Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[C:4]([Cl:9])[C:3]=1[N:10]1[N:15]=[C:14]([N:16]([CH:20]([CH:24]2[CH2:26][CH2:25]2)[CH:21]2[CH2:23][CH2:22]2)[CH2:17][CH2:18][CH3:19])[CH:13]=[C:12](Cl)[NH:11]1.[CH3:28][S-:29].[Na+].C(OCC)(=O)C.O>CN(C)C=O>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[C:4]([Cl:9])[C:3]=1[N:10]1[N:15]=[C:14]([N:16]([CH:20]([CH:24]2[CH2:26][CH2:25]2)[CH:21]2[CH2:23][CH2:22]2)[CH2:17][CH2:18][CH3:19])[CH:13]=[C:12]([S:29][CH3:28])[NH:11]1
Reactant: CCCN(C1=NN(c2c(Cl)cc(Cl)cc2Cl)NC(Cl)=C1)C(C1CC1)C1CC1
Reactant: C[S-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: CCCN(C1=NN(c2c(Cl)cc(Cl)cc2Cl)NC(SC)=C1)C(C1CC1)C1CC1
Temperature: 23 °C
Reaction time: 1 h
Yield: 79.7 %

Procedure:
A solution of 2-(2',4',6'-trichlorophenyl)-4-(N-dicyclopropylmethyl-N-propylamino)-6-chlorotriazine (130 mg, 0.3 mmole) in 2.5 mL of dimethylformamide was treated with sodium thiomethylate (0.04 mg, 0.57 mmole) with stirring at 23° C. for 1 hour, the mixture was then poured into ethyl acetate/water. The organic phase was washed with water, 0.1M aqueous hydrochloric acid and brine, dried over magnesium sulfate and concentrated. The residue was purified by preparative TLC (5% diethyl ether/hexane) to give 2-(2',4',6'-trichlorophenyl)-4-(N-dicyclopropylmethyl-N-propylamino)-6-methylthiotriazin (110 mg, 80% yield). 1H NMR (CDCl3): 0.2-0.7 (bm, 8H), 0.7-1.2 (bm, 5H), 1.7-1.8 (bm, 2H), 2.3-2.6 (m, 3H), 3.2-3.5 (bm, 3H), 4.8-5.1 (bm, 2H), 7.35 (5, 1H) and 7.38 (s, 1H). Mass (ion spray): 457 (M+H).
Reaction SMILES: [CH2:1]([N:3]1[CH:7]=[C:6]([C:8]([NH2:10])=O)[C:5]([CH3:11])=[N:4]1)[CH3:2].COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:21])=CC=1>C1(C)C=CC=CC=1>[CH2:1]([N:3]1[CH:7]=[C:6]([C:8](=[S:21])[NH2:10])[C:5]([CH3:11])=[N:4]1)[CH3:2]
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: CCn1cc(C(N)=O)c(C)n1
Solvent: Cc1ccccc1
Product: CCn1cc(C(N)=S)c(C)n1
Temperature: 25 °C
Yield: 23.9 %

Procedure:
To a suspension of 1-ethyl-3-methyl-1H-pyrazole-4-carboxamide (1.7 g, 11 mmol) produced above in toluene (80 mL) was added Lawesson's reagent (7.0 g, 17 mmol), and the mixture was heated under reflux for 1.5 hr. The reaction solution was cooled to room temperature and purified by basic silica gel column chromatography (ethyl acetate/hexane=0/100→20/80) to give the title compound (445 mg, 24%) as a yellow oil.
Reaction SMILES: O[C:2]1[CH:7]=[C:6](O)[C:5](O)=[CH:4][C:3]=1O.[NH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[NH2:18]>>[CH:7]1[C:6]2[NH:18][C:13]3[C:12](=[CH:17][C:16]4[NH:11][C:12]5[C:13]([NH:18][C:15]=4[CH:14]=3)=[CH:14][CH:15]=[CH:16][CH:17]=5)[NH:11][C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: Oc1cc(O)c(O)cc1O
Reactant: Nc1ccccc1N
Product: c1ccc2[nH]c3cc4[nH]c5ccccc5[nH]c4cc3[nH]c2c1

