Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1([CH3:38])[C:10]2[C:5](=[CH:6][C:7](B3OC(C)(C)C(C)(C)O3)=[CH:8][CH:9]=2)[N:4]([C:20]2[C:29]3[C:24](=[CH:25][C:26]([F:30])=[CH:27][CH:28]=3)[N:23]=[C:22]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][N:32]=3)[C:21]=2[CH3:37])[CH2:3]1.Cl[C:40]1[C:45]([Cl:46])=[CH:44][N:43]=[C:42]([NH2:47])[N:41]=1.C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1.O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[Cl:46][C:45]1[C:40]([C:7]2[CH:6]=[C:5]3[C:10]([C:2]([CH3:38])([CH3:1])[CH2:3][N:4]3[C:20]3[C:29]4[C:24](=[CH:25][C:26]([F:30])=[CH:27][CH:28]=4)[N:23]=[C:22]([C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][N:32]=4)[C:21]=3[CH3:37])=[CH:9][CH:8]=2)=[N:41][C:42]([NH2:47])=[N:43][CH:44]=1
Reactant: Cc1c(-c2ccccn2)nc2cc(F)ccc2c1N1CC(C)(C)c2ccc(B3OC(C)(C)C(C)(C)O3)cc21
Reactant: Nc1ncc(Cl)c(Cl)n1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: Cc1c(-c2ccccn2)nc2cc(F)ccc2c1N1CC(C)(C)c2ccc(-c3nc(N)ncc3Cl)cc21
Temperature: 120 °C

Procedure:
Prepared according to procedure P using 4-(3,3-dimethyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)indolin-1-yl)-7-fluoro-3-methyl-2-(pyridin-2-yl)quinoline (68.7 mg, 0.14 mmol) (described herein), 4,5-dichloropyrimidin-2-amine (22.1 mg, 0.14 mmol), bis(triphenylphosphine)palladium(ii) chloride (9.5 mg, 0.013 mmol), and sodium carbonate (42.9 mg, 0.41 mmol) in 1,4-dioxane (2.9 mL) and water (0.73 mL), and heating in a microwave at 120° C. for 60 min. After purification 5-chloro-4-(1-(7-fluoro-3-methyl-2-(2-pyridinyl)-4-quinolinyl)-3,3-dimethyl-2,3-dihydro-1H-indol-6-yl)-2-pyrimidinamine was obtained as a yellow solid. 1H NMR (400 MHz, chloroform-d) δ ppm 8.74 (1H, dd, J=3.9, 1.2 Hz), 8.19 (1H, s), 7.76-7.99 (4H, m), 7.35-7.42 (1H, m), 7.28-7.30 (1H, m), 7.23-7.27 (1H, m), 7.16 (1H, dd, J=7.4, 1.2 Hz), 6.36 (1H, s), 4.94-5.21 (2H, br. s.), 3.76-3.88 (2H, m), 2.37 (3H, s), 1.58 (3H, s), 1.52 (3H, s). Mass Spectrum (ESI) m/e=511 (M+1).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[CH2:5]2.[N:12]1[CH:17]=[CH:16][C:15]([CH2:18][NH:19][C:20]([C:22]2[C:26]([CH3:27])=[C:25]([CH:28]=O)[NH:24][C:23]=2[CH3:30])=[O:21])=[CH:14][CH:13]=1>>[N:12]1[CH:13]=[CH:14][C:15]([CH2:18][NH:19][C:20]([C:22]2[C:26]([CH3:27])=[C:25]([CH:28]=[C:5]3[C:4]4[C:8](=[CH:9][CH:10]=[C:2]([Br:1])[CH:3]=4)[NH:7][C:6]3=[O:11])[NH:24][C:23]=2[CH3:30])=[O:21])=[CH:16][CH:17]=1
Reactant: O=C1Cc2cc(Br)ccc2N1
Reactant: Cc1[nH]c(C=O)c(C)c1C(=O)NCc1ccncc1
Product: Cc1[nH]c(C=C2C(=O)Nc3ccc(Br)cc32)c(C)c1C(=O)NCc1ccncc1
Yield: 4 %

