Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:7]2[C:8]([C:11]3[CH:16]=[CH:15][C:14]([NH:17][C:18]([C:20]4[N:21]([CH3:29])[C:22]5[C:27]([CH:28]=4)=[CH:26][CH:25]=[CH:24][CH:23]=5)=[O:19])=[C:13]([O:30][CH3:31])[CH:12]=3)=[CH:9][S:10][C:6]=2[C:5](/[CH:32]=[CH:33]/[CH2:34][OH:35])=[CH:4][N:3]=1.CO.[BH4-].[Na+].C(=O)([O-])[O-].[Na+].[Na+]>CN(C)C=O>[NH2:1][C:2]1[C:7]2[C:8]([C:11]3[CH:16]=[CH:15][C:14]([NH:17][C:18]([C:20]4[N:21]([CH3:29])[C:22]5[C:27]([CH:28]=4)=[CH:26][CH:25]=[CH:24][CH:23]=5)=[O:19])=[C:13]([O:30][CH3:31])[CH:12]=3)=[CH:9][S:10][C:6]=2[C:5]([CH2:32][CH2:33][CH2:34][OH:35])=[CH:4][N:3]=1
Reactant: COc1cc(-c2csc3c(/C=C/CO)cnc(N)c23)ccc1NC(=O)c1cc2ccccc2n1C
Agent: O=C([O-])[O-]
Agent: [BH4-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CO
Product: COc1cc(-c2csc3c(CCCO)cnc(N)c23)ccc1NC(=O)c1cc2ccccc2n1C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 19 %

Procedure:
N-(4-{4-Amino-7-[(1E)-3-hydroxyprop-1-enyl]thieno[3,2-c]pyridin-3-yl}-2-methoxyphenyl)-1-methyl-1H-indole-2-carboxamide (110 mg, 0.228 mmol), methanol (2 mL) and N,N-dimethylformamide (2 mL) was added sodium borohydride (26.9 mg, 0.684 mmol) under an atmosphere of nitrogen. Mixture stirred for 30 minutes at room temperature after which it was treated with 1M sodium carbonate (5 mL) and extracted with dichloromethane (3×5 mL). The organic layer was separated, dried over magnesium sulfate, and filtered, and the solvent was removed under reduced pressure. The product was purified via flash chromatography to furnish the title compound as a pale yellow powder (21.1 mg, 0.0434 mmol): LCMS (Thermoquest AQA single-quad MS, Genesis C18 column, 3 min particle size, 33×4.6 min; 70% 50 mM ammonium Acetate in Water to 95% Acetonitrile over 4.5 mM, 0.8 mL/min): MH+=487 RT=3.23 minutes; 1H NMR (DMSO-d6, 400 MHz) δ 9.51 (1H), 7.99 (1H), 7.70 (2H), 7.60 (1H), 7.55 (1H), 7.32-7.35 (2H), 7.21 (1H), 7.15 (1H), 7.07 (1H), 5.34 (2H), 4.04 (3H), 3.91 (3H), 3.47 (2H), 2.75 (2H), 1.83 (4H).
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:13]3[CH:14]=[C:15]([C:18]4[O:22][C:21]([NH2:23])=[N:20][N:19]=4)[CH:16]=[CH:17][C:12]=3[O:11][CH:10]=2)=[CH:5][CH:4]=1.[OH:24]OS([O-])=O.[K+]>O1CCCC1.O>[CH3:1][S:2]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:13]3[CH:14]=[C:15]([C:18]4[O:22][C:21]([NH2:23])=[N:20][N:19]=4)[CH:16]=[CH:17][C:12]=3[O:11][CH:10]=2)=[CH:5][CH:4]=1)=[O:24]
Reactant: O=S([O-])OO
Reactant: CSc1ccc(-c2coc3ccc(-c4nnc(N)o4)cc23)cc1
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: CS(=O)c1ccc(-c2coc3ccc(-c4nnc(N)o4)cc23)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 5.8 %

