Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [ClH:1].[NH:2]1[CH:6]=[C:5]([CH2:7][C:8]([OH:10])=[O:9])[N:4]=[CH:3]1.Cl.[CH:12](OC)(OC)OC>CO>[ClH:1].[NH:2]1[CH:6]=[C:5]([CH2:7][C:8]([O:10][CH3:12])=[O:9])[N:4]=[CH:3]1
Reactant: O=C(O)Cc1c[nH]cn1
Reactant: COC(OC)OC
Agent: Cl
Solvent: CO
Product: COC(=O)Cc1c[nH]cn1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 4-imidazoleacetic acid hydrochloride (4.0 g, 24.6 mmol) in MeOH (100 mL) was saturated with HCl gas at ambient temperature. Trimethyl orthoformate (10 mL) was added, and the mixture was stirred at ambient temperature overnight then concentrated to dryness in vacuo. The solid was redissolved in MeOH (100 mL) and the above procedure repeated to yield the titled compound as a white solid.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([C:9]2[N:13]([CH3:14])[N:12]=[CH:11][CH:10]=2)[CH:3]=1.Br[CH2:16][C@H:17]([NH:19][C:20](=[O:26])[O:21][C:22]([CH3:25])([CH3:24])[CH3:23])[CH3:18].C(=O)([O-])[O-].[Cs+].[Cs+]>CC(C)=O>[NH2:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:18][C@H:17]([NH:19][C:20](=[O:26])[O:21][C:22]([CH3:23])([CH3:25])[CH3:24])[CH3:16])=[C:4]([C:9]2[N:13]([CH3:14])[N:12]=[CH:11][CH:10]=2)[CH:3]=1
Reactant: C[C@H](CBr)NC(=O)OC(C)(C)C
Reactant: Cn1nccc1-c1cc(N)ccc1O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(C)=O
Product: C[C@H](COc1ccc(N)cc1-c1ccnn1C)NC(=O)OC(C)(C)C
Temperature: 100 °C
Yield: 53.3 %

Procedure:
4-amino-2-(1-methyl-1H-pyrazol-5-yl)phenol (500 mg, 2643 μmol), (R)-tert-butyl 1-bromopropan-2-ylcarbamate (755 mg, 3171 μmol) and cesium carbonate (1205 mg, 3700 μmol) were weighed into a vial with anhydrous acetone (3.0 mL). The reaction was heated in a microwave at 100° C. for an hour. After this time, the crude LC/MS showed that the reaction was nearly complete. Thus, the solvent was evaporated and the resulting material was extracted (3 mL each of H2O and CH2Cl2). The aqueous layer was extracted again with CH2Cl2 (3 mL). The combined organic layer was dried over MgSO4, filtered, and concentrated. The product was purified by column chromatography (0, 20, 50, 70, 100% EtOAc/Hexanes) to yield tert-butyl (R)-1-(4-amino-2-(1-methyl-1H-pyrazol-5-yl)phenoxy)propan-2-ylcarbamate (487 mg, 1.41 mmol, 50.7%) as a light brown colored oil. LCMS m/z 347.1 (M+H); 1H NMR (400 MHz, MeOH-d4) δ ppm 0.92 (d, J=6.57 Hz, 3 H), 1.32 (s, 9 H), 3.60 (s, 3 H), 3.69-3.76 (m, 1 H), 3.79-3.94 (m, 2 H), 6.13 (d, J=1.77 Hz, 1 H), 6.57 (d, J=2.78 Hz, 1 H), 6.72 (dd, J=8.59, 2.78 Hz, 1 H), 6.83 (d, J=8.84 Hz, 1 H), 7.36 (d, J=2.02 Hz, 1 H).
