Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[O:15])[CH:10]([C:24](=[O:29])NCOC)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[F:30][C:31]1[CH:32]=[CH:33][C:34]2[O:38][CH:37]=[CH:36][C:35]=2[CH:39]=1>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[O:15])[CH:10]([C:24]([C:37]2[O:38][C:34]3[CH:33]=[CH:32][C:31]([F:30])=[CH:39][C:35]=3[CH:36]=2)=[O:29])[CH2:9]1)=[O:7])([CH3:3])([CH3:4])[CH3:2]
Reactant: Fc1ccc2occc2c1
Reactant: COCNC(=O)C1CN(C(=O)OC(C)(C)C)CCN1C(=O)OCc1ccccc1
Product: CC(C)(C)OC(=O)N1CCN(C(=O)OCc2ccccc2)C(C(=O)c2cc3cc(F)ccc3o2)C1

Procedure:
The title compound was prepared from (RS)-2-(methoxymethylcarbamoyl)piperazine-1,4-dicarboxylic acid 1-benzyl ester 4-tert-butyl ester (1.25 g, 3.07 mmol) (WO01/00214) and 5-fluorobenzofuran (0.42 g, 3.09 mmol) (WO99/51575) by the method of Description 2 as a pale green gum (0.81 g, 55%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[C:4]1[CH:9]=[CH:8][C:7]([CH2:10]O)=[N:6][C:5]=1[Cl:12].S(Cl)(C)(=O)=O.[N-:19]=[N+:20]=[N-:21].[Na+]>ClCCl.C(OCC)(=O)C>[CH3:1][O:2][C:3](=[O:13])[C:4]1[CH:9]=[CH:8][C:7]([CH2:10][N:19]=[N+:20]=[N-:21])=[N:6][C:5]=1[Cl:12]
Reactant: [N-]=[N+]=[N-]
Reactant: COC(=O)c1ccc(CO)nc1Cl
Agent: CS(=O)(=O)Cl
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: COC(=O)c1ccc(CN=[N+]=[N-])nc1Cl
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 84.7 %

Procedure:
To a cold (0° C.) solution of 2-chloro-6-hydroxymethyl-nicotinic acid methyl ester (4.98 g, 24.8 mmol) in dichloromethane (161 mL) was added mesyl chloride (2.5 mL, 29.8 mmol). The reaction mixture was allowed to warm to room temperature and stirred for 30 minutes. The mixture was diluted with ethyl acetate and washed with a saturated aqueous solution of sodium bicarbonate, water and brine. The organic phase was isolated, dried (Na2SO4), filtered and concentrated in vacuo. The resultant residue was taken up in dimethylformamide (62 mL) and sodium azide (4.03 g, 62 mmol) added. After stirring at room temperature for 16 hours, the reaction mixture was cooled to 0° C., quenched with water (ca. 50 mL), and extracted three times with ethyl acetate. The combined organic extracts were washed with water and brine, dried (Na2SO4), filtered and concentrated in vacuo. The residue was subjected to flash chromatography (Si-PPC, gradient 0% to 50%, ethyl acetate in hexane) to afford the title compound as a pale yellow oil (4.76 g, 85%). LCMS (method B): RT=3.22 min, [M+H]+=227.
