Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]=[CH:2][C@H:3]([C@@H:5]([C@@H:7]([C@H:9]([CH3:11])[OH:10])[OH:8])[OH:6])[OH:4].C(O[C:16](=[O:18])[CH3:17])(=O)C>>[C:2]([O:4][C@@H:3]([C@@H:5]([C@@H:7]([C@H:9]([CH3:11])[O:10][C:16](=[O:18])[CH3:17])[O:8][C:9](=[O:10])[CH3:11])[O:6][C:5](=[O:6])[CH3:7])[CH:2]=[O:1])(=[O:1])[CH3:3]
Reactant: C[C@H](O)[C@@H](O)[C@@H](O)[C@H](O)C=O
Reactant: CC(=O)OC(C)=O
Product: CC(=O)O[C@H]([C@H](OC(C)=O)[C@H](C)OC(C)=O)[C@@H](C=O)OC(C)=O

Procedure:
L-Fucose is then acetylated with acetic anhydride to produce fucose tetraacetate. Preferably, the reaction is carried out by suspending the L-fucose in a solvent, such as pyridine, and slowly adding the acetic anhydride. The mixture is stirred, poured into a separating funnel containing ice water, and extracted with chloroform. The organic extracts are washed with water, aqueous sodium bicarbonate, and dried over magnesium sulfate. The mixture is filtered and the solvent removed under reduced pressure. The residue is co-evaporated with toluene to remove any remaining pyridine or acetic acid. The fucose tetraacetate is then brominated to produce 2,3,4-tri-O-acetyl-L-fucopyranosyl bromide having the formula: ##STR13## It is to be noted that in the above formula, and elsewhere herein, the use of "Ac" is understood to represent the acetyl radical, i.e., ##STR14## The fucose tetraacetate is brominated with hydrogen bromide in acetic acid. The mixture is worked up similarly to that just described for preparing fucose tetraacetate, i.e., chloroform extraction from ice water.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([O:30][CH2:31][C:32]2[CH:37]=[CH:36][C:35]([C:38]3[CH:43]=[CH:42][C:41]([CH3:44])=[CH:40][CH:39]=3)=[CH:34][CH:33]=2)=[C:6]([CH2:8][CH2:9][N:10]([CH2:19][C:20]2[CH:29]=[CH:28][C:23]([C:24]([O:26]C)=[O:25])=[CH:22][CH:21]=2)[CH2:11][CH2:12][CH2:13][CH2:14][C:15]([O:17]C)=[O:16])[CH:7]=1.[OH-].[Na+].ClCCl>CO>[C:15]([CH2:14][CH2:13][CH2:12][CH2:11][N:10]([CH2:19][C:20]1[CH:29]=[CH:28][C:23]([C:24]([OH:26])=[O:25])=[CH:22][CH:21]=1)[CH2:9][CH2:8][C:6]1[CH:7]=[C:2]([F:1])[CH:3]=[CH:4][C:5]=1[O:30][CH2:31][C:32]1[CH:37]=[CH:36][C:35]([C:38]2[CH:43]=[CH:42][C:41]([CH3:44])=[CH:40][CH:39]=2)=[CH:34][CH:33]=1)([OH:17])=[O:16]
Reactant: COC(=O)CCCCN(CCc1cc(F)ccc1OCc1ccc(-c2ccc(C)cc2)cc1)Cc1ccc(C(=O)OC)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: ClCCl
Product: Cc1ccc(-c2ccc(COc3ccc(F)cc3CCN(CCCCC(=O)O)Cc3ccc(C(=O)O)cc3)cc2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
0.45 g (0.69 mmol) of methyl 4-{[(2-{5-fluoro-2-[(4′-methyl-1,1′-biphenyl-4-yl)methoxy]phenyl}ethyl)(5-methoxy-5-oxopentyl)amino]methyl}benzoate from Ex. 185 is dissolved in 8 ml of methanol. 0.5 ml of aqueous sodium hydroxide solution (45%) and 1.5 ml of dichloromethane are added, and the solution is stirred at RT for 8 hours. The reaction is extracted with diethyl ether, the aqueous phase is acidified using sulphuric acid and extracted with ethyl acetate and the extract is filtered through Extrelut and concentrated.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](O)=[O:7])=[CH:4][CH:3]=1.[CH3:11][O:12][C:13](=[O:24])[C:14]1[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[C:16]([CH3:22])[C:15]=1[NH2:23].O>ClCCl.N1C=CC=CC=1>[CH3:11][O:12][C:13](=[O:24])[C:14]1[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[C:16]([CH3:22])[C:15]=1[NH:23][C:6](=[O:7])[C:5]1[CH:9]=[CH:10][C:2]([F:1])=[CH:3][CH:4]=1
Reactant: COC(=O)c1ccc(OC)c(C)c1N
Reactant: O=C(O)c1ccc(F)cc1
Solvent: O
Solvent: ClCCl
Solvent: c1ccncc1
Product: COC(=O)c1ccc(OC)c(C)c1NC(=O)c1ccc(F)cc1
Yield: 60.9 %

