Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[C:3](=[O:19])[NH:4][N:5]=[CH:6][C:7]=1[NH:8][C@@H:9]1[CH2:14][C@@H:13]2[CH2:15][C@@H:11]([C:12]2([CH3:17])[CH3:16])[C@H:10]1[CH3:18].Br[CH2:21][CH2:22][CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25].C(=O)([O-])[O-].[K+].[K+].[Cl-].[NH4+]>CN(C)C=O>[Br:1][C:2]1[C:3](=[O:19])[N:4]([CH2:21][CH2:22][CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25])[N:5]=[CH:6][C:7]=1[NH:8][C@@H:9]1[CH2:14][C@@H:13]2[CH2:15][C@@H:11]([C:12]2([CH3:16])[CH3:17])[C@H:10]1[CH3:18]
Reactant: C[C@@H]1[C@H]2C[C@@H](C[C@H]1Nc1cn[nH]c(=O)c1Br)C2(C)C
Reactant: CCOC(=O)CCCBr
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)CCCn1ncc(N[C@@H]2C[C@@H]3C[C@H]([C@H]2C)C3(C)C)c(Br)c1=O
Temperature: 80 °C
Reaction time: 2 h
Yield: 149.8 %

Procedure:
4-Bromo-5-[(1R,2R,3R,5S)-2,6,6-trimethylbicyclo[3.1.1]hept-3-ylamino]pyridazin-3(2H)-one (224 mg, 0.688 mmol) in N,N-dimethylformamide (2.2 mL) was mixed with ethyl 4-bromobutyrate (0.148 mL, 1.03 mmol) and potassium carbonate (142 mg, 1.03 mmol) at room temperature and stirred at 80° C. for 2 hours. After cooling, the reaction solution was mixed with saturated aqueous ammonium chloride and extracted with ethyl acetate. The resulting organic layer was washed with saturated aqueous ammonium chloride and saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate and evaporated under reduced pressure to give the desired product (454 mg, quant.).
Reaction SMILES: [OH-].[K+].O[C:4]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:5]=1[CH2:6][CH2:7][CH:8]2[N:13]1[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1.[Br:19][CH2:20][CH2:21][CH2:22]Br>[Cl-].C([N+](CCCC)(CCCC)CCCC)CCC>[Br:19][CH2:20][CH2:21][CH2:22][C:4]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:5]=1[CH2:6][CH2:7][CH:8]2[N:13]1[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1
Reactant: Oc1cccc2c1CCC2N1CCCCC1
Reactant: BrCCCBr
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Cl-]
Agent: [K+]
Product: BrCCCc1cccc2c1CCC2N1CCCCC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Potassium hydroxide (53 g, 87%) is added over a period of 1 hour 15 min to a stirred suspension of 4-hydroxy-1-piperidinylindan (30 g), and tetrabutylammonium chloride (4.1 g) in 1,3-dibromopropane (140 ml) and the resulting mixture stirred at RT under nitrogen for two hours. The reaction mixture is partitioned between ice-water and ether and the aqueous layer separated and extracted with ether. The combined organic extracts are washed with water and ice cold 5% aqueous HCl forming a precipitate which is filtered and washed with ether. The acidic fraction is made strongly alkaline forming an oil precipitate which is extracted into ether. The combined ether layers are washed, dried over Na2SO4, filtered and concentrated in vacuo yielding the desired product as an oil which is used in the next step without further treatment.