Reaction SMILES: [CH3:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([C:12]([F:15])([F:14])[F:13])=[CH:9][CH:10]=2)[C:5](=[O:16])O[C:3]=1[C:17]([OH:19])=[O:18].[CH2:20]([NH2:23])[CH2:21][CH3:22].Cl>CCO.O.S(=O)(=O)(O)O>[CH3:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([C:12]([F:15])([F:14])[F:13])=[CH:9][CH:10]=2)[C:5](=[O:16])[N:23]([CH2:20][CH2:21][CH3:22])[C:3]=1[C:17]([OH:19])=[O:18]
Reactant: Cc1c(C(=O)O)oc(=O)c2cc(C(F)(F)F)ccc12
Reactant: CCCN
Agent: Cl
Agent: O=S(=O)(O)O
Solvent: CCO
Solvent: O
Product: CCCn1c(C(=O)O)c(C)c2ccc(C(F)(F)F)cc2c1=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 88.4 %

Procedure:
A solution of 350 mg (1.3 mmol) 4-methyl-1-oxo-7-(trifluoromethyl)-1H-isochromene-3-carboxylic acid in EtOH (15 ml) was cooled to 0° C. and treated dropwise with a solution of 1.1 ml (12.9 mmol) n-propylamine in EtOH (2 ml) at this temperature. The RS was then stirred at RT for 2 h followed by concentration in vacuo. The residue obtained was diluted with water and acidified with 2M hydrochloric acid to pH˜2 while cooling (ice-water-bath). Afterwards the RS was extracted with a MeOH/EtOAc mixture (1:9 v/v, 100 ml). The organic layer was washed with water (30 ml) and brine (20 ml), dried over Na2SO4 and concentrated in vacuo. This residue obtained was diluted with EtOH (15 ml) and 1 ml conc. sulfuric acid was added slowly at 0° C. The RS was the heated at 80° C. for 2 h. After cooling to RT, the RS was concentrated in vacuo. The residue obtained was diluted with water and extracted with a MeOH/EtOAc mixture (1:9 v/v, 100 ml). The organic layer was washed with water (30 ml) and brine (20 ml), dried over Na2SO4 and concentrated in vacuo to give 360 mg (1.1 mmo, 89%) 4-methyl-1-oxo-2-propyl-7-(trifluoromethyl)-1,2-dihydroisoquinoline-3-carboxylic acid, which was used in the next step without further purification.
Reaction SMILES: O.[OH-].[Li+].[C:4]([O:8][C:9]([N:11]([CH2:13][C:14]1[N:15]([CH2:27][C:28]2[CH:33]=[CH:32][C:31]([C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=3[C:40]([C:42]([O:44]C)=[O:43])=[O:41])=[CH:30][CH:29]=2)[C:16]([C:23]([O:25]C)=[O:24])=[C:17]([C:19]([OH:22])([CH3:21])[CH3:20])[N:18]=1)[CH3:12])=[O:10])([CH3:7])([CH3:6])[CH3:5]>O.O1CCOCC1>[C:4]([O:8][C:9]([N:11]([CH2:13][C:14]1[N:15]([CH2:27][C:28]2[CH:33]=[CH:32][C:31]([C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=3[C:40]([C:42]([OH:44])=[O:43])=[O:41])=[CH:30][CH:29]=2)[C:16]([C:23]([OH:25])=[O:24])=[C:17]([C:19]([OH:22])([CH3:21])[CH3:20])[N:18]=1)[CH3:12])=[O:10])([CH3:5])([CH3:6])[CH3:7]
Reactant: COC(=O)C(=O)c1ccccc1-c1ccc(Cn2c(CN(C)C(=O)OC(C)(C)C)nc(C(C)(C)O)c2C(=O)OC)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: CN(Cc1nc(C(C)(C)O)c(C(=O)O)n1Cc1ccc(-c2ccccc2C(=O)C(=O)O)cc1)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 93.7 %

Procedure:
A solution of 81 mg of lithium hydroxide monohydrate dissolved in 5 ml of water was added to a solution of 380 mg of methyl 2-(N-t-butoxycarbonyl-N-methylaminomethyl)-4-(1-hydroxy-1-methylethyl)-1-[(2'-methoxalylbiphenyl-4-yl)methyl]imidazole-5-carboxylate [prepared as described in step (a) above] dissolved in 5 mg of dioxane, and the resulting mixture was stirred at room temperature for 2.5 hours. At the end of this time, the dioxane was removed by distillation under reduced pressure, and then 1.93 ml of 1N aqueous hydrochloric acid was added to the residue. The material which precipitated was collected by filtration to give 339 mg of the title compound as an amorphous powder.
