Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]2[C:9]([C:10](=[O:26])[C:11]3[CH:16]=[CH:15][C:14]([O:17][CH2:18][CH2:19][N:20]4[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]4)=[CH:13][CH:12]=3)=[C:8]([C:27]3[CH:32]=[CH:31][C:30]([O:33][CH:34](C)C)=[CH:29][CH:28]=3)[S:7][C:6]=2[CH:37]=1.[C:38]([O-])(=O)CCC([O-])=O>>[CH3:38][O:1][C:2]1[CH:3]=[CH:4][C:5]2[C:9]([C:10](=[O:26])[C:11]3[CH:16]=[CH:15][C:14]([O:17][CH2:18][CH2:19][N:20]4[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25]4)=[CH:13][CH:12]=3)=[C:8]([C:27]3[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[CH:29][CH:28]=3)[S:7][C:6]=2[CH:37]=1
Reactant: O=C([O-])CCC(=O)[O-]
Reactant: CC(C)Oc1ccc(-c2sc3cc(O)ccc3c2C(=O)c2ccc(OCCN3CCCCC3)cc2)cc1
Product: COc1ccc(-c2sc3cc(OC)ccc3c2C(=O)c2ccc(OCCN3CCCCC3)cc2)cc1

Procedure:
6-hydroxy-2-(4-isopropoxyphenyl)-3-[4-(2-piperidinoethoxy)benzoyl]benzo[b]thiophene, succinate
Reaction SMILES: [F:1][C:2]([F:9])([F:8])[C:3]([O:5]CC)=O.[CH:10]1([NH2:16])[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1>>[CH:10]1([NH:16][C:3](=[O:5])[C:2]([F:1])([F:8])[F:9])[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1
Reactant: NC1CCCCC1
Reactant: CCOC(=O)C(F)(F)F
Product: O=C(NC1CCCCC1)C(F)(F)F
Temperature: 118 °C
Yield: 42.1 %

Procedure:
In a manner similar to Example 6, ethyl trifluoroacetate (102 g, 0.72 m) was reacted with cyclohexylamine (70 g, 0.7 m). By-products/unreacted material were removed by heating the reaction mixture under increasing vacuum (final pressure 3 mm Hg) to 118° C. The pot residue was then recrystallized from hot ethyl acetate (~60 g) plus hexanes (~100 g) to yield 58 g solid which melted at 93°-95° C.
Reaction SMILES: CO[CH:3]([O:14][CH3:15])[CH2:4][O:5][C:6](=[O:13])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[SH:16][CH2:17]CO>O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C1(C)C=CC=CC=1>[C:6]([O:5][CH2:4][CH:3]1[S:16][CH2:17][CH2:15][O:14]1)(=[O:13])[C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1
Reactant: COC(COC(=O)c1ccccc1)OC
Reactant: OCCS
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: O=C(OCC1OCCS1)c1ccccc1
Temperature: 25 °C
Yield: 102.9 %

Procedure:
Aliquots of 2-benzoyloxyacetaldehyde dimethyl acetal (50.0 g) prepared according to Example 1, 2-mercaptoethanol (20.4 g), p-toluenesulfonic acid monohydrate (0.90 g) and toluene (250 mL) were placed in a three-neck flask, followed by heating. By-produced methanol was distilled off with the solvent. After distilling off about 150 mL, the reaction mixture was cooled to room temperature, was washed with a saturated aqueous sodium hydrogen carbonate solution and water and was dried over anhydrous sodium carbonate. After filtration and vacuum distillation at 144-147° C. and at 0.60 mmHg, the target compound (54.9 g) was obtained in a yield of 100%.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:10]=[C:11]([S:19](=[O:22])(=[O:21])[NH2:20])[C:12]=1[O:13][CH2:14][C:15]([F:18])([F:17])[F:16])[C:7]([OH:9])=[O:8])([O-])=O.[OH-].[Li+].[H][H]>O>[NH2:1][C:4]1[CH:5]=[C:6]([CH:10]=[C:11]([S:19](=[O:21])(=[O:22])[NH2:20])[C:12]=1[O:13][CH2:14][C:15]([F:17])([F:16])[F:18])[C:7]([OH:9])=[O:8]
Reactant: NS(=O)(=O)c1cc(C(=O)O)cc([N+](=O)[O-])c1OCC(F)(F)F
Reactant: [H][H]
Agent: [Li+]
Agent: [OH-]
Solvent: O
Product: Nc1cc(C(=O)O)cc(S(N)(=O)=O)c1OCC(F)(F)F