Procedure:
5-Bromo-1,3-dihydroindol-2-one (170 mg, 0.8 mmol) was condensed with 5-formyl-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (pyridin-4-ylmethyl)amide (200 mg) to give 14 mg (4%) of the title compound as a yellow solid.
Reaction SMILES: [Br:1][C:2]1[C:3]([O:20][CH3:21])=[N:4][CH:5]=[CH:6][C:7]=1[NH:8][CH:9]=[C:10]1[C:15](=[O:16])OC(C)(C)OC1=O.C1(OC2C=CC=CC=2)C=CC=CC=1>CCCCCC>[Br:1][C:2]1[C:3]([O:20][CH3:21])=[N:4][CH:5]=[C:6]2[C:7]=1[NH:8][CH:9]=[CH:10][C:15]2=[O:16]
Reactant: COc1nccc(NC=C2C(=O)OC(C)(C)OC2=O)c1Br
Solvent: CCCCCC
Solvent: c1ccc(Oc2ccccc2)cc1
Product: COc1ncc2c(=O)cc[nH]c2c1Br
Temperature: 250 °C

Procedure:
A two neck round bottomed flask equipped with an air condenser was charged with 5-[(3-Bromo-2-methoxy-pyridin-4-ylamino)-methylene]-2,2-dimethyl-[1,3]dioxane-4,6-dione (23 g, 64 mmol) and diphenyl ether (230 mL). The reaction mixture was heated at 250° C. for 30 min under nitrogen atmosphere after which it was cooled to RT, diluted with hexane and filtered to obtain a dark solid. The crude product was refluxed in hexane for 30 min and filtered to obtained 8-Bromo-7-methoxy-1H-[1,6]naphthyridin-4-one as a brown solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:20]=[CH:19][C:6]([C:7]([NH:9][C:10]2[CH:18]=[CH:17][CH:16]=[C:15]3[C:11]=2[CH:12]=[CH:13][NH:14]3)=[O:8])=[C:5]([OH:21])[CH:4]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:28]([CH:30]1[O:32][CH2:31]1)Cl>CC(C)=O>[CH3:1][O:2][C:3]1[CH:20]=[CH:19][C:6]([C:7]([NH:9][C:10]2[CH:18]=[CH:17][CH:16]=[C:15]3[C:11]=2[CH:12]=[CH:13][NH:14]3)=[O:8])=[C:5]([O:21][CH2:28][CH:30]2[CH2:31][O:32]2)[CH:4]=1
Reactant: ClCC1CO1
Reactant: COc1ccc(C(=O)Nc2cccc3[nH]ccc23)c(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COc1ccc(C(=O)Nc2cccc3[nH]ccc23)c(OCC2CO2)c1

Procedure:
Using the procedure of Step D of Example 52, 5 g of the product of Step A, 150 ml of acetone, 2.45 g of potassium carbonate and 14 ml of epichlorohydrin were reacted to obtain 7.3 g of 4-methoxy-2-[(2-oxiranyl)-methoxy]-N-(1H-indol-4-yl)-benzamide melting at 157° C.
Reaction SMILES: C(O)C.C(=O)(O)O.[NH2:8][C:9]([NH2:11])=[NH:10].[C:12](OCC)(=[O:17])[CH2:13][C:14]([CH3:16])=O>O>[NH2:10][C:9]1[NH:11][C:12](=[O:17])[CH:13]=[C:14]([CH3:16])[N:8]=1
Reactant: CCOC(=O)CC(C)=O
Reactant: N=C(N)N
Agent: O=C(O)O
Solvent: O
Solvent: CCO
Product: Cc1cc(=O)[nH]c(N)n1
Temperature: 25 °C
Yield: 68 %

