Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: N#N.[CH3:3][C:4]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:7](=[O:14])[NH:6][CH:5]=1.[O-:15]S(OOS([O-])(=O)=O)(=O)=O.[Na+].[Na+].O>CS(C)=O>[O:14]=[C:7]1[C:8]2[C:13](=[CH:12][CH:11]=[CH:10][CH:9]=2)[C:4]([CH:3]=[O:15])=[CH:5][NH:6]1
Reactant: Cc1c[nH]c(=O)c2ccccc12
Reactant: O=S(=O)([O-])OOS(=O)(=O)[O-]
Agent: N#N
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: O=Cc1c[nH]c(=O)c2ccccc12
Temperature: 50 °C
Reaction time: 2 h

Procedure:
In an apparatus equipped with a mechanical stirrer (N2 gas), 135 g (848 mmol) of 4-methyl-2H-isoquinolin-1-one in 2.0 l of DMSO are heated to 50° C. After removing the oil bath, 108 g (447 mmol) of Cu(NO3)2.3H2O are added. Then, whilst cooling, 432 g (1.81 mol) of Na2S2O8 are added in portions, and finally 162 g (1.91 mol) of NaNO3. After stirring for 2 h at 50° C., the mixture is cooled to 10° C., mixed with 4 l of water and stirred for 10 min. 1-oxo-1,2-dihydro-isoquinoline-4-carbaldehyde can be filtered from the light green suspension and washed with water; m.p. 222-223° C. The filtrate is extracted 3 more times with EtOAc. The EtOAc phases are washed with water (3×) and brine, dried (Na2SO4) and concentrated by evaporation. Column chromatography of the residue (SiO2, methylene chloride/toluene/acetone 2:2:1) yields further 1-oxo-1,2-dihydro-isoquinoline-4-carbaldehyde.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:25]=[CH:24][C:6]2[C:7]([CH2:10][O:11][C:12]3[CH:20]=[CH:19][CH:18]=[C:17]4[C:13]=3[CH:14]=[C:15]([C:21]([OH:23])=O)[NH:16]4)=[CH:8][O:9][C:5]=2[CH:4]=1.Cl.Cl.Cl.[NH2:29][CH:30]1[CH2:35][CH2:34][N:33]([CH2:36][C@@H:37]([N:39]2[CH2:44][CH2:43][C@H:42]([OH:45])[C@@H:41]([CH3:46])[CH2:40]2)[CH3:38])[CH2:32][CH2:31]1>>[OH:45][C@H:42]1[CH2:43][CH2:44][N:39]([C@@H:37]([CH3:38])[CH2:36][N:33]2[CH2:32][CH2:31][CH:30]([NH:29][C:21]([C:15]3[NH:16][C:17]4[C:13]([CH:14]=3)=[C:12]([O:11][CH2:10][C:7]3[C:6]5[CH:24]=[CH:25][C:3]([O:2][CH3:1])=[CH:4][C:5]=5[O:9][CH:8]=3)[CH:20]=[CH:19][CH:18]=4)=[O:23])[CH2:35][CH2:34]2)[CH2:40][C@@H:41]1[CH3:46]
Reactant: COc1ccc2c(COc3cccc4[nH]c(C(=O)O)cc34)coc2c1
Reactant: C[C@H]1CN([C@@H](C)CN2CCC(N)CC2)CC[C@@H]1O
Agent: Cl
Product: COc1ccc2c(COc3cccc4[nH]c(C(=O)NC5CCN(C[C@H](C)N6CC[C@H](O)[C@@H](C)C6)CC5)cc34)coc2c1

Procedure:
This compound is synthesized analogously to example 1 from 4-(6-methoxy-benzofuran-3-ylmethoxy)-1H-indole-2-carboxylic acid, 120 (see example 86) and amine 56.
Reaction SMILES: [NH2:1][CH:2]([CH2:7][C:8]1[CH:13]=[CH:12][C:11]([N+:14]([O-:16])=[O:15])=[CH:10][CH:9]=1)[C:3]([O:5][CH3:6])=[O:4].C(Cl)Cl.[K+].[Br-]>CO.C(Cl)Cl>[CH3:6][O:5][C:3]([CH2:2][NH:1][CH:2]([CH2:7][C:8]1[CH:13]=[CH:12][C:11]([N+:14]([O-:16])=[O:15])=[CH:10][CH:9]=1)[C:3]([O:5][CH3:6])=[O:4])=[O:4]
Reactant: COC(=O)C(N)Cc1ccc([N+](=O)[O-])cc1
Agent: [Br-]
Agent: [K+]
Solvent: ClCCl
Solvent: CO
Product: COC(=O)CNC(Cc1ccc([N+](=O)[O-])cc1)C(=O)OC
Yield: 36 %