Reaction SMILES: N[C@@H:2]([C:7]([OH:9])=[O:8])[CH2:3][C:4]([OH:6])=[O:5].[BrH:10].N([O-])=O.[Na+]>O.C(OCC)C>[Br:10][C@H:2]([CH2:3][C:4]([OH:6])=[O:5])[C:7]([OH:9])=[O:8]
Reactant: N[C@H](CC(=O)O)C(=O)O
Reactant: Br
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Solvent: CCOCC
Product: O=C(O)C[C@@H](Br)C(=O)O
Temperature: 2.5 °C
Reaction time: 12 h
Yield: 45 %

Procedure:
To a 500 mL round bottom flask was added D-aspartic acid ((R)-aspartic acid, 25 g, 188 mmol) and 245 mL of 5 N HBr. The reaction was cooled in an ice bath to 0-5° C., followed by the dropwise addition of sodium nitrite (20.7 g, 301 mmol) in 75 mL of water over five hours. The temperature was maintained below 5° C. during the addition. After the addition was complete, the reaction was allowed to stir for 12 hours at 23-25° C. The reaction was diluted with diethyl ether (120 mL). The aqueous layer was removed and the organic phase was washed with 1 N HCl (100 mL). The combined aqueous phases were washed with EtOAc (100 mL). The combined organic extracts were dried (MgSO4), filtered and concentrated under reduced pressure to leave the product as a slightly yellow solid. The solid was recrystallized from EtOAc (˜100 mL) and hexanes (˜10 mL) to obtain the product (16.58 g, 84 mmol, 45%) as a white crystalline solid.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]2[N:13]=[C:12]([C:14]3[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[C:16]([O:24][CH2:25][C:26]([F:29])([F:28])[F:27])[CH:15]=3)[CH:11]=[C:10]([C:30]([F:33])([F:32])[F:31])[N:9]=2)[CH:5]=[CH:4][N:3]=1.[NH2:34][C:35]1[CH:40]=[CH:39][C:38](B2OC(C)(C)C(C)(C)O2)=[CH:37][N:36]=1>>[F:27][C:26]([F:29])([F:28])[CH2:25][O:24][C:16]1[CH:15]=[C:14]([C:12]2[CH:11]=[C:10]([C:30]([F:33])([F:32])[F:31])[N:9]=[C:8]([C:6]3[CH:5]=[CH:4][N:3]=[C:2]([C:38]4[CH:37]=[N:36][C:35]([NH2:34])=[CH:40][CH:39]=4)[CH:7]=3)[N:13]=2)[CH:19]=[CH:18][C:17]=1[C:20]([F:23])([F:22])[F:21]
Reactant: CC1(C)OB(c2ccc(N)nc2)OC1(C)C
Reactant: FC(F)(F)COc1cc(-c2cc(C(F)(F)F)nc(-c3ccnc(Cl)c3)n2)ccc1C(F)(F)F
Product: Nc1ccc(-c2cc(-c3nc(-c4ccc(C(F)(F)F)c(OCC(F)(F)F)c4)cc(C(F)(F)F)n3)ccn2)cn1

Procedure:
The title compound was prepared from 2-(2-chloro-pyridin-4-yl)-4-[3-(2,2,2-trifluoroethoxy)-4-trifluoromethyl-phenyl]-6-trifluoromethyl-pyrimidine (example E.56) (0.25 g, 0.5 mmol) and commercially available 2-amino-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (0.13 g, 0.6 mmol) according to the general procedure VI. Obtained as a light brown solid (0.21 g, 77%). MS (ISP) 560.0 [(M+H)+]; mp 223° C.
Reaction SMILES: [F:1][C:2]1([F:30])[CH2:7][CH2:6][N:5]([C:8]([C:10]2[NH:11][C:12]3[C:17]([CH:18]=2)=[CH:16][C:15]([C:19]([N:21]2[CH2:26][CH2:25][N:24]([CH:27]([CH3:29])[CH3:28])[CH2:23][CH2:22]2)=[O:20])=[CH:14][CH:13]=3)=[O:9])[CH2:4][CH2:3]1.[F:31][C:32]([F:43])([F:42])[C:33]1[CH:34]=[C:35](B(O)O)[CH:36]=[CH:37][CH:38]=1.N1C=CC=CC=1>ClCCl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[F:30][C:2]1([F:1])[CH2:7][CH2:6][N:5]([C:8]([C:10]2[N:11]([C:37]3[CH:36]=[CH:35][CH:34]=[C:33]([C:32]([F:43])([F:42])[F:31])[CH:38]=3)[C:12]3[C:17]([CH:18]=2)=[CH:16][C:15]([C:19]([N:21]2[CH2:22][CH2:23][N:24]([CH:27]([CH3:28])[CH3:29])[CH2:25][CH2:26]2)=[O:20])=[CH:14][CH:13]=3)=[O:9])[CH2:4][CH2:3]1
Reactant: OB(O)c1cccc(C(F)(F)F)c1
Reactant: CC(C)N1CCN(C(=O)c2ccc3[nH]c(C(=O)N4CCC(F)(F)CC4)cc3c2)CC1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(C)N1CCN(C(=O)c2ccc3c(c2)cc(C(=O)N2CCC(F)(F)CC2)n3-c2cccc(C(F)(F)F)c2)CC1
Yield: 33 %

Procedure:
The title compound was synthesized in analogy to example 66, from (4,4-difluoro-piperidin-1-yl)-[5-(4-isopropyl-piperazine-1-carbonyl)-1H-indol-2-yl]-methanone (example 32), 3-(trifluoromethyl)phenylboronic acid, copper(II) acetate and pyridine in dichloromethane, to give the desired product as a white foam (33%).
