Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][CH2:2][N:3]1[C:9]2[N:10]=[C:11]([N:14]3[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]3)[N:12]=[CH:13][C:8]=2[C:6](=[O:7])[C:5]([C:20]([OH:22])=[O:21])=[CH:4]1.[Cl:23][C:24]1[CH:25]=[C:26]([N:30]=[C:31]=[S:32])[CH:27]=[CH:28][CH:29]=1.C(N(CC)CC)C>>[Cl:23][C:24]1[CH:25]=[C:26]([NH:30][C:31]([N:17]2[CH2:18][CH2:19][N:14]([C:11]3[N:12]=[CH:13][C:8]4[C:6](=[O:7])[C:5]([C:20]([OH:22])=[O:21])=[CH:4][N:3]([CH2:2][CH3:1])[C:9]=4[N:10]=3)[CH2:15][CH2:16]2)=[S:32])[CH:27]=[CH:28][CH:29]=1
Reactant: CCn1cc(C(=O)O)c(=O)c2cnc(N3CCNCC3)nc21
Reactant: S=C=Nc1cccc(Cl)c1
Solvent: CCN(CC)CC
Product: CCn1cc(C(=O)O)c(=O)c2cnc(N3CCN(C(=S)Nc4cccc(Cl)c4)CC3)nc21

Procedure:
Pipemidic acid (25 mg, 0.0824 mmol), 3-chlorophenyl isothiocyanate (11 μL, 0.0824 mmol) and triethylamine (23 μL, 0.165 mmol) were used. Purification on silica yielded compound 14 in Table 1, below (8.2 mg, 21%). 1H NMR (300 MHz, CDCl3) δ 9.03 (s, 1H), 8.51 (s, 1H), 7.10 (s, 1H), 7.04-6.93 (m, 2H), 6.90-6.84 (m, 1H), 4.14 (q, J=6.90 Hz, 2H), 4.00-3.74 (m, 8H), 1.23 (t, J=7.01 Hz, 3H) ppm.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@@H:12]([CH2:31][CH:32]2[CH2:36][CH2:35][CH2:34][CH2:33]2)[C:13]([NH:15][C:16]2[CH:20]=[CH:19][N:18]([CH2:21][C:22]3[CH:23]=[C:24]([CH:28]=[CH:29][CH:30]=3)[C:25](Cl)=[O:26])[N:17]=2)=[O:14])[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:10])=[O:9].ClC1C=C([C@@H](CC2CCCC2)C(NC2C=CN(CC3C=[C:60]([CH:64]=[CH:65]C=3)[C:61]([NH2:63])=O)N=2)=O)C=CC=1S(C)(=O)=O.NCC1CC1>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([C@@H:12]([CH2:31][CH:32]2[CH2:36][CH2:35][CH2:34][CH2:33]2)[C:13]([NH:15][C:16]2[CH:20]=[CH:19][N:18]([CH2:21][C:22]3[CH:23]=[C:24]([CH:28]=[CH:29][CH:30]=3)[C:25]([NH:63][CH2:61][CH:60]3[CH2:64][CH2:65]3)=[O:26])[N:17]=2)=[O:14])[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:10])=[O:9]
Reactant: CS(=O)(=O)c1ccc([C@@H](CC2CCCC2)C(=O)Nc2ccn(Cc3cccc(C(=O)Cl)c3)n2)cc1Cl
Reactant: CS(=O)(=O)c1ccc([C@@H](CC2CCCC2)C(=O)Nc2ccn(Cc3cccc(C(N)=O)c3)n2)cc1Cl
Agent: NCC1CC1
Solvent: ClCCl
Product: CS(=O)(=O)c1ccc([C@@H](CC2CCCC2)C(=O)Nc2ccn(Cc3cccc(C(=O)NCC4CC4)c3)n2)cc1Cl
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 36 %