Procedure:
To a solution of 5-[3-[4-(methylthio)phenyl]-1-benzofuran-5-yl]-1,3,4-oxadiazol-2-amine (0.25 g, 0.77 mmol) in tetrahydrofuran (10 mL) was added a solution of oxone (registered trade mark, 0.24 g, 0.77 mmol) in water (3 mL) at 0° C., and the mixture was stirred at 0° C. for 30 min and at room temperature for 1 hr. Water was added to the reaction mixture, and the precipitate was collected by filtration and purified by preparative HPLC to give the title compound (15.2 mg, yield 6%) as colorless crystals.
Reaction SMILES: Cl.[CH2:2]([O:4][C:5]([C@@H:7]1[C@@H:11]([C:12](=[O:28])[NH:13][C:14]2[CH:19]=[CH:18][C:17]([N:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]3=[O:26])=[CH:16][C:15]=2[F:27])[CH2:10][NH:9][CH2:8]1)=[O:6])[CH3:3].C(N(CC)C(C)C)(C)C.[CH3:38][S:39](Cl)(=[O:41])=[O:40]>C(#N)C>[CH2:2]([O:4][C:5]([C@@H:7]1[C@@H:11]([C:12](=[O:28])[NH:13][C:14]2[CH:19]=[CH:18][C:17]([N:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]3=[O:26])=[CH:16][C:15]=2[F:27])[CH2:10][N:9]([S:39]([CH3:38])(=[O:41])=[O:40])[CH2:8]1)=[O:6])[CH3:3]
Reactant: CCOC(=O)[C@H]1CNC[C@@H]1C(=O)Nc1ccc(-n2ccccc2=O)cc1F
Reactant: CS(=O)(=O)Cl
Agent: Cl
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)[C@H]1CN(S(C)(=O)=O)C[C@@H]1C(=O)Nc1ccc(-n2ccccc2=O)cc1F
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Compound 28c (3.1 g; 8 mmol) is suspended in acetonitrile (20 ml) under addition of N,N-diisopropyl ethyl amine (3.24 ml; 19 mmol). Methanesulfonylchloride (1.3 g; 11 mmol) is added and the mixture is stirred for 18 h at 25° C. The reaction mixture is evaporated to dryness and purified by silica gel chromatography. Yield: 3.5 g (102.5%), ESI-MS: m/z=450 [M−H]−
Reaction SMILES: [CH3:1][O:2][C:3](=[O:14])[C:4]1[CH:9]=[C:8]([C:10]#[N:11])[C:7](O)=[N:6][C:5]=1[CH3:13].P(Cl)(Cl)(Cl)(Cl)[Cl:16]>O=P(Cl)(Cl)Cl>[Cl:16][C:7]1[C:8]([C:10]#[N:11])=[CH:9][C:4]([C:3]([O:2][CH3:1])=[O:14])=[C:5]([CH3:13])[N:6]=1
Reactant: COC(=O)c1cc(C#N)c(O)nc1C
Reactant: ClP(Cl)(Cl)(Cl)Cl
Solvent: O=P(Cl)(Cl)Cl
Product: COC(=O)c1cc(C#N)c(Cl)nc1C
Temperature: 110 °C
Yield: 137 %

Procedure:
A mixture of methyl-5-cyano-6-hydroxy-2-methylnicotinate (2.0 g, 10.41 mmol), POCl3 (40 mL) and PCl5 (1.08 g, 5.2 mmol) was heated to 110° C. for 24 h. The reaction mixture was concentrated under reduced pressure and quenched with ice-water. The organic product was extracted with EtOAc and the organic layer was washed with H2O and brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude product was purified by column chromatography (silica gel 60-120 mesh, eluent 10-15% EtOAc in petroleum ether) to afford methyl 6-chloro-5-cyano-2-methylnicotinate (1.5 g, yield 68%). 1H NMR (300 MHz, CDCl3) δ 8.48 (s, 1H), 3.96 (s, 3H), 2.90 (s, 3H).
Reaction SMILES: C(O[C:4]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1[NH:16][CH:17]1[CH2:21][CH2:20][CH2:19][CH2:18]1)=[CH:13][CH:12]=[CH:11][C:10]=2[O:22][CH3:23])=[O:5])C.[F:24][C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([N:31]=[C:32]=[O:33])[CH:26]=1>>[CH:17]1([N:16]2[C:15]3[C:14]4[CH:13]=[CH:12][CH:11]=[C:10]([O:22][CH3:23])[C:9]=4[N:8]=[CH:7][C:6]=3[C:4](=[O:5])[N:31]([C:27]3[CH:28]=[CH:29][CH:30]=[C:25]([F:24])[CH:26]=3)[C:32]2=[O:33])[CH2:18][CH2:19][CH2:20][CH2:21]1
Reactant: O=C=Nc1cccc(F)c1
Reactant: CCOC(=O)c1cnc2c(OC)cccc2c1NC1CCCC1
Product: COc1cccc2c1ncc1c(=O)n(-c3cccc(F)c3)c(=O)n(C3CCCC3)c12
Yield: 56.7 %

