Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:9]2[N:8]=[CH:7][C:6]3[N:12]([CH3:23])[C:13](=[O:22])[N:14]([C:15]4[C:16]([CH3:21])=[N:17][N:18]([CH3:20])[CH:19]=4)[C:5]=3[C:4]=2[CH:3]=1.[CH2:24]([N:26]([CH3:42])[C:27]1[CH:32]=[CH:31][C:30](B2OC(C)(C)C(C)(C)O2)=[CH:29][N:28]=1)[CH3:25]>>[CH3:20][N:18]1[CH:19]=[C:15]([N:14]2[C:5]3[C:4]4[CH:3]=[C:2]([C:30]5[CH:29]=[N:28][C:27]([N:26]([CH2:24][CH3:25])[CH3:42])=[CH:32][CH:31]=5)[CH:11]=[CH:10][C:9]=4[N:8]=[CH:7][C:6]=3[N:12]([CH3:23])[C:13]2=[O:22])[C:16]([CH3:21])=[N:17]1
Reactant: Cc1nn(C)cc1-n1c(=O)n(C)c2cnc3ccc(Br)cc3c21
Reactant: CCN(C)c1ccc(B2OC(C)(C)C(C)(C)O2)cn1
Product: CCN(C)c1ccc(-c2ccc3ncc4c(c3c2)n(-c2cn(C)nc2C)c(=O)n4C)cn1

Procedure:
The title compound was synthesized in a similar manner as described for Example 1.1 using 8-bromo-1-(1,3-dimethyl-1H-pyrazol-4-yl)-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one (Intermediate A) and ethyl-methyl-[5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyridin-2-yl]-amine (stage 98.1.1) to give the title compound as a white solid. (HPLC: tR 2.18 min (Method A); M+H=428 MS-ES; 1H-NMR (d6-DMSO, 400 MHz) 8.90 (s, 1H), 8.26-8.24 (m, 1H), 8.14-8.12 (m, 1H), 8.04-8.01 (m, 1H), 7.88-7.84 (m, 1H), 7.57-7.52 (m, 1H), 7.43-7-40 (m, 1H), 6.73-6.69 (m, 1H), 3.93 (s, 3H), 3.62-3.53 (m, 51-1), 3.01 (s, 3H), 1.96 (s, 3H), 1.07 (t, 3H))
Reaction SMILES: Br[C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4]1([C:25]3=[CH:26][C:27]4[O:31][CH2:30][O:29][C:28]=4[CH:32]=[C:24]3[O:23][CH2:22]1)[C:5](=[O:21])[N:6]2[CH2:11][C:12]1[O:13][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:15][CH:16]=1.[Cl-].[Li+].[CH3:35][Sn](C)(C)C>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].CN1CCCC1=O>[CH3:35][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4]1([C:25]3=[CH:26][C:27]4[O:31][CH2:30][O:29][C:28]=4[CH:32]=[C:24]3[O:23][CH2:22]1)[C:5](=[O:21])[N:6]2[CH2:11][C:12]1[O:13][C:14]([C:17]([F:19])([F:18])[F:20])=[CH:15][CH:16]=1
Reactant: C[Sn](C)(C)C
Reactant: O=C1N(Cc2ccc(C(F)(F)F)o2)c2cccc(Br)c2C12COc1cc3c(cc12)OCO3
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: [Cl-]
Solvent: CN1CCCC1=O
Product: Cc1cccc2c1C1(COc3cc4c(cc31)OCO4)C(=O)N2Cc1ccc(C(F)(F)F)o1
Temperature: 60 °C
Yield: 15.8 %

