Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][CH:2]([CH2:5][CH2:6][CH2:7][NH2:8])[CH2:3][NH2:4].[C:9]([O:18][CH2:19][CH3:20])(=[O:17])/[CH:10]=[CH:11]\[C:12]([O:14][CH2:15][CH3:16])=[O:13]>>[CH3:1][CH:2]([CH2:5][CH2:6][CH2:7][NH:8][CH:10]([CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])[C:9]([O:18][CH2:19][CH3:20])=[O:17])[CH2:3][NH:4][CH:10]([CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])[C:9]([O:18][CH2:19][CH3:20])=[O:17]
Reactant: CCOC(=O)/C=C\C(=O)OCC
Reactant: CC(CN)CCCN
Product: CCOC(=O)CC(NCCCC(C)CNC(CC(=O)OCC)C(=O)OCC)C(=O)OCC

Procedure:
1 mol of 2-methyl-1,5-diaminopentane was slowly added dropwise, under a nitrogen atmosphere, to 2 mol of diethyl maleate, in such a manner that the reaction temperature did not exceed 60° C. Heating was then carried out at 60° C. until no further diethyl maleate could be detected in the reaction mixture. The product was obtained quantitatively in the form of a yellow liquid.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[CH:4][CH:3]=1.[C:10]([N:13]1[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1)(=[O:12])[CH3:11].S(=O)(=O)(O)O>[Ni].CO>[C:10]([N:13]1[CH2:18][CH2:17][N:16]([CH2:6][C:5]2[CH:8]=[CH:9][C:2]([OH:1])=[CH:3][CH:4]=2)[CH2:15][CH2:14]1)(=[O:12])[CH3:11]
Reactant: O=Cc1ccc(O)cc1
Reactant: CC(=O)N1CCNCC1
Agent: [Ni]
Agent: O=S(=O)(O)O
Solvent: CO
Product: CC(=O)N1CCN(Cc2ccc(O)cc2)CC1
Temperature: 80 °C
Reaction time: 4 h

Procedure:
A mixture of 22.4 g=0.2 mole of p-hydroxybenzaldehyde, 25.6 g=0.2 mole of acetylpiperazine, 200 ml of methanol, 10 g of Raney nickel and 0.1 ml of concentrated sulfuric acid is stirred for 4 hours in an autoclave at 80° C. and under a hydrogen pressure of 100 atmospheres. After cooling, and releasing the pressure, the catalyst is filtered off, the solvent is removed in vacuo on a rotary evaporator, the residue is taken up in methylene chloride, the mixture is washed with 2 N sodium carbonate solution, the organic phase is dried with sodium sulfate, the solvent is removed as above and the residue is recrystallized from a mixture of ethyl acetate and diisopropyl ether. This gives 33.4 g (71% of theory), melting point: 130°-132° C.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([CH3:9])[N+:5]([O-:8])=[CH:6][CH:7]=1.[F:10][C:11]1[CH:16]=[C:15]([F:17])[CH:14]=[CH:13][C:12]=1[OH:18].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C(=O)C>[F:10][C:11]1[CH:16]=[C:15]([F:17])[CH:14]=[CH:13][C:12]=1[O:18][C:2]1[CH:3]=[C:4]([CH3:9])[N+:5]([O-:8])=[CH:6][CH:7]=1
Reactant: Cc1cc(Cl)cc[n+]1[O-]
Reactant: Oc1ccc(F)cc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Solvent: O
Product: Cc1cc(Oc2ccc(F)cc2F)cc[n+]1[O-]
Temperature: 140 °C

Procedure:
4.3 g (30 mmol) of 4-chloro-2-picoline-N-oxide are added to a mixture of 4.6 g (35 mmol) of 2,4-difluorophenol in 25 ml of N,N-dimethylacetamide and 4.9 g (35 mmol) of finely powdered potassium carbonate and the mixture is warmed to 140° C. for 3 hours with stirring. After cooling, the reaction mixture is poured into 250 ml of water, extracted three times using dichloromethane, and the organic phases are dried over MgSO4 and concentrated. The residue is taken up in dichloromethane and extracted by shaking with saturated aqueous NaCl solution. After drying and freeing from solvent, the extract is brought to crystallization using diisopropyl ether and washed with ethyl acetate. Colorless crystals, m.p. 112°-124° C.
Reaction SMILES: [CH:1]1([OH:13])[C:11]2=[C:12]3[C:7](=[CH:8][CH:9]=[CH:10]2)[CH:6]=[CH:5][CH:4]=[C:3]3[CH2:2]1.[Br:14]N1C(=O)CCC1=O>CN(C=O)C>[Br:14][C:6]1[C:7]2[C:12]3[C:3]([CH2:2][CH:1]([OH:13])[C:11]=3[CH:10]=[CH:9][CH:8]=2)=[CH:4][CH:5]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: OC1Cc2cccc3cccc1c23
Solvent: CN(C)C=O
Product: OC1Cc2ccc(Br)c3cccc1c23
Reaction time: 3 h