Procedure:
To a 0.166 M solution of crude 3-{3-[2-(R)-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-propionylamino]-pyrazol-1-ylmethyl}-benzoyl chloride in methylene chloride (prepared in example 63, 1.71 mL, 0.28 mmol) was added aminomethyl cyclopropane (20 mg, 0.28 mmol) and the reaction stirred at 25° C. for 30 min. The solution was diluted with methylene chloride (40 mL), washed with water (2×20 mL), saturated aqueous brine solution (2×20 mL), dried over magnesium sulfate and concentrated in vacuo to an off white foam. Purification by flash column chromatography (Merck silica gel 60, 40-63 μm; 0% ethyl acetate/methylene chloride to 100% ethyl acetate/methylene chloride) afforded 3-{3-[2-(R)-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-propionylamino]-pyrazol-1-ylmethyl}-N-cyclopropylmethyl-benzamide (60 mg, 36%) as a white powder: ESI-LRMS m/e calcd for C30H35ClN4O4S [M+] 582.21, found 583.33 [M+H+]; 1H NMR (400 MHz, DMSO-d6) δ ppm 0.17-0.27 (m, 2H, CH2), 0.39-0.046 (m, 2H, CH2), 0.98-1.17 (m, 3H, CH and CH2), 1.37-1.78 (m, 8H, 4×CH2), 2.02-2.17 (m, 1H, CH), 3.12 (t, J=6.0 Hz, 2H, NCH2), 3.32 (s, 3H, SO2CH3), 3.83-3.91 (m, 1H, CH), 5.22 (s, 2H, NCH2), 6.46 (d, J=2.0 Hz, 1H, Ar), 7.28-7.36 (m, 1H, Ar), 7.39 (t, J=8.0 Hz, 1H, Ar), 7.56 (d, Jo=7.8 Hz, 1H, Ar), 7.65 (d, Jm=1.2 Hz, 1H, Ar), 7.69-7.80 (m, 3H, Ar), 7.97 (d, Jo=8.2 Hz, 1H, Ar), 8.51 (m, 1H, NH), 10.77 (s, 1H, NH).
Reaction SMILES: C([C@@H]1CSC(=S)N1[C:10](=[O:26])[CH2:11][C@H:12]([O:18][Si:19]([CH2:24][CH3:25])([CH2:22][CH3:23])[CH2:20][CH3:21])[CH2:13][CH2:14][CH2:15][CH:16]=[CH2:17])(C)C.CC(C[AlH]CC(C)C)C.C(C(C(C([O-])=O)O)O)([O-])=O.[K+].[Na+]>C1(C)C=CC=CC=1>[CH2:24]([Si:19]([CH2:20][CH3:21])([CH2:22][CH3:23])[O:18][C@H:12]([CH2:13][CH2:14][CH2:15][CH:16]=[CH2:17])[CH2:11][CH:10]=[O:26])[CH3:25]
Reactant: C=CCCC[C@H](CC(=O)N1C(=S)SC[C@H]1C(C)C)O[Si](CC)(CC)CC
Agent: CC(C)C[AlH]CC(C)C
Agent: O=C([O-])C(O)C(O)C(=O)[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: C=CCCC[C@H](CC=O)O[Si](CC)(CC)CC
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 93.4 %

Procedure:
The title compound from Example 7 (6.08 g, 14.2 mmol) was dissolved in toluene (70 mL) under an atmosphere of nitrogen and the mixture was cooled to −78° C. DIBAL (1 M in hexane, 32 mL, 32 mmol) was added over 10 min, and the mixture was stirred at −78° C. for 30 min. The reaction mixture was poured onto half-saturated sodium potassium tartrate solution at 0° C. and stirred for 3 h. The phases were separated and the aqueous phase was extracted twice with 1:9 ethyl acetate/hexanes. The combined organic phases were dried and evaporated, and the residue was diluted with hexane. The resulting solid was filtered off and the filtrate was concentrated and filtered through a silica plug to provide the title compound (3.40 g, 93%) as an oil.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]([N:10]2[CH2:15][CH2:14][N:13]([C:16]3[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][C:17]=3[CH3:23])[CH2:12][CH2:11]2)=[O:9])=[CH:4][C:3]=1[Cl:24].[O:25]1[CH2:29][CH2:28][NH:27][C:26]1=[O:30]>>[Cl:24][C:3]1[CH:4]=[C:5]([C:8]([N:10]2[CH2:15][CH2:14][N:13]([C:16]3[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][C:17]=3[CH3:23])[CH2:12][CH2:11]2)=[O:9])[CH:6]=[CH:7][C:2]=1[N:27]1[CH2:28][CH2:29][O:25][C:26]1=[O:30]
Reactant: O=C1NCCO1
Reactant: Cc1ccc(N2CCN(C(=O)c3ccc(Br)c(Cl)c3)CC2)c(C)c1
Product: Cc1ccc(N2CCN(C(=O)c3ccc(N4CCOC4=O)c(Cl)c3)CC2)c(C)c1
Yield: 57.8 %