Procedure:
This compound (7) was synthesized from compound 5 using a method analogous to the synthesis described in Example 4. FC (silica gel, first CH2Cl2, then 5% MeOH/CH2Cl2). Yield: 36%. IR (KBr): 3342 (N--H), 1740 (C=O), 1519,1347 (NO2), 1203 (C--O). 1N-NMR (CDCl3): 3.04 (dd, J=7.3, 13.7, 1H); 3.13 (dd, J=6.3, 13.7, 1H); 3.36 (d, J=17.3, 1H); 3.42 (d, J=17.3, 1H); 3.63 (dd, J=6.3, 7.3, 1H); 3.69 (s, 3H); 3.70 (s, 3H); 7.39 (d, J=8.8, 2H); 8.16 (d, J=8.8, 2H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH2:8])[CH:5]=[N:6][CH:7]=1.N1C=CC=CC=1.Cl[C:16]([O:18][CH2:19][CH3:20])=[O:17]>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[C:4]([NH:8][C:16](=[O:17])[O:18][CH2:19][CH3:20])[CH:5]=[N:6][CH:7]=1
Reactant: CCOC(=O)Cl
Reactant: Nc1cncc(Br)c1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCOC(=O)Nc1cncc(Br)c1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 75.9 %

Procedure:
5-bromopyridin-3-amine (20 g, 116 mmol) was dissolved in DCM (500 mL) and pyridine (28.0 mL, 347 mmol) was added, followed by ethyl chloroformate (11.44 mL, 119 mmol) dropwise. The reaction mixture was stirred for 1.5 h at room temperature. The reaction mixture was diluted with DCM. The two phases were separated and the organic phase was washed with 10% CuSO4 solution (2×) sat. NaHCO3 solution (1×) Brine (1×) dried (Na2SO4) and evaporated. The residue was triturated with diethyl ether filtered and dried obtaining ethyl (5-bromopyridin-3-yl)carbamate (21.58 g, 76%) as a white solid. LCMS (m/z): 247.0 (MH+), 0.58 min; 1H NMR (400 MHz, CDCl3) δ ppm 8.62-8.15 (m, 3H) 7.00 (br. s., 1H) 4.27 (q, J=7.0 Hz, 2H) 1.34 (t, J=7.0 Hz, 3H).
Reaction SMILES: [CH2:1]([C@H:8]1[CH2:12][O:11][C:10](=[O:13])[NH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([Li])CCC.[F:19][C:20]1[CH:25]=[CH:24][C:23]([N:26]2[CH:30]=[CH:29][C:28]([CH2:31][C:32](O)=[O:33])=[CH:27]2)=[CH:22][CH:21]=1.C(N(CC)CC)C.C(Cl)(=O)C(C)(C)C>C1COCC1>[CH2:1]([C@H:8]1[CH2:12][O:11][C:10](=[O:13])[N:9]1[C:32](=[O:33])[CH2:31][C:28]1[CH:29]=[CH:30][N:26]([C:23]2[CH:24]=[CH:25][C:20]([F:19])=[CH:21][CH:22]=2)[CH:27]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)Cc1ccn(-c2ccc(F)cc2)c1
Reactant: O=C1N[C@@H](Cc2ccccc2)CO1
Agent: CC(C)(C)C(=O)Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=C(Cc1ccn(-c2ccc(F)cc2)c1)N1C(=O)OC[C@@H]1Cc1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 68.7 %

