Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[F:2][C:3]1[CH:4]=[CH:5][C:6]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][C:17]([C:20]3[CH:25]=[CH:24][C:23]([C:26]([F:29])([F:28])[F:27])=[CH:22][CH:21]=3)=[CH:16][CH:15]=2)=[C:7]([CH2:9][CH2:10][NH2:11])[CH:8]=1.FC1C=CC(OCC2C=CC(C3C=CC(C(F)(F)F)=CC=3)=CC=2)=C(CCN)C=1.Cl.C(N(CC)CC)C.Br[CH2:67][CH2:68][CH2:69][CH2:70][C:71]([O:73][CH2:74][CH3:75])=[O:72]>O1CCOCC1.O>[F:2][C:3]1[CH:4]=[CH:5][C:6]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][C:17]([C:20]3[CH:25]=[CH:24][C:23]([C:26]([F:27])([F:28])[F:29])=[CH:22][CH:21]=3)=[CH:16][CH:15]=2)=[C:7]([CH2:9][CH2:10][NH:11][CH2:67][CH2:68][CH2:69][CH2:70][C:71]([O:73][CH2:74][CH3:75])=[O:72])[CH:8]=1
Reactant: CCOC(=O)CCCCBr
Reactant: NCCc1cc(F)ccc1OCc1ccc(-c2ccc(C(F)(F)F)cc2)cc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Solvent: O
Product: CCOC(=O)CCCCNCCc1cc(F)ccc1OCc1ccc(-c2ccc(C(F)(F)F)cc2)cc1
Temperature: 62.5 °C
Reaction time: 12 h

Procedure:
13.8 g (30 mmol) of 2-(5-fluoro-2-{[4′-(trifluoromethyl)biphenyl-4-yl]methoxy}phenyl)ethylamine hydrochloride [obtainable by taking up the compound of Example 45A in a 1 M solution of hydrogen chloride in dioxane, reconcentrating the solution and drying the resulting residue] are introduced into 200 ml of DMF, mixed with 32.4 ml (0.23 mol) of triethylamine and heated to 60-65° C. At this temperature, 9.48 g (0.05 mol) of ethyl 5-bromovalerate are added dropwise, and the mixture is stirred for 12 hours. After cooling, the mixture is added to water, adjusted to pH 5 with 1 M hydrochloric acid and extracted with ethyl acetate. The organic phase is dried over sodium sulfate and the solvent is removed in vacuo. The resulting residue is purified by chromatography on silica gel (mobile phase: dichloromethane/methanol 10:1). 4.5 g (8.9 mmol, 18% of theory) of the title compound are obtained.
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]1[CH2:7][CH2:6][N:5]([CH2:8][CH2:9][N:10]2[C:19]3[C:14](=[CH:15][CH:16]=[C:17]([F:20])[CH:18]=3)[CH:13]=[CH:12][C:11]2=[O:21])[CH2:4]1.[O:22]=[C:23]1[CH2:28][O:27][C:26]2[CH:29]=[CH:30][C:31]([CH:33]=O)=[N:32][C:25]=2[NH:24]1.[O-]S([O-])(=O)=O.[Na+].[Na+].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>>[F:20][C:17]1[CH:18]=[C:19]2[C:14]([CH:13]=[CH:12][C:11](=[O:21])[N:10]2[CH2:9][CH2:8][N:5]2[CH2:6][CH2:7][C@@H:3]([CH2:2][NH:1][CH2:33][C:31]3[CH:30]=[CH:29][C:26]4[O:27][CH2:28][C:23](=[O:22])[NH:24][C:25]=4[N:32]=3)[CH2:4]2)=[CH:15][CH:16]=1
Reactant: O=Cc1ccc2c(n1)NC(=O)CO2
Reactant: NC[C@@H]1CCN(CCn2c(=O)ccc3ccc(F)cc32)C1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=S(=O)([O-])[O-]
Agent: [Na+]
Product: O=C1COc2ccc(CNC[C@@H]3CCN(CCn4c(=O)ccc5ccc(F)cc54)C3)nc2N1
Temperature: 25 °C
Reaction time: 18 h
Yield: 51 %