Procedure:
To 1,2-dihydro-1-acenaphthylenol (0.34 g, 2 mmol) in dry DMF (10 mL) was added recrystallised N-bromosuccinimide (0.39 g, 2.2 mmol), and the mixture stirred for 3 h under nitrogen. The solution was poured onto water (500 mL) and the precipitate filtered off. The resultant solid was redissolved in methanol, filtered and evaporated in vacuo to yield the title compound as a brown solid.
Reaction SMILES: FC(F)(F)C(O)=O.[Cl:8][C:9]1[C:10]([N:15]2[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]2)=[N:11][CH:12]=[N:13][CH:14]=1.[Br:21][C:22]1[C:30]2[N:29]=[C:28](Cl)[NH:27][C:26]=2[CH:25]=[C:24]([C:32]([F:35])([F:34])[F:33])[CH:23]=1.C(N(CC)C(C)C)(C)C>>[Br:21][C:22]1[C:30]2[N:29]=[C:28]([N:18]3[CH2:17][CH2:16][N:15]([C:10]4[C:9]([Cl:8])=[CH:14][N:13]=[CH:12][N:11]=4)[CH2:20][CH2:19]3)[NH:27][C:26]=2[CH:25]=[C:24]([C:32]([F:35])([F:34])[F:33])[CH:23]=1
Reactant: FC(F)(F)c1cc(Br)c2nc(Cl)[nH]c2c1
Reactant: Clc1cncnc1N1CCNCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: O=C(O)C(F)(F)F
Product: FC(F)(F)c1cc(Br)c2nc(N3CCN(c4ncncc4Cl)CC3)[nH]c2c1

Procedure:
The reaction of 1-(5-chloropyrimidin-4-yl)piperazine trifluoroacetic acid salt (0.414 g, 0.97 mmol, Example 33d), 4-bromo-2-chloro-6-trifluoromethyl-1H-benzoimidazole (0.29 g, 0.97 mmol, Example 9b) and N,N-diisopropylethylamine (0.5 mL, 2.91 mmol, Aldrich) under the conditions of Example 1d gave the title compound as an amorphous solid. MS (ESI, pos. ion) m/z: 461 (M+1).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([O:27][CH3:28])[C:5]([O:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[C:6]2[C:11]=1[N:10]=[CH:9][CH:8]=[C:7]2[CH3:12].Br[CH:30]([CH3:45])[CH2:31][CH2:32][CH2:33][N:34]1[C:38](=[O:39])[C:37]2=[CH:40][CH:41]=[CH:42][CH:43]=[C:36]2[C:35]1=[O:44]>CCN(CC)CC>[CH3:28][O:27][C:4]1[C:5]([O:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[C:6]2[C:11](=[C:2]([NH:1][CH:30]([CH3:45])[CH2:31][CH2:32][CH2:33][N:34]3[C:38](=[O:39])[C:37]4=[CH:40][CH:41]=[CH:42][CH:43]=[C:36]4[C:35]3=[O:44])[CH:3]=1)[N:10]=[CH:9][CH:8]=[C:7]2[CH3:12]
Reactant: COc1cc(N)c2nccc(C)c2c1OCCCCCCCc1ccccc1
Reactant: CC(Br)CCCN1C(=O)c2ccccc2C1=O
Solvent: CCN(CC)CC
Product: COc1cc(NC(C)CCCN2C(=O)c3ccccc3C2=O)c2nccc(C)c2c1OCCCCCCCc1ccccc1
Reaction time: 3 h
Yield: 76.5 %

