Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]([CH2:17][C:18]2[CH:23]=[CH:22][C:21]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)=[CH:20][CH:19]=2)([C:14](O)=[O:15])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH:30]1([CH2:36][NH2:37])[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]1.C(N(C(C)C)CC)(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C.C(OCC)(=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]([CH2:17][C:18]2[CH:19]=[CH:20][C:21]([C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=3)=[CH:22][CH:23]=2)([C:14](=[O:15])[NH:37][CH2:36][CH:30]2[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC(Cc2ccc(-c3ccccc3)cc2)(C(=O)O)CC1
Reactant: NCC1CCCCC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1CCC(Cc2ccc(-c3ccccc3)cc2)(C(=O)NCC2CCCCC2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 4-biphenyl-4-ylmethyl-piperidine-1,4-dicarboxylic acid mono-tert-butyl ester (6.32 mmol; 2.5 g) in DMF (50 mL) was added cyclohexylmethylamine (7.59 mmol; 0.99 mL), N,N-diisopropyl-N-ethylamine (15.8 mmol; 2.80 mL) and HBTU (7.59 mmol; 2.88 g), and the resulting mixture was stirred at room temperature overnight. Ethyl acetate (200 mL) was added, and the resulting solution was washed with a 1N hydrochloric acid solution (2×25 mL), and brine (25 mL), and dried over magnesium sulfate. After filtration and evaporation, the residue was purified via flash column chromatography (eluent gradient: 0 to 50% EtOAc in heptane) to yield 4-biphenyl-4-ylmethyl-4-(cyclohexylmethyl-carbamoyl)-piperidine-1-carboxylic acid tert-butyl ester after evaporation. The material thus obtained was dissolved in THF (8 mL) and a 4N HCl solution in 1,4-dioxane (15 mL) was added. The resulting mixture was stirred overnight at room temperature and evaporated. The residue was triturated with diethyl ether and dried to yield 4-biphenyl-4-ylmethyl-piperidine-4-carboxylic acid cyclohexylmethylamide as a hydrochloride salt. MS (ESI) m/z 391.09 [M+H]+.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([C:8]2[N:9]=[N:10][N:11]([CH2:13][C:14]3[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=3)[CH:12]=2)[CH:5]=[CH:4][N:3]=1.[Br:22][C:23]1[CH:28]=[C:27]([CH3:29])[CH:26]=[C:25]([NH2:30])[N:24]=1.CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.C([O-])([O-])=O.[Cs+].[Cs+]>CC([O-])=O.CC([O-])=O.[Pd+2]>[Br:22][C:23]1[N:24]=[C:25]([NH:30][C:2]2[CH:7]=[C:6]([C:8]3[N:9]=[N:10][N:11]([CH2:13][C:14]4[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=4)[CH:12]=3)[CH:5]=[CH:4][N:3]=2)[CH:26]=[C:27]([CH3:29])[CH:28]=1
Reactant: Cc1cc(N)nc(Br)c1
Reactant: COc1ccc(Cn2cc(-c3ccnc(Br)c3)nn2)cc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Product: COc1ccc(Cn2cc(-c3ccnc(Nc4cc(C)cc(Br)n4)c3)nn2)cc1
Temperature: 100 °C
Yield: 59.3 %