Procedure:
1-Cyclopentyl-3-(3-fluoro-phenyl)-7-methoxy-1H-pyrimido[5,4-c]quinoline-2,4-dione (23 mg) was prepared from 4-cyclopentylamino-8-methoxy-quinoline-3-carboxylic acid ethyl ester (0.1 mmol) and 1-fluoro-3-isocyanato-benzene (0.5 mmol) following general procedure C. LCMS: m/z 406 [M+1]+. 1H NMR (400 MHz, CDCl3): δ 9.45 (s, 1H), 7.84 (d, 1H), 7.62 (d, 1H), 7.51 (t, 1H), 7.20 (m, 1H), 7.18 (m, 1H), 7.12 (m, 1H), 7.09 (s, 1H), 5.06 (p, 1H), 4.15 (s, 3H), 2.42 (m, 2H), 2.06-2.18 (m, 4H), 1.26 (m, 2H) ppm.
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[N:8]=[CH:7][C:6]([OH:9])=[CH:5][CH:4]=1.[F:12][C:13]1[CH:14]=[C:15]([CH:18]=[C:19]([F:22])[C:20]=1F)[CH:16]=[O:17]>>[F:12][C:13]1[CH:14]=[C:15]([CH:18]=[C:19]([F:22])[C:20]=1[O:9][C:6]1[CH:7]=[N:8][C:3]([C:2]([F:1])([F:10])[F:11])=[CH:4][CH:5]=1)[CH:16]=[O:17]
Reactant: O=Cc1cc(F)c(F)c(F)c1
Reactant: Oc1ccc(C(F)(F)F)nc1
Product: O=Cc1cc(F)c(Oc2ccc(C(F)(F)F)nc2)c(F)c1

Procedure:
The title compound was prepared by a procedure similar to those described for D4 starting from 6-(trifluoromethyl)3-pyridinol and 3,4,5-trifluorobenzaldehyde.
Reaction SMILES: [CH2:1]([N:4]([CH2:10][CH2:11][CH3:12])[CH2:5][CH2:6][CH2:7][C:8]#[N:9])[CH2:2][CH3:3].[OH-].[Na+].[H][H]>[Ni].C(O)C>[CH2:10]([N:4]([CH2:1][CH2:2][CH3:3])[CH2:5][CH2:6][CH2:7][CH2:8][NH2:9])[CH2:11][CH3:12]
Reactant: [H][H]
Reactant: CCCN(CCC)CCCC#N
Agent: [Ni]
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCCN(CCC)CCCCN
Yield: 66.8 %

Procedure:
30 g (0.178 mol) of 4-dipropylaminobutyronitrile (3) was charged in a 500 ml three-necked flask, 150 ml of ethanol and 90 ml of a 1N sodium hydroxide aqueous solution was added thereto, and the mixture was stirred. 3.0 g of(10 wt %) the Raney nickel prepared in Example 1 was slowly added to the solution. After replacing the atmosphere in the flask with nitrogen and then with hydrogen, the mixture was allowed to react at room temperature for seven days with stirring while using a hydrogen balloon. After confirming that the raw material content had decreased to 1% or less by GC, the reaction solution was filtered through celite and washed with 400 ml of ethanol. After concentrating the filtrate, the residue was dissolved in 400 ml of chloroform and extracted with 200 ml of water. The chloroform layer was washed with 400 ml of a saturated sodium chloride aqueous solution, dried over anhydrous sodium sulfate, and concentrated, thereby obtaining 27.8 g of a colorless oily substance (yield: 90%). The resulting substance was distilled under reduced pressure to obtain 20.5 g of 4-dipropylaminobutylamine (4) (yield: 66.7%, GC: 99%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][CH:10]([C:12]2[CH:13]=[C:14]([C:29]([OH:31])=O)[CH:15]=[C:16]3[C:21]=2[O:20][C:19]([N:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)=[CH:18][C:17]3=[O:28])[CH3:11])[CH:5]=[CH:6][C:7]=1[F:8].[CH3:32][NH:33][CH2:34][CH2:35][OH:36]>>[Cl:1][C:2]1[CH:3]=[C:4]([NH:9][CH:10]([C:12]2[CH:13]=[C:14]([C:29]([N:33]([CH2:34][CH2:35][OH:36])[CH3:32])=[O:31])[CH:15]=[C:16]3[C:21]=2[O:20][C:19]([N:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)=[CH:18][C:17]3=[O:28])[CH3:11])[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: CNCCO
Reactant: CC(Nc1ccc(F)c(Cl)c1)c1cc(C(=O)O)cc2c(=O)cc(N3CCOCC3)oc12
Product: CC(Nc1ccc(F)c(Cl)c1)c1cc(C(=O)N(C)CCO)cc2c(=O)cc(N3CCOCC3)oc12
Yield: 70 %