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([NH:13][C:14]([CH:16]2[CH2:25][CH2:24][C:23]3[C:18](=[CH:19][C:20]([O:26][C:27]4[CH:32]=[CH:31][N:30]=[C:29]([C:33]([N:35]5[CH2:39][CH2:38][CH2:37][CH2:36]5)=[O:34])[CH:28]=4)=[CH:21][CH:22]=3)[CH2:17]2)=[O:15])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1)#[N:2]>N.CO.[Ni]>[NH2:2][CH2:1][C:3]1[CH:4]=[C:5]([NH:13][C:14]([CH:16]2[CH2:25][CH2:24][C:23]3[C:18](=[CH:19][C:20]([O:26][C:27]4[CH:32]=[CH:31][N:30]=[C:29]([C:33]([N:35]5[CH2:36][CH2:37][CH2:38][CH2:39]5)=[O:34])[CH:28]=4)=[CH:21][CH:22]=3)[CH2:17]2)=[O:15])[CH:6]=[C:7]([C:9]([F:11])([F:12])[F:10])[CH:8]=1
Reactant: N#Cc1cc(NC(=O)C2CCc3ccc(Oc4ccnc(C(=O)N5CCCC5)c4)cc3C2)cc(C(F)(F)F)c1
Agent: [Ni]
Agent: N
Solvent: CO
Product: NCc1cc(NC(=O)C2CCc3ccc(Oc4ccnc(C(=O)N5CCCC5)c4)cc3C2)cc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of N-[3-cyano-5-(trifluoromethyl)phenyl]-7-{[2-(pyrrolidin-1-ylcarbonyl)pyridin-4-yl]oxy}-1,2,3,4-tetrahydronaphthalene-2-carboxamide (0.310 g, 0.58 mmol) and Raney Ni (50% v/v in water, 2.0 mL) in 7M ammonia in MeOH (30 mL) was allowed to stir at rt under an atmosphere of hydrogen overnight. The reaction mixture was filtered over Celite, the Celite rinsed with MeOH, and the solution concentrated to give N-[3-(aminomethyl)-5-(trifluoromethyl)phenyl]-7-{[2-(pyrrolidin-1-ylcarbonyl)pyridin-4-yl]oxy}-1,2,3,4-tetrahydronaphthalene-2-carboxamide I-362 (0.205 g, 55%). 1H NMR (400 MHz, CD3OD, HCl Salt) δ: 8.69 (d, 1H), 8.08 (s, 1H), 8.02 (s, 1H), 7.70 (d, 1H), 7.54 (s, 1H), 7.45-7.42 (dd, 1H), 7.31 (d, 2H), 7.09-7.03 (m, 2H), 4.20 (s, 2H), 3.65-3.59 (m, 4H), 3.15-2.91 (m, 5H), 2.25-2.21 (m, 1H), and 2.02-1.93 (m, 5H). LCMS: (FA) ES+ 539.8, ES− 537.5.
Reaction SMILES: C1(P([N:15]=[N+:16]=[N-:17])(C2C=CC=CC=2)=O)C=CC=CC=1.C(N(CC)CC)C.[C:25]1([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[CH:30]=[CH:29][CH:28]=[C:27]([C:31](O)=[O:32])[CH:26]=1>C(O)(C)C>[C:25]1([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[CH:30]=[CH:29][CH:28]=[C:27]([C:31]([N:15]=[N+:16]=[N-:17])=[O:32])[CH:26]=1
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Reactant: O=C(O)c1cccc(-c2ccccc2)c1
Solvent: CCN(CC)CC
Solvent: CC(C)O
Product: [N-]=[N+]=NC(=O)c1cccc(-c2ccccc2)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 119.5 %

Procedure:
To a vial (8 mL) diphenylphosphoryl azide (0.39 mL, 1.8 mmol) and triethylamine (0.25 mL, 1.8 mmol) were added to a stirred solution of biphenyl-3-carboxylic acid (0.30 g, 1.5 mmol) in isopropanol (3 mL). The vial was closed with a lid, and the reaction mixture was stirred for 16 hours at room temperature. The reaction mixture was concentrated, and water (50 mL) was added. The mixture was extracted with ethyl acetate (3×50 mL). The combined extracts were dried over sodium sulfate, filtered, and concentrated to provide the title compound (0.40 g, 100%) was used in the next reaction without characterization or purification.