Procedure:
To a flask was added 2-bromo-4-(1-(4-methoxybenzyl)-1H-1,2,3-triazol-4-yl)pyridine (329 mg, 0.953 mmol), 2-bromo-4-methyl-6-aminopyridine (178 mg, 0.953 mmol), Pd(OAc)2 (21.4 mg, 0.095 mmol), Xantphos (83 mg, 0.143 mmol), and Cs2CO3 (621 mg, 1.91 mmol), and the mixture was vacuum-purged with argon 3 times. Degassed 1,4-Dioxane (3.8 mL) was added and the reaction was heated to 100° C. for 30 min. after which time the reaction was cooled and diluted with EtOAc (20 mL). The reaction was filtered then dry loaded onto silica and purified by silica gel chromatography using a gradient solvent system of 30-60% EtOAc/Hexanes. Concentration of the product-containing fractions yielded 6-bromo-N-(4-(1-(4-methoxybenzyl)-1H-1,2,3-triazol-4-yl)pyridin-2-yl)-4-methylpyridin-2-amine (255 mg, 59%) as a tan solid. MS ESI calcd for C21H19BrN6O [M+H]+ 451, found 451.
Reaction SMILES: [CH2:1]([N:3]([CH2:30][CH3:31])[CH2:4][C:5]1[S:6][C:7]([C:11]2[O:15][N:14]=[C:13]([C:16]3[CH:21]=[C:20]([CH3:22])[C:19]([O:23][CH2:24][C@@H:25]4[CH2:27][O:26]4)=[C:18]([CH2:28][CH3:29])[CH:17]=3)[N:12]=2)=[CH:8][C:9]=1[CH3:10])[CH3:2].[NH3:32]>CO>[NH2:32][CH2:27][C@H:25]([OH:26])[CH2:24][O:23][C:19]1[C:20]([CH3:22])=[CH:21][C:16]([C:13]2[N:12]=[C:11]([C:7]3[S:6][C:5]([CH2:4][N:3]([CH2:30][CH3:31])[CH2:1][CH3:2])=[C:9]([CH3:10])[CH:8]=3)[O:15][N:14]=2)=[CH:17][C:18]=1[CH2:28][CH3:29]
Reactant: CCc1cc(-c2noc(-c3cc(C)c(CN(CC)CC)s3)n2)cc(C)c1OC[C@@H]1CO1
Reactant: N
Solvent: CO
Product: CCc1cc(-c2noc(-c3cc(C)c(CN(CC)CC)s3)n2)cc(C)c1OC[C@@H](O)CN

Procedure:
To a solution of 4-[5-(5-diethylaminomethyl-4-methyl-thiophen-2-yl)-[1,2,4]oxadiazol-3-yl]-2-ethyl-6-methyl-phenol (1.49 g, 3.87 mmol) in isopropanol (70 mL) and 3 N aq. NaOH (19 mL), (R)-epichlorohydrine is added. The mixture is stirred at rt for 41 h. The mixture is diluted with EA and washed with 1 M aq. NaOH. The washing is extracted back with EA. The organic extracts are combined, dried over MgSO4, filtered and concentrated. The crude product is purified by prep. HPLC (XBridge C18, 50×50 mm, 10 μm, eluting with a gradient of acetonitrile in water containing 0.5% of concentrated aq. ammonia) to give diethyl-{5-[3-((S)-3-ethyl-5-methyl-4-oxiranylmethoxy-phenyl)-[1,2,4]oxadiazol-5-yl]-3-methyl-thiophen-2-ylmethyl}-amine (990 mg) as a pale yellow resin; LC-MS: tR=0.65 min; [M+1]+=442.09. b) A solution of diethyl-{5-[3-((S)-3-ethyl-5-methyl-4-oxiranylmethoxy-phenyl)-[1,2,4]oxadiazol-5-yl]-3-methyl-thiophen-2-ylmethyl}-amine (450 mg, 1.02 mmol) in 7 N NH3 in methanol is stirred in a sealed vessel at 65° C. for 16 h. The solvent is evaporated and the crude product is purified by prep. HPLC. The product containing fractions are filtered over Amberlyst A21. The filtrate is concentrated and dried to give the title compound (381 mg) as a yellow resin; LC-MS: tR=0.44 min; [M+1]+=459.10; 1H NMR (D6-DMSO): δ1.03 (t, J=7.0 Hz, 6H), 1.23 (t, J=7.5 Hz, 3H), 2.22 (s, 3H), 2.35 (s, 3H), 2.58 (q, J=7.0 Hz, 4H), 2.73 (q, J=7.5 Hz, 2H), 2.88 (dd, J=12.8, 9.0 Hz, 1H), 3.10 (dd, J=12.5, 3.0 Hz, 1H), 3.73 (s, 2H), 3.81 (d, J=5.3 Hz, 2H), 4.04-4.12 (m, 1H), 7.75 (s, 2H), 7.80 (s, 1H).
Reaction SMILES: Cl[C:2]1[CH:18]=[CH:17][C:5]([C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][CH:10]=2)=[O:7])=[CH:4][N:3]=1.[CH:19]1([CH2:22][NH:23][C:24](=[O:41])[C:25]2[CH:30]=[CH:29][C:28]([CH3:31])=[C:27](B3OC(C)(C)C(C)(C)O3)[CH:26]=2)[CH2:21][CH2:20]1>>[CH:19]1([CH2:22][NH:23][C:24]([C:25]2[CH:26]=[CH:27][C:28]([CH3:31])=[C:29]([C:2]3[CH:18]=[CH:17][C:5]([C:6]([NH:8][C:9]4[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][CH:10]=4)=[O:7])=[CH:4][N:3]=3)[CH:30]=2)=[O:41])[CH2:21][CH2:20]1
Reactant: Cc1ccc(C(=O)NCC2CC2)cc1B1OC(C)(C)C(C)(C)O1
Reactant: COc1ccc(NC(=O)c2ccc(Cl)nc2)cc1
Product: COc1ccc(NC(=O)c2ccc(-c3cc(C(=O)NCC4CC4)ccc3C)nc2)cc1