Procedure:
8-(1-(3-chloro-4-fluorophenylamino)ethyl)-2-morpholino-4-oxo-4H-chromene-6-carboxylic acid (78 mg, 0.17 mmol) was reacted with 2-(methylamino)ethanol (0.017 mL, 0.21 mmol) using a procedure similar to the one described in Example 2.00 to give 8-(1-(3-chloro-4-fluorophenylamino)ethyl)-N-(2-hydroxyethyl)-N-methyl-2-morpholino-4-oxo-4H-chromene-6-carboxamide (60.0 mg, 68.2%) as a white solid. Mass Spectrum: M+H+ 504. NMR Spectrum: (DMSOd6) at 323° K: 1.51 (d, 3H), 2.82 (bs, 1.5H), 2.90 (bs, 1.5H), 3.42 (bs, 4H), 3.49-3.63 (m, 4H), 3.69-3.79 (m, 4H), 4.60 (bs, 1H), 4.92-5.01 (m, 1H), 5.56 (s, 1H), 6.37 (dd, 1H), 6.42 (ddd, 1H), 6.61 (dd, 1H), 7.02 (dd, 1H), 7.57 (d, 1H), 7.80 (d, 1H).
Reaction SMILES: [NH2:1][C:2]1[C:3](=[O:22])[N:4]([CH2:8][C:9]([NH:11][CH:12]([CH:19]([CH3:21])[CH3:20])[CH:13]([OH:18])[C:14]([F:17])([F:16])[F:15])=[O:10])[CH:5]=[CH:6][CH:7]=1.[C:23]1([N:29]=[C:30]=[O:31])[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.C(OCC)(=O)C>ClCCl>[O:22]=[C:3]1[C:2]([NH:1][C:30]([NH:29][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[O:31])=[CH:7][CH:6]=[CH:5][N:4]1[CH2:8][C:9]([NH:11][CH:12]([CH:19]([CH3:20])[CH3:21])[C:13](=[O:18])[C:14]([F:15])([F:16])[F:17])=[O:10]
Reactant: O=C=Nc1ccccc1
Reactant: CC(C)C(NC(=O)Cn1cccc(N)c1=O)C(O)C(F)(F)F
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CC(C)C(NC(=O)Cn1cccc(NC(=O)Nc2ccccc2)c1=O)C(=O)C(F)(F)F
Reaction time: 8 h
Yield: 92 %

Procedure:
2-(3-Amino-2-oxo-1,2-dihydro-1-pyridyl)-N-(3,3,3-trifluoro-2-hydroxy-1-isopropylpropyl)acetamide (0.43 g) and phenylisocyanate (0.175 g) were combined in dichloromethane (5 mL) and allowed to stir overnight. The mixture was poured into ethyl acetate, washed (saturated aqueous sodium bicarbonate, brine), evaporated, and purified using chromatography, eluting with ethyl acetate:dichloromethane (gradient, 0:100, 50:50, 100:0), to give the urea (0.54 g).
Reaction SMILES: [N+]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[N+:10]([O-:12])=[O:11])([O-])=O.[CH3:13][P:14]([O:18]CC)[O:15][CH2:16][CH3:17]>C(#N)C>[CH3:13][P:14]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[N+:10]([O-:12])=[O:11])(=[O:18])[O:15][CH2:16][CH3:17]
Reactant: CCOP(C)OCC
Reactant: O=[N+]([O-])c1ccccc1[N+](=O)[O-]
Solvent: CC#N
Product: CCOP(C)(=O)c1ccccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 1,2-dinitrobenzene (2.48 mmol), diethyl methylphosphonite (3.72 mmol) and acetonitrile (3 ml) is stirred at RT overnight. The reaction is concentrated to dryness, and the residue is purified by preparative thin layer chromatography (TLC) to yield ethyl P-methyl-2-nitrophenyl-phosphinate.
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[C:7]([C:9]2[N:13]=[C:12]([C:14]3[CH:19]=[C:18]([CH3:20])[N:17]=[C:16]([CH2:21][CH:22]([CH3:24])[CH3:23])[CH:15]=3)[O:11][N:10]=2)[CH:6]=[C:5]([CH3:25])[C:4]=1[OH:26])[CH3:2].[CH3:27][C:28]1([CH3:40])[O:33][CH2:32][CH:31]([CH2:34]OS(C)(=O)=O)[CH2:30][O:29]1>C(O)(C)C.[OH-].[Na+].CC(=O)OCC>[CH3:27][C:28]1([CH3:40])[O:33][CH2:32][CH:31]([CH2:34][O:26][C:4]2[C:5]([CH3:25])=[CH:6][C:7]([C:9]3[N:13]=[C:12]([C:14]4[CH:19]=[C:18]([CH3:20])[N:17]=[C:16]([CH2:21][CH:22]([CH3:23])[CH3:24])[CH:15]=4)[O:11][N:10]=3)=[CH:8][C:3]=2[CH2:1][CH3:2])[CH2:30][O:29]1
Reactant: CC1(C)OCC(COS(C)(=O)=O)CO1
Reactant: CCc1cc(-c2noc(-c3cc(C)nc(CC(C)C)c3)n2)cc(C)c1O
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CC(C)O
Product: CCc1cc(-c2noc(-c3cc(C)nc(CC(C)C)c3)n2)cc(C)c1OCC1COC(C)(C)OC1
Temperature: 60 °C
Reaction time: 24 h