Procedure:
4-Fluoro benzoic acid (700 mg, 5 mmol) was dissolved in dichloromethane (20 ml) and pyridine (2 ml). 2-Amino-4-methoxy-3-methyl-benzoic acid methyl ester (878 mg, 4.5 mmol) was added and the mixture was refluxed for 5 h. Water was added and the mixture was extracted with dichloromethane. The organic phase was dried, filtered and evaporated and the afforded residue was purified by column chromatography on silica gel, eluted with ether-pentane 1:1 which gave pure title compound (870 mg, 61%).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([NH:11][C:12]([CH:14]2[CH2:18][CH:17]([O:19][C:20]3[CH:25]=[C:24]([O:26][CH3:27])[N:23]=[C:22]([C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)[N:21]=3)[CH2:16][CH:15]2[C:34](=[O:43])[N:35]([CH2:37][CH2:38][CH2:39][CH2:40][CH:41]=[CH2:42])[CH3:36])=[O:13])[CH2:8][CH:7]1C=C)=[O:5])[CH3:2]>CC1C=C(C)C(N2C(=[Ru](Cl)(Cl)=CC3C=CC=CC=3OC(C)C)N(C3C(C)=CC(C)=CC=3C)CC2)=C(C)C=1>[CH2:1]([O:3][C:4]([C:6]12[CH2:8][CH:7]1[CH:42]=[CH:41][CH2:40][CH2:39][CH2:38][CH2:37][N:35]([CH3:36])[C:34](=[O:43])[CH:15]1[CH:14]([CH2:18][CH:17]([O:19][C:20]3[CH:25]=[C:24]([O:26][CH3:27])[N:23]=[C:22]([C:28]4[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=4)[N:21]=3)[CH2:16]1)[C:12](=[O:13])[NH:11]2)=[O:5])[CH3:2]
Reactant: C=CCCCCN(C)C(=O)C1CC(Oc2cc(OC)nc(-c3ccccc3)n2)CC1C(=O)NC1(C(=O)OCC)CC1C=C
Agent: Cc1cc(C)c(N2CCN(c3c(C)cc(C)cc3C)C2=[Ru](Cl)(Cl)=Cc2ccccc2OC(C)C)c(C)c1
Product: CCOC(=O)C12CC1C=CCCCCN(C)C(=O)C1CC(Oc3cc(OC)nc(-c4ccccc4)n3)CC1C(=O)N2
Yield: 38.1 %