Reaction SMILES: [H-].[Na+].[CH2:3]([N:10]1[C:22]2[CH:21]=[CH:20][CH:19]=[C:18]([OH:23])[C:17]=2[C:16]2[C:11]1=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.Cl.Cl[CH2:26][CH2:27][NH2:28]>CCCCC.CN(C=O)C>[CH2:3]([N:10]1[C:22]2[CH:21]=[CH:20][CH:19]=[C:18]([O:23][CH2:26][CH2:27][NH2:28])[C:17]=2[C:16]2[C:11]1=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: Oc1cccc2c1c1ccccc1n2Cc1ccccc1
Reactant: NCCCl
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCCCC
Product: NCCOc1cccc2c1c1ccccc1n2Cc1ccccc1
Reaction time: 0.08 h
Yield: 71.6 %

Procedure:
Sodium hydride (60% in oil; 0.934 g, 23.36 mmol) is washed three times with pentane. DMF (5 mL) is added, followed by 9-benzyl-9H-Carbazol-4-ol (1.52 g, 5.56 mmol) dissolved in DMF (10 mL) added over 10 min. The mixture is stirred an additional 5 min and then cooled in an ice-water bath. A solution of 2-chloroethylamine hydrochloride (1.29 g, 11.12 mmol) dissolved in DMF (5 mL) is added dropwise over about 5 min. The cooling bath is removed and the mixture is allowed to stir at room temperature over the weekend. Aq. sodium bicarbonate is added and the mixture partitioned between EtOAc, brine, and aq. sodium bicarbonate. The organic layers are dried over MgSO4 and taken to dryness. The residue is chromatographed on silica gel (120 mL) using CH3OH—CH2Cl2 (4/96) to give 1.26 g (72%) of the title compound as a white solid. An aliquot is crystallized from CH2Cl2-EtOAc-hexane; IR (drift) 1597, 1587, 1458, 1441, 1342, 1329, 1269, 1156, 1145, 1110, 1045, 860, 785, 749, 726 cm−1; 1H NMR (CDCl3) δ3.30, 4.29, 5.51, 6.70, 7.00, 7.12, 7.2-7.4, 8.34. Anal. Calcd for C21H20N2O: C, 79.72; H, 6.37; N, 8.85. Found: C, 78.70; H, 6.41; N, 8.70.
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16]Cl.[OH-].[Na+]>S([O-])(O)(=O)=O.C([N+](CCCC)(CCCC)CCCC)CCC>[Cl:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][O:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: ClCCCCCCCCCl
Reactant: Oc1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=S(=O)([O-])O
Agent: [Na+]
Product: ClCCCCCCCCOc1ccccc1
Yield: 72 %

Procedure:
A two phase mixture of phenol (5 g, 53 mmol), 1,8-dichlorooctane (25 ml), tetrabutylammonium hydrogensulphate (0.3 g, 1 mmol), and sodium hydroxide solution (25 ml, 6M) was refluxed for 16 h. The organic layer was separated, washed with water (2×50 ml), dried (MgSO4), and concentrated in vacuo. The residues were columned (silica; eluant: dichloromethane/petrol 1:10) to give the title compound as a colourless mobile oil (9.20 g, 72%). bp 50° C. at 4.6 mm Hg. NMR (CDCl3) δ=1.27-1.52 (8H, m), 1.70-1.81 (4H, m), 3.53 (2H,t,J=6 Hz), 3.93 (2H,t,J=6 Hz), 6.83-6.93 (3H,m), 7.00-7.10 (2H,m). IR (liq, cm-1) 2992, 2937, 2858, 1601, 1587 MS(EI) m/e=240 (M+, 1%)
Reaction SMILES: O[CH2:2][N:3]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4]1.S(Cl)([Cl:13])=O>C(Cl)(Cl)Cl>[Cl:13][CH2:2][N:3]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4]1
Reactant: O=S(Cl)Cl
Reactant: O=[N+]([O-])c1ccn(CO)c1
Solvent: ClC(Cl)Cl