Procedure:
By reaction and treatment in the same manner as in Example 1 and using (4-bromo-3-chlorophenyl)[4-(2,4-dimethylphenyl)piperazin-1-yl]methanone (815 mg) described in Preparation Example 3 and oxazolidin-2-one (174 mg), the title compound (478 mg) was obtained.
Reaction SMILES: FC(F)(F)C(O)=O.[CH2:8]([NH:12][C:13]1[NH:21][C:20]2[C:16]([N:17]=[C:18]([O:22][CH3:23])[N:19]=2)=[C:15]([NH2:24])[N:14]=1)[CH2:9][CH2:10][CH3:11].Br[CH2:26][CH2:27][CH2:28][CH:29]1[CH2:33][CH2:32][CH2:31][O:30]1>>[CH2:8]([NH:12][C:13]1[N:21]=[C:20]2[C:16]([N:17]=[C:18]([O:22][CH3:23])[N:19]2[CH2:26][CH2:27][CH2:28][CH:29]2[CH2:33][CH2:32][CH2:31][O:30]2)=[C:15]([NH2:24])[N:14]=1)[CH2:9][CH2:10][CH3:11]
Reactant: CCCCNc1nc(N)c2nc(OC)nc-2[nH]1
Reactant: BrCCCC1CCCO1
Solvent: O=C(O)C(F)(F)F
Product: CCCCNc1nc(N)c2nc(OC)n(CCCC3CCCO3)c2n1

Procedure:
Prepared similarly to Intermediate 216 from N2-butyl-8-(methyloxy)-3H-purine-2,6-diamine trifluoroacetate and 2-(3-bromopropyl)tetrahydrofuran.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][CH2:7][C:8]2([CH3:12])[CH3:11])=[CH:4][C:3]=1[O:13]C.B(Br)(Br)Br>C(Cl)Cl>[Br:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][CH2:7][C:8]2([CH3:11])[CH3:12])=[CH:4][C:3]=1[OH:13]
Reactant: COc1cc2c(cc1Br)C(C)(C)CC2
Agent: BrB(Br)Br
Solvent: ClCCl
Product: CC1(C)CCc2cc(O)c(Br)cc21
Temperature: 25 °C
Reaction time: 2 h
Yield: 90 %

Procedure:
To 6-bromo-5-methoxy-1,1-dimethyl-indan (0.6 g, 2.35 mmol) in CH2Cl2 (30 mL) was added BBr3 (1M in CH2Cl2, 4.70 mmol) dropwise at −78° C. Following addition the mixture was allowed to warm to room temperature and subsequently stirred at room temperature for 2 h. The reaction mixture was then quenched with MeOH (5 mL). Aqueous sodium hydrogen carbonate (10 mL) was added. The reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was extracted with CH2Cl2. The organic phase was washed with brine, dried (Na2SO4) and concentrated. Silica gel chromatography (EtOAc/heptane) provided 0.51 g (90%) of 6-bromo-1,1-dimethyl-indan-5-ol.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[C:10]2[C:6]([CH2:7][CH2:8][CH:9]2[C:12]([OH:14])=O)=[CH:5][CH:4]=1.[CH2:15]([N:17]1[CH:21]=[C:20]([CH2:22][NH:23][C:24]2[CH:29]=[CH:28][C:27]([CH:30]([CH3:32])[CH3:31])=[CH:26][CH:25]=2)[CH:19]=[N:18]1)[CH3:16]>>[CH2:15]([N:17]1[CH:21]=[C:20]([CH2:22][N:23]([C:24]2[CH:25]=[CH:26][C:27]([CH:30]([CH3:31])[CH3:32])=[CH:28][CH:29]=2)[C:12]([CH:9]2[C:10]3[C:6](=[CH:5][CH:4]=[C:3]([O:2][CH3:1])[CH:11]=3)[CH2:7][CH2:8]2)=[O:14])[CH:19]=[N:18]1)[CH3:16]
Reactant: COc1ccc2c(c1)C(C(=O)O)CC2
Reactant: CCn1cc(CNc2ccc(C(C)C)cc2)cn1
Product: CCn1cc(CN(C(=O)C2CCc3ccc(OC)cc32)c2ccc(C(C)C)cc2)cn1
Yield: 55.6 %