Procedure:
To a solution of 1-{2-[(3S)-3-(aminomethyl)-1-pyrrolidinyl]ethyl}-7-fluoro-2(1H)-quinolinone (87 mg, 0.30 mmol) and 3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazine-6-carboxaldehyde (for a synthesis see WO2003087098, Example 31(e)) (54 mg, 0.302 mmol) was added Na2SO4 (355 mg, 2.50 mmol) and the reaction was stirred at ambient temperature for 18 h. The intermediate imine was treated with sodium triacetoxyborohydride (160 mg, 0.75 mmol) and stirred for an additional 16 h). The solvents were removed under reduced pressure; the residue was partitioned between dichloromethane and aqueous sodium bicarbonate, and the organic layer was dried (Na2SO4). Purification by column chromatography on silica gel, (1% to 20% methanol:dichloromethane gradient) yielded the title compound as an amorphous off-white solid (69 mg, 51%).
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:14]=[CH:13][C:12]2[C:7](=[CH:8][CH:9]=[C:10]([O:17][CH3:18])[C:11]=2[CH:15]=O)[CH:6]=1)=[O:4].Cl.[NH2:20][CH2:21][C:22]1[CH:27]=[CH:26][C:25]([S:28]([NH2:31])(=[O:30])=[O:29])=[CH:24][CH:23]=1>>[NH2:31][S:28]([C:25]1[CH:24]=[CH:23][C:22]([CH2:21][NH:20][CH2:15][C:11]2[C:10]([O:17][CH3:18])=[CH:9][CH:8]=[C:7]3[C:12]=2[CH:13]=[CH:14][C:5]([C:3]([OH:2])=[O:4])=[CH:6]3)=[CH:27][CH:26]=1)(=[O:29])=[O:30]
Reactant: COC(=O)c1ccc2c(C=O)c(OC)ccc2c1
Reactant: NCc1ccc(S(N)(=O)=O)cc1
Agent: Cl
Product: COc1ccc2cc(C(=O)O)ccc2c1CNCc1ccc(S(N)(=O)=O)cc1

Procedure:
The title compound was prepared as a white solid (0.245 g, 34% for two steps) from 6-methoxy-5-formyl-2-naphthoic acid methyl ester using p-aminomethyl-benzenesulfonamide hydrochloride and a procedure similar to steps 3-4 of Example 1, mp 283-285° C. (decomp.); 1H NMR (DMSO-d6) δ3.94 (s, 3H), 4.37 (s, 2H), 4.53 (s, 2H), 7.46 (s, 2H), 7.60 (d, J=9.2 Hz, 1H), 7.77 (d, J=8.2 Hz, 2H), 7.90 (d, J=8.2 Hz, 2H), 8.01 (dd, J=1.4, 9.0 Hz, 1H), 8.16 (d, J=9.0 Hz, 1H), 8.28 (d, J=9.2 Hz, 1H), 8.61 (s, 1H), 9.25-9.46 (bs, 2H), 12.78-13.18 (bs, 1H); IR (neat) 2380-3300, 1670, 1625, 1600, 1485, 1470, 1455, 1430, 1420, 1325, 1310, 1285, 1265, 1220, 1185, 1165, 1105, and 1040 cm−1; mass spectrum [(+) ESI], m/z401 (M+H)+ and [(−) ESI], m/z 399 (M−H)−; Anal. Calcd. for C20H20N2O5S.HCl: C, 54.98; H, 4.84; N, 6.41, Found: C, 54.60; H, 4.93; N, 6.17.
Reaction SMILES: [C:1](=[O:4])(O)O.[F:5][C:6]1[C:11]([F:12])=[C:10]([F:13])[CH:9]=[CH:8][C:7]=1[NH:14][C:15]([NH2:17])=[NH:16].[C:18]1(C)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>O>[F:5][C:6]1[C:11]([F:12])=[C:10]([F:13])[CH:9]=[CH:8][C:7]=1[NH:14][C:15]1[N:17]=[C:1]([OH:4])[C:19]2[CH2:20][CH2:21][CH2:22][CH2:23][C:18]=2[N:16]=1
Reactant: O=C(O)O
Reactant: Cc1ccccc1
Reactant: N=C(N)Nc1ccc(F)c(F)c1F
Solvent: O
Product: Oc1nc(Nc2ccc(F)c(F)c2F)nc2c1CCCC2
Temperature: 25 °C
Yield: 54.6 %

