Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O-:2].[Na+].Cl[C:5]1[N:6]=[N:7][C:8]([C:11]2[CH:16]=[CH:15][N:14]=[CH:13][CH:12]=2)=[CH:9][CH:10]=1>CO>[CH3:1][O:2][C:5]1[N:6]=[N:7][C:8]([C:11]2[CH:16]=[CH:15][N:14]=[CH:13][CH:12]=2)=[CH:9][CH:10]=1
Reactant: Clc1ccc(-c2ccncc2)nn1
Reactant: C[O-]
Agent: [Na+]
Solvent: CO
Product: COc1ccc(-c2ccncc2)nn1

Procedure:
63 ml of a 32% sodium methoxide solution in methanol are added to a solution of 57 g 3-chloro-6-pyridin-4-yl-pyridazine in methanol and the reaction mixture stirred under reflux for 1.5 h. The solvens is removed under reduced pressure, the residue suspended in 0.7 L water and the pH adjusted to 7. Extraction with dichloromethane yielded 57 g 3-methoxy-6-pyridin-4-yl-pyridazine, which is used without further purification.
Reaction SMILES: CN1[C@@]2(CO)SS[C@]3(N(C2=O)[C@H]2NC4C([C@@]2(N2[C:32]5[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=5)[C:26]([CH2:33][C:34]56SS[C@@](CO)(C(N5C)=O)N(C)[C:35]6=[O:36])=C2)C3)=CC=CC=4)C1=O.[OH2:48]>>[C:35]([OH:36])(=[O:48])[CH2:34][CH2:33][CH2:26][CH2:27][CH2:32][CH2:31][CH2:30]/[CH:29]=[CH:28]\[CH2:34][CH2:33][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31]
Reactant: O
Reactant: CN1C(=O)[C@]2(CO)SSC1(Cc1cn([C@]34C[C@@]56SS[C@@](CO)(C(=O)N5[C@H]3Nc3ccccc34)N(C)C6=O)c3ccccc13)C(=O)N2C
Product: CCCCCCCC/C=C\CCCCCCCC(=O)O

Procedure:
Four hundred grams of oleic acid (SO-90L, produced by Kao Corporation), 16 g of activated clay (CS-1, mean inter-layer distance of 4 Å, produced by Mizusawa Kagaku) and 8 g of water were placed in an autoclave. After the inside atmosphere of the autoclave was replaced with nitrogen, the mixture was stirred. The inside of the autoclave was heated to 240° C. and kept in a steam atmosphere of 14 kgf/cm2 for 6 hours. After cooling, the reaction mixture obtained was taken out from the autoclave, and the semisynthetic clay was filtered off. The filtrate was distilled under a reduced pressure to yield 167.6 g of monomeric acids.
Reaction SMILES: [CH:1]1([NH2:4])[CH2:3][CH2:2]1.[CH3:5][O:6][C:7]1[CH:8]=[C:9]([CH:12]=[CH:13][C:14]=1[O:15][CH3:16])[CH:10]=O>>[CH:1]1([NH:4][CH2:10][C:9]2[CH:12]=[CH:13][C:14]([O:15][CH3:16])=[C:7]([O:6][CH3:5])[CH:8]=2)[CH2:3][CH2:2]1
Reactant: COc1ccc(C=O)cc1OC
Reactant: NC1CC1
Product: COc1ccc(CNC2CC2)cc1OC

Procedure:
prepared by reaction of cyclopropylamine with 3,4-dimethoxy-benzaldehyde
Reaction SMILES: [H-].[Na+].[C:3](=[O:8])([O:6][CH3:7])OC.[CH3:9][O:10][C:11]1[CH:12]=[C:13]2[C:18](=[CH:19][CH:20]=1)[C:17](=[O:21])[CH2:16][CH2:15][CH2:14]2.C(O)(=O)C>O1CCCC1>[CH3:9][O:10][C:11]1[CH:12]=[C:13]2[C:18](=[CH:19][CH:20]=1)[C:17](=[O:21])[CH:16]([C:3]([O:6][CH3:7])=[O:8])[CH2:15][CH2:14]2
Reactant: COC(=O)OC
Reactant: COc1ccc2c(c1)CCCC2=O
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: COC(=O)C1CCc2cc(OC)ccc2C1=O
Temperature: 0 °C
Yield: 95.2 %