Procedure:
By the reaction and treatment in the same manner as in Example 12 using 6-methoxyindan-1-carboxylic acid (0.29 g) and [(1-ethylpyrazol-4-yl)methyl](4-isopropylphenyl)amine (0.37 g) as starting materials, N-[(1-ethylpyrazol-4-yl)methyl]-N-(4-isopropylphenyl)-6-methoxyindan-1-carboxamide (0.35 g) was obtained.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[C:10]([O:12][CH3:13])[C:9]([OH:14])=[CH:8][C:3]=1[C:4](OC)=[O:5].CC(O)=O.O.[CH:20]([NH2:22])=O>>[OH:14][C:9]1[CH:8]=[C:3]2[C:2](=[CH:11][C:10]=1[O:12][CH3:13])[N:1]=[CH:20][NH:22][C:4]2=[O:5]
Reactant: COC(=O)c1cc(O)c(OC)cc1N
Reactant: NC=O
Solvent: CC(=O)O
Solvent: O
Product: COc1cc2nc[nH]c(=O)c2cc1O
Temperature: 140 °C
Yield: 89 %

Procedure:
A mixture of methyl 2-amino-5-hydroxy-4-methoxybenzoate (3.1 g, 15.7 mmol) and AcOH (7.1 mL) in formamide (15.5 mL) was heated at 140° C. overnight. To it was added water (20 mL) and filtered to afford 6-hydroxy-7-methoxyquinazoline-4(3H)-one as a solid (2.7 g, 89%). 1H NMR (300 MHz, DMSO-d6) δ 9.82 (s, 1H), 7.9 (s, 1H), 7.4 (s, 1H), 7.1 (s, 1H), 3.9 (s, 3H).
Reaction SMILES: C[O:2][C:3]1[N:11]([CH:12]2[CH2:15][N:14]([C:16]([O:18]C(C)(C)C)=O)[CH2:13]2)[C:6]2=[N:7][CH:8]=[CH:9][CH:10]=[C:5]2[N:4]=1.FC(F)(F)C(O)=O.N1CC(N2C3=NC=CC=C3NC2=O)C1.[NH:44]1[C:48]2[CH:49]=[CH:50][CH:51]=[CH:52][C:47]=2[N:46]=[C:45]1C(O)=O.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C>O.CN(C)C=O.ClCCl>[NH:44]1[C:48]2[CH:49]=[CH:50][CH:51]=[CH:52][C:47]=2[N:46]=[C:45]1[C:16]([N:14]1[CH2:13][CH:12]([N:11]2[C:6]3=[N:7][CH:8]=[CH:9][CH:10]=[C:5]3[NH:4][C:3]2=[O:2])[CH2:15]1)=[O:18]
Reactant: O=C(O)c1nc2ccccc2[nH]1
Reactant: COc1nc2cccnc2n1C1CN(C(=O)OC(C)(C)C)C1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: O=c1[nH]c2cccnc2n1C1CNC1
Solvent: CCN(CC)CC
Solvent: O
Solvent: CN(C)C=O
Product: O=C(c1nc2ccccc2[nH]1)N1CC(n2c(=O)[nH]c3cccnc32)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 8 %