Reaction SMILES: C1C(=O)N(Br)C(=O)C1.[Cl:9][C:10]1[C:15](/[C:16](/O)=[CH:17]\[C:18]2[CH:23]=[CH:22][N:21]=[C:20]([Cl:24])[N:19]=2)=[CH:14][CH:13]=[CH:12][C:11]=1[NH:26][S:27]([C:30]1[C:35]([F:36])=[CH:34][CH:33]=[CH:32][C:31]=1[F:37])(=[O:29])=[O:28].[O:38]1[CH2:43][CH2:42][CH:41]([C:44](=[S:46])[NH2:45])[CH2:40][CH2:39]1>CC(N(C)C)=O.O>[Cl:9][C:10]1[C:15]([C:16]2[N:45]=[C:44]([CH:41]3[CH2:42][CH2:43][O:38][CH2:39][CH2:40]3)[S:46][C:17]=2[C:18]2[CH:23]=[CH:22][N:21]=[C:20]([Cl:24])[N:19]=2)=[CH:14][CH:13]=[CH:12][C:11]=1[NH:26][S:27]([C:30]1[C:35]([F:36])=[CH:34][CH:33]=[CH:32][C:31]=1[F:37])(=[O:29])=[O:28]
Reactant: O=S(=O)(Nc1cccc(/C(O)=C\c2ccnc(Cl)n2)c1Cl)c1c(F)cccc1F
Reactant: NC(=S)C1CCOCC1
Agent: O=C1CCC(=O)N1Br
Solvent: CC(=O)N(C)C
Solvent: O
Product: O=S(=O)(Nc1cccc(-c2nc(C3CCOCC3)sc2-c2ccnc(Cl)n2)c1Cl)c1c(F)cccc1F
Temperature: 25 °C
Yield: 50.1 %

Procedure:
Recrystallized NBS (1.56 g, 8.8 mmol) was added to a suspension of N-{2-chloro-3-[(E)-2-(2-chloro-4-pyrimidinyl)-1-hydroxyethenyl]phenyl}-2,6-difluorobenzenesulfonamide (4.02 g, 8.80 mmol) in DMA (15 mL) in an ice-bath. The reaction was immediately removed from the ice bath and allowed to warm to rt over 0.5 h. Tetrahydro-2H-pyran-4-carbothioamide (1.27 g, 8.80 mmol) was added and the reaction warmed in an oil bath (rt to 65° C.). The reaction was diluted with water (100 mL) which caused the precipitation of a yellow solid. The solid was then dissolved by the addition of EtOAc (100 mL) and the phases separated. The aqueous phase was extracted with EtOAc (50 mL). The combined organic phase was filtered through Whatman 1 PS (phase separating) paper and concentrated under vacuum to a crude orange residue. The residue was purified by silica gel chromatography eluting with 0-100% EtOAc/hexanes to give the title compound of Step A as a bright yellow solid (2.56 g; 50.1% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 10.88 (s, 1H), 8.55 (d, J=5.4 Hz, 1H), 7.62-7.74 (m, 1H), 7.48-7.57 (m, 2H), 7.42-7.47 (m, 1H), 7.22 (t, J=9.1 Hz, 2H), 6.54 (d, J=5.3 Hz, 1H), 3.92 (d, J=11.0 Hz, 2H), 3.41-3.51 (m, 2H), 2.03 (br. s., 2H), 1.69-1.83 (m, J=12.1, 12.1, 11.9, 4.2 Hz, 2H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([CH:11]=O)=[CH:5]2.[F:13][C:14]([F:31])([F:30])[C:15]1[CH:16]=[CH:17][C:18]([N:21]2[CH2:25][C@@H:24]3[C@@H:26]([NH2:29])[CH2:27][CH2:28][C@@H:23]3[CH2:22]2)=[N:19][CH:20]=1.C(O)(=O)C.C([BH3-])#N>ClCCl>[F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([CH2:11][NH:29][C@@H:26]1[C@@H:24]3[C@@H:23]([CH2:22][N:21]([C:18]4[CH:17]=[CH:16][C:15]([C:14]([F:31])([F:30])[F:13])=[CH:20][N:19]=4)[CH2:25]3)[CH2:28][CH2:27]1)=[CH:5]2
Reactant: N[C@H]1CC[C@@H]2CN(c3ccc(C(F)(F)F)cn3)C[C@@H]21
Reactant: O=Cc1cc2cc(F)ccc2[nH]1
Agent: [BH3-]C#N
Solvent: ClCCl
Solvent: CC(=O)O
Product: Fc1ccc2[nH]c(CN[C@H]3CC[C@@H]4CN(c5ccc(C(F)(F)F)cn5)C[C@@H]43)cc2c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