Procedure:
In some particular embodiments, one molar unit of the 1,2,4,5-tetrahydroxybenzene compound is reacted with about one molar unit of a first 1,2-diaminobenzene compound to form an intermediate, and the intermediate is subsequently reacted with about one molar unit of a second 1,2-diaminobenzene compound to form the 5,7,12,14-tetrahydro-5,7,12,14-tetraazapentacene compound. The first 1,2-diaminobenzene compound and the second 1,2-diaminobenzene compound are different.
Reaction SMILES: [CH3:1][O:2][N:3]=[CH:4][C:5]1[CH:10]=[CH:9][C:8]([F:11])=[CH:7][C:6]=1[S:12][CH3:13].FC(F)(F)C(O)=O.C([SiH](CC)CC)C.[ClH:28].CCOCC>C(Cl)Cl.CCOCC>[ClH:28].[F:11][C:8]1[CH:9]=[CH:10][C:5]([CH2:4][NH:3][O:2][CH3:1])=[C:6]([S:12][CH3:13])[CH:7]=1
Reactant: CON=Cc1ccc(F)cc1SC
Agent: CC[SiH](CC)CC
Agent: Cl
Solvent: CCOCC
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CONCc1ccc(F)cc1SC
Reaction time: 6 h
Yield: 93 %

Procedure:
To a stirred solution of 4-fluoro-2-methylsulfanyl-benzaldehyde-O-methyl-oxime (5.982 g, 29.58 mmol) in CH2Cl2 (30 mL) was added trifluoroacetic acid (30 mL) followed by triethylsilane (14 mL, 90 mmol). After stirring for 6 h, the reaction mixture was concentrated and the resulting residue was taken up in saturated aqueous NaHCO3 (100 mL) and extracted with ethyl acetate (3×75 mL). The combined organic extracts were dried over anhydrous Na2SO4, filtered, and concentrated to give a viscous oil. The crude product was re-dissolved in anhydrous ether and 2M HCl/ether w (18 mL) was added. The resulting white solid was filtered and dried to yield the desired product as the HCl salt (6.666 g, 93% yield). 1HNMR (500 MHz, DMSO-d6) δ: 11.44 (1H, br s), 7.66–7.59 (1H, m), 7.24 (1H, dd, J=10.1, 2.1 Hz), 7.08 (1H, td, J=8.6, 2.4 Hz), 4.85 (2H, s), 3.82 (3H, s), 2.53 (3H, s). MS calcd for C9H13FNOS (M+H): 202.07. found: 202.07.
Reaction SMILES: C([Li])CCC.Br[C:7]1[CH:12]=[CH:11][C:10]([C:13]([O:17][CH3:18])([O:15][CH3:16])[CH3:14])=[CH:9][CH:8]=1.[CH3:19][C:20]1([CH3:26])[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1.[O:27]1CCCC1>C1CCCCC1>[CH3:16][O:15][C:13]([C:10]1[CH:11]=[CH:12][C:7]([C:23]2([OH:27])[CH2:24][CH2:25][C:20]([CH3:26])([CH3:19])[CH2:21][CH2:22]2)=[CH:8][CH:9]=1)([O:17][CH3:18])[CH3:14]
Reactant: CC1(C)CCCCC1
Reactant: COC(C)(OC)c1ccc(Br)cc1
Reactant: C1CCOC1
Agent: [Li]CCCC
Solvent: C1CCCCC1
Product: COC(C)(OC)c1ccc(C2(O)CCC(C)(C)CC2)cc1
Temperature: -78 °C
Reaction time: 2 h