Procedure:
To a solution of 2-ethyl-4-[5-(2-isobutyl-6-methyl-pyridin-4-yl)-[1,2,4]oxadiazol-3-yl]-6-methyl-phenol (200 mg, 0.569 mmol) in isopropanol (10 mL) and 3 N aq. NaOH (3 mL), methanesulfonic acid 2,2-dimethyl-[1,3]dioxan-5-ylmethyl ester (290 mg, 1.71 mmol) is added. The mixture is stirred at 60° C. for 24 h. The mixture is diluted with EA and washed with sat. aq. NaHCO3 solution. The org. extract is dried over MgSO4, filtered and evaporated. The crude product is purified by chromatography on prep. TLC plates with heptane:EA 3:1 to give 4-{3-[4-(2,2-dimethyl-[1,3]dioxan-5-ylmethoxy)-3-ethyl-5-methyl-phenyl]-[1,2,4]oxadiazol-5-yl}-2-isobutyl-6-methyl-pyridine which is dissolved in THF (5 mL), water (0.5 mL) and TFA (0.25 mL). The solution is stirred at rt for 1 h before the solvent is evaporated. The remaining residue is separated by chromatography on prep. TLC plates with DCM containing 10% of MeOH to give 2-{2-ethyl-4-[5-(2-isobutyl-6-methyl-pyridin-4-yl)-[1,2,4]oxadiazol-3-yl]-6-methyl-phenoxymethyl}-propane-1,3-diol (20 mg) as a colourless oil; LC-MS: tR=0.86 min, [M+1]+=440.12.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([Cl:17])[CH:12]=2)=[CH:4][C:5]([C:8]([OH:10])=O)=[N:6][CH:7]=1.[NH2:18][C:19]([CH3:23])([CH3:22])[CH2:20][OH:21]>>[OH:21][CH2:20][C:19]([NH:18][C:8]([C:5]1[CH:4]=[C:3]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([Cl:17])[CH:12]=2)[C:2]([Cl:1])=[CH:7][N:6]=1)=[O:10])([CH3:23])[CH3:22]
Reactant: O=C(O)c1cc(-c2cccc(Cl)c2)c(Cl)cn1
Reactant: CC(C)(N)CO
Product: CC(C)(CO)NC(=O)c1cc(-c2cccc(Cl)c2)c(Cl)cn1

Procedure:
The title compound was synthesized in analogy to Example 1, using 5-chloro-4-(3-chlorophenyl)-pyridine-2-carboxylic acid and 2-amino-2-methyl-1-propanol (CAN 124-68-5) as starting materials and isolated (13 mg, 38%) as colorless oil; MS (ESI, m/z): 339.0, 341.0 (MH+).
Reaction SMILES: [CH2:1]([C@:3]12[CH2:11][CH2:10][C:9]3[C:12]4[CH:13]=[CH:14][C:15]([O:20][CH3:21])=[CH:16][C:17]=4[CH2:18][CH2:19][C:8]=3[C@@H:7]1[CH2:6][CH2:5][C:4]2=[O:22])[CH3:2].[BH4-].[Na+].C(O)(=O)C>CO>[CH2:1]([C@:3]12[CH2:11][CH2:10][C:9]3[C:12]4[CH:13]=[CH:14][C:15]([O:20][CH3:21])=[CH:16][C:17]=4[CH2:18][CH2:19][C:8]=3[C@@H:7]1[CH2:6][CH2:5][C@@H:4]2[OH:22])[CH3:2]
Reactant: CC[C@]12CCC3=C(CCc4cc(OC)ccc43)[C@@H]1CCC2=O
Agent: [BH4-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: CC[C@]12CCC3=C(CCc4cc(OC)ccc43)[C@@H]1CC[C@@H]2O