Procedure:
To a solution of (S)-(−)-4-benzyl-2-oxazolidinone (710 mg, 4 mmol) in dry THF (10 mL) at −78° C. was added n-butyllithium (2.5 mL of 1.6 M in hexanes). In a separate reaction vessel, to a solution of 2-[1-(4-fluorophenyl)-1H-pyrrol-3-yl]-acetic acid (920 mg, 4.2 mmol) and triethylamine (0.7 mL, 5 mmol) in dry THF (20 mL) at −78° C. was added dropwise pivaloyl chloride (0.5 mL, 4 mmol). After stirring at −78° to 0° C. over 1 hour, then recooling to −78° C., the above solution was added via cannula. The resultant mixture was allowed to warm to ambient temperature over 17 hours, then partitioned with EtOAc and aqueous NH4Cl. The separated aqueousueous phase was extracted with EtOAc. The combined organic layers were washed with brine, dried over Na2SO4, and concentrated to an oil, which was purified via flash column chromatography with 15-20% EtOAc/hex gradient eluant. The oily product crystallized from benzene to give 1.04 g (69%) of 1-(4(S)-benzyl-oxazolidin-2-on-3-yl)-2-[1-(4-fluorophenyl)-1H-pyrrol-3-yl]-ethanone as a solid, mp 106-8° C.
Reaction SMILES: C([O:8][C:9]1[C:14](=[O:15])[N:13]=[C:12]([CH2:16][C:17]2([C:22]3[CH:27]=[C:26]([Cl:28])[CH:25]=[CH:24][C:23]=3[Cl:29])[CH2:21][CH2:20][CH2:19][CH2:18]2)[N:11]2[CH2:30][CH2:31][N:32]([CH:35]([CH3:37])[CH3:36])[C:33](=[O:34])[C:10]=12)C1C=CC=CC=1.Cl.C(OCC)(=O)C>CO>[Cl:29][C:23]1[CH:24]=[CH:25][C:26]([Cl:28])=[CH:27][C:22]=1[C:17]1([CH2:16][C:12]2[N:11]3[CH2:30][CH2:31][N:32]([CH:35]([CH3:37])[CH3:36])[C:33](=[O:34])[C:10]3=[C:9]([OH:8])[C:14](=[O:15])[N:13]=2)[CH2:21][CH2:20][CH2:19][CH2:18]1
Reactant: CC(C)N1CCn2c(CC3(c4cc(Cl)ccc4Cl)CCCC3)nc(=O)c(OCc3ccccc3)c2C1=O
Agent: Cl
Solvent: CO
Solvent: CCOC(C)=O
Product: CC(C)N1CCn2c(CC3(c4cc(Cl)ccc4Cl)CCCC3)nc(=O)c(O)c2C1=O
Reaction time: 20 h
Yield: 7.6 %

Procedure:
To a stirred solution of 9-benzyloxy-6-[1-(2,5-dichlorophenyl)-cyclopentylmethyl]-2-isopropyl-3,4-dihydro-2H-pyrazino[1,2-c]pyrimidine-1,8-dione (208) (500 mg, 0.93 mmol) in methanol (5.5 mL) was added concentrated HCl (4 mL) and the mixture was stirred for 20 h. Silica thin layer chromatography was performed (100% ethyl acetate, Rf=0.3). Methanol was removed, water was added, the mixture was basified (pH˜8) with solid NaHCO3, extracted with ethyl acetate (3×20 mL), and the organic part was dried and concentrated. The crude product was purified by preparative HPLC purification to get 6-[1-(2,5-dichlorophenyl)-cyclopentylmethyl]-9-hydroxy-2-isopropyl-3,4-dihydro-2H-pyrazino[1,2-c]pyrimidine-1,8-dione (209) (32 mg, 11.34%) as a light brown solid.
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]=1[CH2:13][O:14][C:15]1[N:16]=[CH:17][C:18]([C:21]([OH:23])=O)=[N:19][CH:20]=1.[CH:24]([NH2:27])([CH3:26])[CH3:25]>>[CH:24]([NH:27][C:21]([C:18]1[CH:17]=[N:16][C:15]([O:14][CH2:13][C:3]2[C:4]([C:7]3[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=3)=[N:5][O:6][C:2]=2[CH3:1])=[CH:20][N:19]=1)=[O:23])([CH3:26])[CH3:25]
Reactant: Cc1onc(-c2ccccc2)c1COc1cnc(C(=O)O)cn1
Reactant: CC(C)N
Product: Cc1onc(-c2ccccc2)c1COc1cnc(C(=O)NC(C)C)cn1
Yield: 33 %