Procedure:
The title compound was prepared according to a literature method (Hirschberg, J. H. K., Beijer, F. H., van Aert, H. A., Magusin, P. C. M., Sijbesma, R. P., Meijer, E. W., Macromolecules, 1999, 32, 2696-2705, the disclosure of which is totally incorporated herein by reference). To a 1 liter round bottom flask under an inert argon atmosphere was added 650 milliliters of dry ethanol and 90.08 grams (0.5 mole) of guanidine carbonate. Thereafter, with good stirring was added dropwise over 2 hours 130.17 grams (1 mole) of ethyl acetoacetate, after which heat was applied and the mixture refluxed for 15 hours. The mixture was then cooled to room temperature and 800 milliliters of deionized water was slowly added to induce precipitation of the product. Subsequent vacuum filtration and washing with cold acetone secured the anticipated product in 68 percent yield (mp 311° C.). All physical properties were in accord with the reported properties.
Reaction SMILES: [CH3:1][C:2]1[NH:6][N:5]=[C:4]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH:3]=1.[Br:12]N1C(=O)CCC1=O>CC#N>[Br:12][C:3]1[C:4]([C:7]([O:9][CH2:10][CH3:11])=[O:8])=[N:5][NH:6][C:2]=1[CH3:1]
Reactant: CCOC(=O)c1cc(C)[nH]n1
Reactant: O=C1CCC(=O)N1Br
Solvent: CC#N
Product: CCOC(=O)c1n[nH]c(C)c1Br
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Ethyl 5-methyl-1H-pyrazole-3-carboxylate (3.24 g) in CH3CN (25 mL) was treated with N-bromosuccinimide (3.92 g) at 0° C. The solution was stirred at room temperature for 2 hours. The solvent was removed, and the residue was purified by flash chromatography on silica gel (ethyl acetate in hexanes) to give the title compound. 1H NMR (500 MHz, DMSO-d6): 13.61 (s, 1H), 4.27 (q, J=6.75 Hz, 2H), 2.21 (s, 3H), 1.28 (t, J=7.06 Hz, 3H).
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1B(O)O.[CH3:9][CH:10]([NH:12][CH2:13][CH2:14][CH2:15][N:16]1[C:25]([S:26][C:27]2[CH:32]=[C:31]3[O:33][CH2:34][O:35][C:30]3=[CH:29][C:28]=2I)=[N:24][C:18]2[C:19]([NH2:23])=[N:20][CH:21]=[N:22][C:17]1=2)[CH3:11].C([O-])(O)=O.[Na+].CN(C=O)C>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O>[O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:28]1[C:27]([S:26][C:25]2[N:16]([CH2:15][CH2:14][CH2:13][NH:12][CH:10]([CH3:11])[CH3:9])[C:17]3[C:18]([N:24]=2)=[C:19]([NH2:23])[N:20]=[CH:21][N:22]=3)=[CH:32][C:31]2[O:33][CH2:34][O:35][C:30]=2[CH:29]=1
Reactant: CC(C)NCCCn1c(Sc2cc3c(cc2I)OCO3)nc2c(N)ncnc21
Reactant: OB(O)c1ccco1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)NCCCn1c(Sc2cc3c(cc2-c2ccco2)OCO3)nc2c(N)ncnc21
Temperature: 90 °C

Procedure:
2-Furanylboronic acid (9.8 mg, 0.0877 mmol) was added to PU-H71 (30 mg, 0.0585 mmol) and NaHCO3 (14.7 mg, 0.1755 mmol). DMF (1 mL) was added and the reaction mixture was evacuated and back filled with nitrogen. This was repeated four times then nitrogen was bubbled through the reaction mixture for 10 minutes. Then H2O (0.1 mL) and Pd(PPh3)2Cl2 (4 mg, 0.00584 mmol) were added and the reaction mixture was heated under nitrogen at 90° C. for 3.5 h. Solvent was removed under reduced pressure and the resulting residue was purified by preparatory TLC (CH2Cl2:MeOH—NH3 (7N), 12.5:1) to give 19.1 mg (72%) of DZ3-4. 1H NMR (500 MHz, CDCl3/MeOH-d4) δ 8.18 (s, 1H), 7.49 (d, J=1.8 Hz, 1H), 7.25 (s, 1H), 6.96 (s, 1H), 6.71 (d, J=3.3 Hz, 1H), 6.47 (dd, J=1.8, 3.2 Hz, 1H), 6.06 (s, 2H), 4.20 (t, J=7.0 Hz, 2H), 2.87 (m, 1H), 2.61 (t, J=6.9 Hz, 2H), 2.00 (m, 2H), 1.14 (d, J=6.3 Hz, 6H); 13C NMR (125 MHz, CDCl3/MeOH-d4) δ 154.3, 152.2, 151.2, 150.9, 149.5, 148.14, 148.08, 142.4, 129.0, 119.2, 117.5, 114.5, 111.5, 110.0, 109.0, 102.3, 42.8, 41.0, 28.5, 21.2; HRMS (ESI) m/z [M+H]+ calcd. for C22H25N6O3S, 453.1709; found. 453.1705; HPLC: method A Rt=6.23, method B Rt=6.82.
Reaction SMILES: CC(C)([O-])C.[K+].[CH3:7][N:8]1[CH2:20][CH2:19][C:11]2[NH:12][C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][C:18]=3[C:10]=2[CH2:9]1.[CH3:21][O:22][C:23](=[O:32])[C:24]1[CH:29]=[CH:28][C:27]([CH2:30]Br)=[CH:26][CH:25]=1>CN(C=O)C.[I-].[K+]>[CH3:21][O:22][C:23](=[O:32])[C:24]1[CH:29]=[CH:28][C:27]([CH2:30][N:12]2[C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][C:18]=3[C:10]3[CH2:9][N:8]([CH3:7])[CH2:20][CH2:19][C:11]2=3)=[CH:26][CH:25]=1
Reactant: CN1CCc2[nH]c3ccccc3c2C1
Reactant: COC(=O)c1ccc(CBr)cc1
Agent: CC(C)(C)[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(Cn2c3c(c4ccccc42)CN(C)CC3)cc1
Temperature: 80 °C
Reaction time: 2 h
Yield: 62.8 %