Product: O=[N+]([O-])c1ccn(CCl)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
The obtained 1-hydroxymethyl-3-nitro-1H-pyrole was dissolved to 3 ml of chloroform, and 3 ml of thionyl chloride was added, followed by stirring at room temperature for 1 hour. After the reaction mixture was cooled to 0° C., it was poured into ice-water. The mixture was extracted with ethyl acetate. The organic layer was washed with saturated aqueous solution of sodium hydrogen carbonate, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to obtain 620 mg of 1-chloromethyl-3-nitro-1H-pyrole.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:15](=O)[C:14]2[C:9](=[C:10]([Cl:17])[CH:11]=[CH:12][CH:13]=2)[N:8]([CH2:18][C:19]2[CH:24]=[CH:23][C:22]([N:25]3[CH:29]=[CH:28][CH:27]=[N:26]3)=[CH:21][CH:20]=2)[N:7]=1)=[O:5])[CH3:2].COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:39])=CC=1>C1(C)C=CC=CC=1>[CH2:1]([O:3][C:4]([C:6]1[C:15](=[S:39])[C:14]2[C:9](=[C:10]([Cl:17])[CH:11]=[CH:12][CH:13]=2)[N:8]([CH2:18][C:19]2[CH:24]=[CH:23][C:22]([N:25]3[CH:29]=[CH:28][CH:27]=[N:26]3)=[CH:21][CH:20]=2)[N:7]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1nn(Cc2ccc(-n3cccn3)cc2)c2c(Cl)cccc2c1=O
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: Cc1ccccc1
Product: CCOC(=O)c1nn(Cc2ccc(-n3cccn3)cc2)c2c(Cl)cccc2c1=S
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
Ethyl-8-chloro-4-oxo-1-[4-(1H-pyrazol-1-yl)benzyl]-1,4-dihydrocinnoline-3-carboxylate (627 mg, 1.53 mmol) was dissolved in toluene (7 mL), treated with Lawesson's Reagent (434 mg, 1.074 mmol, 0.7 equiv) and placed into an oil bath preheated at 105° C. for 5 minutes. The mixture was cooled to ambient temperature, concentrated in vacuo and the residue was purified by silica gel gradient chromatography (100:0 to 60:40; hexanes:ethyl acetate), providing the titled compound.
Reaction SMILES: C(OC([NH:8][CH2:9][CH2:10][N:11]1[C:19]2[C:14](=[C:15]([CH3:20])[CH:16]=[CH:17][CH:18]=2)[CH:13]=[C:12]1[C:21]([O:23][CH2:24][CH3:25])=[O:22])=O)(C)(C)C.FC(F)(F)C(O)=O.N.[C:34]1([CH3:44])[CH:39]=[CH:38][C:37]([S:40](Cl)(=[O:42])=[O:41])=[CH:36][CH:35]=1>ClCCl>[CH3:44][C:34]1[CH:39]=[CH:38][C:37]([S:40]([NH:8][CH2:9][CH2:10][N:11]2[C:19]3[C:14](=[C:15]([CH3:20])[CH:16]=[CH:17][CH:18]=3)[CH:13]=[C:12]2[C:21]([O:23][CH2:24][CH3:25])=[O:22])(=[O:42])=[O:41])=[CH:36][CH:35]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CCOC(=O)c1cc2c(C)cccc2n1CCNC(=O)OC(C)(C)C
Agent: N
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)c1cc2c(C)cccc2n1CCNS(=O)(=O)c1ccc(C)cc1
Temperature: 0 °C
Reaction time: 3 h
Yield: 87.8 %

Procedure:
A mixture of ethyl 1-(2-tert-butoxycarbonylaminoethyl)-4-methyl-1H-indole-2-carboxylate (27.2 g, 78.5 mmol), trifluoroacetic acid (75 ml) and dichloromethane (250 ml) was stirred at 0°C. for 3 hours, slowly poured into cold aqueous ammonia, and then extracted twice with ethyl acetate. The extract solution was washed with a 5% aqueous sodium chloride solution and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, after which the residue was dissolved in pyridine (150 