Procedure:
As described for example 2b, 5-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-pyrazine-2-carboxylic acid (100 mg, 0.32 mmol), was converted, using isopropylamine instead of aminomethylcyclopropane, to the title compound (SiO2, heptane:ethyl acetate=90:10 to 60:40, 37 mg, 33%) which was obtained as an off-white solid. MS: m/e=353.2 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[C:3]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([I:17])=[CH:13][C:12]=2[F:18])=[CH:4][C:5](=[O:9])[N:6]([CH3:8])[CH:7]=1.[CH:19]1([S:22](Cl)(=[O:24])=[O:23])[CH2:21][CH2:20]1.Cl>N1C=CC=CC=1>[F:18][C:12]1[CH:13]=[C:14]([I:17])[CH:15]=[CH:16][C:11]=1[NH:10][C:3]1[C:2]([NH:1][S:22]([CH:19]2[CH2:21][CH2:20]2)(=[O:24])=[O:23])=[CH:7][N:6]([CH3:8])[C:5](=[O:9])[CH:4]=1
Reactant: O=S(=O)(Cl)C1CC1
Reactant: Cn1cc(N)c(Nc2ccc(I)cc2F)cc1=O
Agent: Cl
Solvent: c1ccncc1
Product: Cn1cc(NS(=O)(=O)C2CC2)c(Nc2ccc(I)cc2F)cc1=O
Temperature: 25 °C
Reaction time: 16 h
Yield: 79 %

Procedure:
To a solution of 5-amino-4-(2-fluoro-4-iodophenylamino)-1-methylpyridin-2(1H)-one (62.3 mg, 0.174 mmol) in dry pyridine (3 mL) at 0° C. (ice-salt bath), was added cyclopropanesulfonyl chloride (29 mg, 0.206 mmol). The resultant reaction mixture was allowed to warm to room temperature and stirred for 16 hours. Aqueous HCl (1N) (5 mL) was added and the mixture stirred for 15 minutes, resulting in the formation of a precipitate which was isolated by filtration, dried under vacuum, to afford the desired compound as a tan solid. (64 mg, 79% yield)
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]([C:23]1[CH:28]=[CH:27][C:26]([OH:29])=[CH:25][CH:24]=1)([C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH:7]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[C:8]([O:10][CH2:11][CH3:12])=[O:9])=[O:5])[CH3:2].Br[CH2:31][C:32](=[O:34])[CH3:33].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH2:21]([O:20][C:18]([C:6]([C:23]1[CH:28]=[CH:27][C:26]([O:29][CH2:31][C:32](=[O:34])[CH3:33])=[CH:25][CH:24]=1)([C:4]([O:3][CH2:1][CH3:2])=[O:5])[CH:7]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[C:8]([O:10][CH2:11][CH3:12])=[O:9])=[O:19])[CH3:22]
Reactant: CC(=O)CBr
Reactant: CCOC(=O)C(C(=O)OCC)C(C(=O)OCC)(C(=O)OCC)c1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)C(C(=O)OCC)C(C(=O)OCC)(C(=O)OCC)c1ccc(OCC(C)=O)cc1

Procedure:
Following a procedure similar to that described in Preparation 3, but using 11.7 g of p-[1,1,2,2-tetrakis(ethoxycarbonyl)ethyl]phenol, 7.9 g of bromoacetone, 7.9 g of potassium carbonate and 100 ml of dimethylformamide, and then purifying the reaction product by column chromatography through silica gel, using a 1:2 by volume mixture of ethyl acetate and hexane as the eluent, the title compound was obtained having an Rf=0.21 (thin layer chromatography over silica gel, using a 1:2 by volume mixture of ethyl acetate and hexane as the developing solvent).
Reaction SMILES: [CH3:1][C:2]([O:5][C:6]([NH:8][C@@H:9]([C:11]([OH:13])=O)[CH3:10])=[O:7])([CH3:4])[CH3:3].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH3:47][C:48]1[CH:53]=[CH:52][C:51]([O:54][CH3:55])=[CH:50][C:49]=1[O:56][C:57]1[CH:63]=[CH:62][C:60]([NH2:61])=[CH:59][CH:58]=1>CN(C)C=O>[CH3:10][C@@H:9]([NH:8][C:6](=[O:7])[O:5][C:2]([CH3:1])([CH3:3])[CH3:4])[C:11]([NH:61][C:60]1[CH:59]=[CH:58][C:57]([O:56][C:49]2[CH:50]=[C:51]([O:54][CH3:55])[CH:52]=[CH:53][C:48]=2[CH3:47])=[CH:63][CH:62]=1)=[O:13]
Reactant: COc1ccc(C)c(Oc2ccc(N)cc2)c1
Reactant: C[C@@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(C)c(Oc2ccc(NC(=O)[C@@H](C)NC(=O)OC(C)(C)C)cc2)c1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 98.6 %