Procedure:
1-(2,3,4-Trifluorophenyl)guanidine carbonate (18.9 g, 100 mmol), β-keto esters (IV-1) (20.4 g, 120 mmol) and 120 mL of toluene were added to 250 mL of flask in sequence, the mixture was heated to reflux with a Dean Stark trap until all the water was removed, and continue refluxing for half an hour. After most of solvent was removed, the reaction solution was cooled to room temperature, the solid was filtered, washed with 20% ethanol aqueous solution and dried to obtain 16.1 g of white solid (II-2) with yield of 54.6%.
Reaction SMILES: [CH:1]1[C:14]2[S:13][C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[S:6](=O)[C:5]=2[CH:4]=[CH:3][CH:2]=1.FC(F)(F)C(OC(=O)C(F)(F)F)=O.[F:29][C:30]([F:45])([F:44])[C:31]([F:43])([F:42])[C:32]([F:41])([F:40])[C:33]([F:39])([F:38])[S:34]([OH:37])(=[O:36])=[O:35].C(O[CH:50]([CH3:52])[CH3:51])(C)C>C1(C)C=CC=CC=1>[F:45][C:30]([F:29])([F:44])[C:31]([F:42])([F:43])[C:32]([F:40])([F:41])[C:33]([F:38])([F:39])[S:34]([O-:37])(=[O:36])=[O:35].[C:50]1([CH3:51])[CH:52]=[CH:33][C:32]([S+:6]2[C:7]3[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=3)[S:13][C:14]3[CH:1]=[CH:2][CH:3]=[CH:4][C:5]2=3)=[CH:31][CH:30]=1
Reactant: O=S(=O)(O)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Reactant: CC(C)OC(C)C
Reactant: O=S1c2ccccc2Sc2ccccc21
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: Cc1ccccc1
Product: Cc1ccc([S+]2c3ccccc3Sc3ccccc32)cc1
Product: O=S(=O)([O-])C(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Reaction time: 1 h

Procedure:
In 10 ml of toluene was dissolved 2 g of thianthrene-S-oxide and the solution was cooled with ice. Then, 2.8 ml of trifluoroacetic anhydride and 1.2 ml of nonafluorobutanesulfonic acid were added thereto, followed by stirring for one hour. Diisopropyl ether was added thereto and the supernatant solution was removed. The residue was purified by a silica gel column (chloroform/methanol=19/1) to obtain 4.4 g of 5-(p-tolyl)thianthrenium nonafluorobutanesulfonate. 1H-NMR (400 MHz, CDCl3): σ 2.34 (s, 3H), 7.08 (d, 2H), 7.22 (d, 2H), 7.78 (m, 6H), 8.65 (d, 2H).
Reaction SMILES: [Cl:1][CH2:2][C:3]([OH:5])=O.C(Cl)CCl.[Cl:10][C:11]1[C:20]([NH2:21])=[CH:19][CH:18]=[C:17]2[C:12]=1[CH:13]=[CH:14][N:15]=[CH:16]2>CN(C=O)C.CN(C1C=CN=CC=1)C>[Cl:1][CH2:2][C:3]([NH:21][C:20]1[C:11]([Cl:10])=[C:12]2[C:17](=[CH:18][CH:19]=1)[CH:16]=[N:15][CH:14]=[CH:13]2)=[O:5]
Reactant: O=C(O)CCl
Reactant: Nc1ccc2cnccc2c1Cl
Agent: CN(C)c1ccncc1
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: O=C(CCl)Nc1ccc2cnccc2c1Cl
Reaction time: 4 h