Procedure:
A mixture of tert-butyl 3-(2-methoxy-3H-imidazo[4,5-b]pyridin-3-yl)azetidine-1-carboxylate (intermediate 55, 450 mg, 1.479 mmol), trifluoroacetic acid (3.29 mL, 44.4 mmol) and dichloromethane (3 mL) was stirred at room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure and dried under high vacuum. The crude 3-(azetidin-3-yl)-1H-imidazo[4,5-b]pyridin-2(3H)-one (250 mg, 0.598 mmol), 1H-benzimidazole-2-carboxylic acid (97 mg, 0.598 mmol), HBTU (227 mg, 0.598 mmol), triethylamine (0.416 mL, 2.99 mmol) and dry dimethylformamide (2 mL) were added to a 50 mL round bottom flask. The reaction mixture was stirred at room temperature for 12 hours. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic extract was washed with saturated ammonium chloride and dried over magnesium sulfate before concentrating in vacuo to give the crude material as a tan solid. The crude material was absorbed onto a plug of silica gel and purified by chromatography through a Redi-Sep pre-packed silica gel column (12 g, hexane to ethyl acetate gradient) to provide 3-(1-(1H-benzo[d]imidazole-2-carbonyl)azetidin-3-yl)-1H-imidazo[4,5-b]pyridin-2(3H)-one (16 mg, 0.048 mmol, 8.01% yield) as off-white solid. M+1=335.1 1H NMR (400 MHz, DMSO-d6) δ ppm 4.42 (t, J=9.29 Hz, 1 H) 4.66 (dd, J=10.27, 6.16 Hz, 1 H) 4.97-5.03 (m, 1 H) 5.21-5.36 (m, 2 H) 6.92 (dd, J=7.82, 5.28 Hz, 1 H) 7.12-7.18 (m, 1 H) 7.18-7.25 (m, 2 H) 7.44 (d, J=7.82 Hz, 1 H) 7.62 (d, J=8.22 Hz, 1 H) 7.84 (dd, J=5.28, 1.37 Hz, 1 H) 11.13 (br. s., 1 H) 13.16 (br. s., 1 H)
Reaction SMILES: [C:1]([O:4][CH2:5][C:6]1[C:11]([N:12]2[C:24](=[O:25])[C:23]3[S:22][C:21]4[CH2:20][CH2:19][CH2:18][CH2:17][C:16]=4[C:15]=3[CH2:14][CH2:13]2)=[CH:10][C:9]([F:26])=[CH:8][C:7]=1[C:27]1[N:35]=[C:34]2[C:30]([N:31]=[CH:32][N:33]2COCC[Si](C)(C)C)=[C:29]([NH:44][C:45]2[CH:50]=[CH:49][C:48]([N:51]3[CH2:56][CH2:55][N:54]([CH:57]4[CH2:60][O:59][CH2:58]4)[CH2:53][CH2:52]3)=[CH:47][CH:46]=2)[N:28]=1)(=[O:3])[CH3:2].C(O)(C(F)(F)F)=O>>[C:1]([O:4][CH2:5][C:6]1[C:11]([N:12]2[C:24](=[O:25])[C:23]3[S:22][C:21]4[CH2:20][CH2:19][CH2:18][CH2:17][C:16]=4[C:15]=3[CH2:14][CH2:13]2)=[CH:10][C:9]([F:26])=[CH:8][C:7]=1[C:27]1[N:35]=[C:34]2[C:30]([N:31]=[CH:32][NH:33]2)=[C:29]([NH:44][C:45]2[CH:46]=[CH:47][C:48]([N:51]3[CH2:52][CH2:53][N:54]([CH:57]4[CH2:58][O:59][CH2:60]4)[CH2:55][CH2:56]3)=[CH:49][CH:50]=2)[N:28]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)OCc1c(-c2nc(Nc3ccc(N4CCN(C5COC5)CC4)cc3)c3ncn(COCC[Si](C)(C)C)c3n2)cc(F)cc1N1CCc2c(sc3c2CCCC3)C1=O
Solvent: O=C(O)C(F)(F)F
Product: CC(=O)OCc1c(-c2nc(Nc3ccc(N4CCN(C5COC5)CC4)cc3)c3nc[nH]c3n2)cc(F)cc1N1CCc2c(sc3c2CCCC3)C1=O
Temperature: 30 °C
Reaction time: 2 h
Yield: 57.6 %

Procedure:
A mixture of 119a (307 mg, 0.360 mmol) and CF3COOH (5 mL) was stirred at 30° C. for 2 h. The mixture was evaporated in vacuo and the residue was diluted with water (5 mL). The pH of the mixture was adjusted to 7 with saturated NaHCO3 solution and extracted with ethyl acetate (3×10 mL). The combined extract was dried over MgSO4 and evaporated to dryness to afford 119b (150 mg, 60%), which was used in the next step without further purification. MS-ESI: [M+H]+ 723.4
Reaction SMILES: ClC1C=C(Cl)C=CC=1C1C(N2C=CN=C2)=CN=C(CCN)N=1.Cl[C:24]1[N:29]=[C:28]([NH2:30])[C:27]([C:31]#[N:32])=[CH:26][N:25]=1.[Cl:33][C:34]1[CH:39]=[C:38]([Cl:40])[CH:37]=[CH:36][C:35]=1[C:41]1[C:46]([C:47]2[NH:48][CH:49]=[CH:50][N:51]=2)=[CH:45][N:44]=[C:43]([NH:52][CH2:53][CH2:54][NH:55]C2C=CC([N+]([O-])=O)=C(OC)N=2)[N:42]=1>>[NH2:30][C:28]1[C:27]([C:31]#[N:32])=[CH:26][N:25]=[C:24]([NH:55][CH2:54][CH2:53][NH:52][C:43]2[N:42]=[C:41]([C:35]3[CH:36]=[CH:37][C:38]([Cl:40])=[CH:39][C:34]=3[Cl:33])[C:46]([C:47]3[NH:51][CH:50]=[CH:49][N:48]=3)=[CH:45][N:44]=2)[N:29]=1
Reactant: N#Cc1cnc(Cl)nc1N
Reactant: COc1nc(NCCNc2ncc(-c3ncc[nH]3)c(-c3ccc(Cl)cc3Cl)n2)ccc1[N+](=O)[O-]
Agent: NCCc1ncc(-n2ccnc2)c(-c2ccc(Cl)cc2Cl)n1
Product: N#Cc1cnc(NCCNc2ncc(-c3ncc[nH]3)c(-c3ccc(Cl)cc3Cl)n2)nc1N