Procedure:
Potassium tert-butoxide (0.95 g, 8.5 mmol) was placed under argon and suspended in 1 mL of anhydrous DMF. To it was added 2-methyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (17) (1.5 g, 8.1 mmol) dissolved in 3 mL of DMF upon which the reaction turned a deep orange in color. The reaction was stirred at room temperature for 15 min after which 4-bromomethyl-benzoic acid methyl ester (1.8 g, 8.1 mmol) was added in 1 mL of DMF along with approximately 5 mg of potassium iodide. The reaction then turned a light orange in color. The reaction was stirred at 80° C. for two hours after which the reaction was quenched by the addition of 15 mL of water. The pH was adjusted to approximately 12 with 2N NaOH and the organic products were extracted with ethyl acetate (3×15 mL). The combined organic layers were washed with water (15 mL), brine (15 mL), dried with anhydrous sodium sulfate, filtered, and concentrated in vacuo. Purification by column chromatography (0-80% gradient of ethyl acetate in hexane) afforded the title compound (1.7 g, 61%) as a yellow oil. 1H NMR (400 MHz, CD3OD): δ 7.83 (d, 2H, J=8.3 Hz), 7.33 (d, 1H, J=7.8 Hz), 7.23 (m, 3H), 7.07 (m, 1H), 6.97 (m, 1H), 4.59 (s, 2H), 4.01 (s, 2H), 3.82 (s, 3H), 2.90 (t, 2H, J=5.5 Hz), 2.84 (t, 2H, J=5.3 Hz), 2.48 (s, 3H). 13C NMR (100 MHz, MeOD): δ 167.1, 147.5, 134.9, 130.4, 129.2, 128.1, 128.0, 127.4, 120.4, 119.2, 177.7, 108.3, 108.1, 65.4, 51.0, 50.0, 40.2, 29.2, 20.3. ESI-MS (m/z): [M+H]+335.2 m/z.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([Cl:14])[C:11]([C:15]([F:18])([F:17])[F:16])=[CH:10][C:9]=1[NH:19][C:20](=[O:39])[CH2:21][C:22]([C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([C:30]2[CH:35]=[CH:34][N:33]=[C:32]([CH:36]([CH3:38])[CH3:37])[CH:31]=2)[CH:25]=1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[Cl:14][C:12]1[C:11]([C:15]([F:16])([F:18])[F:17])=[CH:10][C:9]2[NH:19][C:20](=[O:39])[CH2:21][C:22]([C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([C:30]4[CH:35]=[CH:34][N:33]=[C:32]([CH:36]([CH3:38])[CH3:37])[CH:31]=4)[CH:25]=3)=[N:7][C:8]=2[CH:13]=1
Reactant: CC(C)c1cc(-c2cccc(C(=O)CC(=O)Nc3cc(C(F)(F)F)c(Cl)cc3NC(=O)OC(C)(C)C)c2)ccn1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)c1cc(-c2cccc(C3=Nc4cc(Cl)c(C(F)(F)F)cc4NC(=O)C3)c2)ccn1

Procedure:
The title compound was prepared from (5-chloro-2-{3-[3-(2-isopropyl-pyridin-4-yl)-phenyl]-3-oxo-propionylamino}-4-trifluoromethyl-phenyl)-carbamic acid tert-butyl ester (Example M252) (0.22 g, 0.38 mmol) by treatment with TFA in CH2Cl2 according to the general procedure N. Obtained as a light yellow solid (150 mg, 86%).
Reaction SMILES: [CH2:1]([O:4][C:5](=[O:34])[C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([CH2:12][O:13][C:14]2[CH:23]=[C:22]3[C:17]([C:18](=[O:33])[C:19]([C:24]4[CH:29]=[CH:28][C:27]([N+:30]([O-])=O)=[CH:26][CH:25]=4)=[CH:20][O:21]3)=[CH:16][CH:15]=2)[CH:7]=1)[CH:2]=[CH2:3].S(S([O-])=O)([O-])=O.[Na+].[Na+]>O1CCCC1.O>[NH2:30][C:27]1[CH:26]=[CH:25][C:24]([C:19]2[C:18](=[O:33])[C:17]3[C:22](=[CH:23][C:14]([O:13][CH2:12][C:8]4[CH:7]=[C:6]([CH:11]=[CH:10][CH:9]=4)[C:5]([O:4][CH2:1][CH:2]=[CH2:3])=[O:34])=[CH:15][CH:16]=3)[O:21][CH:20]=2)=[CH:29][CH:28]=1
Reactant: C=CCOC(=O)c1cccc(COc2ccc3c(=O)c(-c4ccc([N+](=O)[O-])cc4)coc3c2)c1
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: C=CCOC(=O)c1cccc(COc2ccc3c(=O)c(-c4ccc(N)cc4)coc3c2)c1
Temperature: 62.5 °C
Reaction time: 8 h
Yield: 64.7 %