Procedure:
A suspension of 24.0 g (0.60 mole) of sodium hydride (60% dispersion in mineral oil) and 49.5 ml (52.9 g; 0.59 mole) of dimethyl carbonate (freshly distilled from sodium hydride) in 240 ml of tetrahydrofuran under a nitrogen atmosphere was stirred and heated to reflux. Reflux was maintained while a solution of 29.7 g (0.17 mole) of 6-methoxy-1-tetralone in 105 ml of tetrahydrofuran was added dropwise over two hours. After addition was complete, the mixture was stirred at reflux for an additional 90 minutes, cooled in ice, and treated dropwise with 36 ml of glacial acetic acid, followed by 450 ml of ice water. The two-phase reaction mixture was extracted with ethyl acetate (4×250 ml), and the combined organic layers were washed with water (1×600 ml), 5% aqueous sodium bicarbonate solution (3×600 ml), and water again. The ethyl acetate extract was dried (anhydrous sodium sulfate and evaporated (vacuum). The residue was pulverized and stirred in 500 ml of hexane. Filtration yielded 37.9 g (96% yield) of the ester product, mp 79°-81°, suitable for further synthesis. A sample purified by bulb-to-bulb distillation followed by recrystallization from hexane/ethyl acetate was analytically pure, mp 82°-84° (a mp of 88°-89° is given by J. Jacques and A. Horeau, Bull. Soc. Chem. France, 512 (1950)).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([OH:8])[CH:5]=[N:6][CH:7]=1.[H-].[Na+].[CH3:11][O:12][CH2:13]Cl>O1CCCC1>[CH3:11][O:12][CH2:13][O:8][C:4]1[CH:5]=[N:6][CH:7]=[C:2]([Cl:1])[CH:3]=1
Reactant: Oc1cncc(Cl)c1
Reactant: COCCl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COCOc1cncc(Cl)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 97.3 %

Procedure:
Under argon atmosphere, into a solution of 5-chloro-3-pyridinol (5.0 g, 38.6 mmol) in 100 mL of dry tetrahydrofuran at room temperature was added 60% sodium hydride (1.85 g, 46.3 mmol). After stirring the mixture for 1 hour at room temperature, a solution of chloromethyl methyl ether (3.42 g, 42.6 mmol) in 10 mL of dry tetrahydrofuran was added over 10 min. The resulting mixture was heated to reflux for 16 hours. The solvent was evaporated, and the residue was diluted with ethyl acetate, then washed with 1N aq. NaOH. The combined organic layer was then concentrated to give the crude material. Column chromatography on silica gel, eluting with ethyl acetate/hexane (30/70, v/v/), gave the desired product (6.52 g, 97%).
Reaction SMILES: [OH:1][N:2]=[C:3]([NH2:10])[C:4]1[CH:9]=[CH:8][CH:7]=[N:6][CH:5]=1.[C:11]([O:15][C:16]([NH:18][C:19]1[CH:20]=[C:21]([CH:25]=[CH:26][CH:27]=1)[C:22](O)=O)=[O:17])([CH3:14])([CH3:13])[CH3:12].N>>[N:6]1[CH:7]=[CH:8][CH:9]=[C:4]([C:3]2[N:10]=[C:22]([C:21]3[CH:20]=[C:19]([NH:18][C:16](=[O:17])[O:15][C:11]([CH3:13])([CH3:12])[CH3:14])[CH:27]=[CH:26][CH:25]=3)[O:1][N:2]=2)[CH:5]=1
Reactant: CC(C)(C)OC(=O)Nc1cccc(C(=O)O)c1
Reactant: NC(=NO)c1cccnc1
Agent: N
Product: CC(C)(C)OC(=O)Nc1cccc(-c2nc(-c3cccnc3)no2)c1

Procedure:
The title compound was prepared according to the procedure of Example 8 using N′-hydroxynicotinimidamide (Aldrich) and 3-(tert-butoxycarbonylamino)benzoic acid (Aldrich). 1H NMR (300 MHz, CDCl3) δ 1.56 (s, 9 H), 6.71 (s, 1 H), 7.39-7.58 (m, 2 H), 7.68 (d, J=7.9 Hz, 1 H), 7.89 (d, J=9.1 Hz, 1 H), 8.24 (s, 1 H), 8.45 (d, J=7.9 Hz, 1 H), 8.77 (d, J=4.8 Hz, 1 H), 9.40 (s, 1 H) ppm; MS (DCI/NH3) m/z 339 (M+H)+, 356 (M+NH4)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]2[O:12][C:11](=[O:13])[N:10]([CH:14]([CH3:24])[CH2:15][C:16]3[CH:21]=[CH:20][C:19]([OH:22])=[C:18]([OH:23])[CH:17]=3)[CH2:9]2)[CH:5]=[CH:6][CH:7]=1.Br[C:26](Br)([C:30]([NH2:32])=[O:31])[C:27]([NH2:29])=[O:28].C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH:8]2[O:12][C:11](=[O:13])[N:10]([CH:14]([CH3:24])[CH2:15][C:16]3[CH:21]=[CH:20][C:19]4[O:22][C:26]([C:30]([NH2:32])=[O:31])([C:27]([NH2:29])=[O:28])[O:23][C:18]=4[CH:17]=3)[CH2:9]2)[CH:5]=[CH:6][CH:7]=1
Reactant: NC(=O)C(Br)(Br)C(N)=O
Reactant: CC(Cc1ccc(O)c(O)c1)N1CC(c2cccc(Cl)c2)OC1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CC(Cc1ccc2c(c1)OC(C(N)=O)(C(N)=O)O2)N1CC(c2cccc(Cl)c2)OC1=O