Procedure:
4-amino-2-[(2-{[4-(2,4-dichlorophenyl)-5-imidazolylpyrimidin-2-yl]amino}ethyl)-amino]pyrimidine-5-carbonitrile was prepared from [4-(2,4-dichlorophenyl)-5-imidazol-1-ylpyrimidin-2-ylethylamine and 2-chloro-4-amino-5-cyanopyrimidine in accordance with the procedure described above for the preparation of [4-(2,4-dichlorophenyl)-5-imidazol-2-ylpyrimidin-2-yl]{2-[(6-methoxy-5-nitro(2-pyridyl))amino]ethyl}amine.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([N+:29]([O-])=O)=[C:13]([S:15][CH2:16][CH2:17][C:18]([O:20][CH2:21][CH:22]([CH2:27][CH3:28])[CH2:23][CH2:24][CH2:25][CH3:26])=[O:19])[CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl>C(O)C>[NH2:29][C:12]1[CH:11]=[CH:10][C:9]([O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[CH:14][C:13]=1[S:15][CH2:16][CH2:17][C:18]([O:20][CH2:21][CH:22]([CH2:27][CH3:28])[CH2:23][CH2:24][CH2:25][CH3:26])=[O:19]
Reactant: CCCCC(CC)COC(=O)CCSc1cc(OCc2ccccc2)ccc1[N+](=O)[O-]
Agent: Cl
Solvent: CCO
Product: CCCCC(CC)COC(=O)CCSc1cc(OCc2ccccc2)ccc1N
Yield: 70.9 %

Procedure:
To a solution of 2-ethylhexyl 3-{[5-(benzyloxy)-2-nitrophenyl]sulfanyl}propanoate (3.60 g) and 6M hydrochloric acid (2.69 mL) in ethanol (46 mL) was added reduced iron (4.51 g), and the mixture was heated under reflux for 3 hr. The insoluble material was removed by filtration, and the solvent of the filtrate was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give the title compound as a dark red liquid (2.38 g).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]([CH:11]1[CH2:13][C:12]1([F:15])[F:14])=[O:10].FC1(F)CC1C(C1C=CC(C(F)(F)F)=CC=1)O>>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[CH:9]([CH:11]1[CH2:13][C:12]1([F:15])[F:14])[OH:10]
Reactant: O=C(c1ccc(Cl)cc1Cl)C1CC1(F)F
Agent: OC(c1ccc(C(F)(F)F)cc1)C1CC1(F)F
Product: OC(c1ccc(Cl)cc1Cl)C1CC1(F)F

Procedure:
The title compound was prepared starting from 9.00 g (35.8 mmol) of the compound from Example 189A in analogy to the synthesis of the compound from Example 190A. 7.30 g (80% of theory) of diastereomer 1 and 1.10 g (12% of theory) of diastereomer 2 of the title compound were obtained.
Reaction SMILES: [CH3:1][C:2]1([CH3:24])[C:6]([C:7]2[CH:12]=[C:11]([C:13]([OH:15])=[O:14])[CH:10]=[CH:9][C:8]=2[C:16]2[CH:21]=[C:20]([OH:22])[CH:19]=[CH:18][C:17]=2[F:23])=[CH:5][CH2:4][CH2:3]1.S(=O)(=O)(O)O.[CH3:30]O>>[CH3:1][C:2]1([CH3:24])[C:6]([C:7]2[CH:12]=[C:11]([C:13]([O:15][CH3:30])=[O:14])[CH:10]=[CH:9][C:8]=2[C:16]2[CH:21]=[C:20]([OH:22])[CH:19]=[CH:18][C:17]=2[F:23])=[CH:5][CH2:4][CH2:3]1
Reactant: CO
Reactant: CC1(C)CCC=C1c1cc(C(=O)O)ccc1-c1cc(O)ccc1F
Agent: O=S(=O)(O)O
Product: COC(=O)c1ccc(-c2cc(O)ccc2F)c(C2=CCCC2(C)C)c1
Yield: 98 %

