Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]([N:4]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[C:8](=[O:15])[NH:7][C:6]2[CH:16]=[CH:17][CH:18]=[N:19][C:5]1=2)=[O:3].[CH2:20]([N:22]([CH2:34][CH3:35])[CH2:23][CH2:24][CH:25]1[CH2:30][CH2:29][N:28]([CH2:31][CH2:32][NH2:33])[CH2:27][CH2:26]1)[CH3:21]>C(OCC)(=O)C>[CH2:34]([N:22]([CH2:20][CH3:21])[CH2:23][CH2:24][CH:25]1[CH2:26][CH2:27][N:28]([CH2:31][CH2:32][NH:33][C:2]([N:4]2[C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=3[C:8](=[O:15])[NH:7][C:6]3[CH:16]=[CH:17][CH:18]=[N:19][C:5]2=3)=[O:3])[CH2:29][CH2:30]1)[CH3:35]
Reactant: O=C1Nc2cccnc2N(C(=O)Cl)c2ccccc21
Reactant: CCN(CC)CCC1CCN(CCN)CC1
Solvent: CCOC(C)=O
Product: CCN(CC)CCC1CCN(CCNC(=O)N2c3ccccc3C(=O)Nc3cccnc32)CC1
Yield: 10 %

Procedure:
Prepared analogously to Example 2 from 11-(chlorocarbonyl)-5,11-dihydro-6H-pyrido[2,3-b][1,4]benzodiazepin-6-one and 2-[4-[2-(diethylamino)ethyl]-piperidin-1-yl]ethanamine in a yield of 10% of theory. Colourless crystals, m.p. 170°-172° C. (ethyl acetate).
Reaction SMILES: Cl[CH2:2][C:3]1[O:4][C:5]([C:8]2[CH:13]=[CH:12][C:11]([N+:14]([O-:16])=[O:15])=[C:10]([O:17][CH3:18])[CH:9]=2)=[N:6][N:7]=1.[NH:19]1[CH2:23][CH2:22][CH2:21][CH2:20]1>O1CCOCC1>[CH3:18][O:17][C:10]1[CH:9]=[C:8]([C:5]2[O:4][C:3]([CH2:2][N:19]3[CH2:23][CH2:22][CH2:21][CH2:20]3)=[N:7][N:6]=2)[CH:13]=[CH:12][C:11]=1[N+:14]([O-:16])=[O:15]
Reactant: COc1cc(-c2nnc(CCl)o2)ccc1[N+](=O)[O-]
Reactant: C1CCNC1
Solvent: C1COCCO1
Product: COc1cc(-c2nnc(CN3CCCC3)o2)ccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 8 h
Yield: 98.7 %