Procedure:
A suspension of 3-[3-(4-nitrophenyl)-4-oxo-4H-chromen-7-yloxymethyl]benzoic acid allyl ester (164.6 mg, 0.36 mmol), prepared as described in Example 5d, and sodium dithionite (188 mg, 1.08 mmol) in tetrahydrofuran (8 ml) and water (4 ml) was heated at 60-65° C. for 1 hour. Additional sodium dithionite (1.13 g, 6.48 mmol) was added in 5 portions over 2 hours. The reaction mixture was stirred at 60-65° C. overnight. 1H NMR of the reaction mixture showed that the product was obtained without starting material. The reaction mixture was mixed with silica gel (2 g), solvent removed under reduced pressure, and the mixture applied to a column. The silica gel mixture was purified by flash chromatography, eluting with methylene chloride/methanol (98/2) to give prop-2-enyl 3-{[3-(4-aminophenyl)-4-oxochromen-7-yloxy]methyl}benzoate as a yellow solid (99.6 mg, 65%); (ESI) m/z 428 (M+H)+.
Reaction SMILES: [CH3:1][N:2]1[CH2:19][CH2:18][C:7]2[CH:8]=[CH:9][CH:10]=[C:11]3[C:12]4[CH2:13][CH2:14][CH2:15][CH2:16][C:17]=4[N:5]([C:6]=23)[CH2:4][CH2:3]1.C([BH3-])#N.[Na+]>C(O)(=O)C>[CH3:1][N:2]1[CH2:19][CH2:18][C:7]2[CH:8]=[CH:9][CH:10]=[C:11]3[CH:12]4[CH:17]([N:5]([C:6]=23)[CH2:4][CH2:3]1)[CH2:16][CH2:15][CH2:14][CH2:13]4
Reactant: CN1CCc2cccc3c4c(n(c23)CC1)CCCC4
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Product: CN1CCc2cccc3c2N(CC1)C1CCCCC31
Temperature: 25 °C
Reaction time: 1 h
Yield: 65 %

Procedure:
To a solution of 3-methyl-2,3,4,5,9,10,11,12-octahydro-1H-[1,4]diazocino[7,8,1-jk]carbazole (0.46 g, 1.8 mmole) in acetic acid (50 mL) was added sodium cyanoborohydride (0.30 g, 4.5 mmol) and the reaction mixture was stirred at room temperature for 1 hour. The solvent was removed in vacuo and the residue was diluted with ethyl acetate (300 mL) and washed with saturated aqueous sodium bicarbonate (150 mL) and saturated aqueous sodium chloride (150 mL), dried (sodium sulfate) and concentrated in vacuo. Purification by flash column chromatography (silica gel, ethyl acetate:hexanes 3:2) provided 0.30 g of the title compound as a light oil. 100 mg of this compound was treated with one equivalent of fumaric acid in ethanol to form a fumarate salt, mp 150-153° C. MS (ESI) m/z 257 ([M+H]+).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]2[CH:16]=[CH:15][C:11]3[O:12][CH2:13][O:14][C:10]=3[CH:9]=2)[C:5]([C:17]#[N:18])=[C:4](S(C)(=O)=O)[N:3]=1.[CH3:23][O:24][CH2:25][CH2:26][OH:27].C1CCN2C(=NCCC2)CC1>COCCOC>[NH2:1][C:2]1[N:7]=[C:6]([C:8]2[CH:16]=[CH:15][C:11]3[O:12][CH2:13][O:14][C:10]=3[CH:9]=2)[C:5]([C:17]#[N:18])=[C:4]([O:27][CH2:26][CH2:25][O:24][CH3:23])[N:3]=1
Reactant: CS(=O)(=O)c1nc(N)nc(-c2ccc3c(c2)OCO3)c1C#N
Reactant: COCCO
Solvent: COCCOC
Solvent: C1CCC2=NCCCN2CC1
Product: COCCOc1nc(N)nc(-c2ccc3c(c2)OCO3)c1C#N