Procedure:
To a flask containing 66.14A (75 mg, 230 μmol) in MeOH (2 mL) was added sulfuric acid (0.61 μL, 11 μmol), and the mixture was stirred at reflux overnight. The reaction was concentrated and then purified by silica gel chromatography (0 to 30% EtOAc/Hexanes) to provide 66.14B (77.0 mg, 98% yield).
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].S(Cl)(Cl)=O.[CH2:18](O)[CH3:19]>>[CH3:1][C:2]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][C:3]=1[C:4]([O:6][CH2:18][CH3:19])=[O:5]
Reactant: Cc1ccc([N+](=O)[O-])cc1C(=O)O
Reactant: CCO
Solvent: O=S(Cl)Cl
Product: CCOC(=O)c1cc([N+](=O)[O-])ccc1C
Temperature: 0 °C

Procedure:
A mixture of 2-methyl-5-nitrobenzoic acid (10.0 g, 55.2 mmol) in ethanol (200 ml) was cooled to 0° C. with an ice bath and thionyl chloride (16.0 mL, 220 mmol) was added dropwise over 10 min. After this time, the mixture was warmed to room temperature for 1 h, then transferred to an oil bath and heated to reflux overnight. The mixture was then cooled to room temperature and concentrated under reduced pressure. Purification by flash chromatography (silica, 9:1 hexanes/ethyl acetate) afforded ethyl 2-methyl-5-nitrobenzoate (12.4 g, quant.) as a pale yellow oil: 1H NMR (300 MHz, CDCl3) δ 8.76 (d, J=2.5 Hz, 1H), 8.24 (dd, J=8.5, 2.5 Hz, 1H), 7.43 (d, J=8.4 Hz, 1H), 4.42 (q, J=7.2 Hz, 2H), 2.72 (s, 3H), 1.44 (t, J=7.1 Hz, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[C:12]([N:14]1[CH2:18][CH2:17][CH2:16][CH2:15]1)=[O:13])[N:8]=[CH:7][N:6]=[C:5]2[NH:19][CH:20]([C:26]1[N:30](C(OC(C)(C)C)=O)[C:29]2[CH:38]=[CH:39][C:40]([Cl:42])=[CH:41][C:28]=2[N:27]=1)[CH2:21][CH2:22][C:23](O)=[O:24].[C:43]1([CH:49]([NH2:51])[CH3:50])[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.FC(F)(F)C(O)=O>C(#N)C.O1CCCC1>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[C:12]([N:14]1[CH2:18][CH2:17][CH2:16][CH2:15]1)=[O:13])[N:8]=[CH:7][N:6]=[C:5]2[NH:19][CH:20]([C:26]1[NH:30][C:29]2[CH:38]=[CH:39][C:40]([Cl:42])=[CH:41][C:28]=2[N:27]=1)[CH2:21][CH2:22][C:23]([NH:51][CH:49]([C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1)[CH3:50])=[O:24]
Reactant: CC(N)c1ccccc1
Reactant: CC(C)(C)OC(=O)n1c(C(CCC(=O)O)Nc2ncnc3cc(C(=O)N4CCCC4)c(Cl)cc23)nc2cc(Cl)ccc21
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: O=C(O)C(F)(F)F
Solvent: CC#N
Solvent: C1CCOC1
Product: CC(NC(=O)CCC(Nc1ncnc2cc(C(=O)N3CCCC3)c(Cl)cc12)c1nc2cc(Cl)ccc2[nH]1)c1ccccc1

Procedure:
Prepared analogously to Example 61 from 6-chloro-4-[1-(1-tert.-butyloxycarbonyl-5-chloro-1H-benzimidazol-2-yl)-3-hydroxycarbonyl-propyl-amino]-7-(pyrrolidin-1-yl-carbonyl)-quinazoline and 1-phenyl-ethylamine with TBTU in acetonitrile/tetrahydrofuran and subsequent reaction with trifluoroacetic acid.
Reaction SMILES: [CH:1]([C:4]([CH:15]([CH3:17])[CH3:16])=[C:5]([C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([OH:14])[CH:9]=1)[O:6][CH3:7])([CH3:3])[CH3:2].[C:18](Cl)(=[O:25])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>C(Cl)Cl.C(N(CC)CC)C>[C:18]([O:14][C:10]1[CH:9]=[C:8]([C:5]([O:6][CH3:7])=[C:4]([CH:1]([CH3:3])[CH3:2])[CH:15]([CH3:17])[CH3:16])[CH:13]=[CH:12][CH:11]=1)(=[O:25])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: COC(=C(C(C)C)C(C)C)c1cccc(O)c1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=C(C(C)C)C(C)C)c1cccc(OC(=O)c2ccccc2)c1
Reaction time: 1 h