Procedure:
Compound 7c (1 g, 1.69 mmol) and Hoveyda-Grubbs catalyst, 2nd generation (100 mg) were dissolved in degassed and dry DCE (1000 ml). The mixture was heated to reflux temperature over night under N2-atmosphere. The material was mixed with silica and the solvent was evaporated. Purification by column chromatography, EtOAc/Heptane 30:70→50:50 gave the title compound (362 mg, 38%), MS (M+H)+563.
Reaction SMILES: [N:1]([CH2:4][C:5]1[CH:10]=[CH:9][N:8]=[C:7]([N:11]2[C:15]([C:16]3[O:17][CH:18]=[CH:19][CH:20]=3)=[CH:14][C:13]([C:21]([F:24])([F:23])[F:22])=[N:12]2)[CH:6]=1)=[N+]=[N-].O.O.[Sn](Cl)Cl>CO>[O:17]1[CH:18]=[CH:19][CH:20]=[C:16]1[C:15]1[N:11]([C:7]2[CH:6]=[C:5]([CH2:4][NH2:1])[CH:10]=[CH:9][N:8]=2)[N:12]=[C:13]([C:21]([F:22])([F:23])[F:24])[CH:14]=1
Reactant: [N-]=[N+]=NCc1ccnc(-n2nc(C(F)(F)F)cc2-c2ccco2)c1
Agent: Cl[Sn]Cl
Solvent: CO
Solvent: O
Product: NCc1ccnc(-n2nc(C(F)(F)F)cc2-c2ccco2)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 92.6 %

Procedure:
To a stirred solution of 39 (205 mg, 0.613 mmol) in MeOH (3.1 mL) at room temperature was added tin(II) chloride dihydrate (415 mg, 1.840 mmol) drop wise. The resulting solution was allowed to stir for 2 h at room temperature. The solvent was evaporated. The mixture was quenched with a saturated sodium carbonate solution and extracted with ethyl acetate, washed with brine, dried (MgSO4) filtered and concentrated. Compound 40 (175 mg, 93%) was isolated and used as is for the next step. LRMS (ESI): calc. 308.1; found 309.1 (MH)+.
Reaction SMILES: [C:1]1([C:7]2[O:8][C:9]3[CH:15]=[C:14]([CH2:16][C:17](OCC)=[O:18])[CH:13]=[CH:12][C:10]=3[N:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[H-].[H-].[H-].[Li+].[Al+3].O.[OH-].[Na+]>C1COCC1>[C:1]1([C:7]2[O:8][C:9]3[CH:15]=[C:14]([CH2:16][CH2:17][OH:18])[CH:13]=[CH:12][C:10]=3[N:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CCOC(=O)Cc1ccc2nc(-c3ccccc3)oc2c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: OCCc1ccc2nc(-c3ccccc3)oc2c1
Reaction time: 2 h
Yield: 62.6 %

Procedure:
To the stirred solution of ethyl 2-(2-phenylbenzo[d]oxazol-6-yl)acetate (Daiichi Pharmaceuticals complay, Ltd, see EP1346982 A1, 2003)(407 mg, 1.37 mmol) in THF (12 mL) was added LAH at 10° C. The reaction mixture was allowed to stir at the same temperature for 2 h, water (0.07 mL), aqueous 15% NaOH (0.07 mL), and water (0.21 mL) were each carefully added to the mixture. The resulting slurry was filtered through a pad of Celite and concentrated in vacuo. The crude product was purified by flash column chromatography to afford the desired product as a clear gel (218 mg, 0.858 mmol, 63%). 1H NMR (DMSO-d6): 2.75 (t, 2H, J=7 Hz), 3.59 (q, 2H, J=7 Hz), 4.62 (t, 1H, J=5.2 Hz), 6.98 (t, 1H, J=7.4 Hz), 7.03 (dd, 1H, J=7.8 Hz, 1.2 Hz), 7.29-7.34 (m, 4H), 7.71 (d, 2H, J=7.6 Hz), 10.51 (s, 1H).
Reaction SMILES: [NH2:1][C:2]1[C:3]2[CH:13]=[C:12](Br)[CH:11]=[CH:10][C:4]=2[S:5][C:6]=1[C:7]([NH2:9])=[O:8].[C:15]1(B(O)O)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C(=O)([O-])[O-].[Na+].[Na+]>CN(C=O)C.CC#N.O>[NH2:1][C:2]1[C:3]2[CH:13]=[C:12]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[CH:11]=[CH:10][C:4]=2[S:5][C:6]=1[C:7]([NH2:9])=[O:8]
Reactant: OB(O)c1ccccc1
Reactant: NC(=O)c1sc2ccc(Br)cc2c1N
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CC#N
Product: NC(=O)c1sc2ccc(-c3ccccc3)cc2c1N
Temperature: 80 °C
Yield: 8.4 %