Procedure:
A stirred mixture of 8-amino-6-methoxy-4-methyl-5-(7-phenylheptoxy) quinoline [Example 1c] (9.2 g, 0.024 mol) and 4-bromo-1-phthalimidopentane (BPP) (15 g, 0.05 mol) was heated at 120°-125° C. while Et3N (5 ml) was added in small portions. After 3 h at 120°-125° C., second portions of BPP (7.5g) and Et3N (2.5 ml) were added and heating was continued for 4 h. Third portions of BPP (3 g) and Et3N (1 ml) were introduced, and heating was continued for 2 h. The reaction was allowed to cool and extracted with Et2O (total, ca. 500 ml). The extract was treated with carbon and then with saturated ethereal hydrogen chloride (300 ml). The resulting dark red semi-solid mass was separated and basified with Et2O - Et3N. Concentration of the ethereal solution left 11.5 g (81%) of brown oil which was dissolved in CHCl3, placed on a silica gel column (200 g) and eluted with CHCl3. The first six eluates (75 ml each) were combined and concentrated to give 10.9 grams of 6-methoxy-4-methyl-8-(1-methyl-4-phthalimidobutylamino)-5-(7-phenylheptoxy) quinoline which was used without further purification.
Reaction SMILES: [F:1][C:2]([F:24])([F:23])[C:3]1[C:13]2[S:12][C:11]3[CH:14]=[CH:15][C:16]([C:18]([F:21])([F:20])[F:19])=[CH:17][C:10]=3[NH:9][C:8](=O)[C:7]=2[CH:6]=[CH:5][CH:4]=1.P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:26].O>N1C=CC=CC=1>[F:1][C:2]([F:24])([F:23])[C:3]1[C:13]2[S:12][C:11]3[CH:14]=[CH:15][C:16]([C:18]([F:21])([F:20])[F:19])=[CH:17][C:10]=3[NH:9][C:8](=[S:26])[C:7]=2[CH:6]=[CH:5][CH:4]=1
Reactant: O=C1Nc2cc(C(F)(F)F)ccc2Sc2c1cccc2C(F)(F)F
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Solvent: O
Solvent: c1ccncc1
Product: FC(F)(F)c1ccc2c(c1)NC(=S)c1cccc(C(F)(F)F)c1S2
Reaction time: 8 h
Yield: 50.8 %

Procedure:
4,8-Bis(trifluoromethyl)-10,11-dihydrodibenzo[b,f][1,4]thiazepin-11-one (0.54 g) was dissolved in pyridine (15 ml). Phosphorus pentasulphide (0.60 g) was added to the solution and the whole was stirred under reflux for 6 hours, then cooled and left overnight. Addition of water (40 ml) and cooling gave a yellow solid which was filtered off, washed with water and recrystallised from ethanol to give the product as yellow needles (0.26 g, m/s. M- =379).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7]2[CH:15]=[CH:14][CH:13]=[C:12]3[C:8]=2[CH2:9][C:10](=[O:16])[NH:11]3)=[CH:3][CH:2]=1.[N:17]1([CH2:23][CH2:24][O:25][C:26]2[CH:27]=[C:28]3[C:32](=[CH:33][CH:34]=2)[NH:31][C:30]([CH:35]=O)=[CH:29]3)[CH2:22][CH2:21][O:20][CH2:19][CH2:18]1>>[N:17]1([CH2:23][CH2:24][O:25][C:26]2[CH:27]=[C:28]3[C:32](=[CH:33][CH:34]=2)[NH:31][C:30]([CH:35]=[C:9]2[C:8]4[C:12](=[CH:13][CH:14]=[CH:15][C:7]=4[C:4]4[CH:5]=[CH:6][N:1]=[CH:2][CH:3]=4)[NH:11][C:10]2=[O:16])=[CH:29]3)[CH2:18][CH2:19][O:20][CH2:21][CH2:22]1
Reactant: O=C1Cc2c(cccc2-c2ccncc2)N1
Reactant: O=Cc1cc2cc(OCCN3CCOCC3)ccc2[nH]1
Product: O=C1Nc2cccc(-c3ccncc3)c2C1=Cc1cc2cc(OCCN3CCOCC3)ccc2[nH]1

Procedure:
4-Pyridin-4-yl-1,3-dihydroindol-2-one was condensed with (5-(2-morpholin-4-yl-ethoxy)-1H-indole-2-carbaldehyde to give the title compound.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:22])[C:4]1[C:9](Cl)=[CH:8][C:7]([CH3:11])=[N:6][C:5]=1[O:12][C:13]1[C:18]([CH3:19])=[CH:17][C:16]([Cl:20])=[CH:15][C:14]=1[CH3:21].[CH2:23]([CH:25]([NH2:28])[CH2:26][CH3:27])[CH3:24]>CS(C)=O>[CH3:1][O:2][C:3](=[O:22])[C:4]1[C:9]([NH:28][CH:25]([CH2:26][CH3:27])[CH2:23][CH3:24])=[CH:8][C:7]([CH3:11])=[N:6][C:5]=1[O:12][C:13]1[C:18]([CH3:19])=[CH:17][C:16]([Cl:20])=[CH:15][C:14]=1[CH3:21]
Reactant: CCC(N)CC
Reactant: COC(=O)c1c(Cl)cc(C)nc1Oc1c(C)cc(Cl)cc1C
Solvent: CS(C)=O
Product: CCC(CC)Nc1cc(C)nc(Oc2c(C)cc(Cl)cc2C)c1C(=O)OC
Temperature: 120 °C