Procedure:
Add 13β-ethyl-3-methoxygona-1,3,5(10),8-tetraen-17-one (16.8 g.) to a solution of sodium borohydride (6 g.) in methanol (500 cc.), swirl the mixture which boils spontaneously. When all the material has been added and the reaction has subsided, add acetic acid (15 cc.). Reduce the mixture in volume by evaporation of most of the solvent, add water and extract the product with ether. Evaporate the washed and dried extracts to obtain crude crystalline product (16.8 g.), m.p. 102°-5° on recrystallization from acetonitrile.
Reaction SMILES: C1(C(C2C=CC=CC=2)[N:8]2[CH2:11][CH:10]([NH:12][C:13](=[O:19])[O:14][C:15]([CH3:18])([CH3:17])[CH3:16])[CH2:9]2)C=CC=CC=1.Cl.O1CCOCC1.[H][H]>CO>[NH:8]1[CH2:11][CH:10]([NH:12][C:13](=[O:19])[O:14][C:15]([CH3:17])([CH3:16])[CH3:18])[CH2:9]1
Reactant: [H][H]
Reactant: CC(C)(C)OC(=O)NC1CN(C(c2ccccc2)c2ccccc2)C1
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: CC(C)(C)OC(=O)NC1CNC1

Procedure:
A solution of 1,1-dimethylethyl [1-(diphenylmethyl)-3-azetidinyl]carbamate in MeOH (10 mL) was treated with of 4.0 N HCl/dioxane (1 mL) and then reacted overnight with hydrogen gas at 50 psi. The reaction mixture was then filtered through a pad of Celite, concentrated and the crude residue was used without further purification.
Reaction SMILES: [C:1](Cl)(=O)[C:2]([Cl:4])=[O:3].[Cl:7][S:8]([C:11]1[CH:19]=[CH:18]C(C(O)=O)=[CH:13][CH:12]=1)(=[O:10])=[O:9].CN(C=O)C>C(Cl)Cl>[Cl:7][S:8]([C:11]1[CH:19]=[CH:18][C:1]([C:2]([Cl:4])=[O:3])=[CH:13][CH:12]=1)(=[O:10])=[O:9]
Reactant: O=C(Cl)C(=O)Cl
Reactant: O=C(O)c1ccc(S(=O)(=O)Cl)cc1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=C(Cl)c1ccc(S(=O)(=O)Cl)cc1
Reaction time: 60 h

Procedure:
Oxalyl chloride (1.179 g, 9.29 mmol) is added to a suspension of 4-chlorosulfonyl-benzoic acid (1.025 g, 4.64 mmol) in 10 mL of DCM at RT. A drop of DMF is added. Stirring is continued for 2.5 days. A pale yellow solution results. The reaction mixture is concentrated under vacuum. Toluene is added and the mixture is concentrated under vacuum again. This last process is repeated twice more, and the mixture is finally dried under vacuum to give 4-chlorosulfonyl-benzoyl chloride as a pale yellow solid.
Reaction SMILES: [CH3:1][C:2]1[CH:13]=[CH:12][CH:11]=[CH:10][C:3]=1[CH2:4][C:5](=[CH2:9])[C:6]([OH:8])=[O:7].[C:14]([OH:17])(=[S:16])[CH3:15]>>[C:14]([S:16][CH2:9][CH:5]([CH2:4][C:3]1[CH:10]=[CH:11][CH:12]=[CH:13][C:2]=1[CH3:1])[C:6]([OH:8])=[O:7])(=[O:17])[CH3:15]
Reactant: CC(O)=S
Reactant: C=C(Cc1ccccc1C)C(=O)O
Product: CC(=O)SCC(Cc1ccccc1C)C(=O)O
Reaction time: 72 h