ml) and the resulting solution was cooled to 5° C. p-Toluenesulfonyl chloride (22.4 g, 118 mmol) was added to the cooled solution in small portions and the resulting mixture was stirred at 5° C. for 3 hours and then allowed to stand overnight at room temperature. The reaction mixture was poured into ice water and extracted twice with ethyl acetate, and the extract solution was washed successively with 1N hydrochloric acid, a saturated aqueous sodium hydrogencarbonate solution and a 5% aqueous sodium chloride solution. The organic layer was dried over anhydrous magnesium sulfate and the solvent was distilled off under reduced pressure. The resulting residue was purified by a silica gel column chromatography (eluent:ethyl acetate/n-hexane= 1/9) to obtain 27.6 g of ethyl 1-[2-(4-methylphenylsulfonyl) aminoethyl]-4-methyl-1H-indole-2-carboxylate
Reaction SMILES: C([NH:5][S:6]([C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([C:15]2[CH:20]=[C:19]([C:21]3[CH:26]=[C:25]([C:27]([F:30])([F:29])[F:28])[CH:24]=[C:23]([C:31]4[CH:36]=[CH:35][C:34]([C:37]([F:40])([F:39])[F:38])=[CH:33][CH:32]=4)[N:22]=3)[CH:18]=[CH:17][N:16]=2)[CH:10]=1)(=[O:8])=[O:7])(C)(C)C.C(O)(C(F)(F)F)=O>ClCCl>[F:30][C:27]([F:28])([F:29])[C:25]1[CH:24]=[C:23]([C:31]2[CH:36]=[CH:35][C:34]([C:37]([F:38])([F:39])[F:40])=[CH:33][CH:32]=2)[N:22]=[C:21]([C:19]2[CH:18]=[CH:17][N:16]=[C:15]([C:11]3[CH:10]=[C:9]([S:6]([NH2:5])(=[O:8])=[O:7])[CH:14]=[CH:13][CH:12]=3)[CH:20]=2)[CH:26]=1
Reactant: CC(C)(C)NS(=O)(=O)c1cccc(-c2cc(-c3cc(C(F)(F)F)cc(-c4ccc(C(F)(F)F)cc4)n3)ccn2)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: NS(=O)(=O)c1cccc(-c2cc(-c3cc(C(F)(F)F)cc(-c4ccc(C(F)(F)F)cc4)n3)ccn2)c1
Yield: 80.9 %

Procedure:
To a stirred and cooled solution of N-tert-butyl-3-[4-trifluoromethyl-6-(4-trifluoromethyl-phenyl)-[2,4′]bipyridinyl-2′-yl]-benzenesulfonamide (example 285) (0.248 g, 0.43 mmol) in dichloromethane (3 mL) was added TFA (3 mL) and the reaction mixture was allowed to stir at room temperature for 16 h. The mixture was evaporated to dryness and saturated NaHCO3 solution (5 mL), diethyl ether and heptane were added. The mixture was stirred at room temperature for 1 h, the precipitate was collected by filtration, washed with water and heptane/diethyl ether and dried to yield the title compound as a white solid (0.182 g, 81%). MS (ISP) 524.3 [(M+H)+]; mp 227° C. (dec.).
Reaction SMILES: [CH:1]1([C:9]([OH:11])=O)[C:3]2([CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]2)[CH2:2]1.C(N1C=CN=C1)(N1C=CN=C1)=O.C(OCC)(=O)C.Cl.[NH2:31][C@@H:32]([CH3:36])[C:33]([NH2:35])=[O:34]>O>[NH2:35][C:33](=[O:34])[C@@H:32]([NH:31][C:9]([C@@H:1]1[C:3]2([CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]2)[CH2:2]1)=[O:11])[CH3:36]
Reactant: O=C(O)C1CC12CCCCC2
Reactant: C[C@H](N)C(N)=O
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: O
Solvent: CCOC(C)=O