Procedure:
6-[5-Cyclopropylmethylcarbamoyl-2-methyl-phenyl]-N-(4-methoxyphenyl)-nicotinamide was prepared from 6-chloro-N-(4-methoxyphenyl)nicotinamide (Intermediate 2) and N-cyclopropylmethyl-4-methyl-3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzamide (intermediate 10) using General Method B. LCMS: retention time 3.12 min, MH+ 416. NMR: δH [2H6]-DMSO 10.39,(1H, s), 9.21,(1H, d), 8.63,(1H, t), 8.41,(1H, dd), 7.96,(1H, s), 7.86,(1H, d), 7.79,(1H, d), 7.71,(2H, d), 7.44,(1H, d), 6.96,(2H, d), 3.76,(3H, s), 3.15,(2H, t), 2.41,(3H, s), 1.03,(1H, m), 0.43,(2H, m), 0.23,(2H, m).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:13]([NH:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[Cl:21])=[C:12]([F:22])[C:8]2[N:9]=[CH:10][NH:11][C:7]=2[CH:6]=1)=[O:4].CC1C=CC(S(O)(=O)=O)=CC=1.O.C1C(=O)N([Br:42])C(=O)C1>C1COCC1.CO>[CH3:1][O:2][C:3]([C:5]1[C:13]([NH:14][C:15]2[CH:20]=[CH:19][C:18]([Br:42])=[CH:17][C:16]=2[Cl:21])=[C:12]([F:22])[C:8]2[N:9]=[CH:10][NH:11][C:7]=2[CH:6]=1)=[O:4]
Reactant: COC(=O)c1cc2[nH]cnc2c(F)c1Nc1ccccc1Cl
Reactant: O=C1CCC(=O)N1Br
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)c1cc2[nH]cnc2c(F)c1Nc1ccc(Br)cc1Cl
Temperature: -78 °C
Reaction time: 0.17 h
Yield: 84.6 %

Procedure:
6-(2-Chloro-phenylamino)-7-fluoro-3H-benzoimidazole-5-carboxylic acid methyl ester 7b (55 mg, 0.172 mmol) is dissolved in 1:1 THF/MeOH (2 mL) and cooled to −78° C. under an atmosphere of nitrogen. TsOH.H2O (49 mg, 0.258 mmol) is added followed by NBS (31 mg, 0.174 mmol). After 10 minutes, the reaction mixture is warmed to 0° C. and then 2 hours later warmed to room temperature. After 16 hours, the reaction mixture is quenched by the addition of 10% Na2S2O3 and diluted with ethyl acetate and water. The layers are separated and the aqueous layer is extracted with ethyl acetate. The combined organic extracts are dried (MgSO4) and concentrated under reduced pressure. The crude product is triturated with methylene chloride to give 58 mg (85%) of pure desired product as a tan solid.
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[C:7]([Cl:9])[CH:6]=[CH:5][C:3]=1[NH2:4].[CH3:10][C:11](OC(C)=O)=[O:12]>CC(O)=O>[Cl:1][C:2]1[CH:8]=[C:7]([Cl:9])[CH:6]=[CH:5][C:3]=1[NH:4][C:11](=[O:12])[CH3:10]
Reactant: Nc1ccc(Cl)cc1Cl
Reactant: CC(=O)OC(C)=O
Solvent: CC(=O)O
Product: CC(=O)Nc1ccc(Cl)cc1Cl
Temperature: 50 °C
Reaction time: 1 h