Procedure:
3-Nitro-5-sulphamyl-4-(β,β,β-trifluoroethoxy)-benzoic acid (2g) in water (30 ml) was adjusted to a pH of 9 by addition of lithium hydroxide, and the resulting solution was hydrogenated at room temperature and at a hydrogen pressure of 1.1 atmospheres after addition of Pd-on-carbon catalyst (0.2 g catalyst containing 10% Pd). After the hydrogen uptake had become negligible, the catalyst was removed by filtration, and the 3-amino-5-sulphamyl-4-(β,β,β-trifluoroethoxy)-benzoic acid was precipitated from the filtrate by addition of 4N hydrochloric acid until a pH of 2.5. After recrystallization from aqueous ethanol and drying, the melting point of the compound was 253°-254° C.
Reaction SMILES: [N:1]1(C(N2C=CN=C2)N)C=CN=[CH:2]1.[CH3:13][O:14][C:15](=[O:24])[C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([OH:22])[C:17]=1[NH2:23]>C1COCC1.CCOC(C)=O>[NH2:1][C:2]1[O:22][C:18]2[C:17](=[C:16]([C:15]([O:14][CH3:13])=[O:24])[CH:21]=[CH:20][CH:19]=2)[N:23]=1
Reactant: NC(n1ccnc1)n1ccnc1
Reactant: COC(=O)c1cccc(O)c1N
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COC(=O)c1cccc2oc(N)nc12
Temperature: 25 °C
Yield: 46.7 %

Procedure:
To a solution of di (1H-imidazole-1-yl)methanamine (2.05 g, 12.26 mmol) in THF (60 mL) was added methyl-2-amino-3-hydroxybenzoate (1.98 g, 12.26 mmol) at room temperature and the resulting reaction mixture was heated to reflux for 17 h. The reaction mixture was cool to room temperature, diluted with EtOAc (100 mL) and washed with H2O (3×100 mL), saturated ammonium chloride (2×100 mL), dried (Na2SO4), filtered and concentrated under reduced pressure. The crude material was purified by recrystallization from diethyl ether to afford methyl 2-aminobenzoxazole-4-carboxylate (1.10 g, 50%) as a brown solid. 1H NMR and MS consistent.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][CH:10]([C:12]([OH:14])=O)[CH3:11])[CH:5]=[CH:6][C:7]=1[Cl:8].[C:15]1([C@@H:21]([CH2:23][OH:24])[NH2:22])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>>[Cl:1][C:2]1[CH:3]=[C:4]([NH:9][CH:10]([C:12]([NH:22][C@@H:21]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:23][OH:24])=[O:14])[CH3:11])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: CC(Nc1ccc(Cl)c(Cl)c1)C(=O)O
Reactant: N[C@H](CO)c1ccccc1
Product: CC(Nc1ccc(Cl)c(Cl)c1)C(=O)N[C@H](CO)c1ccccc1

Procedure:
Following General Procedure E and using N-(3,4-dichlorophenyl)-D,L-alanine (from Example A above) and (S)-(+)-2-phenylglycinol (Aldrich), the title compound was prepared as a solid (mp=66-70° C.). The reaction was monitored by tlc on silica gel (Rf=0.25 in 5% methanol/methylene chloride) and purification was by flash column chromatography (silica gel using 5% methanol/methylene chloride as eluent).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[C:8]([NH:10][C:11](=[O:14])[CH2:12][CH3:13])[CH:7]=[CH:6][C:5]=1[O:15][CH3:16])([O-])=O.C(O)CC.N.[H][H]>[Pd].O>[CH3:16][O:15][C:5]1[CH:6]=[CH:7][C:8]([NH:10][C:11](=[O:14])[CH2:12][CH3:13])=[CH:9][C:4]=1[NH2:1]
Reactant: [H][H]
Reactant: CCC(=O)Nc1ccc(OC)c([N+](=O)[O-])c1
Agent: [Pd]
Agent: N
Solvent: CCCO
Solvent: O
Product: CCC(=O)Nc1ccc(OC)c(N)c1
Reaction time: 1 h