The title compound was prepared by combining 5-fluoro-1H-indole-2-carbaldehyde (30.1 mg, 0.184 mmol) and (3aR,4S,6aS)-2-(5-(trifluoromethyl)pyridin-2-yl)octahydrocyclopenta[c]pyrrol-4-amine (50 mg, 0.184 mmol) from Example 262 Step B in dichloromethane (0.2 mL) to give a colorless solution. 0.2 mL of acetic acid was added. The reaction was stirred at ambient temperature for 30 minutes, then PS-cyanoborohydride (166 mg, 0.369 mmol) was added. After 18 hours, the reaction was filtered and the solvent was removed in vacuo. The crude material was purified using a 12 g silica gel cartridge eluted with 1-10% methanol (2 N ammonia)/dichloromethane to give the title compound: 1H NMR (500 MHz, pyridine-d5) δ ppm 12.14 (s, 1H), 8.64 (dd, J=1.5, 0.7, 1H), 7.69 (dd, J=8.9, 2.5, 1H), 7.54-7.46 (m, 2H), 7.14-7.07 (m, 1H), 6.61 (d, J=1.2, 1H), 6.36 (d, J=8.9, 1H), 4.12-4.00 (m, 2H), 3.56 (ddd, J=21.0, 9.4, 3.4, 2H), 3.48-3.40 (m, 1H), 3.28 (ddd, J=3.7, 2.1, 0.9, 1H), 3.04 (dd, J=11.0, 5.8, 1H), 2.78-2.68 (m, 1H), 2.57-2.50 (m, 1H), 2.31-2.04 (m, 1H), 2.02-1.91 (m, 2H), 1.55-1.44 (m, 1H), 1.38-1.28 (m, 1H); MS (ESI+) m/z 419 (M+H)+.
Reaction SMILES: [CH3:1][Si]([N-][Si](C)(C)C)(C)C.[K+].[NH2:11][C:12]1[C:17]([C:18]([C:20]2[CH:21]=[N:22][C:23]([NH2:26])=[CH:24][CH:25]=2)=O)=[CH:16][C:15]([C:27]2[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[C:29]([O:35][CH3:36])[CH:28]=2)=[CH:14][N:13]=1>C1COCC1>[CH3:36][O:35][C:29]1[CH:28]=[C:27]([C:15]2[CH:16]=[C:17]3[C:18]([C:20]4[CH:25]=[CH:24][C:23]([NH2:26])=[N:22][CH:21]=4)=[CH:1][NH:11][C:12]3=[N:13][CH:14]=2)[CH:32]=[CH:31][C:30]=1[O:33][CH3:34]
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Reactant: COc1ccc(-c2cnc(N)c(C(=O)c3ccc(N)nc3)c2)cc1OC
Agent: [K+]
Solvent: C1CCOC1
Product: COc1ccc(-c2cnc3[nH]cc(-c4ccc(N)nc4)c3c2)cc1OC
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 28.9 %

Procedure:
To a suspension of(methoxymethyl)triphenylphosphonium chloride (166 mg, 0.485 mmol) in THF (1 ml) at 0° C. under nitrogen was added potassium bis(trimethylsilyl)amide (97 mg, 0.485 mmol). The mixture was stirred at room temperature for 30 min, then it was added to [2-amino-5-(3,4-dimethoxy-phenyl)-pyridin-3-yl]-(6-amino-pyridin-3-yl)-methanone (34 mg, 0.097 mmol) in one portion. The reaction mixture was stirred for 2 hours, then quenched with wet methanol and concentrated in vacuo. The crude was diluted with 2 ml of 1,4-dioxane and treated with 0.1 ml of aqueous 70% perchloric acid. The mixture was stirred at 80° C. for 19 hours, diluted with THF/methanol (1:1), and treated with 2.0 g of PS-trisamine (Argonaut Technologies, 4 equivalents per equivalent of acid used) for 30 minutes. The resin was filtered off and washed with THF/MeOH (1:1). Purification was accomplished by flash chromotography on silica gel with a gradient of methanol/dichloromethane afforded 5-[5-(3,4-dimethoxy-phenyl)-1H-pyrrolo[2,3-b]pyridin-3-yl]-pyridin-2-ylamine as a yellow solid (9.7 mg, 29% yield). 1H NMR (DMSO-d6): δ 11.8 (s, 1H), 8.51 (d, J=2.0 Hz, 1H), 8.31 (d, J=2.0 Hz, 1H), 8.25 (d, J=2.0 Hz, 1H), 7.77 (dd, J=2.0, 10.0 Hz, 1H), 7.70 (d, J=2.5 Hz, 1H), 7.28 (d, J=2.0 Hz, 1H), 7.24 (dd, J=2.0, 7.5 Hz, 1H), 7.04 (d, J=8.5 Hz, 1H), 6.55 (d, J=8.5 Hz, 1H), 5.90 (broad s, 2H), 3.86 (s, 3H), 3.79 (s, 3H). HPLC/MS m/z: 347.1 [MH]+.