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([CH:36]=[CH:37][CH:38]=1)[CH2:8][NH:9][C@@H:10]1[C@@H:15]([OH:16])[C@H:14]([CH2:17][C:18]2[CH:23]=[C:22]([O:24][CH2:25][C:26]([F:29])([F:28])[F:27])[C:21]([N+:30]([O-:32])=[O:31])=[C:20]([F:33])[CH:19]=2)[CH2:13][S:12](=[O:35])(=[O:34])[CH2:11]1)([CH3:4])([CH3:3])[CH3:2].[C:39](C1NC=CN=1)(C1NC=CN=1)=[O:40].CCN(C(C)C)C(C)C>C(#N)C.CN(C=O)C.CN(C1C=CN=CC=1)C>[C:1]([C:5]1[CH:6]=[C:7]([CH:36]=[CH:37][CH:38]=1)[CH2:8][N:9]1[C@@H:10]2[C@H:15]([C@H:14]([CH2:17][C:18]3[CH:23]=[C:22]([O:24][CH2:25][C:26]([F:28])([F:29])[F:27])[C:21]([N+:30]([O-:32])=[O:31])=[C:20]([F:33])[CH:19]=3)[CH2:13][S:12](=[O:35])(=[O:34])[CH2:11]2)[O:16][C:39]1=[O:40])([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C(c1ncc[nH]1)c1ncc[nH]1
Reactant: CC(C)(C)c1cccc(CN[C@H]2CS(=O)(=O)C[C@@H](Cc3cc(F)c([N+](=O)[O-])c(OCC(F)(F)F)c3)[C@@H]2O)c1
Agent: CN(C)c1ccncc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Solvent: CN(C)C=O
Product: CC(C)(C)c1cccc(CN2C(=O)O[C@H]3[C@H](Cc4cc(F)c([N+](=O)[O-])c(OCC(F)(F)F)c4)CS(=O)(=O)C[C@@H]32)c1

Procedure:
To a solution of (3R,4S,5S)-3-(3-tert-Butyl-benzylamino)-5-[3-fluoro-4-nitro-5-(2,2,2-trifluoro-ethoxy)-benzyl]-1,1-dioxo-hexahydro-1lambda*6*-thiopyran-4-ol (1.39 g, 2.47 mmol) in ACN (4 mL) and DMF (2 mL) was added carbonyl-diimidazole (0.8 g 4.94 mmol), DIPEA (4.8 g, 3.71 mmol) and DMAP (30 mg, 0.247 mmol). The reaction mixture was refluxed for 2 days and then concentrated in vacuo. The title compound was obtained after flash-chromatography on silica gel (toluene-EtOAc 1:1): ESIMS [M+NH4]+=606; UPLC RtD=1.913 min; 1H NMR (600 MHz, DMSO-d6): δ 7.42 (s, 1H), 7.32 (d, 1H), 7.28 (t, 1H), 7.21 (s, 1H), 7.16 (d, 1H), 7.13 (d, 1H), 4.98 (q, 2H), 4.45 (d, 1H), 4.21 (m, 2H), 3.78 (m, 1H), 3.63 (m, 1H), 3.46 (t, 1H), 3.13 (m, 2H), 3.02 (m, 1H), 2.60 (m, 2H), 1.25 (s, 9H).
Reaction SMILES: Br[C:2]1[S:3][C:4]([C:7]([NH:9][CH2:10][C:11]2[C:20](=[O:21])[C:19]3[C:14](=[CH:15][C:16]([Cl:22])=[CH:17][CH:18]=3)[N:13]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[CH:12]=2)=[O:8])=[CH:5][N:6]=1.[OH:29][CH2:30][CH:31]1[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]1>>[Cl:22][C:16]1[CH:15]=[C:14]2[C:19]([C:20](=[O:21])[C:11]([CH2:10][NH:9][C:7]([C:4]3[S:3][C:2]([N:34]4[CH2:35][CH2:36][CH:31]([CH2:30][OH:29])[CH2:32][CH2:33]4)=[N:6][CH:5]=3)=[O:8])=[CH:12][N:13]2[C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[CH:18][CH:17]=1
Reactant: O=C(NCc1cn(-c2ccccc2)c2cc(Cl)ccc2c1=O)c1cnc(Br)s1
Reactant: OCC1CCNCC1
Product: O=C(NCc1cn(-c2ccccc2)c2cc(Cl)ccc2c1=O)c1cnc(N2CCC(CO)CC2)s1

Procedure:
2-(4-Hydroxymethyl-piperidin-1-yl)-thiazole-5-carboxylic acid (7-chloro-4-oxo-1-phenyl-1,4-dihydro-quinolin-3-ylmethyl)-amide was prepared starting from intermediate F and 4-hydroxymethyl piperidine. MS calcd. for C26H25ClN4O3S [(M+H)+] 509.1, obsd. 509.