Procedure:
To chloroacetic acid in DMF is added EDC, DMAP and 5-chloro-6-aminoisoquinoline. This mixture is stirred for 4 hours. The reaction is washed with NaHCO3(sat), extracted with EtOAc, dried (Na2SO4), filtered and evaporated. Column chromatography (SiO2, 5% MeOH/CH2Cl2) gives 2-chloro-N-(5-chloro-isoquinolin-6-yl) acetamide.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[C:4]([N:17]2[CH2:22][CH2:21][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:19][CH2:18]2)[C:5]2[CH2:12][CH2:11][CH2:10][C:9]3[CH:13]=[CH:14][CH:15]=[CH:16][C:8]=3[C:6]=2[N:7]=1.N1C=CC=CC=1.[C:36](OC(=O)C)(=[O:38])[CH3:37]>C(Cl)(Cl)Cl>[C:36]([NH:1][C:2]1[N:3]=[C:4]([N:17]2[CH2:18][CH2:19][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:21][CH2:22]2)[C:5]2[CH2:12][CH2:11][CH2:10][C:9]3[CH:13]=[CH:14][CH:15]=[CH:16][C:8]=3[C:6]=2[N:7]=1)(=[O:38])[CH3:37]
Reactant: CC(=O)OC(C)=O
Reactant: CC(C)(C)OC(=O)N1CCN(c2nc(N)nc3c2CCCc2ccccc2-3)CC1
Solvent: c1ccncc1
Solvent: ClC(Cl)Cl
Product: CC(=O)Nc1nc2c(c(N3CCN(C(=O)OC(C)(C)C)CC3)n1)CCCc1ccccc1-2
Temperature: 60 °C

Procedure:
The product from Example 83A (20 mg, 0.051 mmol) was treated with CHCl3 (0.080 mL), pyridine (0.020 mL, 0.25 mmol), and acetic anhydride (0.006 mL, 0.061 mmol), then heated at 60° C. overnight, cooled and purified by chromatography (eluting with 9:1, 4:1 and 2:1 CH2Cl2:EtOAc) to provide the title compound. MS (M+H)+ m/z 438.
Reaction SMILES: CO[C:3](=[O:44])[C:4]1[C:5](=[CH:10][C:11]([NH:29][C:30]2[CH:35]=[CH:34][C:33]([O:36][CH2:37][C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=3)=[CH:32][CH:31]=2)=[C:12]([NH:14][C:15]2[CH:20]=[CH:19][C:18]([O:21][CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)=[CH:17][CH:16]=2)[CH:13]=1)[C:6](OC)=[O:7].[NH3:45]>C(O)CO>[CH2:22]([O:21][C:18]1[CH:17]=[CH:16][C:15]([NH:14][C:12]2[CH:13]=[C:4]3[C:3](=[O:44])[NH:45][C:6](=[O:7])[C:5]3=[CH:10][C:11]=2[NH:29][C:30]2[CH:31]=[CH:32][C:33]([O:36][CH2:37][C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=3)=[CH:34][CH:35]=2)=[CH:20][CH:19]=1)[C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1
Reactant: N
Reactant: COC(=O)c1cc(Nc2ccc(OCc3ccccc3)cc2)c(Nc2ccc(OCc3ccccc3)cc2)cc1C(=O)OC
Solvent: OCCO
Product: O=C1NC(=O)c2cc(Nc3ccc(OCc4ccccc4)cc3)c(Nc3ccc(OCc4ccccc4)cc3)cc21
Reaction time: 16 h

Procedure:
Analogously to Example 1, 294.4 mg (0.5 mmol) of 4,5-bis(4-benzyloxy-anilino)phthalic acid dimethyl ester in 22 ml of ethylene glycol are heated at 120°, ammonia gas being passed through the mixture, with stirring, for 16 hours. The reaction mixture is cooled and extracted with ethyl acetate. The ethyl acetate phases are washed in succession three times with water and once with saturated sodium chloride solution, dried with sodium sulfate and concentrated by evaporation. The evaporation residue is chromatographed on silica gel with dichloromethane/methanol 50:1 and the product fractions are combined and concentrated by evaporation, yielding the title compound in the form of red crystals, m.p.187°-189° C., FAB-MS: 542 [M+ +H].
Reaction SMILES: C[Al](C)C.C1(C)C=CC=CC=1.[Cl-].[NH4+:13].[F:14][C:15]1[CH:22]=[CH:21][C:18]([C:19]#[N:20])=[CH:17][CH:16]=1>C(Cl)(Cl)Cl>[F:14][C:15]1[CH:22]=[CH:21][C:18]([C:19](=[NH:13])[NH2:20])=[CH:17][CH:16]=1
Reactant: [NH4+]
Reactant: N#Cc1ccc(F)cc1
Agent: C[Al](C)C
Agent: [Cl-]
Solvent: Cc1ccccc1
Solvent: ClC(Cl)Cl
Product: N=C(N)c1ccc(F)cc1
Temperature: 85 °C
Reaction time: 1.5 h
Yield: 71 %