Procedure:
A mixture of 4-chloro-6-methyl-2-(4-Chloro-2,6-dimethyl-phenoxy)-nicotinic acid methyl ester (77 mg, 0.226 mmol) and 1-ethyl-propyl-amine in DMSO was heated at 120° C. for 4 hr. The mixture was quenched with sat. ammonium chloride, water, brine and extracted with ethyl acetate. The organic layer was dried and concentrated to give 140 mg of yellow solid. 1HNMR(CDCl3) d 8.10(d,1H), 7.03(s,2H), 6.09(s,1H), 3.88(s,3H), 3.35(m,1H), 2.10(s,3H), 2.08(s,6H), 1.5–1.7(m,4H), 0.96(t,6H) ppm.
Reaction SMILES: [NH2:1][CH:2]([C:11]1[C:16]([O:17][CH3:18])=[CH:15][CH:14]=[CH:13][C:12]=1[O:19][CH3:20])[CH2:3][CH:4]([CH3:10])[C:5]([O:7]CC)=O.[CH:21]([O:24][C:25]1[CH:32]=[CH:31][C:28]([CH:29]=O)=[CH:27][CH:26]=1)([CH3:23])[CH3:22]>>[CH3:18][O:17][C:16]1[CH:15]=[CH:14][CH:13]=[C:12]([O:19][CH3:20])[C:11]=1[CH:2]1[N:1]([CH2:29][C:28]2[CH:31]=[CH:32][C:25]([O:24][CH:21]([CH3:23])[CH3:22])=[CH:26][CH:27]=2)[C:5](=[O:7])[CH:4]([CH3:10])[CH2:3]1
Reactant: CCOC(=O)C(C)CC(N)c1c(OC)cccc1OC
Reactant: CC(C)Oc1ccc(C=O)cc1
Product: COc1cccc(OC)c1C1CC(C)C(=O)N1Cc1ccc(OC(C)C)cc1