Procedure:
To 2-(chloromethyl)-5-[3-(methyloxy)-4-nitrophenyl]-1,3,4-oxadiazole (Example 26, step C) (1.01 g, 3.75 mmol) in dioxane (10 mL) was added pyrrolidine (0.800 mL, 9.58 mmol). The reaction was stirred at rt overnight. Upon completion by TLC, the reaction mixture was treated with BOC-anhydride (0.371 g, 1.69 mmol) and cooled to 0° C. The mixture was treated with TEA (0.279 mL, 2.00 mmol). Purification by flash chromatography provided the title compound of step A (1.13 g, 3.70 mmol, 99%). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.64-1.72 (m, 4H), 2.56 (br. s., 4H), 3.92-3.96 (m, 2H), 3.98-4.02 (m, 3H), 7.64-7.69 (m, 1H), 7.79 (br. s., 1H), 8.01-8.06 (m, 1H).
Reaction SMILES: C(N([CH2:6][CH3:7])CC)C.C(Cl)(=O)CC.Cl.[CH3:14][O:15][C:16](=[O:21])[CH2:17][C:18](C)=[O:19]>O1CCCC1>[CH3:14][O:15][C:16](=[O:21])[CH2:17][C:18](=[O:19])[CH2:6][CH3:7]
Reactant: CCN(CC)CC
Reactant: COC(=O)CC(C)=O
Agent: CCC(=O)Cl
Agent: Cl
Solvent: C1CCOC1
Product: CCC(=O)CC(=O)OC
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
51.7 g (0.2 mol) of acetoacetic acid methyl ester magnesium enolate in 750 ml of tetrahydrofuran was suspended under nitrogen, 24.3 g (0.24 mol) of triethylamine was added and 38.9 g (0.408 mol) of propionyl chloride was instilled in 15 minutes. The reaction mixture was refluxed for 2 hours, cooled with ice water and hydrolyzed with 285 ml of 1 N HCl. The phases were separated and the water phase was extracted with tert-butyl methyl ether. The organic phases were combined and 140 ml of 10 percent ammonia solution was added with vigorous stirring within 15 minutes. After 1 hour, the phases were separated, dried with sodium sulfate and concentrated by evaporation. The residue was distilled with a Spaltrohr column (split-tube column) at 100 mbars. There was a yield of 23.9 g of 3-oxovaleric acid methyl ester with a purity of 96.0 percent, corresponding to 44 percent of theory. The acetoacetic acid methyl ester separated as the first runnings was able to be used again. The yield thus increased, relative to reacted acetoacetic acid methyl ester, to 69 percent. The boiling point of the product was 109° to 111 C./100 mbars.
Reaction SMILES: [Na].Cl[C:3]1[N:11]=[CH:10][CH:9]=[CH:8][C:4]=1[C:5]([OH:7])=[O:6].[OH:12][C:13]1[CH:20]=[CH:19][C:16]([C:17]#[N:18])=[CH:15][CH:14]=1>CO>[C:17]([C:16]1[CH:19]=[CH:20][C:13]([O:12][C:3]2[N:11]=[CH:10][CH:9]=[CH:8][C:4]=2[C:5]([OH:7])=[O:6])=[CH:14][CH:15]=1)#[N:18]
Reactant: O=C(O)c1cccnc1Cl
Reactant: N#Cc1ccc(O)cc1
Agent: [Na]
Solvent: CO
Product: N#Cc1ccc(Oc2ncccc2C(=O)O)cc1
Reaction time: 6 h
Yield: 49.6 %

Procedure:
To a solution of 6.9 g of metallic sodium in 90 ml of methanol are added 24 g of 2-chloronicotinic acid and 18 g of 4-hydroxybenzonitrile. The methanol is distilled off under reduced pressure, 60 ml of nitrobenzene is added, and the mixture is allowed to stand at 180° C to 190° C for 6 hours. After cooling, an aqueous potassium carbonate solution is added to the reaction mixture, and the whole mixture is filtered off. The aqueous layer is separated, washed with ethyl acetate and made acid with hydrochloric acid. The crystalline precipitate is recrystallized from aqueous ethanol to give 18 g of 2-(4-cyanophenoxy)nicotinic acid melting at 198° C to 200° C.
Reaction SMILES: [CH3:1][C:2]1[C:3]([N+:9]([O-:11])=[O:10])=[C:4]([OH:8])[CH:5]=[CH:6][CH:7]=1.C([O-])([O-])=O.[K+].[K+].[CH2:18](Br)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>CN(C=O)C>[CH2:18]([O:8][C:4]1[C:3]([N+:9]([O-:11])=[O:10])=[C:2]([CH3:1])[CH:7]=[CH:6][CH:5]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: BrCc1ccccc1
Reactant: Cc1cccc(O)c1[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1cccc(OCc2ccccc2)c1[N+](=O)[O-]
Temperature: 90 °C
Reaction time: 3 h
Yield: 88.3 %

Procedure:
A mixture of 3-methyl-2-nitrophenol (50 g, 0.326 mol), K2CO3 (45 g, 0.326 mol) and benzylbromide (61.4 g, 42.6 mL, 0.359 mol) in dry DMF (200 mL) was stirred at 90° C. for 3 hours under nitrogen. Most of the DMF was removed at reduced pressure and the residue was partitioned between water (300 mL) and ether (300 mL). The organic layer was washed with brine and dried (Na2SO4). Removal of the solvent provided (70 g, 88%) of 3-benzyloxy-2-nitrotoluene as an orange oil.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[N:4][N:5]([C:7]2[CH:15]=[CH:14][C:10]([C:11](Cl)=[O:12])=[CH:9][CH:8]=2)[CH:6]=1.[CH:16]1[CH:17]=[CH:18][N:19]2[CH2:25][C:24]3[CH:26]=[CH:27][CH:28]=[CH:29][C:23]=3[NH:22][CH2:21][C:20]=12.C(N(C(C)C)CC)(C)C>ClCCl>[CH3:1][C:2]1[CH:3]=[N:4][N:5]([C:7]2[CH:15]=[CH:14][C:10]([C:11]([N:22]3[C:23]4[CH:29]=[CH:28][CH:27]=[CH:26][C:24]=4[CH2:25][N:19]4[CH:18]=[CH:17][CH2:16][C:20]4=[CH:21]3)=[O:12])=[CH:9][CH:8]=2)[CH:6]=1
Reactant: c1ccc2c(c1)Cn1cccc1CN2
Reactant: Cc1cnn(-c2ccc(C(=O)Cl)cc2)c1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cc1cnn(-c2ccc(C(=O)N3C=C4CC=CN4Cc4ccccc43)cc2)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 62.5 %