Procedure:
A mixture of 4′-bromo-1′-((5-(trifluoromethyl)furan-2-yl)methyl)-6H-spiro[benzofuro[6,5-d][1,3]dioxole-7,3′-indolin]-2′-one (0.51 g, 1.00 mmol), lithium chloride (0.09 mg, 2.00 mmol), Pd2(dba)3 (0.09 mg, 10 mole %) was flushed with nitrogen. To the above mixture was added anhydrous 1-methyl-2-pyrrolidinone (5.00 mL) and tetramethyltin (0.27 mg, 0.20 mL, 1.50 mmol). The reaction mixture was heated at 60° C. for 16 h and quenched with saturated ammonium chloride (10.0 mL). The reaction mixture was extracted with ethyl acetate (3×10.0 mL). The combined organic layers was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated in vacuo to dryness. The residue was subjected to column chromatography eluting with ethyl acetate:hexane (20%) to afford the title compound (0.07 g, 16%) as a colorless solid: mp 117-119° C.; 1H NMR (300 MHz, CDCl3) δ 7.18 (t, 1H), 6.82 (t, 2H), 6.72 (d, 1H), 6.47 (s, 1H), 6.37 (d, 1H), 6.09 (s, 1H), 5.86 (d, 2H), 4.95 (ABq, 2H), 4.83 (ABq, 2H), 2.03 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 177.6, 156.2, 152.0, 149.1, 142.3, 141.3, 135.6, 129.4, 128.9, 126.0, 120.6, 117.2, 112.7, 112.6, 109.2, 106.5, 102.9, 101.6, 93.3, 78.4, 58.3, 37.0, 17.1; MS (ES+) m/z 444.1 (M+1).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9](=[O:28])[C:10]1[CH:15]=[CH:14][C:13]([CH2:16][N:17]2[CH2:25][C:24]3[C:19](=[CH:20][CH:21]=[CH:22][C:23]=3Br)[C:18]2=[O:27])=[CH:12][CH:11]=1.[F:29][C:30]1[CH:35]=[CH:34][C:33](B(O)O)=[CH:32][CH:31]=1>>[NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9](=[O:28])[C:10]1[CH:15]=[CH:14][C:13]([CH2:16][N:17]2[CH2:25][C:24]3[C:19](=[CH:20][CH:21]=[CH:22][C:23]=3[C:33]3[CH:34]=[CH:35][C:30]([F:29])=[CH:31][CH:32]=3)[C:18]2=[O:27])=[CH:12][CH:11]=1
Reactant: Nc1ccccc1NC(=O)c1ccc(CN2Cc3c(Br)cccc3C2=O)cc1
Reactant: OB(O)c1ccc(F)cc1
Product: Nc1ccccc1NC(=O)c1ccc(CN2Cc3c(cccc3-c3ccc(F)cc3)C2=O)cc1
Yield: 29 %

Procedure:
The procedure of Example 2 was repeated except for using N-(2-aminophenyl)-4-((4-bromo-1-oxoisoindolin-2-yl)methyl)benzamide obtained in Example 9 instead of N-(2-aminophenyl)-4-((4-bromo-5,6-dimethoxy-1-oxoisoindolin-2-yl)methyl)benzamide, and 4-fluorophenyl boronic acid instead of phenyl boronic acid, to obtain the title compound (29%).
Reaction SMILES: Cl[C:2]1[S:6][N:5]=[C:4]([N:7]2[CH2:11][CH2:10][CH2:9][CH2:8]2)[N:3]=1.FC(F)(F)C(O)=O.[O:19]1[C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=2[C:21]([NH:28][C:29]([N:31]2[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]2)=[O:30])=[N:20]1.C(N(CC)CC)C.O>CN(C)C=O>[O:19]1[C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=2[C:21]([NH:28][C:29]([N:31]2[CH2:36][CH2:35][N:34]([C:2]3[S:6][N:5]=[C:4]([N:7]4[CH2:11][CH2:10][CH2:9][CH2:8]4)[N:3]=3)[CH2:33][CH2:32]2)=[O:30])=[N:20]1
Reactant: O=C(Nc1noc2ccccc12)N1CCNCC1
Reactant: Clc1nc(N2CCCC2)ns1
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=C(Nc1noc2ccccc12)N1CCN(c2nc(N3CCCC3)ns2)CC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 5-chloro-3-pyrrolidin-1-yl-1,2,4-thiadiazole (158 mg, 0.833 mmol) and N-1,2-benzisoxazol-3-ylpiperazine-1-carboxamide trifluoroacetate (300 mg, 0.833 mmol) in N,N-dimethylformamide (3 ml) was added triethylamine (0.581 ml, 4.17 mmol) at room temperature, and the mixture was stirred at room temperature for 30 minutes. The reaction mixture was poured to water and extracted with ethyl acetate. The extract was washed with water and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=1:1) to give the desired product as a solid. The resulting solid was recrystallized from a mixed solvent of hexane and ethyl acetate to give 28.5 mg (8.58%) of the desired product.
Reaction SMILES: [CH:1]1([NH:6][C:7]2[CH:8]=[C:9]([CH2:23][N:24]3C(=O)C4C(=CC=CC=4)C3=O)[CH:10]=[C:11]3[C:15]=2[NH:14][C:13]([C:16]2[S:17][CH2:18][C@@H:19]([CH2:21][OH:22])[N:20]=2)=[CH:12]3)[CH2:5][CH2:4][CH2:3][CH2:2]1.O.NN>C(O)C>[NH2:24][CH2:23][C:9]1[CH:10]=[C:11]2[C:15](=[C:7]([NH:6][CH:1]3[CH2:5][CH2:4][CH2:3][CH2:2]3)[CH:8]=1)[NH:14][C:13]([C:16]1[S:17][CH2:18][C@@H:19]([CH2:21][OH:22])[N:20]=1)=[CH:12]2
Reactant: O=C1c2ccccc2C(=O)N1Cc1cc(NC2CCCC2)c2[nH]c(C3=N[C@H](CO)CS3)cc2c1
Agent: NN
Solvent: O
Solvent: CCO
Product: NCc1cc(NC2CCCC2)c2[nH]c(C3=N[C@H](CO)CS3)cc2c1
Temperature: 80 °C
Reaction time: 3 h
Yield: 29 %