Procedure:
To the acid from Step 3 (11.4 g, 65 mmol) add thioacetic acid (9.8 g, 129 mmol). After 3 days, concentrate, treat with toluene, and concentrate again to obtain a solid. Recrystallize from CH2Cl2 :hexane to obtain the title compound, m.p. 63°-70°.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[CH:8]=[C:9]([C:11]([N:13]3[CH2:17][CH2:16][C@@H:15]([OH:18])[CH2:14]3)=[O:12])[S:10][C:3]=12.[CH3:19][NH:20][C:21]([C:23]1[C:24]2[CH:33]=[CH:32][C:31]([OH:34])=[CH:30][C:25]=2[S:26][C:27]=1[CH2:28][CH3:29])=[O:22].C([O-])([O-])=O.[Cs+].[Cs+]>>[CH3:19][NH:20][C:21]([C:23]1[C:24]2[CH:33]=[CH:32][C:31]([O:34][C:2]3[CH:7]=[CH:6][N:5]=[C:4]4[CH:8]=[C:9]([C:11]([N:13]5[CH2:17][CH2:16][C@@H:15]([OH:18])[CH2:14]5)=[O:12])[S:10][C:3]=34)=[CH:30][C:25]=2[S:26][C:27]=1[CH2:28][CH3:29])=[O:22]
Reactant: O=C(c1cc2nccc(Cl)c2s1)N1CC[C@@H](O)C1
Reactant: CCc1sc2cc(O)ccc2c1C(=O)NC
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: CCc1sc2cc(Oc3ccnc4cc(C(=O)N5CC[C@@H](O)C5)sc34)ccc2c1C(=O)NC
Yield: 63.1 %

Procedure:
This material was prepared by reacting 7-chloro-2-{[(3R)-3-hydroxypyrrolidin-1-yl]carbonyl}thieno[3,2-b]pyridine 4a (71 mg, 0.25 mmole) with 2-ethyl-6-hydroxybenzo[b]thiophene-3-carboxylic acid methylamide 134d (71 mg, 0.30 mmole) and Cs2CO3 (244 mg, 0.75 mmole) in a manner analogous to that described for example 1 to give a light brown solid (76 mg, 63%). 1H NMR (DMSO-d6, 300 MHz), δ 8.58 (1H, d, J=5.56 Hz), 8.32 (1H, q, J=4.38 Hz), 8.07, 8.00 (1H, s), 7.98 (1H, d, J=2.27 Hz), 7.80 (1H, d, J=8.84 Hz), 7.33 (1H, dd, J=2.27, 8.59 Hz), 6.75 (1H, d, J=5.31 Hz), 4.38, 4.33 (1H, br s), 4.01–3.93 (2H, m), 3.67–3.45 (3H, m), 3.00 (2H, t, J=7.49 Hz), 2.83 (3H, d, J=4.55 Hz), 2.06–1.80 (2H, m), 1.28 (3H, t, J=7.58 Hz).
Reaction SMILES: C[O:2][C:3]([C:5]1[S:6][C:7]([C:11]([CH3:14])([CH3:13])[CH3:12])=[CH:8][C:9]=1[NH2:10])=O.C(O)(=O)C.[CH:19](N)=[NH:20]>C(OCCO)C>[C:11]([C:7]1[S:6][C:5]2[C:3]([OH:2])=[N:20][CH:19]=[N:10][C:9]=2[CH:8]=1)([CH3:14])([CH3:13])[CH3:12]
Reactant: COC(=O)c1sc(C(C)(C)C)cc1N
Reactant: N=CN
Solvent: CC(=O)O
Solvent: CCOCCO
Product: CC(C)(C)c1cc2ncnc(O)c2s1
Yield: 99.3 %

Procedure:
3-Amino-5-tert-butyl-thiophene-2-carboxylic acid methyl ester (1.00 g, 4.69 mmol, 1 eq.), formamidine acetate (1.46 g, 4.69 mmol, 3 eq.) and 2-ethoxyethanol (10 mL) were refluxed under nitrogen for 4 hours. Purified over silica gel in 3:1 to 1:1 Hexanes/ethyl acetate to 100% ethyl acetate to obtain 970 mg of yellow solids as product. LCMS detects (M+H)+=209.
Reaction SMILES: [C:1]([O:9][CH:10]1[C:18]2[C:13](=[CH:14][CH:15]=[C:16](C)[CH:17]=2)[N:12]([CH2:20][CH3:21])[C:11]1=[O:22])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:23](N1C2C(=CC=CC=2)C(=O)C1=O)[CH2:24][CH:25](C)C>>[C:1]([O:9][CH:10]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[N:12]([CH2:20][CH2:21][CH:24]([CH3:25])[CH3:23])[C:11]1=[O:22])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCN1C(=O)C(OC(=O)c2ccccc2)c2cc(C)ccc21
Reactant: CC(C)CCN1C(=O)C(=O)c2ccccc21
Product: CC(C)CCN1C(=O)C(OC(=O)c2ccccc2)c2ccccc21