Procedure:
One equivalent of 5-(3-chlorophenyl) -3-(2-(3,4-dihydroxyphenyl)-1-methylethyl )-2-oxazolidinone, prepared by the procedure of U.S. Pat. No. 5,061,727; Example 1, one equivalent of dibromomalonamide, acetonitrile, and 4 equivalents of potassium carbonate are stirred at room temperature for 18 hours. The reaction mixture is filtered and evaporated in vacuo to give 5-(2-(5-(3-chlorophenyl)-2-oxo-3-oxazolidinyl)propyl)-1,3 -benzodioxole-2,2-dicarboxamide.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]([C:18]2[C:23]([O:24][CH3:25])=[C:22]([CH3:26])[C:21]([CH3:27])=[C:20]([CH:28]([OH:30])[CH3:29])[C:19]=2[CH3:31])[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C:14]([O:16][CH3:17])=[O:15])=[CH:4][CH:3]=1.[Cr](Cl)([O-])(=O)=O.[NH+]1C=CC=CC=1.C(OCC)C>ClCCl>[C:28]([C:20]1[C:19]([CH3:31])=[C:18]([C@@H:8]([C:5]2[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=2)[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C:14]([O:16][CH3:17])=[O:15])[C:23]([O:24][CH3:25])=[C:22]([CH3:26])[C:21]=1[CH3:27])(=[O:30])[CH3:29]
Reactant: COC(=O)CCCCC[C@H](c1ccc(F)cc1)c1c(C)c(C(C)O)c(C)c(C)c1OC
Agent: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Solvent: CCOCC
Solvent: ClCCl
Product: COC(=O)CCCCC[C@H](c1ccc(F)cc1)c1c(C)c(C(C)=O)c(C)c(C)c1OC
Reaction time: 2 h
Yield: 95.8 %

Procedure:
A solution of methyl (R)-7-(4-fluorophenyl)-7-[3-(1-hydroxyethyl)-6-methoxy-2,4,5-trimethylphenyl]heptanoate (4.1 g, 9.5 mmol) in dichloromethane (10 ml) was added to a solution of pyridinium chlorochromate (3.3 g, 15.2 mmol) in dichloromethane (20 ml) at room temperature. The mixture was stirred for 2 hours at the same temperature. To the mixture was added diethyl ether. Insolubles were filtered off, and the filtrate was concentrated under reduced pressure. The residue was subjected to a silica gel column chromatography to give methyl (R)-7-(3-acetyl-6-methoxy-2,4,5-trimethylphenyl)-7-(4-fluorophenyl)heptanoate (3.9 g). Physico-chemical properties and spectral data are shown in [Table 5].
Reaction SMILES: Br.Br[CH2:3][C:4]1[C:9]([Cl:10])=[CH:8][N:7]=[CH:6][C:5]=1[Cl:11].[NH2:12][C:13]1[CH:18]=[C:17]([CH3:19])[N:16]=[C:15]([SH:20])[N:14]=1.C(N(CC)CC)C>CCO>[Cl:11][C:5]1[CH:6]=[N:7][CH:8]=[C:9]([Cl:10])[C:4]=1[CH2:3][S:20][C:15]1[N:14]=[C:13]([NH2:12])[CH:18]=[C:17]([CH3:19])[N:16]=1
Reactant: Clc1cncc(Cl)c1CBr
Reactant: Cc1cc(N)nc(S)n1
Agent: Br
Solvent: CCN(CC)CC
Solvent: CCO
Product: Cc1cc(N)nc(SCc2c(Cl)cncc2Cl)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 88.8 %