Reaction SMILES: O[CH:2]1[C:10]2[C:5](=[CH:6][C:7]([N+:11]([O-:13])=[O:12])=[CH:8][CH:9]=2)[C:4](=[O:14])[O:3]1.[CH2:15]([SH:19])[CH2:16][CH2:17][SH:18].B(F)(F)F.CCOCC.S([O-])([O-])(=O)=O.[Mg+2]>C(Cl)(Cl)Cl>[S:18]1[CH2:17][CH2:16][CH2:15][S:19][CH:2]1[C:10]1[CH:9]=[CH:8][C:7]([N+:11]([O-:13])=[O:12])=[CH:6][C:5]=1[C:4]([OH:3])=[O:14]
Reactant: O=C1OC(O)c2ccc([N+](=O)[O-])cc21
Reactant: SCCCS
Agent: FB(F)F
Agent: O=S(=O)([O-])[O-]
Agent: [Mg+2]
Solvent: ClC(Cl)Cl
Solvent: CCOCC
Product: O=C(O)c1cc([N+](=O)[O-])ccc1C1SCCCS1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To an ice-cooled mixture of the Compound 3a (5.00 g, 25.6 mmol) and propane-1,3-dithiol (2.92 g, 27 mmol) in chloroform (75 mL) was added boron trifluoride etherate (2 mL). The mixture was stirred and allowed to warm to room temperature. After stirring for 3 hours, most of the solid had dissolved. Magnesium sulfate was added to dry the solution, and stirring was continued overnight. Filtration and evaporation of the solvent afforded a light yellow solid. This material was triturated with butyl chloride to give the Compound 3b; m.p. 192°-194° C.; 1H NMR (CDCl3 +MeSO-d6 +D2O)δ1.8-2.3 (m, 2H, CH2CH2CH2, 2.9-3.2 (m, 4H, --CH2CH2CH2 --), 6.56 (s, 1H, --SCHS--), 7.6-8.8 (m, 3H, ArH).
Reaction SMILES: [C:1](Cl)(=[O:5])[CH2:2][CH2:3][CH3:4].[Cl-].[Cl-].[Cl-].[Al+3].[C:11]1([C:21]2[N:25]3[CH:26]=[CH:27][CH:28]=[CH:29][C:24]3=[CH:23][N:22]=2)[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:14]=[CH:13][CH:12]=1>ClCCl>[C:11]1([C:21]2[N:25]3[CH:26]=[CH:27][CH:28]=[CH:29][C:24]3=[C:23]([C:1](=[O:5])[CH2:2][CH2:3][CH3:4])[N:22]=2)[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:14]=[CH:13][CH:12]=1
Reactant: CCCC(=O)Cl
Reactant: c1ccc2c(-c3ncc4ccccn34)cccc2c1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: CCCC(=O)c1nc(-c2cccc3ccccc23)n2ccccc12
Reaction time: 0.17 h
Yield: 7 %

Procedure:
To a solution of butyroylchloride (100 μL, 1.13 mmol) in dichloromethane (10 mL) was added aluminum trichloride (195 mg, 1.47 mmol). The mixture was allowed to stir for 10 min. then a solution of 3-naphthalen-1-yl-imidazo[1,5-a]pyridine (276 mg, 1.13 mmol) in dichloromethane (5 mL) was added. The mixture was stirred for 30 min. at ambient temperature then washed with saturated aqueous sodium bicarbonate and the organic layer was dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was chromatographed on silica to yield the title compound (25 mg, 8%). 1H NMR (DMSO-d6) δ 8.27 (1H), 8.19 (1H), 8.10 (1H), 7.95 (1H), 7.85 (1H), 7.68 (1H), 7.60 (2H), 7.55 (1H), 7.40 (1H), 6.95 (1H), 3.04 (2H), 1.70 (2H), 0.90 (3H); m/z (M+H)=315.2.