Procedure:
114 parts of 2-nitro-4-propionamidoanisole, 160 parts of propanol, 3.4 parts of a 30% aqueous solution of ammonia and 2 parts of a 50% suspension of palladium on activated charcoal, moist with water, in 3 parts of water are charged to an autoclave equipped with an aerating stirrer. The autoclave is pressurised with hydrogen and, at a pressure of 25 bar and a temperature of 120° C., hydrogenation is carried out for 1 hour. 2-Methoxy-5-propionamidoaniline is obtained in quantitative yield in a purity of >97% (analysis by liquid chromatography).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Cl.C(N=C=NCCCN(C)C)C.[CH3:19][O:20][C:21]1[C:22]([CH3:51])=[C:23]([C:42]([O:49][CH3:50])=[C:43]([O:47][CH3:48])[C:44]=1[O:45][CH3:46])[CH2:24][C:25]1[CH:26]=[CH:27][C:28]([O:34][CH2:35][C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)=[C:29]([CH:33]=1)[C:30](O)=[O:31]>C(Cl)Cl>[CH3:19][O:20][C:21]1[C:22]([CH3:51])=[C:23]([C:42]([O:49][CH3:50])=[C:43]([O:47][CH3:48])[C:44]=1[O:45][CH3:46])[CH2:24][C:25]1[CH:26]=[CH:27][C:28]([O:34][CH2:35][C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)=[C:29]([CH:33]=1)[C:30]([N:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1)=[O:31]
Reactant: COc1c(C)c(Cc2ccc(OCc3ccccc3)c(C(=O)O)c2)c(OC)c(OC)c1OC
Reactant: C1CCNCC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Product: COc1c(C)c(Cc2ccc(OCc3ccccc3)c(C(=O)N3CCCCC3)c2)c(OC)c(OC)c1OC
Temperature: 25 °C
Reaction time: 12 h
Yield: 99.5 %

Procedure:
Piperidine (0.358 g, 4.20 mmol) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (1.21 g, 6.30 mmol) were added to a methylene chloride solution (50 ml) of 5-(3,4,5,6-tetramethoxy-2-methylbenzyl)-2-benzyloxybenzoic acid (0.95 g, 2.10 mmol) and the resulting solution was stirred at room temperature for 12 hours. The reaction solution was poured into ice water and then extracted with methylene chloride. The extract was washed with water and then dried, and the solvent was removed by distillation. The obtained residue was purified by silica gel column chromatography (chloroform:methanol=50:1) to obtain the titled compound (1.02 g, 2.09 mmol, 99%).
Reaction SMILES: [CH3:1][C:2]1[S:3][CH:4]2[CH2:9][N:8]([S:10]([C:13]3[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][CH:14]=3)(=[O:12])=[O:11])[CH2:7][C:5]2(O)[N:6]=1.CS(Cl)(=O)=O.C(N(CC)CC)C>ClCCl>[CH3:1][C:2]1[S:3][C:4]2[CH2:9][N:8]([S:10]([C:13]3[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][CH:14]=3)(=[O:11])=[O:12])[CH2:7][C:5]=2[N:6]=1
Reactant: CC1=NC2(O)CN(S(=O)(=O)c3ccc(C)cc3)CC2S1
Agent: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1ccc(S(=O)(=O)N2Cc3nc(C)sc3C2)cc1
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
To a solution of the product from Step A (150 mg) in dichloromethane (2 mL) was added methanesulfonyl chloride (0.074 mL) at 0° C. followed by triethylamine (0.67 mL). After 15 min the reaction mixture was warmed to ambient temperature and stirred for 45 min. The mixture was concentrated in vacuo and purified by preparative thin layer chromatography using an Analtech® 1500 micron plate (8% ethyl acetate/dichloromethane) to give the title compound as a white solid. LC/MS 295.2 (M+1).
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][N:6]=[C:5]2[CH:12]1[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1.[N+](C1C=CC([O:27][C:28](=O)[NH:29][C:30]2[CH:35]=[CH:34][C:33]([O:36][CH:37]([CH3:39])[CH3:38])=[CH:32][CH:31]=2)=CC=1)([O-])=O.CCN(C(C)C)C(C)C>C(Cl)(Cl)Cl>[CH:37]([O:36][C:33]1[CH:34]=[CH:35][C:30]([NH:29][C:28]([N:15]2[CH2:16][CH2:17][CH:12]([C:5]3[C:4]4[C:9](=[CH:10][CH:11]=[C:2]([I:1])[CH:3]=4)[N:8]=[CH:7][N:6]=3)[CH2:13][CH2:14]2)=[O:27])=[CH:31][CH:32]=1)([CH3:39])[CH3:38]
Reactant: CC(C)Oc1ccc(NC(=O)Oc2ccc([N+](=O)[O-])cc2)cc1
Reactant: Ic1ccc2ncnc(C3CCNCC3)c2c1
Solvent: ClC(Cl)Cl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)Oc1ccc(NC(=O)N2CCC(c3ncnc4ccc(I)cc34)CC2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 42.3 %