Procedure:
To a stirred solution of 3-amino-5-bromo-benzo[b]thiophene-2-carboxylic acid amide (90 mg, 0.33 mmol) in DMF (5 mL) was added phenylboronic acid (1.2 eq., 50 mg) at room temperature, under nitrogen. The resulting mixture was degassed and placed under nitrogen after which time sodium carbonate (1.2 eq., 43 mg) and Pd(Ph3)4 (0.4 eq., 155 mg) were added. The reaction was degassed again and warmed to 80° C. overnight, under nitrogen. Upon cooling to room temperature, the reaction was concentrated to dryness and the remaining residue was purified via flash column chromatrography (5 g SiO2, 0-40% EtOAc/dichloromethane). The product-containing fractions were concentrated to give the product which was still contaminated. The brown solid was diluted with 1:1 CH3CN/H2O and the remaining solids were removed via filtration. The filtrate was re-purified using preparatory reverse phase HPLC to give 7.4 mg (8%) of the title compound as a white solid.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH:6]=[C:7]1[CH2:12][CH2:11][CH2:10][NH:9][C:8]1=[O:13].CO>[Ir].ClCCl>[O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][CH:7]1[CH2:12][CH2:11][CH2:10][NH:9][C:8]1=[O:13]
Reactant: O=C1NCCCC1=Cc1ccco1
Agent: [Ir]
Solvent: ClCCl
Solvent: CO
Product: O=C1NCCCC1Cc1ccco1
Yield: 91.7 %

Procedure:
This example describes the preparation of I where n=2 and R1=2-furanyl. In a nitrogen-filled glove box, a Fisher-Porter tube was charged with iridium catalyst prepared as in Example 1 (10 mg, 0.012 mmol) and 3-(2-furanylmethylidene)-2-piperidone (250 mg, 1.4 mmol). Methanol (3 mL) and dichloromethane (3 mL) were added and the system was flushed 4 times with hydrogen and pressured to 60 psi (0.5 MPa) H2. After 18 h the reaction mixture was filtered through a short pad of silica. The solvent was removed at reduced pressure to afford 3-(2-furanylmethyl)-2-piperidone (230 mg, 92%) as a white crystalline solid. Chiral HPLC analysis (Chiralpak AD, 85% heptane, 15% ethanol, 30° C.) indicated that conversion was 100% and the enantiomeric excess was 95%. 13C NMR: δ 21.55, 26.12, 29.99, 40.91, 42.57, 106.80, 110.39, 141.38, 153.99, 174.20; 1H NMR: δ 1.49 (m, 1H), 1.68 (m, 1H), 1.75-1.91 (m, 2H), 2.62 (m, 1H), 2.82 (m, 1H), 3.29 (m, 3H), 6.06 (m, 1H), 6.29 (m, 1H), 7.29 (m, 1H), 7.34 (br s, 1H).
Reaction SMILES: Br.[CH3:2][N:3]([CH3:25])[CH2:4][CH2:5][CH2:6][C:7]1([C:18]2[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=2)[C:11]2[CH:12]=[CH:13][C:14]([C:16]#[N:17])=[CH:15][C:10]=2[CH2:9][O:8]1.[NH:26]1[CH2:31][CH2:30][O:29][CH2:28][CH2:27]1>>[CH3:25][N:3]([CH3:2])[CH2:4][CH2:5][CH2:6][C:7]1([C:18]2[CH:19]=[CH:20][C:21]([F:24])=[CH:22][CH:23]=2)[C:11]2[CH:12]=[CH:13][C:14]([C:16]([N:26]3[CH2:31][CH2:30][O:29][CH2:28][CH2:27]3)=[NH:17])=[CH:15][C:10]=2[CH2:9][O:8]1
Reactant: CN(C)CCCC1(c2ccc(F)cc2)OCc2cc(C#N)ccc21
Reactant: C1COCCN1
Agent: Br
Product: CN(C)CCCC1(c2ccc(F)cc2)OCc2cc(C(=N)N3CCOCC3)ccc21
Temperature: 80 °C
Yield: 15 %