Procedure:
2-[7-Cyclopentylamino-2-((R)-4-hydroxymethyl-4,5-dihydro-thiazol-2-yl)-1H-indol-5-ylmethyl]-isoindol-1,3-dione (27 mg, 0.07 mmol) prepared in Example 64 was dissolved in ethanol (3 mL). Hydrazine hydrate (0.6 mL, 0.11 mmol) was added thereto, and the mixture was stirred for 3 h at 80° C. After completion of the reaction, the reaction mixture was distilled under reduced pressure, and purified by column chromatography to give the title compound (7 mg, Yield 37%).
Reaction SMILES: [O:1]=[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][N:3]1[C:11]([NH:13][CH2:14][CH2:15][C:16]1[CH:21]=[CH:20][C:19]([S:22]([NH:25][C:26]([NH:28][CH:29]2[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]2)=S)(=[O:24])=[O:23])=[CH:18][CH:17]=1)=[O:12].[OH2:35]>CO.[Hg]=O>[O:1]=[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][N:3]1[C:11]([NH:13][CH2:14][CH2:15][C:16]1[CH:21]=[CH:20][C:19]([S:22]([NH:25][C:26]([NH:28][CH:29]2[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]2)=[O:35])(=[O:24])=[O:23])=[CH:18][CH:17]=1)=[O:12]
Reactant: O
Reactant: O=C(NCCc1ccc(S(=O)(=O)NC(=S)NC2CCCCC2)cc1)N1Cc2ccccc2C1=O
Agent: O=[Hg]
Solvent: CO
Product: O=C(NC1CCCCC1)NS(=O)(=O)c1ccc(CCNC(=O)N2Cc3ccccc3C2=O)cc1
Reaction time: 3 h

Procedure:
0.3 g of mercury oxide is added to 0.3 g of N-(4-[2-(1-oxo-isoindoline-2-carboxamido)-ethyl]-benzenesulfonyl)-N'-cyclohexyl-thiourea (melting point 194°-196° C., prepared from 4-[2-(1-oxo-isoindoline-2-carboxamido)-ethyl]-benzenesulfonamide and cyclohexyl mustard oil) in a mixture of 50 ml of water and 50 ml of methanol and the whole is stirred for 3 hours at 40°-45° C. The precipitated mercury sulfide is filtered off with suction, the filtrate is concentrated under reduced pressure, the residue is treated with very dilute ammonia, filtered and the filtrate is acidified with dilute hydrochloric acid. The precipitated N-(4-[2-(1-oxo-isoindoline-2-carboxamido)-ethyl]-benzenesulfonyl)-N'-2,5-cyclohexyl-urea is recrystallized from dilute acetone and melts at 211°-213° C. The mixed melting point with the compound obtained according to Example 1 is without depression.
Reaction SMILES: [C:1]([CH:4]([C:12](=O)[CH3:13])[CH:5]([C:9](=[O:11])[CH3:10])[C:6](=O)[CH3:7])(=[O:3])[CH3:2].[NH2:15][C:16]1[CH:21]=[CH:20][C:19]([OH:22])=[CH:18][C:17]=1[CH3:23]>>[C:9]([C:5]1[C:4]([C:1](=[O:3])[CH3:2])=[C:12]([CH3:13])[N:15]([C:16]2[CH:21]=[CH:20][C:19]([OH:22])=[CH:18][C:17]=2[CH3:23])[C:6]=1[CH3:7])(=[O:11])[CH3:10]
Reactant: CC(=O)C(C(C)=O)C(C(C)=O)C(C)=O
Reactant: Cc1cc(O)ccc1N
Product: CC(=O)c1c(C(C)=O)c(C)n(-c2ccc(O)cc2C)c1C