Procedure:
328 ml of a 1.6 M solution of butyllithium in cyclohexane are added at −78° C. to 117 g of 1-bromo-4-(1,1-dimethoxyethyl)benzene in 1100 ml of tetrahydrofuran and the reaction mixture is stirred at −78° C. for 2 hours. 66 g of 4,4-dimethylcyclohexane dissolved in 210 ml of tetrahydrofuran are added at this same temperature and the reaction mixture is stirred for 1 hour at −78° C. The reaction mixture is hydrolysed by addition of crushed ice. The organic phase is separated out after settling of the phases has taken place, it is dried over sodium sulphate and the solvents are evaporated off under reduced pressure. The compound obtained is recrystallized from 500 ml of n-hexane; m.p.=88° C.
Reaction SMILES: [Cl:1][C:2]1[C:7]2[C:8]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[F:21])=[N:9][CH2:10][C:11](=[O:14])[N:12]([CH3:13])[C:6]=2[CH:5]=[C:4]([Cl:22])[C:3]=1[N:23]=[C:24]=[O:25].ClC1[C:32]2C(C3C=CC=CC=3F)=[N:34][CH2:35][C:36](=O)[N:37]([CH3:38])[C:31]=2C=C(Cl)C=1NC(=O)N(C)C.NC1C(Cl)=CC2N(C)[C:63](=[O:66])CN=C(C3C=CC=CC=3F)C=2C=1Cl.C(=O)([O-])[O-].[Na+].[Na+]>NCCN1CCOCC1.ClC(Cl)C.ClCCCl>[Cl:1][C:2]1[C:7]2[C:8]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[F:21])=[N:9][CH2:10][C:11](=[O:14])[N:12]([CH3:13])[C:6]=2[CH:5]=[C:4]([Cl:22])[C:3]=1[NH:23][C:24]([NH:34][CH2:35][CH2:36][N:37]1[CH2:31][CH2:32][O:66][CH2:63][CH2:38]1)=[O:25]
Reactant: CN(C)C(=O)Nc1c(Cl)cc2c(c1Cl)C(c1ccccc1F)=NCC(=O)N2C
Reactant: CN1C(=O)CN=C(c2ccccc2F)c2c1cc(Cl)c(N=C=O)c2Cl
Reactant: CN1C(=O)CN=C(c2ccccc2F)c2c1cc(Cl)c(N)c2Cl
Agent: NCCN1CCOCC1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCCl
Solvent: CC(Cl)Cl
Product: CN1C(=O)CN=C(c2ccccc2F)c2c1cc(Cl)c(NC(=O)NCCN1CCOCC1)c2Cl
Reaction time: 114 h

Procedure:
A 1,2-dichloroethane solution of [6,8-dichloro-5-(o-fluorophenyl)-2,3-dihydro-1-methyl-2-oxo-1H-1,4-benzodiazepin-7-yl]isocyanate, prepared in analogy to the procedure described in paragraph (a) of Example 4 from 5.5 g (15.62 mmol) of 7-amino-6,8-dichloro-5-(o-fluorophenyl)-1,3-dihydro-1-methyl-2H-1,4-benzodiazepin-2-one, is treated at room temperature all at once with a suspension of 6.11 g of sodium carbonate in 6.1 ml of N-(2-aminoethyl)morpholine and 40 ml of dichloroethane and the mixture is stirred for 114 hours. The mixture is extracted with methylene chloride/ethanol (4:1), the organic phase is washed with water, dried and evaporated. The residue is chromatographed on 250 g of silica gel using chloroform for the elution, there being obtained 1-[6,8-dichloro-5-(o-fluorophenyl)-2,3-dihydro-1-methyl-2-oxo-1H-1,4-benzodiazepin-7-yl]-3-(2-morpholinoethyl)urea. After recrystallisation from ether, the product melts at 174°-176° C.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:8]=[CH:9][C:10]([N+:27]([O-])=O)=[C:11]([CH2:13][S:14]([C:17]2[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[CH:20]=[CH:19][CH:18]=2)(=[O:16])=[O:15])[CH:12]=1.C(O)=O>C1COCC1.CO.[Pd]>[Cl:1][CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:8]=[CH:9][C:10]([NH2:27])=[C:11]([CH2:13][S:14]([C:17]2[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[CH:20]=[CH:19][CH:18]=2)(=[O:16])=[O:15])[CH:12]=1
Reactant: O=[N+]([O-])c1ccc(OCCCCCl)cc1CS(=O)(=O)c1cccc2ccccc12
Agent: [Pd]
Solvent: O=CO
Solvent: C1CCOC1
Solvent: CO
Product: Nc1ccc(OCCCCCl)cc1CS(=O)(=O)c1cccc2ccccc12
Reaction time: 20 h
Yield: 84.4 %