Procedure:
A solution of impure 6-iodo-4-piperidin-4-yl-quinazoline (4.00 g, “11.8 mmol”), as prepared in the preceding step, in CHCl3 (20 mL) was treated with (4-isopropoxy-phenyl)-carbamic acid 4-nitro-phenyl ester (4.10 g, 13.0 mmol), prepared as described in Example 1a, in one portion at rt under air. DIEA (2.15 mL, 13.0 mmol) was then added in one portion, and residual nitrophenyl ester and DIEA was transferred to the reaction with additional CHCl3 (20 mL). After 8 h rt stirring, the reaction was washed in succession with 1 M NaH2PO4 (50 mL) and 2 M K2CO3 (1×50 mL). The organic phase was filtered, the filter cake was washed with DCM (2×10 mL), and the combined filtrates were dried (Na2SO4) and concentrated under reduced pressure. Flash chromatography of the residue (1:2 hex/EtOAc) afforded the title compound as a beige foam (2.58 g, 42%). 1H-NMR (300 MHz, CDCl3) δ 9.26 (s, 1H), 8.52 (d, 1H), 8.13 (dd, 1H), 7.80 (d, 1H), 7.25 (m, 2H), 6.83 (m, 2H), 6.33 (br s, 1H), 4.48 (heptet, 1H), 4.32-4.22 (m, 2H), 3.68 (tt, 1H), 3.17 (td, 2H), 2.21-1.92 (m, 4H), 1.32 (d, 6H). LC/MS (ESI): calcd mass 516.1, found 517.2 (MH)+.
Reaction SMILES: [CH:1]1([N:4]2[C:13]([CH3:15])([CH3:14])[CH:12](C(O)=O)[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]2=[O:19])[CH2:3][CH2:2]1.C([O-])(=[O:22])C.[K+].C([O-])(=O)C.[Pb+4].C([O-])(=O)C.C([O-])(=O)C.C([O-])(=O)C.O[Li].O>C(O)(=O)C.O.C1C=CC=CC=1>[CH:1]1([N:4]2[C:13]([CH3:15])([CH3:14])[CH:12]([OH:22])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]2=[O:19])[CH2:3][CH2:2]1
Reactant: CC1(C)C(C(=O)O)c2ccccc2C(=O)N1C1CC1
Reactant: CC(=O)[O-]
Agent: [K+]
Agent: [Li]O
Agent: [Pb+4]
Solvent: CC(=O)O
Solvent: c1ccccc1
Solvent: O
Product: CC1(C)C(O)c2ccccc2C(=O)N1C1CC1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of 2-cyclopropyl-3,3-dimethyl-1-oxo-1,2,3,4-tetrahydro-isoquinoline-4-carboxylic acid (4.1 g, 15.8 mmol) in acetic acid (300 mL) is added benzene (150 mL), potassium acetate (10.9 g, 111 mmol), cupric acetate (0.145 g, 0.8 mmol) and lead (IV) acetate (12.7 g, 28.6 mmol). The green reaction mixture is heated to reflux for 2.5 h. The reaction mixture is then cooled to room temperature and quenched by the addition of ethylene glycol (ca. 6 mL). The resulting solution is the concentrated in vacuo to near dryness. The resulting dark green oil is dissolved in ethyl acetate (ca. 500 mL) and stirred vigorously while cautiously treating with saturated aqueous sodium bicarbonate (ca. 200 mL), followed by solid NaHCO3 until the aqueous layer reached a pH greater than 8. The layers are separated and the aqueous layer is extracted three times with ethyl acetate. The organic layer is dried with Na2SO4 filtered and concentrated. The resulting brown oil is then dissolved in THF (150 mL). Water (30 ml) and LiOH H2O (3.5 g, 83.4 mmol) are added. The reaction mixture is placed at 45° C. for 18 h, whereupon it is cooled to room temperature. The reaction is concentrated in vacuo to ca. ¾ of its original volume, diluted with methylene chloride and saturated aqueous NaHCO3. The layers are separated and the aqueous layer is extracted three times with ethyl acetate. The organic layers are combined, dried with Na2SO4, filtered and concentrated in vacuo to afford a brown oil. Purification by silica gel flash chromatography (ethyl acetate-dichloromethane, 1:19 to 1:4) gave 2-cyclopropyl-4-hydroxy-3,3-dimethyl-3,4-dihydro-2H-isoquinolin-1-one as an off-white solid; MS (ESI) m/z 232.1 (M+H).
Reaction SMILES: [C:1]([C:4]1[CH:13]=[CH:12][C:7]2[NH:8][C:9](=[O:11])[O:10][C:6]=2[CH:5]=1)(=[O:3])[CH3:2].N([CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])=C=O>>[C:1]([C:4]1[CH:13]=[CH:12][C:7]2[NH:8][C:9](=[O:11])[O:10][C:6]=2[CH:5]=1)(=[O:3])[CH3:2].[CH3:22][CH2:21][CH:20]([C:9]([NH2:8])=[O:10])[CH2:19][CH2:18][CH3:17]
Reactant: CCCCCCN=C=O
Agent: CC(=O)c1ccc2[nH]c(=O)oc2c1
Product: CCCC(CC)C(N)=O