Procedure:
4.12 mL (8.24 mmol) of trimethyl aluminum (2.0 M toluene solution) was dropwise added to a 10 mL of toluene containing 441 mg (8.24 mmol) of ammonium chloride at room temperature. After stirring for 1.5 hours, 1 g (8.25 mmol) of 4-fluorobenzonitrile was added thereto and the resulting mixture was heated to 85° C. for 9 hours. After completion of a reaction, the reaction solution was cooled, then poured into 100 mL of chloroform containing 500 g of silica gel and filtered off. The residue was washed with 100 mL of methanol and distillation was conducted to give 821 mg (5.9 mmol) of the title compound in a yield of 71%.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([Mg]Br)[CH:6]=[CH:7][CH:8]=1.C[O:12][C:13](=[O:20])[C:14](=[O:19])[CH:15]=[C:16]([CH3:18])[CH3:17].C[Si](C)(C)Cl.Cl>O1CCCC1.C(OCC)(=O)C.CN1CCCN(C)C1=O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:16]([CH3:18])([CH3:17])[CH2:15][C:14](=[O:19])[C:13]([OH:20])=[O:12])[CH:6]=[CH:7][CH:8]=1
Reactant: COC(=O)C(=O)C=C(C)C
Reactant: COc1cccc([Mg]Br)c1
Agent: C[Si](C)(C)Cl
Agent: Cl
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CN1CCCN(C)C1=O
Product: COc1cccc(C(C)(C)CC(=O)C(=O)O)c1
Temperature: -40 °C
Reaction time: 0.33 h

Procedure:
4.2 ml of a 0.6 m solution of 3-methoxyphenylmagnesium bromide in tetrahydrofuran is mixed at −70° C. with 257 mg of copper bromide-dimethylsulfide complex and then stirred at −40° C. for 20 minutes. It is cooled again to −70° C., and 0.33 ml of 1,3-dimethyl-tetrahydro-2-1H-pyrimidinone and a mixture of 400 mg of 4-methyl-2-oxo-3-pentenoic acid methyl ester (Liebigs Annalen [Liebigs Annals] 1974, 477) and 0.71 ml of trimethylchlorosilane in 3.5 ml of tetrahydrofuran are slowly added. It is stirred for one hour at −70° C. and then heated to room temperature. Then, 2N hydrochloric acid and ethyl acetate are added, the ethyl acetate phase is separated, it is concentrated by evaporation, and the residue is dissolved in 5 ml of dichloromethane. After 200 mg of tetrabutylammonium fluoride is added, it is left at room temperature for one hour, then washed with water, and the dichloromethane phase is dried (Na2SO4) and concentrated by evaporation. After chroma-tography on silica gel with hexane/ethyl acetate (97:3), 63 mg of 4-(3-methoxyphenyl)-4-methyl-2-oxo-valeric acid-methyl ester, which is mixed with 1 ml of potassium hydroxide in methanol (10%), is obtained. After 45 minutes, it is concentrated by evaporation, the residue is dissolved in water and extracted with diethyl ether. The aqueous phase is then acidified with 6N hydrochloric acid and extracted with diethyl ether. The diethyl ether phase is dried (Na2SO4) and concen-trated by evaporation. 50 mg of 4-(3-methoxyphenyl)-4-methyl-2-oxo-valeric acid is obtained.
Reaction SMILES: [F:1][CH:2]([F:30])[O:3][CH:4]=[C:5]([C:20]1[CH:29]=[CH:28][C:27]2[CH2:26][CH2:25][CH2:24][CH2:23][C:22]=2[CH:21]=1)[C:6]([NH:8][CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[C:13]([OH:19])[CH:12]=1)=[O:7].CN(C)C=O.Cl[CH2:37][C:38]#[CH:39].[H-].[Na+]>O>[F:1][CH:2]([F:30])[O:3][CH:4]=[C:5]([C:20]1[CH:29]=[CH:28][C:27]2[CH2:26][CH2:25][CH2:24][CH2:23][C:22]=2[CH:21]=1)[C:6]([NH:8][CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[C:13]([O:19][CH2:39][C:38]#[CH:37])[CH:12]=1)=[O:7]
Reactant: C#CCCl
Reactant: COc1ccc(CCNC(=O)C(=COC(F)F)c2ccc3c(c2)CCCC3)cc1O
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: C#CCOc1cc(CCNC(=O)C(=COC(F)F)c2ccc3c(c2)CCCC3)ccc1OC
Temperature: 25 °C
Reaction time: 3 h
Yield: 35.6 %