Procedure:
Utilizing the general procedure outlined in Example 48, 1,1,2,2-tetraacetylethane (200 mg, 1.0 mol) and 4-amino-3-methyl-phenol (123 mg, 1.0 mmol) reacted to give 1-[4-acetyl-1-(4-hydroxy-2-methyl-phenyl)-2,5-dimethyl-1H-pyrrol-3-yl]-ethanone as a brown solid: MS (ESI) 306 (M+H)+.
Reaction SMILES: [CH:1]([C:9]1[NH:13][C:12]2[CH:14]=[CH:15][CH:16]=[CH:17][C:11]=2[N:10]=1)=[CH:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[Cl:18][C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([CH3:25])[N:20]=1.N1C=CC=CC=1N1C2C=CC=CC=2N=C1/C=C/C1C=CC=CC=1.Cl>CO>[ClH:18].[CH3:25][C:21]1[N:20]=[C:19]([N:13]2[C:12]3[CH:14]=[CH:15][CH:16]=[CH:17][C:11]=3[N:10]=[C:9]2/[CH:1]=[CH:2]/[C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:24]=[CH:23][CH:22]=1
Reactant: C(=Cc1nc2ccccc2[nH]1)c1ccccc1
Reactant: Cc1cccc(Cl)n1
Agent: C(=C/c1nc2ccccc2n1-c1ccccn1)\c1ccccc1
Agent: Cl
Solvent: CO
Product: Cc1cccc(-n2c(/C=C/c3ccccc3)nc3ccccc32)n1

Procedure:
Free base of the titled compound was prepared from 2-styryl-1H-benzimidazole and 2-Chloro-6-methylpyridine according to the preparation of (E)-1-(2-pyridyl)-2-styryl-1H-benzimidazole (Example 1, method B). The free base was treated with a 10% methanol solution of hydrogen chloride and concentrated to dryness. The residue was recrystallized from ethyl acetate/n-hexane to give the titled compound. MW: 347.85; mp: 216.0-217.0° C.; 1H-NMR (DMSO-d6) δ: 8.20 (1H, br s), 8.10 (1 H, t, J=7.7 Hz), 7.87 (1H, d, J=7.7 Hz), 7.71-7.44 (10H, m), 7.22 (1H, d, J=16.1 Hz), 2.63 (3H, s).
Reaction SMILES: C([O:3][C:4](=[O:34])[CH:5]([CH2:29][S:30]C(=O)C)[CH2:6][C:7]1[CH:8]=[N:9][C:10]([N:14](C(OC(C)(C)C)=O)C(OC(C)(C)C)=O)=[C:11]([CH3:13])[CH:12]=1)C>Cl>[NH2:14][C:10]1[N:9]=[CH:8][C:7]([CH2:6][CH:5]([CH2:29][SH:30])[C:4]([OH:34])=[O:3])=[CH:12][C:11]=1[CH3:13]
Reactant: CCOC(=O)C(CSC(C)=O)Cc1cnc(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)c(C)c1
Agent: Cl
Product: Cc1cc(CC(CS)C(=O)O)cnc1N
Yield: 115.7 %