Procedure:
From 2-amino-4-benzo [1,3]dioxol-5-yl-6-methanesulfonyl-pyrimidine-5-carbonitrile, 2-methoxyethanol and DBU in DME. EI-MS m/e (%): 314 (M+, 54), 256 ([M—MeOCH═CH2]+, 100), 214 (59).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([F:25])=[C:6]([C:8]2[CH:17]=[C:16]([C:18]3[CH:19]=[CH:20][C:21]([NH2:24])=[N:22][CH:23]=3)[C:15]3[C:10](=[N:11][CH:12]=[CH:13][CH:14]=3)[N:9]=2)[CH:7]=1.ClCCl.[Br:29]Br>>[Br:29][C:20]1[C:21]([NH2:24])=[N:22][CH:23]=[C:18]([C:16]2[C:15]3[C:10](=[N:11][CH:12]=[CH:13][CH:14]=3)[N:9]=[C:8]([C:6]3[CH:7]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]=3[F:25])[CH:17]=2)[CH:19]=1
Reactant: Nc1ccc(-c2cc(-c3cc(Cl)ccc3F)nc3ncccc23)cn1
Reactant: BrBr
Solvent: ClCCl
Product: Nc1ncc(-c2cc(-c3cc(Cl)ccc3F)nc3ncccc23)cc1Br
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 429 mg (1.22 mmol) 5-[2-(5-Chloro-2-fluoro-phenyl)-[1,8]naphthyridin-4-yl]-pyridin-2-ylamine in 5 ml dichloromethane 195 mg (1.84 mmol) sodium bicarbonate was added. Then 94 μl (1.84 mmol) bromine were added slowly. The reaction mixture was stirred for 1 hour at room temperature and subsequently was partitioned between water and dichloromethane. The organic phase was dried over sodium sulfate and evaporated yielding 3-bromo-5-[2-(5-chloro-2-fluoro-phenyl)-[1,8]naphthyridin-4-yl]-pyridin-2-ylamine as brown amorphous solid; HPLC-MS: 2.18 min, [M+H] 431.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][C:5]([C:7]1[CH:12]=[CH:11][C:10]([F:13])=[CH:9][CH:8]=1)=[O:6].[NH:14]1[CH2:19][CH2:18][CH:17]([C:20]2[CH:21]=[C:22]([NH:26][C:27](=[O:30])[CH2:28][CH3:29])[CH:23]=[CH:24][CH:25]=2)[CH2:16][CH2:15]1>>[F:13][C:10]1[CH:11]=[CH:12][C:7]([C:5](=[O:6])[CH2:4][CH2:3][CH2:2][N:14]2[CH2:19][CH2:18][CH:17]([C:20]3[CH:21]=[C:22]([NH:26][C:27](=[O:30])[CH2:28][CH3:29])[CH:23]=[CH:24][CH:25]=3)[CH2:16][CH2:15]2)=[CH:8][CH:9]=1
Reactant: CCC(=O)Nc1cccc(C2CCNCC2)c1
Reactant: O=C(CCCCl)c1ccc(F)cc1
Product: CCC(=O)Nc1cccc(C2CCN(CCCC(=O)c3ccc(F)cc3)CC2)c1

Procedure:
Prepared by Procedure K and Scheme B1 using 4-chloro-1-(4-fluorophenyl)-1-butanone and N-[3-(4-piperidinyl)phenyl]propanamide: ESMS m/e: 397.2 (M+H)+.
Reaction SMILES: [O:1]=[S:2]1(=[O:23])[CH2:6][CH2:5][CH2:4][N:3]1[C:7]1[CH:12]=[CH:11][C:10]([C:13]23[CH2:21][CH:17]4[CH2:18][CH:19]([CH2:20]2)[C:15]([NH2:22])([CH2:16]4)[CH2:14]3)=[CH:9][CH:8]=1.C([O-])([O-])=O.[K+].[K+].Cl[CH2:31][C:32]([N:34]1[CH2:38][C@@H:37]([F:39])[CH2:36][C@H:35]1[C:40]#[N:41])=[O:33]>CS(C)=O.CCOC(C)=O>[O:1]=[S:2]1(=[O:23])[CH2:6][CH2:5][CH2:4][N:3]1[C:7]1[CH:8]=[CH:9][C:10]([C:13]23[CH2:21][CH:17]4[CH2:16][C:15]([NH:22][CH2:31][C:32]([N:34]5[CH2:38][C@@H:37]([F:39])[CH2:36][C@H:35]5[C:40]#[N:41])=[O:33])([CH2:14]2)[CH:19]([CH2:18]4)[CH2:20]3)=[CH:11][CH:12]=1
Reactant: NC12CC3CC1CC(c1ccc(N4CCCS4(=O)=O)cc1)(C3)C2
Reactant: N#C[C@@H]1C[C@H](F)CN1C(=O)CCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: N#C[C@@H]1C[C@H](F)CN1C(=O)CNC12CC3CC1CC(c1ccc(N4CCCS4(=O)=O)cc1)(C3)C2
Temperature: 25 °C
Reaction time: 3 h
Yield: 37 %