Reaction SMILES: [SH:1][C:2]1[S:6][C:5]([CH3:7])=[N:4][N:3]=1.[CH2:8](Br)[CH2:9][CH2:10][CH3:11]>C[Si](C)(C)N[Si](C)(C)C.C1(C)C=CC=CC=1.CN(C)P(=O)(N(C)C)N(C)C.S1(C2C(=CC=CC=2)C(=O)N1)(=O)=O>[CH2:8]([S:1][C:2]1[S:6][C:5]([CH3:7])=[N:4][N:3]=1)[CH2:9][CH2:10][CH3:11]
Reactant: CCCCBr
Reactant: Cc1nnc(S)s1
Agent: C[Si](C)(C)N[Si](C)(C)C
Agent: O=C1NS(=O)(=O)c2ccccc21
Solvent: Cc1ccccc1
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: CCCCSc1nnc(C)s1
Reaction time: 3 h
Yield: 89.1 %

Procedure:
Using the procedure of Example 19, 1.32 g (10 mmoles) of 5-mercapto-2-methyl-1,3,4-thiadiazole were silylated with 2.6 ml (15 mmoles) of hexamethyldisilazane in 10 ml of toluene and 2.6 ml of hexamethylphosphoric triamide using 5 mg (0.027 mmole) of saccharin as a catalyst by refluxing for 1.5 hour. After concentration by evaporation, 5 ml of acetonitrile were added thereto and the solution obtained was heated at 50° C. while 2.1 ml (20 mmoles) of butyl bromide were added. The conversion was complete after stirring for 3 hours at this temperature and according to quantitative HPLC analysis, there had been formed 8.91 mmoles (89.1%) of 5-butylthio-2-methyl-1,3,4-thiadiazole, while 5.3% of 3-butyl-5-methyl-Δ4 -1,3,4-thiadiazoline-2-thione was found as a by-product.
Reaction SMILES: [CH3:1][N:2]1[C:11](=[O:12])[C:10]2[NH:9][CH:8]=[N:7][C:6]=2[N:5]([CH3:13])[C:3]1=[O:4].C(=O)([O-])[O-].[K+].[K+].[Br:20][CH2:21][C:22]1[CH:37]=[CH:36][C:25]([C:26]([C:28]2[CH:35]=[CH:34][C:31]([CH2:32]Br)=[CH:30][CH:29]=2)=[O:27])=[CH:24][CH:23]=1>CN(C=O)C.O>[Br:20][CH2:21][C:22]1[CH:37]=[CH:36][C:25]([C:26]([C:28]2[CH:29]=[CH:30][C:31]([CH2:32][N:9]3[C:10]4[C:11](=[O:12])[N:2]([CH3:1])[C:3](=[O:4])[N:5]([CH3:13])[C:6]=4[N:7]=[CH:8]3)=[CH:34][CH:35]=2)=[O:27])=[CH:24][CH:23]=1
Reactant: O=C(c1ccc(CBr)cc1)c1ccc(CBr)cc1
Reactant: Cn1c(=O)c2[nH]cnc2n(C)c1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Cn1c(=O)c2c(ncn2Cc2ccc(C(=O)c3ccc(CBr)cc3)cc2)n(C)c1=O
Yield: 40.1 %

Procedure:
A solution of 1,3-dimethylxanthine (990 mg), potassium carbonate (1348 mg) and 4-(4-bromomethylbenzoyl)benzyl bromide (2007 mg) in DMF (10 ml) was stirred at 60° C. for 5 hours. This reaction mixture was poured in water and extracted with ethyl acetate. The extract was washed with water, dried, and concentrated. The residue was purified by silica gel column chromatography (hexane: ethyl acetate =1:5) and recrystallized from ethyl acetate-isopropyl ether to provide the title compound as colorless solid (1021 mg).