Procedure:
2-Acetylsulfanylmethyl-3-(6-[N,N-bis(tert-butoxycarbonyl)amino]-5-methyl-pyridin-3-yl)-propionic acid ethyl ester (17 mg, 0.034 mmol) was dissolved in conc. HCl (3.0 mL). The solution was heated to reflux for 1 h. Concentration under reduced pressure gave the title compound (8.9 mg, 100%) as the hydrochloride salt.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([N:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)[C:5]2[S:10][C:9]([CH:11]=O)=[C:8]([CH3:13])[C:6]=2[N:7]=1.C(O)(=O)C(O)=O.[OH:26][C@@H:27]([CH3:36])[C:28]([N:30]1[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]1)=[O:29].CN1CCOCC1.COC(OC)OC.B.C(C1C=CC(C)=NC=1)C>CO>[Cl:1][C:2]1[N:3]=[C:4]([N:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)[C:5]2[S:10][C:9]([CH2:11][N:33]3[CH2:32][CH2:31][N:30]([C:28](=[O:29])[C@@H:27]([OH:26])[CH3:36])[CH2:35][CH2:34]3)=[C:8]([CH3:13])[C:6]=2[N:7]=1
Reactant: Cc1c(C=O)sc2c(N3CCOCC3)nc(Cl)nc12
Reactant: C[C@H](O)C(=O)N1CCNCC1
Agent: B
Agent: CCc1ccc(C)nc1
Agent: O=C(O)C(=O)O
Solvent: CN1CCOCC1
Solvent: COC(OC)OC
Solvent: CO
Product: Cc1c(CN2CCN(C(=O)[C@H](C)O)CC2)sc2c(N3CCOCC3)nc(Cl)nc12
Temperature: 57.5 °C
Reaction time: 4 h
Yield: 81 %

Procedure:
2-Chloro-7-methyl-4-morpholinothieno[3,2-d]pyrimidine-6-carbaldehyde IV (15.0 g, 50 mmol) was charged to a suitably sized reactor, followed by methanol (306 mL), (S)-2-hydroxy-1-(piperazin-1-yl)propan-1-one oxalate V (18.8 g, 75 mmol), N-methyl morpholine (10.2 g, 100 mmol) and trimethylorthoformate (53.1 g, 500 mmol). The slurry was heated to 55-60° C. and stirred for 4 hrs. 5-Ethyl-2-methylpyridine borane (8.7 g, 60.0 mmol) were slowly added and the solution was stirred for 2 h. The reaction mixture was partially concentrated under reduced pressure. Me-THF (350 mL) was added and the reaction mixture was concentrated under reduced pressure to an end volume of 300 mL. The mixture was cooled to 5° C. 3.3% Sulfuric acid in water (401 g) was added and pH 1.6 was reached. The organic phase was removed. The pH of the aqueous phase was adjusted to 7.9 with 10% aqueous sodium carbonate solution (300 g) at 0-5° C. The mixture was warmed to 25° C. and the organic phase was separated. The organic phase was concentrated under reduced pressure to 75 mL. The solution was warmed to 35° C. and seeded with 41 mg (S)-1-(4-((2-chloro-7-methyl-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)piperazin-1-yl)-2-hydroxypropan-1-one II. The suspension was cooled to 0° C. and n-heptane (200 g) was added. The resulting slurry was aged at −5° C., filtered and washed with n-heptane. The cake was dried at 70° C. under reduced pressure to afford (S)-1-(4-((2-chloro-7-methyl-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)piperazin-1-yl)-2-hydroxypropan-1-one II (17.8 g, 81% yield)
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH:9]1[C:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[C:13]([CH2:20]Br)[NH:12][C:11]([N:22]2[CH:26]=[N:25][CH:24]=[N:23]2)=[N:10]1.Cl.[NH:28]1[CH2:33][CH2:32][O:31][CH2:30][CH:29]1[C:34]([OH:36])=[O:35]>>[Br:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH:9]1[N:10]=[C:11]([N:22]2[CH:26]=[N:25][CH:24]=[N:23]2)[NH:12][C:13]([CH2:20][N:28]2[CH2:33][CH2:32][O:31][CH2:30][CH:29]2[C:34]([OH:36])=[O:35])=[C:14]1[C:15]([O:17][CH2:18][CH3:19])=[O:16]
Reactant: O=C(O)C1COCCN1
Reactant: CCOC(=O)C1=C(CBr)NC(n2cncn2)=NC1c1ccc(F)cc1Br
Agent: Cl
Product: CCOC(=O)C1=C(CN2CCOCC2C(=O)O)NC(n2cncn2)=NC1c1ccc(F)cc1Br
Yield: 31 %