Procedure:
To a solution of N-{[(1,1-dimethylethyl)oxy]carbonyl}-D-alanine (89 mg, 0.471 mmol) in dry N,N-dimethylformamide (5 mL), DIPEA (0.103 mL, 0.589 mmol) then HATU (179 mg, 0.471 mmol) were added and the reaction mixture was stirred for 15 minutes at room temperature under argon. Then 4-{[2-methyl-5-(methyloxy)phenyl]oxy}aniline (Intermediate 14, 90 mg) was added and the reaction mixture was stirred at 60° C. under argon for 1 hour 30 min. The reaction mixture was evaporated. The residues obtained was purified by silica gel chromatography (Companion instrument, 40 g silica cartridge) eluting with a gradient cHex/EtOAc 100/0 to 75/25 during 15 min and then 75/25 during 30 min to afford the title compound (155 mg).
Reaction SMILES: [Br:1][C:2]1[C:10]2[N:9]=[C:8]([CH3:11])[NH:7][C:6]=2[CH:5]=[C:4]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)[CH:3]=1.Br[CH2:19][C:20]1[C:25]2[S:26][CH:27]=[CH:28][C:24]=2[CH:23]=[CH:22][CH:21]=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[S:26]1[CH:27]=[CH:28][C:24]2[CH:23]=[CH:22][CH:21]=[C:20]([CH2:19][N:7]3[C:6]4[CH:5]=[C:4]([N:12]5[CH2:17][CH2:16][O:15][CH2:14][CH2:13]5)[CH:3]=[C:2]([Br:1])[C:10]=4[N:9]=[C:8]3[CH3:11])[C:25]1=2
Reactant: Cc1nc2c(Br)cc(N3CCOCC3)cc2[nH]1
Reactant: BrCc1cccc2ccsc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1nc2c(Br)cc(N3CCOCC3)cc2n1Cc1cccc2ccsc12
Temperature: 90 °C
Reaction time: 2 h
Yield: 57.8 %

Procedure:
To the mixture of 4-(4-bromo-2-methyl-1H-benzo[d]imidazol-6-yl)morpholine (0.8 g, 2.70 mmol) in N,N-Dimethylformamide (DMF) (10 mL) was added 7-(bromomethyl)benzo[b]thiophene (0.920 g, 4.05 mmol)) and potassium carbonate (1.120 g, 8.10 mmol). The resulting reaction mixture was stirred at 90° C. for 2 h, then more 7-(bromomethyl)benzo[b]thiophene (0.920 g, 4.05 mmol) was added in and the reaction mixture was stirred at 100° C. for 4 h. It was cooled to room temperature and poured into water (100 mL). The aqueous mixture was extracted with DCM (100 mL×2). The combined organic phase was washed with Brine (100 mL) and concentrated. The crude material was purified on silica column (20˜90% EtOAc in Hexane) to give the product as solid (0.69 g, 58% %). 1H NMR (400 MHz, DMSO-d6) δ ppm 2.42 (s, 3H) 2.95-3.07 (m, 4H) 3.66-3.72 (m, 4H) 5.69 (s, 2H) 6.81 (d, J=7.07 Hz, 1H) 7.00 (d, J=2.02 Hz, 1H) 7.09 (d, J=2.02 Hz, 1H) 7.36 (t, J=7.58 Hz, 1H) 7.53 (d, J=5.56 Hz, 1H) 7.79 (d, J=5.56 Hz, 1H) 7.85 (d, J=7.65 Hz, 1H); MS (ES+) m/e 442.0 [M+H]+.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([OH:15])[CH:13]=2)[N:8]([C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=2)[C:7]=1[CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25])=[O:5])[CH3:2].[F:29][C:30]([F:41])([F:40])[C:31]1[CH:36]=[CH:35][C:34](B(O)O)=[CH:33][CH:32]=1>>[CH2:1]([O:3][C:4]([C:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([O:15][C:34]3[CH:35]=[CH:36][C:31]([C:30]([F:41])([F:40])[F:29])=[CH:32][CH:33]=3)[CH:13]=2)[N:8]([C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=2)[C:7]=1[CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25])=[O:5])[CH3:2]
Reactant: CCOC(=O)Cc1c(C(=O)OCC)c2cc(O)ccc2n1-c1ccc(Cl)cc1
Reactant: OB(O)c1ccc(C(F)(F)F)cc1
Product: CCOC(=O)Cc1c(C(=O)OCC)c2cc(Oc3ccc(C(F)(F)F)cc3)ccc2n1-c1ccc(Cl)cc1