Procedure:
A mixture of 1-[5-(4-chloro-butoxy)-2-nitro-phenyl-methanesulfonyl]-naphthalene (1.94 g, 4.5 mmoles) and 10% Pd/C in THF (20 mL), methanol (20 mL), and formic acid (5 mL) was hydrogenated in a Parr hydrogenation bottle (250 mL) at 40 lb/in2 for 20 hours. The mixture was filtered through Celite, and the filtrate was diluted with EtOAc, washed with water, dried over Na2SO4, and concentrated under vacuum. The crude product was purified by flash chromatography using as eluent 5% EtOAc/CH2Cl2 to afford the title compound as an off-white solid (1.54 g, 3.8 mmoles).
Reaction SMILES: [CH3:1][NH2:2].[Cl:3][CH2:4][C:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:8]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[CH:7][N:6]=1>CO>[ClH:3].[CH3:1][NH:2][CH2:4][C:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:8]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[CH:7][N:6]=1
Reactant: ClCc1ncc(-c2ccccc2)c2ccccc12
Reactant: CN
Solvent: CO
Product: CNCc1ncc(-c2ccccc2)c2ccccc12
Product: Cl
Temperature: 25 °C
Reaction time: 72 h

Procedure:
To a stirred solution of monomethylamine (200 ml) and methanol (1 liter) maintained under nitrogen and cooled in an ice bath was added a solution of 1-chloromethyl-4-phenylisoquinoline (24.3 g, 0.093 m) in methanol (100 ml) and the mixture allowed to warm to ambient temperature and stirred for 3 days. The solvents were evaporated and the dark oily residue dissolved in methanol (50 ml) and isopropanol and acidified with HCl gas. Upon cooling and standing, a white solid crystallized which was collected by filtration and dried to give 16.3 g 1-methylaminomethyl-4-phenylisoquinoline hydrochloride, m.p. 212°-213°. An analytical sample, recrystallized from methanol/ethanol, had m.p. 215°-216°.
Reaction SMILES: C([O:8][C:9]1[CH:25]=[C:12]2[C:13](=[O:24])[N:14]([C:17]3[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=3)[CH2:15][CH2:16][N:11]2[N:10]=1)C1C=CC=CC=1>CCOC(C)=O.CN(C=O)C.[OH-].[OH-].[Pd+2]>[F:23][C:20]1[CH:19]=[CH:18][C:17]([N:14]2[CH2:15][CH2:16][N:11]3[N:10]=[C:9]([OH:8])[CH:25]=[C:12]3[C:13]2=[O:24])=[CH:22][CH:21]=1
Reactant: O=C1c2cc(OCc3ccccc3)nn2CCN1c1ccc(F)cc1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: O=C1c2cc(O)nn2CCN1c1ccc(F)cc1
Yield: 88.2 %

Procedure:
A solution of 2-(benzyloxy)-5-(4-fluorophenyl)-6,7-dihydropyrazolo[1,5-a]pyrazin-4(5H)-one (0.79 g, 2.34 mmol) in a mixture of AcOEt (30 mL) and DMF (30 mL) was hydrogenated in a H-Cube reactor (1.5 ml/min, 70 mm Pd(OH)2/C cartridge, full H2 mode, 80° C., 1 cycle). The solvents were evaporated in vacuo to yield 5-(4-fluorophenyl)-2-hydroxy-6,7-dihydropyrazolo[1,5-a]pyrazin-4(5H)-one (0.51 g, 88% yield) as a white solid, that was used in the next step without further purification.
Reaction SMILES: C1(NC2C(C)=NC3C(N=2)=C(C2NC4[C@H]([C@H](O)C)NC(=O)C=4C=2)C(F)=CC=3)CC1.Br[CH2:30][C:31]([C:33]1[C:42]([F:43])=[CH:41][CH:40]=[C:39]2[C:34]=1[N:35]=[C:36]([NH:45][CH:46]1[CH2:48][CH2:47]1)[C:37]([CH3:44])=[N:38]2)=[O:32].[C:49]([O:53][C:54]([NH:56][C@H:57]([C@@H:66]([O:68][Si:69]([C:72]([CH3:75])([CH3:74])[CH3:73])([CH3:71])[CH3:70])[CH3:67])[C:58](=[O:65])[CH2:59][C:60]([O:62][CH2:63][CH3:64])=[O:61])=[O:55])([CH3:52])([CH3:51])[CH3:50].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.CCO.CC(O)=O>[C:49]([O:53][C:54]([NH:56][C@H:57]([C@@H:66]([O:68][Si:69]([C:72]([CH3:74])([CH3:73])[CH3:75])([CH3:70])[CH3:71])[CH3:67])[C:58](=[O:65])[CH:59]([CH2:30][C:31]([C:33]1[C:42]([F:43])=[CH:41][CH:40]=[C:39]2[C:34]=1[N:35]=[C:36]([NH:45][CH:46]1[CH2:48][CH2:47]1)[C:37]([CH3:44])=[N:38]2)=[O:32])[C:60]([O:62][CH2:63][CH3:64])=[O:61])=[O:55])([CH3:52])([CH3:50])[CH3:51]
Reactant: Cc1nc2ccc(F)c(C(=O)CBr)c2nc1NC1CC1
Reactant: CCOC(=O)CC(=O)[C@H](NC(=O)OC(C)(C)C)[C@H](C)O[Si](C)(C)C(C)(C)C
Agent: Cc1nc2ccc(F)c(-c3cc4c([nH]3)[C@H]([C@@H](C)O)NC4=O)c2nc1NC1CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)O
Solvent: CN(C)C=O
Solvent: CCO
Product: CCOC(=O)C(CC(=O)c1c(F)ccc2nc(C)c(NC3CC3)nc12)C(=O)[C@H](NC(=O)OC(C)(C)C)[C@H](C)O[Si](C)(C)C(C)(C)C
Yield: 96 %