Procedure:
Using 400 mg of 1-[3-(dimethylamino)propyl]-1-(4-fluorophenyl)-1,3-dihydro-2-benzofuran-5-carbonitrile hydrobromide (citalopram HBr) and morpholine (1.5 equiv) gave, after heating at 80° C. for 28 h, title product (75 mg, 15% yield) as a white solid.
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[CH2:10][NH:11][CH:12]1[CH2:17][CH2:16][N:15]([CH2:18][CH:19]([CH2:21][O:22][C:23]2[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=2)[OH:20])[CH2:14][CH2:13]1.[OH:30][CH:31]([CH:35]([OH:39])[C:36]([OH:38])=[O:37])[C:32]([OH:34])=[O:33]>C(O)C>[S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[CH2:10][NH:11][CH:12]1[CH2:13][CH2:14][N:15]([CH2:18][CH:19]([CH2:21][O:22][C:23]2[CH:24]=[CH:25][C:26]([F:29])=[CH:27][CH:28]=2)[OH:20])[CH2:16][CH2:17]1.[OH:30][CH:31]([CH:35]([OH:39])[C:36]([O-:38])=[O:37])[C:32]([O-:34])=[O:33]
Reactant: O=C(O)C(O)C(O)C(=O)O
Agent: OC(COc1ccc(F)cc1)CN1CCC(NCc2nc3ccccc3s2)CC1
Solvent: CCO
Product: O=C([O-])C(O)C(O)C(=O)[O-]

Procedure:
To a stirred solution of 5 parts of 4-[(2-benzothiazolyl)methylamino]-α-[(4-fluorophenoxy)methyl]-1-piperidineethanol in 80 parts of ethanol were added 1.8 parts of (+)-[R-(R*,R*)]-2,3-dihydroxybutanedioic acid while boiling. The product was allowed to crystallize. It was filtered off and dried, yielding 5.5 parts (94%) of (+)-4-[(2-benzothiazolyl)methylamino]-α-[(4-fluorophenoxy)methyl]-1-piperidineethanol [R-(R*,R*)]-2,3-dihydroxybutanedioate (2:1); mp. 189.1° C. (457).
Reaction SMILES: [CH:1]1([CH:7]([NH:19][C:20]2[CH:25]=[CH:24][C:23]([C:26]([N:28]([CH3:36])[CH2:29][CH2:30][C:31]([O:33]CC)=[O:32])=[O:27])=[CH:22][CH:21]=2)[C:8]2[O:9][C:10]3[CH:17]=[CH:16][C:15]([F:18])=[CH:14][C:11]=3[C:12]=2[CH3:13])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.CCCCCC.C(O)C.C(O)C.[OH-].[Na+]>O1CCCC1>[CH:1]1([CH:7]([NH:19][C:20]2[CH:21]=[CH:22][C:23]([C:26]([N:28]([CH3:36])[CH2:29][CH2:30][C:31]([OH:33])=[O:32])=[O:27])=[CH:24][CH:25]=2)[C:8]2[O:9][C:10]3[CH:17]=[CH:16][C:15]([F:18])=[CH:14][C:11]=3[C:12]=2[CH3:13])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CCOC(=O)CCN(C)C(=O)c1ccc(NC(c2oc3ccc(F)cc3c2C)C2CCCCC2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Solvent: CCCCCC
Product: Cc1c(C(Nc2ccc(C(=O)N(C)CCC(=O)O)cc2)C2CCCCC2)oc2ccc(F)cc12
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
Ethyl 3-{[(4-{[cyclohexyl (5-fluoro-3-methyl-1-benzofuran-2-yl)methyl]amino}phenyl) carbonyl](methyl)amino}propanoate (564 mg) synthesized above was fractionated by high performance liquid chromatography (column: CHIRALPAK AD (50 mm ID×500 mL, manufactured by Daicel Chemical Industries, Ltd., mobile phase: hexane/ethanol (400/600), flow rate: 60 mL/min, column temperature: 30° C.). The fraction containing an optically active form having a shorter retention time under the above-mentioned high performance liquid chromatography conditions was concentrated to give an amorphous form (274 mg, 99.9% ee). To a mixture of the obtained amorphous form, ethanol (5 mL) and tetrahydrofuran (5 mL) was added 1N aqueous sodium hydroxide solution (1.00 mL), and the mixture was stirred at room temperature for 1.5 hr, and concentrated under reduced pressure. The residue was dissolved in water (10 mL), and 1N hydrochloric acid (1.00 mL) was added at 0° C. The resulting precipitate was collected by filtration to give the title object compound (249 mg, 47%, 99.9% ee) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([F:11])[C:8]([N+:12]([O-:14])=[O:13])=[CH:7][C:3]=1[C:4](O)=[O:5].S(Cl)([Cl:17])=O.C1(P(=O)(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>>[Cl:1][C:2]1[CH:10]=[C:9]([F:11])[C:8]([N+:12]([O-:14])=[O:13])=[CH:7][C:3]=1[C:4]([Cl:17])=[O:5]
Reactant: O=S(Cl)Cl
Reactant: O=C(O)c1cc([N+](=O)[O-])c(F)cc1Cl
Agent: O=P(c1ccccc1)(c1ccccc1)c1ccccc1
Product: O=C(Cl)c1cc([N+](=O)[O-])c(F)cc1Cl