Procedure:
To a solution of 2,4-dichloroaniline (42.0 g, 260 mmol) in AcOH (40.0 mL) is added Ac2O (80 mL). The reaction mixture is warmed up to 50° C. and stirred at this temperature for 1 hour. The reaction is cooled to room temperature and poured into ice water (500 mL). A solid precipitated and the mixture is stirred for additional 1 hour at room temperature. The solid is filtered and washed with water, hexanes and air dried to give N-(2,4-dichlorophenyl)acetamide.
Reaction SMILES: [Br:1]Br.[CH3:3][O:4][C:5]1[CH:13]2[CH:8]([CH:9]3[O:14][CH:12]2[CH2:11][CH2:10]3)[C:7](=[O:15])[CH:6]=1.C(N(CC)CC)C>ClCCl>[Br:1][C:6]1[C:7](=[O:15])[CH:8]2[CH:13]([C:5]=1[O:4][CH3:3])[CH:12]1[O:14][CH:9]2[CH2:10][CH2:11]1
Reactant: BrBr
Reactant: COC1=CC(=O)C2C3CCC(O3)C12
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC1=C(Br)C(=O)C2C3CCC(O3)C12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of bromine (0.14 ml, 2.8 mmol) in dichloromethane (5 ml) is added dropwise to a solution of the enol ether (0.48 g, 2.6 mmol) prepared in step 1 in dichloromethane (40 ml) at 0° C. and the reaction mixture is stirred for 1 hour. Triethylamine (0.64 ml, 4.6 mmol) is then added and the reaction mixture is allowed to warm to room temperature and then stirred for 3 hours. The reaction mixture is washed with 2M aqueous hydrochloric acid and brine, dried over anhydrous magnesium sulfate, filtered and the filtrate evaporated under reduced pressure. The residue is purified by column chromatography on silica gel to give (1RS,2SR,6RS,7SR)-4-bromo-5-methoxy-10-oxatricyclo[5.2.1.02,6]dec-4-en-3-one.
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[CH:15]=[C:14]([CH2:17][CH2:18][O:19][CH3:20])[N:13]=[C:12]([NH:21]CC3C=CC=CC=3)[C:11]=2[NH:10][C:9]1=[O:29])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.C([O-])(O)=O.[Na+]>S(=O)(=O)(O)O>[NH2:21][C:12]1[C:11]2[NH:10][C:9](=[O:29])[N:8]([CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[C:16]=2[CH:15]=[C:14]([CH2:17][CH2:18][O:19][CH3:20])[N:13]=1
Reactant: COCCc1cc2c([nH]c(=O)n2Cc2ccccc2)c(NCc2ccccc2)n1
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Product: COCCc1cc2c([nH]c(=O)n2Cc2ccccc2)c(N)n1
Yield: 12.7 %

Procedure:
1-Benzyl-4-benzylamino-6-(2-methoxy-ethyl)-1,3-dihydro-imidazo[4,5-c]pyridine-2-one (32 mg, 0.082 mmol) was stirred in concentrated sulphuric acid (2 ml) for 30 minutes. Water (5 ml) was added and the mixture added drop-wise to a stirred solution of saturated NaHCO3 to achieve a basic pH. The aqueous was extracted with 2×EtOAc and the combined organics dried and concentrated to afford a yellow solid. The mixture of isomers was separated by column chromatography on silica, eluting with DCM:MeOH, 97:3 with increasing gradient to DCM:MeOH:NH3 95:5:0.5 to afford the title compound as a pale yellow solid, (3.1 mg, 13%)
Reaction SMILES: [Cl:1][C:2]1[CH:13]=[C:12]([F:14])[C:11]([N:15]2[C:20](=[O:21])[CH:19]=[C:18]([CH3:22])[NH:17][C:16]2=[O:23])=[CH:10][C:3]=1[C:4]([O:6][CH:7]([CH3:9])[CH3:8])=[O:5].[Na].[CH:25](O)(C)C>>[Cl:1][C:2]1[CH:13]=[C:12]([F:14])[C:11]([N:15]2[C:20](=[O:21])[CH:19]=[C:18]([CH3:22])[N:17]([CH3:25])[C:16]2=[O:23])=[CH:10][C:3]=1[C:4]([O:6][CH:7]([CH3:9])[CH3:8])=[O:5]
Reactant: Cc1cc(=O)n(-c2cc(C(=O)OC(C)C)c(Cl)cc2F)c(=O)[nH]1
Reactant: CC(C)O
Agent: [Na]
Product: Cc1cc(=O)n(-c2cc(C(=O)OC(C)C)c(Cl)cc2F)c(=O)n1C