Procedure:
100 mg (0.565 mmol) of 6-acetyl-3H-benzooxazol-2-one were reacted in analogy to Example 1 with 86.2 mg (0.678 mmol) of 1-isocyanatohexane. Yield: 77 mg (45%), M+H+: 305.15.
Reaction SMILES: [CH2:1]([Cl:11])[CH2:2][CH:3]([CH2:5][CH2:6][CH:7]=[C:8]([CH3:10])[CH3:9])[CH3:4].CCCCC.O.[ClH:18]>C(O)(=O)C>[Cl:11][CH2:1][CH2:2][CH:3]([CH3:4])[CH2:5][CH2:6][CH2:7][C:8]([Cl:18])([CH3:10])[CH3:9]
Reactant: CC(C)=CCCC(C)CCCl
Reactant: Cl
Solvent: CCCCC
Solvent: CC(=O)O
Solvent: O
Product: CC(CCCl)CCCC(C)(C)Cl
Reaction time: 4 h

Procedure:
Into a well stirred solution of citronellyl chloride (8-chloro-2,6-dimethyl-2-octene; 26.1 g, 0.15 mol) in glacial acetic acid (600 ml), hydrochloric acid gas is passed for 4 hours at room temperature. Pentane (300 ml) and water (150 ml) are then added, the mixture stirred and transferred to a separatory funnel with additional pentane and water. The layers are separated, and the pentane layer is washed with several portions of water followed by saturated sodium bicarbonate solution. The pentane layer is then dried, and the solvent evaporated giving a quantitative yield of the product, boiling point 90° C to 93° C at 1.9 mm.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3[CH:19]=[CH:18][C:17]4[C:12](=[CH:13][CH:14]=[C:15]([N+:20]([O-])=O)[CH:16]=4)[N:11]=3)=[CH:9][C:4]=2[O:3][CH2:2]1>CO.C1COCC1.[Pd]>[NH2:20][C:15]1[CH:16]=[C:17]2[C:12](=[CH:13][CH:14]=1)[N:11]=[C:10]([C:8]1[CH:7]=[CH:6][C:5]3[O:1][CH2:2][O:3][C:4]=3[CH:9]=1)[CH:19]=[CH:18]2
Reactant: O=[N+]([O-])c1ccc2nc(-c3ccc4c(c3)OCO4)ccc2c1
Agent: [Pd]
Solvent: CO
Solvent: C1CCOC1
Product: Nc1ccc2nc(-c3ccc4c(c3)OCO4)ccc2c1
Reaction time: 2 h
Yield: 72.9 %