Procedure:
Alkene 1b (4.5 g, 1.9 mmol) was dissolved in 50 mL of dry CH2Cl2 with 5.3 mL of anhydrous triethylamine. The flask was purged with argon and cooled in an ice bath. Benzoyl chloride (4.05 g, 2.9 mmol) was added dropwise. The cooling bath was removed and stirring continued for 1 hour at room temperature. The mixture was filtered and the solution was washed with water, dried over MgSO4 and evaporated. The residue was suspended in hexane, the solid filtered away and the solution evaporated. The residue was purified by column chromatography on silica gel, eluting with 1% ethyl acetate in hexane yielding 3.7 g of dioxetane 1d: 1H NMR (CDCl3) δ 8.25-7.05 (m, 9H), 3.25 (s, 1H), 2.54 (sept, 1H, J=6.9 Hz), 2.40 (sept, 1H, J=6.9 Hz), 2.29 (s, 3H), 1.26 (d, 6H, J=6.9 Hz), 0.95 (d, 6H, J=6.9 Hz).
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[N:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[CH2:17][CH2:18][CH2:19][OH:20].O>C(Cl)Cl>[N:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[CH2:17][CH2:18][CH:19]=[O:20]
Reactant: OCCCc1ccccn1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CS(C)=O
Solvent: O
Product: O=CCCc1ccccn1
Temperature: -70 °C
Reaction time: 0.25 h

Procedure:
35 ml (0.41 mol) of oxalyl chloride were dissolved in 700 ml of dry DCM and cooled to −70° C. A mixture of 62 ml (0.87 mol) of DMSO and 40 ml of dry DCM was added dropwise to this solution over a period of 25 min. During this, the temperature was kept strictly below −65° C. (exothermic reaction). After stirring at −70° C. for 15 min, 50 g (0.36 mol) of freshly distilled 3-(2-pyridyl)propanol dissolved in 150 ml of dry DCM were added dropwise at below −65° C. over a period not exceeding 15 min. 218 ml (0.37 mol) of TEA were added in 40 min, and then the mixture was slowly warmed to RT. 190 ml of water were added to dissolve the salts which had formed. The phases were separated, the DCM phase was concentrated in vacuo, and the product was then purified by distillation (2 mbar, 59-70° C.).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[CH2:7][CH2:6]2.[F:13][C:14]([Si](C)(C)C)([F:16])[F:15].[F-].C([N+](CCCC)(CCCC)CCCC)CCC.Cl>C1COCC1.C(Cl)Cl.O>[OH:12][C:8]1([C:14]([F:16])([F:15])[F:13])[C:9]2[C:5](=[CH:4][C:3]([O:2][CH3:1])=[CH:11][CH:10]=2)[CH2:6][CH2:7]1
Reactant: C[Si](C)(C)C(F)(F)F
Reactant: COc1ccc2c(c1)CCC2=O
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: Cl
Agent: [F-]
Solvent: C1CCOC1
Solvent: ClCCl
Solvent: O
Product: COc1ccc2c(c1)CCC2(O)C(F)(F)F
Temperature: 25 °C
Reaction time: 21 h
Yield: 73.3 %

Procedure:
To a stirred solution of 5-methoxy-1-indanone (1.00 g, 6.17 mmol) and trifluoromethyltrimethylsilane (1.32 g, 9.26 mmol) in dry THF (15 ml) was added 1.0M THF solution of tetrabutylammonium fluoride (0.05 ml) with ice-cooling.The reaction mixture was stirred at room temperature for 21 h. To a mixture was 1N HCl (20 ml). and stirred at room temperature for 25 h. The reaction mixture was diluted with CH2Cl2-water. The organic layer was separated and the aqueous layer was extracted with CH2Cl2. The combined solution was washed with water and brine, dried (MgSO4) and concentrated in vacuo to give crude product as a dark yellow oil. The crude product was purified by column chromatography on silica gel with hexane-ethyl acetate(5:1-3:1) to give Compound 62 (1.05 g, 73%) as a yellow oil.