Reaction SMILES: [CH:1]([N:4]1[C:12]2[CH:11]=[C:10]([O:13][CH3:14])[CH:9]=[C:8]([C:15]([OH:17])=[O:16])[C:7]=2[CH:6]=[CH:5]1)([CH3:3])[CH3:2].OS(O)(=O)=O.[CH3:23]O>>[CH3:23][O:16][C:15]([C:8]1[C:7]2[CH:6]=[CH:5][N:4]([CH:1]([CH3:3])[CH3:2])[C:12]=2[CH:11]=[C:10]([O:13][CH3:14])[CH:9]=1)=[O:17]
Reactant: COc1cc(C(=O)O)c2ccn(C(C)C)c2c1
Reactant: CO
Agent: O=S(=O)(O)O
Product: COC(=O)c1cc(OC)cc2c1ccn2C(C)C
Yield: 32.4 %

Procedure:
To a stirred suspension of 1-isopropyl-6-methoxy-1H-indole-4-carboxylic acid (700 mg, 3.00 mmol) in MeOH was added H2SO4 (440 mg, 4.50 mmol) and then heated at reflux for 3 h. Methanol was distilled off completely under reduced pressure and the residue basified with saturated aqueous NaHCO3 solution and extracted with ethyl acetate (2×5 mL). The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated. The residue was purified by column chromatography (SiO2, 100-200) by eluting 5% ethyl acetate in petroleum ether to afford 1-isopropyl-6-methoxy-1H-indole-4-carboxylic acid methyl ester (240 mg, 32.4%) as white solid. 1H NMR (400 MHz, DMSO-d6): δ 1.45 (d, J=6.8 Hz, 6H), 3.84 (s, 3H), 3.88 (s, 3H), 4.81-4.78 (m, 1H), 6.86 (d, J=3.2 Hz, 1H), 7.34 (d, J=2.4 Hz, 1H), 7.39 (d, J=2 Hz, 1H), 7.54 (d, J=3.6 Hz, 1H). LCMS (ES+): m/z=248.16 [M+H].
Reaction SMILES: C[O:2][C:3](=[O:33])[C:4]([C:7]1[CH:12]=[CH:11][C:10]([C:13]#[C:14][C:15]2[C:24]([CH3:25])=[CH:23][C:22]3[CH:21]([N:26]([CH:28]4[CH2:30][CH2:29]4)[CH3:27])[CH2:20][CH2:19][C:18]([CH3:32])([CH3:31])[C:17]=3[CH:16]=2)=[CH:9][CH:8]=1)([CH3:6])[CH3:5].[OH-].[Na+]>CO.O1CCCC1>[CH:28]1([N:26]([CH3:27])[CH:21]2[CH2:20][CH2:19][C:18]([CH3:31])([CH3:32])[C:17]3[CH:16]=[C:15]([C:14]#[C:13][C:10]4[CH:9]=[CH:8][C:7]([C:4]([CH3:6])([CH3:5])[C:3]([OH:33])=[O:2])=[CH:12][CH:11]=4)[C:24]([CH3:25])=[CH:23][C:22]2=3)[CH2:29][CH2:30]1
Reactant: COC(=O)C(C)(C)c1ccc(C#Cc2cc3c(cc2C)C(N(C)C2CC2)CCC3(C)C)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: Cc1cc2c(cc1C#Cc1ccc(C(C)(C)C(=O)O)cc1)C(C)(C)CCC2N(C)C1CC1
Yield: 64 %

Procedure:
A solution of 2-{4-[5-(cyclopropyl-methyl-amino)-3,8,8-trimethyl-5,6,7,8-tetrahydro-naphthalen-2-ylethynyl]-phenyl}-2-methyl-propionic acid methyl ester (Intermediate 175, 0.035 g, 0.08 mmol) in methanol (2 mL) and tetrahydrofuran (2 mL) was treated with a 2M solution of sodium hydroxide (2 mL, 4 mmol) and the resulting reaction mixture was refluxed for 2 days. The volatiles were evaporated in vacuo and the residue was neutralized with 5% aqueous hydrochloric acid and extracted with ethyl acetate. The organic phase was washed with water and brine, dried over anhydrous sodium sulfate, filtered and evaporated in vacuo to a residue that was purified by preparative reverse phase HPLC using 10% water in acetonitrile as the mobile phase to afford the title product (0.022 g, 