Procedure:
The 4-(4-methylpyrazol-1-yl)benzoyl chloride (0.72 g) was added to an ice-cooled solution of 10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine (0.60 g) and diisopropylethylamine (0.48 g) in dichloromethane (25 ml). After stirring at room temperature for 18 hours, the reaction mixture was washed with water and saturated aqueous sodium bicarbonate. The dichloromethane solution was dried over anhydrous sodium sulfate and filtered through a short column of hydrous sodium magnesium silicate and further eluted with several volumes of dichloromethane. The combined organic phase was concentrated on a hot plate with the gradual addition of hexane until crystallization occurred. After cooling, the crystals were collected by filtration to yield the title compound (0.75 g), m.p. 179-181° C.; MS m/z: 369 (M+H)+.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([OH:11])[CH:8]=[CH:9][CH:10]=1)([F:4])([F:3])[F:2].[CH2:12]([CH:14]1[O:16][CH2:15]1)[Cl:13].C([O-])([O-])=O.[K+].[K+]>>[Cl:13][CH2:12][CH:14]([OH:16])[CH2:15][O:11][C:7]1[CH:8]=[CH:9][CH:10]=[C:5]([C:1]([F:3])([F:2])[F:4])[CH:6]=1
Reactant: ClCC1CO1
Reactant: Oc1cccc(C(F)(F)F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: OC(CCl)COc1cccc(C(F)(F)F)c1
Temperature: 70 °C
Reaction time: 2 h
Yield: 99.8 %

Procedure:
A mixture of m-CF3C6H4OH (48.6 g, 0.30 mol), epichlorohydrin (138.8 g, 1.50 mol) and K2CO3 (20.7 g, 0.15 mol) was stirred at 70° C. for 2 h. Epichlorohydrin was evaporated in vacuo. Water (250 mL) was added and the resulting mixture was extracted with CH2Cl2 (2×50 mL). The combined organic extract was stirred with 32% HCl (50 mL) for 0.5 h at rt. The organic layer separated, dried over Na2SO4, filtered and concentrated in vacuo to give 76.2 g of crude 1-chloro-3-[3-(trifluoromethyl)phenoxy]-2-propanol which was used in next step without additional treatment.
Reaction SMILES: CS(Cl)(=O)=O.[CH3:6][O:7][C:8](=[O:20])[C@H:9]([CH2:18]O)[NH:10][C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12].C(N(CC)CC)C.[NH:28]1[CH2:33][CH2:32][O:31][CH2:30][CH2:29]1>ClCCl>[C:14]([O:13][C:11]([NH:10][C@@H:9]([CH2:18][N:28]1[CH2:33][CH2:32][O:31][CH2:30][CH2:29]1)[C:8]([O:7][CH3:6])=[O:20])=[O:12])([CH3:17])([CH3:16])[CH3:15]
Reactant: COC(=O)[C@H](CO)NC(=O)OC(C)(C)C
Reactant: C1COCCN1
Agent: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)[C@H](CN1CCOCC1)NC(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 0.75 h