Procedure:
A mixture of 4-(bromomethyl)-3,5-dichloropyridine hydrobromide (2.9 g, 10.5 mmol), 4-amino-6-methylpyrimidine-2-thiol (1.0 g, 7.1 mmol), and triethylamine (3 mL, 21.5 mmol) in absolute EtOH (80 mL) was stirred at room temperature overnight. The mixture was evaporated, co-evaporated with EtOAc (20 mL), and dried in vacuo. The solid residue was treated with water (150 mL). The solid product was recovered by filtration, washed with water (2×25 mL), diethyl ether (2×25 mL), and hexanes (2×25 mL), and dried in vacuo, affording the title compound (1.9 g, 92% yield); 1H NMR (400 MHz, DMSO-d6): δ 2.29 (s, 3H), 4.78 (s, 2H), 6.29 (s, 1H), 8.45 (s (br), 2H), 8.69 (s, 2H); M+ 302.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9](=[O:13])[CH2:8][CH2:7][CH2:6]2.CO[CH:16](OC)[N:17]([CH3:19])[CH3:18]>>[CH3:16][N:17]([CH:19]=[C:8]1[CH2:7][CH2:6][C:5]2[C:10](=[CH:11][CH:12]=[C:3]([O:2][CH3:1])[CH:4]=2)[C:9]1=[O:13])[CH3:18]
Reactant: COc1ccc2c(c1)CCCC2=O
Reactant: COC(OC)N(C)C
Product: COc1ccc2c(c1)CCC(=CN(C)C)C2=O

Procedure:
The 3,4-dihydro-2-(dimethylaminomethylene)-6-methoxy-1(2H)-naphthalenone starting material was prepared from 6-methoxy-1-tetralone (5.29 g, 30 mmol) and N,N-dimethylformamide dimethyl acetal (24 ml, 180 mmol) to give the desired product as a brown oil (2.67 g). δH (CDCl3) 8.00 (1H, d, J 8.6 Hz), 7.67 (1H, s), 6.81 (1H, dd, J 8.6, 2.6 Hz), 6.65 (1H, d, J 2.6 Hz), 3.83 (3H, s), 3.11 (6H, s), 2.95-2.90 (2H, m) and 2.88-2.79 (2H, m).
Reaction SMILES: O.[NH2:2][NH2:3].Cl[C:5]1[CH:13]=[CH:12][C:11]([N+:14]([O-:16])=[O:15])=[CH:10][C:6]=1[C:7](O)=[O:8].Cl>C(O)C>[N+:14]([C:11]1[CH:10]=[C:6]2[C:5](=[CH:13][CH:12]=1)[NH:3][NH:2][C:7]2=[O:8])([O-:16])=[O:15]
Reactant: NN
Reactant: O=C(O)c1cc([N+](=O)[O-])ccc1Cl
Agent: Cl
Solvent: O
Solvent: CCO
Product: O=c1[nH][nH]c2ccc([N+](=O)[O-])cc12
Temperature: 0 °C
Yield: 45 %

Procedure:
Hydrazine hydrate (4 mL, 124 mmol) was added to a solution of 2-chloro-5-nitro benzoic acid (5 g, 24.8 mmol) in absolute ethanol (30 mL), and the resulting mixture was refluxed for 16 h. The reaction mixture was concentrated under reduced pressure. Residue was trituated with methanol to give 6.5 g of crude intermediate. 2N aq. HCl (40 mL) was added to the crude product, and the mixture was refluxed for 8 h. Reaction mixture was cooled to 0° C., solids were collected via filtration, washed with cold water and dried under vacuum. Residue was purified by flash chromatography using 1% methanol in chloroform as eluent to afford title compound (2 g, 27%) as a solid. 1H NMR (400 MHz, DMSO-d6): δ 12.4 (bs, 1H), 11.3 (bs, 1H), 8.67 (s, 1H), 8.12 (dd, J1=2.1 Hz, J2=9.0 Hz, 1H), 7.5 (d, J=9.0 Hz, 1H); ESI-MS m/z: 179 (M+H)+.
Reaction SMILES: [CH2:1]([N:5]([CH2:27]CCC)[CH2:6][CH2:7][CH2:8][O:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[C:16]1[N:17]=[C:18]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[S:19][CH:20]=1)[CH2:2]CC.ClC1C=CC(C2SC=C(C3C=CC=CC=3OCCCN(CCCC)CCCC)[N:42]=2)=CC=1>>[N:5]1([CH2:6][CH2:7][CH2:8][O:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[C:16]2[N:17]=[C:18]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[S:19][CH:20]=2)[CH:1]=[CH:2][N:42]=[CH:27]1
Reactant: CCCCN(CCCC)CCCOc1ccccc1-c1csc(-c2ccc(Cl)cc2)n1
Reactant: CCCCN(CCCC)CCCOc1ccccc1-c1csc(-c2ccccc2)n1
Product: c1ccc(-c2nc(-c3ccccc3OCCCn3ccnc3)cs2)cc1