Procedure:
417 mg (1.00 mmol) of 3-difluoromethoxy-N-[2-(3-hydroxy-4-methoxyphenyl)ethyl]-2-(5,6,7,8-tetrahydronaphthalen-2-yl)acrylamide, 5 ml of anhydrous N,N-dimethylformamide, 74 mg (1.00 mmol) of 3-chloropropyne and 50 mg (1.25 mmol) of 60% sodium hydride were mixed and stirred at room temperature for 3 hours. Water was added to to the reaction mixture, which was followed by extracted with ethyl acetate, washed with 5% hydrochrolic acid, saturated aqueous sodium bicarbonate solution and saturated brine subsequently, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to give 162 mg of 3-difluoromethoxy-N-[2-{4-methoxy-3-(2-propynyloxy)phenyl}ethyl]-2-(5,6,7,8-tetrahydronaphthalen-2-yl)acrylamide (the present compound 1299).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[CH:4][C:3]=1[CH3:11].S(Cl)(Cl)=O.[CH:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.[Cl-].[Cl-].[Cl-].[Al+3].Cl>CN(C=O)C>[Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[O:8])=[CH:4][C:3]=1[CH3:11]
Reactant: Cc1cc(C(=O)O)ccc1Br
Reactant: c1ccccc1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: O=S(Cl)Cl
Solvent: CN(C)C=O
Product: Cc1cc(C(=O)c2ccccc2)ccc1Br
Temperature: 25 °C
Reaction time: 1 h

Procedure:
In an oven dried flask was added 4-bromo-3-methylbenzoic acid (1.00 g, 4.65 mmol), thionyl chloride (0.77 mL, 0.010 mol) and a drop of DMF and the reaction was refluxed for 2 h. The excess thionyl chloride was then distilled off and the residual thionyl chloride was removed on the pump. Benzene (20 mL, 0.2 mol) and aluminum trichloride (0.676 g, 5.07 mmol) were added to the reaction mixture. The reaction mixture turned yellow in color on addition of AlCl3. The reaction mixture was stirred at room temp for 1 h. The crude reaction mixture was poured onto ice and conc HCl (15 mL). The organic layer was separated and the aqueous layer extracted with EtOAc. The combined organic phases were washed with 5% aq NaOH solution, water and dried (Na2SO4). The organic phase was concentrated in vacuo to give a residue which was purified by silica gel chromatography, eluting with 2% EtOAc in hexane.
Reaction SMILES: C([Si](C)(C)[O:6][CH:7]1[CH2:11][CH2:10][N:9]([S:12]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[NH:21][C:22]2[C:27]([Cl:28])=[CH:26][N:25]=[C:24](Cl)[N:23]=2)(=[O:14])=[O:13])[CH2:8]1)(C)(C)C.[NH2:32][C:33]1[CH:34]=[CH:35][C:36]2[CH2:42][CH2:41][CH2:40][C:39](=[O:43])[NH:38][C:37]=2[CH:44]=1>>[Cl:28][C:27]1[C:22]([NH:21][C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=2[S:12]([N:9]2[CH2:10][CH2:11][CH:7]([OH:6])[CH2:8]2)(=[O:13])=[O:14])=[N:23][C:24]([NH:32][C:33]2[CH:34]=[CH:35][C:36]3[CH2:42][CH2:41][CH2:40][C:39](=[O:43])[NH:38][C:37]=3[CH:44]=2)=[N:25][CH:26]=1
Reactant: CC(C)(C)[Si](C)(C)OC1CCN(S(=O)(=O)c2ccccc2Nc2nc(Cl)ncc2Cl)C1
Reactant: Nc1ccc2c(c1)NC(=O)CCC2
Product: O=C1CCCc2ccc(Nc3ncc(Cl)c(Nc4ccccc4S(=O)(=O)N4CCC(O)C4)n3)cc2N1