64%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6](B2OC(C)(C)C(C)(C)O2)[C:5]([O:17][CH3:18])=[CH:4][C:3]=1[C:19]1[CH:20]=[N:21][NH:22][CH:23]=1.Cl[C:25]1[N:30]=[N:29][C:28]([N:31]([CH3:42])[CH:32]2[CH2:37][C:36]([CH3:39])([CH3:38])[NH:35][C:34]([CH3:41])([CH3:40])[CH2:33]2)=[CH:27][CH:26]=1>>[Cl:1][C:2]1[C:3]([C:19]2[CH:23]=[N:22][NH:21][CH:20]=2)=[CH:4][C:5]([O:17][CH3:18])=[C:6]([C:25]2[N:30]=[N:29][C:28]([N:31]([CH3:42])[CH:32]3[CH2:37][C:36]([CH3:38])([CH3:39])[NH:35][C:34]([CH3:41])([CH3:40])[CH2:33]3)=[CH:27][CH:26]=2)[CH:7]=1
Reactant: COc1cc(-c2cn[nH]c2)c(Cl)cc1B1OC(C)(C)C(C)(C)O1
Reactant: CN(c1ccc(Cl)nn1)C1CC(C)(C)NC(C)(C)C1
Product: COc1cc(-c2cn[nH]c2)c(Cl)cc1-c1ccc(N(C)C2CC(C)(C)NC(C)(C)C2)nn1
Yield: 86.7 %

Procedure:
Following standard GENERAL METHOD 1-4 for Suzuki coupling using 4-(2-chloro-5-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-1H-pyrazole (118 mg, 0.35 mmol) and 6-chloro-N-methyl-N-(2,2,6,6-tetramethylpiperidin-4-yl)pyridazin-3-amine (Intermediate 1-1,100 mg, 0.35 mmol) afforded 6-(5-chloro-2-methoxy-4-(1H-pyrazol-4-yl)phenyl)-N-methyl-N-(2,2,6,6-tetramethylpiperidin-4-yl)pyridazin-3-amine (138 mg) MS [M+H+]=455.0.
Reaction SMILES: C(N(C1C=CC([C:14]2[N:15]=[C:16]3[N:20]([CH:21]=2)[CH2:19][CH2:18][S:17]3)=CC=1)C(=O)C)CC.ClC(OCC)=O.C1C2C(CCCC2)CCC1.[S].[N:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1>C(Cl)Cl>[N:39]1[CH:44]=[CH:43][C:42]([C:21]2[N:20]3[C:16]([S:17][CH2:18][CH2:19]3)=[N:15][CH:14]=2)=[CH:41][CH:40]=1
Reactant: c1ccncc1
Reactant: CCCN(C(C)=O)c1ccc(-c2cn3c(n2)SCC3)cc1
Agent: CCOC(=O)Cl
Agent: [S]
Solvent: C1CCC2CCCCC2C1
Solvent: ClCCl
Product: c1cc(-c2cnc3n2CCS3)ccn1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
The N-propylacetamido Formula (III) compound (0.60 g, 0.002 mole), prepared as described above in part a, was then suspended in CH2Cl2 (10 ml) and dry pyridine (0.47 ml, 0.006 mole) was added. The suspension was heated to aid in dissolving the solid, then cooled to ice-bath temperature. Ethyl chloroformate (0.72 ml, 0.648 g, 0.006 mole) in 2 ml CH2Cl2 was added dropwise to this mixture over a one hour period. The solution was stirred at room temperature for one hour and then heated at reflux for 10 min. The reaction was then cooled to 10° C. and an additional equivalent of pyridine (161 μl) and ethyl chloroformate (240 μl) was added. After heating at reflux for 10 min., the reaction was left to stir at room temperature overnight. The reaction was then washed with water (3×100 ml) and the organic layer stripped then decalin (5 ml) and sulfur (0.063 g, 0.002 mole) were added and the mixture was heated to 170° C. This temperature was maintained for one hour. The reaction was then diluted with CH2Cl2 and extracted with a 12% HCl solution. The acidic layer was basified with solid K2CO3 and then extracted with CH2Cl2. After treating with brine and MgSO4, the CH2Cl2 was removed, and the residue was flash chromatographed (0.10% MeOH/100-90% CH2Cl2) to give 0.2 g of a (Formula (I) compound), 6-4-(N-propylacetamido)phenyl)-5-(4-pyridyl)-2,3-dihydroimidazo[2,1-b]thiazole (TLC: Rf =0.22 5% MeOH/95% CH2Cl2.