Procedure:
Methanesulphonyl chloride (0.86 mL, 11 mmol) was added dropwise to a cooled (0° C.), stirred solution of Boc-L-serine methyl ester (2.10 g, 9.6 mmol) and triethylamine (1.53 mL, 11 mmol) in dichloromethane (20 mL) under nitrogen. The mixture was stirred for 45 min, then morpholine (4.5 mL, 52 mmol) was added and the mixture stirred for a further 30 min at 0° C. followed by 1 h at room temperature. Solvent was removed in vacuo and the residue partitioned between ethyl acetate and aq. Na2CO3 solution. The layers were separated and the organic phase concentrated. The residue was azeotroped with toluene and the resulting title compound used without further purification. m/z (ES+) 289 (M+H).
Reaction SMILES: [Cl-].[CH3:2][O:3][C:4]1[CH:5]=[CH:6][CH:7]=[C:8]2[C:12]=1[NH:11][CH:10]=[C:9]2[S+:13](C)[CH3:14]>CS(C)=O>[CH3:2][O:3][C:4]1[CH:5]=[CH:6][CH:7]=[C:8]2[C:12]=1[NH:11][CH:10]=[C:9]2[S:13][CH3:14]
Reactant: COc1cccc2c([S+](C)C)c[nH]c12
Agent: [Cl-]
Solvent: CS(C)=O
Product: COc1cccc2c(SC)c[nH]c12
Yield: 87.4 %

Procedure:
(7-Methoxy-1H-indol-3-yl)-dimethyl-sulfonium chloride (0.742 g) prepared in the manner described in Step 1 above was dissolved in DMSO (3 ml) and placed under reduced pressure (house vacuum, ca. 20-50 torr) in a round-bottom flask. The flask was placed on a steam bath and heated until the bubbling stopped. When no more starting material was present, the reaction mixture was cooled and partitioned between ether and water. The organic layer was dried and filtered and then evaporated to dryness to afford 7-methoxy-3-methylsulfanyl-1H-indole (0.514 g, 87.5%).
Reaction SMILES: C[O:2][C:3]([C:5]1[S:9][C:8]([N:10]2[C:14]3[CH:15]=[C:16]([O:21][CH3:22])[C:17]([O:19][CH3:20])=[CH:18][C:13]=3[N:12]=[CH:11]2)=[N:7][C:6]=1Br)=[O:4].[Cl:24][C:25]1[CH:26]=[C:27](B(O)O)[CH:28]=[C:29]([Cl:31])[CH:30]=1>>[Cl:24][C:25]1[CH:26]=[C:27]([C:6]2[N:7]=[C:8]([N:10]3[C:14]4[CH:15]=[C:16]([O:21][CH3:22])[C:17]([O:19][CH3:20])=[CH:18][C:13]=4[N:12]=[CH:11]3)[S:9][C:5]=2[C:3]([OH:2])=[O:4])[CH:28]=[C:29]([Cl:31])[CH:30]=1
Reactant: OB(O)c1cc(Cl)cc(Cl)c1
Reactant: COC(=O)c1sc(-n2cnc3cc(OC)c(OC)cc32)nc1Br
Product: COc1cc2ncn(-c3nc(-c4cc(Cl)cc(Cl)c4)c(C(=O)O)s3)c2cc1OC
Yield: 51.1 %

Procedure:
In a similar manner as described for Example 26, 4-bromo-2-(5,6-dimethoxy-benzoimidazol-1-yl)-thiazole-5-carboxylic acid methyl ester (40 mg, 0.1 mmol) and 3,5-dichlorophenylboronic acid (27 mg, 0.15 mmol) gave 4-(3,5-Dichloro-phenyl)-2-(5,6-dimethoxy-benzoimidazol-1-yl)-thiazole-5-carboxylic acid (23 mg, 51%) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.84 (s, 1 H); 8.15 (s, 2 H); 7.83 (s, 1 H); 7.73 (s, 1 H); 7.39 (s, 1 H); 3.89 (s, 3 H); 3.85 (s, 3 H). MS 450 m/z (M+1).
Reaction SMILES: FC(F)(F)C(O)=O.C(O[C:13]([NH:15][CH2:16][C:17]1[S:18][C:19]([CH2:22][N:23]2[C:27](=[O:28])[C:26]3=[CH:29][CH:30]=[CH:31][CH:32]=[C:25]3[C:24]2=[O:33])=[CH:20][N:21]=1)=O)(C)(C)C.C(=O)(O)[O-].[Na+]>>[C:27]1(=[O:28])[N:23]([CH2:22][C:19]2[S:18][C:17]3=[CH:16][N:15]=[CH:13][N:21]3[CH:20]=2)[C:24](=[O:33])[C:25]2=[CH:32][CH:31]=[CH:30][CH:29]=[C:26]12
Reactant: CC(C)(C)OC(=O)NCc1ncc(CN2C(=O)c3ccccc3C2=O)s1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Product: O=C1c2ccccc2C(=O)N1Cc1cn2cncc2s1
Temperature: 100 °C
Reaction time: 1 h
Yield: 33.1 %