Procedure:
The sub-title compound was prepared in accordance with step (c) Example 1 from 1-(4-chlorophenyl)-2-ethoxycarbonylmethyl-5-hydroxyindole-3-carboxylic acid ethyl ester (185 mg, 0.46 mmol, see step (b) Example 2) and 4-trifluoromethylbenzeneboronic acid (129 mg, 0.68 mmol). Yield 145 mg (58%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[CH:18][C:17]=1[F:23].C(O)C.[Cl:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1[C:34]([N:36]=[C:37]=[S:38])=[O:35]>C1(C)C=CC=CC=1>[Cl:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1[C:34]([NH:36][C:37]([NH:20][C:19]1[CH:21]=[CH:22][C:16]([O:15][C:6]2[C:5]3[C:10](=[CH:11][C:12]([O:13][CH3:14])=[C:3]([O:2][CH3:1])[CH:4]=3)[N:9]=[CH:8][CH:7]=2)=[C:17]([F:23])[CH:18]=1)=[S:38])=[O:35]
Reactant: COc1cc2nccc(Oc3ccc(N)cc3F)c2cc1OC
Reactant: O=C(N=C=S)c1ccccc1Cl
Solvent: Cc1ccccc1
Solvent: CCO
Product: COc1cc2nccc(Oc3ccc(NC(=S)NC(=O)c4ccccc4Cl)cc3F)c2cc1OC
Temperature: 25 °C
Reaction time: 2 h
Yield: 75 %

Procedure:
4-[(6,7-Dimethoxy-4-quinolyl)oxy]-3-fluoroaniline (50 mg) was dissolved in toluene (5 ml) and ethanol (1 ml) to prepare a solution. Commercially available 2-chloro-1-benzenecarbonyl isothiocyanate (50 μl) was then added to the solution, and the mixture was stirred at room temperature for 2 hr. The reaction solution was concentrated, and the residue was purified by chromatography on silica gel using chloroform/acetone for development to give the title compound (61 mg, yield 75%).
Reaction SMILES: Br[CH:2]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[CH2:3][CH2:4][CH:5]1[C:8](=[O:9])[N:7]([C:10]2[CH:17]=[CH:16][C:13]([C:14]#[N:15])=[CH:12][CH:11]=2)[CH:6]1[C:18]1[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=1.FC(F)(F)C([O-])=[O:35].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCOCC1>[OH:35][CH:2]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[CH2:3][CH2:4][CH:5]1[C:8](=[O:9])[N:7]([C:10]2[CH:17]=[CH:16][C:13]([C:14]#[N:15])=[CH:12][CH:11]=2)[CH:6]1[C:18]1[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=1
Reactant: O=C([O-])C(F)(F)F
Reactant: COc1ccc(C2C(CCC(Br)c3ccccc3)C(=O)N2c2ccc(C#N)cc2)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: C1COCCO1
Product: COc1ccc(C2C(CCC(O)c3ccccc3)C(=O)N2c2ccc(C#N)cc2)cc1
Reaction time: 1 h