Procedure:
using isopropyl 2-chloro-4-fluoro-5-[3,6-dihydro-4-methyl-2,6-dioxo-1(2H)-pyrimidinyl]-benzoate with sodium isopropylate in isopropanol there is obtained isopropyl 2-chloro-4-fluoro-5-[3,6-dihydro-3,4-dimethyl-2,6-dioxo-1(2H)-pyrimidinyl]-benzoate, 1H--NMR (CDCl3, 60 MHz) 7.88 ppm (d, 1H), 7.38 ppm (d, 1H), 5.77 ppm (s, 1H), 5.30 ppm (m, 1H), 3.50 ppm (s, 3H), 2.36 ppm (s, 3H), 1.40 ppm (d, 6H),
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]2[N:8]([CH3:11])[N:9]=[CH:10][C:5]2=[C:4]([NH:12][C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([O:19][CH3:20])[CH:14]=2)[N:3]=1.[N:21]1[CH:26]=[CH:25][C:24](B2OC(C)(C)C(C)(C)O2)=[CH:23][CH:22]=1>>[CH3:20][O:19][C:15]1[CH:14]=[C:13]([NH:12][C:4]2[N:3]=[C:2]([C:24]3[CH:25]=[CH:26][N:21]=[CH:22][CH:23]=3)[N:7]=[C:6]3[N:8]([CH3:11])[N:9]=[CH:10][C:5]=23)[CH:18]=[CH:17][CH:16]=1
Reactant: COc1cccc(Nc2nc(Cl)nc3c2cnn3C)c1
Reactant: CC1(C)OB(c2ccncc2)OC1(C)C
Product: COc1cccc(Nc2nc(-c3ccncc3)nc3c2cnn3C)c1

Procedure:
6-Chloro-N-(3-methoxyphenyl)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine 6 was reacted with pyridine-4-boronic acid pinacol ester using General Procedure A. Purification on silica yielded 123. NMR: (CDCl3): 3.89 (s, 3H, CH3), 4.14 (s, 3H, CH3), 6.89-6.92 (m, H, ArH), 7.16 (m, H, ArH), 7.25 (s, H, ArH), 7.41 (t, H, ArH, J=8.1 HZ), 7.49 (sbr, H, NH), 8.39 (dd, 2H, 2×ArH, J=1.5 Hz, 4.5 Hz), 8.80 (dd, 2H, 2×ArH, J=1.5 Hz, 4.5 Hz). MS: (ESI+) MH+=333.24
Reaction SMILES: [CH2:1]([NH2:13])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].Cl[CH2:15][CH:16]([OH:36])[CH2:17][N:18]([CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH3:35])[CH2:19][CH:20]([OH:23])[CH2:21]Cl>C1(C)C(C)=CC=CC=1>[OH:36][CH:16]([CH2:17][N:18]([CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH3:35])[CH2:19][CH:20]([OH:23])[CH2:21][NH:13][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])[CH2:15][NH:13][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: CCCCCCCCCCCCN
Reactant: CCCCCCCCCCCCN(CC(O)CCl)CC(O)CCl
Solvent: Cc1ccccc1C
Product: CCCCCCCCCCCCNCC(O)CN(CCCCCCCCCCCC)CC(O)CNCCCCCCCCCCCC
Temperature: 80 °C
Yield: 49.4 %