Procedure:
A 25 ml potion of trifluoroacetic acid was added to 1.64 g of 2-(N-t-butoxycarbonylamino)methyl-5-phthalimidomethylthiazole under ice-cooling, and the mixture was then allowed to stand at room temperature for 1 hour. The solvent was evaporated under reduced pressure, and to the resulting residue, 75 ml of dichloromethane and 25 ml of an aqueous saturated sodium bicarbonate solution were added under ice-cooling, followed by stirring. After the aqueous layer was separated, the organic layer was similarly washed once with the aqueous saturated sodium bicarbonate solution, dried over anhydrous sodium sulfate, and then filtered, and the solvent was evaporated under reduced pressure. Afterward, 997 mg of the resulting residue was dissolved in 9 ml of dichloromethane, and a mixed acid anhydride solution comprising a mixed solution of 0.446 ml of acetic anhydride and 0.446 ml of formic acid which had been beforehand reacted with each other at 50° C. for 30 minutes was then added thereto under ice-cooling. After 2 hours, 9 ml of the aqueous saturated sodium bicarbonate solution was added to the reaction solution. The solution was extracted with dichloromethane (9 ml×2). The combined organic layer was washed with the aqueous saturated sodium bicarbonate solution, dried over anhydrous sodium sulfate, and then filtered, and the solvent was evaporated under reduced pressure. Then, to 1.22 g of the resulting residue, 8.9 ml of phosphorus oxychloride was added, followed by stirring under heating at 100° C. for 1 hour. The reaction solution was concentrated under reduced pressure, and the resulting residue was then diluted with 21 ml of dichloromethane under ice-cooling. To this solution, 9 ml of the aqueous saturated sodium bicarbonate solution and 3.2 ml of an aqueous saturated potassium carbonate solution were added under ice-cooling, and after stirring, the organic layer was separated. Furthermore, the aqueous layer was extracted with dichloromethane (27 ml×2). The combined organic layer was washed with the aqueous saturated sodium bicarbonate solution, and the organic layer was dried over anhydrous sodium sulfate, and then filtered. Afterward, the solvent was evaporated under reduced pressure, and the resulting residue was then purified by a silica gel column chromatograph and Cephadex LH-20 in succession to obtain 412 mg of 2-phthalimidomethylimidazo[5,1-b]thiazole.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:16])[C:4](=O)[CH:5](Cl)[C:6]1[CH:11]=[CH:10][C:9]([C:12]#[N:13])=[CH:8][CH:7]=1.[CH:17]1([C:20](=[S:22])[NH2:21])[CH2:19][CH2:18]1>>[CH3:1][O:2][C:3]([C:4]1[N:21]=[C:20]([CH:17]2[CH2:19][CH2:18]2)[S:22][C:5]=1[C:6]1[CH:11]=[CH:10][C:9]([C:12]#[N:13])=[CH:8][CH:7]=1)=[O:16]
Reactant: NC(=S)C1CC1
Reactant: COC(=O)C(=O)C(Cl)c1ccc(C#N)cc1
Product: COC(=O)c1nc(C2CC2)sc1-c1ccc(C#N)cc1

Procedure:
prepared by reaction of 3-chloro-3-(4-cyano-phenyl)-2-oxo-propionic acid methyl ester with cyclopropanecarbothioic acid amide.
Reaction SMILES: CC1(C)[O:6][C:5](=[CH:7][C:8]([N:10]([CH2:13][C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=2)[O:11][CH3:12])=[O:9])[C:4](=[O:21])O1.[CH3:23][N:24]1[CH:28]=[C:27]([S:29]([NH2:32])(=[O:31])=[O:30])[N:26]=[CH:25]1>>[F:20][C:17]1[CH:16]=[CH:15][C:14]([CH2:13][N:10]([O:11][CH3:12])[C:8](=[O:9])[CH:7]=[C:5]([OH:6])[C:4]([NH:32][S:29]([C:27]2[N:26]=[CH:25][N:24]([CH3:23])[CH:28]=2)(=[O:31])=[O:30])=[O:21])=[CH:19][CH:18]=1
Reactant: Cn1cnc(S(N)(=O)=O)c1
Reactant: CON(Cc1ccc(F)cc1)C(=O)C=C1OC(C)(C)OC1=O
Product: CON(Cc1ccc(F)cc1)C(=O)C=C(O)C(=O)NS(=O)(=O)c1cn(C)cn1