Procedure:
This compound (2.43 g, 73% yield) as a bright yellow crystalline solid was prepared according to the procedures described for Intermediate 352b, using 2-bromo-1-(3-(cyclopropylamino)-6-fluoro-2-methylquinoxalin-5-yl)ethanone (613) (1.82 g, 5.39 mmol) and (4R,5S)-ethyl 4-((tert-butoxycarbonyl)amino)-5-((tert-butyldimethylsilyl)oxy)-3-oxohexanoate (615) (2.61 g, 6.47 mmol) and K2CO3 (0.931 g, 6.73 mmol) in DMF (10 mL) as the strafing materials, followed by subsequent treatment of the resulting (4R,5S)-ethyl 4-((tert-butoxycarbonyl)amino)-5-((tert-butyldimethylsilyl)oxy)-2-(2-(3-(cyclopropylamino)-6-fluoro-2-methylquinoxalin-5-yl)-2-oxoethyl)-3-oxohexanoate (353a) (3.42 g, 96% yield, LC-MS m/z 661.1, [M+H]+) with NH4OAc (5.98 g, 78 mmol) in 10 mL of EtOH and 5 mL of AcOH. 19F NMR (DMSO-d6; 376 MHz): δ −110.91 (s, 1F). LC-MS m/z 642.2, [M+H]+.
Reaction SMILES: [CH2:1]([NH:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)[CH3:2].[F:10][C:11]([F:23])([F:22])[C:12]1[CH:16]=[C:15]([O:17][CH2:18][C:19](O)=[O:20])[O:14][N:13]=1.C1(N=C=NC2CCCCC2)CCCCC1.C(O)(=O)C>C1COCC1>[CH2:1]([N:3]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)[C:19](=[O:20])[CH2:18][O:17][C:15]1[O:14][N:13]=[C:12]([C:11]([F:23])([F:10])[F:22])[CH:16]=1)[CH3:2]
Reactant: O=C(O)COc1cc(C(F)(F)F)no1
Reactant: CCNc1ccccc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: CCN(C(=O)COc1cc(C(F)(F)F)no1)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 85.7 %

Procedure:
1.30 ml (2.37 mmole) of N-ethylaniline and 0.50 g (2.37 mmole) of 2-(3-trifluoromethyl-5-isoxazolyloxy)acetic acid were dissolved in 2.4 ml of dry THF and to the solution was added 0.60 g (2.61 mmole) of dicyclohexylcarbodiimide. After being stirred at room temperature for one hour, the reaction mixture was allowed to stand overnight at room temperature. After the addition of glacial acetic acid (0.2 ml), the mixture was stirred at room temperature for 30 minutes and the precipitated crystals were filtered off. The filtrate was evaporated under reduced pressure and the residue was purified by chromatography on silica gel to give 638 mg of the titled compound as a pale red viscous liquid, yield 85.7%.
Reaction SMILES: Cl.[NH2:2][C:3]1[C:4]2[CH:16]=[C:15]([CH3:17])[S:14][C:5]=2[NH:6][C:7]2[CH:13]=[CH:12][CH:11]=[CH:10][C:8]=2[N:9]=1.CS(C)=O.C1(C)C=CC=CC=1.[NH:29]1[CH2:34][CH2:33]N[CH2:31][CH2:30]1>O>[CH3:17][C:15]1[S:14][C:5]2[NH:6][C:7]3[CH:13]=[CH:12][CH:11]=[CH:10][C:8]=3[N:9]=[C:3]([N:2]3[CH2:33][CH2:34][NH:29][CH2:30][CH2:31]3)[C:4]=2[CH:16]=1
Reactant: Cc1cc2c(s1)Nc1ccccc1N=C2N
Reactant: C1CNCCN1
Agent: Cl
Solvent: Cc1ccccc1
Solvent: O
Solvent: CS(C)=O
Product: Cc1cc2c(s1)Nc1ccccc1N=C2N1CCNCC1
Temperature: 125 °C
Reaction time: 0.5 h
Yield: 69 %