Procedure:
The title compound was prepared by combining {2-[3-(tert-butyl-dimethyl-silanyloxy)-pyrrolidine-1-sulfonyl]-phenyl}-(2,5-dichloro-pyrimidin-4-yl)-amine (Example N?, 100.4 mg, 0.199 mmol) and 8-amino-1,3,4,5-tetrahydro-benzo[b]azepin-2-one (38.4 mg, 0.218 mmol) in an analogous manner described in Example 1492 and was obtained as a white powder (57 mg, 54%) that had the following properties: m.p: 155-160° C.; LC/MS (m/e): 529 (M+H); 1H-NMR (DMSO-d6, 400 MHz): δ 9.56 (s, 1H), 9.44 (m, 2H), 8.65 (m, 1H), 8.29 (s, 1H), 7.85 (d, J=7.9, 1H), 7.66 (m, 1H), 7.40-7.20 (series of m, 3H), 7.10 (d, J=8.2, 1H), 4.99 (d, J=2.8, 1H), 4.18 (m, 1H), 3.26 (m, 3H), 3.05 (d, J=10.1, 1H), 2.63 (m, 2H), 2.16 (m, 2H), 2.08 (m, 2H), 1.82 (m, 1H), 1.67 (m, 1H).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH3:7][N:8]1[C:16]2[N:15]=[CH:14][N:13]([CH2:17][CH2:18][CH3:19])[C:12]=2[C:11](=[O:20])[NH:10][C:9]1=[O:21].Cl[CH2:23][CH2:24][CH2:25][CH2:26][C:27]([OH:37])([CH3:36])[C:28]#[C:29][CH2:30][N:31]([CH2:34][CH3:35])[CH2:32][CH3:33].O>CN(C)C=O>[CH2:34]([N:31]([CH2:32][CH3:33])[CH2:30][C:29]#[C:28][C:27]([OH:37])([CH3:36])[CH2:26][CH2:25][CH2:24][CH2:23][N:10]1[C:11](=[O:20])[C:12]2[N:13]([CH2:17][CH2:18][CH3:19])[CH:14]=[N:15][C:16]=2[N:8]([CH3:7])[C:9]1=[O:21])[CH3:35]
Reactant: CCCn1cnc2c1c(=O)[nH]c(=O)n2C
Reactant: CCN(CC)CC#CC(C)(O)CCCCCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCn1cnc2c1c(=O)n(CCCCC(C)(O)C#CCN(CC)CC)c(=O)n2C
Temperature: 60 °C
Reaction time: 1 h

Procedure:
2.12 g (15.3 mmol) of potassium carbonate were added to a solution of 2.0 g (9.6 mmol) of 3-methyl-7-propylxanthine in 60 ml of dimethylformamide at 60° C. and the mixture was stirred at 60° C. for one hour. Then 3.07 g (12.5 mmol) of 1-chloro-8-diethylamino-5-hydroxy-5-methyl-6-octyne from stage A1) were added dropwise and the mixture was stirred at 80° C. for 12.5 hours. It was then allowed to cool to room temperature, water was added, and three extractions with tert-butyl methyl ether were carried out. The organic phase was dried over magnesium sulfate, concentrated under reduced pressure and purified by flash chromatography, dichloromethane/methanol=19/1.
Reaction SMILES: C([Li])CCC.I[C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([I:13])[CH:8]=1.F[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=1.O>CCOCC>[I:13][C:9]1[CH:8]=[C:7]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=2)[CH:12]=[CH:11][CH:10]=1
Reactant: Ic1cccc(I)c1
Reactant: Fc1ccccn1
Agent: [Li]CCCC
Solvent: O
Solvent: CCOCC
Product: Ic1cccc(-c2ccccn2)c1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 23.1 %