Product: C[C@H](NC(=O)[C@H]1CC12CCCCC2)C(N)=O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A 1000 mL flask was charged with the product from Example 1B (47.8 g, 0.31 mol), 1,1′-carbonyldiimidazole (60.8 g, 0.37 mol) and 500 mL of ethyl acetate. The mixture was stirred at ambient temperature for 2 hours then (2S)-2-aminopropanamide hydrochloride (46.7 g, 0.70 mol, commercially available from Aldrich) and 30 mL of water were charged to the flask. The reaction mixture was heated at 65° C. for 19 hours. After cooling to ambient temperature, the reaction flask was charged with 500 mL of water and stirred for 4 hours resulting in formation of a crystalline solid. The solid was filtered, rinsed with 100 mL of ethyl acetate, and dried to provide the title compound in 97% diastereomeric excess (de) as determined by HPLC: Zobax RX-C8 column, 5 μm, 4.6×250 mm; detector λ=205 nm, eluted with 15% CH3CN/0.03 M KH2PO4 for 10 minutes then 35% CH3CN/0.03 M KH2PO4 over 15 minutes; retention time 20.01 minutes. Stereochemistry was determined by x-ray crystallography. X-ray data: MW=224.30, C12H20N2O2, crystal dimensions 0.40X0.40X0.40 mm, primitive orthorhombic, P212121 (#19), a=6.9845(9) Å, b=8.642(1) Å, c=22.081(3) Å, V=1332.8(3) Å3, Z=4, Dcalc=1.118 g/cm3. Crystallographic data were collected using MoKα graphite monochromated radiation (λ=0.71069 Å). Refinement of the structure using full matrix least squares refinement of 2049 observed reflections (I>3.00σ(I)) and 145 variable parameters and converged with unweighted and weighted agreement factors of R=0.068 and Rw=0.075. 1H NMR (DMSO-d6, 300 MHz) δ 8.00 (d, 1H), 7.19 (s, 1H), 6.91 (s, 1H), 4.22 (p, 1H), 1.50 (dd), 1.3-1.6 (m, 10H), 1.19 (d, 3H), 0.85 (dd), 0.59 (dd, 1H); 13C NMR (DMSO-d6, 100 MHz) δ 174.1, 169.8, 47.9, 37.0, 28.3, 28.1, 26.7, 25.9, 25.2, 25.2, 18.5, 18.1; MS m/z 225 (M+H)+.
Reaction SMILES: [C:1]([O:4][C@@H:5]1[C@@:25]2([CH3:26])[C:9](=[CH:10][CH:11]=[C:12]3[C@@H:24]2[CH2:23][CH2:22][C@@:21]2([CH3:27])[C@H:13]3[CH2:14][CH2:15][C@@H:16]2[CH:17]([CH:19]=[O:20])[CH3:18])[CH2:8][C@@H:7]([O:28][C:29](=[O:31])[CH3:30])[CH2:6]1)(=[O:3])[CH3:2].C[O:33]C(O[C@@H]1[C@@]2(C)C(=CC=C3[C@@H]2CC[C@@]2(C)[C@H]3CC[C@@H]2C(C=O)C)C[C@@H](OC(OC)=O)C1)=O>>[C:1]([O:4][C@@H:5]1[C@@:25]2([CH3:26])[C:9](=[CH:10][CH:11]=[C:12]3[C@@H:24]2[CH2:23][CH2:22][C@@:21]2([CH3:27])[C@H:13]3[CH2:14][CH2:15][C@@H:16]2[CH:17]([C:19]([OH:33])=[O:20])[CH3:18])[CH2:8][C@@H:7]([O:28][C:29](=[O:31])[CH3:30])[CH2:6]1)(=[O:3])[CH3:2]
Reactant: COC(=O)O[C@@H]1CC2=CC=C3[C@@H]4CC[C@H](C(C)C=O)[C@@]4(C)CC[C@@H]3[C@@]2(C)[C@@H](OC(=O)OC)C1
Reactant: CC(=O)O[C@@H]1CC2=CC=C3[C@@H]4CC[C@H](C(C)C=O)[C@@]4(C)CC[C@@H]3[C@@]2(C)[C@@H](OC(C)=O)C1
Product: CC(=O)O[C@@H]1CC2=CC=C3[C@@H]4CC[C@H](C(C)C(=O)O)[C@@]4(C)CC[C@@H]3[C@@]2(C)[C@@H](OC(C)=O)C1
Yield: 81.7 %

Procedure:
