14][CH2:13][N:12]1[S:20]([C:23]1[CH:24]=[CH:25][C:26]([O:29][C:30]([F:33])([F:31])[F:32])=[CH:27][CH:28]=1)(=[O:21])=[O:22])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NC(=S)N1CCN(S(=O)(=O)c2ccc(OC(F)(F)F)cc2)[C@@H](C(=O)OCc2ccccc2)C1
Reactant: CC(=O)C(Br)C(=O)OC(C)(C)C
Solvent: CC#N
Product: Cc1nc(N2CCN(S(=O)(=O)c3ccc(OC(F)(F)F)cc3)[C@@H](C(=O)OCc3ccccc3)C2)sc1C(=O)OC(C)(C)C
Temperature: 80 °C
Reaction time: 0.5 h
Yield: 67.4 %

Procedure:
A mixture of the compound (2.12 g) obtained in Step 4 and 2-bromo-3-oxobutyric acid tert-butyl ester (2.0 g) in acetonitrile (20 ml) was stirred at 80° C. for 30 min. The reaction mixture was concentrated under reduced pressure, and the residue was partitioned by adding ethyl acetate and saturated aqueous sodium carbonate solution. The organic layer was washed successively with saturated aqueous sodium carbonate solution and saturated brine, dried over anhydrous sodium sulfate, filtrated, and concentrated under reduced pressure. The residue was purified by column chromatography (ethyl acetate:n-hexane=1:2) to give the title compound (1.82 g).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]2[N:8]([C:9]=1[CH:10]=[O:11])[N:7]=[C:6]([CH2:12][O:13][CH3:14])[S:5]2.[BH4-].[Na+].[NH4+].[Cl-]>C(O)C>[Cl:1][C:2]1[N:3]=[C:4]2[N:8]([C:9]=1[CH2:10][OH:11])[N:7]=[C:6]([CH2:12][O:13][CH3:14])[S:5]2
Reactant: COCc1nn2c(C=O)c(Cl)nc2s1
Agent: [BH4-]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Product: COCc1nn2c(CO)c(Cl)nc2s1
Temperature: 0 °C
Reaction time: 8 h
Yield: 66 %

Procedure:
6-chloro-2-(methoxymethyl)imidazo[2,1-b][1,3,4]thiadiazole-5-carbaldehyde a16 (2.97 g, 12.94 mmol, 1 eq) is dissolved in ethanol (80 ml), cooled at 0° C. and sodium borohydride (578 mg, 15.53 mmol, 1.2 eq) is added portionwise at 0° C. The reaction mixture is stirred overnight at room temperature, then cooled at 0° C. and a saturated NH4Cl aqueous solution (100 ml) is added. The organic solvent is evaporated under reduced pressure and the precipitate is filtered, dried under vacuum at 20° C. to afford 1.99 g of [6-chloro-2-(methoxymethyl)imidazo[2,1-b][1,3,4]thiadiazol-5-yl]methanol a17.
Reaction SMILES: Cl.[N:2]1[CH:6]=[C:5]([CH:7]2[CH2:12][CH2:11][CH2:10][NH:9][CH2:8]2)[NH:4][N:3]=1.[CH2:13]([N:15]1[C:27]2[CH:26]=[CH:25][C:24]([CH:28]=O)=[CH:23][C:22]=2[C:21]2[C:16]1=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH3:14].C(N(C(C)C)C(C)C)C.C(O)(=O)C.[BH3-]C#N.[Na+].C(=O)(O)[O-].[Na+].O>C(O)C.CO.C(Cl)Cl>[N:2]1[CH:6]=[C:5]([CH:7]2[CH2:12][CH2:11][CH2:10][N:9]([CH2:28][C:24]3[CH:25]=[CH:26][C:27]4[N:15]([CH2:13][CH3:14])[C:16]5[C:21]([C:22]=4[CH:23]=3)=[CH:20][CH:19]=[CH:18][CH:17]=5)[CH2:8]2)[NH:4][N:3]=1
Reactant: CCn1c2ccccc2c2cc(C=O)ccc21
Reactant: c1nn[nH]c1C1CCCNC1
Agent: Cl
Agent: O=C([O-])O
Agent: [BH3-]C#N
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CC(=O)O
Product: CCn1c2ccccc2c2cc(CN3CCCC(c4cnn[nH]4)C3)ccc21
Temperature: 40 °C
Yield: 42.3 %