Procedure:
Starting material C (prepared according to the above, 140 mg, 0.53 mmol) was added to a mixture of dry dimethyl sulfoxide (1 ml), dry toluene (1 ml), and piperazine (140 mg, 1.6 mmol). The stirred solution was then heated at 125° C. under nitrogen for 5 h and cooled to room temperature. Then distilled water (2 ml) was added, while the temperature is kept below 25° C. After stirring at 5° C. for 30 minute, the suspension was cooled overnight and the solid D was filtered, washed with chilled water, and dried at 70° C. under reduced pressure; yield 69%.
Reaction SMILES: C(=O)([O-])[O-].[Na+].[Na+].[O:7]([C:14]1[CH:19]=[CH:18][C:17](B(O)O)=[CH:16][CH:15]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.Br[C:24]1[C:25]([NH2:31])=[N:26][CH:27]=[C:28]([F:30])[CH:29]=1>COCCOC.O.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>[F:30][C:28]1[CH:29]=[C:24]([C:17]2[CH:18]=[CH:19][C:14]([O:7][C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=3)=[CH:15][CH:16]=2)[C:25]([NH2:31])=[N:26][CH:27]=1
Reactant: OB(O)c1ccc(Oc2ccccc2)cc1
Reactant: Nc1ncc(F)cc1Br
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: O
Solvent: COCCOC
Product: Nc1ncc(F)cc1-c1ccc(Oc2ccccc2)cc1
Temperature: 80 °C
Reaction time: 8 h
Yield: 81.8 %

Procedure:
A mixture of sodium carbonate (122 mg), tetrakis(triphenylphosphine)palladium(0) (33.2 mg), 4-phenoxyphenylboronic acid (160 mg) and 3-bromo-5-fluoropyridin-2-amine (110 mg) in DME (10 mL) and water (3 mL) was stirred at 80° C. overnight. The mixture was added with silica gel, concentrated in vacuo, and purified by column chromatography (silica gel, eluted with EtOAc in hexane) to give the title compound (132 mg) as a pale yellow solid.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[N:5][C:6](Cl)=[CH:7][CH:8]=2)[N:3]=1.[CH3:13][N:14]([CH3:19])[CH2:15][CH2:16][CH2:17][SH:18].[OH-].[K+].CS(C)=O>C(OCC)C.O>[NH2:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[N:5][C:6]([S:18][CH2:17][CH2:16][CH2:15][N:14]([CH3:19])[CH3:13])=[CH:7][CH:8]=2)[N:3]=1
Reactant: CN(C)CCCS
Reactant: Nc1ccc2ccc(Cl)nc2n1
Agent: [K+]
Agent: [OH-]
Solvent: CCOCC
Solvent: CS(C)=O
Solvent: O
Product: CN(C)CCCSc1ccc2ccc(N)nc2n1
Temperature: 90 °C
Yield: 77 %