Procedure:
By substituting m-hydroxyacetophenone for the p-hydroxyacetophenone, p-hydroxypropiophenone or p-hydroxybutyrophenone of Examples 1-26, the corresponding 4-(3-aminoalkoxyphenyl)-2-substituted thiazoles are produced. For example, 4-(3-dibutylaminopropoxyphenyl)-2-phenylthiazole, 4-[3-(4-methylpiperazol-1-yl)propoxyphenyl]-2-phenylthiazole and 2-(4-chlorophenyl)-4-(3-dibutylaminopropoxyphenyl)thiazole are produced by using m-hydroxyacetophenone in Examples 1, 6 and 16, respectively.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]([CH2:14][C@H:15]([OH:20])[C:16]([F:19])([F:18])[F:17])[C:10](=[O:13])[NH:11][N:12]=2)=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[Cl:27][C:28]1[S:29][C:30]([CH2:33]Cl)=[CH:31][CH:32]=1.O>C(#N)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]([CH2:14][C@H:15]([OH:20])[C:16]([F:18])([F:19])[F:17])[C:10](=[O:13])[N:11]([CH2:33][C:30]3[S:29][C:28]([Cl:27])=[CH:32][CH:31]=3)[N:12]=2)=[CH:4][CH:3]=1
Reactant: O=c1[nH]nc(-c2ccc(Cl)cc2)n1C[C@H](O)C(F)(F)F
Reactant: ClCc1ccc(Cl)s1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: O=c1n(Cc2ccc(Cl)s2)nc(-c2ccc(Cl)cc2)n1C[C@H](O)C(F)(F)F
Temperature: 25 °C

Procedure:
119 mg (0.39 mmol) of the compound from Example 5A and 107 mg (0.77 mmol) of potassium carbonate were dissolved in 5 ml of acetonitrile, and 65 mg (0.39 mmol) of 2-chloro-5-(chloromethyl)thiophene were added. The mixture was stirred under reflux for 2 h. After cooling to RT, 10 ml of water were added and the mixture was extracted three times with in each case 10 ml of ethyl acetate. The combined organic phases were washed with 10 ml of saturated sodium chloride solution, dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by chromatography on silica gel (mobile phase: cyclohexane/ethyl acetate 10:1→8:1→5:1→1:1). This gave 114 mg (65% of theory) of the target compound.
Reaction SMILES: O1CCCCC1[O:7][CH2:8][CH2:9][N:10]1[CH:14]=[C:13]([C:15]2[N:20]=[C:19]3[N:21]([C:24]([C:27]4[CH:28]=[C:29]5[C:34](=[CH:35][CH:36]=4)[N:33]=[CH:32][CH:31]=[CH:30]5)([CH3:26])[CH3:25])[N:22]=[N:23][C:18]3=[CH:17][CH:16]=2)[CH:12]=[N:11]1.C12(CS(O)(=O)=O)C(C)(C)C(CC1)CC2=O.CO>O>[N:33]1[C:34]2[C:29](=[CH:28][C:27]([C:24]([N:21]3[C:19]4=[N:20][C:15]([C:13]5[CH:12]=[N:11][N:10]([CH2:9][CH2:8][OH:7])[CH:14]=5)=[CH:16][CH:17]=[C:18]4[N:23]=[N:22]3)([CH3:25])[CH3:26])=[CH:36][CH:35]=2)[CH:30]=[CH:31][CH:32]=1
Reactant: CC(C)(c1ccc2ncccc2c1)n1nnc2ccc(-c3cnn(CCOC4CCCCO4)c3)nc21
Agent: CC1(C)C2CCC1(CS(=O)(=O)O)C(=O)C2
Solvent: O
Solvent: CO
Product: CC(C)(c1ccc2ncccc2c1)n1nnc2ccc(-c3cnn(CCO)c3)nc21