Procedure:
22.3 g (0.1 mol) of 2-chloro-4-fluoro-5-nitrobenzoic acid 16.8 g (0.14 mol) of thionyl chloride 0.1 g (0.00036 mol) of triphenyl phosphine oxide Yield*: 46.5 g (>99% of theory) of the title compound as a solution in chlorobenzene * In these examples, the yield was determined by means of 19F-NMR with internal standard. Fluoride value: 0.01 g/l
Reaction SMILES: Cl[C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[C:7]([NH:12][C:13](=[O:19])[O:14][C:15]([CH3:18])([CH3:17])[CH3:16])[N:8]=[CH:9]2)=[CH:4][N:3]=1.[CH3:20][C:21]1[CH:26]=[CH:25][N:24]=[CH:23][C:22]=1B(O)O.C(=O)([O-])[O-].[Na+].[Na+]>C(#N)C.C(OCC)(=O)C.CC(P(C(C)(C)C)C1C=CC(N(C)C)=CC=1)(C)C.CC(P(C(C)(C)C)C1C=CC(N(C)C)=CC=1)(C)C.Cl[Pd]Cl>[CH3:20][C:21]1[CH:26]=[CH:25][N:24]=[CH:23][C:22]=1[C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[C:7]([NH:12][C:13](=[O:19])[O:14][C:15]([CH3:18])([CH3:17])[CH3:16])[N:8]=[CH:9]2)=[CH:4][N:3]=1
Reactant: CC(C)(C)OC(=O)Nc1cc2cnc(Cl)cc2cn1
Reactant: Cc1ccncc1B(O)O
Agent: Cl[Pd]Cl
Agent: CN(C)c1ccc(P(C(C)(C)C)C(C)(C)C)cc1
Agent: O=C([O-])[O-]
Solvent: CC#N
Solvent: CCOC(C)=O
Product: Cc1ccncc1-c1cc2cnc(NC(=O)OC(C)(C)C)cc2cn1
Temperature: 130 °C
Yield: 34.2 %