Procedure:
Prepared according to the described general procedure 2 (GP2) by reaction of ethyl 4-amino-4-(2,6-dimethoxyphenyl)-2-methylbutanoate with commercially available 4-isopropoxybenzaldehyde. Subsequent purification by preparative HPLC afforded the target compound. LC-MS (conditions A): tR=0.90 min.; [M+H]+: 384.12 g/mol.
Reaction SMILES: [CH:1]1([N:7]2[C:11]3[CH:12]=[CH:13][C:14]([CH2:16][N:17]4[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]4)=[CH:15][C:10]=3[N:9]=[C:8]2[NH2:23])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[N:24]1([C:29]2[CH:30]=[C:31]([CH:35]=[CH:36][CH:37]=2)[C:32](O)=[O:33])[CH:28]=[N:27][N:26]=[N:25]1.ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=N>CN(C)C=O.O>[CH:1]1([N:7]2[C:11]3[CH:12]=[CH:13][C:14]([CH2:16][N:17]4[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22]4)=[CH:15][C:10]=3[N:9]=[C:8]2[NH:23][C:32](=[O:33])[C:31]2[CH:35]=[CH:36][CH:37]=[C:29]([N:24]3[CH:28]=[N:27][N:26]=[N:25]3)[CH:30]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: Nc1nc2cc(CN3CCCCC3)ccc2n1C1CCCCC1
Reactant: O=C(O)c1cccc(-n2cnnn2)c1
Agent: CN(C)CCCN=C=N
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Product: O=C(Nc1nc2cc(CN3CCCCC3)ccc2n1C1CCCCC1)c1cccc(-n2cnnn2)c1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of 1-cyclohexyl-5-piperidin-1-ylmethyl-1H-benzimidazol-2-amine (100 mg, 0.32 mmol, prepared above) and 3-(1-tetrazolyl)-benzoic acid (76 mg, 0.40 mmol) in N,N-dimethylformamide (2 mL) was added 1-hydroxybenzotriazole (57 mg, 0.42 mmol) followed by 1-(3-dimethylaminopropyl)carbodiimide hydrochloride (80 mg, 0.42 mmol). N,N-diisoproplethylamine (100 mg, 0.77 mmol) was then added and the solution was allowed to stir at room temperature. After 18 hr, the reaction mixture was diluted with N,N-dimethylformamide (2 mL) and water (1 mL), filtered, and purified without work-up by preparative scale HPLC. Freeze-drying afforded (N-(1-cyclohexyl-5-piperidin-1-ylmethyl-1H-benzimidazol-2-yl)-3-(1-tetrazolyl) benzamide) as a cream solid (27 mg, 0.056 mmol): 1H NMR (DMSO-d6, 300 MHz) δ 10.20 (s, 1 H,), 9.30 (broad s, 1 H), 8.63 (s, 1 H), 8.34 (d, J=10.0 Hz, 1 H), 8.02 (d, J=10 Hz, 1 H), 7.81–7.64 (m, 2 H), 7.64 (s, 1H), 7.33 (d, J=10.0 Hz, 1 H), 4.83–4.63 (m, 1 H), 4.41–4.29 (m, 2 H), 2.99–1.33 (m, 18 H). MS: API m/z 485 (M+H+)
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[C:8](=[O:10])[CH3:9].[CH3:11][N:12]1[C:16]2[CH:17]=[C:18](B3OC(C)(C)C(C)(C)O3)[CH:19]=[CH:20][C:15]=2[O:14][C:13]1=[O:30].C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1.C(O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:8]([C:7]1[CH:6]=[CH:5][N:4]=[CH:3][C:2]=1[C:18]1[CH:19]=[CH:20][C:15]2[O:14][C:13](=[O:30])[N:12]([CH3:11])[C:16]=2[CH:17]=1)(=[O:10])[CH3:9]
Reactant: Cn1c(=O)oc2ccc(B3OC(C)(C)C(C)(C)O3)cc21
Reactant: CC(=O)c1ccncc1Br
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCO
Product: CC(=O)c1ccncc1-c1ccc2oc(=O)n(C)c2c1
Temperature: 90 °C
Yield: 55.2 %

Procedure:
A mixture of 1-(3-bromopyridin-4-yl)ethanone (50 mg, 0.250 mmol), 3-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzo[d]oxazol-2(3H)-one (68.8 mg, 0.250 mmol), polymer bound PalladiumTetrakis (56.8 mg, 6.25 μmol) and sodium carbonate (250 μl, 0.500 mmol) in toluene (1 mL) and ethanol (1 mL) was heated to 90° C. in microwave for 45 min. After filtration through a pad of Na2SO4, the solvent was removed in vacuum. The residue was purified by flash column (MeOH—CH2Cl2, v/v, 1%-1.5%) and yielded colorless solid (37 mg). ESI-MS m/z: 269.0 [M+1]+, Retention time 1.03 min; 1H NMR (400.3 MHz, CDCl3): δ 2.13 (s, 3H), 344 (s, 3H), 6.95 (d, J=1.48 Hz, 1H), 7.07 (dd, J=8.2, 1.68 Hz, 1H), 7.29 (d, J=8.2 Hz, 1H), 7.37 (d J=5 Hz, 1H), 8.69 (s, 1H), 8.73 (d, J=5 Hz, 1H).
Reaction SMILES: [F:1][C:2]1[CH:34]=[CH:33][C:5]([CH2:6][N:7]2[C:16](=[O:17])[C:15]([C:18]3[NH:23][C:22]4[CH:24]=[CH:25][C:26](I)=[CH:27][C:21]=4[S:20](=[O:30])(=[O:29])[N:19]=3)=[C:14]([OH:31])[C@H:13]3[C@@H:8]2[C@H:9]2[CH2:32][C@@H:12]3[CH2:11][CH2:10]2)=[CH:4][CH:3]=1.[Cu][C:36]#[N:37].CN(C)C=O>C(OCC)(=O)C>[F:1][C:2]1[CH:34]=[CH:33][C:5]([CH2:6][N:7]2[C:16](=[O:17])[C:15]([C:18]3[NH:23][C:22]4[CH:24]=[CH:25][C:26]([C:36]#[N:37])=[CH:27][C:21]=4[S:20](=[O:30])(=[O:29])[N:19]=3)=[C:14]([OH:31])[C@H:13]3[C@@H:8]2[C@H:9]2[CH2:32][C@@H:12]3[CH2:11][CH2:10]2)=[CH:4][CH:3]=1
Reactant: O=C1C(C2=NS(=O)(=O)c3cc(I)ccc3N2)=C(O)[C@@H]2[C@H]3CC[C@H](C3)[C@@H]2N1Cc1ccc(F)cc1
Reactant: N#C[Cu]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: N#Cc1ccc2c(c1)S(=O)(=O)N=C(C1=C(O)[C@@H]3[C@H]4CC[C@H](C4)[C@@H]3N(Cc3ccc(F)cc3)C1=O)N2
Temperature: 120 °C
Reaction time: 24 h
Yield: 96.2 %