Procedure:
The title compound was prepared by following the procedure described for example 146 from example 189 (0.050 g, 0.104 mmol), camphor sulphonic acid (0.121 g. 0.521 mmol), methanol (0.5 ml) and water (0.5 ml). Brown solid (0.031 g, 74%). M.P.: 95-98° C. 1H-NMR (δ ppm, DMSO-d6, 400 MHz): 8.85 (d, J=2.8 Hz, 1H), 8.46 (d, J=8.7 Hz, 1H), 8.40 (d, J=7.9 Hz, 1H), 8.22 (s, 1H), 8.00 (d, J=1.8 Hz, 1H), 7.91 (d, J=8.9 Hz, 1H), 7.85 (s, 1H), 7.68 (d, J=8.7 Hz, 1H), 7.53 (m, 2H), 4.87 (t, J=5.3 Hz, 1H), 4.11 (t, J=5.4 Hz, 2H), 3.70 (q, J=5.4 Hz, 2H), 2.46 (s, 6H).
Reaction SMILES: [CH2:1]([N:3]1[CH2:7][CH2:6][C@@H:5]([CH2:8][C:9]2[CH:14]=[C:13]([F:15])[CH:12]=[CH:11][C:10]=2[S:16]([Cl:19])(=[O:18])=[O:17])[CH2:4]1)[CH3:2].[CH2:20](N1CCC[C@H]1CCC1C=CC=C(F)C=1)C>>[CH2:1]([N:3]1[CH2:7][CH2:6][CH2:20][C@H:4]1[CH2:5][CH2:8][C:9]1[CH:14]=[C:13]([F:15])[CH:12]=[CH:11][C:10]=1[S:16]([Cl:19])(=[O:17])=[O:18])[CH3:2]
Reactant: CCN1CCC[C@H]1CCc1cccc(F)c1
Reactant: CCN1CC[C@@H](Cc2cc(F)ccc2S(=O)(=O)Cl)C1
Product: CCN1CCC[C@H]1CCc1cc(F)ccc1S(=O)(=O)Cl

Procedure:
Prepared by proceeding in a similar manner to intermediate 96, starting from (R)-1-ethyl-2-[2-(3-fluorophenyl)ethyl]pyrrolidine (intermediate 231).
Reaction SMILES: C(N(CC)CC)C.[C:8](Cl)(=[O:10])[CH3:9].[Br:12][C:13]1[CH:14]=[CH:15][C:16]2[N:17]([CH2:27][CH:28]([OH:39])[CH2:29][NH:30][C:31]3[CH:36]=[CH:35][CH:34]=[C:33]([O:37][CH3:38])[CH:32]=3)[C:18]3[C:23]([C:24]=2[CH:25]=1)=[CH:22][C:21]([Br:26])=[CH:20][CH:19]=3.C([Sn](=O)CCCC)CCC>C1(C)C=CC=CC=1>[Br:26][C:21]1[CH:20]=[CH:19][C:18]2[N:17]([CH2:27][CH:28]([OH:39])[CH2:29][N:30]([C:31]3[CH:36]=[CH:35][CH:34]=[C:33]([O:37][CH3:38])[CH:32]=3)[C:8](=[O:10])[CH3:9])[C:16]3[C:24]([C:23]=2[CH:22]=1)=[CH:25][C:13]([Br:12])=[CH:14][CH:15]=3
Reactant: CC(=O)Cl
Reactant: COc1cccc(NCC(O)Cn2c3ccc(Br)cc3c3cc(Br)ccc32)c1
Agent: CCCC[Sn](=O)CCCC
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: COc1cccc(N(CC(O)Cn2c3ccc(Br)cc3c3cc(Br)ccc32)C(C)=O)c1
Temperature: 150 °C

Procedure:
Following a literature procedure (Morcuende, A.; Ors, M.; Valverde, S.; Herradón, B. J. Org. Chem. 1996, 5264-5270) triethylamine (14 μl, 0.10 mmol) and acetyl chloride (8 μl, 0.11 mmol) were added to a heterogeneous mixture of 1-(3,6-dibromo-9H-carbazol-9-yl)-3-(3-methoxyphenylamino)propan-2-ol (53 mg, 0.11 mmol) and dibutyltin oxide (5.5 mg, 0.022 mmol) in anhydrous toluene (1.5 ml). The reaction vessel was purged with nitrogen, sealed and heated under microwave radiation to 150° C. for 9 minutes. The reaction was monitored by 1 c/ms and all SM had been consumed. The heterogeneous solution was filtered under vacuum to yield a white solid. The crude product was used without purification.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[CH:6][C:5]([O:8][CH2:9][C:10]#[CH:11])=[CH:4][CH:3]=1.CO.[OH-].[Na+].[I:16]I>O>[I:16][C:11]#[C:10][CH2:9][O:8][C:5]1[CH:6]=[N:7][C:2]([CH3:1])=[CH:3][CH:4]=1
Reactant: C#CCOc1ccc(C)nc1
Reactant: II
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: Cc1ccc(OCC#CI)cn1
Reaction time: 0.5 h
Yield: 83.2 %