Procedure:
10% Pd/C (0.29 g, 0.27 mmol) is added to 2-(1,3-benzodioxol-5-yl)-6-nitroquinoline (2.0 g, 6.80 mmol) in methanol/THF (80 ml/80 ml). The mixture is hydrogenated at r.t. for 2 hours. The catalyst is filtered off and the filtrate is concentrated to afford 1.31 g (73%) of the titled product.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][N:3]=1.[CH2:9]([O:11][C:12]1[CH:13]=[C:14](B(O)O)[CH:15]=[CH:16][CH:17]=1)[CH3:10]>>[Br:8][C:5]1[CH:6]=[CH:7][C:2]([C:16]2[CH:15]=[CH:14][CH:13]=[C:12]([O:11][CH2:9][CH3:10])[CH:17]=2)=[N:3][CH:4]=1
Reactant: CCOc1cccc(B(O)O)c1
Reactant: Brc1ccc(Br)nc1
Product: CCOc1cccc(-c2ccc(Br)cn2)c1
Yield: 45 %

Procedure:
Obtained (0.977 g, yield 45%) following the procedure described in Intermediate 27, starting with 2,5-dibromopyridine (8.44 mmol, 2.0 g), 3-ethoxyphenylboronic acid (8.44 mmol, 1.40 g).
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:5]([C:16]#[N:17])=[C:4](Cl)[N:3]=1.CC(C)([O-])C.[K+].[OH:25][CH2:26][C:27]1[CH:32]=[CH:31][N:30]=[CH:29][CH:28]=1>CS(C)=O.C(O)(=O)C>[NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:5]([C:16]#[N:17])=[C:4]([O:25][CH2:26][C:27]2[CH:32]=[CH:31][N:30]=[CH:29][CH:28]=2)[N:3]=1
Reactant: OCc1ccncc1
Reactant: N#Cc1c(N)nc(Cl)c(C#N)c1-c1ccccc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CC(=O)O
Solvent: CS(C)=O
Product: N#Cc1c(N)nc(OCc2ccncc2)c(C#N)c1-c1ccccc1
Temperature: 60 °C
Reaction time: 16 h

Procedure:
102 mg (0.4 mmol) of 2-amino-6-chloro-4-phenyl-3,5-pyridinedicarbonitrile [Quintela et al., Heterocycles 38, 1299-1305 (1994)] are, together with 54 mg (0.48 mmol) of potassium tert-butoxide and 131 mg (1.2 mmol) of 4-hydroxymethylpyridine, dissolved in 1.5 ml of DMSO, and the mixture is stirred at 60° C. for about 16 h. The reaction mixture is acidified with two drops of glacial acetic acid. The solution is purified by preparative HPLC on reversed-phase silica gel (gradient: water+0.1% formic acid/acetonitrile 90:1010:90 in 12 minutes).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH:11]2[CH:13]([CH2:33][OH:34])[CH:14]([NH:16][C:17](=[O:32])[CH2:18][NH:19][C:20](=[O:31])[C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([C:27]([F:30])([F:29])[F:28])[CH:22]=3)[CH2:15][CH:10]2[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].I[CH3:36]>[Ag]=O.CN(C=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH:11]2[CH:13]([CH2:33][O:34][CH3:36])[CH:14]([NH:16][C:17](=[O:32])[CH2:18][NH:19][C:20](=[O:31])[C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([C:27]([F:30])([F:29])[F:28])[CH:22]=3)[CH2:15][CH:10]2[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CC2CC(NC(=O)CNC(=O)c3cccc(C(F)(F)F)c3)C(CO)C2C1
Reactant: CI
Agent: O=[Ag]
Solvent: CN(C)C=O
Product: COCC1C(NC(=O)CNC(=O)c2cccc(C(F)(F)F)c2)CC2CN(C(=O)OC(C)(C)C)CC21
Temperature: 25 °C