Procedure:
(1R,2S,7R,8S)-3-(4-Fluoro-benzyl)-6-hydroxy-5-(7-iodo-1,1-dioxo-1,4-dihydro-1λ6-benzo[1,2,4]thiadiazin-3-yl)-3-aza-tricyclo[6.2.1.02,7]undec-5-en-4-one (0.5 g, 0.84 mmol) and copper(I) cyanide (0.151 g, 1.7 mmol) were suspended anhydrous N,N-dimethylformamide (4 mL). The mixture was stirred at 120° C., under nitrogen for 24 h. Upon cooling, the mixture was diluted with ethyl acetate (20 mL) and washed with saturated aqueous ammonium chloride solution (3×15 mL). The organic phase was passed through a short plug of Celite followed by a short plug of silica gel (Merck silica gel 60, 40-63 μm), eluting with ethyl acetate. The filtrate was concentrated in vacuo to afford a yellow solid. Purification by flash column chromatography (Teledyne Isco RediSep column; 25-100% ethyl acetate in hexanes) followed by concentration in vacuo afforded the desired product, (1R,2S,7R,8S)-3-[3-(4-fluoro-benzyl)-6-hydroxy-4-oxo-3-aza-tricyclo[6.2.1.02,7]undec-5-en-5-yl]-1,1-dioxo-1,4-dihydro-1λ6-benzo[1,2,4]thiadiazine-7-carbonitrile (0.398 g, 0.808 mmol, 96%), as a white, brittle foam. 1H NMR (400 MHz, DMSO-d6) δ: 1.15-1.15 (1H, m), 1.34-1.61 (5H, m), 2.48-2.48 (1H, m), 2.60 (1H, d, J=3.3 Hz), 2.90 (1H, d, J=9.4 Hz), 3.48 (1H, d, J=9.4 Hz), 4.38 (1H, d, J=15.6 Hz), 4.96 (1H, d, J=15.4 Hz), 7.11-7.16 (2H, m), 7.31 (2H, dd, J1=8.6 Hz, J2=5.4 Hz), 7.60 (1H, d, J=8.6 Hz), 8.02 (1H, dd, J1=8.6 Hz, J2=2.5 Hz), 8.37 (1H, s). LC-MS (ESI) calculated for C25H21FN4O4S 492.13. found 493.1 [M+H+].
Reaction SMILES: N[C@H](C(O)=O)CC1C=C2C(C=CC=C2)=CC=1.[OH-].[K+].[Br:19][C:20]1[CH:21]=[C:22]([OH:26])[CH:23]=[CH:24][CH:25]=1.[CH3:27][CH:28]([CH2:32][CH2:33][CH2:34][CH:35]([CH3:37])[CH3:36])[CH2:29][CH2:30]Cl>C(O)C>[CH3:27][CH:28]([CH2:32][CH2:33][CH2:34][CH:35]([CH3:37])[CH3:36])[CH2:29][CH2:30][O:26][C:22]1[CH:21]=[C:20]([Br:19])[CH:25]=[CH:24][CH:23]=1
Reactant: Oc1cccc(Br)c1
Reactant: CC(C)CCCC(C)CCCl
Agent: N[C@@H](Cc1ccc2ccccc2c1)C(=O)O
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: CC(C)CCCC(C)CCOc1cccc(Br)c1
Temperature: 25 °C
Reaction time: 96 h