Procedure:
A reactor was charged with 286.3 g (1.54 moles) of dodecylamine and 90 g of xylene, and the contents were heated to 80° C. To the contents, a solution with 57 g (0.15 mole) of N,N-bis(3-chloro-2-hydroxypropyl)dodecylamine dissolved in 50 g of xylene was added dropwise over 1.5 hours. The resultant mixture was aged further for 4 hours. Thereafter, xylene was distilled off under reduced pressure, and unreacted dodecylamine was then distilled off at 100° C. and 0.5 mmHg. The residue was added with 500 ml of hexane and 2000 ml of acetone to be dissolved therein. The solution was then subjected to extraction and washing with a mixture of 500 ml of xylene and 500 ml of 5% aqueous sodium hydroxide. Thereafter, a xylene layer was taken out and concentrated, thereby obtaining 49.5 g (yield: 48%) of 15,19-dihydroxy-17-dodecyl-13,17,21-triazatritriacontane represented by the following formula. ##STR10##
Reaction SMILES: C(O[BH-](O[C:11](=[O:13])[CH3:12])OC(=O)C)(=O)C.[Na+].[Br:15][C:16]1[CH:21]=[CH:20][C:19]([N:22]2C[CH2:26][NH:25][CH2:24][C:23]2=O)=[CH:18][CH:17]=1.C=O.O>C(Cl)Cl>[Br:15][C:16]1[CH:17]=[CH:18][C:19]([N:22]2[CH2:23][CH2:24][N:25]([CH3:26])[CH2:12][C:11]2=[O:13])=[CH:20][CH:21]=1
Reactant: O=C1CNCCN1c1ccc(Br)cc1
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: C=O
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: CN1CCN(c2ccc(Br)cc2)C(=O)C1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Sodium triacetoxyborohydride (0.25 g, 1.2 mmol) was added to a solution of 1-(4-bromophenyl)piperazin-2-one (200.0 mg, 0.7840 mmol, from J&W PharmLab product) and 11.0 M formaldehyde in water (0.21 mL, 2.4 mmol) in methylene chloride (3 mL, 50 mmol) and then the reaction was stirred at rt for 1 hour. The mixture was diluted with methylene chloride, washed with saturated NaHCO3, water, brine, then dried over Na2SO4, filtered and concentrated to provide the product which was used in the next step. LCMS calculated for C11H14BrN2O (M+H)+: m/z=269.0. Found 269.0.
Reaction SMILES: [C:1]12([NH:11][C:12](=[O:30])[C:13]3[CH:18]=[C:17]([N+:19]([O-:21])=[O:20])[C:16]([O:22]C(=O)C)=[C:15]([O:26]C(=O)C)[CH:14]=3)[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.S(=O)(=O)(O)O.O>CO>[C:1]12([NH:11][C:12](=[O:30])[C:13]3[CH:18]=[C:17]([N+:19]([O-:21])=[O:20])[C:16]([OH:22])=[C:15]([OH:26])[CH:14]=3)[CH2:10][CH:5]3[CH2:4][CH:3]([CH2:9][CH:7]([CH2:6]3)[CH2:8]1)[CH2:2]2
Reactant: CC(=O)Oc1cc(C(=O)NC23CC4CC(CC(C4)C2)C3)cc([N+](=O)[O-])c1OC(C)=O
Agent: O=S(=O)(O)O
Solvent: O
Solvent: CO
Product: O=C(NC12CC3CC(CC(C3)C1)C2)c1cc(O)c(O)c([N+](=O)[O-])c1
Yield: 88.8 %