Procedure:
Ethyl 4-(2-bromo-4-fluorophenyl)-6-(bromomethyl)-2-(1H-1,2,4-triazol-1-yl)-1,4-dihydropyrimidine-5-carboxylate (1.75 g, 3.6 mmol) was reacted with morpholine-3-carboxylic acid hydrochloride (0.6 g, 3.6 mmol) according to the procedure as described in Example 1, Step C to give the title compound as a pale yellow solid (0.6 g, 31%). The compound was characterized by the following spectroscopic data:
Reaction SMILES: [CH:1]([N:4]1[C:8]([C:9]2[S:10][C:11]3[CH2:12][CH2:13][O:14][C:15]4[CH:22]=[C:21]([CH:23]5[CH2:26][N:25]([C:27]([C:29]6([NH:32]C(=O)O)[CH2:31][CH2:30]6)=[O:28])[CH2:24]5)[CH:20]=[CH:19][C:16]=4[C:17]=3[N:18]=2)=[N:7][CH:6]=[N:5]1)([CH3:3])[CH3:2].Cl.O1CCOCC1>CO>[NH2:32][C:29]1([C:27]([N:25]2[CH2:26][CH:23]([C:21]3[CH:20]=[CH:19][C:16]4[C:17]5[N:18]=[C:9]([C:8]6[N:4]([CH:1]([CH3:3])[CH3:2])[N:5]=[CH:6][N:7]=6)[S:10][C:11]=5[CH2:12][CH2:13][O:14][C:15]=4[CH:22]=3)[CH2:24]2)=[O:28])[CH2:30][CH2:31]1
Reactant: CC(C)n1ncnc1-c1nc2c(s1)CCOc1cc(C3CN(C(=O)C4(NC(=O)O)CC4)C3)ccc1-2
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: CC(C)n1ncnc1-c1nc2c(s1)CCOc1cc(C3CN(C(=O)C4(N)CC4)C3)ccc1-2
Reaction time: 18 h
Yield: 59 %

Procedure:
To a suspension of (1-{3-[2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulen-8-yl]-azetidine-1-carbonyl}-cyclopropyl)-carbamic acid tent-butyl ester (225 mg, 0.41 mmol) in MeOH (3.1 mL) was added 4N HCl/dioxan (1.0 mL, 4.1 mmol) and the reaction mixture was stirred for 18 hours. The resulting solid was filtered off and washed with diethyl ether before being partitioned between DCM and an aqueous saturated sodium bicarbonate solution. The phases were separated and the aqueous phase was extracted with DCM (×2). The combined organic extracts were washed with brine, dried (Na2SO4) and concentrated in vacuo. The resultant residue was purified by flash chromatography (SiO2, 0-8% 2N NH3/MeOH in DCM). The resulting solid was suspended in ether and collected by filtration to give 425 as a white solid (108 mg, 59%). LCMS: RT=7.96 min, [M+H]+=451. 1H NMR δ (ppm) (DMSO-d6): 8.35 (1 H, d, J=8.20 Hz), 8.02 (1 H, s), 7.20 (1 H, dd, J=8.22, 1.81 Hz), 7.05 (1 H, s), 5.86-5.78 (1 H, m), 4.59 (2 H, t, J=9.01 Hz), 4.40 (2H, t, J=5.07 Hz), 4.20 (2 H, d, J=7.67 Hz), 3.85 (1 H, t, J=7.50 Hz), 3.44 (2H, t, J=5.08 Hz), 2.18 (2 H, s), 1.58 (6H, d, J=6.59 Hz), 1.09-1.06 (2H, m), 0.70 (2H, q, J=3.28 Hz)
Reaction SMILES: [Br:1][C:2]1[C:10]2[N:9]=[C:8]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[NH:7][C:6]=2[CH:5]=[C:4]([O:17][CH3:18])[CH:3]=1.ClCCl>N1C=CC=CC=1.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[Br:1][C:2]1[C:10]2[N:9]=[C:8]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[N:7]([C:14]3[CH:15]=[CH:16][C:11]([CH3:8])=[CH:12][CH:13]=3)[C:6]=2[CH:5]=[C:4]([O:17][CH3:18])[CH:3]=1
Reactant: COc1cc(Br)c2nc(-c3ccccc3)[nH]c2c1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: ClCCl
Solvent: c1ccncc1
Product: COc1cc(Br)c2nc(-c3ccccc3)n(-c3ccc(C)cc3)c2c1