Procedure:
A solution of 160 g (1.10 moles) 6-methyl-3-(2-propynyloxy) pyridine and 2000 ml methanol was cooled to 0° C. and 750 g 25% sodium hydroxide solution was slowly added. Iodine (362 g. 1.4 moles) was added portionwise and the resulting suspension stirred at 0°-10° C. for an additional 30 min. The reaction mixture was then poured into 4000 ml water and the solids filtered to give 250 g 3-(3-iodo-2-propynyloxy)-6-methylpyridine. Yield=90% Recrystallization from methanol gave analytically pure material, mp 155°-157° C.
Reaction SMILES: [N+:1]([C:4]1[C:5]([NH:10][C:11]2[CH:16]=[CH:15][CH:14]=[C:13](/[CH:17]=[CH:18]/[C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH:12]=2)=[N:6][CH:7]=[CH:8][CH:9]=1)([O-])=O>[Pd].CO.O1CCOCC1>[NH2:1][C:4]1[C:5]([NH:10][C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([CH2:17][CH2:18][C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=3)[CH:12]=2)=[N:6][CH:7]=[CH:8][CH:9]=1
Reactant: O=[N+]([O-])c1cccnc1Nc1cccc(/C=C/c2ccccc2)c1
Agent: [Pd]
Solvent: C1COCCO1
Solvent: CO
Product: Nc1cccnc1Nc1cccc(CCc2ccccc2)c1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 88.9 %

Procedure:
A mixture of 3-nitro-2-((E)-3-styrylphenylamino)pyridine (1.03 g) and 10% palladium on carbon (0.3 g) in methanol (20 ml) and 1,4-dioxane (20 ml) was stirred under hydrogen (3 atm) at room temperature for 1.5 hours. The catalyst was removed by filtration and the solvent was evaporated. The resulting solid was collected and washed with isopropyl ether to give 3-amino-2-(3-phenethylphenylamino)pyridine (835 mg).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]2[O:9][CH:10]=[CH:11][CH:12]=2)[C:5]([C:13]#[N:14])=[C:4](S(C)=O)[N:3]=1.[NH2:18][CH2:19][CH2:20][NH:21][C:22]1[CH:23]=[CH:24][C:25]([N+:29]([O-:31])=[O:30])=[C:26]([NH2:28])[CH:27]=1>COCCOC>[NH2:1][C:2]1[N:3]=[C:4]([NH:18][CH2:19][CH2:20][NH:21][C:22]2[CH:23]=[CH:24][C:25]([N+:29]([O-:31])=[O:30])=[C:26]([NH2:28])[CH:27]=2)[C:5]([C:13]#[N:14])=[C:6]([C:8]2[O:9][CH:10]=[CH:11][CH:12]=2)[N:7]=1
Reactant: NCCNc1ccc([N+](=O)[O-])c(N)c1
Reactant: CS(=O)c1nc(N)nc(-c2ccco2)c1C#N
Solvent: COCCOC
Product: N#Cc1c(NCCNc2ccc([N+](=O)[O-])c(N)c2)nc(N)nc1-c1ccco1

Procedure:
From 2-amino-4-furan-2-yl-6-methanesulfinyl-pyrimidine-5-carbonitrile and N5-(2-amino-ethyl)-2-nitro-benzene-1,5-diamine in DME. ES-MS m/e (%): 403 (M+Na+, 50), 381 (M+H+, 100), 269 (46).
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([C:7]([NH:9][C@H:10]2[CH2:14][N:13]([CH2:15][C:16](=[O:32])[NH:17][C:18]3[CH:23]=[CH:22][C:21]([N:24]4[CH:29]=[CH:28][CH:27]=[CH:26][C:25]4=[O:30])=[CH:20][C:19]=3[F:31])[CH2:12][C@@H:11]2[O:33][CH2:34][C:35]([OH:37])=O)=[O:8])=[CH:4][CH:3]=1.Cl.[CH3:39][NH:40][CH3:41]>>[CH3:39][N:40]([CH3:41])[C:35]([CH2:34][O:33][C@H:11]1[CH2:12][N:13]([CH2:15][C:16](=[O:32])[NH:17][C:18]2[CH:23]=[CH:22][C:21]([N:24]3[CH:29]=[CH:28][CH:27]=[CH:26][C:25]3=[O:30])=[CH:20][C:19]=2[F:31])[CH2:14][C@@H:10]1[NH:9][C:7]([C:5]1[S:6][C:2]([Cl:1])=[CH:3][CH:4]=1)=[O:8])=[O:37]
Reactant: O=C(O)CO[C@H]1CN(CC(=O)Nc2ccc(-n3ccccc3=O)cc2F)C[C@@H]1NC(=O)c1ccc(Cl)s1
Reactant: CNC
Agent: Cl
Product: CN(C)C(=O)CO[C@H]1CN(CC(=O)Nc2ccc(-n3ccccc3=O)cc2F)C[C@@H]1NC(=O)c1ccc(Cl)s1