Procedure:
A mixture composed of 2-amino-7-chloro-1,8-naphthyridine (8 g), 3-dimethylaminopropanethiol (11.4 g), potassium hydroxide pellets (85% pure; 6.26 g) and dimethyl sulphoxide (87 cc) is heated to 90° C. for 3 hours 30 minutes. The reaction mixture is then poured into water (1500 cc) and extracted with methylene chloride (5×400 cc). The organic extracts are combined and washed with distilled water (400 cc), dried over magnesium sulphate and concentrated to dryness at 40° C. under reduced pressure (4 kPa). The residue obtained is treated with ethyl ether (100 cc). The insoluble product is separated by filtration, washed with ethyl ether (10 cc) and dried at 40° C. under reduced pressure (0.07 kPa). 2-Amino-7-(3-dimethylaminopropylthio)-1,8-naphthyridine (9 g), m.p. 164° C., is obtained.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:12]=[C:11]2[C:6]([C:7]([C:25]3[CH:30]=[CH:29][C:28]([CH3:31])=[C:27]([CH3:32])[CH:26]=3)=[C:8]([CH:15]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])[C:16]([O:18][CH3:19])=[O:17])[N:9]([CH3:14])[C:10]2=[O:13])=[CH:5][CH:4]=1.CCN(CC)CC.[CH3:40][N:41]([CH3:46])[S:42](Cl)(=[O:44])=[O:43]>ClCCl>[C:21]([O:20][CH:15]([C:8]1[N:9]([CH3:14])[C:10](=[O:13])[C:11]2[C:6]([C:7]=1[C:25]1[CH:30]=[CH:29][C:28]([CH3:31])=[C:27]([CH3:32])[CH:26]=1)=[CH:5][CH:4]=[C:3]([CH2:2][NH:1][S:42](=[O:44])(=[O:43])[N:41]([CH3:46])[CH3:40])[CH:12]=2)[C:16]([O:18][CH3:19])=[O:17])([CH3:22])([CH3:23])[CH3:24]
Reactant: CN(C)S(=O)(=O)Cl
Reactant: COC(=O)C(OC(C)(C)C)c1c(-c2ccc(C)c(C)c2)c2ccc(CN)cc2c(=O)n1C
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)C(OC(C)(C)C)c1c(-c2ccc(C)c(C)c2)c2ccc(CNS(=O)(=O)N(C)C)cc2c(=O)n1C
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 73.7 %

Procedure:
An ice cold solution of methyl 2-(7-(aminomethyl)-4-(3,4-dimethylphenyl)-2-methyl-1-oxo-1,2-dihydroisoquinolin-3-yl)-2-(tert-butoxy)acetate (25 mg, 0.057 mmol) in dichloromethane (DCM) (1 mL) was treated with Et3N (0.012 mL, 0.086 mmol) and dimethylsulfamoyl chloride (7.33 μL, 0.069 mmol), stirred for 15 min, and then warmed to rt for 1 hour. Additional Et3N (25 uL) and dimethylsulfamoyl chloride (15 uL) were added, the reaction was stirred at rt overnight. The reaction was concentrated and purified by column chromatography (0-10% MeOH/DCM) to afford methyl 2-(tert-butoxy)-2-(4-(3,4-dimethylphenyl)-7-(((N,N-dimethylsulfamoyl)amino)methyl)-2-methyl-1-oxo-1,2-dihydroisoquinolin-3-yl)acetate (22.6 mg, 0.042 mmol, 72.6% yield) as clear oil. The methyl ester was hydrolyzed in a manner similar to that described in Example 165 Step C and purified by reverse phase HPLC to afford 2-(tert-butoxy)-2-(4-(3,4-dimethylphenyl)-7-(((N,N-dimethylsulfamoyl)amino)methyl)-2-methyl-1-oxo-1,2-dihydroisoquinolin-3-yl)acetic acid (18.4 mg, 0.034 mmol, 82% yield) as white solid: 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 8.42 (s, 1 H), 7.54 (td, J=1.9, 8.2 Hz, 1 H), 7.41-7.30 (m, 1 H), 7.30-7.23 (m, 1 H), 7.16 (dd, J=8.4, 12.9 Hz, 1 H), 7.09-6.99 (m, 1 H), 5.35 (s, 1 H), 4.53 (br. s., 1 H), 4.36 (br. s., 2 H), 3.69 (d, J=1.0 Hz, 3 H), 2.81 (s, 3 H), 2.80 (s, 3 H), 2.36 (s, 3 H), 2.32 (s, 3 H), 1.07 (s, 4.5 H), 1.06 (s, 4.5 H); LCMS (m/z) ES+=530 (M+1).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][O:7][C:8]2=[C:11]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[NH:13][C:12]2=[O:20])=[CH:4][CH:3]=1.C(N(CC)C(C)C)(C)C.[CH:30]1([C:33](Cl)=[O:34])[CH2:32][CH2:31]1>C1COCC1>[O:20]=[C:12]1[C:11](=[C:8]2[C:9]3[C:5](=[CH:4][CH:3]=[C:2]([NH:1][C:33]([CH:30]4[CH2:32][CH2:31]4)=[O:34])[CH:10]=3)[CH2:6][O:7]2)[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[NH:13]1
Reactant: Nc1ccc2c(c1)C(=C1C(=O)Nc3ccccc31)OC2
Reactant: O=C(Cl)C1CC1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: O=C1Nc2ccccc2C1=C1OCc2ccc(NC(=O)C3CC3)cc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 71.2 %