Procedure:
To a stirred mixture of 1-[4-(1,1-dioxidoisothiazolidin-2-yl)phenyl]tricyclo[3.3.1.03,7]nonan-3-amine (as obtained in example 8 Step II) (0.17 g, 0.5 mmol) and K2CO3 (0.21 g, 1.5 mmol) in DMSO (2 mL) at an ice bath temperature was added (2S,4S)-1-(chloroacetyl)-4-fluoropyrrolidine-2-carbonitrile (0.1 g, 0.5 mmol). The reaction mixture was gradually warmed to room temperature and stirred for 3 h. Upon completion of the reaction (checked by TLC), the reaction mixture was diluted with EtOAc and washed with water and brine, dried over Na2SO4, and the solvent was removed under reduced pressure. The crude product was purified by column chromatography to obtain (2S,4S)-1-{N-[2-[4-(1,1-dioxidoisothiazolidin-2-yl)phenyl]hexahydro-2,5-methanopentalen-3a(1H)-yl]glycyl}-4-fluoropyrrolidine-2-carbonitrile as an off-white powder (0.09 g) in 37% yield as a 3:1 mixture of two rotomers. IR cm−1 3438, 2953, 2776, 1673, 1518, 1427, 1301, 1135, 1078, 955; m/z (M+1) 487; 1H NMR (CDCl3) 300 MHz δ 7.25 (d, J=6.2 Hz, 2H), 7.20 (d, J=8.6 Hz, 2H), 5.42 (d (br), J=51.0 Hz, 0.8H), 5.34 (d (br), J=50.4 Hz, 0.2H), 5.15 (d, J=10.2 Hz, 0.2H), 4.98 (d, J=7.4 Hz, 0.8H), 4.0-3.50 (m, 4H), 3.76 (t, J=6.5H, 2H), 3.35 (t, J=6.5 Hz, 2H), 2.80-2.28 (m, 6H), 2.15-1.58 (m, 10H).
Reaction SMILES: [CH3:1][O:2][C:3]([N:5]1[C@@H:13]2[C@@H:8]([C@@:9]([OH:23])([C:14]#[C:15][C:16]3[CH:17]=[C:18]([CH3:22])[CH:19]=[CH:20][CH:21]=3)[CH2:10][CH2:11][CH2:12]2)[CH2:7][CH2:6]1)=[O:4].[NH2:24][C:25](=[O:30])[CH2:26][C:27](O)=[O:28]>>[NH2:24][C:25](=[O:30])[CH2:26][C:27]([O:23][C@@:9]1([C:14]#[C:15][C:16]2[CH:17]=[C:18]([CH3:22])[CH:19]=[CH:20][CH:21]=2)[CH2:10][CH2:11][CH2:12][C@@H:13]2[C@H:8]1[CH2:7][CH2:6][N:5]2[C:3]([O:2][CH3:1])=[O:4])=[O:28]
Reactant: NC(=O)CC(=O)O
Reactant: COC(=O)N1CC[C@H]2[C@@H]1CCC[C@]2(O)C#Cc1cccc(C)c1
Product: COC(=O)N1CC[C@@H]2[C@H]1CCC[C@]2(C#Cc1cccc(C)c1)OC(=O)CC(N)=O