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:17]([F:18])=[CH:16][CH:15]=[C:14]2[C:10]=1[C:11]([C:19](=[O:25])[C:20]([N:22]([CH3:24])[CH3:23])=[O:21])=[CH:12][NH:13]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(OC1C=C2C(C=CN2)=CC=1F)C1C=CC=CC=1>>[CH2:1]([O:8][C:9]1[CH:10]=[C:14]2[C:15]([C:11]([C:19](=[O:25])[C:20]([N:22]([CH3:23])[CH3:24])=[O:21])=[CH:12][NH:13]2)=[CH:16][C:17]=1[F:18])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CN(C)C(=O)C(=O)c1c[nH]c2ccc(F)c(OCc3ccccc3)c12
Agent: Fc1cc2cc[nH]c2cc1OCc1ccccc1
Product: CN(C)C(=O)C(=O)c1c[nH]c2cc(OCc3ccccc3)c(F)cc12
Yield: 82 %

Procedure:
Following the procedure used to prepare compound 1-6a (step 5, scheme 1), compound 4-3 gave compound 4-4 in 82% yield as a white solid. 1H NMR (CDCl3, 300 MHz) □ 3.06 (s, 3H), 3.08 (s, 3H), 5.14 (s, 2H), 6.94 (d, 1H, J=6.9), 7.32-7.47 (m, 5H), 7.82 (d, 1H, J=3.0), 8.05 (d, 1H, J=11.3), 8.96 (bs, 1H). APCI [M+1]: 386.2.
Reaction SMILES: I[CH2:2][CH:3]([CH3:5])[CH3:4].[C:6]([C:9]1[CH:18]=[C:13]([C:14]([O:16][CH3:17])=[O:15])[C:12]([OH:19])=[CH:11][CH:10]=1)(=[O:8])[CH3:7].C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[C:6]([C:9]1[CH:10]=[CH:11][C:12]([O:19][CH2:2][CH:3]([CH3:5])[CH3:4])=[C:13]([CH:18]=1)[C:14]([O:16][CH3:17])=[O:15])(=[O:8])[CH3:7]
Reactant: CC(C)CI
Reactant: COC(=O)c1cc(C(C)=O)ccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COC(=O)c1cc(C(C)=O)ccc1OCC(C)C
Temperature: 60 °C
Reaction time: 18 h

Procedure:
1-Iodo-2-methylpropane (13.35 ml, 117 mmol) was added to a mixture of methyl 5-acetylsalicylate (15 g, 77 mmol) and potassium carbonate (16 g, 117 mmol) in acetonitrile (500 ml), and the reaction stirred at 60° C. for 18 hours. TLC analysis showed starting material remaining, so additional 1-iodo-2-methylpropane (26.7 ml, 234 mmol) and potassium carbonate (16 g, 117 mmol) were added and the reaction stirred at 60° C. for a further 72 hours. TLC analysis showed starting material still remaining, so additional 1-iodo-2-methylpropane (13.35 ml, 117 mmol) and potassium carbonate (16 g, 117 mmol) were added and the reaction stirred at reflux for a further 3 hours. The cooled mixture was concentrated under reduced pressure and the residue partitioned between ethyl acetate and 1N sodium hydroxide solution. The phases were separated, the aqueous extracted with further ethyl acetate, and the combined organic solutions washed with brine, dried (MgSO4) and evaporated under reduced pressure to give the title compound as a brown oil, 8.3 g.