Procedure:
A solution containing 1.2 g of the product obtained in Example 43 and a catalytic amount of sulfuric acid in 10 ml of methanol was refluxed for 3 h. 20 ml of water was added and on cooling 0.85 g (89.5%) of the desired product was crystallized, m.p. 207°614 208° C.
Reaction SMILES: [OH-].[Na+].CO.C[O:6][C:7](=[O:23])[CH2:8][C:9]1[C:17]2[C:12](=[CH:13][C:14]([C:18]([F:21])([F:20])[F:19])=[CH:15][CH:16]=2)[NH:11][C:10]=1[CH3:22]>O>[CH3:22][C:10]1[NH:11][C:12]2[C:17]([C:9]=1[CH2:8][C:7]([OH:23])=[O:6])=[CH:16][CH:15]=[C:14]([C:18]([F:20])([F:19])[F:21])[CH:13]=2
Reactant: COC(=O)Cc1c(C)[nH]c2cc(C(F)(F)F)ccc12
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: Cc1[nH]c2cc(C(F)(F)F)ccc2c1CC(=O)O
Yield: 6 %

Procedure:
A 2 N sodium hydroxide aqueous solution (1 ml) and methanol (1 ml) were added to the obtained 2-(2-methyl-6-trifluoromethyl-1H-indol-3-yl)acetic acid methyl ester, and the mixture was heated to reflux for one hour. Water was added to the reaction mixture, which was then rendered acidic with concentrated aqueous hydrochloric acid, extracted with ethyl acetate, dried over sodium sulfate and concentrated under reduced pressure, to obtain 79 mg of the title compound as a colorless powder (6% yield).
Reaction SMILES: [F:1][C:2]1[C:3]([NH:9][C:10](=[O:18])[C:11]2[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][CH:12]=2)=[N:4][C:5]([OH:8])=[N:6][CH:7]=1.[C:19]([O-])([O-])=O.[K+].[K+].IC>CN(C=O)C>[F:1][C:2]1[C:3]([NH:9][C:10](=[O:18])[C:11]2[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][CH:12]=2)=[N:4][C:5](=[O:8])[N:6]([CH3:19])[CH:7]=1
Reactant: O=C([O-])[O-]
Reactant: Cc1ccc(C(=O)Nc2nc(O)ncc2F)cc1
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Product: Cc1ccc(C(=O)Nc2nc(=O)n(C)cc2F)cc1
Temperature: 60 °C
Yield: 8 %

Procedure:
To N-(5-fluoro-2-hydroxypyrimidin-4-yl)-4-methylbenzamide (200 mg, 0.81 mmol) in DMF (5 mL) was added K2CO3 (224 mg, 1.6 mmol), and iodomethane (230 mg, 1.6 mmol). The mixture was stirred and heated to 60° C. for 30 min and then stirred for 16 h at room temperature. The mixture was partitioned between ethyl acetate (EtOAc) and water (H2O). The organic phase was dried over magnesium sulfate (MgSO4), filtered and evaporated. The crude material was purified by reverse phase chromatography to yield the title compound as a white solid (17 mg, 8%): mp 229-230° C.; 1H NMR (300 MHz, CDCl3) δ13.2 (br s, 1H), 8.23-8.15 (br m, 2H), 7.42-7.37 (br m, 1H), 7.30-7.25 (br m, 2H), 3.45 (s, 3H), 2.44 (s, 3H); ESIMS m/z 262 ([M+H]+), m/z 260 ([M−H]−).
Reaction SMILES: [CH2:1]([C:4]1[N:5]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[C:6]2[C:11]([C:12]=1[CH2:13][C:14]([O:16]C)=[O:15])=[CH:10][CH:9]=[CH:8][CH:7]=2)[CH:2]=[CH2:3].[Li+].[OH-]>C1COCC1.CO.O>[CH2:1]([C:4]1[N:5]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[C:6]2[C:11]([C:12]=1[CH2:13][C:14]([OH:16])=[O:15])=[CH:10][CH:9]=[CH:8][CH:7]=2)[CH:2]=[CH2:3]
Reactant: C=CCc1c(CC(=O)OC)c2ccccc2n1C(=O)OC(C)(C)C
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: C=CCc1c(CC(=O)O)c2ccccc2n1C(=O)OC(C)(C)C
Reaction time: 2 h
Yield: 104.2 %