Procedure:
2-(2,2-Dimethyl-5-oxo-[1,3]dioxolan-4-ylidene)-N-(4-fluoro-benzyl)-N-methoxy-acetamide was treated with 1-methyl-1H-imidazole-4-sulfonic acid amide as described in the preparation of compound 1 to yield the title compound. 1H NMR (500 MHz, CDCl3) δ: 3.63 (s, 3), 3.83 (s, 3), 4.75 (s, 2), 6.40 (s, 1), 7.02 (m, 2), 7.27 (m, 2), 7.74 (s, 1), 7.80 (s, 1). 13C NMR (125 MHz, CDCl3) δ: 34.75, 48.21, 63.10, 92.33, 115.65, 115.82, 127.65, 130.24, 130.34, 131.11, 136.85, 139.42, 159.30, 159.55, 161.67, 163.63, 170.81.
Reaction SMILES: [CH2:1]([N:3]1[C:9]2[N:10]=[CH:11][C:12]([CH2:14][CH2:15][C:16]3[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=3)=[CH:13][C:8]=2[C:7](=[O:22])[N:6]([CH3:23])[C:5]2[CH:24]=[CH:25][C:26]([Sn](C)(C)C)=[N:27][C:4]1=2)[CH3:2].[I:32]I>C(Cl)(Cl)Cl>[CH2:1]([N:3]1[C:9]2[N:10]=[CH:11][C:12]([CH2:14][CH2:15][C:16]3[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=3)=[CH:13][C:8]=2[C:7](=[O:22])[N:6]([CH3:23])[C:5]2[CH:24]=[CH:25][C:26]([I:32])=[N:27][C:4]1=2)[CH3:2]
Reactant: CCN1c2ncc(CCc3ccncc3)cc2C(=O)N(C)c2ccc([Sn](C)(C)C)nc21
Reactant: II
Solvent: ClC(Cl)Cl
Product: CCN1c2ncc(CCc3ccncc3)cc2C(=O)N(C)c2ccc(I)nc21
Reaction time: 24 h
Yield: 21 %

Procedure:
To a solution of 5,11-dihydro-11-ethyl-8-[2-(4-pyridyl)ethyl]-2-trimethylstannyl-5-methyl-6H-dipyrido[3,2-b:2',3'-e][1,4]diazepin-6-one (47 mg, 0.09 mmol) in chloroform was added a solution of iodine in chloroform (0.1M, 4 mL, 0.4 mmol). After 24 hours, the reaction mixture was washed with saturated aqueous KF, 5% NaHSO3, and saturated aq. sodium chloride. Purification by flash chromatography (elution with methanol-dichloromethane) and recrystallization (ethyl acetate-hexanes) afforded 15 mg (21%) of the title compound, m.p. 174° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([Cl:17])[CH:12]=2)(Cl)Cl)[CH:5]=[CH:6][CH:7]=1.[F:18][C:19]1[CH:24]=[C:23]([OH:25])[C:22]([OH:26])=[CH:21][C:20]=1[C:27]([N:29]1[CH2:34][CH2:33][O:32][CH2:31][CH2:30]1)=[O:28]>>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]2([C:11]3[CH:16]=[CH:15][CH:14]=[C:13]([Cl:17])[CH:12]=3)[O:25][C:23]3[CH:24]=[C:19]([F:18])[C:20]([C:27]([N:29]4[CH2:34][CH2:33][O:32][CH2:31][CH2:30]4)=[O:28])=[CH:21][C:22]=3[O:26]2)[CH:5]=[CH:6][CH:7]=1
Reactant: Clc1cccc(C(Cl)(Cl)c2cccc(Cl)c2)c1
Reactant: O=C(c1cc(O)c(O)cc1F)N1CCOCC1
Product: O=C(c1cc2c(cc1F)OC(c1cccc(Cl)c1)(c1cccc(Cl)c1)O2)N1CCOCC1