Procedure:
2.5 g of 4-bromo-6-methoxy-2-phenyl-1H-benzimidazole and 2.24 g of 4-(methylbenzene)boronic acid were stirred with 1.5 g of anhydrous copper(II) acetate and about 3 g of molecular sieve in 35 ml of pyridine for 7 hours at 100° C. After dichloromethane and Celite were added, it was concentrated by evaporation and chromatographed on silica gel with a hexane/ethyl acetate mixture.
Reaction SMILES: [CH3:1][N:2]([CH3:18])[C:3]1[N:8]=[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:6]([C:15]([OH:17])=O)=[CH:5][N:4]=1.[CH2:19]([O:26][C:27]1[CH:28]=[C:29]([CH:33]([OH:39])[CH2:34][NH:35][CH2:36][CH2:37][OH:38])[CH:30]=[CH:31][CH:32]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>CN(C)C=O>[CH2:19]([O:26][C:27]1[CH:28]=[C:29]([CH:33]([OH:39])[CH2:34][N:35]([CH2:36][CH2:37][OH:38])[C:15]([C:6]2[C:7]([C:9]3[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=3)=[N:8][C:3]([N:2]([CH3:1])[CH3:18])=[N:4][CH:5]=2)=[O:17])[CH:30]=[CH:31][CH:32]=1)[C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: CN(C)c1ncc(C(=O)O)c(-c2ccccc2)n1
Reactant: OCCNCC(O)c1cccc(OCc2ccccc2)c1
Solvent: CN(C)C=O
Product: CN(C)c1ncc(C(=O)N(CCO)CC(O)c2cccc(OCc3ccccc3)c2)c(-c2ccccc2)n1
Temperature: 25 °C
Reaction time: 18 h
Yield: 29.5 %

Procedure:
To activated 2-dimethylamino-4-phenylpyrimidine-5-carboxylic acid (1.48 g, 1 mmol/g, 1.48 mmol) bound to PS-TFP resin, N,N-dimethylformamide (20 ml), then after 5 minutes of swelling 1-(3-benzyloxyphenyl)-2-(2-hydroxyethylamino)ethanol (0.40 g, 1.39 mmol) is added. The reaction mixture is stirred at room temperature for 18 hours, then filtered and washed consecutively with 50-50 ml of NAN-dimethylformamide, tetrahydrofuran and dichloromethane. After evaporation the resulting oil (0.36 g) is chromatographed on silicagel using chloroform, and chloroform-ethyl acetate 9:1, 4:1 mixtures as eluents. 0.21 g of the title amide is obtained as white solid material, m.p. 89° C.
Reaction SMILES: [CH:1]([NH:4][C:5]1[C:18]2[C:17](=[O:19])[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][C:15]=3[N+]([O-])=O)[C:10](=[O:23])[C:9]=2[CH:8]=[CH:7][CH:6]=1)([CH3:3])[CH3:2].[CH3:24][O:25][CH2:26][CH2:27][OH:28].[OH-].[K+]>O>[CH:1]([NH:4][C:5]1[C:18]2[C:17](=[O:19])[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][C:15]=3[O:28][CH2:27][CH2:26][O:25][CH3:24])[C:10](=[O:23])[C:9]=2[CH:8]=[CH:7][CH:6]=1)([CH3:3])[CH3:2]
Reactant: COCCO
Reactant: CC(C)Nc1cccc2c1C(=O)c1c(cccc1[N+](=O)[O-])C2=O
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: COCCOc1cccc2c1C(=O)c1c(NC(C)C)cccc1C2=O
Reaction time: 1 h