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[C:13]([O:16][CH3:17])(=[O:15])[CH3:14].[Cl:18][C:19]1[C:24]([F:25])=[CH:23][CH:22]=[CH:21][C:20]=1/[CH:26]=[N:27]/[S:28]([C:30]([CH3:33])([CH3:32])[CH3:31])=[O:29].[Cl-].[NH4+]>C1COCC1.CC(C)[O-].CC(C)[O-].CC(C)[O-].Cl[Ti+3].C(OCC)(=O)C>[CH3:17][O:16][C:13](=[O:15])[CH2:14][C@@H:26]([C:20]1[CH:21]=[CH:22][CH:23]=[C:24]([F:25])[C:19]=1[Cl:18])[NH:27][S@@:28]([C:30]([CH3:33])([CH3:32])[CH3:31])=[O:29]
Reactant: CC(C)(C)S(=O)/N=C/c1cccc(F)c1Cl
Reactant: COC(C)=O
Agent: Cl[Ti+3]
Agent: CC(C)[O-]
Agent: [Cl-]
Solvent: CC(C)NC(C)C
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COC(=O)C[C@H](N[S@](=O)C(C)(C)C)c1cccc(F)c1Cl
Temperature: -75 °C

Procedure:
To diisopropylamine (4.13 ml), dissolved in THF (200 ml), was slowly added dropwise 1.6 N butyllithium (17.55 ml) at 0° C., and then the mixture was stirred for thirty minutes. Subsequently, the mixture was cooled to −75° C. and methyl acetate (2.13 ml) dissolved in THF (5 ml) was added, and the mixture was stirred for a further thirty minutes. Then chlorotitanium triisopropoxide (56.15 ml, 1 molar in hexane) was added dropwise at the same temperature and the mixture was stirred again for thirty minutes. N-[1-(2-Chloro-3-fluorophenyl)meth-(E)-ylidene]-2-methylpropane-2-sulfinamide was dissolved in THF (10 ml) and added dropwise at −75° C., and the mixture was stirred at the same temperature for three hours. The mixture was poured onto cold saturated ammonium chloride solution and admixed with ethyl acetate, and stirred for fifteen minutes. The phase mixture was then clarified using kieselguhr, the organic phase was removed and the aqueous phase was extracted with ethyl acetate (2×50 ml). The combined organic phases were dried (Na2SO4), filtered and concentrated. The residue was purified by chromatography (silica gel 40-63 μm, ethyl acetate). This gave the product (4.1 g) with a de of 72% by NMR.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:7]([Cl:10])=[CH:6][C:3]=1[CH:4]=O.[C:11](#[N:15])[CH2:12][C:13]#[N:14].[OH-].[K+].O>C(O)C>[Cl:1][C:2]1[CH:9]=[CH:8][C:7]([Cl:10])=[CH:6][C:3]=1[CH:4]=[C:12]([C:11]#[N:15])[C:13]#[N:14]
Reactant: O=Cc1cc(Cl)ccc1Cl
Reactant: N#CCC#N
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: N#CC(C#N)=Cc1cc(Cl)ccc1Cl
Temperature: 25 °C
Reaction time: 2 h
Yield: 94.8 %

Procedure:
To a solution of 2,5-dichlorbenzaldehyde (4.0 g, 0.0228 mole) in ethanol (6 ml) was added malononitrile (1.52 g, 0.0228 mole), followed by 100 μL of 10% KOH/H2O. The mixture was stirred at room temperature for 2 hrs and then filtered to give the title compound (4.82 g) in 95% yield. 1H-NMR (400 MHz, d6-DMSO): δ ppm 8.66 (s, 1H), 8.07 (d, J=2.0 Hz, 1H), 7.74 (s, 1H), 7.74 (s, 1H). MS [m+H] calc'd for C10H4Cl2N2, 223.0, 224.8; found 223.0, 224.8.
Reaction SMILES: [CH3:1][C:2]1[S:14][C:5]2[C:6](=O)[C:7]3[S:8][C:9]([CH3:12])=[CH:10][C:11]=3[C:4]=2[CH:3]=1.C(O)COCCO.O.NN.[OH-].[K+]>O>[CH3:12][C:9]1[S:8][C:7]2[CH2:6][C:5]3[S:14][C:2]([CH3:1])=[CH:3][C:4]=3[C:11]=2[CH:10]=1
Reactant: Cc1cc2c(s1)C(=O)c1sc(C)cc1-2
Agent: NN
Agent: [K+]
Agent: [OH-]
Solvent: OCCOCCO
Solvent: O
Product: Cc1cc2c(s1)Cc1sc(C)cc1-2
Temperature: 80 °C
Reaction time: 1 h

Procedure:
A mixture of 45 g (205 mmol) of 2,5-dimethyl-7H-thieno[3′,2′:3,4]cyclopenta[1,2-b]thiophen-7-one, 600 mL of diethylene glycol and 70 mL of hydrazine monohydrate was placed into the bulb. The mixture was warmed to 80° C. and kept at this temperature in 1 h at stirring. Then the mixture was intensively refluxed in 1 h, cooled to r.t. treated with solution of 70 g KOH in 230 mL of water. The resulting mixture was carefully heated and the gas started to bubble. The mixture was refluxed for 2 hours, then it was cooled to 70-80° C. and poured into 3 L water. The precipitate was decanted, filtered, washed 7 times with 200-300 mL of water and dried. Yield 32 g (78%).