Procedure:
17 g of 4-[3-(3-bromo-3-phenylpropyl)-2-(4-methoxyphenyl)-4-oxoazetidin-1-yl]-benzonitrile are dissolved in 500 ml of dioxane and, after addition of 34 ml of ˜40 percent tetrabutylammonium trifluoroacetate solution, heated to reflux for 24 h. The mixture was concentrated to about half the volume, mixed with water and methyl tert-butyl ether and separated into the phases. The organic phase is concentrated, and the residue is stirred with 500 ml of ethanol and 200 ml of concentrated ammonia at room temp. for 1 h. It is then again concentrated in vacuo, and the crude product is purified on silica gel with dichloromethane/methanol =30:1 as mobile phase. The alcohol is obtained as an oil. MS (ESI): 413 (M+H+), 395 (M+H+-H2O) [C26H24N2O3 M=412].
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[O:9][CH3:10].[Cl:11][C:12]1[CH:13]=[C:14]2[C:18](=[CH:19][CH:20]=1)[NH:17][C:16](=[O:21])[C:15]2=[O:22]>>[Cl:11][C:12]1[CH:13]=[C:14]2[C:18](=[CH:19][CH:20]=1)[NH:17][C:16](=[O:21])[C:15]2([C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[O:9][CH3:10])[OH:22]
Reactant: O=C1Nc2ccc(Cl)cc2C1=O
Reactant: COc1ccc(Cl)cc1Br
Product: COc1ccc(Cl)cc1C1(O)C(=O)Nc2ccc(Cl)cc21
Yield: 93.1 %

Procedure:
With 14.6 g of 2-bromo-4-chloro anisole and 8.00 g of 5-chloroisatin as starting materials, 13.3 g of the title compound (yellow solid) was obtained by a similar method to Step 21-1.
Reaction SMILES: [C:1]([OH:9])(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[N:4][CH:3]=1.C(N(CC)CC)C.OC1C2N=NNC=2C=CC=1.[C:27]([C:31]1[N:36]=[C:35]([N:37]2[CH2:42][CH2:41][N:40]([CH2:43][CH2:44][CH2:45][CH2:46][NH2:47])[CH2:39][CH2:38]2)[CH:34]=[C:33]([CH:48]2[CH2:51][CH2:50][CH2:49]2)[N:32]=1)([CH3:30])([CH3:29])[CH3:28].Cl.C(N=C=NCCCN(C)C)C>CN(C)C=O>[C:27]([C:31]1[N:36]=[C:35]([N:37]2[CH2:38][CH2:39][N:40]([CH2:43][CH2:44][CH2:45][CH2:46][NH:47][C:1](=[O:9])[C:2]3[CH:7]=[CH:6][CH:5]=[N:4][CH:3]=3)[CH2:41][CH2:42]2)[CH:34]=[C:33]([CH:48]2[CH2:51][CH2:50][CH2:49]2)[N:32]=1)([CH3:30])([CH3:28])[CH3:29]
Reactant: CC(C)(C)c1nc(C2CCC2)cc(N2CCN(CCCCN)CC2)n1
Reactant: O=C(O)c1cccnc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: Oc1cccc2[nH]nnc12
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(C)(C)c1nc(C2CCC2)cc(N2CCN(CCCCNC(=O)c3cccnc3)CC2)n1
Reaction time: 16 h
Yield: 58.6 %

Procedure:
0.35 g of nicotinic acid (2.84 mmol) and 0.87 g of triethylamine (8.62 mmol) were dissolved in 30 ml of dimethylformamide. 0.45 g of hydroxybenzotriazole (HOBt, 3.33 mmol), 1.1 g of 4-[4-(2-tert-butyl-6-cyclobutyl-pyrimidin-4-yl)-piperazin-1-yl]-butylamine (3.18 mmol), and 0.6 g of N-ethyl-N′-(3-dimethylaminopropyl)-carbodiimide hydrochloride (EDCl, 3.13 mmol) were added at room temperature, and the reaction mixture was stirred for 16 h. The reaction mixture was partitioned between water and ethyl acetate. The organic phase was dried over magnesium sulfate, filtered, and concentrated to dryness. The crude product was purified by chromatography on silica gel using dichloromethane-methanol (2-10%). The residue was treated with acetonitrile, filtered and dried to yield 0.75 g of the title compound as a white solid.
Reaction SMILES: [BH4-].[Na+].[CH3:3][C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][C:11]=1[S:12][CH3:13])[CH:7]=[O:8].Cl>C(O)C>[CH3:3][C:4]1[CH:5]=[C:6]([CH2:7][OH:8])[CH:9]=[CH:10][C:11]=1[S:12][CH3:13]
Reactant: CSc1ccc(C=O)cc1C
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: CSc1ccc(CO)cc1C
Reaction time: 1 h