Procedure:
A mixture of tert-butyl N-(7-chloro-2,6-naphthyridin-3-yl)carbamate (460 mg, 1.65 mmol), (4-methyl-3-pyridyl)boronic acid (450 mg, 3.3 mmol), bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium(II) (117 mg, 0.165 mmol) and saturated aqueous sodium carbonate solution (0.5 mL) in acetonitrile (5 mL) was heated under microwave irradiation (Biotage) at 130° C. for 30 minutes. The reaction mixture was diluted with ethyl acetate (150 mL) and washed with water (50 mL). The organic layer was separated, dried over sodium sulfate, filtered and concentrated in vacuo to provide a residue that was purified by flash chromatography (12 g, Silica, 0-10% methanol in dichloromethane). Desired fractions were combined and evaporated in vacuo to afford the title compound as a white solid (190 mg, 34%), which was used in the next step without further purification.
Reaction SMILES: [F:1][C:2]([F:35])([F:34])[C:3]1[CH:4]=[C:5]([CH:27]=[C:28]([C:30]([F:33])([F:32])[F:31])[CH:29]=1)[C:6]([N:8]1[CH2:26][CH2:25][C:11]2([N:15]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[CH3:22])[CH:14]([CH3:23])[NH:13][C:12]2=[O:24])[CH2:10][CH2:9]1)=[O:7].Br[CH2:37][CH:38]=[C:39]([CH3:41])[CH3:40]>>[F:35][C:2]([F:1])([F:34])[C:3]1[CH:4]=[C:5]([CH:27]=[C:28]([C:30]([F:33])([F:32])[F:31])[CH:29]=1)[C:6]([N:8]1[CH2:9][CH2:10][C:11]2([N:15]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[CH3:22])[CH:14]([CH3:23])[N:13]([CH2:37][CH:38]=[C:39]([CH3:41])[CH3:40])[C:12]2=[O:24])[CH2:25][CH2:26]1)=[O:7]
Reactant: CC(C)=CCBr
Reactant: Cc1ccccc1N1C(C)NC(=O)C12CCN(C(=O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1)CC2
Product: CC(C)=CCN1C(=O)C2(CCN(C(=O)c3cc(C(F)(F)F)cc(C(F)(F)F)c3)CC2)N(c2ccccc2C)C1C

Procedure:
The title compound, MS: m/e=568.2 (M+H+), was prepared in accordance with the general method of example 99 from (rac)-8-(3,5-bis-trifluoromethyl-benzoyl)-2-methyl-1-o-tolyl-1,3,8-triaza-spiro[4.5]decan-4-one and 1-bromo-3-methyl-2-butene.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]([C:19]2[CH:29]=[CH:28][C:22]([C:23]([N:25]([CH3:27])[CH3:26])=[O:24])=[CH:21][CH:20]=2)[CH2:9][C:10]([C:12]2[CH:17]=[CH:16][N:15]=[C:14]([CH3:18])[CH:13]=2)=O)=[C:4]([CH3:30])[CH:3]=1.Cl.[NH2:32][OH:33].C(=O)([O-])O.[Na+]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]([C:19]2[CH:29]=[CH:28][C:22]([C:23]([N:25]([CH3:27])[CH3:26])=[O:24])=[CH:21][CH:20]=2)[CH2:9]/[C:10](=[N:32]\[OH:33])/[C:12]2[CH:17]=[CH:16][N:15]=[C:14]([CH3:18])[CH:13]=2)=[C:4]([CH3:30])[CH:3]=1
Reactant: NO
Reactant: Cc1cc(C(=O)C[C@@H](c2ccc(C(=O)N(C)C)cc2)c2ccc(Cl)cc2C)ccn1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: Cc1cc(/C(C[C@@H](c2ccc(C(=O)N(C)C)cc2)c2ccc(Cl)cc2C)=N/O)ccn1

Procedure:
In analogy to example 132, step 6, from 4-[(S)-1-(4-chloro-2-methyl-phenyl)-3-(2-methyl-pyridin-4-yl)-3-oxo-propyl]-N,N-dimethyl-benzamide and hydroxylamine hydrochloride in the presence of sodium hydrogencarbonate was prepared the title compound as a white foam, MS (ESI+): m/z=436.3 ([M+H]+).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:15])[CH2:5][CH2:6][NH:7][CH:8]1[CH2:12][CH2:11][CH2:10][C:9]1([CH3:14])[CH3:13])[CH3:2].[Cl:16][C:17]1[N:22]=[C:21](Cl)[C:20]([N+:24]([O-:26])=[O:25])=[CH:19][N:18]=1.C(=O)(O)[O-].[K+]>O.C(OCC)C>[CH2:1]([O:3][C:4](=[O:15])[CH2:5][CH2:6][N:7]([C:19]1[C:20]([N+:24]([O-:26])=[O:25])=[CH:21][N:22]=[C:17]([Cl:16])[N:18]=1)[CH:8]1[CH2:12][CH2:11][CH2:10][C:9]1([CH3:14])[CH3:13])[CH3:2]
Reactant: O=[N+]([O-])c1cnc(Cl)nc1Cl
Reactant: CCOC(=O)CCNC1CCCC1(C)C
Agent: O=C([O-])O
Agent: [K+]
Solvent: CCOCC
Solvent: O
Product: CCOC(=O)CCN(c1nc(Cl)ncc1[N+](=O)[O-])C1CCCC1(C)C
Temperature: 25 °C
Reaction time: 3 h
Yield: 89 %