Procedure:
According to general procedure D ((3S,4S)-4-[(5-chloro-thiophene-2-carbonyl)-amino]-1-{[2-fluoro-4-(2-oxo-pyridin-1-yl)-phenylcarbamoyl]-methyl}-pyrrolidin-3-yloxy)-acetic acid (example 97) was reacted with dimethylamine hydrochloride to give 5-chloro-thiophene-2-carboxylic acid ((3S,4S)-4-dimethylcarbamoylmethoxy-1-{[2-fluoro-4-(2-oxo-pyridin-1-yl)-phenylcarbamoyl]-methyl}-pyrrolidin-3-yl)-amide. Off-white solid. MS576.3 ([M+H]+)
Reaction SMILES: Br[C:2]1[CH:28]=[CH:27][CH:26]=[CH:25][C:3]=1[CH2:4][N:5]1[C:9]([CH3:11])([CH3:10])[C:8](=[O:12])[N:7]([C:13]2[CH:18]=[CH:17][C:16]([F:19])=[C:15]([C:20]([F:23])([F:22])[F:21])[CH:14]=2)[C:6]1=[O:24].[NH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>>[F:19][C:16]1[CH:17]=[CH:18][C:13]([N:7]2[C:8](=[O:12])[C:9]([CH3:11])([CH3:10])[N:5]([CH2:4][C:3]3[CH:25]=[CH:26][CH:27]=[CH:28][C:2]=3[NH:29][C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[C:6]2=[O:24])=[CH:14][C:15]=1[C:20]([F:23])([F:22])[F:21]
Reactant: Nc1ccccc1
Reactant: CC1(C)C(=O)N(c2ccc(F)c(C(F)(F)F)c2)C(=O)N1Cc1ccccc1Br
Product: CC1(C)C(=O)N(c2ccc(F)c(C(F)(F)F)c2)C(=O)N1Cc1ccccc1Nc1ccccc1
Yield: 81 %

Procedure:
To prepare the compound of example 23, the procedure may be according to process “A”. Analogously to the method for example 1, stage 3, compound 23.2 was reacted with aniline. Compounds 23 was obtained in a yield of 81%. Molecular weight 471.14 (C25H21F4N3O2); retention time Rt=2.34 min. [B]; MS (ESI): 472.11 (MH+).
Reaction SMILES: C(OC([N:8]1[C:17]2[C:12](=[CH:13][C:14]([C:18]3[CH:19]=[N:20][CH:21]=[C:22]([CH2:24][O:25][C:26]4[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=4)[CH:23]=3)=[CH:15][N:16]=2)[CH2:11][CH2:10][CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O>C(Cl)Cl>[F:32][C:29]1[CH:30]=[CH:31][C:26]([O:25][CH2:24][C:22]2[CH:23]=[C:18]([C:14]3[CH:13]=[C:12]4[C:17](=[N:16][CH:15]=3)[NH:8][CH2:9][CH2:10][CH2:11]4)[CH:19]=[N:20][CH:21]=2)=[CH:27][CH:28]=1
Reactant: CC(C)(C)OC(=O)N1CCCc2cc(-c3cncc(COc4ccc(F)cc4)c3)cnc21
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Fc1ccc(OCc2cncc(-c3cnc4c(c3)CCCN4)c2)cc1
Reaction time: 16 h
Yield: 102.5 %

Procedure:
6-[5-(4-Fluoro-phenoxymethyl)-pyridin-3-yl]-3,4-dihydro-2H-[1,8]naphthyridine-1-carboxylic acid tert-butyl ester (42 mg, 0.096 mmol) is dissolved in 1.0 mL of DCM and trifluoroacetic acid (0.3 mL) is added. The mixture is stirred for 16 hrs and then the solvent is removed. The residue is dissolved in MeOH and filtered through Varian PL-HCO3 MP resin catridge to give 33 mg of 6-[5-(4-Fluoro-phenoxymethyl)-pyridin-3-yl]-1,2,3,4-tetrahydro-[1,8]naphthyridine which is used in the next step without purification.