Procedure:
A 100-mL round-bottomed flask was charged with a solution of 3-(3H-1,2,3-triazol-4-yl)piperidine hydrochloride (500 mg, 3.29 mmol, 1.00 equiv) in ethanol (50 mL), 9-ethyl-9H-carbazole-3-carbaldehyde (890 mg, 3.99 mmol, 1.50 equiv), N-ethyl-N-isopropylpropan-2-amine (1.37 g, 10.62 mmol, 4.00 equiv), acetic acid (640 mg, 10.67 mmol, 4.00 equiv) and NaBH3CN (510 mg, 8.10 mmol, 3.00 equiv). The resulting solution was heated to 40° C. in an oil bath for 16 hours. The reaction progress was monitored by TLC (DCM: MeOH=10:1). Upon completion, pH was adjusted to 8 with sodium bicarbonate/water. The resulting mixture was then extracted with dichloromethane (4×80 mL). Combined organic layers were dried over anhydrous sodium sulfate, filtered off and concentrated on a rotary evaporator. The residue was purified by a silica gel column chromatography eluted with dichloromethane/methanol (40/1) affording 3-((3-(3H-1,2,3-triazol-4-yl)piperidin-1-yl)methyl)-9-ethyl-9H-carbazole as white solid (0.5 g, 42%). LCMS: [M+H]+: 360. 1H NMR (CDCl3, 300 MHz) δ 8.08 (d, 1H), 8.03 (s, 1H), 7.47 (m, 3H), 7.26 (m, 2H), 4.35 (d, 2H), 3.80 (m, 2H), 3.30 (s, 1H), 2.99 (s, 2H), 2.80 (s, 1H), 2.61 (s, 2H), 1.94 (s, 1H), 1.73 (s, 2H), 1.54 (s, 1H), 1.42 (t, 3H).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:10])[CH2:5][C:6]([CH2:8][Cl:9])=[O:7])[CH3:2].C(=O)[C:12]1[O:16][CH:15]=[CH:14][CH:13]=1.N1CCCCC1.C(O)(=O)C>C1C=CC=CC=1.CCOCC.O>[CH2:1]([O:3][C:4](=[O:10])[C:5](=[C:12]1[CH2:13][CH:14]=[CH:15][O:16]1)[C:6](=[O:7])[CH2:8][Cl:9])[CH3:2]
Reactant: CCOC(=O)CC(=O)CCl
Reactant: O=Cc1ccco1
Solvent: c1ccccc1
Solvent: CCOCC
Solvent: C1CCNCC1
Product: CCOC(=O)C(C(=O)CCl)=C1CC=CO1
Reaction time: 5 h
Yield: 86.8 %

Procedure:
200 g of 4-chloroacetoacetic acid ethyl ester, 125.6 g of freshly distilled furfural, 2.6 ml of piperidine and 7 ml of glacial acetic acid were dissolved in 120 ml of benzene and the solution was boiled for 5 hours, using a water separator. 1 liter of ether was added to the cooled solution and the mixture was then extracted in each case once by shaking with saturated sodium bicarbonate solution, water, 2 M citric acid solution and again with water. After the extract had been dried over magnesium sulphate and concentrated, an oil was obtained and was subjected to incipient distillation under a high vacuum. The product remained as a viscous oil and the E/Z isomer ratio was 4:1. Yield: 86.8%.