Procedure:
450 ml of ethanol were placed in the reaction vessel and admixed with Nal (10.5 g; 70 mmol) and KOH (67.3 g; 1.2 mol). A temperature rise from 25 to 40° C. was observed after addition of the KOH. After cooling to room temperature, 3-bromophenol (175.5 g; 1 mol) was added. The white suspension became beige during this addition. 3,7-dimethyloctyl chloride (186.32 g; 212.94 ml; 1.05 mol) was added over a period of 3 minutes by means of a dropping funnel. The mixture was stirred further for 2 hours at RT and subsequently for 96 hours at an internal temperature of 80° C. Ethanol was distilled off. The residue was taken up in ethyl acetate and the precipitate was separated off by filtration. The organic phase was extracted three times with 10% strength by weight aqueous NaOH solution, washed once with H2O, three times with H2O which had been acidified with CO2 and again with H2O. After drying over MgSO4, the solvent was again taken off on a rotary evaporator and the crude product was purified by fractional vacuum distillation.
Reaction SMILES: [NH2:1][C:2]1[C:10]([NH2:11])=[C:9]([Br:12])[C:5]2=[N:6][S:7][N:8]=[C:4]2[C:3]=1[Br:13].[CH3:14][C:15](=O)[C:16](=O)[CH3:17].O>C(O)(=O)C>[Br:13][C:3]1[C:4]2[C:5](=[N:6][S:7][N:8]=2)[C:9]([Br:12])=[C:10]2[C:2]=1[N:1]=[C:16]([CH3:17])[C:15]([CH3:14])=[N:11]2
Reactant: Nc1c(N)c(Br)c2nsnc2c1Br
Reactant: CC(=O)C(C)=O
Solvent: O
Solvent: CC(=O)O
Product: Cc1nc2c(Br)c3nsnc3c(Br)c2nc1C
Temperature: 25 °C
Reaction time: 19 h

Procedure:
5,6-Diamino-4,7-dibromobenzo[c][1,2,5]thiadiazole (0.257 g, 7.93×10−4 mol) was dissolved in acetic acid (30 ml). 2,3-Butanedione (0.30 ml, 3.4×10−3 mol) was added, and the reaction mixture was stirred for 19 h at room temperature under N2. Water (50 ml) was added, and the resulting precipitate was filtered, dissolved in CH2Cl2, washed with water, and dried over Na2SO4. After the solvent was evaporated, the residue was chromatographed on silica gel with CHCl3. Yield=0.256 g (86% based on 0.257 g of 5,6-diamino-4,7-dibromobenzo[c][1,2,5]thiadiazole). 1H NMR (360 MHz, CDCl3): δ 2.88 (s, 6H, —CH3). Chemical Ionization MS m/z: 371.8675 (M+) (calcd 371.868).
Reaction SMILES: O.O.[Sn](Cl)(Cl)(Cl)Cl.Cl.[C:9]([C:11]1[C:16](=[S:17])[NH:15][C:14]([C:18]2[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=2)=[C:13]([C:26]([O:28]CC)=O)[C:12]=1[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=1[N+:37]([O-:39])=O)#[N:10].[CH2:40](O)C>>[OH:39][N:37]1[C:32]2[CH:33]=[CH:34][CH:35]=[CH:36][C:31]=2[C:12]2[C:11]([C:9]#[N:10])=[C:16]([S:17][CH3:40])[N:15]=[C:14]([C:18]3[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=3)[C:13]=2[C:26]1=[O:28]
Reactant: CCOC(=O)c1c(-c2ccc(OC)cc2)[nH]c(=S)c(C#N)c1-c1ccccc1[N+](=O)[O-]
Reactant: CCO
Agent: Cl
Agent: Cl[Sn](Cl)(Cl)Cl
Solvent: O
Product: COc1ccc(-c2nc(SC)c(C#N)c3c2c(=O)n(O)c2ccccc32)cc1
Reaction time: 4 h
Yield: 80 %