Procedure:
To a solution of tert-butyl 2-allyl-3-(2-methoxy-2-oxoethyl)-1H-indole-1-carboxylate (0.94 g, 2.74 mmol) in THF (15 mL) and MeOH (5 mL) was added a solution of LiOH (170 mg, 6.8 mmol) in H2O (5 mL). The solution was stirred for 2 h. The reaction was partitioned between EtOAc and 20% aqueous KH2PO4. The organics were separated, dried over sodium sulfate, and the solvents removed in vacuo to provide 2-(2-allyl-1-(tert-butoxycarbonyl)-1H-indol-3-yl)acetic acid (900 mg). MS (m/z) 316 [M+H]+.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:16][CH:15]2[CH:17]([CH:18]=[O:19])[CH:10]([CH2:11][CH2:12][CH2:13][CH2:14]2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].O.O.O.O.O.O.C(OO)(=O)C1C(=CC=CC=1)C(O)=[O:30].[Mg]>CCO.O>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH:10]2[CH:17]([C:18]([OH:30])=[O:19])[CH:15]([CH2:14][CH2:13][CH2:12][CH2:11]2)[CH2:16]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: O=C(O)c1ccccc1C(=O)OO
Reactant: CC(C)(C)OC(=O)N1CC2CCCCC(C1)C2C=O
Agent: [Mg]
Solvent: O
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CC2CCCCC(C1)C2C(=O)O

Procedure:
2.86 g of 10-formyl-8-aza-bicyclo[4.3.1]decane-8-carboxylic acid tert-butyl ester and 5.8 g of magnesium monoperoxyphthalic acid hexahydrate in 170 ml of EtOH/H2O (1:1) are stirred at RT. The mixture obtained is diluted with EtAc. The mixture obtained is extracted with aqueous 1M HCl and brine. The organic layer obtained is dried, solvent is evaporated and the evaporation residue is crystallized from MeOH/H2O. 8-aza-bicyclo[4.3.1]decane-8,10-dicarboxylic acid 8-tert-butyl ester is obtained. m.p.: 218-222°; 13C-NMR: 179.88, 155.31, 80.00, 52.43, 50.98, 47.63, 33.14, 32.31, 28.91, 27.06.
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[C:9](/[C:11](/[S:18][CH3:19])=[N:12]/[CH2:13][Si:14]([CH3:17])([CH3:16])[CH3:15])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[S:20]1[CH2:23][CH:22]([NH2:24])[CH2:21]1.CCN(C(C)C)C(C)C.F[B-](F)(F)F.BrC1C=CC=C[N+]=1CC>ClCCl.O>[CH3:19][S:18][C:11](=[N:12][CH2:13][Si:14]([CH3:17])([CH3:16])[CH3:15])[C:9]1[CH:8]=[CH:7][C:3]([C:4](=[O:6])[NH:24][CH:22]2[CH2:23][S:20][CH2:21]2)=[C:2]([CH3:1])[CH:10]=1
Reactant: NC1CSC1
Reactant: CS/C(=N\C[Si](C)(C)C)c1ccc(C(=O)O)c(C)c1
Agent: CC[n+]1ccccc1Br
Agent: F[B-](F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: CSC(=NC[Si](C)(C)C)c1ccc(C(=O)NC2CSC2)c(C)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 12.1 %

Procedure:
To a solution of 2-methyl-4-{methylsulfanyl-[(Z)-trimethylsilanyl methylimino]methyl}-benzoic acid (Example I18) (107 mg) in dichloromethane (6 ml) was added thietan-3-ylamine (88 mg), Hünigs base (0.248 ml) and 2-bromo-1-ethyl-pyridinium tetrafluoroborate (169 mg). The reaction mixture was stirred at ambient temperature for 2 hours. Water was added and the mixture was extracted twice with dichloromethane. The combined organic phases were washed with brine, dried over sodium sulfate and concentrated. The residue was purified by chromatography on silica gel (eluent: ethyl acetate/heptanes 1:3) to give 3-methyl-4-(thietan-3-ylcarbamoyl)-N-trimethylsilanylmethyl-thiobenzimidic acid methyl ester (16 mg). 1H-NMR (400 MHz, CDCl3): 7.40-7.20 (m, 3H), 6.20 (d, 1H); 5.30 (m, 1H), 3.55 (s, 2H), 3.35 (m, 2H), 3.25 (m, 2H), 2.35 (s, 3H), 1.95 (s, 3H), 0.00 (s, 9H) ppm.