Procedure:
Sodium borohydride (1.40 g, 0.037 mol) was added to an ice-bath cooled solution of the product of example 28 step a) (6.16 g, 0.037 mol) in ethanol (50 ml). After 1 hour, the reaction mixture was neutralised by careful addition of aqueous hydrochloric acid (2 molar) and concentrated in vacuo to remove the organic solvent. The remaining aqueous solution was then extracted with ethyl acetate (×3). The combined organic layers were dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo to yield the subtitle compound as a brown oil (6 g) in quantitative yield.
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5]1[C:11](=O)[CH2:10][CH:9]([C:13]([O:15][CH3:16])=[O:14])[C:7](=O)[CH2:6]1)=[O:4].[F:17][C:18]1[CH:24]=[CH:23][C:21]([NH2:22])=[CH:20][CH:19]=1.Cl>CO>[F:17][C:18]1[CH:24]=[CH:23][C:21]([NH:22][C:7]2[CH2:6][C:5]([C:3]([O:2][CH3:1])=[O:4])=[C:11]([NH:22][C:21]3[CH:23]=[CH:24][C:18]([F:17])=[CH:19][CH:20]=3)[CH2:10][C:9]=2[C:13]([O:15][CH3:16])=[O:14])=[CH:20][CH:19]=1
Reactant: COC(=O)C1CC(=O)C(C(=O)OC)CC1=O
Reactant: Nc1ccc(F)cc1
Agent: Cl
Solvent: CO
Product: COC(=O)C1=C(Nc2ccc(F)cc2)CC(C(=O)OC)=C(Nc2ccc(F)cc2)C1
Yield: 181.6 %

Procedure:
Dimethyl 1,4-cyclohexanedione-2,5-dicarboxylate (9.12 gm; 40 mmol) and methanol (200 ml) were heated to boiling, then 4-fluoroaniline (8.35 ml (9.78 gm); 42 mmol) was added followed by conc. hydrochloric acid (400 μl). The mixture was refluxed for 3 hours under a nitrogen atmosphere. On cooling a yellow solid precipitated out which was collected by filtration, washed with methanol and dried under vacuum to give 15.8 gm (96%) of dimethyl 2,5-bis{(4-fluorophenyl)amino}cyclohexa-1,4-diene-1,4-dicarboxylate.
Reaction SMILES: [OH:1][CH2:2][C:3]1([CH2:15][OH:16])[CH2:9][CH2:8][S:7][C:6]2[CH:10]=[CH:11][CH:12]=[CH:13][C:5]=2[C:4]1=[O:14].C(N(CC)CC)C.[F:24][C:25]1[CH:30]=[C:29]([F:31])[CH:28]=[CH:27][C:26]=1[N:32]=[C:33]=[S:34]>O1CCCC1>[OH:16][CH2:15][C:3]1([CH2:2][O:1][C:33](=[S:34])[NH:32][C:26]2[CH:27]=[CH:28][C:29]([F:31])=[CH:30][C:25]=2[F:24])[CH2:9][CH2:8][S:7][C:6]2[CH:10]=[CH:11][CH:12]=[CH:13][C:5]=2[C:4]1=[O:14]
Reactant: Fc1ccc(N=C=S)c(F)c1
Reactant: O=C1c2ccccc2SCCC1(CO)CO
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=C1c2ccccc2SCCC1(CO)COC(=S)Nc1ccc(F)cc1F

Procedure:
To a solution of 4,4-bis(hydroxymethyl)-3,4-dihydro-2H-benzo[b]thiepin-5-one (720 mg, 3.02 mmol) in 38 ml of tetrahydrofuran were added, at room temperature, triethylamine (0.46 ml, 3.32 mmol) and 2,4-difluorophenyl isothiocyanate (985 μl, 7.55 mmol). The mixture was heated to reflux for 72 hours, concentrated and purified by column chromatography on silica gel (eluent: 1:2 ethyl acetate/hexane). The product was obtained in a yield of 170 mg (14%).