Procedure:
Synthesis in analogy to the General Method 1 starting from (3aS,4R,7aS)-4-hydroxy-4-m-tolylethynyl-octahydro-indole-1-carboxylic acid methyl ester and 3-amino-3-oxopropanoic acid to yield (3aR,4S,7aR)-methyl 4-(3-amino-3-oxopropanoyloxy)-4-(m-tolylethynyl)octahydro-1H-indole-1-carboxylate. MS [M+H]=296 (ester elimination ion); RT=0.96 min; UPLC Method I
Reaction SMILES: [NH2:1][C:2]([C:4]([NH2:6])=[S:5])=[S:3].[CH3:7][O:8][C:9]1[CH:16]=[CH:15][CH:14]=[CH:13][C:10]=1[CH:11]=O>>[CH3:7][O:8][C:9]1[CH:16]=[CH:15][CH:14]=[CH:13][C:10]=1[C:11]1[S:3][C:2]2[N:1]=[C:11]([C:10]3[CH:13]=[CH:14][CH:15]=[CH:16][C:9]=3[O:8][CH3:7])[S:5][C:4]=2[N:6]=1
Reactant: NC(=S)C(N)=S
Reactant: COc1ccccc1C=O
Product: COc1ccccc1-c1nc2sc(-c3ccccc3OC)nc2s1

Procedure:
2,5-bis(2-methoxyphenyl)thiazolo[5,4-d]thiazole was prepared from dithiooxamide and o-methoxybenzaldehyde. o-Methoxybenzaldehyde was purchased from Aldrich Chemical Company, Milwaukee, Wis.
Reaction SMILES: Br[C:2]1[C:10]2[CH:9]=[CH:8][S:7][C:6]=2[CH:5]=[CH:4][CH:3]=1.[Mg].II.CON(C)[C:17](=[O:20])[CH2:18][CH3:19]>O1CCCC1>[S:7]1[CH:8]=[CH:9][C:10]2[C:2]([C:17](=[O:20])[CH2:18][CH3:19])=[CH:3][CH:4]=[CH:5][C:6]1=2
Reactant: CCC(=O)N(C)OC
Reactant: Brc1cccc2sccc12
Agent: II
Agent: [Mg]
Solvent: C1CCOC1
Product: CCC(=O)c1cccc2sccc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 64.5 %

Procedure:
Approximately 5 ml of a solution of 4-bromobenzo[b]thiophene (9.55 g) in tetrahydrofuran (100 ml) was added under nitrogen to magnesium turnings (1.5 g). Two crystals of iodine were added and heat was applied to initiate the reaction. The remainder of the 4-bromobenzo[b]thiophene solution was added at reflux temperature over 20 minutes, then the mixture was heated under reflux for 15 minutes. A solution of N-methoxy-N-methylpropionamide (6.0 g) in tetrahydrofuran (50 ml) was added, the mixture was heated under reflux for 40 minutes, then it was allowed to cool to ambient temperature and quenched by the addition of 2M hydrochloric acid (125 ml). The mixture was stirred at ambient temperature for 1 hour, then the product was extracted into ethyl acetate (300 ml). The extract was washed with water (3×200 ml) and saturated aqueous sodium chloride solution (200 ml), dried (Na2SO4), and the solvents were removed in vacuo. The residue was purified by flash chromatography over silica using petroleum ether (b.p. 60-80° C.) followed by a 97:3 mixture of petroleum ether (b.p. 60-80° C.) and ethyl acetate as eluant. Appropriate fractions were combined and the solvents removed in vacuo to give 1-(benzo[b]thiophen-4-yl)propan-1-one (5.5 g) as a colourless oil which was used without further purification.
Reaction SMILES: C([O-])([O-])=O.[K+].[K+].Cl[CH2:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][CH:10]=1.[NH:17]1[CH:21]=[C:20]([C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH:19]=[N:18]1>C(#N)C>[CH3:16][O:15][C:12]1[CH:13]=[CH:14][C:9]([CH2:8][N:17]2[CH:21]=[C:20]([C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH:19]=[N:18]2)=[CH:10][CH:11]=1
Reactant: COc1ccc(CCl)cc1
Reactant: CCOC(=O)c1cn[nH]c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCOC(=O)c1cnn(Cc2ccc(OC)cc2)c1
Yield: 99.1 %

Procedure:
According to Scheme 1 Step 1: K2CO3 (803 mmol, 111 g) followed by 1-(chloromethyl)-4-methoxybenzene (562 mmol, 76.0 mL) were added slowly to a solution of ethyl 1H-pyrazole-4-carboxylate (535 mmol, 75.0 g) in acetonitrile (500 mL) at room temperature. Then the suspension was heated under reflux for 4 hours. At room temperature, the reaction mixture was filtered, was concentrated under reduced pressure and was slurried in petroleum ether to yield ethyl 1-(4-methoxybenzyl)-1H-pyrazole-4-carboxylate (530 mmol, 138 g, 99%) as a white solid.