Reaction SMILES: CN(C)C=O.[C:6]([O:10][C:11](=[O:46])[N:12]([CH:24]1[CH2:29][CH2:28][N:27]([CH2:30][CH2:31][N:32]2[C:41]3[C:36](=[C:37](Br)[CH:38]=[C:39]([O:42][CH3:43])[CH:40]=3)[CH:35]=[CH:34][C:33]2=[O:45])[CH2:26][CH2:25]1)[CH2:13][C:14]1[CH:23]=[CH:22][C:17]2[O:18][CH2:19][CH2:20][O:21][C:16]=2[CH:15]=1)([CH3:9])([CH3:8])[CH3:7].[C:47]([O:51][CH2:52][CH3:53])(=[O:50])[CH:48]=[CH2:49]>CC(C)([P](C(C)(C)C)([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)C(C)(C)C)C.C(N(CC)CC)C>[C:6]([O:10][C:11]([N:12]([CH2:13][C:14]1[CH:23]=[CH:22][C:17]2[O:18][CH2:19][CH2:20][O:21][C:16]=2[CH:15]=1)[CH:24]1[CH2:29][CH2:28][N:27]([CH2:30][CH2:31][N:32]2[C:41]3[C:36](=[C:37](/[CH:49]=[CH:48]/[C:47]([O:51][CH2:52][CH3:53])=[O:50])[CH:38]=[C:39]([O:42][CH3:43])[CH:40]=3)[CH:35]=[CH:34][C:33]2=[O:45])[CH2:26][CH2:25]1)=[O:46])([CH3:9])([CH3:8])[CH3:7]
Reactant: COc1cc(Br)c2ccc(=O)n(CCN3CCC(N(Cc4ccc5c(c4)OCCO5)C(=O)OC(C)(C)C)CC3)c2c1
Reactant: C=CC(=O)OCC
Agent: CC(C)(C)[P]([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)(C(C)(C)C)C(C)(C)C
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCOC(=O)/C=C/c1cc(OC)cc2c1ccc(=O)n2CCN1CCC(N(Cc2ccc3c(c2)OCCO3)C(=O)OC(C)(C)C)CC1
Temperature: 90 °C

Procedure:
To 4.0 mL of an N,N-dimethylformamide solution containing 0.15 g of tert-butyl(1-(2-(5-bromo-7-methoxy-2-oxoquinolin-1(2H)-yl)ethyl)piperidin-4-yl)(2,3-dihydro-1,4-benzodioxin-6-ylmethyl)carbamate, 39 μl of ethyl acrylate, 50 μL of triethylamine and 6.1 mg of bis(tri-tert-butylphosphine)palladium(0) were added and heated under nitrogen atmosphere at 90° C. for 1.5 hours. The reaction mixture was cooled to the room temperature, and the solvent was removed under reduced pressure. The residue thus obtained was purified by silica gel column chromatography [eluent; chloroform:methanol=20:1] to give 0.15 g of ethyl (2E)-3-(1-(2-(4-((tert-butoxycarbonyl)(2,3-dihydro-1,4-benzodioxin-6-ylmethyl)amino)piperidin-1-yl)ethyl)-7-methoxy-2-oxo-1,2-dihydroquinolin-5-yl)acrylate as a light brown foam.