Reaction SMILES: C([O:9][C@H:10]1[C@@H:15]([O:16]C(=O)C2C=CC=CC=2)[C@H:14]([O:25]C(=O)C2C=CC=CC=2)[C@@H:13]([CH2:34][O:35]C(=O)C2C=CC=CC=2)[O:12][C@@H:11]1[O:44][C@H:45]1[C@H:50]([O:51][CH2:52][C:53]2[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=2)[C@@H:49]([CH2:59][O:60][C@H:61]2[O:93][C@H:92]([CH2:94][O:95]C(=O)C3C=CC=CC=3)[C@@H:82]([O:83]C(=O)C3C=CC=CC=3)[C@H:72]([O:73]C(=O)C3C=CC=CC=3)[C@@H:62]2[O:63]C(=O)C2C=CC=CC=2)[O:48][C@@H:47]([O:104][CH2:105][CH2:106][NH:107][C:108](=[O:117])[O:109][CH2:110][C:111]2[CH:116]=[CH:115][CH:114]=[CH:113][CH:112]=2)[C@@H:46]1[O:118]C(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1.O(C)[Na]>CO>[C@H:11]1([O:44][C@H:45]2[C@H:50]([O:51][CH2:52][C:53]3[CH:54]=[CH:55][CH:56]=[CH:57][CH:58]=3)[C@@H:49]([CH2:59][O:60][C@H:61]3[O:93][C@H:92]([CH2:94][OH:95])[C@@H:82]([OH:83])[C@H:72]([OH:73])[C@@H:62]3[OH:63])[O:48][C@@H:47]([O:104][CH2:105][CH2:106][NH:107][C:108](=[O:117])[O:109][CH2:110][C:111]3[CH:112]=[CH:113][CH:114]=[CH:115][CH:116]=3)[C@@H:46]2[OH:118])[O:12][C@H:13]([CH2:34][OH:35])[C@@H:14]([OH:25])[C@H:15]([OH:16])[C@@H:10]1[OH:9]
Reactant: O=C(NCCO[C@@H]1O[C@H](CO[C@H]2O[C@H](COC(=O)c3ccccc3)[C@@H](OC(=O)c3ccccc3)[C@H](OC(=O)c3ccccc3)[C@@H]2OC(=O)c2ccccc2)[C@@H](OCc2ccccc2)[C@H](O[C@H]2O[C@H](COC(=O)c3ccccc3)[C@@H](OC(=O)c3ccccc3)[C@H](OC(=O)c3ccccc3)[C@@H]2OC(=O)c2ccccc2)[C@H]1OC(=O)c1ccccc1)OCc1ccccc1
Agent: CO[Na]
Solvent: CO
Product: O=C(NCCO[C@@H]1O[C@H](CO[C@H]2O[C@H](CO)[C@@H](O)[C@H](O)[C@@H]2O)[C@@H](OCc2ccccc2)[C@H](O[C@H]2O[C@H](CO)[C@@H](O)[C@H](O)[C@@H]2O)[C@H]1O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a solution of benzyl (2-{[2,3,4,6-tetra-O-benzoyl-α-D-mannopyranosyl-(1→3)-[2,3,4,6-tetra-O-benzoyl-α-D-mannopyranosyl-(1→6)]-2-O-benzoyl-4-O-benzyl-β-D-glucopyranosyl]oxy}ethyl)carbamate (3.39 g, 1.984 mmol) in CH3OH (30 mL) was added NaOCH3 (0.4 mL, 0.2 mmol, 0.5 M in CH3OH). After stirring at rt for 24 hr, amberlite IR 120 (H) ion exchange resin (pre-washed with CH3OH 3×30 mL) was added to the reaction mixture. The resulting mixture was allowed to stir for additional 15 min. The resin was filtered off and washed with CH3OH (3×5 mL). The filtrate was concentrated to give the title compound. UPLC Method B: calculated for C35H49NO18 771.29, observed m/e: 772.42 [M+1]; Rt=2.51 min.