Procedure:
To a solution of 3-(6-Amino-3H-isobenzofuran-1-ylidene)-1,3-dihydro-indol-2-one (50.0 mg, 0.189 mmol) and N,N-diisopropylethylamine (98.8 μL, 0.567 mmol) in 2.0 mL THF was added cyclopropane carbonyl chloride (17.2 μL, 0.189 mmol). After stirring at room temperature for 1 h, the slurry was warmed briefly, stirred 10 min at room temperature, filtered and rinsed with MeOH and EtOAc/hexanes (1:1) to afford the title compound (44.7 mg, 71%) as a yellow solid.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[C:10]([CH3:11])=[CH:9][C:8]([CH3:12])=[CH:7][C:6]=1[CH3:13])=O.[NH2:14][C:15]([NH2:17])=[S:16]>C(O)C>[C:6]1([CH3:13])[CH:7]=[C:8]([CH3:12])[CH:9]=[C:10]([CH3:11])[C:5]=1[C:3]1[N:14]=[C:15]([NH2:17])[S:16][CH:2]=1
Reactant: Cc1cc(C)c(C(=O)CBr)c(C)c1
Reactant: NC(N)=S
Solvent: CCO
Product: Cc1cc(C)c(-c2csc(N)n2)c(C)c1
Yield: 107 %

Procedure:
2-Bromo-1-mesitylethanone (2.43 g, 10.1 mmol) and thiourea (0.810 g, 10.6 mmol) were dissolved in 95% ethanol (20 mL). The reaction mixture was heated at reflux for 2.0 h. The solution was concentrated under reduced pressure, and the residue was recrystallized from 2-propanol to give the desired 4-mesitylthiazol-2-amine (2.36 g) as white solids: 1H NMR (500 MHz, CD3OD) δ 7.00 (2 H, s), 6.67 (1 H, s), 2.31 (3 H, s), 2.19 (6 H, s).
Reaction SMILES: C(O)(=O)C.[F:5][C:6]([F:26])([F:25])[O:7][C:8]1[CH:13]=[CH:12][C:11]([N:14]2[CH2:18][CH2:17][C:16]3([CH2:23][CH2:22][NH:21][CH2:20][CH2:19]3)[C:15]2=[O:24])=[CH:10][CH:9]=1.[CH3:27][C:28]1[O:32][N:31]=[C:30]([CH2:33][S:34](Cl)(=[O:36])=[O:35])[CH:29]=1>>[CH3:27][C:28]1[O:32][N:31]=[C:30]([CH2:33][S:34]([N:21]2[CH2:20][CH2:19][C:16]3([C:15](=[O:24])[N:14]([C:11]4[CH:12]=[CH:13][C:8]([O:7][C:6]([F:5])([F:25])[F:26])=[CH:9][CH:10]=4)[CH2:18][CH2:17]3)[CH2:23][CH2:22]2)(=[O:36])=[O:35])[CH:29]=1
Reactant: O=C1N(c2ccc(OC(F)(F)F)cc2)CCC12CCNCC2
Reactant: Cc1cc(CS(=O)(=O)Cl)no1
Solvent: CC(=O)O
Product: Cc1cc(CS(=O)(=O)N2CCC3(CCN(c4ccc(OC(F)(F)F)cc4)C3=O)CC2)no1

Procedure:
The title compound was prepared in analogy to example 180 step D from 2-(4-trifluoromethoxy-phenyl)-2,8-diaza-spiro[4.5]decan-1-one acetic acid salt (described in example 180 step C) and (5-Methyl-isoxazol-3-yl)-methanesulfonyl chloride. Light yellow solid. MS (ESI): 474.13 (MH+)