Procedure:
A solution of 4-hydroxymethyl-5-[2-(3-trifluoromethylbenzoylamino)acetylamino]octahydrocyclopenta[c]-pyrrole-2-carboxylic acid tert-butyl ester in a small amount of DMF and a large excess of iodomethane is treated with silver oxide and stirred at room temperature until the reaction is complete. The reaction mixture is filtered through Celite and concentrated under vacuum yielding a residue. The residue is purified by flash column chromatography providing the title product.
Reaction SMILES: [CH3:1][C@H:2]1[C@@H:6]([CH3:7])[N:5]([CH2:8][CH2:9][C:10]#[N:11])[C@H:4]([CH2:12][OH:13])[CH2:3]1.C(N(CC)[C:17](=[O:26])[C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([CH3:24])[C:19]=1[CH3:25])C>>[CH3:1][C@H:2]1[C@@H:6]([CH3:7])[N:5]([CH2:8][CH2:9][C:10]2[NH:11][C:17](=[O:26])[C:18]3[C:19]([CH:25]=2)=[C:20]([CH3:24])[CH:21]=[CH:22][CH:23]=3)[C@H:4]([CH2:12][OH:13])[CH2:3]1
Reactant: CCN(CC)C(=O)c1cccc(C)c1C
Reactant: C[C@@H]1C[C@@H](CO)N(CCC#N)[C@@H]1C
Product: Cc1cccc2c(=O)[nH]c(CCN3[C@H](CO)C[C@@H](C)[C@H]3C)cc12

Procedure:
In the same manner as in Example 1b (a) and using ethyl (2S,4R,5R)-4,5-dimethylpyrrolidine-2-carboxylate described in Tetrahedron Lett., Vol. 34, No. 3, pp. 537-540 (1993), ethyl (2S,4R,5R)-1-tert-butoxycarbonyl-4,5-dimethylpyrrolidine-2-carboxylate is obtained. In the same manner as in Example 1b (b) and using ethyl (2S,4R,5R)-1-tert-butoxycarbonyl-4,5-dimethylpyrrolidine-2-carboxylate, (2S,4R,5R)-1-tert-butoxycarbonyl-4,5-dimethyl-2-hydroxymethylpyrrolidine is obtained. In the same manner as in Example 1b (c) and using (2S,4R,5R)-1-tert-butoxycarbonyl-4,5-dimethyl-2-hydroxymethylpyrrolidine, (2S,4R,5R)-4,5-dimethyl-2-hydroxymethylpyrrolidine-hydrochloride is obtained. In the same manner as in Example 1b (d) and using (2S,4R,5R)-4,5-dimethyl-2-hydroxymethylpyrrolidine hydrochloride, 3-[(2S,4R,5R)-4,5-dimethyl-2-hydroxymethylpyrrolidin-1-yl]propionitrile is obtained. In the same manner as in Example 1b (e) and using 3-[(2S,4R,5R)-4,5-dimethyl-2-hydroxymethylpyrrolidin-1-yl]propionitrile and N,N-diethyl-2,3-dimethylbenzamide, 3-(2-[(2S,4R,5R)-4,5-dimethyl-2-hydroxymethylpyrrolidin-1-yl]ethyl)-5-methyl-2H-isoquinolin-1-one is obtained.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:23]=[CH:22][C:6]([C:7]([C:9]2[CH:20]=[CH:19][C:12]([O:13][CH2:14][C:15]([O:17]C)=[O:16])=[C:11]([CH3:21])[CH:10]=2)=[O:8])=[CH:5][CH:4]=1.[OH-].[Na+]>O1CCOCC1>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:7]([C:9]2[CH:20]=[CH:19][C:12]([O:13][CH2:14][C:15]([OH:17])=[O:16])=[C:11]([CH3:21])[CH:10]=2)=[O:8])=[CH:22][CH:23]=1
Reactant: COC(=O)COc1ccc(C(=O)c2ccc(OC)cc2)cc1C
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: COc1ccc(C(=O)c2ccc(OCC(=O)O)c(C)c2)cc1