Procedure:
This compound was prepared from bis-(3-chloro-phenyl)-dichloromethane and (2-fluoro-4,5-dihydroxy-phenyl)-morpholin-4-yl-methanone according to Example 276b; viscous brown oil, MS: m/e=474 ([M+H]+).
Reaction SMILES: [CH:1]1([NH:7][C:8]([NH:10][C:11]2[N:12]=[C:13]3[CH:19]=[C:18]([CH3:20])[N:17](COCC[Si](C)(C)C)[C:14]3=[N:15][CH:16]=2)=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(N)CN>Cl.CC(O)=O.CO.O.CCN(CC)CC>[CH:1]1([NH:7][C:8]([NH:10][C:11]2[N:12]=[C:13]3[CH:19]=[C:18]([CH3:20])[NH:17][C:14]3=[N:15][CH:16]=2)=[O:9])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: Cc1cc2nc(NC(=O)NC3CCCCC3)cnc2n1COCC[Si](C)(C)C
Agent: Cl
Solvent: CC(=O)O
Solvent: O
Solvent: CO
Product: Cc1cc2nc(NC(=O)NC3CCCCC3)cnc2[nH]1
Temperature: 50 °C
Reaction time: 8 h
Yield: 31.6 %

Procedure:
1-Cyclohexyl-3-[6-methyl-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazin-2-yl]-urea (56 mg, 0.139 mmol) was dissolved in a solution of HCl in AcOH (1M, 2.8 mL), and heated at 50° C. in the sealed tube overnight. The reaction mixture was concentrated to dryness, dissolved in 1.5 mL of MeOH:H2O:Et3N 8:1:1 and ethylenediamine (93 ul, 1.39 mmol) was added. The reaction mixture was stirred overnight, concentrated and purified by and purified by SiO2 chromatography (8 g SiO2, DCM/MeOH 0-5% MeOH) to give 12 mg of 1-cyclohexyl-3-(6-methyl-5H-pyrrolo[2,3-b]pyrazin-2-yl)-urea as a white solid (32% yield).
Reaction SMILES: [CH:1]([S:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7](I)[CH:6]=1)([CH3:3])[CH3:2].C([Li])CCC.[Cl:17][C:18]1[CH:19]=[C:20]([C:26]([F:29])([F:28])[F:27])[CH:21]=[C:22]([Cl:25])[C:23]=1F.O>C1C=CC=CC=1.CCCCCC.C(OCC)C>[Cl:17][C:18]1[CH:19]=[C:20]([C:26]([F:27])([F:28])[F:29])[CH:21]=[C:22]([Cl:25])[C:23]=1[C:7]1[CH:6]=[C:5]([S:4][CH:1]([CH3:3])[CH3:2])[CH:10]=[CH:9][CH:8]=1
Reactant: CC(C)Sc1cccc(I)c1
Reactant: Fc1c(Cl)cc(C(F)(F)F)cc1Cl
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: O
Solvent: c1ccccc1
Product: CC(C)Sc1cccc(-c2c(Cl)cc(C(F)(F)F)cc2Cl)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 38 %

Procedure:
1.0 g (3.6 mmol) of 3-iodophenyl isopropyl sulfide was stirred in 10 ml of dry benzene in a nitrogen stream at room temperature, while 2.8 ml of a n-butyllithium solution in hexane (1.56 mol/l) was added dropwise. The resulting reaction mixture was stirred at room temperature for another 2 hours and cooled to 10° C., and 1.0 g (4.3 mmol) of 3,5-dichloro-4-fluorobenzotrifluoride in 50 ml of diethyl ether was added dropwise. The resulting reaction mixture was stirred at room temperature for further 12 hours and poured into 100 ml of water for separation. The organic layer was washed with 50 ml of water twice and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. Purification of the residue by silica gel column chromatography afforded 0.5 g of [3-(2,6-dichloro-4-trifluoromethylphenyl)phenyl]isopropyl sulfide (yield 38.0%) as a colorless liquid (nD20 1.5675).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[F:9].C(=O)([O-])[O-].[K+].[K+].FC(F)(F)S(O[CH2:22][C:23]([F:28])([F:27])[CH:24]([F:26])[F:25])(=O)=O>CN(C=O)C.C([O-])(O)=O.[Na+].C(OCC)(=O)C>[Cl:1][C:2]1[C:3]([F:9])=[CH:4][C:5]([O:8][CH2:22][C:23]([F:28])([F:27])[CH:24]([F:26])[F:25])=[CH:6][N:7]=1
Reactant: Oc1cnc(Cl)c(F)c1
Reactant: O=S(=O)(OCC(F)(F)C(F)F)C(F)(F)F
Agent: O=C([O-])O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Fc1cc(OCC(F)(F)C(F)F)cnc1Cl
Temperature: 25 °C
Reaction time: 18 h
Yield: 82.9 %