The procedure of Example 6 was repeated except that 105 mg of 1α,3β-diacetoxypregna-5,7-diene-20-carbaldehyde was used in lieu of 120 mg of 1α,3β-bis(methoxycarbonyloxy)pregna-5,7-diene-20-carbaldehyde to give 89 mg of 1α,3β-diacetoxypregna-5,7-diene-20-carboxylic acid.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([N:7]2[CH2:12][CH2:11][CH:10]([C:13](Cl)=[O:14])[CH2:9][CH2:8]2)=[CH:3][CH:2]=1.[OH:16][CH2:17][CH:18]1[CH2:23][N:22]([S:24]([C:27]2[CH:36]=[CH:35][C:34]3[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=3)[CH:28]=2)(=[O:26])=[O:25])[CH2:21][CH2:20][NH:19]1>>[OH:16][CH2:17][CH:18]1[CH2:23][N:22]([S:24]([C:27]2[CH:36]=[CH:35][C:34]3[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=3)[CH:28]=2)(=[O:26])=[O:25])[CH2:21][CH2:20][N:19]1[C:13]([CH:10]1[CH2:11][CH2:12][N:7]([C:4]2[CH:5]=[CH:6][N:1]=[CH:2][CH:3]=2)[CH2:8][CH2:9]1)=[O:14]
Reactant: O=C(Cl)C1CCN(c2ccncc2)CC1
Reactant: O=S(=O)(c1ccc2ccccc2c1)N1CCNC(CO)C1
Product: O=C(C1CCN(c2ccncc2)CC1)N1CCN(S(=O)(=O)c2ccc3ccccc3c2)CC1CO
Yield: 42 %

Procedure:
Using an analogous procedure to that described in Example 1, 1-(4-pyridyl)piperidine-4-carbonyl chloride was reacted with 2-hydroxymethyl-4-(2-naphthylsulphonyl)piperazine to give 2-hydroxymethyl-4-(2-naphthylsulphonyl)-1-[1-(4-pyridyl)piperidin-4-ylcarbonyl]piperazine in 42% yield;
Reaction SMILES: [BH4-].[Na+].CO.[CH3:5][O:6][C:7](=[O:32])[CH2:8][O:9][CH2:10][CH2:11][CH2:12][CH2:13][N:14]1[C@@H:19](/[CH:20]=[CH:21]/[C:22](=[O:30])[CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH2:18][CH2:17][CH2:16][C:15]1=[O:31]>C(Cl)Cl>[CH3:5][O:6][C:7](=[O:32])[CH2:8][O:9][CH2:10][CH2:11][CH2:12][CH2:13][N:14]1[C:15](=[O:31])[CH2:16][CH2:17][CH2:18][C@@H:19]1/[CH:20]=[CH:21]/[CH:22]([OH:30])[CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: COC(=O)COCCCCN1C(=O)CCC[C@@H]1/C=C/C(=O)Cc1ccccc1
Agent: [BH4-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Product: COC(=O)COCCCCN1C(=O)CCC[C@@H]1/C=C/C(O)Cc1ccccc1
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 78.5 %

Procedure:
Sodium borohydride (4 mg, 0.11 mmol), followed by MeOH (0.25 mL), was added to a solution of {4-[(R)-2-oxo-6-((E)-3-oxo-4-phenyl-but-1-enyl)-piperidin-1-yl]-butoxy}-acetic acid methyl ester (28 mg, 0.072 mmol) in CH2Cl2 (0.75 mL) at 0° C. The mixture was allowed to warm to rt. After 40 min at rt, the reaction was quenched with aqueous HCl (0.5 M) and extracted with EtOAc (3×7 mL). The combined organic phase was dried (Na2SO4), filtered and concentrated in vacuo to afford 22 mg (78%) of the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[F:12])[CH2:8][N:7](C(=O)C(F)(F)F)[CH2:6][CH2:5]2.C([O-])([O-])=O.[K+].[K+].Cl>CO.O>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[F:12])[CH2:8][NH:7][CH2:6][CH2:5]2
Reactant: O=C(N1CCc2cc(Cl)c(F)cc2C1)C(F)(F)F
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CO
Product: Fc1cc2c(cc1Cl)CCNC2
Temperature: 25 °C
Reaction time: 2 h
Yield: 49.3 %

Procedure:
To a solution of 1-(6-chloro-7-fluoro-3,4-dihydro-1H-isoquinolin-2-yl)-2,2,2-trifluoroethanone (400 mg) in MeOH (15 mL) was added K2CO3 (572 mg, 4 mmol) in H2O (10 mL). The resulting reaction mixture was stirred at room temperature for 2 hours before it was acidified with HCl (1N) to pH 8. It was then extracted with EtOAc and the organic layer was washed with H2O (2×25 mL), dried over anhy. Na2SO4, filtered and concentrated in vacuo to tive the crude title product together with a regioisomer (170 mg). Prep-TLC separation (30% EtOAc in petroleum ether) then gave the desired title compound (130 mg) as a white solid.