Procedure:
n-Butyllithium (2.0 M in cyclohexane, 8 cm3) was added dropwise to a solution of 1,3-diiodobenzene (5.19 g, 16 mmol) in ether (50 cm3), cooled in a salt-ice bath, and the solution was stirred for 10 minutes. 2-Fluoropyridine (1.4 cm3, 16 mmol) was added, at which the pale yellow cloudy solution turned dark brown, and the reaction was allowed to warm to room temperature over 1 hour. Water (50 cm3) and ether (20 cm3) were added, and the layers were separated. The aqueous layer was extracted with ether (3×50 cm3). The combined organic extracts were washed with brine (150 cm3), and dried over magnesium sulfate. The solvent was removed to leave a brown oil. Purification of the crude product by column chromatography over silica using dichloromethane: light petroleum (1:1) as eluent gave (15) as an orange oil (1.04 g, 24%).
Reaction SMILES: Br[CH2:2][C:3]([O:5]C)=O.[C:7]([N:10]1[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]1)(=[O:9])[CH3:8].C(=O)([O-])[O-].[K+].[K+].[NH2:22][NH2:23]>C(O)C>[C:7]([N:10]1[CH2:15][CH2:14][N:13]([CH2:2][C:3]([NH:22][NH2:23])=[O:5])[CH2:12][CH2:11]1)(=[O:9])[CH3:8]
Reactant: NN
Reactant: CC(=O)N1CCNCC1
Reactant: COC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: CC(=O)N1CCN(CC(=O)NN)CC1
Temperature: 85 °C
Reaction time: 24 h
Yield: 80 %

Procedure:
The procedure described for Example 283 A was followed using methyl bromoacetate (1.5 g, 0.01 mol), 1-acetyl piperazine (1.4 g, 0.011 mol), and potassium carbonate (1.52 g, 0.011 mol). After one day, an additional 0.3 equivalent of methyl bromoacetate was added to the reaction. The crude material was taken up in approximately 2 mL of ethanol and hydrazine was added to the solution (0.25 mL, 0.008 mol). This was heated in a sealed tube at 85° C. for 4 hours. The solvent was removed to yield the title compound (1.6 g, 80% yield). 1H NMR (DMSO-d6) δ 9.0 (s, 1H), 4.2 (br s, 2H), 3.5 (m, 4H), 2.9 (s, 2H), 2.4 (m, 4H), 2.0 (s, 3H).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:7]2[C:8](=[O:25])[N:9]([CH2:16][C:17](=[O:24])[C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][C:15]=3[C:6]=2[N:5]([CH3:26])[C:4]=1[C:27]([NH:29][CH:30]1[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]1)=[O:28].C(=O)([O-])[O-].[K+].[K+].C(N(CC)CC)C.Br[C:50]1[CH:55]=[CH:54][N:53]=[C:52]([C:56]([F:59])([F:58])[F:57])[CH:51]=1>CN(C=O)C.O>[CH3:1][O:2][C:3]1[C:7]2[C:8](=[O:25])[N:9]([CH2:16][C:17](=[O:24])[C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][C:15]=3[C:6]=2[N:5]([CH3:26])[C:4]=1[C:27]([NH:29][CH:30]1[CH2:31][CH2:32][N:33]([C:50]2[CH:55]=[CH:54][N:53]=[C:52]([C:56]([F:59])([F:58])[F:57])[CH:51]=2)[CH2:34][CH2:35]1)=[O:28]
Reactant: FC(F)(F)c1cc(Br)ccn1
Reactant: COc1c(C(=O)NC2CCNCC2)n(C)c2c1c(=O)n(CC(=O)c1ccccc1)c1ccccc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COc1c(C(=O)NC2CCN(c3ccnc(C(F)(F)F)c3)CC2)n(C)c2c1c(=O)n(CC(=O)c1ccccc1)c1ccccc21
Temperature: 100 °C
Reaction time: 23 h
Yield: 34.6 %

Procedure:
A solution of the compound of Example 77 (300 mg, 0.59 mmol), potassium carbonate (204 mg, 1.5 mmol) and triethylamine (0.082 mL, 0.59 mmol) in DMF (3.0 mL) was heated to 80° C., 4-bromo-2-(trifluoromethyl)pyridine (133 mg, 0.59 mmol) was added, and the mixture was stirred at 100° C. for 23 hr. The reaction mixture was diluted with water, and extracted 3 times with ethyl acetate. The extract was dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by aminosilica gel chromatography (eluate; ethyl acetate/hexane=50/50-100/0) and recrystallized from ethyl acetate-hexane to give the title compound (126 mg, 35%) as a white solid.