Reaction SMILES: [C:1]([C:4]1[CH:13]([C:14]2[CH:21]=[CH:20][C:17]([C:18]#[N:19])=[CH:16][C:15]=2[CH2:22][CH3:23])[C:12]2[C:11](=[O:24])[NH:10][CH:9]=[CH:8][C:7]=2[NH:6][C:5]=1[CH3:25])(=[O:3])[CH3:2].F[B-](F)(F)F.[CH2:31]([O+](CC)CC)[CH3:32].CO>ClCCl>[C:1]([C:4]1[CH:13]([C:14]2[CH:21]=[CH:20][C:17]([C:18]#[N:19])=[CH:16][C:15]=2[CH2:22][CH3:23])[C:12]2[C:7](=[CH:8][CH:9]=[N:10][C:11]=2[O:24][CH2:31][CH3:32])[NH:6][C:5]=1[CH3:25])(=[O:3])[CH3:2]
Reactant: CCc1cc(C#N)ccc1C1C(C(C)=O)=C(C)Nc2cc[nH]c(=O)c21
Reactant: CC[O+](CC)CC
Agent: F[B-](F)(F)F
Solvent: CO
Solvent: ClCCl
Product: CCOc1nccc2c1C(c1ccc(C#N)cc1CC)C(C(C)=O)=C(C)N2
Temperature: 25 °C
Reaction time: 12 h

Procedure:
275 mg (0.82 mmol) of 4-(3-acetyl-2-methyl-5-oxo-1,4,5,6-tetrahydro-1,6-naphthyridin-4-yl)-3-ethylbenzonitrile are suspended under an argon atmosphere in dichloromethane (10 ml), 313 mg (1.65 mmol) of triethyloxonium tetrafluoroborate are added, and the mixture is stirred at RT for 12 h. The reaction mixture is then mixed with methanol and concentrated. The residue is purified by preparative HPLC to result in 152 mg (50% of theory) of the title compound as a white solid.
Reaction SMILES: [CH3:1][NH:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][C:8]([OH:10])=[O:9].C(=O)([O-])[O-].[K+].[K+].Cl[C:18]([O:20][CH3:21])=[O:19].Cl>O.O1CCOCC1>[CH3:21][O:20][C:18]([N:2]([CH3:1])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][C:8]([OH:10])=[O:9])=[O:19]
Reactant: CNCCCCCC(=O)O
Reactant: COC(=O)Cl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: COC(=O)N(C)CCCCCC(=O)O
Temperature: 25 °C
Yield: 81.3 %

Procedure:
N-methyl-caprolactam (15 g, 118 mmol) was combined with barium hydroxide (10.1 g, 72 mmol) and water (150 ml). The suspension was warmed to 110° C. for 18 hours then cooled over an ice bath. Gaseous carbon dioxide was bubbled through the solution for 20 minutes. The suspension was filtered through a celite pad and the filtrate was concentrated to dryness. The residue was triturated with acetonitrile, collected, rinsed with ether and dried in vacuo to yield 6-(methylamino)hexanoic acid as a white solid (10.7 g). 6-(Methylamino)hexanoic acid (5 g, 34.5 mmol), and potassium carbonate (18 g, 130 mmol) were suspended in water (50 ml) and dioxane (25 ml) then cooled to 0° C. Methyl chloroformate (13 ml, 168 mmol) was added over 1 minute, then the mixture was stirred and allowed to warm slowly to room temperature for 16 hours. Conc. HCl (20 ml) was added then the mixture was diluted with water and extracted with ethyl acetate. The organic layer was dried over magnesium sulfate, evaporated and dried in vacuo to give 6-[(methoxycarbonyl)(methyl)amino]hexanoic acid as a thick clear oil (5.7 g).
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([CH2:9][C:10]([O:12][CH3:13])=[O:11])=[C:4]([CH2:14][CH3:15])[CH:3]=1.[Cu](C#N)[C:17]#[N:18]>CN(C)C=O.O>[C:17]([C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([CH2:9][C:10]([O:12][CH3:13])=[O:11])=[C:4]([CH2:14][CH3:15])[CH:3]=1)#[N:18]
Reactant: N#C[Cu]C#N
Reactant: CCc1cc(Br)cc(C)c1CC(=O)OC
Solvent: O
Solvent: CN(C)C=O
Product: CCc1cc(C#N)cc(C)c1CC(=O)OC
Temperature: 130 °C

Procedure:
7.5 g of methyl 4-bromo-2-ethyl-6-methylphenylacetate were dissolved in 140 ml of dimethylformamide, 5.5 g of copper cyanide were added, and the mixture was heated for 18 hours at 130° C., until the reaction was complete. The mixture was then cooled to room temperature and diluted with water, and the product was extracted repeatedly using tert-butyl methyl ether. The combined organic phases were dried over magnesium sulphate, concentrated and distilled. This gave 3.4 g (52% of theory) of methyl 4-cyano-2-ethyl-6-methylphenylacetate of a boiling point of 123-130° C. and a melting point of 65-72° C.