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[C:5]([C:10]3[N:11]=[C:12]([N:24]4[CH2:29][CH2:28][O:27][CH2:26][CH2:25]4)[C:13]4[S:18][C:17]([CH:19]([CH3:23])C(O)=O)=[CH:16][C:14]=4[N:15]=3)[CH:6]=[CH:7][CH:8]=2)[CH:3]=[N:2]1.[C:30](N1C=CN=C1)([N:32]1[CH:36]=CN=[CH:33]1)=[O:31].C(N(CC)CC)C.Cl.CNC>CN(C=O)C>[NH:1]1[C:9]2[C:4](=[C:5]([C:10]3[N:11]=[C:12]([N:24]4[CH2:25][CH2:26][O:27][CH2:28][CH2:29]4)[C:13]4[S:18][C:17]([CH2:19][CH2:23][C:30]([N:32]([CH3:36])[CH3:33])=[O:31])=[CH:16][C:14]=4[N:15]=3)[CH:6]=[CH:7][CH:8]=2)[CH:3]=[N:2]1
Reactant: CC(C(=O)O)c1cc2nc(-c3cccc4[nH]ncc34)nc(N3CCOCC3)c2s1
Reactant: O=C(n1ccnc1)n1ccnc1
Agent: CNC
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CN(C)C(=O)CCc1cc2nc(-c3cccc4[nH]ncc34)nc(N3CCOCC3)c2s1
Temperature: 25 °C
Reaction time: 1 h
Yield: 62.1 %

Procedure:
To a solution of 3-[2-(1H-indazol-4-yl-4-morpholin-4-yl-thieno[3,2-d]pyrimidin-6-yl]-propionic acid (145 mg) in DMF (5 mL) at room temperature was added carbonyldiimidazole (115 mg). The reaction mixture was then stirred at room temperature for 1 h. Then, triethylamine (0.15 mL) and dimethylamine hydrochloride (58 mg) were added and the solution was stirred at room temperature for 16 h. The reaction was then quenched with water (20 mL) and extracted into ethyl acetate (2×20 mL). The combined organics were washed with aqueous brine solution (3×20 mL), dried (MgSO4), concentrated and purified using column chromatography to give 148 as a white solid (96 mg). NMR: DMSO: 2.68-2.84 (2 H, m, CH2), 2.86 (3 H, s, Me), 3.02 (3 H, s, Me), 3.18 (2 H, t, J 7.22, CH2), 3.79-3.84 (4 H, m, CH2), 3.98-4.02 (4 H, m, CH2), 7.40 (1 H, s, Ar), 7.44 (1 H, t, J 8.0, Ar), 7.62 (1 H, d, J 8.15, Ar), 8.21 (1 H, d, J 7.35, Ar), 8.85 (1 H, s, Ar) and 13.15 (1 H, s, NH). MS: (ESI+): MH+ 437.22
Reaction SMILES: [CH3:1][O:2][C:3](=[O:14])[C:4]1[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[C:6]([OH:13])[CH:5]=1.I[CH:16]([CH3:18])[CH3:17].C(=O)([O-])[O-].[Cs+].[Cs+].CN(C)C=O>O>[CH3:1][O:2][C:3](=[O:14])[C:4]1[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[C:6]([O:13][CH:16]([CH3:18])[CH3:17])[CH:5]=1
Reactant: CC(C)I
Reactant: COC(=O)c1ccc([N+](=O)[O-])c(O)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1ccc([N+](=O)[O-])c(OC(C)C)c1
Yield: 67.7 %

Procedure:
A mixture of 2.0 g (10 mmole) of 3-hydroxy-4-nitro-benzoic acid methyl ester, 1.32 mL (13 mmole) of 2-iodopropane, 6.6 g (20 mole) of cesium carbonate and 60 mL of dimethylformamide was heated at 85 degrees overnight. The mixture was cooled, diluted with water and extracted twice with ethyl acetate. The combined organic layers were washed three times with sodium carbonate, three times with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. Purification by silica gel chromatography, eluting with ethyl acetate-hexane (gradient, 100:0-70:30) gave 1.62 g of 3-isopropoxy-4-nitro-benzoic acid methyl ester as a yellow liquid.