Procedure:
A solution of 2.2 g (0.011 mole) of (rac)-3-(2,2-dimethyl-cyclopentylamino)-propanoic acid ethyl ester in 30 mL of water was added dropwise to a solution of 1.94 g (0.01 mole) of 2,4-dichloro-5-nitro-pyrimidine in 30 mL of ethyl ether. At 0 degrees, 2.0 g (0.010 mole) of potassium bicarbonate was added. The mixture was stirred at ambient temperature for 3 hours. The layers were then separated, and the aqueous layer extracted twice with 30 mL of ether. The combined organic layers were dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. Purification by silica gel chromatography, eluting with hexanes-ethyl acetate (100:0-92:8) gave 3.3 g of (rac)-3-[(2-chloro-5-nitro-pyrimidin-4-yl)-(2,2-dimethyl-cyclopentyl)-amino]-propanoic acid ethyl ester (IV-59).
Reaction SMILES: [ClH:1].[C:2]([C:5]1[CH:13]=[CH:12][C:8]([C:9](N)=[O:10])=[CH:7][CH:6]=1)(=[NH:4])[NH2:3].C(O)(=[O:16])C>Cl>[ClH:1].[C:2]([C:5]1[CH:13]=[CH:12][C:8]([C:9]([OH:16])=[O:10])=[CH:7][CH:6]=1)(=[NH:4])[NH2:3]
Reactant: N=C(N)c1ccc(C(N)=O)cc1
Reactant: CC(=O)O
Agent: Cl
Product: N=C(N)c1ccc(C(=O)O)cc1
Temperature: 110 °C

Procedure:
4-Amidinobenzamide hydrochloride (10 g) was dissolved in a mixed solution of 6N HCl (300 ml) and acetic acid (50 ml) and the solution was refluxed at 110° C. for 6 hours. The reaction solution was cooled with ice and the resulting precipitate was filtered to yield a crystal of 4-amidinobenzoic acid hydrochloride (10.4 g).
Reaction SMILES: [CH2:1]([C:5]1[CH:10]=[CH:9][C:8]([NH:11][CH2:12][C:13]2[CH:18]=[CH:17][C:16]([N:19]([CH3:21])[CH3:20])=[CH:15][CH:14]=2)=[CH:7][CH:6]=1)[CH2:2][CH2:3][CH3:4].[CH:22]([C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([CH:31]([CH3:33])[CH3:32])[C:26]=1[N:34]=[C:35]=[O:36])([CH3:24])[CH3:23]>C1C=CC=CC=1>[CH2:1]([C:5]1[CH:10]=[CH:9][C:8]([N:11]([CH2:12][C:13]2[CH:18]=[CH:17][C:16]([N:19]([CH3:21])[CH3:20])=[CH:15][CH:14]=2)[C:35]([NH:34][C:26]2[C:25]([CH:22]([CH3:23])[CH3:24])=[CH:30][CH:29]=[CH:28][C:27]=2[CH:31]([CH3:33])[CH3:32])=[O:36])=[CH:7][CH:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CC(C)c1cccc(C(C)C)c1N=C=O
Reactant: CCCCc1ccc(NCc2ccc(N(C)C)cc2)cc1
Solvent: c1ccccc1
Product: CCCCc1ccc(N(Cc2ccc(N(C)C)cc2)C(=O)Nc2c(C(C)C)cccc2C(C)C)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of (4-butylphenyl)[(4-dimethylaminophenyl)methyl]amine (0.6 g) in benzene (5 mL) was added 2,6-diisopropylphenyl isocyanate (0.46 mL) and the mixture was stirred overnight at room temperature. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography to give N-(4-butylphenyl)-N′-(2,6-diisopropylphenyl)-N-[(4-dimethylaminophenyl)methyl]urea (0.34 g).