Procedure:
12.05 g (53.4 mmol) of tin chloride dihydrate and 14 ml of concentrated hydrochloric acid are added to 4 g (8.9 mmol) of ethyl 5-cyano-2-(4-methoxyphenyl)-4-(2-nitrophenyl)-6-thioxo-1,6-dihydropyridine-3-carboxylate dissolved in 160 ml of ethanol. The reaction medium is carried at 65° C. for 4 hours. The precipitate obtained is filtered, rinsed with isopropanol and then dried to yield 2.78 g (80%) of 6-hydroxy-4-(4-methoxyphenyl)-2-(methylthio)-5-oxo-5,6-dihydrobenzo[c][2,7]naphthyridine-1-carbonitrile in the form of a yellow solid.
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:10]=[N:11][S:12][CH:13]=2)=[CH:5][CH:4]=1.[ClH:14].[CH3:15][O:16][C:17]1[CH:18]=[C:19]([C:25]2[C@@H:34]3[C@@H:29]([CH2:30][CH:31]=[CH:32][CH2:33]3)[C:28](=[O:35])[N:27]([CH:36]3[CH2:41][CH2:40][N:39](CC4C=C5C(C=CC(=O)O5)=CC=4)[CH2:38][CH2:37]3)[N:26]=2)[CH:20]=[CH:21][C:22]=1[O:23][CH3:24]>>[ClH:14].[ClH:14].[CH3:15][O:16][C:17]1[CH:18]=[C:19]([C:25]2[C@@H:34]3[C@@H:29]([CH2:30][CH:31]=[CH:32][CH2:33]3)[C:28](=[O:35])[N:27]([CH:36]3[CH2:41][CH2:40][N:39]([CH2:2][C:3]4[CH:8]=[CH:7][C:6]([C:9]5[N:10]=[N:11][S:12][CH:13]=5)=[CH:5][CH:4]=4)[CH2:38][CH2:37]3)[N:26]=2)[CH:20]=[CH:21][C:22]=1[O:23][CH3:24]
Reactant: BrCc1ccc(-c2csnn2)cc1
Reactant: COc1ccc(C2=NN(C3CCN(Cc4ccc5ccc(=O)oc5c4)CC3)C(=O)[C@@H]3CC=CC[C@H]23)cc1OC
Agent: Cl
Product: COc1ccc(C2=NN(C3CCN(Cc4ccc(-c5csnn5)cc4)CC3)C(=O)[C@@H]3CC=CC[C@H]23)cc1OC

Procedure:
Prepared from starting compound A1 and 4-(4-Bromomethyl-phenyl)-[1,2,3]thiadiazole as described for compound 18. M.p. 243-245° C.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH2:8])=[CH:4][C:3]=1[O:9][C:10]([F:13])([F:12])[F:11].[Cl:14]N1C(=O)CCC1=O>C(#N)C>[Br:1][C:2]1[C:3]([O:9][C:10]([F:12])([F:11])[F:13])=[CH:4][C:5]([NH2:8])=[C:6]([Cl:14])[CH:7]=1
Reactant: O=C1CCC(=O)N1Cl
Reactant: Nc1ccc(Br)c(OC(F)(F)F)c1
Solvent: CC#N
Product: Nc1cc(OC(F)(F)F)c(Br)cc1Cl
Temperature: 60 °C
Yield: 61.8 %

Procedure:
To a mixture of 4-bromo-3-trifluoromethoxy-phenylamine (2.0 g, 7.8 mmol) in ACN (60 mL) was slowly added a solution of N-chlorosuccinimide (1.0 g, 7.8 mmol) in ACN (40 mL). The reaction mixture was heated at 60° C. overnight and extracted with ethyl actetate/water. The organic layer was dried over sodium sulfate and purified by flash chromatography (40 g column, 100% hexanes to 10% EtOAc: hexanes) to produce the desired product as an orange-ish-colored oil (1.4 g, 64% yield).
Reaction SMILES: [CH3:1][Si:2]([CH3:7])([CH3:6])[CH2:3][CH2:4][SH:5].[H-].[Na+].[F:10][C:11]1[CH:16]=[C:15]([C:17]([OH:26])([C:22]([F:25])([F:24])[F:23])[C:18]([F:21])([F:20])[F:19])[CH:14]=[C:13](F)[CH:12]=1.O>CN(C=O)C>[F:10][C:11]1[CH:16]=[C:15]([C:17]([OH:26])([C:18]([F:19])([F:20])[F:21])[C:22]([F:24])([F:25])[F:23])[CH:14]=[C:13]([S:5][CH2:4][CH2:3][Si:2]([CH3:7])([CH3:6])[CH3:1])[CH:12]=1
Reactant: C[Si](C)(C)CCS
Reactant: OC(c1cc(F)cc(F)c1)(C(F)(F)F)C(F)(F)F
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: C[Si](C)(C)CCSc1cc(F)cc(C(O)(C(F)(F)F)C(F)(F)F)c1
Temperature: 70 °C
Reaction time: 0.33 h
Yield: 55 %

Procedure:
2-Trimethylsilylethane thiol (2.9 g, 21.9 mmol) was added dropwise to a suspension of NaH (1.8 g, 43.8 mmol) in dry DMF (60 mL) and stirred for 20 min. Then 1,3-difluoro-5-(hexafluoro-2-hydroxyprop-2-yl)benzene (Step 1 ) was added in dry DMF and the resulting reaction mixture was heated at 70° C. for 16 h. The reaction mixture was then added carefully to H2O and extracted with EtOAc. The combined organic phases were washed with brine, dried and evaporated to give a residue which was chromatographed on silica gel, eluting with 95:5 mixture of hexane:EtOAc to afford the title compound (3.2 g, 55%).