Procedure:
15 g of 1-isopropylamino-8-nitro-anthraquinone are stirred into a solution of 60 ml of ethylene glycol monomethyl ether and 15 g of potassium hydroxide at 55° and the mixture is further stirred at 60°-65° (approx. 1 hour being required) until only a trace of the starting material remains chromatographically detectable. The mixture is diluted with 120 ml of water and the product is filtered off, washed with water until neutral and dried in vacuo at 60°. Yield: 16.7 g.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:30])[CH2:5][C:6]1([CH2:27][CH2:28][CH3:29])[C:11]2[NH:12][C:13]3[C:18]([C:10]=2[CH2:9][CH2:8][O:7]1)=[CH:17][C:16]([O:19]CC1C=CC=CC=1)=[CH:15][CH:14]=3)[CH3:2]>[Pd].C(O)C>[CH2:1]([O:3][C:4](=[O:30])[CH2:5][C:6]1([CH2:27][CH2:28][CH3:29])[C:11]2[NH:12][C:13]3[C:18]([C:10]=2[CH2:9][CH2:8][O:7]1)=[CH:17][C:16]([OH:19])=[CH:15][CH:14]=3)[CH3:2]
Reactant: CCCC1(CC(=O)OCC)OCCc2c1[nH]c1ccc(OCc3ccccc3)cc21
Agent: [Pd]
Solvent: CCO
Product: CCCC1(CC(=O)OCC)OCCc2c1[nH]c1ccc(O)cc21
Reaction time: 6 h
Yield: 89.2 %

Procedure:
A suspension of the 6-benzyloxypyranoindole (5.4 g, 13.25 mmol) of Step A, and 10% Pd/C catalyst (600 mg) in ethanol (150 mL) is hydrogenated for 6 hours in a Parr shaker. Filtration of the catalyst and evaporation of the solvent affords the title compound (3.75 g, 89%) as a cream-colored foam homogeneous by TLC.
Reaction SMILES: [Cl-].[Cl-].[Cl-].[Al+3].[CH2:5]([NH:7][CH2:8][CH3:9])[CH3:6].[OH:10][C@@H:11]1[CH2:14][C@H:13]([C:15]([O:17]CC2C=CC=CC=2)=O)[CH2:12]1.C(=O)(O)[O-].[Na+]>ClCCl>[CH2:5]([N:7]([CH2:8][CH3:9])[C:15]([C@H:13]1[CH2:12][C@@H:11]([OH:10])[CH2:14]1)=[O:17])[CH3:6]
Reactant: CCNCC
Reactant: O=C(OCc1ccccc1)[C@H]1C[C@@H](O)C1
Agent: O=C([O-])O
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: CCN(CC)C(=O)[C@H]1C[C@@H](O)C1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a solution of aluminum trichloride (533 mg, 4 mmol) in dichloromethane (4 mL) were added diethylamine (1.67 mL, 16 mmol) and benzyl cis-3-hydroxycyclobutane carboxylate (413 mg, 2.0 mmol) at 0° C., and then the mixture was stirred at room temperature for 24 hours. To the reaction solution was added saturated aqueous sodium bicarbonate, and the mixture was filtered through celite, and then extracted with ethyl acetate, dried over magnesium sulfate and filtered. The filtrate was evaporated and purified by silica gel column chromatography (n-hexane/ethyl acetate=3/1 to 0/1, ethyl acetate/methanol=9/1) to give the titled compound (321 mg, 94%).
Reaction SMILES: [NH2:1][CH2:2][CH:3]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:15]=[C:14]([C:16]3[CH:21]=[C:20]([CH3:22])[N:19]=[C:18]([NH:23][CH:24]([CH3:26])[CH3:25])[N:17]=3)[O:13][N:12]=2)=[CH:7][CH:6]=1)[OH:4].[C:27](O)(=[O:30])[CH2:28][OH:29]>>[OH:30][CH2:27][C:28]([NH:1][CH2:2][CH:3]([OH:4])[C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:15]=[C:14]([C:16]3[CH:21]=[C:20]([CH3:22])[N:19]=[C:18]([NH:23][CH:24]([CH3:26])[CH3:25])[N:17]=3)[O:13][N:12]=2)=[CH:7][CH:6]=1)=[O:29]
Reactant: O=C(O)CO
Reactant: Cc1cc(-c2nc(-c3ccc(C(O)CN)cc3)no2)nc(NC(C)C)n1
Product: Cc1cc(-c2nc(-c3ccc(C(O)CNC(=O)CO)cc3)no2)nc(NC(C)C)n1

Procedure:
The title compound is prepared in analogy to Example 127 using rac-2-amino-1-{4-[5-(2-isopropylamino-6-methyl-pyrimidin-4-yl)-[1,2,4]oxadiazol-3-yl]-phenyl}-ethanol (Example 144) and glycolic acid; LC-MS: tR=0.81 min; [M+H]+=413.03.