Procedure:
6-Chloro-5-fluoro-pyridin-3-ol (300 mg, 2.03 mmol) is dissolved in DMF (10 mL). Potassium carbonate (562 mg, 4.07 mmol) is added followed by 2,2,3,3-tetrafluoropropyl trifluoromethanesulfonate (591 mg, 2.24 mmol) (For preparation of this reagent, see US2013/143900, Ex 1). The reaction is stirred at room temperature for 18 hours then allowed to stand at room temperature for 4 days. The reaction is diluted with aqueous NaHCO3 and ethyl acetate. The layers are separated and the aqueous layer is extracted with ethyl acetate (2×). The combined organic layers are washed with brine and concentrated. The crude material is purified via silica gel chromatography using a 0-10% ethyl acetate/hexanes gradient to give the title compound (440 mg, 83%). ES/MS (m/e): 262.0 (M+1).
Reaction SMILES: [ClH:1].[NH:2]1[CH:6]=[CH:5][N:4]=[C:3]1[CH2:7][C:8]1[CH:9]=[C:10]2[C:15](=[CH:16][CH:17]=1)[CH2:14][CH:13]([C:18]([O:20]CC)=[O:19])[CH2:12][CH2:11]2.Cl>CO>[ClH:1].[NH:2]1[CH:6]=[CH:5][N:4]=[C:3]1[CH2:7][C:8]1[CH:9]=[C:10]2[C:15](=[CH:16][CH:17]=1)[CH2:14][CH:13]([C:18]([OH:20])=[O:19])[CH2:12][CH2:11]2
Reactant: CCOC(=O)C1CCc2cc(Cc3ncc[nH]3)ccc2C1
Agent: Cl
Solvent: CO
Product: O=C(O)C1CCc2cc(Cc3ncc[nH]3)ccc2C1
Yield: 61.4 %

Procedure:
4.5 g of ethyl 6-(1-imidazolylmethyl)-1,2,3,4-tetrahydro-2-naphthalenecarboxylate hydrochloride was added to a mixture of 15 ml of concentrated hydrochloric acid and 30 ml of methanol and then the mixture was heated under reflux for 20 hours. The reaction mixture was concentrated in vacuo to give 2.52 g of 6-(1-imidazolylmethyl)-1,2,3,4-tetrahydro-2-naphthalenecarboxylic acid hydrochloride as colorless prisms with m.p. 193°-223° C.
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:16])=[C:11](F)[C:12]=3[F:14])[C:7](=[O:17])[C:6]([C:18]([OH:20])=[O:19])=[CH:5]2)[CH2:3][CH2:2]1.C1[N:26]2[CH2:27][CH2:28]N([CH2:24][CH2:25]2)C1>>[CH:24]12[CH2:25][N:26]([C:11]3[C:12]([F:14])=[C:13]4[C:8]([C:7](=[O:17])[C:6]([C:18]([OH:20])=[O:19])=[CH:5][N:4]4[CH:1]4[CH2:3][CH2:2]4)=[CH:9][C:10]=3[F:16])[CH2:27][CH:28]1[CH2:8][CH2:7][CH:6]=[CH:5]2
Reactant: O=C(O)c1cn(C2CC2)c2c(F)c(F)c(F)cc2c1=O
Reactant: C1CN2CCN1CC2
Product: O=C(O)c1cn(C2CC2)c2c(F)c(N3CC4C=CCCC4C3)c(F)cc2c1=O
Yield: 240 %

Procedure:
Heat 1.4 g (5 mmol) of 1-cyclopropyl-6,7,8-trifluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid, 0.6 g (5 mmol) of DABCO and 0.8 g (6 mmol) of the title compound from Example A to reflux for 3 h in a mixture consisting of 15 ml of acetonitrile and 7.5 ml of DMF. After cooling, add 25 ml of water and 2.5 ml of acetic acid, and filter off the precipitate with suction, wash it with water, and dry it at 50° C.