Procedure:
Was made in an analogous fashion to 1-ethyl-5-methyl-2-oxoindolin-3-yl benzoate using 1-isopentylindoline-2,3-dione. 1H-NMR δ 8.10 (d, 2H), 7.59 (t, 1H), 7.46 (dd, 2H), 7.61-7.34 (m, 2H), 7.06 (t, 1H), 6.88 (d, 1H), 6.18 (s, 1H), 3.78 (m, 2H), 1.77-1.60 (m, 3H), 1.02 (dd, 6H).
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][CH2:5][C:6]([O-:8])=[O:7].[Na+].[CH2:10](Br)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>CC(C)=O.[Br-].C([N+](CCCC)(CCCC)CCCC)CCC>[OH:1][CH2:2][CH2:3][CH2:4][CH2:5][C:6]([O:8][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:7]
Reactant: BrCc1ccccc1
Reactant: O=C([O-])CCCCO
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [Na+]
Solvent: CC(C)=O
Product: O=C(CCCCO)OCc1ccccc1
Temperature: 45 °C
Yield: 176.2 %

Procedure:
To a suspension of 569 mg (4.06 mmol) of sodium 5-hydroxypentanoate 69 in 3 mL of acetone was added 1.39 g (0.97 mL, 8.11 mmol, 2.0 equiv) of benzyl bromide and 65 mg (0.203 mmol, 0.05 equiv) of tetrabutylammonium bromide. The mixture was heated at 45° C. for 24 hours, cooled, and concentrated. The residue was dissolved in 200 mL of ethyl acetate, washed with 50 mL portions of 1N aqueous sodium bisulfate, saturated aqueous sodium bicarbonate and saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate and concentrated to give 1.49 g of a pale yellow oil. Purification by MPLC (Lobar C-column, 45% ethyl acetate/hexane) have 641 mg (76%) of the title compound as an oil: 1H NMR (300 MHz, CDCl3) δ7.38-7.26 (m, 5H), 5.12 (s, 2H), 3.64 (t, 2H, J=6.3 Hz), 2.41 (t, 2H, J=7.2 Hz), 1.80-1.71 (m, 2H), 1.64-1.54 (m, 3H).
Reaction SMILES: O.[NH2:2][NH2:3].[CH2:4]([NH:11][C:12]1[CH:17]=[CH:16][C:15]([C:18](=O)[CH:19]([CH3:24])[CH2:20][C:21](O)=[O:22])=[CH:14][C:13]=1[OH:26])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1>C(O)(=O)C>[CH2:4]([NH:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[CH:19]([CH3:24])[CH2:20][C:21](=[O:22])[NH:2][N:3]=2)=[CH:14][C:13]=1[OH:26])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: CC(CC(=O)O)C(=O)c1ccc(NCc2ccccc2)c(O)c1
Reactant: NN
Solvent: O
Solvent: CC(=O)O
Product: CC1CC(=O)NN=C1c1ccc(NCc2ccccc2)c(O)c1
Temperature: 110 °C
Reaction time: 1.5 h

Procedure:
While cooling with the ice bath 69.9 ml (1396 mmol) hydrazine hydrate are added dropwise to 220 ml glacial acetic acid, then 54.7 g (175 mmol) 4-(4-benzylamino-3-hydroxy-phenyl)-3-methyl-4-oxo-butyric acid are added and the mixture is stirred for 1.5 h at 110° C. Then the mixture is cooled somewhat and poured onto ice water, the precipitated product is suction filtered, washed first with copious amounts of water, then with a little acetone and then dried in the vacuum dryer.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9]Cl)=[CH:5][CH:4]=1.[I-:11].[Na+].[CH2:13]([N:17]([CH2:22][CH2:23][CH2:24][CH3:25])[CH2:18][CH2:19][CH2:20][CH3:21])[CH2:14][CH2:15][CH3:16]>CC(C)=O>[I-:11].[I:11][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][N+:17]([CH2:13][CH2:14][CH2:15][CH3:16])([CH2:18][CH2:19][CH2:20][CH3:21])[CH2:22][CH2:23][CH2:24][CH3:25])=[CH:5][CH:4]=1
Reactant: CCCCN(CCCC)CCCC
Reactant: ClCc1ccc(CCl)cc1
Agent: [I-]
Agent: [Na+]
Solvent: CC(C)=O
Product: CCCC[N+](CCCC)(CCCC)Cc1ccc(CI)cc1
Temperature: 25 °C

Procedure:
To a mixture of α,α'-dichloro-p-xylene (50 g, 28.6 mmol) and sodium iodide (8.6 g, 57 mmol) in acetone (100 mL) was added tri-n-butylamine (3.7 g, 20.0 mmol). The reaction mixture was stirred at room temperature under argon for several days after which time TLC examination showed completion of the reaction. The reaction mixture was filtered and the solvent was removed under reduced pressure to give an oily residue. The residue was washed with pentane several times and dried to give a yellow solid. The product was used without further purification.