Procedure:
35.8 g of methyl 4-(4-methoxybenzoyl)-2-methylphenoxyacetate are stirred with a mixture of 240 ml of dioxane and 240 ml of 0.5N NaOH at room temperature. After the reaction is complete, the organic solvent is removed in vacuo, and the aqueous phase is adjusted to pH 3 with 2N HCl and extracted with ethyl acetate. The organic phase is washed with water, dried over magnesium sulfate and concentrated. Pale yellow crystals remain.
Reaction SMILES: [Cl:1][C:2]1[CH:6]=[CH:5][S:4][C:3]=1[CH2:7][CH:8]([NH2:11])[CH2:9][CH3:10].C(N(CC)CC)C.[N+:19]([C:22]1[CH:27]=[CH:26][C:25]([S:28](Cl)(=[O:30])=[O:29])=[CH:24][CH:23]=1)([O-:21])=[O:20]>C(Cl)Cl>[Cl:1][C:2]1[CH:6]=[CH:5][S:4][C:3]=1[CH2:7][C@H:8]([NH:11][S:28]([C:25]1[CH:24]=[CH:23][C:22]([N+:19]([O-:21])=[O:20])=[CH:27][CH:26]=1)(=[O:29])=[O:30])[CH2:9][CH3:10]
Reactant: CCC(N)Cc1sccc1Cl
Reactant: O=[N+]([O-])c1ccc(S(=O)(=O)Cl)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC[C@H](Cc1sccc1Cl)NS(=O)(=O)c1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 95.3 %

Procedure:
Six grams of 3-chloro-2-(2-aminobutyl)thiophene is dissolved in 10 ml of methylene chloride in a 3-neck round bottomed flask blanketed with an inert atmosphere at 0° C. Triethylamine (6.6 ml) is added in one portion followed by 7.8 g of 4-nitrobenzenesulfonyl chloride which had been previously dissolved in 10 ml of methylene chloride. After stirring for 1 hour at ambient temperature, the methylene chloride is removed under vacuum and 40 ml of methanol is added with warming to dissolve all solids. The resulting solution is poured into cold water, agitated for 30 minutes, filtered and washed with cold water, and the isolated material is dried in a vacuum oven to provide (R)-N-[1-[(3-chlorothien-2-yl)methyl]propyl]-4-nitrobenzenesulfonamide (11.3 g) as a tan solid. MS: m/z (E1, 70EV) 375(10%). 1H NMR (200 MHz; CDCl3): δ 0.95 (3H, t, CH3), 1.7 (2H, m, CH2), 2.85 (2H, m, CH2), 3.5 (1H, m, CH), 6.65 (1H, d, CH), 7.0 (1H, d, CH), 7.9 (2H, d, Ph), 8.2 (2H, d, Ph).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][N:13]2[C:17](=[O:18])[C:16]3=[CH:19][CH:20]=[CH:21][CH:22]=[C:15]3[C:14]2=[O:23])[N:3]=1.[CH2:24]([N:27]=[C:28]=[S:29])[CH2:25][CH3:26]>N1C=CC=CC=1>[CH2:24]([NH:27][C:28](=[S:29])[NH:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][N:13]2[C:14](=[O:23])[C:15]3=[CH:22][CH:21]=[CH:20][CH:19]=[C:16]3[C:17]2=[O:18])[N:3]=1)[CH2:25][CH3:26]
Reactant: CCCN=C=S
Reactant: Nc1ccnc(CCCCCN2C(=O)c3ccccc3C2=O)n1
Solvent: c1ccncc1
Product: CCCNC(=S)Nc1ccnc(CCCCCN2C(=O)c3ccccc3C2=O)n1
Yield: 64.1 %

Procedure:
A mixture of 4-amino-2-(5-phthalimidopentyl)pyrimidine (2 g.) and propylisothiocyanate (1 g.) in pyridine (5 ml.) was heated under reflux for 16 hours then evaporated to dryness. The residual solid was triturated with acetonitrile to give 4-(3-propylthioureido)-2-(5-phthalimidopentyl)pyrimidine (1.7 g.), m.p. 146°-9°.